PMID- 20701717 TI - Insulin resistance and protein energy metabolism in patients with advanced chronic kidney disease. AB - Insulin resistance (IR), the reciprocal of insulin sensitivity is a known complication of advanced chronic kidney disease (CKD) and is associated with a number of metabolic derangements. The complex metabolic abnormalities observed in CKD such as vitamin D deficiency, obesity, metabolic acidosis, inflammation, and accumulation of "uremic toxins" are believed to contribute to the etiology of IR and acquired defects in the insulin-receptor signaling pathway in this patient population. Only a few investigations have explored the validity of commonly used assessment methods in comparison to gold standard hyperinsulinemic hyperglycemic clamp technique in CKD patients. An important consequence of insulin resistance is its role in the pathogenesis of protein energy wasting, a state of metabolic derangement characterized by loss of somatic and visceral protein stores not entirely accounted for by inadequate nutrient intake. In the general population, insulin resistance has been associated with accelerated protein catabolism. Among end-stage renal disease (ESRD) patients, enhanced muscle protein breakdown has been observed in patients with Type II diabetes compared to ESRD patients without diabetes. In the absence of diabetes mellitus (DM) or severe obesity, insulin resistance is detectable in dialysis patients and strongly associated with increased muscle protein breakdown, primarily mediated by the ubiquitin proteasome pathway. Recent epidemiological data indicate a survival advantage and better nutritional status in insulin-free Type II DM patients treated with insulin sensitizer thiazolidinediones. Given the high prevalence of protein energy wasting in ESRD and its unequivocal association with adverse clinical outcomes, insulin resistance may represent an important modifiable target for intervention in the ESRD population. PMID- 20701718 TI - To eat or not to eat: dietary fat in uremia is the question. AB - Although a diet low in protein is well known to reduce the risk of progression in patients with chronic kidney disease (CKD), the impact of dietary fat content and fat quality has largely been ignored. As a reduced protein intake results in an obligatory reduction in energy intake, and as CKD patients often suffer from energy malnutrition, this issue deserves greater attention. The present review aims to summarize what is currently known about dietary fat intake in CKD and suggests areas for further study. We conclude that although overweight per se is an important risk factor for the development of CKD, the role of obesity as a risk factor for complications in manifest CKD remains unclear. Current data support a balanced increase in dietary fat intake in patients with CKD to compensate for reduced energy intake in protein-restricted diets and anorexic patients. However, patients who are obese should be encouraged to lose weight while maintaining or, preferably, increasing muscle mass. PMID- 20701719 TI - Omega-3 fatty acid supplementation in advanced kidney disease. AB - Long-chain polyunsaturated omega-3 fatty acids (n-3 PUFA), which are obtained primarily from dietary sources such as coldwater fish, have diverse and potent mediating effects on the immune, inflammatory, and metabolic pathways, signal transduction, and cell membrane physiology. N-3 PUFA are increasingly being studied for their clinical benefits in a variety of medical conditions, some of which are relevant to individuals with advanced chronic kidney disease (CKD). These include, among others, renoprotection in IgA nephropathy, cardioprotective effects via a variety of mechanisms including blood pressure and triglyceride reduction, maintenance of dialysis access patency, sparing of inflammation associated muscle loss, and even mortality. However, further confirmatory work needs to be performed before establishing formal intake recommendations and dosing goals for advanced CKD patients. In the meantime, the current American Heart Association n-3 PUFA intake guidelines can be applied to CKD patients, especially given n-3 PUFA's potential benefits and negligible risk profile. Over time, it will be incumbent upon the nephrology community to more clearly define the utility and optimal dosing of n-3 PUFA in CKD patients with advanced disease via randomized clinical trials. PMID- 20701720 TI - Dietary vitamin D intake in advanced CKD/ESRD. AB - In healthy individuals, vitamin D produced in the skin or derived from nutritional sources is converted to 25-hydroxyvitamin D (25[OH]D) in the liver, and then 1,25-dihydroxyvitamin D (1,25[OH](2)D) by 1 alpha-hydroxylase in the kidney. Chronic kidney disease (CKD) is accompanied by a progressive decline in the ability to produce 1,25(OH)(2)D; thus, replacement of this hormonal form of vitamin D has been the focus of therapeutic interventions to prevent and treat complications such as hypocalcemia, and secondary hyperparathyroidism. New research suggests that conversion of 25(OH)D to 1,25(OH)(2)D outside of the kidney may have important biological roles beyond those traditionally ascribed to vitamin D. 25(OH)D levels have increasingly been linked to important clinical outcomes in CKD. This article reviews vitamin D metabolism, emerging new roles for vitamin D, and data surrounding the potential importance of nutritional sources of vitamin D in the management of patients with CKD. PMID- 20701721 TI - What should define optimal correction of metabolic acidosis in chronic kidney disease? AB - Correction of metabolic acidosis is an important goal in the management of patients with chronic kidney disease (CKD). However, there is no consensus as to what constitutes an optimal correction of metabolic acidosis in this setting - various expert groups from around the world have set different goals for serum bicarbonate levels for patients with CKD. Accumulating evidence seems to indicate that achieving an arterial pH closer to the upper limit of the reference range may have even greater benefits than maintaining the arterial pH closer to the lower limit of the reference range. This benefit seems to be particularly relevant for patients with protein-energy wasting and we present a review of the evidence that supports this argument. Routine measurement of arterial pH, however, is not feasible in clinical practice; using the Henderson equation, a high-normal arterial pH is generally expected to be associated with a serum bicarbonate level of 24-30 mEq/l and should be the therapeutic goal for chronic kidney disease patients with protein-energy wasting. PMID- 20701722 TI - Exercise in end-stage renal disease. AB - This article will outline the clinical reasoning for exercise counseling in end stage renal disease (ESRD) patients and give healthcare providers detailed information on the different programs that can be implemented in this population according to patients' specific needs. End-stage renal disease patients often have other health problems that can be improved by participation in regular exercise programs. Research accumulated during the last 30 years on exercise for the ESRD population supports its numerous beneficial effects including those on cardiovascular capacity, sarcopenia, and health-related quality of life. We describe the different types of exercise, aerobic and resistance programs (including their frequency, intensity and progression) that are recommended for the ESRD population, as well as the potential goals of each program. Groups with special needs among the ESRD population are considered, as well as safety, potential adverse events, and adherence to exercise programs. Finally, recommendations for future researches are highlighted. PMID- 20701723 TI - Brachial artery aneurysms associated with arteriovenous access for hemodialysis. AB - Brachial artery aneurysm (BAA) is a rare condition. We describe a series of cases of BAA with arteriovenous access. Thirteen patients were retrospectively identified between January 2006 and July 2009 using a patient database. All were associated with brachio-cephalic fistulas. Mean age was 51.2 +/- 13.8 years. Twelve males (93.3%) were identified. Characteristics were: diabetes 1, hypertension 8, hypercholesterolemia 2, ischemic heart disease 2, family history of aneurysmal disease 2. Five BAA developed after access ligation, eight while it was working, one after trauma. One was associated with a venous aneurysm. While the average life of the access was 161 +/- 115 months, the average time for BAA formation was 40 +/- 35.8 months. BAA was asymptomatic in three patients, whereas 10 presented with ischemic and neurologic symptoms. None presented with a rupture. All patients underwent surgical repair, seven an aneurysm excision and end-to-end reconstruction of the brachial artery. Venous conduits were utilized: four long saphenous veins, one cephalic, and one basilic vein. All patients had patent brachial arteries with a complete relief of symptoms at 14 months. BAA is a rare but significant complication of vascular access. The surgical approaches presented offer a reasonable outcome. PMID- 20701727 TI - Estimating the post-neonatal prevalence of sickle cell disease in a Brazilian population. AB - SUMMARY OBJECTIVE: To estimate the prevalence of individuals with sickle cell disease (SCD) in Aracaju, Brazil, using the capture-recapture (CRC) method. SCD is a significant public health problem with long-term life-threatening complications. There are no reliable estimates of the number of individuals with this condition in Aracaju, north-east Brazil. The CRC method has been used to quantify other ubiquitous populations. METHOD: Three independent lists of individuals with homozygous (HbSS) SCD were constructed from patients attending the main specialist ambulatory service, all patients with SCD admitted to three government hospitals and a clinic providing specialist immunisation services to patients with SCD. Individuals were matched to ascertain whether they appeared in one, two or three lists, and population size was estimated using the log-linear model. RESULTS: The lists identified 374 individuals. Two hundred and one appeared in one, 99 in two and 74 in three lists with an estimated number 400 (95% CI 387-418) HbSS SCD individuals; 51.6% patients with SCD were men and age ranged from 1-62 years (median 14). CONCLUSION: The CRC method resulted in a smaller population estimate than expected. The causes of this discrepancy may include list dependence, high mortality with a survival cohort effect and the method of identifying the more severe cases. The CRC method has potential to estimate the size of this population and could supplement neonatal screening to further characterise the SCD population in this region. PMID- 20701726 TI - Mortality measurement in transition: proof of principle for standardised multi country comparisons. AB - SUMMARY OBJECTIVE: To demonstrate the viability and value of comparing cause specific mortality across four socioeconomically and culturally diverse settings using a completely standardised approach to VA interpretation. METHODS: Deaths occurring between 1999 and 2004 in Butajira (Ethiopia), Agincourt (South Africa), FilaBavi (Vietnam) and Purworejo (Indonesia) health and socio-demographic surveillance sites were identified. VA interviews were successfully conducted with the caregivers of the deceased to elicit information on signs and symptoms preceding death. The information gathered was interpreted using the InterVA method to derive population cause-specific mortality fractions for each of the four settings. RESULTS: The mortality profiles derived from 4784 deaths using InterVA illustrate the potential of the method to characterise sub-national profiles well. The derived mortality patterns illustrate four populations with plausible, markedly different disease profiles, apparently at different stages of health transition. CONCLUSIONS: Given the standardised method of VA interpretation, the observed differences in mortality cannot be because of local differences in assigning cause of death. Standardised, fit-for-purpose methods are needed to measure population health and changes in mortality patterns so that appropriate health policy and programmes can be designed, implemented and evaluated over time and place. The InterVA approach overcomes several longstanding limitations of existing methods and represents a valuable tool for health planners and researchers in resource-poor settings. PMID- 20701728 TI - Use of nutritional and water hygiene packages for diarrhoeal prevention among HIV exposed infants in Lilongwe, Malawi: an evaluation of a pilot prevention of mother-to-child transmission post-natal care service. AB - SUMMARY OBJECTIVE: To evaluate a pilot prevention of mother-to-child transmission post-natal programme in Lilongwe, Malawi, through observed retention and infant diarrhoeal rates. METHODS: Free fortified porridge and water hygiene packages were offered to mothers to encourage frequent post-natal visits and to reduce diarrhoeal rates in infants on replacement feeding. Participant retention and infant health outcome were assessed. RESULTS: Of 474 patients enrolled, 357 (75.3%) completed 3-month follow-up visits. Ninety-nine percent of women reported hygiene package use, and only 17.7% (95% CI 13.8-22.0%) of the infants had diarrhoea at least once over the 3-month period. Being 12 months or younger, confirmed HIV positive, access to tap water, and having a mother with diarrhoea were all associated with increased risk of infant diarrhoea. CONCLUSION: The majority of participants adhered to their scheduled visits and retention was favourable, possibly because of the introduction of hygiene and nutrition incentives. The infant diarrhoeal rate was low, suggesting benefits of regular medical care with hygiene package usage and reliable replacement feeding options. Continuation and expansion of the programme would allow further studies and improve the post-natal care of HIV-exposed infants in Malawi and in other resource-constrained countries. PMID- 20701729 TI - Health technology assessment and economic evaluation: arguments for a national approach. PMID- 20701730 TI - Health technology assessment and economic evaluation across jurisdictions. PMID- 20701731 TI - Apheresis platelet concentrates contain platelet-derived and endothelial cell derived microparticles. AB - BACKGROUND AND OBJECTIVES: Microparticles (MP) are membrane vesicles with thrombogenic and immunomodulatory properties. We determined MP subgroups from resting platelets, activated platelets and endothelial cells in donors and apheresis platelet concentrates (PC). MATERIAL AND METHODS: MP were double stained with annexin V and CD61 (platelet-derived MP; PMP), P-selectin or CD63 (MP from activated platelets) and CD144 plus E-selectin (endothelial cell-derived MP; EMP) and detected by flow cytometry in platelet donors (n=36) and apheresis PC (n=11; TrimaTM). RESULTS: PC contained MP, mainly from resting platelets [93% (90-95)], and minor fractions of PMP from activated platelets [P-selectin(+) or CD63(+); 4.8% (3.2-7.7) and 2.6% (2.0-4.0)]. Compared to donors, levels of annexin V+ MP, PMP, P-selectin(+) and CD63(+) MP were 1.7-, 2.3-, 8.6- and 3.1 fold higher in PC (all P<0.05). During storage (1-5 days), levels of annexin V+ MP and PMP did not increase, although small increases in the fraction of P selectin(+) or CD63(+) MP occurred (both P<0.05). PC also contained EMP, which were 2.6- to 3.7-fold enriched in PC compared to donors (P<0.05). CONCLUSIONS: Transfusion of apheresis PC also results in transfusion of HLA-carrying PMP and EMP. This might counteract the aim of reducing transfused HLA load by leucodepletion. The increases in PMP exposing P-selectin or CD63 reflect mild platelet activation during storage. We conclude that in leucodepleted platelet apheresis using fluidized particle bed technology, MP are harvested mainly from the donor by apheresis. Improvement in apheresis technology might reduce MP load. PMID- 20701733 TI - Hepatitis B virus blood screening: impact of nucleic amplification technology testing implementation on identifying hepatitis B surface antigen non-reactive window period and chronic infections. AB - BACKGROUND: Despite improvements in hepatitis B surface antigen (HBsAg) test sensitivity, post-transfusion hepatitis B virus (HBV) infection still occurs because HBsAg is undetectable during the early window phase (WP) of the infection, in the convalescence core window phase of the infection, or in serologically silent chronic hepatitis or in mutant forms of HBV. HBV-DNA screening using high sensitivity nucleic amplification technology (NAT) assays has recently been introduced to reduce the residual risk of transmission of HBV by transfusion of blood components. MATERIALS: Over 1 year 75 063 donations were individually screened for HBV-DNA by the Ultrio Procleix assay on the Tigris platform. The donations were collected in the Latium region, an area of the central Italy, and they accounted for the 40% of the total blood units collected in this area per year. The initial reactive samples were re-tested and confirmed by the discriminatory HBV assay. Additional HBV serological markers were also performed. Suspected WP infections were followed-up to monitor the development of the immune response. All HBV-DNA-positive donors were called back to check up their infectious status. RESULTS: The results of testing the 75 063 donations are: 33 donations HBsAg positive, 31 out of them HBV-DNA-positive and two HBV-DNA negative; 22 donations HBsAg-negative but HBV-DNA positive with low viral load. Six of the 22 were found to be consistently HBV-DNA reactive whereas the remaining 16 donations showed inconsistent results on multiple NAT retesting. One WP infection was confirmed by the follow-up of the donor for 3 months following the index blood donation. CONCLUSIONS: In the donor population of the Latium region, NAT screening has revealed a higher than expected number of donors who were HBsAg non-reactive but HBV-DNA-positive with three donors showing HBV-DNA as the only marker of infection. The adoption of genome screening has increased the safety of the blood supply and has also contributed to the protection of donor health by identifying either WP or clinically silent infections. PMID- 20701734 TI - An inquiry into the relationship between ABO blood group and thrombotic thrombocytopenic purpura. AB - BACKGROUND AND OBJECTIVES: ABO blood group accounts for up to 40% of the variability in plasma von Willebrand factor (VWF) levels, which vary in the rank order AB > B > A > O > Bombay. This may be due in part to the influence of ABO associated oligosaccharides on the proteolysis of VWF by the metalloprotease ADAMTS13, which is markedly deficient in thrombotic thrombocytopenic purpura (TTP). Using ABO blood group as a surrogate for baseline VWF levels as well as susceptibility to proteolysis by ADAMST13, we set out to determine whether ABO blood group influences the clinical course of TTP. METHODS: We conducted a retrospective analysis of the clinical course of 76 patients with primary, sporadic TTP treated at two institutions over the past 10 years. RESULTS: We found no significant differences between group O and non-O patients with respect to presenting platelet count and lactate dehydrogenase concentration, maximum serum creatinine concentration, and total number of therapeutic plasma exchanges per episode. CONCLUSIONS: Substrate-related contributors to the highly variable phenotype and clinical course of TTP warrant further investigation. PMID- 20701738 TI - Diaphragm weakness and mechanical ventilation--what's the critical issue? AB - While animal studies indicate that controlled mechanical ventilation (MV) induces diaphragm weakness and myofiber atrophy, there are no data in humans that confirm MV per se produces diaphragm weakness. Whether or not diaphragm weakness results from MV, sepsis, corticosteroids, hyperglycemia, or a combination of these factors, however, is not the most important issue raised by the recent study from Hermans and colleagues. This study makes an important contribution by providing additional evidence that many critically ill patients have profound diaphragm weakness. If diaphragm weakness of this magnitude is present in most mechanically ventilated patients, a strong argument can be made that respiratory muscle weakness is a major contributor to respiratory failure. PMID- 20701739 TI - Shared pathways to infectious disease susceptibility? AB - The recent advent of genomic approaches for association testing is starting to enable a more comprehensive understanding of the role of human immune response in determining infectious disease outcomes. Progressing from traditional linkage approaches using microsatellite markers to high-resolution genome-wide association scans, these new approaches are leading to the robust discovery of a large number of disease susceptibility genes and the beginnings of an appreciation of their connections. In this commentary, we discuss how this technology development has led to increasingly complex and common infectious diseases being unraveled, and how this is starting to dissect pathogen-specific human responses. Intriguingly, these still preliminary findings suggest that pathogen innate detection mechanisms may not be as shared among diseases as immune response mechanisms. PMID- 20701740 TI - Osteoarthritis and a high-fat diet: the full 'OA syndrome' in a small animal model. AB - Obesity is one of the main risk factors for osteoarthritis (OA) and due to the global rise in obesity this will increasingly contribute to OA development. The article of Griffin and co-workers in this issue of Arthritis Research and Therapy shows that a high-fat diet leads to obesity and OA in the studied animals and that this is related to alterations in locomotor function. Furthermore, a high fat diet leads to pain sensitization and depression/anxiety-like behavior unrelated to structural OA changes in the knee. Their findings demonstrate that the majority of features of the human 'OA syndrome' can be reproduced in a small animal model. PMID- 20701741 TI - New developments in osteoarthritis. Sex differences in magnetic resonance imaging based biomarkers and in those of joint metabolism. AB - Sex differences in the prevalence, incidence, and severity of osteoarthritis (OA) have long been known. Some differences in the evaluation of this issue across studies may be related to differences in study design, sampling, study size, study populations, targeted joint sites, and definitions of OA. This report highlights recent studies of sex differences in individual joint components imaged by magnetic resonance imaging and in systemic biomarkers of joint metabolism. Particularly important are those studies that examine this issue in young unaffected adults and children before the development of disease. Despite some variation across studies, women appear for the most part to have a thinner and more reduced volume of cartilage in the knee than men, and this may occur from early childhood. It is not clear whether women have a more accelerated rate of cartilage volume loss than men. Few data exist on sex differences in systemic biomarkers of joint metabolism. In these studies, it is critically important to characterize the total body burden of OA and the presence of comorbid conditions likely to influence a given biomarker. Lastly, future research should dovetail studies of sex differences in imaging and biochemical biomarkers with genetics to maximize insight into the mechanisms behind observed sex differences. PMID- 20701742 TI - Ancestral state reconstruction reveals multiple independent evolution of diagnostic morphological characters in the "Higher Oribatida" (Acari), conflicting with current classification schemes. AB - BACKGROUND: The use of molecular genetic data in phylogenetic systematics has revolutionized this field of research in that several taxonomic groupings defined by traditional taxonomic approaches have been rejected by molecular data. The taxonomic classification of the oribatid mite group Circumdehiscentiae ("Higher Oribatida") is largely based on morphological characters and several different classification schemes, all based upon the validity of diagnostic morphological characters, have been proposed by various authors. The aims of this study were to test the appropriateness of the current taxonomic classification schemes for the Circumdehiscentiae and to trace the evolution of the main diagnostic traits (the four nymphal traits scalps, centrodorsal setae, sclerits and wrinkled cuticle plus octotaxic system and pteromorphs both in adults) on the basis of a molecular phylogenetic hypothesis by means of parsimony, likelihood and Bayesian approaches. RESULTS: The molecular phylogeny based on three nuclear markers (28S rDNA, ef-1alpha, hsp82) revealed considerable discrepancies to the traditional classification of the five "circumdehiscent" subdivisions, suggesting paraphyly of the three families Scutoverticidae, Ameronothridae, Cymbaeremaeidae and also of the genus Achipteria. Ancestral state reconstructions of six common diagnostic characters and statistical evaluation of alternative phylogenetic hypotheses also partially rejected the current morphology-based classification and suggested multiple convergent evolution (both gain and loss) of some traits, after a period of rapid cladogenesis, rendering several subgroups paraphyletic. CONCLUSIONS: Phylogenetic studies revealed non-monophyly of three families and one genus as a result of a lack of adequate synapomorphic morphological characters, calling for further detailed investigations in a framework of integrative taxonomy. Character histories of six morphological traits indicate that their evolution followed a rather complex pattern of multiple independent gains (and losses). Thus, the observed pattern largely conflicts with current morphological classifications of the Circumdehiscentiae, suggesting that the current taxonomic classification schemes are not appropriate, apart from a recently proposed subdivision into 24 superfamilies. PMID- 20701743 TI - Identification, expression and serological evaluation of the recombinant ATP synthase beta subunit of Mycoplasma pneumoniae. AB - BACKGROUND: Mycoplasma pneumoniae is responsible for acute respiratory tract infections (RTIs) common in children and young adults. As M. pneumoniae is innately resistant to beta-lactams antibiotics usually given as the first-line treatment for RTIs, specific and early diagnosis is important in order to select the right treatment. Serology is the most used diagnostic method for M. pneumoniae infections. RESULTS: In this study, we identified the M. pneumoniae ATP synthase beta subunit (AtpD) by serologic proteome analysis and evaluated its usefulness in the development of a serological assay. We successfully expressed and purified recombinant AtpD (rAtpD) protein, which was recognised by serum samples from M. pneumoniae-infected patient in immunoblots. The performance of the recombinant protein rAtpD was studied using a panel of serum samples from 103 infected patients and 86 healthy blood donors in an in-house IgM, IgA and IgG enzyme-linked immunosorbent assay (ELISA). The results of this assay were then compared with those of an in-house ELISA with a recombinant C-terminal fragment of the P1 adhesin (rP1-C) and of the commercial Ani Labsystems ELISA kit using an adhesin P1-enriched whole-cell extract. Performances of the rAtpD and rP1-C antigen combination were further assessed by binary logistic regression analysis. We showed that combination of rAtpD and rP1-C discriminated maximally between the patients infected with M. pneumoniae (children and adults) and the healthy subjects for the IgM class, performing better than the single recombinant antigens or the commercial whole-cell extract. CONCLUSION: These results suggest that AtpD can be used as an antigen for the immunodiagnosis of early and acute M. pneumoniae infection in association with adhesin P1, providing an excellent starting point for the development of point-of-care diagnostic assays. PMID- 20701744 TI - Challenges in mass drug administration for treating lymphatic filariasis in Papua, Indonesia. AB - BACKGROUND: The World Health Organization (WHO) Global Program to Eliminate Lymphatic Filariasis relies on mass drug administration (MDA) of two drugs annually for 4 to 6 years. The goal is to reduce the reservoir of microfilariae in the blood to a level insufficient to maintain transmission by the mosquito vector. In 2008, the international medical aid organization Medecins Sans Frontieres (MSF) performed the first round of a MDA in the high-burden area of Asmat district, in Papua, Indonesia. We report the challenges faced in this MDA on a remote Indonesian island and propose solutions to overcome these hurdles in similar future contexts. RESULTS: During the MDA, we encountered difficult challenges in accessing as well as persuading the patient population to take the antifilarial drugs. Health promotion activities supporting treatment need to be adapted and repetitive, with adequate time and resources allocated for accessing and communicating with local, seminomadic populations. Distribution of bednets resulted in an increase in MDA coverage, but it was still below the 80-85% target. CONCLUSIONS: MDA for lymphatic filariasis is how the WHO has planned to eliminate the disease from endemic areas. Our programmatic experience will hopefully help inform future campaign planning in difficult-to-access, high burden areas of the world to achieve target MDA coverage for elimination of lymphatic filariasis. PMID- 20701745 TI - Karyopherin alpha7 (KPNA7), a divergent member of the importin alpha family of nuclear import receptors. AB - BACKGROUND: Classical nuclear localization signal (NLS) dependent nuclear import is carried out by a heterodimer of importin alpha and importin beta. NLS cargo is recognized by importin alpha, which is bound by importin beta. Importin beta mediates translocation of the complex through the central channel of the nuclear pore, and upon reaching the nucleus, RanGTP binding to importin beta triggers disassembly of the complex. To date, six importin alpha family members, encoded by separate genes, have been described in humans. RESULTS: We sequenced and characterized a seventh member of the importin alpha family of transport factors, karyopherin alpha 7 (KPNA7), which is most closely related to KPNA2. The domain of KPNA7 that binds Importin beta (IBB) is divergent, and shows stronger binding to importin beta than the IBB domains from of other importin alpha family members. With regard to NLS recognition, KPNA7 binds to the retinoblastoma (RB) NLS to a similar degree as KPNA2, but it fails to bind the SV40-NLS and the human nucleoplasmin (NPM) NLS. KPNA7 shows a predominantly nuclear distribution under steady state conditions, which contrasts with KPNA2 which is primarily cytoplasmic. CONCLUSION: KPNA7 is a novel importin alpha family member in humans that belongs to the importin alpha2 subfamily. KPNA7 shows different subcellular localization and NLS binding characteristics compared to other members of the importin alpha family. These properties suggest that KPNA7 could be specialized for interactions with select NLS-containing proteins, potentially impacting developmental regulation. PMID- 20701746 TI - Genome wide screen identifies microsatellite markers associated with acute adverse effects following radiotherapy in cancer patients. AB - BACKGROUND: The response of normal tissues in cancer patients undergoing radiotherapy varies, possibly due to genetic differences underlying variation in radiosensitivity. METHODS: Cancer patients (n = 360) were selected retrospectively from the RadGenomics project. Adverse effects within 3 months of radiotherapy completion were graded using the National Cancer Institute Common Toxicity Criteria; high grade group were grade 3 or more (n = 180), low grade group were grade 1 or less (n = 180). Pooled genomic DNA (gDNA) (n = 90 from each group) was screened using 23,244 microsatellites. Markers with different inter group frequencies (Fisher exact test P < 0.05) were analyzed using the remaining pooled gDNA. Silencing RNA treatment was performed in cultured normal human skin fibroblasts. RESULTS: Forty-seven markers had positive association values; including one in the SEMA3A promoter region (P = 1.24 x 10(-5)). SEMA3A knockdown enhanced radiation resistance. CONCLUSIONS: This study identified 47 putative radiosensitivity markers, and suggested a role for SEMA3A in radiosensitivity. PMID- 20701747 TI - Bayesian bias adjustments of the lung cancer SMR in a cohort of German carbon black production workers. AB - BACKGROUND: A German cohort study on 1,528 carbon black production workers estimated an elevated lung cancer SMR ranging from 1.8-2.2 depending on the reference population. No positive trends with carbon black exposures were noted in the analyses. A nested case control study, however, identified smoking and previous exposures to known carcinogens, such as crystalline silica, received prior to work in the carbon black industry as important risk factors.We used a Bayesian procedure to adjust the SMR, based on a prior of seven independent parameter distributions describing smoking behaviour and crystalline silica dust exposure (as indicator of a group of correlated carcinogen exposures received previously) in the cohort and population as well as the strength of the relationship of these factors with lung cancer mortality. We implemented the approach by Markov Chain Monte Carlo Methods (MCMC) programmed in R, a statistical computing system freely available on the internet, and we provide the program code. RESULTS: When putting a flat prior to the SMR a Markov chain of length 1,000,000 returned a median posterior SMR estimate (that is, the adjusted SMR) in the range between 1.32 (95% posterior interval: 0.7, 2.1) and 1.00 (0.2, 3.3) depending on the method of assessing previous exposures. CONCLUSIONS: Bayesian bias adjustment is an excellent tool to effectively combine data about confounders from different sources. The usually calculated lung cancer SMR statistic in a cohort of carbon black workers overestimated effect and precision when compared with the Bayesian results. Quantitative bias adjustment should become a regular tool in occupational epidemiology to address narrative discussions of potential distortions. PMID- 20701748 TI - Diet as prophylaxis and treatment for venous thromboembolism? AB - BACKGROUND: Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored. METHODS AND FINDINGS: The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment.Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial. CONCLUSIONS: Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials. PMID- 20701749 TI - Health workforce responses to global health initiatives funding: a comparison of Malawi and Zambia. AB - BACKGROUND: Shortages of health workers are obstacles to utilising global health initiative (GHI) funds effectively in Africa. This paper reports and analyses two countries' health workforce responses during a period of large increases in GHI funds. METHODS: Health facility record reviews were conducted in 52 facilities in Malawi and 39 facilities in Zambia in 2006/07 and 2008; quarterly totals from the last quarter of 2005 to the first quarter of 2008 inclusive in Malawi; and annual totals for 2004 to 2007 inclusive in Zambia. Topic-guided interviews were conducted with facility and district managers in both countries, and with health workers in Malawi. RESULTS: Facility data confirm significant scale-up in HIV/AIDS service delivery in both countries. In Malawi, this was supported by a large increase in lower trained cadres and only a modest increase in clinical staff numbers. Routine outpatient workload fell in urban facilities, in rural health centres and in facilities not providing antiretroviral treatment (ART), while it increased at district hospitals and in facilities providing ART. In Zambia, total staff and clinical staff numbers stagnated between 2004 and 2007. In rural areas, outpatient workload, which was higher than at urban facilities, increased further. Key informants described the effects of increased workloads in both countries and attributed staff migration from public health facilities to non-government facilities in Zambia to PEPFAR. CONCLUSIONS: Malawi, which received large levels of GHI funding from only the Global Fund, managed to increase facility staff across all levels of the health system: urban, district and rural health facilities, supported by task-shifting to lower trained staff. The more complex GHI arena in Zambia, where both Global Fund and PEPFAR provided large levels of support, may have undermined a coordinated national workforce response to addressing health worker shortages, leading to a less effective response in rural areas. PMID- 20701750 TI - Highly-multiplexed SNP genotyping for genetic mapping and germplasm diversity studies in pea. AB - BACKGROUND: Single Nucleotide Polymorphisms (SNPs) can be used as genetic markers for applications such as genetic diversity studies or genetic mapping. New technologies now allow genotyping hundreds to thousands of SNPs in a single reaction.In order to evaluate the potential of these technologies in pea, we selected a custom 384-SNP set using SNPs discovered in Pisum through the resequencing of gene fragments in different genotypes and by compiling genomic sequence data present in databases. We then designed an Illumina GoldenGate assay to genotype both a Pisum germplasm collection and a genetic mapping population with the SNP set. RESULTS: We obtained clear allelic data for more than 92% of the SNPs (356 out of 384). Interestingly, the technique was successful for all the genotypes present in the germplasm collection, including those from species or subspecies different from the P. sativum ssp sativum used to generate sequences. By genotyping the mapping population with the SNP set, we obtained a genetic map and map positions for 37 new gene markers. CONCLUSION: Our results show that the Illumina GoldenGate assay can be used successfully for high throughput SNP genotyping of diverse germplasm in pea. This genotyping approach will simplify genotyping procedures for association mapping or diversity studies purposes and open new perspectives in legume genomics. PMID- 20701751 TI - Construction and characterization of two BAC libraries representing a deep coverage of the genome of chicory (Cichorium intybus L., Asteraceae). AB - BACKGROUND: The Asteraceae represents an important plant family with respect to the numbers of species present in the wild and used by man. Nonetheless, genomic resources for Asteraceae species are relatively underdeveloped, hampering within species genetic studies as well as comparative genomics studies at the family level. So far, six BAC libraries have been described for the main crops of the family, i.e. lettuce and sunflower. Here we present the characterization of BAC libraries of chicory (Cichorium intybus L.) constructed from two genotypes differing in traits related to sexual and vegetative reproduction. Resolving the molecular mechanisms underlying traits controlling the reproductive system of chicory is a key determinant for hybrid development, and more generally will provide new insights into these traits, which are poorly investigated so far at the molecular level in Asteraceae. FINDINGS: Two bacterial artificial chromosome (BAC) libraries, CinS2S2 and CinS1S4, were constructed from HindIII-digested high molecular weight DNA of the contrasting genotypes C15 and C30.01, respectively. C15 was hermaphrodite, non-embryogenic, and S2S2 for the S-locus implicated in self-incompatibility, whereas C30.01 was male sterile, embryogenic, and S1S4. The CinS2S2 and CinS1S4 libraries contain 89,088 and 81,408 clones. Mean insert sizes of the CinS2S2 and CinS1S4 clones are 90 and 120 kb, respectively, and provide together a coverage of 12.3 haploid genome equivalents. Contamination with mitochondrial and chloroplast DNA sequences was evaluated with four mitochondrial and four chloroplast specific probes, and was estimated to be 0.024% and 1.00% for the CinS2S2 library, and 0.028% and 2.35% for the CinS1S4 library. Using two single copy genes putatively implicated in somatic embryogenesis, screening of both libraries resulted in detection of 12 and 13 positive clones for each gene, in accordance with expected numbers. CONCLUSIONS: This indicated that both BAC libraries are valuable tools for molecular studies in chicory, one goal being the positional cloning of the S-locus in this Asteraceae species. PMID- 20701752 TI - Evaluation of mobile learning: students' experiences in a new rural-based medical school. AB - BACKGROUND: Mobile learning (ML) is an emerging educational method with success dependent on many factors including the ML device, physical infrastructure and user characteristics. At Gippsland Medical School (GMS), students are given a laptop at the commencement of their four-year degree. We evaluated the educational impact of the ML program from students' perspectives. METHODS: Questionnaires and individual interviews explored students' experiences of ML. All students were invited to complete questionnaires. Convenience sampling was used for interviews. Quantitative data was entered to SPSS 17.0 and descriptive statistics computed. Free text comments from questionnaires and transcriptions of interviews were thematically analysed. RESULTS: Fifty students completed the questionnaire (response rate 88%). Six students participated in interviews. More than half the students owned a laptop prior to commencing studies, would recommend the laptop and took the laptop to GMS daily. Modal daily use of laptops was four hours. Most frequent use was for access to the internet and email while the most frequently used applications were Microsoft Word and PowerPoint. Students appreciated the laptops for several reasons. The reduced financial burden was valued. Students were largely satisfied with the laptop specifications. Design elements of teaching spaces limited functionality. Although students valued aspects of the virtual learning environment (VLE), they also made many suggestions for improvement. CONCLUSIONS: Students reported many educational benefits from school provision of laptops. In particular, the quick and easy access to electronic educational resources as and when they were needed. Improved design of physical facilities would enhance laptop use together with a more logical layout of the VLE, new computer-based resources and activities promoting interaction. PMID- 20701753 TI - Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone. AB - BACKGROUND: Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT) images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM) to SPECT. METHODS: After linear spatial normalization of brain perfusion SPECT using 99mTc-ethyl cysteinate dimer (99mTc ECD) to a Talairach space, high-dimension-warping was done using an original 99mTc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2) between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C) patients and 73 age matched normal controls. This comparison was also performed in conventionally warped SPECT images. RESULTS: SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a 99mTc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution. CONCLUSIONS: The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPECT. PMID- 20701754 TI - Cloud-scale RNA-sequencing differential expression analysis with Myrna. AB - As sequencing throughput approaches dozens of gigabases per day, there is a growing need for efficient software for analysis of transcriptome sequencing (RNA Seq) data. Myrna is a cloud-computing pipeline for calculating differential gene expression in large RNA-Seq datasets. We apply Myrna to the analysis of publicly available data sets and assess the goodness of fit of standard statistical models. Myrna is available from http://bowtie-bio.sf.net/myrna. PMID- 20701755 TI - Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility. AB - BACKGROUND: CYP1B1 is a P450 enzyme which is involved in the activation of pro carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. METHODS: We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. RESULTS: The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. CONCLUSION: Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations. PMID- 20701756 TI - The two alpha-dox genes of Nicotiana attenuata: overlapping but distinct functions in development and stress responses. AB - BACKGROUND: Plant fatty acid alpha-dioxygenases (alpha-DOX) are oxylipin-forming enzymes induced by biotic and abiotic stresses, which also participate in developmental processes. In Nicotiana attenuata, herbivory strongly induces the expression of an alpha-dox1 gene. To determine its role, we silenced its expression using Agrobacterium-mediated plant transformation with an inverted repeat construct. More than half of the transformed lines showed a severe dwarf growth phenotype that was very similar to the phenotype of tomato plants mutated at a second alpha-dox isoform. This led us to identify the corresponding alpha dox2 gene in N. attenuata and examine the regulation of both alpha-dox genes as well as the consequences of their silencing in plant development and anti herbivore defense. RESULTS: The transformed lines exhibiting a dwarf growth phenotype are co-silenced for both alpha-dox genes resulting in a nearly complete suppression of alpha-DOX activity, which is associated with increases in ABA, JA and anthocyanin levels, all metabolic signatures of oxidative stress. The other lines, only silenced for alpha-dox1, developed similarly to wild-type plants, exhibited a 40% reduction of alpha-DOX activity resulting in a 50% reduction of its main product in planta (2-HOT) and showed no signs of oxidative stress. In contrast to alpha-dox1, the expression of alpha-dox2 gene is not induced by wounding or elicitors in the oral secretions of Manduca sexta. Instead, alpha dox2 is expressed in roots and flowers which lack alpha-dox1 expression, but both genes are equally regulated during leaf maturation. We transiently silenced alpha dox gene copies with gene-specific constructs using virus induced gene silencing and determined the consequences for plant development and phytohormone and 2-HOT levels. While individual silencing of alpha-dox1 or alpha-dox2 had no effects on plant growth, the co-suppression of both alpha-dox genes decreased plant growth. Plants transiently silenced for both alpha-dox genes had increased constitutive levels of JA and ABA but silencing alpha-dox1 alone resulted in lower M. sexta induced levels of JA, 2-HOT and ABA. CONCLUSIONS: Thus, both alpha-dox isoforms function in the development of N. attenuata. In leaf maturation, the two alpha dox genes have overlapping functions, but only alpha-dox2 is involved in root and flower development and only alpha-dox1 functions in anti-herbivore defense. PMID- 20701758 TI - Nutritional status of children in India: household socio-economic condition as the contextual determinant. AB - BACKGROUND: Despite recent achievement in economic progress in India, the fruit of development has failed to secure a better nutritional status among all children of the country. Growing evidence suggest there exists a socio-economic gradient of childhood malnutrition in India. The present paper is an attempt to measure the extent of socio-economic inequality in chronic childhood malnutrition across major states of India and to realize the role of household socio-economic status (SES) as the contextual determinant of nutritional status of children. METHODS: Using National Family Health Survey-3 data, an attempt is made to estimate socio-economic inequality in childhood stunting at the state level through Concentration Index (CI). Multi-level models; random-coefficient and random-slope are employed to study the impact of SES on long-term nutritional status among children, keeping in view the hierarchical nature of data. MAIN FINDINGS: Across the states, a disproportionate burden of stunting is observed among the children from poor SES, more so in urban areas. The state having lower prevalence of chronic childhood malnutrition shows much higher burden among the poor. Though a negative correlation (r = -0.603, p < .001) is established between Net State Domestic Product (NSDP) and CI values for stunting; the development indicator is not always linearly correlated with intra-state inequality in malnutrition prevalence. Results from multi-level models however show children from highest SES quintile posses 50 percent better nutritional status than those from the poorest quintile. CONCLUSION: In spite of the declining trend of chronic childhood malnutrition in India, the concerns remain for its disproportionate burden on the poor. The socio-economic gradient of long-term nutritional status among children needs special focus, more so in the states where chronic malnutrition among children apparently demonstrates a lower prevalence. The paper calls for state specific policies which are designed and implemented on a priority basis, keeping in view the nature of inequality in childhood malnutrition in the country and its differential characteristics across the states. PMID- 20701757 TI - Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. AB - BACKGROUND: Much of our current understanding of microvascular permeability is based on the findings of classic experimental studies of blood capillary permeability to various-sized lipid-insoluble endogenous and non-endogenous macromolecules. According to the classic small pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the transcapillary flow rates of various-sized systemically or regionally perfused endogenous macromolecules, transcapillary exchange across the capillary wall takes place through a single population of small pores that are approximately 6 nm in diameter; whereas, according to the dual pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the accumulation of various-sized systemically or regionally perfused non-endogenous macromolecules in the locoregional tissue lymphatic drainages, transcapillary exchange across the capillary wall also takes place through a separate population of large pores, or capillary leaks, that are between 24 and 60 nm in diameter. The classification of blood capillary types on the basis of differences in the physiologic upper limits of pore size to transvascular flow highlights the differences in the transcapillary exchange routes for the transvascular transport of endogenous and non-endogenous macromolecules across the capillary walls of different blood capillary types. METHODS: The findings and published data of studies on capillary wall ultrastructure and capillary microvascular permeability to lipid-insoluble endogenous and non-endogenous molecules from the 1950s to date were reviewed. In this study, the blood capillary types in different tissues and organs were classified on the basis of the physiologic upper limits of pore size to the transvascular flow of lipid-insoluble molecules. Blood capillaries were classified as non-sinusoidal or sinusoidal on the basis of capillary wall basement membrane layer continuity or lack thereof. Non-sinusoidal blood capillaries were further sub-classified as non-fenestrated or fenestrated based on the absence or presence of endothelial cells with fenestrations. The sinusoidal blood capillaries of the liver, myeloid (red) bone marrow, and spleen were sub-classified as reticuloendothelial or non-reticuloendothelial based on the phago-endocytic capacity of the endothelial cells. RESULTS: The physiologic upper limit of pore size for transvascular flow across capillary walls of non sinusoidal non-fenestrated blood capillaries is less than 1 nm for those with interendothelial cell clefts lined with zona occludens junctions (i.e. brain and spinal cord), and approximately 5 nm for those with clefts lined with macula occludens junctions (i.e. skeletal muscle). The physiologic upper limit of pore size for transvascular flow across the capillary walls of non-sinusoidal fenestrated blood capillaries with diaphragmed fenestrae ranges between 6 and 12 nm (i.e. exocrine and endocrine glands); whereas, the physiologic upper limit of pore size for transvascular flow across the capillary walls of non-sinusoidal fenestrated capillaries with open 'non-diaphragmed' fenestrae is approximately 15 nm (kidney glomerulus). In the case of the sinusoidal reticuloendothelial blood capillaries of myeloid bone marrow, the transvascular transport of non-endogenous macromolecules larger than 5 nm into the bone marrow interstitial space takes place via reticuloendothelial cell-mediated phago-endocytosis and transvascular release, which is the case for systemic bone marrow imaging agents as large as 60 nm in diameter. CONCLUSIONS: The physiologic upper limit of pore size in the capillary walls of most non-sinusoidal blood capillaries to the transcapillary passage of lipid-insoluble endogenous and non-endogenous macromolecules ranges between 5 and 12 nm. Therefore, macromolecules larger than the physiologic upper limits of pore size in the non-sinusoidal blood capillary types generally do not accumulate within the respective tissue interstitial spaces and their lymphatic drainages. In the case of reticuloendothelial sinusoidal blood capillaries of myeloid bone marrow, however, non-endogenous macromolecules as large as 60 nm in diameter can distribute into the bone marrow interstitial space via the phago endocytic route, and then subsequently accumulate in the locoregional lymphatic drainages of tissues following absorption into the lymphatic drainage of periosteal fibrous tissues, which is the lymphatic drainage of myeloid bone marrow. When the ultrastructural basis for transcapillary exchange across the capillary walls of different capillary types is viewed in this light, it becomes evident that the physiologic evidence for the existence of aqueous large pores ranging between 24 and 60 nm in diameter in the capillary walls of blood capillaries, is circumstantial, at best. PMID- 20701759 TI - Network, degeneracy and bow tie. Integrating paradigms and architectures to grasp the complexity of the immune system. AB - Recently, the network paradigm, an application of graph theory to biology, has proven to be a powerful approach to gaining insights into biological complexity, and has catalyzed the advancement of systems biology. In this perspective and focusing on the immune system, we propose here a more comprehensive view to go beyond the concept of network. We start from the concept of degeneracy, one of the most prominent characteristic of biological complexity, defined as the ability of structurally different elements to perform the same function, and we show that degeneracy is highly intertwined with another recently-proposed organizational principle, i.e. 'bow tie architecture'. The simultaneous consideration of concepts such as degeneracy, bow tie architecture and network results in a powerful new interpretative tool that takes into account the constructive role of noise (stochastic fluctuations) and is able to grasp the major characteristics of biological complexity, i.e. the capacity to turn an apparently chaotic and highly dynamic set of signals into functional information. PMID- 20701760 TI - Ethnomedicinal uses of Hagenia abyssinica (Bruce) J.F. Gmel. among rural communities of Ethiopia. AB - Ethiopian communities highly depend on local plant resources to secure their subsistence and health. Local tree resources are exploited and used intensively for medicinal purposes. This study provides insight into the medicinal importance of Hagenia abyssinica as well as the degree of threat on its population. An ethnobotanical study was carried out to document medicinal uses of Hagenia abyssinica by rural communities of North and Southeastern Ethiopia. The study was conducted using an integrated approach of group discussions, observation, a local market survey and interviews. A total of 90 people were interviewed among whom elderly and traditional healers were the key informants. Societies in the study sites still depend on Hagenia abyssinica for medicine. All plant parts are used to treat different aliments. Tree identification, collection and utilization were different among the studied communities. In spite of its significance, interest in utilizing flowers of Hagenia abyssinica as an anthelmintic seems to be diminishing, notably among young people. This is partly because the medicine can be harmful when it is taken in large quantities. Nowadays, the widely used Hagenia abyssinica is endangered primarily due to various anthropogenic impacts. This in turn may become a threat for the associated knowledge. It is recommended to assist communities in documenting their traditional knowledge. Measures for conserving species are urgently needed. PMID- 20701761 TI - Molecular epidemiology of salmonid alphavirus (SAV) subtype 3 in Norway. AB - BACKGROUND: Pancreas disease (PD) is a viral fish disease which in recent years has significantly affected Norwegian salmonid aquaculture. In Norway, the aetiological agent salmonid alphavirus (SAV) has been found to be represented by the subtype 3 only. SAV subtype 3 has in previous analyses been found to show a lower genetic divergence than the subtypes found to cause PD in Ireland and Scotland. The aim of this study was to evaluate the nucleotide (nt) and amino acid divergence and the phylogenetic relationship of 33 recent SAV subtype 3 sequences. The samples from which the sequences were obtained originated from both PD endemic and non-endemic regions in an attempt to investigate agent origin/spread. Multiple samples throughout the seawater production phase from several salmonid populations were included to investigate genetic variation during an outbreak. The analyses were mainly based on partial sequences from the E2 gene. For some samples, additional partial 6 K and nsP3 gene sequences were available. RESULTS: The nucleotide divergence for all gene fragments ranged from total identity (0.0% divergence) to 0.45% (1103 nt fragment of E2), 1.11% (451 nt fragment of E2), 0.94% (6 K) and 0.28% (nsP3). This low nucleotide divergence corresponded well to previous reports on SAV 3 sequences; however the observed divergence for the short E2 fragment was higher than that previously reported. When compared to SAVH20/03 (AY604235), amino acid substitutions were detected in all assessed gene fragments however the in vivo significance of these on for example disease outbreak mortality could not be concluded on. The phylogenetic tree based on the 451 nt E2 fragment showed that the sequences divided into two clusters with low genetic divergence, representing only a single SAV subtype. CONCLUSIONS: The analysed sequences represented two clusters of a single SAV subtype; however some of the observed sequence divergence was higher than that previously reported by other researchers. Larger scale, full length sequence analyses should be instigated to allow further phylogenetic and molecular epidemiology investigations of SAV subtype 3. PMID- 20701762 TI - Why do some women still prefer traditional birth attendants and home delivery?: a qualitative study on delivery care services in West Java Province, Indonesia. AB - BACKGROUND: Trained birth attendants at delivery are important for preventing both maternal and newborn deaths. West Java is one of the provinces on Java Island, Indonesia, where many women still deliver at home and without the assistance of trained birth attendants. This study aims to explore the perspectives of community members and health workers about the use of delivery care services in six villages of West Java Province. METHODS: A qualitative study using focus group discussions (FGDs) and in-depth interviews was conducted in six villages of three districts in West Java Province from March to July 2009. Twenty FGDs and 165 in-depth interviews were conducted involving a total of 295 participants representing mothers, fathers, health care providers, traditional birth attendants and community leaders. The FGD and in-depth interview guidelines included reasons for using a trained or a traditional birth attendant and reasons for having a home or an institutional delivery. RESULTS: The use of traditional birth attendants and home delivery were preferable for some community members despite the availability of the village midwife in the village. Physical distance and financial limitations were two major constraints that prevented community members from accessing and using trained attendants and institutional deliveries. A number of respondents reported that trained delivery attendants or an institutional delivery were only aimed at women who experienced obstetric complications. The limited availability of health care providers was reported by residents in remote areas. In these settings the village midwife, who was sometimes the only health care provider, frequently travelled out of the village. The community perceived the role of both village midwives and traditional birth attendants as essential for providing maternal and health care services. CONCLUSIONS: A comprehensive strategy to increase the availability, accessibility, and affordability of delivery care services should be considered in these West Java areas. Health education strategies are required to increase community awareness about the importance of health services along with the existing financing mechanisms for the poor communities. Public health strategies involving traditional birth attendants will be beneficial particularly in remote areas where their services are highly utilized. PMID- 20701763 TI - The effects of summer temperature, age and socioeconomic circumstance on acute myocardial infarction admissions in Melbourne, Australia. AB - BACKGROUND: Published literature detailing the effects of heatwaves on human health is readily available. However literature describing the effects of heat on morbidity is less plentiful, as is research describing events in the southern hemisphere and Australia in particular. To identify susceptible populations and direct public health responses research must move beyond description of the temperature morbidity relationship to include social and spatial risk factors. This paper presents a spatial and socio-demographic picture of the effects of hot weather on persons admitted to hospital with acute myocardial infarction (AMI) in Melbourne. RESULTS: In this study, the use of a spatial and socio-economic perspective has identified two groups within the population that have an increased 'risk' of AMI admissions to hospital during hot weather. AMI increases during hot weather were only identified in the most disadvantaged and the least disadvantaged areas. Districts with higher AMI admissions rates during hot weather also had larger proportions of older residents. Age provided some explanation for the spatial distribution of AMI admissions on single hot days whereas socio-economic circumstance did not. During short periods (3-days) of hot weather, age explained the spatial distribution of AMI admissions slightly better than socioeconomic circumstance. CONCLUSIONS: This study has demonstrated that both age and socioeconomic inequality contribute to AMI admissions to hospital in Melbourne during hot weather. By using socioeconomic circumstance to define quintiles, differences in AMI admissions were quantified and demographic differences in AMI admissions were described. Including disease specificity into climate-health research methods is necessary to identify climate-sensitive diseases and highlight the burden of climate-sensitive disease in the community. Cardiac disease is a major cause of death and disability and identifying cardiac specific climate thresholds and the spatio-demographic characteristics of vulnerable groups within populations is an important step towards preventative health care by informing public health officials and providing a guide for an early heat-health warning system. This information is especially important under current climatic conditions and for assessing the future impact of climate change. PMID- 20701764 TI - Neuropeptide delivery to the brain: a von Willebrand factor signal peptide to direct neuropeptide secretion. AB - BACKGROUND: Multiple neuropeptides, sometimes with opposing functions, can be produced from one precursor gene. To study the roles of the different neuropeptides encoded by one large precursor we developed a method to overexpress minigenes and establish local secretion. RESULTS: We fused the signal peptide from the Von Willebrand Factor (VWF) to a furin site followed by a processed form of the Agouti related protein (AgRP), AgRP(83-132) or alpha-melanocyte stimulating hormone. In vitro, these minigenes were secreted and biologically active. Additionally, the proteins of the minigenes were not transported into projections of primary neurons, thereby ensuring local release. In vivo administration of VWF-AgRP(83-132), using an adeno-associated viral vector as a delivery vehicle, into the paraventricular hypothalamus increased body weight and food intake of these rats compared to rats which received a control vector. CONCLUSIONS: This study demonstrated that removal of the N-terminal part of full length AgRP and addition of a VWF signal peptide is a successful strategy to deliver neuropeptide minigenes to the brain and establish local neuropeptide secretion. PMID- 20701765 TI - Characterisation of the role of Vrp1 in cell fusion during the development of visceral muscle of Drosophila melanogaster. AB - BACKGROUND: In Drosophila muscle cell fusion takes place both during the formation of the somatic mesoderm and the visceral mesoderm, giving rise to the skeletal muscles and the gut musculature respectively. The core process of myoblast fusion is believed to be similar for both organs. The actin cytoskeleton regulator Verprolin acts by binding to WASP, which in turn binds to the Arp2/3 complex and thus activates actin polymerization. While Verprolin has been shown to be important for somatic muscle cell fusion, the function of this protein in visceral muscle fusion has not been determined. RESULTS: Verprolin is specifically expressed in the fusion competent myoblasts of the visceral mesoderm, suggesting a role in visceral mesoderm fusion. We here describe a novel Verprolin mutant allele which displays subtle visceral mesoderm fusion defects in the form of mislocalization of the immunoglobulin superfamily molecule Duf/Kirre, which is required on the myoblast cell surface to facilitate attachment between cells that are about to fuse, indicating a function for Verprolin in visceral mesoderm fusion. We further show that Verprolin mutant cells are capable of both migrating and fusing and that the WASP-binding domain of Verprolin is required for rescue of the Verprolin mutant phenotype. CONCLUSIONS: Verprolin is expressed in the visceral mesoderm and plays a role in visceral muscle fusion as shown by mislocalization of Duf/Kirre in the Verprolin mutant, however it is not absolutely required for myoblast fusion in either the visceral or the somatic mesoderm. PMID- 20701766 TI - Simulation methods with extended stability for stiff biochemical Kinetics. AB - BACKGROUND: With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, tau, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where tau can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called tau-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as tau grows. RESULTS: In this paper we extend Poisson tau-leap methods to a general class of Runge-Kutta (RK) tau-leap methods. We show that with the proper selection of the coefficients, the variance of the extended tau-leap can be well-behaved, leading to significantly larger step sizes. CONCLUSIONS: The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original tau-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems. PMID- 20701767 TI - HMGA1 down-regulation is crucial for chromatin composition and a gene expression profile permitting myogenic differentiation. AB - BACKGROUND: High mobility group A (HMGA) proteins regulate gene transcription through architectural modulation of chromatin and the formation of multi-protein complexes on promoter/enhancer regions. Differential expression of HMGA variants has been found to be important for distinct differentiation processes and deregulated expression was linked to several disorders. Here we used mouse C2C12 myoblasts and C2C12 cells stably over-expressing HMGA1a-eGFP to study the impact of deregulated HMGA1 expression levels on cellular differentiation. RESULTS: We found that induction of the myogenic or osteogenic program of C2C12 cells caused an immediate down-regulation of HMGA1. In contrast to wild type C2C12 cells, an engineered cell line with stable over-expression of HMGA1a-eGFP failed to differentiate into myotubes. Immunolocalization studies demonstrated that sustained HMGA1a-eGFP expression prevented myotube formation and chromatin reorganization that normally accompanies differentiation. Western Blot analyses showed that elevated HMGA1a-eGFP levels affected chromatin composition through either down-regulation of histone H1 or premature expression of MeCP2. RT-PCR analyses further revealed that sustained HMGA1a expression also affected myogenic gene expression and caused either down-regulation of genes such as MyoD, myogenin, Igf1, Igf2, Igfbp1-3 or up-regulation of the transcriptional repressor Msx1. Interestingly, siRNA experiments demonstrated that knock-down of HMGA1a was required and sufficient to reactivate the myogenic program in induced HMGA1a over expressing cells. CONCLUSIONS: Our data demonstrate that HMGA1 down-regulation after induction is required to initiate the myogenic program in C2C12 cells. Sustained HMGA1a expression after induction prevents expression of key myogenic factors. This may be due to specific gene regulation and/or global effects on chromatin. Our data further corroborate that altered HMGA1 levels influence the expression of other chromatin proteins. Thus, HMGA1 is able to establish a specific chromatin composition. This work contributes to the understanding of how differential HMGA1 expression is involved in chromatin organization during cellular differentiation processes and it may help to comprehend effects of HMGA1 over-expression occurring in malign or benign tumours. PMID- 20701768 TI - Treatment of specific macrovascular beds in patients with diabetes mellitus. AB - In 2007, over 23 million people had diabetes in the United States and death from cardiovascular disease is estimated to occur in 80% of those Americans. Risk factor reduction is the most important therapy for primary and secondary prevention of macrovascular disease in patients with and without diabetes mellitus. Despite this, presentation and response to therapy is often different for patients with diabetes compared to their non-diabetic counterparts. This paper will review the current targets for therapy of cardiovascular disease, peripheral vascular disease, and cerebrovascular disease in patients with diabetes. PMID- 20701769 TI - Effect of acute hypoxia on respiratory muscle fatigue in healthy humans. AB - BACKGROUND: Greater diaphragm fatigue has been reported after hypoxic versus normoxic exercise, but whether this is due to increased ventilation and therefore work of breathing or reduced blood oxygenation per se remains unclear. Hence, we assessed the effect of different blood oxygenation level on isolated hyperpnoea induced inspiratory and expiratory muscle fatigue. METHODS: Twelve healthy males performed three 15-min isocapnic hyperpnoea tests (85% of maximum voluntary ventilation with controlled breathing pattern) in normoxic, hypoxic (SpO2 = 80%) and hyperoxic (FiO2 = 0.60) conditions, in a random order. Before, immediately after and 30 min after hyperpnoea, transdiaphragmatic pressure (P(di,tw)) was measured during cervical magnetic stimulation to assess diaphragm contractility, and gastric pressure (P(ga,tw)) was measured during thoracic magnetic stimulation to assess abdominal muscle contractility. Two-way analysis of variance (time x condition) was used to compare hyperpnoea-induced respiratory muscle fatigue between conditions. RESULTS: Hypoxia enhanced hyperpnoea-induced P(di,tw) and P(ga,tw) reductions both immediately after hyperpnoea (P(di,tw) : normoxia -22 +/ 7% vs hypoxia -34 +/- 8% vs hyperoxia -21 +/- 8%; P(ga,tw) : normoxia -17 +/- 7% vs hypoxia -26 +/- 10% vs hyperoxia -16 +/- 11%; all P < 0.05) and after 30 min of recovery (P(di,tw) : normoxia -10 +/- 7% vs hypoxia -16 +/- 8% vs hyperoxia -8 +/- 7%; P(ga,tw) : normoxia -13 +/- 6% vs hypoxia -21 +/- 9% vs hyperoxia -12 +/- 12%; all P < 0.05). No significant difference in (di,tw) or P(ga,tw) reductions was observed between normoxic and hyperoxic conditions. Also, heart rate and blood lactate concentration during hyperpnoea were higher in hypoxia compared to normoxia and hyperoxia. CONCLUSIONS: These results demonstrate that hypoxia exacerbates both diaphragm and abdominal muscle fatigability. These results emphasize the potential role of respiratory muscle fatigue in exercise performance limitation under conditions coupling increased work of breathing and reduced O2 transport as during exercise in altitude or in hypoxemic patients. PMID- 20701770 TI - SNP discovery by high-throughput sequencing in soybean. AB - BACKGROUND: With the advance of new massively parallel genotyping technologies, quantitative trait loci (QTL) fine mapping and map-based cloning become more achievable in identifying genes for important and complex traits. Development of high-density genetic markers in the QTL regions of specific mapping populations is essential for fine-mapping and map-based cloning of economically important genes. Single nucleotide polymorphisms (SNPs) are the most abundant form of genetic variation existing between any diverse genotypes that are usually used for QTL mapping studies. The massively parallel sequencing technologies (Roche GS/454, Illumina GA/Solexa, and ABI/SOLiD), have been widely applied to identify genome-wide sequence variations. However, it is still remains unclear whether sequence data at a low sequencing depth are enough to detect the variations existing in any QTL regions of interest in a crop genome, and how to prepare sequencing samples for a complex genome such as soybean. Therefore, with the aims of identifying SNP markers in a cost effective way for fine-mapping several QTL regions, and testing the validation rate of the putative SNPs predicted with Solexa short sequence reads at a low sequencing depth, we evaluated a pooled DNA fragment reduced representation library and SNP detection methods applied to short read sequences generated by Solexa high-throughput sequencing technology. RESULTS: A total of 39,022 putative SNPs were identified by the Illumina/Solexa sequencing system using a reduced representation DNA library of two parental lines of a mapping population. The validation rates of these putative SNPs predicted with low and high stringency were 72% and 85%, respectively. One hundred sixty four SNP markers resulted from the validation of putative SNPs and have been selectively chosen to target a known QTL, thereby increasing the marker density of the targeted region to one marker per 42 K bp. CONCLUSIONS: We have demonstrated how to quickly identify large numbers of SNPs for fine mapping of QTL regions by applying massively parallel sequencing combined with genome complexity reduction techniques. This SNP discovery approach is more efficient for targeting multiple QTL regions in a same genetic population, which can be applied to other crops. PMID- 20701771 TI - Production of glycoprotein vaccines in Escherichia coli. AB - BACKGROUND: Conjugate vaccines in which polysaccharide antigens are covalently linked to carrier proteins belong to the most effective and safest vaccines against bacterial pathogens. State-of-the art production of conjugate vaccines using chemical methods is a laborious, multi-step process. In vivo enzymatic coupling using the general glycosylation pathway of Campylobacter jejuni in recombinant Escherichia coli has been suggested as a simpler method for producing conjugate vaccines. In this study we describe the in vivo biosynthesis of two novel conjugate vaccine candidates against Shigella dysenteriae type 1, an important bacterial pathogen causing severe gastro-intestinal disease states mainly in developing countries. RESULTS: Two different periplasmic carrier proteins, AcrA from C. jejuni and a toxoid form of Pseudomonas aeruginosa exotoxin were glycosylated with Shigella O antigens in E. coli. Starting from shake flask cultivation in standard complex medium a lab-scale fed-batch process was developed for glycoconjugate production. It was found that efficiency of glycosylation but not carrier protein expression was highly susceptible to the physiological state at induction. After induction glycoconjugates generally appeared later than unglycosylated carrier protein, suggesting that glycosylation was the rate-limiting step for synthesis of conjugate vaccines in E. coli. Glycoconjugate synthesis, in particular expression of oligosaccharyltransferase PglB, strongly inhibited growth of E. coli cells after induction, making it necessary to separate biomass growth and recombinant protein expression phases. With a simple pulse and linear feed strategy and the use of semi-defined glycerol medium, volumetric glycoconjugate yield was increased 30 to 50-fold. CONCLUSIONS: The presented data demonstrate that glycosylated proteins can be produced in recombinant E. coli at a larger scale. The described methodologies constitute an important step towards cost-effective in vivo production of conjugate vaccines, which in future may be used for combating severe infectious diseases, particularly in developing countries. PMID- 20701772 TI - Ranked retrieval of Computational Biology models. AB - BACKGROUND: The study of biological systems demands computational support. If targeting a biological problem, the reuse of existing computational models can save time and effort. Deciding for potentially suitable models, however, becomes more challenging with the increasing number of computational models available, and even more when considering the models' growing complexity. Firstly, among a set of potential model candidates it is difficult to decide for the model that best suits ones needs. Secondly, it is hard to grasp the nature of an unknown model listed in a search result set, and to judge how well it fits for the particular problem one has in mind. RESULTS: Here we present an improved search approach for computational models of biological processes. It is based on existing retrieval and ranking methods from Information Retrieval. The approach incorporates annotations suggested by MIRIAM, and additional meta-information. It is now part of the search engine of BioModels Database, a standard repository for computational models. CONCLUSIONS: The introduced concept and implementation are, to our knowledge, the first application of Information Retrieval techniques on model search in Computational Systems Biology. Using the example of BioModels Database, it was shown that the approach is feasible and extends the current possibilities to search for relevant models. The advantages of our system over existing solutions are that we incorporate a rich set of meta-information, and that we provide the user with a relevance ranking of the models found for a query. Better search capabilities in model databases are expected to have a positive effect on the reuse of existing models. PMID- 20701773 TI - Effects of mitochondrial dysfunction on the immunological properties of microglia. AB - BACKGROUND: Neurodegenerative diseases are characterized by both mitochondrial dysfunction and activation of microglia, the macrophages of the brain. Here, we investigate the effects of mitochondrial dysfunction on the activation profile of microglial cells. METHODS: We incubated primary mouse microglia with the mitochondrial toxins 3-nitropropionic acid (3-NP) or rotenone. These mitochondrial toxins are known to induce neurodegeneration in humans and in experimental animals. We characterized lipopolysaccharide- (LPS-) induced microglial activation and the alternative, interleukin-4- (IL-4-) induced microglial activation in these mitochondrial toxin-treated microglial cells. RESULTS: We found that, while mitochondrial toxins did not affect LPS-induced activation, as measured by release of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta), they did inhibit part of the IL-4-induced alternative activation, as measured by arginase activity and expression, induction of insulin-like growth factor 1 (IGF-1) and the counteraction of the LPS induced cytokine release. CONCLUSIONS: Mitochondrial dysfunction in microglial cells inhibits part of the IL-4-induced alternative response. Because this alternative activation is considered to be associated with wound healing and an attenuation of inflammation, mitochondrial dysfunction in microglial cells might contribute to the detrimental effects of neuroinflammation seen in neurodegenerative diseases. PMID- 20701774 TI - A novel function for vimentin: the potential biomarker for predicting melanoma hematogenous metastasis. AB - BACKGROUND: The incidence of malignant melanoma (MM) was occurring at a faster rate than for most neoplasm worldwide, and melanoma metastasis is still the most formidable problem. So it is necessarily to find some biomarkers associated with melanoma metastasis. METHODS: In our study, 8 spontaneous lung metastatic mice models were created by B16F10 subcutaneously transplantation. The differential protein profiles of two kinds of subcutaneous transplanted tumor tissues, which was parental B16F10 (B16 group) and corresponding lung metastases (B16M group) were detected by two-dimensional differential in-gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS). Western blotting was used to validate the results, and the clinical significance of individual protein was detected furtherly in a set of human samples. RESULT: In this study, thirty proteins were found to be differentially expressed (ratio > 2 or < -2, P < 0.01) and thirteen of them were identified by MS. Highly expressed proteins in B16M group included cytoskeleton/structure proteins (vimentin, gamma-actin, beta-actin, laminin binding protein), the chaperone family of proteins (heavy-chain binding protein, Bip), immunoproteasome assembly (proteasome activator REG alpha) and others involved in glycolysis activity (PGK1, enolase, TPI, human skeletal muscle GAPDH) and protein transport (myoglobin). Vimentin was significantly up-regulated in B16M group compared with B16 group which was validated by western blotting. Immunohistochemistry was performed in a set of clinical samples, the results showed that over-expression of vimentin was frequently observed in primary melanoma patients with hematogenous metastasis (P < 0.05), not associated with lymph node metastasis (P > 0.05). The presence of TNM stage was a independent indicator of poor prognosis for melanoma patients (P = 0.004). CONCLUSION: The aberrant immunohistochemical expression of vimentin in primary melanoma tissues may help to call attention for patients with high risk of hematogenous metastasis. That might be as a novel metastatic indicator for melanoma. In a word, vimentin is not only the diagnostic marker but also the hematogenous metastasis predictor for melanomas clinically. PMID- 20701775 TI - Reliability of computed tomography measurements in assessment of thigh muscle cross-sectional area and attenuation. AB - BACKGROUND: Advancement in technology of computer tomography (CT) and introduction of new medical imaging softwares enables easy and rapid assessment of muscle cross-sectional area (CSA) and attenuation. Before using these techniques in clinical studies there is a need for evaluation of the reliability of the measurements. The purpose of the study was to evaluate the inter- and intra-observer reliability of ImageJ in measuring thigh muscles CSA and attenuation in patients with anterior cruciate ligament (ACL) injury by computer tomography. METHODS: 31 patients from an ongoing study of rehabilitation and muscle atrophy after ACL reconstruction were included in the study. Axial CT images with slice thickness of 10 mm at the level of 150 mm above the knee joint were analyzed by two investigators independently at two times with a minimum of 3 weeks between the two readings using NIH ImageJ. CSA and the mean attenuation of individual thigh muscles were analyzed for both legs. RESULTS: Mean CSA and mean attenuation values were in good agreement both when comparing the two observers and the two replicates. The inter- and intraclass correlation (ICC) was generally very high with values from 0.98 to 1.00 for all comparisons except for the area of semimembranosus. All the ICC values were significant (p < 0,001). Pearson correlation coefficients were also generally very high with values from 0.98 to 1.00 for all comparisons except for the area of semimembranosus (0.95 for intraobserver and 0.92 for interobserver). CONCLUSION: This study has presented ImageJ as a method to monitor and evaluate CSA and attenuation of different muscles in the thigh using CT-imaging. The method shows an overall excellent reliability with respect to both observer and replicate. PMID- 20701776 TI - Responsiveness of the Eating Disorders Quality of Life Scale (EDQLS) in a longitudinal multi-site sample. AB - BACKGROUND: In eating disorders (EDs), treatment outcome measurement has traditionally focused on symptom reduction rather than functioning or quality of life (QoL). The Eating Disorders Quality of Life Scale (EDQLS) was recently developed to allow for measurement of broader outcomes. We examined responsiveness of the EDQLS in a longitudinal multi-site study. METHODS: The EDQLS and comparator generic QoL scales were collected in person at baseline, and 3 and 6 months from 130 participants (mean age 25.6 years; range 14-60) in 12 treatment programs in four Canadian provinces. Total score differences across the time points and responsiveness were examined using both anchor- and distribution based methods. RESULTS: 98 (75%) and 85 (65%) responses were received at 3 and 6 months respectively. No statistically significant differences were found between the baseline sample and those lost to follow-up on any measured characteristic. Mean EDQLS total scores increased from 110 (SD = 24) to 124.5 (SD = 29) at 3 months and 129 (SD = 28) at 6 months, and the difference by time was tested using a general linear model (GLM) to account for repeated measurement (p < .001). Responsiveness was good overall (Cohen's d = .61 and .80), and confirmed using anchor methods across 5 levels of self-reported improvement in health status (p < .001). Effect sizes across time were moderate or large for for all age groups. Internal consistency (Chronbach's alpha=.96) held across measurement points and patterns of responsiveness held across subscales. EDQLS responsiveness exceeded that of the Quality of Life Inventory, the Short Form-12 (mental and physical subscales) and was similar to the 16-dimension quality of life scale. CONCLUSIONS: The EDQLS is responsive to change in geographically diverse and clinically heterogeneous programs over a relatively short time period in adolescents and adults. It shows promise as an outcome measure for both research and clinical practice. PMID- 20701777 TI - Experimental comparison of relative RT-qPCR quantification approaches for gene expression studies in poplar. AB - BACKGROUND: RT-qPCR is a powerful tool for analysing gene expression. It depends on measuring the increase in fluorescence emitted by a DNA-specific dye during the PCR reaction. For relative quantification, where the expression of a target gene is measured in relation to one or multiple reference genes, various mathematical approaches are published. The results of relative quantification can be considerably influenced by the chosen method. RESULTS: We quantified gene expression of superoxide dismutase (SOD) and ascorbate peroxidase (APX) in the roots of two black poplar clones, 58-861 and Poli, which were subjected to drought stress. After proving the chosen reference genes actin (ACT), elongation factor 1 (EF1) and ubiquitin (UBQ) to be constantly expressed in the different watering regimes, we applied different approaches for relative quantification to the same raw fluorescence data. The results obtained using the comparative Cq method, LinRegPCR, qBase software and the Pfaffl model showed a good correlation, whereas calculation according to the Liu and Saint method produced highly variable results. However, it has been shown that the most reliable approach for calculation of the amplification efficiency is using the mean increase in fluorescence during PCR in each individual reaction. Accordingly, we could improve the quality of our results by applying the mean amplification efficiencies for each amplicon to the Liu and Saint method. CONCLUSIONS: As we could show that gene expression results can vary depending on the approach used for quantification, we recommend to carefully evaluate different quantification approaches before using them in studies analysing gene expression. PMID- 20701778 TI - Perforated Meckel's diverticulum presenting with combined bowel and urinary obstruction and mimicking Crohn's disease: a case report. AB - INTRODUCTION: Meckel's diverticulum is a common congenital anomaly of the gastrointestinal tract, but is an uncommon cause of serious complications in adults. Although cases of patients with hemorrhage, bowel obstruction or perforation associated with Meckel's diverticulum have been reported, there have been no prior reports of patients with combined urinary and bowel obstruction due to abscess formation. CASE PRESENTATION: We describe the case of a 21-year-old man with a history of recurrent papillary thyroid cancer, but no prior abdominal surgeries, who presented with a one-month history of rectal pain and new-onset obstipation with urinary retention. He reported night sweats and weight loss, and had a second-degree relative with known Crohn's disease. A digital rectal examination was notable and revealed marked tenderness with proximal induration. A computed tomography scan of the patient's abdomen revealed a large, complex, circumferential perirectal abscess compressing the rectal lumen and base of the urinary bladder, associated with terminal ileal thickening and an ileocecal fistula. A flexible sigmoidoscopy with an endorectal ultrasound scan displayed a complex abscess with extensive mucosal and surrounding inflammation. An exploratory laparotomy revealed a Meckel's diverticulum with a large perforation at its base, positioned near the ileocecal fistula and immediately superior to the perirectal abscess. The section of small bowel containing the Meckel's diverticulum, the terminal ileum, and the cecum, were all resected, and the abscess was debrided. CONCLUSIONS: Pre-operative diagnosis of Meckel's diverticulum can be difficult. If the nature of the complication makes ultimate surgical management likely, an early laparoscopic or open exploration should be performed to prevent the morbidity and mortality associated with late complications. PMID- 20701779 TI - Diagnosis of systemic toxoplasmosis with HIV infection using DNA extracted from paraffin-embedded tissue for polymerase chain reaction: a case report. AB - INTRODUCTION: Toxoplasmosis can be a life-threatening disease when it occurs in patients with HIV infection. In particular, meningioencephalitis has been regarded as the most common toxoplasmic complication in such patients. However, toxoplasmic meningitis in a patient with HIV infection is extremely rare and purulent or tuberculous meningitis should be considered initially as a disease for differential diagnosis in Japan. CASE PRESENTATION: Toxoplasmic meningitis in a patient with HIV infection is reported. A 36-year-old Japanese man presented with fever, pulsating headache, lumbago, nausea, and vomiting. No examinations suggested toxoplasmosis including cerebrospinal fluid examinations, images, and serological tests. The result of a polymerase chain reaction assay using paraffin embedded section was regarded as the conclusive evidence for the diagnosis. CONCLUSIONS: We wish to emphasize the usefulness of polymerase chain reaction assays with nucleic acid extracted from paraffin-embedded tissue sections processed for routine histopathological examination, if the section shows the infectious agents or findings suggesting some infectious diseases. PMID- 20701780 TI - The Escherichia coli K-12 ORFeome: a resource for comparative molecular microbiology. AB - BACKGROUND: Systems biology and functional genomics require genome-wide datasets and resources. Complete sets of cloned open reading frames (ORFs) have been made for about a dozen bacterial species and allow researchers to express and study complete proteomes in a high-throughput fashion. RESULTS: We have constructed an open reading frame (ORFeome) collection of 3974 or 94% of the known Escherichia coli K-12 ORFs in Gateway entry vector pENTR/Zeo. The collection has been used for protein expression and protein interaction studies. For example, we have compared interactions among YgjD, YjeE and YeaZ proteins in E. coli, Streptococcus pneumoniae, and Staphylococcus aureus. We also compare this ORFeome with other Gateway-compatible bacterial ORFeomes and show its utility for comparative functional genomics. CONCLUSIONS: The E. coli ORFeome provides a useful resource for functional genomics and other areas of protein research in a highly flexible format. Our comparison with other ORFeomes makes comparative analyses straighforward and facilitates direct comparisons of many proteins across many genomes. PMID- 20701781 TI - Assessing motor deficits in compressive neuropathy using quantitative electromyography. AB - BACKGROUND: Studying the changes that occur in motor unit potential trains (MUPTs) may provide insight into the extent of motor unit loss and neural re organization resulting from nerve compression injury. The purpose of this study was to determine the feasibility of using decomposition-based quantitative electromyography (DQEMG) to study the pathophysiological changes associated with compression neuropathy. METHODS: The model used to examine compression neuropathy was carpal tunnel syndrome (CTS) due to its high prevalence and ease of diagnosis. Surface and concentric needle electromyography data were acquired simultaneously from the abductor pollicis brevis muscle in six individuals with severe CTS, eight individuals with mild CTS and nine healthy control subjects. DQEMG was used to detect intramuscular MUPTs during constant-intensity contractions and to estimate parameters associated with the surface- and needle detected motor unit potentials (SMUPs and MUPs, respectively). MUP morphology and stability, SMUP morphology and motor unit number estimates (MUNEs) were compared among the groups using Kruskal-Wallis tests. RESULTS: The severe CTS group had larger amplitude and longer duration MUPs and smaller MUNEs than the mild CTS and control groups, suggesting that the individuals with severe CTS had motor unit loss with subsequent collateral reinnervation, and that DQEMG using a constant intensity protocol was sensitive to these changes. SMUP morphology and MUP complexity and stability did not significantly differ among the groups. CONCLUSIONS: These results provide evidence that MUP amplitude parameters and MUNEs obtained using DQEMG, may be a valuable tool to investigate pathophysiological changes in muscles affected by compressive motor neuropathy to augment information obtained from nerve conduction studies. Although there were trends in many of these measures, in this study, MUP complexity and stability and SMUP parameters were, of limited value. PMID- 20701782 TI - Systematic Development of the YouRAction program, a computer-tailored physical activity promotion intervention for Dutch adolescents, targeting personal motivations and environmental opportunities. AB - BACKGROUND: Increasing physical activity (PA) among adolescents is an important health promotion goal. PA has numerous positive health effects, but the majority of Dutch adolescents do not meet PA requirements. The present paper describes the systematic development of a theory-based computer-tailored intervention, YouRAction, which targets individual and environmental factors determining PA among adolescents. DESIGN: The intervention development was guided by the Intervention Mapping protocol, in order to define clear program objectives, theoretical methods and practical strategies, ensure systematic program planning and pilot-testing, and anticipate on implementation and evaluation. Two versions of YouRAction were developed: one that targets individual determinants and an extended version that also provides feedback on opportunities to be active in the neighbourhood. Key determinants that were targeted included: knowledge and awareness, attitudes, self-efficacy and subjective norms. The extended version also addressed perceived availability of neighbourhood PA facilities. Both versions aimed to increase levels of moderate-to-vigorous PA among adolescents. The intervention structure was based on self-regulation theory, comprising of five steps in the process of successful goal pursuit. Monitoring of PA behaviour and behavioural and normative feedback were used to increase awareness of PA behaviour; motivation was enhanced by targeting self-efficacy and attitudes, by means of various interactive strategies, such as web movies; the perceived environment was targeted by visualizing opportunities to be active in an interactive geographical map of the home environment; in the goal setting phase, the adolescents were guided in setting a goal and developing an action plan to achieve this goal; in the phase of active goal pursuit adolescents try to achieve their goal and in the evaluation phase the achievements are evaluated. Based on the results of the evaluation adolescents could revise their goal or choose another behaviour to focus on. The intervention is delivered in a classroom setting in three lessons. YouRAction will be evaluated in a cluster-randomized trial, with classes as unit of randomization. Evaluation will focus on PA outcomes, cognitive mediators/moderators and process measures. DISCUSSION: The planned development of YouRAction resulted in two computer-tailored interventions aimed at the promotion of PA in a Dutch secondary school setting. TRIAL REGISTRATION: NTR1923. PMID- 20701783 TI - Supportive treatment using a compression garment vest of painful sternal instability following deep surgical wound infection: a case report. AB - INTRODUCTION: Sternal dehiscence and instability poses a significant cause of persistent pain and limited quality of life following hospital discharge for 0.2% to 5% of patients who have undergone median sternotomy for open heart surgery. We report a successful, conservative, supportive long-term therapy of painful sternal non-union using a customized compression garment vest. CASE PRESENTATION: We report a case of painful sternal instability following open heart surgery in a 74-year-old Caucasian man. The complicating factors of obesity (body mass index of 40), renal failure, insulin-dependent diabetes mellitus and absolute arrhythmia with atrial fibrillation were present. CONCLUSION: A number of studies have demonstrated the efficacy of surgical interventions for secondary sternal stabilization, but individual patients may reject this option or may be, for other reasons, no longer operable. The task of primary care physicians and other health care providers is to offer this group of patients an alternative option for pragmatic, inexpensive and effective supportive therapy, of which compression garments are an example. PMID- 20701784 TI - Computing H/D-exchange rates of single residues from data of proteolytic fragments. AB - BACKGROUND: Protein conformation and protein/protein interaction can be elucidated by solution-phase Hydrogen/Deuterium exchange (sHDX) coupled to high resolution mass analysis of the digested protein or protein complex. In sHDX experiments mutant proteins are compared to wild-type proteins or a ligand is added to the protein and compared to the wild-type protein (or mutant). The number of deuteriums incorporated into the polypeptides generated from the protease digest of the protein is related to the solvent accessibility of amide protons within the original protein construct. RESULTS: In this work, sHDX data was collected on a 14.5 T FT-ICR MS. An algorithm was developed based on combinatorial optimization that predicts deuterium exchange with high spatial resolution based on the sHDX data of overlapping proteolytic fragments. Often the algorithm assigns deuterium exchange with single residue resolution. CONCLUSIONS: With our new method it is possible to automatically determine deuterium exchange with higher spatial resolution than the level of digested fragments. PMID- 20701785 TI - Lack of germline A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) gene in familial papillary thyroid cancer. AB - Thyroid cancer may have a familial predisposition but a specific germline alteration responsible for the disease has not been discovered yet. We have shown that familial papillary thyroid cancer (FPTC) patients have an imbalance in telomere-telomerase complex with short telomeres and increased telomerase activity. A germline mutation (A339V) in thyroid transcription factor-1 has been described in patients with multinodular goiter and papillary thyroid cancer. In this report, the presence of the A339V mutation and the telomere length has been studied in FPTC patients and unaffected family members. All samples analyzed displayed a pattern typical of the homozygous wild type revealing the absence of the A339V mutation. Shortening of telomeres was confirmed in all patients. We concluded that the A339V mutation in thyroid transcription factor-1 (TITF 1/NKX2.1) is not correlated with the familial form of PTC, even when the tumor was in the context of multinodular goiter. PMID- 20701786 TI - Cyclosporine-A therapy-induced multiple bilateral breast and accessory axillary breast fibroadenomas: a case report. AB - INTRODUCTION: Breast adenoma is common. However, in the setting of post transplantation immune suppression it may be expressed differently. CASE PRESENTATION: A 35-year-old Sudanese woman, with a history of renal transplantation two and half years prior to presentation, was on a single immune suppression therapy in the form of cyclosporine-A since the transplantation. During a regular follow-up visit, she was noticed to have gingival hypertrophy and bilateral breast and axillary swellings. She underwent successful surgical resection of the bilateral fibroadenomas. CONCLUSIONS: Cyclosporine-A therapy post renal transplantation is associated with an increased incidence of benign breast changes as fibroadenoma. Regular follow-up and appropriate selection of immunosuppressant therapy are essential in the post transplantation management of these patients. PMID- 20701787 TI - The use of exenatide in severely burned pediatric patients. AB - INTRODUCTION: Intensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered. METHODS: This open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups. RESULTS: Glucose values and variability were similar in both groups: Daily average was 130 +/- 28 mg/dl in the intervention group and 138 +/- 25 mg/dl in the control group (P = 0.31), MAGE 41 +/- 6 vs. 45 +/- 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 +/- 14 IU patients/day in the intervention group and 76 +/- 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month). CONCLUSIONS: Patients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting. TRIAL REGISTRATION: NCT00673309. PMID- 20701788 TI - KCNQ1 gene polymorphisms are associated with lipid parameters in a Chinese Han population. AB - BACKGROUND: Four single nucleotide polymorphisms (SNPs) (rs2237892, rs2237895, rs2237897, and rs2283228) in KCNQ1 are reported to be associated with type 2 diabetes mellitus (T2DM), possibly caused by a reduction in insulin secretion and higher fasting glucose, but the results are inconsistent. We investigated whether these 4 genetic markers are associated with serum lipid metabolism in a middle aged Chinese Han population. METHODS: We enrolled 398 consecutive patients, including 180 with premature coronary artery disease (CAD) (male < 55 years, female < 65 years) and 218 controls without documented CAD. All subjects were genotyped for 4 SNPs by using the ligase detection reaction method. Fasting blood sugar (FBS) and plasma concentrations of total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1(apo A1), and apolipoprotein B (apo B) were determined by standard biochemical methods. Main anthropometric and metabolic characteristics are analyzed among 3 genotypes at rs2283228, rs2237895, rs2237897, or rs2237892 in KCNQ1. RESULTS: The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, and TT were present in rs2237897 and rs2237892. The minor genotypes CC at rs2283228 and TT at rs2237892 were associated with higher levels of TG (P = 0.007 and 0.026, respectively). Furthermore, subjects with the CC genotype at rs2283228 had lower levels of HDL-C and apo A1 than in the other 2 genotype groups (P = 0.052 and 0.055, respectively). No other associations were detected between these 4 SNPs and FBS or other lipid parameters. CONCLUSIONS: Our data suggest that rs2283228 and rs2237892 in KCNQ1 are associated with lipid metabolism in a middle-aged Chinese Han population. PMID- 20701789 TI - "Sleep disparity" in the population: poor sleep quality is strongly associated with poverty and ethnicity. AB - BACKGROUND: Little is known about the social determinants of sleep attainment. This study examines the relationship of race/ethnicity, socio-economic status (SES) and other factors upon sleep quality. METHODS: A cross-sectional survey of 9,714 randomly selected subjects was used to explore sleep quality obtained by self-report, in relation to socioeconomic factors including poverty, employment status, and education level. The primary outcome was poor sleep quality. Data were collected by the Philadelphia Health Management Corporation. RESULTS: Significant differences were observed in the outcome for race/ethnicity (African American and Latino versus White: unadjusted OR = 1.59, 95% CI 1.24-2.05 and OR = 1.65, 95% CI 1.37-1.98, respectively) and income (below poverty threshold, unadjusted OR = 2.84, 95%CI 2.41-3.35). In multivariable modeling, health indicators significantly influenced sleep quality most prominently in poor individuals. After adjusting for socioeconomic factors (education, employment) and health indicators, the association of income and poor sleep quality diminished, but still persisted in poor Whites while it was no longer significant in poor African-Americans (adjusted OR = 1.95, 95% CI 1.47-2.58 versus OR = 1.16, 95% CI 0.87-1.54, respectively). Post-college education (adjusted OR = 0.47, 95% CI 0.31-0.71) protected against poor sleep. CONCLUSIONS: A "sleep disparity" exists in the study population: poor sleep quality is strongly associated with poverty and race. Factors such as employment, education and health status, amongst others, significantly mediated this effect only in poor subjects, suggesting a differential vulnerability to these factors in poor relative to non poor individuals in the context of sleep quality. Consideration of this could help optimize targeted interventions in certain groups and subsequently reduce the adverse societal effects of poor sleep. PMID- 20701790 TI - Evidence that adiponectin receptor 1 activation exacerbates ischemic neuronal death. AB - BACKGROUND: Adiponectin is a hormone produced in and released from adipose cells, which has been shown to have anti-diabetic and anti-inflammatory actions in peripheral cells. Two cell surface adiponectin receptors (ADRs) mediate the majority of the known biological actions of adiponectin. Thus far, ADR expression in the brain has been demonstrated in the arcuate and the paraventricular nucleus of hypothalamus, where its activation affects food intake. Recent findings suggest that levels of circulating adiponectin increase after an ischemic stroke, but the role of adiponectin receptor activation in stroke pathogenesis and its functional outcome is unclear. METHODS: Ischemic stroke was induced in C57BL/6 mice by middle cerebral artery occlusion (MCAO) for 1 h, followed by reperfusion. Primary cortical neuronal cultures were established from individual embryonic neocortex. For glucose deprivation (GD), cultured neurons were incubated in glucose-free Locke's medium for 6, 12 or 24 h. For combined oxygen and glucose deprivation (OGD), neurons were incubated in glucose-free Locke's medium in an oxygen-free chamber with 95% N2/5% CO2 atmosphere for either 3, 6, 9, 12 or 24 h. Primary neurons and brain tissues were analysed for Adiponectin and ADRs using reverse transcriptase polymerase chain reaction (RT-PCR), immunoblot and immunochemistry methods. RESULTS: Cortical neurons express ADR1 and ADR2, and that the levels of ADR1 are increased in neurons in response to in vitro or in vivo ischemic conditions. Neurons treated with either globular or trimeric adiponectin exhibited increased vulnerability to oxygen and glucose deprivation which was associated with increased activation of a pro-apoptotic signaling cascade involving p38 mitogen-activated protein kinase (p38MAPK) and AMP activated protein kinase (AMPK). CONCLUSIONS: This study reveals a novel pathogenic role for adiponectin and adiponectin receptor activation in ischemic stroke. We show that cortical neurons express ADRs and reveal a pro-apoptotic role for ADR1 activation in neurons, which may render them vulnerable to ischemic death. PMID- 20701791 TI - Violence against female sex workers in Karnataka state, south India: impact on health, and reductions in violence following an intervention program. AB - BACKGROUND: Violence against female sex workers (FSWs) can impede HIV prevention efforts and contravenes their human rights. We developed a multi-layered violence intervention targeting policy makers, secondary stakeholders (police, lawyers, media), and primary stakeholders (FSWs), as part of wider HIV prevention programming involving >60,000 FSWs in Karnataka state. This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk, and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them. METHODS: FSWs were randomly selected to participate in polling booth surveys (PBS 2006-2008; short behavioural questionnaires administered anonymously) and integrated behavioural biological assessments (IBBAs 2005-2009; administered face-to-face). RESULTS: 3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS. Overall, 11.0% of FSWs in the IBBAs and 26.4% of FSWs in the PBS reported being beaten or raped in the past year. FSWs who reported violence in the past year were significantly less likely to report condom use with clients (zero unprotected sex acts in previous month, 55.4% vs. 75.5%, adjusted odds ratio (AOR) 0.4, 95% confidence interval (CI) 0.3 to 0.5, p < 0.001); to have accessed the HIV intervention program (ever contacted by peer educator, 84.9% vs. 89.6%, AOR 0.7, 95% CI 0.4 to 1.0, p = 0.04); or to have ever visited the project sexual health clinic (59.0% vs. 68.1%, AOR 0.7, 95% CI 0.6 to 1.0, p = 0.02); and were significantly more likely to be infected with gonorrhea (5.0% vs. 2.6%, AOR 1.9, 95% CI 1.1 to 3.3, p = 0.02). By the follow-up surveys, significant reductions were seen in the proportions of FSWs reporting violence compared with baseline (IBBA 13.0% vs. 9.0%, AOR 0.7, 95% CI 0.5 to 0.9 p = 0.01; PBS 27.3% vs. 18.9%, crude OR 0.5, 95% CI 0.4 to 0.5, p < 0.001). CONCLUSIONS: This program demonstrates that a structural approach to addressing violence can be effectively delivered at scale. Addressing violence against FSWs is important for the success of HIV prevention programs, and for protecting their basic human rights. PMID- 20701792 TI - Cellular apoptosis susceptibility (CSE1L/CAS) protein in cancer metastasis and chemotherapeutic drug-induced apoptosis. AB - The cellular apoptosis susceptibility (CSE1L/CAS) protein is highly expressed in cancer, and its expression is positively correlated with high cancer stage, high cancer grade, and worse outcomes of patients. CSE1L (or CAS) regulates chemotherapeutic drug-induced cancer cell apoptosis and may play important roles in mediating the cytotoxicities of chemotherapeutic drugs against cancer cells in cancer chemotherapy. CSE1L was originally regarded as a proliferation-associated protein and was thought to regulate the proliferation of cancer cells in cancer progression. However, the results of experimental studies showed that enhanced CSE1L expression is unable to increase proliferation of cancer cells and CSE1L regulates invasion and metastasis but not proliferation of cancer cells. Recent studies revealed that CSE1L is a secretory protein, and there is a higher prevalence of secretory CSE1L in the sera of patients with metastatic cancer. Therefore, CSE1L may be a useful serological marker for screening, diagnosis and prognosis, assessment of therapeutic responses, and monitoring for recurrence of cancer. In this paper, we review the expression of CSE1L in cancer and discuss why CSE1L regulates the invasion and metastasis rather than the proliferation of cancer. PMID- 20701793 TI - Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets. AB - The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of chance associations that lead to overestimation of true clinical accuracy. These methods will identify molecular pathways important for survival and growth of RCC cells and particular targets suitable for therapeutic development. Importantly, our results may enable individualized treatment of RCC, reducing ineffective therapy in drug-resistant disease, leading to improved quality of life and higher cost efficiency, which in turn should broaden patient access to beneficial therapeutics, thereby enhancing clinical outcome and cancer survival. The consortium will also establish and consolidate a European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding of molecular mechanisms driving resistance to anti angiogenesis agents, the current limitations of laboratory and clinical trial strategies and how the PREDICT consortium will endeavor to identify a new generation of predictive biomarkers. PMID- 20701794 TI - Income-, education- and gender-related inequalities in out-of-pocket health-care payments for 65+ patients - a systematic review. AB - BACKGROUND: In all OECD countries, there is a trend to increasing patients' copayments in order to balance rising overall health-care costs. This systematic review focuses on inequalities concerning the amount of out-of-pocket payments (OOPP) associated with income, education or gender in the Elderly aged 65+. METHODS: Based on an online search (PubMed), 29 studies providing information on OOPP of 65+ beneficiaries in relation to income, education and gender were reviewed. RESULTS: Low-income individuals pay the highest OOPP in relation to their earnings. Prescription drugs account for the biggest share. A lower educational level is associated with higher OOPP for prescription drugs and a higher probability of insufficient insurance protection. Generally, women face higher OOPP due to their lower income and lower labour participation rate, as well as less employer-sponsored health-care. CONCLUSIONS: While most studies found educational and gender inequalities to be associated with income, there might also be effects induced solely by education; for example, an unhealthy lifestyle leading to higher payments for lower-educated people, or exclusively gender-induced effects, like sex-specific illnesses. Based on the considered studies, an explanation for inequalities in OOPP by these factors remains ambiguous. PMID- 20701795 TI - A comparison of meningococcal carriage by pregnancy status. AB - Neisseria meningitidis is the second leading cause of invasive meningitis. A prerequisite for infection is colonization of the nasopharynx, and asymptomatic carrier rates are widely reported in the range of 10-15%. Recent reports have indicated an increased likelihood that a pediatric admission for Neisseria meningitidis will have a mother who is pregnant in the home. We hypothesized that this association may relate to immunologic changes in pregnancy leading to higher carrier rates.We compared the carrier status by performing nasopharyngeal swabs for Neisseria meningitidis in 100 pregnant and 99 non-pregnant women.Average age of the participants was 28.9 +/- 6.7 years. The average gestational age at specimen collection was 27.5 +/- 9.4 weeks. Non pregnant women were significantly more likely to use tobacco (38% vs 24%, p < 0.0001). In the entire 199 patients, only one pregnant patient tested positive for Neisseria meningitidis (0.5%; 95% CI: 0.01%-2.8%).The meningococcal carrier rate in our population is well below what is widely reported in the literature. Assuming a 1% carrier rate in the pregnant group and a 0.5% carrier rate in the non pregnant group, 4,763 patients would be required to detect a difference of this magnitude, given 80% power and an alpha of 0.05. PMID- 20701796 TI - Evaluation of HIV protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice. AB - BACKGROUND: Protease inhibitors (PI's) and reverse transcriptase drugs are important components of highly active antiretroviral therapy (HAART) for treating human acquired immunodeficiency syndrome (AIDS). Long-term clinical therapeutic efficacy and treatment compliance of these agents have been limited by undesirable side-effects, such as diarrhea. This study aims to investigate the effects of selected antiretroviral agents on intestinal histopathology and function in vivo and on cell proliferation and death in vitro. METHODS: Selected antiretroviral drugs were given orally over 7 days, to Swiss mice, as follows: 100 mg/kg of nelfinavir (NFV), indinavir (IDV), didanosine (DDI) or 50 mg/kg of zidovudine (AZT). Intestinal permeability measured by lactulose and mannitol assays; net water and electrolyte transport, in perfused intestinal segments; and small intestinal morphology and cell apoptosis were assessed in treated and control mice. In vitro cell proliferation was evaluated using the WST-1 reagent and apoptosis and necrosis by flow cytometry analysis. RESULTS: NFV, IDV, AZT and DDI caused significant reductions in duodenal and in jejunal villus length (p < 0.05). IDV and AZT increased crypt depth in the duodenum and AZT increased crypt depth in the jejunum. NFV, AZT and DDI significantly decreased ileal crypt depth. All selected antiretroviral drugs significantly increased net water secretion and electrolyte secretion, except for DDI, which did not alter water or chloride secretion. Additionally, only NFV significantly increased mannitol and lactulose absorption. NFV and IDV caused a significant reduction in cell proliferation in vitro at both 24 h and 48 h. DDI and AZT did not alter cell proliferation. There was a significant increase in apoptosis rates in IEC-6 cells after 24 h with 70 ug/mL of NFV (control: 4.7% vs NFV: 22%) while IDV, AZT and DDI did not show any significant changes in apoptosis compared to the control group. In jejunal sections, IDV and NFV significantly increased the number of TUNEL positive cells. CONCLUSION: The PI's, NFV and IDV, increased cell apoptosis in vivo, water and electrolyte secretion and intestinal permeability and decreased villus length and cell proliferation. NFV was the only drug tested that increased cell apoptosis in vitro. The nucleoside reverse transcriptase inhibitors, AZT and DDI, did not affect cell apoptosis or proliferation. These findings may partly explain the intestinal side-effects associated with PI's. PMID- 20701797 TI - Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes. AB - BACKGROUND: There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-beta signalling pathways, and the disease phenotype appears to be unmasked or provoked by angiogenesis in man and animal models. In a previous study, we mapped a new locus for HHT (HHT3) to a 5.7 Mb region of chromosome 5. Some of the polymorphic markers used had been uninformative in key recombinant individuals, leaving two potentially excludable regions, one of which contained loci for attractive candidate genes encoding VE Cadherin-2, Sprouty4 and FGF1, proteins involved in angiogenesis. METHODS: Extended analyses in the interval-defining pedigree were performed using informative genomic sequence variants identified during candidate gene sequencing. These variants were amplified by polymerase chain reaction; sequenced on an ABI 3730xl, and analysed using FinchTV V1.4.0 software. RESULTS: Informative genomic sequence variants were used to construct haplotypes permitting more precise citing of recombination breakpoints. These reduced the uninformative centromeric region from 141.2-144 Mb to between 141.9-142.6 Mb, and the uninformative telomeric region from 145.2-146.9 Mb to between 146.1-146.4 Mb. CONCLUSIONS: The HHT3 interval on chromosome 5 was reduced to 4.5 Mb excluding 30% of the coding genes in the original HHT3 interval. Strong candidates VE cadherin-2 and Sprouty4 cannot be HHT3. PMID- 20701799 TI - Repositioning and stabilization of the radial styloid process in comminuted fractures of the distal radius using a single approach: the radio-volar double plating technique. AB - BACKGROUND: A possible difficulty in intra-articular fracture of the distal radius is the displacement tendency of the radial styloid process due to the tension of the brachioradialis tendon. METHODS: Ten patients treated within one year for complex distal radius fractures by double-plating technique with a radial buttress plate and volar locking plate, through a single volar approach, were followed prospectively during 24 months. Outcome measures included radiographic follow-up, range of motion, grip strength and score follow-up (VAS, Gartland-Werley score and patient-rated wrist evaluation). RESULTS: Ten patients with intraarticular distal radius fractures with dislocation of the radial styloid process were treated with this technique. This resulted after 24 months in good clinical outcome (mean visual analog scale 0.9; almost symmetric range of motion; mean Gartland-Werley score 2 +/- 3; mean patient-rated wrist evaluation 3.2 +/- 2.4). Radiologic evaluation according to the Dresdner Score revealed anatomic reduction without secondary dislocation during the follow-up and uneventful consolidation. CONCLUSIONS: The described technique strongly facilitates anatomic reduction and stable fixation of intra-articular distal radius fractures with dislocation of the radial styloid process and leads to satisfactory clinical and radiographic outcome. PMID- 20701798 TI - MiTF links Erk1/2 kinase and p21 CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells. AB - As a survival factor for melanocytes lineage cells, MiTF plays multiple roles in development and melanomagenesis. What role MiTF plays in the DNA damage response is currently unknown. In this report we observed that MiTF was phosphorylated at serine 73 after UVC radiation, which was followed by proteasome-mediated degradation. Unlike after c-Kit stimulation, inhibiting p90RSK-1 did not abolish the band shift of MiTF protein, nor did it abolish the UVC-mediated MiTF degradation, suggesting that phosphorylation on serine 73 by Erk1/2 is a key event after UVC. Furthermore, the MiTF-S73A mutant (Serine 73 changed to Alanine via site-directed mutagenesis) was unable to degrade and was continuously expressed after UVC exposure. Compared to A375 melanoma cells expressing wild type MiTF (MiTF-WT), cells expressing MiTF-S73A mutant showed less p21 WAF1/CIP1 accumulation and a delayed p21 WAF1/CIP1 recovery after UVC. Consequently, cells expressing MiTF-WT showed a temporary G1 arrest after UVC, but cells expressing MiTF-S73A mutant or lack of MiTF expression did not. Finally, cell lines with high levels of MiTF expression showed higher resistance to UVC-induced cell death than those with low-level MiTF. These data suggest that MiTF mediates a survival signal linking Erk1/2 activation and p21 WAF1/CIP1 regulation via phosphorylation on serine 73, which facilitates cell cycle arrest. In addition, our data also showed that exposure to different wavelengths of UV light elicited different signal pathways involving MiTF. PMID- 20701800 TI - Testicular fusocellular rhabdomyosarcoma as a metastasis of elbow sclerosing rhabdomyosarcoma: A clinicopathologic, immunohistochemical and molecular study of one case. AB - Sclerosing rhabdomyosarcoma (SRMS) is an infrequent variant of rhabdomyosarcoma characterized by extensive intercellular hyaline fibrosis. We report the case of a 37 year-old male with a 9 x 6 cm SRMS on the right elbow. Histologically, the tumor showed an abundant extracellular hyaline matrix with extratumoral vascular emboli and microscopic foci of fusocellular embryonal rhabdomyosarcoma (FRMS) separated by a fibrotic band from the sclerosing areas. One year later the patient presented with a right intratesticular tumor of 1.2 x 0.8 cm, which was reported as pure FRMS. Immunohistochemically, SRMS was positive only for MyoD1 and Vimentin and negative for Myogenin and Desmin. Both the elbow emboli with the extratumoral foci of FRMS and the intratesticular tumor were positive for Myogenin, MyoD1, Vimentin and Desmin. Using fluorescent in situ hybridization (FISH), the SRMS and the FRMS tumor cells of the elbow and the FRMS tumor cells of the testis were found to be negative for FOXO1A translocation in chromosome 13. PCR chimeric transcriptional products PAX3-FKHR and PAX7-FKHR were not found. Six months following testicular resection, the patient died of multiple metastases in the mediastinum, lung and right thigh. PMID- 20701801 TI - Potassium deficiency induces the biosynthesis of oxylipins and glucosinolates in Arabidopsis thaliana. AB - BACKGROUND: Mineral fertilization and pest control are essential and costly requirements for modern crop production. The two measures go hand in hand because plant mineral status affects plant susceptibility to pests and vice versa. Nutrient deficiency triggers specific responses in plants that optimize nutrient acquisition and reprogram metabolism. K-deficient plants illustrate these strategies by inducing high-affinity K-uptake and adjusting primary metabolism. Whether and how K deficient plants also alter their secondary metabolism for nutrient management and defense is not known. RESULTS: Here we show that K deficient plants contain higher levels of the phytohormone jasmonic acid (JA), hydroxy-12-oxo-octadecadienoic acids (HODs) and 12-oxo-phytodienoic acid (OPDA) than K-sufficient plants. Up-regulation of the 13-LOX pathway in response to low K was evident in increased transcript levels of several biosynthetic enzymes. Indole and aliphatic glucosinolates accumulated in response to K-deficiency in a manner that was respectively dependent or independent on signaling through Coronatine-Insensitive 1 (COI1). Transcript and glucosinolate profiles of K deficient plants resembled those of herbivore attacked plants. CONCLUSIONS: Based on our results we propose that under K-deficiency plants produce oxylipins and glucosinolates to enhance their defense potential against herbivorous insects and create reversible storage for excess S and N. PMID- 20701802 TI - A concept for major incident triage: full-scaled simulation feasibility study. AB - BACKGROUND: Efficient management of major incidents involves triage, treatment and transport. In the absence of a standardised interdisciplinary major incident management approach, the Norwegian Air Ambulance Foundation developed Interdisciplinary Emergency Service Cooperation Course (TAS). The TAS-program was established in 1998 and by 2009, approximately 15 500 emergency service professionals have participated in one of more than 500 no-cost courses. The TAS triage concept is based on the established triage Sieve and Paediatric Triage Tape models but modified with slap-wrap reflective triage tags and paediatric triage stretchers. We evaluated the feasibility and accuracy of the TAS-triage concept in full-scale simulated major incidents. METHODS: The learners participated in two standardised bus crash simulations: without and with competence of TAS-triage and access to TAS-triage equipment. The instructors calculated triage accuracy and measured time consumption while the learners participated in a self-reported before-after study. Each question was scored on a 7-point Likert scale with points labelled "Did not work" (1) through "Worked excellent" (7). RESULTS: Among the 93 (85%) participating emergency service professionals, 48% confirmed the existence of a major incident triage system in their service, whereas 27% had access to triage tags. The simulations without TAS triage resulted in a mean over- and undertriage of 12%. When TAS-Triage was used, no mistriage was found. The average time from "scene secured to all patients triaged" was 22 minutes (range 15-32) without TAS-triage vs. 10 minutes (range 5 21) with TAS-triage. The participants replied to "How did interdisciplinary cooperation of triage work?" with mean 4,9 (95% CI 4,7-5,2) before the course vs. mean 5,8 (95% CI 5,6-6,0) after the course, p < 0,001. CONCLUSIONS: Our modified triage Sieve tool is feasible, time-efficient and accurate in allocating priority during simulated bus accidents and may serve as a candidate for a future national standard for major incident triage. PMID- 20701803 TI - An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing. AB - BACKGROUND: Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). The cAMP-specific PDE family 4 (PDE4) is widely expressed in vertebrates. Each of the four PDE4 gene isoforms (PDE4 A-D) undergo extensive alternative splicing via alternative transcription initiation sites, producing unique amino termini and yielding multiple splice variant forms from each gene isoform termed long, short, super-short and truncated super-short. Many species across the vertebrate lineage contain multiple splice variants of each gene type, which are characterized by length and amino termini. RESULTS: A phylogenetic approach was used to visualize splice variant form genesis and identify conserved splice variants (genome conservation with EST support) across the vertebrate taxa. Bayesian and maximum likelihood phylogenetic inference indicated PDE4 gene duplication occurred at the base of the vertebrate lineage and reveals additional gene duplications specific to the teleost lineage. Phylogenetic inference and PDE4 splice variant presence, or absence as determined by EST screens, were further supported by the genomic analysis of select vertebrate taxa. Two conserved PDE4 long form splice variants were found in each of the PDE4A, PDE4B, and PDE4C genes, and eight conserved long forms from the PDE4 D gene. Conserved short and super-short splice variants were found from each of the PDE4A, PDE4B, and PDE4 D genes, while truncated super-short variants were found from the PDE4C and PDE4 D genes. PDE4 long form splice variants were found in all taxa sampled (invertebrate through mammals); short, super-short, and truncated super-short are detected primarily in tetrapods and mammals, indicating an increasing complexity in both alternative splicing and cAMP metabolism through vertebrate evolution. CONCLUSIONS: There was a progressive independent incorporation of multiple PDE4 splice variant forms and amino termini, increasing PDE4 proteome complexity from primitive vertebrates to humans. While PDE4 gene isoform duplicates with limited alternative splicing were found in teleosts, an expansion of both PDE4 splice variant forms, and alternatively spliced amino termini predominantly occurs in mammals. Since amino termini have been linked to intracellular targeting of the PDE4 enzymes, the conservation of amino termini in PDE4 splice variants in evolution highlights the importance of compartmentalization of PDE4-mediated cAMP hydrolysis. PMID- 20701804 TI - Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. AB - BACKGROUND: The Janus kinase (JAK) family of tyrosine kinases includes JAK1, JAK2, JAK3 and TYK2, and is required for signaling through Type I and Type II cytokine receptors. CP-690,550 is a potent and selective JAK inhibitor currently in clinical trials for rheumatoid arthritis (RA) and other autoimmune disease indications. In RA trials, dose-dependent decreases in neutrophil counts (PBNC) were observed with CP-690,550 treatment. These studies were undertaken to better understand the relationship between JAK selectivity and PBNC decreases observed with CP-690,550 treatment. METHODS: Potency and selectivity of CP-690,550 for mouse, rat and human JAKs was evaluated in a panel of in vitro assays. The effect of CP-690,550 on granulopoiesis from progenitor cells was also assessed in vitro using colony forming assays. In vivo the potency of orally administered CP 690,550 on arthritis (paw edema), plasma cytokines, PBNC and bone marrow differentials were evaluated in the rat adjuvant-induced arthritis (AIA) model. RESULTS: CP-690,550 potently inhibited signaling through JAK1 and JAK3 with 5-100 fold selectivity over JAK2 in cellular assays, despite inhibiting all four JAK isoforms with nM potency in in vitro enzyme assays. Dose-dependent inhibition of paw edema was observed in vivo with CP-690,550 treatment. Plasma cytokines (IL-6 and IL-17), PBNC, and bone marrow myeloid progenitor cells were elevated in the context of AIA disease. At efficacious exposures, CP-690,550 returned all of these parameters to pre-disease levels. The plasma concentration of CP-690,550 at efficacious doses was above the in vitro whole blood IC50 of JAK1 and JAK3 inhibition, but not that of JAK2. CONCLUSION: Results from this investigation suggest that CP-690,550 is a potent inhibitor of JAK1 and JAK3 with potentially reduced cellular potency for JAK2. In rat AIA, as in the case of human RA, PBNC were decreased at efficacious exposures of CP-690,550. Inflammatory end points were similarly reduced, as judged by attenuation of paw edema and cytokines IL-6 and IL-17. Plasma concentration at these exposures was consistent with inhibition of JAK1 and JAK3 but not JAK2. Decreases in PBNC following CP-690,550 treatment may thus be related to attenuation of inflammation and are likely not due to suppression of granulopoiesis through JAK2 inhibition. PMID- 20701805 TI - Determinants of glycemic control in female diabetic patients: a study from Iran. AB - BACKGROUND: Since microvascular and macrovascular complications are reduced through strict glycemic control, this study carried out to identify the factors that affect glycemic control. METHODS: A cross-sectional design was carried out to examine the role of demographic, anthropometric, clinical and other relevant characteristics in a sample of 103 female diabetic patients in Tehran, Iran. Personal interviews were conducted to collect data. Then blood sampling collected and the patients were divided into two outcome groups (controlled and uncontrolled diabetes). The groups were compared on the basis of their characteristics using both univariate and multivariate analyses. RESULTS: In all 103 patients were entered into the study. The mean age of patients was 46.38 (SD = 11.42) years. Overall, the mean value of HbA1c for the whole sample was 7.5 (SD = 2.35) and 56.3% had HbA1c > or = 7%. The findings obtained from univariate analysis revealed that there were no significant differences between controlled and uncontrolled patients. However, in multivariate analysis the waist circumference was found to be a significant predictor of increased level of HbA1c (OR = 1.04, 95% CI = 1-1.08, P = 0.04). CONCLUSIONS: The findings suggest that increased level of HbA1c is associated with waist circumference that is a modifiable factor. It seems that physical activity might be a solution to overcome this health problem. A larger study to identify other factors also is recommended. PMID- 20701806 TI - The long path to pregnancy: early experience with dual anonymous gamete donation in a European in vitro fertilisation referral centre. AB - BACKGROUND: This investigation describes features of patients undergoing in vitro fertilisation (IVF) and embryo transfer (ET) where both gametes were obtained from anonymous donors. METHODS: Gamete unsuitability or loss was confirmed in both members of seven otherwise healthy couples presenting for reproductive endocrinology consultation over a 12-month interval in Ireland. IVF was undertaken with fresh oocytes provided by anonymous donors in Ukraine; frozen sperm (anonymous donor) was obtained from a licensed tissue establishment. For recipients, saline-enhanced sonography was used to assess intrauterine contour with endometrial preparation via transdermal estrogen. RESULTS: Among commissioning couples, mean+/-SD female and male age was 41.9 +/- 3.7 and 44.6 +/ 3.5 yrs, respectively. During this period, female age for non dual anonymous gamete donation IVF patients was 37.9 +/- 3 yrs (p < 0.001). Infertility duration was >/=3 yrs for couples enrolling in dual gamete donation, and each had >/=2 prior failed fertility treatments using native oocytes. All seven recipient couples proceeded to embryo transfer, although one patient had two transfers. Clinical pregnancy was achieved for 5/7 (71.4%) patients. Non-transferred cryopreserved embryos were available for all seven couples. CONCLUSIONS: Mean age of females undergoing dual anonymous donor gamete donation with IVF is significantly higher than the background IVF patient population. Even when neither partner is able to contribute any gametes for IVF, the clinical pregnancy rate per transfer can be satisfactory if both anonymous egg and sperm donation are used concurrently. Our report emphasises the role of pre-treatment counselling in dual anonymous gamete donation, and presents a coordinated screening and treatment approach in IVF where this option may be contemplated. PMID- 20701807 TI - Associations between insulin and glucose concentrations and anthropometric measures of fat mass in Australian adolescents. AB - BACKGROUND: One of the most serious, yet common co-morbidities of obesity is insulin resistance, which if untreated may progress to type 2 diabetes. This paper describes the insulin and glucose concentration distributions, the prevalence of elevated insulin, the associations between insulin and body mass index (BMI), waist circumference, waist-to-height ratio (WHtR) and fat mass index in a representative sample of Australian adolescents. METHODS: Cross-sectional population-based study of adolescent boys and girls (N = 496, mean age 15.3 years) attending schools in metropolitan Sydney, Australia. Fasting venous blood collected and analysed for insulin and glucose concentrations. Height, weight, waist circumference measured, BMI and waist-to-height ratio calculated. Pubertal status self-reported. RESULTS: Glucose concentrations were normally distributed and were not associated with adiposity. Insulin concentrations were distributed logarithmically, were higher among girls than boys overall and within the same ranges of BMI and waist circumference, but were lower among girls than boys within the same ranges of fat mass adjusted for height. The prevalence of elevated insulin concentration (defined as > 100 pmol/L) was 15.9% and 17.1% among boys and girls, respectively. Correlations between insulin concentration and BMI, waist circumference, WHtR and fat mass adjusted for height were 0.53, 0.49, 0.51 and 0.55, among boys, respectively, and 0.35, 0.40, 0.42 and 0.34, among girls, respectively. CONCLUSIONS: Elevated insulin is highly correlated with adiposity in adolescents. BMI and WHtR are simple measures that can be used to identify young people who should be screened for insulin resistance and other co-morbidities. PMID- 20701808 TI - Role of risk and protective factors in risky sexual behavior among high school students in Cambodia. AB - BACKGROUND: In many developing countries, adolescents have become increasingly prone to engage in habitual risky sexual behavior such as early sexual initiation and unprotected sex. The objective of this study was to identify the operation of risk and protective factors in individual, family, peer, school, and community domains in predicting risky sexual behavior among male and female adolescents in Cambodia. METHODS: From October 2007 to January 2008, we collected data from 1,049 students aged 14 to 20 years. Risky sexual behavior was measured using a scale consisting of four items: sexual intercourse during the past three months, number of sex partners during the past three months, age at first experience of sexual intercourse, and use of condom in last sexual intercourse. The risk factors examined included substance use, depression, peer delinquency, family violence, and community violence. Studied protective factors included family support function, frequency of family dinner, and school attachment. RESULTS: Of the 1,049 students surveyed, 12.7% reported sexual intercourse during the past three months. Out of those sexually active students, 34.6% reported having two or more sex partners over the same period, and 52.6% did not use a condom during their last sexual intercourse. After controlling for other covariates, a higher likelihood of risky sexual behavior remained significantly associated among male participants with higher levels of substance use, higher levels of peer delinquency, and higher family income. In contrast, risky sexual behavior did not retain its associations with any of the measured protective factors among male participants. Among female participants, a higher likelihood of risky sexual behavior remained significantly associated with higher levels of substance use, higher levels of community-violence witnessing, and lower levels of family support. CONCLUSIONS: The findings suggest the importance of considering gender related differences in the effects of risk and protective factors when designing and implementing prevention programs. In interventions for both male and female adolescents, prevention of substance use and risky sexual behavior should be integrated. For boys, efforts should focus on the reduction of peer delinquency, while, for girls, improvement of family support should be emphasized. PMID- 20701809 TI - Reconstructing CNV genotypes using segregation analysis: combining pedigree information with CNV assay. AB - BACKGROUND: Repeated blocks of genome sequence have been shown to be associated with genetic diversity and disease risk in humans, and with phenotypic diversity in model organisms and domestic animals. Reliable tests are desirable to determine whether individuals are carriers of copy number variants associated with disease risk in humans and livestock, or associated with economically important traits in livestock. In some cases, copy number variants affect the phenotype through a dosage effect but in other cases, allele combinations have non-additive effects. In the latter cases, it has been difficult to develop tests because assays typically return an estimate of the sum of the copy number counts on the maternally and paternally inherited chromosome segments, and this sum does not uniquely determine the allele configuration. In this study, we show that there is an old solution to this new problem: segregation analysis, which has been used for many years to infer alleles in pedigreed populations. METHODS: Segregation analysis was used to estimate copy number alleles from assay data on simulated half-sib sheep populations. Copy number variation at the Agouti locus, known to be responsible for the recessive self-colour black phenotype, was used as a model for the simulation and an appropriate penetrance function was derived. The precision with which carriers and non-carriers of the undesirable single copy allele could be identified, was used to evaluate the method for various family sizes, assay strategies and assay accuracies. RESULTS: Using relationship data and segregation analysis, the probabilities of carrying the copy number alleles responsible for black or white fleece were estimated with much greater precision than by analyzing assay results for animals individually. The proportion of lambs correctly identified as non-carriers of the undesirable allele increased from 7% when the lambs were analysed alone to 80% when the lambs were analysed in half sib families. CONCLUSIONS: When a quantitative assay is used to estimate copy number alleles, segregation analysis of related individuals can greatly improve the precision of the estimates. Existing software for segregation analysis would require little if any change to accommodate the penetrance function for copy number assay data. PMID- 20701810 TI - Time needed to achieve completeness and accuracy in bedside lung ultrasound reporting in intensive care unit. AB - BACKGROUND: The use of lung ultrasound (LUS) in ICU is increasing but ultrasonographic patterns of lung are often difficult to quantify by different operators. The aim of this study was to evaluate the accuracy and quality of LUS reporting after the introduction of a standardized electronic recording sheet. METHODS: Intensivists were trained for LUS following a teaching programme. From April 2008, an electronic sheet was designed and introduced in ICU database in order to uniform LUS examination reporting. A mark from 0 to 24 has been given for each exam by two senior intensivists not involved in the survey. The mark assigned was based on completeness of a precise reporting scheme, concerning the main finding of LUS. A cut off of 15 was considered sufficiency. RESULTS: The study comprehended 12 months of observations and a total of 637 LUS. Initially, although some improvement in the reports completeness, still the accuracy and precision of examination reporting was below 15. The time required to reach a sufficient quality was 7 months. A linear trend in physicians progress was observed. CONCLUSIONS: The uniformity in teaching programme and examinations reporting system permits to improve the level of completeness and accuracy of LUS reporting, helping physicians in following lung pathology evolution. PMID- 20701811 TI - The attrition rate of licensed chiropractors in California: an exploratory ecological investigation of time-trend data. AB - BACKGROUND: The authors hypothesized the attrition rate of licensed chiropractors in California has gradually increased over the past several decades. "Attrition" as determined for this study is defined as a loss of legal authority to practice chiropractic for any reason during the first 10 years after the license was issued. The percentage of license attrition after 10 years was determined for each group of graduates licensed in California each year between 1970 and 1998. The cost of tuition, the increase in the supply of licensed chiropractors and the ratio of licensed chiropractors to California residents were examined as possible influences on the rate of license attrition. METHODS: The attrition rate was determined by a retrospective analysis of license status data obtained from the California Department of Consumer Affairs. Other variables were determined from US Bureau of Census data, survey data from the American Chiropractic Association and catalogs from a US chiropractic college. RESULTS: The 10-year attrition rate rose from 10% for those graduates licensed in 1970 to a peak of 27.8% in 1991. The 10-year attrition rate has since remained between 20-25% for the doctors licensed between 1992-1998. CONCLUSIONS: Available evidence supports the hypothesis that the attrition rate for licensed chiropractors in the first 10 years of practice has risen in the past several decades. PMID- 20701812 TI - Quit in general practice: a cluster randomised trial of enhanced in-practice support for smoking cessation. AB - BACKGROUND: This study will test the uptake and effectiveness of a flexible package of smoking cessation support provided primarily by the practice nurse (PN) and tailored to meet the needs of a diversity of patients. METHODS/DESIGN: This study is a cluster randomised trial, with practices allocated to one of three groups 1) Quit with Practice Nurse 2) Quitline referral 3) GP usual care. PNs from practices randomised to the intervention group will receive a training course in smoking cessation followed by access to mentoring. GPs from practices randomised to the Quitline referral group will receive information about the study and the process of written referral and GPs in the usual care group will receive information about the study. Eligible patients are those aged 18 and over presenting to their GP who are daily or weekly smokers and who are able to give informed consent. Patients on low incomes in all three groups will be able to access free nicotine patches.Primary outcomes are sustained abstinence and point prevalence abstinence at the three month and 12 month follow-up points; and incremental cost effectiveness ratios at 12 months. Process evaluation on the reach and acceptability of the intervention approached will be collected through Computer Assisted Telephone Interviews (CATI) with patients and semi-structured interviews with PNs and GPs.The primary analysis will be by intention to treat. Cessation outcomes will be compared between the three arms at three months and 12 month follow-up using multiple logistic regression. The incremental cost effectiveness ratios will be estimated for the 12 month quit rate for the intervention groups compared to usual care and to each other. Analysis of qualitative data on process outcomes will be based on thematic analysis. DISCUSSION: High quality evidence on effectiveness of practice nurse interventions is needed to inform health policy on development of practice nurse roles. If effective, flexible support from the PN in partnership with the GP and the Quitline could become the preferred model for providing smoking cessation advice in Australian general practice. TRIAL REGISTRATION: ACTRN12609001040257. PMID- 20701813 TI - Understanding immune dysfunctions in sepsis patients. PMID- 20701814 TI - Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies. AB - In recent years there has been a rapid growth of interest in exploring the relationship between nutritional therapies and the maintenance of cognitive function in adulthood. Emerging evidence reveals an increasingly complex picture with respect to the benefits of various food constituents on learning, memory and psychomotor function in adults. However, to date, there has been little consensus in human studies on the range of cognitive domains to be tested or the particular tests to be employed. To illustrate the potential difficulties that this poses, we conducted a systematic review of existing human adult randomised controlled trial (RCT) studies that have investigated the effects of 24 d to 36 months of supplementation with flavonoids and micronutrients on cognitive performance. There were thirty-nine studies employing a total of 121 different cognitive tasks that met the criteria for inclusion. Results showed that less than half of these studies reported positive effects of treatment, with some important cognitive domains either under-represented or not explored at all. Although there was some evidence of sensitivity to nutritional supplementation in a number of domains (for example, executive function, spatial working memory), interpretation is currently difficult given the prevailing 'scattergun approach' for selecting cognitive tests. Specifically, the practice means that it is often difficult to distinguish between a boundary condition for a particular nutrient and a lack of task sensitivity. We argue that for significant future progress to be made, researchers need to pay much closer attention to existing human RCT and animal data, as well as to more basic issues surrounding task sensitivity, statistical power and type I error. PMID- 20701815 TI - Predictors of subjective and objective caregiving burden in older female caregivers of adults with intellectual disabilities. AB - BACKGROUND: Informal, unpaid, and lifelong older caregivers of adults with intellectual disabilities (ID) are usually female and most often are mothers of adults with ID. However, research exploring different predictors of subjective and objective burden among these older female caregivers is sparse. The objective of this study was to examine whether the subjective and objective burden as well as positive appraisals are predicted by the same or different variables linked to the caregivers and the adults with ID. METHODS: Face-to-face interview questionnaires were administered in a city in Taiwan in 2006-2007 and 350 female family caregivers aged 55 years and older completed the interview in their homes. The independent variables included adult care demands and caregiver variables, while the dependent variables were caregivers' subjective burden, caregivers' objective burden and caregivers' positive appraisals. RESULTS: The results demonstrated that adult care demands were associated more with the objective than the subjective caregiving burden. The strongest predictors of both subjective and objective burden were the care recipient's instrumental activities of daily living functionality, caregiver's age, and caregiver's health status. The significant predictors for positive caregiving appraisals were the caregiver's age and the caregiver's level of social support. CONCLUSIONS: The results indicate that both the subjective and objective burdens were mostly related to the same factors, that is, to the characteristics of the older female caregivers and the recipients of care with ID. On the other hand, positive attitudes towards caregiving roles were only associated with caregiver variables. PMID- 20701816 TI - Quality of life in dementia patients in Athens, Greece: predictive factors and the role of caregiver-related factors. AB - BACKGROUND: Quality of life (QOL) is increasingly recognized as the main target of currently available dementia care. Its assessment has grown exponentially in the dementia field, but few studies have examined predictive factors for QOL taking caregiver variables into account. We examined patient and caregiver factors related to the QOL of dementia patients. METHODS: The study design was cross-sectional. 161 couples of community residing dementia patients and their primary caregivers were interviewed. QOL was measured by the ADRQL, a proxy rated, dementia-specific QOL instrument. Demographic factors were collected and clinical characteristics assessed using validated scales. RESULTS: In univariate analyses several patient and caregiver characteristics appeared associated with patient QOL. In multivariate analyses, independent predictors of worse patient QOL were behavioral and depressive symptoms of dementia patients, dependency in basic activities of daily living, poorer cognitive function, use of antipsychotic medication, caregiver burden, and caregiver not being an adult child. The adjusted R2 of the final, seven-factor model was 0.598. CONCLUSIONS: QOL for a person with dementia is a complex issue that is associated with several patient and caregiver factors. Efforts to improve patients' QOL should be addressed for both patients and caregivers. The measurement of QOL should be included, when possible, as a standard measurement tool, in everyday dementia clinical practice. PMID- 20701817 TI - Leg length, skull circumference, and the prevalence of dementia in low and middle income countries: a 10/66 population-based cross sectional survey. AB - BACKGROUND: Adult leg length is influenced by nutrition in the first few years of life. Adult head circumference is an indicator of brain growth. There is a limited literature linking short legs and small skulls to an increased risk for cognitive impairment and dementia in late life. METHODS: One phase cross sectional surveys were carried out of all residents aged over 65 years in 11 catchment areas in China, India, Cuba, Dominican Republic, Venezuela, Mexico and Peru (n = 14,960). The cross-culturally validated 10/66 dementia diagnosis, and a sociodemographic and risk factor questionnaire were administered to all participants, and anthropometric measures taken. Poisson regression was used to calculate prevalence ratios for the effect of leg length and skull circumference upon 10/66 dementia, controlling for age, gender, education and family history of dementia. RESULTS: The pooled meta-analyzed fixed effect for leg length (highest vs. lowest quarter) was 0.82 (95% CI, 0.68-0.98) and for skull circumference 0.75 (95% CI, 0.63-0.89). While point estimates varied between sites, the proportion of the variability attributable to heterogeneity between studies as opposed to sampling error (I2) was 0% for leg length and 22% for skull circumference. The effects were independent and not mediated by family history of dementia. The effect of skull circumference was not modified by educational level or gender, and the effect of leg length was not modified by gender. CONCLUSIONS: Since leg length and skull circumference are said to remain stable throughout adulthood into old age, reverse causality is an unlikely explanation for the findings. Early life nutritional programming, as well as neurodevelopment may protect against neurodegeneration. PMID- 20701818 TI - Dietary profile of urban adult population in South India in the context of chronic disease epidemiology (CURES-68). AB - OBJECTIVE: Few dietary surveys have been done with reference to chronic diseases, such as diabetes, in India, which is considered to be the diabetes capital of the world. We report on the dietary intake of urban adults living in Chennai, South India. DESIGN: A population-based cross-sectional study. SETTING: A representative population of urban Chennai in southern India. SUBJECTS: The study population comprised 2042 individuals aged>=20 years selected from the Chennai Urban Rural Epidemiological Study (CURES). Dietary intake was measured using a validated and previously published interviewer-administered semi-quantitative meal-based FFQ. RESULTS: The mean daily energy intake was 10,393 (sd 2347) kJ (male: 10953 (sd 2364) kJ v. female: 9832 (sd 233) kJ). Carbohydrates were the major source of energy (64%), followed by fat (24%) and protein (12%). Refined cereals contributed to the bulk of the energy (45.8%), followed by visible fats and oils (12.4%) and pulses and legumes (7.8%). However, energy supply from sugar and sweetened beverages was within the recommended levels. Intake of micronutrient-rich foods, such as fruit and vegetable consumption (265 g/d), and fish and seafoods (20 g/d), was far below the FAO/WHO recommendation. Dairy and meat products intake was within the national recommended intake. CONCLUSIONS: The diet of this urban South Indian population consists mainly of refined cereals with low intake of fish, fruit and vegetables, and all of these could possibly contribute to the risk of non-communicable diseases such as diabetes in this population. PMID- 20701819 TI - Is participation in food and income assistance programmes associated with obesity in California adults? Results from a state-wide survey. AB - OBJECTIVE: Public assistance programmes may increase risk of obesity among adults. The current study assessed whether participation in the Supplemental Nutrition Assistance Program (SNAP; formerly the Food Stamp Program), Supplemental Security Income (SSI) or California Work Opportunities and Responsibilities to Kids (CalWorks) was associated with obesity, independent of socio-economic status and food insecurity. DESIGN: A cross-sectional analysis of the 2007 Adult California Health Interview Survey. Outcome measures included BMI and obesity. Distribution of BMI and prevalence of obesity were compared by participation in each programme, using weighted linear and binomial regression models in which BMI or obesity was the outcome, respectively, and programme participation was the predictor. SETTING: A population survey of various health measures. SUBJECTS: Non-institutionalized adults (n 7741) whose household income was <=130% of the federal poverty level. RESULTS: The prevalence of obesity was 27.4%. After adjusting for sociodemographic characteristics, food insecurity and participation in other programmes, the prevalence of obesity was 30% higher in SNAP participants (95% CI 6%, 59%; P=0.01) than in non-participants. This association was more pronounced among men than women. SSI participation was related to an adjusted 50% higher prevalence of obesity (95% CI 27%, 77%; P<0.0001) compared with no participation. SNAP and SSI participants also reported higher soda consumption than non-participants of any programme. CalWorks participation was not associated with obesity after multivariable adjustment. CONCLUSIONS: Participation in SNAP or SSI was associated with obesity independent of food insecurity or socio-economic status. The suggestion that these associations may be mediated by dietary quality warrants further investigation among low-income populations. PMID- 20701820 TI - Young urban women and the nutrition transition in Jordan. AB - OBJECTIVE: To determine the nutrition transition stage of female Jordanian college students. DESIGN: A cross-sectional survey was used to assess eating styles, disordered eating attitudes and behaviours, body esteem and dissatisfaction, and media influence. SETTING: Public and private universities in Jordan. SUBJECTS: A total of 255 subjects were recruited through a government initiated youth campaign. RESULTS: The majority of participants had a normal BMI (70.6%) with almost all (99.4%) reporting restrained eating behaviour. Scores on the Eating Attitudes Test (EAT-26) indicated that 45.2% of these female college students should be screening for eating disorders. Subscales of the Body Esteem Scale (BES) showed that these women did not have substantial body esteem issues and mean scores on the Sociocultural Attitudes Towards Appearance Questionnaire (SATAQ-3) indicated that overall these women did not feel the media was dictating the way their body should look. Where Jordanian women did feel pressure from Western media, there was a 6.7-fold increase in the likelihood that they wanted to lose weight. In addition, 48.2% of the female college students desired to lose weight and 14.4% desired weight gain, indicating a certain level of body dissatisfaction. CONCLUSIONS: With low levels of overweight and obesity and a propensity towards eating based on external hunger cues, college-aged Jordanian women may be less advanced in their development through the nutrition transition than the general population of women. However, high levels of restrained eating and disordered eating attitudes and behaviours indicate the need for an intervention to address healthy weight-loss strategies, assess eating disorders and help maintain healthy body esteem. PMID- 20701821 TI - The impact of the food-based and nutrient-based standards on lunchtime food and drink provision and consumption in primary schools in England. AB - OBJECTIVE: To assess lunchtime provision of food and drink in English primary schools and to assess both choices and consumption of food and drink by pupils having school lunches. These findings were compared with similar data collected in 2005. DESIGN: Cross-sectional data collected between February and April 2009. In each school, food and drink provision, including portion weights and number of portions of each item served at lunchtime, were recorded over five consecutive days. Caterers provided school lunchtime menus and recipes. SETTING: England. SUBJECTS: A random selection of 6696 pupils having school lunches in a nationally representative sample of 136 primary schools in England. RESULTS: Compared with 2005, schools in 2009 provided significantly more fruit, fruit-based desserts, vegetables and salad, water and fruit juice, and less ketchup, sauces and gravy, starchy foods cooked in fat, snacks and confectionery (P < 0.01). Pupils were also making healthier choices, choosing an average of 2.2 portions of fruit and vegetables from their 'five a day', but about one-third to two-fifths of these were wasted. CONCLUSIONS: Lunchtime food provision and consumption in primary schools have improved substantially since 2005, following the introduction of new standards for school food in 2008. However, improvements still need to be made to increase the Fe and Zn content and to decrease the Na content of recipes, and in encouraging pupils to eat more of the fruits and vegetables taken at lunchtime. PMID- 20701822 TI - Socio-economic and demographic variations in school lunch participation of French children aged 3-17 years. AB - OBJECTIVE: To assess school canteen attendance in a French nationally representative sample of children and to analyse its association with the socio economic and demographic characteristics of the children and their families. DESIGN: Data from the second French national cross-sectional food consumption survey (INCA2), performed in 2006-2007, were used. Information on usual weekly school canteen attendance was collected through a self-reported questionnaire, and demographic and socio-economic variables through a face-to-face questionnaire. The associations between school canteen attendance and the socio economic and demographic variables were investigated by multivariate logistic regression analyses. SETTING: The INCA2 sample was representative of the children aged 3-17 years in France. SUBJECT: Analysis was performed on 1413 schoolchildren who completed the school canteen attendance questions. RESULTS: Some 65.6 % of schoolchildren aged 3-17 years had school lunch at least once weekly. This rate of attendance was positively correlated with age. Whatever the school level, school canteen attendance was positively associated with the educational level of the caregiver/parent. In pre- and elementary-school children, enrolment at the school canteen was also higher when the caregiver/parent worked, or in single parent families. In secondary-school children, school lunch participation decreased with children living in more densely populated areas and increased with the level of the household's living standards. CONCLUSIONS: School canteen attendance was positively associated with children's socio-economic background. This could reduce the effectiveness of the forthcoming school meal composition regulations designed to improve the diet of children from deprived backgrounds, who are more likely to have unhealthy food habits. PMID- 20701823 TI - Progressive striatal and hippocampal volume loss in initially antipsychotic naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms. AB - First-generation antipsychotics have been associated with striatal volume increases. The effects of second-generation antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research. PMID- 20701824 TI - PCLO rs2522833 modulates HPA system response to antidepressant treatment in major depressive disorder. AB - Variant rs2522833 of the Piccolo-encoding gene PCLO has recently been found to be associated with major depressive disorder (MDD). PCLO encodes a presynaptic cytomatrix protein which influences monoamine neurotransmitter release. Piccolo could therefore play an important role in treatment response to antidepressant therapy and the improvement of alterations in HPA system reactivity. We investigated the influence of the coding variant rs2522833 in the PCLO gene on treatment response in 205 in-patients with unipolar depression. Treatment response was measured (1) at the level of psychopathology using the Hamilton Depression Rating Scale (HAMD) and (2) with the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which is a refined tool for showing dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system, a neurobiological finding in depression. While we did not find an association between variation in PCLO and HAMD scores, HPA dysregulation was less pronounced in carriers of the AA genotype than in carriers of one or two C alleles. HPA activity of individuals with the AA genotype only marginally changed during 4-wk antidepressant treatment, whereas C allele carriers showed a higher hormonal secretion at admission than carriers of the AA genotype but lower responsivity to the Dex/CRH challenge after 4 wk. Our results point to a moderating role of PCLO SNP rs2522833 on HPA regulation during antidepressant treatment, which may represent a neurobiological feature of stability of clinical response. PMID- 20701825 TI - Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. AB - The superior efficacy of atypical vs. classical antipsychotic drugs to treat negative symptoms and cognitive deficits in schizophrenia appears related to their ability to enhance mesocortical dopamine (DA) function. Given that noradrenergic (NE) transmission contributes to cortical DA output, we assessed the ability of NE-targeting drugs to modulate DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), with the aim of selectively increasing mesocortical DA. Extracellular DA was measured using brain microdialysis in rat mPFC and NAc after local/systemic drug administration, electrical stimulation and selective brain lesions. Local GBR12909 [a selective DA transporter (DAT) inhibitor] administration increased DA output more in NAc than in mPFC whereas reboxetine [a selective NE transporter (NET) inhibitor] had an opposite regional profile. DA levels increased comparably in both regions of control rats after local nomifensine (DAT+NET inhibitor) infusion, but this effect was much lower in PFC of NE-lesioned rats (DSP-4) and in NAc of 6-OHDA-lesioned rats. Electrical stimulation of the locus coeruleus preferentially enhanced DA output in mPFC. Consistently, the administration of reboxetine+RX821002 (an alpha2-adrenoceptor antagonist) dramatically enhanced DA output in mPFC (but not NAc). This effect also occurred when reboxetine+RX821002 were co-administered with haloperidol or clozapine. The preferential contribution of the NE system to PFC DA allows selective enhancement of DA transmission by simultaneously blocking NET and alpha2-adrenoceptors, thus preventing the autoreceptor-mediated negative feedback on NE activity. Our results highlight the importance of NET and alpha2 adrenoceptors as targets for treating negative/cognitive symptoms in schizophrenia and related psychiatric disorders. PMID- 20701826 TI - The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. AB - Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of Delta9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/DeltaFosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/DeltaFosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions. PMID- 20701827 TI - Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor. AB - The acetylcholine esterase inhibitor/cholinergic nicotinic receptor (nAChR) allosteric modulator galantamine (Gal) is used against cognitive impairment in Alzheimer's disease. Negative/cognitive and psychotic symptom improvement in schizophrenia by adjunct Gal to antipsychotic drugs (APDs) has been reported. Cognitive symptoms in schizophrenia may involve brain prefrontal hypo dopaminergia. Experimental data by others indicate nAChR involvement in animal pro-cognitive effects of Gal. The role of nAChRs in antipsychotic effects by Gal has, however, not been elucidated. Using the conditioned avoidance response (CAR) and the catalepsy tests for antipsychotic activity and extrapyramidal side-effect (EPS) liability, respectively, we here investigated the effects of adjunct Gal (1.25 mg/kg) to the typical APD haloperidol (Hal) (0.05 mg/kg), or the atypical APD risperidone (Ris) (0.2 mg/kg), in rats. Adjunct Gal significantly enhanced APD-like effects by low doses of Hal or Ris, but showed a safe EPS liability profile only in combination with Ris. Pretreatment with the muscarinic receptor (mAChR) antagonist scopolamine, but not the nAChR antagonist mecamylamine, completely reversed the enhancing effects of adjunct Gal to Hal treatment, in the CAR test. While the nAChR-modulating properties of Gal probably contribute to pro cognitive activity, as shown by others, the present data suggest that any contribution to antipsychotic activity by Gal is mediated primarily via mAChRs. This property combination of Gal may offer a unique, favourable therapeutic profile for schizophrenia treatment. PMID- 20701828 TI - Information-oriented patients and physician career satisfaction: is there a link? AB - Patients' increasing use of alternative sources of information besides their physician and more active involvement in medical decision making may be changing relationships between physicians and their patients. We term patients who provide medical information to their physicians from sources other than their physician as information-oriented patients and investigate the relationship between having such patients and physician career satisfaction. We find that having more information-oriented patients is significantly associated with lower physician career satisfaction. Though healthcare information from alternative sources other than their physicians is thought to promote better-informed patient choices, the adverse relationship with physician career satisfaction found in this study may have important implications for patient access and quality of care. PMID- 20701829 TI - Choice and privatisation in Swedish primary care. AB - In 2007, a new wave of local reforms involving choice for the population and privatisation of providers was initiated in Swedish primary care. Important objectives behind reforms were to strengthen the role of primary care and to improve performance in terms of access and responsiveness. The purpose of this article was to compare the characteristics of the new models and to discuss changes in financial incentives for providers and challenges regarding governance from the part of county councils. A majority of the models being introduced across the 21 county councils can best be described as innovative combinations between a comprehensive responsibility for providers and significant degrees of freedom regarding choice for the population. Key financial characteristics of fixed payment and comprehensive financial responsibility for providers may create financial incentives to under-provide care. Informed choices by the population, in combination with reasonably low barriers for providers to enter the primary care market, should theoretically counterbalance such incentives. To facilitate such competition is indeed a challenge, not only because of difficulties in implementing informed choices but also because the new models favour large and/or horizontally integrated providers. To prevent monopolistic behaviour, county councils may have to accept more competition as well as more governance over clinical practice than initially intended. PMID- 20701830 TI - Health technology appraisal and the courts: accountability for reasonableness and the judicial model of procedural justice. AB - Recommendations issued by agencies undertaking appraisals of health technologies at the national level may impact upon the availability of certain treatments and services in some publicly funded health systems, and, as such, have regularly been subject to challenge, including by way of litigation. In addition to expertise in the evaluation of evidence, fairness of procedures has been identified as a necessary component of a claim to legitimacy in such circumstances. This article analyses the assessment of courts in three jurisdictions of the fairness of decision-making by such agencies and evaluates the judicial reading of procedural justice developed in this particular context against the conditions of 'accountability for reasonableness'. PMID- 20701831 TI - Variation in the helminth community structure of three sympatric sigmodontine rodents from the coastal Atlantic Forest of Rio de Janeiro, Brazil. AB - One hundred and eighty specimens of sigmodontine rodents living in sympatric conditions were collected in the Atlantic Forest in the state of Rio de Janeiro, Brazil (25 Akodon cursor, 98 Akodon montensis and 57 Oligoryzomys nigripes) to examine whether the helminth structure and component communities can be characterized among these three closely related rodents. The parasite species richness was 9 in A. cursor, 12 in A. montensis and 12 in O. nigripes. Five species were common to the three rodent species, and eight were common to A. cursor and A. montensis. The trichostrongylids - Stilestrongylus eta in A. cursor, S. aculeata in A. montensis and S. lanfrediae in O. nigripes - were the species with highest dominance frequency and determined the characterization of individual community structures. The prevalence and abundance of concurrent helminth species among rodents were significantly different. Canonical multivariate analysis demonstrated a similar helminth community structure between A. cursor and A. montensis but a high discrepancy between Akodon spp. and O. nigripes. Thus, the data indicated that small rodents such as A. cursor, A. montenis and O. nigripes that are sympatric and phylogenetically related have a different community structure, but similar component community, suggesting the role of helminth specificity and the hosts' habitats as determinants in structuring their helminth communities. PMID- 20701832 TI - Morphological and molecular analysis of metacercariae of Diphtherostomum brusinae (Stossich, 1888) Stossich, 1903 from a new bivalve host Mytilus galloprovincialis. AB - The digenean trematode Diphtherostomum brusinae (Stossich, 1888) Stossich, 1903 presents a complex life cycle that may involve more than one intermediate host. The present study represents the first description of the metacercariae from D. brusinae infecting the labial palps of a new intermediate host, Mytilus galloprovincialis, in the Aveiro estuary, Portugal. The morphology of this parasitic stage was studied by light (LM) and scanning electron microscopy (SEM) and some differences were reported (body and sucker sizes, and spine distribution and shape). In this work, the 18S partial region of the ribosomal DNA was sequenced from D. brusinae metacercariae isolated from M. galloprovincialis collected in different localities of the Aveiro estuary. In addition, sequences from the same region of the 18S rDNA were obtained from D. brusinae cercariae and metacercariae, hosted by Nassarius reticulatus and Cerastoderma edule, respectively. No intraspecific polymorphism was detected in the 18S partial region, since there was 100% homology among all the sequences analysed. The same comparison was made for the ITS1, and we observed intraspecific polymorphism in this region. To our knowledge, this is the first report of D. brusinae metacercariae infecting the mussel M. galloprovincialis with support from morphological and molecular data. PMID- 20701833 TI - Single-subject-oriented research. PMID- 20701834 TI - Safety of audiology direct access for medicare patients complaining of impaired hearing. AB - BACKGROUND: Allowing Medicare beneficiaries to self-refer to audiologists for evaluation of hearing loss has been advocated as a cost-effective service delivery model. Resistance to audiology direct access is based, in part, on the concern that audiologists might miss significant otologic conditions. PURPOSE: To evaluate the relative safety of audiology direct access by comparing the treatment plans of audiologists and otolaryngologists in a large group of Medicare-eligible patients seeking hearing evaluation. RESEARCH DESIGN: Retrospective chart review study comparing assessment and treatment plans developed by audiologists and otolaryngologists. STUDY SAMPLE: 1550 records comprising all Medicare eligible patients referred to the Audiology Section of the Mayo Clinic Florida in 2007 with a primary complaint of hearing impairment. DATA COLLECTION AND ANALYSIS: Assessment and treatment plans were compiled from the electronic medical record and placed in a secured database. Records of patients seen jointly by audiology and otolaryngology practitioners (Group 1: 352 cases) were reviewed by four blinded reviewers, two otolaryngologists and two audiologists, who judged whether the audiologist treatment plan, if followed, would have missed conditions identified and addressed in the otolaryngologist's treatment plan. Records of patients seen by audiology but not otolaryngology (Group 2: 1198 cases) were evaluated by a neurotologist who judged whether the patient should have seen an otolaryngologist based on the audiologist's documentation and test results. Additionally, the audiologist and reviewing neurotologist judgments about hearing asymmetry were compared to two mathematical measures of hearing asymmetry (Charing Cross and AAO-HNS [American Academy of Otolaryngology-Head and Neck Surgery] calculations). RESULTS: In the analysis of Group 1 records, the jury of four judges found no audiology discrepant treatment plans in over 95% of cases. In no case where a judge identified a discrepancy in treatment plans did the audiologist plan risk missing conditions associated with significant mortality or morbidity that were subsequently identified by the otolaryngologist. In the analysis of Group 2 records, the neurotologist judged that audiology services alone were all that was required in 78% of cases. An additional 9% of cases were referred for subsequent medical evaluation. The majority of remaining patients had hearing asymmetries. Some were evaluated by otolaryngology for hearing asymmetry in the past with no interval changes, and others were consistent with noise exposure history. In 0.33% of cases, unexplained hearing asymmetry was potentially missed by the audiologist. Audiologists and the neurotologist demonstrated comparable accuracy in identifying Charing Cross and AAO-HNS pure-tone asymmetries. CONCLUSIONS: Of study patients evaluated for hearing problems in the one-year period of this study, the majority (95%) ultimately required audiological services, and in most of these cases, audiological services were the only hearing health-care services that were needed. Audiologist treatment plans did not differ substantially from otolaryngologist plans for the same condition; there was no convincing evidence that audiologists missed significant symptoms of otologic disease; and there was strong evidence that audiologists referred to otolaryngology when appropriate. These findings are consistent with the premise that audiology direct access would not pose a safety risk to Medicare beneficiaries complaining of hearing impairment. PMID- 20701835 TI - The use of frequency compression by cochlear implant recipients with postoperative acoustic hearing. AB - BACKGROUND: The number of cochlear implant (CI) recipients who have usable acoustic hearing in at least one ear is continuing to grow. Many such CI users gain perceptual benefits from the simultaneous use of acoustic and electric hearing. In particular, it has been shown previously that use of an acoustic hearing aid (HA) with a CI can often improve speech understanding in noise. PURPOSE: To determine whether the application of frequency compression in an HA would provide perceptual benefits to CI recipients with usable acoustic hearing, either when used in combination with the CI or when the HA was used by itself. RESEARCH DESIGN: A repeated-measures experimental design was used to evaluate the effects on speech perception of using a CI either alone or simultaneously with an HA that had frequency compression either enabled or disabled. STUDY SAMPLE: Eight adult CI recipients who were successful users of acoustic hearing aids in their nonimplanted ears participated as subjects. INTERVENTION: The speech perception of each subject was assessed in seven conditions. These required each subject to listen with (1) their own HA alone; (2) the Phonak Naida HA with frequency compression (SoundRecover) enabled; (3) the Naida with SoundRecover disabled; (4) their CI alone; (5) their CI and their own HA; (6) their CI and the Naida with SoundRecover enabled; and (7) their CI and the Naida with SoundRecover disabled. Test sessions were scheduled over a period of about 10 wk. During part of that time, the subjects were asked to use the Phonak Naida HA with their CIs in place of their own HAs. DATA COLLECTION AND ANALYSIS: The speech perception tests included measures of consonant identification from a closed set of 12 items presented in quiet, and measures of sentence understanding in babble noise. The speech materials were presented at an average level of 60 dB SPL from a loudspeaker. RESULTS: Speech perception was better, on average, in all conditions that included use of the CI in comparison with any condition in which only an HA was used. For example, consonant recognition improved by approximately 50 percentage points, on average, between the HA-alone listening conditions and the CI-alone condition. There were no statistically significant score differences between conditions with SoundRecover enabled and disabled. There was a small but significant improvement in the average signal-to-noise ratio (SNR) required to understand 50% of the words in the sentences presented in noise when an HA was used simultaneously with the CI. CONCLUSIONS: Although each of these CI users readily accepted the Phonak Naida HA with SoundRecover frequency compression, no benefits related specifically to the use of SoundRecover were found in the particular tests of speech understanding applied in this study. The relatively high levels of perceptual performance attained by these subjects with use of a CI by itself are consistent with the finding that the addition of an HA provided little further benefit. However, the use of an HA with the CI did provide better performance than the CI alone for understanding sentences in noise. PMID- 20701836 TI - Initial development of a spatially separated speech-in-noise and localization training program. AB - OBJECTIVE: This article describes the initial development of a novel approach for training hearing-impaired listeners to improve their ability to understand speech in the presence of background noise and to also improve their ability to localize sounds. DESIGN: Most people with hearing loss, even those well fit with hearing devices, still experience significant problems understanding speech in noise. Prior research suggests that at least some subjects can experience improved speech understanding with training. However, all training systems that we are aware of have one basic, critical limitation. They do not provide spatial separation of the speech and noise, therefore ignoring the potential benefits of training binaural hearing. In this paper we describe our initial experience with a home-based training system that includes spatially separated speech-in-noise and localization training. RESULTS: Throughout the development of this system patient input, training and preliminary pilot data from individuals with bilateral cochlear implants were utilized. Positive feedback from subjective reports indicated that some individuals were engaged in the treatment, and formal testing showed benefit. Feedback and practical issues resulted from the reduction of an eight-loudspeaker to a two-loudspeaker system. CONCLUSIONS: These preliminary findings suggest we have successfully developed a viable spatial hearing training system that can improve binaural hearing in noise and localization. Applications include, but are not limited to, hearing with hearing aids and cochlear implants. PMID- 20701837 TI - Auditory temporal gap detection in children with and without auditory processing disorder. AB - BACKGROUND: Auditory gap detection is a measure of temporal acuity. The paradigm comes in two forms, distinguished by whether the sounds bounding the silent period are the same (within channel [WC]) or different (between channel [BC]). PURPOSE: The purpose of this study was to test normal children and children referred for auditory processing disorder (APD) assessment, with both gap detection paradigms. RESEARCH DESIGN: Best gap durations (i.e., shortest reliably detected gaps) were measured in a two-interval, two-alternative forced-choice design embedded within a modified method of limits, for both WC and BC paradigms, with stimuli presented at 55 dB HL. STUDY SAMPLE: Sixteen control children and 20 children referred for APD assessment participated in the study. Of the 20 referred children, 9 were diagnostically positive for APD (APD+), and 11 were negative (APD-). The mean age of children in all three groups was 10-11 yr. DATA COLLECTION AND ANALYSIS: Data collected were best gap durations for each paradigm, for each child. Group differences were assessed using Kruskal-Wallis analyses of variance. RESULTS: WC best gap durations were very similar across the three participant groups. BC best gap durations varied significantly between listener groups, with the greatest difference being between controls and APD+ samples. CONCLUSIONS: BC best gap durations differed among the listener groups while WC ones did not. This suggests that the relative timing perceptual operations required by the BC task are more susceptible to the perceptual disturbances in APD than is the simple event detection required by the WC task. PMID- 20701839 TI - Bridge building in the global world of public health. PMID- 20701838 TI - Tinnitus onset rates from chemotherapeutic agents and ototoxic antibiotics: results of a large prospective study. AB - BACKGROUND AND PURPOSE: To report on the incidence and relative risk of tinnitus onset from a variety of drug therapies known to be ototoxic. Two main questions were asked: (1) What is the prevalence and incidence of tinnitus among patients treated with cisplatin, carboplatin, or ototoxic antibiotic therapies? (2) Do commonly reported treatment or subject factors confound or modify the incidence of tinnitus onset? DATA COLLECTION AND ANALYSIS: A prospective observational study design was used to evaluate occurrence of significant otologic changes in 488 veterans (962 ears) receiving chemotherapeutic agents (cisplatin, carboplatin), ototoxic antibiotics (primarily aminoglycoside), or nonototoxic drugs (control medications). A subset of 260 veterans lacking tinnitus prior to drug exposure was used to compare rates of tinnitus onset. Subjects were tested prior to, during, and following their treatment. Planned comparisons using logistic regression, analysis of variance (ANOVA), and chi(2) statistics were made among groups by the type of medication taken, age, presence of preexisting hearing loss, days on drug, and cumulative dose of drug. RESULTS: Baseline tinnitus rates were high (nearly 47%) relative to the general population of a similar age. Subjects with exposure to ototoxic medications had significantly increased risk for developing tinnitus. Those on chemotherapeutic agents were found to have the greatest risk. Cisplatin elevated the risk by 5.53 times while carboplatin increased the risk by 3.75 over nonototoxic control medications. Ototoxic antibiotics resulted in borderline risk (2.81) for new tinnitus. Contrary to other reports, we did not find that subject factors (increased age or pre-existing hearing loss) or treatment factors (days on drug or cumulative dose) contributed to rates of tinnitus onset during treatment. CONCLUSIONS: This large prospective study confirms that new tinnitus during treatment is associated with chemotherapy and with certain ototoxic antibiotic treatment. Cisplatin and carboplatin were found to be the most potent ototoxic agents causing tinnitus at much greater numbers than the other drugs studied. Implications for counseling and audiological resource allocation are discussed. PMID- 20701840 TI - The WHO Clean Care is Safer Care programme: field-testing to enhance sustainability and spread of hand hygiene improvements. AB - The World Alliance for Patient Safety is an evolving programme of the WHO, established to raise the profile of patient safety within the global health care agenda. The decision taken in 2004 to focus the effort and attention of the First Global Patient Safety Challenge on the problem of health care-associated infection (HAI) is testimony to the fact that HAI is a significant patient safety hazard and continues to harm patients in the 21st century. Much of this harm is avoidable through better application of measures which already exist including universal implementation of hand hygiene improvement methods. Action on hand hygiene improvement is therefore at the core of the First Challenge, and field testing of the WHO implementation strategies developed in conjunction with the WHO Guidelines on Hand Hygiene in Health Care (Advanced Draft) is on track to complete by the end of 2008. Following this, a revised and updated guideline and suite of implementation tools will be published by the WHO. It is important to note that the First Global Patient Safety Challenge has mobilized an unprecedented number of countries over a short timeframe to commit to take action on HAI. PMID- 20701841 TI - Infections in the natural environment of British Columbia, Canada. AB - The Canadian province of British Columbia has a luxurious environment, complete with the multitude of wildlife and insects, and would at first glance appear to be suitable for the transmission of diseases in nature communicable to humans. Despite this potential, such diseases are relatively uncommon, although several have the potential for serious consequences. Attention has been recently focused on hantavirus infection, water-borne toxoplasmosis and parasitic diarrheal diseases, cryptococcosis on Vancouver Island, and rabies. West Nile virus has not yet caused endemic human infection in this province as of 2008. We review the cumulative science in this area. PMID- 20701842 TI - Hajj: health lessons for mass gatherings. AB - The potential for spread of infectious diseases associated with mass gatherings is well recognised. Hajj, the unique annual mass gathering of over 2 million Muslims from all over the world, presents enormous challenges to the authorities in Saudi Arabia. They have a comprehensive programme updated annually, to ensure that all aspects of Hajj rituals are conducted safely and without major incident. The inevitable overcrowding in a confined area of such large numbers increases the risk of respiratory infections. Of these 'Hajj cough' is the most frequently reported complaint and is caused by a variety of viruses and bacteria. The outbreaks of meningococcal W135 strains in 2000 and 2001 with the associated high mortality showed the potential for international spread at mass gatherings. Collaboration between health policy makers and community leaders in the UK resulted in a rapid and impressive reduction of these infections. On-going disease surveillance and data analysis is necessary to better understand health risks and strengthen evidence base for health policy and prevention. The battle against spread of travel-related infections is a shared responsibility. Countries sending pilgrims should co-ordinate preventive measures by healthcare professionals and community groups. A multi-pronged approach involving awareness programme for pilgrims and their health advisers, supported by rapid diagnosis, timely treatment, prevention by vaccine, community measures, infection prevention and control practices are necessary. The benefits from such measures go beyond the Hajj to protect health and reduce inequalities. Establishing an international centre for public health relating to the Hajj will enable co-ordinating international health action and appropriate intervention. PMID- 20701843 TI - Food animal transport: a potential source of community exposures to health hazards from industrial farming (CAFOs). AB - Use of antimicrobial feed additives in food animal production is associated with selection for drug resistance in bacterial pathogens, which can then be released into the environment through occupational exposures, high volume ventilation of animal houses, and land application of animal wastes. We tested the hypothesis that current methods of transporting food animals from farms to slaughterhouses may result in pathogen releases and potential exposures of persons in vehicles traveling on the same road. Air and surface samples were taken from cars driving behind poultry trucks for 17 miles. Air conditioners and fans were turned off and windows fully opened. Background and blank samples were used for quality control. Samples were analyzed for susceptible and drug-resistant strains. Results indicate an increase in the number of total aerobic bacteria including both susceptible and drug-resistant enterococci isolated from air and surface samples, and suggest that food animal transport in open crates introduces a novel route of exposure to harmful microorganisms and may disseminate these pathogens into the general environment. These findings support the need for further exposure characterization, and attention to improving methods of food animal transport, especially in highly trafficked regions of high density farming such as the Delmarva Peninsula. PMID- 20701844 TI - Nasopharyngeal carriage rate of Streptococcus pneumoniae in children with sickle cell disease before and after the introduction of heptavalent pneumococcal conjugate vaccine. AB - Children with sickle cell disease (SCD) are at high risk of severe infection with Streptococcus pneumoniae (SP). From 2002, all children aged <5 years in the UK with SCD were recommended 7-valent pneumococcal conjugate vaccine (PCV-7) in infancy and 23-valent pneumococcal polysaccharide vaccine boosting, in addition to regular penicillin prophylaxis. Our objective was to determine the nasopharyngeal (NP) carriage rate of SP in children aged <5 years with SCD before and after vaccination with PCV-7 (by vaccine, cross-protection and non-vaccine serotypes). NP swabs were obtained from 63 children attending the Royal London Hospital or Newham General Hospital paediatric haematology clinic between April 2001 and April 2002. Later, NP swabs were obtained from 43 children attending the clinic between June and December 2004 after a PCV-7 vaccination programme. All SP isolated by culture were serotyped and susceptibility to penicillin measured. In the first study group, 13 samples grew SP with 1 sample containing 2 different serotypes, giving a carriage rate of 21%. Four (31%) were intermediately susceptible to penicillin. In the second group overall NP carriage rate had decreased to 9% (n=4), and the proportion directly or indirectly covered by the PCV-7 vaccine fell from 13/14 to 2/4 (P=0.11). One (25%) of these isolates was intermediately susceptible to penicillin. The introduction of PCV-7 appears to be associated with a shift in distribution of serotypes carried by children with SCD. This may have implications for vaccine effectiveness. PMID- 20701845 TI - Outer membrane protein analysis of ampicillin-resistant isolates of Haemophilus influenzae from Saudi Arabia. AB - Haemophilus influenzae isolates characterized in a previously published study from the Kingdom of Saudi Arabia were analysed by outer membrane protein (OMP) profiling. Isolates from patients with confirmed respiratory tract infections were investigated. Antibiotic susceptibility tests in vitro showed 25/129 (19.4%) had various degrees of reduced susceptibility to ampicillin although all were fully susceptible to ceftazidime and ciprofloxacin. OMP profiles of the beta lactamase mediated ampicillin-resistant and beta-lactamase negative; ampicillin intermediate resistant strains (BLNAI) isolated were investigated. Dendrograms of scanned SDS-PAGE of these strains showed 15 different groupings from the 15 non typable (NTHi) isolates tested demonstrating a high degree of heterogeneity whereas the 5 Hib isolates demonstrated significantly closer relatedness and were probably clonal. The present study demonstrates the groupings of H. influenzae strains by OMP profile analysis which did not correlate with the beta-lactamase production ability, BLNAI isolates, geographical origin or biotype. PMID- 20701846 TI - Epidemiology of animal bites and stings in Khuzestan, Iran, 1997-2006. AB - OBJECTIVES: To determine the incidence and characteristics of the injuries caused by animals among the population of Khuzestan region, Iran admitted to teaching hospital emergency departments. STUDY: Retrospective study. PLACE AND DURATION OF STUDY: From 1997 to 2006 in teaching hospitals in Ahvaz, Iran. METHODOLOGY: The medical records of 894 patients admitted to hospital with animal bites or stings were studied. Data including epidemiological aspects, clinical findings and outcomes of treatment were analyzed using descriptive statistics and the chi(2) test. RESULTS: Of 894 patients 62.0% were male, and the median age of males and females was 24.4 years and 26.2 years, respectively. Dogs, scorpions, mice and snakes were the most commonly involved animal species, causing injuries with a frequency of 69%, 12.5%, 8.8% and 4.4%, respectively. Feet (58.1%) and hands (30.6%) were the most commonly affected body parts, followed by the face and other parts. Infectious complications were seen in 127 patients, among them 94 soft tissue infections (74.1%), 28 cases of sepsis (22.0%) and five of endocarditis (3.9%). Thirty-five cases (3.9%) died following animal bites and stings, among them 28 (80%) due to scorpion stings, four (11.4%) related to dogs and three (8.6%) from snake bites. No cases of rabies were observed in these patients. CONCLUSION: Animal bite is a major public health problem in Khuzestan, with a high frequency, a high percentage of hospitalization and considerable mortality. PMID- 20701847 TI - The impact of U.S. policies to protect healthcare workers from bloodborne pathogens: the critical role of safety-engineered devices. AB - In the United States (U.S.), federal legislation requiring the use of safety engineered sharp devices, along with an array of other protective measures, has played a critical role in reducing healthcare workers' (HCWs) risk of occupational exposure to bloodborne pathogens over the last 20 years. We present the history of U.S. regulatory and legislative actions regarding occupational blood exposures, and review evidence of the impact of these actions. In one large network of U.S. hospitals using the Exposure Prevention Information Network (EPINet) sharps injury surveillance program, overall injury rates for hollow-bore needles declined by 34%, with a 51% decline for nurses. The U.S. experience demonstrates the effectiveness of safety-engineered devices in reducing sharps injuries, and the importance of national-level regulations (accompanied by active enforcement) in ensuring wide-scale availability and implementation of protective devices to decrease healthcare worker risk. PMID- 20701848 TI - Travel and public health. AB - Increasing international travel and migration can interfere with public health in both the country of destination and back home. The revised International Health Regulations (IHR) and travel disease sentinel networks are means to protect public and individual health. Public health risks related to infectious disease are higher in mass gatherings, in travellers visiting friends and relatives and in sexual encounters away from home. In contrast, in-flight transmission of infections plays only a limited role. PMID- 20701849 TI - The role of healthcare personnel in the maintenance and spread of methicillin resistant Staphylococcus aureus. AB - Healthcare workers may acquire methicillin-resistant Staphylococcus aureus (MRSA) from patients, both hospital and home environments, other healthcare workers, family and public acquaintances, and pets. There is a consensus of case reports and series which now strongly support the role for MRSA-carrying healthcare personnel to serve as a reservoir and as a vehicle of spread within healthcare settings. Carriage may occur at a number of body sites and for short, intermediate, and long terms. A number of approaches have been taken to interrupt the linkage of staff-patient spread, but most emphasis has been placed on handwashing and the treatment of staff MRSA carriers. The importance of healthcare workers in transmission has been viewed with varying degrees of interest, and several logistical problems have arisen when healthcare worker screening is brought to the forefront. There is now considerable support for the screening and treatment of healthcare workers, but it is suggested that the intensity of any such approach must consider available resources, the nature of the outbreak, and the strength of epidemiological associations. The task of assessing healthcare personnel carriage in any context should be shaped with due regard to national and international guidelines, should be honed and practiced according to local needs and experience, and must be patient-oriented. PMID- 20701850 TI - Respiratory tract infections in a military recruit setting: a prospective cohort study. AB - BACKGROUND: Acute respiratory tract infections (RTIs) are an important cause of morbidity in the military setting. Respiratory viruses are the most frequently implicated pathogens, especially adenovirus and respiratory syncytial virus. We performed this study to investigate the role of factors such as obesity, cigarette smoking, and educational level on the development of respiratory tract infections in a military recruit setting. METHODS: A cohort of 472 military recruits was prospectively followed up for the basic training period of 3 weeks. Symptoms of infections were monitored during this period. RESULTS: Eighty-four of 472 recruits (17.8%) were diagnosed with infection; 55 (65.5%) with upper RTI (mainly rhinitis), 23 (27.4%) with flu-like syndrome, and 6 (7.1%) with tonsillitis. There was no association between age, BMI, or smoking status and symptomatic RTI (p>0.05). CONCLUSIONS: Occurrence of respiratory tract infections in military recruits is common, at least in some populations and settings. We did not find an association between risk factors such as BMI and smoking and symptomatic respiratory infection in our population, a result that may be associated with the limited power of this study. PMID- 20701851 TI - Unexpected induction of resistant Pseudomonas aeruginosa biofilm to fluoroquinolones by diltiazem: a new perspective of microbiological drug-drug interaction. AB - The increase of multi-drug resistant Pseudomonas aeruginosa infections is a worldwide dilemma. At the heart of the problem is the inability to treat established P. aeruginosa biofilms with standard antibiotic therapy, including fluoroquinolones. We address a previously unstudied question as to the effect of a commonly prescribed calcium channel blocker (CCB) diltiazem on the biofilm growth. Real-time monitoring of the overall growth and killing of P. aeruginosa biofilm during fluoroquinolones therapy in the presence and absence of diltiazem was performed. In this study, we demonstrate that for P. aeruginosa biofilms, resistance to the first-line fluoroquinolones may be induced by the commonly prescribed calcium channel blocker diltiazem. PMID- 20701852 TI - Risk factors for typhoid fever in children in squatter settlements of Karachi: a nested case-control study. AB - Typhoid fever remains a major public health problem in developing countries such as Pakistan. A great majority of cases occur in children living in poor sanitary conditions in squatter settlements in large cities. We conducted a case-control study to identify risk factor for typhoid fever in children under the age of 16 years residing in squatter settlements of Karachi. We enrolled 88 typhoid fever patients, diagnosed by positive blood culture or Typhidot test, between June 1999 and December 2001. Simultaneously, we enrolled 165 age-matched neighborhood controls. Multivariate analysis done through conditional binary logistic regression analysis technique showed that increasing number of persons in the household (odds ratio [OR]=1.9; 95% confidence interval [CI] 1.2-3.1), non availability of soap near hand washing facility (OR=2.6; 95% CI 1.1-6.3), non-use of medicated soap (OR=11.2; 95% CI 1.3-97.6) and lack of awareness about contact with a known case of typhoid fever (OR=3.7; 95% CI 1.6-8.4) were independent risk factors of the disease. Health education with emphasis on hand washing may help decrease the burden of typhoid fever in developing countries. PMID- 20701853 TI - Oncogenic human papilloma virus and cervical pre-cancerous lesions in brothel based sex workers in India. AB - A community-based cross-sectional study was conducted in brothel-based sex workers of West Bengal, Eastern India, to determine their oncogenic human papillomavirus (HPV) status and the presence of pre-cancerous lesions. A total of 229 sex workers from three districts of West Bengal participated in the study. All the study participants were interviewed with the aid of a pre-tested questionnaire to determine their sociodemographics, risk behaviour and risk perceptions after obtaining informed verbal consent. The interview was followed by collection of cervical cells from all participants using a disposable vaginal speculum and cervical cytobrush. Oncogenic HPV DNA was detected by real-time polymerase chain reaction (PCR). A simultaneous Papanicolaou test ('Pap smear') was performed to detect cervical cytological abnormalities. Overall, the prevalence of oncogenic HPV was found to be 25% (58/229) among the studied population. A subset (n=112) of the sample was tested separately to determine the existence and magnitude of HPV genotypes 16 and 18. The results showed that genotype 16 was prevalent in 10% (11/112), genotype 18 in 7% (8/112) and both genotype 16 and 18 in 7% (8/112). The HPV prevalence rate showed a decreasing trend with age, being 71.4% in the 10-19 years age group, 32.3% in the 20-29 years age group, 18.3% in the 30-39 years age group and 2.5% in the >or=40 years age group (statistically significant differences, P1 year, respectively. This difference was found to be statistically significant both by univariate and multivariate analysis. In this study, it was observed that sex workers with an average number of daily clients of six or more had an HPV prevalence of 67% (n=6), those with four to five clients had a prevalence of 45% (n=9), those with two to three clients had a prevalence of 30% (n=34) and those with one or less clients had a prevalence of 10% (n=9) (statistically significant differences, P=0.00003). Multivariate analysis showed a statistical association only with a duration of sex work of or=101 (OR=2.5; 95% CI 1.3-5). Regarding pre-cancerous lesions, 2 of 229 sex workers showed the presence of a low-grade squamous intraepithelial lesion along with high-risk HPV. Thus, 1% of the studied population suffer from a pre-cancerous lesion caused by high-risk HPV. This study concludes that young sex workers are particularly vulnerable to high-risk HPV, similar to human immunodeficiency virus (HIV). The observation of older sex workers relatively free from HPV supports the view of acquired immunity against HPV, which needs to be studied in-depth further. There is a need for a suitable community-based intervention programme targeted towards sex workers, with special reference to younger sex workers, for control and prevention of HPV and cervical cancer. Vaccination against HPV for newly entrant sex workers may be an important component for a successful intervention programme. PMID- 20701854 TI - Empyema as an orphan disease: So many approaches and so few data. PMID- 20701855 TI - Premarital HIV screening in Saudi Arabia, is antenatal next? PMID- 20701856 TI - Infective complications of tattooing and skin piercing. AB - Body piercing appears to be gaining popularity and social acceptance. With the increase in the number of piercings and tattoos, it is likely that health care providers may see an increase in the complications resulting from these piercings. These may include the transmission of hepatitis viruses and bacteria at the time of the piercing or in the course of wound care. We review the infectious complications that have resulted from body piercing and tattooing that has been documented in the medical literature. PMID- 20701857 TI - The role of infections in the emergence of non-communicable diseases (NCDs): Compelling needs for novel strategies in the developing world. AB - The emergence of non-communicable diseases (NCDs) follows multiple aetiological pathways requiring recognition for effective control and prevention. Infections are proving to be conventional, emerging and re-emerging aetiological factors for many NCDs. This review explores the possible mechanisms by which infections induce NCDs citing examples of studies in Africa and elsewhere where NCDs and infections are proposed or confirmed to be causally linked and also discusses the implications and challenges of these observations for science and medicine. The need to re-evaluate and expand early community and individual preventive and control strategies that will lead to reduction and even elimination of NCDs especially in Africa and other developing countries where infections are prevalent is highlighted. PMID- 20701858 TI - Knowledge, attitudes, and practices relating to Dengue fever among females in Jeddah high schools. AB - Dengue is increasingly recognized as one of the world's major infectious diseases. Dengue vectors, human knowledge and human behavior have each been reported to play an important role in the transmission of the disease. A cross sectional approach was conducted to assess knowledge, attitudes and practice (KAP) of high school female students, teachers and supervisors towards Dengue fever (DF), and to determine scoring predictors of high school students' knowledge and practice scores. A multistage, stratified, random sample method was applied. A total of 2693 students, 356 teachers and 115 supervisors completed confidential self-administered questionnaires. RESULTS: Students obtained the lowest mean knowledge score compared to the other two groups (F=51.5, P<0.001). A positive family history of DF (a OR=2.05; 95% CI=1.15-3.64), having literate mothers (>or=secondary education), and students' age >or=17 were the predictors of high students' knowledge score. The only predictor of high practice score was obtaining high knowledge score (a OR=2.06; 95% CI=1.73-2.44). CONCLUSION: KAP towards DF was deficient among target populations, especially among students. School-based educational campaigns and social mobilization for raising knowledge and changing it into sound practice is urgently needed for controlling dengue epidemics in Jeddah. PMID- 20701859 TI - Human papillomavirus infection is principally found with cervical intra epithelial neoplasia-III in Toluca, State of Mexico. AB - INTRODUCTION: To describe the prevalence of human papillomavirus infection (HPV) in cases of cervical intra-epithelial neoplasia (CIN), micro-invasive carcinoma and invasive carcinoma in Toluca, State of Mexico. MATERIALS AND METHODS: Cross sectional study analysing slides with the diagnosis of CIN I to invasive carcinoma for one year and reporting the presence of HPV; also identifying these cervical-uterine cancer stages noted during one semester in the registery of histopathological studies, at the Department of Pathology, General Regional Hospital 220, Instituto Mexicano del Seguro Social (IMSS). RESULTS: In one year, from a total of 5755 studies, 731 (13%) were of cervical-uterine cancer, 112 (16%) of these were positive for some stage of cervical cancer and 46.43% had HPV infection. In one semester, 2918 histopathological studies were done, 341 (11.68%) of these were cervix uterine biopsies, colposcopies and hysterectomies. 62 women (18.18%) diagnosed with CIN II-III, carcinoma in situ (CIS), micro invasive carcinoma or invasive carcinoma and finding HPV infection in 51.92% of total cases. CONCLUSIONS: The prevalence of HPV was higher than that reported in developed world and CIN II-III are the most common stages in Toluca, State of Mexico. PMID- 20701860 TI - Seroprevalence study of HCV among hospitalized intravenous drug users in Ahvaz, Iran (2001-2006). AB - BACKGROUND AND AIMS: Prevalence of hepatitis C virus (HCV) in intravenous drug users (IDU) varies in different areas according to socioeconomic and geographical circumstances. The present study was performed to determine seroprevalence of HCV in IDU individuals in Ahvaz, Iran. MATERIALS AND METHODS: 142 IDU patients were included in this retrospective study in Ahvaz southwest Iran from 2001 to 2006. Patients were placed in two groups determined by HCV Ab positive or negative status. Data were analyzed using SPSS for Windows (version 11.5; SPSS Inc., USA) software. RESULTS: Out of total 142 cases, 74 persons (52.11%) had a positive HCV Ab test according to the ELISA method. There was no difference in age, sex, level of education, residency and co-infection with HIV and hepatitis B virus between HCV-Ab positive (HAP) and HCV-Ab negative (HAN) groups (p>0.05). HCV-Ab positivity was significantly related to imprisonment and duration spent in prison [OR: 3.22, 95% (CI) 2.61-3.76, p<0.0001]. CONCLUSION: Patients with IDU constitute a high-risk group for acquisition of HCV infection. Transmission of HCV via sharing syringe and needle as well as blood transfusion has been a significant source of hepatitis C infection for patients with intravenous drug addiction. PMID- 20701861 TI - The medical literature and the discipline of infection control. PMID- 20701862 TI - Reclassifying bioterrorism risk: are we preparing for the proper pathogens? AB - Existing classifications of potential biological weapons, acknowledge only limited important parameters of biological weapon potential. Certain pathogen factors would further influence the outcome of a potential attack in context with social and political aspects of the time and space of the attack. The importance of these factors was investigated through various attack scenarios that have been developed by the authors, and an individual score for each of these factors was calculated, based on the overall effect their variation had in the scenario outcome. A new classification score for potential biological weapons was subsequently developed, one, which drastically alters the perception of risk for certain pathogens, such as filoviruses and anthrax. This frame further allows for more accurate evaluation of the bioweapon potential of agents such as avian flu. Recognition of intervening factors and proper assessment of the actual risk might augment in proper distribution of interest and funds on relevant medical research. PMID- 20701863 TI - Antibiotic therapeutic options for infections caused by drug-resistant Gram positive cocci. AB - Serious infections caused by Gram-positive bacteria are currently difficult to treat because many of these pathogens are now resistant to standard antimicrobial agents. As a result of the emergence and spread of multidrug-resistant Gram positive pathogens, new antimicrobial agents are urgently needed for clinical use. In recent years, there has been an increase in the number of drugs that have activity against these Gram-positive pathogens. Daptomycin, tigecycline, linezolid, quinupristin/dalfopristin and dalbavancin are five antimicrobial agents that are useful for the treatment of infections due to drug-resistant Gram positive cocci. This review focuses on their mechanism of action, pharmacokinetics, spectrum of activity, clinical effectiveness, drug interaction and safety. These antimicrobial agents provide the clinician with additional treatment options among the limited therapies for resistant Gram-positive bacterial infection. PMID- 20701864 TI - Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt. AB - In December 2006, three human specimens were received that were suspected positive for influenza A(H5N1). The specimens were tested using real time PCR. And the presence of A(H5N1) virus was confirmed in 2 patients (16F and 26M), The NA sequence from A(H5N1) positive specimens collected before and after antiviral therapy revealed a mutation (N294S) (N295S according to N1 numbering), previously associated with resistance to oseltamivir. When tested with NA inhibition assays, the two N294S viruses from Egypt exhibited from 57 to 138-fold reduction in susceptibility to oseltamivir, depending on the assay. To our knowledge, this is the first time oseltamivir resistance has been detected in A(H5N1) infecting a human prior to treatment. PMID- 20701865 TI - A 24-year study of the epidemiology of human brucellosis in a health-care system in Eastern Saudi Arabia. AB - OBJECTIVE: The aim of the study was to examine the epidemiology of human brucellosis in a helath-care system in Eastern Saudi Arabia. METHODS: All cases of human brucellosis from 1983 to 2007 were analyzed. RESULTS: In the study period, there were 913 patients with brucellosis in the Saudi Aramco health-care system. There were 608 males and 305 females with a male to female ratio of (2:1). The annual incidence rate per 100,000 populations increased from 13 to 70 in 1983 and 1987, respectively, then decreased to 9 in 2006. The age of the patients ranged from 1 to 83 years with a mean age of 35.8+/-17.9 years and a median of 36 years. Of the total patients, 195 (21%) and 155 (17%) cases occurred in those between 20-30 and 31-40 years of age, respectively. Children (< or =10 years of age) constituted 5% of all the patients. The adjusted rate per 100,000 population showed that the highest rate was in those 40-49 years of age (100/100,000) and the lowest rate was in patients less than 10 years of age (2.9/100,000). The number of cases was highest in April to June (n=361; 39.5%) and the lowest reported cases were in January. Of the 219 patients whom their families had animals, 125 (57.1%) had camels, 49 (22.4%) had sheep, 24 (11%) had goats, and 21 (9.6%) had cows. Blood cultures were positive in 80.7% (201/247) of cases. There was no association between age group and the rate of positive blood culture (P value=0.244). The titer of brucella serology was 1:320 in 34.3%, 1:640 in 31%, 1:1280 in 24.7%, > or =1:2560 in 10%. The higher brucella titers were associated with higher rate of positive cultures (P value=0.0002). CONCLUSION: There was a decrease in the incidence of brucellosis over the study period. The highest incidence was in patients 40-49 years of age. Continued surveillance and efforts are needed to further decrease the cases of brucellosis. PMID- 20701866 TI - Vaginal carriage and antibiotic susceptibility profile of group B Streptococcus during late pregnancy in Ismailia, Egypt. AB - Group B Streptococcus (GBS) infection has long been recognized as a frequent cause of morbidity and mortality in newborn infants. The purpose of this study was to determine the colonization rate with GBS and the antibiotic susceptibility profile in pregnant women attending Gynecological clinics in Egypt. One-hundred and fifty vaginal swabs were collected from pregnant women at 35-40 weeks of gestation. In comparison to culture, direct latex agglutination testing revealed 100% sensitivity and 93.75% specificity. Thirty-eight specimens (25.3%) were found to be positive for GBS. Each isolate was tested for susceptibility to penicillin G, ampicillin, cefotaxime, erythromycin, clindamycin and vancomycin. Erythromycin-resistant isolates were further classified by double-disk method. All isolates were susceptible to penicillin G, ampicillin and vancomycin. Resistance to cefotaxime was detected in three isolates (7.89%). Five isolates (13.15%) were resistant to erythromycin and nine isolates (23.68%) were resistant to clindamycin. Four (80%) isolates had constitutive macrolide-lincosamide Streptogramin(B) resistance (cMLSB(B)) resistance and one (20%) isolate had inducible resistance (iMLS(B)) resistance. GBS colonization was found to be high in our region. Latex agglutination testing and Islam medium are reliable methods to detect GBS in late pregnancy; however, latex agglutination test is rapid and simpler. Penicillin G remains the first choice antibiotic for treatment of GBS infections. PMID- 20701867 TI - A survey of traditional Iranian food products for contamination with toxigenic Clostridium botulinum. AB - This study aimed to determine the rate of Clostridium botulinum contamination in some traditional Iranian food products (cheese, kashk and salted fish) and evaluate the efficacy of the mouse bioassay method in detection of C. botulinum toxins in these foods. A total of 131 samples (57 cheese, 11 kashk and 63 salted fish) were collected and examined to determine the rate of contamination by C. botulinum. Standard monovalent anti-toxins were used to determine the types of toxin. C. botulinum bacteria were detected in 4.58% of the examined samples (1.52% of cheese and 3.06% of salted fish samples). While no contamination was detected in the kashk samples, C. botulinum types A and E were found to be dominant in cheese and salted fish samples, respectively. These results indicate some traditional Iranian foods may be contaminated with different types of C. botulinum, and the consumption of these products, either raw or cooked, may contribute to food-borne intoxications. PMID- 20701868 TI - Is Chlamydia pneumoniae seropositivity associated with atherothrombotic cerebrovascular infarction? AB - BACKGROUND AND OBJECTIVE: Several studies suggested that Chlamydia pneumoniae (CP) infection may be a risk factor for cerebrovascular disease. Since these studies have reported controversial results, we performed this study to identify whether Cp-immunoglobulin was associated with atherothrombotic cerebrovascular infarction (ACI) in Iranian patients. MATERIALS AND METHODS: Forty-five patients admitted with ACI, and 45 control without ACI were enrolled in this case-control study. Using an enzyme-linked immunosorbed assay kit (ELISA), the presence of CP immunoglobulin (CP-IgG) in studied patient's sera was determined. RESULTS: The seroprevalence of CP-IgG was 35(77.7%) in the ACI group (mean age=73.3 years) and 29(64.4%) in the control group (mean age=70.1 years) (P>0.05). There was no difference in sex, age, hypertension, smoking, hyperlipidemia, diabetes and obesity between cases and control groups (P>0.05). No association was observed between CP seropositivity and ACI [OR: 1.95 (95% CI, 0.081-2.03), P=0.16]. CONCLUSION: Our finding suggests that there is no association between ACI and positive CP-IgG in Iranian patients. PMID- 20701869 TI - Urinary tract infections caused by Pseudomonas aeruginosa: a minireview. AB - Urinary tract infections (UTIs) are a serious health problem affecting millions of people each year. Infections of the urinary tract are the second most common type of infection in the body. Catheterization of the urinary tract is the most common factor, which predisposes the host to these infections. Catheter associated UTI (CAUTI) is responsible for 40% of nosocomial infections, making it the most common cause of nosocomial infection. CAUTI accounts for more than 1 million cases in hospitals and nursing homes annually and often involve uropathogens other than Escherichia coli. While the epidemiology and pathogenic mechanisms of uropathogenic Escherichia coli have been extensively studied, little is known about the pathogenesis of UTIs caused by other organisms like Pseudomonas aeruginosa. Scanty available information regarding pathogenesis of UTIs caused by P. aeruginosa is an important bottleneck in developing effective preventive approaches. The aim of this review is to summarize some of the advances made in the field of P. aeruginosa induced UTIs and draws attention of the workers that more basic research at the level of pathogenesis is needed so that novel strategies can be designed. PMID- 20701870 TI - Demographic, laboratory and clinical characteristics of HIV-positive tuberculosis cases in Canada. AB - BACKGROUND: Human immunodeficiency virus (HIV) is an important risk factor for the global incidence and mortality of tuberculosis (TB) and has had a tremendous impact on the epidemiology and the control of the disease. The purpose of this study was to determine the demographic, laboratory and clinical characteristics of HIV-positive TB cases in Canada as compared to HIV-negative cases. METHODS: TB cases reported to the Canadian TB Reporting System (CTBRS) from 1997 to 2006 were retrospectively reviewed and for those with known HIV serostatus, the distributions of age, sex, country of birth, smear and culture positivity, drug resistance, site of disease and treatment outcome were compared. RESULTS: 2710 TB cases had a report of an HIV test with a 12.9% positivity rate. HIV-positive cases were more likely to be 30-44 years old, male, Canadian born non-Aboriginal or African born. Sputum and lymph node biopsies were significantly more likely to be smear-positive and sputum was more likely to be culture positive. Anti-TB drug resistant rates were similar, except for lower streptomycin resistance in new HIV positive cases. HIV-positive cases were significantly more likely to present with miliary or central nervous system TB, to have multi-system disease, to have lower treatment success rates (66.4% versus 88.5%) and to have a 5.6 higher case fatality rate. INTERPRETATION: HIV-positive cases have a different demographic profile, present with more advanced and severe forms of disease, have poorer treatment outcomes and higher mortality. All TB cases should be tested for HIV so as to offer appropriate case management and treatment. PMID- 20701871 TI - Novel in vitro pharmacodynamic model simulating ofloxacin pharmacokinetics in the treatment of Pseudomonas aeruginosa biofilm-associated infections. AB - OBJECTIVES: The conventional in vitro models simulate pharmacodynamics of antibiotics in the treatment of planktonic Pseudomonas aeruginosa. In this study, we propose a novel pharmacodynamic model of ofloxacin activity in the treatment of P. aeruginosa biofilm. METHODS: P. aeruginosa biofilm carrying coupons were suspended in a continuous flow central compartment bioreactor (CCB). In the CCB, the pharmacokinetics of different ofloxacin dosing regimens were simulated. Samples from the coupons and the CCB were assessed for viability of the biofilm and the shedding planktonic cells, respectively, over 24h. In addition, ofloxacin concentrations were assessed in each sample withdrawn for the CCB using bioassay method. RESULTS: The microbiological outcomes on P. aeruginosa biofilm and the shedding planktonic cells in response to different ofloxacin dosing regimens were not parallel and this may explain the non-coincidence of microbiological and clinical outcomes with biofilm associated infections. CONCLUSION: The current study has introduced unprecedented novel dynamic model for the assessment of the microbiological outcome on both biofilm and shedding planktonic cells of P. aeruginosa in response to different dosing regimens of ofloxacin which in turn can simulate the clinical outcomes in biofilm associated infections of P. aeruginosa, e.g. cystic fibrosis. Furthermore, different scenarios of antibiotic dosing regimens against biofilm related infections can be mimicked using such model. PMID- 20701872 TI - Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae in Bahrain. AB - OBJECTIVES: To determine the occurrence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in Bahrain. METHODS: Retrospective analysis of records (January 2005-December 2006) at the Microbiology Laboratory of the Salmaniya Medical Complex, Bahrain which is the major national diagnostic laboratory. RESULTS: Out of a total of 11,886 member of family of Enterobacteriaceae isolated, 2695 (22.6%) were ESBL producers. Majority of ESBL isolates were from inpatients (n=2363; 87.7%). Escherichia coli (52.2%) and Klebsiella pneumoniae (24.3%) were predominant and distributed comparatively in the hospital wards while Proteus spp. (17.6%) was predominant in medical wards. Urine was the major source (52.2%) with low occurrence in blood cultures. No carbapenem resistant isolates was identified but resistance to three classes of antibiotics was exhibited by >25% of the isolated ESBL strains. Nitrofurantoin resistance was identified in 38.2% of urinary isolates. CONCLUSION: This is the first report from Bahrain and it indicates that the prevalence of ESBL-producing isolates is high. Carbapenems were the most active drug against the ESBL producing isolates. We recommend strict infection control to prevent trafficking into the community. PMID- 20701873 TI - Evaluation of interleukin-10 production in Pseudomonas aeruginosa induced acute pyelonephritis. AB - Pseudomonas aeruginosa is an opportunistic pathogen of immunocompromised hosts. This pathogen has a tendency to form biofilms on the surface of indwelling catheters leading to acute and chronic urinary tract infections that result in significant morbidity and mortality. In the present study, kinetics of interleukin-10 (IL-10) production in mouse renal tissue was studied employing experimental mouse model of acute pyelonephritis induced with planktonic and biofilm cells of P. aeruginosa. IL-10 production was found to be significantly lower in biofilm cell instilled mice compared to planktonic cell infected animals, which corroborated with higher bacterial load and tissue damage. The data suggests that downregulation of IL-10 production may be novel strategy employed by biofilm cells to cause tissue damage and hence bacterial persistence. The results of the present study may open up avenues of research that will ultimately provide the foundation for the development of preventative measures and therapeutic strategies to successfully treat P. aeruginosa biofilm infections based on the administration of anti-inflammatory agents. PMID- 20701874 TI - Improvement in vancomycin utilization in adults in a Saudi Arabian Medical Center using the Hospital Infection Control Practices Advisory Committee guidelines and simple educational activity. AB - OBJECTIVE: To evaluate vancomycin utilization according to the adapted criteria of the Centers for Disease Control and Prevention (CDC) with a report of the effect of education program on the utilization. METHOD: We evaluated the utilization of vancomycin over a 3-month period pre- and post-intervention using educational activity. RESULTS: In the pre-intervention period, of the 74 adult patients vancomycin was prescribed for specific treatment in 66% (n=49), empirical therapy in 26% (n=19) and as a prophylaxis in 8% (n=6). Vancomycin utilization was considered appropriate based on the CDC recommendations in 48 (65%) patients. Forty-seven (64%) patients received an appropriate dose regimen based on weight, age and creatinine clearance. Only 31% (n=23) of patients had both peak and trough levels taken around the third dose. In the post-intervention period, vancomycin was used as specific therapy in 41% (n=14) and empirically in 59% (n=20). Compliance with guidelines for empirical use of vancomycin improved from 21% in the pre-intervention phase to 85% after the intervention (P=.0001). In addition, compliance with vancomycin use in specific therapy was 100% compared to 82%. Compliance rate with vancomycin trough level monitoring increased from 35% in the pre-intervention period to 67.7% in the post-intervention period (P=0.0002). CONCLUSION: In conclusion, in addition to the utilization of CDC based criteria for vancomycin, we had shown that patient's chart review by a clinical pharmacists with a feed back to the physicians when guidelines were not met coupled with and educational efforts are effective methods to decrease inappropriate vancomycin usage. PMID- 20701875 TI - Resistance pattern of breakthrough urinary tract infections in children on antibiotic prophylaxis. AB - Prophylactic antibiotics are commonly used for prevention of urinary tract infections (UTIs) in children. It was postulated that the organisms and resistance patterns of breakthrough infections would differ with the choice of antimicrobial prophylaxis. This was a retrospective descriptive study of all breakthroughs UTI from 2000 to 2006 in children over 1 month of age discharged from a referral children's hospital in Tehran, Iran on continuous antibiotic prophylaxis for UTIs. Fifty-seven children discharged on prophylaxis had breakthrough UTIs of which 32 (56%) had a previously diagnosed urinary tract anomaly. Escherichia coli was responsible for the majority of infections irrespective of choice of prophylaxis. Thirty-three of 56 breakthrough UTIs (59%) were with organisms that were resistant to the prophylactic antibiotic. There was an increased incidence of resistance to prophylaxis in children on cefixime (16 of 22; 78%) when compared with children on cephalexin (7 of 19; 37%; p=0.02) and a trend toward increased resistance when compared with children on trimethoprim sulfamethoxasole (3 of 8; 37%) (p=0.10). In conclusion, the resistance pattern of organisms causing breakthrough UTIs varies with the choice of prophylaxis which should be taken into consideration in chosing empiric therapy for such infections. PMID- 20701876 TI - HIV/AIDS education as a supportive tool for premarital HIV screening. PMID- 20701877 TI - Swine flu. AB - The recent outbreak of human infection with a novel Swine-Origin Influenza A (H1N1) virus is spreading rapidly through sustained human-to-human transmission in multiple countries. Human-to-human transmission occurs by inhalation of infectious droplets and droplet nuclei, and by direct contact, which is facilitated by air and land travel and social gatherings. The most frequently reported symptoms are fever, cough, myalgia, and sore throat. Detailed contact and travel histories and knowledge of viral activity in community are essential for prompt case detection by the health personnel. Real-time Reverse Transcriptase-Polymerase Chain Reaction analysis of throat swabs or lower respiratory samples is a sensitive means of diagnosis. Use of oral oseltamivir may be warranted for the treatment of severe illness. PMID- 20701878 TI - Epidemiology and outcome of snake bite cases evaluated at a Tertiary Care Hospital in Oman. AB - OBJECTIVES: To study the epidemiology of snake bite patients evaluated at the Royal Hospital, Muscat, Sultanate of Oman, and to study their clinical course and outcome. METHODS: A retrospective study of 65 adult patients presenting at Royal Hospital following a snake bite from May 2006 to August 2008. RESULTS: The main symptoms were local pain at the bite site (26 patients, 40%) and swelling (17 patients, 26%). Only five patients (7.7%) had signs of bleeding. After assessment, only 47 of the 65 patients were admitted. White cell count (WCC) was raised in 15 cases (23%) on presentation to the emergency room. Prothrombin time was prolonged in 34 patients (52%) and APTT was prolonged in 25 patients (38%) on presentation. Thirty-six patients received anti-snake venom (antivenom) at a mean time of 8h after the bite and 4h after arrival in the emergency department. Patients with deranged coagulation profile needed a mean of fourteen vials of antivenom for correction of the abnormal coagulation profile. Two patients died: both had delayed presentation to the hospital. CONCLUSION: Patients with envenoming following snakebite should receive antivenom as soon as possible: delayed presentation or administration may be very dangerous. The decision to give antivenom should be initiated as soon as possible after patients' arrival at the Emergency Department and the use of the whole blood clotting test (WBCT) may facilitate the early administration of antivenom. PMID- 20701879 TI - Prevalence of malaria from peripheral blood smears examination: a 1-year retrospective study from the Serbo Health Center, Kersa Woreda, Ethiopia. AB - Malaria is a major public health problem in Ethiopia. Over the past years, the disease has been consistently reported as the first leading cause of outpatient visits, hospitalization and death in health facilities across the country. Thus, a retrospective study was conducted to determine the prevalence of malaria from peripheral blood smear examination from the Serbo Health Center of Ethiopia. The case notes of all malaria cases treated between July 2007 and June 2008 were carefully reviewed and analyzed. Of the total 6863 smears, 3009 were found to be positive and contribute 43.8% of diagnostic yield. Plasmodium falciparum constituted the most predominant [64.6% (1946/3009 cases)], while Plasmodium vivax confirmed with 34.9% (1052/3009) cases. Among patients who underwent diagnostic testing and treatment for malaria, males [63.8% (1918/3009 cases)] were more prone to have a positive malaria smear than females [36.2% (1091/3009 cases)]. Chi-square statistical analysis shown that there was a statistically significant association found between male cases and number of positive blood smear (chi(2)=28.1; df=7; p-value=0.001). The present study results clearly suggest that the catchment area of Serbo Health Center is prone for epidemic malaria and the situation is quite deteriorating. At the moment, although we are not equipped with magic bullet for malaria effective low-cost strategies are available for its treatment, prevention, and control. Therefore, creating awareness by active health education campaigns and applying integrated malaria control strategy could bring the constructive outcome in the near future. PMID- 20701880 TI - Social network methodology for studying HIV epidemiology in men having sex with men. AB - A self-administered network-based questionnaire survey was conducted on 91 HIV positive Chinese men having sex with men (MSM). Affiliation matrices were created to assess their networking pattern. The individuals' preferential use of venues for sex partnership before HIV infection has changed over three time periods of 1997-2000, 2001-2003 and 2004-2006. Over time, there was a parallel increase in network density (density scores from 0.26, through 0.36, to 0.53) and degree centrality (from a median score of 9, through 12, to 16), suggesting that connectivity of MSM was becoming higher through sexual networks. The overall practice of unprotected sex has, however, remained the same. The study demonstrated how the application of social network analysis could enrich the epidemiologic description of HIV infection in the population. PMID- 20701881 TI - A combined molecular typing approach does not discriminate Legionella pneumophila serogroup 1 strains of a predominant sequence-based type in Palermo, Italy. AB - The sequence-based type 1,4,3,1,1,1 of Legionella pneumophila sg.1 is predominant in the Palermo city environment since several years. In this study, extended sequence-based typing and pulsed field gel electrophoresis were used in a combined approach in the aim to enhance discriminatory power of the molecular typing procedures. However, probably due to a common environmental reservoir and genetic stability, most of the strains circulating in the geographic area under study belong to the same clone and are, consequently, indistinguishable by molecular typing. Investigations of clinical cases and tracing to their environmental source require caution and support from sound epidemiological data. PMID- 20701882 TI - Self-medication with antibiotics in the ambulatory care setting within the Euro Mediterranean region; results from the ARMed project. AB - Anecdotal data from the southern and eastern Mediterranean region suggests that self-medication with antibiotics is commonly practiced in many countries. In order to provide proper information on the situation, we undertook short structured interviews in out-patients clinics or primary health centres in Cyprus, Egypt, Jordan, Lebanon, Libya, Tunisia and Turkey. A total of 2109 interviews were undertaken of which 1705 completed the full questionnaire. Self medication was reported by 19.1% (<0.1% in Cyprus to 37% in Lebanon) of respondents. Intended self-medication ranged from 1.3% (95% CI 0%, 3%) in Cyprus to 70.7% (95% CI 64%, 77%) in Jordan. Upper respiratory tract symptoms were the most frequent reasons for which respondents indicated they would self-medicate. 48.4% of the whole group replied that they kept antibiotics at home, being highest in Lebanon (60%, 95% CI 51%, 69%). We found a significant association between antibiotic hoarders and intended users of antibiotics for self medication. Our data confirms that non-prescribed antibiotic use is high within ambulatory care in southern and eastern Mediterranean countries, being almost twice that reported in a similar European study. Corrective efforts are clearly required in the region to ensure proper use of antimicrobials so as to reduce pressure for antimicrobial resistance. PMID- 20701883 TI - Evidence for the exacerbation of lymphedema of geochemical origin, podoconiosis, by onchocerciasis. AB - The study was conducted to investigate a variation in the distribution of endemic elephantiasis previously determined to be of geochemical origin in three neighbouring and essentially homogenous villages, Bambili, Bambui and Finge of the Bambui Health District of NW Cameroon. A total of 301 subjects were examined for onchocerciasis and lymphatic filariasis in the area using standard procedures. The onchocercal microfilarial prevalence varied from 6.5% in Bambili through 20.4% in Bambui to 60.4% in Finge. The onchocercal serological prevalence based on IgG4 detection followed a similar trend. By contrast, blood microfilariae were absent in the area as verified by use of sensitive techniques. The community prevalence of elephantiasis varied from 1.1% in Bambili to 4.4% in Bambui and 10.4% in Finge. The correlation between the parasitological prevalence of onchocerciasis and the prevalence of lymphedema in the three villages was strong (r=0.99, p<0.05). We confirm that the elephantiasis in the area is of geochemical origin and the results suggest that it is being exacerbated by onchocercal lymphadenitis. PMID- 20701884 TI - Frequency of Helicobacter pylori vacA genotypes in Iranian patients with gastric and duodenal ulcer. AB - Helicobacter pylori infection is a risk factor for developing chronic peptic ulcers and gastric cancer. The purpose of this study was to investigate the frequency of Helicobacter pylori vacA genotypes in patients with gastric and duodenal ulcer. A total of 100 biopsy specimens of patients with gastric (n=50) and duodenal (n=50) ulcer were collected. The specimens were cultured on selective media and incubated in a microaerophilic atmosphere at 37 degrees C for 5-10 days. The isolates were characterized to species level by conventional biochemical tests. The extracted DNA from isolates was used to perform a polymerase chain reaction based, simultaneous analysis of the cagA status, allelic variation of the signal regions (s1, s2) and the middle regions (m1, m2) of the vacA gene. H. pylori isolated from 50 specimens of patients and the vacA gene was detected in all isolates. Among vacA genotypes the s1/m1 was the most common in H. pylori isolates from patients with gastric ulcer (56%) and duodenal ulcer (68%). This study demonstrated that vacA slml is common genotype of H. pylori in patients with peptic ulcer and the vacA allele s1 of this bacterium is associated with ulcer. PMID- 20701885 TI - Pharmaco-EcoMicrobiology: a newer component of medical sciences bridging pharmacovigilance, ecology, and environmental microbiology. AB - Environmental scientists are now raising great concern on the impact of drugs on the environment and microbiologists are concerned about increasing antibiotic resistance due to irrational usage. However, a focus on the impact by the use of antibiotics (irrational/prescribed) to the environment at therapeutic doses has not been instituted. Even the World Health Organization (WHO) defined "Pharmacovigilance" activities as the monitoring, detection, assessment, understanding and prevention of any adverse reactions to drugs at therapeutic concentration on animals and humans. Nevertheless, there is little attention being given to identifying the adverse effects (ADEs) of antimicrobial agents on the environment (given at therapeutic doses). This issue has been highlighted in the present commentary and a new domain, "Pharmaco-EcoMicrobiology", has been proposed which should deal with and monitor such adverse effects. The term "Pharmaco-EcoMicrobiology" has been proposed to define the interplay between antimicrobial pharmacological agents and animate microbial ecology. This new domain, "Pharmaco-EcoMicrobiology", has been derived by the aggregation of three important branches of science (pharmacology+ecology+microbiology) and would be responsible for studying the ADEs due to antimicrobial drugs excreted in environment. PMID- 20701886 TI - Pyogenic spondylodiscitis: an overview. AB - Although uncommon, spontaneous and postoperative pyogenic spondylodiscitis entail major morbidity and may be associated with serious long-term sequelae. A review of the literature was done to advance our understanding of the diagnosis, treatment, and outcome of these infections. The principles of conservative treatment are to establish an accurate microbiological diagnosis, treat with appropriate antibiotics, immobilize the spine, and closely monitor for spinal instability and neurological deterioration. The purpose of surgical treatment is to obtain multiple intraoperative cultures of bone and soft tissue, perform a thorough debridement of infected tissue and decompression of neural structures, and reconstruct the unstable spinal column with bone graft with or without concomitant instrumentation. Appropriate management requires aggressive medical treatment and, at times, surgical interventions. If recognized early and treated appropriately, a full recovery can often be expected. Therefore, clinicians should be aware of the clinical presentation of such infections to improve patient outcome. PMID- 20701887 TI - Tuberculosis in Saudi Arabia: can we change the way we deal with the disease? AB - Infection from Mycobacterium tuberculosis results in the death of three million people worldwide per annum of which an estimated one thousand are in Saudi Arabia. The WHO has set a target for successful treatment of 85% but Saudi Arabia is currently not meeting that target. We believe that the first step in improving the control of tuberculosis in Saudi Arabia is to improve and unify the standards of diagnostic services and laboratories responsible for tuberculosis. This paper reviews the current status and suggests possible improvements. PMID- 20701888 TI - Factors determining poor practice in alcoholic gel hand rub technique in hospital workers. AB - BACKGROUND: Hand hygiene of healthcare personnel is one of the most important interventions for reducing transmission of nosocomial pathogens. Previous studies have demonstrated that the use of alcohol-based hand gel increases hand hygiene compliance, but that effective use of this product cannot be taken for granted. OBJECTIVE: Evaluate factors associated with poor hand hygiene effectiveness of hospital workers using an alcohol-based hand gel and the effect of an education program. DESIGN: A direct observational prospective study of hand hygiene effectiveness prior to training and immediately after training. SETTING AND SUBJECTS: 3067 hospital workers of different professional categories in several hospital units in the University Hospital of Nancy (France). RESULTS: Time after program start (OR 0.97, 95%CI 0.96-0.97) and being female (OR 0.37, 0.24-0.58) were highly associated with increased effectiveness of hand hygiene prior to training. Wearing rings other than a wedding ring (OR 1.8, 1.2-2.7), a bracelet (OR 2.0, 1.1-3.6), a watch (OR 1.9, 1.3-2.9) and having long nails were associated with ineffective hand rub use. Professional background was also a strong predictor with nurses and especially senior nurses demonstrating much better effectiveness than all other professional groups. Wearing wedding rings or long sleeves, and having varnished nails, visibly dirty hands prior to washing and cutaneous lesions were not associated with effective gel use. CONCLUSION: These results demonstrate that an educational program can significantly improve the proper practices for using hand rub and hand washing compliance. This study has also demonstrated that wearing rings, bracelets, watches and long nails impair hand gel application but that wedding rings, long sleeves and varnished nails do not. The finding of that hand hygiene effectiveness increased with time even prior to training indicates that knowledge gained by staff trained early diffused into those who had not yet been trained. PMID- 20701889 TI - Comparative in vitro activity of tigecycline and other antimicrobial agents against Shigella species from Kuwait and the United Arab of Emirates. AB - Shigella species isolated from stool samples of symptomatic patients of all age groups at the Mubarak Al Kabir Hospital and Infectious Diseases Hospital, Kuwait and Tawam Hospital, UAE during a 2-year period were investigated for their susceptibility to tigecycline and several other antibiotics by determining the minimum inhibitory concentrations (MICs) using the E test method. A total of 100 and 42 strains were collected from UAE and Kuwait, respectively. The extent of drug resistance in the Shigella spp. isolates from these two countries was analyzed by criteria recommended by the Clinical and Laboratory Standards Institute (CLSI). Amikacin, cefotaxime, cefuroxime, ciprofloxacin, imipenem, meropenem, piperacillin-tazobactam and tigecycline had excellent activities against all isolates from UAE and Kuwait with MIC(90s) of 12, 0.094, 4, 0.012, 0.25, 0.032, 3 and 0.25 microg/ml and 4, 1, 4, 0.125, 0.38, 0.19, 3 and 0.25 microg/ml, respectively. Half of all isolates from both countries were resistant to ampicillin. None of the isolates in Kuwait was resistant to amoxicillin clavulanic acid compared with 22% in UAE. Resistance to chloramphenicol was recorded in 50 and 36% of the isolates in Kuwait and UAE, respectively. The percentages of non-susceptibility to trimethoprim-sulfamethoxazole and tetracycline were very high in Kuwait and UAE (76% vs. 92% and 76% vs. 98%, respectively). Notably, one isolate, S. flexneri, from UAE had reduced susceptibility to ciprofloxacin (MIC, 0.25 microg/ml). Four (2.8%) of the isolates were ESBL producers by the E test ESBL method but could not be confirmed by PCR using primers for bla(CTX-M), bla(SHV) and bla(TEM). In conclusion, Shigella spp. isolated from symptomatic patients in Kuwait and the UAE demonstrated high rates of resistance to the first-line antibiotics but very susceptible to the carbapenems, cephalosporins, fluoroquinolones and tigecycline. Tigecycline holds promise as a potential drug of choice for the therapy of severe shigellosis. PMID- 20701890 TI - An unusual case of myiasis. AB - Myiasis-the feeding of fly larvae on living mammals, may have various clinical presentations depending on the tissues or organs involved. Myiasis is a common travel associated skin disorder as a consequence of short visits to developing countries. It is the fourth most common travel associated disease. The most common clinical manifestations of fly larvae infestation include inflammatory and allergic reactions. Ear, eye and respiratory tract infestations are not uncommon and the human botfly Dermatobia hominis is the most recognised causative organism. We present an unusual case report of a myiasis in the upper lip of a patient admitted under the maxillofacial team at South Manchester Hospital. PMID- 20701891 TI - Prevention or treatment: the benefits of Trichomonas vaginalis vaccine. AB - Trichomoniasis (infection with Trichomonas vaginalis) is the most common non viral sexually transmitted disease (STI) in the world. Although treatment is available, most cases occur in developing countries, where accessing healthcare is difficult and facilities are limited. Additionally, infection is often asymptomatic and as such goes untreated, creating reservoirs of T. vaginalis that allow the disease to spread within the community. Because of this there has been little success in controlling the incidence of trichomoniasis, especially amongst the underprivileged. The development of a vaccine against T. vaginalis could reduce the human costs (pregnancy complications, infertility), medical costs (repeated doctor visits, increased susceptibility to human immunodeficiency virus (HIV) infection), and societal costs (stigma of STI, cycles of untreated infection) associated with trichomoniasis. PMID- 20701892 TI - Studies on West Nile virus infection in Egypt. AB - We conducted a prospective cohort study to determine prevalence and incidence of West Nile virus (WNV) in Egypt. Cohorts were established in Upper (UE), Middle (ME), and Lower (LE) Egypt. Additionally, a cross-sectional serosurvey was performed in the North (NS) and South (SS) Sinai. Cohorts were bled initially and 1 year later. Sera were tested for WNV-IgG by ELISA and positive sera were confirmed by plaque reduction neutralization test (PRNT). Sentinel chicken flocks placed in the above sites were bled monthly for virus isolation and serology. Mosquitoes were collected monthly from the above sites and tested for WNV. Human seroprevalence rates were 35%, 27%, 14%, 1% and 7% in UE, ME, LE, NS and SS, respectively. Seroconversion rates were 18%, 17% and 7% in UE, ME and LE, respectively; 49% of the seroconverters reported undiagnosed febrile illness. Sentinel chickens showed seroconversion in all study sites. WNV was isolated from both sentinel chickens and mosquitoes in cohort sites. This study demonstrates that WNV was actively circulating during the study period in different areas in Egypt and causing febrile illness in a considerable proportion of individuals in the study sites. PMID- 20701893 TI - Antimicrobial resistance in clinical isolates of Streptococcus pneumoniae in a tertiary hospital in Kuwait, 1997-2007: implications for empiric therapy. AB - OBJECTIVE: This study evaluated antibiotic resistance trends in Streptococcus pneumoniae isolated in a tertiary hospital in Kuwait and its implications for empiric therapy. MATERIALS AND METHODS: Antimicrobial susceptibility of 1353 strains of S. pneumoniae isolated from clinical specimens during 1997-2007 was performed by disc diffusion method. MIC was determined by E test. The results were compared for 1997-2001, 2002-2005 and 2006-2007. RESULTS: The prevalence of resistance for the respective periods were as follows: penicillin, 51.3%, 61.3% and 54.5%; erythromycin, 31.2%, 36.7% and 37.7%; tetracycline, 30.8%, 45.3% and 41.3%; co-trimoxazole, 49.5%, 58.5% and 62.8%; clindamycin, 20.4%, 20.6% and 24.5% and chloramphenicol, 8.1%, 8.9% and 3.7%. All were susceptible to vancomycin and rifampicin. For oxacillin-resistant isolates, penicillin resistance was rare (0.8%) with the new non-meningeal breakpoint. However, using the meningeal breakpoints, resistance increased for penicillin from 0.6%, to 28.7%, for cefotaxime from none to 16.5%, and for ceftriaxone from none to 7%. Intermediate resistance to meropenem increased from 1.7% to 22.4%. Multiple drug resistance increased from 22.4% to 37.8%. CONCLUSION: The study demonstrated that antimicrobial resistance of S. pneumoniae is increasing in Kuwait. However, the results of MIC determinations indicated that penicillin can still be used for therapy of non-meningeal infections. High prevalence of erythromycin resistance suggests that therapy of pneumonia with a macrolide alone may result in failure and should be based on results of susceptibility testing. PMID- 20701894 TI - Evaluation of a school-based program for diagnosis and treatment of latent tuberculosis infection in immigrant children. AB - OBJECTIVE: To evaluate a 10-year school-based latent tuberculosis infection (LTBI) screening program, targeting immigrant children in Montreal, Canada, and to identify predictive factors for refusal and, poor adherence to treatment. METHODS: Immigrant children were screened for LTBI with Tuberculin Skin Test (TST). Isoniazid was, given when LTBI was diagnosed. Predictors of LTBI, of refusal of follow-up and treatment and of poor, adherence to isoniazid were analyzed. RESULTS: Four thousand three hundred and seventy-five children were offered screening, 82.3% consented to TST and 22.8% were positive. An, older age at migration (odds ratio (OR)=1 [95% CI: 1.0-1.01]), as well as migration from a none, established market economy country (OR varying from 2.41 to 4.23) were significantly associated with, positive TST. Among positive children, further evaluation was refused in 5.7%, mainly in migrants from, Eastern Europe (OR=4.05 [95% CI: 2.14-7.69]). Refusal of treatment (11.2%) was more frequent in, Eastern European when compared to South-eastern Asian (OR=6.91 [95% CI: 1.56-30.75]), in, blended families (OR=3.25 [95% CI: 1.25-8.46]) and when the first visit to hospital was delayed (OR=1.01 [95% CI: 1.0-1.02]). Adequate completion of treatment was noted in 61.3%. Age>16 years (OR=1.82 [95% CI: 1.82-2.99]), a delay between TST and first visit>15 days (OR=1.6 [95% CI: 1.12-2.28]), as well as the presence of relative>18 years in the household (OR=1.56 [95% CI: 1.0-2.43]), were associated with poor adherence to treatment. CONCLUSION: Sociocultural and behavioural factors are involved in acceptance of LTBI treatment in, immigrant children. Adherence to treatment is challenging and requires comperhension of sociocultural beliefs and accessibility to TB clinic. PMID- 20701895 TI - Prevalence of periodontal bacteria in saliva of Kuwaiti children at different age groups. AB - Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Tannerella forsythensis and Porphyromonas gingivalis and to a lesser extent Prevotella intermedia and Prevotella nigrescens, are Gram-negative species that are associated with destructive periodontitis. Studies from different parts of the world have shown variable detection rates of periodontal organisms. Hardly any data exist on their carriage in children living in the Middle East. This study was designed to determine the detection of these species in the oral cavity of 240 generally healthy Kuwaiti children, divided into five age groups: <6 years (n=40), 6-9 years (n=60), 10-12 years (n=40), 13-15 years (n=40) and 16-18 years (n=60). Saliva was used as the microbiological specimen, and the samples were analyzed by molecular methods using multiplex PCR. A total of 185 (77.1%) of the 240 children were colonized by at least one of the target periodontal bacteria. In all age groups, P. nigrescens was the most prominent and detected in saliva of 15%, 32%, 63%, 50%, and 47% of the children at the five age groups, respectively. P. gingivalis was detected only occasionally. Only few pathogens were found before the permanent dentition, i.e. at the age of <6 years. The highest carriage rates were from the groups between 6 and 15 years of age. The salivary carriage of the pathogens was essentially similar in the age groups of 10-12 years and 13 15 years. In conclusion, except for P. gingivalis, the examined periodontal pathogens are relatively common findings in Kuwaiti children and colonize the oral cavity from childhood onwards. PMID- 20701896 TI - Role of neostigmine and polyvalent antivenom in Indian common krait (Bungarus caeruleus) bite. AB - Bungarus caeruleus (Indian common krait) bite during monsoons is common in Northwest India. This study was undertaken to find the effectiveness of neostigmine and polyvalent antivenom in improving neuromuscular paralysis following bite. All the consecutive patients admitted between June 2007 and December 2008 with common krait bite, identified either from brought snake or circumstantial evidence were studied. Ten vials of polyvalent antivenom and three doses of 2.5 mg neostigmine at 30 min intervals after administration of 0.6 mg of atropine were administered I.V. and patients were assessed for any improvement in neuroparalysis. Seventy-two patients were admitted during the study period. All the patients except two came from rural areas and were brought between June and September. Sixty-two patients were bitten during the day while clearing bricks, cutting grass or walking. The mean time interval between bite and arrival to hospital was 4.5 h. None of the patients showed any improvement following treatment and all patients developed respiratory paralysis, requiring assisted ventilation. Seventy survived and two died. Neostigmine is ineffective in reversing or improving neuroparalytic features in patients with B. caeruleus bite even at higher dose than normally recommended. PMID- 20701897 TI - Risk of blood-borne infections in barber shops. PMID- 20701898 TI - Neural activation for conceptual identification of correct versus incorrect tool object pairs. AB - Appropriate tool-object pairing is a natural part of our lives. When preparing to clean our teeth, we know that a toothbrush is useful, but not a screwdriver. The neural correlates of this pairing process remain unclear. We recorded 64-channel electroencephalography to determine neural correlates of identification of tool object matches and mismatches. Subjects were shown a target tool (e.g. spoon) later paired with an object that was either a conceptual match (e.g. bowl) or mismatch (e.g. wood). To verify that activity was not related to general concept of match-mismatch, in a second condition subjects saw non-tool environmental items (e.g. bird) later paired with a conceptual match (e.g. nest) or mismatch (e.g. spider web). Analysis was focused on time bins after each picture, using standardized low-resolution brain electromagnetic tomography (sLORETA). Tool object match versus mismatch revealed significant differences in the posterior cingulate, precuneus, left insula and superior temporal gyrus. These patterns were not present for environmental match versus mismatch. This work suggests a specific network in comprehending tool-based pairings, but not extensive to other pairings. The posterior cingulate, precuneus, insula and superior temporal gyrus preferentially differentiates tool-object matching and mismatching, identifying a potential locus related to impairments in comprehending appropriate and inappropriate tool-object relationships that arise after neural injury. PMID- 20701899 TI - Further studies on the composition and structure of a fucoidan preparation from the brown alga Saccharina latissima. AB - The polysaccharide composition of a fucoidan preparation isolated from the brown alga Saccharina latissima (formerly Laminaria saccharina) was reinvestigated. The preparation was fractionated by anion-exchange chromatography, and the fractions obtained were analyzed by chemical methods combined with NMR spectroscopy. Several 2D procedures, including HSQC, HMQC-TOCSY, and HMQC-NOESY, were used to obtain reliable structural information from the complex spectra, and the signal assignments were additionally confirmed by comparison with the literature spectra of the related polysaccharides and synthetic oligosaccharides. In accordance with the previous data, the main polysaccharide component was shown to be a fucan sulfate containing a backbone of 3-linked alpha-l-fucopyranose residues sulfated at C-4 and/or at C-2 and branched at C-2 by single sulfated alpha-l-fucopyranose residues. In addition, three other types of sulfated polysaccharide molecules were detected in the total fucoidan preparation: (i) a fucogalactan having a backbone of 6-linked beta-d-galactopyranose residues branched mainly at C-4 and containing both terminal galactose and fucose residues; (ii) a fucoglucuronomannan having a backbone of alternating 4-linked beta-d glucopyranosyluronic acid and 2-linked alpha-d-mannopyranose residues with alpha l-fucopyranose residues as single branches at C-3 of alpha-d-Manp; and (iii) a fucoglucuronan having a backbone of 3-linked beta-d-glucopyranosyluronic acid residues with alpha-l-fucopyranose residues as single branches at C-4. Hence, even a single algal species may contain, at least in minor amounts, several sulfated polysaccharides differing in molecular structure. Partial resolution of these polysaccharides has been accomplished, but unambiguous evidence on their presence as separate entities was not obtained. PMID- 20701900 TI - [Retroperitoneal fibromatosis with parietal and left inguinoscrotal extension]. PMID- 20701901 TI - [Charlson index and the surgical risk scale in the analysis of surgical mortality]. AB - INTRODUCTION: There is controversy over how to assess surgical mortality risks after different operations. The purpose of this study was to assess the surgical factors that influenced surgical mortality and the ability of the Charlson Index and The Surgical Risk Scale (SRS) to determine low risk patients. MATERIAL AND METHODS: All patients who died during the period 2004-2007 were included. The score of both indices (Charlson and SRS) were recorded. A score of "0" for the Charlson Index and "8" for the SRS were chosen as the cut-off point between a low and high probability of death. Three risk groups were established: Low when the Charlson was =0 and SRS was <8; Intermediate when the Charlson was >0 and the SRS <8 or Charlson=0 and SRS >=8; and high when the Charlson was>0 and the SRS >=8. The risks factors before, during and after surgery were compared between the groups. RESULTS: A total of 72,771 patients were surgically intervened, of which 7011 were urgent. One in every 1455 patients died during surgery and 1 in every 112 died during their hospital stay. Thirteen (2%) patients who died belonged to the low risk group, 199 (30.7%) to the intermediate risk group, and 434 (67.2%) to the high risk group. Heart disease was associated with the high risk group. The urgency of the operation was a determining factor associated with surgical complexity. Re-intervention and sepsis predominated as a cause of death in the low risk group, and in the rest of the groups a cardiac cause was the predominant factor. CONCLUSIONS: The combination of the Charlson Index and SRS detected those patients with a low risk of death, thus making it a useful tool to audit surgical results. PMID- 20701902 TI - [Efficacy, safety and comfort of compression therapy models in the immediate post operative period after a greater saphenectomy. A prospective randomised study]. AB - INTRODUCTION: There is still controversy on the best compression therapy after performing a greater saphenectomy. The purpose of this study is to establish whether the use of a controlled compression stocking has the same level of safety and efficacy as a compression bandage in the immediate post-operative period after a greater saphenectomy. MATERIAL AND METHODS: A prospective, randomised, open-labelled study, comparing three groups: a) a conventional compression bandage for one week, b) a conventional compression bandage replaced by a controlled tubular compression stocking at 5h of its putting in place, c) immediate direct use of the controlled tubular compression stocking, was conducted on fifty-five consecutive outpatients with a greater saphenectomy in one of their legs, and who fulfilled the inclusion criteria. The working hypothesis was that the controlled tubular compression stocking could replace, in terms of efficacy, safety and comfort, the usual controlled compression in the immediate post-operative period after saphenous vein stripping. The analysis variables were pain, control of bleeding, analgesics in the post-operative period, bruising, incapacity during the first week after the operation and comfort level. RESULTS: There were no statistically significant differences found between the three types of compressions studied as regards, safety, efficacy, comfort level, pain and analgesic consumption, but there was as regards the level of convenience in favour of the use of the stocking. CONCLUSION: The controlled tubular compression stocking can replace the compression bandage with more advantages after greater saphenous vein stripping in outpatients, having the same safety and efficacy. PMID- 20701903 TI - [Resident training in breast surgery]. PMID- 20701904 TI - Early life environment, neurodevelopment and the interrelation with atopy. AB - Both neurological and immunological systems are vulnerable to early life exposures. Neurological disorders and atopy have been related in animals and humans. Our main objective was to assess whether multiple exposures to early life determinants remain associated with neurodevelopment after considering the potential intermediate role of atopy. A second objective was to assess whether genes associated with atopy may inform about the potential neurotoxical mechanisms. Children were members of the AMICS birth cohort in Menorca (n=418, 87% of the recruited). General cognition was measured with the McCarthy Scales at age 4 and atopy through specific IgE at age 4 and prick test at age 6; 85 single nucleotide polymorphisms (SNPs) in 16 atopy and detoxification genes were genotyped. Among the 27 risk factors assessed, lower maternal social class, maternal smoking during pregnancy, being first born, shorter breastfeeding, higher DDT levels in cord blood, and higher indoor levels of NO2 (among the non detoxifiers by GSTP1 polymorphism) were independently associated with poorer cognition. These associations were apparently not mediated by the relation between atopy and general cognition. Among the candidate atopic genes, variants in NQ01 (a detoxification gene) and NPRS1 (related with affective disorders like anxiety and stress management) had a significant association with general cognition (p-value<0.001). However, adjustment for the corresponding SNPs did not change the association between the early life determinants and general cognition. Multiple environmental pre-natal exposures were associated with neurodevelopment independently of their role in the immunological system. Atopic genes related to neurodevelopment suggest some potential mechanisms. PMID- 20701905 TI - Five mutations of mitochondrial DNA polymerase-gamma (POLG) are not a prevalent etiology for spontaneous 46,XX primary ovarian insufficiency. AB - The study objective was to determine if mutations in mitochondrial DNA polymerase gamma (POLG) are associated with spontaneous 46,XX primary ovarian insufficiency (sPOI) using restriction fragment length polymorphism analysis of genomic DNA. Of 201 women with 46,XX sPOI analyzed, we found only one case (0.5%, 95% confidence interval 0-3%) of heterozygosity for a POLG mutation, suggesting that this is not a common genetic etiology for this form of infertility. PMID- 20701906 TI - Ischemia-modified albumin and cardiovascular risk markers in polycystic ovary syndrome with or without insulin resistance. AB - The aim of this study was to evaluate ischemia-modified albumin levels (IMA) in polycystic ovary syndrome (PCOS) cases with and without insulin resistance and the correlation of IMA with carotid intima media thickness, homocysteine, and high-sensitivity C-reactive protein levels. Significantly higher levels of IMA in young lean PCOS cases, more relevant in insulin resistant cases, indicates chronic hypoxia and oxidative stress which might play a role in the metabolic consequences in PCOS. PMID- 20701907 TI - Ovarian stimulation, in vitro fertilization, and effects of culture conditions on baboon preimplantation embryo development. AB - OBJECTIVE: To evaluate the effects of ovarian stimulation and intracytoplasmic sperm injection (ICSI)-induced fertilization and efficacy of various culture systems on in vitro development of baboon embryos. DESIGN: In vitro study, animal model. SETTING: Research laboratory. ANIMAL(S): Baboons in laboratory animal research facility. INTERVENTION(S): Baboons received FSH (75 IU daily) for 7 to 8 days and FSH/LH (75/75 IU daily) for 3 days, followed by hCG (2,000 IU). Oocytes were retrieved laparoscopically 36 hours after hCG. Intracytoplasmic sperm injection was performed on metaphase II (MII) oocytes. Fertilized embryos were placed into different culture conditions and feeder cell coculture. Embryo development was observed through the most advanced stages, including blastocyst formation. MAIN OUTCOME MEASURE(S): Oocytes retrieved, fertilization rates, multicell embryo rates, and blastocyst rates. RESULT(S): Baboon oocytes (n = 1,924, from 49 cycles) were retrieved. Significant heterogeneity was seen in ovarian response to exogenous gonadotropins and subsequent oocyte maturation. The percentage of MII oocytes showed no significant difference among individual female baboons and stimulation cycles. Nearly two thirds of MII oocytes were successfully fertilized with ICSI. Blastocyst rates varied significantly among embryos in different treatments. Coculture with feeder cells in P1/Blast, Quinn's Advantage, and Sydney IVF media generated better blastocyst rates. CONCLUSION(S): We tested multiple media and feeder cell combinations to optimize culture conditions in baboon embryo culture and obtained a high blastocyst rate similar to those reported for rhesus monkey embryos cultured in vitro, but still lower than with assisted reproductive technologies in women. PMID- 20701908 TI - What is the utility of the Focused Assessment with Sonography in Trauma (FAST) exam in penetrating torso trauma? AB - STUDY OBJECTIVE: A recent Cochrane Review has demonstrated that emergency ultrasonography decreases the amount of computerised tomographic scans in blunt abdominal trauma.13 However, there is no systematic review that has evaluated the utility of the Focused Assessment with Sonography for Trauma(FAST) exam in penetrating torso trauma. We systematically reviewed the medical literature for the utility of the FAST exam to detect free intraperitoneal blood after penetrating torso trauma. METHODS: We searched PUBMED and EMBASE databases for randomised controlled trials from 1965 through December 2009 using a search strategy derived from the following PICO formulation of our clinical question: PATIENTS: patients (12+ years) sustaining penetrating trauma to the torso. INTERVENTION: FAST exam during their initial trauma workup. Comparator: either local wound exploration (LWE),computerised tomography (CT), diagnostic peritoneal lavage (DPL), or laparotomy. OUTCOME: intraperitoneal and pericardial free fluid. The methodological quality of the studies was assessed.Qualitative methods were used to summarise the study results. ANALYSIS: Sensitivities and specificities were compared using a Forest Plot (95% CI) calculated by Revman 5 (Review Manager Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration,2008) between the FAST exam and definitive diagnostic modalities such as LWE, CT, DPL, or laporotomy. RESULTS: We identified eight observational studies (n=565 patients) that met our selection criteria. The prevalence of a positive FAST exam after penetrating trauma was fairly low ranging from 24.2% to 56.3%.The FAST exam for penetrating trauma is a highly specific (94.1-100.0%), but not very sensitive (28.1-100%) diagnostic modality. CONCLUSION: From the review of the literature, a positive FAST exam has a high incidence of intraabdominal injury and should prompt an exploratory laparotomy. However, a negative initial FAST exam after penetrating trauma should prompt further diagnostic studies such as LWE, CT, DPL, or laparotomy. PMID- 20701909 TI - On violations management: lessons from aviation. PMID- 20701910 TI - The timing of definitive fixation for major fractures in polytrauma--a matched pair comparison between a US and European level I centres: analysis of current fracture management practice in polytrauma. AB - PURPOSE: Early definitive stabilisation is usually the treatment of choice for major fractures in polytrauma patients. Modifications may be made when patients are in critical condition, or when associated injuries dictate the timing of surgery. The current study investigates whether the timing of fracture treatment is different in different trauma systems. MATERIALS AND METHODS: Consecutive patients treated a Level I trauma centre were documented (Group US) and a matched pair group was gathered from the German Trauma Registry (Group GTR). INCLUSION CRITERIA: New Injury Severity Score (NISS)>16, >2 major fractures and >1 organ/soft tissue injury. The timing and type of surgery for major fractures was recorded, as were major complications. RESULTS: 114 patients were included, n=57 Group US (35.1% F, 64.9% M, mean age: 44.1 yrs+/-16.49, mean NISS: 27.4+/-8.65, mean ICU stay: 10+/-7.49) and n=57 Group GTR (36.8% F, 63.1% M, mean age: 41.2 yrs+/-15.35, mean NISS: 29.4+/-6.88, mean ICU stay: 15.6+/-18.25). 44 (57.1%) out of 77 fractures in Group US received primary definitive fracture fixation compared to 61 (65.5%) out of 93 fractures in Group GTR (n.s.). The average duration until definitive treatment was comparable in all major extremity fractures (pelvis: 5 days+/-2.8 Group US, 7.1 days+/-9.6 Group GTR (n.s.), femur: 7.9 days+/-8.3 Group US, 5.5 days+/-7.9 (n.s.), tibia: 6.2 days+/-5.6 Group US, 6.2 days+/-9.1 Group GTR (n.s.), humerus: 5 days+/-3.7 Group US, 6.6 days+/-6.1 Group GTR (n.s.), radius: 6 days+/-4.7 Group US, 6.1 days+/-8.7 Group GTR (n.s.). CONCLUSION: The current matched-pair analysis demonstrates that the timing of initial definitive fixation of major fractures is comparable between the US and Europe. Certain fractures are stabilised internally in a staged fashion regardless the trauma system, thus discounting previous apparent contradictions. PMID- 20701911 TI - Children at risk of residual physical problems after public road traffic injuries -a 1-year follow-up study. AB - OBJECTIVES: To describe the residual physical problems 1 year after traffic injuries in children with respect to age, gender, extraction (Swedish or foreign), type of care, type of accident and use of protective equipment, type of injury, and the impact on daily living activities. METHODS: Hospital data were analysed for children, aged 15 or under, after road traffic accidents in the Gothenburg region in 2000. Age, gender, type of road user, counterpart, use of protective equipment, type and severity of each injury, and type of care were related to follow-up data obtained by a self-completed questionnaire answered 1 year after the accident. The AIS90 was used for injury classification. Residual physical problems were specified, graded, and mapped on anatomical pictures of the body by the respondents. Logistic regression was used to explore independent factors for residual problems. RESULTS: A total of 341 children (81%) fulfilled the study. Cyclists dominated, 60%, followed by moped users, car occupants and pedestrians. The mean age was 11 years, 61% were boys, 16% were of foreign extraction, 26% were treated as inpatients, and 11% had at least one serious (AIS3+) injury. Residual problems were reported for 16% of the study group (n=53), and of these 31% were located to the lower extremities (mostly knee problems), upper extremities in 20%, face in 14%, neck in 14%, upper trunk in 8%, lower trunk in 8%, and skull/brain in 3%. Significant permanent impairment was reported in one case. Cyclists reported problems significantly less frequently than others. Children reporting problems tended to be older and were most often injured as moped users. Problems to the neck and the upper trunk were reported to a higher rate than the injury rate in these regions. Children with residual problems reported limitations in daily living activities after the accident more often than those without residual physical problems. CONCLUSIONS: Residual physical problems were reported in about one sixth of the study group, few with serious problems. The risk of residual problems should be recognised in older children, especially after moped accidents, and also in children with neck problems. PMID- 20701912 TI - Hypochlorite-oxidized LDL induces intraplatelet ROS formation and surface exposure of CD40L--a prominent role of CD36. AB - OBJECTIVE: OxLDL represents a central player in atherogenesis and has been shown to activate human blood platelets. In light of the pivotal role of CD40L in inflammation, it was the aim of this work to clarify if platelet-activating effects of oxidized LDL result in surface exposure and liberation of CD40L and to explore the role of platelet scavenger receptor CD36 in this process. METHODS: Binding and functional studies were performed with hypochlorite-oxidized LDL in absence and presence of (potential) competitors in normal and CD36-deficient human platelets. To determine functional effects of hypochlorite-oxidized LDL on human platelets, formation of reactive oxygen species, intraplatelet calcium, CD40L and CD62P as well as platelet aggregation were quantified. RESULTS: Addition of OxLDL to resting human platelets results in intracellular calcium flux, platelet aggregation and surface expression of CD62P. OxLDL triggers the formation of intracellular reactive oxygen species and surface exposure of CD40L, with both being sensitive to the NADPH oxidase inhibitor apocynin. In CD36 deficient human platelets, functional effects as well as high affinity binding of hypochlorite-oxidized LDL appears to be significantly reduced compared with platelets positive for CD36. CONCLUSIONS: Our results prove a prominent--however, not exclusive--role of CD36 in platelet binding of hypochlorite-oxidized LDL. CD36 appears to be the major receptor responsible for hypochlorite-oxidized LDL induced platelet activation that accumulates in the release of CD40L. As platelets represent the major source of CD40L, our findings emphasize an important pro-inflammatory role of platelets, especially in conditions of oxidative stress. PMID- 20701914 TI - Influence of joint constraints on lower limb kinematics estimation from skin markers using global optimization. AB - In order to obtain the lower limb kinematics from skin-based markers, the soft tissue artefact (STA) has to be compensated. Global optimization (GO) methods rely on a predefined kinematic model and attempt to limit STA by minimizing the differences between model predicted and skin-based marker positions. Thus, the reliability of GO methods depends directly on the chosen model, whose influence is not well known yet. This study develops a GO method that allows to easily implement different sets of joint constraints in order to assess their influence on the lower limb kinematics during gait. The segment definition was based on generalized coordinates giving only linear or quadratic joint constraints. Seven sets of joint constraints were assessed, corresponding to different kinematic models at the ankle, knee and hip: SSS, USS, PSS, SHS, SPS, UHS and PPS (where S, U and H stand for spherical, universal and hinge joints and P for parallel mechanism). GO was applied to gait data from five healthy males. Results showed that the lower limb kinematics, except hip kinematics, knee and ankle flexion extension, significantly depend on the chosen ankle and knee constraints. The knee parallel mechanism generated some typical knee rotation patterns previously observed in lower limb kinematic studies. Furthermore, only the parallel mechanisms produced joint displacements. Thus, GO using parallel mechanism seems promising. It also offers some perspectives of subject-specific joint constraints. PMID- 20701913 TI - Receptor for advanced glycation endproducts mediates pro-atherogenic responses to periodontal infection in vascular endothelial cells. AB - OBJECTIVE: A link between periodontal infections and an increased risk for vascular disease has been demonstrated. Porphyromonas gingivalis, a major periodontal pathogen, localizes in human atherosclerotic plaques, accelerates atherosclerosis in animal models and modulates vascular cell function. The receptor for advanced glycation endproducts (RAGE) regulates vascular inflammation and atherogenesis. We hypothesized that RAGE is involved in P. gingivalis's contribution to pro-atherogenic responses in vascular endothelial cells. METHODS AND RESULTS: Murine aortic endothelial cells (MAEC) were isolated from wild-type C57BL/6 or RAGE-/- mice and were infected with P. gingivalis strain 381. P. gingivalis 381 infection significantly enhanced expression of RAGE in wild-type MAEC. Levels of pro-atherogenic advanced glycation endproducts (AGEs) and monocyte chemoattractant protein 1 (MCP-1) were significantly increased in wild-type MAEC following P. gingivalis 381 infection, but were unaffected in MAEC from RAGE-/- mice or in MAEC infected with DPG3, a fimbriae deficient mutant of P. gingivalis 381. Consistent with a role for oxidative stress and an AGE-dependent activation of RAGE in this setting, both antioxidant treatment and AGE blockade significantly suppressed RAGE gene expression and RAGE and MCP-1 protein levels in P. gingivalis 381-infected human aortic endothelial cells (HAEC). CONCLUSION: The present findings implicate for the first time the AGE-RAGE axis in the amplification of pro-atherogenic responses triggered by P. gingivalis in vascular endothelial cells. PMID- 20701915 TI - Experimental study of the depth influence on the band broadening effect in a cyclo-olefin polymer column containing an array of ordered pillars. AB - An experimental study of a micromachined non-porous pillar array column performance under non-retentive conditions is presented. The same pillar structure has been fabricated in cyclo-olefin polymer (COP) chips with three different depths via hot embossing and pressure-assisted thermal bonding. The influence of the depth on the band broadening along with the already known contribution arising from the top and bottom cover plates has been studied. The experimental results exhibit reduced plate heights as low as 0.2, which are in agreement with the previous experimental work. Moreover, the constant values of the reduced Van Deemter expression are also in accordance with the previous studies. A more exhaustive study of the C-term band broadening is also presented, showing that comparing the space between the pillars with different open tubular rectangular channels offers a good estimation of the C-term band broadening that is obtained experimentally. These experimental results, hence, confirm that micromachined pillar array columns fabricated in COP can achieve the same performance as the ones fabricated in silicon for the presently studied pillar channel design. PMID- 20701916 TI - Hyphenated technique for the extraction and determination of isoflavones in algae: ultrasound-assisted supercritical fluid extraction followed by fast chromatography with tandem mass spectrometry. AB - New hyphenated technique for the extraction and determination of isoflavones in sea and freshwater algae and cyanobacteria was developed. The method consists of sonication sample pretreatment, extraction by supercritical CO(2) modified by 3% (v/v) of MeOH/H(2)O mixture (9:1, v/v) at 35 MPa and 40 degrees C for 60 min, fast chromatography analysis by the means of Agilent 1200 Series Rapid Resolution and MS/MS determination. Agilent 1200 Series RRLC was used with Zorbax SB-CN chromatographic column (100 mm * 2.1mm, particle size 3.5 MUm), 3MUl injection volume, mobile phase consisting of 0.2% (v/v) acetic acid in water (solvent A) and acetonitrile (solvent B) and used with linear gradient (30% B at 0 min, from 0 min to 3 min up to 50% B, from 3 to 6 min up to 80% B and from 6 to 10 min down to 30% B). The flow-rate was 0.4 mL/min, column oven temperature 35 degrees C. MS detector Agilent Technologies 6460 Triple quadrupole LC/MS with Agilent Jet Stream was used in a negative ESI mode under following conditions: gas temperature 350 degrees C, gas flow 13 L/min, nebulizer gas pressure 50 psi, sheath gas temperature 400 degrees C, sheath gas flow 12L/min, capillary voltage was 4 kV. Samples were analysed in the multiple reaction monitoring (MRM) mode. Eight isoflavone compounds were found for the first time in seven real samples of sea algae and in three control samples of freshwater algae and cyanobacteria. Usual optimisation study of extraction parameters was performed. Pressure and temperature optima for algae matrix are different from those obtained sooner for other matrices for most of the analytes, but the results of modifier optimisation study are in good accordance with those obtained sooner for spiked samples and red clover matrix. It seems that matrix has very small or no effect on the modifier selection. Two different approaches of sonication pretreatment were tested: sonication bath and the thorn instrument. In longer extraction time experiments, thorn sonication was more efficient and recovery of following supercritical fluid extraction was higher. PMID- 20701917 TI - Application of mixed mode resins for the purification of antibodies. AB - The downstream processing of monoclonal antibodies from cell culture supernatant is usually done by a number of chromatographic and non-chromatographic steps. Efforts are taken to reduce the costs associated to those steps, while maintaining a high product purity. A possibility to reach this goal is the reduction of the number of chromatographic steps using mixed mode resins that offer more than one functionality in one chromatographic step. In this work, a commercially available mixed mode resin was evaluated systematically with respect to the adsorption of proteins. The Henry coefficient, which quantifies the adsorption strength, was measured for the full working range of the stationary phase as a function of the salt concentration and the pH. The results were compared to a conventional anion exchange and a hydrophobic interaction resin. Furthermore, the resin was applied for the polishing step of an antibody from an industrial clarified cell culture supernatant. PMID- 20701918 TI - Co dendrite based bimetallic structures with nanoflake-built Pt covers and strong catalytic activity. AB - Platinum-cobalt bimetallic structures have been synthesized in high yield via a galvanic replacement of Co dendrites in an aqueous K(2)PtCl(6) solution at room temperature. Increasing the K(2)PtCl(6) concentration results in different surface morphologies. Starting from furry coatings, a higher Pt/Co ratio leads to very rough surfaces built with upright standing nanoflakes, and finally a relatively smooth, cauliflower-like cover is obtained. The growth is discussed as the interplay of several mechanisms like the concentration driven nucleation, consumption of Co substrate, stoichiometry of the replacement reaction, and the electron transfer through the growing flakes. While the mono metallic structures are catalytically inactive towards the reduction of 4-nitrophenol by sodium borohydride, the catalytic activity of the bimetallic structures is quite high and optimized by a Pt atomic percentage of 27%. This indicates a catalytic role of the bimetallic interfaces. PMID- 20701919 TI - Using jet mixing to prepare polyelectrolyte complexes: complex properties and their interaction with silicon oxide surfaces. AB - The influence of mixing procedure on the properties of polyelectrolyte complexes (PECs) was investigated using two complexation techniques, polyelectrolyte titration and jet mixing, the latter being a new method for PEC preparation. For the low-molecular-weight polyelectrolytes polyacrylic acid (PAA) and polyallyl amine hydrochloride (PAH), shorter mixing times produced smaller PECs, whereas for higher molecular weights of the same polyelectrolytes, PEC size first decreased with decreasing mixing time to a certain level, after which it started increasing again. This pattern was likely due to the diffusion-controlled formation of "pre-complexes", which, in the case of low-molecular-weight polymers, occurs sufficiently quickly to form stable complexes; when polyelectrolytes are larger, however, non-equilibrium pre-complexes, more prone to aggregation, are formed. Comparing the techniques revealed that jet mixing produced smaller complexes, allowing PEC size to be controlled by mixing time, which was not the case with polyelectrolyte titration. Higher polyelectrolyte concentration during jet mixing led to the formation of larger PECs. It was also demonstrated that PEC size could be changed after preparation: increasing the pH of the PEC dispersion led to an irreversible increase in PEC size, whereas lowering the pH did not influence PEC size. The adsorption behavior of PECs formed from weak polyelectrolytes on model substrates was studied using QCM-D, SPAR, and AFM imaging; the results indicated that increasing the pH increased the amount of PECs adsorbed to model surfaces. However, the amount of PECs adsorbed to the model surfaces was low compared with other systems in all studied cases. PMID- 20701920 TI - Silicone oil emulsions stabilized by semi-solid nanostructures entrapped at the interface. AB - Oil-in-water (O/W) emulsions are typically stabilized using water-soluble surfactants, which anchor to the surface of oil droplets dispersed in an aqueous solution. The structure of the anchored surfactants is often susceptible to physical and chemical stresses because of their highly mobile properties. Here we introduce a new approach to prepare stable silicone oil emulsions under various external stresses using a water-insoluble amphiphilic block copolymer, poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL). Above the melting temperature (around 60 degrees C) of the hydrophobic segment (PCL), PEO-b-PCL can be dissolved in silicone oil. When the polymer/oil mixture is dispersed in water, PEO-b-PCL is irreversibly reorganized into solid nanostructures at the interface of the aqueous/organic phases. The resulting interfacial structures provide a robust physical barrier to the emulsion coarsening processes. Accordingly, the prepared emulsions exhibit excellent structural tolerance against external stresses, including variations in pH, ionic strength, and temperature. PMID- 20701921 TI - Insights into cyclodextrin-modulated interactions between protein and surfactant at specific and nonspecific binding stages. AB - Cyclodextrin (CD) modulated interactions between ionic surfactants with opposite charge and bovine serum albumin (BSA) at specific and nonspecific binding stages have been studied by isothermal titration calorimetry (ITC), fluorescence spectra and circular dichroism spectral measurements. At the specific binding stage with high affinity, the effectiveness of both alpha- and beta-CD for hindering BSA-SDS interactions is quite weak; however, CD is more effective in hindering BSA-CTAB specific interactions. This is due to the cooperative electrostatic and hydrophobic interaction between BSA and SDS, and to the absence of the cooperative interaction between BSA and CTAB at the specific binding stage. For both BSA-SDS and BSA-CTAB systems (especially in the former system), alpha-CD is more effective in hindering BSA-surfactant interactions than beta-CD. At the nonspecific binding stage, the addition of both alpha- and beta-CD can hinder totally both BSA-SDS and BSA-CTAB hydrophobic interactions. This is caused by the more specific hydrophobic interaction between CD and surfactant compared with the hydrophobic interaction between BSA and surfactant. Our results show that the CD effect on the protein-surfactant interaction depends on both the nature of the protein-surfactant interaction and the complexing ability of CD with surfactant. PMID- 20701922 TI - Effect of Au and Au@Ag core-shell nanoparticles on the SERS of bridging organic molecules. AB - Gold nanoparticles (AuNPs) with about 6 nm size were produced and stabilized with mercaptopropionic acid (MPA) film to produce a monolayer protected cluster (MPC) of AuS(CH(2))(2)COOH. 4-Aminothiophenol (ATP) molecules were introduced to the activated carboxylic acid ends of the film surrounding the AuNPs to produce AuS(CH(2))(2)CONHPhSH MPC. These modified AuNPs were again self-assembled with Au@Ag core-shell bimetallic nanoparticles via the -SH groups to produce an organic bridge between Au and Au@Ag metallic nanoparticles. An unusually strong enhancement of the Raman signals was observed and assigned to the plasmon coupling between the AuNPs and Au@Ag NPs bridged assembly. Formation of AuS(CH(2))(2)COOH and AuS(CH(2))(2)CONHPhSH clusters and AuS(CH(2))(2)CONHPhS(Au@Ag) assembly is confirmed by UV-Vis, reflection absorption IR spectroscopy (RAIRS) and X-ray photoelectron spectroscopy (XPS), as well as by TEM analysis. The SERS activity of the AuNPs and Au@Ag NPs was tested using the HS(CH(2))(2)CONHPhSH molecule as a probe to compare the effectiveness of monometallic and bimetallic systems. SERS spectra show that Au@Ag bimetallic nanoparticles are very effective SERS-active substrates. PMID- 20701923 TI - SANS study to probe nanoparticle dispersion in nanocomposite membranes of aromatic polyamide and functionalized silica nanoparticles. AB - Silica nanoparticles produced from organically functionalized silicon alkoxide precursors were incorporated into polyamide film to produce a silica-polyamide nanocomposite membrane with enhanced properties. The dispersion of the silica nanoparticles in the nanocomposite membrane was characterized by performing small angle neutron scattering (SANS) measurements on dilute reactant systems and dilute solution suspensions of the final product. Clear scattering of monodisperse spherical particles of 10-18 A R(g) were observed from dilute solutions of the initial reactant system. These silica nanoparticles initially reacted with diamine monomers of polyamide and subsequently were transformed into polyamide-coated silica nanoparticles; finally nanoparticle aggregates of 27-45 A R(g) were formed. The nanoparticle dispersion of the membrane as the nanosized aggregates is in corroboration with ring- or chain-like assemblies of the nanoparticles dispersed in the bulk polyamide phase as observed by transmission electron microscopy. It is demonstrated that dispersions of silica nanoparticles as the nanosized aggregates in the polyamide phase could be achieved in the nanocomposite membrane with a silica content up to about 2 wt.%. Nanocomposite membranes with higher silica loading approximately 10 wt.% lead to the formation of large aggregates of sizes over 100 A R(g) in addition to the nanosized aggregates. PMID- 20701924 TI - Time evolution of the thermotropic behavior of spontaneous liposomes and disks of the DMPC-DTAC aqueous system. AB - In this work, solubilization of the phospholipid 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) by the cationic detergent n-dodecyltrimethylammonium chloride (DTAC) was studied in aqueous solution, at a fixed DMPC concentration and variable detergent:lipid (D:L) molar ratios. The colloidal nanostructures present in different stages of the solubilization process were characterized using micro-differential scanning calorimetry (DSC) and dynamic light scattering (DLS) techniques. For total (analytical) D:L molar ratios below approximately 1, DTAC monomers incorporate into the DMPC liposome bilayers, forming smaller and more fluid vesicles than pure DMPC liposomes. At D:L approximately 1-2, vesicles begin to rupture, coexisting with intact vesicles and bilayer fragments. At D:L approximately 2-12.5, discoidal and spherical micelles are formed and coexist with vesicles; a slow structural rearrangement of the system, monitored in successive DSC heating/cooling cycles, was observed, and is reported for the first time. Finally, for D:L above approximately 15-20, the bilayers are completely dissolved, and the main aggregates in solution become spherical micelles, which slowly evolve to cylindrical (threadlike) micelles. Based on the dependence of the temperature and enthalpy of transitions on the total D:L molar ratio, at constant DMPC concentration, a schematic model, showing the different colloidal nanostructures present in the solubilization process, is proposed. PMID- 20701925 TI - The volume-outcomes relationship for United States Level I trauma centers. AB - BACKGROUND: Previous studies of the center volume-outcomes relationship for severe trauma care have yielded conflicting findings regarding the presence or nature of such a relationship. Few studies have confined their analysis to Level I centers. METHODS: We performed a retrospective analysis of severely injured adults treated from 2001 through 2006 in United States Level I trauma centers using data from the National Trauma Data Bank version 7.1. The post-injury in hospital mortality rates for patients treated at high- or medium-volume Level I trauma centers were compared with the rates for patients treated at low-volume Level I centers before and after adjustment for patient demographic and injury characteristics. Subgroup comparisons were performed for those Level I centers with and without American College of Surgeons (ACS) verification of Level I designation. RESULTS: Overall, medium-volume Level I trauma centers had significantly lower mortality than low-volume centers (14.3% versus 15.6%), both before and after adjustment for patient demographic and injury characteristics. Of those trauma centers without ACS verification of Level I designation, high volume centers had significantly greater mortality than low-volume centers. CONCLUSIONS: Our findings support the current utilization by the American College of Surgeons of minimum annual volume requirements for the verification of Level I trauma center designation, and suggest that the presence of such verification may enable Level I centers to effectively manage high volume of severely injured adult patients. PMID- 20701926 TI - The Simple Prognostic Index (SPI)--a pathophysiologic prognostic scoring tool for emergency laparotomy. AB - BACKGROUND: Laparotomy is commonly performed as an emergency operation. It is often performed on elderly patients with high risks of mortality and morbidity. Currently, there is no accurate scoring system to predict mortality and morbidity, preoperatively, in these circumstances. This study was conducted to develop a scoring system that can accurately predict the risk of in-hospital mortality and complications for these patients in the emergency department prior to surgery. PATIENTS AND METHODS: Middlemore Hospital data were searched for patients who underwent emergency laparotomy for an acute abdominal condition between January 1997 and December 2006. Data collected included age, gender, presenting diagnosis, indications for surgery, acute physiologic parameters, and also data on associated comorbidities. We categorized patients for the risk of morbidity and 30-d mortality. The risk categorization was based on preoperative existing comorbidities and acute disturbances of physiologic parameters. Regression analysis was used to correlate between acute laboratory parameters, patients age and gender, clinical premorbid conditions, and surgical procedures with the risk of mortality and rates of complications. RESULTS: Emergency laparotomy was performed on 1712 patients. The median age was 58 and there were 896 male patients. Patients with one or two minor comorbidities had comparable mortality and complication rate to those with no comorbidities. There was high correlation between factors that denoted the onset of multiple organ failure with in-hospital mortality and complication rates. This allowed us to divide patients into four prognostic groups with increasing mortality and morbidity. CONCLUSIONS: Mortality and morbidity after emergency laparotomy are closely related to the presence or absence of acute physiologic impairment and the presence or absence of chronic organ system failure. The Simple Prognostic Index (SPI) is a simple scoring system for prediction of mortality and morbidity prior to emergency laparotomy. PMID- 20701927 TI - Changes in the mechanical and biochemical properties of aortic tissue due to cold storage. AB - BACKGROUND: Temporary cold storage is a common procedure for preserving tissues for a short time before using them in a clinical or experimental setting. The process of storing tissues at refrigeration or freezing temperatures can affect the mechanical properties of the tissue. Previous studies were limited to uniaxial tensile tests and did not have substantial explanations for what was structurally occurring in the tissue to account for the changes in mechanical properties. MATERIALS AND METHODS: This study involved biaxial tensile testing of bovine thoracic aortas that had been stored at common storage temperatures (4 degrees C, -20 degrees C, or -80 degrees C) for three different time points (48 h, 1 wk, or 3 wk). The slopes of the initial and stiff region of the stress strain curves were measured. The knee point of the stress-strain curves was also determined. Collagen content before and after storage was quantified using a Sircol collagen assay kit. RESULTS: The stored arteries showed decreased initial slope and increased stiff slope after 48 h of 4 degrees C refrigeration. The -20 degrees C and -80 degrees C storage conditions had similar initial slopes compared with the fresh ones but an increase in the stiff slope. There was also a significant shift of the knee point to a higher strain and stress. The soluble and insoluble collagen content decreased significantly due to storage but the percentage of cross-linked collagen was unchanged. CONCLUSIONS: Cold storage causes several changes in the mechanical properties due to structural and biochemical changes in the tissue. Overall, freezing protocols (either -20 degrees C or -80 degrees C) are suggested over refrigeration (4 degrees C) for maintaining the initial stress-strain behavior. PMID- 20701928 TI - Crustacean assemblages in a polluted estuary from South-Western Spain. AB - The spatial-temporal variation in crustacean assemblages of the Odiel-Tinto estuary, one of the most polluted areas in the world, was studied in 2000, 2002 and 2004. The crustacean assemblages were mainly established according to the natural gradient from estuarine to marine environment (based on water and sediment characteristics such as dissolved oxygen, salinity, granulometry or organic content). Pollutants such as copper, zinc or phosphates could also explain partially this pattern based on BIOENV and canonical correspondence analyses. However, there were clear symptoms of perturbation, mainly in the inner areas, such as a low number of species and a low abundance, especially in relation to the typical estuarine species (e.g. Cyathura carinata, Corophium spp.). This study provides baseline information which can be used as a reference point in a long-term perspective. PMID- 20701929 TI - First health and pollution study on harbor seals (Phoca vitulina) living in the German Elbe estuary. AB - The Elbe is one of the major rivers releasing pollutants into the coastal areas of the German North Sea. Its estuary represents the habitat of a small population of harbor seals (Phoca vitulina). Only little is known about the health status and contamination levels of these seals. Therefore, a first-ever seal catch was organized next to the islands of Neuwerk and Scharhorn in the region of the Hamburg Wadden Sea National Park. The investigations included a broad set of health parameters and the analysis of metals and organic pollutants in blood samples. Compared to animals of other Wadden Sea areas, the seals showed higher gamma-globulin levels, suggesting higher concentrations of pathogens in this near urban area, elevated concentrations for several metals in particular for V, Sn, Pb, and Sr, and comparable ranges for chlorinated organic contaminants, except for elevated levels of hexachlorobenzene, which indicates characteristic inputs from the Elbe. PMID- 20701930 TI - Analysis of the reliability of a statistical oil spill response model. AB - A statistical oil spill response model is developed and validated by means of actual oil slick observations reported during the Prestige accident and trajectories of drifter buoys. The model is based on the analysis of a database of hypothetical oil spill scenarios simulated by means of a Lagrangian transport model. To carry out the simulations, a re-analysis database consisting of 44-year hindcast dataset of wind and waves and climatologic daily mean surface currents is used. The number of scenarios required to obtain statistically reliable results is investigated, finding that 200 scenarios provide an optimal balance between the accuracy of the results and the computational effort. The reliability of the model was analyzed by comparing the actual data with the numerical results. The agreement found between actual and numerical data shows that the developed statistical oil spill model is a valuable tool to support spill response planning. PMID- 20701931 TI - [Reduction of haemorrhagic risk in acute coronary syndromes]. PMID- 20701932 TI - [Factors related with the performance of a proper hand hygiene]. AB - OBJECTIVE: To identify factors related with the performance of a proper hand hygiene technique in a hand hygiene campaign. METHODS: We developed two cross sectional studies on 15 hospital units. The outcome variable was complied HH with proper technique and the exposures variables were care factors (unit, professional group, etc) and other factors related with the HH campaign (training on hand washing). STATISTICAL ANALYSIS: The strength of association was measured using odds ratios (OR) with their 95% confidence interval (CI). Adjusting for confounders was performed using multiple logistic regression. RESULTS: 12% of the observed 1241 hand hygiene were performed with proper technique. The strongest associated factors were ICUS (OR: 4.07 (CI 95% (1.95-8.51)), surgical wards (OR: 3.24 (CI 95% (1.52-6.92), procedures with high risk of contamination (OR: 2,56 CI 95% (1.34-4.70)), and physicians (OR: 2.52 CI 95% (0.93-6.85)). Training increased by 21% the probability of hand hygiene with proper technique for every 10% increase in trained health care workers (OR: 1.21 CI 95% (1.01-1.45). CONCLUSIONS: Hand Washing Training was associated with proper technique especially in surgical services and physicians. PMID- 20701933 TI - Convergent validity of a questionnaire for assessing physical activity in Spanish adolescents with overweight. AB - OBJECTIVE: To evaluate the convergent validity of the PAQ-A for assessing physical activity (PA) in overweight (including obese) adolescents. MATERIAL AND METHOD: Two hundred and three Spanish adolescents (96 females), aged 13-17 years, were selected for this study. Levels of PA were self-reported by 3-day activity diary, activity rating and PAQ-A. Adolescents wore the ActiGraph accelerometer for 7 days. Overweight was classified according to International Obesity Task Force age- and sex-specific body mass index cut offs. RESULTS: Fifty-four (33 male and 21 female) adolescents (27%) were classified as overweight or obese. The PAQ-A was moderately related in the overweight adolescent group to an activity rating (rho=0.52), total PA and moderate-to-vigorous PA assessed by activity monitor (rho=0.52 and 0.43) and total PA and moderate-to-vigorous PA assessed by activity diary (rho=0.32 and 0.47). There were no significant differences in the correlation coefficients between non-overweight and overweight adolescents. CONCLUSION: The PAQ-A shows a reasonable validity for assessing PA in Spanish overweight adolescents. PMID- 20701934 TI - Plants contain two distinct classes of functional tryptophan synthase beta proteins. AB - Tryptophan synthase beta-subunits (TSBs) catalyze the last step in tryptophan biosynthesis, i.e. the condensation of indole and serine yielding tryptophan. In microorganisms two subfamilies of TSBs (here designated as type 1 and type 2) are known, which are only distantly related. Surprisingly, in all genomes of multicellular plants analyzed genes encoding both types are present. While type 1 enzymes are well established as components of tryptophan synthase complexes, type 2 enzymes in plants have not yet been characterized. Tissue specific expression of the TSB genes from Arabidopsis thaliana was analyzed. While AtTSB1 is the predominantly expressed isoform in vegetative tissues, AtTSB1 and AtTSBtype2 reach similar transcript levels in seeds. AtTSBtype2 protein was expressed in Escherichia coli and purified. It converted indole and serine to tryptophan with a strikingly low K(m)-value for indole of ca. 74 nM. Attsbtype2 T-DNA insertion mutants showed no obvious deviation from the wild type phenotype, indicating that AtTSBtype2 function is not essential under standard growth conditions. As example for a monocot enzyme, maize TSBtype 2 was analyzed and found to be transcribed in various tissues. ZmTSBtype2 was also catalytically active and here a K(m)-value for indole of ca. 7 microM was determined. These data indicate that TSB type 2 enzymes generally are functionally expressed in plants. Their potential biological role is discussed. PMID- 20701935 TI - Two cytotoxic stereoisomers of malyngamide C, 8-epi-malyngamide C and 8-O-acetyl 8-epi-malyngamide C, from the marine cyanobacterium Lyngbya majuscula. AB - Two epimers of malyngamide C, 8-O-acetyl-8-epi-malyngamide C (1) and 8-epi malyngamide C (3) have been isolated along with known compounds 6-O acetylmalyngamide F (5), H (6), J (7) K (8), and characterized from a Grenada field collection of the marine cyanobacterium Lyngbya majuscula. The structures of these compounds were deduced by 1D and 2D NMR spectroscopic and mass spectral data interpretation. Absolute configurations were determined by a combination of CD-spectroscopy, chemical degradation and the variable temperature Mosher's method. Compounds 1-5, 7 and 8 displayed moderate cytotoxicity to NCI-H460 human lung tumor and neuro-2a cancer cell lines, with IC(50) values ranging between 0.5 and 20 microg/mL. PMID- 20701936 TI - Suppression of homodimerization of toll-like receptor 4 by isoliquiritigenin. AB - Toll-like receptors (TLRs) play important inductive roles in innate immune responses for host defense against invading microbial pathogens. Activation of TLR4 by lipopolysaccharide (LPS) induces dimerization of TLR4 and, subsequently, activation of downstream signaling pathways including nuclear factor-kappa B and interferon regulatory factor 3. TLR4 dimerization may be an early regulatory event in activating signaling pathways induced by LPS. Here, biochemical evidence is reported that isoliquiritigenin, one of the major ingredients derived from licorice root, inhibits LPS-induced TLR4 dimerization resulting in inhibition of nuclear factor-kappa B and interferon regulatory factor 3 activation, and cyclooxygenase-2 and inducible nitric oxide synthase expression. These results suggest that isoliquiritigenin modulates TLR-mediated signaling pathways at the receptor level. Furthermore, these results suggest that TLRs themselves may be important targets for the prevention of chronic inflammatory diseases. PMID- 20701937 TI - [Usefulness of magnetic resonance imaging in prostate cancer]. AB - In the last decade, technical advances in magnetic resonance imaging (MRI) have made it the technique of choice in the overall management of patients with suspected or confirmed prostate cancer. MR makes it possible to acquire information about morphology and function in the same examination by using techniques like spectroscopy, diffusion, and dynamic sequences with intravenous contrast material administration. Moreover, MRI enables both focused study of the prostate gland and of regional and/or whole-body involvement, depending on the clinical indications, in less than an hour. The main clinical indications for MRI of the prostate are a) staging local, regional, and/or remote disease; b) detecting prostate cancer or guiding prostate biopsy in cases of clinical suspicion or negative findings in previous biopsy specimens; and c) monitoring the response to treatment. It is important to know the different protocols with specific MRI sequences for the prostate, depending on the different clinical indications, to ensure that they are performed and interpreted correctly. This article provides up-to-date information about the use of MRI for the study of the prostate to show how the morphological and functional information can be used in clinical practice. PMID- 20701938 TI - Experimental infection of camels with bluetongue virus. AB - Three camels aged 4-5 years were experimentally infected with Bluetongue virus serotype 1 (BTV-1) and were observed for 75 days. No clinical signs of disease were observed throughout the experiment, however all three animals seroconverted and developed BTV-1 specific neutralising antibodies after challenge. All three camels developed a viraemia from 7 days post infection albeit at a lower level than that usually observed in experimental infections of sheep and cattle. Virus was isolated from the blood of all three animals suggesting that camels may act as a reservoir for BTV and play an important role in its transmission. PMID- 20701939 TI - Orbital lobular panniculitis in Weber-Christian disease: sustained response to anti-TNF treatment and review of the literature. AB - Weber-Christian disease is a febrile, relapsing, non-suppurative panniculitis of unknown etiology. Lobular panniculitis is the essential feature in biopsy specimens and evolves through three recognizable stages. We report a case of Weber-Christian disease with bilateral orbital involvement, at different stages, affecting the orbital fat along with enophthalmos in one orbit, and the upper preaponeurotic fat pad in the other. Weber-Christian disease was refractory to treatment with conventional immunosuppressive regimens; however, early inflammatory-but not chronic fibrotic-orbital lesions responded dramatically to anti-tumor necrosis factor (TNF) therapy. A literature review revealed five additional cases of orbital Weber-Christian disease, none treated with anti-TNF antibodies. Of these, four presented initially with proptosis, representing early stages of inflammation, and two subsequently developed enophthalmos, representing late, inactive stage of the disease. Although orbital Weber-Christian disease is rare, ophthalmologists need to be aware of this entity. Depending on the stage of inflammation, Weber-Christian disease should be included in the differential diagnosis of both proptosis and enophthalmos. Anti-TNF antibodies can successfully treat patients at the early inflammatory stage. PMID- 20701940 TI - Porcine reproductive and respiratory syndrome virus non-structural protein 1 suppresses tumor necrosis factor-alpha promoter activation by inhibiting NF kappaB and Sp1. AB - The objective of this study was to identify porcine reproductive and respiratory syndrome virus (PRRSV)-encoded proteins that are responsible for the inhibition of TNF-alpha expression and the mechanism(s) involved in this phenomenon. Using a TNF-alpha promoter reporter system, the non-structural protein 1 (Nsp1) was found to strongly suppress the TNF-alpha promoter activity. Such inhibition takes place especially at the promoter's proximal region. Both Nsp1alpha and Nsp1beta, the two proteolytic fragments of Nsp1, were shown to be involved in TNF-alpha promoter suppression. Furthermore, using reporter plasmids specific for transcription factors (TFs) that bind to TNF-alpha promoter, Nsp1alpha and Nsp1beta were demonstrated to inhibit the activity of the TFs that bind CRE kappaB(3) and Sp1 elements respectively. Subsequent analyses showed that Nsp1alpha moderately inhibits NF-kappaB activation and that Nsp1beta completely abrogates the Sp1 transactivation. These findings reveal one of the important mechanisms underlying the innate immune evasion by PRRSV during infection. PMID- 20701941 TI - A comparative analysis of the substrate permissiveness of HCV and GBV-B NS3/4A proteases reveals genetic evidence for an interaction with NS4B protein during genome replication. AB - The hepatitis C virus (HCV) serine protease (NS3/4A) processes the NS3-NS5B segment of the viral polyprotein and also cleaves host proteins involved in interferon signaling, making it an important target for antiviral drug discovery and suggesting a wide breadth of substrate specificity. We compared substrate specificities of the HCV protease with that of the GB virus B (GBV-B), a distantly related nonhuman primate hepacivirus, by exchanging amino acid sequences at the NS4B/5A and/or NS5A/5B cleavage junctions between these viruses within the backbone of subgenomic replicons. This mutagenesis study demonstrated that the GBV-B protease had a broader substrate tolerance, a feature corroborated by structural homology modeling. However, despite efficient polyprotein processing, GBV-B RNAs containing HCV sequences at the C-terminus of NS4B had a pseudo-lethal replication phenotype. Replication-competent revertants contained second-site substitutions within the NS3 protease or NS4B N-terminus, providing genetic evidence for an essential interaction between NS3 and NS4B during genome replication. PMID- 20701942 TI - Structure of a Venezuelan equine encephalitis virus assembly intermediate isolated from infected cells. AB - Venezuelan equine encephalitis virus (VEEV) is a prototypical enveloped ssRNA virus of the family Togaviridae. To better understand alphavirus assembly, we analyzed newly formed nucleocapsid particles (termed pre-viral nucleocapsids) isolated from infected cells. These particles were intermediates along the virus assembly pathway, and ultimately bind membrane-associated viral glycoproteins to bud as mature infectious virus. Purified pre-viral nucleocapsids were spherical with a unimodal diameter distribution. The structure of one class of pre-viral nucleocapsids was determined with single particle reconstruction of cryo-electron microscopy images. These studies showed that pre-viral nucleocapsids assembled into an icosahedral structure with a capsid stoichiometry similar to the mature nucleocapsid. However, the individual capsomers were organized significantly differently within the pre-viral and mature nucleocapsids. The pre-viral nucleocapsid structure implies that nucleocapsids are highly plastic and undergo glycoprotein and/or lipid-driven rearrangements during virus self-assembly. This mechanism of self-assembly may be general for other enveloped viruses. PMID- 20701943 TI - Roles of the respiratory syncytial virus trailer region: effects of mutations on genome production and stress granule formation. AB - The 5' extragenic trailer region of respiratory syncytial virus (RSV) is known to be necessary for genome replication, but is more than three times the length of the 3' leader replication promoter, raising the possibility that trailer might play an additional role in viral replication. To examine this, mutant recombinant viruses were constructed in which the trailer region was truncated or substituted with leader-complement sequence. This analysis showed that the complete trailer increased promoter activity, facilitating genome production and viral multiplication. In addition, trailer-containing viruses did not induce stress granules, whereas the leader-complement virus mutant did, resulting in poor multi cycle viral growth. These data demonstrate that although the RSV trailer does not contain a unique essential sequence, it augments virus growth by enabling optimal genome production. In addition, a sequence at the 5' terminal end of the trailer region allows RSV to subvert stress granule formation. PMID- 20701945 TI - Efficient recovery of nano-sized iron oxide particles from synthetic acid-mine drainage (AMD) water using fuel cell technologies. AB - Acid mine drainage (AMD) is an important contributor to surface water pollution due to the release of acid and metals. Fe(II) in AMD reacts with dissolved oxygen to produce iron oxide precipitates, resulting in further acidification, discoloration of stream beds, and sludge deposits in receiving waters. It has recently been shown that new fuel cell technologies, based on microbial fuel cells, can be used to treat AMD and generate electricity. Here we show that this approach can also be used as a technique to generate spherical nano-particles of iron oxide that, upon drying, are transformed to goethite (alpha-FeOOH). This approach therefore provides a relatively straightforward way to generate a product that has commercial value. Particle diameters ranged from 120 to 700 nm, with sizes that could be controlled by varying the conditions in the fuel cell, especially current density (0.04-0.12 mA/cm(2)), pH (4-7.5), and initial Fe(II) concentration (50-1000 mg/L). The most efficient production of goethite and power occurred with pH = 6.3 and Fe(II) concentrations above 200 mg/L. These results show that fuel cell technologies can not only be used for simultaneous AMD treatment and power generation, but that they can generate useful products such as iron oxide particles having sizes appropriate for used as pigments and other applications. PMID- 20701944 TI - Mechanistic interplay among the M184I HIV-1 reverse transcriptase mutant, the central polypurine tract, cellular dNTP concentrations and drug sensitivity. AB - We recently reported that the M184I 3TC resistant mutation reduces RT binding affinity to dNTP substrates. First, the HIV-1 M184I mutant vector displays reduced transduction efficiency compared to wild type (WT) RT vector, which could be rescued by both elevating the cellular dNTP concentration and incorporating WT RT molecules into the M184I vector particles. Second, the central polypurine tract (cPPT) mutation and M184I mutation additively reduced the vector transduction to almost undetectable levels, particularly in nondividing cells. Third, the M184I (-) cPPT vector became significantly more sensitive to 3TC than the M184I (+) cPPT vector, but not to AZT or Nevirapine in the dividing cells. Finally, this 3TC sensitizing effect of the cPPT inactivation of the M184I vector was reversed by elevating the dCTP level, but not by the other three dNTPs. These data support a mechanistic interaction between cPPT and M184I RT with respect to viral replication and sensitivity to 3TC. PMID- 20701946 TI - Monitoring associations between clade-level variation, overall community structure and ecosystem function in enhanced biological phosphorus removal (EBPR) systems using terminal-restriction fragment length polymorphism (T-RFLP). AB - The role of Candidatus "Accumulibacter phosphatis" (Accumulibacter) in enhanced biological phosphorus removal (EBPR) is well established but the relevance of different Accumulibacter clades to the performance of EBPR systems is unknown. We developed a terminal-restriction fragment length polymorphism (T-RFLP) technique to monitor changes in the relative abundance of key members of the bacterial community, including Accumulibacter clades, in four replicate mini-sequencing batch reactors (mSBRs) operated for EBPR over a 35-day period. The ability of the T-RFLP technique to detect trends was confirmed using fluorescence in situ hybridisation (FISH). EBPR performance varied between reactors and over time; by day 35, performance was maintained in mSBR2 whilst it had deteriorated in mSBR1. However, reproducible trends in structure-function relationships were detected in the mSBRs. EBPR performance was strongly associated with the relative abundance of total Accumulibacter. A shift in the ratio of the dominant Accumulibacter clades was also detected, with Type IA associated with good EBPR performance and Type IIC associated with poor EBPR performance. Changes in ecosystem function of the mSBRs in the early stages of the experiment were more closely associated with changes in the abundance of (unknown) members of the flanking community than of either Accumulibacter or Candidatus "Competibacter phosphatis". This study therefore reveals a hitherto unrecorded and complex relationship between Accumulibacter clades, the flanking community and ecosystem function of laboratory-scale EBPR systems. PMID- 20701947 TI - Improved strategies and optimization of calibration models for real-time PCR absolute quantification. AB - Real-time PCR absolute quantification applications are becoming more common in the recreational and drinking water quality industries. Many methods rely on the use of standard curves to make estimates of DNA target concentrations in unknown samples. Traditional absolute quantification approaches dictate that a standard curve must accompany each experimental run. However, the generation of a standard curve for each qPCR experiment set-up can be expensive and time consuming, especially for studies with large numbers of unknown samples. As a result, many researchers have adopted a master calibration strategy where a single curve is derived from DNA standard measurements generated from multiple instrument runs. However, a master curve can inflate uncertainty associated with intercept and slope parameters and decrease the accuracy of unknown sample DNA target concentration estimates. Here we report two alternative strategies termed 'pooled' and 'mixed' for the generation of calibration equations from absolute standard curves which can help reduce the cost and time of laboratory testing, as well as the uncertainty in calibration model parameter estimates. In this study, four different strategies for generating calibration models were compared based on a series of repeated experiments for two different qPCR assays using a Monte Carlo Markov Chain method. The hierarchical Bayesian approach allowed for the comparison of uncertainty in intercept and slope model parameters and the optimization of experiment design. Data suggests that the 'pooled' model can reduce uncertainty in both slope and intercept parameter estimates compared to the traditional single curve approach. In addition, the 'mixed' model achieved uncertainty estimates similar to the 'single' model while increasing the number of available reaction wells per instrument run. PMID- 20701948 TI - Aerobic treatment of N-nitrosodimethylamine in a propane-fed membrane bioreactor. AB - N-Nitrosodimethylamine (NDMA) is a suspected human carcinogen that has recently been detected in wastewater, groundwater and drinking water. Treatment of this compound to low part-per-trillion (ng/L) concentrations is required to mitigate cancer risk. Current treatment generally entails UV irradiation, which while effective, is also expensive. The objective of this research was to explore potential bioremediation strategies as alternatives for treating NDMA to ng/L concentrations. Batch studies revealed that the propanotroph Rhodococcus ruber ENV425 was capable of metabolizing NDMA from 8 MUg/L to <2 ng/L after growth on propane, and that the strain produced metabolites that do not pose a significant risk at the concentrations generated (Fournier et al., 2009). A laboratory-scale membrane bioreactor (MBR) was subsequently constructed to evaluate the potential for long-term ex situ treatment of NDMA. The MBR was seeded with ENV425 and received propane as the primary growth substrate and oxygen as an electron acceptor. At an average influent NDMA concentration of 7.4 MUg/L and a 28.5 h hydraulic residence time, the reactor effluent concentration was 3.0 +/- 2.3 ng/L (>99.95% removal) over more than 70 days of operation. The addition of trichloroethene (TCE) to the reactor resulted in a significant increase in effluent NDMA concentrations, most likely due to cell toxicity from TCE-epoxide produced during its cometabolic oxidation by ENV425. The data suggest that an MBR system can be a viable treatment option for NDMA in groundwater provided that high concentrations of TCE are not present. PMID- 20701949 TI - Kinetics and mechanisms of sulfate radical oxidation of beta-lactam antibiotics in water. AB - The quantitative removal of contaminant antibiotic activity from waters intended for reuse is one of the biggest problems facing water utilities today. As conventional water treatments are not sufficient, advanced Oxidation and Reduction Processes (AO/RPs) are being considered for additional remediation. In support of the potential use of sulfate radical based AO/RPs, we have determined the reaction rate constants for the sulfate radical with a large library of beta lactam antibiotics. The SO(4)(-)() reactivity with the five-member ring species was found to have an extrapolated zero ionic strength average rate constant of (1.6+/-0.9) x 10(9)M(-1)s(-1), slightly slower than for the six-member antibiotics at (2.1+/-0.6) x 10(9)M(-1)s(-1). Transient spectral studies indicated that the majority of these radicals reacted at the five- or six-member rings adjacent to the beta-lactam core, predominately at the sulfur atom and the double bond, respectively. As these oxidations occur next to the beta-lactam moiety, rather than at the peripheral aromatic rings observed for hydroxyl radical reaction, sulfate radical remediation through the use of added persulfate might result in more efficient antibiotic activity removal than when using a traditional AO/RP treatment. PMID- 20701950 TI - An estimate of phthalate exposure among pregnant women living in Trujillo, Peru. AB - Phthalates are a group of phthalic acid esters which are used as plasticizers and additives. In laboratory animals, several phthalates are known endocrine disruptors. Several studies have described phthalate exposure in the United States and developed countries but little is known about phthalate exposure in the developing world, particularly during pregnancy. To assess exposure to six different phthalates, we measured the concentrations of nine phthalate metabolites in spot urine samples collected during the first, second, and third trimester of pregnancy from a group of 72 women living in Trujillo, Peru. Additionally, women completed questionnaires to provide demographic characteristics. Statistical analysis via linear models was used to evaluate potential differences in the concentrations of phthalate metabolites by trimester, cooking fuel type, socioeconomic status, and education. All metabolites were detected in>40% of samples analyzed, and mono-n-butyl phthalate, mono (2-ethyl-5-carboxypentyl) phthalate, and monoethyl phthalate were found in>90% of samples. Five of nine unadjusted urinary metabolites and four of nine creatinine-adjusted urinary metabolites were significantly lower in this group of pregnant women living in Peru compared to pregnant women in the US general population. PMID- 20701951 TI - Studying associations between urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and cardiovascular diseases in the United States. AB - The association between background, enduring environmental exposure to polycyclic aromatic hydrocarbons (PAHs) and cardiovascular diseases has not been well studied in the general population. In this study, we used the National Health and Nutrition Examination Survey (NHANES) 2001-2004 to investigate the associations between eight monohydroxy PAHs (OH-PAHs) and self-report CVD. In a logistic regression model adjusting for cigarette smoking and other covariates, phenanthrene metabolite, 2-hydroxyphennathrene (2-PHEN), was significantly associated with self-report CVD. Compared to subjects within the lowest tertile of 2-PHEN, subjects within the middle and highest tertiles had higher self-report CVD (the 2nd tertile: AOR=1.29, 95%CI: 0.97-1.72; the 3rd tertile: AOR=1.45, 95%CI: 1.01-2.07; p for trend=0.04). In addition, fluorene metabolite (i.e. 2 hydroxyfluorene) also showed a marginally significant linear trend with self report CVD (p for trend=0.07). Further studies are necessary to explore the associations between these highly prevalent pollutants and CVD. PMID- 20701952 TI - Combined exposure to cyanobacterial biomass, lead and the Newcastle virus enhances avian toxicity. AB - Under environmental conditions, wild birds can be exposed to multiple stressors including natural toxins, anthropogenic pollutants and infectious agents at the same time. This experimental study was successful in testing the hypothesis that adverse effects of cyanotoxins, heavy metals and a non-pathogenic immunological challenge combine to enhance avian toxicity. Mortality occurred in combined exposures to naturally occurring cyanobacterial biomass and lead shots, lead shots and Newcastle vaccination as well as in single lead shot exposure. Mostly acute effects around day 10 were observed. On day 30 of exposure, there were no differences in the liver accumulation of lead in single and combined exposure groups. Interestingly, liver microcystin levels were elevated in birds co-exposed to cyanobacterial biomass together with lead or lead and the Newcastle virus. Significant differences in body weights between all Pb-exposed and Pb-non-exposed birds were found on days 10 and 20. Single exposure to cyanobacterial biomass resulted in hepatic vacuolar dystrophy, whereas co-exposure with lead led to more severe granular dystrophy. Haematological changes were associated with lead exposure, in particular. Biochemical analysis revealed a decrease in glucose and an increase in lactate dehydrogenase in single and combined cyanobacterial and lead exposures, which also showed a decreased antibody response to vaccination. The combined exposure of experimental birds to sub-lethal doses of individual stressors is ecologically realistic. It brings together new pieces of knowledge on avian health. In light of this study, investigators of wild bird die-offs should be circumspect when evaluating findings of low concentrations of contaminants that would not result in mortality on a separate basis. As such it has implications for wildlife biologists, veterinarians and conservationists of avian biodiversity. PMID- 20701953 TI - Complex nanominerals and ultrafine particles assemblages in phosphogypsum of the fertilizer industry and implications on human exposure. AB - Phosphogypsum (CaSO(4).2H(2)O), a by-product of phosphate-rock processing, contains high amounts of impurities such P(2)O(5), F, radioactive elements, organic substances, secondary nanominerals, and ultrafine particles (UFP) enriched in metals and metalloids. In this study, we examine phosphogypsum (PG) collected from abandoned fertilizer industry facility in south Brazil (Santa Catarina state). The fragile nature of nanominerals and UFP assemblages from fertilizer industry systems required novel techniques and experimental approaches. The investigation of the geochemistry of complex nanominerals and UFP assemblages was a prerequisite to accurately assess the environmental and human health risks of contaminants and cost-effective chemical and biogeological remediation strategies. Particular emphasis was placed on the study and characterization of the complex mixed nanominerals and UFP containing potentially toxic elements. Nanometer-sized phases in PG were characterized using energy dispersive X-ray spectrometer (EDS), field-emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscopy (HR-TEM) images. The chemical composition and possible correlations with morphology of nanominerals and UFP, as well as aspects of nanominerals and UFP, are discussed in the context of human health exposure, as well as in relation to management of the nanominerals and UFP in PG environments. PMID- 20701954 TI - Atypical neurologic complications in patients with primary Sjogren's syndrome: report of 4 cases. AB - BACKGROUND: Neurologic involvement occurs in approximately 25% of patients with primary Sjogren's syndrome. Manifestations are diverse and can affect the entire neuroaxis. Central nervous system dysfunction involves the brain as well as the spinal cord and may recur over time. Due to a variety of presentations, Sjogren's syndrome with neurologic involvement may be difficult to diagnose. METHODS: We report 4 cases of patients with primary Sjogren's syndrome who presented with atypical neurologic manifestations. RESULTS: The first case describes a patient with a pseudotumoral lesion. The second patient was a 54-year-old woman suffering from a multiple mononeuropathy. The third case describes a 66-year-old man whose primary Sjogren's syndrome presented as progressive multiple sclerosis, and the fourth case reports a 57-year-old woman patient suffering from myelitis along with progressive cognitive disorders. CONCLUSIONS: Neurologic impairment in Sjogren's syndrome is probably underestimated and the diagnosis is often delayed. Primary Sjogren's syndrome should be suspected in patients presenting with atypical clinical and radiologic neurologic manifestations. PMID- 20701955 TI - Validation of psoriatic arthritis diagnoses in electronic medical records using natural language processing. AB - OBJECTIVES: To test whether data extracted from full text patient visit notes from an electronic medical record would improve the classification of psoriatic arthritis (PsA) compared with an algorithm based on codified data. METHODS: From the >1,350,000 adults in a large academic electronic medical record, all 2318 patients with a billing code for PsA were extracted and 550 were randomly selected for chart review and algorithm training. Using codified data and phrases extracted from narrative data using natural language processing, 31 predictors were extracted and 3 random forest algorithms were trained using coded, narrative, and combined predictors. The receiver operator curve was used to identify the optimal algorithm and a cut-point was chosen to achieve the maximum sensitivity possible at a 90% positive predictive value (PPV). The algorithm was then used to classify the remaining 1768 charts and finally validated in a random sample of 300 cases predicted to have PsA. RESULTS: The PPV of a single PsA code was 57% (95% CI 55%-58%). Using a combination of coded data and natural language processing (NLP), the random forest algorithm reached a PPV of 90% (95% CI 86% 93%) at a sensitivity of 87% (95% CI 83%-91%) in the training data. The PPV was 93% (95% CI 89%-96%) in the validation set. Adding NLP predictors to codified data increased the area under the receiver operator curve (P < 0.001). CONCLUSIONS: Using NLP with text notes from electronic medical records improved the performance of the prediction algorithm significantly. Random forests were a useful tool to accurately classify psoriatic arthritis cases to enable epidemiological research. PMID- 20701956 TI - Clinical, radiologic, and therapeutic analysis of 14 patients with transverse myelitis associated with antiphospholipid syndrome: report of 4 cases and review of the literature. AB - OBJECTIVE: To analyze the clinical, radiologic, therapeutic, and developmental characteristics of transverse myelitis (TM) and antiphospholipid syndrome (APS). METHODS: We systematically searched English, Spanish, and Japanese articles on the subjects of TM and APS that had English abstracts in PubMed from 1966 to 2010. In addition, we reported on 4 patients with APS and TM that were treated by the Rheumatology Division of the Hospital das Clinicas da Faculdade de Medicina da Universidade in Sao Paulo, Brazil. RESULTS: Fourteen cases of patients with APS and TM were reviewed. The age of these patients ranged from 8 to 83, and cases of TM predominantly occurred among patients with primary APS (9/14). The clinical presentation of TM was characterized by effects on the thoracic spinal cord (9/14) that were associated with sphincter disturbances (8/14). The onset of symptoms was sudden in 8/14 cases, and the symptoms of myelitis were recurring in 3 cases. One case resulted in death. In most cases, treatment was based on corticosteroid pulse therapy (12/14), but some patients were treated with pulse cyclophosphamide (5/14), plasmapheresis (3/14), or rituximab (1/14). Generally, the therapeutic response was satisfactory, and complete improvement was seen in 9/14 patients. CONCLUSION: In light of the severe clinical presentation of TM and its morbidity and mortality, early diagnosis and aggressive treatment are vital for therapeutic success. We can verify the excellent therapeutic response, as we saw a complete improvement in 64% of patients. PMID- 20701957 TI - Growth-suppressing function of glypican-3 (GPC3) via insulin like growth factor II (IGF-II) signaling pathway in ovarian clear cell carcinoma cells. AB - OBJECTIVE: Ovarian clear cell carcinoma (CCC) is well known to be highly resistant to platinum-based chemotherapy. Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, is overexpressed in only CCC of epithelial ovarian carcinoma subtypes. The purpose of this study was to identify the role of GPC3 in ovarian CCC. METHODS: To evaluate the function of GPC3 in ovarian CCC cells, we generated an ovarian cancer cell line, KOC7C cells stably transfected with plasmids encompassing shRNA targeting GPC3 (shGPC cells), and compared cell growth and the colony-forming ability to control shRNA-transfected cells (shCon cells). RESULTS: We showed that shGPC3 cells significantly increased cell growth and the colony-forming potential compared with shCon cells in 1% serum containing medium with 100 ng/ml IGF-II. Furthermore, these effects were significantly attenuated by pretreatment with 1 MUM wortmannin (an inhibitor of PI3K/Akt). CONCLUSIONS: We have demonstrated for the first time the presence of elevated levels of GPC3 protein associated with cell growth inhibition in CCC cells. Our data suggest that GPC3 has the potential to become a novel therapeutic target for ovarian CCC patients. PMID- 20701958 TI - Laparoscopic nerve-sparing radical hysterectomy: description of the technique and patients' outcome. AB - OBJECTIVE: The radical hysterectomy type three can be accompanied by postoperative morbidity, such as dysfunction of the lower urinary tract with loss of bladder or rectum sensation. We describe the technique of laparoscopic nerve sparing radical hysterectomy and patient's outcome. METHODS: Thirty-two patients underwent laparoscopic nerve-sparing radical hysterectomy with pelvic lymphadenectomy. Both the hypogastric and the splanchnic nerves were identified bilaterally during pelvic lymphadenectomy. RESULTS: The median age of the patients was 52 years, and the average operating time was 221 min. There were no intraoperative or postoperative complications considering the nerve-spring radical hysterectomy. Postoperatively, in all patients spontaneous voiding was possible on the third postoperative day with a median residual urine volume of <50 ml. CONCLUSIONS: Laparoscopic identification (neurolysis) of the inferior hypogastric nerve and inferior hypogastric plexus is a feasible procedure for trained laparoscopic surgeons who have a good knowledge not only of the retroperitoneal anatomy but also of the pelvic neuro-anatomy as this qualification could prohibit long-term bladder and voiding dysfunction during nerve-sparing radical hysterectomy. PMID- 20701959 TI - Motor knowledge is one dimension for concept organization: further evidence from a Chinese semantic dementia case. AB - Neuropsychological and neuroimaging studies have indicated that motor knowledge is one potential dimension along which concepts are organized. Here we present further direct evidence for the effects of motor knowledge in accounting for categorical patterns across object domains (living vs. nonliving) and grammatical domains (nouns vs. verbs), as well as the integrity of other modality-specific knowledge (e.g., visual). We present a Chinese case, XRK, who suffered from semantic dementia with left temporal lobe atrophy. In naming and comprehension tasks, he performed better at nonliving items than at living items, and better at verbs than at nouns. Critically, multiple regression method revealed that these two categorical effects could be both accounted for by the charade rating, a continuous measurement of the significance of motor knowledge for a concept or a semantic feature. Furthermore, charade rating also predicted his performances on the generation frequency of semantic features of various modalities. These findings consolidate the significance of motor knowledge in conceptual organization and further highlights the interactions between different types of semantic knowledge. PMID- 20701960 TI - Dynamic versus static bond-strength testing of adhesive interfaces. AB - A static bond-strength test is often regarded as clinically less relevant, since such abrupt loading of the adhesive-tooth bond clinically never occurs. Therefore, dynamic fatigue testing is often claimed to better predict the clinical effectiveness of adhesives. OBJECTIVES: To measure the micro-tensile fatigue resistance (MUTFR) of adhesives bonded to dentin, and to compare their MUTFR to their micro-tensile bond strength (MUTBS). METHODS: The bonding effectiveness (including fracture analysis) of three adhesives (OptiBond FL, Kerr: 3-step etch-and-rinse adhesive or 3-E&Ra; Clearfil SE, Kuraray: 2-step self etch adhesive or 2-SEa; G-Bond, GC: 1-step self-etch adhesive or 1-SEa) was measured by means of both a dynamic MUTFR and a static MUTBS approach. Preparation and test set-up of the micro-specimens were identical for both tests. In fatigue, specimens were tested with a wide range of selected loads at 2Hz and at 10Hz until failure, or until 10(4) cycles were reached. At 2Hz, the MUTFR was also measured after 3-month water storage. The MUTFR was determined using a logistic regression model. Two-way ANOVA and Tukey HSD multiple comparisons test were used to determine statistical differences in MUTBS. RESULTS: The 1-SEa recorded significantly lower values in MUTFR at 10Hz and in MUTBS than the 2-SEa and 3-E&Ra. The 1-SEa and the 2-SEa performed significantly lower in MUTFR than the 3-E&Ra, when tested at 2Hz after 3-month water storage. Fatigue testing at 2Hz after 1-week water storage did not reveal any differences in MUTFR between the three adhesives. SIGNIFICANCE: The 3-E&Ra performed best in terms of bonding effectiveness, irrespective of the experimental condition or test used. The MUTBS test proved once more to be a reliable laboratory test in ranking contemporary adhesives on their bonding effectiveness. PMID- 20701961 TI - A comparison of two-dimensional and three-dimensional measurements of wear in a laboratory investigation. AB - OBJECTIVES: The aim of this research was to compare two-dimensional (2D) and three-dimensional (3D) tooth measuring techniques after subjecting enamel samples to tooth wear in vitro on an erosion-abrasion model. METHOD: 80 polished mid coronal enamel sections were subjected to 10 wear cycles. Each cycle consisted of remineralization for 2 h in artificial saliva, followed by 10 min immersion in one of four acidic fruit drinks or distilled water and finally toothbrush abrasion with a non-fluoridated tooth paste. The resulting wear scars were measured using 2D and 3D techniques using surface matching software. RESULTS: The 2D step heights measurements from the exposure to the four acidic drinks showed no statistically significant differences (median wear range=22.4-32.5 microm) between them (p=0.99) but there were differences with distilled water (median wear=10.0 microm) (p=0.01). The 3D measurements showed that two drinks produced more wear compared to the others and water when the whole surface and volume exposed to wear was accounted for (p=0.01). SIGNIFICANCE: The difference in data from the two techniques showed that 3D measurements gave a more accurate assessment of the impact of the wear regime. PMID- 20701962 TI - Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial. AB - BACKGROUND: Percutaneous vertebroplasty is increasingly used for treatment of pain in patients with osteoporotic vertebral compression fractures, but the efficacy, cost-effectiveness, and safety of the procedure remain uncertain. We aimed to clarify whether vertebroplasty has additional value compared with optimum pain treatment in patients with acute vertebral fractures. METHODS: Patients were recruited to this open-label prospective randomised trial from the radiology departments of six hospitals in the Netherlands and Belgium. Patients were aged 50 years or older, had vertebral compression fractures on spine radiograph (minimum 15% height loss; level of fracture at Th5 or lower; bone oedema on MRI), with back pain for 6 weeks or less, and a visual analogue scale (VAS) score of 5 or more. Patients were randomly allocated to percutaneous vertebroplasty or conservative treatment by computer-generated randomisation codes with a block size of six. Masking was not possible for participants, physicians, and outcome assessors. The primary outcome was pain relief at 1 month and 1 year as measured by VAS score. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00232466. FINDINGS: Between Oct 1, 2005, and June 30, 2008, we identified 431 patients who were eligible for randomisation. 229 (53%) patients had spontaneous pain relief during assessment, and 202 patients with persistent pain were randomly allocated to treatment (101 vertebroplasty, 101 conservative treatment). Vertebroplasty resulted in greater pain relief than did conservative treatment; difference in mean VAS score between baseline and 1 month was -5.2 (95% CI -5.88 to -4.72) after vertebroplasty and 2.7 (-3.22 to -1.98) after conservative treatment, and between baseline and 1 year was -5.7 (-6.22 to -4.98) after vertebroplasty and -3.7 (-4.35 to -3.05) after conservative treatment. The difference between groups in reduction of mean VAS score from baseline was 2.6 (95% CI 1.74-3.37, p<0.0001) at 1 month and 2.0 (1.13-2.80, p<0.0001) at 1 year. No serious complications or adverse events were reported. INTERPRETATION: In a subgroup of patients with acute osteoporotic vertebral compression fractures and persistent pain, percutaneous vertebroplasty is effective and safe. Pain relief after vertebroplasty is immediate, is sustained for at least a year, and is significantly greater than that achieved with conservative treatment, at an acceptable cost. FUNDING: ZonMw; COOK Medical. PMID- 20701963 TI - Another chapter for vertebral compression fractures. PMID- 20701964 TI - Influence of silica particle internalization on adhesion and migration of human dermal fibroblasts. AB - In spite of significant advantages exhibiting in the applications of silicon dioxide particles in biological and medicine fields, their adverse effects still remain a big concern. Herein monodisperse spherical SiO(2) particles with diameters of 80 nm and 500 nm were used to study their interactions with human dermal fibroblasts. Both the particles were readily internalized into the fibroblasts within a short time. The 500 nm particles were taken up in a larger amount through macropinocytosis and clathrin-mediated endocytosis pathways, whereas uptake of the 80 nm SiO(2) particles was mediated corporately by macropinocytosis, clathrin-mediated and caveolae-mediated endocytosis. The particles mainly dispersed in the cytoplasm or resided within the lysosomal vesicles, but could not enter into the cell nucleus within 24 h culture in vitro. Treatment with the 80 nm SiO(2) particles caused apparently decrease of cell viability and also weakened the mitochondrial membrane potential. Further experiments demonstrated that the cell adhesion and migration were greatly affected by uptake of the SiO(2) particles regardless of their size. RT-PCR results indicated down regulation of the mRNA expression of adhesion relevant genes, i.e. fibronectin, laminin and focal adhesion kinase (FAK). PMID- 20701965 TI - Chitosan-based responsive hybrid nanogels for integration of optical pH-sensing, tumor cell imaging and controlled drug delivery. AB - We report a new class of chitosan-based hybrid nanogels by in-situ immobilization of CdSe quantum dots (QDs) in the chitosan-poly(methacrylic acid) (chitosan-PMAA) networks. The covalently crosslinked hybrid nanogels with chitosan chains semi interpenetrating in the crosslinked PMAA networks exhibit excellent colloidal and structural stability as well as reversible physical property change in response to a pH variation cross the physiological condition. In contrast, the hybrid nanogels formed by non-covalent physical association exhibit a significant change in the structure and composition upon exposure to physiological pH. This distinction in the structural stability of hybrid nanogels produces very different outcomes for their biomedical applications. The covalently crosslinked hybrid nanogels are low-cytotoxic and could illuminate the B16F10 cells, sense the environmental pH change, and regulate the release of anticancer drug in the typical abnormal pH range of 5-7.4 found in pathological zone, thus successfully combine multiple functionality into a single nano-object. However, the physically associated hybrid nanogels exhibit a non-reversible pH-sensitive PL property and a significant cytotoxicity after 24 h treatment. It is critical to construct a highly stable biopolymer-QD hybrid nanogel, via a rational design for safe bionanomaterials, to simultaneously combine the biosensing, bioimaging, and effective therapy functions. PMID- 20701966 TI - Neutron capture nuclei-containing carbon nanoparticles for destruction of cancer cells. AB - HeLa cells were incubated with neutron capture nuclei (boron-10 and gadolinium) containing carbon nanoparticles, followed by irradiation of slow thermal neutron beam. Under a neutron flux of 6 x 10(11) n/cm(2) (or 10 min irradiation at a neutron flux of 1 x 10(9) n/cm(2) s), the percentages of acute cell death at 8 h after irradiation are 52, 55, and 28% for HeLa cells fed with BCo@CNPs, GdCo@CNPs, and Co@CNPs, respectively. The proliferation capability of the survived HeLa cells was also found to be significantly suppressed. At 48 h after neutron irradiation, the cell viability further decreases to 35 +/- 5% as compared to the control set receiving the same amount of neutron irradiation dose but in the absence of carbon nanoparticles. This work demonstrates "proof-of concept" examples of neutron capture therapy using (10)B-, (157)Gd-, and (59)Co containing carbon nanoparticles for effective destruction of cancer cells. It will also be reported the preparation and surface functionalization of boron or gadolinium doped core-shell cobalt/carbon nanoparticles (BCo@CNPs, GdCo@CNPs and Co@CNPs) using a modified DC pulsed arc discharge method, and their characterization by various spectroscopic measurements, including TEM, XRD, SQUID, FT-IR, etc. Tumor cell targeting ability was introduced by surface modification of these carbon nanoparticles with folate moieties. PMID- 20701967 TI - The influence of size and charge of chitosan/polyglutamic acid hollow spheres on cellular internalization, viability and blood compatibility. AB - Polymeric hollow spheres can be tailored as efficient carriers of various therapeutic molecules due to their tunable properties. However, the entry of these synthetic vehicles into cells, their cell viability and blood compatibility depend on their physical and chemical properties e.g. size, surface charge. Herein, we report the effect of size and surface charge on cell viability and cellular internalization behaviour and their effect on various blood components using chitosan/polyglutamic acid hollow spheres as a model system. Negatively charged chitosan/polyglutamic acid hollow spheres of various sizes 100, 300, 500 and 1000 nm were fabricated using a template based method and covalently surface modified using linear polyethylene glycol and methoxyethanol amine to create a gradient of surface charge from negative to neutrally charged spheres respectively. The results here suggest that both size and surface charge have a significant influence on the sphere's behaviour, most prominently on haemolysis, platelet activation, plasma recalcification time, cell viability and internalization over time. Additionally, cellular internalization behaviour and viability was found to vary with different cell types. These results are in agreement with those of inorganic spheres and liposomes, and can serve as guidelines for tailoring polymeric solid spheres for specific desired applications in biological and pharmaceutical fields, including the design of nanometer to submicron-sized delivery vehicles. PMID- 20701968 TI - Localisation of ABCA1 in first trimester and term placental tissues--a reply. PMID- 20701969 TI - Contribution of potassium in human placental steroidogenesis. AB - The role of K(+) on steroidogenesis in isolated mitochondria from the human placenta was explored. Cholesterol uptake and progesterone synthesis were stimulated by K(+), and by the further addition of ATP. In the presence of glibenclamide or quinine (inhibitors of the K(+) channel mito-K(ATP)), the synthesis of progesterone was improved, indicating that K(+) acts outside the mitochondria. Valinomycin, a K(+)-ionophore, inhibited mitochondrial steroidogenesis only in the absence of K(+). The mitochondrial K(+) channel in human placental mitochondria is formed by the subunit Kir 6.1 which was detected by Western blot with polyclonal antibodies. These results suggest that K(+) contributes placental mitochondrial steroidogenesis facilitating cholesterol uptake and intermembrane translocation through a mechanism non-dependent of the transport of K(+) inside the mitochondria. PMID- 20701970 TI - Proplatelet production and stromal fibrosis in myeloproliferative neoplasms. PMID- 20701971 TI - Extramedullary tumors presenting double vision in patients with t(8;21)(q22;q22) acute myeloid leukemia lacking mutations in the receptor tyrosine kinase genes KIT or FLT3. PMID- 20701972 TI - Intersex in feral indigenous freshwater Oreochromis mossambicus, from various parts in the Luvuvhu River, Limpopo Province, South Africa. AB - This study reports on intersex in Oreochromis mossambicus, an indigenous fish species inhabiting most aquatic systems throughout South Africa (SA). Male fish were collected from three sites in the Luvuvhu River, Limpopo Province, SA: Albasini Dam (AD), Nandoni Dam (ND), and Xikundu Weir (XW). The latter two sites are situated in a currently dichloro-diphenyl-trichloroethane (DDT) sprayed area. A laboratory-bred reference group (Aq R) were included for a histological comparison. 48% of the fish at AD were intersex individuals compared with 63% at ND, and 58% at XW. The Aq R fish had no cases of intersex. o,p'- and p,p'-DDT and metabolites dichlorodiphenyldichloroethane (DDD) and dichlorodiphenyldichloroethylene (DDE) were detected in fat samples, indicative of contamination of the aquatic environment and subsequent exposure of fish to these chemicals. Although some of the fat samples contained levels of DDTs no association could be established between intersex and chemical contaminants in fish. PMID- 20701973 TI - Response and recovery of acetylcholinesterase activity in freshwater shrimp, Paratya australiensis (Decapoda: Atyidae) exposed to selected anti-cholinesterase insecticides. AB - The toxicity of carbaryl, chlorpyrifos, dimethoate and profenofos to the freshwater shrimp, Paratya australiensis was assessed by measuring acetylcholinesterase (AChE) inhibition after 96h exposures. Shrimp exposed to these pesticides exhibited significant AChE inhibition, with mortality in shrimp corresponding to 70-90% AChE inhibition. The sensitivity of P. australiensis to the four pesticides based on AChE inhibition can be given as chlorpyrifos > profenofos > carbaryl > dimethoate. Recovery of AChE activity was followed in shrimp after 96 h exposures to carbaryl, chlorpyrifos and dimethoate. Recovery after exposure to the carbamate pesticide carbaryl was more rapid than for the two organophosphorus pesticides, chlorpyrifos and dimethoate. The slow recovery of depressed AChE activity may mean that affected organisms in the natural system are unable to sustain physical activities such as searching for food or eluding predators. To investigate the ecological significance of AChE inhibition, chemotaxis behaviour was assessed in shrimp exposed to profenofos for 24h. Abnormal chemotaxis behaviour in the exposed shrimp was observed at concentrations representing 30-50% AChE inhibition. A clear relationship existed between the depression of AChE activity and observed chemotaxis responses, such as approaching and grasping the chemoattractant source. These results suggest that in vivo toxicity tests based on this specific biomarker are sensitive and present advantages over conventional acute tests based on mortality. Behavioural studies of test organisms conducted in conjunction with measurement of AChE inhibition will provide data to clarify the toxic effects caused by sublethal chemical concentrations of anti-cholinesterase compounds. PMID- 20701974 TI - Impacts of simulated acid rain on soil enzyme activities in a latosol. AB - Acid rain pollution is a serious environmental problem in the world. This study investigated impacts of simulated acid rain (SAR) upon four types of soil enzymes, namely the catalase, acid phosphatase, urease, and amylase, in a latosol. Latosol is an acidic red soil and forms in the tropical rainforest biome. Laboratory experiments were performed by spraying the soil columns with the SAR at pH levels of 2.5, 3.0, 3.5., 4.0, 4.5, 5.0, and 7.0 (control) over a 20-day period. Mixed results were obtained in enzyme activities for different kinds of enzymes under the influences of the SAR. The catalase activities increased rapidly from day 0 to 5, then decreased slightly from day 5 to 15, and finally decreased sharply to the end of the experiments, whereas the acid phosphatase activities decreased rapidly from day 0 to 5, then increased slightly from day 5 to 15, and finally decreased dramatically to the end of the experiments. A decrease in urease activities was observed at all of the SAR pH levels for the entire experimental period, while an increase from day 0 to 5 and then a decrease from day 5 to 20 in amylase activities were observed at all of the SAR pH levels. In general, the catalase, acid phosphatase, and urease activities increased with the SAR pH levels. However, the maximum amylase activity was found at pH 4.0 and decreased as the SAR pH increased from 4.0 to 5.0 or decreased from 4.0 to 2.5. It is apparent that acid rain had adverse environmental impacts on soil enzyme activities in the latosol. Our study further revealed that impacts of the SAR upon soil enzyme activities were in the following order: amylase>catalase>acid phosphatase>urease. These findings provide useful information on better understanding and managing soil biological processes in the nature under the influence of acid rains. PMID- 20701975 TI - Design of novel iron compounds as potential therapeutic agents against tuberculosis. AB - In the search for new therapeutic tools against tuberculosis two novel iron complexes, [Fe(L-H)(3)], with 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives (L) as ligands, were synthesized, characterized by a combination of techniques, and in vitro evaluated. Results were compared with those previously reported for two analogous iron complexes of other ligands of the same family of quinoxaline derivatives. In addition, the complexes were studied by cyclic voltammetry and EPR spectroscopy. Cyclic voltammograms of the iron compounds showed several cathodic processes which were attributed to the reduction of the metal center (Fe(III)/Fe(II)) and the coordinated ligand. EPR signals were characteristic of magnetically isolated high-spin Fe(III) in a rhombic environment and arise from transitions between m(S) = +/- 1/2 (g(eff) ~ 9) or m(S) = +/- 3/2 (g(eff) ~ 4.3) states. Mossbauer experiments showed hyperfine parameters that are typical of high-spin Fe(III) ions in a not too distorted environment. The novel complexes showed in vitro growth inhibitory activity on Mycobacterium tuberculosis H(37)Rv (ATCC 27294), together with very low unspecific cytotoxicity on eukaryotic cells (cultured murine cell line J774). Both complexes showed higher inhibitory effects on M. tuberculosis than the "second-line" therapeutic drugs. PMID- 20701976 TI - Mo(II) complexes: a new family of cytotoxic agents? AB - Several molybdenum complexes, [Mo(eta(3)-C(3)H(5))X(CO)(2)(N-N)] (N-N = 1,10 phenanthroline, phen: X = CF(3)SO(3)T1, X = Br B1, X = Cl C1; N-N = 2,2' bipyridyl, X = CF(3)SO(3)T2, X = Br B2) and [W(eta(3)-C(3)H(5))Br(CO)(2)(phen)] (W1) have been synthesized and characterized. Their antitumor properties have been tested in vitro against human cancer cell lines cervical carcinoma (HeLa) and breast carcinoma (MCF-7) using a metabolic activity test (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT), leading to IC(50) values ranging from 3 to 45 MUM, approximately. Most complexes exhibited significant antitumoral activity. Complexes B1 and T2 were chosen for subsequent studies aiming to understand their mechanism of action. Cellular uptake of molybdenum and octanol/water partition assays revealed that both B1 and T2 exhibit a selective uptake by cells and intermediate partition coefficients. The binding constants of B1 and T2 with ct DNA, as determined by absorption titration, are 2.08 (+/- 0.98) * 10(5) and 3.68 (+/- 2.01)x 10(5)M(-1), respectively. These results suggest that they interact with DNA changing its conformation and possibly inducing cell death, and may therefore provide a valuable tool in cancer chemotherapy. PMID- 20701977 TI - The development of infants' use of property-poor sounds to individuate objects. AB - There is evidence that infants as young as 4.5 months use property-rich but not property-poor sounds as the basis for individuating objects (Wilcox, Woods, Tuggy, & Napoli, 2006). The current research sought to identify the age at which infants demonstrate the capacity to use property-poor sounds. Using the task of Wilcox et al., infants aged 7 and 9 months were tested. The results revealed that 9- but not 7-month-olds demonstrated sensitivity to property-poor sounds (electronic tones) in an object individuation task. Additional results confirmed that the younger infants were sensitive to property-rich sounds (rattle sounds). These are the first positive results obtained with property-poor sounds in infants and lay the foundation for future research to identify the underlying basis for the developmental hierarchy favoring property-rich over property-poor sounds and possible mechanisms for change. PMID- 20701978 TI - Efficacy and safety of nonbenzodiazepine hypnotics for chronic insomnia in patients with bipolar disorder. AB - BACKGROUND: Insomnia in patients with bipolar disorder (BD) can cause distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD patients with insomnia although no hypnotic has a specific FDA indication for this use. In this study, the patterns of use, efficacy and safety of five nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients with BD. METHOD: A chart review was performed for all older adolescents and adult BD outpatients in a private outpatient clinic. Clinical data was collected for any patient who had ever been prescribed a NBZH for insomnia and included successful current use, past unsuccessful treatments, side effects, duration of use, concurrent psychiatric medications, and absence or presence of untoward events often associated with chronic use of hypnotics. RESULTS: A significant number of BD patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success rates; ramelteon was limited in efficacy. Some patients experienced satisfactory results from a NBZH after unsuccessful trials with one or more other NBZHs. About half of the current NBZH users are taking them on a daily long-term basis, and none of these patients have experienced unacceptable untoward events. About three quarters of the chronic NBZH users are taking antimanic medications concurrently, and less than half of the chronic users are taking antidepressants. LIMITATIONS: The results may not be generalizable to other BD populations. A control group was not included in the design. Chronic users of NBZHs were not asked to discontinue their NBZH in order to confirm indication for long-term use. CONCLUSIONS: Most NBZHs can be effective and safe agents for selected BD outpatients with episodic or chronic insomnia. Failure to respond to one or more NBZH does not preclude a satisfactory response to a different NBZH. Some BD patients who take maintenance antimanic agents also require NBZH treatment. Overactivation from antidepressant treatment does not contribute to chronic NBZH use in most BD patients. PMID- 20701979 TI - Expression and role of interleukin-23 in human endometrium throughout the menstrual cycle and early pregnancy. AB - Interleukin-23 (IL-23) is a novel cytokine involved in the regulation of organ specific immune responses. We hypothesized that expression of IL-23 in the human endometrium is menstrual cycle and pregnancy dependent, and is involved in endometrial immune regulation. IL-23 expression and regulation was investigated in the human endometrium and placenta in vivo using immunohistochemistry and in vitro using Western blot and cell viability analyses. IL-23 immunoreactivity in endometrial glandular cells was highest in the late proliferative and early secretory phases, as compared to other cycle phases and first trimester tissues. Endometrial stromal cells (ESC) showed weak IL-23 immunoreactivity without significant changes in intensity and distribution throughout the menstrual cycle. First trimester decidual cells revealed significantly stronger IL-23 staining compared to ESC from non-pregnant endometrium. Both villous cytotrophoblasts and syncytiotrophoblasts also showed positive IL-23 immunoreactivity, with a higher staining in syncytiotrophoblasts. In the trophoblastic cell line HRT8, IL-23 expression increased in a time-dependent manner, but was undetectable in stromal cells under all treatment conditions. ESC treated with recombinant IL-23 showed significantly decreased IL-8 secretion and cell viability. These results suggest a possible regulatory role for IL-23 in the menstrual cycle and in early pregnancy, although the extent and function of this role are yet to be determined. PMID- 20701980 TI - Alexithymia, social detachment and cognitive processing. AB - Using lexical content analysis (linguistic inquiry and word count), the hypotheses that social detachment and impaired cognitive processing are typical for alexithymia are investigated. Based on clinical interviews with 32 outpatients (mixed diagnoses), we found support for the hypotheses for the externally oriented thinking facet of alexithymia only. PMID- 20701981 TI - Sensitive detection of Foxp3 expression in bovine lymphocytes by flow cytometry. AB - The transcription factor forkhead-box p3 (Foxp3) has been designated as a master regulator for the function of regulatory T cells (Treg). Therefore, the identification of Foxp3 expression in T cells is indispensable for the study of Treg. However, studies on Foxp3 expression in bovine lymphocytes are still sparse, probably due to a lack of Foxp3-specific antibodies with reliable performance in flow cytometry. Our group recently demonstrated that a monoclonal antibody (FJK-16s) developed against murine Foxp3 also binds to porcine Foxp3 and performs well in flow cytometry. A protein sequence alignment of the binding region of the FJK-16s antibody revealed, that within this region the sequences of porcine and bovine Foxp3 are identical. Therefore, we tested this antibody for its suitability in flow cytometry with bovine peripheral blood mononuclear cells (PBMC). By using nonspecific isotype-matched antibodies and competition labeling with non-fluorescent FJK-16s antibodies as negative controls, we readily observed a specific staining of a small subpopulation of CD25(high) lymphocytes within PBMC. Co-staining with monoclonal antibodies against CD3, CD4, CD8beta and TCR gammadelta revealed that all Foxp3+ cells co-expressed CD3, and were in their vast majority CD4+. However, minor populations of Foxp3+CD8beta+ and Foxp3+TCR gammadelta+ lymphocytes could also be identified. In summary, our data demonstrate that the FJK-16s antibody is a valuable tool to promote the study of Foxp3+ T cells and their biological relevance in cattle. PMID- 20701982 TI - Anti-SOX1 antibodies in patients with paraneoplastic and non-paraneoplastic neuropathy. AB - Anti-SOX1 antibodies have been described to be positive in patients with paraneoplastic Lambert-Eaton myasthenic syndrome and, in a lower amount, in patients with anti-Hu positive paraneoplastic neurological syndromes, and with SCLC alone, respectively. We found 5/32 patients with paraneoplastic neuropathy and, surprisingly, 4/22 patients with neuropathy of unknown origin positive for anti-SOX1 antibodies, whereas no patient with inflammatory neuropathy and no healthy controls showed any reactivity (p=0.007). All patients with neuropathy of unknown origin where followed up for four years without diagnosis of a tumour so far. Anti-SOX1 antibodies are associated with paraneoplastic neuropathies and may define another group of non-paraneoplastic, immune-mediated neuropathies. PMID- 20701983 TI - Haloperidol: a possible medication for the treatment of exacerbation of intractable psychogenic sneezing. AB - Sneezing is one of the physiological defense mechanisms that develops generally due to nasal irritation. But intractable sneezing episodes are uncommon and generally detected among the adolescents. It is difficult to distinguish physiologic sneezing from psychogenic sneezing. Herein, we report a 12-year-old girl who was complaint with intractable sneezing. She was diagnosed as intractable psychogenic sneezing and haloperidol treatment was started. All symptoms had resolved completely within 2 weeks. As a result, haloperidol can be considered as a different treatment modality for intractable psychogenic sneezing. PMID- 20701984 TI - Dopamine reveals neural circuit mechanisms of fly memory. AB - A goal of memory research is to understand how changing the weight of specific synapses in neural circuits in the brain leads to an appropriate learned behavioral response. Finding the relevant synapses should allow investigators to probe the underlying physiological and molecular operations that encode memories and permit their retrieval. In this review I discuss recent work in Drosophila that implicates specific subsets of dopaminergic (DA) neurons in aversive reinforcement and appetitive motivation. The zonal architecture of these DA neurons is likely to reveal the functional organization of aversive and appetitive memory in the mushroom bodies. Combinations of fly DA neurons might code negative and positive value, consistent with a motivational systems role as proposed in mammals. PMID- 20701985 TI - Mitochondrial energetic metabolism perturbations in skeletal muscles and brain of zebrafish (Danio rerio) exposed to low concentrations of waterborne uranium. AB - Anthropogenic release of uranium (U), originating from the nuclear fuel cycle or military activities, may considerably increase U concentrations in terrestrial and aquatic ecosystems above the naturally occurring background levels found throughout the environment. With a projected increase in the world-wide use of nuclear power, it is important to improve our understanding of the possible effects of this metal on the aquatic fauna at concentrations commensurate with the provisional drinking water guideline value of the World Health Organization (15 MUg U/L). The present study has examined the mitochondrial function in brain and skeletal muscles of the zebrafish, Danio rerio, exposed to 30 and 100 MUg/L of waterborne U for 10 and 28 days. At the lower concentration, the basal mitochondrial respiration rate was increased in brain at day 10 and in muscles at day 28. This is due to an increase of the inner mitochondrial membrane permeability, resulting in a decrease of the respiratory control ratio. In addition, levels of cytochrome c oxidase subunit IV (COX-IV) increased in brain at day 10, and those of COX-I increased in muscles at day 28. Histological analyses performed by transmission electron microscopy revealed an alteration of myofibrils and a dilatation of endomysium in muscle cells. These effects were largest at the lowest concentration, following 28 days of exposure. PMID- 20701986 TI - Toxicity of proton-metal mixtures in the field: linking stream macroinvertebrate species diversity to chemical speciation and bioavailability. AB - Understanding metal and proton toxicity under field conditions requires consideration of the complex nature of chemicals in mixtures. Here, we demonstrate a novel method that relates streamwater concentrations of cationic metallic species and protons to a field ecological index of biodiversity. The model WHAM-F(TOX) postulates that cation binding sites of aquatic macroinvertebrates can be represented by the functional groups of natural organic matter (humic acid), as described by the Windermere Humic Aqueous Model (WHAM6), and supporting field evidence is presented. We define a toxicity function (F(TOX)) by summing the products: (amount of invertebrate-bound cation) x (cation specific toxicity coefficient, alpha(i)). Species richness data for Ephemeroptera, Plecoptera and Trichoptera (EPT), are then described with a lower threshold of F(TOX), below which all organisms are present and toxic effects are absent, and an upper threshold above which organisms are absent. Between the thresholds the number of species declines linearly with F(TOX). We parameterised the model with chemistry and EPT data for low-order streamwaters affected by acid deposition and/or abandoned mines, representing a total of 412 sites across three continents. The fitting made use of quantile regression, to take into account reduced species richness caused by (unknown) factors other than cation toxicity. Parameters were derived for the four most common or abundant cations, with values of alpha(i) following the sequence (increasing toxicity) H+ < Al < Zn < Cu. For waters affected mainly by H+ and Al, F(TOX) shows a steady decline with increasing pH, crossing the lower threshold near to pH 7. Competition effects among cations mean that toxicity due to Cu and Zn is rare at lower pH values, and occurs mostly between pH 6 and 8. PMID- 20701987 TI - Responses in the brain proteome of Atlantic cod (Gadus morhua) exposed to methylmercury. AB - The molecular mechanisms underlying the neurotoxicity of methylmercury (MeHg), a ubiquitous environmental contaminant, are not yet fully understood. Furthermore, there is a lack of biomarkers of MeHg neurotoxicity for use in environmental monitoring. We have undertaken a proteomic analysis of brains from Atlantic cod (Gadus morhua) exposed to 0, 0.5 and 2 mg/kg MeHg administered by intraperitoneal injection. The doses were given in two injections, half of the dose on the first day and the second half after 1 week, and the total exposure period lasted 2 weeks. Using 2-DE coupled with MALDI-TOF MS and MS/MS, we observed the level of 71 protein spots to be 20% or more significantly altered following MeHg exposure, and successfully identified 40 of these protein spots. Many of these proteins are associated with main known molecular targets and mechanisms of MeHg-induced neurotoxicity in mammals, such as mitochondrial dysfunction, oxidative stress, altered calcium homeostasis and tubulin/disruption of microtubules. More interestingly, several of the affected proteins, with well-established or recently demonstrated critical functions in nervous system-specific processes, have not previously been associated with MeHg exposure in any species. These proteins include the strongest up-regulated protein, pyridoxal kinase (essential for synthesis of several neurotransmitters), G protein (coupled to neurotransmitter receptors), nicotinamide phosphoribosyl-transferase (protection against axonal degeneration), dihydropyrimidinase-like 5 (or collapsin response mediator protein 5, CRMP-5) (axon guidance and regeneration), septin (dendrite development), phosphatidylethanolamine binding protein (precursor for hippocampal cholinergic neurostimulating peptide) and protein phosphatase 1 (control of brain recovery by synaptic plasticity). The results of the present study aid our understanding of molecular mechanisms underlying MeHg neurotoxicity and defense responses, and provide a large panel of protein biomarker candidates for aquatic environmental monitoring. PMID- 20701989 TI - Transcriptomic signatures in Chlamydomonas reinhardtii as Cd biomarkers in metal mixtures. AB - In the natural environment, toxicant effects can be monitored by the signature mRNA expression patterns of genes that they generate in test organisms. The specificity and sensitivity of these transcriptome-based bioassays to a given toxicant can be confounded by temporal changes in biomarker mRNA expression, effects of other toxicants and hardness ions, and non-linear mRNA expression responses of genes. This study provides the foundation for the development of a transcriptomic-based bioassay for bioavailable Cd in the freshwater alga, Chlamydomonas reinhardtii. It characterizes: (1) the Cd regulation of nine genes with respect to their mRNA induction kinetics; (2) the effects of two additional metals common to freshwaters, Cu2+ and Pb2+, and (3) the relationships between metal bioaccumulation and the transcriptomic responses. Quantitative real time PCR was used to monitor mRNA levels of nine Cd-induced genes following an exposure to 0.01, 0.11 and 1.16 MUM Cd2+. Several distinct mRNA expression patterns were observed with time. While the presence of Cu2+ and Pb2+ decreased Cd biouptake, mRNA levels increased for six genes, showing lack of Cd2+ specificity. Nonetheless, the transcriptomic effects of binary metal exposures rarely adhered to a simple additive model based on single metal exposures; rather most exhibited synergistic or antagonistic interactions. While none of these genes could be used as a specific Cd biomarker, the signature mRNA expression profile obtained from a select subset of Cd sensitive genes was a useful biomarker of sublethal effects. PMID- 20701988 TI - Subacute developmental exposure of zebrafish to the organophosphate pesticide metabolite, chlorpyrifos-oxon, results in defects in Rohon-Beard sensory neuron development. AB - Organophosphate pesticides (OPs) are environmental toxicants known to inhibit the catalytic activity of acetylcholinesterase (AChE) resulting in hypercholinergic toxicity symptoms. In developing embryos, OPs have been hypothesized to affect both cholinergic and non-cholinergic pathways. In order to understand the neurological pathways affected by OP exposure during embryogenesis, we developed a subacute model of OP developmental exposure in zebrafish by exposing embryos to a dose of the OP metabolite chlorpyrifos-oxon (CPO) that is non-lethal and significantly inhibited AChE enzymatic activity compared to control embryos (43% at 1 day post-fertilization (dpf) and 11% at 2dpf). Phenotypic analysis of CPO exposed embryos demonstrated that embryonic growth, as analyzed by gross morphology, was normal in 85% of treated embryos. Muscle fiber formation was similar to control embryos as analyzed by birefringence, and nicotinic acetylcholine receptor (nAChR) cluster formation was quantitatively similar to control embryos as analyzed by alpha-bungarotoxin staining. These results indicate that partial AChE activity during the early days of zebrafish development is sufficient for general development, muscle fiber, and nAChR development. Rohon-Beard (RB) sensory neurons exhibited aberrant peripheral axon extension and gene expression profiling suggests that several genes responsible for RB neurogenesis are down-regulated. Stability of CPO in egg water at 28.5 degrees C was determined by HPLC-UV-MS analysis which revealed that the CPO concentration used in our studies hydrolyzes in egg water with a half-life of 1 day. The result that developmental CPO exposure affected RB neurogenesis without affecting muscle fiber or nAChR cluster formation demonstrates that zebrafish are a strong model system for characterizing subtle neurological pathologies resulting from environmental toxicants. PMID- 20701990 TI - Does modifying electrode placement of the 12 lead ECG matter in healthy subjects? AB - BACKGROUND: Limb electrodes for the 12 lead ECG are routinely placed on the torso during exercise stress testing or when limbs are clinically inaccessible. It is unclear whether such electrode modification produces ECG changes in healthy male or female subjects that are clinically important according to the 2009 AHA, ACCF, HRS guidelines. We therefore measured whether ECG modification produced clinically important or false positive ECG changes e.g., appearance of Q waves in leads V(1-3), ST changes greater than 0.1 mV, T wave changes greater than 0.5 mV (frontal plane) or 1 mV (transverse plane), QRS axis shifts or alterations to QTc/P-R/QRS intervals. METHODS: The 12 lead ECG was measured in 18 healthy and semi-recumbent subjects using the standard and Takuma modified limb placements. RESULTS: In the frontal plane we demonstrate that the modification of limb electrode placement produces small Q, R and T wave amplitude and QRS axis changes that are statistically but not clinically significant. In the transverse plane it produces no statistically or clinically significant changes in the ECG or in ST segment morphology, P-R, QRS or QTc intervals. CONCLUSIONS: We provide better and more robust evidence that routine modification of limb electrode placement produces only minor changes to the ECG waveform in healthy subjects. These are not clinically significant according to the 2009 guidelines and thus have no effect on the clinical specificity of the 12 lead ECG. PMID- 20701991 TI - Increased red cell count in diabetes and pre-diabetes. AB - The aim of this study was to test whether an increased red cell count (RCC) is present in pre-diabetes, obesity and the metabolic syndrome. The results demonstrate that these diabetes precursor states are associated with an increased RCC. This relationship can be explained, in part, by an increased HbA1c. PMID- 20701992 TI - Application of spatio-temporal filtering to fetal electrocardiogram enhancement. AB - In this paper we propose a new structure of the instrumentation for electrocardiographic fetal monitoring. We apply a single-channel approach to maternal electrocardiogram suppression in the recorded four abdominal bioelectric signals. Then we exploit spatial and temporal properties of the extracted four channel fetal electrocardiogram to construct a new channel with higher signal-to noise ratio. Finally, we perform detection of fetal QRS complexes. The proposed approach is investigated with the help of the constructed database of the maternal abdominal signals. During the detection tests, the spatio-temporal filtering allowed us to decrease significantly the number of the detection errors of different detectors applied. Moreover, we present visually that even if the fetal QRS complexes are buried in noise, the spatio-temporal filtering can produce the signal with the discernible ones. PMID- 20701993 TI - Perception of alopecia by patients requiring chemotherapy for non-small-cell lung cancer: a willingness to pay study. AB - OBJECTIVE: Chemotherapy-induced alopecia may have a substantial impact on the quality of life (QOL) of lung cancer patients, but very few data are available. The aim of this study was to assess the perceived impact of alopecia based on a "willingness to pay" (WTP) approach. METHODS: We conducted a prospective multicenter WTP study of patients receiving chemotherapy for non-small-cell lung cancer (NSCLC). The perceived impact of alopecia was assessed with a visual analogue scale (VAS; 0: no impact, 10: major impact), and from the patients' willingness to pay for chemotherapy that had the same efficacy, dosing schedule and tolerability as the standard treatment but that cut the risk of alopecia from 40% to 5%. RESULTS: Among the 135 patients enrolled in this study, the mean score on the VAS for the perceived likely impact of alopecia was 4.4 +/- 0.3. The mean WTP for a 3-week chemotherapy cycle reducing the risk of alopecia from 40% to 5% was ?83.4 +/- 10.2 (?median 37.5), representing 2.1% of total income, while 27% of patients were unwilling to pay anything. There was a significant association between WTP and gender (women, p < 0.01), annual incomes (p < 0.01), but not with marital status, level of education or occupations. CONCLUSION: Alopecia appears to be an important outcome for patients receiving chemotherapy for NSCLC. Women and patients with high annual incomes were more willing to pay. PMID- 20701994 TI - A combined PHREEQC-2/parallel fracture model for the simulation of laminar/non laminar flow and contaminant transport with reactions. AB - A combination of a parallel fracture model with the PHREEQC-2 geochemical model was developed to simulate sequential flow and chemical transport with reactions in fractured media where both laminar and turbulent flows occur. The integration of non-laminar flow resistances in one model produced relevant effects on water flow velocities, thus improving model prediction capabilities on contaminant transport. The proposed conceptual model consists of 3D rock-blocks, separated by horizontal bedding plane fractures with variable apertures. Particle tracking solved the transport equations for conservative compounds and provided input for PHREEQC-2. For each cluster of contaminant pathways, PHREEQC-2 determined the concentration for mass-transfer, sorption/desorption, ion exchange, mineral dissolution/precipitation and biodegradation, under kinetically controlled reactive processes of equilibrated chemical species. Field tests have been performed for the code verification. As an example, the combined model has been applied to a contaminated fractured aquifer of southern Italy in order to simulate the phenol transport. The code correctly fitted the field available data and also predicted a possible rapid depletion of phenols as a result of an increased biodegradation rate induced by a simulated artificial injection of nitrates, upgradient to the sources. PMID- 20701995 TI - Role and regulation of plastid sigma factors and their functional interactors during chloroplast transcription - recent lessons from Arabidopsis thaliana. AB - Chloroplasts and other plastids within plant cells together are responsible for autotrophic growth and biosynthesis of metabolic key components. Genetically, the plastids are hybrid organelles composed of proteins that are either products of their own organellar genes or are nucleus-encoded and imported from the cytosol. This dual genetic principle is evident in the case of the multi-subunit RNA polymerase, i.e. a major enzyme of the plastid transcription apparatus, consisting of an organelle-encoded core surrounded by imported regulatory proteins. Representatives of the latter are the members of the plastid sigma factor family as well as a Ser/Thr-protein kinase (PTK/cpCK2) that functionally modifies these factors and controls transcription. The plant sigma factors contain regulatory phosphoacceptor sites within their unconserved (factor specific) portion that precedes the conserved catalytic region. Phosphorylation state changes of these regulatory sites help establish the activity and promoter selectivity of individual members of this plant transcription factor family. The protein kinase itself responds to SH-group regulation by glutathione and transmits the redox signal via its phosphorylation activity to the plastid transcription apparatus. Other functional interactors include a set of sigma binding proteins that confer enhanced promoter binding in vitro and are thought to be involved in pathogenic stress responses of the chloroplast in vivo. PMID- 20701996 TI - The small serine-threonine protein SIP2 interacts with STE12 and is involved in ascospore germination in Sordaria macrospora. AB - In fungi, the homoeodomain protein STE12 controls diverse developmental processes, and derives its regulatory specificity from different protein interactions. We recently showed that in the homothallic ascomycete Sordaria macrospora, STE12 is essential for ascospore development, and is able to interact with the alpha-domain mating-type protein SMTA-1 and the MADS box protein MCM1. To further evaluate the functional roles of STE12, we used the yeast two-hybrid approach to identify new STE12-interacting partners. Using STE12 as bait, a small, serine-threonine-rich protein (designated STE12-interacting protein 2, SIP2) was identified. SIP2 is conserved among members of the fungal class Sordariomycetes. In vivo localization studies revealed that SIP2 was targeted to the nucleus and cytoplasm. The STE12/SIP2 interaction was further confirmed in vivo by bimolecular fluorescence complementation. Nuclear localization of SIP2 was apparently mediated by STE12. Unlike deletion of ste12, deletion of sip2 in S. macrospora led to only a slight decrease in ascospore germination, and no other obvious morphological phenotype. In comparison to the Deltaste12 single knockout strain, ascospore germination was significantly increased in a Deltasip2/ste12 double knockout strain. Our data provide evidence for a regulatory role of the novel fungal protein SIP2 in ascospore germination. PMID- 20701997 TI - Indole-3-acetamide-dependent auxin biosynthesis: a widely distributed way of indole-3-acetic acid production? AB - During the course of evolution plants have evolved a complex phytohormone-based network to regulate their growth and development. Herein auxins have a pivotal function, as they are involved in controlling virtually every aspect related to plant growth. Indole-3-acetic acid (IAA) is the major endogenous auxin of higher plants that is already known for more than 80 years. In spite of the long standing interest in this topic, IAA biosynthesis is still only partially uncovered. Several pathways for the formation of IAA have been proposed over the past years, but none of these pathways are yet completely defined. The aim of this review is to summarize the current knowledge on the indole-3-acetamide (IAM) dependent pathway of IAA production in plants and to discuss the properties of the involved proteins and genes, respectively. Their evolutionary relationship to known bacterial IAM hydrolases and other amidases from bacteria, algae, moss, and higher plants is discussed on the basis of phylogenetic analyses. Moreover, we report on the transcriptional regulation of the Arabidopsis AMI1 gene. PMID- 20701998 TI - Prevalence of nosocomial infections in a tertiary heart centre in Iran, 2006 and 2007. PMID- 20701999 TI - [Attitudes of intensive care nurses toward visits]. PMID- 20702000 TI - [Location of the central venous catheter tip in the right atrium: description in 2348 critical patients]. AB - OBJECTIVE: to document possible complications related to the location of central venous catheter (CVC) tip in the right atrium (RA) in two medical-surgical intensive care units (ICU). DESIGN: An observational, retrospective study of critically ill patients. SETTING: two medical-surgical ICUs. PATIENTS: adult patients in need of CVC insertion admitted consecutively in ICU between September 2004 and September 2009. MAIN VARIABLES: Gender, age, condition at admission, severity scale (APACHE II), days with catheter, in addition to clinical variables associated with perforation, cardiac tamponade and death attributable to catheter. RESULTS: 2581 patients were included in the study; with mean age of 50.2 years (SD +/- 20). Out of these, 2348 (91%) remained with the tip in the RA territory and 233 (9%) in superior vena cava (SVC). Arrhythmias were registered during insertion of the guide in 51.2% with the tip in RA and 46.5% with the tip in SVC, p=0.18. A total of 14.5% of the patients with the tip in the RA had arrhythmias during their stay in the ICU and 14.6% of the patients with the tip in SVC, (p=0.95). No statistically significant differences were found between the average days in the ICU, days with catheter, APACHE II, mortality in general or attributable to catheter of patients with CVC in RA compared with those with the catheter tip located in the SVC. CONCLUSIONS: no difference was found in the incidence of complications that could be related to having the catheter in RA or in the mortality attributable to catheter compared to the patients who had the tip in the SVC. PMID- 20702001 TI - [Intrapulmonary inflammatory response in critically ill patients with pneumonia]. AB - OBJECTIVE: to evaluate the relationship between the microbiology result and cytokine expression in bronchoalveolar lavage (BAL). DESIGN: An observational, prospective study. SETTING: a 17-bed medical and surgical intensive care unit. PATIENTS: Mechanically-ventilated patients with suspected pneumonia admitted to the ICU during a 27-month time period were consecutively enrolled. INTERVENTIONS: BAL was performed with 150ml sterile isotonic saline solution in three aliquots of 50ml. Local anesthetics were not used during the procedure. A BAL sample was processed for a microbiologic quantitative culture and BAL cytokines IL-6, IL 8, TNFalpha, granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) were measured. MAIN VARIABLES OF INTEREST: age, APACHE II score within the first 24 hours of admission, time on mechanical ventilation, ICU length of stay, mortality, previous antibiotic therapy, isolated bacteria and cytokines concentration were analyzed. RESULTS: fifty-nine consecutive patients were included, and most of the patients (79.7%) had prior antibiotic therapy. Twenty-two patients (37.2%) had a positive BAL. In the group of patients with positive BAL, the TNFalpha concentration was significantly higher in the group of patients with positive BAL than in the BAL negative group. CONCLUSIONS: there is a significant correlation between the microbiology result and the TNFalpha concentration in the BAL fluid. In mechanically-ventilated patients, TNFalpha in BAL has been associated with positive cultures despite prior antibiotic therapy. PMID- 20702002 TI - [Prognostic factors in patients with acute coronary syndrome admitted to an intensive care unit]. PMID- 20702003 TI - [Impact of an additional inspiration CT scan on the conventional protocol of the 18F-FDG PET-CT in the detection of small pulmonary nodes]. AB - AIM: To determine the impact of an additional inspiration CT scan on the conventional 18F-FDG PET-CT protocol in the detection of small pulmonary nodules. METHOD: One hundred consecutive patients who presented with one or various nodules were studied. Whole-body PET-CT was performed using Gemini (Philips). CT acquisition parameters were 120 kV/25 mAs, the same as those for the transmission/fusion CT (mild expiration) and inspiratory CT. RESULTS: A total of 188 nodules were detected in the inspiratory CT with sizes between 0.3-3 cm. Non inspiratory CT did not show 20/188 nodules (10.6%) with sizes between 0.3-1cm, this corresponding to 17 patients. The most frequent localization of non detectable nodules in non-inspiratory CT was the lower lobes. 18F-FDG uptake was detected by the PET in 83.9% and 72% of nodules with > 1 cm and between 0.7 and 1cm, respectively. However, only 10.5% of nodules <0.7 cm showed increased metabolic activity. CONCLUSION: In selected patients, inspiratory CT added to conventional PET-CT significantly improves the detection of small nodules (10.6%), especially in those lesions located in the lower lobes, due to respiratory movements, and may have an impact on patient management. PMID- 20702004 TI - FDG uptake in brown adipose tissue-a brief report on brown fat with FDG uptake mechanisms and quantitative analysis using dual-time-point FDG PET/CT. AB - AIMS: Brown adipose tissue (BAT) is a potential source of false-positive findings on [(18)F] FDG PET. In this report, we have discussed the (18)F-FDG uptake mechanisms in BAT and have aimed to determine if dual time point PET imaging helps to differentiate BAT from malignant lesions. METHODS: Patients with dual time-point PET/CT scans were reviewed retrospectively and 31 cases (11 males, 20 females, age: 28.6+/-9.7) having hypermetabolic BAT were included for this study. (18)F-FDG uptake in BAT was quantitatively analyzed by maximum standardized uptake values (SUVmax), and average percent change in SUVmax of BAT between early and delayed images was calculated. RESULTS: Compared to the initial scans, (18)F FDG uptakes in BAT in delayed images were higher in 26 of the patients, and lower in one patient. In terms of body regions, (18)F-FDG uptake increased in 80.6%, remained unchanged in 5.5% and decreased in 13.9% of the body regions. Mean percent change in SUVmax, including all BAT regions, was 19.8+/-19.1% while the mean percent increase was calculated as 69+/-25% in regions where progressive accumulation was observed. The increase in SUVmax correlated with the time interval between the two scans. CONCLUSION: Physiologic (18)F-FDG uptake in BAT increases over time and may mimic the behavior of malignant lesions on dual time point PET imaging. Without the exact anatomic definition of the CT scan, false positive interpretation of PET data may be possible in cases with atypical BAT. PMID- 20702005 TI - Synthesis of new 3-aryl-4,5-dihydropyrazole-1-carbothioamide derivatives. An investigation on their ability to inhibit monoamine oxidase. AB - Some differently substituted 3-aryl-4,5-dihydropyrazoles-1-carbothioamides have been synthesised with the aim to investigate their monoamine oxidase inhibitory activity. The chemical structures of the compounds have been characterized by means of their IR, (1)H NMR, (13)C NMR spectroscopic data and elemental analyses. All the active compounds showed a selective activity towards the B isoform of the enzyme, regardless of the substitution on the heterocyclic ring. The inhibition of the enzymatic activity was measured on human recombinant MAO isoforms, expressed in baculovirus infected BTI insect cells. Docking experiments were carried out with the aim to rationalize the mechanism of inhibition of the most active and selective compound. PMID- 20702006 TI - Synthesis and antimicrobial activities of novel 1H-dibenzo[a,c]carbazoles from dehydroabietic acid. AB - A series of novel 1H-dibenzo[a,c]carbazole derivatives were synthesized in good yield through reaction of methyl 7-oxo-dehydroabietate with a variety of substituted phenylhydrazines. The structures of the newly synthesized compounds were confirmed by IR, (1)H NMR, MS spectral studies and elemental analysis. All compounds were investigated for their activity against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas fluorescens) and three fungi (Trichophyton rubrum, Candida albicans and Aspergillus niger). Among the compound tested, 6d, 6e, 6f and 6m exhibited pronounced antibacterial activities and 6e and 6m also showed moderate antifungal activities. Particularly, 6d exhibited stronger antibacterial activity against B. subtilis comparable to positive control. PMID- 20702007 TI - Novel 6,12-disubstituted chrysene as potent anticancer agent: synthesis, in vitro and in vivo study. AB - We describe herein the synthesis of novel 6,12-distributed chrysene as potent anticancer agents. In vitro and in vivo studies are also reported here. PMID- 20702008 TI - Synthesis and pharmacological study of 1-acetyl/propyl-3-aryl-5-(5-chloro-3 methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazoline. AB - A series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) 2-pyrazolines were synthesized in one step by condensing suitably substituted propenones, hydrazine and acetic/propionic acid. The newly synthesized pyrazolines were characterized by analytical and spectral data. The new compounds were screened for analgesic and anti-inflammatory activity and most of them showed good activity comparable with that of standard drugs Pentazocin and Diclofinac sodium respectively. PMID- 20702010 TI - Born after infant loss: the experiences of subsequent children. AB - OBJECTIVE: to gain an in-depth understanding of subsequent children's experiences of being born into and raised in a family following an infant death. DESIGN: an exploratory qualitative study. SETTING: semi-structured interview in the participants' homes. Data were collected over a five-month period in 2009 and analysed using thematic analysis. PARTICIPANTS: a purposive sample of 10 subsequent children (five boys and five girls) was used. Children whose parents had accessed the support services offered by two bereavement support agencies were recruited. Participants were asked to describe their experiences of being a subsequent child. Interviews were conducted when the subsequent child was at least 13 years of age. FINDINGS: all participants spent time describing how they felt about being a subsequent child. They described how they had experienced life as a subsequent child, how they considered others felt about them (especially their mother), and finally how they felt about their deceased sibling. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: all participants in this study provided a picture of emotional well-being. They were aware of their family history, and all appreciated the grief and loss which their parents had suffered. However, they did not believe that this had impacted negatively on them; rather, most talked about positive effects including feeling loved and special because of the circumstances resulting in their birth. Even those who recognised that they may not have been born had their sibling lived accepted this and appeared to be emotionally secure and well adjusted. These findings suggest that intervention with bereaved parents at the time of the perinatal/infant death and soon after is beneficial to the experiences of the subsequent child. Further research to determine the nature and extent of this benefit is warranted. PMID- 20702009 TI - Face value: an exploration of the psychological impact of orthognathic surgery. AB - We explored the experiences of a group of participants with craniofacial conditions before, during, and after orthognathic surgery. Semi-structured interviews were conducted, recorded, transcribed, and analysed using interpretative phenomenological analysis, and purposive sampling focused on a homogenous group was selected. Participants described unpleasant experiences related to their appearance, the difficulties they had in adjusting to facial changes as a result of surgery, and the differences these changes had made to their body image. The superordinate themes identified after interpretive phenomenological analysis were: self-awareness of facial appearance; attitudes of others and facial appearance; treatment issues; impact of surgery; and support and coping. The accounts provide information about living with an unusual appearance, medical aspects of facial operations over time, changes in body image before, during, and after operation, and the effects of support and coping styles on resilience. PMID- 20702011 TI - A comparison of two stomatal conductance models for ozone flux modelling using data from two Brassica species. AB - In this study we tested and compared a multiplicative stomatal model and a coupled semi-empirical stomatal-photosynthesis model in their ability to predict stomatal conductance to ozone (gst) using leaf-level data from oilseed rape (Brassica napus L.) and broccoli (Brassica oleracea L. var. italica Plenck). For oilseed rape, the multiplicative model and the coupled model were able to explain 72% and 73% of the observed gst variance, respectively. For broccoli, the models were able to explain 53% and 51% of the observed gst variance, respectively. These results support the coupled semi-empirical stomatal-photosynthesis model as a valid alternative to the multiplicative stomatal model for O3 flux modelling, in terms of predictive performance. PMID- 20702012 TI - Soil acidity reconstruction based on tree ring information of a dominant species Abies fabri in the subalpine forest ecosystems in southwest China. AB - To assess the suitability of dendrochemistry as an indicator of soil acidification, soil chemistry and tree ring information of Abies fabri were measured at two distinct sites (severe acid deposition site-Emei Mountain and clean site-Gongga Mountain) of the subalpine forest ecosystems of western Sichuan, southwest China. The actual soil acidity (pH) was significantly correlated with some of the recent xylem cation (Ca, Mg, Mn, Al, Sr and Ba) concentrations and their molar ratios. Xylem Ca/Mg and Ca/Mn of A. fabri were ultimately selected to reconstruct the historical changes of soil pH in Emei Mountain and Gongga Mountain, respectively. The validity of those rebuild was also verified to a certain extent. We conclude that xylem cation molar ratios of A. fabri were superior to the single cation concentrations in soil acidity rebuild at the study sites due to normalizing for concentration fluctuations. PMID- 20702013 TI - Lean healthcare: rhetoric, ritual and resistance. AB - This paper presents an ethnographic account of the implementation of Lean service redesign methodologies in one UK NHS hospital operating department. It is suggested that this popular management 'technology', with its emphasis on creating value streams and reducing waste, has the potential to transform the social organisation of healthcare work. The paper locates Lean healthcare within wider debates related to the standardisation of clinical practice, the re configuration of occupational boundaries and the stratification of clinical communities. Drawing on the 'technologies-in-practice' perspective the study is attentive to the interaction of both the intent to transform work and the response of clinicians to this intent as an ongoing and situated social practice. In developing this analysis this article explores three dimensions of social practice to consider the way Lean is interpreted and articulated (rhetoric), enacted in social practice (ritual), and experienced in the context of prevailing lines of power (resistance). Through these interlinked analytical lenses the paper suggests the interaction of Lean and clinical practice remains contingent and open to negotiation. In particular, Lean follows in a line of service improvements that bring to the fore tensions between clinicians and service leaders around the social organisation of healthcare work. The paper concludes that Lean might not be the easy remedy for making both efficiency and effectiveness improvements in healthcare. PMID- 20702014 TI - Niche players in health policy: medical specialty societies in Congress 1969 2002. AB - Scholars and commentators alike have long used 'organized medicine' as shorthand for the American Medical Association (AMA). However, organized medicine has increasingly shown signs of fragmentation into specialty societies over the last two decades. While the AMA remains the largest association of physicians, and wields a great deal of influence in political circles, its use as a proxy for organized medicine may warrant reevaluation due to the changing political organization of medicine. We developed a unique database of specialty medical society appearances before all Congressional committees by combining records from Lexis-Nexis Congressional and the Policy Agendas database. Descriptive statistics were used to evaluate the participation of specialty societies by committee and by hearing type. The Herfindahl-Hirschman Index (HHI) was used to measure whether specialty societies develop niche roles with specific committees, and the Chi Square Goodness of Fit test was used to study the distribution of specialty society testimonies in health hearings more formally. We found that although the AMA participates in Congressional hearings at a higher rate than any other individual medical specialty society, it accounts for a decreasing percentage of all specialty society appearances over time. In addition, specialty societies have developed niche and monopoly roles in health policymaking as well as relationships with particular congressional committees over time. We conclude that the increasing participation of specialty medical societies in the policymaking process is important because medical societies do not testify solely to promote the economic self-interest of their members. Specialization in medicine has segmented lobbying roles, such that specialty societies have a different focus than the AMA. Thus, 'organized medicine' and the AMA are no longer synonymous. PMID- 20702015 TI - [The sheep as a large animal experimental model in respiratory diseases research]. PMID- 20702016 TI - Accidental hypothermia: rewarming treatments, complications and outcomes from one university medical centre. AB - AIM OF THE STUDY: Accidental hypothermia (AH) is a complex and life threatening condition. Knowledge about epidemiology, rewarming treatments, complications and outcome is limited. This study was initiated to obtain data on causes, rewarming treatments and complications. METHODS: A retrospective cohort study of all patients with a body temperature <= 35 degrees C admitted to the Emergency Department (ED) of the VU university medical centre, Amsterdam, The Netherlands, between January 1, 2000 and August 31, 2008. A predefined set of epidemiological and clinical data was retrieved. RESULTS: Eighty-four patients were included (median age: 47 years). Categories of hypothermia included immersion (18), submersion (29) and exposure to cold (37); concomitant factors were intoxication (26), trauma (40) and homelessness (7). Temperature at admission in the ED was 31.6 +/- 2.6 degrees C (mean +/- SD), lowest temperature 24.2 degrees C. Fourteen different rewarming treatments were used resulting in a wide range of rewarming speeds. Seventy-nine complications occurred: pulmonary, renal and neurological complications in 20, 17 and 10 patients respectively. Seventeen patients had 2 or more late complications. Twenty-four patients (28.6%) died: 10 during rewarming and 14 after rewarming was completed. Prognosis was poor in older and colder patients and after indoor exposure and submersion. CONCLUSION: AH is a rare diagnosis in an inhomogeneous population, treated with a large variety of rewarming techniques. Most complications and death occurred late, after rewarming was completed. Because individual teams gain little clinical experiences, we suggest multiple centre data collection as a first step towards an evidence-based standard of care. PMID- 20702017 TI - Press coverage of hormone replacement therapy and menopause. AB - OBJECTIVE: To evaluate the information reported by Italian press articles about hormone replacement therapy (HRT) and menopause, in terms of completeness, clarity of language and transparency. STUDY DESIGN: In the framework of the Consensus Conference Informing women about hormone replacement therapy, 225 articles published from 2000 to 2007 in Italian lay press were evaluated. Health magazines, weekly news magazines, newspapers, women's magazines and medical practitioners' journals were selected. A form covering graphic layout, completeness of information, clarity of language and transparency was applied to each article by a reviewer. The form was tested in a pilot phase. RESULTS: HRT was recommended to treat menopausal symptoms in more than half of articles (56%) and was described as a preventive measure in almost half (48%). Risks related to HRT were under-reported (58% of the articles). Information on conflicts of interest was lacking (88%). Opinions of experts were the main source of information cited in the articles (66%). CONCLUSIONS: The information reported by the articles is lacking in several aspects. Many women are likely to receive unbalanced information from the press. Qualified sources of information delivered on the scientific knowledge available are needed, reporting advantages and disadvantages of HRT, pharmacological and non-pharmacological alternative treatments and their effectiveness. Scientific journalism needs to grow through training. The role of researchers and clinicians is discussed. PMID- 20702018 TI - Different injection sites of radionuclide for sentinel lymph node detection in breast cancer: single institution experience. AB - OBJECTIVE: The sentinel node is defined as the first lymph node in a regional basin that receives lymph flow from the primary tumor. There is still a controversy over deep versus superficial injection administration in the breast. STUDY DESIGN: From June 2006 to June 2008, 133 patients with biopsy proven breast carcinoma and clinically negative axilla have been treated with conservative surgery and a study of their axillary sentinel lymph nodes (SLN) has been conducted. RESULTS: The median number of SLN detected was significantly higher in the periareolarly injected (PA) group (2.43) than in the intratumorally injected (IT) group (1.92) (p=0.008). The incidence of positive SLN in the PA group was not significantly different from the incidence observed in the IT group (p=0.22). CONCLUSION: Both techniques seem to reliably identify the true SLN in the axilla. Although intradermal as compared with intratumoral injection has numerous advantages, including ease of injection, shorter time between injection and sentinel node identification, and increased radiotracer nodal uptake, nevertheless, intradermal injection allows almost exclusive identification of axillary nodes, and only on rare occasions, of non-axillary nodes. We therefore think that intratumoral injection must be preferred to intradermal when possible to identify the node that is the first draining step of the tumoral tissue. PMID- 20702019 TI - Oligomenorrhoea in adolescents with type 1 diabetes mellitus: relationship to glycaemic control. AB - OBJECTIVE: To investigate oligomenorrhoea in adolescents with type 1 diabetes and the possible relationship with glycaemic control. STUDY DESIGN: The study group consisted of 81 female adolescents with type 1 diabetes whose mean age was 15.0 years (range 12-18). The control group consisted of 205 healthy adolescents with a mean age of 15.5 years (range 12-18). Data on menstruation were collected by two parallel self-administered questionnaires. Oligomenorrhoea was defined as having a menstrual cycle longer than 36 days throughout the past year (5-6/year). The metabolic control of diabetes was evaluated by calculating the mean value of HbA1c during the past year. RESULTS: Age of menarche was greater for adolescents with type 1 diabetes (12.2 +/- 1.4 vs. 11.7 +/- 1.2, p < 0.000) compared to healthy age-matched controls. Logistic regression analysis with oligomenorrhoea as the dependent binary variable revealed an odds ratio equal to 7.8 (95% CI 3.411-17.853) for adolescents with type 1 diabetes (p < 0.000). Finally, a second logistic regression analysis, concerning only adolescents with type 1 diabetes and with the same binary variable, estimated an odds ratio of 4.8 (95% CI 1.784 13.057, p < 0.002) for HbA1c, and an odds ratio of 5.3 (95% CI 1.821-15.130, p < 0.002) for the frequency of hypoglycaemia. CONCLUSION: In adolescents with type 1 diabetes, menarche occurs later and oligomenorrhoea is more frequent. The relative risk of having oligomenorrhoea is greater when there is an increased value of HbA1c or when hypoglycaemia is more frequent. PMID- 20702020 TI - Norwegian farmers ceasing certified organic production: characteristics and reasons. AB - This article examines the characteristics of and reasons for Norwegian farmers' ceasing or planning to cease certified organic production. We gathered cross sectional survey data in late 2007 from organic farmers deregistering between January 2004 and September 2007 (n=220), and similar data from a random sample of farmers with certified organic management in 2006 (n=407). Of the respondents deregistering by November 2007, 17% had quit farming altogether, 61% now farmed conventionally, and 21% were still farming by organic principles, but without certification. Nearly one in four organic farmers in 2007 indicated that they planned to cease certification within the next 5-10 years. From the two survey samples, we categorised farmers who expect to be deregistered in 5-10 years into three groups: conventional practices (n=139), continuing to farm using organic principles (uncertified organic deregistrants, n=105), and stopped farming (n=33). Of the numerous differences among these groups, two were most striking: the superior sales of uncertified organic deregistrants through consumer-direct marketing and the lowest shares of organic land among conventional deregistrants. We summarised a large number of reasons for deregistering into five factors through factor analysis: economics, regulations, knowledge-exchange, production, and market access. Items relating to economics and regulations were the primary reasons offered for opting out. The regression analysis showed that the various factors were associated with several explanatory variables. Regulations, for example, figured more highly among livestock farmers than crop farmers. The economic factor strongly reflected just a few years of organic management. Policy recommendations for reducing the number of dropouts are to focus on economics, environmental attitudes, and the regulatory issues surrounding certified organic production. PMID- 20702021 TI - Ectomycorrhizal fungi as an alternative to the use of chemical fertilisers in nursery production of Pinus pinaster. AB - Addition of fertilisers is a common practice in nursery production of conifer seedlings. The aim of this study was to evaluate whether ectomycorrhizal (ECM) fungi can be an alternative to the use of chemical fertilisers in the nursery production of Pinus pinaster. A greenhouse nursery experiment was conducted by inoculating seedlings obtained from seeds of P. pinaster plus trees with a range of compatible ECM fungi: (1) Thelephora terrestris, (2) Rhizopogon vulgaris, (3) a mixture of Pisolithus tinctorius and Scleroderma citrinum, and (4) a mixture of Suillus bovinus, Laccaria laccata and Lactarius deterrimus, using forest soil as substrate. Plant development was assessed at two levels of N-P-K fertiliser (0 or 600 mg/seedling). Inoculation with a mixture of mycelium from S. bovinus, L. laccata and L. deterrimus and with a mixture of spores of P. tinctorius and S. citrinum improved plant growth and nutrition, without the need of fertiliser. Results indicate that selected ECM fungi can be a beneficial biotechnological tool in nursery production of P. pinaster. PMID- 20702022 TI - Application of membrane bioreactor technology for wastewater treatment and reuse in the Mediterranean region: focusing on removal efficiency of non-conventional pollutants. AB - The Mediterranean Region is a semi-arid area whose land is facing serious erosion, causing adverse impacts on agriculture. To improve the water availability, researchers have proposed the reclamation and reuse of treated wastewater. In this paper, we report the main findings of 10 years of research on the efficiencies of a conventional activated sludge process and a submerged membrane bioreactor, with particular emphasis on the removal of non-conventional pollutants. The studies showed that the membrane bioreactor produced a virtually solids-free, high-quality permeate: most nutrients, heavy metals, and persistent organic pollutants were removed, and in particular, dioxins, furans, and polychlorinated biphenyls were typically present at concentrations below the detection limit. Moreover, the total coliforms count decreased by 4-5 log and Escherichia coli was absent from the membrane bioreactor permeate. These results, combined with the continuing reduction of the capital and operating costs for this approach, suggest that membrane bioreactors are an increasingly cost effective technology to produce treated effluents that are suitable for reuse. PMID- 20702023 TI - Data model for the collaboration between land administration systems and agricultural land parcel identification systems. AB - The Common Agricultural Policy (CAP) of the European Union (EU) has dramatically changed after 1992, and from then on the CAP focused on the management of direct income subsidies instead of production-based subsidies. For this focus, Member States (MS) are expected to establish Integrated Administration and Control System (IACS), including a Land Parcel Identification System (LPIS) as the spatial part of IACS. Different MS have chosen different solutions for their LPIS. Currently, some MS based their IACS/LPIS on data from their Land Administration Systems (LAS), and many others use purpose built special systems for their IACS/LPIS. The issue with these different IACS/LPIS is that they do not have standardized structures; rather, each represents a unique design in each MS, both in the case of LAS based or special systems. In this study, we aim at designing a core data model for those IACS/LPIS based on LAS. For this purpose, we make use of the ongoing standardization initiatives for LAS (Land Administration Domain Model: LADM) and IACS/LPIS (LPIS Core Model: LCM). The data model we propose in this study implies the collaboration between LADM and LCM and includes some extensions. Some basic issues with the collaboration model are discussed within this study: registration of farmers, land use rights and farming limitations, geometry/topology, temporal data management etc. For further explanation of the model structure, sample instance level diagrams illustrating some typical situations are also included. PMID- 20702024 TI - Integrated emergy, energy and economic evaluation of rice and vegetable production systems in alluvial paddy fields: implications for agricultural policy in China. AB - China is the largest rice producing and consuming country in the world, but rice production has given way to the production of vegetables during the past twenty years. The government has been trying to stop this land-use conversion and increase the area in rice-vegetable rotation. Important questions that must be answered to determine what strategy is best for society are, "What is the reason behind this conversion?"; "Which system is more productive and which is more sustainable?"; and "How can economic policy be used to adjust the pattern of farmland use to attain sustainable development?" To answer these questions, a combined evaluation of these agricultural production systems was done using emergy, energy and economic methods. An economic analysis clearly showed that the reason for this conversion was simply that the economic output/input ratio and the benefit density of the vegetable production system were greater than that of rice. However, both energy and emergy evaluations showed that long-term rice was the best choice for sustainable development, followed by rotation systems. The current price of rice is lower than the em-value of rice produced from the long term rice system, but higher than that of rice produced from the rotation system. Scenario analysis showed that if the government increases the price of rice to the em-value of rice produced from the long-term rice system, US$0.4/kg, and takes the value of soil organic matter into account, the economic output/input ratios of both the rice and rotation systems will be higher than that of the vegetable system. The three methods, energy, emergy and economics, are different but complementary, each revealing a different aspect of the same system. Their combined use shows not only the reasons behind a system's current state or condition, but also the way to adjust these systems to move toward more sustainable states. PMID- 20702025 TI - Watershed-scale assessment of arsenic and metal contamination in the surface soils surrounding Miyun Reservoir, Beijing, China. AB - Concentrations of As and selected metals were determined in surface soils of the Miyun Reservoir watershed of Beijing, China. The degree to which concentrations of As and metals exceeded the corresponding background concentration of soils was: Cr>Cu>Zn>As>Ni with no apparent anthropogenic contamination with Cd and Pb. Based on the results of a combination of multivariate statistics and geostatistical analysis, greater concentrations of Cr and Ni in soils were determined to be primarily from iron ore mining near where the Chaohe River enters the northeast portion of the reservoir. Agricultural activities were responsible for the observed elevated concentrations of Cu and Zn in soils. Relatively great concentrations of As were found in soils near the upstream regions of the Baihe River in Chicheng County where small gold mining activities have taken place. The greatest potential for adverse effects of Cr and Cu occurred along the eastern shore of Miyun Reservoir. PMID- 20702026 TI - Using expert opinion to prioritize impacts of climate change on sea turtles' nesting grounds. AB - Managers and conservationists often need to prioritize which impacts from climate change to deal with from a long list of threats. However, data which allows comparison of the relative impact from climatic threats for decision-making is often unavailable. This is the case for the management of sea turtles in the face of climate change. The terrestrial life stages of sea turtles can be negatively impacted by various climatic processes, such as sea level rise, altered cyclonic activity, and increased sand temperatures. However, no study has systematically investigated the relative impact of each of these climatic processes, making it challenging for managers to prioritize their decisions and resources. To address this we offer a systematic method for eliciting expert knowledge to estimate the relative impact of climatic processes on sea turtles' terrestrial reproductive phase. For this we used as an example the world's largest population of green sea turtles and asked 22 scientists and managers to answer a paper based survey with a series of pair-wise comparison matrices that compared the anticipated impacts from each climatic process. Both scientists and managers agreed that increased sand temperature will likely cause the most threat to the reproductive output of the nGBR green turtle population followed by sea level rise, then altered cyclonic activity. The methodology used proved useful to determine the relative impact of the selected climatic processes on sea turtles' reproductive output and provided valuable information for decision-making. Thus, the methodological approach can potentially be applied to other species and ecosystems of management concern. PMID- 20702027 TI - Comparing forest fragmentation and its drivers in China and the USA with Globcover v2.2. AB - Forest loss and fragmentation are of major concern to the international community, in large part because they impact so many important environmental processes. The main objective of this study was to assess the differences in forest fragmentation patterns and drivers between China and the conterminous United States (USA). Using the latest 300-m resolution global land cover product, Globcover v2.2, a comparative analysis of forest fragmentation patterns and drivers was made. The fragmentation patterns were characterized by using a forest fragmentation model built on the sliding window analysis technique in association with landscape indices. Results showed that China's forests were substantially more fragmented than those of the USA. This was evidenced by a large difference in the amount of interior forest area share, with China having 48% interior forest versus the 66% for the USA. China's forest fragmentation was primarily attributed to anthropogenic disturbances, driven particularly by agricultural expansion from an increasing and large population, as well as poor forest management practices. In contrast, USA forests were principally fragmented by natural land cover types. However, USA urban sprawl contributed more to forest fragmentation than in China. This is closely tied to the USA's economy, lifestyle and institutional processes. Fragmentation maps were generated from this study, which provide valuable insights and implications regarding habitat planning for rare and endangered species. Such maps enable development of strategic plans for sustainable forest management by identifying areas with high amounts of human induced fragmentation, which improve risk assessments and enable better targeting for protection and remediation efforts. Because forest fragmentation is a long term, complex process that is highly related to political, institutional, economic and philosophical arenas, both nations need to take effective and comprehensive measures to mitigate the negative effects of forest loss and fragmentation on the existing forest ecosystems. PMID- 20702029 TI - Intra-abdominal fire due to insufflating oxygen instead of carbon dioxide during robot-assisted radical prostatectomy: case report and literature review. AB - We report the first case of intra-abdominal combustion involving the plastic covering of monopolar scissors secondary to use of incorrect gas (oxygen [O(2)] instead of carbon dioxide [CO(2)]) during robot-assisted laparoscopic radical prostatectomy (RALP). The insufflating system was connected to a provisional O(2) gate into the operating theater. A patient underwent RALP and extended pelvic lymph node dissection for localized prostate cancer, according to standard technique. Approximately 1.5 h after the start of surgery, flames arose from the scissor tips during monopolar coagulation. After extinguishing the fire, we promptly withdrew and changed instruments before recognizing and resolving the cause of the incident. The procedure was carried out without patient injury, and the postoperative period was uneventful. PMID- 20702030 TI - Robotic laparoendoscopic single-site radical prostatectomy: technique and early outcomes. AB - BACKGROUND: Laparoendoscopic single-site (LESS) surgery is challenging. To help overcome current technical and ergonomic limitations, the da Vinci robotic platform can be applied to LESS. OBJECTIVES: Our aim was to describe the surgical technique and to report the early outcomes of robotic LESS (R-LESS) radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of prospectively captured R-LESS RP data was performed between May 2008 and May 2010. A total of 20 procedures were scheduled (12 with and 8 without pelvic lymph node dissection). SURGICAL PROCEDURE: R-LESS prostatectomy was performed using the methods outlined in the paper and in the supplemental video material. INTERVENTIONS: All patients underwent R-LESS RP by one high-volume surgeon. Single-port access was achieved via a commercially available multichannel port. The da Vinci S and da Vinci Si surgical platform was used with pediatric and standard instruments. MEASUREMENTS: Preoperative, perioperative, pathologic, and functional outcomes data were analyzed. RESULTS AND LIMITATIONS: The mean age was 60.4 yr; body mass index was 25.4 kg/m(2). The mean operative time was 189.5 min; estimated blood loss was 142.0 ml. The average length of stay was 2.7 d, and the visual analog pain score at discharge was 1.4 of 10. Four focal positive margins were encountered, with two occurring during the first three cases. Pathology revealed a Gleason score of 3+3 in 3 patients, 3+4 in 11 patients, 4+3 in 4 patients, and 4+4 in 2 patients. There were a total of four complications according to the Clavien system including one grade 1, two grade 2, and one grade 4. The median follow-up has been 4 mo (range: 1-24 mo). Study limitations include the small sample size, the short follow-up, and the lack of comparative cohort. CONCLUSIONS: The R-LESS RP is technically feasible and reduces some of the difficulties encountered with conventional LESS RP. PMID- 20702031 TI - Reconstruction of skull base defects in sphenoid wing dysplasia associated with neurofibromatosis I with titanium mesh. AB - Sphenoid wing dysplasia occurs in 3-7% of patients with neurofibromatosis type 1 (NF1). The typical radiological features are partial or complete absence of the greater wing of the sphenoid. This condition is slowly progressive and may result in temporal lobe herniation into the orbital cavity, producing pulsating exophthalmos and gross facial deformity. Thus, reconstruction of the orbit is important for both cosmetic and functional reasons. Traditional surgical treatment of sphenoid dysplasia involves split bone grafting and repair of the anterior skull base defect. However, several reports have demonstrated complications of graft resorption and recurrence of proptosis and pulsating exopthalmos. In this case series, we present two patients suffering from pulsating exophthalmos due to sphenoid dysplasia. Radiological and MRI studies demonstrated orbital enlargement and complete absence of the greater wing of the sphenoid. Surgical management of these patients involved dural defect repair, and the use of titanium mesh in conjunction with bone graft to act as a barrier between the orbit and the middle cranial fossa. The mesh was fixed by fine screws. Proptosis improved markedly post-operatively and resolved within a few weeks. Ocular pulsation subsided and remained quiescent with at least 1-year follow-up. PMID- 20702032 TI - Blood pressure management in acute intracerebral haemorrhage guidelines are poorly implemented in clinical practice. AB - BACKGROUND: Optimal management of blood pressure (BP) in spontaneous intracerebral haemorrhage (ICH) is controversial. We assessed adherence to BP guidelines and its management in ICH in a tertiary Canadian Stroke Centre. METHODS: We conducted a retrospective analysis of 142 CT confirmed primary ICH patients admitted within 24h of symptoms between 2005 and 2006. Initial practice with respect to BP control was reviewed and compared with current guidelines. This retrospective sample was compared with a prospective cohort participating in a BP lowering trial for the attainment of pre-defined BP targets. We also assessed the effect of BP treatment on hematoma expansion and mortality. RESULTS: Blood pressure treatment orders were established in 73% of the 142 patients (median age 71 years, 61% male). Only 26% of patients had target orders as advised in the current AHA guidelines. Only 54% achieved BP targets as compared with 83% of the prospective cohort within 1h. Patients with established BP orders were more likely to have repeat brain imaging (70.2%) than those without (39.5%; p=0.001 Mortality rates were 29.8% and 47.4% in those with and without BP targets respectively (p=0.051). CONCLUSIONS: Management of BP varies considerably and there appears to be little adherence to recommended guidelines. Targets are achieved more rapidly if a BP treatment protocol is utilized. PMID- 20702033 TI - Tumor microenvironment modifications induced by soluble VEGF receptor expression in a rat liver metastasis model. AB - Vascular endothelial growth factor is a potent pro-angiogenic growth factor which is also known to alter tumor microenvironment by inhibiting dendritic cell differentiation and promoting accumulation of myeloid-derived suppressor cells. In the present study, we analyzed the modifications induced by intratumoral expression of sFLT-1, a soluble VEGF receptor, in a rat metastatic colon carcinoma model. We generated colon cancer cell lines stably expressing sFLT-1 or a mock construct. Human umbilical vein endothelial cells cultured with conditioned medium from sFLT-1-expressing tumor cells exhibit a significantly decreased survival, demonstrating the functionality of the secreted sFLT-1. Invivo, sFLT-1 expression induced a 30% decrease in microvessel density in 15-day old experimental liver metastasis from colon carcinoma. Tumor growth was inhibited by 63% and 52% in left and right liver lobes respectively within 25days. In these tumors, sFLT-1 expression was associated with a decreased myeloid cell infiltration and a modification in the expression of several cytokines/chemokines. Altogether, these results suggest that VEGF trapping by sFLT-1 intratumoral expression results in reduced vascularization, tumor growth inhibition and modification of immune tumor microenvironment. PMID- 20702034 TI - Processing-structure-property relationships of Bi2WO6 nanostructures as visible light-driven photocatalyst. AB - QDS modified Bi(2)WO(6) (BWO) nanostructures were processed by calcination at different temperatures. A strong correlation was found among the processing, structure and properties of the samples. With increasing calcination temperature from 200 degrees C to 500 degrees C, the crystallinity increased and the BWO QDS gradually disappeared from the nanostructures. Both surface area and band gap of the samples decreased. The light absorption of the samples became lower for the long-wavelength range, accompanied by a red shift of the absorption edge. The photocatalytic activity of the samples decreased after calcination at higher temperature. The competitive relations between crystallinity and surface area in affecting photocatalytic activity were discussed. The role of BWO QDS that played in enhancement of photocatalytic activity was also revealed by studying structure and property evolution of the calcined samples. PMID- 20702035 TI - Optimization of biodemulsifier production from Alcaligenes sp. S-XJ-1 and its application in breaking crude oil emulsion. AB - A biodemulsifier-producing strain of Alcaligenes sp. S-XJ-1, isolated from petroleum-contaminated soil of the Karamay Oilfield, exhibited excellent demulsifying ability. The application of this biodemulsifier significantly improved the quality of separated water compared with the chemical demulsifier, polyether, which clearly indicates that it has potential applications in the crude oil extraction industry. To optimize its biosynthesis, the impacts of carbon sources, nitrogen sources and pH were studied in detail. Paraffin, a hydrophobic carbon source, favored the synthesis of this cell wall associated biodemulsifier. The nitrogen source ammonium citrate stimulated the production and demulsifying performance of the biodemulsifier. An alkaline environment (pH 9.5) of the initial culture medium favored the strain's growth and improved its demulsifying ability. The results showed paraffin, ammonium citrate and pH had significant effects on the production of the biodemulsifier. These three variables were further investigated using a response surface methodology based on a central composite design to optimize the biodemulsifier yield. The optimal yield conditions were found at a paraffin concentration of 4.01%, an ammonium citrate concentration of 8.08 g/L and a pH of 9.35. Under optimal conditions, the biodemulsifier yield from Alcaligenes sp. S-XJ-1 was increased to 3.42 g/L. PMID- 20702036 TI - Occurrence, temporal evolution and risk assessment of pharmaceutically active compounds in Donana Park (Spain). AB - Donana National Park (Southern Spain) is one of the most emblematic protected areas in Europe and is included in UNESCO's World Heritage List. A 1-year monitoring study was carried out to investigate the presence of 16 pharmaceutical compounds belonging to seven therapeutic groups in wastewater discharges, rivers and streams affecting Donana Park. Fourteen pharmaceuticals were detected in effluent wastewater at concentration levels up to 26.8 MUg L(-1) and thirteen were detected in surface water at concentration levels up to 4.55 MUg L(-1). Ibuprofen was the compound at the highest concentration levels. An increase of the concentration levels in surface water was observed in summer months due to the reduction of the flow rates of the rivers. Nevertheless, risk quotient values estimated in surface water were lower than one so no toxicological effect is suspected to occur. The highest average risk quotients were obtained for ibuprofen (risk quotient 0.67+/-0.28), gemfibrozil (risk quotient 0.52+/-0.33), propranolol (0.13+/-0.06) and naproxen (0.10+/-0.09). Nevertheless, in summer months, risk quotient values up to 9.3 and 10.7 were estimated for the estrogenic compounds 17alpha-ethinylestradiol and 17beta-estradiol. PMID- 20702037 TI - A new statistical framework for parameter subset selection and optimal parameter estimation in the activated sludge model. AB - A new model-calibration method has been proposed to solve the problems associated with parameter subset selection and parameter estimation of the activated sludge model (ASM). We propose the use of a statistical methodology for reasonable parameter selection and parameter estimation that consists of sensitivity analysis, similarity measures, hierarchical clustering and response surface methods (RSM). The introduction of effluent quality index (EQI) can reduce all of the outputs of the ASM model into one factor. The EQI was used to calculate a sensitivity matrix. Then, the hierarchical clustering algorithm was used for parameter subset selection. This selection was based on a similarity measure using the sensitivity matrix and was used to reduce the number of model parameters by selecting only one parameter per cluster group (parameter subset selection step). Lastly, a RSM analysis was conducted in order to determine the optimal parameter values. This study was conducted in order to develop a new statistical framework that can greatly reduce the computational effort required to find the optimal solution by reducing the number of parameters. The experimental results indicated that the calibrated model can improve the prediction quality of the ASM model and the efficiency of the modeling. PMID- 20702038 TI - Defluoridation from aqueous solution by lanthanum hydroxide. AB - This research was undertaken to evaluate the feasibility of lanthanum hydroxide for fluoride removal from aqueous solutions. A batch sorption experiments were conducted to study the influence of various factors such as pH, presence of competing anions, contact time, initial fluoride concentration and temperature on the sorption of fluoride on lanthanum hydroxide. The optimum fluoride removal was observed in the pH(eq)<=7.5. The presence of competing anions showed no adverse effect on fluoride removal. The equilibrium data reasonably fitted the Langmuir isotherm model, and the maximum monolayer sorption capacity was found to be 242.2 mg/g at pH(eq)<=7.5 and 24.8 mg/g at pH(eq)>10.0. The pseudo-second-order kinetic model described well the kinetic data, and resulted in the activation energy of 53.4-68.8 kJ/mol. It was suggested that the overall rate of fluoride sorption is likely to be controlled by the chemical process. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees indicated that the nature of fluoride sorption is spontaneous and endothermic. The used lanthanum hydroxide could be regenerated by washing with NaOH solution. Results from this study demonstrate the potential usability of lanthanum hydroxide as a good fluoride selective sorbent. PMID- 20702039 TI - Kinetic analysis and modeling of oleate and ethanol stimulated uranium (VI) bio reduction in contaminated sediments under sulfate reduction conditions. AB - Microcosm tests with uranium contaminated sediments were performed to explore the feasibility of using oleate as a slow-release electron donor for U(VI) reduction in comparison to ethanol. Oleate degradation proceeded more slowly than ethanol with acetate produced as an intermediate for both electron donors under a range of initial sulfate concentrations. A kinetic microbial reduction model was developed and implemented to describe and compare the reduction of sulfate and U(VI) with oleate or ethanol. The reaction path model considers detailed oleate/ethanol degradation and the production and consumption of intermediates, acetate and hydrogen. Although significant assumptions are made, the model tracked the major trend of sulfate and U(VI) reduction and describes the successive production and consumption of acetate, concurrent with microbial reduction of aqueous sulfate and U(VI) species. The model results imply that the overall rate of U(VI) bioreduction is influenced by both the degradation rate of organic substrates and consumption rate of intermediate products. PMID- 20702040 TI - Mechanisms of decoherence in electron microscopy. AB - The understanding and where possible the minimisation of decoherence mechanisms in electron microscopy were first studied in plasmon loss, diffraction contrast images but are of even more acute relevance in high resolution TEM phase contrast imaging and electron holography. With the development of phase retrieval techniques they merit further attention particularly when their effect cannot be eliminated by currently available energy filters. The roles of electronic excitation, thermal diffuse scattering, transition radiation and bremsstrahlung are examined here not only in the specimen but also in the electron optical column. Terahertz-range aloof beam electronic excitation appears to account satisfactorily for recent observations of decoherence in electron holography. An apparent low frequency divergence can emerge for the calculated classical bremsstrahlung event probability but can be ignored for photon wavelengths exceeding the required coherence distance or path lengths in the equipment. Most bremsstrahlung event probabilities are negligibly important except possibly in large-angle bending magnets or mandolin systems. A more reliable procedure for subtracting thermal diffuse scattering from diffraction pattern intensities is proposed. PMID- 20702041 TI - A new model for investigating the flexural vibration of an atomic force microscope cantilever. AB - A new model for the flexural vibration of an atomic force microscope cantilever is proposed, and a closed-form expression is derived. The effects of angle, damping and tip moment of inertia on the resonant frequency were analysed. Because the tip is not exactly located at one end of the cantilever, the cantilever is modelled as two beams. The results show that the frequency first increases with increase in angle and then decreases to a constant value for high values of the angle. Moreover, the damping is increased at lower contact positions. The tip moment of inertia is also sensitive to the resonant frequency at small values for the odd modes and large values for the even modes. PMID- 20702042 TI - In vitro isolation and identification of the first Neospora caninum isolate from European bison (Bison bonasus bonasus L.). AB - Peripheral blood from European bison (Bison bonasus bonasus L.) living in Bialowieza Forest, north-east Poland, were investigated for the presence of antibodies to Neospora caninum and isolation of parasite. Out of 23 animals three of them showed a strong positive response to N. caninum (13%). The white blood cells from two positive and two negative bison were loaded on monolayer Vero cells culture. The first viable tachyzoites were detected only in positive samples at days 60 and 70 after incubation. For the purpose of the identification the isolates, tachyzoites were evaluated by PCR and sequence analysis of fragment of the Nc-5 region. The sequences of N. caninum-specific Nc5 region were found to be identical to those of other N. caninum isolates found in the public database. The isolate was subsequently named NC-PolBb1 and NC-PolBb2. This is the first record of in vitro isolation of N. caninum from naturally infected European bison (Bison bonasus bonasus L.) and the first isolate obtained from the peripheral blood. PMID- 20702043 TI - Determinants of serum brain-derived neurotrophic factor. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors and affects the survival and plasticity of neurons in the adult central nervous system. The high correlation between cortical and serum BDNF levels has led to many human studies on BDNF levels in various populations, however knowledge about determinants that influence BDNF is lacking. AIMS: To gain insight into the factors that influence BDNF levels in humans. METHODS: In 1168 people aged 18 through 65, free of antidepressants and current psychiatric disease, from the Netherlands study of depression and anxiety four categories of determinants (sampling, sociodemographics, lifestyle indicators and diseases) were measured as well as BDNF level. We used univariate analyses as well as multivariate linear regression analyses in particular to determine which of the possible determinants significantly influenced serum BDNF levels. RESULTS: The mean BDNF level was 8.98ng/ml (SD 3.1ng/ml) with a range from 1.56ng/ml through 18.50ng/ml. Our final multivariate regression analysis revealed that a non fasting state of blood draw (beta=-.067; p=.019), later measurement (beta=-.065; p=.022), longer sample storage (beta=-.082; p=.004) and being a binge drinker (beta=-.063; p=.035) all resulted in attenuated BDNF levels. This was in contrast to smoking (beta=.098; p=.001) and living in an urban area (beta=.109; p<.001), which resulted in increased BDNF levels. Moreover we found that older subjects also had higher BDNF levels, but this only applied to women (beta=.226; p<.001). CONCLUSIONS: Future studies on serum levels of BDNF in humans should correct for the time of blood withdrawal, storage, urbanicity, age, sex, smoking status and food and alcohol intake. PMID- 20702044 TI - Spontaneous remission of cancer: steady and aggressive malignant growth faced with hypoxia or hypoglycemia. AB - A sudden disappearance of cancer and all its signs and symptoms and markers without any medical intervention is considered as a spontaneous remission of cancer. In the past reports of spontaneous remission of cancer was dismissed as a misdiagnosis. Today, with so many bonafide reports of spontaneous remission of cancer (pathology, blood test, radio imaging, etc.) its existence is accepted by the medical community without any recognized beneficial medical explanation. PMID- 20702045 TI - Arsenic eaters and altitude sickness: an epigenetic strategy for improving fitness in a hostile environment? PMID- 20702046 TI - Flupirtine may stop the progressive course of subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis (SSPE) is a progressive devastating disease. Along with the slow measles virus infection, apoptotic cell death has shown to be one of the major mechanisms at the pathogenesis. Volume reduction in frontotemporal cortex has seen in patients at early stages of disease. At present, there is no effective treatment to completely cure SSPE. Oral isoprinosine and intrathecal or intraventricular alpha-interferon are anti viral therapies with limited success. Flupirtine is an anti apoptotic agent which has been used with limited success in Alzheimer disease, prion diseases and neuronal ceroid lipofuscinosis which is a inherited disease of apoptosis related genes. Therefore, we hypothesize that flupirtine with combination of antiviral therapy may halt the progressive course of the disease. PMID- 20702047 TI - The study of pediatric catatonia supports a home of its own for catatonia in DSM 5. AB - The study of pediatric catatonia has not received much attention. During the last few years, progress has been made in delineating this syndrome in children and adolescents across a wide range of disorders. Catatonia is a potentially life threatening but treatable syndrome that also occurs in children and adolescents with autistic, developmental, and tic disorders, and in its idiopathic form. In many of these cases, catatonia cannot be accounted for by an associated psychotic, affective, or medical disorder. These findings are imminently relevant for classification where catatonia is currently restricted to sections of the psychotic, affective, or medical disorders. Catatonia should always be the primary diagnosis in children, adolescents, and adults, as specific treatments for catatonia, i.e., benzodiazepines and electroconvulsive therapy, lower risk of worsening catatonia or precipitating Neuroleptic Malignant Syndrome when antipsychotic medications are used as first-line or sole treatment. The creation of a separate diagnostic class for catatonia is the safest approach to ensure proper diagnosis and treatment of this syndrome in patients of all ages and the best approach to promote research. PMID- 20702048 TI - Regulation of NK-cell function by mucins via antigen-presenting cells. AB - Decidual antigen-presenting cells including dendritic cells (DCs) and CD14(+) macrophages, as mediators of the first encounter with fetal antigens, appear to be critically involved in the initiation of primary immune response by regulating innate- and adaptive immunity. Interleukin-15, produced by them, permits the proliferation and differentiation of CD3(-)CD16(-)CD94(+)NKG2A(+)CD56(+bright) decidual NK cells that identify trophoblast cells. These cells are able to kill them after Th1 cytokine overstimulation and by increasing the release of preformed cytotoxic mediators. Thus, the local microenvironment is a potent modulator of antigen-presenting cell functions. Tumor associated glycoprotein-72 (TAG-72) and mucine 1 (MUC-1) are glycoproteins secreted by uterine epithelial cells. Our hypothesis is that TAG-72 and MUC-1 are the natural ligands for carbohydrate recognition domains (CRDs) of endocytic mannose receptor (MR or CD206) and DC-specific ICAM non-integrin (DC-SIGN or CD209) expressed on decidual CD14(+) macrophages and CD1a(+) DCs. They might be able to condition antigen presenting cells to produce distinct profiles of cyto/chemokines with consequential reduction in NK-cell numbers and cytotoxic potential leading to insufficient control over trophoblast growth. This hypothesis could explain the disappearance of MUC-1 beneath the attached embryo during the process of successful implantation when tight regulation of trophoblast invasion is needed. As IL-15 is the earliest and the most important factor in NK-cell proliferation, differentiation, and maturation, we expected primarily an increase of IL-15 expression in antigen-presenting cells concomitant with the disappearance of mucins and the enhancement in NK cells numbers and of cytotoxic potential after their close contact with early pregnancy decidual antigen-presenting cells. If our hypothesis is correct, it would contribute to the understanding of the role of mucins in the redirection of immune response via antigen-presenting cells and could help explain the mechanism of IL-15 regulation at the maternal-fetal interface of normal, ectopic-, and pathological pregnancies with effects on NK cell proliferation, cytolytic mediator expression, and regulation of trophoblast growth control. PMID- 20702049 TI - Opioid maintenance patients with QTc prolongation: congenital long QT syndrome mutation may be a contributing risk factor. AB - OBJECTIVES: This study investigates opioid maintenance treatment (OMT) patients found to have corrected QT (QTc) interval above 500 ms, with particular focus on past medical history, genetic testing and cardiac investigations. METHODS: Detailed medical and cardiac history was obtained, with particular focus upon risk factors. Cardiac investigations, including genetic testing for the five most common long QT syndrome (LQTS) mutations, exercise electrocardiography (ECG) and 24-h ECG recordings, were performed. RESULTS: Of 200 OMT patients assessed with ECG, seven methadone maintained patients identified with QTc interval above 500 ms participated in this study. Two were identified as heterozygous LQTS mutation carriers. Both had experienced cardiac symptoms prior to and during OMT. No other risk factors for QTc prolongation were detected among the seven patients. Six of the seven patients underwent further cardiac investigations. QTc intervals fluctuated widely over 24h and during exercise for all patients. Only one of the LQTS mutation carriers switched to buprenorphine and started on a beta-blocker. Despite strong medical advice and information, none of the other patients wanted to switch to buprenorphine or take other cardiac protective measures. CONCLUSION: Findings indicate the importance of recording a thorough past medical history, focusing specifically on previous cardiac symptoms, and on other known risk factors for QTc prolongation, prior to initiating patients on methadone. PMID- 20702050 TI - Multiple invasions of O1 FMDV serotype into Israel revealed by genetic analysis of VP1 genes of Israeli's isolates from 1989 to 2007. AB - Foot-and-mouth disease virus (FMDV), one of the most dangerous viruses affecting cloven-hoofed animals, comprises seven serotypes that do not mutually cross protect, with a total of about 80 subtypes. The Middle East is an FMD-endemic region, with repeated FMD outbreaks and In spite of its compulsory vaccination policy in Israel, outbreaks occur repeatedly. In order to compare the Israeli isolates, the complete viral VP1 genes of representative viruses isolated during the major outbreaks from 1989 to 2007 were sequenced and subjected to phylogenetic analysis, which showed that each outbreak was initiated by introduction of a new virus lineage and not by endemic and resident viruses. The differences between the nucleotide sequences of the viruses from the various outbreaks were too big to fit a model of outbreaks caused by endemic virus. Based on this approach, it was revealed that the 2002 outbreak was originated by viruses that circulated in the Arabian peninsula in 1997-1998. PMID- 20702051 TI - Molecular pathology and age estimation. AB - Over the course of our lifetime a stochastic process leads to gradual alterations of biomolecules on the molecular level, a process that is called ageing. Important changes are observed on the DNA-level as well as on the protein level and are the cause and/or consequence of our 'molecular clock', influenced by genetic as well as environmental parameters. These alterations on the molecular level may aid in forensic medicine to estimate the age of a living person, a dead body or even skeletal remains for identification purposes. Four such important alterations have become the focus of molecular age estimation in the forensic community over the last two decades. The age-dependent accumulation of the 4977bp deletion of mitochondrial DNA and the attrition of telomeres along with ageing are two important processes at the DNA-level. Among a variety of protein alterations, the racemisation of aspartic acid and advanced glycation endproducs have already been tested for forensic applications. At the moment the racemisation of aspartic acid represents the pinnacle of molecular age estimation for three reasons: an excellent standardization of sampling and methods, an evaluation of different variables in many published studies and highest accuracy of results. The three other mentioned alterations often lack standardized procedures, published data are sparse and often have the character of pilot studies. Nevertheless it is important to evaluate molecular methods for their suitability in forensic age estimation, because supplementary methods will help to extend and refine accuracy and reliability of such estimates. PMID- 20702052 TI - Effects of low-dose hydrochlorothiazide on urolithiasis and bone metabolism in severely disabled individuals: a pilot study. AB - To clarify the effects of hydrochlorothiazide (HCT) on calcium metabolism in subjects with severe motor and intellectual disabilities (SMID), we examined four patients (16-48years old) with a history of urolithiasis and/or bone fracture and increased urinary calcium/creatinine ratio (U-Ca/Cr). U-Ca/Cr, blood markers of bone turnover, and bone-mineral density (BMD) were measured before and after administration of low-dose HCT (0.25-0.5mg/kg/day). Three months after the initiation of HCT, U-Ca/Cr decreased in all patients, but this effect was less evident at 9-18months. Bone-turnover marker of bone-specific alkaline phosphatase also showed a tendency to decrease, but BMD remained unchanged during the follow up period. In SMID patients, HCT is beneficial for the treatment of hypercalciuria but its effects can be transient in certain cases. HCT may also ameliorate the increase in bone turnover, but its effects on the prevention of bone fractures remain uncertain. Hyponatremia is the most frequent and significant adverse effect of HCT, for which a close observation is mandatory in HCT application for patients with SMID. PMID- 20702053 TI - Microsporidiosis: epidemiology, clinical data and therapy. AB - Microsporidiosis is an emerging and opportunistic infection in AIDS patients, organ transplant recipients, children, travelers, contact lens wearers and the elderly. It is associated with a wide range of clinical syndromes of microsporidiosis in humans. The disease is caused by microsporidia, obligate intracellular microorganisms that were recently reclassified from protozoa to fungi. The 14 species of microsporidia currently known to infect humans, Enterocytozoon bieneusi and Encephalitozoon intestinalis, are the most common causes of human infections and are associated with diarrhea and systemic disease. Species of microsporidia infecting humans have been identified in water sources as well as in wild, domestic and food-producing farm animals, raising concerns of water-borne, food-borne and zoonotic transmission. Various molecules have been tested for treating microsporidiosis in humans with variable success. Albendazole is effective against Encephalitozoon species such us Encephalitozoon intestinalis but not against Enterocytozoon bieneusi. This species has shown excellent clinical therapeutic response to direct action with fumagillin, but this drug is toxic when administered systematically to mammals. Its analog, TNP 470, could be promising alternative. Further work is necessary to identify other drugs, which are both effective and devoid of adverse effects. PMID- 20702054 TI - Chromatographic analysis of local anesthetics in biological samples. AB - This paper reviews gas and liquid chromatographic methods for screening, identification and quantification of local anesthetics and/or their metabolites in biological samples. Basic information about sample preparation, separation, detection, and quantification of each procedure is summarised. The pros and cons of the various procedures are critically discussed. PMID- 20702055 TI - "I wish I'd told them": a qualitative study examining the unmet psychosexual needs of prostate cancer patients during follow-up after treatment. AB - OBJECTIVE: To gain insight into patients' experiences of follow-up care after treatment for prostate cancer and identify unmet psychosexual needs. METHODS: Semi-structured interviews were conducted with a purposive sample of 35 patients aged 59-82 from three UK regions. Partners were included in 18 interviews. Data were analyzed using constant comparison. RESULTS: (1) Psychosexual problems gained importance over time, (2) men felt they were rarely invited to discuss psychosexual side effects within follow-up appointments and lack of rapport with health care professionals made it difficult to raise problems themselves, (3) problems were sometimes concealed or accepted and professionals' attempts to explore potential difficulties were resisted by some, and (4) older patients were too embarrassed to raise psychosexual concerns as they felt they would be considered 'too old' to be worried about the loss of sexual function. CONCLUSION: Men with prostate cancer, even the very elderly, have psychosexual issues for variable times after diagnosis. These are not currently always addressed at the appropriate time for the patient. PRACTICE IMPLICATIONS: Assessments of psychosexual problems should take place throughout the follow-up period, and not only at the time of initial treatment. Further research examining greater willingness or reluctance to engage with psychosexual interventions may be particularly helpful in designing future interventions. PMID- 20702056 TI - Comparing the use of evidence and culture in targeted colorectal cancer communication for African Americans. AB - OBJECTIVE: This study examined the effects (affective reactions, cognitive reactions and processing, perceived benefits and barriers and intent to screen) of targeted peripheral+evidential (PE) and peripheral+evidential+socio-cultural (PE+SC) colorectal cancer communications. METHODS: This study was a two-arm randomized control study of cancer communication effects on affective, cognitive processing, and behavioral outcomes over a 22-week intervention. There were 771 African American participants, 45-75 years, participating in the baseline survey related to CRC screening. Three follow-up interviews that assessed intervention effects on affective response to the publications, cognitive processing, and intent to obtain CRC screening were completed. RESULTS: There were no statistically significant differences between PE and PE+SC intervention groups for affect, cognitive processing or intent to screen. However, there were significant interactions effects on outcome variables. CONCLUSIONS: The advantages and disadvantages of PE+SC targeted cancer communications and implications of sex differences are considered. PRACTICE IMPLICATIONS: While there do not appear to be significant differences in behavioral outcomes when using PE and PE+SC strategies, there appear to be subtle differences in affective and cognitive processing outcomes related to medical suspicion and ethnic identity, particularly as it relates to gender. PMID- 20702057 TI - Toward patient-tailored education in COPD. PMID- 20702058 TI - Effect of a group-based rehabilitation programme on glycaemic control and cardiovascular risk factors in type 2 diabetes patients: the Copenhagen Type 2 Diabetes Rehabilitation Project. AB - OBJECTIVE: To compare the effectiveness of a group-based rehabilitation programme with an individual counselling programme at improving glycaemic control and cardiovascular risk factors among patients with type 2 diabetes. METHODS: We randomised 143 adult type 2 diabetes patients to either a 6-month multidisciplinary group-based rehabilitation programme or a 6-month individual counselling programme. Outcome measures included glycated haemoglobin (HbA(1c)), blood pressure, lipid profile, weight, and waist circumference. RESULTS: Mean HbA(1c) decreased 0.3%-point (95% confidence interval [CI] = -0.5, -0.1) in the rehabilitation group and 0.6%-point (95% CI = -0.8, -0.4) among individual counselling participants (p<0.05). Within both groups, equal reductions occurred in body weight, waist circumference, systolic blood pressure and diastolic blood pressure, but no significant between-group differences between occurred for any of the cardiovascular outcomes. The group-based rehabilitation programme consumed twice as many personnel resources. CONCLUSION: The group-based rehabilitation programme resulted in changes in glycaemic control and cardiovascular risk factor reduction that were equivalent or inferior to those of an individual counselling programme. PRACTICE IMPLICATIONS: The group-based rehabilitation programme, tested in the current design, did not offer additionally improved outcomes and consumed more personnel resources than the individual counselling programme; its broad implementation is not supported by this study. Trial registration Clinicaltrials.gov NCT00284609. PMID- 20702059 TI - The "two-week wait" referral pathway allows prompt treatment but does not improve outcome for patients with oesophago-gastric cancer. AB - INTRODUCTION: The Two Week Wait Referral Service (2WW) has been implemented as a means of fast-tracking patients with suspected upper gastrointestinal cancers for endoscopy. Whether or not it impacts on the outcome of these patients is unclear. The aim of this study was to compare the outcome of patients referred through 2WW with that of patients with oesophago-gastric cancer identified through alternate referral pathways (routine, emergency). METHODS: The study population was 340 patients with oesophago-gastric carcinoma (gastric 154) diagnosed during the time period 01/2006-12/2007 at University Hospitals of Leicester NHS Trust. Data were collected prospectively by the MDT co-ordinator and analysed retrospectively. RESULTS: 135 of the 340 patients with oesophago-gastric cancer were diagnosed through the 2WW, 115 patients through routine referral pathways, and 90 patients were admitted on an emergency basis. Patients referred through 2WW had a median referral to 1st treatment time of 47 days (routine 79, emergency 28, p < 0.001 all group comparisons). The number of patients treated with potentially curative intent was 37 of 135 for the 2WW, 42 of 115 for the routine referrals and 10 of 90 for patients admitted as emergencies. The corresponding median survivals for the groups were 239 days (2WW), 405 days (routine) and 121 days (emergency), p < 0.001 (log rank). CONCLUSIONS: Referral by 2WW resulted in more rapid treatment than routine referral but this did not translate into an improvement in survival. This suggests that the targeting of endoscopy to patients with alarm symptoms is flawed and a less selective approach should be promoted if curable cancers are to be detected. PMID- 20702060 TI - Comparison of VO2 maximum obtained from 20 m shuttle run and cycle ergometer in children with and without developmental coordination disorder. AB - Oxygen consumption at peak physical exertion (VO(2) maximum) is the most widely used indicator of cardiorespiratory fitness. The purpose of this study was to compare two protocols for its estimation, cycle ergometer testing and the 20 m shuttle run, among children with and without probable developmental coordination disorder (pDCD). The shuttle run test was conducted during regular school hours, usually in the gymnasium. Children were then invited to a lab to complete the cycle ergometer protocol. Children were categorized as possible cases of DCD using the Movement-ABC-2. The analysis was performed using cut-points at both the 5th (n=38) and 15th (n=51) percentiles. The average age of children in the study was 12 years (SD=0.5). Children with pDCD had poorer VO(2) maximum when compared to typically developing children based on both the shuttle run and the cycle ergometer. The correlation between tests is in the moderate to high range (r=0.71, p<0.001); 0.78 for girls, and 0.73 for boys. The overall difference in correlations between typically developing children and children with pDCD based on the 15th percentile was 0.12 (p=0.27). For children with pDCD based on the 5th percentile however, the difference between groups was larger (difference in r=0.25), and was statistically significant (p=0.02). In multivariate analyses, there was no difference in the effect of the shuttle run results in predicting VO(2) maximum obtained through the cycle ergometer test for children with pDCD compared to those without the condition. Regardless of the test, the patterns of association between children with pDCD and typically developing children were the same reinforcing the findings of previous field-based reports. Moderate to good correlations, at the 15th percentile cut-point, between tests suggests that the shuttle run test is a reliable substitute in this population when lab based assessments of VO(2) maximum are not feasible. PMID- 20702061 TI - Development of a preschool developmental assessment scale for assessment of developmental disabilities. AB - The aim of this paper was to describe the development of the cognitive domain of the Preschool Developmental Assessment Scale (PDAS) for assessment of preschool children with developmental disabilities. The initial version of the cognitive domain consisted of 87 items. They were administered to 324 preschool children, including 240 children from preschools and 84 children with developmental disabilities. Initial Rasch analysis results indicated that the fit statistics of 42 of the items were outside the acceptable range. Based on the fit statistics and considering the overall structure of the scale, the revised version consisted of 40 items and this version conformed to the Rasch expectations. The revised 40 item scale could differentiate between children with typical development and children with developmental disabilities. It could also differentiate between children from different age groups. The internal consistency estimate (KR-20) was .93. The cognitive domain of the PDAS is considered a promising developmental assessment tool for assessment of developmental disabilities. PMID- 20702062 TI - Effects of vocal training on singing and speaking voice characteristics in vocally healthy adults and children based on choral and nonchoral data. AB - OBJECTIVES: This prospective cross-sectional study examines the effects of voice training on vocal capabilities in vocally healthy age and gender differentiated groups measured by voice range profile (VRP) and speech range profile (SRP). METHODS: Frequency and intensity measurements of the VRP and SRP using standard singing and speaking voice protocols were derived from 161 trained choir singers (21 males, 59 females, and 81 prepubescent children) and from 188 nonsingers (38 males, 89 females, and 61 children). RESULTS: When compared with nonsingers, both genders of trained adult and child singers exhibited increased mean pitch range, highest frequency, and VRP area in high frequencies (P<0.05). Female singers and child singers also showed significantly increased mean maximum voice intensity, intensity range, and total VRP area. The logistic regression analysis showed that VRP pitch range, highest frequency, maximum voice intensity, and maximum-minimum intensity range, and SRP slope of speaking curve were the key predictors of voice training. Age, gender, and voice training differentiated norms of VRP and SRP parameters are presented. CONCLUSIONS: Significant positive effect of voice training on vocal capabilities, mostly singing voice, was confirmed. The presented norms for trained singers, with key parameters differentiated by gender and age, are suggested for clinical practice of otolaryngologists and speech language pathologists. PMID- 20702063 TI - Feasibility of pulmonary valve imaging using three-dimensional transthoracic echocardiography. AB - BACKGROUND: The pulmonary valve (PV) is rarely visualized in short axis with conventional two-dimensional transthoracic echocardiography (TTE). Thus, the true incidence of abnormal PV morphology in patients undergoing TTE is unknown. This study sought to evaluate the feasibility of using three-dimensional echocardiography in the morphologic assessment of the PV in short-axis. METHODS: A total of 200 consecutive patients referred for routine TTE were prospectively evaluated (mean age 64 +/- 16 years; 113 males). Live3D and full-volume 3D (FV3D) were performed with the feasibility of visualizing PV morphology assessed. McNemar's test was used as a nonparametric comparator between Live3D and FV3D results and to assess for any significant learning curve. Chi-square test was used to determine the association between variables. RESULTS: PV morphology detection rates were significantly different (P < .0001) between Live3D (60%) and FV3D (23%). The optimal plane for Live3D was the parasternal view (99%), using zoom over the PV and rotating to a short-axis image. PV short-axis cusp detection using Live3D was dependent on the initial two-dimensional PV image quality (P < .0001). CONCLUSION: Live3D is feasible in evaluating PV short-axis morphology and provides incremental value in the TTE examination. PMID- 20702064 TI - Current concepts in mitral valve prolapse--diagnosis and management. AB - Although mitral valve prolapse as a disease entity has been recognized for over 50 years, its precise definition has been elusive. Initial reports based the diagnosis on auscultatory findings (late systolic click - murmur), with left ventricular angiography as a confirmative test. Echocardiography, first the M mode, and subsequently the two-dimensional, became the dominant diagnostic modality. However, the early reports did not distinguish between billowing valve and flail valve. The advent of surgical repair techniques provided a different perspective; the surgical definition of mitral valve prolapse is often different from that of cardiologists. Intraoperative echocardiography gained wide acceptance necessitating a common language to describe precise terminology of the leaflet anatomy and definition of valve prolapse. The present report proposes a terminology and definitions of valve prolapse with relevance to surgical mitral valve repair. The addition of real-time 3D transesophageal echocardiography now provides highly accurate localization of lesions and the multi segment assessment of valve pathology. The etiologic considerations and surgical repair techniques with the role of echo - surgery team in improved patient outcome are described. PMID- 20702065 TI - Vancomycin minimum inhibitory concentrations (MICs) for meticillin-resistant Staphylococcus aureus (MRSA) in Hong Kong. PMID- 20702066 TI - Stability of doripenem, imipenem and meropenem at elevated room temperatures. PMID- 20702067 TI - Evidence of female-specific glial deficits in the hippocampus in a mouse model of prenatal stress. AB - Prenatal stress (PS) has been associated with an increased incidence of numerous neuropsychiatric disorders, including depression, anxiety, schizophrenia, and autism. To determine the effects of PS on hippocampal-dependent behaviour hippocampal morphology, we examined behavioural responses and hippocampal cytoarchitecture of a maternal restraint stress paradigm of PS in C57BL6 mice. Female offspring only showed a reduction in hippocampal glial count in the pyramidal layer following PS. Additionally, only PS females showed increased depressive-like behaviour with cognitive deficits predominantly in female offspring when compared to males. This data provides evidence for functional female-specific glial deficits within the hippocampus as a consequence of PS. PMID- 20702068 TI - Efficacy and safety of second-generation antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders: comprehensive review of prospective head-to-head and placebo-controlled comparisons. AB - OBJECTIVE: To review data on efficacy and safety of second-generation antipsychotics (SGAs) in children and adolescents with psychotic and bipolar spectrum disorders. METHODS: Medline/PubMed/Google Scholar search for studies comparing efficacy and/or tolerability: (i) between two or more SGAs; (ii) between SGAs and placebo; and (iii) between at least one SGA and one first generation antipsychotic (FGA). The review focused on three major side-effect clusters: 1. body weight, body mass index, and cardiometabolic parameters, 2. prolactin levels, and 3. neuromotor side effects. RESULTS: In total, 34 studies with 2719 children and adolescents were included. Studies lasted between 3 weeks and 12 months, with most studies (79.4%) lasting 3 months or less. Nine studies (n=788) were conducted in patients with schizophrenia, 6 (n=719) in subjects with bipolar disorder, and 19 (n=1212) in a mixed population. Data on efficacy showed that, except for clozapine being superior for refractory schizophrenia, there were no significant differences between SGAs. By contrast, safety assessments showed relevant differences between SGAs. Mean weight gain ranged from 3.8 kg to 16.2 kg in patients treated with olanzapine (n=353), from 0.9 kg to 9.5 kg in subjects receiving clozapine (n=97), from 1.9 kg to 7.2 kg in those on risperidone (n=571), from 2.3 kg to 6.1 kg among patients taking quetiapine (n=133), and from 0 kg to 4.4 kg in those treated with aripiprazole (n=451). Prolactin levels increased the most in subjects on risperidone (mean change ranging from 8.3 ng/mL to 49.6 ng/mL), followed by olanzapine (-1.5 ng/mL to +13.7 ng/mL). Treatment with aripiprazole was associated with decreased prolactin levels, while clozapine and quetiapine were found to be mostly neutral. With respect to neuromotor side effects, SGAs were associated with less parkinsonism and akathisia than FGAs. Most of the studies comparing neuromotor side effects between SGAs found no significant differences. CONCLUSIONS: SGAs do not behave as a homogeneous group in children and adolescents with psychotic and mood disorders. Except for clozapine, the heterogeneity within the SGA group is mainly due to differences in the rates and severity of adverse events, especially regarding weight gain as a proxy for the risk of cardiometabolic disturbances. PMID- 20702069 TI - Autobiographical memories of anger in violent and non-violent individuals: a script-driven imagery study. AB - Numerous studies have implicated frontal lobe dysfunction in anger-related impulsive violent behavior; however, few studies have looked at frontal activity during angry states in violent individuals. Using PET and a script-driven imagery paradigm, we report on autobiographical memories of angry vs. neutral memories in violent patients and psychiatric matched controls. Relative to recall of neutral memories, recall of anger-laden memories was associated with an activation of frontal regions among control subjects but not violent subjects. Violent subjects demonstrated relatively greater activations in the left amygdala, pontine, and cerebellar regions compared to control subjects. PMID- 20702070 TI - The role of hippocampus dysfunction in deficient memory encoding and positive symptoms in schizophrenia. AB - BACKGROUND: Declarative memory disturbances, known to substantially contribute to cognitive impairment in schizophrenia, have previously been attributed to prefrontal as well as hippocampal dysfunction. AIMS: To characterize the role of prefrontal and mesolimbic/hippocampal dysfunction during memory encoding in schizophrenia. METHOD: Neuronal activation in schizophrenia patients and controls was assessed using functional magnetic resonance imaging (fMRI) during encoding of words in a deep (semantic judgement) and shallow (case judgment) task. A free recall (no delay) and a recognition task (24h delay) were performed. RESULTS: Free recall, but not recognition performance was reduced in patients. Reduced performance was correlated with positive symptoms which in turn were related to increased left hippocampal activity during successful encoding. Furthermore, schizophrenia patients displayed a hippocampal hyperactivity during deep encoding irrespective of encoding success along with a reduced anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (DMPFC) activity in successful encoding but an intact left inferior frontal cortex (LIFC) activity. CONCLUSIONS: This study provides the first evidence directly linking positive symptoms and memory deficits to dysfunctional hippocampal hyperactivity. It thereby underscores the pivotal pathophysiological role of a hyperdopaminergic mesolimbic state in schizophrenia. PMID- 20702071 TI - Structural and functional imaging approaches in attention deficit/hyperactivity disorder: does the temporal lobe play a key role? AB - Attention deficit/hyperactivity disorder (ADHD) is characterized by widespread structural and functional abnormalities in the brain. We applied different structural imaging techniques such as voxel-based morphometry (VBM), diffusion tensor imaging (DTI), and magnetization transfer imaging (MTI) to study anatomical differences between boys with ADHD and healthy controls, as well as functional magnetic resonance imaging (fMRI) together with independent component analysis (ICA) to detect functional alterations. 14 boys with ADHD and 12 controls were included in our study. Results of DTI showed the expected differences in frontal and cerebellar white matter. VBM and MTI indicated group differences in the temporal lobe. Applying ICA to fMRI data, we extracted four components; two positively correlated to our working memory paradigm and two negatively correlated. Positive components included activation in frontal and parietal regions. Negative components showed activation in anterior and posterior cingulate cortex/precuneus and temporal regions, and were interpreted as forming part of the default mode network. Group differences in the inferior temporal lobe were detected. Applying different techniques, we found differences between boys with ADHD and controls mainly located in the temporal lobe. Therefore, we postulate that research on ADHD should broaden its scope by including the temporal lobe as a potentially important locus of abnormalities in ADHD. PMID- 20702072 TI - PDMS-based porous particles as support beds for cell immobilization: bacterial biofilm formation as a function of porosity and polymer composition. AB - The objective of this work is to test the performance of new synthetic polydimethylsiloxane (PDMS)-based bed particles acting as carriers for bacteria biofilms. The particles obtained have a highly interconnected porous structure which offers a large surface adsorption area to the bacteria. In addition, PDMS materials can be cross-linked by copolymerization with other polymers. In the present work we have chosen two hydrophilic polymers: xanthan gum polysaccharide and tetraethoxysilane (TEOS). This versatile composition helps to modulate the interfacial hydrophobic/hydrophilic balance at the particle surface level and the roughness topology and pore size distribution, as revealed by scanning electron microscopy. Biofilm formation of a consortium isolated from a tannery effluent enriched in Sulphate Reducing Bacteria (SRB), and pure Acidithiobacillus ferrooxidans (AF) strains were assayed in three different bed particles synthesized with pure PDMS, PDMS-xanthan gum and PDMS-TEOS hybrids. Bacterial viability assays using confocal laser scanning fluorescence microscopy indicate that inclusion of hydrophilic groups on particle's surface significantly improves both cell adhesion and viability. PMID- 20702073 TI - The influence of NaCl on hydrophobicity of selected, pharmacologically active bile acids expressed with chromatographic retention index and critical micellar concentration. AB - Many of bile acids' (BA) physiological properties, as receptor binding, activation of ionic channels, binding to blood proteins, etc. are due to their hydrophobicity. On the other hand, hydrophobicity determines BAs' physico chemical characteristics as micelle forming and adsorption (surface activity). However, BA hydrophobicity is not determined solely by their structure. Medium composition, especially the concentration of electrolytes has influence on BA hydrophobicity. Thus, the objective of this work was to examine the effect of NaCl on hydrophobicity of selected bile acids. This influence is specified with the retention factor k (reversed phase high pressure liquid chromatography (RPHPLC)) and critical micellar concentration (CMC) determined by non-invasive NMR method. The value of lnk elevates with the increase in mobile phase NaCl concentration i.e. Deltalnk/Deltac(NaCl) depends on the number of water molecules not stabilised by hydrogen bonds in bile acid hydration sheath. For bile acids that contain hydroxyl groups (except those with beta equatorial hydroxyl groups) the value of |DeltalnCMC/Deltac(NaCl)| rises with the increase in the number of non-stabilized water molecules in their hydration sheath. Even though oxo derivatives of cholic acid have similar chromatographic parameters they behave differently when it comes to CMC. In fact with the introduction of oxo groups the value of its |DeltalnCMC/Deltac(NaCl)| elevates but it results in a decrease in the number of non-stabilized water molecules i.e. hydrophobicity falls. Different behaviour of oxo derivatives implicate that, besides "hydrophobic interactions" in their micelles, there are also hydrogen bonds i.e. fiord effect exists. PMID- 20702074 TI - Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohydrogel. AB - Poly(NIPAAm)-CS based nanohydrogels (NHGs) and iron oxide (Fe(3)O(4)) magnetic nanoparticles encapsulated magnetic nanohydrogels (MNHGs) were synthesized by free radical polymerization of N-isopropylacrylamide (NIPAAm) at 60 degrees C in presence of chitosan (CS) in different feed ratios. The polymerization of NIPAAm and the presence of CS as well as Fe(3)O(4) in hydrogels were confirmed from Fourier transform infrared (FTIR) spectra and X-ray diffraction (XRD), respectively. (13)C solid state nuclear magnetic resonance (NMR) spectra clearly revealed the grafting of CS into poly(NIPAAm). The scanning electron microscopy (SEM) and atomic force microscopy (AFM) images showed the formation of spherical shaped NHGs of different sizes ranging from 50 nm to 200 nm depending upon the feed ratios of CS and NIPAAm, which was further supported by mean hydrodynamic diameter measured by dynamic light scattering (DLS). It has been observed that CS not only served as a cross linker during polymerization but also plays a critical role in controlling the growth of NHG and enhancement in lower critical solution temperature (LCST). The encapsulation of Fe(3)O(4) nanoparticles (10-12 nm) into NHGs ( approximately 200 nm) was confirmed by transmission electron microscopy (TEM) and further corroborated with magnetic force microscopy (MFM) image. The LCST of poly(NIPAAm) was found to increase with increasing weight ratio of CS to NIPAAm. Furthermore, the encapsulation of iron oxide nanoparticles into hydrogels also caused an increment in LCST. Specifically, temperature optimized NHG and MNHG were fabricated having LCST close to 42 degrees C (hyperthermia temperature). The MNHG shows optimal magnetization, good specific absorption rate (under external AC magnetic field) and excellent cytocompatibility with L929 cell lines, which may find potential applications in hyperthermia treatment of cancer and targeted drug delivery. PMID- 20702075 TI - Spinal surgery for palliation in malignant spinal cord compression. AB - Malignant spinal cord compression is an important neuro-oncological emergency, the management of which has been changing throughout the last 30 years. We hereby attempt to present an overview of this pathological entity with general management concepts, paying special attention to the palliative surgical treatments available, the decision-making process and the new emerging treatment modalities. PMID- 20702076 TI - Predictive factors for evaluation of response to fluticasone propionate/salmeterol combination in severe COPD. AB - BACKGROUND: The predictive factors for treatment response in patients with severe chronic obstructive pulmonary disease (COPD) are unknown. We investigated predictive factors for response to fluticasone propionate/salmeterol (FSC) in severe COPD patients. METHODS: This prospective, open-label, non-comparative study included 921 adult patients with severe COPD (baseline forced expiratory volume in 1 s (FEV(1)) <50% of predicted), a history of repeated exacerbations, and symptoms despite bronchodilator treatment. FSC (500 MUg/50 MUg) was delivered via an inhaler, twice a day, for 12 weeks. The primary efficacy endpoint was the response rate for inspiratory capacity (IC), FEV(1), or quality of life (QoL), assessed with the Saint George's respiratory questionnaire, at week 6 and week 12. RESULTS: The overall response rate to FSC at 6 and 12 weeks was 79%. The corresponding rates for FEV(1), IC, and QoL were 38%, 55%, and 62%, respectively. More than 40% of patients showed a response for IC and/or QoL without being responders for FEV(1.) Overall lung function and QoL were improved. FSC was well tolerated with a safety profile consistent with that observed previously. CONCLUSION: Nearly 80% of patients responded to FSC treatment in this real-life study. Improvements in IC and QoL at 12 weeks revealed a clinically relevant response in patients with no improvement in FEV(1). IC reversibility to salbutamol before treatment might represent, better than FEV1, a prognostic factor of response to FSC in severe COPD. Moreover these tests are easy to perform routinely and in large numbers of patients. PMID- 20702077 TI - Kinetochore assembly: if you build it, they will come. AB - Accurate chromosome segregation requires the interaction of chromosomes with the microtubules from the mitotic spindle. This interaction is mediated by the macro molecular kinetochore complex, which assembles only at the centromeric region of each chromosome. However, how this site is specified and how assembly of the kinetochore structure is regulated in coordination with cell cycle progression remains unclear. Recent studies have begun to shed light on the mechanisms underlying assembly of this complex structure. PMID- 20702078 TI - An overview of metals recovery from thermal power plant solid wastes. AB - Thermal power plants (TPPs) that burn fossil fuels emit several pollutants linked to the environmental problems of acid rain, urban ozone, and the possibility of global climate change. As coal is burned in a power plant, its noncombustible mineral content is partitioned into bottom ash, which remains in the furnace, and fly ash, which rises with flue gases. Two other by-products of coal combustion air-pollution control technologies are flue gas desulfurization (FGD) wastes and fluidized-bed combustion (FBC) wastes. This paper analyzed and summarized the generation, characteristics and application of TPP solid wastes and discussed the potential effects of such solid wastes on the environment. On this basis, a review of a number of methods for recovery of metals from TPP solid wastes was made. They usually contain a quantity of valuable metals and they are actually a secondary resource of metals. By applying mineral processing technologies and hydrometallurgical and biohydrometallurgical processes, it is possible to recover metals such as Al, Ga, Ge, Ca, Cd, Fe, Hg, Mg, Na, Ni, Pb, Ra, Th, V, Zn, etc., from TPP solid wastes. Recovery of metals from such wastes and its utilization are important not only for saving metal resources, but also for protecting the environment. PMID- 20702079 TI - Development of a novel antioxidant assay technique based on G-quadruplex DNAzyme. AB - Study on antioxidants' radical scavenging processes and antioxidant capabilities is important for understanding the protective role of antioxidants against oxidative damages associated with some chronic diseases and food degradation. Traditional methods to monitor the radical scavenging by antioxidant require expensive instrument and sophisticated synthesis process. Herein, we report a novel, simple, colorimetric DNAzyme-based method to detect radical-scavenging capacity of antioxidant. In this new strategy, horseradish peroxidase (HRP) mimicking DNAzyme catalyzes the oxidation of ABTS2- (2,2'-azinobis-(3 ethylbenzothiazoline-6-sulfonic acid)) by H2O2 to generate blue/green ABTS.- radical, which can be scavenged by antioxidants resulting in color change. The typical kinetic curve of antioxidant-inhibited generation of ABTS.- shows distinct biphasic pattern, involving a lag phase (stage I) and a linear increase phase (stage II). kt value, the product of lag time (t) and the slope of the curve in stage II (k), was used as the parameter for antioxidant capacity determination. This DNAzyme-based antioxidant assay has been effectively used to quantitatively detect the concentrations of antioxidants and evaluate the antioxidant capabilities of a variety of antioxidants and some real samples. Compared with traditional antioxidant assays, this method is thermostable, pH stable, and time-saving, which presents a promising platform for antioxidant assay. PMID- 20702080 TI - Development of a (PQQ)-GDH-anode based on MWCNT-modified gold and its application in a glucose/O2-biofuel cell. AB - In this study a biofuel cell anode is developed on the basis of multi-walled carbon nanotubes (MWCNTs). Recombinant pyrroloquinoline quinone (PQQ) dependent glucose dehydrogenase (GDH) is covalently coupled to a PQQ-layer which is adsorbed onto thiol-modified MWCNTs at a gold electrode. In the presence of glucose a catalytic current starts at a potential of -80 mV vs. Ag/AgCl, 1M KCl. Under substrate saturation current densities of 170-200 MUA/cm2 can be achieved. The operation is based on mediated electron transfer of the enzyme. This (PQQ) GDH-MWCNT-electrode is combined with a MWCNT-modified electrode to which bilirubin oxidase (BOD) is covalently coupled. The resulting membrane-free biofuel cell has an open cell potential of 600 mV and can achieve a power density in the range of 23 MUW/cm2. PMID- 20702081 TI - Programming cells: towards an automated 'Genetic Compiler'. AB - One of the visions of synthetic biology is to be able to program cells using a language that is similar to that used to program computers or robotics. For large genetic programs, keeping track of the DNA on the level of nucleotides becomes tedious and error prone, requiring a new generation of computer-aided design (CAD) software. To push the size of projects, it is important to abstract the designer from the process of part selection and optimization. The vision is to specify genetic programs in a higher-level language, which a genetic compiler could automatically convert into a DNA sequence. Steps towards this goal include: defining the semantics of the higher-level language, algorithms to select and assemble parts, and biophysical methods to link DNA sequence to function. These will be coupled to graphic design interfaces and simulation packages to aid in the prediction of program dynamics, optimize genes, and scan projects for errors. PMID- 20702082 TI - Non-invasive mechanical ventilation with spinal anesthesia for cesarean delivery. AB - We present the successful use of perioperative non-invasive mechanical ventilation in a morbidly obese pregnant woman with bronchial asthma, severe preeclampsia and pulmonary edema undergoing an emergency cesarean delivery with spinal anesthesia. The combination of non-invasive mechanical ventilation with neuraxial anesthesia may be of value in selected parturients with acute or chronic respiratory insufficiency requiring surgery. PMID- 20702083 TI - Self-reported post-discharge symptoms following obstetric neuraxial blockade. AB - BACKGROUND: Economic pressures are leading to earlier hospital discharge following delivery, before complications of obstetric neuraxial block may become apparent. Our aim was to estimate the incidence of symptoms presenting post discharge at a single tertiary obstetric centre. METHODS: From June 2004 to June 2007, a prospective observational study of all women receiving neuraxial block for labour and delivery in our hospital was conducted. Patients were reviewed in hospital by the acute pain team and provided with a discharge advice form to take home to identify potential block-related complications. We collected data on those contacting us with new-onset symptoms after hospital discharge. RESULTS: Ninety-eight patients (1.4%) made contact post-discharge following neuraxial block. The time range overall for presentation of symptoms was 2-260 days, with headache reported significantly earlier than backache. Many symptoms were self limiting. Headache was the commonest primary complaint in 43 patients (44%) with four receiving an epidural blood patch. Sensorimotor symptoms of pain, paraesthesia or weakness was the primary complaint in 33 patients (34%), and backache in 21 (21%). Sixteen percent of patients with headache, 24% with sensorimotor symptoms and 14% with backache were referred to neurologists. There was a late self-report of obstetric palsy (1:15,033). CONCLUSIONS: New post discharge symptoms were self-reported by 1.4% of patients following neuraxial blockade. These were not detected during hospital stay despite routine directed post-block review. Only 4% of these symptoms could be directly attributable to neuraxial block. PMID- 20702084 TI - Anaesthetic management of a patient with pituitary adenoma for caesarean section. PMID- 20702085 TI - Chromatin remodeling in heart development. AB - Heart development is a complex process that relies on networks of interacting transcription factors. Mutations in genes encoding some of these transcription factors result in many inherited congenital heart defects and point to the importance of these networks. Chromatin remodeling complexes are intimately associated with these transcriptional networks, adding an additional layer of complexity and fine-tuning to the regulation of heart development. Understanding these relationships will be crucial to understand fundamental concepts in tissue specific gene regulation in organogenesis, in unraveling the mechanisms of congenital heart disease, as well as providing new avenues for reprogramming new cardiomyocytes for heart repair. PMID- 20702086 TI - Growth and excitement in membrane protein structural biology. PMID- 20702087 TI - Novel biodegradable polymeric flocculant based on polyacrylamide-grafted tamarind kernel polysaccharide. AB - Novel biodegradable polymeric flocculants were produced by conventional redox grafting, microwave-initiated and microwave-assisted grafting of acrylamide to tamarind kernel polysaccharide (TKP). The graft copolymers were characterized by viscometry, elemental analysis, molecular weight determination using SLS analysis, and NMR spectroscopy. The flocculation efficiency of the grafting products in kaolin suspension, municipal sewage wastewater and textile industry wastewater was primarily dependent on the length of the grafted polyacrylamide chain. The flocculant obtained by microwave-assisted grafting method was superior to TKP and polyacrylamide-based commercial flocculant (Rishfloc 226 LV) in flocculation tests. PMID- 20702088 TI - Environmentally benign periphyton bioreactors for controlling cyanobacterial growth. AB - Microporous suspended bioreactors immobilized with periphytons were submerged between sediments and overlying water to control phosphorus release and cyanobacterial (Microcystis aeruginosa) growth. The results showed that the periphyton mainly consisted of bacteria and diatoms. The application of periphyton bioreactor decreased the levels of exchange phosphorus (Exch-P) in sediments from 1.69 to 0.49 mg g(-1) and total phosphorus (TP) from 0.75 to 0.30 mg L(-1). The significant reduction of the total dissolved phosphorus (TDP) content was not only beneficial for the decrease of the cyanobacterial growth, but also stimulates the periphyton to produce natural cyanobacterial inhibitors such as gallic acid and ethyl-2-methylacetoacetate. These synergistic effects led to the growth inhabitation of M. aeruginosa when the initial concentrations of M. aeruginosa were less than 119.3 microg L(-1). This study provides an environmentally-friendly and publically acceptable method of controlling bacterial blooms when compared to traditional addition of chemicals. PMID- 20702089 TI - Factors influencing cellulosome activity in consolidated bioprocessing of cellulosic ethanol. AB - The cellulosome, a multi-subunit protein complex catalyzing cellulose degradation in cellulolytic Clostridium thermocellum, plays a crucial role in Consolidated Bioprocessing (CBP) of lignocellulose into ethanol. Here, activity of cellulosome was tested under varying concentrations of chemical compounds derived from lignocellulose pretreatment and fermentation. We found that, firstly, the cellulolytic activity of cellulosome was actually promoted by formate, acetate and lactate; secondly, cellulosome was tolerant up to 5mM furfural, 50mM p hydroxybenzoic acid and 1mM catechol. Furthermore, the cellulosome exhibited higher ethanol tolerance and thermostability than commercialized fungal (Trichoderma reesei) cellulase. To probe the implication of these unique enzyme features, C. thermocellum JYT01 was cultured under conditions optimal for cellulosome activity. This CBP system yielded 491 mM ethanol, the highest level reported thus far for C. thermocellum monocultures. These findings demonstrate the potential advantages of bacterial cellulosome, and provide a novel strategy for design, selection and optimization of the cellulosome-ethanologen partnership. PMID- 20702090 TI - Biodiesel production from tung (Vernicia montana) oil and its blending properties in different fatty acid compositions. AB - The feasibility of biodiesel production from tung (Vernicia montana) oil was investigated with respect to the transesterification yield and biodiesel properties. Tung oil has poor oxidation stability due to the instability of the conjugated carbon-carbon double bonds in the alpha-elaeostearic acid. The methyl elaeostearate is the predominant component (82.2 wt.%) of the tung oil biodiesel. The tung oil biodiesel has the low cold filter plugging point of -11 degrees C, ester content of 94.9 wt.%, and oxidation stability (110 degrees C) of 0.3h. Moreover, the tung oil biodiesel exhibits the high density of 903 kg/m(3)at 15 degrees C, kinematic viscosity of 7.84 mm(2)/s at 40 degrees C, and iodine value of 161.1g I(2)/100g. The properties of the tung oil biodiesel can be improved by blending with canola and palm oil biodiesels to satisfy the biodiesel specifications. In addition, multiple linear correlations between biodiesel properties and its methyl ester composition were established. PMID- 20702091 TI - Effect of pH on nutrient dynamics and electricity production using microbial fuel cells. AB - The aim of this work was to study the effect of pH on electricity production and contaminant dynamics using microbial fuel cells (MFCs). To investigate these effects, an air-cathode MFC was used to treat urban wastewater by adjusting the pH between 6 and 10. The short-term tests showed that the highest power production (0.66 W.m(-3)) was at pH 9.5. The MFC operation in continuous control mode for 30 days and at the optimal pH improved the performance of the cell relative to power generation to 1.8 W.m(-3). Organic matter removal (77% of influent COD) and physical ammonium loss were directly influenced by pH and followed the same behavior as the power generation. At a pH higher than the optimal one, anodic bacteria were affected, and power generation ceased. However, biological nitrogen processes and phosphorus dynamics were independent of the exoelectrogenic bacteria. PMID- 20702092 TI - Lanostane triterpenes from Ganoderma lucidum suppress the adipogenesis in 3T3-L1 cells through down-regulation of SREBP-1c. AB - Several lanostane triterpenes [butyl ganoderate A (1), butyl ganoderate B (2), butyl lucidenate N (3), and butyl lucidenate A (4)] bearing a butyl ester side chain from the fruiting bodies of Ganoderma lucidum exhibited considerable inhibitory effects on adipogenesis in 3T3-L1 cells. The inhibitory mechanism of 1 and 3 on adipogenesis in 3T3-L1 cells was investigated; we found that the mRNA and protein expression levels of SREBP-1c were reduced by treatment with 1 and 3 versus the untreated control. Furthermore, compounds 1 and 3 suppressed the mRNA expression levels of FAS and ACC. These results demonstrate that inhibition of adipogenesis in 3T3-L1 cells by treatment with 1 and 3 may be mediated in part through down-regulation of the adipogenic transcription factor SREBP-1c and its target genes, such as FAS and ACC. PMID- 20702093 TI - [17(20)E]- and [17(20)Z]-pregna-5,17(20)-dien-21-oylamides. Facile synthesis and primary evaluation for cancer cells proliferation. AB - Reaction of 17alpha-bromo-21-iodo-3beta-acetoxypregn-5-en-20-one with ammonia, primary, and secondary amines is simple and convenient method for preparation of [17(20)E]- and [17(20)Z]-pregna-5,17(20)-dien-21-oylamides. Synthesis and characteristics of 12 related amides are presented. Primary testing on cells proliferation indicated differing effects of synthesized compounds on androgen insensitive MCF-7 cells and androgen sensitive LNCaP cells. PMID- 20702094 TI - Role of the premotor cortex in leg selection and anticipatory postural adjustments associated with a rapid stepping task in patients with stroke. AB - The premotor cortex (PMC) plays an important role in selecting and preparing for movement. This study investigates how stroke-induced PMC lesions affect stepping leg selection and anticipatory postural adjustments (APAs) preparation. Fifteen hemi-paretic patients (eight with PMC lesions (PMC(Lesion)) and seven PMC spared (PMC(Spared))) and eight age- and sex-matched healthy adults participated in the study. The subjects performed rapid forward stepping with the right or left leg under simple and choice reaction time conditions. The percentage of trials in which the subject showed the correct initial vertical ground reaction force pattern before lift-off of the stepping leg indicated the accuracy in selecting the designated stepping leg. The latency of bilateral contractions in the tibialis anterior (TA) and the reaction time (RT) of the stepping leg represented the time needed to prepare for stepping-related APAs and stepping movement, respectively. All three groups demonstrated a similar rate of accuracy of the stepping leg selection under both conditions. However, in both conditions, the PMC(Lesion) group exhibited a longer RT and TA contraction latency of the affected leg than the healthy and PMC(Spared) groups. The PMC(Lesion) group also presented a longer TA contraction latency of the unaffected leg than the healthy group in both conditions. These results suggest that the PMC is involved in APAs associated with leg stepping movement and that a PMC lesion in one hemisphere impairs APAs of both the contralateral and ipsilateral legs during stepping. PMID- 20702095 TI - Combined endoscopic endonasal and posterior cervical approach to a clival chordoma. AB - Chordomas in the clival-cervical region present challenges to the neurosurgical team due to their encroaching nature, proximity to critical neurovascular structures and often large size due to late presentation. This report illustrates the utility of a staged approach when confronted with such a pervasive tumour. We describe the adaptive combination of two approaches, the endoscopic endonasal transsphenoidal plus posterior cervical approaches, in the surgical management of a clival chordoma extending inferiorly to C3 in an 18-year-old male. PMID- 20702096 TI - Synthesis and in vitro antitumor activity of new 4,5-dihydropyrazole derivatives. AB - A series of 3,5-diaryl-4,5-dihydropyrazole regioisomers, and their 1-acetylated derivatives, bearing a 3,4,5-trimethoxyphenyl moiety combined with a variety of substituted phenyl rings, was synthesized and evaluated for antitumor activity. Results of the in vitro assay against a non-small cell lung carcinoma cell line (NCI-H460) showed several compounds to be endowed with cytotoxicity in micromolar to sub-micromolar range, depending on substitution pattern and position of aryl rings on 4,5-dihydropyrazole core. Potent and selective activity was also observed in the NCI 60 human cancer cell line panel. 5-(3,4,5 Trimethoxyphenyl)pyrazolines 31 and 39 were found to possess potent antiproliferative activity against SR and MDA-MB-435, with GI(50) inhibitory values in nanomolar range. Structure-activity relationships revealed that introduction of a (hydroxy)acetyl group at N-1 of inactive 5-(3,4,5 trimethoxyphenyl)pyrazolines, results in a clear in vitro activating effect. Compound 31 (IC(50)=5.16 microM) showed inhibition of tubulin polymerization comparable to that of CA-4 (IC(50)=4.92 microM). PMID- 20702097 TI - Genitalic morphology and copulatory mechanism of the scorpionfly Panorpa jilinensis (Mecoptera: Panorpidae). AB - Specific genitalic morphology reflects vital sexual functions in insects and examination of genitalic structures is important in understanding copulatory mechanisms. The morphology of male and female genitalia was investigated in the scorpionfly Panorpa jilinensis using light and scanning electron microscopy. The male genitalia are located between the epandrium and hypandrium of the ninth abdominal segment. The hypandrium comprises a broad basal stalk and two long hypovalvae. The gonopods are two-segmented, each consisting of a basal gonocoxite and a distal gonostylus. The parameres are Y-shaped, with a basal stalk and two apical branches (ventral and dorsal parameres), each of which terminates into a flattened lobe. The aedeagus bears a pair of well-developed ventral and a pair of small dorsal valves with the phallotrema situated centrally. In the female genitalia, the subgenital plate is emarginated in a V-shape at the distal end and seems to be paired in the origin, with the gonopore (the opening of the common oviduct) at its base. The genital plate is composed of a plate, two long posterior arms, and a long broad axis, the ventral groove of which bears the spermathecal duct. The copulatory pore (the spermathecal opening) is situated medially at the posterior end of the genital plate. Based on the morphology of the male and female genitalia and mating behaviour observations, the copulatory mechanism of P. jilinensis is briefly discussed. PMID- 20702098 TI - Measurement of 60Co high gamma dose using gamma activation of 115 In and 111 Cd foils. AB - Cobalt-60 gamma irradiation facilities are used in many industrial and medical applications. Gamma activation technique of (115)In and (111)Cd foils was used in this work to assess the performance of ethanol-chlorobenzene gamma dosimeter at high dose range of (60)Co irradiation facility. Dose mapping was also performed using (115)In foils. These measurements are required to control the irradiation quality and to validate dose calculations. PMID- 20702099 TI - Effective atomic number of composite materials for Compton effect in the gamma ray region 280-1115 keV. AB - In this paper, we report the effective atomic number, Z(eff), of composite materials for Compton effect in the gamma ray region 280-1115 keV based on the theoretically obtained Klein-Nishina scattering cross sections in the angular range 50-100 degrees as well as experimentally measured differential incoherent (Compton) scattering cross sections of some composite materials at three scattering angles of 60 degrees , 80 degrees , and 100 degrees . The Z(eff) values so obtained were found to be both angle and energy independent in the region of interest so that it could be concluded that it is possible to represent such composite materials by a mean atomic number in this region as suggested in earlier reports recently. PMID- 20702100 TI - Changes in apolar metabolites during in vitro organogenesis of Pancratium maritimum. AB - Calli, shoot-clumps and regenerated plants were initiated from young fruits of Pancratium maritimum L. Their genetic stability was monitored by flow cytometry before chemical studies. Apolar metabolites (alkaloids extracted at pH > 7, free fatty acids and fatty alcohols, sterols etc.) were qualitatively and quantitatively analyzed by GC-MS. The results clearly demonstrated that alkaloid synthesis in P. maritimum is closely related with tissue differentiation. The highest amounts of alkaloids and presence of homolycorine and tazettine type compounds (end products of the biosynthetic pathway of the Amaryllidaceae alkaloids) were found in highly differentiated tissues. Galanthamine accumulated in the leaves of plantlets. The amount of hordenine, a protoalkaloid, is related with the ability of tissues to synthesize alkaloids. Saturated fatty acids were found in considerably higher levels in undifferentiated callus cultures and partially differentiated shoot-clumps than in regenerated plants. Mono- and dienoic fatty acids were found at higher levels in non-photosynthesizing tissues calli, and in vitro and intact bulbs, while alpha-linolenic acid (trienoic acid) was found in higher amounts in the photosynthesizing leaves of shoot-clumps and regenerated plants than in bulbs and calli. Fatty alcohols were found mainly in leaves, while sterols tended to accumulate in photosynthesizing and undifferentiated tissues. PMID- 20702101 TI - Storage time of allogeneic red blood cells is associated with risk of severe postoperative infection after coronary artery bypass grafting. AB - OBJECTIVE: The storage time of allogeneic red blood cells (RBCs) has been linked with the risk of severe postoperative infections following cardiac surgery. However, existing data are sparse and inconsistent. We therefore examined the association between the age of transfused RBCs and development of severe postoperative infection following coronary artery bypass grafting (CABG) in a large population-based cohort study. METHODS: The study included patients undergoing CABG with or without concomitant cardiac surgery between June 2003 and July 2008 in the North and Central Denmark regions. Data on demography, perioperative variables, allogeneic blood transfusion and severe postoperative infections (deep sternal wound infection, bacteremia or septicemia) were retrieved from medical databases and medical records. We used logistic regression analyses to compute the crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the association between storage time of transfused RBCs and the risk of severe infection. RESULTS: A total of 4240 patients were included in the final analyses, and 1748 of these patients (41%) were transfused with RBCs. Among transfused patients, 953 were exclusively transfused with RBC stored for < 14 days and 548 were exclusively transfused with RBC stored for >= 14 days. Severe infection was identified in 165 patients (3.9%). The adjusted ORs for severe infection among all transfused patients and patients transfused with RBCs stored exclusively for either < 14 days or >= 14 days were 1.6 (95% CI: 0.9-2.8), 1.1 (95% CI: 0.6-2.1), and 2.3 (95% CI: 1.2-4.2), respectively, when compared with non-transfused patients. There was a dose-response relationship between the number of transfused RBC units and the risk of severe infection among patients exclusively transfused with RBCs stored for >= 14 days. CONCLUSION: Although the risk of possible confounding could not be eliminated entirely in this observational study, the findings add further support for the hypothesis that storage time of RBCs is positively associated with the risk of transfusion related severe postoperative infection in patients undergoing CABG. PMID- 20702102 TI - Value of diastolic flow with transit-time flow meters in coronary artery bypass surgery. PMID- 20702103 TI - Right coronary artery obstruction by tricuspid anuloplasty ring. PMID- 20702104 TI - Peripheral T-cell lymphoma--not otherwise specified. AB - Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) does correspond to a heterogeneous group of nodal and extranodal mature T-cell lymphomas, with a low prevalence in Western countries. PTCL-NOS accounts for about 25% of all PTCL, which represent over 15% of all lymphomas. In the lymph node, PTCL-NOS shows paracortical or diffuse infiltrates with effacement of the normal architecture, with a broad cytological spectrum and a frequently observed inflammatory background. Some morphological variants include: lymphoepithelioid or Lennert's type, T-zone, and follicular. PTCL-NOS is characterized by an aberrant T-cell phenotype, with frequent loss of CD5 and CD7. A CD4+/CD8- phenotype predominates in nodal cases. CD4/CD8 +/+ or -/- is at times seen, as is CD8, CD56 and cytotoxic granule expression. Ki-67 rate is typically high. TCR beta-chain is usually expressed; TCR genes are most often clonally rearranged. PTCL-NOS typically occurs in adults (median age 55-60 years), with a higher prevalence in males. It presents more often as disseminated disease, occasionally with eosinophilia, pruritis or hemophagocytic syndrome. Patients often have B symptoms, generalized lymphadenopathy, bone marrow infiltration, and extranodal involvement, with high or high-intermediate IPI score in 50-70% of cases. Prognosis is poor, with a 5-year OS of 20-30%. Some variables, like ST2(L), CXCR5, CXCR3, EBV infection, cytotoxic granule expression, high proliferative index, NF-kappaB expression, were proposed as prognostic indicators, but the IPI score, and its variant called PIT, remains the most effective prognostic factor. Patients with PTCL-NOS should be treated with anthracycline-containing chemotherapy, followed by radiotherapy in cases of stage I-II disease. This strategy is associated with an overall response rate higher than 60%, but the 5 year overall survival is only 20-30%. Upfront high-dose chemotherapy supported by autologous or allogeneic SCT is an investigational approach, with a 4-year overall survival of about 40%. Patients with chemosensitive relapse respond favorably to high-dose chemotherapy and ASCT, with long-term survival rates of 35 45%. Graft-versus-lymphoma effect following allogeneic SCT has been observed; and reduced intensity conditioning emerges as an attractive strategy for frail patients. Most patients with PTCL-NOS are enrolled in prospective trials to explore new approaches, and new agents, like gemcitabine, alemtuzumab and pralatrexate, are being investigated. PMID- 20702105 TI - Antiangiogenic strategies in breast cancer management. AB - Angiogenesis is considered one of the key mechanisms of tumour growth and survival. Therefore it represents an ideal pharmaceutical target. Many antiangiogenic agents have been developed so far in several solid tumours and also in breast cancer. Vascular endothelial growth factor (VEFG) is the main target and both monoclonal antibodies and small molecules belonging to the tyrosine kinase inhibitors directed against VEGF(R) have been developed. Some other therapeutic approaches have shown to exert some antiangiogenic activity, such as hormonal agents, metronomic chemotherapy, bisphosphonates and others. In this paper we provide an introduction of the current data supporting the angiogenesis in breast cancer and a review of the most relevant antiagiogenic therapies which have been investigated so far. PMID- 20702106 TI - Evidence that metyrapone in the presence of inflammation modulates cytokine mRNA expression. AB - OBJECTIVE: Metyrapone (MT) has been used clinically to decrease glucocorticoid levels in human and animal studies. However, the potential effects of MT in the presence of inflammation are poorly understood. Thus, the aim of this study was to evaluate the effects of the administration of MT on the mRNA levels of pro inflammatory cytokines in the presence of inflammation induced by the well established model of ligature-induced periodontitis in rats. MATERIAL AND METHODS: Sixty animals were randomly assigned into three experimental groups of 20 rats each: G1-control; G2-periodontal disease (PD) induced by cotton ligature; G3-PD associated with 3 daily doses of MT (50mg/kg/3*3h). After 30 days, all animals were killed by decapitation. Blood samples were taken and the concentrations of corticosterone and catecholamines measured. Marginal tissues around ligated and non-ligated teeth were harvested and gene expression was assessed by quantitative polymerase chain reaction technique (qPCR). Moreover, the area of interradicular bone loss (ABL) was histometrically determined. RESULTS: Data analysis showed that: (i) ligature placement resulted in a significant ABL, as compared to non-ligated sites of G1 group; (ii) mRNA levels of all the pro-inflammatory factors assessed (INF-gamma, TNF-alpha, IL-1beta and IL-6) were increased in the PD group (G2) (p<0.05) when compared to G1; (iii) there were no significant differences in corticosterone and catecholamine plasmatic levels between the three groups; (iv) MT administration, in the presence of inflammation, induces an increased ABL and significantly increased mRNA levels of all pro-inflammatory cytokines analyzed (p<0.05). CONCLUSION: Within the limits of this study, it can be concluded that MT in the presence of inflammation may modulate expression of pro-inflammatory cytokines, regardless of its effect on plasma corticosterone levels. PMID- 20702107 TI - Applicability of bacterial endotoxins test to various blood products by the use of endotoxin-specific lysates. AB - Endotoxin contamination is a serious threat to the safety of parenteral drugs, and the rabbit pyrogen test has played a crucial role in controlling this contamination. Although the highly sensitive endotoxin test has replaced the pyrogen test for various pharmaceuticals, the pyrogen test is still implemented as the control test for most blood products in Japan. We examined the applicability of the endotoxin test to blood products for reliable detection and quantification of endotoxin. Nineteen types of blood products were tested for interfering factors based on spike/recovery of endotoxin by using 2 types of endotoxin-specific lysate reagents for photometric techniques. Interfering effects on the endotoxin test by the products could be eliminated by diluting from 1/2 to 1/16, with the exception of antithrombin III. However, conventional lysate reagents that also react with non-pyrogenic substances, such as (1-3)-beta D-glucan, produced results that were not relevant to endotoxin content or pyrogenicity. Our results showed that the endotoxin test would be applicable to most blood products if used with appropriate endotoxin-specific lysate reagents. PMID- 20702108 TI - Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation. AB - This meeting was successful in achieving its main goals: (1) summarize currently available information on the origin, detection, quantification and characterization of sub-visible particulates in protein products, available information on their clinical importance, and potential strategies for evaluating and mitigating risk to product quality, and (2) foster communication among academic, industry, and regulatory scientists to define the capabilities of current analytical methods, to promote the development of improved methods, and to stimulate investigations into the impact of large protein aggregates on immunogenicity. There was a general consensus that a considerable amount of interesting scientific information was presented and many stimulating conversations were begun. It is clear that this aspect of protein characterization is in its initial stages. As the development of these new methods progress, it is hoped that they will shed light on the role of protein particulates on product quality, safety, and efficacy. A topic which seemed appropriate for short term follow up was to hold further discussions concerning the development and preparation of one or more standard preparations of protein particulates. This would be generally useful to facilitate comparison of results among different studies, methods, and laboratories, and to foster further development of a common understanding among laboratories and health authorities which is essential to making further progress in this emerging field. PMID- 20702109 TI - Assessment of allergen sensitization in a general population-based survey (European Community Respiratory Health Survey I). AB - PURPOSE: Exposed to a common environment, the IgE-mediated immune response differs, for instance, among sensitized subjects, some of them reacting toward one allergen (monosensitized) whereas others are sensitized to a wide array of allergens (polysensitized). However, a better phenotypic characterization is needed for epidemiologic studies. Using the data collected during the ECRHS I (European Community Respiratory Health Survey), several assessments of skin prick tests and serum-specific IgE to identify mono- and polysensitized patients were compared. METHODS: Subjects took part in the ECRHS-I. The CAP-System was used for serum allergen-specific IgE, and allergen-coated Phazet was used for prick tests. Four allergens (Dermatophagoides pteronyssinus, cat, timothy grass, and Cladosporium) were measured using IgE and nine (the same ones plus olive pollen, birch, Alternaria, Parietaria, and ragweed) were skin tested. One to two local allergens were also tested, depending on countries. RESULTS: Prevalence of sensitization in 11,355 subjects (34.0 [27.9-40.1] years, 49.9% men) ranged from 32.3% (four specific IgE, 19.3% mono- and 13.0% polysensitized) to 41.8% (four specific IgE combined to nine prick tests, 19.6% mono- and 22.2% polysensitized). Concordance between four specific IgE and four prick tests was weak (weighted kappa 0.65 [0.64-0.66]). Concordance between seven and nine prick tests was high (weighted kappa 0.99 [0.98-1.00]). Local allergens induced small changes in the prevalence of sensitization, and reclassified some subjects from mono- to polysensitized. CONCLUSIONS: Skin tests or serum-specific IgE may be chosen to identify allergenic sensitivity, mono- and polysensitized subjects without being strictly interchangeable. PMID- 20702110 TI - Gestational weight gain and birth outcome in relation to prepregnancy body mass index and ethnicity. AB - PURPOSE: The obesity epidemic raises concerns about the impact of excessive and insufficient weight gain during pregnancy. METHODS: We examined the association between gestational weight gain (GWG) and preterm birth, term small- and large for-gestational-age (SGA and LGA), term birthweight, and term primary Cesarean delivery, considering prepregnancy body mass index (BMI) and ethnicity in a cohort of 33,872 New York City residents who gave birth between 1995 and 2003 and delivered in hospitals elsewhere in New York State. RESULTS: Preterm birth (<37 weeks' gestation) showed a modest U-shaped relationship, with projected GWG of <10 kg and 20+ kg associated with odds ratios of 1.4 and 1.3, respectively, relative to 10 to 14 kg. The pattern was stronger for preterm birth <32 weeks' and for underweight women with low GWG and overweight/obese women with high GWG. Term SGA decreased and term LGA and birthweight increased monotonically with increasing GWG. Primary Cesarean delivery followed the same pattern as LGA, but less strongly. CONCLUSIONS: Although the study is limited by potential selection bias and measurement error, our findings support the contention that GWG may be a modifiable predictor of pregnancy outcome that warrants further investigation, particularly randomized trials, to assess whether the relation is causal. PMID- 20702111 TI - Effect of knee joint cooling on the electromyographic activity of lower extremity muscles during a plyometric exercise. AB - During sporting events, injured athletes often return to competition after icing because of the reduction in pain. Although some controversy exists, several studies suggest that cryotherapy causes a decrease in muscle activity, which may lead to a higher risk of injury upon return to play. The purpose of this study was to investigate the effect of a 20-min knee joint cryotherapy application on the electromyographic activity of leg muscles during a single-leg drop jump in twenty healthy subjects, randomly assigned to an experimental and a control group. After the pre-tests, a crushed-ice bag was applied to the knee joint of the experimental group subjects for 20 min, while the control group subjects rested for 20 min. All subjects were retested immediately after this period and retested again after another 20 min of rest. Average electromyographic activity and ground contact time were calculated for the pre- and post-test sessions. Decreases in electromyographic activity of the lower extremity musculature were found in pre-activation, eccentric (braking), and concentric (push-off) phases immediately after the icing, and after 20 min of rest. The results lend support to the suggestion that cryotherapy during sporting events may place the individuals in a vulnerable position. PMID- 20702112 TI - How should we normalize electromyograms obtained from healthy participants? What we have learned from over 25 years of research. AB - Electromyograms (EMGs) need to be normalized if comparisons are sought between trials when electrodes are reapplied, as well as between different muscles and individuals. The methods used to normalize EMGs recorded from healthy individuals have been appraised for more than a quarter of a century. Eight methods were identified and reviewed based on criteria relating to their ability to facilitate the comparison of EMGs. Such criteria included the magnitude and pattern of the normalized EMG, reliability, and inter-individual variability. If the aim is to reduce inter-individual variability, then the peak or mean EMG from the task under investigation should be used as the normalization reference value. However, the ability of such normalization methods to facilitate comparisons of EMGs is questionable. EMGs from MVCs can be as reliable as those from submaximal contractions, and do not appear to be affected by contraction mode or joint kinematics, particularly for the elbow flexors. Thus, the EMG from an isometric MVC is endorsed as a normalization reference value. Alternatively the EMG from a dynamic MVC can be used, although it is recognized that neither method is guaranteed to be able to reveal how active a muscle is in relation to its maximal activation capacity. PMID- 20702113 TI - Computed tomography perfusion imaging in spectacular shrinking deficit. AB - Spectacular shrinking deficit (SSD) is characterized by abrupt onset of a major hemispheric stroke syndrome, followed by dramatic and rapid improvement. We retrospectively identified patients with SSD diagnosed at our institution between December 1, 2007, and June 30, 2009. We reviewed computed tomography perfusion (CTP) imaging to determine perfusion defect as a measure of initial ischemic penumbra, and magnetic resonance imaging diffusion-weighted imaging (DWI) to determine the final infarct core. Among the 472 consecutive ischemic stroke patients, 126 (27%) presented with major hemispheric ischemic stroke syndrome, defined as National Institutes of Health Stroke Scale score (NIHSS) >=8 in the territory of the middle cerebral artery (MCA) or internal carotid artery (ICA). Out of these patients, we identified 8 SSD patients with available CTP data. In these 8 patients, the mean time to dramatic recovery was 3.4 hours (range, 0.75-7 hours), and the mean time from onset to CTP was 12.7 hours (range, 3-30 hours). All 8 patients had perfusion abnormalities in portions of the MCA territory (partial MCA territory in 5 patients and complete MCA territory in 3 patients). The mean time from onset to MRI DWI was 15.5 hours (range, 7.9-34 hours). Restricted diffusion was present in all patients in the corresponding MCA distribution. Vascular imaging revealed MCA occlusion in 2 patients. Cervical vascular imaging revealed carotid occlusion in 2 patients and high-grade carotid stenosis in 2 patients. The stroke mechanisms were cardioembolism in 2 patients, large artery in 4 patients, and unknown in 2 patients. Four patients had repeat CTP imaging available that demonstrated eventual resolution of the perfusion defect. SSD is associated with a "shrinking" clinical syndrome and a "shrinking" perfusion pattern on CTP that lags behind clinical recovery. CTP imaging corroborates that a larger territory is at risk in SSD and contributes to better understanding of SSD. PMID- 20702114 TI - Renin-angiotensin system blockade safely reduces blood pressure in patients with minor ischemic stroke during the acute phase. AB - The ACCESS (Acute Candesartan Cilexetil Therapy in Stroke Survivors) study found that administration of candesartan in the acute phase of stroke confers a long term benefit in patients who have sustained acute ischemic stroke. This treatment did not significantly reduce blood pressure (BP) during the acute phase, however. We assessed the short-term safety of reducing BP with renin-angiotensin system blockade in hypertensive patients who sustained acute ischemic stroke. Our randomized study compared the effects of 14 days of oral candesartan (4 mg/day), perindopril (4 mg/day), or conventional therapy (topical nitrate only when systolic BP (SBP) was >=220 mm Hg or diastolic BP (DBP) was >=120 mm Hg) administered to hypertensive patients within 72 hours of the onset of minor ischemic stroke. We assessed neurologic symptoms using the National Institutes of Health Stroke Scale and the modified Rankin Scale within 72 hours of stroke onset before and after drug therapy. A total of 40 patients completed the protocol. Therapy with candesartan and perindopril reduced SBP/DBP values by 23/11 mm Hg (SBP, P<.01; DBP, P=.07) and 14/0 mm Hg (SBP, P=.07), respectively, compared with conventional treatment. Neurologic symptoms worsened in 2 patients who received perindopril, which has no statistical significance, despite the BP reduction in patients given candesartan or perindopril. Our findings indicate that low doses of candesartan or perindopril safely reduce SBP in hypertensive patients with acute ischemic stroke. PMID- 20702115 TI - Middle cerebral artery infarct following multiple bee stings. AB - Neurologic events following bee stings are very rare. We report a 59-year-old man who became drowsy with slurred speech following multiple bee stings. In the hospital, he was found to have left-sided hemplegia, seventh cranial nerve palsy, and left conjugate gaze palsy. Further investigation revealed dyslipidemia, impaired glucose tolerance, and a middle cerebral artery territory infarct. His limb weakness and speech improved before his discharge from the hospital. PMID- 20702116 TI - Transcatheter aortic valve implantation: is general anesthesia superior to conscious sedation? PMID- 20702117 TI - Progress in perioperative medicine: focus on statins. AB - Beyond cholesterol reduction, statins have multiple beneficial influences on vascular endothelial function, atherosclerotic plaque stability, inflammation, and thrombosis. These favorable pleiotropic effects may be the basis for their perioperative risk reduction in cardiothoracic and vascular procedures. The published evidence suggests that statins offer significant outcome benefits throughout perioperative practice. Because statin therapy significantly reduces the perioperative risk for patients undergoing cardiovascular procedures, they already are recommended in published guidelines. Beyond cardiac risk reduction, statin therapy also may protect the brain and the kidney in the perioperative setting, both in cardiac and vascular surgery. The pleiotropic effects of statins also appear to have therapeutic roles in the progression of valve disease, sepsis, and venous thrombosis. Further trials are required to provide data to drive their safe and comprehensive perioperative application for optimal patient outcome both in the short term and the long term. Because there are multiple randomized trials currently in progress throughout perioperative medicine, it is very likely that the indications for statins will be expanded significantly. PMID- 20702118 TI - A mitral valve mass: tumor, thrombus, or vegetation? PMID- 20702119 TI - Cardiac surgery-associated acute renal injury: new paradigms and innovative therapies. PMID- 20702120 TI - The eustachian valve as a pitfall in persistent foramen ovale and atrial septum defect closure. PMID- 20702121 TI - Motor function in children with cryptogenic localization related epilepsy. AB - INTRODUCTION: In CLRE specific learning difficulties and motor problems may occur. The aim of this study is to examine whether CLRE or the accompanying specific learning difficulties are associated with the occurring problems in motor function. METHODS: Motor functioning in 140 children with CLRE and without epilepsy, as well as with and without specific learning difficulties is compared using Chi-square. RESULTS: In the CLRE group 35% score below the 5th percentile (poor motor function). No correlations with epilepsy variables or the occurrence of specific learning difficulties is found. DISCUSSION: A subgroup of about one third of children with CLRE are at risk for poor motor function. Their development is best monitored using a multi-dimensional approach, including cognitive development and motor functioning. PMID- 20702122 TI - Personality traits and social behaviors predict the psychological adjustment of Chinese people with epilepsy. AB - Very little is known about the psychosocial correlates of psychological morbidity among Chinese people with epilepsy (PWE). No studies have investigated the association between social relationships and psychological morbidity, while most studies examined only the negative impact of maladaptive personalities on psychological adjustment in PWE. This study examined the association of psychological morbidity with a broad array of personality traits and social skills in a sample of 54 Chinese PWE. Respondents completed the Temperament and Character Inventory (TCI), the Social Performance Survey Schedule (SPSS), and the Hospital Anxiety and Depression Scale (HADS) via semi-structured interview. Regression analyses revealed that, independent of demographic and medical variables and perceived impact, Harm Avoidance was positively associated with anxiety and depression whereas Self-Directedness was negatively associated with anxiety and depression; that Cooperativeness was inversely associated with anxiety. Social skills were inversely associated with depression whereas negative social skills were inversely associated with anxiety. Clinical implications of adaptive personality traits and social skills functioning are discussed. PMID- 20702123 TI - Evolution in VNS therapy for refractory epilepsy, experience with Demipulse devices at Ghent University Hospital. AB - RATIONALE: Vagus nerve stimulation (VNS) is a frequently used treatment for patients with refractory epilepsy who are unsuitable candidates for epilepsy surgery. There has been a steady evolution in VNS technology, as generators' volumes have become smaller and battery life expectancy longer. This pilot study is an open-label retrospective study that describes our experience with the latest commercially available generator, i.e. the VNS Therapy Demipulse Model 103. Treatment efficacy and side effects, as well as technical and practical enhancements useful for the patient and for the medical staff are discussed in this study. METHODS: Twenty patients (11F/9M) with a mean age of 40 years (range 8-61), who were considered unsuitable candidates for resective surgery, were implanted with a VNS Therapy Demipulse Model 103. Mean monthly seizure frequency reduction and side effects were evaluated 1 year after implantation. RESULTS: Mean monthly seizure frequency decreased significantly from 54 seizures/month (SEM 30; range 1-555) before treatment to 33 (SEM 24, range 0-445) following 12 months of treatment (p<0.05). Seven patients (39%) were considered responders with a reduction in seizure frequency of more than 50%. One of those seven patients became seizure free. Side effects were stimulation-related tingling sensation in the throat and/or hoarseness, a painful sensation in the left neck or ear region and a lead breakage In addition; one case of SUDEP was reported. CONCLUSION: Patients treated with VNS Therapy Demipulse generators proved to have a significant decrease in seizure frequency. In this patient group, VNS was well tolerated. The main technical advances are the decrease in size and improved options for battery life follow-up. PMID- 20702124 TI - Lipopolysaccharide: a complex role in the pathogenesis of brucellosis. PMID- 20702125 TI - PERFIDI filters to suppress and/or quantify relaxation time components in multi component systems: an example for fat-water systems. AB - Parametrically Enabled Relaxation FIlters with Double and multiple Inversion (PERFIDI) is an experimental NMR/MRI technique devised to analyze samples/voxels characterized by multi-exponential longitudinal relaxation. It is based on a linear combination of NMR sequences with suitable preambles composed of inversion pulses. Given any standard NMR/MRI sequence, it permits one to modify it in a way which will attenuate, in a predictable manner and before data acquisition, signals arising from components with different r rates (r=1/T1). Consequently, it is possible to define relatively simple protocols to suppress and/or to quantify signals of different components. This article describes a simple way to construct low-pass, high-pass and band-pass PERFIDI filters. Experimental data are presented in which the method has been used to separate fat and water proton signals. We also present a novel protocol for very fast determination of the ratio between the fat signal and the total signal which avoids any time-consuming magnetization recovery multi-array data acquisition. The method has been validated also for MRI, producing well T1-contrasted images. PMID- 20702126 TI - [The primordial follicle: outline of a portrait]. AB - Ovarian primordial follicles present original features of quiescence and long survival. Follicular growth is triggered by withdrawal of inhibitory mechanisms maintaining the quiescence and supported by a finely tuned molecular dialogue between the oocyte and its surrounding granulosa cells. The reserve of primordial follicles is oversized and functionally heterogeneous. Different spatiotemporal components can account for this heterogeneity. PMID- 20702127 TI - Scleral buckling biomaterials and implants for retinal detachment surgery. AB - Scleral buckling is a widely used surgical procedure that aims at repairing retinal detachments. Many materials and procedural techniques have been variously proposed and tested in an attempt to find the best combination for providing optimal results to the patient. This review highlights the evolution of scleral buckling implants and chronicles the main advances that have been made in such a context. Specifically, the limitations of the materials and implants fallen in disuse, as well as the advantages of currently adopted devices are critically examined and discussed. Future directions for the research are considered, underlining in particular the great potential carried by the development of accurate mathematical models for describing the postoperative evolution of buckled eye. These analytical models, supported by a comprehensive data set provided by advanced techniques of medical investigations, may become useful tools for helping surgeons to choose, and to design if necessary, the best buckling material and configuration to be used in each specific clinical case. PMID- 20702128 TI - Mitral valve dynamics in structural and fluid-structure interaction models. AB - Modelling and simulation of heart valves is a challenging biomechanical problem due to anatomical variability, pulsatile physiological pressure loads and 3D anisotropic material behaviour. Current valvular models based on the finite element method can be divided into: those that do model the interaction between the blood and the valve (fluid-structure interaction or 'wet' models) and those that do not (structural models or 'dry' models). Here an anatomically sized model of the mitral valve has been used to compare the difference between structural and fluid-structure interaction techniques in two separately simulated scenarios: valve closure and a cardiac cycle. Using fluid-structure interaction, the valve has been modelled separately in a straight tubular volume and in a U-shaped ventricular volume, in order to analyse the difference in the coupled fluid and structural dynamics between the two geometries. The results of the structural and fluid-structure interaction models have shown that the stress distribution in the closure simulation is similar in all the models, but the magnitude and closed configuration differ. In the cardiac cycle simulation significant differences in the valvular dynamics were found between the structural and fluid-structure interaction models due to difference in applied pressure loads. Comparison of the fluid domains of the fluid-structure interaction models have shown that the ventricular geometry generates slower fluid velocity with increased vorticity compared to the tubular geometry. In conclusion, structural heart valve models are suitable for simulation of static configurations (opened or closed valves), but in order to simulate full dynamic behaviour fluid-structure interaction models are required. PMID- 20702129 TI - Autonomic failures in Perry syndrome with DCTN1 mutation. AB - Perry syndrome is a familial parkinsonism associated with central hypoventilation, mental depression, and weight loss. Previously, this very rare syndrome has been reported in only 7 families worldwide including in one Japanese family. We recently identified an additional family with Perry syndrome with DCTN1 mutation residing in Japan. The pedigree contains 19 family members spanning three generations, with four affected individuals. Affected members with early stage disease in this family presented with marked autonomic dysfunction including orthostatic hypotension and decreased cardiac uptake with [123]I metaiodobenzylguanidine scintigram features that have not been described in previous cases. Because of central hypoventilation, all affected members need ventilation assistance, which is thought beneficial for prolongation of survival time as well as improving quality of life in this syndrome. PMID- 20702130 TI - FMR1 gene expansion and scans without evidence of dopaminergic deficits in parkinsonism patients. AB - PURPOSE: To determine if patients with parkinsonism and fragile X mental retardation 1 (FMR1) gene expansions have a striatal dopamine deficit similar to Parkinson disease (PD) patients. SCOPE: The authors studied three patients with parkinsonism carrying small expansions in the FMR1 gene (41-60 CGG) with [(123)I]beta-CIT SPECT imaging. The patients responded to dopaminergic medications, but had preserved dopamine transporter density. CONCLUSIONS: These results suggest that parkinsonism associated with smaller FMR1 expansions may be related to mechanisms other than pre-synaptic dopaminergic changes and may represent a potential explanation for at least some parkinsonian cases with scans without evidence of dopaminergic deficits (SWEDD). PMID- 20702131 TI - What does proprioception testing tell us about patellofemoral pain? PMID- 20702132 TI - Synthesis, crystal structure and photoelectric property of two new coordination polymers constructed by longer-spanning suberic acid and 4,4'-bipyridine ligands. AB - Two-dimensional coordination polymers, [M(C8H12O4)(C10H8N2)].H2O [M=Co (1), Cd (2); C10H8N2 = 4,4-bipyridine, C8H14O4=subaric acid] were obtained from the reaction of the metal salts, bipy and subaric acid at 180 degrees C and characterized by elemental analysis, infrared spectrum, and single-crystal X-ray diffraction and surface photovoltage spectrum (SPS). The single-crystal X-ray diffraction showed that the subaric ligand in the two complexes exhibits two types of modes coordinating to transition metal ions, resulting in the formation of a 1D infinite chain along the c-axis. In addition, the results of SPS for complexes 1 and 2 indicate that these two complexes exhibit positive surface photovoltage responses in the range of 300-800 nm, which can be assigned to LMCT and MLCT, respectively. And the SPS of complex 1 also can be assigned to the d >d* electronic transition. The SPS spectra of the two complexes are consistent with their UV-vis spectra. PMID- 20702133 TI - Anisotropic media effect on the dipole moment of some coumarin dyes. AB - The ground state (MU(g)) and the excited state (MU(e)) dipole moments of two coumarin laser dyes, C500 and C503, were studied at room temperature in various solvents, viz., aprotic solvents, alcohols and liquid crystals at 298 K. We report dipole moment of laser dyes in different anisotropic (liquid crystals) and isotropic environments. The dipole moments values in different media help to investigate environment effects on the molecular dipole moment and provide a straightforward method for comparing their properties. Ground and excited state dipole moments of coumarin dyes were evaluated by means of solvatochromic shift method. It was observed that dipole moment values of excited states (MU(e)) were higher than corresponding ground state values (MU(g)), indicating a substantial redistribution of the pi-electron densities in a more polar excited state for the dyes investigated. PMID- 20702134 TI - Prevalence and clinical characteristics of human CoV-HKU1 in children with acute respiratory tract infections in China. AB - BACKGROUND: Human CoV-HKU1 (HCoV-HKU1) has been isolated from a 71-year-old man with pneumonia; however, the impact and role of emerging HCoV-HKU1 have not been defined in children with acute respiratory tract infection (ARTI). OBJECTIVE: To investigate the Prevalence and clinical characteristics of HCoV-HKU1 in children with ARTI in Lanzhou, China. STUDY DESIGN: The reverse transcription polymerase chain reaction (RT-PCR) or PCR was employed to screen HCoV-HKU1 and other common respiratory viruses in 645 nasopharyngeal aspirate (NPA) specimens collected from children with ARTI from November 2006 to October 2008. All PCR positive products were sequenced. And the demographic and clinical data were collected for all patients. RESULTS: Nineteen of 645 (2.95%) specimens tested positive for HCoV HKU1, and all HCoV-HKU1 positive specimens were distributed in the winter and spring season. The HCoV-HKU1 co-infection rate with other respiratory viruses was 47.37% (9/19). There was no statistically significant difference in the detection rate between groups by age or gender, except between patients with and without underlying diseases. The phylogenetic analysis indicated that HCoV-HKU1 genotype B was circulating in the years 2007 and 2008 in children with ARTI in Lanzhou, China. CONCLUSIONS: HCoV-HKU1 is an uncommon virus existing among Chinese children with ARTI. Children with underlying diseases are more vulnerable to viral infection. Only HCoV-HKU1 genotype B circulated locally. PMID- 20702135 TI - More prolonged brain activity related to gaze cueing in schizophrenia. AB - OBJECTIVE: The ability to use the gaze direction of another person to guide attention is important for social functioning, but behavioral reports on this topic among individuals with schizophrenia are inconclusive. Event Related Potentials (ERPs) can very accurately pinpoint the shifting of attention, and can therefore shed more light on cueing abilities in schizophrenia. METHODS: ERPs were measured during two spatial attention tasks in 14 high-functioning, young adult schizophrenic individuals and 19 age- and IQ-matched controls. In one task neutral faces were used as cues, and in the other arrows. RESULTS: Speeded behavioral and ERP responses were found to validly cued targets compared with responses to invalidly cued targets in both groups. However, we found more prolonged cueing effects in the patient group in later stages of processing, indicated by enhanced validity effects of late ERP latencies to gaze cues but not to arrow cues. CONCLUSIONS: Our study provides evidence for normal attentional orienting at behavioral level and early cognitive processing, but more prolonged cognitive evaluation of gaze cues in young adults with schizophrenia. SIGNIFICANCE: Evidence from this study excludes a specific attentional orienting deficit from being a possible endophenotype for the disorder. PMID- 20702136 TI - Comparing potential COI and SSU rDNA barcodes for assessing the diversity and phylogenetic relationships of cyphoderiid testate amoebae (Rhizaria: Euglyphida). AB - The mitochondrial Cytochrome Oxidase Subunit 1 gene (COI) has been promoted as an ideal "DNA barcode" for animal species and other groups of eukaryotes. However, the utility of the COI marker for species level discrimination and for phylogenetic analyses has yet to be tested within the Rhizaria. Accordingly, we analysed mitochondrial COI gene sequences and nuclear small subunit rDNA (SSU) sequences from several morphospecies of euglyphid testate amoebae (Cercozoa, Rhizaria) in order to evaluate the utility of these DNA markers for species discrimination and phylogenetic reconstructions. Sequences were obtained from eleven populations belonging to sixCyphoderiamorphospecies that were isolated from field samples in North America and Europe. Mean inter-population COI sequence dissimilarities were on average 2.9 times greater than in the SSU, while the intra-population sequence dissimilarities were higher in the SSU (0-0.95%) than in the COI (0%); this suggests that the COI fragment is valuable for discriminating Cyphoderiidae isolates. Our study also demonstrated that COI sequences are useful for inferring phylogenetic relationships among Cyphoderiidae isolates. COI and SSU tree topologies were very similar even though the COI fragment used in these analyses (500bp) was much shorter than the SSU sequences (1600bp). Altogether, these results demonstrate the utility of the COI as a potential taxonomic DNA barcode for assessing cyphoderiid species diversity and for inferring phylogenetic relationships within the group. PMID- 20702137 TI - Endovascular treatment of superior vena cava syndrome by percutaneous venoplasty. AB - Thrombosis of the superior vena cava leads to obstruction of venous outflow of the head and upper extremities and causes severe clinical symptoms. The management of SVC syndrome depends on aetiology and acuity at clinical presentation and ranges from conservative medical treatment to bypass surgery. Endovascular treatment can provide rapid relief of symptoms and substantial clinical improvement independent of aetiology. We report a case of successful interventional treatment in a patient with catheter-induced SVC thrombosis and present a review of the literature. PMID- 20702138 TI - Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. AB - BACKGROUND: The FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) regimen has been shown to be better than FOLFIRI (fluorouracil, folinate, and irinotecan) in a phase 3 trial in patients with metastatic colorectal cancer. Results of various studies have shown that the addition of bevacizumab to chemotherapy increases treatment efficacy. We therefore assessed the safety and activity of the combination of FOLFOXIRI plus bevacizumab in patients with colorectal cancer. METHODS: In a phase 2 study, patients (aged 18-75 years) with colorectal cancer, which was judged to be unresectable for metastatic disease, were given the combination of intravenous bevacizumab (5 mg/kg on day 1) and intravenous FOLFOXIRI (irinotecan 165 mg/m(2) on day 1, oxaliplatin 85 mg/m(2) on day 1, folinate 200 mg/m(2) on day 1, and fluorouracil 3200 mg/m(2) for 48 h continuous infusion starting on day 1 and repeated every 2 weeks) as first-line treatment in seven centres in Italy. Induction treatment (FOLFOXIRI and bevacizumab) was administered for a maximum of 6 months, followed by maintenance treatment with bevacizumab (5 mg/kg intravenously on day 1, repeated every 2 weeks). The primary endpoint was progression-free survival (PFS) at 10 months from study entry in the intention-to-treat population. This study has been completed and is registered with ClinicalTrials.gov, number NCT01163396. FINDINGS: From July 2, 2007, to April 1, 2008, 57 patients were enrolled; all patients were assessed for safety and efficacy. Median follow-up time was 28.8 months (95% CI 24.9-32.5). PFS at 10 months was 74% (95% CI 62-85). Main grade 3 or 4 adverse events during induction treatment were neutropenia (n=28 [49%], including one case of febrile neutropenia), diarrhoea (n=8 [14%]), stomatitis (n=2 [4%]), neurotoxicity (n=1 [2%]), deep-vein thrombosis (n=4 [7%]), and hypertension (n=6 [11%]). No treatment-related deaths occurred. Six serious adverse events occurred during the induction treatment: febrile neutropenia (n=1 [2%]), grade 3 diarrhoea with dehydration (n=2 [4%]), grade 4 stomatitis (n=1 [2%]), grade 4 hypertension (n=1 [2%]), and fluorouracil-related cardiac ischaemia (n=1 [2%]). The most common grade 3 or 4 adverse events noted in the 37 patients who received maintenance treatment were hypertension (n=5 [14%]) and neurotoxicity (n=3 [8%]). One case of acute myocardial infarction due to coronary thrombosis was noted during the maintenance treatment. INTERPRETATION: Bevacizumab can be safely used with FOLFOXIRI without causing unforeseen adverse events. Treatment achieved promising results in terms of PFS. A phase 3 study for the comparison of FOLFOXIRI plus bevacizumab with FOLFIRI plus bevacizumab is in progress. FUNDING: Gruppo Oncologico Nord Ovest, ARCO Foundation, and Roche. PMID- 20702139 TI - The platelet storage defect as measured in Costa Rica. AB - The platelet storage defect emcompasses all untoward effects on platelet morphology structure and function with storage and the mechanisms responsible are not fully understood but are clearly multifactorial. The presence of swirling may correlate with acceptable pH values and the volume of suspending plasma to be effective to maintain a pH greater than 6,4 is between 75-85 g. PMID- 20702140 TI - Stable feature selection for biomarker discovery. AB - Feature selection techniques have been used as the workhorse in biomarker discovery applications for a long time. Surprisingly, the stability of feature selection with respect to sampling variations has long been under-considered. It is only until recently that this issue has received more and more attention. In this article, we review existing stable feature selection methods for biomarker discovery using a generic hierarchical framework. We have two objectives: (1) providing an overview on this new yet fast growing topic for a convenient reference; (2) categorizing existing methods under an expandable framework for future research and development. PMID- 20702141 TI - Food-related attitudes and behaviors at home, school, and restaurants: perspectives from racially diverse, urban, low-income 9- to 13-year-old children in Minnesota. AB - OBJECTIVE: This qualitative study explored low-income children's food-related attitudes and behaviors, and current weight status. DESIGN: Two researchers conducted 14 audiotaped, 60-minute focus groups. Height and weight were measured. SETTING: Libraries, homeless shelters, and a community center. PARTICIPANTS: Ninety-two low-income children aged 9-13 years. PHENOMENON OF INTEREST: How environmental, personal, and behavioral factors affect food choices and food related behavior at home, in school, and at restaurants, and how these factors potentially influence weight status. ANALYSIS: Transcripts were coded, reconciled, and analyzed for themes and subthemes. RESULTS: At home, children's food choices were often unhealthful because of the types of food available, and some reported restricted eating styles and night eating. At school, children were largely dissatisfied with the quality of lunches provided, and some skipped the meal. Most children preferred buffets as their favorite type of restaurant, where they could eat unlimited quantities of their favorite food items. Over half of the children were overweight (19%) or obese (36%). CONCLUSIONS AND IMPLICATIONS: Future research may examine the prevalence of night eating, meal skipping, and other irregular eating behaviors among low-income children and their long-term relationship to weight status. Increasing parents' knowledge of these behaviors, while emphasizing the importance of family mealtimes, is encouraged. PMID- 20702142 TI - High-dose rate brachytherapy in the treatment of penile carcinoma--first experience. AB - PURPOSE: Interstitial low-dose rate brachytherapy (BRT) allows a conservative treatment of T1-T2 penile carcinoma. High-dose rate (HDR) BRT is often considered as a dangerous method for interstitial implants because of higher risk of complications. However, numerous reports suggest that results of HDR-BRT may be comparable to low-dose rate BRT. There are no data available in the literature regarding HDR interstitial BRT for carcinoma of the penis. METHODS AND MATERIALS: Ten patients with early penile carcinoma were treated by interstitial hyperfractionated HDR-BRT at the dose of 18 times 3Gy twice daily between years 2002 and 2009. Breast interstitial BRT template was used for fixation and precise geometry reconstruction of stainless hollow needles. RESULTS: Median followup was 20 months. Our BRT technique and fractionation schedule was well tolerated by all patients. Acute reaction consisted predominantly of penis edema and Grade 2 radiation mucositis that dissolved during 8 weeks after the treatment. We neither observed any postradiation necrosis nor urethral stenosis. The worst late side effects recorded were mild telanagiectasias in the treatment region. At the last followup, all patients were alive without evidence of the tumor and with fully functional organ. CONCLUSIONS: Hyperfractionated interstitial HDR-BRT with 18 times 3 Gy per fraction twice daily is a promising method in selected patients of penile carcinoma and deserves further evaluation in a larger prospective study. PMID- 20702143 TI - Anemia after bariatric surgery cannot be explained by iron deficiency alone: results of a large cohort study. AB - BACKGROUND: We sought to identify the frequency and mechanisms of anemia after bariatric surgery in a bariatric surgery program at the Medical College of Wisconsin, (Milwaukee, WI). Anemia after bariatric surgery has often been attributed to iron deficiency, although an inflammatory component might be present, making the anemia after surgery mechanistically complex. METHODS: The body mass index and hemoglobin (Hb), vitamin B(12), folate, iron, and ferritin levels were extracted from the records of 1125 patients for <=4 years after Roux en-Y gastric bypass. Anemia was defined using the World Health Organization criteria. RESULTS: The mean body mass index, Hb, and ferritin decreased after surgery. The body mass index decreased from 50.1 kg/m(2) (95% confidence interval [CI] 49.6-50.6) at baseline to 33.0 kg/m(2) (95% CI 32.3-33.6) at 12 months and remained unchanged thereafter. The Hb level decreased from 13.4 g/dL (95% CI 13.3 13.5) to 12.8 (95% CI 12.6-13.1) and ferritin from 87.5 ng/mL (95% CI 75.2-99.7) to 55.4 (95% CI 42.9-68.0) at 24-48 months, and serum iron increased from 68.4 MUg/dL (95% CI 66.8-70.0) to 82.8 (95% CI 76.4-88.7); all P values were <.01. Anemia was present in 12% (95% CI 10-14%) of patients at baseline and had increased to 23% (95% CI 16-30%) at 24-48 months. The changes in ferritin, Hb, and the percentage of patients with anemia were most pronounced in premenopausal women. Vitamin B(12) and folate levels were unaffected. CONCLUSION: The baseline incidence of anemia was greater than expected and increased significantly after surgery. The percentage of those with anemia and low ferritin was most significant in premenopausal women; however, the overall iron bioavailability improved significantly with pronounced weight loss, suggesting a reduction in inflammation. These findings indicate that anemia after bariatric surgery cannot be explained on the basis of iron availability and suggest that other mechanisms, currently undefined, contribute to the development of anemia in these patients. PMID- 20702144 TI - Improvement of esophageal dysmotility after conversion from gastric banding to gastric bypass. AB - BACKGROUND: Patients undergoing adjustable gastric banding can develop clinically apparent alterations in esophageal motility. There is little data on how such patients do after band removal and revision to other bariatric operations. One article in the literature describes long term manometric evidence of dysmotility in a band patient converted to gastric bypass. METHODS: 132 patients undergoing placement of an adjustable gastric band by a single surgeon in a university hospital setting were followed over a two year period. 15 (11%) developed unrelenting dysphagia, reflux and regurgitation despite conservative management including complete deflation, and were revised to gastric bypass. Pre-revision contrast studies demonstrated esophageal dysmotility in all patients. The first seven were converted in a staged fashion, with a period of six to eight weeks between band removal and gastric bypass. During this time, motility was again studied to confirm a return to normal. The last eight were converted at the time of band removal and motility was restudied after gastric bypass. RESULTS: Esophageal motility normalized radiologically after band removal and remained normal after conversion to bypass in all patients. Symptoms of dysphagia similarly resolved. The revisional complication rate was acceptable. CONCLUSION: The presence of a gastric band may be sufficient in some patients to bring about esophageal dysmotility. However, many will bring this about through forced eating against the band. When the band is poorly tolerated and further weight loss is required, such patients can safely convert to gastric bypass and can expect a return to normal motility. PMID- 20702145 TI - Unusual case of upper gastrointestinal bleeding after laparoscopic gastric bypass: erosion of gastric remnant involving a diaphragmatic vessel. PMID- 20702146 TI - Laparoscopic Roux-en-Y gastric bypass versus laparoscopic adjustable gastric banding: five years of follow-up. AB - BACKGROUND: Bariatric surgery is an effective treatment for morbid obesity. Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic adjustable gastric banding (LAGB) are commonly performed procedures. The aim of the present study was to evaluate and compare the long-term outcomes after LRYGB and LAGB. METHODS: We studied the data from a prospective database of all patients undergoing LRYGB or LAGB with 5 years of follow-up. RESULTS: From July 2001 to September 2003, 91 and 62 patients underwent LRYGB and LAGB, respectively. Of these patients, 73.6% of the LRYGB and 91.9% of the LAGB patients had 5 years of follow-up. Of the 91 and 62 patients, 89% and 82% were women, respectively. The mean age and body mass index was 34.5 +/- 11.0 years and 39.6 +/- 4.9 kg/m(2) for the LRYGB group and 38.4 +/- 13.1 years and 35.8 +/- 4.0 kg/m(2) for the LAGB group, respectively. The mean operative time was 150 +/- 58 minutes for LYRGB and 73 +/- 23 minutes for LAGB (P <.05). The conversion and reoperation rate was 8% and 4.3%, respectively, for the LRYGB group versus 0% for the LAGB group. Early postoperative complications were observed in 12 and 1 patient (P = .014) after LRYGB and LAGB, respectively. Late complications developed in 33 and 17 patients after LYRGB and LAGB, respectively (P = NS). The percentage of excess weight loss at 5 years postoperatively was 92.9% +/- 25.6% and 59.1% +/- 46.8% (P <.001) for LRYGB and LAGB, respectively. Surgical failure (percentage of excess weight loss <50%) at 5 years was 6% for LRYGB and 45.6% for LAGB. A late reoperation was needed in 24.1% of the LAGB patients. CONCLUSION: A greater percentage of excess weight loss at 1 and 5 years was observed after LRYGB than LAGB. The LAGB group had a >40% rate of surgical failure and a 24.1% reoperation rate at 5 years of follow-up. PMID- 20702147 TI - Revisional bariatric surgery: who, what, where, and when? AB - BACKGROUND: Revisional bariatric surgery (RBS) outcomes have been poorly characterized. We compared the RBS and primary bariatric surgery (PBS) outcomes at the Penn State Milton S. Hershey Medical Center in the United States. METHODS: A total of 72 RBS cases from 2000 to 2007 were reviewed and grouped by indication: failure of weight loss, gastrojejunal complications, or other. The RBS patients were compared with the 856 PBS patients who underwent Roux-en-Y gastric bypass. The mean follow-up time was 12.6 +/- 1.2 months for the RBS group and 16 +/- 0.5 months for the PBS group. Weight loss was analyzed as the kilograms lost and patients with >= 50% excess body weight loss (EBWL). Outcomes included mortality, leaks, surgical site infections, and length of stay. RESULTS: The weight loss was 23 +/- 2.8 kg after RBS and 41.3 +/- 0.7 kg after PBS (P <.05 versus PBS). The post-RBS weight loss varied by surgical indication: failure of weight loss, 27.1 +/- 2 kg; gastrojejunal complications, 8.7 +/- 3.4 kg; and other 23.5 +/- 10.6 kg. Also, 29% of the RBS patients had >= 50% excess body weight loss (versus the prerevision weight) and 61% (versus the initial weight) compared with 52.7% after PBS. Only age <= 50 years was associated with >= 50% excess body weight loss after RBS for the failure of weight loss group. No RBS patients died. However, leaks, surgical site infections, and length of stay were increased after RBS. CONCLUSION: The results of our study have shown that weight loss after RBS varies with the surgical indication and is affected by age >50 years. Although the RBS patients had decreased weight loss and increased complications compared with the PBS patients, >= 50% EBWL was achieved by a significant number of RBS patients. PMID- 20702148 TI - Roux-en-Y gastric bypass alters tumor necrosis factor-alpha but not adiponectin signaling in immediate postoperative period in obese rats. AB - BACKGROUND: Adiponectin has anti-inflammatory properties and is increased with weight loss. Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine that negatively regulates adiponectin. Previously, we have demonstrated that Roux en-Y gastric bypass (RYGB) induces weight loss and improves steatosis in obese rats. We hypothesized that RYGB would alter the interplay of TNF-alpha and adiponectin signaling in the postoperative period. METHODS: Obese Sprague-Dawley male rats that had undergone RYGB (n = 5) or sham (n = 4) were euthanatized at 9 weeks postoperatively. The adiponectin levels from serial serum samples were measured by enzyme-linked immunosorbent assay. Adiponectin, adiponectin receptor 2, and TNF-alpha mRNA from adipose and liver samples were quantified by reverse transcriptase-polymerase chain reaction. Data are presented as mean +/- standard deviation; using a t test, P <.05 was significant. RESULTS: RYGB did not change the serum adiponectin, adipose tissue adiponectin mRNA, or hepatic adiponectin receptor 2 levels compared with the levels in the sham-operated rats (P >.05). However, the TNF-alpha mRNA levels had decreased in the adipose tissue (P >.05) but remained unchanged in the liver compared with the sham controls (P >.05). CONCLUSION: Surgically-induced weight loss in a rat model of RYGB did not increase adiponectin signaling in the immediate postoperative period but was associated with decreased pro-inflammatory signaling in the adipose tissue. During this period, pro-inflammatory signaling might play a more important role than adiponectin. Additional studies with longer follow-up are necessary to determine whether adiponectin plays a role in weight loss and improvement of steatosis after RYGB. PMID- 20702149 TI - Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). AB - A sensitive and rapid HTLC-ESI-MS/MS method with an advanced online sample preparation was developed for determination of the gamma-secretase inhibitor MK 0752 in human plasma using an internal standard. Plasma samples (100 microL) were diluted and injected directly onto an online extraction column (Cohesive Cyclone MAX 0.5 mm x 50 mm, > 30 microm), the sample matrix was washed out with an aqueous solution, and retained analytes were eluted out and transferred directly to the analytical column (Phenomenex Gemini 3 micron C18 110A, 50 mm x 2.0 mm at 50 degrees C) for separation using a gradient mobile phase. The eluted analytes were then detected on an API-3000 LC-MS/MS System with ESI and a negative multiple reaction monitoring mode. The monitored ion transitions were m/z 441- >175 for MK-0752 and 496-->175 for the internal standard. Online extraction recoveries were 81%. The method was validated and was linear in the range of 0.05 50 microg/mL. Within-day and between-day precisions were<8.6%, and accuracies were 0.7 and 7.1%. This method was applied to the measurement of plasma MK-0752 levels in a Phase I study of pediatric patients with recurrent or refractory brain tumors. PMID- 20702150 TI - Measurement of urinary oxypurinol by high performance liquid chromatography tandem mass spectrometry. AB - Oxypurinol is the active metabolite of allopurinol which is used to treat hyperuricaemia associated with gout. Both oxypurinol and allopurinol inhibit xanthine oxidase which forms uric acid from xanthine and hypoxanthine. Plasma oxypurinol concentrations vary substantially between individuals and the source of this variability remains unclear. The aim of this study was to develop an HPLC tandem mass spectrometry method to measure oxypurinol in urine to facilitate the study of the renal elimination of oxypurinol in patients with gout. Urine samples (50 microL) were prepared by dilution with a solution of acetonitrile/methanol/water (95/2/3, v/v; 2 mL) that contained the internal standard (8-methylxanthine; 1.5 mg/L), followed by centrifugation. An aliquot (2 microL) was injected. Chromatography was performed on an Atlantis HILIC Silica column (3 microm, 100 mm x 2.1mm, Waters) at 30 degrees C, using a mobile phase comprised of acetonitrile/methanol/50 mM ammonium acetate in 0.2% formic acid (95/2/3, v/v). Using a flow rate of 0.35 mL/min, the analysis time was 6.0 min. Mass spectrometric detection was by selected reactant monitoring (oxypurinol: m/z 150.8-->108.0; internal standard: m/z 164.9-->121.8) in negative electrospray ionization mode. Calibration curves were prepared in drug-free urine across the range 10-200 mg/L and fitted using quadratic regression with a weighting factor of 1/x (r(2) > 0.997, n=7). Quality control samples (20, 80, 150 and 300 mg/L) were used to determine intra-day (n=5) and inter-day (n=7) accuracy and imprecision. The inter-day accuracy and imprecision was 96.1-104% and <11.2%, respectively. Urinary oxypurinol samples were stable when subjected to 3 freeze thaw cycles and when stored at room temperature for up to 6h. Samples collected from 10 patients, not receiving allopurinol therapy, were screened and showed no significant interferences. The method was suitable for the quantification of oxypurinol in the urine of patients (n=34) participating in a clinical trial to optimize therapy of gout with allopurinol. PMID- 20702152 TI - Cholangiocarcinoma: A position paper by the Italian Society of Gastroenterology (SIGE), the Italian Association of Hospital Gastroenterology (AIGO), the Italian Association of Medical Oncology (AIOM) and the Italian Association of Oncological Radiotherapy (AIRO). AB - The incidence of Cholangiocellular carcinoma (CCA) is increasing, due to a sharp increase of the intra-hepatic form. Evidence-ascertained risk factors for CCA are primary sclerosing cholangitis, Opistorchis viverrini infection, Caroli disease, congenital choledocal cist, Vater ampulla adenoma, bile duct adenoma and intra hepatic lithiasis. Obesity, diabetes, smoking, abnormal biliary-pancreatic junction, bilio-enteric surgery, and viral cirrhosis are emerging risk factors, but their role still needs to be validated. Patients with primary sclerosing cholangitis should undergo surveillance, even though a survival benefit has not been clearly demonstrated. CCA is most often diagnosed in an advanced stage, when therapeutic options are limited to palliation. Diagnosis of the tumor is often difficult and multiple imaging techniques should be used, particularly for staging. Surgery is the standard of care for resectable CCA, whilst liver transplantation should be considered only in experimental settings. Metal stenting is the standard of care in inoperable patients with an expected survival >4 months. Gemcitabine or platinum analogues are recommended in advanced CCA whilst there are no validated neo-adjuvant treatments or second-line chemotherapies. Even though promising results have been obtained in CCA with radiotherapy, further randomized controlled trials are needed. PMID- 20702151 TI - [Thyroid dysfunction in patients with advanced renal cell carcinoma treated with sunitinib: a multifactorial issue]. AB - OBJECTIVE: Several studies have reported the substantial prevalence of sunitinib induced thyroid dysfunction. However, the underlying mechanism and the benefit of thyroid hormone replacement therapy remain to be determined. To evaluate the effect of sunitinib on thyroid function, we carried out a descriptive study in patients with advanced renal cell carcinoma. PATIENTS AND METHODS: A total of 24 patients treated by sunitinib between 2006 and 2008 at Hospital Clinico San Carlos were included. The data were collected retrospectively and analyzed with SPSS 15.0. RESULTS: Treatment duration was 30 weeks (18-42) [median (IQR)]. Five patients (20.8%) developed subclinical hypothyroidism and three (12.5%) developed overt hypothyroidism. The number of weeks needed to observe an increase in thyroid-stimulating hormone (TSH) values in these patients was 15 (6-20) [median (IQR)]. TSH levels were below the normal range in five patients (20.8%) before or during the treatment period, but the diagnosis of subclinical hyperthyroidism could not be established because of concomitant factors. Fourteen patients (58.3%) showed sunitinib adverse events, but these were not related to the development of hypothyroidism (p=0.388). CONCLUSIONS: Because of the high prevalence of sunitinib-induced hypothyroidism, thyroid function should be systematically monitored in patients with renal cell carcinoma treated with this drug. However, several pathophysiological and pharmacological factors may interfere with monitoring. Consequently, it might be useful to determine not only TSH and free T4 but also free T3 and, ideally, reverse T3. Evidence-based recommendations to manage hypothyroidism in oncology patients are not available at present. PMID- 20702153 TI - Surgical management of a painful lipoatrophy. PMID- 20702154 TI - Acute disassembly of a bipolar radial head arthroplasty. AB - The GUEPAR((r)) implant is a metallic bipolar radial head prosthesis designed to treat comminuted radial head fractures when anatomic realignment of the articular surface of the radiocapitellar joint is not possible. We report herein the rare case of an acute complete disassembly of this implant, discuss the reason for this occurrence and review the literature. In the presented case, the complete removal of the prosthesis provided a satisfactory outcome with an excellent Mayo Elbow Performance Score at 12months follow-up. PMID- 20702155 TI - A higher prediagnostic insulin level is a prospective risk factor for incident prostate cancer. AB - A higher insulin level has been linked to the risk of prostate cancer promotion. However, several reports claim that there is no association between a higher insulin level and the risk of incident prostate cancer. In the present report, the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder. Three hundred and eighty-nine consecutive patients referred with lower urinary tract symptoms without clinical prostate cancer were included during 1994-2002. Follow-up was performed in 2006. Data were obtained from the Swedish National Cancer Register and the Regional Cancer Register, Oncological Centre, Goteborg, Sweden. At this follow-up, 44 of the patients included had developed prostate cancer. Men with prostate cancer diagnosis had a higher systolic (P<0.001) and diastolic blood pressure (P<0.000), were more obese as measured by BMI (P=0.010), waist (P=0.007) and hip measurements (P=0.041) than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level (P=0.040), and a higher fasting serum insulin level (P=0.023) than men who did not have prostate cancer diagnosis at follow-up. Following exclusion of T1a/b prostate cancer cases, the difference of the fasting serum insulin level between the groups was still significant (P=0.038). Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer. PMID- 20702158 TI - Primary cultures of rabbit renal proximal tubule cells: II. Selected phase I and phase II metabolic capacities. AB - Specific characteristics of cells vary as a function of time in culture. We have determined the stability of selected Phase I and Phase II biotransformation capacities in rabbit renal proximal tubule cells in primary culture. When grown in hormonally-defined medium, proximal tubule cells lost Phase I metabolic capacity. Cytochrome P-450 content and associated mixed-function oxidase activities present in kidney cortex microsomes were not detectable after 14 days in culture. Phase II glutathione-dependent metabolic functions were well retained in cultured cells compared with freshly isolated proximal tubules (FIPT). Cellular total glutathione content was 2.8 mug/mg protein in FIPT compared with approximately 10 mug/mg protein in stable confluent cultures. A higher total glutathione content of 20.6 mug/mg was noted in preconfluent cultures. The glutathione redox state was initially perturbed in FIPT with 37% of the total glutathione present found in its oxidized form. Tubule cells recovered to a normal ratio (6-13% of total glutathione in the oxidized form) while in culture. The glutathione S-transferase activity in 4-day-old cells in culture was reduced to 50% of the 4 U/mg protein level found in FIPT. No appreciable further decline in glutathione S-transferase activity was detected during 15 days in culture. The level of gamma-glutamyl-transpeptidase (a brush-border enzyme necessary for glutathione uptake into proximal tubule cells) declined from 1499 mU/mg protein in homogenates of FIPT to 636 mU/mg in homogenates of 8-day-old cultured cells. A further decline in activity occurred during the next 7 days in culture. In conclusion, although Phase I metabolic functions were diminished in primary cultured rabbit proximal tubule cells, Phase II metabolic functions were retained at levels comparable with FIPT and well above those found in several established kidney cell lines. PMID- 20702156 TI - Intake of dietary fats and colorectal cancer risk: prospective findings from the UK Dietary Cohort Consortium. AB - INTRODUCTION: Epidemiologic evidence for an association between colorectal cancer (CRC) risk and total dietary fat, saturated fat (SF), monounsaturated fat (MUFA) and polyunsaturated fat (PUFA) is inconsistent. Previous studies have used food frequency questionnaires (FFQ) to assess diet, but data from food diaries may be less prone to severe measurement error than data from FFQ. METHODS: We conducted a case-control study nested within seven prospective UK cohort studies, comprising 579 cases of incident CRC and 1996 matched controls. Standardized dietary data from 4- to 7-day food diaries and from FFQ were used to estimate odds ratios for CRC risk associated with intake of fat and subtypes of fat using conditional logistic regression. We also calculated multivariate measurement error corrected odds ratios for CRC using repeated food diary measurements. RESULTS: We observed no associations between intakes of total dietary fat or types of fat and CRC risk, irrespective of whether dietary data were obtained using food diaries or FFQ. CONCLUSION: Our results do not support the hypothesis that intakes of total dietary fat, SF, MUFA or PUFA are linked to risk of CRC. PMID- 20702159 TI - Induction of micronuclei in cultured human bronchial epithelial cells by direct acting carcinogens. AB - The sensitivity of human bronchial epithelial cells to induction of micronuclei was determined in cultures derived from seven different donors. Two direct-acting carcinogens, dl-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and N methyl-N'-nitro-N-nitrosoguanidine were used to induce micronuclei. Both agents increased the incidence of micronuclei in a concentration-dependent fashion in cells from most donors, event at concentrations that did not produce appreciable cytotoxicity; there were considerable variations in the responses of different donors. Cytokinesis was blocked with cytochalasin B so that micronuclei were counted only in binucleate cells, thereby decreasing the total number of cells that needed to be examined and also eliminating variations due to possible differences in cell growth rates. The results demonstrate the potential usefulness of the micronucleus assay as a sensitive measure of genetic damage in human epithelial cells from the lung. PMID- 20702160 TI - Implication of alterations in intracellular calcium ion homoeostasis in the advent of paracetamol-induced cytotoxicity in primary mouse hepatocyte monolayer cultures. AB - We have examined the fluctuation of free cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) using the fluorescent probe quin-2 during the cytotoxic response induced by low concentrations (100-250 mum) of the model hepatotoxin paracetamol (APAP) in primary mouse hepatocyte cultures over 5 days. APAP-associated increases in [Ca(2+)](i) were recorded prior to APAP-associated cytotoxicity, and correlated with the subsequent loss of cell viability as measured by intracellular lactate dehydrogenase and K(+) efflux. Co-incubation with promethazine (1 mum) or ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N' tetraacetic 0215 acid (4 mm) attenuated both the APAP-associated [Ca(2+)](i) changes and cytotoxicity. These results support the hypothesis that mobilization of intracellular Ca(2+) may be an important early event in APAP-induced hepatotoxicity. PMID- 20702161 TI - Comparative assessment of in vitro toxicity of xenobiotics using flow cytometry and spectrophotometry. AB - Cell viability and cell proliferation are endpoints that can be used to identify cytotoxic effects. In a study of the cytotoxicity of four biomaterials and drugs, these two criteria were determined by different techniques. There were notable similarities and differences among the different methods used. Cell viability, which was determined by the trypan blue exclusion test, spectrophotometric microtitration (neutral red) and flow cytometry (fluorescein diacetate) gave similar results. However, the neutral red assay was found to be the most sensitive method for determining the cytotoxicity of these biomaterials and drugs. Cell proliferation measurement, by cell counts and quantitative protein estimation (coomassie blue), revealed important variations between the two methods and indicated poor sensitivity for the protein assay. A slight variability in the determination of the inhibitory concentration 50 (IC(50)) for the two drugs was observed for all the techniques. PMID- 20702162 TI - The effects of ethylene oxide sterilization on the in vitro cytotoxicity of a bone replacement material. AB - The effect of degassing on the cytotoxicity of an ethylene oxide (EtO)-sterilized copolymer constituent of a bone replacement material, was determined using the (51)Cr release assay. An initial experiment used mouse L929 cells and a copolymer with an ambient pressure and temperature (APT) degassing time of 24 hr. Both copolymer and nylon control discs caused a significantly (P chlortetracycline > tetracycline. The kidney lines produced the rankings as follows: LLC-PK(1): amikacin > neomycin > gentamicin; MDCK: neomycin > amikacin > gentamicin. The results from the tetracyclines are consistent with the expectation that these compounds would not be nephrotoxic in vitro since in vivo investigations suggest hormonal mediation is required, and would be hepatotoxic in vitro because of direct action of these xenobiotics on liver cells in vivo. Similarly, the aminoglycosides were more toxic to the proximal kidney cells than to the distal cells as seen in vivo. These results suggest that continuous cell lines may provide important information in the assessment of xenobiotic cytotoxicity. PMID- 20702200 TI - The neurotoxic effect of carbon disulphide, N-hexane and its metabolites studied with erythrocyte and synaptosome membranes in vitro. AB - The aim of the present study was to find a method for in vitro studies of the neurotoxic mechanism of industrial solvents. The effects of carbon disulphide and n-hexane and its metabolites were studied. Cell membrane changes were studied by measuring changes in the activity of the integral cell membrane enzymes acetylcholinesterase (AChE) and adenosinetriphosphatase (ATPase). The erythrocyte membranes were isolated from human peripheral blood samples and the synaptosome membranes from rat brain by using the non-toxic iso-osmotic Percoll gradient system. The cell membrane samples were incubated at +37 degrees C in an incubation mixture with known solvent concentrations. In erythrocyte membranes, n hexane decreased the activity of AChE more than did carbon disulphide. In synaptosome membranes, 2-hexanone and 2,5-hexanedione inhibited AChE significantly more than did n-hexane. On ATPase, n-hexane, as well as the metabolites of n-hexane, had a slightly activating effect in erythrocyte membranes, and no or a slightly inactivating effect in synaptosome membranes. Carbon disulphide had a clear inactivating effect on ATPase in synaptosome membranes. The action of the neurotoxic organic solvents may be mediated by way of the integral membrane proteins, especially AChE. Thus, in neural synaptosome membranes, the metabolites of n-hexane had a greater effect on AChE activity than did n-hexane. The in vitro membrane model can be applied in studies of the neurotoxicity of organic solvents, and in predicting their neurotoxic potency. PMID- 20702201 TI - Cyclosporin nephrotoxicity assessed in isolated human glomeruli and cultured mesangial cells. PMID- 20702202 TI - Cis-platin cytotoxicity in human and rat tubular cell cultures. PMID- 20702203 TI - Respiratory tract epithelium in primary culture: Effects of ciliotoxic compounds. AB - Acrolein ciliotoxicity was studied on primary cultures from rabbit tracheal epithelium. The inhibition of ciliary beat was chosen as a criterion for ciliotoxicity. The measurement of ciliary beat was accomplished using an original image analysis process. PMID- 20702204 TI - Studies of nephrotoxic agents in an improved renal proximal tubule system. AB - Renal proximal tubule fragments (RPT) were prepared from young-adult, male F-344 rats by deferoxamine/collagenase perfusion and evaluated as a potential model for mechanistic studies and screening, using known nephrotoxins. Chloroform and S (1,2- dichlorovinyl )- l - cysteine (DCVC) produced depressed O(2) consumption rates (basal and/or nystatin-stimulated) and lactate dehydrogenase (LDH) release during 8-hr incubations at 0.5 mg RPT protein/ml. Cytochrome P-450 inhibitors piperonyl butoxide and metyrapone were either without effect or potentiated chloroform-induced toxicity. DCVC was more cytotoxic to RPT than to rat hepatocytes. The cytotoxic potency for cephalothin relative to cefazolin decreased as RPT content in the medium was increased to 3.0 mg protein/ml, giving a rank order more in accord with results reported in vivo. Cephalosporins markedly depressed brush border alkaline phosphatase (ALP) activity, without affecting gamma-glutamyltranspeptidase activity; the effect on ALP was less sensitive to the RPT level. Acetaminophen (25 mm) and p-aminophenol (1.0 mm) induced LDH release without ALP depression and inhibited mitochondrial respiration. These results in general corresponded well with in vivo responses and indicate that this RPT system may be valuable for studies of chemical-induced nephrotoxicity. PMID- 20702205 TI - Nephrotoxicity in vitro: Role of ion deregulation in signal transduction following injury-Studies utilizing digital imaging fluorescence microscopy. AB - Over the years, many approaches have been utilized for studying in vitro toxicity in the kidney. These have included the use of isolated perfused kidneys, renal slices, isolated nephron explants and cultured tubular epithelium. Currently, in vitro systems of either primary cultures or cell lines make it possible to use newly developed fluorescent probes and digital imaging fluorescence microscopy coupled with image analysis to quantify various ions (e.g. [Ca(2+)](i), [Mg(2+)](i), [Na(+)](i) and [H(+)](i)) in individual live cells. Methods have been developed for the primary culture of rat, rabbit and human proximal tubular epithelium and these cultures are being utilized for the study of acute cell injury and for the comparison of animal cell data with that of human cells. In the current studies, the fluorescent probe, Fura 2, was used to observe changes in [Ca(2+)](i) as they relate to cell injury. The results show that changes in [Ca(2+)](i) begin very early after treatments with a variety of agents that produce lethal and sublethal toxic injuries. These injuries can increase [Ca(2+)](i) from its normal 100 nm level to a 2 mum level. The rise in [Ca(2+)](i) precedes early bleb formation and cell death. Elevated [Ca(2+)](i) may also activate enzymes such as lipases and proteases that lead to cell death. PMID- 20702206 TI - Long-term culture of functional hepatocytes. AB - Recent studies have clearly demonstrated that the hepatocyte requires a complex and well defined environment to survive and maintain differentiated functions in vitro. Soluble factors as well as cell-matrix and cell-cell interactions have been found to affect markedly hepatocyte functions. Thus co-culturing hepatocytes with another rat liver cell type results in a prolonged expression of liver functions including phase I and phase II drug-metabolizing enzymes. Addition of corticosteroids to the co-culture medium is a prerequisite, and accumulation of insoluble matrix components is observed within a few days primarily between the two cell types. Hepatocyte cultures have been widely used for pharmacology and toxicology studies during recent years, but most studies deal with short-term investigations. Although specific functions are not completely stabilized the use of long-term hepatocyte cultures represents a promising tool to investigate enzyme induction and inhibition, and drug chronic toxicity. PMID- 20702207 TI - The significance of in vitro studies on peroxisome proliferation. AB - Peroxisome proliferation in rodents is associated with hepatocarcinogenicity. This association has led to increased interest in the phenomenon and to the search for in vitro tests to detect peroxisome proliferators and to study the mechanisms by which proliferation occurs. Primary cultures of adult rat hepatocytes provide such a system: peroxisomal enzymes, cytochrome P-452 and replicative DNA synthesis may all be induced and the response to treatment with many peroxisome proliferators is observed in a manner similar to that in the liver in vivo. Cultured hepatocytes, therefore, provide an optimal system: (i) to screen for potential peroxisome proliferators; (ii) to study structure-activity relationships; (iii) to investigate species differences in the effects of peroxisome proliferators on hepatocytes; and (iv) to study the molecular mechanisms underlying peroxisome proliferation and its relationship to tumour formation. PMID- 20702208 TI - Comparison of cultured human hepatocytes isolated from surgical biopsies or cold stored organ donor livers. AB - The purpose of this work was to compare yield, attachment rate and specific metabolic functions (stimulation of ketone body production by glucagon) of human hepatocytes isolated from surgical biopsies and from organ donor livers cold stored with a modified University of Wisconsin (MUW) solution. A significantly greater number of hepatocytes was isolated from MUW-stored livers than from surgical biopsies. On average, 60% of hepatocytes isolated from surgical biopsies attached to uncoated flask whereas the attachment rate of hepatocytes isolated from MUW-stored livers was inconsistent and always below 40%. Glucagon significantly enhanced the rate of ketone body production of hepatocytes isolated from surgical biopsies; in contrast, glucagon had marginal effects on the rate of ketone body production in hepatocytes isolated from MUW-stored livers. These results demonstrate that human hepatocytes isolated from surgical biopsies maintain liver-specific and non-specific functions better than hepatocytes isolated from MUW-stored livers. Human hepatocytes isolated from surgical biopsies should be preferentially used for the study of metabolism in human liver. PMID- 20702209 TI - Adult rat liver slices as a model for studying the hepatotoxicity of vincaalkaloids. AB - There are certain disadvantages associated with the use of isolated or cultured cells including the need to use proteolytic enzymes for their isolation and loss of tissue organization. In order to provide an in vitro system for toxicological studies that preserves tissue integrity, a method for preparation and incubation of adult rat liver slices has been developed. Fresh ultra-thin liver slices were produced in large quantities at a rapid rate under conditions that cause minimal tissue trauma. They were incubated in a system that has been designed to allow optimum gas and nutrient diffusion. Several biochemical parameters (lactate dehydrogenase (LDH) leakage, ATP content, protein synthesis and secretion) were monitored during a 20-hr incubation period. This liver slice model was used to study the toxicity of four vincaalkaloids: vincristine, vindesine, vinblastine and navelbine. Treatment with the vincaalkaloids resulted in an inhibition of protein synthesis and secretion without any effect on LDH leakage. PMID- 20702210 TI - Effects of dimethylsulphoxide on phase I and II biotransformation in cultured rat hepatocytes. AB - Addition of 2% dimethylsulphoxide (DMSO) to the medium has been described to retain biochemical and morphological differentiation of cultured rat hepatocytes. The maintenance of differentiated hepatocytes for a long time with stable phase I and II biotransformation capacities provides an important model for pharmacological and toxicological studies. This work has been undertaken to study the effects of DMSO on phase I and II parameters in cultured hepatocytes. For phase I cytochrome P-450 content, 7-ethoxycoumarin O-deethylase and aldrin epoxidase activities and for phase II glutathione S-transferase (GST) activity and its isoenzyme profile have been measured. In control cells cytochrome P-450 content and the enzymic activities measured declined as a function of culture time. Addition of DMSO partially prevented the loss of all parameters measured. The changes in GST activity were related to changes in its isoenzyme pattern. In control cells subunits 1 and 2 decreased, 3 and 4 increased and de novo expression of 7 was observed. When DMSO was added, the subunit profile better resembled that observed in vivo and the expression of subunit 7 was suppressed. In conclusion DMSO protects cultured hepatocytes from dedifferentiation and stabilizes the cells. PMID- 20702211 TI - Toxicity of paracetamol and cyclophosphamide in monolayer cultures of rat and human hepatocytes. AB - Hepatocyte structural and functional integrity was characterized in short-term primary monolayer cultures. Ethoxycoumarin-O-deethylase activity, cellular glutathione, ATP and ADP content, protein synthesis and lactate dehydrogenase (LDH) leakage were monitored. Cytotoxicity and perturbation of hepatocyte function involving measurement of these biochemical parameters was investigated following exposure to paracetamol and cyclophosphamide. Evaluation of several biochemical parameters appears to be a more appropriate assay of a perturbation in cellular integrity than the use of a single parameter. In the case of paracetamol the response of human hepatocyte cultures was broadly similar to that observed in rat hepatocyte cultures. An increase in LDH leakage occurred following exposure to high dose levels and was associated with depletion of cellular glutathione levels. At both toxic and non-toxic dose levels protein synthesis was impaired and a decrease in the cellular ATP/ADP ratio was evident. A decrease in protein synthesis and cellular glutathione was observed in both rat and human hepatocytes following exposure to cyclophosphamide. The data highlight the potential use of hepatocyte cultures for investigation of specific cytotoxic events and also emphasize the incorporation of human tissue in such systems. PMID- 20702212 TI - The liver slice system: An in vitro acute toxicity test for assessment of hepatotoxins and their antidotes. AB - A simple method for rapid and reliable assessment of hepatotoxic agents is described. Liver slices from rats and mice of two age groups were incubated with the test hepatotoxins. Exposure of liver slices from 3-month-old mice to acetaminophen (6.8 mg/ml) resulted in 80% leakage of lactate dehydrogenase into the incubation medium, whereas liver slices from one-day-old mice showed only 12% leakage. Similar results were obtained with rat liver slices. The relative lack of response by livers of newborn rats was also demonstrated with carbon tetrachloride. The in vitro liver slice system has also been used to test the potency of N-acetylcysteine (NAC) as an antidote to acetaminophen toxicity. NAC protected mouse liver slices against acetaminophen toxicity in a dose-dependent manner. Addition of the antidote (10 mm) 20 min following hepatotoxin application reduced enzyme leakage by 75% as compared with the system with acetaminophen only. These findings demonstrate that the liver slice system provides the same type of information about hepatotoxins that is usually obtained by the use of acute in vivo tests on a large number of animals. It can be used for testing potential antidotes against hepatotoxins as well as for demonstration of species and age differences in the toxicity of various substances. PMID- 20702213 TI - Biliary excretion of fluorescent cholephiles in hepatocyte couplets: An in vitro model for hepatobiliary and hepatotoxicity studies. AB - Hepatocyte couplets (26.8% of cell preparation with >85% viability) were prepared from rat livers. The preparation maintained the activity of 7-ethoxycoumarin-O deethylase throughout an 8-hr incubation. Couplets extensively secreted the fluorescent cholephiles, fluorescein and cholyl-lysyl-fluorescein isothiocyanate, into sealed canalicular spaces within 2 hr and 15-30 min, respectively, which is indicative of functional tight junctions. The time scale for biliary secretion of the cholephiles correlated well with the relative kinetics of biliary excretion reported in vivo. Hepatocyte couplets may prove useful for studies on toxicity directed towards the hepatobiliary system. PMID- 20702214 TI - Effects of various inducers on the expression of cytochromes P-450 IIC8, 9, 10 and IIIA in cultured adult human hepatocytes. AB - Primary cultures of adult human hepatocytes were used to determine the capability of the human liver to respond to phenobarbital, 3-methylcholanthrene, troleandomycin and rifampicin, four compounds known to be potent inducers of hepatic cytochrome P-450 in various animal species. Both mRNA and corresponding protein of two major isoenzymes, that is, P-450 IIC8, 9, 10 and P-450 IIIA, were measured after daily exposure to the drugs for 3 days. Phenobarbital and rifampicin were found to increase the levels of P-450 IIC8, 9, 10 mRNA and protein while troleandomycin and 3-methylcholanthrene were ineffective. Different effects were obtained for P-450 IIIA. Both mRNA and related protein were markedly increased by troleandomycin and rifampicin and decreased by 3-methylcholanthrene. mRNAs were slightly increased by phenobarbital. The results demonstrate that human hepatocytes retain drug-inducible P-450 isoenzymes in primary culture and represent a unique approach to investigate regulation of human liver drug metabolizing enzymes. PMID- 20702215 TI - Prolonged expression of biotransformation activities of rat hepatocytes co cultured with established cell lines. AB - Co-culture of hepatocytes with fibroblastic cells (C3H/10T1 2 and 3T3) allowed the expression of phase I and II biotransformation enzymes for a prolonged time in culture. After 7 days in co-culture, cytochrome P-450 and monooxygenase activities were still 20-30% of the initial value, while in pure hepatocyte cultures they were undetectable. NADPH-cytochrome c reductase and conjugation activities remained at nearly initial levels for at least 7 days in co-cultured hepatocytes. Finally, in co-cultures a clear and prolonged induction of monooxygenase activities by 3-methylcholanthrene and phenobarbital was observed. PMID- 20702216 TI - Competing pathways in metabolism-mediated cytotoxicity in vitro. AB - The metabolism of most xenobiotics to reactive metabolites is accompanied by competition with inactivation pathways, and the balance of these activation/inactivation pathways is critical in determining the precise circumstances in which metabolism-mediated cytotoxicity may be detected in vitro. Discussion of the importance of this balance must also take into account the nature of the question posed at the start of an in vitro study, and the choice of metabolizing system used. In quantitative terms, liver microsomal cytochrome P 450-mediated monooxygenase activity and conjugation with glutathione (GSH) are the major routes of activation and inactivation, respectively. Results of recent studies on the cytotoxicity of cyclophosphamide, bromobenzene and paracetamol measured in a liver homogenate fraction-cultured cell co-incubation have confirmed the importance of activation/inactivation balance and stability of the reactive metabolite as determinants of metabolism-mediated cytotoxicity in vitro. Competition between metabolism by P-450-mediated enzyme activity and conjugation with GSH may be used as the basis of a screen for detection of reactive metabolites by measurement of GSH depletion or conjugation with GSH. The use of cells in culture for studies of metabolism-mediated cytotoxicity is confounded by the time-dependent alterations in various enzyme activities that occur and so distort the balance of activation/inactivation. This, in turn, reduces the reliability of such systems as predictors of the events likely to occur in vivo; the lack of a distribution component in the in vitro system further distorts this in vivo/in vitro comparison. Rational development of in vitro systems for detection of reactive metabolites can only occur with an understanding of the role of competing pathways in metabolism. PMID- 20702217 TI - A study of the metabolism and kinetics of SK&F 94120 and two structural analogues in rat hepatocytes and in vivo. AB - The major route of metabolism of 5-(4-acetamidophenyl)pyrazin-2(1H)-one (SK&F 94120) was by glucuronidation at the oxygen of the pyrazinone ring. Other metabolites originated from metabolism by gut microflora with subsequent hepatic metabolism (Ross et al., 1988). SK&F 94120 was metabolized by cultures of rat hepatocytes to a glucuronide conjugate and was rapidly cleared in the hepatocyte system (Cl(int) = 0.320 ml/hr/mg protein). A structural analogue (SK&F 94467) was not glucuronidated by rat hepatocytes and therefore its clearance in vitro could not be detected. In vivo SK&F 94120 was rapidly cleared from the plasma. Plasma clearance was greater for SK&F 94120 than for SK&F 94467, which is consistent with data from the hepatocyte system. Thus the mean retention time of SK&F 94467 in vivo is longer than for SK&F 94120. PMID- 20702218 TI - Xenobiotic metabolism in the isolated conceptus. AB - The development of culture systems using either pre- or post-implantation embryos has made it possible to study the metabolizing capacity of the isolated conceptus in vitro. In the rodent pre-implantation embryo and post-implantation conceptus (embryo and its membranes), constitutive levels and inducibility of different enzyme systems involved in drug metabolism have been shown in vitro to lead to the formation of embryotoxic metabolites of different xenobiotics. This indicated the presence of enzyme systems during early organogenesis. For example, using the rat post-implantation embryo culture, we could show that incubation with the lipoxygenase inhibitor N-hydroxy-N-methyl-7-propoxy-2-naphthalenethanamine (QAB) led to high levels of the main in vivo metabolite 7-propoxy-naphthalene-2 ylacetic acid (QAA) and two as yet unidentified products, M5 and M6, in the conceptus. QAB was not found in tissues and QAA itself did not enter the embryonic compartments. In addition, accumulation in tissue was dependent on the time and duration of exposure. It started at 10.5 days of development. A similar metabolite pattern was obtained after yolk-sac tissue had been cultured alone, which suggests metabolizing capacity of mainly the yolk-sac tissue. The enzyme reactions involved might have included oxidative N-demethylation and oxidative deamination, probably also including the formation of reactive intermediate metabolites. In conclusion, our data demonstrate that not only maternal metabolism may play an important role in the toxic action of xenobiotics, but also the metabolizing capacity of the conceptus itself may be crucial, since the formation of (intermediate, highly reactive) metabolites takes place at the target site. PMID- 20702219 TI - Reactive metabolite formation catalysed by cytochrome P-450j. AB - Cytochrome P-450j is induced by ethanol, isoniazid, fasting and in diabetes mellitus; the hepatotoxicity of paracetamol and N,N-dimethylnitrosamine is increased following such induction. We have assessed the potential of liver microsomes isolated from control and isoniazid-treated rats to convert some hepatotoxins to reactive metabolites using loss of glutathione, added to microsomal incubations, as an index of reactive metabolite generation. No change or a decrease in glutathione depletion, compared with controls, was found when 4 ipomeanol, cyclophosphamide, toluene, coumarin and butylated hydroxytoluene were incubated with liver microsomes from isoniazid-treated rats. No glutathione depletion was caused by trichloroethylene. Increased glutathione depletion was shown for paracetamol and bromobenzene and their non-hepatotoxic analogues 3 hydroxyacetanilide and p-bromophenol. This confirmed that the glutathione depletion assay fails to distinguish between toxic and non-toxic reactive metabolites. Increased glutathione depletion was also observed for 2-methyl furan, aniline, allyl alcohol, thiophene and chloroform. Analysis of glutathione depletion/concentration relationships demonstrated that P-450j has high affinity for chloroform, as judged by reactive metabolite formation. PMID- 20702220 TI - The susceptibility of various cultured cells to induction of clear cytoplasmic vacuoles by disobutamide. AB - Cultured cells were found to be highly useful for investigating intracellular storage of amphiphilic compounds using disobutamide as a model agent. To select types of cultured cells most suitable for investigations, cells of dog coronary artery muscle, rabbit aorta muscle, rat urinary bladder carcinoma, rat basophilic leukaemia, human skin fibroblasts, bovine aorta endothelium, Chinese hamster ovary tumour and mouse fibroblasts were incubated with 0, 1, 2, 4, 6, 8 and 10 x 10(-4)m-disobutamide for 24 hr. Cultures were examined in situ by phase light microscopy for the presence of clear cytoplasmic vacuoles, cell death (cell detachment), and for drug effect on confluency/cell count. Disobutamide induced vacuoles in all cell types except rat leukaemia. The drug induced cell death and reduction in confluency or cell count in cultures of all cell types except rat carcinoma and rabbit aorta muscle. Release of lactic dehydrogenase from cells confirmed the relative resistance of the rat carcinoma and rabbit cells, and susceptibility of rat leukaemia, to drug-induced cell death. By means of electron microscopy of rat carcinoma and rabbit cells, it was established that vacuoles were membrane-bound and their content was predominantly electron-lucent. PMID- 20702221 TI - Variations in the response of cell lines to metabolism-mediated toxicity. AB - One major criticism of cytotoxicity tests is the negligible capacity for metabolism of foreign compounds, which exists in most cell lines. We have investigated the use of an exogenous metabolizing system, comprising 9000 g supernatant of liver from Aroclor 1254-pretreated rats (S-9) and an NADPH regenerating system, in the kenacid blue test. BCL-D1 cells (a human embryonic lung finite cell line) appeared to be sensitive to the toxicity of active metabolites of several model toxins. Other cell lines appeared to be less sensitive but the effects varied with the cell line and the test compound. These differences may, in part, be due to differences in the intrinsic ability of different cell lines to detoxify the active metabolites. It is therefore possible to use this type of test system for mechanistic studies but results with unknown compounds should be treated with caution. PMID- 20702222 TI - The in vitro effects and metabolism-mediated cytotoxicity of phorone, a glutathione-depleting agent. AB - The use of S-9 liver fractions to examine metabolism-mediated cytotoxicity in vitro has the inherent problem that not only are activating enzyme systems added, but also deactivation pathways, such as that involving glutathione. The in vivo manipulation of these activating and deactivating systems prior to S-9 preparation is possible with animals, but not with humans. Hence, the possibility of depleting glutathione in target cells and S-9 fractions was evaluated using phorone, a known glutathione-depleting agent. 3T3-L1 mouse fibroblast-like cells and V79 Chinese hamster lung fibroblasts were used as the target cells, and cytotoxicity was assessed by the FRAME (Fund for the Replacement of Animals in Medical Experiments) kenacid blue method. Phorone was found to have a moderate intrinsic cytotoxicity and to effectively deplete cellular glutathione. When phorone was used in the two-component S-9 fraction/target cell system, its toxicity to 3T3-L1 cells was markedly increased, which suggests transformation to a toxic metabolite. The use of S-9 fractions from animals pretreated with phenobarbitone and beta-naphthoflavone resulted in greatly increased phorone toxicity, which indicates the involvement of cytochrome P-450 enzymes in its metabolism. The metabolism-mediated toxicity of phorone was reduced by the addition of exogenous glutathione. PMID- 20702223 TI - Glutathione conjugation and cytochrome P-450 metabolism of methyl chloride in vitro. AB - Possible carcinogenic properties of methyl chloride (CH(3)Cl) have been under discussion since an increase of renal tumours was observed in male B6C3F(1) mice after a 2-yr inhalation exposure to the substance. This was, however, only observed following exposure of male mice to the highest concentration level and not after exposure of females or F344 rats of both sexes. Accumulation of formaldehyde in the kidneys was thought to be responsible for tumour production. In the experiments presented here, cytosolic enzymes from the liver and kidneys of different mouse strains and F344 rats were incubated in head-space vials with methyl chloride or methyl bromide. Following equilibration, the decrease in the concentration of the gases was monitored by gas chromatography as a parameter for metabolic elimination. The metabolic turnover of the methyl halides was found to be significantly higher in female animals than in the males. In parallel experiments, the glutathione content of the liver and kidneys of mice exposed by inhalation to 1000 ppm methyl chloride was determined. In both organs, the glutathione content diminished rapidly after exposure to the methyl halide. The glutathione depletion was slightly greater in females than in males. Finally, the content of cytochromes P-450, P-420 and b5 was determined in liver and kidneys of different mouse strains by difference spectroscopy. Female mice were found to have a lower content of P-450 and b5 than males in the kidneys; there was no such sex difference in liver tissue. The results show that a sex difference in metabolism is unlikely to be responsible for the unique kidney tumour production in male B6C3F(1) mice. Other possible explanations are discussed. PMID- 20702224 TI - Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes. AB - Rat hepatocyte suspensions have been used as a model system for some studies on the mechanism of coumarin-induced hepatotoxicity. Hepatocytes were isolated from male Sprague-Dawley rats and subjected to Percoll centrifugation to obtain preparations with >/=92% viability. Coumarin produced time- and concentration dependent cytotoxic effects in rat hepatocytes as indicated by loss of cell viability and glutathione depletion. [3-(14)C]Coumarin was metabolized by rat hepatocytes to polar metabolites including o-hydroxyphenylacetic acid and to metabolites that became covalently bound to hepatocyte proteins. The addition of 10 mum-ellipticine significantly reduced coumarin cytotoxicity, coumarin metabolism and covalent binding in rat hepatocytes. These results demonstrate that coumarin-induced liver injury in the rat can be modelled in hepatocyte suspensions and that toxicity appears to be due to one or more cytochrome P-450 generated metabolites. PMID- 20702225 TI - Continuous culture of human faecal bacteria as an in vitro model for the colonic microflora. AB - To investigate the role of human gut bacteria in the metabolism of potentially reactive compounds we have developed an in vitro model of the human faecal microflora using a two-stage continuous culture inoculated with human faeces. The cultured bacterial population retained many of the bacteriological and biochemical characteristics of the flora present in the faecal sample used for inoculation. Obligate anaerobes were the predominant bacterial types found in vitro and included Bacteroides ovatus and Bifidobacterium adolescentis. A comparison of in vivo (faeces) and in vitro bacterial enzyme activities that are known to be involved in the biotransformation of potentially toxic compounds found the activities of hydrolytic enzymes to be similar but reductive enzymes exhibited higher activities in the continuous culture model. When substrates of the enzymes were added to the culture vessel, the enzymes were induced to varying extents. The short-chain fatty acid profile in the culture was almost identical to that in faeces with the order of abundance being the same in two systems. These results indicate that the continuous culture of faecal bacteria can provide a suitable model for studying bacterial interactions and biotransformation of the human colonic flora. PMID- 20702226 TI - Toxicokinetic-toxicodynamic models describing the relation of plasma and red blood cell potassium with plasma digitalis in acute human digitalis poisoning. AB - Toxicity of cardiac glycosides involves the inhibition of the Na(+)-K(+) ATPase pump. As a consequence, extracellular K(+) concentration rises and intracellular K(+) concentration strongly decreases. Red blood cell (RBC) K(+) is a practical marker of ATPase inhibition. In a group of 15 patients intoxicated by digitoxin and lanatoside C, correlations between the calculated digitoxin ingested dose or plasma digitoxin levels and the kinetics of plasma K(+) and RBC K(+) have been assessed using kinetic-effect modelling. A correlation between the calculated ingested dose of digitoxin with RBC K(+) was found (r = 0.64). A direct relation based on the linear model fitted the relation between extracellular K(+) and digitalis concentration. An indirect relation based on the Emax sigmoid model fitted the relation between RBC K(+) and digitoxin concentrations. Specific parameters were obtained from the linear model with a = 0.0196 +/- 0.0272 and b = 0.455 +/- 0.035. Specific parameters were derived from the Emax sigmoid model with k(eo) = 0.0139 +/- 0.0052/hr and EC(50) = 91.95 +/- 20.55 ng/ml, where k(eo) = first-order rate constant of the disappearance of the toxic effect and EC(50) = digitoxin concentration decreasing the RBC K(+) concentration by 50%. These data showed that the in vitro assays of plasma K(+) and RBC K(+) are convenient and predictive assays for evaluating the severity of human digitoxin poisoning. PMID- 20702227 TI - An apparatus to simulate metabolism of ingested substances. AB - A prototype in vitro, closed in-line apparatus was designed to simulate the passage of a substance through the gastro-intestinal tract and absorption by internal body organs with appropriate metabolism at each stage, with computer controlled culture conditions to resemble normal in vivo physiology. In tests to define conditions of use, comparisons of tests using water-bath and metabolic simulator techniques showed formation of similar metabolites of sodium lauryl sulphate. Comparison of in vivo and in vitro results showed the advantage of the in vitro system to identify metabolites. The end-product butyric acid-4-sulphate excreted in the urine of rats after a single oral dose of [(14)C]sodium lauryl sulphate was also formed by hepatocytes in vitro in a water-bath vessel, which indicates the relevance of the intermediary metabolites detected by sequential sampling over 24 hr in the metabolic simulator. The intermediary metabolites identified were 11- and 12-hydroxy dodecyl sulphate, 12-carboxy dodecyl sulphate and probably 11-keto dodecyl sulphate. This evidence was not readily obtainable from the in vivo test. Once limitations of this prototype design are overcome, the system should enable comparison of the metabolism of test substances between species, including man, and eventually the use of laboratory-adapted cultures of relevant organs to replace primary in vivo sources of tissues. PMID- 20702228 TI - Trichloroethylene biotransformation in human and rat primary hepatocytes. AB - The biotransformation of trichloroethylene (TCY) was studied in male Sprague Dawley rats and in human hepatocyte suspensions to aid in estimating the potential for hepatocarcinogenesis in humans. The major metabolites were qualitatively identical in both species, but rat hepatocytes metabolized about four times more TCY than did human hepatocytes under the same experimental conditions. The quantities of chloral hydrate, trichloroethanol (free plus conjugated) and trichloroacetic acid (TCA) were 15, 5 and 20 times greater, respectively, in rat hepatocyte suspensions. Since the TCA metabolite has been implicated in TCY-induced peroxisomal proliferation and hepatocarcinogenesis and rats form less TCA than do mice, which are susceptible to these effects, the results suggest that humans are at low risk from TCY exposure. PMID- 20702229 TI - Recent advances in testicular cell culture: Implications for toxicology. PMID- 20702230 TI - Development of in vitro tests of human sperm function: A diagnostic tool and model system for toxicological analyses. AB - The mammalian spermatozoon is a highly specialized cell which, during the process of evolution, has developed a unique compartmentalized structure in order to express the diverse array of biological properties (movement, cell recognition, secretion, membrane fusion) required to fertilize the egg. This paper describes an integrated battery of tests that can be used to obtain information on certain key aspects of human sperm function in vitro. These tests include computerized digital image analysis systems to record the movement characteristics of the spermatozoa, in vitro assays of sperm-zona recognition based on human ova stored in high ionic strength salt solutions, the use of fluorescein-conjugated lectins to detect the acrosome reaction and inter-species in vitro fertilization procedures to assess the ability of human spermatozoa to fuse with the vitelline membrane of the oocyte. In combination these assays provide information that is predictive of the fertilizing capacity of human spermatozoa in vitro and in vivo, and, as such, should find application in assessing the influence of xenobiotics on male fertility. In addition, such tests may be of value in developing model in vitro systems employing human spermatozoa for the analysis of toxicity at the cellular level, particularly in relation to the influence of xenobiotics on the properties of biological membranes. PMID- 20702231 TI - In vitro embryotoxicity and teratogenicity studies. AB - During the past decade many publications have appeared describing test methods for in vitro toxicological research and emphasizing their desirability, appropriations and necessity. One reason for this might be the pressure imposed on regulatory, industrial and academic communities by society to reduce the number of animals used in research and testing strategies. In addition, sophisticated analytical techniques have been developed that allow the measurement of small quantities of biologically important material. Moreover, the present knowledge gained in the area of tissue culture and in vitro embryo culture allows the application of these techniques for more routine studies on the one hand, and studies on mechanisms of action of teratogens in model systems of isolated developmental processes on the other hand. With respect to reproductive toxicity, embryotoxicity and teratogenicity there are now diverse systems available ranging in organizational complexity from bacteria, insects, invertebrates, lower vertebrates, avian embryos and mammalian cells, tissues and organs to whole rodent embryos. This presentation serves only as an introduction to the complex issues raised by the many methods available. The concomitant application of both in vivo and in vitro methodologies will improve the quality of teratological research, and therefore will contribute to a critical evaluation of developmental hazards. PMID- 20702232 TI - Studies on variability of the micromass teratogen test. AB - The micromass assay is an in vitro test that can be used to predict the teratogenic potential of compounds being developed in the pharmaceutical and chemical industries. The assay is currently undergoing validation by an interlaboratory blind trial at several national and international institutions. The present paper investigates some areas of the assay system where variability in technique may influence the reproducibility of the test results. The main areas identified are possible variations in the micromass preparation procedure (for example in terms of the precise source of tissue and the time taken), degrees of subjectivity in the endpoint measurement and possible variations in the experiment design. Control of these sources of variability increases the reproducibility of the results. PMID- 20702233 TI - The Hydra assay as an early screen for teratogenic potential. PMID- 20702234 TI - Seminal plasma superoxide dismutase activity following radiotherapy: Protection by the exogenous enzyme and effects of intracellular inhibition. AB - For referred subfertile, radiation-exposed and known fertile males seminal plasma superoxide dismutase activity did not correlate with sperm density, % sperm motility, sperm velocity or penetration in the sperm penetration assay (SPA), but was found to correlate positively with seminal plasma zinc. A study of seminal plasma superoxide dismutase in relation to post-irradiation clinical treatment time provided tentative evidence that following a radiation challenge, superoxide dismutase might be subject to induction. When sperm intracellular superoxide dismutase was inhibited by incubation with diethyldithiocarbamate (DDC) in defined culture medium, motility ceased within 30 min but there was no associated rise in lipid peroxidation. Sperm pretreatment with DDC at concentrations as low as 10 mum could abolish penetration in the SPA provided sperm were prepared by passive incubation. Cells electropermeabilized in the presence of calcium could overcome the DDC block. Exogenous addition of superoxide dismutase and catalase could provide effective protection to sperm against the effects of ultraviolet treatment. PMID- 20702235 TI - The potential usefulness of a differentiating teratocarcinoma cell line in in vitro toxicity testing. AB - A number of in vitro systems have been put forward as potential alternative methods for testing chemicals for teratogenic potential. The most promising of these systems, for example mammalian whole embryo culture and the micromass technique, are currently undergoing further interlaboratory validation. However, such tests involve the use of a considerable number of animals. It was therefore decided to investigate the possible use of a permanent cell line that possessed many of the properties of embryonic cells, that is a differentiating cell line, F9 (derived from a mouse teratocarcinoma), in the development of an in vitro teratogenicity test. In a preliminary study, six chemicals were tested for their modulating effects on differentiation in undifferentiated, differentiating and differentiated F9 cells. These effects were assessed morphologically and by measuring the production of laminin (a biochemial marker of F9 differentiation). The use of the F9 cell line in in vitro teratogenicity testing shows promise, but further work is necessary before its potential can be fully evaluated. PMID- 20702236 TI - Changes in visceral yolk sac ultrastructure after exposure of rat embryos to selected teratogens in vitro. AB - It has been determined that a number of teratogens alter the osmotic environment around the rat embryo, an effect that is associated with abnormal fluid accumulation (and ultimately abnormality) in the embryo. At least one of these teratogens, trypan blue, changes lysosomal structure in the visceral yolk sac (VYS), an extra-embryonic membrane that envelops the extra-embryonic fluid compartment. The osmotic and ultrastructural effects are comparable in the in vivo and in vitro rat embryo. In the present study, the effects of other osmotic teratogens on VYS ultrastructure were investigated in rat whole embryo culture. Leupeptin (10 mug/ml) and E-64 (10 mug/ml) both caused a marked increase in the size of VYS lysosomes. Both chemicals inhibit cysteine proteinases, which are abundant in lysosomes. Suramin (750 mug/ml), an inhibitor of a number of lysosomal hydrolases, caused vacuolization of large areas of VYS cells. Ethylenethiourea (120 mug/ml) produced no marked ultrastructural changes, although the endocytotic apparatus of VYS cells appeared to have increased electron density, an effect that was also observed after treatment with the other teratogens. These results indicate that teratogens which alter embryonic osmotic balance also affect structures involved in endocytosis or lysosomal degradation of material by VYS cells. PMID- 20702237 TI - Bovine serum: An alternative to rat serum as a culture medium for the rat whole embryo culture. AB - The results reported here demonstrate the ability of supplemented bovine serum to serve as a culture medium for rat whole embryos. After 48 hours' culture in bovine serum supplemented with Tyrode's buffer and methionine, 9.5-day-old rat embryos were at a stage of development comparable with that of embryos cultivated in homologous serum, although some deficiency in the formation of haemoglobin in embryonic blood cells could be observed. However, supplementation of the culture medium with haemoglobin overcame this deficiency. The procedure used for preparing the culture medium is described in detail and some advantages of bovine serum are discussed. PMID- 20702238 TI - Embryonic micromass limb bud and midbrain cultures: Different cell cycle kinetics during differentiation in vitro. AB - Rat embryo micromass limb bud (LB) and midbrain (CNS) cultures have been proposed as a screening system for teratogenic potential as well as a model system for differentiation. To further characterize these in vitro differentiating cultures, their population kinetics have been examined. Cellular proliferation, cell cycle kinetics and cell differentiation were monitored at days 1, 2 and 5 in culture. For cell cycle analysis, cellular DNA was stained with 4,6-diamidino-2-phenyl indole and nuclei were analysed by flow cytometry. Cell viability was assessed using trypan blue and differentiation was monitored using haematoxylin (CNS) or alcian blue (LB) stain. CNS cultures underwent 2-3 cell doublings during the 5 days of culture. There was a gradual accumulation of cells in the G(0)/G(1) compartment (54% +/- 10%, day 1 to 78% +/- 2%, day 5) (P < 0.05, chi(2) test). This accumulation appeared to occur at the expense of the S and G(2) + M compartments since both decreased over this same period of time. LB cultures underwent 1-2 cell doublings during the same culture period. In contrast to the CNS cultures, the limb bud cultures exhibited only minimal changes in the size and distribution of the cell cycle compartments during the 5 days in culture. Characterization of the cellular kinetics of these two widely used embryo cell culture systems should help to delineate potential sites and mechanisms of developmental toxicity. PMID- 20702240 TI - Application of the Hydra regeneration assay: Assessment of the potential teratogenic activity of engine exhaust emissions. PMID- 20702239 TI - In vitro micromass teratogen test: Interpretation of results from a blind trial of 25 compounds using three separate criteria. AB - The results are presented on an interlaboratory study to validate the Micromass assay by testing compounds under code using a similar protocol, with an assessment of results for 25 compounds tested without S-9 mix. Four of these were co-tested with S-9 mix. Three separate sets of criteria have been proposed (Flint, 1986 and 1987; Flint and Orton, 1984) for interpreting the results for teratogenic hazard from in vitro data using IC(50) values: (i) the '< 500 mug/ml rule', (ii) the '< 50 mug/ml rule' and (iii) the 'specific inhibition of cell differentiation 2-fold rule'. The data were decoded and assessed using the criteria for their sensitivity, specificity and accuracy. Using the '< 500 mug/ml rule' a higher sensitivity was obtained but at the expense of a high false positive frequency (50%). Conversely, the '2-fold rule' gave a high specificity with only 10% false positives. Diphenhydramine and furazolidone gave false positive responses; the teratogens beta-aminopropionitrile and methotrexate were not detected. Selective inhibition of cell differentiation was related to high potential teratogenicity. In the application of the test, it is suggested that if there was an indication of teratogenic hazard using the '2-fold rule' the compound should be rejected without recourse to animal testing. In its present form the assay cannot be used to unequivocally identify non-teratogens. PMID- 20702241 TI - Effects of inorganic nitrates on growth and development of Hydra. PMID- 20702242 TI - Rat post-implantation culture: Production of 5-8-somite embryos by a time controlled mating procedure. AB - The use of in vitro studies allows a reduction in the number of test animals needed to perform a study. In 24-hr post-implantation embryo culture (from day 10 to day 11 post-insemination) the 5-8 somite stage is considered to be the best starting point. A time-controlled mating procedure has been developed using a positive lordosis reaction and a short period for mating to synchronize pregnancy in rats. With this procedure, 243 hr post-mating 97% of embryos are in a stage of development ranging between 5 and 8 somites. The pregnancy rate (96%) and embryo viability rate (93.4%) are excellent. In these conditions only two or three females are needed to obtain 20 embryos at the required somitic stage. Compared with commonly used mating procedures, this technique reduces considerably the number of females needed for each experiment and workload involved. Furthermore, it allows better planning of whole embryo culture studies and can be easily adapted to obtain embryos at any somitic stage. PMID- 20702243 TI - Data on development of post-implantation rat embryos in a 24-hr culture. AB - Cumulative data on growth, differentiation and development of control rat embryos over a 24-hr culture period (day 10-11 post-insemination) are presented. Cultures were performed in pure rat serum supplemented with 0.5% gelatin, with embryos at 5-8 somites at the start of the culture, according to New's technique. The embryos were evaluated according to the morphological scoring system of Brown and Fabro. Results are given, showing the repartition for each final somitic age, for the following parameters: yolk sac diameter, crown-rump length, head length, total score of development, and scores of development of 16 different territories. Viability of embryos, and the number and type of anomalies are also presented. Data were collected on 144 control embryos. PMID- 20702244 TI - The micromass test: Is it subject to strain variation? AB - Strain difference in the teratogenic response in vivo is an important consideration in the design and interpretation of regulatory studies. The importance of strain difference in vitro has been examined using all trans retinoic acid. Effects on development of the forelimb in vivo and on differentiation and survival of embryonic limb bud and midbrain cells in vitro were compared for three strains of rat, Allen & Hanbury Albino (AHA), Random Hooded (RH) and Alderley Park (AP). Transformed dose-response curves for the incidence of shortened forelimb in vivo were parallel. Comparison of ED(50) values (the concentration at which 50% of embryos respond with the index abnormality) allowed the strains to be ranked in order of susceptibility in vivo: AHA > RH = AP (ED(50) values 93, 124 and 123 mg/kg, respectively). In vitro, there was little difference in cytotoxicity or in effects on midbrain cell differentiation between strains. However, marked differences for effects on limb bud cell differentiation allowed the three strains to be ranked as follows: AHA > RH > AP (IC(50) values 0.008, 0.09 and 0.25 mug/ml, respectively). These findings suggest that for retinoic acid, the micromass test is subject to strain variation, although this had no effect on the prediction of teratogenic potential. Furthermore, the order of susceptibility of the three strains examined was the same in vivo and in vitro. Thus, target tissue sensitivity may play an important part in strain variation in the teratogenic response, although differences in vitro were much more marked than those seen in vivo. PMID- 20702245 TI - In vitro micromass teratogen test: Results from a blind trial of 25 compounds. AB - The results obtained by Huntingdon Research Centre participating in a blind trial of the micromass assay for the prediction of teratogenic potential are presented. Twenty-five coded compounds were tested without S-9 mix using a pre-agreed protocol; three compounds were later tested with S-9. The data were assessed for sensitivity, specificity and accuracy using three separate sets of criteria based on either concentration (the <500 mug/ml rule (i) and the <50 mug/ml rule (ii)) or specific inhibition of cell differentiation at relatively non-cytotoxic concentrations (the 2-fold rule (iii)). The best in vivo/in vitro correlation was obtained using the 2-fold rule; the <500 mug/ml rule was the most sensitive but gave a high false positive rate and the <50 mug/ml rule was of low overall accuracy (60%). It is suggested that selective inhibition of differentiation of one cell type and cytotoxicity at low dose levels may also indicate risk of embryo-foeto toxicity, a factor to be considered with the pharmacokinetics of the compound. The teratogens procarbazine, methotrexate and caffeine were not detected; diphenhydramine and furazolidone initially classified as non-teratogens in vivo, were predicted as teratogens by the micromass assay. PMID- 20702246 TI - In vitro transformation of human skin epithelial cells: Role of RAS oncogene in malignant progression. AB - Immortalized human skin epithelial cell lines provide useful models to study progressive stages in human carcinogenesis. Alterations have been examined occurring with immortalization and malignant progression of the human keratinocyte cell line HaCaT, which developed spontaneously in a long-term culture from trunk skin keratinocytes. The cell line has maintained many features of epidermal growth and differentiation in vitro and has acquired clonogenicity. HaCaT cells exhibited a transformed phenotype (aneuploidy and clonogenicity in soft agar) but remained non-tumorigenic. On transplantation they formed normally structured and differentiating epithelia, but did not grow invasively. Following transfection with the c-Ha-ras oncogene (EJ) randomly selected (G418-resistant) clones exhibited different stages of tumour progression. They formed either (1) rapidly regressing cysts, as seen with the parental line, (2) slowly growing benign tumours or (3) progressively enlarging well differentiated carcinomas. Tumorigenic (benign and malignant) clones had higher levels of mRNA expression and produced mutated p21. However, no correlation existed between both parameters and malignant growth. Ras-transfected clones showed improved morphological differentiation in vitro, in transplants, and in tumours and expressed differentiation-specific keratins. Tumorigenic HaCaT-ras clones were clonogenic in serum-free medium but had lost their ability to grow in soft agar. Thus, c-Ha ras oncogene expression initiated tumour progression in immortalized human keratinocytes by altering growth regulation in vitro and in vivo, but per se was insufficient for malignant transformation. PMID- 20702247 TI - In vitro analysis of modulators of intercellular communication: Implications for biologically, based risk assessment models for chemical exposure. PMID- 20702248 TI - Practical application of new approaches in genetic toxicology. PMID- 20702249 TI - Studies of human bronchial epithelium in vitro: Changes of [Ca(2+)](i) in relation to injury, growth and differentiation. AB - The objectives of the present work included the study of the response of normal human bronchial epithelial (NHBE) cells to injury following treatment with several agents, especially those associated with tumour promotion. The effects of putative tumour promoters including 12-O-tetradecanoylphorbol acetate (TPA), a series of aldehydes, and H(2)O(2) on the regulation of cytosolic ionized calcium ([Ca(2+)](i)) were compared with the effects of growth and squamous differentiation stimuli, including serum and transforming growth factor-beta. The cells studied included primary cultures of NHBE cells and the BEAS-2B cell line, created by transformation of NHBE cells with the adenovirus 12-Simian virus 40 hybrid. The results indicate that, with several stimuli, the onset of terminal squamous differentiation is preceded by a rise in [Ca(2+)](i). The results are interpreted in terms of a general hypothesis regarding the interaction between acute and chronic cell injury. PMID- 20702250 TI - Induction of sister chromatid exchanges in NIH 3T3 cells transformed by DNA from mice given cyclophosphamide. AB - The rationale behind this experiment was to investigate the role of sister chromatid exchange (SCE) in the transformation process in vitro. High molecular weight DNA was extracted from bone marrow cells of mice given 20 mg cyclophosphamide/kg body weight. 30 mug of this DNA was used to transfect NIH 3T3 in Eagle's medium seeded at 0.7 x 10(6) cells/plate. Morphologically visible foci were picked up after 16-21 days. The foci were trypsinized, washed and allowed to grow in the presence of bromodeoxyuridine (25 mum) for 72 hr in the dark. Analysis of SCE per chromosome indicated a 20-fold increase in the frequency of exchanges as compared with the induction seen in negative controls. These data suggest that the transformation process of NIH 3T3 cells by DNA from mice treated with cyclophosphamide is associated with an increased induction of SCEs. PMID- 20702251 TI - Transformation of ras transfected BALB 3T3 clone (Bhas 42) by promoters: Application for screening and specificity of promoters. AB - BALB 3T3 cells transfected by v-Ha-ras (Bhas 42 clone) were found to be sensitive to contact inhibition, but were susceptible to drastic transformation by 12-O tetradecanoylphorbol-13-acetate. These results indicate that Bhas 42 cells are the initiated cells in the two-stage transformation process. By plating Bhas 42 cells together with BALB 3T3 cells followed by treatment with known promoters, a transformation assay system was established for the detection of tumour promoters. The Bhas 42 system showed advantages over conventional chemically induced transformation assays at several points, but some promoters did not induce transformation of Bhas 42 cells. PMID- 20702252 TI - DNA-binding studies with allylchloride and allylbromide using the isolated perfused rat liver technique. AB - The isolated perfused liver technique has been adapted for DNA-binding studies of allyl compounds without the need for expensive radioactive labelled compounds or complex and protracted methods such as that including monoclonal antibodies. The technique was found to be easy to perform and gave reproducible results. The portioned administration of the test compounds (200-600 mg) was less damaging to the liver than the addition in a single dose. The liver functions could be held at nearly physiological values over a period of 10 hr. Three allylguanine adducts (O(6)-allylguanine, N(2)-allylguanine, 7-allylguanine) and two adenine adducts (N(6)-allyladenine and 3-allyladenine) could be detected in the hydrolysed DNA obtained from isolated perfused livers. These adducts demonstrate the modifications of DNA in mammalian liver and that a potential cancer-initiating effect must be considered with allyl compounds that possess alkylating activities. PMID- 20702253 TI - Strategic considerations in industry's use of in vitro toxicology. AB - Industrial concerns have a legal and ethical responsibility to provide information that allows products to be used safely. Current toxicological practice and legal requirements rely on animal experiments to provide much of this information on safety. Nevertheless, there is a clear role for in vitro methods in the overall development and testing of chemicals. During the early stages of development of a new chemical, in vitro tests provide information used in the selection of appropriate candidates from among the many that may be available. Such use of in vitro tests for screening of chemicals must be preceded by adequate validation. The interpretation of results of screening chemicals requires a detailed knowledge of the sensitivity and specificity of the test and of the structures of the chemicals under test. Once in vivo toxicological data are available, in vitro tests may have a key role in providing an understanding of species differences in toxic responses. Examples of the use of in vitro techniques to improve the specificity of animal studies are given and these include studies of trichloroethylene, di(2-ethylhexyl) phthalate, hexachlorobutadiene and a substituted triazole. In the overall process of risk assessment, extrapolation of animal data to the assessment of human hazard is a prerequisite. In vitro techniques can be used to assess species differences in transdermal absorption. They may also help in assessing quantitative differences in metabolic conversion between species. Examples of the use of in vitro techniques to improve the sensitivity of animal studies include the study of the toxicity of methylene chloride. In vitro techniques have developed rapidly over the last decade. Nevertheless, there is only one category of testing within regulatory guidelines that specifies in vitro methods, namely mutagenicity. At the moment, in vivo methods are considered to provide the best general information for risk assessment, with in vitro methods contributing as screening techniques and as adjuncts to improve the sensitivity and specificity of animal studies. PMID- 20702254 TI - Acceptance of in vitro testing by regulatory authorities. AB - National regulatory authorities have responsibility for taking decisions that possibly affect the health of whole populations and it is therefore to be expected that they will be reluctant to substitute alternative in vitro toxicity test methods for conventional animal studies unless the new procedures have been demonstrated to be reliable and have been adequately validated. Validation of in vitro methods presents particularly difficult problems because whilst they tend to produce consistent and objective results, the test systems used are incapable of mirroring the complexity of the biochemical processes seen in animals. As a result, a single animal study would need a large battery of in vitro studies to replace it to cover the various endpoints that are involved in the in vivo study; each of these in vitro tests would need to be validated with regard to the specific endpoint that it is investigating. Although great advances have been made in recent years in the development of alternative methods, few have been validated to an extent that makes them acceptable to regulatory authorities as replacements for in vivo studies. Rather, they are largely seen and used as screening techniques whereby decisions can be taken on the value of further development of newly discovered compounds, and as aids in the interpretation of animal studies and in their extrapolation to man, that is, they are of value in 'mechanism of action' studies. Nevertheless, certain in vitro procedures are already accepted by regulatory authorities and their use, for example, in 'screening out' compounds that have severe irritant properties, and in identifying compounds with potential mutagenic and carcinogenic activity, has had a profound effect on both the number of animal studies carried out and on the welfare of those animals still used. PMID- 20702255 TI - Computer modelling and in vitro tests in the safety evaluation of chemicals Strategic applications. AB - The cytochromes P-450 detoxicate most chemicals, but activate carcinogens and other toxic chemicals by oxygenating them to reactive intermediates. A new strategy based on the P-450s has resulted in the development of a computer program (COMPACT) and of a programme of enzyme induction studies, as short-term tests to predict the potential toxicity/carcinogenicity of chemicals. Most carcinogens are metabolically activated by P450 I (P-448); P450 IIE and P450 IV also mediate chemical toxicity by producing oxygen radicals. P450 IIB mostly results in detoxication, but where chemicals are oxygenated with difficulty (e.g. phenobarbitone), the cytochrome is induced and futile cycling and oxygen radical formation may result. Oxygen radicals are highly toxic, mutagenic and carcinogenic and mediate much chemical toxicity in small rodents. As P450 genes of man differ from those of rodents, the latter have limited value as surrogates for man in chemical safety evaluation; many short-term tests, such as the Ames test, although valuable in detecting genotoxic chemicals, are similarly limited by their rat liver microsomal activation (S-9) systems. COMPACT is able to overcome both of these limitations, requires no laboratory animals or tissues, and can be conducted from a knowledge of the structure of the chemical, even prior to its synthesis. As the rodent tumorigenicity assay and the Ames test are currently regarded as the standard procedures for safety evaluation, COMPACT was validated against these in a study of 100 miscellaneous chemicals and showed excellent correlations. A quantitative structure-activity relationship (QSAR) for a series of 14 methyl benzanthracenes shows good correlation of mutagenicity with the energy of the lowest empty molecular orbital [E(LEMO)] values of the chemicals. A strategy for COMPACT and P-450 induction studies in chemical safety evaluation is presented. PMID- 20702256 TI - A quantitative structure-activity/dose relationship for contact allergenic potential of alkyl group transfer agents. AB - Since no in vitro model is available, or indeed likely, to predict or investigate skin sensitization potential of substances, an approach based on a model using physicochemical criteria is the most likely route to a reduced requirement for animal testing. As part of the investigation of structure-activity relationships in contact allergy, it was shown that methyl transfer agents are capable of acting as skin sensitizers. This work has now been extended to a more general examination of alkyl transfer reactions. In vivo dose responses to challenge and the patterns of cross reactivity between C(12), C(16), unsaturated C(16) and methyl transfer agents were examined to form the basis of the mathematical model. All alkyl transfer agents examined were potent sensitizers, with evidence of mutual cross reactivity between them. The sensitization data have been accurately modelled using a mathematical equation. Analysis in terms of a modified relative alkylation index model showed evidence of an overload effect. PMID- 20702257 TI - Preliminary results from the Scandinavian multicentre evaluation of in vitro cytotoxicity (MEIC). AB - The multicentre evaluation study of in vitro cytotoxicity tests (MEIC) is organized by the Scandinavian Society of Cell Toxicology. All interested laboratories are invited to test a published list of 50 reference chemicals in their various in vitro assays with a bearing on general toxicity. Submitted results will be centrally evaluated for their relevance to human toxicity, including a comparison with the efficiency of conventional animal tests. This brief communication presents the very first preliminary results of the study, that is, prediction of human acute lethal toxicity for the first 10 MEIC chemicals by all the results submitted to date, that is, five in vitro cytotoxicity assays. As a baseline for judging the efficiency of the cytotoxicity tests, rat and mouse LD(50) values were compared with human acute lethal dosage of the chemicals. Rat LD(50) prediction was relatively poor, but mouse LD(50) values correctly predicted the human lethal dose for six out of the 10 substances. A multivariate method of comparison including all cytotoxicity test results, predicted human lethal blood concentrations as well as the mouse LD(50) prediction of dosage. Since the blood concentrations used in the comparison were derived from human lethal dosage with the help of two simple pharmacokinetic factors (absorbed fraction in the intestine and distribution volume of chemicals), the cytotoxicity assays were found also to be able to predict human dosage, as well as did the mouse LD(50) prediction. PMID- 20702258 TI - Validation of alternative toxicity tests: Principles, practices and cases. AB - In vitro toxicity tests must be properly developed and scientifically validated for relevance and reliability before they are independently evaluated for possible inclusion in toxicity testing schemes and promoted for regulatory and legal acceptance. Some lessons learned in the administration of the FRAME Alternative Test Validation Scheme are reported, using as an example correlations between the results obtained in cell growth inhibition tests, both with each other and with rat oral and mouse intraperitoneal LD(50) values. Some recommendations are given for consideration for the design of future validation schemes. PMID- 20702259 TI - Hazard and risk based on in vitro test data. PMID- 20702260 TI - Comparison of two in vitro and two in vivo methods for the measurement of irritancy. AB - A number of in vitro assays have recently been developed that need further validation in order to judge their value for local tolerance testing. For this purpose, results from the following experiments were compared: (A) cytotoxicity testing in cell culture (neutral red assay); (B) tests with the chorioallantoic membrane of fertilized chicken eggs; (C) rabbit eye mucous membrane tests; and (D) occluded epicutaneous testing in human volunteers. The data presented indicate that in vitro testing with the first two methods yields reliable results with respect to the eye and human skin irritation data within homologous substance classes. A test procedure is proposed that involves comparative testing of the chemicals with unknown irritant properties together with known weak and strong irritants from the same class of chemicals as standards in the test series. This procedure seems to be suitable as a preliminary screen for identifying severe irritants prior to the performance of any in vivo studies. It would reduce the number of animals to be used in vivo and lead to the avoidance of exposure of animals to harmful substances. PMID- 20702261 TI - A national validation project of alternative methods to the Draize rabbit eye test. AB - In June 1988, a 2.5-yr inter-laboratory study involving 13 toxicology laboratories was started in West Germany to validate alternative methods to the Draize rabbit eye test. The aim of this collaborative study is to validate the classification of chemicals with regard to their irritation potential using the neutral red/kenacid blue (NR/KB) cytotoxicity assay and the hen's egg test chorioallantoic membrane (HET-CAM) assay. The results should make it possible to decide whether and to what extent the NR/KB cytotoxicity test and the HET-CAM assay can replace the Draize test. After two test trials, standard testing procedures and protocols were agreed on. In addition, to facilitate management of the data and to reduce costs, personal computer (PC) software was developed for both tests, which allows storage of all data on floppy discs and statistical analysis on PCs. During the preliminary phase, the applicability of the software was tested and corrected according to the experimental conditions of the validation study. Tests on the following chemicals have so far been completed, and reproducibility and repeatability have been determined: sodium dodecyl sulphate, triethanolamine, zinc pyridinethione, dimethylsulphoxide and butoxyethanol. Only zinc pyridinethione, which is severely irritating in vivo, could not be tested in the HET-CAM test. The preliminary phase has shown that the number of chemicals that can be tested in the HET-CAM test during the validation project will be limited by costs and management problems of manpower and time. PMID- 20702262 TI - INVITTOX: The ERGATT/FRAME data bank of in vitro techniques in toxicology. PMID- 20702263 TI - In vitro toxicity testing of implantation materials used in medicine: Effects on cell morphology, cell proliferation and DNA synthesis. AB - Modern medicine depends in many cases on implantation of xenobiotic materials into the human body. Toxicity evaluation of these materials (plastic, metal alloy, ceramics) is rather difficult, mainly because of their intricate chemical nature and insolubility. There are two main approaches to the toxicity testing of implantation materials: cells are either placed in direct contact with materials to be tested or are treated with eluates made from the materials under study. Cell proliferation and cell morphology were chosen as principal endpoints in general cytotoxicity testing. Two modified methods were used as a measure of cell proliferation: first, direct cell counting within defined areas during subsequent time intervals; secondly, determination of DNA synthesis based on incorporation of radiolabelled thymidine. Prelabelling with [(14)C]thymidine was used and [(3)H]thymidine was applied after treatment with the substance tested. Changes in the (3)H:(14)C ratio are proportional to changes in DNA synthesis. The potential usefulness of all three methods was evaluated by testing a new bioactive ceramic (BAS) to be used in orthopaedics, and a new polymer, EVICROL ESTHETIC, to be used in dentistry. Similar results were obtained with all three methods. PMID- 20702264 TI - Cytotoxicity detected by image analysis: A new method for the quantification of survival, mortality, recovery and growth of mammalian cell cultures. AB - The use of in vitro methods is increasingly recommended for the assessment and evaluation of cytotoxic effects resulting in cell damage. In most cases, cellular response and reaction of cell populations is determined by endpoint measurements. Even if a battery of such test systems is applied, information about the dynamics of cell damage and recovery is obtained only in part. However, phenomena of damage and recovery can be followed by observing the fate of individual cells and their progeny in culture over several days, which means over several cell cycles, by using light microscopy combined with image analysis. We have developed a recording system for such continuous observation and registration of toxic effects, based on image analysis. Growth rate, generation time, delay or shifting of cell cycle, identification of the progeny (pedigrees) and cellular locomotion can be recorded simultaneously. PMID- 20702266 TI - Concluding remarks. PMID- 20702265 TI - Validation of cell substrates used for human biologicals: An overview of international regulatory documents. AB - The acceptability of continuous cell lines as substrates for pharmaceutical products for human use has been a subject of controversy since 1978. In this paper the authors highlight the guidelines that the US FDA, European and Japanese regulatory agencies have issued in recent years regarding the characterization of the cell lines used as substrates, the validation of the purification process and the characterization of the product. PMID- 20702267 TI - In vitro thermal inactivation of hepatic Ah receptors from several mammalian species. AB - The thermal inactivation of the hepatic cytosolic Ah receptor was studied in vitro for several immature male rodents. The activation energies for receptor inactivation in C57BL/6 mice, Mongolian gerbils, golden Syrian hamsters, Hartley guinea-pigs, Sprague-Dawley rats and Wistar rats were 170, 142, 112, 131, 120 and 112 kJ/mol, respectively. The magnitude of the activation parameters pointed to a substantial change on inactivation, but not to complete unfolding of the protein. Statistical analysis indicated that attempts to interpret these results in terms of receptor heterology should be treated with caution. Among the species studied, the Ah receptor from the mouse offered the best possibility for in vitro studies at low temperature, free from the problem of thermal inactivation. PMID- 20702268 TI - Effect of proteins and lipids of the alveolar lining layer on particle binding and phagocytosis. AB - The initial interactions between macrophages and particles on alveolar surfaces could be significant events in the pathogenesis of certain lung diseases, since these cells are known to secrete a variety of inflammatory mediators and growth factors. It has been determined that the protein and lipid fractions of the extracellular alveolar lining layer (ALL) affect alveolar macrophage morphology and function in vitro and that these fractions can block the binding of iron and glass spheres to macrophage membranes. Protein-rich and lipid-rich fractions were prepared for treatment of alveolar macrophages in vitro. The 'normal' (i.e. non concentrated) lavage diluted by saline caused no measurable changes in macrophage morphology or function. In contrast, concentrated lavage, as well as the protein and lipid fractions, caused loss of cell viability and blocked the binding of positively and negatively charged particles to macrophage membranes. The blocking effect could be reversed when the cells were pretreated with the lavage fraction and then washed. Blocking of binding could not be reversed when the particles were pretreated. The binding of particles to macrophage membranes appears to be mediated through an interaction between the particles and the ALL. PMID- 20702269 TI - Effects of 3-methylsulphonyl-4,5,3',4'-tetrachlorobiphenyl and 7,8-benzoflavone on mouse liver aryl hydrocarbon hydroxylase activity in vitro. AB - The activity of aryl hydrocarbon hydroxylase (AHH) in mouse liver microsomes was assayed in the presence of 3-methylsulphonyl-4,5,3',4'-tetrachlorobiphenyl (3-MSF TCB). The mice had been previously injected with a fixed amount of the AHH inducer 3-methylcholanthrene (MC) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or with the vehicle (olive oil) alone. The dose-effect patterns for 3-MSF-TCB were markedly different according to the genetic responsiveness of the mice towards aromatic hydrocarbons (Ah responsiveness); in Ah responsive strains 3-MSF TCB inhibited the MC-induced AHH activity as did 7,8-benzoflavone (ANF), which is known to be a potent inhibitor of AHH, whereas in Ah non-responsive strains 3-MSF TCB (and ANF) greatly enhanced the same activity. On the other hand, the dose response patterns were similar for both types of mice for TCDD-induced activity or basal activity (mice injected with the vehicle alone). The dose-effect curves for 3-MSF-TCB were quite distinct from those for ANF, particularly with respect to the basal AHH activity, for both Ah responsive and non-responsive strains. These results indicate that both ANF and 3-MSF-TCB can have either an inhibitory or an activating effect on AHH, depending on the dose, the Ah phenotype and previous induction with MC or TCDD. PMID- 20702270 TI - Cytoskeletal modifications induced by organotin compounds in human neutrophils. AB - The polymerization of actin, a basic component of the cystoskeleton, was evaluated in human neutrophils after treatment with tributyltin (TBT), trimethyltin (TMT), triphenyltin (TPT), triethyltin (TET) or SnCl(2) for 2-30 min at 37 degrees C. TBT and TPT decreased the content of the polymerized form (F actin) in resting neutrophils at all the times studied; in addition, after TBT and TPT treatment the response of the cells to a polymerizing stimulus (chemotactic peptide) was no longer detectable. These effects were observed under conditions where a cytotoxicity marker such as lactate dehydrogenase leakage remained unaffected. These results may explain the observed inhibition by TBT and TPT of basic cellular functions involving cell shape and motility, which are regulated by the cytoskeleton. PMID- 20702271 TI - An in vitro technique to detect dominant lethal mutations induced in mouse oocytes by ethyl methanesulphonate exposure in vivo. AB - Administration of chemical mutagens to the female rodent can induce dominant lethal mutations in oocytes and affect embryo development after fertilization. Traditional in vivo dominant lethal assays cannot separate specific genotoxic effects on the embryo from generalized cytotoxic effects. We have used embryo culture, after in vivo exposure of oocytes, to separate the genotoxic effects of a chemical on oocytes from effects due to maternal toxicity. Pre- and post implantation development in culture was monitored in embryos recovered at the two cell stage from females dosed ip, 30-32 hr before ovulation, with 125 or 250 mg/kg ethyl methanesulphonate (EMS)/kg body weight. In vitro zygote development progressed from two-cell to trophectoderm outgrowth and inner cell mass formation. All stages of development were affected by the EMS treatment. The morula stage showed a dose-related decrease in development; blastula formation and inner-cell mass formation were also significantly decreased. This study indicates that an in vitro dominant lethal test can be useful in evaluating damage to metaphase-1 oocytes. The in vitro test can be used to study the effects of chemicals on all stages of zygote development thereby separating induced genotoxic effects from the possible effects of maternal toxicity on zygote development. PMID- 20702272 TI - Comparison of cadmium cytotoxicity in human versus rat nasal epithelial cells in vitro. AB - Differences in the sensitivity of human and Fischer 344 rat tissues to cadmium sulphate (CdSO(4)) toxicity were investigated in an in vitro model using human and rat nasal turbinate epithelial (NTE) cells. Both rat and human NTE cells were obtained from fresh, normal tissue. Methods were developed for isolating and culturing NTE cells from rat and human tissue using identical procedures, and for measuring the cellular nucleotides by high-performance liquid chromatography. Changes in adenylate energy charge and nucleotide levels were used as toxicity endpoints. Cellular Cd levels were measured by graphite-furnace atomic absorption spectrometry and expressed per unit DNA. Cd uptake was significantly greater in human NTE cells than in rat cells, particularly at the highest exposure concentration (4.8 mm-CdSO(4)). The effects of CdSO(4) on the adenylate energy charge of human and rat NTE cells were similar except at high exposure concentrations and after long exposure times; after a 2-4-hr exposure to 4.8 mm CdSO(4) the adenylate energy charge of human cells was significantly less than that of the rat cells. PMID- 20702273 TI - Interaction between mercuric chloride and zinc in rat whole-embryo culture. AB - Ten-day-old rat embryos were cultured in rat serum for 24 or 28 hr in the presence of mercuric chloride and zinc chloride alone or together, at concentrations ranging from 15 to 35 mum and 7 to 220 mum, respectively. At the end of the culture period, embryos were observed microscopically for growth parameters and malformations, and examined biochemically for protein and DNA contents. The effects of HgCl(2) on growth and development were related to concentration. Yolk-sac diameter, and head length, number of somites, protein and DNA contents were significantly reduced at 20 and 25 mum-HgCl(2), respectively. Viability decreased at 30 mum-HgCl(2), and malformations appeared at 20 mum HgCl(2). These mainly consisted of lateral dilatation of prosencephale, swollen mandibular arches, protrusion of the allantois and the extremity of the caudal neural tube from the yolk-sac, turning failure, poor or absent yolk-sac circulation and open cranial neural folds. Embryos exposed to ZnCl(2) developed normally at all doses tested. Addition of ZnCl(2) to the culture medium at concentrations of up to 220 mum, simultaneously or 4 hr before the addition of 25 mum-HgCl(2), failed to ameliorate HgCl(2)-induced teratogenicity. It is concluded that zinc has no influence on the effects induced by HgCl(2) in the whole-embryo culture system. PMID- 20702274 TI - The in vitro percutaneous absorption of diquat: A species comparison. AB - The in vitro absorption of diquat ion from aqueous solution has been measured through human, rat, mouse, rabbit and guinea-pig skin. Diquat was absorbed poorly through human skin, which was the least permeable. At the lowest concentration applied (1 mg diquat ion/ml) rat skin had the most similar permeability to human skin but was four times more permeable. This similarity in permeability was studied further using a range of concentrations (up to 50 mg/ml). As the concentration increased, so did the factor of difference between human and rat skin. Thus, whilst animal skin might appear to be a good model for human skin at a particular applied concentration, the similarity might decrease when the skin samples are examined with a range of concentrations and formulations. PMID- 20702275 TI - Differential toxicity of cytosine arabinoside to cell kinetics in normal sheep sinus cells and sheep tumour cell line in vitro. AB - The effects of 1-beta-d-arabinofuranosylcytosine (ara-c) on cell proliferation, morphology and cycle progression were compared in a sheep tumour cell line and normal sheep sinus cells. The effects were found to be dose and time dependent and reversible, and were accompanied by increased cell size and cytosolic synthetic activities. Ara-c induced a concentration-dependent inhibition of cell proliferation in both normal and tumour cells. However, normal cells were less sensitive than tumour cells when exposed to a low concentration of ara-c (10( 6)m). The two cell types exhibited equal sensitivity to higher drug concentrations (10(-5) and 10(-4)m). Flow cytometric analysis (FCM) of cell cycle progression and right-angle scatter using these two cell types confirmed that a concentration of 10(-6)m-ara-c had little or no effect on normal cells while tumour cells showed increases in size and accumulation in the S phase. These findings may provide new insights into how ara-c cytotoxicity may be reduced or avoided in normal tissue provided that tumour cells are selectively affected by low-dose ara-c in vivo. PMID- 20702276 TI - Morphogenesis and quantification of the development of post-implantation mouse embryos. AB - This paper describes potential improvements in the quantitative assessment of the differentiation of rodent embryos used for in vitro embryotoxicity studies. A chart of schematic illustrations of the developmental stages of seventeen morphological features observed macroscopically in mouse embryos aged 8-10 days (0-30 somites) has been drawn up. The chart is based on the morphological scoring system proposed by Brown and Fabro (1981) for rat embryos and complements the original descriptions. Some intermediate stages have been added to the scoring system. The original and the modified scoring systems were applied to 310 mouse embryos in 31 groups of ten embryos, each with 0 to 30 somites. The modified score is consistently about 25% higher than the original score. The correlation of both the original and the modified scores with the number of somites is best expressed by an asymmetric sigmoid. The chart and the modified scoring system could also be used, with minor adaptations, to assess rat embryos at corresponding developmental stages. PMID- 20702277 TI - Temporal effects of ethanol on growth, thymidine uptake, protein and collagen production in human foetal lung fibroblasts. AB - Foetal Alcohol Syndrome is observed in 2/1000 live births worldwide and is characterized by decreased pre-natal and postnatal growth, physical anomalies and mental retardation. To determine the effects of ethanol (Et) on foetal cells cultured in the absence of hormones or growth factors, human foetal lung (HFL1) fibroblasts were exposed to Et-supplemented media (0.1-2% Et) for 6 hr to 7 days. Growth rates, thymidine incorporation into DNA, protein synthesis and degradation, and collagen production were assessed. For growth experiments, cells were seeded at 1 3 confluent density and incubated in Et-supplemented medium 24 hr later. Metabolic labelling was performed on confluent monolayers using [(3)H]thymidine (TdR), [(3)H]leucine or [(3)H]proline. Exposure to Et for 3 or 7 days decreased cell numbers but normal proliferation resumed when cells were re plated in control medium. Exposure to 0.5% Et for 7 days resulted in a 3.5-fold increase in [(3)H]TdR uptake. Et suppressed protein production and enhanced degradation. The most significant decrease was seen at 6 hr, but was influenced by the amino acid used for labelling. Agarose-gel chromatography suggests that Et preferentially alters the lower-molecular-weight species. The percentage of the total protein secreted into the medium was not changed. Collagen production, as a percentage of total protein, decreased after a 48-hr label and a 7-day incubation with Et. The percentage of total collagen that was secreted into the medium was also not influenced by Et. The results indicate that, in the absence of endocrine or nutritional manipulation, acute exposure to Et in vitro inhibits cell growth and protein production; protein secretion, however, remains intact. PMID- 20702278 TI - Cellular effects of an anionic surfactant detected in V79 fibroblasts by different cytotoxicity tests. AB - Several cytotoxicity tests were employed to detect the cellular effects of low concentrations of the anionic surfactant linear alkylbenzene sulphonate (LAS). When added to growth medium containing 5% foetal calf serum, LAS did not affect V79 cell growth, nor did it alter the permeability of cell membranes. The inactivity depended on the serum component of the medium. When treatments were carried out in serum-free saline, LAS inhibited cell proliferation, made the plasma membrane permeable to otherwise-undiffusible compounds, and reduced the uptake of tritiated thymidine. The alterations in membrane permeability were evaluated from the release of cytoplasmic molecules of different size (lactate dehydrogenase, adenine nucleotides, RNA) into the medium. The sensitivity of the spectrophotometric lactate dehydrogenase assay was inadequate for the conditions of treatment required to detect the cytotoxicity of LAS. In cultures pre incubated with tritiated adenine instead, the release of labelled ATP pool components was time and dose dependent and allowed discrimination between levels of membrane damage causing the same degree of trypan blue staining. Also, macromolecular nucleic acids were detected outside the treated cells at doses of 4-6 mg LAS/litre, which indicated severe membrane damage. PMID- 20702279 TI - The detection of DNA-protein complexes in vitro by an immunological assay. AB - We have developed an immunological assay to detect DNA-protein complexes (DPCs) in cell cultures treated with environmental toxicants. The assay uses an antiserum developed against K(2)CrO(4)-induced DPCs, which recognizes an acidic protein with a molecular weight of 95 kDaltons. The method uses a filter-binding assay to trap the DPCs from SDS-lysed cell cultures on polycarbonate filters, after which they are immunologically probed with the DPC antiserum. Cultures of Chinese hamster ovary cells were treated with K(2)CrO(4), formaldehyde or UV irradiation. DPCs were detected immunologically in cells treated with K(2)CrO(4) or UV irradiation, but not in those treated with formaldehyde. These results were similar to those obtained when DPCs were detected by filter-binding assay using radiolabelled cell cultures to measure the adherence of protein and DNA to the filters. In addition, both methods gave analogous dose responses of DPC formation in K(2)CrO(4)-treated cells. This novel immunological assay for detecting DNA lesions allows the rapid analysis of samples, which do not need to be radiolabelled, and thus it may have an application as a non-invasive test to screen for DNA-protein complexes. PMID- 20702280 TI - Effects of DDT and permethrin on neurite growth in cultured neurons of chick embryo brain and Lymnaea stagnalis. AB - The pesticides permethrin and 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT), dissolved in either ethanol (EtOH) or dimethylsulphoxide (DMSO), were studied to determine their effect on neurite growth from cultured neurons of Lymnaea stagnalis and embryonic chicks. Both of these toxins decreased the percentage of neurons growing neurites, mean neurite length, and number of neurites/cell in a dose-dependent manner. DMSO increased the toxicity of permethrin and DDT in L. stagnalis neurons. EtOH was not used as a solvent with the embryonic chick cultures. Pre-existing neurites of L. stagnalis neurons exposed to permethrin regressed in a dose- and time-dependent manner. These two toxins may affect neurite outgrowth through interference with intracellular calcium regulation. PMID- 20702281 TI - Studies on the thyroid stimulating hormone-activated Na(+)K(+)-ATPase and iodide transporter in cultured rat thyroid cells and the effects of drugs. AB - Exposure of rat thyroid FRTL-5 cells to high concentrations of thyroid stimulating hormone (TSH) for 24 hr in vitro activated (125)iodide but not ouabain-sensitive (86)Rb transport in the cells, whereas after 27 hr and above there were significant increases in the activity of both transporters. This was similar to results obtained in propylthiouracil-treated rats in vivo where, unlike the early reported increases in iodide transport, activation of thyroidal Na(+)K(+)-ATPase activity in thyroid membranes occurred around 24-48 hr following rises in serum TSH. These data confirm the presence of a Na(+)K(+)-ATPase in cultured rat FRTL-5 thyroid cells, which is activated several hours later than iodide accumulation by TSH stimulation. This pump is sensitive to the cardiac glycoside ouabain as well as other agents affecting intracellular Na(+) ion concentrations such as monensin and amiloride. PMID- 20702282 TI - Cyanide-induced cytotoxicity to isolated hepatocytes. AB - The responses of various cell functional parameters to potassium cyanide (KCN) were investigated in isolated rat hepatocytes to examine their quantitative and temporal relationship to inhibition of mitochondrial respiration. Both cultures and suspensions of hepatocytes, maintained in hormone-supplemented culture medium at 37 degrees C under an air: CO(2) (95:5) atmosphere, were used in these studies. The earliest and most sensitive change detected was inhibition of O(2) consumption (EC (50) = 78 mu m ); other early changes included depression in ATP and ATP/ADP, inhibition of urea synthesis, and elevation in lactate/pyruvate. The effect on ATP depression at 10 min was reversed by replacement with fresh medium containing no cyanide (t (1 2 )=9 min ). Increased release of lactate dehydrogenase and acid phosphatase occurred much later during the incubation (120 or 240 min) and at much higher KCN concentrations (>/=0.5 mm) than the other changes. These observations are consistent with inhibition of mitochondrial respiration being the initiating or major contributing factor in cyanide-induced cytotoxicity in hepatocytes, but because of the difference in EC(50) values for depression of O(2) consumption and energy-dependent parameters and for intracellular enzyme release, other mechanisms may also contribute to cell death. Reduced glutathione content and lipid peroxidation in the cells, assessed by measuring thiobarbituric acid reactants, were not significantly changed, and the mechanism leading up to cell death remains uncharacterized. The cyanide concentrations in vitro that produced inhibition of O(2) consumption were in the same range as those in blood and liver that inhibited cytochrome oxidase in vivo at lethality. The results in the hepatocyte model, therefore, can explain why the liver is not a target organ in massive, acute cyanide poisoning, in that overt signs develop at higher concentrations and after longer times than are applicable for the death of the animal. PMID- 20702283 TI - Bull sperm as a potential model system for cytotoxicity testing in vitro. AB - The possibility of using frozen/thawed bovine sperm as a model system for cytotoxicity was explored using progressive motility (EC(50)), ATP content (ATP(50)) and cell death (CD(50)) as endpoints. ATP content and motility of sperm were relatively constant after 15 min in culture, enabling measurements to be made over the following 30 min. ATP content was lower in an 'extender' (1.4 x 10( 16) mol/sperm) than in the final diluent (2.3 x 10(-16) mol/sperm), which was Eagle's minimum essential medium (MEM) containing 5% (v/v) foetal calf serum. Nonylphenoxypolyethoxyethanol (nonoxynol-9), Gynol II((c)) containing 2% (v/w) of this surfactant, and dl-propranolol were the toxicants chosen for the evaluation. There was little difference between the three endpoints for Gynol II((c)) and nonoxynol-9 but the former caused a relatively greater effect on motility. dl Propranolol (ATP(50) 1.39 mg/ml) was considerably less toxic than nonoxynol-9 (ATP(50) 53 mug/ml) but its CD(50) could not be measured for technical reasons. Results with Gynol II((c)) suggested that the effectiveness of the active ingredient of this compound, nonoxynol-9, was reduced by the excipients. It has been claimed that this compound causes membrane ultrastructural damage but, at 75 mug/ml, no disruption was observed under the scanning electron microscope. Measurement of sperm ATP content is the preferred assessment for cytotoxicity because it is automated and can give clues to the mechanism of toxic action. PMID- 20702284 TI - Effects of zinc on the binding of cadmium to DNA: Assessment with testicular interstitial cell and calf thymus DNAs. AB - To clarify the mechanism of the protective action of zinc against the tumorigenicity of cadmium in rat testes, the effect of in vivo zinc pretreatment (zinc acetate, 1.0 mmol/kg, sc, 24 hr before the examination) on in vitro binding of cadmium to rat testicular interstitial cell (IC) DNA was studied. The competition between zinc and cadmium for binding to purified calf thymus DNA, as assessed by acridine orange dye binding, was also examined. In vivo zinc pretreatment significantly elevated the level of zinc in DNA isolated from ICs and reduced binding of cadmium to DNA following in vitro exposure. Both zinc and cadmium individually inhibited the formation of the acridine orange dye and calf thymus DNA complex, although co-operative inhibition with co-exposure was not observed. It is known that zinc has a higher affinity for the phosphate groups of DNA than does cadmium, which favours base binding, and that interactions with the phosphate groups of DNA stabilize the macromolecule structure. The present data suggest that zinc may, in part, prevent tumorigenicity of cadmium in rat testes by reducing its binding to DNA through a structural stabilization as well as through direct competition for binding sites. PMID- 20702285 TI - Toxicity of cadmium sulphate and methylmercuric chloride applied singly or in combination to early mouse embryos in vitro. AB - The joint action of cadmium and methylmercury was studied at pre-implantation and early post-implantation stages of mouse embryos in vitro. Embryos were exposed to the heavy metals from the two-cell to the blastocyst stage. Toxicity was monitored using developmental (formation of blastocysts, hatching of blastocysts, trophoblast outgrowth, formation of inner cell mass), proliferative (cell numbers) and cytogenetic (micronucleus formation) endpoints. Under some conditions (e.g. 1 mum-CdSO(4) + 0.6 mum-CH(3)HgCl), a combination risk was observed that significantly exceeded the risk expected from the addition of the single effects. This increase in risk, however, was due to the shape of the dose response curves; that is, cadmium and mercury behaved as if they were the same substance. PMID- 20702286 TI - Studies on the in vitro trophic effects of a novel thyromimetic. AB - Since fibroplasia has been reported in rats treated with SK&F l-94901, a novel thyromimetic drug, studies were undertaken to investigate: (i) the trophic effect of the agent in a number of in vitro proliferation assays and (ii) its ability to cause in vitro cell transformation. There was no effect in any of these assays when SK&F l-94901 was incubated directly with the cells, so consideration was given to the possibility that the chemical could be having an indirect mitogenic effect by stimulating the production of growth factors from other tissues such as the pituitary. However, since the conditioned medium from pituitary superfusates also failed to show any evidence of a mitogenic effect, the proliferative lesions do not appear to be associated with an over-production of growth factors by the pituitary. The in vivo growth-promoting activity of SK&F l-94901 does not appear to be caused by a direct mitogenic effect in the cells resulting in cell transformation or by stimulation of growth factors from the pituitary. PMID- 20702287 TI - The cellular effects of a unique pesticide sulfluramid (N-ethylperfluorooctane sulphonamide) on rabbit renal proximal tubules. AB - The cellular effects of sulfluramid (N-ethylperfluorooctane sulphonamide, NEPFOS) and its major metabolite perfluorooctane sulphonamide (PFOS) were examined using a suspension of rabbit renal proximal tubules as a model. NEPFOS and PFOS were potent stimulators of proximal tubule basal oxygen consumption (QO(2)), with initial effects exhibited at 5-10 mum and maximal effects at 50-200 mum. The increase in basal QO(2) was ouabain insensitive, which suggests that NEPFOS and PFOS may act by uncoupling oxidative phosphorylation. Exposure of tubule suspensions to NEPFOS or PFOS concentrations of 100 mum or higher for 60 min produced tubule death, indicated by an increase in the release of lactate dehydrogenase. The tubule death did not appear to result from alkylation or lipid peroxidation, since glutathione and malondialdehyde levels were unaffected. To determine the mechanism by which NEPFOS and PFOS increased tubule QO(2), the effects of NEPFOS and PFOS on isolated renal cortical mitochondria were examined. NEPFOS (10 mum) and PFOS (5 mum) increased state-4 respiration of mitochondria in the absence of a phosphate acceptor. These results suggest that NEPFOS and PFOS uncouple oxidative phosphorylation and may produce cytotoxicity through this mechanism. PMID- 20702288 TI - Comparison of human versus Syrian hamster cells in culture for induction of mitotic inhibition, binucleation and multinucleation, following treatment with four aneuploidogens. AB - The responses of human and rodent cells in vitro to aneuploidy-inducing chemicals were compared. Normal human fibroblasts and Syrian hamster embryo fibroblasts were treated with four aneuploidogens; Colcemid, vincristine, and the oestrogens diethylstilboestrol and oestra-1,3,5(10)-triene-3,17beta-diol (17beta oestradiol). All compounds at a critical dose inhibited cell growth of both cell types. The concentrations of the two oestrogens required to inhibit growth of human and hamster cells were similar, whereas for the two mitotic inhibitors Colcemid and vincristine, the concentrations required for growth-inhibitory effects were lower for human cells than for hamster cells. The growth inhibition was reversible for all treatments except Colcemid. Doses that inhibited cell growth also resulted in large numbers of mitotic cells appearing in a time dependent manner, indicating that both cell types were arrested in mitosis by all four compounds. The time required for maximum increases in the mitotic indices was greater for human cells, which is consistent with the longer cell cycle of these cells in culture. Few binucleated cells of either type were induced by any treatment except 17beta-oestradiol, which induced a high level of binucleated hamster cells, but not human cells. With time, the mitotic index of all treated cells decreased. For hamster cells, this was always accompanied by a large increase in multinucleated cells. The percentage of multinucleated hamster cells reached 50-60% in the Colcemid- and vincristine-treated cultures and 30-35% in the oestrogen-treated cultures. In contrast, the level of multinucleated human cells was significantly lower for all treatments. Colcemid and vincristine treatments induced 20-25% multinucleated human cells, and the oestrogens induced <5% multinucleated human cells. This latter finding appears to be the most significant difference between the two cell types. These results indicate that human cells respond differently from rodent cells to agents that induce mitotic arrest. This may help in understanding the decreased induction of aneuploidy in human cells by these compounds. PMID- 20702289 TI - Localization and identification of cytochrome P-450 in differentiating rat embryo cells in vitro and in foetal tissue in vivo by immunocytochemistry. AB - The presence of the isoenzymes b, e and c of cytochrome P-450 in foetal rat limb bud and mid-brain tissue has been investigated in vivo and in micromass cell cultures of limb-bud and mid-brain cells derived from rat embryos by a sensitive immunocytochemical technique. The cytochromes could not be detected by antibody staining at the start of the culture nor in 13-day-old embryos from which cultures were prepared. Two different antibodies directed against cytochrome P 450 revealed the ontogenic profile of the phenobarbitone-inducible b and e forms, which appeared at an earlier stage of development, day 1 of culture (equivalent to day 14 of gestation), than did the 3-methylcholanthrene-inducible c form, which appeared on day 3 of culture (equivalent to day 16 of gestation). These isoenzymes were not tissue specific. Comparison of the localization and intensity of staining of cells cultured in vitro for 5 days with tissue from the equivalent foetal developmental stage (day 18) in vivo revealed the presence of cytochrome P 450 in corresponding areas. In day 18 limb sections, cytochrome P-450 was localized in the perichondrial and myogenic tissue, which corresponded to the cells in the periphery of the chondrogenic foci in vitro. In mid-brain whole tissue, the enzyme was located in connective tissue and neurofibrils, corresponding to cells in the periphery of the foci of neurones in vitro. The correlation between in vitro and in vivo observations from time course, location and quantitative aspects, illustrated that the micromass culture technique is a valid model for metabolism studies with these specific isoenzymes. PMID- 20702290 TI - Inducibility and functionality of rat embryonic/foetal cytochrome P-450: A study of differentiating limb-bud and mid-brain cells in vitro. AB - The presence of constitutive levels of cytochrome P-450 isoenzymes in cultures derived from rat embryo limb-bud (LB) and mid-brain (CNS) cells was demonstrated immunocytochemically by staining with specific monoclonal and polyclonal antibodies of cytochrome P-450. The b and e forms of cytochrome P-450 were found to be non-inducible by either in vitro co-incubation for 5 days or by transplacental maternal induction with phenobarbitone (PB), 3-methylcholanthrene (3MC) or beta-naphthoflavone (betaNF) in either cell type. Consistent with this lack of response was the observation that both in vitro and in vivo inducer treatment did not alter the toxicity of the teratogens diphenylhydantoin (DPH) or cyclophosphamide (CPA). In contrast, 3MC induction was achieved by both in vitro and transplacental regimens as gauged by the increased intensity of peroxidase staining using a monoclonal antibody to cytochrome t-450 c, in both cell types. There was also a concomitant increase in DPH toxicity (>20% gauged by a decrease in IC(50) values) in LB cells by both induction regimens but the CNS cells were refractory. betaNF induction of cytochrome P-450 was observed following in vitro and in vivo exposures in both cell types. There was no modulation of DPH or CPA toxicity after in vitro exposure to the inducers, but in vivo induction caused a strong staining reaction in both cell types, commensurate with a 30% increase in DPH toxicity in LB cells and activation of the pro-teratogen CPA. The b and e forms of cytochrome P-450 were non-inducible but it is highly likely that the c form was both inducible (by 3MC and betaNF) and functional, the latter being assessed by modulation of DPH toxicity and CPA activation. It may be possible to induce cytochrome P-450 in cells derived from embryos. The system used may be suitable for detailed investigations of the types of metabolizing systems involved in the mechanisms underlying toxicity/teratogenicity. PMID- 20702291 TI - Use of monolayers of primary rat kidney cortex cells for nephrotoxicity studies. AB - Kidney cells were isolated from rat kidney cortex and maintained in short-term monolayer cultures. A number of important parameters were studied in order to establish the usefulness of these cells for toxicity studies. Despite morphological differences between the cultured cells and similar cells in vivo, many relevant enzyme systems remained present and functional. Intracellular glutathione levels were stable up to 5 days in culture. The glutathione S transferase activity during culture remained stable although at a lower level than in freshly isolated cells. Whereas rat kidney cytosol contained subunits 4, 7, 2 and 1, 3- and 5-day-old cultures contained glutathione transferase subunits 7, 2 and a small amount of subunit 1. Cytochrome P-450, although measurable in microsomes from freshly isolated cells, could not be determined after 1 day in culture. Organic anion transporters on the basolateral side and gamma-glutamyl transpeptidase on the apical side were present. Through cytotoxicity studies, beta-lyase activity could be demonstrated in the culture. Hence this monolayer culture system, which can be used in combination with filters, seems to be suitable for studying various mechanisms of nephrotoxicity. PMID- 20702292 TI - Effects of carbon tetrachloride on embryonic development studied in the post implantation rat embryo culture system and in chick embryos in ovo. AB - The effects of carbon tetrachloride on embryonic development were investigated in a mammalian and a non-mammalian system. In the former, whole-rat embryos, taken at 9.5 days of gestation, were exposed in vitro to different concentrations of CCl(4) (10, 100, 300, 600 and 1000 mug/ml) in rat serum with or without a rat liver microsomal activating system (S-9 mix). In the latter system, chick embryos in ovo were exposed to different concentrations of CCl(4) vapour (25, 35 and 75 ppm). When studied in the whole-rat embryo culture system without metabolic activation, concentrations of up to 300 mug CCl(4)/ml had no effect on the overall development. Concentrations -600 mug CCl(4)/ml affected the somite number, growth and morphology of the embryos, which can be interpreted as general toxicity. In the presence of S-9 mix, toxicity occurred at concentrations -300 mug/ml. In ovo exposure to CCl(4) showed that 25 ppm caused a decrease in the number of somites. At 35 ppm, CCl(4) induced further toxicity, as indicated by reduced somite number and growth and increased malformation rates. The results indicate that effects on morphogenic events appeared in both systems at concentration levels that also affected the overall development and that, independently of the choice of species or route of administration, CCl(4) has no potential to induce specific malformation patterns. The presence of a metabolic system in the rat embryo cultures approximately doubled the toxicity of CCl(4). PMID- 20702293 TI - Interaction of cadmium with actin microfilaments in vitro. AB - Cadmium, an environmental and occupational health hazard, can substitute for calcium in the activation of calmodulin in several in vitro assays. It was shown that Cd(2+) can substitute for Ca(2+) in the induction of actin-based gelation in cytoplasmic extracts from rat liver; gelation induced by either Ca(2+) or Cd(2+) is inhibited by trifluoperazine, a well known calmodulin inhibitor; and in MDCK cells there is a Cd(2+)-induced redistribution of actin filaments with the loss of stress fibres and the appearance of actin bundles at the periphery of these cells. PMID- 20702294 TI - A possible mechanism of toxicity by the antidepressant amoxapine based on its effects in three in vitro models. AB - When the antidepressant amoxapine is taken in overdose, it can cause metabolic acidosis, brain damage and sometimes death. In previous studies, biochemical evidence has been presented that amoxapine disrupts reactions of membrane associated multi-enzyme complexes, and mitochondrial energy conservation may be one of the first systems affected. Three in vitro systems were investigated to determine whether general membrane disruption or more specific mitochondrial effects of amoxapine could be responsible for toxicity and for lactic acid accumulation. In Saccharomyces cerevisiae, increased amoxapine concentrations led to decreased oxygen uptake associated with decreased survival of cells. In Chinese hamster ovary cells in culture, an initial increase in oxygen uptake was observed up to 10 mug amoxapine/ml and a decrease thereafter. At drug levels that caused an increased oxygen uptake, there was increased lactic acid output by cells, but no observable toxicity. At higher drug levels, the decreased oxygen uptake was accompanied by cell death, reduced lactic acid output and a change in the mitochondrial cristae configuration. Cell death in both of the above systems was attributed to interference with energy conservation. Isolated, beating guinea pig hearts perfused with 5 mug amoxapine/ml stopped after 13 min, but no lactic acid accumulated. This may be explained by the membrane-stabilizing activity of the drug. In an arrested perfused heart, increased concentrations of amoxapine stimulated oxygen consumption and lactic acid production. Hence, membrane stabilizing activity alone is not adequate to explain the action of amoxapine on isolated cells, and on the perfused arrested heart, or the clinical pattern of overdose, and disruption of energy conservation in cells is likely to be involved also. PMID- 20702295 TI - The antioxidant effects of copper sulphate on the actions of a phorbol ester and a xanthine-xanthine oxidase superoxide-anion generating system in murine epidermal cells. AB - Aqueous solutions of CuSO(4) were shown to inhibit cytochrome c reduction by xanthine-xanthine oxidase. Such copper solutions also significantly inhibited oxidant production, induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), measured as chemiluminescence, in murine epidermal cells in vitro. At the non toxic level of 250 mum, CuSO(4) inhibited by 40% the induction of ornithine decarboxylase by TPA in murine epidermal cultures. The superoxide generating system xanthine-xanthine oxidase was shown to induce ornithine decarboxylase by two- to threefold; such induction was partially inhibited by CuSO(4). Superoxide dismutase slightly inhibited TPA-induced, but not basal DNA synthesis in cultured epidermal cells. For unknown reasons, DNA synthesis was enhanced by CuSO(4) alone and was further enhanced in the presence of TPA. It appears that oxidants generated in response to TPA partially mediate the induction of ornithine decarboxylase and to a lesser extent DNA synthesis. PMID- 20702296 TI - Evolution of structural changes leading to haemolysis in human erythrocytes treated with SK&F 95018, an antihypertensive compound with combined vasodilator and beta-adrenoceptor antagonist properties. AB - SK&F 95018 is an antihypertensive compound with combined vasodilator and beta adrenoceptor antagonist properties, which, when given to dogs by intravenous infusion, rapidly produced symptoms of intravascular haemolysis. The haemolytic potency of SK&F 95018 was confirmed in vitro using human erythrocytes, was concentration dependent and was associated with dose-specific morphological changes as determined by scanning and transmission electron microscopy. Treatment of washed human erythrocytes with 0.5 mm-SK&F 95018 for up to 30 min resulted in gradual transformation from the biconcave discocyte to stomatocyte forms. Stomatocytes developed more rapidly on exposure to 2 mm-SK&F 95018, exhibited unilateral, multifocal invaginations by 2 min and evolved into spherocytic erythrocytes showing many membrane protuberances and invaginations. At the highest treatment level (10 mm) the crenated erythrocytes seen at time 0 transformed rapidly into spherocytes with many membrane-bound, surface projections that were retained in erythrocyte membrane 'ghosts'. The membrane active properties of SK&F 95018 were investigated in a phospholipid-membrane model (an aqueous dispersion of side-chain perdeuterated dipalmitoylphosphatidylcholine) by proton and deuterium nuclear magnetic resonance spectroscopy. The results suggest that SK&F 95018, with its molecular dual polarity, inserts into and effectively disrupts the intergrity of biological membranes by micellar reorganization of the bilayer plasmalemma. The slow change in shape from discocyte to stomatospherocyte at the lowest concentration (without the development of membrane-associated protuberances) suggests a disruptive effect on the erythrocyte osmotic balance by gradual cumulative drug insertion into the membrane. At higher concentrations this initial effect (leading to cell swelling) appears to proceed contemporaneously with micellar membrane reordering, producing membrane protuberances. PMID- 20702297 TI - Effects of the Fusarium mycotoxins zearalenone and deoxynivalenol on the mitochondrial methylthiazol tetrazolium-cleavage activity of monolayer cells. AB - The application of a modified colorimetric assay for the evaluation of mycotoxin derived cytotoxicity is reported. Using four mammalian monolayer cell types (swine kidney, African green monkey kidney, Madin Darbin canine kidney and bovine embryonic lung cells), the influence of the mycotoxins zearalenone and deoxynivalenol on the cellular methylthiazoltetrazolium (MTT)-cleavage activity was evaluated after different toxin exposure times. The yellow tetrazolium salt is converted by mitochondrial enzymes of metabolically active cells into purple formazan products. These crystals were dissolved in dimethylsulphoxide to obtain a homogeneous solution, the optical density of which was suitable for precise spectrophotometric measurement by a plate reader. Zearalenone proved to be less cytotoxic than deoxynivalenol and even enhanced the cleavage activity of the cell types tested. At concentrations of 10 and 100 mug/ml, deoxynivalenol showed a marked suppressive effect on the activity of all cell types, depending on the length of the incubation time. The results indicate that monolayers are useful targets in the MTT assay for investigating the action of mycotoxins and for performing comparative studies in mammalian cells. PMID- 20702298 TI - Cytotoxicity test with simplified crystal violet staining method using microtitre plates and its application to injection drugs. AB - A cytotoxicity test with the crystal violet staining method was developed using Chinese hamster lung and HeLa S3 cells in 96-well microtitre plates with an automatic plate reader, to facilitate examination of serial dilutions of the test substance. A good correlation was observed between this procedure and routine cell counting. However, for some chemicals results of the microtitre plate method differed from colony formation counts, particularly when the chemical induced cell stasis. In an application of the microtitre cytotoxicity assay to injection drugs, some drugs that are widely used proved to be very cytotoxic. PMID- 20702299 TI - N-phenyl-p-phenylenediamine uptake onto reconstituted collagen fibrils. AB - N-Phenyl-p-phenylenediamine (N-PPDA) is known to cause strong skin irritation and a sensitization reaction in exposed persons. In a previous in vitro study with portions of skin, N-PPDA exhibited appreciable binding affinity, which suggests a likely involvement of collagen. The present study was therefore undertaken to assess the potential and kinetics of N-PPDA uptake onto collagen. A linear relationship between t-PPDA concentration and its uptake on collagen fibrils was observed. The higher the exposure or contact time the greater the uptake, until a saturation of available sites was reached. The binding was dependent on temperature, with greatest uptake noted at 35 degrees C, and a sharp decline observed at about 50 degrees C. The importance of the intact helical structure of collagen fibrils in offering optimal binding sites was evident from the diminished binding response of collagen denaturated by heat and urea and from the limited affinity towards gelatin. There appeared to be no involvement of sulphydryl groups in the N-PPDA uptake on collagen. A striking resemblance between the binding kinetics of t-PPDA onto collagen and that observed previously with skin portions in vitro, suggests that the collagen fibril model may have a use as a simple preliminary tool to screen chemicals that show binding potential towards skin, in order to make predictions about their dermal toxicity. PMID- 20702300 TI - Use of primary rabbit cornea cells to replace the Draize rabbit eye irritancy test. AB - The Draize ocular irritancy test was compared with cytotoxicity determined from colony forming ability in cells freshly isolated from rabbit cornea (RC). The primary RC cells grew well and cloning efficiency ranged between 80 and 100% during early passages. We used 52 chemicals used in consumer products as test agents. There was a close correlation between the cytotoxicity in RC cells in vitro and the Draize score in vivo in response to the 52 chemicals. With a few exceptions, the cationic detergents appeared to be more toxic than the anionic or nonionic compounds tested. These data suggest that the cytotoxicity test in vitro using primary RC cells may be useful as a substitute for the Draize eye irritancy test. PMID- 20702301 TI - An in vitro screening test for the assessment of the irritant potential of parenteral formulations. AB - A HeLa cell/neutral red cytotoxicity assay has been investigated as an in vitro screen for assessing the irritancy potential of parenteral formulations. Five commercially available intramuscular injectables, three irritants and two non irritants, were examined for cytotoxic effects in this system. The ranking of the injectables tested, in order of decreasing cytotoxic effects, correlated with both previously reported qualitative in vitro data and their reported irritancy when administered to man. The results show that the HeLa cell/neutral red cytotoxicity assay may provide an alternative to animal studies for the assessment of the irritancy potential of parenteral formulations during the preliminary stages of their development. PMID- 20702302 TI - Evaluation of organic nephrotoxins in rabbit renal cortical slices. AB - An in vitro cortical-slice system was used to assess the toxicity of several organic nephrotoxins that require transport and/or bioactivation in order to induce toxicity. The toxins cephaloridine, hexachlorobutadiene, S-(1,2- dichlorovinyl)- l -cysteine and gentamicin all produce site-specific proximal tubular injury when administered in vivo. Damage was assessed in vitro by observing alterations in intracellular potassium, intracellular lactate dehydrogenase, and organic anion and cation accumulation. Histopathology was studied to assess the localization of injury. All four compounds produced dose- and time-dependent decreases in the biochemical parameters as well as site specific lesions in the S(3) region. The results illustrate the usefulness of renal cortical slices in acute studies of organic nephrotoxins. PMID- 20702303 TI - Quantitative structure-activity relationships. PMID- 20702304 TI - Effects of some purified saponins on transmural potential difference in mammalian small intestine. AB - The effect of a range of saponins, commonly present in foods or dietary supplements, on the potential difference (PD) across the mucosa of the rat small intestine in vitro has been examined. Saponins from Gypsophila, guar, alfalfa, Quillaja, clover and liquorice together with glycoalkaloids from the potato and tomato were examined. The typical response was an immediate reduction in PD, although there was considerable variation in the response to particular compounds. Amongst the factors affecting the nature and magnitude of the de polarizing effect were pH, solubility and the chemical form of the saponin. In agreement with the findings of others, glycyrrhizic acid, isolated from liquorice root, was found to exhibit a protective effect against the activity of a more potent saponin. The observations are discussed in the light of the known physiological activities of plant saponins and the regular, or excessive, consumption of certain foods or dietary supplements. PMID- 20702305 TI - An in vitro evaluation of the potential toxicities and interactions of carbamate pesticides. AB - The inhibition of rat plasma cholinesterase was used to screen the toxicity of carbamate pesticides in vitro. All three carbamates studied-aldicarb, carbofuran and oxamyl-inhibited the rat cholinesterase in a dose-dependent manner, as determined by the Ellman technique. The concentrations that produced 25 and 50% inhibition of cholinesterase (IC(25) and IC(50)) were, respectively, 1 x 10(-8) and 5 x 10(-7)m for aldicarb, 1 x 10(-9) and 1.5 x 10(-7)m for carbofuran, 5 x 10(-11) and 5 x 10(-8)m for oxamyl and 4 x 10(-11) and 6.5 x 10(-8)m for a mixture consisting of equal proportions of all three carbamates. In the interaction study, based on the data for the mixture of all three carbamates, and for the individual carbamates, cholinesterase inhibition by aldicarb was found to be potentiated by carbofuran and oxamyl. The effects of carbofuran were also potentiated by aldicarb and oxamyl but the presence of carbofuran and aldicarb was found to reduce cholinesterase inhibition by oxamyl. PMID- 20702306 TI - Cytotoxicity of fly-ash in alveolar macrophages from hypothyroid rats. AB - Fly-ash particles of a diameter smaller than 2 mu were collected from the electrostatic precipitator of a coal-fired power plant, and their cytotoxicity was studied in culture using alveolar macrophages from healthy and hypothyroid rats. The mortality rate and the secretion rates of cytoplasmic (lactate dehydrogenase) and lysosomal (acid phosphatase and beta-glucuronidase) enzymes into the culture medium were greater in the alveolar macrophages from hypothyroid rats than in the control macrophages. Electron microscopy showed a retraction of filapodia, loss of ruffled membrane and distortion of cell shape in the alveolar macrophages from hypothyroid rats. These results demonstrate that the cytotoxicity of fly-ash particles was enhanced in the macrophages from hypothyroid rats, and indicate that the normal functions of alveolar macrophages are impaired by changes in thyroid status. PMID- 20702307 TI - In vitro cytotoxic effects of enzymatically induced oxygen radicals in human fibroblasts: Experimental procedures and protection by radical scavengers. AB - Introduction of hypoxanthine and xanthine oxidase into human fibroblast cultures induces a dose-dependent cytotoxicity as a result of free-radical formation. The influence of medium, cell density and the power of recovery after free-radical attack were investigated. It appears that toxicity is higher in physiological Dulbecco phosphate buffer or Hanks' balanced salt solution than in modified Eagle medium, is inversely proportional to cell density and that damage is most often irreversible. Using this model, we studied the protective effects of a hydrosoluble flavonoid, silybin, and of a well known antioxidant, BHT (butylated hydroxytoluene). These molecules were administered before and during free-radical attack. With BHT significant protection was observed when it was added before free-radical attack (24% protection at a concentration of 10(-4)m) and before and during exposure (20% protection at a concentration of 10(-5)m). When silybin is applied during radical attack maximal activity is recorded at a concentration of 8 x 10(-4)m (45%), but the most interesting results are observed when 1 x 10(-4) and 8 x 10(-4)m are used, respectively, before and during radical exposure (63% of activity). PMID- 20702308 TI - The acute and subchronic effects of organophosphorus and carbamate pesticides on cholinesterase activity in aggregate cultures of neural cells from the foetal rat brain. AB - The biochemical and morphological effects of five organophosphorus and carbamate pesticides were examined in aggregate cultures of neural cells from rat brains. Acute cholinesterase inhibition assays with carbofuran were performed on culture days 5, 10 and 17. No significant age-related differences in the median inhibitory concentrations (IC(50)s) were detected. When the cholinesterase IC(50) values for malaoxon, fenitrothion, carbaryl and carbofuran, determined on culture day 17, were plotted against the previously published median lethal dose (oral LD(50)s) of the same compounds in rats and mice, there was a good linear relationship between IC(50) and LD(50) values. In a 14-day subchronic study with fenitrothion, total protein levels in the cultures were significantly lower than control values at all doses tested (4, 8 and 20 mug/ml medium) while cholinesterase activity was unaffected at all but the highest dose. Central necrosis was observed at the intermediate dose, while cultures exposed to the highest dose exhibited extensive cell death and abnormal cell arrangement within the aggregate. PMID- 20702309 TI - Cholinesterase inhibition by organophosphorus and carbamate pesticides in aggregate cultures of neural cells from the foetal rat brain: The effects of metabolic activation and pesticide mixtures. AB - The effects of pesticide mixtures on cholinesterase activity in aggregate cultures of neural cells were investigated; we also determined whether exogenous rat-liver microsomal fraction (S-9) might be used in conjunction with the cultures to mimic the in vivo activation of pesticides such as malathion. Studies of the effects of pesticide mixtures on the cholinesterase activity of cultures demonstrated that a hepatic microsomal fraction (S-9) played a major role in the nature of the interaction between combinations of malathion and fenitrothion or carbofuran. In the absence of S-9, malathion potentiated the anti-cholinesterase effect of fenitrothion, while neither synergistic nor antagonistic interactions occurred with mixtures of carbofuran and malathion. When S-9 was added to cultures with the pesticide mixtures, malathion's interaction with fenitrothion was antagonistic, and a synergistic response was observed for the mixtures of malathion and carbofuran. The antagonistic interaction of mixtures of fenitrothion and carbofuran was demonstrated to be independent of exogenously added S-9. Neither antagonistic nor synergistic interactions were observed for mixtures of triallate and fenitrothion or carbofuran. The data indicate that the addition of exogenous S-9 may be used to mimic certain aspects of the in vivo biotransformation of pesticides in aggregate cultures of neural cells from rat brain. Furthermore, the effects on cholinesterase activity of several of the pesticide mixtures tested were dependent upon the presence of exogenous S-9. PMID- 20702310 TI - Effect of continuous beta-blockade on collagen synthesis in interstitial fibroblasts isolated from adult rat lung. An in vitro model of progressive pulmonary fibrogenesis. AB - Continuous administration of propranolol to adult rats resulted in pulmonary changes indicative of fibrogenesis in the absence of an extensive inflammatory infiltrate. Interstitial fibroblasts, isolated from the lungs of rats continuously exposed to 0.5 mg propranolol-HCl/hr via subcutaneous osmotic pumps for 1 or 3 wk synthesized more acid-insoluble collagenase-sensitive protein than matched controls. This effect could be decreased, but not prevented, by administering zinc salts to the animals in drinking-water during drug treatment. A larger percentage of the overall protein synthesis of the propranolol-treated cells was devoted to collagenous proteins as well. Isolated fibroblasts placed in tissue culture and treated with propranolol secreted more total lactate dehydrogenase than controls; this change was due to increased secretion of lactate dehydrogenase isoenzyme 5. Three weeks of propranolol treatment caused a 31% decrease in the number of beta-adrenergic lung receptors, with no change in their affinity. These results suggest that this in vitro model may be useful in elucidating mechanisms of progressive lung disease following long-term exposure to injurious agents. PMID- 20702311 TI - Toxicity of combinations of chlorinated aliphatic hydrocarbons in vitro and in vivo. AB - Hepatocyte suspensions were exposed to carbon tetrachloride (CT), chloroform (CF) or 1,1,1-trichloroethane (TE) or the various combinations of these three chemicals over a 3-hr incubation period. Enhanced toxicity, as determined by loss of intracellular potassium ion and cytoplasmic enzyme leakage, was demonstrated for each combination in hepatocyte suspensions. Other rats were exposed to these chlorinated hydrocarbons by ip injection and blood samples were taken 24 hr later to determine plasma enzyme levels as indicators of hepatotoxicity. Exposure in vivo resulted in a positive interaction of CT + CF and CF + TE but not for CT + TE or CT + CF + TE. The data indicate that, while there is some correlation of response between results in vitro and in vivo, there is not complete agreement. This indicates that care is necessary in extrapolating results obtained in vitro to predict responses in vivo for toxicity of chemical combinations. Nevertheless, the positive correlation demonstrated for some of the combinations supports further investigations of the use of toxicity testing in vitro for the prediction of enhanced toxicity on exposure to chemical mixtures. PMID- 20702312 TI - Correlation between in vivo and in vitro toxicity of some chlorinated aliphatics. AB - The release of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) from rat and mouse hepatocytes was used to rank the in vitro cytotoxic potential of eight chlorinated aliphatic compounds. The rankings were compared with toxicity rankings based on the maximum tolerated doses for each species. Significant correlations between the rankings were obtained when air: water partition coefficients were factored into the in vitro data (EC(50)s) in order to adjust for differences in volatility and the retention of the compounds in vivo. For both rats and mice, as an indicator of cytotoxic potency, LDH release correlated better with hydrocarbon toxicity than AST release did. These data support the use of isolated hepatocytes for screening of chemicals for relative toxicity. PMID- 20702313 TI - Genotoxicity of haloalkene and haloalkane glutathione S-conjugates in porcine kidney cells. AB - The genotoxicity of the glutathione S-conjugates S-(12-dichlorovinyl)glutathione (DCVG), S-(1,2,2-trichlorovinyl)glutathione (TCVG), S-(1,2,3,4,4 pentachlorobutadienyl)glutathione (PCBG) and S-(2-chloroethyl)glutathione (CEG) was investigated in LLC-PK1, a cultured line of porcine kidney cells that exhibits many properties of proximal tubular cells. DNA damage caused by treatment of the cells with the S-conjugates was estimated by determining the induction of unscheduled DNA synthesis (UDS) after inhibition of replicative DNA synthesis in confluent LLC-PK1 monolayers. DCVG-, TCVG- and PCBG-induced dose dependent UDS at concentrations not causing cytotoxicity, as determined by the release of lactate dehydrogenase into the medium. Acivicin, which inhibits irreversibly gamma-glutamyl-transpeptidase (GGT) and aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, blocked DCVG-, TCVG- and PCBG-induced genotoxicity. CEG, however, was genotoxic in subconfluent cells and this was not dependent on GGT and beta-lyase activities. The DNA damaging effects in kidney cells of DCVG, TCVG and PCBG, which are metabolites of the nephrocarcinogens trichloroethylene, tetrachloroethylene and hexachlorobutadiene, respectively, suggest that the parent haloalkenes are potentially genotoxic in the rat kidney, the target organ for both acute toxicity and carcinogenicity. PMID- 20702314 TI - Irritancy testing-A cultured approach. PMID- 20702315 TI - Neurotoxicology in vitro: Model systems and practical applications. PMID- 20702316 TI - Antagonist studies using the erythrocyte osmotic fragility membrane stabilization assay. AB - d-Propoxyphene, diazepam, chloroquine and propranolol were studied in an erythrocyte membrane stabilization assay involving osmotic stress. d-Propoxyphene and diazepam appear to be considerably less potent membrane-stabilizing agents than propranolol; chloroquine showed the weakest membrane-stabilizing potency. All of the drugs exerted this effect on erythrocytes at concentrations, in buffer, similar to the plasma concentrations associated with severe toxicity or lethality in man. Neither caffeine nor l-histidine reversed the stabilization of the erythrocyte membrane by propranolol. Similarly, theophylline did not reverse the effects of d-propoxyphene. Chloroquine did not alter the membrane-stabilizing effects of diazepam but a low level of diazepam slightly enhanced the membrane stabilizing effects of chloroquine. The erythrocyte osmotic fragility assay is a simple, sensitive assay for studying drug-induced membrane stabilization at concentrations similar to those occurring in human plasma in vivo. Antidotal reversal of membrane stabilization was not demonstrable in this model. This may be because this model tests the physical but not functional integrity of membranes, and suggests that the mode of action of antidotes to membrane stabilizing agents should be examined in models for studying the functional capacities of cells or organisms. PMID- 20702317 TI - Effect of acute ethanol administration and nutritional status on secretory protein synthesis in isolated rat liver cells. AB - Treatment of isolated rat liver cells with 20 mm-ethanol inhibited basal secretory protein synthesis by 30% only when the donors were starved for 48 hr, immediately before they were killed. This inhibition was unaffected by the presence of ethanol in the diet of the donor animals. Independently, d-glucose and l-proline enhanced rates of secretory protein synthesis in a dose-dependent manner but only in cells from 48-hr-fasted donors. This latter stimulation was prevented by the presence of 20 mm-ethanol in the incubation medium. By contrast, up to 100 mm-ethanol did not alter polypeptide synthesis by a post-mitochondrial supernatant from rat liver. PMID- 20702318 TI - Inhibition of replicative DNA synthesis by paracetamol in V79 Chinese hamster cells. AB - Low concentrations of paracetamol (0.1 mm) inhibited DNA synthesis in V79 Chinese hamster cells within minutes of addition. RNA and protein synthesis were inhibited only after longer exposure (3 hr) to considerably higher concentrations of paracetamol (3-10 mm). Flow-cytometry studies showed that V79 cells exposed to paracetamol were blocked initially in the G(1)-phase and subsequently slowly passed through the S-phase. No metabolites were detected by high-performance liquid chromatography after exposure of V79 cells to paracetamol for 50 hr. Furthermore, metyrapon and SKF 525-A (inhibitors of cytochrome P-450), indomethacine (inhibitor of prostaglandin H synthetase), and paraoxon (inhibitor of deacetylase) did not prevent paracetamol-induced inhibition of DNA synthesis. On the other hand, low concentrations of ascorbate (2 mum) reduced the effect of paracetamol. No effect was observed with the non-reductive precursor of ascorbate, gulonolactone. Neither catalase nor superoxide dismutase reduced the effect of paracetamol on DNA synthesis. Ascorbate also partly reduced paracetamol induced sister-chromatid exchange (SCE). The inhibition of DNA synthesis caused by hydroxyurea, an inhibitor of ribonucleotide reductase, was also counteracted by ascorbate. Both paracetamol and hydroxyurea caused increased frequencies of SCE in V79 cells. We suggest that a specific enzyme involved in the synthesis of DNA is inactivated by the oxidation of paracetamol. PMID- 20702319 TI - Sister-chromatid exchanges in human bronchial epithelial cells. AB - One method of assessing the genotoxic effects of exposure to environmental agents is by determining the frequency of sister chromatid exchanges in exposed cells. In the present study, a procedure for observing sister chromatid exchanges in adult human bronchial epithelial cells exposed to a carcinogen has been developed. Using this procedure, the frequencies of sister chromatid exchanges in untreated cells from two individuals were found to be 5.1 +/- 1.8 and 6.5 +/- 1.4 per metaphase (mean +/- SD). Cells from the first individual exposed to 7,12 dimethylbenz[a]anthracene at 0.5, 1 and 2 mug/ml had 7.8 +/- 2.2, 13 +/- 3.1, 18.7 +/- 3.7 sister chromatid exchanges per metaphase, respectively. This method is likely to be particularly useful for observing sister chromatid exchanges in cells that have a relatively slow growth rate in the presence of bromodeoxyuridine and for which preparation of a large number of metaphase chromosomes is difficult. In addition, the procedure provides a means of assessing genotoxic effects in the lung by examining the direct effects of pollutants on the chromosomes of the target cells for human lung cancer. PMID- 20702320 TI - An investigation of the cardiotoxic action of vancomycin in the isolated working rat heart. AB - The mechanism of cardiotoxic action of vancomycin was examined in preparations of isolated working rat hearts and spontaneously beating right atria. Vancomycin produced a concentration-dependent decrease in aortic flow, coronary flow and heart rate in the isolated working rat heart, with no significant effect on other haemodynamic parameters. At 5 mm, vancomycin produced a statistically significant decrease (compared with control values) in aortic flow (24.1 +/- 7.5%) and in the basal heart rate (34.3 +/- 3.5%) after 15 min incubation. Coronary flow was also reduced by 23.5 +/- 9.2%. Prolonged exposure of the preparation to 5 mm vancomycin produced a marked time-dependent bradycardia accompanied by a time dependent increase in the leakage of lactic dehydrogenase (LDH) into the perfusion medium. Moreover, a correlation (r = -0.94) was found between the time dependent bradycardia and LDH leakage induced by Vancomycin. In the isolated spontaneously beating right atria pretreated with atropine, vancomycin (5 mm) also produced a time-dependent bradycardia similar to that found in the isolated working rat heart. Moreover, (45)Ca(2+)-flux studies indicated that vancomycin had no significant effect on the (45)Ca(2+) uptake into the right atrial muscle. These data suggest that: (1) vancomycin has a direct and acute cardiotoxic action at high concentrations (> 1 mm); (2) time-dependent bradycardia is a sensitive functional index for the cardiotoxicity induced by vancomycin; (3) the bradycardia elicited by vancomycin is due neither to the release of acetylcholine from the parasympathetic nerves innervating the heart nor to blockade of Ca(2+) entry. PMID- 20702321 TI - Effects of 2,2',4,4',5,5'-hexachlorobiphenyl on testosterone production in vitro. AB - Mouse Leydig cells were incubated with 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB, 2.9 or 14.3 mug/ml). Testosterone production increased during the first 3-4 hr of incubation without addition of gonadotropin. The substance also affected cell viability in that the concentration of Leydig cells began to decrease soon after the start of the incubation and the percentage of dead cells increased throughout the incubation period. A technical mixture of polychlorinated biphenyls (Clophen A50(R)) was used as a control to test the relationship between cell death and testosterone production. This preparation, which was slightly more toxic to the cells than was 6-CB, did not stimulate basal testosterone production. No binding of (14)C-labelled 6-CB to the Leydig-cell gonadotropin receptors could be demonstrated. PMID- 20702322 TI - Effects of endogenous and tobacco-related amines and nitrosamines on cell growth and morphology of a cell line derived from a human neuroendocrine lung cancer. AB - This report is part of a comprehensive research programme to elucidate the role of physiological functions and pathways of pulmonary neuroendocrine cells in the cascade of events that lead to the development of neuroendocrine lung cancer. In this study, a well differentiated neuroendocrine cell line (NCI-H727) derived from a human lung carcinoid was used to investigate the ability of endogenous and tobacco-related amines to stimulate cell proliferation in neuroendocrine tumour cells. Cell line NCI-H727 was exposed in vitro to the endogenous amine serotonin and its precursor 5-hydroxytryptophan (5-HTP), to the tobacco-related amine nicotine, and the tobacco-related nitrosamines N-nitrosodiethylamine (DEN) and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The experiments were conducted in both 8% CO(2)-92% air and in 5% CO(2)-95% air. The effect on growth kinetics and ultrastructure of these conditions were studied. All amines had a dose-dependent stimulating effect on cell growth when tested in 8% CO(2)-92% air with nicotine exerting the strongest effect. No such effect was observed in 5% CO(2)-95% air and the control cells did not grow under these conditions. DEN, 5 HTP, serotonin and NNK all caused dedifferentiation of cytoplasmic organelles. Nicotine caused a change in size and ultrastructure of dense-cored granules suggestive of a change in the nature of stored neuroendocrine material. PMID- 20702323 TI - Inter-species variation in hepatocyte activation of 2-acetylaminofluorene in salmonella mutagenicity assays with TA98 and TA98/1,8DNP(6). AB - In Salmonella typhimurium mutagenicity assays the metabolic activation of 2 acetylaminofluorene (2AAF) was greater by isolated hepatocytes from two species resistant to 2AAF-induced hepatocarcinogenesis, the guinea-pig and rabbit, than by hepatocytes from the highly susceptible rat liver. S. typhimurium strain TA98/1,8DNP(6) was less sensitive to 2AAF-induced mutagenesis than strain TA98. Even in the absence of bacterial esterification (TA98/1,8DNP(6)), 2AAF mutagenicity was always lowest following activation by rat hepatocytes. Paraoxon (an inhibitor of deacetylase) inhibited by more than 90% the mutagenicity of 2AAF with rat and guinea-pig hepatocytes, but only partially inhibited the mutagenicity of N-hydroxy-2-acetylaminofluorene-a metabolite of 2AAF-particularly at low substrate concentrations. In a modified mutagenicity assay in which hepatocytes and 2AAF were pre-incubated before the addition of TA98, a reduction of 2AAF mutagenicity was observed with guinea-pig but not rat hepatocytes. Thus, even when the integrity of the cells used for metabolic activation is maintained, and when bacterial esterification is avoided, conventional Salmonella assays do not show a correlation between the mutagenicity of 2AAF in vitro and its carcinogenicity in vivo. The correlation may, however, be improved by modification of in vitro conditions. PMID- 20702324 TI - Genotoxic effects of paraquat and diquat evaluated by sister-chromatid exchange, chromosomal aberration and cell-cycle rate. AB - We studied the induction of sister-chromatid exchanges (SCEs) and chromosomal aberrations in cultured mammalian cells exposed to paraquat or diquat in order to elucidate the genotoxic effects of these two common herbicides. The effects of paraquat and diquat were studied at various concentrations with special attention given to concentrations that are thought to be non-toxic. With increasing concentrations of paraquat and diquat (0.08-20.0 mum), increasing frequencies of SCEs were found in Chinese hamster lung cells. The effects of the herbicides on the cell-cycle rate were also studied: the cycle rate was stimulated at low concentrations but inhibited at higher concentrations. There was no significant induction of chromosomal aberrations at herbicide concentrations that stimulated the cell-cycle rate. However, at concentrations found to inhibit the cell-cycle rate, an increased number of chromatid gaps and breaks were observed, especially after long incubation periods, although no chromatid exchanges were noted during our experiments. These results show that the genotoxic effects of paraquat and diquat occur not only at high concentrations, but also at concentrations low enough to stimulate the cell-cycle rate. The role of superoxide anions and/or hydrogen peroxide, produced by herbicide action, in the induction of sister chromatid exchanges and chromosomal aberrations was demonstrated by further studies using catalase and/or superoxide dismutase treatment. PMID- 20702325 TI - Comparison of metabolic effects of carbon tetrachloride and 1,2-dichloroethane added in vitro to slices of rat liver. AB - Carbon tetrachloride and 1,2-dichloroethane (1,2DCE) were added in vitro to freshly prepared slices of rat liver and the time- and concentration-dependence of their toxic effects on several metabolic parameters determined. With each agent, the most sensitive effect was an increase of malondialdehyde production by a microsomal preparation isolated from the treated slices. The next most sensitive parameter was the inhibition of amino acid incorporation into slice proteins, followed by inhibition of net K(+) accumulation and the induction of early necrotic changes, as indicated by loss of histological staining with azure II. Substantially greater exposures were required to reduce cellular ATP and to initiate entry of Ca(2+). This sequence was similar with both agents, but CCl(4) was the more potent in each case. When added in combinations of submaximally effective concentrations, the two agents produced at least additive inhibitions of protein synthesis and K(+) accumulation. We conclude that metabolic effects in liver slices can be a useful in vitro test for potential toxicity of chlorinated hydrocarbons. Amino acid incorporation and K(+) transport are the most convenient indicator systems, combining considerable sensitivity to relatively low levels of exposure with convenience of measurement. PMID- 20702326 TI - Use of organ cultures in human risk assessment: Comparisons of benzo[a]pyrene-DNA adducts in mouse and human skin. AB - Human and mouse skin explant systems have been developed as models that qualitatively mimic the genotoxic metabolism in vivo of benzo[a]pyrene, a representative carcinogenic polycyclic aromatic hydrocarbon. High-performance liquid chromatography profiles of DNA adducts isolated from CD-1 mouse skin treated with [(3)H]benzo[a]pyrene either in vivo or in vitro were qualitatively very similar. (32)P-Post-radiolabelling and thin-layer chromatography analysis of these DNA adducts also yielded profiles that were qualitatively similar both in vivo and in vitro. The presence of a component that did not appear to correspond to those detected by direct labelling was also revealed by (32)P-postlabelling. These approaches have been applied in order to develop valid risk models for chemical carcinogens, and in addition, to provide valuable reference standards for the detection of human genotoxic metabolism. Thus the coupling of human skin explant systems with (32)P-postlabelling techniques has provided a direct in vitro model for the prospective detection of human carcinogens. PMID- 20702327 TI - Effect of mono-(2-ethylhexyl) phthalate on the metabolism of energy-yielding substrates in rat sertoli cell-enriched cultures. AB - The effect of the testicular toxin mono-(2-ethylhexyl) phthalate (MEHP) on the metabolism of energy-yielding substrates in Sertoli cell-enriched cultures has been studied. MEHP stimulated glucose utilization and oxidation. Stimulation of (14)CO(2) production was greater with [1-(14)C]- than with [6-(14)C]glucose. Oxidation of [1-(14)C]pyruvate and [U-(14)C]acetate to (14)CO(2) was reduced by MEHP treatment in the presence but unaffected in the absence of glucose. MEHP increased the incorporation of radioactivity from [1-(14)C]- and [6-(14)C]glucose but not from [U-(14)C]acetate into fatty acids. MEHP markedly increased the production of lactate by Sertoli cells cultured in the presence of 5.5 mm-glucose and 0.5 mm-pyruvate. Decreasing the glucose concentration reduced this stimulatory effect. In glucose-free medium containing 0.5 or 2.5 mm-pyruvate MEHP had no effect on Sertoli cell lactate production. Thus, MEHP appears to stimulate the utilization of glucose by the Sertoli cell but does not appear to have a direct effect on the conversion of pyruvate to lactate, on the conversion of pyruvate to acetyl CoA or a direct effect on the metabolism of acetyl CoA through the Krebs cycle. Increased glucose utilization appears to be a consequence of the increased metabolism of glucose that occurs through the glycolytic and pentose phosphate pathways. These results suggest that in contrast to its effects on the liver, MEHP does not exert a primary effect on the Sertoli cell mitochondrion. PMID- 20702328 TI - Preface. PMID- 20702329 TI - Histology of the rat embryo cultivated in vitro (18-22 somites). AB - When rat embryos are grown in culture, the morphological scoring system of Brown & Fabro (Teratology 1981, 24, 65-78) is usually employed at the end of culture to assess normal development and the effects of drugs and other chemicals. The morphological scoring system has proved very satisfactory, but its criteria only involves the external appearance of the embryo. It seems desirable to study also the internal anatomy of the embryo by histological methods. Thus, the object of this study was to gain data on the morphology of the main organ systems, with special attention given to the cardiovascular system during the developmental period most often employed in teratogenicity and embryotoxicity studies (day 9 10; 18-22-somites stage). The microscopic findings in this study agreed well with the morphological scoring system, with only one exception; whereas only two branchial arches were visible externally at the 18-22-somites stage, microscopy revealed that the third arch was also present. PMID- 20702330 TI - Embryonic metabolism of foetal fuels in whole-embryo culture. AB - The whole-embryo culture technique has been extensively used to evaluate embryonic growth and development using morphological criteria. However, the system also provides an opportunity to assess the status of embryonic metabolism to determine biochemical maturation and alterations induced by xenobiotics or changes in substrate availability. For example, using (14)C-labelled substrates the rates of product formation may be determined for a variety of foetal fuels such as glucose and the ketone body, beta-hydroxybutyrate. During organogenesis glucose metabolism is characterized by high rates of glycolytic metabolism at the early-somite stage and an increased dependence on Krebs cycle concomitant with the establishment of the chorioallantoic placenta (c. 30-somite stage) to initiate an increasingly 'foetal' type of pattern. The dependence of the neurulating embryo on glucose as a fuel is further demonstrated by the embryotoxic effects of insulin-induced hypoglycaemia. Although decreased glycolytic metabolism is the earliest effect of this treatment, both the Krebs cycle and oxidative pentose phosphate pathway are also inhibited. Therefore, the induction of malformations by hypoglycaemia is the result of a multifactorial biochemical alteration. In addition to glucose, mouse conceptuses have the capacity to metabolize alternative foetal fuels such as the ketone bodies d- and dl-BOHB at rates that are concentration dependent. However, the energy production from these substrates is limited by the low rates of Krebs-cycle metabolism at the early-somite stage. PMID- 20702331 TI - Pharmacokinetic aspects of drug effects in vitro (II) placental transfer to the embryo and activity of some carboxylic acids structurally related to valproic acid in whole embryos in culture. AB - The transfer of a group of short/medium chain-length carboxylic acids, related to the antiepileptic drug valproic acid (VPA), to the whole rat embryo in vitro was investigated. The protein binding of the drugs in the culture medium determined the placental transfer in vitro: at comparable total concentrations, the substances that bound to a lesser degree (VPA and its metabolite 2-propyl-4 pentenoic acid; 4-en-VPA) reached higher embryonic levels than the more highly bound substances, octanoic acid (OA), 2-methyl-2-ethylcaproic acid (MEC), and the VPA metabolite, 2-propyl-2-pentenoic acid (2-en-VPA). Consequently, the amount of drug added to the culture did not correlate with the transfer to the embryo, but the concentration of the free drug in the culture medium correlated highly with embryonic exposure. The concentration of the drugs in the cultured embryos, the embryonic membranes and the subembryonic fluid were higher than the corresponding free concentrations in the medium. The difference in the teratogenic potency of the substances tested was clearly related to their intrinsic activity, since even high embryonic concentrations of 2-en-VPA, MEC and OA did not produce adverse effects in contrast to VPA and 4-en-VPA which were effective at levels several fold lower. The effective concentrations of VPA in the cultured embryos were almost ten times lower than those in embryos in vivo. The factors responsible for the high vulnerability of the cultured embryos to the action of VPA are as yet unknown. Our results indicate that the determination of drug concentrations in cultured embryonic tissue is imperative for a rational interpretation of experimental data obtained from in vitro studies; a full validation of in vitro systems must incorporate pharmacokinetic studies. PMID- 20702332 TI - The role of pharmacokinetics in determining the response of rodent embryos to teratogens in whole-embryo culture. AB - The rodent embryo's response to teratogenic insult in whole-embryo culture during the period of neurulation was characterized by determining the role of pharmacokinetics and embryonic recovery in producing abnormal growth and development. Five known teratogens, hydroxyurea, cyclophosphamide, cadmium, diphenylhydantoin, and the ketone body beta-hydroxybutyrate were employed. The dose and exposure times in vitro were designed to reproduce the peak serum concentrations and half-life of the compounds present following the administration of a teratogenic or maximum maternally tolerated dose of the agents in vivo. The results showed: first, that both the serum concentration and duration of exposure to an agent play a role in determining the embryonic response in vitro; secondly, that compounds that do not produce effects during the period of neurulation or that require maternal metabolic activation are not teratogenic in culture; and thirdly, that embryos have the capacity to recover from certain teratogenic insults in vitro. Thus, both pharmacokinetics and the potential for embryonic recovery should be considered when applying the whole embryo culture technique to studies in teratology and toxicology. PMID- 20702333 TI - The effects of different chemical forms of a test compound on embryotoxicity, distribution and metabolism in vitro. AB - The lipoxygenase inhibitor N-hydroxy-N-methyl-7-propoxy-2-naphthalenethanamine (QA 208-199) was tested in vitro for its general embryotoxicity and, in particular, for its teratogenic potential. QA 208-199 was either added as the base (QA-base) or as its citric acid salt (QA-citrate) and its effects were compared with the effects of the salt, sodium citrate (Na-citrate). In addition, the main in vivo metabolite 209-668 (QA-acid) was tested. The in vitro no-effect levels of QA-base and QA-citrate on embryonic growth, differentiation and morphology were dependent on the chemical form of the compound added to the culture medium as well as on the use of a drug-activating system (S-9 mix). QA acid and Na-citrate were not embryotoxic in vitro up to the highest concentration tested. The metabolites formed in the culture medium after the addition of QA base or QA-citrate were quantitatively and qualitatively limited. After embryo cultivation in the presence of QA-acid, no metabolites could be detected in the yolk-sac and embryonic tissue. QA-acid by itself was stable in the culture. In contrast, in yolk-sac and embryonic tissues grown in the presence of QA-base or QA-citrate, no QA-base was detected at the end of the culture period, but high levels of QA-acid and of two unknown metabolites M5 and M6 were measured. The tissue concentrations found for these metabolites correlated with the extent of the observed embryotoxicity under the different culture conditions. It can be concluded that varying in vitro embryotoxic responses could be obtained depending on the chemical form of the test compound added to the culture. Furthermore, these effects could be enhanced by co-incubation with an activating system (S-9 mix). By measuring drug and metabolic levels in the culture medium and tissues during and at the end of the culture period it was possible to determine, in part, the mode of the in vitro embryotoxic action of QA 208-199. PMID- 20702334 TI - The application of whole-embryo culture to new product development. AB - Whole-embryo culture is employed routinely in our laboratories as one aspect in the early toxicity screening of new compounds. More than 150 experimental compounds have been examined to date, in addition to a number of known teratogenic agents. The rationale and study design are discussed and results are presented for cyclophosphamide, retinoic acid, lithium, thalidomide and mercury, all of which demonstrate good correlation between effects in vitro and those reported in vivo. The system has proved to be a rapid, cost-effective screen with marked economies in the numbers of animals, amount of compound and time required; as yet, no false positive or false negative results have been observed. It is considered, therefore, that taken in conjunction with other aspects of biological activity, the results from embryo-culture studies can make a valuable contribution to the selection process of new product development. PMID- 20702335 TI - Use of the whole-embryo culture system in drug safety assessment? AB - The embryotoxicity and, in particular, the teratogenic potential of three new drug combinations were investigated. The interactions of the single components (all already on the market) in the different drug mixtures were determined by testing the single components in addition to the drug combinations. In order to evaluate the usefulness of these results for safety assessment, the no-effect concentrations (NEC) of the single compounds or the mixed drug preparations, with respect to embryonic growth and differentiation and the presence of anomalies, were compared with human plasma/serum levels during therapeutic use. In addition, in vivo animal data of the single components were used to put into perspective the NEC values after direct in vitro exposure of embryos. Embryotoxicity, measured as a retardation of growth and of differentiation, as well as an increased percentage of cultured embryos with morphological abnormalities, was present at concentrations of 100 mug/ml for the preparation KT 1/300 (ketotifen/theophylline). These effects could be attributed to the component theophylline, as ketotifen was free of an embryotoxic/teratogenic potential in vitro. In the case of the compound mix VKB/BQ, a combination of pindolol, clopamide and endralazine, the in vitro effects of the mixture on embryonic development could also be attributed to one of the compounds (pindolol) in the mixture. In the case of HYCT 4520, the effects of the components hydergine (co dergocrine mesylate), clopamide and triamterene on embryonic growth, differentiation and anomalies were additive in the drug mixture. None of the compounds was reported to be associated with human teratogenicity. The NEC of the components in the whole-embryo culture system, tested either as a mixture or as individual compounds, were higher than the human peak plasma levels measured during therapeutic use of the compounds. In addition, the single components were reported to be non-teratogenic in in vivo teratogenicity studies up to doses many times higher than the therapeutic dose levels in humans. This study illustrates the usefulness of the whole-embryo culture system as a suitable tool for investigating the embryotoxicity/teratogenicity potential of newly registered drug combinations and the synergistic effects of their single components as part of registration toxicology. PMID- 20702336 TI - Cocaine-induced cardiotoxicity in vitro. AB - A growing number of reports have related cocaine use with the onset of myocardial infarction in young otherwise healthy individuals. Although the cardiac effects of cocaine have traditionally been attributed to sympathomimetic stimulation, several studies have suggested that cocaine may be directly cardiotoxic. The purpose of this study was to evaluate the cardiotoxic effects of cocaine in an in vitro preparation devoid of sympathetic innervation. Primary cultures of rat cardiac muscle and non-muscle cells were prepared from hearts excised from 3-5 day-old Sprague-Dawley rats. Cultures were exposed to various cocaine concentrations (1 x 10(-7)-1 x 10(-3)m) for 1-24 hr. Beating activity, morphological status and lactate dehydrogenase (LDH) leakage were evaluated following cocaine exposure. A decrease in the beating activity of cultured muscle cells was observed 1 hr after exposure to the highest cocaine concentrations (1 x 10(-5)-1 x 10(-3)m) tested. Similar results were obtained 24 hr after exposure. Morphological alterations in muscle cells were evident only after exposure to the highest concentration (1 x 10(-3)m). Vacuoles appeared 1 hr after cocaine exposure and were replaced by dark granules within 24 hr. LDH release was significantly elevated in the muscle cell cultures exposed to 1 x 10(-3)m cocaine for 24 hr. The pattern of cocaine-induced morphological alterations and enzyme leakage was similar in non-muscle cells. These data suggest that cocaine induces direct toxic effects on both cardiac muscle and non-muscle cells maintained in an environment free of neuronal and hormonal influences. PMID- 20702337 TI - In vitro modulation of macrophage functions by 1,1-dimethylhydrazine (UDMH): Possible mechanism for UDMH-induced immuno-enhancement. AB - The in vitro effects of 1,1-dimethylhydrazine (UDMH) on prostaglandin E(2) (PGE(2)) synthesis, chemiluminescence, phagocytosis, microbicidal activity and chemotaxis in murine enriched-macrophage populations were evaluated. PGE(2) synthesis by resident peritoneal macrophages and chemiluminescence by activated macrophages were markedly suppressed in the presence of UDMH; phagocytosis and microbicidal activity were slightly to moderately suppressed, and chemotaxis was not affected. Two of these functions (PGE(2) synthesis and chemiluminescence) reflect macrophage immunoregulatory properties, and the UDMH-induced abrogation of these functions may be related to the previously reported immuno-enhancing effects of UDMH. PMID- 20702338 TI - Toxic effects of the histamine H(2) receptor antagonist metiamide on bone-marrow haemopoietic and stromal progenitor cells in vitro. AB - The histamine H(2)-receptor antagonist, metiamide has been shown to cause agranulocytosis in vivo. In vitro colony forming assays for bone-marrow stromal fibroblast progenitors (CFU-F) and granulocyte/macrophage progenitor cells (CFU GM) were performed, using murine bone marrow, to assess the relative sensitivity of committed haemopoietic cells, and the marrow stromal microenvironment to metiamide toxicity. CFU-F were more susceptible than CFU-GM to inhibition by metiamide, with 50% inhibition of colony formation (ID(50)) at 17 and 180 mug/ml in the CFU-F and CFU-GM assays, respectively. Inhibition of CFU-GM required the continuous presence of the drug, while CFU-F were inhibited similarly by either short-term (20-hr) or prolonged (10-day) incubation with metiamide (ID(50) 27 and 17 mug/ml, respectively). It is suggested that bone-marrow stromal cell damage may be an important contributory factor in the haemopoietic toxicity of metiamide. PMID- 20702339 TI - A rapid, simple in vitro screening test, using [(3)H]glutathione and l [(35)S]cysteine as trapping agents, to detect reactive intermediates of xenobiotics. AB - Reactive intermediates, formed by biotransformation of xenobiotics, play an important role in drug toxicity. We have developed a rapid in vitro screening test for the detection of such intermediates. The unlabelled xenobiotic substrate is incubated with a post-mitochondrial supernatant, or a microsomal fraction of rat liver in the presence of NADPH and [(3)H]glutathione (GSH). Reactive intermediates formed are trapped with GSH, forming a radiolabelled GSH adduct. Analysis of the incubation medium by HPLC shows the formation of a new radioactive peak, corresponding to this adduct. To make the test more specific, similar incubations are done with l-[(35)S]cysteine: reactive intermediates are likely to be trapped by this agent, while substrates for GSH-transferase give a negative response with l-[(35)S]cysteine. The test has been used with 44 substrates; of the 18 expected to be positive, 16 were positive, and two negative. PMID- 20702340 TI - Effect of acrylamide on cerebellar astrocyte proliferation in vitro. AB - Cerebellar astrocyte cultures derived from 7-day-old rats were exposed to acrylamide. Acrylamide dose-dependently inhibited the proliferation of astrocytes, 50% inhibition occurring at about 0.52 mm. Acrylamide reduced [(3)H]thymidine incorporation into DNA, but did not affect it when cytosine arabinoside was present. The main cause of the inhibition of astrocyte proliferation may be the suppression of mitosis. Interleukin-1, one of the factors that produce astrocyte proliferation after brain injury, increased [(3)H]thymidine incorporation into DNA in astrocyte cultures. Acrylamide was found to abolish this proliferative effect of interleukin-1 completely. It is suggested that acrylamide may influence the astrocytic response to brain injury and the regenerative process. PMID- 20702341 TI - The cytotoxicity of halothane in isolated hepatocytes: Evidence for two different mechanisms. AB - The effect of halothane on the functional properties of isolated hepatocytes was investigated. Glycogen levels and the oxygen consumption of hepatocytes, isolated from both control and phenobarbital-induced rats, decreased dose-dependently after exposure to halothane, irrespective of the oxygen concentration of the incubation (5, 12 or 95% oxygen and 5% CO(2)). Halothane did not affect albumin synthesis in hepatocytes, but there was a loss of albumin from cells isolated from control rats, after exposure to the anaesthetic. Hepatocytes from phenobarbital-induced rats, incubated under hypoxic conditions, showed an increased production of ethane and thiobarbituric acid reactants, indicating lipid peroxidation. The cytochrome P-450 contents of the hepatocytes from phenobarbital-induced rats were decreased by halothane. All these effects of halothane were detected without observing any effects on the integrity of the cells, as determined by the leakage of lactate dehydrogenase. PMID- 20702342 TI - Effects of mono-(2-ethylhexyl) phthalate and mono-n-pentyl phthalate on the ultrastructural morphology of rat Sertoli cells in Sertoli/germ cell co-cultures: Correlation with the in vivo effects of di-n-pentyl phthalate. AB - The effects of mono-(2-ethylhexyl) phthalate (MEHP) and mono-n-pentyl phthalate (MPP) on the ultrastructure of Sertoli cells in primary co-cultures of rat Sertoli and germ cells has been examined and compared with the in vivo effects of di-n-pentyl phthalate (DPP) on Sertoli cells in the rat. MEHP and MPP produced changes in the configuration of the plasma membrane, resulting in long thin cytoplasmic processes or filopodia. This was accompanied by changes in microfilament distribution and an increased density of ribosomes, smooth endoplasmic reticulum and the Golgi complex. Changes were qualitatively similar for both monoesters, but MEHP was effective at lower concentrations than MPP. In vivo, DPP produced extensive convolutions in the basal plasma membranes separating adjacent Sertoli cells and retraction of the lateral processes surrounding germ cells. The similarity of the membrane changes in vivo and in vitro suggests a comparable response by the Sertoli cell in the two systems. Furthermore, the similarity of the in vitro response to the two monoesters suggests a shared mechanism of toxicity. PMID- 20702343 TI - Transformation of C3H/10T1 2 cells and induction of EBV-early antigen in Raji cells by altertoxins I and III. AB - Moulds of the genus Alternaria are common contaminants of some food crops. Some isolates have been shown to produce mutagenic compounds called altertoxins. Altertoxin I (ATX-I) and altertoxin III (ATX-III) were examined for activity in the Raji cell Epstein-Barr virus early antigen (EBV-EA) induction system and in the C3H/10T1 2 murine fibroblast cell transformation system. Exposure of Raji cells to ATX-I or ATX-III activated EBV-EA expression by 8- and 9.5-fold, respectively. A single exposure of C3H/10T1 2 cultures to ATX-I or ATX-III resulted in significant increases in cell transformation, and the response to ATX I was stronger. Both altertoxins enhanced the transformation of C3H/10T1 2 cells, and chronic exposure of non-initiated C3H/10T1 2 cells to ATX-I and ATX-III, starting 6 days after cells were plated, resulted in cell transformation in 8 59 and 12 37 dishes, respectively, compared with transformation in only 2 63 control dishes. Since activation of EBV-EA in Raji cells has been positively correlated with tumour promoters, these data together indicate that ATX-I and ATX-III are not just mutagens but have a potential role in cell transformation. PMID- 20702344 TI - An interlaboratory evaluation of the Syrian hamster embryo cell transformation assay using eighteen coded chemicals. AB - Eighteen coded chemicals were evaluated in the Syrian hamster embryo (SHE) cell transformation assay in three different laboratories using the same basic experimental protocol with minor modifications. In addition, individual cell and serum sources were selected. Major factors influencing intra-and interlaboratory reproducibility were the source of cells and serum, the toxicity of the chemicals, and the dose-range selected for transformation evaluation. Two or three assays from each laboratory were required to determine the transformation inducing potential of a chemical because of the low number of transformants scored in any single assay and the difficulty of interpreting morphological variations. Rodent carcinogenicity data were available for 16 of the 18 chemicals tested and the transformation response of 14 of those chemicals was in agreement with the rodent carcinogenicity data (if the positive results are adopted for the four chemicals that produced contradictory results). Four rodent carcinogens, di (2-ethylhexyl) phthalate, diphenylhydantoin, methapyrilene hydrochloride and o toluidine hydrochloride, that were negative in the Salmonella/microsome assay, induced morphological transformation in the SHE assay. Although the labour, cost and lack of reproducibility might preclude application of this transformation assay for routine screening, it might, nevertheless, prove valuable for distinguishing between non-mutagenic carcinogens and non-carcinogens. PMID- 20702345 TI - Lipid peroxidation in rat alveolar macrophages exposed to chrysotile fibres. AB - Lipid peroxidation induced in rat alveolar macrophages incubated with chrysotile asbestos fibres was assessed by measuring the production of malondialdehyde. The rapid onset of lipid peroxidation in macrophages caused by these fibres suggests the process occurs during the attachment of the fibres on the macrophage membranes or during the very early steps of phagocytosis. Metal-ion chelators such as diethylenetriaminepentaacetic acid, 1,10-phenantroline and ethylenediaminetetraacetic acid, as well as iron-complexing agents such as bathophenantrolinesulphonate and desferrioxamine were found to substantially inhibit chrysotile-induced lipid peroxidation. These results suggest a possible role for the iron present in the asbestos structure in catalysing lipid peroxidation in alveolar macrophages. These observations also indicate that asbestos-catalysed lipid peroxidation may be one of the factors involved in asbestos-induced cell damage. PMID- 20702346 TI - Toxicity of airborne particulate matter to rat alveolar macrophages: A comparative study of five extracts collected indoors and outdoors. AB - The toxicity of indoor and outdoor air samples to rat alveolar macrophages was determined by studying the phagocytic activity of these cells in vitro. Clean air samples did not affect phagocytosis at concentrations up to 60 m(3)/plate, but polluted outdoor samples caused a dose-dependent inhibition of the phagocytosis at concentrations varying from 6 m(3) to 60 m(3)/plate. Indoor air samples, especially when polluted with wood smoke, affected phagocytosis at concentrations below 2 m(3)/plate. PMID- 20702347 TI - Liposomes as an in vitro model for predicting the eye irritancy of chemicals. AB - Liposomes containing 4-methylumbelliferyl phosphate (Um-P) were prepared using the lipid extracts from bovine eyes and were incubated with seven surface-active agents. The Um-P released from the liposomes by each test agent was hydrolysed with alkaline phosphatase and the resultant 4-methylumbelliferone was assayed spectrofluorometrically. The values for Um-P(50) (the concentration of test material at which 50% of Um-P is released) showed a good inverse correlation with the irritation scores obtained by the Draize eye test. The results suggest that the liposomal assay reported here may be useful as an in vitro model for predicting the eye irritancy of chemicals. PMID- 20702348 TI - In vitro cytotoxicity of deferoxamine on human marrow haematopoietic progenitors. AB - Deferoxamine (DFO), a widely used clinical chelator of ferric iron, was found to inhibit human bone-marrow (BM) stem-cell colony formation as measured by assays on the proliferation of the haematopoietic progenitor cell populations: the granulocyte-macrophage, colony forming unit in culture (CFU-C) lineage and the erythroid lineages-erythroid colony forming unit (CFU-E) and erythroid burst forming unit (BFU-E). DFO (5-20 mum) markedly reduced the proliferation of CFU-C, CFU-E and BFU-E in a dose-dependent fashion, whereas ferrioxamine, the chelated form of DFO, had no effect on colony growth. CFU-E and BFU-E colonies were more sensitive than CFU-C to the growth-inhibitory effect of DFO. The removal of either adherent cells or T lymphocytes or both from the BM did not affect the inhibitory properties of DFO, indicating that DFO interacts directly with the haematopoietic progenitor cells rather than through another cell population. These in vitro findings suggest that DFO may cause myelosuppression if administered to patients whose plasma iron levels are normal or low. PMID- 20702349 TI - Human and rat erythrocyte membranes as a model for studying the effects of organic solvents on membrane-bound acetylcholinesterase in vitro. AB - The effects of toluene, trichloroethylene and ethanol on membrane acetylcholinesterase (AChE) activity in human and rat intact erythrocytes and erythrocyte ghosts were studied in vitro over a range of concentrations (300-3000 ppm) and at three different incubation temperatures (37, 15 and 5 degrees C). Toluene and trichloroethylene decreased the AChE activity in intact erythrocytes and in erythrocyte ghosts in both species. Trichloroethylene had a more marked effect on erythrocyte ghosts than on intact cells. At low concentrations, toluene generally had greater AChE-inhibiting potency than trichloroethylene. At the concentrations studied, ethanol had no effect on AChE activity. The effects of decreases in incubation temperature on solvent-induced AChE inhibition were very variable. We consider both the human and rat erythrocyte membrane to be a good model for studies of the anaesthetic effects of organic solvents on cell membranes. The effects of organic solvents on AChE, an integral component of the cell membrane, may be one of the critical factors determining the membrane effects of organic solvents even in nerve cells. PMID- 20702350 TI - Carbadox-induced inhibition of aldosterone production in porcine adrenals in vitro. AB - Carbadox, a growth promoter used in pig husbandry, inhibited aldosterone production in sliced porcine adrenals in vitro. The adrenal slices, obtained from 3-5-wk-old piglets, were maintained in a Krebs solution and exposed to 1-40 mug carbadox/ml for 1 hr. Aldosterone was estimated (using a solid-phase radioimmunoassay kit) in samples taken hourly for up to 5 hr after carbadox exposure. The results showed a dose-dependent inhibition of aldosterone production by carbadox, with 25-35% inhibition by a concentration of 40 mug/ml. The findings support the hypothesis, based on clinical and histopathological evidence from in vivo experiments in pigs, that carbadox interferes with aldosterone production in the adrenal zona glomerulosa. PMID- 20702351 TI - Comparisons of two in vitro cytotoxicity assays-The neutral red (NR) and tetrazolium MTT tests. AB - The neutral red (NR) and tetrazolium MTT in vitro cytotoxicity assays were compared for 28 test agents of widely varying potency using the BALB/c mouse 3T3 fibroblast cell line as the bioindicator. For any given cell density in the microtitre plate well, the optical density absorbance with the NR assay was about twice that obtained with the MTT assay. However, there was good agreement (r = 0.939) between the ranking of the test agents on the basis of midpoint cytotoxicity values (NR(50) and MTT(50)), although the assays were based on different physiological endpoints. Nevertheless, the two assays were found to differ in sensitivity for a few test agents, such as chloroquine sulphate and several antineoplastic drugs. Both assays were capable of demonstrating a reduction in the cytotoxicity of methotrexate by leucovorin. PMID- 20702352 TI - An in vitro model for identifying skin-corrosive chemicals. I. Initial validation. AB - An in vitro epidermal slice technique has been developed for identifying chemicals with the potential to cause a corrosive lesion in animal skin in vivo. Skin-corrosive potential has been correlated with the ability to reduce the skin's penetration barrier by lysis of the stratum corneum. This effect was measured as a lowering of the electrical resistance of an epidermal slice following chemical contact in vitro. An initial validation with 68 chemicals showed the technique to have a high sensitivity for corrosive chemicals. The model has potential as a pre-screen for conventional animal tests and, in contrast to in vivo screening methods, has the advantage of providing quantitative and objective data. PMID- 20702353 TI - Classification as corrosive or irritant to skin of preparations containing acidic or alkaline substances, without testing on animals. AB - A method is proposed by which substances or preparations may be classified as irritant or corrosive to skin, without being tested on animals, when the irritant or corrosive properties are due to the acidity/alkalinity of the substances or preparations. Results from the application of this approach to a range of commercial cleaning/maintenance/detergent preparations are in good overall agreement with results based on patch testing in rabbits. Variations in the results obtained from analysis of pH and acid/alkali data were no greater than might be expected from variations in results from animal test methods. It is stressed that this approach may not be applicable to preparations containing non acidic/non-alkaline corrosive or irritant substances, and it cannot be used to classify other aspects of the toxicology of preparations or their ingredients. An official proposal for a calculation method based on concentration limits for corrosivity or irritancy gives similar results, but is limited in application by the lack of identified concentration limits. PMID- 20702354 TI - Metabolism of alternariol monomethyl ether by porcine liver and intestinal mucosa in vitro. AB - The in vitro metabolism of alternariol monomethyl ether (AME) was investigated in intestinal mucosa and liver samples from gilts. Homogenized tissue samples were incubated with AME in the presence of NADPH, UDPGA or glutathione. The results indicate that conjugation with glucuronic acid is the predominant metabolic route of AME in the gilt. This occurs to a greater extent in the intestinal mucosa than in the liver (65.7 +/- 25.3 and 5.0 +/- 3.3 nmol AME conjugated/mg protein/hr, respectively). Demethylation of AME to alternariol (AOH) was a minor metabolic route, occurring only in liver in the presence of NADPH (0.31 +/- 0.26 nmol AOH formed/mg protein/hr). No glutathione conjugation of AME was found in this investigation. PMID- 20702355 TI - Differential effects of raising and lowering intracellular glutathione levels on the cytotoxicity of allyl isothiocyanate, tert-butylhydroperoxide and chlorodinitrobenzene. AB - The influence of intracellular glutathione (GSH) on cytotoxicity was studied in vitro by altering the intracellular GSH level of Chang liver cells. Lowering the GSH level was achieved by treating cells with diethyl maleate (155 mum), while the intracellular GSH level was raised by cellular incubation with the monoethyl ester of glutathione (20 mm). The cytoxicity of three compounds that are known to react differently with GSH was tested using the cloning efficiency assay. Allyl isothiocyanate reacts reversibly with GSH and in previous work it was shown that the toxicity of the GSH conjugate was due to the release of the free isothiocyanate. In this study we found that changing the intracellular GSH level had no influence on the cytotoxicity of this compound. This points to the cell membrane as the primary target, although the possibility of GSH being involved as a transporting agent cannot be completely excluded. Chlorodinitrobenzene conjugates easily with GSH, and in bacterial assays it was found that depletion of intracellular GSH enhanced the mutagenic effect. After raising the intracellular GSH level in Chang cells this compound was found to be more toxic, and after lowering the GSH level less toxicity was found, indicating a role for GSH in the activation of chlorodinitrobenzene. For comparison tert butylhydroperoxide was chosen, because it is known to be detoxified by GSH. Lowering the intracellular GSH level did indeed result in higher cytotoxicity, but after elevating the GSH level no increase in cloning efficiency was observed, indicating that there are more factors involved in tert-butylhydroperoxide cytotoxicity. PMID- 20702356 TI - Effects of isobutyl 2-cyanoacrylate polymer on cultured cells derived from murine cerebral microvessels. AB - The initial and delayed effects of isobutyl 2-cyanoacrylate (IBCA) polymer on cells cultured from the wall of mouse cerebral microvessels were examined using a simple cytotoxicity assay. Cell cultured media were conditioned by exposure to IBCA polymer for 24-hr periods over the 15 days following polymerization and the media were then added to confluent endothelial or smooth muscle cell monolayers. The resulting cell detachment was assessed as a measure of cytotoxicity. The results indicated that immediately or a few days after polymerization and at approximately 12-13 days after polymerization, IBCA released material(s) that caused significant cell detachment from cell monolayers. This finding may explain some of the observed toxic effects of IBCA, particularly on vascular lesions within the brain. This simple bioassay may be used to study early and delayed effects of other potential embolotherapy materials on components of the blood vessel wall. PMID- 20702357 TI - Perturbations of cellular functions integral to neural tube formation by the putative teratogen sodium valproate. AB - The effect of therapeutic concentrations of sodium valproate (VPA) on the cell acquisition rate and adhesive properties of glioma (C6) and neuroblastoma (Neuro 2a) cell lines was evaluated. VPA impaired the mitotic rate in neuroblastoma and glioma cells with an IC(50) value of approximately 1.0 mm, and with no apparent cytotoxicity. Using a centrifugal shear adhesion assay the glioma cells showed a 2.5-fold increase in cell-substratum adhesivity at VPA concentrations of 1 mm. This effect could not be demonstrated in the neuroblastoma cell line as these cells were inherently more adhesive than the glioma cells. However, the neuroblastoma cells assumed a differentiated phenotype when cultured in the presence of 1 mm-VPA and extended numerous fibres with branching points. These findings are related to the ability of VPA to induce neural tube defects. PMID- 20702358 TI - Barium cardiotoxicity: Relationship between ultrastructural damage and mechanical effects. AB - The ultrastructural damage in guinea-pig ventricular strips caused by barium was analysed. At a concentration of 1 mmol/litre, barium chloride caused a dramatic increase in the developed tension associated with the onset of automaticity. The ultrastructural analysis demonstrated that barium caused notable and consistent alterations which affected most myocyte components. Various degenerative aspects were observed in mitochondria and in the contractile apparatus. Glycogen deposits were completely depleted. Preparations driven at 4 Hz (i.e. the rate of spontaneous firing of barium-treated preparations) showed moderate ultrastructural alterations, thus demonstrating that the increase in the rate of beating is not the only determinant of the observed damage. These results suggest that the myocardial toxicity of barium is due not only to the well-known modifications in membrane permeability, but possibly also to alterations in cell function. PMID- 20702359 TI - Translocation of cadmium from cytosol to membrane fraction in cadmium-loaded red blood cells of rats. AB - When rat red blood cells were incubated in a cadmium (Cd)-free medium for up to 14 hr following a 1-hr treatment with 0.5 mm-CdCl(2), the incorporated Cd, which was predominantly in the cytosol at the beginning of the incubation, progressively accumulated in the membrane fraction. In parallel with the Cd accumulation, several cytosolic proteins including haemoglobin increased in the membrane fraction, resulting in an increase in the protein to phospholipid ratio of the membrane fraction. The membrane fraction was solubilized with sodium deoxycholate and analysed by gel-filtration chromatography. Cd was detected in the high-molecular-weight fraction containing membrane proteins at the beginning of incubation, and the Cd content of this fraction did not alter appreciably during the incubation. On the other hand, Cd in the low-molecular-weight fraction, where haemoglobin is most abundant, increased progressively during the incubation. The Cd-binding capacity of proteins in the membrane fraction was assessed by (109)Cd-autoradiography using the western blotting technique. In addition to membrane proteins, haemoglobin and other cytosolic proteins, which increased in the membrane fraction during the incubation, exhibited a significant ability to bind Cd. These results indicate that Cd, once incorporated into red cell cytosol, progressively accumulates in the membrane fraction together with cytosolic proteins with Cd-binding capacity. This accumulation of Cd-cytosolic proteins may affect the membrane properties of red blood cells. PMID- 20702360 TI - Absence of chromosome damage in Chinese hamster ovary cells exposed to detergents. AB - No increase in chromosome aberrations was detected in cultured Chinese hamster ovary cells exposed to cytotoxic concentrations of three detergents. The absence of an effect in these studies appears to be inconsistent with the view that the clastogenic effect of some surface-active compounds may be mediated through the liberation of lysosomal enzymes. PMID- 20702361 TI - Metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline IQ and 2-amino-3,4 dimethylimidazo[4,5-f]quinoline (MeIQ) in suspensions of isolated rat-liver cells. AB - Suspensions of rat-liver cells metabolized (14)C-labelled 2-amino-3 methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5 f]quinoline (MeIQ) to metabolites that were ethyl acetate extractable, water soluble or covalently bound to macromolecules. The major ethyl acetate extractable metabolite(s) had a retention time on the high-performance liquid chromatograph (HPLC), an ultraviolet spectrum and an R(f) value on the thin-layer chromatograph that corresponded to those of the N-acetylated derivative. Relatively more of this metabolite was formed from MeIQ than from IQ. In contrast, IQ was more easily converted to water-soluble metabolites than was MeIQ. The amount of covalently bound metabolite(s) found with MeIQ as test substance was larger than that found with IQ. No major increase in the ethyl acetate-extractable metabolites was obtained after incubation of the aqueous phase with beta-glucuronidase or aryl sulphatase in comparison with untreated controls. HPLC analysis showed that after acid hydrolysis of the water-soluble metabolites, about 55 and 20% of the hydrolysed metabolites had retention times that were the same as those of IQ and MeIQ, respectively. The ratio between covalently bound (activated) metabolites and water-soluble (detoxified) metabolites was larger for MeIQ than for IQ. From these data, one would expect MeIQ to be more potent than IQ as a liver carcinogen in male rats. PMID- 20702362 TI - Differential effects of tumour promoters on the growth of normal human bronchial epithelial cells and human lung tumour cell lines. AB - The effects of the tumour promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) on the colony-forming efficiency and growth of normal human bronchial epithelial (NHBE) cells and five lung squamous carcinoma cell lines were compared in medium containing 1% foetal bovine serum. TPA (0.1-5.0 ng/ml) inhibited the growth of NHBE cells and one carcinoma cell line, while four of the five carcinoma lines were less sensitive to the growth inhibitory properties of TPA but were slightly inhibited at higher TPA concentrations. The responses of NHBE cells and carcinoma cells to TPA, and the related compounds, mezerein, 4-O-methyl TPA, and phorbol were then compared in serum-free medium. In general, the removal of serum from the medium increased the differences in the responses to TPA between normal and tumour cells. Two carcinoma lines inhibited by TPA in 1% serum were stimulated by TPA in the absence of serum. Mezerein and, to a lesser extent, 4-O-methyl TPA also produced differential responses in colony-forming efficiencies between tumour lines and NHBE cells. Phorbol had no effect on either NHBE cells or on carcinoma cell lines. The relative insensitivity of carcinoma cell lines to the growth inhibitory effects of tumour promoters is consistent with the hypothesis that tumour promotion involves selection against normal cells to permit clonal expansion of preneoplastic or neoplastic cell types. PMID- 20702363 TI - A method for accelerating progression to a malignant phenotype in rodent cells. AB - This report describes a system of suspension culturing that enhances the expression of transformed cells in carcinogen-treated rodent cells and decreases the time required to observe clear evidence of the neoplastic or malignant phenotype by 2-8 wk or more. Retrovirus-infected Fischer rat embryo cells, uninfected Balb/c 3T3 mouse cells and Syrian hamster embryo cells in monolayer culture were treated with the chemical carcinogens, dimethylbenzanthracene, benzo[a]pyrene or N-methyl-N'-nitro-N-nitrosoguanidine, following a protocol appropriate to each cell type. The cultures were divided into two groups, one seeded directly onto a plastic surface, and the other suspended in liquid medium over agar before seeding onto a plastic surface. In all three cell types incluson of the suspension phase accelerated chemically induced transformation as indicated by clonogenicity in soft agarose (rat, mouse and hamster cells) and by morphological transformation and formation of tumours in athymic nude mice (hamster cells). PMID- 20702364 TI - A selection procedure for the rapid expression of carcinogen-induced malignant transformation of retrovirus-infected Fischer rat embryo cells. AB - This study evaluates a procedure that accelerates the expression of the transformation of retrovirus-infected Fischer rat embryo cells. The endpoints used were anchorage-independent growth (formation of colonies in soft agarose) and formation of foci on a contact-inhibited monolayer. The cells were treated in monolayer with chemical, solvent (negative control) or medium alone for 3 days; then the chemical was removed and the cultures re-fed with medium alone for an additional 3 days. Cells in monolayer were disaggregated, suspended in liquid medium over solid agar for 4 days, disaggregated again and seeded into monolayer. After 2-4 wk without additional subculturing, cells from monolayer were seeded in soft agarose. Suspension of retrovirus-infected rat embryo cells above agar after chemical treatment resulted in rapid expression of neoplastic phenotypes. Cells treated in monolayer with the carcinogens, benzidine dichloride, dimethyl benzanthracene, 4,4-oxydianiline, 4-nitroquinoline-N-oxide and N-methyl-N'-nitro N-nitrosoguanidine demonstrated colony formation in soft agarose or morphological transformation within 2-4 wk after being held in suspension for 4 days. In addition two carcinogens, benzo[a]pyrene and N-2-acetylaminofluorene and two noncarcinogens, benzo[e]pyrene and N-4-acetylaminofluorene did not induce neoplastic changes in this time period. The suspension technique may be a useful modification of this assay because it selectively amplifies neoplastic transformation after treatment with a number of chemicals. PMID- 20702365 TI - DNA and protein contents of hepatocytes in primary cultures monitored by flow cytometry: Effect of phenobarbital and dimethylsulphoxide. AB - Primary rat hepatocyte cultures were analysed by two-parameter flow cytometry (FCM) analysis. The simultaneous highly reproducible measurements of DNA and protein contents of hepatocytes showed a high resolution and allowed individual ploidy classes to be monitored during culture. Among both the 2N- and 4N-cell populations of freshly isolated hepatocytes two subpopulations were detectable by their different protein contents. From day 1 to day 7 in culture, the relative contributions of the 2N-, 4N- and 8N-cell populations remained more or less unchanged. The protein content decreased with prolonged culture time to 30% of the original level at day 7. The subpopulations within the 2N- and 4N-cells were no longer detectable. After chronic treatment with phenobarbital (PB, 3 mm), cell detachment was reduced. The contributions of the 2N- and 8N-cell populations decreased whereas that of the 4N-cell population increased. Furthermore, compared to untreated cultures, the cellular protein content was enhanced in all ploidy classes. These PB-induced effects in vitro reflect the hyperplastic and hypertrophic activities of PB that have been observed in vivo. FCM data are compatible with the hypothesis that phenobarbital exerts its tumour promoting activity in vivo by an inhibition of apoptosis. After chronic exposure to dimethylsulphoxide (DMSO, 2%, v/v), a reduction only in the 2N-cell population but an increase in the 8N-cell population was found. The protein content of individual hepatocytes was not enhanced. It seemed that DMSO stabilizes liver cells in vitro at a level that corresponds to the adult stage in vivo. DNA/protein FCM analysis was an efficient tool which was suitable to describe the dynamics of the reactions of hepatocytes in culture after nontoxic, chronic exposure to the growth and differentiation modifying drugs PB and DMSO. PMID- 20702366 TI - Background DNA repair synthesis in rat hepatocyte cultures used for genotoxicity testing. AB - DNA repair synthesis in primary rat hepatocyte cultures (HPC) was investigated using the bromodeoxyuridine (BrdUrd) density-shift method and autoradiography. Analysis by density-gradient centrifugation of DNA labelled with BrdUrd and [(3)H]deoxycytidine ([(3)H]dCyd) for 18-20 hr showed that considerable DNA repair replication occurs in HPC even in the absence of an added genotoxic agent. Repair was demonstrated to be most probably a consequence of DNA damage caused by the collagenase perfusion of the liver during hepatocyte isolation, and by beta-decay of the (3)H-labelled DNA precursor. Autoradiographic analysis of the distribution of silver grains over nuclei in intact non-S-phase cells, and over isolated nuclei from HPC exposed to [(3)H]dCyd for 18-20 hr, showed that the vast majority of the radioactivity was incorporated into the nuclei themselves, and not into overlying cytoplasm or mitochondria. In addition, direct localization of mitochondria in hepatocytes using the mitochondrion-specific dye rhodamine 123 showed that very few mitochondria were actually located over the nucleus. The results suggest that cytosolic labelling of control HPC in autoradiographs is mainly caused by mitochondrial DNA synthesis whereas nuclear labelling essentially reflects repair synthesis. They call into question the commonly applied practice of evaluating unscheduled DNA synthesis (UDS) in HPC by subtracting the number of cytosolic silver grains from nuclear grains and expressing repair synthesis as net grains per nucleus. PMID- 20702367 TI - In vitro embryotoxicity and teratogenic potential of etretinate and etretin. AB - The embryotoxicity and teratogenic potential of etretinate and its main metabolite, etretin, with or without enzymatic drug activation, were investigated in vitro using the rat whole embryo culture system. The metabolizing system used was either a rat liver homogenate (S-9 mix) or esterase (carboxylic-ester hydrolase). Groups of 8-14 rat embryos (explanted on day 9.5 of pregnancy) were cultured for 48 hr with 0, 3, 10, 30 or 100 mug etretinate/ml with or without S-9 mix, or with 0, 0.03, 0.1, 0.3, 1, 3 or 10 mug etretinate/ml in the presence of 0.5 or 1 U esterase/culture flask. Yolk-sac diameters and vascularization and crown-rump and head lengths were unaffected by etretinate treatment alone but somite numbers and morphological scores were reduced at 30 and 100 mug etretinate/ml. The number of embryos with morphological anomalies was increased in the presence of 10 mug etretinate/ml but not significantly so. At higher concentrations the incidence of embryos with anomalies was 100%. Activation of etretinate in the presence of S-9 mix led to increased teratogenic activity of the test compound in vitro, although embryonic crown-rump and head lengths were comparable to control measurements up to the highest concentrations tested. When it was co-incubated with esterase, etretinate became 100 times more active, and its effects occurred in the same concentration range as the embryotoxic effects of etretin added to the culture directly. Without activation etretinate was approximately 100 times less active than etretin in producing general embryotoxicity as well as anomalies in the in vitro culture. The anomalies found after in vitro exposure of rat embryos to etretinate or etretin in this study resembled to a great extent the malformations found in vivo in several species including man. The pattern of anomalies was specific for the compounds used and was similar to that induced by other retinoids. The concentrations of etretin eliciting teratogenic effects in vitro were in the range of etretin peak plasma levels during etretinate therapy in man. Our results indicate that the whole embryo culture system is a sensitive and valuable model for assessing the embryotoxic and teratogenic potential of retinoids in vitro. PMID- 20702368 TI - Stimulating effect of methylmercury chloride on [(3)H]acetylcholine release from guinea-pig striatal slices. AB - The effect of methylmercury (MeHg) chloride on the release of [(3)H]acetylcholine ([(3)H]ACh) was examined using guinea-pig striatal slices. When the Hg concentration in the striatal slices was less than 10 ppm, MeHg chloride had no effect on spontaneous [(3)H]ACh release. However, electrically evoked release of [(3)H]ACh was significantly increased when the tissue Hg concentration was between 0.08 and 3 ppm and was about 160% of the control value at around 0.7 ppm. The increase in evoked ACh release induced by MeHg chloride at low tissue concentrations was partly due to inhibition of the re-uptake of choline. These results suggest that MeHg chloride-induced hyperactivation of cholinergic transmission may be involved in some of the early signs of mercury intoxication. PMID- 20702369 TI - Membranolytic activities of quartz standards. AB - The membranolytic activity of ten quartz specimens, determined quantitatively as the percentage of erythrocytes lysed as a function of mineral concentration, varied by up to 100 times depending on particle size, method of size reduction, thermal treatment, dispersal in the experimental system, and quartz variety. Five specimens that are currently used as standard fibrogenic dusts in pneumoconiosis research laboratories were obtained as fine powders. Two other specimens obtained as large single crystals and three additional ones obtained as massive crystalline specimens required pulverization before testing. The specimens were studied as size-heterogeneous powders, and after fractionation into narrow size bands. The membranolytic activity of the size fractions increased by an average of 30 times as the Stokes' diameter of the particles decreased from 20 to 1 mum. The five specimens that were reduced to powders in a carborundum mortar and pestle lost activity after hydration in the water-fractionation process. When these inactive quartz specimens were heated to 400-500 degrees C for 6 hr, their activities were restored. The active and inactive quartz specimens were indistinguishable by electron microscopy, powder X-ray diffraction and optical microscopy. The physico-chemical properties of quartz are variable and therefore the mineral's biological potential varies considerably. PMID- 20702370 TI - Cytogenetic damage induced in human lymphocytes by adriamycin and vincristine: A comparison between micronucleus and chromosomal aberration assays. AB - A quantitative comparison was made between the induction of micronuclei and of chromosomal aberrations in human lymphocytes using a clastogen (adriamycin) and a non-disjunctional agent (vincristine) as model compounds. Cytochalasin B, an inhibitor of cytokinesis, was used to make it possible to evaluate the frequency of micronuclei only in cells that had divided after the treatment. The results showed that for the assessment of clastogenic damage due to adriamycin, the sensitivity of the micronucleus assay was comparable to that of conventional chromosomal analysis. For the non-disjunctional effect of vincristine, the micronucleus assay was much more sensitive than conventional chromosomal analysis. PMID- 20702371 TI - Editorial. PMID- 20702372 TI - Structure-activity relationship (SAR) models established in vitro with the neutral red cytotoxicity assay. AB - The neutral red (NR) cytotoxicity assay has been applied to the determination of structure-activity relationships (SARs). The in vitro cytotoxic potency of a series of alcohols with varying chain lengths, of chlorinated phenolics, of nitro and methyl-containing phenolics and of chlorinated toluenes could be directly correlated with the lipophilicity of the molecules, expressed in terms of their log octanol/water partition coefficients (log P values). Dinitrotoluenes were outliers, in that their cytotoxicity was not a function of their lipophilicity. The sequence of cytotoxicity for a series of divalent cationic metals was a function of softness: the softer the metal (i.e. the lower its chemical softness parameter, sigma(p)), the greater its cytotoxicity. The SAR models developed with the NR assay were consistent with similar models developed in vivo. The NR assay has been further modified to include, when useful, total protein determinations. PMID- 20702373 TI - Teratogenicity in vitro-A comparative study of four antimycotic drugs using the whole-embryo culture system. AB - The embryotoxic effects caused in vitro by the four antimycotic compounds griseofulvin, ketoconazole, naftifine and terbinafine were compared. Rat embryos (9.5 days old) were cultivated in rat serum for 48 hr both in the presence and in the absence of the individual test compounds. A rat liver microsomal preparation and NADPH were added to the cultures. Effects on growth and differentiation were evaluated and dysmorphogenic effects on various embryonic features were recorded. The compounds could be ranked as follows: in terms of the concentrations that affected growth in vitro, griseofulvin = naftifine = ketoconazole < terbinafine, and, with regard to retarded differentation, griseofulvin = ketoconazole = naftifine < terbinafine, while for morphological findings, ketoconazole < griseofulvin = naftifine < terbinafine. The ratio between the concentration affecting rat embryonic morphology in vitro and the human peak plasma levels after multiple drug application was approximately 0.2 for ketoconazole, 3 for griseofulvin, 20 for terbinafine and 2000 for naftifine. The results of this study verified that this in vitro system can be used to classify test compounds according to their embryotoxic effects. The findings reported here were in agreement with those of in vivo studies. In both systems, ketoconazole and griseofulvin had relatively high teratogenic potential and terbinafine and naftifine had none. PMID- 20702374 TI - Use of continuous culture to study the gastric microflora of a hypochlorhydric patient. AB - A method of maintaining the microflora obtained from the hypochlorhydric stomach of a patient suffering from hypogammaglobulinaemia has been developed using continuous culture (chemostat) techniques. The culture was maintained at pH 8.0 (the pH of the original gastric juice) and subsequently at pH 7.0 and pH 6.0. Throughout the experiment the total population of the culture remained constant, although the populations of individual bacterial strains varied. Two enzyme parameters, nitrate reductase and beta-glycosidase, were also measured. Optimal enzyme activity was observed at pH 7.0. The results suggest that at the physiological pH values found in hypochlorhydric patients, the gastric flora may play a role in the generation of genotoxins and/or their precursors. PMID- 20702375 TI - Cephaloridine toxicity in primary cultures of rat renal cortical epithelial cells. AB - Primary cultures of rat renal cortical epithelial cells were used to assess the in vitro nephrotoxicity of cephaloridine (Cph). Several different indices were used to follow the course of Cph-induced nephrotoxicity in the cultures. Plasma membrane integrity was determined by the effect of Cph on lactate dehydrogenase (LDH) leakage, cellular K(+) content and plasma membrane Na(+)/K(+) ATPase activity. Significant LDH leakage and decreased cellular K(+) content occurred after 8 hr of exposure to Cph. Na(+)/K(+) ATPase activity was depressed as early as 4 hr after Cph treatment. Brush border integrity was assessed by the effect of Cph on the activity of the brush border enzyme alkaline phosphatase, which was significantly decreased following 12 hr of exposure to Cph. Treatment with Cph resulted in an initial elevation of cellular glutathione (GSH)-as indicated by cellular non-protein sulphydryl content-followed by a decrease in GSH content 16 hr later. The mitochondrial response to Cph was assessed by determining mitochondrial succinate dehydrogenase (SDH) activity and cellular ATP content. SDH activity was significantly depressed after 4 hr of Cph exposure; ATP content was not significantly depressed until 12 hr after treatment. The time course of Cph-induced injury in our culture system suggests that early injury involves alterations at the level of the mitochondrial membrane and the plasma membrane. The most sensitive indicators of Cph-induced toxicity in this system were mitochondrial SDH activity and plasma membrane Na(+)/K(+) ATPase activity. PMID- 20702376 TI - Toxicity and metabolism of 1,3-dinitrobenzene in rat testicular cell cultures. AB - The testicular toxicity of 1,3-dinitrobenzene (DNB) has been modelled in primary cultures of rat testis. The morphological response obtained in vitro following direct addition of the compound to the cultures was analogous to that seen in vivo. This was characterized by Sertoli cell vacuolation and germ cell detachment. The effect could be quantified using germ cell exfoliation into the culture medium, with a significant response occurring at toxicologically relevant concentrations of DNB (5 x 10(-6)m and above). Both Sertoli-germ cell co-cultures and Sertoli cell cultures were shown to be capable of xenobiotic metabolism, with nitroreduction of DNB being the predominant route. It is postulated that DNB or a Sertoli cell metabolite (probably an intermediate of nitroreduction produced in situ) is responsible for the testicular damage observed following administration of the compound in vivo. PMID- 20702377 TI - Attenuation of ethanol toxicity in primary myocardial cell cultures from offspring of swim-trained pregnant rats. AB - Primary myocardial cell cultures were obtained from 3-5-day-old offspring of Sprague-Dawley rats (dams) that were swim-trained during pregnancy. Lactate dehydrogenase (LDH) release, succinate dehydrogenase (SDH) activity, beating rates and morphology were examined after treatment of these cultures with ethanol concentrations of 600, 800 and 1000 mg/100 ml for 1, 4 or 24 hr. In these cultures, ethanol exposure had no effect on SDH activity, and LDH release was only observed after 24-hr exposure to the higher concentrations of ethanol. Vacuolization and granulation occurred only in cultures exposed to 1000 mg ethanol/100 ml for 4 or 24 hr and complete loss of beating was observed only after 24-hr exposure to 1000 mg/100 ml. In a previous study (Butler et al. Toxicology 1985, 36, 61-70), the same parameters of toxicity were examined in myocardial cell cultures derived from offspring of sedentary dams; the latter cultures exhibited extensive toxic effects on LDH release, SDH activity, morphology and beating activity within shorter times and with lower concentrations of ethanol. Thus, in this exercise study, patterns of ethanol toxicity were established and the data obtained suggest that maternal swim training during pregnancy induces adaptations in the primary myocardial cells from the offspring, resulting in temporal protection from ethanol-induced damage. PMID- 20702378 TI - Activation of mutagenic and carcinogenic heterocyclic amines by S-9 from the liver of a rhesus monkey. AB - The mutagenicity of a series of heterocyclic amines isolated from various cooked foods and from pyrolysates of amino acids and protein was assayed in Salmonella typhimurium TA98 in the presence of an S-9 fraction prepared from the liver of an untreated male rhesus monkey (Macaca mulatta). All the compounds showed mutagenicity, which ranged from 1 to 2500 revertants/mug chemical/mg S-9 protein. 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) showed the highest specific mutagenic activity, followed by 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4,8 trimethylimidazo[4,5-f]quinoxaline 4,8-DiMeIQx, 3-amino-1-methyl-5H-pyrido[4,3 b]indole (Trp-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 2 amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-6-methyldipyrido[1,2 a:3',2'-d]imidazole (Glu-P-1) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC). 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) and 2-aminodipyrido[1,2 a:3',2'-d]imidazole (Glu-P-2) also showed definite but weak mutagenicity. When compared with previously reported data, these specific mutagenic activities were very close to those of some heterocyclic amines assayed with the S-9 of human liver, slightly lower than those determined with the S-9 of untreated rat liver and much lower than those determined with S-9 from the liver of the untreated hamster or mouse. Most of the heterocyclic amines tested in this experiment have shown carcinogenicity in mice and rats. The experimental results now reported suggest the possible carcinogenicity of these heterocyclic amines in primates as well, including humans. PMID- 20702379 TI - Lack of di-(2-ethylhexyl) phthalate activity in the C3H 10T 1 2 cell transformation system. AB - The widely used plasticizer and rodent carcinogen di-(2-ethylhexyl) phthalate (DEHP) was examined for activity in the C3H 10T 1 2 murine fibroblast cell transformation system. Treatment with DEHP or its metabolite, mono-(2-ethylhexyl) phthalate, did not produce oncogenic transformation, initiate the process of transformation in cultures treated with a tumour promoter or promote the process of transformation in cultures pretreated with a chemical carcinogen. These findings are consistent with the suggestion that the carcinogenicity of DEHP is mediated by an indirect mechanism and not by covalent interaction of DEHP with DNA. PMID- 20702380 TI - Increase in chromosomal abnormalities in Chinese hamster ovary cells treated with butylated hydroxytoluene in vitro. AB - Cytogenetic studies showed that treatment of Chinese hamster ovary (CHO) cells with 1, 5 or 10 mug BHT/ml for 48 hr increased the number of cells with chromosomal abnormalities. CHO cultures treated with 1.0 mug BHT/ml demonstrated a 35% level of abnormal cell types. These abnormalities included chromosome gaps, triradials, polycentrics, endoreduplications and polyploids. When CHO cells were exposed to 5.0 mug BHT/ml, 36% of the cells were found to be abnormal. However, in cells treated with 10 mug BHT/ml, a 20% level of cell abnormalities was noted. The incidence of polyploid cells was dose dependent, but the dose dependency ceased at 10 mug BHT/ml, at which a decrease in polyploids as well as in the total percentage of abnormal cells was observed compared with the cells exposed to lower concentrations of BHT. PMID- 20702382 TI - Time to re-evaluate gender segregation in athletics? AB - The case of Caster Semenya provides a vivid illustration of the ways in which natural genetic variation can generate large differences in athletic performance. But since we normally segregate athletic sports along the lines of this particular variation-gender-her case also highlights problems with the current approach to justice in sporting competition. Female athletes seem to have a valid complaint when they are made to compete against athletes who are, in one sense or another, male. But once we recognise that gender is not a binary quantity, sex segregation in competitive sport must be seen as an inconsistent and unjust policy, no matter what stance we take on the goals of sport or on the regulation of doping. PMID- 20702387 TI - Coeliac disease and type 1 diabetes: 7 years experience versus NICE guidance 2009. PMID- 20702388 TI - Seroprevalence of Borrelia IgG antibodies among young Swedish children in relation to reported tick bites, symptoms and previous treatment for Lyme borreliosis: a population-based survey. AB - BACKGROUND: Lyme borreliosis (LB) is the most common tickborne infection in Sweden and the seroprevalence of Borrelia immunoglobulin G (IgG) antibodies varies between 2% and 26%. The seroprevalence in young Swedish children is unknown and the relation to clinical data has not been previously studied. OBJECTIVE: To determine the seroprevalence of Borrelia IgG antibodies in serum of young Swedish children and to relate it to gender, geographical location, reported tick bites, symptoms and previous treatment for LB. METHODS: 2000 healthy 5-year-old children (n=2000) were randomly selected from among participants of a larger prospective population-based study, the ABIS (All Babies in Southeast Sweden) study. Serum samples were collected and a Borrelia specific ELISA test (Dako) were performed for IgG antibody detection. Clinical data were collected from questionnaires completed by the parents. RESULTS: The seroprevalence of Borrelia IgG antibodies was 3.2% (64/2000). Previous tick bite had been noted in 66% of these seropositive children but the majority (94%) had not previously been treated for LB. In addition, another 55 children reported a history of LB but were negative to Borrelia IgG antibodies in serum. Many of these seronegative children had received treatment for erythema migrans (n=24), which is a clinical diagnosis. Whether children were correctly treated or overtreated for LB is however unknown. No differences in gender, geographical location or reported tick bites were found when comparing Borrelia-seropositive children (n=64) and seronegative children with previous LB (n=55). CONCLUSION: This population-based study demonstrates a Borrelia IgG antibody seroprevalence of 3.2% in young Swedish children. Very few of these seropositive children report previous symptoms or treatment for LB. Thus the findings suggest that exposure to the Borrelia spirochaete (with subsequent antibody response in serum) does occur in young children, mostly without giving rise to clinical LB. Future studies on cell-mediated immune responses are needed to investigate explanatory immunological mechanisms. PMID- 20702389 TI - Lest we forget... research ethics in children: perhaps onerous, yet absolutely necessary. PMID- 20702390 TI - Prescribing in a pandemic: best use of oseltamivir in paediatric intensive care. PMID- 20702391 TI - Electrical stimulation accelerates motor functional recovery in the rat model of 15-mm sciatic nerve gap bridged by scaffolds with longitudinally oriented microchannels. AB - BACKGROUND: Electrical stimulation (ES) can enhance the regenerative capacity of axotomized motor and sensory neurons. However, the impact of ES on axonal regeneration and functional recovery has not been investigated in an animal model of a lengthy peripheral nerve defect. OBJECTIVE: To determine whether ES accelerates axonal regeneration and functional recovery of a 15-mm sciatic nerve defect in rats. METHODS: A 15-mm excision of the sciatic nerve was bridged with a chitosan scaffold with longitudinally or randomly oriented pores or with autologous grafting of the segment. In half of the animals with chitosan grafts, the proximal nerve stump was electrically stimulated for 1 hour at 20 Hz immediately after the nerve repair with the scaffolds. Axonal regeneration was investigated by retrograde labeling and morphometric analysis. The rate of motor functional recovery was evaluated by electrical nerve stimulation, behavioral tests of stepping, and histological appearance of the target muscles. RESULTS: Axonal regeneration and motor functional recovery were improved by ES in animals that received longitudinal pore grafts as compared with others. The maximal number of axons that regenerated across the longitudinal graft was achieved 2 to 4 weeks earlier in rats with ES. In addition, the latency of compound muscle action potentials (CMAPs), the peak amplitude of CMAPs, and nerve conduction velocity were improved by ES. Stepping indices were better, with less atrophy of target muscle in ES rats managed with longitudinal pores. CONCLUSION: Brief ES may accelerate axonal regeneration and motor recovery after focal peripheral nerve transection when repaired with optimally tissue-engineered grafts. PMID- 20702392 TI - Recovery of the sit-to-stand movement after stroke: a longitudinal cohort study. AB - BACKGROUND AND OBJECTIVE: To present quantitative data on sit-to-stand (STS) related functioning and recovery during the first year after stroke. STS-related functioning was used to evaluate independent STS movement, rising speed, and actual STS performance during normal daily life. METHODS: This was a prospective cohort study of 50 patients poststroke. Assessments were made at 0, 3, 6, 9, 12, 24, and 48 weeks poststroke. Actual STS performance was assessed at 0, 12, and 48 weeks. The main outcome measures were the following: ability to rise independently, rising speed (power chair stand up), number of STS movements, percentage of time walking and standing during daily life (using an activity monitor), and clinical outcomes, measured among others by the Barthel index (BI). RESULTS: During year 1, the percentage of patients able to rise increased from 54% to 83%. Most improvements occurred during weeks 0 to 12, whereas no significant changes were observed during weeks 12 to 24. Rising speed similarly increased from 0.15 to 0.26 s(-1) during weeks 0 to 12 and to 0.30 s(-1) at week 48. Gait speed and BI also significantly increased. The number of STS movements increased significantly during weeks 0 to 12 (from 10.6 to 17.7) but not during weeks 12 to 48. CONCLUSIONS: STS-related functioning improved significantly in the first year after stroke, with the most improvement occurring during the first 12 weeks. After 12 weeks, rising speed, gait speed, and BI continue to improve. PMID- 20702393 TI - NF-kappaB regulates the expression of Nucling, a novel apoptosis regulator, with involvement of proteasome and caspase for its degradation. AB - Nucling is identified as a novel regulator of apoptosis. In this study, we investigated the nuclear factor-kappaB (NF-kappaB)-dependent mechanism of Nucling expression, as well as the degradation pathways mediated by proteasome system and caspase activation. Using chromatin immunoprecipitation assay in wild-type mouse embryonic fibroblasts (WT MEFs), we found that NF-kappaB p65 could bind to the kappaB motifs in the promoter regions of Nucling gene at four putative-binding sites. By real-time PCR and immunoblot, we confirmed that Nucling expression was up-regulated by tumour necrosis factor-alpha (TNF-alpha) stimulation in WT MEFs, but not in NF-kappaB p50 knockout MEFs. On the other hand, we investigated the degradation of Nucling in connection with proteasome and caspase by using cycloheximide chase. The results showed that Nucling is a short-lived protein, and its degradation was recovered by proteasome inhibitor MG132. Moreover, under TNF-alpha stimulation, degradation of Nucling was recovered by pan-caspase inhibitor zVAD-fmk. Taken together, we propose a mechanism of Nucling intracellular metabolism. Nucling expression is induced by canonical NF-kappaB signalling pathway, whereas Nucling is undergoing proteasome degradation, as well as being cleaved by caspase system under stress conditions. This opens a new perspective for studying the NF-kappaB dependent regulation mechanism of cell death and survival. PMID- 20702394 TI - RBSDesigner: software for designing synthetic ribosome binding sites that yields a desired level of protein expression. AB - MOTIVATION: RBSDesigner predicts the translation efficiency of existing mRNA sequences and designs synthetic ribosome binding sites (RBSs) for a given coding sequence (CDS) to yield a desired level of protein expression. The program implements the mathematical model for translation initiation described in Na et al. (Mathematical modeling of translation initiation for the estimation of its efficiency to computationally design mRNA sequences with a desired expression level in prokaryotes. BMC Syst. Biol., 4, 71). The program additionally incorporates the effect on translation efficiency of the spacer length between a Shine-Dalgarno (SD) sequence and an AUG codon, which is crucial for the incorporation of fMet-tRNA into the ribosome. RBSDesigner provides a graphical user interface (GUI) for the convenient design of synthetic RBSs. AVAILABILITY: RBSDesigner is written in Python and Microsoft Visual Basic 6.0 and is publicly available as precompiled stand-alone software on the web (http://rbs.kaist.ac.kr). CONTACT: dhlee@kaist.ac.kr PMID- 20702395 TI - BDVal: reproducible large-scale predictive model development and validation in high-throughput datasets. AB - High-throughput data can be used in conjunction with clinical information to develop predictive models. Automating the process of developing, evaluating and testing such predictive models on different datasets would minimize operator errors and facilitate the comparison of different modeling approaches on the same dataset. Complete automation would also yield unambiguous documentation of the process followed to develop each model. We present the BDVal suite of programs that fully automate the construction of predictive classification models from high-throughput data and generate detailed reports about the model construction process. We have used BDVal to construct models from microarray and proteomics data, as well as from DNA-methylation datasets. The programs are designed for scalability and support the construction of thousands of alternative models from a given dataset and prediction task. AVAILABILITY AND IMPLEMENTATION: The BDVal programs are implemented in Java, provided under the GNU General Public License and freely available at http://bdval.campagnelab.org. PMID- 20702396 TI - Cross-species queries of large gene expression databases. AB - MOTIVATION: Expression databases, including the Gene Expression Omnibus and ArrayExpress, have experienced significant growth over the past decade and now hold hundreds of thousands of arrays from multiple species. Since most drugs are initially tested on model organisms, the ability to compare expression experiments across species may help identify pathways that are activated in a similar way in humans and other organisms. However, while several methods exist for finding co-expressed genes in the same species as a query gene, looking at co expression of homologs or arbitrary genes in other species is challenging. Unlike sequence, which is static, expression is dynamic and changes between tissues, conditions and time. Thus, to carry out cross-species analysis using these databases, we need methods that can match experiments in one species with experiments in another species. RESULTS: To facilitate queries in large databases, we developed a new method for comparing expression experiments from different species. We define a distance metric between the ranking of orthologous genes in the two species. We show how to solve an optimization problem for learning the parameters of this function using a training dataset of known similar expression experiments pairs. The function we learn outperforms previous methods and simpler rank comparison methods that have been used in the past for single species analysis. We used our method to compare millions of array pairs from mouse and human expression experiments. The resulting matches can be used to find functionally related genes, to hypothesize about biological response mechanisms and to highlight conditions and diseases that are activating similar pathways in both species. AVAILABILITY: Supporting methods, results and a Matlab implementation are available from http://sb.cs.cmu.edu/ExpQ/. PMID- 20702397 TI - A Bayesian method for 3D macromolecular structure inference using class average images from single particle electron microscopy. AB - MOTIVATION: Electron cryo-microscopy can be used to infer 3D structures of large macromolecules with high resolution, but the large amounts of data captured necessitate the development of appropriate statistical models to describe the data generation process, and to perform structure inference. We present a new method for performing ab initio inference of the 3D structures of macromolecules from single particle electron cryo-microscopy experiments using class average images. RESULTS: We demonstrate this algorithm on one phantom, one synthetic dataset and three real (experimental) datasets (ATP synthase, V-type ATPase and GroEL). Structures consistent with the known structures were inferred for all datasets. AVAILABILITY: The software and source code for this method is available for download from our website: http://compbio.cs.toronto.edu/cryoem/. PMID- 20702398 TI - NoiseMaker: simulated screens for statistical assessment. AB - High-throughput screening (HTS) is a common technique for both drug discovery and basic research, but researchers often struggle with how best to derive hits from HTS data. While a wide range of hit identification techniques exist, little information is available about their sensitivity and specificity, especially in comparison to each other. To address this, we have developed the open-source NoiseMaker software tool for generation of realistically noisy virtual screens. By applying potential hit identification methods to NoiseMaker-simulated data and determining how many of the pre-defined true hits are recovered (as well as how many known non-hits are misidentified as hits), one can draw conclusions about the likely performance of these techniques on real data containing unknown true hits. Such simulations apply to a range of screens, such as those using small molecules, siRNAs, shRNAs, miRNA mimics or inhibitors, or gene over-expression; we demonstrate this utility by using it to explain apparently conflicting reports about the performance of the B score hit identification method. AVAILABILITY AND IMPLEMENTATION: NoiseMaker is written in C#, an ECMA and ISO standard language with compilers for multiple operating systems. Source code, a Windows installer and complete unit tests are available at http://sourceforge.net/projects/noisemaker. Full documentation and support are provided via an extensive help file and tool-tips, and the developers welcome user suggestions. PMID- 20702399 TI - Automated analysis of time-lapse fluorescence microscopy images: from live cell images to intracellular foci. AB - MOTIVATION: Complete, accurate and reproducible analysis of intracellular foci from fluorescence microscopy image sequences of live cells requires full automation of all processing steps involved: cell segmentation and tracking followed by foci segmentation and pattern analysis. Integrated systems for this purpose are lacking. RESULTS: Extending our previous work in cell segmentation and tracking, we developed a new system for performing fully automated analysis of fluorescent foci in single cells. The system was validated by applying it to two common tasks: intracellular foci counting (in DNA damage repair experiments) and cell-phase identification based on foci pattern analysis (in DNA replication experiments). Experimental results show that the system performs comparably to expert human observers. Thus, it may replace tedious manual analyses for the considered tasks, and enables high-content screening. AVAILABILITY AND IMPLEMENTATION: The described system was implemented in MATLAB (The MathWorks, Inc., USA) and compiled to run within the MATLAB environment. The routines together with four sample datasets are available at http://celmia.bigr.nl/. The software is planned for public release, free of charge for non-commercial use, after publication of this article. PMID- 20702400 TI - Identifying informative subsets of the Gene Ontology with information bottleneck methods. AB - MOTIVATION: The Gene Ontology (GO) is a controlled vocabulary designed to represent the biological concepts pertaining to gene products. This study investigates the methods for identifying informative subsets of GO terms in an automatic and objective fashion. This task in turn requires addressing the following issues: how to represent the semantic context of GO terms, what metrics are suitable for measuring the semantic differences between terms, how to identify an informative subset that retains as much as possible of the original semantic information of GO. RESULTS: We represented the semantic context of a GO term using the word-usage-profile associated with the term, which enables one to measure the semantic differences between terms based on the differences in their semantic contexts. We further employed the information bottleneck methods to automatically identify subsets of GO terms that retain as much as possible of the semantic information in an annotation database. The automatically retrieved informative subsets align well with an expert-picked GO slim subset, cover important concepts and proteins, and enhance literature-based GO annotation. AVAILABILITY: http://carcweb.musc.edu/TextminingProjects/. PMID- 20702401 TI - MetDAT: a modular and workflow-based free online pipeline for mass spectrometry data processing, analysis and interpretation. AB - SUMMARY: Analysis of high throughput metabolomics experiments is a resource intensive process that includes pre-processing, pre-treatment and post-processing at each level of experimental hierarchy. We developed an interactive user friendly online software called Metabolite Data Analysis Tool (MetDAT) for mass spectrometry data. It offers a pipeline of tools for file handling, data pre processing, univariate and multivariate statistical analyses, database searching and pathway mapping. Outputs are produced in the form of text and high-quality images in real-time. MetDAT allows users to combine data management and experiment-centric workflows for optimization of metabolomics methods and metabolite analysis. AVAILABILITY: MetDAT is available free for academic use from http://smbl.nus.edu.sg/METDAT2/. CONTACT: sanjay@nus.edu.sg PMID- 20702402 TI - Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. AB - Genevar (GENe Expression VARiation) is a database and Java tool designed to integrate multiple datasets, and provides analysis and visualization of associations between sequence variation and gene expression. Genevar allows researchers to investigate expression quantitative trait loci (eQTL) associations within a gene locus of interest in real time. The database and application can be installed on a standard computer in database mode and, in addition, on a server to share discoveries among affiliations or the broader community over the Internet via web services protocols. AVAILABILITY: http://www.sanger.ac.uk/resources/software/genevar. PMID- 20702403 TI - Role of H-1 and H-2 subunits of soybean seed ferritin in oxidative deposition of iron in protein. AB - Naturally occurring phytoferritin is a heteropolymer consisting of two different H-type subunits, H-1 and H-2. Prior to this study, however, the function of the two subunits in oxidative deposition of iron in ferritin was unknown. The data show that, upon aerobic addition of 48-200 Fe(2+)/shell to apoferritin, iron oxidation occurs only at the diiron ferroxidase center of recombinant H1 (rH-1). In addition to the diiron ferroxidase mechanism, such oxidation is catalyzed by the extension peptide (a specific domain found in phytoferritin) of rH-2, because the H-1 subunit is able to remove Fe(3+) from the center to the inner cavity better than the H-2 subunit. These findings support the idea that the H-1 and H-2 subunits play different roles in iron mineralization in protein. Interestingly, at medium iron loading (200 irons/shell), wild-type (WT) soybean seed ferritin (SSF) exhibits a stronger activity in catalyzing iron oxidation (1.10 +/- 0.13 MUm iron/subunit/s) than rH-1 (0.59 +/- 0.07 MUm iron/subunit/s) and rH-2 (0.48 +/- 0.04 MUm iron/subunit/s), demonstrating that a synergistic interaction exists between the H-1 and H-2 subunits in SSF during iron mineralization. Such synergistic interaction becomes considerably stronger at high iron loading (400 irons/shell) as indicated by the observation that the iron oxidation activity of WT SSF is ~10 times larger than those of rH-1 and rH-2. This helps elucidate the widespread occurrence of heteropolymeric ferritins in plants. PMID- 20702404 TI - Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti malarial activity in the mouse model. AB - Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1 yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates. PMID- 20702405 TI - Ablation of succinate production from glucose metabolism in the procyclic trypanosomes induces metabolic switches to the glycerol 3 phosphate/dihydroxyacetone phosphate shuttle and to proline metabolism. AB - Trypanosoma brucei is a parasitic protist that undergoes a complex life cycle during transmission from its mammalian host (bloodstream forms) to the midgut of its insect vector (procyclic form). In both parasitic forms, most glycolytic steps take place within specialized peroxisomes, called glycosomes. Here, we studied metabolic adaptations in procyclic trypanosome mutants affected in their maintenance of the glycosomal redox balance. T. brucei can theoretically use three strategies to maintain the glycosomal NAD(+)/NADH balance as follows: (i) the glycosomal succinic fermentation branch; (ii) the glycerol 3-phosphate (Gly-3 P)/dihydroxyacetone phosphate (DHAP) shuttle that transfers reducing equivalents to the mitochondrion; and (iii) the glycosomal glycerol production pathway. We showed a hierarchy in the use of these glycosomal NADH-consuming pathways by determining metabolic perturbations and adaptations in single and double mutant cell lines using a combination of NMR, ion chromatography-MS/MS, and HPLC approaches. Although functional, the Gly-3-P/DHAP shuttle is primarily used when the preferred succinate fermentation pathway is abolished in the Deltapepck knock out mutant cell line. In the absence of these two pathways (Deltapepck/(RNAi)FAD GPDH.i mutant), glycerol production is used but with a 16-fold reduced glycolytic flux. In addition, the Deltapepck mutant cell line shows a 3.3-fold reduced glycolytic flux compensated by an increase of proline metabolism. The inability of the Deltapepck mutant to maintain a high glycolytic flux demonstrates that the Gly-3-P/DHAP shuttle is not adapted to the procyclic trypanosome context. In contrast, this shuttle was shown earlier to be the only way used by the bloodstream forms of T. brucei to sustain their high glycolytic flux. PMID- 20702406 TI - Regulation of MRP2/ABCC2 and BSEP/ABCB11 expression in sandwich cultured human and rat hepatocytes exposed to inflammatory cytokines TNF-{alpha}, IL-6, and IL 1{beta}. AB - In the present study MRP2/ABCC2 and BSEP/ABCB11 expression were investigated in sandwich cultured (SC) human and rat hepatocytes exposed to the proinflammatory cytokines. The investigation was also done in lipopolysaccharide (LPS)-treated rats. In SC human hepatocytes, both absolute protein and mRNA levels of MRP2/ABCC2 were significantly down-regulated by TNF-alpha, IL-6, or IL-1beta. In contrast to mRNA decrease, which was observed for BSEP/ABCB11, the protein amount was significantly increased by IL-6 or IL-1beta. A discrepancy between the change in BSEP/ABCB11 mRNA and protein levels was encountered in SC human hepatocytes treated with proinflammatory cytokines. In SC rat hepatocytes, Mrp2/Abcc2 mRNA was down-regulated by TNF-alpha and IL-6, whereas the protein level was decreased by all three cytokines. Down-regulations of both Bsep/Abcb11 mRNA and protein levels were found in SC rat hepatocytes exposed to TNF-alpha or IL-1beta. Administration of LPS triggered the release of the proinflammatory cytokines and caused the decrease of Mrp2/Abcc2 and Bsep/Abcb11 protein in liver at 24 h post treatment; however, the Mrp2 and Bsep protein levels rebounded at 48 h post-LPS treatment. In total, our results indicate that proinflammatory cytokines regulate the expression of MRP2/Mrp2 and BSEP/Bsep and for the first time demonstrate the differential effects on BSEP/Bsep expression between SC human and rat hepatocytes. Furthermore, the agreement between transporter regulation in vitro in SC rat hepatocytes and in vivo in LPS-treated rats during the acute response phase demonstrates the utility of in vitro SC hepatocyte models for predicting in vivo effects. PMID- 20702407 TI - Regulation of response regulator autophosphorylation through interdomain contacts. AB - DNA-binding response regulators (RRs) of the OmpR/PhoB subfamily alternate between inactive and active conformational states, with the latter having enhanced DNA-binding affinity. Phosphorylation of an aspartate residue in the receiver domain, usually via phosphotransfer from a cognate histidine kinase, stabilizes the active conformation. Many of the available structures of inactive OmpR/PhoB family proteins exhibit extensive interfaces between the N-terminal receiver and C-terminal DNA-binding domains. These interfaces invariably involve the alpha4-beta5-alpha5 face of the receiver domain, the locus of the largest differences between inactive and active conformations and the surface that mediates dimerization of receiver domains in the active state. Structures of receiver domain dimers of DrrB, DrrD, and MtrA have been determined, and phosphorylation kinetics were analyzed. Analysis of phosphotransfer from small molecule phosphodonors has revealed large differences in autophosphorylation rates among OmpR/PhoB RRs. RRs with substantial domain interfaces exhibit slow rates of phosphorylation. Rates are greatly increased in isolated receiver domain constructs. Such differences are not observed between autophosphorylation rates of full-length and isolated receiver domains of a RR that lacks interdomain interfaces, and they are not observed in histidine kinase-mediated phosphotransfer. These findings suggest that domain interfaces restrict receiver domain conformational dynamics, stabilizing an inactive conformation that is catalytically incompetent for phosphotransfer from small molecule phosphodonors. Inhibition of phosphotransfer by domain interfaces provides an explanation for the observation that some RRs cannot be phosphorylated by small molecule phosphodonors in vitro and provides a potential mechanism for insulating some RRs from small molecule-mediated phosphorylation in vivo. PMID- 20702408 TI - CCAAT/enhancer-binding protein beta and NF-kappaB mediate high level expression of chemokine genes CCL3 and CCL4 by human chondrocytes in response to IL-1beta. AB - A large set of chemokines is highly up-regulated in human chondrocytes in response to IL-1beta (Sandell, L. J., Xing, X., Franz, C., Davies, S., Chang, L. W., and Patra, D. (2008) Osteoarthr. Cartil. 16, 1560-1571). To investigate the mechanism of transcriptional regulation, deletion constructs of selected chemokine gene promoters, the human CCL3 (MIP-1alpha) and CCL4 (MIP-1beta), were transfected into human chondrocytes with or without IL-1beta. The results show that an IL-1beta-responsive element is located between bp -300 and -140 of the CCL3 promoter and between bp -222 and -100 of the CCL4 promoter. Because both of these elements contain CCAAT/enhancer-binding protein beta (C/EBPbeta) motifs, the function of C/EBPbeta was examined. IL-1beta stimulated the expression of C/EBPbeta, and the direct binding of C/EBPbeta to the C/EBPbeta motif was confirmed by EMSA and ChIP analyses. The -300 bp CCL3 promoter and -222 bp CCL4 promoter were strongly up-regulated by co-transfection with the C/EBPbeta expression vector. Mutation of the C/EBPbeta motif and reduction of C/EBPbeta expression by siRNA decreased the up-regulation. Additionally, another cytokine related transcription factor, NF-kappaB, was also shown to be involved in the up regulation of chemokines in response to IL-1beta, and the binding site was identified. The regulation of C/EBPbeta and NF-kappaB was confirmed by the inhibition by C/EBPbeta and NF-kappaB and by transfection with C/EBPbeta and NF kappaB expression vectors in the presence or absence of IL-1beta. Taken together, our results suggest that C/EBPbeta and NF-kappaB are both involved in the IL 1beta-responsive up-regulation of chemokine genes in human chondrocytes. Time course experiments indicated that C/EBPbeta gradually and steadily induces chemokine up-regulation, whereas NF-kappaB activity was highest at the early stage of chemokine up-regulation. PMID- 20702409 TI - Tyrosine phosphorylation of integrin beta3 regulates kindlin-2 binding and integrin activation. AB - Kindlins are essential for integrin activation in cell systems and do so by working in a cooperative fashion with talin via their direct interaction with integrin beta cytoplasmic tails (CTs). Kindlins interact with the membrane-distal NxxY motif, which is distinct from the talin-binding site within the membrane proximal NxxY motif. The Tyr residues in both motifs can be phosphorylated, and it has been suggested that this modification of the membrane-proximal NxxY motif negatively regulates interaction with the talin head domain. However, the influence of Tyr phosphorylation of the membrane-distal NxxY motif on kindlin binding is unknown. Using mutational analyses and phosphorylated peptides, we show that phosphorylation of the membrane-distal NITY(759) motif in the beta(3) CT disrupts kindlin-2 recognition. Phosphorylation of this membrane-distal Tyr also disables the ability of kindlin-2 to coactivate the integrin. In direct binding studies, peptides corresponding to the non-phosphorylated beta(3) CT interacted well with kindlin-2, whereas the Tyr(759)-phosphorylated peptide failed to bind kindlin-2 with measurable affinity. These observations indicate that transitions between the phosphorylated and non-phosphorylated states of the integrin beta(3) CT determine reactivity with kindlin-2 and govern the role of kindlin-2 in regulating integrin activation. PMID- 20702410 TI - The caspase-8 dimerization/dissociation balance is a highly potent regulator of caspase-8, -3, -6 signaling. AB - Apoptosis is driven by positive feedback activation between aspartate-specific cysteinyl proteases (caspases). These feedback loops ensure the swift and efficient elimination of cells upon initiation of apoptosis execution. At the same time, the signaling network must be insensitive to erroneous, mild caspase activation to avoid unwanted, excessive cell death. Sublethal caspase activation in fact was shown to be a requirement for the differentiation of multiple cell types but might also occur accidentally during short, transient cellular stress conditions. Here we carried out an in silico comparison of the molecular mechanisms that so far have been identified to impair the amplification of caspase activities via the caspase-8, -3, -6 loop. In a systems model resembling HeLa cervical cancer cells, the dimerization/dissociation balance of caspase-8 potently suppressed the amplification of caspase responses, surprisingly outperforming or matching known caspase-8 and -3 inhibitors such as bifunctional apoptosis repressor or x-linked inhibitor of apoptosis protein. These findings were further substantiated in global sensitivity analyses based on combinations of protein concentrations from the sub- to superphysiological range to screen the full spectrum of biological variability that can be expected within cell populations and between distinct cell types. Additional modeling showed that the combined effects of x-linked inhibitor of apoptosis protein and caspase-8 dimerization/dissociation processes can also provide resistance to larger inputs of active caspases. Our study therefore highlights a central and so far underappreciated role of caspase-8 dimerization/dissociation in avoiding unwanted cell death by lethal amplification of caspase responses via the caspase-8, -3, -6 loop. PMID- 20702411 TI - Structure and metal loading of a soluble periplasm cuproprotein. AB - A copper-trafficking pathway was found to enable Cu(2+) occupancy of a soluble periplasm protein, CucA, even when competing Zn(2+) is abundant in the periplasm. Here, we solved the structure of CucA (a new cupin) and found that binding of Cu(2+), but not Zn(2+), quenches the fluorescence of Trp(165), which is adjacent to the metal site. Using this fluorescence probe, we established that CucA becomes partly occupied by Zn(2+) following exposure to equimolar Zn(2+) and Cu(2+). Cu(2+)-CucA is more thermodynamically stable than Zn(2+)-CucA but k((Zn >Cu)exchange) is slow, raising questions about how the periplasm contains solely the Cu(2+) form. We discovered that a copper-trafficking pathway involving two copper transporters (CtaA and PacS) and a metallochaperone (Atx1) is obligatory for Cu(2+)-CucA to accumulate in the periplasm. There was negligible CucA protein in the periplasm of DeltactaA cells, but the abundance of cucA transcripts was unaltered. Crucially, DeltactaA cells overaccumulate low M(r) copper complexes in the periplasm, and purified apoCucA can readily acquire Cu(2+) from DeltactaA periplasm extracts, but in vivo apoCucA fails to come into contact with these periplasmic copper pools. Instead, copper traffics via a cytoplasmic pathway that is coupled to CucA translocation to the periplasm. PMID- 20702412 TI - Pro-inflammatory genes as biomarkers and therapeutic targets in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is a major health problem worldwide, and patients have a particularly poor 5-year survival rate. Thus, identification of the molecular targets in OSCC and subsequent innovative therapies are greatly needed. Prolonged exposure to alcohol, tobacco, and pathogenic agents are known risk factors and have suggested that chronic inflammation may represent a potential common denominator in the development of OSCC. Microarray analysis of gene expression in OSCC cell lines with high basal NF-kappaB activity and OSCC patient samples identified dysregulation of many genes involved in inflammation, wound healing, angiogenesis, and growth regulation. In particular IL-8, CCL5, STAT1, and VEGF gene expression was up-regulated in OSCC. Moreover, IL-8 protein levels were significantly higher in OSCC cell lines as compared with normal human oral keratinocytes. Targeting IL-8 expression by siRNA significantly reduced the survival of OSCC cells, indicating that it plays an important role in OSCC development and/or progression. Inhibiting the inflammatory pathway by aspirin and the proteasome/NF-kappaB pathway by bortezomib resulted in marked reduction in cell viability in OSCC lines. Taken together our studies indicate a strong link between inflammation and OSCC development and reveal IL-8 as a potential mediator. Treatment based on prevention of general inflammation and/or the NF kappaB pathway shows promise in OSCCs. PMID- 20702413 TI - A novel pathway for inducible nitric-oxide synthase activation through inflammasomes. AB - Innate immune recognition of flagellin is shared by transmembrane TLR5 and cytosolic Nlrc4 (NOD-like receptor family CARD (caspase activation recruitment domain) domain containing 4)/Naip5 (neuronal apoptosis inhibitory protein 5). TLR5 activates inflammatory genes through MYD88 pathway, whereas Nlrc4 and Naip5 assemble multiprotein complexes called inflammasomes, culminating in caspase-1 activation, IL-1beta/IL-18 secretion, and pyroptosis. Although both TLR5 and Naip5/Nlrc4 pathways cooperate to clear infections, little is known about the relative anti-pathogen effector mechanisms operating through each of them. Here we show that the cytosolic flagellin (FLA-BSDot) was able to activate iNOS, an enzyme previously associated with TLR5 pathway. Using Nlrc4- or Naip5-deficient macrophages, we found that both receptors are involved in iNOS activation by FLA BSDot. Moreover, distinct from extracellular flagellin (FLA-BS), iNOS activation by intracellular flagellin is completely abrogated in the absence of caspase-1. Interestingly, IL-1beta and IL-18 do not seem to be important for FLA-BSDot mediated iNOS production. Together, our data defined an additional anti-pathogen effector mechanism operated through Naip5 and Nlrc4 inflammasomes and illustrated a novel signaling transduction pathway that activates iNOS. PMID- 20702414 TI - The p97 ATPase dislocates MHC class I heavy chain in US2-expressing cells via a Ufd1-Npl4-independent mechanism. AB - The human cytomegalovirus (HCMV) protein US2 hijacks the endoplasmic reticulum (ER)-associated degradation machinery to dispose of MHC class I heavy chain (HC) at the ER. This process requires retrotranslocation of newly synthesized HC molecules from the ER membrane into the cytosol, but the mechanism underlying the dislocation reaction has been elusive. Here we establish an in vitro permeabilized cell assay that recapitulates the retrotranslocation of MHC HC in US2-expressing cells. Using this assay, we demonstrate that the dislocation process requires ATP and ubiquitin, as expected. The retrotranslocation also involves the p97 ATPase. However, the mechanism by which p97 dislocates MHC class I HC in US2 cells is distinct from that in US11 cells: the dislocation reaction in US2 cells is independent of the p97 cofactor Ufd1-Npl4. Our results suggest that different retrotranslocation mechanisms can employ distinct p97 ATPase complexes to dislocate substrates. PMID- 20702415 TI - MTA1 coregulator regulates LPS response via MyD88-dependent signaling. AB - Although metastasis tumor antigen 1 (MTA1) contributes to the responsiveness of macrophages to LPS, the underlying mechanism remains unknown. Here, we investigated the role of MTA1 in the regulation of expression and function of MyD88, a proximal component of NF-kappaB signaling. We discovered that MTA1 targets MyD88 and that MyD88 is a NF-kappaB-responsive gene in LPS-stimulated macrophages. We found that MTA1 is required for MyD88-dependent stimulation of NF kappaB signaling and expression of proinflammatory cytokines such as IL-1beta, MIP2, and TNF-alpha as MTA1 depletion leads to a substantial reduction in the expression of NF-kappaB target genes. In addition, LPS-mediated stimulation of MyD88 transcription was accompanied by an enhanced recruitment of MTA1, RNA polymerase II, and p65RelA complex to the NF-kappaB consensus sites in the MyD88 promoter. Interestingly, the recruitment of both MTA1 and MyD88 expression is effectively blocked by NF-kappaB inhibitor parthenolide. Selective knockdown of MyD88 by a dominant negative mutant of MyD88 or selective siRNA also impairs the ability of LPS to stimulate the NF-kappaB target genes. These findings reveal an inherent coregulatory role of MTA1 upon the expression of MyD88 and suggest that MTA1 regulation of MyD88 may constitute at least one of the mechanisms by which MTA1 stimulates LPS-induced NF-kappaB signaling in stimulated macrophages. PMID- 20702416 TI - Diversity of innate immune recognition mechanism for bacterial polymeric meso diaminopimelic acid-type peptidoglycan in insects. AB - In Drosophila, the synthesis of antimicrobial peptides in response to microbial infections is under the control of the Toll and immune deficiency (Imd) signaling pathway. The Toll signaling pathway responds mainly to the lysine-type peptidoglycan of Gram-positive bacteria and fungal beta-1,3-glucan, whereas the Imd pathway responds to the meso-diaminopimelic acid (DAP)-type peptidoglycan of Gram-negative bacteria and certain Gram-positive bacilli. Recently we determined the activation mechanism of a Toll signaling pathway biochemically using a large beetle, Tenebrio molitor. However, DAP-type peptidoglycan recognition mechanism and its signaling pathway are still unclear in the fly and beetle. Here, we show that polymeric DAP-type peptidoglycan, but not its monomeric form, formed a complex with Tenebrio peptidoglycan recognition protein-SA, and this complex activated the three-step proteolytic cascade to produce processed Spatzle, a Toll receptor ligand, and induced Drosophila defensin-like antimicrobial peptide in Tenebrio larvae similarly to polymeric lysine-type peptidoglycan. Monomeric DAP type peptidoglycan induced Drosophila diptericin-like antimicrobial peptide in Tenebrio hemocytes. In addition, both polymeric and monomeric DAP-type peptidoglycans induced expression of Tenebrio peptidoglycan recognition protein SC2, which is DAP-type peptidoglycan-selective N-acetylmuramyl-l-alanine amidase that functions as a DAP-type peptidoglycan scavenger, appearing to function as a negative regulator of the DAP-type peptidoglycan signaling by cleaving DAP-type peptidoglycan in Tenebrio larvae. Taken together, these results demonstrate that molecular recognition mechanism for polymeric DAP-type peptidoglycan is different between Tenebrio larvae and Drosophila adults, providing biochemical evidences of biological diversity of innate immune responses in insects. PMID- 20702417 TI - Porphyromonas gingivalis peptidoglycans induce excessive activation of the innate immune system in silkworm larvae. AB - Porphyromonas gingivalis, a pathogen that causes inflammation in human periodontal tissue, killed silkworm (Bombyx mori, Lepidoptera) larvae when injected into the blood (hemolymph). Silkworm lethality was not rescued by antibiotic treatment, and heat-killed bacteria were also lethal. Heat-killed bacteria of mutant P. gingivalis strains lacking virulence factors also killed silkworms. Silkworms died after injection of peptidoglycans purified from P. gingivalis (pPG), and pPG toxicity was blocked by treatment with mutanolysin, a peptidoglycan-degrading enzyme. pPG induced silkworm hemolymph melanization at the same dose as that required to kill the animal. pPG injection increased caspase activity in silkworm tissues. pPG-induced silkworm death was delayed by injecting melanization-inhibiting reagents (a serine protease inhibitor and 1 phenyl-2-thiourea), antioxidants (N-acetyl-l-cysteine, glutathione, and catalase), and a caspase inhibitor (Ac-DEVD-CHO). Thus, pPG induces excessive activation of the innate immune response, which leads to the generation of reactive oxygen species and apoptotic cell death in the host tissue. PMID- 20702418 TI - SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. AB - SIRT1 is a protein deacetylase that has emerged as a therapeutic target for the development of activators to treat diseases of aging. SIRT1-activating compounds (STACs) have been developed that produce biological effects consistent with direct SIRT1 activation. At the molecular level, the mechanism by which STACs activate SIRT1 remains elusive. In the studies reported herein, the mechanism of SIRT1 activation is examined using representative compounds chosen from a collection of STACs. These studies reveal that activation of SIRT1 by STACs is strongly dependent on structural features of the peptide substrate. Significantly, and in contrast to studies reporting that peptides must bear a fluorophore for their deacetylation to be accelerated, we find that some STACs can accelerate the SIRT1-catalyzed deacetylation of specific unlabeled peptides composed only of natural amino acids. These results, together with others of this study, are at odds with a recent claim that complex formation between STACs and fluorophore-labeled peptides plays a role in the activation of SIRT1 (Pacholec, M., Chrunyk, B., Cunningham, D., Flynn, D., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., Qiu, X., Stockman, B., Thanabal, V., Varghese, A., Ward, J., Withka, J., and Ahn, K. (2010) J. Biol. Chem. 285, 8340-8351). Rather, the data suggest that STACs interact directly with SIRT1 and activate SIRT1-catalyzed deacetylation through an allosteric mechanism. PMID- 20702419 TI - Foxm1 transcription factor is required for maintenance of pluripotency of P19 embryonal carcinoma cells. AB - Transcription factor Foxm1 plays a critical role during embryonic development and its expression is repressed during retinoic acid (RA)-induced differentiation of pluripotent P19 embryonal carcinoma cells at the early stage, correlated with downregulation of expression of pluripotency markers. To study whether Foxm1 participates in the maintenance of pluripotency of stem cells, we knock down Foxm1 expression in P19 cells and identify that Oct4 are regulated directly by Foxm1. Knockdown of Foxm1 also results in spontaneous differentiation of P19 cells to mesodermal derivatives, such as muscle and adipose tissues. Maintaining Foxm1 expression prevents the downregulation of pluripotency-related transcription factors such as Oct4 and Nanog during P19 cell differentiation. Furthermore, overexpression of FOXM1 alone in RA-differentiated P19 cells (4 days) or human newborn fibroblasts restarts the expression of pluripotent genes Oct4, Nanog and Sox2. Together, our results suggest a critical involvement of Foxm1 in maintenance of stem cell pluripotency. PMID- 20702420 TI - Atomic resolution structure of CAG RNA repeats: structural insights and implications for the trinucleotide repeat expansion diseases. AB - CAG repeats occur predominantly in the coding regions of human genes, which suggests their functional importance. In some genes, these sequences can undergo pathogenic expansions leading to neurodegenerative polyglutamine (poly-Q) diseases. The mutant transcripts containing expanded CAG repeats possibly contribute to pathogenesis in addition to the well-known pathogenic effects of mutant proteins. We have analysed two crystal forms of RNA duplexes containing CAG repeats: (GGCAGCAGCC)(2). One of the structures has been determined at atomic resolution (0.95 A) and the other at 1.9 A. The duplexes include non-canonical A A pairs that fit remarkably well within a regular A-helix. All the adenosines are in the anti-conformation and the only interaction within each A-A pair is a single C2-H2...N1 hydrogen bond. Both adenosines in each A-A pair are shifted towards the major groove, although to different extents; the A which is the H bond donor stands out more (the 'thumbs-up' conformation). The main effect on the helix conformation is a local unwinding. The CAG repeats and the previously examined CUG structures share a similar pattern of electrostatic charge distribution in the minor groove, which could explain their affinity for the pathogenesis-related MBNL1 protein. PMID- 20702421 TI - Selection systems based on dominant-negative transcription factors for precise genetic engineering. AB - Diverse tools are available for performing genetic modifications of microorganisms. However, new methods still need to be developed for performing precise genomic engineering without introducing any undesirable side-alteration. Indeed for functional analyses of genomic elements, as well as for some industrial applications, only the desired mutation should be introduced at the locus considered. This article describes a new approach fulfilling these requirements, based on the use of selection systems consisting in truncated genes encoding dominant-negative transcription factors. We have demonstrated dominant negative effects mediated by truncated Gal4p and Arg81p proteins in Saccharomyces cerevisiae, interfering with galactose and arginine metabolic pathways, respectively. These genes can be used as positive and negative markers, since they provoke both growth inhibition on substrates and resistance to specific drugs. These selection markers have been successfully used for precisely deleting HO and URA3 in wild yeasts. This genetic engineering approach could be extended to other microorganisms. PMID- 20702422 TI - Sequence-specific cleavage of RNA by Type II restriction enzymes. AB - The ability of 223 Type II restriction endonucleases to hydrolyze RNA-DNA heteroduplex oligonucleotide substrates was assessed. Despite the significant topological and sequence asymmetry introduced when one strand of a DNA duplex is substituted by RNA we find that six restriction enzymes (AvaII, AvrII, BanI, HaeIII, HinfI and TaqI), exclusively of the Type IIP class that recognize palindromic or interrupted-palindromic DNA sequences, catalyze robust and specific cleavage of both RNA and DNA strands of such a substrate. Time-course analyses indicate that some endonucleases hydrolyze phosphodiester bonds in both strands simultaneously whereas others appear to catalyze sequential reactions in which either the DNA or RNA product accumulates more rapidly. Such strand specific variation in cleavage susceptibility is both significant (up to orders of magnitude difference) and somewhat sequence dependent, notably in relation to the presence or absence of uracil residues in the RNA strand. Hybridization to DNA oligonucleotides that contain endonuclease recognition sites can be used to achieve targeted hydrolysis of extended RNA substrates produced by in vitro transcription. The ability to 'restrict' an RNA-DNA hybrid, albeit with a limited number of restriction endonucleases, provides a method whereby individual RNA molecules can be targeted for site-specific cleavage in vitro. PMID- 20702423 TI - A network of conserved co-occurring motifs for the regulation of alternative splicing. AB - Cis-acting short sequence motifs play important roles in alternative splicing. It is now possible to identify such sequence motifs as conserved sequence patterns in genome sequence alignments. Here, we report the systematic search for motifs in the neighboring introns of alternatively spliced exons by using comparative analysis of mammalian genome alignments. We identified 11 conserved sequence motifs that might be involved in the regulation of alternative splicing. These motifs are not only significantly overrepresented near alternatively spliced exons, but they also co-occur with each other, thus, forming a network of cis elements, likely to be the basis for context-dependent regulation. Based on this finding, we applied the motif co-occurrence to predict alternatively skipped exons. We verified exon skipping in 29 cases out of 118 predictions (25%) by EST and mRNA sequences in the databases. For the predictions not verified by the database sequences, we confirmed exon skipping in 10 additional cases by using both RT-PCR experiments and the publicly available RNA-Seq data. These results indicate that even more alternative splicing events will be found with the progress of large-scale and high-throughput analyses for various tissue samples and developmental stages. PMID- 20702424 TI - O6-methylguanine induces altered proteins at the level of transcription in human cells. AB - O(6)-Methylguanine (O(6)-meG), which is produced in DNA following exposure to methylating agents, instructs human RNA polymerase II to mis-insert bases opposite the lesion during transcription. In this study, we examined the effect of O(6)-meG on transcription in human cells and investigated the subsequent effects on protein function following translation of the resulting mRNA. In HEK293 cells, O(6)-meG induced incorporation of uridine or cytidine in nascent RNA opposite the adduct. In cells containing active O(6)-alkylguanine-DNA alkyltransferase (AGT), which repairs O(6)-meG, 3% misincorporation of uridine was observed opposite the lesion. In cells where AGT function was compromised by addition of the AGT inhibitor O(6)-benzylguanine, ~ 58% of the transcripts contained a uridine misincorporation opposite the lesion. Furthermore, the altered mRNA induced changes to protein function as demonstrated through recovery of functional red fluorescent protein (RFP) from DNA coding for a non-fluorescent variant of RFP. These data show that O(6)-meG is highly mutagenic at the level of transcription in human cells, leading to an altered protein load, especially when AGT is inhibited. PMID- 20702425 TI - Structural basis for the bacterial transcription-repair coupling factor/RNA polymerase interaction. AB - The transcription-repair coupling factor (TRCF, the product of the mfd gene) is a widely conserved bacterial protein that mediates transcription-coupled DNA repair. TRCF uses its ATP-dependent DNA translocase activity to remove transcription complexes stalled at sites of DNA damage, and stimulates repair by recruiting components of the nucleotide excision repair pathway to the site. A protein/protein interaction between TRCF and the beta-subunit of RNA polymerase (RNAP) is essential for TRCF function. CarD (also called CdnL), an essential regulator of rRNA transcription in Mycobacterium tuberculosis, shares a homologous RNAP interacting domain with TRCF and also interacts with the RNAP beta-subunit. We determined the 2.9-A resolution X-ray crystal structure of the RNAP interacting domain of TRCF complexed with the RNAP-beta1 domain, which harbors the TRCF interaction determinants. The structure reveals details of the TRCF/RNAP protein/protein interface, providing a basis for the design and interpretation of experiments probing TRCF, and by homology CarD, function and interactions with the RNAP. PMID- 20702426 TI - Codon reassignment in the Escherichia coli genetic code. AB - Most organisms, from Escherichia coli to humans, use the 'universal' genetic code, which have been unchanged or 'frozen' for billions of years. It has been argued that codon reassignment causes mistranslation of genetic information, and must be lethal. In this study, we successfully reassigned the UAG triplet from a stop to a sense codon in the E. coli genome, by eliminating the UAG-recognizing release factor, an essential cellular component, from the bacterium. Only a few genetic modifications of E. coli were needed to circumvent the lethality of codon reassignment; erasing all UAG triplets from the genome was unnecessary. Thus, UAG was assigned unambiguously to a natural or non-natural amino acid, according to the specificity of the UAG-decoding tRNA. The result reveals the unexpected flexibility of the genetic code. PMID- 20702430 TI - Sustained elevation of intraocular pressure after intravitreal injections of anti VEGF agents. AB - AIMS: To report the rate of intraocular pressure (IOP) elevation associated with repeated intravitreal injections of antivascular endothelial growth factor (VEGF) agents and to determine if a pre-existing diagnosis of glaucoma is a risk factor for this phenomenon. METHODS: The charts of 215 eyes undergoing intravitreal injection with anti-VEGF agents for wet age-related macular degeneration (AMD) were retrospectively examined with respect to frequency of injections, number of injections and changes in IOP. Data were analysed independently for two groups (1) pre-existing glaucoma and (2) no history of glaucoma. RESULTS: Of the 215 eyes receiving injections with bevacizumab and/or ranibizumab, 6% (n=13) had sustained IOP elevation requiring medical or laser interventions. Of the eyes receiving only bevacizumab, 9.9% (10/101) had sustained elevated IOP, while 3.1% (3/96) of eyes receiving only ranibizumab experienced increases (p=0.049). Patients with pre-existing glaucoma experienced higher rates of elevated IOP when compared with patients without pre-existing glaucoma (33% vs 3.1% respectively; p<0.001). The glaucoma subgroup had a lower median number of injections (6; interquartile range 5-10) compared with the non-glaucoma group (9.5; interquartile range 6-13.7; p=0.031). CONCLUSIONS: The incidence of sustained elevated IOP in patients receiving intravitreal anti-VEGF injections is significant. Additionally, these data suggest the possibility of a heightened risk for further elevation of IOP in patients with pre-existing glaucoma who receive either bevacizumab or ranibizumab. Prospective studies are needed to verify these results and better understand the implications of these findings. PMID- 20702431 TI - The ophthalmic side-effects of imiquimod therapy in the management of periocular skin lesions. AB - AIM: To describe the ophthalmic side-effects of topical imiquimod for periocular actinic keratoses, squamous cell carcinoma in situ and basal cell carcinoma. METHOD: A retrospective study was carried out in two centres of all patients who underwent topical imiquimod therapy between January 2004 and January 2009. Imiquimod was applied three times weekly for 4-6 weeks. Diagnosis of the lesions, complications, clinical resolution and long-term ophthalmic side-effects was recorded. Patients on therapy were reviewed fortnightly and then every 6 weeks following completion of treatment. RESULTS: 47 patients were identified; the mean age was 74 years. 37 patients had actinic keratoses, seven patients had Bowen disease, and three patients had BCC. The lower lid was the commonest site involved (68%). Application site erythema occurred in all patients. Conjunctivitis occurred in 15 patients, and six patients complained of ocular stinging on application of imiquimod. One patient had a staphylococcal keratitis, which responded to topical antibiotic and steroid therapy. Two patients required oral antibiotics for preseptal cellulitis. Three patients had delayed conjunctivitis at a mean of 2.3 weeks. Nine patients discontinued imiquimod due to ocular irritation and conjunctivitis, of whom four patients recommenced and finished the treatment after a rest period. At a mean follow-up of 16 weeks, 34 patients had clinical resolution of the periocular lesions and no patient had any residual ophthalmic side-effects from imiquimod. CONCLUSION: Conjunctivitis and ocular stinging were the commonest ophthalmic side-effects encountered with the application of imiquimod for periocular skin lesions. These effects were temporary and resolved on terminating the imiquimod therapy. PMID- 20702432 TI - Onchocerciasis in Anambra State, Southeast Nigeria: endemicity and clinical manifestations. AB - BACKGROUND: A cross-sectional study was performed to determine the current endemicity of onchocerciasis in Ayamelum Local Council, Anambra State, Southeast Nigeria, where community-directed treatment with ivermectin has been implemented for over a decade. METHODS: An estimate of the endemicity of onchocerciasis was obtained using the rapid assessment method in 894 subjects from 13 communities selected by multistage sampling. Dermatological and ocular manifestations were analysed and classified using standard criteria. RESULTS: Onchocerca volvulus nodules were recorded in 86 (9.6 +/- 1.9%) of the subjects, and 186 (20.8 +/- 3.7%) had one or more of the various classes of onchocercal skin diseases (OSD). Prevalence was dependent on age (p = 0.001), but not on sex (p = 0.31). There was a total absence of symptoms in the youngest age group and a low prevalence among subjects in their second decade of life. Pearson's correlation showed a strong positive correlation between nodular rate and prevalence of chronic papular onchodermatitis (r = 0.943) and a poor correlation with acute papular onchodermatitis (r = 0.259). Age-dependent analysis of various classes of OSDs showed that the rate of acute papular onchodermatitis increased with age up to the third decade of life and decreased steadily thereafter, while the chronic forms of OSD increased with age for both sexes. Infection was dependent on occupation and proximity of the village to the vector breeding sites. CONCLUSIONS: Generally low prevalence in the population and absence of symptoms among the youngest age group emphasise the success of the intervention, but the persistent occurrence of acute disease may suggest a shortfall due to low coverage or non-compliance with the mass chemotherapeutic regimen. PMID- 20702433 TI - Considerations and proposals for the management of patients after prolonged intensive care unit admission. AB - The majority of patients admitted to the intensive care unit (ICU) have a short stay of only a few days. However a small but significant number require prolonged intensive care. This is typically due to persisting, and sometimes complex, medical/surgical problems. Discharge of such ICU patients requires a comprehensive, multidisciplinary, verbal and written handover to the receiving ward team. As with any acutely ill adult in hospital, post-ICU patients should be carefully monitored with 'track and trigger' systems such as the Early Warning Score. Those with unexpected physiological deterioration should be promptly reviewed by senior clinicians and/or medical emergency/critical care outreach teams and considered for ICU re-admission where appropriate. Patients who have received prolonged organ support in the ICU are often affected by a number of specific medical problems such as ventilatory insufficiency, cardiac dysfunction, kidney injury, nutritional deficiency, ICU acquired weakness, and brain injury. They also frequently experience physical disability and psychosocial problems including delirium, anxiety, depression, post-traumatic stress disorder, cognitive dysfunction, and disturbed sleep. Structured rehabilitation programmes for post-ICU patients, tailored to individual needs, should be commenced on the ICU and continued through to and beyond hospital discharge. Care bundles, which are widely used on the ICU, are groups of interventions employed to optimise treatments or minimise complication rates. They may be additionally useful in the post-ICU ward setting by prompting clinicians to focus on, and address, commonly occurring medical and psychosocial problems in these patients. PMID- 20702434 TI - Understanding the experiences of allergy testing: a qualitative study of people with perceived serious allergic disorders. AB - PURPOSE: To investigate the experience of patients with perceived severe allergic disorders in obtaining allergen testing. DESIGN: In-depth interviews with 20 purposively sampled adults and parents of children with, or at perceived risk of, serious allergic problems. Data were analysed thematically, drawing on Frank's classification of narratives to help interpret patient/career accounts. RESULTS: Accounts fell into four main groups: (i) children with anaphylaxis occurring 'out of the blue' (ii) children in whom the recognition of severe allergy by professionals was perceived as delayed; (iii) adults with anaphylaxis who adapted; and (iv) adults who remained in search of an answer. Whereas children had eventually been assessed and tested in a specialist clinic, adults had difficulty in obtaining testing, and most-including those for whom current guidelines would recommend testing-had not been tested. Participants incorporated their past experience of testing into narrative accounts, which included current ways of dealing with their allergy. They saw testing as only one component of appropriate allergy management which required interpretive expertise in professionals who ordered tests. Despite the limitations in NHS allergy testing provision, there was relatively little interest among patients/carers in using complementary and alternative providers of allergy testing. CONCLUSIONS: Patients perceived major shortfalls in relation to NHS allergy testing provision, focusing on both the availability of testing and expertise in interpreting the results. Any increased provision of testing needs to be matched by access to specialist interpretation of these tests. PMID- 20702435 TI - A structured women's preventive health clinic for residents: a quality improvement project designed to meet training needs and improve cervical cancer screening rates. AB - INTRODUCTION: Multiple resident-related factors contribute to 'missed opportunities' in providing comprehensive preventive care for female patients, including comfort level, knowledge and experience--all of which are compounded by resident turnover rates. Of particular concern among Internal Medicine (IM) residents is their knowledge and comfort level in performing pelvic exams. AIM: To evaluate the impact of a quality improvement project of implementing a Women's Preventive Health Clinic (WPHC) on addressing gaps identified by needs assessments: residents' comfort and knowledge with female preventive care and cervical cancer screening. PROGRAMME DESCRIPTION: The WPHC, a multidisciplinary weekly clinic, focused on preventive services for women with chronic conditions. The alternating didactic and clinic sessions emphasised women's preventive health topics for IM residents. PROGRAMME EVALUATION: Sixty-three IM residents participated in WPHC between 2002 and 2005. Pre- and post-test design was used to assess resident knowledge and comfort levels. Cervical cancer screening rates of residents' patients were assessed pre- and post-WPHC initiation. There was a significant improvement in general knowledge (64% correct at pretest vs 73% at post-test, p=0.0002), resident comfort level in discussing women's health topics and performing gynaecological exams (p<0.0002). Cervical cancer screening rates among IM residents' patients improved from 54% (pre-WPHC initiation) to 65% (post WPHC initiation period). DISCUSSION: The results indicate that a focused resident preventive programme can meet gaps identified by education and needs assessments, and simultaneously have a positive impact on cervical cancer screening rates and thus may serve as a model for other residency programmes. PMID- 20702436 TI - Quality measures for primary mental healthcare: a multistakeholder, multijurisdictional Canadian consensus. AB - OBJECTIVE: To develop quality measures using a consensus-based, multistakeholder process to improve delivery of mental health services within primary healthcare settings. METHODS: A three-stage consensus model culminating in a two-round, modified Delphi postal survey ranking quality measures according to 'actionability,' relevance and overall importance. PARTICIPANTS: More than 800 people from all 10 provinces and three territories in Canada participated in the study, representing consumers/advocates, clinicians, academics and government decision-makers from regional, provincial and federal levels. A small group with expertise in First Nations and rural-setting health issues was also included, as well as international experts. RESULTS: The top overall pan-Canadian measure was 'Education about Depression.' 'Actionability' was a key criterion for many of the top 30 measures. Fifty per cent of these measures focused on three major themes: depression, self-harm and access to a broader spectrum of treatment (such as outreach services and psychotherapy). Additional themes included the need for greater collaboration, respectful treatment of patients and families, and improved evaluation of patients. One-way ANOVA results indicated statistically significant differences (p <0.05) between academics, clinicians, consumers and decision-makers on approximately 5% of quality measure ratings. The majority (85% of the 5%) of these differences involved consumer stakeholders. CONCLUSION: A small set of specific consensus measures were identified through a rigorous, evidence-informed process. These measures can be used for system-wide changes or at the individual practice level. Although these measures have been developed within a Canadian context, the methodology utilised and the measures selected can be adapted elsewhere. PMID- 20702438 TI - Medication errors in paediatric outpatients. AB - BACKGROUND: Medication errors are common in many settings and have important ramifications. Although there is growing research on rates and characteristics of medication errors in adult ambulatory settings, less is known about the paediatric ambulatory setting. OBJECTIVE: To assess medication error rates in paediatric patients in ambulatory settings. METHODS: The authors conducted a prospective cohort study of paediatric patients in six outpatient offices in Massachusetts. Data were collected using duplicate prescription review, two parental surveys and chart review. A research nurse classified all medication errors by stage and type of error. RESULTS: The authors identified 1205 medication errors with minimal potential for harm (rate: 68% of patients, 95% CI 64 to 72%; 53% of Rx, 95% CI 50 to 56%) and 464 potentially harmful medication errors (ie, near misses) (rate: 26% of patients, 95% CI 24 to 28%; 21% of Rx, 95% CI 19 to 22%). Overall, 94% of the medication errors with minimal potential for harm and 60% of the near misses occurred at the prescribing stage. The most common types of errors were inappropriate abbreviations followed by dosing errors. The most frequent cause of errors was illegibility. CONCLUSION: With paper prescribing, half the prescriptions had medication errors, and one in five had a potentially harmful error. These rates are very high. Interventions targeting the ordering and administration stages have the greatest potential benefit. PMID- 20702439 TI - Improving prenatal HIV screening with tailored educational interventions: an approach to guideline implementation. AB - BACKGROUND: A healthy, uncomplicated pregnancy undergoes approximately 13 tests performed over an average of 12.5 prenatal visits. Published rates of compliance with routine prenatal testing are generally >90%, with lower rates for newer tests or those that require additional inputs prior to ordering. New CDC guidelines for prenatal HIV testing highlight the importance of prenatal testing and motivated the authors to explore our routine prenatal testing performance. The authors found the conceptual framework of simple/complicated/complex problems in healthcare helpful in understanding the rates for tests and for developing interventions. METHODS: The setting for this work was a single, rural, academic tertiary care centre. Baseline rates of four routine prenatal tests (HBsAg, 1 h GTT, GBS, HIV) were determined by analysing 12 months of data from a web-based delivery registry. All rates were >90% except HIV, which was 79.2%. Process mapping and discussions with ordering providers were performed to plan the improvement intervention. Targeted educational interventions specific to each ordering provider type were followed by audit and feedback. HIV testing rates were monitored and analysed monthly using process control charts. RESULTS: The HIV testing rate increased significantly from 79.2% to 94.2%. Rates greater than 90% were maintained for 10 of 11 months reported. CONCLUSIONS: Targeted educational interventions combined with audit and feedback can increase rates of routine testing successfully in an outpatient setting. These interventions can be used to improve implementation and compliance with new guidelines when informed by an understanding of local context and processes coupled with an appropriate conceptual framework. PMID- 20702437 TI - How "should" we write guideline recommendations? Interpretation of deontic terminology in clinical practice guidelines: survey of the health services community. AB - OBJECTIVE: To describe the level of obligation conveyed by deontic terms (words such as "should", "may", "must" and "is indicated") commonly found in clinical practice guidelines. DESIGN: Cross-sectional electronic survey. SETTING: A clinical scenario was developed by the researchers, and recommendations containing 12 deontic terms and phrases were presented to the participants. PARTICIPANTS: All 1332 registrants of the 2008 annual conference of the US Agency for Healthcare Research and Quality. MAIN OUTCOME MEASURES: Participants indicated the level of obligation they believed guideline authors intended by using a slider mechanism ranging from "No obligation" (leftmost position recorded as 0) to "Full obligation" (rightmost position recorded as 100.) RESULTS: 445/1332 registrants (36%) submitted the on-line survey; 254/445 (57%) reported that they have experience in developing clinical practice guidelines; 133/445 (30%) indicated that they provide healthcare. "Must" conveyed the highest level of obligation (median = 100) and least amount of variability (interquartile range = 5.) "May" (median = 37) and "may consider" (median = 33) conveyed the lowest levels of obligation. All other terms conveyed intermediate levels of obligation characterised by wide and overlapping interquartile ranges. CONCLUSIONS: Members of the health services community believe guideline authors intend variable levels of obligation when using different deontic terms within practice recommendations. Ranking of a subset of terms by intended level of obligation is possible. Matching deontic terminology to the intended recommendation strength can help standardise the use of deontic terminology by guideline developers. PMID- 20702440 TI - Economic evaluation of healthcare safety: which attributes of safety do healthcare professionals consider most important in resource allocation decisions? AB - INTRODUCTION: There is an increasing need to assess the value of safety improvements to society. Concerns exist, however, as to what extent standard health economic methods appropriately reflect this value because these methods do not typically incorporate the non-health or extra-consequentialist value of avoiding healthcare incidents, which may--for example, be associated with a decreased trust of patients and citizens in healthcare systems and providers. OBJECTIVES: (1) To identify health and non-health attributes of safety from the literature and (2) to prioritise those that are considered most important by healthcare decision-makers and could be included in a subsequent conjoint analysis to determining the relative value of safety interventions and the willingness to pay of decision-makers. METHODS: A literature review and 25 semistructured interviews have been conducted with healthcare decision-makers experienced in safety management, considering a general healthcare, Methicillin resistant Staphylococcus aureus (MRSA) and sharps injuries context. RESULTS: The literature review showed that in addition to likelihood of an incident and its direct medical and cost consequences, factors such as preventability, dread, controllability and trust in safety devices or systems affect the value of safety and decision-makers' willingness to pay. The interview results consistently indicated that "preventability of healthcare incidents", "health consequences", "financial consequences" and "trust in safety systems/devices" are the most important attributes across all contexts. In addition, context-specific attributes were identified. CONCLUSION: A set of four common and two context specific attributes, including health and non-health aspects of safety, was identified. The next step is to attaching appropriate levels to these attributes and to incorporate them into a series of case studies among various groups of decision-makers, healthcare professionals, patient groups and the general public. PMID- 20702441 TI - Departures from the protocol during conduct of a clinical trial: a pattern from the data record consistent with a learning curve. AB - OBJECTIVE: Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinised. The VALsartan In Acute myocardial iNfarcTion, a large multinational, pragmatic, randomised, double-blind, multicentre trial, was retrospectively evaluated for evidence of research conduct consistent with a performance "learning curve". DESIGN: Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (eg, first, second), recruitment rate and first enrollment relative to study start date. SETTING: Computerised data from a trial coordinated by an academic research organisation collaborating with 10 academic and 2 commercial research organisations and an industry sponsor. Interventions 931 sites enrolled 14,703 patients. Departures were restricted to the first year. Exclusions included patient's death or loss to follow-up within 12 months and subjects enrolled 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment and later start date. METHODS AND RESULTS: 12,367 patients at 931 sites were analysed. Departures were more common for patients enrolled earlier at a site (p<0.0001). For example, compared with the 30th patient, the first had 47% more departures. Departures were also more common with slower enrollment and site start closer to the trial start date (p<0.0001). Similar patterns existed for queries. CONCLUSIONS: Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a "learning curve". Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct. PMID- 20702442 TI - Tracing the foundations of a conceptual framework for a patient safety ontology. AB - BACKGROUND: In work for the World Alliance for Patient Safety on research methods and measures and on defining key concepts for an International Patient Safety Classification (ICPS), it became apparent that there was a need to try to understand how the meaning of patient safety and underlying concepts relate to the existing safety and quality frameworks commonly used in healthcare. OBJECTIVES: To unfold the concept of patient safety and how it relates to safety and quality frameworks commonly used in healthcare and to trace the evolution of the ICPS framework as a basis of the electronic capture of the component elements of patient safety. CONCLUSION: The ICPS conceptual framework for patient safety has its origins in existing frameworks and an international consultation process. Although its 10 classes and their semantic relationships may be used as a reference model for different disciplines, it must remain dynamic in the ever changing world of healthcare. By expanding the ICPS by examining data from all available sources, and ensuring rigorous compliance with the latest principles of informatics, a deeper interdisciplinary approach will progressively be developed to address the complex, refractory problem of reducing healthcare-associated harm. PMID- 20702443 TI - Use of an electronic information system to identify adverse events resulting in an emergency department visit. AB - OBJECTIVE: There is limited information about the nature of adverse events (AEs) that necessitate an emergency department (ED) visit. The objective of the current study was to demonstrate the feasibility of using routinely collected electronic data to identify AEs in patients presenting to EDs in one Canadian health authority. METHODS: This retrospective cross-sectional study occurred in EDs in two community hospitals, an outpatient community health centre and a tertiary care facility in the Capital District Health Authority in Nova Scotia, Canada between 1 November 2007 and 31 October 2008. The primary outcome was identification of an AE as the main reason for the ED visit. AEs were identified from electronic diagnostic data using previously validated screening criteria. RESULTS: There were 142,433 patient visits to the four EDs during the study period. A total of 1870 (1.3%) AEs were identified using the screening criteria. This included 1133 (0.8%) procedure-related, 673 (0.5%) drug-related, 63 (0.04%) device-related and one radiation-related AE. The AEs identified using this method were most likely the manifestation of treatment decisions made prior to the ED visit and/or related to care in other settings (eg, primary or long-term care, acute hospital care) including previous ED visits. INTERPRETATION: Although the use of electronic data significantly underestimates AEs treated in the ED, for relatively low cost, it provides new information on AEs arising from a variety of care settings that may otherwise not be captured. Significant and clinically important differences in healthcare utilisation underscore the value in identifying these AEs. PMID- 20702444 TI - Assessing teamwork attitudes in healthcare: development of the TeamSTEPPS teamwork attitudes questionnaire. AB - INTRODUCTION: The report, To Err is Human, indicated that a large number of deaths are caused by medical error. A central tenet of this report was that patient safety was not only a function of sophisticated healthcare technology and treatments, but also the degree to which healthcare professionals could perform effectively as teams. Research suggests that teamwork comprises four core skills: Leadership, Situation Monitoring, Mutual Support and Communication. In healthcare, team training programmes, such as TeamSTEPPS(r), are designed to improve participant knowledge of, attitudes towards, and skills in these core areas. If such training programmes are effective, changes in knowledge, attitudes and skills should be observed. The purpose of this study was to develop and validate the TeamSTEPPS Teamwork Attitudes Questionnaire (T-TAQ), a measure designed to assess attitudes towards the core components of teamwork in healthcare. METHOD: A pilot test version of the survey was developed and administered to 495 respondents from various healthcare organisations. RESULTS: Classical item statistics were used to select the final T-TAQ items. Based on this analysis, 30 of the original 110 items were selected for inclusion in the final instrument. Scale reliabilities exceed 0.7, and scales were found to be moderately correlated. DISCUSSION: The T-TAQ provides a useful, reliable and valid tool for assessing individual attitudes related to the role of teamwork in the delivery of healthcare. Issues related to its use and interpretation are discussed. PMID- 20702445 TI - Clinical handover in the trauma setting: a qualitative study of paramedics and trauma team members. AB - BACKGROUND: Clinical handover between paramedics and the trauma team is undertaken in a time-pressured environment. Paramedics are often required to handover complex problems to a multitude of staff. There is evidence that information loss occurs at this transition. The aims of this project were to (1) develop a minimum dataset to assist paramedics provide handover; (2) identify attributes of effective and ineffective handover; (3) determine the feasibility of advanced data transmission; and (4) identify how to best display data in trauma bays. METHODS: Qualitative study of paramedics and trauma team members. A thematic analysis was undertaken using grounded theory. RESULTS: Ten paramedics and 17 trauma team members were interviewed. A minimum dataset modified on an existing template was developed to include fields required by the trauma team to inform immediate treatment. Respondents stated that an effective handover was one which was delivered succinctly and in a structured manner, and contained only vital data necessary to direct immediate treatment. Advanced transmission of data to the receiving hospital was widely supported. While computers carried by paramedics were capable of exporting data to the receiving hospital, barriers such as time constraints, workflow issues and infection control issues impeded the ability to do this in the current environment. DISCUSSION: There is support for the adoption and further evaluation of a handover template. It can provide valuable structure to the face-to-face handover, and experience from other specialties suggests it can reduce information loss. Strategies to enable information to be transmitted in advance of the patients' arrival must address concerns voiced by paramedics. PMID- 20702446 TI - That's a good idea--forget it or test it? The case of sudden infant death. PMID- 20702447 TI - Cooperative medical insurance and the cost of care in Shandong, PR China: perspectives of patients and community members. AB - This research was conducted to identify the cost of care associated with utilization of village clinics and membership of the New Cooperative Medical Scheme (NCMS) in 2 counties of Shandong province, PR China. A total of 397 community members and 297 patients who used the village clinics were interviewed. The average cost for primary care treatment of 1 episode of illness was about 55 yuan (about US$8). Although more than 50% of people had NCMS membership, many consider the monetary reimbursements as insufficient. The low insurance reimbursement rates and inability to pay out-of-pocket expenses compromise access to care. Delays can cause more serious illnesses with potential to overburden the secondary care at the township and county hospitals. Those rural people who have not yet enjoyed the benefits of China's economic development may not benefit from recent health care reform and finance mechanisms unless schemes such as the NCMS provide more substantial subsidies. PMID- 20702448 TI - Lipopolymer gradient diffusion in supported bilayer membranes. AB - We measure the gradient diffusion coefficient of a model lipopolymer in supported lipid bilayer membranes from Fourier-transform post-electrophoresis relaxation. The experiments and accompanying quantitative interpretation furnish the concentration dependence of the gradient diffusion coefficient. In striking contrast to the recent measurements of the self-diffusion coefficient from fluorescence recovery after photobleaching, the lipopolymer gradient diffusion coefficient increases with concentration. We interpret the enhancement at small but finite concentrations using the Scalettar-Abney-Owicki (SAO) statistical mechanical theory (1988) and the Bussell-Koch-Hammer (BKH) hydrodynamic theory (1995), which are customarily adopted to model membrane protein dynamics. The SAO theory furnishes an effective disc radius and soft repulsive interaction radius that are comparable to the Flory radius of the unperturbed polyethylene glycol chains. On the other hand, the BKH theory predicts a gradient diffusion coefficient that decreases with disc/membrane protein concentration. Thus, in contrast to membrane proteins, we conclude that lipopolymer hydrodynamic interactions are weak because the principal disturbances are in the low-viscosity aqueous phase. Accordingly, lipopolymer interactions are dominated by thermodynamic interactions among polymer chains. Interestingly, our experiments suggest that increasing (decreasing) the polymer molecular weight should increase (decrease) the relaxation rate of lipopolymer concentration fluctuations. PMID- 20702450 TI - Hibernation does not affect memory retention in bats. AB - Long-term memory can be critically important for animals in a variety of contexts, and yet the extreme reduction in body temperature in hibernating animals alters neurochemistry and may therefore impair brain function. Behavioural studies on memory impairment associated with hibernation have been almost exclusively conducted on ground squirrels (Rodentia) and provide conflicting results, including clear evidence for memory loss. Here, we for the first time tested memory retention after hibernation for a vertebrate outside rodents-bats (Chiroptera). In the light of the high mobility, ecology and long life of bats, we hypothesized that maintenance of consolidated memory through hibernation is under strong natural selection. We trained bats to find food in one out of three maze arms. After training, the pre-hibernation performance of all individuals was at 100 per cent correct decisions. After this pre-test, one group of bats was kept, with two interruptions, at 7 degrees C for two months, while the other group was kept under conditions that prevented them from going into hibernation. The hibernated bats performed at the same high level as before hibernation and as the non-hibernated controls. Our data suggest that bats benefit from an as yet unknown neuroprotective mechanism to prevent memory loss in the cold brain. PMID- 20702449 TI - Response dynamics of phosphorelays suggest their potential utility in cell signalling. AB - Phosphorelays are extended two-component signalling systems found in diverse bacteria, lower eukaryotes and plants. Only few of these systems are characterized, and we still lack a full understanding of their signalling abilities. Here, we aim to achieve a global understanding of phosphorelay signalling and its dynamical properties. We develop a generic model, allowing us to systematically analyse response dynamics under different assumptions. Using this model, we find that the steady-state concentration of phosphorylated protein at the final layer of a phosphorelay is a linearly increasing, but eventually saturating function of the input. In contrast, the intermediate layers can display ultrasensitivity. We find that such ultrasensitivity is a direct result of the phosphorelay biochemistry; shuttling of a single phosphate group from the first to the last layer. The response dynamics of the phosphorelay results in tolerance of cross-talk, especially when it occurs as cross-deactivation. Further, it leads to a high signal-to-noise ratio for the final layer. We find that a relay length of four, which is most commonly observed, acts as a saturating point for these dynamic properties. These findings suggest that phosphorelays could act as a mechanism to reduce noise and effects of cross-talk on the final layer of the relay and enforce its input-response relation to be linear. In addition, our analysis suggests that middle layers of phosphorelays could embed thresholds. We discuss the consequence of these findings in relation to why cells might use phosphorelays along with enzymatic kinase cascades. PMID- 20702451 TI - Orangutan pantomime: elaborating the message. AB - We present an exploratory study of forest-living orangutan pantomiming, i.e. gesturing in which they act out their meaning, focusing on its occurrence, communicative functions, and complexities. Studies show that captive great apes may elaborate messages if communication fails, and isolated reports suggest that great apes occasionally pantomime. We predicted forest-living orangutans would pantomime spontaneously to communicate, especially to elaborate after communication failures. Mining existing databases on free-ranging rehabilitant orangutans' behaviour identified 18 salient pantomimes. These pantomimes most often functioned as elaborations of failed requests, but also as deceptions and declaratives. Complexities identified include multimodality, re-enactments of past events and several features of language (productivity, compositionality, systematicity). These findings confirm that free-ranging rehabilitant orangutans pantomime and use pantomime to elaborate on their messages. Further, they use pantomime for multiple functions and create complex pantomimes that can express propositionally structured content. Thus, orangutan pantomime serves as a medium for communication, not a particular function. Mining cases of complex great ape communication originally reported in functional terms may then yield more evidence of pantomime. PMID- 20702453 TI - Genomics in the ecological arena. AB - This meeting report presents the cutting-edge research that is developing around the waterflea Daphnia, an emerging model system in environmental genomics. Daphnia has been a model species in ecology, toxicology and evolution for many years and is supported by a large community of ecologists, evolutionary biologists and ecotoxicologists. Thanks to new advances in genomics and transciptomics and to the sustained efforts of the Daphnia Genomics Consortium (DGC), Daphnia is also rapidly developing as a model system in environmental genomics. Advances in this emerging field were presented at the DGC 2010, held for the first time in a European University. During the meeting, a plethora of elegant studies were presented on the mechanisms of responses to environmental challenges using recently developed genomic tools. The DGC 2010 is a concrete example of the new trends in ecology and evolution. The times are mature for the application of innovative genomic and transcriptomic tools for studies of environmental genomics in non-model organisms. PMID- 20702452 TI - Evidence for heterozygote instability in microsatellite loci in house wrens. AB - Microsatellite loci have high mutation rates and high levels of allelic variation, but the factors influencing their mutation rate are not well understood. The proposal that heterozygosity may increase mutation rates has profound implications for understanding the evolution of microsatellite loci, but currently has limited empirical support. We examined 20 microsatellite mutations identified in an analysis of 12 260 meiotic events across three loci in two populations of a songbird, the house wren (Troglodytes aedon). We found that for an allele of a given length, mutation was significantly more likely when there was a relatively large difference in size between the allele and its homologue (i.e. a large 'allele span'). Our results support the proposal of heterozygote instability at microsatellite loci. PMID- 20702455 TI - Women's health across the life span: contributions from nursing science. PMID- 20702454 TI - Temperature effects on parasite prevalence in a natural hybrid complex. AB - Both host susceptibility and parasite infectivity commonly have a genetic basis, and can therefore be shaped by coevolution. However, these traits are often sensitive to environmental variation, resulting in genotype-by-environment interactions. We tested the influence of temperature on host-parasite genetic specificity in the Daphnia longispina hybrid complex, exposed to the protozoan parasite Caullerya mesnili. Infection rates were higher at low temperature. Furthermore, significant differences between host clones, but not between host taxa, and a host genotype-by-temperature interaction were observed. PMID- 20702456 TI - The association between the rs2234693 and rs9340799 estrogen receptor alpha gene polymorphisms and risk factors for cardiovascular disease: a review. AB - Although estrogen is primarily thought of as the hormone involved in female reproduction, it also plays a role in many additional physiological and pathological processes. Recent studies have demonstrated an association between estrogen and clustered risk factors for cardiovascular disease (CVD), such as lipid and glucose metabolism and obesity-related phenotypes, as well as occurrence and severity of CVD. Evidence suggesting a genetic basis for this link is accumulating. Several polymorphisms of the estrogen receptor (ER) alpha (ESR1) gene exist that may influence the impact of estrogen, leading to clinically relevant phenotypes. Based on the relationship ERS1 seems to exhibit with CVD risk factors, these polymorphisms may play a role in the mediation of vasoprotective effects, modulation of cardiovascular physiology, and development of risk factors for CVD. The two most frequently studied polymorphisms located in ESR1 are often identified by their restriction endonucleases Pvull (rs2234693) and Xbal (rs9340799). ln this review, we have evaluated and summarized the results of studies involving rs2234693 and rs9340799 and clustered risk factors accompanying development of CVD. Despite inconsistent findings, together these studies provide some support for a relationship between polymorphisms in ESR1 and risk factors for CVD. These summarized findings do not yet support inclusion of ESR1 genotypes in genetic testing algorithms for predisposition to CVD, but they do indicate that further investigation into the potential connection between ESR1 and risk factors for CVD is warranted. PMID- 20702457 TI - Bones as biofuel: a review of whale bone composition with implications for deep sea biology and palaeoanthropology. AB - Whales are unique among vertebrates because of the enormous oil reserves held in their soft tissue and bone. These 'biofuel' stores have been used by humans from prehistoric times to more recent industrial-scale whaling. Deep-sea biologists have now discovered that the oily bones of dead whales on the seabed are also used by specialist and generalist scavenging communities, including many unique organisms recently described as new to science. In the context of both cetacean and deep-sea invertebrate biology, we review scientific knowledge on the oil content of bone from several of the great whale species: Balaenoptera musculus, Balaenoptera physalus, Balaenoptera borealis, Megaptera novaeangliae, Eschrichtius robustus, Physeter macrocephalus and the striped dolphin, Stenella coeruleoalba. We show that data collected by scientists over 50 years ago during the heyday of industrial whaling explain several interesting phenomena with regard to the decay of whale remains. Variations in the lipid content of bones from different parts of a whale correspond closely with recently observed differences in the taphonomy of deep-sea whale carcasses and observed biases in the frequency of whale bones at archaeological sites. PMID- 20702458 TI - Conditions for mutation-order speciation. AB - Two models for speciation via selection have been proposed. In the well-known model of 'ecological speciation', divergent natural selection between environments drives the evolution of reproductive isolation. In a second 'mutation-order' model, different, incompatible mutations (alleles) fix in different populations adapting to the same selective pressure. How to demonstrate mutation-order speciation has been unclear, although it has been argued that it can be ruled out when gene flow occurs because the same, most advantageous allele will fix in all populations. However, quantitative examination of the interaction of factors influencing the likelihood of mutation-order speciation is lacking. We used simulation models to study how gene flow, hybrid incompatibility, selective advantage, timing of origination of new mutations and an initial period of allopatric differentiation affect population divergence via the mutation-order process. We find that at least some population divergence can occur under a reasonably wide range of conditions, even with moderate gene flow. However, strong divergence (e.g. fixation of different alleles in different populations) requires very low gene flow, and is promoted when (i) incompatible mutations have similar fitness advantages, (ii) less fit mutations arise slightly earlier in evolutionary time than more fit alternatives, and (iii) allopatric divergence occurs prior to secondary contact. PMID- 20702459 TI - A congruent solution to arthropod phylogeny: phylogenomics, microRNAs and morphology support monophyletic Mandibulata. AB - While a unique origin of the euarthropods is well established, relationships between the four euarthropod classes-chelicerates, myriapods, crustaceans and hexapods-are less clear. Unsolved questions include the position of myriapods, the monophyletic origin of chelicerates, and the validity of the close relationship of euarthropods to tardigrades and onychophorans. Morphology predicts that myriapods, insects and crustaceans form a monophyletic group, the Mandibulata, which has been contradicted by many molecular studies that support an alternative Myriochelata hypothesis (Myriapoda plus Chelicerata). Because of the conflicting insights from published molecular datasets, evidence from nuclear coding genes needs corroboration from independent data to define the relationships among major nodes in the euarthropod tree. Here, we address this issue by analysing two independent molecular datasets: a phylogenomic dataset of 198 protein-coding genes including new sequences for myriapods, and novel microRNA complements sampled from all major arthropod lineages. Our phylogenomic analyses strongly support Mandibulata, and show that Myriochelata is a tree reconstruction artefact caused by saturation and long-branch attraction. The analysis of the microRNA dataset corroborates the Mandibulata, showing that the microRNAs miR-965 and miR-282 are present and expressed in all mandibulate species sampled, but not in the chelicerates. Mandibulata is further supported by the phylogenetic analysis of a comprehensive morphological dataset covering living and fossil arthropods, and including recently proposed, putative apomorphies of Myriochelata. Our phylogenomic analyses also provide strong support for the inclusion of pycnogonids in a monophyletic Chelicerata, a paraphyletic Cycloneuralia, and a common origin of Arthropoda (tardigrades, onychophorans and arthropods), suggesting that previous phylogenies grouping tardigrades and nematodes may also have been subject to tree-reconstruction artefacts. PMID- 20702460 TI - Irrational decision-making in an amoeboid organism: transitivity and context dependent preferences. AB - Most models of animal foraging and consumer choice assume that individuals make choices based on the absolute value of items and are therefore 'economically rational'. However, frequent violations of rationality by animals, including humans, suggest that animals use comparative valuation rules. Are comparative valuation strategies a consequence of the way brains process information, or are they an intrinsic feature of biological decision-making? Here, we examine the principles of rationality in an organism with radically different information processing mechanisms: the brainless, unicellular, slime mould Physarum polycephalum. We offered P. polycephalum amoebas a choice between food options that varied in food quality and light exposure (P. polycephalum is photophobic). The use of an absolute valuation rule will lead to two properties: transitivity and independence of irrelevant alternatives (IIA). Transitivity is satisfied if preferences have a consistent, linear ordering, while IIA states that a decision maker's preference for an item should not change if the choice set is expanded. A violation of either of these principles suggests the use of comparative rather than absolute valuation rules. Physarum polycephalum satisfied transitivity by having linear preference rankings. However, P. polycephalum's preference for a focal alternative increased when a third, inferior quality option was added to the choice set, thus violating IIA and suggesting the use of a comparative valuation process. The discovery of comparative valuation rules in a unicellular organism suggests that comparative valuation rules are ubiquitous, if not universal, among biological decision makers. PMID- 20702461 TI - Host plant quality, selection history and trade-offs shape the immune responses of Manduca sexta. AB - Immune defences are an important component of fitness. Yet susceptibility to pathogens is common, suggesting the presence of ecological and evolutionary limitations on immune defences. Here, we use structural equation modelling to quantify the direct effects of resource quality and selection history, and their indirect effects mediated via body condition prior to an immune challenge on encapsulation and melanization immune defences in the tobacco hornworm, Manduca sexta. We also investigate allocation trade-offs among immune defences and growth rate following an immune challenge. We found considerable variation in the magnitude and direction of the direct effects of resource quality and selection history on immune defences and their indirect effects mediated via body condition and allocation trade-offs. Greater resource quality and evolutionary exposure to pathogens had positive direct effects on encapsulation and melanization. The indirect effect of resource quality on encapsulation mediated via body condition was substantial, whereas indirect effects on melanization were negligible. Individuals in better condition prior to the immune challenge had greater encapsulation; however, following the immune challenge, greater encapsulation traded off with slower growth rate. Our study demonstrates the importance of experimentally and analytically disentangling the relative contributions of direct and indirect effects to understand variation in immune defences. PMID- 20702464 TI - Reference dose levels for dental panoramic radiography in Gwangju, South Korea. AB - This study assessed the reference dose levels for dental panoramic radiography in Gwangju city, South Korea based on the dose width product (DWP) and compared them with those already established elsewhere. A total of 44 panoramic dental radiographic sets (36 digital and 8 analogue panoramic sets) in 41 dental clinics in Gwangju city were chosen. The third quartile DWP was determined from 429 surface dose measurements of the adult surface dose in panoramic dental radiography. The third quartile DWP for panoramic radiography was 60.1 mGy mm. The proposed DWP reference levels of 60.1 mGy mm were less than or equal to those previously reported in other countries, such as Italy and UK, and acceptable for panoramic radiography in Gwangju, South Korea. PMID- 20702466 TI - The serrated polyp: getting it right! PMID- 20702465 TI - Abscisic acid activates a Ca2+-calmodulin-stimulated protein kinase involved in antioxidant defense in maize leaves. AB - The role of a calcium-dependent and calmodulin (CaM)-stimulated protein kinase in abscisic acid (ABA)-induced antioxidant defense was determined in leaves of maize (Zea mays). In-gel kinase assays showed that treatments with ABA or H(2)O(2) induced the activation of a 49-kDa protein kinase and a 52-kDa protein kinase significantly. Furthermore, we showed that the 52-kDa protein kinase has the characteristics of CaM-stimulating activity and is sensitive to calcium-CaM dependent protein kinase II (CaMK II) inhibitor KN-93 or CaM antagonist W-7. Treatments with ABA or H(2)O(2) not only induced the activation of the 52-kDa protein kinase, but also enhanced the total activities of the antioxidant enzymes, including catalase, ascorbate peroxidase, glutathione reductase, and superoxide dismutase. Such enhancements were blocked by pretreatment with a CaMK inhibitor and a reactive oxygen species (ROS) inhibitor or scavenger. Pretreatment with the CaMK inhibitor also substantially arrested the ABA-induced H(2)O(2) production. Kinase activity enhancements induced by ABA were attenuated by pretreatment with an ROS inhibitor or scavenger. These results suggest that the 52-kDa CaMK is involved in ABA-induced antioxidant defense and that cross talk between CaMK and H(2)O(2) plays a pivotal role in ABA signaling. We infer that CaMK acts both upstream and downstream of H(2)O(2), but mainly acts between ABA and H(2)O(2) in ABA-induced antioxidant-defensive signaling. PMID- 20702463 TI - IL-2 therapy: potential impact of the CD4 cell count at initiation on clinical efficacy--results from the ANRS CO4 cohort. AB - OBJECTIVES: We investigated why, despite its beneficial effect on the CD4 cell count, IL-2 therapy had no clinical benefit as shown in the ESPRIT and SILCAAT trials. We focused on subgroups of patients defined according to CD4 cell counts at baseline and over time to assess the threshold above which IL-2 therapy was no longer beneficial in a large cohort of HIV-1 infected patients. METHODS: Within the French Hospital Database on HIV, a total of 953 IL-2-treated patients were compared with 27 750 IL-2-untreated patients, matched for the date of enrolment, sex, age, and the baseline CD4 cell count and plasma HIV-1 RNA level. The risk of clinical progression, defined as the occurrence of a new AIDS-defining event or death, was studied with multivariable Cox proportional hazards models and Poisson regression models. RESULTS: We found no clinical benefit in patients starting IL 2 with CD4 count >=200 cells/mm(3) [hazard ratio (HR) =1.13; 95% confidence interval (CI), 0.81-1.57], while a benefit was observed in patients with CD4 count <200 cells/mm(3) (HR=0.64; 95% CI, 0.48-0.86). The observed benefit was due to the risk reduction in the 100-350/mm(3) stratum of updated CD4 cell counts (relative rate=0.30; 95% CI, 0.09-1.03). CONCLUSIONS: Higher CD4 cell counts at enrolment and shorter follow-up with low to intermediate CD4 cell counts may explain why IL-2 therapy had no observed clinical benefit in the SILCAAT study. Our findings suggest that the benefit of IL-2 is restricted to a narrow range of CD4 cell counts, arguing against the use of IL-2 in HIV infection to reduce the risk of clinical events. PMID- 20702467 TI - Does a gating policy for ANCA overlook patients with ANCA associated vasculitis? An audit of 263 patients. AB - BACKGROUND: Antineutrophil cytoplasm antibodies (ANCA) are used as diagnostic markers for small-vessel vasculitis of the Wegener Granulomatosis-microscopic polyangiitis (WG-MPA) spectrum, but if testing is applied indiscriminately, its value is diminished. The authors measured the effect of a targeted ANCA testing policy introduced in our institution in an attempt to improve the diagnostic value of testing in patients with suspected vasculitis. METHODS: The authors measured the rate of ANCA requests at a single regional centre in the year prior to and following the introduction of clinical guidelines to ensure appropriate test usage. The authors also audited clinical outcomes in patients in whom ANCA testing was declined. RESULT: Following implementation of the antineutrophil cytoplasm antibodies (ANCA) gating policy, the number of monthly ANCA tests carried out fell from 287+/-30 to 143+/-18 (p<0.0001) and was associated with an increased rate of positivity, from 18.5% (95% CI 17.0 to 20.1%) to 30.3% (27.5 to 33.1%; p<0.0001). The authors undertook a careful review of the case records from 263 patients in whom testing was declined according to the gating policy over an 8-month period. After 6 months' follow-up, no diagnoses of small-vessel vasculitis of the WG-MPA spectrum were reached. CONCLUSIONS: The rational use of ANCA testing to aid in the diagnosis of vasculitis should include a clinical gating policy to improve diagnostic performance. Adherence to a gating policy for ANCA testing coupled with close liaison between clinician and laboratory does not result in either a missed or delayed diagnosis of small-vessel vasculitis belonging to the WG-MPA spectrum. PMID- 20702468 TI - Age-dependent prognostic effects of EGFR/p53 alterations in glioblastoma: study on a prospective cohort of 140 uniformly treated adult patients. AB - AIMS: To assess the prognostic influence of EGFR amplification/overexpression, p53 immunoreactivity and their age-dependent prognostic effects in a large prospective cohort of uniformly treated adult patients with newly diagnosed glioblastoma. METHODS: Tumours from a uniformly treated prospective cohort of adult patients with newly diagnosed glioblastoma (n=140) were examined for EGFR amplification by fluorescence in situ hybridisation and EGFR/p53 expression by immunohistochemistry. Statistical methods were employed to assess the degree of association between EGFR amplification/overexpression and p53 immunopositivity. Survival analyses were performed by employing Cox proportional hazard models to assess the independent prognostic value of EGFR/p53 alterations and test the propensity for risk with age by assessing their interaction with patient age. RESULTS: A strong positive correlation between EGFR amplification and EGFR overexpression (rho=0.5157; p<0.0001; CI 0.3783 to 0.6309) and a negative association of EGFR amplification (rho=-0.3417; p<0.0001; CI -0.4842 to -0.1816) and EGFR overexpression (rho=-0.3095; p<0.001; CI -0.4561 to -0.1465) with p53 immunopositivity was observed. Only patient age (HR: 1.029; p=0.004; CI 1.009 to 1.049) was associated with shorter survival by univariate Cox regression analysis. Multivariable Cox proportional hazards models revealed a statistically significant interaction between EGFR overexpression and age to be associated with shorter survival (HR: 1.001; p<0.0001; CI 1.000 to 1.002), thus predicting a higher hazard with increasing age. No age interaction of EGFR amplification status (HR: 1.001; p=0.642; CI 0.995 to 1.008) and p53 immunopositivity (HR: 1.000; p=0.841; CI 0.999 to 1.001) was noted in this cohort. CONCLUSIONS: The prognostic value of EGFR overexpression is age-dependent, and there is a propensity for a higher hazard with increasing patient age. Identifying such groups of patients with more aggressive disease becomes mandatory, since they would benefit from intense therapeutic protocols targeting EGFR. PMID- 20702462 TI - Complete DNA barcode reference library for a country's butterfly fauna reveals high performance for temperate Europe. AB - DNA barcoding aims to accelerate species identification and discovery, but performance tests have shown marked differences in identification success. As a consequence, there remains a great need for comprehensive studies which objectively test the method in groups with a solid taxonomic framework. This study focuses on the 180 species of butterflies in Romania, accounting for about one third of the European butterfly fauna. This country includes five eco regions, the highest of any in the European Union, and is a good representative for temperate areas. Morphology and DNA barcodes of more than 1300 specimens were carefully studied and compared. Our results indicate that 90 per cent of the species form barcode clusters allowing their reliable identification. The remaining cases involve nine closely related species pairs, some whose taxonomic status is controversial or that hybridize regularly. Interestingly, DNA barcoding was found to be the most effective identification tool, outperforming external morphology, and being slightly better than male genitalia. Romania is now the first country to have a comprehensive DNA barcode reference database for butterflies. Similar barcoding efforts based on comprehensive sampling of specific geographical regions can act as functional modules that will foster the early application of DNA barcoding while a global system is under development. PMID- 20702470 TI - Association of metabolic syndrome and IgA nephropathy. AB - BACKGROUND: The disorders associated with metabolic syndrome (MS) can lead to renal disease. IgA nephropathy is the most common form of glomerulonephritis, and many patients with this disorder progress to renal failure. AIMS: To identify the effect of MS on IgA nephropathy by retrospectively comparing patients who had IgA nephropathy and MS with those who had IgA nephropathy alone. METHODS: 30 patients with MS and IgA nephropathy (MS group), and 30 matched controls with IgA nephropathy alone (non-MS group) were enrolled. IgA nephropathy was diagnosed by renal biopsy; activity and severity was graded by two classification systems. MS was diagnosed by criteria of the Diabetes Society of the Chinese Medical Association. RESULTS: Simple and multiple linear regression models (which adjusted for age, gender and body surface area) showed that only hypertension significantly affected serum creatinine, an indicator of the clinical severity of renal disease. Simple and multiple linear regression models (which adjusted for age, gender and body surface area) also showed that hypertensive patients had higher Katafuchi scores, an indicator of the pathological severity of renal disease. CONCLUSION: Among the disorders associated with MS, hypertension is the most important factor for renal disease. PMID- 20702469 TI - Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis. AB - AIM: To test the contribution of programmed cell death 4 (PDCD4) tumour suppressor gene in Barrett's carcinogenesis. METHODS: PDCD4 immunohistochemical expression was assessed in 88 biopsy samples obtained from histologically proven long-segment Barrett's mucosa (BM; 25 non-intestinal columnar metaplasia, 25 intestinal metaplasia (IM), 16 low-grade intraepithelial neoplasia (LG-IEN), 12 high-grade IEN (HG-IEN) and 10 Barrett's adenocarcinoma (BAc)). As controls, 25 additional samples of native oesophageal mucosa (N) were obtained from patients with dyspepsia. To further support the data, the expression levels of miR-21, an important PDCD4 expression regulator, in 14 N, 5 HG-IEN and 11 BAc samples were determined by quantitative real-time PCR analysis. Results PDCD4 immunostaining decreased progressively and significantly with the progression of the phenotypic changes occurring during Barrett's carcinogenesis (p<0.001). Normal basal squamous epithelial layers featured strong PDCD4 nuclear immunoreaction (mostly coexisting with weak-moderate cytoplasmic staining). Non-intestinal columnar metaplasia and intestinal metaplasia preserved a strong nuclear immunostaining; conversely, a significant decrease in PDCD4 nuclear expression was seen in dysplastic (LG-IEN and HG-IEN) and neoplastic lesions. Weak-moderate cytoplasmic immunostaining was evident in cases of LG-IEN, while HG-IEN and BAc samples showed weak cytoplasmic or no protein expression. As expected, miR-21 expression was significantly upregulated in HG-IEN and BAc samples, consistently with PDCD4 dysregulation. CONCLUSIONS: These data support a significant role for PDCD4 downregulation in the progression of BM to BAc, and confirm miR-21 as a negative regulator of PDCD4 in vivo. Further efforts are needed to validate PDCD4 as a potential prognostic marker in patients with Barrett's oesophagus. PMID- 20702472 TI - Leiomyosarcoma of the urinary bladder: a clinicopathological study of 34 cases. AB - BACKGROUND: Leiomyosarcomas of the urinary bladder (LMS-UB) are rare, usually aggressive neoplasms. Owing to their rarity, only a limited number of cases with clinical follow-up information have been published. There is no current consensus on LMS-UB grading, and it is unknown whether the widely accepted Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) and National Cancer Institute (NCI) grading systems of soft-tissue sarcomas are applicable to LMS-UB. METHODS: The authors studied 34 well-characterised LMS-UB and compared the prognostic power of the FNCLCC and NCI systems with that of one published grading scheme for LMS-UB (Mayo). All available slides from 34 LMS-UB were retrieved and evaluated with regards to degree of differentiation, mitotic rate/10 high-powered fields (HPF), and % necrosis. Cases were graded using published criteria for the FNCLCC, NCI and Mayo schemes. Follow-up information was obtained. RESULTS: The tumours occurred in 17 females and 17 males, ranging from 31 to 91 years (median 65), and measured 2-12 cm in size. One tumour was well differentiated, 17 tumours were moderately differentiated, and 16 tumours were poorly differentiated. Mitotic rates ranged from 1 to >30/10 HPF (median 12/10 HPF), and tumours showed 0-60% necrosis (median 25%). FNCLCC grades were 1 (3), 2 (12) and 3 (19). NCI grades were 1 (2), 2 (11) and 3 (21). Mayo grades were low (7) and high (27). FNCLCC and NCI grades were identical in 23/34 cases (68%). Four cases were FNCLCC/NCI grade 2 or 3 and Mayo low-grade. Clinical follow-up was available for 25 of 34 patients (74%). Clinical follow-up of > or =12 months was available for 17 of these 25 cases (68%) with a median follow-up duration of 52 months (range 12-120 months). Adverse outcome was seen in nine of these 17 patients (53%). Seven of the eight cases (88%) with a clinical follow-up duration of <12 months died of their disease. Overall, adverse outcome was documented in 16 of 25 (64%) cases. Metastatic disease was seen in 13 of 25 (52%) cases, with the lungs being the most common site of metastasis (62%). Adverse outcome was noted in 15 of 23 (65%) of FNCLCC grade 2 or 3 LMS-UB, as compared with zero of two (0%) FNCLCC grade 1 tumours (p=0.15), in 15 of 23 (65%) NCI grade 2 or 3 LMS-UB, versus zero of two (0%) NCI grade 1 sarcomas (p=0.17) and in 13 of 20 (65%) Mayo high grade LMS-UB, as opposed to two of five (40%) low-grade lesions (all results not statistically significant). CONCLUSIONS: The authors conclude that LMS-UB occurs in older adults of either sex and is characterised by aggressive behaviour, with adverse outcome in >60% of cases. Certain advantages of the FNCLCC system may support its more widespread adoption for future studies. PMID- 20702471 TI - Expression of intestinal MUC17 membrane-bound mucin in inflammatory and neoplastic diseases of the colon. AB - AIM: To determine the cellular location and expression of MUC17 mucin in specimens of normal, inflamed and neoplastic colon. METHODS: Immunohistochemical analysis of human surgical resection specimens (n=106) was performed with a specific antibody to the MUC17 apomucin protein. A semi-quantitative scoring system was used to measure MUC17 expression. In various colon cancer cell lines, the MUC17 expression was examined by immunoblot analysis and normal RT-PCR. RESULTS: MUC17 was highly expressed on the surface epithelium and crypts of colonic mucosa. In contrast, the expression of MUC17 was significantly decreased in colonic mucosa of chronic ulcerative colitis (p<0.0001) and ischaemic colitis (p=0.003). Similarly, MUC17 expression was decreased in hyperplastic polyps (p=0.0003), tubular and tubulovillous adenomas (p<0.0001) and colon cancers (p<0.0001). Furthermore, of eight different colon cancer cell lines, MUC17 expression was only detected in LS174T and LS180 cells. CONCLUSION: Results indicate that the potential protective effects of this membrane-bound mucin are primarily or secondarily diminished in inflammatory and neoplastic conditions. Further research is needed to determine the specific role of MUC17 in the pathogenesis of these conditions. PMID- 20702473 TI - Different patterns of BK and JC polyomavirus reactivation following renal transplantation. AB - AIM: Reactivation of latent BK polyomavirus (BKV) infection is relatively common following renal transplantation and BKV-associated nephropathy has emerged as a significant complication. JC polyomavirus (JCV) reactivation is less well studied. The aim of the study was to determine reactivation patterns for these polyomaviruses in renal transplant recipients using an in-house quantitative real time multiplex PCR assay and IgG serological assays using recombinant BK and JC virus-like particles. METHODS: Retrospective analysis of urine and plasma samples collected from 30 renal transplant patients from February 2004 to May 2005 at Leeds Teaching Hospitals NHS Trust. Samples were collected at 5 days and thereafter at 1, 3, 6 and 12 months post-transplantation. RESULTS: Eight patients (26.7%) were positive for BK viruria; three of these patients submitted plasma samples and two had BK viraemia. Five patients (16.7%) were positive for JC viruria. A corresponding rise in BKV and JCV antibody titres was seen in association with high levels of viruria. CONCLUSIONS: Different patterns of reactivation were observed: BK viruria was detected after 3-6 months, and JC viruria was observed as early as 5 days post-transplantation. One patient had biopsy-proven BKV nephropathy. No dual infections were seen. In order to ensure better graft survival, early diagnosis of these polyomaviruses is desirable. PMID- 20702474 TI - Lyophilised plasma: evaluation of clotting factor activity over 6 days after reconstitution for transfusion. AB - AIMS: Little is known about long-term stability of clotting factors in dissolved human lyophilised plasma. This study evaluated clotting factor and inhibitor activity in reconstituted lyophilised plasma after storage for up to 6 days at 4 degrees C. METHODS: Five samples from different lots of pooled lyophilised plasma (LyoPlas; German Red Cross Blood Transfusion Service West) were reconstituted. The activity of fibrinogen, factor II (FII), FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, antithrombin, plasmin inhibitor, von Willebrand factor antigen, free protein S and protein C were determined immediately and at 2, 4, 6, 24, 48, 72, 96, 120 and 144 h after reconstitution. Tests for bacterial contamination were performed after 12, 72 and 144 h from each plasma bottle. RESULTS: Storage at 4 degrees C for 6 h led to a decrease in the activity of FVIII (Delta -14.9%), FIX (Delta -6.9%) and FXI (Delta -6.3%), and an increase in the activity of plasmin inhibitor (Delta +10.2%). Storage for up to 6 days resulted in a further decrease in activity of FVIII (Delta -24.3%), FIX (Delta -13.4%) and FXI (Delta -22.9%), and, additionally, a decrease in the activity of FV (Delta -15.0%), fibrinogen (Delta -6.9%) and plasmin inhibitor (Delta -17.5%). Other factors and inhibitors, with exception of protein C (Delta +8.2%), remained almost unchanged over time. Blood cultures were sterile and showed no bacterial growth. CONCLUSIONS: The activity of all measured coagulation factors and inhibitors in a time course of up to 6 days met required quality standards. Further in vivo testing is required to demonstrate safety and efficacy of extended clinical use of refrigerated reconstituted lyophilised plasma. PMID- 20702475 TI - Oropharyngeal lesions and cervical lymphadenopathy: syphilis is a differential diagnosis that is still relevant. AB - BACKGROUND: Syphilis (lues), a chronic infectious disease caused by Treponema pallidum, has been increasing in incidence during the last few years. Therefore, while clinically it is often not suspected, syphilis is increasingly becoming a differential diagnosis in routine pathology. AIM: To report our experience with five cases of cervical lymphadenopathy and/or oropharyngeal lesions, clinically thought to be lymphomas, lymph node metastases or carcinoma, in which we made the mostly clinically unsuspected diagnosis of syphilis. METHODS: Fine needle aspiration of enlarged cervical lymph nodes was evaluated by cytology and flow cytometry (fluorescence-activated cell sorting analysis), and biopsies were examined by using histology. In addition, all materials were also subjected to immunostaining, silver staining and molecular (PCR) testing. RESULTS: Fine needle aspiration cytology revealed follicular hyperplasia in two cases and granulomatous lymphadenitis in one case. In three patients, concomitant biopsy of co-existing oropharyngeal lesions revealed histological findings compatible with syphilis. T pallidum was detected in all cytological and histological samples by immunohistochemistry/immunocytochemistry and PCR. Subsequently, a diagnosis of syphilis was confirmed clinically and by serology. CONCLUSIONS: Syphilitic lymphadenitis is still a relevant differential diagnosis of cervical lymphadenopathy, and it is clinically often not suspected. Co-existing oropharyngeal lesions should alert the physician to this differential diagnosis; and lesions with compatible morphology should be tested with immunohistochemistry and immunocytochemistry and/or molecular analysis to confirm the diagnosis of syphilis. PMID- 20702477 TI - Quetiapine-associated cholestasis causing lipoprotein-X and pseudohyponatraemia. AB - A case of intrahepatic cholestasis secondary to treatment with quetiapine in combination with lamotrigine and zopiclone, resulting in severe hypercholesterolaemia without overt lactescence of the plasma, is presented. Abundant lipoprotein-X was seen on lipoprotein electrophoresis. The patient was diagnosed and treated for hyponatraemia which was likely factitious and caused by hypercholesterolaemia. Cholestasis and hypercholesterolaemia resolved over a period of several months after the discontinuation of quetiapine. PMID- 20702476 TI - E355G mutation appearing in a patient with e19a2 chronic myeloid leukaemia resistant to imatinib. AB - The development of imatinib is a milestone in the treatment of chronic myeloid leukaemia (CML), and its therapeutic effect has been extensively investigated in patients with CML who carry M-bcr and m-bcr BCR-ABL fusion transcripts. However, knowledge about its therapeutic effect on patients with CML who have the rare BCR ABL fusion transcript e19a2 (mu-bcr) remains sparse. This report describes a patient with Philadelphia-positive chronic myeloid leukaemia with e19a2 rearrangement, in whom E355G mutation had been acquired. The patient was resistant to imatinib treatment based on conventional cytogenetic and fluorescence in situ hybridisation analysis. PMID- 20702478 TI - Expression of high-molecular-weight cytokeratin (34betaE12) is an independent predictor of disease-free survival in patients with triple-negative tumours of the breast. AB - One-fifth of breast cancers have the triple-negative phenotype; a good prognostic marker has yet not been described for these tumours. Tumour microarrays from 58 triple-negative patients treated with surgery followed by chemotherapy were analysed for expression of cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), vimentin, p63 and cytokeratin 34betaE12. The mean patient age was 59.2 years with a follow-up from 39 to 168 months. Clinicopathological variables and survival data were correlated with biomarker expression. The frequency of expression of cytokeratin 5/6, EGFR, vimentin, p63 and 34betaE12 was 33%, 65%, 50%, 19% and 85%, respectively. Each of 34betaE12, p63, EGFR and T stage significantly correlated with both disease-free survival and overall survival. T stage and 34betaE12 were independent predictors of overall survival in a multivariate analysis. Expression of 34betaE12 predicts disease-free and overall survival in patients with triple-negative tumours. Additional studies are planned to confirm these initial findings. PMID- 20702481 TI - TNM and mesorectal excisions. PMID- 20702482 TI - Phaeochromocytoma and thrombotic microangiopathy: favourable outcome despite advanced renal failure. PMID- 20702483 TI - Keratocystoma of the parotid gland: case report and immunohistochemical investigation. PMID- 20702485 TI - Increased cysteinyl-leukotrienes and 8-isoprostane in exhaled breath condensate from systemic sclerosis patients. AB - OBJECTIVES: SSc is a systemic CTD characterized by fibrosis in skin and internal organs. Interstitial lung disease is a frequent complication with fibrosis in the lung parenchyma. The fibrotic process is believed to be influenced by leukotrienes (LTs) and also by oxidative stress. The aim of this study was to investigate the amount of LTs and 8-isoprostane, a marker of oxidative stress, in exhaled breath condensate (EBC) from SSc patients. METHODS: Twenty-two SSc patients with median disease duration of 2.1 years were investigated. Fifteen patients had lcSSc, four patients had dcSSc and three patients only fulfilled criteria for limited SSc. Sixteen healthy controls were enrolled. Cysteinyl-LTs (CysLTs), LTB4 and 8-isoprostane were measured in EBC with EIA and related to the radiologic extent of pulmonary fibrosis. RESULTS: Compared with controls, SSc patients displayed higher median (interquartile range) CysLT [6.1 (5.3-6.8) vs 4.9 (3.7-6.3) pg/ml; P=0.040], 8-isoprostane [0.23 (0.20-0.46) vs 0.19 (0.12 0.20) pg/ml; P=0.0020], but similar levels of LTB4 [0.70 (0.50-0.83) vs 0.60 (0.42-0.70) pg/ml]. CysLT correlated to LTB4, while 8-isoprostane did not correlate to any of the LTs. None of the biomarkers measured in EBC correlated to radiologic findings. CONCLUSION: Increased levels of CysLT and 8-isoprostane in EBC from patients with SSc reflect the inflammatory pattern involving LTs as well as oxidative stress. These findings may indicate a possible non-invasive assessment of pulmonary involvement in SSc with a potential value for assessment of disease progress and therapy evaluation. PMID- 20702486 TI - Concurrent evaluation of data quality, reliability and validity of the Australian/Canadian Osteoarthritis Hand Index and the Functional Index for Hand Osteoarthritis. AB - OBJECTIVES: Concurrent evaluation of data quality, internal consistency, test retest reliability and validity of two patient-reported outcome measures (PROMs) for measuring functional impairment in hand OA (HOA); the Australian/Canadian Osteoarthritis Hand Index (AUSCAN; 15 items) and the Functional Index of HOA (FIHOA; 10 items). METHODS: Patients from an HOA cohort [n=128, mean age 68.6 (s.d. 5.8) years, 91% women] completed PROMs and performance measures during routine follow-up. One week later, a subsample (n=40) reporting no change on an HOA-specific transition question contributed with test-retest data. RESULTS: Both instruments had satisfactory levels of data quality, internal consistency, test retest reliability and construct validity. The AUSCAN performed slightly better than the FIHOA relating to levels of missing data (0 vs 5%), floor effects, principal component analysis loadings (0.62-0.83 vs 0.52-0.83), item-total correlation (0.77-0.91 vs 0.45-0.76) and Cronbach's alpha (0.94-0.96 vs 0.90), respectively. AUSCAN items had slightly lower test-retest kappa-values (0.29-0.77 vs FIHOA 0.41-0.77) and AUSCAN scales lower intra-class correlations (0.80-0.92 vs FIHOA 0.94). Correlations between the two instruments ranged from 0.58 to 0.88 for the AUSCAN scales of stiffness and physical function, respectively. AUSCAN physical function scale was generally slightly strongly correlated with the other PROMS and performance measures. CONCLUSION: The AUSCAN and the FIHOA are reliable and valid instruments suitable for measuring physical functioning in HOA. The FIHOA had higher test-retest reliability and is shorter, but the AUSCAN performed slightly better concerning data quality and construct validity. PMID- 20702487 TI - An experimental study on the antileukemia effects of gypenosides in vitro and in vivo. AB - PURPOSE: Gypenosides (Gyp), found in Gynostemma pentaphyllum Makino, have been used as folk medicine for centuries and have exhibited diverse pharmacological effects, including antileukemia effects in vitro and in vivo. In the present study, Gyp were used to examine effects on cell viability, cell cycle, and induction of apoptosis in vitro. They were administered in the diet to mice injected with WEHI-3 cells in vivo. EXPERIMENTAL DESIGN: Effects of Gyp on WEHI-3 cells were determined by flow cytometric assay and Western blotting. RESULTS: Gyp inhibited the growth of WEHI-3 cells. These effects were associated with the induction of G0/G1 arrest, morphological changes, DNA fragmentation, and increased sub-G1 phase. Gyp promoted the production of reactive oxygen species, increased Ca(2+) levels, and induced the depolarization of the mitochondrial membrane potential. The effects of Gyp were dose and time dependent. Moreover, Gyp increased levels of the proapoptotic protein Bax, reduced levels of the antiapoptotic proteins Bcl-2, and stimulated release of cytochrome c, AIF (apoptosis-inducing factor), and Endo G (endonuclease G) from mitochondria. The levels of GADD153, GRP78, ATF6-alpha, and ATF4-alpha were increased by Gyp, resulting in ER (endoplasmic reticular) stress in WEHI-3 cells. Oral consumption of Gyp increased the survival rate of mice injected with WEHI-3 cells used as a mouse model of leukemia. CONCLUSIONS: Results of these experiments provide new information on understanding mechanisms of Gyp-induced effects on cell cycle arrest and apoptosis in vitro and in an in vivo animal model. PMID- 20702489 TI - Cancer chemoprevention by 7-prenyloxycoumarins: a role for 5-lipoxygenase inhibition? PMID- 20702488 TI - Regulation of p21, MMP-1, and MDR-1 expression in human colon carcinoma HT29 cells by Tian Xian liquid, a chinese medicinal formula, in vitro and in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tian-Xian liquid (TXL), a commercially available Chinese medicine decoction, has been used as an anticancer dietary agent for more than 10 years without reported side effects. AIM OF THE STUDY: The safety and quality consistency of TXL and its mechanisms of action on antiproliferation, antimetastasis, and reversion of multidrug resistance (MDR) regimens were explored. MATERIALS AND METHODS: In this study, an atomic absorption spectrophotometer and reversed phase high performance liquid chromatography with photodiode array detection (HPLC-DAD) were used to evaluate the main toxic elements and the quality consistency among different batches of TXL extracts, respectively. HT29 human colon cancer cell line and tumor-bearing nude mice were used. TXL was provided by China-Japan Feida Union Company Limited. The effect of TXL on in vitro proliferation of HT29 human colon cancer cell line was examined. The percentages of treated cells distributed in different phases of the cell cycles were analyzed by flow cytometry. Antiproliferative effect after treatment with TXL was assessed by determination of the protein levels of p21, cyclinD1, PCNA, and cdk-2, which are the key regulators for cell cycle progression. Meanwhile, the protein levels of MMP-1 and MDR-1 (multidrug resistance protein-1) were also determined to assess the effect of TXL on antimetastasis and reversion of MDR regimen, respectively. RESULTS: The contents of main toxic elements were lower in TXL extract compared with the standard set by the Department of Health of the Government of Hong Kong Special Administrative Region (SAR). Our HPLC results showed that the relative standard deviations of the amount of the 5 standards were less than 5% in different batches of TXL. Immunoblotting analysis revealed a dramatic induction of cyclin kinase inhibitor p21 as well as an inhibition of cyclinD1, PCNA, and cdk-2 in the TXL-treated in vitro models, thereby, impeding cell progression from G1/S phase. Results obtained from the in vivo study also demonstrated that TXL upregulated the protein level of p21 and downregulated the protein levels of MMP-1 and MDR-1. CONCLUSIONS: Results obtained from the present investigation not only demonstrate the safety and quality of TXL extract but also demonstrate that TXL possesses antiproliferative and antimetastatic activities and brings about reversion of MDR on HT29 cell and on xenografted tissue in tumor-implanted nude mice. PMID- 20702490 TI - Integrative medicine consultation service in a comprehensive cancer center: findings and outcomes. AB - OBJECTIVES: This study portrays the characteristics of patients who attended an integrative oncology clinic at a large comprehensive cancer center and evaluated whether this service addressed patients' concerns about complementary and integrative medicine (CIM). METHODS: Patient information was collected prior to an integrative consultation, including demographics, previous use of CIM, and primary reason for requesting the consultation. Concerns and outcomes were measured using the Measure Yourself Concerns and Well-being (MYCaW) Scale at the consultation and then again at follow-up (6-12 weeks later). Patients met with a physician for an integrative consultation that included a discussion of nutrition, supplements, physical activity, useful complementary therapies, and the mind-body-spirit connection. RESULTS: A total of 238 patients were referred for consultation regarding the integration of CIM into their care. The majority of participants were female (60%, n = 143), and the mean age was 56 years (range, 21-90 years), with all major cancer types represented. Patients' leading concerns were related to "What else can I do?" and "How can I better cope?" Although distressed over these concerns at the initial consultation, intense distress (5-6 out of 6 on the MYCaW scale) was reduced to less than half (31%) by the follow-up visit. Additional qualitative data revealed that patients value the process of obtaining reliable information that empowers them to be more involved in managing their care. CONCLUSIONS: Integrative medicine consultations at a large comprehensive cancer center appear to provide some benefit in addressing patients' concerns about CIM use. PMID- 20702491 TI - Hematoporphyrin monomethyl ether enhances the killing of ultrasound on osteosarcoma cells involving intracellular reactive oxygen species and calcium ion elevation. AB - OBJECTIVE: The present study aims to investigate the possible mechanisms of hematoporphyrin monomethyl ether (HMME) enhancing the cytotoxicity of ultrasound in osteosarcoma cells. METHODS: Osteosarcoma cell line UMR-106 was treated by HMME and ultrasound radiation, with the HMME concentration kept at 20 MUg/mL and ultrasound radiation for 10 seconds at the intensity of 0.5 W/cm2. Cell proliferation was investigated at 12, 24, 36, and 48 hours using MTT assay after ultrasound and HMME treatment. Ultrastructural morphology was observed using transmission electron microscopy (TEM). Intracellular reactive oxygen species (ROS) was measured using a flow cytometry with DCFH-DA staining and intracellular free calcium ion (Ca(2+)) with Fluo-3-AM staining. RESULTS: The UMR-106 cells proliferated rapidly in the sham radiation and HMME treatment alone group, but ultrasound-treated cells and HMME-ultrasound-treated cells proliferated slowly. There was a significant difference between HMME-ultrasound treatment and the controls, including ultrasound radiation, HMME treatment alone, and sham radiation (P < .05). TEM showed endoplasmic reticulum and mitochondrial swelling in the ultrasound-treated cells, and more cells presented apoptosis and necrosis after treatment with ultrasound and HMME together. Intracellular ROS and Ca(2+) in the cells increased more significantly after both ultrasound and HMME treatment than after ultrasound treatment alone. CONCLUSIONS: HMME could effectively enhance the inhibition effect of ultrasound on osteosarcoma cells. Intracellular ROS and Ca(2+) in the UMR-106 cells increased more significantly after the treatment of HMME and ultrasound together, indicating that the enhancement of HMME on ultrasound cytotoxicity to osteosarcoma cells possibly involves both intracellular ROS and Ca(2+) elevation. PMID- 20702492 TI - Use of chemoprotectants in chemotherapy and radiation therapy: the challenges of selecting an appropriate agent. AB - Chemoprotection refers to the protection from the toxicity of one chemical by the intervention of another. Conflicting preclinical and clinical reports make it difficult to either ignore or accept the use of chemoprotectants during cancer chemotherapy or radiotherapy. The selection of anticancer drugs depends on the type and stage of cancer development. However, very little attention has been paid to the selection of chemoprotectants. The answer to the use of chemoprotectants during cancer therapy lies in their appropriate selection in a case-specific and/or issue-specific manner. The need of the hour is to find better answers on the rationality of chemoprotectants selection during cancer therapy using cutting-edge science. In this commentary, we have presented few examples to justify our view-points. PMID- 20702494 TI - Alstonia scholaris Linn R Br in the treatment and prevention of cancer: past, present, and future. AB - Alstonia scholaris, commonly known as devil's tree, is an important medicinal plant in the various folk and traditional systems of medicine in Asia, Australia, and Africa. The decoction, mostly prepared from the bark, is used to treat a variety of diseases of which the most important is malaria. Furthermore, ethnomedicinal practices also suggest it to be of use in treating cancer, and preclinical studies performed with cultured neoplastic cells and tumor-bearing animals having validated these observations. Additionally, the phytochemicals like echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol are also reported to possess antineoplastic effects. In addition to the cytotoxic effects, A scholaris is also observed to possess radiomodulatory, chemomodulatory, and chemopreventive effects and free-radical scavenging, antioxidant, anti-inflammatory, antimutagenic, and immunomodulatory activities, all of which are properties efficacious in the treatment and prevention of cancer. The current review for the first time summarizes the results related to these properties. An attempt is also made to address the lacunae in these published studies and emphasize aspects that need further investigations for it to be of use in clinics in the future. PMID- 20702493 TI - Ultrasound-induced cell death of nasopharyngeal carcinoma cells in the presence of curcumin. AB - OBJECTIVES: Curcumin, a natural pigment from a traditional Chinese herb, has been attracting extensive attention. The present study aims to investigate cell death of nasopharyngeal carcinoma (NPC) cells induced by ultrasound sonication in the presence of curcumin in vitro. METHODS: The NPC cell line CNE2 was chosen as a tumor model, and curcumin concentration was kept constant at 10 uM while the cells were subjected to ultrasound exposure for 8 s at an intensity of 0.46 W/cm(2). Cell death was evaluated using flow cytometry with annexinV-FITC and propidium iodine staining, and nuclear staining with Hoechst 33258. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) were analyzed using flow cytometry with rhodamine 123 and dichlorodihydrofluorecein diacetate staining. RESULTS: Flow cytometry showed that the combination of ultrasound and curcumin significantly increased the necrotic or late apoptotic rate by up to 31.37% compared with the controls. Nuclear condensation was observed in the nuclear staining, and collapse of DeltaPsim and ROS increase were found in the CNE2 cells after the treatment with curcumin and ultrasound. CONCLUSIONS: The findings demonstrate that the presence of curcumin significantly enhances the ultrasound-induced cell death and ROS level, and induces the collapse of DeltaPsim, suggesting that ultrasound sonication can increase the cell death of NPC cells in the presence of curcumin and that the treatment using curcumin and ultrasound together is a potential therapeutic modality in the management of malignant tumors. PMID- 20702496 TI - Aqueous extracts of Fructus Ligustri Lucidi enhance the sensitivity of human colorectal carcinoma DLD-1 cells to doxorubicin-induced apoptosis via Tbx3 suppression. AB - Chemoresistance has imposed a great challenge for cancer therapy. Fructus Ligustri Lucidi (FLL) is one of the commonest Chinese herbs that has been used for thousand years. This study shows that the aqueous extract of FLL (AFLL) enhanced the sensitivity of DLD-1 colon cancer cells to doxorubicin-induced apoptosis. Furthermore, Tbx3 expression was found to be suppressed by AFLL when the expression of tumor suppressor genes p14 and p53 were activated. Therefore, reduction of Tbx3 rescued the dysregulated P14(ARF)-P53 signaling, which in turn contributed to the sensitivity of DLD-1 cells to doxorubicin-induced apoptosis. As a conclusion, the findings suggest that FLL has a potential of being an appealing agent for auxiliary chemotherapy in treatment of human colorectal carcinoma. PMID- 20702497 TI - Amelioration of radiation-induced hematological and biochemical alterations in Swiss albino mice by Panax ginseng extract. AB - BACKGROUND: This study was carried out to observe the radioprotective effect of Panax ginseng root extract (PGE) against radiation-induced hematological and biochemical alterations in blood and liver of mice. Materials and methods. Adult Swiss albino mice were exposed to 6 Gy gamma radiation in the presence (experimental) or absence (control) of PGE to study the quantitative and qualitative alterations in the blood and liver. RESULTS: Radiation exposure resulted in a significant decline (P<.001) in erythrocyte count, hemoglobin (Hb), and hematocrit (Hct) in peripheral blood. Maximum changes in all the parameters were observed on day 3 after irradiation. In contrast, PGE-pretreated irradiated animals showed a significant increase in erythrocyte, Hct, and Hb values compared with irradiated controls. Furthermore, a significant elevation in lipid peroxidation level over normal was recorded in irradiated control mice, whereas this increase was considerably lesser in PGE pretreated animals. Likewise, pretreatment with PGE caused a significant increase in glutathione levels in serum as well as in liver in comparison to irradiated controls. CONCLUSION: From this study, it is clearly evident that PGE provides protection against radiation induced hematological and biochemical alterations in Swiss albino mice. PMID- 20702498 TI - The molecular mechanisms of traditional Chinese medicine ZHENG syndromes on pancreatic tumor growth. AB - BACKGROUND: Traditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) are the abstraction from the comprehensive analysis of clinical information gained by the four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses. Proper TCM diagnosis is the most important principle to guide the prescribing of Chinese herbs. OBJECTIVE: To evaluate the specific effect of TCM ZHENG on tumor growth and to examine the molecular mechanisms underlying ZHENG and tumor growth. METHODS: The authors established subcutaneous tumor models of pancreatic cancer ZHENG syndromes of Damp heat (Shi-Re) and Spleen deficiency (Pi Xu). Tissue samples of the subcutaneous transplanted tumors from each model were studied versus control tumors. CCR5 and CXCR4 proteins in these tissues were assayed by immunohistochemical staining. The expression of CCR5/CCL5/CCL4/CCL3 and CXCR4/SDF-1 mRNA was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR). SDF-1, CCL4, CCL5, and CCL3, which are ligands of CXCR4 and CCR5, were examined by ELISA. RESULTS: The study found that tumor models with different ZHENG were successfully established in each group; the tumor growth of Shi-Re group was slower than that of the control group. It was found that there was a significant difference in CCR5 mRNA expression levels among the Pi-Xu, Shi Re, and control groups. The results of immunohistochemistry staining revealed that the positive rate of CCR5 protein in Shi-Re group, Pi-Xu group, and control group was 25.00%, 53.33%, 83.33%, respectively. The Shi-Re group expressed the lowest levels of CCL5 and CCL4. CONCLUSION: The results of the study suggest that the existence of TCM ZHENG may influence the tumor growth in pancreatic cancer, which might be mediated by the expression of CCR5/CCL5/CCL4. This finding may lead to the development of TCM ZHENG as a prognostic indicator in pancreatic tumor growth. PMID- 20702499 TI - Association of IL-6, hypothalamus-pituitary-adrenal axis function, and depression in patients with cancer. AB - BACKGROUND: Evidence suggests that cytokines (IL-6) and alteration of the hypothalamic-pituitary-adrenal (HPA) axis play a crucial role in the etiology of depression. Patients with cancer show elevated prevalence rates for depression. The objective of this cross-sectional study was to investigate the associations between these abnormalities and depression. METHODS: Plasma concentrations of IL 6 and cortisol were measured in cancer patients with (N = 31) and without depression (N = 83). The relative diurnal variation of cortisol (cortisol VAR), expressed in percentage, was calculated. RESULTS: There was a significant difference in median plasma concentration of IL-6 between the patients with depression and those without (18.7 vs 2.7 pg/mL; P < .001). Relative cortisol VAR was decreased in depressed patients as compared with patients without depression (11.72% vs 60.6%, P = .037). A positive correlation between the depressive symptoms and IL-6 concentration was found (r = 0.469, P < .001). Negative correlations were found between cortisol VAR versus depressive symptoms and cortisol VAR versus IL-6 (r = -0.6, P < .001 and r = -0.52, P < .001, respectively). IL-6 (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0 1.2; P = .006) and cortisol VAR (OR = 1.3; 95%CI = 1.0-1.4; P = .02) are independently associated with depression. CONCLUSIONS: Depression in cancer is associated with increased plasma IL-6 concentrations and dysfunction of the HPA axis. PMID- 20702500 TI - Backward masked fearful faces enhance contralateral occipital cortical activity for visual targets within the spotlight of attention. AB - Spatial attention has been argued to be adaptive by enhancing the processing of visual stimuli within the 'spotlight of attention'. We previously reported that crude threat cues (backward masked fearful faces) facilitate spatial attention through a network of brain regions consisting of the amygdala, anterior cingulate and contralateral visual cortex. However, results from previous functional magnetic resonance imaging (fMRI) dot-probe studies have been inconclusive regarding a fearful face-elicited contralateral modulation of visual targets. Here, we tested the hypothesis that the capture of spatial attention by crude threat cues would facilitate processing of subsequently presented visual stimuli within the masked fearful face-elicited 'spotlight of attention' in the contralateral visual cortex. Participants performed a backward masked fearful face dot-probe task while brain activity was measured with fMRI. Masked fearful face left visual field trials enhanced activity for spatially congruent targets in the right superior occipital gyrus, fusiform gyrus and lateral occipital complex, while masked fearful face right visual field trials enhanced activity in the left middle occipital gyrus. These data indicate that crude threat elicited spatial attention enhances the processing of subsequent visual stimuli in contralateral occipital cortex, which may occur by lowering neural activation thresholds in this retinotopic location. PMID- 20702501 TI - Acceptance of wearable technology by people with Alzheimer's disease: issues and accommodations. AB - The increasing number of cognitively impaired older adults who exhibit wandering tendencies raises safety concerns. The purpose of the current study was to research the State-of the-Art in Wearable Technologies for persons with Alzheimer's Disease and identify challenges unique to this population and lessons learned. Inclusion criteria specified systems/devices that completed laboratory testing and were commercially available for usage by community-based Alzheimer's family caregivers. Methods included a series of Internet product searches and telephone interviews with related corporate representatives and participant's referrals. Results indicated many products in development or academic research use but only a limited number were available that met the study criteria. The interviews with key informants revealed features necessary to consider when making products to be worn by persons with cognitive impairment. In conclusion, there is no ideal solution and opportunities remain for marketplace innovations and for addressing the challenges associated with balancing safety and security. PMID- 20702502 TI - Review: omega-3 and memory function: to eat or not to eat. AB - At present it is estimated that 25% of the population older than 85 years have significant cognitive impairment. The global prevalence of cognitive impairment and dementia including Alzheimer's disease is expected to rise significantly in proportion to increased life expectancy. Deterioration of memory function and ultimately establishment of Alzheimer's disease (AD) severely debilitates the affected individual, uncompromisingly decreasing the quality of life of both affected patients and their care givers. Moreover, the cost of providing adequate care to patients with AD is a significant burden to both family and the health care providers. Therefore, various attempts have been made to identify means of either delaying the onset of cognitive impairment or improving memory function in patients affected by AD. Among a number of participants, importance of dietary fatty acids in particular omega-3 based fatty acids have gained significant momentum. This article aims to review published evidences for the role of omega-3 in memory function. PMID- 20702503 TI - Differential patterns of interhemispheric functional disconnection in mild and advanced multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis may present altered patterns of connectivity between the two brain hemispheres. To date, only transcallosal connectivity between the two primary motor cortices (M1) has been investigated functionally in patients with multiple sclerosis. OBJECTIVES: The aim of this study was to investigate whether connectivity between the dorsal premotor cortex and the contralateral M1 was altered in patients with multiple sclerosis, and to see whether clinical progression is accompanied by exacerbated dorsal premotor cortex-M1 disconnectivity. METHODS: A twin-coil transcranial magnetic stimulation approach was used to investigate both excitatory and inhibitory interhemispheric connections between the left dorsal premotor cortex and the contralateral M1 in 18 multiple sclerosis patients without disability, in 18 multiple sclerosis patients with advanced disease and in 12 age-matched healthy subjects. To activate distinct inhibitory and facilitatory transcallosal pathways, the intensity of dorsal premotor cortex stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). RESULTS: Our sample of patients with multiple sclerosis showed altered patterns of interhemispheric dorsal premotor cortex-M1 functional connectivity even in the absence of clinical deficits. Facilitatory connections originating from dorsal premotor cortex were reduced in multiple sclerosis patients with or without disability, while inhibitory dorsal premotor cortex-M1 connections were altered only in disabled patients. CONCLUSIONS: The current study demonstrates that functional excitatory connectivity originating from non primary motor areas is compromised in multiple sclerosis patients even in the absence of clinical disability. Clinical disease progression leads to an impairment of both excitatory and inhibitory transcallosal connections. PMID- 20702504 TI - Renin-angiotensin system gene polymorphisms in children with Henoch-Schonlein purpura in West China. AB - It has been suggested that renin-angiotensin system (RAS) gene polymorphism is involved in the pathogenesis of Henoch-Schonlein purpura (HSP) with conflicting reports. We therefore investigate the effect of RAS gene polymorphism on HSP susceptibility and severity in a Chinese cohort. The study included 142 children with HSP and 218 healthy controls that were genotyped for RAS gene polymorphisms. Significantly, differences of T174M-T and ACE-D frequency were found between HSP patients and controls (p(alleo) = .002, OR(alleo) = 2.001; p(alleo) = .007, OR(alleo) = 1.533, respectively). We also found correlations between ACE-I/D and Agt T174M with multiple organ involvements, with significant differences in ACE-D in renal groups (p < 0.05) and Agt T174M in non-renal (p(joint) = .002, p(GI) = .042). Furthermore, decreasing M235T-T and increasing ACE-D were found associated with serious renal complications (p = .019, p = .016). Additionally, ACE-I/D and T174M were significantly associated with high clinical score patients, as opposed to low clinical score patients, when patients were scored depending on the severity of overall complications (p = .045, p = .026). We suggest that RAS gene polymorphisms (ACE-I/D, M235T or T174M) are significantly associated with susceptibility to HSP, organ involvement, and disease severity, which largely account for individual prognosis. PMID- 20702505 TI - Molecular evidence of a (pro)renin/ (pro)renin receptor system in human intrauterine tissues in pregnancy and its association with PGHS-2. AB - Prorenin stimulates decidual prostaglandin (PG) production in vitro, the (pro)renin receptor ((P)RR) may mediate this action. The role of prorenin in amnion PG synthesis has not been examined, despite this being the key site of PG synthesis. To determine if (P)RR, prorenin and PGHS-2 are co-localized in gestational tissues and if expression is altered by labour, term amnion, chorion, decidua and placenta were collected during elective caesarean section or after spontaneous labour. Prorenin, (P)RR and PGHS-2 mRNA abundance was determined by real-time RT-PCR. (P)RR protein was examined by immunohistochemistry. The effect of recombinant human (rh) prorenin on PGHS-2 mRNA abundance in amnion explants was determined. Prorenin and (P)RR mRNA were highest in decidua and placenta, respectively. Decidual prorenin, (P)RR and placental (P)RR mRNA abundance decreased with labour. (P)RR protein was present in all gestational tissues. After labour, decidual prorenin was positively correlated with amnion PGHS-2 mRNA and rh-prorenin significantly increased PGHS-2 mRNA abundance in amnion explants. We conclude that the decidua is the principal source of prorenin and is downregulated with labour. All gestational tissues are targets for prorenin. Decidual prorenin may be involved in the labour-associated increase in amnion PGHS-2 abundance via the (P)RR. PMID- 20702506 TI - Life-course analysis of a fat mass and obesity-associated (FTO) gene variant and body mass index in the Northern Finland Birth Cohort 1966 using structural equation modeling. AB - The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body mass index (BMI; weight (kg)/height (m)(2)) is well replicated. More thorough analyses utilizing phenotypic data over the life course may deepen our understanding of the development of BMI and thus help in the prevention of obesity. The authors used a structural equation modeling approach to explore the network of variables associated with BMI from the prenatal period to age 31 years (1965-1997) in 4,435 subjects from the Northern Finland Birth Cohort 1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in the analyses without separate imputation steps, as well as differentiation between direct and indirect effects. There was an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years that persisted after controlling for several relevant factors during the life course. The total effect of the FTO variant on adult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects on earlier BMI development. In addition to well established genetic determinants, many life-course factors such as physical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI. PMID- 20702508 TI - Evidence that the sweetness of odors depends on experience in rats. AB - Humans describe their perception of certain odorants in terms of taste qualities (e.g., sweet). It has also been found that in humans, novel odorants can rapidly and irreversibly acquire a taste, even after just a single pairing with a taste. It remains unclear whether flavor objects in general, and odor-taste generalizations in particular, are experience-dependent. Interactions might result from a failure by humans to sufficiently analyze the olfactory and gustatory components of compound flavorants. Here, we tested odor-taste generalizations in rats with or without paired exposure to an odorant and a tastant. We evaluated the generalization of conditioned odor aversion to tastants by rats. Our findings suggest that rats behave toward putatively tasteless retronasal odorants as if they were sweet only after prior paired experience of the odorant with a sweet tastant. These data support the hypothesis that taste like qualities of odors are learned and are not innate. Furthermore, the present results suggest that acquisition of a taste quality by an odor need not depend on higher cognitive abilities. This study helps to establish the rat as a model for the study of behavioral neuroscience of flavor. PMID- 20702507 TI - Chronic and acute effects of coal tar pitch exposure and cardiopulmonary mortality among aluminum smelter workers. AB - Air pollution causes several adverse cardiovascular and respiratory effects. In occupational studies, where levels of particulate matter and polycyclic aromatic hydrocarbons (PAHs) are higher, the evidence is inconsistent. The effects of acute and chronic PAH exposure on cardiopulmonary mortality were examined within a Kitimat, Canada, aluminum smelter cohort (n = 7,026) linked to a national mortality database (1957-1999). No standardized mortality ratio was significantly elevated compared with the province's population. Smoking-adjusted internal comparisons were conducted using Cox regression for male subjects (n = 6,423). Ischemic heart disease (IHD) mortality (n = 281) was associated with cumulative benzo[a]pyrene (B(a)P) exposure (hazard ratio = 1.62, 95% confidence interval: 1.06, 2.46) in the highest category. A monotonic but nonsignificant trend was observed with chronic B(a)P exposure and acute myocardial infarction (n = 184). When follow-up was restricted to active employment, the hazard ratio for IHD was 2.39 (95% confidence interval: 0.95, 6.05) in the highest cumulative B(a)P category. The stronger associations observed during employment suggest that risk may not persist after exposure cessation. No associations with recent or current exposure were observed. IHD was associated with chronic (but not current) PAH exposure in a high-exposure occupational setting. Given the widespread workplace exposure to PAHs and heart disease's high prevalence, even modest associations produce a high burden. PMID- 20702509 TI - Evidence of disagreement between patient-perceived change and conventional longitudinal evaluation of change in health-related quality of life among older adults. AB - OBJECTIVE: To identify agreement levels between conventional longitudinal evaluation of change (post-pre) and patient-perceived change (post-then test) in health-related quality of life. DESIGN: A prospective cohort investigation with two assessment points (baseline and six-month follow-up) was implemented. SETTING: Community rehabilitation setting. SUBJECTS: Frail older adults accessing community-based rehabilitation services. INTERVENTION: Nil as part of this investigation. MAIN MEASURES: Conventional longitudinal change in health-related quality of life was considered the difference between standard EQ-5D assessments completed at baseline and follow-up. To evaluate patient-perceived change a 'then test' was also completed at the follow-up assessment. This required participants to report (from their current perspective) how they believe their health-related quality of life was at baseline (using the EQ-5D). Patient-perceived change was considered the difference between 'then test' and standard follow-up EQ-5D assessments. RESULTS: The mean (SD) age of participants was 78.8 (7.3). Of the 70 participants 62 (89%) of data sets were complete and included in analysis. Agreement between conventional (post-pre) and patient-perceived (post-then test) change was low to moderate (EQ-5D utility intraclass correlation coefficient (ICC) = 0.41, EQ-5D visual analogue scale (VAS) ICC = 0.21). Neither approach inferred greater change than the other (utility P =0.925, VAS P =0.506). Mean (95% confidence interval (CI)) conventional change in EQ-5D utility and VAS were 0.140 (0.045,0.236) and 8.8 (3.3,14.3) respectively, while patient-perceived change was 0.147 (0.055,0.238) and 6.4 (1.7,11.1) respectively. CONCLUSIONS: Substantial disagreement exists between conventional longitudinal evaluation of change in health-related quality of life and patient-perceived change in health related quality of life (as measured using a then test) within individuals. PMID- 20702510 TI - Long-term effects of an expanded cardiac rehabilitation programme after myocardial infarction or coronary artery bypass surgery: a five-year follow-up of a randomized controlled study. AB - OBJECTIVE: To investigate the long-term effect of expanded cardiac rehabilitation on a composite end-point, consisting of cardiovascular death, myocardial infarction or readmission for cardiovascular disease, in patients with coronary artery disease. DESIGN: Single-centre prospective randomized controlled trial. SETTING: University hospital. SUBJECTS: Two hundred and twenty-four patients with acute myocardial infarction or undergoing coronary artery by-pass grafting. INTERVENTION: Patients were randomized to expanded cardiac rehabilitation (a one year stress management programme, increased physical training, staying at a 'patient hotel' for five days after the event, and cooking sessions), or to standard cardiac rehabilitation. MAIN MEASURES: Data on cardiovascular death, myocardial infarction, readmission for cardiovascular disease and days at hospital for cardiovascular reasons were obtained from national registries of the Swedish National Board of Health and Welfare. RESULTS: The primary end-point occurred in 121 patients altogether (54%). The number of cardiovascular events were reduced in the expanded rehabilitation group compared with the standard cardiac rehabilitation (53 patients (47.7%) versus 68 patients (60.2%); hazard ratio 0.69; P =0.049). This was mainly because of a reduction of myocardial infarctions in the expanded rehabilitation group. During the five years 12 patients (10.8%) versus 23 patients (20.3%); hazard ratio 0.47; P =0.047 had a myocardial infarction. Days at hospital for cardiovascular reasons were significantly reduced in patients who received expanded cardiac rehabilitation (median 6 days) compared with standard cardiac rehabilitation (median 10 days; P =0.02). CONCLUSION: Expanded cardiac rehabilitation after acute myocardial infarction or coronary artery bypass grafting reduces cardiovascular morbidity and days at hospital for cardiovascular reasons. PMID- 20702511 TI - A systematic review of arm activity measures for children with hemiplegic cerebral palsy. AB - OBJECTIVE: To identify psychometrically sound and clinically feasible assessments of arm activities in children with hemiplegic cerebral palsy for implementation in research and clinical practice. DATA SOURCES: PubMed, CINAHL, Cochrane Library, Web of Science and reference lists of relevant articles were searched. REVIEW METHODS: A systematic search was performed based on the following inclusion criteria: (1) evaluative tools at the activity level according to the International Classification of Functioning, Disability and Health; (2) previously used in studies including children with hemiplegic cerebral palsy aged 2-18 years; (3) at least one aspect of reliability and validity in children with cerebral palsy should be established. Descriptive information, psychometric properties and clinical utility were reviewed. RESULTS: Eighteen assessments were identified of which 11 met the inclusion criteria: eight functional tests and three questionnaires. Five functional tests were condition-specific, three were generic. All functional tests measure different aspects of activity, including unimanual capacity and performance during bimanual tasks. The questionnaires obtain information about the child's abilities at home or school. The reliability and validity have been established, though further use in clinical trials is necessary to determine the responsiveness. CONCLUSIONS: To obtain a complete view of what the child can do and what the child actually does, we advise a capacity based test (Melbourne Assessment of Unilateral Upper Limb Function), a performance-based test (Assisting Hand Assessment) and a questionnaire (Abilhand Kids). This will allow outcome differentiation and treatment guidance for the arm in children with cerebral palsy. PMID- 20702512 TI - Effects of tai chi exercise on posturography, gait, physical function and quality of life in postmenopausal women with osteopaenia: a randomized clinical study. AB - OBJECTIVE: to evaluate the effects of tai chi exercise on risk factors for falls in postmenopausal women with osteopaenia through measurements of balance, gait, physical function and quality of life. DESIGN: a randomized, controlled, single blinded, 24-week trial with stratification by age and bone mass. SETTING: general community. PARTICIPANTS: Sixty-one independently living elderly females aged 65 years and older with low bone mass. INTERVENTIONS: subjects were recruited and randomly assigned to 24 weeks of tai chi (60 minutes/session, three sessions/week, n = 30) or a control group (n = 31). OUTCOME MEASURES: computerized dynamic posturography, gait, 'timed up and go', five-chair sit-to stand and quality of life assessed at baseline, 12 and 24 weeks. RESULTS: after 24 weeks, subjects in the tai chi group demonstrated an increase in stride width (P = 0.05) and improvement in general health (P = 0.008), vitality (P = 0.02) and bodily pain (P = 0.03) compared with those in the control group. There was no significant difference in balance parameters, 'timed up and go', five-chair sit to-stand and other domains of quality of life. CONCLUSION: tai chi exercise may reduce risk factors for falls by increasing the stride width, and may improve quality of life in terms of general health, vitality and bodily pain in postmenopausal women with osteopaenia. PMID- 20702513 TI - The effect of electrical stimulation in combination with Bobath techniques in the prevention of shoulder subluxation in acute stroke patients. AB - OBJECTIVE: To examine the efficiency of electrical stimulation in combination with Bobath techniques in the prevention of inferior and anterior shoulder subluxation in acute stroke patients. DESIGN: A prospective randomized controlled trial. SETTING: Intensive care unit and inpatient clinics of neurology in a university hospital. SUBJECTS: Forty-eight patients with acute stroke, divided equally into control and study groups. INTERVENTION: Subjects in both groups were treated in accordance with the Bobath concept during the early hospitalization period. In addition to Bobath techniques, electrical stimulation was also applied to the supraspinatus muscle, mid and posterior portions of the deltoid muscle of patients in the study group. MAIN MEASURES: Two radiological methods were used to measure the horizontal, vertical and total asymmetry and vertical distance values of the shoulder joint. Motor functions of the arm were evaluated with the Motor Assessment Scale. RESULTS: The hospitalization period was 12.62 +/- 2.24 days for the control group and 11.66 +/- 1.88 days for the study group. Shoulder subluxation occurred in 9 (37.5%) subjects in the control group, whereas it was not observed in the study group. All shoulder joint displacement values were higher in the control group than in the study group (horizontal asymmetry P = 0.0001, vertical asymmetry P = 0.0001, total asymmetry P = 0.0001, vertical range P = 0.002). CONCLUSION: Application of electrical stimulation combined with the Bobath approach proved to be efficient in preventing inferior and anterior shoulder subluxation in the acute stages of stroke. PMID- 20702514 TI - A randomized controlled trial investigating the effects of craniosacral therapy on pain and heart rate variability in fibromyalgia patients. AB - CONTEXT: Fibromyalgia is a prevalent musculoskeletal disorder associated with widespread mechanical tenderness, fatigue, non-refreshing sleep, depressed mood and pervasive dysfunction of the autonomic nervous system: tachycardia, postural intolerance, Raynaud's phenomenon and diarrhoea. OBJECTIVE: To determine the effects of craniosacral therapy on sensitive tender points and heart rate variability in patients with fibromyalgia. DESIGN: A randomized controlled trial. SUBJECTS: Ninety-two patients with fibromyalgia were randomly assigned to an intervention group or placebo group. INTERVENTIONS: Patients received treatments for 20 weeks. The intervention group underwent a craniosacral therapy protocol and the placebo group received sham treatment with disconnected magnetotherapy equipment. MAIN MEASURES: Pain intensity levels were determined by evaluating tender points, and heart rate variability was recorded by 24-hour Holter monitoring. RESULTS: After 20 weeks of treatment, the intervention group showed significant reduction in pain at 13 of the 18 tender points (P < 0.05). Significant differences in temporal standard deviation of RR segments, root mean square deviation of temporal standard deviation of RR segments and clinical global impression of improvement versus baseline values were observed in the intervention group but not in the placebo group. At two months and one year post therapy, the intervention group showed significant differences versus baseline in tender points at left occiput, left-side lower cervical, left epicondyle and left greater trochanter and significant differences in temporal standard deviation of RR segments, root mean square deviation of temporal standard deviation of RR segments and clinical global impression of improvement. CONCLUSION: Craniosacral therapy improved medium-term pain symptoms in patients with fibromyalgia. PMID- 20702515 TI - Rehabilitation in practice: Hemispatial neglect: approaches to rehabilitation. AB - This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'The trainee consistently demonstrates a knowledge of the pathophysiology of various specific impairments including cognitive dysfunction including perception' and 'management approaches for specific impairments including cognitive dysfunction including perception'. The article focuses on hemispatial neglect as a common and difficult to manage problem in clinical practice. PMID- 20702516 TI - Letter to the editor: Re: Safety of botulinum toxin type A among children with spasticity secondary to cerebral palsy: a systematic review of randomized clinical trials. PMID- 20702518 TI - Perceived need and actual usage of the family support agreement in rural China: results from a nationally representative survey. AB - PURPOSE: The Family Support Agreement (FSA) is a voluntary but legal contract between older parents and adult children on parental support in China. As the first comprehensive empirical study on the FSA, this study aims to understand the prevalence and covariates of older parents' perceived need and actual use of this agreement. DESIGN AND METHODS: Using logistic regression analyses, t-tests and chi-square tests, this study analyzed data from a nationally representative sample of 9,587 rural parents aged 60 years and above from the 2006 Sample Survey on Aged Population in Urban/Rural China, which had a 99% response rate. RESULTS: More than 11% of the subjects regarded the FSA as necessary, and more than 6% have signed it, respectively, representing 160 million and 30.7 million older Chinese. Perceiving the need for the FSA was associated with living arrangement, number of daughters-in-law, care needs, filial piety assessment and concerns, family harmony, sociodemographics, individual characteristics related to rights protection, and the existence of rights protection-related local community organizations. Having signed the FSA was associated with the above last 3 factors, traditional old-age support strategy, and FSA need assessment. IMPLICATIONS: Individuals regarding the FSA as necessary or using it are characterized by personal, familial, and sociocultural factors that render them more in need of parental support but less likely to receive it. They are also better informed about their rights, are more willing to take actions to protect their rights, and have more exposure to rights protection--related community organizations. PMID- 20702519 TI - Expression of CD200/CD200R regulatory molecules on granulocytes and monocytes is modulated by cardiac surgical operation. AB - AIMS: Cardiac surgical operation is inseparably linked to the induction of an inflammatory response. Both humoral and cellular regulatory mechanisms are operating to maintain body homeostasis. We followed the changes in the expression of CD200/CD200R regulatory molecules on monocytes and granulocyte of cardiac surgical patients operated on using either standard (OP) or modified "mini invasive" cardiopulmonary bypass (MOP). METHODS: Expression of CD200/CD200R regulatory molecules was determined by flow cytometry. RESULTS: The expression of CD200R on granulocytes was increased after surgery in both groups of patients, but the increase was statistically significant only in OP patients (p<0.01). At this time point, there was a significant difference in CD200R expression on granulocytes when comparing OP to MOP patients, being higher in the former group (p<0.01). The expression of CD200R on monocytes was diminished after surgery and during an early postoperative period in both groups of patients. The expression of CD200 on monocytes was significantly diminished after surgery in both groups (p<0.01). Nonetheless, we observed an increase in CD200 expression in OP patients at the 3rd postoperative day. There was a statistically significantly increased CD200 expression on monocytes of OP patients (p<0.001) at the 3rd postoperative day when we compared OP and MOP groups. The expression of CD200 on granulocytes was significantly higher after surgery and at the 3rd postoperative day in OP when compared to MOP patients. CONCLUSIONS: CD200R expression on granulocytes was significantly increased, while CD200 and CD200R expression on monocytes was decreased after cardiac surgery. PMID- 20702520 TI - Maternal BMI, parity, and pregnancy weight gain: influences on offspring adiposity in young adulthood. AB - CONTEXT: The prevalence of obesity among women of childbearing age is increasing. Emerging evidence suggests that this has long-term adverse influences on offspring health. OBJECTIVE: The aim was to examine whether maternal body composition and gestational weight gain have persisting effects on offspring adiposity in early adulthood. DESIGN AND SETTING: The Motherwell birth cohort study was conducted in a general community in Scotland, United Kingdom. PARTICIPANTS: We studied 276 men and women whose mothers' nutritional status had been characterized in pregnancy. Four-site skinfold thicknesses, waist circumference, and body mass index (BMI), were measured at age 30 yr; sex adjusted percentage body fat and fat mass index were calculated. MAIN OUTCOME MEASURE: Indices of offspring adiposity at age 30 yr were measured. RESULTS: Percentage body fat was greater in offspring of mothers with a higher BMI at the first antenatal visit (rising by 0.35%/kg/m2; P<0.001) and in offspring whose mothers were primiparous (difference, 1.5% in primiparous vs. multiparous; P=0.03). Higher offspring percentage body fat was also independently associated with higher pregnancy weight gain (7.4%/kg/wk; P=0.002). There were similar significant associations of increased maternal BMI, greater pregnancy weight gain, and parity with greater offspring waist circumference, BMI, and fat mass index. CONCLUSIONS: Adiposity in early adulthood is influenced by prenatal influences independently of current lifestyle factors. Maternal adiposity, greater gestational weight, and parity all impact on offspring adiposity. Strategies to reduce the impact of maternal obesity and greater pregnancy weight gain on offspring future health are required. PMID- 20702521 TI - High copeptin concentrations in umbilical cord blood after vaginal delivery and birth acidosis. AB - CONTEXT: The pituitary-secreted nonapeptide arginine-vasopressin (AVP) is unstable and therefore unsuited for diagnostic use, but its secretion can be estimated by measuring copeptin, the C-terminal portion of the AVP precursor (pro AVP). OBJECTIVE: Our objective was to investigate perinatal factors affecting copeptin concentrations in infants at birth and at 3 d of life. DESIGN AND SETTING: We conducted a prospective cross-sectional study at a tertiary university hospital. PATIENTS: Copeptin plasma concentrations were evaluated in 177 infants at birth, including 117 paired arterial/venous umbilical cord and 102 venous blood samples obtained at 3 d of life. MAIN OUTCOME MEASURE: Copeptin concentrations were determined by a C-terminal pro-AVP luminescence immunoassay. RESULTS: Arterial umbilical cord copeptin concentrations were consistently higher than matched venous ones (median 18 vs. 10 pmol/liter, P < 0.001), but both values were closely related (R(s) = 0.825; P < 0.001), and both were negatively related to arterial umbilical cord pH (R(s) arterial/venous = -0.578/-0.639; P < 0.001). Although exceedingly high copeptin concentrations were observed after vaginal birth in umbilical cord arterial [median (5-95% range) = 1610 (85-5000) pmol/liter] and venous [793 (6-4836) pmol/liter] plasma, copeptin concentrations were low after primary cesarean section [arterial/venous = 8 (3-907)/5 (5-504) pmol/liter]. Postnatal body weight loss was associated with increased copeptin concentrations at d 3 (R(s) = 0.438; P < 0.001) and was inversely related to copeptin concentrations at birth (R(s) = -0.289 and -0.309; both P = 0.001). CONCLUSION: Vaginal birth is associated with a large release of copeptin that exceeds all values published so far, including those in critically ill adult patients with shock or brain injury. Thus, vaginal birth is arguably the most intense stressor in life. PMID- 20702522 TI - Relation of direct and surrogate measures of insulin resistance to cardiovascular risk factors in nondiabetic finnish offspring of type 2 diabetic individuals. AB - CONTEXT: Methods to directly measure insulin resistance are invasive, complex, and costly. Surrogate indexes derived from the oral glucose tolerance test (OGTT) have been developed, but few studies have systematically analyzed these indexes. OBJECTIVE: We examined the relation of surrogate and direct measures of insulin resistance to metabolic variables. DESIGN AND SETTING: We conducted a cross sectional analysis of the validation cohort of the Metabolic Syndrome in Men study. PARTICIPANTS: Participants included 272 nondiabetic Finnish offspring of type 2 diabetic individuals (age, 24-50 yr; 55% female). INTERVENTION: Surrogate indexes of insulin resistance were computed according to published formulas. Insulin sensitivity was also directly measured by the euglycemic-hyperinsulinemic clamp. RESULTS: The strength of the correlation of the Matsuda index with directly measured insulin sensitivity (r = 0.77) was similar to that of Avignon's insulin sensitivity index (r = 0.76; P = 0.581) and simple index assessing insulin sensitivity using OGTT measurements (r = 0.74; P = 0.060) and stronger than that of indexes derived from fasting measurements [e.g. fasting insulin (r = 0.72; P = 0.011) and homeostasis model assessment of insulin resistance (r = 0.71; P = 0.001)]. Surrogate indexes were similar to directly measured insulin sensitivity in their relationships with metabolic abnormalities including definitive measures of fat distribution. Some indexes, however, had distinctive correlations: McAuley index with lipoproteins and Avignon insulin sensitivity and Stumvoll indexes with adiposity and fibrinogen. CONCLUSIONS: Surrogate indexes are valid measures of insulin resistance. Multiple sampling times during an OGTT may not be mandatory to adequately estimate insulin resistance in clinical and epidemiological studies. PMID- 20702523 TI - One year of growth hormone treatment in adults with Prader-Willi syndrome improves body composition: results from a randomized, placebo-controlled study. AB - CONTEXT: Prader-Willi syndrome (PWS) is a multisymptomatic disease that shares many similarities with the GH deficiency syndrome, including altered body composition with more body fat than lean body mass. OBJECTIVE: Our objective was to investigate the effect of GH on body composition in adults with PWS. DESIGN AND PATIENTS: Forty-six adults with PWS were randomized to GH or placebo treatment for 12 months in a double-blind trial. MAIN OUTCOME MEASURES: We evaluated change in regional body composition of the abdomen and thigh as measured by computed tomography and change in total body composition as measured by dual-energy x-ray absorptiometry. RESULTS: Forty patients completed the study. Baseline median IGF-I sd score was -0.4. GH treatment increased IGF-I by 125 MUg/liter (1.51 sd score), and based upon computed tomography, body composition improved with a decrease in visceral fat mass of 22.9 ml (P = 0.004), abdominal sc fat mass 70.9 ml (P = 0.003), and thigh fat mass 21.3 ml (P = 0.013), whereas thigh muscle mass increased 6.0 ml (P = 0.005). By dual-energy x-ray absorptiometry, lean body mass improved 2.25 kg (P = 0.005), and total fat mass decreased 4.20 kg (P < 0.001). No major side effects were seen. CONCLUSION: Unrelated to the GH-IGF-I levels at baseline, our results showed that long-term treatment with GH effectively improved body composition and represents a safe, potential treatment option, relieving some of the negative consequences of PWS. PMID- 20702524 TI - RET-mediated cell adhesion and migration require multiple integrin subunits. AB - CONTEXT: The RET receptor tyrosine kinase is an important mediator of several human diseases, most notably of neuroendocrine cancers. These diseases are characterized by aberrant cell migration, a process tightly regulated by integrins. OBJECTIVE: Our goals were to investigate the role of integrins in RET mediated migration in two neoplastic cell models: the neural-derived cell line SH SY5Y, and the papillary thyroid carcinoma cell line TPC-1. We also evaluated whether multiple integrin subunits have a role in RET-mediated cell migration. DESIGN: We evaluated the expression and activation of integrins in response to RET activation using standard cell adhesion and migration (wound-healing) assays. We examined focal adhesion formation, using integrin-paxillin coimmunoprecipitations and immunofluorescence, as an indicator of integrin activity. RESULTS: Our data indicate that beta1 integrin (ITGB1) is expressed in both SH-SY5Y and TPC-1 cell lines and that these cells adhere strongly to matrices preferentially associated with ITGB1. We showed that RET can activate ITGB1, and that RET-induced cell adhesion and migration require ITGB1. Furthermore, we showed that beta3 integrin (ITGB3) also plays a role in RET mediated cell adhesion and migration in vitro and ITGB3 expression correlates with RET-mediated invasion in a mouse tumor xenograft model, suggesting that RET mediates the activity of multiple integrin subunits. CONCLUSIONS: Our data are the first to show that multiple integrin subunits contribute to cell adhesion and migration downstream of RET, suggesting that coordinated signaling through these pathways is important for cell interactions with the microenvironment during tumor invasion and progression. PMID- 20702526 TI - Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. AB - BACKGROUND: The impact of antidiabetic medications on clinical outcomes in patients developing acute myocardial infarction (MI) is controversial. We sought to determine whether in-hospital outcomes in patients who were on sulfonylureas (SUs) when they developed their MIs differed from that of diabetic patients not receiving SUs and whether clinical outcomes were related to the pancreatic cells specificity of SUs. METHODS AND RESULTS: We analyzed the outcomes of the 1310 diabetic patients included in the nationwide French Registry of Acute ST Elevation and Non-ST-Elevation Myocardial Infarction in 2005. Medications used before the acute episode were recorded. In-hospital complications were analyzed according to prior antidiabetic treatment. Mortality was lower in patients previously treated with SUs (3.9%) vs. those on other oral medications (6.4%), insulin (9.4%), or no medication (8.4%) (P = 0.014). Among SU-treated patients, in-hospital mortality was lower in patients receiving pancreatic cells-specific SUs (gliclazide or glimepiride) (2.7%), compared with glibenclamide (7.5%) (P = 0.019). Arrhythmias and ischemic complications were also less frequent in patients receiving gliclazide/glimepiride. The lower risk in patients receiving gliclazide/glimepiride vs. glibenclamide persisted after multivariate adjustment (odds ratio 0.15; 95% confidence interval 0.04-0.56) and in propensity score matched cohorts. CONCLUSION: In this nationwide registry of patients hospitalized for acute MI, no hazard was associated with the use of SUs before the acute episode. In addition, patients previously receiving gliclazide/glimepiride had improved in-hospital outcomes, compared with those on glibenclamide. PMID- 20702525 TI - Altered retinoid uptake and action contributes to cell survival in endometriosis. AB - CONTEXT: Retinoic acid (RA) controls multiple biological processes via exerting opposing effects on cell survival. Retinol uptake into cells is controlled by stimulated by RA 6 (STRA6). RA is then produced from retinol in the cytosol. Partitioning of RA between the nuclear receptors RA receptor alpha and peroxisome proliferator-activated receptor beta/delta is regulated by cytosol-to-nuclear shuttling proteins cellular RA binding protein 2 (CRABP2) and fatty acid binding protein 5 (FABP5), which induce apoptosis or enhance survival, respectively. The roles of these mechanisms in endometrium or endometriosis remain unknown. OBJECTIVE: The aim was to determine the regulation of retinoid uptake and RA action in primary stromal cells from endometrium (n = 10) or endometriosis (n = 10). RESULTS: Progesterone receptor was necessary for high STRA6 and CRABP2 expression in endometrial stromal cells. STRA6, which was responsible for labeled retinoid uptake, was strikingly lower in endometriotic cells compared to endometrial cells. CRABP2 knockdown in endometrial cells increased survival, and FABP5 knockdown in endometriotic cells decreased survival without altering the expression of downstream nuclear retinoic acid receptor alpha and peroxisome proliferator-activated receptor beta/delta. CONCLUSIONS: In endometrial stromal cells, progesterone receptor up-regulates expression of STRA6 and CRABP2, which control retinol uptake and growth-suppressor actions of RA. In endometriotic stromal cells, decreased expression of these genes leads to decreased retinol uptake and dominant FABP5-mediated prosurvival activity. PMID- 20702527 TI - Prevalence of vertebral fractures independent of BMD and anticancer treatment in patients with testicular germ cell tumors. AB - CONTEXT: The prognosis of testicular germ cell tumors (GCT) is excellent, and survival of GCT patients has significantly increased. However, skeletal morbidity may potentially be increased in these patients due to chemotherapy-associated hypogonadism. OBJECTIVE: Our objective was assessment of skeletal fragility in testicular GCT patients. DESIGN AND SETTING: We conducted a cross-sectional study in long-term survivors and newly diagnosed patients at a single center with recruitment over a 2-yr period. PATIENTS AND METHODS: We studied 199 cured long term survivors of GCT, a mean of 7.4 yr after unilateral orchidectomy, and 45 newly diagnosed patients within 3 months of unilateral orchidectomy but before anticancer treatment. Bone mineral density (BMD) measurements were performed, and the presence of vertebral fractures (VF) was assessed in lateral thoracolumbar x rays of the spine using the Genant's semiquantitative method. RESULTS: Sixty three patients (25.8%) had Z-scores between -1 and -2 sd, and 12 patients (5.7%) had Z-scores below -2 sd. Moderate and severe VF (grade 2 or higher) were observed in 13.6% of cured long-term survivors and in 15.6% of newly diagnosed patients. Including mild (grade 1) VF, the prevalence was 40.2 and 31.1%, respectively. There was no relationship between severity or number of VF and age, tumor type, staging, previous chemotherapy, gonadal status, vitamin D levels, or BMD values. CONCLUSION: We identify a relatively high prevalence of mild to moderate VF independently of BMD or previous chemotherapy in long-term survivors and in newly diagnosed patients with GCT. Although the pathogenesis of these fractures remains unclear, their presence represents a potential cause of skeletal morbidity in otherwise healthy survivors of testicular GCT. PMID- 20702528 TI - Neuroretinitis as an initial presentation of lupus-like illness with antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis, recurrent fetal losses or other pregnancy complications, and the presence of antiphospholipid antibodies (aPL). Ocular manifestations occur in 8-88% of patients with APS and are typically due to vaso occlusive disease involving retinal and choroidal vessels. We report an unusual case of neuroretinitis as a first presentation of lupus-like illness with APS. PMID- 20702529 TI - Endoluminal colonization as a risk factor for coagulase-negative staphylococcal catheter-related bloodstream infections in haemodialysis patients. AB - BACKGROUND: Approximately 25% of haemodialysis (HD) patients use catheters as vascular access. Catheter-related bloodstream infections (CRBSI) are a major risk in this population. The objective of our study was to determine whether endoluminal catheter colonization (ECC) predicts CRBSI. METHODS: We followed up a cohort of HD patients in our institution who underwent HD with tunnelled cuffed central venous catheters (TCC) between December 2006 and June 2008. Colonization of the inner catheter lumen was assessed every 15 days immediately before HD by culture of blood-heparin mixture and the time to positivity (TTP) was recorded by the BacT/Alert automated system. CRBSI was confirmed by differential TTP (> 2 h) between TCC and peripheral blood cultures. RESULTS: We studied 51 patients who required 64 TCC. The incidence of CRBSI was 1.65 episodes per 1000 catheter-days, with Staphylococcus epidermidis being the most common cause of infection (76.2%). ECC was more frequent in the CRSBI group than in the non-CRBSI group (100 vs 5.4%, P < 0.001). For S. epidermidis CRBSIs, the median time from ECC to CRBSI was 31.5 days (interquartile range, 27.0-79.0). The sensitivity, specificity and negative and positive predictive values of arterial lumen cultures for S. epidermidis CRBSIs were 100, 96.3, 92.3 and 100%, respectively, while for venous culture, these values were 92.3, 96.3, 92.3 and 96.3%, respectively. For predicting S. epidermidis CRBSI, endoluminal cultures with a TTP of <= 14 h had sensitivity and specificity of 52.1 and 97.7%, respectively. CONCLUSIONS: This study shows that ECC may predict the risk of developing CRSBI. Surveillance cultures could, therefore, be used to triage individual HD patients who might benefit from specific intervention measures. PMID- 20702530 TI - Selection on albuminuria enhances the efficacy of screening for cardiovascular risk factors. AB - BACKGROUND: As many subjects with a cardiovascular (CV) risk factor are undiagnosed, guidelines to prevent cardiovascular disease argue for case finding on those risk factors. Such an approach is, however, labour and cost intensive. An elevated urinary albumin loss is an early marker of vascular damage and is associated with an increased CV risk. As albuminuria is easy to measure, we tested whether a screening approach in which detailed risk factor measurement is done only after selection of subjects with an elevated albuminuria results in a higher yield of subjects at risk. METHODS: A random sample of the general population as investigated in the Prevention of Renal and Vascular End-Stage Disease study was used. Plasma glucose, blood pressure, serum cholesterol and renal function were measured in an overall random sample of the population, in subgroups according to their urinary albumin concentration (UAC) of one first morning urine void and in subgroups in whom the elevated albuminuria level was confirmed with two 24 h urine collections for measurement of urinary albumin excretion (UAE). RESULTS: In the overall population, the number of subjects with any newly found CV risk factor was higher than the number of subjects already known with any CV risk factor (n = 1331 versus 370; 39.2 versus 10.9%). The prevalence of subjects with any newly diagnosed CV risk factor was higher in the group of 267 subjects with a first morning UAC of >= 20 mg/L (61.0%; P < 0.05) compared to the overall population (39.2%). Although the sensitivity of a UAC >= 20 mg/L to detect a subject with at least one CV risk factor was relatively low (12%), the specificity was very high (96%). The positive predictive value was 70%. When the elevated UAC could be confirmed in two subsequent 24-h urine collections, the diagnostic yield still further improved. CONCLUSION: The prevalence of undiagnosed CV risk factors in the general population is much higher than the prevalence of known risk factors. After a selection of subjects with an elevated albuminuria, the relative prevalence of subjects with newly diagnosed CV risk factors increases while the number of subjects to test for presence of CV risk factors is smaller. Such an approach facilitates a more effective and simple strategy for risk factor screening. PMID- 20702531 TI - Rethinking targets of blood pressure and guidelines for hypertension clinical management. PMID- 20702532 TI - Acute kidney injury in tropical acute febrile illness in a tertiary care centre- RIFLE criteria validation. AB - BACKGROUND: Acute febrile illnesses are a common cause of tropical acute kidney injury (AKI). The incidence and severity of AKI in tropical febrile illnesses and validity of RIFLE classification are unclear. METHODS: Consecutive adult inpatients of a tertiary hospital in southern India with tropical acute febrile illness between January 2007 and January 2008 were prospectively studied for the incidence and severity of AKI based on RIFLE classification and its association with mortality and dialysis requirement. RESULTS: The 367 patients (mean age 39.7+/-16.9 years; 60% males) with tropical acute febrile illness due to scrub typhus (51.2%), falciparum malaria (10.4%), enteric fever (8.7%), dengue (7.6%), mixed malaria (6.5%), leptospirosis (3.3%), undifferentiated acute febrile illness (8.4%) and others (3.8%) (spotted fever, vivax malaria and Hantaan virus infection) had an overall mortality rate of 12.3%. The incidence of AKI was 41.1%; of which, 17.4%, 9.3% and 14.4% were in the Risk, Injury and Failure classes, respectively. Of the patients, 7.9% required dialysis. Among the Risk, Injury and Failure groups, there was an incremental risk of mortality (OR 6.9, 20.2 and 25.6; P<0.001) and dialysis requirement (OR 3.4, 28.8 and 178.8; P<0.001). CONCLUSIONS: The incidence of AKI in the common tropical acute febrile illnesses in our study such as scrub typhus, falciparum malaria, enteric fever, dengue and leptospirosis is 41.1%. RIFLE classification is valid and applicable in AKI related to tropical acute febrile illnesses, with an incremental risk of mortality and dialysis requirement. PMID- 20702533 TI - CD4+ CD25+ regulatory T cells partially mediate the beneficial effects of FTY720, a sphingosine-1-phosphate analogue, during ischaemia/reperfusion-induced acute kidney injury. AB - BACKGROUND: The synthetic sphingosine-1-phosphate (S1P) analogue, FTY720, attenuates ischaemia/reperfusion (I/R) injury by inducing peripheral lymphopaenia. Recent studies suggest that FTY720 may also exert protective effects by modulating dendritic cell (DC) function or directly affecting regulatory T cells (Tregs). The purpose of the present study was to examine whether the beneficial effect of FTY720 in I/R-induced acute kidney injury (AKI) involves modulation of DCs or Tregs. METHODS: Mice underwent bilateral ischaemia, and FTY720 or vehicle was then administered. Biochemical values, histological kidney damage and tissue inflammation were assessed. Phenotype and function of DCs in blood/spleen or kidney were also examined by flow cytometry or mixed lymphocyte reaction (MLR) assay. Percent Tregs or FoxP3 mRNA expression was examined in kidney and spleen, and depletion and adoptive transfer of Tregs were also performed. RESULTS: Treatment with FTY720 attenuated I/R kidney injury and reduced inflammation. The beneficial effect of FTY720 was associated with expansion of peripheral CD11b( +) CD11c( +) DC and with maturation of spleen CD11c( +) DC, which showed impaired allostimulatory capacity. FTY720-treated animals also showed a higher frequency of CD4( +) CD25( +) Tregs and an upregulation of FoxP3 mRNA expression in spleen and kidney. In vitro experiments showed that FTY720 induced expansion of Tregs, possibly via conversion from non Tregs to Tregs. Depletion and adoptive transfer of Tregs were associated with loss and recovery of the beneficial effects of FTY720. CONCLUSION: These results suggest that the beneficial effects of FTY720 in I/R injury may be partially mediated by DC modulation or by increasing Treg activity. Further studies that identify tolerance induction mechanisms will be useful for developing strategies for the prevention or treatment of AKI. PMID- 20702534 TI - Association of severity of conjunctival and corneal calcification with all-cause 1-year mortality in maintenance haemodialysis patients. AB - BACKGROUND: Conjunctival and corneal calcification (CCC) is the most common form of metastatic calcification in patients with chronic renal failure. The aim of this study is to investigate if severity of CCC correlates with vascular calcification and mortality in maintenance haemodialysis (MHD) patients. METHODS: One hundred and nine MHD patients were recruited. CCC was evaluated by external eye photographs, and was graded and scored according to modified Porter and Crombie classification system described by Tokuyama et al. Chest X-ray examination was used to evaluate aortic arch calcification. Geographic, haematological, biochemical and dialysis-related data were obtained. The patients were analysed for traditional and non-traditional risk factors for cardiovascular disease stratified by severity of CCC. All patients were followed up for 1 year to investigate the risks for mortality. RESULTS: Forty-three, 35 and 31 patients had mild (scores <= 4), moderate and severe (scores >= 9) CCC at baseline, respectively. With trend estimation, patients with severe CCC had a significantly higher percentage of severe aortic arch calcification. Multiple linear regression analysis showed that hypertension, haemodialysis duration and corrected calcium level were associated with scores of CCC in MHD patients. Moreover, age, corrected calcium-phosphate level, and moderate and severe CCC were associated with grades of aortic arch calcification. At 1-year follow-up, 11 of 109 (10.1%) patients had died. Multivariate Cox proportional hazards model showed that age, corrected calcium and severe CCC were significant risk factors for all-cause 1 year mortality in MHD patients. Each increment of one score of CCC is associated with a 26.4% increased risk for all-cause mortality. CONCLUSIONS: Severity of CCC, which is easily obtained at bedside, acts as an independent predictor for all-cause 1-year mortality in MHD patients. PMID- 20702535 TI - Granulomatous interstitial nephritis in chronic lymphocytic leukaemia. AB - We present a case of granulomatous interstitial nephritis (GIN) associated with chronic lymphocytic leukaemia (CLL). GIN is a rare pathological finding noted in renal biopsy specimens. Furthermore, CLL does not usually cause GIN. In this case, acute renal injury probably resulted from GIN, and urgent dialysis was required, despite sufficient chemotherapy. Immunohistochemical analyses of a biopsy specimen revealed invasion of CD20( +) CLL cells, surrounded by reactive T cells, and granuloma formation. Thus, CLL may induce secondary interstitial nephritis as a granulomatous reaction. PMID- 20702536 TI - Preferential streaming of the ductus venosus and inferior caval vein towards the right heart is associated with left heart underdevelopment in human fetuses with left-sided diaphragmatic hernia. AB - OBJECTIVE: Left heart underdevelopment is commonly observed in fetuses with left diaphragmatic hernia. This finding has been attributed to compression of the left atrium by herniated abdominal organs, redistribution of fetal cardiac output and/or low pulmonary venous return. As preferential right or left heart underdevelopment is usually not a feature of right diaphragmatic hernia, we searched for an alternative mechanism. Since in normal fetuses the major fraction of left heart filling is provided by the ductus venosus via the inferior caval vein and oval foramen, our study focused in particular on the streaming direction of these structures. PATIENTS AND METHODS: We prospectively studied 32 fetuses with left diaphragmatic hernia between 19 + 6 weeks and 38 + 6 weeks of gestation by echocardiography. The fetuses were divided into two groups: Group I fetuses exhibited abnormal streaming of ductus venosus and inferior caval vein blood flow towards the right side of the heart; group II fetuses did not exhibit this abnormal flow direction. Cardiac inflow and outflow dimensions were compared in the two groups. RESULTS: 18 of 19 group I fetuses with left diaphragmatic hernia exhibited disproportionately smaller left than right heart dimensions; 12 of 13 group II fetuses exhibited similar sized left and right cardiac inflow and outflow dimensions (p<0.05). CONCLUSIONS: Preferential ductus venosus and inferior caval vein streaming towards the fetal right heart offers another haemodynamic mechanism for left heart underdevelopment in fetuses with left diaphragmatic hernia. The pathoanatomical basis of this abnormal flow pattern results from intrathoracic abdominal organ herniation and rightward displacement of the heart. PMID- 20702537 TI - 'Pill-in-the-pocket' treatment for recent-onset atrial fibrillation. PMID- 20702538 TI - Adiponectin and left ventricular diastolic dysfunction. PMID- 20702539 TI - Comments on an acute myocardial infarction study. PMID- 20702540 TI - Evidence of the role of short-term exposure to ozone on ischaemic cerebral and cardiac events: the Dijon Vascular Project (DIVA). AB - OBJECTIVES: To confirm the effects of short-term exposure to ozone (O(3)) on ischaemic heart and cerebrovascular disease. METHODS: Daily levels of urban O(3) pollution, the incidence of first-ever, recurrent, fatal and non-fatal ischaemic cerebrovascular events (ICVE) and myocardial infarction (MI) were correlated using a case-crossover design. The authors analysed 1574 ICVE and 913 MI that occurred in Dijon, France (150,000 inhabitants) from 2001 to 2007. Sulfur dioxide (SO(2)), nitrogen dioxide (NO(2)), carbon monoxide (CO) and particulate matter with an aerodiameter of <=10 MUg/m(3) (PM(10)) were used to create bi-pollutant models. Using the adjusted OR, the effects of O(3) exposure were calculated for every 10 MUg/m(3) increase in pollutants in multivariate logistic models adjusted for temperature, humidity, flu outbreaks and holidays. RESULTS: The authors found a significant association between exposure to O(3) and recurrent ICVE with a 3 day lag (OR=1.115; 95% CI 1.027 to 1.209). The direction and magnitude of the association between exposure to O(3) and recurrent MI were similar but not statistically significant. For incident events, the authors detected only a non significant association for ICVE with a 2-day lag (OR=1.041; 95% CI 0.996 to 1.089). In the subgroup analysis for ICVE, the authors observed an increased association with cardiovascular risk factors (OR=1.523; 95% CI 1.149 to 2.018). For MI, the authors found an association with O(3) when hypercholesterolaemia was present (OR=1.111; 95% CI 1.020 to 1.211), and the association became stronger with the number of cardiovascular risk factors. The authors found a marked dose response relationship. CONCLUSION: Recurrent ICVE and MI could be triggered by short-term exposure to even low levels of O(3), especially among subjects with severe vascular risk factors. PMID- 20702541 TI - Differing effect of modifiable cardiovascular risk factors on intima-media thickening and plaque formation at different sites of the arterial vasculature. AB - OBJECTIVE: The effects of cardiovascular risk factors on the vascular anatomy at differing sites of the arterial vasculature have not been well described. The aim of this study was to compare the effect of cardiovascular risk factors on the intima media thickness (IMT) of the wall of the right and left common carotid artery (CCA) at their bifurcation and proximal from their bifurcation, and the effects on the presence of plaque at carotid and femoral arteries. DESIGN: Cross sectional population-based study. SETTING/PARTICIPANTS: Random samples of men (n=425) and women (n=367) aged 56-77 years were recruited from two general practices participating in the British Regional Heart Study. MAIN OUTCOME MEASURES: Ultrasound examination ascertained IMT and the presence of atheromatous plaque. A model for correlated outcomes was used to simultaneously model all risk factor on all measured vascular sites. RESULTS: All cardiovascular risk factors (HbA(1c), waist-to-hip ratio, hypertension, LDL and smoking) showed a larger association with IMT thickening at the wall of the CCA at its bifurcation than proximal to its bifurcation. The IMT was greater on the left wall of the CCA than on the right. The association between hypertension with the wall of the CCA depended on age. Smoking was the only risk factor that demonstrated an increased odds (45%, 95% CI 14% to 65%) of the presence of plaque at the femoral arteries when compared with the CCA. CONCLUSIONS: The associations of cardiovascular risk factors with the vascular anatomy are not uniform for IMT thickening or the presence of plaque. These differences in local arterial anatomy may result in differences between trial outcomes that investigate surrogate endpoints such as IMT. PMID- 20702542 TI - Mutational analysis of RUNX2 gene in Chinese patients with cleidocranial dysplasia. AB - Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor-encoding gene, RUNX2. To correlate different RUNX2 mutations with CCD clinical spectrum, we studied six independent Chinese CCD patients. In five patients, mutations were detected in the coding region of the RUNX2 gene, including two frameshift mutations and three missense mutations. Of these mutations, four were novel and one had previously been reported. All the detected mutations were exclusively clustered within the Runt domain that affected conserved residues in the Runt domain. In vitro green fluorescent protein fusion studies showed that the three mutations--R225L, 214fs and 172fs--interfered with nuclear accumulation of RUNX2 protein, while T200I mutation had no effect on the subcellular distribution of RUNX2. There was no marked phenotypic difference between patients in craniofacial and clavicles features, while the expressivity of supernumerary teeth in our patient cohort had a striking variation, even among family members. The occurrence of intrafamilial clinical variability raises the view that hypomorphic effects and genetic modifiers may alter the clinical expressivity of these mutations. Our results provide new genetic evidence that mutations involved in RUNX2 contribute to CCD. PMID- 20702543 TI - Inadequate post-publication review of medical research. PMID- 20702547 TI - Loss of consciousness on turning the patient. PMID- 20702548 TI - Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. AB - OBJECTIVE: To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries. DESIGN: Retrospective trend analysis. Data source WHO mortality database on causes of deaths Subjects reviewed Female deaths from breast cancer from 1989 to 2006 MAIN OUTCOME MEASURES: Changes in breast cancer mortality for all women and by age group (<50, 50-69, and >or=70 years) calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in all age mortality began to change. RESULTS: From 1989 to 2006, there was a median reduction in breast cancer mortality of 19%, ranging from a 45% reduction in Iceland to a 17% increase in Romania. Breast cancer mortality decreased by >or=20% in 15 countries, and the reduction tended to be greater in countries with higher mortality in 1987-9. England and Wales, Northern Ireland, and Scotland had the second, third, and fourth largest decreases of 35%, 29%, and 30%, respectively. In France, Finland, and Sweden, mortality decreased by 11%, 12%, and 16%, respectively. In central European countries mortality did not decline or even increased during the period. Downward mortality trends usually started between 1988 and 1996, and the persistent reduction from 1999 to 2006 indicates that these trends may continue. The median changes in the age groups were -37% (range 76% to -14%) in women aged <50, -21% (-40% to 14%) in 50-69 year olds, and -2% ( 42% to 80%) in >or=70 year olds. CONCLUSIONS: Changes in breast cancer mortality after 1988 varied widely between European countries, and the UK is among the countries with the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also in countries where screening at that age is uncommon. The increasing mortality in some central European countries reflects avoidable mortality. PMID- 20702549 TI - Unequal access to health care in England. PMID- 20702551 TI - UK cancer survival statistics. PMID- 20702554 TI - The politics of pain. PMID- 20702550 TI - Equity in access to total joint replacement of the hip and knee in England: cross sectional study. AB - OBJECTIVE: To explore geographical and sociodemographic factors associated with variation in equity in access to total hip and knee replacement surgery. DESIGN: Combining small area estimates of need and provision to explore equity in access to care. SETTING: English census wards. SUBJECTS: Patients throughout England who needed total hip or knee replacement and numbers who received surgery. MAIN OUTCOME MEASURES: Predicted rates of need (derived from the Somerset and Avon Survey of Health and English Longitudinal Study of Ageing) and provision (derived from the hospital episode statistics database). Equity rate ratios comparing rates of provision relative to need by sociodemographic, hospital, and distance variables. RESULTS: For both operations there was an "n" shaped curve by age. Compared with people aged 50-59, those aged 60-84 got more provision relative to need, while those aged >or=85 received less total hip replacement (adjusted rate ratio 0.68, 95% confidence interval 0.65 to 0.72) and less total knee replacement (0.87, 0.82 to 0.93). Compared with women, men received more provision relative to need for total hip replacement (1.08, 1.05 to 1.10) and total knee replacement (1.31, 1.28 to 1.34). Compared with the least deprived, residents in the most deprived areas got less provision relative to need for total hip replacement (0.31, 0.30 to 0.33) and total knee replacement (0.33, 0.31 to 0.34). For total knee replacement, those in urban areas got higher provision relative to need, but for total hip replacement it was highest in villages/isolated areas. For total knee replacement, patients living in non-white areas received more provision relative to need (1.04, 1.00 to 1.07) than those in predominantly white areas, but for total hip replacement there was no effect. Adjustment for hospital characteristics did not attenuate the effects. CONCLUSIONS: There is evidence of inequity in access to total hip and total knee replacement surgery by age, sex, deprivation, rurality, and ethnicity. Adjustment for hospital and distance did not attenuate these effects. Policy makers should examine factors at the level of patients or primary care to understand the determinants of inequitable provision. PMID- 20702558 TI - WHO declares that H1N1 pandemic is officially over. PMID- 20702559 TI - Experimental evidence for the ectodermal origin of the epithelial anlage of the chicken bursa of Fabricius. AB - The bursa of Fabricius (BF) is a central lymphoid organ of birds responsible for B-cell maturation within bursal follicles of epithelial origin. Despite the fundamental importance of the BF to the birth of B lymphocytes in the immune system, the embryological origin of the epithelial component of the BF remains unknown. The BF arises in the tail bud, caudal to the cloaca and in close association with the cloacal membrane, where the anal invagination (anal sinus) of ectoderm and the caudal endodermal wall of the cloaca are juxtaposed. Serial semi-thin sections of the tail bud show that the anal sinus gradually transforms into the bursal duct and proctodeum, which joins the distal part of the cloaca during late embryogenesis. These anatomical findings raise the possibility that the ectoderm may contribute to the epithelial anlage of the BF. The expression of sonic hedgehog and its receptor in the embryonic gut, but not in the BF, further supports an ectodermal origin for the bursal rudiment. Using chick-quail chimeras, quail tail bud ectoderm was homotopically transplanted into ectoderm ablated chick, resulting in quail-derived bursal follicle formation. Chimeric bursal anlagen were generated in vitro by recombining chick bursal mesenchyme with quail ectoderm or endoderm and grafting the recombination into the chick coelomic cavity. After hematopoietic cell colonization, bursal follicles formed only in grafts containing BF mesenchyme and tail bud ectoderm. These results strongly support the central role of the ectoderm in the development of the bursal epithelium and hence in the maturation of B lymphocytes. PMID- 20702560 TI - BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors. AB - The anterior heart field (AHF) encompasses a niche in which mesoderm-derived cardiac progenitors maintain their multipotent and undifferentiated nature in response to signals from surrounding tissues. Here, we investigate the signaling mechanism that promotes the shift from proliferating cardiac progenitors to differentiating cardiomyocytes in chick embryos. Genomic and systems biology approaches, as well as perturbations of signaling molecules, in vitro and in vivo, reveal tight crosstalk between the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling pathways within the AHF niche: BMP4 promotes myofibrillar gene expression and cardiomyocyte contraction by blocking FGF signaling. Furthermore, inhibition of the FGF-ERK pathway is both sufficient and necessary for these processes, suggesting that FGF signaling blocks premature differentiation of cardiac progenitors in the AHF. We further revealed that BMP4 induced a set of neural crest-related genes, including MSX1. Overexpression of Msx1 was sufficient to repress FGF gene expression and cell proliferation, thereby promoting cardiomyocyte differentiation. Finally, we show that BMP induced cardiomyocyte differentiation is diminished following cranial neural crest ablation, underscoring the key roles of these cells in the regulation of AHF cell differentiation. Hence, BMP and FGF signaling pathways act via inter- and intra-regulatory loops in multiple tissues, to coordinate the balance between proliferation and differentiation of cardiac progenitors. PMID- 20702561 TI - Arterial pole progenitors interpret opposing FGF/BMP signals to proliferate or differentiate. AB - During heart development, a subpopulation of cells in the heart field maintains cardiac potential over several days of development and forms the myocardium and smooth muscle of the arterial pole. Using clonal and explant culture experiments, we show that these cells are a stem cell population that can differentiate into myocardium, smooth muscle and endothelial cells. The multipotent stem cells proliferate or differentiate into different cardiovascular cell fates through activation or inhibition of FGF and BMP signaling pathways. BMP promoted myocardial differentiation but not proliferation. FGF signaling promoted proliferation and induced smooth muscle differentiation, but inhibited myocardial differentiation. Blocking the Ras/Erk intracellular pathway promoted myocardial differentiation, while the PLCgamma and PI3K pathways regulated proliferation. In vivo, inhibition of both pathways resulted in predictable arterial pole defects. These studies suggest that myocardial differentiation of arterial pole progenitors requires BMP signaling combined with downregulation of the FGF/Ras/Erk pathway. The FGF pathway maintains the pool of proliferating stem cells and later promotes smooth muscle differentiation. PMID- 20702562 TI - The iron exporter ferroportin 1 is essential for development of the mouse embryo, forebrain patterning and neural tube closure. AB - Neural tube defects (NTDs) are some of the most common birth defects observed in humans. The incidence of NTDs can be reduced by peri-conceptional folic acid supplementation alone and reduced even further by supplementation with folic acid plus a multivitamin. Here, we present evidence that iron maybe an important nutrient necessary for normal development of the neural tube. Following implantation of the mouse embryo, ferroportin 1 (Fpn1) is essential for the transport of iron from the mother to the fetus and is expressed in the visceral endoderm, yolk sac and placenta. The flatiron (ffe) mutant mouse line harbors a hypomorphic mutation in Fpn1 and we have created an allelic series of Fpn1 mutations that result in graded developmental defects. A null mutation in the Fpn1 gene is embryonic lethal before gastrulation, hypomorphic Fpn1(ffe/ffe) mutants exhibit NTDs consisting of exencephaly, spina bifida and forebrain truncations, while Fpn1(ffe/KI) mutants exhibit even more severe NTDs. We show that Fpn1 is not required in the embryo proper but rather in the extra-embryonic visceral endoderm. Our data indicate that loss of Fpn1 results in abnormal morphogenesis of the anterior visceral endoderm (AVE). Defects in the development of the forebrain in Fpn1 mutants are compounded by defects in multiple signaling centers required for maintenance of the forebrain, including the anterior definitive endoderm (ADE), anterior mesendoderm (AME) and anterior neural ridge (ANR). Finally, we demonstrate that this loss of forebrain maintenance is due in part to the iron deficiency that results from the absence of fully functional Fpn1. PMID- 20702564 TI - Sall1-dependent signals affect Wnt signaling and ureter tip fate to initiate kidney development. AB - Development of the metanephric kidney depends on precise control of branching of the ureteric bud. Branching events represent terminal bifurcations that are thought to depend on unique patterns of gene expression in the tip compared with the stalk and are influenced by mesenchymal signals. The metanephric mesenchyme derived signals that control gene expression at the ureteric bud tip are not well understood. In mouse Sall1 mutants, the ureteric bud grows out and invades the metanephric mesenchyme, but it fails to initiate branching despite tip-specific expression of Ret and Wnt11. The stalk-specific marker Wnt9b and the beta-catenin downstream target Axin2 are ectopically expressed in the mutant ureteric bud tips, suggesting that upregulated canonical Wnt signaling disrupts ureter branching in this mutant. In support of this hypothesis, ureter arrest is rescued by lowering beta-catenin levels in the Sall1 mutant and is phenocopied by ectopic expression of a stabilized beta-catenin in the ureteric bud. Furthermore, transgenic overexpression of Wnt9b in the ureteric bud causes reduced branching in multiple founder lines. These studies indicate that Sall1-dependent signals from the metanephric mesenchyme are required to modulate ureteric bud tip Wnt patterning in order to initiate branching. PMID- 20702563 TI - The role of Drosophila Lamin C in muscle function and gene expression. AB - The inner side of the nuclear envelope (NE) is lined with lamins, a meshwork of intermediate filaments that provides structural support for the nucleus and plays roles in many nuclear processes. Lamins, classified as A- or B-types on the basis of biochemical properties, have a conserved globular head, central rod and C terminal domain that includes an Ig-fold structural motif. In humans, mutations in A-type lamins give rise to diseases that exhibit tissue-specific defects, such as Emery-Dreifuss muscular dystrophy. Drosophila is being used as a model to determine tissue-specific functions of A-type lamins in development, with implications for understanding human disease mechanisms. The GAL4-UAS system was used to express wild-type and mutant forms of Lamin C (the presumed Drosophila A type lamin), in an otherwise wild-type background. Larval muscle-specific expression of wild type Drosophila Lamin C caused no overt phenotype. By contrast, larval muscle-specific expression of a truncated form of Lamin C lacking the N-terminal head (Lamin C DeltaN) caused muscle defects and semi lethality, with adult 'escapers' possessing malformed legs. The leg defects were due to a lack of larval muscle function and alterations in hormone-regulated gene expression. The consequences of Lamin C association at a gene were tested directly by targeting a Lamin C DNA-binding domain fusion protein upstream of a reporter gene. Association of Lamin C correlated with localization of the reporter gene at the nuclear periphery and gene repression. These data demonstrate connections among the Drosophila A-type lamin, hormone-induced gene expression and muscle function. PMID- 20702565 TI - An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain. AB - Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma aminobutyric acid (GABA)-expressing neurons of the forebrain, including local circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease. PMID- 20702566 TI - A CESA from Griffithsia monilis (Rhodophyta, Florideophyceae) has a family 48 carbohydrate-binding module. AB - Cellulose synthases form rosette terminal complexes in the plasma membranes of Streptophyta and various linear terminal complexes in other taxa. The sequence of a putative CESA from Griffithsia monilis (Rhodophyta, Floridiophyceae) was deduced using a cloning strategy involving degenerate primers, a cDNA library screen, and 5' and 3' rapid amplification of cDNA ends (RACE). RACE identified two alternative transcriptional starts and four alternative polyadenylation sites. The first translation start codon provided an open reading frame of 2610 bp encoding 870 amino acids and was PCR amplified without introns from genomic DNA. Southern hybridization indicated one strongly hybridizing gene with possible weakly related genes or pseudogenes. Amino acid sequence analysis identified a family 48 carbohydrate-binding module (CBM) upstream of the protein's first predicted transmembrane domain. There are broad similarities in predicted 3D structures of the family 48 modules from CESA, from several glycogen- and starch binding enzymes, and from protein kinases, but there are substitutions at some residues thought to be involved in ligand binding. The module in G. monilis CESA will be on the cytoplasmic face of the plasma membrane so that it could potentially bind either low molecular weight ligands or starch which is cytosolic rather than inside membrane-bound plastids in red algae. Possible reasons why red algal CESAs have evolved family 48 modules perhaps as part of a system to regulate cellulose synthase activity in relation to cellular carbohydrate status are briefly discussed. PMID- 20702567 TI - UV radiation reduces epidermal cell expansion in leaves of Arabidopsis thaliana. AB - Plants have evolved a broad spectrum of mechanisms to ensure survival under changing and suboptimal environmental conditions. Alterations of plant architecture are commonly observed following exposure to abiotic stressors. The mechanisms behind these environmentally controlled morphogenic traits are, however, poorly understood. In this report, the effects of a low dose of chronic ultraviolet (UV) radiation on leaf development are detailed. Arabidopsis rosette leaves exposed for 7, 12, or 19 d to supplemental UV radiation expanded less compared with non-UV controls. The UV-mediated decrease in leaf expansion is associated with a decrease in adaxial pavement cell expansion. Elevated UV does not affect the number and shape of adaxial pavement cells, nor the stomatal index. Cell expansion in young Arabidopsis leaves is asynchronous along a top-to base gradient whereas, later in development, cells localized at both the proximal and distal half expand synchronously. The prominent, UV-mediated inhibition of cell expansion in young leaves comprises effects on the early asynchronous growing stage. Subsequent cell expansion during the synchronous phase cannot nullify the UV impact established during the asynchronous phase. The developmental stage of the leaf at the onset of UV treatment determines whether UV alters cell expansion during the synchronous and/or asynchronous stage. The effect of UV radiation on adaxial epidermal cell size appears permanent, whereas leaf shape is transiently altered with a reduced length/width ratio in young leaves. The data show that UV-altered morphogenesis is a temporal- and spatial dependent process, implying that common single time point or single leaf zone analyses are inadequate. PMID- 20702568 TI - Endosymbiotic gene transfer and transcriptional regulation of transferred genes in Paulinella chromatophora. AB - Paulinella chromatophora is a cercozoan amoeba that contains "chromatophores," which are photosynthetic inclusions of cyanobacterial origin. The recent discovery that chromatophores evolved independently of plastids, underwent major genome reduction, and transferred at least two genes to the host nucleus has highlighted P. chromatophora as a model to infer early steps in the evolution of photosynthetic organelles. However, owing to the paucity of nuclear genome sequence data, the extent of endosymbiotic gene transfer (EGT) and host symbiont regulation are currently unknown. A combination of 454 and Illumina next generation sequencing enabled us to generate a comprehensive reference transcriptome data set for P. chromatophora on which we mapped short Illumina cDNA reads generated from cultures from the dark and light phases of a diel cycle. Combined with extensive phylogenetic analyses of the deduced protein sequences, these data revealed that 1) about 0.3-0.8% of the nuclear genes were obtained by EGT compared with 11-14% in the Plantae, 2) transferred genes show a distinct bias in that many encode small proteins involved in photosynthesis and photoacclimation, 3) host cells established control over expression of transferred genes, and 4) not only EGT, but to a minor extent also horizontal gene transfer from organisms that presumably served as food sources, helped to shape the nuclear genome of P. chromatophora. The identification of a significant number of transferred genes involved in photosynthesis and photoacclimation of thylakoid membranes as well as the observed transcriptional regulation of these genes strongly implies import of the encoded gene products into chromatophores, a feature previously thought to be restricted to canonical organelles. Thus, a possible mechanism by which P. chromatophora exerts control over the performance of its newly acquired photosynthetic organelle may involve controlling the expression of nuclear-encoded chromatophore-targeted regulatory components of the thylakoid membranes. PMID- 20702569 TI - Perspectives in quality: designing the WHO Surgical Safety Checklist. AB - The World Health Organization's Patient Safety Programme created an initiative to improve the safety of surgery around the world. In order to accomplish this goal the programme team developed a checklist with items that could and, if at all possible, should be practised in all settings where surgery takes place. There is little guidance in the literature regarding methods for creating a medical checklist. The airline industry, however, has more than 70 years of experience in developing and using checklists. The authors of the WHO Surgical Safety Checklist drew lessons from the aviation experience to create a safety tool that supports essential clinical practice. In order to inform the methodology for development of future checklists in health care, we review how we applied lessons learned from the aviation experience in checklist development to the development of the Surgical Safety Checklist and also discuss the differences that exist between aviation and medicine that impact the use of checklists in health care. PMID- 20702570 TI - Liability regimes, reputation loss, and defensive medicine. PMID- 20702571 TI - Identification of a novel corticotropin-releasing hormone type 1beta-like receptor variant lacking Exon 13 in human pregnant myometrium regulated by estradiol-17beta and progesterone. AB - Two types of CRH receptors mediate the diverse biological functions of CRH and CRH-related peptides. The type 1 CRH-R (CRH-R1) is extensively targeted by pre mRNA splicing mechanisms that give rise to multiple mRNA splice variants. RT-PCR amplification of CRH-R1 sequences from human myometrium yielded cDNAs that encode a novel CRH-R1 splice variant with structural characteristics identical with CRH R1beta except a 14-amino acid deletion in the seventh transmembrane domain characteristic of the CRH-R1d. Transient expression of the hybrid CRH-R1 variant (CRH-R1beta/d) in human embryonic kidney 293 cells revealed primarily intracellular expression, although some plasma membrane protein expression was also detectable. CRH bound to CRH-R1beta/d with affinity comparable with the CRH R1beta; however, it was unable to stimulate adenylyl cyclase or other second messengers. Using a semiquantitative RT-PCR assay, CRH-R1beta/d mRNA transcript was detected in human pregnant, but not nonpregnant, myometrium as early as 31 wk of gestation. Furthermore, in human pregnant myometrial cells, the relative expression of CRH-R1beta and CRH-R1beta/d mRNA appeared to be regulated by steroids; CRH-R1beta/d mRNA expression was increased by estradiol-17beta, whereas CRH-R1beta mRNA levels were increased by progesterone. Progesterone also substantially increased CRH-R1alpha mRNA levels and cellular responsiveness to CRH as determined by increased agonist binding and cAMP production as well as resistance to CRH-R heterologous desensitization by phorbol esters. These results provide novel evidence for distinct patterns of CRH-R1 splicing and identify specific steroid-mediated regulation of CRH-R1 variant expression, which might be important for modulating CRH actions during human pregnancy and labour. PMID- 20702572 TI - Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary thyroid axis in mice. AB - In patients, inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels. PMID- 20702573 TI - Mechanism of attenuation of skeletal muscle atrophy by zinc-alpha2-glycoprotein. AB - The mechanism by which the adipokine zinc-alpha2-glycoprotein (ZAG) increases the mass of gastrocnemius, but not soleus muscle of diabetic mice, has been evaluated both in vivo and in vitro. There was an increased phosphorylation of both double stranded RNA-dependent protein kinase and its substrate, eukaryotic initiation factor-2alpha, which was attenuated by about two-thirds in gastrocnemius but not soleus muscle of ob/ob mice treated with ZAG (50 MUg, iv daily) for 5 d. ZAG also reduced the expression of the phospho forms of p38MAPK and phospholipase A2, as well as expression of the ubiquitin ligases (E3) muscle atrophy F-box/atrogin-1 and muscle RING finger protein, and the increased activity of both caspase-3 and casapse-8 to values found in nonobese controls. ZAG also increased the levels of phospho serine-threonine kinase and mammalian target of rapamycin in gastrocnemius muscle and reduced the phosphorylation of insulin receptor substrate-1 (Ser307) associated with insulin resistance. Similar changes were seen with ZAG when murine myotubes were incubated with high glucose concentrations (10 and 25 mm), showing that the effect of ZAG was direct. ZAG produced an increase in cAMP in murine myotubes, and the effects of ZAG on protein synthesis and degradation in vitro could be replicated by dibutyryl cAMP. ZAG increased cAMP levels of gastrocnemius but not soleus muscle. These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions. PMID- 20702574 TI - Concomitant enzyme-linked immunosorbent assay measurements of rat insulin, rat C peptide, and rat proinsulin from rat pancreatic islets: effects of prolonged exposure to different glucose concentrations. AB - Until now, there have been few assays to measure C-peptide and proinsulin in the rat. We used a well-established rat insulin ELISA and validated two novel ELISAs for rat C-peptide and rat/mouse proinsulin to examine secretion and content of insulin, proinsulin, and C-peptide from rat islets cultured for 72 h at different glucose concentrations in culture medium. To examine long-term effects in vitro rather than short-term effects of exposure to low, normal, and high glucose, the exposure time to the different glucose concentrations was set to 72 h. The measurement uncertainty of the values obtainable from the ELISAs was determined by calculation of the variation pattern from the intraassay variation generated by unknown samples, and repeatability was determined by analysis of controls. The precision study and the analysis of controls confirm that the validated ELISAs for rat C-peptide and proinsulin would be useful for further studies on the effects of preculture in different glucose concentrations. The higher the glucose concentration used during the 72-h culture period of rat islets, the higher insulin, C-peptide and proinsulin values were obtained in a subsequent short-term glucose-challenge experiment. The proportion of proinsulin to insulin secreted increased, as did islet content, with increasing glucose concentration during preculture. We also observed a nonequimolar, glucose-dependent secretion and content of rat insulin over rat C-peptide after culture at 11.1 and 28 mM glucose. PMID- 20702575 TI - Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. AB - Glucocorticoid hormones are secreted in response to stimuli that activate the hypothalamo-pituitary-adrenocortical (HPA) axis and self-regulate through negative feedback. Negative feedback that occurs on a rapid time scale is thought to act through nongenomic mechanisms. In these studies, we investigated fast feedback inhibition of HPA axis stress responses by direct glucocorticoid action at the paraventricular nucleus of the hypothalamus (PVN). Local infusion of dexamethasone or a membrane-impermeant dexamethasone-BSA conjugate into the PVN rapidly inhibits restraint-induced ACTH and corticosterone release in a manner consistent with feedback actions at the cell membrane. The dexamethasone fast feedback response is blocked by the cannabinoid CB1 receptor antagonist AM-251, suggesting that fast feedback requires local release of endocannabinoids. Hypothalamic tissue content of the endocannabinoid 2-arachidonoyl glycerol is elevated by restraint stress, consistent with endocannabinoid action on feedback processes. These data support the hypothesis that glucocorticoid-induced fast feedback inhibition of the HPA axis is mediated by a nongenomic signaling mechanism that involves endocannabinoid signaling at the level of the PVN. PMID- 20702576 TI - LIM homeodomain transcription factor Isl-1 enhances follicle stimulating hormone beta and luteinizing hormone-beta gene expression and mediates the activation of leptin on gonadotropin synthesis. AB - The Lin-11, Isl-1, and Mec-3 (LIM) homeodomain transcription factor Isl-1 has been reported to be involved in pituitary development in the early stages of mouse embryogenesis. Our recent studies have shown that Isl-1 is mainly located in the pituitary gonadotropes throughout pituitary development and persists to adulthood. We still do not know the physiological functions of Isl-1 expression and its related mechanisms in the pituitary gland. The aim of the present study was to examine the hypothesis that Isl-1 is involved in regulating pituitary gonadotropin hormone (FSH/LH) production by activating FSHbeta and LHbeta gene expressions. We have shown that Isl-1 activates FSHbeta and LHbeta subunit promoters and endogenous gene transcription in LbetaT2 cells. In addition, Isl-1 overexpression significantly increased FSH synthesis and secretion but not LH. The actions of Isl-1 were not observed when the homeodomain or LIM1 domains are mutated. This demonstrates that Isl-1 induction of FSHbeta and LHbeta is by both direct and indirect binding of Isl-1 to DNA sequences. Furthermore, Isl-1 expressional level was up-regulated in LbetaT2 cells after exposure to GnRH, activin, and leptin. However, RNA interference-induced knockdown of Isl-1 significantly reduced the effect of leptin but did not obviously influence the stimulating effects of GnRH and activin on LH and FSH production. In conclusion, the results demonstrate that the LIM-homeodomain transcription factor Isl-1 functions to increase FSHbeta/LHbeta gene transcription, and mediates the effects of leptin on gonadotropin synthesis. PMID- 20702577 TI - Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. AB - Sexual differentiation of the rodent brain occurs during a perinatal critical period when androgen production from the male testis is locally converted to estradiol in neurons, resulting in masculinization of adult sexual behavior. Adult brain responses to hormones are programmed developmentally by estradiol exposure, but the mechanism(s) by which these changes are permanently organized remains poorly understood. Activation of steroid receptors plays a major role in organization of the brain, and we hypothesized that estradiol-induced alteration of steroid-receptor gene methylation is a critical component to this process. Estrogen receptor (ER)-alpha and ER-beta and progesterone receptor are expressed at high levels within the preoptic area (POA) and the mediobasal hypothalamus, two brain regions critical for the expression of male and female sexual behavior. The percent methylation on the ER-alpha promoter increased markedly across development. During the critical period of sexual differentiation, females had significantly increased methylation than males or females masculinized with estradiol at two CpG sites. By adulthood, the neonatal sex difference and hormonal modulation of methylation were replaced with a new pattern at a different CpG site on the ER-alpha promoter. In contrast, the percent methylation on the progesterone receptor and ER-beta promoter did not change developmentally but was modulated by hormones and exhibited only late emerging transient sex differences. These data indicate that sex differences in the methylation pattern of genes important for sexual behavior are epigenetically modified during development, but the specific changes observed do not endure and are not necessarily temporally associated with neonatal hormone exposure. PMID- 20702578 TI - Local induction of adiponectin reduces lipopolysaccharide-triggered skeletal muscle damage. AB - Adiponectin (ApN) exhibits metabolic and antiinflammatory properties. This hormone is exclusively secreted by adipocytes under normal conditions. We have shown that ApN was induced in tibialis anterior muscle of mice injected with lipopolysaccharide (LPS) and in C2C12 myotubes cultured with proinflammatory cytokines. We hypothesized that muscle ApN could be a local protective mechanism to counteract excessive inflammatory reaction and oxidative damage. To test this paradigm, we examined whether muscles of ApN-knockout (KO) mice exhibit a higher degree of oxidative stress and apoptosis than wild-type mice when challenged by ip LPS and whether these abnormalities may be corrected by local administration of ApN. Eventually we investigated the effects of ApN in vitro. When compared with wild-type mice, ApN-KO mice exhibited myocyte degenerescence, especially after LPS. Myocytes of ApN-KO mice also displayed much stronger immunolabeling for markers of oxidative stress (peroxiredoxin-3/5 and heme oxygenase-1) as well as for a lipid peroxidation product (hydroxynonenal). Expression of TNF-alpha, caspase-6, a marker of apoptosis, and nuclear factor-kappaB was enhanced as well. Eventually muscle electrotransfer of the ApN gene, which did not induce any rise of systemic ApN, corrected all these abnormalities in LPS-injected ApN-KO mice. Likewise, ApN attenuated LPS-induced production of proinflammatory cytokines and activation of nuclear factor-kappaB in C2C12 cells. Thus, induction of ApN into skeletal muscle in response to an inflammatory aggression appears to be a crucial mechanism to counteract in an autocrine or paracrine fashion excessive inflammatory damage, oxidative stress, and subsequent apoptosis. PMID- 20702579 TI - Defining the epigenetic actions of growth hormone: acute chromatin changes accompany GH-activated gene transcription. AB - Many of the long-term physiological effects of GH require hormone-mediated changes in gene expression. The transcription factor signal transducer and activator of transcription 5b (Stat5b) plays a critical role in the actions of GH on growth and metabolism by regulating a large number of GH-dependent genes by incompletely understood mechanisms. Here we have assessed the impact of GH initiated and Stat5b-mediated signaling on the chromatin landscape of hormone regulated genes in the liver of pituitary-deficient young adult male rats. In the absence of GH there was minimal ongoing transcription at the Socs2, Cish, Igfals, and Spi 2.1 promoters, minimal occupancy of Stat5b at proximal promoter sites, and relatively closed chromatin, as evidenced by low levels of core histone acetylation. In contrast, transcriptionally silent Igf1 promoter 1 appeared poised to be activated, based on binding of coactivators p300 and Med1/Trap220, high levels of histone acetylation, and the presence of RNA polymerase II. GH treatment led to a 8- to 20-fold rise in transcriptional activity of all five genes within 30-60 min and was accompanied by binding of Stat5b to the proximal Socs2, Cish, Igfals, and Spi 2.1 promoters and to seven distal Igf1 Stat5b elements, by enhanced histone acetylation at all five promoters, by recruitment of RNA polymerase II to the Socs2, Cish, Igfals, and Spi 2.1 promoters, and by loss of the transcriptional repressor Bcl6 from Socs2, Cish, and Igfals Stat5b sites, but not from two Igf1 Stat5b domains. We conclude that GH actions induce rapid and dramatic changes in hepatic chromatin at target promoters and propose that the chromatin signature of Igf1 differs from other GH-and Stat5b-dependent genes. PMID- 20702580 TI - Endogenous activation of glucokinase by 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase is glucose dependent. AB - Glucokinase (GK) plays a crucial role as glucose sensor in glucose-induced insulin secretion in pancreatic beta-cells. The bifunctional enzyme 6 phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) acts as an endogenous GK activator. Therefore, the goal of this study was the analysis of GK PFK-2/FBPase-2 complex formation and its effect on metabolic stimulus-secretion coupling in beta-cells in dependence upon glucose. The interaction between GK and PFK-2/FBPase-2 was analyzed in insulin-secreting MIN6 cells with a new fluorescence-based mammalian two-hybrid system. In contrast to the commonly used mammalian two-hybrid systems that require sampling before detection, the system used allows monitoring of the effects of environmental changes on protein-protein interactions on the single-cell level. Increasing the glucose concentration in the cell culture medium from 3 to 10 and 25 mmol/liter amplified the interaction between the enzymes stepwise. Importantly, in line with these results, overexpression of PFK-2/FBPase-2 in MIN6 cells evoked only at 10 and 25 mmol/liter, an increase in insulin secretion. Furthermore, a PFK-2/FBPase-2 mutant with an abolished GK-binding motif neither showed a glucose-dependent GK binding nor was able to increase insulin secretion. The results obtained with the mammalian two-hybrid system could be confirmed by fluorescence resonance energy transfer experiments in COS cells. Furthermore, the established interaction between GK and the liver GRP served in all experiments as a control. Thus, this study clearly showed that binding and activation of GK by PFK-2/FBPase-2 in beta cells is promoted by glucose, resulting in an enhancement of insulin secretion at stimulatory glucose concentrations, without affecting basal insulin secretion. PMID- 20702581 TI - Coordination of substrate binding and ATP hydrolysis in Vps4-mediated ESCRT-III disassembly. AB - ESCRT-III undergoes dynamic assembly and disassembly to facilitate membrane exvagination processes including multivesicular body (MVB) formation, enveloped virus budding, and membrane abscission during cytokinesis. The AAA-ATPase Vps4 is required for ESCRT-III disassembly, however the coordination of Vps4 ATP hydrolysis with ESCRT-III binding and disassembly is not understood. Vps4 ATP hydrolysis has been proposed to execute ESCRT-III disassembly as either a stable oligomer or an unstable oligomer whose dissociation drives ESCRT-III disassembly. An in vitro ESCRT-III disassembly assay was developed to analyze Vps4 function during this process. The studies presented here support a model in which Vps4 acts as a stable oligomer during ATP hydrolysis and ESCRT-III disassembly. Moreover, Vps4 oligomer binding to ESCRT-III induces coordination of ATP hydrolysis at the level of individual Vps4 subunits. These results suggest that Vps4 functions as a stable oligomer that acts upon individual ESCRT-III subunits to facilitate ESCRT-III disassembly. PMID- 20702582 TI - Small molecule inhibition of HIV-1-induced MHC-I down-regulation identifies a temporally regulated switch in Nef action. AB - HIV-1 Nef triggers down-regulation of cell-surface MHC-I by assembling a Src family kinase (SFK)-ZAP-70/Syk-PI3K cascade. Here, we report that chemical disruption of the Nef-SFK interaction with the small molecule inhibitor 2c blocks assembly of the multi-kinase complex and represses HIV-1-mediated MHC-I down regulation in primary CD4(+) T-cells. 2c did not interfere with the PACS-2 dependent trafficking of Nef required for the Nef-SFK interaction or the AP-1 and PACS-1-dependent sequestering of internalized MHC-I, suggesting the inhibitor specifically interfered with the Nef-SFK interaction required for triggering MHC I down-regulation. Transport studies revealed Nef directs a highly regulated program to down-regulate MHC-I in primary CD4(+) T-cells. During the first two days after infection, Nef assembles the 2c-sensitive multi-kinase complex to trigger down-regulation of cell-surface MHC-I. By three days postinfection Nef switches to a stoichiometric mode that prevents surface delivery of newly synthesized MHC-I. Pharmacologic inhibition of the multi-kinase cascade prevents the Nef-dependent block in MHC-I transport, suggesting the signaling and stoichiometric modes are causally linked. Together, these studies resolve the seemingly controversial models that describe Nef-induced MHC-I down-regulation and provide new insights into the mechanism of Nef action. PMID- 20702583 TI - V-ATPase-mediated granular acidification is regulated by the V-ATPase accessory subunit Ac45 in POMC-producing cells. AB - The vacuolar (H(+))-ATPase (V-ATPase) is an important proton pump, and multiple critical cell-biological processes depend on the proton gradient provided by the pump. Yet, the mechanism underlying the control of the V-ATPase is still elusive but has been hypothesized to involve an accessory subunit of the pump. Here we studied as a candidate V-ATPase regulator the neuroendocrine V-ATPase accessory subunit Ac45. We transgenically manipulated the expression levels of the Ac45 protein specifically in Xenopus intermediate pituitary melanotrope cells and analyzed in detail the functioning of the transgenic cells. We found in the transgenic melanotrope cells the following: i) significantly increased granular acidification; ii) reduced sensitivity for a V-ATPase-specific inhibitor; iii) enhanced early processing of proopiomelanocortin (POMC) by prohormone convertase PC1; iv) reduced, neutral pH-dependent cleavage of the PC2 chaperone 7B2; v) reduced 7B2-proPC2 dissociation and consequently reduced proPC2 maturation; vi) decreased levels of mature PC2 and consequently reduced late POMC processing. Together, our results show that the V-ATPase accessory subunit Ac45 represents the first regulator of the proton pump and controls V-ATPase-mediated granular acidification that is necessary for efficient prohormone processing. PMID- 20702584 TI - The rapamycin-sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. AB - Regulation of cell growth requires extensive coordination of several processes including transcription, ribosome biogenesis, translation, nutrient metabolism, and autophagy. In yeast, the protein kinases Target of Rapamycin (TOR) and protein kinase A (PKA) regulate these processes and are thereby the main activators of cell growth in response to nutrients. How TOR, PKA, and their corresponding signaling pathways are coordinated to control the same cellular processes is not understood. Quantitative analysis of the rapamycin-sensitive phosphoproteome combined with targeted analysis of PKA substrates suggests that TOR complex 1 (TORC1) activates PKA but only toward a subset of substrates. Furthermore, we show that TORC1 signaling impinges on BCY1, the negative regulatory subunit of PKA. Inhibition of TORC1 with rapamycin leads to BCY1 phosphorylation on several sites including T129. Phosphorylation of BCY1 T129 results in BCY1 activation and inhibition of PKA. TORC1 inhibits BCY1 T129 phosphorylation by phosphorylating and activating the S6K homolog SCH9 that in turn inhibits the MAP kinase MPK1. MPK1 phosphorylates BCY1 T129 directly. Thus, TORC1 activates PKA toward some substrates by preventing MPK1-mediated activation of BCY1. PMID- 20702585 TI - Keeping the vimentin network under control: cell-matrix adhesion-associated plectin 1f affects cell shape and polarity of fibroblasts. AB - Focal adhesions (FAs) located at the ends of actin/myosin-containing contractile stress fibers form tight connections between fibroblasts and their underlying extracellular matrix. We show here that mature FAs and their derivative fibronectin fibril-aligned fibrillar adhesions (FbAs) serve as docking sites for vimentin intermediate filaments (IFs) in a plectin isoform 1f (P1f)-dependent manner. Time-lapse video microscopy revealed that FA-associated P1f captures mobile vimentin filament precursors, which then serve as seeds for de novo IF network formation via end-to-end fusion with other mobile precursors. As a consequence of IF association, the turnover of FAs is reduced. P1f-mediated IF network formation at FbAs creates a resilient cage-like core structure that encases and positions the nucleus while being stably connected to the exterior of the cell. We show that the formation of this structure affects cell shape with consequences for cell polarization. PMID- 20702586 TI - Cdk phosphorylation of a nucleoporin controls localization of active genes through the cell cycle. AB - Many inducible genes in yeast are targeted to the nuclear pore complex when active. We find that the peripheral localization of the INO1 and GAL1 genes is regulated through the cell cycle. Active INO1 and GAL1 localized at the nuclear periphery during G1, became nucleoplasmic during S-phase, and then returned to the nuclear periphery during G2/M. Loss of peripheral targeting followed the initiation of DNA replication and was lost in cells lacking a cyclin-dependent kinase (Cdk) inhibitor. Furthermore, the Cdk1 kinase and two Cdk phosphorylation sites in the nucleoporin Nup1 were required for peripheral targeting of INO1 and GAL1. Introduction of aspartic acid residues in place of either of these two sites in Nup1 bypassed the requirement for Cdk1 and resulted in targeting of INO1 and GAL1 to the nuclear periphery during S-phase. Thus, phosphorylation of a nuclear pore component by cyclin dependent kinase controls the localization of active genes to the nuclear periphery through the cell cycle. PMID- 20702587 TI - ZFP36L1 negatively regulates erythroid differentiation of CD34+ hematopoietic stem cells by interfering with the Stat5b pathway. AB - ZFP36L1 is a member of a family of CCCH tandem zinc finger proteins (TTP family) able to bind to AU-rich elements in the 3'-untranslated region of mRNAs, thereby triggering their degradation. The present study suggests that such mechanism is used during hematopoiesis to regulate differentiation by posttranscriptionally modulating the expression of specific target genes. In particular, it demonstrates that ZFP36L1 negatively regulates erythroid differentiation by directly binding the 3' untranslated region of Stat5b encoding mRNA. Stat5b down regulation obtained by ZFP36L1 overexpression results, in human hematopoietic progenitors, in a drastic decrease of erythroid colonies formation. These observations have been confirmed by silencing experiments targeting Stat5b and by treating hematopoietic stem/progenitor cells with drugs able to induce ZFP36L1 expression. Moreover, this study shows that different members of ZFP36L1 family act redundantly, because cooverexpression of ZFP36L1 and family member ZFP36 determines a cumulative effect on Stat5b down-regulation. This work describes a mechanism underlying ZFP36L1 capability to regulate hematopoietic differentiation and suggests a new target for the therapy of hematopoietic diseases involving Stat5b/JAK2 pathway, such as chronic myeloproliferative disorders. PMID- 20702588 TI - A novel framework for predicting in vivo toxicities from in vitro data using optimal methods for dense and sparse matrix reordering and logistic regression. AB - In this work, we combine the strengths of mixed-integer linear optimization (MILP) and logistic regression for predicting the in vivo toxicity of chemicals using only their measured in vitro assay data. The proposed approach utilizes a biclustering method based on iterative optimal reordering (DiMaggio, P. A., McAllister, S. R., Floudas, C. A., Feng, X. J., Rabinowitz, J. D., and Rabitz, H. A. (2008). Biclustering via optimal re-ordering of data matrices in systems biology: rigorous methods and comparative studies. BMC Bioinformatics 9, 458 474.; DiMaggio, P. A., McAllister, S. R., Floudas, C. A., Feng, X. J., Rabinowitz, J. D., and Rabitz, H. A. (2010b). A network flow model for biclustering via optimal re-ordering of data matrices. J. Global. Optim. 47, 343 354.) to identify biclusters corresponding to subsets of chemicals that have similar responses over distinct subsets of the in vitro assays. The biclustering of the in vitro assays is shown to result in significant clustering based on assay target (e.g., cytochrome P450 [CYP] and nuclear receptors) and type (e.g., downregulated BioMAP and biochemical high-throughput screening protein kinase activity assays). An optimal method based on mixed-integer linear optimization for reordering sparse data matrices (DiMaggio, P. A., McAllister, S. R., Floudas, C. A., Feng, X. J., Li, G. Y., Rabinowitz, J. D., and Rabitz, H. A. (2010a). Enhancing molecular discovery using descriptor-free rearrangement clustering techniques for sparse data sets. AIChE J. 56, 405-418.; McAllister, S. R., DiMaggio, P. A., and Floudas, C. A. (2009). Mathematical modeling and efficient optimization methods for the distance-dependent rearrangement clustering problem. J. Global. Optim. 45, 111-129) is then applied to the in vivo data set (21.7% sparse) in order to cluster end points that have similar lowest effect level (LEL) values, where it is observed that the end points are effectively clustered according to (1) animal species (i.e., the chronic mouse and chronic rat end points were clearly separated) and (2) similar physiological attributes (i.e., liver- and reproductive-related end points were found to separately cluster together). As the liver and reproductive end points exhibited the largest degree of correlation, we further analyzed them using regularized logistic regression in a rank-and-drop framework to identify which subset of in vitro features could be utilized for in vivo toxicity prediction. It was observed that the in vivo end points that had similar LEL responses over the 309 chemicals (as determined by the sparse clustering results) also shared a significant subset of selected in vitro descriptors. Comparing the significant descriptors between the two different categories of end points revealed a specificity of the CYP assays for the liver end points and preferential selection of the estrogen/androgen nuclear receptors by the reproductive end points. PMID- 20702589 TI - An information-rich alternative, chemicals testing strategy using a high definition toxicogenomics and zebrafish (Danio rerio) embryos. AB - Large-scale toxicogenomic screening approaches offer great promise for generating a bias-free system-wide view of toxicological effects and modes-of-action of chemicals and ecotoxicants. However, early applications of microarray technology have identified relatively small groups of responding genes with which to define new targets for analysis by conventional means. We have trialled a more intensive approach to the design and interpretation of array experiments incorporating a balanced interwoven ANOVA design with higher levels of biological replication, a more thorough analysis of errors and false discovery rates, and an analysis of response patterns using gene network models. Zebrafish embryos were exposed from 1.5 h post-fertilization for 72 h to ecotoxicants representing different classes- 2,4-dichlorophenol, 3,4-dichloroaniline, pentachlorophenol, and cadmium chloride- at low concentrations producing a developmental disturbance to 10% of embryos and half of this dose. Extracted whole embryo RNA was then analyzed on microarrays. Analysis revealed responses of 3000-5000 genes, which is 10-1000 times greater than previously reported, with significance at lower levels of fold change. Some gene responses were common to multiple toxicants, and others were restricted to just one or two toxicants. The gene expression profiles for the different toxicants were distinctive, and analysis using network-based models provided a high level of detail of affected processes, some of which were novel. This approach provides a more highly refined view of toxic effects, from which meaningful patterns of response can be discerned and related to functional deficits and from which more reliable indicators of toxicological effect can be predicted. PMID- 20702590 TI - Induction of the aryl hydrocarbon receptor-responsive genes and modulation of the immunoglobulin M response by 2,3,7,8-tetrachlorodibenzo-p-dioxin in primary human B cells. AB - Past studies in rodent models identified the suppression of primary humoral immune responses as one of the most sensitive sequela associated with 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) exposure. Yet, the sensitivity of humoral immunity to TCDD in humans represents an important toxicological data gap. Therefore, the objectives of this investigation were two-fold. The first was to assess the induction of known aryl hydrocarbon receptor (AHR)-responsive genes in primary human B cells as a measure of early biological responses to TCDD. The second was to evaluate the direct effect of TCDD on CD40 ligand-induced immunoglobulin M (IgM) secretion by human primary B cells. The effects of TCDD on induction of AHR-responsive genes and suppression of the IgM response were also compared with B cells from a TCDD-responsive mouse strain, C57BL/6. AHR responsive genes in human B cells exhibited slower kinetics and reduced magnitude of induction by TCDD when compared with mouse B cells. Evaluation of B-cell function from 12 donors identified two general phenotypes; the majority of donors exhibited similar sensitivity to suppression by TCDD of the IgM response as mouse B cells, which was not attributable to decreased B-cell proliferation. In a minority of donors, no suppression of the IgM response by TCDD was observed. Although donor-to-donor variation in sensitivity to TCDD was observed, human B cells from the majority of donors evaluated showed impairment of effector function by TCDD. Collectively, data presented in this series of studies demonstrate that TCDD impairs the humoral immunity of humans by directly targeting B cells. PMID- 20702591 TI - Comparison of the toxicity of smoke from conventional and harm reduction cigarettes using human embryonic stem cells. AB - This study evaluated the hypothesis that smoke from harm reduction cigarettes impedes attachment and proliferation of H9 human embryonic stem cells (hESCs). Smoke from three harm reduction brands was compared with smoke from a conventional brand. Doses of smoke were measured in puff equivalents (PE) (1 PE = the amount of smoke in one puff that dissolves in 1 ml of medium). Cytotoxic doses were determined using morphological criteria and trypan blue staining, and apoptosis was confirmed using Magic Red staining. Attachment and proliferation of hESC were followed at a noncytotoxic dose in time-lapse videos collected using BioStation technology. Data were mined from videos either manually or using video bioinformatics subroutines developed with CL-Quant software. Mainstream (MS) and sidestream (SS) smoke from conventional and harm reduction cigarettes induced apoptosis in hESC colonies at 1 PE. At 0.1 PE (noncytotoxic), SS smoke from all brands inhibited attachment of hESC colonies to Matrigel with the strongest inhibition occurring in harm reduction brands. At 0.1 PE, SS smoke, but not MS smoke, from all brands inhibited hESC growth, and two harm reduction brands were more potent than the conventional brand. In general, hESC appeared more sensitive to smoke than their mouse ESC counterparts. Although harm reduction cigarettes are often marketed as safer than conventional brands, our assays show that SS smoke from harm reduction cigarettes was at least as potent or in some cases more potent than smoke from a conventional brand and that SS smoke was more inhibitory than MS smoke in all assays. PMID- 20702592 TI - TIM2 gene deletion results in susceptibility to cisplatin-induced kidney toxicity. AB - T-cell Immunoglobulin and Mucin domain 2 (TIM2) belongs to the receptor family of cell surface molecules expressed on kidney, liver, and T cells. Previous studies have revealed that TIM2-deficient mice (TIM2(-/-)) are more susceptible to the Th2-mediated immune response in an airway inflammation model. Here, we investigated the phenotypic response of TIM2(-/-) mice to cisplatin-induced kidney toxicity. A lethality study in male BALB/c wild-type (TIM2(+/+)) and TIM2( /-) mice, administered with 20 mg/kg cisplatin ip, resulted in 80% mortality of TIM2(-/-) mice as compared with 30% mortality in the TIM2(+/+) group by day 5. The TIM2(-/-) mice showed approximately fivefold higher injury as estimated by blood urea nitrogen and serum creatinine at 48 h that was confirmed by significantly increased proximal tubular damage assessed histologically (H & E staining). A significantly higher expression of Th2-associated cytokines, TNF alpha, IL-1beta, IL-6, and TGFbeta, with a significant reduction of Th1 associated cytokines, RANTES and MCP-1, by 72 h was observed in the TIM2(-/-) mice as compared with TIM2(+/+) mice. A higher baseline protein expression of caspase-3 (approximately twofold) coupled with an early onset of p53 protein activation by 48 h resulted in an increased apoptosis by 48-72 h in TIM2(-/-) compared with TIM2(+/+). In conclusion, the increased expression of the proinflammatory and proapoptotic genes, with a higher number of apoptotic cells, and a pronounced increase in injury and mortality of the TIM2-deficient mice collectively suggest a protective role of TIM2 in cisplatin-induced nephrotoxicity. PMID- 20702593 TI - Transcriptomic profile indicative of immunotoxic exposure: in vitro studies in peripheral blood mononuclear cells. AB - Investigating the immunotoxic effects of exposure to chemicals usually comprises evaluation of weight and histopathology of lymphoid tissues, various lymphocyte parameters in the circulation, and immune function. Immunotoxicity assessment is time consuming in humans or requires a high number of animals, making it expensive. Furthermore, reducing the use of animals in research is an important ethical and political issue. Immunotoxicogenomics represents a novel approach to investigate immunotoxicity able of overcoming these limitations. The current research, embedded in the European Union project NewGeneris, aimed to retrieve gene expression profiles that are indicative of exposure to immunotoxicants. To this end, whole-genome gene expression was investigated in human peripheral blood mononuclear cells in response to in vitro exposure to a range of immunotoxic chemicals (4-hydroxy-2-nonenal, aflatoxin B1, benzo[a]pyrene, deoxynivalenol, ethanol, malondialdehyde, polychlorinated biphenyl 153, and 2,3,7,8 tetrachlorodibenzo-p-dioxin) and nonimmunotoxic chemicals (acrylamide, dimethylnitrosamine, 2-amino-3-methyl-3H-imidazo[4,5-F]quinoline, and 2-amino-1 methyl-6-phenylimidazo[4,5-b]pyridine). Using Agilent oligonucleotide microarrays, whole-genome gene expression profiles were generated, which were analyzed using Genedata's Expressionist software. Using Recursive Feature Elimination and Support Vector Machine, a set of 48 genes was identified that distinguishes the immunotoxic from the nonimmunotoxic compounds. Analysis for enrichment of biological processes showed the gene set to be highly biologically and immunologically relevant. We conclude that we have identified a promising transcriptomic profile indicative of immunotoxic exposure. PMID- 20702595 TI - Progressive mitochondrial compromise in brains and livers of primates exposed in utero to nucleoside reverse transcriptase inhibitors (NRTIs). AB - Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8 51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function. PMID- 20702594 TI - Automated dose-response analysis and comparative toxicogenomic evaluation of the hepatic effects elicited by TCDD, TCDF, and PCB126 in C57BL/6 mice. AB - The toxic equivalency factor (TEF) approach recommended by the World Health Organization is used to quantify dioxin-like exposure concentrations for mixtures of polychlorinated dibenzo-dioxins, -furans, and polychlorinated biphenyls (PCBs), including 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 3,3',4,4',5 pentachlorobiphenyl (PCB126) relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Whole-genome microarrays were used to evaluate the hepatic gene expression potency of TCDF and PCB126 relative to TCDD with complementary histopathology, tissue level analysis, and ethoxyresorufin-O-deethylase (EROD) assay results. Immature ovariectomized C57BL/6 mice were gavaged with 0.001, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, and 300 MUg/kg TCDD and TEF-adjusted doses (TEF for TCDF and PCB126 is 0.1) of TCDF or PCB126 (1, 3, 10, 30, 100, 300, 1000, and 3000 MUg/kg of TCDF or PCB126) or sesame oil vehicle and sacrificed 24 h post dose. In general, TCDD, TCDF, and PCB126 tissue levels, as well as histopathological effects, were comparable when comparing TEF-adjusted doses. Automated dose-response modeling (ToxResponse Modeler) of the microarray data identified 210 TCDF and 40 PCB126 genes that exhibited sigmoidal dose-response curves with comparable slopes when compared with TCDD. These similar responses were used to calculate a median TCDF gene expression relative potency (REP) of 0.06 and a median PCB126 gene expression REP of 0.02. REPs of 0.02 were also calculated for EROD induction for both compounds. Collectively, these data suggest that differences in the ability of the liganded aryl hydrocarbon receptor:AhR nuclear translocator complex to elicit differential hepatic gene expression, in addition to pharmacokinetic differences between ligands, influence their potency in immature ovariectomized C57BL/6 mice. PMID- 20702596 TI - Evolution of gene regulation--on the road towards computational inferences. AB - If fragments of DNA are transcribed (expressed), they deserve to be called (parts of) a gene. Whether transcription takes place depends on the 'gene regulatory network'. This network is defined as the complex interplay of the sequence, biochemical modifications and structure of the chromosomal DNA with the regulatory proteins/RNA (transcription factors, co-factors, regulating RNA and the transcriptional apparatus itself). Gene regulatory networks play a role in various stages of development as well as in the maintenance of the organism; in this review we will concentrate on the former. Their evolutionary reconstruction is daunting (to say the least), and bioinformatics tools are in their infancy. However, gain of understanding offers a reward beyond itself, since evolutionary considerations can enable discoveries in the first place, e.g. the computational identification of conserved transcription factor binding sites. We discuss the evolution of gene regulation in the context of the 'Genetic Theory of Morphological Evolution' as described by Carroll, identifying those parts of the theory that are relevant for bioinformatics, and their implications. We discuss the important question of how bioinformatics analysis results on the evolution of gene regulation may be validated. Finally, we briefly exemplify use of the UCSC genome browser, exploiting its pre-computed alignments to describe the evolution of gene regulation. PMID- 20702597 TI - Cohort profile: the 2004 Pelotas (Brazil) birth cohort study. PMID- 20702599 TI - Mediation of T-cell activation by actin meshworks. AB - Although the actin cytoskeleton and T-cell receptor (TCR) signaling complexes are seemingly distinct molecular structures, they are tightly integrated in T cells. The signaling pathways initiated by TCRs binding to peptide MHC complexes are extensively influenced by the actin cytoskeletal activities of the motile phase before TCR signaling, the signalosome scaffolding function of the cytoskeleton, and the translocation of signaling clusters that precedes the termination of signaling at these complexes. As these three successive phases constitute essentially all the steps consequent to immune synapse formation, it has become clear that the substantial physical forces and signaling interactions generated by the actin cytoskeleton dominate the signaling life cycle of TCR signalosomes. We discuss the contributions of the actin cytoskeleton to TCR signaling phases and model some remaining questions about how specific cytoskeletal factors regulate TCR signaling outcomes. PMID- 20702598 TI - Cell-matrix interactions in mammary gland development and breast cancer. AB - The mammary gland is an organ that at once gives life to the young, but at the same time poses one of the greatest threats to the mother. Understanding how the tissue develops and functions is of pressing importance in determining how its control mechanisms break down in breast cancer. Here we argue that the interactions between mammary epithelial cells and their extracellular matrix (ECM) are crucial in the development and function of the tissue. Current strategies for treating breast cancer take advantage of our knowledge of the endocrine regulation of breast development, and the emerging role of stromal epithelial interactions (Fig. 1). Focusing, in addition, on the microenvironmental influences that arise from cell-matrix interactions will open new opportunities for therapeutic intervention. We suggest that ultimately a three-pronged approach targeting endocrine, growth factor, and cell-matrix interactions will provide the best chance of curing the disease. PMID- 20702600 TI - Intrinsic nitric oxide and superoxide production regulates descending vasa recta contraction. AB - Descending vasa recta (DVR) are 12- to 15-MUm microvessels that supply the renal medulla with blood flow. We examined the ability of intrinsic nitric oxide (NO) and reactive oxygen species (ROS) generation to regulate their vasoactivity. Nitric oxide synthase (NOS) inhibition with N(omega)-nitro-l-arginine methyl ester (l-NAME; 100 MUmol/l), or asymmetric N(G),N(G)-dimethyl-l-arginine (ADMA; 100 MUmol/l), constricted isolated microperfused DVR by 48.82 +/- 4.34 and 27.91 +/- 2.91%, respectively. Restoring NO with sodium nitroprusside (SNP; 1 mmol/l) or application of 8-Br-cGMP (100 MUmol/l) reversed DVR vasoconstriction by l NAME. The superoxide dismutase mimetic Tempol (1 mmol/l) and the NAD(P)H inhibitor apocynin (100, 1,000 MUmol/l) also blunted ADMA- or l-NAME-induced vasoconstriction, implicating a role for concomitant generation of ROS. A role for ROS generation was also supported by an l-NAME-associated rise in oxidation of dihydroethidium that was prevented by Tempol or apocynin. To test whether H(2)O(2) might play a role, we examined its direct effects. From 1 to 100 MUmol/l, H(2)O(2) contracted DVR whereas at 1 mmol/l it was vasodilatory. The H(2)O(2) scavenger polyethylene glycol-catalase reversed H(2)O(2) (10 MUmol/l) induced vasoconstriction; however, it did not affect l-NAME-induced contraction. Finally, the previously known rise in DVR permeability to (22)Na and [(3)H]raffinose that occurs with luminal perfusion was not prevented by NOS blockade. We conclude that intrinsic production of NO and ROS can modulate DVR vasoactivity and that l-NAME-induced vasoconstriction occurs, in part, by modulating superoxide concentration and not through H(2)O(2) generation. Intrinsic NO production does not affect DVR permeability to hydrophilic solutes. PMID- 20702601 TI - Nucleofection disrupts tight junction fence function to alter membrane polarity of renal epithelial cells. AB - Here, we compared the effects of nucleofection and lipid-based approaches to introduce siRNA duplexes on the subsequent development of membrane polarity in kidney cells. Nucleofection of Madin-Darby canine kidney (MDCK) cells, even with control siRNA duplexes, disrupted the initial surface polarity as well as the steady-state distribution of membrane proteins. Transfection using lipofectamine yielded slightly less efficient knockdown but did not disrupt membrane polarity. Polarized secretion was unaffected by nucleofection, suggesting a selective defect in the development of membrane polarity. Cilia frequency and length were not altered by nucleofection. However, the basolateral appearance of a fluorescent lipid tracer added to the apical surface of nucleofected cells was dramatically enhanced relative to untransfected controls or lipofectamine-treated cells. In contrast, [(3)H]inulin diffusion and transepithelial electrical resistance were not altered in nucleofected cells compared with untransfected ones. We conclude that nucleofection selectively hinders development of the tight junction fence function in MDCK cells. PMID- 20702602 TI - Effects of dietary K on cell-surface expression of renal ion channels and transporters. AB - Changes in apical surface expression of ion channels and transporters in the superficial rat renal cortex were assessed using biotinylation and immunoblotting during alterations in dietary K intake. A high-K diet increased, and a low-K diet decreased, both the overall and surface abundance of the beta- and gamma-subunits of the epithelial Na channel (ENaC). In the case of gamma-ENaC, the effect was specific for the 65-kDa cleaved form of the protein. The overall amount of alpha ENAC was also increased with increasing K intake. The total expression of the secretory K(+) channels (ROMK) increased with a high-K diet and decreased with a low-K diet. The surface expression of ROMK increased with high K intake but was not significantly altered by a low-K diet. In contrast, the amounts of total and surface protein representing the thiazide-sensitive NaCl cotransporter (NCC) decreased with increasing K intake. We conclude that modulation of K(+) secretion in response to changes in dietary K intake involves changes in apical K(+) permeability through regulation of K(+) channels and in driving force subsequent to alterations in both Na delivery to the distal nephron and Na(+) uptake across the apical membrane of the K(+) secretory cells. PMID- 20702605 TI - Latitude, local ecology, and hunter-gatherer dietary acid load: implications from evolutionary ecology. AB - BACKGROUND: Past estimations of the net base-producing nature of the Paleolithic "Diet of Evolutionary Adaptedness" derived primarily from interpretations of ethnographic data of modern historically studied hunter-gatherers. In our recent ethnographic analyses, we observed large variations in diet-dependent net endogenous acid production (NEAP) among hunter-gatherer diets. OBJECTIVE: We proposed to determine whether differences in ecologic environments influence estimations of NEAP. DESIGN: By using ethnographic data of plant-to-animal subsistence ratios and mathematical models established previously, we computed frequency distributions of estimated NEAP in relation to latitude in 229 worldwide modern hunter-gatherer societies. Four different models of animal fat density were used: models A (3%), B (10%), C (15%), and D (20%). In addition, we estimated NEAP by primary ecologic environments in those hunter-gatherer societies (n = 63) for which data were documented. RESULTS: With increasing latitude intervals, 0 degrees -10 degrees to >60 degrees , NEAP increased in all 4 models. For models A, B, and C, the diets tend to be net acid-producing at >40 degrees latitude and net base-producing at <40 degrees ; the same held for model D (>50 degrees and <50 degrees , respectively). For models A, B, and C, the diets of hunter-gatherers living in northern areas (tundra and coniforest) and in temperate grassland and tropical rainforests are net acid-producing. In all other ecologic niches, hunter-gatherers seem to consume a neutral or net base-producing diet. CONCLUSIONS: Latitude and ecologic environments codetermine the NEAP values observed in modern hunter-gatherers. The data support the hypothesis that the diet of Homo sapiens' East African ancestors was predominantly net base producing. PMID- 20702603 TI - Image-guided breast tumor therapy using a small interfering RNA nanodrug. AB - Iron oxide nanoparticles offer a feasible tool for combined imaging and delivery of small interfering RNA (siRNA) to tumors, stimulating active interest in exploring different imaging and delivery platforms suitable for detection by a variety of modalities. In this study, we describe the synthesis and testing of a tumor-targeted nanodrug (MN-EPPT-siBIRC5) that is designed to specifically shuttle siRNA to human breast tumors. The nanodrug binds the tumor-specific antigen uMUC-1, which is found in >90% of human breast adenocarcinomas. MN-EPPT siBIRC5 consists of superparamagnetic iron oxide nanoparticles [for magnetic resonance imaging (MRI)], the dye Cy 5.5 (for near-IR optical imaging), peptides (EPPT) that specifically target uMUC-1, and a synthetic siRNA that targets the tumor-specific antiapoptotic gene BIRC5. Nanodrug uptake by human breast adenocarcinoma cells resulted in a significant downregulation of BIRC5. Following i.v. delivery into subcutaneous mouse models of breast cancer, the nanodrug showed a preferential tumor uptake, which could be visualized by MRI and near-IR optical imaging. Furthermore, MRI could be used to quantitatively monitor nanodrug bioavailability in the tumor tissue throughout the course of treatment. Intravenous injection of the agent once a week over 2 weeks resulted in the induction of considerable levels of necrosis and apoptosis in the tumors, translating into a significant decrease in tumor growth rate. Our strategy permits the simultaneous tumor-specific delivery of siRNA to tumors and the imaging of the delivery process. More generally, it illustrates the potential to apply this approach to many human cancer studies, including for basic tumor biology and therapy. PMID- 20702604 TI - Drinking caloric beverages increases the risk of adverse cardiometabolic outcomes in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: Intake of caloric beverages is hypothesized to contribute to adverse health outcomes, but the beverages and populations studied vary considerably. OBJECTIVE: Our objective was to examine the relation between consumption of low- and whole-fat milk, fruit juice, and sugar-sweetened beverages (SSBs) and cardiometabolic risk factors. DESIGN: We used data from a prospective 20-y cohort of 2774 adults. Data are taken from CARDIA (Coronary Artery Risk Development in Young Adults) Study examination years 0 (1985-1986), 7 (1992-1993), and 20 (2005 2006). Beverage intake was averaged across years 0 and 7, and continuous and categorical (quartile) distributions were used. Incident (year 20) high waist circumference (WC), high triglycerides, high LDL cholesterol, low HDL cholesterol, hypertension, and metabolic syndrome were examined by using multivariable-adjusted Poisson regression models. RESULTS: Higher SSB consumption (across quartiles) was associated with higher risk of high WC [adjusted relative risk (aRR): 1.09; 95% CI: 1.04, 1.14; P for trend < 0.001]; high LDL cholesterol (aRR: 1.18; 95% CI: 1.02, 1.35; P for trend = 0.018), high triglycerides (aRR: 1.06; 95% CI: 1.01, 1.13; P for trend = 0.033), and hypertension (aRR: 1.06; 95% CI: 1.01, 1.12; P for trend = 0.023). Whole-fat milk consumption was associated with lower risk of high triglycerides (aRR: 0.91; 95% CI: 0.81, 1.00; P for trend = 0.046). With the use of continuous beverage intake, results were similar. Consumers of whole-fat milk and SSBs were more likely to be younger, black, and male and to have lower levels of physical activity and higher total energy intake in comparison with nonconsumers (P < 0.05). CONCLUSIONS: Our findings suggest that higher SSB consumption is associated with cardiometabolic risk. Recommendations to limit consumption of these caloric beverages may help reduce the burden of these risk factors in US adult populations. PMID- 20702606 TI - Associations between parental and offspring adiposity up to midlife: the contribution of adult lifestyle factors in the 1958 British Birth Cohort Study. AB - BACKGROUND: Parent-offspring associations in adiposity are well known, but the extent to which they are explained by modifiable environmental and lifestyle factors remains to be elucidated. OBJECTIVES: The objectives were to assess whether 1) parent-offspring associations in body mass index (BMI; in kg/m(2)) persist from childhood to midadulthood, 2) parental BMI is associated with the offspring's adult lifestyle, and 3) parent-offspring BMI associations in midadulthood are explained by lifestyle factors. DESIGN: Participants in the 1958 British Birth Cohort Study and their parents (n = 9346) were examined. Parental BMI was assessed in 1969; offspring (ie, cohort members) BMI was ascertained prospectively at 11 and 44-45 y. Lifestyle factors of the offspring, including diet, physical activity, alcohol consumption, and smoking, were assessed prospectively in adulthood. RESULTS: Maternal and paternal BMI were positively associated with offspring BMI in both childhood and midadulthood, and the strength of the association did not diminish with offspring age. Maternal BMI was associated with several offspring lifestyle factors across adulthood; fewer associations were observed for paternal BMI. Parent-offspring BMI associations in adulthood were largely maintained after adjustment for multiple lifestyle and socioeconomic factors at different life stages: if parental BMI was 1 unit higher, offspring BMI at 44-45 y was higher by between 0.21 and 0.29 units in adjusted models. CONCLUSIONS: Strong parent-offspring BMI associations are maintained into midlife. These associations are largely unaffected by adjustment for a wide range of lifestyle factors. Offspring of obese parents are an important target for interventions aimed at reducing population levels of overweight and obesity. PMID- 20702607 TI - Sustained improvement in mild obstructive sleep apnea after a diet- and physical activity-based lifestyle intervention: postinterventional follow-up. AB - BACKGROUND: Obesity is the most important risk factor for obstructive sleep apnea (OSA). Weight-reduction programs have been observed to represent effective treatment of overweight patients with OSA. However, it is not known whether beneficial changes remain after the end of the intervention. OBJECTIVE: The aim of the study was to assess the long-term efficacy of a lifestyle intervention based on a healthy diet and physical activity in a randomized, controlled, 2-y postintervention follow-up in OSA patients. DESIGN: Eighty-one consecutive overweight [body mass index (in kg/m(2)): 28-40] adult patients with mild OSA were recruited. The intervention group completed a 1-y lifestyle modification regimen that included an early 12-wk weight-reduction program with a very-low calorie diet. The control group received routine lifestyle counseling. During the second year, no dietary counseling was offered. Change in the apnea-hypopnea index (AHI) was the main objective outcome variable, and changes in symptoms were used as a subjective measurement. RESULTS: A total of 71 patients completed the 2 y follow-up. The mean (+/- SD) changes in diet and lifestyle with simultaneous weight reduction (-7.3 +/- 6.5 kg) in the intervention group reflected sustained improvements in findings and symptoms of OSA. After 2 y, the reduction in the AHI was significantly greater in the intervention group (P = 0.049). The intervention lowered the risk of OSA at follow-up; the adjusted odds ratio for OSA was 0.35 (95% CI: 0.12-0.97; P = 0.045). CONCLUSION: Favorable changes achieved by a 1-y lifestyle intervention aimed at weight reduction with a healthy diet and physical activity were sustained in overweight patients with mild OSA after the termination of supervised lifestyle counseling. This trial was registered at clinicaltrials.gov as NCT00486746. PMID- 20702608 TI - Associations of dietary fat with albuminuria and kidney dysfunction. AB - BACKGROUND: Diet represents a potentially important target for intervention in nephropathy, yet data on this topic are scarce. OBJECTIVES: The objective was to investigate associations between dietary fats and early kidney disease. DESIGN: We examined cross-sectional associations between dietary fats and the presence of high albuminuria (an established independent predictor of kidney function decline, cardiovascular disease, and mortality) or estimated glomerular filtration rate (eGFR) <60 mL ? min(-1) ? 1.73 m(-2) at baseline in 19,256 participants of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, an ongoing cohort study in US adults aged >=45 y at time of enrollment. We used logistic regression to assess associations between quintiles of total fat and subtypes of dietary fat (saturated, monounsaturated, polyunsaturated, and trans fat) and presence of high albuminuria or eGFR <60 mL ? min(-1) ? 1.73 m(-2). RESULTS: After multivariable adjustment, only saturated fat intake was significantly associated with high albuminuria [for quintile 5 compared with quintile 1, odds ratio (OR): 1.33; 95% CI: 1.07, 1.66; P for trend = 0.04]. No significant associations between any type of fat and eGFR <60 mL . min(-1) . 1.73 m(-2) were observed. ORs between the highest quintile of saturated fat and eGFR <60 mL . min(-1) . 1.73 m(-2) varied by race with a borderline significant interaction term (ORs: 1.24 in whites compared with 0.74 in blacks; P for interaction = 0.05) in multivariable-adjusted models, but no other associations were significantly modified by race or diabetes status. CONCLUSION: Higher saturated fat intake is significantly associated with the presence of high albuminuria, but neither total nor other subtypes of dietary fat are associated with high albuminuria or eGFR <60 mL . min(-1) . 1.73 m(-2). PMID- 20702609 TI - Breast-milk iodine concentration declines over the first 6 mo postpartum in iodine-deficient women. AB - BACKGROUND: Little is known about the iodine status of lactating mothers and their infants during the first 6 mo postpartum or, if deficient, the amount of supplemental iodine required to improve status. OBJECTIVE: The objective was to determine maternal and infant iodine status and the breast-milk iodine concentration (BMIC) over the first 6 mo of breastfeeding. DESIGN: A randomized, double-blind, placebo-controlled supplementation trial was conducted in lactating women who received placebo (n = 56), 75 MUg I/d (n = 27), or 150 MUg I/d (n = 26) after their infants' birth until 24 wk postpartum. Maternal and infant urine samples and breast-milk samples were collected at 1, 2, 4, 8, 12, 16, 20, and 24 wk. Maternal serum thyrotropin and free thyroxine concentrations were measured at 24 wk. RESULTS: Over 24 wk, the median urinary iodine concentration (UIC) of unsupplemented women and their infants ranged from 20 to 41 MUg/L and 34 to 49 MUg/L, respectively, which indicated iodine deficiency (ie, UIC < 100 MUg/L). Mean maternal UIC was 2.1-2.4 times higher in supplemented than in unsupplemented women (P < 0.001) but did not differ significantly between the 2 supplemented groups. BMIC in the placebo group decreased by 40% over 24 wk (P < 0.001) and was 1.3 times and 1.7 times higher in women supplemented with 75 MUg I/d (P = 0.030) and 150 MUg I/d (P < 0.001), respectively, than in unsupplemented women. Thyrotropin and free thyroxine did not differ significantly between groups. CONCLUSION: BMIC decreased in the first 6 mo in these iodine-deficient lactating women; supplementation with 75 or 150 MUg I/d increased the BMIC but was insufficient to ensure adequate iodine status in women or their infants. The study was registered with the Australian New Zealand Clinical Trials Registry as ACTRN12605000345684. PMID- 20702610 TI - Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance. AB - PURPOSE: The objectives of this study were to determine the incidence of the MYB NFIB fusion in salivary adenoid cystic carcinoma (ACC), to establish the clinicopathologic significance of the fusion, and to analyze the expression of MYB in ACCs in the context of the MYB-NFIB fusion. EXPERIMENTAL DESIGN: We did an extensive analysis involving 123 cancers of the salivary gland, including primary and metastatic ACCs, and non-ACC salivary carcinomas. MYB-NFIB fusions were identified by reverse transcriptase-PCR (RT-PCR) and sequencing of the RT-PCR products, and confirmed by fluorescence in situ hybridization. MYB RNA expression was determined by quantitative RT-PCR and protein expression was analyzed by immunohistochemistry. RESULTS: The MYB-NFIB fusion was detected in 28% primary and 35% metastatic ACCs, but not in any of the non-ACC salivary carcinomas analyzed. Different exons in both the MYB and NFIB genes were involved in the fusions, resulting in expression of multiple chimeric variants. Notably, MYB was overexpressed in the vast majority of the ACCs, although MYB expression was significantly higher in tumors carrying the MYB-NFIB fusion. The presence of the MYB-NFIB fusion was significantly associated (P = 0.03) with patients older than 50 years of age. No correlation with other clinicopathologic markers, factors, and survival was found. CONCLUSIONS: We conclude that the MYB-NFIB fusion characterizes a subset of ACCs and contributes to MYB overexpression. Additional mechanisms may be involved in MYB overexpression in ACCs lacking the MYB-NFIB fusion. These findings suggest that MYB may be a specific novel target for tumor intervention in patients with ACC. PMID- 20702611 TI - Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. AB - Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action. PMID- 20702612 TI - A novel chemoimmunomodulating property of docetaxel: suppression of myeloid derived suppressor cells in tumor bearers. AB - PURPOSE: Myeloid-derived suppressor cells (MDSC) accumulate in tumor-bearing hosts and are associated with immune suppression. To date, there have only been few studies that evaluate the direct effect of chemotherapeutic agents on MDSCs. Agents that inhibit MDSCs may be useful in the treatment of patients with various cancers. EXPERIMENTAL DESIGN: We investigated the in vivo effects of docetaxel on immune function in 4T1-Neu mammary tumor-bearing mice to examine if a favorable immunomodulatory effect accompanies tumor suppression. Primary focus was on the differentiation status of MDSCs and their ability to modulate T-cell responses. RESULTS: Docetaxel administration significantly inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC proportion in the spleen. The treatment also selectively increased CTL responses. Docetaxel-pretreated MDSCs cocultured with OT-II splenocytes in the presence of OVA(323-339) showed OT-II specific CD4 activation and expansion in vitro. In characterizing the phenotype of MDSCs for M1 (CCR7) and M2 [mannose receptor (CD206)] markers, MDSCs from untreated tumor bearers were primarily MR(+) with few CCR7(+) cells. Docetaxel treatment polarized MDSCs toward an M1-like phenotype, resulting in 40% of MDSCs expressing CCR7 in vivo and in vitro, and macrophage differentiation markers such as MHC class II, CD11c, and CD86 were upregulated. Interestingly, docetaxel induced cell death selectively in MR(+) MDSCs while sparing the M1-like phenotype. Finally, inhibition of signal transducer and activator of transcription 3 may in part be responsible for the observed results. CONCLUSIONS: These findings suggest potential clinical benefit for the addition of docetaxel to current immunotherapeutic protocols. PMID- 20702613 TI - Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor. AB - PURPOSE: Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma. EXPERIMENTAL DESIGN: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye- and Annexin V positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase transfected, pseudometastatic, and orthotopic neuroblastoma animal models. RESULTS: EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/necrosis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1alpha/HIF-2alpha expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Histone H2ax staining as well as decreased vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 expression in tumors removed from EZN-2208 treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes. CONCLUSIONS: EZN-2208 should be considered a most promising novel antineuroblastoma agent. An ongoing phase I study in pediatric patients should identify the optimal dose for a phase II study. PMID- 20702614 TI - Intragenic recombination as a mechanism of genetic diversity in bluetongue virus. AB - Bluetongue (BT), caused by Bluetongue virus (BTV), is an economically important disease affecting sheep, deer, cattle, and goats. Since 1998, a series of BT outbreaks have spread across much of southern and central Europe. To study why the epidemiology of the virus happens to change, it is important to fully know the mechanisms resulting in its genetic diversity. Gene mutation and segment reassortment have been considered as the key forces driving the evolution of BTV. However, it is still unknown whether intragenic recombination can occur and contribute to the process in the virus. We present here several BTV groups containing mosaic genes to reveal that intragenic recombination can take place between the virus strains and play a potential role in bringing novel BTV lineages. PMID- 20702615 TI - The ESEV PDZ-binding motif of the avian influenza A virus NS1 protein protects infected cells from apoptosis by directly targeting Scribble. AB - The NS1 protein from influenza A viruses contains a four-amino-acid sequence at its carboxyl terminus that is termed the PDZ-binding motif (PBM). The NS1 PBM is predicted to bind to cellular PDZ proteins and functions as a virulence determinant in infected mice. ESEV is the consensus PBM sequence of avian influenza viruses, while RSKV is the consensus sequence of human viruses. Currently circulating highly pathogenic H5N1 influenza viruses encode an NS1 protein with the ESEV PBM. We identified cellular targets of the avian ESEV PBM and identified molecular mechanisms involved in its function. Using glutathione S transferase (GST) pull-down assays, we found that the ESEV PBM enables NS1 to associate with the PDZ proteins Scribble, Dlg1, MAGI-1, MAGI-2, and MAGI-3. Because Scribble possesses a proapoptotic activity, we investigated the interaction between NS1 and Scribble. The association between NS1 and Scribble is direct and requires the ESEV PBM and two Scribble PDZ domains. We constructed recombinant H3N2 viruses that encode an H6N6 avian virus NS1 protein with either an ESEV or mutant ESEA PBM, allowing an analysis of the ESEV PBM in infections in mammalian cells. The ESEV PBM enhanced viral replication up to 4-fold. In infected cells, NS1 with the ESEV PBM relocalized Scribble into cytoplasmic puncta concentrated in perinuclear regions and also protected cells from apoptosis. In addition, the latter effect was eliminated by small interfering RNA (siRNA)-mediated Scribble depletion. This study shows that one function of the avian ESEV PBM is to reduce apoptosis during infection through disruption of Scribble's proapoptotic function. PMID- 20702616 TI - Toll-like receptor 4-mediated activation of p38 mitogen-activated protein kinase is a determinant of respiratory virus entry and tropism. AB - Respiratory viruses exert a heavy toll of morbidity and mortality worldwide. Despite this burden there are few specific treatments available for respiratory virus infections. Since many viruses utilize host cell enzymatic machinery such as protein kinases for replication, we determined whether pharmacological inhibition of kinases could, in principle, be used as a broad antiviral strategy for common human respiratory virus infections. A panel of green fluorescent protein (GFP)-expressing recombinant respiratory viruses, including an isolate of H1N1 influenza virus (H1N1/Weiss/43), was used to represent a broad range of virus families responsible for common respiratory infections (Adenoviridae, Paramyxoviridae, Picornaviridae, and Orthomyxoviridae). Kinase inhibitors were screened in a high-throughput assay that detected virus infection in human airway epithelial cells (1HAEo-) using a fluorescent plate reader. Inhibition of p38 mitogen-activated protein kinase (MAPK) signaling was able to significantly inhibit replication by all viruses tested. Therefore, the pathways involved in virus-mediated p38 and extracellular signal-regulated kinase (ERK) MAPK activation were investigated using bronchial epithelial cells and primary fibroblasts derived from MyD88 knockout mouse lungs. Influenza virus, which activated p38 MAPK to approximately 10-fold-greater levels than did respiratory syncytial virus (RSV) in 1HAEo- cells, was internalized about 8-fold faster and more completely than RSV. We show for the first time that p38 MAPK is a determinant of virus infection that is dependent upon MyD88 expression and Toll like receptor 4 (TLR4) ligation. Imaging of virus-TLR4 interactions showed significant clustering of TLR4 at the site of virus-cell interaction, triggering phosphorylation of downstream targets of p38 MAPK, suggesting the need for a signaling receptor to activate virus internalization. PMID- 20702617 TI - Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection. AB - Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1-/-), and STAT1 knockout (STAT1-/-) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1-/- mice, contributing to clearance of the virus. In contrast, STAT1-/- mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1-/- mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a TH2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15 infected STAT1-/- mice. PMID- 20702618 TI - Ultrastructural analysis of ICP34.5- herpes simplex virus 1 replication in mouse brain cells in vivo. AB - Replication-competent forms of herpes simplex virus 1 (HSV-1) defective in the viral neurovirulence factor infected cell protein 34.5 (ICP34.5) are under investigation for use in the therapeutic treatment of cancer. In mouse models, intratumoral injection of ICP34.5-defective oncolytic HSVs (oHSVs) has resulted in the infection and lysis of tumor cells, an associated decrease in tumor size, and increased survival times. The ability of these oHSVs to infect and lyse cells is frequently characterized as exclusive to or selective for tumor cells. However, the extent to which ICP34.5-deficient HSV-1 replicates in and may be neurotoxic to normal brain cell types in vivo is poorly understood. Here we report that HSV-1 defective in ICP34.5 expression is capable of establishing a productive infection in at least one normal mouse brain cell type. We show that gamma34.5 deletion viruses replicate productively in and induce cellular damage in infected ependymal cells. Further evaluation of the effects of oHSVs on normal brain cells in animal models is needed to enhance our understanding of the risks associated with the use of current and future oHSVs in the brains of clinical trial subjects and to provide information that can be used to create improved oHSVs for future use. PMID- 20702619 TI - Neuropeptide Y has a protective role during murine retrovirus-induced neurological disease. AB - Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules. Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin- and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS. In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus infected cells. Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS. PMID- 20702620 TI - Endogenous CD317/Tetherin limits replication of HIV-1 and murine leukemia virus in rodent cells and is resistant to antagonists from primate viruses. AB - Human CD317 (BST-2/tetherin) is an intrinsic immunity factor that blocks the release of retroviruses, filoviruses, herpesviruses, and arenaviruses. It is unclear whether CD317 expressed endogenously in rodent cells has the capacity to interfere with the replication of the retroviral rodent pathogen murine leukemia virus (MLV) or, in the context of small-animal model development, contributes to the well-established late-phase restriction of human immunodeficiency virus type 1 (HIV-1). Here, we show that small interfering RNA (siRNA)-mediated knockdown of CD317 relieved a virion release restriction and markedly enhanced the egress of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) in rat cells, including primary macrophages. Moreover, rodent CD317 potently inhibited MLV release, and siRNA-mediated depletion of CD317 in a mouse T-cell line resulted in the accelerated spread of MLV. Several virus-encoded antagonists have recently been reported to overcome the restriction imposed by human or monkey CD317, including HIV-1 Vpu, envelope glycoproteins of HIV-2 and Ebola virus, Kaposi's sarcoma associated herpesvirus K5, and SIV Nef. In contrast, both rat and mouse CD317 showed a high degree of resistance to these viral antagonists. These data suggest that CD317 is a broadly acting and conserved mediator of innate control of retroviral infection and pathogenesis that restricts the release of retroviruses and lentiviruses in rodents. The high degree of resistance of the rodent CD317 restriction factors to antagonists from primate viruses has implications for HIV 1 small-animal model development and may guide the design of novel antiviral interventions. PMID- 20702621 TI - Structure of Penaeus stylirostris densovirus, a shrimp pathogen. AB - Penaeus stylirostris densovirus (PstDNV), a pathogen of penaeid shrimp, causes significant damage to farmed and wild shrimp populations. In contrast to other parvoviruses, PstDNV probably has only one type of capsid protein that lacks the phospholipase A2 activity that has been implicated as a requirement during parvoviral host cell infection. The structure of recombinant virus-like particles, composed of 60 copies of the 37.5-kDa coat protein, the smallest parvoviral capsid protein reported thus far, was determined to 2.5-A resolution by X-ray crystallography. The structure represents the first near-atomic resolution structure within the genus Brevidensovirus. The capsid protein has a beta-barrel "jelly roll" motif similar to that found in many icosahedral viruses, including other parvoviruses. The N-terminal portion of the PstDNV coat protein adopts a "domain-swapped" conformation relative to its twofold-related neighbor similar to the insect parvovirus Galleria mellonella densovirus (GmDNV) but in stark contrast to vertebrate parvoviruses. However, most of the surface loops have little structural resemblance to any of the known parvoviral capsid proteins. PMID- 20702622 TI - Stably expressed APOBEC3F has negligible antiviral activity. AB - APOBEC3F (A3F) is a member of the family of cytidine deaminases that is often coexpressed with APOBEC3G (A3G) in cells susceptible to HIV infection. A3F has been shown to have strong antiviral activity in transient-expression studies, and together with A3G, it is considered the most potent cytidine deaminase targeting HIV. Previous analyses suggested that the antiviral properties of A3F can be dissociated from its catalytic deaminase activity. We were able to confirm the deaminase-independent antiviral activity of exogenously expressed A3F; however, we also noted that exogenous expression was associated with very high A3F mRNA and protein levels. In analogy to our previous study of A3G, we produced stable HeLa cell lines constitutively expressing wild-type or deaminase-defective A3F at levels that were more in line with the levels of endogenous A3F in H9 cells. A3F expressed in stable HeLa cells was packaged into Vif-deficient viral particles with an efficiency similar to that of A3G and was properly targeted to the viral nucleoprotein complex. Surprisingly, however, neither wild-type nor deaminase defective A3F inhibited HIV-1 infectivity. These results imply that the antiviral activity of endogenous A3F is negligible compared to that of A3G. PMID- 20702623 TI - Viral cell death inhibitor MC159 enhances innate immunity against vaccinia virus infection. AB - Viral inhibitors of host programmed cell death (PCD) are widely believed to promote viral replication by preventing or delaying host cell death. Viral FLIPs (Fas-linked ICE-like protease [FLICE; caspase-8]-like inhibitor proteins) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. Surprisingly, transgenic expression of the viral FLIP MC159 from molluscum contagiosum virus (MCV) in mice enhanced rather than inhibited the innate immune control of vaccinia virus (VV) replication. This effect of MC159 was specifically manifested in peripheral tissues such as the visceral fat pad, but not in the spleen. VV-infected MC159 transgenic mice mounted an enhanced innate inflammatory reaction characterized by increased expression of the chemokine CCL-2/MCP-1 and infiltration of gammadelta T cells into peripheral tissues. Radiation chimeras revealed that MC159 expression in the parenchyma, but not in the hematopoietic compartment, is responsible for the enhanced innate inflammatory responses. The increased inflammation in peripheral tissues was not due to resistance of lymphocytes to cell death. Rather, we found that MC159 facilitated Toll-like receptor 4 (TLR4)- and tumor necrosis factor (TNF)-induced NF-kappaB activation. The increased NF-kappaB responses were mediated in part through increased binding of RIP1 to TNFRSF1A-associated via death domain (TRADD), two crucial signal adaptors for NF-kappaB activation. These results show that MC159 is a dual function immune modulator that regulates host cell death as well as NF-kappaB responses by innate immune signaling receptors. PMID- 20702624 TI - Mutation at a single position in the V2 domain of the HIV-1 envelope protein confers neutralization sensitivity to a highly neutralization-resistant virus. AB - Understanding the determinants of neutralization sensitivity and resistance is important for the development of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. In these studies, we have made use of the swarm of closely related envelope protein variants (quasispecies) from an extremely neutralization resistant clinical isolate in order to identify mutations that conferred neutralization sensitivity to antibodies in sera from HIV-1-infected individuals. Here, we describe a virus with a rare mutation at position 179 in the V2 domain of gp120, where replacement of aspartic acid (D) by asparagine (N) converts a virus that is highly resistant to neutralization by multiple polyclonal and monoclonal antibodies, as well as antiviral entry inhibitors, to one that is sensitive to neutralization. Although the V2 domain sequence is highly variable, D at position 179 is highly conserved in HIV-1 and simian immunodeficiency virus (SIV) and is located within the LDI/V recognition motif of the recently described alpha4beta7 receptor binding site. Our results suggest that the D179N mutation induces a conformational change that exposes epitopes in both the gp120 and the gp41 portions of the envelope protein, such as the CD4 binding site and the MPER, that are normally concealed by conformational masking. Our results suggest that D179 plays a central role in maintaining the conformation and infectivity of HIV 1 as well as mediating binding to alpha4beta7. PMID- 20702625 TI - Soluble HLA-G inhibits myeloid dendritic cell function in HIV-1 infection by interacting with leukocyte immunoglobulin-like receptor B2. AB - Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons. PMID- 20702626 TI - Primary human mammary epithelial cells endocytose HIV-1 and facilitate viral infection of CD4+ T lymphocytes. AB - The contribution of mammary epithelial cells (MEC) to human immunodeficiency virus type 1 (HIV-1) in breast milk remains largely unknown. While breast milk contains CD4(+) cells throughout the breast-feeding period, it is not known whether MEC directly support HIV-1 infection or facilitate infection of CD4(+) cells in the breast compartment. This study evaluated primary human MEC for direct infection with HIV-1 and for indirect transfer of infection to CD4(+) target cells. Primary human MEC were isolated and assessed for expression of HIV 1 receptors. MEC were exposed to CCR5-, CXCR4- and dual-tropic strains of HIV-1 and evaluated for viral reverse transcription and integration and productive viral infection. MEC were also tested for the ability to transfer HIV to CD4(+) target cells and to activate resting CD4(+) T cells. Our results demonstrate that MEC express HIV-1 receptor proteins CD4, CCR5, CXCR4, and galactosyl ceramide (GalCer). While no evidence for direct infection of MEC was found, HIV-1 virions were observed in MEC endosomal compartments. Coculture of HIV-exposed MEC resulted in productive infection of activated CD4(+) T cells. In addition, MEC secretions increased HIV-1 replication and proliferation of infected target cells. Overall, our results indicate that MEC are capable of endosomal uptake of HIV-1 and can facilitate virus infection and replication in CD4(+) target cells. These findings suggest that MEC may serve as a viral reservoir for HIV-1 and may enhance infection of CD4(+) T lymphocytes in vivo. PMID- 20702627 TI - Papillomavirus infection requires gamma secretase. AB - The mechanism by which papillomaviruses breach cellular membranes to deliver their genomic cargo to the nucleus is poorly understood. Here, we show that infection by a broad range of papillomavirus types requires the intramembrane protease gamma secretase. The gamma-secretase inhibitor (S,S)-2-[2-(3,5 difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H benzo[e][1,4]diazepin-3-yl)-propionamide (compound XXI) inhibits infection in vitro by all types of papillomavirus pseudovirions tested, with a 50% inhibitory concentration (IC(50)) of 130 to 1,000 pM, regardless of reporter construct and without impacting cellular viability. Conversely, XXI does not inhibit in vitro infection by adenovirus or pseudovirions derived from the BK or Merkel cell polyomaviruses. Vaginal application of XXI prevents infection of the mouse genital tract by human papillomavirus type 16 (HPV16) pseudovirions. Nicastrin and presenilin-1 are essential components of the gamma-secretase complex, and mouse embryo fibroblasts deficient in any one of these components were not infected by HPV16, whereas wild-type and beta-secretase (BACE1)-deficient cells were susceptible. Neither the uptake of HPV16 into Lamp-1-positive perinuclear vesicles nor the disassembly of capsid to reveal both internal L1 and L2 epitopes and bromodeoxyuridine (BrdU)-labeled encapsidated DNA is dependent upon gamma secretase activity. However, blockade of gamma-secretase activity by XXI prevents the BrdU-labeled DNA encapsidated by HPV16 from reaching the ND10 subnuclear domains. Since prior studies indicate that L2 is critical for endosomal escape and targeting of the viral DNA to ND10 and that gamma secretase is located in endosomal membranes, our findings suggest that either L2 or an intracellular receptor are cleaved by gamma secretase as papillomavirus escapes the endosome. PMID- 20702628 TI - Nuclear factor NF45 interacts with viral proteins of infectious bursal disease virus and inhibits viral replication. AB - Two of the central issues in developing new strategies to interfere with viral infections concern the identification of cellular proteins involved in viral replication and/or antiviral measures and the dissection of the underlying molecular mechanisms. To gain initial insight into the role of host proteins in the life cycle of infectious bursal disease virus (IBDV), a double-stranded RNA virus, we examined the cellular nuclear factor 45 (NF45). NF45 was previously indicated to be involved in the replication process of other types of RNA viruses. Interestingly, by performing immunofluorescence studies, we found that in IBDV-infected cells the mainly nuclear NF45 accumulated at the sites of viral replication in the cytoplasm. NF45 was shown to specifically colocalize with the viral RNA-dependent RNA polymerase VP1, the capsid protein VP2, and the ribonucleoprotein VP3. Immunoprecipitation experiments indicated protein-protein associations between NF45 and VP1, VP2, and VP3. Expression of the individual VP3 or the combination of expression of VP1 and VP3 did not result in a cytoplasmic accumulation of NF45, which, among other data, showed that recruitment of the cellular protein in infected cells functionally correlates with the viral replication process. Since small interfering RNA(siRNA)-mediated downregulation of NF45 resulted in an approximately 5-fold increase of virus yield, our study suggests that NF45, by association with viral proteins, is part of a yet uncharacterized cellular defense mechanism against IBDV infections. PMID- 20702629 TI - Antibody 2G12 recognizes di-mannose equivalently in domain- and nondomain exchanged forms but only binds the HIV-1 glycan shield if domain exchanged. AB - The broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibody 2G12 targets the high-mannose cluster on the glycan shield of HIV-1. 2G12 has a unique V(H) domain-exchanged structure, with a multivalent binding surface that includes two primary glycan binding sites. The high-mannose cluster is an attractive target for HIV-1 vaccine design, but so far, no carbohydrate immunogen has elicited 2G12-like antibodies. Important questions remain as to how this domain exchange arose in 2G12 and how this unusual event conferred unexpected reactivity against the glycan shield of HIV-1. In order to address these questions, we generated a nondomain-exchanged variant of 2G12 to produce a conventional Y/T-shaped antibody through a single amino acid substitution (2G12 I19R) and showed that, as for the 2G12 wild type (2G12 WT), this antibody is able to recognize the same Manalpha1,2Man motif on recombinant gp120, Candida albicans, and synthetic glycoconjugates. However, the nondomain-exchanged variant of 2G12 is unable to bind the cluster of mannose moieties on the surface of HIV 1. Crystallographic analysis of 2G12 I19R in complex with Manalpha1,2Man revealed an adaptable hinge between V(H) and C(H)1 that enables the V(H) and V(L) domains to assemble in such a way that the configuration of the primary binding site and its interaction with disaccharide are remarkably similar in the nondomain exchanged and domain-exchanged forms. Together with data that suggest that very few substitutions are required for domain exchange, the results suggest potential mechanisms for the evolution of domain-exchanged antibodies and immunization strategies for eliciting such antibodies. PMID- 20702630 TI - Strain-specific differences in the impact of human TRIM5alpha, different TRIM5alpha alleles, and the inhibition of capsid-cyclophilin A interactions on the infectivity of HIV-1. AB - HIV-1 infectivity is strongly restricted by TRIM5alpha from certain primate species but has been described as being only marginally susceptible to human TRIM5alpha. In this study, we evaluated the effects of the modulation of human TRIM5alpha activity (pretreatment of target cells with alpha interferon, expression of a pre-miRNA targeting TRIM5alpha, and/or overexpression of TRIM5gamma), the inhibition of cyclophilin A (CypA)-CA interactions, and the expression of different allelic variants of human TRIM5alpha on the infectivity of a series of recombinant viruses carrying different patient-derived Gag protease sequences. We show that HIV-1 displays virus-specific differences in its sensitivity to human TRIM5alpha and in its sensitivity to different TRIM5alpha alleles. The effect of inhibiting CypA-CA interactions is also strain specific, and blocking these interactions can either inhibit or improve viral infectivity, depending on the isolate studied. The inhibition of CypA-CA interactions also modulates viral sensitivity to human TRIM5alpha. In the absence of CypA-CA interactions, most viruses displayed increased sensitivity to the inhibitory effects of TRIM5alpha on viral replication, but one isolate showed a paradoxical decrease in sensitivity to TRIM5alpha. Taken together, these findings support a model in which three interlinked factors--capsid sequence, CypA levels, and TRIM5alpha--interact to determine capsid stability and therefore viral infectivity. PMID- 20702631 TI - Characterization of essential domains and plasticity of the classical Swine Fever virus Core protein. AB - Pestiviruses are pathogens of cloven-hoofed animals, belonging to the Flaviviridae. The pestiviral particle consists of a lipid membrane containing the three envelope glycoproteins Erns, E1, and E2 and a nucleocapsid of unknown symmetry, which is composed of the Core protein and the viral positive-sense RNA genome. The positively charged pestiviral Core protein consists of 86 to 89 amino acids. To analyze the organization of essential domains, N- and C-terminal truncations, as well as internal deletions, were introduced into the Core coding sequence in the context of an infectious cDNA clone of classical swine fever virus strain Alfort. Amino acids 179 to 180, 194 to 198, and 208 to 212 proved to be of special importance for the generation of progeny virus. The results of transcomplementation of a series of C-terminally truncated Core molecules indicate the importance of Ala255 at the C terminus. The plasticity of Core protein was examined by the construction of concatemeric arrays of Core coding regions and the insertion of up to three yellow fluorescent protein (YFP) genes between two Core genes. Even a Core fusion protein with more than 10-fold increased molecular mass was integrated into the viral particle and supported the production of infectious progeny virus. The unexpected plasticity of Core protein brings into question the formation of a regular icosahedric particle and supports the idea of a histone-like protein-RNA interaction. All viruses with a duplicated Core gene were unstable and reverted to the wild-type sequence. Interestingly, a nonviable YFP-Core construct was rescued by a mutation within the C-terminal domain of the nonstructural protein NS3. PMID- 20702632 TI - PB2 and hemagglutinin mutations are major determinants of host range and virulence in mouse-adapted influenza A virus. AB - Serial mouse lung passage of a human influenza A virus, A/Hong Kong/1/68 (H3N2) (HK-wt), produced a mouse-adapted variant, MA, with nine mutations that was >10(3.8)-fold more virulent. In this study, we demonstrate that MA mutations of the PB2 (D701N) and hemagglutinin (HA) (G218W in HA1 and T156N in HA2) genes were the most adaptive genetic determinants for increased growth and virulence in the mouse model. Recombinant viruses expressing each of the mutated MA genome segments on the HK-wt backbone showed significantly increased disease severity, whereas only the mouse-adapted PB2 gene increased virulence, as determined by the 50% lethal dose ([LD(50)] >10(1.4)-fold). The converse comparisons of recombinant MA viruses expressing each of the HK-wt genome segments showed the greatest decrease in virulence due to the HA gene (10(2)-fold), with lesser decreases due to the M1, NS1, NA, and PB1 genes (10(0.3)- to 10(0.8)-fold), and undetectable effects on the LD(50) for the PB2 and NP genes. The HK PB2 gene did, however, attenuate MA infection, as measured by weight loss and time to death. Replication of adaptive mutations in vivo and in vitro showed both viral gene backbone and host range effects. Minigenome transcription assays showed that PB1 and PB2 mutations increased polymerase activity and that the PB2 D701N mutation was comparable in effect to the mammalian adaptive PB2 E627K mutation. Our results demonstrate that host range and virulence are controlled by multiple genes, with major roles for mutations in PB2 and HA. PMID- 20702633 TI - Quantitative proteomic analyses of influenza virus-infected cultured human lung cells. AB - Because they are obligate intracellular parasites, all viruses are exclusively and intimately dependent upon host cells for replication. Viruses, in turn, induce profound changes within cells, including apoptosis, morphological changes, and activation of signaling pathways. Many of these alterations have been analyzed by gene arrays, which measure the cellular "transcriptome." Until recently, it has not been possible to extend comparable types of studies to globally examine all the host cellular proteins, which are the actual effector molecules. We have used stable isotope labeling by amino acids in cell culture (SILAC), combined with high-throughput two-dimensional (2-D) high-performance liquid chromatography (HPLC)/mass spectrometry, to determine quantitative differences in host proteins after infection of human lung A549 cells with human influenza virus A/PR/8/34 (H1N1) for 24 h. Of the 4,689 identified and measured cytosolic protein pairs, 127 were significantly upregulated at >95% confidence, 153 were significantly downregulated at >95% confidence, and a total of 87 proteins were upregulated or downregulated more than 5-fold at >99% confidence. Gene ontology and pathway analyses indicated differentially regulated proteins and included those involved in host cell immunity and antigen presentation, cell adhesion, metabolism, protein function, signal transduction, and transcription pathways. PMID- 20702634 TI - MicroRNA 203 expression in keratinocytes is dependent on regulation of p53 levels by E6. AB - A screen of microRNA (miRNA) expression following differentiation in human foreskin keratinocytes (HFKs) identified changes in several miRNAs, including miRNA 203 (miR-203), which has previously been shown to play an important role in epithelial cell biology by regulating p63 levels. We investigated how expression of human papillomavirus type 16 (HPV16) oncoproteins E6 and E7 affected miR-203 expression during proliferation and differentiation of HFKs. We demonstrated that miR-203 expression is reduced in HFKs where p53 function is compromised, either by the viral oncoprotein E6 or by knockout of p53 using short hairpin RNAs (p53i). We show that the induction of miR-203 observed during calcium-induced differentiation of HFKs is significantly reduced in HFKs expressing E6 and in p53i HFKs. Induction of miR-203 in response to DNA damage is also reduced in the absence of p53. We report that proliferation of HFKs is dependent on the level of miR-203 expression and that overexpression of miR-203 can reduce overproliferation in E6/E7-expressing and p53i HFKs. In summary, these results indicate that expression of miR-203 is dependent on p53, which may explain how expression of HPV16 E6 can disrupt the balance between proliferation and differentiation, as well as the response to DNA damage, in keratinocytes. PMID- 20702635 TI - Evidence for a new avian paramyxovirus serotype 10 detected in rockhopper penguins from the Falkland Islands. AB - The biological, serological, and genomic characterization of a paramyxovirus recently isolated from rockhopper penguins (Eudyptes chrysocome) suggested that this virus represented a new avian paramyxovirus (APMV) group, APMV10. This penguin virus resembled other APMVs by electron microscopy; however, its viral hemagglutination (HA) activity was not inhibited by antisera against any of the nine defined APMV serotypes. In addition, antiserum generated against this penguin virus did not inhibit the HA of representative viruses of the other APMV serotypes. Sequence data produced using random priming methods revealed a genomic structure typical of APMV. Phylogenetic evaluation of coding regions revealed that amino acid sequences of all six proteins were most closely related to APMV2 and APMV8. The calculation of evolutionary distances among proteins and distances at the nucleotide level confirmed that APMV2, APMV8, and the penguin virus all were sufficiently divergent from each other to be considered different serotypes. We propose that this isolate, named APMV10/penguin/Falkland Islands/324/2007, be the prototype virus for APMV10. Because of the known problems associated with serology, such as antiserum cross-reactivity and one-way immunogenicity, in addition to the reliance on the immune response to a single protein, the hemagglutinin-neuraminidase, as the sole base for viral classification, we suggest the need for new classification guidelines that incorporate genome sequence comparisons. PMID- 20702637 TI - Mutations in the stalk region of the measles virus hemagglutinin inhibit syncytium formation but not virus entry. AB - Measles virus (MV) entry requires at least 2 viral proteins, the hemagglutinin (H) and fusion (F) proteins. We describe the rescue and characterization of a measles virus with a specific mutation in the stalk region of H (I98A) that is able to bind normally to cells but infects at a lower rate than the wild type due to a reduction in fusion triggering. The mutant H protein binds to F more avidly than the parent H protein does, and the corresponding virus is more sensitive to inhibition by fusion-inhibitory peptide. We show that after binding of MV to its receptor, H-F dissociation is required for productive infection. PMID- 20702638 TI - Side chain packing below the fusion peptide strongly modulates triggering of the Hendra virus F protein. AB - Triggering of the Hendra virus fusion (F) protein is required to initiate the conformational changes which drive membrane fusion, but the factors which control triggering remain poorly understood. Mutation of a histidine predicted to lie near the fusion peptide to alanine greatly reduced fusion despite wild-type cell surface expression levels, while asparagine substitution resulted in a moderate restoration in fusion levels. Slowed kinetics of six-helix bundle formation, as judged by sensitivity to heptad repeat B-derived peptides, was observed for all H372 mutants. These data suggest that side chain packing beneath the fusion peptide is an important regulator of Hendra virus F triggering. PMID- 20702636 TI - Gag-protease-mediated replication capacity in HIV-1 subtype C chronic infection: associations with HLA type and clinical parameters. AB - The mechanisms underlying HIV-1 control by protective HLA class I alleles are not fully understood and could involve selection of escape mutations in functionally important Gag epitopes resulting in fitness costs. This study was undertaken to investigate, at the population level, the impact of HLA-mediated immune pressure in Gag on viral fitness and its influence on HIV-1 pathogenesis. Replication capacities of 406 recombinant viruses encoding plasma-derived Gag-protease from patients chronically infected with HIV-1 subtype C were assayed in an HIV-1 inducible green fluorescent protein reporter cell line. Viral replication capacities varied significantly with respect to the specific HLA-B alleles expressed by the patient, and protective HLA-B alleles, most notably HLA-B81, were associated with lower replication capacities. HLA-associated mutations at low-entropy sites, especially the HLA-B81-associated 186S mutation in the TL9 epitope, were associated with lower replication capacities. Most mutations linked to alterations in replication capacity in the conserved p24 region decreased replication capacity, while most in the highly variable p17 region increased replication capacity. Replication capacity also correlated positively with baseline viral load and negatively with baseline CD4 count but did not correlate with the subsequent rate of CD4 decline. In conclusion, there is evidence that protective HLA alleles, in particular HLA-B81, significantly influence Gag protease function by driving sequence changes in Gag and that conserved regions of Gag should be included in a vaccine aiming to drive HIV-1 toward a less fit state. However, the long-term clinical benefit of immune-driven fitness costs is uncertain given the lack of correlation with longitudinal markers of disease progression. PMID- 20702639 TI - The African swine fever virus DP71L protein recruits the protein phosphatase 1 catalytic subunit to dephosphorylate eIF2alpha and inhibits CHOP induction but is dispensable for these activities during virus infection. AB - The African swine fever virus (ASFV) DP71L protein is present in all isolates as either a short form of 70 to 72 amino acids or a long form of about 184 amino acids, and both of these share sequence similarity to the C-terminal domain of the herpes simplex virus ICP34.5 protein and cellular protein GADD34. In the present study we expressed DP71L in different mammalian cells and demonstrated that DP71L causes dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) in resting cells and during chemical-induced endoplasmic reticulum stress and acts to enhance expression of cotransfected reporter genes. We showed that DP71L binds to all the three isoforms (alpha, beta, and gamma) of the protein phosphatase 1 catalytic subunit (PP1c) and acts by recruiting PP1c to eIF2alpha. We also showed that DP71L inhibits the induction of ATF4 and its downstream target, CHOP. We investigated the eIF2alpha phosphorylation status and induction of CHOP in porcine macrophages infected by two ASFV field isolates, Malawi Lil20/1 and Benin 97/1, and two DP71L deletion mutants, MalawiDeltaNL and E70DeltaNL. Our results showed that deletion of the DP71L gene did not cause an increase in the level of eIF2alpha phosphorylation or induction of CHOP, indicating that DP71L is not the only factor required by the virus to control the phosphorylation level of eIF2alpha during infection. We therefore hypothesize that ASFV has other mechanisms to prevent the eIF2alpha phosphorylation and the subsequent protein synthesis inhibition. PMID- 20702640 TI - Very few substitutions in a germ line antibody are required to initiate significant domain exchange. AB - 2G12 is a broadly neutralizing anti-HIV-1 monoclonal human IgG1 antibody reactive with a high-mannose glycan cluster on the surface of glycoprotein gp120. A key feature of this very highly mutated antibody is domain exchange of the heavy chain variable region (V(H)) with the V(H) of the adjacent Fab of the same immunoglobulin, which assembles a multivalent binding interface composed of two primary binding sites in close proximity. A non-germ line-encoded proline in the elbow between V(H) and C(H)1 and an extensive network of hydrophobic interactions in the V(H)/V(H)' interface have been proposed to be crucial for domain exchange. To investigate the origins of domain exchange, a germ line version of 2G12 that behaves as a conventional antibody was engineered. Substitution of 5 to 7 residues for those of the wild type produced a significant fraction of domain exchanged molecules, with no evidence of equilibrium between domain-exchanged and conventional forms. Two substitutions not previously implicated, A(H14) and E(H75), are the most crucial for domain exchange, together with I(H19) at the V(H)/V(H)' interface and P(H113) in the elbow region. Structural modeling gave clues as to why these residues are essential for domain exchange. The demonstration that domain exchange can be initiated by a small number of substitutions in a germ line antibody suggests that the evolution of a domain exchanged antibody response in vivo may be more readily achieved than considered to date. PMID- 20702641 TI - Envelope-modified single-cycle simian immunodeficiency virus selectively enhances antibody responses and partially protects against repeated, low-dose vaginal challenge. AB - Immunization of rhesus macaques with strains of simian immunodeficiency virus (SIV) that are limited to a single cycle of infection elicits T-cell responses to multiple viral gene products and antibodies capable of neutralizing lab-adapted SIV, but not neutralization-resistant primary isolates of SIV. In an effort to improve upon the antibody responses, we immunized rhesus macaques with three strains of single-cycle SIV (scSIV) that express envelope glycoproteins modified to lack structural features thought to interfere with the development of neutralizing antibodies. These envelope-modified strains of scSIV lacked either five potential N-linked glycosylation sites in gp120, three potential N-linked glycosylation sites in gp41, or 100 amino acids in the V1V2 region of gp120. Three doses consisting of a mixture of the three envelope-modified strains of scSIV were administered on weeks 0, 6, and 12, followed by two booster inoculations with vesicular stomatitis virus (VSV) G trans-complemented scSIV on weeks 18 and 24. Although this immunization regimen did not elicit antibodies capable of detectably neutralizing SIV(mac)239 or SIV(mac)251(UCD), neutralizing antibody titers to the envelope-modified strains were selectively enhanced. Virus specific antibodies and T cells were observed in the vaginal mucosa. After 20 weeks of repeated, low-dose vaginal challenge with SIV(mac)251(UCD), six of eight immunized animals versus six of six naive controls became infected. Although immunization did not significantly reduce the likelihood of acquiring immunodeficiency virus infection, statistically significant reductions in peak and set point viral loads were observed in the immunized animals relative to the naive control animals. PMID- 20702642 TI - A maraviroc-resistant HIV-1 with narrow cross-resistance to other CCR5 antagonists depends on both N-terminal and extracellular loop domains of drug bound CCR5. AB - CCR5 antagonists inhibit HIV entry by binding to a coreceptor and inducing changes in the extracellular loops (ECLs) of CCR5. In this study, we analyzed viruses from 11 treatment-experienced patients who experienced virologic failure on treatment regimens containing the CCR5 antagonist maraviroc (MVC). Viruses from one patient developed high-level resistance to MVC during the course of treatment. Although resistance to one CCR5 antagonist is often associated with broad cross-resistance to other agents, these viruses remained sensitive to most other CCR5 antagonists, including vicriviroc and aplaviroc. MVC resistance was dependent upon mutations within the V3 loop of the viral envelope (Env) protein and was modulated by additional mutations in the V4 loop. Deep sequencing of pretreatment plasma viral RNA indicated that resistance appears to have occurred by evolution of drug-bound CCR5 use, despite the presence of viral sequences predictive of CXCR4 use. Envs obtained from this patient before and during MVC treatment were able to infect cells expressing very low CCR5 levels, indicating highly efficient use of a coreceptor. In contrast to previous reports in which CCR5 antagonist-resistant viruses interact predominantly with the N terminus of CCR5, these MVC-resistant Envs were also dependent upon the drug-modified ECLs of CCR5 for entry. Our results suggest a model of CCR5 cross-resistance whereby viruses that predominantly utilize the N terminus are broadly cross-resistant to multiple CCR5 antagonists, whereas viruses that require both the N terminus and antagonist-specific ECL changes demonstrate a narrow cross-resistance profile. PMID- 20702643 TI - Resistance to rabies virus infection conferred by the PMLIV isoform. AB - Various reports implicate PML and PML nuclear bodies (NBs) in an intrinsic antiviral response targeting diverse cytoplasmic replicating RNA viruses. PML conjugation to the small ubiquitin-like modifier (SUMO) is required for its localization within NBs. PML displays antiviral effects in vivo, as PML deficiency renders mice more susceptible to infection with the rhabdovirus vesicular stomatitis virus (VSV). Cells derived from these mice are also more sensitive to infection with rabies virus, another member of the rhabdovirus family. Alternative splicing from a single gene results in the synthesis of several PML isoforms, and these are classified into seven groups, designated PMLI to -VII. We report here that expression of PMLIV or PMLIVa, which is missing exon 5, inhibited viral mRNA and protein synthesis, leading to a reduction in viral replication. However, the expression of other nuclear isoforms (PMLI to -VI) and cytoplasmic PMLVIIb failed to impair viral production. This antiviral effect required PMLIV SUMOylation, as it was not observed with PMLIV 3KR, in which the lysines involved in SUMO conjugation were mutated. Thus, PMLIV and PMLIVa may exert this isoform-specific function through interaction with specific NB protein partners via their common C-terminal region. PMID- 20702644 TI - Genotype-specific neutralization and protection by antibodies against dengue virus type 3. AB - Dengue viruses (DENV) comprise a family of related positive-strand RNA viruses that infect up to 100 million people annually. Currently, there is no approved vaccine or therapy to prevent infection or diminish disease severity. Protection against DENV is associated with the development of neutralizing antibodies that recognize the viral envelope (E) protein. Here, with the goal of identifying monoclonal antibodies (MAbs) that can function as postexposure therapy, we generated a panel of 82 new MAbs against DENV-3, including 24 highly neutralizing MAbs. Using yeast surface display, we localized the epitopes of the most strongly neutralizing MAbs to the lateral ridge of domain III (DIII) of the DENV type 3 (DENV-3) E protein. While several MAbs functioned prophylactically to prevent DENV-3-induced lethality in a stringent intracranial-challenge model of mice, only three MAbs exhibited therapeutic activity against a homologous strain when administered 2 days after infection. Remarkably, no MAb in our panel protected prophylactically against challenge by a strain from a heterologous DENV-3 genotype. Consistent with this, no single MAb neutralized efficiently the nine different DENV-3 strains used in this study, likely because of the sequence variation in DIII within and between genotypes. Our studies suggest that strain diversity may limit the efficacy of MAb therapy or tetravalent vaccines against DENV, as neutralization potency generally correlated with a narrowed genotype specificity. PMID- 20702645 TI - Structural and functional characterization of an influenza virus RNA polymerase genomic RNA complex. AB - The replication and transcription of influenza A virus are carried out by ribonucleoproteins (RNPs) containing each genomic RNA segment associated with nucleoprotein monomers and the heterotrimeric polymerase complex. These RNPs are responsible for virus transcription and replication in the infected cell nucleus. Here we have expressed, purified, and analyzed, structurally and functionally, for the first time, polymerase-RNA template complexes obtained after replication in vivo. These complexes were generated by the cotransfection of plasmids expressing the polymerase subunits and a genomic plasmid expressing a minimal template of positive or negative polarity. Their generation in vivo was strictly dependent on the polymerase activity; they contained mainly negative-polarity viral RNA (vRNA) and could transcribe and replicate in vitro. The three dimensional structure of the monomeric polymerase-vRNA complexes was similar to that of the RNP-associated polymerase and distinct from that of the polymerase devoid of template. These results suggest that the interaction with the template is sufficient to induce a significant conformation switch in the polymerase complex. PMID- 20702646 TI - Coexistence of different genotypes in the same bat and serological characterization of Rousettus bat coronavirus HKU9 belonging to a novel Betacoronavirus subgroup. AB - Rousettus bat coronavirus HKU9 (Ro-BatCoV HKU9), a recently identified coronavirus of novel Betacoronavirus subgroup D, from Leschenault's rousette, was previously found to display marked sequence polymorphism among genomes of four strains. Among 10 bats with complete RNA-dependent RNA polymerase (RdRp), spike (S), and nucleocapsid (N) genes sequenced, three and two sequence clades for all three genes were codetected in two and five bats, respectively, suggesting the coexistence of two or three distinct genotypes of Ro-BatCoV HKU9 in the same bat. Complete genome sequencing of the distinct genotypes from two bats, using degenerate/genome-specific primers with overlapping sequences confirmed by specific PCR, supported the coexistence of at least two distinct genomes in each bat. Recombination analysis using eight Ro-BatCoV HKU9 genomes showed possible recombination events between strains from different bat individuals, which may have allowed for the generation of different genotypes. Western blot assays using recombinant N proteins of Ro-BatCoV HKU9, Betacoronavirus subgroup A (HCoV-HKU1), subgroup B (SARSr-Rh-BatCoV), and subgroup C (Ty-BatCoV HKU4 and Pi-BatCoV HKU5) coronaviruses were subgroup specific, supporting their classification as separate subgroups under Betacoronavirus. Antibodies were detected in 75 (43%) of 175 and 224 (64%) of 350 tested serum samples from Leschenault's rousette bats by Ro BatCoV HKU9 N-protein-based Western blot and enzyme immunoassays, respectively. This is the first report describing coinfection of different coronavirus genotypes in bats and coronavirus genotypes of diverse nucleotide variation in the same host. Such unique phenomena, and the unusual instability of ORF7a, are likely due to recombination which may have been facilitated by the dense roosting behavior and long foraging range of Leschenault's rousette. PMID- 20702647 TI - The glycosylated Gag protein of a murine leukemia virus inhibits the antiretroviral function of APOBEC3. AB - APOBEC proteins have evolved as innate defenses against retroviral infections. Human immunodeficiency virus (HIV) encodes the Vif protein to evade human APOBEC3G; however, mouse retroviruses do not encode a Vif homologue, and it has not been understood how they evade mouse APOBEC3. We report here a murine leukemia virus (MuLV) that utilizes its glycosylated Gag protein (gGag) to evade APOBEC3. gGag is critical for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted for replication in wild type mice replicates efficiently in APOBEC3 knockout mice, implying a novel role of gGag in circumventing the action of APOBEC3 in vivo. PMID- 20702648 TI - Cabergoline monotherapy in the long-term treatment of Cushing's disease. AB - BACKGROUND: Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D(2) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD). OBJECTIVE: To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD. METHODS: Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5-1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1-3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC >= 125% of it. RESULTS: Within 3-6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders. CONCLUSIONS: Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments. PMID- 20702649 TI - Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. AB - CONTEXT: Somatic mutations at residue R132 of isocitrate dehydrogenase 1 (IDH1) were recently discovered in gliomas and leukaemia at a high frequency. IDH1 is a metabolic gene, and the R132 mutations create a new enzymatic activity. OBJECTIVES: To determine whether IDH1 had somatically acquired mutations in thyroid carcinomas. DESIGN: Exons 4 and 6 of IDH1 were sequenced in a large panel of thyroid tumours (n=138) and compared with the patients normal DNA (n=26). We also correlated IDH1 mutations with clinical-pathological data and BRAF and RAS mutational status. RESULTS: We identified four novel and two previously described non-synonymous variants in thyroid carcinomas, which were absent in benign tumours and paired normal thyroid. Although IDH1 variants occurred at higher frequency in follicular thyroid carcinomas, follicular variant of papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinomas than the observed variants in classical PTC (15/72 vs 3/37), it was not significant (P=0.1). Sequence alignment across several species shows that all IDH1 genetic alterations occurred at evolutionarily conserved residues located within the active site, and therefore, are likely to affect protein function. Unlike other tumours, IDH1 and BRAF or RAS mutations are not mutually exclusive. There was no association between IDH1 mutational status and clinical characteristics. CONCLUSION: IDH1 acquired genetic alterations are highly prevalent in thyroid carcinomas (16%). Our findings not only extend our understanding of the molecular mechanism underlying pathogenesis of thyroid tumours, but also emphasize the biological differences between tumour types. Those tumours with IDH1 mutations might benefit from therapies that exploit this alteration. PMID- 20702650 TI - Mumps virus small hydrophobic protein targets ataxin-1 ubiquitin-like interacting protein (ubiquilin 4). AB - The small hydrophobic (SH) protein of mumps virus has been reported to interfere with innate immunity by inhibiting tumour necrosis factor alpha-mediated apoptosis. In a yeast two-hybrid screen we have identified the ataxin-1 ubiquitin like interacting protein (A1Up) as a cellular target of the SH protein. A1Up contains an amino-terminal ubiquitin-like (UbL) domain, a carboxy-terminal ubiquitin-associated (UbA) domain and two stress-inducible heat shock chaperonin binding (Sti1) motifs. This places it within the ubiquitin-like protein family that is involved in proteasome-mediated activities. Co-immunoprecipitation confirmed the binding of SH and A1Up and demonstrates that a truncated protein fragment corresponding to aa 136-270 of A1Up, which represents the first Sti1-like repeat and an adjacent hydrophobic region, was sufficient for interaction, whereas neither the UbL nor the UbA domains were required for interaction. The ectopic expression of A1Up leads to a redistribution of SH to punctate structures that co-localize with the 20S proteasome in transfected or infected mammalian cells. PMID- 20702651 TI - Plasminogen promotes influenza A virus replication through an annexin 2-dependent pathway in the absence of neuraminidase. AB - Proteolytic cleavage of haemagglutinin (HA) is essential for the infectivity of influenza A viruses (IAVs). This is usually mediated by trypsin-like proteases present in the respiratory tract. However, the ability to use plasminogen (PLG) as an alternative protease may contribute to pathogenesis of IAV infections and virus replication outside the respiratory tract. It was demonstrated previously that neuraminidase (NA) of the IAV strain A/WSN/33 can sequester PLG, allowing this virus to replicate in a PLG-dependent fashion. However, PLG also promotes replication of other IAVs, although its mode of action is poorly understood. Here, using NA-deficient viruses, we demonstrate that NA is not required for the binding of PLG and subsequent cleavage of HA. However, we demonstrate that the cellular protein annexin 2 (A2) can bind PLG and contributes to PLG-dependent cleavage of HA and subsequent IAV replication. Collectively, these results indicate that PLG promotes IAV replication in an A2-dependent fashion in the absence of NA. PMID- 20702652 TI - Genome organization and translation products of Providence virus: insight into a unique tetravirus. AB - Providence virus (PrV) is a member of the family Tetraviridae, a family of small, positive-sense, ssRNA viruses that exclusively infect lepidopteran insects. PrV is the only known tetravirus that replicates in tissue culture. We have analysed the genome and characterized the viral translation products, showing that PrV has a monopartite genome encoding three ORFs: (i) p130, unique to PrV and of unknown function; (ii) p104, which contains a read-through stop signal, producing an N terminal product of 40 kDa (p40) and (iii) the capsid protein precursor (p81). There are three 2A-like processing sequences: one at the N terminus of p130 (PrV 2A1) and two more (PrV-2A2 and PrV-2A3) at the N terminus of p81. Metabolic radiolabelling identified viral translation products corresponding to all three ORFs in persistently infected cells and showed that the read-through stop in p104 and PrV-2A3 in p81 are functional in vivo and these results were confirmed by in vitro translation experiments. The RNA-dependent RNA polymerase domain of the PrV replicase is phylogenetically most closely related to members of the families Tombusviridae and Umbraviridae rather than to members of the family Tetraviridae. The unique genome organization, translational control systems and phylogenetic relationship with the replicases of (+ve) plant viruses lead us to propose that PrV represents a novel family of small insect RNA viruses, distinct from current members of the family Tetraviridae. PMID- 20702653 TI - Isolation and full-length sequence analysis of Armigeres subalbatus totivirus, the first totivirus isolate from mosquitoes representing a proposed novel genus (Artivirus) of the family Totiviridae. AB - During an investigation of arboviruses in China, a novel dsRNA virus was isolated from adult female Armigeres subalbatus. Full genome sequence analysis showed the virus to be related to members of the family Totiviridae, and was therefore named 'Armigeres subalbatus totivirus' (AsTV). Transmission electron microscopy identified icosahedral, non-enveloped virus particles with a mean diameter of 40 nm. The AsTV genome is 7510 bp in length, with two ORFs. ORF1 (4443 nt) encodes the coat-protein and a dsRNA-binding domain (which may be involved in the evasion of 'gene silencing'), while ORF2 (2286 nt) encodes the viral RNA-dependent RNA polymerase (RdRp). The AsTV coat protein shows a higher level of amino acid identity with Drosophila totivirus (DTV, 52 %) than with infectious myonecrosis virus (IMNV, 29 %). Similarly, the RdRp shows higher identity levels with DTV (51 %) than with IMNV (44 %). Identity levels to other members of the family Totiviridae, in either the coat protein or the RdRp, ranged from 6 to 11 %. Based on a recent reassessment of the coding strategy used by IMNV, we suggest that an AsTV coat-RdRp fusion protein could be synthesized via a -1 frameshift. Elements favouring -1 frameshift such as 'slippery heptamers' and pseudonkots, were identified in the AsTV, DTV and IMNV genomes. AsTV was shown to grow in both mosquito and mammalian cells, suggesting that it is an arbovirus that can infect mammals. PMID- 20702654 TI - Experimental evidence of recombination in murine noroviruses. AB - Based on sequencing data, norovirus (NoV) recombinants have been described, but no experimental evidence of recombination in NoVs has been documented. Using the murine norovirus (MNV) model, we investigated the occurrence of genetic recombination between two co-infecting wild-type MNV isolates in RAW cells. The design of a PCR-based genotyping tool allowed accurate discrimination between the parental genomes and the detection of a viable recombinant MNV (Rec MNV) in the progeny viruses. Genetic analysis of Rec MNV identified a homologous recombination event located at the ORF1-ORF2 overlap. Rec MNV exhibited distinct growth curves and produced smaller plaques than the wild-type MNV in RAW cells. Here, we demonstrate experimentally that MNV undergoes homologous recombination at the previously described recombination hot spot for NoVs, suggesting that the MNV model might be suitable for in vitro studies of NoV recombination. Moreover, the results show that exchange of genetic material between NoVs can generate viruses with distinct biological properties from the parental viruses. PMID- 20702655 TI - Mentoring reviewers: the Journal of Pediatric Psychology experience. AB - OBJECTIVES: To describe a program designed to meet the need to mentor trainees in manuscript reviewing. METHODS: Mentors (n = 25) and mentees (n = 32) participating in the Journal of Pediatric Psychology's Manuscript Review Mentoring Program completed an online survey assessing their experiences and satisfaction with the program, perceptions of benefits and challenges to participating, and desirable characteristics of mentors and mentees. RESULTS: Participants reported using several methods to create mentored reviews. Satisfaction was generally high, and participants reported benefits related to manuscript review training and professional development. Challenges to participating in the program were primarily logistical. Participants noted personal characteristics and behaviors that were desirable for mentors and mentees. CONCLUSIONS: Providing mentored manuscript review experiences through a structured program appears to be feasible and well received by mentors and mentees. Future programs might provide guidance on how participants can discuss their expectations, benchmarks for review quality, and evaluations of the quality of reviews. PMID- 20702656 TI - Plasma concentration of malaria parasite-derived macrophage migration inhibitory factor in uncomplicated malaria patients correlates with parasitemia and disease severity. AB - Host macrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of malaria infections. Several Plasmodium parasite-derived MIFs were identified to have the potential to regulate host immune response. However, the role of Plasmodium MIFs in the immunopathogenesis of malaria infection and the relationships between these mediators and inflammatory cytokines remained unclear. In this study, we have investigated two Plasmodium MIFs in peripheral blood of uncomplicated malaria patients and analyzed their correlations with several major factors during malaria infection. We found that both Plasmodium falciparum MIF (PfMIF) and Plasmodium vivax MIF (PvMIF) levels in patients were positively correlated with parasitemia, tumor necrosis factor alpha, interleukin 10 (IL-10), and monocyte chemoattractant protein 1 but were not correlated with transforming growth factor beta1 and IL-12. Of interest was that the PvMIF level was positively correlated with host body temperature and human MIF (HuMIF) concentrations. Moreover, multiple stepwise regression analysis also showed that parasitemia, IL-10, and HuMIF expression were significant predictors of Plasmodium MIF production. In addition, during antimalarial drug treatment, the decreasing of Plasmodium MIF concentrations was followed by parasitemia in most patients. Our results suggested that the Plasmodium MIF circulating level reflects the level of parasitemia and thus was closely correlated with disease severity in uncomplicated malaria. Therefore, this factor has the potential to be a promising disease predictor and is applicable in clinical diagnosis. PMID- 20702658 TI - Detection of Plasmodium falciparum, P. vivax, P. ovale, and P. malariae merozoite surface protein 1-p19 antibodies in human malaria patients and experimentally infected nonhuman primates. AB - Approximately 3.2 billion people live in areas where malaria is endemic, and WHO estimates that 350 to 500 million malaria cases occur each year worldwide. This high prevalence, and the high frequency of international travel, creates significant risk for the exportation of malaria to countries where malaria is not endemic and for the introduction of malaria organisms into the blood supply. Since all four human infectious Plasmodium species have been transmitted by blood transfusion, we sought to develop an enzyme-linked immunosorbent assay (ELISA) capable of detecting antibodies elicited by infection with any of these species. The merozoite surface protein 1 (MSP1), a P. falciparum and P. vivax vaccine candidate with a well-characterized immune response, was selected for use in the assay. The MSP1 genes from P. ovale and P. malariae were cloned and sequenced (L. Birkenmeyer, A. S. Muerhoff, G. Dawson, and S. M. Desai, Am. J. Trop. Med. Hyg. 82:996-1003, 2010), and the carboxyl-terminal p19 regions of all four species were expressed in Escherichia coli. Performance results from individual p19 ELISAs were compared to those of a commercial test (Lab 21 Healthcare Malaria enzyme immunoassay [EIA]). The commercial ELISA detected all malaria patients with P. falciparum or P. vivax infections, as did the corresponding species specific p19 ELISAs. However, the commercial ELISA detected antibodies in 0/2 and 5/8 individuals with P. malariae and P. ovale infections, respectively, while the p19 assays detected 100% of individuals with confirmed P. malariae or P. ovale infections. In experimentally infected nonhuman primates, the use of MSP1-p19 antigens from all four species resulted in the detection of antibodies within 2 to 10 weeks postinfection. Use of MSP1-p19 antigens from all four Plasmodium species in a single immunoassay would provide significantly improved efficacy compared to existing tests. PMID- 20702657 TI - Safety and immunogenicity of a recombinant nonglycosylated erythrocyte binding antigen 175 Region II malaria vaccine in healthy adults living in an area where malaria is not endemic. AB - Erythrocyte binding antigen region II (EBA-175) is a conserved antigen of Plasmodium falciparum that is involved in binding of the parasite to the host's erythrocytes. We evaluated the safety and immunogenicity of a recombinant EBA-175 vaccine with aluminum phosphate adjuvant in healthy young adults living in the United States. Eighteen subjects/group received ascending doses (5, 20, 80, or 160 MUg) of the vaccine at 0, 1, and 6 months; 8 subjects received placebo. Most of the injection site and systemic reactions were mild to moderate in intensity. After 2 or 3 doses of the vaccine at any concentration, antibody levels measured by enzyme-linked immunosorbent assay were significantly higher than those for the placebo group. Sera from subjects who received 3 doses of the vaccine at any concentration inhibited the growth of erythrocyte-stage P. falciparum at low levels compared to sera from placebo recipients or preimmune sera. In conclusion, the EBA-175 vaccine with adjuvant was safe and immunogenic in malaria-naive subjects. PMID- 20702660 TI - Complex febrile seizures followed by complete recovery in an infant with high titer 2009 pandemic influenza A (H1N1) virus infection. AB - We describe a 2009 H1N1 virus infection with a high viral load in a previously healthy infant who presented with complex febrile seizures and improved on oseltamivir without neurologic sequelae. Febrile seizures may be a complication in young children experiencing infection with high viral loads of 2009 H1N1 influenza virus. PMID- 20702659 TI - Use of acyclovir for suppression of human immunodeficiency virus infection is not associated with genotypic evidence of herpes simplex virus type 2 resistance to acyclovir: analysis of specimens from three phase III trials. AB - Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcer disease and is a cofactor for HIV-1 acquisition and transmission. We analyzed specimens from three separate phase III trials of acyclovir (ACV) for prevention of HIV-1 acquisition and transmission to determine if failure of ACV to interrupt HIV acquisition and transmission was associated with genotypic ACV resistance. Acyclovir (400 mg twice daily) or placebo was provided to HSV-2-infected persons at risk of HIV-1 infection in the Mwanza and HPTN 039 trials and to persons dually infected with HSV-2 and HIV-1 who had an HIV-negative partner in the Partners in Prevention study. We extracted HSV DNA from genital ulcer swabs or cervicovaginal lavage fluids from 68 samples obtained from 64 participants randomized to ACV and sequenced the HSV-2 UL23 gene encoding thymidine kinase. The UL23 sequences were compared with published and unpublished data. Variants were observed in 38/1,128 (3.4%) nucleotide positions in the UL23 open reading frame, with 58% of these encoding amino acid changes. No deletions, insertions, or mutations known to be associated with resistance were detected. Thirty-one of the variants (81.5%) are newly reported, 15 of which code for amino acid changes. Overall, UL23 is highly polymorphic compared to other loci in HSV-2, but no drug resistance mutations were detected that could explain the failure to reduce HIV incidence or to prevent HIV-1 transmission in these studies. PMID- 20702661 TI - Corynebacterium macginleyi conjunctivitis in Canada. AB - This report describes for the first time Corynebacterium macginleyi as a cause of conjunctivitis in Canada, where menaquinone analysis was done as part of the strain characterization. This species is typically isolated from ocular surfaces of patients from Europe and Japan. The isolate was resistant to erythromycin and clindamycin. PMID- 20702662 TI - Comparison of combined nose-throat swabs with nasopharyngeal aspirates for detection of pandemic influenza A/H1N1 2009 virus by real-time reverse transcriptase PCR. AB - Data assessing the diagnostic accuracies of use of different respiratory samples for the detection of the novel influenza A/H1N1 2009 virus by molecular methods are lacking. The objective of this study was to compare the sensitivity of combined nose and throat swabs (CNTS) with that of nasopharyngeal aspirates (NPA). This was a prospective study of adults and children with suspected influenza. Real-time reverse transcriptase PCR testing was used for the virological diagnosis. Of the 2,473 patients included, 264 with paired CNTS and NPA were randomly selected. Novel influenza A/H1N1 virus was identified in at least one sample for 115 (43.6%) patients, the majority of them young adults. In 109 patients (94.8%) the virus was identified in the CNTS, and in 98 (85.2%) it was identified in the NPA (P = 0.02). In 93 patients (80.1%), the virus was identified in both specimens. Spearman's rho correlation coefficient between the two methods was 0.82 (P < 0.001). There were no significant differences in accuracy between the specimens when patients were stratified according to demographic or clinical characteristics except in the case of women, in whom the sensitivity of CNTS was higher (P = 0.01). The combination of CNTS and NPA had a significantly higher sensitivity in identifying the virus than did each method alone (P = 0.02 for the comparison of the combination of both sampling methods with CNTS, and P < 0.001 for the comparison with NPA). We conclude that in patients with the novel influenza A/H1N1 virus, the diagnostic yield of CNTS is higher than that of NPA. The combination of both sampling methods increases the likelihood of diagnosing the virus. PMID- 20702663 TI - Multiplex amplified nominal tandem-repeat analysis (MANTRA), a rapid method for genotyping Mycobacterium tuberculosis by use of multiplex PCR and a microfluidic laboratory chip. AB - A variable-number tandem-repeat genotyping method for Mycobacterium tuberculosis was converted to run in a multiplex PCR format on a 12-well microfluidic laboratory chip. Epidemiologically and genotypically distinct isolate clusters of M. tuberculosis were identified. This rapid genotyping method has potential application in smaller clinical laboratories and public health field investigations. PMID- 20702665 TI - Comparison of midturbinate flocked-swab specimens with nasopharyngeal aspirates for detection of respiratory viruses in children by the direct fluorescent antibody technique. AB - Paired nasopharyngeal aspirate (NPA) and midturbinate flocked-swab specimens from 153 children with respiratory symptoms were examined by the direct fluorescent antibody (DFA) technique. Seventy-four infants (49%) had a viral infection documented by DFA. The flocked-swab specimens had 93% sensitivity and 96.7% agreement with the NPA specimens, with a kappa coefficient of 93.4% (95% confidence interval, 0.877, 0.991). PMID- 20702664 TI - Erythema nodosum and bilateral breast abscesses due to Salmonella enterica serotype Poona. AB - A woman presented with erythema nodosum followed by bilateral breast abscesses without a gastrointestinal manifestation, due to a rare serotype of Salmonella, namely, Salmonella enterica serotype Poona. This is the first reported case of erythema nodosum presumably associated with Salmonella infection without a gastrointestinal manifestation. PMID- 20702666 TI - Accurate and sensitive detection of Plasmodium species in humans by use of the dihydrofolate reductase-thymidylate synthase linker region. AB - A nested-PCR protocol based on the linker region of the Plasmodium dihydrofolate reductase-thymidylate synthase gene (dhfr-ts) was developed. This provides highly sensitive specific detection and identification of the five parasite species that infect humans. PMID- 20702667 TI - Rapid drug susceptibility testing with a molecular beacon assay is associated with earlier diagnosis and treatment of multidrug-resistant tuberculosis in California. AB - To assess the clinical impact of a molecular beacon (MB) assay that detects multidrug-resistant tuberculosis (MDR TB), we retrospectively reviewed records of 127 MDR TB patients with and without MB testing between 2004 and 2007. Use of the MB assay reduced the time to detection and treatment of MDR TB. PMID- 20702669 TI - Gentamicin-resistant Enterococcus faecalis sequence type 6 with reduced penicillin susceptibility: diagnostic and therapeutic implications. PMID- 20702668 TI - Comparison of two multilocus variable-number tandem-repeat methods and pulsed field gel electrophoresis for differentiating highly clonal methicillin-resistant Staphylococcus aureus isolates. AB - In the United Kingdom, EMRSA-15 and EMRSA-16 account for the majority (~90%) of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infections. Currently, the standard typing technique, pulsed-field gel electrophoresis (PFGE), is laborious and insufficient for discriminating between closely related subtypes of EMRSA-15 and -16. The objective of the present study was to compare the usefulness of multilocus variable-number tandem-repeat fingerprinting (MLVF) and multilocus variable-number tandem-repeat analysis (MLVA) with PFGE for subtyping these highly clonal MRSA lineages. A panel of 85 MRSA isolates (41 EMRSA-15, 20 EMRSA-16, and 24 MRSA isolates with diverse PFGE patterns) was investigated. In addition, a further 29 EMRSA-15s with identical PFGE patterns from two geographically linked but epidemiologically distinct outbreaks and several sporadic cases were analyzed. PFGE, MLVF, and MLVA resolved 66 (Simpson's index of diversity [SID] = 0.984), 51 (SID = 0.95), and 42 (SID = 0.881) types, respectively, among the 85 MRSA isolates. MLVF was more discriminatory than MLVA for EMRSA-15 and -16 strains, but both methods had comparable discriminatory powers for distinguishing isolates in the group containing diverse PFGE types. MLVF was comparable to PFGE for resolving the EMRSA-15s but had a lower discriminatory power for the EMRSA-16s. MLVF and MLVA resolved the 29 isolates with identical PFGE patterns into seven and six subtypes, respectively. Importantly, both assays indicated that the two geographically related outbreaks were caused by distinct subtypes of EMRSA-15. Taken together, the data suggest that both methods are suitable for identifying and tracking specific subtypes of otherwise-indistinguishable MRSA. However, due to its greater discriminatory power, MLVF would be the most suitable alternative to PFGE for hospital outbreak investigations. PMID- 20702670 TI - Novel IS711-specific chromosomal locations useful for identification and classification of marine mammal Brucella strains. AB - We report five new IS711 chromosomal locations that are specific for marine mammal Brucella groups of strains and useful for their identification and classification. Our data support their current classification into two species, Brucella ceti and B. pinnipedialis, with subgroups in each, but also the possibility of additional species. PMID- 20702671 TI - Neurobrucellosis associated with syndrome of inappropriate antidiuretic hormone with resultant diabetes insipidus and hypothyroidism. AB - Neurological involvement of the central nervous system in brucellosis is uncommon. We describe a rare case of meningoencephalitis due to Brucella melitensis infection, associated with the syndrome of inappropriate antidiuretic hormone secretion and leading to diabetes insipidus and hypothyroidism. Neurobrucellosis, although rare, should be considered in cases of neurological disease of unknown etiology. PMID- 20702672 TI - Quantitation of major human cutaneous bacterial and fungal populations. AB - Because the human skin microbiota may play roles in the causation or modification of skin diseases, we sought to provide initial quantitative analysis from different cutaneous locations. We developed quantitative PCRs to enumerate the total bacterial and fungal populations, as well as the most common bacterial and fungal genera present in six locales, in eight healthy subjects. We used a set of primers and TaqMan MGB probes based on the bacterial 16S rRNA and fungal internally transcribed spacer region, as well as bacterial genus-specific probes for Propionibacterium, Corynebacterium, Streptococcus, and Staphylococcus and a fungal genus-specific probe for Malassezia. The extent of human DNA contamination of the specimen was determined by quantitating the human housekeeping GAPDH gene. The highest level of 16S rRNA copies of bacteria was present in the axilla (4.44 +/- 0.18 log(10) copies/MUl [mean +/- standard error of the mean]), with normalization based on GAPDH levels, but the other five locations were similar to one another (range, 2.48 to 2.89 log(10) copies/MUl). There was strong symmetry between the left and right sides. The four bacterial genera accounted for 31% to 59% of total bacteria, with the highest percent composition in the axilla and the lowest in the forearm. Streptococcus was the most common genus present on the forehead and behind the ear. Corynebacterium spp. were predominant in the axilla. Fungal levels were 1 to 2 log(10) lower than for bacteria, with Malassezia spp. accounting for the majority of fungal gene copies. These results provide the first quantitation of the site and host specificities of major bacterial and fungal populations in human skin and present simple methods for their assessment in studies of disease. PMID- 20702673 TI - The Pan Genera Detection immunoassay: a novel point-of-issue method for detection of bacterial contamination in platelet concentrates. AB - Bacterial contamination of platelet concentrates (PCs) still represents an ongoing risk in transfusion-transmitted sepsis. Recently the Pan Genera Detection (PGD) system was developed and FDA licensed for screening of bacterial contamination of PCs directly prior to transfusion. The test principle is based on the immunological detection of lipopolysaccharide (for Gram-negative bacteria) or lipoteichoic acid (for Gram-positive bacteria). In the present study we analyzed the applicability of this method with regard to detection limit, practicability, implementation, and performance. PCs were spiked with Staphylococcus aureus, Bacillus subtilis, and five different Klebsiella pneumoniae strains, as well as eight different Escherichia coli strains. The presence of bacteria was assessed by the PGD immunoassay, and bacteria were enumerated by plating cultures. Application of the PGD immunoassay showed that it is a rapid test with a short hands-on time for sample processing and no demand for special technical equipment and instrument operation. The lower detection limits of the assay for Gram-positive bacteria showed a good agreement with the manufacturer's specifications (8.2 * 10(3) to 5.5 * 10(4) CFU/ml). For some strains of K. pneumoniae and E. coli, the PGD test showed analytical sensitivities (>10(6) CFU/ml) that were divergent from the designated values (K. pneumoniae, 2.0 * 10(4) CFU/ml; E. coli, 2.8 * 10(4) CFU/ml). Result interpretation is sometimes difficult due to very faint bands. In conclusion, our study demonstrates that the PGD immunoassay is an easy-to-perform bedside test for the detection of bacterial contamination in PCs. However, to date there are some shortcomings in the interpretation of results and in the detection limits for some strains of Gram-negative bacteria. PMID- 20702674 TI - Rapid molecular identification of pathogenic yeasts by pyrosequencing analysis of 35 nucleotides of internal transcribed spacer 2. AB - Rapid identification of yeast species isolates from clinical samples is particularly important given their innately variable antifungal susceptibility profiles. Here, we have evaluated the utility of pyrosequencing analysis of a portion of the internal transcribed spacer 2 region (ITS2) for identification of pathogenic yeasts. A total of 477 clinical isolates encompassing 43 different fungal species were subjected to pyrosequencing analysis in a strictly blinded study. The molecular identifications produced by pyrosequencing were compared with those obtained using conventional biochemical tests (AUXACOLOR2) and following PCR amplification and sequencing of the D1-D2 portion of the nuclear 28S large rRNA gene. More than 98% (469/477) of isolates encompassing 40 of the 43 fungal species tested were correctly identified by pyrosequencing of only 35 bp of ITS2. Moreover, BLAST searches of the public synchronized databases with the ITS2 pyrosequencing signature sequences revealed that there was only minimal sequence redundancy in the ITS2 under analysis. In all cases, the pyrosequencing signature sequences were unique to the yeast species (or species complex) under investigation. Finally, when pyrosequencing was combined with the Whatman FTA paper technology for the rapid extraction of fungal genomic DNA, molecular identification could be accomplished within 6 h from the time of starting from pure cultures. PMID- 20702675 TI - Human coinfection with Bartonella henselae and two hemotropic mycoplasma variants resembling Mycoplasma ovis. AB - Two variants of an organism resembling the ovine hemoplasma, Mycoplasma ovis, were detected by PCR in blood samples from a veterinarian in Texas. Coinfection with similar variants has been described in sheep. This represents the first report of human infection with this organism. The veterinarian was coinfected with Bartonella henselae. PMID- 20702677 TI - Mycobacterium tuberculosis Beijing lineage favors the spread of multidrug resistant tuberculosis in the Republic of Georgia. AB - High rates and transmission of multidrug-resistant (MDR) tuberculosis (TB) have been associated with the Mycobacterium tuberculosis complex (MTBC) Beijing lineage, pointing to the importance of pathogen genetic factors for the modulation of infection outcome and epidemiology. We present here an in-depth analysis of the population structure of MTBC strains from the Republic of Georgia, a high-incidence setting at the Black Sea Coast. Phylogenetic lineages were identified based on 24-locus MIRU-VNTR (for mycobacterial interspersed repetitive unit-variable number tandem repeat) and spoligotyping analysis. Clusters of strains with identical genotyping profiles were determined as an indicator for the rate of recent transmission. Among the 183 M. tuberculosis isolates investigated, the most prominent lineage found was Beijing (26%), followed by the LAM (18%), Ural (12%), and Haarlem (5%) strains. A closely related previously undefined phylogenetic group (62 strains) showed a genotyping pattern similar to laboratory strain H37RV and was denominated as "Georgia-H37RV like." Although isoniazid resistance was found among strains of different lineages, MDR TB was nearly completely restricted to Beijing strains (P < 0.0001). Approximately 50% of the isolates were grouped in clusters, indicating a high rate of recent transmission. Our data indicate that, in addition to the confirmation of the importance of Beijing genotype strains for the TB epidemiology in former Soviet Union countries, a high-population diversity with strains of the LAM, Ural, Haarlem, and a previously undefined lineage represents nearly two-thirds of the strains found in Georgia. Higher rates among previously treated and MDR TB patients point to a higher potential of lineage Beijing to escape therapy and develop MDR TB. PMID- 20702676 TI - Impact of strain type on detection of toxigenic Clostridium difficile: comparison of molecular diagnostic and enzyme immunoassay approaches. AB - A multicenter clinical trial assessed the performance of the Cepheid Xpert C. difficile assay on stool specimens collected from patients suspected of having Clostridium difficile infection (CDI). A total of 2,296 unformed stool specimens, collected from seven study sites, were tested by Xpert C. difficile enrichment culture followed by cell culture cytotoxicity testing of the isolates (i.e., toxigenic culture with enrichment) and the study sites' standard C. difficile test methods. The methods included enzyme immunoassay (EIA), direct cytotoxin testing, and two- and three-step algorithms using glutamate dehydrogenase (GDH) screening followed by either EIA or EIA and an in-house PCR assay. All C. difficile strains were typed by PCR-ribotyping. Compared to results for toxigenic culture with enrichment, the sensitivity, specificity, and positive and negative predictive values of the Xpert assay were 93.5, 94.0, 73.0, and 98.8%, respectively. The overall sensitivity of the EIAs compared to that of enrichment culture was 60.0%, and the sensitivity of combined GDH algorithms was 72.9%; both were significantly lower than that of Xpert C. difficile (P < 0.001 and P = 0.03, respectively). The sensitivity of the EIA was significantly lower than that of the Xpert C. difficile assay for detection of ribotypes 002, 027, and 106 (P < 0.0001, P < 0.0001, and P = 0.004, respectively, Fisher's exact test), and the sensitivity of GDH algorithms for ribotypes other than 027 was lower than that for Xpert C. difficile (P < 0.001). The Xpert C. difficile assay is a simple, rapid, and accurate method for detection of toxigenic C. difficile in unformed stool specimens and is minimally affected by strain type compared to EIA and GDH based methods. PMID- 20702678 TI - Health in all policies: where to from here? PMID- 20702679 TI - Pilot testing of a medication self-management transition intervention for heart failure patients. AB - This pilot study examined the impact of a hospital transition intervention for older adults (>= 65 years of age) with heart failure (HF) to promote medication use self-management. Forty subjects, hospitalized with either primary or secondary HF, had a mean age of 76.9 +/- 6.5 years; 65% were males. The majority of subjects (55%) had NYHA Class III HF. A prospective, repeated measures experimental design was used. Baseline and follow-up data (1- and 3-months after hospitalization) were obtained using the Medication Regimen Complexity Index, Brief Medication Questionnaire, Drug Regiment Unassisted Grading Scale, and Kansas City Cardiomyopathy Questionnaire. Using repeated measures analysis of covariance (ANCOVA), with baseline measures as covariates, the transition intervention group had higher levels of medication adherence (F(1,35) = 13.4, p < .001), self-efficacy for HF self-care (F(1,35) = 17.9, p < .001) and had significantly fewer HF related symptoms that impaired health related quality of life (F(1,35) = 9.1, p = .006). PMID- 20702680 TI - Reproductive decisions in people with sickle cell disease or sickle cell trait. AB - In the context of an inherited condition such as sickle cell disease (SCD), it is critical to understand how people with SCD or carriers (sickle cell trait [SCT]) face the challenges of making informed reproductive health decisions. The purpose of this analysis was to examine the beliefs, attitudes, and personal feelings of people with sickle cell disease or sickle cell trait related to making informed reproductive health decisions. Three focus groups were conducted with a total of 15 people who had either SCD or SCT. Five themes were identified: health-related issues in sickle cell disease, testing for sickle cell trait, partner choice, sharing sickle cell status with partners, and reproductive options. These findings enhance understanding of the reproductive experiences in people with SCD and SCT and provide the groundwork for developing an educational intervention focused on making informed decisions about becoming a parent. PMID- 20702681 TI - Discovering client and intervention patterns in home visiting data. AB - Family home visiting is a widely accepted strategy used with disadvantaged families to mitigate the effects of poverty. However, gaps persist in knowledge of effective intervention approaches for home visiting relative to specific client risks such as parenting and psychosocial problems. The purpose of this study was to inductively create clusters from electronic health records of 484 public health nursing clients, using client characteristics and intervention data. Four clinically relevant client clusters were generated using Mixed Membership Naive Bayes methods. Fourteen distinct intervention clusters were generated using KMETIS, a graph partitioning method. The content of the intervention clusters illustrates the complexity of public health nursing practice. This study leverages current nursing documentation technology capacity to advance nursing knowledge. Future research is needed to explore relationships between client and intervention clusters and their associations with client outcomes, with the end goals of improving home visiting practice and client outcomes. PMID- 20702682 TI - Factors associated with increased pain communication by older adults. AB - The purpose of this secondary analysis study was to identify factors associated with increased pain communication by older adults. Data were obtained from 312 older adults with osteoarthritis pain. Content analysis was conducted using criteria from the American Pain Society's "Guidelines for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis" to identify important pain management information described by the older adults in response to general questions about their pain. Gender was the only factor associated with increased pain communication from the predictor variables of age, education, gender, ethnicity, race, marital status, pain intensity, functional pain interference, treatment from a practitioner for arthritis and for pain, and pain relief. The lack of association between pain communication and factors such as pain intensity suggests that practitioners should routinely elicit specific pain information from older adults who have a history of chronic painful conditions such as osteoarthritis. PMID- 20702683 TI - A questionnaire for assessing community health nurses' learning needs. AB - Learning needs assessment is an important stage of every educational process that aims to inform changes in practice and policy for continuing professional development. Professional competencies have been widely used as a basis for the development of learning needs assessment. The Canadian Community Health Nursing Standards of Practices (CCHN Standards) were released in 2003. However, it is not known whether community health nurses (CHNs) have the educational background to enable them to meet these standards. This article reports on the development of a learning needs assessment questionnaire for CHNs. Exploratory and confirmatory factor analyses were conducted to examine the consistency of factors underpinning the CCHN Standards. Also, validity and reliability of the questionnaire were evaluated using appropriate techniques. This process resulted in a valid and reliable CHN learning needs assessment questionnaire to measure learning needs of large groups of practitioners, where other forms of measurement cannot be feasibly conducted. PMID- 20702684 TI - Intervention components promoting adherence to strength training exercise in breast cancer survivors with bone loss. AB - Numerous studies have reported that exercise is safe and beneficial for breast cancer survivors; however, long-term adherence to exercise programs is not easy to accomplish. This secondary analysis examined the demographic and clinical characteristics, adherence to exercise, and cognitive-behavioral intervention components data collected on 120 postmenopausal women with a history of breast cancer and bone loss who had been randomized to the exercise group in a 24-month study. Hierarchical regression was used to identify variables that predicted adherence to exercise. Mean adherence to exercises was 61.89%. Feedback and support were the most frequently used cognitive-behavioral intervention components. In hierarchical regression, predictors for adherence to exercise were feedback (beta = .40, p < .001) and adherence to exercise in the previous time period (beta = .31, p < .001). Participants receiving more frequent feedback had higher adherence to exercise. PMID- 20702685 TI - Publishing pilot intervention work. AB - Pilot intervention studies can be viewed as rehearsals for subsequent full-scale trials. They can help investigators fine-tune later larger studies as well as explore issues related to project management and budget. Pilot studies permit testing of sampling strategies, participant recruitment, intervention content, delivery methods, data collection, and analysis. They also allow researchers to experience the more practical aspects of implementing a study, such as determining the number of study staff members needed to handle recruitment and data collection or identifying special equipment needs. Because pilot study findings may be generalizable, publication is encouraged as long as the preliminary nature of the work is clearly indicated in both the abstract and the article. The present article provides an overview of the types of information that can be gleaned from pilot intervention studies that are suitable for publication. PMID- 20702686 TI - CFTR channels and wound healing. Focus on "Cystic fibrosis transmembrane conductance regulator is involved in airway epithelial wound repair". PMID- 20702687 TI - Effect of Ca2+ binding properties of troponin C on rate of skeletal muscle force redevelopment. AB - To investigate effects of altering troponin (Tn)C Ca(2+) binding properties on rate of skeletal muscle contraction, we generated three mutant TnCs with increased or decreased Ca(2+) sensitivities. Ca(2+) binding properties of the regulatory domain of TnC within the Tn complex were characterized by following the fluorescence of an IAANS probe attached onto the endogenous Cys(99) residue of TnC. Compared with IAANS-labeled wild-type Tn complex, V43QTnC, T70DTnC, and I60QTnC exhibited ~1.9-fold higher, ~5.0-fold lower, and ~52-fold lower Ca(2+) sensitivity, respectively, and ~3.6-fold slower, ~5.7-fold faster, and ~21-fold faster Ca(2+) dissociation rate (k(off)), respectively. On the basis of K(d) and k(off), these results suggest that the Ca(2+) association rate to the Tn complex decreased ~2-fold for I60QTnC and V43QTnC. Constructs were reconstituted into single-skinned rabbit psoas fibers to assess Ca(2+) dependence of force development and rate of force redevelopment (k(tr)) at 15 degrees C, resulting in sensitization of both force and k(tr) to Ca(2+) for V43QTnC, whereas T70DTnC and I60QTnC desensitized force and k(tr) to Ca(2+), I60QTnC causing a greater desensitization. In addition, T70DTnC and I60QTnC depressed both maximal force (F(max)) and maximal k(tr). Although V43QTnC and I60QTnC had drastically different effects on Ca(2+) binding properties of TnC, they both exhibited decreases in cooperativity of force production and elevated k(tr) at force levels <30%F(max) vs. wild-type TnC. However, at matched force levels >30%F(max) k(tr) was similar for all TnC constructs. These results suggest that the TnC mutants primarily affected k(tr) through modulating the level of thin filament activation and not by altering intrinsic cross-bridge cycling properties. To corroborate this, NEM-S1, a non-force-generating cross-bridge analog that activates the thin filament, fully recovered maximal k(tr) for I60QTnC at low Ca(2+) concentration. Thus TnC mutants with altered Ca(2+) binding properties can control the rate of contraction by modulating thin filament activation without directly affecting intrinsic cross-bridge cycling rates. PMID- 20702689 TI - Theory and applications of geometric scaling of localized calcium release events. AB - Geometric measures of localized calcium release (LCR) events have been used to understand their biophysical basis. We found power law scaling between three such metrics-maximum amplitude (MA), mass above half-maximum amplitude (MHM), and area at half-maximum amplitude (AHM). In an effort to understand this scaling a minimal analytic model was employed to simulate LCR events recorded by confocal line scan. The distribution of logMHM as a function of logAHM, pMHM(pAHM), was dependent on model parameters such as channel open time, current size, line scan offset, and apparent diffusion coefficient. The distribution of log[MHM/AHM] as a function of logMA, p[MHM/AHM](pMA), was invariant, reflecting the gross geometry of the LCR event. The findings of the model were applied to real LCR line scan data from rabbit portal vein myocytes, rat cerebral artery myocytes, and guinea pig fundus knurled cells. pMHM(pAHM) could be used to distinguish two populations of LCR events in portal vein, even at the scale of "calcium noise," and to calculate the relative current of the two. The relative current was 2. pMHM(pAHM) could also be used to study pharmacological effects. The pMHM(pAHM) distribution of knurled cell LCR events was markedly contracted by ryanodine, suggesting a reduction in channel open time. The p[MHM/AHM](pMA) distributions were invariant across all cell types and were consistent with the model, underlying the common physical basis of their geometry. The geometric scaling of LCR events demonstrated here may help with their mechanistic characterization. PMID- 20702688 TI - SV2 regulates neurotransmitter release via multiple mechanisms. AB - Among the proteins that mediate calcium-stimulated transmitter release, the synaptic vesicle protein 2 (SV2) stands out as a unique modulator specific to the neurons and endocrine cells of vertebrates. In synapses, SV2 regulates the expression and trafficking of the calcium sensor protein synaptotagmin, an action consistent with the reduced calcium-mediated exocytosis observed in neurons lacking SV2. Yet SV2 contains amino acid motifs consistent with it performing other actions that could regulate presynaptic functioning and that might underlie the mechanism of drug action. To test the role of these functional motifs, we performed a mutagenic analysis of SV2A and assessed the ability of mutant SV2A proteins to restore normal synaptic transmission in neurons from SV2A/B knockout mice. We report that SV2A-R231Q, harboring a mutation in a canonical transporter motif, restored normal synaptic depression (a measure of release probability and signature deficit of neurons lacking SV2). In contrast, normal synaptic depression was not restored by SV2A-W300A and SV2A-W666A, harboring mutations of conserved tryptophans in the 5th and 10th transmembrane domains. Although they did not rescue normal neurotransmission, SV2A-W300A and SV2A-W666A did restore normal levels of synaptotagmin expression and internalization. This indicates that tryptophans 300 and 666 support an essential action of SV2 that is unrelated to its role in synaptotagmin expression or trafficking. These results indicate that SV2 performs at least two actions at the synapse that contribute to neurotransmitter release. PMID- 20702692 TI - A study of clustered data and approaches to its analysis. AB - Statistical analysis is critical in the interpretation of experimental data across the life sciences, including neuroscience. The nature of the data collected has a critical role in determining the best statistical approach to take. One particularly prevalent type of data is referred to as "clustered data." Clustered data are characterized as data that can be classified into a number of distinct groups or "clusters" within a particular study. Clustered data arise most commonly in neuroscience when data are compiled across multiple experiments, for example in electrophysiological or optical recordings taken from synaptic terminals, with each experiment providing a distinct cluster of data. However, there are many other types of experimental design that can yield clustered data. Here, we provide a statistical model for intracluster correlation and systematically investigate a range of methods for analyzing clustered data. Our analysis reveals that it is critical to take data clustering into account and suggests appropriate statistical approaches that can be used to account for data clustering. PMID- 20702690 TI - Cross-species comparison of genomewide gene expression profiles reveals induction of hypoxia-inducible factor-responsive genes in iron-deprived intestinal epithelial cells. AB - Molecular mechanisms mediating the induction of metal ion homeostasis-related genes in the mammalian intestine during iron deficiency remain unknown. To elucidate relevant regulatory pathways, genomewide gene expression profiles were determined in fully differentiated human intestinal epithelial (Caco-2) cells. Cells were deprived of iron (or not) for 6 or 18 h, and Gene Chip analyses were subsequently performed (Affymetrix). More than 2,000 genes were differentially expressed; genes related to monosaccharide metabolism, regulation of gene expression, hypoxia, and cell death were upregulated, while those related to mitotic cell cycle were downregulated. A large proportion of induced genes are hypoxia responsive, and promoter enrichment analyses revealed a statistical overrepresentation of hypoxia response elements (HREs). Immunoblot experiments demonstrated a >60-fold increase in HIF2alpha protein abundance in iron-deprived cells; HIF1alpha levels were unchanged. Furthermore, comparison of the Caco-2 cell data set with a Gene Chip data set from iron-deficient rat intestine revealed 29 common upregulated genes; the majority are hypoxia responsive, and their promoters are enriched for HREs. We conclude that the compensatory response of the intestinal epithelium to iron deprivation relates to hypoxia and that stabilization of HIF2alpha may be the primary event mediating metabolic and morphological changes observed during iron deficiency. PMID- 20702693 TI - A novel role for Kv1.3 blockers: protecting neural progenitor cells from a hostile inflammatory environment. PMID- 20702694 TI - Describing the brain in autism in five dimensions--magnetic resonance imaging assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. AB - Autism spectrum disorder (ASD) is a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. This makes the neuroanatomy of autism inherently difficult to describe. Here, we demonstrate how a multiparameter classification approach can be used to characterize the complex and subtle structural pattern of gray matter anatomy implicated in adults with ASD, and to reveal spatially distributed patterns of discriminating regions for a variety of parameters describing brain anatomy. A set of five morphological parameters including volumetric and geometric features at each spatial location on the cortical surface was used to discriminate between people with ASD and controls using a support vector machine (SVM) analytic approach, and to find a spatially distributed pattern of regions with maximal classification weights. On the basis of these patterns, SVM was able to identify individuals with ASD at a sensitivity and specificity of up to 90% and 80%, respectively. However, the ability of individual cortical features to discriminate between groups was highly variable, and the discriminating patterns of regions varied across parameters. The classification was specific to ASD rather than neurodevelopmental conditions in general (e.g., attention deficit hyperactivity disorder). Our results confirm the hypothesis that the neuroanatomy of autism is truly multidimensional, and affects multiple and most likely independent cortical features. The spatial patterns detected using SVM may help further exploration of the specific genetic and neuropathological underpinnings of ASD, and provide new insights into the most likely multifactorial etiology of the condition. PMID- 20702696 TI - CRMP5 interacts with tubulin to inhibit neurite outgrowth, thereby modulating the function of CRMP2. AB - Collapsin response mediator proteins (CRMPs) are involved in signaling of axon guidance and neurite outgrowth during neural development and regeneration. Among these, CRMP2 has been identified as an important actor in neuronal polarity and axon outgrowth, these activities being correlated with the reorganization of cytoskeletal proteins. In contrast, the function of CRMP5, expressed during brain development, remains obscure. Here, we find that, in contrast to CRMP2, CRMP5 inhibits tubulin polymerization and neurite outgrowth. Knockdown of CRMP5 expression by small interfering RNA confirms its inhibitory functions. CRMP5 forms a ternary complex with MAP2 and tubulin, the latter involving residues 475 522 of CRMP5, exposed at the molecule surface. Using different truncated CRMP5 constructs, we demonstrate that inhibition of neurite outgrowth by CRMP5 is mediated by tubulin binding. When both CRMP5 and CRMP2 are overexpressed, the inhibitory effect of CRMP5 abrogates neurite outgrowth promotion induced by CRMP2, suggesting that CRMP5 acts as a dominant signal. In cultured hippocampal neurons, CRMP5 shows no effect on axon growth, whereas it inhibits dendrite outgrowth and formation, at an early developmental stage, correlated with its strong expression in neurites. At later stages, when dendrites begin to extend, CRMP5 expression is absent. However, CRMP2 is constantly expressed. Overexpression of CRMP5 with CRMP2 inhibits CRMP2-induced outgrowth both on the axonal and dendritic levels. Deficiency of CRMP5 expression enhanced the CRMP2 effect. This antagonizing effect of CRMP5 is exerted through a tubulin-based mechanism. Thus, the CRMP5 binding to tubulin modulates CRMP2 regulation of neurite outgrowth and neuronal polarity during brain development. PMID- 20702695 TI - Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. AB - Fragile X syndrome (FXS) is an inherited neurologic disease caused by loss of fragile X mental retardation protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess activity of phosphoinositide 3 kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knock-out neurons, excess synaptic PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in FMRP-deficient non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110beta, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110beta translation, p110beta protein expression, and PI3K activity. In contrast, both p110beta protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knock-out. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization, and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS. PMID- 20702697 TI - Drosophila larvae establish appetitive olfactory memories via mushroom body neurons of embryonic origin. AB - Insect mushroom bodies are required for diverse behavioral functions, including odor learning and memory. Using the numerically simple olfactory pathway of the Drosophila melanogaster larva, we provide evidence that the formation of appetitive olfactory associations relies on embryonic-born intrinsic mushroom body neurons (Kenyon cells). The participation of larval-born Kenyon cells, i.e., neurons that become gradually integrated in the developing mushroom body during larval life, in this task is unlikely. These data provide important insights into how a small set of identified Kenyon cells can store and integrate olfactory information in a developing brain. To investigate possible functional subdivisions of the larval mushroom body, we anatomically disentangle its input and output neurons at the single-cell level. Based on this approach, we define 10 subdomains of the larval mushroom body that may be implicated in mediating specific interactions between the olfactory pathway, modulatory neurons, and neuronal output. PMID- 20702699 TI - The association of dynamin with synaptophysin regulates quantal size and duration of exocytotic events in chromaffin cells. AB - Although synaptophysin is one of the most abundant integral proteins of synaptic vesicle membranes, its contribution to neurotransmitter release remains unclear. One possibility is that through its association with dynamin it controls the fine tuning of transmitter release. To test this hypothesis, we took advantage of amperometric measurements of quantal catecholamine release from chromaffin cells. First, we showed that synaptophysin and dynamin interact in chromaffin granule rich fractions and that this interaction relies on the C terminal of synaptophysin. Experimental maneuvers that are predicted to disrupt the association between these two proteins, such as injection of antibodies against dynamin or synaptophysin, or peptides homologous to the C terminal of synaptophysin, increased the quantal size and duration of amperometric spikes. In contrast, the amperometric current that precedes the spike remained unchanged, indicating that synaptophysin/dynamin association does not regulate the initial fusion pore, but it appears to target a later step of exocytosis to control the amount of catecholamines released during a single vesicle fusion event. PMID- 20702698 TI - Intralaminar and interlaminar activity within the rodent superior colliculus visualized with voltage imaging. AB - The superior colliculus (SC) is a midbrain structure that plays a role in converting sensation into action. Most SC research focuses on either in vivo extracellular recordings from behaving monkeys or patch-clamp recordings from smaller mammals in vitro. However, the activity of neuronal circuits is necessary to generate behavior, and neither of these approaches measures the simultaneous activity of large populations of neurons that make up circuits. Here, we describe experiments in which we measured changes in membrane potential across the SC map using voltage imaging of the rat SC in vitro. Our results provide the first high temporal and spatial resolution images of activity within the SC. Electrical stimulation of the SC evoked a characteristic two-component optical response containing a short latency initial-spike and a longer latency after depolarization. Single-pulse stimulation in the superficial SC evoked a pattern of intralaminar and interlaminar spread that was distinct from the spread evoked by the same stimulus applied to the intermediate SC. Intermediate layer stimulation produced a more extensive and more ventrally located activation of the superficial layers than did stimulation in the superficial SC. Together, these results indicate the recruitment of dissimilar subpopulations of circuitry depending on the layer stimulated. Field potential recordings, pharmacological manipulations, and timing analyses indicate that the patterns of activity were physiologically relevant and largely synaptically driven. Therefore, voltage imaging is a powerful technique for the study of spatiotemporal dynamics of electrical signaling across neuronal populations, providing insight into neural circuits that underlie behavior. PMID- 20702700 TI - Temporally extended dopamine responses to perceptually demanding reward predictive stimuli. AB - Midbrain dopamine neurons respond to reward-predictive stimuli. In the natural environment reward-predictive stimuli are often perceptually complicated. Thus, to discriminate one stimulus from another, elaborate sensory processing is necessary. Given that previous studies have used simpler types of reward predictive stimuli, it has yet to be clear whether and, if so, how dopamine neurons obtain reward information from perceptually complicated stimuli. To investigate this, we recorded the activities of monkey dopamine neurons while they were performing discrimination between two coherent motion directions in random-dot motion stimuli. These coherent directions were paired with different magnitudes of reward. We found that dopamine neurons showed reward-predictive responses to random-dot motion stimuli. Moreover, dopamine neurons showed temporally extended activity correlated with changes in reward prediction (i.e., reward prediction error) from coarse to fine scales between initial motion detection and subsequent motion discrimination phases. Noticeably, dopamine reward-predictive responses became differential in a later phase than previously reported. This response pattern was consistent with the time course of processing required for the estimation of expected reward value that parallels the motion direction discrimination processing. The results demonstrate that dopamine neurons are able to reflect the reward value of perceptually complicated stimuli, and suggest that dopamine neurons use the moment-to-moment reward prediction associated with environmental stimuli to compute a reward prediction error. PMID- 20702701 TI - Autophagy-dependent rhodopsin degradation prevents retinal degeneration in Drosophila. AB - Recent studies have demonstrated protective roles for autophagy in various neurodegenerative disorders, including the polyglutamine diseases; however, the role of autophagy in retinal degeneration has remained unclear. Accumulation of activated rhodopsin in some Drosophila mutants leads to retinal degeneration, and although it is known that activated rhodopsin is degraded in endosomal pathways in normal photoreceptor cells, the contribution of autophagy to rhodopsin regulation has remained elusive. This study reveals that activated rhodopsin is degraded by autophagy in collaboration with endosomal pathways to prevent retinal degeneration. Light-dependent retinal degeneration in the Drosophila visual system is caused by the knockdown or mutation of autophagy-essential components, such as autophagy-related protein 7 and 8 (atg-7/atg-8), or genes essential for PE (phosphatidylethanolamine) biogenesis and autophagosome formation, including Phosphatidylserine decarboxylase (Psd) and CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase (Ept). The knockdown of atg-7/8 or Psd/Ept produced an increase in the amount of rhodopsin localized to Rab7-positive late endosomes. This rhodopsin accumulation, followed by retinal degeneration, was suppressed by overexpression of Rab7, which accelerated the endosomal degradation pathway. These results indicate a degree of cross talk between the autophagic and endosomal/lysosomal pathways. Importantly, a reduction in rhodopsin levels rescued Psd knockdown-induced retinal degeneration. Additionally, the Psd knockdown-induced retinal degeneration phenotype was enhanced by Ppt1 inactivation, which causes infantile neuronal ceroid lipofuscinosis, implying that autophagy plays a significant role in its pathogenesis. Collectively, the current data reveal that autophagy suppresses light-dependent retinal degeneration in collaboration with the endosomal degradation pathway and that rhodopsin is a key substrate for autophagic degradation in this context. PMID- 20702702 TI - Why variability facilitates spinal learning. AB - Spinal Wistar Hannover rats trained to step bipedally on a treadmill with manual assistance of the hindlimbs have been shown to improve their stepping ability. Given the improvement in motor performance with practice and the ability of the spinal cord circuitry to learn to step more effectively when the mode of training allows variability, we examined why this intrinsic variability is an important factor. Intramuscular EMG electrodes were implanted to monitor and compare the patterns of activation of flexor (tibialis anterior) and extensor (soleus) muscles associated with a fixed-trajectory and assist-as-needed (AAN) step training paradigms in rats after a complete midthoracic (T8-T9) spinal cord transection. Both methods involved a robotic arm attached to each ankle of the rat to provide guidance during stepping. The fixed trajectory allowed little variance between steps, and the AAN provided guidance only when the ankle deviated a specified distance from the programmed trajectory. We hypothesized that an AAN paradigm would impose fewer disruptions of the control strategies intrinsic to the spinal locomotor circuitry compared with a fixed trajectory. Intrathecal injections of quipazine were given to each rat to facilitate stepping. Analysis confirmed that there were more corrections within a fixed trajectory step cycle and consequently there was less coactivation of agonist and antagonist muscles during the AAN paradigm. These data suggest that some critical level of variation in the specific circuitry activated and the resulting kinematics reflect a fundamental feature of the neural control mechanisms even in a highly repetitive motor task. PMID- 20702703 TI - The role of the BDNF Val66Met polymorphism for the synchronization of error specific neural networks. AB - Behavioral adaptation depends on the recognition of response errors and processing of this error-information. Error processing is a specific cognitive function crucial for behavioral adaptation. Neurophysiologically, these processes are reflected by an event-related potential (ERP), the error negativity (Ne/ERN). Even though synchronization processes are important in information processing, its role and neurobiological foundation in behavioral adaptation are not understood. The brain-derived neurotrophic factor (BDNF) strongly modulates the establishment of neural connectivity that determines neural network dynamics and synchronization properties. Therefore altered synchronization processes may constitute a mechanism via which BDNF affects processes of error-induced behavioral adaptation. We investigate how variants of the BDNF gene regulate EEG synchronization processes underlying error processing. Subjects (n=65) were genotyped for the functional BDNF Val66Met polymorphism (rs6265). We show that Val/Val genotype is associated with stronger error-specific phase-locking, compared with Met allele carriers. Posterror behavioral adaptation seems to be strongly dependent on these phase-locking processes and efficacy of EEG-phase locking-behavioral coupling was genotype dependent. After correct responses, neurophysiological processes were not modulated by the polymorphism, underlining that BDNF becomes especially necessary in situations requiring behavioral adaptation. The results suggest that alterations in neural synchronization processes modulated by the genetic variants of BDNF Val66Met may be the mechanism by which cognitive functions are affected. PMID- 20702704 TI - Network bistability mediates spontaneous transitions between normal and pathological brain states. AB - Little is known about how cortical networks support the emergence of remarkably different activity patterns. Physiological activity interspersed with epochs of pathological hyperactivity in the epileptic brain represents a clinically relevant yet poorly understood case of such rich dynamic repertoire. Using a realistic computational model, we demonstrate that physiological sparse and pathological tonic-clonic activity may coexist in the same cortical network for identical afferent input level. Transient perturbations in the afferent input were sufficient to switch the network between these two stable states. The effectiveness of the potassium regulatory apparatus determined the stability of the physiological state and the threshold for seizure initiation. Our findings contrast with the common notions of (1) pathological brain activity representing dynamic instabilities and (2) necessary adjustments of experimental conditions to elicit different network states. Rather, we propose that the rich dynamic repertoire of cortical networks may be based on multistabilities intrinsic to the network. PMID- 20702705 TI - Neural mechanisms of belief inference during cooperative games. AB - Humans have the arguably unique ability to understand the mental representations of others. For success in both competitive and cooperative interactions, however, this ability must be extended to include representations of others' belief about our intentions, their model about our belief about their intentions, and so on. We developed a "stag hunt" game in which human subjects interacted with a computerized agent using different degrees of sophistication (recursive inferences) and applied an ecologically valid computational model of dynamic belief inference. We show that rostral medial prefrontal (paracingulate) cortex, a brain region consistently identified in psychological tasks requiring mentalizing, has a specific role in encoding the uncertainty of inference about the other's strategy. In contrast, dorsolateral prefrontal cortex encodes the depth of recursion of the strategy being used, an index of executive sophistication. These findings reveal putative computational representations within prefrontal cortex regions, supporting the maintenance of cooperation in complex social decision making. PMID- 20702707 TI - Nicotine blocks the hyperpolarization-activated current Ih and severely impairs the oscillatory behavior of oriens-lacunosum moleculare interneurons. AB - In the brain, high cognitive functions are encoded by coherent network oscillations. Key players are inhibitory interneurons that, by releasing GABA into principal cells, pace targeted cells. Among these, oriens-lacunosum moleculare (O-LM) interneurons that provide a theta frequency patterned output to distal dendrites of pyramidal cells are endowed with HCN channels responsible for the slowly activating inwardly rectifying Ih current and their pacemaking activity. Here we show that, in transgenic mice expressing EGFP (enhanced green fluorescent protein) in a subset of stratum oriens somatostatin-containing interneurons that mostly comprise O-LM cells, nicotine, the active component of tobacco, reduced Ih and the oscillatory behavior of O-LM interneurons. In cells hyperpolarized at -90 mV, nicotine suppressed the theta resonance in the same way as ZD 7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), a selective blocker of Ih. Nicotine blocked Ih in a concentration-dependent way with an EC50 of 62 nm. Similar effects were produced by epibatidine, a structural analog of nicotine. The effects of nicotine and epibatidine were independent on nicotinic ACh receptor (nAChR) activation because they persisted in the presence of nAChR antagonists. Furthermore, nicotine slowed down the interspike depolarizing slope and the firing rate, thus severely disrupting the oscillatory behavior of O-LM cells. Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers. PMID- 20702706 TI - Monoamine oxidases regulate telencephalic neural progenitors in late embryonic and early postnatal development. AB - Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain. PMID- 20702708 TI - NCAM-induced neurite outgrowth depends on binding of calmodulin to NCAM and on nuclear import of NCAM and fak fragments. AB - The neural cell adhesion molecule NCAM plays important functional roles not only during nervous system development, but also in the adult after injury and in synaptic plasticity. Homophilic binding of NCAM triggers intracellular signaling events resulting in cellular responses such as neurite outgrowth that require NCAM palmitoylation-dependent raft localization and activation of the nonreceptor tyrosine kinases fyn and fak. In this study, we show that stimulation of NCAM by a function-triggering NCAM antibody results in proteolytic processing of NCAM and fak. The C-terminal fragment of NCAM, consisting of the intracellular domain, the transmembrane domain, and a stub of the extracellular domain, and the N-terminal fragment of fak are imported into the nucleus. NCAM-stimulated fak activation, generation, and nuclear import of NCAM and fak fragments as well as neurite outgrowth are abolished by mutation of the calmodulin binding motif in the intracellular domain of NCAM that is responsible for the calcium-dependent binding of calmodulin to NCAM. This mutation interferes neither with NCAM cell surface expression, palmitoylation, and raft localization nor with fyn activation. The way by which the transmembrane NCAM fragment reaches the nucleus in a calmodulin- and calcium-dependent manner is by endocytotic transport via the endoplasmic reticulum and the cytoplasm. The generation and nuclear import of NCAM and phosphorylated fak fragments resulting from NCAM stimulation may represent a signal pathway activating cellular responses in parallel or in association with classical kinase- and phosphorylation-dependent signaling cascades. PMID- 20702709 TI - Appetitive and aversive goal values are encoded in the medial orbitofrontal cortex at the time of decision making. AB - An essential feature of choice is the assignment of goal values (GVs) to the different options under consideration at the time of decision making. This computation is done when choosing among appetitive and aversive items. Several groups have studied the location of GV computations for appetitive stimuli, but the problem of valuation in aversive contexts at the time of decision making has been ignored. Thus, although dissociations between appetitive and aversive components of value signals have been shown in other domains such as anticipatory and outcome values, it is not known whether appetitive and aversive GVs are computed in similar brain regions or in separate ones. We investigated this question using two different functional magnetic resonance imaging studies while human subjects placed real bids in an economic auction for the right to eat/avoid eating liked/disliked foods. We found that activity in a common area of the medial orbitofrontal cortex and the dorsolateral prefrontal cortex correlated with both appetitive and aversive GVs. These findings suggest that these regions might form part of a common network. PMID- 20702710 TI - The membrane potential waveform of bursting pacemaker neurons is a predictor of their preferred frequency and the network cycle frequency. AB - Many oscillatory networks involve neurons that exhibit intrinsic rhythmicity but possess a large variety of voltage-gated currents that interact in a complex fashion, making it difficult to determine which factors control frequency. Yet these neurons often have preferred (resonance) frequencies that can be close to the network frequency. Because the preferred frequency results from the dynamics of ionic currents, it can be assumed to depend on parameters that determine the neuron's oscillatory waveform shape. The pyloric network frequency in the crab Cancer borealis is correlated with the preferred frequency of its bursting pacemaker neurons anterior burster and pyloric dilator (PD). We measured the preferred frequency of the PD neuron in voltage clamp, which allows control of the oscillation voltage range and waveforms (sine waves and realistic oscillation waveforms), and showed that (1) the preferred frequency depends on the voltage range of the oscillating voltage waveform; (2) the slope of the waveform near its peak has a strongly negative correlation with the preferred frequency; and (3) correlations between parameters of the PD neuron oscillation waveform and its preferred frequency can be used to predict shifts in the network frequency. As predicted by these results, dynamic clamp shifts of the upper or lower voltage limits of the PD neuron waveform during ongoing oscillations changed the network frequency, consistent with the predictions from the preferred frequency. These results show that the voltage waveform of oscillatory neurons can be predictive of their preferred frequency and thus the network oscillation frequency. PMID- 20702711 TI - Mkp1 is a c-Jun target gene that antagonizes JNK-dependent apoptosis in sympathetic neurons. AB - Developing sympathetic neurons depend on NGF for survival. When sympathetic neurons are deprived of NGF in vitro, a well documented series of events, including c-Jun N-terminal kinase (JNK) pathway activation, release of cytochrome c from the mitochondria, and caspase activation, culminates in the death of the neuron by apoptosis within 24-48 h. This process requires de novo gene expression, suggesting that increased expression of specific genes activates the cell death program. Using rat gene microarrays, we found that NGF withdrawal induces the expression of many genes, including mkp1, which encodes a MAPK phosphatase that can dephosphorylate JNKs. The increase in mkp1 mRNA level requires the MLK-JNK-c-Jun pathway, and we show that Mkp1 is an important regulator of JNK-dependent apoptosis in sympathetic neurons. In microinjection experiments, Mkp1 overexpression can inhibit JNK-mediated phosphorylation of c Jun and protect sympathetic neurons from apoptosis, while Mkp1 knockdown accelerates NGF withdrawal-induced death. Accordingly, the number of superior cervical ganglion (SCG) neurons is reduced in mkp1-/- mice at P1 during the period of developmental sympathetic neuron death. We also show that c-Jun and ATF2 bind to two conserved ATF binding sites in the mkp1 promoter in vitro and in chromatin. Both of these ATF sites contribute to basal promoter activity and are required for mkp1 promoter induction after NGF withdrawal. These results demonstrate that Mkp1 is part of a negative feedback loop induced by the MLK-JNK c-Jun signaling pathway that modulates JNK activity and the rate of neuronal death in rat sympathetic neurons following NGF withdrawal. PMID- 20702712 TI - The Gata3 transcription factor is required for the survival of embryonic and adult sympathetic neurons. AB - The transcription factor Gata3 is essential for the development of sympathetic neurons and adrenal chromaffin cells. As Gata3 expression is maintained up to the adult stage, we addressed its function in differentiated sympathoadrenal cells at embryonic and adult stages by conditional Gata3 elimination. Inactivation of Gata3 in embryonic DBH-expressing neurons elicits a strong reduction in neuron numbers due to apoptotic cell death and reduced proliferation. No selective effect on noradrenergic gene expression (TH and DBH) was observed. Interestingly, Gata3 elimination in DBH-expressing neurons of adult animals also results in a virtually complete loss of sympathetic neurons. In the Gata3-deficient population, the expression of anti-apoptotic genes (Bcl-2, Bcl-xL, and NFkappaB) is diminished, whereas the expression of pro-apoptotic genes (Bik, Bok, and Bmf) was increased. The expression of noradrenergic genes (TH and DBH) is not affected. These results demonstrate that Gata3 is continuously required for maintaining survival but not differentiation in the sympathetic neuron lineage up to mature neurons of adult animals. PMID- 20702713 TI - Cholesterol defect is marked across multiple rodent models of Huntington's disease and is manifest in astrocytes. AB - Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis. In postnatal life, the cholesterol-dependent activities of neurons mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles. Our data show that mRNA levels of cholesterol biosynthesis and efflux genes are severely reduced in primary HD astrocytes, along with impaired cellular production and secretion of ApoE. Consistently, in CSF of HD mice, ApoE is mostly associated with smaller lipoproteins, indicating reduced cholesterol transport on ApoE-containing lipoproteins circulating in the HD brain. These findings indicate that cholesterol defect is robustly marked in HD animals, implying that strategies aimed at selectively modulating brain cholesterol metabolism might be of therapeutic significance. PMID- 20702714 TI - Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. AB - Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP 43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity. PMID- 20702716 TI - Sensory input drives multiple intracellular information streams in somatosensory cortex. AB - Stable perception arises from the interaction between sensory inputs and internal activity fluctuations in cortex. Here we analyzed how different types of activity contribute to cortical sensory processing at the cellular scale. We performed whole-cell recordings in the barrel cortex of anesthetized rats while applying ongoing whisker stimulation and measured the information conveyed about the time varying stimulus by different types of input (membrane potential) and output (spiking) signals. We found that substantial, comparable amounts of incoming information are carried by two types of membrane potential signal: slow, large (up-down state) fluctuations, and faster (>20 Hz), smaller-amplitude synaptic activity. Both types of activity fluctuation are therefore significantly driven by the stimulus on an ongoing basis. Each stream conveys essentially independent information. Output (spiking) information is contained in spike timing not just relative to the stimulus but also relative to membrane potential fluctuations. Information transfer is favored in up states relative to down states. Thus, slow, ongoing activity fluctuations and finer-scale synaptic activity generate multiple channels for incoming and outgoing information within barrel cortex neurons during ongoing stimulation. PMID- 20702715 TI - Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds. AB - To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that inflammatory pain was attenuated or abolished. Inflammatory mediators failed to enhance excitability of Nav1.8+ sensory neurons from null mutant mice. Acute noxious input into the dorsal horn of the spinal cord was apparently normal, but the increased input associated with inflammatory pain measured using c-Fos staining was diminished. Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8+ sensory neurons that may regulate nociceptor gene expression. PMID- 20702717 TI - Leading tip drives soma translocation via forward F-actin flow during neuronal migration. AB - Neuronal migration involves coordinated extension of the leading process and translocation of the soma, but the relative contribution of different subcellular regions, including the leading process and cell rear, in driving soma translocation remains unclear. By local manipulation of cytoskeletal components in restricted regions of cultured neurons, we examined the molecular machinery underlying the generation of traction force for soma translocation during neuronal migration. In actively migrating cerebellar granule cells in culture, a growth cone (GC)-like structure at the leading tip exhibits high dynamics, and severing the tip or disrupting its dynamics suppressed soma translocation within minutes. Soma translocation was also suppressed by local disruption of F-actin along the leading process but not at the soma, whereas disrupting microtubules along the leading process or at the soma accelerated soma translocation. Fluorescent speckle microscopy using GFP-alpha-actinin showed that a forward F actin flow along the leading process correlated with and was required for soma translocation, and such F-actin flow depended on myosin II activity. In migrating neurons, myosin II activity was high at the leading tip but low at the soma, and increasing or decreasing this front-to-rear difference accelerated or impeded soma advance. Thus, the tip of the leading process actively pulls the soma forward during neuronal migration through a myosin II-dependent forward F-actin flow along the leading process. PMID- 20702719 TI - Local neural processing and the generation of dynamic motor commands within the saccadic premotor network. AB - The ability to accurately control movement requires the computation of a precise motor command. However, the computations that take place within premotor pathways to determine the dynamics of movements are not understood. Here we studied the local processing that generates dynamic motor commands by simultaneously recording spikes and local field potentials (LFPs) in the network that commands saccades. We first compared the information encoded by LFPs and spikes recorded from individual premotor and motoneurons (saccadic burst neurons, omnipause neurons, and motoneurons) in monkeys. LFP responses consistent with net depolarizations occurred in association with bursts of spiking activity when saccades were made in a neuron's preferred direction. In contrast, when saccades were made in a neuron's nonpreferred direction, neurons ceased spiking and the associated LFP responses were consistent with net hyperpolarizations. Surprisingly, hyperpolarizing and depolarizing LFPs encoded movement dynamics with equal robustness and accuracy. Second, we compared spiking responses at one hierarchical level of processing to LFPs at the next stage. Latencies and spike triggered averages of LFP responses were consistent with each neuron's place within this circuit. LFPs reflected relatively local events (<500 microm) and encoded important features not available from the spiking train (i.e., hyperpolarizing response). Notably, quantification of their time-varying profiles revealed that a precise balance of depolarization and hyperpolarization underlies the production of precise saccadic eye movement commands at both motor and premotor levels. Overall, simultaneous recordings of LFPs and spiking responses provides an effective means for evaluating the local computations that take place to produce accurate motor commands. PMID- 20702718 TI - Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration. AB - After CNS injuries, axon growth inhibitors from the myelin and the scar tissue at the injury site are considered major impediments to axon regeneration. The presence of several classes of inhibitors with multiple members in each class suggests functional redundancy in growth inhibition. To test redundancy within the myelin inhibitory pathway, we analyzed raphe spinal serotonergic (5-HT) axon regeneration in mice deficient in two major myelin inhibitors, Nogo and MAG, and their common receptor NgR1 (or NgR). After a complete transection spinal cord injury, there was no significant enhancement of 5-HT axon regeneration beyond the injury site in either Nogo/MAG/NgR1 triple mutants or NgR1 single mutants. Occasional, genotype-independent traversal of 5-HT axons through GFAP-positive tissue bridges at the injury site implicates GFAP-negative lesion areas as especially inhibitory to 5-HT axons. To assess the contribution of class 3 Semaphorins that are expressed by GFAP-negative meningeal fibroblasts at the injury site, we analyzed mice deficient in PlexinA3 and PlexinA4, two key receptors for class 3 Semaphorins, with or without additional NgR1 deletion. No enhanced regeneration of 5-HT or corticospinal axons was detected in PlexinA3/PlexinA4 double mutants or PlexinA3/PlexinA4/NgR1 triple mutants through a complete transection injury. In contrast with previous reports, these data demonstrate that attenuating myelin or Semaphorin-mediated inhibition of axon growth is insufficient to promote 5-HT axon regeneration and further indicate that even attenuating both classes of inhibitory influences is insufficient to promote regeneration of injured axons through a complete transection spinal cord injury. PMID- 20702720 TI - Chronic electrical stimulation of the intact corticospinal system after unilateral injury restores skilled locomotor control and promotes spinal axon outgrowth. AB - Injury to the brain or spinal cord usually preserves some corticospinal (CS) connections. These residual circuits sprout spontaneously and in response to activity-based treatments. We hypothesized that augmenting activity in spared CS circuits would restore the skilled motor control lost after injury and augment outgrowth of CS terminations in the spinal cord. After selective injury of one half of the CS tract (CST) in the rat, we applied 10 d of electrical stimulation to the forelimb area of motor cortex of the spared half and tested motor performance for 30 d. Rats with injury and CST stimulation showed substantial improvements in skilled paw placement while walking over a horizontal ladder. By the end of the testing period, the walking errors of the previously impaired forelimb in rats with injury and stimulation returned to baseline, while the errors remained elevated in rats with injury only. Whereas the time to perform the task returned to normal in all animals, the pattern of errors returned to normal only in the stimulated group. Electrical stimulation also caused robust outgrowth of CST axon terminations in the ipsilateral spinal cord, the side of impairment, compared with rats with injury only. The outgrowth was directed to the normal gray matter territory of ipsilateral CST axon terminations. Thus, stimulation of spared CS circuits induced substantial axon outgrowth to the largely denervated side of the spinal cord and restored normal motor control in the previously impaired limbs. PMID- 20702721 TI - Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons. AB - B-type natriuretic peptide (BNP) has been known to be secreted from cardiac myocytes and activate its receptor, natriuretic peptide receptor-A (NPR-A), to reduce ventricular fibrosis. However, the function of BNP/NPR-A pathway in the somatic sensory system has been unknown. In the present study, we report a novel function of BNP in pain modulation. Using microarray and immunoblot analyses, we found that BNP and NPR-A were expressed in the dorsal root ganglion (DRG) of rats and upregulated after intraplantar injection of complete Freund's adjuvant (CFA). Immunohistochemistry showed that BNP was expressed in calcitonin gene-related peptide (CGRP)-containing small neurons and IB4 (isolectin B4)-positive neurons, whereas NPR-A was present in CGRP-containing neurons. Application of BNP reduced the firing frequency of small DRG neurons in the presence of glutamate through opening large-conductance Ca2+-activated K+ channels (BKCa channels). Furthermore, intrathecal injection of BNP yielded inhibitory effects on formalin induced flinching behavior and CFA-induced thermal hyperalgesia in rats. Blockade of BNP signaling by BNP antibodies or cGMP-dependent protein kinase (PKG) inhibitor KT5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1 oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine 10-carboxylic acid methyl ester] impaired the recovery from CFA-induced thermal hyperalgesia. Thus, BNP negatively regulates nociceptive transmission through presynaptic receptor NPR-A, and activation of the BNP/NPR-A/PKG/BKCa channel pathway in nociceptive afferent neurons could be a potential strategy for inflammatory pain therapy. PMID- 20702722 TI - Synaptic activity and activity-dependent competition regulates axon arbor maturation, growth arrest, and territory in the retinotectal projection. AB - In the retinotectal projection, synapses guide retinal ganglion cell (RGC) axon arbor growth by promoting branch formation and by selectively stabilizing branches. To ask whether presynaptic function is required for this dual role of synapses, we have suppressed presynaptic function in single RGCs using targeted expression of tetanus toxin light-chain fused to enhanced green fluorescent protein (TeNT-Lc:EGFP). Time-lapse imaging of singly silenced axons as they arborize in the tectum of zebrafish larvae shows that presynaptic function is not required for stabilizing branches or for generating an arbor of appropriate complexity. However, synaptic activity does regulate two distinct aspects of arbor development. First, single silenced axons fail to arrest formation of highly dynamic but short-lived filopodia that are a feature of immature axons. Second, single silenced axons fail to arrest growth of established branches and so occupy significantly larger territories in the tectum than active axons. However, if activity-suppressed axons had neighbors that were also silent, axonal arbors appeared normal in size. A similar reversal in phenotype was observed when single TeNT-Lc:EGFP axons are grown in the presence of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10 imine maleate]. Although expansion of arbor territory is prevented when neighbors are silent, formation of transient filopodia is not. These results suggest that synaptic activity by itself regulates filopodia formation regardless of activity in neighboring cells but that the ability to arrest growth and focusing of axonal arbors in the target is an activity-dependent, competitive process. PMID- 20702723 TI - The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor. AB - The chemokine CXCL1 is elevated in plasma and ascites from patients with ovarian cancer. We have previously shown that CXCL1 is a marker of phosphatidylinositol 3 kinase signalling in epithelial ovarian cancer (EOC) cell lines, a pathway that is commonly activated in ovarian tumours. To investigate whether CXCL1 also has functional significance in ovarian cancer, this chemokine was either down regulated using siRNAs or overexpressed by transfection of CXCL1 into the EOC cell lines SKOV3 and OVCAR-3 and proliferation assessed over 7 days. Overexpression of CXCL1 increased proliferation of ovarian cancer cells over 7 days, while down-regulation was inhibitory. Treatment of cells with recombinant CXCL1 induced epidermal growth factor receptor (EGFR) phosphorylation at Y1068, indicating crosstalk between the CXCL1 G-protein-coupled receptor CXCR2 and the EGFR. CXCL1-induced proliferation was also decreased by inhibition of EGFR kinase activity and was dependent on extracellular matrix metalloproteinase-mediated release of heparin-binding EGF (HB-EGF). Involvement of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signalling was also evident since inhibition of both Ras and MEK activity decreased CXCL1 induced proliferation. CXCL1-induced ERK1/2 phosphorylation was inhibited by the MEK1 inhibitor PD98059; however, EGFR phosphorylation was unaffected, indicating that CXCL1 activation of MAPK signalling is downstream of the EGFR. Taken together, these data show that CXCL1 functions through CXCR2 to transactivate the EGFR by proteolytic cleavage of HB-EGF, leading to activation of MAPK signalling and increased proliferation of EOC cells. PMID- 20702725 TI - Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. AB - As incidence data on gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have so far only been retrospectively obtained and based on inhomogeneous material, we conducted a prospective study in Austria collecting all newly diagnosed GEP-NETs during 1 year. Using the current WHO classification, the tumor, nodes, metastases (TNM) staging and Ki67 grading and the standard diagnostic procedure proposed by the European Neuroendocrine Tumor Society (ENETS), GEP-NETs from 285 patients (male: 148; female: 137) were recorded. The annual incidence rates were 2.51 per 100,000 inhabitants for men, 2.36 per 100,000 for women. The stomach (23%) was the main site, followed by appendix (21%), small intestine (15%) and rectum (14%). Patients with appendiceal tumours were significantly younger than patients with tumours in any other site. About 46.0% were classified as benign, 15.4% as uncertain, 31.9% as well differentiated malignant and 6.7% as poorly differentiated malignant. Patients with benign or uncertain tumours were significantly younger than patients with malignant tumours. Among the malignant tumours of the digestive tract, 1.49% arose from neuroendocrine cells. For malignant gastrointestinal NETs, the incidence was 0.80 per 100,000: 40.9% were ENETS stage I, 23.8% stage II, 11.6% stage III and 23.8% stage IV. The majority (59.7%) were grade 1, 31.2% grade 2 and 9.1% grade 3. NETs of the digestive tract are more common than previously reported; the majority show benign behaviour, are located in the stomach and are well differentiated. G3 tumours are very rare. PMID- 20702724 TI - SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling. AB - Prediction of malignant behaviour of pheochromocytomas/sympathetic paragangliomas (PCCs/PGLs) is very difficult if not impossible on a histopathological basis. In a familial setting, it is well known that succinate dehydrogenase subunit B (SDHB)-associated PCC/PGL very often metastasise. Recently, absence of SDHB expression as measured through immunohistochemistry was shown to be an excellent indicator of the presence of an SDH germline mutation in PCC/PGL. SDHB loss is believed to lead to tumour formation by activation of hypoxia signals. To clarify the potential use of SDHB immunohistochemistry as a marker of malignancy in PCC/PGL and its association with classic hypoxia signalling we examined SDHB, hypoxia inducible factor-1alpha (Hif-1alpha) and its targets CA-9 and GLUT-1 expression on protein level using immunohistochemistry on a tissue micro array on a series of familial and sporadic tumours of 115 patients. Survival data was available for 66 patients. SDHB protein expression was lost in the tumour tissue of 12 of 99 patients. Of those 12 patients, 5 had an SDHB germline mutation, in 4 patients no germline mutation was detected and mutational status remained unknown in parts in 3 patients. Loss of SDHB expression was not associated with increased classic hypoxia signalling as detected by Hif-1alpha, CA-9 or GLUT-1 staining. Loss of SDHB expression was associated with an adverse outcome. The lack of correlation of SDHB loss with classic hypoxia signals argues against the current hypoxia hypothesis in malignant PCC/PGL. We suggest SDHB protein loss as a marker of adverse outcome both in sporadic and in familial PCC/PGL. PMID- 20702726 TI - The seed composition of Arabidopsis mutants for the group 3 sulfate transporters indicates a role in sulfate translocation within developing seeds. AB - Sulfate is required for the synthesis of sulfur-containing amino acids and numerous other compounds essential for the plant life cycle. The delivery of sulfate to seeds and its translocation between seed tissues is likely to require specific transporters. In Arabidopsis (Arabidopsis thaliana), the group 3 plasmalemma-predicted sulfate transporters (SULTR3) comprise five genes, all expressed in developing seeds, especially in the tissues surrounding the embryo. Here, we show that sulfur supply to seeds is unaffected by T-DNA insertions in the SULTR3 genes. However, remarkably, an increased accumulation of sulfate was found in mature seeds of four mutants out of five. In these mutant seeds, the ratio of sulfur in sulfate form versus total sulfur was significantly increased, accompanied by a reduction in free cysteine content, which varied depending on the gene inactivated. These results demonstrate a reduced capacity of the mutant seeds to metabolize sulfate and suggest that these transporters may be involved in sulfate translocation between seed compartments. This was further supported by sulfate measurements of the envelopes separated from the embryo of the sultr3;2 mutant seeds, which showed differences in sulfate partitioning compared with the wild type. A dissection of the seed proteome of the sultr3 mutants revealed protein changes characteristic of a sulfur-stress response, supporting a role for these transporters in providing sulfate to the embryo. The mutants were affected in 12S globulin accumulation, demonstrating the importance of intraseed sulfate transport for the synthesis and maturation of embryo proteins. Metabolic adjustments were also revealed, some of which could release sulfur from glucosinolates. PMID- 20702727 TI - Existence of CD8alpha-like dendritic cells with a conserved functional specialization and a common molecular signature in distant mammalian species. AB - The mouse lymphoid organ-resident CD8alpha(+) dendritic cell (DC) subset is specialized in Ag presentation to CD8(+) T cells. Recent evidence shows that mouse nonlymphoid tissue CD103(+) DCs and human blood DC Ag 3(+) DCs share similarities with CD8alpha(+) DCs. We address here whether the organization of DC subsets is conserved across mammals in terms of gene expression signatures, phenotypic characteristics, and functional specialization, independently of the tissue of origin. We study the DC subsets that migrate from the skin in the ovine species that, like all domestic animals, belongs to the Laurasiatheria, a distinct phylogenetic clade from the supraprimates (human/mouse). We demonstrate that the minor sheep CD26(+) skin lymph DC subset shares significant transcriptomic similarities with mouse CD8alpha(+) and human blood DC Ag 3(+) DCs. This allowed the identification of a common set of phenotypic characteristics for CD8alpha-like DCs in the three mammalian species (i.e., SIRP(lo), CADM1(hi), CLEC9A(hi), CD205(hi), XCR1(hi)). Compared to CD26(-) DCs, the sheep CD26(+) DCs show 1) potent stimulation of allogeneic naive CD8(+) T cells with high selective induction of the Ifngamma and Il22 genes; 2) dominant efficacy in activating specific CD8(+) T cells against exogenous soluble Ag; and 3) selective expression of functional pathways associated with high capacity for Ag cross-presentation. Our results unravel a unifying definition of the CD8alpha(+)-like DCs across mammalian species and identify molecular candidates that could be used for the design of vaccines applying to mammals in general. PMID- 20702728 TI - Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity. AB - Less developed countries have a low incidence of immunological diseases like inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections in their populations. In the Rag IL-10(-/-) T cell transfer model of colitis, Heligmosomoides polygyrus, an intestinal helminth, prevents and reverses intestinal inflammation. This model of colitis was used to explore the importance of innate immunity in H. polygyrus protection from IBD. Rag mice briefly exposed to H. polygyrus before reconstitution with IL-10(-/-) colitogenic T cells are protected from colitis. Exposure to H. polygyrus before introduction of IL-10(-/-) and OT2 T cells reduced the capacity of the intestinal mucosa to make IFN-gamma and IL-17 after either anti-CD3 mAb or OVA stimulation. This depressed cytokine response was evident even in the absence of colitis, suggesting that the downmodulation in proinflammatory cytokine secretion was not just secondary to improvement in intestinal inflammation. Following H. polygyrus infection, dendritic cells (DCs) from the lamina propria of Rag mice displayed decreased expression of CD80 and CD86, and heightened expression of plasmacytoid dendritic cell Ag-1 and CD40. They were also less responsive to lamina proprias, producing less IL-12p40 and IL-10. Also diminished was their capacity to present OVA to OT2 T cells. These experiments infer that H. polygyrus does not require direct interactions with T or B cells to render animals resistant to colitis. DCs have an important role in driving both murine and human IBD. Data suggest that phenotypic alternations in mucosal DC function are part of the regulatory process. PMID- 20702729 TI - Abnormal immune complex processing and spontaneous glomerulonephritis in complement factor H-deficient mice with human complement receptor 1 on erythrocytes. AB - Complement receptor 1 (CR1) on human erythrocytes (Es) and complement factor H (CFH) on rodent platelets perform immune adherence, which is a function that allows the processing of immune complexes (ICs) bearing C3 by the mononuclear phagocyte system. Similar immune adherence occurs in the glomerular podocyte by CR1 in humans and CFH in rodents. As a model for human IC processing, we studied transgenic mice lacking CFH systemically but with human CR1 on Es. These CR1(hu)Tg/CFH(-/-) mice spontaneously developed proliferative glomerulonephritis, which was accelerated in a chronic serum sickness model by active immunization with heterologous apoferritin. ICs containing Ag, IgG and C3 bound to Es in CR1(hu)Tg/CFH(-/-) mice. In this setting, there was increased IC deposition in glomeruli, attributable to the presence of CR1 on Es, together with the absence of CFH on platelets and podocytes. In the absence of plasma CFH, the accumulated ICs activated complement, which led to spontaneous and chronic serum sickness induced proliferative glomerulonephritis. These findings illustrate the complexities of complement-dependent IC processing by blood cells and in the glomerulus, and the importance of CFH as a plasma complement regulator. PMID- 20702730 TI - Emergence of simian immunodeficiency virus-specific cytotoxic CD4+ T cells and increased humoral responses correlate with control of rebounding viremia in CD8 depleted macaques infected with Rev-independent live-attenuated simian immunodeficiency virus. AB - Indian rhesus macaques infected with the Rev-independent live-attenuated SIVmac239 strains control viremia to undetectable levels, have persistent but low cellular and humoral anti-SIV responses, and show no signs of immune deficiency. To analyze the immune mechanisms responsible for viral control, five macaques infected at day 1 after birth were subjected to CD8(+) cell depletion at 6.7 y postinfection. This resulted in viremia increases to 3.7-5.5 log(10) RNA copies, supporting a role of CD8-mediated responses in the control of viral replication. The rebounding viremia was rapidly controlled to levels below the threshold of detection, and occurred in the absence of SIV-specific CD8(+) T cells and significant CD8(+) T cell recovery in four of the five animals, suggesting that other mechanisms are involved in the immunological control of viremia. Monitoring immune responses at the time of viral control demonstrated a burst of circulating SIV-specific CD4(+) T cells characterized as CD45RA(-)CD28(+)CD95(+)CCR7(-) and also granzyme B(+), suggesting cytotoxic ability. Control of viremia was also concomitant with increases in humoral responses to Gag and Env, including a transient increase in neutralizing Abs against the neutralization-resistant SIVmac239 in four of five animals. These data demonstrate that a combination of cellular responses mediated by CD4(+) T cells and humoral responses was associated with the rapid control of the rebounding viremia in macaques infected by the Rev-independent live-attenuated SIV, even in the absence of measurable SIV specific CD8(+) T cells in the blood, emphasizing the importance of different components of the immune response for full control of SIV infection. PMID- 20702733 TI - CpG-oligodeoxynucleotide inhibits Smad-dependent bone morphogenetic protein signaling: effects on myeloma cell apoptosis and in vitro osteoblastogenesis. AB - The TLR9 agonist CpG-oligodeoxynucleotide (CpG-ODN) with a phosphorothioate backbone (PTO-CpG-ODN) is evaluated in clinical trials as a vaccine adjuvant or as treatment of cancers. Bone morphogenetic proteins (BMPs) regulate growth and differentiation of several cell types, and also induce apoptosis of cancer cells. Cross-talk between BMP- and TLR-signaling has been reported, and we aimed to investigate whether CpG-ODN influenced BMP-induced osteoblast differentiation or BMP-induced apoptosis of malignant plasma cells. We found that PTO-CpG-ODN inhibited BMP-2-induced osteoblast differentiation from human mesenchymal stem cells. Further, PTO-CpG-ODN counteracted BMP-2- and BMP-6-induced apoptosis of the human myeloma cell lines IH-1 and INA-6, respectively. In contrast, PTO-CpG ODN did not antagonize the antiproliferative effect of BMP-2 on hMSCs or IH-1 cells. Inhibition of Smad-signaling and p38 MAPK-signaling indicated that apoptosis of IH-1 cells is dependent on Smad-signaling downstream of BMP, whereas the antiproliferative effect of BMP-2 on IH-1 cells also involves p38 MAPK signaling. Together, the data suggested a specific inhibition by PTO-CpG-ODN on BMP-Smad-signaling. Supporting this we found that PTO-CpG-ODN inhibited BMP induced phosphorylation of receptor-Smads in human mesenchymal stem cells and myeloma cell lines. This effect appeared to be independent of TLR9 because GpC ODN and other ODNs with the ability to form multimeric structures inhibited Smad signaling as efficiently as PTO-CpG-ODNs, and because knockdown of TLR9 by small interfering RNA in INA-6 cells did not blunt the effect of PTO-CpG-ODN. In conclusion, our results demonstrate that PTO-CpG-ODN inhibits BMP-signaling, and thus might provoke unwanted TLR9-independent side effects in patients. PMID- 20702731 TI - Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. AB - Chromatin modifications, such as reversible histone acetylation, play a key role in the regulation of T cell development and function. However, the role of individual histone deacetylases (HDACs) in T cells is less well understood. In this article, we show by conditional gene targeting that T cell-specific loss of HDAC1 led to an increased inflammatory response in an in vivo allergic airway inflammation model. Mice with HDAC1-deficient T cells displayed an increase in all critical parameters in this Th2-type asthma model, such as eosinophil recruitment into the lung, mucus hypersecretion, parenchymal lung inflammation, and enhanced airway resistance. This correlated with enhanced Th2 cytokine production in HDAC1-deficient T cells isolated from diseased mice. In vitro polarized HDAC1-deficient Th2 cells showed a similar enhancement of IL-4 expression, which was evident already at day 3 of Th2 differentiation cultures and restricted to T cell subsets that underwent several rounds of cell divisions. HDAC1 was recruited to the Il4 gene locus in ex vivo isolated nonstimulated CD4(+) T cells, indicating a direct control of the Il4 gene locus. Our data provide genetic evidence that HDAC1 is an essential HDAC that controls the magnitude of an inflammatory response by modulating cytokine expression in effector T cells. PMID- 20702732 TI - A unique feature of Toll/IL-1 receptor domain-containing adaptor protein is partially responsible for lipopolysaccharide insensitivity in zebrafish with a highly conserved function of MyD88. AB - MyD88 and Toll/IL-1R domain-containing adaptor protein (TIRAP) are required for the TLR4 response to LPS stimulation in mammals, but the functions of the two adaptors and their involvement in zebrafish insensitivity to LPS remains unknown. We present a functional analysis of zebrafish Myd88 and Tirap and suggest that Myd88 is more important than Tirap for the activation of Tlr-mediated NF-kappaB, which may be a novel mechanism of Myd88-dependent TLR signaling in teleosts. Zebrafish Tirap lacks the phosphatidylinositol 4,5-bisphosphate binding motif required for human TIRAP location and has leucine at position 233 rather than the conserved proline of human TIRAP, as well as 105 additional aa at the N terminus. Overexpression of zebrafish Tirap in HEK293T cells did not activate NF-kappaB and IFN-beta, but slightly activated NF-kappaB in carp leukocyte cells. Zebrafish Myd88 alone strongly induced the activation of NF-kappaB and IFN-beta both in HEK293T and carp leukocyte cells. The function of Myd88 was dependent on its cellular location and the proline in the Toll/IL-1R domain. Although zebrafish Tirap was distributed throughout the cell rather than localized to the cytoplasmic membrane, its impaired ability to activate downstream Tlr molecules was unlikely to be related to its location because chimera TIRAP with a human TIRAP N terminus and membrane-binding domain also did not activate NF-kappaB. However, the mutation of leucine to proline increased the ability of Tirap to activate NF-kappaB. We suggest that the zebrafish Tirap needs a longer N terminus to perform its function and could be partially responsible for the resistance to LPS in zebrafish. PMID- 20702734 TI - Agreement on radiological diagnosis of acute lower respiratory tract infection in children. AB - Chest radiographs are often used to support the decision to use antibiotics in children aged <5 years with moderate to severe lower acute respiratory infection (ARI). This study aimed to evaluate inter-observer agreement in the interpretation of chest radiographs of children with suspected lower ARI. Three experienced paediatric sub-specialists: a radiologist, an intensivist and a pulmonologist were provided with basic clinical information on each of 48 cases, but the individual standardized evaluations were blinded for clinical diagnoses and for the assessment by the other two specialists. While for specific radiographic findings Kappa agreement values revealed considerable variation, agreement was higher (fair to substantial) on overall diagnostic impression. These findings reiterate that radiographs of children with a clinical suspicion of lower ARI are a limited but potentially useful resource for case management. PMID- 20702735 TI - Intrinsic constraint of asymmetry acting as a control parameter on rapid, rhythmic bimanual coordination: a study of professional drummers and nondrummers. AB - Expert musicians show experience-dependent reduced asymmetry in the structure of motor-related brain areas and in the maximum tapping frequency between the hands. Therefore we hypothesized that a reduced hand-skill asymmetry is strongly related to rapid and rhythmical bimanual coordination and developed a dynamical model including a symmetry-breaking parameter Deltaomega, for human bimanual coordination. We conducted unimanual and bimanual drumming experiments to test the following model predictions. 1) The asymmetry in the maximum tapping frequency is more pronounced in nondrummers than that in drummers. If so, 2) a larger number of phase wanderings (i.e., succession of taps by the same hand), 3) larger SD of the relative phase between the hands (SD ), and 4) larger deviation of mean relative phase (mean ) from 180 degrees would be observed in nondrummers than that in professional drummers during antiphase bimanual drumming at the maximum speed. In a unimanual tapping task, the asymmetry in maximum tapping frequency of nondrummers was more pronounced than that of professional drummers. In a bimanual coordination task, phase wanderings were observed only in nondrummers and SD of the nondrummers is significantly larger than that of professional drummers. On the other hand, there was no significant difference between the mean of the two groups. All these observations were successfully reproduced by changing Deltaomega, which corresponded to the asymmetry in the maximum tapping frequency. These results support the hypothesis indicating that the prominent bimanual coordination pattern emerges spontaneously after a nonspecific change in Deltaomega or symmetry restoration of the nonlinear dynamical systems. PMID- 20702736 TI - Estimated cochlear delays in low best-frequency neurons in the barn owl cannot explain coding of interaural time difference. AB - The functional role of the low-frequency range (<3 kHz) in barn owl hearing is not well understood. Here, it was tested whether cochlear delays could explain the representation of interaural time difference (ITD) in this frequency range. Recordings were obtained from neurons in the core of the central nucleus of the inferior colliculus. The response of these neurons varied with the ITD of the stimulus. The response peak shared by all neurons in a dorsoventral penetration was called the array-specific ITD and served as criterion for the representation of a given ITD in a neuron. Array-specific ITDs were widely distributed. Isolevel frequency response functions obtained with binaural, contralateral, and ispilateral stimulation exhibited a clear response peak and the accompanying frequency was called the best frequency. The data were tested with respect to predictions of a model, the stereausis model, assuming cochlear delays as source for the best ITD of a neuron. According to this model, different cochlear delays determined by mismatches between the ipsilateral and contralateral best frequencies are the source for the ITD in a binaural neuron. The mismatch should depend on the best frequency and the best ITD. The predictions of the stereausis model were not fulfilled in the low best-frequency neurons analyzed here. It is concluded that cochlear delays are not responsible for the representation of best ITD in the barn owl. PMID- 20702737 TI - Collateral actions of premotor interneurons on ventral spinocerebellar tract neurons in the cat. AB - Strong evidence that premotor interneurons provide ventral spinocerebellar tract (VSCT) neurons with feedback information on their actions on motoneurons was previously found for Ia inhibitory interneurons and Renshaw cells, while indications for similar actions of other premotor interneurons were weaker and indirect. Therefore the aim of the present study was to reexamine this possibility with respect to interneurons relaying actions of group Ib afferents from tendon organs and group II afferents from muscle spindles. In all, 133 VSCT neurons in the L3-L5 segments (including 41 spinal border neurons) were recorded from intracellularly in deeply anesthetized cats to verify that stimuli applied in motor nuclei evoked monosynaptic inhibitory postsynaptic potentials (IPSPs) attributable to stimulation of axon collaterals of premotor interneurons. IPSPs were found in over two thirds of the investigated neurons. When intraspinal stimuli were preceded by stimuli applied to a muscle nerve at critical intervals, IPSPs evoked from motor nuclei were considerably reduced, indicating a collision of nerve volleys in axons of interneurons activated by group I and group II afferents. In individual VSCT neurons monosynaptic IPSPs were evoked from both biceps-semitendinosus and gastrocnemius-soleus motor nuclei, in parallel with disynaptic IPSPs from group Ib and group II as well as group Ia afferents. These observations indicate that individual VSCT neurons may monitor the degree of inhibition of both flexor and extensor motoneurons by premotor interneurons in inhibitory pathways from group Ib and group II afferents to motoneurons. They may thus be providing the cerebellum with feedback information on actions of these premotor interneurons on motoneurons. PMID- 20702738 TI - Level-dependent latency shifts quantified through binaural processing. AB - The mammalian binaural system compares the timing of monaural inputs with microsecond precision. This temporal precision is required for localizing sounds in azimuth. However, temporal features of the monaural inputs, in particular their latencies, highly depend on the overall sound level. In a combined psychophysical, electrophysiological, and modeling approach, we investigate how level-dependent latency shifts of the monaural responses are reflected in the perception and neural representation of interaural time differences. We exploit the sensitivity of the binaural system to the timing of high-frequency stimuli with binaurally incongruent envelopes. Using these novel stimuli, both the perceptually adjusted interaural time differences and the time differences extracted from electrophysiological recordings systematically depend on overall sound pressure level. The perceptual and electrophysiological time differences of the envelopes can be explained in an existing model of temporal integration only if a level-dependent firing threshold is added. Such an adjustment of firing threshold provides a temporally accurate neural code of the temporal structure of a stimulus and its binaural disparities independent of overall sound level. PMID- 20702739 TI - Evidence for opponent-channel coding of interaural time differences in human auditory cortex. AB - In humans, horizontal sound localization of low-frequency sounds is mainly based on interaural time differences (ITDs). Traditionally, it was assumed that ITDs are converted into a topographic (or rate-place) code, supported by an array of neurons with parametric tuning to ITDs within the behaviorally relevant range. Although this topographic model has been confirmed in owls, its applicability to mammals has been challenged by recent physiological results suggesting that, at least in small-headed species, ITDs are represented by a nontopographic population rate code, which involves only two opponent (left and right) channels, broadly tuned to ITDs from the two auditory hemifields. The current study investigates which of these two models of ITD processing is more likely to apply to humans. For that, evoked responses to abrupt changes in the ITDs of otherwise continuous sounds were measured with electroencephalography. The ITD change was either away from ("outward" change) or toward the midline ("inward" change). According to the opponent-channel model, the response to an outward ITD change should be larger than the response to the corresponding inward change, whereas the topographic model would predict similar response sizes for both conditions. The measured response sizes were highly consistent with the predictions of the opponent-channel model and contravened the predictions of the topographic model, suggesting that, in humans, ITDs are coded nontopographically. The hemispheric distributions of the ITD change responses suggest that the majority of ITD sensitive neurons in each hemisphere are tuned to ITDs from the contralateral hemifield. PMID- 20702740 TI - Strength-duration relationship for extracellular neural stimulation: numerical and analytical models. AB - The strength-duration relationship for extracellular stimulation is often assumed to be similar to the classical intracellular stimulation model, with a slope asymptotically approaching 1/tau at pulse durations shorter than chronaxy. We modeled extracellular neural stimulation numerically and analytically for several cell shapes and types of active membrane properties. The strength-duration relationship was found to differ significantly from classical intracellular models. At pulse durations between 4 MUs and 5 ms stimulation is dominated by sodium channels, with a slope of -0.72 in log-log coordinates for the Hodgkin Huxley ion channel model. At shorter durations potassium channels dominate and slope decreases to -0.13. Therefore the charge per phase is decreasing with decreasing stimulus duration. With pulses shorter than cell polarization time (~0.1-1 MUs), stimulation is dominated by polarization dynamics with a classical 1 slope and the charge per phase becomes constant. It is demonstrated that extracellular stimulation can have not only lower but also upper thresholds and may be impossible below certain pulse durations. In some regimes the extracellular current can hyperpolarize cells, suppressing rather than stimulating spiking behavior. Thresholds for burst stimuli can be either higher or lower than that of a single pulse, depending on pulse duration. The modeled thresholds were found to be comparable to published experimental data. Electroporation thresholds, which limit the range of safe stimulation, were found to exceed stimulation thresholds by about two orders of magnitude. These results provide a biophysical basis for understanding stimulation dynamics and guidance for optimizing the neural stimulation efficacy and safety. PMID- 20702741 TI - Adaptation and reintegration of proprioceptive information in young and older adults' postural control. AB - We investigated age-related changes in adaptation and sensory reintegration in postural control without vision. In two sessions, participants adapted their posture to sway reference and to reverse sway reference conditions, the former reducing (near eliminating) and the latter enhancing (near doubling) proprioceptive information for posture by means of support-surface rotations in proportion to body sway. Participants stood on a stable platform for 3 min (baseline) followed by 18 min of sway reference or reverse sway reference (adaptation) and finally again on a stable platform for 3 min (reintegration). Results showed that when inaccurate proprioception was introduced, anterior posterior (AP) sway path length increased in comparable levels in the two age groups. During adaptation, young and older adults reduced postural sway at the same rate. On restoration of the stable platform in the reintegration phase, a sizeable aftereffect of increased AP path length was observed in both groups, which was greater in magnitude and duration for older adults. In line with linear feedback models of postural control, spectral analyses showed that this aftereffect differed between the two platform conditions. In the sway-referenced condition, a switch from low- to high-frequency COP sway marked the transition from reduced to normal proprioceptive information. The opposite switch was observed in the reverse sway referenced condition. Our findings illustrate age related slowing in participants' postural control adjustments to sudden changes in environmental conditions. Over and above differences in postural control, our results implicate sensory reweighting as a specific mechanism highly sensitive to age-related decline. PMID- 20702742 TI - Influence of near threshold visual distractors on perceptual detection and reaching movements. AB - Providing evidence against a dissociation between conscious vision for perception and unconscious vision for action, recent studies have suggested that perceptual and motor decisions are based on a unique signal but distinct decisional thresholds. The aim of the present study was to provide a direct test of this assumption in a perceptual-motor dual task involving arm movements. In 300 trials, 10 participants performed speeded pointing movements toward a highly visible target located at 10 degrees from the fixation point and +/- 45 degrees from the body midline. The target was preceded by one or two close to threshold distractor(s) (80 ms stimulus onset asynchrony) presented +/- 30 degrees according to the target location. After each pointing movement, participants judged whether the distractor was present or not on either side of the target. Results showed a robust reaction time facilitation effect and a deviation toward the distractor when the distractor was both present and consciously perceived (Hit). A small reaction time facilitation was also observed when two distractors were physically present but undetected (double-miss)--this facilitation being highly correlated with the physical contrast of the distractors. These results are compatible with the theory proposing that perceptual and motor decisions are based on a common signal but emerge from a contrast dependent fixed threshold for motor responses and a variable context dependent criterion for perceptual responses. This paper thus extends to arm movement control previous findings related to oculomotor control. PMID- 20702743 TI - Neuromodulation by GABA converts a relay into a coincidence detector. AB - Modulation of synaptic strength by gamma-aminobutyric acid receptors (GABARs) is a common feature in sensory pathways that contain relay cell types. However, the functional impact of these receptors on information processing is not clear. We considered this issue at bushy cells (BCs) in the cochlear nucleus, which relay auditory nerve (AN) activity to higher centers. BCs express GABA(A)Rs, and synaptic inputs to BCs express GABA(B)Rs. We tested the effects of GABAR activation on the relaying of AN activity using patch-clamp recordings in mature mouse brain slices at 34 degrees C. GABA affected BC firing in response to trains of AN activity at concentrations as low as 10 MUM. GABA(A)Rs reduced firing primarily late in high-frequency trains, whereas GABA(B)Rs reduced firing early and in low-frequency trains. BC firing was significantly restored when two converging AN inputs were activated simultaneously, with maximal effect over a window of <0.5 ms. Thus GABA could adjust the function of BCs, to suppress the relaying of individual inputs and require coincident activity of multiple inputs. PMID- 20702745 TI - Long-term intermittent multiple micronutrient supplementation enhances hemoglobin and micronutrient status more than iron + folic acid supplementation in Bangladeshi rural adolescent girls with nutritional anemia. AB - Previous short-term supplementation studies showed no additional hematologic benefit of multiple micronutrients (MMN) compared with iron + folic acid (IFA) in adolescent girls. This study examines whether long-term once- or twice-weekly supplementation of MMN can improve hemoglobin (Hb) and micronutrient status more than twice-weekly IFA supplementation in anemic adolescent girls in Bangladesh. Anemic girls (n = 324) aged 11-17 y attending rural schools were given once- or twice-weekly MMN or twice-weekly IFA, containing 60 mg iron/dose in both supplements, for 52 wk in a randomized double-blind trial. Blood samples were collected at baseline and 26 and 52 wk. Intent to treat analysis showed no significant difference in the Hb concentration between treatments at either 26 or 52 wk. However, after excluding girls with hemoglobinopathy and adjustment for baseline Hb, a greater increase in Hb was observed with twice-weekly MMN at 26 wk (P = 0.045). Although all 3 treatments effectively reduced iron deficiency, once weekly MMN produced significantly lower serum ferritin concentrations than the other treatments at both 26 and 52 wk. Both once- and twice-weekly MMN significantly improved riboflavin, vitamin A, and vitamin C status compared with IFA. Overall, once-weekly MMN was less efficacious than twice-weekly MMN in improving iron, riboflavin, RBC folic acid, and vitamin A levels. Micronutrient supplementation beyond 26 wk was likely important in sustaining improved micronutrient status. These findings highlight the potential usefulness of MMN intervention in this population and have implications for programming. PMID- 20702744 TI - Adherence to an (n-3) fatty acid/fish intake pattern is inversely associated with metabolic syndrome among Puerto Rican adults in the Greater Boston area. AB - Combinations of fatty acids may affect risk of metabolic syndrome. Puerto Ricans have a disproportionate number of chronic conditions compared with other Hispanic groups. We aimed to characterize fatty acid intake patterns of Puerto Rican adults aged 45-75 y and living in the Greater Boston area (n = 1207) and to examine associations between these patterns and metabolic syndrome. Dietary fatty acids, as a percentage of total fat, were entered into principle components analysis. Spearman correlation coefficients were used to examine associations between fatty acid intake patterns, nutrients, and food groups. Associations with metabolic syndrome were analyzed by using logistic regression and general linear models with quintiles of principal component scores. Four principal components (factors) emerged: factor 1, short- and medium-chain SFA/dairy; factor 2, (n-3) fatty acid/fish; factor 3, very long-chain (VLC) SFA and PUFA/oils; and factor 4, monounsaturated fatty acid/trans fat. The SFA/dairy factor was inversely associated with fasting serum glucose concentrations (P = 0.02) and the VLC SFA/oils factor was negatively related to waist circumference (P = 0.008). However, these associations were no longer significant after additional adjustment for BMI. The (n-3) fatty acid/fish factor was associated with a lower likelihood of metabolic syndrome (Q5 vs. Q1: odds ratio: 0.54, 95% CI: 0.34, 0.86). In summary, principal components analysis of fatty acid intakes revealed 4 dietary fatty acid patterns in this population. Identifying optimal combinations of fatty acids may be beneficial for understanding relationships with health outcomes given their diverse effects on metabolism. PMID- 20702746 TI - Dietary antioxidant and mineral intake in humans is associated with reduced risk of esophageal adenocarcinoma but not reflux esophagitis or Barrett's esophagus. AB - The role of antioxidants in the pathogenesis of reflux esophagitis (RE), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) remains unknown. We evaluated the associations among dietary antioxidant intake and these diseases. We performed an assessment of dietary antioxidant intake in a case control study of RE (n = 219), BE (n = 220), EAC (n = 224), and matched population controls (n = 256) (the Factors Influencing the Barrett's Adenocarcinoma Relationship study) using a modification of a validated FFQ. We found that overall antioxidant index, a measure of the combined intake of vitamin C, vitamin E, total carotenoids, and selenium, was associated with a reduced risk of EAC [odds ratio (OR) = 0.57; 95% CI = 0.33-0.98], but not BE (OR = 0.95; 95% CI = 0.53-1.71) or RE (OR = 1.60; 95% CI = 0.86-2.98), for those in the highest compared with lowest category of intake. Those in the highest category of vitamin C intake had a lower risk of EAC (OR = 0.37; 95% CI = 0.21-0.66; P-trend = 0.001) and RE (OR = 0.46; 95% CI = 0.24 0.90; P-trend = 0.03) compared with those in the lowest category. Vitamin C intake was not associated with BE, and intake of vitamin E, total carotenoids, zinc, copper, or selenium was not associated with EAC, BE, or RE. In conclusion, the overall antioxidant index was associated with a reduced risk of EAC. Higher dietary intake of vitamin C was associated with a reduced risk of EAC and RE. These results suggest that antioxidants may play a role in the pathogenesis of RE and EAC and may be more important in terms of progression rather than initiation of the disease process. PMID- 20702747 TI - Grape polyphenols do not affect vascular function in healthy men. AB - Data suggest that polyphenol-rich products may improve endothelial function and other cardiovascular health risk factors. Grape and wine contain high amounts of polyphenols, but effects of these polyphenols have hardly been investigated in isolation in randomized controlled studies. Our objective in this study was to test the chronic effect of polyphenol-rich solids derived from either a wine grape mix or grape seed on flow-mediated dilation (FMD). Blood pressure and other vascular function measures, platelet function, and blood lipids were secondary outcomes. Thirty-five healthy males were randomized in a double-blind, placebo controlled crossover study consisting of three 2-wk intervention periods separated by 1-wk washout periods. The test products, containing 800 mg of polyphenols, were consumed as capsules. At the end of each intervention period, effects were measured after consumption of a low-fat breakfast (~751 kJ, 25% fat) and a high-fat lunch (~3136 kJ, 78% fat). After the low-fat breakfast, the treatments did not significantly affect FMD. The absolute difference after the wine grape solid treatment was -0.4% (95% CI = -1.8 to 0.9; P = 0.77) and after grape seed solids, 0.2% (95% CI = -1.2 to 1.5; P = 0.94) compared with after the placebo treatment. FMD effects after the high-fat lunch and effects on secondary outcomes also showed no consistent differences between both of the grape solids and placebo treatment. In conclusion, consumption of grape polyphenols has no major impact on FMD in healthy men. Future studies should address whether grape polyphenols can improve FMD and other cardiovascular health risk factors in populations with increased cardiovascular risk. PMID- 20702748 TI - Chronic alcohol intake upregulates hepatic expression of carotenoid cleavage enzymes and PPAR in rats. AB - Excessive and chronic alcohol intake leads to a lower hepatic vitamin A status by interfering with vitamin A metabolism. Dietary provitamin A carotenoids can be converted into vitamin A mainly by carotenoid 15,15'-monooxygenase 1 (CMO1) and, to a lesser degree, carotenoid 9'10'-monooxygenase 2 (CMO2). CMO1 has been shown to be regulated by several transcription factors, such as the PPAR, retinoid X receptor, and thyroid receptor (TR). The regulation of CMO2 has yet to be identified. The impact of chronic alcohol intake on hepatic expressions of CMO1 and CMO2 and their related transcription factors are unknown. In this study, Fischer 344 rats were pair-fed either a liquid ethanol Lieber-DeCarli diet (n = 10) or a control diet (n = 10) for 11 wk. Hepatic retinoid concentration and expressions of CMO1, CMO2, PPARgamma, PPARalpha, and TRbeta as well as plasma thyroid hormones levels were analyzed. We observed that administering alcohol decreased hepatic retinoid levels but increased mRNA concentrations of CMO1, CMO2, PPARgamma, PPARalpha, and TRbeta and upregulated protein levels of CMO2, PPARgamma, and PPARalpha. There was a positive correlation of PPARgamma with CMO1 (r = 0.89; P < 0.0001) and both PPARgamma and PPARalpha with CMO2 (r = 0.72, P < 0.001 and r = 0.62, P < 0.01, respectively). Plasma thyroid hormone concentrations did not differ between the control rats and alcohol-fed rats. This study suggests that chronic alcohol intake significantly upregulates hepatic expression of CMO1 and, to a much lesser extent, CMO2. This process may be due to alcohol-induced PPARgamma expression and lower vitamin A status in the liver. PMID- 20702749 TI - Dietary patterns are associated with metabolic syndrome in an urban Mexican population. AB - The role that diet plays in the origin of metabolic syndrome (MetS) is not completely understood. Certain foods and nutrients have been established as dietary risk factors for MetS. However, the dietary patterns associated with MetS risk have been minimally studied with factor analysis. Our objective in this study was to use exploratory factor analysis to examine whether particular dietary patterns are related to risk of MetS in Mexican adults. We characterized the dietary patterns among 5240 men and women aged 20-70 y in the Health Workers Cohort Study. Information on participants' sociodemographic conditions and physical activity was collected via self-administered questionnaires. We also obtained anthropometric and clinical measurements and fasting blood samples for biochemical analyses. In a cross-sectional analysis, we examined dietary patterns in relation to MetS, defined using criteria from the Adult Treatment Panel III. Factor analysis revealed 3 major dietary patterns: prudent, Western, and high protein/fat. The prevalence of MetS was 26.6%. After adjustment for potential confounders, compared with participants in the lowest tertile of the Western pattern, those in the highest tertile had higher odds ratios (OR) for high fasting glucose (OR, 1.67; 95% CI: 1.36-2.06), low serum HDL cholesterol (OR, 1.55; 95% CI: 1.31-1.83), and MetS (OR, 1.56; 95% CI, 1.31-1.88). However, we found no significant associations between other patterns and MetS. In summary, a diet high in soft drinks, refined grains, corn tortillas, pastries, seafood, and whole grains was associated with MetS risk. This result emphasizes the importance of preventive nutrition interventions. PMID- 20702750 TI - Americans do not meet federal dietary recommendations. AB - A longstanding goal of dietary surveillance has been to estimate the proportion of the population with intakes above or below a target, such as a recommended level of intake. However, until now, statistical methods for assessing the alignment of food intakes with recommendations have been lacking. The purposes of this study were to demonstrate the National Cancer Institute's method of estimating the distribution of usual intake of foods and determine the proportion of the U.S. population who does not meet federal dietary recommendations. Data were obtained from the 2001-2004 NHANES for 16,338 persons, aged 2 y and older. Quantities of foods reported on 24-h recalls were translated into amounts of various food groups using the MyPyramid Equivalents Database. Usual dietary intake distributions were modeled, accounting for sequence effect, weekend/weekday effect, sex, age, poverty income ratio, and race/ethnicity. The majority of the population did not meet recommendations for all of the nutrient rich food groups, except total grains and meat and beans. Concomitantly, overconsumption of energy from solid fats, added sugars, and alcoholic beverages ("empty calories") was ubiquitous. Over 80% of persons age >= 71 y and over 90% of all other sex-age groups had intakes of empty calories that exceeded the discretionary calorie allowances. In conclusion, nearly the entire U.S. population consumes a diet that is not on par with recommendations. These findings add another piece to the rather disturbing picture that is emerging of a nation's diet in crisis. PMID- 20702751 TI - Early life exposure to the 1959-1961 Chinese famine has long-term health consequences. AB - The Chinese famine of 1959-1961 was the largest in human history. We used data on 35,025 women born in 1957-1963 to assess the impact of famine exposure on height, BMI, and hypertension at ~32 y of age. The data were from the China-U.S. Collaborative Project for Neural Tube Defect Prevention. The famine varied in intensity across provinces and counties and affected rural areas disproportionately. We used a measure of famine intensity at the county level based on the size of birth year cohorts in a difference-in-difference model, which compared each cohort to the unexposed 1963 cohort, after correcting for age and time trends, and estimated impact for the average level of intensity across counties. The impact was confined to rural areas, but this could be due to small sample sizes in urban areas. Height was reduced in the 1958 and 1959 cohorts by 1.7 and 1.3 cm, respectively. This corresponded to exposures during 0.5-3.5 y for the 1958 cohort and late pregnancy and 0-2.5 y for the 1959 cohort. BMI increased by 0.92 kg/m(2) in the 1957 cohort, exposed from 1.5 to 4.5 y, but decreased by 0.3 kg/m(2) in the 1960-1961 cohorts, exposed during pregnancy and infancy. Famine exposure was associated with a 3-fold increase in the odds of hypertension for the 1958 cohort. In general, postnatal exposure during the first 2-3 y of life reduced height and increased BMI and hypertension, whereas exposure during pregnancy and infancy reduced BMI. PMID- 20702752 TI - Vitamin D status of Inuit preschoolers reflects season and vitamin D intake. AB - Rickets ascribed to hypovitaminosis D remains a public health concern among Aboriginal children in Canada and the United States. Our primary objective in this study was to investigate the prevalence and risk factors (gender, age, vitamin D intake, and socioeconomic status) for low vitamin D status of Inuit preschoolers living in 16 Arctic communities (51(o)N-70(o)N) and participating in the 2007-2008 Nunavut Child Inuit Health Survey. Children were selected randomly in summer (n = 282) and a follow-up was performed in winter for a subsample (n = 52). Dietary intake was assessed through the administration of a 24-h dietary recall and a FFQ. Anthropometric measurements (height, weight) were assessed. Plasma 25-hydroxy vitamin D was measured using a chemiluminescent assay (Liaison, Diasorin). Prevalence of vitamin D insufficiency (<75 nmol/L) among preschoolers was 78.6% and 96.8% in summer and winter, respectively. Median vitamin D concentrations and interquartile ranges in summer and winter were 48.3 (32.8 71.3) and 37.7 (21.4-52.0) nmol/L, respectively. The prevalence of vitamin D deficiency < 25 and < 37.5 nmol/L was 13.6 and 36.5%, respectively. Children who met or exceeded the adequate intake, those who consumed 2 or more milk servings (1 serving = 250 mL), and those who lived in households without crowding (47.7%) had a better vitamin D status than those who did not. The predictors of vitamin D status were dietary intake and age. Given low traditional food consumption and low consumption of milk, interventions promoting vitamin D supplementation may be required. PMID- 20702753 TI - Cyclooxygenase-2 mediates anandamide metabolism in the mouse brain. AB - Cyclooxygenase-2 (COX-2) mediates inflammation and contributes to neurodegeneration. Best known for its pathological up-regulation, COX-2 is also constitutively expressed within the brain and mediates synaptic transmission through prostaglandin synthesis. Along with arachidonic acid, COX-2 oxygenates the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol in vitro. Inhibition of COX-2 enhances retrograde signaling in the hippocampus, suggesting COX-2 mediates endocannabinoid tone in healthy brain. The degree to which COX-2 may regulate endocannabinoid metabolism in vivo is currently unclear. Therefore, we explored the effect of COX-2 inhibition on [(3)H]AEA metabolism in mouse brain. Although AEA is hydrolyzed primarily by fatty acid amide hydrolase (FAAH), ex vivo autoradiography revealed that COX-2 inhibition by nimesulide redirected [(3)H]AEA substrate from COX-2 to FAAH in the cortex, hippocampus, thalamus, and periaqueductal gray. These data indicate that COX-2 possesses the capacity to metabolize AEA in vivo and can compete with FAAH for AEA in several brain regions. Temporal fluctuations in COX-2 expression were observed in the brain, with an increase in COX-2 protein and mRNA in the hippocampus at midnight compared with noon. COX-2 immunolocalization was robust in the hippocampus and several cortical regions. Although most regions exhibited no temporal changes in COX-2 immunolocalization, increased numbers of immunoreactive cells were detected at midnight in layers II and III of the somatosensory and visual cortices. These temporal variations in COX-2 distribution reduced the enzyme's contribution toward [(3)H]AEA metabolism in the somatosensory cortex at midnight. Taken together, our findings establish COX-2 as a mediator of regional AEA metabolism in mouse brain. PMID- 20702754 TI - Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants. AB - Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6beta hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 +/- 2.7 to 18.0 +/- 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible. PMID- 20702756 TI - Health-care reform 2010: how will it impact you and your practice? AB - There are several transformative features of the 2 landmark health-care reform laws passed by the Congress and signed into law by the President in March. The most critical elements that will impact pharmacists and patients are categorized into 6 key areas in this commentary: health insurance reform; improvements in Medicare and Medicaid; pharmacy practice expansion; health professions education and workforce initiatives; prevention and wellness; and enhanced access to affordable medications. The relevant features of these new opportunities are presented and the implications for pharmacists and their patients are discussed. PMID- 20702755 TI - Predictors of nonadherence to statins: a systematic review and meta-analysis. AB - BACKGROUND: Nonadherence to statins limits the benefits of this common drug class. Individual studies assessing predictors of nonadherence have produced inconsistent results. OBJECTIVE: To identify reliable predictors of nonadherence to statins through systematic review and meta-analysis. METHODS: Multiple databases, including MEDLINE, EMBASE, and PsycINFO, were searched (from inception through February 2009) to identify studies that evaluated predictors of nonadherence to statins. Studies were selected using a priori defined criteria, and each study was reviewed by 2 authors who abstracted data on study characteristics and outcomes. Relative risks were then pooled, using an inverse variance weighted random-effects model. RESULTS: Twenty-two cohort studies met inclusion criteria. Age had a U-shaped association with adherence; the oldest (>/=70 years) and youngest (<50 years) subjects had lower adherence than the middle-aged (50-69 years) subjects. Women and patients with lower incomes were more likely to be nonadherent than were men (odds of nonadherence 1.07; 95% CI 1.04 to 1.11) and those with higher incomes (odds of nonadherence 1.18; 95% CI 1.10 to 1.28), respectively. A history of cardiovascular disease predicted better adherence to statins (odds of nonadherence 0.68; 95% CI 0.66 to 0.78). Similarly, a diagnosis of hypertension or diabetes was associated with better adherence. Although there were too few studies for quantitative pooling, increased testing of lipid levels and lower out-of-pocket costs appeared to be associated with better adherence. There was substantial (I(2) range 68.7-96.3%) heterogeneity between studies across factors. CONCLUSIONS: Several sociodemographic, medical, and health-care utilization characteristics are associated with statin nonadherence. These factors may be useful guides for targeting statin adherence interventions. PMID- 20702757 TI - Health-care reform's great expectations and physician reality. AB - The Patient Protection and Affordable Care Act will not prove to be the reform for which physicians were long hoping. Private insurance rates will climb sharply, forcing people onto government programs; physician reimbursement will plummet; the physician shortage will worsen; rationing in the form of waiting lists is certain; health care as a whole will worsen; and once fully engaged, nationalization of health care will be irreversible. PMID- 20702758 TI - Intravenous to oral conversion of antihypertensives: a toolkit for guideline development. AB - OBJECTIVE: To provide a toolkit of information for hospitals to use in developing intravenous to oral conversion protocols for antihypertensives. DATA SOURCES: Articles describing intravenous to oral conversion protocols for any therapeutic category were identified in an English-language MEDLINE search (1990-April 2010) using a wide variety of MeSH terms. References from selected articles were reviewed for additional material. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational English-language studies and review articles that focused on oral transition of intravenous drugs were selected. DATA SYNTHESIS: Most of the literature on conversion from intravenous to oral formulations involves antimicrobials. There is considerable evidence documenting reduced costs and improved patient flow through the health-care system following implementing these protocols with drugs like antimicrobials, histamine-2 receptor antagonists, and proton pump inhibitors. Although antihypertensives have not been studied, principles and implementation strategies used for other drug classes can be applied to antihypertensives. Guidance is provided on framing the problem, issues surrounding oral absorption principles, information pertaining to oral conversion in specific disease states, and implementation and documentation strategies. Detailed tables of oral and intravenous antihypertensives are provided. CONCLUSIONS: We recommend that hospitals consider developing protocols on conversion of intravenous to oral antihypertensives in an attempt to reduce unnecessarily prolonged intravenous therapy. Information contained in this article can be used as a toolkit to select information specific to the characteristics of individual health-care systems. PMID- 20702759 TI - Infliximab-induced lichen planopilaris. AB - OBJECTIVE: To report a case of lichen planopilaris in a patient treated with infliximab for longstanding refractory psoriasis. CASE SUMMARY: A 37-year-old man with recalcitrant plaque psoriasis was being treated with infliximab at a dosage of 5 mg/kg every 8 weeks, with good response. However, 11 months later the patient developed follicular keratotic papulo-pustules, perifollicular erythema, and scaling, with progressive hair loss of the frontal and parietal regions of the scalp and eyebrows. A skin biopsy from a representative lesion was consistent with the diagnosis of lichen planopilaris. DISCUSSION: Anti-tumor necrosis factor (TNF) agents have been associated with numerous cutaneous adverse events. Lichenoid reactions are uncommon but are an emerging cutaneous adverse effect. At least 13 cases of these eruptions have been recently described. Although lichenoid reactions in patients treated with TNF-alpha inhibitors may be clinically very diverse, we have found no previously reported cases of lichen planopilaris induced by these agents. An objective causality assessment revealed that the adverse event was probable. CONCLUSIONS: Since anti-TNF agents are being used for a rapidly expanding number of rheumatic, digestive, and dermatologic diseases, it is expected that lichenoid eruptions and other skin toxicities are likely to be seen with increasing frequency in clinical practice. PMID- 20702760 TI - Alternate-day statin therapy for the treatment of hyperlipidemia. AB - OBJECTIVE: To evaluate the safety, efficacy, and cost of alternate-day statin therapy in the treatment of hyperlipidemia. DATA SOURCES: Systematic searches were conducted for primary literature sources involving alternative statin regimens using PubMed, EMBASE, Google Scholar, and International Pharmaceutical Abstracts (January 1966-March 2010). Articles selected were limited to those published in the English language. Reference citations from relevant publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English language articles identified were reviewed and 17 trials (14 prospective and 3 retrospective) involving alternate-day statin dosing were included. Studies involving alternative statin dosing regimens other than alternating days were excluded from this review. DATA SYNTHESIS: Daily administration of statins is the standard of therapy used to reduce low-density lipoprotein cholesterol (LDL-C) levels as well as atherosclerosis that may lead to coronary events. Through LDL-C lowering and pleiotropic effects, statins decrease cardiovascular morbidity and mortality. Unfortunately, due to cost and adverse effects of statins, some patients are nonadherent to statin therapy. Several small studies have found alternate-day statin therapy to be as effective at reducing LDL-C as daily administration, while also lowering the incidence of adverse reactions and potentially lowering cost. CONCLUSIONS: Alternate-day statin therapy may decrease cost and therapy-limiting adverse reactions while potentially increasing regimen adherence and positively affecting the lipid panel. Further research is needed to determine whether this alternative regimen produces similar cardiovascular outcomes as those with daily statin therapy. PMID- 20702762 TI - Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors. AB - Auraptene is a prenyloxycoumarin from Citrus species with chemopreventive properties against colitis-related colon and breast cancers through a yet undefined mechanism. To decipher its mechanism of action, we used a ligand structure based approach. We established that auraptene fits with a pharmacophore involved in both the inhibition of acyl-CoA:cholesterol acyl transferase (ACAT) and the modulation of estrogen receptors (ERs). We confirmed experimentally that auraptene inhibits ACAT and binds to ERs in a concentration-dependent manner and that it inhibited ACAT in rat liver microsomes and in intact cancer cells of murine and human origins, with an IC(50) value in the micromolar range. Auraptene bound to ERs with affinities of 7.8 MUM for ERalpha and 7.9 MUM for ERbeta, stabilized ERs, and modulated their transcriptional activity via an ER-dependent reporter gene and endogenous genes. We further established that these effects correlated well with the control of growth and invasiveness of tumor cells. Our data shed light on the molecular mechanism underlying the anticancer and chemopreventive effects of auraptene. PMID- 20702761 TI - The MU-opioid receptor variant N190K is unresponsive to peptide agonists yet can be rescued by small-molecule drugs. AB - The MU-opioid receptor (MOR) plays an important role in modulating analgesia, feeding behavior, and a range of autonomic functions. In the current study, we investigated the degree to which 13 naturally occurring missense mutations affect the pharmacological properties of the human MOR. After expression of each receptor in human embryonic kidney 293 cells, signaling (Galpha(i/o)-mediated) induced by peptide agonists was assessed using luciferase reporter gene assays. Multiple mutants (S66F, S147C, R260H, R265C, R265H, and S268P) show a significant reduction in agonist potency. At the N190K variant, agonist-mediated signaling was essentially absent. Enzyme-linked immunosorbent assay, microscopic analysis, and radioligand binding assays revealed that this mutant shows markedly reduced cell-surface expression, whereas all other receptor variants were expressed at normal levels. Surface expression of the N190K variant could be increased by incubation with the alkaloid agonist buprenorphine or with either naltrexone or naloxone, structurally related MOR antagonists. We were surprised to find that both putative antagonists, despite being inactive at the wild-type MOR, triggered a concentration-dependent increase in N190K receptor-mediated signaling. In contrast, peptidic ligands failed to promote expression or rescue function of the N190K mutant. Subsequent analysis of the N190K variant in an ethnically diverse cohort identified this isoform in a subgroup of African Americans. Taken together, our studies reveal that the N190K mutation leads to severe functional alterations and, in parallel, changes the response to established MOR ligands. The extent to which this mutation results in physiological abnormalities or affects drug sensitivity in selected populations (e.g., those with chronic pain or addiction) remains to be investigated. PMID- 20702763 TI - The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors. AB - In view of the therapeutic importance of dopamine D(3) and D(2) receptors, there remains considerable interest in novel ligands. Herein, we show that the tetrahydroisoquinoline 1H-indole-2-carboxylic acid {4-[2-(cyano-3,4-dihydro-1H isoquinolin-2-yl)-ethyl]-cyclohexyl}-amide (SB269,652) behaves as an atypical, allosteric antagonist at D(3) and D(2) receptors. Accordingly, SB269,652 potently (low nanomolar range) abolished specific binding of [(3)H]nemanopride and [(3)H]spiperone to Chinese hamster ovary-transfected D(3) receptors when radioligands were used at 0.2 and 0.5 nM, respectively. However, even at high concentrations (5 MUM), SB269,652 only submaximally inhibited the specific binding of these radioligands when they were employed at 10-fold higher concentrations. By analogy, although SB269,652 potently blocked D(3) receptor mediated activation of Galpha(i3) and phosphorylation of extracellular-signal regulated kinase (ERK)1/2, when concentrations of dopamine were increased by 10 fold, from 1 MUM to 10 MUM, SB269,652 only submaximally inhibited dopamine induced stimulation of Galpha(i3). SB269,652 (up to 10 MUM) only weakly and partially (by approximately 20-30%) inhibited radioligand binding to D(2) receptors. Likewise, SB269,652 only submaximally suppressed D(2) receptor mediated stimulation of Galpha(i3) and Galpha(qi5) (detected with the aequorin assay) and phosphorylation of ERK1/2 and Akt. Furthermore, SB269,652 only partially (35%) inhibited the dopamine-induced recruitment of beta-arrestin2 to D(2) receptors. Finally, Schild analysis using Galpha(i3) assays, and studies of radioligand association and dissociation kinetics, supported allosteric actions of SB269,652 at D(3) and D(2) receptors. PMID- 20702764 TI - Serotonin stimulation of cAMP-dependent plasticity in Aplysia sensory neurons is mediated by calmodulin-sensitive adenylyl cyclase. AB - Calmodulin (CaM)-sensitive adenylyl cyclase (AC) in sensory neurons (SNs) in Aplysia has been proposed as a molecular coincidence detector during conditioning. We identified four putative ACs in Aplysia CNS. CaM binds to a sequence in the C1b region of AC-AplA that resembles the CaM-binding sequence in the C1b region of AC1 in mammals. Recombinant AC-AplA was stimulated by Ca(2+)/CaM. AC-AplC is most similar to the Ca(2+)-inhibited AC5 and AC6 in mammals. Recombinant AC-AplC was directly inhibited by Ca(2+), independent of CaM. AC-AplA and AC-AplC are expressed in SNs, whereas AC-AplB and AC-AplD are not. Knockdown of AC-AplA demonstrated that serotonin stimulation of cAMP dependent plasticity in SNs is predominantly mediated by this CaM-sensitive AC. We propose that the coexpression of a Ca(2+)-inhibited AC in SNs, together with a Ca(2+)/CaM-stimulated AC, would enhance the associative requirement for coincident Ca(2+) influx and serotonin for effective stimulation of cAMP levels and initiation of plasticity mediated by AC-AplA. PMID- 20702766 TI - Comprehensive microRNA expression profiling of the hematopoietic hierarchy. AB - The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are critical players in orchestrating this differentiation. Here, we report the development and application of a high throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity. PMID- 20702765 TI - Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. AB - Inositol-requiring enzyme 1 (IRE1) is a proximal endoplasmic reticulum (ER) stress sensor and a central mediator of the unfolded protein response. In a human glioma model, inhibition of IRE1alpha correlated with down-regulation of prevalent proangiogenic factors such as VEGF-A, IL-1beta, IL-6, and IL-8. Significant up-regulation of antiangiogenic gene transcripts was also apparent. These transcripts encode SPARC, decorin, thrombospondin-1, and other matrix proteins functionally linked to mesenchymal differentiation and glioma invasiveness. In vivo, using both the chick chorio-allantoic membrane assay and a mouse orthotopic brain model, we observed in tumors underexpressing IRE1: (i) reduction of angiogenesis and blood perfusion, (ii) a decreased growth rate, and (iii) extensive invasiveness and blood vessel cooption. This phenotypic change was consistently associated with increased overall survival in glioma-implanted recipient mice. Ectopic expression of IL-6 in IRE1-deficient tumors restored angiogenesis and neutralized vessel cooption but did not reverse the mesenchymal/infiltrative cell phenotype. The ischemia-responsive IRE1 protein is thus identified as a key regulator of tumor neovascularization and invasiveness. PMID- 20702767 TI - Sequence dependence of DNA bending rigidity. AB - For many aspects of DNA-protein interaction, it is vital to know how DNA bending rigidity (or persistence length, a) depends on its sequence. We addressed this problem using the method based on cyclization of short DNA fragments, which allows very accurate determination of a. Our approach was based on assigning specific values of a to each of 10 distinct dinucleotide steps. We prepared DNA fragments, each about 200 bp in length, with various quasi-periodic sequences, measured their cyclization efficiencies (j factors), and fitted the data by the theoretical equation to obtain the values of a for each fragment. From these data, we obtained a set of a for the dinucleotide steps. To test this set, we used it to design DNA sequences that should correspond to very low and very high values of a, prepared the corresponding fragments, and determined their values of a experimentally. The measured and calculated values of a were very close to one another, confirming that we have found the correct solution to this long-standing problem. The same experimental data also allowed us to determine the sequence dependence of DNA helical repeat. PMID- 20702768 TI - Probing in vivo Mn2+ speciation and oxidative stress resistance in yeast cells with electron-nuclear double resonance spectroscopy. AB - Manganese is an essential transition metal that, among other functions, can act independently of proteins to either defend against or promote oxidative stress and disease. The majority of cellular manganese exists as low molecular-weight Mn(2+) complexes, and the balance between opposing "essential" and "toxic" roles is thought to be governed by the nature of the ligands coordinating Mn(2+). Until now, it has been impossible to determine manganese speciation within intact, viable cells, but we here report that this speciation can be probed through measurements of (1)H and (31)P electron-nuclear double resonance (ENDOR) signal intensities for intracellular Mn(2+). Application of this approach to yeast (Saccharomyces cerevisiae) cells, and two pairs of yeast mutants genetically engineered to enhance or suppress the accumulation of manganese or phosphates, supports an in vivo role for the orthophosphate complex of Mn(2+) in resistance to oxidative stress, thereby corroborating in vitro studies that demonstrated superoxide dismutase activity for this species. PMID- 20702769 TI - Slipknotting upon native-like loop formation in a trefoil knot protein. AB - Protein knots and slipknots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Recent experimental results show that knotting, starting from a fully extended polypeptide, has not yet been observed. Understanding the nucleation process of folding knots is thus a natural challenge for both experimental and theoretical investigation. In this study, we employ energy landscape theory and molecular dynamics to elucidate the entire folding mechanism. The full free energy landscape of a knotted protein is mapped using an all-atom structure-based protein model. Results show that, due to the topological constraint, the protein folds through a three-state mechanism that contains (i) a precise nucleation site that creates a correctly twisted native loop (first barrier) and (ii) a rate-limiting free energy barrier that is traversed by two parallel knot-forming routes. The main route corresponds to a slipknot conformation, a collapsed configuration where the C-terminal helix adopts a hairpin-like configuration while threading, and the minor route to an entropically limited plug motion, where the extended terminus is threaded as through a needle. Knot formation is a late transition state process and results show that random (nonspecific) knots are a very rare and unstable set of configurations both at and below folding temperature. Our study shows that a native-biased landscape is sufficient to fold complex topologies and presents a folding mechanism generalizable to all known knotted protein topologies: knotting via threading a native-like loop in a preordered intermediate. PMID- 20702771 TI - Effects of a commonly occurring genetic polymorphism of human CYP3A4 (I118V) on the metabolism of anandamide. AB - The endocannabinoid system plays an important role in numerous physiological processes including mood, appetite, and pain sensation. A critical compound in maintaining cannabinoid tone is the endocannabinoid anandamide (AEA). We have recently shown that AEA is metabolized by several different human cytochromes P450 (P450) to form a number of metabolites, one of which exhibits increased biological activity. CYP3A4, one of the major P450s involved in the metabolism of AEA, produces four major metabolites. One of these metabolites, 5,6 epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA), exhibits a much higher affinity than AEA for the cannabinoid 2 receptor (CB-2), which leads to a marked decrease in intracellular cAMP levels in cells expressing CB-2. There are multiple human alleles of CYP3A4, and the CYP3A4.4 allele has been shown to exhibit a significant decrease in activity. Recombinant CYP3A4*4 was expressed in Escherichia coli and was demonstrated to produce 60% less 6-hydroxytestosterone than the wild-type (WT) 3A4 in a reconstituted system. The metabolism of AEA by the WT and the CYP3A4.4 variant was investigated. The mutant produced 60% less of the four EET-EA metabolites than the WT. The mutant also produced a new peak on liquid chromatography-mass spectrometry not seen with the WT, which corresponded to 19-hydroxyeicosatetraenoic acid-ethanolamide. In addition, the mutant produces four novel peaks at m/z 380, which correspond to the addition of two oxygen atoms, possibly to form a peroxide bond. These data indicate that individuals expressing the CYP3A4.4 allele may exhibit significant variations in the metabolism of AEA as well as any other compounds resembling AEA. PMID- 20702772 TI - Prediction of the intestinal first-pass metabolism of CYP3A substrates in humans using cynomolgus monkeys. AB - To select high bioavailability compounds, it is necessary to predict the first pass metabolism in the intestine. However, in vitro-in vivo predictions of the intestinal metabolism have proven both challenging and less definitive. The purpose of this study was to investigate prediction of intestinal first-pass metabolism in humans using cynomolgus monkeys. First, we investigated intrinsic metabolic activities in intestinal microsomes of monkeys (MIM) and humans (HIM) (CL(int, MIM) and CL(int, HIM), respectively) of 18 CYP3A substrates. The CL(int, MIM) values were found to be relatively high and showed excellent correlation with the CL(int, HIM) values. Subsequently, we determined the plasma concentrations of 9 CYP3A substrates (buspirone, carbamazepine, diazepam, felodipine, midazolam, nicardipine, nifedipine, saquinavir, and verapamil) in monkeys after an oral dose of 2 mg/kg with or without an oral dose of 5 mg/kg ketoconazole and calculated AUC((+vehicle))/AUC((+ketoconazole)), defined as F(g, monkey(observed)); we confirmed that the dose of ketoconazole inhibited only intestinal CYP3A metabolism by preliminary in vitro and in vivo experiments using ketoconazole. The F(g, monkey(observed)) was lower than the F(g, human(observed)) for most compounds, but moderate correlation was observed. Furthermore, using these data, we established a new methodology to estimate F(g, human(predicted)) more precisely on the basis of the assumption that intestinal physiological conditions other than intrinsic metabolic activity would be the same between monkeys and humans. In conclusion, the in vivo model using cynomolgus monkeys in this study is useful for prediction of intestinal first-pass metabolism by CYP3A in humans because it was able to predict F(g, human) of all nine compounds investigated. PMID- 20702773 TI - Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis. AB - The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-kappaB activation compared to wild types. Up regulation of a discrete set of inflammatory genes, including Il-1beta, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-gamma-MSH, attenuated disease incidence and severity in wild type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis. PMID- 20702770 TI - Diagnosis and management of Waldenstrom macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. AB - Waldenstrom macroglobulinemia is a B-cell malignancy with lymphoplasmacytic infiltration in the bone marrow or lymphatic tissue and a monoclonal immunoglobulin M protein (IgM) in the serum. It is incurable with current therapy, and the decision to treat patients as well as the choice of treatment can be complex. Using a risk-adapted approach, we provide recommendations on timing and choice of therapy. Patients with smoldering or asymptomatic Waldenstrom macroglobulinemia and preserved hematologic function should be observed without therapy. Symptomatic patients with modest hematologic compromise, IgM-related neuropathy that requires therapy, or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy. Patients who have severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyperviscosity should be treated with the DRC (dexamethasone, rituximab, cyclophosphamide) regimen. Any patient with symptoms of hyperviscosity should first be treated with plasmapheresis. For patients who experience relapse after a response to initial therapy of more than 2 years' duration, the original therapy should be repeated. For patients who had an inadequate response to initial therapy or a response of less than 2 years' duration, an alternative agent or combination should be used. Autologous stem cell transplant should be considered in all eligible patients with relapsed disease. PMID- 20702774 TI - IRF2BP2 is a skeletal and cardiac muscle-enriched ischemia-inducible activator of VEGFA expression. AB - We sought to identify an essential component of the TEAD4/VGLL4 transcription factor complex that controls vascular endothelial growth factor A (VEGFA) expression in muscle. A yeast 2-hybrid screen was used to clone a novel component of the TEAD4 complex from a human heart cDNA library. We identified interferon response factor 2 binding protein 2 (IRF2BP2) and confirmed its presence in the TEAD4/VGLL4 complex in vivo by coimmunoprecipitation and mammalian 2-hybrid assays. Coexpression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 alone potently activated, whereas knockdown of IRF2BP2 reduced, VEGFA expression in C(2)C(12) muscle cells. Thus, IRF2BP2 is required to activate VEGFA expression. In mouse embryos, IRF2BP2 was ubiquitously expressed but became progressively enriched in the fetal heart, skeletal muscles, and lung. Northern blot analysis revealed high levels of IRF2BP2 mRNA in adult human heart and skeletal muscles, but immunoblot analysis showed low levels of IRF2BP2 protein in skeletal muscle, indicating post transcriptional regulation of IRF2BP2 expression. IRF2BP2 protein levels are markedly increased by ischemia in skeletal and cardiac muscle compared to normoxic controls. IRF2BP2 is a novel ischemia-induced coactivator of VEGFA expression that may contribute to revascularization of ischemic cardiac and skeletal muscles. PMID- 20702775 TI - Structural basis for tandem L27 domain-mediated polymerization. AB - The establishment of epithelial cell polarity requires the assembly of multiprotein complexes and is crucial during epithelial morphogenesis. Three scaffolding proteins, Dlg1, MPP7, and Mals3, can be assembled to form a complex that functions in the establishment and maintenance of apicobasal polarity in epithelial tissues through their L27 domains. Here we report the crystal structure of a 4-L27-domain complex derived from the human tripartite complex Dlg1-MPP7-Mals3 in combination with paramagnetic relaxation enhancement measurements. The heterotrimer consists of 2 pairs of heterodimeric L27 domains. These 2 dimers are asymmetric due to the large difference between the N- and C terminal tandem L27 domain of MPP7. Structural analysis combined with biochemical experiments further reveals that the loop alphaA-alphaB and helix alphaB of the C terminal L27 domain of MPP7 play a critical role in assembling the entire tripartite complex, suggesting a synergistic tandem L27-mediated assembling event. PMID- 20702776 TI - The chemokine CCL18 generates adaptive regulatory T cells from memory CD4+ T cells of healthy but not allergic subjects. AB - The purpose of this study was to assess the direct effect of CCL18, a chemokine elevated in allergic diseases and induced by Th2 cytokines, on the polarization of human CD4(+) T cells. Purified human T cells from healthy subjects were pretreated or not with CCL18, and evaluated for cytokine production. CCL18 pretreated memory but not naive CD4(+) T cells exhibited an increased production of IL-10 (12.3 +/- 2.6 vs. 5.6 +/- 0.9 ng/ml for medium) and TGF-beta1 but not IL 4, IFN-gamma, and IL-17 compared with control cells. Pretreatment of highly purified CD4(+)CD25(-) memory T cells with CCL18 led to their conversion to CD4(+)CD25(+)Foxp3(+) regulatory T cells able to inhibit the proliferation of CD4(+)CD25(-) effector T cells by both cytokine and cell contact-dependent mechanisms. However, this regulatory effect of CCL18 was lost when T cells originated from allergic subjects in relation with a decreased binding of CCL18 to these cells [0.7 +/- 0.3 mean fluorescence intensity (MFI)] as compared to those from healthy subjects (6.0 +/- 1.7 MFI). This study is the first to define a chemokine that generates adaptive regulatory T cells from CD4(+)CD25(-) memory T cells. This mechanism appears defective in allergic patients and may underlie the decreased tolerance observed in allergic diseases. PMID- 20702777 TI - Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements. AB - Podosomes are recently rediscovered highly dynamic actin-rich structural and functional modules that form close contact with the surrounding substrate. They play a role in the control of migration, tissue invasion, and matrix remodeling of highly motile cells, including lymphocytes, macrophages, dendritic cells, and osteoclasts. In osteoclasts, the compaction of podosomes induces the formation of a tight adhesive contact, the sealing zone, which defines a subosteoclastic environment specialized for bone resorption. Integrins and the Rho family small GTPases are key regulators of podosome rearrangements. However, it remains to be determined how the activation of integrins and Rho family GTPases is regulated during osteoclast podosome rearrangements. Here, we demonstrate a crucial role for the FERM domain-containing guanine nucleotide exchange factor (GEF), FARP2, in osteoclast podosome rearrangements and resorbing activity. We determine by live cell imaging and biochemical assays that FARP2 is required for localized activation of GTP-bound Rac1 into podosome-ring like structures. In addition, FARP2 is relevant to integrin beta3 activity during osteoclastogenesis. Furthermore, FARP2 deficiency results in reduced formation of multinucleated osteoclasts and resorption pits compared to wild-type osteoclasts (controls). Collectively, our findings reveal an integral role of FARP2 for regulation of Rac1 and integrin beta3 throughout podosome rearrangement in osteoclastogenesis. PMID- 20702778 TI - The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. AB - Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi city to subsets of normal cells. PMID- 20702779 TI - Different molecular behavior of CD40 mutants causing hyper-IgM syndrome. AB - CD40/CD40 ligand (CD40L) cross-talk plays a key role in B-cell terminal maturation in the germinal centers. Genetic defects affecting CD40 cause a rare form of hyper-immunoglobulin M (IgM) syndrome, a disorder characterized by low or absent serum IgG and IgA, associated with recurrent infections. We previously reported on a few patients with homozygous CD40 mutations resulting in lack or severe reduction of CD40 cell surface expression. Here we characterize the 3 CD40 mutants due to missense mutations or small in-frame deletions, and show that the mutated proteins are synthesized but retained in the endoplasmic reticulum (ER), likely due to protein misfolding. Interestingly, the intracellular behavior and fate differ significantly among the mutants: progressive accumulation of the P2 mutant causes endoplasmic reticulum stress and the activation of an unfolded protein response; the mutant P4 is rather efficiently disposed by the ER associated degradation pathway, while the P5 mutant partially negotiates transport to the plasma membrane, and is competent for CD40L binding. Interestingly, this latter mutant activates downstream signaling elements when overexpressed in transfected cells. These results give new important insights into the molecular pathogenesis of HIGM disease, and suggest that CD40 deficiency can also be regarded as an ER-storage disease. PMID- 20702780 TI - Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential. AB - Antibody-mediated pure red cell aplasia is a rare but serious event resulting from the induction of neutralizing erythropoietin (Epo)-specific antibodies provoked by treatment with recombinant Epo. Because of the crucial role of CD4 T cells in humoral response, we have quantified the number of Epo-specific CD4 T cells in the blood of normal donors by in vitro stimulation. An important repertoire of preexisting Epo-specific T cells was observed in almost half of the donors, comparable with that of non-self-proteins. This observation suggests that, at the steady state, endogenous Epo weakly contributes to tolerance induction and may be ignored by the immune system. As a result, circulating Epo specific CD4 T cells could be prone to be activated by altered batches of Epo, providing them with costimulatory signals. Our data also highlight the relevance of T-cell assays performed with normal donors to evaluate the potential immunogenicity of therapeutic proteins. PMID- 20702781 TI - Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease. AB - Radioimmunotherapy (RIT) with alpha-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of alpha-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target alpha-emitters with short half lives, such as bismuth-213 (213Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [213Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)4SA was 16.5% +/- 7.0% injected dose per gram compared with 2.3% +/- .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 MU Ci [213Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 +/- .02 vs. 203.38 +/- 83.03 mm3 after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with 213Bi-labeled anti-CD20 PRIT. PMID- 20702782 TI - Who is fit for allogeneic transplantation? AB - The use of allogeneic hematopoietic cell transplantation (HCT) has expanded progressively, facilitated by the increasing availability of unrelated donors and cord blood, and the inclusion of older patients as transplantation candidates. Indications remain diagnosis-dependent. As novel nontransplantation modalities have been developed concurrently, many patients come to HCT only when no longer responding to such therapy. However, patients with refractory or advanced disease frequently relapse after HCT, even with high-dose conditioning, and more so with reduced-intensity regimens as used for patients of older age or with comorbid conditions. Thus, patients with high-risk malignancies who have substantial comorbidities or are of advanced age are at high risk of both relapse and nonrelapse mortality and should probably not be transplanted. Being in remission or at least having shown responsiveness to pre-HCT therapy is generally associated with increased transplantation success. In addition, to handle the stress associated with HCT, patients need a good social support system and a secure financial net. They must be well informed, not only about the transplantation process, but also about expected or potential post-HCT events, including graft-versus-host disease and delayed effects that may become manifest only years after HCT. PMID- 20702784 TI - Patient misidentifications caused by errors in standard bar code technology. AB - BACKGROUND: Bar code technology has decreased transcription errors in many healthcare applications. However, we have found that linear bar code identification methods are not failsafe. In this study, we sought to identify the sources of bar code decoding errors that generated incorrect patient identifiers when bar codes were scanned for point-of-care glucose testing and to develop solutions to prevent their occurrence. METHODS: We identified misread wristband bar codes, removed them from service, and rescanned them by using 5 different scanner models. Bar codes were reprinted in pristine condition for use as controls. We determined error rates for each bar code-scanner pair and manually calculated internal bar code data integrity checks. RESULTS: As many as 3 incorrect patient identifiers were generated from a single bar code. Minor bar code imperfections, failure to control for bar code scanner resolution requirements, and less than optimal printed bar code orientation were confirmed as sources of these errors. Of the scanner models tested, the Roche ACCU-CHEK(r) glucometer had the highest error rate. The internal data integrity check system did not detect these errors. CONCLUSIONS: Bar code-related patient misidentifications can occur. In the worst case, misidentified patient results could have been transmitted to the incorrect patient medical record. This report has profound implications not only for point-of-care testing but also for bar coded medication administration, transfusion recipient certification systems, and other areas where patient misidentifications can be life-threatening. Careful control of bar code scanning and printing equipment specifications will minimize this threat to patient safety. Ultimately, healthcare device manufacturers should adopt more robust and higher fidelity alternatives to linear bar code symbologies. PMID- 20702783 TI - Identification of essential filovirion-associated host factors by serial proteomic analysis and RNAi screen. AB - An assessment of the total protein composition of filovirus (ebolavirus and marburgvirus) virions is currently lacking. In this study, liquid chromatography linked tandem mass spectrometry of purified ebola and marburg virions was performed to identify associated cellular proteins. Host proteins involved in cell adhesion, cytoskeleton, cell signaling, intracellular trafficking, membrane organization, and chaperones were identified. Significant overlap exists between this data set and proteomic studies of disparate viruses, including HIV-1 and influenza A, generated in multiple cell types. However, the great majority of proteins identified here have not been previously described to be incorporated within filovirus particles. Host proteins identified by liquid chromatography linked tandem mass spectrometry could lack biological relevance because they represent protein contaminants in the virus preparation, or because they are incorporated within virions by chance. These issues were addressed using siRNA library-mediated gene knockdown (targeting each identified virion-associated host protein), followed by filovirus infection. Knockdown of several host proteins (e.g. HSPA5 and RPL18) significantly interfered with ebolavirus and marburgvirus infection, suggesting specific and relevant virion incorporation. Notably, select siRNAs inhibited ebolavirus, but enhanced marburgvirus infection, suggesting important differences between the two viruses. The proteomic analysis presented here contributes to a greater understanding of filovirus biology and potentially identifies host factors that can be targeted for antiviral drug development. PMID- 20702785 TI - Calcium homeostasis and skeletal integrity in individuals with familial hypercholesterolemia and aortic calcification. AB - BACKGROUND: Familial hypercholesterolemia (FH) due to mutations in the low density lipoprotein receptor (LDLR) gene exhibit severe, premature aortic calcification in a gene-dosage, age-dependent fashion. We sought to determine potential associations with mineral and skeletal indices. METHODS: We obtained computed tomography (CT) scan aortic calcium scores (AoCSs) in 19 (age 49 [SD 14] years) FH patients heterozygous for the 15-kb deletion at the LDLR gene and examined associations with various indices of mineral and skeletal homeostasis. RESULTS: We found that mean bone mineral density (BMD) at the femoral neck in these patients did not differ from age-, sex-, and province-matched mean BMD, and we observed no association of AoCS with any marker of bone resorption. However, there were negative correlations between AoCS and serum concentrations of osteocalcin, a marker of bone formation (r = -0.64, P = 0.0034), urinary calcium (r = -0.59, P = 0.0085), and estimated glomerular filtration rate (r = -0.67, P = 0.0019). CONCLUSIONS: We found that LDLR-deficient FH was not associated with obvious bone loss or a major disturbance in calcium homeostasis. The lack of LDLR, however, may modify osteoblast function or extracellular calcium distribution, manifesting as lower bone formation, and reduced calcium excretion, resulting in increased deposition in calcifying vascular tissue. PMID- 20702786 TI - Bring your best to the table. PMID- 20702787 TI - European Atherosclerosis Society screening recommendations for lipoprotein(a) and high-sensitivity C-reactive protein: double standard or failure of evidence-based medicine? PMID- 20702788 TI - First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging. AB - BACKGROUND: Both bevacizumab and erlotinib have clinical activity in non-small cell lung cancer (NSCLC). Preclinical data suggest synergistic activity. PATIENTS AND METHODS: Chemonaive patients with stage IIIb or IV non-squamous NSCLC were treated with bevacizumab 15 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Primary end point was non-progression rate (NPR) at 6 weeks. Tumor response was measured with computed tomography, 2-[fluorine-18]fluoro-2-deoxy-D glucose (FDG-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). KRAS and EGFR mutations were assessed in tumor samples. RESULTS: Forty seven patients were included. Median follow-up was 15.2 months. NPR at 6 weeks was 75%. Median progression-free survival (PFS) was 3.8 [95% confidence interval (CI) 2.3-5.4] months and median overall survival (OS) was 6.9 (95% CI 5.5-8.4) months. Toxicity was mainly mild. The presence of KRAS (n = 10) or EGFR mutations (n = 5) did not influence outcome. After 3 weeks of treatment, >20% decrease in standard uptake value as measured with positron emission tomography predicted for longer PFS (9.7 versus 2.8 months; P = 0.01) and >40% decrease in K(trans) as assessed by DCE-MRI did not predict for longer PFS. CONCLUSIONS: First-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG-PET is the best predictive test for PFS. PMID- 20702789 TI - What does the pedunculopontine nucleus do? PMID- 20702790 TI - Involvement of the human pedunculopontine nucleus region in voluntary movements. AB - OBJECTIVE: The pedunculopontine nucleus region (PPNR) is being investigated as a target for deep brain stimulation (DBS) in Parkinson disease (PD), particularly for gait and postural impairment. A greater understanding of how PPNR activities and oscillations are modulated with voluntary movements is crucial to the development of neuromodulation strategies. METHODS: We studied 7 patients with PD who underwent DBS electrode implantations in the PPNR. PPNR local field potential and EEG were recorded while patients performed self-paced wrist and ankle movements. RESULTS: Back-averaging of the PPNR recording showed movement-related potentials before electromyography onset. Frequency analysis showed 2 discrete movement-related frequency bands in the theta (6- to 10-Hz) and beta (14- to 30 Hz) ranges. The PPNR theta band showed greater event-related desynchronization with movements in the ON than in the OFF medication state and was coupled with the sensorimotor cortices in the ON state only. Beta event-related desynchronization was observed in the PPNR during the premovement and movement execution phases in the OFF state. In contrast, premovement PPNR beta event related synchronization occurred in the ON state. Moreover, beta band coherence between the PPNR and the midline prefrontal region was observed during movement preparation in the ON but not the OFF state. CONCLUSIONS: Activities of PPNR change during movement preparation and execution in patients with PD. Dopaminergic medications modulate PPNR activities and promote the interactions between the cortex and PPNR. Beta oscillations may have different functions in the basal ganglia and PPNR, and may be prokinetic rather than antikinetic in the PPNR. PMID- 20702791 TI - The core network in absence epilepsy. Differences in cortical and thalamic BOLD response. AB - OBJECTIVES: We used EEG-fMRI to study epileptiform activity in a cohort of untreated children with typical absence seizures (AS). Our aim was to identify cortical and subcortical regions involved in spike and wave events and to explore the timing of activity in these regions. METHODS: Eleven children with AS confirmed on video-EEG underwent EEG-fMRI. An event-related analysis of epileptiform activity was performed. Regions of interest (ROIs), identified in the event-related analysis, were used to study the time course of the blood oxygen level-dependent (BOLD) signal prior to and immediately following events of interest in these ROIs. RESULTS: Group analysis confirmed positive BOLD in the thalamus and negative BOLD in the lateral and mesial parietal lobe, caudate nuclei, and additionally the brainstem reticular formation. The event-related time course differed between the thalamus, the parietal cortex, and the pons and caudate nuclei. In the subcortical structures, BOLD signal change occurred at, or immediately after, electrographic onset. Importantly, in the parietal cortex, but not in other cortical regions, there was a subtle BOLD signal increase for 10 seconds prior to the onset of epileptiform activity. CONCLUSIONS: In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity. PMID- 20702792 TI - Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. AB - OBJECTIVE: To determine factors associated with baseline neurocognitive performance in HIV-infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy. METHODS: Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores <-2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression. RESULTS: The 292 participants had a median CD4 cell count of 536 cells/mm(3), 88% had an HIV viral load < or =400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was -0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not. CONCLUSIONS: In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation. PMID- 20702793 TI - Is the lithium-for-ALS genie back in the bottle?: Not quite. PMID- 20702795 TI - FXYD-11 associates with Na+-K+-ATPase in the gill of Atlantic salmon: regulation and localization in relation to changed ion-regulatory status. AB - The Na(+)-K(+)-ATPase is the primary electrogenic component driving transepithelial ion transport in the teleost gill; thus regulation of its level of activity is of critical importance for osmotic homeostasis. In the present study, we examined the dynamics of the gill-specific FXYD-11 protein, a putative regulatory subunit of the pump, in Atlantic salmon during seawater (SW) acclimation, smoltification, and treatment with cortisol, growth hormone, and prolactin. Dual-labeling immunohistochemistry showed that branchial FXYD-11 is localized in Na(+)-K(+)-ATPase immunoreactive cells, and coimmunoprecipitation experiments confirmed a direct association between FXYD-11 and the Na(+)-K(+) ATPase alpha-subunit. Transfer of freshwater (FW)-acclimated salmon to SW induced a parallel increase in total alpha-subunit and FXYD-11 protein expression. A similar concurrent increase was seen during smoltification in FW. In FW fish, cortisol induced an increase in both alpha-subunit and FXYD-11 abundance, and growth hormone further stimulated FXYD-11 levels. In SW fish, prolactin induced a decrease in FXYD-11 and alpha-subunit protein levels. In vitro cortisol (18 h, 10 MUg/ml) stimulated FXYD-11, but not FXYD-9, mRNA levels in gills from FW and SW salmon. The data show that Na(+)-K(+)-ATPase expressed in branchial mitochondrion rich cells is accompanied by FXYD-11, and that regulation of the two proteins is highly coordinated. The demonstrated association of FXYD-11 and alpha-subunit strengthens our hypothesis that FXYD-11 has a role in modulating the pump's kinetic properties. The presence of putative phosphorylation sites on the intracellular domain of FXYD-11 suggests the possibility that this protein also may transmit external signals that regulate Na(+)-K(+)-ATPase activity. PMID- 20702794 TI - Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose finding trial. AB - BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs. PMID- 20702797 TI - Editorial Focus: role for neural growth factor in autonomically driven arrhythmogenesis? Focus on: "Structural neuroplasticity following T5 spinal cord transection: increased cardiac sympathetic innervation density and SPN arborization". PMID- 20702798 TI - Adenoviral inhibition of AT1a receptors in the paraventricular nucleus inhibits acute increases in mean arterial blood pressure in the rat. AB - Brain and peripheral renin-angiotensin systems are important in blood pressure maintenance. Circulating ANG II stimulates brain RAS to contribute to the increase mean arterial pressure (MAP). This mechanism has not been fully clarified, so it was hypothesized that reducing angiotensin type 1a (AT(1a)) receptors (AT(1a)Rs) in the paraventricular nucleus (PVN) would diminish intravenous ANG II-induced increases in MAP. Adenoviruses (Ad) encoding AT(1a) small hairpin RNA (shRNA) or Ad-LacZ (marker gene) were injected into the PVN [1 * 10(9) plaque-forming units/ml, bilateral (200 nl/site)] of male Sprague-Dawley rats instrumented with radiotelemetry transmitters for MAP and heart rate measurements and with venous catheters for drug administration. No differences in weight gain or basal MAP were observed. ANG II (30 ng.kg(-1).min(-1) iv, 15 MUl/min for 60 min) was administered 3, 7, 10, and 14 days after PVN Ad injection to increase blood pressure. ANG II-induced elevations in MAP were significantly reduced in PVN Ad-AT(1a) shRNA rats compared with Ad-LacZ rats (32 +/- 6 vs. 8 +/ 9 mmHg at 7 days, 35 +/- 6 vs. 10 +/- 6 mmHg at 10 days, and 32 +/- 2 vs. 1 +/- 5 mmHg at 14 days; P < 0.05). These observations were confirmed by acute administration of losartan (20 nmol/l, 100 nl/site) in the PVN prior to short term infusion of ANG II; the ANG II-pressor response was attenuated by 69%. In contrast, PVN Ad-AT(1a) shRNA treatment did not influence phenylephrine-induced increases in blood pressure (30 MUg.kg(-1).min(-1) iv, 15 MUl/min for 30 min). Importantly, PVN Ad-AT(1a) shRNA did not alter superior mesenteric arterial contractility to ANG II or norepinephrine; ACh-induced arterial relaxation was also unaltered. beta-Galactosidase staining revealed PVN Ad transduction, and Western blot analyses revealed significant reductions of PVN AT(1) protein. In conclusion, PVN-localized AT(1)Rs are critical for short-term circulating ANG II mediated elevations of blood pressure. A sustained suppression of AT(1a)R expression by single administration of shRNA can interfere with short-term actions of ANG II. PMID- 20702796 TI - Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet. AB - Despite numerous clinical studies supporting a link between type 2 diabetes (T2D) and Parkinson's disease (PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IkappaBalpha in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure. PMID- 20702799 TI - Sex differences in nitrosative stress during renal ischemia. AB - Females suffer a less severe ischemic acute renal failure than males, apparently because of higher nitric oxide (NO) bioavailability and/or lower levels of oxidative stress. Because the renal ischemic injury is associated with outer medullary (OM) endothelial dysfunction, the present study evaluated sex differences in OM changes of NO and peroxynitrite levels (by differential pulse voltammetry and amperometry, respectively) during 45 min of ischemia and 60 min of reperfusion in anesthetized Sprague-Dawley rats. Endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) protein expression and their phosphorylated forms [peNOS(Ser1177) and pnNOS(Ser1417)], 3-nitrotyrosine, reduced sulfhydryl groups (-SH), and glomerular filtration rate (GFR) were also determined. No sex differences were observed in monomeric eNOS and nNOS expression, NO, or 3-nitrotyrosine levels in nonischemic kidneys, but renal -SH content was higher in females. Ischemia increased dimeric/monomeric eNOS and nNOS ratio more in females, but the dimeric phosphorylated peNOS(Ser1177) and pnNOS(Ser1417) forms rose similarly in both sexes, indicating no sex differences in nitric oxide synthase activation. However, NO levels increased more in females than in males (6,406.0 +/- 742.5 and 4,058.2 +/- 272.35 nmol/l respectively, P < 0.05), together with a lower increase in peroxynitrite current (5.5 +/- 0.7 vs. 12.7 +/- 1.5 nA, P < 0.05) and 3-nitrotyrosine concentration, (28.7 +/- 3.7 vs. 48.7 +/- 3.7 nmol/mg protein, P < 0.05) in females than in males and a better preserved GFR after ischemia in females than in males (689.7 +/- 135.0 and 221.4 +/- 52.5 MUl.min(-1).g kidney wt(-1), P < 0.01). Pretreatment with the antioxidants N-acetyl-L-cysteine or ebselen abolished sex differences in peroxynitrite, nitrotyrosine, and GFR, suggesting that a greater oxidative and nitrosative stress worsens renal damage in males. PMID- 20702800 TI - Maturation and long-term hypoxia-induced acclimatization responses in PKC mediated signaling pathways in ovine cerebral arterial contractility. AB - In the developing fetus, cerebral arteries (CA) show striking differences in signal transduction mechanisms compared with the adult, and these differences are magnified in response to high-altitude long-term hypoxia (LTH). In addition, in the mature organism, cerebrovascular acclimatization to LTH may be associated with several clinical problems, the mechanisms of which are unknown. Because PKC plays a key role in regulating CA contractility, in fetal and adult cerebral arteries, we tested the hypothesis that LTH differentially regulates the PKC mediated Ca(2+) sensitization pathways and contractility. In four groups of sheep [fetal normoxic (FN), fetal hypoxic (FH), adult normoxic (AN), and adult hypoxic (AH)], we examined, simultaneously, responses of CA tension and intracellular Ca(2+) concentration and measured CA levels of PKC, ERK1/2, RhoA, 20-kDa myosin light chain, and the 17-kDa PKC-potentiated myosin phosphatase inhibitor CPI-17. The PKC activator phorbol 12,13-dibutyrate (PDBu) produced robust contractions in all four groups. However, PDBu-induced contractions were significantly greater in AH CA than in the other groups. In all CA groups except AH, in the presence of MEK inhibitor (U-0126), the PDBu-induced contractions were increased a further 20 30%. Furthermore, in adult CA, PDBu led to increased phosphorylation of ERK1, but not ERK2; in fetal CA, the reverse was the case. PDBu-stimulated ERK2 phosphorylation also was significantly greater in FH than FN CA. Also, although RhoA/Rho kinase played a significant role in PDBu-mediated contractions of FN CA, this was not the case in FH or either adult group. Also, whereas CPI-17 had a significant role in adult CA contractility, this was not the case for the fetus. Overall, in ovine CA, the present study demonstrates several important maturational and LTH acclimatization changes in PKC-induced contractile responses and downstream pathways. The latter may play a key role in the pathophysiologic disorders associated with acclimatization to high altitude. PMID- 20702802 TI - Heme oxygenase activity as a determinant of the renal hemodynamic response to low dose ANG II. AB - ANG II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. PMID- 20702801 TI - Contractile properties of muscle fibers from the deep and superficial digital flexors of horses. AB - Equine digital flexor muscles have independent tendons but a nearly identical mechanical relationship to the main joint they act upon. Yet these muscles have remarkable diversity in architecture, ranging from long, unipennate fibers ("short" compartment of DDF) to very short, multipennate fibers (SDF). To investigate the functional relevance of the form of the digital flexor muscles, fiber contractile properties were analyzed in the context of architecture differences and in vivo function during locomotion. Myosin heavy chain (MHC) isoform fiber type was studied, and in vitro motility assays were used to measure actin filament sliding velocity (V(f)). Skinned fiber contractile properties [isometric tension (P(0)/CSA), velocity of unloaded shortening (V(US)), and force Ca(2+) relationships] at both 10 and 30 degrees C were characterized. Contractile properties were correlated with MHC isoform and their respective V(f). The DDF contained a higher percentage of MHC-2A fibers with myosin (heavy meromyosin) and V(f) that was twofold faster than SDF. At 30 degrees C, P(0)/CSA was higher for DDF (103.5 +/- 8.75 mN/mm(2)) than SDF fibers (81.8 +/- 7.71 mN/mm(2)). Similarly, V(US) (pCa 5, 30 degrees C) was faster for DDF (2.43 +/- 0.53 FL/s) than SDF fibers (1.20 +/- 0.22 FL/s). Active isometric tension increased with increasing Ca(2+) concentration, with maximal Ca(2+) activation at pCa 5 at each temperature in fibers from each muscle. In general, the collective properties of DDF and SDF were consistent with fiber MHC isoform composition, muscle architecture, and the respective functional roles of the two muscles in locomotion. PMID- 20702803 TI - Is tonic sympathetic vasoconstriction increased in the skeletal muscle vasculature of aged canines? AB - We tested the hypothesis that tonic adrenergic and nonadrenergic receptor mediated sympathetic vasoconstriction would increase at rest and during exercise with advancing age. Young (n = 6; 22 +/- 1 mo; means +/- SE) and old (n = 6; 118 +/- 9 mo) beagles were studied. Selective antagonists for alpha-1, alpha-2, neuropeptide Y (NPY), and purinergic (P(2x)) receptors were infused at rest and during treadmill running at 2.5 mph and 4 mph with 2.5% grade. Prazosin produced similar increases in vascular conductance in young and old beagles at rest (Young: 158 +/- 34%; Old: 98 +/- 19%) and during exercise at 2.5 mph (Young: 80 +/- 10%; Old: 58 +/- 12%) and 4 mph and 2.5% grade (Young: 57 +/- 5%; Old: 26 +/- 4%). Rauwolscine caused similar (P > 0.05) increases in vascular conductance in old compared with young dogs at rest (Young: 119 +/- 25%; Old: 64 +/- 22%) and at 2.5 mph (Young: 86 +/- 13%; Old: 60 +/- 7%) and 4 mph with 2.5% grade (Young: 61 +/- 5%; Old: 43 +/- 7%). N2-(diphenylacetyl)-N-[4-hydroxyphenyl)methyl]-d arginine amide (BIBP) caused a smaller increase (P < 0.05) in vascular conductance in old compared with young dogs at rest (Young: 179 +/- 44%; Old: 91 +/- 22%), whereas similar increases (P > 0.05) of experimental limb vascular conductance in young and old dogs occurred following BIBP during exercise at 2.5 mph (Young: 56 +/- 16%; Old: 50 +/- 12%) and 4 mph and 2.5% grade (Young: 45 +/- 10%; Old: 25 +/- 7%). Pyridoxal-phosphate-6-azophenyl-2'-4'-disulfonic acid infusion produced a larger increase in vascular conductance in old compared with young beagles at rest (Young: 88 +/- 14%; Old: 191 +/- 58%), whereas similar increases were observed at 2.5 mph (Young: 47 +/- 18%; Old: 31 +/- 11%) and 4 mph with 2.5% grade (Young: 26 +/- 13%; Old: -18 +/- 8%). At rest, NPY receptor mediated restraint of skeletal muscle blood flow was reduced with advancing age, whereas P(2x) receptor-mediated restraint of skeletal muscle blood flow was increased. During exercise, the magnitude of adrenergic and nonadrenergic sympathetic vasoconstriction was not different between young and old dogs. Overall, these data demonstrate that adrenergic receptor-mediated vasoconstriction was not elevated at rest, but nonadrenergic sympathetic vasoconstriction was altered under basal conditions in aged beagles. PMID- 20702805 TI - Memory may not be the first thing to go: focus on "Drinking and arterial blood pressure responses to ANG II in young and old rats". PMID- 20702804 TI - Taste does not determine daily intake of dilute sugar solutions in mice. AB - When a rodent licks a sweet-tasting solution, taste circuits in the central nervous system that facilitate stimulus identification, motivate intake, and prepare the body for digestion are activated. Here, we asked whether taste also determines daily intake of sugar solutions in C57BL/6 mice. We tested several dilute concentrations of glucose (167, 250, and 333 mM) and fructose (167, 250, and 333 mM). In addition, we tested saccharin (38 mM), alone and in binary mixture with each of the sugar concentrations, to manipulate sweet taste intensity while holding caloric value constant. In experiment 1, we measured taste responsiveness to the sweetener solutions in two ways: chorda tympani nerve responses and short-term lick tests. For both measures, the mice exhibited the following relative magnitude of responsiveness: binary mixtures > saccharin > individual sugars. In experiment 2, we asked whether the taste measures reliably predicted daily intake of the sweetener solutions. No such relationship was observed. The glucose solutions elicited weak taste responses but high daily intakes, whereas the fructose solutions elicited weak taste responses and low daily intakes. On the other hand, the saccharin + glucose solutions elicited strong taste responses and high daily intakes, while the saccharin + fructose solutions elicited strong taste responses but low daily intakes. Overall, we found that 1) daily intake of the sweetener solutions varied independently of the magnitude of the taste responses and 2) the solutions containing glucose stimulated substantially higher daily intakes than did the solutions containing isomolar concentrations of fructose. Given prior work demonstrating greater postoral stimulation of feeding by glucose than fructose, we propose that the magnitude of postoral nutritive stimulation plays a more important role than does taste in determining daily intake of dilute sugar solutions. PMID- 20702806 TI - Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. AB - Dietary nitrate (NO(3)(-)) supplementation with beetroot juice (BR) over 4-6 days has been shown to reduce the O(2) cost of submaximal exercise and to improve exercise tolerance. However, it is not known whether shorter (or longer) periods of supplementation have similar (or greater) effects. We therefore investigated the effects of acute and chronic NO(3)(-) supplementation on resting blood pressure (BP) and the physiological responses to moderate-intensity exercise and ramp incremental cycle exercise in eight healthy subjects. Following baseline tests, the subjects were assigned in a balanced crossover design to receive BR (0.5 l/day; 5.2 mmol of NO(3)(-)/day) and placebo (PL; 0.5 l/day low-calorie juice cordial) treatments. The exercise protocol (two moderate-intensity step tests followed by a ramp test) was repeated 2.5 h following first ingestion (0.5 liter) and after 5 and 15 days of BR and PL. Plasma nitrite concentration (baseline: 454 +/- 81 nM) was significantly elevated (+39% at 2.5 h postingestion; +25% at 5 days; +46% at 15 days; P < 0.05) and systolic and diastolic BP (baseline: 127 +/- 6 and 72 +/- 5 mmHg, respectively) were reduced by ~4% throughout the BR supplementation period (P < 0.05). Compared with PL, the steady-state Vo(2) during moderate exercise was reduced by ~4% after 2.5 h and remained similarly reduced after 5 and 15 days of BR (P < 0.05). The ramp test peak power and the work rate at the gas exchange threshold (baseline: 322 +/- 67 W and 89 +/- 15 W, respectively) were elevated after 15 days of BR (331 +/- 68 W and 105 +/- 28 W; P < 0.05) but not PL (323 +/- 68 W and 84 +/- 18 W). These results indicate that dietary NO(3)(-) supplementation acutely reduces BP and the O(2) cost of submaximal exercise and that these effects are maintained for at least 15 days if supplementation is continued. PMID- 20702807 TI - Differential control of renal and lumbar sympathetic nerve activity during freezing behavior in conscious rats. AB - The present study was designed to document changes in sympathetic nerve activity and cardiovascular function when conscious rats were challenged with a noise stressor to induce freezing behavior. The potential contribution of the arterial baroreceptors in regulating sympathetic nerve activity and cardiovascular adjustments during the freezing behavior was then examined. Wistar male rats were assigned to sham-operated (SO) and sinoaortic-denervated (SAD) groups and instrumented chronically with electrodes for measurements of renal (RSNA) and lumbar (LSNA) sympathetic nerve activity, electroencephalogram, electromyogram, and electrocardiogram and catheters for measurements of systemic arterial and central venous pressure. Both SO and SAD rats were exposed to 90 dB of white noise for 10 min, causing freezing behavior in both groups. In SO rats, freezing behavior was associated with an immediate and significant (P < 0.05) increase in RSNA, no changes in LSNA or mean arterial pressure, and a significant (P < 0.05) decrease in heart rate. SAD attenuated the magnitude of the immediate increase in RSNA and had no influence on the response in LSNA during freezing behavior compared with SO rats. Moreover, in SAD rats, mean arterial pressure increased significantly (P < 0.05) while heart rate did not change during the freezing behavior. These data indicate that freezing behavior evokes regionally different changes in sympathetic outflows, which may be involved in generating the patterned responses of cardiovascular function to stressful or threatening sensory stimulation. Moreover, it is suggested that the arterial baroreceptors are involved in generating the differential changes in RSNA and LSNA and thus the patterned changes in cardiovascular functions observed during freezing behavior in conscious rats. PMID- 20702808 TI - Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome. AB - Although complement activation is known to occur in the setting of severe hemorrhagic shock and tissue trauma (HS/T), the extent to which complement drives the initial inflammatory response and end-organ damage is uncertain. In this study, complement factor 3-deficient (C3(-/-)) mice and wild-type control mice were subjected to 1.5-h hemorrhagic shock, bilateral femur fracture, and soft tissue injury, followed by 4.5-h resuscitation (HS/T). C57BL/6 mice were also given 15 U of cobra venom factor (CVF) or phosphate-buffered saline injected intraperitoneally, followed by HS/T 24 h later. The results showed that HS/T resulted in C3 consumption in wild-type mice and C3 deposition in injured livers. C3(-/-) mice had significantly lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and circulating DNA levels, together with much lower circulating interleukin (IL)-6, IL-10, and high-mobility group box 1 (HMGB1) levels. Temporary C3 depletion by CVF preconditioning also led to reduced transaminases and a blunted cytokine release. C3(-/-) mice displayed well preserved hepatic structure. C3(-/-) mice subjected to HS/T had higher levels of heme oxygenase-1, which has been associated with tissue protection in HS models. Our data indicate that complement activation contributes to inflammatory pathways and liver damage in HS/T. This suggests that targeting complement activation in the setting of severe injury could be useful. PMID- 20702810 TI - Acidic extracellular environments strongly impair ABCA1-mediated cholesterol efflux from human macrophage foam cells. AB - OBJECTIVE: In the deep microenvironments of advanced human atherosclerotic lesions, the intimal fluid becomes acidic. We examined the effect of an acidic extracellular pH on cholesterol removal (efflux) from primary human macrophages. METHODS AND RESULTS: When cholesterol efflux from acetyl-low-density lipoprotein loaded macrophages to various cholesterol acceptors was evaluated at pH 7.5, 6.5, or 5.5, the lower the pH the more was cholesterol efflux reduced. The reduction of efflux to lipid-free apolipoprotein A-I was stronger than to high-density lipoprotein(2) or to plasma. Cholesterol efflux to every acceptor was severely compromised also at neutral pH when the macrophages had been loaded with cholesterol at acidic pH, or when both loading and efflux were carried out at acidic pH. Compatible with these observations, the typical upregulation of ABCA1 and ABCG1 mRNA levels in macrophages loaded with cholesterol at neutral pH was rapidly attenuated in acidic medium. The secondary structure of apolipoprotein A I did not changed over the pH range studied, supporting the notion that the inhibitory effect of acidic pH on cholesterol efflux rather impaired the ability of the foam cells to facilitate ABCA1-mediated cholesterol release. Secretion of apolipoprotein E from the foam cells was fully inhibited when the pH was 5.5, which further reduced cholesterol efflux. CONCLUSIONS: An acidic pH reduces cholesterol efflux via different pathways and particularly impairs the function of the ABCA1 transporter. The pH-sensitive function of human macrophage foam cells in releasing cholesterol may accelerate lipid accumulation in deep areas of advanced atherosclerotic plaques where the intimal fluid is acidic. PMID- 20702809 TI - High-density lipoproteins suppress chemokines and chemokine receptors in vitro and in vivo. AB - OBJECTIVE: To investigate whether high-density lipoproteins (HDLs) suppress chemokine (CCL2, CCL5, and CX(3)CL1) and chemokine receptor (CCR2 and CX(3)CR1) expression, a mechanism for the atheroprotective properties of HDLs. METHODS AND RESULTS: Apolipoprotein (apo) E(-/-) mice were fed a high-fat diet for 12 weeks. Before being euthanized, the mice received 5 consecutive daily injections of lipid-free apoA-I, 40 mg/kg, or saline (control). The injection of apoA-I reduced CCR2 and CX(3)CR1 expression in plaques compared with controls (P<0.05). ApoA-I injected mice had lower plasma CCL2 and CCL5 levels. Hepatic CCL2, CCL5, and CX(3)CL1 levels were also reduced (P<0.05). In vitro studies found that reconstituted HDL (rHDL) reduced monocyte CCR2 and CX(3)CR1 expression and inhibited their migration toward CCL2 and CX(3)CL1 (P<0.05). Preincubation with rHDL reduced CCL2, CCL5, and CX(3)CL1 expression in monocytes and human coronary artery endothelial cells. The stimulation of CX(3)CR1 with peroxisome proliferator-activated receptor gamma agonist CAY10410 was suppressed by preincubation with rHDL but did not affect the peroxisome proliferator-activated receptor gamma antagonist (GW9664)-mediated increase in CCR2. In monocytes and human coronary artery endothelial cells, rHDL reduced the expression of the nuclear p65 subunit, IkappaB kinase activity, and the phosphorylation of IkappaBalpha (P<0.05). CONCLUSIONS: Lipid-free apoA-I and rHDL reduce the expression of chemokines and chemokine receptors in vivo and in vitro via modulation of nuclear factor kappaB and peroxisome proliferator-activated receptor gamma. PMID- 20702811 TI - Resolvin E1 regulates adenosine diphosphate activation of human platelets. AB - OBJECTIVE: To investigate the ability of resolvin E1 (RvE1) to regulate adenosine diphosphate (ADP) activation of platelets via specific receptors because RvE1 reduces platelet aggregation with certain agonists, including ADP. METHODS AND RESULTS: RvE1 is an eicosapentaenoic acid-derived specialized proresolving mediator generated during the resolution of acute inflammation. RvE1 exhibits potent organ-protective actions in vivo and acts on specific cell types, including platelets. RvE1, 0.1 to 100 nmol/L, incubated with platelets gave reduced ADP-stimulated P-selectin mobilization (IC(50), approximately 1.6*10(-12) mol/L) and polymerized actin content compared with control platelets. RvE1, 1 to 100 nmol/L, did not stimulate or block intracellular Ca(2+) mobilization. By using a new P2Y(12)-beta-arrestin-coupled cell system, ADP-activated P2Y(12) with an EC(50) of 5*10(-6) mol/L and RvE1 did not directly stimulate P2Y(12) or block the ADP-P2Y(12) signals. In this system, another eicosanoid, leukotriene E(4) (LTE(4)) (EC(50), 1.3*10(-11) mol/L), dose dependently activated P2Y(12). When recombinant P2Y(12)-expressing cells were transiently transfected with an RvE1 receptor, human ChemR23 (present on human platelets), with the addition of RvE1 (0.1-10.0 nmol/L), blocked ADP signals (IC(50), approximately 1.6*10(-11) mol/L) in P2Y(12)-ChemR23-expressing cells compared with mock transfections. CONCLUSIONS: RvE1's regulatory actions (ie, reducing ADP-stimulated P-selectin mobilization and actin polymerization) are human (h)ChemR23-dependent. Moreover, specific platelet actions of RvE1 selectively engaged with ADP-activated platelets that illuminate a new cellular mechanism and affect omega-3 eicosapentaenoic acid, which may contribute to both resolution of vascular inflammation and ADP-dependent platelet activation relevant in pathological cardiovascular events. PMID- 20702812 TI - Endothelium-dependent coronary vasodilatation requires NADPH oxidase-derived reactive oxygen species. AB - OBJECTIVE: To determine the functional significance of physiological reactive oxygen species (ROS) levels in endothelium-dependent nitric oxide (NO)-mediated coronary vasodilatation. METHODS AND RESULTS: Endothelium-derived NO is important in regulating coronary vascular tone. Excess ROS have been shown to reduce NO bioavailability, resulting in endothelial dysfunction and coronary diseases. NADPH oxidase is a major source of ROS in endothelial cells (ECs). By using lucigenin-based superoxide production and dichlorfluorescein diacetate (DCFH-DA) fluorescence-activated cell sorter assays, we found that mouse heart ECs from NADPH oxidase-knockdown (p47(phox-/-)) animals have reduced NADPH oxidase activity (>40%) and ROS levels (>30%) compared with wild-type mouse heart ECs. Surprisingly, a reduction in ROS did not improve coronary vasomotion; rather, endothelium-dependent vascular endothelial growth factor-mediated coronary vasodilatation was reduced by greater than 50% in p47(phox-/-) animals. Western blots and L-citrulline assays showed a significant reduction in Akt/protein kinase B (PKB) and endothelial NO synthase phosphorylation and NO synthesis, respectively, in p47(phox-/-) coronary vessels and mouse heart ECs. Adenoviral expression of constitutively active endothelial NO synthase restored vascular endothelial growth factor-mediated coronary vasodilatation in p47(phox-/-) animals. CONCLUSIONS: Endothelium-dependent vascular endothelial growth factor regulation of coronary vascular tone may require NADPH oxidase-derived ROS to activate phosphatidylinositol 3-kinase-Akt-endothelial NO synthase axis. PMID- 20702814 TI - Tobacco control policy in developed countries: yesterday, today, and tomorrow. AB - INTRODUCTION: Tobacco control policies have contributed to dramatic declines in smoking in the developed nations. However, the circumstances under which these policies altered the smoking landscape have changed and are likely to change further. As well, decreases in smoking prevalence may have "stalled" at current levels. Because today's smokers differ significantly from yesterday's and the environment in which smokers consume their cigarettes has changed, it is plausible that several of the evidence-based tobacco control policies soon will have run their course in the most advanced tobacco control environments. We ask, therefore, what developed nations can expect of these policies in the future and what novel policy measures may be needed to continue the assault on tobacco. DISCUSSION: After summarizing tobacco control success in the United States and the findings from tobacco control policy research, we consider the remaining problem focusing on the characteristics of remaining smokers and their circumstances. We then examine constraints on the continuing effectiveness of evidence-based policy interventions. We employ a model to project U.S. smoking prevalence decades into the future, with and without improvements in initiation and cessation rates. We then speculate about novel policy directions that will be needed to further move the needle of tobacco control. CONCLUSION: Without substantial innovation in tobacco control policy, further reductions in smoking in developed nations will come frustratingly slowly. Needed policy innovations might be quite radical, such as legislating entirely smoke-free outdoor environments or regulators reducing allowable nicotine in cigarettes to non addicting levels. PMID- 20702813 TI - Sphingosine 1-phosphate receptor 2 signals through leukemia-associated RhoGEF (LARG), to promote smooth muscle cell differentiation. AB - OBJECTIVE: The goals of this study were to identify the signaling pathway by which sphingosine 1-phosphate (S1P) activates RhoA in smooth muscle cells (SMC) and to evaluate the contribution of this pathway to the regulation of SMC phenotype. METHODS AND RESULTS: Using a combination of receptor-specific agonists and antagonists we identified S1P receptor 2 (S1PR2) as the major S1P receptor subtype that regulates SMC differentiation marker gene expression. Based on the known coupling properties of S1PR2 and our demonstration that overexpression of Galpha(12) or Galpha(13) increased SMC-specific promoter activity, we next tested whether the effects of S1P in SMC were mediated by the regulator of G protein signaling-Rho guanine exchange factors (RGS-RhoGEFs) (leukemia-associated RhoGEF [LARG], PDZ-RhoGEF [PRG], RhoGEF [p115]). Although each of the RGS-RhoGEFs enhanced actin polymerization, myocardin-related transcription factor-A nuclear localization, and SMC-specific promoter activity when overexpressed in 10T1/2 cells, LARG exhibited the most robust effect and was the only RGS-RhoGEF activated by S1P in SMC. Importantly, siRNA-mediated depletion of LARG significantly inhibited the activation of RhoA and SMC differentiation marker gene expression by S1P. Knockdown of LARG had no effect on SMC proliferation but promoted SMC migration as measured by scratch wound and transwell assays. CONCLUSIONS: These data indicate that S1PR2-dependent activation of RhoA in SMC is mediated by LARG and that this signaling mechanism promotes the differentiated SMC phenotype. PMID- 20702815 TI - Optic neuropathy due to microbead-induced elevated intraocular pressure in the mouse. AB - PURPOSE: To characterize a glaucoma model of mice, the authors adopted and modified a method of inducing the chronic elevation of intraocular pressure (IOP) by anterior chamber injection of polystyrene microbeads. METHODS: Chronic elevation of IOP was induced unilaterally in adult C57BL/6J mice by injecting polystyrene microbeads to the anterior chamber. Effectiveness of microbeads of different sizes (small, 10 MUm; large, 15 MUm) on inducing IOP elevation was compared, and IOP was measured every other day using a tonometer. After maintaining elevated IOP for 2, 4, or 8 weeks, the degree of RGC and axon degeneration was assessed quantitatively using electron microscopy, fluorogold, retrograde labeling, and immunohistochemistry. RESULTS: Eighty-one of 87 mice that received anterior chamber injection of microbeads exhibited consistent IOP elevation above that of control eyes. Injection of small microbeads induced longer and higher peak value of IOP elevation compared with that of the large microbeads. A single injection of small microbeads resulted in a 4-week elevation of IOP that was maintained to an 8-week period after a second injection of microbeads in week 4. As the duration of IOP elevation increased, RGC bodies and their axons degenerated progressively and reached an approximately 50% loss after an 8-week elevation of IOP. CONCLUSIONS: Anterior chamber injection of microbeads effectively induced IOP elevation and glaucomatous optic neuropathy in mice. Development of an inducible mouse model of elevated IOP will allow applications of mouse genetic technology to the investigation of the mechanisms and the evaluation of treatment strategies of glaucoma. PMID- 20702816 TI - Glucose uptake in rat extraocular muscles: effect of insulin and contractile activity. AB - PURPOSE: Extraocular muscles show specific adaptations to fulfill the metabolic demands imposed by their constant activity. One aspect that has not been explored is the availability of substrate for energy pathways in extraocular muscles. In limb muscles, glucose enters by way of GLUT1 and GLUT4 transporters in a process regulated by insulin and contractile activity to match metabolic supply to demand. This mechanism may not apply to extraocular muscles because their constant activity may require high basal (insulin- and activity-independent) glucose uptake. The authors tested the hypothesis that glucose uptake by extraocular muscles is not regulated by insulin or contractile activity. METHODS: Extraocular muscles from adult male Sprague-Dawley rats were incubated with 100 nM insulin or were electrically stimulated to contract (activity); glucose uptake was measured with 2-deoxy-d[1,2-(3)H]glucose. The contents of GLUT1, GLUT4, total and phosphorylated protein kinase B (Akt), phosphorylated AMP-activated protein kinase (AMPK), and glycogen synthase kinase 3 (GSK3) underwent Western blot analysis. RESULTS: Insulin and activity increased glucose uptake over the basal rate to 108% and 78%, respectively. GLUT1 and GLUT4 were detectable in extraocular muscles. Phosphorylated AKT/total AKT increased by twofold after insulin stimulation, but there was no change with activity. AMPK phosphorylation increased 35% with activity. Phosphorylated-GSK3/total GSK3 did not change with insulin or activity. CONCLUSIONS: Glucose uptake in extraocular muscles is regulated by insulin and contractile activity. There is evidence of differences in the insulin signaling pathway that may explain the low glycogen content in these muscles. PMID- 20702817 TI - Green tea polyphenols attenuating ultraviolet B-induced damage to human retinal pigment epithelial cells in vitro. AB - PURPOSE: To examine the protective effect of green tea polyphenols against ultraviolet B (UVB)-induced damage to retinal pigment epithelial (RPE) cells. METHODS: Green tea polyphenols (GTP) was used to treat RPE cells before or after exposure to UVB. Viability of RPE cells was tested by 3,(4,5-dimethylthiazol-2 yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Survivin gene expression was examined by real-time PCR analysis. Ultrastructure of RPE cells was examined by transmission electron microscopy. RESULTS: GTP effectively suppressed the decrease in viability of the UVB stressed RPE cells and the UVB suppression of survivin gene expression level. GTP alleviated mitochondria dysfunction and DNA fragmentation induced by UVB. CONCLUSIONS: GTP protected RPE cells from UVB damage through its increase in the survivin gene expression and its attenuation of mitochondria dysfunction and DNA fragmentation. GTP is a potential candidate for further development as a chemoprotective factor for the primary prevention of age-related eye diseases such as age-related macular degeneration. PMID- 20702818 TI - Two different regulatory T cell populations that promote corneal allograft survival. AB - PURPOSE: To compare and contrast the T regulatory cells (Tregs) induced by anterior chamber (AC) injection of antigen with those induced by orthotopic corneal allografts. METHODS: Anterior chamber-associated immune deviation (ACAID) Tregs were induced by injecting C57BL/6 spleen cells into the AC of BALB/c mice. Delayed-type hypersensitivity responses to C57BL/6 alloantigens were evaluated by a conventional ear swelling assay. Corneal allograft Tregs were induced by applying orthotopic C57BL/6 corneal allografts onto BALB/c hosts. The effects of anti-CD25, anti-CD8, anti-interferon-gamma (IFN-gamma), anti-IL-17A, or cyclophosphamide treatments on corneal allograft survival and ACAID were evaluated. RESULTS: Administration of either anti-CD25 or anti-IFN-gamma antibodies prevented the expression of ACAID and abolished the immune privilege of corneal allografts. By contrast, in vivo treatment with anti-CD8 antibody abrogated ACAID but had no effect on corneal allograft survival. Further discordance between ACAID and corneal allograft survival emerged in experiments in which the induction of allergic conjunctivitis or the administration of anti IL-17A abolished the immune privilege of corneal allografts but had no effect on the induction or expression of ACAID. CONCLUSIONS: Although orthotopic corneal allografts are strategically located for the induction of ACAID by the sloughing of corneal cells into the AC, the results reported here indicate that the Tregs induced by orthotopic corneal allografts are remarkably different from the Tregs that are induced by AC injection of alloantigen. Although both of these Treg populations promote corneal allograft survival, they display distinctly different phenotypes. PMID- 20702819 TI - Detection and gram discrimination of bacterial pathogens from aqueous and vitreous humor using real-time PCR assays. AB - PURPOSE: To develop and apply real-time PCR protocols to the detection and classification of the Gram status of bacterial pathogens in aqueous and vitreous humor collected from clinically suspected intraocular infections. METHODS: The analytical specificity of two PCR assays, SYBR Green 16S rDNA-Based Universal PCR (SGRU-PCR), and a Multiplex Gram-Specific TaqMan-Based PCR (MGST-PCR), was determined with 31 clinically important pathogens, including 20 Gram-positive and 11 Gram-negative. Analytical sensitivity was determined with a 10-fold dilution of Staphylococcus epidermidis and Escherichia coli DNA. Assays were further tested on aqueous (n = 10) and vitreous humor (n = 11) samples collected from patients with clinically diagnosed intraocular infections. RESULTS: DNA was amplified from all control bacterial isolates when using SGRU-PCR. MGST-PCR correctly classified the Gram status of all these isolates. The SGRU-PCR limit of detection of S. epidermidis and E. coli DNA was 100 fg/MUL (E = 0.82 and 0.86; r(2) = 0.99) and for MGST-PCR, 1 pg/MUL (E = 0.66 and 0.70; r(2) = 0.99. For clinical intraocular samples, positivity of culture was 47.6% and for real-time PCR assays, 95.2%. Gram classification was achieved in 100% of MGST-PCR-positive samples. Among microbiologically negative samples, real-time PCR assays were positive in 90% of cases. The false-positive rate in control aqueous was 3.2%, and control samples of vitreous were negative. CONCLUSIONS: The real-time PCR assays demonstrated good correlation, with culture-proven RESULTS: With the use of these methods, bacterial detection was improved from 47.6% to 95.3%, demonstrating them to be sensitive, rapid tests for diagnosis of bacterial endophthalmitis. PMID- 20702820 TI - Clinical and antiviral efficacy of an ophthalmic formulation of dexamethasone povidone-iodine in a rabbit model of adenoviral keratoconjunctivitis. AB - PURPOSE: To determine the efficacy of a new formulation of topical dexamethasone 0.1%/povidone-iodine 0.4% (FST-100) in reducing clinical symptoms and infectious viral titers in a rabbit model of adenoviral keratoconjunctivitis. METHODS: Rabbit corneas were inoculated bilaterally with 2*10(6) plaque-forming-units (PFU) of adenovirus type 5 (Ad5) after corneal scarification. Animals were randomized 1:1:1:1 (five rabbits per group) to FST-100, 0.5% cidofovir, tobramycin/dexamethasone (Tobradex; Alcon Laboratories, Fort Worth, TX) ophthalmic suspension, and balanced salt solution (BSS; Alcon Laboratories). Treatment began 12 hours after viral inoculation and continued for 7 consecutive days. The eyes were clinically scored daily for scleral inflammation (injection), ocular neovascularization, eyelid inflammation (redness), friability of vasculature, inflammatory discharge (pus), and epiphora (excessive tearing). Eye swabs were collected daily before treatment for the duration of the study. Virus was eluted from the swabs and PFU determined by titration on human A549 cells, according to standard procedures. RESULTS: The FST-100 treatment resulted in significantly lower clinical scores (P<0.05) than did the other treatments. The 0.5% cidofovir exhibited the most ocular toxicity compared with FST-100, tobramycin/dexamethasone, and balanced salt solution treatments. FST-100 and 0.5% cidofovir significantly (P<0.05) reduced viral titers compared with tobramycin/dexamethasone or balanced salt solution. CONCLUSIONS: FST-100 was the most efficacious in minimizing the clinical symptoms of adenovirus infection in rabbit eyes. FST-100 and 0.5% cidofovir were both equally effective in reducing viral titers and decreasing the duration of viral shedding. By providing symptomatic relief in addition to reducing infectious virus titers, FST-100 should be a valuable addition to treatment of epidemic adenoviral keratoconjunctivitis. PMID- 20702821 TI - Potentiation of bortezomib-induced apoptosis by TGF-beta in cultured human Tenon's fibroblasts: contribution of the PI3K/Akt signaling pathway. AB - PURPOSE: To investigate the effects of bortezomib on cell apoptosis and proliferation in human Tenon's capsule fibroblasts (HTFs) after cotreatment with TGF-beta. METHODS: The effect of bortezomib on the apoptosis and cell proliferation of cultured HTFs was determined with FACS analysis and 3-[4,5 demethylthiazol-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assay with or without cotreatment of TGF-beta. The apoptotic effect of cotreatment of bortezomib and TGF-beta through the PI3K/Akt pathway was determined by Western blot analysis. The mRNA level of Bcl-2 and Bax was determined by RT-PCR. p53 expression, DNA PKcs cleavage, and c-Jun phosphorylation were determined. RESULTS: Cotreatment with bortezomib (5 MUM) and TGF-beta (10 MUM) increased the proportion of apoptotic cells in HTFs on FACS analysis, whereas either bortezomib or TGF-beta treatment alone did not. The MTT assay also showed that when bortezomib was cotreated with TGF-beta, the cell proliferation of HTFs induced by TGF-beta treatment was significantly decreased at 72-hour incubation. The cotreatment of bortezomib and TGF-beta specifically decreased the Akt phosphorylation induced by TGF-beta, indicating on Western blot analysis that these changes are mediated by the PI3K/Akt pathway. The mRNA level of an apoptosis-related factor, Bcl-2, was significantly reduced, and p53 expression, DNA-PKcs cleavage, and c-Jun phosphorylation were increased after cotreatment. CONCLUSIONS: Bortezomib-induced apoptosis is potentiated by TGF-beta cotreatment in cultured HTFs by inhibition of the PI3K/Akt pathway, indicating that the effect of bortezomib may be potentiated when the level of TGF-beta is elevated, as is observed in the postoperative period. PMID- 20702822 TI - Human retinal disease from AIPL1 gene mutations: foveal cone loss with minimal macular photoreceptors and rod function remaining. AB - PURPOSE: To determine the human retinal phenotype caused by mutations in the gene encoding AIPL1 (Aryl hydrocarbon receptor-interacting protein-like 1) now that there are proof-of-concept results for gene therapy success in Aipl1-deficient mice. METHODS: Leber congenital amaurosis (LCA) patients (n = 10) and one patient with a later-onset retinal degeneration (RD) and AIPL1 mutations were studied by ocular examination, retinal imaging, perimetry, full-field sensitivity testing, and pupillometry. RESULTS: The LCA patients had severe visual acuity loss early in life, nondetectable electroretinograms (ERGs), and little or no detectable visual fields. Hallmarks of retinal degeneration were present in a wide region, including the macula and midperiphery; there was some apparent peripheral retinal sparing. Cross-sectional imaging showed foveal cone photoreceptor loss with a ring of minimally preserved paracentral photoreceptor nuclear layer. Features of retinal remodeling were present eccentric to the region of detectable photoreceptors. Full-field sensitivity was reduced by at least 2 log units, and chromatic stimuli, by psychophysics and pupillometry, revealed retained but impaired rod function. The RD patient, examined serially over two decades (ages, 45-67 years), retained an ERG in the fifth decade of life with abnormal rod and cone signals; and there was progressive loss of central and peripheral function. CONCLUSIONS: AIPL1-LCA, unlike some other forms of LCA with equally severe visual disturbance, shows profound loss of foveal as well as extrafoveal photoreceptors. The more unusual late-onset and slower form of AIPL1 disease may be better suited to gene augmentation therapy and is worthy of detection and further study. PMID- 20702823 TI - A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. AB - PURPOSE: To examine the ocular malformations and identify the molecular genetic basis for autosomal recessive ectopia lentis et pupillae in five Norwegian families. METHODS: Ten affected persons and 11 first-degree relatives of five Norwegian families underwent ophthalmic and general medical examination. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and RT-PCR analysis. RESULTS: Ocular signs in affected persons were increased median corneal thickness and astigmatism, angle malformation with prominent iris processes, displacement of the pupil and lens, lens coloboma, spherophakia, loss of zonular threads, early cataract development, glaucoma, and retinal detachment. No cardiac or metabolic abnormalities known to be associated with ectopia lentis were detected. Affected persons shared a 0.67 cM region of homozygosity on chromosome 1. DNA sequencing revealed a novel mutation in ADAMTSL4, c.767_786del20. This deletion of 20 base pairs (bp) results in a frameshift and an introduction of a stop codon 113 bp downstream, predicting a C terminal truncation of the ADAMTSL4 protein (p.Gln256ProfsX38). Expression of truncated ADAMTSL4 mRNA was confirmed by RT-PCR analysis. Three of 190 local blood donors were carriers of this mutation. CONCLUSIONS: Ectopia lentis et pupillae is associated with a number of malformations primarily in the anterior segment of the eye. The causative mutation, which is the first to be described in ectopia lentis et pupillae, disrupts the same gene function previously shown to cause isolated ectopia lentis. The mutation is ancient and may, therefore, be spread to a much larger population than the investigated one. PMID- 20702824 TI - In vivo measurement of blood velocity in human major retinal vessels using the laser speckle method. AB - PURPOSE: To develop a simple, noninvasive method of determining blood velocity and flow through human retinal vessels (RVs), by using the laser speckle method and validating the results by bidirectional laser Doppler velocimetry (LDV). METHOD: The square blur rate (SBR), a quantitative blurring index of the laser speckle pattern that parallels the velocity of moving substances, obtained from blood flowing through glass capillary tubes (RV analogues), correlated with tube diameter, background reflectance and absorption, flow velocity, and the SBR obtained from blood flowing through underlying glass capillary tubes (choroidal vessel analogues). A nomogram was constructed to calculate the blood velocity in human RVs from the SBR values obtained in vivo. Blood velocities in RVs were determined in 12 normal eyes by using the laser speckle method and bidirectional LDV. Measurements were performed twice at the same site at 1-hour intervals. RESULTS: Measurements from a temporal superior artery (n = 12; mean +/- SD) were blood velocity (V(mean)), 41.7 +/- 4.2 mm/s; flow, 13.0 +/- 3.2 MUL/min; and diameter, 119.5 +/-15.7 MUm and time to complete one measurement, 65 +/- 18 seconds, with the laser speckle apparatus; and V(mean), 37.7 +/- 6.7 mm/s; flow, 11.7 +/-3.0 MUL/min; diameter, 111.1 +/-16.6 MUm; and measurement time, 112 +/- 25 seconds, with the bidirectional LDV apparatus. The results obtained by the two methods correlated with each other (V(mean), r = 0.59, P = 0.023; flow, r = 0.83, P = 0.005; and diameter, r = 0.56, P = 0.032). The coefficients of reproducibility for V(mean), blood flow, and diameter measurement were 9.5% +/- 2.5%, 10.5% +/- 3.2%, and 5.3% +/- 2.7% for the former and 15.3% +/- 4.2%, 18.5% +/- 4.1%, and 6.2% +/- 2.2% for the latter, respectively. CONCLUSIONS: The laser speckle method accurately and reproducibly determines blood velocity in human RVs in less time than the LDV apparatus requires. PMID- 20702825 TI - GLUT-1 expression in bovine retinal capillary endothelial cells and pericytes exposed to advanced glycation end products. AB - PURPOSE: Glucose uptake and glucose transporter GLUT-1 expressions are characteristic of retinal capillary endothelial cells and pericytes in response to high glucose. In this study, the effects of advanced glycation end product (AGE-BSA) exposure on these parameters were tested. METHODS: Primary cultures of bovine retinal capillary endothelial cells (BRECs) and bovine retinal capillary pericytes (BRPs) were exposed to AGE-BSA (100 MUg/mL) for 6 days. Glucose uptake was measured using U (14)C-glucose and the GLUT-1 mRNA expression by RT-PCR. GLUT 1 protein was detected by immunofluorescence and subjected to FACS analysis. RESULTS: The authors observed that there was no significant decrease in the GLUT 1 protein expression, and this was confirmed by glucose uptake by (14)C-labeled glucose in both BRECs and BRPs. Even though there was a slight decrease in the mRNA expression of GLUT-1 in AGE-BSA-treated cells compared with both untreated control and BSA treated, the decrease was not significant. CONCLUSIONS: This is the first report to show that there is no difference in glucose uptake in BRECs and BRPs on exposure to AGE-BSA. PMID- 20702826 TI - Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. AB - PURPOSE: To determine the pharmacokinetics and pharmacodynamics of a sustained release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.). METHODS: Thirty-four male monkeys (Macaca fascicularis) received bilateral 0.7-mg DEX implants. Blood, vitreous humor, and retina samples were collected at predetermined intervals up to 270 days after administration. DEX was quantified by liquid chromatography-tandem mass spectrometry, and cytochrome P450 3A8 (CYP3A8) gene expression was analyzed by real-time reverse transcription polymerase chain reaction. RESULTS: DEX was detected in the retina and vitreous humor for 6 months, with peak concentrations during the first 2 months. After 6 months, DEX was below the limit of quantitation. The C(max) (T(max)) and AUC for the retina were 1110 ng/g (day 60) and 47,200 ng . d/g, and for the vitreous humor were 213 ng/mL (day 60) and 11,300 ng . d/mL, respectively. The C(max) (T(max)) of DEX in plasma was 1.11 ng/mL (day 60). Compared with the level in the control eyes (no DEX implant), CYP3A8 expression in the retina was upregulated threefold up to 6 months after injection of the implant (0.969 +/- 0.0565 vs. 3.07 +/- 0.438; P < 0.05 up to 2-month samples). CONCLUSIONS: The in vivo release profile of the DEX implant in an animal eye was similar to the pharmacokinetics achieved with pulse administration of corticosteroids (high initial drug concentration, followed by a prolonged period of low concentration). These results are consistent with those in clinical studies supporting the use of the DEX implant for the extended management of posterior segment diseases. PMID- 20702827 TI - Retinal gene expression after central retinal artery ligation: effects of ischemia and reperfusion. AB - PURPOSE: To investigate the morphologic and molecular consequences of 30- and 90 minute central retinal artery ligation (CRAL)-induced retinal ischemia, followed by 3 and 12 hours of reperfusion, and to identify potential targets for therapy. METHODS: Retinal ischemia was induced for 30 and 90 minutes by ligating the rat central retinal artery, and corresponding effects were examined histologically, immunocytochemically, and molecularly at 3 hours and 12 hours of reperfusion. Patterns of gene expression revealed significantly upregulated and downregulated genes by gene array analyses and were verified by quantitative RT-PCR. Functional pathways were correlated using gene set enrichment analysis. RESULTS: Substantial morphologic changes occurred from 3 hours to 7 days after CRAL in rats, resulting in a cellular loss in most retinal layers, particularly in inner nuclear and ganglion cell layers. After 30 minutes of CRAL and 3 hours of reperfusion, transcription-related genes such as ATF3, ID2, Klf4, BTG2, c-Fos, and c-Jun were activated. After 12 hours of reperfusion, the genes associated with kinase and caspase molecular pathways-including MAP kinases, Casp3 and Casp9-were upregulated. CRAL of 90 minutes and 3 hours of reperfusion induced glycolysis and gluconeogenesis-related genes such as G6PC. However, prolonged reperfusion of 12 hours was characterized by prominent activation of apoptosis-related genes, including Tp53, Akt1, Akt3, Pik3R1, Prkcb1, caspases (Casp3, Casp7, Casp9), and TNF. CONCLUSIONS: CRAL is a clinically relevant retinal ischemia model, and gene expression analysis can provide information regarding the molecular mechanisms underlying the pathophysiological processes during retinal ischemia. In addition, CRAL represents an effective experimental model with which to study retinal inflammation, development, aging, and, neurodegeneration. PMID- 20702828 TI - Enhancement of angiogenic potential of endothelial cells by contact with retinal pigment epithelial cells in a model simulating pathological conditions. AB - PURPOSE: Choroidal neovascularization (CNV) is the leading cause of vision loss in chorioretinal diseases involving contact between retinal pigment epithelial (RPE) and endothelial cells (ECs). The aim of this study was to investigate changes in the angiogenic potential of ECs induced by RPE-EC interaction in two models of RPE-EC coculture. METHODS: RPE and ECs were grown in contact or noncontact coculture. Selection of ECs was achieved using magnetic beads coated with antibodies specific for EC surface proteins. Angiogenesis was assessed by analyzing the expression of EC genes involved in angiogenesis by RT-PCR. Tube formation on Matrigel was used as a functional angiogenesis assay. Expression and activity of matrix metalloproteases (MMPs) were examined by RT-PCR and zymography, respectively. RESULTS: Coculture of ECs with RPE in the contact model under normoxic conditions induced markedly upregulated EC mRNA expression of 16 genes involved in positive regulation of angiogenesis. Solo ECs subjected to hypoxia demonstrated upregulated expression of the same 16 genes, including VEGF and HIF1. The EC VEGF level was not affected by coculture with RPE in the noncontact model. ECs demonstrated enhanced tube formation on Matrigel after contact coculture with RPE. EC MMP2 mRNA and activity levels were elevated in contact, but not in noncontact, coculture. CONCLUSIONS: Coculture of ECs with RPE under conditions enabling direct EC-RPE contact enhances the proangiogenic potential of ECs under normoxia, to an extent similar to that induced by hypoxia, suggesting that ECs in direct contact with RPE cells might be more prone to pathologic angiogenesis involved in CNV formation. PMID- 20702829 TI - In vitro lipid deposition on hydrogel and silicone hydrogel contact lenses. AB - PURPOSE: To understand various soft contact lens materials' ability to adsorb common tear lipids. METHODS: Ten unworn polymers of nine types were individually soaked in 1.0 mL of 1.75 MUg/mL cholesterol oleate or 1.0 mL of 0.5 MUg/mL phosphatidylcholine solutions for 1 or 14 days. The adsorbed lipids were extracted with chloroform-methanol, which underwent assay quantification for cholesterol oleate and inorganic phosphate. RESULTS: More phosphatidylcholine was extracted after 14 days than after 1 day in only lotrafilcon B, balafilcon A, and enfilcon A (all P < 0.005). After 1 day of incubation in phosphatidylcholine, 0.54 to 4.17 MUg/lens phosphatidylcholine was recovered from the polymers, and after 14 days of incubation in phosphatidylcholine, 0.58 to 5.77 MUg/lens phosphatidylcholine was recovered from the polymers. Etafilcon A had significantly more cholesterol oleate at 1 day than at 14 days, and lotrafilcon A, lotrafilcon B, and balafilcon A had significantly more cholesterol oleate at 14 days than at 1 day (P < 0.005). After 1 day of incubation in cholesterol oleate, 0.14 to 4.80 MUg/lens cholesterol oleate was recovered from the polymers. After 14 days of incubation in cholesterol oleate, 1.40 to 6.84 MUg/lens cholesterol oleate was recovered from the polymers. CONCLUSIONS: Hydrogel and most silicone hydrogels appear to adsorb lipids relatively quickly (i.e., within the first day). Although there is some variability in the amounts recovered across materials, it is uncertain whether these differences have any clinical significance. PMID- 20702830 TI - Focal, periocular delivery of 2-deoxy-D-glucose as adjuvant to chemotherapy for treatment of advanced retinoblastoma. AB - PURPOSE: The aim of this study was to evaluate the changes in tumor burden and hypoxia in the LH(BETA)T(AG) retinal tumors after treatment with a focal, single modality, and combination therapy using periocular carboplatin and 2-deoxy-d glucose (2-DG). METHODS: Seventeen-week-old LH(BETA)T(AG) transgenic mice (n = 25) were treated with periocular injections of varying doses of 2-DG (62.5, 125, 250, 500 mg/kg) to obtain a dose response. Same-aged mice (n = 30) received periocular injections of saline, carboplatin, and 2-DG. Mice were divided into six groups: saline; carboplatin (31.25 MUg/20 MUL, subtherapeutic dose); 2-DG (250 mg/kg); 2-DG (500 mg/kg); carboplatin (31.25 MUg/20 MUL) and 2-DG (250 mg/kg); and carboplatin (31.25 MUg/20 MUL) and 2-DG (500 mg/kg). Injections were administered twice weekly for three consecutive weeks. Eyes were enucleated at 20 weeks of age, snap frozen, and analyzed for hypoxic regions and tumor volume. RESULTS: The difference in percentage of hypoxia after treatment with 500 mg/kg 2 DG was statistically significant from the other dose groups (P < 0.015). The difference in tumor burden was statistically significant from the 250 mg/kg dose (P < 0.015) and 500 mg/kg dose (P < 0.001). Highly significant differences were found between the treatment types for tumor burden, percentage of hypoxia, and pimonidazole intensity (P < 0.001). Tumor burden decreased significantly after all forms of treatment (P < 0.001); however, tumor burden became significantly more reduced after treatment with combination therapy of carboplatin and 2-DG than with either treatment alone (P < 0.001). The percentage of hypoxia and pimonidazole intensity decreased after treatment with 2-DG alone and in combination with carboplatin (P < 0.001) in all treatment groups using 2-DG regardless of the 2-DG dose used. There was no percentage reduction of hypoxia after treatment with carboplatin alone (P = 0.25). CONCLUSIONS: This study demonstrates the efficacy of focal, periocular 2-DG as an adjunct to carboplatin chemotherapy to decrease both intratumoral hypoxia and tumor burden. Hypoxia is increasingly present in advanced disease of LH(BETA)T(AG) retinal tumors. The use of glycolytic inhibitors as a therapeutic strategy has the potential to enhance current retinoblastoma treatments. PMID- 20702832 TI - GITR ligand-mediated local expansion of regulatory T cells and immune privilege of corneal allografts. AB - PURPOSE: The pathway between the glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) and GITR ligand (GITRL) has been shown to control the function of regulatory T cells (Treg). The present study was conducted to investigate the role of this pathway and Treg in establishing immune privilege status for corneal allografts. METHODS: Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of BALB/c mice, and graft survival was assessed. A separate set of BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allo-specific anterior chamber-associated immune deviation was assessed. Recipients were intraperitoneally administrated anti-GITRL, anti-CD25 monoclonal antibodies (mAb), or control immunoglobulin (IgG). Expressions of GITRL, GITR, and Foxp3 in the allografts were assessed. In vitro, cornea pretreated with anti-GITRL mAb or control IgG was incubated with T cells, and destruction of corneal endothelial cells and the population of Foxp3(+)CD25(+)CD4(+) T cells were assessed. RESULTS: GITRL was expressed constitutively in the cornea and iris-ciliary body. GITRL-expressing allografts were infiltrated with Foxp3+GITR+CD25+CD4(+) T cells. Blockade of GITRL did not affect allo-specific ACAID but led to infiltration of Foxp3(-)CD4(+) T cells and allograft rejection. Depletion of CD25+CD4(+) Treg also accelerated allograft rejection. Destruction of corneal endothelial cells by T cells was significantly enhanced in GITRL-blocked cornea compared with control cornea. Foxp3+CD25+CD4(+) T cells were increased after incubation with GITRL-expressing cornea, but not with GITRL-blocked cornea. CONCLUSIONS: Presence of Foxp3+CD25+CD4(+) Treg in the allograft is necessary for allograft survival. GITRL-dependent expansion of Treg within the cornea is one mechanism underlying immune privilege in corneal allografts. PMID- 20702831 TI - Docosahexaenoic acid improves the nitroso-redox balance and reduces VEGF-mediated angiogenic signaling in microvascular endothelial cells. AB - PURPOSE: Disturbances to the cellular production of nitric oxide (NO) and superoxide (O(2)(-)) can have deleterious effects on retinal vascular integrity and angiogenic signaling. Dietary agents that could modulate the production of these signaling molecules from their likely enzymatic sources, endothelial nitric oxide synthase (eNOS) and NADPH oxidase, would therefore have a major beneficial effect on retinal vascular disease. The effect of omega-3 polyunsaturated fatty acids (PUFAs) on angiogenic signaling and NO/superoxide production in retinal microvascular endothelial cells (RMECs) was investigated. METHODS: Primary RMECs were treated with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) for 48 hours. RMEC migration was determined by scratch-wound assay, proliferation by the incorporation of BrdU, and angiogenic sprouting using a three-dimensional model of in vitro angiogenesis. NO production was quantified by Griess assay, and phospho-eNOS accumulation and superoxide were measured using the fluorescent probe dihydroethidine. eNOS localization to caveolin-rich microdomains was determined by Western blot analysis after subfractionation on a linear sucrose gradient. RESULTS: DHA treatment increased nitrite and decreased superoxide production, which correlated with the displacement of eNOS from caveolar subdomains and colocalization with the negative regulator caveolin-1. In addition, both omega-3 PUFAs demonstrated reduced responsiveness to VEGF stimulated superoxide and nitrite release and significantly impaired endothelial wound healing, proliferation, and angiogenic sprout formation. CONCLUSIONS: DHA improves NO bioavailability, decreases O(2)(-) production, and blunts VEGF mediated angiogenic signaling. These findings suggest a role for omega-3 PUFAs, particularly DHA, in maintaining vascular integrity while reducing pathologic retinal neovascularization. PMID- 20702833 TI - Remaining rod activity mediates visual behavior in adult Rpe65-/- mice. AB - PURPOSE: C57/Bl6, Cpfl1(-/-) (cone photoreceptors function loss 1; pure rod function), Gnat1a(-/-) (rod alpha-transducin; pure cone function), and Rpe65(-/ );Rho(-/-) double-knockout mice were studied to distinguish the respective contributions of the different photoreceptor (PR) systems that enable light perception and mediate a visual reflex in adult Rpe65(-/-) mice, with a simple behavioral procedure. METHODS: Visual function was estimated using a rotating automated optomotor drum covered with vertical black-and-white stripes at spatial frequencies of 0.025 to 0.5 cycles per degree (cyc/deg) in both photopic and scotopic conditions. Mouse strains with different luminances were tested to evaluate the contribution and the light-intensity threshold of each PR system. RESULTS: Stripe rotation elicited head movements in the wild-type (WT) animals in photopic and scotopic conditions, depending on the spatial frequency, whereas the Cpfl1(-/-) mice show a reduced activity in the photopic condition and the Gnat1a( /-) mice an almost absent response in the scotopic condition. A robust visual response was obtained with Rpe65(-/-) knockout mice at 0.075 and 0.1 cyc/deg in the photopic condition. The residual rod function in the Rpe65(-/-) animals was demonstrated by testing Rpe65(-/-);Rho(-/-) mice that present no response in photopic conditions. CONCLUSIONS: The optomotor test is a simple method of estimating the visual function and evaluating the respective contributions of rod and cone systems. This test was used to demonstrate that in Rpe65(-/-) mice, devoid of functional cones and of detectable 11-cis-retinal protein, the rods mimic cone function in part, by mediating vision in photopic conditions. PMID- 20702835 TI - Nutrition care for children. Editor's note. PMID- 20702834 TI - Deformation of the early glaucomatous monkey optic nerve head connective tissue after acute IOP elevation in 3-D histomorphometric reconstructions. AB - PURPOSE: To retest the hypothesis that monkey ONH connective tissues become hypercompliant in early experimental glaucoma (EEG), by using 3-D histomorphometric reconstructions, and to expand the characterization of EEG connective tissue deformation to nine EEG eyes. METHODS: Trephinated ONH and peripapillary sclera from both eyes of nine monkeys that were perfusion fixed, with one normal eye at IOP 10 mm Hg and the other EEG eye at 10 (n=3), 30 (n=3), or 45 (n=3) mm Hg were serial sectioned, 3-D reconstructed, 3-D delineated, and quantified with 3-D reconstruction techniques developed in prior studies by the authors. Overall, and for each monkey, intereye differences (EEG eye minus normal eye) for each parameter were calculated and compared by ANOVA. Hypercompliance in the EEG 30 and 45 eyes was assessed by ANOVA, and deformations in all nine EEG eyes were separately compared by region without regard for fixation IOP. RESULTS: Hypercompliant deformation was not significant in the overall ANOVA, but was suggested in a subset of EEG 30/45 eyes. EEG eye deformations included posterior laminar deformation, neural canal expansion, lamina cribrosa thickening, and posterior (outward) bowing of the peripapillary sclera. Maximum posterior laminar deformation and scleral canal expansion co-localized to either the inferior nasal or superior temporal quadrants in the eyes with the least deformation and involved both quadrants in the eyes achieving the greatest deformation. CONCLUSIONS: The data suggest that, in monkey EEG, ONH connective tissue hypercompliance may occur only in a subset of eyes and that early ONH connective tissue deformation is maximized in the superior temporal and/or inferior nasal quadrants. PMID- 20702837 TI - Nutrition in pediatric inflammatory bowel disease. AB - Nutrition interventions play a central role in the treatment and management of inflammatory bowel disease in children. Malnutrition is a common presenting symptom in both pediatric ulcerative colitis and Crohn's disease and is associated with increased morbidity. Providing macronutrients can improve growth; likewise, identifying and correcting micronutrient deficiencies can improve comorbid conditions like osteopenia and anemia. Although many patients manipulate their diets to help treat their inflammatory bowel disease, only parenteral nutrition with bowel rest and exclusive enteral nutrition therapy have been shown effective for the treatment of inflammatory bowel disease. PMID- 20702836 TI - Multidisciplinary treatment of pediatric obesity: nutrition evaluation and management. AB - Assessment and treatment methods for pediatric obesity are rapidly evolving. Thought to be caused by an imbalance of caloric intake and expenditure, obesity requires a comprehensive evaluation of patient, familial, environmental, genetic, and cultural characteristics so clinicians can design successful interventions. Quantitative nutrition assessment of caloric intake is difficult and time consuming and should be used only in isolated settings, such as in the research setting, or if initial approaches to management have been unsuccessful. As an alternative, providers should identify dietary patterns or behaviors that have been linked to obesity and are promising targets for change. Clinicians should tailor interventions by considering patient and family motivation and readiness to change. Current guidelines recommend stepwise increases in treatment plans, and multidisciplinary treatment teams are recommended for patients who require intense intervention. Providers involved at the multidisciplinary level must incorporate their area of expertise into that of the team to develop a comprehensive management plan. This article reviews current recommendations for the evaluation and treatment of pediatric obesity with a focus on nutrition evaluation as part of a multidisciplinary team. PMID- 20702838 TI - Update in pediatrics: focus on fat-soluble vitamins. AB - This article provides an update on fat-soluble vitamins (A, D, E, and K) in the healthy pediatric population and in children with chronic disease states that commonly cause deficiencies, specifically cystic fibrosis and cholestatic liver disease. For each fat-soluble vitamin, the biological function, nutrition availability, absorption, deficiency, toxic states, and monitoring parameters are defined. PMID- 20702839 TI - Pediatric inflammatory bowel disease and bone health. AB - Childhood and adolescence are important periods for bone development. Any disease that affects bone health has the potential to affect the bones not only in the short term but also later in life. Bone health abnormalities in patients with inflammatory bowel disease are being increasingly recognized. Screening the at risk patient is important so that appropriate treatments can be instituted. Treatment options are limited to vitamin D and calcium supplementation, control of underlying disease activity, and appropriate physical activity. The role of bisphosphonates in these patients needs to be better studied, and treatment with bisphosphonates may be considered for some patients in consultation with a bone health expert. PMID- 20702840 TI - Calcium and phosphate solubility in neonatal parenteral nutrient solutions containing TrophAmine. AB - Significant amounts of calcium and phosphate are required in neonatal parenteral nutrition (PN) regimens to ensure adequate supplementation and prevention of metabolic bone disease. Current clinical recommendations for calcium and phosphate requirements in neonatal PN cannot be achieved with traditional amino acid formulations. The solubility curves of these amion acids do not allow the appropriate doses of calcicum and phosphate to be achieved, therefore placing the neonate at risk of receiving a precipitated infusion. Fitzgerald and MacKay investigated the calcium and phosphate solubility of TrophAmine, an amino acid injection developed for neonatal PN. The results of their findings allow higher concentrations of calcium and phosphate to be added to each pediatric PH regimen while maintaing solubility, therefore safely allowing higher concentrations of calcium and phosphate to be added to each prediatric PN regimen. The pivotal nature of Fitzgerald and MacKay's paper changed how practitioners address calcium and phosphate supplementation in the nutrition support of the neonatal patient. PMID- 20702841 TI - Growth in cerebral palsy. AB - Cerebral palsy is often accompanied by abnormalities of growth and nutrition; children with severe motor impairments are most at risk. Nutrition, neurological, and endocrine factors all contribute to suboptimal growth. Poor growth and nutrition are associated with poor general health outcomes and reduced levels of participation, and therefore warrant careful evaluation and appropriate intervention. The lack of normative data combined with the complex interaction of nutrition and nonnutrition factors contributing to growth in this population present real difficulties in management. Particular care is needed to avoid overfeeding and the resultant increase in fat mass and associated morbidity. PMID- 20702842 TI - Nutrition treatment of deficiency and malnutrition in chronic pancreatitis: a review. AB - Chronic pancreatitis results in exocrine and endocrine dysfunction, affecting normal digestion and absorption of nutrients. In individuals with chronic pancreatitis, nutrition status may be further affected by poor dietary intake, often related to alcoholism. However, some deficiencies may be overlooked, potentially leading to nutrition-related problems with bone health and fatigue. The aim of this article is to describe the deficiencies that occur and to propose an evidence-based algorithm for the nutrition assessment and treatment of patients with chronic pancreatitis. PMID- 20702843 TI - Parkinson's disease: mitochondrial molecular pathology, inflammation, statins, and therapeutic neuroprotective nutrition. AB - Pathological hallmarks of Parkinson's disease are destruction of dopaminergic neurons in the basal ganglia, especially the substantia nigra, and the presence of Lewy bodies within nerve cells. Environmental toxins are associated with the disease and, in a minority of cases, genetic factors have been identified. Inflammation-with activation of phagocytic microglia, release of cytokines, invasion by T cells, and complement activation-plays a role in damaging these neurons. Excessive production of reactive oxygen species, mitochondrial dysfunction leading to apoptosis, accumulation and oligomerization of the protein alpha-synuclein, and defective protein disposal by the ubiquitin proteasome system are involved in the complex web of events mediating nigral cell demise. Two agents of current interest, coenzyme Q10 and creatine, may be disease modifying, and large studies are in progress. Related mechanisms of other substances, including omega-3 fatty acids and vitamin D, are included in this review. The association with serum cholesterol levels and the effects of statin drugs are uncertain but important. PMID- 20702844 TI - Effects of oral folate supplementation on serum total homocysteine and cholesterol levels in hyperhomocysteinemic children. AB - BACKGROUND: Hyperhomocysteinemia may be a risk factor for cardiovascular disease even among children. Increased levels of total serum homocysteine (tHcy) may initiate atherosclerosis by modulating increased cholesterol synthesis in the liver. Folate supplementation has been found to reduce homocysteine levels. However, no data have been reported about the relationship between folate supplementation and cholesterol levels in children. METHODS: Twenty of 26 hyperhomocysteinemic (>95th percentile for age) children underwent a therapeutic intervention of 5 mg of oral folate supplementation twice per week for 2 months. RESULTS: After the 2-month intervention with folate supplement, tHcy levels were statistically significantly decreased (P < .001), folate levels were significantly increased (P < .001), while total cholesterol levels were significantly improved from 183.8 (115-296 mg/dL) to 160.8 (109-265 mg/dL) (P < .05). CONCLUSIONS: Folate supplementation may reduce tHcy, serum folate, and total serum cholesterol levels in hyperhomocysteinemic children. PMID- 20702845 TI - Vitamin D--deficient rickets in a child with cow's milk allergy. AB - This article describes the case of a 16-month-old Hispanic male toddler with cow's milk allergy living in northern California who was admitted to a children's hospital for weight loss and markedly elevated levels of serum alkaline phosphatase and parathyroid hormone. At a routine outpatient well-child visit, his mother expressed concern about a decrease in his appetite and activity level. A detailed diet history revealed that breast milk was his primary source of nutrition during his first year of life and he had not been given supplemental vitamins. With attempts to introduce cow's milk formula, he had developed a rash and swelling around the mouth. Shortly after his first birthday, his mother weaned him from breast milk and introduced unfortified rice milk as a palatable milk substitute. Upon admission he was pale and lethargic; his laboratory studies were remarkable for elevated serum alkaline phosphatase and parathyroid hormone and low levels of phosphorus, 25-hydroxy-vitamin D, and ferritin. Lower extremity radiographic studies were consistent with rickets. After 5 weeks of therapy with vitamin D(3) and iron, his serum 25-hydroxy-vitamin D level normalized. Within 12 weeks following therapy, the child demonstrated significant clinical improvement, with resolution of growth failure and bone reossification. His activity level had returned to normal. This case emphasizes the importance of adequate vitamin D intake for children with special attention to those who might have nutrition deficiencies attributable to milk allergy. PMID- 20702846 TI - Rapid infusion of fish oil-based emulsion in infants does not appear to be associated with fat overload syndrome. AB - BACKGROUND: Inadvertent rapid infusion of parenteral lipid emulsion is an inherent risk when fats are infused separately from the dextrose-amino acid solution. Patients may experience hypertriglyceridemia that resolves upon discontinuation of the infusion; in other cases, complications such as fat overload syndrome can occur. Since 2004, fish oil-based emulsions have been used investigationally for the treatment of parenteral nutrition-associated liver disease. Anecdotal reports suggest that patients who receive rapid infusions of this emulsion do not develop symptoms consistent with fat overload syndrome. The aim of this investigation was to determine whether infants receiving a rapid infusion of a fish oil lipid emulsion exhibited symptoms consistent with fat overload syndrome. METHODS: The medical records of patients treated at Children's Hospital Boston with a fish oil emulsion from September 2004 to August 2008 were reviewed for cases of rapid infusion. RESULTS: Six of 99 patients (6%) received a dose of fish oil emulsion at an infusion rate that exceeded 0.17 g/kg/h. Infusion rates as high as 5 g/kg/h were accidentally administered (range, 0.2-5 g/kg/h) without evidence of fat overload syndrome. Transient elevations in serum triglyceride levels were observed but promptly returned to acceptable levels. CONCLUSIONS: Rapid infusion of a fish oil-based emulsion in 6 infants were well tolerated. No patients developed signs or symptoms of fat overload syndrome. PMID- 20702847 TI - Standards for nutrition support: adult hospitalized patients. PMID- 20702848 TI - The use of complementary and alternative therapies by children. PMID- 20702849 TI - What makes an egg unique? Clues from evolutionary scenarios of egg-specific genes. AB - The avian egg, which contains the egg yolk, the egg white, and the eggshell, represents the mostly advanced amniotic egg in oviparous vertebrates. In mammals, this reproductive strategy of laying egg has gradually evolved toward placentation. In order to better understand the unique status of the avian egg in the evolution of the vertebrate reproduction, we investigated the evolution of some Gallus gallus egg-specific protein-coding genes. Based on our finding and other recent research, we have summarized here that gene formation (such as ovalbumin genes, ovocalyxin-36 and apovitellenin-1 encoding genes in the G. gallus), gene divergence between G. gallus and mammals (such as the ovocalyxin-32 gene with its ortholog, the mammalian RARRES1, and the ovocleidin-116 with its ortholog, the mammalian MEPE), and gene loss (egg-expressed genes lost during the evolution of the mammals, such as vitellogenin and RBP encoding genes) play significant roles in the evolution of egg-specific genes. PMID- 20702850 TI - Aberrant growth and pattern formation in Peromyscus hybrid placental development. AB - Crosses between the North American deer mouse species Peromyscus maniculatus (BW) and P. polionotus (PO) produce dramatic asymmetric developmental effects. BW females mated to PO males (female bw * male po) produce viable growth-retarded offspring. In contrast, PO females mated to BW males (female PO * male BW) produce overgrown but dysmorphic conceptuses. Most female PO * male BW offspring are dead by midgestation; those surviving to later time points display numerous defects reminiscent of several diseases. The hybrid effects are particularly pronounced in the placenta. Here we examine placental morphological defects via histology and in situ hybridization as well as the relationship between growth and mortality in the female PO * male BW cross. These assays indicate altered hybrid fetal:placental ratios by the equivalent of mouse (Mus) Embryonic Day (E) 13 and disorganization and labyrinth defects in female PO * male BW placentas and confirm earlier suggestions of a severely reduced junctional zone in the female bw * male po hybrids. Further, we show that both cellular proliferation and death are abnormal in the hybrids through BrdU incorporation and TUNEL assays, respectively. Together the data indicate that the origin of the effects is prior to the equivalent of Mus E10. Finally, as the majority of these assays had not previously been performed on Peromyscus, these studies provide comparative data on wild-type placentation. PMID- 20702852 TI - Proliferation of mouse spermatogonial stem cells in microdrop culture. AB - It is now possible to make mouse spermatogonial stem cells (SSCs) proliferate in vitro. However, these cultured cells, called germ-line stem (GS) cells, consist of not only SSCs but also a greater number of progenitor spermatogonia. Moreover, isolated GS cells barely proliferate. To elucidate the nature of SSCs and progenitor spermatogonia, we adapted a microdrop culture system to GS cells. Using a micromanipulator, individual microdrops were seeded with clusters or dissociated known numbers of GS cells. The number of surviving colonies was determined after 30 days. The proliferation rate of GS cells in microdrops increased as the number of GS cells seeded increased. It was observed that as few as three GS cells seeded in a microdrop can proliferate and expand the colony size. Those GS cells of expanded colonies were able to proliferate following subculture and underwent spermatogenesis in the host testis after transplantation into the seminiferous tubules of recipient mice. These data revealed that SSCs can multiply in a microdrop culture system. Microdrop culture offers a novel tool to elucidate the nature of SSCs in regard to their self-renewing capacity and can serve as a monitoring system of culture conditions for the self-renewal of SSCs. PMID- 20702851 TI - Does bone morphogenetic protein 6 (BMP6) affect female fertility in the mouse? AB - Bone morphogenetic protein 6 (BMP6) is a transforming growth factor beta superfamily member produced by mammalian oocytes as well as other cell types. Despite well-characterized effects of recombinant BMP6 on granulosa cells in vitro, the function of BMP6 in vivo has been ill-defined. Therefore, the effects of genetic deletion of the Bmp6 gene on female mouse fertility were assessed. The mean litter size of Bmp6(-/-) females was reduced by 22% (P < 0.05) compared to Bmp6(+/+) controls. Not only did Bmp6(-/-) females naturally ovulate 24% fewer eggs, but competence of in vitro-matured oocytes to complete preimplantation development after fertilization in vitro was decreased by 50%. No apparent effect of Bmp6 deletion on either the morphology or the dynamics of follicular development was apparent. Nevertheless, levels of luteinizing hormone (LH)/human chorionic gonadotropin (hCG)-induced transcripts, which encode proteins required for cumulus expansion (HAS2, PTGS2, PTX3, and TNFAIP6), and of epidermal growth factor-like peptides (AREG, BTC, and EREG) were lower in Bmp6(-/-) mice than in controls after administration of a reduced dose of hCG (1 IU) in vivo. LH receptor (Lhcgr) transcript levels were not significantly lower in Bmp6(-/-) granulosa cells, suggesting that BMP6 is required for processes downstream of LH receptors. To assess whether another oocyte-derived BMP, BMP15, could have BMP6 redundant functions in vivo, the fertility of Bmp15/Bmp6 double mutants was assessed. Fertility was not significantly reduced in double-homozygous mutants compared with that in double-heterozygous controls. Therefore, BMP6 promotes normal fertility in female mice, at least in part, by enabling appropriate responses to LH and normal oocyte quality. Thus, Bmp6 probably is part of the complex genetic network that determines female fertility. PMID- 20702854 TI - Pharmacy benefit managers, pharmacies, and pharmacogenomic testing: prescription for progress? AB - Few would argue that the ability to match individual patients with the safest and most effective drugs and doses would be a major advance for clinical medicine. But while clinicians have been reluctant to routinely use pharmacogenomic analyses to guide their prescribing practices, pharmacy benefit managers and drugstores are proceeding with major pharmacogenetic initiatives. PMID- 20702853 TI - Side-by-side comparison of five commercial media systems in a mouse model: suboptimal in vitro culture interferes with imprint maintenance. AB - Assisted reproductive technologies (ARTs) are becoming increasingly prevalent and are generally considered to be safe medical procedures. However, evidence indicates that embryo culture may adversely affect the developmental potential and overall health of the embryo. One of the least studied but most important areas in this regard is the effects of embryo culture on epigenetic phenomena, and on genomic imprinting in particular, because assisted reproduction has been linked to development of the human imprinting disorders Angelman and Beckwith Wiedemann syndromes. In this study, we performed side-by-side comparisons of five commercial embryo culture systems (KSOMaa, Global, Human Tubal Fluid, Preimplantation 1/Multiblast, and G1v5PLUS/G2v5PLUS) in relation to a best-case (in vivo-derived embryos) and a worst-case (Whitten culture) scenario. Imprinted DNA methylation and expression were examined at three well-studied loci, H19, Peg3, and Snrpn, in mouse embryos cultured from the 2-cell to the blastocyst stage. We show that embryo culture in all commercial media systems resulted in imprinted methylation loss compared to in vivo-derived embryos, although some media systems were able to maintain imprinted methylation levels more similar to those of in vivo-derived embryos in comparison to embryos cultured in Whitten medium. However, all media systems exhibited loss of imprinted H19 expression comparable to that using Whitten medium. Combined treatment of superovulation and embryo culture resulted in increased perturbation of genomic imprinting, above that from culture alone, indicating that multiple ART procedures further disrupt genomic imprinting. These results suggest that time in culture and number of ART procedures should be minimized to ensure fidelity of genomic imprinting during preimplantation development. PMID- 20702855 TI - Coupled for cross-presentation in tumor immunotherapy. AB - Antigen cross-presentation is a critical step in the elicitation of cell-mediated immune responses. Much research has been aimed at manipulating antigen cross presentation to improve tumor immunotherapy and vaccination. In this issue of Science Translational Medicine, Saccheri et al. describe a mechanism for spurring successful antitumor responses by enhancing the transfer, to antigen-presenting cells, of tumor-specific antigens that leave the cancer cells via gap junctions induced by Salmonella infection of the melanoma tumor. Salmonella turns from foe to friend by promoting cross-presentation for strong antitumor immunity and tumor eradication. PMID- 20702856 TI - Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity. AB - Antigen-presenting dendritic cells (DCs) trigger the activation of cytotoxic CD8 T cells that target and eliminate cells with the antigen on their surface. Although DCs usually pick up and process antigens themselves, they can also receive peptide antigens from other cells via gap junctions. We demonstrate here that infection with Salmonella can induce, in both human and murine melanoma cells, the up-regulation of connexin 43 (Cx43), a ubiquitous protein that forms gap junctions and that is normally lost during melanoma progression. Bacteria treated melanoma cells can establish functional gap junctions with adjacent DCs. After bacterial infection, these gap junctions transferred preprocessed antigenic peptides from the tumor cells to the DCs, which then presented those peptides on their surface. These peptides activated cytotoxic T cells against the tumor antigen, which could control the growth of distant uninfected tumors. Melanoma cells in which Cx43 had been silenced, when infected in vivo with bacteria, failed to elicit a cytotoxic antitumor response, indicating that this Cx43 mechanism is the principal one used in vivo for the generation of antitumor responses. The Cx43-dependent cross-presentation pathway is more effective than standard protocols of DC loading (peptide, tumor lysates, or apoptotic bodies) for generating DC-based tumor vaccines that both inhibit existing tumors and prevent tumor establishment. In conclusion, we exploited an antimicrobial response present in tumor cells to activate cytotoxic CD8 T cells specific for tumor-generated peptides that could directly recognize and kill tumor cells. PMID- 20702857 TI - Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. AB - Pulmonary arterial hypertension is caused by excessive growth of vascular cells that eventually obliterate the pulmonary arterial lumen, causing right ventricular failure and premature death. Despite some available treatments, its prognosis remains poor, and the cause of the vascular remodeling remains unknown. The vascular smooth muscle cells that proliferate during pulmonary arterial hypertension are characterized by mitochondrial hyperpolarization, activation of the transcription factor NFAT (nuclear factor of activated T cells), and down regulation of the voltage-gated potassium channel Kv1.5, all of which suppress apoptosis. We found that mice lacking the gene for the metabolic enzyme malonyl coenzyme A (CoA) decarboxylase (MCD) do not show pulmonary vasoconstriction during exposure to acute hypoxia and do not develop pulmonary arterial hypertension during chronic hypoxia but have an otherwise normal phenotype. The lack of MCD results in an inhibition of fatty acid oxidation, which in turn promotes glucose oxidation and prevents the shift in metabolism toward glycolysis in the vascular media, which drives the development of pulmonary arterial hypertension in wild-type mice. Clinically used metabolic modulators that mimic the lack of MCD and its metabolic effects normalize the mitochondrial-NFAT-Kv1.5 defects and the resistance to apoptosis in the proliferated smooth muscle cells, reversing the pulmonary hypertension induced by hypoxia or monocrotaline in mice and rats, respectively. This study of fatty acid oxidation and MCD identifies a critical role for metabolism in both the normal pulmonary circulation (hypoxic pulmonary vasoconstriction) and pulmonary hypertension, pointing to several potential therapeutic targets for the treatment of this deadly disease. PMID- 20702859 TI - Prevalence of nonanatomical graft placement in a series of failed anterior cruciate ligament reconstructions. AB - BACKGROUND: Anterior cruciate ligament reconstruction employing transtibial tunnel techniques may result in less than ideal femoral and tibial vertical graft placement, with a residual pivot shift and instability symptoms. HYPOTHESIS: Nonanatomical graft placement is highly prevalent among knees with failed primary and revision anterior cruciate ligament grafts. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 122 consecutive patients presented to the authors' center with a failed anterior cruciate ligament reconstruction. Radiographs, magnetic resonance imaging, and operative reports were used to define graft placement. Arthroscopic confirmation of graft placement was obtained in 92 knees during subsequent revision surgery. A nonanatomical graft placement was assigned when >=50% of the graft was outside of the native tibial and femoral insertions. All patients prospectively completed Cincinnati Knee Rating System questionnaires. RESULTS: A nonanatomical graft placement occurred in 107 of 122 (88%) knees; 61% of the grafts were entirely on the intercondylar femoral roof, and 35% extended posterior to the anterior cruciate ligament tibial attachment. A transtibial technique had been used in 83%. The mean values for the coronal and sagittal graft placement showed a significantly increased vertical orientation in comparison with a control group (P < .01). Forty-two of the 107 nonanatomical grafts had undergone 1 or more revisions without correction of the misplaced graft tunnels, and these subsequently failed. CONCLUSION: The occurrence of nonanatomical graft placement in primary and revision knees may represent an inadequacy of transtibial tunnel drilling techniques to obtain graft placement within the native femoral and tibial footprints. In revision cases, the prior graft location requires close scrutiny so the new graft tunnels are placed at the native anterior cruciate ligament attachments. Independent drilling of tibial and femoral tunnels is recommended using either 2-incision or anteromedial portal techniques. PMID- 20702858 TI - Biomechanical measures during landing and postural stability predict second anterior cruciate ligament injury after anterior cruciate ligament reconstruction and return to sport. AB - BACKGROUND: Athletes who return to sport participation after anterior cruciate ligament reconstruction (ACLR) have a higher risk of a second anterior cruciate ligament injury (either reinjury or contralateral injury) compared with non anterior cruciate ligament-injured athletes. HYPOTHESES: Prospective measures of neuromuscular control and postural stability after ACLR will predict relative increased risk for a second anterior cruciate ligament injury. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Fifty-six athletes underwent a prospective biomechanical screening after ACLR using 3-dimensional motion analysis during a drop vertical jump maneuver and postural stability assessment before return to pivoting and cutting sports. After the initial test session, each subject was followed for 12 months for occurrence of a second anterior cruciate ligament injury. Lower extremity joint kinematics, kinetics, and postural stability were assessed and analyzed. Analysis of variance and logistic regression were used to identify predictors of a second anterior cruciate ligament injury. RESULTS: Thirteen athletes suffered a subsequent second anterior cruciate ligament injury. Transverse plane hip kinetics and frontal plane knee kinematics during landing, sagittal plane knee moments at landing, and deficits in postural stability predicted a second injury in this population (C statistic = 0.94) with excellent sensitivity (0.92) and specificity (0.88). Specific predictive parameters included an increase in total frontal plane (valgus) movement, greater asymmetry in internal knee extensor moment at initial contact, and a deficit in single-leg postural stability of the involved limb, as measured by the Biodex stability system. Hip rotation moment independently predicted second anterior cruciate ligament injury (C = 0.81) with high sensitivity (0.77) and specificity (0.81). CONCLUSION: Altered neuromuscular control of the hip and knee during a dynamic landing task and postural stability deficits after ACLR are predictors of a second anterior cruciate ligament injury after an athlete is released to return to sport. PMID- 20702860 TI - Clinical results of arthroscopic single-bundle transtibial posterior cruciate ligament reconstruction: a systematic review. AB - BACKGROUND: Reconstruction of the posterior cruciate ligament has traditionally been performed using an arthroscopically assisted single-bundle transtibial technique. Unfortunately, clinical studies evaluating this procedure are rare. In addition, there are no pooled analyses evaluating the effectiveness of this procedure for isolated posterior cruciate ligament tears. HYPOTHESIS: Patients who undergo arthroscopically assisted, single-bundle, transtibial posterior cruciate ligament reconstruction will exhibit subjective improvement in knee function despite persistent objective knee laxity. STUDY DESIGN: Systematic review. METHODS: A structured literature search was performed to identify those clinical studies assessing the results of an arthroscopically assisted single bundle transtibial posterior cruciate ligament reconstruction for isolated posterior cruciate ligament tears. The published data meeting the inclusion criteria were systematically reviewed with an emphasis on residual posterior laxity, subjective and objective functional outcome, activity level, patient satisfaction, incidence of osteoarthritis, and postoperative complications. RESULTS: A total of 10 studies were identified that met the inclusion criteria. Mean postoperative instrumented posterior knee laxity varied from 1.96 mm to 5.90 mm, which was considerably improved from preoperative values (range, 8.38-12.3 mm). The range of mean values of the Lysholm knee scores was 81 to 100 points. The overall International Knee Documentation Committee rating was categorized as "normal" or "nearly normal" in 75% of patients and the mean Tegner activity score varied from 4.7 to 6.3 points. Degenerative osteoarthritis was frequently noted at the time of the most recent follow-up. There were few complications reported. CONCLUSION: Arthroscopically assisted single-bundle transtibial posterior cruciate ligament reconstruction for isolated posterior cruciate ligament tears can improve posterior knee laxity by 1 grade, although this procedure does not reliably restore normal knee stability. Return to recreational and athletic activity was predictable, with 75% of patients exhibiting a normal or nearly normal objective outcome, although degenerative osteoarthritis was not prevented by this procedure. PMID- 20702861 TI - Preoperative factors correlating with prolonged range of motion deficit after anterior cruciate ligament reconstruction. AB - BACKGROUND: Impaired postoperative range of motion remains one of the most frequent complications after anterior cruciate ligament reconstruction. PURPOSE: This study was undertaken to determine the preoperative factors associated with prolonged range of motion deficit after anterior cruciate ligament reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between January 2007 and March 2008, a consecutive series of 217 patients underwent anterior cruciate ligament reconstruction and were reviewed at 6 weeks and 3 months after surgery. In this series, all data of patients who required a further surgery for arthrolysis until December 2009 were studied. Goniometric range of motion measurement was performed the day before surgery and at 6 weeks and 3 months postoperatively. Bone contusions were analyzed on preoperative magnetic resonance imaging (MRI). All MRI scans were performed in the 6 months before surgery. Seven potential risk factors-age, sex, limited preoperative range of motion, meniscal lesions, bone contusion(s), operative delay less than 45 days, and rehabilitation-were assessed using univariate analysis. The correlations between the significant factors previously identified were analyzed further using multivariate logistic regression analysis. RESULTS: Limited preoperative range of motion (P < .001), typical bone contusions of the lateral compartment (P < .001), operative delay less than 45 days (P = .003), and female sex (P = .049) were found to be significantly correlated with delayed recovery. The limited preoperative mobility and the presence of typical contusions were strongly correlated (P < .001). In the group of patients who underwent surgery within 45 days, delayed recovery was strongly correlated with limited preoperative mobility (P = .0008) and to the presence of typical contusions (P < .001). Arthrolysis was correlated with delayed range of motion (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.9-50; P =.001) and bone bruise (OR, 7.6; 95% CI, 1.7-46.1; P = .002). CONCLUSION: Preoperative limited range of motion and typical bone bruises of the lateral femoral condyle and tibial plateau are major risk factors for a difficult rehabilitation after anterior cruciate ligament reconstruction. PMID- 20702863 TI - Exemplar models as a mechanism for performing Bayesian inference. AB - Probabilistic models have recently received much attention as accounts of human cognition. However, most research in which probabilistic models have been used has been focused on formulating the abstract problems behind cognitive tasks and their optimal solutions, rather than on mechanisms that could implement these solutions. Exemplar models are a successful class of psychological process models in which an inventory of stored examples is used to solve problems such as identification, categorization, and function learning. We show that exemplar models can be used to perform a sophisticated form of Monte Carlo approximation known as importance sampling and thus provide a way to perform approximate Bayesian inference. Simulations of Bayesian inference in speech perception, generalization along a single dimension, making predictions about everyday events, concept learning, and reconstruction from memory show that exemplar models can often account for human performance with only a few exemplars, for both simple and relatively complex prior distributions. These results suggest that exemplar models provide a possible mechanism for implementing at least some forms of Bayesian inference. PMID- 20702862 TI - Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome. AB - Smith-Lemli-Opitz syndrome (SLOS) is a metabolic and developmental disorder caused by mutations in the gene encoding the enzyme 7-dehydrocholesterol reductase (Dhcr7). This reductase catalyzes the last step in cholesterol biosynthesis, and levels of 7-dehydrocholesterol (7-DHC), the substrate for this enzyme, are elevated in SLOS patients as a result of this defect. Our group has previously shown that 7-DHC is extremely prone to free radical autoxidation, and we identified about a dozen different oxysterols formed from oxidation of 7-DHC. We report here that 7-DHC-derived oxysterols reduce cell viability in a dose- and time-dependent manner, some of the compounds showing activity at sub-micromolar concentrations. The reduction of cell survival is caused by a combination of reduced proliferation and induced differentiation of the Neuro2a cells. The complex 7-DHC oxysterol mixture added to control Neuro2a cells also triggers the gene expression changes that were previously identified in Dhcr7-deficient Neuro2a cells. Based on the identification of overlapping gene expression changes in Dhcr7-deficient and 7-DHC oxysterol-treated Neuro2a cells, we hypothesize that some of the pathophysiological findings in the mouse SLOS model and SLOS patients might be due to accumulated 7-DHC oxysterols. PMID- 20702864 TI - Toward a complete decision model of item and source recognition: A discrete-state approach. AB - In source-monitoring experiments, participants study items from two sources (A and B). At test, they are presented Source A items, Source B items, and new items. They are asked to decide whether a test item is old or new (item memory) and whether it is a Source A or a Source B item (source memory). Hautus, Macmillan, and Rotello (2008) developed models, couched in a bivariate signal detection framework, that account for item and source memory across several data sets collected in a confidence-rating response format. The present article enlarges the set of candidate models with a discrete-state model. The model is a straightforward extension of Bayen, Murnane, and Erdfelder's (1996) multinomial model of source discrimination to confidence ratings. On the basis of the evaluation criteria adopted by Hautus et al., it provides a better account of the data than do Hautus et al.'s models. PMID- 20702865 TI - Supertaskers: Profiles in extraordinary multitasking ability. AB - Theory suggests that driving should be impaired for any motorist who is concurrently talking on a cell phone. But is everybody impaired by this dual-task combination? We tested 200 participants in a high-fidelity driving simulator in both single- and dual-task conditions. The dual task involved driving while performing a demanding auditory version of the operation span (OSPAN) task. Whereas the vast majority of participants showed significant performance decrements in dual-task conditions (compared with single-task conditions for either driving or OSPAN tasks), 2.5% of the sample showed absolutely no performance decrements with respect to performing single and dual tasks. In single-task conditions, these "supertaskers" scored in the top quartile on all dependent measures associated with driving and OSPAN tasks, and Monte Carlo simulations indicated that the frequency of supertaskers was significantly greater than chance. These individual differences help to sharpen our theoretical understanding of attention and cognitive control in naturalistic settings. PMID- 20702866 TI - The action dynamics of overcoming the truth. AB - A convincing deceiver must act in discordance with their knowledge of the truth. To do so requires the deceiver to resolve competition between what is known to be true and what is intended to be false. We investigated the temporal signature of this competition by examining the action dynamics of arm movement while participants responded falsely or truthfully to autobiographical information. The participants answered no or yes by navigating a Nintendo Wii Remote to no and yes regions on a large projector screen. Trajectory analyses of the fine-grained arm movements show increased complexity in false responding relative to truthful responding, with the greatest difference in false yes answers. The dynamic motor movements also reveal greater strength of competition during the act of false responding, thereby extending traditional response time measures that capture latent competition alone. These results suggest that deceptive processes may be detectable when action is allowed to covary with thought. Supplemental figures and a list of the sentence stimuli may be downloaded from http://pbr.psychonomic journals.org/content/supplemental. PMID- 20702867 TI - Subjective recalibration of advisors' probability estimates. AB - Are decision makers sensitive to the statistical properties (i.e., calibration) of probability estimates that they receive from advisors? After specifying the ideal use of such estimates, we derive the roughly ideal forecast consumer (RIFC) and generalize it to account for how humans might use the estimates. We report an experiment in which participants first experienced various advisors by seeing their probability estimates and the associated outcomes and then provided confidence judgments in the presence of the advisors' estimates. The generalized model described the data well and showed that the participants were appropriately sensitive to the statistical properties of the advisors. Models of the individuals were better calibrated than the participants themselves, but still inferior to the RIFC. A detailed description of our model-testing procedure can be found in an appendix to the article. PMID- 20702868 TI - Sample size bias in the estimation of means. AB - The present research concerns the hypothesis that intuitive estimates of the arithmetic mean of a sample of numbers tend to increase as a function of the sample size; that is, they reflect a systematic sample size bias. A similar bias has been observed when people judge the average member of a group of people on an inferred quantity (e.g., a disease risk; see Price, 2001; Price, Smith, & Lench, 2006). Until now, however, it has been unclear whether it would be observed when the stimuli were numbers, in which case the quantity need not be inferred, and "average" can be precisely defined as the arithmetic mean. In two experiments, participants estimated the arithmetic mean of 12 samples of numbers. In the first experiment, samples of from 5 to 20 numbers were presented simultaneously and participants quickly estimated their mean. In the second experiment, the numbers in each sample were presented sequentially. The results of both experiments confirmed the existence of a systematic sample size bias. PMID- 20702869 TI - Pseudocontingencies can override genuine contingencies between multiple cues. AB - The cognitive process of contingency assessment has traditionally been conceived as an inference from the joint frequencies (table cell entries) of correlated cues. Alternatively, pseudocontingency (PC) inferences are derived from the alignment of separate base rate trends (table marginals). The present research extends PCs to the simultaneous assessment of six contingencies between four personality cues. Consistently obtained PC effects, reflecting accurately assessed base rate trends, were unaffected by the actual cue intercorrelations, which were zero or consistent or inconsistent with the PCs. The functional value of PC inferences is discussed. Although PCs can be misleading, they afford approximations of actually existing correlations that suffice under many, although not under all, conditions. PMID- 20702870 TI - Time scale similarity and long-term memory for autobiographical events. AB - We examine the extent to which retrieval from very long-term autobiographical memory is similar when participants are asked to retrieve from widely differing periods of time. Three groups of 20 participants were given 4 min to recall autobiographical events from the last 5 weeks, 5 months, or 5 years. Following recall, the participants dated their events. Similar retrieval rates, relative recency effects, and relative lag-recency effects were found, despite the fact that the considered time scales varied by a factor of 52. These data are broadly consistent with the principle of recency, the principle of contiguity (Howard & Kahana, 2002), and scale similarity in the rates of recall (Brown, Neath, & Chater, 2007; Maylor, Chater, & Brown, 2001). These findings are taken as support for models of memory that predict time scale similarity in retrieval, such as SIMPLE (Brown et al., 2007) and TCM (Howard & Kahana, 2002). PMID- 20702871 TI - Visual working memory is disrupted by covert verbal retrieval. AB - If working memory (WM) depends on a central resource-as is posited in some theories, but not in others-it should be possible to observe interference between tasks that share few features with each other. We investigated whether interference with WM for visual arrays would occur, even if the interfering task required neither visual processing nor overt responding. In an auditory-verbal interfering task, a response was to be made if a word was recognized as having come from one of two prelearned lists, but not from the other list. As compared with nonretrieval control conditions, even covert verbal memory retrieval disrupted the storage of visual items held in WM. A second experiment ruled out verbal recoding of the visual arrays as the basis of interference. The results indicate that visual WM and verbal long-term retrieval share a central resource (e.g., attention). PMID- 20702872 TI - Adaptation to different mouth shapes influences visual perception of ambiguous lip speech. AB - We investigated the effects of adaptation to mouth shapes associated with different spoken sounds (sustained /m/ or /u/) on visual perception of lip speech. Participants were significantly more likely to label ambiguous faces on an /m/-to-/u/ continuum as saying /u/ following adaptation to /m/ mouth shapes than they were in a preadaptation test. By contrast, participants were significantly less likely to label the ambiguous faces as saying /u/ following adaptation to /u/ mouth shapes than they were in a preadaptation test. The magnitude of these aftereffects was equivalent when the same individual was shown in the adaptation and test phases of the experiment and when different individuals were presented in the adaptation and test phases. These findings present novel evidence that adaptation to natural variations in facial appearance influences face perception, and they extend previous research on face aftereffects to visual perception of lip speech. PMID- 20702873 TI - Cuing effects of faces are dependent on handedness and visual field. AB - Faces are unlike other visual objects we encounter, in that they alert us to potentially relevant social information. Both face processing and spatial attention are dominant in the right hemisphere of the human brain, with a stronger lateralization in right- than in left-handers. Here, we demonstrate behavioral evidence for an effect of handedness on performance in tasks using faces to direct attention. Nonpredictive, peripheral cues (faces or dots) directed exogenous attention to contrast-varying stimuli (Gabor patches)-a tilted target, a vertical distractor, or both; observers made orientation discriminations on the target stimuli. Whereas cuing with dots increased contrast sensitivity in both groups, cuing with faces increased contrast sensitivity in right- but not in left-handers, for whom opposite hemifield effects resulted in no net increase. Our results reveal that attention modulation by face cues critically depends on handedness and visual hemifield. These previously unreported interactions suggest that such lateralized systems may be functionally connected. PMID- 20702874 TI - Value associations of irrelevant stimuli modify rapid visual orienting. AB - In familiar environments, goal-directed visual behavior is often performed in the presence of objects with strong, but task-irrelevant, reward or punishment associations that are acquired through prior, unrelated experience. In a two phase experiment, we asked whether such stimuli could affect speeded visual orienting in a classic visual orienting paradigm. First, participants learned to associate faces with monetary gains, losses, or no outcomes. These faces then served as brief, peripheral, uninformative cues in an explicitly unrewarded, unpunished, speeded, target localization task. Cues preceded targets by either 100 or 1,500 msec and appeared at either the same or a different location. Regardless of interval, reward-associated cues slowed responding at cued locations, as compared with equally familiar punishment-associated or no-value cues, and had no effect when targets were presented at uncued locations. This localized effect of reward-associated cues is consistent with adaptive models of inhibition of return and suggests rapid, low-level effects of motivation on visual processing. PMID- 20702875 TI - Looking versus seeing: Strategies alter eye movements during visual search. AB - Visual search can be made more efficient by adopting a passive cognitive strategy (i.e., letting the target "pop" into mind) rather than by trying to actively guide attention. In the present study, we examined how this strategic benefit is linked to eye movements. Results show that participants using a passive strategy wait longer before beginning to move their eyes and make fewer saccades than do active participants. Moreover, the passive advantage stems from more efficient use of the information in a fixation, rather than from a wider attentional window. Individual difference analyses indicate that strategies also change the way eye movements are related to search success, with a rapid saccade rate predicting success among active participants, and fewer and larger amplitude saccades predicting success among passive participants. A change in mindset, therefore, alters how oculomotor behaviors are harnessed in the service of visual search. PMID- 20702876 TI - Viewing-position effects in the Stroop task: Initial fixation position modulates Stroop effects in fully colored words. AB - In two experiments that we conducted with adult (Experiment 1) and child (Experiment 2) participants, we experimentally controlled the eyes' first fixation in the word using a variable viewing-position technique in a classical all-letter-coloring Stroop procedure. We explored the impact of initial-fixation position (optimal viewing position [OVP] vs. end of the word) on the magnitude of Stroop effects (both interference and facilitation). The results showed that both interference and facilitation effects were reduced when the first fixation was located at the end of the word rather than at the OVP. These data make a new contribution to the study of the role of low-level processes in Stroop effects and add support to the growing body of research indicating that oculomotor processes can act as moderators of cognitive processes in the determination of Stroop effects. PMID- 20702877 TI - Personality predicts temporal attention costs in the attentional blink paradigm. AB - Accuracy for a second target is reduced when it is presented within 500 msec of a first target. This phenomenon is called the attentional blink (AB). A diffused attentional state (via positive affect or an additional task) has been shown to reduce the AB, whereas a focused attentional state (via negative affect) has been shown to increase the AB, purportedly by influencing the amount of attentional investment and flexibility. In the present study, individual differences in personality traits related to positive affect, negative affect, and cognitive flexibility were used to predict individual differences in AB magnitude. As hypothesized, greater extraversion and openness predicted smaller ABs. Greater openness also predicted higher overall target accuracy. Greater neuroticism predicted larger ABs and lower overall target accuracy. Conscientiousness, associated with less cognitive flexibility, predicted lower overall target accuracy. Personality may modulate the AB by influencing overinvestment via dispositional tendencies toward more or less stringent or capable cognitive control. PMID- 20702878 TI - Time flies when we read taboo words. AB - Does time fly or stand still when one is reading highly arousing words? A temporal bisection task was used to test the effects of sexual taboo words on time perception. Forty participants judged the duration of sexual taboo, high arousal negative, high-arousal positive, low-arousal negative, low-arousal positive, and category-related neutral words. The results support the hypothesis that sexual taboo stimuli receive more attention and reduce the perceived time that has passed ("time flies")-the duration of high sexual taboo words was underestimated for taboo-word stimuli relative to all other word types. The findings are discussed in the context of internal clock theories of time perception. PMID- 20702879 TI - Cognitive load and semantic analogies: Searching semantic space. AB - The aim of the present study is to investigate the performance of children of different ages on an analogy-making task involving semantic analogies in which there are competing semantic matches. We suggest that this can best be studied in terms of developmental changes in executive functioning. We hypothesize that the selection of common relational structure requires the inhibition of other salient features, in particular semantically related matches. Our results show that children's performance in classic A: B:: C: D analogy-making tasks seems to depend crucially on the nature of the distractors and the association strength between both the A and B terms and the C and D terms. These results agree with an analogy-making account (Richland, Morrison, & Holyoak, 2006) based on different limitations in executive functioning at different ages. PMID- 20702880 TI - Function and context affect spatial information packaging at multiple levels. AB - In the present study, we examined how context of instruction and information in the visual array to be described affect spatial information packaging across a range of levels of spatial description. Participants described complex scenes containing 3-D dollhouse furniture across two different arrays (functional vs. nonfunctional arrangements of objects) and across instructional contexts (living room context, furniture showroom context, no context). Knowledge about the visual scene and instructional context both had an impact on spatial descriptions, but separately, and at different levels of granularity. The influence of visual context was particularly striking, with marked differences across conditions at multiple levels of information packaging-descriptive trajectories (the order in which objects in the spatial array were described), amount of detail, and explicit mention of atypical object orientation. The importance of visual context as a means of accessing context frames in common ground is discussed. PMID- 20702881 TI - Biased feedback in spatial recall yields a violation of delta rule learning. AB - This study investigates whether inductive processes influencing spatial memory performance generalize to supervised learning scenarios with differential feedback. After providing a location memory response in a spatial recall task, participants received visual feedback showing the target location. In critical blocks, feedback was systematically biased either 4 degrees toward the vertical axis (toward condition) or 4 degrees farther away from the vertical axis (away condition). Results showed that the weaker teaching signal (i.e., a smaller difference between the remembered location and the feedback location) produced a stronger experience-dependent change over blocks in the away condition than in the toward condition. This violates delta rule learning. Subsequent simulations of the dynamic field theory of spatial cognition provide a theoretically unified account of these results. PMID- 20702882 TI - Recognition-based inference: When is less more in the real world? AB - Common wisdom tells us that more information can only help and never hurt. Goldstein and Gigerenzer (2002) highlighted an instance violating this intuition. Specifically, in an analysis of their recognition heuristic, they found a counterintuitive less-is-more effect in inference: An individual recognizing fewer objects than another individual can, nevertheless, make more accurate inferences. Goldstein and Gigerenzer emphasized that a sufficient condition for this effect is that the recognition validity be higher than the knowledge validity, assuming that the validities are uncorrelated with the number of recognized objects, n. But how is the occurrence of the less-is-more effect affected when this independence assumption is violated? I show that validity dependencies (i.e., correlations of the validities with n) abound in empirical data sets, and I demonstrate by computer simulations that these dependencies often have a strong limiting effect on the less-is-more effect. Moreover, I discuss what cognitive (e.g., memory) and ecological (e.g., distribution of the criterion variable, environmental frequencies) factors can give rise to a dependency of the recognition validity on the number of recognized objects. Supplemental materials may be downloaded from http://pbr.psychonomic journals.org/content/supplemental. PMID- 20702883 TI - Do young chimpanzees have extraordinary working memory? AB - Do chimpanzees have better spatial working memory than humans? In a previous report, a juvenile chimpanzee outperformed 3 university students on memory for briefly displayed digits in a spatial array (Inoue & Matsuzawa, 2007). The authors described these abilities as extraordinary and likened the chimpanzee's performance to eidetic memory. However, the chimpanzee received extensive practice on a non-time-pressured version of the task; the human subjects received none. Here we report that, after adequate practice, 2 university students substantially outperformed the chimpanzee. There is no evidence for a superior or qualitatively different spatial memory system in chimpanzees. PMID- 20702884 TI - Recommendations for echocardiography use in the diagnosis and management of cardiac sources of embolism: European Association of Echocardiography (EAE) (a registered branch of the ESC). AB - Embolism of cardiac origin accounts for around 15-30% of ischaemic strokes. Strokes due to cardioembolism are generally severe and early and long-term recurrence and mortality are high. The diagnosis of a cardioembolic source of stroke is frequently uncertain and relies on the identification of a potential cardiac source of embolism in the absence of significant autochthone cerebrovascular occlusive disease. In this respect, echocardiography (both transthoracic and/or transoesophageal) serves as a cornerstone in the evaluation, diagnosis, and management of these patients. A clear understanding of the various types of cardiac conditions associated with cardioembolic stroke and their intrinsic risk is therefore very important. This article reviews potential cardiac sources of embolism and discusses the role of echocardiography in clinical practice. Recommendations for the use of echocardiography in the diagnosis of cardiac sources of embolism are given including major and minor conditions associated with the risk of embolism. PMID- 20702886 TI - Accounting for health-care outcomes: implications for intensive care unit practice and performance. AB - The aim of this study was to understand the environment of health care, and how clinicians and managers respond in terms of performance accountability. A qualitative method was used in a tertiary metropolitan teaching intensive care unit (ICU) in Sydney, Australia, including interviews with 15 clinical managers and focus groups with 29 nurses of differing experience. The study found that a managerial focus on abstract goals, such as budgets detracted from managing the core business of clinical work. Fractures were evident within clinical units, between clinical units and between clinical and managerial domains. These fractures reinforced the status quo where seemingly unconnected patient care activities were undertaken by loosely connected individual clinicians with personalized concepts of accountability. Managers must conceptualize health services as an interconnected entity within which self-directed teams negotiate and agree objectives, collect and review performance data and define collective practice. Organically developing regimens of care within and across specialist clinical units, such as in ICUs, directly impact upon health service performance and accountability. PMID- 20702887 TI - Spotting the pantomime villain: do the usual approaches correctly indicate when waiting times got shorter? AB - To assess whether changes in length of wait are correlated (directly) with changes in size of list, i.e. whether census-, event- and enrolment-based estimates of the percentage that waited 0-2 months are valid measures. EyeNet Sweden supplied dates of extraction and enrolment for 1,061,246 cataracts extracted between 1992 and 2009 inclusive. Changes in size of list were calculated as enrolments minus extractions. Fifty-nine times out of 62 the enrolment-based measure reported an increase in length of wait when size of list increased or a decrease in length when size decreased (L(B) = 90%, 95% confidence interval = 80-100). But 47 times out of 62 the event-based measure reported a decrease in length of wait when size of list increased, or an increase in length when size decreased (L(B) = 40%, 95% confidence interval = 6-74). The census based measure did likewise 34 times out of 63 (L(B) = 6%). The three approaches gave different results despite using the same combination of cohorts and categories, the same point on the distribution of waits, the same rules about which waits (and which parts of these) count and the same length of follow-up. Census- and event-based measures often concealed the true direction of change in length of wait. PMID- 20702888 TI - Forecasting the stochastic demand for inpatient care: the case of the Greek national health system. AB - The aim of this study is to estimate the unexpected demand of Greek public hospitals. A multivariate model with four explanatory variables is used. These are as follows: the weekend effect, the duty effect, the summer holiday and the official holiday. The method of the ordinary least squares is used to estimate the impact of these variables on the daily hospital emergency admissions series. The forecasted residuals of hospital regressions for each year give the estimated stochastic demand. Daily emergency admissions decline during weekends, summer months and official holidays, and increase on duty hospital days. Stochastic hospital demand varies both among hospitals and over the five-year time period under investigation. Variations among hospitals are larger than time variations. Hospital managers and health policy-makers can be availed by forecasting the future flows of emergent patients. The benefit can be both at managerial and economical level. More advanced models including additional daily variables such as the weather forecasts could provide more accurate estimations. PMID- 20702889 TI - From bed-blocking to delayed discharges: precursors and interpretations of a contested concept. AB - Delayed hospital discharges have been identified as a problem for the English National Health Service and have prompted several policy and service development responses in the last decade. However, bed-blocking is an issue surrounded by rival interpretations on how and why hospital delays occur and the way in which they are measured. To better understand this contested concept, this paper provides a brief description of the historical accounts that framed the emergence of delayed hospital discharges as a phenomenon. Three key features of the bed blocking concept are also analysed: the reduction of patients' length of stay to improve efficiency, the intrinsic methodological difficulties of measuring hospital delays and the most common reasons for delayed discharges. A description of the characteristics of the patients frequently labelled as delayed discharge, their common traits and how these have been examined by previous research is also provided. Finally, this paper argues that the presence of hospital delays in a health system tends to be considered as an indicator of two possible system inefficiencies: a failure in the discharge planning process, which generally blames social services departments for not ensuring timely services, or a shortage of alternative forms of care for this group of patients. PMID- 20702890 TI - A configurational view of executive selection behaviours: a taxonomy of USA acute care hospitals. AB - Health-care organizations, particularly hospitals, are among the most complex organizations to manage. However, the executive selection processes these organizations have in place are poorly understood. The purpose of this study is to explore the executive selection processes employed by USA acute care hospitals and discern if such processes are related to environmental, structural and strategic organizational characteristics. We conceptualize this model using a configurational approach. We present an empirically derived taxonomy of hospitals based on executive selection processes, structural and environmental characteristics, and organizational strategy based on the Porter framework. Based on the analyses, three types of hospitals are identified: (1) small, rural, cost leaders with limited selection processes; (2) large, urban, differentiators, with a plan; and (3) small, rural, caught in the middle muddlers. PMID- 20702891 TI - Effect of the Iranian hospital grading system on patients' and general practitioners' behaviour: an examination of awareness, belief and choice. AB - There is considerable international interest in the use of performance measurement and their public release in order to improve the quality of care. However, few studies have assessed stakeholders' awareness and use of performance data. Iranian hospitals have been graded annually since 1998 and hospital hotel charges vary by grade, but this system has never been evaluated. We conducted a cross-sectional survey of 104 outpatients at eight Teheran hospitals and 103 general practitioners (GPs) to assess the awareness of and attitudes towards hospital grading system. Only 5.8% of patients (95% CI: 1.3-10.3%) and 11.7% of GPs (95% CI: 5.5-17.9%) were aware of grading results. Patients' awareness was positively associated with their education level (P = 0.016). No patient used the grading results for choosing a hospital and only one GP (1%, 95% CI: 0-2%) reported using hospital grade to influence referral decisions. Patients were more influenced by hospitals' public reputation and that of their specialists. GPs believed that the grading system did not reflect the quality of care in hospitals. When developing performance measurement systems, public release of data should be accompanied by evaluation of its impact on awareness and health care choices. PMID- 20702892 TI - Musite, a tool for global prediction of general and kinase-specific phosphorylation sites. AB - Reversible protein phosphorylation is one of the most pervasive post translational modifications, regulating diverse cellular processes in various organisms. High throughput experimental studies using mass spectrometry have identified many phosphorylation sites, primarily from eukaryotes. However, the vast majority of phosphorylation sites remain undiscovered, even in well studied systems. Because mass spectrometry-based experimental approaches for identifying phosphorylation events are costly, time-consuming, and biased toward abundant proteins and proteotypic peptides, in silico prediction of phosphorylation sites is potentially a useful alternative strategy for whole proteome annotation. Because of various limitations, current phosphorylation site prediction tools were not well designed for comprehensive assessment of proteomes. Here, we present a novel software tool, Musite, specifically designed for large scale predictions of both general and kinase-specific phosphorylation sites. We collected phosphoproteomics data in multiple organisms from several reliable sources and used them to train prediction models by a comprehensive machine learning approach that integrates local sequence similarities to known phosphorylation sites, protein disorder scores, and amino acid frequencies. Application of Musite on several proteomes yielded tens of thousands of phosphorylation site predictions at a high stringency level. Cross-validation tests show that Musite achieves some improvement over existing tools in predicting general phosphorylation sites, and it is at least comparable with those for predicting kinase-specific phosphorylation sites. In Musite V1.0, we have trained general prediction models for six organisms and kinase-specific prediction models for 13 kinases or kinase families. Although the current pretrained models were not correlated with any particular cellular conditions, Musite provides a unique functionality for training customized prediction models (including condition-specific models) from users' own data. In addition, with its easily extensible open source application programming interface, Musite is aimed at being an open platform for community-based development of machine learning based phosphorylation site prediction applications. Musite is available at http://musite.sourceforge.net/. PMID- 20702894 TI - Oscillating in synchrony with a metronome: serial dependence, limit cycle dynamics, and modeling. AB - We analyzed serial dependencies in periods and asynchronies collected during oscillations performed in synchrony with a metronome. Results showed that asynchronies contain 1/f fluctuations, and the series of periods contain antipersistent dependence. The analysis of the phase portrait revealed a specific asymmetry induced by synchronization. We propose a hybrid limit cycle model including a cycle-dependent stiffness parameter provided with fractal properties, and a parametric driving function based on velocity. This model accounts for most experimentally evidenced statistical features, including serial dependence and limit cycle dynamics. We discuss the results and modeling choices within the framework of event-based and emergent timing. PMID- 20702893 TI - Motor synergies and the equilibrium-point hypothesis. AB - The article offers a way to unite three recent developments in the field of motor control and coordination: (1) The notion of synergies is introduced based on the principle of motor abundance; (2) The uncontrolled manifold hypothesis is described as offering a computational framework to identify and quantify synergies; and (3) The equilibrium-point hypothesis is described for a single muscle, single joint, and multijoint systems. Merging these concepts into a single coherent scheme requires focusing on control variables rather than performance variables. The principle of minimal final action is formulated as the guiding principle within the referent configuration hypothesis. Motor actions are associated with setting two types of variables by a controller, those that ultimately define average performance patterns and those that define associated synergies. Predictions of the suggested scheme are reviewed, such as the phenomenon of anticipatory synergy adjustments, quick actions without changes in synergies, atypical synergies, and changes in synergies with practice. A few models are briefly reviewed. PMID- 20702895 TI - Implicit motor learning in patients with Parkinson's and Alzheimer's disease: differences in learning abilities? AB - Experimental studies show intact implicit motor learning in patients with Alzheimer's disease (AD) but the results for patients with Parkinson's disease (PD) are inconclusive. This study tests implicit sequence learning in AD and PD patients, and healthy controls, using the classical Serial Reaction Time Task (SRTT), and a somewhat similar Pattern Learning Task (PLT), which involves stylus movements in different directions, and which allows detailed movement analysis. As expected, the time measures showed less implicit motor learning in the PD patients relative to the other groups in both tasks, but their error percentages increased when the sequence changed from a fixed to a random order, which is indicative of implicit learning. The AD patients showed a reversed pattern of results. Arguably, errors and time measures may reflect the involvement of separate processes, e.g., spatial and motor components, which could be differently affected in AD and PD. PMID- 20702896 TI - The effects of visual information and perceptual style on static and dynamic balance. AB - This study investigated the influence of visual cues and perceptual style on static and dynamic balance performance. Twenty-five field dependent (FD) and twenty-five field independent (FI) participants performed tests of static and dynamic balance under five different vision conditions. Balance performance was measured using the Biodex Balance System. The vision conditions included: eyes open with visual feedback (EOFB), without visual feedback (EOEC), viewing lines tilted 18 degrees (EOTL), eyes open without any visual cues (EONC), and eyes closed (EC). All participants were more stable when visual cues were present. Results revealed no significant difference between the two groups on the static balance task in any of the vision conditions. A significant difference was found between the two groups on the dynamic balance task. In three of the vision conditions (EOFB, EOEC, EOTL), the FI group was found to be more stable than the FD group. Movement of the body required during a dynamic balance task generates vestibular and somatosensory information which FI individuals may be more efficient in translating into greater stability as compared with FD individuals. PMID- 20702897 TI - The effects of physical activity in the anticipatory postural adjustments in elderly people. AB - Exercise seems to attenuate the postural control system and anticipatory postural adjustments (APAs) decline, but no conclusive findings are available. This study analyzes, in elderly people, the exercise effect in APAs during the raising of a load with both arms in the sagittal plane. Twenty eight males over the age of 60 (65.8 +/- 4.07 yr old)-9 veterans in exercising, 9 who exercise recently, and 10 sedentary-were asked to raise a load with both arms simultaneously to shoulder level, in standing position, as fast as possible. The electromyography (EMG) pattern of the main muscles was studied. The APAs were quantified through the time integral of EMG records (iEMG). Anticipatory changes in the postural muscles were seen in all groups. We observed, in the tibialis anterior activity, a higher significant activation in the sedentary compared with the other groups, suggesting that exercise can modulate the postural control system. PMID- 20702898 TI - Temporal organization of complex onsets and codas in American English: testing the predictions of a gestural coupling model. AB - This study systematically investigates the temporal organization of American English onset and coda consonant clusters on the basis of kinematic data. Results from seven speakers suggest that consonants in complex onsets are organized globally with respect to the following vowel, while consonants in complex codas are organized locally relative to the preceding vowel. These results support the competitive coupling model hypothesized for complex onsets, a model according to which consonant gestures in onsets are each coupled in-phase to the vowel, and antiphase with each other. The results are overall also consistent with the noncompetitive coupling relations assumed for codas, by which only the first consonant in a cluster is coupled antiphase with the vowel, and any subsequent consonants are coupled antiphase to each other. However, our data also show that the segmental composition of the cluster affects the timing relationship in codas, particularly/lC/coda clusters pattern differently from other clusters and do not adhere to the predicted timing relations. The data contribute to our understanding of the interaction of linguistic structure and motor control of the articulators in speech production. PMID- 20702899 TI - Research on physical activity and health: where is Latin America? PMID- 20702900 TI - Project GUIA: A model for understanding and promoting physical activity in Brazil and Latin America. PMID- 20702901 TI - Physical activity and public health in Latin America-moving forward. PMID- 20702902 TI - Promoting physical activity through community-wide policies and planning: findings from Curitiba, Brazil. AB - BACKGROUND: Community programs have been suggested to be an important and promising strategy for physical activity (PA) promotion. Limited evidence is available regarding knowledge of and participation in these programs in Latin America. OBJECTIVE: To describe participation in and knowledge of community PA programs and to explore associations with leisure-time PA in the city of Curitiba, Brazil. METHODS: A cross sectional telephone survey was conducted among adults in Curitiba, Brazil (n = 2097). The International Physical Activity Questionnaire was used to determine levels of PA, and specific questions were used to evaluate the extent to which respondents knew about or participated in the programs conducted by the municipality. Logistic regression was used to assess the meeting of PA recommendations in leisure time based on program knowledge and participation. RESULTS: Knowledge of PA programs was high (91.6%) and 5.6% of population participated in the programs. After adjusting for individual characteristics, exposure to Curitiba's PA community programs was associated with leisure-time PA (POR = 2.9, 95% CI = 2.9-3.0) and walking for leisure (POR = 2.4; 95% CI = 2.3-2.4). The associations were stronger among men than among women. CONCLUSIONS: Knowledge and participation in Curitiba's community PA programs were associated with meeting recommended levels of PA in leisure time. PMID- 20702903 TI - Using observational methods to evaluate public open spaces and physical activity in Brazil. AB - BACKGROUND: Open public spaces have been identified as important facilities to promote physical activity (PA) at the community level. The main goals of this study are to describe open public spaces user's characteristics and to explore to what extent these characteristics are associated with PA behavior. METHODS: A system of direct observation was used to evaluate the PA levels on parks and squares (smaller parks) and users's characteristics (gender and age). The 4 parks and 4 squares observed were selected from neighborhoods with different socioeconomic status and environmental characteristics. The settings were observed 3 times a day, 6 days per week, during 2 weeks. RESULTS: More men than women were observed in parks (63.1%) and squares (70.0%) as well as more adults and adolescents than older adults and children. Users were more physically active in parks (men = 34.1%, women = 36.1%) than in squares (men = 25.5%, women 22.8%). CONCLUSIONS: The characteristics of public open spaces may affect PA in the observed places. Initiatives to improve PA levels in community settings should consider users' characteristics and preferences to be more effective and reach a larger number of people. PMID- 20702904 TI - Using logic models as iterative tools for planning and evaluating physical activity promotion programs in Curitiba, Brazil. AB - BACKGROUND: The Guide for Useful Interventions for Activity in Brazil and Latin America (GUIA), a systematic review of community-based physical activity (PA) interventions in Latin American literature, selected the CuritibAtiva program for a comprehensive evaluation. We describe the process of developing logic models (LM) of PA community interventions from Curitiba, Brazil, and discuss influential factors. METHODS: The year-long process included engaging stakeholders involved in the promotion of PA in Curitiba, working with stakeholders to describe the programs and their goals, and developing LMs for the 2 main secretaries promoting PA in the city. RESULTS & CONCLUSIONS: As a result of stakeholder interviews and discussion and the development of the LMs, local officials are coordinating programming efforts and considering ways the programs can be more complementary. The process has prompted program managers to identify overlapping programs, refine program goals, and identify gaps in programming. It also helped to frame evaluation questions, identify data sources, describe realistic outcomes, and reinforce the importance of intersectoral alliances for public health impact. Developing LMs proved to be feasible in the Latin American context, therefore adaptable and useful for other PA promotion programs in the region. PMID- 20702905 TI - The Ciclovia-Recreativa: A mass-recreational program with public health potential. AB - BACKGROUND: The Ciclovia-Recreativa is a free, community-based program in which streets are closed temporarily to motorized transport, allowing access to walkers, runners, rollerbladers, and cyclists only. We assessed existing information about the Ciclovia as a public health strategy and proposed next steps for research and public health practice. METHODS: We conducted a systematic search of peer-reviewed and other literature, which was complemented by expert interviews and consultation. RESULTS: We reviewed 38 Ciclovias from 11 countries. Most programs (84.2%) take place in urban settings. The programs range from 18-64 events per year (54 + or - 24.6; 52 [mean + or - standard deviation; median]) with events lasting from 2-12 hours (6 + or - 2.4; 6). The length of the streets ranges from 1-121 km (14.6 + or - 22.1; 7), and the estimated number of participants per event ranges from 60-1,000,000 persons (61,203 + or - 186,668; 3810). Seventy-one percent of the programs include physical activity classes and in 89% of the Ciclovias, the streets are connected with parks. CONCLUSIONS: Ciclovias have potential for positive public health outcomes, but evidence on their effectiveness is limited. The different stages of new and established programs offer a unique opportunity for transnational studies aimed at assessing their public health impact. PMID- 20702906 TI - Quality of life, physical activity, and built environment characteristics among colombian adults. AB - BACKGROUND: Studies assessing the association between health-related quality of life (HR-QOL) with physical activity (PA) and built environment (BE) characteristics are limited. METHODS: A cross-sectional study was conducted among 1,334 adults from Bogota, to assess the associations between HR-QOL with PA and BE characteristics. HR-QOL was measured using the World Health Organization and the Centers for Disease Control and Prevention instruments. PA was measured using the International PA Questionnaire. BE characteristics included the dimensions of density, diversity, design, and access to mass-transit. Analysis included multilevel modeling. RESULTS: Adults who reported meeting PA recommendations and participating in the Ciclovia were more likely to have a high mean score of HR QOL and were more likely to perceive their health status as good/excellent. Adults who reported biking for transportation were more likely to have a high mean score of HR-QOL. Regarding BE characteristics, land-use heterogeneity was associated with HR-QOL, perceived good health status and being positive about the future. Park density was associated with HR-QOL, perceived health status good/excellent and being positive about the future. Mass-transit stations availability was negatively associated with HR-QOL. CONCLUSION: This study provides preliminary evidence that HR-QOL is associated with PA and BE characteristics among adults in an urban setting of the developing world. PMID- 20702908 TI - Physical activity levels according to physical and social environmental factors in a sample of adults living in South Brazil. AB - OBJECTIVE: To evaluate the association between the physical and social environment and physical activity (leisure-time and transport-related) in a population-based sample of adults. METHODS: Cross-sectional study including 972 adults (20-69 years) living in the urban area of Pelotas, Brazil. Physical activity was measured using the long International Physical Activity Questionnaire. Environmental variables were assessed using a modified version of the Neighborhood Environment Walkability Scale. RESULTS: 69.8% (95% CI = 66.9 72.7) and 51.9% (95% CI = 48.8-55.1) of the subjects did not reach 150 min/wk on leisure-time and transport-related physical activity, respectively. Subjects living near green areas were more likely to be active in leisure-time, as well as those who reported to live in safe neighborhoods. Transport-related physical activity was higher among individuals living in areas with garbage accumulation, and was lower among those living in neighborhoods which are difficult to walk or cycle due to traffic. Social support was strongly associated with leisure-time physical activity. CONCLUSIONS: Safety investments, which are urgently required in Brazil, are likely to have a desirable side effect at increasing physical activity at the population level. Building enjoyable and safe public spaces for physical activity practice must be prioritized. PMID- 20702907 TI - Characteristics of the built environment associated with leisure-time physical activity among adults in Bogota, Colombia: a multilevel study. AB - BACKGROUND: Even though there is increasing evidence that the built environment (BE) has an influence on leisure-time physical activity (LTPA), little is known about this relationship in developing countries. The objective of this study was to assess the associations between objective built environment characteristics and LTPA. METHODS: A cross-sectional multilevel study was conducted in 27 neighborhoods in which 1315 adults aged 18-65 years were surveyed. An adapted version of the IPAQ (long version) was used to assess LTPA. Objective BE characteristics were obtained using Geographic Information Systems. Associations were assessed using multilevel polytomous logistic regression. RESULTS: Compared with inactive people, those who resided in neighborhoods with the highest tertile dedicated to parks (7.4% to 25.2%) were more likely to be regularly active (POR = 2.05, 95% CI = 1.13-3.72; P = 0.021). Those who resided in neighborhoods with presence of TransMilenio stations (mass public transportation system) were more likely to be irregularly active (POR = 1.27, 95% CI = 1.07-1.50, P = 0.009) as compared with inactive people. CONCLUSIONS: These findings showed that park density and availability of TransMilenio stations at neighborhood level are positively associated with LTPA. Public health efforts to address physical inactivity should consider the potential influences of urban planning and mass public transportation systems on health. PMID- 20702909 TI - Association between perceived environmental attributes and physical activity among adults in Recife, Brazil. AB - BACKGROUND: To evaluate the association between perceived environmental factors and leisure-time and transport-related physical activity. METHODS: A random-digit dialing telephone cross-sectional survey in Recife, Brazil, was conducted among individuals aged 16 years or older (n = 2046). Leisure-time and transport-related physical activity were measured using the long version of the International Physical Activity Questionnaire. Three outcome variables were used: leisure-time physical activity (min/wk), transport-related physical activity (min/wk), and walking for leisure (min/wk). A cutoff of 150 min/wk was used for all outcome variables. The environmental module of the questionnaire was based on the short version of the Neighborhood Environment Walkability Scale (A-NEWS), and included 12 environmental items. RESULTS: The proportions of subjects reaching the 150 minutes per week threshold were 30.6% for leisure-time physical activity, 26.6% for transport-related physical activity and 18.2% for walking for leisure. Lack of sidewalks and low access to recreational facilities were associated with a lower likelihood of performing 150 minutes per week or more of leisure-time physical activity. Lack of sidewalks was associated with low levels of walking for leisure. Neighborhood aesthetics was inversely associated with transport related physical activity. CONCLUSIONS: Lack of sidewalks and low access to recreational facilities were predictors of low levels of leisure-time physical activity, suggesting that policy strategies aimed at improving these environmental features may be warranted. PMID- 20702910 TI - Exposure to a community-wide physical activity promotion program and leisure-time physical activity in Aracaju, Brazil. AB - BACKGROUND: Evaluation studies of large scale physical activity promotion programs are rare in Latin America. The aim of the current study was to evaluate the association between various forms of exposure to Academia da Cidade (PAC), a professionally supervised intervention in Aracaju (Brazil), and leisure-time physical activity (LTPA). METHODS: A population-based study including 2267 adults was carried out. LTPA was assessed using the long version of the International Physical Activity Questionnaire, and a cut-off of 150 minutes per week was used in the analyses. RESULTS: In fully adjusted models, having ever heard about PAC was related to an odds of 1.8 (95% CI 1.4-2.2) for reaching the 150-minutes per week LTPA threshold. Equivalent odds ratios were 1.6 (95% CI 1.1-2.3) for having ever seen a PAC class, 14.3 (95% CI 12.3-16.4) for current and 4.0 (95% CI 1.4 11.3) for past PAC participation. CONCLUSION: Different sources of exposure to PAC were significantly associated with LTPA, which may suggest that professionally-supervised community classes offered for free may be a successful alternative for promoting physical activity in Brazil. If PAC happens to be expanded to other Brazilian areas, intervention studies may be carried out to evaluate its effectiveness. PMID- 20702911 TI - Cross-sectional associations of health-related quality of life measures with selected factors: a population-based sample in recife, Brazil. AB - BACKGROUND: We used data from a random telephone survey of 2045 adults in Recife, Brazil to investigate the associations of health-related quality of life (HRQoL) with selected factors. METHODS: We generated odds ratios of 4 HRQoL measures (perception of overall health, mentally unhealthy days, physically unhealthy days, and physically and mentally unhealthy days impeding usual activities) by levels of environmental factors (number of destinations, neighborhood aesthetics, neighborhood crime safety, neighborhood traffic interference, and neighborhood walkability), physical activity behavior, and participation in the Academia da Cidade Program (ACP). RESULTS: Perception of overall health was associated with age, gender, education, body mass index (BMI) level, chronic disease, and having heard or seen an ACP activity. Mentally unhealthy days were associated with age, sex, BMI level, neighborhood aesthetics, and neighborhood crime safety. Physically unhealthy days were associated with age, sex, chronic diseases, leisure time physical activity, and neighborhood crime safety, and neighborhood traffic interference. Physically and mentally unhealthy days impeding usual activities were associated with chronic disease neighborhood crime safety, and traffic interference. CONCLUSIONS: The associations of HRQoL with environmental factors and health promoting programs may have public health policy implications and highlight the need for additional research into HRQoL in Brazil. PMID- 20702912 TI - Assembling the puzzle for promoting physical activity in Brazil: a social network analysis. AB - BACKGROUND: Physical inactivity is a significant public health problem in Brazil that may be addressed by partnerships and networks. In conjunction with Project GUIA (Guide for Useful Interventions for Physical Activity in Brazil and Latin America), the aim of this study was to conduct a social network analysis of physical activity in Brazil. METHODS: An online survey was completed by 28 of 35 organizations contacted from December 2008 through March 2009. Network analytic methods examined measures of collaboration, importance, leadership, and attributes of the respondent and organization. RESULTS: Leadership nominations for organizations studied ranged from 0 to 23. Positive predictors of collaboration included: south region, GUIA membership, years working in physical activity, and research, education, and promotion/practice areas of physical activity. The most frequently reported barrier to collaboration was bureaucracy. CONCLUSION: Social network analysis identified factors that are likely to improve collaboration among organizations in Brazil. PMID- 20702913 TI - Description of the countrywide physical activity network coordinated by the Brazilian Ministry of Health: 2005-2008. AB - BACKGROUND: Based on the Brazilian National Health Promotion Policy (PNPS), the Ministry of Health (MoH) started stimulating and funding physical activity interventions in 2005, leading to the establishment of a countrywide network. The aim of the present article is to geographically describe this network (2005-2008) and to present structure and process evaluation indicators of interventions funded in 2006 and 2007. METHODS: In 2005, the 27 state capitals received funding for carrying out physical activity-related interventions. From 2006 onwards, public calls for proposals were announced, and cities were selected through a competitive basis. Coordinators of interventions in cities who got funding in 2006 and 2007 answered to survey questions on structure and process aspects of the interventions. RESULTS: The network currently comprises 469 projects, out of which over 60% are carried out in small cities (<30,000 inhabitants). The most frequently used public spaces for the interventions are squares and indoor sports courts. The main physical activity-related topic of the PNPS prioritized in the projects is healthy diet. The main partnerships developed are between City's Health and Education Secretariats. CONCLUSION: Expanding the network to 1000 cities by 2010 and continuing the evaluation efforts are the next goals of the Brazilian MoH. PMID- 20702914 TI - Lessons learned after 10 years of IPAQ use in Brazil and Colombia. AB - BACKGROUND: To describe the lessons learned after 10 years of use of the International Physical Activity Questionnaire (IPAQ) in Brazil and Colombia, with special emphasis on recommendations for future research in Latin America using this instrument. METHODS: We present an analytical commentary, based on data from a review of the Latin American literature, as well as expert consultation and the authors' experience in administering IPAQ to over 43,000 individuals in Brazil and Colombia between 1998 and 2008. RESULTS: Validation studies in Latin America suggest that the IPAQ has high reliability and moderate criteria validity in comparison with accelerometers. Cognitive interviews suggested that the occupational and housework sections of the long IPAQ lead to confusion among respondents, and there is evidence that these sections generate overestimated scores of physical activity. Because the short IPAQ considers the 4 physical activity domains altogether, people tend to provide inaccurate answers to it as well. CONCLUSIONS: Use of the leisure-time and transport sections of the long IPAQ is recommended for surveillance and studies aimed at documenting physical activity levels in Latin America. Use of the short IPAQ should be avoided, except for maintaining consistency in surveillance when it has already been used at baseline. PMID- 20702915 TI - Physical activity interventions in Latin America: what value might be added by including conference abstracts in a literature review? AB - BACKGROUND: This review assessed whether conference abstracts yield useful information on the types and effectiveness of community-based physical activity (PA) interventions in Latin America, beyond that from interventions included in a recent systematic review of peer-reviewed literature. METHODS: Abstracts from 9 conferences were searched for community-based interventions to promote PA in Latin America and summarized. Three reviewers classified and screened abstracts. Evaluated interventions that were not included in the previous review were assessed. RESULTS: Search of abstracts from 31 proceedings of 9 conferences identified 87 abstracts of studies on community-based interventions focused on increasing PA. Only 31 abstracts reported on studies with a control group and an outcome related to PA. Ten of these abstracts represented interventions that had not been included in the previous review of peer-reviewed literature, but the abstracts were insufficient in number or detail to make a practice recommendation for any single intervention. CONCLUSIONS: This review highlighted the challenges and low added value of including conference abstracts in a systematic review of community PA interventions in Latin America. Stronger evaluation design and execution and more published reports of evaluated interventions are needed to build an evidence base supporting interventions to increase PA in Latin America. PMID- 20702916 TI - Early detection of cardiac ischemia using a conductometric pCO(2) sensor: real time drift correction and parameterization. AB - For detection of cardiac ischemia based on regional pCO(2) measurement, sensor drift becomes a problem when monitoring over several hours. A real-time drift correction algorithm was developed based on utilization of the time-derivative to distinguish between physiological responses and the drift, customized by measurements from a myocardial infarction porcine model (6 pigs, 23 sensors). IscAlert conductometric pCO(2) sensors were placed in the myocardial regions supplied by the left anterior descending coronary artery (LAD) and the left circumflex artery (LCX) while the LAD artery was fully occluded for 1, 3, 5 and 15 min leading to ischemia in the LAD-dependent region. The measured pCO(2), the drift-corrected pCO(2) (DeltapCO(2)) and its time-derivative (TDpCO(2)) were compared with respect to detection ability. Baseline stability in the DeltapCO(2) led to earlier, more accurate detection. The TDpCO(2) featured the earliest sensitivity, but with a lower specificity. Combining DeltapCO(2) and TDpCO(2) enables increased accuracy. Suggestions are given for the utilization of the parameters for an automated early warning and alarming system. In conclusion, early detection of cardiac ischemia is feasible using the conductometric pCO(2) sensor together with parameterization methods. PMID- 20702917 TI - A model for investigating the control of muscle blood flow: the masseteric artery in conscious rabbits. AB - The complex interplay of neural, metabolic, myogenic and mechanical mechanisms that regulate blood flow in skeletal muscle (MBF) is still incompletely understood. For the first time, a method is presented for high time-resolution recording of MBF from a purely muscular artery in physiological conditions. Ultrasound perivascular flow probes were implanted (n = 15) mono- or bilaterally around the masseteric branch of the facial artery in nine rabbits and tested up to 16 days after implant. Reliable and stable recordings were achieved in 50% of implants. Blood flow was observed to increase from a resting level of 0.2-0.3 ml min(-1) up to 4.0-6.0 ml min(-1) during spontaneous masticatory activity. In addition, within single masticatory cycles marked back flow transients could be observed (peak flow = -10 ml min(-1)) during powerful masticatory strokes but not during mild mastication. The possibility of (1) surgically removing the sympathetic supply to the relevant vascular bed and of (2) bilaterally monitoring the perfusion of masseter muscles thus allowing to use one side as control side for different types of interventions makes this model a useful tool for disentangling the different mechanisms involved in the control of MBF. PMID- 20702918 TI - A new method to measure local oxygen consumption in human skeletal muscle during dynamic exercise using near-infrared spectroscopy. AB - Near infrared spectroscopy (NIRS) can readily report on changes in blood volume and oxygenation. However, it has proved more problematic to measure real-time changes in blood flow and oxygen consumption. Here we report the development of a novel method using NIRS to measure local oxygen consumption in human muscle. The method utilizes the blood volume changes induced by the muscle pump during rhythmically contracting exercising skeletal muscle. We found that the saturation of the blood during the contraction phase was lower than that during the relaxation phase. The calculated oxygen drop was then divided by the contraction time to generate a value for the muscle oxygen consumption in the optical region of interest. As a test we measured the muscle oxygen consumption in the human vastus lateralis during exercise on a cycle ergometer by 11 trained male athletes (32 +/- 11 years old) at 40% and 110% peak aerobic power. We saw an increase from 13.78 micromol 100 g(-1) min(-1) to 19.72 micromol 100 g(-1) min(-1) with the increase in power. The measurements are theoretically exempt from usual NIRS confounders such as myoglobin and adipose tissue and could provide a useful tool for studying human physiology. PMID- 20702919 TI - Photoplethysmography pulse rate variability as a surrogate measurement of heart rate variability during non-stationary conditions. AB - In this paper we assessed the possibility of using the pulse rate variability (PRV) extracted from the photoplethysmography signal as an alternative measurement of the HRV signal in non-stationary conditions. The study is based on analysis of the changes observed during a tilt table test in the heart rate modulation of 17 young subjects. First, the classical indices of HRV analysis were compared to the indices from PRV in intervals where stationarity was assumed. Second, the time-varying spectral properties of both signals were compared by time-frequency (TF) and TF coherence analysis. Third, the effect of replacing PRV with HRV in the assessment of the changes of the autonomic modulation of the heart rate was considered. Time-invariant HRV and PRV indices showed no statistically significant differences (p > 0.05) and high correlation (>0.97). Time-frequency analysis revealed that the TF spectra of both signals were highly correlated (0.99 +/- 0.01); the difference between the instantaneous power, in the LF and HF bands, obtained from HRV and PRV was small (<10(-3) s( 2)) and their temporal patterns were highly correlated (0.98 +/- 0.04 and 0.95 +/ 0.06 in the LF and HF bands, respectively) and TF coherence in the LF and HF bands was high (0.97 +/- 0.04 and 0.89 +/- 0.08, respectively). Finally, the instantaneous power in the LF band was observed to significantly increase during head-up tilt by both HRV and PRV analysis. These results suggest that although some differences in the time-varying spectral indices extracted from HRV and PRV exist, mainly in the HF band associated with respiration, PRV could be used as a surrogate of HRV during non-stationary conditions, at least during the tilt table test. PMID- 20702920 TI - ENVIRONMENT: a computational platform to stochastically simulate reacting and self-reproducing lipid compartments. AB - 'ENVIRONMENT' is a computational platform that has been developed in the last few years with the aim to simulate stochastically the dynamics and stability of chemically reacting protocellular systems. Here we present and describe some of its main features, showing how the stochastic kinetics approach can be applied to study the time evolution of reaction networks in heterogeneous conditions, particularly when supramolecular lipid structures (micelles, vesicles, etc) coexist with aqueous domains. These conditions are of special relevance to understand the origins of cellular, self-reproducing compartments, in the context of prebiotic chemistry and evolution. We contrast our simulation results with real lab experiments, with the aim to bring together theoretical and experimental research on protocell and minimal artificial cell systems. PMID- 20702921 TI - Non-Gaussian space-variant resolution modelling for list-mode reconstruction. AB - Partial volume effect is an important source of bias in PET images that can be lowered by accounting for the point spread function (PSF) of the scanner. We measured such a PSF in various points of a clinical PET scanner and modelled it as a product of matrices acting in image space, taking the asymmetrical, shift varying and non-Gaussian character of the PSF into account (AMP modelling), and we integrated this accurate image space modelling into a conventional list-mode OSEM algorithm (EM-AMP reconstruction). We showed on the one hand that when a sufficiently high number of iterations are considered, the AMP modelling lead to better recovery coefficients at reduced background noise compared to reconstruction where no or only partial resolution modelling is performed, and on the other hand that for a small number of iterations, a Gaussian modelling gave the best recovery coefficients. Moreover, we have demonstrated that a deconvolution based on the AMP system response model leads to the same recovery coefficients as the corresponding EM-AMP reconstruction, but at the expense of an increased background noise. PMID- 20702922 TI - Adapting a generic BEAMnrc model of the BrainLAB m3 micro-multileaf collimator to simulate a local collimation device. AB - This work is focussed on developing a commissioning procedure so that a Monte Carlo model, which uses BEAMnrc's standard VARMLC component module, can be adapted to match a specific BrainLAB m3 micro-multileaf collimator (microMLC). A set of measurements are recommended, for use as a reference against which the model can be tested and optimized. These include radiochromic film measurements of dose from small and offset fields, as well as measurements of microMLC transmission and interleaf leakage. Simulations and measurements to obtain microMLC scatter factors are shown to be insensitive to relevant model parameters and are therefore not recommended, unless the output of the linear accelerator model is in doubt. Ultimately, this note provides detailed instructions for those intending to optimize a VARMLC model to match the dose delivered by their local BrainLAB m3 microMLC device. PMID- 20702923 TI - An oscillating sweeping gap test for VMAT quality assurance. AB - The objective of this study was to develop an oscillating sweeping gap test for volumetric modulated arc therapy (VMAT) quality assurance (QA). A novel test was designed and used to simultaneously determine uncertainties associated with linac performance, dose calculation and dosimetric MLC parameters during VMAT delivery. Delivered doses were measured with Matrixx, ionization chamber A12 and EDR2 films, and compared to calculations from the treatment planning system (TPS) Eclipse. A new gantry and MLC motion pattern, called here 'oscillating sweeping gap', is developed as an extension of the standard sweeping gap MLC pattern developed for IMRT QA. Specifically, in the oscillating sweeping gap test, a uniform MLC gap is moving repeatedly back and forth across the field at a constant speed during a full rotation of the gantry. The dose distribution generated by the combined gantry and MLC motion pattern is designed to be quasi uniform within a cylindrical target volume with a sharp penumbra. The test design allows for an easy detection of dose errors as deviations from the uniform background. MLC gap sizes, gantry and MLC speeds and monitor units (MU) are selected according to a formula determining the magnitude of dose delivered to the target. Both measured and calculated dose distributions were analyzed as a function of the number of control points in the TPS, MLC gap size and magnitude of the gantry angle error. Dose calculation errors due to the insufficient number of control points in the gantry and MLC motion pattern appear as streak artifacts. The magnitude of these artifacts is increasing with the decreased number of control points, and with the decreased MLC gap size. The spatial distribution of dose errors due to the gantry angle errors (unsteady rocking motion) appears as high-frequency noise for higher wobble frequencies and as large hot/cold spots for lower wobble frequencies. The actual MLC leaf position as a function of time (or the gantry angle), determined from the Matrixx snaps (dose images measured per time interval) of the moving gap and compared to the ideal leaf positions, reveal discrepancies in agreement with theoretical calculations. The MLC parameters determined for VMAT with the oscillating sweeping gap test, their uncertainties and the associated dose errors are similar to those determined for IMRT with the standard sweeping gap test. The oscillating sweeping gap test has been developed for the gantry and MLC QA. Applications include commissioning of the planning system for VMAT and performing routine linac QA. The test is sensitive to several errors in dose calculation and delivery. PMID- 20702924 TI - Measurement of microdosimetric spectra with a wall-less tissue-equivalent proportional counter for a 290 MeV/u 12C beam. AB - The frequency distribution of the lineal energy, y, of a 290 MeV/u carbon beam was measured to obtain the dose-weighted mean of y and compare it with the linear energy transfer (LET). In the experiment, a wall-less tissue-equivalent proportional counter (TEPC) in a cylindrical volume with a simulated diameter of 0.72 microm was used. The measured frequency distribution of y as well as its dose-mean value agrees within 10% uncertainty with the corresponding data from microdosimetric calculations using the PHITS code. The ratio of the measured dose mean lineal energy to the LET of the 290 MeV/u carbon beam is 0.73, which is much smaller than the corresponding data obtained by a wall TEPC. This result demonstrates that a wall-less TEPC is necessary to precisely measure the dose mean of y for energetic heavy ion beams. PMID- 20702925 TI - Measurement of the linear attenuation coefficients of breast tissues by synchrotron radiation computed tomography. AB - The measurement of the linear attenuation coefficients of breast tissues is of fundamental importance in the field of breast x-ray diagnostic imaging. Different groups have evaluated the linear attenuation coefficients of breast tissues by carrying out direct attenuation measurements in which the specimens were thin and selected as homogeneous as possible. Here, we use monochromatic and high intensity synchrotron radiation computed tomography (SR CT) to evaluate the linear attenuation coefficients of surgical breast tissues in the energy range from 15 to 26.5 keV. X-ray detection is performed by a custom digital silicon micro-strip device, developed in the framework of the PICASSO INFN experiment. Twenty-three human surgical breast samples were selected for SR CT and histological study. Six of them underwent CT, both as fresh tissue and after formalin fixation, while the remaining 17 were imaged only as formalin-fixed tissues. Our results for fat and fibrous tissues are in good agreement with the published values. However, in contrast to the published data, our measurements show no significant differences between fibrous and tumor tissues. Moreover, our results for fresh and formalin-fixed tissues demonstrate a reduction of the linear attenuation coefficient for fibrous and tumor tissues after fixation. PMID- 20702926 TI - Fully three-dimensional OSEM-based image reconstruction for Compton imaging using optimized ordering schemes. AB - Although the ordered subset expectation maximization (OSEM) algorithm does not converge to a true maximum likelihood solution, it is known to provide a good solution if the projections that constitute each subset are reasonably balanced. The Compton scattered data can be allocated to subsets using scattering angles (SA) or detected positions (DP) or a combination of the two (AP (angles and positions)). To construct balanced subsets, the data were first arranged using three ordering schemes: the random ordering scheme (ROS), the multilevel ordering scheme (MLS) and the weighted-distance ordering scheme (WDS). The arranged data were then split into J subsets. To compare the three ordering schemes, we calculated the coefficients of variation (CVs) of angular and positional differences between the arranged data and the percentage errors between mathematical phantoms and reconstructed images. All ordering schemes showed an order-of-magnitude acceleration over the standard EM, and their computation times were similar. The SA-based MLS and the DP-based WDS led to the best-balanced subsets (they provided the largest angular and positional differences for SA- and DP-based arrangements, respectively). The WDS exhibited minimum CVs for both the SA- and DP-based arrangements (the deviation in mean angular and positional differences between the ordered subsets was smallest). The combination of AP and WDS yielded the best results with the lowest percentage errors by providing larger and more uniform angular and positional differences for the SA and DP arrangements, and thus, is probably optimal Compton camera reconstruction using OSEM. PMID- 20702927 TI - A study on repainting strategies for treating moderately moving targets with proton pencil beam scanning at the new Gantry 2 at PSI. AB - Treating moving targets using a scanning gantry for proton therapy is a promising but very challenging, not yet clinically demonstrated treatment modality. The interference of organ motion with the sequence of the beam delivery produces uncontrolled dose inhomogeneities within the target. One promising approach to overcome this difficulty is to increase the speed of scanning in order to apply the dose repeatedly (so-called repainting). To obtain sufficiently high scanning speeds a new, technologically improved gantry-Gantry 2-has been designed and is currently under construction at PSI. As there are many possible repainting strategies, the way repainting will be implemented on Gantry 2 will depend on the result of a careful analysis of the various treatment delivery strategies available. To achieve this aim, and prior to the start of experimental work with Gantry 2, simulations of dose distribution errors due to organ motion under various beam delivery strategies were investigated. The effects of motion on the dose distribution were studied for moderate motion amplitudes (5 mm) for spherical target volumes in a homogeneous medium and with homogeneous dose. In total over 200,000 dose distributions have been simulated and analyzed and selected results are discussed. From the obtained results we are confident to be able to treat moderately moving targets on Gantry 2 using repainted pencil-beam spot scanning. Continuous line scanning seems to be the most elegant solution; it provides higher repainting rates and produces superior results but is probably more difficult to realize. For larger motion amplitudes, continuous line scanning still shows good results, but we plan anyways to use a gating system for these cases, not only to reduce the inhomogeneity within the target volume but also to reduce safety margins. PMID- 20702928 TI - The resolution integral: visual and computational approaches to characterizing ultrasound images. AB - The resolution integral is a figure of merit that characterizes ultrasound images in terms of the ratio of the penetration of an ultrasound beam in soft tissue to the ultrasound beam width. This concept has been implemented using a novel tissue mimicking test object (the Edinburgh pipe phantom) that comprises a series of anechoic cylinders of different diameters embedded in a block of tissue-mimicking material. The resolution integral is calculated by imaging each cylinder in turn and measuring the depth range over which it can be detected. We have carried out these measurements using two complementary approaches: by visual assessment and using a computational approach. Data were collected from 12 transducers used on 12 different models of ultrasound scanner of various makes, ages and clinical performance. Transducer centre frequencies were in the range of 3 to 7.5 MHz. The computational approach makes use of standard image processing techniques to detect and segment anechoic structures in images of the test object. This was optimized against visual assessment results for one of the transducers, and subsequently used to evaluate the resolution integral for the others. The values of the resolution integral ranged from 40 to 69 and computed values were within +/-11% of the corresponding visual assessments. The repeatability of both approaches was +/-2-3%. The computational approach functions well compared to visual assessment and adds to the overall robustness of resolution integral measurements by providing an objective assessment algorithm. PMID- 20702929 TI - Rhodium and silicon system: II. Rhodium silicide formation. AB - Detailed characterizations of rhodium/silicon films prepared by co-deposition using magnetron sputtering have been carried out on silicon substrates at room temperature up to 900 degrees C. The properties of the films were investigated using XPS/UPS, XRD, SIMS, SEM and AFM techniques. It should be emphasized that XPS/UPS measurements are carried out without breaking the vacuum to avoid any contamination of the film. Up to 500 degrees C an interdiffusion between the oxidized silicon wafer and the deposited Rh/Si film occurred leading to hole formation in the entire film at 900 degrees C. Diffraction patterns for the compounds Rh(2)Si, Rh(5)Si(3), RhSi and Rh(3)Si(4) were measured. Upon annealing the covalent character is increased and for the samples forming the compound RhSi the valence band structure is markedly changed. Depth profiling (XPS and SIMS) reveals a stable composition in the bulk of the film. For these measurements the silicon-rich alloy in the interfacial layer is probably an effect of sputtering, by implanting the Rh atoms into the silicon substrate. A previously reported negative shift for the compound Rh(5)Si(3) could be connected to the sample preparation, as sputtering of the surface is reducing the silicon content and inducing a glassy state. For the first phase Rh(2)Si formed on the rhodium-rich side the shift in binding energy is unclear, for all the other compounds encountered in this work a positive shift relative to pure rhodium was found. PMID- 20702930 TI - Nanofabrication of insulated scanning probes for electromechanical imaging in liquid solutions. AB - In this paper, the fabrication and electrical and electromechanical characterization of insulated scanning probes have been demonstrated in liquid solutions. The silicon cantilevers were sequentially coated with chromium and silicon dioxide, and the silicon dioxide was selectively etched at the tip apex using focused-electron-beam-induced etching (FEBIE) with XeF(2). The chromium layer acted not only as the conductive path from the tip, but also as an etch resistant layer. This insulated scanning probe fabrication process is compatible with any commercial AFM tip and can be used to easily tailor the scanning probe tip properties because FEBIE does not require lithography. The suitability of the fabricated probes is demonstrated by imaging of a standard topographical calibration grid as well as piezoresponse force microscopy (PFM) and electrical measurements in ambient and liquid environments. PMID- 20702931 TI - Laser-assisted hydrothermal growth of size-controlled ZnO nanorods for sensing applications. AB - Pulsed laser irradiation is used to seed the low-temperature hydrothermal growth of ZnO nanorods. UV laser irradiation produces ZnO nanoparticles in solution that act as nucleation seeds for the subsequent hydrothermal growth of the nanorods. By systematically varying the seed density and/or the concentration of the reactants, the diameter of the nanorods can be controlled over a wide range with a narrow size distribution. The nanorods are linked into multi-pod structures, due to nucleation at a central seed, but ultrasonic processing of the solutions is shown to yield isolated nanorods. Three-dimensional networks of these multi pod structures are fabricated by drop-casting the solutions onto inter-digitated electrodes. These devices are used to detect ethanol, water vapour and UV light exposure. PMID- 20702932 TI - Self-induced growth of vertical free-standing InAs nanowires on Si(111) by molecular beam epitaxy. AB - We report self-induced growth of vertically aligned (i.e. along the [111] direction), free-standing InAs nanowires on Si(111) substrates by solid-source molecular beam epitaxy. Implementation of an ultrathin amorphous SiO(x) mask on Si(111) facilitated epitaxial InAs nanowire growth, as confirmed by high resolution x-ray diffraction 2theta-omega scans and transmission electron microscopy. Depending on growth temperature (in the range of 400-520 degrees C) substantial size variation of both nanowire length and diameter was found under preservation of uniform, non-tapered hexagon-shaped geometries. The majority of InAs nanowires exhibited phase-pure zinc blende crystal structure with few defective regions consisting of stacking faults. Photoluminescence spectroscopy at 20 K revealed peak emission of the InAs nanowires at 0.445 eV, which is approximately 30 meV blueshifted with respect to the emission of the bulk InAs reference due to radial quantum confinement effects. These results show a promising route towards integration of well-aligned, high structural quality InAs based nanowires with the desired aspect ratio and tailored emission wavelengths on an Si platform. PMID- 20702933 TI - Rhodium and silicon system: I. Glassy metallic alloy formation. AB - Detailed characterizations of rhodium/silicon films prepared by co-deposition using magnetron sputtering have been carried out on silicon substrates at room temperature. Effects of the silicon content incorporated in the film on the chemical bonding state and crystallinity were investigated using XPS/UPS, XRD and SEM. It should be emphasized that XPS/UPS measurements are carried out without breaking the vacuum to avoid any contamination of the film. All x-ray diffraction patterns revealed a high degree of amorphization. There is only a weak Rh pattern and a weak Rh(2)Si pattern for 20 and 37 at.% of Si, respectively, i.e. showing a formation of glassy metallic alloy. A negative shift in the Rh core level binding energy for rhodium-rich alloys is mainly referred to relaxation effects due to a high density of d-states near the Fermi level. The filling of the d-states is completed between 25 and 40 atomic concentration of Si. Valence orbital transformation due to the Si-Rh interactions is causing the progressive positive shift in the binding energy for higher silicon content. PMID- 20702934 TI - Nanocompression of individual multilayered polyhedral nanoparticles. AB - Inorganic layered materials can form hollow multilayered polyhedral nanoparticles. The size of these multi-wall quasi-spherical structures varies from 4 to 300 nm. These materials exhibit excellent tribological and wear resisting properties. Measuring and evaluating the stiffness of individual nanoparticle is a non-trivial problem. The current paper presents an in situ technique for stiffness measurements of individual WS(2) nanoparticles which are 80 nm or larger using a high resolution scanning electron microscope (HRSEM). Conducting the experiments in the HRSEM allows elucidation of the compression failure strength and the elastic behavior of such nanoparticles under uniaxial compression. PMID- 20702935 TI - Chemical-state-selective mapping at nanometer scale using synchrotron radiation and photoelectron emission microscopy. AB - For surface analyses of semiconductor devices and various functional materials, it has become indispensable to analyze valence states at nanometer scale due to the rapid developments of nanotechnology. Since a method for microscopic mapping dependent on the chemical bond states has not been established so far, we have developed a photoelectron emission microscopy (PEEM) system combined with synchrotron soft X-ray excitation. The samples investigated were Si/SiO(x) micro patterns prepared by O(2)(+) ion implantation in Si(001) wafer using a mask. PEEM images excited by various photon energies around the Si K-edge were observed. The lateral spatial resolution of the system was about 41 nm. The brightness of each spot in PEEM images changed depending on the photon energy, due to the X-ray absorption intensity of the respective chemical state. Since the surface of this sample was topographically flat, it has been demonstrated that the present method can be applied to observations of the microscopic pattern, depending not on the morphology, but only on the valence states of silicon. We have also in-situ measured the changes of the PEEM images upon annealing, and elucidated the mechanism of the lateral diffusion of oxygen and valence states of silicon at the nanometer scale. PMID- 20702936 TI - Trace analysis of polycyclic aromatic hydrocarbons using gas chromatography-mass spectrometry based on nanosecond multiphoton ionization. AB - Gas chromatography/resonance-enhanced multiphoton ionization/time-of-flight mass spectrometry (GC/REMPI-TOFMS) using an ultraviolet nanosecond laser was employed in the trace analysis of polycyclic aromatic hydrocarbons (PAHs). A standard sample that contained 16 PAHs on the priority list of the Environmental Protection Agency of the United States of America (U.S. EPA) was measured. A sample of river water that had been pretreated by means of solid-phase extraction was analyzed by GC/MS based on electron impact ionization (EI) and REMPI to evaluate the performance of the analytical instrument. The results suggested that REMPI is superior to EI for soft ionization, and suppresses the background signal due to aliphatic hydrocarbons. Thus, GC/REMPI-TOFMS is a more reliable method for the determination of PAHs present in the environment. PMID- 20702937 TI - Determination of urea in serum based on the combination of an enzymatic reaction with immobilized urease and ion chromatographic analysis. AB - A quantitative method for the determination of urea in serum was studied. An ion chromatograph (IC) with a conductivity detector was used in this method, where the chromatograph was modified by placing an immobilized urease column between the injection loop and a guard column of the cation analysis column. Immobilized urease was prepared by the adsorption of urease on cedar sawdust with triethylenetetramine. The adsorption capacity of urease was 190 mg g(-1), and its activity was 3500 U g(-1). The conversion efficiency of urea to ammonium ion was 100%, and the half life of immobilized urease was 60 days. It was possible to use the immobilized urease in a pH range of 3.0 to 9.0, and at temperatures up to 60 degrees C. The determination of urea was attempted by IC attaching an immobilized urease column. The limit of detection of urea was 0.2 mg L(-1), and the calibration curves of urea were very linear over 0.8-25 mg L(-1). The urea concentration in the human serum could be determined with a standard deviation of 0.06-0.13 within 5 min after injecting the serum sample. PMID- 20702939 TI - Rapid and simultaneous determination of tetrafluoroborate, thiocyanate and hexafluorophosphate by high-performance liquid chromatography using a monolithic column and direct conductivity detection. AB - A method was developed for fast and simultaneous determination of tetrafluoroborate (BF(4)(-)), thiocyanate (SCN(-)) and hexafluorophosphate (PF(6)(-)) by high-performance liquid chromatography using a silica-based monolithic column and direct (non-suppressed) conductivity detection. Chromatographic separation was performed on a Chromolith Speed ROD RP-18e column with tetrabutylammonium hydroxide (TBA) + citric acid + acetonitrile as eluent. The effects of the types of eluent, TBA concentration, acetonitrile volume fraction, eluent pH, column temperature and flow rate on the retention of anions were investigated. The optimized chromatographic conditions were selected. Under the optimal conditions, the baseline separation of BF(4)(-), SCN(-) and PF(6)(-) was achieved without any interference by other anions (F(-), Cl(-), Br(-), I(-), NO(3)(-), ClO(3)(-) and SO(4)(2-)). The detection limit (S/N = 3) was 0.42, 0.46 and 1.42 mg L(-1) for BF(4)(-), SCN(-) and PF(6)(-), respectively. The present method was successfully applied to the determination of BF(4)(-), SCN(-) and PF(6)(-) in ionic liquids. PMID- 20702938 TI - Multivariate optimization and validation of a capillary electrophoresis method for the simultaneous determination of dextromethorphan hydrobromur, phenylephrine hydrochloride, paracetamol and chlorpheniramine maleate in a pharmaceutical preparation using response surface methodology. AB - A fast, accurate, precise and sensitive capillary electrophoresis method for the simultaneous determination of dextromethorphan hydrobromide, phenylephrine hydrochloride, paracetamol and chlorpheniramine maleate has been developed. Response surface methodology with a central composite design was used for optimization of the concentration of the buffer, pH of the buffer and applied voltage. Therefore, working with Na(2)HPO(4) buffer (pH 8.00, 0.01 M) at 20 kV as an applied voltage in the capillary electrophoresis method were found to be suitable; under these optimal conditions, these four active ingredients were separated in about 7 min. This developed method was validated and successfully applied to a pharmaceutical preparation, sugar-coated tablet, and the results were compared with a high-performance liquid chromatographic method developed by us. PMID- 20702940 TI - Application of a dynamic reaction cell (DRC) ICP-MS in chromium and iron determinations in rock, soil and terrestrial water samples. AB - Despite environmental and geochemical interests, Cr and Fe have been left beyond the reach of determinations by ICP-MS due to severe interferences originating from Ar. The applicability of a dynamic reaction cell (DRC)-ICP-MS has been examined for determinations in environmental and geochemical samples. The reaction with NH(3) in the DRC system provides an eligible technique to determine Cr, because of a greater improvement in the signal/noise (S/N) ratio due to an effective elimination of interferences arising from Ar (ArC, ArN and ArO), and makes it possible to analyze Cr even at sub-microg L(-1) levels. As compared to non-DRC mode analyses, the DRC technique using m/z 56 appeared to be preferable for Fe determination in most terrestrial waters because of effective suppression of (40)Ar(16)O(+). In addition, the effects of cluster ions, such as (39)K(14)N(1)H(3)(+) and (40)Ca(14)N(1)H(2)(+), on Fe determination were also negligibly small. Measurements using (54)Fe by the DRC mode are also advantageous for Ca-rich samples, such as limestone and dolomite. PMID- 20702941 TI - Statistical analysis of rice samples for compositions of multiple light elements (H, C, N, and O) and their stable isotopes. AB - Stable isotopic compositions and elemental contents of the H, C, N, and O in 163 rice samples were analyzed. The samples were taken from three different farming countries; Japan (n = 103), United States of America (n = 30), and Australia (n = 21), in addition of Asian rice samples from Thailand (n = 2), Vietnam (n = 1), and China (n = 6) as comparison. They were mostly short grain samples known as "Koshihikari," with several samples of middle and long grains included. All samples were grown in the presence of either natural manure or artificial fertilizer. The climate of the rice farming environment was diverse, from arid to humid. Excluding deltaD data showing large uncertainty, according to the statistical analysis of the principal components based on the stable isotopic compositions such as delta(13)C, delta(15)N, and delta(18)O of rice samples, the Japanese rice samples were clearly distinctive from the Australian and the American rice samples. This fact may be explained by the regional differences in isotopic signatures of the climate, utilized nutrition, and/or quality of irrigation water among the farming countries. This statistical distinction could be one of the useful tools to extract the rice samples grown in Japan from those grown in the other countries. PMID- 20702942 TI - L-cysteine-capped CdTe quantum dots as a fluorescence probe for determination of cardiolipin. AB - This paper described the investigation of surface-modified quantum dots (QDs) as a fluorescence probe for the detection of cardiolipin. A single-step method for preparation of non-toxic and photo-stable cadmium telluride (CdTe) QDs capped by L-cysteine in aqueous solution was developed. The prepared QDs were characterized by high-resolution transmission electron microscopy, X-ray diffraction spectrometry, Fourier transform infrared spectrometry and spectrofluorometry. These functional QDs were used as a fluorescence probe for cardiolipin determination based on the fluorescence quenching. The optimum fluorescence intensity was found to be at pH 7.4 with QDs concentration of 4 x 10(-5) mol L( 1). The effect of other phospholipids on the intensity of CdTe QDs showed a low interference response. Under optimized conditions, the quenched fluorescence intensity was linear with the concentration of cardiolipin in the range of 1.33 x 10(-7) - 10.4 x 10(-7) mol L(-1) (r = 0.9976) and a detection limit (S/N = 3) of 18.5 nmol L(-1). The proposed method was applied to the determination of cardiolipin content of HepG2 cell samples before and after oxidative stress with satisfactory results. PMID- 20702943 TI - Chemical effects of CeL(gamma4) emission spectra for Ce compounds. AB - High-resolution CeL(gamma4) emission spectra of CeF(3), Ce(2)S(3), CeF(4), and CeO(2) have been measured using a multicrystal, multidetector spectrometer. The spectra exhibited substantial differences depending on the chemical environment of the Ce ions. By comparing the observed CeO(2) spectrum with the band calculations, we determined that the observed chemical effects of the main emission line were primarily attributable to the transitions of the Ce5p band; the high-energy tail at around 6.539 keV was assigned to the ligand p-->Ce2s cross transition. Further, a key difference between CeL(gamma4) and EuL(gamma4) is discussed with reference to CeL(1)- and EuL(1)-X-ray absorption fine structures (XAFS). Possible applications of CeL(gamma4) emissions to material characterization are also suggested. PMID- 20702944 TI - Simultaneous determination of albendazole and praziquantel by second derivative spectrophotometry and multivariated calibration methods in veterinary pharmaceutical formulation. AB - The simultaneous determination of albendazole (ABZ) and praziquantel (PZQ) was performed by different mathematical approaches: second derivative spectrophotometry (SDS), classical least squares, regression of partial least squares and principal components regression based on spectral data of drugs dissolved in methanol-hydrochloric acid solution. The detection limits for multivariate calibrations were determined by creating a surrogate variable signal. SDS presented the best analytical features. The recoveries of ABZ and PZQ from the synthetic samples were near to 100 +/- 5%. The methods were applied in veterinary pharmaceutical formulation whose mass ratio ABZ:PZQ is 10:1; the results obtained were according to nominal content. PMID- 20702945 TI - A QSAR study for modeling of 8-azaadenine analogues proposed as A1 adenosine receptor antagonists using genetic algorithm coupling adaptive neuro-fuzzy inference system (ANFIS). AB - A quantitative structure activity relationship (QSAR) study of 8-azaadenine, as antagonists for the A1 receptor, is described. A genetic algorithm (GA) method was used as the feature selection tool, and an adaptive neuro-fuzzy inference system (ANFIS) was employed for feature mapping. The best descriptors (GATS4v and BELv7) were applied to train the ANFIS model. The optimum number and shape of related functions were obtained through a subtractive clustering algorithm. The ability and robustness of the GA-ANFIS model in predicting the affinity of 8 azaadenine derivatives (pK(i)) are illustrated by validation techniques of Leave One Out, heuristic and randomized methods. The results have indicated that the proposed model of ANFIS in this work is superior over two other methods, radial basis function (RBF) and multiple linear regression (MLR). PMID- 20702946 TI - Application of an oxygen electrode to evaluate superoxide anion-scavenging ability. AB - The ability to scavenge superoxide anion radicals ((*)O(2)(-)) was determined using an oxygen electrode. The method is based on the determination of (*)O(2)(-) generated by the reaction of nitrilotriacetatoiron(III) with hydrogen peroxide and a decrease in the concentration of (*)O(2)(-) by a scavenging reaction, converting into a change in the generation of oxygen molecules through an electron-transfer reaction from (*)O(2)(-) to nitrilotriacetatoiron(III). Oxygen generation, which enhanced proportionally with an increase in the concentration of hydrogen peroxide, was inhibited depending on the concentration of superoxide dismutase. Hence, we applied the present reaction system to evaluate the (*)O(2)( )-scavenging abilities of an antioxidant, measuring the degree of inhibition of oxygen generation using an oxygen electrode. A good correlation was obtained between the present method and conventional colorimetry, monitoring the formation of blueformazan by the reaction of nitro blue tetrazolium with (*)O(2)(-), to estimate the (*)O(2)(-)-scavenging activities of antioxidants. PMID- 20702947 TI - Voltammetric determination of ferulic acid by didodecyldimethylammonium bromide/nafion composite film-modified carbon paste electrode. AB - A simple and rapid method for the determination of ferulic acid in pharmaceutical formulations by didodecyldimethylammonium bromide (DDAB)/Nafion composite film modified carbon paste electrode is presented. The electrochemical behavior of ferulic acid at the proposed electrode was investigated by cyclic voltammetry and a well-defined oxidation peak was observed at +0.44 V versus saturated calomel electrode in 0.1 M acetate buffer (pH 5.5) solutions. Some experimental parameters affecting the electrochemical response of the modified electrode were optimized. Under optimal conditions, the oxidation peak currents of ferulic acid increase linearly with the concentration of ferulic acid in the range from 2.0 x 10(-6) to 1.2 x 10(-4) M with a detection limit of 3.9 x 10(-7) M (S/N = 3). The proposed method was successfully applied to the determination of ferulic acid in pharmaceutical tablets. PMID- 20702948 TI - Potential utility of DNA sequence analysis of long-term-stored plant leaf fragments for forensic discrimination and identification. AB - This study examined the potential utility of DNA sequence analysis to discriminate and identify plant material in forensic investigations. DNA was extracted from plant leaf fragments of 11 species stored for 5 to 22 years after collection. The trnH-psbA intergenic spacer and 316 bp of the rbcL gene were successfully amplified and sequenced for all fragments except for the trnH-psbA spacer of one sample. All of the plant samples were discriminated in pairwise comparisons of the sequences. Using a combination of local and global genetic databases is likely to provide greater reliability in search results to identify forensic samples from sequence data. PMID- 20702949 TI - Determination of fatty acids in human sweat during fasting using GC/MS. AB - Fatty acids (FAs) are biological molecules that are used as major metabolic fuels, and are concerned in important metabolic processes. We have performed a non-invasive and technically rapid and simple method for collecting sweat from humans, followed by GC/MS determination. The sweat was collected from each volunteer (the middle finger) by spraying 70% ethanol aqueous solution (no harmful solvent) into a 1.5-cm(3) plastic vial. Analysis of FAs in sweat showed that the sweat solution contains lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), oleic acid (C18:1), and stearic acid (C18:0). Here, it is demonstrated that FA concentrations for 4 young subjects correlated positively with percent of body fat (r = 0.78) and that the total FA levels for them increased progressively with increasing fasting time when a subject fasted throughout the experiment. PMID- 20702950 TI - A fast way to make a monolithic column for a high pressure electroosmotic pump. AB - A simple way was proposed to make a monolithic column for a high pressure electroosmotic pump (EOP). It is in-situ synthesized inside the silica capillary from potassium silicate solution and no frit is required. Compared with common approaches to make columns for EOP, the present method is robust and fast (<4 h). For pure water, a stand-alone EOP operated at 15 kV applied voltage is capable of generating a flow rate of 3.1 microL/min and a maximum static pressure of approximately 5.4 MPa. PMID- 20702952 TI - Role of renin-angiotensin system inhibitors in patients undergoing off-pump coronary artery bypass grafting. PMID- 20702953 TI - Class differences in calcium-channel blockers in vasospastic angina. PMID- 20702955 TI - Could circulating progenitor cell count be a barometer for coronary artery disease progression? PMID- 20702956 TI - Potential use of statins in reducing atrial fibrillation after off-pump coronary artery bypass grafting surgery. PMID- 20702957 TI - Systemic acidosis in acute myocardial ischemia--cause or result of life threateningventricular arrhythmia? PMID- 20702958 TI - Is there an evening peak in the occurrence of out-of-hospital cardiac arrest in Japanese?--special situations with circadian variation. PMID- 20702960 TI - Even isolated left ventricular hypertrabeculation may indicate multisystem disease. PMID- 20702961 TI - Drug-eluting stents vs bypass surgery for multivessel disease. PMID- 20702962 TI - Interventions for drug-eluting stent restenosis--to cut, or not to cut: is that the question? PMID- 20702964 TI - [Telemetric monitoring of cardiovascular function in drug discovery]. PMID- 20702965 TI - [Application of selective acetylcholine-sensitive K+ -channel blockade as a therapeutic strategy for atrial fibrillation]. PMID- 20702966 TI - [Research and development strategy of antithrombotic agents: pharmacology of the oral factor Xa-inhibitor edoxaban]. PMID- 20702967 TI - [Do orally active factor Xa (FXa) inhibitors have potential as innovative new anticoagulants? Future perspective from preclinical data]. PMID- 20702968 TI - [Purinergic regulation of microglia]. PMID- 20702969 TI - [Regulation of seven-transmembrane receptor (GPCR) by nitric oxide]. PMID- 20702970 TI - [New model of Takotsubo-like left ventricular dysfunction in cynomolgus monkey]. PMID- 20702971 TI - [Clinical pharmacology as translational research]. PMID- 20702972 TI - [Pharmacological, pharmacokinetic, and clinical profile of palonosetron hydrochloride (ALOXI I.V. Injection 0.75 mg), a novel antiemetic 5-HT3-receptor antagonist]. PMID- 20702973 TI - Ezetimibe, oxidized low density lipoprotein, Lp (a), and dyslipidemia. PMID- 20702974 TI - Pravastatin potentiates increases in serum adiponectin concentration in dyslipidemic patients receiving thiazolidinedione: the DOLPHIN study. AB - AIM: A reduced risk of type 2 diabetes has been reported following treatment with pravastatin. Adiponectin is an adipocyte-derived protein that has an antidiabetic property. The objective of this study was to evaluate the effect of pravastatin on serum adiponectin concentration and other influencing factors. METHODS: This study was a multicenter observational study: Dyslipidemia Open-labeled observational study by Lipid-lowering therapy with Pravastatin of the effect on High-molecular weight adiponectin in Nippon Yokohama (DOLPHIN). The protocol was registered in the UMIN Clinical Trial Registry as UMIN000000791. All patients received pravastatin 10 mg/day for 6 months and the change in concentration of total and high molecular weight adiponectin was assessed before and after follow up. The difference in the change in total adiponectin concentration by patient characteristics was analyzed by an unpaired t-test. Influences of continuous variable factors on the change in total adiponectin concentration were estimated by simple linear regression analyses. Finally, in order to estimate the influences of factors that potentially affect the change in total adiponectin concentration induced by pravastatin, multiple linear regression analysis was conducted. RESULTS: After 6 months, total adiponectin concentration was increased significantly by 23.2% from 11.7+/-6.4 to 13.7+/-8.6 ug/mL (p=0.002). The use of thiazolidinedione as a concomitant medication was the only significant influencing factor (beta=0.580, p<0.001). CONCLUSION: Pravastatin increased the serum adiponectin concentration in Japanese dyslipidemic patients without previous coronary artery disease. Interestingly, this effect was seen synergistically in combination with thiazolidinedione. PMID- 20702975 TI - Impairment of the vasodilatation capability of the brachial artery in patients with idiopathic venous thrombosis. AB - AIM: Determination of the functional capability of the peripheral arteries is increasingly used as an early marker of vessel disease. The aim of this study was to evaluate flow-mediated (FMD) and glyceryl trinitrate-mediated (NMD) dilation of the brachial artery in patients with idiopathic venous thrombosis (VT). METHODS: Flow-mediated brachial artery dilatation and the dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 97 subjects (49 eligible patients of both sexes, mean age 51.5 +/- 14.6 years, with idiopathic venous thrombosis, and 48 age-matched healthy controls). RESULTS: Compared to the control group, FMD was significantly reduced in the group of patients with idiopathic venous thrombosis -4.9% (95% CI 1.1-8.7%) vs. 12.7% (95% CI 7.8-17.6%), p<0.001. Patients also had diminished NMD of the brachial artery 12.5% (95% CI 6.6-18.4%) vs. 18.5% (95% CI 10.1-26.9%), p<0.001. In patients, significantly higher levels of circulatory markers (P-selectin, von Willebrand factor) of endothelial dysfunction were registered. CONCLUSIONS: Idiopathic venous thrombosis is associated with impaired flow- and GTN-mediated vasodilatory response of the brachial artery. This may suggest involvement of the functional deterioration of the vessel wall in the pathogenesis of idiopathic VT and indicate a relationship between VT and atherothrombosis. PMID- 20702977 TI - [Analysis of radioactivation induced by high-energy X-rays in medical linear accelerators -estimation of short-lived radioactivated nuclides-]. AB - In medical linear accelerators, radioactivation is induced on the target and neighborhood parts by photoneutrons accompanying a photo-nuclear reaction and leading to higher acceleration energy. We measured the residual radiation from the radioactivated materials according to the time, and tried to identify radioactivated nuclides and their relative quantities by means of measurement results. It was presumed that the main source of residual radiations was the Target, Flattening filter and Primary collimator in the linac head. Among those materials (copper, tungsten), we calculated decrement curves of residual radiations from radioactivated nuclides generated with photo-nuclear reaction or thermal neutron capture reaction by various ratios, and we investigated the ratio that best fit the measured data. Consequently, it was presumed that (66)Cu generated with thermal neutron capture reaction contributed the most to residual radiation, followed by (62)Cu generated with photo-nuclear reaction contributed. It is important to understand various characteristics of these nuclides and to undertake management of the device. PMID- 20702976 TI - Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion. AB - AIM: Present study aimed to elucidate the suppression of serum lipids by gamma- and delta-tocotrienol (gammadeltaT3). METHODS: The lipid-lowering effects of gammadeltaT3 were investigated using HepG2 liver cell line, hypercholesterolemic mice and borderline-high cholesterol patients. RESULTS: In-vitro results demonstrated two modes of action. First, gammadeltaT3 suppressed the upstream regulators of lipid homeostasis genes (DGAT2, APOB100, SREBP1/2 and HMGCR) leading to the suppression of triglycerides, cholesterol and VLDL biosyntheses. Second, gammadeltaT3 enhanced LDL efflux through induction of LDL receptor (LDLr) expression. Treatment of LDLr-deficient mice with 1 mg/day (50 mg/kg/day) gammadeltaT3 for one-month showed 28%, 19% reduction in cholesterol and triglyceride levels respectively, whereas HDL level was unaltered. The lipid lowering effects were not affected by alpha-tocopherol (alphaTP). In a placebo controlled human trial using 120 mg/day gammadeltaT3, only serum triglycerides were lowered by 28% followed by concomitant reduction in the triglyceride-rich VLDL and chylomicrons. In contrast, total cholesterol, LDL and HDL remained unchanged in treated and placebo groups. The discrepancies between in-vitro, in vivo and human studies may be attributed to the differential rates of post absorptive gammadeltaT3 degradation and LDL metabolism. CONCLUSION: Reduction in triglycerides synthesis and transport may be the primary benefit caused by ingesting gammadeltaT3 in human. PMID- 20702978 TI - [Usefulness of the collimator detector response (CDR) recovery and the scatter correction by the effective scatter source estimation (ESSE) method in myocardial SPECT study]. AB - The aim of this study was to evaluate the usefulness of the collimator detector response (CDR) recovery and the effective scatter source estimation (ESSE) method which is the scatter correction method built into the ordered subsets expectation maximization (OSEM) method. METHOD: The SPECT quality evaluation phantom and the anthropomorphic torso phantom were used in this study, and image contrast and uniformity were evaluated. The effect of each image correction method on the quantification of absolute radioactivity was also assessed. RESULTS AND CONCLUSION: Image contrast and uniformity were improved with the combination of the CDR recovery and triple energy window (TEW) method or the ESSE method. The combination of the CDR recovery and the ESSE method was the best method for the estimation of absolute radioactivity. Image quality of the SPECT is improved by the combination of CDR recovery and scatter correction in addition to attenuation correction. CDR recovery in addition to attenuation and scatter correction is also useful for the quantification of absolute radioactivity. PMID- 20702979 TI - [Application of flow-sensitive alternating inversion recovery (FAIR) to brain functional imaging]. AB - Flow-sensitive alternating inversion recovery (FAIR), which is an excellent method of non-invasive assessment of cerebral blood flow (CBF), was applied to brain function. Because blood oxygenation level dependent (BOLD) is an established method at present, brain functional imaging by FAIR was compared with BOLD. A few minutes is the necessary scanning time in FAIR targeted for brain ischemia. For BOLD, however, scanning time in a state is several seconds. A method of improving problems with scanning time was examined. There was no problem about the stability of the signal when scanning in design method, and a similar signal change was able to be confirmed. Additionally, there was no difference between each method concerning the activated part (p > 0.05). However, the activated area in FAIR was smaller than in BOLD (p < 0.01). Brain functional imaging by FAIR offers fewer advantages than BOLD. Yet it seems that reliability increases when measurements are made by the two methods using different mechanisms. PMID- 20702980 TI - [Development of a linear stage compatible for magnetic resonance imaging systems]. AB - A magnetic resonance imaging (MRI) system compatible linear stage was developed. The stage was made of acrylic plastic and moving power was applied by an ultrasonic motor. Moving distance of the stage was detected by counting the number of motor rotations using a optic fiber sensor. Accuracy and precision of the stage control were measured inside and outside the magnet using a micrometer and a laser distance meter. As a result, a value of more than 95% was achieved in both of them in the 1.5 T magnetic field when it was applied for more than a 0.3 mm movement. Measurement of the slice sensitivity profile (SSP) by the delta method was performed. Slice selection by this linear stage and by radio frequency (RF) offset were compared. The result by linear stage was in good agreement with the result by RF offset. With this linear stage, a performance evaluation test of MRI equipments that need micromotion can be performed. PMID- 20702981 TI - [Potential of helical scan technique in acute cerebral infarction assessment]. AB - The high convenience of data collection by helical scanning, such as making multi planner reformat (MPR) and shortening scan time, means that the technique is widely used to diagnose various body parts. However, non-helical scanning is still a main current for plane brain computed tomography. The possibility of diagnosing acute cerebral infarction by helical scanning MPR was examined. It was found that image degradation in helical scanning had little influence on the physical evaluation of the characteristics of modulation transfer function and the noise power spectrum, etc. In the evaluation of the ischemic change occurring at the early stage made by examination of clinical images, the result was almost equal to that obtained by non-helical scanning, as the reported sensitivity was 52% and the specificity was 95%. This suggested that brain helical scanning MPR might be applied clinically. However, a disadvantage was confirmed as helical scanning had a higher exposure dose than non-helical scanning at the start and end of scanning. The results of this study indicated that helical scanning demonstrates sufficient convenience for the assessment of acute cerebral infarction at the basal nucleus level. PMID- 20702982 TI - [IVR: Stent technology]. PMID- 20702983 TI - [Relationship between X-ray quality and object contrast]. PMID- 20702984 TI - [Ethics in clinical research]. PMID- 20702985 TI - [Fundamental of 3DCG animation making with personal computer system]. PMID- 20702986 TI - [Let's begin the imaging of sentinel lymph node scintigraphy]. PMID- 20702987 TI - [Development of an automated processing method to detect coronary motion for coronary magnetic resonance angiography]. AB - PURPOSE: On coronary MR angiography (CMRA), cardiac motions worsen the image quality. To improve the image quality, detection of cardiac especially for individual coronary motion is very important. Usually, scan delay and duration were determined manually by the operator. We developed a new evaluation method to calculate static time of individual coronary artery. METHODS AND MATERIALS: At first, coronary cine MRI was taken at the level of about 3 cm below the aortic valve (80 images/R-R). Chronological change of the signals were evaluated with Fourier transformation of each pixel of the images were done. Noise reduction with subtraction process and extraction process were done. To extract higher motion such as coronary arteries, morphological filter process and labeling process were added. Using these imaging processes, individual coronary motion was extracted and individual coronary static time was calculated automatically. We compared the images with ordinary manual method and new automated method in 10 healthy volunteers. RESULTS: Coronary static times were calculated with our method. Calculated coronary static time was shorter than that of ordinary manual method. And scan time became about 10% longer than that of ordinary method. Image qualities were improved in our method. CONCLUSION: Our automated detection method for coronary static time with chronological Fourier transformation has a potential to improve the image quality of CMRA and easy processing. PMID- 20702988 TI - [Patient skin injury in cardiac intervention procedures]. AB - PURPOSE: To discuss the circumstances of patient skin injury in cardiac interventional radiology (IVR). To demonstrate the importance of evaluating the patient radiation dose in IVR. To show the need for the appropriate patient follow-up after IVR to identify radiation effects. To highlight the incidence of skin injuries during IVRs. CONTENT ORGANIZATION: Evaluation of 400 consecutive percutaneous coronary interventions (PCIs). The radiation dose, number of cine runs, and fluoroscopic time were recorded for all patients. The skin on the patients' backs was reviewed periodically after PCI to identify radiation injury. The relationships between patient skin effects and factors such as the radiation dose were investigated. Reviewing previous reports of patient radiation injury occurrence rate, fluoroscopic time, radiation dose (if available), etc. SUMMARY: Although increasing numbers of case reports of patient radiation injury resulting from IVR are being published, these reports likely represent a small fraction of actual cases. Radiation skin injury in IVR is overlooked clinically in many patients. Patients who receive a high radiation dose while undergoing IVR should be followed to identify radiation skin effects, and physicians should seek to establish whether a patient has had previous IVR, together with the entrance site and radiation dose. PMID- 20702989 TI - [Evaluation of image quality of multiplanar reconstruction images: Effect of Z increment of original axial images]. AB - PURPOSE: The aim of our study was to evaluate the image quality of multiplanar reconstruction images (MPRs) focusing on the effect of z-increment of original axial images using signal to noise ratio (SNR) measurement in in- plane and longitudinal directions. METHODS AND MATERIALS: SNRs of MPRs were calculated using modulation transfer function (MTF) and noise power spectrum (NPS). We scanned a bead phantom with a diameter of 0.1 mm and a water phantom with a diameter of 250 mm for calculating MTF and NPS using a MDCT with 0.5 s per rotation, 1.0 pitch and 64 x 0.6 mm collimation, and 50 mm field of view. Axial images for generating MPRs were reconstructed with standard kernel (B40), and 1.00 mm slice width. Coronal images were generated from two datasets with 0.1 mm and 0.5 mm z-increments of axial images respectively. For measuring the SNRs, the MTFs and NPSs in in-plane and longitudinal directions of each dataset were calculated from coronal bead images and coronal uniform noise images, respectively. Differences of MTF, NPS, and SNR were compared in in-plane and longitudinal directions. RESULTS: The MTF of longitudinal direction of the dataset with 0.1 mm z-increment was higher than the dataset with 0.5 mm z increment. 10% MTFs of longitudinal direction with 0.1 mm and 0.5 mm z-increments were 0.75 cycles/mm and 0.68 cycles/mm, respectively. Conversely, the NPS of longitudinal direction of the dataset with a 0.1 mm z-increment was lower than the dataset with a 0.5 mm z-increment. As a consequence, the SNRs of longitudinal direction had relatively no difference between the datasets. In in-plane direction, MTFs, NPSs and SNRs had no differences between the datasets. CONCLUSION: A tradeoff relationship was indicated between spatial resolution and noise characteristic in the longitudinal direction due to the effects of different z-increment of original axial images used in generating MPRs. MPR using 0.5 mm z-increment of axial images had comparable SNR to MPR using 0.1 mm z increment of axial images in our experimental condition. CLINICAL RELEVANCE/APPLICATION: Using 0.5 mm z-increment of original axial images for generating MPRs is effective for reducing the data volume, reconstruction time and transfer time without reducing image quality. PMID- 20702991 TI - [Status of the IHE activity]. PMID- 20702990 TI - [Effect of a comprehensive image processing on radiologists' performance in differential diagnosis of liver lesions using CT and MRI]. AB - PURPOSE: To evaluate whether a comprehensive image processing method as CAD using CT and MRI can improve the radiologists' diagnosis performance in the differentiation of focal liver lesions. METHOD AND MATERIALS: A clinical image database used in this study consists of 14 cases of each lesion including hepatic cysts, hepatocellular carcinoma (HCC), metastatic liver cancer, and hemangioma. This technique by using MR images obtained with various imaging sequences and a series of dynamic MR and dynamic CT images is designed for the enhancement of liver lesions pixel by pixel. In this method, we make the pixel sizes of MR images the same size of CT image by using tri-linear interpolation technique. Then the 3D image registration technique based on mutual information is applied for the matching of images. The image intensity pattern with and without contrast enhancement is determined as the template for the differential detection of each lesion. Pixel-by-pixel cross-correlation coefficient is calculated for the enhancement of each lesion. The radiologists' performance in distinguishing between the liver lesion was evaluated by receiver operating characteristic analysis (ROC) with a continuous rating scale. RESULTS: In free-response ROC analysis, true positive fractions were 75%, 87%, 85%, and 86% for hepatic cysts, HCC, metastatic liver cancer and hemangioma, respectively. Furthermore, average number of false positive and false negatives per image was 3.4 and 0.3, respectively. When radiologists made differential diagnosis of the liver lesions with the images of this technique, diagnostic accuracy was statistically significantly improved compared to the diagnostic accuracy without the images of this technique. The average area under the ROC curve (Az value) improved from 0.881 to 0.964 (p=0.069) for the differential diagnosis of hepatic cysts. Furthermore, the Az value of HCC, metastatic liver cancer, and hemangioma improved from 0.951 to 0.979 (p=0.040), from 0.946 to 0.976 (p=0.226), and from 0.966 to 0.987(p=0.045), respectively. CONCLUSION: A comprehensive image processing method as CAD using CT and MRI can improve the radiologists' diagnostic performance in the differentiation of focal liver lesions. CLINICAL RELEVANCE/APPLICATION: This method improved the performance of differential detection of liver lesions from a large number of images and it would save radiologists' reading time, and thus could assist their diagnosis. PMID- 20702992 TI - Evaluation of RF heating on hip joint implant in phantom during MRI examinations. AB - PURPOSE: We evaluate radiofrequency (RF) heating of two kinds of hip joint implants of different sizes, shapes and materials. Temperature rises at various positions of each implant are measured and compared with a computer simulation based on electromagnetic-field analysis. METHODS: Two kinds of implants made of cobalt-chromium alloy and titanium alloy were embedded at a 2-cm depth of tissue equivalent gel-phantom. The phantom was placed parallel to the static magnetic field of a 1.5 T MRI device. Scans were conducted at the specific absorption rate of 2.5 W/kg for 15 min, and temperatures were recorded with RF-transparent fiberoptic sensors. Temperatures of the implant surface were measured at 6 positions, from the tip to the head. Measured temperature rises were compared with the results of electromagnetic-field analysis. RESULTS: The maximum temperature rise was observed at the tip of each implant, and it was 9.0 degrees C for the cobalt- chromium implant and 5.3 degrees C for the titanium implant. The simulated heating positions with electromagnetic-field analysis accorded with experimental results. However, a difference in temperature rise was seen with the titanium implant. CONCLUSION: RF heating was confirmed to take place at both ends of the implants in spite of their different shapes. The maximum temperature rise was observed at the tip where there is large curvature. The value was found to depend on physical properties of the implant materials. The discrepancy between experimental and simulated temperature rises was presumed to be the result of an incomplete model for the titanium implant. PMID- 20702993 TI - [Investigation of error factors in analysis of digital noise power spectrum]. AB - The noise power spectrum (NPS) measurement is important for assessing noise properties of digital radiography systems, and its measurement method was standardized in International Electrotechnical Commission 62220-1 (IEC). However, improvement of its accuracy is not easy due to random data analysis. In this study, regarding error factors in the NPS measurement using 2-dimensional (2D) Fast Fourier transform, we investigated effects of overlap of region of interests (ROIs), number of average lines in 2D frequency space, directional dependence of frequency property, and detrending techniques. If the number of average lines was set so as to obtain a similar frequency range to IEC, total matrix size was the most important factor and error rate was decreased with increasing of the size. For images, including many trends, detrending using 256 x 256-pixels ROI and second-order polynomial fitting was the most effective. Consistent with the previous report, the overlap of ROIs was not effective for improving accuracy. Contrary to the previous report that indicated effectiveness of 128 x 128-pixels ROI for detrending, we demonstrated less affectivity of the ROI size, other than 256 x 256-pixels. PMID- 20702994 TI - [Respiratory management of CT-transmission for accuracy fusion in PET/CT: a comparison between normal expiration and free breathing in 600 experiences]. AB - Image misregistration can occur in fusion PET/CT, because of motion artifacts caused by the management of respiration. The standard imaging protocol of the CT component of PET/CT is normal expiration (NormExp) or free breathing (FB). The objective of this study was to compare NormExp and FB for the optimal breathing protocol for PET/CT scans. A total of 600 consecutive patients were examined using lutetium oxyorthosilicate (LSO)-based PET/CT. CT was acquired during NormExp (i.e., the level reached when the patient exhaled without forcing expiration and then held the breath) in 300 patients and during FB in 300 patients. The profile of liver measured along body axis was assessed. The distance of profile centers between the PET image and the CT image was measured. The misalignment between profile centers (PET) and profile centers (CT) was compared between NormExp and FB using the histogram of patients. An F test was used to test if the variances of two misalignments are equal. Next, the relationship between misalignment and age was evaluated in two managements of respiration. There was no significant difference between NormExp and FB in the histogram. However, significant misalignments (>10 cm) were found with NormExp. Patient age may have influenced the mismatch. FB is recommended for geriatric patients during acquisition of attenuation correction CT data sets. PMID- 20702995 TI - [Comparison MR cholangiopancreatography with 3D-fast recovery fast spin echo in several different slice thicknesses]. AB - PURPOSE: To evaluate the technical quality and visibility of the biliary tree and pancreatic duct on magnetic resonance cholangiopancreatography (MRCP) images obtained with a single-breath-hold three-dimensional (3D) fast-recovery fast spin echo (FRFSE) sequence in several different slice thicknesses. MATERIALS AND METHODS: As a fundamental study, tubes of various inside diameters filled gadolinium solutions were acquired at 1.5 T in 3D-FRFSE. We observed error rate changes of volume inside the tubes and the visibility of thinner tubes. MRCP was performed at 1.5 T in 8 consecutive patients (4 men and 4 women, aged 22-58 years). Seven radiologists graded images obtained with each slice thickness in a blind fashion. Furthermore, we compared 1.4 mm slice thickness images with 1.8 mm slice thickness images in a continuous rating scale for the same patient. We assessed differences in technical quality, overall visibility, and six individual ductal segments of the biliary tree and pancreatic duct. RESULTS: If slice thickness were thinner relative to diameter, the error rate would be closer to zero. But, when slice thickness was 0.8 mm, the error rate became clearly higher because of low intensity. In the fundamental study, we thought that the appropriate slice thickness is between 1.0 mm and 2.4 mm. The visibility of images of thinner tubes could be improved by having a thinner slice thickness. In particular, MRCP overall images generated from a 1.4 mm slice thickness were found to be significantly superior to those generated from a 1.8 mm slice thickness (p<0.001); this was also true as regards the pancreatic duct and cystic duct (p<0.01, p<0.05). CONCLUSION: We conclude that a 1.4 mm slice thickness is appropriate for MRCP. PMID- 20702996 TI - [Improvement of method of determining fluoroscopy loading factor in digital angiographic x-ray system with a flat panel detector]. AB - A catheterization study and treatment of coronary arteriopathy are performed by investigating the coronary artery from different angles to find the region to be treated. In doing so, our system always started from the initial value of the loading factor, using this only for the first time, and the system started from the last loading factor the second time and later, at all angles. Therefore, depending on the angle, the loading factor at the start of fluoroscopy sometimes became unstable, and it took time to stabilize. This made the starting image too dark (undershoot x-ray condition) or fogged by halation (overshoot x-ray condition). With the system manufacturer, we developed a tube voltage and tube current setting method for the initial value of the loading factor. We installed software which preset the loading factor at the start of fluoroscopy depending on the angle, and an auto memory function of the last loading factor for each angle. This function allows the system to control the tube voltage and tube current for any angle. As a result, the system can acquire a more stabilized image from the start of fluoroscopy. This method of determining the initial loading factor is an effective way to stabilize the fluoroscopy image quickly. PMID- 20702997 TI - [Underlying examination in the imaging of 89Sr bremsstrahlung radiation]. AB - The radiopharmaceutical strontium chloride ((89)Sr) has been released as a new means of pain relief for painful bone metastasis in cancer patients. Because (89)Sr is a pure beta-emitting nuclide, it was considered difficult to know its distribution in the body from outside. Imaging with a gamma camera using bremsstrahlung radiation has been reported as one method, but there has been little detailed basic examination. We examined the optimal energy window and collimator when imaging with a gamma camera using bremsstrahlung radiation produced from (89)Sr beta rays. The results showed that setting the energy window at 75 keV, which is the peak formed by the characteristic X-ray of lead that is produced by the interaction of bremsstrahlung radiation and lead, is optimal for imaging. Also important are the material of the collimator and the use of an MELP collimator. PMID- 20702998 TI - [Radiation dose reduction effects of prospective ECG-gated helical scan with high helical pitch in coronary multidetector computed tomography]. AB - BACKGROUND: High radiation dose of conventional retrospective ECG-gated coronary MDCT (multidetector computed tomography) with regular helical pitch (HP) continuous scan has disturbed wide clinical use. The purpose was to estimate the radiation dose reduction effects of FlashScan, which was a prospective ECG-gated helical scan with high HP. METHOD: Coronary MDCT was performed by Aquilion 64 Super Heart (Toshiba) in 474 patients (M/F=280/194, mean age: 65+/-11 years old, mean height: 161+/-10 cm, body weight: 62+/-13 kg, BMI: 23.9+/-3.4) with HR50% (in extreme obesity) of body mass and is biologically active through its secretion of numerous peptides and release and storage of nutrients such as free fatty acids. Studies in rodents and humans have revealed that body fat distribution, including visceral fat (VF), subcutaneous (SC) fat and ectopic fat are critical for determining the risk posed by obesity. Specific depletion or expansion of the VF depot using genetic or surgical strategies in animal models has proven to have direct effects on metabolic characteristics and disease risk. In humans, there is compelling evidence that abdominal obesity most strongly predicts mortality risk, while in rats, surgical removal of VF improves mean and maximum life span. There is also growing evidence that fat deposition in ectopic depots such as skeletal muscle and liver can cause lipotoxicity and impair insulin action. Conversely, expansion of SC adipose tissue may confer protection from metabolic derangements by serving as a 'metabolic sink' to limit both systemic lipids and the accrual of visceral and ectopic fat. Treatments targeting the prevention of fat accrual in these harmful depots should be considered as a primary target for improving human health span and longevity. PMID- 20703053 TI - Obesity paradox during aging. AB - Although obesity in young people is a risk factor for morbidity and mortality, the effect of obesity in the elderly is much more complex. For example, the body weight associated with maximal survival increases with increasing age. Even more striking is the 'obesity paradox' in the elderly, in which overweight is associated with increased risk for cardiovascular disease but decreased mortality from these diseases. Thus, although intentional weight loss by obese older people is probably safe, and likely to be beneficial if they have obesity-related morbidities, caution should be exercised in recommending weight loss to overweight older people on the basis of body weight alone. Methods of achieving weight loss in older adults are the same as in younger adults. Weight loss diets should be combined with an exercise program, if possible, to preserve muscle mass, as dieting results in loss of muscle as well as fat, and older people have reduced skeletal muscle mass compared to younger adults. Weight-loss drugs have not been extensively studied in older people and there is the potential for drug side effects and interactions. Weight loss surgery appears to be safe and effective, although it probably produces less weight loss than in younger adults. Little is yet known about the outcomes of such surgery in people over 65 years. PMID- 20703054 TI - Central control of food intake in aging. AB - Energy homeostasis and fuel metabolism undergo significant modifications in the course of aging. This presents in elderly subjects either as increased body mass and glucose intolerance - which may lead to obesity and type 2 diabetes - or loss of appetite, which may also seriously compromise health. The hypothalamic expression of neuropeptide Y (NPY), the most potent orexigen, and its receptors, was highly suppressed in old rats. Moreover, induction of the NPY-dependent responses was severely blunted in old animals. Similar reductions, although of a lower magnitude, were reported for other hypothalamic orexigens, A and orexins. Orexigenic activity of ghrelin, the only peripheral orexigen, was clearly suppressed in old humans and rats. However, aging did not alter hypothalamic expression of key anorexigens, alpha-MSH and CART. Age-related decrease of central anorexigenic action of leptin was likely caused by the impaired leptin signal transduction. Thus, aging in rodents is associated with the general down regulation of orexigenic hypothalamic pep-tides - and unchanged expression of anorexigenic hypothalamic peptides - which may lead to weight loss at the end of life. If similar changes at the level of CNS underlie the 'anorexia of aging' observed in some elderly, therapeutic interventions at this regulatory level may be possible in the future. PMID- 20703055 TI - Changes in food intake and its relationship to weight loss during advanced age. AB - The results of extensive human and animal studies suggest that declining food intake and body weight observed in the later stages of life may be part of the normal progression of physiological decline observed during aging. Proposed etiologies cover a wide range of biological and psychological conditions. Studies in humans suggest an imbalance in homeostatic mechanisms governing hunger and satiety. That is, while older vs. younger individuals retain a similar drive (hunger) to eat, satiety occurs sooner during a meal in aged people and leads to an overall decrease in daily food intake. Age-related weight loss and a reduction in food intake have also been observed in laboratory animals. Alterations in neurochemical control of energy balance, especially as they relate to long-term regulation of food intake, have received much attention in recent years as the likely mechanism underlying age-related spontaneous weight loss. Age-related changes to neuroendocrine factors such as neuropeptide Y, GABA, CCK, leptin, and insulin have been linked to spontaneous weight loss observed during late life. This brief review provides an update on putative mechanisms underlying the dysregulation of feeding during advanced age that result in body weight loss. PMID- 20703056 TI - Changes in body composition in response to challenges during aging in rats. AB - Body composition changes over the lifespan of Brown Norway rats, in patterns similar to those of humans. Young adults are lean, with little fat, much of which is intra-abdominal. As they age, rats exhibit linear growth, and both lean and fat mass increase until late middle to early old age. Fat mass continues to accumulate throughout the lifespan, both viscerally and subcutaneously; aging animals carry a higher proportion of their fat mass peripherally. After middle age, skeletal muscle mass begins to decline, and sarcopenia develops when animals reach senescence. Finally, in late old age, or senescence, body weights begin to decline, and both fat and lean mass are lost. Healthy aged rats generally respond to negative energy balance challenges less robustly than younger adult animals, although they do appropriately regulate adipose tissue stores and preserve lean mass. The response to a positive energy balance challenge (high fat feeding) is less well regulated in aging animals, and dietary-induced obesity develops rapidly in aged animals. Here we present a summary of several studies of body composition in response to challenges of energy balance in aging male Brown Norway rats, with special emphasis on adipose tissue partitioning. PMID- 20703058 TI - Sarcopenia: prevalence, mechanisms, and functional consequences. AB - Aging is associated with significant decline in neuromuscular function and performance. Sarcopenia, often defined as age-related loss of muscle mass, strength, and functional decline, is the most characteristic feature of age related changes in the neuromuscular system. Strength decline in upper and lower limb muscles is typically 20-40% by the 7th decade and greater in older adults. This is accompanied by similar losses of limb muscle cross-sectional area. Whole body or appendicular muscle mass determination has become the method of choice for defining sarcopenia. Large population studies have reported that sarcopenia affects over 20% of 60- to 70-year-olds, and approaches 50% in those over 75 years. While loss of muscle mass explains a significant component of weakness, other factors are emerging as important contributors. In particular changes at the level of the motor neuron and motor unit are discussed. Muscle power has emerged as an important indicator of function in older adults, and we discuss knee osteoarthritis as a model of accelerated limb sarcopenia. PMID- 20703057 TI - New haystacks reveal new needles: using Caenorhabditis elegans to identify novel targets for ameliorating body composition changes during human aging. AB - Dramatic changes in body composition accompany aging in humans, particularly with respect to adiposity and the musculature. People accumulate fat as they age and lose muscle mass and strength. Caenorhabditis elegans nematodes are small, hermaphroditic soil nematodes that offer a flexible model for studying genetic pathways regulating body composition in humans. While there are significant physiological differences between worms and people, many of the genetic pathways relevant to human lipid and muscle homeostasis are present in worms. Initial studies indicate that adiposity increases in C. elegans during aging, as occurs in humans. Furthermore, substantial evidence demonstrates age-related loss of muscle mass in worms. Possible mechanisms for these changes in C. elegans are presented. Recent studies have highlighted neuroendocrine and environmental signals regulating C. elegans fat metabolism. Potential dysfunction of these pathways during aging could affect overall fat accumulation. By contrast, muscle decline in aging worms results from accumulated damage and 'wear-and-tear' over life span. However, neuroendocrine pathways also regulate muscle mass in response to food availability. Such pathways might provide useful therapeutic approaches for combating muscle loss during aging. From this chapter, readers will develop a deeper understanding of the ways that C.elegans can be used for mechanistic gerontological studies. PMID- 20703059 TI - mTOR signaling as a target of amino acid treatment of the age-related sarcopenia. AB - Sarcopenia is an age-related structural and functional impairment of skeletal muscle leading to loss of strength, contractile capacity and endurance. Among factors implicated in sarcopenia, deregulation of muscle protein synthesis (MPS) has frequently been reported. Thus, the attempts aiming at identifying possible countermeasures to sarcopenia require consideration of a complex coordinated interaction of factors contributing to the balance between protein synthesis and breakdown and the identification of several regulators on their function. We will focus here on the signaling pathways controlling protein synthesis in skeletal muscle, specifically on one of the downstream effectors of the kinase Akt/PKB, the mammalian target of rapamycin (mTOR) kinase which is now recognized as a key regulator of cell growth and a pivotal sensor of nutritional status over the lifespan. Dysfunction of mTOR signaling in the elderly and its potential role as a target of amino acids in the treatment of age-related sarcopenia will be discussed. PMID- 20703060 TI - Mitochondrial theory of aging in human age-related sarcopenia. AB - Understanding age-related sarcopenia and, more importantly, devising counterstrategies require an intimate knowledge of the underlying mechanism(s) of sarcopenia. The mitochondrial theory of aging (MTA) has been a leading theory on aging for the last decade; however, there is relatively little information from human tissue to support or rebut the involvement of the MTA in aging skeletal muscle. It is believed that mitochondria may contribute to sarcopenia in a stochastic fashion where regions of fibers containing dysfunctional mitochondria are forced to atrophy. Resistance exercise, a known hypertrophic stimulus, has been shown to improve the mitochondrial phenotype of aged skeletal muscle. Furthermore, activation of skeletal muscle stem cells by resistance exercise may attenuate sarcopenia in two ways. First by inducing nuclear addition to postmitotic fibers, and, second, by increasing the proportion of functional mitochondria donated by muscle stem cells in a process termed 'gene shifting'. In this chapter we review the evidence supporting the MTA, the potential to attenuate the MTA with a known hypertrophic stimuli and explore the role of muscle stem cells in gene shifting to determine the connection between mitochondrial dysfunction and age-related sarcopenia. PMID- 20703061 TI - Exercise as a calorie restriction mimetic: implications for improving healthy aging and longevity. AB - Calorie restriction (CR) is the only paradigm that has consistently increased lifespan in a wide variety of model organisms. Many hypotheses have been proposed as the underlying mechanism, including a reduction in body size and adiposity, which is commonly observed in calorie-restricted animals. This has led to investigations as to whether similar changes in body composition produced by increasing energy expenditure via exercise can replace or enhance the benefits of reducing energy intake. The goal of this chapter is to review and discuss the evidence regarding exercise as a CR mimetic for healthy aging and longevity. In rodents, the data clearly show that exercise, regardless of body weight changes, can improve health and survival, but unlike CR, fails to extend lifespan. In humans, short-term weight loss studies show that exercise and CR produce similar improvements in disease risk factors and biomarkers of aging, while some parameters clearly benefit more with exercise. Epidemiologic evidence in humans supports exercise as a strategy to reduce the risk of morbidity and mortality, but not to extend lifespan. It is unknown whether CR can extend human lifespan, but the metabolic profile of humans engaged in long-term CR shares many similarities with calorie restricted rodents and nonhuman primates. In conclusion, like CR, exercise can limit weight gain and adiposity, but only CR can extend lifespan. Therefore, in rodents, the ability of CR to slow aging is apparently more dependent on decreasing nutrient flux, rather than changes in energy balance and body composition. PMID- 20703062 TI - Clinical, cellular and molecular phenotypes of aging bone. AB - Our understanding of gerontological bone loss and osteoporosis has grown substantially in the recent past. Clinical as well as basic and translational studies have been pivotal in providing us with the pathophysiology of this condition. They have also informed us of the various cellular and molecular mechanisms underlying age related bone loss. This chapter focuses on the current concepts and paradigms of age related bone loss in humans and how various animal and cellular models have broadened our understanding in this fascinating but complex area. Changes in hormonal, neuronal and biochemical cues with age and their effect on bone have been discussed. This chapter also outlines recent studies on the relationship between bone and fat in the marrow, and the fate of the marrow mesenchymal stromal cell population which can give rise to either bone forming osteoblasts or fat-forming adipocytic cells as a function of age. PMID- 20703063 TI - [Biologic response modifiers for children]. PMID- 20703065 TI - [The brief commentary on Practical Guideline for the Management of Allergic Rhinitis in Japan, 2009--the point of treatment for the pregnant]. PMID- 20703064 TI - [Use of biological agents in adult asthma]. PMID- 20703066 TI - [Identification of natural helper cell]. PMID- 20703067 TI - [Hygiene hypothesis and allergic diseases]. PMID- 20703068 TI - [Relation of the time course of Japanese Pediatric Asthma Control Test (JPAC) and Childhood Asthma Control Test (C-ACT) score with respiratory function and fractional exhaled nitric oxide (FENO)]. AB - BACKGROUND AND OBJECT: Two major convenient questionnaires of asthma control in childhood, Japanese Pediatric Asthma Control Program (JPAC) and Childhood Asthma Control Test (C-ACT) have been available in Japan. The aim of this study is to evaluate relationship of two questionnaires in terms of the changes of respiratory function and fractional nitric oxide (FENO) in each individual. SUBJECT AND METHODS: The 102 samples from patients with asthma aged 6 to 11 years old and their parents' answers for the two questionnaires at regular visits were collected. At the same time, respiratory functions and FENO were measured. The correlations of each difference of scores (+/-JPAC or +/-C-ACT), correlations of +/-JPAC or +/-C-ACT and increased ratio of respiratory functions and FENO (DeltaFENO%) were examined. We analyzed the factors that influences on respiratory functions and FENO. Moreover, the correlations of increased ratio of respiratory functions and DeltaFENO% were examined. RESULTS: Changes of JPAC and C-ACT correlated with each other. (rho=0.725, p<0.0001) DeltaFENO% was influenced by medications, especially ICS. +/-JPAC weakly correlated with DeltaFEV1% and DeltaFEF25-75% and DeltaPEF%, so did C-ACT. +/-JPAC correlated most strongly with the change of DeltaFEF25-75% among the parameters of respiratory functions. (rho=0.357, p=0.0003)+/-JPAC, but not +/-C-ACT weakly correlated with DeltaFENO%. (rho=-0.2045, p=0.0401) CONCLUSION: JPAC and C-ACT reflect the change of the respiratory function of each patient rather than those at random visit. Furthermore, JPAC may reflect FENO. In conclusion, recognition of the changes of the scores of these questionnaires may increase the utilities of the same scores obtained at a single visit. It is needed further study how to use FENO added on these questionnaires. PMID- 20703069 TI - [A survey of perioperative asthmatic attack among patients with bronchial asthma underwent general anesthesia]. AB - BACKGROUND: We investigated the risk factor of perioperative asthmatic attack and effectiveness of preventing treatment for asthmatic attack before operation. METHODS: We performed retrospective chart review of one hundred eleven patients with asthma underwent general anesthesia and surgical intervention from January 2006 to October 2007 in our hospital. RESULTS: The rate of perioperative asthmatic attack were as follows; 10.2% (5 in 49 cases) in no pretreatment group, 7.5% (3 in 40 cases) in any pretreatments except for systemic steroid, and 4.5% (1 in 22 cases) in systemic steroid pretreatment group. Neither preoperative asthma severity nor duration from the last attack had significant relevancy to perioperative attack rate. The otolaryngological surgery, especially those have nasal polyp and oral surgery had high perioperative asthma attack rate, although there was no significant difference. CONCLUSION: We recommend the systemic steroid pretreatment for asthmatic patients, especially when they have known risk factor such as administration of the systemic steroid within 6 months, or possibly new risk factor such as nasal polyp, otolaryngological and oral surgery. PMID- 20703070 TI - [Usefulness of skin prick test using bifurcated needle for the diagnosis of food allergy among infantile atopic dermatitis--second report. In the case of cow's milk allergy]. AB - OBJECTIVE: We investigated the usefulness of skin prick test (SPT) using bifurcated needle (BN) for the diagnosis of cow's milk allergy (CMA) in early infancy. SUBJECTS AND METHODS: Among atopic dermatitis infants with suspicion of food allergy who visited Sagamihara National hospital from January 2001 to April in 2005, 168 cases had received both SPT and IgE ImmunoCAP of CM (CM-IgE) at first visit. We analyzed results of SPT and CM-IgE, focused on infants with negative CM-IgE to examine the usefulness of SPT, and checked positive conversion of CM-IgE with aging. RESULTS: Among 124 infants (73.8%) with negative CM-IgE, 34 infants (27.4%) showed positive SPT results. Forty two infants (33.6%) among the 124 cases were diagnosed as CMA by combination of elimination and provocation test, and 21 infants (50.0%) had positive SPT. In the follow up study of 39 negative CM-IgE cases with CMA, 21 CM-IgE (53.8%) turned positive later infantile period (mean CM-IgE: 4.2+/-4.8 Ua/ml at 9.3+/-5.3 months old). CONCLUSIONS: SPT using BN seemed to be more useful than CM-IgE for the diagnosis of CMA in early infancy with AD. But, the sensitivity is lower than in the egg case. PMID- 20703072 TI - [Prediction and prevention of allergic diseases--no therapy is better than prevention]. PMID- 20703071 TI - [A case of primary ciliary dyskinesia who had been treated as asthma]. AB - We report a case of 18-old girl with primary ciliary dyskinesia (PCD) who had been diagnosed as asthma. Since birth, she had presented with unexplained productive cough, sputum, rhinorrhea, and stridor with situs solitus. Her familial history was negative for PCD. At 2 years of age, ciliary beat frequency and beat pattern were normal. She was diagnosed as rhinosinusitis, chronic secretory otitis media. At 3 years of age, she was diagnosed as asthma because of wheezing not associated with respiratory infection. Various asthma medications were then administered, including DSCG, inhaled corticosteroids, and salmeterol, but varying responses to the treatment were noted. Spirometry revealed persistent severe small airway obstruction. Beta2 agonist reversibility was recognized by impulse oscillation system, not with FEV1. At age of 18, chest CT disclosed bronchiectasis, and nasal nitric oxide concentration was very low, 98 ppb and a diagnostic approach for PCD was performed. Electron microscopic analysis of nasal cilia demonstrated defects of the outer and inner dynein arms, and the diagnosis of PCD was made. Mutations in DNAH1 and DNAI1 genes were found. The diagnosis of PCD is often difficult in the absence of situs inversus totalis. Recurrent wheeze with chronic rhinosinusitis, chronic otitis media, and brochiectasis may warrant detailed investigations for PCD, especially with nasal NO measurement. PMID- 20703073 TI - Genetic mutants illuminate the roles of RecQ helicases in recombinational repair or response to replicational stress. PMID- 20703074 TI - Transcription elongation takes central stage: the P-TEFb connection. PMID- 20703075 TI - The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors. AB - The tumor suppressor gene, p53, in response to DNA damage/hypoxia, induces growth arrest and/or apoptosis. Inactivation of p53, by mutations and/or overexpression of the mdm2 gene, confers a selective advantage to tumor cells under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its life underground at low-oxygen tensions and hence has developed a wide range of respiratory/molecular adaptations to hypoxic stress. We previously reported that the highly conserved p53 Arg(R)-174 is substituted by lysine (K) in Spalax, identical to a tumor-associated mutation. Functionality assays revealed that Spalax p53 and human R174K-mutated p53 were unable to induce human/Spalax apaf1, an apoptotic target gene, while over-activating the mdm2 gene. Moreover, cells transfected with human p53 underwent more extensive apoptosis (44.8%) as compared to Spalax p53 (23.2%) transfected cells. To support our hypothesis that the pattern of activity in Spalax is related to hypoxia tolerance, we quantified apaf1 and mdm2 mRNA levels under normoxia (21% O(2)), short-acute hypoxic stress (5 h at 6% O(2)) and long-mild hypoxic insult (44 h at 10% O(2)). Results were compared to those of rats under similar conditions. Following hypoxia, Spalax apaf1 mRNA levels decreased significantly, but increased in rats. apip mRNA levels, a negative regulator of apaf1, increased in Spalax and decreased in rats. mdm2 mRNA levels under hypoxia were significantly higher in Spalax. We conclude that, similar to our previous in-vitro work, two parallel hypoxia-adaptive mechanisms evolved in Spalax: mutated p53 and p53 response element leading to a bias against apoptosis and increased mdm2, which are analogous to observations in tumor development. PMID- 20703076 TI - Overeating yeast display fatty acid-induced necrotic cell death. PMID- 20703077 TI - Three-step model for condensin activation during mitotic chromosome condensation. AB - Chromosomes undergo a major structural reorganization during mitosis. The first step in this reorganization is the compaction of interphase chromatin into highly condensed mitotic chromosomes. An evolutionarily conserved multi-subunit ATPase, the condensin complex, plays a critical role in establishing chromosome architecture and promoting chromosome condensation in mitosis. How does condensin promote chromosome condensation and how, in turn, is the cell cycle machinery activating or restraining condensin activity during the cell cycle are fundamental questions for cell biology. In this review, we examine the role of post-translational modifications, and in particular multi-site phosphorylation, in the regulation of condensin activity during the cell cycle. Remarkably, inspection of phosphorylation sites identified through multiple proteome-wide mass spectrometry analyses reveals that the phosphorylation landscape of condensin is highly conserved evolutionarily and that several kinases regulate condensin in vivo. This analysis leads us to propose a model, the ultrasensitive/kinase switch model, whereby the phosphorylation of condensin by multiple kinases allows the process of chromosome condensation to be maintained and even increased under fluctuating levels of cyclin-CDK activity during mitosis. Our model reconciles how chromosome condensation might be highly sensitive to low levels of CDK activity in early mitosis and subsequently insensitive to the declining levels of CDK activity in late mitosis. PMID- 20703078 TI - p38alpha as an inducer of aneuploidy in p53-/- tetraploid cells. PMID- 20703080 TI - A spotlight on regulatory networks connecting EMT and cancer stem cells. PMID- 20703079 TI - PML promotes senescence via JAK/STAT signaling. PMID- 20703081 TI - A feedback loop between mTOR and tRNA expression? PMID- 20703082 TI - P-TEFb joins the family of cdks in oncology, promotes cell growth of cancer cells. PMID- 20703083 TI - Cooperativity of Cdk4R24C and Ras in melanoma development. AB - The importance of the CDK4 protein in human cancer first became evident following the identification of a germ line mutation in the Cdk4 locus that predisposes humans to melanoma. This mutation results in substitution of arginine with cysteine at position 24 (R24C). In an earlier study, we introduced the R24C mutation into the Cdk4 locus of mice using Cre-loxP-mediated "knock-in" technology and observed a very low incidence of spontaneous melanomas in Cdk4(R24C/R24C) mice. This suggested that additional oncogenic mutations might be required for development of melanomas. Here we report an increased incidence of spontaneous cutaneous melanoma in mice expressing the oncogene HRAS(G12V) in melanocytes on a Cdk4(R24C) background. Treatment of Tyr-HRas:Cdk4(R24C/R24C) mice with the carcinogen, DMBA/TPA resulted in a further increase in the number of nevi and melanomas developed when compared with Tyr-HRas:Cdk4(+/+) mice. In summary, in Tyr-HRas:Cdk4(R24C/R24C) mice, we observed that activated CDK4 cooperates with the oncogenic HRAS(G12V) protein to increase the susceptibility of melanoma development in vivo. PMID- 20703084 TI - S-phase lengthening induced by p16(INK4a) overexpression in malignant cells with wild-type pRb and p53. AB - The p16(INK4a) protein is considered to regulate the cell cycle progression mainly by inhibiting cyclin-dependent kinases (CDKs) 4 and 6 activity and leading to an arrest in G(0)/G(1). Here, we report that ectopic expression of p16(INK4a) in three p16-/pRb(Wt)/p53(Wt) human cancer cell lines MCF7, U2OS and U87 induces S-phase lengthening along with G(1) accumulation. S-phase lengthening is suggested by the discrepancy between the unchanged or even increased percentage of cells in S phase found by flow cytometry DNA content analysis and the drop of BrdU labelling, and demonstrated by IdU/BrdU double labelling. p16(INK4a) induces a profound decrease in the CDK4/6-mediated pRb phosphorylation on Ser-807/811, a downregulation of CDK2 and CDK1 protein expression independently of G(1) accumulation, and a decrease in Thr/Pro phosphorylation in part carried out by CDKs. In MCF7 cells, overexpression of the p16 G101W mutant, which is unable to inhibit CDK4/6 kinase activity and shows a modified subcellular localization, does not provoke the S-phase lengthening and the inhibition of Ser807/811-pRB and of Thr/Pro phosphorylation as wild-type p16(INK4a) does. Our results demonstrate that p16(INK4a) induces a S-phase lengthening independently of cellular origin. The CDK4/6 kinase activity inhibition together with the reduced expression of CDK2 and CDK1 acting downstream of G(1) phase may prevent cells from any possible kinasic compensatory mechanisms, and thus lead to a cell cycle progression inhibition. PMID- 20703085 TI - Catching a glimpse of nucleosome dynamics. PMID- 20703086 TI - miR-33-mediated downregulation of p53 controls hematopoietic stem cell self renewal. AB - Hematopoietic stem cells (HSCs) are defined by their exclusive capacity to both self-renew and to give rise to multipotent progenitors (MPPs) that in turn differentiate into the mature blood cell lineages. The tumor suppressor p53, in addition to its role in the regulation of the cell cycle, plays an important role in HSC self-renewal, although it has not fully resolved. Here we report that in super-p53 mice (sp53), which carry one extra gene dose of p53, the miR-33 is downregulated in HSCs and highly expressed in MPPs. Transplantation assays of miR 33-transduced sp53 HSC results in a significant acquisition of repopulating capacity and a decrease of recipients survival. Moreover, high levels of miR-33 represses the endogenous level of p53 protein in murine embryonic fibroblasts (MEFs), leads both to neoplastic transformation and anchorage independent growth of MEFs, and displays a decrease of apoptotic response using tumor-derived cell lines. Accordingly, we demonstrate that miR-33-mediated downregulation of p53 is dependent on the binding of miR-33 to two conserved motifs in the 3'UTR of p53. Together, these data show that the miR-33 modifies HSC repopulating efficiency of sp53 mice by impairing the p53 function. Defining the role of miR-33 in controlling the HSC self-renewal through p53 may lead to the prevention and treatment of hematopoietic disorders. PMID- 20703087 TI - Methylation of polyphenols with vicinal hydroxyl groups: A protection pathway increasing organismal lifespan. PMID- 20703088 TI - Localization of CDK5 in the midbody and increased aneuploidy in CDK5-/- cells. PMID- 20703089 TI - Nucleostemin: Another nucleolar "Twister" of the p53-MDM2 loop. AB - Several nucleolar proteins, such as ARF, ribosomal protein (RP) L5, L11, L23 and S7, have been shown to induce p53 activation by inhibiting MDM2 E3 ligase activity and consequently to trigger cell cycle arrest and/or apoptosis. Our recent study revealed another nucleolar protein called nucleostemin (NS), a nucleolar GTP binding protein, as a novel regulator of the p53-MDM2 feedback loop. However, unlike other known nucleolar regulators of this loop, NS surprisingly plays a dual role, as both up and downregulations of its levels could turn on p53 activity. Here, we try to offer some prospective views for this unusual phenomenon by reconciling previously and recently published studies in the field in hoping to better depict the role of NS in linking the p53 pathway with ribosomal biogenesis during cell growth and proliferation as well as to propose NS as another potential molecular target for anti-cancer drug development. PMID- 20703091 TI - gammaH2AX: Applications for the evaluation of telomerase-based cancer therapy. PMID- 20703090 TI - Eco1 is important for DNA damage repair in S. cerevisiae. AB - The cohesin network has an essential role in chromosome segregation, but also plays a role in DNA damage repair. Eco1 is an acetyltransferase that targets subunits of the cohesin complex and is involved in both the chromosome segregation and DNA damage repair roles of the network. Using budding yeast as a model system, we find that mutations in Eco1, including a genocopy of a human Roberts syndrome allele, do not cause gross defects in chromosome cohesion. We examined how mitotic and meiotic DNA damage repair is affected by mutations in Eco1. Strains containing mutations in Eco1 are sensitive to DNA damaging agents that cause double-strand breaks, such as X-rays and bleomycin. While meiotic crossing over is relatively unaffected in strains containing the Roberts mutation, reciprocal mitotic crossovers occur with extremely low frequency in this mutant background. Our results suggest that Eco1 promotes the reciprocal exchange of chromosome arms and maintenance of heterozygosity during mitosis. PMID- 20703092 TI - Targeting autophagy to fight hematopoietic malignancies. AB - Macroautophagy, referred hereafter to as autophagy is an evolutionary conserved catabolic process for the degradation and recycling of macromolecules, bulk cytoplasm and dammaged organelles. Autophagy is activated under stress conditions induced by nutrient deprivation, hypoxia and drug treatments. Morphologically, autophagic cells are characterized by the accumulation of double membrane cytoplasmic vesicules called autophagosomes that surrounds cytoplasmic proteins and/or organelles. Autophagosomes next fuse with lysosomes to generate autolysosomes, the structures in which the retained constituents are digested before recycling into the cytoplasm. In this context, autophagy promotes cell survival under adverse conditions. In contrast, under certain circumstances autophagic cells may engage a specific mode of cell death called type II cell death or autophagic cell death (ACD). Considering the strategic positionnement of this process at the crossroads of cell death and survival, it is not surprising that defects in autophagy have been linked to a plethora of human diseases, including hematopoietic malignancies. Finally, autophagy induction is repressed by the mammalian target of rapamycin complex 1 (mTORC1) and favored by the adenosine-monophosphate activated-protein kinase (AMPK). In the present review, we focus on the functions of autophagy in normal and malignant hematopoiesis and discuss the opportunity to target the AMPK/mTOR pathways as a new therapeutic strategy to fight hematopoietic malignancies with a special emphasis on Chronic Myelogenous Leukemia (CML). PMID- 20703093 TI - RAF associates with phosphorylated nuclear BubR1 during endoreduplication induced by JAK inhibition. AB - The role of JAK signaling in cell cycle transit and maintenance of genomic stability was determined in HL-60 human myeloblastic leukemia cells. We have previously reported that a pan-JAK inhibitor caused ERK-dependent endoreduplication. In the current study we find that JAK inhibition caused nuclear re-localization of RAF-1 which could be inhibited by RAF inhibitor GW5074. GW5074 also inhibited JAK inhibitor-induced appearance of nuclear phosphorylated RAF-1(pS621RAF) and MEK; and it inhibited the JAK inhibitor induced co-immunoprecipitation of nuclear RAF-1 and MEK. JAK inhibition also increased nuclear BubR1 phosphorylation, which was diminished by RAF inhibitor GW5074. RAF-1 and BubR1 in the nucleus co-immunoprecipitated; and GW5074 eliminated this. Furthermore, inhibiting RAF with GW5074 blocked the pan-JAK inhibitor-induced endoreduplication. These data thus show that JAK inhibition causes nuclear relocalization and phosphorylation of RAF and MEK where RAF binds BubR1 with ensuing nuclear RAF-dependent BubR1 phosphorylation. Inhibiting RAF inhibited this and endoreduplication. The results suggest that there is a JAK/RAF/MEK/BubR1 axis that can regulate genomic stability. In this hypothetical model JAK suppresses RAF/MEK phosphorylation and nuclear re-localization, but JAK inhibition induces the phosphorylations and relocalization with association of RAF and phosphorylated BubR1 in the nucleus leading to endoreduplication. PMID- 20703095 TI - Induction of cellular apoptosis in human breast cancer by DLBS1425, a Phaleria macrocarpa compound extract, via down-regulation of PI3-kinase/AKT pathway. AB - Phaleria macrocarpa, also known as Mahkota dewa, is an Indonesian native plant that has been used as a remedy for many diseases. However, the molecular mechanism of Phaleria macrocarpa is still limited. In this study, we evaluate its molecular mechanism using a bioactivity-guided DLBS1425, an extract of Phaleria macrocarpa on MDA-MB-231 breast cancer cell line. DLBS1425 exhibited inhibition of proliferative, migratory and invasive potential of MDA-MB-231 in a dose dependent manner, and significantly reduced phosphoinositide-3 (PI3) kinase/protein kinase B (AKT) signalling by reducing PI3K transcript level and subsequent reduction in AKT phosphorylation. Further, it induced pro-apoptotic genes including BAX, BAD and PUMA and consequently induces cellular death signal by caspase-9 activation, promoting PARP cleavage and DNA fragmentation. Our results suggest that DLBS1425 is a potential anticancer agent which targets genes involved in both cell survival and apoptosis in MDA-MB-231 breast cancer cells. PMID- 20703096 TI - Cyclin independent role for cdk4/6 during B cell lymphoma survival. PMID- 20703094 TI - Does Huntingtin play a role in selective macroautophagy? AB - The accumulation of protein aggregates in neurons appears to be a basic feature of neurodegenerative disease. In Huntington's Disease (HD), a progressive and ultimately fatal neurodegenerative disorder caused by an expansion of the polyglutamine repeat within the protein Huntingtin (Htt), the immediate proximal cause of disease is well understood. However, the cellular mechanisms which modulate the rate at which fragments of Htt containing polyglutamine accumulate in neurons is a central issue in the development of approaches to modulate the rate and extent of neuronal loss in this disease. We have recently found that Htt is phosphorylated by the kinase IKK on serine (S) 13, activating its phosphorylation on S16 and its acetylation and poly-SUMOylation, modifications that modulate its clearance by the proteasome and lysosome in cells. In the discussion here I suggest that Htt may have a normal function in the lysosomal mechanism of selective macroautophagy involved in its own degradation which may share some similarity with the yeast cytoplasm to vacuole targeting (Cvt) pathway. Pharmacologic activation of this pathway may be useful early in disease progression to treat HD and other neurodegenerative diseases characterized by the accumulation of disease proteins. PMID- 20703097 TI - New therapies for prostate cancer? PMID- 20703099 TI - Genes essential for cell viability that are linked to tumor suppressor genes play a role in cancer susceptibility. PMID- 20703098 TI - Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence. AB - Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence. This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa. However, the mechanism that switches from cell cycle arrest to apoptosis is still unknown. In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice. p53(R172P) embryonic fibroblasts (MEFs) are hypersensitive to UVB and prematurely senesce after UVB exposure, in stark contrast to wild-type MEFs, which undergo apoptosis. However, these mutant cells are able to repair UV-induced DNA lesions, indicating that the UV hypersensitive phenotype results from the subsequent damage response. Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa. Importantly, p53(R172P) MEFs failed to downregulate anti-apoptotic protein Bcl-2, which has been shown to play an important role in p53-dependent apoptosis. Taken together, these data demonstrate that in the absence of p53-mediated apoptosis, cells undergo cellular senescence to prevent genomic instability. Our results also indicate that p53-dependent apoptosis may play an active role in balancing cellular growth. PMID- 20703100 TI - H2AX post-translational modifications in the ionizing radiation response and homologous recombination. AB - Histone H2AX phosphorylation on a C-terminal serine residue to form "gamma-H2AX" is a critical early event in the chromatin response to chromosomal DNA double strand breaks in eukaryotes. In mammalian cells, gamma-H2AX is formed when H2AX is phosphorylated on serine 139 by ATM or by other DNA damage response kinases. H2AX prevents genomic instability and tumorigenesis, and supports class-switch recombination at immunoglobulin heavy chain loci in mammals. We showed previously that H2AX controls double strand break repair by homologous recombination (HR) between sister chromatids. The HR functions of H2AX are mediated by interaction of gamma-H2AX with the chromatin-associated adaptor protein MDC1. H2AX is potentially subject to additional post-translational modifications associated with the DNA damage response and with other chromatin functions. To test this idea, we used mass spectroscopy to identify H2AX residues additional to serine 139 that are post-translationally modified following exposure of cells to ionizing radiation (IR) and identified several new IR-responsive residues of H2AX. We determined the impact of IR-responsive H2AX residues on cellular resistance to IR and on H2AX-dependent HR, and also analyzed the contribution to HR of other known or potential post-translationally modified residues of H2AX. The results suggest that the HR and IR-resistance functions of H2AX are controlled in large part by specific MDC1-interacting residues of H2AX, but that additional H2AX residues modulate these core functions of H2AX. PMID- 20703101 TI - Theraputic targeting of Trk supresses tumor proliferation and enhances cisplatin activity in HNSCC. AB - Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive disease that has been modestly impacted by improvements in therapeutic strategies. Several lines of evidence support the role of TrkB for invasion and metastasis in various solid tumor models, and we have shown an important function of this receptor in HNSCC tumor biology. Therapeutic modulation of TrkB function has been supported in the literature by the development of small molecule inhibitors (SMI) with minimal success. To assess the validity of targeting TrkB in HNSCC, we tested a novel agent, AZ64 and show significant dose and time dependent inhibition of cellular proliferation in cell lines. Genetic studies revealed the specificity of this compound for the TrkB receptor, as exposure of cells that had genetic suppression of TrkB did not demonstrate abrogated oncogenic signaling. We next assessed the impact of AZ64 as a chemotherapy sensitizer and identified an enhancement of cisplatin-mediated anti-proliferation across all cell lines. We then demonstrated that AZ64 can overcome chemotherapy resistance in a novel model of cisplatin resistance in HNSCC. Modulation of the pro-oncogenic STAT3 and Src pathways was identified, suggesting molecular mechanisms of action for AZ64. In this study, we demonstrate the feasibility of targeting TrkB and suggest a novel approach for the treatment of some chemotherapy-resistant HNSCC. PMID- 20703102 TI - MicroRNA miR-17-5p is overexpressed in pancreatic cancer, associated with a poor prognosis, and involved in cancer cell proliferation and invasion. AB - The microRNA-17-92 cluster is an oncogene in human B cell lymphomas and lung cancers. Previous microRNA microarray data revealed that miR-17-5p, a member of the miR-17-92 cluster, is upregulated in pancreatic cancer. However, the involvement of miR-17-5p expression in pancreatic carcinogenesis has not well been studied. In the present study, we measured the miR-17-5p expression levels in pancreatic cancer cell lines, primary cultures of normal human pancreatic ductal cells, formalin-fixed paraffin-embedded (FFPE) tissue samples derived from 80 patients who underwent pancreatectomy for pancreatic cancer and microdissected cells (including normal ductal epithelial, pancreatic intraepithelial neoplasia 1B and invasive ductal carcinoma cells) by qRT-PCR. Furthermore, we investigated the effects of upregulation of miR-17-5p expression on the proliferation and invasion of pancreatic cancer cells. We found that pancreatic cancer cells expressed higher levels of miR-17-5p than primary cultured normal ductal cells. miR-17-5p was also overexpressed in pancreatic cancer in FFPE and microdissected samples. Furthermore, analysis of macrodissected FFPE samples revealed that high miR-17-5p expression was associated with a poor prognosis (p = 0.03). In addition, in vitro experiments revealed that SUIT-2 and KP-2 pancreatic cancer cells transfected with the miR-17-5p precursor showed significantly higher cell growth ratios than the corresponding control cells (p < 0.001 and p = 0.012, respectively), as well as significantly higher numbers of invading cells (p < 0.0001 for both). The present findings suggest that miR-17-5p plays important roles in pancreatic carcinogenesis and cancer progression, and is associated with a poor prognosis in pancreatic cancer. PMID- 20703103 TI - Pulmonary embolism in young males and females in Germany: data from the Federal Statistical Office. AB - With the introduction of diagnosis-related groups (DRG) for reimbursement in 2003, detailed description of the prevalence of pulmonary embolism in hospitalized patients in Germany was possible for the first time. Thus, we analysed the incidence of pulmonary embolism in hospitalized young people and looked for a sex-specific difference in comorbidity. Detailed lists of all pulmonary embolism coded as I26 in hospitalized patients aged 10-40 years in 2005, 2006 and 2007 were provided by the Federal Statistical Office. Beginning at the age of 12-13 years females have higher numbers of pulmonary embolism and DVT documented as principal diagnosis compared with men. This sex-specific difference disappears at the ages of 32-33 years. The total numbers of pulmonary embolism distinguishing males and females within this 20 years life period is low and varied from 318-463 in the 3 years. The sex-specific difference is highest in the group of 16 to 17-year-old people (ratio of females to males varies from 3 to 5 in 2005-2007). Specific patterns of comorbidities associated with the higher numbers of pulmonary embolism in younger females could not be detected. Pregnancies account for a maximum of 73 in 2007, which reached only less than one fifth of the absolute difference in pulmonary embolism between males and females in the single years. The presented data derived from the most reliable data basis for the estimation of pulmonary embolism in Germany show that compared with males there is a sharp increase in hospitalization for pulmonary embolism in females beginning at the age of 12-13 years. Males catch up by the ages of 32-33 year. PMID- 20703105 TI - Recombinant activated factor VII for hemoperitoneum after transjugular intrahepatic portosystemic shunt. PMID- 20703104 TI - Haematuria in a young patient with severe haemophilia and inhibitor presence receiving prophylactic treatment with recombinant factor VIIa. PMID- 20703107 TI - Nutrition and gastrointestinal tract: still a long way to go, after 10 years. PMID- 20703108 TI - Current world literature. PMID- 20703110 TI - Acute nonvariceal upper gastrointestinal bleeding. AB - PURPOSE OF REVIEW: To review recent literature (2009-2010) on acute nonvariceal upper gastrointestinal hemorrhage. RECENT FINDINGS: There is a decreasing trend in the incidence and hospitalization for acute nonvariceal upper gastrointestinal hemorrhage worldwide, with significant improvement in rebleeding and mortality. One study showed that Glasgow-Blatchford score was superior to Rockall score in predicting the need of intervention or death. None of those categorized as low risk required any intervention. Another database research from United States demonstrated that those managed as outpatients upon clinician decision had 6.3% mortality. Recent meta-analysis demonstrated that epinephrine injection should be used in combination with one other modality for hemostasis in bleeding ulcers, whereas thermal, sclerosant, clips and thrombin/fibrin glue appeared to be effective alone. Despite meta-analysis showing that second look endoscopy with thermal therapy reduced rebleeding, international consensus from experts recommended proton pump inhibitor infusion as the preferred strategy to prevent ulcer rebleeding. SUMMARY: Epidemiological studies worldwide confirmed reduction in the incidence and improvement in clinical outcomes for acute nonvariceal upper gastrointestinal bleeding. Patients categorized as low risk may be managed as outpatients. Endoscopic therapy remained the mainstay of ulcer hemostasis and high dose proton pump inhibitor infusion should be employed to prevent rebleeding. PMID- 20703111 TI - The evolution of endoscopic ultrasound: improved imaging, higher accuracy for fine needle aspiration and the reality of endoscopic ultrasound-guided interventions. AB - PURPOSE OF REVIEW: Endoscopic ultrasound (EUS) is one of the fastest growing areas within gastrointestinal endoscopy. Although the growth in the United States has been steady, EUS is exploding in areas of Asia and Eastern Europe. As utilization of EUS is increasing, so is the evolution of the discipline itself. As a result, it is critically important to periodically review the current state of the art. From its inception, EUS has been primarily utilized for staging cancer, assessment of pancreatic disease and evaluation of submucosal lesions. RECENT FINDINGS: EUS has evolved and is now dominated by the application of EUS guided fine needle aspiration cytology (EUS-FNA), and the newest emerging application is EUS-guided interventions. The recent literature is a reflection of these trends, with some articles devoted to the standard applications for EUS, but most of the emphasis is on EUS-FNA and EUS-guided interventions. SUMMARY: This current review has important clinical implications, as it contains new information on standard applications for endoscopic ultrasound that should be adopted into clinical practice and also provides a glimpse into the future through EUS-guided interventions. PMID- 20703113 TI - Bibliography. Endoscopy. Current world literature. PMID- 20703115 TI - Evaluation of thrombocytopenia in the acute coronary syndrome. AB - PURPOSE OF REVIEW: Thrombocytopenia is relatively common in patients with acute coronary syndromes and is associated with an increased risk of adverse outcomes, regardless of the etiology of the low platelet count. Treatment strategies, both medical and mechanical, may cause thrombocytopenia. This review will introduce a differential diagnosis, diagnostic strategies, and treatment options for patients with an acute coronary syndrome. RECENT FINDINGS: Recent data has strengthened the relationship between thrombocytopenia and adverse outcomes, particularly death and bleeding, in this population of cardiac patients. In addition, bleeding is recognized as a strong independent predictor of an adverse event. Thrombocytopenia may be a marker for acuity of illness and often may be only an association between a low platelet count and therapeutic interventions in this population. Nevertheless, thrombocytopenia due to glycoprotein 2b3a receptor inhibitors, heparins, thienopyridines, and intra-aortic balloon pumps must be recognized and managed appropriately. SUMMARY: Surveillance for and early recognition of thrombocytopenia, an appropriate differential diagnosis, and early institution of treatment are critically important in the management of patients with acute coronary syndromes. PMID- 20703112 TI - Endoscopic mucosal resection and endoscopic submucosal dissection in esophageal and gastric cancers. AB - PURPOSE OF REVIEW: To summarize the literature to date on endoscopic mucosal removal techniques as applied to the upper gastrointestinal tract, predominantly the stomach and esophagus. This is an area that has rapidly advanced in terms of new procedures and techniques with a large body of outcomes that support their use. RECENT FINDINGS: The resection techniques can be divided into two forms, mucosal resection and submucosal dissection. Mucosal resection is typically done with cap techniques and is more suitable for removable of neoplastic lesions that are less than 1.5 cm in size. Submucosal dissection techniques are more difficult, associated with increased complications, and typically reserved for lesions greater than 1.5 cm and less than 3 cm in size. Ideal lesions for mucosal resection are generally flat and are located in areas easily accessible by the endoscope. SUMMARY: Endoscopic tissue removal methods are capable of removing neoplastic lesions en bloc in the upper gastrointestinal tract. These techniques fulfill cancer treatment guidelines by having histological confirmation of total removal of neoplastic lesions with assessment of the margins of resections. Long term clinical outcomes of these techniques are emerging and seem promising in terms of disease-free and overall survival. PMID- 20703116 TI - Bibliography. Hemostasis and thrombosis. Current world literature. PMID- 20703118 TI - Current world literature. PMID- 20703120 TI - Update on botulinum toxin and dermal fillers. AB - PURPOSE OF REVIEW: The art and science of facial rejuvenation is an ever-evolving field of medicine, as evidenced by the continual development of new surgical and nonsurgical treatment modalities. Over the past 10 years, the use of botulinum toxin and dermal fillers for aesthetic purposes has risen sharply. Herein, we discuss properties of several commonly used injectable products and provide basic instruction for their use toward the goal of achieving facial rejuvenation. RECENT FINDINGS: The demand for nonsurgical injection-based facial rejuvenation products has risen enormously in recent years. Used independently or concurrently, botulinum toxin and dermal filler agents offer an affordable, minimally invasive approach to facial rejuvenation. SUMMARY: Botulinum toxin and dermal fillers can be used to diminish facial rhytides, restore facial volume, and sculpt facial contours, thereby achieving an aesthetically pleasing, youthful facial appearance. PMID- 20703123 TI - Plagiarism again. PMID- 20703124 TI - Registered nurses and moral distress. AB - Nurses spend more time with patients at the end of life than any other member of the health care team, giving them early insight into futility-of-care issues for a particular patient. Providing futile care to dying patients is a well-known source of moral distress for nurses. Traditional ethical models are not always effective in dealing with these issues. The purpose of this article was to describe moral distress that is often experienced by nurses providing care to patients at the end of life and to propose the use of a model in dealing with associated ethical dilemmas in an effort to decrease the incidence of moral distress. PMID- 20703125 TI - Monitoring intrathoracic impedance in heart failure patients: implications for inpatient use. AB - Monitoring of intrathoracic impedance to evaluate heart failure status has been used for some years in the outpatient setting. Recent technological advances in pacemaker and internal cardioverter-defibrillator design allow for easier access to that same information in the inpatient setting. This has implications for earlier and more precise recognition and treatment of heart failure in the hospitalized patient and for reducing hospital length of stay. PMID- 20703127 TI - Animal-assisted therapy: evaluation and implementation of a complementary therapy to improve the psychological and physiological health of critically ill patients. AB - Animal-assisted therapy has gained widespread support in a variety of health care settings, including critical care units. This article seeks to review some of the current animal-assisted therapy, define a structured program, and evaluate the potential ability of the therapy to enhance the progress and health of our patients. PMID- 20703128 TI - Coronary artery disease in women: the myth still exists, unfortunately. AB - There is a large media effort available in an effort to increase awareness of coronary artery disease in women. Despite this, there is still a misconception among some people and, unfortunately, some health care providers that heart disease is a man's disease. This article reviews some of the information about women as related to coronary artery disease; a short review of the literature, symptoms, diagnostic tests, and treatment pertinent to women; and action nurses can take to help educate the public, and other health care providers, about this deadly threat. PMID- 20703129 TI - Innovative solutions: sample financial management business plan: neurosurgical intensive care unit. AB - This article describes one institution's intention to implement a financial management business plan for a neurosurgical intensive care unit in a level I trauma center. The financial objective of this proposed business plan includes a service increase in the patient population requiring critical care in a way that will help control costs. PMID- 20703130 TI - Life-support technology and the dying experience: implications for critical-care nursing practice. AB - The purpose of this article was to explore the historical, social, and philosophical factors related to life-support technology and its effects on patients dying in an intensive care unit environment. The article examines how technology has affected the right of individuals to experience a peaceful death. Implications for nursing practice in critical care are also addressed. PMID- 20703132 TI - Nurturing nursing students during intensive care unit clinical practicum. AB - Approximately one-third of new graduates will quit their jobs in the first year. When nurses leave, vacant positions result in increased overtime for the remaining staff, which eventually results in burnout. Burnout leads to even more turnover. This article describes how the staff transformed a neurosurgical intensive care unit and nurture students through the application of Jean Watson's 10 Caritas processes. When nursing students complete their clinical practicum in the unit, learning is enhanced, the students seek to continue to work in the intensive care unit, recruitment and retention are encouraged, and burnout may be prevented. PMID- 20703134 TI - Vulnerable populations in research. AB - Clinical research studies, both nursing and medical, occur in many critical care units. As with any clinical study, it is necessary to obtain informed consent from any person participating in the study. Although many patients are able to agree or refuse to participate in the study, many are unable to do so for a variety of reasons. These patients make up vulnerable populations or people with questionable capacity. This brief article will review patients who may be vulnerable and define the role of the critical-care nurse when caring for these patients. PMID- 20703138 TI - Archibald Edward Garrod and alcaptonuria: "Inborn errors of metabolism" revisited. PMID- 20703139 TI - The Human Genome Project at 10 years: a teachable moment. PMID- 20703142 TI - Pulmonary and systemic expression of monocyte chemotactic proteins in preterm sheep fetuses exposed to lipopolysaccharide-induced chorioamnionitis. AB - Monocyte chemoattractant proteins (MCP-1 and MCP-2) mediate monocyte and T lymphocyte chemotaxis, and IL-1 contributes to the pathogenesis of chorioamnionitis-induced lung inflammation and fetal inflammatory responses. We tested the hypothesis that IL-1 mediates the systemic and pulmonary induction of MCP-1 and MCP-2 in response to lipopolysaccharide (LPS)-induced chorioamnionitis. MCP-1 mRNA, MCP-2 mRNA, and MCP-1 protein expression were measured in two models: 1) intra-amniotic LPS and 2) intra-amniotic recombinant sheep IL-1alpha given at varying intervals before preterm delivery at 124 d GA. Intra-amniotic LPS or IL 1alpha induced MCP-1 mRNA and protein and MCP-2 mRNA in fetal lung many fold at 1 2 d. LPS induced intense MCP-1 expression in subepithelial mesenchymal cells and interstitial inflammatory cells in the lung. Inhibition of IL-1 signaling with recombinant human IL-1 receptor antagonist (rhIL-1ra) did not attenuate LPS induced increase in MCP-1 or MCP-2 expression. MCP-1 and MCP-2 were not induced in liver or chorioamnion, but MCP-1 increased in cord plasma. LPS or IL-1 can induce robust expression of MCP-1 or MCP-2 in the fetal lung. LPS induction of MCP-1 is not IL-1 dependent in fetal sheep. MCP-1 and MCP-2 may be significant contributors to fetal inflammation. PMID- 20703143 TI - Arginine catabolic mobile element is associated with low antibiotic resistance and low pathogenicity in Staphylococcus epidermidis from neonates. AB - The arginine catabolic mobile element (ACME) in Staphylococci encodes several putative virulence factors. ACME appears to have been transferred from Staphylococcus epidermidis into Staphylococcus aureus and is strongly associated with the epidemic and virulent S. aureus USA300. We sought to determine the distribution of ACME in 128 S. epidermidis blood culture isolates from neonates and to assess ACME's impact on antibiotic resistance, biofilm production, invasive capacity, and host inflammatory response. ACME was detected in 15/64 (23%) invasive blood culture isolates and 26/64 (40%) blood culture contaminants (p = 0.02). ACME-positive S. epidermidis isolates displayed less antibiotic resistance (p < 0.001) and were collected from more mature neonates (p = 0.001). Biofilm production was more prevalent among ACME-negative isolates (61/87) compared with ACME positive (18/41; p = 0.004). Among the 64 children considered having an invasive infection, ACME did not influence the maximum C-reactive protein level. In an in vitro whole-blood sepsis model, there were no differences in the inflammatory response between ACME-positive and ACME-negative isolates. We conclude that ACME in S. epidermidis from neonates was associated with less antibiotic resistance and also does not seem to be associated with increased pathogenicity. PMID- 20703145 TI - Using simulation to teach and study healthcare handoffs. PMID- 20703144 TI - Inflammatory response in preterm infants is induced early in life by oxygen and modulated by total parenteral nutrition. AB - The i.v. lipid emulsion (LIP) is a source of oxidants, which may stimulate inflammation. Coadministration of parenteral multivitamins (MVP) with LIP prevents lipid peroxidation in light-exposed total parenteral nutrition (TPN). We hypothesized that this modality of TPN administration affects systemic inflammation, which may be modulated by exposure to oxygen. Premature infants were allocated to three TPN regimens: control regimen - MVP coadministered with amino acid/dextrose exposed to ambient light, LIP provided separately (n = 9) - LIP+MVP light exposed (LE): MVP coadministered with light-exposed LIP (n = 9) - LIP+MVP light protected (LP): MVP coadministered with light-protected LIP (n = 8). In LE and LP, amino acid/dextrose was provided separately. On reaching full TPN, infants were sampled for IL-6 and IL-8 in plasma and the redox potential of glutathione in whole blood (E, mV). Data were compared (ANOVA) in infants exposed to low (<0.25) versus high (> or =0.25) FiO2. Patients (mean +/- SD: birth weight 797 +/- 172 g; GA 26 +/- 1 wk) had similar clinical characteristics in TPN groups. Cytokine levels correlated positively (p < 0.01) with FiO2 and E. High FiO2 stimulated an increase (p < 0.01) in cytokines in control regimen, whereas these markers remained unaffected by oxygen in the LE and LP groups. The choice of a TPN admixture may have important consequences on the systemic inflammatory response triggered by an oxidant stress. PMID- 20703147 TI - Not so fast with the prettiest baby award please! PMID- 20703148 TI - Commentary: Putting evidence to work: an expanded research agenda for academic medicine in the era of health care reform. AB - The historic Patient Protection and Affordable Care Act (HR 3590) signed into law by President Obama has brought into sharp focus the need and opportunity for an expanded continuum of biomedical research. An updated research agenda must build on basic science and classical clinical investigation to place a more deliberate emphasis on patient- and population-outcome-oriented science and to apply science to help transform our current inefficient and expensive health care system into a more evidence-based system of effective, coordinated, safe, and patient-centered health care. If academic medicine is to play a leading role in this 21st-century transformation of health care through research, as it did in the 20th century, those in the community must think strategically about what needs to be done to be part of the solution for transforming the nation's health care delivery systems and prevention strategies, and the changes in institutional, organizational, and individual behaviors and values required to get there. Not all institutions will engage in the science called for in health care reform, but for those institutions with the interest, capacity, and resources to move forward, what is needed? PMID- 20703149 TI - Perspective: The language of leadership. AB - Human meaning is not given before language in and by some detached, prelinguistic domain and then labeled with words. Rather, language itself, always already ardently at play in our lives, is constitutive of the realities of our experience, opening up to us a uniquely human world. Language is the bridge between the created present and the uncreated future, affording leaders of medical schools with an underused opportunity to transform academic medicine. In creating and exchanging meaning, good leaders translate ambiguity into clear messages that convey the rationale for change and enroll others in a compelling strategy that fosters alignment and commitment. Because language influences our thinking and emotions, it is most powerful and effective for tackling challenges that rely heavily on conceptual, innovative solutions as opposed to those problems whose solutions are simple and technical in nature. However, many leaders in academic medicine spend much of their time in the domain of content, where issues are understandable, strategies are familiar, and solutions are seemingly apparent. Complex problems cannot be tackled by solely addressing content; the issue in question must be situated within an appropriate conversational context to provide a basis for action. Leaders do this by creating linguistic distinctions that prompt cognitive shifts in others, jarring them loose from their entrenched worldviews. This property of language--its ability to bring forth, out of the unspoken realm, innovative ideas and possibilities--will determine the future of our health care system and our world. PMID- 20703150 TI - Computerized virtual patients in health professions education: a systematic review and meta-analysis. AB - PURPOSE: Educators increasingly use virtual patients (computerized clinical case simulations) in health professions training. The authors summarize the effect of virtual patients compared with no intervention and alternate instructional methods, and elucidate features of effective virtual patient design. METHOD: The authors searched MEDLINE, EMBASE, CINAHL, ERIC, PsychINFO, and Scopus through February 2009 for studies describing virtual patients for practicing and student physicians, nurses, and other health professionals. Reviewers, working in duplicate, abstracted information on instructional design and outcomes. Effect sizes were pooled using a random-effects model. RESULTS: Four qualitative, 18 no intervention controlled, 21 noncomputer instruction-comparative, and 11 computer assisted instruction-comparative studies were found. Heterogeneity was large (I2>50%) in most analyses. Compared with no intervention, the pooled effect size (95% confidence interval; number of studies) was 0.94 (0.69 to 1.19; N=11) for knowledge outcomes, 0.80 (0.52 to 1.08; N=5) for clinical reasoning, and 0.90 (0.61 to 1.19; N=9) for other skills. Compared with noncomputer instruction, pooled effect size (positive numbers favoring virtual patients) was -0.17 (-0.57 to 0.24; N=8) for satisfaction, 0.06 (-0.14 to 0.25; N=5) for knowledge, -0.004 ( 0.30 to 0.29; N=10) for reasoning, and 0.10 (-0.21 to 0.42; N=11) for other skills. Comparisons of different virtual patient designs suggest that repetition until demonstration of mastery, advance organizers, enhanced feedback, and explicitly contrasting cases can improve learning outcomes. CONCLUSIONS: Virtual patients are associated with large positive effects compared with no intervention. Effects in comparison with noncomputer instruction are on average small. Further research clarifying how to effectively implement virtual patients is needed. PMID- 20703151 TI - An innovative residency program designed to develop leaders to improve the health of children. AB - Physician-leaders are needed to address the widening gap in health disparities in an increasingly complex health care system. To be effective leaders, physicians need specific training; yet despite its importance, leadership training is rarely addressed during graduate medical education. As a result, most physician leadership training occurs after residency training. To address this gap in medical education, in 2004 the authors developed the Pediatric Leadership for the Underserved (PLUS) program at the University of California, San Francisco. The PLUS program incorporates leadership development into the framework of standard clinical training by providing specific sessions in personal leadership development and in related skills such as team building, negotiation, and conflict management. Leadership training is explicitly tied to clinical experiences to maximize relevance and opportunities for "real-time" application of new skills and knowledge. In addition, the curriculum includes sessions to develop and implement a three-year longitudinal child health project. Trainees are organized into advising groups to provide structured faculty and peer-peer advising. Key lessons learned in the implementation include the importance of having a skill-based, rather than a topic-based curriculum, and of exposing trainees to concrete examples of the many career paths of physician-leaders. Early outcomes from 2004 to 2009 include program evaluation data, trainee accomplishments, and postgraduate careers. This paper aims to inform other training programs about the development and feasibility of a residency program that incorporates leadership and underserved medicine curricula into the framework of standard clinical training. PMID- 20703152 TI - Evaluation of orientation strategies in laparoscopic cholecystectomy. AB - OBJECTIVE: Using eye-tracking technology, we aim to examine if there are common patterns of visual attention strategies employed by surgeons which are associated with a greater chance of successful reorientation when disorientated during laparoscopic cholecystectomy. SUMMARY BACKGROUND DATA: Laparoscopic cholecystectomy is one of the most commonly practiced and minimally invasive procedures with a recognized morbidity relating to bile duct injuries. It has been suggested that the majority of bile duct injuries occur as a result of operator disorientation. METHODS: A total of 21 surgeons of varying experience participated in the study. Attention as represented by gaze was captured, as subjects were presented with 8 images of various stages of a laparoscopic cholecystectomy with the task of interpreting the orientation of the image. Subject fixations on relevant anatomic structures within the images were analyzed and a visual behavior profiling algorithm was applied to compare the behavior of individual surgeons. RESULTS: No difference in orientation performance between seniority levels or with laparoscopic experience was found. Key structures used as "anchor objects" to successfully orientate at various stages of a laparoscopic cholecystectomy were unveiled, and a representative successful visual attention behavior for each stage of the operation was described. CONCLUSION: There are discernable and quantifiable visual attention strategies used by surgeons during laparoscopic cholecystectomy associated with successful orientation. By quantifying visual behavior and by inference attention processes of surgeons, this study represents an initial step in attempting to decrease the morbidity associated with disorientation. This study raises some important questions. First, can these common reorientation strategies be taught to aspiring surgeons as part of a curriculum thereby decreasing the learning curve associated with the apparent need for experience in laparoscopy? Second, can these common reorientation strategies be taught to those surgeons who consistently performed below average to increase their performance? PMID- 20703154 TI - New approaches to treating and preventing bone metastases. AB - PURPOSE OF REVIEW: Treatment and prevention of bone metastases is a major problem in patients with cancer. New treatment of bone metastases are needed to maintain the quality of life of our patients with metastastic bone disease. In addition, promising preliminary results suggest that bone-directed therapies may be able to prevent both skeletal and extraskeletal metastases RECENT FINDINGS: For the past decade intravenous bisphosphonates have been the mainstay of treatment of patients with bone metastases. New therapies such as the antibody to RANKL (denosumab) are undergoing phase III clinical testing. In addition, confirmatory studies suggesting that bisphosphonates can prevent metastatic disease are underway. SUMMARY: Understanding the biology of bone metastases has uncovered many new potential therapies for the treatment and prevention of bone metastases. Many of these potential new approaches are discussed in the enclosed article. PMID- 20703155 TI - Current world literature. PMID- 20703156 TI - Ocular surface inflammation mediated by innate immunity. AB - This review addresses three subjects: the innate immunity of the ocular surface epithelium, innate immunity and ocular surface inflammation, and Stevens-Johnson syndrome (SJS) and abnormality of innate immunity. In innate immunity of the ocular surface epithelium, ocular surface epithelial cells respond selectively to microbial components and induce limited inflammation, whereas immune-competent cells such as macrophages can recognize various microbial components through Toll like receptors (TLRs) and induce inflammation to exclude the microbes. The difference between macrophages and ocular surface epithelial cells may be caused by the dissimilarity in the degree of coexistence with commensal bacteria. The unique innate immune response of ocular surface epithelium might contribute to coexistence with commensal bacteria. In innate immunity and ocular surface inflammation, we speculate that an abnormality in the proper innate immunity of the ocular surface may result in ocular surface inflammation. Our investigation shows that TLR3 positively regulates the late-phase reaction of experimental allergic conjunctivitis, which causes reduced eosinophilic conjunctival inflammation in TLR3KO (knockout) mice and pronounced eosinophilic conjunctival inflammation in TLR3Tg mice. We also demonstrate that human ocular surface epithelial cells can be induced to express many transcripts, including antiviral innate immune response-related genes and allergy-related genes, through polyI:C stimulation. Furthermore, we show that IkappaBzeta KO mice exhibit severe, spontaneous ocular surface inflammation accompanied by the eventual loss of almost all goblet cells and spontaneous perioral inflammation. IkappaBzeta is induced by diverse pathogen-associated molecular patterns and regulates nuclear factor-kappaB activity, possibly to prevent excessive inflammation in the presence of bacterial components. The spontaneous ocular surface inflammation observed in IkappaBzeta KO mice suggested that dysfunction/abnormality of innate immunity can play a role in ocular surface inflammation. In SJS and abnormality of innate immunity, we considered the possibility that there may be an association between SJS and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that IL4R gene expression was different in patients with SJS/toxic epidermal necrolysis (TEN) and controls on lipopolysaccharide stimulation, being downregulated in patients with SJS/TEN and slightly upregulated in the controls. The expression of IkappaBzeta- and interleukin (IL)-1alpha-specific mRNA in patients with SJS/TEN was lower than in normal controls after 1-hour culture. Although SJS/TEN can be induced by drugs, not all individuals treated with these drugs developed SJS/TEN. Because the incidence of SJS/TEN is very low, we suspected a genetic predisposition and performed single-nucleotide polymorphism (SNP) association analysis using candidate genes associated with innate immunity, apoptosis, or allergy. We found that TLR3 SNP rs.3775296 and IL4R SNP rs.1801275 (Gln551Arg) were strongly associated (P<0.0005) with SJS/TEN with ocular surface complications, FasL rs.3830150 SNP was mildly associated (P<0.005), and IL13 rs.20541 (Arg110Gln) and IkappaBzeta SNP rs.595788G/A exhibited a weak association (P<0.05). Genetic and environmental factors may play a role in an integrated cause of SJS, and there is the possibility of an association between SJS and a disordered innate immunity. PMID- 20703157 TI - Population dynamics of HIV-1 subtype B in a cohort of men-having-sex-with-men in Rome, Italy. AB - A recent increase in HIV diagnoses among men-having-sex-with-men (MSM) has been shown by surveillance data from Europe and Italy, and new approaches to inferring viral population dynamics from heterochronously sampled gene sequences have been developed. The aim of this study was to reconstruct the epidemiological history of HIV-1 subtype B in a homogeneous group of Italian MSM using a coalescent-based Bayesian framework. A total of 125 HIV-1 subtype B pol sequences were analyzed using Bayesian methods and a relaxed molecular clock to reconstruct their dated phylogeny and estimate population dynamics. At least 10 epidemiological clusters of 3-9 isolates were identified: half including the largest clades originated in the early 1990s and the other half radiated from 1999. Demographic analysis showed that the HIV epidemic grew in accordance with a logistic model characterized by a rapid exponential increase in the effective number of infections (r = 1.54 year) starting from the early 1980s and reaching a plateau 10 years later. Our data suggest that the HIV B epidemic entered our MSM population through multiple transmission chains about 20 years later than in other Western European country. Epidemiological clusters originating in the early 2000s suggest a recent re-emergence of HIV in Italian MSM. PMID- 20703158 TI - Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. AB - BACKGROUND: Maraviroc, the first approved CCR5 antagonist, demonstrated 48-week safety and virologic efficacy in CCR5-tropic HIV-infected, treatment-experienced patients; however, critical longer-term safety and durability of responses are unknown. METHODS: Two-year follow-up of 2 prospective, randomized, blinded studies of maraviroc once daily or twice daily, or placebo in treatment experienced patients with R5-tropic HIV-1 receiving an optimized background regimen. Unblinding occurred after the week-48 visit of the last enrolled patient. Safety and virologic parameters were assessed through week 96. RESULTS: One thousand forty-nine patients were randomized and received study drugs. HIV-1 RNA was <50 copies per milliliter at week 96 in 39% and 41% of patients receiving maraviroc every day or twice a day, respectively. Among patients with HIV-1 RNA <50 copies per milliliter at week 48, 81% and 87% of patients receiving maraviroc every day or twice a day, respectively, maintained this response at week 96. At week 96, median CD4+ T-cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day, respectively. Exposure-adjusted rates of adverse events were similar with maraviroc or placebo. No new or unexpected events were observed after week 48. CONCLUSIONS: Maraviroc containing antiretroviral regimens maintained durable responses in treatment experienced patients with R5 HIV-1 through 96 weeks of treatment with a safety profile similar to placebo. PMID- 20703159 TI - A six-week neuromuscular training program for competitive junior tennis players. AB - This study evaluated the effectiveness of a tennis-specific training program on improving neuromuscular indices in competitive junior players. Tennis is a demanding sport because it requires speed, agility, explosive power, and aerobic conditioning along with the ability to react and anticipate quickly, and there are limited studies that evaluate these indices in young players after a multiweek training program. The program designed for this study implemented the essential components of a previously published neuromuscular training program and also included exercises designed to improve dynamic balance, agility, speed, and strength. Fifteen junior tennis players (10 girls, 5 boys; mean age, 13.0 +/- 1.5 years) who routinely participated in local tournaments and high-school teams participated in the 6-week supervised program. Training was conducted 3 times a week, with sessions lasting 1.5 hours that included a dynamic warm-up, plyometric and jump training, strength training (lower extremity, upper extremity, core), tennis-specific drills, and flexibility. After training, statistically significant improvements and large-to-moderate effect sizes were found in the single-leg triple crossover hop for both legs (p < 0.05), the baseline forehand (p = 0.006) and backhand (p = 0.0008) tests, the service line (p = 0.0009) test, the 1-court suicide (p < 0.0001), the 2-court suicide (p = 0.02), and the abdominal endurance test (p = 0.01). Mean improvements between pretrain and posttrain test sessions were 15% for the single-leg triple crossover hop, 10-11% for the baseline tests, 18% for the service line test, 21% for the 1-court suicide, 10% for the 2-court suicide, and 76% for the abdominal endurance test. No athlete sustained an injury or developed an overuse syndrome as a result of the training program. The results demonstrate that this program is feasible, low in cost, and appears to be effective in improving the majority of neuromuscular indices tested. We accomplished our goal of developing training and testing procedures that could all be performed on the tennis court. PMID- 20703160 TI - The metabolic and muscular differences between two stair-climbing strategies of young adults. AB - When climbing stairs, there are 2 practical strategies, contact each step with alternating feet (single) or contact every other step (double) with alternating feet. Our purpose was to evaluate the metabolic cost and muscular activity of these single and double stair-climbing strategies. We hypothesized that metabolic cost would not differ between the 2 strategies, because the subjects would complete the 2 protocols with a similar speed that would minimize cost. Likewise, we hypothesized that muscle activity during stance would not differ between the 2 stepping strategies. Twelve subjects completed baseline and experimental protocols. For the baseline protocol, the subjects walked up a stairwell with a single-step and a double-step strategy. For the experimental protocol, each subject walked on a treadmill inclined to the same degree as the stairs at the speed and step frequency determined from the baseline protocol. Every subject completed the baseline testing with a faster average speed during the double-step protocol. After mimicking each strategy with our experimental methods, we calculated that the double-step strategy would yield a greater use of metabolic energy, equal to approximately 1.0-1.3 kcalxkg-1xh-1, on average 70-90 additional kcalxh-1. This double-step strategy required a greater activity for propulsion during stance for the ankle and knee extensors. In summary, to maximize metabolic cost and muscular activity, we recommend a double-stair-climbing (skip a step) strategy. PMID- 20703161 TI - Relation between in-game role and service characteristics in elite women's volleyball. AB - The aim of this study was to determine whether the in-game role of players (setter, outside, middle, or opposite player) in elite women's volleyball is significantly related to the characteristics of their service. The sample consisted of 1,300 service deliveries (total serves for all matches) made by players in the 8 teams participating in 2 Final 4 stages of the Indesit European Champions League. The variables recorded were in-game role of the server, service type, speed of delivery, service area, target zone, and effectiveness of delivery. Results showed a significant relation between the server's in-game role and service type (p 0.05) in sprinters vs. untrained subjects. Further comparison of the results of the basal serum T concentration in 8 sprinters showed its significant changes during an annual training period. Significantly higher T concentration during a low-intensity training period (beginning of December) than during heavy sprint specific training period (end of March) was observed in these athletes (n = 8) (mean +/- SD; 23.37 +/- 5.28 vs. 20.99 +/- 4.74 nmol . L(-1), respectively, p = 0.04). We have concluded that basal gonadal hormone concentration in high and top-class athletes (sprinters and jumpers) did not appear to be significantly different when compared with untrained subjects. Moreover, basal T concentration in sprinters can differ significantly during an annual training period. This fact should be taken into consideration when interpreting the results of gonadal hormone status in athletes at varied training stages. PMID- 20703174 TI - Age does not affect exercise intensity progression among women. AB - It has been recommended that the intensity of exercise training (ET) should progress slowly with lower increments in older than in young people. However, scientific evidence supporting this recommendation is lacking. Our aim was to examine possible influences of age on exercise intensity progression in healthy women. Seventeen young (29.1 +/- 5.7 years) and 16 older women (64.5 +/- 4.5 years) underwent 13 weeks of ET consisting of cycle ergometry (CE, 65-75% of reserve heart rate), whole-body resistance exercise (RE, 60% of 1 repetition maximum [1RM]), and stretching. Muscle strength was assessed before and after ET by the 1RM. Cycle ergometry and RE workloads were recorded for each exercise session, and increases of 5-10% were made whenever adaptation occurred. Absolute muscle strength after ET improved (p < 0.001) in both groups, and there were no significant differences between groups. Relative exercise intensity progression was not significantly different between groups for RE (Pearson's correlation = 0.98 +/- 0.01), but it was greater in older women for CE (p = 0.047). The ET was safe because no injuries or major muscle pain was observed in either group. These results suggest that healthy older women are capable of exercising and increasing exercise intensity in the same way as young women. PMID- 20703175 TI - Aerobic, anaerobic, and excess postexercise oxygen consumption energy expenditure of muscular endurance and strength: 1-set of bench press to muscular fatigue. AB - We use a new approach to the estimation of energy expenditure for resistance training involving nonsteady state measures of work (weight * displacement), exercise O2 uptake, blood lactate, and recovery O2 uptake; all lifts were performed to muscular failure. Our intent was to estimate and compare absolute and relative aerobic and anaerobic exercise energy expenditure and recovery energy expenditure. Single-set bench press lifts of ~ 37, ~ 46, and ~ 56% (muscular endurance-type exercise) along with 70, 80, and 90% (strength-type exercise) of a 1 repetition maximum were performed. Collectively, the muscular endurance lifts resulted in larger total energy expenditure (60.2 +/- 14.5 kJ) as compared with the strength lifts (43.2 +/- 12.5 kJ) (p = 0.001). Overall work also was greater for muscular endurance (462 +/- 131 J) as opposed to strength (253 +/- 93 J) (p = 0.001); overall work and energy expenditure were related (r = 0.87, p = 0.001). Anaerobic exercise and recovery energy expenditure were significantly larger for all strength lifts as compared with aerobic exercise energy expenditure (p < 0.001). For the muscular endurance lifts, anaerobic energy expenditure was larger than recovery energy expenditure (p < 0.001) that in turn was larger than aerobic exercise energy expenditure (p < 0.001). We conclude that for a single set of resistance training to fatigue, the anaerobic and recovery energy expenditure contributions can be significantly larger than aerobic energy expenditure during the exercise. To our surprise, recovery energy expenditure was similar both within strength and muscular-endurance protocols and between protocols; moreover, recovery energy expenditure had little to no relationship with aerobic and anaerobic exercise energy expenditure or work. PMID- 20703176 TI - Pharmacological management of migraine headaches. PMID- 20703177 TI - Anatomic and visual outcomes in early versus late macula-on primary retinal detachment repair. AB - PURPOSE: The purpose of this study was to describe the single surgery anatomic success rates and visual outcomes of primary macula-on retinal detachment repaired within 24 hours compared with later than 24 hours. METHODS: This is a retrospective, comparative, interventional, consecutive case series. All eyes underwent primary surgical repair of the macula-on retinal detachment with a scleral buckle, pars plana vitrectomy, or combination of both procedures. The duration from the initial examination to the time of surgical repair was categorized as early (<24 hours) versus late (>24 hours). RESULTS: Sixty-six eyes, 42 phakic and 24 preoperative pseudophakic, had retinal detachment repair with a median time to surgery of 1.0 +/- 2.1 days (0.8 +/- 0.4 days in early group versus 3.7 +/- 2.2 days in late group, P < 0.005). The overall single surgery anatomic success rate was 59 of 66 eyes (89%). The single surgery anatomic success rate between the early (32 of 37 [87%]) versus late (27 of 39 [93%]) repair groups showed no statistical difference (P = 0.45). The mean time of follow-up was 13.1 months (range 0.9-39.2 months) with the mean final logarithm of the minimum angle of resolution best-corrected visual acuity showing no statistical difference between the 2 groups (early [0.10 +/- 0.02] versus late [0.12 +/- 0.03], t-test; P = 0.52). The rates of postoperative glaucoma (P = 0.5) and hemorrhage (P = 0.19) did not differ significantly between the 2 groups. CONCLUSION: Delaying the repair of primary macula-on retinal detachment by more than 24 hours does not appear to cause worse visual or anatomic outcomes compared with early (<24 hours) surgical intervention. There was no significant difference in the complication rates between the two groups. PMID- 20703178 TI - Favorable outcomes with machine perfusion and longer pump times in kidney transplantation: a single-center, observational study. AB - BACKGROUND: Hypothermic machine perfusion (MP) preservation is used for all deceased donor kidney transplants at our center. Kidneys are placed in cold storage at retrieval, then transferred to MP on arrival. Because a lack of consensus regarding optimal use of MP still exists, we evaluated the overall impact of using MP at our center and the prognostic value of MP (Pump) time. METHODS: We retrospectively analyzed 339 adult, primary deceased donor kidney transplant recipients who were pooled across three prospective, randomized immunosuppression trials (since 2000) at our center. In addition to providing overall results for delayed graft function (DGF) (requirement for dialysis in the first week), slow graft function (SGF), first biopsy-proven acute rejection (BPAR), and graft failure, stepwise logistic and Cox regression analyses were used to determine the prognostic value of pump time, particularly after controlling for other significant prognosticators. RESULTS: Mean cold storage and pump times were 6.6 and 26.7 hr, consistent across immunosuppression protocols. Overall DGF and SGF rates were 4.4% (15/339) and 12.1% (41/339). DGF was equally low for pump time less than 24 vs. more than or equal to 24 hr, 5.2% (6/116) vs. 4.0% (9/223) (P=0.63), with similar results after adjusting for known DGF predictors. A significantly lower first BPAR rate was observed for longer pump time (as a continuous variable) among more immunologically active recipients (those having more risk factors: DGF, age <50 yr, and non-white) (univariable P=0.005; multivariable P=0.009), with an estimated hazard ratio of 0.43 (P=0.006) favoring pump time more than or equal to 24 hr among those with more than or equal to two risk factors. CONCLUSIONS.: In this single-center, observational study, MP with prolonged pump times was associated with low DGF/SGF and first BPAR rates, supporting continued use of MP. PMID- 20703179 TI - Prevention and risk factors of the HBV recurrence after orthotopic liver transplantation: 160 cases follow-up study. AB - BACKGROUND: The aim of this study was to analyze the combination with long-term, low-dose hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogs as prophylaxis for hepatitis B virus (HBV) recurrence and to assess the risk factors of HBV recurrence after orthotopic liver transplantation (OLT). METHODS: One hundred sixty patients undergoing OLT with HBV-related liver disease make up the cohort studied. Long-term, low dosage of HBIG in combination with nucleos(t)ide analogs were used as prophylaxis for HBV recurrence after OLT. Patient preoperative data were collected by a retrospective method, and the rate and risk factors of HBV recurrence post-OLT after a long-term follow-up were analyzed. RESULTS: Nineteen patients developed hepatitis B recurrence for a rate of recurrence of 11.88% (19/160). There was no significant correlation between HBV recurrence after OLT and the level of HBV DNA, HBeAg state pre-OLT, or the use of nucleoside analog drug therapy pre-OLT (P>0.05). Of 19 patients with HBV recurrence, 17 patients used Lamivudine, and HBV YMDD mutants were detected in nine cases. The HBV-YMDD mutation was the major reason for recurrence of HBV in our study (P<0.001). CONCLUSIONS: Long-term use of combination prophylaxis with nucleoside analogs and low-dose HBIG can effectively prevent hepatitis B recurrence after OLT, and that a positive preoperative serum HBV DNA status did not affect the recurrence rate of HBV post-OLT. Preoperative nucleoside analogs therapy is unlikely to be obligatory if the patients received effective combination prophylaxis postoperatively. HBV YMDD mutation is the primary reason for HBV recurrence in patients treated with Lamivudine after OLT. PMID- 20703180 TI - Animal models of chronic allograft injury: contributions and limitations to understanding the mechanism of long-term graft dysfunction. AB - Advances in immunosuppression have reduced the incidence of acute graft loss after transplantation, but long-term allograft survival is still hindered by the development of chronic allograft injury, a multifactorial process that involves both immunologic and nonimmunologic components. Because these components become defined in the clinical setting, development of animal models enables exploration into underlying mechanisms leading to long-term graft dysfunction. This review presents animal models that have enabled investigation into chronic allograft injury and discusses pivotal models currently being used. The mechanisms uncovered by these models will ultimately lead to development of new therapeutic options to prevent long-term graft dysfunction. PMID- 20703181 TI - Brucellosis: past, present and future. AB - AIM: To present an overview and the specificities of the biology and epidemiology, pathogenesis and diagnostics, public health aspects, vaccination and control of brucellosis as a global zoonosis. METHODS: Of the various methods to control brucellosis in animals such as vaccination, hygiene, and test and slaughter of infected animals, widespread vaccination is the most rapid, efficient and effective procedure. RESULTS: Despite much progress in the control and sometimes eradication of brucellosis in cattle in many countries, the situation with the disease in small ruminants is proving to be much more difficult. Political and socioeconomic problems are deterrents to success. It is a veterinary responsibility to accept the challenge to control animal brucellosis, which will then control the disease in humans. The success of the control effects will be primarily measured by a decrease in human cases. CONCLUSION: Effective control of brucellosis requires a long-term commitment from many governmental agencies. Assistance from international animal and human health organizations in resources and expertise is necessary in many developing countries. There are no easy solutions. Research on alternative strategies in vaccines and their usage, diagnostic tests, and treatments should be encouraged. PMID- 20703182 TI - Epidemiological and public health aspects of brucellosis in the Republic of Macedonia. AB - AIM: To analyze and present epidemiological patterns of human brucellosis cases and the main factors for the appearance and spread of B. melitensis infection among animals and humans in R. Macedonia in the period from 1980 to 2009. METHODS: Retrospective study based on the epidemiological reports and official data on brucellosis cases from the Institute for Public Health in Skopje and other institutions from the health and veterinary sectors in R. Macedonia, and a review of the relevant literature. RESULTS: From 1980 until December 2009, a total of 11,451 brucellosis cases were reported in R. Macedonia, with a mean annual incidence rate of 18.9/100,000. The highest morbidity rate during this period was recorded in 1992 (922 cases and an incidence rate of 47.6/100,000), and the lowest one in 1983 (12 cases and an incidence rate of 0.6/100,000). From the total number of cases reported in R. Macedonia from 1980 to 2009, 66.2% were males and 33.8% were females. Only 7.2% of patients were under the age of 10, and the most of the patients were from the age group 20-39 (31.9%). Seasonal characteristics of the disease were expressed with the highest occurrence in May (15.9%), June (16.3%) and July (15.1%). Within the total number of 3,284 brucellosis cases in the period 2001-2009, 2320 (70.6%) were from rural settlements and 964 (29.4%) from urban areas. 385 of all cases of brucellosis (8.4%) reported in the period 1998-2009 were from the ranks of professional staff. CONCLUSION: Brucellosis was, currently is and will be a significant disease problem and concern in R. Macedonia which should be approached in a more comprehensive and organized way in the coming years. There is a need to establish intersectoral collaboration by joint efforts of all relevant factors in the prevention and eradication of brucellosis, as well as collaboration between all countries in the SEE region. PMID- 20703183 TI - Epidemiological characteristics of brucellosis in sheep and goats in Bulgaria: 2005-2008. AB - AIM: To analyse and present the epidemiological and epizootological situation of brucellosis in humans, sheep and goats caused by Brucella melitensis. METHODS: The veterinary health services analyzsd epidemiological reports, as well as other official documents, in relation to the epidemiology and the measures undertaken for control of brucellosis in Bulgaria, 2005-08. RESULTS: In Bulgaria animal infections caused by Brucella melitensis have been eradicated since 1941. In 2005 several Bulgarian citizens with Brucella infection were diagnosed in the National Reference Laboratory. All the cases were imported, mostly by employees on sheep and goat farms in Greece. For a period of four years, the number of infected humans was 120 and distributed in 12 districts. Epidemiological investigations suggested that 45 persons (37.5%) were infected in Greece and 4 in Cyprus, Turkey, Italy and Tanzania respectively. All other patients were considered to be infected in Bulgaria. They were owners of infected sheep and goats or consumers of contaminated dairy products with Brucella melitensis. In June 2006, the first outbreaks of brucellosis in sheep and goat farms were recorded in the Smolyan district. By the end of 2008, the infection was registered in 16 villages of 4 districts. The average prevalence rate in the infected herds was 12.2% in goats and 1.8% in sheep. In order to achieve eradication 496 goats and 117 sheep were slaughtered. CONCLUSION: A farm where goats from Greece were introduced illegally in 2005 was identified as the primary source of the infection. the negative epidemiological aspects of free movement of goods and persons in the European Union are considered. PMID- 20703184 TI - Serological diagnosis of brucellosis. AB - AIM: To present a review and to describe the most widely used laboratory tests for serology diagnosis of brucellosis along with their pros and cons. METHODS: Review the recent literature on brucellosis serology diagnostic tests. The choice of the testing strategy depends on the prevailing brucellosis epidemiological situation and the goal of testing. RESULTS: The 'gold standard' for the diagnosis of brucellosis is isolation and identification of the causative bacterium, a member of Brucella sp. Isolation of Brucella sp. requires high security laboratory facilities (biological containment level 3), highly skilled personnel, an extended turnaround time for results and it is considered a hazardous procedure. Hence brucellosis is generally diagnosed by detection of an elevated level of antibody in serum or other body fluid. This is a presumptive diagnosis as other microorganisms and perhaps environmental factors can also cause increased antibody levels. CONCLUSION: A large number of serological tests for brucellosis have been devised over the 100+ years since its initial isolation, starting with a simple agglutination test and progressing to sophisticated primary binding assays available today. However, no test devised to date is 100% accurate so generally serological diagnosis consists of testing sera by several tests, usually a screening test of high sensitivity, followed by a confirmatory test of high specificity. PMID- 20703185 TI - Evaluation of some diagnostic methods for the brucellosis in humans--a five year study. AB - Brucellosis is a worldwide zoonosis with a high degree of morbidity in humans. In Bosnia and Herzegovina a progressive increase of brucellosis among humans is evident. As the clinical picture of human brucellosis is fairly non-specific, a definitive diagnosis requires isolation of the causative organism, or the demonstration of the high levels of specific antibodies, or seroconversion. AIM: To analyse the diagnostic value of the Rose Bengal test, blood culture and immunoenzymatic test (ELISA IgM and IgG) in patients with brucellosis and to examine the relationship between these diagnostic methods. METHODS: We analysed the diagnostic methods in 525 brucellosis patients from 2004 to 2008. All patients were treated at the Infectious Diseases Clinic, University of Sarajevo Clinics Centre. The disease was diagnosed by positive blood culture results and/or by positive relevant serologic test results (ELISA, Rose-Bengal plate agglutination test). RESULTS: In total 162/525 (30.8%) patients had positive blood cultures. The Rose Bengal test was positive in all patients--525/525 (100.0%). Brucella IgM antibodies with ELISA were positive in 341/525 (64.8%). Early in infection, antibodies of the IgM class predominate. Brucella IgG antibodies with ELISA were positive in 236/525 (56%). CONCLUSION: This study clearly showed that only a combination of blood culture, Rose Bengal test and ELISA ensured early and precise diagnosis of human brucellosis. The Rose Bengal test is excellent for screening. Blood culture gave excellent results in patients with primary infections. ELISA(IgM, IgG) is the method of choice for the diagnosis of chronic disease and relapse. PMID- 20703186 TI - Diagnostic validation of ovine and caprine brucellosis using serum- and milk ELISA. AB - AIM: To introduce and validate the new method of diagnosing ovine and caprine brucellosis in a rapid, accurate and inexpensive manner by using i-ELISA (serum/milk) technique. METHODS: Serum and milk samples from brucella RB and CFT negative (n=881) and positive (n=755) animals were used. Standardization of tests was through the Bommeli ELISA-BESW (Brucella Bang) standard and our Institute's (MKD) working standards (positive serum and milk based on B. melitensis antigen). RESULTS: Validation of serum/milk ELISA for detecting ovine and caprine brucellosis was completed. The specificity obtained for the serum ELISA was 99.0% for the Bommeli system (at cut-off of 30% of positivity--PP) and 99.4% for the MKD system (at cut-off 15% PP). The sensitivities of serum ELISAs at the same cut off were 98.5% for the Bommeli and 96.6% for the MKD test. Parallel milk samples from the same animals showed a specificity of 99.5% in the Bommeli system (at cut of 30% PP) and 99.8% in the MKD system (at cut-off 25% PP). The sensitivity of the milk ELISAs were 94.6% for the Bommeli test and 95.6% for the MKD test. CONCLUSION: The Bommeli ELISA and MKD ELISA were successfully standardized and validated as confirmatory tests for the diagnosis of B. melitensis in sheep and goat samples (milk/sera). Using our Institute's milk standard, we confirmed successful screening of brucellosis in pooled milk samples from 100 sheep and 100 goats. PMID- 20703187 TI - Isolation, identification and antimicrobial susceptibility of brucella blood culture isolates. AB - Isolation of slowly growing and fastidious Brucella spp strains from clinical specimens is difficult, because of varying factors, including species specificities, stadium of disease, and previous antibiotic treatment of the patients. The use of automated blood culture systems has overcome some cultivation problems. The automated identification system such as VITEK 2 compact allows more precise identification, as well. AIM: To present our own experience in the isolation of Brucella species from blood cultures, by the Bact/Alert automated system, identification by the VITEK 2 compact system and antimicrobial susceptibility of isolated strains. MATERIAL AND METHODS: Patients from various regions of Macedonia hospitalized in the University Infectious Diseases and Febrile Condition Clinic in Skopje. FAN blood culture bottles (aerobic and anaerobic) of the Bact/Alert system were used, inoculated with 5-10 ml of blood, incubated under continuous agitation and monitored for up to 5 days or until they became positive (in our cases for 2-3 days). Confirmations of all isolates were made by the VITEK 2 automated system on GN cards. RESULTS: During a period of three years, 113 blood cultures from patients with diagnosis of brucellosis hospitalized at the above-mentioned clinic were examined. A total of 16 blood cultures from different patients were positive (14.2%), showing Gram negative bacilli, oxidase positive small colonies on Columbia agar media. The isolates were identified as four biochemically different types of B. mellitensis, mainly within 8 hours. Susceptibility testing by the disk diffusion method on Muller Hinton agar showed sensitivity of all strains to cephalosporin, tetracycline, aminoglycoside and quinolone antibiotic groups. CONCLUSION: With the BacT/Alert system Brucella spp. were isolated in 14.2% of suspected cases of brucellosis. Isolation was done within 2-3 days. Only B. melitensis from the Brucella genus could be identified by the VITEK 2 system and some biochemical differences could be detected. The VITEK 2 system is not able to determine the susceptibility of B. melitensis. The Disk-diffusion method used in this study showed sensitivity to all tested antibiotics, although not recommended by CLSI for the Brucella genus. PMID- 20703188 TI - Evaluation of the Fluorescence Polarization Assay (FPA) for diagnosis of brucella melitensis infection of goats in Argentina. AB - AIM: Determine the optimal cut-off and the use of Fluorescence Polarization Assay (FPA) to improve the detection of brucellosis in individual goats in Argentina. METHODS: Sera from 96 goats from a flock with abortion due to B. melitensis biovar 1 were used to assess the efficacy of the FPA to detect brucellosis in goats. FPA results were compared with those of the Buffered Antigen Plate Agglutination test (BPAT) confirmed by Seroagglutination in tube (SAT), the competitive enzyme-linked immunosorbent assay (c-ELISA) and the indirect enzyme linked immunosorbent assay (i-ELISA). Sera from 554 goats free from brucellosis were tested with the BPAT, SAT, c-ELISA and i-ELISA to determine its Specificity. Vaccination had not been performed in the flocks evaluated. RESULTS: The most appropriate cut-off was selected for the FPA by using MedCalc software. It was fixed at 87 mP giving a sensitivity and specificity of 98.1% (CI 89.9-99.7) and 92.8% (CI 90.4-94.7). The relative sensitivity compared with i-ELISA and c-ELISA was 97% and 92.9% respectively. The relative specificity compared with i-ELISA and c-ELISA was 97.5% and 98% respectively. The kappa measures of agreement between tests was higher than 0.75 CONCLUSION: The high correlation between FPA results and other serological methods with sera goats is indicative of the excellent performance of FPA technique in diagnosis of caprine brucellosis and we endorse it as a recommended method. PMID- 20703190 TI - Insights into the problem of B. Melitensis and rationalizing a vaccination programme in Israel. AB - AIM: To present the problem of brucellosis caused by B. melitensis in Israel and to develop a rationalized control programme and eradication campaign in small ruminants. METHODS: CFT, an OIE prescribed test and a confirmatory method, was used as a confirmatory test in support of legislation to compensate the farmers following a stamping-out policy. Positive reactors were cultured for Brucella spp. in order to establish epidemiological data. Vaccination using Rev. 1 Elberg vaccine strain, passage 101, 1970, has been implemented as an ocular method since November 1997. RESULTS: Brucellosis due to B. abortus in cattle has been eradicated in Israel in beef cattle and in dairy cattle since 1984 and 1985, respectively. B. melitensis has emerged in small ruminants since 1970 and become endemic in the country. An eradication campaign has been carried out since 1993, as an interim programme between 1993 to 1995 and as a full programme up to 1997. The vaccination of pregnant animals has led to abortions and, as a result, this policy was abandoned. To date, only young replacement females are vaccinated. CONCLUSION: Following a national eradication campaign the number of human cases declined significantly but ceasing the campaign has led to re-emergence of the disease. Cattle brucellosis due to B. melitensis has been successfully controlled with limited sporadic emerging events that have occurred since this campaign. A test and slaughter programme that is integrated with due vaccination of young replacement animals is proposed to facilitate control of the disease with the intention of achieving complete eradication. PMID- 20703189 TI - Control and eradication strategies for brucella melitensis infection in sheep and goats. AB - AIM: To describe the various strategies for the control and eradication of B. melitensis infection in sheep and goats. METHODS: The advantages and drawbacks of these strategies are discussed on the basis of the author's personal experience and a revision of the relevant literature. RESULTS: Vaccination programmes in various combinations can be applied either to decrease the prevalence of infection in the animal population or, when combined with adequate complementary eradication measures, to achieve a brucellosis-free status. CONCLUSION: Controlling the disease should be the primary goal of the veterinary services involved. However, eradication should be the final objective of any control programme implemented. The selection of an eradication or control strategy is of paramount relevance, and a frequent cause of controversy among decision-makers. The final strategy should be established according to the quality of the veterinary services organisation, the economic resources available and the extent and prevalence of disease. Cooperation with farmers is essential to succeed with the application of even the most elementary control programme. When brucellosis is highly prevalent, mass (whole-flock) vaccination is the choice to control the disease, independently of the socioeconomic situation. Once effective control of the disease has been accomplished, its eradication is feasible. For successful eradication, the adequate quality and organisation of veterinary services, the strict control of animal movements and the provision of adequate economic compensation to affected farmers are compulsory. When the disease is fully eradicated, a surveillance strategy has to be implemented for the early detection of eventual new outbreaks or disease reintroduction. PMID- 20703191 TI - Brucellosis control in small ruminants in the Republic of Macedonia. AB - AIM: To present the main goals and activities of the strategy for control of brucellosis caused by B. melitensis in sheep and goats in the Republic of Macedonia. METHODS: Relevant documents and reports from the Veterinary Directorate were used to present the approaches for control of the disease in small ruminants in R. Macedonia. The new strategy for control and eradication of brucellosis started its implementation in 2008 with combination of measures for test and slaughter of the sero-positive sheep and goats, mass vaccination and vaccination of young replacements. RESULTS: In 2008, a total of 596,213 animals have been tested in 5,820 flocks out of which 16,853 (2.8%) had Brucella positive results in 636 (10.9%) flocks. In 2009, a total of 543,011 sheep and goats had been tested in 5,507 flocks out of which 9,606 (1.8%) animals showed positive results in 666 (12.1%) flocks. While the number of positive flocks does not indicate great improvement, the individual number of Brucella-positive animals has decreased dramatically. The number of human cases in 2008 and 2009 were 490 and 287 respectively. Direct savings only from compensation to farmers for slaughtered animals for 2008 and 2009 are estimated to be more than 100,000,000 denars (~1.6 million Euro). CONCLUSION: RESULTS from 2009 have been evaluated and foreseen amendments will allow that the country will be systematically divided in a more detailed epidemiological fashion, i.e. division of the country into epidemiological units based on the disease status and accepted risk and implementation of appropriate measures therein. PMID- 20703192 TI - Integrated regional bioengagement framework to combat brucellosis. AB - AIM: To evaluate the current practices in laboratory disease detection, biosafety and biosecurity measures and information-sharing systems available to the public health systems in R. Macedonia and the Balkan region. METHODS: Epidemiological studies were reviewed from the region to examine the high incidence of localized forms of human brucellosis. RESULTS: There is clearly a need for the development of a South Eastern European regional network for sharing information aimed at disease surveillance, early reporting and efficient containment of human brucellosis. Given the zoonotic nature of the disease's onset and progression, public health strategies aimed at containing and eventually eliminating human brucellosis require a broader national and regional bioengagement framework that involves human and veterinary diseases detection systems, deployment of medical countermeasures, epidemiology and a supportive laboratory infrastructure, strategic stockpiles and information sharing. CONCLUSIONS: A systems-centric framework for a national and regional strategy to combat human brucellosis is essential, and should be comprised of: a) a disease threat and surveillance framework at the national and broader regional level, b) laboratory performance evaluation metrics, c) best practices for information-sharing and regional coordination, and d) a coordinated regional strategy to improve biosafety and biosecurity. PMID- 20703193 TI - Brucellosis: new demands in a changing world. AB - AIM: To provide an up-to-date overview on the role of Brucella as a possible biological (B-) agent to be used in biological warfare, biological crimes and biological terrorism (with special respect to agroterrorism) scenarios. METHODS: An analysis of current literature and of Internet-based sources was made. RESULTS: Brucella spp. have always been in the focus of military decision. The main reason for military research on Brucella was driven by the finding that the organism can easily be transmitted via aerosols. Confronted with the new challenge of global terrorism in the last decades of the 20th century, experts tried to evaluate the risk that Brucella spp. are used against the civilian population. Based on criteria concerning public health demands brucellosis was rated to have only a lower medical and public impact. Nevertheless, small-scale outbreaks in humans will pose problems in all those countries where first responders are usually not aware of the clinical syndrome. Countries which have eradicated brucellosis from their livestock successfully may face another severe threat: agroterrorism. Brucella spp. might be introduced intentionally into livestock (cattle, small ruminants, pigs). Undeterminable losses for a state's economy may be the result of such an attack. CONCLUSIONS: The world has become safer in the last decades due to the intensive efforts of the global community to effectively ban the use of weapons of mass destruction. However, bio- and agroterrorism especially an attack against the agricultural infrastructure is considered to be a permanent danger. PMID- 20703194 TI - Brucellosis: need of public health intervention in rural India. AB - AIM: To present the epidemiology of brucellosis and to assess and suggest public health intervention strategies to control brucellosis in rural India. METHODS: The paper is based on a review of various serological and other studies and evidence on brucellosis in India. RESULTS: Brucellosis is present in all livestock systems. Although the true incidence for human brucellosis is not available, various state specific studies and extrapolated incidence (321 cases annually) have shown that it is a serious disease present in the population. The studies also show that there is a conducive condition and environment for wide spread human infection on account of unhygienic conditions and poverty in rural areas which need public health attention and intervention. CONCLUSION: The paper suggests that brucellosis needs to be included in public health education and public awareness programmes, particularly in the rural areas of India. It also suggests promoting safe livestock practices, active co-operation between health and veterinary services and a paradigm shift from the current 'biomedical model' to a 'sociocultural model' for the elimination of brucellosis in India. PMID- 20703195 TI - My Mother's Levetiracetam. PMID- 20703196 TI - Play it Again: The Master Psychopharmacology Program as an Example of Interval Learning in Bite-Sized Portions. PMID- 20703197 TI - One-year open-label safety and efficacy study of paliperidone extended-release tablets in patients with schizophrenia. AB - INTRODUCTION: This 52-week open-label extension (OLE) to a double-blind placebo controlled recurrence prevention study examined the long-term safety and efficacy of flexibly-dosed paliperidone extended-release (ER) tablets in patients with schizophrenia. METHODS: Patients entering the OLE either entered from the double blind phase (placebo or paliperidone ER treatment) or entered directly from the run-in or stabilization phase (paliperidone ER) of the earlier study. During the OLE, patients were treated with flexibly-dosed paliperidone ER (3-15 mg/day; 9 mg starting dose). Safety and tolerability assessments included incidence of adverse events and extrapyramidal symptoms. Efficacy was also assessed. RESULTS: The study population (n=235) was predominantly men (66%), 18-58 years of age. Twelve patients (5%) experienced an adverse event requiring treatment discontinuation. One or more serious treatment-emergent adverse events were reported in 13 patients (6%). There was one death. The mean Positive and Negative Syndrome Scale total score decreased from open-label baseline to endpoint for all groups, regardless of previous double-blind treatment (placebo or paliperidone ER). CONCLUSION: This year-long OLE provides information on the long-term safety and tolerability of paliperidone ER in patients with schizophrenia. The resulting safety and tolerability profile was similar to that seen in earlier short-term studies. PMID- 20703199 TI - A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder. AB - Although cognitive-behavioral therapy (CBT) is an effective treatment for posttraumatic stress disorder (PTSD), many patients fail to attain remission with CBT. The authors propose augmentation of CBT with oxytocin in the treatment of PTSD. Oxytocin has a combination of pharmacologic effects that result in a "sense of safety" for the patient, which is a prerequisite to successful treatment of PTSD. We suggest a dual explanatory mechanism as to why oxytocin may be effective: through a reduction of fear response (decreasing amygdala activation, inhibiting fear response, and enhancing extinction learning) and through an increase of social interaction (activating social reward-related brain regions increasing engagement in the therapeutic alliance). Given that PTSD is marked by deficits in anxiety/stress regulation and in social functioning, and that oxytocin is implicated in both of these areas, oxytocin seems a likely candidate for treatment of patients with PTSD. Further clinical studies of the therapeutic value of oxytocin are indicated. PMID- 20703198 TI - Psychoticism and paranoid ideation in patients with nonpsychotic major depressive disorder: prevalence, response to treatment, and impact on short- and long-term treatment outcome. AB - Objective/Introduction: We sought to characterize the impact of the 90-item Symptom Checklist (SCL-90) subscales for paranoid ideation (PI) and psychoticism (P) in patients with major depressive disorder (MDD), on acute antidepressant response and on relapse prevention. METHODS: Subjects with Structured Clinical Interview for DSM Disorders-diagnosed nonpsychotic MDD were recruited into a clinical trial of open-label fluoxetine 10-60 mg/day for 12 weeks, followed by double-blind randomization of responders (n=262) to fluoxetine continuation or placebo for 12 months. PI and P were assessed with the patient-rated SCL-90. The association of these symptoms with response to treatment was assessed by logistic regression. RESULTS: We found significant decreases in PI and P during acute treatment phase for fluoxetine responders and nonresponders, although only 10.3% and 7.5% of patients experienced a >50% reduction in PI and P scores, respectively. Neither PI nor P scores significantly predicted time to relapse. P scores predicted a lower response rate to treatment with fluoxetine. DISCUSSION: The results of the present study suggest that there is a significant relationship between the presence of psychoticism in patients with nonpsychotic MDD, and the likelihood of overall depressive symptom improvement following a trial of monotherapy with fluoxetine. CONCLUSION: An increased burden of psychoticism in depressed subjects may confer poorer response to fluoxetine, but not increased risk of relapse among fluoxetine responders. PMID- 20703200 TI - Burst transcranial magnetic stimulation for the treatment of tinnitus. PMID- 20703201 TI - Response from the author. PMID- 20703202 TI - Lamotrigine-associated Depersonalization Symptoms. PMID- 20703203 TI - Auditory hallucinations associated with headaches following traumatic brain injury. PMID- 20703204 TI - Surveillance for foodborne disease outbreaks --- United States, 2007. AB - Foodborne agents cause an estimated 76 million illnesses annually in the United States. Outbreak surveillance provides insights into the causes of foodborne illness, types of implicated foods, and settings of foodborne infections that can be used in food safety strategies to prevent and control foodborne disease. CDC collects data on foodborne disease outbreaks submitted from all states and territories. This report summarizes epidemiologic data for the 1,097 reported outbreaks occurring during 2007 (the most recent finalized data), which resulted in 21,244 cases of foodborne illness and 18 deaths. Among the 497 foodborne outbreaks with a laboratory-confirmed single etiologic agent reported, norovirus was the most common cause, followed by Salmonella. Among the 18 reported deaths, 11 were attributed to bacterial etiologies (five Salmonella, three Listeria monocytogenes, two Escherichia coli O157:H7, and one Clostridium botulinum), two to viral etiologies (norovirus), and one to a chemical (mushroom toxin). Four deaths occurred in outbreaks with unknown etiologies. Among the 235 outbreaks attributed to a single food commodity, poultry (17%), beef (16%), and leafy vegetables (14%) were most often the cause of illness. Public health, regulatory, and agricultural professionals can use this information when creating targeted control strategies and to support efforts to promote safe food preparation practices among food employees and the public. PMID- 20703205 TI - CDC Grand Rounds: additional opportunities to prevent neural tube defects with folic acid fortification. AB - Neural tube defects (NTDs) are serious birth defects that result from the failure of the neural tube to close in the cranial region (anencephaly) or more caudally along the spine (spina bifida) by the 28th day of gestation. Infants born with anencephaly usually die within a few days of birth, and those with spina bifida have life-long disabilities with varying degrees of paralysis. Currently, identified risk factors for NTDs include a mother who previously had an NTD affected pregnancy, maternal diabetes, obesity, hyperthermia, certain antiseizure medications, genetic variants, race/ethnicity, and nutrition (particularly folic acid insufficiency). In the United States, during 1995-1996, approximately 4,000 pregnancies were affected by an NTD. This number declined to 3,000 pregnancies in 1999-2000 after fortification of enriched cereal grain products with folic acid was mandated. Worldwide, in 1998, approximately 300,000 births were affected by an NTD. PMID- 20703206 TI - Completion of national laboratory inventories for wild poliovirus containment --- region of the Americas, March 2010. AB - In May 1988, the World Health Assembly resolved to eradicate wild poliovirus (WPV) transmission globally. By 2006, transmission of indigenous WPV was eliminated in all but four countries (Afghanistan, India, Nigeria, and Pakistan). In May 1999, the World Health Assembly urged member states to begin the process leading to laboratory containment of WPV. Containment of infectious and potentially infectious WPV materials after eradication is essential to minimize the risk for reintroducing WPV into poliomyelitis-free communities. The staged containment approach begins with a national survey of all biomedical facilities, which alerts facilities to the need for containment, encourages reduction of WPV materials, and develops a national inventory of facilities holding such materials (Phase I). In May 2008, the World Health Assembly reiterated the need for progress in containment and urged polio-free states to complete Phase I. This report describes completion of Phase I by the countries and territories in the World Health Organization (WHO) Region of the Americas during 2001-2010. Of 67,362 biomedical facilities, all 15,541 (23.1%) that were classified as high risk or medium-risk facilities were surveyed. Of the remaining 51,821 (76.9%) facilities, all classified as low-risk, 44,077 (85.1%) were surveyed; sampling ranged from 12.8% to 100% among countries. After voluntary destruction of some materials during Phase I, a total of 215 facilities in nine countries of the Region of the Americas reported retaining WPV materials as of March 2010. The survey provides a facility registry for use in subsequent steps that will lead to global poliovirus containment. PMID- 20703210 TI - Retraction. A microarray study of altered gene expression in Ara-C resistance in acute myeloid leukemia. PMID- 20703207 TI - Update: Recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010-11. AB - During the 2010 influenza season in Australia, administration of a 2010 Southern Hemisphere seasonal influenza trivalent inactivated vaccine (TIV) (Fluvax Junior and Fluvax) manufactured by CSL Biotherapies was associated with increased frequency of fever and febrile seizures in children aged 6 months through 4 years. Postmarketing surveillance indicated increased reports of fever in children aged 5-8 years after vaccination with Fluvax compared to previous seasons. An antigenically equivalent 2010-11 Northern Hemisphere seasonal influenza TIV (Afluria) manufactured by CSL Biotherapies is approved by the Food and Drug Administration (FDA) for persons aged >or=6 months in the United States. Prescribing information for the 2010-11 Afluria formulation includes a warning that "Administration of CSL's Southern Hemisphere influenza vaccine has been associated with increased postmarketing reports of fever and febrile seizures in children predominantly below the age of 5 years as compared to previous years". In the United States, annual influenza vaccination is recommended for all persons aged >or=6 months. On August 5, 2010, the Advisory Committee on Immunization Practices (ACIP) recommended that the 2010-11 Afluria vaccine not be administered to children aged 6 months through 8 years. Other age-appropriate, licensed seasonal influenza vaccine formulations should be used for prevention of influenza in these children. If no other age-appropriate, licensed inactivated seasonal influenza vaccine is available for a child aged 5-8 years who has a medical condition that increases their risk for influenza complications, Afluria can be used; however, providers should discuss with the parents or caregivers the benefits and risks of Afluria use before administering this vaccine to children aged 5-8 years. PMID- 20703212 TI - New paradigms in cell death in human diabetic nephropathy. AB - Cell death is thought to contribute to progressive renal cell depletion in diabetic nephropathy. Unbiased gene expression profiling identified novel cell death molecules in human diabetic nephropathy. The expression of TNF-related apoptosis-inducing ligand (TRAIL), its decoy receptor osteoprotegerin, and receptors Fas (a Fas ligand receptor) and CD74 (a migration inhibitory factor (MIF) receptor) were induced in human diabetic nephropathy. Cell culture studies supported the functional relevance of this observation and the relationship to a high glucose environment. To define novel proapoptotic proteins upregulated in diabetic nephropathy, functional genomic screens for novel apoptosis mediators were integrated with genome-wide expression profiling and identified candidates for further functional analysis, including brain acid-soluble protein 1 (BASP1). Several lines of evidence point toward induction of endoplasmic reticulum stress response in human diabetic nephropathy. Functional studies defining an unequivocal contribution of endoplasmic reticulum stress to cell death in this setting are still needed. Further comparative studies will be required to define whether there is a specific aspect of apoptosis in progressive human diabetic nephropathy or whether the mechanisms are shared among all patients with chronic kidney disease. The next challenge will be to define the consequence of therapeutic interference of the apoptosis pathways in diabetic nephropathy and chronic kidney disease. PMID- 20703211 TI - Maintenance immunosuppressive therapy with everolimus preserves humoral immune responses. AB - While the guidelines for vaccination in renal transplant recipients recommend the use of pneumococcal polysaccharide (PPS) and tetanus toxoid (TT), their efficacy in immunocompromised renal transplant recipients is not known. Here we tested the effect of everolimus on immune responses after vaccination by measuring the capacity of 36 stable renal transplant recipients to mount cellular and humoral responses after vaccination. Twelve patients in each treatment arm received immunosuppressive therapy consisting of prednisolone (P) plus cyclosporine (CsA), mycophenolate sodium (MPA), or everolimus. Patients were vaccinated with the T cell-dependent antigens immunocyanin and TT, and the T-cell-independent PPS. Treatment with CsA partially inhibited and MPA completely abolished the capacity to mount a primary humoral response, whereas everolimus left this largely intact. Recall responses were inhibited by MPA only. All drug combinations inhibited cellular responses against TT. In patients treated with MPA, B-cell numbers were severely reduced. Thus, combined with P, treatment with MPA completely disturbed primary and secondary humoral responses. Everolimus or CsA allowed the boosting of T-cell-dependent and -independent secondary humoral responses. Treatment with everolimus allowed a primary response. PMID- 20703213 TI - The width of the basement membrane does not influence clinical presentation or outcome of thin glomerular basement membrane disease with persistent hematuria. AB - Thin basement membrane disease (TBMD) typically presents with persistent microscopic hematuria, and is usually defined as a glomerular basement membrane (GBM) thickness < 250 nm. Previous studies showed that neither the degree of thinning nor the extent of the abnormality correlate with the patient's clinical presentation or prognosis. To further define this, we enrolled a study group of 41 patients with isolated microscopic hematuria and a normal renal biopsy, except those with a GBM thickness of 250-320 nm, and compared them with 33 patients with traditional TBMD. We found no difference in baseline demographic or clinical parameter between the groups. After follow-up averaging 110 months, there was no significant difference in the risk of detectable or overt proteinuria, hypertension, or impaired renal function between the groups. By the end of the study, only five patients from the study group and four from the TBMD group had no outcome event. By Cox regression analysis, independent predictors of overt proteinuria were male gender, age at biopsy, baseline renal function, proteinuria, and hypertension. Age at biopsy was the only independent predictor for hypertension, and baseline proteinuria was the only independent predictor for impaired renal function. GBM thickness did not predict any outcome event. Hence, lifelong follow-up is advised, as the clinical features and prognosis of these patients with persistent microscopic hematuria and marginally thin GBM are similar to traditional TBMD. PMID- 20703214 TI - Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is associated with complement alternative pathway defects in over half the cases. Point mutations that affect complement surface regulation are common in factor H (CFH); however, sometimes individuals have null mutations in heterozygosis. The latter are difficult to identify, although a consistently low plasma factor H (fH) concentration is suggestive; definitive proof requires demonstration that the mutant sequence is not expressed in vitro. Here, novel reagents and assays that distinguish and individually quantify the common factor H-Y402H polymorphic variants were used to identify alleles of the CFH gene, resulting in low or null expression of full length fH and also normal or increased expression of the alternative splice product factor H-like-1 (FHL-1). Our assay identified three Y402H heterozygotes with low or absent fH-H402 but normal or increased FHL-1-H402 levels in a cohort of affected patients. Novel mutations explained the null phenotype in two cases, which was confirmed by family studies in one. In the third case, family studies showed that a known mutation was present on the Y allele. The cause of reduced expression of the H allele was not found, although the data suggested altered splicing. In each family, inheritance of low expression or null alleles for fH strongly associated with aHUS. Thus, our assays provide a rapid means to identify fH expression defects without resorting to gene sequencing or expression analysis. PMID- 20703215 TI - Acid regulation of NaDC-1 requires a functional endothelin B receptor. AB - Metabolically generated acid is the major physiological stimulus for increasing proximal tubule citrate reabsorption, which leads to a decrease in citrate excretion. The activity of the Na-citrate cotransporter, NaDC-1, is increased in vivo by acid ingestion and in vitro by an acidic pH medium. In opossum kidney cells the acid stimulatory effect and the ability of endothelin-1 (ET-1) to stimulate NaDC-1 activity are both blocked by the endothelin B (ET(B)) receptor antagonist, BQ788. Acid feeding had no effect on brush border membrane NaDC-1 activity in mice in which ET(B) receptor expression was knocked out, whereas a stimulatory effect was found in wild-type mice. Using ET(A)/ET(B) chimeric and ET(B) C-terminal tail truncated constructs, ET-1 stimulation of NaDC-1 required a receptor C-terminal tail from either ET(A) or ET(B). The ET-1 effect was greatest when either the ET(B) transmembrane domain and C-terminal tail were present or the ET(B) C-terminal tail was linked to the ET(A) transmembrane domain. This effect was smaller when the ET(B) transmembrane domain was linked to the ET(A) C terminal tail. Thus, the acid-activated pathway mediating stimulation of NaDC-1 activity requires a functional ET(B) receptor in vivo and in vitro, as does acid stimulation of NHE3 activity. Since increased NaDC-1 and NHE3 activities constitute part of the proximal tubule adaptation to an acid load, these studies indicate that there are similarities in the signaling pathway mediating these responses. PMID- 20703216 TI - Exosomes/microvesicles as a mechanism of cell-to-cell communication. AB - Microvesicles (MVs) are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes of most cell types. An increasing body of evidence indicates that they play a pivotal role in cell-to-cell communication. Indeed, they may directly stimulate target cells by receptor-mediated interactions or may transfer from the cell of origin to various bioactive molecules including membrane receptors, proteins, mRNAs, microRNAs, and organelles. In this review we discuss the pleiotropic biologic effects of MVs that are relevant for communication among cells in physiological and pathological conditions. In particular, we discuss their potential involvement in inflammation, renal disease, and tumor progression, and the evidence supporting a bidirectional exchange of genetic information between stem and injured cells. The transfer of gene products from injured cells may explain stem cell functional and phenotypic changes without the need of transdifferentiation into tissue cells. On the other hand, transfer of gene products from stem cells may reprogram injured cells to repair damaged tissues. PMID- 20703217 TI - Sirolimus for calcineurin inhibitors in organ transplantation: contra. AB - Sirolimus (SRL) is an antiproliferative agent inhibiting the mammalian target of rapamycin (mTOR) proposed as a non-nephrotoxic alternative to calcineurin inhibitors for the prevention of acute rejection in renal transplantation. Despite initial encouraging results, enthusiasm faded with large trials showing an increased risk of acute rejection with this molecule that did not provide superior graft function over cyclosporin or tacrolimus. Recent data showed that SRL, along with an immunosuppressive activity on CD4+ T cells, exerts a paradoxical stimulatory effect on innate immunity, which may explain its incomplete control of alloimmune response. Moreover, SRL therapy is burdened by a concerning safety profile including high risk of delayed graft function and onset of proteinuria. This adds to many other adverse effects, including dyslipidemia, diabetes, myelosuppression, delayed wound healing, infertility, ovarian cysts, and mouth ulcers, that further limit the use of this molecule. Severe cases of interstitial pneumonia have also been reported with this therapy, raising additional concerns. Incomplete control of immune response, along with a poor tolerability, makes SRL far from being the ideal antirejection drug. Progressive restrictions of SRL indication in renal transplantation have, however, been paralleled by evidence showing mTOR abnormalities involved in many pathogenic conditions, thus opening the avenue to new possible applications of this molecule. PMID- 20703218 TI - Novel functions for NFkappaB: inhibition of bone formation. AB - NFkappaB is a family of transcription factors involved in immunity and the normal functioning of many tissues. It has been well studied in osteoclasts, and new data indicate an important role for NFkappaB in the negative regulation of bone formation. In this article, we discuss how NFkappaB activation affects osteoblast function and bone formation. In particular, we describe how reduced NFkappaB activity in osteoblasts results in an increase in bone formation via enhanced c Jun N-terminal kinase (JNK) activity, which regulates FOSL1 (also known as Fra1) expression. Furthermore, we discuss how estrogen and NFkappaB crosstalk in osteoblasts acts to oppositely regulate bone formation. Future NFkappaB-targeting treatments for osteoporosis, rheumatoid arthritis and other inflammatory bone diseases could lead to increased bone formation concurrent with decreased bone resorption. PMID- 20703220 TI - Assessing microvascular changes in systemic sclerosis diagnosis and management. AB - Microvascular damage and dysfunction represent the earliest morphological and functional markers of systemic sclerosis (SSc), a progressive connective tissue disease characterized by vascular abnormalities and diffuse fibrosis in the skin and internal organs. These early microvascular changes are clinically mirrored by Raynaud phenomenon, which can be primary (idiopathic) or secondary to several different conditions including SSc. Morphological and functional assessment of the cutaneous microvasculature have crucial implications for diagnosis, prognosis and therapy in SSc and secondary Raynaud phenomenon. Most importantly, imaging with nailfold videocapillaroscopy (NVC) enables the early differentiation between primary and secondary Raynaud phenomenon by identifying morphological patterns specific to various stages of SSc ('early', 'active' and 'late' patterns); the inclusion of these NVC patterns could increase the sensitivity of classification criteria for SSc. Findings on NVC are also markers of SSc severity and progression, as reduced capillary density has been associated with a high risk of developing digital skin ulcers and pulmonary arterial hypertension. Laser Doppler imaging and thermal imaging demonstrate the dysfunctional cutaneous blood flow in response to cold stimuli. Therapies targeting underlying vascular disease in SSc have been successfully designed to improve the symptoms of Raynaud phenomenon and to reduce ischemic injury to involved organs, and NVC patterns have been found to improve following targeted therapy; however, treatment of later fibrosis remains a challenge. PMID- 20703219 TI - Inherited human diseases of heterotopic bone formation. AB - Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation-fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells. PMID- 20703221 TI - Neural substrates of attentional bias for smoking-related cues: an FMRI study. AB - Attentional bias for drug-related stimuli, as measured by emotional Stroop (ES) tasks, is predictive of treatment outcomes for tobacco smoking and other abused drugs. Characterizing relationships between smoking-related attentional bias and brain reactivity to smoking images may help in identifying neural substrates critical to relapse vulnerability. To this end, we investigated putative relationships between interference effects in an offline smoking ES task and functional MRI (fMRI) measures of brain reactivity to smoking vs neutral images in women smokers. Positive correlations were found between attentional bias and reactivity to smoking images in brain areas involved in emotion, memory, interoception, and visual processing, including the amygdala, hippocampus, parahippocampal gyrus, insula, and occipital cortex. These findings suggest that smokers with elevated attentional biases to smoking-related stimuli may more readily shift attention away from other external stimuli and toward smoking stimuli-induced internal states and emotional memories. Such attentional shifts may contribute to increased interference by smoking cues, possibly increasing relapse vulnerability. Treatments capable of inhibiting shifts to drug cue induced memories and internal states may lead to personalized tobacco dependence treatment for smokers with high attentional bias to smoking-related stimuli. PMID- 20703223 TI - Inflammatory mediators may have divergent roles in cancer and in Alzheimer's disease. PMID- 20703222 TI - Effect of single-dose rifampin on the pharmacokinetics of warfarin in healthy volunteers. AB - Based on in vitro rat and human hepatocyte uptake studies showing inhibition of warfarin uptake in the presence of the nonspecific organic anion-transporting polypeptide (OATP) inhibitor rifampin, a clinical study was conducted in 10 healthy volunteers to examine the in vivo relevance of OATP hepatic uptake on the pharmacokinetics of warfarin. In a randomized, single-dose, two-period, crossover design, subjects received a 7.5-mg dose of warfarin, either alone or immediately following a 600-mg intravenous dose of rifampin. Rifampin did not significantly alter the R- or S-warfarin area under the concentration-time curves (AUCs) from 0 to 12 h (period of hepatic OATP inhibition by rifampin) or the maximum plasma concentration (C(max)) value. AUC(0-infinity) was decreased on days rifampin was administered, for both R-warfarin (25% reduction; P < 0.001) and S-warfarin (15% reduction; P < 0.05). No differences were seen in the area under the international normalized ratio (INR)-time curve. Our study suggests that hepatic uptake via OATPs may not be clinically important in the pharmacokinetics of warfarin. PMID- 20703224 TI - Academic medical centers and the pharmaceutical industry. PMID- 20703225 TI - Are we prepared to deal with the Alzheimer's disease pandemic? PMID- 20703226 TI - Statistical inference for noisy nonlinear ecological dynamic systems. AB - Chaotic ecological dynamic systems defy conventional statistical analysis. Systems with near-chaotic dynamics are little better. Such systems are almost invariably driven by endogenous dynamic processes plus demographic and environmental process noise, and are only observable with error. Their sensitivity to history means that minute changes in the driving noise realization, or the system parameters, will cause drastic changes in the system trajectory. This sensitivity is inherited and amplified by the joint probability density of the observable data and the process noise, rendering it useless as the basis for obtaining measures of statistical fit. Because the joint density is the basis for the fit measures used by all conventional statistical methods, this is a major theoretical shortcoming. The inability to make well-founded statistical inferences about biological dynamic models in the chaotic and near-chaotic regimes, other than on an ad hoc basis, leaves dynamic theory without the methods of quantitative validation that are essential tools in the rest of biological science. Here I show that this impasse can be resolved in a simple and general manner, using a method that requires only the ability to simulate the observed data on a system from the dynamic model about which inferences are required. The raw data series are reduced to phase-insensitive summary statistics, quantifying local dynamic structure and the distribution of observations. Simulation is used to obtain the mean and the covariance matrix of the statistics, given model parameters, allowing the construction of a 'synthetic likelihood' that assesses model fit. This likelihood can be explored using a straightforward Markov chain Monte Carlo sampler, but one further post-processing step returns pure likelihood based inference. I apply the method to establish the dynamic nature of the fluctuations in Nicholson's classic blowfly experiments. PMID- 20703227 TI - Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. AB - The use of homologous recombination to modify genes in embryonic stem (ES) cells provides a powerful means to elucidate gene function and create disease models. Application of this technology to engineer genes in rats has not previously been possible because of the absence of germline-competent ES cells in this species. We have recently established authentic rat ES cells. Here we report the generation of gene knockout rats using the ES-cell-based gene targeting technology. We designed a targeting vector to disrupt the tumour suppressor gene p53 (also known as Tp53) in rat ES cells by means of homologous recombination. p53 gene-targeted rat ES cells can be routinely generated. Furthermore, the p53 gene-targeted mutation in the rat ES-cell genome can transmit through the germ line via ES-cell rat chimaeras to create p53 gene knockout rats. The rat is the most widely used animal model in biological research. The establishment of gene targeting technology in rat ES cells, in combination with advances in genomics and the vast amount of research data on physiology and pharmacology in this species, now provide a powerful new platform for the study of human disease. PMID- 20703228 TI - Usefulness of assessing masked and white-coat hypertension by ambulatory blood pressure monitoring for determining prevalent risk of chronic kidney disease: the Ohasama study. AB - Masked hypertension (MHT) is considered to be associated with organ damage, whereas the association of white-coat hypertension (WCHT) with organ damage remains controversial. Using home blood pressure measurements, we have previously reported that MHT is associated with a risk of chronic kidney disease (CKD) compared with sustained normal blood pressure (SNBP), although WCHT was not significantly related to CKD in a general Japanese population. The objective of this study was to examine CKD risk associated with WCHT and MHT as determined by ambulatory blood pressure (ABP) monitoring. Among 1023 residents in the general Japanese population of Ohasama, ABP and casual blood pressure (CBP) levels were recorded and blood and urine samples were collected. CKD was defined as a positive proteinuria and/or estimated glomerular filtration rate <60 ml min-1 per 1.73 m2. Participants were categorized into four groups using daytime ABP of 140/85 mm Hg and CBP of 140/90 mm Hg as cutoff points: SNBP, 60.0%; WCHT, 15.4%; MHT, 15.0%; and sustained hypertension (SHT), 9.6%. Odds ratios (ORs) for prevalence of CKD were calculated using a multiple logistic regression model. Compared with SNBP, risk of CKD was significantly higher in SHT (OR, 2.81; 95% confidence interval (CI), 1.66-4.75; P=0.0001), MHT (OR, 2.29; 95% CI, 1.45-3.63; P=0.0004) and WCHT (OR, 1.67; 95% CI, 1.03-2.71; P=0.0368). CKD was significantly associated with MHT and WCHT on the basis of ABP monitoring compared with SNBP in the general Japanese population. PMID- 20703229 TI - The counterregulating role of ACE2 and ACE2-mediated angiotensin 1-7 signaling against angiotensin II stimulation in vascular cells. AB - To clarify the role of endogenous angiotensin (Ang)-converting enzyme 2 (ACE2) and its cleavage product, Ang 1-7, in the atherogenic stimulation of vascular cells, we investigated the effect of pharmacological inhibition of ACE2 and Mas, an Ang 1-7 receptor, on cellular responses against Ang II stimulation. We measured extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by western blot, smooth muscle cell (SMC) proliferation by WST assay and the adhesion of monocytes labeled with PKH67 to endothelial cells (ECs) by fluorescence microplate reader. Cells were pretreated with Ang 1-7, olmesartan (Ang II type 1 receptor (AT1) blocker), DX600 (ACE2 inhibitor), -Ala7-Ang1-7 (D Ala; Mas antagonist), or combinations of treatments before the application of Ang II. Treatment with Ang II increased phosphorylated ERK 1/2 of SMC and EC, proliferation of SMC and adhesion of monocyte to EC, which were blocked by olmesartan. Pretreatment with DX600 either did not accelerate or only slightly accelerated these cellular responses. However, when Ang II signaling through AT1 was reduced by olmesartan, the additional treatment with DX600 significantly blunted some of the effect of olmesartan. Similarly, pretreatment with D-Ala reduced the inhibitory effect of olmesartan in response to Ang II stimulation. Endogenous ACE2 in vascular cells may contribute to counteracting the Ang II mediated cellular response partly by upregulating the Ang 1-7 signaling through Mas. PMID- 20703230 TI - Strong suppression of the renin-angiotensin system has a renal-protective effect in hypertensive patients: high-dose ARB with ACE inhibitor (Hawaii) study. AB - The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0+/-1.8 g g-1 to 0.8+/ 0.8 g g-1 (P=0.0242) in Olm-G and from 1.4+/-1.3 g g-1 to 0.9+/-1.0 g g-1 (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients. PMID- 20703231 TI - Stage of chronic kidney disease is an outcome-predicting factor of angioplasty for atheromatous renal artery stenosis. AB - Angioplasty with insertion of an endoprosthesis is an effective treatment for atheromatous renal artery stenosis (ARAS). However, this procedure may cause deterioration in renal function, and it is imperative to define the cases that could benefit from angioplasty. From 456 suspected renovascular hypertension cases, 33 were given a diagnosis of unilateral ARAS on renal arteriography. These unilateral ARAS cases were treated by angioplasty, and their baseline variables were evaluated with respect to the improvement achieved in post-angioplastic renal function of the treated side as measured by renal scintigram. The estimated glomerular filtration rate (eGFR) was the only variable that was significantly different between cases that showed improvement in renal function and those that did not. Cases that showed improvement in renal function had lower pre angioplasty eGFR compared with cases that did not show improvement (59+/-24 ml min-1 1.73 m-2 vs. 76+/-12 ml min-1 1.73 m-2, P=0.04), and cases showing improvement were generally at later stages of chronic kidney disease (CKD). Most patients without improvement, who were generally at earlier stages of CKD, had a systemic blood pressure reduction after angioplasty. The present findings indicate that the baseline CKD stage could be used to predict the outcome of angioplasty for ARAS. PMID- 20703232 TI - Head-to-head comparison of the cardio-ankle vascular index between patients with acute coronary syndrome and stable angina pectoris. AB - We aimed to evaluate whether there was a difference in the arterial stiffness assessed by the cardio-ankle vascular index (CAVI) between patients with acute coronary syndrome (ACS) and those with stable angina pectoris (SAP). A total of 199 consecutive patients, 79 with ACS and 120 with SAP, who underwent emergency or elective coronary revascularization were enrolled. The CAVI was measured within 2 days after the procedures, and was compared between the ACS and SAP patients. As parameters related to arteriosclerosis, carotid intima-media thickness (IMT) and number of stenotic coronary vessels were also evaluated. Although IMT was significantly greater in SAP patients (2.1+/-1.1 vs. 2.4+/-0.9; P=0.022), CAVI was significantly higher in ACS patients (10.0+/-1.7 vs. 9.3+/ 1.3; P=0.0012). After an adjustment for the clinical parameters with a significant difference between the two patient groups, CAVI remained significantly higher in ACS patients than in SAP patients (odds ratio 1.92, 95% confidence interval 1.30-3.02; P=0.0023). A multiple linear regression analysis revealed that age (beta=0.44; P<0.0001) and ACS (beta=0.3; P<0.0001) were the independent determinants of CAVI. A significant decrease in CAVI was observed at 6 months of follow-up as compared with the acute phase in 18 patients with ACS (10.9+/-1.6 vs. 10.0+/-1.5; P=0.019). In conclusion, CAVI was significantly and independently higher in patients with ACS than in those with SAP, which might result from a transient increase in the CAVI caused by acute myocardial ischemia. PMID- 20703233 TI - Brachial-ankle pulse wave velocity as a risk stratification index for the short term prognosis of type 2 diabetic patients with coronary artery disease. AB - The incidence of diabetes is increasing, and the disease has become an important predictor of prognosis in patients with coronary artery disease (CAD), although adverse events often occur without warning. Thus, risk stratification of diabetic CAD patients is important for secondary prevention. This study tests the hypothesis that brachial-ankle pulse wave velocity (baPWV), a marker for arterial stiffness obtained by simple and noninvasive automated devices, can be a risk stratification index to predict prognosis in diabetic patients with CAD. The prognosis of CAD patients with diabetes in the Shinken Database cohort study was investigated by dividing patients into two groups based on baPWV measurements. The composite endpoint was death, nonfatal myocardial infarction, repeat revascularization or readmission for heart failure. Data were available on 564 CAD patients, with a median follow-up of 25.4 months. Of these patients, 191 had type 2 diabetes. The higher baPWV among diabetic patients was defined as a median baPWV of 1730 cm s(-1) or more. The 3-year Kaplan-Meier estimates of event-free survival were 72.8% in diabetic patients with lower baPWV and 51.3% in those with higher baPWV, respectively (P=0.031). Multivariate analysis revealed that a higher baPWV was independently associated with poorer short-term prognosis (hazard ratio, 1.97; 95% confidence interval, 1.01-3.84) in diabetic CAD patients. In conclusion, baPWV, a marker for arterial stiffness, can be a risk stratification index for short-term prognosis in clinical practice, suggesting the need for further aggressive treatment and strict follow-up in CAD patients with diabetes and higher baPWV. PMID- 20703234 TI - Association of the angiotensin II type I receptor gene +1166 A>C polymorphism with hypertension risk: evidence from a meta-analysis of 16474 subjects. AB - Mounting evidence suggests the potential susceptibility of individuals with a mutation in the angiotensin II type I receptor (AT1R) gene to hypertension. One polymorphism, +1166 A>C, has been extensively studied, but the results have often been irreproducible. We therefore aimed to meta-analyze all available case control studies from the English language literature to explore the association of this polymorphism with hypertension. A total of 22 studies with 24 populations involving 8249 patients and 8225 controls were identified as of 25 February 2010. A random-effects model was performed regardless of the between-study heterogeneity. The study quality was assessed in duplicate. The data were analyzed using RevMan software (version 5.0.23). Overall, the presence of the +1166 C allele significantly conferred an increased risk of hypertension (odds ratio (OR)=1.14; 95% confidence interval, 1.00-1.30; P=0.05). Under the assumption of three genetic modes of inheritance, an elevated hypertension risk was observed for each comparison (codominant: AC vs. AA, OR=1.10 (P=0.20) and CC vs. AA, OR=1.21 (P=0.36); dominant: OR=1.13 (P=0.09); recessive: OR=1.21 (P=0.36)). Upon stratification by study design, more obvious associations were observed for the population-based design, whereas there were no changes in direction and only slight changes in magnitude upon stratification by sample size and geographical area. No publication biases were indicated by the fail-safe number. Our study pooled previous findings and showed that the AT1R +1166 C allele conferred an increased risk of hypertension. We suggest that confirmation in a large, well-designed study or from functional aspects of this polymorphism is critical. PMID- 20703235 TI - C-reactive protein is associated with cigarette smoking-induced hyperfiltration and proteinuria in an apparently healthy population. AB - Although cigarette smoking is known to be an important risk factor for renal disease, the mechanism by which smoking induces progressive renal disease in a healthy population has not been established. We hypothesized that oxidative stress (measured as 8-iso-prostaglandin F(2alpha), 8-iso-PGF2a), inflammation (highly sensitive C-reactive protein (CRP), hs-CRP) and nitric oxide may be associated with an alteration in the estimated glomerular filtration rate (eGFR) and proteinuria in otherwise healthy smokers. A total of 649 eligible subjects were classified according to their smoking status. Plasma NOx was measured using ozone-based chemiluminescence, urinary 8-iso-PGF2a was measured using enzyme immunoassay and serum hs-CRP was measured using a latex aggregation nephelometry method. The levels of 8-iso-PGF2a and hs-CRP increased in current smokers (P=0.001 and P=0.029, respectively), although there was not an increase in the NOx level. The prevalence of a high eGFR increased in light smokers (odds ratio (OR) 1.15 (95% confidence interval (CI), 0.61-2.17)) and heavy smokers (OR 2.33 (95% CI, 1.06-5.10)) when compared with non- and past smokers (P for trend=0.024). The multivariable-adjusted mean values of the eGFR in current smokers, reported from the lowest to the highest quintiles of hs-CRP levels, were 82.1, 85.1, 86.4 and 88.5 ml per min per 1.73 m2 (P for trend=0.027). The mean values of proteinuria were 28.6, 34.6, 37.2 and 39.5 mg g-1 creatinine (P for trend=0.003). The correlation coefficient between hs-CRP and eGFR was increased significantly (P=0.03) across non- (r=0.03), past (r=-0.17), light (r=0.13) and heavy smokers (r=0.31). In conclusion, cigarette smoking is a risk factor for renal function alteration in healthy smokers and is characterized by a high eGFR and a high urinary protein associated with an increase in the hs-CRP. This finding suggests that hs-CRP may help mediate the alteration of renal function in smokers. PMID- 20703236 TI - A new variant of bile duct duplication with coexistence of distal cholangiocarcinoma. AB - BACKGROUND: A 72-year-old hypertensive woman presented with a 2-month history of right upper quadrant abdominal pain. She had a 15-day history of jaundice, fever with chills and shivering, nausea, vomiting, weight loss and generalized pruritus. INVESTIGATIONS: Physical examination, laboratory evaluation, transabdominal ultrasonography, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, brush cytology, laparotomy and histopathology. DIAGNOSIS: Bile duct duplication with coexistence of distal cholangiocarcinoma. MANAGEMENT: En bloc resection (including the duodenum, pancreatic head and adjacent lymph nodes), hepaticojejunostomy and pylorus-saving Whipple operation. PMID- 20703237 TI - Mechanisms, diagnosis and management of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver disease. Symptoms of HE can include confusion, disorientation and poor coordination. A general consensus exists that the synergistic effects of excess ammonia and inflammation cause astrocyte swelling and cerebral edema; however, the precise molecular mechanisms that lead to these morphological changes in the brain are unclear. Cerebral edema occurs to some degree in all patients with HE, regardless of its grade, and could underlie the pathogenesis of this disorder. The different grades of HE can be diagnosed by a number of investigations, including neuropsychometric tests (such as the psychometric hepatic encephalopathy score), brain imaging and clinical scales (such as the West Haven criteria). HE is best managed by excluding other possible causes of encephalopathy alongside identifying and the precipitating cause, and confirming the diagnosis by a positive response to empiric treatment. Empiric therapy for HE is largely based on the principle of reducing the production and absorption of ammonia in the gut through administration of pharmacological agents such as rifaximin and lactulose, which are approved by the FDA for the treatment of HE. PMID- 20703239 TI - Human endogenous retrovirus K14C drove genomic diversification of the Y chromosome during primate evolution. AB - The male-specific region of Y chromosome (MSY) has accumulated a higher density of human endogenous retroviruses (HERVs) and related sequences when compared with other regions of the human genome. Here, we focused on one HERV family, HERV-K14C that seemed to integrate preferentially into the Y chromosome in humans. To identify every copies of HERV-K14C in the human genome, we applied computational screening to map precisely the locus of individual HERV-K14C copies. Interestingly, 29 of all 146 copies were located in Y chromosome, and these 29 copies were mostly dispersed in the palindromic region. Three distinct HERV-K14C related transcripts were found and were exclusively expressed in human testis tissue. Based on our phylogenetic analysis of the solitary LTRs derived from HERV K14C on the Y chromosome we suggested that these sequences were generated as pairs of identical sequences. Specifically, analysis of HERV-K14C-related sequences in the palindromic region demonstrated that the Y chromosomal amplicons existed in our common ancestors and the duplicated pairs arose after divergence of great apes approximately 8-10 million years ago. Taken together, our observation suggested that HERV-K14C-related sequences contributed to genomic diversification of Y chromosome during speciation of great ape lineage. PMID- 20703238 TI - Etiology and diagnosis of acute biliary pancreatitis. AB - Establishing a biliary etiology in acute pancreatitis is clinically important because of the potential need for invasive treatment, such as endoscopic retrograde cholangiopancreatography. The etiology of acute biliary pancreatitis (ABP) is multifactorial and complex. Passage of small gallbladder stones or biliary sludge through the ampulla of Vater seems to be important in the pathogenesis of ABP. Other factors, such as anatomical variations associated with an increased biliopancreatic reflux, bile and pancreatic juice exclusion from the duodenum, and genetic factors might contribute to the development of ABP. A diagnosis of a biliary etiology in acute pancreatitis is supported by both laboratory and imaging investigations. An increased serum level of alanine aminotransferase (>1.0 microkat/l) is associated with a high probability of gallstone pancreatitis (positive predictive value 80-90%). Confirmation of choledocholithiasis is most accurately obtained using endoscopic ultrasonography or magnetic resonance cholangiopancreatography. This Review discusses the pathogenesis of ABP and the clinical techniques used to predict and establish a biliary origin in patients with suspected ABP. PMID- 20703241 TI - Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a novel mutation in intron 14, which activates a cryptic splice site. AB - Familial hypercholesterolemia (FH) is caused by a defective low-density lipoprotein receptor (LDLR), and >1000 mutations in LDLR have been identified. However, in some patients with clinically defined FH, no mutation can be detected within the exons and adjacent intronic segments of the LDLR. We have analyzed RNA extracted from blood samples of patients with clinically defined FH and identified an aberrantly spliced mRNA containing an 81-bp insert from intron 14. The aberrant splicing was caused by a novel intronic mutation, c.2140+86C>G, which activated a cryptic splice site. Although the cryptic splice site does not completely surpass the normal splice site, the mutation was found to cosegregate with high cholesterol levels in a family, which supports the notion that c.2140+86C>G causes FH. The insertion of 81 bp in LDLR mRNA encodes an in-frame insertion of 27 amino acids in the LDLR. However, the insertion was found to hamper LDLR activity by preventing the receptor from leaving the endoplasmic reticulum, probably because of misfolding of the protein. In patients with clinically defined hypercholesterolemia, despite normal results from sequencing of exonic regions of the LDLR gene, characterization of the LDLR mRNA might identify the underlying genetic defect. PMID- 20703240 TI - Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population. AB - The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist-hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist-hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2beta (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P=0.0039 and 0.0039, respectively), SFA (P=0.0027 and 0.0023, respectively) and VFA (P=0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects. PMID- 20703242 TI - Genome-wide association analysis of copy number variations in subarachnoid aneurysmal hemorrhage. AB - Subarachnoid aneurysmal hemorrhage (SAH) due to cerebral aneurysm rupture is a very serious disease resulting in high mortality rate. It has been known that genetic factors are involved in the risk of SAH. A recent breakthrough in genomic variation called copy number variation (CNV) has been revealed to be involved in risks of human diseases. In this study, we hypothesized that CNVs can predict the risk of SAH. We used the Illumina HumanHap300 BeadChip (317 503 markers) to genotype 497 individuals in a Japanese population. Furthermore, individual CNVs were identified using signal and allelic intensities. The genetic effect of CNV on the risk of SAH was evaluated using multivariate logistic regression controlling for age and gender in 187 common CNV regions (frequency >1%). From a total of 4574 individual CNVs identified in this study (9.7 CNVs per individual), we were able to discover 1644 unique CNV regions containing 1232 genes. The identified variations were validated using visual examination of the genoplot image, overlapping analysis with the Database of Genomic Variants (73.2%), CNVpartition (72.4%) and quantitative PCR. Interestingly, two CNV regions, chr4:153210505-153212191 (deletion, 4q31.3, P=0.0005, P(corr) (corrected P value)=0.04) and chr10:6265006-6267388 (duplication, 10p15.1, P=0.0006, P(corr)=0.05), were significantly associated with the risk of SAH after multiple testing corrections. Our results suggest that the newly identified CNV regions may contribute to SAH disease susceptibility. PMID- 20703243 TI - Polymorphisms and allele frequencies of the ABO blood group gene among the Jomon, Epi-Jomon and Okhotsk people in Hokkaido, northern Japan, revealed by ancient DNA analysis. AB - To investigate the genetic characteristics of the ancient populations of Hokkaido, northern Japan, polymorphisms of the ABO blood group gene were analyzed for 17 Jomon/Epi-Jomon specimens and 15 Okhotsk specimens using amplified product length polymorphism and restriction fragment length polymorphism analyses. Five ABO alleles were identified from the Jomon/ Epi-Jomon and Okhotsk people. Allele frequencies of the Jomon/Epi-Jomon and Okhotsk people were compared with those of the modern Asian, European and Oceanic populations. The genetic relationships inferred from principal component analyses indicated that both Jomon/Epi-Jomon and Okhotsk people are included in the same group as modern Asian populations. However, the genetic characteristics of these ancient populations in Hokkaido were significantly different from each other, which is in agreement with the conclusions from mitochondrial DNA and ABCC11 gene analyses that were previously reported. PMID- 20703244 TI - High frequency of p16(INK4A) promoter methylation in NRAS-mutated cutaneous melanoma. AB - The p16(INK4A) tumor suppressor is often deleted, or otherwise inactivated, in malignant melanoma. To investigate the loss of p16(INK4A) in greater detail, we analyzed 77 cutaneous melanoma metastases. Of these 56 retained at least one p16(INK4A) allele, and 21 had biallelic deletions. Using methylation-specific PCR, direct sequencing, and immunohistochemical methods, we analyzed p16(INK4A) promoter methylation, mutations, and protein expression, respectively. In addition, 14 corresponding primary tumors were analyzed for protein expression. Results were compared to clinicopathological parameters and previously obtained data regarding mutations in proto-oncogenes NRAS and BRAF. Results revealed that p16(INK4A) promoter methylation was present in 15 of 59 (25%) metastases; nonsynonymous mutations in 9 of 56 (16%) metastases; and protein expression in 12 of 67 (18%) metastases. Protein expression was lost during progression from primary to metastatic tumors, 71% (10 of 14) and 43% (6 of 14) being positive, respectively. However, the genetic and epigenetic alterations of p16(INK4A) observed could not explain the lack of p16(INK4A) protein in 27 metastases, indicating the presence of additional inactivating mechanisms for p16(INK4A). Interestingly, p16(INK4A) promoter methylation was significantly overrepresented in NRAS-mutated samples compared to NRAS wild-type samples (P=0.0004), indicating an association between these two events. PMID- 20703245 TI - Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. AB - Netherton syndrome (NS) is a severe genodermatosis characterized by abnormal scaling and constant atopic manifestations. NS is caused by mutations in SPINK5 (Serine Protease INhibitor Kazal-type 5), which encodes LEKTI (LymphoEpithelial Kazal Type-related Inhibitor). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. Whereas a skin barrier defect is generally regarded as a major cause for atopy, we previously identified a cell autonomous signaling cascade that triggers pro-Th2 cytokine thymic stromal lymphopoietin (TSLP) production in LEKTI-deficient epidermis. This signaling is initiated by unrestricted kallikrein 5 (KLK5) activity, which directly activates proteinase-activated receptor 2 (PAR2)-mediated expression of TSLP and favors a cutaneous proallergic microenvironment independently of the environment and of the adaptive immune system. To further confirm these results in vivo, we generated Spink5/Par2 double knockout (DKO) mice. At embryonic day 19.5, these mice display a dramatic decrease in TSLP expression, although stratum corneum detachment persists, confirming the role of the KLK5-PAR2 cascade in TSLP mediated early proallergic signaling. However, deletion of Par2 in adult DKO grafted skin does not rescue the inflammatory phenotype probably resulting from stratum corneum detachment. We conclude that several mechanisms trigger and maintain the inflammatory phenotype in NS. These include skin barrier impairment, mechanical stress secondary to stratum corneum detachment, as well as protease induced proinflammatory and proallergic pathways, including PAR2-mediated overexpression of TSLP. PMID- 20703246 TI - Comparative pharmacokinetic assessments of topical drugs: evaluation by dermatopharmacokinetics, microdialysis, and systemic measurement. PMID- 20703247 TI - Functional redundancy of Langerhans cells and Langerin+ dermal dendritic cells in contact hypersensitivity. AB - The relative roles of Langerhans cells (LC), dermal dendritic cells (DC), and, in particular, the recently discovered Langerin(+) dermal DC subset in the induction and control of contact hypersensitivity (CHS) responses remain controversial. Using an inducible mouse model, in which LC and other Langerin(+) DC can be depleted by injection of diphtheria toxin, we previously reported impaired transport of topically applied antigen to draining lymph nodes and reduced CHS in the absence of all Langerin(+) skin DC. In this study, we demonstrate that mice with a selective depletion of LC exhibit attenuated CHS only upon sensitization with a low hapten dose but not with a high hapten dose. In contrast, when painting a higher concentration of hapten onto the skin, which leads to increased antigen dissemination into the dermis, CHS is still diminished in mice lacking all Langerin(+) skin DC. Taken together, these data suggest that the magnitude of a CHS reaction depends on the number of skin DC, which have access to the hapten, rather than on the presence or absence of a particular skin DC population. LC and (Langerin(+)) dermal DC thus seem to have a redundant function in regulating CHS. PMID- 20703251 TI - Integrating biobanks: addressing the practical and ethical issues to deliver a valuable tool for cancer research. AB - Cancer is caused by complex interactions between genes, environment and lifestyles. Biobanks of well-annotated human tissues are an important resource for studying the underlying mechanisms of cancer. Although such biobanks exist, their integration to form larger biobanks is now required to provide the diversity of samples that are needed to study the complexity and heterogeneity of cancer. Clear guidelines and policies are also required to address the challenges of integrating individual institutional or national biobanks and build public trust. This Science and Society article highlights some of the main practical and ethical issues that are undergoing discussion in the integration of tissue biobanks for cancer. PMID- 20703253 TI - Innate immunity as orchestrator of stem cell mobilization. AB - Hematopoietic stem and progenitor cells (HSPCs), as well as other types of stem cells, circulate under steady-state conditions at detectable levels in peripheral blood (PB), with their numbers increasing in response to stress, inflammation and tissue/organ injury. This mobilization process may be envisioned as a danger sensing response mechanism triggered by hypoxia or mechanical or infection induced tissue damage that recruits into PB different types of stem cells that have a role in immune surveillance and organ/tissue regeneration. Mobilization is also significantly enhanced by the administration of pharmacological agents, which has been exploited in hematological transplantology as a means to obtain HSPCs for hematopoietic reconstitution. In this review we will present mounting evidence that innate immunity orchestrates this evolutionarily conserved mechanism of HSPC mobilization. PMID- 20703252 TI - Activity-based protein profiling for biochemical pathway discovery in cancer. AB - Large-scale profiling methods have uncovered numerous gene and protein expression changes that correlate with tumorigenesis. However, determining the relevance of these expression changes and which biochemical pathways they affect has been hindered by our incomplete understanding of the proteome and its myriad functions and modes of regulation. Activity-based profiling platforms enable both the discovery of cancer-relevant enzymes and selective pharmacological probes to perturb and characterize these proteins in tumour cells. When integrated with other large-scale profiling methods, activity-based proteomics can provide insight into the metabolic and signalling pathways that support cancer pathogenesis and illuminate new strategies for disease diagnosis and treatment. PMID- 20703255 TI - Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma. PMID- 20703254 TI - The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma. PMID- 20703256 TI - Analysis of genomic breakpoints in p190 and p210 BCR-ABL indicate distinct mechanisms of formation. AB - We sought to understand the genesis of the t(9;22) by characterizing genomic breakpoints in chronic myeloid leukemia (CML) and BCR-ABL-positive acute lymphoblastic leukemia (ALL). BCR-ABL breakpoints were identified in p190 ALL (n=25), p210 ALL (n=25) and p210 CML (n=32); reciprocal breakpoints were identified in 54 cases. No evidence for significant clustering and no association with sequence motifs was found except for a breakpoint deficit in repeat regions within BCR for p210 cases. Comparison of reciprocal breakpoints, however, showed differences in the patterns of deletion/insertions between p190 and p210. To explore the possibility that recombinase-activating gene (RAG) activity might be involved in ALL, we performed extra-chromosomal recombination assays for cases with breakpoints close to potential cryptic recombination signal sequence (cRSS) sites. Of 13 ALL cases tested, 1/10 with p190 and 1/3 with p210 precisely recapitulated the forward BCR-ABL breakpoint and 1/10 with p190 precisely recapitulated the reciprocal breakpoint. In contrast, neither of the p210 CMLs tested showed functional cRSSs. Thus, although the t(9;22) does not arise from aberrant variable (V), joining (J) and diversity (D) (V(D)J) recombination, our data suggest that in a subset of ALL cases RAG might create one of the initiating double-strand breaks. PMID- 20703257 TI - The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry. AB - We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high resolution ('well matched' unrelated donor, WMUD), and 139 were mismatched (MM), including 30 matched in low resolution; 266 patients (72%) received reduced-intensity conditioning and 102 (28%) received standard. According to the EBMT risk score, 11% were in scores 1-3, 23% in score 4, 40% in score 5, 22% in score 6 and 4% in score 7. There was no difference in overall survival (OS) at 5 years between HLA identical siblings (55% (48-64)) and WMUD (59% (41-84)), P=0.82. In contrast, OS was significantly worse for MM (37% (29-48) P=0.005) due to a significant excess of transplant-related mortality. Also OS worsened significantly when EBMT risk score increased. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), P=0.11 and MM: 21% (18-24), P=0.81); alemtuzumab T cell depletion and stem cell source (peripheral blood) were associated with an increased risk. Our findings support the use of WMUD as equivalent alternative to HLA-matched sibling donors for allogeneic HSCT in CLL, and justify the application of EBMT risk score in this disease. PMID- 20703258 TI - Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies. AB - Mammalian target of rapamycin (mTOR) is a protein kinase implicated in the regulation of various cellular processes, including those required for tumor development, such as the initiation of mRNA translation, cell-cycle progression and cellular proliferation. In a wide range of hematological malignancies, the mTORC1 signaling pathway has been found to be deregulated and has been designed as a major target for tumor therapy. Given that pre-clinical studies have clearly established the therapeutic value of mTORC1 inhibition, numerous clinical trials of rapamycin and its derivates (rapalogs) are ongoing for treatment of these diseases. At this time, although disease stabilization and tumor regression have been observed, objective responses in some tumor types have been modest. Nevertheless, some of the mechanisms underlying cancer-cell resistance to rapamycin have now been described, thereby leading to the development of new strategy to efficiently target mTOR signaling in these diseases. In this review, we discuss the rationale for using mTOR inhibitors as novel therapies for a variety of hematological, malignancies with a focus on promising new perspectives for these approaches. PMID- 20703259 TI - HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance. PMID- 20703260 TI - The prion protein as a receptor for amyloid-beta. AB - Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Lauren et al. suggested that binding between oligomeric amyloid beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta mediated synaptic defects do not require PrP(c). PMID- 20703262 TI - Cheap shots. PMID- 20703263 TI - Standard issue. PMID- 20703269 TI - Journal club. A glaciologist ponders iceberg calving from a safe distance. PMID- 20703275 TI - Upbeat oil report questioned. PMID- 20703276 TI - Power struggle hits Swedish institute. PMID- 20703277 TI - France digs deep for nuclear waste. PMID- 20703278 TI - Mountain mining damages streams. PMID- 20703280 TI - Supercomputing for the birds. PMID- 20703281 TI - Francis Collins: One year at the helm. PMID- 20703282 TI - Oceanography: Dead in the water. PMID- 20703283 TI - Difference between interim and final acid-rain reports. PMID- 20703284 TI - Press release and media distort complex message. PMID- 20703286 TI - Concerns regarding sinking of South Korean warship. PMID- 20703285 TI - Problems in Turkish science run deeper than petty disputes. PMID- 20703287 TI - Which way for genetic-test regulation? Leave test interpretation to specialists. PMID- 20703288 TI - Which way for genetic-test regulation? Assign regulation appropriate to the level of risk. PMID- 20703291 TI - Information theory: A signal take on speech. PMID- 20703292 TI - Geochemistry: Relict mantle from Earth's birth. PMID- 20703293 TI - Neuroscience: A mine of imprinted genes. PMID- 20703294 TI - Plant pathology: Sudden larch death. PMID- 20703295 TI - High-temperature superconductivity: The benefit of fractal dirt. PMID- 20703297 TI - Behavioural neuroscience: Genes and the anxious brain. PMID- 20703298 TI - Palaeoanthropology: Australopithecine butchers. PMID- 20703299 TI - Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. AB - The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs. PMID- 20703300 TI - Mammalian microRNAs predominantly act to decrease target mRNA levels. AB - MicroRNAs (miRNAs) are endogenous approximately 22-nucleotide RNAs that mediate important gene-regulatory events by pairing to the mRNAs of protein-coding genes to direct their repression. Repression of these regulatory targets leads to decreased translational efficiency and/or decreased mRNA levels, but the relative contributions of these two outcomes have been largely unknown, particularly for endogenous targets expressed at low-to-moderate levels. Here, we use ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels. For both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for most (>/=84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output. PMID- 20703301 TI - Scale-free structural organization of oxygen interstitials in La(2)CuO(4+y). AB - It is well known that the microstructures of the transition-metal oxides, including the high-transition-temperature (high-T(c)) copper oxide superconductors, are complex. This is particularly so when there are oxygen interstitials or vacancies, which influence the bulk properties. For example, the oxygen interstitials in the spacer layers separating the superconducting CuO(2) planes undergo ordering phenomena in Sr(2)O(1+y)CuO(2) (ref. 9), YBa(2)Cu(3)O(6+y) (ref. 10) and La(2)CuO(4+y) (refs 11-15) that induce enhancements in the transition temperatures with no changes in hole concentrations. It is also known that complex systems often have a scale invariant structural organization, but hitherto none had been found in high-T(c) materials. Here we report that the ordering of oxygen interstitials in the La(2)O(2+y) spacer layers of La(2)CuO(4+y) high-T(c) superconductors is characterized by a fractal distribution up to a maximum limiting size of 400 mum. Intriguingly, these fractal distributions of dopants seem to enhance superconductivity at high temperature. PMID- 20703302 TI - Nanoscale scanning probe ferromagnetic resonance imaging using localized modes. AB - The discovery of new phenomena in layered and nanostructured magnetic devices is driving rapid growth in nanomagnetics research. Resulting applications such as giant magnetoresistive field sensors and spin torque devices are fuelling advances in information and communications technology, magnetoelectronic sensing and biomedicine. There is an urgent need for high-resolution magnetic-imaging tools capable of characterizing these complex, often buried, nanoscale structures. Conventional ferromagnetic resonance (FMR) provides quantitative information about ferromagnetic materials and interacting multicomponent magnetic structures with spectroscopic precision and can distinguish components of complex bulk samples through their distinctive spectroscopic features. However, it lacks the sensitivity to probe nanoscale volumes and has no imaging capabilities. Here we demonstrate FMR imaging through spin-wave localization. Although the strong interactions in a ferromagnet favour the excitation of extended collective modes, we show that the intense, spatially confined magnetic field of the micromagnetic probe tip used in FMR force microscopy can be used to localize the FMR mode immediately beneath the probe. We demonstrate FMR modes localized within volumes having 200 nm lateral dimensions, and improvements of the approach may allow these dimensions to be decreased to tens of nanometres. Our study shows that this approach is capable of providing the microscopic detail required for the characterization of ferromagnets used in fields ranging from spintronics to biomagnetism. This method is applicable to buried and surface magnets, and, being a resonance technique, measures local internal fields and other magnetic properties with spectroscopic precision. PMID- 20703303 TI - Precipitation-generated oscillations in open cellular cloud fields. AB - Cloud fields adopt many different patterns that can have a profound effect on the amount of sunlight reflected back to space, with important implications for the Earth's climate. These cloud patterns can be observed in satellite images of the Earth and often exhibit distinct cell-like structures associated with organized convection at scales of tens of kilometres. Recent evidence has shown that atmospheric aerosol particles-through their influence on precipitation formation help to determine whether cloud fields take on closed (more reflective) or open (less reflective) cellular patterns. The physical mechanisms controlling the formation and evolution of these cells, however, are still poorly understood, limiting our ability to simulate realistically the effects of clouds on global reflectance. Here we use satellite imagery and numerical models to show how precipitating clouds produce an open cellular cloud pattern that oscillates between different, weakly stable states. The oscillations are a result of precipitation causing downward motion and outflow from clouds that were previously positively buoyant. The evaporating precipitation drives air down to the Earth's surface, where it diverges and collides with the outflows of neighbouring precipitating cells. These colliding outflows form surface convergence zones and new cloud formation. In turn, the newly formed clouds produce precipitation and new colliding outflow patterns that are displaced from the previous ones. As successive cycles of this kind unfold, convergence zones alternate with divergence zones and new cloud patterns emerge to replace old ones. The result is an oscillating, self-organized system with a characteristic cell size and precipitation frequency. PMID- 20703304 TI - Evidence for the survival of the oldest terrestrial mantle reservoir. AB - Helium is a powerful tracer of primitive material in Earth's mantle. Extremely high (3)He/(4)He ratios in some ocean-island basalts suggest the presence of relatively undegassed and undifferentiated material preserved in Earth's mantle. However, terrestrial lavas with high (3)He/(4)He ratios have never been observed to host the primitive lead-isotopic compositions that are required for an early (roughly 4.5 Gyr ago) formation age. Here we show that Cenozoic-era Baffin Island and West Greenland lavas, previously found to host the highest terrestrial-mantle (3)He/(4)He ratios, exhibit primitive lead-isotope ratios that are consistent with an ancient mantle source age of 4.55-4.45 Gyr. The Baffin Island and West Greenland lavas also exhibit (143)Nd/(144)Nd ratios similar to values recently proposed for an early-formed (roughly 4.5 Gyr ago) terrestrial mantle reservoir. The combined helium-, lead- and Nd-isotopic compositions in Baffin Island and West Greenland lavas therefore suggest that their source is the most ancient accessible reservoir in the Earth's mantle, and it may be parental to all mantle reservoirs that give rise to modern volcanism. PMID- 20703305 TI - Evidence for stone-tool-assisted consumption of animal tissues before 3.39 million years ago at Dikika, Ethiopia. AB - The oldest direct evidence of stone tool manufacture comes from Gona (Ethiopia) and dates to between 2.6 and 2.5 million years (Myr) ago. At the nearby Bouri site several cut-marked bones also show stone tool use approximately 2.5 Myr ago. Here we report stone-tool-inflicted marks on bones found during recent survey work in Dikika, Ethiopia, a research area close to Gona and Bouri. On the basis of low-power microscopic and environmental scanning electron microscope observations, these bones show unambiguous stone-tool cut marks for flesh removal and percussion marks for marrow access. The bones derive from the Sidi Hakoma Member of the Hadar Formation. Established (40)Ar-(39)Ar dates on the tuffs that bracket this member constrain the finds to between 3.42 and 3.24 Myr ago, and stratigraphic scaling between these units and other geological evidence indicate that they are older than 3.39 Myr ago. Our discovery extends by approximately 800,000 years the antiquity of stone tools and of stone-tool-assisted consumption of ungulates by hominins; furthermore, this behaviour can now be attributed to Australopithecus afarensis. PMID- 20703306 TI - Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. AB - Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression. PMID- 20703307 TI - Structure of the LexA-DNA complex and implications for SOS box measurement. AB - The eubacterial SOS system is a paradigm of cellular DNA damage and repair, and its activation can contribute to antibiotic resistance. Under normal conditions, LexA represses the transcription of many DNA repair proteins by binding to SOS 'boxes' in their operators. Under genotoxic stress, accumulating complexes of RecA, ATP and single-stranded DNA (ssDNA) activate LexA for autocleavage. To address how LexA recognizes its binding sites, we determined three crystal structures of Escherichia coli LexA in complex with SOS boxes. Here we report the structure of these LexA-DNA complexes. The DNA-binding domains of the LexA dimer interact with the DNA in the classical fashion of a winged helix-turn-helix motif. However, the wings of these two DNA-binding domains bind to the same minor groove of the DNA. These wing-wing contacts may explain why the spacing between the two half-sites of E. coli SOS boxes is invariant. PMID- 20703309 TI - Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. AB - The purpose of this study was to evaluate whether immune responses interfered with gene therapy rescue using subretinally delivered recombinant adeno associated viral vector serotype 2 carrying the RPE65 cDNA gene driven by the human RPE65 promoter (rAAV2.hRPE65p.hRPE65) in the second eye of RPE65-/- dogs that had previously been treated in a similar manner in the other eye. Bilateral subretinal injection was performed in nine dogs with the second eye treated 85 180 days after the first. Electroretinography (ERG) and vision testing showed rescue in 16 of 18 treated eyes, with no significant difference between first and second treated eyes. A serum neutralizing antibody (NAb) response to rAAV2 was detected in all treated animals, but this did not prevent or reduce the effectiveness of rescue in the second treated eye. We conclude that successful rescue using subretinal rAAV2.hRPE65p.hRPE65 gene therapy in the second eye is not precluded by prior gene therapy in the contralateral eye of the RPE65-/- dog. This finding has important implications for the treatment of human LCA type II patients. PMID- 20703310 TI - Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution. AB - Newly isolated serotypes of AAV readily cross the endothelial barrier to provide efficient transgene delivery throughout the body. However, tissue-specific expression is preferred in most experimental studies and gene therapy protocols. Previous efforts to restrict gene expression to the myocardium often relied on direct injection into heart muscle or intracoronary perfusion. Here, we report an AAV vector system employing the cardiac troponin T (cTnT) promoter. Using luciferase and enhanced green fluorescence protein (eGFP), the efficiency and specificity of cardiac reporter gene expression using AAV serotype capsids: AAV 1, 2, 6, 8 or 9 were tested after systemic administration to 1-week-old mice. Luciferase assays showed that the cTnT promoter worked in combination with each of the AAV serotype capsids to provide cardiomyocyte-specific gene expression, but AAV-9 followed closely by AAV-8 was the most efficient. AAV9-mediated gene expression from the cTnT promoter was 640-fold greater in the heart compared with the next highest tissue (liver). eGFP fluorescence indicated a transduction efficiency of 96% using AAV-9 at a dose of only 3.15 * 10(10) viral particles per mouse. Moreover, the intensity of cardiomyocyte eGFP fluorescence measured on a cell-by-cell basis revealed that AAV-mediated gene expression in the heart can be modeled as a Poisson distribution, requiring an average of nearly two vector genomes per cell to attain an 85% transduction efficiency. PMID- 20703311 TI - The combination of immunosuppression and carrier cells significantly enhances the efficacy of oncolytic poxvirus in the pre-immunized host. AB - Pre-existing antipoxvirus immunity in cancer patients presents a severe barrier to poxvirus-mediated oncolytic virotherapy. We have explored strategies of immunosuppression (IS) and/or immune evasion for efficient delivery of an oncolytic double-deleted vaccinia virus (vvDD) to tumors in the pre-immunized mice. Transient IS using immunosuppressive drugs, including tacrolimus, mycophenolate mofetil and methylprednisolone sodium succinate, have been used successfully in organ transplantation. This drug cocktail alone did not enhance viral recovery from subcutaneous tumor after systemic viral delivery. Using B cell knockout mice, we confirmed that the neutralizing antibodies had a significant role in preventing poxvirus infection. Using a MC38 peritoneal carcinomatosis model, we found that the combination of IS and tumor cells as carriers led to the most effective viral delivery, viral replication and viral spread inside the tumor mass. We found that our immunosuppressive drug cocktail facilitated recruitment of tumor-associated macrophages and conversion into an immunosuppressive M2 phenotype (interleukin (IL)-10(hi)/IL-12(low)) in the tumor microenvironment. A combination of IS and carrier cells led to significantly prolonged survival in the tumor model. These results showed the feasibility of treating pre-vaccinated patients with peritoneal carcinomatosis using an oncolytic poxvirus and a combined immune intervention strategy. PMID- 20703312 TI - Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models. AB - Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA. PMID- 20703313 TI - Combinatorial gene therapy induces regression of hepatic encephalopathy. AB - Capillarization of the sinusoid impedes the clearance of neurotoxic substances in liver fibrosis. These events may result in hepatic encephalopathy. Neurological and hepatic features of rats after bile duct ligation (BDL) supplemented with Manganese (BDL+Mn(2+)) were examined. The 4-week-old BDL rats had elevated levels of ammonia and were concomitantly fed with 1 mg ml(-1) of MnCl(2) in drinking water (BDL/Mn(+2)). Five out of fifteen rats were killed and the serum, liver and brain tissue (striatum and substantia nigra) were recovered. Of the remaining BDL/Mn(+2)-cirrhotic animals (n=10), five were injected with a combination of Adenovirus-human plasminogen activator (Ad-huPA) and Adenovirus-matrix metalloproteinase-8 (Ad-MMP-8) (3 * 10(11)+1.5 * 10(11) vector particles per kg), and five with 4.5 * 10(11) vector particles per kg of Adenovirus-beta galactosidase (Ad-beta-Gal). This treatment was carried on for 10 days. The BDL/Mn(+2) rats displayed tremor, rigidity and gait abnormalities, which improved notably with combinatorial gene therapy, as well as motor coordination. Liver fibrosis was evidently less after treatment with Ad-huPA+Ad-MMP-8 (25%). In the brain (striatum), Ad-huPA+Ad-MMP-8 treatment rendered higher concentrations of dopamine compared with Ad-beta-Gal-treated encephalopathic rats (210 and 162 ng g(-1) of tissue, respectively). The BDL/Mn(+2) animals and controls treated with Ad-beta-Gal showed abnormal morphology in astrocytes (gliosis) in striatum and substantia nigra, in which expressions of green fibrillar acidic protein and tyrosine hydroxylase were altered. These abnormalities decreased with Ad-huPA+Ad MMP-8 treatment. Importantly, the latter animals showed an increment in sprouting of nervous fibers in substantia nigra. Combinatorial gene therapy improves neuroanatomical and neurochemical characteristics similar to human hepatic encephalopathy. PMID- 20703314 TI - Looking inside the box: using Raman microspectroscopy to deconstruct microbial biomass stoichiometry one cell at a time. AB - Stoichiometry of microbial biomass is a key determinant of nutrient recycling in a wide variety of ecosystems. However, little is known about the underlying causes of variance in microbial biomass stoichiometry. This is primarily because of technological constraints limiting the analysis of macromolecular composition to large quantities of microbial biomass. Here, we use Raman microspectroscopy (MS), to analyze the macromolecular composition of single cells of two species of bacteria grown on minimal media over a wide range of resource stoichiometry. We show that macromolecular composition, determined from a subset of identified peaks within the Raman spectra, was consistent with macromolecular composition determined using traditional analytical methods. In addition, macromolecular composition determined by Raman MS correlated with total biomass stoichiometry, indicating that analysis with Raman MS included a large proportion of a cell's total macromolecular composition. Growth phase (logarithmic or stationary), resource stoichiometry and species identity each influenced each organism's macromolecular composition and thus biomass stoichiometry. Interestingly, the least variable peaks in the Raman spectra were those responsible for differentiation between species, suggesting a phylogenetically specific cellular architecture. As Raman MS has been previously shown to be applicable to cells sampled directly from complex environments, our results suggest Raman MS is an extremely useful application for evaluating the biomass stoichiometry of environmental microorganisms. This includes the ability to partition microbial biomass into its constituent macromolecules and increase our understanding of how microorganisms in the environment respond to resource heterogeneity. PMID- 20703315 TI - Determinants of the distribution of nitrogen-cycling microbial communities at the landscape scale. AB - Little information is available regarding the landscape-scale distribution of microbial communities and its environmental determinants. However, a landscape perspective is needed to understand the relative importance of local and regional factors and land management for the microbial communities and the ecosystem services they provide. In the most comprehensive analysis of spatial patterns of microbial communities to date, we investigated the distribution of functional microbial communities involved in N-cycling and of the total bacterial and crenarchaeal communities over 107 sites in Burgundy, a 31,500 km(2) region of France, using a 16 * 16 km(2) sampling grid. At each sampling site, the abundance of total bacteria, crenarchaea, nitrate reducers, denitrifiers- and ammonia oxidizers were estimated by quantitative PCR and 42 soil physico-chemical properties were measured. The relative contributions of land use, spatial distance, climatic conditions, time, and soil physico-chemical properties to the spatial distribution of the different communities were analyzed by canonical variation partitioning. Our results indicate that 43-85% of the spatial variation in community abundances could be explained by the measured environmental parameters, with soil chemical properties (mostly pH) being the main driver. We found spatial autocorrelation up to 739 km and used geostatistical modelling to generate predictive maps of the distribution of microbial communities at the landscape scale. The present study highlights the potential of a spatially explicit approach for microbial ecology to identify the overarching factors driving the spatial heterogeneity of microbial communities even at the landscape scale. PMID- 20703316 TI - Comparative genomics reveals a deep-sea sediment-adapted life style of Pseudoalteromonas sp. SM9913. AB - Deep-sea sediment is one of the most important microbial-driven ecosystems, yet it is not well characterized. Genome sequence analyses of deep-sea sedimentary bacteria would shed light on the understanding of this ecosystem. In this study, the complete genome of deep-sea sedimentary bacterium Pseudoalteromonas sp. SM9913 (SM9913) is described and compared with that of the closely related Antarctic surface sea-water ecotype Pseudoalteromonas haloplanktis TAC125 (TAC125). SM9913 has fewer dioxygenase genes than TAC125, indicating a possible sensitivity to reactive oxygen species. Accordingly, experimental results showed that SM9913 was less tolerant of H(2)O(2) than TAC125. SM9913 has gene clusters related to both polar and lateral flagella biosynthesis. Lateral flagella, which are usually present in deep-sea bacteria and absent in the related surface bacteria, are important for the survival of SM9913 in deep-sea environments. With these two flagellar systems, SM9913 can swim in sea water and swarm on the sediment particle surface, favoring the acquisition of nutrients from particulate organic matter and reflecting the particle-associated alternative lifestyle of SM9913 in the deep sea. A total of 12 genomic islands were identified in the genome of SM9913 that may confer specific features unique to SM9913 and absent from TAC125, such as drug and heavy metal resistance. Many signal transduction genes and a glycogen production operon were also present in the SM9913 genome, which may help SM9913 respond to food pulses and store carbon and energy in a deep-sea environment. PMID- 20703317 TI - 'Candidatus Accumulibacter' gene expression in response to dynamic EBPR conditions. AB - Enhanced biological phosphorus removal (EBPR) activated sludge communities enriched in 'Candidatus Accumulibacter' relatives are widely used in wastewater treatment, but much remains to be learned about molecular-level controls on the EBPR process. The expression of genes found in the carbon and polyphosphate metabolic pathways in Accumulibacter was investigated using reverse transcription quantitative PCR. During a normal anaerobic/aerobic EBPR cycle, gene expression exhibited a dynamic change in response to external acetate, oxygen, phosphate concentrations and probably internal chemical pools. Anaerobic acetate addition induced expression of genes associated with the methylmalonyl-CoA pathway enabling the split mode of the tricarboxylic acid (TCA) cycle. Components of the full TCA cycle were induced after the switch to aerobic conditions. The induction of a key gene in the glyoxylate shunt pathway was observed under both anaerobic and aerobic conditions, with a higher induction by aeration. Polyphosphate kinase 1 from Accumulibacter was expressed, but did not appear to be regulated by phosphate limitation. To understand how Accumulibacter responds to disturbed electron donor and acceptor conditions, we perturbed the process by adding acetate aerobically. When high concentrations of oxygen were present simultaneously with acetate, phosphate-release was almost completely inhibited, and polyphosphate kinase 1 transcript abundance decreased. Genes associated with the methylmalonyl-CoA pathway were repressed and genes associated with the aerobic TCA cycle exhibited higher expression under this perturbation, suggesting that more acetyl-CoA was metabolized through the TCA cycle. These findings suggest that several genes involved in EBPR are tightly regulated at the transcriptional level. PMID- 20703318 TI - Archaea in artificial environments: their presence in global spacecraft clean rooms and impact on planetary protection. AB - The presence and role of Archaea in artificial, human-controlled environments is still unclear. The search for Archaea has been focused on natural biotopes where they have been found in overwhelming numbers, and with amazing properties. However, they are considered as one of the major group of microorganisms that might be able to survive a space flight, or even to thrive on other planets. Although still concentrating on aerobic, bacterial spores as a proxy for spacecraft cleanliness, space agencies are beginning to consider Archaea as a possible contamination source that could affect future searches for life on other planets. This study reports on the discovery of archaeal 16S rRNA gene signatures not only in US American spacecraft assembly clean rooms but also in facilities in Europe and South America. Molecular methods revealed the presence of Crenarchaeota in all clean rooms sampled, while signatures derived from methanogens and a halophile appeared only sporadically. Although no Archaeon was successfully enriched in our multiassay cultivation approach thus far, samples from a European clean room revealed positive archaeal fluorescence in situ hybridization (FISH) signals of rod-shaped microorganisms, representing the first visualization of Archaea in clean room environments. The molecular and visual detection of Archaea was supported by the first quantitative PCR studies of clean rooms, estimating the overall quantity of Archaea therein. The significant presence of Archaea in these extreme environments in distinct geographical locations suggests a larger role for these microorganisms not only in natural biotopes, but also in human controlled and rigorously cleaned environments. PMID- 20703319 TI - Reply: Is There Any Genetic Instability in Human Cancer? PMID- 20703320 TI - A Validated Stability-indicating Reverse Phase HPLC Assay Method for the Determination of Memantine Hydrochloride Drug Substance with UV-Detection Using Precolumn Derivatization Technique. AB - This present paper deals with the development and validation of a stability indicating high performance liquid chromatographic method for the quantitative determination of Memantine hydrochloride. Memantine hydrochloride was derivatized with 0.015 M 9-fluorenylmethyl chloroformate (FMOC) and 0.5 M borate buffer solution by keeping it at room temperature for about 20 minutes and the chromatographic separation achieved by injecting 10 muL of the derivatized mixture into a Waters HPLC system with photodiode array detector using a kromasil C18 column (150 x 4.6 mm), 5 mu. The mobile phase consisting of 80% acetonitrile and 20% phosphate buffer solution and a flow rate of 2 milliliter/minute. The Memantine was eluted at approximately 7.5 minutes. The volume of FMOC used in derivatization, concentration of FMOC and derivatization time was optimized and used. Forced degradation studies were performed on bulk sample of Memantine hydrochloride using acid (5.0 Normal (N) hydrochloric acid), base (1.0 N sodium hydroxide), oxidation (30% hydrogen peroxide), thermal (105 degrees C), photolytic and humidity conditions. The developed LC method was validated with respect to specificity, precision (% RSD about 0.70%), linearity (linearity of range about 70-130 mug/mL), ruggedness (Overall % RSD about 0.35%), stability in analytical solution (Cumulative % RSD about 0.11% after 1450 min.) and robustness. PMID- 20703321 TI - LSOSS: Detection of Cancer Outlier Differential Gene Expression. AB - Detection of differential gene expression using microarray technology has received considerable interest in cancer research studies. Recently, many researchers discovered that oncogenes may be activated in some but not all samples in a given disease group. The existing statistical tools for detecting differentially expressed genes in a subset of the disease group mainly include cancer outlier profile analysis (COPA), outlier sum (OS), outlier robust t statistic (ORT) and maximum ordered subset t-statistics (MOST). In this study, another approach named Least Sum of Ordered Subset Square t-statistic (LSOSS) is proposed. The results of our simulation studies indicated that LSOSS often has more power than previous statistical methods. When applied to real human breast and prostate cancer data sets, LSOSS was competitive in terms of the biological relevance of top ranked genes. Furthermore, a modified hierarchical clustering method was developed to classify the heterogeneous gene activation patterns of human breast cancer samples based on the significant genes detected by LSOSS. Three classes of gene activation patterns, which correspond to estrogen receptor (ER)+, ER- and a mixture of ER+ and ER-, were detected and each class was assigned a different gene signature. PMID- 20703322 TI - Detection of homocysteine and C-reactive protein in the saliva of healthy adults: comparison with blood levels. AB - Inflammation and cardiovascular disease are associated with elevated serum levels of C-Reactive Protein (CRP) and homocysteine. The presence of both molecules in saliva provides an opportunity for development of non-invasive assessments of disease risk. However, salivary CRP and homocysteine reference ranges and their correlation with serum levels are unknown. This study investigated if CRP and homocysteine could be routinely detected in the saliva of healthy adults and the relationship between salivary and blood levels. CRP and homocysteine concentrations were determined using ELISA and enzymatic assays respectively. Homocysteine was detected in only two saliva samples (n = 55). CRP was measurable in all saliva samples (range: 0.05 to 64.3 mug/L; median = 1.2 mug/L) and plasma samples (range: 0.14 to 31.1 mg/L; median = 2.0 mg/L). Regression analysis demonstrated no relationship between CRP concentration in saliva and plasma (R(2) = 0.001). Generalized linear models including variables such as saliva flow rate and time since eating or drinking also did not pass lack of fit testing. Therefore, a relationship between CRP concentration in saliva and blood could not be established in this group of subjects. More sensitive detection methods are needed to determine if a correlation between salivary and serum homocysteine levels exists. PMID- 20703323 TI - Decreased Serum Hepatocyte Growth Factor (HGF) in Individuals with Depression Correlates with Severity of Disease. AB - AIM: To assess serum Hepatocyte Growth Factor (HGF) levels in individuals with depression and to test the hypothesis that there is a relationship between severity of depression and HGF concentration. SUBJECTS AND METHODS: Serum from 26 clinically depressed individuals and 19 controls were tested for serum HGF using ELISAs. Correlation was established between HGF concentration and disease severity. RESULTS: Depressed individuals had significantly lower serum levels of HGF compared to controls (P < 0.0001). HGF concentration correlated with overall depressive behavior (P = 0.03) and specifically depression (P = 0.02), but not anxiety (P = 0.36). DISCUSSION: These results suggest an association between HGF serum levels and clinically depressed individuals and demonstrate a correlation between severity of depression and HGF levels. Further studies of the predictive strength of HGF as a biomarker for depression may be warranted. PMID- 20703324 TI - Early Diagnosis of Invasive Aspergillosis in Neutropenic Patients. Comparison between Serum Galactomannan and Polymerase Chain Reaction. AB - BACKGROUND: Invasive aspergillosis (IA) is a major cause of morbidity and mortality in profoundly neutropenic patients, so early diagnosis is mandatory. AIM: Consecutive patients with hematological malignancies undergoing intensive chemotherapy were screened for IA with two different methods which were compared. METHODS: From October 2000 to August 2003 we tested 1311 serum samples from 172 consecutive patients with a polymerase chain reaction assay and between April 2005 and April 2008 we tested 806 serum samples from 169 consecutive patients with a Galactomannan (GM) test. Bronchoalveolar (BAL) samples were obtained whenever the patient's condition allowed and tested with either method. RESULTS: The serum PCR assay had a sensitivity of 75.0% and a specificity of 91.9% and the serum GM assay had a sensitivity of 87.5% and a specificity of 93.1%, (P > 0.05). The presence of two or more consecutive positive serum samples was predictive of IA for both assays. BAL GM/PCR was positive in some patients without serum positivity and in patients with 2 or more positive serum GM/PCR. CONCLUSIONS: No significant differences between the 2 serum tests were found. The GM assay has the advantage of being standardized among several laboratories and is incorporated in the criteria established by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG), however is much more expensive. BAL GM and PCR sampling aids in IA diagnosis but needs further validation studies to differentiate between colonization and true infection in cases where serum GM or PCR are negative. PMID- 20703325 TI - CD4 Count and Anti Retroviral Therapy for HIV Positive Patients With Cancer in Nigeria -A Pilot Study. AB - BACKGROUND: Highly Active Anti Retroviral Treatment (HAART) improves the outcome of HIV positive patients treated for cancer. In our center HAART is only commenced in HIV positive patients with malignancy if the CD4 T lymphocyte count is less than 200 cells/ul. Presently, the outcome of treatment in these patients is poor. OBJECTIVE: To evaluate the influence of CD4 T-cell count and HAART on treatment outcome of HIV positive patients with cancer managed at the oncology service of The University College Hospital, Ibadan-South West Nigeria. PATIENTS AND METHODS: Twenty two adult HIV positive patients with malignancies who presented for treatment at our hospital from 2007 to 2009 were closely monitored by the investigators. Relevant clinical data collected included age, sex, HIV status, type of malignancy, CD4 counts, history of ART, ECOG performance status, prescribed oncology treatment with regularity of treatment and to follow up conditions. RESULTS: Twenty two patients aged between 26 and 67 years were evaluated. The performance status of all patients was at least ECOG 2. Three ART naive patients with initial CD4 counts 450 cells/ul and above were able to complete oncology treatment without HAART with good malignant disease control. Five other patients on HAART before the diagnosis of malignancy with CD4 counts 350 cells/ul and above were also able to complete their treatments on schedule with good outcome. Eight HAART naive patients with initial CD4 counts less than 370 cells/ul had inconsistent treatments with poor outcome. CONCLUSION: Based on these observations, we propose that HAART should be commenced on all HIV positive patients diagnosed with malignancy with an initial CD4 count less than 450 cells/ul in our environment. Further studies in low resource settings with appropriate sample sizes are however needed to validate these findings. PMID- 20703327 TI - Fractal topology of gene promoter networks at phase transitions. AB - Much is known regarding the structure and logic of genetic regulatory networks. Less understood is the contextual organization of promoter signals used during transcription initiation, the most pivotal stage during gene expression. Here we show that promoter networks organize spontaneously at a dimension between the 1 dimension of the DNA and 3-dimension of the cell. Network methods were used to visualize the global structure of E. coli sigma (sigma) recognition footprints using published promoter sequences (RegulonDB). Footprints were rendered as networks with weighted edges representing bp-sharing between promoters (nodes). Serial thresholding revealed phase transitions at positions predicted by percolation theory, and nuclei denoting short steps through promoter space with geometrically constrained linkages. The network nuclei are fractals, a power-law organization not yet described for promoters. Genome-wide promoter abundance also scaled as a power-law. We propose a general model for the development of a fractal nucleus in a transcriptional grammar. PMID- 20703326 TI - Trends in cancer immunotherapy. AB - Modulation of the immune system for therapeutic ends has a long history, stretching back to Edward Jenner's use of cowpox to induce immunity to smallpox in 1796. Since then, immunotherapy, in the form of prophylactic and therapeutic vaccines, has enabled doctors to treat and prevent a variety of infectious diseases, including cholera, poliomyelitis, diphtheria, measles and mumps. Immunotherapy is now increasingly being applied to oncology. Cancer immunotherapy attempts to harness the power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for cancer immunotherapy is to apply advances in cellular and molecular immunology and develop strategies that effectively and safely augment antitumor responses. PMID- 20703328 TI - Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions. AB - Central pain is an enigmatic, intractable condition, related to destruction of thalamic areas, resulting in likely loss of inhibitory synaptic transmission mediated by GABA. It is proposed that treatment of central pain, a localized process, may be treated by GABA supplementation, like Parkinson's disease and depression. At physiologic pH, GABA exists as a zwitterion that is poorly permeable to the blood brain barrier (BBB). Because the pH of the cerebral spinal fluid (CSF) is acidic relative to the plasma, ion trapping may allow a GABA ester prodrug to accumulate and be hydrolyzed within the CSF. Previous investigations with ester local anesthetics may be applicable to some GABA esters since they are weak bases, hydrolyzed by esterases and cross the BBB. Potential non-toxic GABA esters are discussed. Many GABA esters were investigated in the 1980s and it is hoped that this paper may spark renewed interest in their development. PMID- 20703331 TI - An unexpected '4+2' [N(3)S]:[NS] rhenium(IV) complex formed upon cleavage of a Re(V) imido bond. AB - The reaction of [Re(NMe)Cl(3)(PPh(3))(2)] with the pentadentate [N(3)S(2)] ligand pyN(2)H(2)S(2)-H(2) [2,6-bis(2-mercaptophenylamino)dimethylpyridine] (1) in the presence of triethylamine did not yield the anticipated six-coordinate complex [Re(NMe)(eta(5)-pyN(2)HS(2))] (2), but rather resulted in cleavage of the Re(V)=NMe bond. A novel six-coordinate Re(IV) [N(3)S]/[NS] complex [Re(eta(4) SC(6)H(4)-2-NCH(2)-C(5)H(3)N-C=NC(6)H(4)-2-S)(eta(2)-NHC(6)H(4)-2-S)] (4) was thus obtained with the simultaneous coordination of 2-aminothiophenol, a dianionic bidentate [NS] donor resulting from the decomposition of the parent ligand and ligand 3, a dianionic tetradentate [N(3)S] donor formed by partial self-condensation and subsequent oxidation of the parent ligand 1. Crystal data for 4: C(25)H(18)N(4)S(3)Re.CH(2)Cl(2), monoclinic, space group P2(1)/n, a = 9.255(2) A, b = 11.181(2) A, c = 25.316(4) A, beta = 97.434(3) degrees , V = 2587.8(7) A(3) and Z = 4. PMID- 20703330 TI - Arabidopsis Histone Lysine Methyltransferases. AB - In eukaryotes, changes in chromatin structure regulate the access of gene regulatory sequences to the transcriptional machinery and play important roles in the repression of transposable elements, thereby protecting genome integrity. Chromatin dynamics and gene expression states are highly correlated, with DNA methylation and histone post-translational modifications playing important roles in the establishment or maintenance of chromatin states in plants. Histones can be covalently modified in a variety of ways, thereby affecting nucleosome spacing and/or higher-order nucleosome interactions directly or via the recruitment of histone-binding proteins. An extremely important group of chromatin modifying enzymes are the histone lysine methyltransferases (HKMTs). These enzymes are involved in the establishment and/or maintenance of euchromatic or heterochromatic states of active or transcriptionally repressed sequences, respectively. The vast majority of HKMTs possess a SET domain named for the three Drosophila proteins that are the founding members of the family: Suppressor of variegation, Enhancer of zeste and Trithorax. It is the SET domain that is responsible for HKMT enzymatic activity. Mutation of Arabidopsis HKMT genes can result in phenotypic abnormalities due to the improper regulation of important developmental genes. Here, we review the different classes of HKMTs present in the model plant Arabidopsis thaliana and discuss what is known about their biochemical and biological functions. PMID- 20703329 TI - The use of divalent metal ions by type II topoisomerases. AB - Type II topoisomerases are essential enzymes that regulate DNA under- and overwinding and remove knots and tangles from the genetic material. In order to carry out their critical physiological functions, these enzymes utilize a double stranded DNA passage mechanism that requires them to generate a transient double stranded break. Consequently, while necessary for cell survival, type II topoisomerases also have the capacity to fragment the genome. This feature of the prokaryotic and eukaryotic enzymes, respectively, is exploited to treat a variety of bacterial infections and cancers in humans. All type II topoisomerases require divalent metal ions for catalytic function. These metal ions function in two separate active sites and are necessary for the ATPase and DNA cleavage/ligation activities of the enzymes. ATPase activity is required for the strand passage process and utilizes the metal-dependent binding and hydrolysis of ATP to drive structural rearrangements in the protein. Both the DNA cleavage and ligation activities of type II topoisomerases require divalent metal ions and appear to utilize a novel variant of the canonical two-metal-ion phosphotransferase/hydrolase mechanism to facilitate these reactions. This article will focus primarily on eukaryotic type II topoisomerases and the roles of metal ions in the catalytic functions of these enzymes. PMID- 20703332 TI - Duty Cycle of Deformational Loading Influences the Growth of Engineered Articular Cartilage. AB - This study examines how variations in the duty cycle (the duration of applied loading) of deformational loading can influence the mechanical properties of tissue engineered cartilage constructs over one month in bioreactor culture. Dynamic loading was carried out with three different duty cycles: 1 h on/1 h off for a total of 3 h loading/day, 3 h continuous loading, or 6 h of continuous loading per day, with all loading performed 5 days/week. All loaded groups showed significant increases in Young's modulus after one month (vs. free swelling controls), but only loading for a continuous 3 and 6 h showed significant increases in dynamic modulus by this time point. Histological analysis showed that dynamic loading can increase cartilage oligomeric matrix protein (COMP) and collagen types II and IX, as well as prevent the formation of a fibrous capsule around the construct. Type II and IX collagen deposition increased with increased with duration of applied loading. These results point to the efficacy of dynamic deformational loading in the mechanical preconditioning of engineered articular cartilage constructs. Furthermore, these results highlight the ability to dictate mechanical properties with variations in mechanical input parameters, and the possible importance of other cartilage matrix molecules, such as COMP, in establishing the functional material properties of engineered constructs. PMID- 20703333 TI - Vision screening in preschool children: do the data support universal screening? AB - BACKGROUND: Comprehensive, systematic reviews on the benefit of vision screening in preschool children were published in 2008 by major national organizations in both Germany and the United Kingdom. These reviews raised public interest in the topic. METHODS: This article contains a discussion of the sensitivity, specificity, efficacy, and cost-effectiveness of preschool vision screening, on the basis of the two national reports mentioned above as well as relevant literature retrieved by a selective PubMed search. RESULTS: All studies that have been published to date on the efficacy of preschool visual screening suffer from methodological flaws. The available data suggest a benefit from screening, though this has not been proven. Model calculations reveal that the positive predictive value of screening tests performed in isolation is inadequate. The authors of the two national reports applied different methods and arrived at similar, but not identical conclusions. Preschool vision screening may also be cost-effective; whether this is the case or not depends on the probability of a long-term benefit -specifically, on the probability of preventing bilateral loss of vision in adulthood. To prevent one such case, it is estimated that 13 cases of childhood amblyopia must be identified and successfully treated (number needed to treat [NNT] = 13). CONCLUSION: The available data do not allow any firm conclusion about the efficacy and cost-effectiveness of preschool vision screening. Further clinical studies are needed to answer these questions. PMID- 20703334 TI - Grades on the second medical licensing examination in Germany before and after the Licensing Reform of 2002: a study in two medical schools in Bavaria. AB - BACKGROUND: When the German national medical licensing regulations were changed in 2002, the second part of the medical licensing examination was supplemented with a practical component and expanded from one day to two. The aim of this study was to assess the written and oral-practical examination grades before and after the licensing reform. METHODS: We compared the results that were obtained on the oral and written components of the second part of the national medical licensing examination under the old and new regulations (M2o and M2n, respectively) by a total of 2056 students at the Technical University (TUM) and Ludwig-Maximilian University (LMU) medical schools, both in Munich, from the spring of 2004 to the spring of 2008. We assessed the grades themselves as well as the correlation between the grades on the oral and written components before and after the reform. RESULTS: Grades on the written component of the examination did not differ to any statistically significant extent before and after the reform (TUM: M2o 2.91+/-0.92, M2n 2.91+/-0.87. LMU: M2o 2.94+/-0.85, M2n 2.78+/ 0.873). There was, however, a significant change in the oral examination grades (TUM: M2o 1.89+/-0.81, M2n 2.22+/-0.96; p<0.001. LMU: M2o 1.94+/-0.86, M2n 2.09+/ 0.93, p<0.001). CONCLUSION: Additional analysis of the grades obtained before and after the reform reveals a significantly increased concordance between grades on the oral and written components of the examination. PMID- 20703335 TI - Differentiation is useful. PMID- 20703336 TI - Legal regulations. PMID- 20703338 TI - The treatment of patients with HIV. AB - BACKGROUND: Infection with the human immunodeficiency virus (HIV) remains a major medical challenge. METHODS: Selective literature review, including the current German/Austrian, European, and American guidelines on the treatment of HIV infection in adults. RESULTS: In Germany, 3000 persons become infected with HIV each year; in 2009, 67,000 persons in Germany were living with HIV. When highly active antiretroviral therapy (HAART) is initiated in time, patients can achieve a nearly normal life expectancy. Nonetheless, in Germany as elsewhere, 30% of patients receive the diagnosis of HIV infection only when they have reached the AIDS stage of the disease or are suffering from advanced immunodeficiency. HAART should be started, at the latest, when the CD4-positive helper cell count drops below 350/microL. Primary drug resistances, accompanying illnesses, and the patient's living circumstances must all be taken into account in the selection of antiretroviral drugs. The goal of treatment is lasting suppression of HIV-RNA to below 50 copies per milliliter of plasma. CONCLUSIONS: HIV testing should be offered to all patients at high risk for HIV infection and all persons newly diagnosed with a sexually transmitted disease. As persons with HIV grow older, their treatment is complicated by increasing comorbidity and requires increased vigilance for possible drug interactions. PMID- 20703339 TI - Responsibility of psychiatrists: Need for pragmatic idealism. PMID- 20703341 TI - Psychological effects of low intensity conflict (LIC) operations. AB - BACKGROUND: A burgeoning clinical and empirical literature has provided incontrovertible evidence that combat operations exact a heavy toll in terms of human suffering not only on combatants but also military support personnel. Though the Indian army is engaged in low intensity conflict (LIC) operations for over five decades, the psychological effects of LIC deployment on soldiers have not been adequately studied. AIMS: To evaluate the psychological effects of deployment in LIC operations on service personnel. METHODS: Five hundred and sixty-eight servicemen engaged in LIC operations and equal number of age- and rank-matched personnel in adjoining peace areas were evaluated with a self-made questionnaire, General Health Questionnaire (GHQ), Carroll Rating Scale for Depression (CRSD), State-Trait Anxiety Inventory (STAI), Michigan Alcoholism Screening Test (MAST), Impact of Events Scale (IES), Perceived Stress Questionnaire (PSQ), Multidimensional Fatigue Inventory (MFI), Hindi PEN inventory, Satisfaction With Life Scale (SWLS) and Locus Of Control (LOC) scale. RESULTS: Respondents from LIC area had significantly higher scores on CRSD, MAST, GHQ, IES, and general fatigue, physical fatigue, and mental fatigue subscale of the MFI in comparison to those located in other areas. Significantly higher number of respondents from highly active LIC and with more than one-year service in LIC scored above cut-off levels on CRSD, MAST and GHQ. CONCLUSIONS: The psychological status of troops was directly related both to the duration of stay and the nature of LIC area. PMID- 20703342 TI - Anti-amnestic properties of Brahmi and Mandookaparni in a rat model. AB - BACKGROUND: We had previously demonstrated that a complex herbal formulation (Mentat; Himalaya Drug Company, Bangalore) attenuated anterograde and retrograde amnesia induced by electroconvulsive shocks (ECS) in rats. We later showed that a simplified formulation (Memorin; Phyto Pharma, Kolhapur) had similar effects. AIMS: In an attempt to identify the ingredients (of the complex formulation), which purveyed the cognitive benefits, we studied two of the constituent herbs, Brahmi and Mandookaparni, separately and together. The experiments included both active (piracetam) and inactive (vehicle) controls. METHODS: Adult, male, Sprague Dawley rats (n=8 per group) were randomized to receive Brahmi, Mandookaparni, a combination of these two herbs (A300), piracetam, or vehicle from days 1 to 15. On days 11 and 12, the rats were trained in a T-maze using a food-driven paradigm. On days 13 and 14, half the rats in each group received 2 ECS (60 mC charge) per day, 5 hours apart. On day 15, recall of pre-ECS learning was assessed. On day 16, transfer of learning was assessed. RESULTS: None of the active treatments facilitated pre-ECS learning or influenced ECS seizure duration; however, all showed varying but generally favourable profiles in the attenuation of ECS-induced retrograde and anterograde amnesia. The combination of Brahmi and Mandookaparni showed no especial advantage over the individual herbs. CONCLUSION: Brahmi and Mandookparni do not in themselves improve learning; however, each attenuates the amnestic effects of ECS without showing synergism in this beneficial action. Exercises in research and development are indicated to further investigate the anti-amnestic properties of these herbs, and to identify the specific chemical constituents which have procognitive effects. PMID- 20703340 TI - Study of childhood onset schizophrenia (COS) using SPECT and neuropsychological assessment. AB - BACKGROUND: In recent years, the development of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging has enhanced our understanding of the physiological functioning of the intact brain. AIM: To study cerebral cortical perfusion defects in patients with childhood onset schizophrenia (COS) and to assess their neuropsychological functioning. METHODS: This cross-sectional study comprised 14 patients with COS with onset at or before 14 years of age, diagnosed as per ICD-10 DCR criteria, attending a tertiary care centre in North India. All the patients were assessed on sociodemographic, clinical profile sheet, Positive and Negative Symptom Scale (PANSS) and Edinburgh Handedness Inventory (EHI). The Wisconsin Card Sorting Test (WCST) was used to assess their neuropsychological functioning. All patients underwent SPECT. A control group of 10 healthy subjects was studied with SPECT for comparison. RESULTS: Nine patients (64.3%) showed perfusion anomaly on SPECT scan specifically in the left temporal and frontal areas of the brain. On WCST score these 9 patients showed a higher percentage of total errors (64.49%+/-9.42%) as compared to the other 5 patients (48.54%+/-12.70%) who showed no abnormality on SPECT scan. All normal control subjects showed no abnormality on SPECT. CONCLUSION: The results from WCST show that COS patients have difficulty in executive functioning. Also, patients had perfusion anomaly in the left temporal, frontal and parietal areas. Deficits found in COS are similar to those found in adult onset schizophrenia (AOS). In view of the findings, the nature of COS and its relationship with AOS are discussed. PMID- 20703343 TI - Randomized controlled trial of standardized Bacopa monniera extract in age associated memory impairment. AB - BACKGROUND: Brahmi (Bacopa monniera) is a traditional Indian medicinal plant which causes multiple effects on the central nervous system. The standardized extract of this plant has shown enhanced behavioural learning in preclinical studies and enhanced information processing in healthy volunteers. AIM: To study the efficacy of standardized Bacopa monniera extract (SBME) in subjects with age associated memory impairment (AAMI) without any evidence of dementia or psychiatric disorder. METHODS: A double-blind, placebo-controlled randomized study design was employed. The subjects received either 125 mg of SBME or placebo twice a day for a period of 12 weeks followed by a placebo period of another 4 weeks (total duration of the trial 16 weeks). Each subject was evaluated for cognition on a battery of tests comprising mental control, logical memory, digit forward, digit backward, visual reproduction and paired associate learning. RESULTS: SBME produced significant improvement on mental control, logical memory and paired associated learning during the 12-week drug therapy. CONCLUSION: SBME is efficacious in subjects with age-associated memory impairment. PMID- 20703345 TI - Professional's progress: Learning from life and mistakes. PMID- 20703344 TI - A profile of substance abusers using the emergency services in a tertiary care hospital in Sikkim. AB - BACKGROUND: Sikkim, a state in Northeast India with a population of more than 500,000 and inhabited by indigenous population of Lepchas, Bhutias and Nepalis, lies in the foothills of the Himalayas sharing borders with Tibet, Nepal and Bhutan. Northeast India is a major source of injection drug users (IDUs) and associated HIV/AIDS. Alcohol use is traditionally prevalent in Sikkim and recently, IDU behaviour has also been reported, although systematic information on epidemiology and treatment availability of substance abuse in Sikkim is not available. AIM: To study the sociodemographic and drug use profile of substance abusers using the emergency services in a tertiary care hospital. METHODS: A retrospective chart review was used. Patients with history of current drug use seeking emergency services for any medical or surgical consequence incident to substance abuse from July 2000 to June 2005 (60 months) were included in the study. Data were generated from emergency case register, hospital records and case sheets. SPSS 10.0 was used for data analysis. RESULTS: Out of 54 patients seeking emergency services with substance abuse (1.16% of all psychiatric consultations), alcohol abusers were 77.8% and other opioid abusers 14.8%. Prevalence of IDU was 16.66%. Common opioids abused were dextrpropoxyphene and pentazocine, both analgesics. A significant number of patients (46.3%) had a history of >20 days/month frequency of abuse. Median of duration of abuse with all drugs was 12 years, while that with IDU population was 3 years. Alcohol withdrawal was the commonest cause (57.4%) of reporting to the emergency. Psychiatric comorbidity was found among 7.4%. Commonest medications used were chlordiazepoxide and clonidine, for withdrawal and naltrexone, for substitution. No standardized treatment protocol for substitution treatment was available. CONCLUSIONS: This is an initial attempt to study the sociodemographic and drug use profile of substance abusers in Sikkim. Demographic and socioeconomic characteristics of substance abusers seeking emergency services are not significantly different from treatment-seeking substance abusers in other parts of India. IDU behaviour has been detected and low median duration of use suggests an emerging problem and need for urgent harm reduction. Alcohol withdrawal was the commonest cause of seeking emergency services, which is related to high prevalence of alcohol abuse in Sikkim. No standardized substitution treatment is available for substance abusers, which may lead to higher rates of relapse. PMID- 20703346 TI - Self-awareness of depression and life events in three groups of patients: Psychotic depression, obsessive-compulsive disorder and chronic medical illness in North India. AB - BACKGROUND: Depression is a common experience across cultures although not all languages have words describing depression. AIM: To identify patients' perception and awareness of depression as an illness. METHODS: Sixty psychiatric patients (each with depression or obsessive-compulsive disorder [OCD]) were compared with 30 medical patients with chronic physical illness and assessed on levels of awareness of depression in relation to life events. RESULTS: Life events were more in patients with OCD compared to other two groups. All the three groups of patients had major depression. CONCLUSION: Absence of help-seeking for depression in patients with OCD and physical illness possibly indicate low level of awareness of depression in these patients. The findings are discussed in context of clinical practice. PMID- 20703347 TI - The course of bipolar disorder in rural India. AB - AIM: To examine the naturalistic course of bipolar disorder in a rural, community based, partially treated cohort. METHODS: All patients diagnosed with bipolar disorder during an epidemiological survey (n=34) in a rural area in India were followed longitudinally using standardized instruments, and the life-chart method used to examine their course. RESULTS: Seven (26%) of the 27 patients evaluated directly had not received any treatment whatsoever. Four patients (15%) had experienced rapid-cycling at some time; patients without rapid-cycling had experienced a mean 0.22 episodes/year. Episodes of mania accounted for 72% of all episodes. None of the variables examined appeared to predict the total number of episodes experienced by individual patients, although rapid-cycling occurred significantly more often if the patients had not received any psychopharmacological treatment. CONCLUSIONS: A mania-predominant course was observed in this small cohort, similar to reports from other developing countries. PMID- 20703348 TI - Conduct disorder-A sequelae of viral encephalitis. AB - An 11-year-old girl presented with a behavioural problem of 2 years' duration, which developed following an attack of viral encephalitis. Her behavioural changes had manifested as conduct disorder and were treated with pharmacotherapy as well as behavioural therapy. PMID- 20703349 TI - Body dysmorphic disorder, dysmorphophobia or delusional disorder-somatic subtype? AB - Excessive concern about the appearance of one's body is the hallmark of body dysmorphic disorder (BDD). A case with recurrent intrusive preoccupation and concern about the appearance of the face, ritualistic behaviours associated with this preoccupation, resulting in social and interpersonal difficulties is presented. The difficulty to draw a discrete boundary between BDD and a delusional disorder of somatic type is highlighted. PMID- 20703350 TI - Angioneurotic oedema with tadalafil: A rare case report. AB - A case is reported where the patient developed angioneurotic oedema of the lip after the use of tadalafil.1 On withdrawal of tadalafil, complete remission was obtained through required symptomatic treatment. Clinicians should be aware of the possibility of development of angioneurotic oedema in patients undergoing treatment with tadalafil. PMID- 20703351 TI - Starvation in obsessive-compulsive disorder due to scrupulosity. AB - This report describes an unusual presentation of obsessive-compulsive disorder (OCD) with predominant religious obsessions and compulsions (scrupulosity) in which the patient starved himself by keeping fast excessively to the extent of emaciation and extreme weakness even in walking and became bedridden. PMID- 20703352 TI - Use of humour in psychiatric practice: Can we do it properly? PMID- 20703353 TI - Awakening the kundalini of humour. PMID- 20703354 TI - The case for humour: Moving one step further. PMID- 20703355 TI - 'Humour-ability' of mental health professionals. PMID- 20703356 TI - Historicizing Indian psychiatry. PMID- 20703357 TI - Author's response-I. PMID- 20703358 TI - Author's response-II. PMID- 20703359 TI - Author's response-III. PMID- 20703360 TI - Indicators of suicidal attempt in depression. PMID- 20703361 TI - Shrink-wrapped isosurface from cross sectional images. AB - This paper addresses a new surface reconstruction scheme for approximating the isosurface from a set of tomographic cross sectional images. Differently from the novel Marching Cubes (MC) algorithm, our method does not extract the iso-density surface (isosurface) directly from the voxel data but calculates the iso-density point (isopoint) first. After building a coarse initial mesh approximating the ideal isosurface by the cell-boundary representation, it metamorphoses the mesh into the final isosurface by a relaxation scheme, called shrink-wrapping process. Compared with the MC algorithm, our method is robust and does not make any cracks on surface. Furthermore, since it is possible to utilize lots of additional isopoints during the surface reconstruction process by extending the adjacency definition, theoretically the resulting surface can be better in quality than the MC algorithm. According to experiments, it is proved to be very robust and efficient for isosurface reconstruction from cross sectional images. PMID- 20703362 TI - Changes in the Ability to Detect Ordinal Numerical Relationships Between 9 and 11 Months of Age. AB - When are the precursors of ordinal numerical knowledge first evident in infancy? Brannon (2002) argued that by 11 months of age, infants possess the ability to appreciate the greater than and less than relations between numerical values but that this ability experiences a sudden onset between 9 and 11 months of age. Here we present 5 experiments that explore the changes that take place between 9 and 11 months of age in infants' ability to detect reversals in the ordinal direction of a sequence of arrays. In Experiment 1, we replicate the finding that 11- but not 9-month-old infants detect a numerical ordinal reversal. In Experiment 2 we rule out an alternative hypothesis that 11-month-old infants attended to changes in the absolute numerosity of the first stimulus in the sequence rather than a reversal in ordinal direction. In Experiment 3, we demonstrate that 9-month-old infants are not aided by additional exposure to each numerosity stimulus in a sequence. In Experiment 4 we find that 11-month-old but not 9-month-old infants succeed at detecting the reversal in a nonnumerical size or area-based rule, casting doubt on Brannon's prior claim that what develops between 9 and 11 months of age is a specifically numerical ability. In Experiment 5 we demonstrate that 9 month-old infants are capable of detecting a reversal in ordinal direction but only when there are multiple converging cues to ordinality. Collectively these data indicate that at 11 months of age infants can represent ordinal relations that are based on number, size, or cumulative area, whereas at 9 months of age infants are unable to use any of these dimensions in isolation but instead require a confluence of cues. PMID- 20703363 TI - Amyloid-beta protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. AB - In recent years, small protein oligomers have been implicated in the aetiology of a number of important amyloid diseases, such as type 2 diabetes, Parkinson's disease and Alzheimer's disease. As a consequence, research efforts are being directed away from traditional targets, such as amyloid plaques, and towards characterization of early oligomer states. Here we present a new analysis method, ion mobility coupled with mass spectrometry, for this challenging problem, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates. We applied these methods to a number of the amyloid-beta protein isoforms of Abeta40 and Abeta42 and showed that their oligomer-size distributions are very different. Our results are consistent with previous observations that Abeta40 and Abeta42 self-assemble via different pathways and provide a candidate in the Abeta42 dodecamer for the primary toxic species in Alzheimer's disease. PMID- 20703365 TI - Empirical Likelihood Based Inferences for Partially Linear Models with Missing Covariates. AB - This paper considers statistical inference for partially linear models Y = X(T)mu + nu(Z) + epsilon when the linear covariate X is missing with missing probability pi depending upon (Y, Z). We propose empirical likelihood based statistics to construct confidence regions for beta and nu(z). The resulting statistics are shown to be asymptotically chi-squared distributed. Finite sample performance of the proposed statistics is assessed by simulation experiments. The proposed methods are applied to a data set from an AIDS clinical trial. PMID- 20703364 TI - Fluorogenic Tagging of Peptide and Protein 3-Nitrotyrosine with 4-(Aminomethyl) benzenesulfonic Acid for Quantitative Analysis of Protein Tyrosine Nitration. AB - Protein 3-nitrotyrosine (3-NT) has been recognized as an important biomarker of nitroxidative stress associated with inflammatory and degenerative diseases, and biological aging. Analysis of protein-bound 3-NT continues to represent a challenge since in vivo it frequently does not accumulate on proteins in amounts detectable by quantitative analytical methods. Here, we describe a novel approach of fluorescent tagging and quantitation of peptide-bound 3-NT residues based on the selective reduction to 3-AT followed by reaction with 4-(amino methyl)benzenesulfonic acid (ABS) in the presence of K(3)Fe(CN)(6) to form a highly fluorescent 2-phenylbenzoxazole product. Synthetic 3-NT peptide (0.005-1 MUM) upon reduction with 10 mM sodium dithionite and tagging with 2 mM ABS and 5 MUM K(3)Fe(CN)(6) in 0.1 M Na(2)HPO(4) buffer (pH 9.0) was converted with yields >95% to a single fluorescent product incorporating two ABS molecules per 3-NT residue, with fluorescence excitation and emission maxima at 360 +/- 2 and 490 +/ 2 nm, respectively, and a quantum yield of 0.77 +/- 0.08, based on reverse-phase LC with UV and fluorescence detection, fluorescence spectroscopy and LC-MS-MS analysis. This protocol was successfully tested for quantitative analysis of in vitro Tyr nitration in a model protein, rabbit muscle phosphorylase b, and in a complex mixture of proteins from C2C12 cultured cells exposed to peroxynitrite, with a detection limit of ca. 1 pmol 3-NT by fluorescence spectrometry, and an apparent LOD of 12 and 40 pmol for nitropeptides alone or in the presence of 100 MUg digested cell proteins, respectively. LC-MS-MS analysis of ABS tagged peptides revealed that the fluorescent derivatives undergo efficient backbone fragmentations, allowing for sequence-specific characterization of protein Tyr nitration in proteomic studies. Fluorogenic tagging with ABS also can be instrumental for detection and visualization of protein 3-NT in LC and gel-based protein separations. PMID- 20703366 TI - Religious Involvement, Humility, and Self-Rated Health. AB - The purpose of this study is to develop and test a conceptual model that assesses the following theoretical linkages: (1) people who go to church more often tend to receive more spiritual support from fellow church members (i.e., encouragement to adopt religious teachings and principles); (2) individuals who get more frequent spiritual support are more likely to be humble; and (3) people with greater humility tend to rate their health more favorably. The data come from the third wave of a nationwide longitudinal survey of older adults. The data provide support for each of the conceptual linkages identified above. PMID- 20703367 TI - Forest clearing in the Ecuadorian Amazon: A study of patterns over space and time. AB - This study tests four hypotheses related to forest clearing over time in Ecuador's northern Amazon: (1) a larger increase in population over time on a farm (finca) leads to more deforestation; (2) rates of forest clearing surrounding four primary reference communities differ (spatial heterogeneity); (3) fincas farther from towns/communities experience lower rates of forest clearing over time; and (4) forest clearing differs by finca settlement cohort, viz., by year of establishment of the finca. In this paper, we examine the relationship between forest clearing and key variables over time, and compare three statistical models-OLS, random effects, and spatial regression-to test hypotheses. Descriptive analyses indicate that 7-15% of forest area was cleared on fincas between 1990 and 1999; that more recently established fincas experienced more rapid forest clearing; and that population size and forest clearing are both related to distance from a major community. Controlling for key variables, model results indicate that an increase in population size is significantly related to more forest clearing; rates of forest clearing around the four major communities are not significantly different; distances separating fincas and communities are not significantly related to deforestation; and deforestation rates are higher among more recently established fincas. Key policy implications include the importance of reducing population growth and momentum through measures such as improving information about and provision of family planning services; increasing the low level of girls education to delay and reduce fertility; and expanding credit and agricultural extension services to increase agricultural intensification. PMID- 20703368 TI - The Effects of Mexican origin family structure on parental monitoring and pre adolescent substance use expectancies and substance use. AB - Substance use among Mexican origin, low-income youths is a serious, but under studied problem. This study examines the relationship between the structure of Mexican origin families (i.e. nuclear, single-parent, blended or extended), and the parental monitoring, substance use expectancies, and substance use reported by pre-adolescents. Family structure did not differentiate the substance use prevalence, expectancies or parental monitoring among the 1224 low-income, Mexican-origin fifth grade participants. Parents from all family types demonstrated similar levels of parental monitoring. More importantly, family composition was not related to pre-adolescents' substance use. Other analyses showed that the relationship between substance use and certain demographic variables (e.g. gender, country of birth, language use) did not differ across family structures. The report concludes by discussing possible developmental and resiliency factors in Mexican origin families that would account for these findings. PMID- 20703369 TI - Measuring Study-Specific Heterogeneity in Meta-Analysis: Application to an Antecedent Biomarker Study of Alzheimer's Disease. AB - This article proposes several new indices that measure the heterogeneity for individual studies in a meta-analysis. These indices directly assess how inconsistent an individual study is compared to the rest of studies used in the meta-analysis, that is, how much impact the specific study has on the scientific conclusion of the meta-analysis and further on the generalization of the conclusion. The proposed indices can be intuitively interpreted as the proportion of total variance from all studies in a meta-analysis that can be accounted for by the heterogeneity from specific studies. Further, each proposed index over all the studies sums to the collective measure of heterogeneity for the meta analysis. Therefore our proposed study-specific indices of heterogeneity can be regarded as a generalization of the collective index of heterogeneity in meta analyses proposed by various authors. We examine the difference among the proposed study-specific measures of heterogeneity and assess the variation associated with each proposed index of heterogeneity through a large simulation study. Finally, we demonstrate the proposed methodology by assessing the effect of individual studies on the overall estimate to the difference of an antecedent biomarker of Alzheimer's disease (AD) between different Apolipoprotein E (ApoE) genotypes. PMID- 20703370 TI - Gender Differences in Functional Health and Mortality Among the Chinese Elderly: Testing an Exposure Versus Vulnerability Hypothesis. AB - In this study, the authors focused on older adults in Beijing with three objectives: to examine gender differences in functional health and mortality at the end of a five-year study period, controlling for initial functional health; to determine the extent to which these differences were a function of exposure versus vulnerability to risk factors; and to analyze the relative importance of social, economic, and psychological risk factors in explaining gender differences. The results show that women were more likely to survive and to be functionally dependent at follow-up compared with men among those functionally independent at baseline. No significant differences among those who were initially dependent were apparent. Differential vulnerability to risk factors, more so than exposure, explained the variation in health outcomes across gender. Smoking, a lack of formal education, a lack of health insurance, a low sense of control, stressful events, and rural living played large roles in explaining the differences. PMID- 20703371 TI - Synthesis of the fluorescent amino acid rac-(7-hydroxycoumarin-4-yl)ethylglycine. AB - The hydrochloride of the racemic amino acid (7-hydroxycoumarin-4-yl)ethylglycine, a versatile fluorescent probe in proteins, has been synthesized in five steps from commercially available (7-hydroxycoumarin-4-yl)acetic acid. The key step involves the alkylation of a glycine-enolate equivalent. PMID- 20703372 TI - Structure and reactivity in neutral organic electron donors derived from 4 dimethylaminopyridine. AB - The effects on the redox properties of modifying the molecular skeleton of neutral bis-2-(4-dimethylamino)pyridinylidene electron donors, derived from 4 dimethylaminopyridine (4-DMAP), have been explored, by varying two parameters: (i) the length of a polymethylene chain linking the two pyridine-derived rings and (ii) the nature of the nitrogen substituents on the 4 and 4' positions of the precursor pyridines. Restricting the bridge length to two methylene units significantly altered the redox profile, while changes in the nitrogen substituents at the 4 and 4' positions led to only slight changes in the redox potentials. PMID- 20703373 TI - Symmetry breaking and structure of a mixture of nematic liquid crystals and anisotropic nanoparticles. AB - Orientational ordering of a homogeneous mixture of uniaxial liquid crystalline (LC) molecules and magnetic nanoparticles (NPs) is studied using the Lebwohl Lasher lattice model. We consider cases where NPs tend to be oriented perpendicularly to LC molecules due to elastic forces. We study domain-type configurations of ensembles, which are quenched from the isotropic phase. We show that for large enough concentrations of NPs the long range uniaxial nematic ordering is replaced by short range order exhibiting strong biaxiality. This suggests that the impact of NPs on orientational ordering of LCs for appropriate concentrations of NPs is reminiscent to the influence of quenched random fields which locally enforce a biaxial ordering. PMID- 20703374 TI - Addition of lithiated enol ethers to nitrones and subsequent Lewis acid induced cyclizations to enantiopure 3,6-dihydro-2H-pyrans - an approach to carbohydrate mimetics. AB - A stereodivergent synthesis of enantiopure 3,6-dihydro-2H-pyrans is presented. The addition of lithiated enol ethers to carbohydrate-derived nitrones afforded syn- or anti-configured hydroxylamine derivatives 4a-d that were cyclized under Lewis acidic conditions to yield functionalized dihydropyrans cis- or trans-5a-d containing an enol ether moiety. This functional group was employed for a variety of subsequent reactions such as dihydroxylation or bromination. Bicyclic enol ether 19 was oxidatively cleaved to provide the highly functionalized ten membered ring lactone 20. The synthesized enantiopure aminopyrans 24, 26, 28 and 30 can be regarded as carbohydrate mimetics. Trimeric versions of 24 and 28 were constructed via their attachment to a tricarboxylic acid core. PMID- 20703375 TI - Suzuki-Miyaura cross-coupling reaction of 1-aryltriazenes with arylboronic acids catalyzed by a recyclable polymer-supported N-heterocyclic carbene-palladium complex catalyst. AB - The Suzuki-Miyaura cross-coupling reaction of 1-aryltriazenes with arylboronic acids catalyzed by a recyclable polymer-supported Pd-NHC complex catalyst has been realized for the first time. The polymer-supported catalyst can be re-used several times still retaining high activity for this transformation. Various aryltriazenes were investigated as electrophilic substrates at room temperature to give biaryls in good to excellent yields and showed good chemoselectivity over aryl halides in the reactions. PMID- 20703376 TI - Synthesis, electronic properties and self-assembly on Au{111} of thiolated (oligo)phenothiazines. AB - (Oligo)phenothiazinyl thioacetates, synthesized by a one-pot sequence, are electrochemically oxidizable and highly fluorescent. SAMs can be readily formed from thiols prepared by in situ deprotection of the thioacetates in the presence of a gold-coated silicon wafer. Monolayer formation is confirmed by ellipsometry and the results compared to those obtained by force field and DFT calculations. PMID- 20703377 TI - Synthesis of oxa-bridged derivatives from Diels-Alder bis-adducts of butadiene and 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene. AB - Bis-adducts of 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene and 1,3-butadiene, generated in situ from 3-sulfolene, have been synthesized in excellent yield. Ruthenium catalyzed oxidation of the bis-adducts followed by a one-pot transformation of the resulting alpha-diketone furnished oxa-bridged compounds. Unambiguous stereochemical assignments of both diastereomeric series are reported. PMID- 20703378 TI - RAFT polymers for protein recognition. AB - A new family of linear polymers with pronounced affinity for arginine- and lysine rich proteins has been created. To this end, N-isopropylacrylamide (NIPAM) was copolymerized in water with a binding monomer and a hydrophobic comonomer using a living radical polymerization (RAFT). The resulting copolymers were water-soluble and displayed narrow polydispersities. They formed tight complexes with basic proteins depending on the nature and amount of the binding monomer as well as on the choice of the added hydrophobic comonomer. PMID- 20703379 TI - Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective. AB - Since the discovery by Yagupolskii and co-workers that S-trifluoromethyl diarylsulfonium salts are effective for the trifluoromethylation of thiophenolates, the design and synthesis of electrophilic trifluoromethylating reagents have been extensively researched in both academia and industry, due to the significant unique features that trifluoromethylated compounds have in pharmaceuticals, agricultural chemicals, and functional materials. Several effective reagents have been developed by the groups of Yagupolskii, Umemoto, Shreeve, Adachi, Magnier, Togni and Shibata. Due to the high stability and reactivity of these reagents, a series of Umemoto reagents, Togni reagent and Shibata reagent are now commercially available. In this review, we wish to briefly provide a historical perspective of the development of so-called "shelf stable electrophilic trifluoromethylating reagents", although this field is in constant development. PMID- 20703380 TI - Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring. AB - We report the synthesis of a novel analogue of Alogliptin via condensation of two key intermediates one of which is an aminopiperidine derivative bearing a spirocyclic ring on the piperidine moiety. Preparation of the aminopiperidine intermediate was carried out by constructing the cyclopropyl ring prior to assembling the piperidine ring. PMID- 20703381 TI - Poly(glycolide) multi-arm star polymers: Improved solubility via limited arm length. AB - Due to the low solubility of poly(glycolic acid) (PGA), its use is generally limited to the synthesis of random copolyesters with other hydroxy acids, such as lactic acid, or to applications that permit direct processing from the polymer melt. Insolubility is generally observed for PGA when the degree of polymerization exceeds 20. Here we present a strategy that allows the preparation of PGA-based multi-arm structures which significantly exceed the molecular weight of processable oligomeric linear PGA (<1000 g/mol). This was achieved by the use of a multifunctional hyperbranched polyglycerol (PG) macroinitiator and the tin(II)-2-ethylhexanoate catalyzed ring-opening polymerization of glycolide in the melt. With this strategy it is possible to combine high molecular weight with good molecular weight control (up to 16,000 g/mol, PDI = 1.4-1.7), resulting in PGA multi-arm star block copolymers containing more than 90 wt % GA. The successful linkage of PGA arms and PG core via this core first/grafting from strategy was confirmed by detailed NMR and SEC characterization. Various PG/glycolide ratios were employed to vary the length of the PGA arms. Besides fluorinated solvents, the materials were soluble in DMF and DMSO up to an average arm length of 12 glycolic acid units. Reduction in the T(g) and the melting temperature compared to the homopolymer PGA should lead to simplified processing conditions. The findings contribute to broadening the range of biomedical applications of PGA. PMID- 20703382 TI - Chromo- and fluorophoric water-soluble polymers and silica particles by nucleophilic substitution reaction of poly(vinyl amine). AB - Novel chromophoric and fluorescent carbonitrile-functionalized poly(vinyl amine) (PVAm) and PVAm/silica particles were synthesized by means of nucleophilic aromatic substitution of 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile (1) with PVAm in water. The water solubility of 1 has been mediated by 2,6-O-beta dimethylcyclodextrin or by pre-adsorption onto silica particles. Furthermore, 1 was converted with isopropylamine into the model compound 1-M. All new compounds were characterized by NMR, FTIR, UV-vis and fluorescence spectroscopy. The solvent-dependent UV-vis absorption and fluorescence emission band positions of the model compound and the carbonitrile-functionalized PVAm were studied and interpreted using the empirical Kamlet-Taft solvent parameters pi(*) (dipolarity/polarizability), alpha (hydrogen-bond donating capacity) and beta (hydrogen-accepting ability) in terms of the linear solvation energy relationship (LSER). The solvent-independent regression coefficients a, b and s were determined using multiple linear correlation analysis. It is shown, that the chains of the polymer have a significant influence on the solvatochromic behavior of 1-P. The structure of the carbonitrile 1-Si bound to polymer-modified silica particles was studied by means of X-ray photoelectron spectroscopy (XPS) and Brunauer-Emmett-Teller (BET) measurements. Fluorescent silica particles were obtained as shown by fluorescence spectroscopy with a diffuse reflectance technique. PMID- 20703383 TI - Synthesis of 2a,8b-Dihydrocyclobuta[a]naphthalene-3,4-diones. AB - On irradiation (lambda = 350 nm) in neat hex-1-yne, naphthalene-1,2-dione monoacetals 1 afford mixtures of pentacyclic photodimers and up to 25% (isolated yield) of mixed photocycloadducts 2. Careful acidic hydrolysis of the acetal function of 2 gives the title compounds 3, the overall sequence representing a first approach to a (formal) [2 + 2] photocycloadduct of a 1,2-naphthoquinone to an alkyne. PMID- 20703384 TI - A surprising new route to 4-nitro-3-phenylisoxazole. AB - A one-pot synthesis of 4-nitro-3-phenylisoxazole has been carried out by treatment of cinnamyl alcohol dissolved in acetic acid with sodium nitrite; in addition, 4-phenyl-3-furoxanmethanol was obtained in 40% yield. PMID- 20703385 TI - Recent advances in carbocupration of alpha-heterosubstituted alkynes. AB - Carbocupration of alpha-heterosubstituted alkynes leads to the formation of stereodefined functionalized vinyl copper species as single isomer. Recent advances in the field show that a simple pre-association of the organometallic derivative with an additional polar functional group in the vicinity of the reaction center may completely change the stereochemical outcome of the reaction. Representative examples are given in this mini-review. PMID- 20703386 TI - Novel tetracyclic structures from the synthesis of thiolactone-isatin hybrids. AB - A simple and straightforward synthetic approach to potential anti-infective thiolactone-isatin hybrids led to the discovery of novel tetracyclic compounds which bear a macrocylic motif containing an unusual bridged amide bond. PMID- 20703388 TI - Three-dimensional modeling of a primary health care clinic in Ho, Ghana: its contribution to student engagement, fundraising, and program planning. AB - Improvements in computer-based technologies can be leveraged to enhance engagement of remote stakeholders with the health needs of a geographically distant community. Three-dimensional (3D) modeling offers a platform to create detailed spatial representations through which stakeholders can experience improvements in shared understanding as well as increased involvement in community health projects occurring anywhere in the world. This case study describes the development of a 3D model of a community health clinic in rural Ghana used to encourage fundraising and sustain global engagement among students at Northwestern University. The resulting 'virtual clinic' was achieved quickly and at little cost, suggesting a broader utility of 3D modeling for global health practitioners for increasing donor engagement and resource mapping. PMID- 20703387 TI - Air pollution and daily hospitalization rates for cardiovascular and respiratory diseases in London, Ontario. AB - In this paper, we examine the role that ambient air pollution plays in exacerbating cardiovascular and respiratory disease hospitalization in London, Ontario from 1 November 1995 to 31 December 2000. The number of daily cardiac and respiratory admissions was linked to concentrations of air pollutants (sulphur dioxide, nitrogen dioxide, ozone, carbon monoxide, coefficient of haze, PM(10)) and weather variables (maximum and minimum of temperature and humidity). Results showed that current day carbon monoxide and coefficient of haze produced significant percentage increase in daily cardiac admissions of 8.0% (95% CI: 1.5 11.5%) and 5.7% (95% CI: 0.9-10.8%) for people < 65 years old. PM(10) was found to be significantly associated with asthma admission in the > 65 group, with percentage increase in cardiac admission of 25% (95% CI: 2.8-52.3%) and 26.0% (95% CI: 5.3-50.9%) for current day and 2-day means, respectively. PMID- 20703389 TI - Comorbidity in psychiatry: Way forward or a conundrum? PMID- 20703390 TI - Failed suicide and deliberate self-harm: A need for specific nomenclature. AB - BACKGROUND: Out of those who attempted self-harm and survived, many actually wanted to die and many did not. Presently, no distinctive nomenclature exists for these two groups, which causes difficulty in understanding as well as in management and research. AIM: To study whether there exist two such groups which are distinct and can be differentiated clinically. METHODS: Seventy-eight persons who attempted self-harm were evaluated in detail by a psychiatrist. The data were recorded in an especially designed proforma which documented sociodemographic variables, psychiatric and physical illnesses, psychosocial stress factors, substance abuse, past and family history and details of suicide attempt. RESULTS: Two groups emerged with distinct characteristics. The two groups were different in factors such as age, diagnosis, intentionality, lethality, mode, motive to kill oneself, past/family history, relation to stress, personality traits and precaution to prevent detection before and/or after the act. The group which had persons who really wanted to die but survived is suggested to be named as the 'failed suicide' group and the other group which had persons who did not actually want to die is suggested to be named as the 'deliberate self-harm' group. CONCLUSION: THOSE WHO CAUSE HARM TO THEMSELVES BUT SURVIVE CAN BE DISTINCTLY PUT INTO TWO GROUPS: (i) the 'failed suicide' group constituting those who actually wanted to kill themselves and (ii) the 'deliberate self-harm' group constituting those who did not actually want to die. The criteria for distinctions are suggested. PMID- 20703391 TI - Assessment of mortality and marital status of schizophrenic patients over a period of 13 years. AB - BACKGROUND: Studies on standardized mortality rates of schizophrenic patients might help to increase the life span of these patients. Such data from developing countries including India are lacking. Investigations that provide clues regarding the quality of their family lives could also be beneficial. AIM: Besides mortality and causes of death, this study was also aimed to examine the marital status of a group of schizophrenic patients over a period of 13 years. METHODS: Out of 121 schizophrenic patients recruited earlier for a different purpose, 60 were re-assessed after a period of 13 years with regard to their mortality and causes of death. The proportion of those who had to remain single because the onset of their illness was before they were 25 years of age were compared with those who had a later onset. RESULTS: Seven deaths were recorded and the standardized mortality ratio (SMR) for all the age groups was 54.2. One patient who had absconded was not counted as a case of death. Furthermore, this trend of a high SMR persisted despite merging both the cohort and un-reassessed group (SMR 25.1) with and without known mortality. Among the deaths, the unnatural causes of death were noteworthy (28.57%)-1 accidental and another suicidal. Some deaths were probably due to poor general medical care. The proportion of patients who had to remain single because their onset of illness was before 25 years of age was significantly more than those with a later onset (p<0.001). CONCLUSION: It is speculated that strengthening the general healthcare delivery system for the mentally ill and sensitizing caregivers about the possible risky behaviours of patients might reduce the mortality. PMID- 20703392 TI - Psychiatric morbidity in geriatric people. AB - BACKGROUND: The number of geropsychiatric patients is increasing but sufficient work has not been done in this area in many parts of India. AIM: This study explored the sociodemographic profile and clinical characteristics of patients aged 60 years and above, attending the psychiatric services of Institute of Medical Sciences and geropsychiatric patients of Mumukshu Bhavan (old age home) in Varanasi from September 1998 to September 1999. METHODS: For the screening of psychiatric patients at Mumukshu Bhavan the Indian Psychiatric Survey Schedule was used. DSM-IV criteria were used for the diagnosis of patients and Chi-square test with Yate correction and Z-test were used for statistical analysis. RESULTS: Depressive disorders were the most common psychiatric illnesses. Many patients had associated physical illnesses and among them hypertension was the most common. Family jointness was adequate for most of the patients. Objective social support was moderate for the majority of patients but perceived social support was poor. Patients of Mumukshu Bhavan perceived their social support to be either moderate or good. CONCLUSION: Depressive disorder was the most common psychiatric illness and among the physical illnesses hypertension was the commonest. People living in the old age home felt better than those who lived with their children's family. PMID- 20703393 TI - Disability associated with mental disorders. AB - BACKGROUND: Disability associated with mental illness is a major contributor to the global burden of disease. The present study looks at some aspects of disability associated with 7 psychiatric disorders: schizophrenia, bipolar affective disorder, anxiety disorders, depression, obsessive-compulsive disorder, dementia, and mental and behavioural disorders due to the use of alcohol. AIMS: (i) To evaluate the nature and quantity of disabilities in the study groups; (ii) to compare the degree of disability with the severity of the disorder; (iii) to compare disability among various disorders; and (iv) to study the longitudinal stability of disability in the disease groups. METHODS: A total of 228 patients attending the OPD, Department of Psychiatry, Assam Medical College, Dibrugarh, between July 2003 and June 2004, who were diagnosed as per ICD-10 guidelines and SCAN, were included in the study. Severity was assessed by the application of some commonly used rating scales for each specific disorder. The level of disability was assessed by using the Indian Disability Evaluation and Assessment Scale (IDEAS). Patients were followed up at 6 and 12 months. Statistical analysis was done on SPSS version 10. RESULTS: All the 7 disorders under study are associated with significant disability; schizophrenia being maximally disabling. Disability associated with alcohol use disorder and anxiety is comparable to disability on account of OCD. Over a period of 12 months, disability due to depression, alcohol use disorder and anxiety tend to remain significant. PMID- 20703394 TI - Neuropsychological disposition and its impact on the executive functions and cognitive style in patients with obsessive-compulsive disorder. AB - BACKGROUND: Recent brain imaging and electrophysiological studies have consistently shown dysfunction of the fronto-striatal thalamic pathways in patients with obsessive-compulsive disorder (OCD). AIM: To study the relationship of neuropsychological disposition with the executive functions and cognitive style in patients with OCD. METHODS: Twenty OCD patients (14 males, 6 females) and 20 normal control subjects, matched for all relevant variables including age, sex and education, were studied. Neuropsychological disposition was assessed on the Adult Neuropsychological Questionnaire (ANQ), the executive functions were assessed through Wisconsin Card Sorting Test (WCST), and the cognitive style was assessed by employing the Embedded Figure Test (EFT). RESULTS: Subcortical cerebellar-spinal domain of ANQ was found to be associated with cognitive style and executive functions. CONCLUSION: The impairment of executive functions and poor activation of specific neurological circuitry in OCD patients affirms the neurobiological basis of the disorder. PMID- 20703395 TI - Psychiatry must not be separated from its historical and cultural context. PMID- 20703396 TI - Psychiatry, colonialism and Indian civilization: A historical appraisal. PMID- 20703397 TI - Author'S response. PMID- 20703398 TI - Psychological assessment of alcoholism in males. AB - BACKGROUND: Little work has been done in India on the personality factors of alcoholics. These personality factors have a significant effect on treatment outcome. AIM: To study the personality characteristics, stressful life events and diagnostic utility of the Michigan Alcoholism Screening Test (MAST) and CAGE (Cutting down, Annoyance by criticism, Guilty feeling, and Eye-opener) Questionnaire in service personnel with alcohol dependence. METHODS: Psychological assessment of 100 consecutive male inpatients meeting the DSM-IV criteria for alcohol dependence, and an equal number of controls matched for age, sex, occupation and regional background was carried out utilizing the MAST, CAGE Questionnaire, State-Trait Anxiety Inventory, Hamilton Rating Scale for Depression, Multiphasic Personality Questionnaire, Maudsley Personality Inventory, Toronto Alexithymia Scale, Self-esteem Inventory and Presumptive Stressful Life Events scale. RESULTS: The MAST and CAGE were of limited value in the diagnosis of alcohol dependence. Alcoholics obtained significantly higher scores on state and trait anxiety, depression, mania scale, paranoia scale, schizophrenia scale, psychopathic deviance, neuroticism, extroversion, and the Presumptive Stressful Life Events scale. Alcohol-dependent individuals had significantly lower self-esteem compared with control subjects, and significantly more alcoholics were identified as alexithymic. CONCLUSION: Alcohol-dependent individuals show significantly high neuroticism, extroversion, anxiety, depression, psychopathic deviation, stressful life events and significantly low self-esteem as compared with normal control subjects. Significantly more alcoholics were found to be alexithymic compared with normal controls. PMID- 20703399 TI - Efficacy and tolerability of injectable sodium valproate in patients with mania. AB - BACKGROUND: Sodium valproate is among the newer mood stabilizers and is also an anticonvulsant. AIM: To assess the effect of intravenous sodium valproate in patients with acute manic episodes of bipolar disorder. METHODS: A 1-week open trial was conducted in the year 2004-2005 at the emergency ward of the Psychiatric Centre, SMS Medical College, Jaipur, in which 30 patients participated. CONCLUSION: Substantial improvement was seen. No major side-effects were noted except marginal elevation of the SGOT and SGPT. The findings suggest that injectable sodium valproate is a safe and effective mood stabilizer for patients with mania. PMID- 20703400 TI - Is this 'complicated' opioid withdrawal? AB - Seven patients with opioid dependence admitted in the de-addiction centre for detoxification developed convulsions and delirium during the withdrawal phase. After ruling out all other possible causes of these complications, opioid withdrawal seemed to emerge as the most likely explanation. The unpredictability of the course of opioid dependence and withdrawal needs to be considered when treating patients with opioid dependence. PMID- 20703401 TI - Ganser syndrome and lesion in the temporoparietal region. AB - Ganser syndrome is a rare dissociative disorder. It has been reported in association with various functional psychiatric disorders and organic states, most often in patients with head injury and stroke, especially those involving the frontal lobes. The present case of Ganser syndrome had features of hysterical dissociation but was found to have haemorrhage in the temporoparietal region of the dominant hemisphere. The complexities of Ganser syndrome in the presence of an organic lesion with an overwhelming emotional component are discussed. PMID- 20703402 TI - Proctalgia fugax with dysthymia. AB - A rare case of proctalgia fugax with dysthymia which was successfully treated with dothiepin and other psychological interventions. PMID- 20703403 TI - Clozapine-induced cardiac failure. AB - A 73-year-old woman with dementia was given clozapine for treatment-resistant psychotic symptoms. Subsequently, she developed cardiac failure. Caution should be exercised when using clozapine, especially in the elderly. PMID- 20703404 TI - Sore throat and obsessions: A causal link? PMID- 20703405 TI - Critical appraisal of an article on factitious schizophrenia. PMID- 20703406 TI - Life as I know it. PMID- 20703407 TI - Evidence-based practices in mental health: Distant dream or emerging reality? PMID- 20703408 TI - Psychiatry in India: Need to focus on geriatric psychiatry. PMID- 20703410 TI - Cognitive and emotional effects of renal transplantation. AB - BACKGROUND: Recent studies have shown a high prevalence of depression and cognitive changes in patients with end-stage renal disease (ERSD) and renal transplant recipients. There are few data available on the cognitive and emotional changes in patients undergoing renal transplantation in India. AIM: To evaluate the changes in cognitive profile and depression in renal transplant recipients. METHODS: Thirty consecutive patients undergoing renal transplantation were evaluated 1 month before and 3 months after successful renal transplant with Beck Depression Inventory (BDI), Weschler Adult Performance Intelligence Scale (WAPIS), Luria Nebraska Neuropsychological battery (LNNB) and Life satisfaction scale. RESULTS: Our study revealed an 86.7% prevalence of depression in ESRD patients as compared to 56.7% in post renal transplant patients. Analysis of neurocognitive functions on LNNB did not reveal any significant impairment. Furthermore, analysis of the Life satisfaction scale revealed most of the patients scored high satisfaction levels despite the stress of their disease. Results on WAPIS brought out significant improvement in intelligence quotient (IQ) after renal transplantation. CONCLUSION: Successful renal transplant is associated with improvement in depression, IQ and life satisfaction. PMID- 20703409 TI - Cognitive deficits in psychiatric disorders: Current status. AB - Cognition denotes a relatively high level of processing of specific information including thinking, memory, perception, motivation, skilled movements and language. Cognitive psychology has become an important discipline in the research of a number of psychiatric disorders, ranging from severe psychotic illness such as schizophrenia to relatively benign, yet significantly disabling, non-psychotic illnesses such as somatoform disorder. Research in the area of neurocognition has started unlocking various secrets of psychiatric disorders, such as revealing the biological underpinnings, explaining the underlying psychopathology and issues related to course, outcome and treatment strategies. Such research has also attempted to uproot a number of previously held concepts, such as Kraepelin's dichotomy. Although the range of cognitive problems can be diverse, there are several cognitive domains, including executive function, attention and information processing, and working memory, which appear more frequently at risk. A broad range of impairment across and within the psychiatric disorders are highlighted in this oration. The oration summarizes the studies investigating cognitive processing in different psychiatric disorders. I will also discuss the findings of my own research on neurocognitive deficits in mood disorders, schizophrenia, obsessive-compulsive disorder, somatoform disorder, including studies on 'high-risk' individuals. Tracing the evaluation of neurocognitive science may provide new insights into the pathophysiology and treatment of psychiatric disorders. PMID- 20703411 TI - A comparison of the level of functioning in chronic schizophrenia with coping and burden in caregivers. AB - BACKGROUND: A chronic mental illness such as schizophrenia is a challenging task for caregivers especially in the current era of de-institutionalization. In India, few studies have attempted to directly determine the relationship between coping mechanisms and burden; in the West, studies have found that improved coping in family members can decrease the perceived burden. AIM: To evaluate the burden and coping of caregivers in relation to the level of functioning in patients with chronic schizophrenia. METHODS: The sample was 100 patients with their primary caregivers attending a Psychiatry OPD. Patients were assessed on the Global Assessment of Functioning (GAF) scale while caregivers were administered the Burden Assessment Schedule (BAS) and Mechanisms of Coping (MOC) scale. RESULTS: Fatalism and problem-solving were the two most preferred ways of coping. Problem-focused coping, i.e. problem-solving and expressive-action decreased the burden of caregivers, while emotion-focused coping, i.e. fatalism and passivity, increased it. As the level of functioning of the patient decreased, the significance with which the coping mechanisms influenced the burden, increased. The use of problem-solving coping by caregivers showed a significant correlation with higher level of functioning in patients. CONCLUSION: Coping mechanisms such as problem-solving can decrease the burden of illness on caregivers and may even improve the level of functioning of patients. PMID- 20703412 TI - ECT: Knowledge and attitude among patients and their relatives. AB - BACKGROUND: It is believed that people lack sound knowledge and appropriate attitude towards electroconvulsive therapy (ECT). However, very little systematic research has gone into this area. AIM: To examine the knowledge and attitude of patients and their relatives towards ECT. METHODS: A 16-item questionnaire with satisfactory face validity and content validity was constructed and translated into Hindi. It was then administered to 89 patients and 83 relatives attending the psychiatry services in a major hospital in north India. RESULTS: More than 65% of the respondents in both the groups-patients as well as relatives-gave correct responses such as ECT is life saving, many times it causes temporary but not permanent memory impairment and that ECT is not a non-scientific treatment. There was non-significant disagreement between the two groups. CONCLUSION: The study is a preliminary exploratory one and is likely to give direction for further research with refined methodology. PMID- 20703413 TI - Weight gain with olanzapine: Drug, gender or age? AB - BACKGROUND: The introduction of atypical antipsychotics was a big step forward in the treatment of schizophrenia and other psychoses. Their limitations, however, became evident over time. AIM: To study the causes of weight gain associated with the use of olanzapine-an atypical antipsychotic drug. METHODS: Eighty patients fulfilling the ICD-10 criteria for schizophrenia, predominantly with negative symptoms, were included in this study to evaluate weight gain as an adverse effect of treatment with olanzapine in relation to age, gender, dose and body mass index (BMI). Sociodemographic data and baseline weight along with height (to calculate the BMI) were recorded before the initiation of treatment. The patients were administered a flexible dose of olanzapine (5-15 mg) as monotherapy. Pregnant patients, smokers and those with endocrine disorders, cardiac problems and organic brain dysfunction were excluded from the study. The increase in weight as a neuroleptic side-effect of olanzapine was recorded and analysed in relation to age, gender, dose and BMI. RESULTS: Of the patients receiving olanzapine, 66.6% had a weight gain of 1-5 kg over a period of 4 weeks. The weight gain was not related to the dose of the drug or BMI. The interesting finding was that the increase in weight was significantly related to age >/=40 years and female sex, indicating that women >/=40 years of age are more prone to gain weight with olanzapine therapy in comparison with women <40 years and men of any age group. CONCLUSION: The potential for weight gain associated with the use of atypical antipsychotics to cause long-term complications will need further study. Clinicians are encouraged to monitor weight, plasma glucose and leptin levels, and lipid parameters in patients receiving olanzapine. PMID- 20703414 TI - A preliminary open trial of olanzapine in paediatric acute and transient psychotic disorders. AB - BACKGROUND: Acute and transient psychotic disorders (ATPD) have been characterized by the development of florid psychotic symptoms within 2 weeks and complete remission of symptoms. Although there are no definite guidelines, these are usually treated by antipsychotic medication. AIM: This preliminary study examined the effectiveness of olanzapine in paediatric ATPD. METHODS: In this 6 week open trial of olanzapine in paediatric ATPD, the patients were rated weekly on the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) Scale and Dosage Record Treatment Emergent Symptom Scale (DOTES). RESULTS: Twenty three patients (11 males, 12 females; mean age 14.0+/-1.3 years; range 11-16 years) were included in the study. The mean olanzapine dosage was 12.7+/-3.9 mg/day (range 5-20 mg/day). All the patients showed significant improvement in 6 weeks. The results showed a significant decrease (p< 0.0001) in scores of BPRS (mean at baseline 46.2+/-7.0 to 21.4+/-3.9 at week 6). Severity of illness (CGI) decreased from 4.7+/-0.8 to 1.6+/-0.9 in 6 weeks. Also, global improvement (CGI) showed marked improvement in 14 (60.9%), good improvement in 8 (34.8%) and minimal improvement in 1 (4.3%) patient. Some common side-effects were dryness of mouth (n=14, 60.9%), increase in appetite (n=12, 52%), weight gain (n=12, 52%) and drowsiness (n=8, 34.8%). No patient developed extrapyramidal symptoms. CONCLUSION: Olanzapine was safe and effective in paediatric ATPD. PMID- 20703415 TI - Set-shifting and selective attentional impairment in alcoholism and its relation with drinking variables. AB - BACKGROUND: Individuals with chronic alcoholism show impairments in visual scanning, set-shifting and response inhibition abilities. AIM: To study the relationship between performance on tests of set-shifting and selective attention, and alcohol intake variables (duration of dependence, amount of alcohol intake, and duration of abstinence during the past year). METHODS: In this cross-sectional, controlled study, inpatients from a tertiary care centre were selected. Thirty patients with alcohol dependence and 15 age-, sex- and education-matched normal controls were administered the Trail Making Test (TMT) and Stroop test to assess visual scanning, set-shifting and response inhibition abilities. The data were analysed using the chi(2) test, t test and ANOVA with post-hoc analysis. RESULTS: The patient group performed poorly on all measures of the tests. The duration of dependence and the amount of alcohol intake (during the past 1 year) were not found to significantly affect the performance on the 2 tests. The duration of abstinence during the past 1 year was significantly related to performance on the Stroop test with patients having a longer duration of abstinence showing lesser impairment. CONCLUSION: Patients with a fewer number of days of alcohol intake during the past 1 year show relatively better visual scanning, set-shifting and response inhibition abilities. PMID- 20703416 TI - Physical illnesses among psychiatric outpatients in a tertiary care health institution: A prospective study. AB - BACKGROUND: The recognition of physical illnesses by mental health professionals has important clinical implications. AIM: This study aimed to find the nature and prevalence of associated physical illnesses in psychiatric outpatients. METHODS: Two hundred fifty consecutive psychiatric outpatients who fulfilled the inclusion criteria of the study were assessed in detail for associated physical illnesses. A conclusive physical diagnosis was based on the clinical history, general physical examination and investigation reports. RESULTS: Forty-eight per cent of the patients were found to have associated physical illnesses. In about one-fifth of the total sample (n=51; 20.4%) the associated physical illness was diagnosed for the first time. Hypertension (29.1%), respiratory diseases (15%), anaemia (12.5%), diabetes mellitus (10%) and liver diseases (5.8%) were some common physical illnesses found in these patients. CONCLUSION: Common physical illnesses of psychiatric patients can be detected mostly by a careful history-taking checklist and physical examination. Psychiatrists must inculcate the habit of conducting a general physical examination of their psychiatric patients. PMID- 20703417 TI - Psychiatric morbidity in non-psychiatric geriatric inpatients. AB - AIM: To evaluate the profile of psychiatric disorders in geriatric inpatients. METHODS: A total of 528 patients (age 65 years and above) admitted to various departments of the teaching hospital attached to the Government Medical College, Amritsar from 15 September 2001 to 14 September 2002 were included in the study. Psychiatric assessment of patients was made on the basis of psychogeriatric assessment scales (PAS) and present state examination (PSE-ninth edition, 1974). The ICD-10 criteria were used for psychiatric diagnoses. General medical conditions were diagnosed by consultants of the respective departments. The patients were finally assessed by the consultant of the Department of Psychiatry. The obtained data were analysed using the chi-square test. RESULTS: Of the 528 patients, 260 (49%) had psychiatric co-morbidity. The most common psychiatric disorder was depression (25.94%), followed by adjustment disorders (11%), anxiety disorders (4.54%), dementias (3.6%), delirium (3%), bipolar disorders (0.8%), and substance-related disorders (0.4%). CONCLUSION: The above findings emphasize the importance of consultation-liaison psychiatry, especially in geriatric patients. PMID- 20703418 TI - Psychosis and enuresis during disulfiram therapy. AB - Disulfiram is the drug that is commonly prescribed for the treatment of alcohol dependence syndrome, and transient functional psychosis has been reported as one of its side-effects. Enuresis is another rare adverse effect reported. This report discusses a case of acute psychosis and enuresis in a patient on disulfiram who had ingested alcohol. PMID- 20703419 TI - Genital self-mutilation in erectile disorder. AB - The majority of cases of genital self-mutilation reported in the literature have been in patients with psychosis. We report an unusual case of genital self mutilation in erectile disorder. It is suggested that genital self-mutilation may be a pathway out of diverse psychological disorders and in non-psychotic cases it could be an expression of a psychotic solution to a conflict and may be influenced by cultural factors. PMID- 20703420 TI - Bipolar disorder associated with tuberous sclerosis: Chance association or aetiological relationship? AB - Tuberous sclerosis is a rare disorder. Mental retardation, epilepsy, autism and hyperactivity are commonly reported neuropsychiatric disorders associated with tuberous sclerosis. Rarely, other psychiatric disorders such as psychosis, depression and anxiety associated with this condition have been reported in the literature. A case of bipolar disorder associated with tuberous sclerosis with onset of the first manic episode at the age of 7 years is reported. The possibility of tuberous sclerosis as one of the causes of secondary mood disorder in very young children is also discussed. PMID- 20703421 TI - Progressive multifocal leucoencephalopathy in AIDS camouflaged with catatonia: A wolf in sheep's clothing. AB - Progressive multifocal leucoencephalopathy (PML) may pose a clinical and diagnostic dilemma. The patient may remain in a protracted psychotic state with negative symptoms, without overt features of dementia. The condition blends with catatonia, and eventually with akinetic mutism in a patient of AIDS in the absence of clinical evidence of an immunocompromised state. The present case report highlights the need for an in-depth clinical, biochemical and MRI assessment of patients with catatonia and akinetic mutism. Stupor of an 'akinetic mutism' pattern seems an important indication for HIV screening, particularly in high-risk patients. PMID- 20703422 TI - Suicide in India: The need for a national policy. PMID- 20703423 TI - Antipsychiatry: Meeting the challenge. PMID- 20703434 TI - Functional alterations of proinflammatory monocytes by T regulatory cells: implications for the prevention and reversal of type 1 diabetes. AB - The onset and development of type 1 diabetes (T1D) occurs in genetically predisposed individuals, and is attributed to autoimmune destruction of pancreatic beta-cells involving a multitude of immune mechanisms. Defects in immune regulation may play a central role in T1D, involving impaired function and communication of both myeloid and lymphoid cells of the innate and adaptive immune compartments. Dendritic cells and regulatory T (Treg) cells are part of this network, which seem to be hampered in their quest to control and regulate tissue-destructive autoimmunity. Recent studies have shown that in vivo activated CD16- blood monocytes exhibiting proinflammatory features are present in diabetic subjects. These monocytes may govern T cell-mediated immune responses towards the development of tissue-destructive Th1 and Th17 subtypes, and give rise to inflammatory macrophages in tissues. Differential effects of cytokines IFN-gamma and IL-4 in the development of inflammatory macrophages, and the distinct developmental pathways of proinflammatory or tissue-repair-associated monocytes suggest that controlling the activity of these monocytes could be part of an immune intervention strategy to prevent T1D. Similarly, strategies to target autoantigens to immature, steady-state dendritic cells could guide the immune response away from Th1 and Th17 immune effectors. This review examines potential approaches to this goal by manipulation of myeloid and lymphoid cell regulatory networks in T1D. PMID- 20703435 TI - Oxidative stress, nitric oxide, and diabetes. AB - In the recent decades, oxidative stress has become focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence from research on several diseases show that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on this research, the emerging concept is that oxidative stress is the "final common pathway", through which risk factors of several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis. In this review, we discuss the role of oxidative stress in the pathogenesis of insulin resistance and beta-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes, and in the pathogenesis of diabetic vascular complications, the leading cause of death in diabetic patients. PMID- 20703436 TI - The role of diet and lifestyle in primary, secondary, and tertiary diabetes prevention: a review of meta-analyses. AB - Prevention of diabetes is crucial to lowering disease incidence, and thus minimizing the individual, familial, and public health burden. The purpose of this review is to gather current information from meta-analyses on dietary and lifestyle practices concerning reduction of risk to develop type 2 diabetes. Low glycemic index dietary patterns reduce both fasting blood glucose and glycated proteins independent of carbohydrate consumption. Diets rich in whole-grain, cereal high fiber products, and non-oil-seed pulses are beneficial. Whereas, frequent meat consumption has been shown to increase risk. Regarding non alcoholic beverages, 4 cups/day of filtered coffee or tea are associated with a reduced diabetes risk. In contrast, the consumption of alcoholic beverages should not exceed 1-3 drinks/day. Intake of vitamin E, carotenoids, and magnesium can be increased to counteract diabetes risk. Obesity is the most important factor accounting for more than half of new diabetes' cases; even modest weight loss has a favorable effect in preventing the appearance of diabetes. Also, physical exercise with or without diet contributes to a healthier lifestyle, and is important for lowering risk. Finally, there is a positive association between smoking and risk to develop type 2 diabetes. As far as secondary and tertiary prevention is concerned, for persons already diagnosed with diabetes, there is limited evidence of the effectiveness of diet or lifestyle modification on glycemic control, but further studies are necessary. PMID- 20703437 TI - Glucose homeostasis in pre-diabetic NOD and lymphocyte-deficient NOD/SCID mice during gestation. AB - BACKGROUND: Unlike other strains, spontaneously type 1 non-obese diabetic (NOD) experience transient hyperinsulinemia after weaning. The same applies for NOD/SCID mice, which lack functional lymphocytes, and unlike NOD mice, do not develop insulitis and diabetes like NOD mice. AIMS: Given that beta-cell stimulation is a natural feature of gestation, we hypothesized that glucose homeostasis is disturbed in gestate pre-diabetic NOD and non-diabetic NOD/SCID mice, which may accelerate the onset of diabetes and increase diabetes prevalence. METHODS: During gestation and postpartum, mice were analyzed under basal feed conditions followed by glucose injection (1 g/kg, i.p.) after overnight fast, using glucose tolerance test (GTT). Glycemia, corticosteronemia, blood and pancreatic insulin, glucagon levels, islet size, and islet morphology were evaluated. Glycemia and mortality were assessed after successive gestations in NOD mice mated for the first time at 2 different ages. RESULTS: 1. Basal glucagonemia rose markedly in first-gestation fed NOD mice. 2. beta-cell hyperactivity was present earlier in first-gestation non-diabetic fasted NOD and NOD/SCID mice than in age-matched C57BL/6 mice, assessed by increased insulin/glucose ratio after GTT. 3. Overnight fasting increased corticosteronemia rapidly and sharply in pre-diabetic gestate NOD and NOD/SCID mice. 4. Islet size increased in non-diabetic gestate NOD mice compared with C57BL/6 mice. 5. Successive gestations accelerated diabetes onset, and contributed to increased mortality in NOD mice. CONCLUSIONS: First-gestation pre-diabetic NOD and non diabetic NOD/SCID mice exhibited beta-cell hyperactivity and deregulation of glucagon and/or corticosterone secretion. This amplified normally occurring insulin resistance, further exhausted maternal beta-cells, and accelerated diabetes in NOD mice. PMID- 20703438 TI - Dendritic cell-targeted pancreatic beta-cell antigen leads to conversion of self reactive CD4(+) T cells into regulatory T cells and promotes immunotolerance in NOD mice. AB - Studies employing T cell receptor transgenic T cells have convincingly shown that selective delivery of non-self model antigens to DEC-205(+) dendritic cells (DCs) in the steady-state can induce Foxp3-expressing CD4(+)CD25(+) regulatory T (Treg) cells from conventional CD4(+)CD25(-)Foxp3(-) T cells. Although of considerable clinical interest, the concept of DC-targeted de novo generation of antigen specific Treg cells has not yet been evaluated for self-antigens and self reactive CD4(+) T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Here, we show in proof-of-principle experiments that targeting a mimotope peptide to the endocytic receptor DEC-205 on DCs in NOD mice induces efficient conversion of pancreatic beta-cell-reactive BDC2.5 CD4(+) T cells into long-lived Foxp3(+) Treg cells. Of note, conversion efficiency in normoglycemic and hyperglycemic mice with early diabetes onset was indistinguishable. While de novo generation of BDC2.5 Treg cells did not interfere with disease progression, anti-DEC-205-mediated targeting of whole proinsulin in prediabetic NOD mice substantially reduced the incidence of diabetes. These results suggest that promoting antigen-specific Treg cells in vivo might be a feasible approach towards cellular therapy in T1D. PMID- 20703439 TI - The humanized NOD/SCID mouse as a preclinical model to study the fate of encapsulated human islets. AB - Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10. PMID- 20703440 TI - [Preoperative prewarming as a routine measure. First experiences]. AB - BACKGROUND: Despite the broad application of intraoperative warming new studies still show a high incidence of perioperative hypothermia. Therefore a prewarming program in the preoperative holding area was started. METHODS: The efficacy of the prewarming program was assessed with an accompanying quality assurance check sheet over a period of 3 months. RESULTS: During the 3 month test period 127 patients were included. The median length from arrival in the holding area to beginning prewarming was 6 min and the average duration of prewarming was 46+/-38 min. During prewarming the core temperature rose by 0.3+/-0.4 degrees C to 37.1+/ 0.5 degrees C and decreased to 36.3+/-0.5 degrees C after induction of anesthesia. At the end of the operation the core temperature was 36.4+/-0.5 degrees C and 14% of the patients were hypothermic. CONCLUSION: These data allow 2 conclusions: 1. Prewarming in the holding area is possible with a sufficient duration. 2. Prewarming is highly efficient even when performed over a relatively short duration. PMID- 20703441 TI - [Direct laryngoscopy or C-MAC video laryngoscopy? Routine tracheal intubation in patients undergoing ENT surgery]. AB - BACKGROUND: Previous studies have shown that video laryngoscopy enhances laryngeal view in patients with apparently normal and difficult airways. The utility of the novel, portable, battery-powered C-MAC video laryngoscope is as yet unproven. It was hypothesized that in routine patients undergoing ENT surgery, the rate of glottic views considered unsatisfactory, i.e. Cormack and Lehane grades IIb, III, and IV, could be significantly reduced with the C-MAC video laryngoscope compared to direct laryngoscopy. METHODS: Following ethical approval and sample size estimates 108 consecutive patients undergoing ENT surgery under general anesthesia were studied. First, direct laryngoscopy was performed with the naked eye. The best view obtained was graded by the first anesthesiologist without looking at the video monitor. A second anesthesiologist blinded to the laryngeal view obtained under direct laryngoscopy graded the laryngeal view on the video monitor. Endotracheal intubation using Ring-Adair Elwyn (RAE) tracheal tubes was then attempted under video-aided visualization. The tubes were not reinforced with a stylet. The C-MAC video laryngoscopy system (Karl Storz, Tuttlingen, Germany) is a novel device that can be used with Macintosh laryngoscope blades in different sizes. A camera and light source are located recessed from the tip of the blade. The camera unit sits in a handle attached to the laryngoscope blade and is connected by a wire to a TFT video monitor. It allows for both direct and indirect laryngoscopy and the low profile of the original British Macintosh blades may prove advantageous in patients with limited mouth opening. RESULTS: A total of 108 patients were enrolled in the study but for various reasons only 94 completed the study (post hoc power 97%). In 89 patients a size 3 Macintosh laryngoscope was used while a size 4 blade was used in the remaining 5 patients. With direct laryngoscopy the glottic view was considered unsatisfactory in 40 patients (42%), but this was the case in only 15 patients (16%) when video laryngoscopy was used (p<0.0001). Endotracheal tube placement was successful in all but one patient where the Bonfils intubation fiberscope needed to be employed. No complications related to the C-MAC system were observed. CONCLUSIONS: Compared to direct laryngoscopy with a Macintosh laryngoscope blade in unselected patients undergoing ENT surgery and thus patients more susceptible to an unexpected difficult airway than a general patient population, the mobile C-MAC video laryngoscope significantly enhanced laryngeal view. Using RAE tracheal tubes seems to compensate the unfavorable deviation of optical and anatomical axes when indirect laryngoscopy is performed with the C-MAC system. PMID- 20703443 TI - [Achilles tendon]. PMID- 20703442 TI - [Surgical treatment for pain syndromes of the Achilles tendon]. AB - Pain syndromes of the Achilles tendon (AT) include both insertional and non insertional tendinopathy, two distinct disorders with different underlying pathophysiologies and management options, characterized by pain, impaired performance and swelling in and around the tendon. This article gives an overview of the operative treatment of pain syndromes of the Achilles tendon, including both insertional tendinopathy of the AT and tendinopathy of the main body of the AT. New minimally invasive techniques for the management of this condition, including endoscopy are also reported. PMID- 20703444 TI - [Psychiatric sequelae of severe burn injuries: emotional distress and resources of occupationally versus non occupationally insured patients 1 year after burn injury]. AB - Severe burn injuries are traumatic events and can have serious impact on all areas of life frequently causing high emotional distress. In a multicentre study resources and emotional distress of patients with serious burn injuries were assessed during the first hospitalization and at 6 and 12 months follow-up. Patients with severe burn injuries after accidents in a private environment (NBG patients) and patients after occupational accidents covered by the German Social Accident Insurance (BG patients) were compared. All patients reported marked emotional impairment, particularly during the hospitalization. At follow-up a reduction of emotional distress was detected. Nearly half of the patients received a diagnosis of one or more mental disorders according to DSM-IV criteria. When treating patients with burns, special attention should be given to their mental health. They should be offered psychological support to cope with the aftermath of the accident, especially after discharge from hospital when returning to their normal surroundings. PMID- 20703445 TI - [S3 guidelines on unipolar depression]. PMID- 20703446 TI - Day/night variations of high-molecular-weight adiponectin and lipocalin-2 in healthy men studied under fed and fasted conditions. AB - AIMS/HYPOTHESIS: Adiponectin and lipocalin-2 are adipocyte-derived plasma proteins that have been proposed to have opposite effects on insulin sensitivity. Given the epidemiological, physiological and molecular links between sleep, the circadian timing system and glucose metabolism, the aim of this study was to assess effects of the sleep/wake cycle and the fasting/feeding cycle on high molecular-weight adiponectin (HMW-adiponectin; the biologically active form) and lipocalin-2. We also aimed to compare the 24 h rhythms in the levels of these proteins with those of cortisol, leptin, leptin-binding protein and total adiponectin. METHODS: Lean men underwent a 3 day in-laboratory study, either in the fed state (n = 8, age: 20.9 +/- 2.1 years, BMI: 22.8 +/- 2.3 kg/m2) or fasting state (3 day fast, n = 4, age: 25.3 +/- 3.9 years, BMI: 23.3 +/- 2.2 kg/m2). The sleep episode was scheduled in darkness from 23:00 to 07:00 hours. Blood was sampled every 15 min for 24 h on the third day of each study. RESULTS: While fed, HMW-adiponectin and lipocalin-2 had large daily rhythms with troughs at night (HMW-adiponectin: ~04:00 hours, peak-to-trough amplitude 36%, p < 0.0001; lipocalin-2: ~04:00 hours, 40%, p < 0.0001). On the third day of fasting, the timing and relative amplitudes were unchanged (HMW-adiponectin: ~04:00 hours, 38%, p = 0.0014; lipocalin-2: ~05:00 hours, 38%, p = 0.0043). CONCLUSIONS/INTERPRETATION: These data show that HMW-adiponectin and lipocalin-2 both have significant day/night rhythms, both with troughs at night, that these are not driven by the feeding/fasting cycle, and that it is important to report and/or standardise the time of day for such assays. Further studies are required to determine whether the daily rhythm of HMW-adiponectin levels influences the daily rhythm of insulin sensitivity. PMID- 20703448 TI - Persistence behaviour of thiamethoxam and lambda cyhalothrin in transplanted paddy. AB - A field study was conducted in Pre-Kharif season 2007 on paddy to determine the persistence of thiamethoxam (12.6%) and lambda cyhalothrin (9.4%) [in a 'Readymix' formulation Alika 247 ZC], following the application of 33 g. a.i. ha 1 (T1) and 66 g. a.i. ha-1 (T2). Spraying of insecticide was done during milking stage of the crop (63 days after transplantation). Thiamethoxam and lambda cyhalothrin residues were estimated by HPLC and GLC respectively. The half-life values were 5.2-5.8 and 4.8 days for thiamethoxam and lambda cyhalothrin respectively. No residue was detected in the harvested paddy, straw, grain, and soil samples. PMID- 20703447 TI - Expression analysis of loci associated with type 2 diabetes in human tissues. AB - AIMS/HYPOTHESIS: Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues. METHODS: We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling. RESULTS: Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver. CONCLUSIONS/INTERPRETATION: This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined. PMID- 20703449 TI - On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039. AB - RATIONALE: Several studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6 dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl] 3-(xan th-9-yl) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear. OBJECTIVES: The aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated. RESULTS: The results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound. CONCLUSIONS: The results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs. PMID- 20703450 TI - Relapse to smoking during unaided cessation: clinical, cognitive and motivational predictors. AB - RATIONALE: Neurobiological models of addiction suggest that abnormalities of brain reward circuitry distort salience attribution and inhibitory control processes, which in turn contribute to high relapse rates. OBJECTIVES: The aim of this study is to determine whether impairments of salience attribution and inhibitory control predict relapse in a pharmacologically unaided attempt at smoking cessation. METHODS: One hundred forty one smokers were assessed on indices of nicotine consumption/dependence (e.g. The Fagerstrom Test of Nicotine Dependence, cigarettes per day, salivary cotinine) and three trait impulsivity measures. After overnight abstinence, they completed experimental tests of cue reactivity, attentional bias to smoking cues, response to financial reward, motor impulsiveness and response inhibition (antisaccades). They then started a quit attempt with follow-up after 7 days, 1 month and 3 months; abstinence was verified via salivary cotinine levels <=20 ng/ml. RESULTS: Relapse rates at each point were 52.5%, 64% and 76.3%. The strongest predictor was pre-cessation salivary cotinine; other smoking/dependence indices did not explain additional outcome variance and neither did trait impulsivity. All experimental indices except responsivity to financial reward significantly predicted a 1-week outcome. Salivary cotinine, attentional bias to smoking cues and antisaccade errors explained unique as well as shared variance. At 1 and 3 months, salivary cotinine, motor impulsiveness and cue reactivity were all individually predictive; the effects of salivary cotinine and motor impulsiveness were additive. CONCLUSIONS: These data provide some support for the involvement of abnormal cognitive and motivational processes in sustaining smoking dependence and suggest that they might be a focus of interventions, especially in the early stages of cessation. PMID- 20703451 TI - The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met. AB - RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects of stressful events on BDNF levels may in part be conditional upon a common variant on the BDNF gene (Val(66)Met; RS6265), with the Met allele being associated with a decrease in activity-dependent secretion of BDNF compared to the Val allele. METHODS: We investigated cross-sectionally in 1,435 individuals with lifetime MDD the impact of childhood abuse (CA) and recent life events on serum BDNF levels and assessed whether the impact of these events was moderated by the BDNF Val(66)Met polymorphism. RESULTS: Overall, BDNF Met carriers had reduced serum BDNF levels when exposed to CA in a dose-dependent way. Moreover, exposure to recent life events was also associated with decreases in BDNF levels, but this was independent of BDNF Val(66)Met. Moreover, when not exposed to CA, Met carriers had higher BDNF levels than the Val/Val individuals, who did not show decreases in BDNF associated with CA. Finally, these findings were only apparent in the MDD group without comorbid anxiety. CONCLUSIONS: These gene-environment interactions on serum BDNF levels suggest that Met carriers are particularly sensitive to (early) stressful life events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events. PMID- 20703452 TI - Long-term use of fluoxetine and multiple skeleton fractures. PMID- 20703453 TI - Respiratory variation in aortic blood flow velocity as a predictor of fluid responsiveness in children after repair of ventricular septal defect. AB - This study aimed to compare respiratory variation in transthoracic echo-derived aortic blood flow velocity (?Vpeak) and inferior vena cava diameter (?IVCD) with central venous pressure (CVP) as predictors of fluid responsiveness in children after repair of ventricular septal defect (VSD). A prospective study conducted in pediatric intensive care unit investigated 21 mechanically ventilated children who had undergone repair of VSD. Standardized volume replacement (VR) was the intervention used. Hemodynamic measurements including CVP, heart rate, mean arterial pressure, transthoracic echo-derived stroke volume (SV), cardiac output, ?Vpeak, and ?IVCD were performed 1 h after patient arrival in the intensive care unit. Hemodynamic measurements were repeated 10 min after VR by an infusion of 6% hydroxyethyl starch 130/0.4 (10 ml/kg) over 20 min. The volume-induced increase in the SV was 15% or more in 11 patients (responders) and less than 15% in 10 patients (nonresponders). Before volume replacement, the ?Vpeak (23.1 +/- 5.7% vs. 14.0 +/- 7.7%; p = 0.006) and ?IVCD (26.5 +/- 16.2% vs. 9.2 +/- 9.1%; p = 0.008) was higher in the responders than in the nonresponders, whereas CVP did not significantly differ between the two groups. The prediction of fluid responsiveness was higher with the DeltaVpeak, as shown by a receiver operating characteristic curve area of 0.83 (95% confidence interval [CI], 0.61-1.00; p = 0.01), a DeltaIVCD of 0.85 (95% CI, 0.69-1.00; p = 0.01), and a CVP of 0.48 (95% CI, 0.22-0.73; nonsignificant difference). The ?Vpeak and ?IVCD measured by transthoracic echocardiography can predict the response of SV after volume expansion in mechanically ventilated children at completion of VSD repair. PMID- 20703455 TI - A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. AB - HLA-mismatched natural killer (NK) cells have shown efficacy in acute myeloid leukemia, and their adoptive transfer in patients with other malignancies has been proven safe. This phase I clinical trial was designed to evaluate safety (primary endpoint) and possible clinical efficacy (secondary endpoint) of repetitive administrations of allogeneic, in vitro activated and expanded NK cells along with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients with unresectable, locally advanced/metastatic NSCLC receiving 1st/2nd line chemotherapy were eligible to receive 2-4 doses of activated NK cells from two relative donors. Donor's CD56(+) cells were cultured for 20-23 days with interleukin-15 (IL-15) and hydrocortisone (HC) and administered intravenously between chemotherapy cycles. Premedication with corticosteroids and/or H1 inhibitors was allowed. Sixteen patients (performance status 0-1) with adenocarcinoma (n = 13) or squamous cell carcinoma (n = 3) at stage IIIb (n = 5) or IV (n = 11) receiving 1st (n = 13) or 2nd (n = 3) line treatment were enrolled. Fifteen patients received 2-4 doses of allogeneic activated NK cells (0.2-29 * 10(6)/kg/dose, median 4.15 * 10(6)/kg/dose). No side effects (local or systemic) were observed. At a median 22-month follow-up (range, 16.5-26 months) 2 patients with partial response and 6 patients with disease stabilization were recorded. Median progression free survival and overall survival were 5.5 and 15 months, respectively. A 56% 1-year survival and a 19% 2 year survival were recorded. In conclusion, repetitive infusions of allogeneic, in vitro activated and expanded with IL-15/HC NK cells, in combination with chemotherapy are safe and potentially clinically effective. PMID- 20703456 TI - Posterior-only surgery with strong halo-femoral traction for the treatment of adolescent idiopathic scoliotic curves more than 100 degrees . AB - The aim of this study was to investigate the feasibility and clinical efficacy of treatment of adolescent idiopathic scoliosis of >100 degrees via posterior-only surgery with strong halo-femoral traction and posterior wide release. From December 2003 to August 2006, 121 patients with adolescent idiopathic scoliosis were treated in our hospital; among them, 29 patients with curves over 100 degrees were included in this study. From December 2003 to June 2005, group A included the first 12 patients who underwent combined anterior release followed by two-week halo-femoral traction and then posterior instrumentation. From July 2005 to August 2006, 17 patients in group B underwent posterior surgery alone with strong halo-femoral traction and posterior wide release. All of the patients were followed-up for a minimum of 31 months (mean, 36 months; range, 31-41 months). There were no severe complications. All of the patients achieved bony fusion without instrumentation breakage or pseudarthrosis. There were no statistically significant differences between the two groups in gender, age, type of adolescent idiopathic scoliosis, preoperative coronal major curve values, major curve flexibility, or final follow-up major curve correction rate. The average operative time, blood loss and hospital stay in group B were less than those in group A. In adolescent idiopathic scoliosis with Cobb >100 degrees , posterior-only surgery with strong halo-femoral traction and posterior wide release can provide comparable curve correction with shorter operative time, less blood loss and shorter hospital stay when compared to combined anteroposterior surgery. PMID- 20703457 TI - Gastric tube reconstruction by laparoscopy-assisted surgery attenuates postoperative systemic inflammatory response after esophagectomy for esophageal cancer. AB - BACKGROUND: Conventional open procedures have been supplanted in part by less invasive approaches, such as laparoscopic surgery developed for treating gastrointestinal malignancies. However, it is unclear whether laparoscopy assisted gastric tube reconstruction (LAGT) can attenuate the postoperative systemic inflammatory response after esophagectomy for esophageal cancer. METHODS: We investigated the postoperative clinical course of the systemic inflammatory response syndrome (SIRS) in patients who underwent an esophagectomy for esophageal cancer by LAGT (LAGT group) and gastric tube reconstruction by conventional open surgery (Open group). RESULTS: Compared with the Open group, the LAGT group had a significantly shorter operative time (539.6 min vs. 639.8 min), shorter duration of postoperative mechanical ventilation (1.1 days vs. 2.8 days), and shorter length of stay in the intensive care unit (2.1 days vs. 4.4 days). The LAGT group also had a significantly shorter SIRS duration (1.4 days vs. 2.7 days), a significantly lower incidence of SIRS, and a smaller number of positive SIRS criteria. Throughout the investigation period, the postoperative white blood cell count was lower in the LAGT group than in the Open group. Additionally, in the LAGT group, the heart rate was lower on each postoperative day (POD), and the respiratory rate was significantly lower on postoperative days (PODs) 1 and 4. There was no difference in postoperative oxygenation, morbidity, and mortality between the groups. The C-reactive protein level on PODs 3 and 4 was significantly lower in the LAGT group than in the Open group. CONCLUSIONS: Laparoscopy-assisted gastric tube reconstruction significantly attenuates postoperative SIRS, and it is therefore a potentially less invasive surgical procedure. PMID- 20703458 TI - Pancreatoduodenectomy with or without early ligation of the inferior pancreatoduodenal artery: comparison of intraoperative blood loss and short-term outcome. AB - BACKGROUND: Some of the significant predictive risk factors for complications after pancreatoduodenectomy are increased intraoperative blood loss and the need for blood transfusion. The impact of pancreatoduodenectomy (PD) with early ligation of the inferior pancreatoduodenal artery (IPDA) on intraoperative blood loss and short-term outcomes is not well known. METHODS: A retrospective review of patients who underwent standard PD (n = 112) and pancreatoduodenectomy with early ligation of the IPDA (n = 175) was undertaken. RESULTS: Early ligation of the IPDA, body mass index, sex, and operative time were independent risk factors for intraoperative blood loss. Intraoperative median blood loss in patients with early ligation of the IPDA was 380 ml, which was significantly lower than 850 ml in patients who had a standard PD (p < 0.001). Although 51 patients (46%) with standard PD needed a perioperative blood transfusion, only four patients (2%) with early ligation of the IPDA received a perioperative red cell transfusion (p < 0.001). The overall complication rates were 61% for patients with standard PD versus 45% for patients with early ligation of the IPDA (p = 0.007). There were five in-hospital deaths (4.5%) of patients with standard PD versus zero in hospital deaths (0.0%) of patients with early ligation of the IPDA (p = 0.002). CONCLUSION: Early ligation of the inferior pancreatoduodenal artery not only reduced intraoperative blood loss during PD but also alleviated postoperative morbidity and mortality. PMID- 20703459 TI - Wound infection following stoma takedown: primary skin closure versus subcuticular purse-string suture. AB - BACKGROUND: Stoma closure has been associated with a high rate of surgical site infection (SSI) and the ideal stoma-site skin closure technique is still debated. The aim of this study was to compare the rate of SSI following primary skin closure (PC) versus a skin-approximating, subcuticular purse-string closure (APS). METHODS: All consecutive patients undergoing stoma closure between 2002 and 2007 by two surgeons at a single tertiary-care institution were retrospectively assessed. Patients who had a new stoma created at the same site or those without wound closure were excluded. The end point was SSI, determined according to current CDC guidelines, at the stoma closure site and/or the midline laparotomy incision. RESULTS: There were 61 patients in the PC group (surgeon A: 58 of 61) and 17 in the APS group (surgeon B: 16 of 17). The two groups were similar in baseline and intraoperative characteristics, except that patients in the PC group were more often diagnosed with benign disease (p = 0.0156) and more often had a stapled anastomosis (p = 0.002). The overall SSI rate was 14 of 78 (18%). All SSIs occurred in the PC group (14 of 61 vs. 0 of 17, p = 0.03). CONCLUSIONS: Our study suggests that a skin-approximating closure with a subcuticular purse-string of the stoma site leads to less SSI than a primary closure. Randomized studies are needed to confirm our findings and assess additional end points such as healing time, cost, and patient satisfaction. PMID- 20703461 TI - Must breast care delivery models from resource-rich environments be applied to resource-limited environments? PMID- 20703463 TI - Clinical implication of the number of central lymph node metastasis in papillary thyroid carcinoma: preliminary report. AB - BACKGROUND: Papillary thyroid cancer (PTC) metastasizes to central lymph node (CLN). CLN metastasis is associated with high risk of locoregional recurrence and distant metastasis. The significance of the number of metastatic CLN has not been addressed. This study was designed to evaluate the clinical implication of the number of metastatic CLN in PTC. METHODS: We reviewed the patients who underwent total thyroidectomy and CLN dissection with or without lateral neck dissection due to PTC, from March 2008 to June 2009. The relationships between the number of CLN and risk factors, including age, gender, tumor size, extrathyroidal extension, and lateral lymph node metastasis, were assessed. Patients were divided into three groups according to the number of CLN: group A = 0; group B = 1-2; and group C = >=3. RESULTS: Of 258 patients enrolled in this study, 113 were in group A, 73 in group B, and 72 in group C. Extrathyroidal extension and lateral neck lymph node metastasis were related to increased rate of CLN metastasis (P < 0.05). Tumor size increased as the number of CLN increased; group C had the largest tumor size (P < 0.05). When evaluating the distribution of patients with extrathyroidal extension, group C had a significant odds ratio (4.213, P < 0.05). When evaluating the distribution of lateral neck lymph node metastasis, groups B and C had significant odds ratio (14.353, 75.403, respectively, P < 0.05). CONCLUSIONS: The number of CLN metastasis correlated with the negative prognostic factors, including tumor size, extrathyroidal extension, and lateral neck lymph node metastasis. This suggests that the number of CLN has prognostic implication. PMID- 20703464 TI - An initial experience with rapid microwave processing in the one-stop breast clinic. AB - BACKGROUND: Rapid microwave processing allows core biopsy results to be obtained within a 3- to 4-h time period. This study was designed to compare the accuracy and reporting time of microwave-processed breast biopsies with samples processed using traditional methods. METHODS: Concordance of the preoperative biopsy report with postoperative histology for tumor type, grade, and detection of lymphovascular invasion was recorded for both techniques. Also reviewed were the time taken between day of biopsy and day of reporting, waiting time between biopsy and surgery, and number of preoperative outpatient appointments. RESULTS: In the microwave-processed group (MG; n = 43), there was a 92% concordance rate between preoperative biopsy and postoperative histology for tumor type. In the traditional group (TG; n = 43), it was 80% (P > 0.05). For tumor grade, there was a concordance rate of 64% in MG and 93% in TG (P > 0.05). For detection of lymphovascular invasion, there was agreement in 88% of cases in MG and 67% in TG (P > 0.05). Twenty-five patients from MG were informed of their diagnosis on the day of biopsy. There was no difference in waiting time from biopsy to surgery or number of preoperative outpatient appointments between MG and TG (P > 0.05). CONCLUSIONS: Microwave processing allows safe and accurate immediate histological reporting. As a result, surgical management can be planned at the initial outpatient consultation. PMID- 20703465 TI - Prognostic significance of ki-67 labeling index in papillary thyroid carcinoma. AB - BACKGROUND: Ki-67 is a useful tool for evaluating cell proliferative activity in various tumors. Although the utility of Ki-67 labeling index (LI) to diagnose thyroid neoplasms has been investigated, little is known regarding the relationship between Ki-67 LI and the biological behavior of papillary thyroid carcinoma. In this study, we examined Ki-67 in 371 patients with papillary thyroid carcinoma to elucidate this issue. METHODS: A total of 371 patients with papillary carcinoma who underwent initial and locally curative surgery between 1996 and 1997 were enrolled in this study. We immunohistochemically investigated Ki-67 LI in their primary lesions and compared this finding with various clinicopathological features, including patient prognosis. RESULTS: Ki-67 LI was <=1% in 213 patients (57%) and among the remaining 158, 35 showed Ki-67 LI >3%. Ki-67 LI was associated with patient age, massive extrathyroid extension, and distant metastasis at surgery. Of 363 patients without distant metastasis at surgery, 54 (15%) showed carcinoma recurrence during follow-up (average 124 months) and the disease-free survival (DFS) of patients with Ki-67 LI >1% was significantly worse than that of those with Ki-67 LI <1% (p < 0.0001). On multivariate analysis, Ki-67 LI was recognized as an independent prognostic factor for the DFS of patients. Although only eight patients died of carcinoma in our series, patients with Ki-67 LI >3% showed a significantly worse cause specific survival (CSS) than those with Ki-67 LI <3% (p < 0.0001). CONCLUSIONS: Careful evaluation of Ki-67 LI in primary lesions can predict DFS and CSS of patients with papillary thyroid carcinoma. PMID- 20703466 TI - Validation of a nomogram for predicting overall survival after resection of pulmonary metastases from colorectal cancer at a single center. AB - BACKGROUND: The goal of this study was to validate a survival nomogram at a single center, originally developed at multiple institutions in Japan, which combines readily available preoperative variables to predict overall survival after resection of pulmonary metastases from colorectal cancer. METHODS: An external patient cohort from a prospective pulmonary metastases database at the Aichi Cancer Center in Japan was used to test the validity of the pulmonary metastases from a colorectal cancer nomogram. The cohort included 58 consecutive patients who had surgery between January 1999 and December 2005. Nomogram predictions for 3- and 5-year overall survival were calculated for each patient and compared with actual survival. The concordance index was used as an accuracy measure. RESULTS: Data for all necessary variables were available for all patients. At the last follow-up, 30 patients were alive, with a median follow-up of 39 (range, 5-94) months. The 1-, 2-, 3-, and 5-year overall survival rates were 96.6, 84.5, 70.5, and 48.9%, respectively. The nomogram concordance index was 0.81 with excellent calibration for both 3- and 5-year overall survival rates. CONCLUSIONS: The high predictive accuracy of pulmonary metastases from a colorectal cancer nomogram demonstrates that this predictive tool derived at multiple institutions can be applied to a small cohort of patients in a single center. PMID- 20703467 TI - Size of the tumor and pheochromocytoma of the adrenal gland scaled score (PASS): can they predict malignancy? AB - BACKGROUND: Size can predict malignancy in adrenocortical tumors, but the same extrapolation for pheochromocytomas (PCC) is controversial. The goal of this study was to find a correlation between the tumor size and malignant potential of PCC and determine whether the "Pheochromocytoma of the adrenal gland scaled score" (PASS) proposed by Thompson can be applied to predict malignancy. METHODS: A retrospective analysis of patients with PCC operated on from 1991 to 2007 revealed 98 PCC removed from 93 patients. Tumor size was available for 90 tumors. Six (6.4%) patients had proven malignancy. Five familial cases were excluded from the PASS analysis. RESULTS: Of the benign cases, none developed recurrence or metastasis. There were 54 (60%) tumors > 6 cm and 36 (40%) tumors <= 6 cm. All 12 PASS parameters were individually present in higher frequency in the >6-cm group; but the difference was not statistically significant except cellular monotony (p = 0.02). Overall, a PASS <= 4 was found in 57 patients. Mean PASS was statistically significantly higher in the >6-cm group (4.4 vs. 3.3, p = 0.04). Of the sporadic benign cases, 21 (41%) patients with tumor size > 6 cm had a PASS of >4, and none of them developed metastasis. PASS <= 4 was found in 25 (81%) PCC in the <=6-cm group, and none developed metastases. PASS >= 4 was found in six (19%) patients in the <=6-cm group, and none developed metastases. 68 patients completed 5-year follow-up, and the remaining had a mean follow-up of 28.7 months. No correlation was found between tumor size and PASS > 4 and PASS <= 4 (7.8 cm vs. 7.1 cm; p = 0.23). CONCLUSIONS: Presently there is not enough evidence to indict a large (>6 cm) PCC as malignant. Furthermore, PASS cannot be reliably applied to PCC for predicting malignancy. PMID- 20703469 TI - Foley catheter enterostomy for postoperative bowel perforation: an effective source control. AB - BACKGROUND: Control of bowel effluents is imperative in cases of postoperative bowel perforation, and this is best achieved by stoma formation. When stoma formation is impossible, the surgeon is often left with less optimal choices. We have used a Foley catheter enterostomy to provide source control in difficult cases of bowel perforation, and the details are reviewed in this report. METHODS: Three patients underwent reoperation for postoperative bowel perforation. Two patients had leaking ileocolic anastomoses, and one patient had a leak from a serosal tear. In all cases a Foley catheter enterostomy was constructed at the point of the leak. The balloon was filled with 3 ml of saline, and the affected bowel segment was fixed to the inside of the abdominal wall by a purse-string suture supplied with a few additional stitches. Moreover, gentle traction was applied to the balloon by external suture fixation of the catheter. RESULTS: Immediate control of bowel effluents from the leak was achieved in all cases. Early enteral feeding was possible in two of the three patients, and the catheter was removed after 17-28 days. Drainage of bowel contents from the catheter wounds stopped within 2 days. CONCLUSIONS: This report demonstrates an effective and safe technique for sealing a postoperative bowel perforation with a Foley catheter enterostomy. It is useful in cases where a stoma cannot be brought out. The technique provides immediate source control and enables early enteral feeding. The utility of the procedure may be limited when the defect is large, when the surrounding bowel wall lacks integrity, and when it is not possible to mobilize the affected bowel segment toward the inside of the abdominal wall without tension. PMID- 20703468 TI - Extracorporeal versus intracorporeal anastomosis after laparoscopic right colectomy for cancer: a case-control study. AB - BACKGROUND: The purpose of this study was to compare the short-term outcome (3 months) of laparoscopic right colectomy, between intra- and extracorporeal anastomosis techniques. METHODS: This study was designed as a case-controlled study from a prospective colorectal cancer database. Forty consecutive patients who underwent laparoscopic right hemicolectomy with intracorporeal anastomosis (totally laparoscopic colectomy, TLC) for adenocarcinoma, with the exception of T4 lesions and metastasis, were compared with 40 patients who underwent laparoscopic right hemicolectomy with extracorporeal anastomosis (laparoscopic assisted colectomy, LAC). Controls were matched for stage, age, and gender via a statistically generated selection of all laparoscopic right hemicolectomies performed between October 2006 and August 2009. RESULTS: In terms of operating time (median 150 min), histopathological results, surgical site complications (5% for LAC and 2.5% for TLC), nonsurgical site complications (2.5% for LAC and 5% for TLC), hospitalization (median 5 days), there were no differences between the groups (p > 0.05). Incision length was significantly shorter for TLC (p < 0.05), but no differences were observed for postoperative use of analgesics. There were six postoperative cases of vomiting with reinsertion of nasogastric tube in the LAC group and only one case in the TLC group (p < 0.05). CONCLUSIONS: TLC seems feasible and safe, it does not significantly affect the length of surgery, and it guarantees maintenance of radical oncological standards. Furthermore, it significantly improves cosmesis and patient comfort postoperatively, reducing the rates of emesis, which leads to higher rates of early regular diet tolerance. PMID- 20703470 TI - Resident workload, pager communications, and quality of care. AB - With the recent regulations limiting resident work hours, it has become more important to understand how residents spend their time. The volume and content of the pages they receive provide a valuable source of information that give insight into their workload and help identify inefficiencies in hospital communication. We hypothesized that above a certain workload threshold, paging data would suggest breakdowns in communication and implications for quality of care. All pages sent to six general surgery interns at the University of Michigan over the course of one academic year (7/1/2008-6/30/2009) were retrospectively categorized by sender type, message type, message modifier, and message quality. Census, discharge, and admission information for each intern service were also collected, and intern duties were further analyzed with respect to schedule. "On-call" days were defined as days on which the intern bore responsibility for care of all admitted floor patients. The interns received a total of 9,843 pages during the study period. During on-call shifts, each intern was paged an average of 57 +/- 3 times, and those on non-call shifts received an average of 12 +/- 3 pages. Floor/intensive care unit (ICU) nurses represented 32% of the page volume received by interns. Interestingly, as patient volume increased, there was a decrease in the number of pages received per patient. By contrast, at higher patient volumes, there was a trend toward an increasing percentage of urgent pages per patient. At high intern workloads, our data suggest no major communication breakdowns but reveal the potential for inferior quality of care. PMID- 20703472 TI - Botulinum toxin injection versus lateral internal sphincterotomy in the treatment of chronic anal fissure: a randomized controlled trial. AB - BACKGROUND: Although lateral internal sphincterotomy has been the gold standard of treatment for chronic anal fissure, the main concern remains its effects on anal continence. Intrasphincteric injection of botulinum toxin seems to be a reliable option providing temporary alleviation of sphincter spasm and allowing the fissure to heal. The aim of the present prospective controlled randomized study was to compare the outcome of lateral internal sphincterotomy and botulinum toxin injection treatments in patients with uncomplicated chronic anal fissure. METHODS: Eighty consecutive patients with uncomplicated chronic anal fissure who had failed conservative treatment were randomized to receive either intrasphincteric injection of botulinum toxin (BT) or lateral internal sphincterotomy (LIS). Postoperative pain relief, healing of fissure, continence scores, and fissure relapse during 18 weeks of follow-up were the outcomes assessed. RESULTS: There was a statistically significantly higher healing in the LIS group than the BT group (p = 0.0086 and 95% CI = 7.38-45.69%). In addition, LIS was associated with a high rate of anal incontinence as compared to BT (p = 0.0338 and 95% CI = -1.64-27.53%). The recurrence rate in the BT group was significantly higher statistically than that in the LIS group (p = 0.0111 and 95% CI = 6.68-46.13%). CONCLUSIONS: Surgical internal sphincterotomy has a higher healing rate and a lower recurrence rate than intrasphincteric injection of botulinum toxin in the treatment of uncomplicated chronic anal fissure. Injection of botulinum toxin, however, is a simple noninvasive technique that avoids the greater risk of incontinence. It could be used as the first therapeutic approach in patients without clinical risk factors of recurrence. PMID- 20703473 TI - Abdominal resection rectopexy with an absorbable polyglactin mesh: prospective evaluation of morphological and functional changes with consecutive improvement of patient's symptoms. AB - BACKGROUND: The pathophysiology of rectal prolapse and intussusception has not yet been clarified. This is reflected in the multiplicity of surgical procedures. The aim of this prospective study was to measure morphological and functional changes of the pelvic floor and the rectum before and after resection rectopexy. METHODS: A total of 21 patients (mean age 60 years; 2 men, 19 women) with manifest rectal prolapse and rectoanal intussusception underwent sigmoidectomy and rectopexy with an absorbable polyglactin mesh graft. The following analyses were performed preoperatively and, on average, 15 months (range 6-21 month) postoperatively: radiologic defecography, rectal volumetry, sphincter manometry, and evaluation of clinical symptoms. RESULTS: Postoperatively there was no patient with rectal prolapse, and only one with an intussusception. Rectal compliance increased from 6.4 to 10.2 ml/mmHg. Rectal volumetry showed a decrease of the thresholds for the sensation of "desire to defecate" and "maximal tolerated volume" (100-75 ml, 175-150 ml). Postoperatively, there was a higher level of the pelvic floor during contraction. The anorectal angle, vector volume, radial asymmetry, sphincter length, and resting and squeezing pressures were unchanged. Surgery improved rectal evacuation (p = 0.03), continence (p = 0.01), stool consistency (p = 0.03), and warning period (p = 0.01). Patients' personal assessment showed an improved overall satisfaction. CONCLUSIONS: Resection rectopexy is a reliable method for treating rectal prolapse and rectoanal intussusception with clear improvement of the patient's clinical symptoms. The restored anorectal function can be attributed to improved rectal compliance, a lower sensory threshold, an elevation of the pelvic floor during squeezing, and an improved rectal evacuation. PMID- 20703471 TI - International preoperative rectal cancer management: staging, neoadjuvant treatment, and impact of multidisciplinary teams. AB - BACKGROUND: Little is known regarding variations in preoperative treatment and practice for rectal cancer (RC) on an international level, yet practice variation may result in differences in recurrence and survival rates. METHODS: One hundred seventy-three international colorectal centers were invited to participate in a survey of preoperative management of rectal cancer. RESULTS: One hundred twenty three (71%) responded, with a majority of respondents from North America, Europe, and Asia. Ninety-three percent have more than 5 years' experience with rectal cancer surgery. Fifty-five percent use CT scan, 35% MRI, 29% ERUS, 12% digital rectal examination and 1% PET scan in all RC cases. Seventy-four percent consider threatened circumferential margin (CRM) an indication for neoadjuvant treatment. Ninety-two percent prefer 5-FU-based long-course neoadjuvant chemoradiation therapy (CRT). A significant difference in practice exists between the US and non US surgeons: poor histological differentiation as an indication for CRT (25% vs. 7.0%, p = 0.008), CRT for stage II and III rectal cancer (92% vs. 43%, p = 0.0001), MRI for all RC patients (20% vs. 42%, p = 0.03), and ERUS for all RC patients (43% vs. 21%, p = 0.01). Multidisciplinary team meetings significantly influence decisions for MRI (RR = 3.62), neoadjuvant treatment (threatened CRM, RR = 5.67, stage II + III RR = 2.98), quality of pathology report (RR = 4.85), and sphincter-saving surgery (RR = 3.81). CONCLUSIONS: There was little consensus on staging, neoadjuvant treatment, and preoperative management of rectal cancer. Regular multidisciplinary team meetings influence decisions about neoadjuvant treatment and staging methods. PMID- 20703474 TI - Laparoscopic (TEP) versus Lichtenstein inguinal hernia repair: a comparison of quality-of-life outcomes. AB - BACKGROUND: Laparoscopic inguinal hernia repair has emerged as a viable alternative to the open procedure. To date, few studies have included validated measures of quality of life as end points. We compared quality-of-life outcomes following laparoscopic versus open repair of inguinal hernia. METHODS: All laparoscopic repairs were performed via the totally extraperitoneal route (TEP). All open procedures were Lichtenstein repairs (LR). Hernia repairs performed between January 1999 and December 2006 were included in the study. Data was recorded prospectively and each TEP repair was matched with a LR for analysis. The SF-36 form was used to assess quality of life. Statistical significance was determined using the two-sample Wilcoxon rank-sum (Mann-Whitney) test. RESULTS: Three hundred fourteen procedures were performed during the study period, 164 (52%) had a TEP repair and 150 (48%) had a LR. Ninety TEP repairs were matched with 90 LR. Recurrence rates were 3% following TEP repair and 2% following LR. There was a significant difference between the laparoscopic and open groups in terms of physical function (p = 0.0001), physical role (p < 0.0001), bodily pain (p = 0.0029), general health (p = 0.0025), and emotional role (p < 0.0001). There was no significant difference between the groups in terms of vitality (p = 0.2501), mental health (p = 0.08), or social functioning (p = 0.1677). CONCLUSIONS: These data suggest that the TEP repair results in less postoperative pain, a quicker return to normal functional status, and improved quality-of-life outcomes with equivalent recurrence rates when compared to the LR. PMID- 20703475 TI - Tube enterostomy: the humble case report and an astute technique in postoperative peritonitis. PMID- 20703476 TI - Molecular testing for somatic mutations improves the accuracy of thyroid fine needle aspiration biopsy. AB - BACKGROUND: Thyroid fine-needle aspiration (FNA) biopsy is indeterminate or suspicious in up to 30% of cases and these patients are commonly subjected to at least a diagnostic hemithyroidectomy. If malignant on histology, a completion thyroidectomy is usually performed, which may be associated with higher morbidity. To determine the clinical utility of genetic testing in thyroid FNA biopsy, we conducted a prospective clinical trial. METHODS: Four hundred seventeen patients with 455 thyroid nodules were enrolled and had genetic testing for common somatic mutations (BRAF, NRAS, KRAS) and gene rearrangements (RET/PTC1, RET/PTC3, RAS, TRK1) by PCR and direct sequencing and by nested PCR, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of genetic testing in thyroid FNA biopsy were determined based on the histologic diagnosis. RESULTS: One hundred twenty-five of 455 thyroid nodule FNA biopsies were indeterminate or suspicious on cytologic examination. Overall, 50 mutations were identified (23 BRAF, 4 RET/PTC1, 2 RET/PTC3, 21 NRAS) in the thyroid FNA biopsies. There were significantly more mutations detected in malignant thyroid nodules than in benign (P = 0.0001). For thyroid FNA biopsies that were indeterminate or suspicious, genetic testing had a sensitivity of 12%, specificity of 98%, PPV of 38%, and NPV of 65%. CONCLUSIONS: Genetic testing for somatic mutations in thyroid FNA biopsy samples is feasible and identifies a subset of malignant thyroid neoplasms that are indeterminate or suspicious on FNA biopsy. Genetic testing for common somatic genetic alterations thus could allow for more definitive initial thyroidectomy in those with positive results. PMID- 20703477 TI - Effectiveness of a surgical glove port for single port surgery. AB - BACKGROUND: A new surgical concept, such as single port surgery (SPS), usually raises many questions regarding safety, usefulness, appropriateness, applicability, and cost. Because many new port devices have been developed, choosing the type of port device for SPS is the most important factor. We herein briefly report our newly developed SPS port made using a standard surgical glove. METHODS: SPS starts with a 1.5-cm skin incision on the umbilicus. Subsequently, a wound retractor of XS size is installed at the umbilical wound. Then, a non powdered surgical glove (5.5 inches) is put on the wound retractor through which three 5-mm slim trocars are inserted via the finger tips. A semi-flexible laparoscopic camera is inserted via the middle finger port. From June to December 2009, 23 cases of SPS (20 cholecystectomies, 1 choledocholithotomy, 1 appendectomy, and 1 gastropexy) were performed in our institute using this technique. RESULTS: All cases were successfully performed without any intra- or postoperative complications. No conversion to other procedures was needed. The median operative time for cholecystectomy was 110 (range, 55-170) min. CONCLUSIONS: This surgical-glove port is easy to install and is made from conventional, commonly used surgical equipment, making it unnecessary to purchase any expensive new devices. This surgical-glove port technique is a promising method to introduce SPS, because developing or purchasing new devices is unnecessary. Our experience demonstrates the efficacy, appropriateness, and cost effectiveness of this simple port technique. PMID- 20703478 TI - Intraoperative sac pressure measurement during endovascular abdominal aortic aneurysm repair. AB - PURPOSE: Intraoperative sac pressure was measured during endovascular abdominal aortic aneurysm repair (EVAR) to evaluate the clinical significance of sac pressure measurement. METHODS: A microcatheter was placed in an aneurysm sac from the contralateral femoral artery, and sac pressure was measured during EVAR procedures in 47 patients. Aortic blood pressure was measured as a control by a catheter from the left brachial artery. RESULTS: The systolic sac pressure index (SPI) was 0.87 +/- 0.10 after main-body deployment, 0.63 +/- 0.12 after leg deployment (P < 0.01), and 0.56 +/- 0.12 after completion of the procedure (P < 0.01). Pulse pressure was 55 +/- 21 mmHg, 23 +/- 15 mmHg (P < 0.01), and 16 +/- 12 mmHg (P < 0.01), respectively. SPI showed no significant differences between the Zenith and Excluder stent grafts (0.56 +/- 0.13 vs. 0.54 +/- 0.10, NS). Type I endoleak was found in seven patients (15%), and the SPI decreased from 0.62 +/- 0.10 to 0.55 +/- 0.10 (P = 0.10) after fixing procedures. Type II endoleak was found in 12 patients (26%) by completion angiography. The SPI showed no difference between type II endoleak positive and negative (0.58 +/- 0.12 vs. 0.55 +/- 0.12, NS). There were no significant differences between the final SPI of abdominal aortic aneurysms in which the diameter decreased in the follow-up and that of abdominal aortic aneurysms in which the diameter did not change (0.53 +/- 0.12 vs. 0.57 +/- 0.12, NS). CONCLUSIONS: Sac pressure measurement was useful for instant hemodynamic evaluation of the EVAR procedure, especially in type I endoleaks. However, on the basis of this small study, the SPI cannot be used to reliably predict sac growth or regression. PMID- 20703480 TI - [2010 TNM system: on the 7th edition of TNM classification of malignant tumors]. PMID- 20703479 TI - A phase II study of paclitaxel by weekly 1-h infusion for advanced or recurrent esophageal cancer in patients who had previously received platinum-based chemotherapy. AB - PURPOSE: To evaluate the efficacy and safety of weekly paclitaxel (Taxol((r))) in patients with advanced or recurrent esophageal cancer. METHODS: Fifty-three patients with recurrent or advanced esophageal cancer who had previously received platinum-based chemotherapy were treated with paclitaxel 100 mg/m(2) once weekly by 1-h infusion on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Fifty-two patients were evaluable for efficacy and 53 for safety. Forty-one (77%) patients had recurrent, and 12 (23%) had advanced disease. Most patients (52/53) had squamous cell carcinoma, and one had adenocarcinoma. RESULTS: A median of 2 cycles was delivered (range 1-8). The overall response rate was 44.2% (23/52; 95% confidence interval (CI) 30.5, 58.7%), with 4 patients (7.7%) achieving complete response. The median duration of response was 4.8 months, and median overall survival was 10.4 months. The most common Grade 3 or 4 adverse events were neutropenia (52.8%), leukopenia (45.3%), anorexia (9.4%), and fatigue (9.4%). Adverse events resulted in treatment discontinuation in 34.0% of patients and dose reductions in 43.4%. There were no treatment-related deaths. CONCLUSIONS: Weekly paclitaxel demonstrated efficacy and manageable toxicity in patients with advanced or recurrent esophageal cancer and may be a treatment option for this population. PMID- 20703482 TI - [Current TNM classification systems for adrenocortical carcinoma]. AB - Adrenocortical carcinoma (ACC) is a rare malignancy and often difficult to diagnose. It was only in 2003 that the UICC proposed the first TNM classification for ACC. However, an analysis based on data from the German ACC Registry revealed several shortcomings of this classification; in particular, the outcome of patients with UICC stage II and III was not significantly different. Therefore, the European Network for the Study of Adrenal Tumours (ENSAT) developed a revised staging system, the superiority of which was recently confirmed in an independent American cohort. In the ENSAT classification, stage I (tumors <= 5 cm) and II (tumors < 5 cm) are non-infiltrating tumors without positive lymph nodes and distant metastases. Stage III is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or venous tumor thrombus. Stage IV is restricted to patients with distant metastasis. Since the ENSAT classification better reflects patient prognosis than the UICC classification, its use for future clinical and research purposes is recommended. Furthermore, exact documentation of the resection status is essential for optimal decisions on treatment. PMID- 20703483 TI - A shoulder-hand syndrome revealing a lung cancer. AB - Shoulder-hand syndrome is a reflex sympathetic dystrophy which is usually associated with minor trauma, fracture or surgical procedures on bones, or follows peripheral nerve injury. In the present report, we describe a patient who developed sympathetic dystrophy which revealed a lung cancer. Reflex sympathetic dystrophy, therefore, should be considered an occasional manifestation of a paraneoplastic syndrome warranting a thorough search for underlying malignancy. PMID- 20703484 TI - Muscle plasticity in hibernating ground squirrels (Spermophilus lateralis) is induced by seasonal, but not low-temperature, mechanisms. AB - During hibernation, ground squirrels (Spermophilus lateralis) show unusually altered expression of skeletal muscle myosin heavy-chains. Some muscle groups show transitions from fast to slower myosin isoforms despite atrophy, which are not predicted from other mammalian studies of inactivity. We measure myosin protein and mRNA expression, and the mRNA expression of genes important in atrophy and metabolism in a time-course of muscle plasticity prior to, and during extended hibernation. We also investigate the role of strictly low-temperature processes by comparing torpid individuals at 20 and 4 degrees C. Shifts in myosin isoform expression happen at both temperatures, before the onset of torpor, or within the first month of torpor, in all muscles demonstrating isoform remodeling. Skeletal muscle atrophy is greatly attenuated in this hibernating species, and even may be absent in some muscles. When present, atrophy develops early in hibernation, and does not progress in the final 3 months of torpor. Myostatin mRNA is down-regulated 50-75% in the soleus and diaphragm, two important muscles that are spared of atrophy. The transcription factor FOXO1, which spurs proteolytic degradation of contractile proteins through regulation of the ubiquitin ligase MAFbx, is also generally down-regulated, and may contribute to reduced atrophy. Hypoxia-inducible factor (HIF-1alpha) mRNA expression was reduced 50% in some muscles, while elevated more than 300% in others. Our collective findings most strongly support early, seasonal, phenotype changes in skeletal muscles which are not uniquely confined to, or prompted by, torpor at 4 degrees C. Such seasonal control of myosin would be a novel mechanism in mammalian skeletal muscle, which otherwise is most susceptible to mechanical loading and limb-activity patterns. PMID- 20703485 TI - Cerebral developmental venous anomalies. AB - INTRODUCTION: Cerebral developmental venous anomalies (DVAs) are the most frequently encountered cerebral vascular malformation. As such, they are often observed incidentally during routine CT and MRI studies. Yet, what DVAs represent from a clinical perspective is frequently not common knowledge and DVAs, therefore, still generate uncertainty and concern amongst physicians. This article reviews our current understanding of developmental venous anomalies. RESULTS: In the majority of cases, DVAs follow a benign clinical course. On rare occasions, DVAs become symptomatic generally due to an underlying associated vascular malformation such as cavernous malformations or thrombosis of the collecting vein. Rare forms of DVAs include arterialized DVAs and DVAs involved in the drainage of sinus pericranii, which warrant additional investigation by digital subtraction angiography. Cerebral abnormalities such as atrophy, white matter lesions and calcifications within the drainage territory of asymptomatic DVAs, are often identified on CT or MR imaging studies and likely represent secondary changes due to venous hypertension. There is increasing evidence that DVAs have a propensity for developing venous hypertension, which is thought to be the cause of associated cavernous malformations and parenchymal abnormalities. CONCLUSIONS: DVAs represent variations of the normal cerebral venous angioarchitecture and by enlargement follow an uneventful clinical course. Complications can, however, occur and their management requires a thorough understanding of the nature of DVAs, including their frequent coexistence with other types of vascular malformation, and the existence of more complex but rare forms of presentation, such as the arterialized DVAs. PMID- 20703486 TI - Regression of subependymal giant cell astrocytomas with RAD001 (Everolimus) in tuberous sclerosis complex. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes and characterized by slow growing tumors in multiple organs. Of the affected individuals, 10% display subependymal giant cell astrocytomas (SEGAs), which can lead to substantial neurological morbidity. The TSC1/TSC2 protein complex is a negative regulator of the mTOR pathway. Hence, mutations in these genes in preclinical models are associated with increased mTOR pathway activation and heightened sensitivity to mTOR inhibitors. We hereby report our experience with RAD001 (Everolimus) therapy, a novel mTOR inhibitor, in inducing a dramatic regression of SEGAs. METHODS: A patient with TSC and SEGAs was treated with 10 mg/day oral RAD001. MRIs and neuro-ophthalmological exams were performed before and at regular intervals following the initiation of therapy. RESULTS: The lesions exhibited significant regression in several tumor locations and stabilization in others, accompanied with an improvement of his visual status. Treatment was well tolerated for 11 months but was than discontinued due to hypertension and elevated CPK, without evidence for rhabdomyolysis. Yet, during 9 months following the interruption of therapy, SEGAs remained unchanged. CONCLUSIONS: Oral RAD001 demonstrated preliminary encouraging results as treatment of astrocytomas associated with TSC. These preliminary results were recently supported by the Novartis announcement of the phase II study of RAD001 for SEGAs, which was not published yet. According to their statement, 75% of the patients showed reduction of SEGAs' volume following treatment with RAD001. Based on these results, RAD001 may be an alternative to surgery in selected patients with TSC and SEGAs. PMID- 20703487 TI - [Selective co-stimulation blockade. CTLA4-Ig (Abatacept)]. AB - Abatacept is a soluble fusion protein comprising the extracellular domain of human CTLA4 linked to the modified Fc portion of human IgG(1). It is approved for the treatment of rheumatoid arthritis (RA) in combination with methotrexate and juvenile chronic arthritis by blocking the co-stimulatory signal required for full T-cell activation. Abatacept has added to the growing armamentarium of targeted therapies for RA, including the challenging group of RA patients who are refractory to TNF-alpha blockade. To date, abatacept has its main application in cases failing to respond to TNF-alpha blockade. In several studies, the efficacy and safety of abatacept was not only shown for TNF-IR patients, but also for DMARD-IR patients. Recently, the EU has approved abatacept in combination with methotrexate in DMARD-IR patients. The significant and similar response rates in TNF-alpha blockade failure to those observed in only DMARD failure implies that the pathways targeted with the two treatments remain distinct. In terms of safety profile, incidence rates of malignancy in the abatacept trials were consistent with those in a comparable RA population. The rate of opportunistic infections does not seem to be increased in patients treated with abatacept. PMID- 20703488 TI - [Non-TNF biologicals in the therapeutic strategy for rheumatoid arthritis]. AB - The spectrum of agents available for the treatment of rheumatoid arthritis (RA) has become more diversified: In addition to TNF-blocking agents, Abatacept, Rituximab and Tocilizumab have now become available for the treatment of RA. All three agents were approved for patients with insufficient response/intolerability to TNF-blockers; Tozilizumab and Abatacept have also been approved for TNF-naive patients with insufficient response to Methorexate.The present article clarifies the efficacy of these three substances in the treatment algorithm of RA. Current data do not suggest differences in general; therefore, individual considerations may result in patient-specific decisions as to which drug should be used after insufficient response to a TNF-blocking agent or Methotrexate. Possible arguments are discussed. PMID- 20703490 TI - [Tocilizumab. What comes after TNF-blockers in clinical routine?]. AB - Tocilizumab, a monoclonal humanized antibody against IL-6, was licensed in January 2009 in combination with Methotrexate for the treatment of adult patients with moderately to severely active rheumatoid arthritis and inadequate response to one or more DMARDs or TNF antagonists. Tocilizumab is given once every 4 weeks as a 60-min single intravenous infusion at a dosage of 8 mg/kg body weight and may be used as a monotherapy in the case of MTX or DMARD incompatibility. Clinical response is rapid and lasting according to clinical measurements such as ACR response rates or DAS28, irrespective of previous therapy. Within 2 weeks of the first infusion, inflammatory parameters such as CRP and ESR decline and the haemoglobin concentration increases. Adverse events often include mild respiratory infections, transient elevation in liver enzymes, decrease in neutrophile counts and increase in serum lipids. In 8% of patients a lipid lowering therapy needs to be initiated. Diverticulitis with perforation has been observed. Serious infections occur in the range known with other biological therapies. The radiological data show a reduced rate of joint destruction after 1 year of therapy. Long-term follow-up shows good clinical efficacy with an increasing percentage of patients with good clinical response and good safety profile. PMID- 20703491 TI - [Non-TNF biologicals in therapy]. PMID- 20703489 TI - [IL-1 antagonists]. AB - Interleukin (IL)-1 plays an important role not only in the mediation of inflammation but also in the destruction of cartilage and bone. Together with TNF alpha it is one of the most important cytokines in the pathogenesis of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). The first IL-1 antagonist to be approved for RA was Anakinra, an IL-1 receptor antagonist. Anakinra appears to be less effective for RA than TNF blockers. Hence, Anakinra is rarely used for the treatment of RA, but more for the treatment of IL-1-mediated diseases such as autoinflammatory syndromes, adult-onset Still's disease and systemic onset JIA. Two newer IL-1 antagonists have recently been approved for the treatment of CAPS (cryopyrin-associated periodic syndromes): Canakinumab, a fully human IL-1beta antibody, and rilonacept, a fusion protein consisting of the ligand-binding domain of the IL-1 receptor and the IL-1-receptor accessory protein, bound to human IgG1. For RA, there is only one proof-of-concept study to date with canakinumab. There are no prospective data for the treatment of patients with RA who did not respond to or tolerate TNF antagonists; in a retrospective analysis, only 8% of anti-TNF pretreated patients achieved an ACR 20 response. PMID- 20703492 TI - HMGB1: the missing link between diabetes mellitus and heart failure. AB - Diabetes mellitus (DM) is a major independent risk factor for cardiovascular disease, but also leads to cardiomyopathy. However, the etiology of the cardiac disease is unknown. Therefore, the aim of this study was to identify molecular mechanisms underlying diabetic heart disease. High glucose treatment of isolated cardiac fibroblasts, macrophages and cardiomyocytes led to a sustained induction of HMGB1 on the RNA and protein level followed by increased NF-kappaB binding activity with consecutively sustained TNF-alpha and IL-6 expression. Short interference (si) RNA knock-down for HMGB1 and RAGE in vitro confirmed the importance of this axis in diabetes-driven chronic inflammation. In a murine model of post-myocardial infarction remodeling in type 1 diabetes, cardiac HMGB1 expression was significantly elevated both on RNA and protein level paralleled by increased expression of pro-inflammatory cytokines up to 10 weeks. HMGB1-specific blockage via box A treatment significantly reduced post-myocardial infarction remodeling and markers of tissue damage in vivo. The protective effects of box A indicated an involvement of the mitogen-activated protein-kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the transcription factor nuclear factor-kappaB. Interestingly, remodeling and tissue damage were not affected by administration of box A in RAGE(-/-) mice. In conclusion, HMGB1 plays a major role in DM and post-I/R remodeling by binding to RAGE, resulting in activation of sustained pro-inflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a therapeutic strategy to reduce post-ischemic remodeling in DM. PMID- 20703493 TI - Gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in advanced non-small-cell lung cancer: a literature-based meta analysis. AB - The combination of gemcitabine plus paclitaxel has been proposed as an alternative to the platinum-based combinations for treatment of advanced non small-cell lung cancer (NSCLC). However, conflicting results have been reported. This meta-analysis was performed to compare the activity, efficacy, and toxicity of gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in patients with untreated advanced NSCLC. Randomized phase II and phase III clinical trials comparing gemcitabine plus paclitaxel with carboplatin plus gemcitabine or paclitaxel were collected from electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. The published languages and years were not limited. Pooled odds ratios (ORs) were calculated for the 1-year survival rate (1 year SR), the overall response rate (ORR), and grade 3 and grade 4 toxicities. Four randomized controlled trials (2186 patients) were identified from 2051 reports. They were all published as full-text articles. No significant heterogeneity was detected in these studies. A significant difference in ORR favoring gemcitabine plus paclitaxel over carboplatin-based doublets was observed [OR = 1.20; 95% confidence interval (95% CI) = 1.02-1.42; P = 0.03], whereas the trend toward an improved 1-year SR was not significant (OR = 1.07; 95% CI = 0.91 1.26; P = 0.41). An increased risk of grade 3-4 toxicities for patients receiving carboplatin-based chemotherapy was statistically demonstrated. The gemcitabine plus paclitaxel combination showed an improved ORR and a better toxicity profile but a similar 1-year SR compared to carboplatin-based doublets. For nonplatinum based chemotherapy, gemcitabine plus paclitaxel is a useful alternative. PMID- 20703494 TI - Nuclear positioning, higher-order folding, and gene expression of Mmu15 sequences are refractory to chromosomal translocation. AB - Nuclear localization influences the expression of certain genes. Chromosomal rearrangements can reposition genes in the nucleus and thus could impact the expression of genes far from chromosomal breakpoints. However, the extent to which chromosomal rearrangements influence nuclear organization and gene expression is poorly understood. We examined mouse progenitor B cell lymphomas with a common translocation, der(12)t(12;15), which fuses a gene-rich region of mouse chromosome 12 (Mmu 12) with a gene-poor region of mouse chromosome 15 (Mmu 15). We found that sequences 2.3 Mb proximal and 2.7 Mb distal to the der(12)t(12;15) breakpoint had different nuclear positions measured relative to the nuclear radius. However, their positions were similar on unrearranged chromosomes in the same tumor cells and normal progenitor B cells. In addition, higher-order chromatin folding marked by three-dimensional gene clustering was not significantly altered for the 7 Mb of Mmu 15 sequence distal to this translocation breakpoint. Translocation also did not correspond to significant changes in gene expression in this region. Thus, any changes to Mmu 15 structure and function imposed by the der(12)t(12;15) translocation are constrained to sequences near (<2.5 Mb) the translocation junction. These data contrast with those of certain other chromosomal rearrangements and suggest that significant changes to Mmu 15 sequence are structurally and functionally tolerated in the tumor cells examined. PMID- 20703495 TI - Prof. Brinkmann formulated guidelines for the submission of manuscripts on short tandem repeat population data. PMID- 20703496 TI - Ocular manifestations of syphilis: recent cases over a 2.5-year period. AB - BACKGROUND: The ocular manifestations of syphilis are protean and can affect every structure of the eye. There has been a recent increase of syphilis infection in Europe. We report recent cases of ocular syphilis infection in a tertiary center. METHODS: During a 2.5-year period (2005-2007) we collected the medical records of eight male patients with ocular syphilis. The diagnosis was based on serological tests on blood samples and cerebrospinal fluid. All patients underwent a check-up to rule out another etiological diagnosis and to detect the presence of any other sexually transmitted infections. RESULTS: The ocular lesions included: chorioretinitis (one case), retinitis (two cases), panuveitis with macular edema (two cases), episcleritis (one case), anterior optic neuritis (one case), and retrobulbar optic neuropathy (one case). Infection of the cerebrospinal fluid was detected in three of the five patients tested. In six cases, the inflammation was unilateral, and the anatomical and functional prognosis was excellent at the 6-month follow-up visit. Co-infection with human immunodeficiency virus was reported in five patients, with a CD4 T lymphocyte count greater than 300/mm(3). Most of the patients were treated with parenteral ceftriaxone (1 g daily) for 3 weeks with good tolerance. One patient was treated with intravenous penicillin G (18 MUI daily). Only one patient with anterior optic neuritis required systemic steroid therapy associated with antibiotics. Sequelae included sectorial atrophy of the optic nerve with visual field loss (n = 1) and abnormalities of the retinal pigment epithelium (n = 3). CONCLUSIONS: All patients with ocular syphilis exhibited functional improvement and resolution of ocular inflammation after a specific antibiotic treatment. As a great imitator, syphilis should be considered in all patients with uveitis, scleritis, episcleritis, or optic neuritis, especially in men with high-risk sexual behavior. PMID- 20703497 TI - Evolution from macular pseudohole to lamellar macular hole - spectral domain OCT study. AB - BACKGROUND: The pathogenesis of macular pseudohole (MPH) is supposed to be different from that of macular lamellar hole (LMH). MPH is thought to be caused by centripetal contraction of previously present epiretinal membrane. LMH is considered to be an effect of abortive process of full-thickness macular hole formation, or a result of de-roofing of a foveal cyst in persistent cystoid macular oedema. In most cases of LMH, epiretinal membranes are present. The aim of this paper is to show that LMH and MPH may have a common origin and that LMH may evolve from MPH as an epiretinal membrane contracts. METHODS: Observational two-case series of patients with MPH and epiretinal membrane. Spectral domain optical coherence tomography (SD-OCT) was performed during follow-up. RESULTS: In 6 months of follow-up in case 1 and 2 months in case 2, MPH progressed to non full-thickness macular defect, fulfilling the criterion of LMH in SD-OCT. Non vitreous interface traction was detected. CONCLUSION: SD-OCT proves that MPH may progress to LMH without any vitreous traction. Progressive contraction of epiretinal membranes may be a cause of both MPH and LMH, being an advanced stage of the same non-full-thickness macular disorder. PMID- 20703499 TI - Effects of a trail running competition on muscular performance and efficiency in well-trained young and master athletes. AB - To determine the acute effects of a trail running competition and the age dependent differences between young and master athletes, 23 subjects [10 young (30.5 +/- 7 years), 13 master (45.9 +/- 5.9 years)] participated in a 55-km trail running competition. The study was conceived as an intervention study compromising pre, post 1, 24, 48 and 72 h measurements. Measurements consisted of blood tests, ergometer cycling and maximal isometric voluntary contractions (MVC). Parameters monitored included MVC, twitch- and M-wave properties, EMG (RMS) of the vastus lateralis, two locomotion efficiency calculations and muscle damage markers in the blood (CK, LDH). Results indicate post-race increases in CK and LDH, decreases in MVC values (-32 vs. -40% in young and master, P < 0.01), decreases in EMG, increases in contraction time and concomitant decreases in peak twitch values, and a decrease in locomotion efficiency (-4.6 vs. -6.3% in young and master, P < 0.05). Masters showed similar fatigue and muscle damage than young but recuperation was slowed in masters. This study shows that trail runs are detrimental to muscle function, and gives indication that training may not halt muscle deterioration through aging, but can help maintain performance level. PMID- 20703498 TI - Inter-individual variability in the adaptation of human muscle specific tension to progressive resistance training. AB - Considerable variation exists between people in the muscle response to resistance training, but there are numerous ways muscle might adapt to overload that might explain this variable response. Therefore, the aim of this study was to quantify the range of responses concerning the training-induced change in maximum voluntary contraction (MVC) knee joint torque, quadriceps femoris (QF) maximum muscle force (F), physiological cross-sectional area (PCSA) and specific tension (F/PCSA). It was hypothesized that the variable change in QF specific tension between individuals would be less than that of MVC. Fifty-three untrained young men performed progressive leg-extension training three times a week for 9 weeks. F was determined from MVC torque, voluntary muscle activation level, antagonist muscle co-activation and patellar tendon moment arm. QF specific tension was established by dividing F by QF PCSA, which was calculated from the ratio of QF muscle volume to muscle fascicle length. MVC torque increased by 26 +/- 11% (P < 0.0001; range -1 to 52%), while F increased by 22 +/- 11% (P < 0.0001; range -1 to 44%). PCSA increased by 6 +/- 4% (P < 0.001; range -3 to 18%) and specific tension increased by 17 +/- 11% (P < 0.0001; range -5 to 39%). In conclusion, training-induced changes in F and PCSA varied substantially between individuals, giving rise to greater inter-individual variability in the specific tension response compared to that of MVC. Furthermore, it appears that the change in specific tension is responsible for the variable change in MVC. PMID- 20703500 TI - A modified fast-track program for pancreatic surgery: a prospective single-center experience. AB - OBJECTIVE: The objective of this study is to evaluate the impact of a fast-track protocol in a high-volume center for patients with pancreatic disorders. BACKGROUND: The concept of fast-track surgery allowing accelerated postoperative recovery is accepted in colorectal surgery, but efficacy data are only preliminary for patients undergoing major pancreatic surgery. We aimed to evaluate the impact of a modified fast-track protocol in a high-volume center for patients with pancreatic disorders. METHODS: Between February 2005 and January 2010, 145 subjects had resective pancreatic surgery and were enrolled in the program. Essential features of the program were no preanaesthetic medication, upper and lower air-warming device, avoidance of excessive i.v. fluids perioperatively, effective control of pain, early reinstitution of oral feeding, and immediate mobilization and restoration of bowel function following surgery. Outcome measures were postoperative complications such as pancreatic fistula, delayed gastric emptying, biliary leak, intra-abdominal abscess, post pancreatectomy hemorrhage, acute pancreatitis, wound infection, 30-day mortality, postoperative hospital stay, and readmission rates. RESULTS: On average, patients were discharged on postoperative day 10 (range 6-69), with a 30-day readmission rate of 6.2%. Percentage of patients with at least one complication was 38.6%. Pancreatic anastomotic leakage occurred in seven of 101 pancreatico jejunostomies, and biliary leak in three of 109 biliary jejunostomies. Postoperative hemorrhage occurred in ten (6.9%) patients and wound infection in nine (6.2%) cases. In-hospital mortality was 2.7%. Fast-track parameters, such as normal food and first stool, correlated significantly with early discharge (<0.05). At multivariate analysis, lack of jaundice, and resumption of normal diet by the 5th postoperative day were independent factors of early discharge. CONCLUSION: Fast-track programs are feasible, easy, and also applicable for patients undergoing a major surgery such as pancreatic resection. PMID- 20703501 TI - Improved oxygen transfer and increased L-lactic acid production by morphology control of Rhizopus oryzae in a static bed bioreactor. AB - Rhizopus oryzae was immobilized on a cotton matrix in a static bed bioreactor. Compared with free cells in a stirred tank bioreactor, immobilized R. oryzae in this bioreactor gave higher lactic acid production but lower ethanol production. The highest lactic acid production rate (2.09 g/L h) with the final concentration of 37.83 g/L from 70 g/L glucose was achieved when operating the bioreactor at 700 rpm and 0.5 vvm air. To better understand the relationship between shear effects (agitation and aeration) and R. oryzae morphology and metabolism, oxygen transfer rate, fermentation kinetics, and lactate dehydrogenase activity were determined. In immobilized cell culture, higher oxygen transfer rate and lactic acid production were achieved but lower lactate dehydrogenase activity was found as compared with those in free cell culture operated at the same conditions. These results clearly imply that mass transport was the rate controlling step in lactic acid fermentation by R. oryzae. PMID- 20703502 TI - Blood glucose monitoring in the normal population: the PREDICA study. AB - In the PREdiction of DIabetes from CApillary blood glucose (PREDICA) study, we propose a novel approach based on multiple capillary blood glucose (CBG) measurements, assuming that weekly measurements performed for 2 months may be an efficient strategy to screen for diabetes. We studied 538 Caucasian subjects (247 men and 291 women) without a history of diabetes, consecutively recruited by 50 GPs from the Italian provinces of Rome and Frosinone. Subjects were asked to perform 8 fasting glucose and 8 post-prandial glucose measurements during a frame time of 2 months (Glucometer Accu-chek AVIVA Roche Diagnostics). Study subjects were 55 +/- 9 years old (range 22-77 years of age), 50% were overweight and 16% obese. Fifty-eight percent of subjects have performed 13 to 16 CBG measurements during the study, 68% of subjects have performed at least 5 out of 8, both fasting and post-prandial measurements. Among 492 subjects who had at least two fasting measurements, 63.6% had normal glucose levels, 25.4% showed IFG, and 11.0% were diabetic. Considering post-prandial measurements, 74.2% had normal glucose levels, 23.0% had IGT, and 2.8% were diabetic. Combined IFG + IGT was detected in 7% of study subjects, while in 0.8% diagnosis of diabetes was confirmed with both fasting and post-prandial measurements. In this study, we found a high adherence to a novel screening strategy based on self-glucose monitoring in the general population. Our results show that multiple CBG measurements may represent a simple and efficient method for diabetes screening. PMID- 20703503 TI - A putative new ampelovirus associated with grapevine leafroll disease. AB - A putative new ampelovirus was detected in Vitis vinifera cv. Carnelian showing mild leafroll symptoms and molecularly characterized. The complete genome consisted of 13,625 nt and had a structure similar to that of members of subgroup I in the genus Ampelovirus (fam. Closteroviridae). In-depth analyses showed that the virus from cv. Carnelian is the most distinct member of the "GLRaV-4 lineage" of ampeloviruses, which comprises GLRaV-4, -5, -6, -9, and the recently characterized GLRaV-Pr, and GLRaV-De. This virus appears to be a new member of the family Closteroviridae, for which the provisional name grapevine leafroll associated Carnelian virus is proposed. PMID- 20703504 TI - TMBP200, a XMAP215 homologue of tobacco BY-2 cells, has an essential role in plant mitosis. AB - TMBP200 from tobacco BY-2 cells is a member of the highly conserved family of microtubule-associated proteins that includes Xenopus XMAP215, human TOGp, and Arabidopsis MOR1/GEM1. XMAP215 homologues have an essential role in spindle assembly and function in animals and yeast, but their role in plant mitosis is not fully clarified. Here, we show by immunoblot analysis that TMBP200 levels in synchronously cultured BY-2 cells increased when the cells entered mitosis, thus indicating that TMBP200 plays an important role in mitosis in tobacco. To investigate the role of TMBP200 in mitosis, we employed inducible RNA interference to silence TMBP200 expression in BY-2 cells. The resulting depletion of TMBP200 caused severe defects in bipolar spindle formation and resulted in the appearance of multinucleated cells with variable-sized nuclei. This finding indicates that TMBP200 has an essential role in bipolar spindle formation and function. PMID- 20703505 TI - The first clinical case in Japan of destination therapy using the Jarvik 2000 left ventricular assist device. AB - A 73-year-old female with a history of surgical ventricular restoration for ischemic cardiomyopathy presented with biventricular heart failure symptoms. After a Toyobo paracorporeal left ventricular assist device (LVAD) was implanted as a bridge, she underwent successful implantation of a Jarvik 2000 LVAD. This device provided excellent symptomatic improvement. This is the first case in Japan of destination therapy using an implantable LVAD. PMID- 20703507 TI - Elevated serum levels of bromine do not always indicate pseudohyperchloremia. AB - BACKGROUND: We encountered a case of bromism that was found to be due to pseudohyperchloremia. Hyperchloremia is known to be able to reveal existing bromism, but the fact that bromine (Br(-)) influences chloride (Cl(-)) in assays that use ion electrode machines is not widely known. METHODS: We assayed samples by an ion electrode method, using four types of machines. Different amounts of Cl(-) or Br(-) were added to each sample. RESULTS: With the addition of Cl(-) to the samples, the assayed Cl(-) concentrations were proportional to the amount of added Cl(-). With the addition of Br(-) to the samples, the assayed Cl(-) concentrations, as measured by all machines, were increased, but the amounts of the increase differed significantly, and were not proportional to the amount of Br(-) added. In particular, in the machine most markedly influenced by additional Br(-), the Cl(-) concentrations increased from 94.9 to 139.6 mEq/l with the addition of 10 mEq/l of Br(-). Conversely, in the least influenced machine, Cl(-) values increased from 95.0 to 103.0 mEq/l with the addition of 10 mEq/l of Br(-). CONCLUSION: The influence on the Cl(-) assay of the addition of Br(-) varied significantly between different ion electrode machines. Clinical nephrologists therefore need to be able to recognize the characteristics of the specific machines used in their hospitals. PMID- 20703506 TI - Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort. AB - In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70 mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of >=1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy. PMID- 20703508 TI - The potential contribution of small-scale intervention projects in the field to the national health information system for HIV and sexually transmitted infections: a case study of a multilevel intervention in Guatemala. AB - OBJECTIVE: Guatemala's efforts to fight sexually transmitted infections and HIV/AIDS are compromised by the lack of timely and accurate data. The strengthening of the national Monitoring and Evaluation system is key for a better understanding of the epidemics and the formulation of effective public health responses. This study assessed how health service providers in resource poor countries can contribute indicators to national health authorities. METHODS: Review of data sources produced by projects of a NGO harmonizing the identified indicators with national and international standards. During a field visit, they were validated with key stakeholders. RESULTS: Study results are 19 original and 13 harmonized indicators. CONCLUSIONS: Findings suggest that small-scale projects can contribute to the strengthening of national health information systems. PMID- 20703509 TI - Nutrition-related habits and associated factors of Brazilian adolescents. AB - OBJECTIVES: To investigate the nutrition-related habits (NRH) of Brazilian adolescents and evaluate the associations with risk factors. METHODS: Cross sectional school-based was carried out among high school adolescents aged 14-18 years (n = 1,759) from public and private schools from two cities. The NRH were investigated by the weekly consumption of vegetables, fruit, sweet food and fried food. Risk factors investigated were: city, sex, age, socioeconomic status and nutritional status. In statistics, Poisson regression was used with robust variance adjustment. RESULTS: Data indicated low consumption of fruits and vegetables, 70.0 and 71.0%, respectively, and high consumption of sweets and fried food, 66.7 and 63%, respectively. Boys showed risk of inadequate intake of vegetables [prevalence ratios (PR) 1.10, 95% CI 1.01-1.16] and fruit (PR 1.09, 95% CI 1.01-1.16). Furthermore, adolescents who live in Maringa had greater likelihood of consuming vegetables and fruit (20 and 25%, respectively). However, they presented risk of inadequate consumption of sweets (PR 1.19, 95% CI 1.11 1.28) for adolescents who live in Presidente Prudente. CONCLUSION: We concluded that inadequate NRH show high prevalence among adolescents and indicate the need to employ educational strategies that promote the adoption of more healthy habits and behaviors. PMID- 20703511 TI - Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy. AB - OBJECTIVE AND DESIGN: The skin retention and penetration characteristics of copper applied as glycyl-L-histidyl-L-lysine cuprate diacetate were evaluated in vitro in order to assess the potential for its transdermal delivery as anti inflammatory agent. MATERIALS AND METHODS: Flow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. Copper as a tripeptide was applied on isolated stratum corneum, on heat-separated epidermis and on dermatomed skin. Receptor fluid collected over 48 h in 4 h intervals was analyzed by inductively coupled plasma mass spectrometry for copper in tissues and receptor fluid. RESULTS: The permeability coefficient of the compound through dermatomed skin was 2.43 +/- 0.51 * 10(-4) cm/h; 136.2 +/- 17.5 MUg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 82 +/- 8.1 MUg/cm(2) of copper were retained there as depot. CONCLUSIONS: Applied tansdermally as the tripeptide on human skin ex vivo, copper permeated the skin and was also retained in skin tissue in amounts potentially effective for the treatment of inflammatory diseases. PMID- 20703512 TI - Philippine alliance of fisherfolk: ecohealth practitioners for livelihood and food security. AB - Pamana Ka Sa Pilipinas (Pamana) is a grassroots fisherfolk alliance of Philippine Marine Protected Areas with more than 6,000 individual fisherfolk and their 30,000 family members. Access to food, education, and health services for Philippine fisherfolk families is directly dependant upon the fish harvest and related health of the marine environment. Pamana represents a unique "ecohealth" strategy, linking the health of coastal people and that of their surrounding marine ecosystem. Pamana's activities are viewed by both their membership and barangay (village) health workers as a contribution to nutritional and community health. The alliance has developed an approach to the empowerment of fisherfolk that has led to improvement in health, food security, and nutritional status of their communities. The development of Pamana provides a model for building capacity in other fishing- and resource-based cultures, through engagement and empowerment. In less developed countries, grassroots initiatives, such as Pamana, may be the only solution for sustainable fisheries contributions to food security, given the challenges of fisherfolk poverty, environmental degradation, and limited finances. PMID- 20703510 TI - Health, alcohol and psychosocial factors in Eastern Europe study: dietary patterns and their association with socio-demographic factors in the Lithuanian urban population of Kaunas city. AB - OBJECTIVES: The purpose of this study was to identify the main dietary patterns in the Lithuanian urban population and to determine their association with socio demographic factors. METHODS: Data from the survey performed in the framework of the HAPIEE (Health, Alcohol, Psychosocial factors In Eastern Europe) study were presented. A random sample of 7,087 individuals aged 45-72 years was screened in 2006-2008. RESULTS: Factor analysis of the main dietary patterns revealed a five factor solution, which accounted for 47.8% of the variance: "fresh vegetables and fruit"; "sweets"; "porridge and cereals"; "potatoes, meat, boiled vegetables and eggs"; "chicken and fish". "Fresh vegetables and fruits" factor and "sweets" factor were inversely associated with age both in men and women: older people consumed less frequent than average of the particular food groups. Dietary patterns of people with good self-rated health and university education were healthier than among people with lower education and poorer health. CONCLUSION: Nutrition education efforts should focus on improving food diversity, with particular targeting of lower educated, single and older people. PMID- 20703513 TI - Dental fluorosis linked to degassing of Ambrym volcano, Vanuatu: a novel exposure pathway. AB - Ambrym in Vanuatu is a persistently degassing island volcano whose inhabitants harvest rainwater for their potable water needs. The findings from this study indicate that dental fluorosis is prevalent in the population due to fluoride contamination of rainwater by the volcanic plume. A dental survey was undertaken of 835 children aged 6-18 years using the Dean's Index of Fluorosis. Prevalence of dental fluorosis was found to be 96% in the target area of West Ambrym, 71% in North Ambrym, and 61% in Southeast Ambrym. This spatial distribution appears to reflect the prevailing winds and rainfall patterns on the island. Severe cases were predominantly in West Ambrym, the most arid part of the island, and the most commonly affected by the volcanic plume. Over 50 km downwind, on a portion of Malakula Island, the dental fluorosis prevalence was 85%, with 36% prevalence on Tongoa Island, an area rarely affected by volcanic emissions. Drinking water samples from West Ambrym contained fluoride levels from 0.7 to 9.5 ppm F (average 4.2 ppm F, n = 158) with 99% exceeding the recommended concentration of 1.0 ppm F. The pathway of fluoride-enriched rainwater impacting upon human health as identified in this study has not previously been recognised in the aetiology of fluorosis. This is an important consideration for populations in the vicinity of degassing volcanoes, particularly where rainwater comprises the primary potable water supply for humans or animals. PMID- 20703514 TI - Inhibition of ATIR by shRNA prevents collagen synthesis in hepatic stellate cells. AB - Currently, strategies aimed at disrupting renin-angiotensin-aldosterone system (RAAS) are extensively investigated for treating liver fibrosis. However, the experiment results remain unsatisfactory, mainly due to excessive level of angiotensin II (AngII) in gene expression. In this article, we aim to investigate whether suppression of AngII-type I receptor (ATIR) expression by short hairpin RNA (shRNA) expression vectors decreases the level of collagen synthesis in hepatic stellate cells (HSCs). Three pairs of ATIR-targeted shRNA expression vectors were transfected into HSC-T6 cells. Compared with the control group, both mRNA and protein levels of ATIR expression were significiently decreased in shRNA treated groups, and the inhibitory effect exhibited a dose- and time-dependent pattern. Accordingly, TGF-beta1 mRNA expression in shRNA1 group was reduced by about 54% compared with the control group. The level of Procollagen type III, hyaluronic acid, and laminin declined by about 46.4, 52.6, and 42%, respectively. In conclusion, shRNA expression vectors targeting ATIR could attenuate collagen synthesis. PMID- 20703516 TI - Electronic medical archives: a different approach to applying re-signing mechanisms to digital signatures. AB - Electronic medical records can be defined as a digital format of the traditionally paper-based anamneses, which contains the history of a patient such as his somewhat illness, current health problems, and his chronic treatments. An electronic anamnesis is meant to make the patient's health information more conveniently accessible and transferable between different medical institutions and also easier to be kept quite a long time. Because of such transferability and accessibility of electronic anamneses, we can use less resource than before on storing the patients' medical information. This also means that medical care providers could save more funds on record-keeping and access a patient's medical background directly since shown on the computer screen more quickly and easily. Overall, the service quality has seemingly improved greatly. However, the usage of electronic anamneses involves in some concerned issues such as its related law declaration, and the security of the patient's confidential information. Because of these concerns, a secure medical networking scheme is taking into consideration. Nowadays, the administrators at the medical institutions are facing more challenges on monitoring computers and network systems, because of dramatic advances in this field. For instance, a trusted third party is authorized to access some medical records for a certain period of time. In regard to the security purpose, all the electronic medical records are embedded with both of the public-key infrastructure (PKI) cryptography and the digital signature technique so as to ensure the records well-protected. Since the signatures will be invalid due to the revocation or time expiration, the security of records under this premise would turn into vulnerable. Hence, we propose a re signing scheme, whose purpose is to make a going-expired digital signature been resigned in time, in keeping with the premise of not conflicting with the laws, morals, and privacy while maintaining the security of the electronic medical records. PMID- 20703515 TI - Measuring hospital efficiency with Data Envelopment Analysis: nonsubstitutable vs. substitutable inputs and outputs. AB - There is a conflict between Data Envelopment Analysis (DEA) theory's requirement that inputs (outputs) be substitutable, and the ubiquitous use of nonsubstitutable inputs and outputs in DEA applications to hospitals. This paper develops efficiency indicators valid for nonsubstitutable variables. Then, using a sample of 87 community hospitals, it compares the new measures' efficiency estimates with those of conventional DEA measures. DEA substantially overestimated the hospitals' efficiency on the average, and reported many inefficient hospitals to be efficient. Further, it greatly overestimated the efficiency of some hospitals but only slightly overestimated the efficiency of others, thus making any comparisons among hospitals questionable. These results suggest that conventional DEA models should not be used to estimate the efficiency of hospitals unless there is empirical evidence that the inputs (outputs) are substitutable. If inputs (outputs) are not substitutes, efficiency indicators valid for nonsubstitutability should be employed, or, before applying DEA, the nonsubstitutable variables should be combined using an appropriate weighting scheme or statistical methodology. PMID- 20703518 TI - Emergency medical support system for extravehicular activity training held at weightless environment test building (WETS) of the Japan Aerospace Exploration Agency (JAXA) : future prospects and a look back over the past decade. AB - The Japan Aerospace Exploration Agency (JAXA) provides extravehicular activity (EVA) training to astronauts in a weightless environment test building (WETS) located in Tsukuba City. For EVA training, Tsukuba Medial Center Hospital (TMCH) has established an emergency medical support system, serving as operations coordinator. Taking the perspective of emergency physicians, this paper provides an overview of the medical support system and examines its activities over the past decade as well as future issues. Fortunately, no major accident has occurred during the past 10 years of NBS. Minor complaints (external otitis, acute otitis media, transient dizziness, conjunctival inflammation, upper respiratory inflammation, dermatitis, abraded wounds, etc.) among the support divers have been addressed onsite by attending emergency physicians. Operations related to the medical support system at the WETS have proceeded smoothly for the former NASDA and continue to proceed without event for JAXA, providing safe, high quality emergency medical services. If an accident occurs at the WETS, transporting the patient by helicopter following initial treatment by emergency physicians can actually exacerbate symptoms, since the procedure exposes a patient who was recently within a hyperbaric environment to the low-pressure environment involved in air transportation. If a helicopter is used, the flight altitude should be kept as low as possible by taking routes over the river. PMID- 20703517 TI - A rule-based clinical decision model to support interpretation of multiple data in health examinations. AB - Health examinations can obtain relatively complete health information and thus are important for the personal and public health management. For clinicians, one of the most important works in the health examinations is to interpret the health examination results. Continuously interpreting numerous health examination results of healthcare receivers is tedious and error-prone. This paper proposes a clinical decision support system to assist solving above problems. In order to customize the clinical decision support system intuitively and flexibly, this paper also proposes the rule syntax to implement computer-interpretable logic for health examinations. It is our purpose in this paper to describe the methodology of the proposed clinical decision support system. The evaluation was performed by the implementation and execution of decision rules on health examination results and a survey on clinical decision support system users. It reveals the efficiency and user satisfaction of proposed clinical decision support system. Positive impact of clinical data interpretation is also noted. PMID- 20703519 TI - New automated detection method of OSA based on artificial neural networks using P wave shape and time changes. AB - This paper describes a new method for automatic detection of obstructive sleep apnea (OSA) based on artificial neural networks (ANN) using regular electrocardiogram (ECG) recordings. ECG signals were pre-processed and segmented to extract the P-waves; then three P-wave features were extracted: the P-wave duration (T ( p )), the P-wave dispersion (P ( d )), and the time interval from the peak of the P-wave to the R-wave (T ( pr )). Combinations of the three features were used as features for classification using ANN. For each feature combination studied, 70% of the input data was used for training the ANN, 15% for validating, and 15% for testing the results. Perfect agreement between expert's scores and the ANN scores was achieved when the ANN was applied on T ( p ), P ( d ), and T ( pr ) taken together, while substantial agreements were achieved when applying the ANN on the feature combinations T ( p ) and P ( d ), and T ( p ) and T ( pr ). PMID- 20703520 TI - Technology enabled knowledge exchange: development of a conceptual framework. AB - As the need for knowledge exchange grows, so does the need to find new ways for researchers, decision makers, and educators to communicate and collaborate with each other on how to improve drug prescribing and use. In this paper, we introduce a conceptual framework for evaluating knowledge exchange activities within drug policy groups. The framework is grounded in the information and communication technologies (ICT) and knowledge exchange literature and is composed of various inputs, processes, and outputs. Inputs into the framework are research task, communication medium (face-to-face, teleconferencing, and web conferencing), group characteristics (size, experience, goals, and roles), and context (description of linkage and exchange within the policy domain and group type). The inputs will affect how the social interaction process, knowledge brokering process, and information exchange process between drug policy groups (decision-makers, researchers, and educators) develop as part of the linkage and exchange knowledge exchange process. The inputs and how they shape the linkage and exchange knowledge exchange process will lead to different levels of engagement outputs and linkage and exchange outputs. Results of a refined conceptual framework based on a 2-year case study are also provided in the model where new inputs and processes are introduced. PMID- 20703521 TI - Time frequency analysis for automated sleep stage identification in fullterm and preterm neonates. AB - This work presents a new methodology for automated sleep stage identification in neonates based on the time frequency distribution of single electroencephalogram (EEG) recording and artificial neural networks (ANN). Wigner-Ville distribution (WVD), Hilbert-Hough spectrum (HHS) and continuous wavelet transform (CWT) time frequency distributions were used to represent the EEG signal from which features were extracted using time frequency entropy. The classification of features was done using feed forward back-propagation ANN. The system was trained and tested using data taken from neonates of post-conceptual age of 40 weeks for both preterm (14 recordings) and fullterm (15 recordings). The identification of sleep stages was successfully implemented and the classification based on the WVD outperformed the approaches based on CWT and HHS. The accuracy and kappa coefficient were found to be 0.84 and 0.65 respectively for the fullterm neonates' recordings and 0.74 and 0.50 respectively for preterm neonates' recordings. PMID- 20703523 TI - Critical elements and lessons learnt from the implementation of an RFID-enabled healthcare management system in a medical organization. AB - Healthcare services are complex and life-critical. One mistake in any procedure may lead to irremediable consequences; numerous researchers, thus, introduce information and communication technology to improve quality of services and enhance patient safety by reducing the medical errors. Radio frequency identification (RFID) is considered as one of the emerging tool assist in meeting the challenges of the present situation. In recent years, RFID has been applied in medical organizations for the purpose of managing and tracking medical equipment, monitoring and identifying patients, ensuring that the right medication is given to the right patient, and preventing the use of counterfeit medicine. However, most of the existing literature focuses on demonstrating how RFID can benefit the healthcare industry, whereas little attention has been given to the management issues involved in constructing an RFID project in medical organizations. In this paper, an exploratory case study is conducted in a medical organization to illustrate the development framework and critical issues that should be taken into consideration in the preparation, implementation and maintenance stage of constructing such a project. All the experiences and results discussed in this paper offer valuable and useful insights to steer those who would like to start their journey using RFID in medical organizations. PMID- 20703522 TI - Rural Health Clinic efficiency and effectiveness: insight from a nationwide survey. AB - This study reports the results of a nationwide survey of Rural Health Clinics (RHCs). The purpose was to identify factors that contribute to efficiency and effectiveness in RHCs. Factors related to cost efficiency were analyzed using multiple regression; factors related to the likelihood of providing preventive diabetic care, an effectiveness indicator, were analyzed using logistic regression. The study found: (1) technical efficiency to be positively related to cost efficiency; (2) non-profit control to be inversely related to cost efficiency in independent RHCs; and (3) provider-based RHCs and technology use to be related to the likelihood of providing preventive diabetic care. Implications for RHCs are: (1) improvement in technical efficiency could enhance cost efficiency; (2) visits to PAs and NPs, an indicator of process efficiency, may not guarantee the provision of preventive diabetic care; and (3) strategies for improving RHC efficiency and effectiveness may be different for provider-based and independent clinics. PMID- 20703524 TI - Integrating clinical information in National Biobank of Korea. AB - The National Biobank of Korea (NBK) is a government supported project that aims at consolidating various human-originated biomedical resources collected by individual hospitals nation-wide and integrating them with their donors' clinical information which researchers can take advantage of. In this paper, we present our experiences in developing the Clinical Information Integration System (CIIS) for NBK. The system automatically extracts clinical data from hospital information systems as much as possible to avoid errors from manual entry by human errors. It maintains the independence of individual hospitals by employing a two-layer approach, one of which takes care of all hospital-specific aspects. Interoperability is achieved by adopting HL7 v2.x messaging between the biobank and hospitals. We report the current status of the biobank and system deployments. We finally identify limitations and discuss how to improve them. PMID- 20703525 TI - A literature review on distance knowledge exchange in healthcare groups: what can we learn from the ICT literature? AB - As healthcare groups continue to communicate and collaborate at a distance on knowledge exchange activities, Information and Communication Technology (ICT) has come to play an increasingly important role in supporting such interactions. However, to date, the literature on knowledge exchange appears disconnected from that of ICT. Research on the effects of ICT on knowledge exchange activities is needed. The literature review explores the potential impacts ICTs can have on knowledge exchange groups, and especially, the social interaction process. A discussion of how ICTs could impact the social interaction process of knowledge exchange activities is made. PMID- 20703526 TI - New indicators based on personnel cost for management efficiency in a hospital. AB - A simple and fair benchmarking system or financial indicators for use on the clinical department level have been lacking to evaluate the management efficiency and activity of each clinical department or division of a hospital. New financial indicators have therefore been developed based on personnel costs. Indicator 1: The ratio of marginal profit after personnel cost per personnel cost (RMP). Indicator 2: The ratio of investment (=indirect cost) per personnel cost (RIP). The difference between RMP and RIP demonstrates the operation profit in US Dollars for personnel cost (OPP). A turning point in profitability similar to the break-even point (BEP) and break-even ratio (BER) could be also defined by the combination of the RMP and RIP. The merits of these two indicators are not only the ability to indicate the relationship between the medical profit and the investments in the hospital, but also the capability to demonstrate such indicators as BEP, BER and OPP on a single graph. The two indicators were applied to the hospitals in the National Hospital Organization and to the clinical department in one hospital. Using these two indicators, it was possible to evaluate the management efficiency and medical activity not only in the whole hospital but also in each department and DPC/DRG group. This will be of use to a manager of a hospital in checking the management efficiency of his/her hospital despite the variations among hospitals, departments and divisions. PMID- 20703527 TI - 3D visualization and simulation in surgical planning system of orbital hypertelorism. AB - Simulation and three-dimensional visualization of object motion is a prerequisite for any surgical planning system. Orbital hypertelorism is a disease, which is most commonly associated with craniofacial malformations. We have developed a surgical planning system for planning and evaluation of orbital hypertelorism surgery. In our system CT-based virtual surface models fitted by oriented bounding boxes (OBB) are manipulated. Three-dimensional motion as well as a correction surgery can be simulated. Both are controlled by collision detection. The computer-based interactive surgery simulation systems (CISSS) presented here can take virtual surgical operation and forecast facial features after the correction of orbital hypertelorism, our surgical planning is cheaper and faster than the current methods, surgical outcome was also better than the current methods. PMID- 20703528 TI - Data consistency in a voluntary medical incident reporting system. AB - Voluntary medical incident reporting systems are a valuable source for studying adverse events and near misses. Unfortunately, such systems usually contain a large amount of incomplete and inaccurate reports which negatively affect their utility for medical error research. To investigate the reporting quality and propose solutions towards quality voluntary reports, we employed a content analysis method to examine one-year voluntary medical incident reports of a University Hospital. Results indicate that there is a large amount of inconsistent records within the reports. About 25% of the reports were labeled as "miscellaneous" and "other". Through an in-depth analysis, those "miscellaneous" and "other" were substituted by their real incident types or error descriptions. Analysis shows that the pre-defined reporting categories serve well in general for the voluntary reporting need. In some cases, human factors play a key role in selecting accurate categories since reporters lack time or information to complete the report. We suggest that a human-centered, ontology based system design for voluntary reporting is feasible. Such a design could help improve the completeness and accuracy, and interoperability among national and international standards. PMID- 20703529 TI - HIT implementation in critical access hospitals: extent of implementation and business strategies supporting IT use. AB - Small rural hospitals face considerable financial and personnel resource shortages which hinder their efforts to implement complex health information technology (HIT) systems. A survey on the use of HIT was completed by 85% of Iowa's 82 Critical Access Hospitals (CAH). Analyses indicate that low IT staffing in CAHs is a barrier to implementing HIT solutions. CAHs with fewer staff tend to employ alternative business strategies. There is a clear relationship between having IT staff at a CAH and the types of technologies used. Many CAHs report having difficulty expanding upon HIT functionalities due to the challenges of finding IT staff with healthcare expertise. Most CAHs are in the transition point of planning for or beginning implementation of complex clinical information systems. Strategies for addressing these challenges will need to evolve as the HIT investments by rural hospitals race to keep pace with the goals for the nation. PMID- 20703530 TI - Health information and communication system for emergency management in a developing country, Iran. AB - Disasters are fortunately rare occurrences. However, accurate and timely information and communication are vital to adequately prepare individual health organizations for such events. The current article investigates the health related communication and information systems for emergency management in Iran. A mixed qualitative and quantitative methodology was used in this study. A sample of 230 health service managers was surveyed using a questionnaire and 65 semi structured interviews were also conducted with public health and therapeutic affairs managers who were responsible for emergency management. A range of problems were identified including fragmentation of information, lack of local databases, lack of clear information strategy and lack of a formal system for logging disaster related information at regional or local level. Recommendations were made for improving the national emergency management information and communication system. The findings have implications for health organizations in developing and developed countries especially in the Middle East. Creating disaster related information databases, creating protocols and standards, setting an information strategy, training staff and hosting a center for information system in the Ministry of Health to centrally manage and share the data could improve the current information system. PMID- 20703531 TI - Local EHR management based on openEHR and EN13606. AB - This article describes handling medical data in a healthcare system based on electronic healthcare records. At a medical unit level, data storage requires both accurate collecting and high security. The proposed information model complies with EN 13606, which is a European health data communication standard approved by the European Committee for Standardization (CEN) and partly approved by the International Organization for Standardization (ISO). PMID- 20703532 TI - WebBio, a web-based management and analysis system for patient data of biological products in hospital. AB - We selected HTML, PHP and JavaScript as the programming languages to build "WebBio", a web-based system for patient data of biological products and used MySQL as database. WebBio is based on the PHP-MySQL suite and is run by Apache server on Linux machine. WebBio provides the functions of data management, searching function and data analysis for 20 kinds of biological products (plasma expanders, human immunoglobulin and hematological products). There are two particular features in WebBio: (1) pharmacists can rapidly find out whose patients used contaminated products for medication safety, and (2) the statistics charts for a specific product can be automatically generated to reduce pharmacist's work loading. WebBio has successfully turned traditional paper work into web-based data management. PMID- 20703533 TI - Evaluation of a content-based retrieval system for blood cell images with automated methods. AB - Content-based image retrieval techniques have been extensively studied for the past few years. With the growth of digital medical image databases, the demand for content-based analysis and retrieval tools has been increasing remarkably. Blood cell image is a key diagnostic tool for hematologists. An automated system that can retrieved relevant blood cell images correctly and efficiently would save the effort and time of hematologists. The purpose of this work is to develop such a content-based image retrieval system. Global color histogram and wavelet based methods are used in the prototype. The system allows users to search by providing a query image and select one of four implemented methods. The obtained results demonstrate the proposed extended query refinement has the potential to capture a user's high level query and perception subjectivity by dynamically giving better query combinations. Color-based methods performed better than wavelet-based methods with regard to precision, recall rate and retrieval time. Shape and density of blood cells are suggested as measurements for future improvement. The system developed is useful for undergraduate education. PMID- 20703534 TI - Development of a portable Linux-based ECG measurement and monitoring system. AB - This work presents a portable Linux-based electrocardiogram (ECG) signals measurement and monitoring system. The proposed system consists of an ECG front end and an embedded Linux platform (ELP). The ECG front end digitizes 12-lead ECG signals acquired from electrodes and then delivers them to the ELP via a universal serial bus (USB) interface for storage, signal processing, and graphic display. The proposed system can be installed anywhere (e.g., offices, homes, healthcare centers and ambulances) to allow people to self-monitor their health conditions at any time. The proposed system also enables remote diagnosis via Internet. Additionally, the system has a 7-in. interactive TFT-LCD touch screen that enables users to execute various functions, such as scaling a single-lead or multiple-lead ECG waveforms. The effectiveness of the proposed system was verified by using a commercial 12-lead ECG signal simulator and in vivo experiments. In addition to its portability, the proposed system is license-free as Linux, an open-source code, is utilized during software development. The cost effectiveness of the system significantly enhances its practical application for personal healthcare. PMID- 20703535 TI - Using health smart cards to check drug allergy history: the perspective from Taiwan's experiences. AB - In Taiwan, national health insurance coverage began in 1994, and the Bureau of National Health Insurance has issued health smart cards since 2004. In addition to tracking medical reimbursements, these smart cards store healthcare information, including electronic prescriptions, medical procedure and vaccination records, drug allergy histories, and information about a patient's willingness to be an organ donor. We conducted this study 4 years after the smart cards had been introduced in order to review how drug allergy history is recorded using this system. Our results reveal that the drug allergy histories are incomplete in many cases, and the format used to record a patient's drug allergy history is not consistent. We offer suggestions to promote the standardization of drug allergy history records. PMID- 20703537 TI - Vocabularies and retrieval tools in biomedicine: disentangling the terminological knot. AB - Terms like "thesaurus", "taxonomy", "classification", "glossary", "ontology" and "controlled vocabulary" can be used in diverse contexts, causing confusion and vagueness about their denotation. Is a thesaurus a tool to enrich a writer's style or an indexing tool used in bibliographic retrieval? Or can it be both? A literature study was to clear the confusion, but rather than giving us consensus definitions, it provided us with conflicting descriptions. We classified these definitions into three domains: linguistics, knowledge management and bibliographic retrieval. The scope of the terms is therefore highly dependent on the context. We propose one definition per term, per context. In addition to this intra-conceptual confusion, there is also inter-conceptual vagueness. This leads to the introduction of misnomers, like "ontology" in the Gene Ontology. We examined some important (bio)medical systems for their compatibility with the definitions proposed in the first part of this paper. To conclude, an overview of these systems and their classification into the three domains is given. PMID- 20703536 TI - Measuring technical efficiency in primary health care: the effect of exogenous variables on results. AB - The aim of this paper is to extend the existing literature about efficiency measurement in primary health care with the application of a recently developed method to deal with exogenous variables. In this context, these variables are represented by the main characteristics of the covered population. The use of this technique allows calculating more accurate efficiency scores that can reflect the performance of units more properly. Our results show that the inclusion of these variables in the evaluation has a great impact on both the values of efficiency scores and the rank of units. This analysis has been carried out using a great amount of data available about primary health care centers in the Spanish region of Extremadura. PMID- 20703538 TI - Polarization sensitive subcutaneous and muscular imaging based on common path optical coherence tomography using near infrared source. AB - In this paper, we describe a polarization sensitive (PS) subcutaneous and muscular imaging system based on common path optical coherence tomography (CP OCT) using a near infrared source. The axial and lateral resolutions of the PS OCT system are 9 and 6 MUm, respectively. The main goal of this work is to build a high-resolution and minimally invasive optical imager for examining various kinds of cutaneous substructures with intrinsic or form birefringence. The internal structural information is extracted by the real-time signal analysis (Fourier Transform) of the modulated spectral intensity depending on the beam and tissue birefringence. The preliminary results using fresh beef longissimus muscle and in vivo Rattus norvegicus (rat) show that it is possible to visualize the birefringence effect of the tissue collagen fibers in the samples in order to achieve superior image contrast and sensitivity for the detection of hidden dermal structures. Compared to conventional CP-OCT, the proposed PS-OCT system provides depth-resolved images, which reflect the tissue birefringence. PMID- 20703539 TI - Computer based synchronization analysis on sleep EEG in insomnia. AB - Inter-hemispheric sleep EEG coherence is studied in 10 subjects with psycho physiological insomnia, in 10 with paradoxical insomnia, and in 10 matched controls through different states of the sleep/wakefulness cycle. Inter hemispheric EEG coherence between central electrode pairs are compared to each other within these groups. A linear measure called as Coherence Function (CF) and a nonlinear measure called as Mutual Information (MI) are performed by using the Information Theory Toolbox in the present sleep EEG synchronization study. Regarding as tests, for all-night EEG recordings of participants, both measures indicate higher degree of EEG coherence for insomnia than for controls. The results further validate inter-hemispheric CF as a sign of activity in insomnia where the EEG series from stage2, REM sleep and the eyes closed waking state. In particular, the CF is found to be more useful tool than the MI for detection of insomnia when the power spectral density estimations of sleep stages are provided by the Burg Method. In conclusion, the CF provides insights into functional connectivity of brain regions during sleep. Since the CF has a characteristic shape for sleep states, it can be proposed to identify the degree of EEG complexity depending on sleep disorders. PMID- 20703540 TI - Medical image on the go! AB - The idea for softcopy viewing of medical image outside the radiology reading room spread among the scientists in various fields for several years. An image could be read on workstation of all types, from desktop across movable to handheld. Benefits are numerous and continue to grow as physicians use them discovering new usage cases. Proposed solutions vary with PACS architecture invasion level, communication and storage image formats, and utilization. We employ JPEG2000 standard because of its high (lossy/lossless) compression ratio with minimal spatial distortion, retrieval-oriented storage, and streaming. It is embedded in PACS as the DICOM Private Data Element containing JPIP parameter string, so called DICOM2000. The DICOM2000 message is transparent for standard DICOM devices at the slightest level of invasion. Thanks to sophisticated JPEG2000 streaming, medical image becomes suitable for any resolution and quality display and (wireless) networks. The solution is validated on the ACR/NEMA standard test set of PACS images. PMID- 20703541 TI - Classifying epilepsy diseases using artificial neural networks and genetic algorithm. AB - In this study, FFT analysis is applied to the EEG signals of the normal and patient subjects and the obtained FFT coefficients are used as inputs in Artificial Neural Network (ANN). The differences shown by the non-stationary random signals such as EEG signals in cases of health and sickness (epilepsy) were evaluated and tried to be analyzed under computer-supported conditions by using artificial neural networks. Multi-Layer Perceptron (MLP) architecture is used Levenberg-Marquardt (LM), Quickprop (QP), Delta-bar delta (DBD), Momentum and Conjugate gradient (CG) learning algorithms, and the best performance was tried to be attained by ensuring the optimization with the use of genetic algorithms of the weights, learning rates, neuron numbers of hidden layer in the training process. This study shows that the artificial neural network increases the classification performance using genetic algorithm. PMID- 20703542 TI - Predicting arterial blood gas values from venous samples in patients with acute exacerbation chronic obstructive pulmonary disease using artificial neural network. AB - Arterial blood gas (ABG) has an important role in the clinical assessment of patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Because of ABG complications, an alternative method is beneficial. We have trained and tested five artificial neural networks (ANNs) with venous blood gas (VBG) values (pH, PCO(2), HCO(3), PO(2), and O(2) saturation) as inputs, to predict ABG values in patients with AECOPD. Venous and arterial blood samples were collected from 132 patients. Using the data of 106 patients, the ANNs were trained and validated by back-propagation algorithm. Subsequently, data from the remainder 26 patients was used for testing the networks. The ability of ANNs to predict ABG values and to detect significant hypercarbia was assessed and the results were compared with a linear regression model. Our results indicate that the ANNs provide an accurate method for predicting ABG values from VBG values and detecting hypercarbia in AECOPD. PMID- 20703544 TI - Statistical approach for brain cancer classification using a region growing threshold. AB - In brain cancer, a biopsy as an invasive procedure is needed in order to differentiate between malignant and benign brain tumor. However, in some cases, it is difficult or harmful to perform such a procedure, to the brain. The aim of this study is to investigate a new method in maximizing the probability of brain cancer type detection without actual biopsy procedure. The proposed method combines both image and statistical analysis for tumor type detection. It employed image filtration and segmentation of the target region of interest with MRI to assure an accurate statistical interpretation of the results. Statistical analysis was based on utilizing the mean, range, box plot, and testing of hypothesis techniques to reach acceptable and accurate results in differentiating between those two types. This method was performed, examined and compared on actual patients with brain tumors. The results showed that the proposed method was quite successful in distinguishing between malignant and benign brain tumor with 95% confident that the results are correct based on statistical testing of hypothesis. PMID- 20703543 TI - Detecting sleep apnea by heart rate variability analysis: assessing the validity of databases and algorithms. AB - Obstructive sleep apnea (OSA) is a serious disorder caused by intermittent airway obstruction which may have dangerous impact on daily living activities. Heart rate variability (HRV) analysis could be used for diagnosing OSA, since this disease affects HRV during sleep. In order to validate different algorithms developed for detecting OSA employing HRV analysis, several public or proprietary data collections have been employed for different research groups. However, for validation purposes, it is obvious and evident the lack of a common standard database, worldwide recognized and accepted by the scientific community. In this paper, different algorithms employing HRV analysis were applied over diverse public and proprietary databases for detecting OSA, and the outcomes were validated in terms of a statistical analysis. Results indicate that the use of a specific database may strongly affect the performance of the algorithms, due to differences in methodologies of processing. Our results suggest that researchers must strongly take into consideration the database used when quoting their results, since selected cases are highly database dependent and would bias conclusions. PMID- 20703545 TI - Singular spectrum analysis of sleep EEG in insomnia. AB - In the present study, the Singular Spectrum Analysis (SSA) is applied to sleep EEG segments collected from healthy volunteers and patients diagnosed by either psycho physiological insomnia or paradoxical insomnia. Then, the resulting singular spectra computed for both C3 and C4 recordings are assigned as the features to the Artificial Neural Network (ANN) architectures for EEG classification in diagnose. In tests, singular spectrum of particular sleep stages such as awake, REM, stage1 and stage2, are considered. Three clinical groups are successfully classified by using one hidden layer ANN architecture with respect to their singular spectra. The results show that the SSA can be applied to sleep EEG series to support the clinical findings in insomnia if ten trials are available for the specific sleep stages. In conclusion, the SSA can detect the oscillatory variations on sleep EEG. Therefore, different sleep stages meet different singular spectra. In addition, different healthy conditions generate different singular spectra for each sleep stage. In summary, the SSA can be proposed for EEG discrimination to support the clinical findings for psycho psychological disorders. PMID- 20703546 TI - Evaluation of a novel integrated sensor system for synchronous measurement of cardiac vibrations and cardiac potentials. AB - The measurement of human body vibrations as a result of heart beating, simultaneously with cardiac potentials have been demonstrated in past studies to bring additional value to diagnostic cardiology through the detection of irregularities in the mechanical movement of the heart. The equipment currently available to the medical community is either large and bulky or difficult to synchronize. To address this problem, a novel integrated sensor system has been developed to record cardiac vibration and cardiac potential simultaneously and synchronously from a single compact site on the chest. The developed sensor system is lightweight, small in size, and suitable for mounting on active moving patients. The sensor is evaluated for its adequacy in measuring cardiac vibrations and potentials. In this evaluation, 45 independent signal recording are studied from 15 volunteers, and the morphology of the recorded signals are analyzed qualitatively (by visual inspection) and quantitatively (by computational methods) against larger devices used in established cardiac vibration studies (reference devices). It is found that the cardiac vibration signals acquired by the integrated sensor has 92.37% and 81.76% identically identifiable systolic and diastolic cardiac complexes, respectively, when compared to the cardiac vibration signals recorded simultaneously from the reference device. Further, the cardiac potential signals acquired by the integrated sensor show a high correlation coefficient of 0.8912 and a high estimated signal-to-noise-ratio of 22.00 dB when compared to the reference electrocardiograph (non-standard leads) acquired through a common clinical machine. The results suggest that the tiny, wearable, integrated sensor system that synchronously measures cardiac vibrations and cardiac potentials may be practical for use as an alternative or assistive cardiac diagnostic tool. PMID- 20703547 TI - Analysis of EEG signals under flash stimulation for migraine and epileptic patients. AB - Migraine and epilepsy are both persistent disorders characterised by recurrent neurological attacks. Visual symptoms and hypersensitivity to light stimuli are frequent in migraine. Analysis of EEG signals under flash stimulation for migraine and epileptic patients is not a new method. But magnitude increasing under flash stimulation for migraine patients has not been studied yet. The aims of this study is the analysis of multichannel electroencephalogram (EEG) in migraine and epileptic patients by visual evoked potentials (VEP) and investigate the existence of magnitude increasing under flash stimulation for migraine patients. In this study as a method of flash stimuli at frequencies of 2, 4 and 6 Hz were applied to different migraine and epileptic patients under pain-free phase with the EEG recorded from 18 scalp electrodes, referred to the linked earlobes. We used AR parametric method to analyze and characterize EEG signals in migraine and epileptic patients. The variations in the EEG power spectra shapes were examined in order to obtain medical information. These power spectra were then used to compare the applied method in terms of their frequency resolution and the effects in determination of migraine and epilepsy. Global performance of the proposed methods was evaluated by means of the visual inspection of power spectral densities (PSDs). For the migraine patients, an increase in amplitude has observed at the beta bands of EEG signals under flash stimulation as compared to EEG signals without stimulation. As opposed to this, for epileptic patients, an increase in amplitude has observed at the alpha bands of EEG signals without flash stimulation. Meanwhile for the control groups, there is no change between EEG signals under flash stimulation and without flash stimulation. PMID- 20703548 TI - A study on hepatitis disease diagnosis using multilayer neural network with levenberg marquardt training algorithm. AB - In this study, a hepatitis disease diagnosis study was realized using neural network structure. For this purpose, a multilayer neural network structure was used. Levenberg-Marquardt algorithm was used as training algorithm for the weights update of the neural network. The results of the study were compared with the results of the previous studies reported focusing on hepatitis disease diagnosis and using same UCI machine learning database. We obtained a classification accuracy of 91.87% via tenfold cross validation. PMID- 20703549 TI - Fuzzy logic-based approach to detecting a passive RFID tag in an outpatient clinic. AB - This study is motivated by the observations on the data collected by radio frequency identification (RFID) readers in a pilot study, which was used to investigate the feasibility of implementing an RFID-based monitoring system in an outpatient eye clinic. The raw RFID data collected from RFID readers contain noise and missing reads, which prevent us from determining the tag location. In this paper, fuzzy logic-based algorithms are proposed to interpret the raw RFID data to extract accurate information. The proposed algorithms determine the location of an RFID tag by evaluating its possibility of presence and absence. To evaluate the performance of the proposed algorithms, numerical experiments are conducted using the data observed in the outpatient eye clinic. Experiments results showed that the proposed algorithms outperform existing static smoothing method in terms of minimizing both false positives and false negatives. Furthermore, the proposed algorithms are applied to a set of simulated data to show the robustness of the proposed algorithms at various levels of RFID reader reliability. PMID- 20703550 TI - An application of business process method to the clinical efficiency of hospital. AB - The concept of Total Quality Management (TQM) has come to be applied in healthcare over the last few years. The process management category in the Baldrige Health Care Criteria for Performance Excellence model is designed to evaluate the quality of medical services. However, a systematic approach for implementation support is necessary to achieve excellence in the healthcare business process. The Architecture of Integrated Information Systems (ARIS) is a business process architecture developed by IDS Scheer AG and has been applied in a variety of industrial application. It starts with a business strategy to identify the core and support processes, and encompasses the whole life-cycle range, from business process design to information system deployment, which is compatible with the concept of healthcare performance excellence criteria. In this research, we apply the basic ARIS framework to optimize the clinical processes of an emergency department in a mid-size hospital with 300 clinical beds while considering the characteristics of the healthcare organization. Implementation of the case is described, and 16 months of clinical data are then collected, which are used to study the performance and feasibility of the method. The experience gleaned in this case study can be used a reference for mid-size hospitals with similar business models. PMID- 20703551 TI - A scalable healthcare information system based on a service-oriented architecture. AB - Many existing healthcare information systems are composed of a number of heterogeneous systems and face the important issue of system scalability. This paper first describes the comprehensive healthcare information systems used in National Taiwan University Hospital (NTUH) and then presents a service-oriented architecture (SOA)-based healthcare information system (HIS) based on the service standard HL7. The proposed architecture focuses on system scalability, in terms of both hardware and software. Moreover, we describe how scalability is implemented in rightsizing, service groups, databases, and hardware scalability. Although SOA-based systems sometimes display poor performance, through a performance evaluation of our HIS based on SOA, the average response time for outpatient, inpatient, and emergency HL7Central systems are 0.035, 0.04, and 0.036 s, respectively. The outpatient, inpatient, and emergency WebUI average response times are 0.79, 1.25, and 0.82 s. The scalability of the rightsizing project and our evaluation results show that the SOA HIS we propose provides evidence that SOA can provide system scalability and sustainability in a highly demanding healthcare information system. PMID- 20703552 TI - Monitoring of medication intake using a camera system. AB - This paper presents a computer vision system for monitoring medication intake in the context of home care services. We use a method based on color and shape to detect the body parts and the medication bottles. Color is used for skin detection, and the shape is used to distinguish the face from the hands and to differentiate bottles of medicine. To track these objects, we use a method based on color histograms, Hu moments, and edges. For the recognition of medication intake, we use a Petri network and event recognition. Our method has an accuracy of more than 75% and allows the detection of the medication intake in various scenarios where the user is cooperative. PMID- 20703553 TI - Two RFID-based solutions to enhance inpatient medication safety. AB - Owing to the low cost and convenience of identifying an object without physical contact, Radio Frequency Identification (RFID) systems provide innovative, promising and efficient applications in many domains. An RFID grouping protocol is a protocol that allows an off-line verifier to collect and verify the evidence of two or more tags simultaneously present. Recently, Huang and Ku (J. Med. Syst, 2009) proposed an efficient grouping protocol to enhance medication safety for inpatients based on low-cost tags. However, the Huang-Ku scheme is not secure; an attacker can easily make up fake grouping records to cheat the verifier. This weakness would seriously endanger the safety of inpatient medication safety. This paper will show the weaknesses, and then propose two RFID-based solutions to enhance medication safety for two different scenarios. The proposed schemes are practical, secure and efficient for medication applications. PMID- 20703555 TI - ITU e-health training program for pacific island community with the support of the Sasakawa peace foundation. AB - Tokai University School of Medicine provided a short-term e-Health training program for persons from Pacific Island Nations from 2006 until 2008 supported by funds from the Sasakawa Peace Foundation. There were lectures on software, hardware and topics relating to e-Health. We could assess the current medical situation in the Pacific Islands through this training course, and also obtain relevant material to analyze appropriate measures deemed necessary to improve the situation. PMID- 20703554 TI - Significant cancer prevention factor extraction: an association rule discovery approach. AB - Cancer is increasing the total number of unexpected deaths around the world. Until now, cancer research could not significantly contribute to a proper solution for the cancer patient, and as a result, the high death rate is uncontrolled. The present research aim is to extract the significant prevention factors for particular types of cancer. To find out the prevention factors, we first constructed a prevention factor data set with an extensive literature review on bladder, breast, cervical, lung, prostate and skin cancer. We subsequently employed three association rule mining algorithms, Apriori, Predictive apriori and Tertius algorithms in order to discover most of the significant prevention factors against these specific types of cancer. Experimental results illustrate that Apriori is the most useful association rule mining algorithm to be used in the discovery of prevention factors. PMID- 20703556 TI - Adopting confidentiality principles for electronic health records in iran: a delphi study. AB - A growing capacity of information technologies in collection, storage and transmission of information has added a great deal of concerns since electronic records can be accessed by numerous consumers at various locations. Thus, the basic question is "what kind of Model is suitable for guaranteeing the confidentiality of EHR information in Iran?" The present study is a descriptive investigation made in Iran in 2007. Based on the collected data the preliminary model was designed and it was assessed through questionnaires and Delphi Technique and finally the noted model was designed and proposed. The findings showed the experts emphasize patient's consent for collecting, using and releasing information in electronic health records. A comprehensive model is presented in six pivots. data ownership, inclusion of information accessibility laws in all organizations, responsibility for inaccessibility to information, and the conditions for movement of data abroad, have been confirmed as new dimensions added based on this study in the model. PMID- 20703557 TI - Tuberculosis disease diagnosis using artificial neural network trained with genetic algorithm. AB - Tuberculosis is a common and often deadly infectious disease caused by mycobacterium; in humans it is mainly Mycobacterium tuberculosis (Wikipedia 2009). It is a great problem for most developing countries because of the low diagnosis and treatment opportunities. Tuberculosis has the highest mortality level among the diseases caused by a single type of microorganism. Thus, tuberculosis is a great health concern all over the world, and in Turkey as well. This article presents a study on tuberculosis diagnosis, carried out with the help of multilayer neural networks (MLNNs). For this purpose, an MLNN with two hidden layers and a genetic algorithm for training algorithm has been used. The tuberculosis dataset was taken from a state hospital's database, based on patient's epicrisis reports. PMID- 20703558 TI - Computerized wrist pulse signal diagnosis using modified auto-regressive models. AB - The wrist pulse signals can be used to analyze a person's health status in that they reflect the pathologic changes of the person's body condition. This paper aims to present a novel time series analysis approach to analyze wrist pulse signals. First, a data normalization procedure is proposed. This procedure selects a reference signal that is 'closest' to a newly obtained signal from an ensemble of signals recorded from the healthy persons. Second, an auto-regressive (AR) model is constructed from the selected reference signal. Then, the residual error, which is the difference between the actual measurement for the new signal and the prediction obtained from the AR model established by reference signal, is defined as the disease-sensitive feature. This approach is based on the premise that if the signal is from a patient, the prediction model previously identified using the healthy persons would not be able to reproduce the time series measured from the patients. The applicability of this approach is demonstrated using a wrist pulse signal database collected using a Doppler Ultrasound device. The classification accuracy is over 82% in distinguishing healthy persons from patients with acute appendicitis, and over 90% for other diseases. These results indicate a great promise of the proposed method in telling healthy subjects from patients of specific diseases. PMID- 20703559 TI - Distributed Agent Based Interoperable Virtual EMR System for Healthcare System Integration. AB - One of the major problems in health care system integration is the formidable cost of mediating between myriad vendors and policy makers for updating existing heterogeneous systems to support a great variety of standards or interfaces. To provide cost-effective healthcare system integration solution, this paper presents a Graphical User Interface state model (GUISM) for automatically exchanging information with existing healthcare software through their GUIs with no modifications needed to them. This can save the huge cost of upgrading, testing and redeploying the existing systems. By using the GUISM model, distributed agents are deployed to the client computers interacting with the local electronic medical system (EMR) for communicating with other EMR systems. The whole system is called virtual EMR system and each client in this system can request needed patient healthcare information without knowing the actual location of the data. PMID- 20703560 TI - Improving financial performance by modeling and analysis of radiology procedure scheduling at a large community hospital. AB - Radiology tests, such as MRI, CT-scan, X-ray and ultrasound, are cost intensive and insurance pre-approvals are necessary to get reimbursement. In some cases, tests may be denied for payments by insurance companies due to lack of pre approvals, inaccurate or missing necessary information. This can lead to substantial revenue losses for the hospital. In this paper, we present a simulation study of a centralized scheduling process for outpatient radiology tests at a large community hospital (Central Baptist Hospital in Lexington, Kentucky). Based on analysis of the central scheduling process, a simulation model of information flow in the process has been developed. Using such a model, the root causes of financial losses associated with errors and omissions in this process were identified and analyzed, and their impacts were quantified. In addition, "what-if" analysis was conducted to identify potential process improvement strategies in the form of recommendations to the hospital leadership. Such a model provides a quantitative tool for continuous improvement and process control in radiology outpatient test scheduling process to reduce financial losses associated with process error. This method of analysis is also applicable to other departments in the hospital. PMID- 20703561 TI - Understanding performance and behavior of tightly coupled outpatient systems using RFID: initial experience. AB - Understanding how clinical systems actually behave in an era of limited medical resources is critical. The purpose of this study was to determine if a radiofrequency-identification-based indoor positioning system (IPS) could objectively and unobtrusively capture outpatient clinic behavior. Primary outcomes were flowtime, wait time and patient/clinician face time. Two contrasting clinics were evaluated: a primary care clinic (PC) with templated scheduling and an urgent care clinic (UC) with unconstrained visit time and first in, first-out scheduling. All staff wore transponders throughout the study period. Patients carried transponders from check in to check out. All patients and staff were allowed to opt out. The study was approved by hospital IRB. Standard descriptive and analytic statistical methods were used. Five hundred twenty-six patients (309 patients (PC), 217 patients (UC)) and 38 clinicians (eight (PC) and 30 (UC)) volunteered between April 30 and July 1, 2008. Total FT was not significantly different across clinics. PC wait time was significantly shorter (7.6 min [SD 15.8]) vs. UC (19.7 min [SD 25.3], p < 0.0001), and PC Face time was significantly longer (29.9 min, [SD 19.1] vs. UC (9.8 min [SD 8.5], p < 0.0001). PC Face time distributions reflected template scheduling structure. In contrast, face time distributions in UC had a smooth log normal distribution with a lower mean value. Our study seems to indicate that an IPS can successfully measure important clinic process measures in live clinical outpatient settings and capture behavioral differences across different outpatient organizational structures. PMID- 20703562 TI - An application of artificial immune recognition system for prediction of diabetes following gestational diabetes. AB - Diabetes mellitus (DM) is a disease prevalent in population and is not easily perceived in its initial stage but may sway a patient very seriously in later stage. In accordance with the estimation of World Health Organization (WHO), there will be 370 million diabetics which are 5.4% of the global people in 2030, so it becomes more and more important to predict whether a pregnant woman has or is likely to acquire diabetes. This study is conducted with the use of the machine learning-Artificial Immune Recognition System (AIRS)-to assist doctors in predicting pregnant women who have premonition of type 2 diabetes. AIRS is proposed by Andrew Watkins in 2001 and it makes use of the metaphor of the vertebrate immune system to recognize antigens, select clone, and memorize cells. Additionally, AIRS includes a mechanism, limited resource, to restrain the number of memory cells from increasing uncontrollably. It has also showed positive results on problems in which it was applied. The objective of this study is to investigate the feasibility in using AIRS to predict gestational diabetes mellitus (GDM) subsequent DM. The dataset of diabetes has imbalanced data, but the overall classification recall could still reach 62.8%, which is better than the traditional method, logistic regression, and the technique which is thought as one of the powerful classification approaches, support vector machines (SVM). PMID- 20703564 TI - Strategic enterprise resource planning in a health-care system using a multicriteria decision-making model. AB - This paper deals with strategic enterprise resource planning (ERP) in a health care system using a multicriteria decision-making (MCDM) model. The model is developed and analyzed on the basis of the data obtained from a leading patient oriented provider of health-care services in Korea. Goal criteria and priorities are identified and established via the analytic hierarchy process (AHP). Goal programming (GP) is utilized to derive satisfying solutions for designing, evaluating, and implementing an ERP. The model results are evaluated and sensitivity analyses are conducted in an effort to enhance the model applicability. The case study provides management with valuable insights for planning and controlling health-care activities and services. PMID- 20703563 TI - Using data mining techniques in monitoring diabetes care. The simpler the better? AB - We aim at evaluating how data-mining statistical techniques can be applied on medical records and administrative data of diabetes and how they differ in terms of capabilities of predicting outcomes (e.g. death). Data on 3,892 outpatient patients with a diagnosis of type 2 diabetes from the San Giovanni Battista Hospital in Torino. Six statistical classifiers were applied: Logistic regression (LR), Generalized Additive Model (GAM), Projection pursuit Regression (PPR), Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Artificial Neural Networks (ANN). All models selected the same subset of covariates. ANN is the model performing worse, whereas simpler models, like LR, GAM and LDA seem to perform better. GAM is associated with a very small misclassification rate. The agreement in predicting individual outcomes among models is 0.23 (SE 0.06, Kappa). Monitoring on the basis of patients' characteristics is highly dependent from the statistical properties of the chosen statistical model. PMID- 20703565 TI - A new accounting system for financial balance based on personnel cost after the introduction of a DPC/DRG system. AB - A hospital director must estimate the revenues and expenses not only in a hospital but also in each clinical division to determine the proper management strategy. A new prospective payment system based on the Diagnosis Procedure Combination (DPC/PPS) introduced in 2003 has made the attribution of revenues and expenses for each clinical department very complicated because of the intricate involvement between the overall or blanket component and a fee-for service (FFS). Few reports have so far presented a programmatic method for the calculation of medical costs and financial balance. A simple method has been devised, based on personnel cost, for calculating medical costs and financial balance. Using this method, one individual was able to complete the calculations for a hospital which contains 535 beds and 16 clinics, without using the central hospital computer system. PMID- 20703566 TI - A unified architecture for biomedical search engines based on semantic web technologies. AB - There is a huge growth in the volume of published biomedical research in recent years. Many medical search engines are designed and developed to address the over growing information needs of biomedical experts and curators. Significant progress has been made in utilizing the knowledge embedded in medical ontologies and controlled vocabularies to assist these engines. However, the lack of common architecture for utilized ontologies and overall retrieval process, hampers evaluating different search engines and interoperability between them under unified conditions. In this paper, a unified architecture for medical search engines is introduced. Proposed model contains standard schemas declared in semantic web languages for ontologies and documents used by search engines. Unified models for annotation and retrieval processes are other parts of introduced architecture. A sample search engine is also designed and implemented based on the proposed architecture in this paper. The search engine is evaluated using two test collections and results are reported in terms of precision vs. recall and mean average precision for different approaches used by this search engine. PMID- 20703567 TI - ASIC design of a digital fuzzy system on chip for medical diagnostic applications. AB - The paper presents the ASIC design of a digital fuzzy logic circuit for medical diagnostic applications. The system on chip under consideration uses fuzzifier, memory and defuzzifier for fuzzifying the patient data, storing the membership function values and defuzzifying the membership function values to get the output decision. The proposed circuit uses triangular trapezoidal membership functions for fuzzification patients' data. For minimizing the transistor count, the proposed circuit uses 3T XOR gates and 8T adders for its design. The entire work has been carried out using TSMC 0.35 um CMOS process. Post layout TSPICE simulation of the whole circuit indicates a delay of 31.27 ns and the average power dissipation of the system on chip is 123.49 mW which indicates a less delay and less power dissipation than the comparable embedded systems reported earlier. PMID- 20703568 TI - Japanese telemedical concept of ambulatory application. AB - Transmission of in-ambulance data without inconveniencing or undue effort by the rescue crew-in other words, automation of in-ambulance activities (measurement/analysis, activity recording, message transmission)-is essential in implementing uniform medical control standards across the nation. However, the 3G mobile phone has propagation problems at urban area and severe congestions after major disaster to support mobile telemedicine. So we are expecting the Quasi zenith satellite with nationwide coverage. In near future, we are expecting the data transmission of image of pharygoscopy, motion picture of light reflex, 12 leads ECG, automated ultrasonic echo and vital signs from ambulances to triage center. For example, Thrombolytic agents are reportedly effective even when injected into a vein, if injected in the early stages of acute myocardial infarction, that will reduce medical costs, resulting in high-quality services available uniformly across the nation. This paper describes our basic concept to support ambulatory application. PMID- 20703569 TI - Cost-effectiveness of clinical pathway in coronary artery bypass surgery. AB - Few studies have been devoted to the exploration of the effect of clinical pathways on coronary artery diseases treated with coronary artery bypass (CAB) surgery. This study was aimed to investigate the cost and effectiveness of the clinical pathway on CAB surgery in a medical center. With a retrospective dataset in 2003-2007, 212 CAB surgery patients were included. Data of the costs and postoperative complication occurrence and length of stays were the focus and patient demographics, surgical risk indicator EuroSCORE, surgical conditions were collected. It revealed that there was differentiation across specified cost items in beating heart CAB surgery patients, but not for heart arrest CAB surgery patients with and without clinical pathways enrolled. In addition, there was no difference in postoperative complication occurrence in CAB surgery patients enrolled into clinical pathways. However, robotic beating heart CAB surgery patients enrolled clinical pathways were shown to have less postoperative ordinary ward stay than those not enrolled clinical pathways. CAB surgery patients' age and surgical risks were related to their postoperative lengths of stay to some extent. PMID- 20703570 TI - Heart monitoring garments using textile electrodes for healthcare applications. AB - We measured the electrical activity signals of the heart through vital signs monitoring garments that have textile electrodes in conductive yarns while the subject is in stable and dynamic motion conditions. To measure the electrical activity signals of the heart during daily activities, four types of monitoring garment were proposed. Two experiments were carried out as follows: the first experiment sought to discover which garment led to the least displacement of the textile electrode from its originally intended location on the wearer's body. In the second, we measured and compared the electrical activity signals of the heart between the wearer's stable and dynamic motion states. The results indicated that the most appropriate type of garment sensing-wise was the "cross-type", and it seems to stabilize the electrode's position more effectively. The value of SNR of ECG signals for the "cross-type" garment is the highest. Compared to the "chest belt-type" garment, which has already been marketed commercially, the "cross type" garment was more efficient and suitable for heart activity monitoring. PMID- 20703571 TI - Fuzzy clustered probabilistic and multi layered feed forward neural networks for electrocardiogram arrhythmia classification. AB - The role of electrocardiogram (ECG) as a noninvasive technique for detecting and diagnosing cardiac problems cannot be overemphasized. This paper introduces a fuzzy C-mean (FCM) clustered probabilistic neural network (PNN) for the discrimination of eight types of ECG beats. The performance has been compared with FCM clustered multi layered feed forward network (MLFFN) trained with back propagation algorithm. Important parameters are extracted from each ECG beat and feature reduction has been carried out using FCM clustering. The cluster centers form the input of neural network classifiers. The extensive analysis using the MIT-BIH arrhythmia database has shown an average classification accuracy of 97.54% with FCM clustered MLFFN and 99.58% with FCM clustered PNN. Fuzzy clustering improves the classification speed as well. The result reveals the capability of the FCM clustered PNN in the computer-aided diagnosis of ECG abnormalities. PMID- 20703572 TI - Toward a human-centered hyperlipidemia management system: the interaction between internal and external information on relational data search. AB - In a distributed information search task, data representation and cognitive distribution jointly affect user search performance in terms of response time and accuracy. Guided by UFuRT (User, Function, Representation, Task), a human centered framework, we proposed a search model and task taxonomy. The model defines its application in the context of healthcare setting. The taxonomy clarifies the legitimate operations for each type of search task of relational data. We then developed experimental prototypes of hyperlipidemia data displays. Based on the displays, we tested the search tasks performance through two experiments. The experiments are of a within-subject design with a random sample of 24 participants. The results support our hypotheses and validate the prediction of the model and task taxonomy. In this study, representation dimensions, data scales, and search task types are the main factors in determining search efficiency and effectiveness. Specifically, the more external representations provided on the interface the better search task performance of users. The results also suggest the ideal search performance occurs when the question type and its corresponding data scale representation match. The implications of the study lie in contributing to the effective design of search interface for relational data, especially laboratory results, which could be more effectively designed in electronic medical records. PMID- 20703573 TI - Region of interest tracking in real-time myocardial contrast echocardiography. AB - The real-time myocardial contrast echocardiography (RT MCE) is a new echocardiography technology, which allows clinicians to noninvasively evaluate the perfusion of myocardial capillary of patients, using the quantitative analysis of RT MCE. But the accurate analysis requires tracking the position of region of interest (ROI) within the myocardial area, so as to compensate for the translation or rotation offsets, which are due to such uncontrollable factors as heart motion. We used diamond search method and Brox's coarse-to-fine warping optical flow technique for this ROI tracking problem. We validated our methods by comparing the quantitative analysis results of RT MCE using our methods with those using Lucas & Kanade's optical flow technique, which had been report to be accurate enough for this ROI tracking. We finally present some examples of animal experiment to show the effectiveness and the clinical application value of our ROI tracking methods. PMID- 20703574 TI - Assessing differences between physicians' realized and anticipated gains from electronic health record adoption. AB - Return on investment (ROI) concerns related to Electronic Health Records (EHRs) are a major barrier to the technology's adoption. Physicians generally rely upon early adopters to vet new technologies prior to putting them into widespread use. Therefore, early adopters' experiences with EHRs play a major role in determining future adoption patterns. The paper's purposes are: (1) to map the EHR value streams that define the ROI calculation; and (2) to compare Current Users' and Intended Adopters' perceived value streams to identify similarities, differences and governing constructs. Primary data was collected by the Texas Medical Association, which surveyed 1,772 physicians on their use and perceptions of practice gains from EHR adoption. Using Bayesian Belief Network Modeling, value streams are constructed for both current EHR users and Intended Adopters. Current Users and Intended Adopters differ significantly in their perceptions of the EHR value stream. Intended Adopters' value stream displays complex relationships among the potential gains compared to the simpler, linear relationship that Current Users identified. The Current Users identify "Reduced Medical Records Costs" as the gain that governs the value stream while Intended Adopters believe "Reduced Charge Capture Costs" define the value stream's starting point. Current Users' versus Intended Adopters' assessments of EHR benefits differ significantly and qualitatively from one another. PMID- 20703575 TI - Efficiency measurement of cardiac care units of isfahan hospitals in iran. AB - The purpose of this study is to evaluate the performance of the Cardiac Care Units (CCU) of hospitals in Isfahan, Iran. The multi-criteria comparison between the wards of different hospitals is not only useful for the patients but also important for the hospitals management to improve their performance and for the medical policy makers to plan strategic decisions. In this paper, it is intended to consider the aspects of efficiency beyond the traditional evaluation of check list. There are some measures which are used in the existing health audit system and several quantified ratios. Among them the most important ones, based on the patient satisfaction and resource efficiency, have been selected using the weights obtained from their paired comparisons. The factors which have been chosen are divided into two subsets: first, input factors consisting of average number of active beds, medical equipment, personnel (such as doctors, nurses and technicians), and technological capabilities, and second, output factors including bed occupancy percentage, average length of stay, total percentage of survival and performance ratio. The input oriented and variable returns to scale model of Data envelopment analysis (DEA) technique is used to evaluate the efficiency of each CCU ward. The model can be used to find out the causes of inefficiency and how to improve the performance. The method has been applied to evaluate and compare 23 CCUs of hospitals in Isfahan. Although the current health audit system, which uses a check list, has reported 21 of them as first class CCU, DEA model reveals that 11 of them are inefficient. The results may be then used to suggest the improvement strategies based on the output factors. PMID- 20703576 TI - Design of the computerized 3D endoscopic imaging system for delicate endoscopic surgery. AB - This paper describes a 3D endoscopic video system designed to improve visualization and enhance the ability of the surgeon to perform delicate endoscopic surgery. In a comparison of the polarized and conventional electric shutter-type stereo imaging systems, the former was found to be superior in terms of both accuracy and speed for suturing and for the loop pass test. Among the groups performing loop passing and suturing, there was no significant difference in the task performance between the 2D and 3D modes, however, suturing was performed 15% (p < 0.05) faster in 3D mode by both groups. The results of our experiments show that the proposed 3D endoscopic system has a sufficiently wide viewing angle and zone for multi-viewing. PMID- 20703577 TI - Evaluation of flow-volume spirometric test using neural network based prediction and principal component analysis. AB - In this work, an attempt has been made to enhance the diagnostic relevance of spirometric pulmonary function test using neural networks and Principal Component Analysis (PCA). For this study, flow-volume curves (N = 175) using spirometers were generated under standard recording protocol. A method based on neural network is used to predict the most significant parameter, FEV(1). Further, PCA is used to analyze the interdependency of the parameters in the measured and predicted datasets. Results show that the back propagation neural network is able to predict FEV(1) both in normal and abnormal cases. The variation in the magnitude and direction of parameters in the contribution of the principal components shows that FEV(1) is a significant discriminator of normal and abnormal datasets and is further confirmed by the percentage variance in the first few principal components. It appears that this method of prediction and principal component analysis on the measured and predicted datasets could be useful for spirometric pulmonary function test with incomplete data. PMID- 20703578 TI - A novel method for diagnosing cirrhosis in patients with chronic hepatitis B: artificial neural network approach. AB - We designed an artificial neural network (ANN) to diagnose cirrhosis in patients with chronic HBV infection. Routine laboratory data (PT, INR, platelet count, direct bilirubin, AST/ALT, AST/PLT) and age were collected from 144 patients. Cirrhosis in these patients was diagnosed by liver biopsy. The ANN's ability was assessed using receiver-operating characteristic (ROC) analysis and the results were compared with a logistic regression model. Our results indicate that the neural network analysis is likely to provide a non-invasive, accurate test for diagnosing cirrhosis in chronic HBV-infected patients, only based on routine laboratory data. PMID- 20703579 TI - Diagnosis of dental deformities in cephalometry images using support vector machine. AB - This paper proposes an automated target recognition algorithm using Support Vector Machine (SVM) to extract landmark points for craniofacial features in cephalometry radiograph. The features are extracted by subjecting the radiograph to the Projected Principle Edge Distribution (PPED) algorithm. Edge flags are accumulated in every four columns and spatial distribution of edge flags are represented by a histogram. The resultants are the front end of support vector machine. Vectors, which possess land marks, are separated from all other vectors. The centroid points, automatically determined from PPED vectors, are the location of landmarks. The landmark points which are serving as a guide for construction and measurement of planes, are used to evaluate the dento-facial relationship, study of growth and development, and also for treatment planning. PMID- 20703580 TI - Apply influence diagrams for utility analysis of paying the weight-reducing expenses: a case study in taiwan. AB - To effectively control the growth of medical expenditure, Bureau of National Health Insurance (NHI) of Taiwan has taken many measures, including the Reasonable Number of Outpatient Services, Ceiling Price, Global Budgets, Strategic Analysis and the Excellence Plan; however, these measures can only scratch the surface. Due to the change of life style and the deteriorating condition of over-nutrition and obesity, people now have a higher risk of diabetes, hypertension, hyperlipidemia, cardiovascular disease, gallbladder disease, cancer, gout, arthritis, and so on, which leads to higher medical expenditure. Therefore, good civil preventive health care is regarded as the solution of surging medical expenditure. According to NHI's statistics, the annual medical expenditure of diabetes is about 13 billion NT dollars. Among these diabetics, over 95% are affected by type 2 diabetes mellitus; at least two thirds--over 80% according to some researches--are overweight or obese. The research says, losing 5% to 10% of the original body weight can lower the risk of chronic diseases effectively; also, giving early therapy for obesity can reduce the complication probability, thus for avoiding the waste of medical resources. By applying influence diagrams of Bayesian Network and Utility Expect of statistics, this paper evaluates the medical expenditure of Taiwan's NHI under the circumstances of providing and not providing benefit for weight-loss outpatient services. The result of this research is that the cost of not providing benefit for weight-loss outpatient services is 3.4 times of the contrary. Therefore, if Taiwan's NHI provides reasonable benefit for weight-loss outpatient services, not only the risk of people suffering from diabetes, hypertension, hyperlipidemia, cardiovascular disease, gallbladder disease, cancer, gout, arthritis, etc. will go down; but also the medical expenditure can be effectively reduced. PMID- 20703581 TI - Parallel algorithm to analyze the brain signals: application on epileptic spikes. AB - In the current work, we have proposed a parallel algorithm for the recognition of Epileptic Spikes (ES) in EEG. The automated systems are used in biomedical field to help the doctors and pathologist by producing the result of an inspection in real time. Generally, the biomedical signal data to be processed are very large in size. A uniprocessor computer is having its own limitation regarding its speed. So the fastest available computer with latest configuration also may not produce results in real time for the immense computation. Parallel computing can be proved as a useful tool for processing the huge data with higher speed. In the proposed algorithm 'Data Parallelism' has been applied where multiple processors perform the same operation on different part of the data to produce fast result. All the processors are interconnected with each other by an interconnection network. The complexity of the algorithm was analyzed as Theta((n + deltan) / N) where, 'n' is the length of the input data, 'N' is the number of processor used in the algorithm and 'deltan' is the amount of overlapped data between two consecutive intermediate processors (IPs). This algorithm is scalable as the level of parallelism increase linearly with the increase in number of processors. The algorithm has been implemented in Message Passing Interface (MPI). It was tested with 60 min recorded EEG signal data files. The recognition rate of ES on an average was 95.68%. PMID- 20703582 TI - Detection of resistivity for antibiotics by probabilistic neural networks. AB - This paper presents the use of probabilistic neural networks (PNNs) for detection of resistivity for antibiotics (resistant and sensitive). The PNN is trained on the resistivity or sensitivity to the antibiotics of each record in the Salmonella database. Estimation of the whole parameter space for the PNN was performed by the maximum-likelihood (ML) estimation method. The expectation maximization (EM) approach can help to achieve the ML estimation via iterative computation. Resistivity and sensitivity of the three antibiotics (ampicillin, chloramphenicol disks and trimethoprim-sulfamethoxazole) were classified with high accuracies by the PNN. The obtained results demonstrated the success of the PNN to help in detection of resistivity for antibiotics. PMID- 20703583 TI - The use of skin surface electropotentials for breast cancer detection- preliminary clinical trial results obtained using the biofield diagnostic system. AB - The purpose of this study is to evaluate the efficiency of the Biofield Diagnostic System (BDS) as an adjunct to established diagnostic techniques such as mammography and ultrasound in differentiating benign and malignant breast lesions. The clinical trial was conducted at the Tan Tock Seng hospital, Singapore. 103 women scheduled for mammography and/or ultrasound tests participated in the study. The BDS test recorded a sensitivity of 100%, specificity of 97.6%, and an accuracy of 98.1%. The area under the ROC curve was 0.988 which was slightly lower than that of ultrasound (0.994) and slightly higher than that of mammography (0.951). The BDS test has demonstrated high sensitivity and specificity values in the studied population. The accuracy is also comparable to that of diagnostic techniques like mammography and ultrasound. Thus, it is evident that BDS can be a fast and reliable adjunct tool for getting a secondary opinion on lesions with indeterminate mammographic and sonographic results. PMID- 20703584 TI - Novel design of low noise preamplifier for medical ultrasound transducers. AB - A novel design of low noise amplifier for medical ultrasound transducers is described in this paper. Unlike conventional low noise preamplifiers, this design proposes a new circuit configuration which has electronically adjustable matching resistance that allows the preamplifier to be compatible with a variety of medical ultrasound transducers. The design employs current feedback operational amplifier to enhance the gain-bandwidth independence and improve the design slew rate. Simulation results show that the proposed design has very low output noise voltage spectral density and the level of this noise does not increase when its tunable matching resistance is increased or decreased. PMID- 20703585 TI - Improving the efficiency of distributive and clinical services in hospital pharmacy. AB - Three problems impede the assessment of hospital pharmacy efficiency. First, although multiple efficiency indicators are utilized to measure a large variety of activities, it has not been possible to validly measure overall efficiency. Second, there have been no widely-used clinical activity indicators, so key outputs often have not been accounted for. Third, there has been no effective methodology for identifying when declines in efficiency are normal random variations and when they represent true decreases in performance. This paper presents a procedure that simultaneously addresses these three problems. It analyzes data from a group of U.S. hospital pharmacies that collect an inclusive set of clinical and distributional indicators. It employs Data Envelopment Analysis to develop comprehensive efficiency measures from the numerous outputs and inputs. It applies statistical Panel Data Analysis to estimate confidence intervals within which each pharmacy's true efficiency resides, and to develop control charts for signaling when a pharmacy's efficiency has declined by more than can be attributed to random variation. This integrated efficiency evaluation system is transferable to other hospital pharmacy systems, thereby offering decision makers a better way of measuring, controlling and improving hospital pharmacy efficiency. PMID- 20703586 TI - Using autoencoders for mammogram compression. AB - This paper presents the results obtained for medical image compression using autoencoder neural networks. Since mammograms (medical images) are usually of big sizes, training of autoencoders becomes extremely tedious and difficult if the whole image is used for training. We show in this paper that the autoencoders can be trained successfully by using image patches instead of the whole image. The compression performances of different types of autoencoders are compared based on two parameters, namely mean square error and structural similarity index. It is found from the experimental results that the autoencoder which does not use Restricted Boltzmann Machine pre-training yields better results than those which use this pre-training method. PMID- 20703587 TI - Single image signal-to-noise ratio estimation for magnetic resonance images. AB - A novel technique to quantify the signal-to-noise ratio (SNR) of magnetic resonance images is developed. The image SNR is quantified by estimating the amplitude of the signal spectrum using the autocorrelation function of just one single magnetic resonance image. To test the performance of the quantification, SNR measurement data are fitted to theoretically expected curves. It is shown that the technique can be implemented in a highly efficient way for the magnetic resonance imaging system. PMID- 20703588 TI - The effect of Computerized Physician Order Entry and decision support system on medication errors in the neonatal ward: experiences from an Iranian teaching hospital. AB - Medication dosing errors are frequent in neonatal wards. In an Iranian neonatal ward, a 7.5 months study was designed in three periods to compare the effect of Computerized Physician Order Entry (CPOE) without and with decision support functionalities in reducing non-intercepted medication dosing errors in antibiotics and anticonvulsants. Before intervention (Period 1), error rate was 53%, which did not significantly change after the implementation of CPOE without decision support (Period 2). However, errors were significantly reduced to 34% after that the decision support was added to the CPOE (Period 3; P < 0.001). Dose errors were more often intercepted than frequency errors. Over-dose was the most frequent type of medication errors and curtailed-interval was the least. Transcription errors did not reduce after the CPOE implementation. Physicians ignored alerts when they could not understand why they appeared. A suggestion is to add explanations about these reasons to increase physicians' compliance with the system's recommendations. PMID- 20703589 TI - A decision support system for automatic screening of non-proliferative diabetic retinopathy. AB - The increasing number of diabetic retinopathy (DR) cases world wide demands the development of an automated decision support system for quick and cost-effective screening of DR. We present an automatic screening system for detecting the early stage of DR, which is known as non-proliferative diabetic retinopathy (NPDR). The proposed system involves processing of fundus images for extraction of abnormal signs, such as hard exudates, cotton wool spots, and large plaque of hard exudates. A rule based classifier is used for classifying the DR into two classes, namely, normal and abnormal. The abnormal NPDR is further classified into three levels, namely, mild, moderate, and severe. To evaluate the performance of the proposed decision support framework, the algorithms have been tested on the images of STARE database. The results obtained from this study show that the proposed system can detect the bright lesions with an average accuracy of about 97%. The study further shows promising results in classifying the bright lesions correctly according to NPDR severity levels. PMID- 20703591 TI - A geographical information system using the Google Map API for guidance to referral hospitals. AB - Our hospital acts as a regional core hospital through inter-hospital collaboration. Geographical information is necessary to guide patients to the other hospitals. Although paper maps, which contain directions, nearest public transportation, etc., are usually provided to guide patients to the hospitals, the geographical information tends to change daily. However, updating the geographical information on the maps is costly. We constructed an electronic geographical information system using the Google Map API ( http://code.google.com/apis/maps/ ) with open source software to improve our ability to collaborate with other clinics. PMID- 20703592 TI - An automated computerized auscultation and diagnostic system for pulmonary diseases. AB - Respiratory sounds are of significance as they provide valuable information on the health of the respiratory system. Sounds emanating from the respiratory system are uneven, and vary significantly from one individual to another and for the same individual over time. In and of themselves they are not a direct proof of an ailment, but rather an inference that one exists. Auscultation diagnosis is an art/skill that is acquired and honed by practice; hence it is common to seek confirmation using invasive and potentially harmful imaging diagnosis techniques like X-rays. This research focuses on developing an automated auscultation diagnostic system that overcomes the limitations inherent in traditional auscultation techniques. The system uses a front end sound signal filtering module that uses adaptive Neural Networks (NN) noise cancellation to eliminate spurious sound signals like those from the heart, intestine, and ambient noise. To date, the core diagnosis module is capable of identifying lung sounds from non lung sounds, normal lung sounds from abnormal ones, and identifying wheezes from crackles as indicators of different ailments. PMID- 20703590 TI - Systematic review of the use of computer simulation modeling of patient flow in surgical care. AB - Computer simulation has been employed to evaluate proposed changes in the delivery of health care. However, little is known about the utility of simulation approaches for analysis of changes in the delivery of surgical care. We searched eight bibliographic databases for this comprehensive review of the literature published over the past five decades, and found 34 publications that reported on simulation models for the flow of surgical patients. The majority of these publications presented a description of the simulation approach: 91% outlined the underlying assumptions for modeling, 88% presented the system requirements, and 91% described the input and output data. However, only half of the publications reported that models were constructed to address the needs of policy-makers, and only 26% reported some involvement of health system managers and policy-makers in the simulation study. In addition, we found a wide variation in the presentation of assumptions, system requirements, input and output data, and results of simulation-based policy analysis. PMID- 20703594 TI - Reliable and robust transmission and storage techniques for medical images with patient information. AB - There is an increased emphasis on the use of digital techniques in all aspects of human life today. Broadcast radio and television, cellular phone services, consumer and entertainment electronics etc are increasingly using digital signal processing techniques to improve the quality of service. Transmission and storage of documentation and images pertaining to patient records cannot remain an exception to this global trend. Hence, patient records (text and image information) are increasingly stored and processed in digital form. Currently, text and image information, which constitute two separate pieces of data are handled as different files. Thus, there is a possibility of the text and message information, pertaining to different patients, being interchanged and thus mishandled. This can be avoided by merging text and image information in such a manner that the two can be separated without perceptible damage to information contained in either file. Digital watermarking techniques can be used to interleave patient information with medical images. In this work, we have employed digital watermarking along with strong cryptographic protocols and powerful error correcting codes. This reduces the probability of sensitive patient information falling into the wrong hands and ensures information integrity when it is conveyed over noisy channels. PMID- 20703595 TI - CEO is a vision of the future role and position of CIO in healthcare organizations. AB - Literature related to chief information officer (CIO) in the developed countries during the past 20 years has been reviewed to identify the future trends of the position. The literature shows that CIO is a growing position in the healthcare industry that has achieved much popularity because today's healthcare has a great focus on information management and technology and that CIO can be future powerful strategist for healthcare organizations. Therefore, a model for an ideal healthcare CIO based on lesson learned from literature was suggested. It seems that in the developed countries, CIOs will achieve many opportunities to come in the highest executive teams of healthcare organizations and may undertake CEO roles. PMID- 20703593 TI - Glaucoma classification model based on GDx VCC measured parameters by decision tree. AB - This study is to propose and evaluate the diagnostic accuracy of decision tree classifiers using the full set of standard GDx VCC measurements for classifying glaucoma in a Taiwan Chinese population. The classifiers were trained and tested using standard GDx VCC parameters from examinations of 74 subjects with glaucoma and 72 normal subjects. Six promising decision rules were generated from decision tree methods and the overall accuracy from tenfold cross validation was 0.801. Classification tree based on GDx VCC data promises to be a diagnostic tool in glaucoma disease. However, its exact clinical application in glaucoma practice should be retested. Further longitudinal study should address this issue. PMID- 20703596 TI - Classification of sleep apnea through sub-band energy of abdominal effort signal using Wavelets + Neural Networks. AB - Detection and classification of sleep apnea syndrome (SAS) is a critical problem. In this study an efficient method for classification sleep apnea through sub-band energy of abdominal effort using a particularly designed hybrid classifier as Wavelets + Neural Network is proposed. The Abdominal respiration signals were separated into spectral sub-band energy components with multi-resolution Discrete Wavelet Transform (DWT). The energy content of these spectral components was applied to the input of the artificial neural network (ANN). The ANN was configured to give three outputs dedicated to SAS cases; obstructive sleep apnea (OSA), central sleep apnea (CSA) and mixed sleep apnea (MSA). Through the network, satisfactory results that rewarding 85.62% mean accuracy in classifying SAS were obtained. PMID- 20703597 TI - Worldwide trends in Universal Service Funds and telemedicine. AB - A survey of recent worldwide trends in Universal Service Funds (USFs) and the assistance provided for their application indicates that industrialized countries and developing nations alike have offered or plan to offer tax-relief measures or reimbursement for communications costs incurred by telemedicine programs, thus finding a way to actively apply USFs in rural areas. There are three main systems used to calculate the amount of reimbursement from a USF. While many countries adopt a service-area net-loss estimation method, Japan uses a benchmark method and provides financial assistance only to unprofitable areas. The USA has proactively introduced telemedicine to rural areas and isolated islands in order to minimize rapidly rising healthcare costs and to improve the efficiency of healthcare services. In the USA, the USF is used to pay back communications costs incurred through telemedicine programs. For instance, the budget allocated from the USF for reimbursements for telemedicine in Alaska reached USD 30 Mil. in 2007. Developing countries in Africa and Asia are operating various forms of telemedicine on a trial basis, but a tax-relief measure or payback of communications costs, which are a large portion of the running costs, will need to be implemented to ensure sustainable and autonomous operation of telemedicine. In Japan, up until January 2007, the USF system assumed the use of an NTS (non traffic sensitive cost) system to obtain funds from connection fees, and this system would receive funds from each telecommunications carrier (payer: the telecommunications carriers). The beneficiaries would be limited to two companies, namely NTT East and NTT West. However, the Japanese USF system was revised in February 2007, and a fee is now collected from each telephone number (payer: the user). The collected funds are used to cover losses in unprofitable areas (not limited to remote areas) among 7,000 business areas in Japan. In view of worldwide trends, the author believes that Japan should also start using the USF system to reimburse communications costs (including costs of telemedicine) in order to achieve sustainable and autonomous operation of public communication systems in rural areas. PMID- 20703598 TI - Analysis of the mobile phone effect on the heart rate variability by using the largest Lyapunov exponent. AB - In this study, the effects of electromagnetic fields (EMFs) emitted by GSM900 based mobile phones (MPs) on the heart rate variability (HRV) were examined by using nonlinear analysis methods. The largest Lyapunov exponent (LLE) calculation was used to evaluate the effect of MP under various real exposure conditions. Sixteen healthy young volunteers were exposed to EMFs emitted by GSM900 based MP at two levels from a very low EMF (MP at stand-by) to a higher EMF (MP at pre ring handshaking and ringing). A blind experimental protocol was designed and utilized with consideration to the physiological and psychological factors that may affect HRV. The results showed that the LLE values increased slightly with higher EMF produced by MP (P < 0.05). This change indicates that the degree of chaos in the HRV signals increased at higher EMF compared to low level EMF. Consequently, we have concluded that high level EMF changed the complexity of cardiac system behavior, significantly. PMID- 20703600 TI - Mammographic mass detection using wavelets as input to neural networks. AB - The objective of this paper is to demonstrate the utility of artificial neural networks, in combination with wavelet transforms for the detection of mammogram masses as malign or benign. A total of 45 patients who had breast masses in their mammography were enrolled in the study. The neural network was trained on the wavelet based feature vectors extracted from the mammogram masses for both benign and malign data. Therefore, in this study, Multilayer ANN was trained with the Backpropagation, Conjugate Gradient and Levenberg-Marquardt algorithms and ten fold cross validation procedure was used. A satisfying sensitivity percentage of 89.2% was achieved with Levenberg-Marquardt algorithm. Since, this algorithm combines the best features of the Gauss-Newton technique and the other steepest descent algorithms and thus it reaches desired results very fast. PMID- 20703599 TI - A novel fuzzy logic inference system for decision support in weaning from mechanical ventilation. AB - Weaning from mechanical ventilation represents one of the most challenging issues in management of critically ill patients. Currently used weaning predictors ignore many important dimensions of weaning outcome and have not been uniformly successful. A fuzzy logic inference system that uses nine variables, and five rule blocks within two layers, has been designed and implemented over mathematical simulations and random clinical scenarios, to compare its behavior and performance in predicting expert opinion with those for rapid shallow breathing index (RSBI), pressure time index and Jabour' weaning index. RSBI has failed to predict expert opinion in 52% of scenarios. Fuzzy logic inference system has shown the best discriminative power (ROC: 0.9288), and RSBI the worst (ROC: 0.6556) in predicting expert opinion. Fuzzy logic provides an approach which can handle multi-attribute decision making, and is a very powerful tool to overcome the weaknesses of currently used weaning predictors. PMID- 20703601 TI - Application of paraconsistent artificial neural networks as a method of aid in the diagnosis of Alzheimer disease. AB - The visual analysis of EEG has shown useful in helping the diagnosis of Alzheimer disease (AD) when the diagnosis remains uncertain, being used in some clinical protocols. However, such analysis is subject to the inherent equipment imprecision, patient movement, electrical records, and physician interpretation of the visual analysis variation. The Artificial Neural Network (ANN) could be a helpful tool, appropriate to address problems such as prediction and pattern recognition. In this work, it has use a new class of ANN, the Paraconsistent Artificial Neural Network (PANN), which is capable of handling uncertain, inconsistent, and paracomplete information, for recognizing predetermined patterns of EEG and to assess its value as a possible auxiliary method for AD diagnosis. Thirty three patients with Alzheimer's disease and 34 controls patients of EEG records were obtained during relaxed wakefulness. It was considered as normal patient pattern, the background EEG activity between 8.0 and 12.0 Hz (with an average frequency of 10 Hz), allowing a range of 0.5 Hz. The PANN was able to recognize waves that belonging to their respective bands of clinical use (theta, delta, alpha, and beta), leading to an agreement with the clinical diagnosis at 82% of sensitivity and at 61% of specificity. Supported with these results, the PANN could be a promising tool to manipulate EEG analysis, bearing in mind the following considerations: the growing interest of specialists in EEG analysis visual and the ability of the PANN to deal directly imprecise, inconsistent and paracomplete data, providing an interesting quantitative and qualitative analysis. PMID- 20703602 TI - A survey on application of quantitative methods on analysis of brain parameters changing with temperature. AB - Brain temperature fluctuations occur in consequence of physiological and pathophysiological conditions and indicate changes in brain metabolism, cerebral blood flow (CBF), brain functions and neural damage. Lowering the brain temperature of patients with traumatic brain injuries achieves considerable improvements. When the human brain is cooled down to 30 degrees C, it switches to a sub functional regime where it can live longer with less oxygen, glucose and other supplies. Fluctuations in brain temperature cause changes in brain parameters which can be measured by electroencephalogram (EEG) and transcranial Doppler (TCD). It is very important to understand the temperature dependencies of brain's electrical activity and blood flow and their interrelations considering the good clinical results achieved by lowering the brain temperature of neurologically injured patients. Since protecting the patient's brain is of primary importance in many fields including cardiology, neurology, traumatology and anesthesia it can be clearly seen that this subject is very important. In this study, we survey the "state-of-the-art" in analysis of EEG and TCD brain parameters changing with temperature and present further research opportunities. PMID- 20703603 TI - An automated method for segmentation of epithelial cervical cells in images of ThinPrep. AB - We present an automated method for segmentation of epithelial cells in images taken from ThinPrep scenes by a digital camera in a cytology lab. The method covers both steps of localization of cell objects in low resolution and detection of cytoplasm and nucleus boundary in high resolution. The underlying method makes use of geometric active contours as a powerful tool of segmentation. We also provide the analysis of the connected cells. For this purpose an automatic circular decomposition method is incorporated and adapted to the application by changing its segmentation condition. The results are evaluated numerically and compared with those of previous work in literature. PMID- 20703604 TI - Integration of IEEE 1451 and HL7 exchanging information for patients' sensor data. AB - HL7 (Health Level 7) is a standard developed for exchanging incompatible healthcare information generated from programs or devices among heterogenous medical information systems. At present, HL7 is growing as a global standard. However, the HL7 standard does not support effective methods for treating data from various medical sensors, especially from mobile sensors. As ubiquitous systems are growing, HL7 must communicate with various medical transducers. In the area of sensor fields, IEEE 1451 is a group of standards for controlling transducers and for communicating data from/to various transducers. In this paper, we present the possibility of interoperability between the two standards, i.e., HL7 and IEEE 1451. After we present a method to integrate them and show the preliminary results of this approach. PMID- 20703605 TI - Forecast on the application of Japanese universal service fund to remote diagnosis for frozen section. AB - Due to the socioeconomic reason in Japan, some cancer patient is sometimes operated at a rural hospital where only several surgeons perform and no pathologist checks its malignancy. Therefore, the system of the remote diagnosis for frozen section has been standing up in this country for 7 years. In Japan, the USF has started from February 2007 to support only telecommunications operator's hardware (NTT's equipment such as digital switch board) in high cost areas, not for the reimbursement of the tariff of the public users, such as telepathology. To solve such social cormorant equality, when the USF and PAs were supported in the present quick frozen intraoperative telepathology diagnosis, the quality of the cancer treatment in rural area will be improved. Based on the past data of the Japanese telepathology with beta distribution function, it can be estimated that user terminals becomes five times more than present users with support of USF and PAs. Moreover, using VPN on the B'FLETS, the effect of other teleconsultations will spread to the nationwide. PMID- 20703607 TI - Diagnosis of renal failure disease using Adaptive Neuro-Fuzzy Inference System. AB - Adaptive Neuro-Fuzzy Inference System (ANFIS) is one of the useful and powerful neural network approaches for the solution of function approximation and pattern recognition problems in the last decades. In this paper, the diagnosis of renal failure disease is investigated using ANFIS approach. Totally the raw data of 112 patients is obtained from Istanbul and Cerrahpasa Medical Faculties of Istanbul University, Turkey. Sixty-four of them are related to renal failures and the rest data belong to healthy persons. In ANFIS model, three rules and Gaussian membership functions are chosen, where rules are determined by the subtractive clustering method. Seven parameters of the patients are considered for the input of the system. These are: Blood Urea Nitrogen (BUN), Creatinine, Uric Acid, Potassium (K), Calcium (Ca), Phosphorus (P) and age. We try to decide whether the patient is ill or not. We have reached 100% success in ANFIS and have better results compared to Support Vector Machine (SVM) and Artificial Neural Networks (ANN). PMID- 20703606 TI - Implementation of a multi-functional ambulatory urodynamics monitoring system based on newly devised abdominal pressure measurement. AB - The measurement of the rectal pressure is considered to be the 'gold standard' for the assessment of the abdominal pressure. However, conventional rectal catheters can cause erroneous results and are not comfortable for the patients. To reduce these problems, we devised a non-invasive technique for the measurement of the abdominal pressure using the parametric curve fitting method, based on linear, polynomial, exponential or sine equation modeling, between the rectal pressure and electromyographic (sEMG) signals recorded simultaneously from the abdomen. The sEMG signals and rectal pressure were obtained simultaneously from 12 patients with neurogenic bladders due to spinal cord injury (age = 53.2 +/- 11.9 years, BMI = 24.4 +/- 2.7, ASIA classification: D). Using our algorithm, the correlation coefficient and root mean square error (RMSE) between the measured and estimated abdominal pressure obtained by the quartic polynomial modeling were 0.86 +/- 0.05 and 4.70 +/- 1.56, respectively. The results obtained herein suggest that the sEMG signals can be used reliably for the indirect measurement of the abdominal pressure in ambulatory urodynamics monitoring systems. PMID- 20703608 TI - A wavelet-based mammographic image denoising and enhancement with homomorphic filtering. AB - Breast cancer continues to be a significant public health problem in the world. The diagnosing mammography method is the most effective technology for early detection of the breast cancer. However, in some cases, it is difficult for radiologists to detect the typical diagnostic signs, such as masses and microcalcifications on the mammograms. This paper describes a new method for mammographic image enhancement and denoising based on wavelet transform and homomorphic filtering. The mammograms are acquired from the Faculty of Medicine of the University of Akdeniz and the University of Istanbul in Turkey. Firstly wavelet transform of the mammograms is obtained and the approximation coefficients are filtered by homomorphic filter. Then the detail coefficients of the wavelet associated with noise and edges are modeled by Gaussian and Laplacian variables, respectively. The considered coefficients are compressed and enhanced using these variables with a shrinkage function. Finally using a proposed adaptive thresholding the fine details of the mammograms are retained and the noise is suppressed. The preliminary results of our work indicate that this method provides much more visibility for the suspicious regions. PMID- 20703609 TI - Analysis of myocardial infarction using discrete wavelet transform. AB - Myocardial infarction (MI), is commonly known as a heart attack, occurs when the blood supply to the portion of the heart is blocked causing some heart cells to die. This information is depicted in the elevated ST wave, increased Q wave amplitude and inverted T wave of the electrocardiogram (ECG) signal. ECG signals are prone to noise during acquisition due to electrode movement, muscle tremor, power line interference and baseline wander. Hence, it becomes difficult to decipher the information about the cardiac state from the morphological changes in the ECG signal. These signals can be analyzed using different signal processing techniques. In this work, we have used multiresolution properties of wavelet transformation because it is suitable tool for interpretation of subtle changes in the ECG signal. We have analyzed the normal and MI ECG signals. ECG signal is decomposed into various resolution levels using the discrete wavelet transform (DWT) method. The entropy in the wavelet domain is computed and the energy-entropy characteristics are compared for 2282 normal and 718 MI beats. Our proposed method is able to detect the normal and MI ECG beat with more than 95% accuracy. PMID- 20703610 TI - Biometrics for electronic health records. AB - Securing electronic health records, in scenarios in which the provision of care services is share among multiple actors, could become a complex and costly activity. Correct identification of patients and physician, protection of privacy and confidentiality, assignment of access permissions for healthcare providers and resolutions of conflicts rise as main points of concern in the development of interconnected health information networks. Biometric technologies have been proposed as a possible technological solution for these issues due to its ability to provide a mechanism for unique verification of an individual identity. This paper presents an analysis of the benefit as well as disadvantages offered by biometric technology. A comparison between this technology and more traditional identification methods is used to determine the key benefits and flaws of the use biometric in health information systems. The comparison as been made considering the viability of the technologies for medical environments, global security needs, the contemplation of a share care environment and the costs involved in the implementation and maintenance of such technologies. This paper also discusses alternative uses for biometrics technologies in health care environments. The outcome of this analysis lays in the fact that even when biometric technologies offer several advantages over traditional method of identification, they are still in the early stages of providing a suitable solution for a health care environment. PMID- 20703611 TI - Diagnosis of airway obstruction or restrictive spirometric patterns by multiclass support vector machines. AB - This paper presents the use of multiclass support vector machines (SVMs) for diagnosis of spirometric patterns (normal, restrictive, obstructive). The SVM decisions were fused using the error correcting output codes (ECOC). The multiclass SVM with the ECOC was trained on three spirometric parameters (forced expiratory volume in 1s--FEV1, forced vital capacity--FVC and FEV1/FVC ratio). The total classification accuracy of the SVM is 97.32%. The obtained results confirmed the validity of the SVMs to help in clinical decision-making. PMID- 20703612 TI - Portable activity monitoring system for temporal parameters of gait cycles. AB - A portable and wireless activity monitoring system was developed for the estimation of temporal gait parameters. The new system was built using three-axis accelerometers to automatically detect walking steps with various walking speeds. The accuracy of walking step-peak detection algorithm was assessed by using a running machine with variable speeds. To assess the consistency of gait parameter analysis system, estimated parameters, such as heel-contact and toe-off time based on accelerometers and footswitches were compared for consecutive 20 steps from 19 individual healthy subjects. Accelerometers and footswitches had high consistency in the temporal gait parameters. The stance, swing, single-limb support, and double-limb support time of gait cycle revealed ICCs values of 0.95, 0.93, 0.86, and 0.75 on the right and 0.96, 0.86, 0.93, 0.84 on the left, respectively. And the walking step-peak detection accuracy was 99.15% (+/-0.007) for the proposed method compared to 87.48% (+/-0.033) for a pedometer. Therefore, the proposed activity monitoring system proved to be a reliable and useful tool for identification of temporal gait parameters and walking pattern classification. PMID- 20703613 TI - Design and implementation of web-based mobile electronic medication administration record. AB - Patients' safety is the most essential, critical issue, however, errors can hardly prevent, especially for human faults. In order to reduce the errors caused by human, we construct Electronic Health Records (EHR) in the Health Information System (HIS) to facilitate patients' safety and to improve the quality of medical care. During the medical care processing, all the tasks are based upon physicians' orders. In National Taiwan University Hospital (NTUH), the Electronic Health Record committee proposed a standard of order flows. There are objectives of the standard: first, to enhance medical procedures and enforce hospital policies; secondly, to improve the quality of medical care; third, to collect sufficient, adequate data for EHR in the near future. Among the proposed procedures, NTUH decides to establish a web-based mobile electronic medication administration record (ME-MAR) system. The system, build based on the service oriented architecture (SOA) as well as embedded the HL7/XML standard, is installed in the Mobile Nursing Carts. It also implement accompany with the advanced techniques like Asynchronous JavaScript and XML (Ajax) or Web services to enhance the system usability. According to researches, it indicates that medication errors are highly proportion to total medical faults. Therefore, we expect the ME-MAR system can reduce medication errors. In addition, we evaluate ME-MAR can assist nurses or healthcare practitioners to administer, manage medication properly. This successful experience of developing the NTUH ME-MAR system can be easily applied to other related system. Meanwhile, the SOA architecture of the system can also be seamless integrated to NTUH or other HIS system. PMID- 20703614 TI - Estimation of medicine amount used anesthesia by an artificial neural network. AB - In this study, Elman's recurrent neural networks using Resilient Back Propagation (RP) algorithm and feed-forward neural networks using adaptive learning rate algorithm (gdx) have been compared in order to determine the depth of anesthesia in the continuation stage of anesthesia and to estimate the amount of medicine to be applied at that moment. EEG data have been recorded by being sampled once in every 2 ms. From 30 patients, 57 distinct EEG recordings have been collected prior to during anaesthesia of different levels. The applied artificial neural network is composed of three layers, namely the input layer, the middle layer and the output layer. The nonlinear activation function sigmoid (sigmoid function) has been used in the hidden layer and the output layer. Prediction has been made by means of ANN. Training and testing the ANN have been used previous anaesthesia amount, total power/normal power and total power/previous. When Elman Resilient BP and feed-forward network are compared, it is observed that resilient back propagation algorithm has generated values which are quite close to the applied anesthesia amount compared to gdx which is an adaptive learning algorithm. The system has been able to correctly purposeful responses in average accuracy of 95% of the cases. This method is also computationally fast and acceptable real-time clinical performance has been obtained. PMID- 20703615 TI - Correlation dimension analysis of Doppler signals in children with aortic valve disorders. AB - In this study, the correlation dimension analysis has been applied to the aortic valve Doppler signals to investigate the complexity of the Doppler signals which belong to aortic stenosis (AS) and aortic insufficiency (AI) diseases and healthy case. The Doppler signals of 20 healthy subjects, ten AS and ten AI patients were acquired via the Doppler echocardiography system that is a noninvasive and reliable technique for assessment of AS and AI diseases. The correlation dimension estimations have been performed for different time delay values to investigate the influence of time delay on the correlation dimension calculation. The correlation dimension of healthy group has been found lower those found in AI and AS disorder groups and the correlation dimension of AS group has also been found higher than those found in AI group, significantly. The results of this study have indicated that the aortic valve Doppler signals exhibit high level chaotic behaviour in AI and AS diseases than healthy case. Additionally, the correlation dimension analysis is sensitive to the time delay and has successfully characterized the blood flow dynamics for proper time delay value. As a result, the correlation dimension can be used as an efficient method to determine the healthy or pathological cases of aortic valve. PMID- 20703616 TI - The impact of inpatient boarding on ED efficiency: a discrete-event simulation study. AB - In this study, a discrete-event simulation approach was used to model Emergency Department's (ED) patient flow to investigate the effect of inpatient boarding on the ED efficiency in terms of the National Emergency Department Crowding Scale (NEDOCS) score and the rate of patients who leave without being seen (LWBS). The decision variable in this model was the boarder-released-ratio defined as the ratio of admitted patients whose boarding time is zero to all admitted patients. Our analysis shows that the Overcrowded(+) (a NEDOCS score over 100) ratio decreased from 88.4% to 50.4%, and the rate of LWBS patients decreased from 10.8% to 8.4% when the boarder-released-ratio changed from 0% to 100%. These results show that inpatient boarding significantly impacts both the NEDOCS score and the rate of LWBS patient and this analysis provides a quantification of the impact of boarding on emergency department patient crowding. PMID- 20703617 TI - Applying non-synchronized e-learning to the nursing clinical ladder system. AB - The time and spatial constraints of face-to-face learning often affect nursing staff's inclination to enroll in ladder system training classes. Hence, their competence in clinical care may be unable to meet the requirements of the hospitals they work at. The e-learning mechanism offers a way to overcome such constraints. However, the differences in learners' achievement and satisfaction between traditional face-to-face and non-synchronized e-learning classes in the nursing clinical ladder system have not been thoroughly investigated. In this study, 155 nursing personnel serving at the case hospital, enrolled in N1/N2 ladder courses, were invited to participate as the subjects. The results showed that those who attended face-to-face learning classes reported higher satisfaction but achieved less in class than those in the e-learning class. The factors which influence the subjects' satisfaction with e-learning were investigated and summarized. PMID- 20703618 TI - A newborn screening system based on service-oriented architecture embedded support vector machine. AB - The clinical symptoms of metabolic disorders are rarely apparent during the neonatal period, and if they are not treated earlier, irreversible damages, such as mental retardation or even death, may occur. Therefore, the practice of newborn screening is essential to prevent permanent disabilities in newborns. In the paper, we design, implement a newborn screening system using Support Vector Machine (SVM) classifications. By evaluating metabolic substances data collected from tandem mass spectrometry (MS/MS), we can interpret and determine whether a newborn has a metabolic disorder. In addition, National Taiwan University Hospital Information System (NTUHIS) has been developed and implemented to integrate heterogeneous platforms, protocols, databases as well as applications. To expedite adapting the diversities, we deploy Service-Oriented Architecture (SOA) concepts to the newborn screening system based on web services. The system can be embedded seamlessly into NTUHIS. PMID- 20703619 TI - ECG/PPG integer signal processing for a ubiquitous health monitoring system. AB - A compact ubiquitous-health monitor operated by single 8-bit microcontroller was made. An integer signal processing algorithm for this microcontroller was developed and digital filtering of ECG (electrocardiogram) and PPG (photoplethysmogram) was performed. Rounding-off errors due to integer operation was solved by increasing the number of effective integer digits during CPU operation; digital filter coefficients and data expressed in decimal points were multiplied by a certain number and converted into integers. After filter operation, the actual values were retrieved by dividing with the same number and selecting available highest bits. Our results showed comparable accuracies to those computed by a commercial software. Compared with a floating-point calculation by the same microcontroller, the computation speed became faster by 1.45 ~ 2.0 times depending on various digital filtering cases. Our algorithm was successfully tested for remote health monitoring with multiple users. If our algorithm were not used, our health monitor should have used additional microcontrollers or DSP chip. The proposed algorithm reduced the size and cost of our health monitor substantially. PMID- 20703620 TI - Outpatients flow management and ophthalmic electronic medical records system in university hospital using Yahgee Document View. AB - General electronic medical records systems remain insufficient for ophthalmology outpatient clinics from the viewpoint of dealing with many ophthalmic examinations and images in a large number of patients. Filing systems for documents and images by Yahgee Document View (Yahgee, Inc.) were introduced on the platform of general electronic medical records system (Fujitsu, Inc.). Outpatients flow management system and electronic medical records system for ophthalmology were constructed. All images from ophthalmic appliances were transported to Yahgee Image by the MaxFile gateway system (P4 Medic, Inc.). The flow of outpatients going through examinations such as visual acuity testing were monitored by the list "Ophthalmology Outpatients List" by Yahgee Workflow in addition to the list "Patients Reception List" by Fujitsu. Patients' identification number was scanned with bar code readers attached to ophthalmic appliances. Dual monitors were placed in doctors' rooms to show Fujitsu Medical Records on the left-hand monitor and ophthalmic charts of Yahgee Document on the right-hand monitor. The data of manually-inputted visual acuity, automatically exported autorefractometry and non-contact tonometry on a new template, MaxFile ED, were again automatically transported to designated boxes on ophthalmic charts of Yahgee Document. Images such as fundus photographs, fluorescein angiograms, optical coherence tomographic and ultrasound scans were viewed by Yahgee Image, and were copy-and-pasted to assigned boxes on the ophthalmic charts. Ordering such as appointments, drug prescription, fees and diagnoses input, central laboratory tests, surgical theater and ward room reservations were placed by functions of the Fujitsu electronic medical records system. The combination of the Fujitsu electronic medical records and Yahgee Document View systems enabled the University Hospital to examine the same number of outpatients as prior to the implementation of the computerized filing system. PMID- 20703621 TI - A decision support system for preventing Legionella disease. AB - Information systems plays an important role in medicine because it helps process more data more efficiently while providing access to more people in different parts of the world. In this research we analyzed the data of legionella pneumophila and other legionella species collected by the public hygiene center (PHC). PHC collected 7,211 water samples from different sources of different locations in different cities in Turkey from year 1995 to 2008. The main goal of this research is to develop a conceptual framework for preventing disease and to design a medical decision support system to help administration assessing the risk of Legionnaires' disease and preventing the outbreaks of the disease. The DSS involves SOM software which was programmed with C# to search for patterns and similarities in data sets by producing SOM risk maps. Thus administrators can decide where to monitor cautiously to prevent the disease. PMID- 20703622 TI - Neural network classifier with entropy based feature selection on breast cancer diagnosis. AB - The aim of this research is to combine the feature selection (FS) and optimization algorithms as the optimal tool to improve the learning performance like predictive accuracy of the Wisconsin Breast Cancer Dataset classification. An ensemble of the reduced data patterns based on FS was used to train a neural network (NN) using the Levenberg-Marquardt (LM) and the Particle Swarm Optimization (PSO) algorithms to devise the appropriate NN training weighting parameters, and then construct an effective Neural Network classifier to improve the Wisconsin Breast Cancers' classification accuracy and efficiency. Experimental results show that the accuracy and AROC improved emphatically, and the best performance in accuracy and AROC are 98.83% and 0.9971, respectively. PMID- 20703623 TI - MIARS: a medical image retrieval system. AB - The next generation of medical information system will integrate multimedia data to assist physicians in clinical decision-making, diagnoses, teaching, and research. This paper describes MIARS (Medical Image Annotation and Retrieval System). MIARS not only provides automatic annotation, but also supports text based as well as image based retrieval strategies, which play important roles in medical training, research, and diagnostics. The system utilizes three trained classifiers, which are trained using training images. The goal of these classifiers is to provide multi-level automatic annotation. Another main purpose of the MIARS system is to study image semantic retrieval strategy by which images can be retrieved according to different levels of annotation. PMID- 20703624 TI - Unsupervised fuzzy based vessel segmentation in pathological digital fundus images. AB - Performing the segmentation of vasculature in the retinal images having pathology is a challenging problem. This paper presents a novel approach for automated segmentation of the vasculature in retinal images. The approach uses the intensity information from red and green channels of the same retinal image to correct non-uniform illumination in color fundus images. Matched filtering is utilized to enhance the contrast of blood vessels against the background. The enhanced blood vessels are then segmented by employing spatially weighted fuzzy c means clustering based thresholding which can well maintain the spatial structure of the vascular tree segments. The proposed method's performance is evaluated on publicly available DRIVE and STARE databases of manually labeled images. On the DRIVE and STARE databases, it achieves an area under the receiver operating characteristic curve of 0.9518 and 0.9602 respectively, being superior to those presented by state-of-the-art unsupervised approaches and comparable to those obtained with the supervised methods. PMID- 20703625 TI - High speed receiver for capsule endoscope. AB - In this study, a high-speed receiver for a capsule endoscope was proposed and implemented. The proposed receiver could receive 20 Mbps data that was sufficient to receive images with a higher resolution than conventional receivers. The receiver used a 1.2 GHz band to receive radio frequency (RF) signal, and demodulated the signal to an intermediate frequency (IF) stage (150 MHz). The demodulated signal was amplified, filtered, and under-sampled by a high-speed analog-to-digital converter (ADC). In order to decode the under-sampled data in real time, a simple frequency detection algorithm was selected and was implemented by using a FPGA. The implemented system could receive 20 Mbps data. PMID- 20703626 TI - A health examination system integrated with clinical decision support system. AB - Health examinations play a key role in preventive medicine. We propose a health examination system named Health Examination Automatic Logic System (HEALS) to assist clinical workers in improving the total quality of health examinations. Quality of automated inference is confirmed by the zero inference error where during 6 months and 14,773 cases. Automated inference time is less than one second per case in contrast to 2 to 5 min for physicians. The most significant result of efficiency evaluation is that 3,494 of 4,356 (80.2%) cases take less than 3 min per case for producing a report summary. In the evaluation of effectiveness, novice physicians got 18% improvement in making decisions with the assistance of our system. We conclude that a health examination system with a clinical decision system can greatly reduce the mundane burden on clinical workers and markedly improve the quality and efficiency of health examination tasks. PMID- 20703627 TI - 3D image analysis and artificial intelligence for bone disease classification. AB - In order to prevent bone fractures due to disease and ageing of the population, and to detect problems while still in their early stages, 3D bone micro architecture needs to be investigated and characterized. Here, we have developed various image processing and simulation techniques to investigate bone micro architecture and its mechanical stiffness. We have evaluated morphological, topological and mechanical bone features using artificial intelligence methods. A clinical study is carried out on two populations of arthritic and osteoporotic bone samples. The performances of Adaptive Neuro Fuzzy Inference System (ANFIS), Support Vector Machines (SVM) and Genetic Algorithm (GA) in classifying the different samples have been compared. Results show that the best separation success (100 %) is achieved with Genetic Algorithm. PMID- 20703628 TI - An approach to identify optic disc in human retinal images using ant colony optimization method. AB - In this work, an attempt has been made to identify optic disc in retinal images using digital image processing and optimization based edge detection algorithm. The edge detection was carried out using Ant Colony Optimization (ACO) technique with and without pre-processing and was correlated with morphological operations based method. The performance of the pre-processed ACO algorithm was analysed based on visual quality, computation time and its ability to preserve useful edges. The results demonstrate that the ACO method with pre-processing provides high visual quality output with better optic disc identification. Computation time taken for the process was also found to be less. This method preserves nearly 50% more edge pixel distribution when compared to morphological operations based method. In addition to improve optic disc identification, the proposed algorithm also distinctly differentiates between blood vessels and macula in the image. These studies appear to be clinically relevant because automated analyses of retinal images are important for ophthalmological interventions. PMID- 20703629 TI - Prediction of the period of psychotic episode in individual schizophrenics by simulation-data construction approach. AB - Although schizophrenia can be treated, most patients still experience inevitable psychotic episodes from time to time. Precautious actions can be taken if the next onset can be predicted. However, sufficient information is always lacking in the clinical scenario. A possible solution is to use the virtual data generated from limited of original data. Data construction method (DCM) has been shown to generate the virtual felt earthquake data effectively and used in the prediction of further events. Here we investigated the performance of DCM in deriving the membership functions and discrete-event simulations (DES) in predicting the period embracing the initiation and termination time-points of the next psychotic episode of 35 individual schizophrenic patients. The results showed that 21 subjects had a success of simulations (RSS) >=70%. Further analysis demonstrated that the co-morbidity of coronary heart diseases (CHD), risks of CHD, and the frequency of previous psychotic episodes increased the RSS. PMID- 20703630 TI - Development of abnormal gait detection and vibratory stimulation system on lower limbs to improve gait stability. AB - The purpose of this study is to develop an abnormal gait detection algorithm and a vibratory stimulation system on a lower limb to improve gait stability and prevent falls. The system consists of a gait measurement module, an abnormal gait detection module, and a vibratory stimulation module. The gait measurement module measures the vertical acceleration of the ankle during walking using an accelerometer. The measured acceleration values are sent to a portable microcontroller, which controls vibratory stimulations to the ankles based on an algorithm that detects the peak acceleration values. If the acceleration peaks are found to occur irregularly, the abnormal gait detection algorithm activates the vibratory stimulation module. To determine the effect of vibratory stimulations under dynamic condition, this study investigated the contribution of ankle muscle proprioception on the control of dynamic stability and lower limb kinematics while walking using vibratory stimulation to alter the muscle spindle output of individuals' left lower limb. Vibrators were attached to the left ankle joint (tibialis anterior, triceps surae). Participants were required to walk along a travel path and step over an obstacle placed in their way. There were four task conditions; an obstacle (10%, 20%, and 30% of the participants' height) was positioned at the midpoint of the walkway, or the participants' walking path remained clear. For each obstacle condition, participants experienced either no vibration, or vibration of the tibialis anterior muscle and the triceps surae muscle of the left lower limb. Vibration began upon detection of an abnormal gait and continued for one second. Vibrating the ankle muscles of the left lower limb while stepping over an obstacle resulted in significant changes in COM behavior on both the anterior/posterior (A/P) and medial/lateral (M/L) planes. The results provide strong evidence that the primary endings of the ankle muscle spindles play a significant role in the control of posture and balance during the swing phase of locomotion by providing information on the movement of the body's COM with respect to the support foot. PMID- 20703631 TI - A novel web-enabled healthcare solution on health vault system. AB - Complicated Electronic Medical Records (EMR) systems have created problems in systems regarding an easy implementation and interoperability for a Web-enabled Healthcare Solution, which is normally provided by an independent healthcare giver with limited IT knowledge and interests. An EMR system with well-designed and user-friendly interface, such as Microsoft HealthVault System used as the back-end platform of a Web-enabled healthcare application will be an approach to deal with these problems. This paper analyzes the patient oriented Web-enabled healthcare service application as the new trend to delivery healthcare from hospital/clinic-centric to patient-centric, the current e-healthcare applications, and the main backend EMR systems. Then, we present a novel web enabled healthcare solution based on Microsoft HealthVault EMR system to meet customers' needs, such as, low total cost, easily development and maintenance, and good interoperability. A sample system is given to show how the solution can be fulfilled, evaluated, and validated. We expect that this paper will provide a deep understanding of the available EMR systems, leading to insights for new solutions and approaches driven to next generation EMR systems. PMID- 20703632 TI - Telemetry design of a vital sign recording system. AB - Blood pressure, respiratory rate, body temperature, and pulse rate are vital signs that under certain pathological conditions require continuous monitoring. In this paper we present a novel design of a system that embeds these signals into a single waveform that can be transmitted without the need for time or frequency division multiplexing. The system depends on changing the frequency of a square wave oscillator. One signal with low frequency contents controls the On time of the oscillator while the Off-time is controlled by another signal. The third and the fourth signals are used to control voltage controlled oscillators. The voltage controlled oscillators outputs are used as fluctuations during the On time and during the Off-time. The main advantage of this system is the reduction in circuit complexity in both transmitter and receiver with accurate recovery of the transmitted signals. The design of the proposed system is presented in this paper along with all the corresponding simulations. PMID- 20703633 TI - Consumer support for health information exchange and personal health records: a regional health information organization survey. AB - In order to characterize consumer support for electronic health information exchange (HIE) and personal health records (PHRs) in a community where HIE is underway, we conducted a survey of English speaking adults who visited primary care practices participating in a regional community-wide clinical data exchange, during August, 2008. Amongst the 117 respondents, a majority supported physicians' use of HIE (83%) or expressed interest in potentially using PHRs (76%). Consumers' comfort sending personal information electronically over the Internet and their perceptions regarding the potential benefits of HIE were independently associated with their support for HIE. Consumers' prior experience using the Internet to manage their healthcare, perceptions regarding the potential benefits of PHRs and college education were independently associated with potential PHR use. Bolstering consumer support for HIE and PHRs will require addressing privacy and security concerns, demonstrating clinical benefits, and reaching out to those who are less educated and computer literate. PMID- 20703634 TI - An ultra low-power and traffic-adaptive medium access control protocol for wireless body area network. AB - Wireless Body Area Network (WBAN) consists of low-power, miniaturized, and autonomous wireless sensor nodes that enable physicians to remotely monitor vital signs of patients and provide real-time feedback with medical diagnosis and consultations. It is the most reliable and cheaper way to take care of patients suffering from chronic diseases such as asthma, diabetes and cardiovascular diseases. Some of the most important attributes of WBAN is low-power consumption and delay. This can be achieved by introducing flexible duty cycling techniques on the energy constraint sensor nodes. Stated otherwise, low duty cycle nodes should not receive frequent synchronization and control packets if they have no data to send/receive. In this paper, we introduce a Traffic-adaptive MAC protocol (TaMAC) by taking into account the traffic information of the sensor nodes. The protocol dynamically adjusts the duty cycle of the sensor nodes according to their traffic-patterns, thus solving the idle listening and overhearing problems. The traffic-patterns of all sensor nodes are organized and maintained by the coordinator. The TaMAC protocol is supported by a wakeup radio that is used to accommodate emergency and on-demand events in a reliable manner. The wakeup radio uses a separate control channel along with the data channel and therefore it has considerably low power consumption requirements. Analytical expressions are derived to analyze and compare the performance of the TaMAC protocol with the well-known beacon-enabled IEEE 802.15.4 MAC, WiseMAC, and SMAC protocols. The analytical derivations are further validated by simulation results. It is shown that the TaMAC protocol outperforms all other protocols in terms of power consumption and delay. PMID- 20703635 TI - Mobile agent application and integration in electronic anamnesis system. AB - Electronic anamnesis is to transform ordinary paper trails to digitally formatted health records, which include the patient's general information, health status, and follow-ups on chronic diseases. Its main purpose is to let the records could be stored for a longer period of time and could be shared easily across departments and hospitals. Which means hospital management could use less resource on maintaining ever-growing database and reduce redundancy, so less money would be spent for managing the health records. In the foreseeable future, building up a comprehensive and integrated medical information system is a must, because it is critical to hospital resource integration and quality improvement. If mobile agent technology is adopted in the electronic anamnesis system, it would help the hospitals to make the medical practices more efficiently and conveniently. Nonetheless, most of the hospitals today are still using paper based health records to manage the medical information. The reason why the institutions continue using traditional practices to manage the records is because there is no well-trusted and reliable electronic anamnesis system existing and accepted by both institutions and patients. The threat of privacy invasion is one of the biggest concerns when the topic of electronic anamnesis is brought up, because the security threats drag us back from using such a system. So, the medical service quality is difficult to be improved substantially. In this case, we have come up a theory to remove such security threats and make electronic anamnesis more appealing for use. Our theory is to integrate the mobile agent technology with the backbone of electronic anamnesis to construct a hierarchical access control system to retrieve the corresponding information based upon the permission classes. The system would create a classification for permission among the users inside the medical institution. Under this framework, permission control center would distribute an access key to each user, so they would only allow using the key to access information correspondingly. In order to verify the reliability of the proposed system framework, we have also conducted a security analysis to list all the possible security threats that may harm the system and to prove the system is reliable and safe. If the system is adopted, the doctors would be able to quickly access the information while performing medical examinations. Hence, the efficiency and quality of healthcare service would be greatly improved. PMID- 20703636 TI - Knowledge extraction algorithm for variances handling of CP using integrated hybrid genetic double multi-group cooperative PSO and DPSO. AB - Although the clinical pathway (CP) predefines predictable standardized care process for a particular diagnosis or procedure, many variances may still unavoidably occur. Some key index parameters have strong relationship with variances handling measures of CP. In real world, these problems are highly nonlinear in nature so that it's hard to develop a comprehensive mathematic model. In this paper, a rule extraction approach based on combing hybrid genetic double multi-group cooperative particle swarm optimization algorithm (PSO) and discrete PSO algorithm (named HGDMCPSO/DPSO) is developed to discovery the previously unknown and potentially complicated nonlinear relationship between key parameters and variances handling measures of CP. Then these extracted rules can provide abnormal variances handling warning for medical professionals. Three numerical experiments on Iris of UCI data sets, Wisconsin breast cancer data sets and CP variances data sets of osteosarcoma preoperative chemotherapy are used to validate the proposed method. When compared with the previous researches, the proposed rule extraction algorithm can obtain the high prediction accuracy, less computing time, more stability and easily comprehended by users, thus it is an effective knowledge extraction tool for CP variances handling. PMID- 20703637 TI - Technological innovations in the development of cardiovascular clinical information systems. AB - Recent studies have shown that computerized clinical case management and decision support systems can be used to assist surgeons in the diagnosis of disease, optimize surgical operation, aid in drug therapy and decrease the cost of medical treatment. Therefore, medical informatics has become an extensive field of research and many of these approaches have demonstrated potential value for improving medical quality. The aim of this study was to develop a web-based cardiovascular clinical information system (CIS) based on innovative techniques, such as electronic medical records, electronic registries and automatic feature surveillance schemes, to provide effective tools and support for clinical care, decision-making, biomedical research and training activities. The CIS developed for this study contained monitoring, surveillance and model construction functions. The monitoring layer function provided a visual user interface. At the surveillance and model construction layers, we explored the application of model construction and intelligent prognosis to aid in making preoperative and postoperative predictions. With the use of the CIS, surgeons can provide reasonable conclusions and explanations in uncertain environments. PMID- 20703638 TI - The Obama EHR experiment. PMID- 20703639 TI - A robust multi-class feature selection strategy based on Rotation Forest Ensemble algorithm for diagnosis of Erythemato-Squamous diseases. AB - In biomedical studies, accuracy of classification algorithms used in disease diagnosis systems is certainly an important task and the accuracy of system is strictly related to extraction of discriminatory features from data. In this paper, we propose a new multi-class feature selection method based on Rotation Forest meta-learner algorithm. The feature selection performance of this newly proposed ensemble approach is tested on Erythemato-Squamous diseases dataset. The discrimination ability of selected features is evaluated by the use of several machine learning algorithms. In order to evaluate the performance of Rotation Forest Ensemble Feature Selection approach quantitatively, we also used various and widely utilized ensemble algorithms to compare effectiveness of resultant features. The new multi-class or ensemble feature selection algorithm exhibited promising results in eliminating redundant attributes. The Rotation Forest selection based features demonstrated accuracies between 98% and 99% in various classifiers and this is a quite high performance for Erythemato-Squamous Diseases diagnosis. PMID- 20703641 TI - Analysis of repetitive flash stimulation frequencies and record periods to detect migraine using artificial neural network. AB - Different kind of methods has been applied to detect the migraine by using flash stimulation. Especially frequency analysis of EEG signal is the most preferred method to detect the migraine by using flash stimulation. Different flash stimulation frequencies at wide frequency range have been used in migraine detection. But the effects of these flash stimulation frequencies and the most effective frequency can be determined by analyzing these frequencies separately. Since each stimulation frequency has been implemented in different time periods, it is necessary to determine the time period to detect magnitude increase in migraine patients. The aim of this study is to determine the most effective flash stimulation frequency and time duration to detect the migraine. In this study, we analyzed the flash stimulation frequencies and time duration separately for detecting migraine. Performance of each flash stimulation frequency has been determined to detect the migraine by analyzing the power spectrums obtained under 2 Hz, 4 Hz and 6 Hz and artificial neural network has been used to determine the which data has a superior performance. Afterwards we analyzed the 2 s, 4 s, 6 s, 8 s and 10 s of flash stimulation periods separately by observing the power spectrums and the results are verified by using artificial neural network. As a result of this study we proposed the 4 Hz of flash stimulation frequency is the most effective frequency and 8 s time period is necessary to detect the migraine at the beta band of EEG's T5-T3 channel. PMID- 20703640 TI - Organizational challenges in developing one of the Nationwide Health Information Network trial implementation awardees. AB - Health care in the United States is rarely delivered in a coordinated manner. Current methods to share patient information are inefficient and may lead to medical errors, higher readmission rates, and delays in the delivery of needed health services. This qualitative study describes lessons learned concerning the early implementation of one Nationwide Health Information Network (NHIN) site in Long Beach, CA during its first year of operation. The Long Beach Network for Health (LBNH) focused on an incremental effort to exchange health information. Despite a limited concentration on emergency department care, virtually all respondents noted concerns regarding the sustainability, or business case, for the exchange of health information. Nevertheless, respondents were encouraged by progress on technological challenges and user requirements during this first year. The early gains in this process may, in turn, have laid the groundwork for future efforts to expand beyond the emergency department. PMID- 20703642 TI - Performance evaluation of a web-based system to exchange Electronic Health Records using Queueing model (M/M/1). AB - Response time measurement of a web-based system is essential to evaluate its performance. This paper shows a comparison of the response times of a Web-based system for Ophthalmologic Electronic Health Records (EHRs), TeleOftalWeb. It makes use of different database models like Oracle 10 g, dbXML 2.0, Xindice 1.2, and eXist 1.1.1. The system's modelling, which uses Tandem Queue networks, will allow us to estimate the service times of the different components of the system (CPU, network and databases). In order to calculate those times, associated to the different databases, benchmarking techniques are used. The final objective of the comparison is to choose the database system resulting in the lowest response time to TeleOftalWeb and to compare the obtained results using a new benchmarking. PMID- 20703643 TI - A neuro-fuzzy identification of ECG beats. AB - This paper presents a fuzzy rule based classifier and its application to discriminate premature ventricular contraction (PVC) beats from normals. An Adaptive Neuro-Fuzzy Inference System (ANFIS) is applied to discover the fuzzy rules in order to determine the correct class of a given input beat. The main goal of our approach is to create an interpretable classifier that also provides an acceptable accuracy. The performance of the classifier is tested on MIT-BIH (Massachusetts Institute of Technology-Beth Israel Hospital) arrhythmia database. On the test set, we achieved an overall sensitivity and specificity of 97.92% and of 94.52% respectively. Experimental results show that the proposed approach is simple and effective in improving the interpretability of the fuzzy classifier while preserving the model performances at a satisfactory level. PMID- 20703645 TI - An efficient automated algorithm to detect ocular surface temperature on sequence of thermograms using snake and target tracing function. AB - Functional infrared (IR) imaging is widely adopted in medical field nowadays, with more emphasis on breast cancer and ocular abnormalities. In this article, an algorithm is presented to accurately locate the eye and cornea in ocular thermographic sequences, which were recorded utilizing functional infrared imaging. The localization is achieved by snake algorithm coupled with a newly proposed target tracing function. The target tracing function enables automated localization, allows the absence of any manual assistance before the algorithm runs. Genetic algorithm is used to perform the search for global minimum on the function to produce desired localization. On all the cases we have studied, in average the region encircled by the algorithm covers 92% of the true ocular region. As for the non-ocular region covered, it only accounts for less than 5% of the encircled region. PMID- 20703644 TI - Prescription-filling process reengineering of an outpatient pharmacy. AB - Shortening waiting times is the most obvious and effective method of increasing service quality. As the workforce is limited, it is necessary to reform current systems of medical care and improve the efficiency of medical care. After process reengineering was proposed in 1990s, however, this concept has not yet been commonly applied to medical centers. The subject of this study was an outpatient pharmacy in a medical center. This study applied the methods of a time study to measure field observations and as an analytic tool in process reengineering. The results show that the pharmacists were hindered in filling prescriptions for the following reasons: the preparation of certain prescription units, the menial sorting of medicines and also storage issues related to medicines. Improving the process will decrease time wasted by 10.41% and enhance service by 8.95%. The reengineering process resulted not only in a reduction in outpatients' waiting time but also enhanced the quality and competitiveness of the Hospital's medical treatment. PMID- 20703646 TI - Automatic classification of heartbeats using wavelet neural network. AB - The electrocardiogram (ECG) signal is widely employed as one of the most important tools in clinical practice in order to assess the cardiac status of patients. The classification of the ECG into different pathologic disease categories is a complex pattern recognition task. In this paper, we propose a method for ECG heartbeat pattern recognition using wavelet neural network (WNN). To achieve this objective, an algorithm for QRS detection is first implemented, then a WNN Classifier is developed. The experimental results obtained by testing the proposed approach on ECG data from the MIT-BIH arrhythmia database demonstrate the efficiency of such an approach when compared with other methods existing in the literature. PMID- 20703647 TI - Statistical analysis of textural features for improved classification of oral histopathological images. AB - The objective of this paper is to provide an improved technique, which can assist oncopathologists in correct screening of oral precancerous conditions specially oral submucous fibrosis (OSF) with significant accuracy on the basis of collagen fibres in the sub-epithelial connective tissue. The proposed scheme is composed of collagen fibres segmentation, its textural feature extraction and selection, screening perfomance enhancement under Gaussian transformation and finally classification. In this study, collagen fibres are segmented on R,G,B color channels using back-probagation neural network from 60 normal and 59 OSF histological images followed by histogram specification for reducing the stain intensity variation. Henceforth, textural features of collgen area are extracted using fractal approaches viz., differential box counting and brownian motion curve . Feature selection is done using Kullback-Leibler (KL) divergence criterion and the screening performance is evaluated based on various statistical tests to conform Gaussian nature. Here, the screening performance is enhanced under Gaussian transformation of the non-Gaussian features using hybrid distribution. Moreover, the routine screening is designed based on two statistical classifiers viz., Bayesian classification and support vector machines (SVM) to classify normal and OSF. It is observed that SVM with linear kernel function provides better classification accuracy (91.64%) as compared to Bayesian classifier. The addition of fractal features of collagen under Gaussian transformation improves Bayesian classifier's performance from 80.69% to 90.75%. Results are here studied and discussed. PMID- 20703648 TI - Usability evaluation of paper-based "Hajji" Health Record format. AB - The study objective was the development and content evaluation of the paper-based Hajji Health Record (PHHR) instrument to make it appropriate for developmental phases of web based electronic Hajji (Pilgrim) Health Record (WEHHR) implementation. A qualitative and quantitative survey was done on 13 December 2008G in Alnoor Specialist Hospital, Makkah, Saudi Arabia. Twenty-two physicians of 19 countries were given a preliminary questionnaire containing basic sociodemographic information, followed by Hajjis' health information sheet (HHIS) with a sample scenario of a case history. A structured evaluation questionnaire about HHIS was given afterwards. Five point Likert scaling was used starting from strongly agree to strongly disagree as 1 to 5. Data was analyzed by using SPSS programme version 16. Two tailed p-value <0.05 was considered as significant. Mean age was 48.6 years with range (35-64). Specialists were 10(45.5%) and teaching hospitals' physicians were 11(50%). Twelve (54.5%) physicians had concept about EHR, while the same number had their Hajjis' health record but only 33.3% (4/12) had sufficient health information. Response rate was 91.9% with average rating of 2.2 +/- 1. Agreement response (78.8%) was noted for "medical history" category followed by "medication history" (76.2%). Average rating of consultants was (2 +/- 0.88), while specialists, residents and general practitioners had 2.3 +/- 1.2, 2.7 +/- 1, 2.1 +/- 0.58, respectively. Physicians without EHR concept had average rating 2.1 +/- 1.16 than other group (2.3 +/- 0.92). Majority of physicians were specialists. Overall response rate was superb with agreement response. No significant difference in rating was found among all categories of physicians. PMID- 20703649 TI - Identification of hand and finger movements using multi run ICA of surface electromyogram. AB - Surface electromyogram (sEMG) based control of prosthesis and computer assisted devices can provide the user with near natural control. Unfortunately there is no suitable technique to classify sEMG when the there are multiple active muscles such as during finger and wrist flexion due to cross-talk. Independent Component Analysis (ICA) to decompose the signal into individual muscle activity has been demonstrated to be useful. However, ICA is an iterative technique that has inherent randomness during initialization. The average improvement in classification of sEMG that was separated using ICA was very small, from 60% to 65%. To overcome this problem associated with randomness of initialization, multi run ICA (MICA) based sEMG classification system has been proposed and tested. MICA overcame the shortcoming and the results indicate that using MICA, the accuracy of identifying the finger and wrist actions using sEMG was 99%. PMID- 20703650 TI - Constructing a model-based software monitor for the insulin pump behavior. AB - Modern medical systems undertaking the task of surveillance of patients are safety-critical systems steered by software. Such systems will bring man's life into hazard if they fail to meet patients' requirements; so, adequate reliability of the algorithms and computations used by software of such systems is a matter of concern. The environment of a medical safety-critical system consisting of a patient has safety requirements that should be satisfied by the system. A safety requirement is the one that if it is violated, the system environment will be subject to severe risk. An effective method to verify the algorithms and computations used by software of such systems against safety requirements is to keep the software under surveillance at run-time. This paper aims to present a model-based method to construct a run-time monitor for a safety-critical medical system called Continuous Infusion Insulin Pump (CIIP). PMID- 20703651 TI - Low cost RFID real lightweight binding proof protocol for medication errors and patient safety. AB - An Institute of Medicine Report stated there are 98,000 people annually who die due to medication related errors in the United States, and hospitals and other medical institutions are thus being pressed to use technologies to reduce such errors. One approach is to provide a suitable protocol that can cooperate with low cost RFID tags in order to identify patients. However, existing low cost RFID tags lack computational power and it is almost impossible to equip them with security functions, such as keyed hash function. To address this issue, a so a real lightweight binding proof protocol is proposed in this paper. The proposed protocol uses only logic gates (e.g. AND, XOR, ADD) to achieve the goal of proving that two tags exist in the field simultaneously, without the need for any complicated security algorithms. In addition, various scenarios are provider to explain the process of adopting this binding proof protocol with regard to guarding patient safety and preventing medication errors. PMID- 20703652 TI - Computer-aided intelligent system for diagnosing pediatric asthma. AB - Asthma is a lung chronic inflammatory disorder estimated between 1.4% and 27.1% in different area of the world. Result of various studies show that asthma is usually underdiagnosed especially in developing countries, because of limitations on access to medical specialists and laboratory facilities. In this paper, we report on the development and evaluation of a novel patient-based fuzzy system that promotes the diagnosis method of asthma. The design of this application addresses five critical issues included: 1) modular representation of asthma diagnostic variables regard to patients' perception of the disease, 2) algorithmic approaches conducting inference of diagnosing based on patient's response to questions, 4) front-end mechanism for capturing data from patient, 5) output for both patient and physician regard to asthma possibility. for the system output score (0-10) the efficacy of this system calculated in the study sample included 139 asthmatic patients and 139 non-asthmatic patients (age range 6-18) reinforce the sensitivity of 88% and specificity of 100% for cut off value 0.7. PMID- 20703654 TI - Field programmable gate array based fuzzy neural signal processing system for differential diagnosis of QRS complex tachycardia and tachyarrhythmia in noisy ECG signals. AB - The paper reports of a Field Programmable Gate Array (FPGA) based embedded system for detection of QRS complex in a noisy electrocardiogram (ECG) signal and thereafter differential diagnosis of tachycardia and tachyarrhythmia. The QRS complex has been detected after application of entropy measure of fuzziness to build a detection function of ECG signal, which has been previously filtered to remove power line interference and base line wander. Using the detected QRS complexes, differential diagnosis of tachycardia and tachyarrhythmia has been performed. The entire algorithm has been realized in hardware on an FPGA. Using the standard CSE ECG database, the algorithm performed highly effectively. The performance of the algorithm in respect of QRS detection with sensitivity (Se) of 99.74% and accuracy of 99.5% is achieved when tested using single channel ECG with entropy criteria. The performance of the QRS detection system has been compared and found to be better than most of the QRS detection systems available in literature. Using the system, 200 patients have been diagnosed with an accuracy of 98.5%. PMID- 20703653 TI - Research on interpolation methods in medical image processing. AB - Image interpolation is widely used for the field of medical image processing. In this paper, interpolation methods are divided into three groups: filter interpolation, ordinary interpolation and general partial volume interpolation. Some commonly-used filter methods for image interpolation are pioneered, but the interpolation effects need to be further improved. When analyzing and discussing ordinary interpolation, many asymmetrical kernel interpolation methods are proposed. Compared with symmetrical kernel ones, the former are have some advantages. After analyzing the partial volume and generalized partial volume estimation interpolations, the new concept and constraint conditions of the general partial volume interpolation are defined, and several new partial volume interpolation functions are derived. By performing the experiments of image scaling, rotation and self-registration, the interpolation methods mentioned in this paper are compared in the entropy, peak signal-to-noise ratio, cross entropy, normalized cross-correlation coefficient and running time. Among the filter interpolation methods, the median and B-spline filter interpolations have a relatively better interpolating performance. Among the ordinary interpolation methods, on the whole, the symmetrical cubic kernel interpolations demonstrate a strong advantage, especially the symmetrical cubic B-spline interpolation. However, we have to mention that they are very time-consuming and have lower time efficiency. As for the general partial volume interpolation methods, from the total error of image self-registration, the symmetrical interpolations provide certain superiority; but considering the processing efficiency, the asymmetrical interpolations are better. PMID- 20703655 TI - An improved brain image classification technique with mining and shape prior segmentation procedure. AB - The shape prior segmentation procedure and pruned association rule with ImageApriori algorithm has been used to develop an improved brain image classification system are presented in this paper. The CT scan brain images have been classified into three categories namely normal, benign and malignant, considering the low-level features extracted from the images and high level knowledge from specialists to enhance the accuracy in decision process. The experimental results on pre-diagnosed brain images showed 97% sensitivity, 91% specificity and 98.5% accuracy. The proposed algorithm is expected to assist the physicians for efficient classification with multiple key features per image. PMID- 20703656 TI - Applying ontology techniques to develop a medication history search and alert system in department of nuclear medicine. AB - Nowadays, patients usually take more than three drugs for diseases such as hypertension, diabetes, and dyslipidemia. Hence, nuclear medicine physicians should be very careful about the medication history of each patient and ensure that their medication will not cause false positive or false negative imaging results, because either condition will interfere with adequate treatment of the patient and result in a wrong diagnosis. The aim of the present paper is to develop an ontology-based medication search and alert system for scintiphotography of Chang Gung Memorial hospital at Kaohsiung. Composed of four sub-systems, including Medication History Collect Agent (MHCA), Medication History Search System (MHSS), Patient Medication Consultation System (PMCS), and Patient Medication Alert System (PMAS), this medication search and alert system for scintiphotography is expected to support decision making of nuclear medicine examination, improve accuracy of image reading, and offer detailed data for further research. The ultimate goal of this system is to ensure patient safety. PMID- 20703657 TI - Building clinical data groups for electronic medical record in China. AB - This article aims at building clinical data groups for Electronic Medical Records (EMR) in China. These data groups can be reused as basic information units in building the medical sheets of Electronic Medical Record Systems (EMRS) and serve as part of its implementation guideline. The results were based on medical sheets, the forms that are used in hospitals, which were collected from hospitals. To categorize the information in these sheets into data groups, we adopted the Health Level 7 Clinical Document Architecture Release 2 Model (HL7 CDA R2 Model). The regulations and legal documents concerning health informatics and related standards in China were implemented. A set of 75 data groups with 452 data elements was created. These data elements were atomic items that comprised the data groups. Medical sheet items contained clinical records information and could be described by standard data elements that exist in current health document protocols. These data groups match different units of the CDA model. Twelve data groups with 87 standardized data elements described EMR headers, and 63 data groups with 405 standardized data elements constituted the body. The later 63 data groups in fact formed the sections of the model. The data groups had two levels. Those at the first level contained both the second level data groups and the standardized data elements. The data groups were basically reusable information units that served as guidelines for building EMRS and that were used to rebuild a medical sheet and serve as templates for the clinical records. As a pilot study of health information standards in China, the development of EMR data groups combined international standards with Chinese national regulations and standards, and this was the most critical part of the research. The original medical sheets from hospitals contain first hand medical information, and some of their items reveal the data types characteristic of the Chinese socialist national health system. It is possible and critical to localize and stabilize the adopted international health standards through abstracting and categorizing those items for future sharing and for the implementation of EMRS in China. PMID- 20703658 TI - An acoustical evaluation of knee sound for non-invasive screening and early detection of articular pathology. AB - Knee sound signals generated by knee movement are sometimes associated with degeneration of the knee joint surface and such sounds may be a useful index for early disease. In this study, we detected the acoustical parameters, such as the fundamental frequency (F0), mean amplitude of the pitches, and jitter and shimmer of knee sounds, and compared them according to the pathological conditions. Six normal subjects (4 males and 2 females, age: 28.3 +/- 2.3 years) and 11 patients with knee problems were enrolled. The patients were divided into the 1st patient group (5 males and 1 female, age: 30.2 +/- 10.3 years) with ruptured wounds of the meniscus and 2nd patient group (2 males and 3 females, age: 42.1 +/- 16.2 years) with osteoarthritis. The mean values of F0, jitter and shimmer of the 2nd patient group were larger than those of the normal group, whereas those of the 1st patient group were smaller (p < 0.05). Also, the F0 and jitter in the standing position were larger than those in the sitting position in both the 1st and 2nd patient groups (p < 0.05). These results showed good potential for the non-invasive diagnosis and early detection of articular pathologies via an auscultation. PMID- 20703659 TI - Analysis of factors causing long patient waiting time and clinic overtime in outpatient clinics. AB - This paper is focused on the factors causing long patient waiting time/clinic overtime in outpatient clinics and how to mitigate them using discrete event simulation. A two-week period of data collection is conducted in an outpatient clinic of a Singapore government hospital. Detailed time study from patient arrival to patient departure is conducted, and the possible factors causing long patient waiting time/clinic overtime are discussed. A discrete simulation model is constructed to illustrate how to improve the clinic performance by mitigating the detected factors. Simulation and implementation results show that significant improvement is achieved if the factors are well addressed. PMID- 20703660 TI - Navigation interface for recommending home medical products. AB - Based on users' health issues, an intelligent personal health record (iPHR) system can automatically recommend home medical products (HMPs) and display them in a sequential order. However, the sequential output interface does not categorize search results and is not easy for users to quickly navigate to their desired HMPs. To address this problem, we developed a navigation interface for retrieved HMPs. Our idea is to use medical knowledge and nursing knowledge to construct a navigation hierarchy based on product categories. This hierarchy is added to the left side of each search result Web page to help users move through retrieved HMPs. We demonstrate the effectiveness of our techniques using USMLE medical exam cases. PMID- 20703661 TI - Automated analysis of retinal vascular tortuosity on color retinal images. AB - Recent advances in medical imaging modality have enabled us to identify new features in retinal vasculature. One of the features is retinal vascular tortuosity which has been shown to become a predictive factor for cardiovascular diseases and diabetes. The changes in retinal vascular tortuosity might be a sign of severity or improvement of the disease. In this paper, we propose a new method for measuring retinal vascular tortuosity. We adopt a new technique to analyze tortuosity that consider vessel-segment's width simultaneously. Our proposed method measures vessel-segment's tortuosity on its edge. A qualitative assessment shows that the method is appropriate for measuring the tortuosity of the vessels in different widths and directions in the image. Finally, a comparison distinguishing tortuous vs. non tortuous vessels demonstrates that the proposed approach may be suitable for predicting or earlier diagnosis of diabetes or cardiovascular diseases. PMID- 20703662 TI - Automated screening of arrhythmia using wavelet based machine learning techniques. AB - Arrhythmia is one of the preventive cardiac problems frequently occurs all over the globe. In order to screen such disease at early stage, this work attempts to develop a system approach based on registration, feature extraction using discrete wavelet transform (DWT), feature validation and classification of electrocardiogram (ECG). This diagnostic issue is set as a two-class pattern classification problem (normal sinus rhythm versus arrhythmia) where MIT-BIH database is considered for training, testing and clinical validation. Here DWT is applied to extract multi-resolution coefficients followed by registration using Pan Tompkins algorithm based R point detection. Moreover, feature space is compressed using sub-band principal component analysis (PCA) and statistically validated using independent sample t-test. Thereafter, the machine learning algorithms viz., Gaussian mixture model (GMM), error back propagation neural network (EBPNN) and support vector machine (SVM) are employed for pattern classification. Results are studied and compared. It is observed that both supervised classifiers EBPNN and SVM lead to higher (93.41% and 95.60% respectively) accuracy in comparison with GMM (87.36%) for arrhythmia screening. PMID- 20703664 TI - Employing post-DEA cross-evaluation and cluster analysis in a sample of Greek NHS hospitals. AB - To increase Data Envelopment Analysis (DEA) discrimination of efficient Decision Making Units (DMUs), by complementing "self-evaluated" efficiencies with "peer evaluated" cross-efficiencies and, based on these results, to classify the DMUs using cluster analysis. Healthcare, which is deprived of such studies, was chosen as the study area. The sample consisted of 27 small- to medium-sized (70-500 beds) NHS general hospitals distributed throughout Greece, in areas where they are the sole NHS representatives. DEA was performed on 2005 data collected from the Ministry of Health and the General Secretariat of the National Statistical Service. Three inputs -hospital beds, physicians and other health professionals- and three outputs -case-mix adjusted hospitalized cases, surgeries and outpatient visits- were included in input-oriented, constant-returns-to-scale (CRS) and variable-returns-to-scale (VRS) models. In a second stage (post-DEA), aggressive and benevolent cross-efficiency formulations and clustering were employed, to validate (or not) the initial DEA scores. The "maverick index" was used to sort the peer-appraised hospitals. All analyses were performed using custom-made software. Ten benchmark hospitals were identified by DEA, but using the aggressive and benevolent formulations showed that two and four of them respectively were at the lower end of the maverick index list. On the other hand, only one 100% efficient (self-appraised) hospital was at the higher end of the list, using either formulation. Cluster analysis produced a hierarchical "tree" structure which dichotomized the hospitals in accordance to the cross-evaluation results, and provided insight on the two-dimensional path to improving efficiency. This is, to our awareness, the first study in the healthcare domain to employ both of these post-DEA techniques (cross efficiency and clustering) at the hospital (i.e. micro) level. The potential benefit for decision-makers is the capability to examine high and low "all-round" performers and maverick hospitals more closely, and identify and address problems typically overlooked by first stage DEA. PMID- 20703665 TI - Neural network diagnostic system for dengue patients risk classification. AB - With the dramatic increase of the worldwide threat of dengue disease, it has been very crucial to correctly diagnose the dengue patients in order to decrease the disease severity. However, it has been a great challenge for the physicians to identify the level of risk in dengue patients due to overlapping of the medical classification criteria. Therefore, this study aims to construct a noninvasive diagnostic system to assist the physicians for classifying the risk in dengue patients. Systematic producers have been followed to develop the system. Firstly, the assessment of the significant predictors associated with the level of risk in dengue patients was carried out utilizing the statistical analyses technique. Secondly, Multilayer perceptron neural network models trained via Levenberg Marquardt and Scaled Conjugate Gradient algorithms was employed for constructing the diagnostic system. Finally, precise tuning for the models' parameters was conducted in order to achieve the optimal performance. As a result, 9 noninvasive predictors were found to be significantly associated with the level of risk in dengue patients. By employing those predictors, 75% prediction accuracy has been achieved for classifying the risk in dengue patients using Scaled Conjugate Gradient algorithm while 70.7% prediction accuracy were achieved by using Levenberg-Marquardt algorithm. PMID- 20703666 TI - A novel handheld device for use in remote patient monitoring of heart failure patients--design and preliminary validation on healthy subjects. AB - Remote patient monitoring (RPM) holds great promise for reducing the burden of congestive heart failure (CHF). Improved sensor technology and effective predictive algorithms can anticipate sudden decompensation events. Enhanced telemonitoring systems would promote patient independence and facilitate communication between patients and their physicians. We report the development of a novel hand-held device, called Blue Box, capable of collecting and wirelessly transmitting key cardiac parameters derived from three integrated biosensors: 2 lead electrocardiogram (ECG), photoplethysmography and bioelectrical impedance (bioimpedance). Blue Box measurements include time intervals between consecutive ECG R-waves (RR interval), time duration of the ECG complex formed by the Q, R and S waves (QRS duration), bioimpedance, heart rate and systolic time intervals. In this study, we recruited 24 healthy subjects to collect several parameters measured by Blue Box and assess their value in correlating with cardiac output measured with Echo-Doppler. Linear correlation between the heart rate measured with Blue Box and cardiac output from Echo-Doppler had a group average correlation coefficient of 0.80. We found that systolic time intervals did not improve the model significantly. However, STIs did inversely correlate with increasing workloads. PMID- 20703667 TI - Experiences with a PDA-based documentation system in clinical research. AB - New clinical treatment concepts and the implementation of algorithms usually require extensive documentation for scientifical evaluation and quality assurance. A consequent electronic documentation approach potentially facilitates data integrity and availablity and decreases the amount of time spent with manual transfer from paper data into computer systems. The development and the components of the "Heidelberg PDA-based Clinical Documentation Suite" are described. This system allows electronic documentation and post-processing in a timely manner using an affordable standard Personal Digital Assistant (PDA). It features almost universal customizability to new documentation requirements and can be used with only minimal prior training. Initial experiences are reported and prospective improvement possibilities are discussed. PMID- 20703668 TI - Topic of special issue: distributed diagnosis and home healthcare. PMID- 20703669 TI - Selection of an optimal treatment method for acute periodontitis disease. AB - The present paper is devoted to selection of an optimal treatment method for acute periodontitis by using fuzzy Choquet integral-based approach. We consider application of different treatment methods depending on development stages and symptoms of the disease. The effectiveness of application of different treatment methods in each stage of the disease is linguistically evaluated by a dentist. The stages of the disease are also linguistically described by a dentist. Dentist's linguistic evaluations are represented by fuzzy sets. The total effectiveness of the each considered treatment method is calculated by using fuzzy Choquet integral with fuzzy number-valued integrand and fuzzy number-valued fuzzy measure. The most effective treatment method is determined by using fuzzy ranking method. PMID- 20703670 TI - A password-based user authentication scheme for the integrated EPR information system. AB - With the rapid development of the Internet, digitization and electronic orientation are required in various applications of our daily life. For e medicine, establishing Electronic patient records (EPRs) for all the patients has become the top issue during the last decade. Simultaneously, constructing an integrated EPR information system of all the patients is beneficial because it can provide medical institutions and the academia with most of the patients' information in details for them to make correct decisions and clinical decisions, to maintain and analyze patients' health. Also beneficial to doctors and scholars, the EPR system can give them record linkage for researches, payment audits, or other services bound to be developed and integrated into medicine. To tackle the illegal access and to prevent the information from theft during transmission over the insecure Internet, we propose a password-based user authentication scheme suitable for information integration. PMID- 20703671 TI - A decision support tool for health service re-design. AB - Many of the outpatient services are currently only available in hospitals, however there are plans to provide some of these services alongside with General Practitioners. Consequently, General Practitioners could soon be based at polyclinics. These changes have caused a number of concerns to Hounslow Primary Care Trust (PCT). For example, which of the outpatient services are to be shifted from the hospital to the polyclinic? What are the current and expected future demands for these services? To tackle some of these concerns, the first phase of this project explores the set of specialties that are frequently visited in a sequence (using sequential association rules). The second phase develops an Excel based spreadsheet tool to compute the current and expected future demands for the selected specialties. From the sequential association rule algorithm, endocrinology and ophthalmology were found to be highly associated (i.e. frequently visited in a sequence), which means that these two specialties could easily be shifted from the hospital environment to the polyclinic. We illustrated the Excel based spreadsheet tool for endocrinology and ophthalmology, however, the model is generic enough to cope with other specialties, provided that the data are available. PMID- 20703672 TI - Modeling and simulation of right ventricular volume measurement system during right heart catheterization. AB - Haemodynamic monitoring is necessary for the effective management of critically ill cardiac patients. Pulmonary artery catheterization has been used for monitoring the circulation, for measurement of intracardiac pressures and to estimate preload and afterload. However, pressures may not be accurate reflection of the circulation and simultaneous measurement of volumes would improve patient treatment. However, measurement of cardiac volumes especially of the right ventricle is difficult in everyday clinical practice In this work we propose the use of pulmonary artery catheter (PAC) with ultrasonic sensors built on it, to calculate the right ventricular end-diastolic (RVEDV) and end-systolic volume (RVESV). This is achieved by using the Ultrasonic (US) beam, to measure the distances between the transducers on the catheter and the RV walls. These distances, will be used as an input to a Volume calculating algorithm, which finally provides the RVEDV and RVESV, using a Neural Network (NN). For that reason, we have used cardiac Magnetic Resonance Imaging (MRI) and have modeled the catheter and the US transducers, to get as input the distances to the surface of the cavity. With these distances, and the known cardiac volumes (calculated using MR images) we trained and validated a NN for volume calculation. The results show that the algorithm accurately calculates the RVEDV. For the RVESV, greater deviations are observed between values calculated with our algorithm and cardiac MRI. PMID- 20703673 TI - Provider stakeholders' perceived benefit from a nascent health information exchange: a qualitative analysis. AB - We sought to better understand the perceived costs and benefits of joining a nascent health information exchange (HIE) from the perspective of potential provider organization participants. We therefore conducted semi-structured interviews with organizational representatives. Interview transcriptions were thematically coded, and coded text was subsequently aggregated to summarize the breadth and depth of responses. Although no respondents expected HIE to result in net financial benefit to their organization, all respondents recognized some potential benefits, and some respondents expected HIE to result in overall organizational benefit. Disproportionate benefit was expected for the poorest, sickest patients. Many respondents had concerns about HIE increasing the risk of data security breaches, and these concerns were most pronounced at larger organizations. We found little evidence of organizational concern regarding loss of patients to other organizations or publication of unfavorable quality data. If HIE's greatest benefactors are indeed the poorest, sickest patients, our current health care financing environment will make it difficult to align HIE costs with benefits. To sustain HIE, state and federal governments may need to consider ongoing subsidies. Furthermore, these governments will need to ensure that policies regulating data exchange have sufficient nationwide coordination and liability limitations that the perceived organizational risks of joining HIEs do not outweigh perceived benefits. HIE founders can address organizational concerns by attempting to coordinate HIE policies with those of their largest founding organizations, particularly for data security policies. Early HIE development and promotional efforts should not only focus on potential benefits, but should also address organizational concerns. PMID- 20703675 TI - An efficiency-based multicriteria strategic planning model for ambulatory surgery centers. AB - Ambulatory surgery centers (ASCs) provide a low-cost alternative to traditional inpatient care. In addition, with health care reform imminent, it is likely that many currently uninsured people will soon acquire health care coverage, significantly increasing the demand for health services. ASCs are among the providers that can expect to see a substantial amount of this new pent-up demand and, therefore, ASCs are likely to continue their current growth into the foreseeable future. Those ASCs that plan accordingly by optimizing procedure mix and volume will benefit most from the increased demand. We propose a two-stage efficiency-based multicriteria decision model to guide an ASC in identifying its optimal procedure mix. The first stage uses Data Envelopment Analysis (DEA) to calculate the efficiency of each procedure based on the resources required to perform the procedure, the revenue it generates, and its risk of complications. The second stage uses the DEA factor efficiency scores in a bottleneck program to optimize the mix of procedures while satisfying the ASC's resource and operational constraints. The criteria are to (1) maximize reimbursement while (2) minimizing the total number of complications. We demonstrate the approach using a data set based in part on data from an actual ASC. PMID- 20703674 TI - Technologies to better serve the millions of diabetic patients: a holistic, interactive and persuasive ICT model to facilitate self care, in extremely poor rural zones of Central America. AB - Health indicators express remarkable gaps between health systems at a world-wide level. Countries of the entire world are overflowed by the need of new strategies, methodologies and technologies to better serve the millions of patients, who demand better medical attention. The present archaic and ephemerally systematized systems widen the gap even more than the quality of medical services that should be provided for the millions of diabetic patients. It is therefore necessary to develop highly familiar environments with diabetic patients and their care needs. A Holistic, Interactive and Persuasive ICT model to facilitate self care of patients with diabetes (hIPAPD), is proposed as an innovative technological development in Panama to health optimized treatment for diabetic patients. Three health centers located in the District of Aguadulce, Province of Cocle, located on Panama's Pacific Coast, were selected to validate the model; the area presents extremely poor population, mostly with one daily meal, without any health insurance and with a high illiteracy rate. A series of experiences in the application and validation process are presented and analyzed in order to confirm the application, value and contribution of ICTs in health care in poor regions of Central America. PMID- 20703676 TI - The impact of non-discretionary factors on DEA and SFA technical efficiency differences. AB - The purpose of this study was to examine if factors of the external operating environment can explain differences in technical efficiency derived from Data Envelopment Analysis (DEA) and Stochastic Frontier Analysis (SFA). In a sample of 124 dialysis facilities, technical efficiency was compared according to ownership, region, years in operation and size. With second-stage Tobit regression, DEA and SFA efficiency was regressed against these environmental factors to determine their potential for predicting technical efficiency, as well as the efficiency differences between the two frontier methods. DEA expectedly generated lower mean efficiency scores than SFA (68.2% vs. 79.4%, P < 0.001), due to the "random effects" term computed by the latter, in addition to "true" inefficiency. This finding was consistent for the subgroups formed on the basis of the environmental factors. Half the variation in the DEA-SFA efficiency differences was explained by environmental factors. This suggests that in addition to market instabilities, luck, and other related phenomena, decision makers in their effort to determine optimal resource allocation, should point their attention to the potentially useful insight provided by environmental factors. PMID- 20703677 TI - Cost and performance: complements for improvement. AB - Activity-based costing (ABC) and Data Envelopment Analysis (DEA) share similar views of resource consumption in the production of outputs. While DEA has a high level focus typically using aggregated data in the form of inputs and outputs, ABC is more detailed and oriented around very disaggregated data. We use a case study of immunisation activities in 24 New Zealand primary care practices to illustrate how DEA and ABC can be used in conjunction to improve performance analysis and benchmarking. Results show that practice size, socio-economic environment, parts of the service delivery process as well as regular administrative tasks are major cost and performance drivers for general practices in immunisation activities. It is worth noting that initial analyses of the ABC results, using contextual information and conventional methods of analysis such as regression and correlations, did not result in any patterns of significance. Reorganising this information using the DEA efficiency scores has revealed trends that make sense to practitioners and provide insights into where to place efforts for improvement. PMID- 20703678 TI - Discovering blood donor arrival patterns using data mining: a method to investigate service quality at blood centers. AB - Blood centers without fixed appointments for collecting blood often experience nonconstant donor arrival rates, which vary due to time-of-day, day-of-week, etc. When a constant workforce size is employed in such blood centers, there is either idle personnel, or donor satisfaction is compromised due to long waiting times, or both conditions alternate over time. Consequently, a method to obtain adaptive workforce requirements might be valuable. This study utilized the Two-Step Cluster method and the Classification and Regression Trees method in succession to identify both daily and hourly donor arrival patterns at Hacettepe University Hospitals' Blood Center. A serial queuing network model of the donation process was then employed for each of the identified donor arrival patterns. By considering and accommodating variations in the donor arrival patterns, required workforce sizes and their decomposition among process steps were predicted to achieve predetermined target values of expected waiting times and to balance workforce utilizations in the blood donation processes. Although a blood center is considered for the proposed methodology, the approach is general and applications in various operations of healthcare organizations are possible. PMID- 20703679 TI - Diagnosing breast masses in digital mammography using feature selection and ensemble methods. AB - Methods that can accurately predict breast cancer are greatly needed and good prediction techniques can help to predict breast cancer more accurately. In this study, we used two feature selection methods, forward selection (FS) and backward selection (BS), to remove irrelevant features for improving the results of breast cancer prediction. The results show that feature reduction is useful for improving the predictive accuracy and density is irrelevant feature in the dataset where the data had been identified on full field digital mammograms collected at the Institute of Radiology of the University of Erlangen-Nuremberg between 2003 and 2006. In addition, decision tree (DT), support vector machine sequential minimal optimization (SVM-SMO) and their ensembles were applied to solve the breast cancer diagnostic problem in an attempt to predict results with better performance. The results demonstrate that ensemble classifiers are more accurate than a single classifier. PMID- 20703680 TI - The effect of an auxiliary stimulation on motor function restoration by FES. AB - Functional Electrical Stimulation (FES) is a technology to generate neural activity in an artificial way to activate muscles. However, as reported by some researchers, the human responses to FES are likely to be affected by several factors, such as spasticity, muscle fatigue, nerve habituation and so forth. Consequently, the function restoration by FES is neither durable, nor stable. In order to realize long-term and stable FES assistance, this study investigated whether and why an Auxiliary Stimulation (AS) to the Gastrocnemius, with current frequency ranged from 2000 to 6000 Hz, could alleviate the symptom of spasticity and muscle fatigue caused by the stimulation to the Tibialis Anterior. We have developed a portable auxiliary stimulator, and performed experiments to verify its effectiveness. The results showed that our approach enabled comparatively stable and durable function restoration assistance. Moreover, for understanding underlying neuromuscular processes elicited by the AS and its qualitative nature, this study also measured the Hoffmann-reflex (H-reflex) in soleus muscle before and after the AS, to interpret the effect of the Auxiliary Stimulation. PMID- 20703681 TI - Estimating the mutual information between bilateral breast in thermograms using nonparametric windows. AB - Comparison between contra lateral breast images is one of the effective methods in breast cancer detection. Asymmetric temperature distribution can be an indicator of abnormality. The mutual information is a good measure of nonlinear correlation. It is a measure that captures linear and nonlinear dependencies, without requiring the specification of any kind of model of dependence. Therefore, it is suitable for our abnormality indicator. Although nonparametric windows is a numerically expensive technique but it is accurate. The reason is that nonparametric windows incorporate an interpolation model which enhances the resolution to a highly oversampled image. For our purposes we worked with sixty simulated breast thermal images. It is shown that the more similar the thermal image of right breast to the thermal image of left breast, the closer the normalized mutual information value to one. PMID- 20703682 TI - Post-operative assessment of an implant fixation in anterior cruciate ligament reconstructive surgery. AB - The objective of this paper is to numerically simulate the behaviour of an anterior cruciate ligament (ACL) reconstructed knee using interference screw fixation under a single cycle loading or a cyclic loading test and to compare the numerical results with experimental tests using porcine samples of knee joint. A hyper-elastic material model was used to model the tendon graft and evaluate its elongation during continuous and cyclic tensile loading. The rigidity of the interference screw fixation was also examined using the finite element based numerical model. The finite element model uses the benefit of an anatomical 3D geometry of the tibial bone and tendon graft which was created from a CT scan of a patient. PMID- 20703683 TI - Development of a telecare system based on ZigBee mesh network for monitoring blood pressure of patients with hemodialysis in health care centers. AB - In Taiwan, the number of the patients needing dialysis increases rapidly in recent years. Because there is risk in every hemodialysis session, monitoring physiological status, such as blood pressure measurement every 30 min to 1 h is needed during about 4 h hemodialysis process. Therefore, an assisted measurement on blood pressure is needful in dialysis care centers. Telecare system (TCS) is regarded as one of important technique in the medical care. In this study, we utilized ZigBee wireless technique to establish a mesh network for monitoring blood pressure automatically and data storage in medical record system for display and further analysis. Moreover, while the blood pressure exceeds the normal range, the system could send a warning signal to remind, or inform the relatives and clinicians in health care center through the personal handy-phone system (PHS) immediately. The proposed system provides an assisted device for monitoring patients' blood pressure during hemodialysis process and saving medical manpower. PMID- 20703684 TI - Evaluating cluster preservation in frequent itemset integration for distributed databases. AB - Medical sciences are rapidly emerging as a data rich discipline where the amount of databases and their dimensionality increases exponentially with time. Data integration algorithms often rely upon discovering embedded, useful, and novel relationships between feature attributes that describe the data. Such algorithms require data integration prior to knowledge discovery, which can lack the timeliness, scalability, robustness, and reliability of discovered knowledge. Knowledge integration algorithms offer pattern discovery on segmented and distributed databases but require sophisticated methods for pattern merging and evaluating integration quality. We propose a unique computational framework for discovering and integrating frequent sets of features from distributed databases and then exploiting them for unsupervised learning from the integrated space. Assorted indices of cluster quality are used to assess the accuracy of knowledge merging. The approach preserves significant cluster quality under various cluster distributions and noise conditions. Exhaustive experimentation is performed to further evaluate the scalability and robustness of the proposed methodology. PMID- 20703685 TI - Probabilistic information structure of human walking. AB - Recently, the area of healthcare has been tremendously benefited from the advent of high performance computing in improving quality of life. Different processing techniques have been developed to understand the hidden complexity of the time series and will help clinicians in diagnosis and treatment. Analysis of human walking helps to study the various pathological conditions affecting balance and the elderly. In an elderly subjects, falls and paralysis are major problems, in terms of both frequency and consequences. Correct postural balance is important to well being and its effects will be felt in every movement and activity. In this paper, Bayesian Network (BN) was applied to recorded muscle activities and joint motions during walking, to extract causal information structure of normal walking and different impaired walking. The aim of this study is to use different BNs to express normal walking and various impaired walking, and identify the most important causal pairs that characterize specific impaired walking, through comparing the BNs for different walking. PMID- 20703686 TI - Accurate automated detection of autism related corpus callosum abnormalities. AB - The importance of accurate early diagnostics of autism that severely affects personal behavior and communication skills cannot be overstated. Neuropathological studies have revealed an abnormal anatomy of the Corpus Callosum (CC) in autistic brains. We propose a new approach to quantitative analysis of three-dimensional (3D) magnetic resonance images (MRI) of the brain that ensures a more accurate quantification of anatomical differences between the CC of autistic and normal subjects. It consists of three main processing steps: (i) segmenting the CC from a given 3D MRI using the learned CC shape and visual appearance; (ii) extracting a centerline of the CC; and (iii) cylindrical mapping of the CC surface for its comparative analysis. Our experiments revealed significant differences (at the 95% confidence level) between 17 normal and 17 autistic subjects in four anatomical divisions, i.e. splenium, rostrum, genu and body of their CCs. PMID- 20703687 TI - Unbiased group-wise image registration: applications in brain fiber tract atlas construction and functional connectivity analysis. AB - We propose an unbiased implicit-reference group-wise (IRG) image registration method and demonstrate its applications in the construction of a brain white matter fiber tract atlas and the analysis of resting-state functional MRI (fMRI) connectivity. Most image registration techniques pair-wise align images to a selected reference image and group analyses are performed in the reference space, which may produce bias. The proposed method jointly estimates transformations, with an elastic deformation model, registering all images to an implicit reference corresponding to the group average. The unbiased registration is applied to build a fiber tract atlas by registering a group of diffusion tensor images. Compared to reference-based registration, the IRG registration improves the fiber track overlap within the group. After applying the method in the fMRI connectivity analysis, results suggest a general improvement in functional connectivity maps at a group level in terms of larger cluster size and higher average t-scores. PMID- 20703688 TI - A hand-held mosaicked multispectral imaging device for early stage pressure ulcer detection. AB - The use of a custom filter mosaic overlaying a CMOS/CCD sensor represents a novel idea to multispectral imaging. The innovation provides simple, miniaturized, low cost instrumentation that has many potential biological applications which require a hand-held detector. This makes it extremely adaptable and can serve as an integrated component to distributed diagnosis and home healthcare (D2H2). A mosaicked sensor is a monolithic array of many sensors, arranged in a geometric pattern with each sensor covered by an optical filter sensitive to a specified wavelength. In this way, only one spectral component is sensed at each pixel and the other spectral components must be estimated from neighbors. Although with great potential, one challenge faced by this device, however, is the reconstruction of the high-resolution full-spectral image from the low-resolution input. Due to the physical limitations in fabrication and the usage of the multispectral filter mosaic, two types of degradations exist, including filter misalignment and the missing spectral components, that must be corrected using intelligent algorithms to take full advantage of the hardware capability of the device. In this paper, we first describe a custom geometric correction method to restore the image from the misalignment distortion. We then present a binary tree based generic demosaicking algorithm to efficiently estimate the missing special components and reconstruct a high-resolution full-spectral image. We choose early detection of pressure ulcer as a targeting area as early stage pressure ulcers and other subcutaneous lesions are nearly invisible in clinical settings, particularly so for dark pigmented skin. We show how the geometric correction and demosaicking algorithms successfully reconstruct a full-spectral image from which apparent contrast enhancement between damaged skin and the normal skin is observed. PMID- 20703689 TI - Inter-greedy technique for fusion of different segmentation strategies leading to high-performance carotid IMT measurement in ultrasound images. AB - User-based estimation of intima-media thickness (IMT) of carotid arteries leads to subjectivity in its decision support systems, while being used as a cardiovascular risk marker. During automated computer-based decision support, we had developed segmentation strategies that follow three main courses of our contributions: (a) signal processing approach combined with snakes and fuzzy K means (CULEXsa), (b) integrated approach based on seed and line detection followed by probability based connectivity and classification (CALEXsa), and (c) morphological approach with watershed transform and fitting (WS). These grayscale segmentation algorithms yielding carotid wall boundaries has certain bias along with their own merits. We recently developed a fusion technique that was helpful in removing bias which combines two carotid wall boundaries using ground truth as an ideal marker. Here we have extended this fusion concept by taking merits of these multiple boundaries, so called, Inter-Greedy (IG) approach. Further we estimate IMT from these fused boundaries from multiple sources. Starting from the technique with the overall least system error (the snake-based one), we iteratively swapped the vertices of the profiles until we minimized its overall distance with respect to ground truth. The fusion boundary was the Inter-Greedy boundary. We used the polyline distance metric for performance evaluation and error minimization. We ran the segmentation protocol over the database of 200 carotid longitudinal B-mode ultrasound images and compared the performance of all the four techniques (CALEXia, CULEXsa, WS, IG). The mean error of Inter-Greedy technique yielded 0.32 +/- 0.44 pixel (20.0 +/- 27.5 um) for the LI boundary (a 33.3% +/- 5.6% improvement over initial best performing technique) and 0.21 +/- 0.34 pixel (13.1 +/- 21.3 um) for MA boundary (a 32.3% +/- 6.7% improvement). IMT measurement error for Greedy method was 0.74 +/- 0.75 pixel (46.3 +/- 46.9 um), a 43.5% +/- 2.4% improvement. PMID- 20703691 TI - Relationship between measurement site and motion artifacts in wearable reflected photoplethysmography. AB - Pulse rates obtained from wearable photoplethysmography (PPG) sensors are important for monitoring cardiovascular condition, especially during exercise. However, it is difficult to precisely count pulse rates during exercise because PPG is sensitive to body movement. The artifacts from body movement are caused by a change in the blood volume at the measurement site, in addition to pulsatile changes. Here, we investigated the influence of motion artifact with respect to light source and anatomical sites. In this study, we compared the signal from green-light PPG to that from infrared PPG at different anatomical sites. In these experiments, 11 subjects were asked to either assume a resting position or generate spontaneous motion artifact by jumping and swinging their arm. As a result, pulse rates obtained from green-light PPG showed a higher correlation with the ECG R-R interval as compared to those obtained with infrared. Additionally, the signal from the upper arm showed less artifact than did the peripheral one. Therefore, the green-light PPG may be useful for pulse rate monitoring. PMID- 20703690 TI - The advantages of wearable green reflected photoplethysmography. AB - This report evaluates the efficacy of reflected-type green light photoplethysmography (green light PPG). Transmitted infrared light was used for PPG and the arterial pulse was monitored transcutaneously. The reflected PPG signal contains AC components based on the heartbeat-related signal from the arterial blood flow and DC components, which include reflectance and scattering from tissue. Generally, changes in AC components are monitored, but the DC components play an important role during heat stress. In this study, we compared the signal of green light PPG to infrared PPG and ECG during heat stress. The wavelengths of the green and infrared light were 525 nm and 880 nm, respectively. Experiments were performed on young healthy subjects in cold (10 degrees C), hot (45 degrees C), and normal environments. The pulse rates were compared among three measurement devices and the AC and DC components of the PPG signal were evaluated during heat stress. The pulse rates obtained from green light PPG were strongly correlated with the R-R interval of an electrocardiogram in all environments, but those obtained from infrared light PPG displayed a weaker correlation with cold exposure. The AC components were of similar signal output for both wavelengths during heat stress. Also, the DC components for green light PPG were similar during heat stress, but showed less signal output for infrared light PPG during hot exposure. The main reason for the reduced DC components was speculated to be the increased blood flow at the vascular bed. Therefore, reflected green light PPG can be useful for pulse rate monitoring because it is less influenced by the tissue and vein region. PMID- 20703692 TI - Human cardiovascular model and applications. AB - Cardiovascular diseases (CVDs) can be known as a class of diseases which affect different parts of the cardiovascular system such as the heart or blood vessels. Hemodynamic signals are an important tool used by doctors to diagnose the type of CVD occurred in a patient. Diagnosing the correct type of CVD in a patient early will allow the patient to have the suitable medical treatment. Some examples of CVDs include coronary heart disease, cerebrovascular disease and peripheral arterial disease. A human cardiovascular model is developed in order to simulate different hemodynamic signals of the cardiovascular system. The hemodynamic signals include the blood pressures, flow rates and volumes in various part of the cardiovascular system. This paper presents a model which is able to simulate hemodynamic signals and they are able to represent the human arterial blood pressure accurately. Hence this model can also be used to simulate hypertensive patients in order to design control systems for regulation of blood pressure. Signal verification has been performed and the stability of the model is being investigated. Applications of the human cardiovascular model are also presented. PMID- 20703693 TI - Thermal shock resistance of skin tissue. AB - Understanding the mechanisms of skin behavior under thermal shock is crucial for medical treatments. However, no reasonable criteria are available for the maximum thermal loadings that skin tissue can survive. To address this, in this paper we analyzed thermal and neural behaviors of skin tissue exposed to thermal loadings by introducing the thermal shock resistance (a parameter widely used for engineering materials) of skin for the first time. Skin thermal shock resistance was analyzed according to two distinct criteria: (1) maximum local temperature at epidermis-dermis (ED) interface defined as the thermal threshold of skin thermal pain; (2) maximum thermal damage at ED interface defined as the first degree burn where irreversible skin damage occurs. Numerical simulation was performed and the results show that the thermal shock resistance of skin tissue depends on the Biot number (which characterizes the features of thermal shock). These results indicate that skin thermal shock resistance can be used as an efficient tool to predict thermal damage (e.g., burn) and the corresponding pain level induced by noxious thermal loadings (e.g., clinical thermal treatments). PMID- 20703694 TI - Direct numerical simulation of single leukocyte deformation in microchannel flow for disease diagnosis. AB - To better understand the physical mechanism of leukocyte separation via microfluidics, a level set method was employed to analyze the coupled deformation flow of individual leukocytes in microfluidic parabolic shear blood flow. The results show that: (1) Weber number and viscosity ratio have great effects on the deformation of single leukocyte, (2) difference between the deformation and motion behavior of different subtypes of leukocytes (i.e., granulocytes, lymphocytes, monocytes) was observed, and (3) the existence of a second leukocyte significantly changes the leukocyte deformation and motion. These results shed light on the understanding of the motion and deformation of leukocytes in microchannel flow and provide a theoretical foundation for separating lymphocytes via microfluidics. PMID- 20703695 TI - An intelligent healthcare management system: a new approach in work-order prioritization for medical equipment maintenance requests. AB - The effective maintenance management of medical technology influences the quality of care delivered and the profitability of healthcare facilities. Medical equipment maintenance in Jordan lacks an objective prioritization system; consequently, the system is not sensitive to the impact of equipment downtime on patient morbidity and mortality. The current work presents a novel software system (EQUIMEDCOMP) that is designed to achieve valuable improvements in the maintenance management of medical technology. This work-order prioritization model sorts medical maintenance requests by calculating a priority index for each request. Model performance was assessed by utilizing maintenance requests from several Jordanian hospitals. The system proved highly efficient in minimizing equipment downtime based on healthcare delivery capacity, and, consequently, patient outcome. Additionally, a preventive maintenance optimization module and an equipment quality control system are incorporated. The system is, therefore, expected to improve the reliability of medical equipment and significantly improve safety and cost-efficiency. PMID- 20703696 TI - A biomedical decision support system using LS-SVM classifier with an efficient and new parameter regularization procedure for diagnosis of heart valve diseases. AB - Classification success of Support Vector Machine (SVM) depends on the characteristic of given data set and some training parameters (C and sigma). In literature, a few studies have been presented for regularization of these parameters which affects classification performance directly. This study proposes a new approach based on Renyi's entropy and Logistic regression methods for parameter regularization. Our regularization procedure runs at two steps. In the first step, optimal value of kernel parameter interval is found via Renyi's entropy method and optimal C value is found via logistic regression using exponential function in the next step. In addition to, this new decision support system is applied to biomedical research area via an application related to Doppler Heart Sounds (DHS). Experimental results show the efficiency of developed regularization procedure. PMID- 20703697 TI - Queueing for healthcare. AB - Patient queues are prevalent in healthcare and wait time is one measure of access to care. We illustrate Queueing Theory-an analytical tool that has provided many insights to service providers when designing new service systems and managing existing ones. This established theory helps us to quantify the appropriate service capacity to meet the patient demand, balancing system utilization and the patient's wait time. It considers four key factors that affect the patient's wait time: average patient demand, average service rate and the variation in both. We illustrate four basic insights that will be useful for managers and doctors who manage healthcare delivery systems, at hospital or department level. Two examples from local hospitals are shown where we have used queueing models to estimate the service capacity and analyze the impact of capacity configurations, while considering the inherent variation in healthcare. PMID- 20703698 TI - Detection of carotid artery disease by using Learning Vector Quantization Neural Network. AB - Doppler ultrasound has been usually preferred for investigation of the artery conditions in the last two decades, because it is a non-invasive, easy to apply and reliable technique. In this study, a biomedical system based on Learning Vector Quantization Neural Network (LVQ NN) has been developed in order to classify the internal carotid artery Doppler signals obtained from the 191 subjects, 136 of them had suffered from internal carotid artery stenosis and rest of them had been healthy subject. The system is composed of feature extraction and classification parts, basically. In the feature extraction stage, power spectral density (PSD) estimates of internal carotid artery Doppler signals were obtained by using Burg autoregressive (AR) spectrum analysis technique in order to obtain medical information. In the classification stage, LVQ NN was used classify features from Burg AR method. In experiments, LVQ NN based method reached 97.91% classification accuracy with 5 fold Cross Validation (CV) technique. In addition, the classification performance of the LVQ NN was compared with some methods such as Multi Layer Perceptron (MLP) NN, Naive Bayes (NB), K Nearest Neighbor (KNN), decision tree and Support Vector Machine (SVM) with sensitivity and specificity statistical parameters. The classification results showed that the LVQ NN method is effective for classification of internal carotid artery Doppler signals. PMID- 20703699 TI - Mobile telemedicine: a survey study. AB - Telemedicine involves the use of advanced and reliable communication techniques to deliver biomedical signals over long distances. In such systems, biomedical information is transmitted using wireline or wireless communication systems. Mobile telemedicine is an improved form of telemedicine, in which advanced wireless communication systems are used to deliver the biomedical signals of patients at any place and any time. Mobile telemedicine employs advanced concepts and techniques from the fields of electrical engineering, computer science, biomedical engineering, and medicine to overcome the restrictions involved in conventional telemedicine and realize an improvement in the quality of service of medicine. In this paper, we study several mobile telemedicine systems, and it is important to gain a good understanding of mobile telemedicine systems because in the further, such systems are expected to become ubiquitous for the delivery of biomedical signals for medicine. PMID- 20703700 TI - A new method for 3D thinning of hybrid shaped porous media using artificial intelligence. Application to trabecular bone. AB - Curve and surface thinning are widely-used skeletonization techniques for modeling objects in three dimensions. In the case of disordered porous media analysis, however, neither is really efficient since the internal geometry of the object is usually composed of both rod and plate shapes. This paper presents an alternative to compute a hybrid shape-dependent skeleton and its application to porous media. The resulting skeleton combines 2D surfaces and 1D curves to represent respectively the plate-shaped and rod-shaped parts of the object. For this purpose, a new technique based on neural networks is proposed: cascade combinations of complex wavelet transform (CWT) and complex-valued artificial neural network (CVANN). The ability of the skeleton to characterize hybrid shaped porous media is demonstrated on a trabecular bone sample. Results show that the proposed method achieves high accuracy rates about 99.78%-99.97%. Especially, CWT (2nd level)-CVANN structure converges to optimum results as high accuracy rate minimum time consumption. PMID- 20703701 TI - A mathematical programming model for scheduling of nurses' labor shifts. AB - In this study, a mathematical programming model is proposed for scheduling problem of nurses' labor shifts. The developed mathematical programming model's aim is to minimize nurses' total idle waiting time during a week planning horizon. In this model, investigated constraints are as follows: (1) Maximum total working time a week for each nurse must not be exceeded. (2) After a nurse works a shift, the nurse can be assigned to another shift after two shifts at least. This constraints-set ensures resting of the nurse after the nurse works a shift. (3) Total number of nurses worked for each shift must be controlled with maximum and minimum bounds given for number of nurses for each shift. In this manner, total number of nurses worked for each shift is between maximum and minimum limit-values given for each shift. This constraint ensures flexibility to the user to determine number of nurses for each shift. (4) The decision variable that shows nurse-shift assignment pairs is 0 or 1. In this study, maximum total working time a week for a nurse, total number of nurses in a health service, maximum and minimum numbers of nurses worked a shift are user-specified parameters. In this way, this model can be adapted for the studies with different values of these parameters. In this study, the developed model is illustrated using a numerical example and then LINGO8.0 software is used to ensure the global optimum solution of the developed model. Results and also sensitivity analysis carried out for this example are presented in the study. PMID- 20703702 TI - A novel strategy for load balancing of distributed medical applications. AB - Current trends in medicine, specifically in the electronic handling of medical applications, ranging from digital imaging, paperless hospital administration and electronic medical records, telemedicine, to computer-aided diagnosis, creates a burden on the network. Distributed Service Architectures, such as Intelligent Network (IN), Telecommunication Information Networking Architecture (TINA) and Open Service Access (OSA), are able to meet this new challenge. Distribution enables computational tasks to be spread among multiple processors; hence, performance is an important issue. This paper proposes a novel approach in load balancing, the Random Sender Initiated Algorithm, for distribution of tasks among several nodes sharing the same computational object (CO) instances in Distributed Service Architectures. Simulations illustrate that the proposed algorithm produces better network performance than the benchmark load balancing algorithms the Random Node Selection Algorithm and the Shortest Queue Algorithm, especially under medium and heavily loaded conditions. PMID- 20703703 TI - Information extraction approaches to unconventional data sources for "Injury Surveillance System": the case of newspapers clippings. AB - Injury Surveillance Systems based on traditional hospital records or clinical data have the advantage of being a well established, highly reliable source of information for making an active surveillance on specific injuries, like choking in children. However, they suffer the drawback of delays in making data available to the analysis, due to inefficiencies in data collection procedures. In this sense, the integration of clinical based registries with unconventional data sources like newspaper articles has the advantage of making the system more useful for early alerting. Usage of such sources is difficult since information is only available in the form of free natural-language documents rather than structured databases as required by traditional data mining techniques. Information Extraction (IE) addresses the problem of transforming a corpus of textual documents into a more structured database. In this paper, on a corpora of Italian newspapers articles related to choking in children due to ingestion/inhalation of foreign body we compared the performance of three IE algorithms- (a) a classical rule based system which requires a manual annotation of the rules; (ii) a rule based system which allows for the automatic building of rules; (b) a machine learning method based on Support Vector Machine. Although some useful indications are extracted from the newspaper clippings, this approach is at the time far from being routinely implemented for injury surveillance purposes. PMID- 20703705 TI - E-portfolio competency metadata: pilot study for a call to action. AB - The six competency domains required by the Accreditation Council for Graduate Medical Education (ACGME) have led to a proliferation of measurement tools, assessment methods, and all forms of data from paper to electronic. The need exists to develop a standardized electronic (e)-portfolio to provide the aggregate data to improve education and patient care. This process requires a sound methodology using XML metadata to allow portability of e-portfolio data. We surveyed publicly available metadata and developed an e-portfolio system for the Henry Ford Hospital General Surgery Residency Program. Based on our implementation of e-portfolios for 70 physicians, we call upon the ACGME, the Residency Review Committees, and the American Board of Medical Specialties to establish a method to formalize and develop a standard for residency competency metadata. Using an approach similar to that of our study can streamline data and lead to improved medical education and ultimately better patient care. PMID- 20703704 TI - AMI screening using linguistic fuzzy rules. AB - This paper aims at identifying the factors that would help to diagnose acute myocardial infarction (AMI) using data from an electronic medical record system (EMR) and then generating structure decisions in the form of linguistic fuzzy rules to help predict and understand the outcome of the diagnosis. Since there is a tradeoff in the fuzzy system between the accuracy which measures the capability of the system to predict the diagnosis of AMI and transparency which reflects its ability to describe the symptoms-diagnosis relation in an understandable way, the proposed fuzzy rules are designed in a such a way to find an appropriate balance between these two conflicting modeling objectives using multi-objective genetic algorithms. The main advantage of the generated linguistic fuzzy rules is their ability to describe the relation between the symptoms and the outcome of the diagnosis in an understandable way, close to human thinking and this feature may help doctors to understand the decision process of the fuzzy rules. PMID- 20703706 TI - Control of sevoflurane anesthetic agent via neural network using electroencephalogram signals during anesthesia. AB - In this study, power spectrum of the EEG data and the heartbeat data obtained from 250 patients has been applied to the designed Neural network system. A backpropagation artificial neural network has been developed which contains 53 nodes in the input layer, 27 nodes in the hidden and 1 node in the output layer. In the artificial neural network inputs, the power spectral density values corresponding 1-50 Hz frequency interval of the EEG slices which has 10 seconds of time interval, the ratio of the total of the PSD values of current EEG slice to the total PSD values of EEG slice of pre-anesthesia, the ratio of the total PSD values of the EEG data to the total PSD values of the previous EEG data, and the previous anaesthetic gas ratio values have been applied and the network has been educated. The designed neural network system has been tested by using 10 data set obtained from 4 different patients. In the anesthetic gas prediction according to the anesthesia level, successful results have been obtained with the designed system. The system has been able to correctly purposeful responses in average accuracy of 94% of the cases. This method is also computationally fast and acceptable real-time clinical performance has been obtained. PMID- 20703708 TI - Patient safety through RFID: vulnerabilities in recently proposed grouping protocols. AB - As RFID-tagged systems become ubiquitous, acceptance of this technology by the general public necessitates addressing related security/privacy issues. The past eight years have seen an increasing number of publications in this direction, specifically using cryptographic approaches. Recently, the Journal of Medical Systems published two papers addressing security/privacy issues through cryptographic protocols. We consider the proposed protocols and identify some existing vulnerabilities. PMID- 20703707 TI - A user-centered, object-oriented methodology for developing Health Information Systems: a Clinical Information System (CIS) example. AB - The aim of this study is to present our perspectives on healthcare analysis and design and the lessons learned from our experience with the development of a distributed, object-oriented Clinical Information System (CIS). In order to overcome known issues regarding development, implementation and finally acceptance of a CIS by the physicians we decided to develop a novel object oriented methodology by integrating usability principles and techniques in a simplified version of a well established software engineering process (SEP), the Unified Process (UP). A multilayer architecture has been defined and implemented with the use of a vendor application framework. Our first experiences from a pilot implementation of our CIS are positive. This approach allowed us to gain a socio-technical understanding of the domain and enabled us to identify all the important factors that define both the structure and the behavior of a Health Information System. PMID- 20703709 TI - Prediction of surgery times and scheduling of operation theaters in ophthalmology department. AB - This paper presents the framework for forecasting the surgery time by taking into account the surgical environment in an ophthalmology department (experience of surgeon in years, experience of anesthetist in years, staff experience in years, type of anesthesia etc.). The estimation of surgery times is done using three techniques, such as the Adaptive Neuro Fuzzy Inference Systems (ANFIS), Artificial Neural Networks (ANN) and Multiple Linear Regression Analysis (MLRA) and the results of estimation accuracy were compared. Though the developed framework is general, it is illustrated for three ophthalmologic surgeries such as the cataract surgery, corneal transplant surgery and Oculoplastic surgery. The framework is validated by using data obtained from a local hospital. It is hypothesized that by accurately knowing the surgery times, one can schedule the operations optimally resulting in the efficient utilization of the operating rooms. This increase in the efficiency is demonstrated through computer simulations of the operating theater. PMID- 20703710 TI - Usage of case-based reasoning, neural network and adaptive neuro-fuzzy inference system classification techniques in breast cancer dataset classification diagnosis. AB - Breast cancer is a common to females worldwide. Today, technological advancements in cancer treatment innovations have increased the survival rates. Many theoretical and experimental studies have shown that a multiple classifier system is an effective technique for reducing prediction errors. This study compared the particle swarm optimizer (PSO) based artificial neural network (ANN), the adaptive neuro-fuzzy inference system (ANFIS), and a case-based reasoning (CBR) classifier with a logistic regression model and decision tree model. It also applied three classification techniques to the Mammographic Mass Data Set, and measured its improvements in accuracy and classification errors. The experimental results showed that, the best CBR-based classification accuracy is 83.60%, and the classification accuracies of the PSO-based ANN classifier and ANFIS are 91.10% and 92.80%, respectively. PMID- 20703711 TI - Forward secure digital signature for electronic medical records. AB - The Technology Safeguard in Health Insurance Portability and Accountability Act (HIPAA) Title II has addressed a way to maintain the integrity and non repudiation of Electronic Medical Record (EMR). One of the important cryptographic technologies is mentioned in the ACT is digital signature; however, the ordinary digital signature (e.g. DSA, RSA, GQ...) has an inherent weakness: if the key (certificate) is updated, than all signatures, even the ones generated before the update, are no longer trustworthy. Unfortunately, the current most frequently used digital signature schemes are categorized into the ordinary digital signature scheme; therefore, the objective of this paper is to analyze the shortcoming of using ordinary digital signatures in EMR and to propose a method to use forward secure digital signature to sign EMR to ensure that the past EMR signatures remain trustworthy while the key (certificate) is updated. PMID- 20703712 TI - Automatic home medical product recommendation. AB - Web-based personal health records (PHRs) are being widely deployed. To improve PHR's capability and usability, we proposed the concept of intelligent PHR (iPHR). In this paper, we use automatic home medical product recommendation as a concrete application to demonstrate the benefits of introducing intelligence into PHRs. In this new application domain, we develop several techniques to address the emerging challenges. Our approach uses treatment knowledge and nursing knowledge, and extends the language modeling method to (1) construct a topic selection input interface for recommending home medical products, (2) produce a global ranking of Web pages retrieved by multiple queries, and (3) provide diverse search results. We demonstrate the effectiveness of our techniques using USMLE medical exam cases. PMID- 20703713 TI - A review of the personal health records in selected countries and Iran. AB - Personal Health Record (PHR) enables patients to access their health information and improves care quality by supporting self-care. The purpose of this study is to provide a comparative analysis of the concept of PHRs in selected countries and Iran in order to investigate the gaps between Iran and more advanced countries in terms of PHRs. The study was carried out in 2008-2009 using a descriptive-comparative method in Australia, the United States, England and Iran. Data was gathered from articles, books, journals and reputed websites in English and Persian published between 1995 and September 2009. After collecting the data, both advantages and disadvantages of each of concepts were analyzed. In the three countries considered in the present study the concepts of PHR, extracted from the literature, are that; a)patient/person be recognized as the owner of PHR; b)information be disclosed only to those authorized by the patient; c) and that PHR is created upon request and consent of the individual involved. Before PHRs can be profitably used in the health administration of a (developing) country, the necessary knowledge, infrastructures, and rules need to be developed. PMID- 20703714 TI - Employment and comparison of different Artificial Neural Networks for epilepsy diagnosis from EEG signals. AB - In this study, it has been intended to analyze Electroencephalography (EEG) signals by Wavelet Transform (WT) for diagnosis of epilepsy, to employ various Artificial Neural Networks (ANNs) for the signals' automatic classification. Furthermore, carrying out a performance comparison has been aimed. Three EEG signals have been decomposed into frequency sub bands by WT and the feature vectors have been extracted from these sub bands. In order to reduce the sizes of the extracted feature vectors, Principal Component Analysis (PCA) method has been applied when necessary and these feature vectors have been classified by five different ANNs as either epileptic or healthy. The performance evaluation has been carried out by conducting ROC analysis for the used ANN models that and their comparisons have also been included. PMID- 20703715 TI - Design and implementation of web-based discharge summary note based on service oriented architecture. AB - Discharge summary note is one of the essential clinical data in medical records, and it concisely capsules a patient's status during hospitalization. In the article, we adopt web-based architecture in developing a new discharge summary system for the Healthcare Information System of National Taiwan University Hospital, to improve the traditional client/sever architecture. The article elaborates the design approaches and implementation illustrations in detail, including patients' summary query and searching, model and phrase quoted, summary check list, major editing blocks as well as other functionalities. The system has been on-line and achieves successfully since October 2009. PMID- 20703716 TI - Improved fuzzy clustering algorithms in segmentation of DC-enhanced breast MRI. AB - Segmentation of medical images is a difficult and challenging problem due to poor image contrast and artifacts that result in missing or diffuse organ/tissue boundaries. Many researchers have applied various techniques however fuzzy c means (FCM) based algorithms is more effective compared to other methods. The objective of this work is to develop some robust fuzzy clustering segmentation systems for effective segmentation of DCE - breast MRI. This paper obtains the robust fuzzy clustering algorithms by incorporating kernel methods, penalty terms, tolerance of the neighborhood attraction, additional entropy term and fuzzy parameters. The initial centers are obtained using initialization algorithm to reduce the computation complexity and running time of proposed algorithms. Experimental works on breast images show that the proposed algorithms are effective to improve the similarity measurement, to handle large amount of noise, to have better results in dealing the data corrupted by noise, and other artifacts. The clustering results of proposed methods are validated using Silhouette Method. PMID- 20703717 TI - Graph-cut energy minimization for object extraction in MRCP medical images. AB - Bile duct identification and extraction in magnetic resonance cholangiopancreatography (MRCP) images, is a necessary step in the development of computer-aided diagnosis systems using such images. MRCP is becoming the de facto modality in the diagnosis of biliary diseases and even in the pre-surgical workup for liver transplants. The energy minimization graph-cut method is a proven technique in the extraction of objects in natural images, and even used in 3D reconstruction. This paper proposes several versions of the graph-cut approach for the extraction of the biliary structures in MRCP images. The schemes include a fully interactive lazy snapping method, a manual point selection method for minimal user interaction and an automated phase unwrapping via max flows (PUMA) implementation. The performance of the algorithms vary, but the results support that the scheme is a promising semi-automated object extraction scheme for the significant biliary structures in medical MRCP images. PMID- 20703718 TI - Adaptive network-based fuzzy inference system for assessment of lower limb peripheral vascular occlusive disease. AB - Detecting lower limb peripheral vascular occlusive disease (PVOD) early is important for patients to prevent disabling claudication, ischaemic rest pain and gangrene. According to previous research, the pulse timing and shape distortion characteristics of photoplethysmography (PPG) signals tend to increase with disease severity and calibrated amplitude decreases with vascular diseases. However, this is not a reliable method of evaluating the condition of PVOD because of noise effect. In this paper, an adaptive network-based fuzzy inference system (ANFIS) is proposed to assess lower limb PVOD based on PPG signals. PPG signals are non-invasively recorded from the right and left sides at the big toe sites from twenty subjects, including normal condition (Nor), lower-grade disease (LG), and higher-grade disease (HG) groups. The number of each group is 10, 8 and 2 respectively, and the ages ranged from 24 to 65 years. With the time-domain technique, the parameters for the absolute bilateral differences (right-to-left side of foot) in pulse delay and amplitude were extracted for analyzing ANFIS. The results indicated that ANFIS based on three timing parameters base bilateral differences, including DeltaPTTf and DeltaPTTp, and DeltaRT has a high rate and noise tolerance of PVOD assessment. PMID- 20703719 TI - Emergency access authorization for personally controlled online health care data. AB - Personally controlled health records (PCHR) systems have emerged to allow patients to control their own medical data. In a PCHR system, all the access privileges to a patient's data are granted by the patient. However, in many emergency cases, it is impossible for the patient to participate in access authorization on site when immediate medical treatment is needed. To solve the emergency access authorization problem in the absence of patients, we consider two cases: a) the requester is already in the PCHR system but has not obtained the access privilege of the patient's health records, and b) the requester does not even have an account in the PCHR system to submit its request. For each of the two cases, we present a method for emergency access authorization, utilizing the weighted voting and source authentication cryptographic techniques. Our methods provide an effective, secure and private solution for emergency access authorization, that makes the existing PCHR system frameworks more practical and thus improves the patients' experiences of health care when using PCHR systems. We have implemented a prototype system as a proof of concept. PMID- 20703720 TI - Detection and localization of myocardial infarction using K-nearest neighbor classifier. AB - This paper presents automatic detection and localization of myocardial infarction (MI) using K-nearest neighbor (KNN) classifier. Time domain features of each beat in the ECG signal such as T wave amplitude, Q wave and ST level deviation, which are indicative of MI, are extracted from 12 leads ECG. Detection of MI aims to classify normal subjects without myocardial infarction and subjects suffering from Myocardial Infarction. For further investigation, Localization of MI is done to specify the region of infarction of the heart. Total 20,160 ECG beats from PTB database available on Physio-bank is used to investigate the performance of extracted features with KNN classifier. In the case of MI detection, sensitivity and specificity of KNN is found to be 99.9% using half of the randomly selected beats as training set and rest of the beats for testing. Moreover, Arif-Fayyaz pruning algorithm is used to prune the data which will reduce the storage requirement and computational cost of search. After pruning, sensitivity and specificity are dropped to 97% and 99.6% respectively but training is reduced by 93%. Myocardial Infarction beats are divided into ten classes based on the location of the infarction along with one class of normal subjects. Sensitivity and Specificity of above 90% is achieved for all eleven classes with overall classification accuracy of 98.8%. Some of the ECG beats are misclassified but interestingly these are misclassified to those classes whose location of infarction is near to the true classes of the ECG beats. Pruning is done on the training set for eleven classes and training set is reduced by 70% and overall classification accuracy of 98.3% is achieved. The proposed method due to its simplicity and high accuracy over the PTB database can be very helpful in correct diagnosis of MI in a practical scenario. PMID- 20703722 TI - Evaluation of fuzzy relation method for medical decision support. AB - The potential of computer based tools to assist physicians in medical decision making, was envisaged five decades ago. Apart from factors like usability, integration with work-flow and natural language processing, lack of decision accuracy of the tools has hindered their utility. Hence, research to develop accurate algorithms for medical decision support tools, is required. Pioneering research in last two decades, has demonstrated the utility of fuzzy set theory for medical domain. Recently, Wagholikar and Deshpande proposed a fuzzy relation based method (FR) for medical diagnosis. In their case studies for heart and infectious diseases, the FR method was found to be better than naive bayes (NB). However, the datasets in their studies were small and included only categorical symptoms. Hence, more evaluative studies are required for drawing general conclusions. In the present paper, we compare the classification performance of FR with NB, for a variety of medical datasets. Our results indicate that the FR method is useful for classification problems in the medical domain, and that FR is marginally better than NB. However, the performance of FR is significantly better for datasets having high proportion of unknown attribute values. Such datasets occur in problems involving linguistic information, where FR can be particularly useful. Our empirical study will benefit medical researchers in the choice of algorithms for decision support tools. PMID- 20703724 TI - Matching of a huge set of MR images with a parallel processing model. AB - Matching medical image data is a key factor for appropriate computer aided diagnosis. For the past several decades, many image processing technologies have been developed and discussed. However, most of the methods are only of theoretical interest because the time complexity of the matching methods is too high for realistic handling of huge amounts of existing medical images. This paper presents a parallel processing model for matching huge amounts of MR images. A feature vector of an MR image is defined by professionals specifically in the area of neuroscience. Then a matching algorithm is developed based on matching the feature vectors. The algorithm is shown to be suitable for parallel process, and provides acceptable results. The experiments show that the overhead of synchronizing the parallel process is less significant than the improvement of the overall efficiency. PMID- 20703721 TI - Systematic review of factors influencing the adoption of information and communication technologies by healthcare professionals. AB - This systematic review of mixed methods studies focuses on factors that can facilitate or limit the implementation of information and communication technologies (ICTs) in clinical settings. Systematic searches of relevant bibliographic databases identified studies about interventions promoting ICT adoption by healthcare professionals. Content analysis was performed by two reviewers using a specific grid. One hundred and one (101) studies were included in the review. Perception of the benefits of the innovation (system usefulness) was the most common facilitating factor, followed by ease of use. Issues regarding design, technical concerns, familiarity with ICT, and time were the most frequent limiting factors identified. Our results suggest strategies that could effectively promote the successful adoption of ICT in healthcare professional practices. PMID- 20703723 TI - Impact of computerized order entry and pre-mixed dialysis solutions for continuous veno-venous hemodiafiltration on selection of therapy for acute renal failure. AB - To investigate the impacts of availability of pre-mixed solutions and computerized order entry on nephrologists' choice of the initial mode of renal replacement therapy in acute renal failure. We studied 898 patients with acute renal failure in 3 consecutive eras: era 1 (custom-mixed solution; n = 309), era 2 (pre-mixed commercial solution; n = 324), and era 3 (post-computerized order entry; n = 265). The proportion of patients treated with renal replacement therapy and the time from consult to initiation of continuous renal replacement therapy was similar in the 3 eras. Following introduction of the pre-mixed solution, the proportion of patients treated with continuous renal replacement therapy increased (20% vs. 33%; p < 0.05), it was initiated at a lower serum creatinine (353 +/- 123 MUmol/L vs. 300 +/- 80 MUmol/L; p < 0.05) and in older patients (53 +/- 12 vs. 61 +/- 14 years; p < 0.05). There was a progressive increase in the use of continuous veno-venous hemodialysis (18% vs. 79% vs. 100%; p < 0.05) and in the total prescribed flow rate (1,382 +/- 546 vs. 2,324 +/- 737 vs. 2,900 +/- 305 mL/hr 3; p < 0.05). There was no significant impact on mortality. The availability of a pre-mixed solution increases the likelihood of initiating continuous renal replacement therapy in acute renal failure, initiating it at a lower creatinine and for older patients, use of continuous veno-venous hemodialysis and higher prescribed continuous renal replacement therapy dose. Computerized order entry implementation is associated with an additional increase in the use of continuous veno-venous hemodialysis, higher total prescribed dialysis dose, and use of CRRT among an increasing number of patients not on mechanical ventilation. The effect of these changes on patient survival is not significant. PMID- 20703725 TI - Measuring pulse wave velocity using ECG and photoplethysmography. AB - Pulse wave velocity (PWV) is a useful method to assess arterial stiffness and predict mortality of atherosclerosis-related diseases. The progression of atherosclerosis is not homogeneous. There must be difference of PWV between sites by site. Therefore we designed a multi-channel instrument to measure PWV at different sites of the body simultaneously. We measured PWV at six different regions simultaneously. Thirty four healthy adults received the measurement. We found that PWVs were higher in the large vessels, by measuring from the heart to toes and heart to fingers as compared with the measurement from the heart to the earlobes (4.76 +/- 0.46 m/s; 4.67 +/- 0.41 m/s; 1.10 +/- 0.16 m/s). The PWV of the left and right sides were the same. Although there were statistically significances, the correlation of PWV between foot and hand is better than those between ear and foot and between ear and hand. Herein we presented a novel and reliable measurement of PWV. The changes of PWV in different regions may be used in predicting disease processes such as stroke, coronary artery diseases and renal diseases, respectively. PMID- 20703726 TI - Functional and mechanical evaluation of nerve stretch injury. AB - Peripheral nerves undergo tensile loading in common physiological conditions, but stretch can also induce nerve pathology, impairing electrophysiological conduction. The level of strain nerves can tolerate and the functional deficits which result from exceeding this threshold are not thoroughly understood. To examine these phenomena, a novel system for tensile electrophysiology was created using a grease gap-recording chamber paired with a computerized micromanipulator and load cell. Guinea pig sciatic nerves were stretched beyond their maximum physiologic length to examine the effects of tension on signal conduction. Mechanical and electrophysiological data such as load, position, compound action potential amplitude, and signal latency were recorded in real-time. While 5% strain did not affect conduction, further elongation decreased amplitude approximately linearly with strain. These experiments verify the findings of prior studies into nerve stretch, and demonstrate the utility of this apparatus for investigating the mechanical and electrophysiological properties of nerves undergoing strain. PMID- 20703727 TI - Energy-efficient key distribution using electrocardiograph biometric set for secure communications in wireless body healthcare networks. AB - Wireless body sensor network (WBSN) has gained significant interests as an important infrastructure for real-time biomedical healthcare systems, while the security of the sensitive health information becomes one of the main challenges. Due to the constraints of limited power, traditional cryptographic key distribution schemes are not suitable for WBSN. This paper proposes a novel energy-efficient approach, BodyKey, which can distribute the keys using the electrocardiograph biometrics. BodyKey represents the biometric features as ordered set, and deals with the biometric variations using set reconciliation. In this way, only limited necessary information needs to be communicated for key agreement, and the total energy consumption for key distribution can thus be reduced. Experiments on the PhysioBank Database show that BodyKey can perform an energy consumption rate of 0.01 mJ/bit with an equal accuracy rate of 97.28%, allowing the system to be used as an energy-efficient key distribution scheme for secure communications in WBSN. PMID- 20703728 TI - Morphological multiscale enhancement, fuzzy filter and watershed for vascular tree extraction in angiogram. AB - This paper presented an automatic morphological method to extract a vascular tree using an angiogram. Under the assumption that vessels are connected in a local linear pattern in a noisy environment, the algorithm decomposes the vessel extraction problem into several consecutive morphological operators, aiming to characterize and distinguish different patterns on the angiogram: background, approximate vessel region and the boundary. It started with a contrast enhancement and background suppression process implemented by subtracting the background from the original angiogram. The background was estimated using multiscale morphology opening operators by varying the size of structuring element on each pixel. Subsequently, the algorithm simplified the enhanced angiogram with a combined fuzzy morphological opening operation, with linear rotating structuring element, in order to fit the vessel pattern. This filtering process was then followed by simply setting a threshold to produce approximate vessel region. Finally, the vessel boundaries were detected using watershed techniques with the obtained approximate vessel centerline, thinned result of the obtained vessel region, as prior marker for vessel structure. Experimental results using clinical digitized vascular angiogram and some comparative performance of the proposed algorithm were reported. PMID- 20703729 TI - Calcaneal osteotomy preoperative planning system with 3D full-sized computer assisted technology. AB - In this study, we developed a CT-based computer-assisted pre-operative planning and simulating system for the calcaneal osteotomy by integrating different software's function. This system uses the full-scaled 3D reverse engineering technique in designing and developing preoperative planning modules for the calcaneal osteotomy surgery. The planning system presents a real-sized three dimensional image of the calcaneus, and provides detailed interior measurements of the calcaneus from various cutting planes. This study applied computer assisted technology to integrate different software's function to a surgical planning system. These functions include 3-D image model capturing, cutting, moving, rotating and measurement for relevant foot anatomy, and can be integrated as the user's function. Furthermore, the system is computer-based and computer assisted technology. Surgeons can utilize it as part of preoperative planning to develop efficient operative procedures. This system also has a database that can be updated and extended and will provide the clinical cases to different users for experienced based learning. PMID- 20703730 TI - Modeling blast induced neurotrauma in isolated spinal cord white matter. AB - Blast-induced neurotrauma (BINT) is a common injury associated with the present military conflicts. Exposure to the shock-wave produced from exploding ordnances leads to significant neurological deficits throughout the brain and spinal cord. Prevention and treatment of this injury requires an appropriate understanding of the mechanisms governing the neurological response. Here, we present a novel ex vivo BINT model where an isolated section of guinea pig spinal cord white matter is exposed to the shock-wave produced from a small scale explosive event. Additionally, we define the relationship between shock-wave impact, tissue deformation and resulting anatomical and functional deficits associated with BINT. Our findings suggest an inverse relationship between the magnitude of the shock-wave overpressure and the degree of functional deficits using a double sucrose gap recording chamber. Similar correlations are drawn between overpressure and degree of anatomical damage of neuronal processes using a dye exclusion assay. The following approach is expected to significantly contribute to the detection, mitigation and eventual treatment of BINT. PMID- 20703731 TI - A study of heating duration and scanning path in focused ultrasound surgery. AB - A conventional method of avoiding normal tissue overheating during focused ultrasound surgery (FUS) is to apply equal heating duration for each sonication in between cooling intervals. However, this method is time-consuming and expensive. A novel method with unequal heating duration in different scanning paths without cooling intervals was investigated in this paper. This method was compared with the conventional method through the ablation of a 10 * 10 cm(2) target. The simulation results indicated that the new method was able to reduce treatment time by more than 50%, with higher than 95% coverage index, and more uniform thermal dose distribution. The method was further verified through the ablation of a circular lesion. Ex vivo experiments were also performed to confirm the simulation results. Both simulation and experimental results have proven that the new method can increase heating efficiency, and are a promising new approach in FUS. PMID- 20703732 TI - Special issue editorial on proceedings of the Second International Conference on Biomedical Engineering and Informatics (BMEI 2009). PMID- 20703733 TI - Highly sensitive computer aided diagnosis system for breast tumor based on color Doppler flow images. AB - A computer-aided diagnosis (CAD) system for breast tumor based on color Doppler flow images is proposed. Our system consists of automatic segmentation, feature extraction, and classification of breast tumors. First, the B-mode grayscale image containing anatomical information was separated from a color Doppler flow image (CDFI). Second, the boundary of the breast tumor was automatically defined in the B-mode image and then morphologic and gray features were extracted. Third, an optimal feature vector was created using K-means cluster algorithm. Then a back-propagation (BP) artificial neural network (ANN) was used to classify breast tumors as benign, malignant or uncertain. Finally, the blood flow feature was extracted selectively from the CDFI, and was used to classify the uncertain tumor as benign or malignant. Experiments on 500 cases show that the proposed system yields an accuracy of 100% for the malignant and 80.8% for the benign classification. Comparing with other systems, the advantage of our system is that it has a much lower percentage of malignant tumor misdiagnosis. PMID- 20703734 TI - Retracted Article: Health effects and safety of magnetic resonance imaging. PMID- 20703735 TI - A knowledge based search tool for performance measures in health care systems. AB - Performance measurement is vital for improving the health care systems. However, we are still far from having accepted performance measurement models. Researchers and developers are seeking comparable performance indicators. We developed an intelligent search tool to identify appropriate measures for specific requirements by matching diverse care settings. We reviewed the literature and analyzed 229 performance measurement studies published after 2000. These studies are evaluated with an original theoretical framework and stored in the database. A semantic network is designed for representing domain knowledge and supporting reasoning. We have applied knowledge based decision support techniques to cope with uncertainty problems. As a result we designed a tool which simplifies the performance indicator search process and provides most relevant indicators by employing knowledge based systems. PMID- 20703736 TI - The integrated information architecture: a pilot study approach to leveraging logistics management with regard to influenza preparedness. AB - Pandemic influenza is considered catastrophic to global health, with severe economic and social effects. Consequently, a strategy for the rapid deployment of essential medical supplies used for the prevention of influenza transmission and to alleviate public panic caused by the expected shortage of such supplies needs to be developed. Therefore, we employ integrated information concepts to develop a simulated influenza medical material supply system to facilitate a rapid response to such a crisis. Various scenarios are analyzed to estimate the appropriate inventory policy needed under different pandemic influenza outbreaks, and to establish a mechanism to evaluate the necessary stockpiles of medications and other requirements in the different phases of the pandemic. This study constructed a web-based decision support system framework prototype that displayed transparent data related to medical stockpiles in each district and integrated expert opinion about the best distribution of these supplies in the influenza pandemic scenarios. A data collection system was also designed to gather information through a daily VPN transmitted into one central repository for reporting and distribution purposes. This study provides timely and transparent medical supplies distribution information that can help decision makers to make the appropriate decisions under different pandemic influenza outbreaks, and also attempts to establish a mechanism of evaluating the stockpiles and requirements in the different phases of the pandemic. PMID- 20703738 TI - 3D web based learning of medical equipment employed in intensive care units. AB - In this paper, both synchronous and asynchronous web based learning of 3D medical equipment models used in hospital intensive care unit have been described over the moodle course management system. 3D medical equipment models were designed with 3ds Max 2008, then converted to ASE format and added interactivity displayed with Viewpoint-Enliven. 3D models embedded in a web page in html format with dynamic interactivity-rotating, panning and zooming by dragging a mouse over images-and descriptive information is embedded to 3D model by using xml format. A pilot test course having 15 h was applied to technicians who is responsible for intensive care unit at Medical Devices Repairing and Maintenance Center (TABOM) of Turkish High Specialized Hospital. PMID- 20703737 TI - The association forecasting of 13 variants within seven asthma susceptibility genes on 3 serum IgE groups in Taiwanese population by integrating of adaptive neuro-fuzzy inference system (ANFIS) and classification analysis methods. AB - Asthma is one of the most common chronic diseases in children. It is caused by complicated coactions between various genetic factors and environmental allergens. The study aims to integrate the concept of implementing adaptive neuro fuzzy inference system (ANFIS) and classification analysis methods for forecasting the association of asthma susceptibility genes on 3 serum IgE groups. The ANFIS model was trained and tested with data sets obtained from 425 asthmatic subjects and 483 non-asthma subjects from the Taiwanese population. We assessed 13 single-nucleotide polymorphisms (SNPs) in seven well-known asthma susceptibility genes; firstly, the proposed ANFIS model learned to reduce input features from the 13 SNPs. And secondly, the classification will be used to classify the serum IgE groups from the simulated SNPs results. The performance of the ANFIS model, classification accuracies and the results confirmed that the integration of ANFIS and classified analysis has potential in association discovery. PMID- 20703739 TI - Distance-constrained orthogonal Latin squares for brain-computer interface. AB - The P300 brain-computer interface (BCI) using electroencephalogram (EEG) signals can allow amyotrophic lateral sclerosis (ALS) patients to instruct computers to perform tasks. To strengthen the P300 response and increase classification accuracy, we proposed an experimental design where characters are intensified according to orthogonal Latin square pairs. These orthogonal Latin square pairs satisfy certain distance constraint so that neighboring characters are not intensified simultaneously. However, it is unknown whether such distance constrained, orthogonal Latin square pairs actually exist. In this paper, we show that for every matrix size commonly used in P300 BCI, thousands to millions of such distance-constrained, orthogonal Latin square pairs can be systematically and efficiently constructed and are sufficient for the purpose of being used in P300 BCI. PMID- 20703740 TI - Algorithms for the automated detection of diabetic retinopathy using digital fundus images: a review. AB - Diabetes is a chronic end organ disease that occurs when the pancreas does not secrete enough insulin or the body is unable to process it properly. Over time, diabetes affects the circulatory system, including that of the retina. Diabetic retinopathy is a medical condition where the retina is damaged because fluid leaks from blood vessels into the retina. Ophthalmologists recognize diabetic retinopathy based on features, such as blood vessel area, exudes, hemorrhages, microaneurysms and texture. In this paper we review algorithms used for the extraction of these features from digital fundus images. Furthermore, we discuss systems that use these features to classify individual fundus images. The classifications efficiency of different DR systems is discussed. Most of the reported systems are highly optimized with respect to the analyzed fundus images, therefore a generalization of individual results is difficult. However, this review shows that the classification results improved has improved recently, and it is getting closer to the classification capabilities of human ophthalmologists. PMID- 20703741 TI - Artificial apnea classification with quantitative sleep EEG synchronization. AB - In the present study, both linear and nonlinear EEG synchronization methods so called Coherence Function (CF) and Mutual Information (MI) are performed to obtain high quality signal features in discriminating the Central Sleep Apnea (CSA) and Obstructive Sleep Apnea (OSA) from controls. For this purpose, sleep EEG series recorded from patients and healthy volunteers are classified by using several Feed Forward Neural Network (FFNN) architectures with respect to synchronic activities between C3 and C4 recordings. Among the sleep stages, stage2 is considered in tests. The NN approaches are trained with several numbers of neurons and hidden layers. The results show that the degree of central EEG synchronization during night sleep is closely related to sleep disorders like CSA and OSA. The MI and CF give us cooperatively meaningful information to support clinical findings. Those three groups determined with an expert physician can be classified by addressing two hidden layers with very low absolute error where the average area of CF curves ranged form 0 to 10 Hz and the average MI values are assigned as two features. In a future work, these two features can be combined to create an integrated single feature for error free apnea classification. PMID- 20703742 TI - Implementing an integrative multi-agent clinical decision support system with open source software. AB - Clinical decision making is a complex multi-stage process. Decision support can play an important role at each stage of this process. At present, the majority of clinical decision support systems have been focused on supporting only certain stages. In this paper we present the design and implementation of MET3-a prototype multi-agent system providing an integrative decision support that spans over the entire decision making process. The system helps physicians with data collection, diagnosis formulation, treatment planning and finding supporting evidence. MET3 integrates with external hospital information systems via HL7 messages and runs on various computing platforms available at the point of care (e.g., tablet computers, mobile phones). Building MET3 required sophisticated and reliable software technologies. In the past decade the open source software movement has produced mature, stable, industrial strength software systems with a large user base. Therefore, one of the decisions that should be considered before developing or acquiring a decision support system is whether or not one could use open source technologies instead of proprietary ones. We believe MET3 shows that the answer to this question is positive. PMID- 20703743 TI - Mobile technology use in medical education. AB - This study was undertaken to determine the PDA functionalities for a problem based learning (PBL) medical curriculum at the Graduate School of Medicine (GSM), the University of Wollongong (UOW). The study determines the factors/aspects of incorporating PDAs, and the attitudes of stakeholders regarding the use of PDAs in such a PBL-based medical curriculum. In-depth interviews were designed and conducted with medical faculty, the medical education technology team and honorary medical academics. Four major PDA functionalities were identified, these being: clinical-log, reference, communication, and general functions. Two major aspects for the incorporation of PDAs into the PBL-medical curriculum at the UOW were determined from the interviews, these being technical and practical aspects. There is a potential for PDAs to be incorporated into the PBL-medical curricula at the UOW. However, a clear strategy needs to be defined as to how best to incorporate PDAs into PBL-medical curricula with minimal impact on students, as well as financial and resource implications for the GSM. PMID- 20703744 TI - Automated detection of breast cancer in thermal infrared images, based on independent component analysis. AB - Breast cancer, among women, is the second-most common cancer and the leading cause of cancer death. It has become a major health issue in the world over the past decades and its incidence has increased in recent years mostly due to increased awareness of the importance of screening and population ageing. Early detection is crucial in the effective treatment of breast cancer. Current mammogram screening may turn up many tiny abnormalities that are either not cancerous or are slow-growing cancers that would never progress to the point of killing a woman and might never even become known to her. Ideally a better screening method should find a way of distinguishing the dangerous, aggressive tumors that need to be excised from the more languorous ones that do not. This paper therefore proposes a new method of thermographic image analysis for automated detection of high tumor risk areas, based on independent component analysis (ICA) and on post-processing of the images resulting from this algorithm. Tests carried out on a database enable tumor areas of 4 * 4 pixels on an original thermographic image to be detected. The proposed method has shown that the appearance of a heat anomaly indicating a potentially cancerous zone is reflected as an independent source by ICA analysis of the YCrCb components; the set of available images in our small series is giving us a sensitivity of 100% and a specificity of 94.7%. PMID- 20703745 TI - Security and privacy issues in wireless sensor networks for healthcare applications. AB - The use of wireless sensor networks (WSN) in healthcare applications is growing in a fast pace. Numerous applications such as heart rate monitor, blood pressure monitor and endoscopic capsule are already in use. To address the growing use of sensor technology in this area, a new field known as wireless body area networks (WBAN or simply BAN) has emerged. As most devices and their applications are wireless in nature, security and privacy concerns are among major areas of concern. Due to direct involvement of humans also increases the sensitivity. Whether the data gathered from patients or individuals are obtained with the consent of the person or without it due to the need by the system, misuse or privacy concerns may restrict people from taking advantage of the full benefits from the system. People may not see these devices safe for daily use. There may also possibility of serious social unrest due to the fear that such devices may be used for monitoring and tracking individuals by government agencies or other private organizations. In this paper we discuss these issues and analyze in detail the problems and their possible measures. PMID- 20703746 TI - An improved medical decision support system to identify the breast cancer using mammogram. AB - An improved Computer Aided Clinical Decision Support System has been developed to classify the tumor and identify the stages of the cancer using neural network and presented in this paper. The texture and shape features have been extracted and the optimal feature set has been obtained using multiobjective genetic algorithm (MOGA). The multilayer back propagation neural network with Ant Colony Optimization and Particle Swarm Optimization has been used. The accuracy of the proposed system has been verified and found that the accuracy of 99.5% can be achieved. The proposed system can provide valuable information to the physicians in clinical pathology. PMID- 20703747 TI - Survival tree and MELD to predict long term survival in liver transplantation waiting list. AB - MELD score is a formula based on laboratory variables used as a predictor of short-term mortality index in cirrhotic patients. It is applied to allocate patients in liver transplantation waiting list in many countries. However, MELD score cutoff point accuracy to predict long term mortality has not been statistically evaluated. The aim of this study was to analyze the MELD score and other variables related to long-term mortality using a new model: the Survival Tree analysis. The variables considered in this study were obtained at the time of liver transplantation list enrollment. The graphical representation of the survival trees showed that MELD 16 was the most statistically significant mortality cutoff point. The results were compatible with the MELD cutoff point reported in the clinical literature. This methodology can be extended to identify significant cutoff points related to other diseases whose severity is not necessarily expressed by MELD. PMID- 20703749 TI - A system for building clinical research applications using semantic web-based approach. AB - In this paper we present a system using Semantic Web by which applications can be effectively constructed for clinical research purposes. We are aware of the immense difficulties and variations involved in clinical research applications. With a purpose of mitigating some of these difficulties in the process of developing clinical research applications we are presenting an approach for building information systems based on Semantic Web. We have developed a working prototype using C-Map tools leveraging the underlying principles of Abstract Software Design Framework to convert domain knowledge into machine-actable information. PMID- 20703748 TI - A biomedical system based on artificial neural network and principal component analysis for diagnosis of the heart valve diseases. AB - Listening via stethoscope is a primary method, being used by physicians for distinguishing normally and abnormal cardiac systems. Listening to the voices, coming from the cardiac valves via stethoscope, upon the flow of the blood running in the heart, physicians examine whether there is any abnormality with regard to the heart. However, listening via stethoscope has got a number of limitations, for interpreting different heart sounds depends on hearing ability, experience, and respective skill of the physician. Such limitations may be reduced by developing biomedical based decision support systems. In this study, a biomedical-based decision support system was developed for the classification of heart sound signals, obtained from 120 subjects with normal, pulmonary and mitral stenosis heart valve diseases via stethoscope. Developed system was mainly comprised of three stages, namely as being feature extraction, dimension reduction, and classification. At feature extraction stage, applying Discrete Fourier Transform (DFT) and Burg autoregressive (AR) spectrum analysis method, features, representing heart sounds in frequency domain, were obtained. Obtained features were reduced in lower dimensions via Principal Component Analysis (PCA), being used as a dimension reduction technique. Heart sounds were classified by having the features applied as input to Artificial Neural Network (ANN). Classification results have shown that, dimension reduction, being conducted via PCA, has got positive effects on the classification of the heart sounds. PMID- 20703750 TI - An emergency medical communications system by low altitude platform at the early stages of a natural disaster in Indonesia. AB - A natural disaster is a consequence of a natural hazard, such as a tsunami, earthquake or volcanic eruption, affecting humans. In order to support emergency medical communication services in natural disaster areas where the telecommunications facility has been seriously damaged, an ad hoc communication network backbone should be build to support emergency medical services. Combinations of requirements need to be considered before deciding on the best option. In the present study we have proposed a Low Altitude Platform consisting of tethered balloons combined with Wireless Fidelity (WiFi) 802.11 technology. To confirm that the suggested network would satisfy the emergency medical service requirements, a communications experiment, including performance service measurement, was carried out. PMID- 20703751 TI - Multi-center, multi-topic heart sound databases and their applications. AB - This paper describes a large resource of multi-center and multi-topic heart sound databases, which were based on the measured data from more than 9,000 heart sound samples (saved in WAV file format). According to different research topics, these samples were respectively stored in different folders (corresponding to different research topics and distributed over various cooperative research centers), most of which as subfolds were stored in a pooled folder in the principal center. According to different research topics, the measured data from these samples were used to create different databases. Relevant data for a specific topic can be pooled in a large database for further analysis. This resource is shared by members of related centers for their own specific topic. The applications of this resource include evaluation of cardiac safety of pregnant women, evaluation of cardiac reserve for children, athletes, addicts, astronauts, and general populations, as well as studies on a bedside method for evaluating cardiac energy, reversal of S1-S2 ratio, etc. PMID- 20703752 TI - Architecture of portable electronic medical records system integrated with streaming media. AB - Due to increasing occurrence of accidents and illness during business trips, travel, or overseas studies, the requirement for portable EMR (Electronic Medical Records) has increased. This study proposes integrating streaming media technology into the EMR system to facilitate referrals, contracted laboratories, and disease notification among hospitals. The current study encoded static and dynamic medical images of patients into a streaming video format and stored them in a Flash Media Server (FMS). Based on the Taiwan Electronic Medical Record Template (TMT) standard, EMR records can be converted into XML documents and used to integrate description fields with embedded streaming videos. This investigation implemented a web-based portable EMR interchanging system using streaming media techniques to expedite exchanging medical image information among hospitals. The proposed architecture of the portable EMR retrieval system not only provides local hospital users the ability to acquire EMR text files from a previous hospital, but also helps access static and dynamic medical images as reference for clinical diagnosis and treatment. The proposed method protects property rights of medical images through information security mechanisms of the Medical Record Interchange Service Center and Health Certificate Authorization to facilitate proper, efficient, and continuous treatment of patients. PMID- 20703753 TI - Evaluation of the efficiency of biofield diagnostic system in breast cancer detection using clinical study results and classifiers. AB - The division of breast cancer cells results in regions of electrical depolarisation within the breast. These regions extend to the skin surface from where diagnostic information can be obtained through measurements of the skin surface electropotentials using sensors. This technique is used by the Biofield Diagnostic System (BDS) to detect the presence of malignancy. This paper evaluates the efficiency of BDS in breast cancer detection and also evaluates the use of classifiers for improving the accuracy of BDS. 182 women scheduled for either mammography or ultrasound or both tests participated in the BDS clinical study conducted at Tan Tock Seng hospital, Singapore. Using the BDS index obtained from the BDS examination and the level of suspicion score obtained from mammography/ultrasound results, the final BDS result was deciphered. BDS demonstrated high values for sensitivity (96.23%), specificity (93.80%), and accuracy (94.51%). Also, we have studied the performance of five supervised learning based classifiers (back propagation network, probabilistic neural network, linear discriminant analysis, support vector machines, and a fuzzy classifier), by feeding selected features from the collected dataset. The clinical study results show that BDS can help physicians to differentiate benign and malignant breast lesions, and thereby, aid in making better biopsy recommendations. PMID- 20703754 TI - Diagnosis of epilepsy from electroencephalography signals using multilayer perceptron and Elman Artificial Neural Networks and Wavelet Transform. AB - In this study, it has been intended to perform an automatic classification of Electroencephalography (EEG) signals via Artificial Neural Networks (ANN) and to investigate these signals using Wavelet Transform (WT) for diagnosing epilepsy syndrome. EEG signals have been decomposed into frequency sub-bands using WT and a set of feature vectors which were extracted from the sub-bands. Dimensions of these feature vectors have been reduced via Principal Component Analysis (PCA) method and then classified as epileptic or healthy using Multilayer Perceptron (MLP) and ELMAN ANN. Performance evaluation of the used ANN models have been carried out by performing Receiver Operation Characteristic (ROC) analysis. PMID- 20703755 TI - Classification of arrhythmia using hybrid networks. AB - Reliable detection of arrhythmias based on digital processing of Electrocardiogram (ECG) signals is vital in providing suitable and timely treatment to a cardiac patient. Due to corruption of ECG signals with multiple frequency noise and presence of multiple arrhythmic events in a cardiac rhythm, computerized interpretation of abnormal ECG rhythms is a challenging task. This paper focuses a Fuzzy C- Mean (FCM) clustered Probabilistic Neural Network (PNN) and Multi Layered Feed Forward Network (MLFFN) for the discrimination of eight types of ECG beats. Parameters such as fourth order Auto Regressive (AR) coefficients along with Spectral Entropy (SE) are extracted from each ECG beat and feature reduction has been carried out using FCM clustering. The cluster centers form the input of neural network classifiers. The extensive analysis of Massachusetts Institute of Technology- Beth Israel Hospital (MIT-BIH) arrhythmia database shows that FCM clustered PNNs is superior in cardiac arrhythmia classification than FCM clustered MLFFN with an overall accuracy of 99.05%, 97.14%, respectively. PMID- 20703756 TI - A multiple stage approach for performance improvement of primary healthcare practice. AB - Chilean primary healthcare practice is analyzed using a Data Envelopment Analysis (DEA) multiple stage approach. We estimate the efficiency level of 259 municipalities nationwide. Since the efficiency score by itself is of limited value for decision making, we use a multivariate tool to help explain the effect of relevant factors. First, we use a cluster analysis to homogenize the units under study. Second, we use DEA to estimate the efficiency levels, which varies from 61% to 71% for urban municipalities, and from 51% to 56% in rural ones. Third, we use bootstrap to estimate confidence intervals for the efficiency scores, and a Biplot method to identify adequate variables to include in the Tobit Model, which is our last stage. We identify six factors associated with rural municipalities' operational efficiency, and two with urban ones. Knowing the efficiency level of municipalities can help determine ways to improve their efficiency. PMID- 20703757 TI - Governance and performance: the performance of Dutch hospitals explained by governance characteristics. AB - This paper describes the efficiency of Dutch hospitals using the Data Envelopment Analysis (DEA) method with bootstrapping. In particular, the analysis focuses on accounting for cost inefficiency measures on the part of hospital corporate governance. We use bootstrap techniques, as introduced by Simar and Wilson (J. Econom. 136(1):31-64, 2007), in order to obtain more efficient estimates of the effects of governance on the efficiency. The results show that part of the cost efficiency can be explained with governance. In particular we find that a higher remuneration of the board as well as a higher remuneration of the supervisory board does not implicate better performance. PMID- 20703759 TI - Influence of dentistry students' e-Learning satisfaction: a questionnaire survey. AB - Dental school graduates operating on patients without having had sufficient practice in school is potentially dangerous to the patients. In order to minimize this danger, it is necessary to establish a virtual learning environment for students. In this study, we incorporated DentSim, a clinical dentistry simulator, into an e-Learning platform. In addition to overcoming the time and space constraints on learning, DentSim can simulate clinical conditions. It also allows students to practice reading case histories and inspecting and diagnosing patients. To construct the research model for this study, we incorporated the four major factors for measuring e-Learner satisfaction-'learner interface', 'learning community', 'content' and 'personalization' with the variable of 'intention to use'. The subjects were 350 dental students studying at the College of Oral Medicine. The structural equation modeling (SEM) results showed that Factors that influenced 'intention to use' include 'learner interface', 'learning community' and 'personalization', and 'intention to use' affect 'e-Learner satisfaction' with the system. PMID- 20703758 TI - Experiences sharing of implementing Template-based Electronic Medical Record System (TEMRS) in a Hong Kong medical organization. AB - This paper aims to investigate the efficacy and feasibility of Template-based Electronic Medical Record System (TEMRS) and factors for its successful implementation. A TEMRS was designed and implemented in one core clinic of a Hong Kong professional multi-disciplinary medical services provider with four core clinics located in different parts of Hong Kong. Eight doctors participated in the study. Surveys and interviews were conducted to acquire the users' feedback and satisfaction level. The design, development, and the factors related to the success of the implementation of TEMRS were analyzed. In the study period, 3,032 cases were collected. The most encountered diagnosis were upper respiratory tract infection (50.59%), gastroenteritis (10.19%), dermatitis (5.87%), dyspepsia (5.28%) and rhinitis (4.82%). The system gained an overall satisfaction by the users and the most satisfied areas were rapid retrieving the necessary information of patient (75%) and fasten the diagnostic selection (75%). TEMRS is an enabling system which can reduce the user resistance in new technology with its flexibility. The consideration of cost, security, human, technical, data migration and standardization issues are essential in the implementation of the TEMRS and further research should be conducted to expand the TEMRS's implementation in health care system. PMID- 20703760 TI - Multiple 3D medical data watermarking for healthcare data management. AB - The rapid development of healthcare information management for 3D digital medical libraries, 3D PACS, and 3D medical diagnosis has addressed the security issues pertaining to medical IT technology. This paper presents multiple watermarking schemes for a healthcare information management system for 3D medical image data for the protection, authentication, indexing, and hiding of diagnosis information. The proposed scheme, which is based on POCS watermarking, embeds a robust watermark for a doctor's digital signature and an information retrieval indexing key to the distribution of vertex curvedness; the scheme also embeds a fragile watermark for diagnosis information and an authentication reference message to the vertex distance difference. The multiple embedding process creates three convex sets for robustness, fragileness, and invisibility and projects the 3D medical image data onto these three convex sets alternately and iteratively. Experimental results confirmed that the proposed scheme has the robustness and fragileness to handle various 3D geometric and mesh modifiers simultaneously. PMID- 20703761 TI - Application of higher order spectra to identify epileptic EEG. AB - Epilepsy is characterized by the spontaneous and seemingly unforeseeable occurrence of seizures, during which the perception or behavior of patients is disturbed. An automatic system that detects seizure onsets would allow patients or the people near them to take appropriate precautions, and could provide more insight into this phenomenon. Various methods have been proposed to predict the onset of seizures based on EEG recordings. The use of nonlinear features motivated by the higher order spectra (HOS) has been reported to be a promising approach to differentiate between normal, background (pre-ictal) and epileptic EEG signals. In this work, we made a comparative study of the performance of Gaussian mixture model (GMM) and Support Vector Machine (SVM) classifiers using the features derived from HOS and from the power spectrum. Results show that the selected HOS based features achieve 93.11% classification accuracy compared to 88.78% with features derived from the power spectrum for a GMM classifier. The SVM classifier achieves an improvement from 86.89% with features based on the power spectrum to 92.56% with features based on the bispectrum. PMID- 20703762 TI - The quality and characteristics of leading general hospitals' websites in China. AB - This paper focuses on the evaluation of quality of hospital websites in China. Leading general hospitals' websites in China are increasingly used by the public, but research on the quality of these websites in China is few and far between. In this article, we conducted a cross-sectional descriptive infodemiology study to assess the quality and to describe the characteristics of these websites. Using a pre-defined objective criterion based on content, function, design, and management & usage, two well-trained reviewers independently reviewed and analyzed websites of 23 nationally prominent leading general hospitals of China from April to June 2009. Hospital election is on the basis of the best Chinese hospitals published by official and non-official sources combined with experts' experiences and the research purpose. Results show that websites of most hospitals showed a good performance in website content, showed a normal performance in website function and design, but showed a bad performance in website management & usage. As the public increasingly looks to hospital websites for information and services, leading general hospitals in China need to keep up with increasingly high standards and demands of health-care consumers. PMID- 20703763 TI - A small-area study of environmental risk assessment of outdoor falls. AB - Falls in public places are an issue of great health concern especially for the elderly. Falls among the elderly is also a major health burden in many countries. This study describes a spatial approach to assess environmental causes of outdoor falls using a small urban community in Hong Kong as an example. The method involves collecting data on fall occurrences and mapping their geographic positions to examine circumstances and environmental evidence that contribute to falls. High risk locations or hot spots of falls are identified on the bases of spatial proximity and concentration of falls within a threshold distance by means of kernel smoothing and standard deviational ellipses. This method of geographic aggregation of individual fall incidents for a small-area study yields hot spots of manageable sizes. The spatial clustering approach is effective in two ways. Firstly, it allows visualisation and isolation of fall hot spots to draw focus. Secondly and especially under conditions of resource decline, policy makers are able to target specific locations to examine the underlying causal mechanisms and strategise effective response and preventive measures based on the types of environmental risk factors identified. PMID- 20703764 TI - A new approach: role of data mining in prediction of survival of burn patients. AB - The prediction of burn patient survivability is a difficult problem to investigate till present times. In present study a prediction Model for patients with burns was built, and its capability to accurately predict the survivability was assessed. We have compared different data mining techniques to asses the performance of various algorithms based on the different measures used in the analysis of information pertaining to medical domain. Obtained results were evaluated for correctness with the help of registered medical practitioners. The dataset was collected from SRT (Swami Ramanand Tirth) Hospital in India, which is one of the Asia's largest rural hospitals. Dataset contains records of 180 patients mainly suffering from burn injuries collected during period from the year 2002 to 2006. Features contain patients' age, sex and percentage of burn received for eight different parts of the body. Prediction models have been developed through rigorous comparative study of important and relevant data mining classification techniques namely, navie bayes, decision tree, support vector machine and back propagation. Performance comparison was also carried out for measuring unbiased estimate of the prediction models using 10-fold cross validation method. Using the analysis of obtained results, we show that Navie bayes is the best predictor with an accuracy of 97.78% on the holdout samples, further, both the decision tree and support vector machine (SVM) techniques demonstrated an accuracy of 96.12%, and back propagation technique resulted in achieving accuracy of 95%. PMID- 20703765 TI - Impact of the Patient-Reported Outcomes Management Information System (PROMIS) upon the design and operation of multi-center clinical trials: a qualitative research study. AB - New technologies may be required to integrate the National Institutes of Health's Patient Reported Outcome Management Information System (PROMIS) into multi-center clinical trials. To better understand this need, we identified likely PROMIS reporting formats, developed a multi-center clinical trial process model, and identified gaps between current capabilities and those necessary for PROMIS. These results were evaluated by key trial constituencies. Issues reported by principal investigators fell into two categories: acceptance by key regulators and the scientific community, and usability for researchers and clinicians. Issues reported by the coordinating center, participating sites, and study subjects were those faced when integrating new technologies into existing clinical trial systems. We then defined elements of a PROMIS Tool Kit required for integrating PROMIS into a multi-center clinical trial environment. The requirements identified in this study serve as a framework for future investigators in the design, development, implementation, and operation of PROMIS Tool Kit technologies. PMID- 20703766 TI - Mathematical models of real geometrical factors in restricted blood vessels for the analysis of CAD (coronary artery diseases) using Legendre, Boubaker and Bessel polynomials. AB - Most cardiovascular emergencies are directly caused by coronary artery disease. Coronary arteries can become clogged or occluded, leading to damage to the heart muscle supplied by the artery. Modem cardiovascular medicine can certainly be improved by meticulous analysis of geometrical factors closely associated with the degenerative disease that results in narrowing of the coronary arteries. There are, however, inherent difficulties in developing this type of mathematical models to completely describe the real or ideal geometries that are very critical in plaque formation and thickening of the vessel wall. Neither the mathematical models of the blood vessels with arthrosclerosis generated by the heart and blood flow or the NMR/MRI data to construct them are available. In this study, a mathematical formulation for the geometrical factors that are very critical for the understanding of coronary artery disease is presented. Based on the Bloch NMR flow equations, we derive analytical expressions to describe in detail the NMR transverse magnetizations and signals as a function of some NMR flow and geometrical parameters which are invaluable for the analysis of blood flow in restricted blood vessels. The procedure would apply to the situations in which the geometry of the fatty deposits, (plague) on the interior walls of the coronary arteries is spherical. The boundary conditions are introduced based on Bessel, Boubaker and Legendre polynomials. PMID- 20703767 TI - A software tool for determination of breast cancer treatment methods using data mining approach. AB - In this work, breast cancer treatment methods are determined using data mining. For this purpose, software is developed to help to oncology doctor for the suggestion of application of the treatment methods about breast cancer patients. 462 breast cancer patient data, obtained from Ankara Oncology Hospital, are used to determine treatment methods for new patients. This dataset is processed with Weka data mining tool. Classification algorithms are applied one by one for this dataset and results are compared to find proper treatment method. Developed software program called as "Treatment Assistant" uses different algorithms (IB1, Multilayer Perception and Decision Table) to find out which one is giving better result for each attribute to predict and by using Java Net beans interface. Treatment methods are determined for the post surgical operation of breast cancer patients using this developed software tool. At modeling step of data mining process, different Weka algorithms are used for output attributes. For hormonotherapy output IB1, for tamoxifen and radiotherapy outputs Multilayer Perceptron and for the chemotherapy output decision table algorithm shows best accuracy performance compare to each other. In conclusion, this work shows that data mining approach can be a useful tool for medical applications particularly at the treatment decision step. Data mining helps to the doctor to decide in a short time. PMID- 20703768 TI - Diagnosis of diabetic retinopathy: automatic extraction of optic disc and exudates from retinal images using marker-controlled watershed transformation. AB - Due to increasing number of diabetic retinopathy cases, ophthalmologists are experiencing serious problem to automatically extract the features from the retinal images. Optic disc (OD), exudates, and cotton wool spots are the main features of fundus images which are used for diagnosing eye diseases, such as diabetic retinopathy and glaucoma. In this paper, a new algorithm for the extraction of these bright objects from fundus images based on marker-controlled watershed segmentation is presented. The proposed algorithm makes use of average filtering and contrast adjustment as preprocessing steps. The concept of the markers is used to modify the gradient before the watershed transformation is applied. The performance of the proposed algorithm is evaluated using the test images of STARE and DRIVE databases. It is shown that the proposed method can yield an average sensitivity value of about 95%, which is comparable to those obtained by the known methods. PMID- 20703769 TI - Implementation and statistical evaluation of a web-based software for bone age assessment. AB - Bone age assessment is a tedious procedure carried out for assessing growth disorders of children using the left hand radiograph. The purpose of this work was to implement and evaluate a web-based software based on the Tanner and Whitehouse method in a pediatric endocrine department of a social security hospital processing 600-1,000 radiographs per year. The system was evaluated by using a statistical technique for comparing measurement methods in order to test the performance of the procedure and a time study to assess its feasibility under local conditions. It was found that the intra-observer variation for the web based Tanner and Whitehouse method was smaller (95% confidence limits, -0.77 to 0.97 vs. -0.45 to 0.37) then the conventional Greulich and Pyle manual method and the average net time required for an age assessment was 2.4 min. We therefore concluded that the web-based system should be adopted for its higher precision and relatively low turnaround time for cases requiring serial readings on the same patient. The statistical method demonstrated in this study can also serve as an example for evaluating similar biomedical parameter assessing software. PMID- 20703770 TI - Bleeding detection in Wireless Capsule Endoscopy based on Probabilistic Neural Network. AB - Wireless Capsule Endoscopy (WCE), which allows clinicians to inspect the whole gastrointestinal tract (GI) noninvasively, has bloomed into one of the most efficient technologies to diagnose the bleeding in GI tract. However WCE generates large amount of images in one examination of a patient. It is hard for clinicians to leave continuous time to examine the full WCE images, and this is the main factor limiting the wider application of WCE in clinic. A novel intelligent bleeding detection based on Probabilistic Neural Network (PNN) is proposed in this paper. The features of bleeding region in WCE images distinguishing from non-bleeding region are extracted. A PNN classifier is built to recognize bleeding regions in WCE images. Finally the intelligent bleeding detection method is implemented through programming. The experiments show this method can correctly recognize the bleeding regions in WCE images and clearly mark them out. The sensitivity and specificity on image level are measured as 93.1% and 85.6% respectively. PMID- 20703771 TI - A generic simulation model to manage a vaccination program. AB - The main purpose of this paper is to demonstrate how a computer model can be used as a decision making tool regarding vaccination programs. These programs include vaccination against traditional influenza, avian influenza, H1N1 (swine flu), or other diseases. Specifically, the proposed simulation model is used to investigate the impact of herd immunity, to estimate the vaccination rate for which a given disease is placed into an endemic state, and to calculate the overall cost of a vaccination program from a societal perspective. In addition, the tool can help to define an optimal vaccination rate which will result in the minimum overall cost for a vaccination program. The paper demonstrates several advantages of simulation over other decision making methods. Simulation is used to "mimic" the behavior of the disease, test a range of alternative solutions for different scenarios, and to finely adjust the model and reflect possible vaccination scenarios. PMID- 20703773 TI - An assessment of patient safety in acupuncture process under EMR support. AB - With the facilitating roles of IT, this study is to investigate the safety issues of the acupuncture process in the current practices under EMR support. A self administered questionnaire survey was conducted in 80 Chinese medicine practice hospitals and clinics in Taiwan. Concerns over patient safety during the acupuncture process were raised, such as an inconsistency between the practice and prescription and a lack of monitoring patient's condition during the treatment. Confirming the physicians' prescription and documenting patients' reaction for patient record management are needed to add to the EMR system for patient safety while performing acupuncture. The results of this study can be used by the government or medical institutes to assess the work flow and set up standards of EMRs design for their acupuncture treatment to ensure patient safety and to enhance healthcare quality. PMID- 20703772 TI - Choosing the most efficient database for a web-based system to store and exchange ophthalmologic health records. AB - Response times are a critically important parameter when implementing any telematics application. Hence, it is important to evaluate those times to check the performance of the system. Different database will get different response times. This paper presents a response time comparative analysis of the Web system of Electronic Health Record (EHRs), TeleOftalWeb, with the four databases used: Oracle 10 g, dbXML 2.0, Xindice 1.2, and eXist 1.1.1. Final goal of the comparison is choosing the database providing lower response times in TeleOftalWeb. Results obtained using the four databases proposed give the native XML database eXist an edge which, added to other features such as being a free software and easy to set up, makes us opting for it. TeleOftalWeb is being used by 20 specialists from the Institute of Applied Ophthalmobiology (Instituto de Oftalmobiologia Aplicada, IOBA) of the University of Valladolid, Spain. At this time, there are more than 1000 EHRs and over 2000 fundus photographs of diabetic patients stored in the system. PMID- 20703774 TI - Towards the systematic development of medical networking technology. AB - Currently, there is a disparity in the availability of doctors between urban and rural areas of developing countries. Most experienced doctors and specialists, as well as advanced diagnostic technologies, are available in urban areas. People living in rural areas have less or sometimes even no access to affordable healthcare facilities. Increasing the number of doctors and charitable medical hospitals or deploying advanced medical technologies in these areas might not be economically feasible, especially in developing countries. We need to mobilize science and technology to master this complex, large scale problem in an objective, logical, and professional way. This can only be achieved with a collaborative effort where a team of experts works on both technical and non technical aspects of this health care divide. In this paper we use a systems engineering framework to discuss hospital networks which might be solution for the problem. We argue that with the advancement in communication and networking technologies, economically middle class people and even some rural poor have access to internet and mobile communication systems. Thus, Hospital Digital Networking Technologies (HDNT), such as telemedicine, can be developed to utilize internet, mobile and satellite communication systems to connect primitive rural healthcare centers to well advanced modern urban setups and thereby provide better consultation and diagnostic care to the needy people. This paper describes requirements and limitations of the HDNTs. It also presents the features of telemedicine, the implementation issues and the application of wireless technologies in the field of medical networking. PMID- 20703775 TI - Kinematics modeling and experimentation of the multi-manipulator tooth arrangement robot for full denture manufacturing. AB - Artificial teeth are very complicated in shape, and not easy to be grasped and manipulated accurately by a single robot. The method of tooth-arrangement by multi-manipulator for complete denture manufacturing proposed in this paper. A novel complete denture manufacturing mechanism is designed based on multi manipulator and dental arch generator. Kinematics model of the multi-manipulator tooth-arrangement robot is built by analytical method based on tooth-arrangement principle for full denture. Preliminary experiments on tooth-arrangement are performed using the multi-manipulator tooth-arrangement robot prototype system. The multi-manipulator tooth-arrangement robot prototype system can automatically design and manufacture a set of complete denture that is suitable for a patient according to the jaw arch parameters. The experimental results verified the validity of kinematics model of the multi-manipulator tooth-arrangement robot and the feasibility of the manufacture strategy of complete denture fulfilled by multi-manipulator tooth-arrangement robot. PMID- 20703776 TI - Identification of deep sleep and awake with computational EEG measures. AB - The objective of the present work was to examine identification of deep sleep and awake with computational analysis of sleep EEG traces from central brain regions. All-night EEG traces from a total of 56 male subjects, 22 healthy control subjects and 34 age-matched apnea patients, were examined. A spectral mean frequency measure, a Hilbert transform based EEG amplitude and a correlation coefficient method were compared. The EEG amplitude provided a good identification of deep sleep, reaching 86.25% but was relatively poor in the identification of wakefulness, reaching 39.06%. Mean frequency provided a relatively good identification of deep sleep and awake, reaching 84.66% and 77.67%, respectively, while the correlation coefficient produced the lowest results of 37.89% and 44.43%. Optimal threshold values for deep sleep and awake identification were determined as 4.20 and 9.76 Hz, respectively, for the mean frequency measure. Mean frequency measure can be used to provide overall context information about sleep depth for automated sleep EEG analysis methods. PMID- 20703777 TI - A new specimen management system using RFID technology. AB - The specimen management system with barcode needs to be improved in order to solve inherent problems in work performance. This study describes the application of Radio Frequency Identification (RFID) which is the solution for the problems associated with specimen labeling and management. A new specimen management system and architecture with RFID technology for clinical laboratory was designed. The suggested system was tested in various conditions such as durability to temperature and aspect of effective utilization of new work flow under a virtual hospital clinical laboratory environment. This system demonstrates its potential application in clinical laboratories for improving work flow and specimen management. The suggested specimen management system with RFID technology has advantages in comparison to the traditional specimen management system with barcode in the aspect of mass specimen processing, robust durability of temperature, humidity changes, and effective specimen tracking. PMID- 20703778 TI - Ubiquitous healthcare computing with SEnsor Grid Enhancement with Data Management System (SEGEDMA). AB - Wireless Sensor Network (WSN) can be deployed to monitor the health of patients suffering from critical diseases. Also a wireless network consisting of biomedical sensors can be implanted into the patient's body and can monitor the patients' conditions. These sensor devices, apart from having an enormous capability of collecting data from their physical surroundings, are also resource constraint in nature with a limited processing and communication ability. Therefore we have to integrate them with the Grid technology in order to process and store the collected data by the sensor nodes. In this paper, we proposed the SEnsor Grid Enhancement Data Management system, called SEGEDMA ensuring the integration of different network technologies and the continuous data access to system users. The main contribution of this work is to achieve the interoperability of both technologies through a novel network architecture ensuring also the interoperability of Open Geospatial Consortium (OGC) and HL7 standards. According to the results, SEGEDMA can be applied successfully in a decentralized healthcare environment. PMID- 20703779 TI - Compressed ECG biometric: a fast, secured and efficient method for identification of CVD patient. AB - Adoption of compression technology is often required for wireless cardiovascular monitoring, due to the enormous size of Electrocardiography (ECG) signal and limited bandwidth of Internet. However, compressed ECG must be decompressed before performing human identification using present research on ECG based biometric techniques. This additional step of decompression creates a significant processing delay for identification task. This becomes an obvious burden on a system, if this needs to be done for a trillion of compressed ECG per hour by the hospital. Even though the hospital might be able to come up with an expensive infrastructure to tame the exuberant processing, for small intermediate nodes in a multihop network identification preceded by decompression is confronting. In this paper, we report a technique by which a person can be identified directly from his / her compressed ECG. This technique completely obviates the step of decompression and therefore upholds biometric identification less intimidating for the smaller nodes in a multihop network. The biometric template created by this new technique is lower in size compared to the existing ECG based biometrics as well as other forms of biometrics like face, finger, retina etc. (up to 8302 times lower than face template and 9 times lower than existing ECG based biometric template). Lower size of the template substantially reduces the one-to many matching time for biometric recognition, resulting in a faster biometric authentication mechanism. PMID- 20703780 TI - An Artificial Neural Network classification approach for use the ultrasound in physiotherapy. AB - In this study, a classification to be used in physiotherapy was realized by means of Artificial Neural Network (ANN). The aim of the classification was to determine the treatment length and appropriate ultrasound value for the age of physiotherapy patients, the area on which ultrasound will be applied, the fat rate in tissue and related factors. For this purpose, the patient information obtained from Selcuk University, Meram School of Medicine Hospital, Physiotherapy Department was used. In order to identify the appropriate ultrasound value and treatment length for the patient, the ultrasound therapy device realized with ANN was placed together in an embedded system. The results obtained by means of the designed and realized embedded system were compared with data gathered from an expert. As a result, the data obtained from the designed system were found out to be in line with the existing data. PMID- 20703781 TI - A smart-phone application and a companion website for the improvement of the communication skills of children with autism: clinical rationale, technical development and preliminary results. AB - Autism is a complex neurobiological disorder that is part of a group of disorders known as autism spectrum disorders (ASD). Today, one in 150 individuals is diagnosed with autism. Lack of social interaction and problems with communication are the main characteristics displayed by children with ASD. The Picture Exchange Communication System (PECS) is a communication system where children exchange visual symbols as a form of communication. The visual symbols are laminated pictures stored in a binder. We have designed, developed and are currently testing a software application, called PixTalk which works on any Windows Mobile Smart-phone. Teachers and caregivers can access a web site and select from an online library the images to be downloaded on to the Smart-phone. Children can browse and select images to express their intentions, desires, and emotions using PixTalk. Case study results indicate that PixTalk can be used as part of ongoing therapy. PMID- 20703782 TI - A new QRS detection method using wavelets and artificial neural networks. AB - We present a new method for detection and classification of QRS complexes in ECG signals using continuous wavelets and neural networks. Our wavelet method consists of four wavelet basis functions that are suitable in detection of QRS complexes within different QRS morphologies in the signal and thresholding technique for denoising and feature extraction. The results demonstrate that the proposed method is not only efficient for normal ECG signal analysis but also for various types of arrhythmic cardiac signals embedded in noise. For the classification stage, a feedforward neural network was trained with standard backpropagation algorithm. The classifier input features consisted of compact wavelet coefficients of QRS complexes that resulted in higher classification rates. We demonstrate the efficiency of our method with the average accuracy 97.2% in classification of normal and abnormal QRS complexes. PMID- 20703783 TI - Selective fluorescence sensing of deoxycytidine 5'-monophosphate (dCMP) employing a bis(diphenylphosphate)diimine ligand. AB - A new bis(diphenylphosphate)diimine ligand (BP1) was prepared and evaluated for its ability for selective detection of deoxycytidine 5'-monophosphate (dCMP). BP1 exhibited off-type fluorescence in the presence of dCMP. The fluorescence of BP1 was significantly quenched upon the addition of 2.5 * 10(-4) M dCMP and the detection limit was 1.25 * 10(-5) M in MeCN-H(2)O (1:1, v/v). The binding ratio between BP1 and dCMP was determined to be 1:1 with the binding constant of 3.98 +/- 0.60 * 10(-3) M(-1). PMID- 20703784 TI - Impaired functions of peripheral blood monocyte subpopulations in aged humans. AB - Aging is associated with increased susceptibility to microbial infections, and monocytes play an important role in microbial defense. In this study, we have identified and compared four subpopulations of monocytes (CD14(++(high))CD16(-), CD14(+(low))CD16(-), CD14(++(high))CD16(+), and CD14(+(low))CD16(+)) in the peripheral blood of young and aged subjects with regard to their numbers, cytokine production, TLR expression, and phosphorylation of ERK1/2 in response to pam3Cys a TLR-1/2 ligand. Proportions and numbers of CD14(++(high))CD16(+) and CD14(+(low))CD16(+) monocytes were significantly increased, whereas proportions of CD14(+(low))CD16(-) monocytes were decreased in aged subjects as compared to young subjects. In aged subjects, IL-6 production by all four subsets of monocytes was significantly decreased, whereas TNF-alpha production was decreased in monocyte subsets, except the CD14(+(low))CD16(-) subset. A significantly reduced expression of TLR1 was observed in CD14(++(high))CD16(+) and CD14(+(low))CD16(+) monocyte subsets in aged subjects. Furthermore, following pam3Cys stimulation, ERK1/2 phosphorylation was significantly lower in CD14(+(low))CD16(+), CD14(++(high))CD16(+), and CD14(+(low))CD16(-) subsets of monocytes from aged subjects. This is the first study of four subpopulations of monocytes in aging, which demonstrates that their functions are differentially impaired with regard to the production of cytokines, expression of TLR, and signaling via the ERK-MAPK pathway. Finally, changes in the number of monocyte subsets, and impairment of TLR1 expression, TNF-alpha production, and EK1/2 phosphorylation was more consistent in CD16(+) monocyte subsets regardless of expression of CD14(high) or CD14(+low), therefore highlighting the significance of further subdivision of monocytes into four subpopulations. PMID- 20703785 TI - Are secondary variants of juvenile psychopathy more reactively violent and less psychosocially mature than primary variants? AB - There is growing support for the disaggregation of psychopathy into primary and secondary variants. This study examines whether variants of psychopathy can be identified in a subsample (n = 116) of juvenile offenders with high scores on the Youth Version of the Psychopathy Checklist (PCL:YV). Model-based cluster analysis of offenders' scores on the PCL:YV and a measure of anxiety suggested a two-group solution. The derived clusters manifested expected differences across theoretically relevant constructs of abuse history, hostility, and psychiatric symptoms. Compared with low-anxious primary variants, high-anxious secondary variants manifested more institutional violence, greater psychosocial immaturity, and more instability in institutional violence over a 2-year period, but similar stability in PCL:YV scores. PMID- 20703787 TI - Robert Stoller's Sex and Gender: 40 years on. AB - By its title, Sex and Gender announced a conceptual breakthrough in distinguishing basic elements of human experience. In Robert Stoller's first book, patients illustrating this divergence were lucidly presented. Transvestites and the newly publicized transsexuals were two examples. Clinical and dynamic distinctions between the two formed a basis for Stoller's criteria for patient selection for "sex change." They remain current. The complex identity of the intersexed was described with sensitivity and insight. It, too, remains timely. An innovative description of the genesis of boyhood transsexualism was presented in considerable detail. This finding is less commonly reported today but is also not looked for. Stoller was sympathetic to the request for sex change. He credited a biological contribution to the development of masculinity and femininity. Both stances were remarkable for a psychoanalyst. Robert Stoller introduced the term "gender identity." It is now our vocabulary when we articulate this bedrock of personhood. PMID- 20703786 TI - Perinatal and socioeconomic risk factors for variable and persistent cognitive delay at 24 and 48 months of age in a national sample. AB - The objective of this paper is to examine patterns of cognitive delay at 24 and 48 months and quantify the effects of perinatal and sociodemographic risk factors on persistent and variable cognitive delay. Using data from 7,200 children in the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B), multiple logistic regression models identified significant predictors of low cognitive functioning at 24 and 48 months. Additional multiple logistic models predicting cognitive delay at 48 months were estimated separately for children with and without delay at 24 months. Of the nearly 1,000 children delayed at 24 months, 24.2% remained delayed by 48 months; 7.9% of the children not delayed at 24 months exhibited delay at 48 months. Low and very low birthweight increased cognitive delay risk at 24, but not 48 months. Low maternal education had a strongly increasing effect (OR = 2.3 at 24 months, OR = 13.7 at 48 months), as did low family income (OR = 1.4 at 24 months, OR = 7.0 at 48 months). Among children delayed at 24 months, low maternal education predicted delay even more strongly at 48 months (OR = 30.5). Low cognitive functioning is highly dynamic from 24 to 48 months. Although gestational factors including low birthweight increase children's risk of cognitive delay at 24 months, low maternal education and family income are more prevalent in the pediatric population and are much stronger predictors of both persistent and emerging delay between ages 24 and 48 months. PMID- 20703788 TI - Disregarding science, clinical utility, and the DSM's definition of mental disorder: the case of exhibitionism, voyeurism, and frotteurism. PMID- 20703789 TI - The number of sexual partners and health-risking sexual behavior: prediction from high school entry to high school exit. AB - Precursors to adolescent health-risking sexual behavior (HRSB) were examined in a normative sample of 373 adolescents (48.0% female, n = 178). Using a variable oriented approach, we regressed the number of sexual partners at high school exit (age 17) on parental monitoring, association with delinquent peers, romantic relationship status, problem behavior, physical maturity, and tobacco and alcohol use at high school entry (age 14); all emerged as significant predictors except alcohol use and physical maturity (we found sex differences in physical maturity and romantic relationship status, with females being more advanced in both areas). Sexual experimentation at high school entry served to partially or fully mediate the impact of these factors. A person-oriented approach, using a broader measure of HRSB, found three subgroups of adolescents: abstainers, low-risk takers, and high-risk-takers. Results predicting membership in these groups generally followed those from the variable-oriented analysis. Implications for the prevention of HRSB and future research directions are discussed. PMID- 20703790 TI - Congenic mouse strains enable discrimination of genetic determinants contributing to fear and fear memory. AB - The ability to learn and remember is variable within a population of a given species, including humans. This is due in part to genetic variation between individuals. However, only few genes have been identified that contribute to variation in learning and memory. Two inbred mouse strains, C57Bl/6J (B6) and DBA/2J (D2), show significant variation both in fear conditioning memory as well as primary responsiveness to fear. Several studies have identified quantitative trait loci (QTL) on chromosomes (Chr) 1 and 12 associated with performance in fear conditioning, but it is unclear if these QTL were associated with fear memory or innate fear responsiveness. To determine if these QTL are associated with fear memory or fear responsiveness, we studied congenic mouse strains harbouring D2-derived DNA from Chr1 or Chr12 on a B6 genetic background. Cohorts of D2, B6 and the congenic mice were tested throughout the process of fear conditioning by measuring a series of fear-related parameters. The Chr1 congenic mice showed clear deficits in fear memory compared to B6 mice, which established the presence of a QTL on Chr1 directly influencing fear memory. The Chr12 congenic mice also showed alterations in fear conditioning, but this was more associated with alterations in fear responsiveness. These findings thus provide evidence for the localisation of independent genetic determinants for fear memory and fear responsiveness. PMID- 20703791 TI - Using non-normal SEM to resolve the ACDE model in the classical twin design. AB - One of the biggest problems in classical twin studies is that it cannot estimate additive genetic (A), non-additive genetic (D), shared environmental (C), and non shared environmental (E) effects, simultaneously, because the model, referred to as the ACDE model, has negative degrees of freedom when using Structural Equation Modeling (SEM). Therefore, instead of the ACDE model, the ACE model or the ADE model is actually used. However, using the ACE or ADE models almost always leads to biased estimates. In the present paper, the univariate ACDE model is developed using non-normal Structural Equation Modeling (nnSEM). In SEM, (1st- and) 2nd order moments, namely, (means and) covariances are used as information. However, nnSEM uses higher-order moments as well as (1st- and) 2nd-order moments. nnSEM has a number of advantages over SEM. One of which is that nnSEM can specify models that cannot be specified using SEM because of the negative degrees of freedom. Simulation studies have shown that the proposed method can decrease the biases. There are other factors that have possible effects on phenotypes, such as higher-order epistasis. Since the proposed method cannot estimate these effects, further research on developing a more exhaustive model is needed. PMID- 20703792 TI - Substance use and the quality of patient-provider communication in HIV clinics. AB - The objective of this study was to estimate the influence of substance use on the quality of patient-provider communication during HIV clinic encounters. Patients were surveyed about unhealthy alcohol and illicit drug use and rated provider communication quality. Audio-recorded encounters were coded for specific communication behaviors. Patients with vs. without unhealthy alcohol use rated the quality of their provider's communication lower; illicit drug user ratings were comparable to non-users. Visit length was shorter, with fewer activating/engaging and psychosocial counseling statements for those with vs. without unhealthy alcohol use. Providers and patients exhibited favorable communication behaviors in encounters with illicit drug users vs. non-users, demonstrating greater evidence of patient-provider engagement. The quality of patient-provider communication was worse for HIV-infected patients with unhealthy alcohol use but similar or better for illicit drug users compared with non-users. Interventions should be developed that encourage providers to actively engage patients with unhealthy alcohol use. PMID- 20703793 TI - A surveillance report of HIV status and high risk behaviors among rapid testing participants in Tallinn, Estonia. AB - Estonia has the second highest adult HIV prevalence in Europe of 1.3%. The primary transmission is among injecting drug users (IDU), who account for 56-90% of HIV infections (Report on the Global AIDS Epidemic: UNAIDS/WHO, July 2008 and Platt et al. AIDS 20(16):2120-2123, 2006). Of those persons newly diagnosed, 50.4% reported injecting drugs in the last 12 months, 16.3% of these reported IDU as the sole risk factor and 31.2% reported IDU among other risk factors. In this sample (n = 790) 170 persons reported a high risk behavior and 51 persons received a positive result through rapid testing. The largest proportion (35.29%) was among persons reporting high risk heterosexual intercourse and second (33.33%) among persons sharing injecting equipment. Covariates in a logistic regression model indicate that male sex (OR = 2.57, 95% CI 1.00-6.59), non Estonian ethnicity (OR = 2.68, 95% CI 1.46-4.93), higher education (OR = 0.56, 95% CI 0.40-0.80), and high risk heterosexual intercourse (OR = 2.68, 95% CI 1.19 6.02) are statistically significant in predicting a positive HIV status. PMID- 20703794 TI - The impact of highly active antiretroviral therapy on activities of daily living in HIV-infected adults in South Africa. AB - This study investigated the relationship between highly active antiretroviral therapy (HAART) and instrumental activities of daily living (IADLs) among two clinical cohorts in South Africa. Between 2003 and 2008 structured questionnaires were administered to HIV-positive patients attending outpatient clinics at an urban hospital (Soweto, n = 3,081) and a rural hospital (Acornhoek, n = 1,247). Among those receiving help, an average of 4.8 and 5.1 h of assistance with IADLs daily was reported (rural and urban participants, respectively), with the patient's mother and children assisting the most. Participants on HAART were 17 and 41% less likely to receive assistance with IADLs in the rural and urban cohorts, respectively, after adjusting for demographic characteristics, healthcare utilization, and CD4 counts. HAART significantly decreased the IADL assistance among patients in South Africa. Alongside clinical benefits, HAART has the potential to reduce the burden of HIV-related care, potentially extending wider social and economic gains to other family members. PMID- 20703795 TI - Effectiveness of an HIV prevention program for women visiting their incarcerated partners: the HOME Project. AB - Having an incarcerated partner presents a unique HIV risk for women, particularly low-income women of color. We developed a population-specific risk reduction intervention for women visiting men in prison that was peer educator-based and included individual and community-level intervention components. Women who were assessed prior to the intervention period had a positive association between the number of unprotected penetrative intercourse (UPI) episodes prior to their partners' incarceration and the number of UPI episodes following partners' release from prison. However, this association was negated among women assessed during the intervention. Intervention participants also were more likely to be tested for HIV, to have partners who got tested, and to talk with their partners about significantly more HIV-related topics. Conducting intervention and evaluation activities with women visiting incarcerated men is feasible and is a useful model for reaching more at-risk women. PMID- 20703796 TI - Transfer of cryopreserved - thawed embryos in hCG induced natural or clomiphene citrate cycles yields similar live birth rates in normo-ovulatory women. AB - INTRODUCTION: the purpose of this retrospective analysis is to compare the efficiency of hCG-induced natural and Clomiphene citrate (CC) cycles in normovulatory patients undergoing frozen embryo transfer (FET). MATERIALS AND METHODS: it was retrospectively conducted in the Dutchspeaking Free University of Brussels and covered the period from April 2003 to August 2006. In particular, 428 day-three FET cycles belonging to the two comparative groups were recruited. Of these FET cycles, 261 were hCG-induced natural and 167 clomiphene citrate induced cycles. RESULTS: no statistically significant difference was observed in live birth rate between CC and natural group (22.2% versus 22.6%), respectively (P = 0.708). Except for the number of embryos transferred (1.72 +/- 0.46 for cc group versus 1.63 +/- 0.48 for natural group, p = 0.045), no other parameters seem to influence the outcome. discussion: To our knowledge, this is the first attempt to investigate which of the above mentioned regimens is optimal for normo ovulatory women in FET cycles. A similar delivery outcome was observed for hCG induced natural and CC-induced cycles used for endometrial preparation in FET. PMID- 20703797 TI - Characterizing photothrombotic distal middle cerebral artery occlusion and YAG laser-induced reperfusion model in the Izumo strain of spontaneously hypertensive rats. AB - No study has systematically studied the relevance of original Izumo strain of spontaneously hypertensive rats (SHR/Izm) as a stroke model. Furthermore, both SHR/Izm and stroke-prone SHR/Izm (SHRSP/Izm) are commercially available, and recent progress in genetic studies allowed us to use several congenic strains of rats constructed with SHR/Izm and SHRSP/Izm as the genetic background strains. A total of 166 male SHR/Izm and 17 male SHRSP/Izm were subjected to photothrombotic middle cerebral artery (MCA) occlusion with or without YAG laser-induced reperfusion. The pattern of distal MCA was recorded. Infarct volumes were determined with 2,3,5-triphenyltetrazolium chloride. At 24 or 48 h after MCA occlusion, infarct volumes in the permanent occlusion and 2-h occlusion groups (88 +/- 22 [SD] and 87 +/- 25 mm3, respectively) were significantly larger than that in the 1-h occlusion group (45 +/- 14 mm3), indicating the presence of sizeable zone of penumbra. Infarct size in SHRSP/Izm determined at 24 h after MCA occlusion was fairly large (124.0 +/- 34.8 mm3, n = 10). Infarct volume in SHR/Izm with simple distal MCA was 76 +/- 19 mm3, which was significantly smaller than 95 +/- 22 mm3 in the other SHR/Izm with more branching MCA. These data suggest that this stroke model in SHR/Izm is useful in the preclinical testing of stroke therapies and elucidating the pathophysiology of cerebral ischemia/reperfusion. PMID- 20703798 TI - Integrated technologies for solid waste bin monitoring system. AB - The integration of communication technologies such as radio frequency identification (RFID), global positioning system (GPS), general packet radio system (GPRS), and geographic information system (GIS) with a camera are constructed for solid waste monitoring system. The aim is to improve the way of responding to customer's inquiry and emergency cases and estimate the solid waste amount without any involvement of the truck driver. The proposed system consists of RFID tag mounted on the bin, RFID reader as in truck, GPRS/GSM as web server, and GIS as map server, database server, and control server. The tracking devices mounted in the trucks collect location information in real time via the GPS. This information is transferred continuously through GPRS to a central database. The users are able to view the current location of each truck in the collection stage via a web-based application and thereby manage the fleet. The trucks positions and trash bin information are displayed on a digital map, which is made available by a map server. Thus, the solid waste of the bin and the truck are being monitored using the developed system. PMID- 20703799 TI - Adaptive responses and latent costs of multigeneration cadmium exposure in parasite resistant and susceptible strains of a freshwater snail. AB - Population response to anthropogenic activities will be influenced by prior adaptation to environmental conditions. We tested how parasite-resistant and susceptible strains of the freshwater snail, Biomphalaria glabrata, responded to cadmium and elevated temperature challenges after having been exposed to low level cadmium continuously for multiple generations. Snails exposed to cadmium for three generations were removed for the fourth generation, and challenged in the fifth generation with (1) chronic cadmium exposure over the entire life cycle; (2) lethal cadmium exposure of adults; and (3) elevated temperature challenge of adults. The parasite susceptible NMRI strain is more cadmium tolerant than the parasite resistant BS90 strain and remained more tolerant than BS90 throughout this study. Additionally, NMRI exhibited greater adaptive capacity for cadmium than BS90 and became more tolerant of both chronic and lethal cadmium challenges, while BS90 became more tolerant of lethal cadmium challenge only. Fitness costs, reflected in population growth rate, were not apparent in fifth generation snails maintained in control conditions. However, costs were latent and expressed as decreased tolerance to a secondarily imposed temperature stress. Adaptation to prior selection pressures can influence subsequent adaptation to anthropogenic stresses and may have associated costs that reduce fitness in novel environments. PMID- 20703800 TI - Normalization strategies for microRNA profiling experiments: a 'normal' way to a hidden layer of complexity? AB - MicroRNA (miRNA) profiling is a first important step in elucidating miRNA functions. Real time quantitative PCR (RT-qPCR) and microarray hybridization approaches as well as ultra high throughput sequencing of miRNAs (small RNA-seq) are popular and widely used profiling methods. All of these profiling approaches face significant introduction of bias. Normalization, often an underestimated aspect of data processing, can minimize systematic technical or experimental variation and thus has significant impact on the detection of differentially expressed miRNAs. At present, there is no consensus normalization method for any of the three miRNA profiling approach. Several normalization techniques are currently in use, of which some are similar to mRNA profiling normalization methods, while others are specifically modified or developed for miRNA data. The characteristic nature of miRNA molecules, their composition and the resulting data distribution of profiling experiments challenges the selection of adequate normalization techniques. Based on miRNA profiling studies and comparative studies on normalization methods and their performances, this review provides a critical overview of commonly used and newly developed normalization methods for miRNA RT-qPCR, miRNA hybridization microarray, and small RNA-seq datasets. Emphasis is laid on the complexity, the importance and the potential for further optimization of normalization techniques for miRNA profiling datasets. PMID- 20703801 TI - A new method for the detection of the H5 influenza virus by magnetic beads capturing quantum dot fluorescent signals. AB - A new method to detect H5 influenza virus using quantum dots (QDs) and magnetic beads (MBs) is described. QDs conjugated with oligonucleotide probes were used to produce fluorescent signals and MBs, that were also conjugated with probes, were used to isolate and concentrate the signals. Target viral RNAs led to a sandwich hybridization between the functionalized QDs and MBs. One-step hybridization facilitated the subtype determination. As little as 0.1 ng viral RNA could be detected. PMID- 20703802 TI - Assigning biological functions to rice genes by genome annotation, expression analysis and mutagenesis. AB - Rice is the first cereal genome to be completely sequenced. Since the completion of its genome sequencing, considerable progress has been made in multiple areas including the whole genome annotation, gene expression profiling, mutant collection, etc. Here, we summarize the current status of rice genome annotation and review the methodology of assigning biological functions to hundreds of thousands of rice genes as well as discuss the major limitations and the future perspective in rice functional genomics. Available data analysis shows that the rice genome encodes around 32,000 protein-coding genes. Expression analysis revealed at least 31,000 genes with expression evidence from full-length cDNA/EST collection or other transcript profiling. In addition, we have summarized various strategies to generate mutant population including natural, physical, chemical, T DNA, transposon/retrotransposon or gene silencing based mutagenesis. Currently, more than 1 million of mutants have been generated and 27,551 of them have their flanking sequence tags. To assign biological functions to hundreds of thousands of rice genes, global co-operations are required, various genetic resources should be more easily accessible and diverse data from transcriptomics, proteomics, epigenetics, comparative genomics and bioinformatics should be integrated to better understand the functions of these genes and their regulatory mechanisms. PMID- 20703803 TI - A novel one-step strategy for the preparation of HLA/HBc(18-27) and HLA/CEA (694 702) complexes with ion exchange chromatography. AB - The heavy chain protein of HLA-peptide complexes (HLA/HBc(18-27) and HLA/CEA(694 702)) immobilized onto an ion exchange chromatography column and then the dilution-refolded HBc(18-27)-fused or CEA(694-702)-fused beta2m protein was able to pass through the column. Using this method, HLA/peptide complexes were prepared within 30 h with a refolding yield of at least 20% (w/w) and purity of over 80% (w/w). This strategy refolds, concentrates, and purifies HLA/peptide complexes in a single integrated step and offers a potential tool to refold multiple-subunit proteins other than the major histocompatibility complex (MHC)/peptide complexes. PMID- 20703804 TI - Acetate accumulation through alternative metabolic pathways in ackA (-) pta (-) poxB (-) triple mutant in E. coli B (BL21). AB - Individual deletions of acs and aceA genes in E. coli B (BL21) showed little difference in the metabolite accumulation patterns but deletion of the ackA gene alone or together with pta showed acetic acid gradually accumulated to 3.1 and 1.7 g/l, respectively, with a minimal extended lag in bacterial growth and a higher pyruvate formation. Single poxB deletion in E. coli B (BL21) or additional poxB deletion in the ackA-pta mutants did not change the acetate accumulation pattern. When the acetate production genes (ackA-pta-poxB) were deleted in E. coli B (BL21) acetate still accumulated. This may be an indication that perhaps acetate is not only a by-product of carbon metabolism; it is possible that acetate plays also a role in other cellular metabolite pathways. It is likely that there are alternative acetate production pathways. PMID- 20703805 TI - A novel, thermostable manganese-containing superoxide dismutase from Bacillus licheniformis. AB - A new, thermostable superoxide dismutase (SOD) from Bacillus licheniformis M20, isolated from Bulgarian mineral springs, was purified 11-fold with 11% recovery of activity. From native PAGE and SDS-PAGE, the enzyme was composed of two subunits of 21.5 kDa each. The SOD was inhibited only by NaN(3), which suggested that this SOD is of the manganese superoxide dismutase type. The purified enzyme had maximum activity at pH 8 and 55 degrees C. The half-life of the SOD was 10 min at 95 degrees C. PMID- 20703806 TI - Endogeneous beta-D: -xylosidase and alpha-L: -arabinofuranosidase activity in flax seed mucilage. AB - Flax seed mucilage (FM) contains a mixture of highly doubly substituted arabinoxylan as well as rhamnogalacturonan I with unusual side group substitutions. Treatment of FM with a GH11 Bacillus subtilis XynA endo 1,4-beta xylanase (BsX) gave limited formation of reducing ends but when BsX and FM were incubated together on different wheat arabinoxylan substrates and birchwood xylan, significant amounts of xylose were released. Moreover, arabinose was released from both water-extractable and water-unextractable wheat arabinoxylan. Since no xylose or arabinose was released by BsX addition alone on these substrates, nor without FM or BsX addition, the results indicate the presence of endogenous beta-D: -xylosidase and alpha-L: -arabinofuranosidase activities in FM. FM also exhibited activity on both p-nitrophenyl alpha-L: -arabinofuranoside (pNPA) and p-nitrophenyl beta-D: -xylopyranoside (pNPX). Based on K ( M ) values, the FM enzyme activities had a higher affinity for pNPX (K ( M ) 2 mM) than for pNPA (K ( M ) 20 mM). PMID- 20703807 TI - Both the constitutive cauliflower mosaic virus 35S and tissue-specific AGAMOUS enhancers activate transcription autonomously in Arabidopsis thaliana. AB - The expression of eukaryotic genes from their cognate promoters is often regulated by the action of transcriptional enhancer elements that function in an orientation-independent manner either locally or at a distance within a genome. This interactive nature often provokes unexpected interference within transgenes in plants, as reflected by misexpression of the introduced gene and undesired phenotypes in transgenic lines. To gain a better understanding of the mechanism underlying enhancer/promoter interactions in a plant system, we analyzed the activation of a beta-glucuronidase (GUS) reporter gene by enhancers contained within the AGAMOUS second intron (AGI) and the Cauliflower Mosaic Virus (CaMV) 35S promoter, respectively, in the presence and absence of a target promoter. Our results indicate that both the AGI and 35S enhancers, which differ significantly in their species of origin and in the pattern of expression that they induce, have the capacity to activate the expression of a nearby gene through the promoter-independent initiation of autonomous transcriptional events. Furthermore, we provide evidence that the 35S enhancer utilizes a mechanism resembling animal- and yeast-derived scanning or facilitated tracking models of long-distance enhancer action in its activation of a remote target promoter. PMID- 20703809 TI - Anti-Leptospira sp. agglutinins in ewes in the Federal District, Brazil. AB - To define the prevalence of anti-Leptospira sp. agglutinins in ewes in the Federal District, Brazil, serum samples from 157 ewes were tested for antibodies against serovars of Leptospira sp. by the microscopic agglutination test. Antibodies were detected in three flocks in a prevalence of 3% (95% CI = 0.4% 5.7%). Considering that sheep and cattle were raised together, the lack of sanitary control could represent a risk to cattle production, which is the most important activity in the Centre-West region of Brazil. PMID- 20703808 TI - Expression of Bt-Cry3A in transgenic Populus alba * P. glandulosa and its effects on target and non-target pests and the arthropod community. AB - During the growing seasons of 2006-2008, feeding tests and field studies were conducted in Beijing, China, to investigate the effects of transgenic Bacillus thuringiensis (Bt) poplar (BGA-5) expressing the Cry3A protein (0.0264-0.0326% of the total soluble protein) on target and non-target pests and the arthropod community. The effects of BGA-5 on the target pest Plagiodera versicolora (Coleoptera, Chrysomelidae) and a non-target pest Clostera anachoreta (Lepidoptera, Notodontidae), were assessed under laboratory conditions. Total mortality of P. versicolora larvae fed with BGA-5 leaves was significantly higher than that of the control (P < 0.05). The exuviation index of P. versicolora larvae fed with BGA-5 tended to be higher than that of CK, but it was not significantly different. The pupation rate and eclosion rate of the survived larvae fed with BGA-5 were lower than that of CK, but it was also not significantly different. Additionally, no significant differences were detected in the mortality, exuviations index, pupation rate, or eclosion rate of C. anachoreta fed with leaves of transgenic and non-transgenic poplars. Furthermore, the arthropod communities in the Bt poplar and CK field stands were similar, as indicated by four diversity indices (Berge-Parker index, Shannon-Wiener indices, evenness index, and Simpson's inverted index) and the Bray-Curtis index. Therefore, the Bt-Cry3A poplar decreased damage by the target pest (P. versicolora), had no effects on a non-target pest (C. anachoreta), and generally did not have any significant negative effect on the poplar arthropod community. PMID- 20703810 TI - Factors that determine use of breeding services by smallholder dairy farmers in Central Kenya. AB - This study examined the determinants of smallholder dairy farmers' use of breeding services in Nyandarua and Kiambu districts, Central Kenya. Data was collected through semi-structured interviews with 140 randomly selected respondents. The breeding services considered were artificial insemination (AI), natural bull service, or a combination of AI and bull services. A multinomial logit econometric model was used fitting AI as the base category. There was a negative relationship between higher levels of education, herd size, and location and the use of bull service. However, education, herd size, and credit were positively related to the combined option. The results indicate that uptake of AI services after the liberalization of the sector is influenced by other factors besides cost-related factors. Factors such as accessibility to breeding services and product markets had influence on the farmer decision to choose among the available breeding services. The effectiveness of the breeding services in terms of successful conception also plays a big role in the choice. A need for concerted efforts to increase farmer's knowledge base on utilization and effectiveness of available breeding services is imperative. Furthermore, smallholder dairy farming could be made more sustainable and economically viable by implementing initiatives geared towards enhancing access to breeding services that would guarantee access to quality genetic material. PMID- 20703811 TI - Impact of preexisting diabetes mellitus on outcome after liver transplantation in patients with hepatitis B virus-related liver disease. AB - BACKGROUND: Preexisting diabetes mellitus (DM) has been reported to have an adverse consequence on patient prognosis after liver transplantation in the West. So far, there are few reports on the effect of preexisting DM on outcome of liver transplant recipients with HBV infection. AIMS: We aimed to examine the impact of preexisting DM on post-transplant outcome in Chinese patients with HBV-related liver disease. METHODS: The post-transplant morbidities and patient survival were compared between 48 diabetes patients (DM group) and 96 non-diabetes patients (control group) matched for age, gender, primary disease and model for end-stage liver diseases score. The DM group was further divided into hyperglycemia patients (fasting blood glucose >8.0 mmol/L, n = 22) and non-hyperglycemia patients (fasting blood glucose <=8.0 mmol/L, n = 26). RESULTS: Patient characteristics were comparable between both groups, except a higher incidence of hepatic encephalopathy in the DM group than that in the control group (22.9% vs. 10.4%, P = 0.045). The incidences of post-transplant complications and patient survival did not differ significantly between the DM and control groups, or between non-hyperglycemia patients and their matched case controls. Hyperglycemia patients showed a higher incidence of post-transplant sepsis (18.2% vs. 2.3%, P = 0.039) and biliary complications (31.8% vs. 6.8%, P = 0.012) than their matched case controls. CONCLUSIONS: Preexisting DM is not a contraindication for liver transplantation in patients with HBV-related liver disease. A tight control of blood glucose to a level of <=8.0 mmol/L was necessary to reduce the risk of complications after liver transplantation. PMID- 20703812 TI - Managing obesity in pharmacy: the Australian experience. AB - OBJECTIVE: To explore pharmacists' opinions about the provision of weight management services in community pharmacy and their attitudes towards the establishment of an accredited training course in weight management in pharmacy. SETTING: Interviews were conducted with practising pharmacists on site in various community pharmacies in metropolitan Sydney, Australia. METHOD: In-depth, semi structured interviews with twenty practising pharmacists were conducted. Of the twenty interviewed pharmacists, sixteen were involved in the provision of one or more pharmacy based weight management programs in their pharmacies. Interviews were audio-recorded, transcribed and analysed using the grounded theory approach. MAIN OUTCOME MEASURE: The data were thematically analysed to identify facilitators and perceived barriers to the provision of high quality services, and pharmacists' willingness to undertake training and accreditation. RESULTS: Participants clearly perceived a role for pharmacy in weight management. Key facilitators to provision of service were accessibility and the perception of pharmacists as trustworthy healthcare professionals. The pharmacists proposed collaboration with other healthcare professionals in order to provide a service incorporating diet, exercise and behavioural therapy. A program that was not product-centred, and supported by ethical marketing was favoured. Appropriate training and accreditation were considered essential to assuring the quality of such services. Barriers to the provision of high quality services identified were: remuneration, pharmacy infrastructure, client demand and the current marketing of product-centred programs. CONCLUSION: Australian pharmacists believe there is a role for pharmacy in weight management, provided training in accredited programs is made available. A holistic, evidence-based, multi disciplinary service model has been identified as ideal. PMID- 20703814 TI - A game-theoretic framework for estimating a health purchaser's willingness-to-pay for health and for expansion. AB - A health purchaser's willingness-to-pay (WTP) for health is defined as the amount of money the health purchaser (e.g. a health maximizing public agency or a profit maximizing health insurer) is willing to spend for an additional unit of health. In this paper, we propose a game-theoretic framework for estimating a health purchaser's WTP for health in markets where the health purchaser offers a menu of medical interventions, and each individual in the population selects the intervention that maximizes her prospect. We discuss how the WTP for health can be employed to determine medical guidelines, and to price new medical technologies, such that the health purchaser is willing to implement them. The framework further introduces a measure for WTP for expansion, defined as the amount of money the health purchaser is willing to pay per person in the population served by the health provider to increase the consumption level of the intervention by one percent without changing the intervention price. This measure can be employed to find how much to invest in expanding a medical program through opening new facilities, advertising, etc. Applying the proposed framework to colorectal cancer screening tests, we estimate the WTP for health and the WTP for expansion of colorectal cancer screening tests for the 2005 US population. PMID- 20703815 TI - Postmortem interval effect on RNA and gene expression in human brain tissue. AB - Banked tissue is essential to the study of neurological disease but using postmortem tissue introduces a number of possible confounds. Foremost amongst these are factors relating to variation in postmortem interval (PMI). Currently there are conflicting reports on how PMI affects overall RNA integrity, and very few reports of how gene expression is affected by PMI. We analyzed total RNA extracted from frozen cerebellar cortex from 79 deceased human subjects enrolled in the Banner Sun Health Research Institute Brain and Body Donation Program. The PMI, which ranged from 1.5 to 45 h, correlated with overall RNA quality measures including RNA Integrity Number (RIN) (r = -0.34, P = 0.002) and RNA quantitative yield (r = -0.25, P = 0.02). Additionally, we determined the expression of 89 genes using a PCR-based gene expression array (RT(2) ProfilerTM PCR Array: Human Alzheimer's Disease; SABiosciencesTM, Frederick, MD). A greater proportion of genes had decreased rather than increased expression with increasing PMI (65/89 vs. 20/89; P < 0.0001). Of these, transcripts from the genes ADAM9, LPL, PRKCG, and SERPINA3 had significantly decreased expression with increasing PMI (P < 0.01). No individual gene transcripts had significantly increased expression with increasing PMI. In conclusion, it is apparent that RNA degrades progressively with increasing PMI and that measurement of gene expression in brain tissue with longer PMI may give artificially low values. For tissue derived from autopsy, a short PMI optimizes its utility for molecular research. PMID- 20703816 TI - Synergetic effect of freeze-drying and gamma irradiation on the mechanical properties of human cancellous bone. AB - Freeze-drying and irradiation are common process used by tissue banks to preserve and sterilize bone allografts. Freeze dried irradiated bone is known to be more brittle. Whether bone brittleness is due to irradiation alone, temperature during irradiation or to a synergetic effect of the freeze-drying-irradiation process was not yet assessed. Using a left-right femoral head symmetry model, 822 compression tests were performed to assess the influence of sequences of a 25 kGy irradiation with and without freeze-drying compared to the unprocessed counterpart. Irradiation of frozen bone did not cause any significant reduction in ultimate strength, stiffness and work to failure. The addition of the freeze drying process before or after irradiation resulted in a mean drop of 35 and 31% in ultimate strength, 14 and 37% in stiffness and 46 and 37% in work to failure. Unlike irradiation at room temperature, irradiation under dry ice of solvent detergent treated bone seemed to have no detrimental effect on mechanical properties of cancellous bone. Freeze-drying bone without irradiation had no influence on mechanical parameters, but the addition of irradiation to the freeze drying step or the reverse sequence showed a detrimental effect and supports the idea of a negative synergetic effect of both procedures. These findings may have important implications for bone banking. PMID- 20703817 TI - Culture and differentiation of osteoblasts on coral scaffold from human bone marrow mesenchymal stem cells. AB - In this paper we describe an approach that aims to provide fundamental information towards a scientific, biomechanical basis for the use of natural coral scaffolds to initiate mesenchymal stem cells into osteogenic differentiation for transplant purposes. Biomaterial, such as corals, is an osteoconductive material that can be used to home human derived stem cells for clinical regenerative purposes. In bone transplantation, the use of biomaterials may be a solution to bypass two main critical obstacles, the shortage of donor sites for autografts and the risk of rejection with allograft procedures. Bone regeneration is often needed for multiple clinical purposes for instance, in aesthetic reconstruction and regenerative procedures. Coral graft Porites lutea has been used by our team for a decade in clinical applications on over a thousand patients with different bone pathologies including spinal stenosis and mandibular reconstruction. It is well accepted that human bone marrow (hBM) is an exceptional source of mesenchymal stem cells (MSCs), which may differentiate into different cell phenotypes such as osteoblasts, chondrocytes, adipocytes, myocytes, cardiomyocytes and neurons. Isolated MSCs from human bone marrow were induced into osteoblasts using an osteogenic medium enriched with two specific growth factors, FGF9 and vitamin D2. Part of the cultured MSCs were directly transferred and seeded onto coral scaffolds (Porites Lutea) and induced to differentiate into osteoblasts and part were cultured in flasks for osteocell culture. The data support the concept that hBM is a reliable source of MSCs which may be easily differentiated into osteoblasts and seeded into coral as an optimal device for clinical application. Within this project we have also discussed the biological nature of MSCs, their potential application for clinical transplantation and the prospect of their use in gene therapy. PMID- 20703818 TI - Hemorrhagic pituitary macroadenoma: characteristics, endoscopic endonasal transsphenoidal surgery, and outcomes. AB - PURPOSE: This study aims to assess the effect of endoscopic endonasal transsphenoidal surgery (EETSS) of hemorrhagic pituitary macroadenoma (HPMA). PATIENTS AND METHODS: We retrospectively reviewed 52 cases with HPMA collected from the Xijing Hospital from April 1995 to April 2009. There were 39 males and 13 females, ranging in age from 18 to 79 years (average 51.6 years). Patients presented with headache or acute ophthalmological symptoms after adenoma hemorrhage. Computed tomography (CT) scan and magnetic resonance imaging (MRI) showed pituitary macroadenoma with hemorrhage in all cases. Twenty-eight adenomas showed marked suprasellar extension, 19 showed moderate extension, and another 5 showed slight extension. All patients were promptly treated by emergency EETSS, usually within 24 h after hospitalization. RESULTS: Total removal of tumor was achieved in 46 cases (88.5%), and subtotal removal in 6 cases (11.5%). Postoperative radiotherapy and reoperation of the tumor were required in five patients with either residual or relapsed tumors. Follow-up ranged from 8 to 93 months (mean 41.6 months) for 43 cases. Visual acuity and visual field recovery and improvement was recorded in 92.1% and 94.3% of patients who had preoperative visual symptoms, respectively. CONCLUSIONS: The majority of macroadenomas are hemorrhagic, and they often occur in middle-aged, male subjects. Detection by imaging in the setting of pituitary apoplexy accurately predicts the nature of the apoplectic process and helps to guide the type and timing of surgery. Early EETSS is the most effective therapy and significantly improves visual outcomes and systemic conditions. PMID- 20703819 TI - Improved testing for microsatellite instability in colorectal cancer using a simplified 3-marker assay. AB - BACKGROUND: In colorectal cancer (CRC), microsatellite instability (MSI) is a valuable marker of defective DNA mismatch repair that identifies cancers with distinct phenotypic properties, including favorable survival. However, the optimal assay for MSI status is unknown. We have evaluated a simplified 3-marker assay for MSI and compared it with the 5-marker (NCI) assay to see if technical variations in MSI testing are important. MATERIALS AND METHODS: DNA samples from 357 CRCs were evaluated for MSI using the 5 microsatellite markers recommended for the NCI assay (BAT 25, BAT26, D2S123, D5S346, and D17S250). Results were compared with a simplified 3-marker assay (BAT25, BAT26, and D2S123). CRCs identified as MSI were evaluated for their clinical, pathological, and genetic characteristics. RESULTS: The 5-marker assay identified 96 cancers as MSI. Only 56 of these were MSI by the 3-marker assay (3-marker+ group), leaving 40 cases identified as MSI only by NCI criteria (3-marker- group). The remaining 261 cancers were microsatellite stable (MSS). The 3-marker+ MSI tumors had features characteristic of MSI tumors: more proximal, poorly differentiated, associated with hereditary nonpolyposis colorectal cancer (HNPCC), more BRAF mutations, fewer KRAS mutations, better 5-year disease-specific survival, more frequent mismatch repair (MMR) protein loss, and less likely to be metastatic on presentation (P < .05). Chromosomal arm loss was observed only in 3-marker- MSI and MSS cancers (P < .05). CONCLUSION: The 3-marker MSI assay outperforms the traditional 5-marker assay for identifying patients with favorable prognosis and homogeneous clinical and genetic features. More accurate MSI testing should improve prognostic and predictive scoring systems for colorectal cancer. PMID- 20703820 TI - Inspiratory airflow dynamics during sleep in veterans with Gulf War illness: a controlled study. AB - PURPOSE: To determine whether veterans with Gulf War Illness (GWI) are distinguished by sleep-disordered breathing, we compared inspiratory airflow dynamics during sleep between veterans with GWI and asymptomatic veterans of the first Gulf War. METHODS: We recruited 18 male veterans with GWI and 11 asymptomatic male veterans of the first Gulf War by advertisement. The two samples were matched for age and body mass index. Each participant underwent a first full-night polysomnogram (PSG) while sleeping supine using standard clinical monitoring of sleep and breathing. A second PSG was performed measuring airflow with a pneumotachograph in series with a nasal mask and respiratory effort with a supraglottic pressure (Psg) catheter to assess the presence of inspiratory airflow limitation during supine N2 sleep. We determined the prevalence of flow-limited breaths by sampling continuous N2 sleep and plotting inspiratory flow against Psg for each breath in the sample. We expressed the prevalence of flow-limited breaths as their percentage in the sample. RESULTS: Compared to controls, veterans with GWI had an increased frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation. During supine N2 sleep, veterans with GWI had 96 +/- 5% (mean +/- SD) of their breaths flow-limited while controls had 36 +/- 25% of their breaths flow limited (p < 0.0001). CONCLUSIONS: Veterans with GWI experience sleep-disordered breathing that may distinguish them from asymptomatic veterans of the first Gulf War. PMID- 20703821 TI - Renal cell carcinoma: ten years of significant advances. PMID- 20703822 TI - Increased lipid peroxidation in LDL from type-2 diabetic patients. AB - Increased oxidative stress is associated with type-2 diabetes and related cardiovascular diseases, but oxidative modification of LDL has been partially characterized. Our aim was to compare the lipid and fatty acid composition as well as the redox status of LDL from diabetic patients and healthy subjects. First, to ensure that isolation of LDL by sequential ultracentrifugation did not result in lipid modifications, lipid composition and peroxide content were determined in LDL isolated either by ultracentrifugation or fast-protein liquid chromatography. Both methods resulted in similar concentrations of lipids, fatty acids, hydroxy-octadecadienoic acid (HODE) and malondialdehyde (MDA). Then, LDLs were isolated by ultracentrifugation from eight type-2 diabetic patients and eight control subjects. Compared to control LDL, diabetic LDL contained decreased cholesteryl esters and increased triglyceride concentrations. Ethanolamine plasmalogens decreased by 49%. Proportions of linoleic acid decreased in all lipid classes, while proportions of arachidonic acid increased in cholesteryl esters. Total HODE concentrations increased by 56%, 12- and 15-hydroxy eicosatetraenoic acid by 161 and 86%, respectively, and MDA levels increased by twofold. alpha-Tocopherol concentrations, expressed relative to triglycerides, were lower in LDL from patients compared to controls, while gamma-tocopherol did not differ. Overall, LDL from type-2 diabetic patients displayed increased oxidative stress. Determination of hydroxylated fatty acids and ethanolamine plasmalogen depletion could be especially relevant in diabetes. PMID- 20703823 TI - A study on the transfer of iron in soil-plant-animal continuum under semi-arid environmental conditions in Sargodha, Pakistan. AB - The present investigation on the iron (Fe) transfer from soil to plant and in turn to animal (cows), as a function of sampling periods was conducted at the Livestock Experimental Station Sargodha, Pakistan which falls under semi-arid conditions. Although the iron transfer from soil to forage increased consistently, the forage Fe content decreased progressively with increase in sampling period. Highest Fe transfer from forage to cow blood plasma was observed during October and lowest during January. The transfer of Fe from forage to animal milk was maximum during the months of October and January and minimum during December. The transfer of Fe to plasma and milk was found to be dependent variably on the growth stage of forage in this investigation. Based on the findings of the present study, it is evident that mineral supplementation with higher Fe availability is urgently warranted to the animals particularly during the months of December and January to enhance plasma Fe in the cows being reared at that livestock farm during the entire grazing period. Thus, obligatory supplementation of Fe to the ruminants is highly recommended. Since the processes involved in iron management system in humans, animals, and plants are basically similar, appropriate elemental management must be provided to the living organisms, otherwise deficient or excessive levels of iron may deteriorate the developing cells of the organisms. PMID- 20703825 TI - Evaluation of status of cadmium, lead, and nickel levels in biological samples of normal and night blindness children of age groups 3-7 and 8-12 years. AB - The causes of night blindness in children are multifactorial, and particular consideration has been given to childhood trace metals toxicity, which is the most common problem found in underdeveloped countries. This study was designed to compare the levels of cadmium (Cd), lead (Pb), and nickel (Ni) in scalp hair, blood, and urine of night blindness children age ranged 3-7 and 8-12 years of both genders, comparing them to sex- and age-matched controls. A microwave assisted wet acid digestion procedure was developed as a sample pretreatment, for the determination of Cd, Pb, and Ni in biological samples of night blindness children. The proposed method was validated by using conventional wet digestion and certified reference samples of hair, blood, and urine. The digests of all biological samples were analyzed for Cd, Pb, and Ni by electrothermal atomic absorption spectrometry. The results indicated significantly higher levels of Cd, Pb, and Ni in the biological samples (blood, scalp hair, and urine) of male and female night blindness children, compared with control subjects of both genders. These data present guidance to clinicians and other professional investigating toxicity of trace metals in biological samples of night blindness children. PMID- 20703826 TI - Effects of forced running exercise on cognitive function and its relation to zinc homeostasis-related gene expression in rat hippocampus. AB - Voluntary exercise has been implicated to be beneficial for overall health and cognitive function in both clinical and experimental studies, but little is presently known about forced physical exercise on cognition and underlying molecular mechanism. We have used real-time RT-PCR to analyze gene expression in hippocampus, in the presence and absence of physical exercise, during spatial learning of rats in the Morris water maze. Our results show distinct zinc homeostasis-related gene expression profiles associated with learning and memory. Rats with physical exercise (EXP) showed a significant up-regulation of mRNA expression of zinc transporter-2 (ZnT-2), ZnT-4, ZnT-5, ZnT-6, and ZnT-7, metallothionein-1 (MT-1)-MT-3, divalent cation transporter-1, and Zrt-Irt-like proteins-7 in hippocampus when compared with control rats. In addition, spatial learning ability was improved in EXP rats compared with that in control group. This study provides the first comparative view of zinc homeostasis-related gene expression in hippocampus following forced physical exercise. These results suggested that forced physical exercise may provide a simple means to maintain brain function and promote learning capacity. Results of this study also suggest that exercise mobilizes zinc homeostasis-related gene expression profiles that would be predicted to benefit brain plasticity processes. PMID- 20703824 TI - Cytocompatibility of medical biomaterials containing nickel by osteoblasts: a systematic literature review. AB - The present review is based on a survey of 21 studies on the cytocompatibility of medical biomaterials containing nickel, as assessed by cell culture of human and animal osteoblasts or osteoblast-like cells. Among the biomaterials evaluated were stainless steel, NiTi alloys, pure Ni, Ti, and other pure metals. The materials were either commercially available, prepared by the authors, or implanted by various techniques to generate a protective layer of oxides, nitrides, acetylides. The observation that the layers significantly reduced the initial release of metal ions and increased cytocompatibility was confirmed in cell culture experiments. Physical and chemical characterization of the materials was performed. This included, e.g., surface characterization (roughness, wettability, corrosion behavior, quantity of released ions, microhardness, and characterization of passivation layer). Cytocompatibility tests of the materials were conducted in the cultures of human or animal osteoblasts and osteoblast-like cells. The following assays were carried out: cell proliferation and viability test, adhesion test, morphology (by fluorescent microscopy or SEM). Also phenotypic and genotypic markers were investigated. In the majority of works, it was found that the most cytocompatible materials were stainless steel and NiTi alloy. Pure Ni was rendered and less cytocompatible. All the papers confirmed that the consequence of the formation of protective layers was in significant increase of cytocompatibility of the materials. This indicates the possible further modifications of the manufacturing process (formation of the passivation layer). PMID- 20703827 TI - Introduction. The UCLA AIDS Institute. PMID- 20703828 TI - Decolorization of naphthol blue black using the horseradish peroxidase. AB - This study evaluates the potential of the enzyme horseradish peroxidase in the decolorization of one common industrial azo dye, naphthol blue black. Studies are carried out to understand the process parameters such as pH, temperature and reaction time. The enzymatic decolorization of the dye was examined by UV-Vis spectrophotometer and LC-MS measurements. Temperature and pH conditions were optimized for obtaining high azo-dye decolorization. Azo-dye removal at a pH range 4-6 was found to be the highest for all temperatures. After 5 minutes of treatment, the color removal of dye was ca. 80-90%. The LC-MS and spectrophotometric analyses indicated that the decolorization of the azo dye with enzyme was due to the reduction of the azo bonds. This study verifies the viability of the use of the horseradish peroxidase in the decolorization of naphthol blue black. PMID- 20703829 TI - Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse. AB - Retinal excitotoxicity is one of the major causes of retinal ganglion cell (RGC) death in glaucoma. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with potent neuroprotective activity; however, whether it exerts such an effect in the retina and the mechanism by which RGCs are protected is still not well understood. In this study, we examined the effect of exogenous and endogenous PACAP on RGC death induced by N-methyl-D: -aspartate acid (NMDA). The vitreous body of anesthetized adult male mice (C57/BL6J) was injected with NMDA (40 nmol in a 2 MUL saline solution). The number of RGCs decreased from days 1 to 7 after NMDA injection, and the number of dUTP end-labeling (TUNEL)-positive cells, an indicator of cell death, peaked at day 3. However, when PACAP38 (10( 8), 10(-10), 10(-12), 10(-14), or 10(-16)M) was co-administered with NMDA, the 10(-10)M dose resulted in significantly increased RGC survival at day 7, and a decrease in the number of TUNEL-positive RGCs at day 3. We next investigated the neuroprotective effect of endogenous PACAP using PACAP heterozygote(+/-) mice. Under normal circumstances, there was no significant difference in the number of RGCs in the PACAP(+/-) mice compared with their wild-type counterparts. However, the number of RGCs significantly decreased in the PACAP(+/-) mice 7 days after NMDA injection, relative to their wild-type counterparts. The number of TUNEL positive RGCs peaked at day 1 in the PACAP(+/-) mice. These effects in the PACAP(+/-) mice were reversed by intravitreous injection of 10(-10)M PACAP38. This suggests that exogenous PACAP is able to counteract NMDA-induced toxicity, and that endogenous PACAP exerts a neuroprotective effect in the retina. PMID- 20703830 TI - Extensive extramedullary disease involving the colon in multiple myeloma: a case report and review of literature. AB - INTRODUCTION: Organ involvement in multiple myeloma (MM) is characterized by infiltrative disease or by a myelomatous mass known as a plasmacytoma. We present a patient with MM who had extensive extramedullary involvement of the colon and a review of the literature on colon plasmacytomas. CASE REPORT: A 57-year-old male with MM presented with disease relapse in 2007, workup showing biopsy confirmed left perinephric extra-medullary disease involving the adjacent colon. Positron emission-tomography (PET) exhibited intense pan-colonic fluoro-deoxyglucose (FDG) uptake and computed-tomography confirmed extensive infiltrating soft tissue thickening in the ascending, transverse, and descending colon representing plasmacytomas. The patient underwent an autologous hematopoietic stem cell transplantation after conditioning with high-dose melphalan. Restaging PET-scan showed complete resolution of colonic extra-medullary plasmacytomas. Extramedullary plasmacytomas (EMP) are rare and constitute 4% of all plasma cell tumors. DISCUSSION AND CONCLUSION: Colonic plasmacytoma is an extremely rare site, with fewer than 25 cases reported in the literature. Colonic plasmacytomas have different presentations depending on the size and location. Treatment options for primary EMPs include surgical resection, radiotherapy, and chemotherapy. The primary treatment option for secondary EMP is systemic chemotherapy. This rare pan-colonic plasmacytoma, as a part of extramedullary myeloma, showed an impressive response to chemotherapy. PMID- 20703831 TI - Functional pancreatic acinar cell carcinoma extending into the main pancreatic duct and splenic vein. AB - INTRODUCTION: Pancreatic acinar cell carcinoma (ACC) has several unique characteristics, such as its progression pattern, spreading into the pancreatic duct and large blood vessels, and its secretion of pancreatic exocrine enzymes, which induces a paraneoplastic syndrome. CASE REPORT: A 79-year-old Japanese man, with medical history of chronic renal failure, was referred to our institution for the examination of his abdominal pain and hyperglycemia. Plain computed tomography demonstrated a mass lesion, 4 cm in diameter, in the body of pancreas. Abdominal ultrasonogram demonstrated a bulky, hypoechoic mass extending into the splenic vein. Multiple hepatic nodules were detected on suspicion of metastasis. Positron emission tomography using 18F-fluorodeoxyglucoase revealed the tumor extended towards the pancreatic head through the main pancreatic duct. We obtained the tumor tissues from the pancreatic body using endoscopic ultrasound guided fine-needle aspiration biopsy. Pathological diagnosis, supported by immunohistochemistry, was that of an ACC. In the follow-up period, he complained of subcutaneous nodules and arthralgia on his lower legs. Serum and intra articular lipase levels were elevated, 6,420 I/U and 594 I/U, respectively. Histology of the skin lesion at the knee joint showed necrotizing panniculitis with eosinophilic infiltration. The patient was treated with weekly gemcitabine, but succumbed to acute respiratory distress unexpectedly 2 months after the initial diagnosis. PMID- 20703832 TI - Cancer pain emergencies: is there a role for radiation therapy? AB - Emergent cancer pain is a difficult entity to manage. Radiation therapy potentially may be used for its treatment. Several key issues must be addressed in patients with emergent cancer pain before initiating radiation. These issues include whether the necessary diagnostic information is available, whether the tumor will respond rapidly to radiation, and whether there are additional patient factors that will affect treatment. If these questions have been addressed, it is more likely that a successful outcome will be obtained if radiation therapy is used for the management of emergent cancer pain. PMID- 20703833 TI - Loss and preservation of beta-cell function: two treatment regimes targeting T or B lymphocytes. PMID- 20703834 TI - Resonance assignment of nsp7alpha from arterivirus. AB - The (1)H, (15)N and (13)C resonance assignment of nsp7alpha, a non-structural protein of unknown function from the equine arteritis virus, is reported. PMID- 20703835 TI - The 1H, 13C and 15N backbone and side-chain assignment of the RRM domain of SC35, a regulator of pre-mRNA splicing. AB - The serine-arginine rich family of proteins play important roles in the regulation of both constitutive and alternative splicing. SC35 (also known as SFRS2 and PR264) is a member of this family and contains one RNA recognition motif (RRM domain) and a RS domain at the C-terminus which is enriched with arginine and serine residues. SC35 is specifically involved in major regulatory pathways for cell proliferation and cell cycle progression. Determining the structure of SC35 would enable greater understanding of how its structure relates to its many functions. Complete (1)H, (13)C and (15)N assignments of the RRM domain of SC35 are presented. The assignments were obtained using 2D heteronuclear and 3D triple-resonance experiments with the uniformly [(15)N,(13)C]-labelled protein. The chemical shifts are used to predict the 3 dimensional structure of this RRM domain in the absence of RNA. PMID- 20703836 TI - 1H, 15N and 13C resonance assignment of darcin, a mouse major urinary protein. AB - Darcin is an important lipocalin of the urinary MUP family. These beta-barrel structures differ subtly in sequence and function and facilitate communication between members of the mouse population via scent marks. Polymorphism within the family has led to the hypothesis that individual MUPs can also contribute to social and physiological information of the scent owner and thus demonstrates the necessity for structural investigation of these variations. Using conventional triple resonance experiments, (1)H (15)N and (13)C assignment of recombinant N terminal hexa-histidine tagged Darcin has been achieved. The corresponding chemical shifts have been deposited in the BioMagResBank; Accession No. 16840. PMID- 20703837 TI - Update on the indications and use of colonic stents. AB - Self-expandable metal stent (SEMS) placement is a minimally invasive option for achieving acute colonic decompression in obstructed colorectal cancer. Colorectal stenting offers nonoperative, immediate, and effective colon decompression and allows bowel preparation for an elective oncologic resection. Patients who benefit the most are high-risk surgical patients and candidates for laparoscopic resection with complete obstruction, because emergency surgery can be avoided in more than 90% of patients. Colonic stent placement also offers effective palliation of malignant colonic obstruction, although it carries risks of delayed complications. When performed by experienced endoscopists, the technical success rate is high with a low procedural complication rate. Despite concerns of tumor seeding following endoscopic colorectal stent placement, no difference exists in oncologic long-term survival between patients who undergo stent placement followed by elective resection and those undergoing emergency bowel resection. Colorectal stents have also been used in selected patients with benign colonic strictures. Uncovered metal stents should be avoided in these patients, and fully covered stents are associated with high risk of migration. Patients with benign colonic stricture with acute colonic obstruction who are at high risk for emergency surgery can gain temporary relief of obstruction after SEMS placement; the stent can be removed en bloc with the colon specimen at surgery. This article reviews the techniques and indications of SEMS placement for benign and malignant colorectal obstructions. PMID- 20703838 TI - Intestinal goblet cells and mucins in health and disease: recent insights and progress. AB - The mucus layer coating the gastrointestinal tract is the front line of innate host defense, largely because of the secretory products of intestinal goblet cells. Goblet cells synthesize secretory mucin glycoproteins (MUC2) and bioactive molecules such as epithelial membrane-bound mucins (MUC1, MUC3, MUC17), trefoil factor peptides (TFF), resistin-like molecule beta (RELMbeta), and Fc-gamma binding protein (Fcgbp). The MUC2 mucin protein forms trimers by disulfide bonding in cysteine-rich amino terminal von Willebrand factor (vWF) domains, coupled with crosslinking provided by TFF and Fcgbp proteins with MUC2 vWF domains, resulting in a highly viscous extracellular layer. Colonization by commensal intestinal microbiota is limited to an outer "loose" mucus layer, and interacts with the diverse oligosaccharides of mucin glycoproteins, whereas an "inner" adherent mucus layer is largely devoid of bacteria. Defective mucus layers resulting from lack of MUC2 mucin, mutated Muc2 mucin vWF domains, or from deletion of core mucin glycosyltransferase enzymes in mice result in increased bacterial adhesion to the surface epithelium, increased intestinal permeability, and enhanced susceptibility to colitis caused by dextran sodium sulfate. Changes in mucin gene expression and mucin glycan structures occur in cancers of the intestine, contributing to diverse biologic properties involved in the development and progression of cancer. Further research is needed on identification and functional significance of various components of mucus layers and the complex interactions among mucus layers, microbiota, epithelial cells, and the underlying innate and adaptive immunity. Further elucidation of the regulatory mechanisms involved in mucin changes in cancer and inflammation may lead to the development of novel therapeutic approaches. PMID- 20703839 TI - Association of depression with antihypertensive medication adherence in older adults: cross-sectional and longitudinal findings from CoSMO. AB - BACKGROUND: Little is known about the associations between depressive symptoms, social support and antihypertensive medication adherence in older adults. PURPOSE: We evaluated the cross-sectional and longitudinal associations between depressive symptoms, social support and antihypertensive medication adherence in a large cohort of older adults. METHODS: A cohort of 2,180 older adults with hypertension was administered questionnaires, which included the Center for Epidemiologic Studies-Depression Scale, the Medical Outcomes Study Social Support Index, and the hypertension-specific Morisky Medication Adherence Scale at baseline and 1 year later. RESULTS: Overall, 14.1% of participants had low medication adherence, 13.0% had depressive symptoms, and 33.9% had low social support. After multivariable adjustment, the odds ratios that participants with depressive symptoms and low social support would have low medication adherence were 1.96 (95% confidence interval (CI) 1.43, 2.70) and 1.27 (95% CI 0.98, 1.65), respectively, at baseline and 1.87 (95% CI 1.32, 2.66) and 1.30 (95% CI 0.98, 1.72), respectively, at 1 year follow-up. CONCLUSION: Depressive symptoms may be an important modifiable barrier to antihypertensive medication adherence in older adults. PMID- 20703840 TI - Genitourinary functioning and depressive symptoms over time in younger versus older men treated for prostate cancer. AB - BACKGROUND/PURPOSE: This study examined the relation of age to genitourinary functioning and depressive symptoms over time and examined how age influences the relation between genitourinary functioning and depressive symptoms over time in men treated for localized prostate cancer. METHODS: Participants were 234 men who completed interviews that assessed genitourinary functioning and depressive symptoms at 2, 4, 10 and 16 months after treatment. Analyses were statistically controlled for potential confounds. RESULTS: Compared with younger men (<= 65.5), older men had significantly poorer sexual function and slower improvement. Level of urinary functioning was inversely associated with level of depressive symptoms regardless of age. Level of sexual functioning was inversely associated with level of depressive symptoms but only in younger men. CONCLUSION: Interventions may be particularly helpful for all men with urinary dysfunction and for younger men with sexual dysfunction in order to improve symptoms of depression. PMID- 20703841 TI - An airway exchange catheter facilitates removal of the intubating laryngeal airway after tracheal intubation in children. PMID- 20703842 TI - Transesophageal echocardiography images of pulmonary artery compression by benign follicular lymphoid hyperplasia. PMID- 20703843 TI - Extracorporeal shock wave lithotripsy (ESWL) for large pancreatic stones: are these shocks worth while? PMID- 20703844 TI - Effects of modified splenocaval shunt plus devascularization on esophagogastric variceal bleeding: a comparative study of this treatment and devascularization only in cirrhotic portal hypertension. AB - BACKGROUND: Pericardial devascularization (PCDV) and portosystemic shunt were reported to have favorable results for the management of portal hypertension in cirrhotic patients in China and the West, respectively. This study was undertaken to investigate the effects of a modified proximal splenocaval shunt plus PCDV on variceal bleeding in patients with portal hypertension. METHODS: From January 1997 to December 2007, 168 patients with portal hypertension of cirrhotic origin received an operation for gastroesophageal variceal bleeding. Of these, 90 patients received a splenocaval shunt plus a PCDV procedure (Combined Group) and the other 78 patients received a PCDV procedure only (PCDV Group). The procedure related morbidity and mortality, rebleeding, encephalopathy, and survival rates were analyzed. RESULTS: Postoperative mortality was 3.3% in the combined group and 5.1% in the PCDV group (P > 0.05). Overall morbidity was 13.3% in the combined group and 15.4% in the PCDV group (P > 0.05). The rate for rebleeding, including variceal bleeding and gastropathy, was 5.1% in the combined group, which was significantly lower than that in the PCDV group, at 16.7% (P < 0.05). The incidence of encephalopathy was 6.63% in the combined group and 6.67% in the PCDV group (P > 0.05). The 1-, 3-, 5- and 10-year survival rates were 97.4, 91.7, 80.0, and 60.0% in the combined group and 96.7, 83.3, 73.3, and 53.3% in the PCDV group (P > 0.05). CONCLUSIONS: The modified splenocaval shunt plus PCDV is a safe and effective procedure for the long-term control of variceal bleeding; the procedure may not only maintain the portal flow to the liver, but may also protect the liver function in cirrhotic patients. The better clinical outcome means that the procedure may be one of the best choices for treating portal hypertension of cirrhotic origin. PMID- 20703845 TI - Intravenous 64-multi-detector row CT-cholangiography of porcine livers: a feasibility study with definition of the temporal window for optimal bile duct delineation. AB - BACKGROUND/PURPOSE: To assess the feasibility of intravenous 64-multi-detector row computed tomography (CT)-cholangiography of porcine livers with definition of the temporal window for optimal bile duct delineation. METHODS: Six healthy Landrace pigs, each weighing 28.97 +/- 2.99 kg, underwent 64-multi-detector row CT-cholangiography. Each pig was infused with 50 ml of meglumine iotroxate continuously over a period of 20 min and, starting with the initiation of the infusion, 18 consecutive CT scans of the abdomen at 2-min intervals were acquired. All series were evaluated for bile duct visualization scores and maximum bile duct diameters as primary study goals and bile duct attenuation and liver enhancement as secondary study goals. RESULTS: Of the 16 analyzed biliary tract segments, maximum bile duct visualization scores ranged between 4.00 +/- 0.00 and 2.83 +/- 1.47. Time to maximum bile duct visualization scores ranged between 10 and 34 min. Average bile duct visualization scores for the 10- to 34 min interval ranged between 3.99 +/- 0.05 and 2.78 +/- 0.10. Maximum bile duct diameters ranged between 6.47 +/- 1.05 and 2.65 +/- 2.23 mm. Time to maximum bile duct diameters ranged between 24 and 34 min. Average bile duct diameters for the 10- to 34-min interval ranged between 6.00 +/- 0.38 and 2.40 +/- 0.13 mm. CONCLUSIONS: Intravenous 64-multi-detector row CT-cholangiography of non-diseased porcine liver is feasible, with the best bile duct delineation acquired between 10 and 34 min after initiation of the contrast agent infusion. PMID- 20703846 TI - Preoperative estimation of asialoglycoprotein receptor expression in the remnant liver from CT/99mTc-GSA SPECT fusion images correlates well with postoperative liver function parameters. AB - BACKGROUND: Accurate preoperative estimation of remnant liver function is critically important for hepatic surgery, and the expression of asialoglycoprotein receptors (ASGPR) is associated with hepatic function. METHODS: Thirty-two patients with hepatocellular carcinoma who underwent surgical resection were studied. To estimate the expression of ASGPR in the remnant liver, simulated surgery was performed on fusion images that combined data from (99m)technetium-galactosyl human serum albumin ((99m)Tc-GSA)/single photon emission computed tomography (SPECT) and computed tomography (CT) scanning. The liver uptake ratio (LUR) of (99m)Tc-GSA and the functional liver volume (FLV) in the remnant liver were predicted and were compared with postoperative liver function parameters. RESULTS: The LUR of (99m)Tc-GSA was strongly correlated with the extent of hepatic ASGPR expression (r = 0.944, p = 5.01 x 10(-16)), being confirmed to be a reliable parameter for the evaluation of liver function. The estimated remnant LUR, but not the estimated remnant FLV, was significantly correlated with postoperative liver function parameters, such as serum total bilirubin (r = -0.430, p < 0.05), prothrombin activity (r = 0.515, p < 0.01), and serum cholinesterase activity (r = 0.546, p < 0.01) at 1 week. CONCLUSION: Preoperative estimation of the extent of ASGPR expression in the remnant liver on CT/GSA-SPECT fusion images correlated well with postoperative liver function parameters, suggesting its usefulness for surgical decisions. PMID- 20703847 TI - Cholecystectomy using single-incision laparoscopic surgery with a new SILS port. AB - INTRODUCTION: Single-incision laparoscopic surgery (SILS) offers the potential advantages of reduced postoperative pain and a lower incidence of port-site complications. Moreover, careful attention to closure can reduce the scarring after surgery. Consequently, this method is a promising technique for reducing postoperative pain, decreasing complications, and improving cosmesis. We have performed cholecystectomy in eight patients by SILS. The umbilicus was the point of entry to the abdomen in all patients. METHODS: Between May 2009 and October 2009, 31 patients underwent cholecystectomy at our hospital. The umbilicus was the point of entry to the abdomen in all patients. Three SILSs were performed using a new SILS port, and five SILSs were performed by the conventional method in which three ports are inserted into the umbilicus; the remaining ten patients underwent multiple-incision laparoscopic cholecystectomy (standard cholecystectomy). The results for the patients who underwent standard cholecystectomy, conventional SILS, and SILS using the new port were compared using the Mann-Whitney U test. The data are expressed as mean +/- standard deviation. RESULT: Of the eight cholecystectomies carried out, three were performed by SILS using the new port. No complications or mortalities were associated with this technique. The mean operating times for conventional SILS, SILS with the new port, and standard cholecystectomy were 154 +/- 57, 120 +/- 11, and 100 +/- 51 min, respectively; these inter-group differences are not significant. The blood loss in conventional SILS, SILS with the new port, and standard cholecystectomy was 9 +/- 16, 1, and 6.1 +/- 11 g, respectively; these inter-group differences are not significant. All umbilical incisions were concealed within the umbilicus. CONCLUSION: Cholecystectomy performed using SILS with the new port is a safe and feasible approach with reasonable operation times. PMID- 20703848 TI - Correlation between angiogenesis and islet graft function in diabetic mice: magnetic resonance imaging assessment. AB - BACKGROUND/PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) was used to evaluate neovascularization after intravenous injection of gadolinium, where contrast leaks out of new vessels and remains within the tissues. We examined the relationship between DCE-MRI and metabolic parameters such as blood glucose, serum insulin and glucose tolerance test (GTT) after intraportal islet transplantation. METHODS: Streptozotocin-induced diabetic BALB/c mice (n = 15) received syngeneic intraportal islet transplantation (500 islet equivalent). Blood glucose, serum insulin and GTT were evaluated till postoperative day (POD) 14. Liver DCE-MRI was performed at POD 3, 7 and 14. Correlations between DCE-MRI and metabolic parameters were examined using regression analysis. RESULTS: Eight mice achieved normoglycemia after intraportal transplantation. At POD 3 a significant but moderate correlation between DCE-MRI and blood glucose was found. No DCE-MRI or metabolic parameters correlated at POD 7. However, at POD 14 strong or moderate correlations between DCE-MRIs were found: negative correlations with blood glucose (R (2) = 0.86) and GTT (R (2) = 0.48) but a positive correlation with serum insulin (R (2) = 0.32). CONCLUSION: We report that DCE-MRI can reflect the metabolic and functional condition of the transplanted islets. PMID- 20703849 TI - Favorable clinical outcome using a covered stent following transjugular intrahepatic portosystemic shunt in patients with portal hypertension. AB - AIMS: To compare retrospectively the clinical outcomes in patients treated with transjugular intrahepatic portosystemic shunt (TIPS) using the novel polytetrafluoroethylene-covered stents (Fluency) and bare stents. MATERIALS AND METHODS: Sixty consecutive patients with portal hypertension treated with TIPS from April 2007 to April 2009 were included. TIPS creation was performed with Fluency stent grafts in 30 patients (group A) and with bare stents in 30 patients (group B). Liver function, TIPS patency and clinical outcomes were evaluated every 3 months after procedures. RESULTS: During hospitalization, there were no cases of hepatic encephalopathy (HE) and recurrence of variceal bleedings. Acute shunt occlusion was found in one patient in each group. Follow-ups were performed in group A with average time of 6.16 +/- 3.89 months and in group B with 8.34 +/- 4.42 months. The rates of recurrent bleeding, shunt occlusion, HE and mortality were 0.03, 0.0, 16.7 and 0% in group A, and 20.0, 30.0, 20.0 and 13.3% in group B, respectively. There was no difference of HE between group A and group B. The decrease of portal pressure and portosystemic pressure gradient, and the increase of portal flow were 34.1 and 23.3%, 60.0 and 52.8%, and 189.5 and 111.1% in group A and B, respectively. There were no differences of liver function between group A and B. CONCLUSION: The Fluency stent graft is relatively safe and effective in TIPS creation, with a high patency rate compared with bare stents. PMID- 20703850 TI - Risk factors for major morbidity after hepatectomy for hepatocellular carcinoma in 293 recent cases. AB - BACKGROUND/PURPOSE: The purpose of this study was to identify risk factors for major morbidity after hepatectomies for hepatocellular carcinoma (HCC). METHODS: Univariate and multivariate analyses of risk factors for major morbidity were performed in 293 patients who underwent hepatectomy for HCC between 2001 and 2008. RESULTS: Two hundred and forty-three patients (82.9%) underwent an anatomic hepatectomy, and a repeat hepatectomy was performed in 50 patients (17.1%). The prevalences of bile leakage and intraabdominal abscess were 12.9% and 9.2%, respectively. The risk factor for bile leakage was an operative time >or= 300 min and the risk factor for intraabdominal abscess was a repeat hepatectomy (odds ratios = 4.9 and 5.3, respectively). The main cause of bile leakage that made endoscopic therapy or percutaneous transhepatic biliary drainage necessary was a latent stricture of the biliary anatomy that had existed preoperatively, caused by previous treatments for HCC. Methicillin-resistant Staphylococcus aureus was the main causative bacteria of intraabdominal abscess after repeat hepatectomies. CONCLUSIONS: Our recent series revealed that prolonged operative time and repeat hepatectomy were independent risk factors for bile leakage and intraabdominal abscess, respectively, after hepatectomies for HCC. Preoperative assessment of the biliary anatomy should be considered for patients who have had previous multiple treatments for HCC, including hepatectomy, to reduce bile leakage that makes invasive treatment necessary. PMID- 20703851 TI - Relapsing acute pancreatitis caused by protein plugs in a remnant choledochal cyst. PMID- 20703852 TI - Peroral videocholangioscopy using narrow band imaging for early bile duct cancer (with video). AB - We described the usefulness of peroral videocholangioscopy for diagnosis of early bile duct cancer. In addition, we introduce the observation of the lesion using narrow band imaging in combination with a conventional white light imaging. PMID- 20703853 TI - Original method of transumbilical single-incision laparoscopic deroofing for liver cyst. PMID- 20703854 TI - Direct determination of the heteronuclear T1/T2 ratio by off-resonance steady state magnetization measurement: Investigation of the possible application to fast exchange characterization of 15N-labeled proteins. AB - The (15)N steady-state magnetization in the presence of off-resonance rf irradiation is an analytical function of the T(1)/T(2) ratio and of the angle between the (15)N effective field axis and the static magnetic field direction. This relation holds whatever the relaxation mechanisms due to motions on the nanosecond time scale, and the size of the spin system. If motions on the micro- to millisecond time scale are present (fast exchange), the same observable depends also on their spectral density at the frequency of the effective field. The cross-peak intensity in each 2D (15)N-(1)H correlation map is directly related to the dynamic parameters, so that the characterization of fast exchange phenomena by this method is in principle less time-consuming than the separate measurement of self-relaxation rates. The theory of this approach is described. Its practical validity is experimentally evaluated on a (15)N-labeled 61 amino acid neurotoxin. It turns out that existing equipments lead to non-negligible biases. Their consequences for the accuracy attainable, at present, by this method are investigated in detail. PMID- 20703855 TI - A 4D TROSY-based pulse scheme for correlating 1HNi,15Ni,13Calphai,13C'i-1 chemical shifts in high molecular weight, 15N,13C, 2H labeled proteins. AB - A 4D TROSY-based triple resonance experiment, 4D-HNCO(i-1)CA(i), is presented which correlates intra-residue (1)HN, (15)N, (13) C(alpha) chemical shifts with the carbonyl ((13)C') shift of the preceding residue. The experiment is best used in concert with recently described 4D TROSY-HNCOCA and -HNCACO experiments [Yang, D. and Kay, L.E. (1999) J. Am. Chem. Soc., 121, 2571-2575]. In cases where degeneracy of ((1)HN,(15)N) spin pairs precludes assignment using the HNCOCA and HNCACO, the HNCO(i-1)CA(i) often allows resolution of the ambiguity by linking the (13)C(alpha) and (13)C' spins surrounding the ((1)HN,(15)N) pair. The experiment is demonstrated on a sample of (15)N, (13)C, (2) H labeled maltose binding protein in complex with beta-cyclodextrin that tumbles with a correlation time of 46 ns. PMID- 20703856 TI - Robust refocusing of 13C magnetization in multidimensional NMR experiments by adiabatic fast passage pulses. AB - We show that adiabatic fast passage (AFP) pulses are robust refocusing elements of transverse (13)C magnetization in multidimensional NMR experiments. A pair of identical AFP pulses can refocus selected parts or a complete (13) C chemical shift range in (13)C spectra. In the constant time (13)C-(1)H HSQC, replacement of attenuated rectangular pulses by selective AFP pulses results in a sensitivity enhancement of up to a factor of 1.8. In the 3D CBCA(CO)NH the signal-to-noise ratio is increased by a factor of up to 1.6. PMID- 20703857 TI - Letter to the Editor: Sequence-specific 1H, 13C and 15N resonance assignments of recombinant onconase/P-30 protein. PMID- 20703858 TI - Beginning and development of lung cancer surgery in Japan. AB - The age of lung cancer surgery is divided into three phases: before 1955, 1955, and after 1955. The year 1955 was memorable for thoracic surgeons in Japan. Special lectures entitled "Lung Tumors" were presented by three thoracic surgeons: Drs. Naoji Kawai, Kingo Shinoi, and Shichiro Ishikawa. Their lectures included the present status of lung cancer in regard to the diagnosis and differential diagnosis, treatment, and pathology; and they played a crucial role in establishing the Japan Lung Cancer Society in 1960. Thereafter, lung cancer surgery progressed rapidly in parallel with the development of surgical techniques, diagnostic modalities, perioperative management, and biomolecular and genetic research. This article reviews the beginning and development of lung cancer surgery in Japan from a historical point of view. PMID- 20703859 TI - Current strategy of endovascular aortic repair for thoracic aortic aneurysms. AB - Thoracic aortic aneurysms are extremely burdensome to treat owing to their surgical complexity. In particular, major postoperative complications lower significantly patients' quality of life. Surgical treatment has recently shifted to thoracic endovascular aortic repair (TEVAR) to respect the patients' needs and improve postoperative quality of life. This procedure is radical and innovated for thoracic aortic pathology, but the devices and the delivery systems are immature because only a little over a decade and a half has passed since starting to use them. Ready-made stent-grafts were originally indicated only for degenerated aortic aneurysms, but aortic dissection and traumatic aortic transection will become the next targets for TEVAR. This review addresses the history and changes in TEVAR as well as the current TEVAR strategy. Finally, we describe a new trial of TEVAR for aortic dissections, traumatic aortic transections, and aortic arch aneurysms. PMID- 20703860 TI - Impact of surgical ventricular reconstruction for ischemic dilated cardiomyopathy on restrictive filling pattern. AB - PURPOSE: Little information related to the effects of surgical ventricular reconstruction on left ventricular diastolic function is available. The aims of this study were to examine the effects of surgical ventricular reconstruction on left ventricular diastolic function and assess the predictive significance of that function on clinical outcome in patients with ischemic cardiomyopathy due to broad anteroseptal myocardial infarction undergoing surgical ventricular reconstruction. METHODS: We studied 21 patients undergoing surgical ventricular reconstruction and combined surgery for ischemic cardiomyopathy with a low ejection fraction (mean ejection fraction 23% +/- 6%). Doppler echocardiography was performed before and 6 +/- 4 months after the operation. RESULTS: There were no deaths within 30 days. Of the 21 patients, 6 reached the clinical endpoint (cardiac death or hospitalization due to congestive heart failure). The Doppler derived restrictive filling pattern--defined as the deceleration time (DcT) <140 ms and the mitral peak early/mitral late diastolic filling velocity (E/A) ratio >1.5--was significantly related to reaching the clinical endpoint (P < 0.01). Furthermore, stepwise multivariate analysis showed that a preoperative restrictive filling pattern was the only independent predictor of reaching the clinical endpoint (P < 0.005, F = 11.2). CONCLUSION: In patients with ischemic cardiomyopathy undergoing surgical ventricular reconstruction and combined surgery, surgical ventricular reconstruction did not change the restrictive filling pattern, and the preoperative restrictive filling pattern was an important marker of postoperative clinical outcome. PMID- 20703861 TI - Correlation between glucose transporter-1 expression and 18F-fluoro-2 deoxyglucose uptake on positron emission tomography in lung cancer. AB - PURPOSE: The aim of this study was to determine if glucose transporter-1 (Glut1) expression correlates with (18)F-FDG ((18)F-fluoro-2-deoxyglucose) uptake on positron emission tomography (PET) in lung cancer and to examine the similarities and differences between them. METHODS: A total of 34 patients with resected primary lung cancers were investigated in this study. There were 17 adenocarcinomas, 12 squamous cell carcinomas, and 5 cancers of other cell types. Immunohistochemical Glut1 intensity was categorized into three groups: negative, positive, and strongly positive. Glut1 frequency was defined by the proportion of positive cells among all cancer cells, and it was graded on a semiquantitative scale as 0-100% in 10% increments. The data are expressed as the mean +/- SD. RESULTS: Maximum standardized uptake values (SUVmax) were 4.8 +/- 6.3 in "negative" Glut1 intensity cases, 4.7 +/- 3.1 in "positive" Glut1 intensity cases, and 11.2 +/- 5.2 in "strongly positive" Glut1 intensity cases. Although SUVmax correlated significantly with tumor size (correlation coefficient 0.58, P = 0.00033), Glut1 frequency did not correlate significantly with tumor size (correlation coefficient 0.18, P = 0.301). Cell type and cell differentiation correlated significantly with Glut1 expression and (18)F-FDG uptake. CONCLUSION: Glut1 expression correlates significantly with (18)F-FDG uptake. There are similarities in cell differentiation and cell type between Glut1 expression and (18)F-FDG uptake. (18)F-FDG uptake correlates significantly with tumor size, but Glut1 expression does not. PMID- 20703862 TI - Intraoperative bronchoscopic resection of a papillary fibroelastoma in the left ventricular outflow tract after aortic mechanical valve replacement. AB - We report the case of an 80-year-old man who 11 years previously had undergone aortic valve replacement (St. Jude Medical mechanical heart valve 23 mm) because of aortic stenosis. At the current presentation, a 7-mm pedunculated tumor was discovered along the septal wall in the left ventricular outflow tract. In an attempt to perform a less invasive procedure because of the patient's advanced age, transaortic valve bronchoscopic resection was undertaken. A bronchoscope (Olympus BF P-200) was fed through a gap in the mechanical aortic valve. The entire tumor was removed using biopsy forceps, with histology revealing a papillary fibroelastoma. By using a bronchoscope, we avoided a second valve replacement. PMID- 20703863 TI - Vacuum-assisted closure with a portable system for treatment of poststernotomy mediastinitis. AB - The patient was a 50-year-old man with diabetes who was on insulin. Complications of mediastinitis developed after coronary bypass surgery, which had been performed for unstable angina. Upon hospital admission, the patient was treated with antibiotics, and the wound was cleaned on a daily basis. However, because the patient's fever persisted, the wound was completely opened surgically and found to be deep and large. Because the patient's condition was relatively stable, minimally invasive vacuum-assisted closure was selected. We fabricated a portable vacuum-assisted closure system that imposed few limitations on individual movement. Vacuum-assisted closure treatment resulted in both rapid abatement of fever and improved granulation. Dressings were changed once a week; the wound was closed 4 weeks after vacuum-assisted closure and healed completely. Vacuum-assisted closure may be an effective therapy for postoperative mediastinitis, and our portable vacuum-assisted closure system may significantly reduce patient distress as well as direct medical care. PMID- 20703864 TI - Asymptomatic papillary fibroelastoma of the mitral valve. AB - We report an asymptomatic case of a papillary fibroelastoma adherent to the mitral anterior leaflet. Transthoracic echocardiography of an 85-year-old man with chronic atrial fibrillation and no thromboembolic episodes, revealed a cardiac tumor on the mitral valve. Transesophageal echocardiography demonstrated typical findings for a papillary fibroelastoma. The tumor was successfully removed using a shave excision technique. Currently, these tumors are found incidentally in asymptomatic patients by advanced diagnostic modalities. PMID- 20703865 TI - Pulmonary artery obstruction due to a metastatic malignant phyllodes tumor of the breast. AB - A 65-year-old woman with a 9-year surgical history of a left breast phyllodes tumor was admitted with progressive chest pain on effort. Computed tomography showed severe stenosis of the main pulmonary artery, with the mass originating from the ventricular septum. We planned to resect the tumor the next day. However, the next morning a pulmonary artery embolism occurred, and she developed dyspnea and lost consciousness. After carrying out cardiopulmonary resuscitation, we performed a life-saving operation. We successfully resected the huge tumor as far as possible from the right ventricle via a right atrial (RA)-tomy. However, her consciousness did not improve to better than Glasgow Coma Scale grade 7. She died from suffocation caused by metastasis invading her airway despite undergoing tracheotomy on the 77 th postoperative day. PMID- 20703866 TI - Suggestive synchronous triple squamous cell carcinoma of the lung in the same lobe. AB - We report a case of suggestive synchronous triple squamous cell carcinoma (Sq) of the lung that occurred in the same lobe. Under a clinical diagnosis of triple lung cancer, lobectomy was performed. Pathological examination revealed two well differentiated Sq and one poorly differentiated Sq. The analysis of epidermal growth factor receptor-tyrosine kinase mutations showed no mutation in each tumor. However, pathological findings and the positive rate of immunochemical reaction of p53 and Ki-67 were different in each tumor. PMID- 20703867 TI - Surgical resection of a primary pulmonary epithelioid hemangioendothelioma in bilateral lungs. AB - Pulmonary epithelioid hemangioendothelioma (PEH) is a rare pulmonary neoplasm that was initially described in 1975 as an intravascular bronchioloalveolar tumor. This report presents the case of a patient with multifocal primary pulmonary PEH (11 tumors) in the bilateral lungs. All of the tumors detected in the preoperative computed tomography scan were surgically resected. The patient has been doing well for 9 years after surgery. No tumor recurred for 8 years after surgery until a single recurrent nodule appeared and was thoracoscopically resected. PMID- 20703868 TI - Sarcoidosis development during induction chemotherapy for lung cancer mimicked progressive disease. AB - We report a rare case of sarcoidosis that developed during induction chemotherapy for primary lung cancer, mimicking progressive disease. A 63-year-old man had an abnormal shadow in the right upper lung, and a bronchoscopic examination revealed a squamous cell carcinoma. Swelling of a pretracheal lymph node was also noted. Thus, we gave induction chemotherapy consisting of paclitaxel (days 1, 8) + carboplatin (days 1, 8) for two cycles under clinical staging of T2N2M0. After induction chemotherapy, (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed positive accumulation of FDG in mediastinal and bilateral hilar lymph nodes that had been negative in a previous FDG-PET examination, which led us to suspect disease progression. Transbronchial lymph node biopsy results showed sarcoid granulomas in the specimens. Following complete resection of the lung cancer, sarcoid granulomas were revealed in both nonneoplastic lung tissue and lymph nodes, which resulted in a diagnosis of lung cancer accompanied with sarcoidosis. PMID- 20703870 TI - Identification of a QTL conferring seedling and adult plant resistance to eyespot on chromosome 5A of Cappelle Desprez. AB - Eyespot is an economically important fungal disease of wheat and other cereals caused by two fungal species: Oculimacula yallundae and Oculimacula acuformis. However, only two eyespot resistance genes have been characterised and molecular markers made available to plant breeders. These resistances are Pch1, introduced into wheat from the relative Aegilops ventricosa, and Pch2, originally identified in the cultivar Cappelle Desprez (CD). There are drawbacks associated with both resistances; Pch1 is linked to deleterious traits carried on the Ae. ventricosa introgression and Pch2 has been shown to have limited effectiveness. An additional resistance has been reported on chromosome 5A of CD that confers resistance to eyespot in adult plants. In the present study, we demonstrate that resistance on this chromosome is effective against both O. yallundae and O. acuformis eyespot pathogens and confers resistance at both seedling and adult plant stages. This resistance was mapped in both seedling bioassays and field trials in a 5A recombinant population derived from a cross between CD and a CD single chromosome substitution line carrying 5A from the susceptible line Bezostaya. The resistance was also mapped using seedling bioassays in a 5A recombinant population derived from a cross between the susceptible line Chinese Spring (CS) and a single chromosome substitution line carrying 5A from CD. A single major QTL on the long arm of chromosome 5A was detected in all experiments. Furthermore, the SSR marker Xgwm639 was found to be closely associated with the resistance and could be used for marker-assisted selection of the eyespot resistance by plant breeders. PMID- 20703869 TI - Oxidative DNA damage: the thyroid hormone-mediated effects of insulin on liver tissue. AB - Thyroid hormone affects glucose homeostasis with its actions between the skeletal muscle and liver and the altered oxidative and non-oxidative glucose metabolism. In our study three chemicals are considered biomarkers associated with oxidative stress for protein modifications were measured; 8-hydroxy-2-deoxyyguanosine (8 OHdG), a major lesion that can be generated by reactive oxygen species for DNA damage, protein carbonyl content (PCO), products of protein oxidation and advanced oxidation protein products (AOPPs) a dithyrosine containing cross-linked protein products. The purpose of the recent study was to determine the effects of insulin and T4 or their combination in diabetic, thyroidectomized, or diabetic thyroidectomized rats and possible relations with oxidative DNA and protein damages. For this purpose, rats were assigned to eight groups: Group 1; control, Group 2; diabetes, Group 3; diabetes+insulin, Group 4; surgically thyroidectomized control, Group 5; thyroidectomized+diabetes, Group 6; thyroidectomized+diabetes+insulin, Group 7; thyroidectomized+diabetes+insulin+thyroid hormone, levothyroxin sodium, 2.5 MUg/kg and Group 8; thyroidectomized+diabetes+insulin+thyroid hormone, levothyroxin sodium, 5.0 MUg/kg for 5 weeks. After the genomic DNA of liver tissues was extracted, the ratio of 8-OHdG to deoxyguanosine and liver tissue protein oxidation markers was determined. The main findings of our recent study were the increased 8-OHdG levels during the diabetes, hypothyroidism, and hypothyroidism with diabetes, which can be regulated in different percentages with the treatment of 2.5 and 5.0 MUg/kg doses of thyroid hormone and the altered protein carbonyl and AOPP levels of liver tissue. Consequently, it was observed that the DNA and protein damage induced by oxidative stress in diabetes could be regulated by dose-dependent thyroid hormone-mediated effects to insulin treatment. PMID- 20703871 TI - A gene encoding an abscisic acid biosynthetic enzyme (LsNCED4) collocates with the high temperature germination locus Htg6.1 in lettuce (Lactuca sp.). AB - Thermoinhibition, or failure of seeds to germinate when imbibed at warm temperatures, can be a significant problem in lettuce (Lactuca sativa L.) production. The reliability of stand establishment would be improved by increasing the ability of lettuce seeds to germinate at high temperatures. Genes encoding germination- or dormancy-related proteins were mapped in a recombinant inbred line population derived from a cross between L. sativa cv. Salinas and L. serriola accession UC96US23. This revealed several candidate genes that are located in the genomic regions containing quantitative trait loci (QTLs) associated with temperature and light requirements for germination. In particular, LsNCED4, a temperature-regulated gene in the biosynthetic pathway for abscisic acid (ABA), a germination inhibitor, mapped to the center of a previously detected QTL for high temperature germination (Htg6.1) from UC96US23. Three sets of sister BC(3)S(2) near-isogenic lines (NILs) that were homozygous for the UC96US23 allele of LsNCED4 at Htg6.1 were developed by backcrossing to cv. Salinas and marker-assisted selection followed by selfing. The maximum temperature for germination of NIL seed lots with the UC96US23 allele at LsNCED4 was increased by 2-3 degrees C when compared with sister NIL seed lots lacking the introgression. In addition, the expression of LsNCED4 was two- to threefold lower in the former NIL lines as compared to expression in the latter. Together, these data strongly implicate LsNCED4 as the candidate gene responsible for the Htg6.1 phenotype and indicate that decreased ABA biosynthesis at high imbibition temperatures is a major factor responsible for the increased germination thermotolerance of UC96US23 seeds. PMID- 20703872 TI - Learning a coordinated rhythmic movement with task-appropriate coordination feedback. AB - A common perception-action learning task is to teach participants to produce a novel coordinated rhythmic movement, e.g. 90 degrees mean relative phase. As a general rule, people cannot produce these novel movements stably without training. This is because they are extremely poor at discriminating the perceptual information required to coordinate and control the movement, which means people require additional (augmented) feedback to learn the novel task. Extant methods (e.g. visual metronomes, Lissajous figures) work, but all involve transforming the perceptual information about the task and thus altering the perception-action task dynamic being studied. We describe and test a new method for providing online augmented coordination feedback using a neutral colour cue. This does not alter the perceptual information or the overall task dynamic, and an experiment confirms that (a) feedback is required for learning a novel coordination and (b) the new feedback method provides the necessary assistance. This task-appropriate augmented feedback therefore allows us to study the process of learning while preserving the perceptual information that constitutes a key part of the task dynamic being studied. This method is inspired by and supports a fully perception-action approach to coordinated rhythmic movement. PMID- 20703873 TI - Sunflower seed oil and oleic acid utilization for the production of rhamnolipids by Thermus thermophilus HB8. AB - The potential production of rhamnolipids was demonstrated using the thermophilic eubacterium Thermus thermophilus HB8 and sunflower seed oil or oleic acid as carbon sources. Sunflower seed oil was directly hydrolyzed by secretion of lipase and became a favorable carbon source for rhamnolipids production. Rhamnolipids levels were attainted high values, comparable to those produced by Pseudomonas strains from similar sources. Rhamnolipids synthesis in oleic acid exhibited a long period of induction, while in sunflower seed oil, the synthesis is more rapid. Glucose resulted in a more protracted period of rhamnolipids production after exhaustion of each or both carbon sources. Both mono- and di-rhamnolipids were identified by thin-layer chromatography (TLC) in the total rhamnolipids extract. The molecular composition of the produced biosurfactant was evaluated by Fourier transform infrared (FTIR) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and LC-MS analysis. Furthermore, secretion of rhamnolipids was confirmed on agar plates. The antimicrobial activity of rhamnolipids was detected against the bacterium Micrococcus lysodeikticus using a lysoplate assay. These results demonstrate that rhamnolipids produced in these substrates can be useful in both environmental and food industry applications by using cheap oil wastes. The alternative use of this thermophilic microorganism opens a new perspective concerning the valorization of wastes containing plant oils or frying oils to reduce the cost of rhamnolipids production. PMID- 20703874 TI - Use of a new gelling agent (Eladium(c)) as an alternative to agar-agar and its adaptation to screen biofilm-forming yeasts. AB - The incidence of yeast-induced infections has increased in the last decade, mainly because of the increasing number of immunodeficient patients. Since biofilm production is believed to be responsible for fungal virulence, we propose screening yeasts of various genera in order to determine their ability to form biofilms. This is an important issue because yeast cells that form biofilms are particularly resistant to anti-fungal agents used in human patients. For screening, we used Eladium(c), a new polysaccharide produced by a Rhizobium sp., as an alternative gelling agent to agar. We also established the conditions necessary to detect biofilm formation. The adapted medium provides the missing link between liquid and solid media. Its advantages include enhancement of growth of microorganisms and facilitation of quick and easy monitoring of biofilm formation. PMID- 20703875 TI - Investigating the coenzyme specificity of phenylacetone monooxygenase from Thermobifida fusca. AB - Type I Baeyer-Villiger monooxygenases (BVMOs) strongly prefer NADPH over NADH as an electron donor. In order to elucidate the molecular basis for this coenzyme specificity, we have performed a site-directed mutagenesis study on phenylacetone monooxygenase (PAMO) from Thermobifida fusca. Using sequence alignments of type I BVMOs and crystal structures of PAMO and cyclohexanone monooxygenase in complex with NADP(+), we identified four residues that could interact with the 2' phosphate moiety of NADPH in PAMO. The mutagenesis study revealed that the conserved R217 is essential for binding the adenine moiety of the nicotinamide coenzyme while it also contributes to the recognition of the 2'-phosphate moiety of NADPH. The substitution of T218 did not have a strong effect on the coenzyme specificity. The H220N and H220Q mutants exhibited a ~3-fold improvement in the catalytic efficiency with NADH while the catalytic efficiency with NADPH was hardly affected. Mutating K336 did not increase the activity of PAMO with NADH, but it had a significant and beneficial effect on the enantioselectivity of Baeyer-Villiger oxidations and sulfoxidations. In conclusion, our results indicate that the function of NADPH in catalysis cannot be easily replaced by NADH. This finding is in line with the complex catalytic mechanism and the vital role of the coenzyme in BVMOs. PMID- 20703876 TI - Radiographic analysis of extracorporeally irradiated autografts. AB - OBJECTIVE: To analyse the long-term radiographic findings of intercalary, pure osteoarticular, and composite bone grafts in patients with primary bone sarcoma who were treated by reimplantation of the bone as an orthotopic autograft. MATERIALS AND METHODS: For this observational clinical study, 107 patients who presented with 108 malignant or locally aggressive benign bone tumours were treated by resection, extracorporeal irradiation (300 Gy), and reimplantation and fixation of the autograft. Bone healing features were evaluated with the International Society of Limb Salvage (ISOLS) graft evaluation method, which assesses fusion, resorption, fracture, graft shortening, fixation, subluxation, joint narrowing, and subchondral bone. A description of normal and abnormal healing patterns and complications comprised the secondary endpoint. RESULTS: Seventy-seven patients with complete radiographic data were selected for review. The mean ISOLS score was 78.2% (range 25.0-100%, median 79.2%). Three patient subgroups were created: intercalary graft, pure osteoarticular graft, and composite reconstruction consisting of an intercalary graft augmented with a prosthesis; the mean ISOLS scores were 81.3%, 70.7%, and 77.4%, respectively. Each item was scored individually, and no significant difference was observed (P = 0.225). CONCLUSION: This reconstruction technique is valid for the three methods described; bone stock is retained and, once the graft has healed, it behaves as normal bone. Close radiographic follow-up detects complications early, allowing timely interventions if necessary. PMID- 20703877 TI - The effects of urbanization on net primary productivity in southeastern China. AB - Net primary productivity (NPP) is one of the major ecosystem products on which human societies rely heavily. However, rapid urban sprawl and its associated dense population and economic conditions have generated great pressure on natural resources, food security, and environments. It is valuable to understand how urban expansion and associated demographic and economic conditions affect ecosystem functions. This research conducted a case study in Southeastern China to examine the impacts of urban expansion and demographic and economic conditions on NPP. The data sources used in research include human settlement developed through a combination of MODIS, DMSP-OLS and Landsat ETM+ images, the annual NPP from MODIS, and the population and gross domestic product (GDP) from the 2000 census data. Multiple regression analysis and nonlinear regression analysis were used to examine the relationships of NPP with settlement, population and GDP. This research indicates that settlement, population and GDP have strongly negative correlation with NPP in Southeastern China, but the outcomes were nonlinear when population or GDP reached certain thresholds. PMID- 20703878 TI - Biological assessment to support ecological recovery of a degraded headwater system. AB - An assessment of the benthic macroinvertebrate community was conducted to characterize the ecological recovery of a channelized main stem and two small tributaries at the Watershed Research and Education Center (WREC, Arkansas, USA). Three other headwater streams in the same basin were also sampled as controls and for biological reference information. A principal components analysis produced stream groupings along an overall gradient of physical habitat integrity, with degraded reaches showing lower RBP habitat scores, reduced flow velocities, smaller substrate sizes, greater conductivity, and higher percentages of sand and silt substrate. The benthic macroinvertebrate assemblage at WREC was dominated by fast-reproducing dipteran larvae (midge and mosquito larvae) and physid snails, which comprised 71.3% of the total macroinvertebrate abundance over three sampling periods. Several macroinvertebrate assemblage metrics should provide effective targets for monitoring overall improvements in the invertebrate assemblage including recovery towards a more complex food web (e.g., total number of taxa, number of EPT taxa, percent 2 dominant taxa). However, current habitat conditions and the extent of existing degradation, system isolation and surrounding urban or agricultural land-uses might affect the level of positive change to the system. We therefore suggest a preliminary restoration strategy involving the addition of pool habitats in the system. At one pool we collected a total of 29 taxa (dominated by water beetle predators), which was 59% of total number of taxa collected at WREC. Maintaining water-retentive pools to collect flows and maintain water permanence focuses on enhancing known biology and habitat, thus reducing the effects of abiotic filters on macroinvertebrate assemblage recovery. Furthermore, biological assessment prior to restoration supports a strategy primarily focused on improving the existing macroinvertebrate community in the current context of the system, thereby reducing costs associated with active channel restoration. Monitoring future biological recovery and determining the contribution of changing assemblages to specific ecological processes would provide a critical underpinning for adaptive management and ecologically-effective restoration. PMID- 20703879 TI - The Leser-Trelat sign is a associated with acute myeloid leukemia. PMID- 20703880 TI - A comparison of two class 10 pathogenesis-related genes from alfalfa and their activation by multiple stresses and stress-related signaling molecules. AB - A collection of 29 pathogenesis-related 10 (PR10) genes of Medicago sativa and Medicago truncatula showed that they were almost all obtained from cDNA libraries of tissues undergoing abiotic or biotic stresses. The predicted proteins could be divided into two subclasses, PR10.1 and PR10.2, but in silico predicted models of their three-dimensional structures revealed that they could be further divided based on size of the hydrophobic internal cavity and number of beta-bulges. A comparison of the expression of two highly similar M. sativa subclass PR10.1 genes, MsPR10.1A and MsPR10.1B, predicted to have similar sized hydrophobic internal cavities, but a different number of beta-bulges revealed differences in their expression patterns. MsPR10.1A was induced faster than MsPR10.1B by ABA, ethylene, and X. campestris pv. alfalfae, but slower than MsPR10.1B by harvesting and wounding. Unlike MsPR10.1A, MsPR10.1B expression was induced in non-harvested tissues following harvesting, but was not induced by heat treatment. Histochemical observations of Nicotiana benthamiana transformed with 657 bp of the MsPR10.1A promoter fused to the beta-glucuronidase (GUS) gene showed that GUS expression was wound-inducible in leaves, which was consistent with MsPR10.1A expression in alfalfa leaves. GUS expression in stems and leaves was mostly in vascular tissue. The MsPR10.1A promoter may be valuable in controlling the expression in vascular tissues and disease resistance. PMID- 20703881 TI - Characterization of the multiple resistance traits of somatic hybrids between Solanum cardiophyllum Lindl. and two commercial potato cultivars. AB - Interspecific somatic hybrids between commercial cultivars of potato Solanum tuberosum L. Agave and Delikat and the wild diploid species Solanum cardiophyllum Lindl. (cph) were produced by protoplast electrofusion. The hybrid nature of the regenerated plants was confirmed by flow cytometry, simple sequence repeat (SSR), amplified fragment length polymorphism (AFLP), microsatellite-anchored fragment length polymorphism (MFLP) markers and morphological analysis. Somatic hybrids were assessed for their resistance to Colorado potato beetle (CPB) using a laboratory bioassay, to Potato virus Y (PVY) by mechanical inoculation and field trials, and foliage blight in a greenhouse and by field trials. Twenty-four and 26 somatic hybrids of cph + cv. Agave or cph + cv. Delikat, respectively, showed no symptoms of infection with PVY, of which 3 and 12, respectively, were also resistant to foliage blight. One hybrid of cph + Agave performed best in CPB and PVY resistance tests. Of the somatic hybrids that were evaluated for their morphology and tuber yield in the field for 3 years, four did not differ significantly in tuber yield from the parental and standard cultivars. Progeny of hybrids was obtained by pollinating them with pollen from a cultivar, selfing or cross-pollination. The results confirm that protoplast electrofusion can be used to transfer the CPB, PVY and late blight resistance of cph into somatic hybrids. These resistant somatic hybrids can be used in pre-breeding studies, molecular characterization and for increasing the genetic diversity available for potato breeding by marker-assisted combinatorial introgression into the potato gene pool. PMID- 20703882 TI - [Eligibility requirements after refractive surgery. Pilots, professional drivers and applicants for the police and armed forces]. AB - Selection of the appropriate refractive procedure is made by the surgeon according to medical criteria. However, some professions in the Federal Republic of Germany require certain eyesight standards and only permit the performance of certain refractive procedures. Therefore it is crucial for the surgeon to know whether a chosen refractive procedure and visual function meet the eligibility requirements of the patients' profession before the refractive procedure is carried out.The following article provides an overview of the current visual requirements after refractive surgery for pilots, professional drivers and applicants for the armed forces and the police force in the Federal Republic of Germany. PMID- 20703883 TI - Technical aspects of the thoracoscopic repair of a late presenting congenital H type fistula. AB - Congenital H-type fistulae are a rare abnormality. They commonly present with only minor respiratory complications and can, therefore, be difficult to identify. Conventionally, correction is via a ligation performed via either a cervical or thoracotomy incision, dependant on the fistula site. Thoracoscopic repair is emerging as a tenable alternative to traditional approaches and offers some advantages. This paper details the technical aspects of the thoracoscopic ligation of an H-type fistula. PMID- 20703884 TI - Can elemental composition data of crop leaves be used to estimate radionuclide transfer to tree leaves? AB - Estimation of radionuclide concentrations in trees may be required to estimate their radiation exposure. However, concentration ratios of radionuclides from soil to tree species are limited for many radionuclide-tree combinations. To fill this gap, it is investigated in the present paper whether stable element concentration data for leafy vegetables are representative of those for wild tree leaves, and consequently, if these stable element data for leafy vegetables can be used as analogues to describe radionuclides transfer from soil to trees. Data for stable elements in leafy vegetables collected in Japan were compared with those in leaves of about 20 tree species worldwide. The correlation coefficients of element concentrations between leafy vegetables and tree leaves were higher than 0.90 with p < 0.001 by Student's t test, and geometric means of concentration data for most elements were within the range of data for leafy vegetables. Thus, transfer parameters derived from stable element data for leafy vegetables could generally be used to estimate concentrations in tree leaves if data for the latter are not available. However, some trees accumulate a few elements (e.g., Al, Co, Mn and Si) in their leaves to higher concentrations than observed for leafy vegetables. PMID- 20703885 TI - Benefit from jejunal levodopa in a patient with apomorphine pump. PMID- 20703886 TI - Perfusion CT in suspected ischaemic stroke: red flags that should have been blue. PMID- 20703887 TI - Fluorescent dye particles as pollen analogues for measuring pollen dispersal in an insect-pollinated forest herb. AB - In flowering plants, pollen dispersal is often the major contributing component to gene flow, hence a key parameter in conservation genetics and population biology. A cost-effective method to assess pollen dispersal consists of monitoring the dispersal of fluorescent dyes used as pollen analogues. However, few comparisons between dye dispersal and realized pollen dispersal have been performed to validate the method. We investigated pollen dispersal in two small populations of the insect-pollinated herb Primula elatior from urban forest fragments using direct (paternity analyses based on microsatellite DNA markers) and indirect (fluorescent dyes) methods. We compared these methods using two approaches, testing for the difference between the distance distributions of observed dispersal events and estimating parameters of a dispersal model, and related these results to dye dispersal patterns in three large populations. Dye and realized (based on paternity inference) pollen dispersal showed exponential decay distributions, with 74.2-94.8% of the depositions occurring at <50 m and a few longer distance dispersal events (up to 151 m). No significant difference in curve shape was found between dye and realized pollen dispersal distributions. The best-fitting parameters characterizing the dye dispersal model were consistent with those obtained for realized pollen dispersal. Hence, the fluorescent dye method may be considered as reliable to infer realized pollen dispersal for forest herbs such as P. elatior. However, our simulations reveal that large sample sizes are needed to detect moderate differences between dye and realized pollen dispersal patterns because the estimation of dispersal parameters suffers low precision. PMID- 20703888 TI - Hemostatic matrix sealant in neurosurgery: a clinical and imaging study. AB - OBJECT: The aim of this study was to investigate prospectively the efficacy and safety of Floseal hemostatic matrix. METHODS: A total of 214 patients (87 males, 127 females; mean age 56.2 years) undergoing cranial (71.4%), craniospinal (0.9%), and spinal (27.5%) procedures with the use of gelatin thrombin hemostatic matrix (Floseal) were included in this prospective study. The indications for its use, surgical techniques, time to bleeding control, and associated complications were recorded. RESULTS: Effective hemostasis, defined as cessation of bleeding, was achieved no later than 3 min after topical agent application in all patients except in 11 cases, in which the hemostatic application was repeated. Rebleeding was disclosed in four patients 1 day after initial surgery. In one case, an intracerebral abscess developed after a malignant glioma removal. No other patient developed allergic reactions or local or systemic complications associated with the hemostatic sealant. CONCLUSION: In this study, matrix hemostatic sealant helped to control operative bleeding in cranial and spinal surgery, reducing damage to the surrounding healthy nervous tissue while shortening surgical timing. Other than safe, the immediate hemostatic effect is an advantage in the settings of refractory bleeding. PMID- 20703889 TI - The first 3 months after BCNU wafers implantation in high-grade glioma patients: clinical and radiological considerations on a clinical series. AB - PURPOSE: Carmustine (1,3-bis[2-chloroetyl]-1-nitrosurea (BCNU)) wafers are approved for the local treatment of newly diagnosed and recurrent malignant glioma. Reassuring data on both safety and efficacy of treatment have been previously reported by phase III studies. Although most of related adverse events are reported in the first few months after surgery, there is a lack in the literature of radiological data regarding this period. Few anecdotal experiences have been reported about surgical bed cyst occurrence. The aim of our study is to analyse the radiological course of patients treated with wafers implantation focusing on the relationship between radiological data, and in particular bed cyst occurrence, and safety data. METHODS: Forty-three patients affected by malignant glioma underwent surgical removal and BCNU wafers implantation at the Department of Neurosurgery of Padova from April 2007 to October 2009. Safety data were collected according to previously reported phase III studies. Patients underwent clinical and radiological evaluation (MRI) postoperatively, then before discharge, at 1 month, then every 2 months. In the study were included only patients whose both 1- and 3-month MRIs were available. Finally, 36 out of 43 patients were available for the revision. FINDINGS: Fifty-eight percent of patients treated with BCNU wafers presented a bed cyst of the surgical cave at the 1-month MRI. Forty-eight percent of them were symptomatic. Conversely, among patients who presented one or more adverse event (27%), bed cyst was detected in up to 90% of cases (OR 7.35), being intracranial hypertension more frequently associated (OR 7.35; p value <0.05). In general, cysts presented a benign behaviour in the sense that patients promptly improved with corticosteroid treatment, never required surgery, never reported permanent neurological deficits. CONCLUSIONS: Surgical bed cyst occurrence in BCNU wafer-treated patients resulted more frequent than expected. Familiarity with the event is important to correctly handle a possible evolving phenomenon. However, only further larger experiences and prospective studies could reveal how the understanding of such event might be helpful to improve safety data. PMID- 20703890 TI - The validity and reliability of the Turkish version of the Revised Fibromyalgia Impact Questionnaire. AB - The Revised Fibromyalgia Impact Questionnaire (FIQR) attempts to address the limitations of the Fibromyalgia Impact Questionnaire (FIQ). As there is no Turkish version of the FIQR available, we aimed to investigate the validity and reliability of a Turkish translation of the FIQR in Turkish female fibromyalgia (FM) patients. After translating the FIQR into Turkish, it was administered to 87 female patients with FM. All of the patients filled out the questionnaire together with a Turkish version of the FIQ, hospital anxiety and depression scales (HADS), short form-36 (SF-36). The tender-point count (TPC) was also calculated from tender points identified by thumb palpation. One week later, FM patients filled out the Turkish FIQR at their second visit. The test-retest reliability of the Turkish FIQR questions ranged from 0.714 to 0.898. The test and retest reliability of total FIQR score was 0.835. Cronbach's alpha was 0.89 for FIQR visit 1 (the first assessment) and 0.91 for FIQR visit 2 (the second assessment), indicating acceptable levels of internal consistency for both assessments. The total scores of the FIQR and FIQ were significantly correlated (r = 0.87, P < 0.01). Significant correlations for construct validity were also obtained between the FIQR total and domain scores and the FIQ, the HADS and the subscales of the SF-36 (FIQR total versus SF-36 physical component score and mental component score were r = -0.63, P < 0.01 and r = -0.51, P < 0.01, respectively). The Turkish FIQR is a reliable and valid instrument for measuring health status in FM, showing sufficient reliability and construct validity. It may be utilized for both clinical practice and research use in the Turkish speaking population in place of FIQ, since its Turkish version has problems in the wording, omissions, concepts, and scoring from the original FIQ. PMID- 20703891 TI - Primary Staphylococcus aureus urinary tract infection: the role of undetected hematogenous seeding of the urinary tract. AB - Staphylococcus aureus (SA) bacteriuria may accompany SA bacteremia, but primary SA urinary tract infection (UTI) may also occur. Our clinical observation of SA UTIs following intravenous catheter-related phlebitis lead us to review hematogenous and ascending route-related risk factors in patients with primary SA UTIs. The charts from all patients with SA UTIs over a 1.5-year period were reviewed for concurrent or recent hospitalization, intravenous catheterization, and for known UTI risk factors. Patients with concurrent SA bacteremia were excluded. Patients with Escherichia coli UTIs during the same period were included as controls. Twenty cases of primary SA UTI were compared with 43 E. coli UTI cases and they did not differ in age, diabetes mellitus, prostatic hypertrophy, previous UTI, or other urinary tract (UT) abnormality. However, cases were more likely than controls to have had recent or concurrent hospitalization, UT catheterization, and history of recent phlebitis. In multivariate analysis, UT catheterization and recent hospitalization retained significant association with SA UTI. Similar results were shown for the methicillin-resistant SA UTI subgroup. Even though UT catheterization is the main predisposing factor for primary SA UTI, some cases may be mediated through unrecognized preceding bacteremia related to intravascular device exposure or other healthcare-related factors. PMID- 20703893 TI - Nutraceuticals and cancer. Preface. PMID- 20703894 TI - Building membrane emulsification into pulmonary drug delivery and targeting. PMID- 20703892 TI - Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. AB - The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems-PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine-to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G(S) that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor. PMID- 20703895 TI - Beta-casein nanoparticles as an oral delivery system for chemotherapeutic drugs: impact of drug structure and properties on co-assembly. AB - PURPOSE: To develop a novel oral drug delivery system comprising a hydrophobic chemotherapeutic drug entrapped within beta casein (beta-CN), a major milk protein, which self-associates into micelles in aqueous solutions. The efficient gastric digestibility of beta-CN suggests possible targeting to gastric cancers. METHODS: Antitumor drug entrapment was performed by stirring its dimethyl sulfoxide solution into a phosphate-buffered saline containing beta-CN. The association of drugs to beta-CN was characterized by spectrophotometry and Trp143 fluorescence quenching; particle-size by dynamic light scattering, and colloidal stability by zeta potential. RESULTS: The optimal drug-to-beta-CN molar loading ratios for paclitaxel and vinblastine at 1 mg/ml beta-CN were found to be 7.3 +/- 1.2 and 5.3 +/- 0.6 and the association constants were (6.3 +/- 1.0) x 10(3) M( 1) and (2.0 +/- 0.3) x 10(4) M(-1), respectively. Zeta potential analysis suggested that nanoencapsulation by beta-CN stabilized all studied drugs in aqueous solution. The initial drug-beta-CN association was apparently governed by hydrophobic interactions and at higher drug concentrations, also by electrostatic interactions. Up to the optimal drug:beta-CN loading-ratio, ~80% of the particles were below 100 nm in diameter. At higher drug concentrations, particle diameter increased, and bi- or tri-modal particle distributions were observed. CONCLUSIONS: Beta-CN forms colloidally-stable nanovehicles of hydrophobic anticancer drugs, and may be used for oral-delivery of chemotherapeutics. PMID- 20703896 TI - A segmentation method of lung cavities using region aided geometric snakes. AB - Segmenting the lungs in medical images is a challenging and important task for many applications. In particular, automatic segmentation of lung cavities from multiple magnetic resonance (MR) images is very useful for oncological applications such as radiotherapy treatment planning. Largely changing lung shapes, low contrast and poorly defined boundaries make the lung cavities hard to be distinguished, even in the absence of prominent neighboring structures. In this paper, we utilized a modified geometric-based snake model which could greatly improve the model's segmentation efficiency in capturing complex geometries and dealing with difficult initialization and weak edges. This model integrates the gradient flow forces with region constraints provided by fuzzy c means clustering. The proposed model has been tested on a database of 30 MR images with 80 slices in each image. The obtained results are compared to manual segmentations of the lung provided by an expert radiologist and with those of previous works, showing encouraging results and high robustness of our approach. PMID- 20703897 TI - Fuzzy approach for determination the optimum therapeutic parameters in neuromuscular stimulation systems. AB - This paper presents a fuzzy system for determination the optimum therapeutic parameters (frequency, amplitude and session duration) in neuromuscular stimulation systems. The developed approach has many clinical benefits and features. These include: capability to determine and adjust the therapeutic parameters online during any treatment session, reduction of time and number of sessions needed to overcome the neuromuscular disorders, preventing patient from fatigue or pain that may occur during or after treatment, considering differences between various patients and improving the efficiency of the available neuromuscular stimulation systems. PMID- 20703898 TI - Frontal plane vectorcardiograms: theory and graphics visualization of cardiac health status. AB - The electrocardiogram (ECG) is a representative signal containing information about the condition of the heart. The shape and size of the P-QRS-T wave, the time intervals between its various peaks, may contain useful information about the nature of disease afflicting the heart. However, these subtle details cannot be directly monitored by the human observer. Besides, these signals are highly subjective, and the symptoms may appear at random in the time scale. It is very taxing and time-consuming to decipher cardiac abnormalities based on these ECG signals. The Vectorcardiogram (VCG) is the vector loop in the 2-D frontal plane, indicating the magnitude and direction of the instantaneous heart electrical activity vector (HAV), which represents the sum of the dipole vectors located along the instantaneous depolarization wavefront. The HAV is constructed from the monitored 3-lead ECG signals, placed at the three vertices of the modified Einthoven triangle formed by the 3-lead system in the frontal plane of the torso. The VCG examines the electrical activities within the heart, using the ECG signals along the three sides of the modified Einthoven triangle, and displays electrical events in the 2-dimensional frontal plane. This study demonstrates the development of the heart-depolarisation vector-locus cardiogram (using modified Einthoven's triangle), as a diagnostic measure of the left ventricular depolarisation strength. Our work involves the reconstruction of the "equivalent heart vector" for the QRS complex from limb lead voltages of a sample ECG, and plotting the progression of the cardiac vector during the QRS complex. We have demonstrated the construction of the frontal plane heart-depolarization vector cardiogram (HDVC), as the path of the locus of the tip of the heart electrical activity vector, with initial and terminal points at the origin. In this work, we have shown characteristic patterns of HDVC for cardiac states namely, normal, bundle branch block, ventricular hypertrophy and myocardial infarction. We have demonstrated how HDVC can be diagnostically employed to characterize cardiac disorders, such as ventricular hypertrophy bundle branch block and inferior myocardial infarction. PMID- 20703899 TI - Detecting road maps for capacity utilization decisions by Clustering Analysis and CHAID Decision Trees. AB - The aims of this study are to provide a standard CUR value, to determine financial and organizational factors which affect the capacity utilization and develop road maps for increasing capacity utilization. To reach these aims by an objective method, we used data mining method that discovers hidden and useful pattern in a large amount of data. Two different method of data mining were used in two stages for this study. In first step, standard value of CUR was determined by K-means Clustering Analysis. CHAID Decision Tree Algorithm as a second method was implemented for determination of impact factors that provided steps for road maps. The study was concerned Turkish Ministry of Health public hospitals. 592 hospitals were covered and financial and operational data of the year 2004 were used in the study. Finally two different road maps were developed and suggestions were made according the results of the study. PMID- 20703901 TI - Using Elman recurrent neural networks with conjugate gradient algorithm in determining the anesthetic the amount of anesthetic medicine to be applied. AB - In this study, Elman recurrent neural networks have been defined by using conjugate gradient algorithm in order to determine the depth of anesthesia in the continuation stage of the anesthesia and to estimate the amount of medicine to be applied at that moment. The feed forward neural networks are also used for comparison. The conjugate gradient algorithm is compared with back propagation (BP) for training of the neural Networks. The applied artificial neural network is composed of three layers, namely the input layer, the hidden layer and the output layer. The nonlinear activation function sigmoid (sigmoid function) has been used in the hidden layer and the output layer. EEG data has been recorded with Nihon Kohden 9200 brand 22-channel EEG device. The international 8-channel bipolar 10-20 montage system (8 TB-b system) has been used in assembling the recording electrodes. EEG data have been recorded by being sampled once in every 2 milliseconds. The artificial neural network has been designed so as to have 60 neurons in the input layer, 30 neurons in the hidden layer and 1 neuron in the output layer. The values of the power spectral density (PSD) of 10-second EEG segments which correspond to the 1-50 Hz frequency range; the ratio of the total power of PSD values of the EEG segment at that moment in the same range to the total of PSD values of EEG segment taken prior to the anesthesia. PMID- 20703900 TI - Statistical analysis of patients' characteristics in neonatal intensive care units. AB - The staff in the neonatal intensive care units is required to have highly specialized training and the using equipment in this unit is so expensive. The random number of arrivals, the rejections or transfers due to lack of capacity and the random length of stays, make the advance knowledge of the optimal staff; equipment and materials requirement for levels of the unit behaves as a stochastic process. In this paper, the number of arrivals, the rejections or transfers due to lack of capacity and the random length of stays in a neonatal intensive care unit of a university hospital has been statistically analyzed. The arrival patients are classified according to the levels based on the required nurse: patient ratio and gestation age. Important knowledge such as arrivals, transfers, gender and length of stays are analyzed. Finally, distribution functions for patients' arrivals, rejections and length of stays are obtained for each level in the unit. PMID- 20703902 TI - Alterations in sleep EEG activity during the hypopnoea episodes. AB - The Obstructive Sleep Apnoea Hypopnoea Syndrome (OSAH) means "cessation of breath" during the sleep hours and the sufferers often experience related changes in the electrical activity of the brain and heart. The aim of this paper is to investigate any possible changes in the human electroencephalographic (EEG) activity due to hypopnoea (mild case of cessation of breath) occurrences by applying the non-linear and linear time series methods. The results from this study indicated significant changes in the human EEG activity due to hypopnoea episodes by applying the non-linear, Lyapunov exponent method at C3 EEG electrode site. This non-linear method can be applied in future evaluation of sleep EEG transients during the OSAH episodes. PMID- 20703903 TI - Determining the amount of anesthetic medicine to be applied by using Elman's recurrent neural networks via resilient back propagation. AB - In this study, Elman recurrent neural networks have been defined by using Resilient Back Propagation in order to determine the depth of anesthesia in the continuation stage of the anesthesia and to estimate the amount of medicine to be applied at that moment. From 30 patients, 57 distinct EEG recordings have been collected prior to during anaesthesia of different levels. The applied artificial neural network is composed of three layers, namely the input layer, the middle layer and the output layer. The nonlinear activation function sigmoid (sigmoid function) has been used in the hidden layer and the output layer. Prediction has been made by means of ANN. Training and testing the ANN have been used previous anaesthesia amount, total power/normal power and total power/previous. The system has been able to correctly purposeful responses in average accuracy of 95% of the cases. This method is also computationally fast and acceptable real-time clinical performance has been obtained. PMID- 20703904 TI - Evaluation of completeness of selected poison control center data fields. AB - Poison control center data are used in research and surveillance. Due to the large volume of information, these efforts are dependent on data being recorded in machine readable format. However, poison center records include non-machine readable text fields and machine readable coded fields, some of which are duplicative. Duplicating this data increases the chance of inaccurate/incomplete coding. For surveillance efforts to be effective, coding should be complete and accurate. Investigators identified a convenience sample of 964 records and reviewed the substance code determining if it matched its text field. They also reviewed the coded clinical effects and treatments determining if they matched the notes text field. The substance code matched its text field for 91.4% of the substances. The clinical effects and treatments codes matched their text field for 72.6% and 82.4% of occurrences respectively. This under-reporting of clinical effects and treatments has surveillance and public health implications. PMID- 20703905 TI - Implementation issues for mobile-wireless infrastructure and mobile health care computing devices for a hospital ward setting. AB - mWard is a project whose purpose is to enhance existing clinical and administrative decision support and to consider mobile computers, connected via wireless network, for bringing clinical information to the point of care. The mWard project allowed a limited number of users to test and evaluate a selected range of mobile-wireless infrastructure and mobile health care computing devices at the neuroscience ward at Southern Health's Monash Medical Centre, Victoria, Australia. Before the project commenced, the ward had two PC's which were used as terminals by all ward-based staff and numerous multi-disciplinary staff who visited the ward each day. The first stage of the research, outlined in this paper, evaluates a selected range of mobile-wireless infrastructure. PMID- 20703906 TI - Newborn screening healthcare information system based on service-oriented architecture. AB - In this paper, we established a newborn screening system under the HL7/Web Services frameworks. We rebuilt the NTUH Newborn Screening Laboratory's original standalone architecture, having various heterogeneous systems operating individually, and restructured it into a Service-Oriented Architecture (SOA), distributed platform for further integrity and enhancements of sample collections, testing, diagnoses, evaluations, treatments or follow-up services, screening database management, as well as collaboration, communication among hospitals; decision supports and improving screening accuracy over the Taiwan neonatal systems are also addressed. In addition, the new system not only integrates the newborn screening procedures among phlebotomy clinics, referral hospitals, as well as the newborn screening center in Taiwan, but also introduces new models of screening procedures for the associated, medical practitioners. Furthermore, it reduces the burden of manual operations, especially the reporting services, those were heavily dependent upon previously. The new system can accelerate the whole procedures effectively and efficiently. It improves the accuracy and the reliability of the screening by ensuring the quality control during the processing as well. PMID- 20703907 TI - Application of portable CDA for secure clinical-document exchange. AB - Health Level Seven (HL7) organization published the Clinical Document Architecture (CDA) for exchanging documents among heterogeneous systems and improving medical quality based on the design method in CDA. In practice, although the HL7 organization tried to make medical messages exchangeable, it is still hard to exchange medical messages. There are many issues when two hospitals want to exchange clinical documents, such as patient privacy, network security, budget, and the strategies of the hospital. In this article, we propose a method for the exchange and sharing of clinical documents in an offline model based on the CDA-the Portable CDA. This allows the physician to retrieve the patient's medical record stored in a portal device, but not through the Internet in real time. The security and privacy of CDA data will also be considered. PMID- 20703908 TI - Can neural network able to estimate the prognosis of epilepsy patients according to risk factors? AB - The aim of this study is to evaluate the underlying etiologic factors of epilepsy patients and to predict the prognosis of these patients by using a Multi-Layer Perceptron Neural Network (MLPNN) according to risk factors. 758 patients with epilepsy diagnosis are included in this study. The MLPNNs were trained by the parameters of demographic properties of the patients and risk factors of the disease. The results show that the most crucial risk factor of the epilepsy patients was constituted by the febrile convulsion (21.9%), the kinship of parents (22.3%), the history of epileptic relatives (21.6%) and the history of head injury (18.6%). We had 91.1 % correct prediction rate for detection of the prognosis by using the MLPNN algorithm. The results indicate that the correct prediction rate of prognosis of the MLPNN model for epilepsy diseases is found satisfactory. PMID- 20703910 TI - Meeting the ONCHIT population health mandate: a proposed model for security in selective transportable distributed environments. AB - Goal Two of the US ONCHIT Plan focuses on enabling the use of electronic health information for critical health improvement activities that promote the health of targeted communities, and the US population as a whole. Because of the focus on communities and populations, the activities under this second goal differ fundamentally from those of the first goal, which focus on the care of individuals. Proposed here is a model for health information management in such population-based environments, which allows selective access and use of information, and maintains transportability while ensuring security and confidentiality. PMID- 20703909 TI - A tree-based decision model to support prediction of the severity of asthma exacerbations in children. AB - This paper describes the development of a tree-based decision model to predict the severity of pediatric asthma exacerbations in the emergency department (ED) at 2 h following triage. The model was constructed from retrospective patient data abstracted from the ED charts. The original data was preprocessed to eliminate questionable patient records and to normalize values of age-dependent clinical attributes. The model uses attributes routinely collected in the ED and provides predictions even for incomplete observations. Its performance was verified on independent validating data (split-sample validation) where it demonstrated AUC (area under ROC curve) of 0.83, sensitivity of 84%, specificity of 71% and the Brier score of 0.18. The model is intended to supplement an asthma clinical practice guideline, however, it can be also used as a stand-alone decision tool. PMID- 20703911 TI - Design of a cervical collar device to facilitate and accelerate implementation of first aid. AB - Frequently there are disasters all over the world-fires, earthquakes, or even some unexpected shocking catastrophes. Hence people injured, or even died. Lifesaving actions begin with the initiation of the chain of survival. With every minute that passes without medical action being taken, the probability of being able to save the patients life decreases by ten percent. After 10 min there is normally no chance of resuscitation being successful. First aid is emergency treatment given before regular medical aid can be obtained. And it is a concept of first hands-on measures performed in a medical emergency by laypersons. The major aim of this study is to develop an easy-feasible cervical collar, for facilitating and accelerating implementation of first aid especially in case of collective injuries. The developed device is different from the cervical collars which are used to treat the neck pain. In the present study, the heartbeat is obtained by detecting pulse with the stethoscope that is a part of the developed device and fixed on the carorid artery. The obtained heartbeat signal has been processed by the electronic control circuit and the used LED has given light according to the patient's life signal. Although there are some disadvantages of the developed system, the precautions for these cases have been taken and the system has been tried to design in order to operate sensibly. PMID- 20703912 TI - Improving the efficiency of physical examination services. AB - The objective of our project was to improve the efficiency of the physical examination screening service of a large hospital system. We began with a detailed simulation model to explore the relationships between four performance measures and three decision factors. We then attempted to identify the optimal physician inquiry starting time by solving a goal-programming problem, where the objective function includes multiple goals. One of our simulation results shows that the proposed optimal physician inquiry starting time decreased patient wait times by 50% without increasing overall physician utilization. PMID- 20703913 TI - Telediagnosis of Parkinson's disease using measurements of dysphonia. AB - Parkinson's disease (PD) is a neurological illness which impairs motor skills, speech, and other functions such as mood, behavior, thinking, and sensation. It causes vocal impairment for approximately 90% of the patients. As the symptoms of PD occur gradually and mostly targeting the elderly people for whom physical visits to the clinic are inconvenient and costly, telemonitoring of the disease using measurements of dysphonia (vocal features) has a vital role in its early diagnosis. Such dysphonia features extracted from the voice come in variety and most of them are interrelated. The purpose of this study is twofold: (1) to select a minimal subset of features with maximal joint relevance to the PD-score, a binary score indicating whether or not the sample belongs to a person with PD; and (2) to build a predictive model with minimal bias (i.e. to maximize the generalization of the predictions so as to perform well with unseen test examples). For these tasks, we apply the mutual information measure with the permutation test for assessing the relevance and the statistical significance of the relations between the features and the PD-score, rank the features according to the maximum-relevance-minimum-redundancy (mRMR) criterion, use a Support Vector Machine (SVM) for building a classification model and test it with a more suitable cross-validation scheme that we called leave-one-individual-out that fits with the dataset in hand better than the conventional bootstrapping or leave one-out validation methods. PMID- 20703914 TI - ONCHIT security in distributed environments: a proposed model for implantable devices. AB - Recent ONCHIT mandates call for increased individual health data collection efforts as well as heightened security measures. To date most healthcare organizations have been reluctant to exchange information, citing confidentiality concerns and unshared costs incurred by specific organizations. Implantable monitoring and treatment devices are rapidly emerging as data collection interface tools in response to such mandates. Proposed here is a translational, device-independent consumer-based solution, which focuses on information controlled by specific patients, and functions within a distributed (organization neutral) environment. While the conceptual applications employed in this technology set are provided by way of illustration, they may also serve as a transformative model for emerging EMR/EHR requirements. PMID- 20703915 TI - Transaction-neutral implanted data collection interface as EMR driver: a model for emerging distributed medical technologies. AB - Electronic Medical Record (EMR) and Electronic Health Record (EHR) adoption continues to lag across the US. Cost, inconsistent formats, and concerns about control of patient information are among the most common reasons for non-adoption in physician practice settings. The emergence of wearable and implanted mobile technologies, employed in distributed environments, promises a fundamentally different information infrastructure, which could serve to minimize existing adoption resistance. Proposed here is one technology model for overcoming adoption inconsistency and high organization-specific implementation costs, using seamless, patient controlled data collection. While the conceptual applications employed in this technology set are provided by way of illustration, they may also serve as a transformative model for emerging EMR/EHR requirements. PMID- 20703916 TI - Identification of cataract and post-cataract surgery optical images using artificial intelligence techniques. AB - Human eyes are most sophisticated organ, with perfect and interrelated subsystems such as retina, pupil, iris, cornea, lens and optic nerve. The eye disorder such as cataract is a major health problem in the old age. Cataract is formed by clouding of lens, which is painless and developed slowly over a long period. Cataract will slowly diminish the vision leading to the blindness. At an average age of 65, it is most common and one third of the people of this age in world have cataract in one or both the eyes. A system for detection of the cataract and to test for the efficacy of the post-cataract surgery using optical images is proposed using artificial intelligence techniques. Images processing and Fuzzy K means clustering algorithm is applied on the raw optical images to detect the features specific to three classes to be classified. Then the backpropagation algorithm (BPA) was used for the classification. In this work, we have used 140 optical image belonging to the three classes. The ANN classifier showed an average rate of 93.3% in detecting normal, cataract and post cataract optical images. The system proposed exhibited 98% sensitivity and 100% specificity, which indicates that the results are clinically significant. This system can also be used to test the efficacy of the cataract operation by testing the post-cataract surgery optical images. PMID- 20703917 TI - Security requirements and solutions in electronic health records: lessons learned from a comparative study. AB - A growing capacity of information technologies in collection, storage and transmission of information in unprecedented amounts has produced significant problems about the availability of wide limit of the consumers of Electronic Health Records of Patients. With regard to the existence of many approaches to developing Electronic Health Records, the basic question is what kind of Model is suitable for the guarantee of the security of Electronic Health Records? The present study is a descriptive-comparative investigation conducted in Iran in 2007, along with comparisons made Electronic health records information security requirements of Australia, Canada, England and U.S.A with. The research was based on the study of texts such as articles, library's books and journals and reliable websites from 1992 to 2006. Based on the collected data, a primary Model was designed. The Delphi Technique was offered to evaluate the questionnaire and final Model was designed and proposed. Australia, Canada, England and U.S.A have requirements related to organizing information security, classifying and controlling information asset, security of human resources, environmental and physical security, Operational and communication management security, information access control security and development and Maintenance security of Electronic Health Records information systems. In the U.S.A, the above security requirements are presented in administrative, Physical and Technical safeguards. Based on the research findings, a comprehensive model of electronic health record security requirements in seven pivots is presented for Iran. This model is a collection of EHR security requirements from studied countries. The studied countries are solely subject to part of elements of this model. The suggested model is different from the ones used in other countries in some respects and is recommended for application in Iran. PMID- 20703918 TI - Recurrent neural networks for diagnosis of carpal tunnel syndrome using electrophysiologic findings. AB - This paper presents the use of recurrent neural networks (RNNs) for diagnosis of carpal tunnel syndrome (CTS) (normal, right CTS, left CTS, bilateral CTS). The RNN is trained with the Levenberg-Marquardt algorithm. The RNN is trained on the features of CTS (right median motor latency, left median motor latency, right median sensory latency, left median sensory latency). The multilayer perceptron neural network (MLPNN) is also implemented for comparison the performance of the classifiers on the same diagnosis problem. The total classification accuracy of the RNN is significantly high (94.80%). The obtained results confirmed the validity of the RNNs to help in clinical decision-making. PMID- 20703920 TI - An approach to access control in electronic health record. AB - OASIS is a non-for-profit consortium that drives the development convergence and adoption of open standards for the global information society. It involves more than 600 organizations and individuals as well as IT leaders Sun, Microsoft, IBM and Oracle. One of its standards is XACML which appeared a few years ago and now there are about 150,000 hits on Google. XACML (eXtensible Access Control Markup Language) is not technology related. Sun published in 2004 open source Sun XACML which is in compliance with XACML 1.0. specification and now works to make it comply with XACML 2.0. The heart of XACML are attributes values of defined type and name that is to be attached to a subject, a resource, an action and an environment in which a subject request action on resource. In that way XACML is to replace Role Based Access Control which dominated for years. The paper examines performances in CEN 13 606 and ISO 22 600 based healthcare system which uses XACML for access control. PMID- 20703919 TI - Achieving standardized medication data in clinical research studies: two approaches and applications for implementing RxNorm. AB - The National Institutes of Health has proposed a roadmap for clinical research. Test projects of this roadmap include centralized data management for distributed research, the harmonization of clinical and research data, and the use of data standards throughout the research process. In 2003, RxNorm was named as a standard for codifying clinical drugs. Clinical researchers looking to implement RxNorm have few template implementation plans. Epidemiological studies and clinical trials (types of clinical research) have different requirements for model standards and best implementation tools. This paper highlights two different (epidemiological and intervention) clinical research projects, their unique requirements for a medication standard, the suitability of RxNorm as a standard for each, and application and process requirements for implementation. It is hoped that our experience of selecting and implementing the RxNorm standard to address varying study requirements in both domestic and international settings will be of value to other efforts. PMID- 20703921 TI - Designing an emergency medical information system for the early stages of disasters in developing countries: the human interface advantage, simplicity and efficiency. AB - The means of designing an effective user interface software package varies from one application to another. Almost the entire ICT infrastructure was damaged following the impact of the tsunami tidal wave. Under such circumstances, transporting critically ill patients is a must and becomes the first priority. Many considerations are needed when designing a specific user interface for emergency situations in developing countries. In this study we proposed how to design the user interface in order to support emergency medical care in the early stages of disasters. The user interface was classified into two tabs, firstly to indicate critically ill patients and secondly to notify details of the medicine having been administered to the patients. Classifying the user interface of emergency medical care information systems by using VHF radio connections will be beneficial, especially for the early stages of disaster-stricken developing countries, in order to preserve the lives of more victims. PMID- 20703923 TI - Advanced data capture in the assisted medical home: a model for distributed and multimedia technologies. AB - Expanding the role of distributed health care, recent ONCHIT initiatives highlight the utilization of remote and home-based monitoring as a model for health care that is accessible, comprehensive and coordinated, delivered in the context of family and community. Extensible information technology in this context can be used to collect and store expanded data about patients and their environment, especially in assisted living and group home environments. Proposed here is a distributed model for meeting related ONC mandates, which include emerging patient data collection opportunities, especially within nursing homes, assisted living, and other group home arrangements. The conceptual applications employed in this technology set are provided by way of illustration, and may also serve as a transformative model for emerging EMR/EHR requirements. PMID- 20703922 TI - A comparison of two-way text versus conventional paging systems in an academic ophthalmology department. AB - Alphanumeric paging systems are unidirectional without prioritization capabilities. Newer electronic communication devices such as two-way text paging systems are capable of bidirectional paging and prioritization. While previous studies have evaluated alphanumeric paging systems in academic hospital settings, bidirectional two-way text paging systems have not been investigated. The goal of this study was to evaluate efficiency and impact on patient care delivery of a two-way text paging system compared to conventional one-way alphanumeric pagers. This unmasked, crossover prospective study was divided into three phases. In phase one, surveys were distributed to all ophthalmology attending physicians, residents, clinical technicians, and secretaries to assess the conventional alphanumeric paging system. In phase two, these participants used two-way text pagers without instruction (unstructured format) that they subsequently compared to the alphanumeric system with devised surveys assessing (on a scale of 0 to 100) time saved, increased daily efficiency, facilitation in patient care, and overall impression (helpfulness).In phase three, participants used a specific communication prioritization protocol (structured format) with the two-way text pagers with subsequent comparison and assessment with the same surveys. Compared to traditional alphanumeric pagers, new digital two-way text pagers were found to be statistically (p < 0.0001) more helpful by participants in all categories: as a time saver (80.33 vs. 56.95) p < 0.0001, increased daily efficiency (78.15 vs. 57.13) p < 0.0001, facilitation in patient care (78.79 vs. 56.95) p < 0.0001, and overall impression (helpfulness) (61.82 vs. 84.33) p < 0.0001. When compared to the alphanumeric pager, the two-way text pager was found to decrease subjectively call backs (73.6% to 45.6%, p < 0.0001), reduce interruptions of learning activities (43.63% to 26.6%, p < 0.0001) and enabled better patient care (59.8% to 42.2%, p < 0.0001). No significant statistical difference was found between the structured and unstructured system. Two-way text paging (structured versus unstructured guidance) was preferred over the conventional one-way alphanumeric paging system in every participant category. Two-way text paging is an effective alternative to alphanumeric paging, demonstrating saved time, increased daily efficiency, reduced call backs and interruptions of educational activities, and facilitation in patient care. PMID- 20703924 TI - Proposed model for ONCHIT pre-case biosurveillance using multiple array sensing and non-invasive data capture. AB - Recent initiatives by the US ONCHIT highlight the need for electronic population health data collection relating to aspects of Public Health Case (PH Case) reporting and Adverse Event (AE) reporting. Proposed solutions to date have been primarily provider-based, limited by organization-wide startup & maintenance costs, and hampered by risk-averse data distribution policies. Little attention has been given to consumer-focused, distributed data collection models, where objective, consumer-provided standardized data can be used prior to case identification to facilitate earlier use of extensible and distributed information networks in biosurveillance. We propose here one promising model for pre-case biosurveillance management, employing the use of breath-based, multiple array sensing and data capture. The conceptual applications employed in this technology set are provided by way of illustration, and may also serve as a transformative model for emerging EMR/EHR requirements. PMID- 20703925 TI - Benefits of pharmacogenomics in drug development-earlier launch of drugs and less adverse events. AB - Currently, pharmaceutical companies are reluctant to introduce pharmacogenomics (PGx) in their practice, since cost-benefit of PGx is obscure and methodology to use PGx in drug development has not been fully established yet. The purpose of this study is to investigate advantages obtained by introducing PGx in clinical trials. Particularly, taking Warfarin as an example, we investigate benefits of Enrichment effect that raises response rate of the drug by PGx. When response rate is raised by only 5%, cost of a clinical trial can be reduced to about 40% of a conventional clinical trial. Furthermore, since period necessary for a trial also can be reduced, development period can be shortened by about 750 days. In summary, PGx enables earlier launch of a drug with less cost, representing benefit to pharmaceutical companies, patients and public as a whole. PMID- 20703926 TI - Three-dimensional texture analysis of renal cell carcinoma cell nuclei for computerized automatic grading. AB - The extraction of important features in cancer cell image analysis is a key process in grading renal cell carcinoma. In this study, we analyzed the three dimensional chromatin texture of cell nuclei based on digital image cytometry. Individual images of 2,423 cell nuclei were extracted from 80 renal cell carcinomas (RCCs) using confocal laser scanning microscopy (CLSM). First, we applied the 3D texture mapping method to render the volume of entire tissue sections. Then, we determined the chromatin texture quantitatively by calculating 3D gray level co-occurrence matrices and 3D run length matrices. Finally, to demonstrate the suitability of 3D texture features for classification, we performed a discriminant analysis. In addition, we conducted a principal component analysis to obtain optimized texture features. Automatic grading of cell nuclei using 3D texture features had an accuracy of 78.30%. Combining 3D textural and 3D morphological features improved the accuracy to 82.19%. PMID- 20703927 TI - Estimation of sleep stages by an artificial neural network employing EEG, EMG and EOG. AB - Analysis and classification of sleep stages is essential in sleep research. In this particular study, an alternative system which estimates sleep stages of human being through a multi-layer neural network (NN) that simultaneously employs EEG, EMG and EOG. The data were recorded through polisomnography device for 7 h for each subject. These collective variant data were first grouped by an expert physician and the software of polisomnography, and then used for training and testing the proposed Artificial Neural Network (ANN). A good scoring was attained through the trained ANN, so it may be put into use in clinics where lacks of specialist physicians. PMID- 20703928 TI - A multi-voting enhancement for newborn screening healthcare information system. AB - The clinical symptoms of metabolic disorders during neonatal period are often not apparent. If not treated early, irreversible damages such as mental retardation may occur, even death. Therefore, practicing newborn screening is essential, imperative to prevent neonatal from these damages. In the paper, we establish a newborn screening model that utilizes Support Vector Machines (SVM) techniques and enhancements to evaluate, interpret the Methylmalonic Acidemia (MMA) metabolic disorders. The model encompasses the Feature Selections, Grid Search, Cross Validations as well as multi model Voting Mechanism. In the model, the predicting accuracy, sensitivity and specificity of MMA can be improved dramatically. The model will be able to apply to other metabolic diseases as well. PMID- 20703929 TI - Building the PHARAOH framework using scenario-based design: a set of pandemic decision-making scenarios for continuity of operations in a large municipal public health agency. AB - Continuity of Operations Planning (COOP) is actions taken before, during and after a disaster to maintain the delivery of an organization's essential services. The application of COOP in public health is necessary to save lives and protect population health when disaster strikes. However, COOP decision-making and COOP decision support technology are under-explored in the public health domain. This work approaches the problem of designing a COOP decision support system for a large municipal public health agency using scenario-based design. Through a series of meetings and informal interviews, we developed a set of 12 scenarios of use for public health decision-making roles during a pandemic. These scenarios were validated as reliable, useful and acceptable by professional public health COOP planners. The results of this work show scenario-based design can be a powerful tool in designing decision support systems for public health leadership information needs during a crisis. PMID- 20703930 TI - Ideal filtering approach on DCT domain for biomedical signals: index blocked DCT filtering method (IB-DCTFM). AB - We proposed Index-Blocked Discrete Cosine Transform Filtering Method (IB-DCTFM) to design ideal frequency range filter on DCT domain for biomedical signal which frequently exposed to specific frequency noise such as motion artifacts and 50/60 Hz powerline interference. IB-DCTFM removes unwanted frequency range signal on time domain by blocking specific DCT index on DCT domain. In simulation, electrocardiography, electromyography, photoplethysmography are used as a signal source and FIR, IIR and adaptive filter are used for comparison with proposed IB DCTFM. To evaluate filter performance, we calculated signal-to-noise ratio and correlation coefficient to clean signal of each signal and filtering method respectively. As a result of filter simulation, average signal to noise ration and correlation coefficient of IB-DCTFM are improved about 75.8 dB/0.477, and FIR, IIR and adaptive filtering results are 24.8 dB/0.130, 54.3 dB/0.440 and 29.5 dB/0.200 respectively. PMID- 20703931 TI - Seizure detection in temporal lobe epileptic EEGs using the best basis wavelet functions. AB - In this paper, we propose a novel method using best basis wavelet functions and double thresholding that are well suited for detecting and localization of important epileptic events from noisy recorded seizure EEG signals. Our technique is based on dyadic wavelet decomposition and is mainly concerned detection of single epileptic transients within the observation sequence, such as ictal and interictal epochs of EEG. In our experiment we use temporal lobe epileptic data recorded during 84 h from four patients diagnosed with epilepsy. We have achieved promising results that demonstrate efficiency and simplicity that can be used in clinical studies as an automatic decision support tool. Thus reduce the physician's workload and provide accurate diagnosis of epileptic seizures. PMID- 20703932 TI - Towards improved healthcare performance: examining technological possibilities and patient satisfaction with wireless body area networks. AB - This paper investigates the benefits of using less intrusive wireless technologies for heart monitoring. By replacing well established heart monitoring devices (i.e. Holter) with wireless ECG based Body Area Networks (BAN), improved healthcare performance can be achieved, reflected in (1) high quality ECG recordings during physical activities and (2) increased patient satisfaction. A small scale clinical trial was conducted to compare both technologies and the results illustrate that the wireless ECG monitor was able to detect ECG signals intended for arrhythmia diagnostics. Furthermore, from a patient's perspective, both technologies were evaluated using three dimensions, namely; hygienic aspects, physical activity, and skin reactions. Results demonstrate that the wireless ECG BAN showed better performance, especially regarding the hygienic aspects. It was also favourable for use during physical activities, and the signal quality of the wireless sensor system demonstrated good performance regarding signal noise and artefact disturbances. This paper concludes that wireless cardiac monitoring systems have significant benefits from a patient's perspective, and further clinical trials should be conducted to further evaluate the new ECG based BAN system, to identify the possibility of widespread adoption and utilisation of wireless technology for arrhythmia diagnostics. PMID- 20703933 TI - Muscle fatigue detection in EMG using time-frequency methods, ICA and neural networks. AB - The electromyography (EMG) signals give information about different features of muscle function. Real-time measurements of EMG have been used to observe the dissociation between the electrical and mechanical measures that occurs with fatigue. The purpose of this study was to detect fatigue of biceps brachia muscle using time-frequency methods and independent component analysis (ICA). In order to realize this aim, EMG activity obtained from activated muscle during a phasic voluntary movement was recorded for 14 healthy young persons and EMG signals were observed in time-frequency domain for determination of fatigue. Time-frequency methods are used for the processing of signals that are non-stationary and time varying. The EMG contains transient signals related to muscle activity. The proposed method for the detection of muscle fatigue is automated by using artificial neural networks (ANN). The results show that ANN with ICA separates EMG signals from fresh and fatigued muscles, hence providing a visualization of the onset of fatigue over time. The system is adaptable to different subjects and conditions since the techniques used are not subject or workload regime specific. PMID- 20703936 TI - Do students' perceptions of school smoking policies influence where students smoke?: Canada's Youth Smoking Survey. AB - OBJECTIVE: The objective of this study was to explore students' perceptions of school policy characteristics that influence the location of smoking while at school. METHODS: Data were collected from a nationally representative sample of Canadian youth in grades 7-12 as part of the 2006-2007 Youth Smoking Survey. We used multilevel logistic regression to examine how students' perceptions of school policies predicted smoking behavior on and off school grounds in 11,881 students who had ever smoked. Separate analyses were conducted for grades 7-9 and 10-12. RESULTS: In both grades 7-9 and 10-12, perceiving clear rules about smoking decreased the likelihood that a student would smoke on school grounds, while perceiving that a high percentage of peers smoke, that there are school rules about smoking, that students obey the rules, and that students can be fined for smoking increased the likelihood that a student would smoke off school grounds. CONCLUSIONS: Clearly perceived rules about smoking encourage students not to smoke on school grounds; however, perceptions of rules, along with strong enforcement, may displace behavior off of school grounds. Non-smoking policies should be part of a comprehensive approach, that supports cessation. PMID- 20703937 TI - Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects. AB - Trinucleotide repeat containing 9 (TNRC9) is a gene located at chromosome 16q12. Although of an uncertain function, it is a newly described risk factor for breast cancer. It contains a putative high-mobility group box motif, suggesting its possible role as transcription factor; it has been implicated in breast cancer metastasis. Published studies on the association between TNRC9 polymorphisms and breast cancer risk remain inconclusive, and a meta-analysis is required to verify the association. This pioneering research performed a meta-analysis of eight studies comprising a total of 25,828 cases and 36,177 controls. Significantly elevated breast cancer risk was associated with TNRC9 rs3803662 polymorphism when all studies were pooled in the meta-analysis (T vs. C allele contrast model: OR 1.18, 95% CI 1.09-1.28; TT vs. CC homozygote codominant model: OR 1.26, 95% CI 1.02-1.55; TT vs. CC+CT recessive model: OR 1.23, 95% CI 1.06-1.42). For TNRC9 rs12443621 polymorphism, no significant association was detected in all genetic models. For TNRC9 rs12443621 polymorphism, meanwhile, no significant association was observed in all comparison models. Conclusively, this meta-analysis suggests that TNRC9 rs3803662 polymorphism was significantly correlated with breast cancer risk and the variant T allele of TNRC9 rs3803662 polymorphism is a low-penetrant risk factor for developing breast cancer. There is no significant association between TNRC9 rs12443621 and rs8051542 polymorphisms and risk of breast cancer in current literature. PMID- 20703935 TI - Interaction of orthopoxviruses with the cellular ubiquitin-ligase system. AB - Protein modification by ubiquitin or ubiquitin-like polypeptides is important for the fate and functions of the majority of proteins in the eukaryotic cell and can be involved in regulation of various biological processes, including protein metabolism (degradation), protein transport to several cellular compartments, rearrangement of cytoskeleton, and transcription of cytoprotective genes. The accumulated experimental data suggest that the ankyrin-F-box-like and BTB-kelch like proteins of orthopoxviruses, represented by the largest viral multigene families, interact with the cellular Cullin-1- and Cullin-3-containing ubiquitin protein ligases, respectively. In addition, orthopoxviruses code for their own RING-domain-containing ubiquitin ligase. In this review, this author discusses the differences between variola (smallpox), monkeypox, cowpox, vaccinia, and ectromelia (mousepox) viruses in the organization of ankyrin-F-box and BTB-kelch protein families and their likely functions. PMID- 20703938 TI - Are breast conservation and mastectomy equally effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort of 1,451 patients aged <= 40 years. AB - To compare the effectiveness of breast-conserving therapy (BCT) and mastectomy, all women aged <= 40 years, treated for early-stage breast cancer in the southern part of the Netherlands between 1988 and 2005, were identified. A total of 562 patients underwent mastectomy and 889 patients received BCT. During follow-up, 23 patients treated with mastectomy and 135 patients treated with BCT developed a local relapse without previous or simultaneous evidence of distant disease. The local relapse risk for patients treated with mastectomy was 4.4% (95% confidence interval (CI) 2.4-6.4) at 5 years and reached a plateau after 6 years at 6.0% (95% CI 3.5-8.5). After BCT, the 5-, 10- and 15-year risks were 8.3% (95% CI 6.3 10.5), 18.4% (95% CI 15.0-21.8) and 28.2% (95% CI 23.0-33.4), respectively (P < 0.0001). Adjuvant systemic therapy following BCT reduced the 15-year local relapse risk from 32.9% (95% CI 26.7-39.1) to 16.1% (95% CI 9.1-23.1), (P = 0.0007). In conclusion, local tumor control in young patients with early-stage breast cancer is worse after BCT than after mastectomy. Adjuvant systemic therapy significantly improves local control following BCT and also for that reason it should be considered for most patients <= 40 years. Long-term follow-up is highly recommended for young patients after BCT, because even with systemic treatment an annual risk of local relapse of 1% remains up to 15 years after treatment. PMID- 20703939 TI - Soy intake in association with menopausal symptoms during the first 6 and 36 months after breast cancer diagnosis. AB - It has been suggested that soy food and its components may relieve menopausal symptoms (MPS) including hot flashes, night sweats, and vaginal dryness in healthy women. However, little is known about the effect of soy food intake on MPS in women with breast cancer. We examined associations of occurrence of MPS with soy food intake in 4,842 Chinese women aged 20-75 years who had non metastatic breast cancer and had not used hormone replacement therapy. MPS were assessed at 6 and 36 months after cancer diagnosis using a standardized questionnaire, and associations with soy food intake were evaluated in multivariate regression analyses. Daily soy food intake was assessed at 6 months postdiagnosis and over the first 36 months postdiagnosis using a validated food frequency questionnaire. The prevalence of MPS was 56% at 6 months and 63% at 36 months postdiagnosis with the hotflash being the most common MPS (~44-55%). Hot flashes occurred mainly in premenopausal breast cancer patients who were in the highest quartile of isoflavone intake at 6 months postdiagnosis (OR = 1.20, 95% CI: 0.98-1.59) compared with the lowest quartile. This association was stronger at 36 months postdiagnosis (OR = 1.59, 95% CI: 1.02-2.48). We found no significant associations for any MPS, night sweats, or vaginal dryness. Neither tamoxifen use nor BMI modified the association between MPS and isoflavone intake. There was no evidence that soy food consumption reduced MPS among breast cancer patients. High soy intake may increase the prevalence of hotflashes among premenopausal patients. Our study suggests that soy acts as an estrogen antagonist in breast cancer patients. PMID- 20703940 TI - Protective effects of hypothalamic proline-rich peptide and cobra venom Naja Naja Oxiana on dynamics of vestibular compensation following unilateral labyrinthectomy. AB - We tested the action of proline-rich peptide (PRP-1) and cobra venom Naja Naja Oxiana (NOX) on Deiters' nucleus neurons at 3rd, 15th and 35th days after unilateral labyrinthectomy (UL). Early and late tetanic, post-tetanic potentiation and depression of Deiters'neurons to bilateral high frequency stimulation of hypothalamic supraoptic and paraventricualar nuclei was studied. The analysis of spike activity was carried out by mean of on-line selection and special program. The complex averaged peri-event time and frequency histograms shows the increase of inhibitory and excitatory reactions of Deiters' neurons at early stage of vestibular compensation following PRP-1 and NOX injection, reaching the norm at the end of tests. In histochemical study the changes in Ca(2+)-dependent acidic phosphatase (AP) activity in neurons was discovered. It was shown that in UL animals the total disappearance or delay of decolorizing of Deiters' neurons lead to neurodegenerative pattern as cellular "shade". AP activity after UL and PRP-1 injection exerts more effective recovery of neurons in comparison with events, observed after the administration of NOX. The data of this study indicate that PRP-1 and NOX are protectors, which may successfully recover the disturbed vestibular functions. PMID- 20703941 TI - Perceived impact of the disclosure of a schizophrenia diagnosis. AB - Stigma against those with schizophrenia has demonstrated deleterious effects. However, less is known about the experience of individuals who disclose this diagnosis and how such disclosures differ by social situations. This study examines diagnosis disclosure in different contexts. A convenience sample of 258 adults with schizophrenia recruited via the internet and e-mail lists completed an online survey. Subjects were more open about their diagnosis with doctors, parents and friends than with employers or police. Those who report very good current mental health or who had fewer types of relationships were more open overall. Although reactions to disclosure varied, many report worse treatment by police and better treatment by parents after disclosure. Many also experienced worse treatment for medical problems after disclosing their schizophrenia diagnosis. These results support targeted anti-stigma interventions. It also suggests that stigma must be understood through individual experience in specific contexts rather than as a unitary experience. PMID- 20703943 TI - ACTH-producing remnants following apoplexy of an ACTH-secreting pituitary macroadenoma. AB - Describe a case of apoplexy of an ACTH-producing pituitary adenoma which resulted not only in an empty sella with concurrent hypothyroidism, hypoprolactinemia, and hypogonadism but persistent hypercortisolemia from two distinct extrasellar remnants of the original adenoma. Review the literature to identify other similar cases. The patient's medical history, physical exam, lab data, imaging exams and histopathological results were analyzed and compiled into a case report, and an extensive review of the literature was performed. Endocrinological data revealed hypercortisolism and an elevated ACTH with an otherwise suppressed pituitary axis. A pituitary MRI showed a macroadenoma in the left cavernous sinus in addition to an empty sella. An octreotide scan revealed lesions in the left sella turcica and the right sphenoid sinus. Tissue samples of both lesions stained positive for ACTH and negative for GH, prolactin, FSH, LH, and TSH. The lesions were surgically removed, and the patient treated with radiation and ketoconazole. This resulted in a significant decrease in ACTH and cortisol as well as a marked improvement in blood glucose control. The review of literature revealed the absence of any similar cases in the past. The patient presented with apoplexy of an ACTH-secreting pituitary macroadenoma with two hormonally active extrasellar remnants. Several cases in the literature describe recurrence of Cushing's disease following infarction of ACTH-secreting adenomas. This is the first documented case of infarction of an ACTH-producing adenoma resulting in two distinct ACTH-producing remnants without recurrence of the original adenoma. PMID- 20703944 TI - [Not Available]. PMID- 20703942 TI - Enzymatic activity, sensitivity to antifungal drugs and Baccharis dracunculifolia essential oil by Candida strains isolated from the oral cavities of breastfeeding infants and in their mothers' mouths and nipples. AB - Candida strains can cause oral candidosis, as well as nipples candidosis and lead to premature weaning or yeast transmission. The aim of this study was to evaluate 51 Candida isolates obtained from the oral cavities of infants during breastfeeding and mothers' oral cavities and nipples, their enzymatic activity and their sensitivity to amphotericin B, fluconazole and Baccharis dracunculifolia essential oil. Among the studied strains, 96.1% produced phospholipase and 78.4% produced proteinase. The antifungal resistance was only observed among isolates of C. albicans, for which three strains showed a resistant activity to fluconazole and one showed a resistant activity to amphotericin B. All strains were sensitive to B. dracunculifolia essential oil with MIC between 0.2 and 6.25 mg/ml. It was concluded that most of the strains showed significant enzymatic activity and were sensitive to amphotericin B and fluconazole. B. dracunculifolia essential oil inhibited the growth of all strains, including the ones resistant to commercial antifungal agents. PMID- 20703945 TI - [Not Available]. PMID- 20703946 TI - [Not Available]. PMID- 20703947 TI - [Not Available]. PMID- 20703948 TI - [Not Available]. PMID- 20703949 TI - [Not Available]. PMID- 20703950 TI - [Georg Forster's outline of a "science of man"]. AB - The major focus of the article is on Georg Forster's mode of elaborating a "science of man" in its theoretical and cultural contexts. The study aims at identifying Forster's distinct interest in the specificity of mankind and his interpretation of both the reasons for its diversity and its different stages of development. Forster, the articles argues, used a historicized version of Enlightenment natural history in order to analyse man a s a natural as well as a cultural being. At the same time, put anachronistically, Forster constituted the reciprocity of physical and cultural anthropology. However, he differs from Enlightenment historical thinking in that he interprets history as a contingency. Finally, the article maintains that Forster deliberately conceived of the "science of man" as a multidisciplinary empirical science. PMID- 20703951 TI - Hablamos Juntos (Together We Speak): interpreters, provider communication, and satisfaction with care. AB - BACKGROUND: The Hablamos Juntos-Together We Speak (HJ)--national demonstration project targeted the improvement of language access for Spanish-speaking Latinos in areas with rapidly growing Latino populations. The objective of HJ was to improve doctor-patient communication by increasing access to and quality of interpreter services for Spanish-speaking patients. OBJECTIVE: To investigate how access to interpreters for adult Spanish-speaking Latinos is associated with ratings of doctor/office staff communication and satisfaction with care. DESIGN: Cross-sectional cohort study. PATIENTS: A total of 1,590 Spanish-speaking Latino adults from eight sites across the United States who participated in the outpatient HJ evaluation. MEASUREMENTS: We analyzed two multi-item measures of doctor communication (4 items) and office staff helpfulness (2 items), and one global item of satisfaction with care by interpreter use. We performed regression analyses to control for patient sociodemographic characteristics, survey year, and clustering at the site of care. RESULTS: Ninety-five percent of participants were born outside the US, 81% were females, and survey response rates ranged from 45% to 85% across sites. In this cohort of Spanish-speaking patients, those who needed and always used interpreters reported better experiences with care than their counterparts who needed but had interpreters unavailable. Patients who always used an interpreter had better adjusted ratings of doctor communication [effect size (ES = 0.51)], office staff helpfulness (ES = 0.37), and satisfaction with care (ES = 0.37) than patients who needed but did not always use an interpreter. Patients who needed and always used interpreters also reported better experiences with care in all three domains measured [doctor communication (ES = 0.30), office staff helpfulness (ES = 0.21), and satisfaction with care (ES = 0.23)] than patients who did not need interpreters. CONCLUSIONS: Among adult Spanish-speaking Latinos, interpreter use is independently associated with higher satisfaction with doctor communication, office staff helpfulness, and ambulatory care. Increased attention to the need for effective interpreter services is warranted in areas with rapidly growing Spanish-speaking populations. PMID- 20703953 TI - The quality of colonoscopy services--responsibilities of referring clinicians: a consensus statement of the Quality Assurance Task Group, National Colorectal Cancer Roundtable. AB - Primary care clinicians initiate and oversee colorectal screening for their patients, but colonoscopy, a central component of screening programs, is usually performed by consultants. The accuracy and safety of colonoscopy varies among endoscopists, even those with mainstream training and certification. Therefore, it is a primary care responsibility to choose the best available colonoscopy services. A working group of the National Colorectal Cancer Roundtable identified a set of indicators that primary care clinicians can use to assess the quality of colonoscopy services. Quality measures are of actual performance, not training, specialty, or experience alone. The main elements of quality are a complete report, technical competence, and a safe setting for the procedure. We provide explicit criteria that primary care physicians can use when choosing a colonoscopist. Information on quality indicators will be increasingly available with quality improvement efforts within the colonoscopy community and growth in the use of electronic medical records. PMID- 20703954 TI - A partially folded state of ovalbumin at low pH tends to aggregate. AB - At pH 2, ovalbumin retains native-like secondary structure as seen by far-UV CD and FTIR, but lacks well-defined tertiary structure as seen by the fluorescence and near-UV CD spectra. Addition of 20 mM Trifluoroacetic acid (TFA) or 30 mM Trichloroacetic acid (TCA) on acid-induced state results in protein aggregation. This aggregated state possesses extensive beta-sheet structure as revealed by far UV CD and FTIR spectroscopy. Furthermore, the aggregates exhibit decreased ANS fluorescence and increased thioflavin T fluorescence. The presence of aggregates was confirmed by size exclusion chromatography. Such a formation of beta-sheet structure is found in the amyloid of a number of neurological diseases such as Alzheimer's and scrapie. Ovalbumin at low pH, in the presence of K(2)SO(4), exists in partially folded state characterized by native-like secondary structure and tertiary folds. PMID- 20703952 TI - Assessing the quality of clinical teachers: a systematic review of content and quality of questionnaires for assessing clinical teachers. AB - BACKGROUND: Learning in a clinical environment differs from formal educational settings and provides specific challenges for clinicians who are teachers. Instruments that reflect these challenges are needed to identify the strengths and weaknesses of clinical teachers. OBJECTIVE: To systematically review the content, validity, and aims of questionnaires used to assess clinical teachers. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and ERIC from 1976 up to March 2010. REVIEW METHODS: The searches revealed 54 papers on 32 instruments. Data from these papers were documented by independent researchers, using a structured format that included content of the instrument, validation methods, aims of the instrument, and its setting. RESULTS: Aspects covered by the instruments predominantly concerned the use of teaching strategies (included in 30 instruments), supporter role (29), role modeling (27), and feedback (26). Providing opportunities for clinical learning activities was included in 13 instruments. Most studies referred to literature on good clinical teaching, although they failed to provide a clear description of what constitutes a good clinical teacher. Instrument length varied from 1 to 58 items. Except for two instruments, all had to be completed by clerks/residents. Instruments served to provide formative feedback ( instruments) but were also used for resource allocation, promotion, and annual performance review (14 instruments). All but two studies reported on internal consistency and/or reliability; other aspects of validity were examined less frequently. CONCLUSIONS: No instrument covered all relevant aspects of clinical teaching comprehensively. Validation of the instruments was often limited to assessment of internal consistency and reliability. Available instruments for assessing clinical teachers should be used carefully, especially for consequential decisions. There is a need for more valid comprehensive instruments. PMID- 20703955 TI - In vitro renaturation of alkaline family G/11 xylanase via a folding intermediate: alpha-crystallin facilitates refolding in an ATP-independent manner. AB - In this study, alkaliphilic family G/11 xylanase from alkali-tolerant filamentous fungi Penicillium citrinum MTCC 6489 was used as a model system to gain insight into the molecular aspects of unfolding/refolding of alkaliphilic glycosyl hydrolase protein family. The intrinsic protein fluorescence suggested a putative intermediate state of protein in presence of 2 M guanidium hydrochloride (GdmCl) with an emission maximum of 353 nm. Here we studied the refolding of GdmCl denatured alkaline xylanase in the presence and the absence of a multimeric chaperone protein alpha-crystallin to elucidate the molecular mechanism of intramolecular interactions of the alkaliphilic xylanase protein that dictates its extremophilic character. Our results, based on intrinsic tryptophan fluorescence and hydrophobic fluorophore 8-anilino-1- naphthalene sulfonate binding studies, suggest that alpha-crystallin formed a complex with a putative molten globule-like intermediate in the refolding pathway of xylanase in an ATP independent manner. A 2 M GdmCl is sufficient to denature alkaline xylanase completely. The hydrodynamic radius (R(H)) of a native alkaline xylanase is 4.0, which becomes 5.0 in the presence of 2 M GdmCl whereas in presence of the higher concentration of GdmCl R(H) value was shifted to 100, indicating the aggregation of denatured xylanase. The alpha-crystallin.xylanase complex exhibited the recovery of functional activity with the extent of approximately 43%. Addition of ATP to the complex did not show any significant effect on activity recovery of the denatured protein. PMID- 20703956 TI - Use of cellulase inhibitors to produce cellobiose. AB - The economics driving biorefinery development requires high value-added products such as cellobiose for financial feasibility. This research describes a simple technology for increasing cellobiose yields during lignocellulosic hydrolysis. The yield of cellobiose produced during cellulose hydrolysis was maximized by modification of reaction conditions. The addition of an inhibitor from the group that includes glucose oxidase, gluconolactone, and gluconic acid during cellulase hydrolysis of cellulose increased the amount of cellobiose produced. The optimal conditions for cellobiose production were determined for four factors; reaction time, cellulase concentration, cellulose concentration, and inhibitor concentration using a Box-Behnken experimental design. Gluconolactone in the cellulase system resulted in the greatest production of cellobiose (31.2%) from cellulose. The yield of cellobiose was 23.7% with glucose oxidase, similar to 21.9% with gluconic acid. PMID- 20703957 TI - Estimation of treatment time for microbial preprocessing of biomass. AB - Biochemical conversion of lignocellulosic biomass to ethanol involves size reduction, preprocessing, pretreatment, enzyme hydrolysis, and fermentation. In recent years, microbial preprocessing has been gaining attention as a means to produce labile biomass for lessening the requirement of pretreatment severity. However, loss of sugars due to microbial consumption is a major consequence, suggesting its minimization through optimization of nutrients, temperature, and preprocessing time. In this work, we emphasized estimation of fungal preprocessing time, at which higher sugar yields can be achieved after preprocessing and enzyme hydrolysis. The estimation is based on the enzymatic activity profile obtained by treating switchgrass with Phanerochaete chrysosporium for 28 days. Enzyme assays were conducted once in every 7 days for 28 days, for activities of phenol oxidase, peroxidase, beta-glucosidase, beta xylosidase, and cellobiohydrolase. We found no activity for phenol oxidase and peroxidase, but the greatest activities for cellulases on the seventh day. We then treated switchgrass for 7 days with P. chrysosporium and observed that the preprocessed switchgrass had higher glucan (39%), xylan (17.5%), and total sugar yields (25.5%) than the unpreprocessed switchgrass (34%, 37.5%, and 20.5%, respectively, p < 0.05). This verifies the utility of using enzyme assays for initial estimation of preprocessing time to enhance sugar yields. PMID- 20703958 TI - Does blockade of the Renin-Angiotensin-aldosterone system slow progression of all forms of kidney disease? AB - The velocity of chronic kidney disease (CKD) progression is only partly dependent on the nature and activity of the underlying disease process. Activation of the renin-angiotensin-aldosterone system (RAAS) is a crucial, and often universal, event responsible for the pathophysiologic mechanisms that accelerate CKD progression. Thus, it would appear that interruption of the RAAS through the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or direct renin inhibitors can play a principal role in slowing CKD progression, regardless of the cause. Unfortunately, applying this generalized approach to all forms of CKD has been delayed by the lack of strong, evidence-based data. The aim of this review is to provide the most current evidence available for the use of RAAS blockade as a method of slowing the progression of the various forms of CKD. PMID- 20703959 TI - Decreased prefrontal cortex activity in mild traumatic brain injury during performance of an auditory oddball task. AB - Up to one-third of patients with mild traumatic brain injury (TBI) demonstrate persistent cognitive deficits in the 'executive' function domain. Mild TBI patients have shown prefrontal cortex activity deficits during the performance of executive tasks requiring active information maintenance and manipulation. However, it is unclear whether these deficits are related to the executive processes themselves, or to the degree of mental effort. To determine whether prefrontal deficits also would be found during less effortful forms of executive ability, fMRI images were obtained on 31 mild TBI patients and 31 control participants during three-stimulus auditory oddball task performance. Although patients and controls had similar topographical patterns of brain activity, region-of-interest analysis revealed significantly decreased activity in right dorsolateral prefrontal cortex for mild TBI patients during target stimulus detection. Between-group analyses found evidence for potential compensatory brain activity during target detection and default-mode network dysfunction only during the detection of novel stimuli. PMID- 20703961 TI - Quantitative estimation of magnitude and orientation of the CSA tensor from field dependence of longitudinal NMR relaxation rates. AB - A method is presented that makes it possible to estimate both the orientation and the magnitude of the chemical shift anisotropy (CSA) tensor in molecules with a pair of spin 1/2 nuclei, typically (13)C-(1)H or (15) N-(1)H. The method relies on the fact that the longitudinal cross-correlation rate as well as a linear combination of the autorelaxation rates of longitudinal heterospin magnetization, longitudinal two-spin order and longitudinal proton magnetization are proportional to the spectral density at the Larmor frequency of the heterospin. Therefore the ratio between the cross-correlation rate and the above linear combination is independent of the dynamics. From the field dependence of the ratio both the magnitude and the orientation of the CSA tensor can be estimated. The method is applicable to molecules in all motional regimes and is not limited to molecules in extreme narrowing or slow tumbling, nor is it sensitive to chemical exchange broadening. It is tested on the 22 amino acid residue peptide motilin, selectively (13) C labeled in the ortho positions in the ring of the single tyrosine residue. In the approximation of an axially symmetric (13)C CSA tensor, the symmetry axis of the CSA tensor makes an angle of 23 degrees +/- 1 degrees to the (13) C-(1)H bond vector, and has a magnitude of 156 +/- 5 ppm. This is in close agreement with solid-state NMR data on tyrosine powder [Frydman et al. (1992) Isr. J. Chem., 32, 161-164]. PMID- 20703960 TI - Optimization of the antitumor activity of sequence-specific pyrrolobenzodiazepine derivatives based on their affinity for ABC transporters. AB - Pyrrolobenzodiazepine (PBD) derivatives are highly potent sequence-specific DNA cross-linking agents. The present study aimed to identify key physicochemical properties influencing the interaction of a series of PBDs (four dimers and 12 monomers) with the three major human ATP-binding cassette (ABC) transporters (P gp, ABCG2, and MRP1). Isogenic cell lines expressing P-gp and ABCG2, cell lines with acquired resistance to cytotoxic agents due to the high expression of ABC transporters, and specific inhibitors against P-gp, ABCG2, and MRP1 were used. P gp and ABCG2 decreased the permeability of the PBD dimers across cell membranes and their interaction with DNA, reducing DNA damage and the overall cytotoxic effect. PBD monomer SG-2823 formed a conjugate with glutathione and interacted with MRP1, reducing its cytotoxic effect in A549 cells. Structure-activity relationship revealed that the interaction of PBDs with the transporters could be predicted considering the molecular weight, the lipophilicity, the number of (N + O) atoms and aromatic rings, the polar surface area, the hydrogen bonding energy, and electrophilic centers. A rational design of novel PBDs with increased potency and reduced interaction with the ABC transporters is proposed. PMID- 20703962 TI - NMR structure determination of the tetramerization domain of the Mnt repressor: An asymmetric alpha-helical assembly in slow exchange. AB - The structure and dynamics of the chymotryptic tetramerization domain of the Mnt repressor of Salmonella bacteriophage P22 have been studied by NMR spectroscopy. Two sets of resonances (A and B) were found, representing the asymmetry within the homotetramer. Triple-resonance techniques were used to obtain unambiguous assignments of the A and B resonances. Intra-monomeric NOEs, which were distinguished from the inter-monomeric NOEs by exploiting (13)C/(15)N-filtered NOE experiments, demonstrated a continuous alpha-helix of approximately seven turns for both the A and B monomers. The asymmetry facilitated the interpretation of inter-subunit NOEs, whereas the antiparallel alignment of the subunits allowed further discrimination of inter-monomeric NOEs. The three-dimensional structure revealed an unusual asymmetric packing of a dimer of two antiparallel right handed intertwined coiled alpha-helices. The A and B forms exchange on a timescale of seconds by a mechanism that probably involves a relative sliding of the two coiled coils. The amide proton solvent exchange rates demonstrate a stable tetrameric structure. The essential role of Tyr 78 in oligomerization of Mnt, found by previous mutagenesis studies, can be explained by the many hydrophobic and hydrogen bonding interactions that this residue participates in with adjacent monomers. PMID- 20703963 TI - Structural constraints from residual tensorial couplings in high resolution NMR without an explicit term for the alignment tensor. AB - Structural restraints from residual tensorial couplings in high resolution NMR are usually incorporated into molecular structure calculation programs by an energy penalty function which depends on the knowledge of the alignment tensor. Here, we show that the alignment tensor enters in linear form into such a function. Therefore, the explicit appearance of the alignment tensor can be eliminated from the penalty function. This avoids the necessity of a determination of magnitude and rhombicity of the alignment tensor in the absence of structural information. The price for this procedure is a slightly shallower energy landscape. Simulations in the vicinity of the energy minimum for the backbone of human ubiquitin show that the reduction in curvature is on the order of a few percent. PMID- 20703964 TI - Letter to the Editor: 1H, 13C and 15N resonance assignments of the AT-rich interaction domain from the Dead Ringer protein. PMID- 20703966 TI - Small-molecule inhibitors of IL-2/IL-2R: lessons learned and applied. AB - The IL-2:IL-2R protein-protein interaction is of central importance to both healthy and diseased immune responses, and is one of the earliest examples of successful small-molecule inhibitor discovery against this target class. Drug like inhibitors of IL-2 have been identified through a combination of fragment discovery, structure-based design, and medicinal chemistry; this discovery approach illustrates the importance of using a diverse range of complementary screening methods and analytical tools to achieve a comprehensive understanding of molecular recognition. The IL-2 story also provides insight into the dynamic nature of protein-protein interaction surfaces, their potential druggability, and the physical and chemical properties of effective small-molecule ligands. These lessons, from IL-2 and similar discovery programs, underscore an increasing awareness of the principles governing the development of drugs for protein protein interactions. PMID- 20703967 TI - On the way to light the dark: a retrospective inquiry into the registered cases of domestic violence towards women over a six year period with a semi quantitative analysis of the corresponding forensic documentation. AB - AIMS: Domestic violence victims are increasingly identified at emergency departments (ED). Studies report a prevalence of 6-30%; women are more frequently affected and to a more serious extent than men. Studies have shown that without screening domestic violence victims are often not recognised. The primary aim of the study is to collect data descriptive of domestic violence victims and to show whether medical documentation meets the requirements of forensic medicine. METHODS: Retrospective analysis of medical records using the ED electronic patient database (Qualicare, Qualidoc Bern) at the ED of Bern University Hospital, Inselspital. Demographics, injuries, perpetrators and a semi quantitative analysis of the medical records have been evaluated for each case. RESULTS: From 1 January 2000 to 31 December 2005, 40 914 women were admitted to the ED. During this time 160 women were identified as victims of domestic violence and met the inclusion criteria for our study. The age ranged from 15-68 years. 63.6% of these women are married or live in a steady relationship. 46% of all victims of domestic violence were treated from Fridays to Sundays. In 70.2% blunt trauma was documented, the head was affected in 49%, 53% showed injuries of only one body area. In 10 cases, strangulation was suspected. 75% of the assaults could be classified as simple assault on the basis of Swiss criminal law. The perpetrator was the husband or partner in 73.4%. 141 cases were included for a semi-quantitative evaluation of the forensic medical documentation. The type of injuries was described in every case, the localisation in 96%, the shape in 26% and the dimensions of the lesions in 36%. CONCLUSIONS: The present retrospective assessment of medical reports over a 6-year period shows that domestic violence against female patients was documented in 0.4%. This figure is far below the proportions to be expected from recent data. If these data are to be believed the majority of female victims of domestic violence must have been overlooked at the ED. The implementation of screening for domestic violence seems to be crucial. The types of injury are chiefly the result of superficial, blunt violence, meaning of mild degree from the viewpoint of criminal law. The quality of the forensic documentation is poor and usually insufficient for criminal prosecution. Clinicians require training in the forensic aspects of medical records. PMID- 20703968 TI - Do youths gamble? You bet! A Swiss population-based study. AB - OBJECTIVES: To establish the gambling prevalence among Swiss resident youths, to estimate the associations between gambling frequency and substance use, poor mental health and social support and to determine the correlation between gambling pattern and gambling frequency. METHODS: Cross-sectional population based survey conducted in 2007. From 1233 eligible participants aged 15-24 years, adequate information was available for 1116 (582 males), distributed into: non- (n=577), occasional (n=388) and frequent gamblers (n=151). OUTCOME MEASURES: Substance use, social activities, presence of a reliable person among friends or family, psychological distress, major depression and gambling pattern. RESULTS: Overall, the 48.3% (n=539) of youths who had gambled during the previous year; were older and more likely to be male than non-gamblers. 13.5% (n=151) gambled at least weekly and could be differentiated from occasional gamblers on the basis of their gambling pattern. After controlling for gender, age and language area, occasional gamblers were significantly more likely to be occasional binge drinkers, whereas frequent gamblers were more likely to be daily smokers. CONCLUSION: Almost half of Swiss resident youths are involved in gambling. Both occasional and frequent gambling are associated with further health compromising behaviour. Practitioners dealing with young people should be aware that gambling is a behaviour that might be part of a more global risky behaviour framework. PMID- 20703965 TI - The role of IL-10 in regulating immunity to persistent viral infections. AB - The immune system has evolved multipronged responses that are critical to effectively defend the body from invading pathogens and to clear infection. However, the same weapons employed to eradicate infection can have caustic effects on normal bystander cells. Therefore, tight regulation is vital and the host must balance engendering correct and sufficient immune responses to pathogens while limiting errant and excessive immunopathology. To accomplish this task, a complex network of positive and negative immune signals are delivered, which in most instances successfully eliminate the pathogen. However, in response to some viral infections, immune function is rapidly suppressed leading to viral persistence. Immune suppression is a critical obstacle to the control of many persistent viral infections such as HIV, hepatitis C, and hepatitis B virus, which together affect more than 500 million individuals worldwide. Thus, the ability to therapeutically enhance immunity is a potentially powerful approach to resolve persistent infections. The host-derived cytokine IL-10 is a key player in the establishment and perpetuation of viral persistence. This chapter discusses the role of IL-10 in viral persistence and explores the exciting prospect of therapeutically blocking IL-10 to increase antiviral immunity and vaccine efficacy. PMID- 20703969 TI - Title Page - thrombophlebitis - what else? PMID- 20703970 TI - Is there still a place for renal artery duplex scanning? PMID- 20703971 TI - Sonography of peripheral lymph nodes part 1: normal findings and B-image criteria. PMID- 20703972 TI - Coumarin embryopathy after intrauterine exposure to vitamin K antagonists within the first 10 postmenstrual weeks. PMID- 20703973 TI - Letter to the editor: Kratzer W et al. Prevalence and risk factors of focal sparing in hepatic steatosis. Ultraschall in Med 2010; 31: 37 - 42. PMID- 20703975 TI - Metabolic alkalosis, recovery and sprint performance. AB - Pre-exercise alkalosis and an active recovery improve the physiological state of recovery through slightly different mechanisms (e. g. directly increasing extracellular bicarbonate (HCO3 (-)) vs. increasing blood flow), and combining the two conditions may provide even greater influence on blood acid-base recovery from high-intensity exercise. Nine subjects completed four trials (Placebo Active ( PLAC A), sodium bicarbonate (NaHCO3) Active ( BICARB A), Placebo Passive ( PLAC P) and NaHCO3 Passive ( BICARB P)), each consisting of three, 30-s maximal efforts with a three min recovery between each effort. Pre-exercisealkalosis was evident in both NaHCO3 conditions, as pH and HCO3 (-) were significantly higher than both Placebo conditions (pH: 7.46 +/- 0.04 vs. 7.39 +/- 0.02; HCO3 (-): 28.8 +/- 1.9 vs. 23.2 +/- 1.4 mmol.L (-1); p<0.001). In terms of performance, significant interactions were observed for average speed (p<0.05), with higher speeds evident in the BICARB A condition (3.9 +/- 0.3 vs. 3.7 +/- 0.4 m.s (-1)). Total distance covered was different (p=0.05), with post hoc differences evident between the BICARB A and PLAC P conditions (368 +/- 33 vs. 364 +/- 35 m). These data suggest that successive 30-s high intensity performance may be improved when coupled with NaHCO3 supplementation. PMID- 20703976 TI - Different training volumes yield equivalent increases in BMD. AB - The purpose of this study was to determine if an exercise threshold existed in stimulating an elevation in bone mineral density (BMD), via resistance training, during the growth period in male rats. 27 male rats were randomly divided into A Control (Con, n=9), 3 ladder climb resistance trained group (3LC, n=9), and 6 ladder climb resistance trained group (6LC, n=9). The 3LC and 6LC groups were conditioned to climb a vertical ladder with weights appended to their tail 3 days/wk for a total of 6 wks, but the 6LC group performed significantly more work than the 3LC group. After 6 weeks, left tibial BMD (mean+/-SD) was significantly greater for 3LC (0.225+/-0.006 g/cm (2)) and 6LC (0.234+/-0.008 g/cm (2)) when compared to Con (0.202+/-0.013 g/cm (2)). Further, bone strength (force to failure in Newtons) was significantly greater for 3LC (132.7+/-13.7) and 6LC (130.0+/-22.8) compared to Con (102.0+/-10.1). There was no significant difference in BMD or bone strength between 3LC and 6LC. The results indicate that both resistance training programs were equally effective in elevating BMD and bone strength in growing rats. These data suggest that during growth, there is a stimulation threshold where more work per exercise session is ineffective in promoting additional bone formation. PMID- 20703977 TI - A comparison of elastic tubing and isotonic resistance exercises. AB - The aim of this study was to assess effects of a short-term resistance program on strength in fit young women using weight machines/free weights or elastic tubing. 42 physically fit women (21.79+/-0.7 years) were randomly assigned to the following groups: (i) the Thera-Band ((r)) Exercise Station Group (TBG); (ii) the weight machines/free weights group (MFWG); or (iii) the control group (CG). Each experimental group performed the same periodised training program that lasted for 8 weeks, with 2-4 sessions per week and 3-4 sets of 8-15 submaximal reps. A load cell (Isocontrol; ATEmicro, Madrid, Spain) was used to test the evolution of the Maximum Isometric Voluntary Contraction (MIVC) in 3 different exercises: Vertical Rowing (VR), Squat (S) and Back Extension (BE). A mixed model MANOVA [group (CG, TBG, MFWG) x testing time (pre-test, post-test)] was applied to determine the effect of the different resistance training devices on strength. The only groups to improve their MIVC (p<0.005) were TBG and MFWG, respectively: VR 19.87% and 19.76%; S 14.07 and 28.88; BE 14.41% and 14.00%. These results indicate that resistance training using elastic tubing or weight machines/free weights have equivalent improvements in isometric force in short-term programs applied in fit young women. PMID- 20703978 TI - Match running performance and fitness in youth soccer. AB - The activity profiles of highly trained young soccer players were examined in relation to age, playing position and physical capacity. Time-motion analyses (global positioning system) were performed on 77 (U13-U18; fullbacks [FB], centre backs [CB], midfielders [MD], wide midfielders [W], second strikers [2 (nd)S] and strikers [S]) during 42 international club games. Total distance covered (TD) and very high-intensity activities (VHIA; >16.1 km.h (-1)) were computed during 186 entire player-matches. Physical capacity was assessed via field test measures (e. g., peak running speed during an incremental field test, VVam-eval). Match running performance showed an increasing trend with age ( P<0.001, partial eta squared (eta (2)): 0.20-0.45). When adjusted for age and individual playing time, match running performance was position-dependent ( P<0.001, eta (2): 0.13-0.40). MD covered the greater TD; CB the lowest ( P<0.05). Distance for VHIA was lower for CB compared with all other positions ( P<0.05); W and S displayed the highest VHIA ( P<0.05). Relationships between match running performance and physical capacities were position-dependent, with poor or non-significant correlations within FB, CB, MD and W (e. g., VHIA vs. VVam-eval: R=0.06 in FB) but large associations within 2 (nd)S and S positions (e. g., VHIA vs. VVam-eval: R=0.70 in 2 (nd)S). In highly trained young soccer players, the importance of fitness level as a determinant of match running performance should be regarded as a function of playing position. PMID- 20703979 TI - Unilateral lung intubation for pulmonary air leak syndrome in neonates: a case series and a review of the literature. AB - Air leak syndrome represents a common set of complications of ventilated premature neonates and includes pneumothorax, pneumomediastinum, pulmonary interstitial emphysema, and pneumatocele. Unilateral intubation is an infrequently utilized treatment option. We report our experience of three cases of air leak syndrome in neonates, each treated with unilateral intubation, including two cases of recalcitrant pneumothorax. A review of the literature of similar neonatal cases is presented. In view of our experience and the review of the literature, we suggest that unilateral intubation is an efficient and relatively safe therapy in cases of neonatal air leak syndrome. It is also suggested that appropriate treatment duration should be at least 48 hours. PMID- 20703980 TI - [Structure and contents of online counselor's responses in the field of eating disorders]. AB - OBJECTIVE: The importance of online counselling for many areas of health care has been increasing over the last years. Nevertheless, there is a lack of systematic research on the quality and specifics of the therapeutic intervention. METHODS: n = 1056 responses written by online counsellors between 12 / 2007 and 11 / 2008 were qualitatively analyzed regarding content and frequencies. RESULTS: Within a generalized counselling structure that contains greeting, mirroring, intervention and closure, further structural aspects could be determined and linked to the counselling goals. CONCLUSIONS: The study's results serve the purpose of creating a better theoretical foundation for online counselling in health care. PMID- 20703981 TI - [PGI-I (patient's global impression) as an outcome and quality indicator of psychiatric in-patient treatment: results and concordance with doctor's assessments]. AB - OBJECTIVE: To examine the Patient Global Impression Scale of Improvement (PGI) as a quality indicator in routine psychiatric in-patient treatment and to determine its concordance with doctors' assessments. METHODS: Patients treated in 2007 in 5 hospitals and 4 day-clinics were included. A set of patient and treatment characteristics (German BADO) and CGI scales were recorded in all patients. Patients were required to give a PGI rating at discharge. RESULTS: PGI ratings could be obtained in 70.3 of the patients (N = 3957). PGI and doctors' CGI-I ratings were in agreement with no more than one degree of difference on the 7 point scale of the PGI in 89.8 %. Characteristics of those patients who significantly deviated from the doctors' assessments were determined. CONCLUSIONS: The PGI scale is appropriate as a quality indicator for routine clinical treatment which can rather easily be obtained. PMID- 20703982 TI - [Patients of immigrant origin in outpatient psychiatric facilities: a comparison between Turkish, eastern European and German patients]. AB - OBJECTIVE: Nationwide representative survey of the use of psychiatric outpatient services in Germany. METHODS: Every fifth patient of several psychiatric outpatient services was surveyed on one index day (27 (th) of May 2008) with respect to sociodemographic characteristics, ICD-10 diagnoses, difficulties in communication, treatment duration, and number of sickness certificates. RESULTS: Patients with immigrant background comprised 32.5 % of all patients. Compared to German patients, patients with immigrant background received significantly more neurotic, stress-related and somatoform disorders (F4). Turkish patients received significantly more mood (affective) disorders diagnoses (F3), compared to German and Eastern Europe patients. Immigrants had shorter treatment duration and a higher number of sickness certificates. Eastern European patients had a significantly higher education, compared to patients with Turkish background. Patients with immigrant background were younger compared to German patients and had significantly more children. CONCLUSIONS: The utilization of outpatient psychiatric services by patients with a migratory background is high. This suggests that immigrants benefit from the multiprofessional team and the low treshold service offered by outpatient units. PMID- 20703983 TI - [Which information do GPs use to rate the cognitive status of elderly non demented patients?]. AB - OBJECTIVE: Knowledge about the informational basis of general practitioners (GPs) when judging their patients' cognitive status is scarce. Deepening this knowledge could help to understand why recognition of mild cognitive impairment and mild dementia is problematic in general practice. METHODS: As part of the German Competence Network Dementia, GPs from Dusseldorf rated the cognitive status of their elderly patients (AgeCoDe study). Furthermore, for each of these ratings the GPs had to specify one or more information they used for their decision. RESULTS: The information "general knowledge of the patient and his social setting" was frequently chosen by GPs, as well as "subjective cognitive complaints of the patient" and "information from significant others". Neuropsychological test results proved to be irrelevant for the GPs' rating. Some of our results suggest that the GPs had problems in the application of the cognitive rating scale. CONCLUSIONS: Against the background of our data and further results of the AgeCoDe study, implications for further research are discussed. PMID- 20703984 TI - [Psychopharmacological therapy in mental retardation--comparison of the years 1991 and 2005]. AB - OBJECTIVE: About psychopharmacological long-term care in individuals with mental retardation there are only a few data. The objective of this investigation was to analyze psychopharmacotherapy over a period of 15 years. METHODS: For the year 1991 291 data sets and for the year 2005 288 data sets of all residents of a home for people with mental retardation were analysed. RESULTS: The number of psychiatric disorders has not changed. But the frequency of medication with neuroleptics and antidepressive compounds has increased. Atypical and typical neuroleptics did not differ significantly in side effects. But the number of side effects in SSRI's is compared with tricyclic antidepressive compounds significantly reduced. CONCLUSIONS: The present study is one of the few, which gives an overview of long-term course of psychiatric disorders in people with mental retardation, the psychopharmacological therapy und side effects of used medication. PMID- 20703985 TI - [Changes in mental health care by a regional budget: results of a pilot Project in Schleswig-Holstein (Germany)]. AB - OBJECTIVES: In a region of Schleswig-Holstein, a regional budget was used to investigate which structural changes would be brought about by a financial plan which enables (clinical) treatment that defies rigid financial limits and makes flexible treatment in various settings possible. RESULTS: In 5 years, the number of inpatient treatment places in the care region was reduced considerably. The length of stay per patient and year decreased by 25 %. Day care and outpatient treatment offers were expanded substantially and new treatment concepts were established. The quality of treatment remained safeguarded. CONCLUSIONS: A regional budget is suitable for bringing about fundamental changes in terms of content and structure in psychiatric care. The result is clearly improved flexibility as compared to previous care structures; incentives for disorders are reduced. The principle "outpatient before inpatient" is strengthened. The financial plan can be transposed onto other regions, whereby modifications according to the structure of the care region seem necessary. PMID- 20703986 TI - [Moving into the community: evaluation of the effects of a structural factor on community based psychiatry and low-threshold psychiatry]. AB - OBJECTIVE: In 2005 the ipw acute care units were relocated from the rural area of Rheinau into the outskirts of Winterthur, the second largest city in the canton Zurich. The objective of the present study is to answer the question whether relocation has made a verifiable contribution to community based psychiatry and low-threshold psychiatry. METHODS: The analysed data were taken from selected items of the cantonal psychiatric basis documentation and the ZUPAZ questionary of patient contentment. For each location, Rheinau and Winterthur, a sample was taken containing data of 12 months. The corresponding data was analysed retrospectively with Chi-Square statistics and paired T-Tests. RESULTS: The distance between patients' residence and the psychiatric institution was reduced significantly by 73 %. Compulsory admission decreased overall by 10 %, with affective disorders showing the most explicit reduction (28 %). Regarding patient's contentment with the clinical treatment, there was a considerable increase. The degree of illness severity at the patient's admission was higher in Winterthur than in Rheinau. CONCLUSIONS: The results indicate that relocation of the acute care units from a rural to an urban area has enhanced community based psychiatry (shorter distance) as well as low-threshold psychiatry (lower rate of compulsory admission, increase in patient's contentment). Nevertheless, there is a major limitation regarding the present study: the two concepts community based psychiatry and low-threshold psychiatry have been operationalised retrospectively. Further prospective empirical evaluations are needed to disclose the relation between community based psychiatry and low-threshold psychiatry. PMID- 20703988 TI - New insight into an old paradigm: wrapping and dangling with lower-extremity free flaps. AB - Flap edema can often compromise an otherwise successful lower-extremity microsurgical reconstruction. To train a flap toward maturity, various wrapping and dangling protocols have been described. Mixed tissue oxygenation of a myocutaneous free flap for lower-extremity reconstruction is examined as measured by ViOptix with wrapping and unwrapping during dangling at different postoperative time points. The results are compared with the nonaffected lower extremity and additional healthy controls. Upon dangling a reconstructed lower extremity, the tissue oximetry recording of a free flap descended rapidly until the leg was reelevated and then continued at this low level with a gradual return to the predangling baseline. The extent of this drop in tissue oxygenation depended upon positioning, and the length of time to reach its baseline upon reelevation decreased as flap matured postoperatively. In addition, wrapping of a reconstructed lower extremity also decreased the overall drop in tissue oxygenation level and the time to recovery while having no effect on the control. Results of this prospective study can lead to an increased understanding of free flap physiology in lower-extremity reconstruction and can further validate and refine our postoperative management strategies regarding dependency and edema control. PMID- 20703987 TI - [Tranylcypromine for chronic therapy-resistant agoraphobia with panic disorder and recurrent depressive disorder]. AB - OBJECTIVE: Tranylcypromine has been recommend as an option for therapy-resistant depressive and anxiety disorders. In this case report the effectiveness of this medication as a part of a combined therapy-program including pharmacological, behavioural and psychodynamic interventions could be demonstrated on an outpatient with a therapy-resistant depression and agoraphobia. METHODS: The development of the illness, clinical symptoms and the 4 year ongoing therapy of a 69-year old patient are described in detail. RESULTS/CONCLUSION: After the failure of 13 antidepressant agents with considerable side effects, a one year sustained remission of depression as well as great improvement of agoraphobia could be achieved with tranylcypromine. In this situation, tranylcypromine showed itself, for the first time, to be a very effective and well tolerated antidepressant. PMID- 20703989 TI - Microsurgeons are superstitious? A statistical survey by questionnaire. AB - In Japan, many people believe in superstitions or omens. Microsurgery results, however, are scientific and thus considered to be black or white. Even if the operator is a proficient master, the possibility of flap necrosis is inevitable. It can be said that microsurgeons live in a world of uncertainty where "might" rules. How do they prepare themselves for an operation? We administered a questionnaire to front-line Japanese microsurgeons and thereby attempted to examine the mental side of these experts. We constructed a detailed questionnaire regarding several factors, including the annual number of microsurgeries, the consciousness of daily life, the physician before and after the operation, and even concerning superstition, habits for good luck, or other beliefs. We sent the survey to the front-line Japanese microsurgeons in our country by e-mail and 20 replies were returned. Many of the surgeons prepare themselves before the operation, from the day before until just before the operation. These surgeons can be divided into three types: type A, microsurgeons who prepare themselves on a daily basis and do not believe in a charm or a jinx; type B, those who do not prepare themselves especially in daily life, but have some charm or jinx; and type C, surgeons who do not have special daily preparation or belief in a superstition. The type C group included a significant number of experienced microsurgeons. Experienced microsurgeons as leaders or trainers of young microsurgeons tend to be natural and not mystic in daily life and thus tend not to be superstitious. PMID- 20703990 TI - Intraoperative decision making by electrophysiological detection of the origin of thoracodorsal nerve in the C7 nerve root transfer procedure. AB - The objective of this article is to discuss the significance of predicting the injury degree of the thoracodorsal nerve by intraoperative electrophysiological examination in the C7 nerve root transfer for brachial plexus injury. Each trunk of the brachial plexus followed by each bundle of C7 was stimulated before the contralateral C7 was disconnected. The ratio of the origination of thoracodorsal nerve controlling the latissimus dorsi muscle was evaluated. The highest ratio of the origination of thoracodorsal nerve controlling the latissimus dorsi muscle was in the middle trunk of the brachial plexus. In the middle trunk, the highest ratio was the posterior division. In the posterior division, the internal fascicles were the predominant ones. The intraoperative electrophysiological examination can precisely locate the origin of the dominated nerve of latissimus dorsi muscle. It is recommended for safety to direct the operative procedure selection in the C7 transfer. PMID- 20703991 TI - [Skeletal muscle tissue engineering--current concepts and future perspectives]. AB - Tissue engineering of skeletal muscle could have great advantages in every clinical setting in need of neurovascular muscle transfer, e. g., facial palsy or Volkmann's contracture. There are 2 great obstacles for the clinical application of engineered muscle tissue at the moment: firstly, finding a three-dimensional matrix that matches the demands concerning biocompatibility, stability and elasticity; secondly, the insufficient differentiation of implanted myoblasts, since myoblast differentiation in vivo is barely controllable and subject to a variety of influences. Furthermore axial vascularisation and neurotisation of such tissue-engineered skeletal muscle constructs play a pivotal role for any later application. An overview of the current status of skeletal muscle tissue engineering technologies and concepts for future perspective in this emerging field is presented in this article. PMID- 20703994 TI - Chest radiography and CT findings in patients with the 2009 pandemic (H1N1) influenza. AB - PURPOSE: To present chest radiography and thoracic computed tomography (CT) findings for patients with pandemic influenza A (H1N1) from November-December 2009 and to explore any differences compared to previously reported imaging findings. MATERIALS AND METHODS: Fifty-two hospitalized patients with pandemic influenza (H1N1) were included in the study. All of the patients underwent chest radiography, and 28 patients were also evaluated by thoracic CT. Group 1 comprised 24 (46%) patients with no identified risk factors for H1N1 influenza infection. Group 2 comprised the remaining 28 (54%) patients with identified risk factors. The distribution of lung involvement, consolidation, ground-glass opacity (GGO), lymph nodes, and pleural effusion were evaluated. RESULTS: Abnormal findings were observed in 85% of the patients. Bilateral lung involvement was present in 80% of the patients. The most common finding was a mixture of GGO and air-space consolidation. Lower zone predominance occurred in 89% of group 1 and 85% of group 2 patients. The involvement was observed most frequently in the peripheral and central perihilar areas of the lung in 80% of the patients. The extent of disease was greater in group 2 patients with the involvement of three or more lung zones in 62% of the patients. CONCLUSION: The most common imaging finding for lung involvement was a mixture of air-space consolidation and GGO with a patchy pattern and lower/middle zone predominance. Pulmonary involvement of the disease was more extensive than that described in previous reports. PMID- 20703995 TI - The value of dynamic contrast-enhanced MRI in the detection of recurrent prostate cancer after external beam radiotherapy: correlation with transrectal ultrasound and pathological findings. AB - PURPOSE: To assess the effectiveness of dynamic contrast-enhanced (DCE) T1- and T2-weighted magnetic resonance imaging (MRI) during the follow-up of patients with prostate cancer after undergoing external beam radiotherapy (EBRT) and to compare these imaging findings to pathological and transrectal ultrasound (TRUS) findings. MATERIALS AND METHODS: In this retrospective study, the MRI findings of 20 patients who had prostate cancer and were treated with EBRT were evaluated to detect tumor recurrence. The MRI findings were compared to those that had been obtained by TRUS and pathological analysis. RESULTS: The sensitivity and specificity of TRUS in the detection of tumor recurrence in patients who had undergone EBRT were 53.3% and 60%, respectively. In the same group of patients, the sensitivity and specificity of T2-weighted MRI were 86% and 100%, respectively. Strikingly, the sensitivity and specificity of DCE T1-weighted MRI in the diagnosis of recurrent prostate cancer were 93% and 100%, respectively. The accuracy of the DCE T1-weighted images in the detection of recurrence was significantly higher in comparison to that obtained using T2-weighted images. CONCLUSION: During the follow-up of these patients, TRUS without the use of any other imaging or biochemical modality is not a sufficient method for the detection of prostate cancer recurrence. DCE T1-weighted MRI increases the sensitivity of MRI alone for the detection of recurrence during the follow-up of prostate cancer patients who have been treated with EBRT. Thus, DCE T1-weighted MRI must be used as part of the routine MRI analysis to check for tumor recurrence in patients with prostate cancer. PMID- 20703996 TI - [Polish Society of Lung Diseases, in years 2006-2010]. PMID- 20703997 TI - [Recommendations of Polish Society of Lung Diseases about diagnosis and therapy of chronic obstructive pulmonary disease (COPD)]. PMID- 20703998 TI - [Diagnosis and treatment of patients with alpha-1 antitrypsin (alpha-1 AT) deficiency]. PMID- 20703999 TI - [Markers of fibrosis and inflammation in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) of patients with pulmonary sarcoidosis -- a pilot study]. AB - INTRODUCTION: Sarcoidosis is a disease of unknown etiology. Little is known of predictive factors of fibrosis. It was suggested that PAI-1, uPA, TGF-beta1, VEGF, IL-8, TNF-alpha influence this process. AIMS: To assess airway inflammatory and fibrosis markers in EBC in sarcoidosis and the effect of fiberoptic bronchoscopy (FOB), bronchoalveolar lavage fluid (BALF), transbronchial lung biopsy (TBLB) and bronchial mucosa membrane biopsy on their production in the airways. MATERIAL AND METHODS: The study group consisted of 11 patients (5 women, 6 men; mean age 40 +/- 9 yrs, mean +/- SD) with sarcoidosis stage I-III. PAI-1 (ng/ml), uPA (ng/ml), TGF-beta1 (pg/ml), VEGF (pg/ml), IL-8 (pg/ml), TNF-alpha (pg/ml) levels were measured in BALF and EBC collected before and 48 hours after FOB. RESULTS: No significant changes in EBC levels of VEGF, PAI-1, TGF-beta1, TNF alpha (respectively: 8.02 +/- 4.97 pg/ml; 1.1 +/- 1.2 ng/ml; 2909.7 +/- 206.6 pg/ml; 10.7 +/- 19.9 pg/ml) after FOB were observed when compared to baseline. In contrast, IL-8 concentration in EBC (pg/ml) decreased after FOB (0.073 +/- 0.13 v. 0.061 +/- 0.1, p = 0.006) and was significantly lower than in BALF (BALF 0.95 +/- 0.62, p < 0.05). Also, mean level of VEGF was higher in BALF than in EBC both pre- and post- FOB (BALF 66.38 +/- 36.95, EBC pre-FOB 6.75 +/- 3.67 and EBC post FOB 8.02 +/- 4.97). Significant relationship between TNF-alpha in post-FOB EBC and BALF was also shown (b = 0.63, p = 0.04). CONCLUSIONS: FOB does not significantly affect levels of airway inflammation and fibrosis markers present in EBC before and after FOB; they were also comparable to the concentrations marked by BALF. The lack of correlation between markers levels in EBC and BALF indicates that these methods are not equivalent. Due to repeatibility, and less invasive, simple method of EBC test it seems reasonable to continue the research on the larger number of patients. PMID- 20704000 TI - [The comparison between two methods for typing of nontuberculous mycobacteria: high pressure liquid chromatography and molecular assay GenoType Mycobacterium CM/AS]. AB - INTRODUCTION: The GenoType Mycobacterium CM and the GenoType Mycobacterium AS (HAIN Lifescience, Germany) were evaluated for the ability to differentiate mycobacterial species of clinical isolates. Serial use of the both assays is aimed to identify 38 different molecular patterns, of which 24 patterns can be assigned to single species, 10 patterns are allocated to two or more Mycobacterium species, and 4 patterns correspond to Mycobacterium species and gram-positive bacteria with a high G + C content. The analysis of mycolic acids by high pressure liquid chromatography (HPLC) was the reference method. MATERIAL AND METHODS: A set of 127 nontuberculous mycobacterial isolates on Loewenstein Jensen slants, derived from different patients between 1999 and 2007, was analyzed. The strains were primary classified by HPLC following the diagnostic procedure, and retyped by GenoType Mycobacterium CM/AS. RESULTS: In total, results obtained by both methods were interpretable for 113 strains. Concordant results were obtained for 105 (93%) mycobacterial strains. One out of 8 inconcordant classified strains, which was classified as M. abscessus/M. chelonae by HPLC, displayed a pattern of M. tuberculosis complex by a molecular method. Eleven clinical strains were differentiated only by one of used methods, either by HPLC (6 strains) or by GenoType CM/ AS (5 strains). Three strains were not classified at all. CONCLUSIONS: Our results show that the GenoType Mycobacterium CM/AS system represents a useful tool to identify mycobacterial clinical isolates. The molecular system is as rapid and reliable as the HPLC, but much easier to perform and more friendly for the environment. PMID- 20704001 TI - [Recurrence of endobronchial lipoma]. AB - Benign tumors of the lung and endobronchial tree are uncommon. Endobronchial lipomas are extremely rare, with incidence ranging from 0.1 to 0.5% of all lung tumors. Endobronchial lipomas originate from fat cells located in the peribronchial and occasionally the submucosal tissue of the main bronchi. The paper presents a case, in whom four years after transbronchial resection of the endobronchial lipoma, recurrence of the lesion in the same lung was confirmed. The diagnosis was made on the basis of CT scan, which detected lesions with previously identified morphology. PMID- 20704002 TI - [Gastric sarcoidosis -- a case report]. AB - Gastrointestinal sarcoidosis is very rare manifestation of the illness. This article presents patient who had been diagnosed for several months because of abdominal pain, vomiting and significant weight loss. Numerous gastric endoscopy examinations showed the difficult healing ulcers in the stomach, progressive thickening of the mucosal folds with narrowing of the lumen, lack of peristalsis and the rigidity of the walls. Histological examination of the specimen of the ventricular mucosa revealed chronic inflammation, as well as suspicion of tumor infiltration. Finally gastric sarcoidosis has been diagnosed on the basis of CT with double contrast, and histopathological examination of biopsis of stomach collected during laparotomy. PMID- 20704005 TI - Hip muscle weakness in individuals with medial knee osteoarthritis. AB - OBJECTIVE: To compare the strength of the hip musculature in people with symptomatic medial knee osteoarthritis (OA) with asymptomatic controls. METHODS: Eighty-nine people with knee OA and 23 controls age >50 years were recruited from the community. The maximal isometric strength (torque relative to body mass) of the hip abductors, adductors, flexors, extensors, and internal and external rotators was evaluated using hand-held dynamometry or a customized force transducer apparatus. Univariate linear models with age and sex included as covariates were used to compare muscle strength between groups. RESULTS: In people with knee OA, significant strength deficits were evident for all hip muscle groups evaluated (P < 0.05). Compared with controls, strength deficits ranged from 16% (hip extensors) to 27% (hip external rotators) after accounting for differences in sex and age between groups. CONCLUSION: People with knee OA demonstrate significant weakness of the hip musculature compared with asymptomatic controls. It is not clear if hip muscle weakness precedes the onset of knee OA or occurs as a consequence of disease. Findings from this study support the inclusion of hip strengthening exercises in rehabilitation programs. PMID- 20704006 TI - Looking for a panacea? Just keep moving. PMID- 20704007 TI - Osteoarthritis: HIF-2alpha drives osteoarthritis development. PMID- 20704009 TI - Therapy: Behcet uveitis: good results for IFN-alpha-2a. PMID- 20704008 TI - IRF5 and B cells in LUPUS development. PMID- 20704010 TI - Lupus nephritis: Activated basophils exacerbate lupus nephritis by amplifying production of autoreactive IgE. PMID- 20704011 TI - An Overview of BioCreative II.5. AB - We present the results of the BioCreative II.5 evaluation in association with the FEBS Letters experiment, where authors created Structured Digital Abstracts to capture information about protein-protein interactions. The BioCreative II.5 challenge evaluated automatic annotations from 15 text mining teams based on a gold standard created by reconciling annotations from curators, authors, and automated systems. The tasks were to rank articles for curation based on curatable protein-protein interactions; to identify the interacting proteins (using UniProt identifiers) in the positive articles (61); and to identify interacting protein pairs. There were 595 full-text articles in the evaluation test set, including those both with and without curatable protein interactions. The principal evaluation metrics were the interpolated area under the precision/recall curve (AUC iP/R), and (balanced) F-measure. For article classification, the best AUC iP/R was 0.70; for interacting proteins, the best system achieved good macroaveraged recall (0.73) and interpolated area under the precision/recall curve (0.58), after filtering incorrect species and mapping homonymous orthologs; for interacting protein pairs, the top (filtered, mapped) recall was 0.42 and AUC iP/R was 0.29. Ensemble systems improved performance for the interacting protein task. PMID- 20704012 TI - Visual symptoms in the Heidenhain variant of Creutzfeldt-Jakob Disease. AB - BACKGROUND AND PURPOSE: The distinguishing feature in Heidenhain variant Creutzfeldt-Jakob Disease (HvCJD) is the presence of visual symptoms preceding the appearance of other clinical manifestations. The purpose of this report is to describe the broad range of visual symptomatology in a patient with HvCJD. METHODS: The authors describe the clinical, neuroimaging, and EEG features of a 51-year-old man with progressive visual symptoms that were most likely due to HvCJD. Migraine and epilepsy were initial diagnostic considerations. RESULTS: Our patient presented with progressive visual decline and superimposed spells of visual dysfunction that had complex characteristics. Evolution of an abnormal signal in the parieto-occipital cortex on diffusion weighted MRI, changes on EEG, and clinical course were consistent with HvCJD. CONCLUSIONS: HvCJD should be considered in all patients who present with unexplained visual phenomena. A remarkable spectrum of visual disturbances can be seen. Close follow-up as well as serial MRI and EEG can help clarify the underlying disease process. Diffusion weighted and FLAIR sequences should be included in the MRI protocol. PMID- 20704013 TI - The author file: Thomas Knopfel. PMID- 20704014 TI - Points of view: Color coding. PMID- 20704015 TI - Jumping genes. PMID- 20704016 TI - Made locally. PMID- 20704017 TI - NMR and the elusive GPCR. PMID- 20704018 TI - How to find TUFs. PMID- 20704019 TI - Protein labeling approaching its PRIME. PMID- 20704020 TI - Polymers for protein detection. PMID- 20704021 TI - [New birth]. PMID- 20704022 TI - Costs and the quality of health care. PMID- 20704023 TI - Physician burnout and the revival of community activism. PMID- 20704024 TI - What ambulatory care imaging suppliers can expect during a survey. PMID- 20704025 TI - [Past and present of pneumonia]. AB - A comparison is made between the most common types of pneumonias usually observed when Vincenzo Cuomo was active and those of the present day. Socially-transmitted pneumonias are contrasted with hospital-acquired pneumonias, mostly due to Gram negative bacteria, often multiresistant to antibiotics. Additional pneumonias are due to mycoplasmas, rickettsiae and Legionella and also to viruses, such as Cytomegalovirus, for example. PMID- 20704026 TI - ["Nurses are applying their experience in a public health approach to the communities." Interview by Sylvie Warnet]. PMID- 20704027 TI - [Better understanding of the new addictions]. PMID- 20704028 TI - Stamp vignette on medical science. Robert F. Curl Jr-Nobel Laureate in Chemistry. PMID- 20704029 TI - TREG cells block bone loss in vivo. PMID- 20704030 TI - Bone: Cdc42 has a key role in modulating osteoclast formation and function. PMID- 20704031 TI - Osteoarthritis: A single genetic factor determines propensity to report musculoskeletal pain at multiple sites. PMID- 20704032 TI - Biomarkers: microRNAs under the spotlight in inflammatory arthritis. PMID- 20704033 TI - Atmospheric remote sensing to detect effects of temperature inversions on sputum cell counts in airway diseases. AB - Temperature inversions result in the accumulation of air pollution, often to levels exceeding air quality criteria. The respiratory response may be detectable in sputum cell counts. This study investigates the effect of boundary layer temperature inversions on sputum cell counts. Total and differential cell counts of neutrophils, eosinophils, macrophages and lymphocytes were quantified in sputum samples of patients attending an outpatient clinic. Temperature inversions were identified using data from the Atmospheric Infrared Sounder, an atmospheric sensor on the Aqua spacecraft which was launched in 2002 by the National Aeronautics and Space Administration. On inversion days, a statistically significant increase in the percent of cells that were neutrophils was observed in stable patients. There was also a statistically significant increase in the percent of cells that were macrophages, in exacerbated patients. Multivariate linear regression models were used to assess the relationship between temperature inversions and cell counts, controlling patients' age, smoking status, medications and meteorological variables of temperature and humidity. The analyses indicate that, in the stable and exacerbated groups, percent neutrophils and macrophages increased by 12.6% and 2.5%, respectively, on inversion days. These results suggest that temperature inversions need consideration as an exacerbating factor in bronchitis and obstructive airway disease. The effects of air pollutants, nitrogen dioxide, carbon monoxide, fine particulate matter and ozone, were investigated. We identified no significant associations with any pollutant. However, we found that monthly averages of total cell counts were strongly correlated with monthly nitrogen dioxide concentrations, an association not previously identified in the literature. PMID- 20704059 TI - SAMHSA report on model program that provides Medicaid coverage on release from state prison. PMID- 20704034 TI - A 2-microm continuous-wave laser system for safe and high-precision dissection during NOTES procedures. AB - INTRODUCTION: Lasers 2-microm in wavelength offer efficient tissue cutting with limited thermal damage in biological tissue. OBJECTIVE: To evaluate the dissection capabilities of a 2-microm continuous-wave laser for NOTES procedures. METHODS AND PROCEDURES: We conducted 18 acute animal experiments. Group 1 (three animals): transcolonic access to the peritoneal cavity (15-W transcolonic laser puncture, balloon dilation over the laser probe). Group 2 (six animals): transcolonic access with needle-knife puncture and balloon dilation. Group 3 (three animals): transgastric access to the peritoneal cavity (similar technique as group 1) followed by laser-assisted dissection of the kidney. In one animal of group 3, a therapeutic target (hematoma) was created by percutaneous puncture of the kidney. Group 4 (six animals): transgastric access (similar to the technique of group 2). RESULTS: Translumenal access to the peritoneal cavity was achieved in 2-3 min in group 1 (significantly shorter than with the needle-knife-assisted technique, 4-5 min, p=0.02) and in 7-10 min in group 3 (compared to 6-17 min in group 4, p=0.88). In group 3, laser dissection of the parietal peritoneum and of perinephric connective tissue allowed access to the retroperitoneum with complete removal of a blood collection in the animal with puncture trauma. Laser dissection demonstrated good maneuverability, clean and rapid cutting, and excellent hemostasis. Peritoneoscopy and necropsy showed no damage of targeted tissue and surrounding organs. CONCLUSIONS: The 2-microm continuous-wave laser system showed promising capabilities for highly precise and safe dissection during NOTES procedures. PMID- 20704060 TI - EMS' seat at the table. PMID- 20704061 TI - MR-guided adaptive focusing of ultrasound. AB - Adaptive focusing of ultrasonic waves under the guidance of a magnetic resonance (MR) system is demonstrated for medical applications. This technique is based on the maximization of the ultrasonic wave intensity at one targeted point in space. The wave intensity is indirectly estimated from the local tissue displacement induced at the chosen focus by the acoustic radiation force of ultrasonic beams. Coded ultrasonic waves are transmitted by an ultrasonic array and an MRI scanner is used to measure the resulting local displacements through a motion-sensitive MR sequence. After the transmission of a set of spatially encoded ultrasonic waves, a non-iterative inversion process is employed to accurately estimate the spatial-temporal aberration induced by the propagation medium and to maximize the acoustical intensity at the target.Both programmable and physical aberrating layers introducing strong distortions (up to 2pi radians) were recovered within acceptable errors (<0.8 rad). This noninvasive technique is shown to accurately correct phase aberrations in a phantom gel with negligible heat deposition and limited acquisition time. These refocusing performances demonstrate a major potential in the field of MR-guided ultrasound therapy in particular for transcranial brain high-intensity focused ultrasound. PMID- 20704062 TI - Subharmonic scattering of phospholipid-shell microbubbles at low acoustic pressure amplitudes. AB - Subharmonic scattering of phospholipid-shell microbubbles excited at relatively low acoustic pressure amplitudes (<30 kPa) has been associated with echo responses from compression-only bubbles having initial surface tension values close to zero. In this work, the relation between sbharmonics and compression only behavior of phospholipid-shell microbubbles was investigated, experimentally and by simulation, as a function of the initial surface tension by applying ambient overpressures of 0 and 180 mmHg. The microbubbles were excited using a 64 cycle transmit burst with a center frequency of 4 MHz and peak-negative pressure amplitudes ranging from 20 of 150 kPa. In these conditions, an increase in subharmonic response of 28.9 dB (P < 0.05) was measured at 50 kPa after applying an overpressure of 180 mmHg. Simulations using the Marmottant model, taking into account the effect of ambient overpressure on bubble size and initial surface tension, confirmed the relation between subharmonics observed in the pressure time curves and compression-only behavior observed in the radius-time curves. The trend of an increase in subharmonic response as a function of ambient overpressure, i.e., as a function of the initial surface tension, was predicted by the model. Subharmonics present in the echo responses of phospholipid-shell microbubbles excited at low acoustic pressure amplitudes are indeed related to the echo responses from compression-only bubbles. The increase in subharmonics as a function of ambient overpressure may be exploited for improving methods for noninvasive pressure measurement in heart cavities or big vessels in the human body. PMID- 20704063 TI - Hanging the crepe. PMID- 20704064 TI - Senescence by the numbers. PMID- 20704065 TI - Pneumonia: introduction. PMID- 20704066 TI - Managing health care facility associated pneumonias: diagnosis, treatment and prevention. PMID- 20704067 TI - Post-influenza pneumonia: everything old is new again. PMID- 20704068 TI - Community-acquired pneumonia in children. PMID- 20704069 TI - Persistent non-cancer pain management in the older adult. AB - Pain is a prevalent symptom affecting as many as 50% of community-dwelling older adults. Pain affects quality of life, functional status, cognition, mood, sleep, and well-being. A multimodal approach to pain management consists of both non pharmacologic and pharmacologic interventions. Prescribing analgesics is safe and effective in older persons if done judiciously by starting low and titrating slowly while monitoring closely for potential side effects. PMID- 20704070 TI - Rhode Island Child Death Review: sudden infant death and sudden unexpected infant deaths, 2008-2009. PMID- 20704071 TI - The celestial bodies: the moon, sun and stars. PMID- 20704073 TI - Participation level of the leprosy patients in society. AB - The present study examines the soci-demographic profile and participation restriction level of the respondents and the association of gender socio-economic status (SES) and deformity status of the respondents with their respective participation restriction level. 245 leprosy patients have been selected for the present study. Socio-economic scale, participation scale and in-depth interviews were used for data collection. Data analysis was done by using statistical package for social sciences (SPSS). 57.1% belonged to poor SES followed by lower middle (21.6%). Only 12% of respondents belonged to high SES. Out of 245 respondents, 32.20% had grade II deformity 31.40% grade I and the rest 36.3% non deformed. The results of the participation scale showed that 54.28% had no significant participation restriction and only 3.67% had extreme participation restriction. SES and deformity status of the respondents have shown significant differences with the level of participation restriction. The lower the SES and the severe the level of deformity of the respondents, the extreme is the level of participation restriction among them. PMID- 20704072 TI - Clinico-epidemiological trends of leprosy in Himachal Pradesh: a five year study. AB - This retrospective study was done to determine the epidemiological and clinical profile of leprosy patients in a tertiary care centre, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India. In this study, we included patients registered from January 2004 to December 2008 with the urban leprosy clinic of our tertiary care centre. Data regarding demographic details, clinical features, treatment and complications was extracted from the records of the leprosy clinic. 163 patients attended the clinic during this period with male to female ratio of 3:1. Majority of patients (47.8%) were in the middle age group (20-40 years) and 13.49% patients were < 20 years of age. In the clinical disease spectrum, 53.98% patients were in the borderline spectrum followed by lepromatous leprosy (33.12%) and polar tuberculoid leprosy (5.52%). Pure neuritic and indeterminate leprosy accounted for 3.06% each. Histoid lesions were present in 7.4% of lepromatous leprosy patients. 9.2% patients had definite history of contact in the family or neighborhood. 28.22% patients were immigrants either from Nepal or adjoining states of Himachal Pradesh. Epidemiological studies and contact tracing can decrease the disease burden and morbidity associated with the disease. Multidrug therapy (MDT) helps preventing and reducing the disease progression, severity and disabilities. PMID- 20704074 TI - Observations from a 'special selective drive' conducted under National Leprosy Elimination Programme in Karjat taluka and Gadchiroli district of Maharashtra. AB - The special selective drive (SSD) was conducted on a request from the Joint Director of Health Services (Leprosy and TB) Government of Maharashtra. The study team comprised the Foundation for Medical Research (FMR), assisted by a member of the Acworth Leprosy Hospital Society for Research, Rehabilitation and Education in Leprosy and two from Kushtrog Nivaran Samiti (KNS). The drive was conducted in select villages covered by 6 primary health centers (PHCs) in Karjat taluka of Raigad district and 45 PHCs in Gadchiroli district from March to May 2009 and had the cooperation of the district and PHC level staff. The aim was to train and deploy community level workers (CWs) for early leprosy case detection and through them, to create leprosy awareness in the community. A total of 1053 CWs (126 in Karjat taluka, 927 in Gadchiroli district) were given intensive training by the team. The CWs then carried out a one-day house-to-house leprosy awareness drive in their areas and listed persons such 'suspects' in both Karjat taluka (no. = 514) and Gadchiroli district (no. = 1325). Around 40% of 'suspects' presented themselves at the PHCs for examination by the medical team; of these 38 (29%) and 281 (45%) respectively turned out to be previously undetected definite cases of leprosy. The PHC-wise NCDR ranged from 5 - 27/10,000 in Karjat (14/10,000) and 2 35/10,000 in Gadchiroli (average 13/10,000), both rates being much higher than the reported State average of 1.1/10,000. There was a high proportion of child cases (14 and 24% respectively) and grade 2 disability (18% and 12% respectively) which indicate continued transmission of leprosy and delayed diagnosis of cases. The study also notes poor diagnostic skills among the PHC staff. Significant shortage and irregular disbursement of MDT from district store PHCs, combined with transport problem which probably contributed to delay in treatment in over 50% of the cases confirmed by the team. PMID- 20704075 TI - Study of leprosy in children. AB - Leprosy, a disease as oId a mankind, has been a public health problem in many developing countries and among children, it reflects disease transmission in the community and efficiency of control programmes study on childhood leprosy was carried out Gandhi Hospital, spread over 4 years. There were 32 children among 280 diagnosed cases of leprosy. The study revealed an incidence of 11.43% among leprosy patients with more number of boy being affected than girls. Most of children presented with hypopigmented anaesthetic patches. Hansen's BT was the most common clinical type of leprosy with extremities being the common site of involvement. Slit-skin smear was positive in 25% of children. We could find significant positive clinico-pathological correlation among 12 children who were subjected to biopsy. Reactional states and deformites were less common in our study. PMID- 20704076 TI - Severe form of type 2 reaction in patients of Hansen's disease after withdrawal of thalidomide: case reports. AB - Thalidomide, a racemic glutamic acid analogue, was first developed in 1954 and subsequently marketed in Europe, Australia and Canada as a sedative and anti emetic. It was approved by the Food and Drug Administration (FDA) in the USA in 1998 for the treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) and suppression of the cutaneous manifestations of ENL recurrences. It is a good choice for management in patients who are dependent on corticosteroids. Common side effects of thalidomide are teratogenicity, peripheral neuropathy, sedation and constipation. We report 4 cases of Hansen's disease with recurrent ENL who were adequately managed on thalidomide. On sudden withdrawal of thalidomide, they relapsed with severe type 2 reaction including necrotic ENL. PMID- 20704078 TI - Does anyone speak "hooah?"--overview of physician training in the military. PMID- 20704077 TI - Annular vesiculobullous eruptions in type 2 reaction in borderline lepromatous leprosy: a case report. AB - An untreated case of BL presented with clinical features of type 2 reaction (T2R) confirmed by histopathology. The case was a 18-year-old female with borderline lepromatous leprosy who developed annular vesiculobullous eruptions oversome of the pre-existing plaques on arms and upper back along with fever and severe neuritis after a short course of ofloxacin intake prescribed for urinary tract infection. In addition to the above lesions, some of the existing lesions showed acute exacerbation characterized by erythema, oedema, tenderness and vesiculobullous eruption. This can be considered as an example of leprous exacerbation as described in older literature. T2Rs are common in lepromatous leprosy and not so uncommonly are observed in borderline lepromatous leprosy. The vesiculobullous and crusted lesions developing over the existing borderline plaques, some of them presenting in an annular pattern in T2R in the form of leprous exacerbation, have been reported rarely in the literature. PMID- 20704079 TI - Meet Larry Riddles: a doctor for disasters. PMID- 20704080 TI - Moving from military medicine to civilian health care. PMID- 20704081 TI - Financial incentives for employed physicians: do they work? PMID- 20704082 TI - Getting quality and cost to the top of the agenda. PMID- 20704083 TI - Virtual ICU case study: St. Mary's Health Center. PMID- 20704084 TI - Addressing hospital-wide patient safety initiatives with high-fidelity simulation. PMID- 20704085 TI - Speak truth to power: the end of bobbleheaded leadership. PMID- 20704086 TI - The clinical voice of managed care. PMID- 20704087 TI - Physician intervention improves coding distribution and reimbursement. PMID- 20704088 TI - Basic economic concepts for physician leaders: broader perspectives for challenging times. PMID- 20704089 TI - The value of an open mind. PMID- 20704090 TI - Creating actionable goals. PMID- 20704091 TI - Physician leaders discuss current state of medicine. PMID- 20704092 TI - Key roles for physician executives in the pharmaceutical industry. PMID- 20704093 TI - Dissatisfaction after bilateral multifocal intraocular lens implantation: an electrophysiology study. AB - PURPOSE: To resolve patient dissatisfaction after bilateral diffractive multifocal intraocular lens (IOL) implantation, a multifocal IOL was exchanged for a monofocal IOL in the dominant eye. The relationship between dissatisfaction and pattern visual evoked cortical potential (P-VECP) was analyzed. METHODS: A 49 year-old man and a 71-year-old woman were implanted with diffractive multifocal IOLs bilaterally. Despite good binocular visual acuity after bilateral multifocal IOL implantation, each patient experienced persistent dissatisfaction with quality and sharpness of vision even when using spectacles and contact lenses. A multifocal IOL was exchanged for a monofocal IOL in the dominant eye of each patient. Pattern visual evoked cortical potential was measured in each patient and the average of each component was calculated. RESULTS: After IOL exchange in the dominant eye, P-VECP amplitude increased, peak latency improved, and the patients' symptoms disappeared. CONCLUSIONS: Monofocal IOL exchange in the dominant eye is an effective approach for dissatisfaction after bilateral multifocal IOL implantation. PMID- 20704094 TI - The effects of various instructional methods on retention of knowledge about pressure ulcers among critical care and medical-surgical nurses. AB - BACKGROUND: To determine whether there was a difference in retention of knowledge about pressure ulcers with a traditional lecture versus computer-based instruction. METHODS: A quasi-experimental, pretest/posttest design was used. Medical-surgical and critical care nurses (N = 60) were randomly assigned to a lecture, to computer-based instruction, or to a control group. Study participants were given the pressure ulcer knowledge test before and immediately after the program and at 3-month and 6-month intervals. RESULTS: Analysis of variance showed statistically significant differences in pretest and posttest scores [F(2, 57) = 35.784, p = .000] and in posttest to 3-month scores [F(2, 57) = 18.427, p = .000] among the three groups. CONCLUSION: The most significant loss of pressure ulcer knowledge, regardless of educational method, occurred within the first 3 months. Based on these findings, quarterly education in pressure ulcer prevention is recommended to maintain knowledge. Computer-based instruction is a viable option for acquisition and retention of knowledge about pressure ulcer prevention. PMID- 20704095 TI - Faculty development and mentorship using selected online asynchronous teaching strategies. AB - The use of distance learning continues to improve accessibility to nursing education programs, yet online teaching remains an intimidating experience for novice educators. An emerging role in professional faculty development is the online educator, who serves as a mentor for novice faculty. This article presents the necessary elements to plan, organize, and manage asynchronous online courses, especially for novice educators and online faculty mentors. Course engagement and faculty-student online communication strategies are explored using examples. Threaded discussion strategies for engaging students in active, collaborative learning are discussed using specific examples. A threaded discussion grading rubric is included. Strategies to sustain interactive learning and evaluate student learning using examples are offered. PMID- 20704096 TI - Knowledge and nursing practice of critical care nurses caring for patients with delirium in intensive care units in Jordan. AB - Delirium can have serious consequences in terms of morbidity, mortality, and increased health care costs. An extensive literature review showed that delirium is not well understood, recognized, or managed by medical and nursing professionals. The goal for this study was to determine the level of knowledge and management skills among critical care nurses caring for patients with delirium who were treated in intensive care units (ICUs) in Jordan. A total of 232 critical care nurses, employed in different ICUs in Jordan, completed self reported questionnaires. The nurses in critical care units who completed the questionnaires identified a need for more delirium-specific knowledge and skills to assess and manage this condition more effectively. To enhance health outcomes for patients treated in the ICU who have delirium, nurses need to receive education on current assessment and management modalities. These regular education programs should be complemented with evaluative research focusing on both nursing care and patient outcomes. PMID- 20704097 TI - Diabetic neuroarthropathy of the shoulder. AB - Neuroarthropathy of the foot and ankle is a relatively common complication of diabetes mellitus. Likewise, neuroarthropathy of the shoulder has been well reported in relation to syringomyelia. Diabetes mellitus, however, has rarely been reported to cause neuroarthropathy of any joint in the upper extremity and has never previously been reported in the shoulder. This article presents a case of a 77-year-old woman who presented with a secondary complaint of mild right shoulder pain, which had been present since she sustained a proximal humerus fracture four months earlier. The patient's past medical history was notably positive for diabetes mellitus with substantial peripheral neuropathy in the upper and lower extremities. Radiographic examination revealed significant degeneration of the humeral head, consistent with neuroarthropathy of the shoulder. Computed tomography and magnetic resonance imaging demonstrated no syrinx within the spinal cord. The patient's medical history included no etiologies of neuroarthropathy of the shoulder that had been previously reported in the literature. After a thorough literature review, we believe this to be the first case of diabetic shoulder neuroarthropathy to be documented. No significant differences in clinical or radiographic presentations appear to be present between reported etiologies of this pathology, including diabetes mellitus. Consequently, we recommend that diabetes mellitus always be considered as an etiology in the differential diagnosis of neuroarthropathy of the shoulder. PMID- 20704099 TI - Osteochondroma of the femoral neck: a rare cause of sciatic nerve compression. AB - A 39-year-old man presented with weakness and a nonmobile mass in the buttock of 5 months' duration. Hip flexion was limited to 70 degrees. Strength was diminished for both ankle/foot plantar and dorsiflexion. Sensation was decreased on the plantar and dorsal foot. A pedunculated osseous mass measuring 6x4 cm on the posterior femoral neck was seen on plain radiographs and magnetic resonance imaging. Electromyography showed moderate sciatic neuropathy of the peroneal and tibial branches. The patient underwent excision of the tumor through a posterior approach. Due to the risk of weakening the neck, two 7.3-mm cannulated screws were passed percutaneously into the head with fluoroscopic guidance. The final pathological report indicated the tumor was an osteochondroma. At 22-month follow up, he had full resolution of the neurologic findings. Postoperatively, the patient reported improvement in numbness and tingling in the leg but continued to have moderate buttock pain. Left hip flexion increased to 115 degrees at last follow-up.The importance of protecting the medial femoral circumflex artery during approaches to the hip is paramount. In this case, the tumor arose from the central aspect of the quadratus femoris, with the superior muscle protecting the medial femoral circumflex artery from harm. Although osteochondromas are a rare cause of mass effect, they should be considered in the differential diagnosis of sciatic nerve compression in this anatomical location. PMID- 20704098 TI - Is obesity protective against wound healing complications in pilon surgery? Soft tissue envelope and pilon fractures in the obese. AB - Open treatment of pilon fractures is associated with wound healing complications. A traumatized, limited soft tissue envelope contributes to wound healing complications. Obese patients have larger soft tissue envelopes around the ankle, theoretically providing a greater area for energy distribution and more accommodation to implants. This led us to test 2 hypotheses: (1) ankle dimensions in obese patients are larger than in lean patients, and (2) the increased soft tissue envelope volume translates into fewer wound complications. A consecutive series of 176 pilon fractures treated from March 2002 to December 2007 were retrospectively reviewed. Inclusion criteria were adults who received a preoperative computed tomography (CT) scan and were treated with a staged protocol including plating. Patients with body mass index (BMI) >30 were compared to those with BMI <30 for CT-derived ankle dimensions and wound complications. Comorbidities were evaluated for their role as potential confounders. Thirty-one fractures in obese patients were compared to 83 in lean patients. The average ratio of bone area to soft tissue area at the tibial plafond was 0.35 for the obese group and 0.38 for the lean group (P=.012). There were 8 major wound healing complications. Four occurred in the obese group (incidence 13%), and 4 in the lean group (incidence 5%) (P=.252). Ankle dimensions in clinically obese patients are larger than in lean patients. Obesity does not appear to be protective of wound-healing complications, but rather there is a trend toward the opposite. PMID- 20704100 TI - Atraumatic avulsion of the distal iliopsoas tendon: an unusual cause of hip pain. AB - While uncommon, isolated avulsion fractures of the lesser trochanter occur in children and adolescents prior to the fusion of this apophysis as a result of athletic activities. In the elderly, isolated fractures of the lesser trochanter are rare but can occur as a result of trauma. They have been identified in patients with primary or secondary bone malignancies, which were previously considered pathognomonic for metastatic disease. In the absence of trauma, weakening of the bone due to systemic disorders such as osteoporosis or osteomalacia chronica renal failure may also be responsible. Diagnosis may be difficult with physical examination and radiographs alone. This case report details this rare fracture in 2 patients suffering from debilitating chronic disease. Patient 1 was a 30-year-old woman with an 18-year history of type 1 diabetes mellitus, a 6-year history of end-stage renal disease, hypertension, hypothyroidism, peripheral vascular disease, and a 3-year history of systemic lupus erythematosus with antiphospholipid syndrome treated with warfarin. Patient 2 was a 66-year-old woman with a history of type 2 diabetes mellitus, peripheral neuropathy, obesity, chronic obstructive pulmonary disease, gout, hypertension, and chronic neck and low back pain. Both were assessed with magnetic resonance imaging following physical examination, which revealed atraumatic avulsion of the distal iliopsoas tendon from the lesser trochanter. Following retraction of the iliopsoas tendon, the patients were treated with conservative therapy and anti inflammatory medication. These 2 cases broaden the range of patients for whom spontaneous avulsion of the distal iliopsoas tendon should be considered in the differential diagnosis. PMID- 20704101 TI - Arthroscopic treatment of acute septic arthritis after meniscal allograft transplantation. AB - We present the 30-month follow-up results of an acute septic arthritis of the knee after meniscal allograft transplantation, which was successfully treated with graft retention. A 21-year-old man presented with a 4-month history of right knee pain following arthroscopic subtotal lateral meniscectomy. Plain radiographs showed there was no arthritic change with neutral limb alignment. Fourteen days after meniscal allograft transplantation, septic arthritis was confirmed with positive cultures for Staphylococcus epidermidis, and arthroscopic debridement and irrigation were performed. The suggested procedures of our treatment regimen include arthroscopic debridement and irrigation with >or=10 L of normal saline as soon as possible after diagnosis or a clinical suspicion is reached, repeated irrigation under the local anesthesia and intravenous antibiotics until clinical symptoms and laboratory results improve. The decision to repeat the debridement was based on clinical and laboratory results. We reevaluated the patients the third or fourth day after every arthroscopic treatment. At last follow-up, 2 years after the final operation, the patient had no clinical sign of infection. Erythrocyte sedimentation rate and C-reactive protein level were normal and plain radiographs indicated no arthritic change. Further the patient had full pain-free range of knee motion. At this time the Lysholm knee score was 89 and the Tegner score was 5. Magnetic resonance imaging 30 months postoperatively revealed slight (3 mm) extrusion without tear. This case is notable because it shows that early aggressive arthroscopic debridement and repeated irrigation with graft retention can be an effective treatment regimen in selected cases. PMID- 20704102 TI - Massive desmoplastic fibroblastoma with scapular invasion. AB - Desmoplastic fibroblastoma is a rare benign tumor usually associated with a favorable outcome. The tumor is characterized by fibroblastic cells that are sparsely distributed in a collagenous and fibromyxoid background. The growth of this tumor is generally indolent, and most tumors are small, subcutaneous lesions. They tend to behave in a nonaggressive manner, and several studies have reported no recurrences even after marginal excision. Invasion and destruction of bone are distinctly uncommon features.This article describes an unusual case of desmoplastic fibroblastoma that presented with a massive 23-cm tumor. The tumor was also unique for its infiltration and destruction of the scapula. The aggressive clinical features prompted the original physicians to administer chemotherapy, but the tumor exhibited no response to systemic treatment. The patient eventually underwent limb-sparing surgery at our hospital, which included en bloc resection, complete scapulectomy, and osteoarticular allograft replacement. The invasiveness of the tumor and its large size are distinctly unusual for desmoplastic fibroblastomas. Following surgical excision, the patient has remained continuously disease free for >5 years, which is in keeping with the intrinsically benign nature of the tumor. This case demonstrates that desmoplastic fibroblastoma can occasionally reach an enormous size and may exhibit invasive characteristics, but this does not necessarily portend subsequent recurrence of disease. PMID- 20704103 TI - Outcome of nonoperative vs operative treatment of humeral shaft fractures: a retrospective study of 213 patients. AB - Standard treatment for most humeral shaft fractures is nonoperative functional bracing; however, certain clinical scenarios necessitate operative intervention. There have been few studies in the literature comparing nonoperative and operative fixation of humeral shaft fractures. Two-hundred thirteen adult patients with a humeral shaft fracture who satisfied inclusion criteria were treated at 2 level 1 trauma centers with either a functional brace (nonoperative treatment group) or compression plating (operative treatment group). Main outcome measures were evaluated retrospectively and included time to union, nonunion, malunion, infection, incidence of radial nerve palsy, and elbow range of motion (ROM). The occurrence of nonunion (20.6% vs 8.7%; P=.0128) and malunion (12.7% vs 1.3%; P=.0011) was statistically significant and more common in the nonoperative group. There was no significant difference in infection rate between nonoperative and operative treatment (3.2% vs 4.7%; P=1.0000). Radial nerve palsy presented after fracture treatment in 9.5% of patients in the nonoperative group and in 2.7% of patients managed operatively (P=.0678). No difference in time to union or ultimate ROM was found between the 2 groups. Closed treatment of humerus fractures had a significantly higher rate of nonunion and malunion while operative intervention demonstrated no significant differences in time to union, infection, or iatrogenic radial nerve palsy. Nonoperative management has historically been the treatment of choice for many humeral shaft fractures, however, in certain clinical scenarios these fractures may be well served by compression plating. PMID- 20704104 TI - Evaluation of a novel osteoporotic drug delivery system in vitro: alendronate loaded calcium phosphate cement. AB - As a new drug delivery system, calcium phosphate cement was fabricated with different concentrations of alendronate (2, 5, 10 wt%), which is widely used to treat diseases related to bone loss. This study investigated the properties of the novel composite alendronate-loaded calcium phosphate cement in vitro, and found that the structure and chemical properties of the composites were not different from the calcium phosphate cement. However, the calcium phosphate cement set time was significantly faster compared with other groups (P<.01), and the strength of the calcium phosphate cement was significantly greater than the other groups (P<.01). The alendronate release rate from the composite increased with increase in drug concentration in the cement, and release was sustained over 21 days. The composite showed good biocompatibility in terms of the proliferation of rat mesenchymal stem cells. The alendronate-loaded calcium phosphate cement displayed satisfactory properties in vitro, which may be of benefit locally for osteoporotic bone in vivo. PMID- 20704105 TI - Pedicle screw placement in the thoracic spine: a comparison study of computer assisted navigation and conventional techniques. AB - The technique of computer-assisted pedicle screw installation and its clinical benefit as compared with conventional pedicle screw installation was evaluated. Twenty-two patients had thoracic screw insertion under 3-dimentional computer assisted navigation (92 screws) and 20 patients under conventional fluoroscopic control (84 screws). The 2 groups were compared for accuracy of screw placement, screw insertion time by postoperative thin-cut computed tomography scans, and statistical analysis. The cortical perforations were graded by 2-mm increments. In the computer group, 88 (95.65%) were grade I (good), 4 (4.35%) were grade II (<2 mm), and 0 were grade III (>2 mm) violations. There were 4 cortical violations (3.57%). In the conventional group, there were 14 cortical violations (16.67%), 70 (83.33%) were grade I (good), 11 (13.1%) were grade II (<2 mm), and 3 (3.57%) were grade III (>2 mm) violations (P<.001). The number (19.57%) of upper thoracic pedicle screws (T1-T4) inserted under 3-dimensional computer assisted navigation was significantly higher than that (3.57%) by conventional fluoroscopic control (P<.001). Average screw insertion time in the conventional group was more than in the computer group (P<.001). Three-dimensional computer assisted navigation pedicle screw placement can increase accuracy, reduce surgical time, and be performed safely and effectively at all levels of the thoracic spine, particularly the upper thoracic spine. PMID- 20704106 TI - Identification of risk factors for neurological deficits in patients with pelvic fractures. AB - This multicenter register study was performed to define injury and fracture constellations that are at risk to develop pelvic associated neural lesions. Data of 3607 patients treated from 2004 to 2009 for pelvic fractures were evaluated for neurological deficits depending on Tile classification, pelvic injury configuration, and treatment.In 223 patients (6.5%), neurological lesions were diagnosed on the day of discharge from the hospital. The degree of instability of the pelvic fracture correlated with occurrence of nerve lesions. Rate of neurological dysfunction increased from 1.5% in type A fractures to 14.4% in type C fractures (P<.001). As the most endangered anatomical regions in pelvic fractures, the roots L5 (18.3%) and S1 (15.6%) and isolated peripheral nerves (19.2%) were identified. Patients sustaining complex pelvic trauma (7.85%) suffered from significantly more neurological dysfunctions (33.5%) compared to patients without peripelvic organ or soft tissue injuries (P<.001). Whereas stable type A3 sacral fractures were not associated with a different risk to develop neurological deficits (3.8%), unstable sacral fractures with the need for operative fixation showed an increased rate of accompanying nerve lesions (15.4%; P<.001). Twenty-one (11.5%) operative sacral stabilizations were supplemented with nerve root decompression (mainly S1). Neurological complications in the course of treatment were seen in 69 cases (1.9%).A high degree of instability, complex pelvic trauma, and unstable sacral fractures predispose for additional neurological deficits in patients with pelvic fractures. PMID- 20704107 TI - Comparison of MRI and arthroscopy after autologous chondrocyte implantation in patients with osteochondral lesion of the talus. AB - No reported postoperative evaluation method is accurately correlated with the clinical outcome of repaired cartilage after autologous chondrocyte implantation. This study investigated the correlation of follow-up magnetic resonance imaging (MRI) evaluation and arthroscopic findings to the clinical outcome of surgically repaired osteochondral lesion of the talus with autologous chondrocyte implantation using the modified magnetic resonance observation of cartilage repair tissue (MOCART) scoring system.The study group comprised 21 consecutive patients with an osteochondral lesion of the talus who underwent autologous chondrocyte implantation. One year postoperatively, a follow-up MRI was obtained and a second-look arthroscopy was performed. Although the arthroscopic findings of the repaired osteochondral lesion of the talus showed better correlation with the clinical outcome when used with the modified MOCART scoring system, the higher correlation occurred only within a statistical error range, thus making the correlation not significantly different from the one determined on MRI. Therefore, a second-look arthroscopy is not necessary to evaluate the repaired talar cartilage after an autologous chondrocyte implantation. Magnetic resonance imaging is a useful method for long-term follow-up of patients with osteochondral lesions of the talus. PMID- 20704108 TI - Long-term results of metasul metal-on-metal total hip arthroplasty. AB - We assessed 90 total hip arthroplasties (THAs) performed with the Metasul metal on-metal hip system (Zimmer, Warsaw, Indiana); the patients were monitored for >10 years. The average Harris Hip Score of the patients was 40.5 points preoperatively and 85.8 points at final follow-up. No adverse reactions to the metal debris were observed in patients presenting with symptoms or phenomena such as unexplained pain, joint effusion, bursitis, or pseudotumor. Radiographically, the acetabular component fixation was stable in 86 hips, possibly unstable in 3 hips, and unstable in 1 hip. The unstable hip required revision of the acetabular component. The femoral component was bone-ingrown in 81 hips and stable-fibrous in 9 hips. Distal femoral cortical hypertrophy was seen in 34.4% of hips.Postoperatively, 6 hips dislocated, of which 2 developed recurrent dislocation and required revision of the acetabular component. Dissociation of the polyethylene liner occurred in 2 hips 6 and 12 years postoperatively, respectively, and required revision of the polyethylene liner and the articular head. The survival rate with the endpoint defined as revision surgery and radiologic loosening was 94.4% at mean follow-up (12.3 years). This study found that the Metasul metal-on-metal THA produces excellent long-term results. PMID- 20704109 TI - Surgical treatment of acute acromioclavicular joint injuries using a modified Weaver-Dunn procedure and clavicular hook plate. AB - Various surgical procedures have been described for the treatment of complete acromioclavicular joint dislocation, but no consensus exists on the optimal therapy. The aim of each type of procedure is to stabilize the clavicle by substitution of the ruptured coracoclavicular ligaments. Treatment modalities have changed with increasing understanding of the nature of the problem and the biomechanics of the joint. This article presents a method consisting of a modified Weaver-Dunn procedure and a clavicular hook plate for the operative management of acute acromioclavicular joint injuries.We performed a retrospective study of 46 patients who had undergone a modified Weaver-Dunn procedure with a clavicular hook plate for acute acromioclavicular joint injuries between July 2002 and December 2006. Average follow-up was 36.6 months (range, 24-46 months). There was 1 skin-deep infection, 1 dislocation of the hook, and 2 redislocations of the acromioclavicular joint. Thirteen patients had some calcification between the clavicle and the coracoid process, which did not cause loss of motion or other symptoms. All but 1 patient returned to work, and all but 1 returned to their preoperative activity level. The mean Constant score was 88.2 points. The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 12.2 points.Treatment of acute acromioclavicular joint injuries using a modified Weaver-Dunn procedure and a clavicular hook plate showed good short-term clinical results with a low complication rate. Further investigation and long-term results are needed to confirm these preliminary findings. PMID- 20704110 TI - Serum TGF-beta2 and TGF-beta3 are increased and positively correlated to pain, functionality, and radiographic staging in osteoarthritis. AB - The goal of this study was to verify or reject the hypothesis that systematic differences exist in various profibrotic or antifibrotic factors between osteoarthritic patients and controls, as well as between different stages of osteoarthritis. The study group comprised 63 patients with knee osteoarthritis and 18 controls. Transforming growth factor-beta (TGF-beta)1, -2, -3; tissue inhibitor of metalloproteinase (TIMP)-1 protein levels; and gelatinolytic activity of matrix metalloproteinase (MMP)-1, -2, -3, -9 activities were measured by enzyme-linked immunosorbent assay and gelatin zymography, respectively. Visual analog scale scores, Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, Lequesne clinical osteoarthritis scales, and Kellgren-Lawrence radiographic grading were recorded for each patient.Transforming growth factor beta2 and -3 (in contrast to TGF-beta1 and TIMP-1) serum protein levels were significantly higher in osteoarthritic patients compared to controls (210%+/-14% [P<.001] and 232%+/-7% [P<10(-7)], respectively). Additionally, TGF-beta2 and -3 were strongly positively correlated to Kellgren-Lawrence radiographic grading of the disease (P<10(-5) and P<10(-7), respectively). Moreover, TGF-beta2 correlated positively with the WOMAC scale (P=.007). However, TIMP-1 decreased as osteoarthritis progressed clinically, but remained irrelevant to radiographic staging. Furthermore, activities of MMP-2 and -9, but not MMP-1+/-3, were lower in patients with osteoarthritis. PMID- 20704111 TI - Correlative study of nerve root palsy and cervical posterior decompression laminectomy and internal fixation. AB - This study investigates the probable causes of nerve root palsy through the retrospective study of pre- and postoperative cervical curvature change for patients with cervical spondylosis and incidences of nerve root palsy. A consecutive series of 91 patients with cervical compressive myelopathy treated by laminectomy and internal fixation were reviewed. Nerve root palsy developed in 21 of 91 patients (23%) (group A). The other 70 patients, 41 men and 29 women, were chosen as controls (group B). A neutral lateral cervical spine radiograph was taken of all patients. The overall curvature of the cervical spine, the cervical curvature index, and the change rate were measured and compared.The pre- and postoperative change rate of cervical curvatures in groups A and B was 19.17+/ 7.62 and 18.03+/-7.62, respectively. The difference was not statistically significant (P>.05). The pre- and postoperative cervical curvature index change rate in groups A and B was 17.52+/-3.46 and 12.43+/-4.12, respectively. There were statistically significant differences between the 2 groups (P<. 05). This indicated the cervical alignment of patients in group A was changed greatly by traction during operation.In this study, we found that tethering the nerve root caused C5 palsy, but excessive intraoperative traction and the use of internal fixation may be one of the most important reasons for this. The cervical curvature index change rate reflected both a change in cervical height and a change in the overall cervical curvature. It is more sensitive in reflecting the degree of cervical traction and the change of the cervical alignment. PMID- 20704112 TI - One- versus two-stage bilateral total hip arthroplasty. AB - We compared the results of 1-stage uncemented bilateral total hip arthroplasty (THA) performed in 49 patients (98 hips) with those of 2-stage uncemented bilateral THA performed during the same hospital stay in 40 patients (80 hips). There was no significant difference in mean Harris Hip Score preoperatively and at final follow-up between the 2 groups. Radiographic evaluation of patients in the 1-stage group revealed the acetabular component was stable in 95 hips and possibly unstable in 3. The femoral component was bone-ingrown in 91 hips and stable fibrous in 7. In the 2-stage group, the acetabular component was stable in 77 hips and possibly unstable in 3. The femoral component was bone-ingrown in 71 hips and stable fibrous in 9. In both groups, no patients exhibited clear signs of loosening, migration or osteolysis.In the 1-stage group, postoperative dislocation occurred in 2 hips and 1 patient had developed deep venous thrombosis and pulmonary embolism. In the 2-stage group, no complications were observed. The incidence of complications was not significantly different between the 2 groups.There was no significant difference in the total blood loss and mean hemoglobin level preoperatively and at discharge between the 2 groups. However, in the 1-stage group, operative time, intraoperative blood loss, procedure cost, and hospital stay were significantly reduced compared with the 2-stage group. Therefore, 1-stage bilateral THA is a safe and effective option for patients with significant arthritic disease of both hips. PMID- 20704113 TI - Effects of antisense transforming growth factor-beta1 gene transfer on the biological activities of tendon sheath fibroblasts. AB - Recent studies have shown the importance of transforming growth factor-beta (TGF beta) in flexor tendon wound healing. Decreased adhesion formation and increased range of motion after the administration of TGF-beta antibodies after tendon repair have been shown. But TGF-beta antibodies have a short biologic half-life, and continuous supplementation of exogenous TGF-beta antibodies is not practical. Transfer of growth factor genes to tenocytes provides an alternative to protein therapeutics, and a gene therapy approach will prolong the availability of therapeutic proteins.We investigated the biological activities effects of rabbit tendon sheath fibroblasts transfected by antisense TGF-beta1 gene. Tendon sheath fibroblasts were isolated from New Zealand white rabbits and transfected by antisense TGF-beta1 gene with Lipofectin (Invitrogen, Carlsbad, California). Reverse transcription polymerase chain reaction was used to measure collagen I, collagen III, and TGF-beta1 expression, and Western blot was used to measure collagen protein I expression in tendon sheath fibroblasts after being transfected by antisense TGF-beta1 gene. Reverse transcription polymerase chain reaction displayed that tendon sheath fibroblasts transfected with antisense TGF beta1 gene showed marked decrease collagen I, collagen III, and TGF-beta1 mRNA expression. Western blot showed that tendon sheath fibroblasts transfected with antisense TGF-beta1 gene showed marked decrease expression of collagen I protein, and there was significant difference compared with the untransfected and empty transfected groups (P<.01). Tendon sheath fibroblasts can transfect with antisense TGF-beta1 gene successfully and can decrease production of collagen I, collagen III, and TGF-beta1, which were factors of tendon adhere formation. PMID- 20704114 TI - Using a cannulated screw as a drill guide and sleeve: a simple technique for multiple-screw fixation for intracapsular femoral neck fracture. AB - Management of femoral neck fractures is a challenge to orthopedic surgeons. Anatomical reduction and stable fixation is mandatory for nondisplaced or impacted intracapsular femoral neck fractures. This article introduces a simple method of parallel screw fixation for intracapsular femoral neck fracture based on the AO technique.We used a cannulated screw as a drill guide and sleeve rather than a commercial kit. With the 2-plane radiographic images, the surgeon could fine-tune the cannulated screw to direct the guide pin insertion and avoid deflection. Then the screw could be inserted for permanent fixation. This method accelerated the procedure and minimized the incisions and soft tissue dissection. The short-term results of 11 patients were compared with those of patients managed with the conventional screw fixation technique and the patients fixed with the dynamic hip system with an anti-rotation screw.This minimally invasive technique is time saving, easy to apply, and useful when commercial kits are unavailable. It facilitates and simplifies the minimally invasive parallel screw fixation procedure for intracapsular femoral neck fractures. PMID- 20704115 TI - The dynamics of proximal femoral nails: a clinical comparison between PFNA and Targon PF. AB - The objective of this study comparing the proximal femoral nails Targon PF (Aesculap, Tuttlingen, Germany) and Proximal Femoral Nail Antirotation (PFNA; Synthes. Oberdorf, Switzerland) was to observe the complications and postoperative results following pertrochanteric femoral fracture fixation, with special attention devoted to the dynamic properties of both implants under physiological load in vivo. The survey was designed as a randomized, prospective study of 80 patients who had sustained a pertrochanteric femoral fracture (AO type 31.A2). Postoperative radiological and clinical examinations were conducted over a period of 12 months on 40 respective patients treated with a PFNA or a Targon PF nail. Average operative time was 66.2 minutes and average fluoroscopy time was 103.6 seconds in the PFNA group, which was significantly lower than in the Targon PF group (84.7 minutes and 164.5 seconds, respectively). No significant difference was found between the 2 groups in terms of range of motion (P=.26) or Harris Hip Score (P=.83). The femoral neck components of the Targon PF showed a significantly higher sliding ability (14.5 mm; P=.04) than the PFNA (11.1 mm).Both implants are suited to treat pertrochanteric femoral fractures and display comparable clinical results. The Targon PF demonstrates better dynamic properties than the PFNA under physiological load in vivo. A disadvantage of the Targon PF, however, is the more complicated surgical technique and the longer operative time. PMID- 20704116 TI - Kyphoplasty does not maintain all restored height postoperatively: a prospective, comparative study. AB - From January to December 2008, balloon kyphoplasty was performed on 45 consecutive female patients with primary single-segment vertebral compression fractures as an inpatient procedure. All of the treated vertebral bodies were located within the thora-columbar region (T11-L2). Demographic data such as age, body mass index, fracture age, hospital stay, lumbar spine bone mineral density, and amount of bone cement injected per vertebrae were recorded. Patients were analyzed clinically by ambulatory status and the visual analog scale (VAS) for pain. Lateral radiographs were used to measure changes in anterior vertebral height. Mean anterior vertebral height increased from 58.9%+/-12.50% pre kyphoplasty to 79.8%+/-7.12% post-kyphoplasty (P<.001).Two groups were defined based on the percentage of height restoration achieved: group A (18 patients) with a height restoration of at least 20%, and group B (27 patients) with a height restoration of 0% to 19.99% post-kyphoplasty. Mean anterior vertebral height restored in groups A and B was 28.2%+/-7.2% and 12.1%+/-6.2%, respectively (P<.05). Four patients in group A and none in group B had height loss at the treated vertebral level (P<.05). Both VAS and ambulatory status were improved after treatment (P<.05) with no significant difference between the 2 groups. Kyphoplasty can restore the collapsed vertebral height, but patients with greater height restoration were more vulnerable to a loss of corrected height. PMID- 20704118 TI - It starts with an idea! PMID- 20704117 TI - Biomechanics of humerus fracture fixation by locking, cortical, and hybrid plating systems in a cadaver model. AB - The goal of this study was to discover how locking or cortical screws or a hybrid of both would perform in stabilizing a simulated humerus fracture. We simulated stripping of screw threads or poor bone quality by overdrilling the screw hole, and also studied a control group with no overdrilling. A total of 38 fresh frozen cadaver humeri were divided into 2 groups: 16 undergoing overdrilling with a drill bit 0.3 mm less than the diameter of the screw and 22 undergoing no overdrilling. A 4-point bending test followed torsional fatigue of 1000 cycles with an amplitude of +/-10 degrees. The post-fatigued samples were retested in the same way after tightening the loose screws if necessary. Finally, each fatigued specimen was tested for failure in torsion at 0.5 Hz by applying a maximum rotational displacement of 60 degrees .The bending stiffness values (Nm/mm) of cortical and locking screws, with the exception of the hybrid system, were significantly higher for the overdrilled group than the non-overdrilled (cortical, 6.9 vs 5.6; locking, 9.1 vs 6.3; hybrid, 8.4 vs 6.8). Fatigue had no effect on the bending stiffness of all the screw/plate systems (cortical, 6.9 vs 7.4; locking, 9.1 vs 8.8; hybrid, 8.5 vs 8.1). The overdrilling had no effect on the failure loads and displacements for all the screws except cortical screws, where the failure displacement was significantly higher for the overdrilling group. The torsional stiffness retentions after 1000 cycles were significantly different for overdrilled specimens in the cortical screws group only.Overdrilling had a minimal effect on bending and torsional properties. The results of the locking and hybrid were close, and the cortical screw had only slightly lower bending stiffness. PMID- 20704119 TI - Seeking balance. AB - This column is intended to offer a mini break from stress, and to be a gentle reminder to seek balance daily to ensure the nurse will be effective when needed. PMID- 20704120 TI - Delegation-better safe than sorry. AB - Occupational health nurses, like other registered nurses, often must decide whether to delegate. They must be familiar with the laws and standards governing delegation of nursing tasks. Many different resources exist for obtaining this information (e.g., jurisdictional nurse practice acts, position papers from boards of nursing, and publications from professional and regulatory organizations). Registered nurses who delegate must know which tasks may be delegated, how to determine the competence of delegates, and the level of supervision necessary. PMID- 20704121 TI - Long-term risk of repeat occupational injury or illness incidents among veterans health administration nursing employees. AB - This retrospective population-based study assessed the long-term risk of repeat reported occupational injury or illness incidents among Veterans Health Administration (VHA) nursing employees. Using fiscal year (FY) 2002 as the start date for the longitudinal surveillance of incidents, descriptive analyses included all VHA nursing employees (N = 25,697) who reported an initial (index) incident that occurred between FY 2002 and FY 2005. Adjusted for total administrative loss rates (e.g., attrition, disability, retirements), approximately half of the "surviving" index cases reported repeat incidents during an ensuing 3-year period. This total increased to approximately two thirds during a 6-year period. Compared to their nurse counterparts, practical nurses and nursing assistants had higher cumulative probabilities of multiple reported repeat occupational injury or illness incidents. Study findings suggest that reported levels of repeat occupational injury or illness incidents represent a complex interplay between environmental factors (e.g., location) and nursing staff demographics (e.g., level of education). PMID- 20704122 TI - Vaccine cold chain: part 1. proper handling and storage of vaccine. AB - The Center of Disease Control and Prevention reports that professionals in clinic setting may not be adequately storing and handling vaccine, leading to insufficient immunity of vaccinated individuals. This article provides information about proper cold chain storage and handling of vaccine and offers resources to begin, or reinforce, proper procedures in the occupational health unit to secure an effective immunization program. PMID- 20704124 TI - The stealth expatriate. AB - Global business practices have created a new category of worker, the stealth expatriate. Tax, immigration, and political risks exist for corporations that do not track this type of worker. Critical implications exist for occupational health nurses in the areas of travel health, fitness for duty, and emergency response. PMID- 20704123 TI - Integrating environmental health into nurse practitioner training-childhood pesticide exposure risk assessment, prevention, and management. AB - The use of pesticides in agriculture, public places, and private homes and gardens is ubiquitous throughout the United States. Children are particularly vulnerable to pesticide exposure because of immature biological and developmental processes. Thus, it is important that primary health care providers identify clients at risk for pesticide exposure and poisoning and know how to respond effectively if clients experience exposure. However, many primary health care providers are not adequately trained or prepared to manage the health-related effects of pesticide exposure. Recent efforts, supported by the U.S. Environmental Protection Agency, have addressed this shortcoming in nursing and medical education. A primary initiative is to find ways to integrate basic environmental health content, specifically regarding pesticide exposure, into nursing and medical curricula. As one strategy to achieve this, a pilot case study was developed by revising and enhancing an existing pediatric case study used in a required course for nurse practitioner students. The aim was to raise students' awareness of risk assessment, prevention, and appropriate care strategies for pesticide exposure. Evaluation of students' experience with the pilot case study suggested it was a meaningful and valued addition to their training, as well as an efficient way to introduce environmental health content into primary health care provider curricula. PMID- 20704125 TI - What does "medical clearance" for psychiatry really mean? PMID- 20704129 TI - Humor as a teaching tool. Use in psychiatric undergraduate nursing. AB - The research and anecdotal literature has suggested therapeutic humor is beneficial in the treatment relationship between nurse and patient; however, the potential effects of therapeutic humor between students and faculty have largely been overlooked. The literature has substantiated that a positive rapport between teacher and student facilitates improved student performance during the clinical experience. The author posits that a teacher's skillful use of humor can be an effective means of establishing and maintaining rapport with a student during potentially stressful clinical experiences. This article discusses the use of appropriate humor and how humor can be leveraged for effective academic and clinical instructional purposes, particularly in high-stress, high-demand settings. The article reflects on the potential for misinterpretation of humor, urging careful consideration of the context for its use. PMID- 20704131 TI - Caring for hospitalized older adults. PMID- 20704135 TI - Addressing emergency care. PMID- 20704136 TI - An opposing view of long-term care. PMID- 20704137 TI - Practical implications of Procedural and Emotional Religion Activity Therapy for nursing. AB - Procedural and Emotional Religious Activity Therapy encapsulates an approach to engaging older adults with Alzheimer's disease in meaningful activities that can be performed within the parameters of their cognitive functioning. Alzheimer's disease disrupts some brain structures more than others, resulting in a disproportionate loss of certain cognitive abilities. Explicit (conscious) memory skills are disrupted first, followed by implicit (unconscious) memory skills, and lastly emotional memory. Activities relying more on implicit and emotional memory, such as specially selected religious activities, are more likely to be used by patients. Steps and caveats of using this approach are provided. PMID- 20704138 TI - Focusing on transitions. PMID- 20704139 TI - The importance of immunizations. PMID- 20704140 TI - This issue: vaccines: addressing the challenges of immunizing our children. PMID- 20704142 TI - A 2-year-old boy with a testicular mass. Diagnosis: testicular tumor of adrenogenital syndrome due to 11-beta-hydroxylase deficiency. PMID- 20704141 TI - A 14-year-old girl with fatigue, weakness, and pallor. PMID- 20704143 TI - Navigating parental vaccine hesitancy. PMID- 20704144 TI - Vaccinating teens: current guidelines, challenges, and opportunities. PMID- 20704145 TI - The necessity of influenza vaccination in children. PMID- 20704146 TI - Invasive pneumococcal disease and the need for the new 13-valent pneumococcal vaccine. PMID- 20704147 TI - Immunizations: best business practices. PMID- 20704148 TI - Immunizations for internationally adopted children. PMID- 20704149 TI - The burden of influenza in children. PMID- 20704150 TI - Radiologic case study. Normal red marrow distribution for an 8-year-old child. PMID- 20704151 TI - Health care reform and physician-owned hospitals. PMID- 20704152 TI - The abduction external rotation (ABER) view for MRI of the shoulder. PMID- 20704153 TI - Lumbar and cervical disk herniations in NFL players: return to action. [An interview with Wellington K. Hsu]. PMID- 20704154 TI - Surgical strategies to achieve a custom-fit TKA with standard implant technique. AB - Recent trends in implant design have been geared toward taking individual differences in knee anatomy into consideration and modifying implants to accommodate these distinctions. The unique anatomy of the female knee gave birth to sex-specific knee implants and began a new era in implant design. This opened the door for the next progression of patient-specific cutting guides and implants. The current trend in implant design addresses individual variation with 3-D modeling that necessitates preoperative magnetic resonance imaging or computed tomography scans. While these innovations may turn out to be worthwhile, their use is currently limited by their expense and debatable clinical significance. Surgeons should not forget the basic surgical strategies to tailor their surgery to customize the fit of the standard implant. The surgical pearls reviewed here will allow surgeons to better understand sizing and customize every total knee arthroplasty with a patient-specific surgery. [corrected] PMID- 20704155 TI - Pharmacologic prevention of skeletal-related events in cancer patients. PMID- 20704156 TI - Preoperative planning in orthopedic trauma: benefits and contemporary uses. PMID- 20704157 TI - The use of spinal osteotomy in the treatment of spinal deformity. PMID- 20704158 TI - The use of spinal osteotomy in the treatment of spinal deformity. PMID- 20704159 TI - Pupillometry using the Procyon pupillometer. PMID- 20704161 TI - Lowering sodium intake can help reduce hypertension. PMID- 20704163 TI - Bilirubin screening in newborns: what should we do? PMID- 20704164 TI - Schizophrenia (maintenance treatment). PMID- 20704165 TI - FPIN's clinical inquiries. Management of alcohol withdrawal syndrome. PMID- 20704166 TI - Dizziness: a diagnostic approach. AB - Dizziness accounts for an estimated 5 percent of primary care clinic visits. The patient history can generally classify dizziness into one of four categories: vertigo, disequilibrium, presyncope, or lightheadedness. The main causes of vertigo are benign paroxysmal positional vertigo, Meniere disease, vestibular neuritis, and labyrinthitis. Many medications can cause presyncope, and regimens should be assessed in patients with this type of dizziness. Parkinson disease and diabetic neuropathy should be considered with the diagnosis of disequilibrium. Psychiatric disorders, such as depression, anxiety, and hyperventilation syndrome, can cause vague lightheadedness. The differential diagnosis of dizziness can be narrowed with easy-to-perform physical examination tests, including evaluation for nystagmus, the Dix-Hallpike maneuver, and orthostatic blood pressure testing. Laboratory testing and radiography play little role in diagnosis. A final diagnosis is not obtained in about 20 percent of cases. Treatment of vertigo includes the Epley maneuver (canalith repositioning) and vestibular rehabilitation for benign paroxysmal positional vertigo, intratympanic dexamethasone or gentamicin for Meniere disease, and steroids for vestibular neuritis. Orthostatic hypotension that causes presyncope can be treated with alpha agonists, mineralocorticoids, or lifestyle changes. Disequilibrium and lightheadedness can be alleviated by treating the underlying cause. PMID- 20704167 TI - What is making me dizzy? PMID- 20704168 TI - Pulmonary arterial hypertension: an update on diagnosis and treatment. AB - Pulmonary arterial hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or 30 mm Hg during physical activity. Pulmonary arterial hypertension is classified into subgroups, including idiopathic, heritable, and pulmonary arterial hypertension associated with other conditions. A detailed history, thorough physical examination, and most importantly, a high index of suspicion are essential to diagnosis. Evaluation includes echocardiography and exclusion of other causes of symptoms. Targeted laboratory testing can help identify the subgroup of pulmonary arterial hypertension. Right heart catheterization is required to confirm the diagnosis. Standard treatment options include oral anticoagulation, diuretics, oxygen supplementation, and for a small percentage of patients, calcium channel blockers. Newer treatments include prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Combination therapy has been shown to improve pulmonary arterial pressure, but more research is needed. Interventional procedures for patients with pulmonary arterial hypertension include balloon atrial septostomy and lung transplantation. PMID- 20704169 TI - Managing the adverse effects of radiation therapy. AB - Nearly two thirds of patients with cancer will undergo radiation therapy as part of their treatment plan. Given the increased use of radiation therapy and the growing number of cancer survivors, family physicians will increasingly care for patients experiencing adverse effects of radiation. Selective serotonin reuptake inhibitors have been shown to significantly improve symptoms of depression in patients undergoing chemotherapy, although they have little effect on cancer related fatigue. Radiation dermatitis is treated with topical steroids and emollient creams. Skin washing with a mild, unscented soap is acceptable. Cardiovascular disease is a well-established adverse effect in patients receiving radiation therapy, although there are no consensus recommendations for cardiovascular screening in this population. Radiation pneumonitis is treated with oral prednisone and pentoxifylline. Radiation esophagitis is treated with dietary modification, proton pump inhibitors, promotility agents, and viscous lidocaine. Radiation-induced emesis is ameliorated with 5-hydroxytryptamine3 receptor antagonists and steroids. Symptomatic treatments for chronic radiation cystitis include anticholinergic agents and phenazopyridine. Sexual dysfunction from radiation therapy includes erectile dysfunction and vaginal stenosis, which are treated with phosphodiesterase type 5 inhibitors and vaginal dilators, respectively. PMID- 20704170 TI - Side effects of radiation therapy. PMID- 20704171 TI - Prostatitis: diagnosis and treatment. AB - Prostatitis ranges from a straightforward clinical entity in its acute form to a complex, debilitating condition when chronic. It is often a source of frustration for the treating physician and patient. There are four classifications of prostatitis: acute bacterial, chronic bacterial, chronic prostatitis/chronic pelvic pain syndrome, and asymptomatic. Diagnosis of acute and chronic bacterial prostatitis is primarily based on history, physical examination, urine culture, and urine specimen testing pre- and post-prostatic massage. The differential diagnosis of prostatitis includes acute cystitis, benign prostatic hyperplasia, urinary tract stones, bladder cancer, prostatic abscess, enterovesical fistula, and foreign body within the urinary tract. The mainstay of therapy is an antimicrobial regimen. Chronic pelvic pain syndrome is a more challenging entity, in part because its pathology is poorly understood. Diagnosis is often based on exclusion of other urologic conditions (e.g., voiding dysfunction, bladder cancer) in association with its presentation. Commonly used medications include antimicrobials, alpha blockers, and anti-inflammatory agents, but the effectiveness of these agents has not been supported in clinical trials. Small studies provide limited support for the use of nonpharmacologic modalities. Asymptomatic prostatitis is an incidental finding in a patient being evaluated for other urologic problems. PMID- 20704172 TI - Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy: recommendation statement. PMID- 20704173 TI - Putting prevention into practice. Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy. PMID- 20704174 TI - Photo quiz. Painful perianal lesions. PMID- 20704175 TI - ICSI releases guideline on chronic pain assessment and management. PMID- 20704176 TI - Mechanism of the aminolysis of Fischer alkoxy and thiocarbene complexes: a DFT study. AB - B3LYP calculations have been carried out to study the reaction mechanism of the aminolysis of Fischer carbene complexes of the type (CO)(5)Cr=C(XMe)R (X = O and S; R = Me and Ph). We have explored different possible reaction mechanisms either through neutral or zwitterionic intermediates as well as a general base catalysis assisted by an ammonia molecule. Our results show that the most favorable pathway for the aminolysis of Fischer carbene complexes is through a stepwise reaction via a zwitterionic intermediate generated by the initial nucleophilic attack. We have found that the ammonia-catalyzed mechanism entails a significantly lower barrier for the rate-determining step than the uncatalyzed one. At lower pressure gas-phase conditions, the rate-determining step corresponds to the concerted proton transfer and MeXH elimination. Thiocarbene complexes show a higher energy barrier for this rate-determining step due to the lower basicity of the MeS(-) substituent. At higher pressure or in solution, the rate-determining step corresponds to the initial nucleophilic attack. Our results indicate that the transition state of the nucleophilic attack is more advanced and has a higher barrier for alkoxycarbene than thiocarbene complexes due to the stronger pi-donor character of the alkoxy group that reduces the electrophilicity of the attacked carbene atom making the nucleophilic attack more difficult. PMID- 20704177 TI - Functionalization of hyaluronic acid with chemoselective groups via a disulfide based protection strategy for in situ formation of mechanically stable hydrogels. AB - Functionalization of hyaluronic acid (HA) with chemoselective groups enables in situ (in vivo) formation of HA-based materials in minimally invasive injectable manner. Current methods of HA modification with such groups primarily rely on the use of a large excess of a reagent to introduce a unique reactive handle into HA and, therefore, are difficult to control. We have developed the new protective group strategy based on initial mild cleavage of a disulfide bond followed by elimination of the generated 2-thioethoxycarbonyl moiety ultimately affording free amine-type functionality, such as hydrazide, aminooxy, and carbazate. Specifically, new modifying homobifunctional reagents have been synthesized that contain a new divalent disulfide-based protecting group. Amidation of HA with these reagents gives rise to either one-end coupling product or to intra/intermolecular cross-linking of the HA chains. However, after subsequent treatment of the amidation reaction mixture with dithiothreitol (DTT), these cross-linkages are cleaved, ultimately exposing free amine-type groups. The same methodology was applied to graft serine residues to the HA backbone, which were subsequently oxidized into aldehyde groups. The strategy therefore encompasses a new approach for mild and highly controlled functionalization of HA with both nucleophilic and electrophilic chemoselective functionalities with the emphasis for the subsequent conjugation and in situ cross-linking. A series of new hydrogel materials were prepared by mixing the new HA-aldehyde derivative with different HA-nucleophile counterparts. Rheological properties of the formed hydrogels were determined and related to the structural characteristics of the gel networks. Human dermal fibroblasts remained viable while cultured with the hydrogels for 3 days, with no sign of cytotoxicity, suggesting that the gels described in this study are candidates for use as growth factors delivery vehicles for tissue engineering applications. PMID- 20704178 TI - Reduction of Se(IV) in boom clay: XAS solid phase speciation. AB - The geochemical fate of selenium is of key importance for today's society due to its role as a highly toxic essential micronutrient and as a significant component of high level radioactive waste (HLRW) originating from the operation of nuclear reactors. Understanding and prediction of the long-term behavior of Se in natural environments requires identification of the in situ speciation of selenium. This article describes an XAS-based investigation into the solid phase speciation of Se upon interaction of Se(IV) with Boom Clay, a reducing, complex sediment selected as model host rock for clay-based deep geological disposal of HLRW in Belgium and Europe. Using a combination of long-term batch sorption experiments, linear combination XANES analysis and ITFA-based EXAFS analysis allowed for the first time to identify Se0 as the dominant solid phase speciation of Se in Boom Clay systems equilibrated with Se(IV). PMID- 20704179 TI - Ion pair formation in multiphoton excitation of NO(2) using linearly and circularly polarized femtosecond light pulses: kinetic energy distribution and fragment recoil anisotropy. AB - The NO(2) ion pair photodissociation dynamics leading to NO(+)(X(1)Sigma(+),v) + O(-)((2)P(3/2) or (2)P(1/2)), induced by a 1 kHz femtosecond laser with wavelengths near 400 nm, has been characterized using the coincidence vector correlation method. The ion pair production after four-photon absorption reaches more than 15% of the primary ionization. The kinetic energy release of the fragments demonstrates a significant vibrational excitation of the NO(+)(X(1)Sigma(+),v) molecular fragment. Recoil ion fragment emission is strongly aligned along the polarization axis of linearly polarized light or preferentially emitted in the plane perpendicular to the propagation axis of circularly polarized light. The formalism describing the recoil anisotropy for bound-to-bound n-photon transition inducing prompt axial recoil dissociation of a nonlinear molecule has been developed to interpret the measured anisotropies in terms of excitation pathways via near-resonant intermediate states of specific symmetries. Possible reaction pathways are discussed that are consistent with the data and supported by calculations of potential energy surfaces and transition moments. PMID- 20704180 TI - Alkaline chymotrypsin from striped seabream (Lithognathus mormyrus) viscera: purification and characterization. AB - An alkaline chymotrypsin from the intestine of striped seabream (Lithognathus mormyrus) was purified by precipitation with ammonium sulfate, Sephadex G-100 gel filtration, Mono Q-Sepharose anion-exchange chromatography, ultrafiltration, second Sephadex G-100 gel filtration, and a second Mono Q-Sepharose anion exchange chromatography with a 80-fold increase in specific activity. The molecular weight of the purified alkaline chymotrypsin was estimated to be 27 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography. The enzyme was highly active over a wide range of pH from 7.0 to 12.0, with an optimum at pH 10.0-11.0 using succinyl-L-ala-ala-pro-l phenylalanine-p-nitroanilide (SAAPNA) as a substrate. The relative activities at pH 7.0 and 12.0 were about 66% and 45.5%, respectively. Further, the enzyme was extremely stable over a broad pH range (6.0-12.0). The optimum temperature for enzyme activity was 50 degrees C, and the enzyme displayed higher enzyme activity at low temperatures when compared to other enzymes. The purified enzyme was strongly inhibited by soybean trypsin inhibitor (SBTI) and phenylmethylsulfonyl fluoride (PMSF), a serine protein inhibitor, and N-toluenesulfonyl-L-lysine chloromethyl ketone (TLCK), a chymotrypsin specific inhibitor. The N-terminal amino acid sequence of the first nine amino acids was IVNGEEAVP. The chymotrypsin kinetic constants, Km and kcat on SAAPNA as a substrate, were 30.7 microM and 14.35 s(-1), respectively, while the catalytic efficiency kcat/Km was 0.465 microM(-1) s(-1). The high activity at high alkaline pH and low temperatures make this protease a potential candidate for future use in detergent processing industries. PMID- 20704181 TI - Distinct extracytoplasmic siderophore binding proteins recognize ferrioxamines and ferricoelichelin in Streptomyces coelicolor A3(2). AB - Under iron limitation, the Gram-positive bacterium Streptomyces coelicolor A3(2) excretes three siderophores of the hydroxamate type: desferrioxamine B, desferrioxamine E, and coelichelin. These sequester iron from insoluble ferric hydroxides, and the resulting ferric complexes are believed to be transported into the cell via siderophore-binding proteins (SBPs) associated with ATP-binding cassette (ABC) transporters. Previous studies indicated that some of the genes in the desferrioxamine (des) and coelichelin (cch) biosynthetic clusters encode ABC transporter components required for efficient uptake of ferrioxamine E and ferricoelichelin, respectively, and a third ABC transporter gene cluster (cdt), not associated with siderophore biosynthesis genes, was implicated in the import of ferrioxamine B. In this study, the putative SBPs associated with these three gene clusters, DesE, CchF, and CdtB, were recombinantly overproduced in Escherichia coli and purified to homogeneity, and their binding affinity for cognate siderophores and noncognate siderophores was examined using fluorescence and circular dichroism spectroscopy. DesE was found to bind all of the ferric tris-hydroxamates tested except ferricoelichelin, while CchF was found to bind only ferricoelichelin efficiently, providing further evidence that the cch cluster is a complete siderophore biosynthesis-export-uptake gene cluster. The picture was more complicated for CdtB, because it was found to be unstable in solution but was found to bind both ferrioxamine B and ferricoelichelin with high affinity. This was surprising because the cch cluster was previously reported to be necessary for efficient ferricoelichelin uptake. The remarkable specificity of the DesE and CchF proteins for different ferric-tris-hydroxamates raises intriguing questions about the molecular basis of their substrate specificity. PMID- 20704183 TI - Directed self-assembly at the 10 nm scale by using capillary force-induced nanocohesion. AB - We demonstrated a new nanoassembly strategy based on capillary force-induced cohesion of high-aspect ratio nanostructures made by electron-beam lithography. Using this strategy, ordered complex pattern were fabricated from individual nanostructures at the 10 nm length scale. This method enables the formation of complex designed networks from a sparse array of nanostructures, suggesting a number of potential applications in fabrication of nanodevices, nanopatterning, and fluid-flow investigations. PMID- 20704182 TI - Investigation of microbial elicitation of trans-resveratrol and trans-piceatannol in peanut callus led to the application of chitin as a potential elicitor. AB - It is well-known that the invasion of microbes such as fungi in some plants, including peanut, can induce the biosynthesis of stilbenoids such as trans resveratrol and trans-piceatannol. However, in a recent study it was found that not all kinds of microorganisms possessed such potential. The Gram-negative bacterium Pseudochrobactrum asaccharolyticum isolated from the peanut callus failed to act as an elicitor. After systematic investigation, the different inductive effects between fungi and Gram-negative bacteria were attributed to the chitin content of the cell wall. Results showed significantly more trans resveratrol and trans-piceatannol was induced by fungi (8.92-16.35 and 2.15-7.01 microg/g of fresh calluses, respectively) than by bacteria (1.77-2.72 and 0.16 0.52 microg/g of fresh calluses, respectively), regardless of species and viability. Such great differences prompted the direct utilization of chitin, the distinctive component of fungal cell wall, as an elicitor. The results that trans resveratrol induced by chitin was about two-thirds the amount induced by sterilized fungi, whereas trans-piceatannol (2.55+/-0.60 microg/g) was close to that by sterilized fungi, revealed chitin is not only an important fungal constituent responsible for the induction of trans-resveratrol and trans piceatannol but also an efficient elicitor by itself. These findings suggested sterilized fungi and chitin can be used as a safe and fast elicitor, as far as the risk of viable microbes is concerned, to induce trans-resveratrol and trans piceatannol in the well-controlled peanut tissue culture. PMID- 20704184 TI - Double diastereoselective, nucleophile-catalyzed aldol lactonizations (NCAL) leading to beta-lactone fused carbocycles and extensions to beta-lactone fused tetrahydrofurans. AB - A double diastereoselective variant of the nucleophile-catalyzed aldol lactonization (NCAL) process is described. This strategy delivers beta-lactone fused carbocycles with good to excellent diastereoselectivities using cinchona alkaloid catalysts with enantioenriched aldehyde acids, which gave low diastereoselectivity based on substrate control alone. beta-Lactone-fused tetrahydrofurans are also prepared for the first time via the NCAL process; however, diastereoselectivity was only modestly improved when applying double diastereodifferentiation to these systems. PMID- 20704186 TI - Transition-metal-free Sonogashira-type coupling of ortho-substituted aryl and alkynyl Grignard reagents by using 2,2,6,6-tetramethylpiperidine-N-oxyl radical as an oxidant. AB - Cross coupling of aryl, alkenyl, and alkynyl magnesium compounds by using 2,2,6,6 tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant is described. This coupling reaction can be performed without adding any transition metal on various ortho-substituted aryl and alkynyl Grignard reagents. Importantly, functional groups such as esters, amides, and cyanides are shown to be tolerated under the reaction conditions. PMID- 20704185 TI - Asymmetric synthesis of gamma-hydroxy alpha-enones by 1,8 diazabicyclo[5.4.0]undec-7-ene-catalyzed stereoselective rearrangement of chiral alpha-sulfinyl enones. AB - The asymmetric rearrangement of optically active alpha-sulfinyl enone 1 induced by catalytic DBU and triphenylphosphine gave optically active gamma-hydroxy alpha enone derivatives (up to 99% ee) in good yield following treatment with aqueous hydrogen peroxide. PMID- 20704187 TI - C1-symmetric dicyclopentadienes as new chiral diene ligands for asymmetric rhodium-catalyzed arylation of N-tosylarylimines. AB - Monosubstituted C(1)-symmetric dicyclopentadienes as a new class of diene ligands have been developed for asymmetric arylation of N-tosylarylimines in excellent yields (98-99%) with high enantioselectivities (90-96%). The preparation of these diene ligands relied on an efficient lipase-catalyzed resolution as the key step. PMID- 20704188 TI - Free energy, entropy, and enthalpy of a water molecule in various protein environments. AB - To examine the wide variety of cavities available to water molecules inside proteins, a model of the protein cavities is developed with the local environment treated at atomic detail and the nonlocal environment treated approximately. The cavities are then changed to vary in size and in the number of hydrogen bonds available to a water molecule inside the cavity. The free energy, entropy, and enthalpy change for the transfer of a water molecule to the cavity from the bulk liquid is calculated from thermodynamic integration. The results of the model are close to those of similar cavities calculated using the full protein and solvent environment. As the number of hydrogen bonds resulting from the addition of the water molecule increases, the free energy decreases, as the enthalpic gain of making a hydrogen bond outweighs the entropic cost. Changing the volume of the cavity has a smaller effect on the thermodynamics. Once the hydrogen bond contribution is taken into account, the volume dependence on DeltaG, DeltaS, and DeltaH is small and roughly the same for a hydrophobic cavity as a hydrophilic cavity. PMID- 20704189 TI - Structural basis for the specificity of the GAE domain of yGGA2 for its accessory proteins Ent3 and Ent5 . AB - Different assemblies of accessory proteins with clathrin are critical for transporting precisely various cargos between intracellular compartments. GGA proteins are adaptors for clathrin-mediated intracellular trafficking, connecting other accessory and cargo proteins to clathrin-coated vesicles. Both binding to the GAE domain of GGA protein yGGA2 in Saccharomyces cerevisia, Ent3 and Ent5 are involved in different trafficking pathways. Ent5 is ubiquitous and localized in a manner independent of yGGA2, and Ent3 functions preferentially through yGGA2. Not known are the sources of these differences. Here we show not all acidic phenylalanine motifs in Ent3/5 are active for yGGA2_GAE domain binding. Two of the three acidic-phenylalanine motifs from Ent3 can bind to the yGGA2_GAE domain, while only one of the two motifs from Ent5 can bind. We also determined the crystal structure of the yGGA2_GAE domain at 1.8 A resolution. Structural docking and mutagenesis analysis shows inactive motifs in Ent3 and Ent5 repel yGGA2_GAE binding through disfavored residues at positions 1 and 3. These results suggest accessory proteins may fine-tune the GGA adaptor dependence by adjusting their non-acidic-phenylalanine residues, thus contributing to the distinct role of Ent3 and Ent5 in trafficking. PMID- 20704190 TI - The Anthropocene forces us to reconsider adaptationist models of human environment interactions. PMID- 20704192 TI - Black and blue and green. PMID- 20704193 TI - The truth about dirty oil: is CCS the answer? AB - Does carbon capture and sequestration (CCS) make sense in the oil sands? PMID- 20704194 TI - A role for analytical chemistry in advancing our understanding of the occurrence, fate, and effects of Corexit oil dispersants. PMID- 20704195 TI - A proactive approach to toxic chemicals: moving green chemistry beyond alternatives in the "Safe Chemicals Act of 2010". PMID- 20704196 TI - Sampling for pharmaceuticals and personal care products (PPCPs) and illicit drugs in wastewater systems: are your conclusions valid? A critical review. AB - The analysis of 87 peer-reviewed journal articles reveals that sampling for pharmaceuticals and personal care products (PPCPs) and illicit drugs in sewers and sewage treatment plant influents is mostly carried out according to existing tradition or standard laboratory protocols. Less than 5% of all studies explicitly consider internationally acknowledged guidelines or methods for the experimental design of monitoring campaigns. In the absence of a proper analysis of the system under investigation, the importance of short-term pollutant variations was typically not addressed. Therefore, due to relatively long sampling intervals, potentially inadequate sampling modes, or insufficient documentation, it remains unclear for the majority of reviewed studies whether observed variations can be attributed to "real" variations or if they simply reflect sampling artifacts. Based on results from previous and current work, the present paper demonstrates that sampling errors can lead to overinterpretation of measured data and ultimately, wrong conclusions. Depending on catchment size, sewer type, sampling setup, substance of interest, and accuracy of analytical method, avoidable sampling artifacts can range from "not significant" to "100% or more" for different compounds even within the same study. However, in most situations sampling errors can be reduced greatly, and sampling biases can be eliminated completely, by choosing an appropriate sampling mode and frequency. This is crucial, because proper sampling will help to maximize the value of measured data for the experimental assessment of the fate of PPCPs as well as for the formulation and validation of mathematical models. The trend from reporting presence or absence of a compound in "clean" water samples toward the quantification of PPCPs in raw wastewater requires not only sophisticated analytical methods but also adapted sampling methods. With increasing accuracy of chemical analyses, inappropriate sampling increasingly represents the major source of inaccuracy. A condensed step-by-step Sampling Guide is proposed as a starting point for future studies. PMID- 20704197 TI - Optimal set anode potentials vary in bioelectrochemical systems. AB - In bioelectrochemical systems (BESs), the anode potential can be set to a fixed voltage using a potentiostat, but there is no accepted method for defining an optimal potential. Microbes can theoretically gain more energy by reducing a terminal electron acceptor with a more positive potential, for example oxygen compared to nitrate. Therefore, more positive anode potentials should allow microbes to gain more energy per electron transferred than a lower potential, but this can only occur if the microbe has metabolic pathways capable of capturing the available energy. Our review of the literature shows that there is a general trend of improved performance using more positive potentials, but there are several notable cases where biofilm growth and current generation improved or only occurred at more negative potentials. This suggests that even with diverse microbial communities, it is primarily the potential of the terminal respiratory proteins used by certain exoelectrogenic bacteria, and to a lesser extent the anode potential, that determines the optimal growth conditions in the reactor. Our analysis suggests that additional bioelectrochemical investigations of both pure and mixed cultures, over a wide range of potentials, are needed to better understand how to set and evaluate optimal anode potentials for improving BES performance. PMID- 20704198 TI - Brazilian agriculture and environmental legislation: status and future challenges. AB - Brazilian agriculture covers about one-third of the land area and is expected to expand further. We assessed the compliance of present Brazilian agriculture with environmental legislation and identified challenges for agricultural development connected to this legislation. We found (i) minor illegal land use in protected areas under public administration, (ii) a large deficit in legal reserves and protected riparian zones on private farmland, and (iii) large areas of unprotected natural vegetation in regions experiencing agriculture expansion. Achieving full compliance with the environmental laws as they presently stand would require drastic changes in agricultural land use, where large agricultural areas are taken out of production and converted back to natural vegetation. The outcome of a full compliance with environmental legislation might not be satisfactory due to leakage, where pristine unprotected areas become converted to compensate for lost production as current agricultural areas are reconverted to protected natural vegetation. Realizing the desired protection of biodiversity and natural vegetation, while expanding agriculture to meet food and biofuel demand, may require a new approach to environmental protection. New legal and regulatory instruments and the establishment of alternative development models should be considered. PMID- 20704199 TI - Characteristics of lead corrosion scales formed during drinking water distribution and their potential influence on the release of lead and other contaminants. AB - Destabilization of the corrosion scale present in lead pipes used in drinking water distribution systems is currently considered a major problem for municipalities serviced in part by lead pipes. Although several lead corrosion strategies have been deployed with success, a clear understanding of the chemistry of corrosion products present in the scale is needed for an effective lead control. This contribution focuses on a comprehensive characterization of the layers present in the corrosion scale formed on the inner surfaces of lead pipes used in the drinking water distribution system of the City on London, ON, Canada. Solid corrosion products were characterized using X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and X ray photoelectron spectroscopy (XPS). Toxic elements accumulated in the corrosion scale were also identified using inductively coupled plasma (ICP) spectrometry after acid digestion. Based on the XRD results, hydrocerussite was identified as the major lead crystalline corrosion phase in most of the pipes sampled, while cerussite was observed as the main crystalline component only in a few cases. Lead oxides including PbO(2) and Pb(3)O(4) were also observed in the inner layers of the corrosion scale. The presence of these highly oxidized lead species is rationalized in terms of the lead(II) carbonate phase transforming into lead(IV) oxide through an intermediate Pb(3)O(4) (2Pb(II)O x Pb(IV)O(2)) phase. In addition to lead corrosion products, an amorphous aluminosilicate phase was also identified in the corrosion scale. Its concentration is particularly high at the outer surface layers. Accumulation of toxic contaminants such as As, V, Sb, Cu, and Cr was observed in the corrosion scales, together with a strong correlation between arsenic accumulation and aluminum concentration. PMID- 20704200 TI - Isotope tracing of atmospheric mercury sources in an urban area of northeastern France. AB - Mercury (Hg) isotope composition was investigated in lichens over a territory of 900 km(2) in the northeast of France over a period of nine years (2001-2009). The studied area was divided into four geographical areas: a rural area, a suburban area, an urban area, and an industrial area. In addition, lichens were sampled directly at the bottom of chimneys, within the industrial area. While mercury concentrations in lichens did not correlate with the sampling area, mercury isotope compositions revealed both mass dependent and mass independent fractionation globally characteristic of each geographical area. Odd isotope deficits measured in lichens were smallest in samples close to industries, with Delta(199)Hg of -0.15 +/- 0.03 per thousand, where Hg is thought to originate mainly from direct anthropogenic inputs. Samples from the rural area displayed the largest anomalies with Delta(199)Hg of -0.50 +/- 0.03 per thousand. Samples from the two other areas had intermediate Delta(199)Hg values. Mercury isotopic anomalies in lichens were interpreted to result from mixing between the atmospheric reservoir and direct anthropogenic sources. Furthermore, the combination of mass-dependent and mass independent fractionation was used to characterize the different geographical areas and discriminate the end-members (industrial, urban, and local/regional atmospheric pool) involved in the mixing of mercury sources. PMID- 20704201 TI - Contribution of synthetic and naturally occurring organobromine compounds to bromine mass in marine organisms. AB - An extraction, separation, and purification method was developed for the identification and quantification of total bromine (TBr), extractable organobromine (EOBr), and five classes of identified EOBrs. Instrumental neutron activation analysis (INAA) was utilized to quantify EOBr and TBr. The method was then applied to liver samples of tuna, albatross, and polar bear collected from remote marine locations. Polybrominated biphenyls (PBBs), polybrominated diphenyl ethers (PBDEs), bromophenols (BRPs), hydroxylated (OH-) and methoxylated (MeO-) PBDEs were analyzed as identified EOBr. The majority of the bromine in these marine organisms was nonextractable or inorganic, with EOBr accounting for 10-28% of the TBr. Of the identified EOBr, in tuna and albatross, naturally occurring compounds, including MeO-PBDEs, OH-PBDEs, and BPRs, were prevalent. However, the identifiable EOBr in polar bears consisted primarily of synthetic compounds, including PBDEs and PBBs. Overall, 0.08-0.11% and 0.008-0.012% of EOBr and TBr, respectively, were identified. The proportion of EOBr that was identified in marine organisms was relatively small compared to the proportions for organofluorine and organochlorine compounds. This could be related to the great diversity of naturally occurring organobromine compounds in the environment. Naturally occurring brominated fatty acids were estimated to be the predominant compounds in the EOBr fraction. PMID- 20704202 TI - Spatiotemporal pattern of soil respiration of terrestrial ecosystems in China: the development of a geostatistical model and its simulation. AB - Quantification of the spatiotemporal pattern of soil respiration (R(s)) at the regional scale can provide a theoretical basis and fundamental data for accurate evaluation of the global carbon budget. This study summarizes the R(s) data measured in China from 1995 to 2004. Based on the data, a new region-scale geostatistical model of soil respiration (GSMSR) was developed by modifying a global scale statistical model. The GSMSR model, which is driven by monthly air temperature, monthly precipitation, and soil organic carbon (SOC) density, can capture 64% of the spatiotemporal variability of soil R(s). We evaluated the spatiotemporal pattern of R(s) in China using the GSMSR model. The estimated results demonstrate that the annual R(s) in China ranged from 3.77 to 4.00 Pg C yr(-1) between 1995 and 2004, with an average value of 3.84 +/- 0.07 Pg C yr(-1), contributing 3.92%-4.87% to the global soil CO(2) emission. Annual R(s) rate of evergreen broadleaved forest ecosystem was 698 +/- 11 g C m(-2) yr(-1), significantly higher than that of grassland (439 +/- 7 g C m(-2) yr(-1)) and cropland (555 +/- 12 g C m(-2) yr(-1)). The contributions of grassland, cropland, and forestland ecosystems to the total R(s) in China were 48.38 +/- 0.35%, 22.19 +/- 0.18%, and 20.84 +/- 0.13%, respectively. PMID- 20704203 TI - Occurrence of cyclic and linear siloxanes in indoor dust from China, and implications for human exposures. AB - Siloxanes are used in a wide variety of personal-care and other consumer products. Although there is clearly a potential for contamination of indoor dust with siloxanes, reports of occurrence of siloxanes in indoor dust were not available, prior to the present study. Here, we have determined the concentrations and profiles of four cyclic siloxanes, octamethylcyclotetrasiloxane (D(4)), decamethylcyclopentasiloxane (D(5)), dodecamethylcyclohexasiloxane (D(6)), and tetradecamethylcycloheptasiloxane (D(7)), as well as 11 linear siloxanes, from L(4)-L(14), in 100 dust samples collected in China. Cyclic and linear siloxanes were found in all dust samples, with the linear siloxanes L(9)-L(14) being the predominant compounds. Concentrations of total siloxanes in dust ranged from 21.5 to 21,000 (mean: 1540 +/- 2850) ng g(-1). The highest concentration of the individual linear siloxanes, L(9)-L(14), ranged between 2680 and 6170 ng g(-1). Concentrations of total linear siloxanes (TLS) were 1-2 orders of magnitude higher than concentrations of total cyclic siloxanes (TCS), in all indoor dust samples. Siloxane concentrations in dust were associated with the number of electrical/electronic appliances, number of occupants, and smokers living in the house. Based on the measured siloxane concentrations and on estimated daily ingestion rates of dust by toddlers and adults, we calculated the daily intake of siloxanes. For adults, daily exposure to total siloxanes, based on an average dust intake rate and median exposure concentration, was calculated to be 15.9 ng day(-1); the corresponding value for toddlers was 32.8 ng d(-1). PMID- 20704204 TI - Fe isotope fractionation during equilibration of Fe-organic complexes. AB - Despite the importance of Fe-organic complexes in the environment, few studies have investigated Fe isotope effects driven by changes in Fe coordination that involve organic ligands. Previous experimental (Dideriksen et al., 2008, Earth Planet Sci. Lett. 269:280-290) and theoretical (Domagal-Goldman et al., 2009, Geochim. Cosmochim. Acta 73:1-12) studies disagreed on the sense of fractionation between Fe-desferrioxamine B (Fe-DFOB) and Fe(H(2)O)(6)(3+). Using a new experimental technique that employs a dialysis membrane to separate equilibrated Fe-ligand pools, we measured the equilibrium isotope fractionations between Fe DFOB and (1) Fe bound to ethylenediaminetetraacetic acid (EDTA) and (2) Fe bound to oxalate. We observed no significant isotope fractionation between Fe-DFOB and Fe-EDTA (Delta(56/54)Fe(Fe-DFOB/Fe-EDTA) approximately 0.02 +/- 0.11 per thousand) and a small but significant fractionation between Fe-DFOB and Fe oxalate (Delta(56/54)Fe(Fe-DFOB/Fe-Ox(3)) = 0.20 +/- 0.11 per thousand). Taken together, our results and those of Dideriksen et al. (2008) reveal a strong positive correlation between measured fractionation factors and the Fe-binding affinity of the ligands. This correlation supports the experimental results of Dideriksen et al. (2008). Further, it provides a simple empirical tool that may be used to predict fractionation factors for Fe-ligand complexes not yet studied experimentally. PMID- 20704205 TI - tet and sul antibiotic resistance genes in livestock lagoons of various operation type, configuration, and antibiotic occurrence. AB - Although livestock operations are known to harbor elevated levels of antibiotic resistant bacteria, few studies have examined the potential of livestock waste lagoons to reduce antibiotic resistance genes (ARGs). The purpose of this study was to determine the prevalence and examine the behavior of tetracycline [tet(O) and tet(W)] and sulfonamide [sul(I) and sul(II)] ARGs in a broad cross-section of livestock lagoons within the same semiarid western watershed. ARGs were monitored for one year in the water and the settled solids of eight lagoon systems by quantitative polymerase chain reaction. In addition, antibiotic residues and various bulk water quality constituents were analyzed. It was found that the lagoons of the chicken layer operation had the lowest concentrations of both tet and sul ARGs and low total antibiotic concentrations, whereas sul ARGs were highest in the swine lagoons, which generally corresponded to the highest total antibiotic concentrations. A marginal benefit of organic and small dairy operations also was observed compared to conventional and large dairies, respectively. In all lagoons, sul ARGs were observed to be generally more recalcitrant than tet ARGs. Also, positive correlations of various bulk water quality constituents were identified with tet ARGs but not sul ARGs. Significant positive correlations were identified between several metals and tet ARGs, but Pearson's correlation coefficients were mostly lower than those determined between antibiotic residues and ARGs. This study represents a quantitative characterization of ARGs in lagoons across a variety of livestock operations and provides insight into potential options for managing antibiotic resistance emanating from agricultural activities. PMID- 20704206 TI - Linking community profiles, gene expression and N-removal in anammox bioreactors treating municipal anaerobic digestion reject water. AB - Anaerobic ammonium oxidation (anammox) requires 60% less oxygen and no external organic carbon compared to conventional biological nitrogen removal (BNR). Nevertheless, full-scale installations of anammox are uncommon, primarily owing to the lack of well-established process monitoring and control strategies that result in stable anammox reactor performance. The overarching goal of this study was to develop and apply molecular biomarkers that link microbial community structure and activity to anammox process performance in a bioreactor fed with actual anaerobic digestion centrate from a full-scale operational wastewater treatment facility. Over long-term operation, Candidatus "Brocadia sp. 40" emerged as the dominant anammox population present in the reactor. There was good correspondence between reactor nitrogen removal performance and anammox bacterial concentrations. During the period of reactor operation, there was also a marked shift in biomass morphology from discrete cells to granular aggregates, which was paralleled by a shift also to more stable nitrogen removal and the succession and establishment of bacteria related to the Chlorobi/Bacteroidetes superfamily. Based on batch assays, hydrazine oxidoreductase (hzo) expression and concentrations of the 16S-23S rRNA intergenic spacer region (ISR) were good quantitative biomarkers of oxygen- and nitrite-mediated inhibition. When applied to a continuous anammox reactor, both molecular biomarkers show promise as monitoring tools for "predicting" reactor performance. PMID- 20704207 TI - Separation of SF6 from gas mixtures using gas hydrate formation. AB - This study aims to examine the thermodynamic feasibility of separating sulfur hexafluoride (SF(6)), which is widely used in various industrial fields and is one of the most potent greenhouse gases, from gas mixtures using gas hydrate formation. The key process variables of hydrate phase equilibria, pressure composition diagram, formation kinetics, and structure identification of the mixed gas hydrates, were closely investigated to verify the overall concept of this hydrate-based SF(6) separation process. The three-phase equilibria of hydrate (H), liquid water (L(W)), and vapor (V) for the binary SF(6) + water mixture and for the ternary N(2) + SF(6) + water mixtures with various SF(6) vapor compositions (10, 30, 50, and 70%) were experimentally measured to determine the stability regions and formation conditions of pure and mixed hydrates. The pressure-composition diagram at two different temperatures of 276.15 and 281.15 K was obtained to investigate the actual SF(6) separation efficiency. The vapor phase composition change was monitored during gas hydrate formation to confirm the formation pattern and time needed to reach a state of equilibrium. Furthermore, the structure of the mixed N(2) + SF(6) hydrate was confirmed to be structure II via Raman spectroscopy. Through close examination of the overall experimental results, it was clearly verified that highly concentrated SF(6) can be separated from gas mixtures at mild temperatures and low pressure conditions. PMID- 20704208 TI - Activity-based concept for transport and partitioning of ionizing organics. AB - Ionizing chemicals, including pesticides, pharmaceuticals, and personal care products, are care products, are widely used chemicals of commerce and have been detected in the environment in large numbers. These "ionics" are subject to a variety of processes, such as dissociation, ion trap, and electrical interactions with organic matter and biota. Conventional chemodynamic concepts and models designed to treat neutral compounds do not necessarily address these processes. A new system of equations, based on activity and analogous to the fugacity approach, is suggested to describe the fate of organic ionics. The total concentration of all molecule species in a bulk compartment is determined from the product of activity 'a' and a bulk activity capacity 'B'. The concentration ratio between compartments in equilibrium depends on the activity ratio and the capacity ratio. Changes in partitioning due to pH, ionic strength, and the ion trap effect are quantified. The calculation is illustrated for two pharmaceuticals, namely the monovalent acid ibuprofen and the monovalent base trimethoprim, in a multimedia lake system. Trimethoprim is neutral at high pH but ionized at low pH, while ibuprofen exhibits the opposite. The concentration ratios of air and biota to water are shown to depend on pH. The activity approach may be used to describe transport and partitioning of multivalent ionizable organic compounds and to build multimedia fate models. PMID- 20704209 TI - Evolution of absorbance spectra of ozonated wastewater and its relationship with the degradation of trace-level organic species. AB - This study examined the evolution of absorbance spectra of wastewater ozonated using varying initial ozone concentrations or treatment times; concomitant changes of concentrations of trace-level pharmaceuticals were also quantified. The absorbance of ozonated wastewater decreased due to the degradation of chromophores in effluent organic matter (EfOM). The relative decrease of absorbance (DeltaA/A(0)) ranged from < 30% for lambda < 250 nm to > 80% for lambda > 320 nm. The removal of atenolol, carbamazepine, DEET, diclofenac, gemfibrozil, ibuprofen, iopromide, naproxen, propranolol, sulfamethoxazole, trimethoprim, and p-chlorobenzoic acid was strongly correlated with DeltaA/A(0) values. The observed features were hypothesized to correspond to the engagement of kinetically distinct groups of EfOM chromophores. Modeling of the evolution of EfOM absorbance and concurrent degradation of trace-level organic species based on this hypothesis confirmed its applicability and utility for practical applications and theoretical exploration. PMID- 20704210 TI - Iron-mediated photochemical decomposition of methylmercury in an arctic Alaskan lake. AB - Sunlight-induced decomposition is the principal sink for methylmercury (CH(3)Hg(+)) in arctic Alaskan lakes and reduces its availability for accumulation in aquatic food webs. However, the mechanistic chemistry of this process in natural waters is unknown. We examined experimentally the mechanism of photochemical CH(3)Hg(+) decomposition in filter-sterilized epilimnetic waters of Toolik Lake in arctic Alaska (68 degrees 38'N, 149 degrees 36'W), a region illuminated by sunlight almost continuously during the summer. Results from in situ incubation tests indicate that CH(3)Hg(+) is not decomposed principally by either direct photolysis (i.e., no degradation in reagent-grade water) or primary photochemical reactions with dissolved organic material. The preeminent role of labile Fe and associated photochemically produced reactive oxygen species is implicated by tests that show 1) additions of Fe(III) to reagent-grade water enhance CH(3)Hg(+) photodecomposition, 2) strong complexation of ambient Fe(III) with desferrioxamine B inhibits the reaction in lake water, and 3) experimental additions of organic molecules that scavenge hydroxyl radicals specifically among reactive oxygen species (dimethylsulfoxide and formic acid) inhibit CH(3)Hg(+) degradation. Lake-water dilution and Fe(III) addition experiments indicate that Fe is not the limiting reactant for CH(3)Hg(+) photodecomposition in Toolik Lake, which is consistent with prior results indicating that photon flux is a major control. These results demonstrate that CH(3)Hg(+) is decomposed in natural surface water by oxidants, apparently hydroxyl radical, generated from the photo Fenton reaction. PMID- 20704211 TI - Iron isotope fractionation during Fe uptake and translocation in alpine plants. AB - The potential of stable Fe isotopes as a tracer for the biogeochemical Fe cycle depends on the understanding and quantification of the fractionation processes involved. Iron uptake and cycling by plants may influence Fe speciation in soils. Here, we determined the Fe isotopic composition of different plant parts including the complete root system of three alpine plant species (Oxyria digyna, Rumex scutatus, Agrostis gigantea) in a granitic glacier forefield, which allowed us, for the first time, to distinguish between uptake and in-plant fractionation processes. The overall range of fractionation was 4.5 per thousand in delta(56)Fe. Mass balance calculations demonstrated that fractionation toward lighter Fe isotopic composition occurred in two steps during uptake: (1) before active uptake, probably during mineral dissolution and (2) during selective uptake of Fe at the plasma membrane with an enrichment factor of -1.0 to -1.7 per thousand for all three species. Iron isotopes were further fractionated during remobilization from old into new plant tissue, which changed the isotopic composition of leaves and flowers over the season. This study demonstrates the potential of Fe isotopes as a new tool in plant nutrition studies but also reveals challenges for the future application of Fe isotope signatures in soil plant environments. PMID- 20704212 TI - Uptake of pharmaceutical and personal care products by soybean plants from soils applied with biosolids and irrigated with contaminated water. AB - Many pharmaceuticals and personal care products (PPCPs) are commonly found in biosolids and effluents from wastewater treatment plants. Land application of these biosolids and the reclamation of treated wastewater can transfer those PPCPs into the terrestrial and aquatic environments, giving rise to potential accumulation in plants. In this work, a greenhouse experiment was used to study the uptake of three pharmaceuticals (carbamazepine, diphenhydramine, and fluoxetine) and two personal care products (triclosan and triclocarban) by an agriculturally important species, soybean (Glycine max (L.) Merr.). Two treatments simulating biosolids application and wastewater irrigation were investigated. After growing for 60 and 110 days, plant tissues and soils were analyzed for target compounds. Carbamazepine, triclosan, and triclocarban were found to be concentrated in root tissues and translocated into above ground parts including beans, whereas accumulation and translocation for diphenhydramine and fluoxetine was limited. The uptake of selected compounds differed by treatment, with biosolids application resulting in higher plant concentrations, likely due to higher loading. However, compounds introduced by irrigation appeared to be more available for uptake and translocation. Degradation is the main mechanism for the dissipation of selected compounds in biosolids applied soils, and the presence of soybean plants had no significant effect on sorption. Data from two different harvests suggest that the uptake from soil to root and translocation from root to leaf may be rate limited for triclosan and triclocarban and metabolism may occur within the plant for carbamazepine. PMID- 20704213 TI - Coatings to reduce wood preservative leaching. AB - The efficiency of semitransparent penetrating stains to reduce leaching of wood preservative components was evaluated. Five commercial wood deck finishes were applied to untreated and chromated copper arsenate (CCA), alkaline copper quat (ACQ), and copper azole (CA) treated wood, and leachates were collected and analyzed during 3 years of natural weathering exposure in Toronto, Canada. All stains evaluated effectively reduced the cumulative leaching of all inorganic preservative components by about 60% on average. Although most coatings showed significant film degradation starting around 12 months, the reduced leaching persisted even after 3 years. This suggests that temporary protection of wood with a coating during the early stages of use resulted in long-term reduction in preservative leaching potential. A two-week screening leaching test was able to predict the long-term leaching performance of different coatings reasonably well. Cured coating glass transition temperature (Tg) and liquid coating viscosity were the most important variables affecting a leaching prediction model. To effectively reduce leaching of preservative components from treated wood, coatings should have Tg low enough to withstand stresses caused by freezing in winter and have adequate viscosity to form a barrier film layer on the wood surface. PMID- 20704214 TI - Isotopic fractionation by transverse dispersion: flow-through microcosms and reactive transport modeling study. AB - Flow-through experiments were carried out to investigate the role of transverse dispersion on the isotopic behavior of an organic compound during conservative and bioreactive transport in a homogeneous porous medium. Ethylbenzene was selected as model contaminant and a mixture of labeled (perdeuterated) and light isotopologues was continuously injected in a quasi two-dimensional flow-through system. We observed a significant fractionation of ethylbenzene isotopologues during conservative transport at steady state. This effect was particularly pronounced at the plume fringe and contrasted with the common assumption that physical processes only provide a negligible contribution to isotope fractionation. Under the experimental steady state conditions, transverse hydrodynamic dispersion was the only process that could have caused the observed fractionation. Therefore, the measured isotope ratios at the outlet ports were interpreted with different parameterizations of the transverse dispersion coefficient. A nonlinear compound-specific parameterization showed the best agreement with the experimental data. Successively, bioreactive experiments were performed in two subsequent stages: a first oxic phase, involving a single strain of ethylbenzene degraders and a second phase with aerobic and anaerobic (i.e., ethylbenzene oxidation coupled to nitrate reduction) degradation. Significant fractionation through biodegradation occurred exclusively due to the metabolic activity of the anaerobic degraders. We performed analytical and numerical reactive transport simulations of the different experimental phases which confirmed that both the effects of physical processes (diffusion and dispersion) and microbially mediated reactions have to be considered to match the observed isotopic fractionation behavior. PMID- 20704215 TI - Glyoxal-methylglyoxal cross-reactions in secondary organic aerosol formation. AB - Glyoxal (G) and methylglyoxal (MG) are potentially important secondary organic aerosol (SOA) precursors. Previous studies of SOA formation by G and MG have focused on either species separately; however, G and MG typically coexist in the atmosphere. We studied the formation of secondary organic material in aqueous aerosol mimic mixtures containing G and MG with ammonium sulfate. We characterized the formation of light-absorbing products using UV-vis spectrophotometry. We found that absorption at 280 nm can be described well using models for the formation of light-absorbing products by G and MG in parallel. Pendant drop tensiometry measurements showed that surface tension depression by G and MG in these solutions can be modeled as a linear combination of the effects of G and MG alone. Product species were identified using chemical ionization mass spectrometry with a volatilization flow tube inlet (Aerosol CIMS). Peaks consistent with G-MG cross-reaction products were observed, accounting for a significant fraction of detected product mass, but most peaks could be attributed to self-reaction. We conclude that cross-reactions contribute to SOA mass from uptake of G and MG, but they are not required to accurately model the effects of this process on aerosol surface tension or light absorption. PMID- 20704216 TI - Remoteness from emission sources explains the fractionation pattern of polychlorinated biphenyls in the northern hemisphere. AB - The global distillation hypothesis states that fractionation patterns of persistent semivolatile chemicals in the environment are determined by the effect of spatially varying environmental temperature on the temperature-dependent phase partitioning coefficients of chemicals. Here, we use a model experiment and an analysis of monitoring data for polychlorinated biphenyls (PCBs) to explore an alternative hypothesis, the differential removal hypothesis, which proposes that fractionation results from different loss rates from the atmosphere, acting along a gradient of remoteness from emission sources. Model calculations for a range of PCB congeners demonstrate that fractionation occurs with distance from sources, regardless of the temperature gradient. We have assembled two independent data sets of PCB concentrations in European air that show fractionation, and quantified the remoteness of monitoring sites from PCB sources using the remoteness index, RI. Regression analysis of these empirical data against RI and temperature demonstrates that RI determines fractionation patterns. Based on this result, we calculate empirical effective residence times in air for a set of PCB congeners from the relationship between measured concentrations and RI. These empirical effective residence times agree well with values calculated by a multimedia mass balance model. Our conclusion from the model experiment and analysis of monitoring data is that temperature is not a driver of the fractionation of PCBs currently observed in European air, but rather that fractionation reflects differential removal from the atmosphere. PMID- 20704217 TI - Evaluation of tree bark as a passive atmospheric sampler for flame retardants, PCBs, and organochlorine pesticides. AB - To investigate the relationship between the levels of persistent organic pollutants in tree bark (a passive sampler) and those in air and precipitation, tree bark and air and precipitation samples were collected during the same time period at the five U.S. Integrated Atmospheric Deposition Network (IADN) sites located in Great Lakes basin. The concentrations of polybrominated diphenyl ethers, Dechlorane Plus, decabromodiphenyl ethane, polychlorinated biphenyls, DDTs, and chlordanes were measured in these samples. Overall, the pollutant concentrations in tree bark are significantly related to the concentrations of these compounds in the air and precipitation collected where the tree was growing. Generally, the highest tree bark and air pollutant concentrations were observed at urban sites, and the lowest concentrations were observed at remote sites. The overall correlation between bark and atmospheric and precipitation concentrations for all the compounds measured in this study was highly significant (P < 0.0001) over 3-4 orders of magnitude. In addition, bark-air partition coefficients, measured for all the chemical categories in this study, were about 10(6), which was in good agreement with previously estimated bark-air partition coefficients for corresponding pollutant groups. PMID- 20704218 TI - Quantifying factors limiting aerobic degradation during aerobic bioreactor landfilling. AB - A bioreactor landfill cell at Yolo County, California was operated aerobically for six months to quantify the extent of aerobic degradation and mechanisms limiting aerobic activity during air injection and liquid addition. The portion of the solid waste degraded anaerobically was estimated and tracked through time. From an analysis of in situ aerobic respiration and gas tracer data, it was found that a large fraction of the gas-filled pore space was in immobile zones where it was difficult to maintain aerobic conditions, even at relatively moderate landfill cell-average moisture contents of 33-36%. Even with the intentional injection of air, anaerobic activity was never less than 13%, and sometimes exceeded 65%. Analyses of gas tracer and respiration data were used to quantify rates of respiration and rates of mass transfer to immobile gas zones. The similarity of these rates indicated that waste degradation was influenced significantly by rates of oxygen transfer to immobile gas zones, which comprised 32-92% of the gas-filled pore space. Gas tracer tests might be useful for estimating the size of the mobile/immobile gas zones, rates of mass transfer between these regions, and the difficulty of degrading waste aerobically in particular waste bodies. PMID- 20704219 TI - Convergence-optimized procedure for applying the NICA-Donnan model to potentiometric titrations of humic substances. AB - Despite the high success of the NICA-Donnan (N-D) model to describe the interaction of protons and metal ions with natural organic matter, the large number of fit parameters is a major hindrance to its capacity to provide unique numerical solutions. This well-known difficulty is reflected in the unusually low value of the generic proton binding constant for carboxylic-type groups of fulvic acid (pK(H1) = 2.34), and to some extent of humic acid (2.93), and by the considerable covariance of the other generic N-D parameters. In some studies, the number of parameters obtained by regression is reduced by estimating some values independently with other techniques. Alternatively, the applicability of the model can be improved by devising a rigorous simulation procedure, which constrains the model-fit to converge toward chemically and physically realistic values. A procedure based on three successive iterations is proposed, and the solution is shown to be stable and invariant with the initial set of parameter values. The new generic parameters, in particular pK(H1)(FA) = 3.54 and pK(H1)(HA) = 3.87, derived from the same data set as the previous generic parameters, are in better agreement with literature data. PMID- 20704220 TI - Semianalytical model predicting transfer of volatile pollutants from groundwater to the soil surface. AB - Volatilization of toxic organic contaminants from groundwater to the soil surface is often considered an important pathway in risk analysis. Most of the risk models use simplified linear solutions that may overpredict the volatile flux. Although complex numerical models have been developed, their use is restricted to experienced users and for sites where field data are known in great detail. We present here a novel semianalytical model running on a spreadsheet that simulates the volatilization flux and vertical concentration profile in a soil based on the Van Genuchten functions. These widely used functions describe precisely the gas and water saturations and movement in the capillary fringe. The analytical model shows a good accuracy over several orders of magnitude when compared to a numerical model and laboratory data. The effect of barometric pumping is also included in the semianalytical formulation, although the model predicts that barometric pumping is often negligible. A sensitivity study predicts significant fluxes in sandy vadose zones and much smaller fluxes in other soils. Fluxes are linked to the dimensionless Henry's law constant H for H < 0.2 and increase by approximately 20% when temperature increases from 5 to 25 degrees C. PMID- 20704221 TI - Modeling hydroxyl radical distribution and trialkyl phosphates oxidation in UV H2O2 photoreactors using computational fluid dynamics. AB - Advanced Oxidation Processes (AOPs) promoted by ultraviolet light are innovative and potentially cost-effective solutions for treating persistent pollutants recalcitrant to conventional water and wastewater treatment. While several studies have been performed during the past decade to improve the fundamental understanding of the UV-H(2)O(2) AOP and its kinetic modeling, Computational Fluid Dynamics (CFD) has only recently emerged as a powerful tool that allows a deeper understanding of complex photochemical processes in environmental and reactor engineering applications. In this paper, a comprehensive kinetic model of UV-H(2)O(2) AOP was coupled with the Reynolds averaged Navier-Stokes (RANS) equations using CFD to predict the oxidation of tributyl phosphate (TBP) and tri(2-chloroethtyl) phosphate (TCEP) in two different photoreactors: a parallel- and a cross-flow UV device employing a UV lamp emitting primarily 253.7 nm radiation. CFD simulations, obtained for both turbulent and laminar flow regimes and compared with experimental data over a wide range of UV doses, enabled the spatial visualization of hydrogen peroxide and hydroxyl radical distributions in the photoreactor. The annular photoreactor displayed consistently better oxidation performance than the cross-flow system due to the absence of recirculation zones, as confirmed by the hydroxyl radical dose distributions. Notably, such discrepancy was found to be strongly dependent on and directly correlated with the hydroxyl radical rate constant becoming relevant for conditions approaching diffusion-controlled reaction regimes (k(C,OH) > 10(9) M( 1) s(-1)). PMID- 20704222 TI - Assessment of physical leaching processes of some elements in soil upon ingestion by continuous leaching and modeling. AB - The physical processes controlling the desorption of some elements (B, Cd, Co, Mn, Ni, and Sr) from soils in a continuous leaching system representing the human stomach are investigated here by fitting experimental leaching data to a mathematical particle diffusion model. Soil samples (50 mg) from Cornwall, UK, contained in a flow-through extraction chamber (ca. 6.5 mL) were intimately contacted with artificial gastric solution at various flow rates (0.42-1.42 mL min(-1)) for up to ca. 4 h, followed by analysis of the fractions collected with inductively coupled plasma mass spectrometry (ICP-MS). The leaching profiles of the various elements were fitted to a mathematical model incorporating two mass transfer processes (liquid film diffusion and apparent solid phase diffusion) to determine the effective external mass transfer coefficient (beta) and the apparent intraparticle soil diffusion coefficient (D(a)). A system of partial differential equations was solved numerically with a finite difference discretization of the computational domain allowing the rate limiting physical desorption process(es) for each element to be determined. The (thermodynamic) driving force of the leaching process is defined by the distribution coefficient (K(d0)) between soil and leachant. Although the K(d0) values investigated are very similar (ca. 6-15 L kg(-1)) for the elements studied with the exception of B (ca. 2.7 L kg(-1)), the leaching profiles are very different due to diffusion limited processes. The elements may be classified as limited by beta (B, Sr, and Cd), by D(a) (Co, and Mn) or by beta and D(a) (Ni). This results in quantifiable parameters for the liability of elements in soil upon ingestion which may be implemented in future risk assessment protocols. PMID- 20704223 TI - Susceptibility of human populations to environmental exposure to organic contaminants. AB - Environmental exposure to organic contaminants is a complex function of environmental conditions, food chain characteristics, and chemical properties. In this study the susceptibility of various human populations to environmental exposure to neutral organic contaminants was compared. An environmental fate model and a linked bioaccumulation model were parametrized to describe ecosystems in different climatic regions (temperate, arctic, tropical, and steppe). The human body burden resulting from constant emissions of hypothetical chemicals was estimated for each region. An exposure susceptibility index was defined as the body burden in the region of interest normalized to the burden of the same chemical in a reference human from the temperate region eating an average diet. For most persistent chemicals emitted to air, the Arctic had the highest susceptibility index (max 520). Susceptibility to exposure was largely determined by the food web properties. The properties of the physical environment only had a marked effect when air or water, not food, was the dominant source of human exposure. Shifting the mode of emission markedly changed the relative susceptibility of the ecosystems in some cases. The exposure arising from chemical use clearly varies between ecosystems, which makes an understanding of ecosystem susceptibility to exposure important for chemicals management. PMID- 20704224 TI - Effects of plug-in hybrid electric vehicles on ozone concentrations in Colorado. AB - This study explores how ozone concentrations in the Denver, CO area might have been different if plug-in hybrid electric vehicles (PHEVs) had replaced light duty gasoline vehicles in summer 2006. A unit commitment and dispatch model was used to estimate the charging patterns of PHEVs and dispatch power plants to meet electricity demand. Emission changes were estimated based on gasoline displacement and the emission characteristics of the power plants providing additional electricity. The Comprehensive Air Quality Model with extensions (CAMx) was used to simulate the effects of these emissions changes on ozone concentrations. Natural gas units provided most of the electricity used for charging PHEVs in the scenarios considered. With 100% PHEV penetration, nitrogen oxide (NO(x)) emissions were reduced by 27 tons per day (tpd) from a fleet of 1.7 million vehicles and were increased by 3 tpd from power plants; VOC emissions were reduced by 57 tpd. These emission changes reduced modeled peak 8-h average ozone concentrations by approximately 2-3 ppb on most days. Ozone concentration increases were modeled for small areas near central Denver. Future research is needed to forecast when significant PHEV penetration may occur and to anticipate characteristics of the corresponding power plant and vehicle fleets. PMID- 20704225 TI - Use of reactive tracers to determine ambient OH radical concentrations: application within the indoor environment. AB - The hydroxyl radical (OH) plays a key role in determining indoor air quality. However, its highly reactive nature and low concentration indoors impede direct analysis. This paper describes the techniques used to indirectly quantify indoor OH, including the development of a new method based on the instantaneous release of chemical tracers into the air. This method was used to detect ambient OH in two indoor seminar rooms following tracer detection by gas chromatography-mass spectrometry (GCMS). The results from these tests add to the small number of experiments that have measured indoor OH which are discussed with regard to future directions within air quality research. PMID- 20704226 TI - Transport and fate of methyl iodide and its pest control in soils. AB - For fumigants, information on transport and fate as well as pest control is needed to develop management practices with the fewest negative environmental effects while offering sufficient pest control efficacy. For this purpose, a 2-D soil chamber with a surface-mounted flux chamber was designed to determine volatilization, real-time soil gas-phase concentration, degradation, and organism survivability after methyl iodide (MeI) fumigation. Three types of pests were used to give a broad spectrum of pest control information. An infected sandy loam soil with a volumetric water content of 10.6% was packed carefully into the 2-D chamber to a bulk density of 1.34 g cm(-3). After MeI fumigation at a rate of 56.4 kg ha(-1) for 24 h, about 28.9% of MeI was emitted into air, 6.8% remained in the soil, and 43.6% degraded in the soil (based on the residual iodide concentration). The uncertainty in the measured MeI degradation using iodide concentration was thought to mainly contribute to the unrecovered MeI (about 20%). The citrus nematodes [Tylenchulus semipenetrans] were effectively eliminated even at low concentration-time (CT) values (<30 microg h mL(-1)), but all Fusarium oxysporum survived. The response of barnyardgrass seeds [Echinochloa crus-galli] spatially varied with the CT values in the chamber. To fully control barnyardgrass seeds, CT of greater than 300 microg h mL(-1) was required. Using this experimental approach, different fumigant emission reduction strategies can be tested, and mathematical models can be verified to determine which strategies produce the least emission to the atmosphere while maintaining sufficient pest control efficacy. PMID- 20704227 TI - Performance of PCR-based assays targeting Bacteroidales genetic markers of human fecal pollution in sewage and fecal samples. AB - There are numerous PCR-based assays available to characterize human fecal pollution in ambient waters. Each assay employs distinct oligonucleotides and many target different genes and microorganisms leading to potential variations in assay performance. Performance comparisons utilizing feces and raw sewage samples are needed to determine which assays are best suited for expensive and time consuming field validation, fate, transport, and epidemiology studies. We report the assessment of five end-point PCR and 10 real-time quantitative PCR (qPCR) assays that target genes from presumptive Bacteroidales microorganisms reported to be associated with human feces. Each assay was tested against a reference collection of 54 primary influent sewage samples collected from different geographical locations across the United States and 174 fecal DNA extracts from 23 different animal sources. Experiments indicate that human-associated genetic markers are distributed across a broad range of human populations but show substantial differences in specificity for human feces suggesting that particular assays may be more suitable than others depending on the abundance of genetic marker required for detection and the animal sources impacting a particular watershed or beach of interest. PMID- 20704228 TI - Sampling for PPCPs in wastewater systems: comparison of different sampling modes and optimization strategies. AB - The aim of this study was to assess uncertainties associated with different sampling modes when evaluating loads of pharmaceuticals and personal care products (PPCPs) in sewers and influents to sewage treatment plants (STPs). The study demonstrates that sampling uncertainty can range from "not significant" to "far greater than the uncertainty due to chemical analysis", which is site- and compound-specific and depends on the (in)accuracy of the analytical method. Conventional sampling devices operated in common time- or flow-proportional sampling modes, and applying traditional sampling intervals of 30 min or longer can result in the collection of nonrepresentative samples. At the influent of a STP, wastewater may appear as a continuous stream, but it is actually composed of a number of intermittently discharged, individual wastewater packets from household appliances, industries, or subcatchments in pressurized sewer systems. The resulting heterogeneity can cause significant short-term variations of pollutant loads. We present different experimental results and a modeling approach showing that the magnitude of sampling uncertainty depends mainly on the number of pollutant peaks and the sampling frequency; sampling intervals of 5 min or shorter may be required to properly account for temporal PPCP variations in influents of STPs. A representative sample is a prerequisite for providing meaningful analytical results and cannot be compensated with a large number of samples, accurate chemical analysis, or sophisticated statistical evaluation. This study highlights that generalizing from one case to another is difficult and hence a careful systems analysis of the catchment under investigation, or precautionary choice for a sophisticated sampling mode, is necessary to prove reproducibility. PMID- 20704229 TI - Estimation of daily intake of organohalogenated contaminants from food consumption and indoor dust ingestion in Romania. AB - We estimated human exposure to organohalogenated contaminants (OHCs), including organochlorine pesticides (OCPs), such as hexachlorocyclohexanes (HCHs), DDT and metabolites, hexachlorobenzene, and chlordanes, but also polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and hexabromocyclododecane (HBCD), through food consumption (mainly food of animal origin) and indoor dust ingestion in Romania. A total of 71 food samples (meat, diary products, vegetable cooking oil, and eggs from urban supermarkets and rural areas) and 18 indoor dust samples were collected from Iasi, Eastern Romania. HCHs and DDTs were the most prevalent OCPs in both food and dust samples. Higher levels of OCPs were measured in food samples collected from rural areas compared to those from urban supermarkets, except milk-based products for which no significant differences could be recorded. However, levels of contamination with HCHs in milk-based products were occasionally higher than current European maximum residue levels (MRLs). Above-MRL levels of DDTs were also recorded in eggs from rural areas. In dust, DDTs (median concentration of 1050 ng/g) were the most prevalent contaminants and p,p'-DDT was consistently the main contributor of sum DDTs, with a contribution between 50 and 75%. Surprisingly, OCPs, mainly DDT, were found at elevated levels in indoor dust samples (median concentrations for sum OCPs of 1200 ng/g dust). This suggests the importance of dust as an exposure route for pesticides (especially at contaminated sites), since dust is not commonly considered in exposure assessments for these chemicals. The main contributor to the sum PBDEs in dust samples was BDE 209 (median concentration of 495 ng/g), with a contribution between 94 and 99%. We estimated that the dietary intake of SigmaHCHs and SigmaDDTs is high for both adults (1500-2100 ng/day) and toddlers (1100-1500 ng/day), while the PCB dietary intake was estimated at 200 ng/day for adults, being compared to other European studies. The contribution of dust ingestion to the daily intake of PBDEs is increased in comparison to intake of other chlorinated contaminants, while food consumption seems to be more important than dust for the HBCD intake. However, neither BDE 209 nor HBCD were measured at levels above method LOQ in any food samples and their dietary intake is probably overestimated because nondetects were replaced by (1)/(2) LOQ. The estimated intakes obtained in the present study are in good agreement with the higher concentrations of OCPs and the low levels of PBDEs reported recently in Romanian human samples. PMID- 20704230 TI - Improving load estimates for NO3 and P in surface waters by characterizing the concentration response to rainfall events. AB - For the evaluation of action programs to reduce surface water pollution, water authorities invest heavily in water quality monitoring. However, sampling frequencies are generally insufficient to capture the dynamical behavior of solute concentrations. For this study, we used on-site equipment that performed semicontinuous (15 min interval) NO(3) and P concentration measurements from June 2007 to July 2008. We recorded the concentration responses to rainfall events with a wide range in antecedent conditions and rainfall durations and intensities. Through sequential linear multiple regression analysis, we successfully related the NO(3) and P event responses to high-frequency records of precipitation, discharge, and groundwater levels. We applied the regression models to reconstruct concentration patterns between low-frequency water quality measurements. This new approach significantly improved load estimates from a 20% to a 1% bias for NO(3) and from a 63% to a 5% bias for P. These results demonstrate the value of commonly available precipitation, discharge, and groundwater level data for the interpretation of water quality measurements. Improving load estimates from low-frequency concentration data just requires a period of high-frequency concentration measurements and a conceptual, statistical, or physical model for relating the rainfall event response of solute concentrations to quantitative hydrological changes. PMID- 20704231 TI - Evolution of hierarchical hexagonal stacked plates of CuS from liquid-liquid interface and its photocatalytic application for oxidative degradation of different dyes under indoor lighting. AB - Blue solution of copper(II) acetylacetonate complex, [Cu(acac)(2)] in dichloromethane (DCM) and an aqueous alkaline solution of thioacetamide (TAA) constitute a biphasic system. The system in a screw cap test tube under a modified hydrothermal (MHT) reaction condition produces a greenish black solid at the liquid-liquid interface. It has been characterized that the solid mass is an assembly of hexagonal copper sulfide (CuS) nanoplates representing a hierarchical structure. The as-synthesized CuS nanoplates are well characterized by several physical techniques. An ethanolic dispersion of CuS presents a high band gap energy (2.2 eV) which assists visible light photocatalytic mineralization of different dye molecules. Thus a cleanup measure of dye contaminated water body even under indoor light comes true. PMID- 20704232 TI - Evaluating adsorption and biodegradation mechanisms during the removal of microcystin-RR by periphyton. AB - Microcystin-RR (MCRR) is among the cyanobacterial toxins of significant concern due to their negative effects on water quality and human health. In this study, periphyton dominated by bacteria and diatoms was applied to remove MCRR from water. The maximum removal rate of MCRR by periphyton was observed in the first day (the latent adaptation period). Within this period, 85.2%, 73.3%, 83.5%, and 86.5% of the total MCRR removed (through adsorption and biodegradation) was by the adsorption of periphyton when the periphyton biomasses were 1.32 g, 3.96 g, 6.60 g, and 9.24 g, respectively. The amount of MCRR adsorbed increased with the increasing ratio of periphyton biomass to MCRR in solution. The adsorption process fitted well to the Freundlich, Langmuir, and Dubinin-Radushkevich (D-R) models, implying that the bioadsorption process has mechanistic relevance. The MCRR adsorption by periphyton is physical in nature and thermodynamically spontaneous. This study provided strong evidence that adsorption was the main mechanism for the removal of MCRR and other microcystins by periphyton and similar microbial aggregates in the latent adaptation period. Thereafter, biodegradation of periphyton dominated the toxin removal process. These results show that periphyton can be employed for an environmentally benign and effective solution for MCRR removal. PMID- 20704233 TI - Electrochemically enhanced removal of polycyclic aromatic basic dyes from dilute aqueous solutions by activated carbon cloth electrodes. AB - Open-circuit (OC) adsorption and electrosorption behaviors of three polycyclic aromatic dyes from dilute aqueous solutions onto activated carbon cloth (ACC) were investigated. The selected dyes were crystal violet (BB-3), basic blue7 (BB 7), and basic blue11 (BB-11). OC adsorption and electrosorption processes were monitored by in situ UV-visible spectrophotometry. Electrosorption was carried out by polarization of an ACC electrode, galvanostatically. Considerable enhancements in removal capacity and duration of the dyes were achieved upon polarization of ACC. Kinetic data for OC adsorption and electrosorption were successfully treated according to pseudo-first-order law, and rate constants were determined. Adsorption isotherms were derived, and the data were treated according to Langmuir and Freundlich equations. Both the rate and extent of adsorption and electrosorption of dyes were found to increase in the order of BB 7 < BB-11 < BB-3. This order was discussed in terms of correlation between sizes of dye species and of ACC pores. Electrodesorption experiments were carried out to explore possibilities of regeneration of ACC. PMID- 20704234 TI - Biodegradation of dieldrin by a soil fungus isolated from a soil with annual endosulfan applications. AB - An aerobic dieldrin-degrading fungus, Mucor racemosus strain DDF, was isolated from a soil to which endosulfan had been annually applied for more than 10 years until 2008. Strain DDF degraded dieldrin to 1.01 microM from 14.3 microM during a 10-day incubation at 25 degrees C. Approximately 0.15 microM (9%) of aldrin trans diol was generated from the dieldrin degradation after a 1-day incubation. The degradation of dieldrin by strain DDF was detected over a broad range of pH and concentrations of glucose and nitrogen sources. Extracellular fluid without mycelia also degraded dieldrin. Strain DDF degraded not only dieldrin but also heptachlor, heptachlor epoxide, endosulfan, endosulfan sulfate, DDT, and DDE. Endosulfan sulfate and heptachlor were degraded by 0.64 microM (95%) and 0.75 microM (94%), respectively, whereas endosulfan and DDE were degraded by 2.42 microM (80%) and 3.29 microM (79%), respectively, and DDT and heptachlor epoxide were degraded by 6.95 microM (49.3%) and 5.36 microM (67.5%), respectively, compared with the control, which had a concentration of approximately 14 microM. These results suggest that strain DDF could be a candidate for the bioremediation of sites contaminated with various persistent organochlorine pesticides including POPs. PMID- 20704235 TI - Virus removal by biogenic cerium. AB - The rare earth element cerium has been known to exert antifungal and antibacterial properties in the oxidation states +III and +IV. This study reports on an innovative strategy for virus removal in drinking water by the combination of Ce(III) on a bacterial carrier matrix. The biogenic cerium (bio-Ce) was produced by addition of aqueous Ce(III) to actively growing cultures of either freshwater manganese-oxidizing bacteria (MOB) Leptothrix discophora or Pseudomonas putida MnB29. X-ray absorption spectroscopy results indicated that Ce remained in its trivalent state on the bacterial surface. The spectra were consistent with Ce(III) ions associated with the phosphoryl groups of the bacterial cell wall. In disinfection assays using a bacteriophage as model, it was demonstrated that bio-Ce exhibited antiviral properties. A 4.4 log decrease of the phage was observed after 2 h of contact with 50 mg L(-1) bio-Ce. Given the fact that virus removal with 50 mg L(-1) Ce(III) as CeNO(3) was lower, the presence of the bacterial carrier matrix in bio-Ce significantly enhanced virus removal. PMID- 20704236 TI - Matching different inorganic compounds as mixture of electron donors to improve CO2 fixation by nonphotosynthetic microbial community without hydrogen. AB - The dominant bacteria in nonphotosynthetic microbial community (NPMC) isolated from the ocean were identified by PCR-DGGE. The results revealed that the dominant microorganisms in cultures of NPMC differed when Na(2)S, Na(2)S(2)O(3), and NaNO(2) were used as the electron donor to reduce CO(2). These findings implied that different microorganisms in the NPMC respond to different inorganic compound as suitable electron donor, indicating that matching of Na(2)S, Na(2)S(2)O(3), and NaNO(2) may provide mixed electron donors that increase the ability of NPMC to fix CO(2). Accordingly, the central composite response surface method (RSM) was used to predict the optimal concentration and match of Na(2)S, Na(2)S(2)O(3), and NaNO(2) as mixed electron donors to improve CO(2) fixation efficiency under aerobic and anaerobic conditions without hydrogen. The results indicated that 0.46% NaNO(2), 0.50% Na(2)S(2)O(3), and 1.25% Na(2)S were the optimal match under aerobic conditions, while 1.04% NaNO(2), 1.07% Na(2)S(2)O(3), and 0.98% Na(2)S were the optimal match under anaerobic conditions. Under these conditions, the fixed CO(2) by NPMC was determined to be 387.51 and 512.57 mg/L, respectively, which obviously exceeded those values obtained prior to optimization (5.94 and 7.14 mg/L, respectively), as well as that obtained when hydrogen was used as the electron donor (91.60 mg/L). PMID- 20704237 TI - Breakage and regrowth of Al-humic flocs--effect of additional coagulant dosage. AB - The growth, breakage and regrowth of flocs formed by aluminum sulfate (alum) with humic acid (HA) in water at neutral pH was investigated by jar testing with continuous optical monitoring. Various initial dosages of alum and different breakage shears were investigated to compare the floc strengths and to explore the growth of flocs and regrowth of broken flocs. In all cases there was significant irreversibility of floc breakage when no additional coagulant was added. On the other hand, when a small additional dosage of alum was added to the suspension during floc breakage, the size of regrown flocs was higher than that before breakage. The result did not change with the variation of the initial dosage of alum, and the intensity and duration of floc breakage, provided that the additional coagulant was added shortly before the end of the breakage process. It seems that aluminum hydroxide is better able to form flocs, when newly precipitated, rather than after an extended period of high shear. PMID- 20704238 TI - Adsorption of aromatic compounds by carbonaceous adsorbents: a comparative study on granular activated carbon, activated carbon fiber, and carbon nanotubes. AB - Adsorption of three aromatic organic compounds (AOCs) by four types of carbonaceous adsorbents [a granular activated carbon (HD4000), an activated carbon fiber (ACF10), two single-walled carbon nanotubes (SWNT, SWNT-HT), and a multiwalled carbon nanotube (MWNT)] with different structural characteristics but similar surface polarities was examined in aqueous solutions. Isotherm results demonstrated the importance of molecular sieving and micropore effects in the adsorption of AOCs by carbonaceous porous adsorbents. In the absence of the molecular sieving effect, a linear relationship was found between the adsorption capacities of AOCs and the surface areas of adsorbents, independent of the type of adsorbent. On the other hand, the pore volume occupancies of the adsorbents followed the order of ACF10 > HD4000 > SWNT > MWNT, indicating that the availability of adsorption site was related to the pore size distributions of the adsorbents. ACF10 and HD4000 with higher microporous volumes exhibited higher adsorption affinities to low molecular weight AOCs than SWNT and MWNT with higher mesopore and macropore volumes. Due to their larger pore sizes, SWNTs and MWNTs are expected to be more efficient in adsorption of large size molecules. Removal of surface oxygen-containing functional groups from the SWNT enhanced adsorption of AOCs. PMID- 20704239 TI - Fe2O3-pillared rectorite as an efficient and stable Fenton-like heterogeneous catalyst for photodegradation of organic contaminants. AB - An efficient Fe(2)O(3)-pillared rectorite (Fe-R) clay was successfully developed as a heterogeneous catalyst for photo-Fenton degradation of organic contaminants. X-ray diffraction analysis and high-resolution transmission electron microscope analysis clearly showed the existence of the Fe(2)O(3) nanoparticles in the Fe-R catalyst. The catalytic activity of the Fe-R catalyst was evaluated by the discoloration and chemical oxygen demand (COD) removal of an azo-dye rhodamine B (RhB, 100 mg/L) and a typical persistent organic pollutant 4-nitrophenol (4-NP, 50 mg/L) in the presence of hydrogen peroxide (H(2)O(2)) under visible light irradiation (lambda > 420 nm). It was found that the discoloration rate of the two contaminants was over 99.3%, and the COD removal rate of the two contaminants was over 87.0%. The Fe-R catalyst showed strong adsorbability for the RhB in the aqueous solution. Moreover, the Fe-R catalyst still showed good stability for the degradation of RhB after five recycles. Zeta potential and Fourier transform infrared spectroscopy were used to examine the photoreaction processes. Finally, a possible photocatalytic mechanism was proposed. PMID- 20704240 TI - Impact of plastics on fate and transport of organic contaminants in landfills. AB - Factors controlling organic contaminant sorption to common plastics in municipal solid waste were identified. Consumer plastics [drinking water container, prescription drug bottle, soda bottle, disposable cold cup, computer casing, furniture foam, carpet, vinyl flooring, formica sheet] and model polymers [high density polyethylene (HDPE), medium-density polyethylene, low-density polyethylene, poly(vinyl chloride) (PVC)] were characterized by X-ray diffractometry, differential scanning calorimetry, and elemental analysis. The material characterization was used to interpret batch isotherm and kinetic data. K(p) values describing toluene sorption to rubbery or "soft" polymers could be normalized by the amorphous polymer fraction (f(amorphous)) but not by the organic carbon fraction (f(oc)). Diffusion coefficients (D) describing the uptake rate of toluene by rubbery plastics (HDPE, drinking water container, prescription drug bottle) were similar (D approximately 10(-10) cm(2)/s), indicating that pure HDPE can be used as a model for rubbery plastics. Toluene diffusivity was similar among glassy or "hard" plastics (PVC, soda bottle, computer casing, disposable cold cup; D approximately 10(-12) cm(2)/s) but lower than for rubbery plastics. Plastics in landfills are potential sinks of hydrophobic organic contaminants (HOCs) because of their higher affinity for HOCs compared to lignocellulosic materials and the slow desorption of HOCs from glassy plastics. PMID- 20704241 TI - Uptake and translocation of CuEDDS complexes by Brassica carinata. AB - The knowledge of the mechanisms that underlie metal complex uptake may lead to the development of new strategies for enhancing metal phytoextraction. As metals such as copper are actively taken up by roots, by inhibiting the proton driving force it is possible to obtain preliminary indications on the metal complex uptake mechanism. For this, Cu, EDDS, and Cu-EDDS uptake kinetics of Brassica carinata excised roots incubated in 30 and 150 microM solutions of either the metal, the chelant, and the complex were determined in the presence or not of the ATPase inhibitor vanadate. Following both Cu and CuEDDS treatments, metal uptake was negatively influenced by vanadate, whereas EDDS uptake did not, suggesting that Cu and the chelant did not enter the roots in their complexed form but by two different routes. The incubation in the same solutions of B. carinata intact plants showed that, differently from Cu, EDDS was largely translocated to shoots, but its low concentration resulted in a Cu to EDDS molar ratio ranging from 2 to 4 depending on metal complex concentration in the solution confirming that the uptake pathways of the two compounds were different. PMID- 20704242 TI - Black carbon-mediated destruction of nitroglycerin and RDX by hydrogen sulfide. AB - The in situ remediation of sediments contaminated with explosives, including nitroglycerin and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), is desirable, particularly at bombing ranges where unexploded ordnance (UXO) renders excavation dangerous. Sulfides generated by biological sulfate reduction in sediments are potent nucleophiles and reductants that may contribute to the destruction of explosives. However, moderately hydrophobic explosives are likely to sorb to black carbons, which can constitute 10-30% of sediment organic carbon. In this study, we evaluated whether the black carbons accelerate these reactions or simply sequester explosives from aqueous phase reactions. Using environmentally relevant sulfide and black carbon concentrations, our results indicated that black carbons accelerated the destruction of both compounds, yielding relatively harmless products on the time scale of hours. For both compounds, destruction increased with sulfide and graphite concentrations. Using sheet graphite as a model for graphene regions in black carbons, we evaluated whether graphene regions mediated the reduction of explosives by promoting electron transfer from sulfides. Our results demonstrated that the process was more complex. Using an electrochemical cell that enabled electron transfer from sulfides to explosives through graphite, but prevented nucleophilic substitution reactions, we found that nitroglycerin destruction, but not RDX destruction, could be explained by an electron transfer mechanism. Furthermore, surface area-normalized destruction rates for the same explosive varied for different black carbons. While black carbon-mediated destruction of explosives by sulfides is likely to be a significant contributor to their natural attenuation in sediments, a fundamental characterization of the reaction mechanisms is needed to better understand the process. PMID- 20704243 TI - Oxidation kinetics of antibiotics during water treatment with potassium permanganate. AB - The ubiquitous occurrence of antibiotics in aquatic environments raises concerns about potential adverse effects on aquatic ecology and human health, including the promotion of increased antibiotic resistance. This study examined the oxidation of three widely detected antibiotics (ciprofloxacin, lincomycin, and trimethoprim) by potassium permanganate [KMnO(4); Mn(VII)]. Reaction kinetics were described by second-order rate laws, with apparent second-order rate constants (k(2)) at pH 7 and 25 degrees C in the order of 0.61 +/- 0.02 M(-1) s( 1) (ciprofloxacin) < 1.6 +/- 0.1 M(-1) s(-1) (trimethoprim) < 3.6 +/- 0.1 M(-1) s(-1) (lincomycin). Arrhenius temperature dependence was observed with apparent activation energies (E(a)) ranging from 49 kJ mol(-1) (trimethoprim) to 68 kJ mol(-1) (lincomycin). Rates of lincomycin and trimethoprim oxidation exhibited marked pH dependences, whereas pH had only a small effect on rates of ciprofloxacin oxidation. The effects of pH were quantitatively described by considering parallel reactions between KMnO(4) and individual acid-base species of the target antibiotics. Predictions from a kinetic model that included temperature, KMnO(4) dosage, pH, and source water oxidant demand as input parameters agreed reasonably well with measurements of trimethoprim and lincomycin oxidation in six drinking water utility sources. Although Mn(VII) reactivity with the antibiotics was lower than that reported for ozone and free chlorine, its high selectivity and stability suggests a promising oxidant for treating sensitive micropollutants in organic-rich matrices (e.g., wastewater). PMID- 20704244 TI - Mechanism of base activation of persulfate. AB - Base is the most commonly used activator of persulfate for the treatment of contaminated groundwater by in situ chemical oxidation (ISCO). A mechanism for the base activation of persulfate is proposed involving the base-catalyzed hydrolysis of persulfate to hydroperoxide anion and sulfate followed by the reduction of another persulfate molecule by hydroperoxide. Reduction by hydroperoxide decomposes persulfate into sulfate radical and sulfate anion, and hydroperoxide is oxidized to superoxide. The base-catalyzed hydrolysis of persulfate was supported by kinetic analyses of persulfate decomposition at various base:persulfate molar ratios and an increased rate of persulfate decomposition in D(2)O vs H(2)O. Stoichiometric analyses confirmed that hydroperoxide reacts with persulfate in a 1:1 molar ratio. Addition of hydroperoxide to basic persulfate systems resulted in rapid decomposition of the hydroperoxide and persulfate and decomposition of the superoxide probe hexachloroethane. The presence of superoxide was confirmed with scavenging by Cu(II). Electron spin resonance spectroscopy confirmed the generation of sulfate radical, hydroxyl radical, and superoxide. The results of this research are consistent with the widespread reactivity reported for base-activated persulfate when it is used for ISCO. PMID- 20704245 TI - Adsorption of monoaromatic compounds and pharmaceutical antibiotics on carbon nanotubes activated by KOH etching. AB - The relatively low surface area and micropore volume of carbon nanotubes limit their potential application as effective adsorbents for hydrophobic organic contaminants. In this study, KOH dry etching was explored to prepare activated single-walled carbon nanotubes (SWNT) and multiwalled carbon nanotubes (MWNT) for adsorption of model monoaromatic compounds (phenol and nitrobenzene) and pharmaceutical antibiotics (sulfamethoxazole, tetracycline, and tylosin) in aqueous solutions. With activation, the specific surface area was increased from 410.7 m(2)/g to 652.8 m(2)/g for SWNT and from 157.3 m(2)/g to 422.6 m(2)/g for MWNT, and substantial pore volumes were created for the activated samples. Consistently, adsorption of the test solutes was enhanced 2-3 times on SWNT and 3 8 times on MWNT. Moreover, the activated carbon nanotubes showed improved adsorption reversibility for the selected monoaromatics, as compared with the pristine counterparts, which was attributed to the more interconnected pore structure and less pore deformation of the activated adsorbents. This is the first study on the adsorption/desorption of aqueous organic contaminants by KOH activated carbon nanotubes. The findings indicate that KOH etching is a useful activation method to improve the adsorption affinity and adsorption reversibility of organic contaminants on carbon nanotubes. PMID- 20704246 TI - Eutrophication potential of food consumption patterns. AB - Although the environmental impacts and carbon footprints of foods are gaining more public attention and scientific debate, few studies have systematically evaluated the life cycle nitrogen and phosphorus flows among different food types. Disruption of natural nitrogen and phosphorus cycles already result in serious environmental quality degradation and economic losses, such as loss of fisheries due to hypoxia in the Gulf of Mexico. This study characterizes the nutrient flows during food production, processing, packaging, and distribution stages for eight food types; compares carbon footprints and nitrogen equivalent footprints of food groups; evaluates solutions to reduce excessive nitrogen outputs; and estimates effectiveness and efficiency of possible solutions. Different food groups exhibit a highly variable nitrogen-intensity; on average, red meat and dairy products require much more nitrogen than cereals/carbohydrates. The ranking of foods' nitrogen footprints is not consistent with their carbon footprints. For example, dairy products and chicken/eggs have relatively high nitrogen footprint and low carbon footprints. Finally, the study evaluates shifting food consumption patterns. Dietary shifts from dairy products and red meat to cereals can be an effective approach for lowering the personal nitrogen footprint. PMID- 20704247 TI - Outlook of the world steel cycle based on the stock and flow dynamics. AB - We present a comprehensive analysis of steel use in the future compiled using dynamic material flow analysis (MFA). A dynamic MFA for 42 countries depicted the global in-use stock and flow up to the end of 2005. On the basis of the transition of steel stock for 2005, the growth of future steel stock was then estimated considering the economic growth for every country. Future steel demand was estimated using dynamic analysis under the new concept of "stocks drive flows". The significant results follow. World steel stock reached 12.7 billion t in 2005, and has doubled in the last 25 years. The world stock in 2005 mainly consisted of construction (60%) and vehicles (10%). Stock in these end uses will reach 55 billion t in 2050, driven by a 10-fold increase in Asia. Steel demand will reach 1.8 billion t in 2025, then slightly decrease, and rise again by replacement of buildings. The forecast of demand clearly represents the industrial shift; at first the increase is dominated by construction, and then, after 2025, demand for construction decreases and demand for vehicles increases instead. This study thus provides the dynamic mechanism of steel stock and flow toward the future, which contributes to the design of sustainable steel use. PMID- 20704248 TI - Wasted food, wasted energy: the embedded energy in food waste in the United States. AB - This work estimates the energy embedded in wasted food annually in the United States. We calculated the energy intensity of food production from agriculture, transportation, processing, food sales, storage, and preparation for 2007 as 8080 +/- 760 trillion BTU. In 1995 approximately 27% of edible food was wasted. Synthesizing these food loss figures with our estimate of energy consumption for different food categories and food production steps, while normalizing for different production volumes, shows that 2030 +/- 160 trillion BTU of energy were embedded in wasted food in 2007. The energy embedded in wasted food represents approximately 2% of annual energy consumption in the United States, which is substantial when compared to other energy conservation and production proposals. To improve this analysis, nationwide estimates of food waste and an updated estimate for the energy required to produce food for U.S. consumption would be valuable. PMID- 20704249 TI - Sustainable biodegradation of phenol by Acinetobacter calcoaceticus P23 isolated from the rhizosphere of duckweed Lemna aoukikusa. AB - Phenol-degrading bacteria were isolated from the rhizosphere of duckweed (Lemna aoukikusa) using an enrichment culture method. One of the isolates, P23, exhibited an excellent ability to degrade phenol and attach to a solid surface under laboratory conditions. Phylogenetic analysis revealed that P23 belongs to the genera Acinetobacter and has the highest similarity to Acinetobacter calcoaceticus. P23 rapidly colonized on the surface of sterilized duckweed roots and formed biofilms, indicating that the conditions provided by the root system of duckweed are favorable to P23. A long-term performance test (160 h) showed that continuous removal of phenol can be attributed to the beneficial symbiotic interaction between duckweed and P23. P23 is the first growth-promoting bacterium identified from Lemna aoukikusa. The results in this study suggest the potential usefulness of dominating a particular bacterium in the rhizosphere of duckweeds to achieve efficient and sustainable bioremediation of polluted water. PMID- 20704250 TI - Environmental reservoirs for enterotoxigenic Escherichia coli in south Asian Gangetic riverine system. AB - Forecasting diarrheagenic E. coli contamination of aquatic resources to prevent outbreaks largely depends on rapid and accurate diagnostic testing in a few hours. Real-time PCR is widely used for quick culture-free quantitative enumeration of pathogenic bacteria in environmental samples. In this study, real time PCR in molecular beacon format was used for detection and culture-free quantitative enumeration of enterotoxigenic Escherichia coli (ETEC) harboring LT1 gene in a sewage-impacted south Asian Gangetic riverine system. The quantitative budget for ETEC in surface water was observed to vary significantly (DMRT, p < 0.05) among the sites. Aquatic flora (Eichhornia crassipes, Potamogeton crispus, Potamogeton pectinatus, Ranunculus sceleratus, Polygonum glabrum, Pontederia cordata, Najas indica and strands of Spirogyra spp.) collected between sites 1 and 9 exhibited significant high levels of ETEC in comparison to their representatives collected from pristine area. The level of ETEC harboring LT1 gene observed in leafy vegetables cultivated along the banks was in the following order: mint leaves > coriander > spinach > methi leaves. The study suggests that the aquatic flora and cultivated leafy vegetables in the south Asian Gangetic riverine system are environmental reservoirs for enterotoxigenic Escherichia coli. PMID- 20704251 TI - Impacts of early life exposure to estrogen on subsequent breeding behavior and reproductive success in zebrafish. AB - Impacts of exposure to environmental estrogens on reproductive development are well documented, but recently wider concern has been raised due to evidence that such exposures can disrupt normal patterns of reproductive behavior, dominance, and parentage, with potential population level implications. It is fundamental therefore to understand any such effects for effective risk assessment. This study investigated the impact of a transient exposure to ethinylestradiol (EE(2)) during early life (from 20-60 days post fertilization), including at a dosing level within the environmental range, on the subsequent reproductive behavior and success in both male and female zebrafish (Danio rerio) in competitive breeding scenarios. There were no obvious effects of the early life EE(2) exposures on the subsequent gonadal phenotypes in either mature males or females. In fact, reproductive success in males exposed to 2.76 ng EE(2)/L was increased in competitive spawning scenarios. In contrast, exposure of females to EE(2) (9.86 ng/L) during early life reduced their subsequent reproductive success in competitive spawning scenarios. Mate choice experiments suggested this was a consequence of the females' diminished courting behavior toward males, rather than any male preference for unexposed females. Reproductive capability of females is generally considered a key determinant in population demographics and dynamics, and therefore the effect of exposure to EE(2) on female reproductive success may have significant implications for exposed fish populations. PMID- 20704252 TI - Effect of secondary phase formation on the carbonation of olivine. AB - Large-scale olivine carbonation has been proposed as a potential method for sequestering CO(2) emissions. For in situ carbonation techniques, understanding the relationship between the formation of carbonate and other phases is important to predict the impact of possible passivating layers on the reaction. Therefore, we have conducted reactions of olivine with carbonated saline solutions in unstirred batch reactors. Altering the reaction conditions changed the Mg carbonate morphology. We propose that this corresponded to changes in the ability of the system to precipitate hydromagnesite or magnesite. During high-temperature reactions (200 degrees C), an amorphous silica-enriched phase was precipitated that was transformed to lizardite as the reaction progressed. Hematite was also precipitated in the initial stages of these reactions but dissolved as the reaction proceeded. Comparison of the experimental observations with reaction models indicates that the reactions are governed by the interfacial fluid composition. The presence of a new Mg-silicate phase and the formation of secondary products at the olivine surface are likely to limit the extent of olivine to carbonate conversion. PMID- 20704253 TI - Comment on "Surface complexation of catechol to metal oxides: an ATR-FTIR, adsorption, and dissolution study". PMID- 20704255 TI - Comment on "Prescribed fire as a means of reducing forest carbon emissions in the western United States". PMID- 20704258 TI - Molecular and structural analysis of mosaic variants of penicillin-binding protein 2 conferring decreased susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae: role of epistatic mutations. AB - Mutations in penicillin-binding protein 2 (PBP 2) encoded by mosaic penA alleles are crucial for intermediate resistance to the expanded-spectrum cephalosporins ceftriaxone and cefixime in Neisseria gonorrhoeae. Three of the ~60 mutations present in mosaic alleles of penA, G545S, I312M, and V316T, have been reported to be responsible for increased resistance, especially to cefixime [Takahata, S., et al. (2006) Antimicrob. Agents Chemother. 50, 3638-3645]. However, we observed that the minimum inhibitory concentrations (MICs) of penicillin, ceftriaxone, and cefixime for a wild-type strain (FA19) containing a penA gene with these three mutations increased only 1.5-, 1.5-, and 3.5-fold, respectively. In contrast, when these three mutations in a mosaic penA allele (penA35) were reverted back to the wild type and the gene was transformed into FA19, the MICs of the three antibiotics were reduced to near wild-type levels. Thus, these three mutations display epistasis, in that their capacity to increase resistance to beta-lactam antibiotics is dependent on the presence of other mutations in the mosaic alleles. We also identified an additional mutation, N512Y, that contributes to the decreased susceptibility to expanded-spectrum cephalosporins. Finally, we investigated the effects of a mutation (A501V) currently found only in nonmosaic penA alleles on decreased susceptibility to ceftriaxone and cefixime, with the expectation that this mutation may arise in mosaic alleles. Transfer of the mosaic penA35 allele containing an A501V mutation to FA6140, a chromosomally mediated penicillin-resistant isolate, increased the MICs of ceftriaxone (0.4 MUg/mL) and cefixime (1.2 MUg/mL) to levels above their respective break points. The proposed structural mechanisms of these mutations are discussed in light of the recently published structure of PBP 2. PMID- 20704260 TI - Simple solid-phase synthesis and biological properties of carbohydrate oligonucleotide conjugates modified at the 3'-terminus. AB - A novel synthesis method for oligonucleotides possessing a functional moiety at the 3'-terminus was established based on solid-phase synthesis. In order to install the functional group at the 3'-terminus of the oligonucleotide, a solid support possessing the functional group was prepared. A carbohydrate was employed in this study for the functionalization of the oligonucleotide. To prepare a glycosylated solid support, a novel glycosyl acceptor (2) was synthesized using 4,4-dihydroxymethyl-cyclopenta-1-ene as the starting compound. The glycosylation reaction proceeded smoothly (yield = 95%) to yield the suitable glycosylated compound (3). After 8 was immobilized on the solid support, it was subjected to solid-phase oligonucleotide synthesis by the standard phosphoramidite coupling method. An oligonucleotide possessing a sugar moiety at the 3'-terminus was obtained after the products were deprotected and cleaved from the solid support. The stability of the carbohydrate-modified oligonucleotide was greatly increased even in the serum buffer, indicating that the sugar moiety at the 3'-position improved the resistance against enzymatic degradation. This technique was also applied to RNA synthesis. Galactose-ended siRNA was prepared and was confirmed to possess enough ability, at a concentration of 10 nM, to regulate the expression of the target gene. PMID- 20704259 TI - TNF receptor-1 (TNF-R1) ubiquitous scaffolding and signaling protein interacts with TNF-R1 and TRAF2 via an N-terminal docking interface. AB - TNF receptor-1 (TNF-R1) signal transduction is mediated through the assembly of scaffolding proteins, adaptors, and kinases. TNF receptor ubiquitous scaffolding and signaling protein (TRUSS), a 90.1 kDa TNF-R1-associated scaffolding protein, also interacts with TRAF2 and IKK and contributes to TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) and c-Jun-NH(2)-terminal kinase (JNK) activation. Little is known about the mechanism of interaction among TRUSS, TNF-R1, and TRAF2. To address this issue, we used deletional and site-directed mutagenesis approaches to systematically investigate (i) the regions of TRUSS that interact with TNF-R1 and TRAF2 and (ii) the ability of TRUSS to self-associate to form higher-order complexes. Here we show that sequences located in the N-terminal (residues 1-248) and central (residues 249-440) regions of TRUSS are required to form a docking interface that supports binding to both TNF-R1 and TRAF2. While the C-terminal region (residues 441-797) did not directly interact with TNF-R1 or TRAF2, sequences located in this region were capable of self-association. Collectively, these data suggest that (i) the interaction between TNF-R1 and TRAF2 requires sequences located in the entire N-terminal half (residues 1-440) of TRUSS, (ii) the binding interface for TNF-R1 is closely linked with the TRAF2 binding interface, and (iii) the assembly of homomeric TRUSS complexes may contribute to its role in TNF-R1 signaling. PMID- 20704262 TI - Mechanism of substrate shuttling by the acyl-carrier protein within the fatty acid mega-synthase. AB - Fatty acid mega-synthases (FAS) are large complexes that integrate into a common protein scaffold all the enzymes required for the elongation of aliphatic chains. In fungi, FAS features two independent dome-shaped structures, each 3-fold symmetric, that serve as reaction chambers. Inside each chamber, three acyl carrier proteins (ACP) are found double-tethered to the FAS scaffold by unstructured linkers; these are believed to shuttle the substrate among catalytic sites by a mechanism that is yet unknown. We present a computer-simulation study of the mechanism of ACP substrate-shuttling within the FAS reaction chamber, and a systematic assessment of the influence of several structural and energetic factors thereon. Contrary to earlier proposals, the ACP dynamics appear not to be hindered by the length or elasticity of the native linkers, nor to be confined in well-defined trajectories. Instead, each ACP domain may reach all catalytic sites within the reaction chamber, in a manner that is essentially stochastic. Nevertheless, the mechanism of ACP shuttling is clearly modulated by volume exclusion effects due to molecular crowding and by electrostatic steering toward the chamber walls. Indeed, the probability of ACP encounters with equivalent catalytic sites was found to be asymmetric. We show how this intriguing asymmetry is an entropic phenomenon that arises from the steric hindrance posed by the ACP linkers when extended across the chamber. Altogether, these features provide a physically realistic rationale for the emergence of substrate-shuttling compartmentalization and for the apparent functional advantage of the spatial distribution of the catalytic centers. PMID- 20704261 TI - Antitumor activity of ribonuclease multimers created by site-specific covalent tethering. AB - Site-specific cross-linking can generate homogeneous multimeric proteins of defined valency. Pancreatic-type ribonucleases are an especially attractive target, as their natural dimers can enter mammalian cells, evade the cytosolic ribonuclease inhibitor (RI), and exert their toxic ribonucleolytic activity. Here, we report on the use of eight distinct thiol-reactive cross-linking reagents to produce dimeric and trimeric conjugates of four pancreatic-type ribonucleases. Both the site of conjugation and, to a lesser extent, the propinquity of the monomers within the conjugate modulate affinity for RI, and hence cytotoxicity. Still, the cytotoxicity of the multimers is confounded in vitro by their increased hydrodynamic radius, which attenuates cytosolic entry. A monomeric RI-evasive variant of bovine pancreatic ribonuclease (RNase A) inhibits the growth of human prostate and lung tumors in mice. An RI-evasive trimeric conjugate inhibits tumor growth at a lower dose and with less frequent administration than does the monomer. This effect is attributable to an enhanced persistence of the trimers in circulation. On a molecular basis, the trimer is ~300-fold more efficacious and as well tolerated as erlotinib, which is in clinical use for the treatment of lung cancer. These data encourage the development of mammalian ribonucleases for the treatment of human cancers. PMID- 20704263 TI - Coexistence of two distinct G-quadruplex conformations in the hTERT promoter. AB - The catalytic subunit of human telomerase, hTERT, actively elongates the 3' end of the telomere in most cancer cells. The hTERT promoter, which contains many guanine-rich stretches on the same DNA strand, exhibits an exceptional potential for G-quadruplex formation. Here we show that one particular G-rich sequence in this region coexists in two G-quadruplex conformations in potassium solution: a (3 + 1) and a parallel-stranded G-quadruplexes. We present the NMR solution structures of both conformations, each comprising several robust structural elements, among which include the (3 + 1) and all-parallel G-tetrad cores, single residue double-chain-reversal loops, and a capping A.T base pair. A combination of NMR and CD techniques, complemented with sequence modifications and variations of experimental condition, allowed us to better understand the coexistence of the two G-quadruplex conformations in equilibrium and how different structural elements conspire to favor a particular form. PMID- 20704264 TI - Quantitative analysis of the effect of supersaturation on in vivo drug absorption. AB - The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI 2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs. PMID- 20704265 TI - Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption. AB - A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship. PMID- 20704266 TI - Dissolution modeling of bead formulations and predictions of bioequivalence for a highly soluble, highly permeable drug. AB - The objective of this study was to assess the impact of observed in vitro dissolution rate differences on in vivo pharmacokinetics for two enteric-coated bead formulations of a highly soluble, highly permeable drug. A new bead dissolution model was developed to quantitatively simulate the dissolution profiles of the two formulations. The model is based on the boundary layer diffusion model and can be used to simulate dissolution profiles for bead formulations using physicochemical properties of the formulation. The model was applied to show that the observed differences in dissolution profiles can be attributed completely to the difference in surface area of the beads for the two formulations. An absorption/pharmacokinetic model (GastroPlus) was used to predict the in vivo plasma concentration time profiles for the formulations using their respective in vitro dissolution profiles as input. The simulation results showed that the plasma concentration-time profiles were not significantly impacted by slower dissolution rates. Additionally, a sensitivity analysis was performed with a range of dissolution rate profiles. The fastest dissolution rate reached 80% dissolved in 41 min, while the slowest reached 80% in 114 min. Over this range, the predicted C(max) decreased by 9% and the AUC decreased by 1%. An in vivo bioequivalence study on the two experimental formulations demonstrated the formulations were bioequivalent, consistent with predictions. The lack of sensitivity is attributable to the high permeability and long elimination half life of the drug. The work presented in this article demonstrates the use of a bead dissolution model and an absorption/PK model to predict in vivo formulation performance. PMID- 20704267 TI - Catalyst-controlled formal [4 + 3] cycloaddition applied to the total synthesis of (+)-barekoxide and (-)-barekol. AB - The tandem cyclopropanation/Cope rearrangement between bicyclic dienes and siloxyvinyldiazoacetate, catalyzed by the dirhodium catalyst Rh(2)(R-PTAD)(4), effectively accomplishes enantiodivergent [4 + 3] cycloadditions. The reaction proceeds by a cyclopropanation followed by a Cope rearrangement of the resulting divinylcyclopropane. This methodology was applied to the synthesis of (+) barekoxide (1) and (-)-barekol (2). PMID- 20704268 TI - Luminescent Au(I)/Cu(I) alkynyl clusters with an ethynyl steroid and related aliphatic ligands: an octanuclear Au4Cu4 cluster and luminescence polymorphism in Au3Cu2 clusters. AB - Gold(I) bis(acetylide) complexes [PPN][AuR(2)] (1-3) where PPN = bis(triphenylphosphine)iminium) and R = ethisterone (1); 1-ethynylcyclopentanol (2); 1-ethynylcyclohexanol (3) have been prepared. The reaction of 1 with [Cu(MeCN)(4)][PF(6)] in a 1:1 or 3:2 ratio provides the octanuclear complex [Au(4)Cu(4)(ethisterone)(8)] (4) or pentanuclear complex [PPN][Au(3)Cu(2)(ethisterone)(6)] (5). Complexes 2 and 3 react with [Cu(MeCN)(4)][PF(6)] to form only pentanuclear Au(I)/Cu(I) complexes [PPN][Au(3)Cu(2)(1-ethynylcyclopentanol)(6)] (6) and [PPN][Au(3)Cu(2)(1 ethynylcyclohexanol)(6)] (7). X-ray crystallographic studies of 1-3 reveal nontraditional hydrogen bonding between hydroxyl groups and the acetylide units of adjacent molecules. Complexes 6 and 7 each form polymorphs in which the structures (6 a,b and 7 a,b,c) differ by Au...Au, Au...Cu, and Cu-C distances. The polymorphs exhibit different emission energies with colors ranging from blue to yellow in the solid state. In solution, pentanuclear clusters 5-7 emit with lambda(max) = 570-580 nm and Phi = 0.05-0.19. Complex 4 emits at 496 nm in CH(2)Cl(2) with a quantum yield of 0.65. Complex 5 exists in equilibrium with 1 and 4 in the presence of methanol, ethanol, ethyl acetate, or water. This equilibrium has been probed by X-ray crystallography, NMR spectroscopy, and luminescence experiments. DFT calculations have been performed to analyze the orbitals involved in the electronic transitions of 4, 6, and 7. PMID- 20704269 TI - Competitive carbon-sulfur vs carbon-carbon bond activation of 2-cyanothiophene with [Ni(dippe)H]2. AB - The processes of C-C and C-S bond cleavage have been studied with the homogeneous organometallic compound [Ni(dippe)H](2) (1). When 1 is reacted with 2 cyanothiophene at room temperature, cleavage of the nitrile-substituted C-S bond occurs, forming the Ni-metallacycle complex (dippe)Ni(kappa(2)-S,C SCH=CHCH=C(CN)) (2a), which has been fully characterized by NMR spectroscopy and X-ray diffraction. 2a was converted to the C-CN cleavage product (dippe)Ni(CN)(2 thiophenyl) (3) when heated in solution. On closer inspection, four other intermediates were observed by (31)P NMR spectroscopy at low temperature. Structures for the intermediates were elucidated through a combination of independent synthesis, theoretical calculations, chemical characterization, and experimental precedent. A kinetic product (dippe)Ni(kappa(2)-S,C-SC(CN)=CHCH=CH) (2b) was formed from cleavage of the nonsubstituted C-S bond, as well as a Ni(0) eta(2)-nitrile intermediate, (dippe)Ni(eta(2)-C,N-2-cyanothiophene) (4), and a dinuclear mixed Ni(0)-Ni(II) product (6b). A complete DFT analysis of this system has been carried out to reveal comparative details about the two bond cleavage transition states. PMID- 20704270 TI - Proteomics, genomics, and pathway analyses of Escherichia coli and Staphylococcus aureus infected milk whey reveal molecular pathways and networks involved in mastitis. AB - Gram-negative and -positive bacteria elicit different response patterns by the host. The proteomic profiles of milk whey samples from cows naturally infected with Escherichia coli or Staphyloccocus aureus as compared to whey from healthy cows were determined by one-dimensional, liquid chromatography-tandem mass spectrometry (LC-MS/MS), bioinformatics processing, and pathway analyses. Since mammary epithelial cells contribute to immune responses in mammary glands, the genes of selected proteins were measured in MAC-T cells by real time quantitative PCR (qPCR) after stimulation with heat inactivated E. coli strain P4 and S. aureus strain Smith CP bacteria. A total of 173 proteins were identified including 73 proteins differentially expressed among normal, E. coli, and S. aureus treatment groups. E. coli was more effective at significantly altering the concentration of the affected proteins. The mRNA of 23 proteins out of 24 measured by qPCR was significantly altered in MAC-T cells. Pathway analyses identified top canonical pathways significantly enriched in our samples, the most significant being the acute phase response signaling pathway. Also, top networks of genes with significant associations to identified proteins were identified. Our study has demonstrated a wider proteome profile of E. coli and S. aureus mastitic milk whey, identified more low abundant defense proteins than reported before, and has linked for the first time identified proteins to several network functions and Biocarta pathways. PMID- 20704271 TI - Geminate charge recombination in polymer/fullerene bulk heterojunction films and implications for solar cell function. AB - We have studied the influence of three different fullerene derivatives on the charge generation and recombination dynamics of polymer/fullerene bulk heterojunction (BHJ) solar cell blends. Charge generation in APFO3/[70]PCBM and APFO3/[60]PCBM is very similar and somewhat slower than charge generation in APFO3/[70]BTPF. This difference qualitatively matches the trend in free energy change of electron transfer estimated from the LUMO energies of the polymer and fullerene derivatives. The first order (geminate) charge recombination rate is significantly different for the three fullerene derivatives studied and increases in the order APFO3/[70]PCBM < APFO3/[60]PCBM < APFO3/[70]BTPF. The variation in electron transfer rate cannot be explained from the LUMO energies of the fullerene derivatives and single-step electron transfer in the Marcus inverted region and simple considerations of expected trends for the reorganization energy and free energy change. Instead we suggest that geminate charge recombination occurs from a state where electrons and holes have separated to different distances in the various materials because of an initially high charge mobility, different for different materials. In a BHJ thin film this charge separation distance is not sufficient to overcome the electrostatic attraction between electrons and holes and geminate recombination occurs on the nanosecond to hundreds of nanoseconds time scale. In a BHJ solar cell, we suggest that the internal electric field in combination with polarization effects and the dynamic nature of polarons are key features to overcome electron-hole interactions to form free extractable charges. PMID- 20704272 TI - Formation, structure, and EPR detection of a high spin Fe(IV)-oxo species derived from either an Fe(III)-oxo or Fe(III)-OH complex. AB - High spin oxoiron(IV) complexes have been proposed to be a key intermediate in numerous nonheme metalloenzymes. The successful detection of similar complexes has been reported for only two synthetic systems. A new synthetic high spin oxoiron(IV) complex is now reported that can be prepared from a well characterized oxoiron(III) species. This new oxoiron(IV) complex can also be prepared from a hydroxoiron(III) species via a proton-coupled electron transfer process--a first in synthetic chemistry. The oxoiron(IV) complex has been characterized with a variety of spectroscopic methods: FTIR studies showed a feature associated with the Fe-O bond at nu(Fe(16)O) = 798 cm(-1) that shifted to 765 cm(-1) in the (18)O complex; Mossbauer experiments show a signal with an delta = 0.02 mm/s and |DeltaE(Q)| = 0.43 mm/s, electronic parameters consistent with an Fe(IV) center, and optical spectra had visible bands at lambda(max) = 440 (epsilon(M) = 3100), 550 (epsilon(M) = 1900), and 808 (epsilon(M) = 280) nm. In addition, the oxoiron(IV) complex gave the first observable EPR features in the parallel-mode EPR spectrum with g-values at 8.19 and 4.06. A simulation for an S = 2 species with D = 4.0(5) cm(-1), E/D = 0.03, sigma(E/D) = 0.014, and g(z) = 2.04 generates a fit that accurately predicted the intensity, line shape, and position of the observed signals. These results showed that EPR spectroscopy can be a useful method for determining the properties of high spin oxoiron(IV) complexes. The oxoiron(IV) complex was crystallized at -35 degrees C, and its structure was determined by X-ray diffraction methods. The complex has a trigonal bipyramidal coordination geometry with the Fe-O unit positioned within a hydrogen bonding cavity. The Fe(IV)-O unit bond length is 1.680(1) A, which is the longest distance yet reported for a monomeric oxoiron(IV) complex. PMID- 20704273 TI - Exploring drug target flexibility using in situ click chemistry: application to a mycobacterial transcriptional regulator. AB - In situ click chemistry has been successfully applied to probe the ligand binding domain of EthR, a mycobacterial transcriptional regulator known to control the sensitivity of Mycobacterium tuberculosis to several antibiotics. Specific protein-templated ligands were generated in situ from one azide and six clusters of 10 acetylenic fragments. Comparative X-ray structures of EthR complexed with either clicked ligand BDM14950 or its azide precursor showed ligand-dependent conformational impacts on the protein architecture. This approach revealed two mobile phenylalanine residues that control the access to a previously hidden hydrophobic pocket that can be further exploited for the development of structurally diverse EthR inhibitors. This report shows that protein-directed in situ chemistry allows medicinal chemists to explore the conformational space of a ligand-binding pocket and is thus a valuable tool to guide drug design in the complex path of hit-to-lead processes. PMID- 20704275 TI - Sensing of transcription factor through controlled-assembly of metal nanoparticles modified with segmented DNA elements. AB - We have developed a unique metal nanoparticle (mNPs)-based assay to detect sequence-specific interactions between transcription factor and its corresponding DNA-binding elements. This assay exploits the interparticle-distance dependent optical properties of noble mNPs as sensing element and utilizes specific protein DNA interactions to control the dispersion status of the mNPs. The assay involves two sets of double-stranded (ds)DNA modified-mNPs, each carrying a half site segment of a functional DNA sequence for the protein of interest. Each of these half sites is designed to contain a short complementary sticky end that introduces base-pairing forces to facilitate particle aggregation and to form a transient full dsDNA sequence. The detection of specific protein-DNA binding is founded on the premise that the mixture of these two sets of dsDNA-mNPs experiences a remarkable particle aggregation under certain salt conditions; whereas the aggregation can be retarded in the presence of a specific protein that binds and stabilizes the transient full dsDNA structure and therefore introduces steric protection forces between particles. We have demonstrated the concept using estrogen receptor alpha and its response elements, with gold and silver NPs as the sensing platform. UV-vis spectroscopy, transmission electron spectroscopy, and dynamic light scattering measurements were conducted to provide full characterization of the particle aggregation/dispersion mechanism. Differing from most of the mNP-based colorimetric sensors that are designed based on the analyte-induced aggregation mechanism, current protein binding-stabilization sensing strategy reduces the false signals caused by unrelated particle destabilizing effects. It is expected that this assay principle can be directed toward other transcription factors by simply changing the recognition sequence to form different segmented dsDNA-mNP constructs. PMID- 20704274 TI - Balance between folding and degradation for Hsp90-dependent client proteins: a key role for CHIP. AB - Cells must regulate the synthesis and degradation of their proteins to maintain a balance that is appropriate for their specific growth conditions. Here we present the results of an investigation of the balance between protein folding and degradation for mammalian chaperone Hsp90-dependent client proteins. The central players are the molecular chaperones Hsp70 and Hsp90, the cochaperone HOP, and ubiquitin ligase, CHIP. Hsp70 and Hsp90 bind to HOP, thus forming a ternary folding complex whereas the binding of CHIP to the chaperones has previously been shown to lead to ubiquitination and ultimately to degradation of the client proteins as well as the chaperones. To understand the folding/degradation balance in more detail, we characterized the stoichiometries of the CHIP-Hsp70 and CHIP Hsp90 complexes and measured the corresponding dissociation constants to be approximately 1 muM and approximately 4.5 muM, respectively. We quantified the rate of ubiquitination of various substrates by CHIP in vitro. We further determined that the folding and degradation machineries cannot coexist in one complex. Lastly, we measured the in vivo concentrations of Hsp70, Hsp90, HOP, and CHIP under normal conditions and when client proteins are being degraded due to inhibition of the folding pathway. These in vivo measurements along with the in vitro data allowed us to calculate the approximate cellular concentrations of the folding and degradation complexes under both conditions and formulate a quantitative model for the balance between protein folding and degradation as well as an explanation for the shift to client protein degradation when the folding pathway is inhibited. PMID- 20704276 TI - Structural basis of low-affinity nickel binding to the nickel-responsive transcription factor NikR from Escherichia coli. AB - Escherichia coli NikR regulates cellular nickel uptake by binding to the nik operon in the presence of nickel and blocking transcription of genes encoding the nickel uptake transporter. NikR has two binding affinities for the nik operon: a nanomolar dissociation constant with stoichiometric nickel and a picomolar dissociation constant with excess nickel [Bloom, S. L., and Zamble, D. B. (2004) Biochemistry 43, 10029-10038; Chivers, P. T., and Sauer, R. T. (2002) Chem. Biol. 9, 1141-1148]. While it is known that the stoichiometric nickel ions bind at the NikR tetrameric interface [Schreiter, E. R., et al. (2003) Nat. Struct. Biol. 10, 794-799; Schreiter, E. R., et al. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 13676 13681], the binding sites for excess nickel ions have not been fully described. Here we have determined the crystal structure of NikR in the presence of excess nickel to 2.6 A resolution and have obtained nickel anomalous data (1.4845 A) in the presence of excess nickel for both NikR alone and NikR cocrystallized with a 30-nucleotide piece of double-stranded DNA containing the nik operon. These anomalous data show that excess nickel ions do not bind to a single location on NikR but instead reveal a total of 22 possible low-affinity nickel sites on the NikR tetramer. These sites, for which there are six different types, are all on the surface of NikR, and most are found in both the NikR alone and NikR-DNA structures. Using a combination of crystallographic data and molecular dynamics simulations, the nickel sites can be described as preferring octahedral geometry, utilizing one to three protein ligands (typically histidine) and at least two water molecules. PMID- 20704277 TI - Characterization of soluble microbial products and their fouling impacts in membrane bioreactors. AB - Membrane bioreactor (MBR) fouling is not only influenced by the soluble microbial products (SMP) concentration but by their characteristics. Experiments of separate producing biomass associated products (BAP) and utilization associated products (UAP) allowed the separation of BAP and UAP effects from sludge water (SW). Thus, filtration of individual SMP components and further characterization becomes possible. Unstirred cell filtration was used to study fouling mechanisms and liquid chromatography--organic carbon detection (LC-OCD) and fluorescence excitation--emission matrix (EEM) were used to characterize the foulant. Generally, the SMP exhibiting characteristics of higher molecular weight, greater hydrophilicity and a more reduced state showed a higher retention percentage. However, the higher retention does not always yield higher fouling effects. The UAP filtration showed the highest specific cake resistance and pore blocking resistance attributed to their higher percentage of low molecular weight molecules, although their retention percentage was lower than the SW and BAP filtration. The UAP produced in the cell proliferation phase appeared to have the highest fouling potential. PMID- 20704278 TI - Binding of the fibronectin-mimetic peptide, PR_b, to alpha5beta1 on pig islet cells increases fibronectin production and facilitates internalization of PR_b functionalized liposomes. AB - Islet transplantation is a promising treatment for type 1 diabetes. Recent studies have demonstrated that human islet allografts can restore insulin independence to patients with this disease. As islet isolation and immunotherapeutic techniques improve, the demand for this cell-based therapy will dictate the need for other sources of islets. Pig islets could provide an unlimited supply for xenotransplantation and have shown promise as an alternative to human islet allografts. However, stresses imposed during islet isolation and transplantation decrease islet viability, leading to loss of graft function. In this study, we investigated the ability of a fibronectin-mimetic peptide, PR_b, which specifically binds to the alpha(5)beta(1) integrin, to re-establish lost extracellular matrix (ECM) around isolated pig islets and increase internalization of liposomes. Confocal microscopy and Western blotting were used to show the presence of the integrin alpha(5)beta(1) on the pig islets on day 0 (day of isolation) as well as on different days of islet culture. Islets cultured in medium supplemented with free PR_b for 48 h were found to have increased levels of ECM fibronectin secretion compared to islets in normal culture conditions. Using confocal microscopy and flow cytometry, we found that PR_b peptide-amphiphile functionalized liposomes delivered to the pig islets internalized into the cells in a PR_b concentration dependent manner and nonfunctionalized liposomes showed minimal internalization. These studies proved that the fibronectin-mimetic peptide, PR_b, is an appropriate peptide bullet for applications involving alpha(5)beta(1) expressing pig islet cells. Fibronectin production stimulated through alpha(5)beta(1) PR_b binding may decrease apoptosis and therefore increase islet viability in culture. In addition, PR_b peptide amphiphile functionalized liposomes may be used for targeted delivery of different agents to pig islet cells. PMID- 20704279 TI - Using a modified electrical aerosol detector to predict nanoparticle exposures to different regions of the respiratory tract for workers in a carbon black manufacturing industry. AB - The present study was set out to characterize nanoparticle exposures in three selected workplaces of the packaging, warehouse, and pelletizing in a carbon black manufacturing plant using a newly developed modified electrical aerosol detector (MEAD). For confirmation purposes, the MEAD results were compared with those simultaneously obtained from a nanoparticle surface area monitor (NSAM) and a scanning mobility particle sizer (SMPS). We found that workplace background nanoparticle concentrations were mainly coming from the outdoor environment. Size distributions of nanoparticles for the three selected process areas during the work hours were consistently in the form of bimodel. Unlike nanoparticles of the second mode (simply contributed by the process emissions), particles of the first mode could be also contributed by the forklift exhaust or fugitive emissions of heaters. The percents of nanoparticles deposited on the alveolar (A) region were much higher than the other two regions of the head airway (H), tracheobronchial (TB) for all selected workplaces in both number and surface area concentrations. However, significant differences were found in percents of nanoparticles deposited on each of the three regions while different exposure metrics were adopted. Both NSAM and MEAD obtained quite comparable results. No significant difference can be found between the results obtained from SMPS and MEAD after being normalized. Considering the MEAD is less expensive, less bulky, and easy to use, our results further support the suitability of using MEAD in the field for nanoparticle exposure assessments. PMID- 20704280 TI - Tunable leuko-polymersomes that adhere specifically to inflammatory markers. AB - The polymersome, a fully synthetic cell mimetic, is a tunable platform for drug delivery vehicles to detect and treat disease (theranostics). Here, we design a leuko-polymersome, a polymersome with the adhesive properties of leukocytes, which can effectively bind to inflammatory sites under flow. We hypothesize that optimal leukocyte adhesion can be recreated with ligands that mimic receptors of the two major leukocyte molecular adhesion pathways, the selectins and the integrins. Polymersomes functionalized with sialyl Lewis X and an antibody against ICAM-1 adhere avidly and selectively to surfaces coated with inflammatory adhesion molecules P-selectin and ICAM-1 under flow. We find that maximal adhesion occurs at intermediate densities of both sialyl Lewis X and anti-ICAM-1, owing to synergistic binding effects between the two ligands. Leuko-polymersomes bearing these two receptor mimetics adhere under physiological shear rates to inflamed endothelium in an in vitro flow chamber at a rate 7.5 times higher than those to uninflamed endothelium. This work clearly demonstrates that polymersomes bearing only a single ligand bind less avidly and with lower selectivity, thus suggesting proper mimicry of leukocyte adhesion requires contributions from both pathways. This work establishes a basis for the design of polymersomes for targeted drug delivery in inflammation. PMID- 20704281 TI - Field measurement of diffusional mass transfer of HOCs at the sediment-water interface. AB - The sediment to water diffusive flux of PAHs and PCBs was measured under field conditions with a novel infinite-sink benthic flux chamber that deployed semipermeable membrane devices (SPMD) as a sorbing material. Fluxes were measured before and after in situ capping of sediments in Oslo Harbour with clean clay. The fluxes of native pyrene and PCB 52 from uncapped contaminated sediment measured with the flux chamber were 0.3-1.6 microg m(-2) d(-1) and 2-8 ng m(-2) d(-1), respectively. Fluxes from the capped sediment were reduced by 93-97%. The in situ measured fluxes were compared to fluxes independently calculated from freely dissolved concentrations in pore water and overlying water, measured using equilibrium passive samplers, diffusive boundary layer (DBL) thickness, measured by an alabaster dissolution method and literature values of diffusion coefficients. Measured fluxes from the uncapped sediment agreed well with calculated fluxes, the median of the ratio of the measured flux over the calculated flux was 0.9 with an inter quartile range of 0.5-1.6. PMID- 20704282 TI - New CO2 capture process for hydrogen production combining Ca and Cu chemical loops. AB - This paper presents a new solids looping process for capturing CO2 while generating hydrogen and/or electricity from natural gas. The process is based on the sorption enhanced reforming of CH4, employing CaO as a high temperature CO2 sorbent, combined with a second chemical loop of CuO/Cu. The exothermic reduction of CuO with CH4 is used to obtain the heat necessary for the decomposition of the CaCO3 formed in the reforming step. The main part of the process is completed by the oxidation of Cu to CuO, which is carried out with air diluted with a product gas recycle of this reactor at sufficiently low temperatures and high pressures to avoid the decomposition of a substantial fraction of CaCO3. PMID- 20704283 TI - Novel process of simultaneous removal of SO2 and NO2 by sodium humate solution. AB - A novel simultaneous flue gas desulfurization and denitrification (FGDD) process using sodium humate (HA-Na) solution was proposed. This study relates to the SO2/NO2 absorption efficiency and products of simultaneous removing SO2 and NO2 in a bubbling reactor, especially the effect of recycled water on the SO2/NO2 absorption. Under alkaline conditions, the sulfate content in S-containing compound decreases with the increase of NO2 concentration, whereas there is a contrary result under acidic conditions. Whether the absorption liquid is alkaline or acidic, the presence of NO2 improves the SO2 absorption into HA-Na solution, because NO2 may promote the oxidation of sulfite to sulfate. It seems that the presence of SO2 is unfavorable for the NO2 absorption, but the NO2 absorption efficiency can be improved with the cycle number rising due to the increasing amount of sulfite. Although all the ion concentrations of Na+,SO4(2 ),SO3(2-), and NO3- have a gradual increase as the cycle number rises, the ion concentrations of SO4(2-) and Na+ are far more than that of the other ions, which results in a slight decrease of the SO2 absorption efficiency. However, the initial pH of HA-Na solution prepared by recycled water decreases from 10 to 8.1 with the cycle number increasing from 1 to 10, whereas the final pH (the pH after absorption reaction is finished) remains almost constant (3.3). The SO2 absorption efficiency is above 98% and the NO2 absorption efficiency may reach above 95% in the optimal condition in this process. The chief byproduct is a compound fertilizer consisting of humic acid (HA), sulfate, and nitrate. PMID- 20704284 TI - Stereoselective synthesis of chiral 4-(1-chloroalkyl)-beta-lactams starting from amino acids and their transformation into functionalized chiral azetidines and pyrrolidines. AB - Chiral short-chain alpha-chloroaldehydes were prepared starting from enantiomerically pure amino acids in a three-step approach, thus providing a practical synthetic alternative for known organocatalytic alpha-chlorination procedures. The latter aldehydes proved to be useful starting materials for the stereoselective Staudinger synthesis of (3S,4S)-4-[(1S)-1-chloroalkyl]azetidin-2 ones in high diastereomeric ratios and good overall yields, which were used as chiral building blocks for the preparation of a number of azetidines and pyrrolidines. PMID- 20704285 TI - Theoretical and experimental simulation of the fate of semifluorinated n-alkanes during snowmelt. AB - Semifluorinated n-alkanes (SFAs) are highly fluorinated anthropogenic chemicals that are released into the environment through their use in ski waxes. Nothing is known about their environmental partitioning in general and their fate during snowmelt in particular. Properties were estimated for a range of SFAs with different chain lengths and degrees of fluorination using the SPARC calculator and poly parameter linear free energy relationships (ppLFERs). The calculations resulted in very low water solubility and vapor pressures and, consequently, high log KOW and log KOA values. Artificially produced snow in a cold room was spiked with a range of SFAs and subsequently melted with infrared lamps. Melt water, particles, and air samples taken during melting were analyzed. Both calculations and experiments showed that SFAs used in ski waxes will bind to particles or snow grain surfaces during snowmelt and thus are predicted to end up on the soil surface in skiing areas. PMID- 20704286 TI - Molecular based modeling of associating fluids via calculation of Wertheim cluster integrals. AB - We examine a virial-like treatment for the equation of state of associating fluids defined in terms of a detailed molecular model. The approach implements Wertheim's formulation of statistical thermodynamics of a classical fluid of molecules having strong directionally dependent association interactions. We employ the theory in its fundamental form, which expresses the pressure as an expansion in two or more aggregation densities, which themselves are related to each other by other series expansions. We employ Mayer-sampling Monte Carlo simulations to evaluate the cluster integrals defining the coefficients appearing in these series, yielding a multidensity virial-like equation of state, appropriate for the molecular system for which the cluster integrals were computed. We demonstrate this approach with a well-studied Lennard-Jones + association model, considering cases of atoms having one and two binding sites, respectively, and including all clusters involving up to four atoms. It is shown for this application that the Wertheim treatment is vastly superior to the standard (single-density) virial formulation, which fails in its description of the associating-fluid equation of state at very low densities. The Wertheim formulation for associating fluids is seen to be effective up to densities where the standard virial treatment to the same order begins to fail when applied to nonassociating fluids. PMID- 20704287 TI - Homoatomic stella quadrangula [Tl8]6- in Cs18Tl8O6, interplay of spin-orbit coupling, and Jahn-Teller distortion. AB - Cs(18)Tl(8)O(6) was synthesized reacting the binary compounds CsTl and Cs(2)O. According to single crystal X-ray analysis, the title compound crystallizes as a novel structure type in the cubic space group I23 and is diamagnetic. The electronic structure of the extended solid and of excised Cs(6)Tl(8) clusters has been examined by relativistic density functional calculations including spin orbit coupling. Cs(18)Tl(8)O(6) comprises a clusteranion [Tl(8)](6-) in the shape of a tetrahedral star. An isoelectronic cluster was found previously in Cs(8)Tl(8)O, however, with the shape of a parallelepiped. Both clusteranions can be derived from a homocubane unit by displacive distortions. It has been shown by quantum mechanical analyses that the closed-shell electronic structure of the parallelepiped is the result of a Jahn-Teller distortion, while in contrast the tetrahedral star in Cs(18)Tl(8)O(6) would still exhibit an open-shell degenerate HOMO within a scalar relativistic approximation. Only if spin-orbit coupling is considered, a closed-shell electronic system is obtained in accordance with the diamagnetic behavior of Cs(18)Tl(8)O(6). PMID- 20704288 TI - Comparative density functional study of methanol decomposition on Cu4 and Co4 clusters. AB - A density functional theory study of the decomposition of methanol on Cu(4) and Co(4) clusters is presented. The reaction intermediates and activation barriers have been determined for reaction steps to form H(2) and CO. For both clusters, methanol decomposition initiated by C-H and O-H bond breaking was investigated. In the case of a Cu(4) cluster, methanol dehydrogenation through hydroxymethyl (CH(2)OH), hydroxymethylene (CHOH), formyl (CHO), and carbon monoxide (CO) is found to be slightly more favorable. For a Co(4) cluster, the dehydrogenation pathway through methoxy (CH(3)O) and formaldehyde (CH(2)O) is slightly more favorable. Each of these pathways results in formation of CO and H(2). The Co cluster pathway is very favorable thermodynamically and kinetically for dehydrogenation. However, since CO binds strongly, it is likely to poison methanol decomposition to H(2) and CO at low temperatures. In contrast, for the Cu cluster, CO poisoning is not likely to be a problem since it does not bind strongly, but the dehydrogenation steps are not energetically favorable. Pathways involving C-O bond cleavage are even less energetically favorable. The results are compared to our previous study of methanol decomposition on Pd(4) and Pd(8) clusters. Finally, all reaction energy changes and transition state energies, including those for the Pd clusters, are related in a linear, Bronsted-Evans Polanyi plot. PMID- 20704290 TI - Synthesis of 1',2'-cis-nucleoside analogues: evidence of stereoelectronic control for SN2 reactions at the anomeric center of furanosides. AB - We are reporting a highly diastereoselective route to 1',2'-cis-nucleoside analogues in the D-ribo, D-lyxo, D-xylo, and D-arabinoside series. Five-membered ring lactols undergo highly selective N-glycosidation reactions in the presence of dimethylboron bromide with different silylated nucleobases. Stereoelectronic control plays a crucial role for the observed induction, and the products are proposed to be formed through S(N)2 "exploded" transition states. This approach shows great potential considering its simplicity and selectivity for the synthesis of nucleoside analogues, an important class of molecules in medicinal chemistry. PMID- 20704289 TI - Degradation and mineralization of bisphenol A by mesoporous Bi2WO6 under simulated solar light irradiation. AB - Bismuth tungstate (Bi2WO6) catalysts of different morphology were synthesized with a hydrothermal method by controlling the pH of the reaction solution. The properties of the synthesized catalysts were characterized and all catalysts presented high photoabsorption capacity in the range of UV light to visible light around 450 nm. The surface area of the catalysts decreased but the crystallinity increased with the pH of the hydrothermal reaction solution in the range of 4-11. It was found that the crystallinity of the catalysts played an important role on their degradation capacity to Bisphenol A (BPA). Bi2WO6 catalyst prepared at pH 11 displayed a mesoporous structure and it showed the highest photocatalytic activity to degrade BPA under simulated solar light irradiation. Nearly 100% of BPA with original concentration at 20 ppm was removed after 30 min irradiation in a solution with pH 10 and Bi2WO6 amount of 1.0 g L(-1). Furthermore, 86.6 and 99.1% of the total organic carbon was eliminated after 60 and 120 min irradiation, respectively. Only one intermediate at m/z 133 was observed by LC/MS and a simple pathway of BPA degradation by Bi2WO6 was proposed. PMID- 20704291 TI - Local self-consistent Ornstein-Zernike integral equation theory and application to a generalized Lennard-Jones potential. AB - Local self-consistent Ornstein-Zernike (OZ) integral equation theory (IET) provides a rapid and easy route for obtaining independently thermodynamic and structural information for a single state point. Because of neglect of information of neighboring state points in determining a self-consistent adjustable parameter performance of the local self-consistent OZ IET is somewhat vulnerable and worthy of intensive investigation. For this reason, we have performed Monte Carlo simulations to obtain thermodynamic and structural properties of fluid with a generalized Lennard-Jones potential, and the present simulation results are employed to verify the quality of a local version of a recently developed global self-consistent OZ IET and a local expression for computation of excess chemical potential directly from the structural functions of the state point of interest. Comprehensive comparison and analysis demonstrate the following (i) the present local self-consistent OZ IET performs quite well for calculation of pressure and excess internal energy; (ii) using the same structural functions from the present local self-consistent OZ IET, the previously derived local expression by the present author has by and large the same accuracy in calculating the excess chemical potential as an exact virial formula for the pressure; (iii) although the excellent performance exhibited for the above thermodynamic quantities persists to very low temperature and very short-ranged potential and remains even in the liquid-solid coexistence region, the excess Helmholtz free energy calculated from the pressure and excess chemical potential shows evident inaccuracy for a density-temperature combination deep in the liquid-solid coexistence region, and this makes it necessary to derive a local formulation for the excess free energy. PMID- 20704295 TI - Reaction mechanism of CH + C(3)H(6): a theoretical study. AB - A detailed theoretical study is performed at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels as an attempt to explore the reaction mechanism of CH with C(3)H(6). It is shown that the barrierless association of CH with C(3)H(6) forms two energy-rich isomers CH(3)-cCHCHCH(2) (1), and CH(2)CH(2)CHCH(2) (4). Isomers 1 and 4 are predicted to undergo subsequent isomerization and dissociation steps leading to ten dissociation products P(1) (CH(3)-cCHCHCH + H), P(2) (CH(3) cCCHCH(2) + H), P(3) (cCHCHCH(2) + CH(3)), P(4) (CH(3)CHCCH(2) + H), P(5) (cis CH(2)CHCHCH(2) + H), P(6) (trans-CH(2)CHCHCH(2) + H), P(7) (C(2)H(4) + C(2)H(3)), P(8) (CH(3)CCH + CH(3)), P(9) (CH(3)CCCH(3) + H) and P(12) (CH(2)CCH(2) + CH(3)), which are thermodynamically and kinetically possible. Among these products, P(5), P(6), and P(7) may be the most favorable products with comparable yields; P(1), P(2), and P(3) may be the much less competitive products, followed by the almost negligible P(4), P(8), P(9), and P(12). Since the isomers and transition states involved in the CH + C(3)H(6) reaction all lie lower than the reactant, the title reaction is expected to be fast, which is consistent with the measured large rate constant in experiment. The present study may lead us to a deep understanding of the CH radical chemistry. PMID- 20704293 TI - ON-OFF switching of transcriptional activity of large DNA through a conformational transition in cooperation with phospholipid membrane. AB - We report that structural transitions of DNA cause the ON-OFF switching of transcriptional activity in cooperation with phospholipid membrane in a reconstituted artificial cell. It has been shown that long DNA of more than 20-30 kilo base-pairs exhibits a discrete conformational transition between a coiled state and highly folded states in aqueous solution, depending on the presence of various condensing agents such as polyamine. Recently, we reported a conformational transition of long DNA through interplay with phospholipid membrane, from a folded state in aqueous phase to an extended coil state on a membrane surface, in a cell-sized water-in-oil microdroplet covered by phosphatidylethanolamine monolayer (Kato, A.; Shindo, E.; Sakaue, T.; Tsuji, A.; Yoshikawa, K. Biophys. J. 2009, 97, 1678-1686). In this study, to elucidate the effects of these conformational changes on the biologically important function of DNA, transcription, we investigated the transcriptional activity of DNA in a microdroplet. Transcriptional activity was evaluated at individual DNA molecule level by a method we developed, in which mRNA molecules are labeled with fluorescent oligonucleotide probes. Transcription proceeded on almost all of the DNA molecules with a coiled conformation in the aqueous phase. In the presence of a tetravalent amine, spermine, the DNA had a folded conformation, and transcription was completely inhibited. When the Mg(2+) concentration was increased, DNA was adsorbed onto the inner surface of the membrane and exhibited an extended conformation. The transcription experiments showed that this conformational transition recovered transcriptional activity; transcription occurred on DNA molecules that were on the membrane. PMID- 20704296 TI - Development and evaluation of a novel method for preclinical measurement of tissue vascular volume. AB - Identification of clinically predictive models of disposition kinetics for antibody therapeutics is an ongoing pursuit in drug development. To encourage translation of drug candidates from early research to clinical trials, clinical diagnostic agents may be used to characterize antibody disposition in physiologically relevant preclinical models. TechneScan PYP was employed to measure tissue vascular volumes (V(v)) in healthy mice. Two methods of red blood cell (RBC) labeling were compared: a direct in vivo method that is analogous to a clinical blood pool imaging protocol, and an indirect method in which radiolabeled blood was transfused from donor mice into recipient mice. The indirect method gave higher precision in RBC labeling yields, lower V(v) values in most tissues, and lower (99m)Tc uptake in kidneys and bladder by single photon emission computed tomographic (SPECT) imaging relative to the direct method. Furthermore, the relative influence of each method on the calculated area under the first 7 days of the concentration-time curve (AUC(0-7)) of an IgG in nude mice was assessed using a physiologically based pharmacokinetic model. The model was sensitive to the source of V(v) values, whether obtained from the literature or measured by either method, when used to predict experimental AUC(0-7) values for radiolabeled trastuzumab in healthy murine tissues. In summary, a novel indirect method for preclinical determination of V(v) offered higher precision in RBC labeling efficiency and lower renal uptake of (99m)Tc than the direct method. In addition, these observations emphasize the importance of obtaining accurate physiological parameter values for modeling antibody uptake. PMID- 20704297 TI - On the absorption spectra of recently synthesized carbonyl dyes: TD-DFT insights. AB - The development of theoretical schemes allowing for efficient reproduction of the features of electronically excited states remains a challenging task. In that framework, time-dependent density functional theory (TD-DFT) has emerged as an efficient approach for reproducing and understanding the UV/visible spectra of large solvated molecules. In this paper, we investigate the ground and excited state properties of two carbonyl dyes presenting very similar structures but possessing absorption peaks differing by both their transition energies and their band shapes. Using a global (PBE0) and a range-separated hybrid (CAM-B3LYP), we obtain consistent conclusions demonstrating, for this couple of dyes, the necessity to go beyond the vertical TD-DFT approximation even for a qualitative interpretation. These simulations are striking examples of the interest of using more refined theoretical schemes for correctly evaluating the transition energies of specific carbonyl dyes. PMID- 20704298 TI - Temperature dependent kinetics (195-798 K) and H atom yields (298-498 K) from reactions of (1)CH(2) with acetylene, ethene, and propene. AB - The rate coefficients for the removal of the excited state of methylene, (1)CH(2) (a(1)A(1)), by acetylene, ethene, and propene have been studied over the temperature range 195-798 K by laser flash photolysis, with (1)CH(2) being monitored by laser-induced fluorescence. The rate coefficients of all three reactions exhibit a negative temperature dependence that can be parametrized as k((1)CH(2)+C(2)H(2)) = (3.06 +/- 0.11) x 10(-10) T ((-0.39+/-0.07)) cm(3) molecule(-1) s(-1), k((1)CH(2)+C(2)H(4)) = (2.10 +/- 0.18) x 10(-10) T ((-0.84+/ 0.18)) cm(3) molecule(-1) s(-1), k((1)CH(2)+C(3)H(6)) = (3.21 +/- 0.02) x 10(-10) T ((-0.13+/-0.01)) cm(3) molecule(-1) s(-1), where the errors are statistical at the 2sigma level. Removal of (1)CH(2) occurs by chemical reaction and electronic relaxation to ground state triplet methylene. The H atom yields from the reactions of (1)CH(2) with acetylene, ethene, and propene have been determined by laser-induced fluorescence over the temperature range 298-498 K. For the reaction with propene, H atom yields are close to the detection limit, but for acetylene and ethene, the fraction of H atom production is approximately 0.88 and 0.71, respectively, at 298 K, rising to unity by 398 K, with the balance of the reaction with acetylene presumed to be electronic relaxation. Experimental constraints limit studies to a maximum of 1 Torr of bath gas; master equation calculations using an approach that allows treatment of intermediates with deep energy wells have been carried out to explore the role of collisional stabilization for the reaction of (1)CH(2) with acetylene. Stabilization is calculated to be insignificant under the experimental conditions, but does become significant at higher pressures. Between pressures of 100 and 1000 Torr, propyne and allene are formed in similar amounts with a slight preference for propyne. At higher pressures propyne formation becomes about a factor two greater than that of allene, and above 10(5) Torr (300 < T (K) < 600) cyclopropene formation starts to become significant. The implications of temperature-dependent (1)CH(2) relaxation on the roles of (1)CH(2) in chemical mechanisms for soot formation are discussed. PMID- 20704299 TI - Solid crystal network of self-assembled cyclodextrin and nonionic surfactant pseudorotaxanes. AB - The title system allows the straightforward formation of three-dimensional crystals of self-assembled pseudorotaxanes formed by the nonionic surfactant Igepal CO-520 and beta-cyclodextrin (beta-CD) in aqueous solution. The work involves a combination of X-ray powder diffraction, high resolution electron transmission microscopy, and (13)C CP/MAS NMR studies of the solid crystal, supported by single crystal structural analysis. The results indicate a lamellar self-assembly of pseudorotaxanes with preferential orientation and disorder in the structure. For the single crystal, the unit cell was found to be triclinic (P1) and contains a beta-CD dimer. The surfactant molecules are located in the channel formed by these dimers along the c axis of the crystal network. The individual pseudorotaxane structure is formed by a dimer of beta-CDs threaded by the oxyethylene hydrophilic segment of Igepal CO-520, and a beta-CD dimer that binds the hydrophobic region of the surfactant. Thus, as in a CD polyrotaxane structure, this system results in an ordered self-assembly of pseudorotaxanes through the formation of a network of hydrogen bonds between head-to-head beta-CD dimers. Moreover, the analysis of the (1)H NMR spectra in solutions of pseudorotaxanes formed by beta-CD and Igepals with different lengths of the hydrophilic tails indicates equal stoichiometry patterns of both oxyethyelene and hydrophobic regions for the different supramolecules. Whereas the common hydrophobic moiety threads two macrocycles, the ratio between complexed oxyehtlyene segments and beta-CD is 2.5 for the hydrophilic tails. All these results show that nonionic surfactants can be used as alternative and effective linear threads to polymers and copolymers in the synthesis of supramolecular polyrotaxane solid crystals with CDs. PMID- 20704300 TI - Excited-state intermolecular proton transfer of the firefly's chromophore D luciferin. 2. Water-methanol mixtures. AB - Steady-state emission and time-resolved techniques were employed to study the photoprotolytic processes d-luciferin undergoes in water-methanol mixtures over a wide range of molar fractions (chi(MeOH)) of methanol. We found that in the concentration range of 0 < chi(MeOH) < 0.8 the rate constant of the excited-state proton transfer (ESPT) to the solvent decreases nearly exponentially with increasing chi(MeOH). At chi(MeOH) > 0.8 the proton transfer rate constant decreases with an even steeper slope. The kinetic isotope effect (KIE) maintains a constant value of 2.4 +/- 0.2 at all the mixture's compositions. PMID- 20704301 TI - Caelestines A-D, brominated quinolinecarboxylic acids from the Australian ascidian Aplidium caelestis. AB - Four new brominated natural products, caelestines A-D (1-4), have been isolated from the Australian ascidian Aplidium caelestis. The structures of 1-4 were determined by analysis of their NMR and MS data. This is the first report of brominated quinolinecarboxylic acids from nature. Compound 1 has been previously synthesized but not spectroscopically characterized. Compounds 1-4 were tested against three mammalian cell lines (MCF-7, NFF, and MM96L) and a panel of microbial strains and showed only minor cytotoxicity. PMID- 20704302 TI - Toward an improved understanding of the dissociation mechanism of gas phase protein complexes. AB - Understanding the dissociation mechanism of multimeric protein complex ions is important for deciphering gas phase dissociation experiments. The dissociation of cytochrome c' dimer ions in the gas phase was investigated in the present study by constrained molecular dynamics simulations. The center of mass (COM) distance between two monomers was selected as the constrained coordinate. The number of intermolecular hydrogen bonds, smallest distance of intermolecular residuals, value of dipole moments, root-mean-square deviations, and potential energy components of the force field as a function of COM distance were examined for different charge partitionings of the +10 total charge state. These data were rationalized with free energy profiles to produce a qualitative description of the dissociation process. When charges are symmetrically distributed between the monomers in the dimer, dissociation occurs at a well-defined distance with only small structural changes in the monomers. There is an elastic type of stretching that initially resists the separation of the monomers but after dissociation the monomers recoil slightly from this and relax. For asymmetrically distributed charges, the dissociation event is not nearly as well-defined because the more highly charged monomer unfolds before dissociation occurs. It is found in almost all cases, a charged N-terminus tethers this unfolding monomer to its dimer partner by binding in a nonspecific manner. This helps encourage monomer unfolding in the dissociation pathway. It is also shown that while the intermolecular Coulomb repulsion between the monomers is not the largest contribution to the overall potential energy, it dominates the potential energy difference between different charge states. PMID- 20704303 TI - Flower micelle of amphiphilic random copolymers in aqueous media. AB - The structure of the flower micelle formed by an amphiphilic random copolymer, sodium (2-acrylamido)-2-methylpropanesulfonate and N-dodecylmethacrylamide p(AMPS/C12), in 0.05 M aqueous NaCl was investigated by fully atomistic molecular dynamics simulation as well as by light scattering, and the results were compared with the flower micelle model of the minimum loop size, recently proposed by Kawata et al. [Macromolecules 2007, 40, 1174-1180]. After a sufficiently long simulation time, simulated p(AMPS/C12) chain with the degree of polymerization of 200 and C12 content of 50 mol % formed a unicore micelle, of which radius of gyration was much smaller than the AMPS homopolymer with the same degree of polymerization. The simulated micellar structure was analyzed in terms of density distribution functions for dodecyl groups, the main chain, and sulfonate groups as functions of the radial distance r from the center of mass of dodecyl groups. Only dodecyl groups exist at r less, similar 1.5 nm, and the main chain and sulfonate groups distribute in the range of r between 1.5 and 3.5 nm, but there were dodecyl groups coexisting with the main chain and sulfonate groups beyond r = 1.5 nm. All these structural features, as well as hydrodynamic radius data for p(AMPS/C12) with C12 contents higher than ca. 20 mol % obtained by light scattering, agreed with the predictions of the flower micelle model of the minimum loop size. PMID- 20704304 TI - Cytotoxic halogenated macrolides and modified peptides from the apratoxin producing marine cyanobacterium Lyngbya bouillonii from Guam. AB - Collections of the marine cyanobacterium Lyngbya bouillonii from shallow patch reefs in Apra Harbor, Guam, afforded three hitherto undescribed analogues of the glycosidic macrolide lyngbyaloside, namely, 2-epi-lyngbyaloside (1) and the regioisomeric 18E- and 18Z-lyngbyalosides C (2 and 3). Concurrently we discovered two new analogues of the cytoskeletal actin-disrupting lyngbyabellins, 27 deoxylyngbyabellin A (4) and lyngbyabellin J (5), a novel macrolide of the laingolide family, laingolide B (6), and a linear modified peptide, lyngbyapeptin D (7), along with known lyngbyabellins A and B, lyngbyapeptin A, and lyngbyaloside. The structures of 1-7 were elucidated by a combination of NMR spectroscopic and mass spectrometric analysis. Compounds 1-6 were either brominated (1-3) or chlorinated (4-6), consistent with halogenation being a hallmark of many marine natural products. All extracts derived from these L. bouillonii collections were highly cytotoxic due to the presence of apratoxin A or apratoxin C. Compounds 1-5 showed weak to moderate cytotoxicity to HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells. PMID- 20704307 TI - There can be shame and punishment in copy and paste. PMID- 20704305 TI - New reagents for enhanced liquid chromatographic separation and charging of intact protein ions for electrospray ionization mass spectrometry. AB - Electrospray ionization produces multiply charged ions, thereby lowering the mass to-charge ratio for peptides and small proteins to a range readily accessed by quadrupole ion trap, orbitrap, and ion cyclotron resonance (ICR) mass analyzers (m/z = 400-2000). For Fourier transform mass analyzers (orbitrap and ICR), higher charge also improves signal-to-noise ratio, mass resolution, and mass accuracy. Addition of m-nitrobenzyl alcohol (m-NBA) or sulfolane has previously been shown to increase the charge states of proteins. Moreover, polar aprotic dimethylformamide (DMF) improves chromatographic separation of proteolytic peptides for mass analysis of solution-phase protein hydrogen/deuterium exchange for improved (78-96%) sequence coverage. Here, we show that addition of each of the various modifiers (DMF, thiodiglycol, dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone) can significantly increase the charge states of proteins up to 78 kDa. Moreover, incorporation of the same modifiers into reversed-phase liquid chromatography solvents improves sensitivity, charging, and chromatographic resolution for intact proteins. PMID- 20704306 TI - Macrocyclic and acyclic molecules synthesized from dipyrrolylmethanes: receptors for anions. AB - A new class of macrocyclic and acyclic molecules was synthesized by the Mannich reactions of dipyrrolylmethanes to investigate anion recognition. The X-ray structures of the macrocycle and sulfate complexes are reported. PMID- 20704308 TI - Synthesis of (-)-sedinine by allene cyclization and iminium ion chemistry. AB - A synthesis of the sedum alkaloid sedinine has been achieved employing silver(I) catalyzed allenic hydroxylamine cyclization and ring-closing metathesis to form a bicyclic N,O-acetal. Ring opening of this acetal with a silyl enol ether under Lewis acidic conditions is exclusively trans selective, leading to the natural product after reduction. On the other hand, conversion of the bicyclic N,O-acetal to a semicyclic N,O-acetal results in no stereoselectivity during such a reaction. The contrasting results can be rationalized by consideration of the conformation of the iminium ions. PMID- 20704309 TI - Application of phase-trafficking methods to natural products research. AB - A novel simultaneous phase-trafficking approach using spatially separated solid supported reagents for rapid separation of neutral, basic, and acidic compounds from organic plant extracts with minimum labor is reported. Acidic and basic ion exchange resins were physically separated into individual sacks ("tea bags") for trapping basic and acidic compounds, respectively, leaving behind in solution neutral components of the natural mixtures. Trapped compounds were then recovered from solid phase by appropriate suspension in acidic or basic solutions. The feasibility of the proposed separation protocol was demonstrated and optimized with an "artificial mixture" of model compounds. In addition, the utility of this methodology was illustrated with the successful separation of the alkaloid skytanthine from Skytanthus acutus Meyen and the main catechins and caffeine from Camellia sinensis L. (Kuntze). This novel approach offers multiple advantages over traditional extraction methods, as it is not labor intensive, makes use of only small quantities of solvents, produces fractions in adequate quantities for biological assays, and can be easily adapted to field conditions for bioprospecting activities. PMID- 20704310 TI - Synthesis and reactivity of sulfur(II) dications stabilized using monodentate ligands. AB - The stoichiometric 1:2:2 reaction of SCl(2), trimethylsilyl trifluoromethanesulfonate, and pyridine produced sulfur(II) dications featuring two pyridine donors. The complexes were reacted with unsaturated organic substrates, which displayed addition with carbon-carbon and carbon-nitrogen double bonds. The substitution on the para position of the ligand was varied by using electron donating, electron withdrawing, and neutral groups. The electronics at this position were determined to have a substantial effect on the outcome of the reaction. The presence of an electron donating group increased the Lewis basicity sufficiently to completely stop the reaction, whereas an electron withdrawing group decreased the reaction time. These observations are unique to the chemistry of sulfur(II) dications and main group polycations as a whole. PMID- 20704312 TI - Lucknolides A and B, tricyclic ketal-lactone metabolites from a terrestrial Streptomyces sp. AB - In a screening of micro-organisms for new secondary metabolites, two unprecedented tricyclic highly functionalized ketal-lactone metabolites, named lucknolide A (1) and lucknolide B (2), have been isolated, and the compounds were characterized by extensive NMR and mass spectroscopic studies. Single-crystal X ray diffraction experiments on 1 and 2 were performed, and the absolute configuration of 1 was determined. PMID- 20704311 TI - Effective enrichment and mass spectrometry analysis of phosphopeptides using mesoporous metal oxide nanomaterials. AB - Mass spectrometry (MS)-based phosphoproteomics remains challenging due to the low abundance of phosphoproteins and substoichiometric phosphorylation. This demands better methods to effectively enrich phosphoproteins/peptides prior to MS analysis. We have previously communicated the first use of mesoporous zirconium dioxide (ZrO(2)) nanomaterials for effective phosphopeptide enrichment. Here, we present the full report including the synthesis, characterization, and application of mesoporous titanium dioxide (TiO(2)), ZrO(2), and hafnium dioxide (HfO(2)) in phosphopeptide enrichment and MS analysis. Mesoporous ZrO(2) and HfO(2) are demonstrated to be superior to TiO(2) for phosphopeptide enrichment from a complex mixture with high specificity (>99%), which could almost be considered as a "purification", mainly because of the extremely large active surface area of mesoporous nanomaterials. A single enrichment and Fourier transform MS analysis of phosphopeptides digested from a complex mixture containing 7% of alpha-casein identified 21 out of 22 phosphorylation sites for alpha-casein. Moreover, the mesoporous ZrO(2) and HfO(2) can be reused after a simple solution regeneration procedure with comparable enrichment performance to that of fresh materials. Mesoporous ZrO(2) and HfO(2) nanomaterials hold great promise for applications in MS-based phosphoproteomics. PMID- 20704313 TI - Bis(hydroxy-isoindolinone)s: synthesis, stereochemistry, polymer chemistry, and supramolecular assembly. AB - Pseudoacid chlorides of 2,5-bis(4-fluorobenzoyl) terephthalic acid and 4,6-bis(4 fluorobenzoyl) isophthalic acid condense with primary amines to afford diastereomeric bis(hydroxyindolinone)s in good isolated yields and with diamines to give high molecular weight poly(hydroxyindolinone)s. Bis-N-pyrenemethyl bis(hydroxyindolinone)s assemble, even in dipolar solvents such as DMSO, with macrocyclic diimide-sulfones to give [3]pseudorotaxanes stabilized by electronically complementary aromatic pi-pi-stacking and shape-complementary van der Waals interactions. PMID- 20704314 TI - Solid-state dye-sensitized solar cells using red and near-IR absorbing Bodipy sensitizers. AB - Boron-dipyrrin dyes, through rational design, yield promising new materials. With strong electron-donor functionalities and anchoring groups for attachment to nanocrystalline TiO(2), these dyes proved useful as sensitizers in dye-sensitized solar cells. Their applicability in a solid-state electrolyte regime offers additional opportunities for practical applications. PMID- 20704315 TI - Synthesis of Microcin SF608 through nucleophilic opening of an oxabicyclo[2.2.1]heptane. AB - The total synthesis of Microcin SF608 is reported. Access to the octahydroindole core structure of Microcin SF608 relies on the TMSOTf/NEt(3)-mediated opening of an oxabicyclic ring system. Additional highlights of the synthetic strategy that is reported include a highly regioselective epoxide reduction and photolytic excision of a 3 degrees alcohol. PMID- 20704316 TI - Thermochemistry and UV spectroscopy of alkyl peroxynitrates. AB - High level ab initio calculations and multiconfigurational methods have been used to characterize the equilibrium structures, vibrational frequencies, enthalpies of formation, and UV-vis spectra of alkyl peroxynitrates R-OONO(2) (R = H, CH(3), C(2)H(5), C(3)H(7)). Excellent agreement with the experimental enthalpy of formation is obtained for HOONO(2) warranting similar accuracy for the rest of compounds for which values are inexistent or measured indirectly. The spectra obtained by MS-CASPT2/CASSCF calculations are very similar in all the species, showing a broad band below 200 nm with a shoulder due to pipi* transitions and a tail at approximately 250 nm due to weak npi* transitions on the NO(2) group. PMID- 20704317 TI - Reaction of bromide with bromate in thin-film water. AB - Thin-film water is ubiquitous in nature, occurring on virtually all surfaces exposed to the ambient environment. In particular, alkali halide salts below their deliquescence point are expected to be coated with water films from one molecular layer to a few nanometers thick. While salt ion mobility in thin-film water has been characterized in the literature, little is known about the chemistry occurring within these films. Here we investigate the surface chemistry change of a mixed bromine salt (KBr/KBrO(3)) using X-ray photoelectron spectroscopy, secondary electron microscopy, and energy-dispersive X-ray spectroscopy. At 68% relative humidity, the Br(-) surface concentration was observed to deplete with increasing water vapor exposure time. Known bulk solution kinetics for the reaction of Br(-) + BrO(3)(-) has a second-order dependence on H(+) concentrations. However, in the present experiments there was no addition of an external acid. These results suggest that the pH and chemical reactions within thin-film water are uniquely differently from bulk solution. Because bromine chemistry in the atmosphere is strongly influenced by pH, these results have implications for the cycling of bromine where thin-film water is present. PMID- 20704318 TI - A comparison of covalent immobilization and physical adsorption of a cellulase enzyme mixture. AB - This paper reports the first use of a linker-free covalent approach for immobilizing an enzyme mixture. Adsorption from a mixture is difficult to control due to varying kinetics of adsorption, variations in the degree of unfolding and competitive binding effects. We show that surface activation by plasma immersion ion implantation (PIII) produces a mildly hydrophilic surface that covalently couples to protein molecules and avoids these issues, allowing the attachment of a uniform monolayer from a cellulase enzyme mixture. Atomic force microscopy (AFM) showed that the surface layer of the physically adsorbed cellulase layer on the mildly hydrophobic surface (without PIII) consisted of aggregated enzymes that changed conformation with incubation time. The evolution observed is consistent with the existence of transient complexes previously postulated to explain the long time constants for competitive displacement effects in adsorption from enzyme mixtures. AFM indicated that the covalently coupled bound layer to the PIII-treated surface consisted of a stable monolayer without enzyme aggregates, and became a double layer at longer incubation times. Light scattering analysis showed no indication of aggregates in the solution at room temperature, which indicates that the surface without PIII-treatment induced enzyme aggregation. A model for the attachment process of a protein mixture that includes the adsorption kinetics for both surfaces is presented. PMID- 20704319 TI - Total syntheses of arylindolizidine alkaloids (+)-ipalbidine and (+)-antofine. AB - This paper presents the first application of two recently developed reactions to natural product synthesis. The first method involves a 6-endo-trig cyclization to prepare a versatile chiral enaminone building block. The second is a direct C-H arylation reaction. As a showcase for the utility of these methods, (+)-antofine and (+)-ipalbidine were synthesized in only 8 steps and 24-26% overall yields. PMID- 20704320 TI - Series of isostructural planar lanthanide complexes [Ln(III)4(mu3 OH)2(mdeaH)2(piv)8] with single molecule magnet behavior for the Dy4 analogue. AB - A series of five isostructural tetranuclear lanthanide complexes of formula [Ln(4)(mu(3)-OH)(2)(mdeaH)(2)(piv)(8)], (mdeaH(2) = N-methyldiethanolamine; piv = pivalate; Ln = Tb (1), Dy (2), Ho (3), Er (4), and Tm (5)) have been synthesized and characterized. These clusters have a planar "butterfly" Ln(4) core. Magnetically, the Ln(III) ions are weakly coupled in all cases; the Dy(4) compound 2 shows Single Molecule Magnet (SMM) behavior. PMID- 20704321 TI - The fermi level dependent electronic properties of the smallest (2,2) carbon nanotube. AB - A metal-semiconductor transition in the smallest (2,2) single-wall carbon nanotube (SWNT) is predicted theoretically as a function of gate voltage. By hole doping (or heavy electron-doping), the energy gap of a neutral (2,2) SWNT vanishes with structural change, and the (2,2) SWNT becomes metallic. The (2,2) tube assumes a doubly degenerate ground state around the charge neutral condition with an energy barrier, while this tube has only one nondegenerate metallic ground state over an energy window of -0.12 to +0.40 eV. Because of a high density of states at the Fermi energy for hole-doped (2,2) SWNTs, a possible superconducting transition is expected. PMID- 20704322 TI - Controlling plasmonic wave packets in silver nanowires. AB - Three-dimensional finite-difference time-domain simulations were performed to explore the excitation of surface plasmon resonances in long silver (Ag) nanowires. In particular, we show that it is possible to generate plasmonic wave packets that can propagate along the nanowire by exciting superpositions of surface plasmon resonances. By using an appropriately chirped pulse, it is possible to transiently achieve localization of the excitation at the distal end of the nanowire. Such designed coherent superpositions will allow realizing spatiotemporal control of plasmonic excitations for enhancing nonlinear responses in plasmonic "circuits". PMID- 20704323 TI - High-performance flexible graphene field effect transistors with ion gel gate dielectrics. AB - A high-performance low-voltage graphene field-effect transistor (FET) array was fabricated on a flexible polymer substrate using solution-processable, high capacitance ion gel gate dielectrics. The high capacitance of the ion gel, which originated from the formation of an electric double layer under the application of a gate voltage, yielded a high on-current and low voltage operation below 3 V. The graphene FETs fabricated on the plastic substrates showed a hole and electron mobility of 203 +/- 57 and 91 +/- 50 cm(2)/(V x s), respectively, at a drain bias of -1 V. Moreover, ion gel gated graphene FETs on the plastic substrates exhibited remarkably good mechanical flexibility. This method represents a significant step in the application of graphene to flexible and stretchable electronics. PMID- 20704325 TI - Subwavelength plasmonic lasing from a semiconductor nanodisk with silver nanopan cavity. AB - We report the experimental demonstration of an optically pumped silver-nanopan plasmonic laser with a subwavelength mode volume of 0.56(lambda/2n)(3). The lasing mode is clearly identified as a whispering-gallery plasmonic mode confined at the bottom of the silver nanopan from measurements of the spectrum, mode image, and polarization state, as well as agreement with numerical simulations. In addition, the significant temperature-dependent lasing threshold of the plasmonic mode contrasts and distinguishes them from optical modes. Our demonstration and understanding of these subwavelength plasmonic lasers represent a significant step toward faster, smaller coherent light sources. PMID- 20704324 TI - Nucleobase recognition in ssDNA at the central constriction of the alpha hemolysin pore. AB - Nanopores are under investigation for single-molecule DNA sequencing. The alpha hemolysin (alphaHL) protein nanopore contains three recognition points capable of nucleobase discrimination in individual immobilized ssDNA molecules. We have modified the recognition point R(1) by extensive mutagenesis of residue 113. Amino acids that provide an energy barrier to ion flow (e.g., bulky or hydrophobic residues) strengthen base identification, while amino acids that lower the barrier weaken it. Amino acids with related side chains produce similar patterns of nucleobase recognition providing a rationale for the redesign of recognition points. PMID- 20704326 TI - Tunable dual emission in doped semiconductor nanocrystals. AB - Colloidal manganese-doped semiconductor nanocrystals have been developed that show pronounced intrinsic high-temperature dual emission. Photoexcitation of these nanocrystals gives rise to strongly temperature dependent luminescence involving two distinct but interconnected emissive excited states of the same doped nanocrystals. The ratio of the two intensities is independent of nonradiative effects. The temperature window over which pronounced dual emission is observed can be tuned by changing the nanocrystal energy gap during growth. This unique combination of properties makes this new class of intrinsic dual emitters attractive for ratiometric optical thermometry applications. PMID- 20704327 TI - Novel three-dimensional metal-azide network induced by a bipyridine-based zwitterionic monocarboxylate ligand: structures and magnetism. AB - The 4,4'-bipyridine-based zwitterionic monocarboxylate ligand, 4,4'-dipyridinio-1 acetate (L), is used as coligand to construct novel magnetic coordination polymers with mixed azide and carboxylate bridges. Two compounds, [Co(2)(L)(2)(N(3))(4)(H(2)O)] x 4 H(2)O (1) and [Mn(6)(L)(4)(N(3))(12)(H(2)O)] x 5 H(2)O (2), have been structurally and magnetically characterized. Compound 1 consists of one-dimensional (1D) coordination chains in which the unprecedented binuclear motifs with mixed (mu-EO-N(3))(mu-COO)(2) (EO = end-on) triple bridges are cross-linked by the 4,4'-dipyridinium-N-methylene spacers. In compound 2, the azide anions link the metal ions into a very complicated three-dimensional (3D) network with unprecedented topology, and the zwitterionic coligand is embedded in and serves as additional supports for the 3D network. Magnetic studies reveal that the mixed (mu-EO-N(3))(mu-COO)(2) triple bridges transmit ferromagnetic coupling in the Co(II) compound, and the overall antiferromagnetic interactions exist in the Mn(II) compound. PMID- 20704328 TI - Breaking the cycle: impact of sterically-tailored tetra(pyrazolyl)lutidines on the self-assembly of silver(I) complexes. AB - A improved preparation of the pentadentate ligand alpha,alpha,alpha',alpha' tetra(pyrazolyl)lutidine, pz(4)lut, and the syntheses of three new alkyl substituted pyrazolyl derivatives pz(4')(4)lut (pz(4') = 4-methylpyrazolyl), pz*(4)lut (pz* = 3,5-dimethylpyrazolyl), and pz(DIP)(4)lut (pz(DIP) = 3,5 diisopropylpyrazolyl) are described. The silver(I) complexes of these ligands were studied to ascertain the impact of pyrazolyl substitution, if any, on their binding modes and on solubility issues. In the solid state, [Ag(pz(4)lut)](BF(4)) (1), [Ag(pz(4')(4)lut)](BF(4)) (2), and [Ag(pz*(4)lut)](BF(4)) (3) give cyclic dications as a result of two ligands sandwiching two silver centers where each ligand binds the metals through only pyrazolyl nitrogen donors. This cyclic motif is similar to those observed in the silver complexes of tetra(pyridyl)lutidine PY5-R derivatives (where the central pyridyl does not bind) and in related tetra(pyrazolyl)-m-xylene complexes. While suitable single crystals of [Ag(pz(DIP)(4)lut)](BF(4)) (4) could not be obtained, those of [Ag(pz(DIP)(4)lut)](OTf) (5) showed infinite polymeric chains secured via silver bound mu-kappa(2)N(pz),kappa(2)N(pz)- ligands. The different binding mode of the latter ligand versus the former three is likely due to unfavorable steric interactions between the bulky iso-propyl (pyrazolyl) substituents and the central pyridyl rings of hypothetical cyclic architectures. The combined electrospray ionization mass spectrometry (ESI(+)-MS), variable-temperature NMR (VT NMR), and diffusion pulsed field-gradient spin-echo (PFGSE) NMR data indicate that the solid state structures of each 1-5 are neither retained nor static in CD(3)CN, rather the cations are monomeric in solution. PMID- 20704330 TI - Extremely large dipole moment in the excited singlet state of tris{[p-(N,N dimethylamino)phenylethynyl]duryl}borane. AB - Solvent effects on the spectroscopic and photophysical properties of tris{[p-(N,N dimethylamino)phenylethynyl]duryl}borane (TMAB) and tris[(phenylethynyl)duryl]borane (TPhB) were studied in detail. Both TMAB and TPhB exhibited broad and structureless absorption and fluorescence bands ascribed to the charge transfer (CT) transition between the pi-orbital of the aryl group (pi(aryl)) and the vacant p-orbital on the boron atom (p(B)): pi(aryl)-p(B) CT. The fluorescence spectra of TMAB and TPhB were dependent on a solvent polarity, and the Stokes shifts of the compounds (Deltanu(S)) were shown to correlate linearly with a solvent polarity parameter: f(X) = (D(s) - 1)/(2D(s) + 1) - (n(2) - 1)/(2n(2) + 1) where D(s) and n are the dielectric constant and refractive index of a solvent, respectively. The slope value of the Deltanu(S) versus f(X) plot gave the excited singlet state dipole moment of TMAB or TPhB to be approximately 60 or approximately 30 D, respectively, demonstrating that the excited singlet state of TMAB possessed an extremely large dipole moment. The fluorescence quantum yields (Phi(f)) and lifetimes (tau(f)) of the compounds were also dependent on f(X). Detailed analysis of the present results demonstrated that the photophysical properties of TMAB were governed by the magnitude of the fluorescence rate constant (k(f)) and the k(f) value decreased almost one-tenth with an increase in f(X), which was the primary origin of the f(X) dependences of Phi(f) and tau(f). The results were discussed in terms of the characteristic pi(aryl)-p(B) CT excited states of the derivatives. PMID- 20704329 TI - Characterization of the epoxide hydrolase NcsF2 from the neocarzinostatin biosynthetic gene cluster. AB - Neocarzinostatin (1) biosynthesis is proposed to involve a vicinal diol intermediate. It is reported that NcsF2, one of two epoxide hydrolases encoded by the NCS gene cluster, catalyzes regiospecific addition of H(2)O to C-2 of both (R)- and (S)-styrene oxides to afford (R)- and (S)-1-phenyl-1,2-ethanediols, respectively, supporting its proposed role in 1 biosynthesis. (R)-1-Phenyl-1,2 ethanediol (87% yield and 99% ee) was obtained from (+/-)-styrene oxide hydrolysis by cocatalysis using NcsF2 and SgcF, the complementary epoxide hydrolase from the C-1027 biosynthetic pathway. PMID- 20704331 TI - Cytotoxic flavonoids from the leaves of Cryptocarya chinensis. AB - Bioassay-guided fractionation led to the isolation of six new tetrahydroflavanones, cryptochinones A-F (1-6), from the neutral CHCl(3) fraction of Cryptocarya chinensis leaves, together with 14 known compounds (7-20). The structures of these new compounds were determined through spectroscopic analyses, including 2D-NMR, MS, CD, and X-ray crystallographic analysis. Among the isolates, infectocaryone (7) showed cytotoxic activities with IC(50) values of 11.0 and 3.7 MUM against NCI-H460 and SF-268 cell lines, respectively, and cryptocaryanone A (9) showed cytotoxic activities with IC(50) values of 5.1, 4.3, and 5.0 MUM against MCF-7, NCI-H460, and SF-268 cell lines, respectively. PMID- 20704332 TI - Separation of geometric isomers of a dicopper complex by using a (19)F-labeled ligand: dynamics, structures, and DFT calculations. AB - Introducing a fluorine group on two pyridines of the HL(CH(3)) ligand (2,6 bis[(bis(2-pyridylmethyl)amino)methyl]-4-methylphenol) allows the separation of two geometric isomers after complexation by two copper(II) ions. Methods for isolating the isomers (1(meso) and 1(rac)) as a mu-phenoxo,mu-hydroxo dicopper(II) complex as a crystalline product have been developed. Both isomers (1(meso) and 1(rac)) have been characterized by X-ray crystallography and (19)F NMR. The isomerism is determined by the disposition of the fluorine atoms with respect to the plane containing the Cu(2)O(2) core. Density functional theory calculations using different functionals were performed to provide additional support for the existence of these two forms. Dissolution of 1(meso) in acetone or acetonitrile causes its spontaneous isomerization into the 1(rac) form at room temperature. Combined experimental studies (UV-vis, (19)F NMR) and theoretical calculations support this process. Paramagnetic (19)F NMR appears as a unique and powerful probe for distinguishing the two isomers and supplying direct evidence of this isomerization process in solution. PMID- 20704333 TI - An efficient approach to functionalized benzo[a]xanthones through reactions of 2 methyl-3-(1-alkynyl)chromones with electron-deficient chromone-fused dienes. AB - An efficient tandem process was developed to synthesize diversified benzo[a]xanthones from 2-methyl-3-(1-alkynyl)chromones with electron-deficient chromone-fused dienes. This unusual reaction, involving multiple steps and not requiring the use of transition metal catalysts or an inert atmosphere, results in the formation of three new C-C bonds and one C-O bond. PMID- 20704334 TI - Pd-catalyzed ortho-C-H acylation/cross coupling of aryl ketone O-methyl oximes with aldehydes using tert-butyl hydroperoxide as oxidant. AB - A Pd-catalyzed protocol for direct C-H bond acylation by cross coupling of aryl ketone oximes and aldehydes using tert-butyl hydroperoxide (TBHP) as oxidant was developed. With oximes as a directing group for the C-H activation, the coupling with aldehydes was achieved with remarkable regioselectivity. The acylation reactions exhibit excellent functional group tolerance, and both aliphatic and heteroaromatic aldehydes can be effectively coupled to the oximes. PMID- 20704335 TI - Multimetallic Au/FePt3 nanoparticles as highly durable electrocatalyst. AB - We report the design and synthesis of multimetallic Au/Pt-bimetallic nanoparticles as a highly durable electrocatalyst for the oxygen reduction reaction (ORR) in proton exchange membrane fuel cells. This system was first studied on well-defined Pt and FePt thin films deposited on a Au(111) surface, which has guided the development of novel synthetic routes toward shape controlled Au nanoparticles coated with a Pt-bimetallic alloy. It has been demonstrated that these multimetallic Au/FePt(3) nanoparticles possess both the high catalytic activity of Pt-bimetallic alloys and the superior durability of the tailored morphology and composition profile, with mass-activity enhancement of more than 1 order of magnitude over Pt catalysts. The reported synergy between well-defined surfaces and nanoparticle synthesis offers a persuasive approach toward advanced functional nanomaterials. PMID- 20704336 TI - Permeabilization of lipid membranes and cells by a light-responsive copolymer. AB - Membrane permeabilization is achieved via numerous techniques involving the use of molecular agents such as peptides used in antimicrobial therapy. Although high efficiency is reached, the permeabilization mechanism remains global with a noticeable lack of control. To achieve localized control and more gradual increase in membrane perturbation, we have developed hydrophobically modified poly(acrylic acid) amphiphilic copolymers with light-responsive azobenzene hydrophobic moieties. We present evidence for light triggered membrane permeabilization in the presence azobenzene-modified polymers (AMPs). Exposure to UV or blue light reversibly switches the polarity of the azobenzene (cis-trans isomerization) in AMPs, hence controlling AMP-loaded lipid vesicles permeabilization via in situ activation. Release of encapsulated probes was studied by microscopy on isolated AMP-loaded giant unilamellar vesicles (pol GUVs). We show that in pH and ionic strength conditions that are biologically relevant pol-GUVs are kept impermeable when they contain predominantly cis-AMPs but become leaky with no membrane breakage upon exposure to blue light due to AMPs switch to a trans-apolar state. In addition, we show that AMPs induce destabilization of plasma membranes when added to mammal cells in their trans apolar state, with no loss of cell viability. These features make AMPs promising tools for remote control of cell membrane permeabilization in mild conditions. PMID- 20704338 TI - Cross-linked network development in compatibilized alkyd/acrylic hybrid latex films for the creation of hard coatings. AB - Hybrids made from an alkyd resin and an acrylic copolymer can potentially combine the desired properties of each component. Alkyd/acrylic hybrid latex particles were synthesized via miniemulsion polymerization and used to create films at room temperature. Comparisons of the alkyd auto-oxidative cross-linking rates and the associated network development are made between two alkyd resins (with differing levels of hydrophilicity as measured by their acid numbers). The effects of increasing the compatibilization between the alkyd and the acrylic phase via functionalization with glycidyl methacrylate (GMA) are investigated. Magnetic resonance profiling and microindentation measurements reveal that film hardening occurs much faster in a GMA-functionalized alkyd hybrid than in the standard hybrid. The film's hardness increases by a factor of 4 over a 5-day period. The rate of cross-linking is significantly slower in nonfunctionalized alkyd hybrid films and when the more hydrophilic alkyd resin is used. Tensile deformation of the hybrid latex films reveals the effects of GMA functionalization and drier concentration in creating a denser cross-linked network. Modeling of the tensile deformation behavior of the hybrid films used a combination of the upper convected Maxwell model (to describe the viscoelastic component) and the Gent model (to describe the elastic component). The modeling provides a correlation between the cross-linked network formation and the resulting mechanical properties. PMID- 20704339 TI - Vesicle-to-micelle oscillations and spatial patterns. AB - A pH oscillator is coupled to and controls rhythmic interconversion of nanoscopic vesicles and micelles made of fatty acids. When changes in pH are combined with diffusion, self-assembly produces spatially extended patterns of vesicle/micelle "stripes" or concentric "shells". PMID- 20704340 TI - Selective capture and identification of pathogenic bacteria using an immobilized siderophore. AB - Rapid identification of infectious pathogens constitutes an important step toward limiting the spread of contagious diseases. Whereas antibody-based detection strategies are often selected because of their speed, mutation of the pathogen can render such tests obsolete. In an effort to develop a rapid yet mutation proof method for pathogen identification, we have explored the use of "immutable ligands" to capture the desired microbe on a detection device. In this "proof-of principle" study, we immobilize pyoverdine, a siderophore that Pseudomonas aeruginosa must bind to obtain iron, onto gold-plated glass chips and then examine the siderophore's ability to capture P. aeruginosa for its subsequent identification. We demonstrate that exposure of pyoverdine-coated chips to increasing dilutions of P. aeruginosa allows detection of the bacterium down to concentrations as low as 10(2)/mL. We further demonstrate that printing of the siderophore in a periodic pattern on the detection chip enables a sensitive method of detecting the bound pathogen by a Fourier transform analysis of light scattered by the patterned chip. Because unrelated bacteria are not captured on the pyoverdine chip, we conclude that pyoverdine can be exploited for the specific binding and identification of P. aeruginosa. It follows that the utilization of other microbe-specific "immutable ligands" may allow the specific identification of their cognate pathogens. PMID- 20704337 TI - Stereocomplexed poly(lactic acid)-poly(ethylene glycol) nanoparticles with dual emissive boron dyes for tumor accumulation. AB - Responsive biomaterials play important roles in imaging, diagnostics, and therapeutics. Polymeric nanoparticles (NPs) containing hydrophobic and hydrophilic segments are one class of biomaterial utilized for these purposes. The incorporation of luminescent molecules into NPs adds optical imaging and sensing capability to these vectors. Here we report on the synthesis of dual emissive, pegylated NPs with "stealth"-like properties, delivered intravenously (IV), for the study of tumor accumulation. The NPs were created by means of stereocomplexation using a methoxy-terminated polyethylene glycol and poly(D lactide) (mPEG-PDLA) block copolymer combined with iodide-substituted difluoroboron dibenzoylmethane-poly(L-lactide) (BF2dbm(I)PLLA). Boron nanoparticles (BNPs) were fabricated in two different solvent compositions to study the effects on BNP size distribution. The physical and photoluminescent properties of the BNPs were studied in vitro over time to determine stability. Finally, preliminary in vivo results show that stereocomplexed BNPs injected IV are taken up by tumors, an important prerequisite to their use as hypoxia imaging agents in preclinical studies. PMID- 20704341 TI - Mesoscale modeling of hydrated morphologies of 3M perfluorosulfonic acid-based fuel cell electrolytes. AB - Dissipative particle dynamics (DPD) simulations have been carried out to study the hydrated morphology of 3M perfluorosulfonic acid (PFSA) fuel cell membranes as a function of the equivalent weight (EW), molecular weight (MW), and hydration level. The 3M PFSA ionomers were modeled using typical EWs of 578, 640, and 790 g/mol, and molecular weights were varied from about 45,000 to 90,000 g/mol in order to be close to the experimental range. The morphology changes corresponding to the EW, MW, and hydration level were comparatively investigated by inspecting the water distributions, followed by quantitative analysis by radial distribution functions and Bragg spacing according to the periodicity of water domains. Compared to the morphologies of short-side-chain PFSA membrane (Wu, D.; Paddison, S. J.; Elliott, J. A. Macromolecules 2009, 42, 3358-3367), the longer side chain in 3M PFSA membrane provides more flexibility for the sulfonate-terminated side chains and generally results in the stronger aggregation of water clusters. This results in lower water uptake for higher EW, corresponding to a lower ion exchange capacity (IEC), which is attributed experimentally to a higher crystallinity of the fluorocarbon phase, although our simulations were not able to observe the crystallites directly. PMID- 20704342 TI - Palladium-catalyzed C-F activation of polyfluoronitrobenzene derivatives in Suzuki-Miyaura coupling reactions. AB - Highly fluorinated nitrobenzene derivatives are suitable substrates for palladium catalyzed C-F bond arylation using readily available palladium catalysts under both conventional heating and microwave conditions. Arylation occurs ortho to the nitro group offering a synthetic route to polyfluorinated 2-arylnitrobenzene systems. The regiochemistry of the arylation reactions suggests that there is a significant directing interaction between the nitro group and the incoming nucleophilic palladium catalyst which is facilitated by the presence of several fluorine atoms attached the ring. Investigations into the regioselectivity and reactivity of several tetrafluoro- and trifluoronitrobenzene derivatives provides further evidence for the highly nucleophilic character of the oxidative addition step in contrast to the concerted mechanism of more conventional Suzuki-Miyaura coupling reactions involving aryl iodides and bromides. PMID- 20704344 TI - Influence of monomer feeding on a fast gold nanoparticles synthesis: time resolved XANES and SAXS experiments. AB - A comprehensive study of the mechanism of gold nanoparticle formation has been conducted using third-generation synchrotrons. The particles were obained by reduction of AuCl(3) by BH(4)(-) in toluene. Gold oxidation state was monitored by X-ray absorption near edge spectroscopy (XANES), while the size and concentration of the nanoparticles were assessed by small-angle X-ray scattering (SAXS). A time-resolution of 100 ms has been achieved for a total formation time of a few seconds. The change with time of the total amount of Au(0) present in the solution is obtained by XANES. The change of the amount of Au(0) inside the nanoparticles is obtained from the SAXS signal. The comparison between these two quantities shows that a measurable amount of Au(0) exists transiently as monomers (or very small entities) in solution and this quantity is linked to an observed burst of nucleation of nanoparticles. The reduction kinetics is strongly influenced by the presence of ligands and a change in temperature. A model coupling the observed reduction kinetics and nucleation and growth laws is able to recover the final size and number densities of the explored experimental conditions. PMID- 20704343 TI - Photoinduced morphology switching of polymer nanoaggregates in aqueous solution. AB - A novel photosensitive C-PNIPAAm comprising hydrophilic PNIPAAm conjugated with a relatively short but very hydrophobic coumarin part was designed and prepared using a coumarin-containing disulfide derivative (C-S-S-C) as transfer agent in the presence of Bu(3)P and water. It was found that C-PNIPAAm can form polymer micelles in aqueous solution. And the micellar morphology in aqueous solution can be photoswitched into hollow spheres according to the photodimerization of coumarin end groups upon 365 nm irradiation and reform the micellar morphology after the subsequent photoscission of dimers upon 254 nm. This instant morphology changing phenomenon was successfully monitored by dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements. TEM observations showed the small spherical shape of micelles with diameter at 30-50 nm before photo cross-linking, the big vesicles with diameter at 200-350 nm after photo-cross linking, and the small micelles with diameter at 30-50 nm after the subsequent photo-de-cross-linking in the first irradiation cycle. The reason for this significant morphology switching can be attributed to the reversible photoinduced amphiphilic structure transformation between the telechelic "hydrophobic end hydrophilic chain" structure and the ABA type of "hydrophilic chain-hydrophobic center-hydrophilic chain" one upon alternating irradiation. PMID- 20704346 TI - Construction of a star-shaped copolymer as a vector for FGF receptor-mediated gene delivery in vitro and in vivo. AB - The success of cancer gene therapy highly relies on the gene delivery vector with high transfection activity and low toxicity. In the present study, eight-armed polyethylene glycol (EAP) and low molecular weight (LMW) polyethylenimine (PEI) were used as basic units to construct the architecture of a new star-shaped EAP PEI copolymer (EAPP). MC11, a peptide capable of selectively binding fibroblast growth factor receptor (FGFR) on tumor cell membranes, was further conjugated to EAPP to produce the vector EAPP-MC11 (EAPPM) to enhance tumor targetability. This tumor-targeting vector EAPPM was observed to retard the plasmids mobility at a nitrogen/phosphorus (N/P) ratio of 3. The vector could efficiently condense plasmids within 300 nm nanoparticles with a positive zeta potential at the N/P ratio of 20 or above. While the cytotoxicity of EAPPM polyplexes was similar to that of LMW PEI, it was significantly lower than that of PEI (25 kDa) in HepG2 and PC3 cell lines. In vitro gene transfection with pDNA mediated by EAPPM showed that the transfection efficiency increased 15 times in HepG2 cells but remained at a similar level in PC3 cells in comparison with that of EAPP. By systemic injection of EAPPM/pDNA complexes into a HepG2-bearing mice model, luciferase expression detected in lung, liver, and tumor tissues demonstrated EAPPM could deliver in a targeted manner a reporter gene into tumor tissues, where the luciferase expression of EAPPM was 4 times higher than that of EAPP and even 23 times higher than that of PEI (25 kDa). Furthermore, it was found that the systemic delivery of EAPPM/pCSK-alpha-interferon complexes in vivo were much more effective in inhibiting tumor growth than EAPP or PEI (25 kDa). These results clearly show that EAPPM is an efficient and safe vector for FGFR-mediated targeted gene delivery both in vitro and in vivo. With low cytotoxicity and high targetability, EAPPM may have great potential as a delivery vector for future cancer gene therapy applications. PMID- 20704345 TI - Nanoparticle-directed self-assembly of amphiphilic block copolymers. AB - Nanoparticles can form unique cavity-like structures in core-shell type assemblies of block copolymers through the cooperative self-assembly of nanoparticles and block copolymers. We show that the self-assembly behavior is general for common as-synthesized alkyl-terminated nanoparticles for a range of nanoparticle sizes. We examined various self-assembly conditions such as solvent compositions, nanoparticle coordinating ligands, volume fraction of nanoparticles, and nanoparticle sizes in order to elucidate the mechanism of the radial assembly formation. These experiments along with strong segregation theory calculations indicated that both the enthalpic interaction and the polymer stretching energy are important factors in the coassembly formation. The slightly unfavorable interaction between the hydrophobic segment of polymers and alkyl terminated nanoparticles causes the accumulation of nanoparticles at the interface between the polymer core and the shell, forming the unique cavity-like structure. The coassemblies were stabilized for a limited range of nanoparticle volume fractions within which the inclusion of nanoparticle layers reduces the polymer stretching. The volume fraction range yielding the well-defined radial coassembly structure was mapped out with varying nanoparticle sizes. The experimental and theoretical phase map provides the guideline for the coassembly formation of as-synthesized alkyl-terminated nanoparticles and amphiphilic block copolymers. PMID- 20704347 TI - Low-frequency vibrational spectrum of water around cyclodextrin and its methyl substituted derivatives. AB - Atomistic molecular dynamics (MD) simulations have been carried out to study the low-frequency intermolecular vibrational spectrum of water present in the surrounding hydration layers and inside the cavities of beta-cyclodextrin (BCD) and its di- and trimethyl substituted derivatives, namely, heptakis(2,6-di-O methyl)-beta-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-beta cyclodextrin (TRIMEB) in aqueous solutions. Attempts have been made to explore the effects of confinement in and around these cyclic macromolecules and the formation of hydrogen bonds between water and the glucopyranose rings on the distribution of the intermolecular vibrational density of states of water. The calculations revealed that compared to bulk water these bands are blue-shifted for water in proximity to these molecules, the extents of the shifts being more pronounced for the cavity water molecules. It is further noticed that the relatively more restricted local motions of water bound to the cyclodextrins by hydrogen bonds result in larger blue shifts of these bands. These results can be verified by suitable experiments. PMID- 20704349 TI - Development of silver-zein composites as a promising antimicrobial agent. AB - Recently, silver, a traditional broad-spectrum antiseptic, drew increasing attentions as a solution against antibiotic resistant bacteria. Various synthetic polymers and nature polymers were applied to form silver polymer composites to cope with the defects (e.g., low hemocompatibility) of silver-loaded antimicrobial agents. In this study, an alcohol-soluble prolamine, zein, was applied to prepare silver-zein composites as novel antiseptics. Both zein in silver (Z]A) and silver nanoparticles (AgNP) in zein (A']Z) structures at two pH conditions (i.e., pH = 3.3 and 6.5) were successfully prepared. Several characterization methods (i.e., zeta potential, FTIR, SEM, and turbidity) confirmed the formation of silver-zein composites through a nitrogen-silver coordination bond and electrostatic interaction. It was found that low pH was critical in facilitating formation and increasing stability of the silver-zein composites, probably by inducing electrostatic interaction between silver and zein. The antiseptic activities (i.e., growth inhibition and bactericidal activity) of different silver-zein composites were studied against Gram negative E. coli and Gram positive S. aureus . It was revealed that the silver-zein composites showed similar or better results against both types of bacteria compared to those of AgNO(3) and AgNP, except for the sample of A']Z-Ac. It had better growth inhibition activity but inferior bactericidal activity than that of AgNP because of its decreased solubility in aqueous medium. Furthermore, addition of zein was proven to be capable of dramatically increasing hemocompatibility of silver-loaded antiseptic agents. Therefore, silver-zein composites prepared in this work may find applications in wound care and food packaging areas. PMID- 20704348 TI - Mass spectrometry-based neuropeptidomics of secretory vesicles from human adrenal medullary pheochromocytoma reveals novel peptide products of prohormone processing. AB - Neuropeptides are required for cell-cell communication in the regulation of physiological and pathological processes. While selected neuropeptides of known biological activities have been studied, global analyses of the endogenous profile of human peptide products derived from prohormones by proteolytic processing in vivo are largely unknown. Therefore, this study utilized the global, unbiased approach of mass spectrometry-based neuropeptidomics to define peptide profiles in secretory vesicles, isolated from human adrenal medullary pheochromocytoma of the sympathetic nervous system. The low molecular weight pool of secretory vesicle peptides was subjected to nano-LC-MS/MS with ion trap and QTOF mass spectrometry analyzed by different database search tools (InsPecT and Spectrum Mill). Peptides were generated by processing of prohormones at dibasic cleavage sites as well as at nonbasic residues. Significantly, peptide profiling provided novel insight into newly identified peptide products derived from proenkephalin, pro-NPY, proSAAS, CgA, CgB, and SCG2 prohormones. Previously unidentified intervening peptide domains of prohormones were observed, thus providing new knowledge of human neuropeptidomes generated from precursors. The global peptidomic approach of this study demonstrates the complexity of diverse neuropeptides present in human secretory vesicles for cell-cell communication. PMID- 20704352 TI - Rotamers of o- and m-dimethoxybenzenes studied by mass-analyzed threshold ionization spectroscopy and theoretical calculations. AB - We applied two-color resonant two-photon mass-analyzed threshold ionization (MATI) spectroscopy to investigate the molecular properties of the selected rotamers of o-dimethoxybenzene (ODMB) and m-dimethoxybenzene (MDMB). The present experimental results show that only one stable configuration is involved in the photoexcitation and ionization processes of ODMB, as predicted by theoretical calculations. The adiabatic ionization energy (IE) of ODMB is measured to be 61 617 +/- 5 cm(-1). In the case of MDMB, both our experimental and calculated results suggest that there are three stable rotamers coexisting in the sample. The adiabatic IEs of rotamers a, b, and c are determined to be 63 523 +/- 5, 64 491 +/- 5, and 63 758 +/- 5 cm(-1). Analysis on the MATI spectra shows that most of the active cation vibrations of these isomeric species result from in-plane ring motions. In addition, different orientations of the two OCH(3) groups have little effect on these vibrations. PMID- 20704353 TI - Consistent treatment of spin-selective recombination of a radical pair confirms the Haberkorn approach. AB - In the present work, we have shown that consistent derivation of the kinetic equations describing the electron spin-selective recombination of radical pairs confirms the conventional Haberkorn approach. The derivation has been based on considering the interaction of the reactive system (radical pair and product state) with the thermal bath. The consistency of this approach has also been substantiated by numerical simulations performed for the purely quantum mechanical model of the recombining radical pair. Finally, we have shown that the quantum Zeno effect on radical pair recombination is not an exclusive feature of the approach recently proposed by Kominis, as it should be present at any rate of the singlet-triplet dephasing in the radical pair, which always accompanies the recombination process. PMID- 20704354 TI - Charge partitioning at gas-solid interfaces: humidity causes electricity buildup on metals. AB - Isolated metals within Faraday cages spontaneously acquire charge at relative humidity above 50%: aluminum and chrome-plated brass become negative, stainless steel is rendered positive, and copper remains almost neutral. Isolated metal charging within shielded and grounded containers confirms that the atmosphere is an electric charge reservoir where OH(-) and H(+) ions transfer to gas-solid interfaces, producing net current. The electricity buildup dependence on humidity, or hygroelectricity, acts simultaneously but in opposition to the well known charge dissipation due to the increase in surface conductance of solids under high humidity. Acknowledging this dual role of humidity improves the reproducibility of electrostatic experiments. PMID- 20704351 TI - p-Trifluoromethyldiazirinyl-etomidate: a potent photoreactive general anesthetic derivative of etomidate that is selective for ligand-gated cationic ion channels. AB - We synthesized the R- and S-enantiomers of ethyl 1-(1-(4-(3-((trifluoromethyl)-3H diazirin-3-yl)phenyl)ethyl)-1H-imidazole-5-carboxylate (trifluoromethyldiazirinyl etomidate), or TFD-etomidate, a novel photoactivable derivative of the stereoselective general anesthetic etomidate (R-(2-ethyl 1-(phenylethyl)-1H imidazole-5-carboxylate)). Anesthetic potency was similar to etomidate's, but stereoselectivity was reversed and attenuated. Relative to etomidate, TFD etomidate was a more potent inhibitor of the excitatory receptors, nAChR (nicotinic acetylcholine receptor) ((alpha1)(2)beta1delta1gamma1) and 5-HT(3A)R (serotonin type 3A receptor), causing significant inhibition at anesthetic concentrations. S- but not R-TFD-etomidate enhanced currents elicited from inhibitory alpha1beta2gamma2L GABA(A)Rs by low concentrations of GABA, but with a lower efficacy than R-etomidate, and site-directed mutagenesis suggests they act at different sites. [(3)H]TFD-etomidate photolabeled the alpha-subunit of the nAChR in a manner allosterically regulated by agonists and noncompetitive inhibitors. TFD-etomidate's novel pharmacology is unlike that of etomidate derivatives with photoactivable groups in the ester position, which behave like etomidate, suggesting that it will further enhance our understanding of anesthetic mechanisms. PMID- 20704355 TI - P-P bond activation of P4 tetrahedron by group 13 carbenoid and its bis molybdenum pentacarbonyl adduct. AB - Activation of white phosphorus with Ga(DDP) (DDP = 2-diiso-propylphenylamino-4 diiso-propylphenylimino-2-pentene) afforded [(DDP)Ga(P(4))] (1) by insertion of the Ga(I) center at one of the six P-P bonded edges of the P(4) tetrahedron. Further reaction of 1 with three equivalents of Mo(CO)(6) results in the formation of [(DDP)Ga(eta(2:1:1)-P(4)){Mo(CO)(5)}(2)] x 2 toluene (2). Compounds 1 and 2 are characterized by (1)H, (13)C, and (31)P NMR spectroscopy, elemental analysis, and single crystal X-ray structural analysis. The solid-state structure of molecule 1 reveals the first example of a structurally characterized GaP(4) core stabilized by a beta-diketiminate ligand. Compound 2 represents a rare type of coordination mode of a gallium supported P(4) butterfly structure. PMID- 20704356 TI - Electrochemical pd nanodeposits on a au nanoisland template supported on Si(100): formation of pd-au alloy and interfacial electronic structures. AB - Palladium nanoparticles have uniformly been electrodeposited on a Au nanoisland template (NIT) supported on a Si(100) substrate, which exhibits Au-rich, Pd-rich, and/or polycrystalline mixed structures upon annealing to 700 degrees C. Glancing-incidence X-ray diffraction (GIXRD) and energy-dispersive X-ray (EDX) elemental analysis of the as-deposited sample both show metallic Pd, while depth profiling X-ray photoelectron spectroscopy (XPS) further reveals the presence of Pd-Au (and PdxSi) at the interfaces of the Pd nanodeposits on the Au NIT. Upon the sample being annealed to 700 degrees C, both Pd 3d(3/2) and Au 4f(7/2) XPS peaks are found to shift to lower binding energies, which further confirms Pd-Au alloy formation. The convergence of respective GIXRD features of metallic Au and Pd toward intermediate peak positions supports the formation of alloy and their crystalline nature. Depth-profiling XPS analysis of the annealed sample further shows that the Pd nanoparticles are found to consist of an ultrathin shell of PdO2, and a PdO-rich (i.e., Pd-poor) inner-core, which is consistent with the observed GIXRD patterns of PdO and Pd-Au alloy but indiscernible PdO2. We compare the above results with the experimental results for electrodeposited Pd on a bare Si(100) substrate. Our study provides new insight into the formation of Pd-Au alloy composite on Si by electrochemistry. The easy control of the Pd, Au, and Pd Au composition in the nanodeposits as illustrated in the present method offers new flexibility for developing hybrid nanocatalysts and other applications. PMID- 20704357 TI - Phosphine-catalyzed domino reaction: highly stereoselective synthesis of trans 2,3-dihydrobenzofurans from salicyl N-thiophosphinyl imines and allylic carbonates. AB - A novel phosphine-catalyzed domino reaction of salicyl N-thiophosphinyl imines and allylic carbonates was developed. The allylic carbonate, in this reaction, serves as a new kind of 1,1-dipolar synthon. This method offered a powerful approach to the construction of a highly substituted trans-2,3-dihydrobenzofuran skeleton with high diastereoselectivity. PMID- 20704358 TI - Is the reactivity of M(II)-arene complexes of 3-hydroxy-2(1H)-pyridones to biomolecules the anticancer activity determining parameter? AB - Hydroxypyr(id)ones are versatile ligands for the synthesis of organometallic anticancer agents, equipping them with fine-tunable pharmacological properties. Herein, we report on the preparation, mode of action, and in vitro anticancer activity of Ru(II)- and Os(II)-arene complexes with alkoxycarbonylmethyl-3 hydroxy-2-pyridone ligands. The hydrolysis and binding to amino acids proceed quickly, as characterized by NMR spectroscopy and ESI mass spectrometry. However, the reaction with amino acids causes cleavage of the pyridone ligands from the metal center because the amino acids act as multidentate ligands. A similar behavior was also observed during the reactions with the model proteins ubiquitin and cytochrome c, yielding mainly [protein + M(eta(6)-p-cymene)] adducts (M = Ru, Os). Notably the ligand cleavage of the Os derivative was significantly slower than of its Ru analogue, which could explain its higher activity in in vitro anticancer assays. Furthermore, the reaction of the compounds to 5'-GMP was characterized and coordination to the N7 of the guanine moiety was demonstrated by (1)H NMR spectroscopy and X-ray diffraction analysis. CDK2/Cyclin A protein kinase inhibition studies revealed potent activity of the Ru and Os complexes. PMID- 20704360 TI - Seleno-auranofin (Et3PAuSe-tagl): synthesis, spectroscopic (EXAFS, 197Au Mossbauer, 31P, 1H, 13C, and 77Se NMR, ESI-MS) characterization, biological activity, and rapid serum albumin-induced triethylphosphine oxide generation. AB - Seleno-auranofin (SeAF), an analogue of auranofin (AF), the orally active antiarthritic gold drug in clinical use, was synthesized and has been characterized by an array of physical techniques and biological assays. The Mossbauer and extended X-ray absorption fine structure (EXAFS) parameters of the solid compound demonstrate a linear P-Au-Se coordination environment at a gold(I) center, analogous to the structure of auranofin. The (31)P, (13)C, and (1)H NMR spectra of SeAF in chloroform solution closely resemble those of auranofin. The (77)Se spectrum consists of a singlet at 481 ppm, consistent with a metal-bound selenolate ligand. The absence of (2)J(PSe) coupling in the (31)P and (77)Se spectra may arise from dynamic processes occurring in solution or because the (2)J(PSe) coupling constants are smaller than the observed bandwidths. Electrospray ionization mass spectrometry (ESI-MS) spectra of SeAF in 50:50 methanol-water exhibited strong signals for [(Et(3)P)(2)Au](+), [(Et(3)PAu)(2)-mu Se-tagl](+), and [Au(Se-tagl)(2)](-), which arise from ligand scrambling reactions. Three assays of the anti-inflammatory activity of SeAF allowed comparison to AF. SeAF exhibited comparable activity in the topically administered murine arachadonic acid-induced and phorbol ester-induced anti inflammatory assays but was inactive in the orally administered carrageenan induced assay in rats. However, in vivo serum gold levels were comparable in the rat, suggesting that differences between the in vivo metabolism of the two compounds, leading to differences in transport to the inflamed site, may account for the differential activity in the carrageenan-induced assay. Reactions of serum albumin, the principal transport protein of gold in the serum, demonstrated formation of AlbSAuPEt(3) at cysteine 34 and provided evidence for facile reduction of disulfide bonds at cysteine 34 and very rapid formation of Et(3)P=O, a known metabolite of auranofin. PMID- 20704359 TI - Mechanism of nitric oxide reactivity and fluorescence enhancement of the NO specific probe CuFL1. AB - The mechanism of the reaction of CuFL1 (FL1 = 2-{2-chloro-6-hydroxy-5-[(2 methylquinolin-8-ylamino)methyl]-3-oxo-3H-xanthen-9-yl}benzoic acid) with nitric oxide (NO) to form the N-nitrosated product FL1-NO in buffered aqueous solutions was investigated. The reaction is first-order in [CuFL1], [NO], and [OH(-)]. The observed rate saturation at high base concentrations is consistent with a mechanism in which the protonation state of the secondary amine of the ligand is important for reactivity. This information provides a rationale for designing faster-reacting probes by lowering the pK(a) of the secondary amine. Activation parameters for the reaction of CuFL1 with NO indicate an associative mechanism (DeltaS(double dagger) = -120 +/- 10 J/mol.K) with a modest thermal barrier (DeltaH(double dagger) = 41 +/- 2 kJ/mol; E(a) = 43 +/- 2 kJ/mol). Variable-pH electron paramagnetic resonance experiments reveal that, as the secondary amine of CuFL1 is deprotonated, electron density shifts to yield a new spin-active species having electron density localized on the deprotonated amine nitrogen atom. This result suggests that FL1-NO formation occurs when NO attacks the deprotonated secondary amine of the coordinated ligand, followed by inner-sphere electron transfer to Cu(II) to form Cu(I) and release of FL1-NO from the metal. PMID- 20704361 TI - Structure and dynamics of the chromate ion in aqueous solution. An ab initio QMCF MD simulation. AB - An ab initio quantum-mechanical charge-field molecular-dynamics (QMCF-MD) simulation of the chromate ion in aqueous solution at ambient temperature was performed to study the structure and dynamics of this ion and its hydration shell. In contrast to conventional quantum-mechanical molecular-mechanics molecular-dynamics (QM/MM-MD) simulations, the QMCF-MD approach offers the possibility of investigating composite systems with the accuracy of a QM/MM method but without the time-consuming construction of solute-solvent potential functions. The data of the simulation give a clear picture of the first hydration shell of the chromate anion, which consists of 14 water molecules. The mean distance between the oxygen atoms of the chromate and the hydrogen atoms of water is 1.82 A. Each chromate oxygen atom is in average coordinated to 2.6 water molecules. The first-shell mean ligand residence time was evalulated as 2.2 ps; the vibrational frequency of the nu(OH) mode was found to be 185 cm(-1). Several structural parameters such as the radial distribution functions, angular distribution functions, and coordination number distributions enable a full characterization of the embedding of the chromate ion in the solvent water. The dynamics of the hydration structure are described by mean residence times of the water molecules in the first hydration shell, distance plots, and velocity autocorrelation functions. PMID- 20704362 TI - Chemical cytometry quantitates superoxide levels in the mitochondrial matrix of single myoblasts. AB - Triphenylphosphonium hydroethidine (TPP-HE) is a membrane-permeable probe that reacts with superoxide and forms hydroxytriphenylphosphonium ethidium (OH-TPP E(+)), a fluorescent product that has been previously used in qualitative measurements of superoxide production. In order to develop quantitative methods to measure superoxide, it is necessary to take into consideration the principles that drive TPP-HE accumulation into various subcellular compartments. In the mitochondria matrix, TPP-HE accumulation depends on the mitochondrial membrane potential, which varies from cell to cell. Here we address this issue by including rhodamine 123 (R123) as an internal mitochondrial membrane potential calibrant in chemical cytometry experiments. After loading with TPP-HE and R123, a single cell is lysed within a separation capillary and its contents are separated and detected by micellar electrokinetic capillary chromatography with laser-induced fluorescence detection (MEKC-LIF). Using theoretical arguments, we show that the ratio [OH-TPP-E(+)]/[R123] is adequate to obtain a relative quantitation of mitochondrial matrix superoxide levels for each analyzed cell. We applied this method to single skeletal muscle myoblasts and determined that the steady state superoxide levels in the mitochondrial matrix is approximately (0.29 +/- 0.10) x 10(-12) M. The development of this quantitative method is a critical step toward establishing the importance of reactive oxygen species in biological systems, including those relevant to aging and disease. PMID- 20704363 TI - Resolving disulfide structural isoforms of IgG2 monoclonal antibodies by ion mobility mass spectrometry. AB - Recombinant monoclonal antibodies are an important class of therapeutic agents that have found widespread use for the treatment of many human diseases. Here, we have examined the utility of ion mobility mass spectrometry (IMMS) for the rapid characterization of disulfide variants in intact IgG2 monoclonal antibodies. It is shown that IMMS reveals 2 to 3 gas-phase conformer populations for IgG2s. In contrast, a single gas-phase conformer is revealed using IMMS for both an IgG1 antibody and a Cys-232 --> Ser mutant IgG2, both of which are homogeneous with respect to disulfide bonding. This provides strong evidence that the observed IgG2 gas-phase conformers are related to disulfide bond heterogeneity. Additionally, IMMS analysis of redox enriched disulfide isoforms allows assignment of the mobility peaks to established disulfide bonding patterns. These data clearly illustrate how IMMS can be used to quickly provide information on the higher order structure of antibody therapeutics. PMID- 20704364 TI - An enzymatic microreactor based on chaotic micromixing for enhanced amperometric detection in a continuous glucose monitoring application. AB - The development of continuous glucose monitoring systems is a major trend in diabetes-related research. Small, easy-to-wear systems which are robust enough to function over many days without maintenance are the goal. We present a new sensing system for continuous glucose monitoring based on a microreactor incorporating chaotic mixing channels. Two different types of chaotic mixing channels with arrays of either slanted or herringbone grooves were fabricated in poly(dimethylsiloxane) (PDMS) and compared to channels containing no grooves. Mixing in channels with slanted grooves was characterized using a fluorescence method as a function of distance and at different flow rates, and compared to the mixing behavior observed in channels with no grooves. For electrochemical detection, a thin-film Pt electrode was positioned at the end of the fluidic channel as an on-chip detector of the reaction product, H(2)O(2). Glucose determination was performed by rapidly mixing glucose and glucose oxidase (GOx) in solution at a flow rate of 0.5 microL/min and 1.5 microL/min, respectively. A 150 U/mL GOx solution was selected as the optimum concentration of enzyme. In order to investigate the dependence of device response on flow rate, experiments with a premixed solution of glucose and GOx were compared to experiments in which glucose and GOx were reacted on-chip. Calibration curves for glucose (0-20 mM, in the clinical range of interest) were obtained in channels with and without grooves, using amperometric detection and a 150 U/mL GOx solution for in-chip reaction. PMID- 20704365 TI - Surface-enhanced Raman spectroscopy as a tool for detecting Ca2+ mobilizing second messengers in cell extracts. AB - Understanding of calcium signaling pathways in cells is essential for elucidating the mechanisms of both normal cell function and cancer development. Calcium messengers play the crucial role for intracellular Ca(2+) release. We propose a new approach to detecting the calcium second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) in cell extracts using surface-enhanced Raman spectroscopy (SERS). Currently available radioreceptor binding and enzymatic assays require extensive sample preparation and take more than 12 h. With a SERS sensor, NAADP can be detected in less than 1 min without any special sample preparation. To the best of our knowledge, this is the first demonstration of using SERS for calcium signaling applications. PMID- 20704366 TI - Highly sensitive fluorescent method for the detection of cholesterol aldehydes formed by ozone and singlet molecular oxygen. AB - Cholesterol oxidation gives rise to a mixture of oxidized products. Different types of products are generated according to the reactive species being involved. Recently, attention has been focused on two cholesterol aldehydes, 3beta-hydroxy 5beta-hydroxy-B-norcholestane-6beta-carboxyaldehyde (1a) and 3beta-hydroxy-5-oxo 5,6-secocholestan-6-al (1b). These aldehydes can be generated by ozone-, as well as by singlet molecular oxygen-mediated cholesterol oxidation. It has been suggested that 1b is preferentially formed by ozone and 1a is preferentially formed by singlet molecular oxygen. In this study we describe the use of 1 pyrenebutyric hydrazine (PBH) as a fluorescent probe for the detection of cholesterol aldehydes. The formation of the fluorescent adduct between 1a with PBH was confirmed by HPLC-MS/MS. The fluorescence spectra of PBH did not change upon binding to the aldehyde. Moreover, the derivatization was also effective in the absence of an acidified medium, which is critical to avoid the formation of cholesterol aldehydes through Hock cleavage of 5alpha-hydroperoxycholesterol. In conclusion, PBH can be used as an efficient fluorescent probe for the detection/quantification of cholesterol aldehydes in biological samples. Its analysis by HPLC coupled to a fluorescent detector provides a sensitive and specific way to quantify cholesterol aldehydes in the low femtomol range. PMID- 20704367 TI - Magnetic nanoparticle enhanced surface plasmon resonance sensing and its application for the ultrasensitive detection of magnetic nanoparticle-enriched small molecules. AB - Magnetic nanoparticles (MNPs) have been frequently used in bioseparation, but their applicability in bioassays is limited due to their extremely small size so that sensitive detection is difficult to achieve using a general technique. Here, we present an amplification technique using MNPs for an enhanced surface plasmon resonance (SPR) bioassay. The amplification effect of carboxyl group modified Fe(3)O(4) MNPs of two sizes on SPR spectroscopy is first demonstrated by assembling MNPs on amino group modified SPR gold substrate. To further evaluate the feasibility of the use of Fe(3)O(4) MNPs in enhancing a SPR bioassay, a novel SPR sensor based on an indirect competitive inhibition assay (ICIA) is developed for detecting adenosine by employing Fe(3)O(4) MNP-antiadenosine aptamer conjugates as the amplification reagent. The results confirm that Fe(3)O(4) MNPs can be used as a powerful amplification agent to provide a sensitive approach to detect adenosine by SPR within the range of 10-10,000 nM, which is much superior to the detection result obtained by a general SPR sensor. Importantly, the present detection methodology could be easily extended to detect other biomolecules of interest by changing the corresponding aptamer in Fe(3)O(4) MNP aptamer conjugates. This novel technique not only explores the possibility of the use of SPR spectroscopy in a highly sensitive detection of an MNP-based separation product but also offers a new direction in the use of Fe(3)O(4) MNPs as an amplification agent to design high performance SPR biosensors. PMID- 20704368 TI - Improved sensitivity mass spectrometric detection of eicosanoids by charge reversal derivatization. AB - Combined liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) is a powerful method for the analysis of oxygenated metabolites of polyunsaturated fatty acids including eicosanoids. Here we describe the synthesis of a new derivatization reagent N-(4-aminomethylphenyl)pyridinium (AMPP) that can be coupled to eicosanoids via an amide linkage in quantitative yield. Conversion of the carboxylic acid of eicosanoids to a cationic AMPP amide improves sensitivity of detection by 10- to 20-fold compared to negative mode electrospray ionization detection of underivatized analytes. This charge reversal derivatization allows detection of cations rather than anions in the electrospray ionization mass spectrometer, which enhances sensitivity. Another factor is that AMPP amides undergo considerable collision-induced dissociation in the analyte portion rather than exclusively in the cationic tag portion, which allows isobaric derivatives to be distinguished by tandem mass spectrometry, and this further enhances sensitivity and specificity. This simple derivatization method allows prostaglandins, thromboxane B(2), leukotriene B(4), hydroxyeicosatetraenoic acid isomers, and arachidonic acid to be quantified in complex biological samples with limits of quantification in the 200-900 fg range. One can anticipate that the AMPP derivatization method can be extended to other carboxylic acid analytes for enhanced sensitivity detection. PMID- 20704369 TI - Delta13C stable isotope analysis of atmospheric oxygenated volatile organic compounds by gas chromatography-isotope ratio mass spectrometry. AB - We present a new method for analyzing the delta(13)C isotopic composition of several oxygenated volatile organic compounds (OVOCs) from direct sources and ambient atmospheric samples. Guided by the requirements for analysis of trace components in air, a gas chromatograph isotope ratio mass spectrometer (GC-IRMS) system was developed with the goal of increasing sensitivity, reducing dead volume and peak band broadening, optimizing combustion and water removal, and decreasing the split ratio to the isotope ratio mass spectrometer (IRMS). The technique relies on a two-stage preconcentration system, a low-volume capillary reactor and water trap, and a balanced reference gas delivery system. The instrument's measurement precision is 0.6 to 2.9 per thousand (1sigma), and results indicate that negligible sample fractionation occurs during gas sampling. Measured delta(13)C values have a minor dependence on sample size; linearity for acetone was 0.06 per thousand ng C(-1) and was best over 1-10 ng C. Sensitivity is approximately 10 times greater than similar instrumentation designs, incorporates the use of a diluted working reference gas (0.1% CO(2)), and requires collection of >0.7 ng C to produce accurate and precise results. With this detection limit, a 1.0 L sample of ambient air provides sufficient carbon for isotopic analysis. Emissions from vegetation and vehicle exhaust are compared and show clear differences in isotopic signatures. Ambient samples collected in metropolitan Miami and the Everglades National Park can be differentiated and reflect multiple sources and sinks affecting a single sampling location. Vehicle exhaust emissions of ethanol, and those collected in metropolitan Miami, have anomalously enriched delta(13)C values ranging from -5.0 to -17.2 per thousand; we attribute this result to ethanol's origin from corn and use as an additive in automotive fuels. PMID- 20704370 TI - Direct voltammetric analysis of DNA modified with enzymatically incorporated 7 deazapurines. AB - Nucleic acids studies use 7-deazaguanine (G*) and 7-deazaadenine (A*) as analogues of natural purine bases incapable of forming Hoogsteen base pairs, which prevents them from being involved in DNA triplexes and tetraplexes. Reduced propensity of the G*- and/or A*-modified DNA to form alternative DNA structures is utilized, for example, in PCR amplification of guanine-rich sequences. Both G* and A* exhibit significantly lower potentials of their oxidation, compared to the respective natural nucleobases. At carbon electrodes, A* yields an oxidation peak which is by about 200-250 mV less positive than the peak due to adenine, but coincides with oxidation peak produced by natural guanine residues. On the other hand, oxidation signal of G* occurs at a potential by about 300 mV less positive than the peak due to guanine, being well separated from electrochemical signals of any natural DNA component. We show that enzymatic incorporation of G* and A* can easily be monitored by simple ex situ voltammetric analysis of the modified DNA at carbon electrodes. Particularly G* is shown as an attractive electroactive marker for DNA, efficiently incorporable by PCR. While densely G*-modified DNA fragments exhibit strong quenching of fluorescence of SYBR dyes, commonly used as fluorescent indicators in both gel staining and real time PCR applications, the electrochemical detection provides G*-specific signal suitable for the quantitation of the amplified DNA as well as for the determination of the DNA modification extent. Determination of DNA amplicons based on the measurement of peak G*(ox) is not affected by signals produced by residual oligonucleotide primers or primary templates containing natural purines. PMID- 20704371 TI - Screening assay of very long chain fatty acids in human plasma with multiwalled carbon nanotube-based surface-assisted laser desorption/ionization mass spectrometry. AB - Peroxisomal disorders are characterized biochemically by elevated levels of very long chain fatty acids (VLCFAs) in serum. Herein, we describe a novel approach for quantification of VLCFAs in serum, namely, eicosanoic acid (C20:0), docosanoic acid (C22:0), tetracosanoic acid (C24:0), and hexacosanoic acid (C26:0). The methodology is based on (i) enrichment of VLCFA derivatives using multiwalled carbon nanotubes (MWCNTs); (ii) quantification using stable isotope labeled internal standards; and (iii) direct detection using MWCNT-based surface assisted laser desorption/ionization-time-of-flight mass spectrometry (SALDI TOFMS). Four kinds of MWCNTs (Aldrich 636843, 636495, 636509, and 636819) of different lengths and diameters were tested using the developed technique. The data show that 636843, the MWCNT with the largest outer diameter (o.d.), the widest wall thickness, and shortest length, had the best limit of detection (0.5 1 microg/mL) We also found that there was no significant difference in enrichment efficiency of VLCFAs between the four MWCNTs, which suggests that the size of the MWCNT may contribute to desorption/ionization efficiency. To our knowledge, this is the first study to test the enrichment of VLCFAs using MWCNTs of different sizes. We have shown that the VLCFAs adsorbed by MWCNTs can be analyzed by SALDI TOFMS. In addition, this method does not require liquid/gas chromatography separation, thereby allowing for high-throughput screening of VLCFAs in peroxisomal disorders. PMID- 20704372 TI - Colorimetric sensing of silver(I) and mercury(II) ions based on an assembly of Tween 20-stabilized gold nanoparticles. AB - We have developed a rapid and homogeneous method for the highly selective detection of Hg(2+) and Ag(+) using Tween 20-modified gold nanoparticles (AuNPs). Citrate ions were found to still be adsorbed on the Au surface when citrate capped AuNPs were modified with Tween 20, which stabilizes the citrate-capped AuNPs against conditions of high ionic strength. When citrate ions had reduced Hg(2+) and Ag(+) to form Hg-Au alloys and Ag on the surface of the AuNPs, Tween 20 was removed from the NP surface. As a result, the AuNPs were unstable under a high-ionic-strength solution, resulting in NP aggregation. The formation of Hg-Au alloys or Ag on the surface of the AuNPs was demonstrated by means of inductively coupled plasma mass spectroscopy and energy-dispersive X-ray spectroscopy. Tween 20-AuNPs could selectively detect Hg(2+) and Ag(+) at concentrations as low as 0.1 and 0.1 microM in the presence of NaCl and EDTA, respectively. Moreover, the probe enables the analysis of AgNPs with a minimum detectable concentration that corresponds to 1 pM. This probe was successfully applied to detect Hg(2+) in drinking water and seawater, Ag(+) in drinking water, and AgNPs in drinking water. PMID- 20704374 TI - Method to determine 226Ra in small sediment samples by ultralow background liquid scintillation. AB - (210)Pb dating of sediment cores is a widely used tool to reconstruct ecosystem evolution and historical pollution during the last century. Although (226)Ra can be determined by gamma spectrometry, this method shows severe limitations which are, among others, sample size requirements and counting times. In this work, we propose a new strategy based on the analysis of (210)Pb through (210)Po in equilibrium by alpha spectrometry, followed by the determination of (226)Ra (base or supported (210)Pb) without any further chemical purification by liquid scintillation and with a higher sample throughput. Although gamma spectrometry might still be required to determine (137)Cs as an independent tracer, the effort can then be focused only on those sections dated around 1963, when maximum activities are expected. In this work, we optimized the counting conditions, calibrated the system for changing quenching, and described the new method to determine (226)Ra in small sediment samples, after (210)Po determination, allowing a more precise determination of excess (210)Pb ((210)Pb(ex)). The method was validated with reference materials IAEA-384, IAEA-385, and IAEA-313. PMID- 20704376 TI - Gas chromatography-combustion-mass spectrometry with postcolumn isotope dilution for compound-independent quantification: its potential to assess HS-SPME procedures. AB - A quadrupole GC-MS instrument with an electron ionization (EI) source has been modified to enable application of postcolumn isotope dilution analysis for the standardless quantification of organic compounds injected in the gas chromatograph. Instrumental modifications included the quantitative conversion of the separated compounds into CO(2), using a postcolumn combustion furnace, and the subsequent mixing of the gas with a constant flow of (13)CO(2) diluted in helium. The online measurement of the (12)CO(2)/(13)CO(2) (44/45) ratio in the EI MS allowed us to obtain quantitative data without resorting to compound-specific standards. Validation of the procedure involved the analysis of standard solutions containing different families of organic compounds (C(9)-C(20) linear hydrocarbons, BTEX and esters) obtaining satisfactory results in all cases in terms of absolute errors (<6%) and precision (<4% RSD). The developed procedure showed excellent linearity over the range assayed (2 orders of magnitude) and adequate detection limits for carbon containing compounds (0.8 pg C s(-1)). The generic value of this compound-independent calibration approach was assessed by studying the quantitative performance of Head Space-Solid Phase Microextraction (HS-SPME). The proposed compound-independent quantification by EI-MS permits comparison of the performance of different fibers by assessing analyte recoveries with extreme robustness, simplicity, and precision. PMID- 20704373 TI - Analysis of inorganic polyphosphates by capillary gel electrophoresis. AB - This paper describes the development of a method that uses capillary gel electrophoresis (CGE) to analyze mixtures of inorganic polyphosphate ((P(i))(n)). Resolution of (P(i))(n) on the basis of n, the number of residues of dehydrated phosphate, is accomplished by CGE using capillaries filled with solutions of poly(N,N-dimethylacrylamide) (PDMA) and indirect detection by the UV absorbance of a chromophore, terephthalate, added to the running buffer. The method is capable of resolving peaks representing (P(i))(n) with n up to approximately 70; preparation and use of authentic standards enables the identification of peaks for (P(i))(n) with n = 1-10. The main advantages of this method over previously reported methods for analyzing mixtures of (P(i))(n) (e.g., gel electrophoresis, CGE using polyacrylamide-filled capillaries) are its resolution, convenience, and reproducibility; gel-filled capillaries are easily regenerated by pumping in fresh, low-viscosity solutions of PDMA. The resolution is comparable to that of ion-exchange chromatography and detection of (P(i))(n) by suppressed conductivity. The method is useful for analyzing (P(i))(n) generated by the dehydration of P(i) at low temperature (125-140 degrees C) with urea, in a reaction that may have been important in prebiotic chemistry. The method should also be useful for characterizing mixtures of other anionic, oligomeric, or polymeric species without an intrinsic chromophore (e.g., sulfated polysaccharides, oligomeric phospho-diesters). PMID- 20704375 TI - Improved sensitivity of DNA microarrays using photonic crystal enhanced fluorescence. AB - DNA microarrays are used to profile changes in gene expression between samples in a high-throughput manner, but measurements of genes with low expression levels can be problematic with standard microarray substrates. In this work, we expand the detection capabilities of a standard microarray experiment using a photonic crystal (PC) surface that enhances fluorescence observed from microarray spots. This PC is inexpensively and uniformly fabricated using a nanoreplica molding technique, with very little variation in its optical properties within- and between-devices. By using standard protocols to process glass microarray substrates in parallel with PCs, we evaluated the impact of this substrate on a one-color microarray experiment comparing gene expression in two developmental stages of Glycine max. The PCs enhanced the signal-to-noise ratio observed from microarray spots by 1 order of magnitude, significantly increasing the number of genes detected above substrate fluorescence noise. PC substrates more than double the number of genes classified as differentially expressed, detecting changes in expression even for low expression genes. This approach increases the dynamic range of a surface-bound fluorescence-based assay to reliably quantify small quantities of DNA that would be impossible with standard substrates. PMID- 20704377 TI - Immunoaffinity purification using anti-PEG antibody followed by two-dimensional liquid chromatography/tandem mass spectrometry for the quantification of a PEGylated therapeutic peptide in human plasma. AB - Quantification of a PEGylated peptide in human plasma using LC-MS/MS to support clinical studies presented challenges in terms of assay sensitivity, selectivity, and ruggedness. To ensure specific recognition of PEGylated species, an immunoaffinity purification method (IAP) using anti-PEG antibody followed by two dimensional (2D) LC-MS/MS was developed for MK-2662, an investigational peptide containing 38 amino acids with a 40 kDa branched PEG [poly(ethylene glycol)] at C terminus. Biotinylated anti-PEG antibody, bound to streptavidin-coated magnetic beads, was used to capture MK-2662 and its stable-isotope-labeled internal standard from human plasma. After on-bead digestion with trypsin, the supernatant was injected on a 2D high-performance liquid chromatography (HPLC) system constructed with strong cation-exchange and reversed-phase columns, followed by MS/MS detection of the surrogate N(1-12)-mer of MK-2662 on an API5000. The assay ruggedness was improved by optimizing the trypsin digestion and sample storage conditions. The intraday validation, conducted in parallel with protein precipitation (PPT) assay, demonstrated 94.8-105.8% accuracy with <9.76% coefficient of variation (CV) for IAP, and 99.0-101.0% accuracy with <3.43% CV for PPT, over a dynamic range of 2-200 nM and 1-1000 nM, respectively. A cross comparison, performed using clinical samples, showed that the values obtained from IAP assay were about 15-30% lower than those from PPT method, which supports more specific PEG recognition provided by IAP. PMID- 20704378 TI - Electrophoretic analysis of biomarkers using capillary modification with gold nanoparticles embedded in a polycation and boron doped diamond electrode. AB - Field-amplified sample stacking using a fused silica capillary coated with gold nanoparticles (AuNPs) embedded in poly(diallyl dimethylammonium) chloride (PDDA) has been investigated for the electrophoretic separation of indoxyl sulfate, homovanillic acid (HVA), and vanillylmandelic acid (VMA). AuNPs (27 nm) exhibit ionic and hydrophobic interactions, as well as hydrogen bonding with the PDDA network to form a stable layer on the internal wall of the capillary. This approach reverses electro-osmotic flow allowing for fast migration of the analytes while retarding other endogenous compounds including ascorbic acid, uric acid, catecholamines, and indoleamines. Notably, the two closely related biomarkers of clinical significance, HVA and VMA, displayed differential interaction with PDDA-AuNPs which enabled the separation of this pair. The detection limit of the three analytes obtained by using a boron doped diamond electrode was approximately 75 nM, which was significantly below their normal physiological levels in biological fluids. This combined separation and detection scheme was applied to the direct analysis of these analytes and other interfering chemicals including uric and ascorbic acids in urine samples without off-line sample treatment or preconcentration. PMID- 20704379 TI - Human plasma copper proteins speciation by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry. Solutions for columns calibration by sulfur detection. AB - Among the hyphenated techniques used to probe and identify metalloproteins, size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS) has shown to have a central place. However, the calibration of SEC columns reveals to be tedious and always involves UV detection prior to ICP-MS. The presence of sulfur in 98% of proteins allows their detection by quadrupole ICP-MS, despite the isobaric interference ((16)O(16)O) on S, by monitoring (32)S(16)O at mass to charge ratio (m/z) 48. The formation of SO occurs spontaneously in the argon plasma but can be optimized by the introduction of oxygen gas into a reaction cell (RC) to achieve nM levels. In this article, sulfur detection was discussed upon instrumental conditions and S detection was then optimized by applying O(2) as a reaction gas. SO formation was used to calibrate SEC columns without UV detection. This simple SEC-ICP-MS method was used for plasma copper proteins in plasma healthy subjects (HS) and an untreated Wilson disease (WD) patient. Copper proteins identified in healthy subjects were transcuprein, ceruloplasmin (Cp) and albumin. The method led to results in good agreement with other methods of determination. Copper bound to Cp in the WD patient was lowered with regard to the HS, and the exchangeable Cu was highly increased. PMID- 20704380 TI - Direct quantification of single-molecules of microRNA by total internal reflection fluorescence microscopy. AB - MicroRNAs (miRNAs) express differently in normal and cancerous tissues and thus are regarded as potent cancer biomarkers for early diagnosis. However, the short length and low abundance of miRNAs have brought challenges to the established detection assay in terms of sensitivity and selectivity. In this work, we present a novel miRNA detection assay in single-molecule level with total internal reflection fluorescence microscopy (TIRFM). It is a solution-based hybridization detection system that does not require pretreatment steps such as sample enrichment or signal amplification. The hsa-miR-21 (miR-21) is chosen as target miRNA for its significant elevated content in a variety of cancers as reported previously. Herein, probes of complementary single-stranded oligonucleotide were hybridized in solution to miR-21 and labeled with fluorescent dye YOYO-1. The fluorescent hybrids were imaged by an electron-multiplying charge-coupled device (EMCCD) coupled TIRFM system and quantified by single-molecule counting. This single molecule detection (SMD) assay shows a good correlation between the number of molecules detected and the factual concentration of miRNA. The detection assay is applied to quantify the miR-21 in extracted total RNA samples of cancerous MCF 7 cells, HepG2 cells, and normal HUVEC cells, respectively. The results agreed very well with those from the prevalent real-time polymerase chain reaction (qRT PCR) analysis. This assay is of high potential for applications in miRNA expression profiling and early cancer diagnosis. PMID- 20704381 TI - Electrochemical modulation for signal discrimination in surface enhanced Raman scattering (SERS). AB - Electrochemical modulation to induce controlled fluctuations in SERS signals is introduced as a method to discriminate and isolate different contributions to the spectra. The modulation--which can be changed in potential range, amplitude, and frequency--acts as a controllable "switch" to turn on, off, or change specific Raman signals which can then be correlated within the spectra by different fluctuation analysis techniques. Principal component analysis (PCA), either by itself or assisted by fast fourier transform (FFT) prefiltering, are shown to provide viable tools to isolate the different components of the spectra. Electrochemical modulation provides, therefore, a technique to study complex cases of coadsorption, and resolve problems of spectral congestion in SERS signals. PMID- 20704382 TI - Study of highly selective and efficient thiol derivatization using selenium reagents by mass spectrometry. AB - This paper reports a systemic mass spectrometry (MS) investigation of a novel strategy for labeling biological thiols, involving the cleavage of the Se-N bond by thiol to form a new Se-S bond. Our data show that the reaction is highly selective, rapid, reversible, and efficient. Among 20 amino acids, only cysteine is reactive toward Se-N containing reagents and the reaction occurs in seconds. With the addition of dithiothreitol, peptides derivatized by selenium reagents can be recovered. The high reaction selectivity and reversibility provide potential in both selective identification and isolation of thiols from mixtures. Also, with dependence on the selenium reagent used, derivatized peptide ions exhibit tunable dissociation behaviors (either facile cleavage or preservation of the formed Se-S bond upon collision-induced dissociation), a feature that is useful in proteomics studies. Equally importantly, the thiol derivatization yield is striking, as reflected by 100% conversion of protein beta-lactoglobulin A using ebselen within 30 s. In addition, preliminary applications such as rapid screening of thiol peptides from mixtures and identification of the number of protein free and bound thiols have been demonstrated. The unique selenium chemistry uncovered in this study would be valuable in the MS analysis of thiols and disulfide bonds of proteins/peptides. PMID- 20704383 TI - Difference between ultramicroelectrodes and microelectrodes: influence of natural convection. AB - Natural convection in macroscopically immobile solutions may still alter electrochemical experiments performed with electrodes of micrometric dimensions. A model accounting for the influence of natural convection allowed delineating conditions under which it interferes with mass transport. Several electrochemical behaviors may be observed according to the time scale of the experiment, electrode dimensions, and intensity of natural convection. The range of parameters in which ultramicroelectrodes behave under a true diffusional steady state was identified. Mapping of concentration profiles was performed experimentally by scanning electrochemical microscopy in the vicinity of microelectrodes of various radii. The results validated remarkably the predictions of the model, evidencing in particular the alteration of the diffusional steady state by natural convection. PMID- 20704384 TI - Determination of double bond location in fatty acids by manganese adduction and electron induced dissociation. AB - Double bond locations in fatty acids can be determined from characteristic charge remote fragmentation patterns of alkali metal-adducted fatty acids following high energy collision activated dissociation (CAD). With low energy CAD, several chemical derivatization methods, including ozonization, epoxidation, and hydroxylation, have been used to generate characteristic fragments. However, high energy CAD is not universally available and involves a high degree of scattering, causing product ion loss. Further, derivatization reactions involve side reactions and sample loss. Here, we analyzed metal-adducted fatty acids to investigate the utility of electron induced dissociation (EID) for determining double bond location. EID has been proposed to involve both electronic excitation, similar to high energy CAD, and vibrational excitation. Various metals (Li, Zn, Co, Ni, Mg, Ca, Fe, and Mn) were investigated to fix one charge at the carboxylate end of fatty acids to promote charge-remote fragmentation. EID of Mn(II)-adducted fatty acids allowed determination of all double bond locations of arachidonic acid, linolenic acid, oleic acid, and stearic acid. For Mn(II) adducted fatty acids, reduced characteristic charge-remote product ion abundances at the double bond positions are indicative of double bond locations. However, other metal adducts did not generally provide characteristic product ion abundances at all double bond locations. PMID- 20704385 TI - Cleavable cross-linker for protein structure analysis: reliable identification of cross-linking products by tandem MS. AB - Chemical cross-linking combined with a subsequent enzymatic cleavage of the created cross-linked complex and a mass spectrometric analysis of the resulting cross-linked peptide mixture presents an alternative approach to high-resolution analysis, such as NMR spectroscopy or X-ray crystallography, to obtain low resolution protein structures and to gain insight into protein interfaces. Here, we describe a novel urea-based cross-linker, which allows distinguishing different cross-linking products by collision-induced dissociation (CID) tandem MS experiments based on characteristic product ions and constant neutral losses. The novel cross-linker is part of our ongoing efforts in developing collision induced dissociative reagents that allow an efficient analysis of cross-linked proteins and protein complexes. Our innovative analytical concept is exemplified for the Munc13-1 peptide and the recombinantly expressed ligand binding domain of the peroxisome proliferator-activated receptor alpha, for which cross-linking reaction mixtures were analyzed both by offline nano-HPLC/MALDI-TOF/TOF mass spectrometry and by online nano-HPLC/nano-ESI-LTQ-orbitrap mass spectrometry. The characteristic fragment ion patterns of the novel cross-linker greatly simplify the identification of different cross-linked species, namely, modified peptides as well as intrapeptide and interpeptide cross-links, from complex mixtures and drastically reduce the potential of identifying false-positive cross-links. Our novel urea-based CID cleavable cross-linker is expected to be highly advantageous for analyzing protein 3D structures and protein-protein complexes in an automated manner. PMID- 20704386 TI - Analyte discrimination from chemiresistor response kinetics. AB - Chemiresistors are polymer-based sensors that transduce the sorption of a volatile organic compound into a resistance change. Like other polymer-based gas sensors that function through sorption, chemiresistors can be selective for analytes on the basis of the affinity of the analyte for the polymer. However, a single sensor cannot, in and of itself, discriminate between analytes, since a small concentration of an analyte that has a high affinity for the polymer might give the same response as a high concentration of another analyte with a low affinity. In this paper we use a field-structured chemiresistor to demonstrate that its response kinetics can be used to discriminate between analytes, even between those that have identical chemical affinities for the polymer phase of the sensor. The response kinetics is shown to be independent of the analyte concentration, and thus the magnitude of the sensor response, but is found to vary inversely with the analyte's saturation vapor pressure. Saturation vapor pressures often vary greatly from analyte to analyte, so analysis of the response kinetics offers a powerful method for obtaining analyte discrimination from a single sensor. PMID- 20704387 TI - Improvement of sensitivity and dynamic range in proximity ligation assays by asymmetric connector hybridization. AB - The proximity ligation assay (PLA) is one of the most sensitive and simple protein assays developed to date, yet a major limitation is the relatively narrow dynamic range compared to other assays such as enzyme-linked immunosorbent assays. In this work, the dynamic range of PLA was improved by 2 orders of magnitude and the sensitivity was improved by a factor of 1.57. To accomplish this, asymmetric DNA hybridization was used to reduce the probability of target independent, background ligation. An experimental model of the aptamer-target connector complex (apt(A)-T-apt(B)-C(20,PLA)) in PLA was developed to study the effects of asymmetry in aptamer-connector hybridization. Connector base pairing was varied from the PLA standard of 20 total bases (C(20)) to an asymmetric combination with 15 total bases (C(15)). The results of this model suggested that weakening the affinity of one side of the connector to one aptamer would significantly reduce target-independent ligation (background) without greatly affecting target-dependent ligation (signal). These predictions were confirmed using PLA with asymmetric connectors for detection of human thrombin. This novel, asymmetric PLA approach should impact any previously developed PLA method (using aptamers or antibodies) by reducing target-independent ligation events, thus generally improving the sensitivity and dynamic range of the assay. PMID- 20704388 TI - Improving pressure robustness, reliability, and versatility of solenoid-pump flow systems using a miniature economic control unit including two simple pressure pulse mathematical models. AB - In this work we have systematically studied the behavior of solenoid pumps (SMP) as a function of flow rate and flow resistance. Using a new, economic, and miniature control unit, we achieved improvements of the systems versatility, transportability, and pressure robustness. A further important improvement with respect to pressure resistance was achieved when a flexible pumping tube was inserted between the solenoid pump and the flow resistance acting as a pressure reservoir and pulsation damper. The experimental data were compared with two pressure pulse models for SMP, which were developed during this work and which were well-suited to describe the SMP operation. PMID- 20704389 TI - Integrated microfluidic system for rapid forensic DNA analysis: sample collection to DNA profile. AB - We demonstrate a conduit for the delivery of a step change in the DNA analysis process: A fully integrated instrument for the analysis of multiplex short tandem repeat DNA profiles from reference buccal samples is described and is suitable for the processing of such samples within a forensic environment such as a police custody suite or booking office. The instrument is loaded with a DNA processing cartridge which incorporates on-board pumps and valves which direct the delivery of sample and reagents to the various reaction chambers to allow DNA purification, amplification of the DNA by PCR, and collection of the amplified product for delivery to an integral CE chip. The fluorescently labeled product is separated using micro capillary electrophoresis with a resolution of 1.2 base pairs (bp) allowing laser induced fluorescence-based detection of the amplified short tandem repeat fragments and subsequent analysis of data to produce a DNA profile which is compatible with the data format of the UK DNA database. The entire process from taking the sample from a suspect, to database compatible DNA profile production can currently be achieved in less than 4 h. By integrating such an instrument and microfluidic cartridge with the forensic process, we believe it will be possible in the near future to process a DNA sample taken from an individual in police custody and compare the profile with the DNA profiles held on a DNA Database in as little as 3 h. PMID- 20704390 TI - Visualization and recovery of the (bio)chemical interesting variables in data analysis with support vector machine classification. AB - Support vector machines (SVMs) have become a popular technique in the chemometrics and bioinformatics field, and other fields, for the classification of complex data sets. Especially because SVMs are able to model nonlinear relationships, the usage of this technique has increased substantially. This modeling is obtained by mapping the data in a higher-dimensional feature space. The disadvantage of such a transformation is, however, that information about the contribution of the original variables in the classification is lost. In this paper we introduce an innovative method which can retrieve the information about the variables of complex data sets. We apply the proposed method to several benchmark data sets and a metabolomics data set to illustrate that we can determine the contribution of the original variables in SVM classifications. The corresponding visualization of the contribution of the variables can assist in a better understanding of the underlying chemical or biological process. PMID- 20704391 TI - Rapid and sensitive detection of protein biomarker using a portable fluorescence biosensor based on quantum dots and a lateral flow test strip. AB - A portable fluorescence biosensor with rapid and ultrasensitive response for protein biomarker has been built up with quantum dots and a lateral flow test strip. The superior signal brightness and high photostability of quantum dots are combined with the promising advantages of a lateral flow test strip and result in high sensitivity and selectivity and speed for protein detection. Nitrated ceruloplasmin, a significant biomarker for cardiovascular disease, lung cancer, and stress response to smoking, was used as model protein biomarker to demonstrate the good performances of this proposed quantum dot-based lateral flow test strip. Quantitative detection of nitrated ceruloplasmin was realized by recording the fluorescence intensity of quantum dots captured on the test line. Under optimal conditions, this portable fluorescence biosensor displays rapid responses for nitrated ceruloplasmin with the concentration as low as 1 ng/mL. Furthermore, the biosensor was successfully utilized for spiked human plasma sample detection in a wide dynamic range with a detection limit of 8 ng/mL (S/N = 3). The results demonstrate that the quantum dot-based lateral flow test strip is capable of rapid, sensitive, and quantitative detection of nitrated ceruloplasmin and hold a great promise for point-of-care and in field analysis of other protein biomarkers. PMID- 20704392 TI - Quantitation, visualization, and monitoring of conformational transitions of human serum albumin by a tetraphenylethene derivative with aggregation-induced emission characteristics. AB - Human serum albumin (HSA) is a major protein component of blood plasma, and its assay is of obvious value to biological research. We, herein, present a readily accessible fluorescent bioprobe for HSA detection and quantitation. A nonemissive tetraphenylethene derivative named sodium 1,2-bis[4-(3-sulfonatopropoxyl)phenyl] 1,2-diphenylethene (BSPOTPE) is induced to emit by HSA, showing a novel phenomenon of aggregation-induced emission (AIE). The AIE bioprobe enjoys a broad working range (0-100 nM), a low detection limit (down to 1 nM), and a superior selectivity to albumins. The fluorescent bioassay is unperturbed by the miscellaneous bioelectrolytes in the artificial urine. The AIE luminogen can also be used as a rapid and sensitive protein stain in gel electrophoresis for HSA visualization. Utilizing the AIE feature of BSPOTPE and the Forster resonance energy transfer from HSA to BSPOTPE, the unfolding process of HSA induced by guanidine hydrochloride is monitored, which reveals a multistep transition with the involvement of molten globule intermediates. Computational modeling suggests that the AIE luminogens dock in the hydrophobic cleft between subdomains IIA and IIIA of HSA with the aid of hydrophobic effect, charge neutralization, and hydrogen bonding interactions, offering mechanistic insight into the microenvironment inside the hydrophobic cavity. PMID- 20704393 TI - Direct fluorescence polarization assay for the detection of glycopeptide antibiotics. AB - Glycopeptide antibiotics are widely used in the treatment of infections caused by Gram-positive bacteria. They inhibit the biosynthesis of the bacterial cell wall through binding to the D-alanyl-D-alanine (D-Ala-D-Ala) terminal peptide of the peptidoglycan precursor. Taking advantage of this highly specific interaction, we developed a direct fluorescence polarization based method for the detection of glycopeptide antibiotics. Briefly, we labeled the acetylated tripeptide Ac-L-Lys D-Ala-D-Ala-OH with a fluorophore to create a peptide probe. Using three glycopeptide antibiotics, vancomycin, teicoplanin, and telavancin, as model compounds, we demonstrated that the fluorescence polarization of the peptide probe increased upon binding to antibiotics in a concentration dependent manner. The dissociation constants (K(d)) between the peptide probes and the antibiotics were consistent with those reported between free d-Ala-d-Ala and the antibiotics in the literature. The assay is highly reproducible and selective toward glycopeptide antibiotics. Its detection limit and work concentration range are 0.5 microM and 0.5-4 microM for vancomycin, 0.25 microM and 0.25-2 microM for teicoplanin, and 1 microM and 1-8 microM for telavancin. Furthermore, we compared our assay in parallel with a commercial fluorescence polarization immunoassay (FPIA) kit in detecting teicoplanin spiked in human blood samples. The accuracy and precision of the two methods are comparable. We expect our assay to be useful in both research and clinical laboratories. PMID- 20704394 TI - Development of a high sensitivity rapid sandwich ELISA procedure and its comparison with the conventional approach. AB - A highly sensitive and rapid sandwich enzyme-linked immunosorbent assay (ELISA) procedure was developed for the detection of human fetuin A/AHSG (alpha2-HS glycoprotein), a specific biomarker for hepatocellular carcinoma and atherosclerosis. Anti-human fetuin A antibody was immobilized on aminopropyltriethoxysilane-mediated amine-functionalized microtiter plates using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and N hydroxysulfosuccinimide-based heterobifunctional cross-linking. The analytical sensitivity of the developed assay was 39 pg/mL, compared to 625 pg/mL for the conventional assay. The generic nature of the developed procedure was demonstrated by performing human fetuin A assays on different polymeric matrixes, i.e., polystyrene, poly(methyl methacrylate), and polycyclo-olefin (Zeonex), in a modified microtiter plate format. Thus, the newly developed procedure has considerable advantages over the existing method. PMID- 20704396 TI - Practical synthesis of quinoxalinones via palladium-catalyzed intramolecular N arylations. AB - A practical and highly efficient route to the synthesis of pharmaceutically interesting quinoxalinone scaffolds is reported. The key step involves an intramolecular palladium-catalyzed N-arylation under microwave irradiation. The developed methodology tolerates a variety of bromoanilides to afford a diverse collection of bicyclic and polycyclic quinoxalinones in high yield. PMID- 20704395 TI - Use of N-allylidene-1,1-diphenylethanamine as a latent acrolein synthon in the double nucleophilic addition reaction of ketene silyl (Thio)acetals and allylborolanes. AB - In the presence of silica gel and water, a mixture of ketene silyl acetals and 2 allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane underwent 1,4- and subsequently 1,2 addition with N-allylidene-1,1-diphenylethanamine to give delta-hydroxyesters in good yields, where the allylideneamine was successfully used as an acrolein equivalent. PMID- 20704397 TI - Highly regioselective palladium-catalyzed direct arylation of oxazole at C-2 or C 5 with aryl bromides, chlorides, and triflates. AB - Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations. PMID- 20704398 TI - Bronsted acid catalyzed asymmetric aldol reaction: a complementary approach to enamine catalysis. AB - A syn-enantioselective aldol reaction has been developed using Bronsted acid catalysis based on H(8)-BINOL-derived phosphoric acids. This method affords an efficient synthesis of various beta-hydroxy ketones, some of which could not be synthesized using enamine organocatalysis. PMID- 20704399 TI - Branch-selective synthesis of oxindole and indene scaffolds: transition metal controlled intramolecular aryl amidation leading to c3 reverse-prenylated oxindoles. AB - In an effort to access biologically important scaffolds, a concise branch selective synthesis of C3 tertiary oxindoles by Cu(I)-catalyzed aryl amidation and 2,2-dimethyl indene by Pd(0)-catalyzed Heck cyclization has been accomplished from acyclic reverse-prenylated intermediates. Oxindole C3-enolate generation using NaH followed by alkylation in the presence of appropriate electrophiles provides a novel route to quaternary C3 reverse-prenylated oxindoles. PMID- 20704400 TI - Enzymatic dynamic kinetic resolution of (+/-)-cis-N-(alkoxycarbonyl)cyclopentane 1,2-diamines based on spontaneous racemization. AB - Lipase B from Candida antarctica is an excellent catalyst for the enantioselective acetylation of different (+/-)-cis-N (alkoxycarbonyl)cyclopentane-1,2-diamines. Depending on the alkoxycarbonyl group, a simple kinetic resolution (Boc-derivative) or an interesting dynamic kinetic resolution (DKR with Cbz-, Alloc, and ethoxycarbonyl derivatives) has been developed. Racemization for the DKR occurred due to the N,N' intramolecular migration of the alkoxycarbonyl group. PMID- 20704401 TI - 12-Helix folding of cyclobutane beta-amino acid oligomers. AB - The hexamer and octamer of trans-2-aminocyclobutane carboxylic acid were prepared and their conformational preferences studied experimentally and using molecular modeling. All observations suggest a marked preference for the folding of these oligomers into a well-defined 12-helical conformation, in both solution and the solid state. PMID- 20704402 TI - Highly selective nickel-catalyzed three-component coupling of alkynes with enones and alkenyl boronic acids: a novel route to substituted 1,3-dienes. AB - A highly regio- and stereoselective nickel-catalyzed three-component coupling of alkynes with enones and alkenyl boronic acids to afford highly substituted 1,3 dienes is described. The reaction can also be extended to cyclization of enynes with coupling to alkenyl boronic acids. A possible reaction mechanism involving a five-membered nickelacycle as a key intermediate is proposed. PMID- 20704403 TI - A direct synthesis of oxazoles from aldehydes. AB - An expedient method for the direct conversion of aldehydes to 2,4-disubstituted oxazoles is presented. The method relies on the oxidation of an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. In contrast to standard methods that start from carboxylic acids, the use of aldehydes as starting materials does not require intermediate purification and affords the oxazoles under relatively mild conditions. PMID- 20704404 TI - KMnO(4)-Mediated oxidation as a continuous flow process. AB - An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and downstream processing of MnO(2) slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow system. PMID- 20704405 TI - Concise total synthesis of (+/-)-pseudotabersonine via double ring-closing metathesis strategy. AB - A concise synthesis of (+/-)-pseudotabersonine from commercially available 1 (phenylsulfonyl)-3-indolecarboxaldehyde has been accomplished. This synthesis features the convergent assembly of a key intermediate via a stepwise variant of a Mannich-type multicomponent coupling process, a double ring-closing metathesis, and a one-pot deprotection/cyclization reaction. PMID- 20704406 TI - Stereocontrol in radical cyclization: change in rate-determining step. AB - Intramolecular cyclization of an alpha-carbon radical of ester carrying a chiral 2,4-pentanediol tether shows low stereoselectivity when the radical carbon has an alkyl substituent, while the selectivity becomes high to give a single stereoisomer (>99% pure) when the substituent is an aryl group. The difference in the selectivity is attributable to the change in the rate-determining step from the conformational process to the cyclization. PMID- 20704407 TI - Controlling binding affinities for anions by a photoswitchable foldamer. AB - A photoswitchable foldamer containing an azobenzene and phenyl-1,2,3-triazole motif was found to show photochemical/dark isomerization in a controllable and reversible manner in both the absence and presence of anions. The transformation in conformation of the foldamer leads to changes in binding affinities for anions to a certain extent that depends on the size and the geometrical shape of the anions. PMID- 20704408 TI - Enantioselective synthesis of polysubstituted cyclopentanones by organocatalytic double Michael addition reactions. AB - The O-TMS-protected diphenylprolinol-catalyzed cascade double Michael addition reactions of alpha,beta-unsaturated aldehydes with a beta-keto ester bearing a highly electron-deficient olefin unit occur smoothly to afford polysubstituted cyclopentanones. This process allows formation of four contiguous stereocenters in the cyclopentanone ring in one-step with excellent enantioselectivity. PMID- 20704409 TI - Kingianin A: a new natural pentacyclic compound from Endiandra kingiana. AB - A new natural pentacyclic compound, named kingianin A, was isolated as a racemic mixture from the barks of Endiandra kingiana (Lauraceae). Its structure was elucidated by comprehensive analysis of NMR spectroscopic data, X-ray crystallography, and ECD calculations. The pentacyclic skeleton may be formed by a Diels-Alder reaction between two monomers having a bicyclo[4.2.0]octadiene backbone formed by a stereospecific electrocyclization of a linear compound of polyketide origin. PMID- 20704410 TI - Preparation of primary amides from functionalized organozinc halides. AB - Organozinc halides, which are prepared either by direct zinc insertion or halogen magnesium exchange and subsequent transmetalation with ZnCl(2), react smoothly with commercially available trichloroacetyl isocyanate to give, after hydrolysis, the corresponding primary amides. This method is compatible with a variety of functional groups such as an ester or a cyano group. Also heterocyclic-, alkenyl, and acetylenic zinc reagents are converted to the corresponding primary amides under these conditions. PMID- 20704411 TI - Near-infrared absorbing merocyanine dyes for bulk heterojunction solar cells. AB - A series of near-infrared absorbing merocyanine dyes bearing the strong electron accepting 2-oxo-5-dicyanomethylene-pyrrolidine unit was synthesized and applied in combination with PC(61)BM and PC(71)BM in solution-processed photoactive layers of bulk heterojunction solar cells, exhibiting a remarkable performance range with power conversion efficiencies from 0.01% to 1.00%. PMID- 20704412 TI - Direct acylation of aryl chlorides with aldehydes by palladium-pyrrolidine Co catalysis. AB - A palladium catalyst system has been developed that allows for the direct acylation of aryl chlorides with aldehydes. The choice of ligand, as well as the presence of pyrrolidine and molecular sieves is shown to be critical to the catalysis, which appears to proceed via an enamine intermediate. The reaction was successful for a wide range of aryl chlorides and tolerant of functionality on the aldehyde component, giving easy access to alkyl aryl ketones in modest to good yields. PMID- 20704413 TI - Sulfur-assisted propargyl-allenyl isomerizations and electrocyclizations for the convenient and efficient synthesis of polyfunctionalized benzenes and naphthalenes. AB - A facile and efficient electrocyclization for the synthesis of polyfunctionalized benzene and naphthalene derivatives was reported. As a result of the ready availability of starting materials and simple operation, this type of reaction has potential utility in organic synthesis. PMID- 20704414 TI - Synthesis of polysubstituted dihydropyridines by four-component reactions of aromatic aldehydes, malononitrile, arylamines, and acetylenedicarboxylate. AB - A practical and efficient procedure for the preparation of the polysubstituted dihydropyridines was developed through a unique four-component reaction of aromatic aldehydes, malononitrile, arylamines, and acetylenedicarboxylate in ethanol in the presence of triethylamine as a base promoter. This four-component reaction is atom-efficient, high-yielding, and applicable to a wide variety of four-component reactions. PMID- 20704415 TI - Copper-catalyzed synthesis of phenanthridine derivatives under an oxygen atmosphere starting from biaryl-2-carbonitriles and Grignard reagents. AB - A copper-catalyzed synthesis of phenanthridine derivatives was developed starting from biaryl-2-carbonitriles and Grignard reagents. The present transformation is carried out by a sequence of nucleophilic addition of Grignard reagents to biaryl 2-carbonitriles to form N-H imines and their Cu-catalyzed C-N bond formation on the aromatic C-H bond, where molecular oxygen is a prerequisite to achieve the catalytic process. PMID- 20704416 TI - Beta-selective arabinofuranosylation using a 2,3-O-xylylene-protected donor. AB - Reported is a novel stereoselective beta-arabinofuranosylation that makes use of a conformationally restricted 2,3-O-xylylene-protected arabinofuranosyl donor. Optimization of the reaction conditions showed that factors including the structure of the acceptor alcohol, substrate concentration, and protecting group on O-5 of the donor affect the stereochemical outcome of the glycosylation. To demonstrate the utility of the methodology, the synthesis of an oligosaccharide fragment from the mycobacterial cell wall polysaccharide lipoarabinomannan was carried out. PMID- 20704417 TI - Acyclic stereocontrol in the catalytic C-H amination of benzylic methylene groups. AB - Diastereotopos-differentiation is the key feature of the catalytic C-H amination at the benzylic position of substrate 1. Essentially independent of the functional group X (X = COOMe, PO(OEt)(2), SO(2)Ph, NO(2), CN, OAc), the depicted products 2 are formed with good (dr = 80/20) to excellent (dr > 95/5) diastereoselectivity. The reaction proceeds without racemization and possesses potential for the C-H amination of open-chain substrates. PMID- 20704418 TI - Pictet-Spengler based synthesis of a bisarylmaleimide glycogen synthase kinase-3 inhibitor. AB - A practical synthesis of the glycogen synthase kinase-3 (GSK3) inhibitor bisarylmaleimide 1 has been accomplished employing Pictet-Spengler methodology to access the indole 7-position in preparing the benzodiazepine tricyclic fragment. A seven-step linear sequence that starts with commercially available 5 fluoroindole 7 affords the bisarylmaleimide 1 in 33% overall yield. PMID- 20704419 TI - Scalable synthetic oligodeoxynucleotide purification with use of a catching by polymerization, washing, and releasing approach. AB - Synthetic oligodeoxynucleotides are purified with use of a catching by polymerization, washing, and releasing approach. The method does not require any chromatography, and purification is achieved by simple operations such as shaking, washing, and extraction. It is therefore useful for large-scale purification of synthetic oligonucleotide drugs. In addition to purification of oligonucleotides, this catching by polymerization concept is expected to be equally useful for purification of other synthetic oligomers such as peptides and oligosaccharides. PMID- 20704420 TI - Synthesis of the C1-C13 tetraenoate subunit of the chivosazoles. AB - Using a combination of asymmetric vinylogous Mukaiyama aldol and Stille cross coupling reactions, an advanced polyene fragment of the chivosazoles was prepared in a highly stereocontrolled manner. This key C1-C13 pentaene subunit, featuring the conjugated (2E,4Z,6E,8Z)-tetraenoate motif and anti-configured C10 and C11 stereocenters of the chivosazoles, terminates in a (Z)-vinyl bromide for the planned cross-coupling to a northern hemisphere fragment. PMID- 20704421 TI - Neopentylglycolborylation of ortho-substituted aryl halides catalyzed by NiCl(2) based mixed-ligand systems. AB - NiCl(2)-based mixed-ligand systems were shown to be very effective catalysts for the neopentylglycolborylation of aryl iodides, bromides, and chlorides bearing electron-rich and electron-deficient ortho-substituents. Although NiCl(2)-based single-ligand catalytic systems were able to mediate neopentylglycolborylation of selected substrates, they were not as effective for all substrates, highlighting the value of the mixed-ligand concept. Optimization of the Ni(II)-catalyzed neopentylglycolborylation of 2-iodoanisole and methyl 2-iodobenzoate demonstrated that, while the role of ligand and coligand in the conversion of Ni(II) precatalyst to Ni(0) active catalyst cannot be ignored, a mixed-ligand complex is likely present throughout the catalytic cycle. In addition, protodeborylation and hydrodehalogenation were demonstrated to be the predominant side reactions of Ni(II)-catalyzed borylation of ortho-substituted aryl halides containing the electron-deficient carboxylate substituents. Ni(II) complexes in the presence of H(2)O and Ni(0) are responsible for the catalysis of these side reactions. PMID- 20704422 TI - Alkali metal ions as probes of structure and recognition properties of macrocyclic pyridyl urea hosts. AB - We report the one-pot synthesis of three symmetrical macrocyclic pyridyl urea hosts. X-ray crystal studies were used to confirm the structures of the free hosts and their host.guest complexes with alkali metal ions. These solid-state studies revealed the interactions that were important for binding cations (Li(+), Na(+), and K(+)). The affinity of these hosts for alkali metal salts were evaluated in solution (CD(3)CN), and the stoichiometries of the solution complexes were compared with their solid-state structures. Two of these hosts showed high affinity for LiBF(4), which was primarily due to strong interactions between the urea oxygens and the cations with pyridine nitrogens contributing additional stabilizing interactions. PMID- 20704423 TI - Solvent and temperature effects on diastereodifferentiating Paterno-Buchi reaction of chiral alkyl cyanobenzoates with diphenylethene upon direct versus charge-transfer excitation. AB - In the Paterno-Buchi reaction of chiral p-cyanobenzoates (1) with 1,1 diphenylethene (2), we revealed that the excited charge-transfer (CT) complex formed upon selective excitation at the CT band is distinctly different in structure and reactivity from the conventional exciplex generated through the direct excitation of acceptor 1 which subsequently associates with donor 2. Thus, the favored diastereoface upon photocycloaddition, as well as the temperature- and solvent-dependent behavior of the product's diastereoselectivity, were highly contrasting, often opposite, to each other upon direct versus CT excitation. From the activation parameters obtained by the Eyring analyses of the diastereoselectivity, we are able to infer that the conventional exciplex is relatively flexible and susceptible to the environmental variants, whereas the CT complex is better pi-pi stacked and more rigid in the ground state and also in the excited state, leading to the significantly smaller differential activation enthalpies and entropies. More interestingly, the signs of the differential activation parameters determined for direct and CT excitation are consistently opposite to each other and the isokinetic temperatures calculated therefrom differ significantly, unambiguously revealing the distinctly different nature in structure and reactivity of these two excited-state complex species. Thus, the combined use of irradiation wavelength, temperature, and solvent provides us with a convenient, powerful tool not only for elucidating the mechanistic details of photoreaction but also for critically controlling the stereochemical outcomes of photochirogenic reaction. PMID- 20704424 TI - [4 + 2] Cycloadditions of 1-phosphono-1,3-butadienes with nitroso heterodienophiles: a versatile synthetic route for polyfunctionalized aminophosphonic derivatives. AB - The hetero-Diels-Alder (HDA) reaction of 1-(diethoxyphosphonyl)-1,3-butadiene, 1 (dibenzyloxyphosphonyl)-1,3-butadiene, and 1-(diethoxyphosphonyl)-3-tert butyldimethylsilyloxy-1,3-butadiene with various nitroso heterodienophiles has been investigated as a new synthetic route for aminophosphonic derivatives. The HDA cycloadditions regioselectively led to the proximal isomers, i.e., presenting the NR(3) group in the meta position regarding the phosphonate substituent. From the resulting 6-phosphono-3,6-dihydro-1,2-oxazine cycloadducts, a limited number of chemical steps were allowed to obtain a significant variety of aminophosphonic compounds of potential interest in medicinal chemistry. This has been illustrated through the synthesis of (Z)-4-(o-tolylamino)-1-hydroxybut-2-enylphosphonic acid, diethyl 3,4-dihydroxy-1-o-tolylpyrrolidin-2-yl-2-phosphonate, 4-(o-tolylamino) 1,2,3-trihydroxybutylphosphonic acid, diethyl 3-(2-(o-tolylamino)-1 hydroxyethyl)oxiran-2-yl-2-phosphonate, and diethyl 4,5-dihydroxymorpholin-6-yl-6 phosphonate. PMID- 20704425 TI - Chiral solvating agents for cyanohydrins and carboxylic acids. AB - We have shown that a structure as simple as an ion pair of (R)- or (S)-mandelate and dimethylamminopyridinium ions possesses structural features that are sufficient for NMR enantiodiscrimination of cyanohydrins. Moreover, (1)H NMR data of cyanohydrins of known configuration obtained in the presence of the mandelate dimethylaminopyridinium ion pair point to the existence of a correlation between chemical shifts and absolute configuration of cyanohydrins. Mandelate-DMAPH(+) ion pair and mandelonitrile form a 1:1 complex with an association constant of 338 M(-1) (DeltaG(0), -3.4 kcal/mol) for the (R)-mandelonitrile/(R)-mandelate DMAPH(+) and 139 M(-1) (DeltaG(0), -2.9 kcal/mol) for the (R)-mandelonitrile/(S) mandelate-DMAPH(+) complex. To understand the origin of enantiodiscrimination, the geometry optimization and energy minimization of the models of ternary complexes of (S)-mandelonitrile/(R)-mandelate/DMAPH(+) and (S)-mandelonitrile/(S) mandelate/DMAPH(+) complexes was performed using DFT methodology (B3LYP) with the 6-31+G(d) basis set in Gaussian 3.0. Further, analysis of optimized molecular model obtained from theoretical studies suggested that (i) DMAP may be replaced with other amines, (ii) the hydroxyl group of mandelic acid is not necessary for stabilization of ternary complex and may be replaced with other groups such as methyl, (iii) the ion pair should form a stable ternary complex with any hydrogen bond donor, provided its OH bond is sufficiently polarized, and (iv) alpha-H of racemic mandelic acid should also get resolved with optically pure mandelonitrile. These inferences were experimentally verified, which not only validated the proposed model but also led to development of a new chiral solvating agent for determination of ee of carboxylic acids and absolute configuration of aryl but not alkyl carboxylic acids. PMID- 20704426 TI - Copper-mediated fluoroalkylation reactions with iododifluoroacetamides: controlling the selectivity among cross-coupling, intramolecular cyclization, and homocoupling reactions. AB - Cu-mediated fluoroalkylation reactions with iododifluoroacetamides 1 have been systematically investigated. It was found that three types of reactions may coexist in Cu-mediated reactions between iododifluoroacetamides and aryl/alkenyl iodides: cross-coupling, intramolecular cyclization, and homocoupling reactions. The selectivity among these three types of reactions could be controlled by tuning the substituents on the nitrogen atom of iododifluoroacetamides, and/or by removing the cross-coupling reaction partner (aryl/alkenyl halides). The general rule is as follows: (a) in the presence of proper aryl/alkenyl iodides, the cross coupling products 2 (or 6) are generally formed as the major products; (b) in the absence of aryl/alkenyl iodides, and when R(1) = alkyl and R(2) = aryl groups, or when R(1) = R(2) = aryl groups, the intramolecular cyclization products 3 can be formed predominantly; and (c) in the absence of aryl/alkenyl iodides, and when R(1) = R(2) = alkyl groups, or when R(1) = H and R(2) = alkyl, aryl groups, the homocoupling products 4 can be formed dominantly. Our experimental results also indicate that in many cases when cross-coupling, homocoupling, and intramolecular cyclization reactions coexist in the Cu-mediated reaction system, the reactivity decreases in the following order: cross-coupling > intramolecular cyclization > homocoupling. PMID- 20704427 TI - Synthesis, photophysical, and DNA binding studies of fluorescent Troger's base derived 4-amino-1,8-naphthalimide supramolecular clefts. AB - The synthesis and characterization of three bis-1,8-naphthalimide-containing Troger's bases 1-3, formed from the corresponding 4-amino-1,8-naphthalimide precursors 7-9 in a single step, is described. The photophysical investigation of 1-3 and 7-9 was carried out in various organic solvents as well as in water and as a function of pH using UV/vis and fluorescence spectroscopy. As for their 4 amino-1,8-naphthalimide precursors 7-9, both the ground-state and excited-state characteristics of 1-3 were dependent on the polarity and the hydrogen-bonding ability of the solvent medium. The DNA-binding affinities of 1-3 were also studied in aqueous solution at pH 7.4, in the presence of calf-thymus DNA (ct DNA), using various UV/vis absorption and fluorescence spectroscopic methods. These molecules exhibited significant DNA-binding ability, where large binding values K(b) in the range of 10(6) M(-1) were determined. Such strong binding to ct-DNA was maintained even in competitive media (50 and 160 mM NaCl) and was also found to be irreversible regardless of the concentration of the ionic strength. Thermal denaturation experiments also demonstrated that the interaction of 1-3 with ct-DNA gave rise to significant stabilization in the double-helical structure of DNA. The binding affinity of 1-3 for ct-DNA was also compared to that of their 4-amino-1,8-naphthalimide precursors 7-9, determined by fitting of data using "intrinsic" methods and ethidium bromide displacement assays. The latter method gives outstanding binding constants for 1-3 in the range of 10(7) M(-1). PMID- 20704428 TI - Chiral sulfur ylides for the synthesis of bengamide E and analogues. AB - A new synthetic methodology of asymmetric epoxidation developed in our laboratories has been employed for the stereoselective synthesis of bengamide E (16) and analogues at the terminal olefinic position. In the event, the chiral sulfonium salt 30 was transformed into its corresponding sulfur ylide and reacted with aldehydes 21 and 44 to efficiently provide epoxy amides 31 and 45, respectively. To access the bengamides from these epoxy amides, we combined a synthetic strategy previously reported by us, using an olefin cross metathesis reaction to introduce various alkyl substituents at the terminal olefinic position of amide 33, with reactions mediated by palladium (Negishi or Suzuki couplings) from amide 49. This latter route of introduction of alkyl groups proved to be more efficient than the metathesis approach and allowed access to the generation of a wide array of new bengamide analogues. PMID- 20704429 TI - Chemoselective synthesis of sialic acid 1,7-lactones. AB - The chemoselective synthesis of the 1,7-lactones of N-acetylneuraminic acid, N glycolylneuraminic acid, and 3-deoxy-d-glycero-d-galacto-nononic acid is accomplished in two steps: a simple treatment of the corresponding free sialic acid with benzyloxycarbonyl chloride and a successive hydrogenolysis of the formed 2-benzyloxycarbonyl 1,7-lactone. The instability of the 1,7-lactones to protic solvents has been also evidenced together with the rationalization of the mechanism of their formation under acylation conditions. The results permit to dispose of authentic 1,7-sialolactones to be used as reference standards and of a procedure useful for the preparation of their isotopologues to be used as inner standards in improved analytical procedures for the gas liquid chromatography mass spectrometry (GLC-MS) analysis of 1,7-sialolactones in biological media. PMID- 20704431 TI - Synthetic studies on lactonamycins: synthesis of the model BCDEF aglycon. AB - The lactonamycin model aglycon 4 was synthesized from the trihalogenated benzene derivative 10. Ethynyltetraol 6 was prepared from 10 via carbon elongations, oxidative demethylation, a cycloaddition reaction with the diene derived from homophthalic anhydride, and dihydroxylation. Final E- and F-ring constructions from 6 were realized via a palladium-catalyzed cyclization-methoxycarbonylation, a stereoselective methanol addition, and lactonization, leading to the production of 4. PMID- 20704432 TI - A multiproduct terpene synthase from Medicago truncatula generates cadalane sesquiterpenes via two different mechanisms. AB - Terpene synthases are responsible for a large diversity of terpene carbon skeletons found in nature. The multiproduct sesquiterpene synthase MtTPS5 isolated from Medicago truncatula produces 27 products from farnesyl diphosphate (1, FDP). In this paper, we report the reaction steps involved in the formation of these products using incubation experiments with deuterium-containing substrates; we determined the absolute configuration of individual products to establish the stereochemical course of the reaction cascade and the initial conformation of the cycling substrate. Additional labeling experiments conducted with deuterium oxide showed that cadalane sesquiterpenes are mainly produced via the protonation of the neutral intermediate germacrene D (5). These findings provide an alternative route to the general accepted pathway via nerolidyl diphosphate (2, NDP) en route to sesquiterpenes with a cadalane skeleton. Mutational analysis of the enzyme demonstrated that a tyrosine residue is important for the protonation process. PMID- 20704430 TI - Synthesis, characterization, mechanism of decomposition, and antiproliferative activity of a class of PEGylated benzopolysulfanes structurally similar to the natural product varacin. AB - Benzopolysulfanes, 4-CH(3)(OCH(2)CH(2))(3)NHC(O)-C(6)H(4)-1,2-S(x) (x = 3-7 and 9) were synthesized with a PEG group attached through an amide bond and examined for water solubility, antitumor activity, and propensity to equilibrate and desulfurate. LCMS and HPLC data show the PEG pentasulfane ring structure predominates, and the tri-, tetra-, hexa-, hepta-, and nonasulfanes were present at very low concentrations. The presence of the PEG group improved water solubility by 50-fold compared to the unsubstituted benzopolysulfanes, C(6)H(4)S(x) (x = 3, 5, and 7), based on intrinsic solubility measurements. Polysulfur linkages in the PEG compounds decomposed in the presence of ethanethiol and hydroxide ion. The PEG pentathiepin desulfurated rapidly, and an S(3) transfer reaction was observed in the presence of norbornene; no S(2) transfer reaction was observed with 2,3-dimethylbutadiene. The antitumor activities of the PEG-substituted benzopolysulfane mixtures were analyzed against four human tumor cell lines PC3 (prostate), DU145 (prostate), MDA-MB-231 (breast), and Jurkat (T-cell leukemia). The PEG-conjugated polysulfanes had IC(50) values 1.2-5.8 times lower than the parent "unsubstituted" benzopolysulfanes. Complete cell killing was observed for the PEG polysulfanes at 4 microM for PC3 and DU145 cells and at 12 muM for MDA-MB-231 cells. The results suggest that solubilization of the polysulfur linkage is a key parameter to the success of these compounds as drug leads. PMID- 20704433 TI - Total synthesis of (+)-ambruticin S: probing the pharmacophoric subunit. AB - An enantioselective synthesis of the antifungal natural product (+)-ambruticin S has been accomplished starting with the readily available methyl alpha-d glucopyranoside, (R)-Roche ester, and (S)-glycidol as chirons, which encompassed seven of the 10 stereogenic centers of the target molecule. The remaining three centers were set by a highly diastereoselective, asymmetric cyclopropanation employing a chiral, nonracemic phosphonamide reagent. Our strategy for the construction of the dihydropyran subunit involved a highly syn-selective Lewis acid catalyzed 6-endo-trig cyclization. Other key steps in the synthesis featured an epoxide opening with a dithiane anion, two efficient phosphonamide-anion based olefinations, and a late-stage C-glycosylation. PMID- 20704434 TI - Strategies and synthetic methods directed toward the preparation of libraries of substituted isoquinolines. AB - Strategies for the production of substituted isoquinoline libraries were developed and explored. Routes involving microwave-assisted variants of the Bischler-Napieralski or Pictet-Spengler reaction allowed for cyclization of substituted beta-arylethylamine derivatives. The dihydroisoquinolines and tetrahydroisoquinolines thus generated could then be oxidized to their corresponding isoquinoline analogues. An alternate strategy, however, involving the preparation and activation of isoquinolin-1(2H)-ones is demonstrated to be a more practical, rapid, and efficient route to C1- and C4-substituted isoquinoline libraries. PMID- 20704435 TI - Palladium-catalyzed cross-coupling of electron-poor terminal alkynes with arylboronic acids under ligand-free and aerobic conditions. AB - Palladium-catalyzed cross-coupling reaction of terminal alkynes with arylboronic acids has been described. In the presence of Pd(OAc)(2) and Ag(2)O, a variety of terminal alkynes, including electron-poor terminal alkynes, smoothly underwent the reaction with numerous boronic acids to afford the corresponding internal alkynes in moderate to good yields. Moreover, this methodology was applied to the synthesis of 1H-isochromenes and diynes. It is noteworthy that the reaction proceeds under ligand-free and relative lower loading Pd conditions, and the maximal TONs (turnover numbers) of the reaction are up to 720,000. PMID- 20704436 TI - Seeking passe-partout in the catalytic asymmetric aziridination of imines: evolving toward substrate generality for a single chemzyme. AB - The asymmetric catalytic aziridination reaction (AZ reaction) of imines derived from dianisylmethyl (DAM) amine and tetra-methyldianisylmethyl (MEDAM) amine were examined with boroxinate catalysts prepared from both the VANOL and VAPOL ligands. This included an evaluation of different protocols for the preparation of the catalyst. The AZ reaction of DAM and MEDAM imines prepared from nine different aryl and aliphatic aldehydes were examined. The MEDAM imines were superior to the DAM imines in the AZ reaction, giving much higher asymmetric inductions and higher overall yields of aziridines. The MEDAM imines were found to also be superior to the previously studied diphenylmethyl (benzhydryl or Bh) and tetra-tert-butyldianisylmethyl (BUDAM) imines especially for imines derived from aliphatic aldehydes. The average asymmetric induction over the nine different MEDAM imines studied was 97% ee with the VAPOL catalyst and 96% ee with the VANOL catalyst. The MEDAM imines can be deprotected to give N-H aziridines in all cases except for some electron-rich aryl aldehydes. The MEDAM imines are much more reactive than benzhydryl imines, and this was most evident when a diazoacetate ester is replaced by a diazoacetamide. The less reactive diazoacetamides give very low yields in their reactions with benzhydryl imines but high yields with MEDAM imines. PMID- 20704437 TI - Synthesis of five- and six-membered dihalogenated heterocyclic compounds by electrophile-triggered cyclization. AB - Highly substituted dihalogenated dihydrofurans, dihydropyrroles, and dihydro-2H pyrans bearing alkyl, vinyl, aryl, and heteroaryl moieties can be prepared in good to excellent yields (up to 99%) by allowing 1,4-butyne-diol, 4-aminobut-2-yn 1-ol, and pent-2-yne-1,5-diol derivatives to react with different electrophiles (I(2), IBr, and ICl) at room temperature. Both halogen atoms generated from electrophiles were used effectively. The resulting halides can be further exploited by using palladium-catalyzed coupling reactions. The presence of trace amount of water is essential for this electrophilic cyclization. PMID- 20704438 TI - Poly(cyclopropenone)s: formal inclusion of the smallest Huckel aromatic into pi conjugated polymers. AB - The synthesis of precursors to pi-conjugated cyclopropenium polymers is described. Monomers for chemical and electrochemical manipulation are easily prepared through electrophilic substitution of in situ generated cyclopropenium cations that are then hydrolyzed to the respective cyclopropenones. The unusually strong dipole moment associated with the cyclopropenone renders this core formally aromatic, an electronic structure that becomes more important within individual monomers upon protonation of the carbonyl function with trifluoroacetic acid or alkylation with triethyloxonium salts. The electronic properties of cyclopropenone polymers in their pristine states and after acidification are discussed along with conjugated carbonyl-containing polymers that are also acid sensitive but without the added element of aromaticity. We find that the increased contributions of cyclopropenium cation aromaticity restrict the quinoidal charge carriers due to the energetically less favorable proposition of disrupting the local aromatic stabilization. PMID- 20704439 TI - Shortcomings of basing radical stabilization energies on bond dissociation energies of alkyl groups to hydrogen. AB - Stabilization energies (SE(H)) of carbon radicals (R(*)) are traditionally defined as the difference between the bond dissociation energy (BDE) of CH(3)-H, as a reference point, and of R-H. The term "stabilization energy" implies that it is an intrinsic property of the radical and a quantitative measure of stability. Applicable only to carbon-centered radicals, SE(H) stabilization energies are not transferable and cannot be used to estimate carbon-carbon BDE[R-R'], symmetrical BDE[R-R], or any other BDE[R-X]. SE(H) values by themselves are neither an intrinsic property nor a quantitative measure of stability. There is available an alternative that is not limited only to carbon-carbon and carbon-hydrogen bonds, does not depend on any one particular molecule or BDE as a reference point, and is accurate with several hundred different types of bonds. PMID- 20704440 TI - FeCl(3)-Diorganyl dichalcogenides promoted cyclization of 2-alkynylanisoles to 3 chalcogen benzo[b]furans. AB - A general synthesis of 3-chalcogen benzo[b]furans from the readily available 2 alkynylanisoles, via FeCl(3)/diorganyl dichalcogenides intramolecular cyclization, has been developed. Aryl and alkyl groups directly bonded to the chalcogen atom were used as cycling agents. The results revealed that the reaction significantly depends on the electronic effects of substituents in the aromatic ring bonded to the selenium atom of the diselenide species. We observed that the pathway of reaction was not sensitive to the nature of substituents in the aromatic ring of anisole since both the electron-donating and the electron withdrawing groups delivered the products in similar yields. In addition, the obtained heterocycles were readily transformed to more complex products by using a chalcogen/lithium exchange reaction with n-BuLi followed by trapping of the lithium intermediate with aldehydes, furnishing the desired secondary alcohols in good yields. PMID- 20704441 TI - Reversal of stereoselectivity in the Cu-catalyzed conjugate addition reaction of dialkylzinc to cyclic enone in the presence of a chiral azolium compound. AB - Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et(2)Zn catalyzed by Cu(OTf)(2) in the presence of an azolium salt derived from a chiral beta-amino alcohol gave (S)-3-ethylcyclohexanone (31) in good enantioselectivity. Among a series of chiral azolium compounds examined, the benzimidazolium salt (10) having both a tert-butyl group at the stereogenic center and a benzyl substituent at the azolium ring was found to be the best choice of ligand in the Cu(OTf)(2)-catalyzed reaction. Good enantioselectivity was observed when the reaction was conducted by employing a benzimidazolium derivative rather than an imidazolium derivative. The influence of the substituent at the azolium ring on the stereoselectivity of the reaction was also examined. In addition, from the results of the reaction catalyzed by Cu(OTf)(2) combined with an azolium compound derived from (S)-leucine methyl ester, it was found that the hydroxy side chain in the chiral ligand is probably crucial for the enantiocontrol of the conjugate addition reaction. On the other hand, it was discovered from a screening test of copper species that the reversal of enantioselectivity was realized by allowing 30 to react with Et(2)Zn in the presence of Cu(acac)(2) combined with the same ligand precursor to afford (R)-31 as a major product. The influence of the stereodirecting group at the chiral ligand on the stereoselectivity in the Cu(acac)(2)-catalyzed reaction differed completely from that observed in the Cu(OTf)(2)-catalyzed reaction. Reaction with a cyclic enone consisting of a seven membered ring such as 2-cyclohepten-1-one (40) resulted in increasing the enantioselectivity of the reaction. Thus, treatment of 40 with Et(2)Zn catalyzed by Cu(OTf)(2) combined with a benzimidazolium salt produced the corresponding (S) conjugate adduct in a 92:8 enantiomer ratio (er), while the Cu(acac)(2)-catalyzed reaction with the same ligand afforded (R)-product in a 9:91 er. PMID- 20704442 TI - Synthesis of tetrahydroisoquinoline alkaloids via anodic cyanation as the key step. AB - We report a new route to tetrahydroisoquinoline (THIQ) alkaloids involving the alkylation of alpha-aminonitrile 2 as a key step. The latter compound was prepared by anodic cyanation of the corresponding tertiary amine 1. Reductive decyanation of alpha-aminonitriles 6a-c proceeded diastereoselectively (up to 95% de) to deliver the C1-substituted alkaloids precursors 9a-c. The syntheses of (+/ )-carnegine, (+/-)-norlaudanosine, and (+/-)-O,O-dimethylcoclaurine have been achieved. PMID- 20704443 TI - Synthesis of mangiferin, isomangiferin, and homomangiferin. AB - Mangiferin, isomangiferin, and homomangiferin, the xanthone C-glycosides with a wide spectrum of pharmacological effects, were synthesized concisely, featuring a C-glycosylation of a xanthene derivative with perbenzylglucopyranosyl N phenyltrifluoroacetimidate. PMID- 20704444 TI - Silylene transfer to allylic sulfides: formation of substituted silacyclobutanes. AB - Silylene transfer to allylic sulfides results in a formal 1,2-sulfide migration. The rearrangement yields substituted silacyclobutanes, not the expected silacyclopropanes. The silacyclobutanes were elaborated by insertions of carbonyl compounds selectively into one carbon-silicon bond. A mechanism for the 1,2 sulfide migration is proposed involving an episulfonium ion intermediate. PMID- 20704445 TI - Synthesis of nucleotidylated poliovirus VPg proteins. AB - Phosphitylation of the side chain hydroxyl function of Fmoc protected tyrosine with 5'-phosphoramidites of suitably protected cytidine, adenosine, and guanosine, followed by oxidation gave three novel nucleotidylated amino acid building blocks. After protective group manipulation, these building blocks were used in a solid phase peptide synthesis to afford the nucleotidylated poliovirus proteins VPgpC, VPgpA, and VPgpG. PMID- 20704447 TI - Photoactivated racemization catalyst for dynamic kinetic resolution of secondary alcohols. AB - Household fluorescent light activates a diruthenium complex to generate catalytic species highly active for the racemization of secondary alcohols under ambient conditions. This catalyst system is applicable for the chemoenzymatic dynamic kinetic resolution of racemic alcohols to give optically pure acetates under mild conditions. PMID- 20704446 TI - Conjugate addition of lithiated methyl pyridines to enones. AB - Preparatively useful conjugate addition of lithiated methyl pyridines to cyclic and acyclic enones is reported. Addition of 2-picoline to 3-penten-2-one led to a concise synthesis of the alkaloids (+/-)-senepodine G and (+/-)-cermizine C. PMID- 20704448 TI - Copper-catalyzed multicomponent reaction: synthesis of 4-arylsulfonylimino-4,5 dihydrofuran derivatives. AB - A series of 4-arylsulfonylimino-4,5-dihydrofurans (14 examples) were efficiently synthesized in good to excellent yields by using the copper-catalyzed three component reaction between sulfonyl azides, phenylacetylene, and beta-ketoesters in tetrahydrofuran (THF) at 40 degrees C for 8 h in the presence of triethylamine (TEA). A plausible mechanism for this process is proposed. PMID- 20704449 TI - Total regioselective control of tartaric acid. AB - An efficient strategy to synthesize tartaric acid building blocks for totally regioselective transformations or derivatizations was disclosed. Starting from l tartaric acid or l-dimethyl tartrate, respectively, we obtained type I and II building blocks with orthogonal sets of protecing groups (4-8 steps, 38-56% overall yield). PMID- 20704450 TI - Short synthesis of the seed germination inhibitor 3,4,5-trimethyl-2(5H)-furanone. AB - 3,4,5-Trimethyl-2(5H)-furanone, a new seed germination inhibitor with very promising agrochemical applications, was efficiently synthesized from 2,3 dimethylmaleic anhydride via nucleophilic addition of methyllithium followed by reduction using sodium borohydride. This two-step synthesis is straightforward and high-yielding and permits the large-scale preparation of the seed germination inhibitor. PMID- 20704451 TI - Stereoselective total synthesis of (-)-cleistenolide. AB - A facile stereoselective total synthesis of cleistenolide (1) from the natural chiral template d-arabinose has been achieved in eight steps and 49% overall yield, employing key steps including Wittig olefination, selective 1,3-trans acetal formation, and modified Yamaguchi esterification. PMID- 20704452 TI - Synthesis of aminooxy and N-alkylaminooxy amines for use in bioconjugation. AB - Five Boc-protected aminooxy and N-alkylaminooxy amines have been synthesized in 60-95% overall yield using a common synthetic strategy from readily available two and three-carbon Cbz-protected amino alcohols. The amines can be linked to biomolecules via amide formation and incorporated directly into peptoids via submonomer synthesis. Subsequent deprotection of the aminooxy and N-alkylaminooxy groups enables conjugation with desired target molecules via established chemoselective ligation methods. The range of derivatives synthesized allows different distances to be established between the conjugated molecules. PMID- 20704454 TI - Dermal toxicity associated with epibatidine exposure. AB - Epibatidine is an alkaloid similar to nicotine, which was originally discovered in the skin of the Ecuadorian poisonous frog. A number of synthetic preparations are available, and it is subject to medical research for a variety of disorders. This article describes a previously healthy 25-year-old researcher who developed an itchy, vesicular rash after working for around 2 h in a laboratory environment with epibatidine hydrochloride (Tocris Bioscience, Ellisville, MO, USA). An urticarial rash developed on the extensor surfaces of forearms, calves, axillae, and upper torso. Mucous membranes were spared, and there was no lymphadenopathy. The patient had a history of asthma, but no documented allergy or skin disorder, and no family history of atopy. He underwent treatment with oral prednisolone 40 mg, and regular oral chlorpheniramine 4 mg three times daily, and the rash had fully resolved in 1 week. PMID- 20704453 TI - Modeling of the endosomolytic activity of HA2-TAT peptides with red blood cells and ghosts. AB - HA2-TAT is a peptide-based delivery agent that combines the pH-sensitive HA2 fusion peptide from influenza and the cell-penetrating peptide TAT from HIV. This chimeric peptide is engineered to induce the cellular uptake of macromolecules into endosomes via the TAT moiety and to respond to the acidifying lumen of endosomes to cause membrane leakage and release of macromolecules into cells via the HA2 moiety. The question of how HA2 and TAT affect the properties of one another remains, however, unanswered, and the behavior of the peptide inside endosomes is mostly uncharacterized. To address these issues, the binding and membrane leakage activity of a glutamic acid-enriched analogue E5-TAT was assessed with red blood cells and giant unilamellar vesicles as membrane models for endosomes. Hemolysis and microscopy assays reveal that E5-TAT binds to membranes in a pH-dependent manner and causes membrane leakage by inducing the formation of pores through which macromolecules can escape. The TAT moiety contributes to this activity by causing a shift in the pH response of E5 and by binding to negatively charged phospholipids. On the other hand, TAT binding to glycosaminoglycans reduces the lytic activity of E5-TAT. Addition of TAT to the C terminus of E5 can therefore either increase or inhibit the activity of E5 depending on the cellular components present at the membrane. Taken together, these results suggest a model for the endosomolytic activity of the peptide and provide the basis for the molecular design of future delivery agents. PMID- 20704455 TI - Utility of serum lactate to predict drug-overdose fatality. AB - CONTEXT: Poisoning is the second leading cause of injury-related fatality in the United States. An elevated serum lactate concentration identifies medical and surgical patients at risk for death; however, its utility in predicting death in drug overdose is controversial and unclear. OBJECTIVE: We aimed to evaluate the prognostic utility of serum lactate concentration for fatality in emergency department (ED) patients with acute drug overdose. MATERIALS AND METHODS: This was a case-control study at two urban university teaching hospitals affiliated with a regional poison control center. Data were obtained from electronic medical records, poison center data, and the office of the chief medical examiner. Controls were consecutive acute drug overdoses over a 1-year period surviving to hospital discharge. Cases were subjects over a 7-year period with fatality because of drug overdose. Serum lactate concentration was obtained from the initial blood draw in the ED and correlated with fatality. RESULTS: During the study period, 873 subjects were screened with 50 cases and 100 controls included. Drug exposures and baseline characteristics were similar between groups. Mean lactate concentration (mmol/L) was 9.88 +/- 6.7 for cases and 2.76 +/- 2.9 for controls (p < 0.001). The receiver operating characteristic area under the curve for prediction of fatality was 0.87 (95% CI: 0.81-0.94). The optimal lactate cutpoint was 3.0 mmol/L (84% sensitivity, 75% specificity), which conferred a 15.8-fold increase in odds of fatality (p < 0.001). CONCLUSION: In this derivation study, serum lactate concentration had excellent prognostic utility to predict drug-overdose fatality. Prospective validation in the ED evaluation of drug overdoses is warranted. PMID- 20704456 TI - Hydrogen sulfide toxicity in a thermal spring: a fatal outcome. AB - INTRODUCTION: Hydrogen sulfide (H(2)S) is a toxic gas with the smells of "rotten egg"; its toxic effects are due to the blocking of cellular respiratory enzymes leading to cell anoxia and cell damage. CASE PRESENTATION: We report two cases with acute H(2)S intoxication caused by inhalation of H(2)S evaporated from the water of a thermal spring. Two victims were found in a hotel room were they could take a thermal bath. A 26-year-old male was found unconscious; he was resuscitated, received supportive treatment and survived. A 25-year-old female was found dead. Autopsy showed diffuse edema and pulmonary congestion. Toxicological blood analysis of the female revealed the following concentrations: 0.68 mg/L sulfide and 0.21 mmol/L thiosulfate. The urine thiosulfate concentration was normal. Forensic investigation established that the thermal water was coming from the hotel's own illegal well. The hotel was closed. CONCLUSION: This report highlights the danger of H(2)S toxicity not only for reservoir and sewer cleaners, but also for individuals bathing in thermal springs. PMID- 20704457 TI - Cobinamide is superior to other treatments in a mouse model of cyanide poisoning. AB - CONTEXT: Cyanide is a rapidly acting cellular poison, primarily targeting cytochrome c oxidase, and is a common occupational and residential toxin, mostly via smoke inhalation. Cyanide is also a potential weapon of mass destruction, with recent credible threats of attacks focusing the need for better treatments, as current cyanide antidotes are limited and impractical for rapid deployment in mass casualty settings. OBJECTIVE: We have used mouse models of cyanide poisoning to compare the efficacy of cobinamide (Cbi), the precursor to cobalamin (vitamin B(12)), to currently approved cyanide antidotes. Cbi has extremely high affinity for cyanide and substantial solubility in water. MATERIALS AND METHODS: We studied Cbi in both an inhaled and intraperitoneal model of cyanide poisoning in mice. RESULTS: We found Cbi more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning. Compared to hydroxocobalamin, Cbi was 3 and 11 times more potent in the intraperitoneal and inhalation models, respectively. Cobinamide sulfite (Cbi-SO(3)) was rapidly absorbed after intramuscular injection, and mice recovered from a lethal dose of cyanide even when given at a time when they had been apneic for over 2 min. In range-finding studies, Cbi-SO(3) at doses up to 2000 mg/kg exhibited no clinical toxicity. DISCUSSION AND CONCLUSION: These studies demonstrate that Cbi is a highly effective cyanide antidote in mouse models, and suggest it could be used in a mass casualty setting, because it can be given rapidly as an intramuscular injection when administered as Cbi-SO(3). Based on these animal data Cbi-SO(3) appears to be an antidote worthy of further testing as a therapy for mass casualties. PMID- 20704458 TI - Formulation and evaluation of diclofenac potassium fast-disintegrating tablets and their clinical application in migraine patients. AB - The aim of this study was to prepare fast-disintegrating tablets (FDTs) of diclofenac potassium with sufficient integrity as well as a pleasant taste, using two different fillers and binders: Tablettose 70((r)) and Di-Pac((r)). Tablets were made with direct compression method. Tablet properties such as porosity, hardness, and disintegration time were determined. Diclofenac potassium determinations were carried out using a validated spectrophotometric method for the analysis of drug. Furthermore, in vivo experiments were carried out to compare the analgesic effect and the time to relieve migraine headache between the commercial tablets and FDTs of diclofenac potassium against placebo. Results showed that FDTs of diclofenac potassium with durable structure and desirable taste can be prepared using both fillers and binders but tablets prepared with Di Pac had a better taste so the tablet formulation containing Di-Pac was chosen for in vivo experiments. Placebo controlled in vivo trial demonstrated that 50 mg diclofenac potassium, administered as a single dose of FDTs or commercial tablets, was effective in relieving the pain and both of them were superior to placebo. PMID- 20704459 TI - Diclofenac fast-dissolving film: suppression of bitterness by a taste-sensing system. AB - CONTEXT: The selection of a proper taste-masking agent (TMA) is a critical issue in the development of fast-dissolving films containing bitter drugs. OBJECTIVE: This work is aimed to evaluate the suppression of the bitter taste of a maltodextrin fast-dissolving film loaded with 13.4 mg sodium diclofenac (DS) by adding TMAs. METHODS: The films were prepared by casting and drying aqueous mixtures of maltodextrin (DE = 6), glycerin, sorbitan oleate, and DS. Films were characterized in terms of thickness, tensile properties, film disintegration time, and drug dissolution time. The bitterness intensity of DS and the masking effect of TMAs were evaluated by an electronic tongue. RESULTS: The 'mint' and 'licorice' flavors and sucralose mixture resulted appropriate to mask DS bitterness as confirmed by a panel of volunteers. The addition of these TMAs did not significantly affect the film disintegration time (15-20 seconds) and DS dissolution rate (about 5 minutes). CONCLUSION: The electronic tongue was allowed to discriminate the effect of the TMA also in the presence of other hydrosoluble constituents of the film. Therefore, because of its simplicity and rapidity, this technique could assist or even replace the sensory evaluation in the development of fast-dissolving films. PMID- 20704460 TI - Pharmacokinetics of a novel nifedipine and pH-sensitive N-succinyl chitosan/alginate hydrogel bead in rabbits. AB - CONTEXT: A novel N-succinyl chitosan/alginate hydrogel bead was prepared by the ionic gelation method for controlled delivery of nifedipine (NF). OBJECTIVE: The delivery behavior of NF from the hydrogel bead was studied in rabbit body. MATERIALS AND METHODS: Nitrendipine was used as the internal standard and the concentration of NF in serum was determined by reversed-phase high-performance liquid chromatography. RESULTS: The assay was linear from 5 to 755 ng/mL. The limit of quantitation for NF was 5 ng/mL in serum, and the recovery was greater than 90%. The method was used to determine the concentration-time profiles of NF in the serum. The pharmacokinetic parameters were calculated by Drug and Statistics (ver 1.0) program. The mean Cmax was 320.2 +/- 71.3 MUg/L, the mean Tmax was 3.2 +/- 0.5 hours, the mean t1/2 was 6.60 +/- 2.17 hours, the mean AUC0 24 was 2.03 +/- 0.25 mg h/L, the mean AUC0-infinity was 2.50 +/- 0.36 mg h/L, the mean MRT0-24 was 8.57 +/- 0.19 hours, and the mean MRT0-infinity was 15.2 +/- 1.8 hours. DISCUSSION AND CONCLUSION: The pharmacokinetic characteristics were found by a two-compartment model following the oral administration of NF-loaded N succinyl chitosan/alginate hydrogel beads in rabbits. PMID- 20704461 TI - An experimental investigation of the effect of the amount of lubricant on tablet properties. AB - BACKGROUND: Magnesium stearate (MgSt) is widely used as a lubricant in the production of tablets. However, the amount added to a formulation is often too high or it is poorly mixed, which can lead to the production of tablets whose properties are out of specifications. METHOD: The objective of this work was to investigate by means of a new method based on gamma-ray flux measurement and to study the impact of the amount of MgSt on the mass, thickness, hardness, friability, and disintegration time of tablets containing a 50 : 50 wt.% microcrystalline cellulose and spray-dried lactose pre-blend. Other blends were lubricated with sodium lauryl sulfate (SLS) to compare the performance of the two lubricants in equal amounts. RESULTS: It was observed that, contrary to SLS, a greater amount of MgSt increased the variability of the tablet mass. The tablet hardness decreased with an increasing amount of MgSt, whereas it remained relatively unaffected by the presence of SLS. No solid conclusion could be drawn concerning the relationship between the lubricant concentration and the tablet friability. CONCLUSION: An amount of 0.25 wt.% MgSt and 0.75 wt.% SLS were found to be sufficient amounts of lubricants to obtain a proper compression. PMID- 20704462 TI - Complete genome sequencing and network modeling to overcome trastuzumab resistance. PMID- 20704467 TI - Dopamine receptor subtypes in the human coronary vessels of healthy subjects. AB - OBJECTIVE: Dopamine D(1)-D(5) receptors subtypes were studied in human coronary vessels of healthy subjects to assess their localization and their expression. METHODS: Samples of intraparenchymal and extraparenchymal branches of human coronary arteries and veins were harvested from four normal native hearts explanted from four young brain dead heart donors in case of orthoptic transplant, not carried out for technical reasons. In all the samples morphological, biochemical, immunochemical, and morphometrical studies were performed including quantitative analysis of images and evaluation of data. RESULTS: Microanatomical section showed healthy coronary vessels, which expressed all dopamine receptors (from D(1) to D(5)) with a different pattern of distribution between the different layers, in the intra and in the extraparenchymal branches.D(1) and D(5) (with a prevalence D(1) over D(5)) were distributed in the adventitia and to a lesser extent in the outer media but they were absent in arterioles, capillaries and venules. Endothelial and the middle layer showed D(2), D(3) and D(4) receptors, with a greater expression of D(2). Immunoblot analysis of dopamine monoclonal antibodies and dopamine receptors showed a different migration band for each receptor: D(1) (45 KDa); D(2) (43 KDa); D(3) (42 kDa); D(4) (40-42 KDa); D(5) (38-40 KDa) CONCLUSION: These findings demonstrate the presence of all dopamine receptor subtypes in the wall of human coronary vessels of healthy subjects. Dopamine D(1) and D(2) receptor subtypes are the most expressed, suggesting their prominent role in the coronary vasoactivity. PMID- 20704468 TI - Defying aches and revaluating daily doing: occupational perspectives on adjusting to chronic pain. AB - The aim of this study was to investigate how people with chronic pain experience their daily doing, with a special focus on possible adjustment to pain and altered life conditions in order to cope with pain and maintain well-being. In depth interviews were guided by themes concerning daily occupation, ways to maintain well-being, and future expectations. Using qualitative content analysis a core concept "Reappraising daily doing" was arrived at, containing the categories of altering doing processes and altering values, each in turn containing four subcategories. The findings showed that along with the grief of having to abandon jobs and former social networks, the participants coped with their everyday lives in ways that opened up the use of imagination and improvisation and the valuing of non-material and altruistic behaviour. An occupation was generally given up when aches (participants' term) became worse, except for when the occupations were so enjoyed that the pain was put out of focus. Using the concept of Occupational Value to enhance coping ability seems a reasonable strategy for occupational therapists when assisting clients in finding or maintaining meaningful daily doing and effective coping strategies for experiencing well-being. This could in turn limit the use of health care resources, which is extensive. PMID- 20704464 TI - Toxicogenetics: population-based testing of drug and chemical safety in mouse models. AB - The rapid decline in the cost of dense genotyping is paving the way for new DNA sequence-based laboratory tests to move quickly into clinical practice, and to ultimately help realize the promise of 'personalized' therapies. These advances are based on the growing appreciation of genetics as an important dimension in science and the practice of investigative pharmacology and toxicology. On the clinical side, both the regulators and the pharmaceutical industry hope that the early identification of individuals prone to adverse drug effects will keep advantageous medicines on the market for the benefit of the vast majority of prospective patients. On the environmental health protection side, there is a clear need for better science to define the range and causes of susceptibility to adverse effects of chemicals in the population, so that the appropriate regulatory limits are established. In both cases, most of the research effort is focused on genome-wide association studies in humans where de novo genotyping of each subject is required. At the same time, the power of population-based preclinical safety testing in rodent models (e.g., mouse) remains to be fully exploited. Here, we highlight the approaches available to utilize the knowledge of DNA sequence and genetic diversity of the mouse as a species in mechanistic toxicology research. We posit that appropriate genetically defined mouse models may be combined with the limited data from human studies to not only discover the genetic determinants of susceptibility, but to also understand the molecular underpinnings of toxicity. PMID- 20704469 TI - Environmental risk factors in inflammatory bowel diseases. Investigating the hygiene hypothesis: a Spanish case-control study. AB - OBJECTIVE: Environmental factors have been implicated in the etiology of inflammatory bowel disease (IBD), but evidence for the hygiene hypothesis is unclear. We investigated the relationship between early-life infection-related exposures and risk of IBD. PATIENTS AND METHODS: A hospital-based case-control study was carried out. A total of 124 cases of Crohn's disease (CD) and 146 of ulcerative colitis (UC) were compared with 235 and 278 well-matched control subjects, respectively. A multi-item questionnaire on familial history of IBD, childhood circumstances and familial socioeconomic status was carried out. RESULTS: In a multivariate model, living in urban areas (odds ratio (OR) 4.58 (95% CI 2.17-10)), high educational level (OR 1.83 (95% CI 14-2.95)) and social status (OR 1.68 (95% CI 1.2-2.35)) were risk factors for CD, whereas childhood respiratory infections (OR 0.35 (95% CI 0.23-0.52)) and gastroenteritis (OR 0.55 (95% CI 0.36-0.85)) were protective factors. Living in urban areas (OR 4.6 (95% CI 2.29-9.9)), a high educational level (OR 10.3 (95% CI 2.54-42.1)) and social status (OR 2.042 (95% CI 1.31-3.17)) were also risk factors for UC, whereas respiratory infections (OR 0.42 (95% CI 0.29-0.6)) and gastroenteritis (OR: 0.6 (95% CI 0.42-0.86)) were protective factors. Appendectomy (OR 0.173 (95% CI 0.06 0.52)) and current smoking (OR 0.75 (95% CI 0.59-0.96)) were also protective for UC. CONCLUSION: These results further support the hypothesis that better living conditions during childhood are associated with an increased risk for IBD, and reinforce the negative association between smoking and appendectomy and the risk of UC. PMID- 20704470 TI - Effect of process conditions on the growth of three-dimensional dermal-equivalent tissue obtained by microtissue precursor assembly. AB - Bottom-up approach is an appealing strategy to build complex three-dimensional (3D) viable tissues in vitro starting from microtissue precursors (MUTP). In this work we biofabricated a thick dermal-like tissue by sequentially combining two steps: a MUTPs production and assembly followed by tissue maturation in a purpose built bioreactor. The MUTPs were produced by first seeding bovine primary fibroblasts on gelatine microparticles and then cultivating them in stirring conditions until a thick layer of ~80 MUm of de novo synthesized extracellular matrix uniformly covered the microparticle surface. The MUTPs were then loaded into a cylindrical chamber (2 mm in depth and 35 mm in diameter) and let to maturate and assemble into a 3D viable biohybrid tissue under specific fluid flow conditions. Several combinations of perfusion and/or tangential fluid flow were applied and their effect on the tissue formation and maturation was assessed. Results show that structural composition and mechanical features of the final 3D bioengineered tissue are strongly affected by the hydrodynamic environment and demonstrate that by optimizing culture conditions a 3D viable tissue with properties similar to that of native derma could be produced. PMID- 20704471 TI - Methods for photocrosslinking alginate hydrogel scaffolds with high cell viability. AB - Methods for seeding high-viability (>85%) three-dimensional (3D) alginate chondrocyte hydrogel scaffolds are presented that employ photocrosslinking of methacrylate-modified alginate with the photoinitiator VA-086. Comparison with results from several other photoinitiators, including Irgacure 2959, highlights the role of solvent, ultraviolet exposure, and photoinitiator cytotoxicity on process viability of bovine chondrocytes in two-dimensional culture. The radicals generated from VA-086 photodissociation are shown to be noncytotoxic at w/v concentrations up to 1.5%, enabling photocrosslinking without significant cell death. The applicability of these photoinitiators for generating 3D tissue engineered constructs is evaluated by measuring cell viability in 3D constructs with aggregate moduli in the 10-20 kPa range. Hydrogels with encapsulated bovine chondrocytes were constructed with >85% viability using VA-086. While the commonly used Irgacure 2959 is noncytotoxic in its native state and crosslinks the alginate at weight fractions much lower than VA-086, the cytotoxicity of IRG2959's photogenerated radical leads to viabilities below 70% in the conditions tested. PMID- 20704472 TI - The effect of adapting speed, duration, and distance on the tactile motion aftereffect. AB - We investigated the effect of adapting speed, duration, and distance on the frequency of occurrence, duration, and vividness of the tactile motion aftereffect (tMAE). Using a cylindrical drum with a patterned surface we adapted the glabrous surface of the right hand at two speeds (14 and 28 cm/s) and three durations (60, 120, and 240 s). Distance was explored in the interaction of adapting speed and duration. The results showed that the frequency of occurrence, duration, and vividness of the tMAE increased with adapting speed. There was also a positive relationship between adapting duration and the frequency of occurrence, but not the duration or vividness, of the illusion. Distance was only a factor when it came to the duration of the tMAE. Taken together, these results show the importance of adapting parameters, particularly speed, on the tMAE. PMID- 20704473 TI - Gender differences in changes of motor cortex excitability during elevated blood lactate levels. AB - Gender differences in cortical excitability have been detected by using transcranial magnetic stimulation (TMS). The present study was carried out to compare the effects of high blood lactate levels, induced by performing a maximal exhausting exercise, on the excitability of the primary motor cortex in young male and female athletes. The study was carried out on 21 young males and 20 females from the Middle Distance Track Team of our university. Before the exercise, at the end, as well as 5 and 10 min after the conclusion, venous blood lactate and glucose were measured and excitability of the motor cortex was evaluated by using TMS. We observed a similar enhancement of excitability of primary motor cortex, concomitantly with an increase of blood lactate, in both young male and female athletes. However, the improvement was significantly higher (p < 0.05) in women (37.4% +/- 3.97) than in men (42.0% +/- 6.43), suggesting a greater sensitiveness of female cerebral cortex to blood lactate. PMID- 20704474 TI - Two case reports of anophthalmia and congenital heart disease: Adding a new dimension to this association. AB - Anophthalmia is the congenital absence of ocular tissue from the orbit. Many syndromes and malformations (e.g., anophthalmia-esophageal-genital syndrome, Matthew-Wood syndrome, CHARGE syndrome, oculo-facial-cardio-dental-syndome, heterotaxy, and Fraser syndrome) have been associated with anophthalmia. However, its relation with congenital heart disease has not been fully elucidated. In this article, we discuss two cases of patients with anophthalmia and congenital heart defects, and we compare these findings with other syndromes with which anophthalmia has been associated. One of our two patients showed complex congenital heart disease with heterotaxia, polysplenia, and normal lung lobation. These findings may reflect a new dimension of anophthalmia, heterotaxia, and congenital heart disease associations. PMID- 20704475 TI - An infantile leiomyosarcoma that metastasized from the small intestine to the adrenal gland. AB - In the literature, there is no reported pediatric leiomyosarcoma case that has metastasized from the small intestine to the adrenal gland. A 10-year-old boy who had anemia and weight loss over 2 years presented with abdominal pain that began 1 week previously. Radiologic examination revealed bilateral adrenal tumors. At the time of surgery, the terminal ileum was resected and a tru-cut biopsy was done from the right adrenal mass. The pathology report was leiomyosarcoma for both of the resection and tru-cut specimens. We present an intestinal leiomyosarcoma that metastasized from the small intestine to both adrenal glands with clinical, morphologic, and immunohistochemical studies with a literature review. PMID- 20704476 TI - A nonsense porcn mutation in severe focal dermal hypoplasia with natal teeth. AB - Focal dermal hypoplasia (FDH, Goltz syndrome), is an X-linked dominant mesoectodermal developmental disorder, involving skin, skeleton, eyes, teeth, and other organs. Mutations in PORCN, which stimulates the secretion of wingless family signal proteins, are found in FDH patients. A female fetus presented at 34 weeks gestation with interuterine growth restriction (IUGR), asymmetry, limb anomalies, microphthalmia, and lung anomaly. Focal dermal hypoplasia was confirmed at birth, with hypoplastic areas of skin, malformation of the limbs, diaphragmatic hernia, and ocular anomalies. Mutation analysis of PORCN revealed a nonsense mutation-Y359X. She presented natal teeth, an unexpected feature considering the role of the Wnt pathway in tooth development. PMID- 20704477 TI - Thanatophoric dysplasia type I associated with increased nuchal translucency in the first trimester: Early prenatal diagnosis using combined ultrasonography and molecular biology. AB - A case of thanatophoric dysplasia (TD) type I associated with severely increased nuchal translucency at first trimester screening for Down syndrome is reported. A 38-year-old woman, G2P1, with previous uneventful pregnancy, was referred for amniocentesis at 16 weeks due to positive first trimester integrated test. Amniocentesis revealed a 46,XX fetus. At 16 weeks gestation, the ultrasound examination of the fetus revealed a narrow chest, short ribs, and a generalized severe shortening of the long bones. The patient underwent a follow-up scan at 19 weeks which demonstrated ultrasound findings consistent with severe rhizomelic micromelia. A wide prenatal panel of gene mutations related with skeletal dysplasia was performed. Nucleotidic sequence using QF-PCR on exons 7,10, 15, 19 of the fibroblast growth factor receptor 3 (FGFR3) demonstrated a 742 C>T (R248C) mutation, which resulted in an Arg248Cys substitution in heterozygous state, leading to a prenatal diagnosis of thanatophoric dysplasia type I. The early diagnosis of this lethal form of skeletal dysplasia directed the prenatal counseling and allowed appropriate obstetric management. Necropsy, post-mortem x ray, and histologic analysis of the growth plate might aid the diagnosis of TD type I. PMID- 20704478 TI - Congenital salivary gland anlage tumor of the nasopharynx. AB - Nasal and upper respiratory tract obstruction in the neonatal period can result from a variety of conditions, and may be present with variable symptoms. Salivary gland anlage tumor, also referred as congenital pleomorphic adenoma, is a very rare benign congenital tumor of the nasopharynx, which may produce nasal obstruction and other associated, nonspecific symptoms. We report a case of congenital salivary gland anlage tumor causing a severe neonatal respiratory distress with pulmonary hypertension. The tumor was removed and the outcome was favourable without recurrence at five years of the follow up. PMID- 20704479 TI - Prenatal diagnsis of intracardiac hamartoma and Turner syndrome. AB - Turner syndrome is associated with a higher frequency of heart defects detected prenatally when compared to postnatal reports. The most common heart defects detected prenatally are hypoplastic left heart syndrome and coarctation of the aorta. We report a case involving a fetus at 16 gestational weeks with a septated cystic hygroma located on the neck and head, an interventricular septal mass, a hypoplastic left ventricle due to aortic stenosis, mitral stenosis, and a hypoplastic aortic arch with a karyotype of mos 45, X, [47 cells]/47, XXX [3 cells]. The autopsy findings confirmed our prenatal diagnosis with a final diagnosis of Turner syndrome and congenital cardiac vascular malformation. PMID- 20704480 TI - Neonatal fulminant type 2 infantile hepatic hemangioendothelioma involving skin, viscera and soft tissue. AB - We present the fulminant case of a neonate whose symptoms, lesions, imaging, and laboratory tests perfectly simulated a neonatal neuroblastoma and the definitive diagnosis was finally given by necropsy as follows: Infantile hepatic hemangioendothelioma type 2 with extrahepatic extension affecting skin, lung, intestine, suprarenal, and soft tissue. PMID- 20704481 TI - Melanotic neuroectodermal tumor of infancy in oral cavity at unusual age. AB - The melanotic neuroectodermal tumor of infancy is an extremely rare, fast-growing but benign lesion, commonly occurring in the maxilla of children within the first year of life. Only about 380 cases of this particular tumor have been documented in the medical literature and very few of them have been reported to have occurred in late childhood. We describe here a relatively uncommon presentation of melanotic neuroectodermal tumor of infancy of maxilla arising from palatal gingiva of a 10 year-old female, its course and management by surgical excision with safe margins. PMID- 20704482 TI - Goldston syndrome in a fetus: case report and literature review. AB - We present a case of the Goldston syndrome which is the association of polycystic kidneys with Dandy-Walker malformation. The diagnosis was made by ultrasound in twenty second week of gestation. Obstetric ultrasound and fetal MRI studies showed hydrocephalus, agenesis of the cerebellar hemispheres, vermian hypoplasia, cystic dilatation of the 4(th) ventricle, enlargement of the posterior fossa, abdominal distension, and oligohydramnios.. The kidneys were symmetrically enlarged and multicystic. To our knowledge this is the third reported case of Goldston syndrome which was diagnosed during intrauterine life. PMID- 20704483 TI - Pathogenic mechanisms of congenital heart disease. AB - Congenital heart disease (CHD) is the most common type of birth defect. Despite the many advances in the understanding of cardiac development and the identification of many genes related to cardiac development, the fundamental etiology for the majority of cases of congenital heart disease remains unknown. This review summarizes normal cardiac development, and outlines the recent discoveries of the genetic causes of congenital heart disease and provides possible strategies for exploring genetic causes. PMID- 20704484 TI - A subtype of a Pseudomonas aeruginosa cystic fibrosis epidemic strain exhibits enhanced virulence in a murine model of acute respiratory infection. AB - BACKGROUND: The Liverpool epidemic strain (LES) of Pseudomonas aeruginosa is a particularly successful cystic fibrosis (CF) pathogen associated with transmissibility, increased patient morbidity, and, unusually, infection of the non-CF parents of a patient with CF. METHODS: Using assays for virulence associated exoproducts, biofilm formation, Caenorhabditis elegans killing, and a murine model of acute respiratory infection, we compared the pathogenic behavior of representatives of 4 subtypes of the LES, including LES431, an isolate associated with the infection of a parent without CF. RESULTS: The quorum-sensing defective lasR mutant LES400 produced less exoproduct and had less C. elegans killing activity than the other LES subtypes, which were represented by LES431, LESB58, and LESB65. LES431 was deficient in biofilm formation, compared with the other LES sub-types. The LES subtypes displayed a range of virulence in the mouse model, with LES431 being by far the most virulent. The genome-sequenced isolate LESB58, effective at establishing infections in a rat model of chronic infection, was the least virulent subtype in the murine acute infection model. CONCLUSIONS: LES isolates display widely variable pathogenic characteristics. LES431, associated with transmission to the non-CF parent of a CF patient, represents a "hypervirulent" subtype more adapted to acute infections than chronic infections. PMID- 20704486 TI - School opening dates predict pandemic influenza A(H1N1) outbreaks in the United States. AB - The opening of schools in the late summer of 2009 may have triggered the fall wave of pandemic influenza A(H1N1) in the United States. We found that an elevated percentage of outpatient visits for influenza-like illness occurred an average of 14 days after schools opened in the fall of 2009. The timing of these events was highly correlated (Spearman correlation coefficient, 0.62; P<.001). This result provides evidence that transmission in schools catalyzes community wide transmission. School opening dates can be useful for future pandemic planning, and influenza mitigation strategies should be targeted at school populations before the influenza season. PMID- 20704485 TI - Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term nonprogression to AIDS. AB - BACKGROUND: The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. METHODS: To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (<100 copies/mL). RESULTS: The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P=2.5 x 10(-7); odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of P(combined)=9.7 x 10(-10). This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms. CONCLUSIONS: The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation. PMID- 20704487 TI - Asymptomatic pancreatic adenocarcinoma presenting as an orbital metastatic tumor. AB - Although rare, orbital metastatic tumors may be the initial presentation of an asymptomatic primary carcinoma. We report a rare case, with clinicopathological correlation, of metastatic pancreatic adenocarcinoma, presenting first in the orbit with symptoms of diplopia, blurring of vision and supraorbital ache. Computed tomography and magnetic resonance imaging of the orbit showed a left solid intraconal tumor with peripheral rim enhancement. The tumor demonstrated hypointensity on both T1- and T2-weighted sequences. Excisional biopsy was performed and histopathology confirmed a metastatic adenocarcinoma. Subsequent gastrointestinal imaging and tumor markers revealed an asymptomatic pancreatic adenocarcinoma, with multiple liver metastases. Our patient developed hepatobiliary sepsis and passed away 44 days after diagnosis. This case highlights the role of early biopsy of atypical orbital tumors in the localization of an asymptomatic primary carcinoma. PMID- 20704488 TI - Periorbital necrotizing fasciitis caused by community-associated methicillin resistant Staphylococcus aureus periorbital necrotizing fasciitis. AB - PURPOSE: To report a case of a patient with periorbital necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Case report. A previously healthy 33-year-old man was presented with pain and rapidly progressive swelling of the right upper eyelid following a minor trauma. Computed tomography scanning revealed soft tissue swelling and fracture of the anterior wall of the right frontal sinus. Oral amoxicillin + klavulanat 1 g, twice daily was started. Over the next 24 hours periorbital necrotizing fasciitis was developed. A wound swab was taken and sent for microscopic evaluation, culture, and antibiotic sensitivity. The patient was started on intravenous crystallized penicillin, third-generation cephalosporin, and metronidazol treatment. An urgent extensive necrotic tissue debridement and frontal sinus curettage were performed. RESULTS: Wound culture yielded MRSA which showed sensitivity to the given antibiotics. The patient responded to the treatment which was continued for 14 days. CONCLUSIONS: Monomicrobial MRSA should be considered in the etiology of periorbital necrotizing fasciitis. Early diagnosis and prompt surgical and medical therapy are essential in the management of periorbital necrotizing fasciitis. PMID- 20704489 TI - Nasolacrimal duct obstruction: clinicopathologic analysis of 205 cases. AB - PURPOSE: To investigate the histopathological results of lacrimal sac biopsies in patients with primary acquired nasolacrimal duct obstruction. METHODS: In this prospective non-comparative study, 205 consecutive patients, who were diagnosed as primary acquired nasolacrimal duct obstruction, were included. Patients with history of trauma and/ or surgery in the periorbital area, punctum or canalicular obstruction were excluded from the study. Patients were evaluated for age, gender, history, and presenting symptoms. Lacrimal drainage system abnormalities were assessed. Lacrimal system irrigation, dacryocystography, and in selected cases dacryoscintigraphy was performed. All patients underwent external dacryocystorhinostomy. Biopsy specimens were obtained from the posterior inferior flap and examined by the same pathologist. RESULTS: Forty-seven male and 158 females with age ranging from 6 to 81 years (mean 47.5 +/- 16.2 years) were included in the study. Only one patient had the diagnosis of chronic leukemia, others had no preexisting history of systemic disease. Pathologic examination revealed chronic inflammation (n= 178), fibrosis without inflammation (n= 19), normal mucosa (n= 4), and lymphoid hyperplasia (n= 1). Three patients had abnormal pathology: Lymphoproliferative disease in the patient with chronic leukemia, granulomatous inflammation, and basosquamous cell carcinoma. CONCLUSION: In primary nasolacrimal duct obstruction, pathological examination of the lacrimal sac revealed chronic inflammatory changes in most patients. Even though rare, malignant or systemic disease in patients with neither specific history nor clinical or radiological finding might be observed in these cases. Thus, we recommend taking biopsy if any suspicion of abnormality of the lacrimal sac exists. PMID- 20704490 TI - Niche dimensions in fishes: an integrative view. AB - Current shifts in ecosystem composition and function emphasize the need for an understanding of the links between environmental factors and organism fitness and tolerance. The examples discussed here illustrate how recent progress in the field of comparative physiology may provide a better mechanistic understanding of the ecological concepts of the fundamental and realized niches and thus provide insights into the impacts of anthropogenic disturbance. Here we argue that, as a link between physiological and ecological indicators of organismal performance, the mechanisms shaping aerobic scope and passive tolerance set the dimensions of an animal's niche, here defined as its capacity to survive, grow, behave, and interact with other species. We demonstrate how comparative studies of cod or killifish populations in a latitudinal cline have unraveled mitochondrial mechanisms involved in establishing a species' niche, performance, and energy budget. Riverine fish exemplify how the performance windows of various developmental stages follow the dynamic regimes of both seasonal temperatures and river hydrodynamics, as synergistic challenges. Finally, studies of species in extreme environments, such as the tilapia of Lake Magadi, illustrate how on evolutionary timescales functional and morphological shifts can occur, associated with new specializations. We conclude that research on the processes and time course of adaptations suitable to overcome current niche limits is urgently needed to assess the resilience of species and ecosystems to human impact, including the challenges of global climate change. PMID- 20704491 TI - Occurrence and characterization of Shiga toxin-producing Escherichia coli in raw meat, raw milk, and street vended juices in Bangladesh. AB - The major objective of this study was to investigate the prevalence of Shiga toxin (Stx)-producing Escherichia coli (STEC) in different types of food samples and to compare their genetic relatedness with STEC strains previously isolated from animal sources in Bangladesh. We investigated a total of 213 food samples, including 90 raw meat samples collected from retail butcher shops, 20 raw milk samples from domestic cattle, and 103 fresh juice samples from street vendors in Dhaka city. We found that more than 68% (n = 62) of the raw meat samples were positive for the stx gene(s); 34% (n = 21) of buffalo meats and 66% (n = 41) of beef. Approximately 10% (n = 2) of the raw milk and 8% (n = 8) of the fresh juice samples were positive for stx. We isolated STEC O157 from seven meat samples (7.8%), of which two were from buffalo meats and five from beef; and no other STEC serotypes could be isolated. We could not isolate STEC from any of the stx positive raw milk and juice samples. The STEC O157 isolates from raw meats were positive for the stx(2), eae, katP, etpD, and enterohemorrhagic E. coli hly virulence genes, and they belonged to three different phage types: 8 (14.3%), 31 (42.8%), and 32 (42.8%). Pulsed-field gel electrophoresis (PFGE) typing revealed six distinct patterns among seven isolates of STEC O157, suggesting a heterogeneous clonal diversity. Of the six PFGE patterns, one was identical and the other two were >=90% related to PFGE patterns of STEC O157 strains previously isolated from animal feces, indicating that raw meats are readily contaminated with fecal materials. This study represents the first survey of STEC in the food chain in Bangladesh. PMID- 20704492 TI - The present and future control of pertussis. PMID- 20704493 TI - Decennial administration of a reduced antigen content diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults. AB - BACKGROUND: Booster vaccination against tetanus and diphtheria at 10-year intervals is commonly recommended. Reduced antigen content diphtheria and tetanus toxoids and acellular pertussis (dTpa) vaccines developed for booster vaccination of preschool children, adolescents, and adults are licensed for once-in-a lifetime use in most countries. Objective. To evaluate decennial administration of a dTpa vaccine. Methods. Young adults vaccinated with dTpa or diphtheria and tetanus toxoids followed by acellular pertussis (DT+ap) 1 month later in a clinical trial 10 years previously received 1 dTpa dose. Blood samples were taken before and 1 month after vaccination. Antibody concentrations against vaccine antigens were measured by enzyme-linked immunosorbent assay. Solicited and unsolicited symptoms and serious adverse events were recorded. RESULTS: Eighty two individuals were enrolled in the study. In the 75 individuals who had received the dTpa vaccine 10 years previously, prevaccination seroprotection or seropositivity rates were 98.8% (diphtheria), 97.5% (tetanus), 64.6% (pertussis toxoid), 100% (filamentous hemagglutinin), and 96.3% (pertactin). One month after the second booster, all study participants were seroprotected or seropositive against all vaccine antigens. Antibody concentrations increased by a similar magnitude as 10 years previously. During the 4-day follow-up, 9.9% of participants recorded grade 3 pain; 17.3% and 18.5% recorded redness and swelling of 50 mm or larger, respectively; and 8.6% recorded fever (temperature, 37.5 degrees C). No serious adverse events were considered causally related to the vaccine. CONCLUSIONS: A second dTpa booster was highly immunogenic and well tolerated in this population of young adults. This study supports the use of this vaccine as a decennial booster. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00610168 . PMID- 20704494 TI - Absence of primary integrase resistance mutations in HIV type 1-infected patients in Venezuela. AB - The preexistence of mutations to integrase inhibitors in HIV-1-infected Venezuelan patients was evaluated. The integrase region of the HIV-1 genome was amplified by nested-PCR and sequenced in 57 isolates from both naive (n = 24) and treated patients who received protease and/or reverse transcriptase inhibitors (PI and RTI, n = 33), but were never exposed to integrase inhibitors. Only one primary integrase resistance mutation, not conferring drug resistance by itself, was found among these patients, although several minor viral mutations, equally distributed among naive and PI- and RTI-treated patients, were also found. In the limited number of samples, no relation was found among the presence of resistance mutations to PI or RTI and the presence of minor mutations to integrase. The absence of resistance to integrase inhibitors may be related to the recent introduction of these drugs in our country. The availability of in-house assays allows for a more comprehensive surveillance of drug resistance to integrase inhibitors in Venezuela. PMID- 20704495 TI - Transmitted HIV drug resistance among HIV-infected voluntary counseling and testing centers (VCTC) clients in Mumbai, India. AB - A survey for transmitted HIV drug resistance (HIVDR) was conducted according to WHO guidelines among clients newly diagnosed with HIV-1 infection at two voluntary counseling and testing centers (VCTC) in Mumbai. HIVDR testing was performed using the ViroSeq RT-PCR method (Abbott). Out of 50 successfully amplified and sequenced specimens, analysis of the first 34 consecutively collected specimens revealed no nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, or protease inhibitor mutations from the 2007 WHO list of mutations for surveillance of transmitted HIVDR, indicating that the prevalence of transmitted HIVDR to all three drug classes was <5% among recently infected VCTC clients in Mumbai. The phylogenetic analysis revealed that all samples belonged to HIV-1 subtype C. Continued ART program monitoring and further evaluation of transmitted HIV drug resistance in coming years are essential in Mumbai as well as in other regions of the country in which ART is being scaled up rapidly. PMID- 20704496 TI - Salmonella isolates with decreased susceptibility to extended-spectrum cephalosporins in the United States. AB - OBJECTIVE: We describe the antimicrobial susceptibility to extended-spectrum cephalosporins in non-Typhi Salmonella (NTS) isolated from humans in the United States and explore resistance mechanisms for isolates displaying decreased susceptibility to ceftriaxone or ceftiofur. We further explore the concordance between the newly revised Clinical and Laboratory Standards Institute (CLSI) breakpoints for ceftriaxone and the presence of a beta-lactamase. METHODS: In 2005 and 2006, public health laboratories in all U.S. state health departments forwarded every 20th NTS isolate from humans to Centers for Disease Control and Prevention as part of the National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria. Minimum inhibitory concentrations (MICs) were determined by broth microdilution. Isolates displaying decreased susceptibility (MIC >= 2 mg/L) to ceftriaxone or ceftiofur were included in the study. The presence of beta-lactamase genes was investigated by polymerase chain reaction amplification and sequencing, targeting six different genes (bla(TEM), bla(OXA), bla(SHV), bla(CTX-M), bla(PSE), and bla(CMY)). Plasmid location of bla(CMY) was confirmed by transforming plasmids into Escherichia coli. RESULTS: Among the 4236 isolates of NTS submitted to NARMS in 2005 and 2006, 175 (4.1%) displayed decreased susceptibility to either ceftriaxone or ceftiofur. By polymerase chain reaction screening, one or more beta-lactamase genes could be detected in 139 (80.8%) isolates. The most prevalent resistance mechanism detected was the AmpC beta-lactamase gene bla(CMY.) Other beta-lactamase genes detected included 11 bla(TEM-1), 3 bla(PSE-1), 2 bla(OXA-1), and 1 bla(CTX-M-15). The ceftriaxone MIC values for the bla(CMY)-containing isolates ranged from 4 to 64 mg/L; all bla(CMY)-bearing isolates were classified as ceftriaxone resistant according to current CLSI guidelines. CONCLUSIONS: Among NTS isolates submitted to NARMS in 2005 and 2006, cephamycinase beta-lactamases are the predominant cause of decreased susceptibility to ceftriaxone. The fact that all bla(CMY)-containing isolates were classified as resistant to ceftriaxone (MIC >= 4 mg/L) supports the newly revised CLSI breakpoints for cephalosporins and Enterobacteriaceae. PMID- 20704497 TI - Syntonic phototherapy. PMID- 20704498 TI - Endovascular laser-tissue interactions redefined: shining light on novel windows of therapeutic opportunity beyond selective photothermolysis. PMID- 20704499 TI - Laser-induced ATP formation: mechanism and consequences. PMID- 20704500 TI - Photomedicine and LLLT Literature Watch. PMID- 20704502 TI - Dirty money: an investigation into the hygiene status of some of the world's currencies as obtained from food outlets. AB - A total of 1280 banknotes were obtained from food outlets in 10 different countries (Australia, Burkina Faso, China, Ireland, the Netherlands, New Zealand, Nigeria, Mexico, the United Kingdom, and the United States), and their bacterial content was enumerated. The presence of bacteria on banknotes was found to be influenced by the material of the notes, and there was a strong correlation between the number of bacteria per square centimeter and a series of indicators of economic prosperity of the various countries. The strongest correlation was found with the "index of economic freedom," indicating that the lower the index value, the higher the typical bacterial content on the banknotes in circulation. Other factors that appear to influence the number of bacteria on banknotes were the age of the banknotes and the material used to produce the notes (polymer based vs. cotton-based). The banknotes were also screened for the presence of a range of pathogens. It was found that pathogens could only be isolated after enrichment and their mere presence does not appear to be alarming. In light of our international findings, it is recommended that current guidelines as they apply in most countries with regard to the concurrent hygienic handling of foods and money should be universally adopted. This includes that, in some instances, the handling of food and money have to be physically separated by employing separate individuals to carry out one task each; whereas in other instances, it could be advantageous to handle food only with a gloved hand and money with the other hand. If neither of these precautions can be effectively implemented, it is highly recommended that food service personnel practice proper hand washing procedures after handling money and before handling food. PMID- 20704503 TI - Genetic characterization of extended-spectrum beta-lactamases in Escherichia coli isolates of pigs from a Portuguese intensive swine farm. AB - There is a great concern by the emergence and the wide dissemination of extended spectrum beta-lactamases (ESBLs) among animal Escherichia coli isolates. We intended to determinate the carriage level and type of ESBLs in E. coli obtained from fecal samples from pigs raised on an intensive pig farm in Portugal; further to characterize other associated resistance genes and their plasmid content, the phylogenetic groups, and the clonal relationship of ESBL-positive isolates. Sixty five fecal samples were seeded in Levine media supplemented with cefotaxime for E. coli recovery. Susceptibility to 16 antimicrobial agents was performed by disk diffusion agar. ESBL-phenotypic detection was carried out by double-disk test; and the presence of the genes encoding TEM, OXA, SHV, and CTX-M type beta lactamases was studied by polymerase chain reaction and sequencing. Other mechanisms of antimicrobial resistance and phylogenetic groups were also determined. Clonal relationship was performed by pulsed-field gel electrophoresis. ESBL-producing E. coli isolates were detected in 16 fecal samples, and one isolate per sample was studied. The CTX-M-1 type ESBL was detected in the 16 isolates. The gene encoding TEM-1 was identified to be associated with eight CTX-M-1-positive isolates. The tet(A) gene was found in 12 of 14 tetracycline-resistant isolates, and the aadA or strA-strB genes were found in the streptomycin-resistant isolates. Fourteen and two ESBL-containing isolates belonged to A and B1 phylogenetic groups, respectively. Clonal relationship of ESBL-containing isolates identified seven unrelated patterns. Swine represent an important reservoir of ESBL-containing E. coli isolates, especially of the CTX-M 1 type. PMID- 20704504 TI - Comparison of the effectiveness of acidified sodium chlorite and sodium hypochlorite in reducing Escherichia coli. AB - This study was designed to compare the effectiveness of acidified sodium chlorite (ASC) and sodium hypochlorite (NaClO) in reducing several Escherichia coli strains isolated from different retail meat and fresh produce. Forty nonpathogenic E. coli strains were isolated and used in this study. A type strain of E. coli (JCM 1649) and four O157:H7 serotypes of E. coli (CR-3, MN-28, MY-29, and DT-66) were used as reference. In vitro assay results revealed that the viable cell counts of each isolated E. coli strain and control strains exhibited a reduction of ~ 4.3 +/- 0.9 log and 7.8 +/- 1.7 log CFU/mL after a 3-minute exposure to 100 mg/L NaClO and 20 mg/L ASC (pH 4.6), respectively, at 25 degrees C, when compared with the viable bacterial counts obtained from phosphate buffered saline. The one exception was the flocs-forming strain, which showed a reduction of only 1.0 log CFU/mL with both disinfectants. However, reductions of only 1.7 +/- 0.3 log and 1.9 +/- 0.4 log CFU/g were observed in lettuce after 5 minutes of washing with NaClO and ASC, respectively. On the other hand, reductions of 1.6 +/- 0.2 log and 1.6 +/- 0.4 log CFU/g were observed in spinach after 5 minutes of washing with NaClO and ASC, respectively. No reduction in the population was observed after washing the inoculated, fresh-cut vegetables with distilled water only. No significant difference in the reduction of E. coli was observed among all the tested strains with both sanitizers in the in vivo assay. These data suggest that the tested sanitizers exhibit a similar reduction of the surface-attached E. coli on leafy vegetables irrespective of the strain source. PMID- 20704505 TI - Foodborne proportion of gastrointestinal illness: estimates from a Canadian expert elicitation survey. AB - The study used a structured expert elicitation survey to derive estimates of the foodborne attributable proportion for nine illnesses caused by enteric pathogens in Canada. It was based on a similar study conducted in the United States and focused on Campylobacter, Escherichia coli O157:H7, Listeria monocytogenes, nontyphoidal Salmonella enterica, Shigella spp., Vibrio spp., Yersinia enterocolitica, Cryptosporidium parvum, and Norwalk-like virus. For each pathogen, experts were asked to provide their best estimate and low and high limits for the proportion of foodborne illness relative to total cases. In addition, they provided background information with regard to food safety experience, including self-evaluated expertise for each pathogen on a 5-point scale. A snowball approach was used to identify 152 experts within Canada. The experts' background details were summarized using descriptive statistics. Factor analysis was used to determine whether the variability in best estimates was related to self-assessed level of expertise or other background information. Cluster analysis followed by beta function fitting was undertaken on best estimates from experts who self-evaluated their expertise 3 or higher. In parallel, Monte Carlo resampling was run using triangular distributions based on each expert's best estimate and its limits. Sixty-six experts encompassing various academic backgrounds, fields of expertise, and experiences relevant to food safety provided usable data. Considerable variation between experts in their estimated foodborne attributable proportions was observed over all diseases, without any relationship to the expert's background. Uncertainty about their estimate (measured by the low and high limits) varied between experts and between pathogens as well. Both cluster analysis and Monte Carlo resampling clearly indicated disagreement between experts for Campylobacter, E. coli O157, L. monocytogenes, Salmonella, Vibrio, and Y. enterocolitica. In the absence of more reliable estimates, the observed discrepancy between experts must be explored and understood before one can judge which opinion is the best. PMID- 20704506 TI - Specialty food safety concerns and multilingual resource needs: an online survey of public health inspectors. AB - The province of Ontario, Canada, has a highly diverse and multicultural population. Specialty foods (i.e., foods from different cultures) are becoming increasingly available at retail food outlets and foods service establishments across the province; as a result, public health inspectors (PHIs) are increasingly required to assess the safety of foods with which they may be unfamiliar. The aim of this study was to investigate the concerns, perceptions, and self-identified needs of PHIs in Ontario with regard to specialty foods and food safety information resources in languages other than English. A cross sectional online survey of 239 PHIs was conducted between April and June 2009. The study found that while some food safety information resources were available in languages other than English, fewer than 25% of respondents (56/239) were satisfied with the current availability of these resources. With regard to specialty foods, 60% of respondents (143/239) reported at least one specialty food with which they were not confident about their current food safety knowledge, and 64% of respondents (153/239) reported at least one specialty food with which they were dissatisfied with the current availability of food safety information. Therefore, the development of additional food safety information resources for specialty foods, and food safety resources in additional languages may provide enhanced support to PHIs involved in protecting and promoting a safe food supply. PMID- 20704507 TI - Detection of Coxiella burnetii in commercially available raw milk from the United States. AB - Unpasteurized (raw) milk can be purchased in 39 U.S. states, with direct consumer purchase for human consumption permitted in 29 of those 39 states. Raw milk (n=21; cow, 14; goat, 7) was purchased in 12 states, and Coxiella burnetii, the agent of Q fever, was detected in 9 of 21 (42.9%) samples tested by polymerase chain reaction. Viability of the pathogen was demonstrated by isolation of the agent in tissue culture. The demonstration of viable C. burnetii in commercially available raw milk poses a potential public health risk. PMID- 20704508 TI - Absorbed EVELISA: a diagnostic test with improved specificity for Johne's disease in cattle. AB - The use of enzyme-linked immunosorbent assays (ELISAs) is recommended for Johne's disease (JD) control in dairy herds. In 2006, we developed a novel ELISA test for JD, named EVELISA (ELISA using ethanol extract of Mycobacterium avium subsp. paratuberculosis), which showed higher sensitivity than commercial ELISA tests. To further investigate the performance of EVELISA, we obtained 38 serum samples from cattle in a JD-free herd with suspected cases of serological false-positive reactions. When these samples were tested using the EVELISA and a commercial ELISA test, more than 70% of the samples were falsely identified as JD positive. Antibodies in the serum samples reacted strongly with antigens of various environmental mycobacteria, suggesting the presence of cross-reactive antibodies in the samples. The possible cross reactions in the EVELISA were inhibited markedly by the use of Mycobacterium phlei antigens for antibody absorption. When these samples were tested, 8 samples were classified as positive for JD by the EVELISA with the antibody absorption, whereas 27 samples were classified as positive for JD by the commercial ELISA. For an estimation of tentative sensitivity and specificity, the ELISA tests were performed on 38 serum samples from JD-negative herds with no suspected cases of serological false-positive reaction and 68 samples from cattle diagnosed as positive for M. avium subsp. paratuberculosis infection by fecal culture test. Sensitivity and specificity of the EVELISA with preabsorption of serum with M. phlei ("ethanol vortex absorbed ELISA" or EVA-ELISA) were estimated to be 97.1% and 100%, respectively, whereas those of the commercial ELISA were 48.5% and 97.4%, respectively. Further, in 85 fecal culture-negative cattle in JD-positive herds, higher sensitivity of the EVA ELISA than the commercial ELISA was demonstrated by a Bayesian analysis. This study indicates that the EVA-ELISA may form a basis for a sensitive diagnostic test with a higher level of specificity than that of the current commercial ELISA test. PMID- 20704509 TI - Comparison of detection methods for Escherichia coli O157 in beef livers and carcasses. AB - Beef organ meat, such as liver, and beef are major food sources contaminated with Escherichia coli O157. This study investigated the detection method of E. coli O157 in beef liver and carcass. In an experiment with beef liver inoculated with E. coli O157, the direct plating method, plating after the immunomagnetic separation (IMS) method, and Shiga toxin (Stx)-producing E. coli detection and E. coli O157 detection loop-mediated isothermal amplification (LAMP) assays were compared for the detection of Stx-producing E. coli O157. Fifty percent and 45% of samples were positive by Stx-producing E. coli detection LAMP assay and E. coli O157 detection LAMP assay, respectively. Thirty-five percent and 10% of samples were positive by the IMS method and direct plating method, respectively. In an examination of beef swab samples, contamination frequencies with E. coli O157 were analyzed by LAMP assays and the IMS method. E. coli O157 was detected in 12 of 230 samples (5.2%). There was no sample positive for E. coli O157 isolation but negative for LAMP assays for Stx gene and O157 antigen gene. Four samples (1.7%) were positive by both LAMP assays but negative by the IMS method. The result that there was no sample positive for the O157 antigen gene, but not the Stx gene, indicated that the IMS method failed to detect E. coli O157. Twenty nine samples (12.6%) were positive for the Stx gene but not the O157 antigen gene. The results indicated that screening of Stx gene and O157 antigen gene by LAMP assays is effective in saving time and effort to isolate E. coli O157 by the IMS method because the LAMP assay is more sensitive. This suggested that samples positive for Stx gene and O157 antigen gene should be examined by the IMS method to isolate E. coli O157. PMID- 20704510 TI - Development of an anti-Salmonella phage cocktail with increased host range. AB - Salmonella shedding in many livestock species can increase significantly after transport and lairage. Preprocessing increases in shedding can amplify the amount of Salmonella that enters the processing facility and the likelihood of end product contamination. We previously produced an anti-Salmonella phage cocktail that reduced colonization in swine when the pigs were exposed to an environment heavily contaminated with Salmonella, similar to what might be seen in a transport trailer or processing facility holding pen. The aim of this study was to increase the efficacy of the phage treatment by (1) expanding the host-range of the cocktail and (2) developing a more cost-effective microencapsulation technique. We collected samples from wastewater treatment facilities and isolated 20 distinct phages belonging to either the Siphoviridae or Myoviridae families. From this library we identified 10 phages that together lysed a mixed culture of Salmonella enterica Typhimurium, Enteriditis, and Kentucky--three serovars commonly associated with meat and poultry products. The phages were microencapsulated using two sodium-alginate-based methods that only reduced the cocktail titer by 1.0-1.5 logs (premicroencapsulation: 10.4 log(10) PFU/mL; postmicroencapsulation method one: 9.2 log(10) PFU/mL; postmicroencapsulation method two: 8.9 log(10) PFU/mL). Microencapsulated phages remained stable at both 4 degrees C and 22 degrees C for up to 14 days with no appreciable drop in titer (mean titer: 8.9 log(10) PFU/mL). These data indicate that phage cocktails with wider host ranges are possible and a cost-effective microencapsulation process can protect the phages over an extended period, making simultaneous treatment of large numbers of animals with feed- or water-based delivery possible. PMID- 20704511 TI - Characterization and transferability of class 1 integrons in commensal bacteria isolated from farm and nonfarm environments. AB - This study assessed the distribution of class 1 integrons in commensal bacteria isolated from agricultural and nonfarm environments, and the transferability of class 1 integrons to pathogenic bacteria. A total of 26 class 1 integron-positive isolates were detected in fecal samples from cattle operations and a city park, water samples from a beef ranch and city lakes, and soil, feed (unused), manure, and compost samples from a dairy farm. Antimicrobial susceptibility testing of class 1 integron-positive Enterobacteriaceae isolates from city locations displayed multi-resistance to 12-13 out of the 22 antibiotics tested, whereas class 1 integron-positive Enterobacteriaceae isolates from cattle operations only displayed tetracycline resistance. Most class 1 integrons had one gene cassette belonging to the aadA family that confers resistance to streptomycin and spectinomycin. One isolate from a dog fecal sample collected from a city dog park transferred its class 1 integron to a strain of Escherichia coli O157:H7 at a frequency of 10(-7) transconjugants/donor by in vitro filter mating experiments under the stated laboratory conditions. Due to the numerous factors that may affect the transferability testing, further investigation using different methodologies may be helpful to reveal the transferability of the integrons from other isolates. The presence of class 1 integrons among diverse commensal bacteria from agricultural and nonfarm environments strengthens the possible role of environmental commensals in serving as reservoirs of antibiotic resistance genes. PMID- 20704512 TI - Characterization of tetracycline resistance in Salmonella enterica strains recovered from irrigation water in the Culiacan Valley, Mexico. AB - The increase of Salmonella enterica strains showing resistance against antibiotics has resulted in limiting the effective treatment of human infections. The present study characterized the resistance to tetracycline in S. enterica serovar Typhimurium strains, recovered from irrigation water in distinct regions in the Culiacan Valley, an important agricultural region in Mexico for horticultural crops that are exported to the United States. Analysis of the genomic diversity by pulse-field gel electrophoresis (PFGE) typing showed that the Salmonella Typhimurium strains were grouped into four distinct genotypic clusters, indicating genomic diversity among 12 strains examined. The polymerase chain reaction and DNA sequencing analysis demonstrated that the tet(A) gene was found on the genomic DNA and was located within a truncated version of transposon Tn1721. The comparative analysis of the tet(A) gene sequence in Salmonella Typhimurium strains identified high sequence similarity to the tet determinant of plasmid RP1, which is homologous to the tet gene in Tn1721. The findings show the presence of tet(A) among the tetracycline-resistant Salmonella Typhimurium strains isolated from irrigation water used for growing fresh fruits and vegetables. PMID- 20704513 TI - First description of bla(CTX-M-14)- and bla(CTX-M-15)-producing Escherichia coli isolates in Brazil. AB - We evaluated the antimicrobial resistance patterns and molecular characteristics of 11 extraintestinal Escherichia coli strains and 1 intestinal E. coli from human infections collected in Brazil. Two E. coli strains were nonsusceptible to extended spectrum cephalosporins (cefotaxime, ceftazidime, and cefepime); one isolated from diarrhea carried bla(CTX-M-14) and bla(TEM-1), whereas the other, isolated from tracheal secretion, carried bla(CTX-M-15) and bla(OXA-1). Five E. coli strains showed resistance to quinolones. Integrase associated with class 1 integron (intl1) was detected in 8 of the 12 E. coli strains belonging to various serotypes and this gene was carried by plasmids showing similar size. Pulsed field gel electrophoresis showed that E. coli strains were genetically diverse, and phylogenetic grouping showed that the E. coli strains belonged to groups A, B2, and D (33.3%), respectively. This is the first report of E. coli isolates carrying bla(CTX-M-14) and bla(CTX-M-15) in Brazil. The presence of mobile elements containing antimicrobial resistance genes is worrisome since it could promote the dissemination of resistance and lead to the acquisition of resistance to other antimicrobials agents such as the carbapenems. PMID- 20704514 TI - Postoperative complications in children undergoing gastrostomy tube placement. AB - BACKGROUND: Gastrostomy tube placement is associated with frequent postoperative complications. The aims of this study were to 1) determine the incidence of postoperative gastrostomy complications and 2) determine if patient demographics, comorbidities, or operative technique could predict these complications. METHODS: A retrospective review was conducted on children who underwent gastrostomy tube placement from June 2006 through August 2009. Patient demographics, comorbidities, operative technique, health care visits, and complications were collected. Data were analyzed by chi-squared analysis (P < 0.05 significant). RESULTS: One hundred and fifty-nine patients were evaluated, with the majority of patients <5 years of age (129/159). Ninety-four patients underwent open gastrostomy, 31 laparoscopic gastrostomy, and 34 laparoscopic-assisted gastrostomy. Granulation tissue was the most common postoperative complication, occurring in 58% of patients (93/159). The majority of patients with granulation tissue had full resolution by the fourth postoperative month. Tube dislodgement was the second most common complication, occurring 69 times in 44 of the patients (28%) and resulting in 59 emergency department (ED) visits. Overall, gastrostomy complications resulted in 100 ED and 462 clinic visits. Ninety-three percent (93/100) of ED visits resulted in discharge home from the ED. Gender, age, insurance status, and operative technique were not predictive of complications. CONCLUSIONS: Granulation tissue and tube dislodgement are the most common complications after gastrostomy placement in children. Gender, age, insurance status, and operative technique were not predictive of complications. Emergency department utilization is high in children with gastrostomy tubes. PMID- 20704515 TI - Omental infarction: preoperative diagnosis and laparoscopic management in children. AB - BACKGROUND: Omental infarction (OI) is an unusual, poorly characterized cause of abdominal pain in children and is often mistaken for appendicitis preoperatively. We present our experience with this disease process over a 5-year period to identify preoperative factors to aid in timely diagnosis and treatment. METHODS: We retrospectively reviewed the medical records of all children that had OI and underwent laparoscopic omentectomy from November 2004 to June 2009. RESULTS: Ten patients with the diagnosis of OI were identified. OI occurred in 9 boys and 1 girl, with a median age at presentation of 8.5 years (range, 7-11). Median body mass index at presentation was 23.7 (range, 17-29), with 1 child categorized as healthy weight for age, 1 child as overweight for age, and 5 children as obese for age, based on Centers for Disease Control and Prevention criteria. All patients complained of right-sided abdominal pain; 4 patients complained of predominantly right-upper quadrant (RUQ) pain, 3 patients of right-lower quadrant (RLQ) pain, and 3 of combined RUQ/RLQ pain. On examination, 6 patients had RUQ tenderness and 4 patients had RLQ tenderness. The median duration of symptoms prior to seeking medical attention was 3 days (range, 2-7). All patients underwent computed tomography and the preoperative diagnosis of OI was established in 9 of 10 cases. Operative time was 48 +/- 14 minutes. All patients underwent resection of the infarcted omentum; 2 patients underwent concurrent appendectomy. Median length of stay was 2 days (range, 2-4). CONCLUSIONS: OI occurs predominantly, but not exclusively, in obese preadolescent males. OI can be reliably distinguished from appendicitis on preoperative history, physical examination, laboratory analysis, and imaging. Laparoscopic omentectomy results in prompt resolution of symptoms and discharge. PMID- 20704516 TI - Acupuncture for refractory cases of sudden sensorineural hearing loss. AB - OBJECTIVES: The aim of this study was to investigate the effect of acupuncture on the treatment of refractory sensorineural hearing loss (SSHL), treatment of which remains a major clinical challenge. DESIGN: The study design was descriptive research to document the effect of acupuncture in a series of SSHL cases. SETTING: The study was conducted in the outpatient clinic of Kyung Hee University Hospital. SUBJECTS: The subjects analyzed were 17 patients with refractory SSHL of more than 3 weeks after a failed trial of conventional treatment including corticosteroids. INTERVENTIONS: Acupuncture sessions were performed twice a week using a modified Saam acupuncture formula and such acupoints as GV14, GV15, and others, in addition to usual patient care educations. MAIN OUTCOME MEASURES: Improvement was defined as increased hearing threshold from initial measurement by more than 20 dB in at least two contiguous frequencies of audiometric testing. An audiogram pattern was also analyzed. RESULTS: The average refractory period before acupuncture treatment was 213.9 days (range 22-1460). First follow-up measurement after 9.5 times of acupuncture treatment for 29.9 days showed improvement in 4 of 16 cases examined (25.0%) and second follow-up measurement after 18.7 times of acupuncture treatment for 70.4 days in another 4 of 12 cases examined (33.3%). A total improvement rate after day 70.4 post initial visit was 47.1% (8 of 17 cases). As to the audiogram pattern, an ascending or midhumping pattern was related to a good prognosis, while a descending pattern was not. CONCLUSIONS: These findings suggest that acupuncture might be effective in refractory sensorineural hearing loss with failure of conventional therapy. PMID- 20704517 TI - HIV cure: controversy, consensus, and a consortium. AB - Despite the significant clinical benefits accruing from antiretroviral treatment, so far there is no evidence that HIV can be cleared by drugs or the immune system, largely because the virus persists in reservoirs, contributing to the belief held by many, if not most, AIDS researchers that a cure for HIV infection is and may always be impossible. Certainly there are many scientific issues that need to be addressed before a cure for HIV infection is likely, and few on which there is universal consensus. Still, these issues are all amenable to research, and may benefit from a collective effort involving the productive collaboration of a number of research groups with different perspectives and skill sets. The view that a cure for HIV is impossible runs the risk of turning parsimony into paralysis. The search for a cure is one of the most challenging and potentially rewarding areas of AIDS research. PMID- 20704518 TI - Participation and quality of life in children and adolescents with congenital limb deficiencies: A narrative review. AB - Children and adolescents with congenital limb deficiencies are visibly and physically different from their peers. They present limitations in activities, depending on the severity of deficiency. Therefore they are at risk for lower participation in social and leisure activities. This might negatively influence the perception on their quality of life. The aim of this narrative review is to describe participation and quality of life in children with congenital limb deficiencies. Participation and quality of life are relatively new concepts. Psychosocial functioning, being closely related to the concept of quality of life, is described as well. A comprehensive review of the literature was conducted on participation, quality of life and psychosocial functioning in children and adolescents with congenital limb deficiencies. The review involved a systematic search using multiple data sources. Fifteen cross-sectional studies were included in this review. The literature to date provides limited knowledge on how children and adolescents with congenital limb deficiencies participate and how they perceive their quality of life. The psychosocial functioning, although described as at risk, appears to be comparable to healthy peers. In conclusion, more research is needed on how children and adolescents with congenital limb deficiencies participate and how they perceive their quality of life. A broader perspective will not only help parents in making the right choices for their children, but can also have implications for health care providers, teachers and agencies funding rehabilitation services. PMID- 20704519 TI - Non-traumatic subarachnoid hemorrhage is associated with subnormal blood creatinine levels. AB - OBJECTIVE: The aim of this study was to examine the hypothesis that patients with non-traumatic subarachnoid hemorrhage (SAH) have statistically significant subnormal creatinine levels and that the creatinine levels are associated with severity of disease. MATERIALS AND METHODS: This was a retrospective observational study over 2 years (2005-2006) in which the SAH patients were divided into patients with severe symptoms and patients with mild/moderate symptoms, and were compared to patients with; traumatic brain injury, trauma without brain injury and patients undergoing elective knee surgery. Blood creatinine levels (day 1-3, and day 7) were recorded. RESULTS: Compared to a normal distribution, SAH patients had statistically significant subnormal creatinine levels day one through seven. SAH patients with severe symptoms had statistically significant subnormal creatinine levels already on day one, in contrast to patients with mild/moderate symptoms. Women with severe symptoms had statistically significant subnormal creatinine levels throughout the study period in contrast to men with severe symptoms who had a normal distribution of creatinine at admission. Women with mild/moderate symptoms had a normal distribution of creatinine only at admission in contrast to men who had a normal distribution of creatinine throughout the study period. Male patients with traumatic brain injury, all trauma patients without brain injury and all patients undergoing elective knee surgery had a normal distribution of creatinine on all studied days. CONCLUSIONS: SAH is associated with subnormal serum creatinine levels. This finding is more pronounced in patients with severe symptoms and in women. PMID- 20704520 TI - Comparison of the effect of topical and systemic melatonin administration on delayed wound healing in rats that underwent pinealectomy. AB - OBJECTIVES: Melatonin is a hormone which has many systemic effects in addition to its strong antioxidant properties. The aim of the present study was to investigate the difference between sytemic and topical administration of melatonin by forming a chronic wound model in rats whose release of basal melatonin was supressed by pinealectomy. MATERIAL AND METHODS: Experimental animals used in the study were divided into four equal groups: (i) a group of normal animals with wound formation (control), (ii) a group of animals who underwent pinelaectomy and wound formation (PINx), (iii) a group that underwent PINx + systemic melatonin administration, and (iv) a group that underwent PINx + topical melatonin administration. Fifteen days after pinealectomy, a bipediculed flap was formed on the back of the rats under anesthesia and then six excisional skin wounds were produced in all groups. Following the treatment that lasted 7 days, on day 8 the wound surface areas were measured and wound tissues were removed under anesthesia. In these tissues the levels of malondialdehit (MDA) and hydroxyproline (OH-proline) and the activities of superoxide dismutase(SOD) and glutathion peroxidase (GSH-Px) were measured. RESULTS: In the PINx group, OH prolin levels decreased significantly compared to the control group and wound surface areas increased. MDA levels increased compared to the control group, and SOD and GSH-Px decreased accordingly. Conversely, in two melatonin groups in which melatonin was administered systemically or topically MDA decreased while SOD ve GSH-Px enzymes increased. CONCLUSION: In conclusion, in the present study it was shown that wound healing was prolonged in experimental animals deprived of melatonin through pinealectomy. Melatonin exerts positive effects on wound healing, whether it is administered topically or systemically. PMID- 20704521 TI - Proteomic profiling of peritoneal rinse fluid sediment separates patients with ovarian cancer from women admitted for cesarean section. A pilot study. AB - OBJECTIVE: There is a great need for additional approaches to discover putative biomarkers for ovarian cancer that accounts for 5% of all cancer deaths among women and is the leading cause of deaths among gynecologic malignancies in the United States. METHODS: Peritoneal rinse fluid sediment from seven patients having ovarian cancer and four women admitted for cesarean section was analysed by proteomic techniques using two-dimensional gel electrophoresis and tandem mass spectrometry. RESULTS: Sixteen protein spots were found to be significantly and highly up-regulated in samples from cancer patients as compared with the cesarean section group. Nine of the protein spots were identified as C-terminal fragments of fibrinogen-beta (spot Nos. 5404 and 5408), haptoglobin-alpha2 (spot Nos. 4101 and 6103), haptoglobin-beta (spot Nos. 2502, 2504, 3502 and 4401) and transthyretin (spot No. 4002). Generally, several isoelectric variants were present of each protein. The protein concentration in the sediment of spot No. 506 and spot No. 5404 (identified as fibrinogen-beta) was significantly (p < 0.05) and negatively correlated with survival rate of the ovarian cancer patients while for three of the spots a borderline significant (p < 0.07) negative correlation was found. CONCLUSIONS: It is suggested that further development of this method may give a basis for identifying suitable diagnostic and prognostic biomarkers for ovarian cancer. PMID- 20704522 TI - Smoking cessation advice in consultations with health problems not related to smoking? Relevance criteria in Danish general practice consultations. AB - OBJECTIVE: To identify frames of interaction that allow smoking cessation advice in general practice consultations. DESIGN: Qualitative study based on individual in-depth interviews with GPs and their patients. Each of the GPs' consultations were observed during a three-day period. Interviews primarily addressed the consultations that had been observed. The concept of "frames" described by Goffman was deployed as an analytic tool. SETTING: Danish general practice. SUBJECTS: Six GPs and 11 of their patients. RESULTS: Both GPs and patients evaluated potential issues to be included during consultations by relevance criteria. Relevance criteria served the purpose of limiting the number of issues in individual consultations. Issues could be included if they connected to something already communicated in a consultation. Smoking cessation advice was subject to these relevance criteria and was primarily discussed if it posed a particular risk to a particular patient. Smoking cessation advice also occurred in conversations addressing the patient's well-being. If occurring without any other readable frame, smoking cessation advice was apt to be perceived by patients as part of a public campaign. CONCLUSIONS: Relevance criteria in the shape of communication of particular risks to particular patients and small-talk about well-being reflect the concept of "frames" by Goffman. Criteria of relevance limit the number of issues in individual consultations. Relevance criteria may explain why smoking cessation advice has not yet been implemented in many more consultations. PMID- 20704523 TI - Influence of CRP testing and clinical findings on antibiotic prescribing in adults presenting with acute cough in primary care. AB - OBJECTIVE: Respiratory tract infections are the most common indication for antibiotic prescribing in primary care. The value of clinical findings in lower respiratory tract infection (LRTI) is known to be overrated. This study aimed to determine the independent influence of a point of care test (POCT) for C-reactive protein (CRP) on the prescription of antibiotics in patients with acute cough or symptoms suggestive of LRTI, and how symptoms and chest findings influence the decision to prescribe when the test is and is not used. DESIGN: Prospective observational study of presentation and management of acute cough/LRTI in adults. SETTING: Primary care research networks in Norway, Sweden, and Wales. SUBJECTS: Adult patients contacting their GP with symptoms of acute cough/LRTI. MAIN OUTCOME MEASURES: Predictors of antibiotic prescribing were evaluated in those tested and those not tested with a POCT for CRP using logistic regression and receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 803 patients were recruited in the three networks. Among the 372 patients tested with a POCT for CRP, the CRP value was the strongest independent predictor of antibiotic prescribing, with an odds ratio (OR) of CRP >= 50 mg/L of 98.1. Crackles on auscultation and a patient preference for antibiotics perceived by the GP were the strongest predictors of antibiotic prescribing when the CRP test was not used. CONCLUSIONS: The CRP result is a major influence in the decision whether or not to prescribe antibiotics for acute cough. Clinicians attach less weight to discoloured sputum and abnormal lung sounds when a CRP value is available. CRP testing could prevent undue reliance on clinical features that poorly predict benefit from antibiotic treatment. PMID- 20704524 TI - Transcatheter embolization for visceral pseudoaneurysm with situs inversus totalis. AB - We present a case of visceral pseudoaneurysm with situs inversus totalis, which was treated by transcatheter embolization. A 58-year-old man with chronic pancreatitis and situs inversus totalis was admitted to our hospital for epigastric pain. On celiac arteriography, a pseudoaneurysm was detected at the anterior superior pancreaticoduodenal artery (ASPD). We catheterized the ASPD with a microcatheter introduced coaxially through a 5Fr catheter, and we isolated the pseudoaneurysm with microcoils. The patient's recovery was uneventful and he was discharged 17 days after the procedure. We describe this case because of the rarity of this anomaly, and it is important in that recognition may help avoid mishaps at interventions, particularly in the emergency setting. PMID- 20704525 TI - A pilot study on a new anchoring mechanism for surgical applications based on mucoadhesives. AB - In order to minimize the invasiveness of laparoscopic surgery, different techniques are emerging from research to clinical practice. Whether the incision is performed on the outside - as in Single Port Laparoscopy (SPL) - or on the inside - as in Natural Orifice Transluminal Endoscopic Surgery (NOTES) - of the patient's body, inserting and operating all the instruments from a single access site seems to be the next challenge in surgery. Magnetic guidance has been recently proposed for controlling surgical tools deployed from a single access. However, the exponential drop of magnetic field with distance makes this solution suitable only for the upper side of the abdominal cavity in nonobese patients. In the present paper we introduce a polymeric anchoring mechanism to lock surgical assistive tools inside the gastric cavity, based on the use of mucoadhesive films. Mucoadhesive properties of four formulations, with different chemical components and concentration, are evaluated by using both in vitro and ex vivo test benches on porcine stomach samples. Hydration of mucoadhesive films by contact with the aqueous mucous layer is analyzed by means of in vitro swelling tests, whereas optimal preloading conditions and adhesion performances, in terms of detachment force, supported weight and size are investigated ex vivo. Mucoadhesion is observed with all the four formulations. For a contact area of 113 mm(2), the maximum normal and shear detachment forces withstood by the adhesive film are 2,6 N and 1 N respectively. These values grow up to 12,14 N and 4,5 N when the contact area increases to 706 mm(2). Lifetime of the bonding on the inner side of the stomach wall was around two hours. Mucoadhesive anchoring represents a fully biocompatible and safe approach to deploy multiple assistive surgical tools on mucosal tissues by minimizing the number of access ports. This technique has been quantitatively assessed ex vivo for anchoring on the inner wall of the gastric cavity or in gastroscopic surgery. By properly varying the chemical formulation, this approach can be extended to other cavities of the human body. PMID- 20704526 TI - Surgeons, surgery, surgical skills. PMID- 20704527 TI - Association between thyroid hormones, lipids and oxidative stress biomarkers in overt hypothyroidism. AB - BACKGROUND: The aim of this study was to investigate the effect of hypothyroidism on lipid peroxidation and the antioxidant profile, as well as to evaluate the interaction between thyroid hormones and biomarkers of oxidative stress in patients with overt hypothyroidism. We also evaluated the influence of cholesterol concentrations on biomarkers of oxidative stress in these same patients. METHODS: Total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and vitamin E were measured in 20 subjects with overt hypothyroidism (OH) and 20 controls. RESULTS: TC, LDL cholesterol, triglycerides, TBARS, SOD, CAT, and vitamin E were significantly higher in the OH group. Significant correlation was observed for TSH and SOD, CAT, vitamin E and TBARS. Correlation was observed for triiodothyronine (T3) and SOD, CAT, vitamin E and TBARS. Significant correlation was also observed for free thyroxine and vitamin E and TBARS. However, correlation between T3 and CAT remained significant after controlling for TC concentrations. CONCLUSIONS: Overt hypothyroidism is associated with an increase in oxidative stress, and hypercholesterolemia has a stronger influence on development of oxidative stress in hypothyroid conditions compared with thyroid hormones. PMID- 20704528 TI - Biochemical markers of particle induced osteolysis in C57BL/6 mice. AB - BACKGROUND: Micro-structural changes associated with ultra high molecular weight polyethylene particle (UHMWPE) induced osteolysis, the most frequent cause of aseptic loosening, have been intensively investigated in the mammalian calvarian model by histomorphometry and micro-computed tomography. However, little is known regarding the serological changes that occur during this process. METHODS: Serological parameters for bone metabolism [calcium, phosphate, osteocalcin (OCN), deoxypyridinoline (DPD)/creatinine, alkaline phosphatase, osteoprotegerin and receptor activator of nuclear factor-kappaB] were analyzed in this animal model for particle induced osteolysis. Ten C57BL/6 mice were divided at random into sham operated and UHM-WPE implanted groups. Blood and urine samples were collected prior to and at 14 days after surgery. RESULTS: Implantation of UHMWPE lead to a significant decrease in bone volume (p=0.027). Both groups (sham/UHMWPE) showed a significant increase in calcium (p=0.004/p=0.027) and phosphate (p=0.001/p=0.001), without correlation to particle implantation. Significantly higher concentrations of DPD/creatinine (p=0.034) and OCN (p=0.022) were found after implantation of UHM-WPE. In addition, parameters could not be correlated to particle induced osteolysis. CONCLUSIONS: DPD can be regarded as a valuable parameter for detecting UHMWPE induced osteolysis in the calvarian model. Further studies of serum parameters should focus on the clinical relevance in aseptic prosthetic loosening. PMID- 20704529 TI - Automated assay for non-transferrin-bound iron in serum samples. AB - BACKGROUND: Non-transferrin-bound iron (NTBI) is a powerful promoter of free radical damage and highly toxic to biological systems, resulting in oxidative damage to proteins, lipids and DNA. METHODS: This assay is based on the binding of serum NTBI by the chelator nitrilotriacetic acid (NTA) and measurement of the ultrafiltrated Fe-NTA complex with the ferrozine reagent kit by a biochemical analyzer. To determine NTBI at extremely low concentrations, the program parameters for serum iron measurement were modified. RESULTS: Linearity was up to 15 MUmol/L with analytical recovery of 93%-103%. The limit of detection was 0.076 MUmol/L. The within-run coefficient of variation was 2.37%, 1.23%, and 0.812% at concentrations of 0.338, 1.717, and 5.916 MUmol/L, respectively. NTBI concentrations measured after exercise in samples obtained from 14 rowers, divided into two groups, were substantially higher in all samples. The median NTBI concentrations (range) before and after exercise were 0.197 (-0.11 to 0.58), and 3.353 (2.39-8.97) MUmol/L, respectively, in older rowers and 0.197 (-0.18 to 1.17), and 1.360 (0.47-2.49) MUmol/L, respectively, in younger rowers. CONCLUSIONS: With the described modification for serum iron determination, NTBI can be measured with high sensitivity and specificity. The data presented are illustrative examples of the applicability of this assay. PMID- 20704530 TI - Mean platelet volume and platelet distribution width are useful in the differential diagnosis of aplastic anemia and idiopathic thrombocytopenic purpura. PMID- 20704531 TI - Kinetics of highly sensitive troponin I and T after eccentric exercise. PMID- 20704532 TI - Real-time polymerase chain reaction quantification of free DNA in serum of patients with polyps and colorectal cancers. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most frequent causes of cancer related deaths worldwide. Recently, the use of cell-free DNA as diagnostic tools to identify cancer has been investigated. The aim of this work was to assess whether circulating DNA could be considered a useful marker for detection of early stage CRC and polyps. METHODS: A total of 118 patients with CRC were included in the study along with 49 patients with colorectal polyps and 26 control subjects. Cell-free DNA was quantified using a real-time TaqMan polymerase chain reaction assay. Non-parametric tests (Mann-Whitney test and Spearman correlation) were utilized for statistical analysis. RESULTS: Serum DNA concentrations were significantly higher in CRC patients and patients with polyps (median value 105.0 ng/mL and 40.0 ng/mL) compared with controls (median value 14.0 ng/mL; p<0.05). Although carcinoembryonic antigen was above the cut-off in only 13/66 (19.7%) patients with early stage CRC, serum free DNA showed values above the threshold identified using receiver operator characteristic (ROC) curve analysis in 53/66 (80.3%) patients. CONCLUSIONS: Our data confirm that serum DNA concentrations are significantly increased in CRC patients with early stage disease and in patients with polyps. This marker might be useful for identifying high-risk individuals. PMID- 20704533 TI - Increased gamma-glutamyltransferase and decreased total bilirubin are associated with metabolic syndrome in Korean postmenopausal women. AB - BACKGROUND: The objective of this study was to determine if there is an association between serum hepatic markers and the metabolic syndrome in postmenopausal women. METHODS: This study involved 1229 postmenopausal women aged 44-85 years, who visited the Center for Health Promotion for a health check-up. We excluded subjects from the analysis if they had a daily alcohol consumption of more than 1.5 drinks (alcohol consumption >=20 g/day) or had chronic viral hepatitis. We also excluded subjects who had abnormal hepatic function, as defined by serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 IU/L, serum gamma-glutamyltransferase (GGT) >100 IU/L, or serum total bilirubin concentrations >2 mg/dL. RESULTS: Serum ALT and GGT concentrations increased in proportion to the number of elements of the metabolic syndrome (p<0.01). However, total bilirubin concentrations decreased (p=0.01). After adjusting for age, body mass index, and the presence of fatty liver in the patients with metabolic syndrome, the odds ratios (95% confidence interval) were 1.38 (0.89-2.15) for log (ALT), 1.69 (1.30-2.20) for log (GGT), and 0.53 (0.33 0.86) for log (total bilirubin). CONCLUSIONS: We found that an increase in GGT and a decrease in total bilirubin was associated with metabolic syndrome in postmenopausal women. Hepatic enzymes could be proposed as simple clinical metabolic markers that identify the metabolic syndrome. PMID- 20704534 TI - Effect of homeostasis model assessment computational method on the definition and associations of insulin resistance. AB - BACKGROUND: Homeostasis model assessment (HOMA) is a surrogate index widely used to study the role of insulin sensitivity or resistance in associated disease states. However, reported values for the definition of insulin resistance (the top 25% of the distribution in non-diabetic subjects) vary widely. This study evaluates the effect of HOMA computational methods [original HOMA model formula (HOMA1) and online calculator computer model (HOMA2)] on the associations and cut off limits for insulin resistance. METHODS: Anthropometric measurements, fasting adiponectin, leptin, leptin receptor, insulin, glucose, high-sensitivity C reactive protein and a lipid profile were measured in type 2 diabetic patients (n=226) and their normoglycemic first degree relatives (n=319). HOMA1 and HOMA2 were used to estimate insulin resistance, beta-cell function and insulin sensitivity. Subjects were classified as metabolic syndrome positive or negative (International Diabetes Federation criteria). Bland-Altmann analysis was used to evaluate agreement between the computational methods. Univariate and multivariate logistic regression analyses were used to relate the HOMA computational methods with metabolic variables and metabolic syndrome status. RESULTS: The two computational methods had different cut-offs for the definition of insulin resistance: HOMA1 formula >=2.5; HOMA2 calculator >=1.4. Correlations of the two HOMA computational methods with anthropometric and metabolic variables showed some degree of variation. The odds ratios of the associations with the metabolic syndrome for the HOMA1 formula and HOMA2 calculator computational methods were 2.04 and 1.43, respectively. Receiver operating characteristic analysis for diagnosis of the metabolic syndrome showed that areas under the receiver operating characteristic curves for the HOMA1 formula and HOMA2 calculator computational methods were 0.741 and 0.680, respectively. CONCLUSIONS: The HOMA computational method is a significant determinant of the associations and classification of insulin resistance. PMID- 20704535 TI - The relationship between three heat shock protein 70 gene polymorphisms and susceptibility to lung cancer. AB - BACKGROUND: Heat shock protein 70 (Hsp70) has been shown to act as a chaperone and be associated with a variety of tumors. We investigated HSP70-1 G+190C, HSP70 2 A+1267G, and HSP70-hom T+2437C polymorphisms to assess whether genetic variation in HSP70 plays a role in the occurrence and development of lung cancer. METHODS: A case-control study was conducted using 159 patients with lung cancer and 202 control subjects. Genomic DNA was typed for HSP70 polymorphisms using polymerase chain reactions with restriction fragment length polymorphism (PCR RFLP). Unconditional logistic regression was used to estimate the relative risks of lung cancer. RESULTS: There were significant differences in genotype and allele distributions between patients and controls for the HSP70-1 G+190C polymorphisms with and without adjustment for age, gender, smoking history, drinking history and family history of cancer (p<0.05). No significant differences were found in the polymorphisms of HSP70-2 A+1267G and HSP70-hom T+2437C. The haplotype analysis showed that the G/A/C and C/G/T haplotypes were associated with a significantly increased risk of lung cancer compared to the G/G/T haplotype. After adjustments for other risk factors, such as age, gender, drinking history and family history of cancer, the interactions between the HSP70 1 and HSP70-hom genotypes and smoking were confirmed [I(AB), 2.56 and 5.12, respectively]. CONCLUSIONS: HSP70-1 G+190C may be a functional polymorphism and affect susceptibility to lung cancer, and homozygous C/C genotype may enhance the risk of lung cancer. In addition, smoking along with HSP70-1 G+190C and HSP70-hom T+2437C, may increase the risk of lung cancer. PMID- 20704536 TI - An on-line solid phase extraction procedure for the routine quantification of urinary methylmalonic acid by liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: The goal of this study was to develop and to validate an improved isotope-dilution-liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of methylmalonic acid (MMA) in urine. METHODS: A previously described sample preparation protocol requires two solvent extraction steps, including evaporation. The first extraction is to extract the analyte from the sample, and second occurs following derivatization of the extract. In the method described here, the second evaporation step was substituted by on-line solid phase extraction employing column-switching and a permanent co-polymer based extraction cartridge. A standard validation protocol was applied to investigate the performance of the method. RESULTS: The method was found to be linear in the clinically relevant range of concentrations (6-100 MUmol/L). Total coefficients of variation were below 10% and inaccuracy was <10% for quality control samples at three concentrations. CONCLUSIONS: By omitting one evaporation step, the semi-automated method described in this article enables for more convenient work-flow in the quantification of urinary MMA compared to the previous protocol. This is of relevance for MMA measurement in the routine clinical laboratory setting. Validation demonstrated acceptable analytical performance. PMID- 20704537 TI - ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of beta-thalassaemia. AB - BACKGROUND: The detection and diagnosis of beta-thalassaemia for populations with molecular heterogeneity, or diverse ethnic groups, has increased the need for the development of an array high-throughput diagnostic tool that can deliver large scale genetic detection. We report on the update and validation of the ThalassoChip, a beta-thalassaemia genetic diagnostic tool which is based on arrayed primer extension (APEX) technology. METHODS: ThalassoChip slides with new and redesigned probes were prepared for testing the microarray. Six hundred and sixty DNA samples collected from eight Mediterranean countries were used for standardisation, optimisation and validation of the ThalassoChip. The beta-globin gene region was amplified by PCR, the products were hybridised to the probes after fragmentation and the APEX reaction followed. RESULTS: The ThalassoChip was updated with new probes and now has the ability to detect 57 beta-globin gene mutations and three single nucleotide polymorphisms (SNPs) in a single test. The ThalassoChip as well as the PCR and APEX reactions were standardised and optimised using 500 DNA samples that were previously genotyped using conventional diagnostic techniques. Some probes were redesigned in order to improve the specificity and sensitivity of the test. Validation of the ThalassoChip performed using 160 samples analysed in blinded fashion showed no error. CONCLUSIONS: The updated version of the ThalassoChip is versatile, robust, cost-effective and easily adaptable, but most notably can provide comprehensive genetic diagnosis for beta-thalassaemia and other haemoglobinopathies. PMID- 20704538 TI - Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry. AB - BACKGROUND: Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. METHOD: A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time <3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. RESULTS: During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in patient samples, but not in spiked calibrator samples. Comparison with LC-MS/MS disclosed a significant bias with higher concentrations measured by LC-MS/MS, while UPLC-MS/MS showed excellent agreement with the commercially available HPLC method. In the LC-MS/MS procedure, comparably wide and left side shifted peaks were noticed. This could be ascribed to in-source fragmentation of conjugate metabolites during electrospray ionisation. Precursor and product ion scans confirmed the assumption that the additional compounds are posaconazole glucuronides. Reducing the cone voltage led to disappearance of the glucuronide peaks. Slight modification of the LC-MS/MS method enabled separation of the main interference, leading to significantly reduced deviation. CONCLUSIONS: These results highlight the necessity to reliably eliminate interference from labile drug metabolites for correct TDM results, either by sufficient separation or selective MS conditions. The presented UPLC-MS/MS method provides a reliable and fast assay for TDM of posaconazole. PMID- 20704539 TI - Proatrial natriuretic peptide is a better predictor of 28-day mortality in septic shock patients than proendothelin-1. AB - BACKGROUND: Septic shock is a major health care problem that affects a heterogeneous population of patients. To improve sepsis management, a key point is to decrease this heterogeneity by stratifying patients according to specific criteria, such as appropriate biomarkers. As the early phase of septic shock is characterized by cardiovascular dysfunction, precursors of vasoactive hormones represent interesting candidates. The objective of the present study was to concomitantly assess the predictive value of C-terminal proendothelin-1 and midregional proatrial natriuretic peptide (CT-proET-1 and MR-proANP, respectively vasoconstrictor and vasodilator) on 28-day mortality following septic shock. METHODS: In this observational study which included 99 patients, concentrations of MR-proANP and CT-proET-1 were measured using an immunoluminometric assay three times within the first week after the onset of septic shock. RESULTS: While MR proANP concentrations were significantly increased in non-survivors in comparison with survivors, no differences were noted for CT-proET-1. Increased MR-proANP concentrations were significantly associated with mortality after both univariate and multivariate analyses, adjusted for usual clinical confounders [SAPS II (simplified acute physiology score II), SOFA (sepsis-related organ failure assessment) scores and number of co-morbidities]. CONCLUSIONS: In septic shock patients, MR-proANP appears to be a good predictor of 28-day mortality, whereas CT-proET-1 does not present any predictive value during monitoring. PMID- 20704540 TI - A simple, fast and inexpensive automated technique for measurement of plasma nitrite. PMID- 20704541 TI - C-reactive protein and venous thromboembolism: causal or casual association? AB - The plasma concentration of C-reactive protein (CRP), the first acute-phase protein to be identified, increases dramatically following tissue injury or inflammation. Although the physiological role of CRP is still not fully known, it has been suggested that concentrations might increase as part of the acute-phase response for facilitating non-specific immune functions, defense against bacterial pathogens, clearance of apoptotic and necrotic cells to prevent immunization against autoantigens and acceleration of the repair process. In agreement with the evidence that inflammation plays a pivotal role in the pathogenesis of atherosclerosis, CRP concentrations have been associated with cardiovascular disease, and measurement of CRP has therefore been proposed as a valuable aid to predict and stratify the risk of myocardial infarction and stroke. Recently, some clinical and biological evidence in support of the hypothesis that CRP might be also involved in the onset of venous thrombosis have emerged. Native and monomeric CRP exert several prothrombotic activities, including activation of blood coagulation, impairment of the endogenous fibrinolytic capacity, and stimulation or enhancement of platelet adhesiveness and responsiveness. Epidemiological investigations have also shown that CRP concentrations are associated with increased risk of venous thromboembolism and, even more interestingly, that statins might be effective in reducing the risk of this pathology. Although there is increasing emphasis that CRP might not only be a marker but also an active player in the development of venous thrombosis, further evidence is needed to establish which event comes first--thrombosis or inflammation. PMID- 20704542 TI - Evaluation of D-dimer in the diagnosis of suspected aortic dissection. AB - BACKGROUND: The goal of this study was to evaluate plasma D-dimer as a diagnostic marker for exclusion of suspected aortic dissection (AD). METHODS: Two-hundred and sixty suspected AD patients were enrolled, including acute AD, n=107; chronic AD, n=17; acute myocardial infarction (AMI), n=70; pulmonary embolism (PE), n=18; non-ST elevation myocardial infarction (NSTEMI), n=28; and unstable angina (UA), n=20. All patients had D-dimer testing performed (Roche Diagnostics GmbH) immediately following admission. RESULTS: The D-dimer concentrations in both the acute AD group [median: 3.47; 95% confidence interval (CI): 2.43-4.50 MUg/mL] and chronic AD group (median: 1.09; 95% CI: 0.36-3.81 MUg/mL) were significantly higher than those in patients in the AMI, NSTEMI and UA groups (p=0.000), but not when compared to the PE group. One (0.8%) patient was identified in the acute AD group who presented with a low D-dimer value (0.04 MUg/mL), indicating the existence of intramural hematoma as demonstrated by CT. CONCLUSIONS: D-dimer may be used as a potential marker for suspected AD, with high sensitivity of up to 99.2% (1/124). Regardless of the cut-off threshold selected, the sensitivity of D dimer was unable to reach 100%. Further examinations, including imaging technology, were necessary to diagnose the suspected AD patients who had negative D-dimer result. PMID- 20704543 TI - Interaction of carbon monoxide with transition metals: evolutionary insights into drug target discovery. AB - The perception that carbon monoxide (CO) is poisonous and life-threatening for mammalian organisms stems from its intrinsic propensity to bind iron in hemoglobin, a reaction that ultimately leads to impaired oxygen delivery to tissues. From evolutionary and chemical perspectives, however, CO is one of the most essential molecules in the formation of biological components and its interaction with transition metals is at the origin of primordial cell signaling. Not surprisingly, mammals have gradually evolved systems to finely control the synthesis and the sensing of this gaseous molecule. Cells are indeed continuously exposed to small quantities of CO produced endogenously during the degradation of heme by constitutive and inducible heme oxygenase enzymes. We have gradually learnt that heme oxygenase-derived carbon monoxide (CO) serves as a ubiquitous signaling mediator which could be exploited for therapeutic purposes. The development of transition metal carbonyls as prototypic carbon monoxide-releasing molecules (CO-RMs) represents a novel stratagem for a safer delivery of CO-based pharmaceuticals in the treatment of various pathological disorders. This review will look back at evolution to analyze and argue that a dynamic interaction of CO with specific intracellular metal centers is the common denominator for the diversified beneficial effects mediated by this gaseous molecule. PMID- 20704544 TI - Potential application of biliverdin reductase and its fragments to modulate insulin/IGF-1/MAPK/PI3-K signaling pathways in therapeutic settings. AB - The range and diversity of functions of biliverdin reductase (BVR) is unmatched by any enzyme characterized to date. BVR is the sole catalyst for the conversion of biliverdin-IXalpha the activity product of the stress-inducible HO-1 and the constitutive HO-2, to bilirubin-IXalpha. Bilirubin is both cytoprotective and cytotoxic, quenches reactive oxygen species (ROS) and inhibits inflammatory and mitogen-induced ROS-mediated responses, and its elevated levels in the newborn adversely effects neuronal cells. Thus, BVR occupies a center stage in cellular defense mechanisms. As a dual specificity (serine/threonine/tyrosine) kinase the human (h) BVR influences transduction of extracellular stimuli to kinases downstream of the insulin/IGF-1(insulin-like growth factor-1)/MAPK/PI3-K signaling pathways. As a bZip-type transcription factor it binds to AP-1 (activator protein-1) and CRE (cAMP response element) sites and stimulates stress inducible gene expression; as a scaffold protein, it is a platform for interaction of kinases; while acting as an intracellular shuttle, it transports regulatory factors to their target sites. hBVR promoter has consensus sequences with several regulatory elements. The gene is subject to negative and positive regulation, respectively, by TNF-alpha (tumor necrosis factor-alpha) and oxidative stress/hypoxia. Small human BVR-based peptides effectively duplicate polypeptide's activating influence on kinases, or mimic inhibitors of cell signaling. This, points to a realistic prospect of their use in clinical settings. The present review will briefly update cytoprotective activity and cytotoxicity of bile pigments and will focus on findings that link hBVR to cell signaling. PMID- 20704545 TI - The heme-heme oxygenase system in wound healing; implications for scar formation. AB - Wound healing is an intricate process requiring the concerted action of keratinocytes, fibroblasts, endothelial cells, and macrophages. Here, we review the literature on normal wound healing and the pathological forms of wound healing, such as hypertrophic or excessive scar formation, with special emphasis on the heme-heme oxygenase (HO) system and the versatile effector molecules that are formed after HO-mediated heme degradation. Excessive scar formation following wounding is thought to relate to prolonged oxidative and inflammatory stress in the skin. Evidence is accumulating that the heme-HO system forms a novel and important target in the control of wound healing. Heme-protein derived heme can act as a potent oxidative and inflammatory stress inducer, and excess levels of heme may thus contribute to delayed resolution of oxidative and inflammatory insults in the skin. This emphasizes the need for a timely reduction of the levels of heme. Heme-binding proteins, heme transporters, and the heme degrading protein, HO, form therefore a necessary defense. Deficiencies in these defense proteins or a disturbed redox status, as in diabetic patients, may render individuals more prone to heme-induced deleterious effects. A better understanding of the heme-heme oxygenase system as target during wound healing may result in novel strategies to reduce scar formation. PMID- 20704546 TI - Heme oxygenase-1 in tumor biology and therapy. AB - Heme oxygenase-1 (HO-1) degrades heme to carbon monoxide (CO), biliverdin, and ferrous iron. As HO-1 expression is highly increased by stressful conditions, the major role of the enzyme is the protection against oxidative injury. Additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis. Beneficial activities of HO-1 have been recognized in many pathological states e.g. atherosclerosis, diabetes, ischemia/reperfusion injury or organ transplantation. Interestingly HO-1 expression is very often boosted in tumor tissues and could be further elevated in response to radio-, chemo-, or photodynamic therapy. A growing body of evidence suggests that HO-1 may play a role in tumor induction and can potently improve the growth and spread of tumors. This review discusses the implications of HO-1 properties for tumor proliferation and cell death, differentiation, angiogenesis and metastasis, and tumor-related inflammation. Finally, it suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies. PMID- 20704547 TI - Heme oxygenase-1 and iron in liver inflammation: a complex alliance. AB - Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 has potent antioxidant and also anti inflammatory functions, the underlying mechanisms of which are not well understood. Together with antioxidant carbon monoxide and biliverdin, HO produces reactive iron, which unambiguously connect this enzyme with the iron metabolism and its potential toxicity. A link between HO-1 and iron homeostasis has been demonstrated in HO-1 knockout mice, which develop major hemosiderosis in solid organs such as liver and kidney. Moreover, genetic HO-1 deficiency causes a chronic inflammatory condition in these animals. As the liver plays a crucial role for the body's iron homeostasis (eg. via secretion of the iron regulatory hormone hepcidin) and also for systemic inflammation, hepatic HO-1 may be important for the regulation of both systems. In particular, cell-specific functions of HO-1 in liver tissue macrophages (Kupffer cells) might be of major significance, because these cells play a key role in iron recycling during erythrophagocytosis and also in the control of hepatic and systemic inflammatory responses. This review discusses the current knowledge on interactions of HO-1 with iron metabolism in the context of systemic as well as hepatic inflammatory disorders. Recent advances in the understanding of the functional role of HO-1 in inflammatory liver diseases, namely viral hepatitis, alcoholic liver disease and non-alcoholic steatohepatitis are summarized. Finally, it is highlighted how targeted modulation of HO-1 may provide specific protection in these inflammatory disorders. PMID- 20704548 TI - Heme oxygenase-1 in lung disease. AB - The lungs are a major target for various inflammatory, oxidative, carcinogenic or infectious stressors, which result in a range of lung diseases. Induction of heme oxygenase-1 (HO-1) during acute and chronic lung processes is a crucial defense mechanism. HO-1 catalyzes the degradation of free cellular heme to iron, carbon monoxide (CO) and biliverdin which is eventually converted to bilirubin by biliverdin reductase. In addition to the degradation of free heme, a pro-oxidant, HO-1 exerts anti-oxidant, anti-inflammatory and anti-apoptotic properties via its reaction products. This review summarizes the regulation and protective roles of HO-1 and its reaction products in several in vitro and in vivo lung disease models, including acute lung injury, ischemia-reperfusion (IR)-induced lung injury, cigarette smoke and chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), lung cancer and asthma. The therapeutic applications of HO-1 in the lung as well as potential complications of excessive HO-1 induction are also covered. In summary, the HO-1 system is a powerful endogenous defense strategy with immense therapeutic potential against a range of lung diseases if optimal levels and tissue targeting can be achieved. PMID- 20704549 TI - Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases. AB - Heme oxygenase-1 (HO-1), an enzyme degrading heme to carbon monoxide, free iron, and biliverdin, participates in the cell defence against oxidative stress and it has been speculated that it might be a new therapeutic target for neuroprotection. In this review, we discuss recent findings on the regulation of the HO-1 gene, Hmox1, in the brain with particular focus on the transcription factors Nrf2 and HIF-1. Functional polymorphisms in Hmox1 have been associated with high risk for Alzheimer's and Parkinson's disease. Hence, we review the current knowledge on the role of HO-1 and its enzymatic products on these two pathologies as well as ischemic brain injury. HO-1 modulates the inflammatory response in several scenarios, and therefore we discuss its role in modulation of the innate immune cell of the brain, microglia. From the therapeutic side, the blood brain barrier represents an obstacle to directly modulate heme oxygenase activity, but drugs activating the transcription actor Nrf2, which have a very diverse molecular structure, may be good candidates to induce HO-1 in concert with other antioxidant and detoxification enzymes. A more complete understanding on the mechanisms regulating HO-1 expression in brain cells and how these mechanisms are involved in neuropathological changes will be essential to develop these new therapeutic approaches. PMID- 20704551 TI - Regulatory role of anesthetics on heme oxygenase-1. AB - As an enzyme, heme oxygenase (HO) can provide substantial cellular protection. By eliminating free heme and generating iron, biliverdin, as well as carbon monoxide, HO exerts anti-inflammatory, anti-proliferative, antioxidative, and vasodilatory effects. The inducible form of HO, heme oxygenase-1 (HO-1) can be upregulated by harmful stimuli in most human cell types. In such a way, cells utilize HO-1 as a mechanism of self-protection. Many studies have shown that upregulation of HO-1 prior to injurious stimuli conferred protection to cells and organs against subsequent injury. Therefore, manipulation of HO-1 gene expression might represent a valuable strategy for the prevention of organ dysfunction. In recent studies, intravenous and inhaled anesthetics (e.g., ketamine, propofol, opioids, isoflurane, sevoflurane, desflurane, etc.) not only upregulate HO-1 to varying extents, but account for organ protection via the HO pathway. The major advantage of anesthetics over other HO-inducing agents is related to their clinically proven safety. Another important issue is that patients receiving anesthetics in anesthesia or intensive care medicine are often suffering from pathological conditions involving pro-oxidative or pro-inflammatory states. Therefore, it would be interesting to know whether the impact of anesthetics on HO-1 regulation might influence outcome of these patients. This overview summarizes the effects of different anesthetics on HO-1 regulation and function in disease models. PMID- 20704552 TI - Heme oxygenase-1/carbon monoxide: novel therapeutic strategies in critical care medicine. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain major causes of morbidity and mortality in critical care medicine despite advances in therapeutic modalities. ALI can be associated with sepsis, trauma, pharmaceutical or xenobiotic exposures, high oxygen therapy (hyperoxia) and mechanical ventilation. The stress protein heme oxygenase-1 (HO-1) provides an inducible defense mechanism that can protect lung cells and tissues against injury. HO-1 degrades heme to biliverdin-IXalpha, carbon monoxide (CO), and iron. Each of these reaction products has been implicated in the cytoprotection associated with HO-1 expression. At low concentrations, CO can confer cyto protective and tissue-protective effects involving the inhibition of inflammatory, proliferative, and apoptotic signaling. Lung protection by HO-1 has been demonstrated in vitro and in vivo in several models of experimental ALI and sepsis. Recent studies have also explored the protective effects of pharmacological or inhalation CO therapy in animal models of ALI/sepsis. CO has shown therapeutic potential in models of oxidative and acid-induced lung injury, ventilator-induced lung injury, endotoxin challenge, and cecal-ligation and puncture induced-sepsis. Despite therapeutic benefit in animal model studies, the efficacy of CO in humans with these conditions remains unclear, and awaits further controlled clinical studies. This review will summarize recent findings on the therapeutic applications of HO-1 and its end-product CO in the lung, with an emphasis on lung injury models relevant to critical care medicine. PMID- 20704553 TI - Therapeutic applications of the heme oxygenase system. PMID- 20704550 TI - Targeting heme oxygenase-1 in vascular disease. AB - Heme oxygenase-1 (HO-1) metabolizes heme to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is subsequently metabolized to bilirubin by biliverdin reductase. HO-1 has recently emerged as a promising therapeutic target in the treatment of vascular disease. Pharmacological induction or gene transfer of HO-1 ameliorates vascular dysfunction in animal models of atherosclerosis, post-angioplasty restenosis, vein graft stenosis, thrombosis, myocardial infarction, and hypertension, while inhibition of HO-1 activity or gene deletion exacerbates these disorders. The vasoprotection afforded by HO-1 is largely attributable to its end products: CO and the bile pigments, biliverdin and bilirubin. These end products exert potent anti-inflammatory, antioxidant, anti apoptotic, and anti-thrombotic actions. In addition, CO and bile pigments act to preserve vascular homeostasis at sites of arterial injury by influencing the proliferation, migration, and adhesion of vascular smooth muscle cells, endothelial cells, endothelial progenitor cells, or leukocytes. Several strategies are currently being developed to target HO-1 in vascular disease. Pharmacological induction of HO-1 by heme derivatives, dietary antioxidants, or currently available drugs, is a promising near-term approach, while HO-1 gene delivery is a long-term therapeutic goal. Direct administration of CO via inhalation or through the use of CO-releasing molecules and/or CO-sensitizing agents provides an attractive alternative approach in targeting HO-1. Furthermore, delivery of bile pigments, either alone or in combination with CO, presents another avenue for protecting against vascular disease. Since HO-1 and its products are potentially toxic, a major challenge will be to devise clinically effective therapeutic modalities that target HO-1 without causing any adverse effects. PMID- 20704554 TI - Disentangling the role of the tau gene locus in sporadic tauopathies. AB - Fibrillar aggregates of abnormally hyperphosphorylated tau protein are the major component of the pathological entities, including intraneuronal neurofibrillary tangles that define the broad class of late-onset neurodegenerative disorders called the tauopathies. Mutations in the tau gene (MAPT) causing familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) confirm that tau protein dysfunction could be a primary cause of neuronal loss. However, in the sporadic tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) where MAPT mutation is absent, common variation in MAPT that defines the H1 and H2 haplotype clades strongly influences disease risk. Surprisingly, this influence on risk extends to sporadic Parkinson's disease (PD), traditionally not defined as a tauopathy. This review will focus on recent work aimed at elucidating the mechanistic basis of this haplotype-specific effect on disease risk, implicating elevated levels of MAPT expression, particularly via increased transcription and/or alterations in splicing. This conforms to an emerging picture of a shared mechanism that underlies the fundamental process(es) leading to neuronal death. Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg alpha synuclein in PD, beta-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively. PMID- 20704555 TI - Involvement of rat hippocampal astrocytes in beta-amyloid-induced angiogenesis and neuroinflammation. AB - Although Alzheimer's disease (AD) is considered a neurodengenerative disorders, in the last few years a large amount of evidence has suggested that it is also a vascular pathology characterized by increased capillary density and expression of angiogenic factors. In AD the endothelium degenerates, promoting local neuroinflammation and activation of brain endothelium, perivascular microglia, pericytes, astrocytes. Excess tumor necrosis factor (TNF) in the cerebrospinal fluid (CSF), at a concentration of 25 times higher than in the control group, has been demonstrated in AD. Recent studies provide evidence that treatment with TNF alpha antagonists may result in a rapid cognitive improvement in AD patients. In the present work we investigated the role of astrocytes in AD angiogenesis and neuroinflammation by means of conditioned media of untreated and Abeta-treated rat hippocampal astrocytes (RHAs) on rat microvascular endothelial cells (RCECs). The results demonstrated that RHA media increase RCEC proliferation and capillary like structure formation. Moreover RHAs secrete IL-1beta and, only after the Abeta1-42 treatment, TNF-alpha promotes RCEC release of IL-1beta, IL-6 and TNF alpha. The removal of IL-1beta, TNF-alpha and/or VEGF, a strong angiogenic inducer highly over-expressed in AD brains, by means of specific antibody-coated beads in RHA media affects RCEC release of IL-1beta, IL-6 and TNF-alpha. We hypothesised that astrocytes contribute to AD angiogenesis and neuroinflammation by the direct release of pro-inflammatory cytokines. The effect of an anti inflammatory agent, such as etanercept, decreased RCEC in vitro cytokine release. This could be compared to the effect found in our experiments with antibody anti TNF-alpha-coated beads. PMID- 20704556 TI - Converging perturbed microvasculature and microglial clusters characterize Alzheimer disease brain. AB - We have investigated physical properties of microvasculature and vessel association with microglial clusters in cortical tissue from Alzheimer disease individuals, classified as severe (ADsev) or mild (ADmild), and nondemented controls (ND). Immunostaining with laminin or von Willerbrand factor demonstrated numbers of microvessels and microvascular density were significantly higher in ADsev cases compared with levels in ADmild or ND cases suggesting proangiogenic activity in ADsev brain. Evidence for extravascular laminin immunoreactivity was found in ADsev tissue and was largely absent in ADmild and ND cases suggesting vascular remodeling in ADsev brain included abnormalities in blood vessels. Microgliosis was progressively increased from ND to ADmild to ADsev with the latter demonstrating areas of clustered microglia (groupings of three or more cells) rarely observed in ADmild or ND cases. Microglial clusters in ADsev brain were in close proximity with extravascular laminin and also plasma protein, fibrinogen, implicating vascular perturbation as a component of inflammatory reactivity. ADsev brain also exhibited elevated levels of the pro inflammatory/angiogenic factors tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) in association, relative to non association, with microglial clusters. The presence of extravascular laminin and fibrinogen and the vascular modifying factors, TNF-alpha and VEGF in localization with clusters of activated microglia, is consistent with microglial-induced vascular remodeling in ADsev brain. Microglial-vascular reciprocal interactions could serve a critical role in the amplification and perpetuation of inflammatory reactivity in AD brain. PMID- 20704557 TI - Inaccuracy in clinical trials: effects and methods to control inaccuracy. AB - The increasing rate of failed trails found in mood and anxiety disorders is now being seen in Alzheimer's studies. Factors related to the administration of clinician rating scales, such as poor inter-rater reliability, poor interview quality and rater bias may be a contributing factor. Studies have found inter rater reliability to be problematic in Alzheimer's studies, even with less subjective outcome measures. Lack of standardization of administration and scoring procedures has been identified as a major contributing factor. Remediation through better training procedures has been found to be successful, although ongoing calibration is needed to prevent rater drift. Expectancy bias and baseline score inflation is more difficult to remediate. Inflation of baseline scores increases placebo response, since lower severity has been found to be associated with higher placebo response. The use of centralized raters that are independent from study sites may help ameliorate these issues. Increased methodological research examining new approaches to these problems is warranted. The increased costs associated with this research should offset the time and expense of continuing with 'business as usual'. PMID- 20704558 TI - Blood-brain-barrier models for the investigation of transporter- and receptor mediated amyloid-beta clearance in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly with more than 26 million people worldwide living with the disease. Besides the main neuropathological hallmarks of AD, provoked by the accumulation of amyloid-beta (Abeta) and tau hyperphosphorylation, other cells and cellular systems such as microglia and the neurovascular unit establishing the blood-brain-barrier (BBB) have been implicated to play a role in AD etiopathology. Insulating the brain from the blood stream, the BBB facilitates supply and disposal of nutrients and metabolites by the expression of transporters and transcytotic receptors at the polarized endothelial cell (EC) surface. Recently, several proteins involved in Abeta transport across the BBB have been identified in in vitro and in vivo studies. In this review, we summarize recent evidence of receptor- and transporter-mediated Abeta clearance across the BBB. Furthermore, we discuss the models used to identify and characterize Abeta transport across the BBB in regard to barrier properties and suitability of the models for the experimental investigation of transport mechanisms involved in Abeta clearance across an EC barrier. PMID- 20704559 TI - Patterns of cognitive decline and rates of conversion to dementia in patients with degenerative and vascular forms of MCI. AB - According to recent criteria, Mild Cognitive Impairment (MCI) represents a clinical condition with multiple cognitive presentations (amnesic and non amnesic) that can be supported by different types of brain lesions (mainly vascular and atrophic). In order to asses if the cognitive presentation and the rate of progression differ according to the type of brain pathology, two populations of MCI patients, characterized by hippocampal atrophy (n: 39) and vascular subcortical pathology (n: 36) respectively, on the basis of MRI findings, were investigated. Patients underwent an extensive neuropsychological test battery twice (at baseline and at two years follow-up), which is made up of the MMSE and various tests of episodic memory, short-term memory, visual-spatial abilities, executive functions, language, attention, praxis and psychomotor speed. Atrophic and vascular MCI patients showed a remarkably different pattern of impairment at the baseline. The former were significantly more impaired in episodic memory tasks. The latter were more impaired in an action naming task. At the follow up examination, the rate of progression to dementia was higher in atrophic (14/39) than in vascular (5/36) MCI patients. The comparison between neuropsychological scores obtained at the baseline and at the follow-up showed that atrophic MCI patients underwent a severe decline in several cognitive domains, whereas vascular MCI patients showed a significant decline only in those tasks requiring executive abilities. Our results confirm that a selective and severe defect of episodic memory is associated with hippocampal atrophy and that MCI patients with atrophic lesions are more likely to convert to Alzheimer's type dementia while MCI patients with vascular lesions are characterized by a slight decline in executive function over time and by a tendency to develop probable vascular forms of dementia. PMID- 20704560 TI - Why so few drugs for Alzheimer's disease? Are methods failing drugs? AB - Recent studies of Alzheimer's disease (AD) and other neuropsychiatric drug developments raise questions whether failures of some drugs occur due to flaws in methods. In three case studies of recent AD drug development failures with phenserine, metrifonate, and tarenflurbil we identified methodological lapses able to account for the failures. Errors in complex systems such as drug developments are both almost inescapable due to human mistakes and most frequently hidden at the time of occurrence and thereafter. We propose preemptive error management as a preventive strategy to exclude or control error intrusions into neuropsychiatric drug developments. We illustrate the functions we anticipate for a preemptive error management preventive strategy with a checklist and identify the limitations of this aspect of the proposal with three drug examples. This strategy applies core scientific practices to insure the quality of data within the current context of AD drug development practices. PMID- 20704561 TI - The ATP-binding cassette transporter-2 (ABCA2) increases endogenous amyloid precursor protein expression and Abeta fragment generation. AB - The ATP binding cassette transporter-2 (ABCA2) has been genetically linked to Alzheimer's disease but the molecular mechanisms are unknown. In this study, the effects of expression of human ABCA2 on endogenous amyloid precursor protein (APP) expression, trafficking and processing were examined in mouse N2a neuronal cells. ABCA2 expression increased the steady-state APP mRNA levels through transcription. ABCA2 also induced increased synthesis of APP holoprotein and altered APP processing and metabolite generation. ABCA2 expression promoted b secretase (BACE1) cleavage of APP not at the common Asp1 amino acid site (beta site) of Abeta in APP but at the Glu11 site (beta'-site) to increase C89 carboxyl terminal fragment levels (beta'-CTF/C89). The levels of N-terminally truncated Abeta11-40 peptides were also increased by ABCA2 expression. The delivery of newly synthesized APP to the cell surface through the secretary pathway was not perturbed by ABCA2 expression; however, ABCA2 expression increased the amount of APP in early-endosomal compartments, which also contained the highest levels of beta'-CTF/C89 and is likely the site of increased BACE1 processing of APP. This report identifies ABCA2 as a key regulator of endogenous APP expression and processing and suggests a possible biochemical mechanism linking ABCA2 expression, APP processing and Alzheimer's disease. PMID- 20704562 TI - A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA. AB - IRIDA (iron-refractory iron-deficiency anaemia) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anaemia, low transferrin saturation and high levels of the iron-regulated hormone hepcidin. The disease is caused by mutations in the transmembrane serine protease TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of HJV (haemojuvelin), an activator of hepcidin transcription. In the present paper, we describe a patient with IRIDA who carries a novel mutation (Y141C) in the SEA domain of the TMPRSS6 gene. Functional characterization of the TMPRSS6(Y141C) mutant protein in cultured cells showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. As a consequence, hepcidin mRNA expression is increased, causing the clinical symptoms observed in this IRIDA patient. The present study provides important mechanistic insight into how TMPRSS6 is activated. PMID- 20704563 TI - Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). AB - S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways. S6K1 regulates numerous processes, such as protein synthesis, growth, proliferation and longevity, and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance. In the present paper we describe a novel cell-permeable inhibitor of S6K1, PF-4708671, which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF 4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF 4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR. PMID- 20704564 TI - Identification of the BCL2/adenovirus E1B-19K protein-interacting protein 2 (BNIP 2) as a granzyme B target during human natural killer cell-mediated killing. AB - Cytotoxic lymphocytes eliminate infected cells and tumours via the perforin mediated delivery of pro-apoptotic serine proteases known as granzymes. Granzyme B triggers apoptosis via the cleavage of a repertoire of cellular proteins, leading to caspase activation and mitochondrial depolarization. A simple bioinformatics strategy identified a candidate granzyme B cleavage site in the widely expressed BNIP-2 (BCL2/adenovirus E1B-19K protein-interacting protein 2). Granzyme B cleaved recombinant BNIP-2 in vitro and endogenous BNIP-2 was cleaved during the NK (natural killer) cell-mediated killing of tumour cells. Cleavage required the site identified in the bioinformatics screen and was caspase independent. Expression of either full-length BNIP-2 or a truncated molecule mimicking the granzyme B cleaved form was pro-apoptotic and led to the caspase dependent cleavage of BNIP-2 at a site distinct from granzyme B cleavage. Inhibition of BNIP-2 expression did not affect the susceptibility to NK cell mediated killing. Furthermore, target cells in which BID (BH3-interacting domain death agonist) expression was inhibited also remained highly susceptible to NK cell-mediated killing, revealing redundancy in the pro-apoptotic response to human cytotoxic lymphocytes. Such redundancy reduces the opportunity for escape from apoptosis induction and maximizes the chances of immune-mediated clearance of infected cells or tumour cells. PMID- 20704565 TI - Key motifs in EBV (Epstein-Barr virus)-encoded protein kinase for phosphorylation activity and nuclear localization. AB - A sole EBV (Epstein-Barr virus)-encoded protein kinase (EBV-PK) (the BGLF4 gene product) plays important roles in viral infection. Although a number of targets of this protein have been identified, the kinase itself remains largely unstudied with regard to its enzymology and structure. In the present study, site-directed mutagenesis has been employed to generate mutations targeting residues involved in nuclear localization of the EBV-PK, core residues in subdomain III of the protein kinase domain conserved in most protein kinases or residues in subdomain VIa conserved only within the HPK (herpesvirus-encoded protein kinase) group. Deletion of amino acids 389-391 resulted in exclusive cytoplasmic localization of the protein, indicating the involvement of this region in nuclear translocation of the EBV-PK. Mutations at the amino acids Glu113 (core component), Phe175, Leu178, Phe184, Leu185 and Asn186 (conserved in HPKs) resulted in loss of EBV-PK autophosphorylation, protein substrate [EBV EA-D (early antigen diffused)] phosphorylation, and ability to facilitate ganciclovir phosphorylation. These results reiterate the unique features of this group of kinases and present an opportunity for designing more specific antiviral compounds. PMID- 20704566 TI - Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner. AB - The extraordinarily high toxicity of botulinum neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven BoNT (botulinum neurotoxin) serotypes A-G inhibit acetylcholine release leading to flaccid paralysis. Uptake of BoNT/A, B, E, F and G requires a dual interaction with gangliosides and the synaptic vesicle proteins synaptotagmin or SV2 (synaptic vesicle glycoprotein 2), whereas little is known about the cell entry mechanisms of the serotypes C and D, which display the lowest amino acid sequence identity compared with the other five serotypes. In the present study we demonstrate that the neurotoxicity of BoNT/D depends on the presence of gangliosides by employing phrenic nerve hemidiaphragm preparations derived from mice expressing the gangliosides GM3, GM2, GM1 and GD1a, or only GM3 [a description of our use of ganglioside nomenclature is given in Svennerholm (1994) Prog. Brain Res. 101, XI-XIV]. High-resolution crystal structures of the 50 kDa cell-binding domain of BoNT/D alone and in complex with sialic acid, as well as biological analyses of single-site BoNT/D mutants identified two carbohydrate binding sites. One site is located at a position previously identified in BoNT/A, B, E, F and G, but is lacking the conserved SXWY motif. The other site, co ordinating one molecule of sialic acid, resembles the second ganglioside-binding pocket (the sialic-acid-binding site) of TeNT (tetanus neurotoxin). PMID- 20704567 TI - Purification of clinical-grade recombinant HSP65-MUCI fusion protein. AB - HSP65-MUCI is a fusion protein between BCG (Bacille Calmette-Guerin)-derived HSP65 (heat-shock protein 65) and human MUCI (mucin I) VNTR (variable number of tandem repeats)-domain peptides that has shown antitumour efficacy. China's Food and Drug Administration has recently approved a Phase I clinical trial using HSP65-MUCI for the treatment of MUCI-positive breast cancer. In order to produce sufficient quantities of clinical-grade HSP65-MUCI, we established a pilot-scale purification scheme comprising two steps of column chromatography: HIC (hydrophobic-interaction chromatography) and IEX (ion-exchange chromatography). The pH values of the buffers used in homogenization and HIC were adjusted to pH 9.0 to maintain protein stability and prevent protein degradation. Using this manufacturing process, we obtained clinical-grade HSP65-MUCI with a yield of 400 mg per 70 g of wet cell pellet and >96% purity. PMID- 20704568 TI - Adipose tissue inflammation and insulin resistance: all obese humans are not created equal. AB - In recent years, it has become widely accepted that obesity is characterized by a chronic low-grade inflammation of adipose tissue that predisposes affected individuals to insulin resistance, Type 2 diabetes and other disorders associated with the metabolic syndrome. On the other hand, a subset of obese individuals appears to be protected against insulin resistance and the disorders to which it predisposes. The comparison between such insulin-sensitive and insulin-resistant obese individuals offers a unique opportunity to identify key factors that either contribute to or prevent the development of insulin resistance in humans, without the confounding effect of a major difference in fat mass. In the previous issue of the Biochemical Journal, Barbarroja et al. reported that insulin-sensitive obese individuals show less inflammation in their visceral adipose tissue than a group of insulin-resistant subjects matched for BMI (body mass index). This finding reinforces the concept that inflammation in adipose tissue may be a cause of insulin resistance in most obese individuals, although it does not prove it. Further studies will be required for this purpose, as well as to identify the pathogenetic factors that determine whether or not adipose tissue of an obese individual becomes inflamed. PMID- 20704569 TI - Structural and mechanistic insight into how antibodies inhibit serine proteases. AB - Antibodies display great versatility in protein interactions and have become important therapeutic agents for a variety of human diseases. Their ability to discriminate between highly conserved sequences could be of great use for therapeutic approaches that target proteases, for which structural features are conserved among family members. Recent crystal structures of antibody-protease complexes provide exciting insight into the variety of ways antibodies can interfere with the catalytic machinery of serine proteases. The studies revealed the molecular details of two fundamental mechanisms by which antibodies inhibit catalysis of trypsin-like serine proteases, exemplified by hepatocyte growth factor activator and MT-SP1 (matriptase). Enzyme kinetics defines both mechanisms as competitive inhibition systems, yet, on the molecular level, they involve distinct structural elements of the active-site region. In the steric hindrance mechanism, the antibody binds to protruding surface loops and inserts one or two CDR (complementarity-determining region) loops into the enzyme's substrate binding cleft, which results in obstruction of substrate access. In the allosteric inhibition mechanism the antibody binds outside the active site at the periphery of the substrate-binding cleft and, mediated through a conformational change of a surface loop, imposes structural changes at important substrate interaction sites resulting in impaired catalysis. At the centre of this allosteric mechanism is the 99-loop, which is sandwiched between the substrate and the antibody-binding sites and serves as a mobile conduit between these sites. These findings provide comprehensive structural and functional insight into the molecular versatility of antibodies for interfering with the catalytic machinery of proteases. PMID- 20704570 TI - Regulation of TGF-beta signalling by protein phosphatases. AB - Tight regulation of TGF-beta (transforming growth factor-beta) superfamily signalling is important for normal cellular functions and tissue homoeostasis. Since TGF-beta superfamily signalling pathways are activated by a short phosphorylation cascade, from receptor phosphorylation to subsequent phosphorylation and activation of downstream signal transducer R-Smads (receptor activated Smads), reversible phosphorylation serves as a critical step to assure proper TGF-beta signalling. The present article will review the current progress on the understanding of dynamic phosphorylation in TGF-beta signalling and the essential role of protein phosphatases in this process. PMID- 20704572 TI - Multimodal strategy in the successful implementation of a stroke unit in a community hospital. AB - OBJECTIVES: Thrombolysis in stroke remains underutilized in daily practice. We analyzed the impact of a multimodal strategy on the rate of thrombolysis and specific procedure times during the implementation of a community hospital stroke unit. MATERIAL AND METHODS: During a period of 2 years before and after implementation of a stroke unit, we prospectively recorded all patients with thrombolysis and specific procedure times. Calculated door-to-needle time (DNT), door-to-CT time (DCT) and CT-to-needle time (CNT) were analyzed. All structural changes before and after the implementation were analyzed. RESULTS: The number of patients with thrombolysis increased from 24 in 2005-2006 (4.8% of all admitted patients with ischemic stroke) to 95 in 2007-2008 (12.8%). DNT was significantly reduced from 62.2+/-36.1 to 38.5+/-22.2 min (P<0.001). DCT remained unchanged at 10.3+/-9.5 to 10.4+/-13.9 min (P=0.974), whereas CNT improved from 45.7+/-23.1 to 28.3+/-20.3 min (P=0.001). Several structural changes concerning staff, logistics, procedures and laboratory were identified which contributed to decreasing DNT. CONCLUSIONS: A multimodal strategy including several structural changes enables the successful implementation of a community hospital stroke unit offering rapid access to thrombolysis with a very short DNT. PMID- 20704574 TI - Antitumor and anti-angiogenesis immunity induced by CR-SEREX-identified Xenopus RHAMM. AB - Immunization with xenogeneic antigens is an attractive approach to induce cross reactive humoral and cellular immunity to inhibit tumor growth or angiogenesis. To identify novel xenogenic targets for immunotherapy, we have developed a modified serological expression cloning (SEREX) strategy, termed Cross-reactive SEREX (CR-SEREX). Among 78 positive clones identified by CR-SEREX, Xenopus receptor for hyaluronic-acid-mediated motility (xRHAMM) was most frequently identified (18 times), indicating the strongest immunogenic potential for xenogenic immunotherapy. A DNA vaccine based on xRHAMM effectively induced a protective antitumor immunity against local tumor and lung metastasis in B16 melanoma mouse models. Angiogenesis was inhibited and cell apoptosis was increased within tumors. Antitumor activity of xRHAMM worked through stimulation of an antigen-specific cellular response as well as through a specific humoral response against RHAMM, as confirmed by the depletion of immune cell subsets in vivo. Thus, a xenogenic vaccine based on xRHAMM induced an effective immunity against B16 melanoma cells and endothelial cells. PMID- 20704571 TI - Survivin and IAP proteins in cell-death mechanisms. AB - From the realization that cell number homoeostasis is fundamental to the biology of all metazoans, and that deregulation of this process leads to human diseases, enormous interest has been devoted over the last two decades to map the requirements of cell death and cell survival. This effort has led to tangible progress, and we can now chart with reasonable accuracy complex signalling circuitries controlling cell-fate decisions. Some of this knowledge has translated into novel therapeutics, and the outcome of these strategies, especially in cancer, is eagerly awaited. However, the function of cell-death modifiers have considerably broadened over the last few years, and these molecules are increasingly recognized as arbiters of cellular homoeostasis, from cell division, to intracellular signalling to cellular adaptation. This panoply of functions is best exemplified by members of the IAP (inhibitor of apoptosis) gene family, molecules originally narrowly defined as endogenous caspase inhibitors, but now firmly positioned at the crossroads of multiple normal and transformed cellular responses. PMID- 20704575 TI - Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis. AB - Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, and treatment with irinotecan (CPT-11) is limited because of side effects. Mutations in the Rearranged during transfection (RET) proto-oncogene are considered the causative event of MTC. The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3/7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3/7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation. PMID- 20704576 TI - Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth. AB - Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrated toward ovarian cancer cells. A [(3)H] thymidine incorporation assay was conducted to measure the proliferative index. Treatment of human epithelial ovarian cancer cell line (SKOV-3, an ovarian adenocarcinoma derived from the ascites of an ovarian cancer patient) with the prodrugs 5 fluorocytosine (5-FC) or camptothecin-11 (CPT-11) in the presence of HB1.F3.CD or HB1.F3.CE cells resulted in the inhibition of ovarian cancer cell growth. Based on the data presented herein, we suggest that GESTECs expressing CD/CE may have a potent advantage to selectively treat ovarian cancers. PMID- 20704577 TI - Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients. AB - In our study we found that pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) mediated apoptosis in primary leukemia cells from 27 chronic myelogenous leukemia (CML) patients at onset through the activation of the caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). The bax:bcl-2 ratio was increased as a consequence of down-regulation of bcl-2 and up-regulation of bax proteins in response to treatment with PBTDs. In addition, PBTDs were able to induce cell death in primary leukemia cells derived from 23 CML-chemoresistant patients. Furthermore, the effects of PBTDs on the Akt-mTOR (mammalian target of rapamycin) pathway were determined by Western blot. PBTDs possessed inhibitory activity against mTOR and also impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. The results presented in this study demonstrate that we have identified the PBTDs as restoring the apoptotic pathways both in primary leukemia cells derived from CML patients at onset and in primary leukemia cells derived from CML-chemoresistant patients, thus showing their ability to undergo apoptosis. These compounds constitute a promising therapeutic approach for patients with leukemia. They provide the basis for new strategies for an additional anticancer drug in leukemia therapies, especially when conventional ones fail. PMID- 20704578 TI - Vasohibin-1 as a potential predictor of aggressive behavior of ductal carcinoma in situ of the breast. AB - Vasohibin-1 is a recently identified negative feedback regulator of angiogenesis induced by VEGF-A and bFGF. In this study, we first evaluated mRNA expression of vasohibin-1 and CD31 in 39 Japanese female breast carcinoma specimens including 22 invasive ductal carcinoma (IDC) and 17 ductal carcinoma in situ (DCIS) using a real-time quantitative RT-PCR (QRT-PCR) with LightCycler system. In addition, we also immunolocalized vasohibin-1 and CD31 and compared their immunoreactivity to nuclear grades and histological grades of 100 carcinoma cases (50 IDC and 50 DCIS). There were no statistically significant differences of CD31 mRNA expression and the number of CD31 positive vessels between DCIS and IDC (P = 0.250 and P = 0.191, respectively), whereas there was a statistically significant difference in vasohibin-1 mRNA expression and the number of vasohibin-1 positive vessels in DCIS and IDC (P = 0.022 and P < or = 0.001, respectively). There was a significant positive correlation between vasohibin-1 mRNA level and Ki-67 labeling index in DCIS (r(2) = 0.293, P < or = 0.001). In addition, vasohibin-1 mRNA expression was correlated with high nuclear and histological grades in DCIS cases and a significant positive correlation was detected between the number of vasohibin-1 positive vessels and Ki-67 labeling index or nuclear grade or Van Nuys classification of carcinoma cells (P < or = 0.001, respectively). These results all indicate the possible correlation between aggressive biological features in DCIS including increased tumor cell proliferation and the status of neovascularization determined by vasohibin-1 immunoreactivity. PMID- 20704586 TI - Clinical and Experimental Ophthalmology: a decade of successful evolution. PMID- 20704587 TI - Everything old is new again. PMID- 20704588 TI - Recurrent idiopathic neuroretinitis: natural history and effect of treatment. AB - BACKGROUND: Previous reports have emphasized the self-limited nature of idiopathic neuroretinitis. There is less information about a subgroup of patients who suffer recurrent episodes with worse visual outcome. We sought to better characterize the clinical features of recurrent idiopathic neuroretinitis including the effects of immunosuppressive treatment. METHODS: Retrospective chart review of neuroretinitis patients from a single institution from 1983 to 2008. Inclusion criteria included two or more episodes of acute visual loss with disc oedema and macular exudates in a star pattern. Cases due to a specific infectious or inflammatory aetiology were excluded. RESULTS: Forty-one patients were included with an average follow up of 67 months. Median age at the time of the first episode was 28 years (range 10-54 years). Attacks were bilateral sequential in 34 patients (83%). We documented a total of 147 episodes in 75 eyes with an average of 3.6 attacks per patient. The average interval between attacks was 3 years. Visual field loss had a nerve fibre bundle pattern in most cases. Only 36% of eyes retained 6/12 or better visual acuity and greater than two thirds of their visual field. Long-term immunosuppressive treatment in 13 patients decreased the attack rate by 72%. CONCLUSIONS: Recurrent idiopathic neuroretinitis typically affects young adults, with no gender preference. Recovery is limited and visual loss is cumulative with repeated attacks, often resulting in severe permanent visual loss. Immunosuppressive treatment appears to lessen the attack frequency. PMID- 20704589 TI - Two types of Ca2+ channel linked to two endocytic pathways coordinately maintain synaptic transmission at the Drosophila synapse. AB - Endocytosis at the presynaptic terminal is initiated by Ca(2+) influx through voltage-gated Ca(2+) channels. At the Drosophila neuromuscular junction, we demonstrated two components of endocytosis linked to distinct Ca(2+) channels. A voltage-gated Ca(2+) channel blocker, (R)-(+)-Bay K8644 (R-BayK), selectively blocked one component (R-BayK-sensitive component) without affecting exocytosis, while low concentrations of La(3+) preferentially depressed the other component (La(3+) -sensitive component). In a temperature-sensitive mutant, shibire(ts), at non-permissive temperatures, dynamin clusters were found immunohistochemically at the active zone (AZ) during the R-BayK-sensitive endocytosis, while they were detected at the non-AZ during the La(3+)-sensitive endocytosis. Immunostaining of the Ca(2+) channel alpha(2)delta subunit encoded by straightjacket (stj) was found within the AZ, and a mutation in stj depressed the R-BayK-sensitive component but enhanced the La(3+) -sensitive one, indicating that the alpha(2)delta subunit is associated with the R-BayK-sensitive Ca(2+) channel. Filipin bound to the non-AZ membrane and inhibited the La(3+) -sensitive component, but not the R-BayK-sensitive one. We concluded that the R-BayK sensitive component of endocytosis occurred at the AZ and termed this AZ endocytosis. We also concluded that the La(3+) -sensitive component occurred at the non-AZ and termed this non-AZ endocytosis. These two types of endocytosis were modulated by various drugs towards opposite directions, indicating that they were differentially regulated. During high-frequency stimulation, AZ endocytosis operated mainly in the early phase, whereas non-AZ endocytosis operated in the late phase. Thus, intense synaptic transmission is coordinately maintained by synaptic vesicle recycling initiated by Ca(2+) influx through the two types of Ca(2+) channel. PMID- 20704591 TI - Neuronal disinhibition in the trigeminal nucleus caudalis in a model of chronic neuropathic pain. AB - The mechanisms underlying neuropathic facial pain syndromes are incompletely understood. We used a unilateral chronic constriction injury of the rat infraorbital nerve (CCI-IoN) as a facial neuropathic model. Pain-related behavior of the CCI-IoN animals was tested at 8, 15 and 26 days after surgery (dps). The response threshold to mechanical stimulation with von Frey hairs on the injured side was reduced at 15 and 26 dps, indicating the presence of allodynia. We performed unitary recordings in the caudalis division of the spinal trigeminal nucleus (Sp5C) at 8 or 26 dps, and examined spontaneous activity and responses to mechanical and thermal stimulation of the vibrissal pad. Neurons were identified as wide dynamic range (WDR) or low-threshold mechanoreceptive (LTM) according to their response to tactile and/or noxious stimulation. Following CCI-IoN, WDR neurons, but not LTM neurons, increased their spontaneous activity at 8 and 26 dps, and both types of Sp5C neurons increased their responses to tactile stimuli. In addition, the on-off tactile response in neurons recorded after CCI-IoN was followed by afterdischarges that were not observed in control cases. Compared with controls, the response inhibition observed during paired-pulse stimulation was reduced after CCI-IoN. Immunohistochemical studies showed an overall decrease in GAD65 immunoreactivity in Sp5C at 26 dps, most marked in laminae I and II, suggesting that following CCI-IoN the inhibitory circuits in the sensory trigeminal nuclei are depressed. Consequently, our results strongly suggest that disinhibition of Sp5C neurons plays a relevant role in the appearance of allodynia after CCI-IoN. PMID- 20704590 TI - Decoding glutamate receptor activation by the Ca2+ sensor protein hippocalcin in rat hippocampal neurons. AB - Hippocalcin is a Ca(2+)-binding protein that belongs to a family of neuronal Ca(2+)sensors and is a key mediator of many cellular functions including synaptic plasticity and learning. However, the molecular mechanisms involved in hippocalcin signalling remain illusive. Here we studied whether glutamate receptor activation induced by locally applied or synaptically released glutamate can be decoded by hippocalcin translocation. Local AMPA receptor activation resulted in fast hippocalcin-YFP translocation to specific sites within a dendritic tree mainly due to AMPA receptor-dependent depolarization and following Ca(2+)influx via voltage-operated calcium channels. Short local NMDA receptor activation induced fast hippocalcin-YFP translocation in a dendritic shaft at the application site due to direct Ca(2+)influx via NMDA receptor channels. Intrinsic network bursting produced hippocalcin-YFP translocation to a set of dendritic spines when they were subjected to several successive synaptic vesicle releases during a given burst whereas no translocation to spines was observed in response to a single synaptic vesicle release and to back-propagating action potentials. The translocation to spines required Ca(2+)influx via synaptic NMDA receptors in which Mg(2+) block is relieved by postsynaptic depolarization. This synaptic translocation was restricted to spine heads and even closely (within 1-2 microm) located spines on the same dendritic branch signalled independently. Thus, we conclude that hippocalcin may differentially decode various spatiotemporal patterns of glutamate receptor activation into site- and time-specific translocation to its targets. Hippocalcin also possesses an ability to produce local signalling at the single synaptic level providing a molecular mechanism for homosynaptic plasticity. PMID- 20704592 TI - Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha synuclein-induced pathology. AB - Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (alphasyn). Among the different modifications that can promote the formation of toxic alphasyn species, C terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated alphasyn aggregates faster and sub-stoichiometric amounts of C-terminal truncated alphasyn promote aggregation of the full-length alphasyn (alphasynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of alphasyn-induced pathology by the presence of truncated alphasyn, we used recombinant adeno associated virus to express either alphasynFL or a C-terminal truncated alphasyn (1-110) in rats. We adjusted the recombinant adeno-associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of alphasyn were co-expressed at these pre-determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C-terminal truncated alphasyn (1-110) but only alphasynFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of alphasynFL and formation of larger pathological accumulations. Moreover, in the co-expression group, three of the eight animals showed apomorphine-induced turning, suggesting prominent post-synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C-terminal truncated alphasyn can interact with and exacerbate the formation of pathological accumulations containing alphasynFL in vivo. PMID- 20704593 TI - Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum. AB - The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs who use psychostimulant 'cognitive enhancers'. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2-5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factor genes zif268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate. PMID- 20704594 TI - The anterior medial amygdala transmits sexual odor information to the posterior medial amygdala and related forebrain nuclei. AB - In Syrian hamsters, reproductive behavior relies on the perception of chemical signals released from conspecifics. The medial amygdala (MEA) processes sexual odors through functionally distinct, but interconnected, sub-regions; the anterior MEA (MEAa) appears to function as a chemosensory filter to distinguish between opposite-sex and same-sex odors, whereas the posterodorsal MEA (MEApd) is critical for generating attraction specifically to opposite-sex odors. To identify how these sub-regions interact during odor processing, we measured odor induced Fos expression, an indirect marker of neuronal activation, in the absence of either MEAa or MEApd processing. In Experiment 1, electrolytic lesions of the MEAa decreased Fos expression throughout the posterior MEA in male hamsters exposed to either female or male odors, whereas MEApd lesions had no effect on Fos expression within the MEAa. These results indicate that the MEAa normally enhances processing of sexual odors within the MEApd and that this interaction is primarily unidirectional. Furthermore, lesions of the MEAa, but not the MEApd, decreased Fos expression within several connected forebrain nuclei, suggesting that the MEAa provides the primary excitatory output of the MEA during sexual odor processing. In Experiment 2, we observed a similar pattern of decreased Fos expression, using fiber-sparing, NMDA lesions of the MEAa, suggesting that the decreases in Fos expression were not attributable exclusively to damage to passing fibers. Taken together, these results provide the first direct test of how the different sub-regions within the MEA interact during odor processing, and highlight the role of the MEAa in transmitting sexual odor information to the posterior MEA, as well as to related forebrain nuclei. PMID- 20704595 TI - Fast-spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward. AB - Although previous in vitro studies revealed inhibitory synaptic connections of fast-spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast-spiking neurons were distinguished from putative medium-sized spiny neurons on the basis of their spike waveforms and rates. Cross-correlograms of fast-spiking and putative medium sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium-sized spiny neuron spiking around fast-spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast-spiking unit firing. Many of these temporal relationships were dependent on the sleep-wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast-spiking units and putative medium-sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast-spiking neurons in a reward searching task, they generally showed a pre-reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed-forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast-spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward-related changes in firing rate. PMID- 20704596 TI - Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes. AB - Environmental and age-related effects on learning and memory were analysed and compared with changes observed in astrocyte laminar distribution in the dentate gyrus. Aged (20 months) and young (6 months) adult female albino Swiss mice were housed from weaning either in impoverished conditions or in enriched conditions, and tested for episodic-like and water maze spatial memories. After these behavioral tests, brain hippocampal sections were immunolabeled for glial fibrillary acid protein to identify astrocytes. The effects of environmental enrichment on episodic-like memory were not dependent on age, and may protect water maze spatial learning and memory from declines induced by aging or impoverished environment. In the dentate gyrus, the number of astrocytes increased with both aging and enriched environment in the molecular layer, increased only with aging in the polymorphic layer, and was unchanged in the granular layer. We suggest that long-term experience-induced glial plasticity by enriched environment may represent at least part of the circuitry groundwork for improvements in behavioral performance in the aged mice brain. PMID- 20704597 TI - Light-dependent adsorption of photosynthetic cyanophages to Synechococcus sp. WH7803. AB - Cyanophages infecting marine Synechococcus strains are abundant in the world's oceans and are of considerable ecological significance by virtue of their hosts' role as prominent primary producers in the marine environment. In nature, cyanobacteria experience diel light-dark (LD) cycles, which may exert significant effects on the phage life cycle. An investigation into the role of light revealed that cyanophage S-PM2 adsorption to Synechococcus sp. WH7803 was a light dependent process. Phage adsorption assays were carried out under illumination at different wavelengths and also in the presence of photosynthesis inhibitors. Furthermore, phage adsorption was also assayed to LD-entrained cells at different points in the circadian cycle. Cyanophage S-PM2 exhibited a considerably decreased adsorption rate under red light as compared with blue, green, yellow light or daylight. However, photosynthesis per se was not required for adsorption as inhibitors such as dichlorophenyldimethyl urea did not affect the process. Neither was S-PM2 adsorption influenced by the circadian rhythm of the host cells. The presence or absence of the photosynthetic reaction centre gene psbA in cyanophage genomes was not correlated with the light-dependent phage adsorption. PMID- 20704598 TI - Comparison and evaluation of volatile oils from three different extraction methods for some Thai fragrant flowers. AB - Several tropical flowers have distinctive fragrances which are very appealing to use in perfumery, cosmetics and spa. However, to obtain a 'natural fragrance' from the flower is a challenge as the scent could change during the extraction process. The aim of the study is to find the suitable procedure for extraction of volatile oils from some Thai fragrant flowers. Three different methods: hydrodistillation, solvent extraction and enfleurage methods have been applied for the extraction of volatile oil from Jasminum sambac L. Aiton; Oleaceae (jasmine). The quantities and quality of jasmine volatile oils obtained from the different tested methods were compared. The solvent extraction method using 95% ethanol provided the greatest level of oil yield. However, sensory evaluation using preference test showed that the scents of the volatile oils from solvent extraction using diethyl ether and from enfleurage method were the closest to the fresh flowers compared with the volatile oils obtained from other methods. Their chemical constituents were analysed using gas chromatography coupled with mass spectrometer. Both volatile oils were then evaluated using a triangle discrimination test. From the triangle test, we found that 14 panellists from the total of 36 could not distinguish between the scents of jasmine oil from enfleurage and fresh jasmine flowers whereas only one panellist could not distinguish between the scent of jasmine oil from the solvent extraction and fresh jasmine flowers. These results suggest that the scent of the volatile oil obtained from the enfleurage method was the closest to fresh flowers compared with that obtained from other methods. This method was then successfully applied for extraction of volatile oils from three other Thai fragrant flowers, Michelia alba DC.; Magnoliaceae, Millingtonia hortensis L.; Bignoniaceae and Hedychium coronarium J. Konig; Zingiberaceae. PMID- 20704599 TI - Highly sensitive spectrometric method for determination of hydroquinone in skin lightening creams: application in cosmetics. AB - A highly sensitive, simpler, faster and economical UV/visible spectrophotometric method has been established for the estimation of hydroquinone (HQ) in dilute organic matrices. The method is based on using ammonium meta-vanadate as an oxidizing catalyst for conversion of HQ to p-benzoquinone (BQ) in the presence of oxygen. As a result of higher absorption of UV light by BQ than by HQ, its signal has been utilized for determining HQ at the trace level. The effect of various parameters such as amount of oxidizing agent, stability time, temperature, acids and bases, solvents and interference by various compounds has been studied upon the absorption of BQ as HQ. Under optimized conditions, Beer's Law was obeyed in the range of 0.025-2.00 MUg ml(-1) HQ at 245.5 nm using 1 : 1 (V/V) 2 propanol/water system with a lower detection limit of 7 ng ml(-1) and linear regression coefficient of 0.9998. Relative standard deviation of 1.5% was observed for 0.5 MUg ml(-1) HQ solution (n = 11). The newly developed method has been successfully applied to diluted samples of various skin lightening creams for free HQ determination at the trace level. Comparison of the results obtained by the proposed method with those by a previously reported method proved its validity. PMID- 20704600 TI - Formulation of sunscreens with enhancement sun protection factor response based on solid lipid nanoparticles. AB - Solid lipid nanoparticle (SLN) was regarded as new topical delivery systems for pharmaceutical and cosmetic active ingredients. The purpose of this study is to develop carrier systems for organic and inorganic sunscreens based on a matrix composed of carnauba wax and decyl oleate. Formulae (F1-F7) were prepared using butyl methoxydibenzoylmethane and octyl methoxycinnamate as organic components, and titanium dioxide (TiO(2) ) was used as inorganic component. Both types of sunscreens were incorporated into SLN formulations using classical method of preparation. To evaluate the effect of the pigments on the nanoparticles, particle size was measured using Mastersizer particle size analyser. UV protection abilities of formulations were investigated by the in vitro sun protection factor test (SPF). Further parameters determined were spreadability as well as viscosity. The rheological behaviour of the formulations was also carried out. From the plot of log of shear stress vs. log of shear rate, the slope of the plot representing flow index and ontology of the y-intercept indicating consistency index was calculated. The formulae showed a flow index of 0.2074 0.4005 indicating pseudoplastic flow behaviour. Significant increases in SPF values up to about 50 were reported after the encapsulation by using organic and inorganic filters in Canada wax and decyl oleate. So, SLN could be appropriate vehicles to carry organic and inorganic sunscreens. The rational combination of cinnamates, titanium dioxide and Zinc oxide has shown a synergistic effect to improve the SPF of cosmetic preparations. PMID- 20704601 TI - A novel anti-ageing mechanism for retinol: induction of dermal elastin synthesis and elastin fibre formation. AB - Dermal elastic fibres are extracellular matrix protein complexes produced by fibroblasts and involved in skin elasticity. Elastin fibres decrease with age as a result of reduced synthesis and increased degradation, resulting in skin sagging and reduced skin elasticity. In this study, we show that retinol (ROL), known to enhance dermal collagen production, is also enhancing elastin fibre formation. ROL induced elastin gene expression and elastin fibre formation in cultured human dermal fibroblasts. Topical treatment of cultured human skin explants with a low dose (0.04%) of ROL increased mRNA and protein levels of tropoelastin and of fibrillin-1, an elastin accessory protein, as documented by QPCR and immunohistochemistry staining. Luna staining confirmed the increased elastin fibre network in the ROL-treated skin explants, as compared with untreated controls. These data demonstrate that ROL exerts its anti-ageing benefits not only via enhanced epidermal proliferation and increased collagen production, but also through an increase in elastin production and assembly. PMID- 20704602 TI - Lack of association of high body mass index with risk for developing polymyalgia rheumatica. AB - BACKGROUND: High body mass index (BMI) may have modulatory effects on the immune system. OBJECTIVES: To determine the association between BMI and polymyalgia rheumatica (PMR) as well as the influence of BMI on glucocorticoid treatment duration and development of giant-cell arteritis (GCA) in patients with PMR. METHODS: The BMI of 364 patients with PMR from a population-based incidence cohort was compared to the BMI of non-PMR subjects from the same population. High and low BMI were defined as > or = 25 and < 18.5 kg/m2, respectively. The association between BMI and case status was determined. The association between BMI and the duration of glucocorticoid therapy, as well as the development of GCA after accounting for relevant variables, were also examined. RESULTS: The mean BMI at index was similar in both groups (PMR: 26 +/- 5.4 kg/m2; non-PMR: 25.9 +/- 4.0 kg/m(2), P = 0.83). There was no association between BMI and the duration of glucocorticoid therapy. No significant association was found between BMI and the development of GCA in patients with PMR. CONCLUSION: Patients with high BMI (> or = 25 kg/m2) are not more likely to develop PMR. BMI did not influence the duration of glucocorticoid therapy or the occurrence of GCA in patients with PMR. PMID- 20704603 TI - Retinopathy due to antimalarial drugs in patients with connective tissue diseases: are they so innocent? A single center retrospective study. AB - INTRODUCTION: Antimalarial medications are basal active drugs used for the treatment of various rheumatological conditions. Their common side-effects include eye damage. AIM: The aim of this study is to determine the safety of antimalarial medications used for rheumatological conditions and the incidence of retinopathy. MATERIAL AND METHODS: Eighty-five patients with rheumatological conditions, who were followed in our rheumatology clinics between 2005 and 2009 while under chloroquine (CQ) and/or hydroxychloroquine (HQ) treatment were included in the study. Indirect ophthalmoscopic examination with 90 dioptry lens, frontal segment examination and macular visual area test were applied to all patients. Severity of retinopathy was evaluated as mild initial defect in the macula, or severe visual area loss. RESULTS: Retinopathy findings were detected in 21 out of 85 patients (24.7%). Of these patients, 12 had mild initial defects while nine had severe visual area loss. Of 21 patients, eight were on HQ and 13 were on CQ treatment. Of the patients seen with findings of retinopathy, 17 had comorbid hypertension (HT) and six had diabetes mellitus (DM). Patients receiving CQ are under higher risk compared to those on HQ treatment (P = 0.001). Patient age, disease duration, HT and DM presence had no statistically significant effect on retinopathy development (P = 0.144, P = 0.305, P = 0.258, P = 0.395, respectively). CONCLUSION: The incidence of retinopathy among patients using antimalarial medications as observed in this study was relatively high. Based on these results, it is essential to emphasize the importance of close monitoring in patients receiving antimalarial medications and evaluation of visual findings before treatment initiation. PMID- 20704604 TI - Chronic necrotizing pulmonary aspergillosis in a patient treated with a tumor necrosis factor-alpha inhibitor. AB - Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine that plays an important role in the pathogenesis of a variety of autoimmune diseases. TNF-alpha inhibitors have been shown to offer clinical benefits in the treatment of autoimmune and inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis (AS), and Crohn's disease. Occasionally, these agents have been associated with infectious complications because of their immunosuppressive activity. Globally, several cases of infections associated with TNF-alpha inhibitors have been reported. However, Aspergillus infection associated with etanercept is very rare. We report a case of chronic necrotizing pulmonary aspergillosis in a 51-year-old man with AS that developed after treatment with etanercept. PMID- 20704605 TI - Pararenal retroperitoneal Castleman's disease mimicking systemic lupus erythematosus. AB - A 41-year-old man diagnosed initially as probable systemic lupus erythematosus (SLE) visited our hospital complaining of a persistent painful oral ulcer and multiple spots like coffee beans on his trunk. Antibodies except for anti-dsDNA and anti-histone antibodies and other serologies were negative. Conventional cytotoxic and immunomodulatory agents did not have any effect on these lesions. Computed tomography for evaluating persistent dry cough incidentally showed a huge mass in the left mid-retroperitoneum. Surgical treatment was done and the final diagnosis was Castleman's disease (CD). CD is a relatively rare disorder characterized by a massive non-malignant tumor of lymphoid tissues, with unknown etiology. It commonly presents as a localized soft tissue mass within the mediastinum or neck, and rarely in the retroperitoneal space. Since some cases of CD may share systemic, immune and histopathologic features of autoimmune disease, exact diagnosis is difficult to make based on the clinical and laboratory clues alone. We report herein an unusual case with pararenal retroperitoneal CD mimicking SLE. PMID- 20704606 TI - Localized calcinosis in juvenile dermatomyositis: successful treatment with intralesional corticosteroids injection. PMID- 20704607 TI - ANCA-positive vasculitis associated with simvastatin/ezetimibe: expanding the spectrum of statin-induced autoimmunity? AB - Although autoimmune syndromes such as systemic lupus erythematosus and dermatomyositis have been previously reported in association with statin use, vasculitis has not been well described. We present a patient with an antineutrophil cytoplasmic antibody-positive, predominantly cutaneous vasculitis, the temporal course of which was associated with simvastatin/ezetimibe use. The patient's serologic findings were consistent with drug-induced disease, with high titer antimyeloperoxidase, in addition to antinuclear and anti-Ro (SSA) antibodies. The patient demonstrated complete resolution of symptoms simply by withdrawing the drug. PMID- 20704608 TI - High-dose unfractionated heparin therapy in a pregnant patient with antiphospolipid syndrome: a case report. AB - A case of a 37-year-old pregnant patient with antiphospholipid syndrome (APS), who has a medical history of both thrombosis and recurrent fetal loss, is presented. She was treated with predonisolone and fixed-dose unfractionated heparin (UFH) infusion, followed by plasmaphereses and fixed-dose low-molecular weight heparin infusion during her fourth pregnancy. Unfortunately, this treatment did not have beneficial effects, resulting in intrauterine growth restriction and finally neonatal death. Continuous intravenous UFH infusion and low-dose aspirin were administrated under the monitoring of the activated partial thromboplastin time to achieve a target level of 120 s during her fifth pregnancy. A healthy baby weighing 1818 g at birth was delivered by Cesarean section at the 34th week of pregnancy. High-dose UFH infusion may be considered to be one of the preferable options to manage pregnant patients with refractory APS. PMID- 20704609 TI - A case of refractory adult-onset Still's disease treated with anakinra. AB - Adult-onset Still's disease (AOSD) often presents both a diagnostic and a therapeutic challenge. We report a 40-year-old Chinese woman, in whom multiple adjustments of drug combinations were required before successful control of the patient's disabling symptoms. The patient failed multiple therapies including non steroidal anti-inflammatory drugs, glucocorticoid, methotrexate (MTX), cyclosporine, leflunomide and infliximab. Treatment was complicated by hyperglycemia, glucocorticoid-induced osteoporosis, worsening hypertension and vaginal candidiasis. She suffered recurrent hospitalisation for active disease, developed carpal joint erosions and lost her employment over the course of 1 year. In view of refractoriness to multiple conventional therapies, anakinra was initiated in combination with MTX with a rapid and sustained improvement in clinical and laboratory parameters over 12 months. However, radiographic damage ensued despite aggressive therapies. PMID- 20704610 TI - Multiple myeloma presenting with musculoskeletal manifestations: a case report. AB - Multiple myeloma (MM) is a malignant plasma cell disorder. Musculoskeletal and skin manifestations of this disorder are rare. Here we report a case of a young male patient presenting with polyarthritis and skin rash resembling vasculitis. Detailed investigations revealed that he was suffering from multiple myeloma in which arthritis was a musculoskeletal complication of the disease. PMID- 20704611 TI - A can of red herrings. AB - Lymphomatoid granulomatosis is a rare disease. Anti-cyclic citrullinated peptide (anti-CCP) antibody is more commonly found in patients with rheumatoid arthritis and less frequently in some of the other rheumatic and non-rheumatic conditions. It is not recognized to be present in lymphoproliferative disease on its own. We report the first case of anti-CCP antibody positivity in lymphomatoid granulomatosis presenting with polyarthritis. This case illustrates the evolving nature of this disease and its characteristics at different stages leading to the challenge of an accurate diagnosis in the setting of a paraneoplastic polyarthritis. PMID- 20704613 TI - The International Journal of Rheumatic Diseases--a journal in evolution. PMID- 20704612 TI - Churg-Strauss syndrome: a retrospective study of 11 cases from a single center in Japan. AB - OBJECTIVE: To investigate the clinical characteristics of patients with Churg Strauss syndrome (CSS), including symptoms, blood chemistry and immunological findings. PATIENTS AND METHODS: We retrospectively investigated the records of 11 patients (six female and five male) with CSS admitted to our hospital from September 2003 to October 2009. RESULTS: Eight patients had preceding symptoms including bronchial asthma and allergic rhinitis. Seven patients showed eosinophilia. Nine patients had mononeuritis multiplex. Positive findings of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) were found in five patients. Neither clinical manifestations nor laboratory findings were correlated with positivity for MPO-ANCA. However, the MPO-ANCA-positive group showed a higher level of blood urea nitrogen and proteinuria than those negative for MPO ANCA. Ten patients recovered after starting steroid or immunosuppressive therapy, although one patient died of unknown etiology. CONCLUSION: Although general assessments based on various factors such as medical history, clinical manifestation and laboratory studies are indispensable in CSS, MPO-ANCA might be useful as a predictor of renal dysfunction in patients with CSS. PMID- 20704614 TI - Assessment of endothelial function as a marker of cardiovascular risk in patients with rheumatoid arthritis. AB - The endothelium is a major regulator of cardiovascular function and maintains an atheroprotective role through several mechanisms, including vasodilatation, inhibition of platelet aggregation, having anticoagulant and profibrinolytic effects, and having an anti-inflammatory effect. Early changes in the normal functioning of the endothelium are key initiating factors in the development and progression of atherosclerosis. These changes are present well before the presentation of clinical symptoms. Thus, researchers have focused much attention on developing methods for reliable non-invasive testing of endothelial function to allow early detection and monitoring and progression of subclinical atherosclerosis. To date, there is a wide range of methods in use to assess endothelial function, each with its own advantages and limitations. Ideally, the tests should be non-invasive to allow repeated measurements and be applicable in normal healthy subjects and also in children. Given the wide range of regulatory functions of the endothelium, it is not surprising that there is no single measure of endothelial function that provides all the necessary information regarding vascular integrity in different vascular beds. Therefore, a combination of tests examining different components of the vascular system is more appropriate. Since patients with rheumatoid arthritis have increased mortality due to cardiovascular disease, assessment of endothelial function could prove to be useful tools in the identification and monitoring of cardiovascular risk. The purpose of this review is to give a brief overview of some of the commonly used techniques for assessment of endothelial function, and in particular on those that have been used in studies of patients with rheumatoid arthritis. PMID- 20704615 TI - Bone marrow lesions in the knee: the clinical conundrum. AB - Osteoarthritis (OA) of the knee is a common, debilitating condition. Twelve percent of people aged 60 years or older have symptomatic knee OA. With increasing global incidence of obesity, the prevalence of OA is set to dramatically rise Cartilage deterioration is a hallmark of the disease, but other areas are equally as important, such as changes to the subchondral bone. Magnetic resonance imaging (MRI) has enabled us to view bone marrow lesions (BMLs) in the subchondral bone, allowing progress to be made in understanding their natural history, effect on pain, structural deterioration and other factors. The focus of this review is to try to put a new clinical perspective for the patients with BMLs in relation to pain, functional decline and prognosis. PMID- 20704616 TI - Development of a questionnaire for identification of the risk factors for osteoarthritis of the knees in developing countries. A pilot study in Iran and Bangladesh. An ILAR-COPCORD phase III study. AB - BACKGROUND: Knee osteoarthritis (OA) is one of the most prevalent rheumatic disorders in the Asia-Pacific region. Identification of modifiable risk factors is important for development of strategies for primary and secondary prevention of knee OA. OBJECTIVE: Developing a core questionnaire for identification of risk factors of knee OA at the community level. METHODS: Steps performed: (1) item generation from literature, existing knee OA questionnaires and patient focus group discussions; (2) development of a preliminary APLAR-COPCORD English questionnaire; (3) translation into target language, back translation and development of a pre-final target language version; (4) adaptation of the pre final target language version through tests of comprehensibility, content validity, test-retest reliability; and (5) finalization of the English questionnaire. Investigators in Bangladesh, Iran, China, Philippines and Indonesia participated in steps 1 and 2. Subsequent steps were carried out by Bangladeshi and Iranian investigators. RESULTS: Fifty-three items were generated. Fourteen were obtainable from physical examination and placed in an examination sheet. Two radiological items were not included. A preliminary English questionnaire comprising the remaining 37 items was constructed and translated into Bengali and Persian. The preliminary Bengali and Persian versions were adapted as a result of tests of comprehensibility, content validity and test retest reliability. The English questionnaire was adapted through repeated exchange of ideas and experiences among participating investigators. A 35-item English core questionnaire was finally developed. CONCLUSION: The questionnaires may be used to identify risk factors of knee OA in Asia-Pacific communities after validation and further adaptation. From these data strategies for primary and secondary prevention of knee OA can be developed. PMID- 20704617 TI - Prevalence and correlates of shoulder pain and stiffness in a population-based study: the North West Adelaide Health Study. AB - AIM: To determine the prevalence, correlates and impact of shoulder pain in a population-based sample. METHODS: The North West Adelaide Health Study is a representative longitudinal cohort study of people aged 18 years and over. The original sample was randomly selected and recruited by telephone interview. Overall, 3206 participants returned to the clinic during the second stage (2004 2006) and were asked to report whether they had pain, aching or stiffness on most days in either of their shoulders. Data was also collected on body mass index; shoulder range of motion, lifestyle and socioeconomic factors; the Shoulder Pain and Disability Index and the Medical Outcomes Study Short Form 36 (SF36) was used. RESULTS: Overall, 22.3% of participants indicated that they had pain, aching or stiffness in either of their shoulders. Women, those aged 50 years and over, current smokers and those classified as obese were all significantly more likely to report shoulder pain. Respondents with shoulder pain scored lower on all domains of the SF36. In those with shoulder symptoms, women had more severe pain and worse shoulder function than men, and older people had worse shoulder function than younger people. CONCLUSION: Shoulder pain affects almost a quarter of people in the Australian community, with a significant detrimental impact on health-related quality of life and physical functioning. PMID- 20704618 TI - Subclinical coronary artery disease in Asian rheumatoid arthritis patients who were in remission: a pilot study. AB - INTRODUCTION: Rheumatoid arthritis (RA) patients who have active disease with longer disease duration have been reported to have increased risk of cardiovascular events compared to the normal population. OBJECTIVE: The primary aim of our study is to ascertain the prevalence of significant asymptomatic coronary artery disease (CAD) in Asian RA patients who are in remission using multi-detector computed tomography (MDCT). The secondary aims of our study are the usage of pulse wave velocity and the biomarkers N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-senstivity C-reactive protein (hs-CRP) to detect subclinical atherosclerosis in RA patients. METHODS: We performed a comparative cross-sectional study of 47 RA patients who were in remission with a control group of non-RA patients with a history of atypical chest pain in Sarawak General Hospital from November 2008 to February 2009. All patients underwent 64 slice MDCT, assessment of arterial stiffness using the SphygmoCor test and blood analysis for NT-proBNP and hsCRP. RESULTS: There were 94 patients in our study with a mean age of 50 +/- 8.8 years. The RA and control patients in each group were matched in terms of traditional CV risk factors. Our RA patients had a median disease duration of 3 years (IQR 5.5). MDCT showed evidence of CAD in nine (19.1%) RA patients and three (6.4%) control patients (P = 0.06). There was no significant association between pulse wave velocity (PWV) and presence of CAD in our RA group. There was no significant correlation between PWV with levels of proBNP or hsCRP in our RA patients. CONCLUSIONS: In our current pilot study with the limitation of small sample size, RA was not associated with an increased risk of CAD in our RA patients who were in remission. Larger studies of CAD in Asian RA patients are needed to confirm our current finding. PMID- 20704619 TI - Measurement of hand bone mineral density in early rheumatoid arthritis using dual energy X-ray absorptiometry. AB - AIMS: The earliest radiological change in rheumatoid arthritis (RA) is periarticular osteopenia, which occurs prior to the appearance of erosions and clinically apparent deformities. The aim of the study was to measure periarticular bone mineral density (BMD) in the hands of patients with early RA, using dual energy X-ray absorptiomentry (DEXA) and to correlate this with markers of disease activity and radiological progression. METHODS: The study population (n = 50) of patients with RA of < 3 years duration underwent measurement of BMD of the non-dominant hand, femoral neck and lumbar spine and clinical assessment at baseline, 6 and 12 months. Hand radiographs were performed at baseline and 12 months. Thirty age- and sex-matched controls also underwent measurement of BMD of the non-dominant hand, femoral neck and lumbar spine. RESULTS: Hand BMD correlated strongly with sex, height, weight and lumbar and femoral neck BMD in both RA subjects and controls. Baseline hand BMD in RA subjects correlated with baseline serum C-reactive protein (r = -0.36, P = 0.01) and 12-month radiographic score (r = 0.36, P = 0.02). There were small non-significant decreases in hand, femoral neck and lumbar spine BMD over the 12-month period. CONCLUSION: Hand BMD measurement using DEXA is a reproducible, well-tolerated procedure that warrants further investigation as a component of routine assessment in early RA. PMID- 20704620 TI - Total hip arthroplasty in patients with chronic autoimmune inflammatory arthroplasties. AB - OBJECTIVE: Patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and ankylosing spondylitis (AS) often require total hip arthroplasties. We present a retrospective review of 32 total hip arthroplasties (THA) performed for patients with SLE, RA or AS from 2003 to 2008 in a tertiary hospital in Singapore. MATERIALS AND METHODS: A total of 323 THAs performed between January 2003 to December 2008 were traced and cases of arthroplasties performed for such patients were isolated. Pre- and post-operative range of motion, Harris hip score, limb length discrepancies and complications were studied. RESULTS: Twenty six patients aged 24-66 years (mean 47 years) were reviewed, with two AS patients (7.7%), 16 RA patients (61.5%), seven SLE patients (26.9%) and one patient (3.8%) with both RA and SLE. Thirty-two THA operations were conducted with six patients requiring bilateral THAs. The average follow-up was 3.3 years. Mean Harris hip score for 25 patients (one excluded due to patient expiry 2 month post-surgery) improved from 41.3 to 86.53 (P < 0.05). Mean pre-operative hip flexion improved from 61.3 degrees (0-120) to 89.7 degrees (30-120) (P < 0.05). Seventeen cases had preoperative limb length discrepancies (median 1 cm) which were all corrected. There were no implants loosening, infective arthritis, dislocations or neurovascular injuries documented. CONCLUSION: Our series demonstrated the excellent outcome of THA for patients with chronic autoimmune arthropathies at the time of follow-up. Careful patient selection remains a priority as long-term outcomes for such patients of a significantly younger population is yet to be determined. PMID- 20704621 TI - Discrimination ability of ASDAS estimating disease activity status in patients with ankylosing spondylitis. AB - OBJECTIVES: To investigate discrimination ability of the Assessment of Spondyloarthritis International Society (ASAS) endorsed disease activity score (ASDAS) versions evaluating low and high disease activity in an unselected group of patients with ankylosing spondylitis (AS). METHODS: Patients consecutively included into the joint database of five university hospitals were analyzed for low or high disease activity according to different criteria. Standardized mean differences (SMD) for two ASDAS versions were evaluated. RESULTS: The ASDAS versions (back pain, morning stiffness, patient global pain, pain/swelling of peripheral joints, plus either erythrocyte sedimentation rate or C-reactive protein) discriminated high and low disease activity in subgroups according to Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) and ASAS remission/partial remission criteria. ASDAS versions were also not influenced by peripheral arthritis and correlated well with other outcome measurements and acute-phase reactants. The ASDAS versions performed better than patient-reported measures or acute-phase reactants discriminating high and low disease activity status. CONCLUSION: Both ASDAS versions, consisting of both patient-reported data and acute-phase reactants, performed well in discriminating low and high disease activity. Further longitudinal data may better estimate the usefulness of ASDAS to assess disease activity subgroups and treatment response. PMID- 20704622 TI - Rituximab in intractable ocular lesions of Behcet's disease; randomized single blind control study (pilot study). AB - BACKGROUND: Ocular lesions, the main morbidity of Behcet's disease (BD), are the most difficult to treat. The aim of this study was to evaluate the efficacy of rituximab. METHODS: Inclusion criteria were retinal vasculitis and edema, resistant to cytotoxic drugs. Twenty patients were randomized to a rituximab group (RG) or cytotoxic combination therapy group (CCTG). Rituximab was given in two 1000-mg courses (15-day interval). Subjects received methotrexate (15 mg/weekly) with prednisolone (0.5 mg/kg per day). The CCTG received pulse cyclophosphamide (1000 mg/monthly), azathioprine (2-3 mg/kg per day) and prednisolone (0.5 mg/kg per day). The primary endpoint was the overall state of patients' eyes and the Total Adjusted Disease Activity Index (TADAI). Secondary endpoints were: visual acuity (VA), posterior uveitis (PU), and retinal vasculitis (RV). The baseline data were compared at 6 months by paired sample t test and analysis of variance. RESULTS: TADAI improved significantly in the RG (t = 3.340, P = 0.009), but not in the CCTG (t = 2.241, P = 0.052). For secondary endpoints (RG/CCTG), the mean VA improved in two patients versus three (2/3), remained unchanged in 1/1, and worsened in 7/6 patients. The mean PU improved significantly in the RG (t = 3.943, P = 0.001), not in the CCTG (t = 2.371, P = 0.028). RV improved, but not statistically (t = 2.027, P = 0.057 vs. t = 1.045, P = 0.31). Edema of retina, disc and macula improved significantly in both, but much better for the RG (t = 2.781, P = 0.012 vs. t = 2.707, P = 0.014). CONCLUSION: Rituximab was efficient in severe ocular manifestations of BD, TADAI improved significantly after 6 months with rituximab, but not with CCT. PMID- 20704623 TI - Pimecrolimus versus placebo in genital aphthous ulcers of Behcet's disease: a randomized double-blind controlled trial. AB - BACKGROUND: Genital aphthous ulcers of Behcet's disease (BD) are painful and usually resistant to local treatments. Pimecrolimus is an ascomycin macrolactam, used in inflammatory skin diseases. OBJECTIVE: To discover if pimecrolimus can accelerate the healing of BD genital aphthous ulcers. METHODS: Ninety patients with genital aphthous ulcers were enrolled. Only patients treated with colchicine alone were selected. All patients signed a written consent form. Patients were randomly assigned to pimecrolimus or placebo cream, applied twice daily for 1 week. The primary outcome was the healing period. Up to 7 days, it was considered as a positive result. Results were compared by chi-square test. The mean healing time was compared by analysis of variance. Analyses were done both by the 'intention-to-treat' and 'treatment-completed' methods. RESULTS: Both groups were similar at the entry (gender, age, ulcer size, pain intensity and treatment delay). By intention-to-treat analysis, in the pimecrolimus group, 18 patients had positive and 27 negative results. In the control group, four had positive and 41 negative results. The difference was significant (chi(2) = 10.167, P = 0.001). By treatment-completed analysis, with pimecrolimus, 18 patients had positive and 22 negative results. With placebo, four had positive, and 41 negative results. The difference was significant (chi(2) = 12.574, P = 0.0004). Comparison of mean healing time in the pimecrolimus versus placebo group, demonstrated a significant acceleration both in intention-to-treat analysis (10.7 vs. 20.7 days, F = 17.466, P < 0.0001) and treatment-completed analysis (8.3 vs. 20.7 days, F = 29.289, P < 0.0001). CONCLUSION: Pimecrolimus is safe and efficient in the treatment of BD genital ulcers, by accelerating the healing process. PMID- 20704624 TI - The frequency of low bone mineral density and its associated risk factors in patients with inflammatory bowel diseases. AB - OBJECTIVE: To detect the frequency and the predictive factors of low bone mineral density in inflammatory bowel disease (IBD) patients, so as to optimize bone mineral density (BMD) monitoring and treatment for those at risk. SUBJECTS AND METHODS: Thirty Asian patients were included in this study and were divided into 18 patients with ulcerative colitis (UC), and 12 patients with Crohn's disease (CD). All patients were diagnosed by colonoscopy and histopathological biopsy and were subjected to routine laboratory investigations in addition to 25 hydroxy vitamin D levels as well as serum calcium, phosphorus and alkaline phosphatise. BMD was measured by using dual-energy X-ray absorptiometry (DEXA) scan at lumbar spine and femoral neck; predictive factors for BMD were analyzed by group comparison and step-wise regression analysis. RESULTS: There was increased frequency of osteoporosis and osteopenia involving the lumbar spine in patients with IBD being more common among CD patients than in the UC group. Positive correlations were found between low BMD measurements and vitamin D levels, body mass index (BMI) (P < 0.001) as well as steroid cumulative dose and duration of therapy (P < 0.001); stepwise regression analysis showed that CD and vitamin D deficiency are predictive factors for both osteoporosis and osteopenia (P = 0.024, P = 0.027, respectively). CONCLUSION: Low BMD was found to be more frequent among patients with CD than UC; in addition CD and vitamin D deficiency act as predictive factors for low BMD. We recommend that calcium and vitamin D should be given to all IBD patients; in addition, bisphosphonate administration should be put into consideration. PMID- 20704625 TI - The effect of Kashin-Beck disease-affected feed and T-2 toxin on the bone development of Wistar rats. AB - OBJECTIVE: To investigate the effect of Kashin-Beck disease (KBD)-affected feed and T-2 toxin on the bone development of Wistar rats. METHODS: Seventy-eight ablactation Wistal rats (50% male and 50% female) weighing approximately 65 g were obtained from Sichuan Medical Center (Chengdu, China), and were randomly assigned to three groups (Groups A, B and C). Group A had 24 rats and were fed with commercial rat feed (control); Group B had 30 rats and were fed with commercial rat feed and T2 toxin by intragastric administration; and Group C had 24 rats and were fed with the KBD-affected feed. The histological sections were stained with hematoxylin and eosin (H&E) and Masson dye. RESULTS: Weight gain was fastest Group A rats and Group C rats had the lowest weight gain (P < 0.05). There were no epiphyseal plate chondrocyte necroses in the control group at the first, second, and fourth weeks. In the T-2 toxin group, two rats had chondrocyte focus necroses at the labrocyte cell zone at the second week. At the fourth week, six rats had chondrocyte-focus or lamellar necroses at the labrocyte cell zone. Three rats had focus necrosis at the proliferation cell zone, and there were three rats with penetration necrosis. In the KBD-affected group, one rat had chondrocyte-focus necrosis at the labrocyte cell zone at the second week and seven rats had chondrocyte-focus necrosis at the labrocyte cell zone at the fourth week. And at the same time, two rats had focus necrosis at the proliferation cell zone, three rats had lamellar necrosis at the labrocyte cell zone, four had focus necrosis at the labrocyte cell zone, and two rats had penetration necrosis. The epiphyseal plate Masson dye of the control group showed deep blue collogen coloration and in the KBD-affected group and T-2 toxin group, collogen showed a pale blue color, the drum dyeing was uneven, and the collogen was showed an absence of color in the region of the necrosis. CONCLUSIONS: With KBD-affected feed or T-2 toxin intervention, rats had focus necrosis and lamellar necrosis at the epiphyseal plate. KBD-affected feed rats had less weight gain than T-2 toxin intervention rats, which means there were other etiological factors in KBD-affected feed. PMID- 20704627 TI - Using evolutionary demography to link life history theory, quantitative genetics and population ecology. AB - 1. There is a growing number of empirical reports of environmental change simultaneously influencing population dynamics, life history and quantitative characters. We do not have a well-developed understanding of links between the dynamics of these quantities. 2. Insight into the joint dynamics of populations, quantitative characters and life history can be gained by deriving a model that allows the calculation of fundamental quantities that underpin population ecology, evolutionary biology and life history. The parameterization and analysis of such a model for a specific system can be used to predict how a population will respond to environmental change. 3. Age-stage-structured models can be constructed from character-demography associations that describe age-specific relationships between the character and: (i) survival; (ii) fertility; (iii) ontogenetic development of the character among survivors; and (iv) the distribution of reproductive allocation. 4. These models can be used to calculate a wide range of useful biological quantities including population growth and structure; terms in the Price equation including selection differentials; estimates of biometric heritabilities; and life history descriptors including generation time. We showcase the method through parameterization of a model using data from a well-studied population of Soay sheep Ovis aries. 5. Perturbation analysis is used to investigate how the quantities listed in summary point 4 change as each parameter in each character-demography function is altered. 6. A wide range of joint dynamics of life history, quantitative characters and population growth can be generated in response to changes in different character demography associations; we argue this explains the diversity of observations on the consequences of environmental change from studies of free-living populations. 7. The approach we describe has the potential to explain within and between species patterns in quantitative characters, life history and population dynamics. PMID- 20704626 TI - Value of serum and synovial fluid activin A and inhibin A in some rheumatic diseases. AB - AIM: The purpose of the study is to measure serum and synovial fluid levels of activin A and inhibin A in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and osteoarthritis (OA) and correlate them with disease activity parameters. SUBJECTS AND METHODS: This study included 60 patients with various rheumatic diseases (20 with RA, 20 with SLE and 20 with OA), as well as 10 healthy controls. All of them were subjected to complete history-taking, examination and estimation of disease activity index. The following investigations were done for all subjects: serum and synovial activin A, inhibin A, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-dsDNA and complements 3 and 4. RESULTS: Serum levels of activin A were significantly higher in RA, SLE and OA than controls and in RA and SLE versus OA The mean values of serum inhibin A were significantly higher in all studied groups than controls. Synovial activin A and inhibin A were significantly higher in RA than OA. Positive correlations were found between serum activin A and disease activity parameters of RA. In SLE, positive correlations were found between serum activin A and inhibin A with ESR and SLE Disease Activity Index. CONCLUSIONS: Serum activin A and inhibin A were significantly higher in RA and SLE. Serum levels correlated positively with disease activity parameters of RA and SLE. However, synovial levels were significantly higher in RA than OA but showed no correlation or negative correlation with disease activity. We recommend further studies to detect the exact role of activin A and inhibin A in these conditions. PMID- 20704628 TI - Measuring professional competency of public health nurses: development of a scale and psychometric evaluation. AB - AIMS AND OBJECTIVES: To develop an instrument to measure public health nurse competencies in Taiwan and to test its psychometric properties. BACKGROUND: Core competencies for public health nursing practice have been established in the USA and elsewhere but no equivalent studies have been undertaken in Taiwan. DESIGN: Postal survey of self-administered questionnaire to 1534 full-time public health nurses (response rate 67.3%). METHODS: The Public Health Nurse Professional Competency Scale was based on a literature review, the six key competencies identified by the Taiwan Nurses Association and the 'typical' tasks reported by nursing researchers. The scale comprised four domains and 38 items using a four point Likert scale. Validity and reliability of the scale were determined by a seven-member professional panel and the content validity calculated for each domain. Discriminatory power and the item-total correlation index were used to analyse and eliminate items. Convergent and discriminant validity were assessed and factor analysis to test the dimensions of the scale--stability was determined by interscale correlations, internal and test-retest reliability. RESULTS: The mean age of respondents was 40.6 years (SD 8.54) with the majority holding an associate degree (67.0%). Participants had worked for an average of 11.7 years (SD 9.20) and 74.4% held a registered nurse license. The scale had strong content validity (Indices > 0.8) and good test-retest reliability (Cronbach's alpha = 0.93-0.97). Nine items were excluded during factor analysis and three factors accounted for 46-82% of the total variance: (1) basic-care, (2) community health management and (3) combined teaching and self-development competencies. The scale had high discriminant validity. CONCLUSIONS: A Public Health Nurse Professional Competency Scale has been developed and shown to have good reliability and validity. RELEVANCE TO CLINICAL PRACTICE: The scale can be used to assess the competencies of Public Health Nurses in Taiwan and improve the quality of clinical services provided. PMID- 20704629 TI - Resurgence of bedbugs in southern France: a local problem or the tip of the iceberg? AB - BACKGROUND: Bedbugs (Cimex lectularius) have been feeding on sleeping human beings since prehistory. In Europe, bed bugs were common and endemic until World War II when improved body and home hygiene, and widespread use of insecticides led to almost complete eradication. Current evidence indicates that bedbugs are making a comeback in Europe, USA, Canada and Australia. In our practice in Southern France, we observed several cases within a period of only 1 year. OBJECTIVES: Based on this experience, we conducted an epidemiological study to evaluate the status of bedbugs in France. METHODS: During summer 2009, we mailed a short questionnaire to all hospital professors in the CEDEF (College des Enseignants de Dermatologie de France) asking four questions: number of suspected diagnosis of bedbugs in the year 2009, and number of certain positive diagnosis, difficulties in treatment, use of a pest control professional for treatment, and finally personal opinion on actual incidence of bedbugs, compared with past years. RESULTS: Of the 84 questionnaires sent, there were only 26 responses despite two reminders. The responses were predominantly southern France, probably as a result of intensive immigration and increased travel and trade. Difficulties encountered during diagnosis and treatment are also mentioned. Utilizing the services of entomological experts and pest control professionals is essential. CONCLUSIONS: France has the same experience regarding the resurgence of bedbugs as several European countries, USA, Canada and Australia, especially the southern regions. This emerging health problem has to be known by dermatologists. A national programme has been launched in France to assess actual incidence and study C. lectularius- related diseases. PMID- 20704630 TI - Can Internet surveys help us understanding allergic disorders? - results from a large survey in urticaria in Greece. AB - BACKGROUND: Urticaria is often underdiagnosed and/or undertreated. We have conducted an Internet-based study to record epidemiological and clinical features as well as therapeutic interventions for urticaria in a large sample of patients in Greece. METHODS: A standard anonymous questionnaire was posted for a 3-month period on 'http://www.in.gr', a Greek popular Internet portal. Each individual participated only once. Participants were screened for the presence or history of urticaria by two key questions and were then asked to provide information on symptomatology and management. RESULTS: A total of 12 396 subjects voluntarily responded to the survey, of which 8440 (5136 females) who reported to have or had urticaria, were finally analysed. A total of 4780 (56.6%) had experienced weals only, 507 (6.0%) angio-oedema only and 3018 (35.8%) both. Weals and angio-oedema were found to be more common in women; 2761(57.8%) and 277(54.6%), respectively. Age of onset significantly correlated with disease duration; a 1% higher possibility of longer duration of urticaria exists (more than 6 weeks compared with less than 6 weeks) for each additional year of age of onset after controlling for gender. Patients with chronic urticaria had increased mean age compared with those reporting the acute form (35.04 vs. 33.88 years, P < 0.001). Dermatologists were the most frequently visited specialists and the most common treatments were antihistamines and topical preparations. The self-reported eliciting factors of urticaria were as follows: physical stimuli (approximately 25%), psychological distress (17.2%), direct contact to metals or chemicals (14.5%), foods and drugs (10%), whereas a third of the participants could not identify any trigger. CONCLUSIONS: Internet surveys can be a useful tool for screening the general population for common allergic disorders, such as urticaria. PMID- 20704631 TI - Evidence-based medicine training and implementation in surgery: the role of surgical cultures. AB - PURPOSE: This qualitative study identifies cultural factors that influence the effective implementation of evidence-based medicine (EBM) in surgical practice among Australian surgeons. METHODS: In-depth interviews (n = 22) were conducted with surgeons from a variety of specialties within a large hospital system in Victoria, Australia. The interviews explored the surgeons' understanding of EBM; and challenges to the adoption of EBM. The canons and procedures of the Miles and Huberman's Matrix Analyses approach to qualitative research guided the coding and organization of the data derived from the semi-structured interviews. RESULTS: Surgeons had a good understanding of EBM, but viewed it as little more than a system of evidence, which was often divorced from actual clinical practice. The data also suggested that surgical culture(s) and typologies of surgical style were important variables in the implementation of EBM. The results suggest that the ideal method of EBM implementation is workplace instruction led by surgeons, who exhibit scientist and/or clinician styles of surgical practice; EBM training should occur early in the surgeons' careers; and EBM practice should be role modelled in the presence of trainees by surgeons who exhibit either a scientist and/or clinician style of surgical practice. CONCLUSIONS: The study findings suggest that using pre-existing surgical culture(s) and styles is an important component in the implementation of EBM in surgery. The effective use of the scientist and/or clinician surgeon within the apprenticeship model and the context-specific collegial networks of the surgical profession appear to be key elements in ensuring the successful implementation of EBM in surgery. PMID- 20704632 TI - Surgical specialization and training - its relation to clinical outcome for colorectal cancer surgery. AB - RATIONALE, AIMS AND OBJECTIVES: Surgical sub-specialization has been considered to be a major factor in improving cancer surgery-related outcomes in terms of 5 year survival and disease-free intervals. In this article we have looked at the evidence supporting the improvement in colorectal cancer outcomes with 'colorectal specialists' performing colon and rectal surgery. METHODS: A literature review was carried out using search engines such as Pubmed, Ovid and Cochrane Databases. Only studies looking at colorectal cancer outcome related to surgery were included in our review. RESULTS: Specialist surgeons performing a high volume of colorectal cancer surgery demonstrated better 5-year survival rates in patients, with less local recurrence. This was most evident in surgery for rectal cancer, where an association with increased sphincter saving surgery was also seen. Total mesorectal excision is now the accepted treatment for rectal cancer and has markedly improved survival rates and decreased local recurrence. CONCLUSION: The outcomes in colorectal surgery continue to steadily improve. The training of specialized colorectal surgeons is a major contributing factor towards this improvement. PMID- 20704633 TI - Reviewing methodologically disparate data: a practical guide for the patient safety research field. AB - This article addresses key questions frequently asked by researchers conducting systematic reviews in patient safety. This discipline is relatively young, and asks complex questions about complex aspects of health care delivery and experience, therefore its studies are typically methodologically heterogeneous, non-randomized and complex; but content rich and highly relevant to practice. Systematic reviews are increasingly necessary to drive forward practice and research in this area, but the data do not always lend themselves to 'standard' review methodologies. This accessible 'how-to' article demonstrates that data diversity need not preclude high-quality systematic reviews. It draws together information from published guidelines and experience within our multidisciplinary patient safety research group to provide entry-level advice for the clinician researcher new to systematic reviewing, to non-biomedical research data or to both. It offers entry-level advice, illustrated with detailed practical examples, on defining a research question, creating a comprehensive search strategy, selecting articles for inclusion, assessing study quality, extracting data, synthesizing data and evaluating the impact of your review. The article concludes with a comment on the vital role of robust systematic reviews in the continuing advancement of the patient safety field. PMID- 20704634 TI - The development of adaptive skills in young people with Down syndrome. AB - BACKGROUND: To help children with Down syndrome reach optimum levels of adaptive behaviour, caretakers need to know how and to what extent children with Down syndrome acquire adaptive skills. METHOD: The adaptive levels of motor, daily living, communicative and social behavioural skills were determined in a group of 984 Dutch children with Down syndrome, aged between 0 and 12 years, and compared with the adaptive levels of typically developing children using a Dutch version of the Vineland Screener. RESULTS: Children with Down syndrome acquire their adaptive skills at a slower pace and reach their ceiling scores at about the age of 12 years, at a substantially lower level than a reference group of typically developing children. CONCLUSIONS: Down children seem to acquire skills in a similar sequence and according to a similar trajectory. Development of adaptive skills varies greatly between participants with Down syndrome. For that reason, cohort studies on the development of individuals with Down syndrome over a prolonged period of time are needed. PMID- 20704635 TI - Distinguishing features of autism in boys with fragile X syndrome. AB - BACKGROUND: Males with fragile X syndrome and autism (FXS/autism) represent a distinct subgroup of males with FXS at risk for markedly poorer outcomes. Early identification and intervention can improve outcomes for males with autism spectrum disorder. METHOD: To advance the development of a specialised autism screening tool for young males with FXS that could assist in early identification, backward regression was used to identify the combination of parent-report questionnaire items that best predicted autism symptoms in a sample of 60 males with FXS, ages 4-18 years old. RESULTS: Both social and repetitive behaviours distinguished males with FXS/autism, with repetitive behaviours playing a more prominent role than previously documented in the literature. CONCLUSIONS: Healthcare workers and early interventionists may be able to interview parents about a few key behaviours to determine if young child with FXS should be formally evaluated for autism. Evidence-based practices identified for children with autism spectrum disorder can be implemented as early as possible. PMID- 20704636 TI - Hospitalisation rates for ambulatory care sensitive conditions for persons with and without an intellectual disability--a population perspective. AB - BACKGROUND: There is evidence that persons with an intellectual disability (ID) face barriers to primary care; however, this has not been extensively studied at the population level. Rates of hospitalisation for ambulatory care sensitive conditions are used as an indicator of access to, and quality of, primary care. The objective of the study was to compare hospitalisation rates for ambulatory care sensitive conditions between persons with and without an ID in a publicly insured population. METHODS: Persons with an ID were identified among the general population of a Canadian province between 1999 and 2003. Using a list of conditions applicable to persons with an ID, rates of hospitalisations for ambulatory care sensitive conditions for persons with and without an ID were calculated and compared. Regression models were used to adjust for age, sex and place of residence. Hospitalisation rates for specific conditions were also compared, controlling for differences in disease prevalence where possible. RESULTS: Persons with an ID were consistently hospitalised for ambulatory care sensitive conditions at a higher rate than persons without an ID. Between 1999 and 2003 the adjusted rate ratio (RR) was 6.1 [95% confidence interval (CI) = 5.6, 6.7]. Rate ratios were highest when comparing persons with, to persons without, an ID between the ages of 30-39 (RR = 13.1; 95% CI = 10.6, 16.2) and among urban area dwellers (RR = 7.0; 95% CI = 6.2, 7.9). Hospitalisation rates for epilepsy and schizophrenic disorders were, respectively, 54 and 15 times higher for persons with compared with persons without an ID. Rate ratios for diabetes and asthma remained significant after controlling for the population prevalence of these diseases. CONCLUSIONS: The large discrepancy in rates of hospitalisation between persons with and without an ID is an indicator of inadequate primary care for this vulnerable population. Decreasing the number of ambulatory care sensitive condition hospitalisations through specialised outpatient programmes for persons with an ID would potentially lead to better health, improved quality of life and cost savings. Future research should include potentially important factors such as disease severity, socio-economic variables and measures of health service organisation in the analysis. International comparisons of ambulatory care sensitive condition hospitalisation rates could point to the benefits and limitations of the health service policy directions adopted by different countries. PMID- 20704639 TI - The effectiveness of 2-implant overdentures - a pragmatic international multicentre study. AB - The purpose of this multicentre observational study was to determine patient satisfaction with either conventional dentures or mandibular 2-implant overdentures in a 'real world' setting. Two hundred and three edentulous patients (mean age 68.8 +/- 10.4 years) were recruited at eight centres located in North America, South America and Europe. The patients were provided with new mandibular conventional dentures or implant overdentures supported by two implants and ball attachments. At baseline and at 6 months post-treatment, they rated their satisfaction with their mandibular prostheses on 100-mm visual analogue scale questionnaires. One hundred and two (50.2%) participants had valid baseline and 6 month satisfaction data. Although both groups reported improvements, the implant overdenture group reported significantly higher ratings of overall satisfaction, comfort, stability, ability to speak and ability to chew. These results suggest that edentulous patients who choose mandibular implant overdentures have significantly greater improvements in satisfaction, despite their relatively higher cost, than those who choose new conventional dentures. PMID- 20704640 TI - Sexual function in a woman with congenital bladder exstrophy and multiple pelvic reconstructive surgeries: a case report. AB - INTRODUCTION: Bladder exstrophy is a rare congenital anomaly isolated to the fetal genitourinary tract. In our patient, this defect necessitated removal of her bladder in her childhood and a distal neovaginoplasty in adolescence. Despite these surgeries, as well as several procedures for pelvic organ prolapse, the patient reports excellent sexual function and ability to achieve vaginal orgasms. AIM: (i) To report on the sexual function of a woman without a bladder or urethra who has undergone multiple pelvic reconstructive surgeries; and (ii) to correlate her self-reported erotic areas with magnetic resonance imaging (MRI) assessment. METHODS: The patient completed a detailed sexual history, the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS), the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12), and the Health Survey Short Form (SF-12). Photodocumentation of her erotic tissue was correlated with a pelvic MRI with contrast. RESULTS: The patient reports ability to achieve vaginal orgasms 100% of the time. Her FSFI score was 29.4/36 with maximum scores noted in arousal, lubrication, orgasm and satisfaction. Her FSDS score was 7/48, which implies no sexually related distress. Her PISQ-12 score was 10/48, demonstrating a small impact on her sexual function related to her pelvic organ prolapse. Her SF-12 scores were 36.6 and 57.9. Photography and mapping of her erotic areas illustrated the superficial and anterior locations of the vaginal opening to be the sites of orgasm. MRI correlated these exact locations with clitoral tissue. CONCLUSION: Intact sexual function is possible in patients after reconstructive surgery for congenital bladder exstrophy. Due to the superficial location of her clitoris and separation of the pubic rami associated with this anatomic variant, sexual function may be enhanced. PMID- 20704641 TI - The serotonin transporter plays an important role in male sexual behavior: a study in serotonin transporter knockout rats. AB - INTRODUCTION: Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels. AIM: To investigate the putative role of the SERT in male sexual behavior. METHODS: After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist +/- 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/ ) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined. MAIN OUTCOME MEASURES: Male rat sexual behaviors of mounts, intromissions, and ejaculations. RESULTS: SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. +/- 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of +/- 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by +/- 8-OH-DPAT of the sexual inhibitory effects of WAY100635. CONCLUSIONS: Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of +/- 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido. PMID- 20704642 TI - Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). AB - INTRODUCTION: Addition of testosterone (T) may improve the action of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with erectile dysfunction not responding to PDE5-Is with low or low-normal T levels. AIMS: To confirm this add-on effect of T in men optimally treated with PDE5-Is and to specify the baseline T levels at which such an effect becomes significant. METHODS: A multicenter, multinational, double-blind, placebo-controlled study of 173 men, 45-80 years, nonresponders to treatment with different PDE5-Is, with baseline total T levels <= 4 ng/mL or bioavailable T <= 1 ng/mL. Men were first treated with tadalafil 10 mg once a day (OAD) for 4 weeks; if not successful, they were randomized in a double-blind, placebo-controlled design to receive placebo or a 1% hydroalcoholic T gel (50 mg/5 g gel), to be increased to 10 mg T if results were clinically unsatisfactory. Main Outcomes Measures. Mean change from baseline in the Erectile Function Domain Score of the International Index of Erectile Function and rate of successful intercourses (Sexual Encounter Profile 3 question). RESULTS: Erectile function progressively improved over a period of at least 12 weeks in both the placebo and T treatment groups. In the overall population with a mean baseline T level of 3.37 +/- 1.48 ng/mL, no additional effect of T administration to men optimally treated with PDE5-Is was encountered. The differences between the T and placebo groups were significant for both criteria only in the men with baseline T <= 3 ng/mL. CONCLUSIONS: The maximal beneficial effects of OAD dosing with 10 mg tadalafil may occur only after as many as 12 weeks. Furthermore, addition of T to this PDE5-I regimen is beneficial, but only in hypogonadal men with baseline T levels <= 3 ng/mL. PMID- 20704643 TI - Sexual complaints, pelvic floor symptoms, and sexual distress in women over forty. AB - INTRODUCTION: The American Psychiatric Association recommends considering sexually related personal distress when assessing female sexual dysfunction. Currently, there is little data regarding the impact of sexual complaints on sexual distress. AIM: To investigate the association between sexual complaints and perceived sexual distress in a population of ambulatory adult women. METHODS: Using the short forms of the Personal Experiences Questionnaire and Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire, we assessed sexual complaints among 305 women seeking outpatient gynecologic care. Depressive symptoms were quantified using the Center for Epidemiologic Studies Depression (CESD) score. Sexual distress was measured using the Female Sexual Distress Scale (FSDS). Using multivariable logistic regression, we compared sexual complaints between distressed and nondistressed women. MAIN OUTCOME MEASURES: Sexual distress, defined by FSDS score >=15. RESULTS: FSDS scores were available for 292/305 participants. Seventy-six (26%) scores reflected distress. Distressed women were more likely to be younger (55.2+/-1.0 years vs. 56.7+/-0.8 years, P=0.017); have higher CESD scores (16.6 vs. 9.5, P=0.001); and report decreased arousal (56.8% vs. 25.1%, P=0.001), infrequent orgasm (54% vs. 28.8%, P=0.001), and dyspareunia (39.7% vs. 10.6%, P=0.001). Women with sexual distress were also more likely to report sexual difficulty related to pelvic floor symptoms, including urinary incontinence with sexual activity (9% vs. 1.3%, P=0.005), sexual avoidance due to vaginal prolapse (13.9% vs. 1%, P=0.001), or sexual activity restriction due to fear of urinary incontinence (14.9% vs. 0.5%, P=0.001). After multivariate analysis, sexual distress was significantly associated with dyspareunia (odds ratio [OR] 3.11, P=0.008) and depression score (OR 1.05, P=0.006), and inversely associated with feelings of arousal during sex (OR 0.19, P=0.001). CONCLUSION: Our results indicate that sexually related personal distress is significantly associated with dyspareunia, depressive symptoms, and decreased arousal during sexual activity. This contributes to our understanding of how sexual complaints may adversely affect women's quality of life. PMID- 20704644 TI - Chronic sleep curtailment impairs the flexible implementation of task goals in new parents. AB - Chronic sleep curtailment is a major concern for health in Western societies. Yet, research on potential consequences of long-term sleep curtailment on cognitive functions is still scarce. The present study investigated the link between chronic sleep limitation and executive functions that enable adaptation to changing environmental demands, i.e. the ability to flexibly implement task goals. To address the effects of chronic sleep restriction under real-life conditions, we considered a sample of adults who often suffer from reduced sleep durations over many months. One-hundred and six new parents (infant's age: 6 18months) were assigned to a sleep-curtailed group (<7h of nighttime sleep) and a non-sleep-curtailed group (>=7h of nighttime sleep), respectively, based on their self-reported average nighttime sleep duration over the preceding 6months. The ability to implement task goals was addressed applying a task-switching paradigm in which participants randomly switched between two tasks. While the two groups did not differ with regard to overall performance level, number of nighttime awakenings, naps during the day, daytime sleepiness, mood, chronic stress level and subjectively perceived cognitive capability, sleep-curtailed new parents showed higher costs for switching between tasks compared with repeating a task than non-sleep-curtailed new parents. This finding on the group level was further substantiated by a negative correlation between nighttime sleep duration and switch costs. With this study, we provide the first evidence for an impairment of the ability to flexibly implement task goals in chronically sleep-deprived new parents and, thus, for a link between chronic sleep curtailment and executive functions. PMID- 20704645 TI - Sleep/wake measurement using a non-contact biomotion sensor. AB - We studied a novel non-contact biomotion sensor, which has been developed for identifying sleep/wake patterns in adult humans. The biomotion sensor uses ultra low-power reflected radiofrequency waves to determine the movement of a subject during sleep. An automated classification algorithm has been developed to recognize sleep/wake states on a 30-s epoch basis based on the measured movement signal. The sensor and software were evaluated against gold-standard polysomnography on a database of 113 subjects [94 male, 19 female, age 53+/ 13years, apnoea-hypopnea index (AHI) 22+/-24] being assessed for sleep-disordered breathing at a hospital-based sleep laboratory. The overall per-subject accuracy was 78%, with a Cohen's kappa of 0.38. Lower accuracy was seen in a high AHI group (AHI >15, 63 subjects) than in a low AHI group (74.8% versus 81.3%); however, most of the change in accuracy can be explained by the lower sleep efficiency of the high AHI group. Averaged across subjects, the overall sleep sensitivity was 87.3% and the wake sensitivity was 50.1%. The automated algorithm slightly overestimated sleep efficiency (bias of +4.8%) and total sleep time (TST; bias of +19min on an average TST of 288min). We conclude that the non contact biomotion sensor can provide a valid means of measuring sleep-wake patterns in this patient population, and also allows direct visualization of respiratory movement signals. PMID- 20704646 TI - Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. AB - BACKGROUND: Although women with antiphospholipid antibodies (APLAs) are at increased risk of recurrent miscarriage, the outcome of a subsequent pregnancy is not clearly elucidated. OBJECTIVES: To assess the pregnancy outcome of a subsequent pregnancy in women with APLAs and compare this outcome with women with unexplained recurrent miscarriage. METHODS: We performed a cohort study among all women who attended the Miscarriage Clinic at Liverpool Women's Hospital between 1987 and 2006 after being referred due to recurrent miscarriage (>=2 consecutive pregnancy losses). All women underwent a standardized investigation sequence. Women with other reasons for recurrent miscarriage were excluded. RESULTS: A total of 693 women fulfilled the selection criteria, of whom 176 (25%) had APLAs. One hundred and twenty-two (69%) women with APLAs had a subsequent live birth compared with 324 (63%) women with unexplained recurrent miscarriage (OR 1.3, 95% CI 0.9-1.9). No differences were found for birth weight, gestational age, and intra-uterine growth restriction. When treatment was analyzed, 53/67 (79%) of women with APLAs who had received aspirin and heparin during their pregnancy had a live birth, compared with 64/104 (62%) of women with APLAs who received aspirin only (adjusted OR 2.7, 95% CI 1.3-5.8). In unexplained recurrent miscarriage, stratification for treatment showed no differences in outcome. CONCLUSION: The prognosis of a subsequent pregnancy in women with APLAs is good. Although this was not a randomized clinical trial, combined treatment of aspirin and heparin seemed associated with a better outcome in women with APLAs, but not in women with unexplained recurrent miscarriage. PMID- 20704647 TI - Thrombin-activatable fibrinolysis inhibitor is degraded by Salmonella enterica and Yersinia pestis. AB - BACKGROUND: Pathogenic bacteria modulate the host coagulation system to evade immune responses or to facilitate dissemination through extravascular tissues. In particular, the important bacterial pathogens Salmonella enterica and Yersinia pestis intervene with the plasminogen/fibrinolytic system. Thrombin-activatable fibrinolysis inhibitor (TAFI) has anti-fibrinolytic properties as the active enzyme (TAFIa) removes C-terminal lysine residues from fibrin, thereby attenuating accelerated plasmin formation. RESULTS: Here, we demonstrate inactivation and cleavage of TAFI by homologous surface proteases, the omptins Pla of Y. pestis and PgtE of S. enterica. We show that omptin-expressing bacteria decrease TAFI activatability by thrombin-thrombomodulin and that the anti fibrinolytic potential of TAFIa was reduced by recombinant Escherichia coli expressing Pla or PgtE. The functional impairment resulted from C-terminal cleavage of TAFI by the omptins. CONCLUSIONS: Our results indicate that TAFI is degraded directly by the omptins PgtE of S. enterica and Pla of Y. pestis. This may contribute to the ability of PgtE and Pla to damage tissue barriers, such as fibrin, and thereby to enhance spread of S. enterica and Y. pestis during infection. PMID- 20704649 TI - von Willebrand factor clearance does not involve proteolysis by ADAMTS-13. PMID- 20704648 TI - In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study. AB - BACKGROUND: Twenty-five percent of new anti-factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non-severe disease, its strength of association and the influence of other factors have remained undefined. OBJECTIVE: To evaluate risk factors for inhibitor development in patients with non-severe hemophilia A. METHODS: Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor. RESULTS: Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those >=30years of age compared with those <30years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76-57.81 vs. OR 2.54; 95% CI, 0.61-10.68]. Having previously received <50days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis. CONCLUSIONS: These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A. PMID- 20704650 TI - Quantification of viral DNA and liver enzymes in plasma improves early diagnosis and management of herpes simplex virus hepatitis. AB - Herpes simplex virus (HSV) hepatitis is a rare and potential life-threatening disease. The diagnosis of HSV hepatitis is hampered by its indifferent clinical presentation, which necessitates confirmatory laboratory data to identify HSV in the affected liver. However, liver biopsies are often contraindicated in the context of coagulopathy, are prone to sampling errors and have low sensitivity in mild HSV hepatitis cases. There is an unmet need for less invasive diagnostic tools. The diagnostic and therapeutic value of HSV DNA load and liver enzyme level kinetics was determined in five patients with HSV hepatitis and twenty disease controls with HSV-DNAemia without hepatitis. At time of hospitalization, patients with HSV hepatitis had a higher median (+/- interquartile range) HSV DNA load (6.0 * 10(6) +/- 1.2 * 10(9)) compared to disease controls (171 +/- 2845). Viral DNA load correlated with liver transaminase levels and disease severity. Antiviral treatment led to rapid decline of HSV DNA load and improvement of liver function of patients with HSV hepatitis. The data advocate the prompt and consecutive quantification of the HSV DNA load and liver enzyme levels in plasma of patients suspected of HSV hepatitis as well as those under antiviral treatment. PMID- 20704651 TI - Determination of microbial diversity in meju, fermented cooked soya beans, using nested PCR-denaturing gradient gel electrophoresis. AB - AIMS: To identify the microbiota in meju, fermented cooked soya beans, that may directly affect the microbial communities of Korean fermented soya bean foods. METHODS AND RESULTS: Using conventional bacterial 16S rDNA, bacilli-specific 16S rDNA or fungi 18S rDNA-specific primers, PCR products were amplified through a series of PCRs using the DNA extracted from ten meju samples. The amplicons were analysed using denaturing gradient gel electrophoresis (DGGE), which showed that Enterococcus durans was commonly detected in nine of ten meju samples. Bacillus subtilis was shown to be the major strain of bacilli in the samples tested. Based on the DGGE analysis of fungi in meju, we determined that Absidia corymbifera, Aspergillus sp. and Candida rugosa were the main fungi in the tested samples. CONCLUSIONS: A variety of bacterial and fungal micro-organisms were identified in meju samples, in addition to the micro-organisms already known to be present. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report showing the differences and similarities in the populations of micro-organisms in meju samples using nested PCR-DGGE, a culture-independent method. The results may be applicable to the development of improved meju, in which the indigenous micro organisms required for fermentation can be standardized. PMID- 20704652 TI - Assessment of hepatic fibrosis by analysis of the dynamic behaviour of microbubbles during contrast ultrasonography. AB - BACKGROUND/AIMS: Microbubble behaviour from the portal vein to the liver parenchyma may reflect haemodynamic changes because of hepatic fibrosis. The aim of this study was to determine the efficacy of contrast-enhanced ultrasound (US) with SonazoidTM for the assessment of the grade of hepatic fibrosis. METHODS: This prospective study evaluated 117 patients with chronic liver disease (chronic hepatitis 85; cirrhosis 32) and 34 controls. All subjects received both contrast enhanced US with SonazoidTM for 1 min after the agent injection and subsequent liver biopsy. Flow velocity and flow volume in the right portal vein, onset time of contrast enhancement in the right hepatic artery and right portal vein, maximum intensity ratio between the intra-hepatic portal vein and liver parenchyma, and time interval between the onset time and the time of maximum intensity ratio were compared with the pathological findings. RESULTS: Among the evaluated parameters, time interval between the onset time and the time of maximum intensity ratio showed the closest relationship with the grade of hepatic fibrosis: 4.21 +/- 1.32 for controls (n=34), 5.58 +/- 1.39 for F1 (n=31), 6.79 +/ 1.77 for F2 (n=28), 8.85 +/- 1.97 for F3 (n=26) and 14.3 +/- 3.49 for cirrhosis (n=32); controls vs. F2, P=0.0004; F1 vs. F3, P<0.0001; F2 vs. F3, P=0.0177; F3 vs. cirrhosis, P<0.0001. The areas under the receiver operating characteristic curves of the time interval were 0.94, 0.96 and 0.98 for the diagnosis of marked fibrosis (>=F2), advanced fibrosis (>=F3) and cirrhosis respectively. CONCLUSIONS: Contrast-enhanced US with SonazoidTM may be a promising method for the indirect evaluation of hepatic fibrosis. PMID- 20704653 TI - The influence of host number on the attraction of biting midges, Culicoides spp., to light traps. AB - A preliminary study was undertaken to investigate how the number of sheep below a light-suction trap affects the number of female Culicoides obsoletus Meigen (Diptera: Ceratopogonidae) caught. As the number of sheep increased from zero to three, the number of midges caught increased, but there appeared to be no further increase when six sheep were used. The lack of increase between three and six sheep is attributable to different activity rates on certain nights, perhaps in response to weather, and suggests, therefore, that catches in light traps increase linearly with sheep numbers, at least for small host numbers. PMID- 20704654 TI - Evaluating levels of PCR efficiency and genotyping error in DNA extracted from engorged and non-engorged female Dermacentor variabilis ticks. AB - Polymerase chain reaction (PCR)-based methods are increasingly used to elucidate tick biology. However, DNA extracted from ticks may provide poor PCR templates as a result of PCR inhibition by mammalian blood or contamination by male DNA (in fertilized females). In this study, the effects of removing the bloodmeal and reproductive organs were evaluated through paired DNA extractions in engorged and non-engorged Dermacentor variabilis (Say) (Acari: Ixodidae), prior to PCR amplification at 12 microsatellites. The first extraction utilized only mouthparts and legs ('mouthpart' samples) and the second utilized tick bodies ('body' samples). The results indicated that contamination by male DNA was an unlikely source of genotyping error in mouthpart and body samples. Engorged females showed higher levels of PCR inhibition in body vs. mouthpart samples, with a 29% decrease in amplification success rates per PCR and a 10-fold increase in levels of missing genotypes in body samples. By contrast, non-engorged females showed little difference in amplification success rates or numbers of missing genotypes in body vs. mouthpart samples. We discuss analytical concerns related to this systematic bias in PCR problems and recommend the removal of the bloodmeal and reproductive organs prior to DNA extraction, especially in engorged female ticks. PMID- 20704655 TI - Real-time and multiplex real-time polymerase chain reactions for the detection of Bartonella henselae within cat flea, Ctenocephalides felis, samples. AB - Bartonella henselae (Rhizobiales: Bartonellacae), the agent of cat-scratch disease, is an emerging bacterial pathogen which can be transmitted via infective faecal material of Ctenocephalides felis Bouche (Siphonaptera: Pulicidae). Worldwide, B. henselae has been identified in 1-53% of felines and 2.9-17.4% of fleas. Although culture is the routine method for detection, the procedure is time-consuming and is rarely used for isolation directly from flea vectors. The current study reports the development of a quantitative real-time polymerase chain reaction (qPCR) to detect and quantify B. henselae organisms from vector samples. The qPCR is specific and detects as few as 2.5 genome copies. To enable direct quantification of Bartonella organisms in different vector samples, we developed a qPCR to detect C. felis DNA that also acts as an extraction control. Combining both PCRs into a multiplex format validates B. henselae results when sampling flea populations, although there is a reduction in sensitivity. This reduction might be counteracted by a different combination of probe fluorophores. PMID- 20704656 TI - Tumour vasculature and angiogenic profile of paediatric pilocytic astrocytoma; is it much different from glioblastoma? AB - AIMS: Pilocytic astrocytomas are the most frequent brain tumours in children. Because of their high vascularity, this study aimed to obtain insights into potential angiogenic related therapeutic targets in these tumours by characterization of the vasculature and the angiogenic profile. In this study 59 paediatric pilocytic astrocytomas were compared with 62 adult glioblastomas, as a prototype of tumour angiogenesis. METHODS: Microvessel density, vessel maturity in terms of basement membrane and pericyte coverage, and turnover of both endothelial and tumour cells, and vascular endothelial growth factor (VEGF) expression were evaluated in tumour tissue, immunohistochemically stained with, respectively, CD34, collagen IV, smooth muscle actin, Ki67/CD34, caspase-3/CD34 and VEGF(-A-D). As an indicator for vessel stability the angiopoietin (ANGPT) 1/ANGPT-2 balance was calculated using Real Time RT-PCR. RESULTS: Pilocytic astrocytoma and glioblastoma showed similar fractions of vessels covered with basement membrane and pericytes. Overlapping ANGPT-1/ANGPT-2 balance and VEGF-A expression were found. Pilocytic astrocytoma had fewer but wider vessels compared with glioblastoma. Turnover of endothelial and tumour cells were relatively lower in pilocytic astrocytoma. Within pilocytic astrocytoma, higher ANGPT-1/ANGPT-2 balance was correlated with fewer apoptotic endothelial cells. Lower numbers of vessels were correlated with higher VEGF-A expression. CONCLUSIONS: Despite the fact that pilocytic astrocytoma showed a different vessel architecture compared with glioblastoma, a critical overlap in vessel immaturity/instability and the angiogenic profile was seen between both tumours. These findings suggest encouraging possibilities for targeting angiogenesis (for instance with anti VEGF) as a therapeutic strategy in pilocytic astrocytoma. PMID- 20704658 TI - The moss Physcomitrella patens contains cyclopentenones but no jasmonates: mutations in allene oxide cyclase lead to reduced fertility and altered sporophyte morphology. AB - * Two cDNAs encoding allene oxide cyclases (PpAOC1, PpAOC2), key enzymes in the formation of jasmonic acid (JA) and its precursor (9S,13S)-12-oxo-phytodienoic acid (cis-(+)-OPDA), were isolated from the moss Physcomitrella patens. * Recombinant PpAOC1 and PpAOC2 show substrate specificity against the allene oxide derived from 13-hydroperoxy linolenic acid (13-HPOTE); PpAOC2 also shows substrate specificity against the allene oxide derived from 12-hydroperoxy arachidonic acid (12-HPETE). * In protonema and gametophores the occurrence of cis-(+)-OPDA, but neither JA nor the isoleucine conjugate of JA nor that of cis (+)-OPDA was detected. * Targeted knockout mutants for PpAOC1 and for PpAOC2 were generated, while double mutants could not be obtained. The DeltaPpAOC1 and DeltaPpAOC2 mutants showed reduced fertility, aberrant sporophyte morphology and interrupted sporogenesis. PMID- 20704659 TI - Stomatal index responses of Agrostis canina to CO2 and sulphur dioxide: implications for palaeo-[CO2] using the stomatal proxy. AB - * Stomatal index values of fossil plants are widely used in reconstructing palaeo [CO(2)]. This depends upon the assumption that the stomatal index is determined by the atmospheric concentration of CO(2) ([CO(2)]). This study investigates whether fumigation with, and resistance to, sulphur dioxide (SO(2)) induces a reduction in the stomatal index that may affect stomatal reconstructions of palaeo-[CO(2)] coinciding with episodes of global-scale volcanism. * Agrostis canina from Mefite di Ansanto, Italy, grow in atmospheres of elevated-[CO(2)], SO(2) and hydrogen sulphide (H(2)S). Mefite A. canina were compared with a control population in a 'common-garden' experiment and a controlled-environment study under elevated-[CO(2)] and SO(2) fumigation. * In A. canina, resistance to toxic volcanic gases is not associated with reduced stomatal index, and fumigation with SO(2) does not cause a decrease in stomatal initiation. The two populations of A. canina analyzed in this study exhibit different stomatal index [CO(2)] 'responses', with control plants showing a reduction in stomatal index and Mefite plants showing no response. * Stomatal reconstructions of palaeo [CO(2)] during past episodes of global-scale volcanism probably reflect atmospheric [CO(2)] and not [SO(2)]. The lack of a reduction in the stomatal index in response to elevated [CO(2)] in the Mefite plants, suggests that resistance to toxic gases and/or long-term growth at high [CO(2)] reduces, or negates, sensitivity of the stomatal index-[CO(2)] relationship, or that stomatal index-[CO(2)] in the Mefite plants is attuned to [CO(2)] fluctuations at much higher concentrations. PMID- 20704660 TI - Accumulation of chlorophyll catabolites photosensitizes the hypersensitive response elicited by Pseudomonas syringae in Arabidopsis. AB - * The staygreen (SGR) gene encodes a chloroplast-targeted protein which promotes chlorophyll degradation via disruption of light-harvesting complexes (LHCs). * Over-expression of SGR in Arabidopsis (SGR-OX) in a Columbia-0 (Col-0) background caused spontaneous necrotic flecking. To relate this to the hypersensitive response (HR), Col-0, SGR-OX and RNAi SGR (SGRi) lines were challenged with Pseudomonas syringae pv tomato (Pst) encoding the avirulence gene avrRpm1. Increased and decreased SGR expression, respectively, accelerated and suppressed the kinetics of HR-cell death. In Col-0, SGR transcript increased at 6 h after inoculation (hai) when tissue electrolyte leakage indicated the initiation of cell death. * Excitation of the chlorophyll catabolite pheophorbide (Pheide) leads to the formation of toxic singlet oxygen ((1)O(2)). Pheide was first detected at 6 hai with Pst avrRpm1 and was linked to (1)O(2) generation and correlated with reduced Pheide a oxygenase (PaO) protein concentrations. The maximum quantum efficiency of photosystem II (F(v)/F(m)), quantum yield of electron transfer at photosystem II (phiPSII), and photochemical quenching (qP) decreased at 6 hai in Col-0 but not in SGRi. Disruption of photosynthetic electron flow will cause light-dependent H(2)O(2) generation at 6 hai. * We conclude that disruption of LHCs, possibly influenced by SGR, and absence of PaO produce phototoxic chlorophyll catabolites and oxidative stress leading to the HR. PMID- 20704661 TI - A maturation model for midazolam clearance. AB - BACKGROUND: Physiological-based pharmacokinetic models have been used to describe midazolam clearance (CL) maturation. There are no maturation descriptors of CL from neonate to adulthood based on reported estimates at different ages. METHODS: Published CL estimates after intravenous administration from time-concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed effects models. RESULTS: There were 16 publications reporting an estimate of CL after intravenous administration in children, although few estimates were available from 44-80 weeks postmenstrual age (PMA). CL maturation, standardized to a 70 -kg person was described using the Hill equation. Mature CL was 523 (CV 32%, 95%CI 469, 597) ml.min(-1) .70 kg(-1) . The maturation half-time was 73.6 (95%CI 59.4, 80.0) weeks PMA and the Hill coefficient 3 (95%CI 2.2, 4.1). Predicted CL changes with age based on this model were in close agreement with physiologically based pharmacokinetic (PBPK) models. A comparison with a published PBPK model predictions revealed a root mean squared prediction error (precision) of 4.0% (95%CI 1.1, 5.8) and bias was -0.9% (95%CI 4.3, 2.6). CONCLUSIONS: Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. If a midazolam sedation target concentration of 0.1 mg.l(-1) , similar to that given to adults, is assumed, then we might anticipate steady-state infusion rates of 0.014 mg.kg(-1) .h(-1) in neonates, 0.05 mg.kg(-1) .h(-1) in a 1-year-old, 0.06 mg.kg(-1) .h(-1) in a 5-year-old and 0.05 mg.kg(-1) .h(-1) in a 12-year-old child. Age-related pharmacodynamic differences that will affect dose and the impact of active metabolites on response are not yet quantified. PMID- 20704662 TI - Demystifying lumbar transforaminal epidural steroids: a seminal efficacy study of a specific spinal injection. PMID- 20704663 TI - Identifying mechanisms underlying the pain and disability relationship in later life: what role does the brain play? PMID- 20704664 TI - Complex regional pain syndrome workshop at Cardiff: editorial. PMID- 20704666 TI - The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. AB - BACKGROUND: Transforaminal injection of steroids is used to treat lumbar radicular pain. Not known is whether the route of injection or the agent injected is significant. STUDY DESIGN: A prospective, randomized study compared the outcomes of transforaminal injection of steroid and local anesthetic, local anesthetic alone, or normal saline, and intramuscular injection of steroid or normal saline. Patients and outcome evaluators were blinded as to agent administered. METHODS: The primary outcome measure was the proportion of patients who achieved complete relief of pain, or at least 50% relief, at 1 month after treatment. Secondary outcome measures were function, disability, patient specified functional outcomes, use of other health care, and duration of relief beyond 1 month. RESULTS: A significantly greater proportion of patients treated with transforaminal injection of steroid (54%) achieved relief of pain than did patients treated with transforaminal injection of local anesthetic (7%) or transforaminal injection of saline (19%), intramuscular steroids (21%), or intramuscular saline (13%). Relief of pain was corroborated by significant improvements in function and disability, and reductions in use of other health care. Outcomes were equivalent for patients with acute or chronic radicular pain. Over time, the number of patients who maintained relief diminished. Only some maintained relief beyond 12 months. The proportions of patients doing so were not significantly different statistically between groups. DISCUSSION: Transforaminal injection of steroids is effective only in a proportion of patients. Its superiority over other injections is obscured when group data are compared but emerges when categorical outcomes are calculated. Over time, the proportion of patients with maintained responses diminishes. PMID- 20704667 TI - Low-level laser therapy for acute neck pain with radiculopathy: a double-blind placebo-controlled randomized study. AB - OBJECTIVE: The objective of the study was to investigate clinical effects of low level laser therapy (LLLT) in patients with acute neck pain with radiculopathy. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: The study was carried out between January 2005 and September 2007 at the Clinic for Rehabilitation at the Medical School, University of Belgrade, Serbia. PATIENTS AND INTERVENTION: Sixty subjects received a course of 15 treatments over 3 weeks with active or an inactivated laser as a placebo procedure. LLLT was applied to the skin projection at the anatomical site of the spinal segment involved with the following parameters: wavelength 905 nm, frequency 5,000 Hz, power density of 12 mW/cm(2), and dose of 2 J/cm(2), treatment time 120 seconds, at whole doses 12 J/cm(2). OUTCOME MEASURES: The primary outcome measure was pain intensity as measured by a visual analog scale. Secondary outcome measures were neck movement, neck disability index, and quality of life. Measurements were taken before treatment and at the end of the 3-week treatment period. RESULTS: Statistically significant differences between groups were found for intensity of arm pain (P = 0.003, with high effect size d = 0.92) and for neck extension (P = 0.003 with high effect size d = 0.94). CONCLUSION: LLLT gave more effective short-term relief of arm pain and increased range of neck extension in patients with acute neck pain with radiculopathy in comparison to the placebo procedure. PMID- 20704668 TI - Introduction to CRPS special issue. PMID- 20704669 TI - Objectification of the diagnostic criteria for CRPS. AB - The current diagnostic criteria for complex regional pain syndrome (CRPS), codified by the International Association for the Study of Pain's taxonomy committee, and newer statistically derived criteria (the "Budapest" criteria), are both deliberately based on bedside testing. Designing criteria that are accessible to any clinician, not requiring any special equipment or training, is very important for clinical diagnosis. However, that approach, albeit pragmatic, forces a very heavy reliance on the subjective (not only the subjective response of the patient, but the subjective impression of the clinician). This is very problematic scientifically and statistically. Fortunately, with some new technologies and new approaches to old technologies, significant improvements can be made not only in terms of quantification, but also in allowing significant objectification of the diagnostic data. We will initiate a discussion of some of these potentially useful approaches. PMID- 20704670 TI - Plasticity of complex regional pain syndrome (CRPS) in children. AB - Complex regional pain syndrome I (CRPS I) is defined by the International Association for the Study of Pain (IASP) criteria to include pain that is disproportionate to the inciting event, sensory disturbances such as allodynia/ hyperalgesia, autonomic dysfunction, and motor dysfunction that usually occurs after trauma that is frequently trivial and generally expressed in an extremity. These symptoms are well described in the adult population, but there are relatively few data or reports of its prevalence in the pediatric population. Recent studies have demonstrated that unlike the adult population, about 90% of the cases reported are females in a range of 8 to 16 years, the youngest being 3 years old. There tends to be delay in recognizing the diagnosis, which may be as long as 4 months. In contrast to adults, the response to treatment, particularly exercise therapy with behavioral management will achieve almost 97% remission. While the pathophysiology is poorly understood, many features, particularly the neurologic abnormalities, suggest both peripheral and central nervous system involvement. Peripheral small fiber neuropathy as an etiology and inflammation involving small nerve fibers (neurogenic inflammatory pain) has been suggested. A tissue inflammatory etiology has been investigated over the past 25 years. However, these inflammatory aspects differ from those seen in other conditions involving tissue inflammation. The suggestion that CRPS in children is a different clinical entity than that seen in the adult, is probably incorrect, as recent evidence would suggest that the pathophysiology is most likely identical involving endocrine, behavioral, developmental, and environmental factors that distinguish clinical presentation in children from the adult. Behavioral management is a mandatory accompaniment of any program of exercise therapy and the sometimes extreme sensory disturbances and parental enmeshment do distinguish the clinical presentation from that in the adult. Interventional procedures may be required in the face of extreme allodynia preventing exercise therapy, and in occasional cases interruption of the sympathetic nerves may reverse this symptom in a few children. Occasionally, continuous analgesia techniques such as that which can be delivered by tunneled epidural catheter or an externalized neurostimulator (spinal cord stimulation) for short periods of time are effective. PMID- 20704672 TI - Role of neuropeptide, cytokine, and growth factor signaling in complex regional pain syndrome. AB - OBJECTIVE: Complex regional pain syndrome (CRPS) patients exhibit multiorgan pathology and inflammatory changes after limb trauma. The objective of this study was to identify how neuro-cutaneous signaling is facilitated after fracture and examine how this altered signaling contributes to the development of CRPS-like changes in the injured limb. DESIGN AND METHODS: These studies used a rat tibia fracture model that reliably generates hindpaw warmth, edema, increased spontaneous protein extravasation, allodynia, unweighting, and periarticular bone loss, a symptom complex resembling the vascular, nociceptive, and bone sequelae observed in early CRPS. Substance P (SP)-evoked extravasation responses, EIA and PCR assays, and immunohistochemical techniques were used to evaluate post fracture up-regulation of neuro-cutaneous inflammatory signaling. A SP NK1 receptor antagonist was used to inhibit CRPS-like changes in the fracture model. RESULTS: In the rat fracture model the SP-evoked extravasation and edema responses were enhanced. SP NK1 receptor expression also increased in the microvascular endothelial cells in the fracture hindpaw skin, leading us to postulate that NK1 receptor up-regulation mediates the facilitated extravasation and edema responses observed after SP injection. The NK1 receptor antagonist LY303870 reversed hindpaw warmth, edema, increased vascular permeability, allodynia, and unweighting observed after tibia fracture in rats. There was also increased keratinocyte proliferation and NK1 receptor expression in the fracture hindpaw. Similar to the rat fracture model, we have observed increased epidermal thickness and keratinocyte NK1 expression in skin biopsies from CRPS patients. There was an up-regulation of inflammatory cytokine expression in the rat hindpaw skin and in keratinocytes at 4 weeks post-fracture. These inflammatory mediators appear to play a crucial role in the development of pain behavior after fracture, as we have repeatedly demonstrated that inhibition of cytokine, and NGF signaling prevents the allodynia and attenuates unweighting at 4 weeks post-fracture. LY303870 treatment also reversed post-fracture keratinocyte proliferation, suggesting that SP might be acting as an intermediate mediator in the inflammatory cascade by causing the up-regulation of inflammatory proteins that can directly sensitize nociceptors in the skin and joints. CONCLUSIONS: Collectively, these data suggest that neuro-cutaneous signaling is up-regulated and can mediate inflammatory changes observed in the hindpaw skin of the fracture rat model and in human CRPS skin. Future translational and clinical studies mapping these inflammatory changes may identify novel therapeutic targets for preventing post-traumatic pain from transitioning into chronic CRPS. PMID- 20704673 TI - Role of minimal distal nerve injury in complex regional pain syndrome-I. PMID- 20704674 TI - Sensory disturbances in complex regional pain syndrome: clinical observations, autonomic interactions, and possible mechanisms. AB - OBJECTIVE: To review mechanisms that might contribute to sensory disturbances and sympathetically-maintained pain in complex regional pain syndrome (CRPS). BACKGROUND: CRPS is associated with a range of sensory and autonomic abnormalities. In a subpopulation of patients, sympathetic nervous system arousal and intradermal injection of adrenergic agonists intensify pain. RESULTS: Mechanisms responsible for sensory abnormalities in CRPS include sensitization of primary afferent nociceptors and spinothalamic tract neurons, disinhibition of central nociceptive neurons, and reorganization of thalamo-cortical somatosensory maps. Proposed mechanisms of sympathetically-maintained pain include adrenergic excitation of sensitized nociceptors in the CRPS-affected limb, and interaction between processes within the central nervous system that modulate nociception and emotional responses. Central mechanisms could involve adrenergic facilitation of nociceptive transmission in the dorsal horn or thalamus, and/or depletion of bulbo-spinal opioids or tolerance to their effects. CONCLUSIONS: Sympathetic neural activity might contribute to pain and sensory disturbances in CRPS by feeding into nociceptive circuits at the site of injury or elsewhere in the CRPS affected limb, within the dorsal horn, or via thalamo-cortical projections. PMID- 20704675 TI - Vasomotor disturbances in complex regional pain syndrome--a review. AB - Complex regional pain syndromes (CRPS) are characterized by vascular disturbances primary affecting the microcirculation in the distal part of the involved extremity. In the acute stage inhibited sympathetic vasoconstriction and exaggerated neurogenic inflammation driven by central and peripheral mechanisms, respectively, seem to be the major pathophysiological mechanisms inducing vasodilation. During the chronic course of the disease as well as early in some patients vasoconstriction dominates the clinical picture induced by changes in the microcirculation itself such as endothelial dysfunction or vascular hyperreactivity, whereas sympathetic vasoconstrictor activity returns and neurogenic inflammation is less severe. It can be suggested that the interaction between different mechanisms underlying vasomotor disturbances as well as the severity of each single mechanism in the individual patient have a great impact on the variety of the overall clinical picture in CRPS. Irrespective of the underlying pathophysiology, measurements of skin temperature differences between the affected and the contralateral extremity can serve as a diagnostic tool in CRPS, in particular when sensitivity and specificity is increased by considering dynamic alterations in skin temperature asymmetries. PMID- 20704671 TI - A hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology. AB - Complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) is a chronic pain condition that usually follows a deep-tissue injury such as fracture or sprain. The cause of the pain is unknown. We have developed an animal model (chronic post-ischemia pain) that creates CRPS-I-like symptomatology. The model is produced by occluding the blood flow to one hind paw for 3 hours under general anesthesia. Following reperfusion, the treated hind paw exhibits an initial phase of hyperemia and edema. This is followed by mechano-hyperalgesia, mechano allodynia, and cold-allodynia that lasted for at least 1 month. Light microscopic analyses and electron microscopic analyses of the nerves at the site of the tourniquet show that the majority of these animals have no sign of injury to myelinated or unmyelinated axons. However, electron microscopy shows that the ischemia-reperfusion injury produces a microvascular injury, slow-flow/no-reflow, in the capillaries of the hind paw muscle and digital nerves. We propose that the slow-flow/no-reflow phenomenon initiates and maintains deep-tissue ischemia and inflammation, leading to the activation of muscle nociceptors, and the ectopic activation of sensory afferent axons due to endoneurial ischemia and inflammation. These data, and a large body of clinical evidence, suggest that in at least a subset of CRPS-I patients, the fundamental cause of the abnormal pain sensations is ischemia and inflammation due to microvascular pathology in deep tissues, leading to a combination of inflammatory and neuropathic pain processes. Moreover, we suggest a unifying idea that relates the pathogenesis of CRPS-I to that of CRPS-II. Lastly, our hypothesis suggests that the role of the sympathetic nervous system in CRPS-I is a factor that is not fundamentally causative, but may have an important contributory role in early-stage disease. PMID- 20704676 TI - Movement disorders in complex regional pain syndrome. AB - About 25% of the patients with complex regional pain syndrome (CRPS) suffer movement disorders, including loss of voluntary control, bradykinesia, dystonia, myoclonus, and tremor. These movement disorders are generally difficult to manage and add considerably to the disease burden. Over the last years, interesting findings have emerged that show how tissue or nerve injury may induce spinal plasticity (central sensitization), which alters sensory transmission and sensorimotor processing in the spinal cord and is associated with disinhibition. These changes, in turn, set the stage for the development of movement disorders seen in CRPS. There are no randomized control studies on the treatment of movement disorders in CRPS but findings from fundamental and clinical research suggest that strategies that enhance the central inhibitory state may benefit these patients. PMID- 20704677 TI - What does the mechanism of spinal cord stimulation tell us about complex regional pain syndrome? AB - Spinal cord stimulation (SCS) can have dramatic effects on painful, vascular, and motor symptoms of complex regional pain syndrome (CRPS), but its precise mechanism of action is unclear. Better understanding of the physiologic effects of SCS may improve understanding not only of this treatment modality but also of CRPS pathophysiology. Effects of SCS on pain perception are likely to occur through activation of inhibitory GABA-ergic and cholinergic spinal interneurons. Increased release of both neurotransmitters has been demonstrated following SCS in animal models of neuropathic pain, with accompanying reductions in pain behaviors. Effects of SCS on vascular symptoms of CRPS are thought to occur through two main mechanisms: antidromic activation of spinal afferent neurons and inhibition of sympathetic efferents. Cutaneous vasodilation following SCS in animal models has been shown to involve antidromic release of calcitonin gene related peptide and possibly nitric oxide, from small-diameter sensory neurons expressing the transient receptor potential V1 (TRPV1) receptor. The involvement of sympathetic efferents in the effects of SCS has not been studied in animal models of neuropathic pain, but has been demonstrated in models of angina pectoris. In conclusion, SCS is of clinical benefit in CRPS, and although its mechanism of action merits further elucidation, what little we do know is informative and can partially explain some of the pathophysiology of CRPS. PMID- 20704678 TI - Long-term ambulatory continuous nerve blocks for terminally ill patients: a case series. AB - OBJECTIVE: Intolerable side effects and dissatisfactory pain control with traditional analgesics prompted the utilization of long-term, ambulatory, continuous peripheral nerve blocks (CPNBs) in terminally ill patients for palliative care. DESIGN: Case series. SETTING: Continuous peripheral nerve catheters were placed in terminally ill patients in an ambulatory setting. The patients were managed at their homes, with nursing services available to manage the infusions and provide routine monitoring and care. PATIENTS: This is a case series of patients with severe peripheral pain and a terminal diagnosis in whom the goals of care were aimed at palliation. All three cases had an unfavorable coagulation status; case 2 had a prior pneumonectomy on the contralateral side and a large tumor on the ipsilateral lung of the continuous brachial plexus block. INTERVENTIONS: Interventions included CPNBs, with infusion of local anesthetic. Specific techniques used include cervical paravertebral block and lumbar paravertebral block. RESULTS: After infusion and titration of local anesthetic doses, oral opioid medication was significantly reduced, which resulted in an improved quality of life. The nerve blocks did not hasten death in any of the patients despite their coexisting conditions. CONCLUSIONS: CPNBs are a reasonably effective modality to decrease opioid usage when side effects are undesirable for end-of-life care. The risk of unfavorable coagulation status, poor lung function, and risk of infection was outweighed by the benefit in this patient population. PMID- 20704681 TI - Comments on: Penetration of a cervical radicular artery during a transforaminal epidural injection. PMID- 20704679 TI - In response to: Are we lemmings going off a cliff? The case against the "interventional" pain medicine label. PMID- 20704683 TI - Paradoxical sensations from a grounding pad during lumbar RF neurotomy. PMID- 20704684 TI - Analgesic techniques in minor painful procedures in neonatal units: a survey in northern Italy. AB - INTRODUCTION: The aim of this survey was to evaluate the current practice regarding pain assessment and pain management strategies adopted in commonly performed minor painful procedures in Northern Italian Neonatal Intensive Care Units (NICUs). METHODS: A multicenter survey was conducted between 2008 and 2009 in 35 NICUs. The first part of the survey form covered pain assessment tools, the timing of analgesics, and the availability of written guidelines. A second section evaluated the analgesic strategies adopted in commonly performed painful procedures. The listed analgesic procedures were as follows: oral sweet solutions alone, non-nutritive sucking (NNS) alone, a combination of sweet solutions and NNS, breast-feeding where available, and topical anesthetics. RESULTS: Completed questionnaires were returned from 30 neonatal units (85.7% response rate). Ten of the 30 NICUs reported using pain assessment tools for minor invasive procedures. Neonatal Infant Pain Scale was the most frequently used pain scale (60%). Twenty neonatal units had written guidelines directing pain management practices. The most frequently used procedures were pacifiers alone (69%), followed by sweet tasting solutions (58%). A 5% glucose solution was the most frequently utilized sweet-tasting solution (76.7%). A minority of NICUs (16.7%) administered 12% sucrose solutions for analgesia and the application of topical anesthetics was found in 27% of NICUs while breast-feeding was performed in 7% of NICUs. DISCUSSION: This study found a low adherence to national and international guidelines for analgesia in minor procedures: the underuse of neonatal pain scales (33%), sucrose solution administration before heel lance (23.3%), topical anesthetics before venipuncture, or other analgesic techniques. The presence of written pain control guidelines in these regions of Northern Italy increased in recent years (from 25% to 66%). PMID- 20704685 TI - Melanoma stem cells--are there devils in the detail? PMID- 20704686 TI - 4E-BPs at the crossroads of oncogenic MAPK and AKT signaling. PMID- 20704687 TI - Concept determination as part of the development of knowledge in caring science. AB - The purpose of this article is to highlight concept determination as part of the development of knowledge in caring science, by describing Eriksson's model of concept determination. Concepts belong to and are developed in science, and it is through concepts that reality is shaped. Concepts and language are closely related, and Gadamer's guiding thought is that language constitutes the middle where I and the world, join together. It is by its very activity of thinking that the meaning is to be heard, and Gadamer emphasizes that the being that can be understood is language and points to a universal ontological structure against the fundamental nature of what is allowing to be understood. The first outlines of the model of concept determination are described as a research design for the development of the care process model. In developing the model of concept determination, the intent has been to fill a void in the international caring science literature, where no model is sufficiently comprehensive to meet the requirement for a model from a humanistic hermeneutic perspective with roots in an explicit ontology and ethos. Eriksson's model of concept determination includes both an ontological and a contextual determination. Concept determination is the main concept in Eriksson's model and includes concept formation and concept analysis. The starting point of concept determination is a hermeneutic epistemology developed in a scientific tradition of caring. The model of concept determination opens itself to versatility in determining concepts and provides a nuanced picture of the concept in question, while the whole-part-whole thinking simultaneously leads to a deeper understanding of the multifaceted caring reality and the current object of knowledge. By constantly returning to the what-questions, the course of events will continue and conceptual determination moves around the substance towards a deeper understanding of the core. PMID- 20704688 TI - Parent perspectives of therapy services for their children with physical disabilities. AB - BACKGROUND: Children who have physical disabilities typically attend occupational and physical therapy services on a regular basis. The importance of being family centred when providing services to children with a disability has been highlighted in recent years. Thus, it was considered important to gather the opinions of parents towards the services their child receives. AIM: To explore the perspectives of parents of children with physical disabilities to occupational and physical therapy services provided to their child. METHOD: Open interviews were conducted with 17 parents (14 mothers and three fathers) of children aged 7-13, selected through a purposeful sample. Data analysis was based on an inductive approach. RESULTS: Nine categories emerged and were organized under three main headings: The role of the therapist, service location and arrangements, and characteristics of good service. Although several positive remarks were made, many parents in this study were poorly informed of intervention goals and what took place during therapy sessions. Most parents wished for mutual respect, joint decision-making in planning intervention, and collaboration with the therapy services. The aspiration for active but manageable roles that did not demand a burdensome amount of the parents' time and energy was evinced. The parents became increasingly critical of the services, as their children grew older. They placed emphasis on services being offered in their local community, and that more specialized service should be centralized, especially for the children with the most complex needs. CONCLUSIONS: The results reflect the importance of the needs and wants of the parents and children being respected. Thus, parents should play an active role in defining priorities and strategies for implementation. The results also indicate that therapists need to put more thought into the conditions and environment of the child instead of focusing solely on underlying issues connected to their impairments. PMID- 20704689 TI - Inverse association between dopaminergic neurotransmission and Iowa Gambling Task performance in pathological gamblers and healthy controls. AB - The dopamine system is believed to affect gambling behavior in pathological gambling. Particularly, dopamine release in the ventral striatum appears to affect decision-making in the disorder. This study investigated dopamine release in the ventral striatum in relation to gambling performance on the Iowa Gambling Task (IGT) in 16 Pathological Gamblers (PG) and 14 Healthy Controls (HC). We used Positron Emission Tomography (PET) to measure the binding potential of [(11)C] raclopride to dopamine D2/3 receptors during a baseline and gambling condition. We hypothesized that decreased raclopride binding potentials in the ventral striatum during gambling (indicating dopamine release) would be associated with higher IGT performance in Healthy Controls, but lower IGT performance in Pathological Gamblers. The results showed that Pathological Gamblers with dopamine release in the ventral striatum had significantly lower IGT performance than Healthy Controls. Furthermore, dopamine release was associated with significantly higher IGT performance in Healthy Controls and significantly lower IGT performance in Pathological Gamblers. The results suggest that dopamine release is involved both in adaptive and maladaptive decision-making. These findings may contribute to a better understanding of dopaminergic dysfunctions in pathological gambling and substance related addictions. PMID- 20704690 TI - Feedback related brain activity in a gambling task: a temporal analysis of EEG correlates. AB - The pattern of neural correlates of feedback processing has been the subject of a number of studies, using both neuroimaging and electrophysiological recordings. A complex functional network was found to be activated after a choice in order to process a feedback and sustain an adaptive behavior. However, many aspects of this network are still unclear and further research is needed to better understand this process. We conducted an EEG study using a simple gambling task. Twenty three subjects participated to the study. We analyzed both EEG power spectrum and ERP components evoked by presentation of a feedback signal (money gain or loss) during a simple gambling task. Our data confirmed that a negative ERP component is present about 270 ms after feedback, particularly relevant following a choice with negative outcome. Furthermore, the theta and delta oscillatory activity seem to be correlated to a dynamic decision-making process within specific cortical networks. In particular, theta activity showed a valence dependent development between 150 and 350 ms post-feedback onset. Differently from previous studies (Cohen, Elger & Ranganath, 2007; Marco-Pallares, Cucurell, Cunillera et al., 2008), we did not find any valence effect in beta range. However, our data are consistent with Christie and Tata (2009), probably due to the nature of the gambling task used in both studies. In conclusion, our data, in line with some prior findings showed that the feedback related response is correlated to a complex pattern of cortical activation probably mediated by theta and delta activity. PMID- 20704691 TI - Noninvasive tests for evaluation of fibrosis in HCV recurrence after liver transplantation: a systematic review. AB - Noninvasive tests (NIT) for evaluation of hepatic fibrosis have not been evaluated extensively in liver transplantation. We systematically reviewed the literature regarding NIT after liver transplantation. We identified 14 studies evaluating NIT based on serum markers and/or liver imaging techniques: 10 studies assessed NIT in recipients with recurrent HCV infection for fibrosis and four studies evaluated predictors of progression of fibrosis in recurrent HCV. Transient Elastography (TE) had good discrimination for significant fibrosis (median AUROC: 0.88). Among the serum NIT, APRI had good performance (median AUROC: 0.75). TE performed better than serum (direct and indirect) NIT for significant fibrosis with median AUROC 0.88 (vs. 0.66, P < 0.001), median sensitivity 0.86 (vs. 0.56, P = 0.002), median NPV 0.90 (vs. 0.74, P = 0.05) and median PPV 0.80 (vs. 0.63, P = 0.02). TE compared to indirect serum NIT, had better performance, but was not superior to APRI score. Finally, direct, compared to indirect NIT, were not significantly different except for specificity: median: 0.83 vs. 0.69, respectively, P = 0.04. In conclusion, NIT could become an important tool in clinical management of liver transplant recipients, but whether they can improve clinical practice needs further evidence. Their optimal combination with liver biopsy and assessment of collagen content requires investigation. PMID- 20704692 TI - In vitro elution of amikacin and vancomycin from impregnated plaster of Paris beads. AB - OBJECTIVE: To describe in vitro elution characteristics of amikacin and vancomycin from calcium sulfate hemihydrate 98% (plaster of Paris, POP) beads and characterize eluent inhibition of Staphylococcus spp. STUDY DESIGN: Experimental study. METHODS: POP beads were impregnated with amikacin or vancomycin alone or in combination and then incubated alone or in combination for 84 days at 37 degrees C in plastic tubes containing sterile phosphate-buffered saline (PBS). Beads containing no antimicrobial served as negative control. Beads were intermittently moved to a new tube containing drug-free PBS. Antimicrobial was measured in the eluent using a polarized fluorescent immunoassay. Eluent inhibition of Staphylococcus spp. was determined at each time point. RESULTS: Antimicrobial release from beads was characterized by an initial rapid phase then a slower phase. Although antimicrobial release from beads occurred throughout the 84 days, most was in the first 24 hours, except for vancomycin alone. Duration of eluent inhibition of Staphylococcus spp. growth ranged from 0.5 (amikacin alone) to 56 days (vancomycin alone). Control eluent did not inhibit bacterial growth. CONCLUSIONS: Amikacin elution from POP beads was rapid, inhibiting growth for <24 hours with or without vancomycin. Vancomycin elution was slower and inhibited growth for 56 days alone or for 5 days with amikacin. CLINICAL RELEVANCE: Vancomycin-impregnated beads appear to be reasonable as a therapeutic option whereas amikacin-impregnated POP beads and amikacin and vancomycin combinations may require further study before considering as a therapeutic option. PMID- 20704693 TI - Maxillomandibular circular external skeletal fixation for repair of bilateral fractures of the caudal aspect of the mandible in a dog. AB - OBJECTIVE: To describe the novel use of circular external skeletal fixation (CESF) for repair of bilateral fractures of the caudal aspect of the mandibles. STUDY DESIGN: Clinical report. ANIMALS: A 5-month-old female Newfoundland. METHODS: A 2-ring CESF was used to immobilize the mandible relative to the maxillae. RESULTS: Anatomic dental occlusion and reduction of the right hemimandible were achieved with mild malalignment of the left hemimandible. Fracture healing occurred within 20 days. Transient epistaxis and reduced temporomandibular joint range of motion occurred at the time of fixator removal but normal use of the mandible was reported 6 months postoperatively. CONCLUSIONS: CESF effectively immobilized the mandible permitting rapid fracture healing with minimal morbidity. CLINICAL RELEVANCE: Maxillomandibular CESF may represent a simple, effective option for the management of challenging fractures involving the caudal aspect of the mandible. PMID- 20704694 TI - Extraluminal, C shaped polyethylene prostheses in two ponies with tracheal collapse. AB - OBJECTIVE: To describe the surgical technique, complications, and outcome after use of extraluminal prostheses in 2 ponies with severe tracheal collapse. STUDY DESIGN: Clinical report. ANIMALS: Ponies (n=2) with severe tracheal collapse. METHODS: A ventral median approach was used to expose the trachea from the larynx to the manubrium. Extraluminal, high-density polyethylene, C-shaped prostheses were sutured to the dorsal tracheal membrane and tracheal rings to provide external tracheal support. RESULTS: The surgical approach provided good tracheal access and placement of the rings was uncomplicated. Initial estimates of the tracheal diameter from preoperative radiographs resulted in prostheses that were too small at surgery requiring a 2nd surgical procedure in 1 pony. Postoperative complications were coughing, right laryngeal hemiplegia, seroma formation, and antimicrobial induced colitis. Both ponies had marked resolution of clinical abnormalities after surgery. Recurrent esophageal obstruction resulted in euthanasia of 1 pony 3.5 years after surgery. The other pony was doing well 1 year after surgery. CONCLUSIONS: Extraluminal support of the trachea resulted in rapid resolution of clinical signs in 2 ponies with tracheal collapse. CLINICAL RELEVANCE: Extraluminal tracheal prostheses can resolve clinical abnormalities in ponies with severe tracheal collapse. PMID- 20704695 TI - Application of highly sensitive saturation labeling to the analysis of differential protein expression in infected ticks from limited samples. AB - BACKGROUND: Ticks are vectors of pathogens that affect human and animal health worldwide. Proteomics and genomics studies of infected ticks are required to understand tick-pathogen interactions and identify potential vaccine antigens to control pathogen transmission. One of the limitations for proteomics research in ticks is the amount of protein that can be obtained from these organisms. In the work reported here, individual naturally-infected and uninfected Rhipicephalus spp. ticks were processed using a method that permits simultaneous extraction of DNA, RNA and proteins. This approach allowed using DNA to determine pathogen infection, protein for proteomics studies and RNA to characterize mRNA levels for some of the differentially expressed proteins. Differential protein expression in response to natural infection with different pathogens was characterized by two dimensional (2-D) differential in gel electrophoresis (DIGE) saturation labeling in combination with mass spectrometry analysis. To our knowledge, this is the first report of the application of DIGE saturation labeling to study tick proteins. RESULTS: Questing and feeding Rhipicephalus spp. adult ticks were collected in 27 farms located in different Sicilian regions. From 300 collected ticks, only 16 were found to be infected: R. sanguineus with Rickettsia conorii and Ehrlichia canis; R. bursa with Theileria annulata; and R. turanicus with Anaplasma ovis. The proteomic analysis conducted from a limited amount of proteins allowed the identification of host, pathogen and tick proteins differentially expressed as a consequence of infection. CONCLUSION: These results showed that DIGE saturation labeling is a powerful technology for proteomics studies in small number of ticks and provided new information about the effect of pathogen infection in ticks. PMID- 20704696 TI - Validation of a French version of the Freiburg Mindfulness Inventory - short version: relationships between mindfulness and stress in an adult population. AB - BACKGROUND: Whereas interest in incorporating mindfulness into interventions in medicine is growing, data on the relationships of mindfulness to stress and coping in management is still scarce. This report first presents a French validation of the Freiburg Mindfulness Inventory-short form (FMI) in a middle aged working population. Secondly, it investigates the relationship between psychological adjustment and mindfulness. METHODS: Five hundred and six non clinical middle-aged working individuals rated themselves on the self-report French version FMI and completed measures of psychological constructs potentially related to mindfulness levels. RESULTS: Results were comparable to results of the original short version. Internal consistency of the scale based on the one-factor solution was .74, and test-retest reliability was good. The one-dimensional solution as the alternative to the two-factor structure solution yielded suboptimal fit indices. Correlations also indicated that individuals scoring high on mindfulness are prone to stress tolerance, positive affects and higher self efficacy. Furthermore, subjects with no reports of stressful events were higher on mindfulness. CONCLUSION: These data showed that mindfulness can be measured validly and reliably with the proposed French version of the FMI. The data also highlighted the relationship between mindfulness and stress in an adult population. Mindfulness appears to reduce negative appraisals of challenging or threatening events. PMID- 20704697 TI - Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysis. AB - BACKGROUND: One of the major challenges in understanding enzyme catalysis is to identify the different conformations and their populations at detailed molecular level in response to ligand binding/environment. A detail description of the ligand induced conformational changes provides meaningful insights into the mechanism of action of enzymes and thus its function. RESULTS: In this study, we have explored the ligand induced conformational changes in H.pylori LuxS and the associated mechanistic features. LuxS, a dimeric protein, produces the precursor (4,5-dihydroxy-2,3-pentanedione) for autoinducer-2 production which is a signalling molecule for bacterial quorum sensing. We have performed molecular dynamics simulations on H.pylori LuxS in its various ligand bound forms and analyzed the simulation trajectories using various techniques including the structure network analysis, free energy evaluation and water dynamics at the active site. The results bring out the mechanistic details such as co-operativity and asymmetry between the two subunits, subtle changes in the conformation as a response to the binding of active and inactive forms of ligands and the population distribution of different conformations in equilibrium. These investigations have enabled us to probe the free energy landscape and identify the corresponding conformations in terms of network parameters. In addition, we have also elucidated the variations in the dynamics of water co-ordination to the Zn2+ ion in LuxS and its relation to the rigidity at the active sites. CONCLUSIONS: In this article, we provide details of a novel method for the identification of conformational changes in the different ligand bound states of the protein, evaluation of ligand-induced free energy changes and the biological relevance of our results in the context of LuxS structure-function. The methodology outlined here is highly generalized to illuminate the linkage between structure and function in any protein of known structure. PMID- 20704698 TI - Serum N-glycome biomarker for monitoring development of DENA-induced hepatocellular carcinoma in rat. AB - BACKGROUND: There is a demand for serum markers for the routine assessment of the progression of liver cancer. We previously found that serum N-linked sugar chains are altered in hepatocellular carcinoma (HCC). Here, we studied glycomic alterations during development of HCC in a rat model. RESULTS: Rat HCC was induced by the hepatocarcinogen, diethylnitrosamine (DENA). N-glycans were profiled using the DSA-FACE technique developed in our laboratory.In comparison with control rats, DENA rats showed a gradual but significant increase in two glycans (R5a and R5b) in serum total N-glycans during progression of liver cirrhosis and cancer, and a decrease in a biantennary glycan (P5). The log of the ratio of R5a to P1 (NGA2F) and R5b to P1 [log(R5a/P1) and log(R5b/P1)] were significantly (p < 0.0001) elevated in HCC rats, but not in rats with cirrhosis or fibrosis or in control rats. We thus propose a GlycoTest model using the above mentioned serum glycan markers to monitor the progression of cirrhosis and HCC in the DENA-treated rat model. When DENA-treated rats were subsequently treated with farnesylthiosalicyclic acid, an anticancer drug, progression to HCC was prevented and GlycoTest markers (P5, R5a and R5b) reverted towards non-DENA levels, and the HCC-specific markers, log(R5a/P1) and log(R5b/P1), normalized completely. CONCLUSIONS: We found an increase in core-alpha-1,6-fucosylated glycoproteins in serum and liver of rats with HCC, which demonstrates that fucosylation is altered during progression of HCC. Our GlycoTest model can be used to monitor progression of HCC and to follow up treatment of liver tumors in the DENA rat. This GlycoTest model is particularly important because a rapid non-invasive diagnostic procedure for tumour progression in this rat model would greatly facilitate the search for anticancer drugs. PMID- 20704699 TI - Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report. AB - INTRODUCTION: Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment. CASE PRESENTATION: We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A. CONCLUSIONS: The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored. PMID- 20704700 TI - Agranulocytosis and hepatic toxicity with ticlopidine therapy: a case report. AB - INTRODUCTION: Ticlopidine is a platelet inhibitor used to prevent thrombosis in patients with cerebrovascular or coronary artery disease. The most common side effects are mild and transitory: diarrhea, dyspepsia, nausea and rashes. More serious, but less frequent, adverse effects are hematological dyscrasia and cholestatic hepatitis. We report a rare case of agranulocytosis associated with hepatic toxicity, probably related to the use of ticlopidine. CASE PRESENTATION: A 70-year-old Caucasian woman, with no previous history of hematological or liver diseases, was treated with ticlopidine 250 mg twice daily immediately after a vertebrobasilar stroke. Upon admission, her blood tests were normal. About four weeks later she developed agranulocytosis and hepatic toxicity. Ticlopidine was discontinued immediately, and aspirin 25 mg and dipyridamole 200 mg were given twice daily. She was treated with hematopoietic growth factors (granulocyte colony stimulating factor), with a rapidly increased white blood count and progressive normalization of liver tests as a result. CONCLUSION: In the first three months following initiation of ticlopidine therapy, regular monitoring of complete blood cell count and of liver function tests is essential for the early detection of serious and unpredictable side effects. PMID- 20704701 TI - Radiosensitization and growth inhibition of cancer cells mediated by an scFv antibody gene against DNA-PKcs in vitro and in vivo. AB - BACKGROUND: Overexpression of DNA-dependent protein kinase catalytic subunit (DNA PKcs) is commonly occurred in cancers and causes radioresistance and poor prognosis. In present study, the single-chain variable antibody fragments (scFv) targeting DNA-PKcs was developed for the application of radiosensitization in vitro and in vivo. A humanized semisynthetic scFv library and the phage-display antibodies technology were employed to screen DNA-PKcs scFv antibody. METHODS: DNA-PKcs epitopes were predicted and cloned. A humanized semisynthetic scFv library and the phage-display antibodies technology were employed to screen DNA PKcs scFv antibody. DNA damage repair was analyzed by comet assay and immunofluorescence detection of gammaH2AX foci. The radiosensitization in vivo was determined on Balb/c athymic mice transplanted tumours of HeLa cells. RESULTS: Four epitopes of DNA-PKcs have been predicted and expressed as the antigens, and a specific human anti-DNA-PKcs scFv antibody gene, anti-DPK3-scFv, was obtained by screening the phage antibody library using the DNA-PKcs peptide DPK3. The specificity of anti-DPK3-scFv was verified, in vitro. Transfection of HeLa cells with the anti-DPK3-scFv gene resulted in an increased sensitivity to IR, decreased repair capability of DNA double-strand breaks (DSB) detected by comet assay and immunofluorescence detection of gammaH2AX foci. Moreover, the kinase activity of DNA-PKcs was inhibited by anti-DPK3-scFv, which was displayed by the decreased phosphorylation levels of its target Akt/S473 and the autophosphorylation of DNA-PKcs on S2056 induced by radiation. Measurement of the growth and apoptosis rates showed that anti-DPK3-scFv enhanced the sensitivity of tumours transplanted in Balb/c athymic mice to radiation therapy. CONCLUSION: The antiproliferation and radiosensitizing effects of anti-DPK3-scFv via targeting DNA-PKcs make it very appealing for the development as a novel biological radiosensitizer for cancer therapeutic potential. PMID- 20704703 TI - Association study between a polymorphism at the 3'-untranslated region of CLOCK gene and attention deficit hyperactivity disorder. AB - BACKGROUND: The circadian locomotor output cycles kaput (CLOCK) gene encodes protein regulation circadian rhythm and also plays some roles in neural transmitter systems including the dopamine system. Several lines of evidence implicate a relationship between attention-deficit hyperactivity disorder (ADHD), circadian rythmicity and sleeping disturbances. A recent study has reported that a polymorphism (rs1801260) at the 3'-untranslated region of the CLOCK gene is associated with adult ADHD. METHODS: To investigate the association between the polymorphism (rs1801260) in ADHD, two samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212) were genotyped and analysed using within family transmission disequilibrium test (TDT). Bonferroni correction procedures were used to just for multiple comparisons. RESULTS: We found evidence of increased transmission of the T allele of the rs1801260 polymorphism in Taiwanese samples (P = 0.010). There was also evidence of preferential transmission of the T allele of the rs1801260 polymorphism in combined samples from the Taiwan and UK (P = 0.008). CONCLUSION: This study provides evidence for the possible involvement of CLOCK in susceptibility to ADHD. PMID- 20704702 TI - Proteomic characterization of an isolated fraction of synthetic proteasome inhibitor (PSI)-induced inclusions in PC12 cells might offer clues to aggresomes as a cellular defensive response against proteasome inhibition by PSI. AB - BACKGROUND: Cooperation of constituents of the ubiquitin proteasome system (UPS) with chaperone proteins in degrading proteins mediate a wide range of cellular processes, such as synaptic function and neurotransmission, gene transcription, protein trafficking, mitochondrial function and metabolism, antioxidant defence mechanisms, and apoptotic signal transduction. It is supposed that constituents of the UPS and chaperone proteins are recruited into aggresomes where aberrant and potentially cytotoxic proteins may be sequestered in an inactive form. RESULTS: To determinate the proteomic pattern of synthetic proteasome inhibitor (PSI)-induced inclusions in PC12 cells after proteasome inhibition by PSI, we analyzed a fraction of PSI-induced inclusions. A proteomic feature of the isolated fraction was characterized by identification of fifty six proteins including twenty previously reported protein components of Lewy bodies, twenty eight newly identified proteins and eight unknown proteins. These proteins, most of which were recognized as a profile of proteins within cellular processes mediated by the UPS, a profile of constituents of the UPS and a profile of chaperone proteins, are classed into at least nine accepted categories. In addition, prolyl-4-hydroxylase beta polypeptide, an endoplasmic reticulum member of the protein disulfide isomerase family, was validated in the developmental process of PSI-induced inclusions in the cells. CONCLUSIONS: It is speculated that proteomic characterization of an isolated fraction of PSI-induced inclusions in PC12 cells might offer clues to appearance of aggresomes serving as a cellular defensive response against proteasome inhibition. PMID- 20704704 TI - Pyelonephritis in slaughter pigs and sows: morphological characterization and aspects of pathogenesis and aetiology. AB - BACKGROUND: Pyelonephritis is a serious disease in pig production that needs to be further studied. The purpose of this study was to describe the morphology, investigate the pathogenesis, and evaluate the aetiological role of Escherichia coli in pyelonephritis in slaughtered pigs by concurrent bacteriological, gross and histopathological examinations. METHODS: From Danish abattoirs, kidneys and corresponding lymph nodes from 22 slaughtered finishing pigs and 26 slaughtered sows with pyelonephritis were collected and evaluated by bacteriology and pathology. Based on gross lesions, each kidney (lesion) was grouped as acute, chronic, chronic active, or normal and their histological inflammatory stage was determined as normal (0), acute (1), sub-acute (2), chronic active (3), or chronic (4). Immunohistochemical identification of neutrophils, macrophages, T lymphocytes, B-lymphocytes, plasma cells, E. coli and Tamm-Horsfall protein (THP) in renal sections was performed. The number of E. coli and the proportion of immunohistochemically visualized leukocytes out of the total number of infiltrating leukocytes were scored semi-quantitatively. RESULTS: Lesions in finishing pigs and sows were similar. Macroscopically, multiple unevenly distributed foci of inflammation mostly affecting the renal poles were observed. Histologically, tubulointerstitial infiltration with neutrophils and mononuclear cells and tubular destruction was the main findings. The significant highest scores of L1 antigen+ neutrophils were in inflammatory stage 1 while the significant highest scores of CD79alphacy+ B-lymphocytes, IgG+ and IgA+ plasma cells were in stage 3 or 4. Neutrophils were the dominant leukocytes in stage 1 while CD3epsilon+ T-lymphocytes dominated in stage 2, 3 and 4. Interstitially THP was seen in 82% and 98% of kidneys with pyelonephritis from finishing pigs and sows, respectively. E. coli was demonstrated in monoculture and/or identified by immunohistochemistry in relation to inflammation in four kidneys from finishing pigs and in 34 kidneys from sows. CONCLUSIONS: E. coli played a significant role in the aetiology of pyelonephritis. Neutrophils were involved in the first line of defence. CD3epsilon+ T-lymphocytes were involved in both the acute and chronic inflammatory response while a humoral immune response was most pronounced in later inflammatory stages. The observed renal lesions correspond with an ascending bacterial infection with presence of intra-renal reflux. PMID- 20704705 TI - Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. AB - Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability. PMID- 20704706 TI - Constitutive activation of glycogen synthase kinase-3beta correlates with better prognosis and cyclin-dependent kinase inhibitors in human gastric cancer. AB - BACKGROUND: Aberrant regulation of glycogen synthase kinase-3beta (GSK-3beta) has been implicated in several human cancers; however, it has not been reported in the gastric cancer tissues to date. The present study was performed to determine the expression status of active form of GSK-3beta phosphorylated at Tyr216 (pGSK 3beta) and its relationship with other tumor-associated proteins in human gastric cancers. METHODS: Immunohistochemistry was performed on tissue array slides containing 281 human gastric carcinoma specimens. In addition, gastric cancer cells were cultured and treated with a GSK-3beta inhibitor lithium chloride (LiCl) for immunoblot analysis. RESULTS: We found that pGSK-3beta was expressed in 129 (46%) of 281 cases examined, and was higher in the early-stages of pathologic tumor-node-metastasis (P < 0.001). The expression of pGSK-3beta inversely correlated with lymphatic invasion (P < 0.001) and lymph node metastasis (P < 0.001) and correlated with a longer patient survival (P < 0.001). In addition, pGSK-3beta expression positively correlated with that of p16, p21, p27, p53, APC, PTEN, MGMT, SMAD4, or KAI1 (P < 0.05), but not with that of cyclin D1. This was confirmed by immunoblot analysis using SNU-668 gastric cancer cells treated with LiCl. CONCLUSIONS: GSK-3beta activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis. Thus, these findings suggest that GSK-3beta activation is a useful prognostic marker for the early-stage gastric cancer. PMID- 20704707 TI - Malaria risk in Corsica, former hot spot of malaria in France. AB - BACKGROUND: The prevalence of Plasmodium falciparum and Plasmodium vivax malaria was very high in Corsica just before the Second World War. The last outbreak was in 1972 and the most recent indigenous case was in 2006. RESULTS: Analysis of historical data shows that anopheline vectors were abundant. Recent surveys demonstrated that potential vectors are still present in Corsica, despite the likely disappearance of Anopheles sacharovi. Moreover, P. falciparum can develop experimentally into these mosquitoes, notably Anopheles labranchiae, which is locally abundant, and parasites are regularly introduced into the island. DISCUSSION, CONCLUSIONS: The presence of vectors, the introduction of parasites and the conducive climate raise questions about the possibility of malaria re emerging and becoming re-established in Corsica. Analysis of historic and current parasitological and entomological data shows that the current theoretical risk of indigenous cases or malaria foci is negligible, particularly since there is very little contact between humans and Anopheles mosquitoes, Plasmodium carriers are reliably treated and there is a widespread vector control on the island. PMID- 20704708 TI - Nutriomes and nutrient arrays - the key to personalised nutrition for DNA damage prevention and cancer growth control. AB - DNA damage at the base-sequence, epigenome and chromosome level is a fundamental cause of developmental and degenerative diseases. Multiple micronutrients and their interactions with the inherited and/or acquired genome determine DNA damage and genomic instability rates. The challenge is to identify for each individual the combination of micronutrients and their doses (i.e. the nutriome) that optimises genome stability and DNA repair. In this paper I describe and propose the use of high-throughput nutrient array systems with high content analysis diagnostics of DNA damage, cell death and cell growth for defining, on an individual basis, the optimal nutriome for DNA damage prevention and cancer growth control. PMID- 20704709 TI - Entrapment neuropathy results in different microRNA expression patterns from denervation injury in rats. AB - BACKGROUND: To compare the microRNA (miRNA) expression profiles in neurons and innervated muscles after sciatic nerve entrapment using a non-constrictive silastic tube, subsequent surgical decompression, and denervation injury. METHODS: The experimental L4-L6 spinal segments, dorsal root ganglia (DRGs), and soleus muscles from each experimental group (sham control, denervation, entrapment, and decompression) were analyzed using an Agilent rat miRNA array to detect dysregulated miRNAs. In addition, muscle-specific miRNAs (miR-1, -133a, and -206) and selectively upregulated miRNAs were subsequently quantified using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). RESULTS: In the soleus muscles, 37 of the 47 miRNAs (13.4% of the 350 unique miRNAs tested) that were significantly downregulated after 6 months of entrapment neuropathy were also among the 40 miRNAs (11.4% of the 350 unique miRNAs tested) that were downregulated after 3 months of decompression. No miRNA was upregulated in both groups. In contrast, only 3 miRNAs were upregulated and 3 miRNAs were downregulated in the denervated muscle after 6 months. In the DRGs, 6 miRNAs in the entrapment group (miR-9, miR-320, miR-324-3p, miR-672, miR-466b, and miR-144) and 3 miRNAs in the decompression group (miR-9, miR-320, and miR-324-3p) were significantly downregulated. No miRNA was upregulated in both groups. We detected 1 downregulated miRNA (miR-144) and 1 upregulated miRNA (miR-21) after sciatic nerve denervation. We were able to separate the muscle or DRG samples into denervation or entrapment neuropathy by performing unsupervised hierarchal clustering analysis. Regarding the muscle-specific miRNAs, real-time RT-PCR analysis revealed an approximately 50% decrease in miR-1 and miR-133a expression levels at 3 and 6 months after entrapment, whereas miR-1 and miR-133a levels were unchanged and were decreased after decompression at 1 and 3 months. In contrast, there were no statistical differences in the expression of miR-206 during nerve entrapment and after decompression. The expression of muscle-specific miRNAs in entrapment neuropathy is different from our previous observations in sciatic nerve denervation injury. CONCLUSIONS: This study revealed the different involvement of miRNAs in neurons and innervated muscles after entrapment neuropathy and denervation injury, and implied that epigenetic regulation is different in these two conditions. PMID- 20704710 TI - Comparison of raw and processed Radix Polygoni Multiflori (Heshouwu) by high performance liquid chromatography and mass spectrometry. AB - BACKGROUND: Radix Polygoni Multiflori is the dried root tuber of Polygonum multiflorum Thunb. (Fam. Polygonaceae). According to Chinese medicine theory, raw (R-RPM) and processed (P-RPM) Radix Polygoni Multiflori possess different properties. The present study investigates the differences in chemistry between raw and processed Radix Polygoni Multiflori. METHODS: Five pairs of R-RPM and P RPM as well as 15 commercial decoction pieces were analyzed with high performance liquid chromatography (HPLC) and mass spectrometry (MS). RESULTS: Two anthraquinones, namely emodin-8-O-(6'-O-malonyl)-glucoside and physcion-8-O-(6'-O malonyl)-glucoside disappeared or decreased significantly and 2,3,5,4' tetrahydroxystilbene-2-O-beta-D-glucopyranoside, emodin-8-O-beta-D glucopyranoside and physcion-8-O-beta-D-glucopyranoside decreased after the R-RPM samples being processed. On the other hand, the contents of emodin and physcion generally increased after processing. CONCLUSION: The present study indicates that processing Radix Polygoni Multiflori may change the contents and types of chemicals in it. These changes are probably responsible for the various pharmacological effects of R-RPM and P-RPM as well as hepatotoxicity. PMID- 20704711 TI - Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo. AB - BACKGROUND: We have previously shown that in vitro radiosensitivity of human tumor cells segregate non-randomly into a limited number of groups. Each group associates with a specific genotype. However we have also shown that abrogation of a single gene (p21) in a human tumor cell unexpectedly sensitized xenograft tumors comprised of these cells to radiotherapy while not affecting in vitro cellular radiosensitivity. Therefore in vitro assays alone cannot predict tumor response to radiotherapy.In the current work, we measure in vitro radiosensitivity and in vivo response of their xenograft tumors in a series of human tumor lines that represent the range of radiosensitivity observed in human tumor cells. We also measure response of their xenograft tumors to different radiotherapy protocols. We reduce these data into a simple analytical structure that defines the relationship between tumor response and total dose based on two coefficients that are specific to tumor cell genotype, fraction size and total dose. METHODS: We assayed in vitro survival patterns in eight tumor cell lines that vary in cellular radiosensitivity and genotype. We also measured response of their xenograft tumors to four radiotherapy protocols: 8 x 2 Gy; 2 x 5 Gy, 1 x 7.5 Gy and 1 x 15 Gy. We analyze these data to derive coefficients that describe both in vitro and in vivo responses. RESULTS: Response of xenografts comprised of human tumor cells to different radiotherapy protocols can be reduced to only two coefficients that represent 1) total cells killed as measured in vitro 2) additional response in vivo not predicted by cell killing. These coefficients segregate with specific genotypes including those most frequently observed in human tumors in the clinic. Coefficients that describe in vitro and in vivo mechanisms can predict tumor response to any radiation protocol based on tumor cell genotype, fraction-size and total dose. CONCLUSIONS: We establish an analytical structure that predicts tumor response to radiotherapy based on coefficients that represent in vitro and in vivo responses. Both coefficients are dependent on tumor cell genotype and fraction-size. We identify a novel previously unreported mechanism that sensitizes tumors in vivo; this sensitization varies with tumor cell genotype and fraction size. PMID- 20704713 TI - Temporal Artery versus Bladder Thermometry during Adult Medical-Surgical Intensive Care Monitoring: An Observational Study. AB - BACKGROUND: We sought to evaluate agreement between a new and widely implemented method of temperature measurement in critical care, temporal artery thermometry and an established method of core temperature measurement, bladder thermometry as performed in clinical practice. METHODS: Temperatures were simultaneously recorded hourly (n = 736 observations) using both devices as part of routine clinical monitoring in 14 critically ill adult patients with temperatures ranging >/=1 degrees C prior to consent. RESULTS: The mean difference between temporal artery and bladder temperatures measured was -0.44 degrees C (95% confidence interval, -0.47 degrees C to -0.41 degrees C), with temporal artery readings lower than bladder temperatures. Agreement between the two devices was greatest for normothermia (36.0 degrees C to < 38.3 degrees C) (mean difference -0.35 degrees C [95% confidence interval, -0.37 degrees C to -0.33 degrees C]). The temporal artery thermometer recorded higher temperatures during hypothermia (< 36 degrees C) (mean difference 0.66 degrees C [95% confidence interval, 0.53 degrees C to 0.79 degrees C]) and lower temperatures during hyperthermia (>/=38.3 degrees C) (mean difference -0.90 degrees C [95% confidence interval, -0.99 degrees C to 0.81 degrees C]). The sensitivity for detecting fever (core temperature >/=38.3 degrees C) using the temporal artery thermometer was 0.26 (95% confidence interval, 0.20 to 0.33), and the specificity was 0.99 (95% confidence interval, 0.98 to 0.99). The positive likelihood ratio for fever was 24.6 (95% confidence interval, 10.7 to 56.8); the negative likelihood ratio was 0.75 (95% confidence interval, 0.68 to 0.82). CONCLUSIONS: Temporal artery thermometry produces somewhat surprising disagreement with an established method of core temperature measurement and should not to be used in situations where body temperature needs to be measured with accuracy. PMID- 20704712 TI - Organ failure and tight glycemic control in the SPRINT study. AB - INTRODUCTION: Intensive care unit mortality is strongly associated with organ failure rate and severity. The sequential organ failure assessment (SOFA) score is used to evaluate the impact of a successful tight glycemic control (TGC) intervention (SPRINT) on organ failure, morbidity, and thus mortality. METHODS: A retrospective analysis of 371 patients (3,356 days) on SPRINT (August 2005 - April 2007) and 413 retrospective patients (3,211 days) from two years prior, matched by Acute Physiology and Chronic Health Evaluation (APACHE) III. SOFA is calculated daily for each patient. The effect of the SPRINT TGC intervention is assessed by comparing the percentage of patients with SOFA <=5 each day and its trends over time and cohort/group. Organ-failure free days (all SOFA components <=2) and number of organ failures (SOFA components >2) are also compared. Cumulative time in 4.0 to 7.0 mmol/L band (cTIB) was evaluated daily to link tightness and consistency of TGC (cTIB >=0.5) to SOFA <=5 using conditional and joint probabilities. RESULTS: Admission and maximum SOFA scores were similar (P = 0.20; P = 0.76), with similar time to maximum (median: one day; IQR: 13 days; P = 0.99). Median length of stay was similar (4.1 days SPRINT and 3.8 days Pre SPRINT; P = 0.94). The percentage of patients with SOFA <=5 is different over the first 14 days (P = 0.016), rising to approximately 75% for Pre-SPRINT and approximately 85% for SPRINT, with clear separation after two days. Organ-failure free days were different (SPRINT = 41.6%; Pre-SPRINT = 36.5%; P < 0.0001) as were the percent of total possible organ failures (SPRINT = 16.0%; Pre-SPRINT = 19.0%; P < 0.0001). By Day 3 over 90% of SPRINT patients had cTIB >=0.5 (37% Pre-SPRINT) reaching 100% by Day 7 (50% Pre-SPRINT). Conditional and joint probabilities indicate tighter, more consistent TGC under SPRINT (cTIB >=0.5) increased the likelihood SOFA <=5. CONCLUSIONS: SPRINT TGC resolved organ failure faster, and for more patients, from similar admission and maximum SOFA scores, than conventional control. These reductions mirror the reduced mortality with SPRINT. The cTIB >=0.5 metric provides a first benchmark linking TGC quality to organ failure. These results support other physiological and clinical results indicating the role tight, consistent TGC can play in reducing organ failure, morbidity and mortality, and should be validated on data from randomised trials. PMID- 20704714 TI - Non-traumatic myositis ossificans mimicking a malignant neoplasm in an 83-year old woman: a case report. AB - INTRODUCTION: Myositis ossificans is a benign, self-limiting condition that usually affects young, athletically active men. To the best of our knowledge, this case report describes the oldest recorded patient with myositis ossificans. CASE PRESENTATION: Our patient was an 83-year-old Japanese woman who presented with a one week history of a palpable mass in the left thigh. She had a history of surgery for transverse colon cancer and lung cancer at the ages of 73 and 80, respectively. Clinical and radiological examinations suggested a malignant neoplasm such as metastatic carcinoma or extraskeletal osteosarcoma. A diagnosis of myositis ossificans was made by core needle biopsy. Our patient was asymptomatic and had no recurrence at one year follow-up. CONCLUSION: Clinicians should consider myositis ossificans as a possible diagnosis for a soft tissue mass in the limb of an older patient, thereby avoiding unnecessarily aggressive therapy. PMID- 20704715 TI - Intronic motif pairs cooperate across exons to promote pre-mRNA splicing. AB - BACKGROUND: A very early step in splice site recognition is exon definition, a process that is as yet poorly understood. Communication between the two ends of an exon is thought to be required for this step. We report genome-wide evidence for exons being defined through the combinatorial activity of motifs located in flanking intronic regions. RESULTS: Strongly co-occurring motifs were found to specifically reside in four intronic regions surrounding a large number of human exons. These paired motifs occur around constitutive and alternative exons but not pseudo exons. Most co-occurring motifs are limited to intronic regions within 100 nucleotides of the exon. They are preferentially associated with weaker exons. Their pairing is conserved in evolution and they exhibit a lower frequency of single nucleotide polymorphism when paired. Paired motifs display specificity with respect to distance from the exon borders and in constitutive versus alternative splicing. Many resemble binding sites for heterogeneous nuclear ribonucleoproteins. Specific pairs are associated with tissue-specific genes, the higher expression of which coincides with that of the pertinent RNA binding proteins. Tested pairs acted synergistically to enhance exon inclusion, and this enhancement was found to be exon-specific. CONCLUSIONS: The exon-flanking sequence pairs identified here by genomic analysis promote exon inclusion and may play a role in the exon definition step in pre-mRNA splicing. We propose a model in which multiple concerted interactions are required between exonic sequences and flanking intronic sequences to effect exon definition. PMID- 20704716 TI - GTPase regulator associated with the focal adhesion kinase (GRAF) transcript was down-regulated in patients with myeloid malignancies. AB - BACKGROUND: GTPase regulator associated with the focal adhesion kinase (GRAF), a putative tumor suppressor gene, is found inactivated in hematopoietic malignancies by either genetic or epigenetic abnormalities. However, the expression level of GRAF gene has not yet been studied in leukemia. The aim of this study was to investigate the expression level of GRAF gene in those patients with myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML). METHODS: The expression levels of GRAF transcript were determined in 94 patients using real-time quantitative PCR (RQ-PCR). Clinical and laboratory data of these patients were collected and analyzed. RESULTS: The significantly decreased level of GRAF transcript was observed in three myeloid malignancies compared to controls. Within AML, there was no difference in the level of GRAF transcript among different FAB subtypes (P > 0.05). Difference was not observed in the amount of GRAF mRNA between CML at chronic phase and controls. As CML progressed, GRAF transcript significantly decreased. In MDS, three cases with 5q deletion had lower GRAF transcript than four without 5q deletion (median 0.76 vs 2.99) (P > 0.05). CONCLUSION: our results demonstrate that the GRAF transcript is decreased in myeloid malignancies. PMID- 20704717 TI - Modeling the global effect of the basic-leucine zipper transcription factor 1 (bZIP1) on nitrogen and light regulation in Arabidopsis. AB - BACKGROUND: Nitrogen and light are two major regulators of plant metabolism and development. While genes involved in the control of each of these signals have begun to be identified, regulators that integrate gene responses to nitrogen and light signals have yet to be determined. Here, we evaluate the role of bZIP1, a transcription factor involved in light and nitrogen sensing, by exposing wild type (WT) and bZIP1 T-DNA null mutant plants to a combinatorial space of nitrogen (N) and light (L) treatment conditions and performing transcriptome analysis. We use ANOVA analysis combined with clustering and Boolean modeling, to evaluate the role of bZIP1 in mediating L and N signaling genome-wide. RESULTS: This transcriptome analysis demonstrates that a mutation in the bZIP1 gene can alter the L and/or N-regulation of several gene clusters. More surprisingly, the bZIP1 mutation can also trigger N and/or L regulation of genes that are not normally controlled by these signals in WT plants. This analysis also reveals that bZIP1 can, to a large extent, invert gene regulation (e.g., several genes induced by N in WT plants are repressed by N in the bZIP1 mutant). CONCLUSION: These findings demonstrate that the bZIP1 mutation triggers a genome-wide de-regulation in response to L and/or N signals that range from i) a reduction of the L signal effect, to ii) unlocking gene regulation in response to L and N combinations. This systems biology approach demonstrates that bZIP1 tunes L and N signaling relationships genome-wide, and can suppress regulatory mechanisms hypothesized to be needed at different developmental stages and/or environmental conditions. PMID- 20704718 TI - The prevalence of dental erosion and associated risk factors in 12-13-year-old school children in Southern China. AB - BACKGROUND: Dental erosion has been investigated in developed and developing countries and the prevalence varies considerably in different countries, geographic locations, and age groups. With the lifestyle of the Chinese people changing significantly over the decades, dental erosion has begun to receive more attention. However, the information about dental erosion in China is scarce. The purpose of this study was to explore the prevalence of dental erosion and associated risk factors in 12-13-year-old school children in Guangzhou, Southern China. METHODS: This cross-sectional survey was performed by two trained, calibrated examiners. A stratified random sample of 12-13-year-old children (774 boys and 725 girls) from 10 schools was examined for dental erosion using the diagnostic criteria of Eccles and the index of O'Sullivan was applied to record the distribution, severity, and amount of the lesions. Data on the socio-economic status, health behaviours, and general health involved in the etiology of dental erosion were obtained from a self-completed questionnaire. The analyses were performed using SPSS software. RESULTS: At least one tooth surface with signs of erosion was found in 416 children (27.3%). The most frequently affected teeth were the central incisors (upper central incisors, 16.3% and 15.9%; lower central incisors, 17.4% and 14.8%). The most frequently affected surface was the incisal or occlusal edge (43.2%). The loss of enamel contour was present in 54.6% of the tooth surfaces with erosion. Of the affected tooth surfaces, 69.3% had greater than one-half of the tooth surface was affected. The results from logistic regression analysis demonstrated that the children who were female, consumed carbonated drinks once a week or more, and those whose mothers were educated to the primary level tended to have more dental erosion. CONCLUSIONS: Dental erosion in 12-13-year-old Chinese school children is becoming a significant problem. A strategy of offering preventive care, including more campaigns promoting a healthier lifestyle for those at risk of dental erosion should be conducted in Chinese children and their parents. PMID- 20704719 TI - Quantification of ETS exposure in hospitality workers who have never smoked. AB - BACKGROUND: Environmental Tobacco Smoke (ETS) was classified as human carcinogen (K1) by the German Research Council in 1998. According to epidemiological studies, the relative risk especially for lung cancer might be twice as high in persons who have never smoked but who are in the highest exposure category, for example hospitality workers. In order to implement these results in the German regulations on occupational illnesses, a valid method is needed to retrospectively assess the cumulative ETS exposure in the hospitality environment. METHODS: A literature-based review was carried out to locate a method that can be used for the German hospitality sector. Studies assessing ETS exposure using biological markers (for example urinary cotinine, DNA adducts) or questionnaires were excluded. Biological markers are not considered relevant as they assess exposure only over the last hours, weeks or months. Self-reported exposure based on questionnaires also does not seem adequate for medico-legal purposes. Therefore, retrospective exposure assessment should be based on mathematical models to approximate past exposure. RESULTS: For this purpose a validated model developed by Repace and Lowrey was considered appropriate. It offers the possibility of retrospectively assessing exposure with existing parameters (such as environmental dimensions, average number of smokers, ventilation characteristics and duration of exposure). The relative risk of lung cancer can then be estimated based on the individual cumulative exposure of the worker. CONCLUSION: In conclusion, having adapted it to the German hospitality sector, an existing mathematical model appears to be capable of approximating the cumulative exposure. However, the level of uncertainty of these approximations has to be taken into account, especially for diseases with a long latency period such as lung cancer. PMID- 20704720 TI - Validation of the PHQ-9 as a screening instrument for depression in diabetes patients in specialized outpatient clinics. AB - BACKGROUND: For the treatment of depression in diabetes patients, it is important that depression is recognized at an early stage. A screening method for depression is the patient health questionnaire (PHQ-9). The aim of this study is to validate the 9-item Patient Health Questionnaire (PHQ-9) as a screening instrument for depression in diabetes patients in outpatient clinics. METHODS: 197 diabetes patients from outpatient clinics in the Netherlands filled in the PHQ-9. Within 2 weeks they were approached for an interview with the Mini Neuropsychiatric Interview. DSM-IV diagnoses of Major Depressive Disorder (MDD) were the criterion for which the sensitivity, specificity, positive- and negative predictive values and Receiver Operator Curves (ROC) for the PHQ-9 were calculated. RESULTS: The cut-off point of a summed score of 12 on the PHQ-9 resulted in a sensitivity of 75.7% and a specificity of 80.0%. Predictive values for negative and positive test results were respectively 93.4% and 46.7%. The ROC showed an area under the curve of 0.77. CONCLUSIONS: The PHQ-9 proved to be an efficient and well-received screening instrument for MDD in this sample of diabetes patients in a specialized outpatient clinic. The higher cut-off point of 12 that was needed and somewhat lower sensitivity than had been reported elsewhere may be due to the fact that the patients from a specialized diabetes clinic have more severe pathology and more complications, which could be recognized by the PHQ-9 as depression symptoms, while instead being diabetes symptoms. PMID- 20704722 TI - Thinking outside the curve, part II: modeling fetal-infant mortality. AB - BACKGROUND: Greater epidemiologic understanding of the relationships among fetal infant mortality and its prognostic factors, including birthweight, could have vast public health implications. A key step toward that understanding is a realistic and tractable framework for analyzing birthweight distributions and fetal-infant mortality. The present paper is the second of a two-part series that introduces such a framework. METHODS: We propose estimating birthweight-specific mortality within each component of a normal mixture model representing a birthweight distribution, the number of components having been determined from the data rather than fixed a priori. RESULTS: We address a number of methodological issues related to our proposal, including the construction of confidence intervals for mortality risk at any given birthweight within a component, for odds ratios comparing mortality within two different components from the same population, and for odds ratios comparing mortality within analogous components from two different populations. As an illustration we find that, for a population of white singleton infants, the odds of mortality at 3000 g are an estimated 4.15 times as large in component 2 of a 4-component normal mixture model as in component 4 (95% confidence interval, 2.04 to 8.43). We also outline an extension of our framework through which covariates could be probabilistically related to mixture components. This extension might allow the assertion of approximate correspondences between mixture components and identifiable subpopulations. CONCLUSIONS: The framework developed in this paper does not require infants from compromised pregnancies to share a common birthweight-specific mortality curve, much less assume the existence of an interval of birthweights over which all infants have the same curve. Hence, the present framework can reveal heterogeneity in mortality that is undetectable via a contaminated normal model or a 2-component normal mixture model. PMID- 20704721 TI - The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear. AB - BACKGROUND: The planar cell polarity (PCP) signalling pathway is fundamental to a number of key developmental events, including initiation of neural tube closure. Disruption of the PCP pathway causes the severe neural tube defect of craniorachischisis, in which almost the entire brain and spinal cord fails to close. Identification of mouse mutants with craniorachischisis has proven a powerful way of identifying molecules that are components or regulators of the PCP pathway. In addition, identification of an allelic series of mutants, including hypomorphs and neomorphs in addition to complete nulls, can provide novel genetic tools to help elucidate the function of the PCP proteins. RESULTS: We report the identification of a new N-ethyl-N-nitrosourea (ENU)-induced mutant with craniorachischisis, which we have named chuzhoi (chz). We demonstrate that chuzhoi mutant embryos fail to undergo initiation of neural tube closure, and have characteristics consistent with defective convergent extension. These characteristics include a broadened midline and reduced rate of increase of their length-to-width ratio. In addition, we demonstrate disruption in the orientation of outer hair cells in the inner ear, and defects in heart and lung development in chuzhoi mutants. We demonstrate a genetic interaction between chuzhoi mutants and both Vangl2Lp and Celsr1Crsh mutants, strengthening the hypothesis that chuzhoi is involved in regulating the PCP pathway. We demonstrate that chuzhoi maps to Chromosome 17 and carries a splice site mutation in Ptk7. This mutation results in the insertion of three amino acids into the Ptk7 protein and causes disruption of Ptk7 protein expression in chuzhoi mutants. CONCLUSIONS: The chuzhoi mutant provides an additional genetic resource to help investigate the developmental basis of several congenital abnormalities including neural tube, heart and lung defects and their relationship to disruption of PCP. The chuzhoi mutation differentially affects the expression levels of the two Ptk7 protein isoforms and, while some Ptk7 protein can still be detected at the membrane, chuzhoi mutants demonstrate a significant reduction in membrane localization of Ptk7 protein. This mutant provides a useful tool to allow future studies aimed at understanding the molecular function of Ptk7. PMID- 20704723 TI - The CONSTANCES cohort: an open epidemiological laboratory. AB - BACKGROUND: Prospective cohorts represent an essential design for epidemiological studies and allow for the study of the combined effects of lifestyle, environment, genetic predisposition, and other risk factors on a large variety of disease endpoints. The CONSTANCES cohort is intended to provide public health information and to serve as an "open epidemiologic laboratory" accessible to the epidemiologic research community. Although designed as a "general-purpose" cohort with very broad coverage, it will particularly focus on occupational and social determinants of health, and on aging. METHODS: The CONSTANCES cohort is designed as a randomly selected representative sample of French adults aged 18-69 years at inception; 200,000 subjects will be included over a five-year period. At inclusion, the selected subjects will be invited to fill a questionnaire and to attend a Health Screening Center (HSC) for a comprehensive health examination: weight, height, blood pressure, electrocardiogram, vision, auditory, spirometry, and biological parameters; for those aged 45 years and older, a specific work-up of functional, physical, and cognitive capacities will be performed. A biobank will be set up. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HSC. Social and work-related events and health data will be collected from the French national retirement, health and death databases. The data that will be collected include social and demographic characteristics, socioeconomic status, life events, behaviors, and occupational factors. The health data will cover a wide spectrum: self-reported health scales, reported prevalent and incident diseases, long-term chronic diseases and hospitalizations, sick-leaves, handicaps, limitations, disabilities and injuries, healthcare utilization and services provided, and causes of death. To take into account non-participation at inclusion and attrition throughout the longitudinal follow-up, a cohort of non-participants will be set up and followed through the same national databases as participants. A field-pilot was performed in 2010 in seven HSCs, which included about 3,500 subjects; it showed a satisfactory structure of the sample and a good validity of the collected data. DISCUSSION: The constitution of the full eligible sample is planned during the last trimester of 2010, and the cohort will be launched at the beginning of 2011. PMID- 20704724 TI - Listening to patients: using verbal data in the validation of the Aberdeen Measures of Impairment, Activity Limitation and Participation Restriction (Ab IAP). AB - BACKGROUND: The purpose of the study was to evaluate the validity of the self administered Aberdeen Measures of Impairment, Activity Limitation and Participation Restriction (Ab-IAP): by investigating how participants interpret and respond to questions using the cognitive interviewing technique. METHODS: Twenty patients with osteoarthritis of the knee or hip participated in a cognitive interview whilst completing the Ab-IAP. Interviews were conducted using the concurrent 'think aloud' design. All interviews were audio recorded and transcribed verbatim and analysed (i) using a standardised classification scheme to identify four types of response problems and (ii) thematically using the constant comparative technique. RESULTS: Participants used various response strategies when answering questions about impairment, activity limitations and participation restriction. Problems were judged to be present in 3.1% of participants' responses for the item Ab-IAP. Thematic analysis provided insight into the type and nature of problems people experienced when completing the Ab IAP measures. The problems identified were mainly comprehension and response problems. CONCLUSIONS: Participants had minimal difficulties completing the Ab IAP; however those difficulties identified have prompted suggestions for improving the measures. The cognitive interviews produced results that were compatible with statistical analysis of the measures.. Cognitive interviewing was beneficial for testing the validity and acceptability of new Ab-IAP measures. The results demonstrates that the Ab-IAP, in addition to being theoretically-based and having good psychometric properties, elicits appropriate responses. PMID- 20704725 TI - Identification, classification and evolution of owl monkeys (Aotus, Illiger 1811). AB - BACKGROUND: Owl monkeys, belonging to the genus Aotus, have been extensively used as animal models in biomedical research but few reports have focused on the taxonomy and phylogeography of this genus. Moreover, the morphological similarity of several Aotus species has led to frequent misidentifications, mainly at the boundaries of their distribution. In this study, sequence data from five mitochondrial regions and the nuclear, Y-linked, SRY gene were used for species identification and phylogenetic reconstructions using well characterized specimens of Aotus nancymaae, A. vociferans, A. lemurinus, A. griseimembra, A. trivirgatus, A. nigriceps, A. azarae boliviensis and A. infulatus. RESULTS: The complete MT-CO1, MT-TS1, MT-TD, MT-CO2, MT-CYB regions were sequenced in 18 Aotus specimens. ML and Bayesian topologies of concatenated data and separate regions allowed for the proposition of a tentative Aotus phylogeny, indicating that Aotus diverged some 4.62 Million years before present (MYBP). Similar analyses with included GenBank specimens were useful for assessing species identification of deposited data. CONCLUSIONS: Alternative phylogenetic reconstructions, when compared with karyotypic and biogeographic data, led to the proposition of evolutionary scenarios questioning the conventional diversification of this genus in monophyletic groups with grey and red necks. Moreover, genetic distance estimates and haplotypic differences were useful for species validations. PMID- 20704726 TI - A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy. AB - BACKGROUND: Treatment with Androgen Deprivation Therapy (ADT) for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT. METHODS: Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home based tailored intervention to meet the following guidelines a) > or = 5 servings vegetables and fruits/day; b) 30%-35% of total energy from fat, and < 10% energy from saturated fat/day; c) 10% of energy from polyunsaturated fat/day; d) limited consumption of processed meats; e) 25-35 gm of fibre/day; f) alcoholic drinks < or = 28 units/week; g) limited intake of foods high in salt and/or sugar. They are also encouraged to include at least 30 minutes of brisk walking, 5 or more days per week. The primary outcomes are change in body composition, fatigue and quality of life scores. Secondary outcomes include dietary intake, physical activity and perceived stress. Baseline information collected includes: socio economic status, treatment duration, perceived social support and health status, family history of cancer, co-morbidities, medication and supplement use, barriers to change, and readiness to change their health behaviour. Data for the primary and secondary outcomes will be collected at baseline, 3 and 6 months from 47 intervention and 47 control patients. DISCUSSION: The results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT. TRIAL REGISTRATION: ISRCTN trial number ISCRTN75282423. PMID- 20704727 TI - Novel cis-trans interactions are involved in post-transcriptional regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 mRNA. AB - BACKGROUND: A variety of pathways target CDKI p21WAF1/CIP1 expression at transcriptional, post-transcriptional as well as translational levels. We previously found that cell growth suppressing retinoid CD437 enhanced expression of p21WAF1/CIP1 and DNA damage inducible GADD45 proteins in part by elevating their mRNA stability. RESULTS: Here, we investigated molecular mechanisms of CD437-dependent post-transcriptional regulation of p21WAF1/CIP1 expression. By utilizing MDA-MB-468 HBC cells expressing chimeric rabbit beta-globin p21WAF1/CIP1 transcripts we mapped multiple CD437-responsive sequences located within positions 1195 to 1795 of the 3'-untranslated region of p21WAF1/CIP1 mRNA. Several cytoplasmic proteins present in MDA-MB-468, MCF-7 HBC as well as HL-60R leukemia cells bound specifically, in vitro, with these CD437-responsive sequences. CD437 treatment of cells resulted in elevated binding of ~85 kD and ~55 kD cytoplasmic proteins with putative CD437-responsive sequences. A 12 nt RNA sequence (5'-UGUGGUGGCACA-3') present within CD437-responsive region of p21WAF1/CIP1 mRNA displayed specific and elevated binding with the above noted proteins. Treatment of cells with ActD or CHX prior to CD437 exposure did not abrogate RNA-protein interactions. However, treatment of cytoplasmic protein extracts with proteinase K or alkaline phosphatase resulted in loss of RNA protein interactions. CONCLUSIONS: CD437 regulates cell growth in part by regulating stability of p21WAF1/CIP1 mRNA that involves specific RNA-protein interactions that are phosphorylation-dependent, while not requiring nascent transcription or protein synthesis. PMID- 20704728 TI - Granulosa cell tumor of the ovary and antecedent of adjuvant tamoxifen use for breast cancer. AB - BACKGROUND: Adult granulosa cell tumor associated with antecedent use of tamoxifen as adjuvant hormonotherapy for breast cancer is rare. The pathogenesis of this occurrence remains difficult to explain. The estrogenic effect of tamoxifen can be one such explanation. CASE PRESENTATION: A 47 year-old women was treated with surgery, chemotherapy, radiotherapy and tamoxifen for stage III estrogen receptor positive breast carcinoma. Ten months after stopping tamoxifen, we diagnosed a stage Ic granulosa cell tumor of the ovary. CONCLUSIONS: Use of tamoxifen has been found to be associated with gynecological tumors like endometrial carcinoma. Its association with granulosa cell tumor of the ovary is uncommon. Only two previous cases have been reported in literature. PMID- 20704729 TI - AlphaS1-casein, which is essential for efficient ER-to-Golgi casein transport, is also present in a tightly membrane-associated form. AB - BACKGROUND: Caseins, the main milk proteins, aggregate in the secretory pathway of mammary epithelial cells into large supramolecular structures, casein micelles. The role of individual caseins in this process and the mesostructure of the casein micelle are poorly known. RESULTS: In this study, we investigate primary steps of casein micelle formation in rough endoplasmic reticulum-derived vesicles prepared from rat or goat mammary tissues. The majority of both alphaS1- and beta-casein which are cysteine-containing casein was dimeric in the endoplasmic reticulum. Saponin permeabilisation of microsomal membranes in physico-chemical conditions believed to conserve casein interactions demonstrated that rat immature beta-casein is weakly aggregated in the endoplasmic reticulum. In striking contrast, a large proportion of immature alphaS1-casein was recovered in permeabilised microsomes when incubated in conservative conditions. Furthermore, a substantial amount of alphaS1-casein remained associated with microsomal or post-ER membranes after saponin permeabilisation in non conservative conditions or carbonate extraction at pH11, all in the presence of DTT. Finally, we show that protein dimerisation via disulfide bond is involved in the interaction of alphaS1-casein with membranes. CONCLUSIONS: These experiments reveal for the first time the existence of a membrane-associated form of alphaS1 casein in the endoplasmic reticulum and in more distal compartments of the secretory pathway of mammary epithelial cells. Our data suggest that alphaS1 casein, which is required for efficient export of the other caseins from the endoplasmic reticulum, plays a key role in early steps of casein micelle biogenesis and casein transport in the secretory pathway. PMID- 20704731 TI - Effect of continuous positive airway pressure therapy on a large hemangioma complicated with obstructive sleep apnea syndrome: a case report. AB - INTRODUCTION: Hemangiomas involving the upper airway can be an uncommon cause of obstructive sleep apnea syndrome. CASE PRESENTATION: A 26-year-old Caucasian man with a known history of a large hemangioma of his head and neck presented with sleep-disordered breathing to the sleep unit of our hospital. Severe obstructive sleep apnea syndrome was revealed on polysomnography. Nasal continuous positive airway pressure was implemented effectively, reducing daytime hypersomnolence and significantly improving sleep parameters. After three years of adherent use, the patient remains in a good condition and the hemangioma is stable. CONCLUSION: Application of continuous positive airway pressure can be an effective treatment for patients with obstructive sleep apnea syndrome complicated with vascular tumors. Periodic follow-up of these patients is necessary, as little is known about the long-term effects of continuous positive airway pressure therapy. PMID- 20704732 TI - Hemolymphangioma of the lower extremities in children: two case reports. AB - BACKGROUND AND PURPOSE: Hemo-lymphangiomas are rare benign tumors that arise from congenital malformation of the vascular system. They are usually diagnosed at birth or early in childhood. The management of hemo-lymphangiomas in children remains challenging because complete resection is often difficult to be achieved and recurrences are common. METHODS: We present the case of two children with a mass on their left tibia. Imaging modalities, plain radiograph, Ultrasonography and Magnetic Resonance were used to investigate the nature of the mass, the anatomical relationship to the neighboring tissues and help planning the surgical resection. The dominant diagnosis was hemo-lymphangioma. Both lesions increased in size in a short period of follow-up thus we decided to proceed to surgical excision.The diagnosis of hemo-lymphangioma was confirmed by histological examination of the surgical specimen.Post-operatively, seroma was formed to the first patient, managed by placing a drainage and immobilizing the limb on a splint.The second patient experienced no complications post-operatively.After 12 months of follow-up both patients had no complications or recurrence. CONCLUSIONS: Very few cases of hemo-lymphangiomas of the extremities have been reported in the literature. Those tumors can grow slowly and remain asymptomatic for a long period of time or may become aggressive and enlarge rapidly, without invasive ability though.Radical resection is the choice of treatment offering the lowest recurrence rates. Other therapeutic methods are: aspiration and drainage, cryotherapy, injection of sclerotic agents and radiotherapy; although none of those offers better results that the surgical excision. PMID- 20704730 TI - The inflammatory cytokine tumor necrosis factor modulates the expression of Salmonella typhimurium effector proteins. AB - Tumor necrosis factor alpha (TNF-alpha)is a host inflammatory factor. Bacteria increase TNF-alpha expression in a variety of human diseases including infectious diseases, inflammatory bowel diseases, and cancer. It is unknown, however, how TNF-alpha directly modulates bacterial protein expression during intestinal infection and chronic inflammation. In the current study, we hypothesize that Salmonella typhimurium senses TNF-alpha and show that TNF-alpha treatment modulates Salmonella virulent proteins (called effectors), thus changing the host bacterial interaction in intestinal epithelial cells. We investigated the expression of 23 Salmonella effectors after TNF-alpha exposure. We found that TNF alpha treatment led to differential effector expression: effector SipA was increased by TNF-alpha treatment, whereas the expression levels of other effectors, including gogB and spvB, decreased in the presence of TNF-alpha. We verified the protein expression of Salmonella effectors AvrA and SipA by Western blots. Furthermore, we used intestinal epithelial cells as our experimental model to explore the response of human intestinal cells to TNF-alpha pretreated Salmonella. More bacterial invasion was found in host cells colonized with Salmonella strains pretreated with TNF-alpha compared to Salmonella without TNF alpha treatment. TNF-alpha pretreated Salmonella induced higher proinflammatory JNK signalling responses compared to the Salmonella strains without TNF-alpha exposure. Exposure to TNF-alpha made Salmonella to induce more inflammatory cytokine IL-8 in intestinal epithelial cells. JNK inhibitor treatment was able to suppress the effects of TNF-pretreated-Salmonella in enhancing expressions of phosphorylated-JNK and c-jun and secretion of IL-8. Overall, our study provides new insights into Salmonella-host interactions in intestinal inflammation. PMID- 20704733 TI - Efflux pumps expression and its association with porin down-regulation and beta lactamase production among Pseudomonas aeruginosa causing bloodstream infections in Brazil. AB - BACKGROUND: Multi-drug efflux pumps have been increasingly recognized as a major component of resistance in P. aeruginosa. We have investigated the expression level of efflux systems among clinical isolates of P. aeruginosa, regardless of their antimicrobial susceptibility profile. RESULTS: Aztreonam exhibited the highest in vitro activity against the P. aeruginosa isolates studied (64.4% susceptibility), whereas susceptibility rates of imipenem and meropenem were both 47.5%. The MexXY-OprM and MexAB-OprM efflux systems were overexpressed in 50.8% and 27.1% of isolates studied, respectively. Overexpression of the MexEF-OprN and MexCD-OprJ systems was not observed. AmpC beta-lactamase was overexpressed in 11.9% of P. aeruginosa isolates. In addition, decreased oprD expression was also observed in 69.5% of the whole collection, and in 87.1% of the imipenem non susceptible P. aeruginosa clinical isolates. The MBL-encoding genes blaSPM-1 and blaIMP-1 were detected in 23.7% and 1.7% P. aeruginosa isolates, respectively. The blaGES-1 was detected in 5.1% of the isolates, while blaGES-5 and blaCTX-M-2 were observed in 1.7% of the isolates evaluated. In the present study, we have observed that efflux systems represent an adjuvant mechanism for antimicrobial resistance. CONCLUSIONS: Efflux systems in association of distinct mechanisms such as the porin down-regulation, AmpC overproduction and secondary beta lactamases play also an important role in the multi-drug resistance phenotype among P. aeruginosa clinical isolates. PMID- 20704734 TI - Granzyme G is expressed in the two-cell stage mouse embryo and is required for the maternal-zygotic transition. AB - BACKGROUND: Detailed knowledge of the molecular and cellular mechanisms that direct spatial and temporal gene expression in pre-implantation embryos is critical for understanding the control of the maternal-zygotic transition and cell differentiation in early embryonic development. In this study, twenty-three clones, expressed at different stages of early mouse development, were identified using differential display reverse transcription polymerase chain reaction (DDRT PCR). One of these clones, which is expressed in 2-cell stage embryos at 48 hr post-hCG injection, shows a perfect sequence homology to the gene encoding the granzyme G protein. The granzyme family members are serine proteases that are present in the secretory granules of cytolytic T lymphocytes. However, the pattern of granzyme G expression and its function in early mouse embryos are entirely unknown. RESULTS: Upon the introduction of an antisense morpholino (2 mM) against granzyme G to knock-down endogenous gene function, all embryos were arrested at the 2- to 4-cell stages of egg cleavage, and the de novo synthesis of zygotic RNAs was decreased. The embryonic survival rate was dramatically decreased at the late 2-cell stage when serine protease-specific inhibitors, 0.1 mM 3,4-dichloroisocoumarin (3,4-DCI), and 2 mM phenyl methanesulphonyl fluoride (PMSF), were added to the in vitro embryonic culture medium. Survival was not affected by the addition of 0.5 mM EDTA, a metalloproteinase inhibitor. CONCLUSION: We characterized for the first time the expression and function of granzyme G during early stage embryogenesis. Our data suggest that granzyme G is an important factor in early mouse embryonic development and may play a novel role in the elimination of maternal proteins and the triggering of zygotic gene expression during the maternal-zygotic transition. PMID- 20704735 TI - Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer. AB - BACKGROUND: Mitochondrial DNA (mtDNA) haplogroups and single nucleotide polymorphisms (mtSNP) have been shown to play a role in various human conditions including aging and some neurodegenerative diseases, metabolic diseases and cancer. METHODS: To investigate whether mtDNA haplogroups contribute to the occurrence of cancer in a specific Chinese population, we have carried out a comprehensive case-control study of mtDNA from large cohorts of patients with three common cancer types, namely, colorectal cancer (n = 108), thyroid cancer (n = 100) and breast cancer (n = 104), in Wenzhou, a southern Chinese city in the Zhejiang Province. RESULTS: We found that patients with mtDNA haplogroup M exhibited an increased risk of breast cancer occurrence [OR = 1.77; 95% CI (1.03 3.07); P = 0.040], and that this risk was even more pronounced in a sub haplogroup of M, D5 [OR = 3.11; 95%CI (1.07-9.06); p = 0.030]. In spite of this, in patients with breast cancer, haplogroup M was decreased in the metastatic group. On the other hand, our results also showed that haplogroup D4a was associated with an increased risk of thyroid cancer [OR = 3.00; 95%CI (1.09 8.29); p = 0.028]. However, no significant correlation has been detected between any mtDNA haplogroups and colorectal cancer occurrence. CONCLUSION: Our investigation indicates that mitochondrial haplogroups could have a tissue specific, population-specific and stage-specific role in modulating cancer development. PMID- 20704737 TI - Surgical treatment of gingival overgrowth with 10 years of follow-up. AB - BACKGROUND: In some pathological conditions, gingivitis caused by plaque accumulation can be more severe, with the result of an overgrowth. Nevertheless, the overgrowth involves the gingival margin with extension to the inter-dental papilla. The lesion may involve the inter-proximal spaces, and become so extensive that the teeth are displaced and their crowns covered. Severe overgrowth may lead to impairment in aesthetic and masticatory functions, requiring surgical excision of the excessive tissue. Aim of this study is to describe an operative protocol for the surgical treatment of localized gingival overgrowth analyzing the surgical technique, times and follow-up. METHODS: A total of 20 patients were enrolled and underwent initial, non surgical, periodontal treatment and training sessions on home oral hygiene training. The treatment plan involved radical exeresis of the mass followed by positioning of an autograft of connective tissue and keratinized gingiva. RESULTS: During 10 years of follow-up, all the grafts appeared well vascularized, aesthetically satisfactory, and without relapse. CONCLUSIONS: Periodontal examinations, surgical procedures, and dental hygiene with follow-up are an essential part of the treatment protocol. However, additional effort is needed from the patient. Hopefully, the final treatment result makes it all worthwhile. PMID- 20704736 TI - Modulation of redox homeostasis under suboptimal conditions by Arabidopsis nudix hydrolase 7. AB - BACKGROUND: Nudix hydrolases play a key role in maintaining cellular homeostasis by hydrolyzing various nuceloside diphosphate derivatives and capped mRNAs. Several independent studies have demonstrated that Arabidopsis nudix hydrolase 7 (AtNUDT7) hydrolyzes NADH and ADP-ribose. Loss of function Atnudt7-1 mutant plants (SALK_046441) exhibit stunted growth, higher levels of reactive oxygen species, enhanced resistance to pathogens. However, using the same T-DNA line, two other groups reported that mutant plants do not exhibit any visible phenotypes. In this study we analyze plausible factors that account for differences in the observed phenotypes in Atnudt7. Secondly, we evaluate the biochemical and molecular consequences of increased NADH levels due to loss of function of AtNUDT7 in Arabidopsis. RESULTS: We identified a novel conditional phenotype of Atnudt7-1 knockout plants that was contingent upon nutrient composition of potting mix. In nutrient-rich Metro-Mix, there were no phenotypic differences between mutant and wild-type (WT) plants. In the nutrient-poor mix (12 parts vermiculite: 3 parts Redi-earth and 1 part sand), mutant plants showed the characteristic stunted phenotype. Compared with WT plants, levels of glutathione, NAD+, NADH, and in turn NADH:NAD+ ratio were higher in Atnudt7-1 plants growing in 12:3:1 potting mix. Infiltrating NADH and ADP-ribose into WT leaves was sufficient to induce AtNUDT7 protein. Constitutive over-expression of AtNudt7 did not alter NADH levels or resistance to pathogens. Transcriptome analysis identified nearly 700 genes differentially expressed in the Atnudt7-1 mutant compared to WT plants grown in 12:3:1 potting mix. In the Atnudt7-1 mutant, genes associated with defense response, proteolytic activities, and systemic acquired resistance were upregulated, while gene ontologies for transcription and phytohormone signaling were downregulated. CONCLUSIONS: Based on these observations, we conclude that the differences observed in growth phenotypes of the Atnudt7-1 knockout mutants can be due to differences in the nutrient composition of potting mix. Our data suggests AtNUDT7 plays an important role in maintaining redox homeostasis, particularly for maintaining NADH:NAD+ balance for normal growth and development. During stress conditions, rapid induction of AtNUDT7 is important for regulating the activation of stress/defense signaling and cell death pathways. PMID- 20704738 TI - Factors associated with whole carcass condemnation rates in provincially inspected abattoirs in Ontario 2001-2007: implications for food animal syndromic surveillance. AB - BACKGROUND: Ontario provincial abattoirs have the potential to be important sources of syndromic surveillance data for emerging diseases of concern to animal health, public health and food safety. The objectives of this study were to: (1) describe provincially inspected abattoirs processing cattle in Ontario in terms of the number of abattoirs, the number of weeks abattoirs process cattle, geographical distribution, types of whole carcass condemnations reported, and the distance animals are shipped for slaughter; and (2) identify various seasonal, secular, disease and non-disease factors that might bias the results of quantitative methods, such as cluster detection methods, used for food animal syndromic surveillance. RESULTS: Data were collected from the Ontario Ministry of Agriculture, Food and Rural Affairs and the Ontario Cattlemen's Association regarding whole carcass condemnation rates for cattle animal classes, abattoir compliance ratings, and the monthly sales-yard price for various cattle classes from 2001-2007. To analyze the association between condemnation rates and potential explanatory variables including abattoir characteristics, season, year and commodity price, as well as animal class, negative binomial regression models were fit using generalized estimating equations (GEE) to account for autocorrelation among observations from the same abattoir. Results of the fitted model found animal class, year, season, price, and audit rating are associated with condemnation rates in Ontario abattoirs. In addition, a subset of data was used to estimate the average distance cattle are shipped to Ontario provincial abattoirs. The median distance from the farm to the abattoir was approximately 82 km, and 75% of cattle were shipped less than 100 km. CONCLUSIONS: The results suggest that secular and seasonal trends, as well as some non-disease factors will need to be corrected for when applying quantitative methods for syndromic surveillance involving these data. This study also demonstrated that animals shipped to Ontario provincial abattoirs come from relatively local farms, which is important when considering the use of spatial surveillance methods for these data. PMID- 20704740 TI - Characterization of immortalized choroid plexus epithelial cell lines for studies of transport processes across the blood-cerebrospinal fluid barrier. AB - BACKGROUND: Two rodent choroid plexus (CP) epithelial cell lines, Z310 and TR CSFB, were compared with primary rat CP epithelial cells and intact CP tissue with respect to transport protein expression, function and tight junction (TJ) formation. METHODS: For expression profiles of transporters and TJ proteins, qPCR and western blot analysis were used. Uptake assays were performed to study the functional activity of transporters and TJ formation was measured by trans epithelial electrical resistance (TEER) and visualized by electron microscopy. RESULTS: The expression of known ATP-binding cassette (Abc) transporter and solute carrier (Slc) genes in CP was confirmed by qPCR. Primary cells and cell lines showed similar, but overall lower expression of Abc transporters and absent Slc expression when compared to intact tissue. Consistent with this Mrp1, Mrp4 and P-gp protein levels were higher in intact CP compared to cell lines. Functionality of P-gp and Mrp1 was confirmed by Calcein-AM and CMFDA uptake assays and studies using [3H]bis-POM-PMEA as a substrate indicated Mrp4 function. Cell lines showed low or absent TJ protein expression. After treatment of cell lines with corticosteroids, RNA expression of claudin1, 2 and 11 and occludin was elevated, as well as claudin1 and occludin protein expression. TJ formation was further investigated by freeze-fracture electron microscopy and only rarely observed. Increases in TJ particles with steroid treatment were not accompanied by an increase in transepithelial electrical resistance (TEER). CONCLUSION: Taken together, immortalized cell lines may be a tool to study transport processes mediated by P-gp, Mrp1 or Mrp4, but overall expression of transport proteins and TJ formation do not reflect the situation in intact CP tissue. PMID- 20704739 TI - Positional differences in the wound transcriptome of skin and oral mucosa. AB - BACKGROUND: When compared to skin, oral mucosal wounds heal rapidly and with reduced scar formation. Recent studies suggest that intrinsic differences in inflammation, growth factor production, levels of stem cells, and cellular proliferation capacity may underlie the exceptional healing that occurs in oral mucosa. The current study was designed to compare the transcriptomes of oral mucosal and skin wounds in order to identify critical differences in the healing response at these two sites using an unbiased approach. RESULTS: Using microarray analysis, we explored the differences in gene expression in skin and oral mucosal wound healing in a murine model of paired equivalent sized wounds. Samples were examined from days 0 to 10 and spanned all stages of the wound healing process. Using unwounded matched tissue as a control, filtering identified 1,479 probe sets in skin wounds yet only 502 probe sets in mucosal wounds that were significantly differentially expressed over time. Clusters of genes that showed similar patterns of expression were also identified in each wound type. Analysis of functionally related gene expression demonstrated dramatically different reactions to injury between skin and mucosal wounds. To explore whether site specific differences might be derived from intrinsic differences in cellular responses at each site, we compared the response of isolated epithelial cells from skin and oral mucosa to a defined in vitro stimulus. When cytokine levels were measured, epithelial cells from skin produced significantly higher amounts of proinflammatory cytokines than cells from oral mucosa. CONCLUSIONS: The results provide the first detailed molecular profile of the site-specific differences in the genetic response to injury in mucosa and skin, and suggest the divergent reactions to injury may derive from intrinsic differences in the cellular responses at each site. PMID- 20704741 TI - Out-of-hours GPs and palliative care-a qualitative study exploring information exchange and communication issues. AB - BACKGROUND: Out-of-hours general practitioners (GPs) cover the community over a significant proportion of a given week, and palliative care patients are seen as a priority. Little is known about how well these GPs feel supported in their line of work and whether communication exchanges work well for the proportion of their patients who have palliative care needs. For this study, GPs who provide out-of hours care were interviewed in order to explore factors that they identified as detrimental or beneficial for good communication between themselves, patients, relatives and other professionals, specifically to palliative care encounters. METHODS: Nine GPs were interviewed using face-to-face semi-structured interviews. All nine GPs worked regular out-of-hours sessions. Data from transcripts was analysed using Interpretative Phenomenological Analysis. RESULTS: A predominant theme expressed by GPs related to constraints within the system provided by the local private company owned out-of-hours provider. A strong feeling of 'being alone out there' emerged, with some GPs more willing to call for help than others, and others expressing their concern at access to pharmacies and medication being very inconsistent.Out-of-hours GPs felt left alone on occasion, unable to access daytime services and not knowing who to call for advice. Information hand-over systems from in-hours to out-of-hours with regard to palliative care were felt to be inadequate. Out-of-hours doctors interviewed felt left out of the care loop; handover sheets from specialist palliative care providers were a rarity. CONCLUSIONS: Out-of-hours services need to be mindful of the needs of the GPs they employ, in particular relating to the palliative care they provide in this setting. Other healthcare professionals should aim to keep their local out-of-hours service informed about palliative care patients they may be called to see. PMID- 20704742 TI - Retinopathy in severe malaria in Ghanaian children--overlap between fundus changes in cerebral and non-cerebral malaria. AB - BACKGROUND: In malaria-endemic areas, reliably establishing parasitaemia for diagnosis of malaria can be difficult. A retinopathy with some features unique to severe malaria with a predictive value on prognosis, has been described. Detection of this retinopathy could be a useful diagnostic tool. This study was designed to determine the diagnostic usefulness of retinopathy on ophthalmoscopy in severe malaria syndromes: Cerebral malaria (CM) and non-cerebral severe malaria (non-CM), i.e. malaria with respiratory distress (RD) and malaria with severe anaemia (SA), in Ghanaian children. Secondly, to determine any association between retinopathy and the occurrence of convulsions in patients with CM. METHODS AND SUBJECTS: A cross-sectional study of consecutive patients on admission with severe malaria who were assessed for retinal signs, at the Department of Child Health, Korle-Bu Teaching Hospital, Accra, from July to August 2002 was done. All children had dilated-fundus examination by direct and indirect ophthalmoscopy. RESULTS: Fifty-eight children aged between six months and nine years were recruited. Twenty six(45%) had CM, 22 with convulsion; 26(45%) had SA and six(10%) had RD.Any retinopathy was seen in: CM 19(73%), SA 14(54%), RD 3(50.0%), CM with convulsion 15(68%) and CM without convulsion 4(100%). Comparison between CM versus non-CM groups showed a significant risk relationship between retinal whitening and CM(OR = 11.0, CI = 2.2- 56.1, p = 0.001). There was no significant association with papilloedema(OR = 0.9, CI = 0.3 - 3.0, p = 0.9), macular whitening(OR = 1.6, CI = 0.5 - 4.8, p = 0.4), macular haemorrhage(OR = 0.28, CI = 0.03 - 2.7 p = 0.2), retinal haemorrhage(OR = 1.9, CI = 0.6 - 5.6, p = 0.3), vessel abnormality(OR = 1.9, CI = 0.6 - 6.1, p = 0.3) and cotton wool spots(OR not calculated, p = 0.08).Tortuous and engorged retinal veins, not previously described as a feature of CM, was the most common vascular abnormality(15/58 = 26%) and was detected even in the absence of papilloedema. CONCLUSION: Retinal whitening, a sign suggestive of retinal ischaemia, was significantly more common in CM than in non-CM syndromes. However, the high prevalence of any retinopathy in the latter suggests that the brain and the retina may be suffering from ischaemia in both CM and non-CM. PMID- 20704743 TI - A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome. AB - BACKGROUND: An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives. METHODS: We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples. RESULTS: The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families. CONCLUSIONS: We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution. PMID- 20704744 TI - Transcription profiling of fertilization and early seed development events in a solanaceous species using a 7.7 K cDNA microarray from Solanum chacoense ovules. AB - BACKGROUND: To provide a broad analysis of gene expression changes in developing embryos from a solanaceous species, we produced amplicon-derived microarrays with 7741 ESTs isolated from Solanum chacoense ovules bearing embryos from all developmental stages. Our aims were to: 1) identify genes expressed in a tissue specific and temporal-specific manner; 2) define clusters of genes showing similar patterns of spatial and temporal expression; and 3) identify stage specific or transition-specific candidate genes for further functional genomic analyses. RESULTS: We analyzed gene expression during S. chacoense embryogenesis in a series of experiments with probes derived from ovules isolated before and after fertilization (from 0 to 22 days after pollination), and from leaves, anthers, and styles. From the 6374 unigenes present in our array, 1024 genes were differentially expressed (>or= +/- 2 fold change, p value /= two-fold ratio, p-value or = 60% by echocardiography, meanwhile < 60% by MRI in these 9 patients. Severity of MR evaluated by effective regurgitant orifice area (EROA) didn't differ with preserved and depressed EFs by MRI (p > 0.05). However, both right upper PV indices (0.16 +/- 0.06 vs. 0.24 +/- 0.08, p: 0.024) and LA EFs (0.19 +/- 0.09 vs. 0.33 +/- 0.14, p: 0.025) were significantly decreased in patients with depressed EFs when compared to patients with normal EFs. CONCLUSIONS: MRI might be preferred when small changes in functional parameters like LV EF, LA EF, and PV index are of clinical importance to disease management like asymptomatic MR patients that we follow up for appropriate surgery timing. PMID- 20704765 TI - LY294002 may overcome 5-FU resistance via down-regulation of activated p-AKT in Epstein-Barr virus-positive gastric cancer cells. AB - BACKGROUND: As EBV-associated gastric cancer has unique features that are different from EBV (-) gastric cancer, EBV is considered to have a key role in gastric carcinogenesis. It has been reported that viral latent membrane protein 2A (LMP2A) in EBV-transformed tumor cells activates the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, which provides a survival signal and chemo-resistance to cytotoxic anti-cancer drugs. This study was to evaluate anti-proliferative effect and cell cycle change when 5-FU and LY294002 (LY), a selective inhibitor of PI3K, were treated separately or combined with different schedules in EBV positive gastric cancer cell line, SNU-719. METHODS: After single treatment and sequential combination of 5-FU and LY, cytotoxic activity was measured by MTS assay. When 5-FU and LY were treated in single and sequential combinations, the expression of p-AKT, p-NFkB, p-p53 and bcl-2 was observed on different concentrations by Western blot analysis. We also investigated the effect on apoptosis and cell cycle distribution using flow cytometry. The LMP2A siRNA inhibition was done to confirm the reversal of decreased 5-FU activity and p-AKT. RESULTS: When 5-FU was sequentially combined with LY, the combination index (CI) value indicated synergistic anti-proliferative effect. The expression of p-AKT and p-NF kappaB was upregulated by 5-FU alone but sequential treatment of 5-FU and LY decreased the expression of both p-AKT and p-NF kappaB. When 5-FU was combined with LY, G0/G1 and sub G1 cell population (%) increased. When 5-FU was added to the cells transfected with LMP2A siRNA, its anti-proliferative effect increased and the expression of p-AKT decreased. In sequential combination of 5 FU and LY, the expression of p-p53 was increased and bcl-2 expression was diminished compared to 5-FU alone. CONCLUSION: These data suggest that sequential combination of 5-FU and LY induce synergistic cytotoxicity and overcome intrinsic and acquired resistance of 5-FU via downregulation of activated p-AKT and mitochondria-dependent apoptosis in EBV gastric cancer cell line, SNU-719. PMID- 20704766 TI - Sleep and psychiatric disorders: a revisit and reconceptualization. PMID- 20704767 TI - Sleep in psychiatric disorders: where are we now? AB - Although the precise function of sleep is unknown, decades of research strongly implicate that sleep has a vital role in central nervous system (CNS) restoration, memory consolidation, and affect regulation. Slow-wave sleep (SWS) and rapid eye movement (REM) sleep have been of significant interest to psychiatrists; SWS because of its putative role in CNS energy recuperation and cognitive function, and REM sleep because of its suggested involvement in memory, mood regulation, and possible emotional adaptation. With the advent of the polysomnogram, researchers are now beginning to understand some of the consequences of disrupted sleep and sleep deprivation in psychiatric disorders. The same neurochemistry that controls the sleep-wake cycle has also been implicated in the pathophysiology of numerous psychiatric disorders. Thus it is no surprise that several psychiatric disorders have prominent sleep symptoms. This review will summarize normal sleep architecture, and then examine sleep abnormalities and comorbid sleep disorders seen in schizophrenia, as well as anxiety, cognitive, and substance abuse disorders. PMID- 20704768 TI - Sleep pathologies in depression and the clinical utility of polysomnography. AB - Abnormal sleep accompanies many psychiatric conditions, but has long been recognized as a particularly conspicuous feature of affective disorders. More than a mere epiphenomenon, the powerful link between sleep and mood regulation is most dramatically demonstrated by the high efficacy of sleep deprivation in alleviating depression. Indeed, the sleep abnormalities that accompany depression may be due to the same neuropathologies that are responsible for its mood and cognitive symptoms. This powerful link between sleep and mood regulation makes polysomnography (PSG) a useful window into the underlying pathophysiology of depression, yet it is underused, particularly in clinical diagnosis. Recent depression research has emphasized the importance of establishing biologically relevant subtypes of depression with treatment specificity and prognostic value. PSG measures, among other biological markers, may be of importance in establishing these subtypes. Two subtypes of depression that appear to have robust biological differences, the melancholic and atypical subtypes, have recently been shown to have different sleep profiles that can aid in differential diagnosis. Further, routine use of PSG in the workup of a depressed patient would minimize the chances of misdiagnosis in those suffering from primary sleep disorders such as sleep apnea, which can present secondary mood symptoms resembling depression. Increased use of PSG in clinical psychiatric practice would enlarge the body of data available for defining new depressive subtypes in the future. It would also serve an immediate purpose in the separation of atypical, compared with melancholic, depression, and the differential diagnosis of depression from primary sleep disorders. PMID- 20704769 TI - Increased depressive symptoms in female but not male adolescents born at low birth weight in the offspring of a national cohort. AB - OBJECTIVES: To test if being born at low birth weight (LBW; <2500 g) or being small for gestational age (SGA; <10th percentile for gestational age [GA]) are associated with increased levels of depressive symptoms in youth and, if so, when these first emerge, if the relation is sex-specific, and whether this effect is direct or mediated by early life difficulties. METHOD: Associations between LBW, SGA, and depressive symptoms at ages 4 to 7 years and 10 to 14 years were tested in 1230 children born to the female participants of the National Longitudinal Study of Youth using linear regression models adjusting for maternal age, ethnicity, education, weight, depressive symptoms, marital status, and income. We also adjusted for GA, the child's age, and depressive symptoms at ages 4 to 7 years. Attention-deficit hyperactivity disorder (ADHD) symptoms and short-term memory at ages 8 to 10 years were also assessed for their putative role in mediating this relation. RESULTS: LBW and SGA were associated with increased levels of depressive symptoms in adolescent girls only. This persisted despite adjustment for perinatal factors and was not accounted for by putative mediators. In males and females, increased levels of depressive symptoms were associated with elevated maternal pre-pregnancy weight, depression, and single marital status, as well as childhood ADHD and depressive symptoms. Similar results were found for infants born SGA. CONCLUSIONS: Our results support the existence of a female-specific association between LBW, SGA, and adolescent depressive symptoms. Differences in exposures to maternal mediators of stress or developmental factors may underlie these findings. PMID- 20704770 TI - Do the Health of the Nation Outcome Scales measure outcome? AB - OBJECTIVE: Among mental health outcome measures that have been developed for routine use, most of the information concerns the Health of the Nation Outcome Scales (HoNOS). This instrument is widely used in Europe, Australia, and New Zealand, but not in Canada. We tested its sensitivity and predictive validity under conditions that would resemble, as closely as possible, routine use. METHOD: Treating clinicians were asked to assess patients of all ages referred to outpatient mental health facilities of 2 district health authorities in Nova Scotia using either the HoNOS for adults or the HoNOS for Children and Adolescents (HoNOSCA). Data were entered using the existing routine administrative data system. RESULTS: We obtained at least 1 rating on 4620 patients, giving a completion rate of 82%. On follow-up, ratings for the global score and most of the individual items were sensitive to change (n = 808). After adjusting for confounders, a baseline HoNOS score was significantly associated with subsequent in and outpatient service use including admissions, bed days, and psychiatric contacts (n = 1359). CONCLUSIONS: HoNOS has satisfactory sensitivity and predictive validity for routine use. We could introduce the adult version and HoNOSCA simultaneously and collect data using routine databases. Given the widespread routine use of HoNOS internationally, using the same outcome measure in Canada would enable comparisons of illness severity and outcomes between jurisdictions. PMID- 20704771 TI - Development and psychometric properties of the Mental Health Knowledge Schedule. AB - OBJECTIVE: Stigma has been conceptualized as comprised of 3 constructs: knowledge (ignorance), attitudes (prejudice), and behaviour (discrimination). We are not aware of a psychometrically tested instrument to assess knowledge about mental health problems among the general public. Our paper presents the results of the development stage and the psychometric properties of the Mental Health Knowledge Schedule (MAKS), an instrument to assess stigma-related mental health knowledge among the general public. METHODS: We describe the development of the MAKS in addition to 3 studies that were carried out to evaluate the psychometric properties of the MAKS. Adults aged 25 to 45 years in socioeconomic groups: B, C1, and C2 completed the instrument via face-to-face interview (n = 92) and online (n = 403). RESULTS: Internal reliability and test-retest reliability is moderate to substantial. Validity is supported by extensive review by experts (including service users and international experts in stigma research). CONCLUSION: The lack of a valid outcome measure to assess knowledge is a shortcoming of evaluations of stigma interventions and programs. The MAKS was found to be a brief and feasible instrument for assessing and tracking stigma related mental health knowledge. This instrument should be used in conjunction with other attitude- and behaviour-related measures. PMID- 20704772 TI - One-year incidence of psychiatric disorders in Quebec's older adult population. AB - OBJECTIVE: To examine the incidence of psychiatric disorders in the Quebec older adult population. METHOD: Data from the Enquete sur la Sante des Aines (ESA) study conducted in 2005 to 2008 using a representative sample (n = 2784) of community-dwelling adults aged 65 years and older were used. RESULTS: The ESA study's results indicate that 12.0% of the respondents met the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition, criteria for depression, mania, anxiety disorders, or benzodiazepine drug dependency at the baseline interview. Our results also indicate that the 12-month rate of incident cases of DSM-IV disorders was 6.2%. The proportion of incident cases was higher for the depression group (3.4%) than for the anxiety disorders group (2.3%). The results showed that the probability to develop an incident psychiatric condition after 1 year of follow-up, compared with the noncases group, varied according to sex (OR 2.18; 95% CI 1.39 to 3.44). Our results also showed that the number of chronic health problems (OR 1.20; 95% CI 1.09 to 1.33) and the change in the number of chronic health problems reported between the baseline and the second interview (OR 1.14; 95% CI 1.01 to 1.30) increased the probability to be an incident case at Time 2. The results indicated that social support did not influence the probability to develop a psychiatric disorder. CONCLUSION: These results indicate that sex and physical health status have an impact on the incidence of DSM-IV disorders in the elderly. This finding underscores the need for improved recognition and treatment of psychiatric disorders associated with physical illness in the older population. PMID- 20704773 TI - [Religious obsessions and religiosity]. AB - OBJECTIVE: To assess the prevalence of religious obsessions in a general psychiatry setting, review sociodemographic and clinical characteristics of patients with religious obsessions, and explore the relation between these obsessions and religiosity. METHOD: In a general psychiatry setting (n = 1500), we have studied patients with an obsessive-compulsive disorder (OCD), and then in this sample, we have identified those who also had religious obsessions. RESULTS: OCD was found in 9.6% (n = 144) of patients. Religious obsessions are the most common and were found in 31.3% (n = 45) of patients in this group. Forty-five subjects (n = 45) with religious obsessions were compared with 99 subjects (n = 99) with other types of obsessions. The total number of obsessions is significantly higher in patients with religious obsessions. Patients with religious obsessions have a significantly higher score at the religiosity scale. CONCLUSION: These results suggest that religious obsessions are common in patients with OCD, and that they are associated with religiosity. PMID- 20704774 TI - Is peacekeeping peaceful? A systematic review. AB - OBJECTIVE: To systematically review the literature on the association between deployment to a peacekeeping mission and distress, mental disorders, and suicide. METHODS: Peer-reviewed English publications were found through key word searches in MEDLINE, PsycINFO, Scopus, and Embase, and by contacting authors in the field. Sixty-eight articles were included in this review. RESULTS: Some studies have found higher levels of postdeployment distress and posttraumatic stress disorder (PTSD) symptoms. Most studies have not shown an increased risk of suicide in former peacekeepers. Correlates of distress and PTSD symptoms included level of exposure to traumatic events during deployment, number of deployments, predeployment personality traits or disorder, and postdeployment stressors. Perceived meaningfulness of the mission, postdeployment social supports, and positive perception of homecoming were associated with lower likelihood of distress. CONCLUSIONS: Most peacekeepers do not develop high levels of distress or symptoms of PTSD. As postdeployment distress is consistently shown to be associated with high levels of exposure to combat during deployment, targeted interventions for peacekeepers who have been exposed to high levels of combat should be considered. PMID- 20704777 TI - Sample size planning with the cost constraint for testing superiority and equivalence of two independent groups. AB - The allocation of sufficient participants into different experimental groups for various research purposes under given constraints is an important practical problem faced by researchers. We address the problem of sample size determination between two independent groups for unequal and/or unknown variances when both the power and the differential cost are taken into consideration. We apply the well known Welch approximate test to derive various sample size allocation ratios by minimizing the total cost or, equivalently, maximizing the statistical power. Two types of hypotheses including superiority/non-inferiority and equivalence of two means are each considered in the process of sample size planning. A simulation study is carried out and the proposed method is validated in terms of Type I error rate and statistical power. As a result, the simulation study reveals that the proposed sample size formulas are very satisfactory under various variances and sample size allocation ratios. Finally, a flowchart, tables, and figures of several sample size allocations are presented for practical reference. PMID- 20704785 TI - Role of laparoscopic nephrectomy for refractory hypertension in poorly functioning kidneys. AB - INTRODUCTION: Hypertension is a common medical problem mainly treated by effective antihypertensive drugs. Persistent hypertension can be difficult to manage and have detrimental effect on vital organs. Nephrectomy of poorly functioning kidneys may be indicated in a minority of such cases. PATIENTS AND METHODS: We performed laparoscopic nephrectomy on 12 patients with refractory hypertension. RESULTS: Eight had complete response, three had partial response and one had no response. CONCLUSIONS: Laparoscopic nephrectomy has a role in carefully selected adult patients with refractory hypertension due to non functioning kidney. Patients need to understand the surgical risks as well as the small risk of failure to treat hypertension. PMID- 20704787 TI - Hypothermic neuroprotection in neonates-cooler head prevails. PMID- 20704788 TI - [Status of iron metabolism and erythropoietic proliferation in children with various genotypes of thalassemia]. AB - OBJECTIVE: To study the status of iron metabolism and erythropoietic proliferation in children with various genotypes of thalassemia. METHODS: Serum concentrations of ferritin (SF), transferrin receptor (sTfR) and erythropoietin (EPO) were measured in 158 children with thalassemia. The differences in the concentrations of the three indices among children with different genotypes of thalassemia were compared. The correlations of the hemoglobin level with sereum SF, sTfR and EPO levels were assessed. RESULTS: Among the 158 children with thalassemia, 52(32.9%) were diagnosed with alpha-thalassemia minor, 27(17.1%) with HbH disease, 59(37.4%) with beta-thalassemia minor, 13(8.2%) with beta thalassemia major, and 7(4.4%) with combining alpha beta thalassemia. The SF levels in children with HbH disease or beta-thalassemia major were significantly higher than those in the other thalassemia groups (P<0.01). The sTfR levels in children with beta-thalassemia major were the highest when compared with those in the other thalassemia groups (P<0.05). The EPO levels in children with beta thalassemia major were also the highest when compared with those in the other thalassemia groups (P<0.01). There was a negative correlation between hemoglobin and EPO levels in children with HbH disease (r=-0.656, P<0.01) and beta thalassemia major (r=-0.641; P<0.05). CONCLUSIONS: The status of iron metabolism and erythropoietic proliferation is different in children with different genotypes of thalassemia. A combined measurement of SF, sTfR and EPO may reflect the status of erythropoietic proliferation. PMID- 20704789 TI - [Biological characteristics of T-lineage acute lymphoblastic leukemia in 23 children]. AB - OBJECTIVE: To investigate the biological characteristics of childhood T-lineage acute lymphoblastic leukemia (T-ALL) and their clinical significance. METHODS: Immunophenotyping was performed by three-color flow cytometry analysis using CD45 /SSC gating in 23 children with newly diagnosed T-ALL. Meanwhile cytogenetic analysis was performed. RESULTS: CD3(+) expression of T-lineage antigens was apparently higher than CD7(+) and CD5(+) expression. CD19(+) expression of B lineage antigens was apparently higher than CD22(+), CD10(+) and CD20(+) expression. Myeloid antigen was expressed in 4 cases (17%). CD34(+) and HLA-DR(+) were observed in 4 cases (17%) and 5 cases (22%), respectively. cCD3(+) and cCD79(+) were expressed in 23 cases (100%) and 22 cases (96%), respectively. The chromosome detection in 8 cases with T-ALL showed hyperdiploid or Ph(+) chromosome (one case each). The fusion gene detection in 5 cases showed MLL rearrangements in two cases and positive SIL/TAL1 fusion gene in one case. CD3 expression was related with the complete remission rate. CONCLUSIONS: Immunophenotyping is an important tool for diagnosis of T-ALL. However, the immunophenotype of T-ALL is heterogeneous. So, immunophenotyping along with cytogenetic and molecular genetic analysis is needed in the treatment and prognosis evaluation of T-ALL. PMID- 20704790 TI - [Clinical features of hepatitis-associated aplastic anemia in children]. AB - OBJECTIVE: To study the clinical features of hepatitis-associated aplastic anemia (HAAA) in children. METHODS: The clinical data of the children with newly diagnosed HAAA from January 2007 to December 2008 were respectively studied, including clinical manifestations, and blood routine, bone marrow examination, viral serology and immune function results as well as treatment and prognosis. RESULTS: A total of 8 children were confirmed as HAAA, accounting for 4.9% in children with aplastic anemia. There were 7 males and 1 female. The median age was 7.5 years (range 4.4 to 10.3 years) at diagnosis. They had negative serologic results and the causes of hepatitis could not be identified. The median interval from hepatitis occurrence to blood cell reduction was 6 weeks. Three cases were diagnosed as severe aplastic anemia and 5 cases as very severe aplastic anemia. Severe T cell immune disorders were found in all 8 cases. The percentage of Ts cells increased and the percentage of Th cells decreased significantly in the 8 children with HAAA. Four children survived after immune suppress treatment, three children died within one month after diagnosis and one child required own discharge without treatment. CONCLUSIONS: HAAA is more frequent in male school children. The children with HAAA have severe T cell immune disorders, with a higher early death rate. Immune suppress treatment is effective. PMID- 20704791 TI - [Antibiotic resistance of Acinetobacter Baumanii isolated from children in Wuhan between 2006 and 2008]. AB - OBJECTIVE: To investigate the variance of antibiotic resistance of Acinetobacter Baumanii isolated from children in Wuhan between 2006 and 2008. METHODS: Bacterial susceptibility testing was carried out by the Kirby-Bauer method in 679 strains of Acinetobacter Baumanii isolated in Wuhan Children's Hospital between 2006 and 2008. The results were assessed according to the guidelines of the Clinical and Laboratory Standards Institute (2008). RESULTS: The nonsusceptible rates of Acinetobacter Baumanii to ceftazidime, cefepime and piperacillin/sulbactam increased significantly in 2007 compared with those in 2006 (P<0.05). By comparing the results of 2007, it was suggested that the nonsusceptible rates of Acinetobacter Baumanii to ceftazidime, cefepime, piperacillin/sulbactam, cefoperazone/sulbactam, imipenem and meropenem increased significantly in 2008 (P < 0.05). CONCLUSIONS: The nonsusceptible rates of Acinetobacter Baumanii to beta-lactam antibiotics in children from Wuhan increased significantly year by year between 2006 and 2008. PMID- 20704792 TI - [Prevalence of upper respiratory tract group A Streptococcus carriage in school age children from Tulufan City and Buerjin County of Xinjiang Province]. AB - OBJECTIVE: To study the prevalence rate of upper respiratory tract group A Streptococcus (GAS) carriage in school-age children from Xinjiang Province. METHODS: A total of 478 children at age of 9-12 years from Tulufan City and Buerjin County of Xinjiang Province were enrolled by random cluster sampling. Throat swab cultures were performed once each season for the determination of presence of GAS. RESULTS: In the 1 827 samples, 196 GAS strains were isolated, with a GAS carrier rate of 10.7%. The prevalence rate of GAS carrier in Tulufan City ranged from 3.7%-16.5% compared with 4.7%-21.4% in Buerjin County (P < 0.05). The prevalence rate of GAS carrier in winter is the highest, followed by in autumn, spring and summer in both regions. There were significant differences in the GAS carriage rate in autumn between the two regions. There were no significant differences in the GAS carriage rate between boys and girls. Of the 196 GAS strains, 133 from Han, 22 from Uygur and 41 from Hazakh children. There were significant differences in the prevalence rate of GAS carriage among children with different ethic groups. CONCLUSIONS: The prevalence rate of GAS carriage is high in school-age children from Tulufan and Buerjin of Xinjiang Province. The GAS carrier rate is associated with the season and ethic group. The children from Buerjin County present a higher GAS carrier rate than those from Tulufan City. PMID- 20704793 TI - [Umbilical venous catheterization related infection in the neonatal intensive care unit]. AB - OBJECTIVE: To study the incidence and pathogens of umbilical venous catheterization (UVC) related infection in the neonatal intensive care unit (NICU). METHODS: A total of 112 neonates (birth weight 1,500 g) who received UVC within 24 hrs after birth were included. Blood culture was performed right after UVC. At 24 hrs and 1 week after UVC, umbilical skin scrub cultures were performed. Skin redness and swelling for more than 24 h, or severe abdominal distension, or poor general condition for unknown reason after UVC, or positive blood culture results, were the criteria for catheterization related infection. RESULTS: The incidence rate for UVC related infection was 8.9%. Total culture positive rate was 9.4%. At 24 hrs and 1 week after UVC, the umbilical skin scrub culture positive rate was 7.1% and 16.2%, respectively. Rate of Gram positive and Gram negative pathogens was 55.2% and 44.8%, respectively. Group B Streptococcus was main Gram positive pathogen. Klebsiella and E.coli were the main Gram negative pathogens. CONCLUSIONS: UVC is, to some extent, related to nosocomial infection in the NICU. Among UVC related infection, Gram positive and Gram negative pathogens take almost the chance. PMID- 20704794 TI - [Risk factors for nosocomial bloodstream infections in a neonatal intensive care unit]. AB - OBJECTIVE: To assess the risk factors for nosocomial blood-stream infection (BSI) in a neonatal intensive care unit (NICU). METHODS: Clinical data from the neonates admitted to the NICU in the St. Louis Children's Hospital in Washington University School of Medicine between January 2005 and December 2006 were retrospectively studied. RESULTS: A total of 1 290 neonates were included. Overall, 175 nosocomial BSIs occurred. Catheter-related BSIs accounted for 62.3% (109 cases). The incidence of nosocomial BSI was 4.22 per 1 000 patient-days. Logistic regression analysis revealed that low gestational age, low Apgar scores at 5 minutes, use of central venous catheter (CVC), and longer CVC use were risk factors for the development of nosocomial BSI. In the subgroup of neonates with CVC, mechanical ventilation was an additional independent risk factor for BSI. CONCLUSIONS: Catheter-related BSI is the major source of nosocomial BSI in the NICU. Prematurity, low Apgar scores at birth and prolonged CVC use are risk factors for the development of BSI. PMID- 20704795 TI - [Primary immunodeficiency diseases in children: clinical analysis of 35 cases]. AB - OBJECTIVE: To summarize clinical features of primary immunodeficiency diseases (PID) in children. METHODS: The clinical data of 35 children with PID from September 2005 to December 2008 were studied retrospectively, including illness history, birth history, family history, clinical manifestations, laboratory findings, diagnosis, treatment and outcome. RESULTS: Of the 35 cases of PID, 6 cases were confirmed with combined T- and B-cell immunodeficiency, 4 cases with X linked agammaglobulinaemia, 22 cases with selective IgG subclass deficiency, 1 case with common variable immunodeficiency and 2 cases with chronic granulomatous disease. All cases had fever and recurrent infections. Respiratory and digestive tract infections were the most common clinical manifestation. Some of the PID cases lagged behind the normal children of the same age in growth and development. Human gamma-globulin transfusion and anti-infection therapy were administered. Two patients discontinued the therapy, one was transferred to the other hospital and the other 32 patients were discharged following improvement in clinical symptoms. CONCLUSIONS: PID should be considered in children who suffer from recurrent infections and autoimmune diseases or do not respond to long-term use of antibiotics. Immunologic tests should be done as early as possible for the children. PMID- 20704796 TI - [Expression of TGF-beta and hepatocyte growth factor in kidney tissues of children with primary focal segmental glomerular sclerosis]. AB - OBJECTIVE: To study the expression of transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF) in kidney tissues of children with primary focal segmental glomerular sclerosis (FSGS) and the possible role of the two growth factors in the development of FSGS. METHODS: Kidney specimens were obtained from 33 children with primary FSGS and 7 children with isolated haematuria but without FSGS (control group). Of the 33 children with primary FSGS, 6 children had no renal tubule interstitial pathological damage (Experimental I group) and 27 children had renal tubule interstitial pathological damage (Experimental II group). Expression of TGF-beta and HGF in kidney tissues was ascertained by the immunohistochemical method. RESULTS: TGF-beta and HGF were expressed in the three groups, but there were significant differences among the three groups. The expression of TGF-beta and HGF in the two experiment groups increased significantly compared with that in the control group. The Experimental II group had increased TGF-beta expression but a significantly decreased HGF expression compared with the Experimental I group. The index of tubule interstitial pathological changes was positively correlated with the TGF-beta expression (r=0.763, P<0.01), but negatively correlated with the HGF expression (r=-0.461, P<0.05) in the Experimental II group. There was a negative correlation between TGF-beta and HGF expression in children with primary FSGS (r=-0.425, P<0.05). CONCLUSIONS: The expression of TGF-beta and HGF in kidney tissues is increased in children with primary FSGS. TGF-beta might be a fibrogenic factor and HGF might be an anti-fibrotic factor in the kidney in primary FSGS. PMID- 20704797 TI - [Expression of GRP78 and GRP94 in the liver tissues and their clinicopathological significance in children with hepatoblastoma]. AB - OBJECTIVE: To study the expression of glucose-regulated protin 78 (GRP78) and glucose-regulated protin 94 (GRP94) in the liver tissues from children with hepatoblastoma (HB) and to investigate the possible clinicopathological values of GRP78 and GRP94 in HB. METHODS: Liver tissue specimens from 15 children with HB and 10 specimens of normal liver tissues were obtained. EnVison immunohistochemistry was used to detect the expression of GRP78 and GRP94 in the conventional paraffin-embedded liver sections. RESULTS: The positive rates of GRP78 expression (53% vs 10%; P<0.05) and GRP94 expression (60% vs 10%; P<0.05) in HB liver tissues were significantly higher than those in the normal liver tissues. The positive rates of GRP78 expression in the cases without lymphnode metastasis or in clinical stage I-II were significantly lower than those in the cases with lymphnode metastasis or in clinical stage III-IV (P<0.05). GRP94 showed a decreased tendency of positive expression in the cases without lymphnode metastasis or in clinical stage I-II when compared with the cases with lymphnode metastasis or in clinical stage III-IV, although there were no statistical differences between them. CONCLUSIONS: GRP78 and GRP94 expression might play important roles in the pathogenesis and progression of pediatric HB. PMID- 20704798 TI - [Clinical manifestations and neuroimaging characteristics of children with moyamoya disease]. AB - OBJECTIVE: To study the clinical manifestations and neuroimaging characteristics of pediatric moyamoya disease. METHODS: The clinical data of 17 children with moyamoya disease were retrospectively studied. RESULTS: The onset age was between 3 and 14 years. The main clinical manifestations included motor weakness of extremities or hemiplegia, sensory disturbance and headache. Cranial CT or/and MRI examinations predominately showed cerebral infarct. Magnetic resonance angiography (MRA) and digital subtraction angiography (DSA) showed stenosis or occlusion at the terminus of the siphon portions of internal carotid arteries and proximal portions of anterior or middle cerebral arteries, and abnormal vascular networks at the base of brain. CONCLUSIONS: Cerebral ischemia is main clinical manifestations in children with moyamoya disease, presenting motor weakness of extremities or hemiplegia, sensory disturbance and headache. DSA is essential to the diagnosis of the disease. PMID- 20704799 TI - [Distribution and expression of TGF-beta2 in the capsule of children with developmental dysplasia of the hip]. AB - OBJECTIVE: This study examined the distribution and expression of transforming growth factor-beta2 (TGF-beta2) in the hip capsule of children with developmental dysplasia (dislocation) of the hip (DDH) and non-DDH children in order to investigate the roles of TGF-beta2 in hip joint laxity. METHODS: Eight children with DDH and eight age- and gender-matched non-DDH children (control group) were enrolled. The immunohistochemical technique (S-P method) was used to examine the distribution and content of TGF-beta2 in the hip capsule. Semiquantitative RT-PCR method was used to detect mRNA expression of TGF-beta2 in the hip capsule. The quantitative analysis of TGF-beta2 was performed by professional image software. RESULTS: A high expression of TGF-beta2 was observed in the synovial layer with fibroblast regularly arranged parallel to the joint surface. There was decreased expression of TGF-beta2 in the fibrous layer of the capsule. The percentage of positive fibroblasts and the gray-scale density in the fibrous layer in the DDH group were significantly lower than those in the control group (P < 0.01). TGF beta2 mRNA expression in the DDH group decreased compared with that in the control group (P < 0.05). CONCLUSIONS: The decreased TGF-beta2 in distribution, content and mRNA expression in the hip capsule might contribute to hip joint laxity in children with DDH. PMID- 20704800 TI - [An epidemiologic survey on blood lead levels in preschool children living in towns of Hunan Province]. AB - OBJECTIVE: To investigate blood lead levels (BLLs) and influencing factors of BLLs among preschool children living in towns of Hunan Province. METHODS: A total of 2 044 preschool children (1,108 boys and 936 girls) from towns of 12 regions in Hunan Province were enrolled by a cluster sampling between September 2008 and June 2009. The average age of the children was 4.4 +/- 1.1 years (range 2 to 6 years). BLLs were determined using the atomic absorption spectrographic method. The influencing factors of BLLs were investigated using a standard questionnaire and logistic regression analysis. RESULTS: The mean BLLs of the children were 81.9 +/- 34.5 MUg/L. BLLs more than 100 MUg/ L were noted in 482 children (23.58%). Of the 482 children, 472 (23.09%) showed BLLs of 100-199 MUg/L and 10 (0.49%) showed BLLs >= 200 MUg/L. There were significant differences in the prevalence of elevated BLLs (>= 100 MUg/L) among different age groups (P < 0.01). The prevalence of elevated BLLs in boys (28.99%) was significantly higher than that in girls (21.98%) (P < 0.01). There were significant differences in the prevalence of elevated BLLs in children from different regions (P < 0.01). The logistic regression analysis showed that the male (OR = 1.449, P < 0.01), father's occupational lead exposure (OR = 1.314, P < 0.01)and maternal frequent use of hair dyes (OR = 1.678, P < 0.05) were risk factor for elevated BLLs. CONCLUSIONS: The prevalence of elevated BLLs is higher in preschool children living in towns of Hunan Province and is associated with a child's region and age. The male, father's occupational lead exposure and maternal frequent use of hair dyes are risk factor for elevated BLLs. PMID- 20704801 TI - [Impact of neonatal bacillus Calmette-Guerin vaccination on lung Th17 cells and IL-17 in murine asthma model]. AB - OBJECTIVE: To study the impact of neonatal bacillus Calmette-Guerin(BCG) vaccination on lung Th17 cells and IL-17 in murine asthma model. METHODS: Neonatal BALB/c mice were divided into three groups: control, OVA and BCG/OVA groups. BCG was administerd in the BCG/OVA group on postnatal day 2 or 3. Except the control group, the mice in the other two groups were sensitized and undergone OVA challenge. Inflammatory cell numbers and morphological identification of leucocytes in bronchoalveolar lavage fluid (BALF) were measured by light microscopy. Cytokine IFN-gamma and IL-17 levels in BALF were measured using ELISA. The percentage of lung Th17 cells were assayed by flow cytometry. RESULTS: There was significantly larger number of total cells, lymphocytes, eosinophils and neutrophils in BALF in the OVA and BCG/OVA groups compared with the control group. The number or percentage of those cells in the BCG/OVA group was lower than that in the OVA group. The level of IL-17 in BALF was significantly higher in the OVA and the BCG/OVA groups compared with the control group, while the level of IFN-gamma was lower. The OVA group had higher level of IL-17 than the BCG/OVA group. The mice in the OVA and the BCG/OVA groups had a higher percentage of Th17 cells in lungs compared with the control group, but there were no significant differences in the percentage of Th17 cells between the OVA and the BCG/OVA groups. CONCLUSIONS: Th17 cells and IL-17 play roles in the pathogenesis of asthma. BCG vaccination can reduce the level of IL-17 in BALF and the reduced IL-17 may be mainly from other IL-17-producing cells in the lungs, not Th17 cells. PMID- 20704802 TI - [Regulative mechanism of budesonide on endogenous hydrogen sulfide, cystathionine gamma-lyase and cystathionine-beta-synthase system in asthmatic rats]. AB - OBJECTIVE: To investigate plasma hydrogen sulfide (H2S) levels and cystathionine gamma- lyase (CSE) and cystathionine-beta-synthase (CBS) mRNA expression in the lung tissues in asthmatic rats and to explore the roles of endogenous H2S, CSE and CBS system in the pathogenesis of asthma. METHODS: Thirty male Sprague-Dawley rats (age 5 to 7 weeks) were randomly divided into three groups: control, asthma and budesonide treatment (n = 10 each). The asthma model was established by ovalbumin (OVA) sensitization and challenge. The budesonide treatment group received inhaled budesonide before challenge. The contents of plasma H2S were measured by spectrophotometry. The levels of CSE and CBS mRNA in the lung tissues were examined by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: The contents of plasma H2S in the asthma group (61 +/- 16 MUmol/L) were significantly lower than those in the control group (84 +/- 15 MUmol/L) (P<0.01). The contents of plasma H2S in the budesonide treatment group (71 +/- 14 MUmol/L) were not statistically different from those in the control and asthma groups. CSE mRNA and CBE mRNA expression in the asthma group were significantly lower than those in the control group (P < 0.01). The budesonide treatment group had a decreased CSE mRNA expression and CBE mRNA expression compared with the control group, but had significantly increased CSE and CBE mRNA expression compared with the asthma group (P < 0.01). There was a significantly negative correlation between H2S contents in plasma and total inflammatory cells in bronchoalveolar lavage fluid (n = 30, r = -0.549, P < 0.01). CONCLUSIONS: Plasma H2S levels and CSE and CBS expression in the lung decrease in asthmatic rats, which possibly promotes inflammatory cell aggregation to the airway. Budesonide may alleviate airway inflammation in asthmatic rats possibly through the system of endogenous H2S, CSE and CBS. PMID- 20704804 TI - [Effect of maternal isolation stress on epilepsy susceptibility in young rats]. AB - OBJECTIVE: To study the effect of maternal isolation stress on the epilepsy susceptibility in young rats and the possible mechanism. METHODS: Sixty Sprague Dawley young rats were randomly divided into a normal control and two maternal isolation groups that were subjected to maternal isolation for 15 min or 3 hrs daily on postnatal days 2-17. On postnatal day 18, an amygdala kindling test was performed to induce seizures. The expression of GABA(A) receptor alpha1 in the hippocampus was determined by immunohistochemisty. RESULTS: The weights were reduced, the threshold of amygdala kindling and the stimulation number for full kindling decreased significantly, and seizures were more severe in the maternal isolation 3 hrs group compared with the normal control group. The expression of GABA(A) receptor alpha(1) in the hippocampus CA1 area in the maternal isolation 3 hrs group decreased significantly compared with that in the normal groups. There were no significant differences in the aspects above mentioned between the maternal isolation 15 min and normal control groups. CONCLUSIONS: The stress of early daily maternal isolation for 3 hrs may affect adversely brain development and increase epilepsy susceptibility in young rats. The decreased expression of GABA(A) receptor alpha1 in the hippocampus may contribute to the potential mechanism. PMID- 20704803 TI - [Effects of Ucf-101 on expression of Omi/HtrA2 in kidneys of postasphyxial neonatal rats]. AB - OBJECTIVE: To investigate the expression of serine protease Omi/HtrA2 in kidneys of postasphyxial neonatal rats, and to study the effects of Ucf-101 on apoptosis and the expression of Omi/HtrA2 in these rats. METHODS: Seventy-two neonatal Wistar rats of 7-10 days old were randomly divided into 3 groups: control, postasphyxial model, Ucf-101-treated postasphyxialThe postasphyxial model was established by normobaric asphyxiaExpression of Omi/HtrA2 was determined with streptavidin-peroxidase immunohistochemistry 2, 24 and 48 hrs after asphyxia. Terminal deoxynuleotidyl-mediated nick end labeling (TUNEL) was used to ascertain the apoptosis of renal cells. RESULTS: Compared with the control group, OmiHtrA2 expression in renal cells began to increase 2 hrs after asphyxia and peaked at 24 hrs. The expression of Omi/HtrA2 in the Ucf-101-treated postasphyxial group was significantly lower than that in the postasphyxial model group (P<0.01). TUNEL positive cells began to increase 2 hrs after asphyxia and peaked at 24 hrs in the postasphyxial model group when compared with the control group. The number of TUNEL-positive cells in the Ucf-101-treated postasphyxial group was significantly lower than that in the postasphyxial model group at all time points (P<0.01). CONCLUSIONS: The expression of Omi/HtrA2 in kidneys is increased in postasphyxial neonatal rats. The increased Omi/HtrA2 expression may play an important role in the development of postasphyxial renal injury. Treatment with Ucf-101 can reduce the expression of Omi/HtrA2 in kidneys of postasphyxial neonatal rats and thus reduce renal tububar epithelial cell apoptosis. PMID- 20704805 TI - [Effect of minimally invasive surgery for intracranial hemorrhage]. PMID- 20704806 TI - [Spontaneous intracranial hemorrhage in children: clinical analysis of 60 cases]. PMID- 20704807 TI - [Surgical treatment for skull or intracranial Langerhan cell histiocytosis in children: experience of 13 cases]. PMID- 20704808 TI - [Operation procedures for esophageal atresia complicated by other digestive malformations]. PMID- 20704809 TI - [Diagnosis of coronary artery dilatation secondary to Kawasaki disease by coronary angiography: analysis of 14 cases]. PMID- 20704810 TI - [Eosinophilic gastroenteritis in a boy]. PMID- 20704811 TI - [Research advance in human bocavirus]. PMID- 20704812 TI - [Sternal bone marrow aspiration in neonates: experience of 28 cases]. PMID- 20704813 TI - [Listing in Medline: a new milestone for the Chinese Journal of Lung Cancer]. PMID- 20704814 TI - [Methylation profile difference in human high-metastatic large cell lung cancer cell line L9981 and low-metastatic large cell lung cancer line NL9980]. AB - BACKGROUND AND OBJECTIVE: Invasion and metastasis is one of malignant phenotype of lung cancer and the important cause of the death of lung cancer patients. The aim of this study is to explore the methylation profile difference in different metastatic potential cell lines. METHODS: To compare the DNA methylation profile of two large cell lung cancer cell lines with different metastatic potential by MeIP chip hybridization, hypermethylated and hypomethylated genes of L9981 cell lines were analyzed online in NIH-DAVID, KEGG and MILANO webside. RESULTS: Compared with NL9980 cell line, 735 genes are hypermethylated in L9981, including 656 known genes and 79 unknown genes; 809 gene are hypermethylated in L9981, including 698 known genes and 111 unknown genes; the different genes are involved in cell process, signal transduction, cell communication, cell adhesion, cell motility, and angiogenesis. CONCLUSION: Hypermethylation of suppressor genes and negative regulator of signal transduction and hopomethylation of oncogene and cell adhesion molecules (CAMs) in L9981 may promote metastasis of tumor cells. PMID- 20704815 TI - [Effects of monoclonal antibody cetuximab on proliferation of non-small cell lung cancer cell lines]. AB - BACKGROUND AND OBJECTIVE: The epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been used widely in non-small cell lung cancer patients. The aim of this study is to explore the effect of lung cancer cells (A549, H460, H1299, SPC-A-1) which were treated by cetuximab in vitro. METHODS: We studied the effects of increasing concentrations of cetuximab (1 nmol/L-625 nmol/L) in four human lung cancer cell lines (A549, SPC-A-1, H460, H1229). CCK8 measured the inhibition of cell proliferation in each group. A549, SPC-A-1 were marked by PI and the statuses of apoptosis were observed. Western blot were used to detect the proliferation-related signaling protein and apoptosis-related protein in A549. RESULTS: The treatment with cetuximab resulted in the effect on cell proliferation and apoptosis in a time- and dosedependent manner. The expression of activated key enzymes (p-AKT, p-EGFR, p-MAPK) in EGFR signaling transduction pathway were down-regulated more obviously. CONCLUSIONS: Cetuximab is an effective targeted drug in the treatment of lung cancer cell lines, tissues, most likely to contribute to the inhibition of key enzymes in EGFR signaling transduction pathway. PMID- 20704816 TI - [Anti-tumor immunity of Newcastle disease virus HN protein is influenced by differential subcellular targeting]. AB - BACKGROUND AND OBJECTIVE: Hemagglutinin-neuraminidase (HN) protein of newcastle disease virus is an important immunogen for oncolysis. We designed three different expression plasmids encoding the HN protein targeted to different subcellular compartments: cytoplasmic (Cy-HN), secreted (Sc-HN) and membrane anchored (M-HN). On the basis of antitumor effect in vitro, the aim of this study is to investigate the anti-tumor immunity effect of HN protein in vivo. METHODS: In the present study, we developed a mouse model in order to evaluate the anti tumor effect of the intratumorally injected modified HN proteins and the anti tumor immunity by lymphocyte proliferative response and CTL activity test. RESULTS: Although all three DNA constructs elicited an immune response, tumor bearing mice intratumorally injected with M-HN demonstrated a significantly better anti-tumor effect than those injected with Cy-HN or Sc-HN (Day 18: P=0.022; Day 21: P<0.01). It also showed that this anti-tumor effect was mediated by higher lymphocyte proliferative response and CTL activity in mice intratumorally injected with M-HN [M-HN vs Cy-HN, P=0.019; M-HN vs Sc-HN, P=0.043; M-HN vs pcDNA3.1(+), P<0.01]. CONCLUSION: The anti-tumor immunity of Newcastle disease virus HN protein is influenced by differential subcellular targeting. The membrane-anchored form of the HN protein appears to be an ideal candidate to improve the specific cellular immunity. PMID- 20704817 TI - [Expression and significance of MTA2 in non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: It has been proven that MTA2 was expressed in many tumor cell lines and was correlated with tumor invasion and metastasis. The aim of this study is to investigate the expression of MTA2 protein in non-small cell lung cancer (NSCLC) and to explore the relationship between the expression of MTA2 and the pathological features. METHODS: The expression of MTA2 protein in 110 cases of NSCLC and 34 cases corresponding lung tissues was detected with immunohistochemistry method. The relationship between the expression of MTA2 and the pathological features in NSCLC was analyzed statistically. RESULTS: There was no expression of MTA2 protein in cancer collateral branch trachea epithelial and alveolar epithelial, but there was some expression in partial NSCLC. The positive rate of MTA2 was 58.18% (64/110) in 110 NSCLC cases. The expression of MTA2 had negative correlation with differentiation degree of NSCLC but had positive correlation with clinical stage and lymph node metastasis (P<0.05), moreover, it had no obvious correlation with age, gender and pathological type (P>0.05). CONCLUSION: There was some expression of MTA2 in partial NSCLC and it was correlated with differentiation degree, clinical stage and lymph node metastasis. The results show that the occurrence and development of lung cancer may be related with MTA2. MTA2 may act as a new symbol and target in the treatment of lung cancer. PMID- 20704818 TI - [Effects of multiple factors on the prognosis of pIIIa/N2 patients with non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Thoracic surgery hasn't got consensus on therapy of pIIIa/N2 non-small cell lung cancer (NSCLC). The aim of this study is to identify prognostic factors in NSCLC with N2 nodal involvement. METHODS: A retrospective review of disease free survival and 5-year survival for NSCLC patients who underwent primary surgical resection without neoadjuvant chemotherapy was performed. Between January 1998 and May 2004, 133 patients were enrolled. Several factors such as age, sex, skip metastasis, number of N2 lymph node stations, type of resection, histology and adjuvant therapy were recorded and analyzed. SPSS 16.0 was used for calculating survival. RESULTS: Overall 5-year survival for 133 patients was 32.33%, and 5-year survival for single N2 station and multiple N2 station sub-group were 39.62% and 27.50%, respectively. 5-year survival for cN0-1 and cN2 sub-group were 37.78% and 20.93%, respectively. Cox regression analysis revealed that number of N2 station (P=0.013, OR=0.490, 95%CI: 0.427-0.781) and cN status (P=0.009, OR=0.607, 95%CI: 0.372-0.992) were two favorable prognostic factors of survival. CONCLUSION: Number of N2 station and cN status are two favorable prognostic factors of survival. In restrict enrolled circumstances, after combined therapy made up of surgery and postoperative adjuvant therapy have been performed, satisfied survival can be achieved. PMID- 20704819 TI - [Association of XAGE-1 gene expression with clinical characteristics of lung cancer]. AB - BACKGROUND AND OBJECTIVE: XAGE-1 is a cancer-testis (CT) antigen which was demonstrated to be expressed at a significant frequency and to be immunogenic in some tumors. The aim of this study is to explore the association between XAGE-1 gene expression and the clinical characteristics of lung cancer. METHODS: Tumor tissue and adjacent lung tissue samples from 85 patients were screened for expression of the four XAGE-1 transcript variants by nest PCR. The correlations between XAGE-1b gene expression and several clinical characteristics were analyzed. RESULTS: 32.94% (28/85) of lung cancer samples were positive for XAGE-1 gene. 59.46% (22/37) of the adencarcinoma samples and 21.74% (5/23) of the squamous cell carcinoma samples were positive for one of the four XAGE-1 transcript variants. The frequent of XAGE-1b gene in adencarcinoma was much higher than that in squamous cell carcinoma. There were not any important correlation between XAGE-1b gene expression and clinical characteristics, such as gender, age and clinical stage. CONCLUSION: XAGE-1 gene is highly expressed in lung adenocarcinoma and XAGE-1 may be a promising immunotherapeutic target for lung cancer. PMID- 20704820 TI - [Expression and significance of gp96 and immune-related gene CTLA-4, CD8 in lung cancer tissues]. AB - BACKGROUND AND OBJECTIVE: It has been proven that gp96 plays an important role in specific cytotoxic immune response which is involved in anti-tumor effect in the body. The aim of this study is to investigate the biological significance of heat shock protein gp96 and immune-related gene CTLA-4, CD8 expressions in lung cancer tissues of different progressive stages. METHODS: We used Envision immunohistochemistry method to detect the levels of expression of gp96, CTLA-4, CD8 in tissue microarray, which contained 89 primary lung cancer tissues, 12 lymph node metastasis lung cancer tissues, 12 precancerous lesions and 10 normal lung tissues, and analyzed the relationship between their expressions and clinicopathological parameters. RESULTS: (1) The positive rate of gp96 in primary lung cancer was remarkably higher than that in precancerous lesion and normal lung tissue (P<0.05). The positive rate of CTLA-4 in primary lung cancer tissue and precancerous lesion was significantly higher than that in normal lung tissue (P<0.05). The positive rate of CD8 in primary lung cancer tissue was significantly higher than that in normal lung tissue (P<0.05). The positive rate of gp96 in CD8-positive lymphocytes in the high expression group was less than that in the low group (P<0.05). (2) The positive rate of gp96 was closely related to sex, differentiation and clinical stage (P<0.05), but not to age, gross type, histological type and lymph node metastasis (P>0.05). The positive rate of CTLA-4 was closely related to age and differentiation (P<0.05), but not to sex, gross type, histological type, clinical stage and lymph node metastasis (P>0.05). CD8 expression was related to clinical stage (P<0.05), but not to sex, age, gross type, histological type, differentiation and lymph node metastasis (P>0.05). The positive rates of gp96, CTLA-4 were higher than that of CD8 in squamous cell carcinoma and SCLC, respectively. (3) There was positive correlation between gp96 and CTLA-4; there was negative correlation between gp96 and CD8, and there was negative correlation between CD8 and CTLA-4 (P<0.05). CONCLUSION: Gene expression of PD-L1 on lung cancer cell line can decrease the cytolytic effect of CTL on target cells. PMID- 20704821 TI - [Overexpression of IL-8 and MMP-9 confer high malignant phenotype in patients with non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: IL-8 (interleukin-8) has been identified as a chemotactic factor, but recent found that IL-8 and matrix metalloproteinase-9 (MMP-9) are important cytokines which are closely related to the growth and metastasis of tumor. The aim of this study is to explore the relationship between IL-8, MMP-9 expressions and clinical pathological features of non-small cell lung cancer (NSCLC) patients and evaluate the diagnostic potential of IL-8, MMP-9 as tumor markers. METHODS: The serum levels of IL-8 and MMP-9 were detected by enzyme-linked immunosorbentassay (ELISA) in 141 NSCLC patients, 40 healthy adults and 40 patients with benign pulmonary disease. The expressions of IL-8 and MMP-9 were detected by immunohistochemical method in 95 NSCLC tissues, and 21 benign disease lung tissues, 25 normal lung tissues as control. RESULTS: The level of expression of IL-8 and MMP-9 in serum and tissue of NSCLC was significantly higher than that of healthy and benign respiratory disease, and the expression was gradually increased with the upgrade of clinicopathological stage. The serum and tissue expression of IL-8 and MMP-9 in NSCLC patients with lymph node metastasis was remarkably higher than that without lymph node metastasis. There is an positive correlation (r=0.765) between IL-8 and MMP-9 in the tissue of NSCLC patients. CONCLUSION: This study has confirmed that IL-8, MMP-9 expressions are related to the development of NSCLC. There is an obvious correlation between IL-8 expression and lymph node metastasis, IL-8 may facilitate the lymph node metastasis by up-regulating MMP-9 expression. Serum level of IL-8 is a valuable auxiliary parameter in diagnosing lymph node metastases of NSCLC with good sensitivity and specificity. PMID- 20704822 TI - The relationships between cyclin D1 expression and prognosis of non-small cell lung cancer. AB - BACKGROUND AND OBJECTIVE: cyclin D1 is a member of the cyclin family, and it has been proven that it plaied an important role in tumorigenesis, invasion and metastasis. We performed a retrospective study on the cyclin D1 expression in non small cell lung cancer (NSCLC) according to the clinical characteristics. METHODS: One hundred fifteen postsurgical NSCLC patients were investigated. Immunohistochemistry was used to evaluate the cyclin D1 expression. RESULTS: Overall survival was significantly lower in patients with cyclin D1-high expression of tumors than those with cyclin D1 low expression of tumors (Chi square=5.132, P=0.023). In early stage patients (stage I, II), the overall survival was significantly lower in patients with cyclin D1-high expression of tumors than those with cyclin D1-low expression of tumors (Chi-square=6.863, P=0.009). cyclin D1 status (hazard ratio=0.630; P=0.035), differentiation (hazard ratio=0.399; P<0.001), and pTNM (hazard ratio=1.576; P<0.001) to be independent prognostic factors for NSCLC patients. Specifically, the cyclin D1 status (hazard ratio=0.188; P=0.008) was a significant prognostic factor for patients with stage I NSCLCs. CONCLUSION: cyclin D1 expression is an independent prognosis factor for postoperative patient in stage I, II NSCLCs. PMID- 20704823 TI - [Clinical investigation of efficacy of pemetrexed in 32 patients with pulmonary adenocarcinoma after failure to chemotherapy and gefitinib]. AB - BACKGROUND AND OBJECTIVE: The relapse-free time of gefitinib as the second or third line therapy in patients with advanced non-small cell lung cancer (NSCLC) was not satisfactory. The aim of this study is to evaluate the efficacy and toxicity of pemetrexed in patients with pulmonary adenocarcinoma after failure to chemotherapy and gefitinib. METHODS: A total of 32 relapsed patients with pulmonary adenocarcinoma after failure to chemotherapy and gefitinib received pemetrexed 500 mg/m2 by the intravenous administration on the first day, with 21 days as a cycle. Dexamethasone, folic acid and vitamin B12 were applied to relieve the drug toxicity. The objective response rate was estimated by Response Evaluation Criteria in Solid Tumors (RECIST) and the toxicity was estimated by National Cancer Institute Common Toxicity Criteria (version 3.0). RESULTS: For a total of 32 patients, 4 patients reached partial response (PR), constituting a total of 12.5%; 11 patients reached stable disease (SD), constituting a total of 34.4%; 17 patients reached progressive disease (PD), constituting a total of 53.1%. The median progression free survival (PFS) was 2.7 months. The median overall survival (OS) was 11.0 months. One-year survival rate was 37.5%. The most common adverse events (AEs) were myelosuppression with grade I and grade II toxicity. Other adverse events were tolerated. CONCLUSION: Pemetrexed was clinically beneficial for the patients with pulmonary adenocarcinoma after the failure of chemotherapy and gefitinib. PMID- 20704824 TI - [Video-assisted mini-thoracoscopy for complete resection of 28 cases of pleomorphic carcinoma of the lung]. AB - BACKGROUND AND OBJECTIVE: Video-assisted mini-thoracoscopy (VAMT) has been used for pulmonary lobectomy for 20 years, which has many merits including small wound, less pain and quick recovery. VAMT is the tendency of pectoral minimally invasive surgical treatment. The aim of this study is to evaluate the efficacy of video-assisted mini-thoracoscopy (VAMT) for radical resection of pleomorphic carcinoma of the lung. METHODS: Complete resection of pleomorphic carcinoma of the lung was performed on 28 patients by VMAT. A 1.5 cm and a 6 cm to 8 cm incision was made during the operation. Both standard surgical instruments and thoracoscopic set were used to treat the pulmonary vessels, perform lobotomy, and remove the lymph nodes in the mediastinum and pulmonary portal. RESULTS: The operation was completed in all of the cases. No peri-operative death occurred. The total volume of hemorrhage was 200 mL to 450 mL (mean, 300 mL). The patients received chest drainage for 3 to 8 days after the operation (mean, 5 d). The time in hospital was 7 d-14 d (mean, 12 d). Five-year overall survival and disease free survival were 39.2% and 47.1%, respectively. Follow-up was available in all 28 patients for up to 2 to 91 months. Among the 28 cases, only 2 patients died 2 months after the operation, the rest all live up over 1 year. 3-year survival rate was 60.7% (95%CI: 40.3%-81.1%). CONCLUSION: VAMT is effective for radical resection of pleomorphic carcinoma of the lung in a short term. Combination the superiority of traditional procedure and VATS, so VAMT is safe and reliable for radical resection of pleomorphic carcinoma of the lung. PMID- 20704825 TI - [Determination of 14 elements in the body fluid and hair of lung cancer patients by microwave digestion with ICP-MS]. AB - BACKGROUND AND OBJECTIVE: The trace element contents in the body fluid and hair are the important monitoring indicators for many diseases. The analysis of the trace element contents in the samples of lung cancer patients is helpful to the early diagnosis and treatment effectiveness evaluation to the patients. The aim of this study is to develop an ICPMS method for the determination of Cr, Fe, Mn, Al, Cd, Cu, Zn, Ni, Se, Pb, Ca, Mg, Sr, P in the body fluid and hair of lung cancer patients. METHODS: Samples of body fluid and hair from lung cancer patients were digested with microwave and 14 trace elements were determined with inductively coupled plasma mass spectrometry RESULTS: GBW09101 standard reference material of human hair was used to validate the accuracy of the established method, and the results indicated that there is no obvious difference between the measured values and the references values. Forty-eight samples from 16 lung cancer patients were analyzed with the established method, and several generalizations were discovered. CONCLUSION: The established method can be used for the multielement simultaneous determination of the samples of lung cancer patients, which are helpful to the diagnosis and treatment of the lung cancer. PMID- 20704826 TI - [DNA methylation and non-small cell lung cancer]. AB - Genomic DNA methylation is a major form of epigenetic modification. Hypermethylation could affect the binding of transcription factors to DNA and change the structure of chromatin resulting in silence of tumor suppressor genes, which plays an important role in cancer initiation and progression. In recent years, the study of DNA methylation in lung cancer, mostly in non-small cell lung cancer, has made great progress and become a new target for early detection, risk assessment, prognosis and cancer therapy. PMID- 20704827 TI - [Progress of CypA and lung cancer-related research]. AB - CypA is the most important member of Cyclophilins. It is a widely expressed protein in nature possessing PPIase and chaperone activities which help the precise folding of protein. Also, it is involved in immunosuppression, inflammation and the balance of cholesterol. As the understanding of CypA function has deepened, people began to realize that there might exist a relationship between CypA and cancer. Lung cancer is the first carcinoma which was found as expressing high level of CypA. CypA plays the roles in increasing proliferation, antiapoptosis, invasion and metastasis in lung cancer. The study of CypA may open a new window for the early diagnosis, prognosis and novel therapeutic drugs targeting. PMID- 20704828 TI - [Complications of cryoablation in 644 lung cancer patients and its treatment]. AB - BACKGROUND AND OBJECTIVE: Most lung cancer patients present an advanced stage at diagnosis without suitable surgical chances. Cryotherapy has been applied to the advanced lung cancer with safety and effectiveness. The aim of this study is to analyze the most common complications that occur after percutaneous cryoablation when applied to advanced lung cancer METHODS: Total 644 lung cancer patients had been treated with percutaneous cryoablation guided by ultrasound and/or CT scan. The cardiovascular and respiratory complications were monitored. RESULTS: Complications were relatively minor and could be controlled with routine methods. Serious complications included cardiac arrest and hemopneumothorax, and thus preventative steps should be taken. CONCLUSION: Percutaneous cryoablation for lung cancer is a simple, effective and relatively safe method, but attention should be paid to the possible complications during cryoablation. PMID- 20704829 TI - [Surgically resected giant tumor in the thoracic cavity]. PMID- 20704830 TI - [Well-differentiated fetal adenocarcinoma of lung: a case report with 14 cases literature review]. PMID- 20704831 TI - Editor's Note. PMID- 20704832 TI - Inherited metastasis susceptibility and the implications for clinical prognosis. AB - Extract: Metastasis, the spread of cancer throughout the body, remains the leading cause of cancer-related death despite decades of investigation and the efforts of thousands of doctors and scientists. Over the past thirty to forty years tremendous strides have been made in understanding the origins of cancer. Advances in new therapeutic agents and strategies have resulted in improved survival and cure rates in many cancers, particularly pediatric cancers. However, the presentation of a cancer patient with symptomatic metastatic disease continues to be a harbinger of poor outcome, given that secondary tumors are frequently both surgically untreatable and are frequently resistant to currently available anti-tumor drugs. To better battle this proximal cause of cancer mortality, a clearer understanding of the origins and mechanisms of the metastatic process are critical for the design of new clinical interventions. Metastasis is an extraordinarily complex process, and to successfully colonize a secondary site a cancer cell must complete a sequential series of steps before it becomes a clinically detectable tumor. These steps include separation from the primary tumor, invasion through surrounding tissues, entry into and survival in blood or lymph vessels, arresting in a distant site, usually followed by penetration into the surrounding tissue, survival in the distant organ site, proliferation, and creation of new blood vessels, all the while evading the immune response and intrinsic apoptosis mechanisms. PMID- 20704833 TI - The nexus of cancer and age. AB - Extract: The incidence and prevalence of cancer increase with age: 50% of all neoplasms occur in the 12% population aged 65 and older. It is expected that, by the year 2030, 70% of all cancers are to occur in the 20% of the population that by then will be 65 and older. Currently, malignant diseases are the principal cause of deaths for Americans up to age 85. Clearly, only if the management of cancer is effective in the older population, it may reduce the mortality and morbidity related to cancer. PMID- 20704834 TI - A biobehavioral perspective of tumor biology. AB - Extract: The perspective that cancer may be causally linked to stress has a long history. In 200 AD, Galen proposed that melancholic women were more susceptible to cancer than women who were sanguine. Rigorous examinations of related observations have lagged over the ensuing centuries. More recently, epidemiologic studies have shown that psychologic and social characteristics (e.g., chronic stress and negative life events, social isolation and support, socioeconomic burden, and emotional processes) might be associated with differential cancer incidence, progression, and mortality. The biologic mechanisms (e.g., signaling pathways) that may account for such observations are being discovered through the convergence of relevant molecular, cellular, and clinical data. In this article, we review the clinical and experimental evidence regarding the effects of stress on tumor development, growth, and progression. Within this context, we define "stress" as an external event ("stressor") or perception of such events that engender psychologic and physiologic changes ("stress responses") designed to approach, avoid, or defend against the external event. PMID- 20704835 TI - Translational research in the development of bortezomib: A core model. AB - Extract: The high price of many innovative drugs, which is in part due to the costs, time and risks involved in drug development, calls for more efficient approaches to bring drugs to the market. Translational research (the bi directional transfer of basic and pre-clinical findings to humans) has been identified as an important component of such strategies. With the aim of understanding what factors underlie success in translational research, this article analyzes the life cycle of bortezomib -- from its earliest days of academic research until its FDA approval in 2003. Bortezomib (Velcade) is a breakthrough treatment for multiple myeloma developed by Myogenics/ProScript and subsequently marketed by Millennium Pharmaceuticals. The development of bortezomib illustrates the key academia-industry/public sector-private sector interactions, as well as the unique power of personal connections among scientists, necessary to succeed in this difficult area. Here, a model is proposed to explain how and why bortezomib reached the market in record time and public policy initiatives are highlighted to improve translational research in general. An extended description of this topic was published elsewhere. PMID- 20704836 TI - Malignancy risk in autoimmune rheumatic diseases. AB - Extract: All domains of medical knowledge are rapidly increasing. For example, we now understand more about the fascinating collection of "autoimmune diseases" that share one common feature: an overactive immune system that reacts against normal tissue, causing inflammation and often damage. Simultaneously, there has been an explosion of knowledge in the field of oncology, particularly related to hematological malignancies, including lymphomas. It is in part because of this increased understanding of both autoimmune disorders and malignancy that we have begun to appreciate the links between autoimmune rheumatic disease and cancer risk. In the world of rheumatology (the speciality responsible, in large part, for autoimmune rheumatic conditions), a large body of evidence has been accumulating regarding cancer risk in rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and scleroderma/systemic sclerosis. A more detailed description of this topic was published elsewhere. PMID- 20704837 TI - Intrabodies: Turning the immune system inside out for new discovery tools and therapeutics. AB - Extract: The human immune system has evolved over millennia to effectively deal with a huge diversity of threats to the integrity of the body. Antibodies, which are the principal agents of the humoral immune system, are masterpieces of evolutionary engineering, combining precise discrimination of target molecules or structures with potent binding capacities. The function of an alien molecule can either be blocked directly by an antibody binding it, or the antibody can recruit effector functions from the immune system to bring about the neutralization, destruction, or removal of the molecule. The potential value of antibodies is nowhere more evident than in the production of new medicines. Technological developments have allowed for the isolation and large scale production of single antibody molecules that can target disease-relevant molecules or structures either in the body fluids or on the surface of cells, resulting in highly precise and potent therapeutic outcomes and, as a result, antibodies currently form the fastest growing group of new drugs being developed and brought to market. PMID- 20704838 TI - Monoclonal antibodies as innovative anti-infective agents. AB - Extract: Monoclonal antibodies (mAbs) are a thriving class of therapeutics with more than 150 products currently in clinical studies. Like antibodies made naturally in the human body, mAbs bind only to specific targets and can recruit elements of the immune system to destroy the targets. However, since the products are genetically engineered, mAbs can be designed to have characteristics suitable for a variety of medical needs. Since the products first entered clinical studies in the 1980s, commercial interest has focused on cancer and immunological disease treatments. Relatively few companies have used mAbs to target pathogens. The versatile nature of mAbs and the need for innovative medicines for infectious diseases, especially for those caused by newly emerging pathogens, should cause both the public and private sector to reconsider mAbs as anti-infective agents. PMID- 20704839 TI - Editor's Note. PMID- 20704840 TI - Regenerative medicine: Stem cell research turns to the spleen. AB - Extract: Though conventional medical wisdom has long considered the spleen a dispensable organ, it appears to be more than it seems. Newly identified stem cell populations have been found in the spleen of adult mice, challenging conventional wisdom and providing a potential source of stem cells for treating disease. These stem cells are relevant to future cellular therapies for diabetes and other diseases. At the interface of the circulatory and immune systems, the spleen normally has dual roles in maintenance and adaptation to stress or disease. The red pulp of the spleen holds macrophages (a type of white blood cell) that normally filter and remove cellular debris and bacteria from the circulation. The white pulp of the spleen -- its lymphoid compartment -- is crucial for immune surveillance and response. It creates antibodies against invading pathogens (infectious agents) and releases platelets and neutrophils (another type of white blood cell) in response to bleeding or infection. The spleen also has a lesser known but well-documented function. It has long been established that the spleen contains a reserve population of hematopoietic, or blood-forming, stem cells that is tapped when the bone marrow cannot fully meet the body's demand in times of stress and disease. PMID- 20704841 TI - The role of chemical sciences in 21st century cancer drug discovery. AB - Extract: The chemical sciences are increasingly overlapping with many aspects of the study of biological molecules at the molecular level. By contrast, the traditional view of chemistry, at least as far as cancer therapeutics is concerned, has been a much narrower one as a tool of the cancer drug discovery process, generally being solely concerned with synthesis. The thesis that we develop in this short review is that the role of the chemical sciences in cancer therapeutics increasingly covers far more than this, and requires the active involvement of many aspects of the subject if the full potential of our knowledge of the cellular, molecular, and genetic basis of cancer is to be translated into clinically useful therapeutics. Effective drug discovery requires an understanding of small molecule and macromolecule physico-chemical properties, mechanism of action, structure and reactivity of individual components (including targets) of pathways, and the ways in which they interact together by means of both covalent and non-covalent recognition and signal transfer. It is no coincidence that several effective clinical agents have been discovered by creative chemists who possess a deep understanding of these topics, especially of the relationships between the structure and reactivity properties of a particular class of molecules, leading to insights into their potential as anticancer agents. PMID- 20704842 TI - Therapeutic wisdom in traditional Chinese medicine: A perspective from modern science. AB - Extract: Misunderstanding usually stems from ignorance. This is the case for comments directed at each other by western medicine and traditional Chinese medicine (TCM). Modern biomedical scientists insist that herbal remedies need quality control, rigorous clinical trials, and illumination of active ingredients and their action mechanisms. In fact, almost all ever-increasing number of research projects on herbal medicine are being conducted based on this belief. Researchers often disrespect those so-called unique, seemingly inaccessible and ridiculous theories in traditional medicine. While, in the eyes of TCM doctors, most published articles about TCM in Western medicine journals haven't felt TCM's "pulse" yet. They thought that such studies are also ridiculous to focus only on herbal drugs instead of the thinking which guides drug's usage. This is like studying Vincent van Gogh's paintbrush instead of his thoughts about art expression. TCM experts are disgruntled with the demand and rebuke from western medicine. They believe the real efficacy and toxicity of herbal agents will not be adequately demonstrated using the present evaluation paradigm for single chemical compounds, since TCM does not focus solely on the disease defined by specific pathological changes (e.g., the level of blood pressure or sugar, the identifying of tumor cells or microorganisms, etc.) but instead concentrates on the overall functional state of the patient. However, because of TCM's classic naming systems, they can not convey their notions effectively to the field of the mainstream medicine. PMID- 20704843 TI - Human cancer over age and time: Lessons from rodents. AB - Extract: Despite tremendous efforts to understand mechanisms of cancer initiation and development, many mysteries of this terrible disease are still unresolved. Why does cancer incidence rate, after a steady increase during adulthood, decelerate or even decline at the oldest ages? It seems counter-intuitive because aging is believed to be associated with increased risks of chronic pathology. Why has overall cancer risk increased along with economic progress, while medical and living conditions have greatly improved in the developed world? Answering these questions is of key importance for developing successful cancer prophylaxis. The latter showed rather few breakthroughes during past decades despite the amount of efforts spent on developing strategies of cancer prevention. Numerous studies have been focused on clinical and genetic aspects of cancer in laboratory animals to help understanding cancer in humans, as well as the role of environmental carcinogenic factors in cancer risk. However, epidemiological aspects of cancer manifestation in different mammalian species have been rather under-represented in the literature. Recent review by Anisimov, Ukraintseva, and Yashin (2005) draws readers' attention to comparative cancer epidemiology in mice and men, claiming this knowledge to be critical for developing successful prophylaxes of human cancers. The focus of the paper is on two most intriguing hallmarks of cancer epidemiology: (i) deceleration or decline in human cancer risk in the oldest age; and (ii) increasing the overall cancer risk in human history. Although some studies suggested plausible explanations of these phenomena, exact reasons for the surprising behavior of cancer incidence rates are not clear so far. PMID- 20704844 TI - Gut peptide signals in the control of food intake. AB - Extract: During and following a meal, ingested nutrients come into contact with multiple sites in the gastrointestinal tract that have the potential to alter peptide and neural signaling. Such signals can serve as feedback mediators influencing current or subsequent food intake. Ingested nutrients accumulate within the stomach, activating gastric mechanoreceptors and providing a signal of gastric fullness. Even during a meal, some ingested nutrients pass from the stomach and contact intestinal receptors. Such contact results in gastrointestinal peptide release and the activation of neural fibers producing reflex alterations in gastrointestinal motor and secretory activity and providing feedback information about the volume and nature of ingested nutrients that could alter the size of the current meal or affect subsequent eating. Recent work has characterized the ability of multiple gut peptides to affect eating and, consistent with their different patterns of release around meals, various roles for these peptides in overall eating control have been suggested. With the current rapid increase in rates of obesity, peripheral peptides with the ability to affect food intake provide attractive targets for antiobesity drug development. PMID- 20704845 TI - Chemicals as tumor-inducing agents. AB - Extract: There is overwhelming evidence that the majority of cancer deaths in Western countries are caused by exogenous factors such as tobacco, alcohol, diet, infections, and occupational exposures. Besides physical and biological factors, such as UV light or oncogenic viruses, chemicals were first considered as carcinogenic agents in the 18th century when two English physicians observed the occurrence of nose polyps or skin cancer due to exposure to snuff and soot. Today it has been established that a great range of chemicals and their mixtures present in our environment are carcinogenic in humans. Examples are metals such as nickel, cadmium or lead, aromatic amines, halogenated olefines (e.g., vinyl chloride) or paraffines, N-nitrosamines, aromatic compounds (e.g., benzo[a]pyrene; 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), estrogen-receptor agonists or antagonists with residual agonistic effects (e.g., tamoxifen), natural compounds (e.g., aflatoxins), and so forth. PMID- 20704846 TI - Measuring antigen-specific immune responses -- What is different and what is better? AB - Extract: In the old days the "blood picture" was an important diagnostic tool in general medicine and in hematology, in particular. It is also referred to as blood film, full-blood count, or differential blood count in more modern terms. Today, rather than having a technician or a medical doctor looking at a microscopic slide, machines analyze the cellular composition of a small amount of peripheral blood and create an easy-to-read output for the physician. The information requested from such an examination today is of the same nature in principle as it was 25 years ago: a summary of the numbers, composition, and characteristic changes of blood cells, including red blood cells, platelets, and white blood cells. In immunology, there is a particular interest for white blood cells, because these represent an important part of the immune system. By looking through a microscope a trained technician can discriminate mainly three populations of white blood cells in an appropriately stained blood smear: granulocytes, lymphocytes and monocytes (in order of frequency). Mostly, changes in their composition or cellular deviations resulting in gross morphologic changes can be picked up this way. Modern cell analyzers, which are based on the principle of measuring cellular impedance, sometimes combined with optical parameters, by contrast, can reveal even smaller changes of red and white blood cells that would remain unnoticed in optical microscopy, and importantly, these measures are based on many more cells than can be evaluated on a blood film, increasing the reliability of the result. PMID- 20704847 TI - Receptor tyrosine kinases as therapeutic targets in cancer. AB - Extract: Tyrosine kinases are a large and diverse family of proteins found only in Metazoans. The ERBB receptor tyrosine kinases (RTK), the main focus of this article, belong to the sub-group encompassing the cell surface proteins. All receptor tyrosine kinases have an extracellular domain that binds peptide ligands, span the membrane once, and have an intracellular portion with protein tyrosine kinase activity. Ligand binding to receptor tyrosine kinases induces the formation of receptor dimers and activates the kinase domain of the receptor, which transfers a phosphate group from the bound ATP to specific tyrosine side chains on the receptor proteins and on intracellular signaling proteins that bind the active receptor tyrosine kinases. In many types of human tumors, ERBB (erythroblastosis group B) receptor tyrosine kinases are aberrantly activated and contribute to cancer development. Accordingly, these receptors have been intensely studied both to understand their roles in cancer biology and to employ them as therapeutic targets. Many ERBB targeted inhibitors are now in clinical use. PMID- 20704849 TI - Industry Trends: Nonprofit biotechnology companies: Friend or foe to for-profit pharmaceutical business? PMID- 20704848 TI - Novel tumor immunotherapy: Targeting dysfunctional antigen presenting cells. AB - Extract: The immune system is similar to the nervous system to some degree. Both systems are highly organized and orchestrated within multiple levels (molecular, cellular, and organ) and have memory capacity. Furthermore, both systems encounter environmental challenges: the nervous system receives social challenges whereas the immune system receives natural challenges. In contrast to the nervous system, where the functional units are connected by nerve fibers and the decisions are made by the brain, the immune response is based on collaboration between functional cellular and molecular units without permanent physical connection or instruction from a centralized organ. Nonetheless, in the immune system, antigen presenting cells (APCs) are some times considered commanders in the immune system whereas T cells, B cells, and NK cells are considered the soldiers. Antigen presenting cells can capture, process, and present antigens; and they initiate and induce antigen specific T cell immunity. Thus, antigen presenting cells are used as adjuvants to treat cancer. Recent studies demonstrated that these commanders, antigen presenting cells, are often found in the tumor microenvironment. Strikingly, these commanders (including macrophages, dendritic cells, and myeloid suppressor cells) in the tumor microenvironment are largely dysfunctional and induce T cell suppression (instead of stimulation) and tumor angiogenesis. Thus, depleting tumor environmental antigen presenting cells may be a novel therapeutic strategy in tumor immunotherapy. PMID- 20704850 TI - Industry Analysis: The future is now -- GE makes a move into personalized molecular diagnostics. PMID- 20704852 TI - Crestor. PMID- 20704851 TI - "Magic cancer bullet". PMID- 20704853 TI - Inspra. PMID- 20704854 TI - Reyataz. PMID- 20704855 TI - Coupling of anti-thrombotic agents to red blood cells offers safer and more effective management of thrombosis. AB - Extract: When we are wounded, either externally (for instance, when we cut ourselves) or internally (for instance, due to gastric ulcer or brain hemorrhage), blood clots -- sponge-like plugs that are rapidly formed in response to the injury by activated blood platelets and fibrin in a process called coagulation -- prevent profound bleeding. Thus, good or hemostatic clots save our lives. However, under pathological conditions blood clots can also form inside vessels. Such bad or thrombotic clots occlude blood vessels and cause oxygen starvation of vital organs including the brain (stroke), heart (acute myocardial infarction) or lungs (pulmonary embolism). Thrombosis is one of the leading causes of morbidity and mortality from cardiovascular and other disease conditions. Diverse anti-thrombotic means are being developed. For instance, anticoagulants (such as heparin) and platelet inhibitors (such as aspirin) help to prevent formation of clots (blood thinners). Fibrinolytics, known as plasminogen activators (such as tissue-type plasminogen activator, or tPA) dissolve formed clots by degrading the fibrin meshwork. Both types of therapeutics are widely used in medical practice, e.g., for treatment of two forms of ischemic heart disease caused by thrombi in coronary vessels -- acute myocardial infarction and unstable angina. PMID- 20704856 TI - RNA interference and interferon. AB - Extract: Over the past 5 years, the phenomenon of RNA interference (RNAi) has progressed from being considered a mysterious response to double-stranded RNA (dsRNA) in the nematode C. elegans to the latest potential therapeutic tool to silence gene expression in certain diseases such as cancer or viral infections. However, the application of this biological phenomenon as a powerful research tool is not as clear-cut as scientists had initially hoped. dsRNA, the initiator of RNAi, is not made as a result of normal cellular processes, but is considered a warning to the cell of potential danger. Foreign dsRNA molecules can be formed through the transcription of potentially harmful transposons that contain inverted repeat sequences, as well as through the replication process of the majority of viruses during an infection. In organisms, such as the aforementioned nematode C. elegans and Drosophila, that respond to dsRNA-containing challenges through RNAi, the foreign dsRNA is recognized and cleaved into 21-23 nucleotide short interfering (si) RNAs. The siRNA is then incorporated into the RNA Induced Silencing Complex, which targets the mRNA of homologous sequence for degradation. PMID- 20704857 TI - Genome analysis as a new and powerful tool to design suitable culture media. Application to tropheryma whipplei. AB - Extract: Tropheryma whipplei is a Gram-positive human pathogen that is the causative agent of Whipple's disease. There have been a number of important findings about this bacterium in the past 13 years. In 2000, almost a century after the initial description of the disease by Whipple in 1907, we succeeded for the first time in isolating and propagating this bacterium from the cardiac valve of a patient with endocarditis. This bacterium is particularly recalcitrant to cultivation. Survival and replication in culture was achieved by inoculating living eukaryotic cells, namely human fibroblasts. Availability of such a reproducible protocol for isolation of the infectious bacteria allowed evaluation of new diagnostic assays and contributed to enhancement of our understanding of both the diversity and the epidemiology of T. whipplei and the infections that it causes. Moreover this step was of importance since it permits further sequencing of the genome of this microorganism about which little was known. In 2003, the genome sequences of two different strains were published. PMID- 20704858 TI - Designer recombinases: Tools to cut and paste genomic DNA sequences. AB - Extract: Gene therapy is still very much in its infancy. In future, we are likely to see more and more sophisticated intervention in order to repair or replace faulty genes, or to introduce beneficial new genes. Site-specific recombinases have the potential to be engineered into tools for "cut and paste" genome editing. Our paper in PNAS shows how this might be done. Site-specific recombinases rearrange DNA sequences, by catalyzing cleavage and rejoining of DNA strands at specific sites to which they bind. They can promote excision, integration, or orientation inversion of DNA segments bounded by the sites. They are now used extensively in mammals and other eukaryotes, for experimental research or projected gene therapy and biotechnology applications. The most commonly used enzymes are Cre and FLP, both "tyrosine recombinases" (so-called because the nucleophilic residue that breaks the DNA strands is a tyrosine), but members of another, unrelated "serine recombinase" family also function in eukaryotes. PMID- 20704859 TI - Targeted mutagenesis in E. coli: A powerful tool for the generation of random mutant libraries. AB - Extract: Mutagenesis is widely used in the fields of genetics, enzyme catalysis, ligand-binding recognition, metabolic regulation, control of gene expression, and to study mechanisms of DNA repair. Mutations are also introduced to optimize enzyme performance. This area has attracted renewed interest with the increased use of biocatalysts in chemical and pharmaceutical synthesis, in bioremediation, and in biotechnology. Individual mutations are introduced, based on detailed structural and functional information, to generate enzymes or other proteins with novel properties and to change the properties of regulatory sequences such as promoters and origins of replication (site-directed mutagenesis). Alternatively, variants of interest can be identified in large libraries harboring random substitutions (random mutagenesis). Unlike site-directed mutagenesis, random mutagenesis requires little or no previous information of the targeted genes. This approach, however, typically allows only a small fraction of all possible mutants to be analyzed. This is due to a number of factors including the inordinate numbers of possible mutations, the need to identify individual mutants of interest from a large pool, the generation of non-functional mutants, and the nature of the genetic code. PMID- 20704860 TI - MudPIT: A powerful proteomics tool for discovery. AB - Extract: Biochemists have broken barriers in the capabilities of proteomics, providing cell biologists and medical researchers unparalleled opportunities to analyze complex protein mixtures. The next task is to generate new ideas in the choice and preparation of materials to analyze. Traditional proteomics methodologies separate complex protein samples by isoelectric point and molecular weight using 2-dimensional gels. Patterns can be compared between samples, but to determine which protein is changing requires isolating individual protein spots, proteolyzing these, and analyzing the mass of each peptide by Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. The measured peptide masses are searched against the predicted mass values for theoretical digestion of proteins in a sequence database, and the protein is identified by a statistically significant number of matches. Multidimensional Protein Identification Technology (MudPIT) eliminates gel separations. Instead, biochemical fractions containing many proteins are directly proteolyzed and the enormous number of peptides generated, are separated by 2-dimensional liquid chromatography before entering the mass spectrometer. Instead of MALDI-TOF, the procedure employs tandem mass spectrometry so that, after the mass of a peptide is measured, the peptide is fragmented using a collision-induced dissociation cell and the masses of the fragmentation products are determined. PMID- 20704861 TI - Increased speed and accuracy of single nucleotide polymorphism (SNP) quantification by quencher extension (QEXT). AB - Extract: Single nucleotide polymorphisms (SNPs) often represent allelic variants of genes. The differences between individuals within a species are mainly due to SNPs. SNPs are commonly used as genetic markers for genetic diseases and other phenotypic traits. Currently, throughput and accuracy are limiting factors in the widespread use of SNPs in diagnostics. A large number of both individuals and SNPs often have to be screened when searching for correlation between specific alleles and phenotypic traits. SNP genotyping analysis of one sample at a time is extremely costly and time consuming. Pooling DNA samples prior to quantitative SNP allele frequency determination in affected and control populations is an attractive way to increase throughput and reduce costs. Individual genotyping is only done when there is a significant discrepancy in allele frequencies between the affected and control populations. Despite extensive efforts, the technology to accurately quantify SNPs in sample pools is still lacking. PMID- 20704862 TI - Getting a grip on antigen-specific CD4 T cells: Tracking autoimmune T cells in vivo. AB - Extract: Autoreactive T cells are part of the normal immune system and are kept under control by mechanisms known as anergy. Autoimmune diseases are caused by the breakdown of this tolerance, and T cell activation leads to severe inflammation and tissue damage. For example, in rheumatoid arthritis, synovial joints will be destroyed whereas in insulin-dependent diabetes mellitus (IDDM, type 1 diabetes), insulin-producing beta cells in the pancreatic islets of Langerhans will be the focus of the attack. The genetic makeup of susceptible individuals and the environmental factors leading to autoimmunity are complex and largely unknown. In many instances, the main genetic locus that has been determined is the MHC (major histocompatibility complex) class II locus. In the case of IDDM this locus encodes alleles such as HLA-DR4, -DR3, and -DQ8 in humans and I-Ag7 in the non-obese diabetic (NOD) mouse. Since MHC class II molecules present peptides to CD4 positive T cells, it is tempting to link genes and function and to study closely CD4+ T cells in the context of autoimmunity. It is now well established that, indeed, these cells are essential for the initiation and development of autoimmunity, however, in-depth investigation of them has been impeded by two major roadblocks. First, potential antigens, and therefore relevant peptides, are scarce and difficult to isolate. Secondly, reagents able to detect T cells in an antigen-specific fashion have remained elusive. PMID- 20704863 TI - High-throughput in vitro translation. AB - Extract: Cell-free systems for the expression of proteins are widely used in basic and clinical research. In molecular diagnostics, the method is used for the detection of mutations in a variety of disease-related genes that lead to premature translation termination caused by nonsense substitutions or frameshift mutations. The use of in vitro transcription and translation (IVTT) assays for population-wide disease screening demands the development of nonisotopic, automatable, and sensitive assay systems. Several recent papers have begun to address these issues. All approaches are based on the protein truncation test, also referred to as in vitro synthesized protein (IVSP) assay, which was first reported by Powell et al. (1993) and Roest et al. (1993). The IVTT assay begins with the purification of genomic RNA or DNA from clinical samples, followed by either RT-PCR or PCR. The forward primer includes all the cis-elements for transcription and translation, i.e., the RNA polymerase binding site (T7 promoter), ribosome binding site (kozak) and a start codon. The amplified DNA is then directly added to the IVTT reaction. PMID- 20704864 TI - Stromal cell-derived factor-1 mediates stem cell homing and tissue regeneration. AB - Extract: The search for alternative treatments for congestive heart failure remains an ongoing venture. Exciting research over the last 2 years has changed the long held dogma that the heart cannot regenerate itself. The work of many groups can be summarized by the following concept: increasing the number of CD117+ (c-kit+) stem cells in cardiac tissue or in the coronary circulation within 2 days of a myocardial infarction results in regeneration of myocardial tissue and improved cardiac function. Animal studies by Orlic, Anversa and colleagues have demonstrated that either the direct injection of bone marrow derived CD117+ stem cells in the infarct border zone at the time of myocardial infarction, or mobilization of these stem cells prior to myocardial infarction results in regeneration of cardiac myocytes and improved left ventricular (LV) function. In a critical experiment, Itescu and colleagues extended the window of therapeutic opportunity by demonstrating that the intravenous infusion of bone marrow-derived stem cells 2 days after myocardial infarction led to decreased infarct size, increased vascular density and improved left ventricular function. PMID- 20704865 TI - Making lentiviral vectors more powerful and universal. AB - Extract: We recently published our work constructing lentiviral vectors (LV) to consistently express two genes simultaneously or independently. In a separate study, we reported efficient gene transfer to human T lymphocytes while retaining the T cell functionality and antigen repertoire. Recombinant vectors based on retroviruses (including both onco-retroviruses and lentiviruses) remain the only choice to efficiently and stably transduce primary mammalian cells. Compared to onco-retroviral vectors (RVs), which have been the mainstay for stable gene delivery in the past 20 years, LVs offer several advantages. First, LVs can transduce both dividing and non-dividing cells such as freshly isolated hematopoietic stem cells (HSCs) and T cells in blood. Second, LVs can accommodate the use of various transcriptional promoters, either ubiquitous or cell-specific. The self-inactivating (SIN) safety modification of LVs, which permanently disables the viral promoter within the viral long-terminal repeat (LTR) after integration, enables transgene expression in the targeted cells to be controlled solely by internal promoters. Importantly, SIN modification of LVs does not reduce viral titers, in sharp contrast to that of RVs. PMID- 20704866 TI - An analysis of cancer-related alternative splicing through a genomics-based approach. AB - Extract: In the past few years, many studies have suggested that alternative splicing is a widespread mechanism of functional regulation in the human genome. Cancer-associated splice variants have also been reported for genes such as EGFR, CD44, and recently many others. High throughput genomics data, such as those obtained from EST (expressed sequence tag) sequencing, have provided a major new opportunity for discovering cancer-specific alterations in splicing. Over 4 million human ESTs have been sequenced, and most can be classified both by their tissue of origin and whether they were derived from a tumor or normal tissue sample. Here, we summarize our work on 1) genome-wide detection of cancer specific splicing, 2) independent validation, 3) functional impact, and 4) discovery of novel transcripts characteristic of normal tissues, followed by an example. PMID- 20704867 TI - Antibody production using genetic immunization. AB - Extract: Antibodies are key tools in proteomics. Their high specificity and affinity allow them to be used to measure individual proteins in complex mixtures, and most importantly to provide quantitative information. There is now great interest in generating proteome-wide sets of antibodies in order to discover biomarkers of disease and to enhance drug development. Antibodies are traditionally produced by injecting a pure form of the protein mixed with an adjuvant into an animal. The pure protein is usually produced either by overexpression in a host such as E. coli and purifying it using a fused tag (e.g., GST, 6-histidines), or by synthesizing small peptide sequences from the whole protein. The breakthrough effort in the last decade of determining the sequences of entire genomes has discovered tens of thousands of new proteins. Antibodies are now the major limiting factor in quantitative proteomics. The protein-based technology has proven too slow and expensive to make it feasible to produce antibodies on the scale now needed by the pharmaceutical and biotechnology industries. PMID- 20704868 TI - Lysosomal targeting and genetic/DNA vaccines development. AB - Extract: In immune responses, externally acquired antigens such as those from bacteria are processed by antigen-presenting cells and presented in the complex with MHC II (major histocompatibility complex class II) to CD4+ T cells. Activation of CD4+ cells leads to cell-mediated inflammatory responses and B cell activation/antibody production. Internally synthesized antigens in antigen presenting cells such as viral proteins form complexes with MHC I molecules. These complexes activate CD8+ cytotoxic T cells and lead to the destruction of virus-infested cells. The DNA vaccine, or as it is sometimes referred to a genetic vaccine, is a new generation of vaccines. Different from the traditional vaccines such as inactivated bacteria, viruses, or recombinant proteins, a DNA vaccine contains the gene that encodes the immunogen from the viruses, bacteria, parasites, or tumors. After a DNA vaccine is delivered into humans, the gene will be internally translated into the immunogen which would invoke the protective immunity against future attacks by the viruses, bacteria, parasites, or tumors. PMID- 20704869 TI - Nanoparticle-directed tissue-specific delivery system for genes and drugs. AB - Extract: Gene therapy is recognized as a promising approach for the treatment of serious diseases including monogenic diseases, infectious diseases, and cancer. Conventional vectors used for delivering therapeutic genes are virus-based vectors, such as the adenovirus, retrovirus, lentivirus, and adeno-associated virus. Since these viruses can infect a wide range of tissues, it is essential to be able to deliver these viruses specifically to the target tissues in vivo. If these viruses are administrated intravenously, the genes will be introduced into unexpected tissues, such as those around the injected place, causing side effects. These situations also make the repetitive administration of genes by conventional virus vectors nearly impossible. Thus, the in vivo targeting of therapeutic genes is now considered as an important issue for the next generation of gene therapy. In addition, conventional virus vectors possess an upper limitation on the size of the therapeutic gene and sometimes introduce parts of the viral genome into the patient's chromosome. Moreover, the production of a large amount of virus vectors is dangerous for manufacturers, because of its high and nonspecific infectivity. This will significantly increase the production cost of viral vectors. PMID- 20704870 TI - Genomic Medicine: Development of DNA as a therapeutic drug for sequence-specific modification of genomic DNA. AB - Extract: Given the recent sequencing of the human genome, we have entered into a new era of medicine, "Genome Medicine," that transcends our traditional notion of pharmacology and drug therapies. We now have the potential to address the genetic root of disease pathology, either by identifying and modifying the function of the gene product responsible for a given pathology through pharmacological means, or by directly modifying the gene with gene therapy. However, as is the case with most new pharmacological treatments, gene therapy has encountered numerous challenges that have limited its efficacy in both preclinical and clinical situations. Some of these challenges have been directly linked to the use of cDNA based "mini-genes" to complement the genetic defect and ultimately correct the pathology stemming from the defect. This has been particularly poignant in the case of inherited diseases such as cystic fibrosis, severe combined immune deficiency and sickle cell anemia. Alternatives to the cDNA-based technologies have been proposed and rely on the correction of mutant sequences in genomic DNA with oligonucleotides or by the correction of mutant mRNA through modulation of cellular RNA splicing. While the RNA-based strategies complement the DNA-based ones, the focus of this article will be on approaches employing DNA oligonucleotides. PMID- 20704871 TI - Editor's Note. PMID- 20704872 TI - What determines longevity: Metabolic rate or stability? AB - Extract: The conventional wisdom about why species age and live as long as they do is based in part on the modern version of the very old and now discredited "rate of living" (ROL) theory of aging. According to the old ROL theory, aging is caused by the loss of some vital substance such as water or hormones - the more rapid the vital substance is used up the shorter the lifespan. The modern and more plausible version of ROL is based on a hypothesis formulated by Raymond Pearl (1921) in the early 20th century where it was suggested that the primary determinant of how long species live is influenced by the relative speed of their resting metabolism. That is, metabolic rate is thought to be inversely proportional to maximum lifespan, which means that species that live fast will die young while those that have a slower metabolic rate live slower and longer. The evolutionary theory of why aging occurs that arose in the 20th century conceptually supports predictions from the metabolic rate theory, although the evolutionary line of reasoning is silent about the mechanisms involved. According to evolution theory, animals that face high extrinsic mortality such as predation and infectious diseases must develop quickly (i.e., live fast) in order to pass their genes onto the next generation before death occurs, while animals that face low extrinsic mortality delay development and reproduction, and thus live slower and longer. PMID- 20704873 TI - Nanotechnology-enabled medicine. AB - Extract: Approximately one person a minute dies of cancer in the United States. Normalized per population size, this corresponds to a current mortality rate that is essentially identical to what it was in 1950 -- a very counterintuitive finding, given the exceptional progress recorded in the fundamental scientific understanding of malignant disease in the last 50 years. Dominant among the reasons for the unsatisfactory progress in the treatment of cancer is our general inability to treat metastatic colonies, when surgical intervention and radiation therapy are no longer available options. Systemic injection with chemical and biological agents is then the choice, with the yet-unsolved problem of selectivity in the intervention on cancer cell population, or the ability to kill cancer without causing intolerable levels of unwanted collateral effects on the patient. This treatment selectivity problem breaks down into three major, related components: the ability for the therapeutic substances to reach the cancer lesion, to recognize it as the target of its action, and to perform the therapeutic intervention solely at the site of the lesion. Many approaches have been developed to address these questions, and have met with different degrees of success. Particularly promising are the recent clinical advances recorded in the field of the so-called molecularly targeted therapies, which intervene in an exquisitely selective fashion on cancer-associated biological features, such as mutations in the receptor of epidermal growth factor in cancers of epithelial origin, or the activation of the BCR-ABL tyrosine kinase pathway in chronic myelogenous leukemia. PMID- 20704874 TI - Rapid generation of high-level antibodies in vitro and in vivo. AB - Extract: During the past decade, important advances in biotechnology include the invention of an array of technologies that have resulted in the generation of monoclonal antibodies with human sequences. These technologies include humanization of mouse antibodies using molecular techniques, development of antibodies from human lymphocyte cDNA libraries by phage or ribosome displays, and the generation of fully human antibodies utilizing transgenic mice that carry the human immunoglobulin genes. These humanized or fully human antibodies are able to overcome the potential problem of eliciting immune responses by human hosts to mouse sequences present in murine antibodies. Monoclonal antibodies have emerged as important therapeutic reagents for the treatment of cancer, autoimmune disorders, and infectious diseases; and, to date, 17 therapeutic antibodies have been approved by the U.S. FDA and several hundred are in various stages of development. PMID- 20704875 TI - The rapidly advancing field of biodefense benefits many other, critical public health concerns. AB - Extract: In 2001, the public was introduced to one of the deadliest of biowarfare agents -- Bacillus anthracis -- the bacterium that causes anthrax. At the time, it was unimaginable that one might come into contact with such a deadly pathogen by simply opening the mail. Today anthrax is a nearly ubiquitous household word. This single act of bioterrorism had a profound effect in that it clearly demonstrated that even a small-scale attack could incur huge repercussions: the loss of life, the need for thousands to be treated with prophylaxis, public panic, and a large economic toll. Following this realization, a major government effort to find new and more effective ways to detect, diagnose, and therapeutically counter biothreat agents was initiated. So, how has this initiative fared? ANSWER: in a very short period of time the scientific community has responded with a massive and productive effort. Driving the research advances described in this review: 1) a vastly improved understanding of the biological mechanisms and machinery used by biothreat agents; 2) state-of-the-art high throughput screening technologies; and 3) more efficient, standardized methods and improved protocols for detecting, identifying, and diagnosing biowarfare agents. Furthermore, as with all good science, many recent biodefense research discoveries/advances have also directly facilitated our understanding and ability to treat other diseases, including antibiotic resistant bacteria and viruses (such as HIV and SARS). PMID- 20704876 TI - Crypticity of self antigenic determinants is the cornerstone of a theory of autoimmunity. AB - Extract: The immune system is designed to keep in check, to kill, and to clear from the body any invading disease-causing microbial agents such as bacteria and viruses. This immunity against foreign pathogens is mediated primarily through T lymphocytes and antibodies. Furthermore, there are in-built regulatory mechanisms that monitor the activity of these immune effector components. However, under certain constellations of genetic predisposition and environmental triggers, the same immune system can turn against the host and cause damage to the body's own ("self") cells and tissues (autoimmunity). Diseases like multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and thyroiditis represent a spectrum of autoimmune diseases caused by a dysregulated immune system. Although the autoimmune nature of many of these disorders is clear, their precise etiology is far from evident. Both the genetic composition of an individual [represented, for example, by the major histocompatibility complex (MHC), which in humans is termed HLA (human leukocyte antigens)] and environmental influences (e.g., microbial agents, stress, etc.) are believed to be the major factors that determine outcome of an immune response against self components. PMID- 20704877 TI - Learning from BCG: Designing a better tuberculosis vaccine. AB - Extract: Prior to the advent of vaccination, disease caused by M. tuberculosis had two age-related peaks: one in the first few 2-3 years of life characterized by a very high incidence of mortality and a later peak in adult life starting in the late teens or early twenties. Today, where most of the global population is vaccinated with BCG, TB mainly manifests as a pulmonary disease in the adult population. The first clinical studies with Mycobacterium bovis bacille Calmette Guerin (BCG) -- an attenuated pathogen and still the only vaccine available -- started in 1921 and demonstrated that BCG was highly efficient in protecting against TB in children. After the Second World War, the vaccine was offered to children throughout Europe, and today WHO recommends that infants should be immunized as soon after birth as possible with a single, intradermal dose of BCG in all countries at high risk of TB infection. To date, more than 3 billion people have received BCG, which makes BCG one of the most widely used vaccines in the world. The current consensus is that neonatal vaccination with BCG protects children efficiently against the early (and often severe) manifestations of TB, such as TB meningitis, regardless of settings. In contrast, its efficacy against pulmonary disease in adults has varied from 0% to 80% in different studies. PMID- 20704878 TI - HMGB1: An immmune odyssey. AB - Extract: Survival has always been a challenge in nature and fast adaptation is the key. To adapt to new situations during evolution, cells learned to reuse available molecules for different purposes. One example of a molecule recruited from an extant cellular pathway into new functions is the high mobility group box 1 (HMGB1) protein. Over the years, HMGB1 has been known by many names (amphoterin, differentiation enhancing factor, sulphoglucuronyl carbohydrate binding protein-1, p30) and relatively recently has been discovered to have a double identity from a functional point of view. When it resides in the nucleus, HMGB1 binds and bends the DNA helix facilitating the formation of protein complexes (multiple proteins binding to the same stretch of DNA) that regulate nuclear biochemical transactions. Once outside the cell it acts as a potent signal of inflammation, which is a fast response set in motion following injury or infection. The inflammatory reaction is mediated by the innate immune system, which constitutes the first line of defense to tissue damage and microbial agents. Processes like elimination of dead cells, protection against invading microorganisms and tissue repair intersect at the level of innate immunity. We will summarize recently published data that point towards HMGB1 as a common signal of tissue injury and infection used by the innate immune system, and highlight its involvement in disease. PMID- 20704879 TI - Intestinal bacteria and development of the antibody repertoire. AB - Extract: The function of the immune system is to protect the host from invasion by pathogenic microorganisms. Accordingly, most studies of host-microbial interactions have focused on pathogenic agents. The most common and intricate host-microbial interactions are, however, those between the host and non pathogenic microorganisms that have taken up residence within the host, especially within the gastrointestinal tract. The lower gastrointestinal tract of mammals provides one of the best examples in nature of mutually beneficial association between host and colonizing foreign microorganisms. Between 500 and 1,000 microbial species colonize the mammalian colon to a density of approximately 1,000,000,000,000 bacteria per gram of content, comprising in total 100 times more cells than those that make up the host itself. Over the period of evolution, mammals have not only developed immunological tolerance mechanisms to accommodate this resident community, but they also have come to rely on these intestinal commensals for their own normal development. Studies of germfree and gnotobiotic animals revealed that the intestinal microbiota influences many aspects of immunity including development and function of mucosal immunity, development of oral tolerance and generation of the antibody repertoire. A recent study demonstrated that capsular polysaccharide produced by the commensal bacteria, Bacteroides fragilis, stimulates maturation of the developing immune system by contributing to the generation of CD4+ T cells and the proper T helper 1/T helper 2 cytokine balance. PMID- 20704880 TI - The sunshine hormone vitamin D and its association with type 1 diabetes. AB - Extract: Type 1 diabetes, formerly known as juvenile diabetes, is an autoimmune disease that affects both children and adults. Researchers discovered that in type 1 diabetic patients the beta-cells of the pancreas are destroyed by their own immune system, leading to a deficiency of insulin production that, if left untreated, is life threatening. Great help in research on the topic has come from animal models of the disease, especially the diabetes-prone non-obese diabetic (NOD) mouse which spontaneously develops type 1 diabetes. As is typical for most autoimmune diseases, type 1 diabetes results from a complex interaction between genetic, immunological, and environmental factors, although the exact etiology of type 1 diabetes remains unclear and until now no prevention or cure is available. Evidence linking vitamin D to type 1 diabetes is accumulating. A poor vitamin D status, caused by insufficient sunlight exposure or dietary shortage, is associated with a "sick" immune system and with an elevated risk of developing childhood-onset type 1 diabetes. Also, certain genetic variations in components of the vitamin D system such as the vitamin D receptor (VDR) account for an increased risk for type 1 diabetes. PMID- 20704881 TI - Attempts to induce differentiation of neoplastic cells to normal. AB - Extract: It was a long time dream of oncologists to find agents which would cause differentiation to normal of neoplastic cells, thus "taming cancer" without harming normal cells. Our group was involved in such attempts for several decades. Here we summarize some of these studies as well as those of other investigators. Regulation of the differentiation of embryonic cells has been the subject of investigation for many decades. It was thought that "original organizers" appear in the upper lip of the gastrula stage of the mammalian embryo which then induces the production of further "sub organizers" and "sub-sub organizers" which are involved in eventually bringing the entire early embryo to a stage of differentiation. In early experiments we found that in tadpole embryos removal of part of the upper lip of the gastula could be substituted by local insertion of gels containing adenosine triphosphate (ATP), adenosine-3-phosphoric acid, or adenosine-5-phosphoric acid. PMID- 20704882 TI - Editor's Note. PMID- 20704883 TI - How molecular profiling is transforming drug discovery. AB - Extract: We now have the technical ability to simultaneously determine the activities of most of the genes in the genome in a particular cell type under a particular drug, genetic, disease, or environmental condition. This ability is rapidly changing the way new targets for therapeutic intervention are chosen, how candidate drugs are prioritized in development for probable toxicity and efficacy, and how patient subgroups are matched with the best treatment options. Diagnostic tests based on these technologies will soon enter clinical practice. More detailed description on this subject was published elsewhere. "Molecular profiling," as considered here, is any combination or individual application of technologies for simultaneously measuring a large number of gene products such as messenger RNAs, proteins, or metabolites. A premier example is mRNA expression profiling with DNA microarrays. Highly parallel protein measurements based on both mass spectrometry and on microarrays of antibodies also are maturing rapidly. Scans of genetic variation among individuals of a given species also can be done encompassing thousands of genome locations. PMID- 20704884 TI - Psoriasis: Clinical manifestations, pathogenesis and therapeutic perspectives. AB - Extract: Psoriasis, a common inflammatory skin disorder, has recently moved into the limelight of both basic and clinical research. On the one hand, research into its pathogenesis has furthered our general understanding of T cell-mediated autoimmune disorders, and, on the other hand, psoriasis is used increasingly as a primary target disorder for novel therapies that are pathogenesis-oriented. Given that psoriasis affects approximately 2% of the population, it is a truly common skin disease. It is, therefore, somewhat surprising that the first description of psoriasis as a distinct entity dates back only to the year 1841. Geographic and ethnic factors appear to have a significant influence on the prevalence of psoriasis: ranges from 0% in the population of the Pacific islands of Samoa to 12% in the Arctic Kasach'ye have been reported. Ethnic influence is particularly evident when looking at the prevalence in African Americans, which is less than half that of the United States in general. Numerous family studies have provided compelling evidence for a genetic predisposition to develop psoriasis, although the inheritance pattern is still unclear. Genome-wide linkage studies have identified several putative psoriasis susceptibility loci, one of which located in the MHC (major histocompatibility complex, a cluster/locus of genes involved in the immune response of rejection) region on chromosome 6 was found to be present in several populations. This locus, termed "PSORiasis Susceptibility 1" (PSORS1), can thus be considered the major susceptibility locus and is associated with up to 50% of psoriasis cases. PMID- 20704885 TI - Redirecting immune cells against bone metastases: Immunotherapy of prostate cancer metastases using genetically programmed immune effector cells. AB - Extract: Metastasis of the bone is common in two of the major gender-specific malignancies -- breast and prostate cancers. Although both primary breast and prostate cancer are manageable by "classical" therapies such as surgery, irradiation, and chemotherapy, when metastases (secondary cancers) disseminate to the bones these diseases are, by and large, incurable. Metastasis to the bone is implicated in around 70% of prostate and breast cancer deaths. The idea of harnessing the immune system to fight disseminated cancer has proven to be effective in experimental animal models against transplanted tumors. Here, both arms of the immune system, namely, the humoral one characterized by anti-tumor antibodies and the cellular one composed of a type of white blood cell, specifically the cytotoxic T-lymphocytes (CTLs), were found to cause tumor rejection either following immunization of the experimental mice before the tumor inoculations (active-vaccination) or after adoptive transfer of cancer-specific antibodies or CTLs into tumor-bearing mice (passive-vaccination). Encouraged by these results, scientists and clinicians have joined forces in extensive efforts to apply both active and passive vaccination for the immunotherapy of cancer patients. These attempts have flourished over the last fifteen years following the discovery of the first human tumor antigens in melanoma patients. PMID- 20704886 TI - Combining immunotherapy with chemotherapy to treat cancer. AB - Extract: Cytotoxic chemotherapy remains one of the most widely available treatment options for cancer. Unfortunately, the efficacy of chemotherapy is limited and, for solid tumors in particular, cures are rarely achieved. Immunotherapy is a more experimental treatment method, aimed at mobilizing the body's immune cells to attack tumor cells, but it is also rarely curative. Few studies have investigated the options for combining chemotherapy and immunotherapy, largely because the two forms of treatment are considered to be antagonistic. Two assumptions have contributed to this view. First, most chemotherapies kill target cells by triggering a process of programmed cell death, or apoptosis, and this mode of cell death has been regarded as non stimulatory or tolerogenic (induces tolerance). Thus, apoptosis-inducing chemotherapy would be expected to induce a state of non-responsiveness in the cytotoxic T lymphocytes that could otherwise potentially destroy tumor cells. Second, lymphocyte depletion (lymphopenia) is a common side effect of many anti cancer drugs, and this too has been assumed to be detrimental to any potential immune response. However, recent advances in our thinking on immune regulation now challenge both of these assumptions. Here, we will review how recent data support the case for combining chemotherapy and immunotherapy in cancer treatment. PMID- 20704887 TI - Breast cancer. AB - Extract: Breast cancer is a major public-health issue on a global scale. According to estimates in 2002, there were 1,151,298 new cases of breast cancer diagnosed world-wide. Between 1951 and 1990, mortality from breast cancer rates rose but have since fallen in most European countries, noticeably in the UK. In Japan the mortality rates have been lower than those in Europe, but at present they are still increasing. The reasons for the decline in breast cancer mortality rates in western Europe, Australia, and the Americas include widespread mammographic screening, precise diagnosis, and an increase in the number of women receiving the best treatment for their conditions. Women who have first-degree relatives with a history of the disease are at an increased risk. In countries where breast cancer is common, the lifetime incidence of breast cancer is 5.5% for women with one affected first-degree relative and 13.3% for those with two. However, eight out of nine women who develop the disease do not have an affected mother, sister, or daughter. PMID- 20704888 TI - Cancer stem cells: Implications for cancer causation and therapy resistance. AB - Extract: The discovery that many cancers arise from alterations of the body's normal stem cells is changing our views of cancer causation as well as therapy. Stem cells have a unique capacity for self-renewal; with each division they give rise to cells with the same differentiation potential as the parental cell. The replication of stem cells is under tight control. Rapidly dividing tissues such as the hematopoietic (blood) system, the skin, and the gut require perpetually dividing cells, whereas in most tissues, the stem cells are quiescent (inactive) unless stimulated by damage or inflammation. Stem cells are long lived, and therefore have the potential to acquire successive mutations and pass these defects on to daughter cell populations. Normal stem cells possess innate properties that ensure their survival over the lifespan of the individual. This includes the expression of several transport proteins that protect cells against toxins, a low rate of cell division, and active DNA repair. To the extent that cancer stem cells retain these same properties, they will be relatively resistant to radiation and chemotherapy, and may survive to regenerate the tumor. A cancer patient's intestinal lining, white blood cell count, and hair growth recover after cytotoxic therapy because these tissues are renewed from stem cells. In a similar fashion, the patient's tumor may shrink or appear to be eliminated during therapy, but subsequently regress, due to the survival of cancer stem cells. PMID- 20704889 TI - Can infections prevent or cure allergy and autoimmunity? AB - Extract: In western countries the prevalence and incidence of allergic and autoimmune diseases have been increasing dramatically over the last 50 years. In the last two decades, significant progress has been made towards understanding the genetic basis for susceptibility to autoimmunity or allergy. Genetic factors, however, cannot explain abrupt changes in disease incidence. It is therefore likely that environmental factors, specifically environmental factors that have changed over the last two generations, are critical for the increasing incidence of allergies and autoimmune diseases. Traditionally, autoimmune diseases such as multiple sclerosis (MS), type I diabetes, or rheumatoid arthritis (RA) are believed to have resulted from aberrant immune response to pathogens. In contrast, the "hygiene hypothesis," first postulated some 20 years ago, proposes that a lack of infections, especially during early childhood, predisposes one to the aberrant immune responses against harmless foreign antigens that cause allergic diseases such as rhinitis, atopic dermatitis, and allergic asthma. Several lines of epidemiological, clinical and experimental research point to more complex connections, either protective or pathogenic, between infection, allergy and autoimmunity. PMID- 20704890 TI - Telomere biology and immune system. AB - Extract: In the 1960s Hayflick reported that normal human somatic cells have a finite replicative capacity and that, after a limited number of cell divisions, cells no longer divide and enter a state termed senescence. Since this observation was made, considerable research energy has focused on identifying molecular pathways that regulate the proliferative capacity of normal somatic (body) cells. One molecular mechanism that has been implicated in the regulation of somatic cell proliferation is mediated by telomeres -- specialized DNA-protein structures that cap the ends of all linear chromosomes. In mammalian cells, telomeres are composed of hexanucleotide repeats (TTAGGG) and a variety of associated proteins. Although all mammalian telomeres are composed of these (TTAGGG) repeats, telomere length varies substantially between different species. The higher order chromatin structure formed by telomeres functions to protect chromosomes ends from degradation and activation of DNA-repair pathways. In the absence of compensatory mechanisms, telomeres shorten progressively with successive rounds of cell division as a result of incomplete replication of telomeric termini, until they reach a critically short length that is no longer protective. Cells that lack protective telomeres fail to proliferate, and they undergo senescence or apoptosis. PMID- 20704891 TI - The role of CD8 T cell replicative senescence in human aging. AB - Extract: Normal somatic cells are strictly limited in the number of times they can divide. This intrinsic barrier to unlimited proliferation, a process known as replicative senescence, was first described by Hayflick and colleagues nearly fifty years ago in cell cultures of normal fibroblasts (connective tissue cells), and has since been documented for a variety of human cell types, including epithelial cells (cells which make up the inner and outer surface of vessels, organs, etc.), keratinocytes (cells that produce keratin which becomes hair, skin and nails), endothelial cells (cells that line, for instance, the circulatory system) and hepatocytes (liver cells) cultured in vitro. Ironically, it was only recently that this cell culture model was adapted to the so-called CD8 (cytotoxic) T cell, the immune cell type that is actually required to undergo extensive proliferation in order to function effectively in controlling infections. The reason that clonal expansion is so crucial for proper immune function is that each lymphocyte expresses a unique antigen receptor, i.e., recognizes one specific "substance." During a viral infection, the few T cells that recognize that particular virus must undergo extensive cell division to produce sufficient effector cells to clear the infection. Once an infection is cleared, most of the CD8 T cells die by apoptosis (programmed cell death), leaving just a few memory cells with the same antigen receptor to deal with possible future encounters with the same pathogen, at which time the process of clonal expansion is repeated. PMID- 20704892 TI - Death of lymphocytes: A clue to immune deficiency in human aging. AB - Extract: There is only one way to conceive; however, there are multiple ways to die. The latter is particularly true with each and every cell in our body. One of the ways to die is by programmed cell death or apoptosis (a suicidal form of cell death), which is a natural form of cell death. Apoptosis is critical in embryogenesis, metamorphosis, cellular homeostasis, and removal of unwanted and mutated cells. In the immune system, apoptosis plays an important role in the development of thymocytes (immature T lymphocytes in the thymus), selection of T cell repertoire, deletion of self-reactive lymphocytes, cytotoxicity towards target cells by natural killer and cytotoxic T lymphocytes, and termination of effector lymphocytes at the end of an immune response. Apoptosis is tightly regulated by a set of genes, which either promote or inhibit apoptosis. There are several signaling pathways that mediate apoptosis, namely the death receptor (extrinsic) pathway, mitochondrial (intrinsic) pathway, and the endoplasmic reticulum (ER) pathway. Common to these pathways is the recruitment of adaptor proteins to form a scaffold complex that activates initiator caspases (cysteine proteases), which in-turn activate effector caspases. These effector caspases act as a molecular chainsaw and cleave a large number of cytoplasmic and nuclear substrates, resulting in the morphological and biochemical changes characteristic of apoptosis. PMID- 20704893 TI - On the importance of incentives in hospital infection control spending. AB - Extract: Each year, nosocomial (acquired in hospital) infections affect nearly 2 million patients and cause over 90,000 deaths in the United States alone. According to the Centers for Disease Control and Prevention (CDC), seventy percent of all nosocomial pathogens are resistant to one or more classes of antibiotics. Antibiotic-resistant bacteria such as vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) are leading causes of hospital acquired infections, and they have proven difficult to eradicate and control. The spread of resistance is ultimately caused by the use and overuse of antibiotics. Antibiotics are effective medicines when used correctly -- as is their purpose. The ability of VRE, MRSA and other antibiotic resistant bacteria in hospitals to spread is affected by the percentage of people who use antibiotics in a population -- the more that antibiotics are used, the quicker resistance to them appears and the faster the resistant strain can spread from person to person. Consequently, the more antibiotics that are used today, the greater the chance antibiotic therapy will fail in the future. PMID- 20704894 TI - How do adult neurons survive? AB - Extract: Apoptotic cell death, also known as cell suicide or programmed cell death, is a series of intracellular biochemical steps that lead to a cell's controlled but inevitable death. Apoptosis plays a crucial role in the normal development of the embryonic nervous system. Many developing neurons are destined to die by apoptosis unless they are "rescued" by their exposure to growth factors that shut off the cell suicide program, enabling their survival. Naturally too many neurons are generated, forcing them to compete for a limited supply of critical growth factors. Only the "fittest" survive -- those that make the right connections at the right time. This enables the survival of only those neurons needed for the appropriate formation and function of the nervous system; surplus neurons are discarded, creating order by cleaning out what is not needed. This is a seemingly wasteful, but effective strategy for setting up the complex and intricate circuits of the nervous system. In stark contrast, the neurons in the adult do not divide and are irreplaceably lost once they are dead, so they need to survive for the entire lifetime of the organism. Their premature death can lead to irreversible functional deficits that underlie many neurodegenerative diseases. Mature neurons possess, through multiple inherent or intrinsic molecular mechanisms, the ability to control or repress inadvertent activation of the cell suicide program that lies dormant within every cell. PMID- 20704895 TI - Acute stroke management. AB - Extract: Stroke is the third leading cause of death in the United States, coming in just behind cancer and coronary artery disease. It is, however, the leading cause of long-term disability. Stroke includes two major categories -- ischemic and hemorrhagic stroke (reduced blood supply and blood leakage, respectively), which both lead to a lack of adequate blood and oxygen supply to brain tissue, resulting in cell death. About 85% of strokes are ischemic. Ischemic strokes can also be divided into different categories based on their etiology and location. Acute ischemic stroke is an emergency, but a treatable condition especially since the TPA (tissue plasminogen activator, which is also a natural substance that helps dissolve blood clots in blood circulation) was approved by the U.S. FDA in 1995. Even though acute strokes are very common, there are still a lot of controversies about their acute management. Some of the major issues with regard to acute management of strokes are discussed here. PMID- 20704896 TI - "Mendel in the Kitchen: A Scientist's View of Genetically Modified Foods". AB - SUMMARY: Is genetically modified food safe? Are concerns over genetically modified food warranted? What is the difference between introducing genes into plants by grafting and by molecular engineering? These and other questions are answered in the book "Mendel in the Kitchen" written by plant biology expert Dr. Nina Fedoroff. PMID- 20704897 TI - Editor's Note. PMID- 20704898 TI - Peering into the future of American longevity. AB - Extract: The trend in the life expectancy of humans during the past thousand years has been generally characterized by a slow, steady increase -- though this pattern is frequently punctuated by volatility in death rates caused by epidemic and pandemic infectious diseases, famines, and war. This volatility was dramatically curtailed in the mid-19th century as infectious agents swiftly succumbed to improved living conditions, advances in public health, and medical interventions. During the past 30 years in the United States, the rise in life expectancy at birth has decelerated relative to this historic pattern, and gains in life expectancy at older ages are now much smaller than they were in previous decades. How much higher can life expectancy rise? This is not just an academic question. The answer formulated today will have substantial influence on the rate at which taxes are levied and the potential solvency of age-entitlement programs. Some researchers predict that life expectancy will rise dramatically in this century, leading public policy makers to raise their estimates of how long Americans will live. It is predicted that historical trends in rising life expectancy will continue throughout this century, fueled primarily by anticipated but yet-to-exist advances in biomedical technology. Some have even predicted that aging itself will soon be mastered by science, enabling people to live well beyond 100 years. PMID- 20704899 TI - Memory dysfunction in clinical practice. AB - Extract: Complaints of impaired memory are amongst the most common symptoms voiced by patients to physicians in the fields of neurology, psychiatry, medicine, and surgery. Impairment of memory is one of the most disabling aspects of many neurological disorders, including neurodegenerative diseases, strokes, tumors, head trauma, hypoxia (reduced exposure of tissue to oxygen), cardiac surgery, malnutrition, attention deficit disorder, depression, anxiety, medication side-effects, and normal aging. This memory loss often impairs the patient's normal daily activities, profoundly affecting both the patients and their families. Research in memory began with neuropsychological studies of patients with focal brain lesions and now includes new methods such as PET (positron emission tomography, where the decay of an injected radioactive element or drug creates an image) and functional MRI (magnetic resonance imaging, where hydrogen atoms are polarized by a magnet and the summation of their spinning energy creates an image). Event-related methodologies have provided us with more refined and improved classification systems. Rather than conceptualizing memory as "short-term" and "long-term," we now think of memory as a collection of mental abilities that use different systems within the brain. In the present article we will summarize the four memory systems that are of clinical relevance: episodic memory, semantic memory, procedural memory, and working memory. PMID- 20704900 TI - Regenerative medicine for diabetes treatment. AB - Extract: Type 1 diabetes (T1D) is an autoimmune disease in which insulin producing beta-cells contained within the pancreatic islet of Langerhans are destroyed by autoreactive T cells. T1D patients are treated via insulin hormone replacement therapy by subcutaneous injection of recombinant insulin (produced by molecular engineering). Blood glucose levels must be monitored many times a day to determine the appropriate quantity of insulin to be injected in order to control blood glucose levels (glycemia). Under the insulin-based treatment, the large and sustained effort that a patient must make to strive for near optimal control of glycemia over many decades, frequently beginning in childhood, often make this approach impractical. As a result, T1D contributes substantially to the high rate of nephropathy, neuropathy, retinopathy, and generalized microvascular disease experienced by this population. Since insulin replacement therapy alone does not completely protect these individuals from severe complications, more appropriate treatments for curing T1D are needed. Transplantation of the whole pancreas or isolated pancreatic islets, have both been proposed in the aim of more effectively treating patients with complicated T1D. However, tempering the initial enthusiasm over transplantation has been the reported worsened survival rate for recipients of the pancreas alone, when compared with the survival of waiting-list patients receiving conventional insulin therapy, and the follow-up studies on islet recipients in which a gradual loss of islet function has been observed with time. PMID- 20704901 TI - Not all Staphylococcus aureus strains are equally pathogenic. AB - Extract: Members of the bacterial species Staphylococcus aureus are considered important human pathogens by all microbiologists and infectious disease specialists. A significant number of humans are persistently colonized in the nose with S. aureus strains, and long term colonization, up to years, has been observed. For 80% of all severe staphylococcal infections, the source seems to be endogenous, so ecological balance during colonization seems to be a key concept. During lifetime, many of the colonized individuals may suffer from mild infections, usually limited to the skin. The occasional furuncle is not a life threatening disease, neither is impetigo or eczema (related to S. aureus carriage). However, once a person becomes severely ill and hospitalized, the opportunities for the Staphylococcus to manifest itself as a dangerous and invasive threat to human life are greater. It has been demonstrated recently that bacteremia (bacteria entered the blood circulation) caused by S. aureus is more frequent among nasal carriers than among non-carriers. The risk for the staphylococcal carriers increases threefold. In contrast, the risk of dying from an S. aureus bacteremic period is significantly higher in non-carriers. So carriage predisposes individuals to the development of infections but the sequels of these infections are less severe than in the case of infection in a non carrier. PMID- 20704902 TI - Macro trends in pharmaceutical innovation. AB - Extract: A lately recycled criticism of the pharmaceutical industry is that it is failing in its mission to innovate. In particular, critics question the industry's incentives to innovate, and they deride those innovations the industry makes as imitative. Industry advocates contend the opposite. The truth is that there are no generally accepted measures of innovation that would conclusively prove either side's point. However, I have found trends in several measures that support both sides of the innovation debate. Overall, the bulk of evidence suggests that the pharmaceutical industry continues to regard pioneering innovations as important (evidenced by the motivation, effort and ability of the industry to create such innovations). However, like other mature manufacturing industries, the pharmaceutical industry relies heavily on incremental innovations (what critics call "me-too" drugs) to sustain its profits. To a large extent, these incremental innovations are themselves medically beneficial and should be encouraged rather than dismissed as merely imitative. PMID- 20704903 TI - Rediscovering natural products as a source of new drugs. AB - Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage. PMID- 20704904 TI - How stress damages immune system and health. AB - Extract: There is an extensive body of scientific literature related to the field of research called psychoneuroimmunology. Clinical studies, backed up by mechanism studies, have provided convincing evidence that the central nervous system (CNS) interacts with the endocrine and immune systems and that these interactions are bi-directional. Stress has been a focal point in this body of literature because it is known that stress can induce immune dysregulation across many aspects of the humoral and cellular immune responses. These studies have dated back to the 1960s and 1970s, and have included some very elegant studies involving animal models. The important outcome of this research is that stress induced immune dysregulation can produce changes that are not only statistically significant but, most importantly, biologically significant in terms of health risk. It is now well established that there are very complex bi-directional interactions between the CNS and the immune system mediated by the endocrine system. Two important aspects of these interactions include the production of stress hormones by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis. The interactions between immune cells also take place through the production of cytokines. Hormones can modulate immune function by binding to their receptors, which are expressed on virtually every type of immune cell. The modulation of cytokines has been shown to feedback to the brain, producing changes in the HPA axis, as well as inducing sickness behavior such as fever, loss of appetite, changes in sleep patterns and depression. PMID- 20704905 TI - Reactivation of human cytomegalovirus in dendritic cells. AB - Extract: Human cytomegalovirus (HCMV) is a member of the Herpesvirus family of viruses and is a ubiquitous human pathogen. Primary infection of immunocompetent individuals is rarely problematic, but congenital or neonatal infection, or infection in immunosuppressed individuals, can cause severe disease. An important biological characteristic of HCMV, with obvious clinical importance, is the ability of the virus to establish lifelong persistence in the host following the initial, normally asymptomatic, infection. A key strategy used by all herpesviruses to persist in the infected individual is the establishment of cellular sites of viral latency. Viral latency is operationally defined as the persistence of the viral genome in absence of the production of infectious virions, but with the ability of the viral genome to reactivate under certain conditions. HCMV can remain latent in peripheral blood cells throughout the host's lifetime and sporadic reactivation events are generally well controlled by cell-mediated immunosurveillance, particularly virus-specific CD4+ and CD8+ T lymphocytes. However, in immunocompromised AIDS patients or immunosuppressed transplant patients, HCMV replication becomes uncontrolled and can cause serious morbidity and mortality, due to disease in the eye (retinitis), lung, nervous system and other organs. Analyses of virus strains during HCMV infection of organ transplant patients have shown that infection is predominantly due to reactivation of the transplant recipient's own HCMV, although it can also result from virus transferred from the donor. Consequently, an understanding of the cellular sites of latency and reactivation, and the mechanisms that control latency in these cells, are of major importance for further understanding of HCMV pathogenesis, as it follows reactivation. PMID- 20704906 TI - Screening for colorectal cancer using stool. AB - Extract: Colorectal cancer (CRC, cancer of the large bowel) is the third commonest malignancy worldwide. There were 945,000 new cases and 492,000 deaths in the year 2000. Lifetime risk of CRC is approximately 1 in 18 and risk rises with age. Many patients present with advanced disease, when chances for curative treatment are low. For these reasons an effective screening test would have substantial clinical benefits. Most CRCs are thought to arise from benign tumors, known as adenomas, over an interval of at least 5-10 years. Moreover, the average time for an asymptomatic early CRC to become an advanced symptomatic CRC is thought to be around 2-3 years. Survival is closely related to the stage at which the cancer is discovered (i.e., how advanced a tumor is), with early CRC having an excellent outcome. CRC has several properties that make it ideally suited for early detection by screening asymptomatic people. It has recognizable early stages and a defined natural history. Surgical treatment is effective, with greater benefit in early stage disease. Removal of pre-malignant adenomas is also feasible using endoscopy; and screening tests are currently available. PMID- 20704907 TI - Accurate genetic testing platform based on haploid templates: Use in inheritable colon cancer. AB - Extract: The misfortune of individuals having inherited a genetic mutation that predisposes them to cancer can become a weapon for their better management of the disease and the rest of their family members. This is what the promise of genetic testing is: to reduce the mortality and morbidity through screening, and hopefully lead to early diagnosis and even prevention of spread or the cancer itself. Inherited forms of cancer represent a good example of the benefits and complications of genetic testing. A single inherited mutant gene usually is enough to confer a high risk of cancer. The mutation is inherited from one of the parents and it is transmitted to the offspring. Other siblings may also have inherited the mutant gene. This way, some members of the family will have that one mutation and some will not. Therefore, when an inherited mutation is identified in one member of a family, the rest of the family members can be screened for the presence of this mutation. So, the mutation can be identified early, before any clinical symptoms, and this allows the potential disorder to be managed appropriately. PMID- 20704908 TI - Preventing autoimmune diabetes through gene therapy. AB - Extract: Type 1 diabetes is an autoimmune disease in which an individual develops T cells that are able to destroy insulin-producing beta cells in the pancreas. Type 1 diabetics require life-long treatment with exogenous insulin for survival. Susceptibility to type 1 diabetes is influenced by both genetic and environmental factors. The first diabetes-susceptibility genes to be identified were the human leukocyte antigen (HLA) genes. Subsequent studies demonstrated an association of these genes with the insulin gene region. High throughput screening of the human genome in families with two or more affected siblings led to the identification of additional chromosomal regions that may contain susceptibility genes for type 1 diabetes. However, linkage between the HLA gene region and susceptibility to disease suggested that the principal genetic component leading to development of diabetes is the inheritance of mutant HLA class II alleles. These are so-called "at-risk" alleles which lack an aspartic acid, a positively amino acid, at position 57 of the major histocompatibility complex (MHC) class II beta chain. PMID- 20704909 TI - Bipolar disorder: Neurochemistry and drug mechanisms. AB - Extract: The alternating states of mania, depression and mood moderation (euthymia) are so distinct that biological research in psychiatry was attracted to the study of bipolar disorders very early on. Moreover, the discovery of lithium as a simple metal ion that had a strong mood-stabilizing effect suggested that a simple biological pathophysiology might be easily discovered in manic depressive illness and that this might lead the way to major biological discoveries in other mental disorders and human behavior in general. Overall this story has been heroic and exciting but it has left us in 2005 still without any biological diagnostic test or clear pathophysiological abnormality in manic depressive illness. Early studies looked for urinary or spinal fluid abnormalities of metabolites of the major monoamine neurotransmitters (chemicals that contain an amino group attached to a carbon backbone in the nervous system, which carry signals between neurons), noradrenaline, serotonin and dopamine. Often, early findings were not replicated, or if replicated they turned out to be secondary to the hyperactivity that occurs in mania or the hypoactivity and weight loss observed in depression. PMID- 20704910 TI - Lactobacilli as natural enhancer of cellular immune response. AB - Extract: Dendritic cells (DCs), widely distributed in lymphoid (containing lymphocytes) and non-lymphoid tissue, are a complex, heterogeneous group of multifunctional antigen-presenting cells that comprise an essential component of the immune system. For well over a decade, dendritic cells have been recognized as an essential component of both the host innate and adaptive immune responses. DCs, due to their differential regulation and initiation of acquired immune responses, are at the forefront of current research in immunobiology and vaccinology. Recent reports suggest that certain types of antigens (a substance capable of inducing an immune response) differentially govern DC activation and maturation, which ultimately influence the entire immune response. Various species of Lactobacillus (a bacterium found ubiquitously in the mouth, intestinal tract, and vagina) have been shown to differentially regulate dendritic cells and enhance their ability to prime specific immune responses and, thus, they may have great utility as future vaccine adjuvants. PMID- 20704911 TI - Cardiac regeneration with novel bone marrow-derived multipotent stem cells. AB - Extract: Congestive heart failure is a growing, worldwide epidemic. The major causes of heart failure are related to irreversible damage resulting from myocardial infarction. The long-standing axiom has been that the myocardium has a limited capacity for self-repair or regeneration; and the irreversible loss of cardiac muscle and accompanying contraction and fibrosis of myocardial scar tissue sets into play a series of events that ultimately lead to progressive heart failure. The loss of cardiomyocyte survival cues is associated with diverse pathways for heart failure, underscoring the importance of maintaining the number of viable cardiomyocytes during heart failure progression. Currently, no medication or procedure used clinically has shown efficacy in replacing the myocardial scar with functioning contractile tissue. Therefore, given the major morbidity and mortality associated with myocardial infarction and heart failure, new approaches have been sought to address the principal pathophysiologic deficits responsible for these conditions, resulting from the loss of cardiomyocytes and viable blood vessels (and hence an adequate oxygen supply). Recently, the identification of stem cells capable of contributing to tissue regeneration has ignited significant interest in the possibility that cell therapy could be employed therapeutically for the repair of damaged myocardium. PMID- 20704912 TI - Catalytic antibodies and severe sepsis. AB - Extract: Sepsis is the leading cause of death in intensive care units. It results from the host's systemic response to infection, which at times can be deleterious. Although initially perceived as potentially harmful, catalytic antibodies have been proposed as participants in the removal of metabolic wastes and protection against infection. We have recently documented that the presence of immunoglobulin G (IgG) in plasma, which has a serine protease-like hydrolytic activity, strongly correlates with survival from sepsis, thus providing the first evidence that hydrolytic antibodies might play a role in recovery from a disease. It remains, however, unclear whether catalytic antibodies play a direct bactericidal role, participate in the control of disseminated microvascular thrombosis, and/or regulate inflammation. We propose that the catalytic potential of natural IgG may be the basis for an alternative complementary treatment of sepsis in the future. PMID- 20704913 TI - Quantum dots for molecular imaging and cancer medicine. AB - Extract: The past few decades have witnessed technical advances that have introduced cell biologists and physicians to a new, dynamic, subcellular world where genes and gene products can be visualized to interact in space and time and in health and disease. The accelerating field of molecular imaging has been critically dependent on indicator probes which show when and where genetically or biochemically defined molecules, signals or processes appear, interact and disappear, with high spatial and temporal resolution in living cells and whole organisms. For example, the use of radionuclide tracers combined with 3 dimensional (3-D) imaging systems such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are now helping clinicians to characterize the molecular status of tumors deep within patients. Other types of imaging probes rely on the bioluminescence and fluorescence of genetically encoded proteins (originally found in fireflies and jellyfish, respectively) or entirely synthetic fluorochromes, or a combination of both. New powerful biological fluorescence microscopes provide the ability to study single molecules within single cells. Multiphoton confocal microscopy has been developed to allow for the capturing of high-resolution, 3-D images of living tissues that have been tagged with highly specific fluorophores. PMID- 20704914 TI - Primate embryonic stem cells as a source of dopaminergic neurons: A novel transplantation for Parkinson's disease. AB - Extract: The most common neurodegenerative movement disorder in man is Parkinson's disease (PD) and it is characterized by the loss of midbrain dopaminergic neurons in the substantia nigra of the brain. The loss of these neurons, which normally project to the striatum, also causes a decrease in striatal dopamine levels. While being the precursor to dopamine synthesis, L dihydroxyphenylalanine (L-DOPA) can initially improve the symptoms of the disease, such as resting tremor and a poverty of movement, its effectiveness diminishes with time. Deep brain stimulation and fetal dopaminergic neuron transplantation are two available treatments for the motor complications that subsequently develop. Transplantation of fetal dopaminergic neurons has been shown to be effective at producing symptomatic relief in both animal models and patients of PD. This therapy is limited, however, due to both the technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue. Embryonic stem (ES) cells are self-renewing, pluripotent cells derived from the inner cell mass of the preimplantation blastocyst. These cells have both proliferative and differentiation capacities, thus fulfilling many of the characteristics required of a cell source for cell-replacement therapy. Stromal cell-derived inducing activity (SDIA) (an activity to induce neural differentiation of ES cells by a soluble factor or a cell surface-anchored molecule) is present on the surface of stromal (connective tissue) cells. PMID- 20704915 TI - "Curing MS: How Science Is Solving the Mysteries of Multiple Sclerosis". AB - SUMMARY: On a grander scale, multiple sclerosis is a battle between a patient's will to fight and the disease's vicious attack on central nerve cells. On a cellular scale, it's between the T helper 1 (Th1) cell, which attacks and destroys the myelin sheath that protects nerve cells, and the Th2 and Th3 cells, which try to bring Th1 cells under control. PMID- 20704916 TI - Editor's Note. PMID- 20704917 TI - Restoration of heart functions using human embryonic stem cells derived heart muscle cells. AB - Extract: Recent advances in molecular and cellular biology and specifically in the areas of stem cell biology and tissue engineering have paved the way for the development of a new field in biomedicine, regenerative medicine. This exciting approach seeks to develop new biological solutions, using the mobilization of endogenous stem cells or delivery of exogenous cells to replace or modify the function of diseased, absent, or malfunctioning tissue. The adult heart represents an attractive candidate for these emerging technologies, since adult cardiomyocytes have limited regenerative capacity. Thus, any significant heart cell loss or dysfunction, such as occurs during heart attack, is mostly irreversible and may lead to the development of progressive heart failure, one of the leading causes of world-wide morbidity and mortality. Similarly, dysfunction of the specialized electrical conduction system within the heart may result in inefficient rhythm initiation or impulse conduction, leading to significant slowing of the heart rate, usually requiring the implantation of a permanent electronic pacemaker. Replacement of the dysfunctional myocardium (heart muscle) by implantation of external heart muscle cells is emerging as a novel paradigm for restoration of the myocardial electromechanical properties, but has been significantly hampered by the paucity of cell sources for human heart cells and by the relatively limited evidence for functional integration between grafted and host cells. The recently described human embryonic stem cell (hESC) lines may provide a possible solution for the aforementioned cell sourcing problem. PMID- 20704918 TI - Adult human stem cells as a platform for gene therapy: Fabricating a biological pacemaker. AB - Extract: Gene therapy and stem cells have become buzz words for future medical management. However, to date attempts to apply these technologies therapeutically have met with little success and, in the case of embryonic stem cells, have engendered political and philosophical debate. In this paper, we emphasize progress in one area of gene/stem cell therapy: the use of adult human mesenchymal stem cells (hMSCs, precursor cells for tissues such as skin, bone and muscle that are found in bone marrow) as a platform for delivering genes. These cells are adult hMSCs, and therefore not subject to the restrictions placed by some societies on use of human embryonic stem cells. In addition, they can be loaded with genes using a technique known as electroporation, by which an electrical charge temporarily makes the cell membrane permeable. This technique carries none of the risks that accompany the use of viral vectors, another method of gene delivery. As an example of the utility of hMSCs as platforms for gene delivery, we will discuss the fabrication of biological pacemakers. PMID- 20704919 TI - Gene-based cancer immunotherapy and vaccines. AB - Extract: Cancer cells are able to escape immune detection and/or rejection by a variety of measures. Cell surface molecules, which are required for the effective policing of tissues by the immune system, are often modified, reduced or eliminated. In addition cancer cells secrete soluble molecules that inhibit the patients' ability to develop an immune response. The ability of the immune system to recognize and reject cancerous growths has been demonstrated in a series of experimental model systems. Efforts are now being made to use this knowledge for the treatment of cancer. Described below are two different gene-based approaches to stimulate the rejection of an established cancer in patients. The first involves procedures which modify the tumor itself, render it a more attractive target to the immune system, and allow immune cells to penetrate the tumor and kill the cancerous cells. The second approach requires a very powerful vaccine to stimulate a strong immune response against the tumor associated antigens in patients with an established cancer. Early efforts to harness the power of the immune system to eliminate cancer were made by Dr. William Coley very early in the 20th century. Dr. Coley injected cancerous tissue, usually sarcomas (tumors of the supportive tissues such as bone, cartilage fat or muscle), with a mix of bacteria and/or their toxins. This would result in an inflammatory response in the tumor and the influx of many immune cells. PMID- 20704920 TI - Pharmacogenomics: Bench to bedside. AB - Extract: Pharmacogenetics is the study of how genetic inheritance affects a person's response to drugs. A major goal for pharmacogenetic research has been the individualization of drug therapy, by which doctors could more precisely cater to an individual's physiological particularities when prescribing drugs, which would both maximize efficacy and minimize toxicity. Advances in pharmacogenetics have converged with rapid developments in human genomics; as a result, pharmacogenetics has evolved into pharmacogenomics. We will briefly review the development of pharmacogenetics and pharmacogenomics, and outline factors that have influenced the "translation" of pharmacogenomics from the research bench to the patients' bedside. The end of the 20th and beginning of the 21st centuries saw the "therapeutic revolution" (which had resulted in the development of drugs to treat diseases ranging from hypertension to childhood leukemia) converge with the "genomic revolution." PMID- 20704921 TI - Turning genes into cancer vaccines. AB - Extract: The current rapid expansion of knowledge in the field of genetics is opening up many opportunities for clinical medicine. Cancer vaccines, in particular, have been a distant goal for many years. Scientists had noted early on that the immune system appeared to suppress cancer growth, an observation that inspired investigators to develop and test vaccination as a treatment for cancer. The failure of these relatively uncharacterized vaccines was perhaps inevitable, but this has not dampened enthusiasm for further attempts. In recent years, vaccine designs have built upon advancements in genetic technology, which has provided new means of vaccine delivery, revealed potential target molecules on tumor cells, and has delineated the fundamental immunological principles of vaccine design. At last, performance of these vaccines in test models and in patients can be measured objectively, allowing for the assessment of specific immune responses. These assessments serve as an interim to the long term goal of clinical efficacy. PMID- 20704922 TI - Islet transplantation and the challenges of treating type 1 diabetes. AB - Extract: Diabetes affects over 18 million people in the United States. Approximately one million have type 1 diabetes mellitus (T1D), previously known as juvenile onset diabetes, with the rest of patients having the type 2 diabetes, previously known as adult onset diabetes. Of these two forms of diabetes, T1D is considered more severe since, if left untreated, it is more rapidly fatal than type 2. Furthermore, achieving blood glucose control in patients with T1D tends to be more difficult. Clinician scientists recognized shortly after the 1921 discovery of insulin that it was a miraculous advance in the treatment of diabetes, but it still fell far short of a cure. Therapy for diabetes has since made major strides but substantial difficulties remain for those afflicted, and a cure is still being sought. Current data strongly suggests that T1D is caused by an attack by the immune system on the the pancreatic beta-cells, the cells that physiologically regulate insulin secretion. These beta-cells are located within cell clusters of the pancreas known as the Islets of Langerhans (or simply "islets"). The islets are essentially mini-organs; they are cell clusters composed of an array of endocrine cell types which variously secrete insulin (to lower the blood sugar, along with other effects), glucagon (a hormone released that raises blood sugar levels), somatostatin (a neuropeptide), pancreatic polypeptide, and the recently described hormone resistin. Before insulin was first used therapeutically in 1922, T1D was uniformly fatal. PMID- 20704923 TI - BRCA1 and BRCA2 in 2005. AB - Extract: In 1994, Mark Skolnick and his colleagues at Myriad Genetics in Salt Lake City announced that they had identified the BRCA1 (BReast CAncer 1) gene. This effectively put an end to a five-year competition that had been raging among several research groups in North America and Europe -- ultimately it was a private company, and not a university-based research group that prevailed. Only a year later a second breast cancer gene, BRCA2 was identified by competing researchers in England. These discoveries are among the most significant in the field of cancer since 1995 in terms of public interest or scientific impact. By 1991 it was known that a gene like BRCA1 conferred a greatly increased risk of breast cancer among women who were born with a mutation of it -- raising the risk from about 8% in their lifetime to 80% or more. The identification of the gene in 1994 permitted the identification of the actual women who were at high risk. Genetic testing for cancer susceptibility soon followed. PMID- 20704924 TI - Radiation for early breast cancer: Is less more? AB - Extract: Women who present with early breast cancer are initially treated with surgical lumpectomy (removal of the tumor mass) followed by radiation therapy. Breast radiation therapy is well established as the "standard of care" for women with early breast cancer as it has consistently been shown, in randomized clinical trials, to reduce the risk of a relapse in the breast by 60-75%. Excellent control rates and survival following lumpectomy and post-operative breast radiation demonstrate that mastectomies (removal of the entire breast, including the tumor) are normally not necessary for early disease. This is consistent with the consensus of multiple experts in the field following their assessment of multiple clinical trials comparing lumpectomy and mastectomy. The increasing use of mammographic screening for breast cancer has resulted in earlier diagnosis of the disease when the tumors are smaller and so they have not yet spread to the axillary lymph nodes (under the armpits). It has been recognized that systemic adjuvant treatment with the anti-estrogen medication, tamoxifen, that prevents estrogen from stimulating receptive tumor cells, also reduces breast cancer relapse as well as preventing metastatic spread of the disease and improving survival. Survival, however, does not appear to be affected by radiation treatment, and women who are diagnosed with the disease early and who have negative pathological findings in their axillary lymph nodes have a lower risk of breast cancer relapse overall. This has led researchers to look for low-risk subgroups of these women who might reasonably be able to avoid the side effects and inconvenience of radiation. PMID- 20704925 TI - Actively immunizing patients with HIV-1: Progress on the development of a therapeutic vaccine. AB - Extract: Despite more than twenty years of research relating to HIV-1, human immunodeficiency virus type-1, HIV-1 infection remains a public health threat of extraordinary proportions. The World Health Organization estimates that in the year 2003 alone, 4.8 million people were newly infected with HIV-1, approximately 38 million people were living with HIV-1 or suffering from acquired immunodeficiency syndrome (AIDS), and 2.9 million individuals died as a result of AIDS-related diseases. Since the first cases of AIDS were identified in 1981, 20 million people have died as a result of HIV-1 infection. With the advent of highly active antiretroviral therapy (HAART), the morbidity and mortality associated with HIV-1 infection have been dramatically reduced. However, additional studies have shown that long term HAART by itself is unlikely to be a cure for HIV infection and that cessation of HAART is inexorably followed by a rebound in HIV replication. Furthermore, the cost of lifelong HAART, the complex dosing regimens required, the toxic side effects of the medications and the limited availability of these drugs in developing countries, all suggest that HAART itself may be ill-suited to constrain the HIV pandemic. These issues indicate that alternative treatment strategies capable of effecting durable and sustained viral suppression are urgently needed. PMID- 20704926 TI - Seasonal variation of rheumatic diseases. AB - Extract: Seasonal variation has been shown in a number of rheumatic diseases (diseases involving the joints and related structures). The incidence of acute gouty attacks (an inflammatory arthritis) is highest in the spring. The onset or exacerbation of rheumatoid arthritis, the onset of Wegener's granulomatosis (chronic tissue inflammation and cellular clumping in the nasal passages, lungs and kidneys), anti-neutrophil cytoplasmic antibodies (ANCA) associated kidney inflammation (glomerulonephritis) and systemic vasculitis are all seen more commonly in the winter. There is a significant increase in the incidence of positive biopsies in giant cell arteritis (vascular inflammation of the temple) in late winter and autumn. In systemic lupus erythematosus (SLE, an autoimmune disease in which antibodies to self components are found in the blood stream and in tissues) there may be a tendency for different organs to be affected during different seasons. In SLE patients, there is an increased incidence of photosensitive skin rashes in the summer and of joint pain in the winter and spring. A significantly higher prevalence in the winter and spring was observed among SLE patients with class V lupus nephritis (LN, inflammation of the kidneys), as compared with the summer and fall. A similar trend was seen for seasonal variation of the percentage of class III lupus nephritis patients. PMID- 20704927 TI - Selective targeting of mitochondria for the treatment of cancer. AB - Extract: Mitochondria fuel cellular activities via the production of ATP. They help control calcium levels within the cell and produce reactive oxygen species that function in cell signaling. The increased permeability of the mitochondrial membranes, known as permeabilization, is one stage, a point of no return, in the death of a cell. The mitochondrion is an attractive drug target because agents that seek and destroy mitochondria should be less prone to the perils of drug resistance. The trick is being able to selectively target mitochondria in one cell type and not another. This is now proving to be possible. When cells wake up from a period of inactivity with a burst of reproductive zeal, their mitochondrial function changes. This allows scientists to selectively target the mitochondria in certain cellular settings. Small positively-charged molecules accumulate at higher concentrations in the mitochondria of carcinomas, the most common type of solid tumor, due to bioenergetic differences between normal and cancerous cells. Most cancer treatments employ agents to interfere with cell division. Recently, growth signals that drive the proliferation and survival of tumor cells and tumor blood vessels have been successfully targeted. Mitochondria are the focal point for a variety of pro- and anti-apoptotic stimuli. The means by which tumor cells acquire resistance to apoptosis (cell suicide or programmed cell death) suggests that targeting of mitochondria or mitochondrial proteins may afford an effective means to circumvent the resistance of most tumor cells to apoptosis. Scientists are looking to exploit the pro-apoptotic function of mitochondria to trigger the death of cancer cells. PMID- 20704928 TI - Pharmacokinetics of drugs administered in nanosuspension. AB - Extract: Nanosuspensions are submicron-sized crystalline drug particles that are stabilized by coatings of surfactant (a surface-active agent which reduces surface tension) to produce stable pharmaceutical formulations. Their development arose in response to the evolving needs of the medicinal chemist over the last twenty years. During this period, the implementation of high throughput screening tests has enabled the identification of molecular drug candidates with greater affinity for protein receptor targets. In general, such lead compounds have proved to be larger and more hydrophobic (water-hating) than previous candidates, thus permitting the exclusion of water from the receptor surface and increasing the hydrophobic interaction with the target. While effective, as demonstrated in in-vitro binding assays, such compounds often lack sufficient water solubility, a parameter required for successful, subsequent development. PMID- 20704929 TI - Mechanism of disease: Pulmonary hypertension. AB - Extract: Pulmonary hypertension (PH) was previously termed primary (idiopathic or of unknown origin, i.e., spontaneous) or secondary (as a result of another disorder) pulmonary hypertension. It is now clear, however, that many of the entities labeled as secondary pulmonary hypertension resemble primary pulmonary hypertension in both their histopathological features and their response to treatment. For this reason, the World Health Organization (WHO) has recently classified PH into five groups on the basis of their proposed underlying mechanism. Group I in this classification, designated pulmonary arterial hypertension, is the focus of this overview. Pulmonary arterial hypertension (PAH) is defined as a sustained elevation of the pulmonary arterial pressure to greater than 25 mmHg at rest or greater than 30 mmHg following exercise, with a mean pulmonary-capillary wedge pressure (an indirect measure of left atrial pressure) of less than 15 mmHg. The entities within the category of PAH include idiopathic pulmonary arterial hypertension (IPAH; formerly, primary pulmonary hypertension), PAH associated with collagen vascular disease (e.g., in limited systemic sclerosis), portal hypertension (high pressure in the vessel that carries blood from the intestines to the liver), congenital left-to-right intra cardiac shunts, infection with the human immunodeficiency virus (HIV), and persistent pulmonary hypertension of the newborn. The histological appearance of lung vessels in each of these conditions is similar: intimal fibrosis (formation of fibrous material in the inner lining of the blood vessel), increased medial thickness, pulmonary arteriolar occlusion (block of arterioles [the vessels that join the arteries and capillaries] in the lung), and plexiform (web-like) lesions predominate. PMID- 20704930 TI - Global gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. AB - Extract: Chronic obstructive pulmonary disease (COPD) is a slowly progressive, and irreversible disorder characterized by airway obstruction, which is a significant cause of morbidity, mortality and health care costs. COPD is a collective term describing two separate chronic lung diseases: emphysema and chronic bronchitis, which have a common culprit -- the cigarette. Cigarette smoke has been generally accepted as the primary factor in the development of COPD; cigarette use accounts for about 80% to 90% of COPD cases in the United States. However, only 15 to 20% of smokers develop clinically significant symptoms of COPD, which suggests there may be a genetic susceptibility to the development of the disease. The genes that determine this genetic susceptibility to cigarette smoking and disease progression to COPD are poorly understood. Individual genes or groups of genes that are expressed differently in smokers with and without COPD can be determined by comparing their corresponding global gene expression profiles. Two approaches, microarray and serial analysis of gene expression (SAGE), are currently used for simultaneous and rapid analysis of the expression levels of thousands of genes in a given cell population. Microarray, involving the binding of labeled nucleic acids targets to immobilized probes, is a relatively rapid and widely used technique. However, microarray is a closed method, meaning that it only measures expression levels of already collected nucleic acids sequences. PMID- 20704931 TI - Obesity: A chronic disease in need of drug targets and safe medicines. AB - Extract: Over the past two decades, urbanization has prompted the availability of an abundance of high caloric foods and has promoted increasingly more sedentary lifestyles, resulting in the rise of obesity as the most common nutritional disorder in the urbanized world. Presently, the majority of people in the United States are considered overweight or obese, making obesity and its complications a major health concern. Consequently, the World Health Organization (WHO) has identified obesity as a major chronic disease, now emerging as a pandemic. Today, there are over one billion overweight people worldwide, 300 million of which are obese. At present rates, the number of obese people is expected to double by 2025 (WHO). In addition to adult obesity, adolescent or childhood obesity has doubled in the past 10 years, with a corresponding doubling of adolescent type 2 diabetes (T2D). The prevalence of obesity in children is on the rise in most urbanized populations, which will impact obesity-associated morbidity and mortality even more in the decades to come. PMID- 20704932 TI - "A change of heart: how the people of framingham, massachusetts, helped unravel the mysteries of cardiovascular disease". AB - SUMMARY: For more than 50 years, Framingham Heart Study has produced over 1,000 scientific papers and identified major risk factors associated with heart disease, stroke, and others. It changed America's heart. Cigarettes were no longer advertised as "your doctor's favorite brands." We knew, from the Study, that LDL is a "bad" cholesterol and HDL is a good one. PMID- 20704933 TI - Editor's Note. PMID- 20704934 TI - Mutations, drift, and the influenza archipelago. AB - Extract: Annual influenza (flu) epidemics in humans affect 5-15% of the population, causing an estimated half million deaths worldwide per year. Antibodies against the viral surface glycoprotein hemagglutinin (HA) provide protective immunity to influenza virus infection and this protein is therefore the primary component of influenza vaccines. However, the antigenic structure of HA has changed significantly over time, a process known as antigenic drift. In as many years, antigenic drift necessitates an update of the influenza vaccine to ensure sufficient efficacy against newly emerging virus variants. Antigenic drift is therefore both the root cause of the enormous public health burden of influenza epidemics, and a primary reason why the virus is such a fascinating pathogen from a scientific perspective. Thousands of influenza viruses are isolated and analyzed each year by the national and international laboratories that form the World Health Organization (WHO) global influenza surveillance network. This worldwide surveillance effort produces the data for the twice yearly vaccine strain selection meetings, and has resulted in the establishment of a remarkable historical record of the global evolution of this important pathogen. The degree to which immunity induced by one strain is effective against another is mostly dependent on the extent of the antigenic difference between the strains. The analysis of antigenic differences between strains is therefore critical for surveillance and vaccine strain selection, and is also a cornerstone of basic and applied research in virology. PMID- 20704935 TI - Highly lethal H5N1 influenza virus in asia: Genesis and options for control. AB - Extract: Unprecedented animal epidemics of avian influenza viruses of the H5N1 subtype have been reported in Asia in 2004. These outbreaks resulted in the destruction of hundreds of millions of poultry. Of the 44 persons in Asia infected with H5N1 viruses, 32 died (20 in Vietnam and 12 in Thailand). It is impossible to predict whether H5 subtype viruses will acquire the ability to spread among humans and cause a new pandemic. The highly pathogenic Z genotype of H5N1 is now endemic in southeastern Asia and will continue to threaten veterinary and human public health. Influenza A viruses belong to the Orthomyxoviridae family and can be divided into 15 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes on the basis of antigenic and sequence differences in these surface glycoproteins (proteins with sugar groups attached). In wild aquatic birds, influenza's natural hosts, the viruses cause no disease. Periodically, influenza viruses are transmitted to other hosts and cause transient infections and occasional deaths. Less frequently, influenza viruses are transmitted to other species and become adapted to the new hosts. Thus permanent lineages of influenza A viruses are established in humans, swine, horses, and domestic poultry. PMID- 20704936 TI - New therapeutic approaches for Alzheimer's disease. AB - Extract: By undergoing a slight change in shape the normally innocuous peptide, amyloid-beta (A-beta) self-assembles forming aggregates, which are toxic to cells and induce a myriad of changes in the brain. It is now thought that the generation of these toxic species is an initial and necessary step in the pathogenic process underlying Alzheimer's disease (AD). The amyloid cascade hypothesis has led to the rational design of anti-amyloid therapeutics, which holds promise for the treatment and prevention of AD. One therapy, AD vaccination, has received a great deal of attention from both the scientific and lay community, and will be the topic of this discussion. The signs and symptoms of AD are familiar to most: seemingly innocent absent-mindedness, giving way to progressive memory impairment, disordered cognitive function, and altered behavior and language deficits. Ultimately the patient becomes entirely dependent on others for every aspect of daily living, with death typically occurring within 8 to 12 years of diagnosis. These symptoms are characteristic of a number of illnesses termed dementia, of which AD is the most common. Affecting over 12 million people worldwide, the American Alzheimer's Association estimates that $100 billion a year is spent on caring for individuals with AD. PMID- 20704937 TI - Novel treatments under development for muscular dystrophy. AB - Extract: There is no specific therapy for the muscular dystrophies, a group of genetic diseases that affect primarily skeletal muscle and compromise patients' quality of life and, in the most severe forms, their survival. New results coming from gene and cell therapy, as well as novel strategies aimed at preventing or delaying muscle degeneration, have raised hopes that clinical experimentation may start in the near future. Muscular dystrophies (MD) primarily affect the skeletal muscle. They are clinically and molecularly diverse and, in the most severe forms, such as Duchenne Muscular Dystrophy (DMD), lead the patient to wheelchair dependency, respiratory failure and premature death. In many cases, the mutation impairs genes that encode proteins forming a complex that links the cytoskeleton to the basal membrane, a collagen scaffold in which cells are embedded. Mutation in one of these proteins often causes a breakdown of the whole complex, leading to an increased fragility of the membrane, especially during intense contractile activity. This, in turn, results in increased calcium entry and subsequently focal or diffuse damage to the muscle fiber. PMID- 20704938 TI - Inheritance of cancer. AB - Extract: A single inherited mutant gene may be enough to cause a very high cancer risk. Single-mutation cases have provided much insight into the genetic basis of carcinogenesis, but they are relatively rare and account for only a small fraction of all cancers. Examples include mutation to the APC gene, causing early onset colon cancer in the syndrome familial adenomatous polyposis (tumorous polyp tissue in the colon); mutation to either the BRCA1 or BRCA2 genes, causing an increased risk of breast cancer; and mutation to the TP53 gene, causing Li Fraumeni syndrome with various early onset cancers such as bone or soft tissue sarcoma. Cancers sometimes cluster in families, but do not follow the rigid inheritance pattern characteristic of a mutation to a single gene. Males with a brother or father who has suffered prostate cancer are more likely to develop the disease. Similarly, females with a sister or mother who has suffered breast cancer are more likely to get a breast tumor. Some of the clustering may arise from the common diet and environment shared by families. Recently, however, researchers have begun to assign a significant fraction of cancer risk to the particular genetic variants that individuals inherit. PMID- 20704939 TI - Echoes of the past: Evolution, development, health and disease. AB - Extract: Well over 90% of our existence as a species was prior to the development of agriculture, which has brought forth many cultural changes. Thus understanding our biology and our capacity to respond to the environment may be enhanced by reference to our own evolutionary history. Moreover, knowledge from our recent past (i.e., the study of life history), particularly the environmental conditions experienced by our parents and grandparents and from our own early life, provide additional insights. These elements come together - our combined ecological, evolutionary, and societal histories -- in understanding the concept known as "developmental origins of adult disease," first described over a decade ago. One genotype (a specific genetic make up) can generate a range of phenotypes (features or characteristics). Much of this diversity is determined by developmental plasticity, processes by which environmental influences induce irreversible changes in the developmental path of the organism. Developmental plasticity must be distinguished from developmental disruption in which an environmental challenge is teratogenic (causes defects in the fetus) and disruptive to the normal pattern of development. PMID- 20704940 TI - Gene therapy: A possible aid to cancer radiotherapy. AB - Extract: Cancer remains a major health problem despite great advances in radiation and other therapeutic modalities. The increasing success of radiotherapy owes to many factors, including the more sophisticated equipment that provides improved treatment techniques and the variety of natural or synthetic subatomic particles available for treatment. This is made possible, in part, by better imaging techniques such as computed tomography (CT, multiple x rays are combined by computer to give a 2-D image), magnetic resonance imaging (MRI, magnet causes hydrogen atoms to become polarized and their "spin" is measured and summated to create an image of an internal structure), and positron emission tomography (PET, images created of positron decay by radioactive isotopes administered and taken up by the tissue of interest -- in this case the tumor). These new technologies allow one to greatly improve tumor targeting and to better visualize the radiation delivered to all anatomic sites within the patient. All forms of ionizing radiation (radiation that can split atoms and molecules into charged particles and radicals) can destroy any type of cancer cell if a sufficiently high dose is delivered. Normal tissue injury limits the dose of radiation a physician can deliver and thus limits the cancer control rate. Photons (x-ray therapy) are the most common particles used in radiation treatment. PMID- 20704941 TI - Bipolar disorder: Treatment. AB - Extract: Acute mania is as close to a medical emergency as we have in psychiatry. A manic patient is likely, if not treated rapidly, to take actions that will endanger his marriage and his job, if not his (and potentially other people's) life. A manic patient driving at 110 miles an hour through the city may have just had a conversation with his family physician where he denied delusions or hallucinations; yet the result of poor judgment on the road can be life threatening. The famous European psychiatrist Manfred Bleuler once wrote "I have seen many cases in which the patient has ruined the happiness, the social condition of himself and of his family for good as he had not been hospitalized at the right time." He went on to point out in his letter to me that the modern emphasis on keeping schizophrenic patients out of the hospital in order to reduce hospitalization and dependency (not to mention cost!) has unfortunately and unduly been generalized with respect to the care of the manic patient. Moreover, laws cherished by well-meaning human rights advocates to guarantee that human beings cannot be incarcerated unjustifiably have led to the increasingly cumbersome and difficult procedure of involuntary hospitalization. PMID- 20704942 TI - New drugs for asthma. AB - Extract: Asthma has now become one of the most common chronic diseases in industrialized countries and is predicted to increase throughout the world over the next decade, particularly in developing countries. Previously, asthma was viewed as a disease of bronchoconstriction (closing of the airways) and treated predominantly with bronchodilators (drugs which open up the airways), but more recently it has been seen as an inflammatory disease of the airways and the mainstay of modern management is treatment with inhaled corticosteroids. The airway inflammation in asthma is characterized by activation of mast cells, infiltration of eosinophils and increased activated T helper 2 (Th2) lymphocytes. Inhaled corticosteroids have revolutionized the management of asthma, leading to better control of asthma, reduced hospital admissions and a reduced mortality. Corticosteroids and long-acting beta2-agonists (salmeterol and formoterol) in fixed combination inhalers are currently the most effective therapy for asthma and are increasingly used in all patients with persistent symptoms. PMID- 20704943 TI - Association of the PTPN1 gene with type 2 diabetes and insulin resistance. AB - Extract: An extensive body of evidence suggests that genes are major contributors to type 2 diabetes (T2DM) susceptibility. Until recently efforts to identify T2DM genes have met with limited success. Application of recent advances in high throughput genetics and genetic analysis has revealed evidence for association of protein tyrosine phosphatase N1 gene (PTPN1, a catalytic protein that removes phosphate groups from phosphorylated tyrosine residues) with T2DM and insulin resistance (a condition whereby the body no longer responds to insulin). The evidence suggests that this association is mediated by DNA sequence differences outside the coding region of the PTPN1 gene. Over 10 different genetic studies have concluded that the long arm of human chromosome 20 (20q) is linked to the inheritance of diabetes. One gene that is located in 20q is PTPN1, which encodes the PTP1B protein, a ubiquitously expressed phosphatase (protein tyrosine phosphatase 1B), which dephosphorylates phosphorylated tyrosine residues of the active insulin receptor protein thereby disrupting the insulin signaling pathway. PMID- 20704944 TI - Drug targets in immunological diseases: Focus on rheumatoid arthritis. AB - Extract: There are a large number of diseases involving inappropriate activation of the immune system. These are often classified as immune-mediated diseases and include autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis, and type I diabetes mellitus, allergic diseases such as asthma, and immune-mediated graft/organ rejection. RA is a chronic systemic inflammatory disease involving the destruction of articular cartilage and bone in joints. Despite the advances in our understanding of RA, the cause remains elusive. It is now recognized that there are two arms to the disease, namely an inflammatory arm and a destructive arm. The inflammation causes many of the symptoms of pain and swelling whereas the joint destruction is the major cause of long term disability associated with this disease. It is clear that the joint destruction occurs early in the course of the disease and mediators, such as cytokines (non-antibody proteins that act as intracellular mediators), are important in this process. PMID- 20704945 TI - Systemic lupus erythematosus (SLE): Trials and issues. AB - Extract: Systemic lupus erythematosus (SLE or lupus) is an autoimmune disorder in which antibodies to self are found in the bloodstream, and tends to develop in cycles or "flares" and "remissions." It is a complex disease, and investigators designing clinical trials are faced with an array of disease manifestations and difficult-to-measure responses to treatment. Ideally, the protocols for clinical trials and the ultimate therapeutic decisions should be guided by evidence-based medicine, considering both the pathophysiologic mechanisms and the epidemiologic principles, which influence the clinical course of the disease. Few large-scale prospective randomized studies have been published, most of them addressing lupus nephritis (autoimmune inflammation of the kidneys), as the disease manifestation with better defined end-points such as changes in serum creatinine (a waste product of protein degradation that signifies kidney damage when found in high concentrations in the bloodstream), urine protein excretion, development of end stage renal disease, and death. Our goal is to provide an overview of the clinical trials and relevant case series in SLE published in the past 2 years, outlining the important developments and reinforcing some of the most significant issues that arise. PMID- 20704946 TI - Mutations of EGFR in lung cancers and their implications for targeted therapy. AB - Extract: The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [enzymes which phosphorylate (add phosphate groups to) tyrosine residues in proteins] is dysregulated in many human cancers and plays important roles in their development and progression. The family has four member molecules: ERBB1/EGFR/HER1 (located on chromosome 7), ERBB2/HER2 (on chromosome 17), ERBB3/ HER3 (on chromosome 12) and ERBB4/HER4 (on chromosome 2). These receptor molecules are composed of an extracellular ligand-binding domain, a transmembrane segment and an intracellular tyrosine kinase domain followed by a regulatory segment. Although tyrosine kinase domains of the family members are highly homologous to each other, they have distinct properties. The binding of a ligand (a small molecule that binds to a receptor) to its specific receptor results in autophosphorylation of specific tyrosine residues of the receptor and triggers the activation of several important downstream signaling pathways. EGFR and HER2 have been widely studied in many human cancers. Overexpression of EGFR is frequently observed in several human cancers, and gene variants (EGFRvIII) (i.e., increased expression and/or proteins with different amino acid sequences, and potentially different reactivity or even functions) are frequently found in glioblastomas (a form of brain tumor). Over-expression of HER2 is found in a subset of breast and ovarian cancers correlating with poor prognosis. PMID- 20704947 TI - Dying dangerously: Necrotic cell death and chronic inflammation promote tumor growth. AB - Extract: We all shudder about untimely deaths or those that we were not prepared for. As such we perceive such "unscheduled" deaths as dangerous. Similarly, apoptotic death (literally falling leaves) or the programmed cell death of cells in multicellular organisms ranging from slime mold and simple worms through to mammals, has a level of tidiness and well-orchestrated activities with literally hundreds if not thousands of gene products employed with either the primary or secondary purpose of coordinating the orderly death of cells throughout life. During inflammation of any sort, driven by tissue damage or injury or infection by pathogens (virus, bacteria, and parasites), apoptotic death similarly serves to quickly rid the host of damaged cells, promote removal and digestion of the infected cell, and prepare the way for tissue remodeling and repair. When this goes awry, for example during periods of chronic inflammation, tissues are subjected to the contrasting needs of driving apoptotic death whilst maintaining the barrier function of the epithelia (such as skin cells) as well as the selective permeability of mucosal sites (i.e., areas where mucus is secreted to protect the cells from their surroundings, such as gut cells protecting themselves from the gastric acids). Prudently, they need to limit and husband local resources sufficiently for the maintenance of tissue integrity and renewal. It is our provocative and novel contention that cancer in adults (and not children) most often arises in a setting of chronic inflammation and disordered cell death rather than one associated primarily with disordered cell growth as it is popularly imagined by scientists, clinicians, and the general public. PMID- 20704948 TI - Hepatitis B and C treatment: New perspectives. AB - Extract: Hepatitis B and C viruses are structurally unrelated viruses that cause a major burden to health throughout the world. It is estimated that there are 350 million carriers of hepatitis B and 170 million carriers of hepatitis C worldwide. Both may cause hepatitis with the eventual risks of cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). Until recently, very few therapeutic options were available to afflicted patients. Several new significant advances have now been made in assessing and treating infected patients and ongoing studies are now targeting more challenging patient groups who have failed to respond to previous treatments or who have associated co-morbidities. Hepatitis B virus (HBV) is a DNA virus that is spread sexually, vertically (mother-to-baby) and via blood products. The structure of the virus includes the hepatitis B surface antigen (HBsAg) that originates from the viral envelope and the hepatitis B e antigen (HBeAg) that is released from the nucleocapsid (virus coat and genome). HBsAg is present in the blood circulation during active infection and chronic hepatitis B is diagnosed if HBsAg is persistent beyond 6 months. HBeAg is present when the virus is actively replicating and is associated with high levels of HBV DNA and an increased risk of progression to cirrhosis and HCC. Recently, a form of virus has been identified called the precore mutant in which high levels of HBV DNA may be present in the absence of eAg due to a mutation in the gene encoding eAg or its upstream regulatory gene. Patients with high levels of HBV DNA and HBeAg are also at a high risk of liver disease. PMID- 20704949 TI - Dendrimer drugs prevent scar tissue formation. AB - Extract: Dendrimers are hyperbranched synthetic macromolecules that can be made with structural precision. So far, their biomedical applications have been limited to drug delivery. Dendrimers with cationic (i.e., amine or NH3+) end groups are toxic after repeated intravenous use or topical ocular application. In contrast, anionic (i.e., carboxy or COO-) dendrimers are not toxic. For example, cationic dendrimers cause substantial changes to red blood cell morphology at 10 mug/ml whilst anionic dendrimers have no such effect at 2,000 mug/ml. We set out to determine whether the receptor-ligand interactions between carbohydrates and proteins, which mediate many important aspects of cell surface-mediated immuno regulation could be pharmacologically manipulated using new anionic dendrimer based drugs. Any such medicine would have to possess multiple and cooperative receptor binding properties. Previous attempts to pharmacologically manipulate such interactions with synthetic linear polymers have failed because of the structural diversity of the polymers used, and because they activated immunological cell death pathways and blood clotting pathways. PMID- 20704950 TI - Aspirin triggers formation of anti-inflammatory mediators: New mechanism for an old drug. AB - Extract: Aspirin is a widely used non-steroidal anti-inflammatory drug (NSAID). It is well documented that aspirin irreversibly inhibits cyclooxygenase (COX) by acetylation of an amino acid serine residue, and thus blocks the subsequent biosynthesis of prostaglandins and thromboxane. COX has at least two forms, COX-1 and COX-2. COX-1 is the main form present in mature platelets in the blood, where it transforms arachidonic acid to the intermediates PG-G/H, which are subsequently converted to thromboxane A2. Thromboxane A2 is a vasoconstrictor and potent platelet activator. Thus, inhibition of thromboxane A2 formation explains aspirin's anti-thrombotic properties. In the early 1990s, a second form of COX was identified, namely COX-2. COX-2 was initially conceptualized as an "inducible" COX that is elevated in its quantity by a wide range of agents that stimulate inflammation or cell division and seems to be responsible for local formation during inflammation and cancer. PMID- 20704951 TI - Helicobacter pylori causes gastric cancer by hijacking cell growth signaling. AB - Extract: Infection with certain strains (carrying the cagA gene) of the bacterium Helicobacter pylori (H. pylori) is associated with the development of gastric carcinoma. Upon introduction into the gastric epithelial cells and its subsequent modification by phosphorylation (adding a phosphate group) at the tyrosine amino acid residue, CagA binds specifically to a cellular oncoprotein (SHP-2) and causes the oncoprotein's phosphatase activity (ridding is a phosphate group from a molecule) to misbehave. Interestingly, species of cagA-positive H. pylori isolated in East Asian countries exhibit stronger oncoprotein binding activity and greater pathological activity than those isolated in Western countries. H. pylori, a spiral-shaped bacterium that colonizes the human gastric mucosa, is estimated to inhabit at least half of the world's human population. H. pylori is primarily acquired in childhood and infection is lifelong in the majority of cases. In many cases, H. pylori is transmitted from infected parents to children. H. pylori infection can also be acquired via common environmental sources such as drinking water and animals particularly in developing countries. H. pylori infection causes gastric diseases such as chronic atrophic gastritis and peptic ulcers. PMID- 20704953 TI - Editor's Note. PMID- 20704952 TI - "The epic story of the deadliest plague in history". AB - SUMMARY: "The Great Influenza" recounts what humanity witnessed and experienced during the 1918 influenza pandemic. Author John M. Barry also describes the remarkable transformation of U.S. medical education just prior to 1918. That transformation not only helped America cope with the pandemic but also continues to influence medical research and practice today. PMID- 20704954 TI - Bipolar disorder: Mania and depression. AB - Extract: Bipolar disorder is one of the most distinct syndromes in psychiatry and has been described in numerous cultures over the course of history, in a manner that suggests considerable similarity of the syndrome in time and place. The unique phase of the illness is mania. However, depression can be the most prominent phase and the ratio of depressions to manias over the life course of the illness is highly variable. Depression in a bipolar disorder is a syndrome that can be understood by any human being, as all of us have experienced sadness and there are at least some commonalities between normal sadness and the state of depression. Mania is often difficult to explain to someone who has not seen a manic patient. In many ways, mania is the opposite of depression and is characterized by the following: an elevated mood or euphoria, an overactivity with a lack of the need for sleep, and an increased optimism that usually becomes so severe that the patient's judgment is impaired and they may make decisions based on their optimism such as the purchase of 500 television sets if they believe that the merchandise will go up in price. PMID- 20704955 TI - Nicotine dependence perpetuating tobacco smoking may be treatable by drugs acting at glutamate receptors. AB - Extract: By the year 2020 tobacco smoking will become the single largest health problem worldwide leading to approximately 8.4 million deaths annually. In the USA alone, tobacco smoking leads to serious illness in an estimated 8.6 million people, causing roughly 440,000 deaths annually, and approximately $157 billion in health-related economic costs. On average, smoking leads to a loss of 12 healthy years and reduces the lifespan by 8 years. Almost a quarter of the USA population are tobacco smokers. The percentage of smokers is even higher in some other countries, and there is an alarming increase of tobacco use in the developing countries. The cost of tobacco smoking to society is tremendous in terms of health problems that frequently lead to death, medical costs and human suffering. In the USA and Europe, 70% of all smokers have considered quitting smoking at least once, and 35% try to quit at least once a year. Yet only approximately 6% succeed in maintaining abstinence. Therefore, there is a great need for the discovery and development of new treatments to assist people in achieving and maintaining abstinence from tobacco smoking. PMID- 20704956 TI - The colorful future of cell analysis by flow cytometry. AB - Extract: Human blood contains hundreds of distinct cell types, which differ by the proteins they produce (including those expressed on the cell surface) and the functions they perform. Numerous clinical and research applications require monitoring of these blood cells for their presence or activity. The great demand for technologies to identify, quantify, and purify subsets of blood cells (particularly those involved in the immune response) has driven rapid technological advances in the field of fluorescence-activated flow cytometry. In this article, we describe the instrumentation, reagents, analysis, and applications for the most recent incarnation of flow cytometric technology: the 17-color flow cytometer. PMID- 20704957 TI - Physical and mental recovery after hematopoietic stem cell transplantation. AB - Extract: Hematologic malignancies such as leukemia and lymphoma can be treated with high-dose chemotherapy and irradiation, but in many cases, the amount of treatment needed to eliminate malignant cells also destroys normal blood-forming cells in the bone marrow. During the past 35 years, this problem has been solved by hematopoietic stem cell transplantation (HCT). With this strategy, normal marrow function can be restored by the transplanted blood-forming stem cells that are infused like a blood transfusion after high-dose chemotherapy. In allogeneic transplantation, the stem cells come from a healthy donor. In autologous transplantation, the cells are taken from the patient and frozen until they are infused after high-dose treatment has been completed. Along with killing malignant and non-malignant immune cells, the treatment given before HCT also kills other rapidly dividing healthy cells, often causing hair loss, mouth sores and sometimes other organ problems. The immune suppression caused by treatment leaves a patient vulnerable to viruses and bacterial infections. After transplantation, immune reconstitution and resolution of acute complications usually begin within two weeks, but other complications, such as graft-versus host disease (GVHD) can continue for years. GVHD occurs when the transplanted allogeneic cells attack (attempt to reject) the host body. PMID- 20704958 TI - Migraine. AB - Extract: Migraine is a very common primary episodic headache disorder characterized by combinations of neurologic, gastrointestinal, and autonomic changes. Diagnosis is based on the headache's characteristics and associated symptoms. The International Headache Society (IHS) diagnostic criteria for headache disorders provide definitions for seven subtypes of migraine. Approximately 28 million Americans have severe, disabling migraine headaches, and 17.6% of American women and 6% of American men had one migraine attack in the previous year. The WHO ranks migraine among the world's most disabling medical illnesses. PMID- 20704959 TI - Hsp90 inhibitors as selective anticancer drugs. AB - Extract: Cancer drug discovery has traditionally focused on targeting DNA synthesis and cell division, resulting in drugs that show efficacy but have severe side effects, due to their lack of selectivity for tumor cells over normal cells. One truly tumor-specific protein, the mutant kinase BCR-ABL, single handedly causes chronic myelogenous leukemia and is the target of the remarkably effective new drug Gleevec. However, BCR-ABL is very much the exception. The majority of new molecularly-targeted drugs, such as kinase inhibitors, aim to exploit the overexpression of a particular kinase in the tumors compared to the normal tissues. However, the pitfall in doing that is that these drugs are aimed at single biological targets, while the vast majority of advanced tumors harbor multiple genetic alterations that drive malignant growth. A newly emerging class of drugs, called heat shock protein 90 (Hsp90) inhibitors, can simultaneously destroy multiple tumor-causing proteins and also have a profound therapeutic selectivity for tumor cells over normal cells. Hsp90 belongs to a family of proteins called molecular chaperones that are involved in the stabilization and folding of many signaling proteins (collectively referred to as Hsp90 "clients") that are dysregulated in cancers. Hsp90 client proteins include key regulators of cell proliferation and survival such as receptor tyrosine kinases, metastable/mutant signaling proteins, transcription factors and cell cycle regulators (Table 1). Hsp90 client proteins are major components of mitogenic signaling pathways that drive cellular proliferation and survival signaling pathways that counteract programmed cell death (apoptosis). Thus, Hsp90 inhibition can concurrently destablize many oncoproteins in numerous signaling pathways, suggesting that Hsp90 inhibitor drugs would be advantageous in destroying cancer cells that can easily overcome the inhibition of a single target or pathway. PMID- 20704960 TI - Leukotrienes: Novel targets for vascular disease. AB - Extract: Atherosclerosis is a chronic disease of the large arteries and the primary cause of heart attacks and stroke. It is a major cause of morbidity and mortality in the Western world and accounts for 50% of all deaths. According to a recent Center for Disease Control and Prevention (CDC, Atlanta, GA) survey, atherosclerosis has now become the single largest cause of death worldwide at 33%, replacing infectious diseases as the developing countries become more prosperous. Among the many risk factors, increased serum cholesterol carried by low-density lipoproteins (LDL), especially in oxidized LDL, is the single greatest contributing factor in the development of the disease. However, atherosclerosis is now recognized as an inflammatory vascular disease, but the molecular events involved in the initiation and development of the disease are still largely unknown. Recruitment of monocytes to specific sites in the arterial wall may be the initiating step, followed by the uptake of oxidized LDL by these monocytes, leading to their conversion into lipid-laden foam cells. PMID- 20704961 TI - The participation of chemokines in atherosclerosis. AB - Extract: Atherosclerosis is a disease of the blood vessels that is characterized by narrowing of the lumen due to plaque buildup within the vessel wall that occurs over decades of life. The atherosclerotic plaque was once thought to be composed mainly of fat and cholesterol, but it is now widely recognized that inflammatory cells of the immune system, especially a phagocytic cell (a cell which will engulf particulate matter as a prelude to its digestion) called the macrophage, plays a pivotal role in its pathogenesis. PMID- 20704962 TI - The development of cancer vaccines. AB - Extract: In the late 19th century, William Coley of the Memorial Sloan-Kettering Cancer Center in New York noticed the rare occurrence of tumors appearing to improve spontaneously, usually following an infection. This led him to propose that the human immune system could respond to tumors. However, his experiments to prove this fact met with limited success. Studies building from these observations conducted in the 1960's, led to the proposal of a theory of "the immune surveillance of cancer" by Burnet. They suggested that vaccines could be produced to promote the immune system's ability to protect against tumors. Unfortunately, subsequent clinical trials and animal models (comparing cancer rates in normal and immuno-compromised subjects) did not show any differences, which was explained by the suggestion that tumors are too similar to normal tissue to be distinguished by the immune system. PMID- 20704963 TI - Magic shotgun methods for developing drugs for CNS disorders. AB - Extract: Development of novel therapeutic entities with which to treat disorders of the central nervous system (CNS) that are both more effective and more specific, poses significant challenges to the drug discovery industry. The normal focus of drug research is the search for a "magic bullet," which acts on a specific protein (or receptor), ideally with no other interactions with other proteins. These are termed "clean" drugs, as they have a single action with few side effects. However, most common CNS disorders are highly polygenic in nature, i.e., they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly-specific drugs largely free of major undesirable side effects ("the magic bullet"). Secondly, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood. PMID- 20704964 TI - Positron emission tomography (PET) and anticancer drug development. AB - Extract: The last ten years saw a rapid increase in the number and type of new agents undergoing clinical evaluation for the treatment of cancer. Unfortunately, this expansion in drug development is associated with a high rate of attrition from success in early clinical evaluation to regulatory approval. Furthermore, a recent analysis showed that innovations around clinically validated mechanisms aimed at being best-in-class have created more value for the pharmaceutical industry than their first-in-class counterparts (i.e., some drugs similar to previous ones may work better and commercially more successful than novel drugs). These developments have stimulated research into finding methods for the early assessment of efficacy and for the demonstration of proof-of-principle (i.e., that the drug is hitting the correct target) of new agents in cancer patients. It is thought that conventional anatomical imaging methods for assessing treatment response are not only less applicable to many of the new agents, but also might contribute to the high rate of attrition of new agents during the drug development process. PMID- 20704965 TI - Where does HIV hide? AB - Extract: Following treatments that advocate the use of multiple antiretroviral drugs immediately after HIV infection were adopted, it soon became clear that long periods of time during which no viral load could be detected within the plasma of patients were often followed by dramatic increases in viral load. The location and exact nature of latent HIV reservoirs within infected individuals remains unclear. Aggressive "Highly Active Anti-Retroviral Therapy" (HAART) regimens currently in use have proven effective in suppressing viral replication and containing viral loads, but the re-emergence of HIV infection following the activation of latent viral reservoirs, often in a drug resistant form, remains a barrier to effective long term therapy. The situation is complicated further by the toxicity of using suppressive antiretroviral drug treatments over prolonged periods of time. Strategies designed to deliberately reactivate latent HIV infection from within sites of archived infection, and subsequently eradicate actively replicating HIV represent a promising alternative to the use of long term suppressive therapies. A better understanding of where latent HIV infections are located, both at the cellular and anatomical levels, and the factors governing which types of cells harbor these reservoirs will be critical to the success of such strategies. PMID- 20704966 TI - Resistance to interferons. AB - Extract: Interferons alpha, beta and gamma are a group of structurally and functionally related proteins, produced in response to viruses or double-stranded RNA and defined by their ability to establish an antiviral state in cells. They were originally discovered by Isaacs and Lindenmann (1957). Since their original discovery, several interferon genes and proteins have been identified. Their mechanisms of action were studied and in addition to the antiviral activity, other biological activities were also uncovered including inhibition of cell proliferation and immunomodulation. Human interferon-alpha is a family of at least 23 polypeptides coded by several related genes. The various interferons exhibit a high level of species specificity with some exceptions. For example, there is a high level of activity of human interferon-alpha subtypes on bovine cells. Interferons have been used for the treatment of certain viral infections, multiple sclerosis, certain cancers including hematologic malignancies and Acquired Immune Deficiency Syndrome (AIDS)-related cancerous complications. PMID- 20704967 TI - A fisherman's tale: Phage display as a discovery tool. AB - Extract: Genome sequencing efforts have produced a wealth of information that remains to be exploited at the protein level. A major area of drug discovery involves the identification of novel peptide ligands which could provide leads for the development of new drugs that mimic the structure and function of proteins. These drugs could be used to modulate the activity or interaction of proteins in cells. In biochemistry, ligand refers to a small molecule that binds to a larger macromolecule. Phage surface display, using viruses that infect bacteria called bacteriophages, is a technique where fragments of foreign peptides are joined to the virus proteins and displayed on the phage surface coat, thus maintaining the spatial structure and activity of the protein, and allowing for its exposure to potential interactors or ligands. Both the genetic information and the phenotype are contained within the phage particle allowing for the peptide sequence to be deduced from the DNA sequence. The technique can be used to analyze the molecular recognition properties of peptides and proteins and to identify new ligands for a protein of interest. This would allow for the study of how proteins recognize each other, such as antibody-antigen epitopes (binding sites) and the isolation of biologically active molecules or novel peptide drugs. It can also be used to isolate new antibodies from antibody libraries or identify new substrates for enzymes. PMID- 20704968 TI - The cell permeable peptide strategy is a promising new tool for the prevention of neurodegeneration. AB - Extract: Neurons are constantly subjected to changes in their environment and consequently they are continuously adapting to these variations. During recent years, important advances have been made in understanding the molecular events underlying the neuronal responses to extracellular signals. The Mitogen-Activated Protein Kinases (MAPKs) are enzymes (catalytic proteins) activated by a variety of extracellular stimuli or signals, that add phosphate groups to specific amino acids within a specific protein. These enzymes form signal transduction cascades within cells. In biology, signal transduction is any process by which a cell converts one kind of signal or stimulus into another, via a sequence of biochemical reactions inside the cell. The MAPKs are the most important cytoplasmic signal transduction enzymes that are involved in many aspects of cellular regulation. The MAPKs signaling event propagates and amplifies the external stimuli, from the plasma membrane to the cytoplasm and finally to the nucleus, with a delicately regulated mechanism, which is organized in sequential steps and involves three different key enzymes. PMID- 20704969 TI - The promise of bispecific antibodies. AB - Extract: While monoclonal antibodies closely resemble the naturally occurring immune defense proteins, bispecific antibodies (i.e., antibodies detecting two different antigens) are not found in nature. Both types of antibodies share the feature of antigen specificity that is mediated by the presence of a unique antigen binding site on the antibody. Antigen binding sites exclusively interact with a particular molecular part of an antigen, known as an epitope. Monoclonal IgG (immunoglobulin G) antibodies carry two antigen binding sites for the same epitope, while bispecific antibodies are equipped with two different antigen binding sites with the potential to link two epitopes that could be present on two different cell types. Murine monoclonal antibodies first became available through the hybridoma technology developed by Kohler and Milstein in 1975. Since then they have been improved for therapeutic use by chimerization (only the antigen binding sites remain murine, all other antibody parts are of human origin, e.g., Erbitux), humanization (only the six subregions of the antigen binding site that actually contact the epitope remain murine, e.g., Avastin) or the recovery of fully human antibodies from phage display libraries or from mice transgenic for human immunoglobulin genes (e.g., ABX-EGF, an investigational drug). Several monoclonal antibodies have been approved for human therapy in various disease indications acting either as receptor antagonists, neutralizers of protein receptor ligands or through the recruitment of immune effector functions against pathogenic cells. PMID- 20704970 TI - Natural killer cells and immunity against cancer. AB - Extract: Under specific conditions, the immune response can eradicate tumors. The specific response against cancer requires the recognition of target molecules (antigens) by a subpopulation of white blood cells, the T lymphocytes. These antigens are exclusively or predominantly expressed by the tumor cells. Since many tumors fail to express specific antigens or express these antigens in a "wrong" way that impairs their recognition, cancer cells frequently escape from the specific immune response. Nonetheless, alternate effector cell populations have been described that are able to destroy tumor cells without any requirement for recognition of cancer-specific antigens. Among these effector populations, natural killer (NK) cells have an important role. Instead of looking for the presence of tumor cell-specific antigens, the NK cells sense the absence of molecules usually present at the surface of normal cells (the so-called human leukocyte antigen (HLA) class I molecules). Very often, these HLA class I molecules are not expressed, or are expressed but in an abnormal way by cancer cells. This "negative" mechanism of tumor cell recognition and destruction is called the "missing self hypothesis" since it postulates that the absence of molecules that identify the cell as "self" induces the destruction of these cells. PMID- 20704971 TI - Treatment of disease through oral tolerance. AB - Extract: The immune response to soluble protein antigens differs markedly depending on the route by which that antigen enters the body. In particular, early studies demonstrated that antigens that were first encountered via the gastrointestinal tract (e.g., via oral administration) led to systemic hyporesponsiveness against that antigen. This phenomenon has been termed oral tolerance. Further studies in mouse models of human disease demonstrated the potential for oral tolerance to protect susceptible animals from developing inflammatory and/or autoimmune diseases. This breakthrough finding lead to a surge in interest in oral tolerance as a potential prophylactic/therapeutic agent in human diseases. Here we briefly describe the underlying mechanisms and important factors influencing oral tolerance elucidated through animal models and conclude with a discussion on the translation of these findings to human beings. Numerous studies in mice have demonstrated that the dose of antigen administered is a critical factor influencing oral tolerance. Moreover, two forms of oral tolerance have been delineated which differ in their mechanism of action. High doses of antigen lead to the deletion of antigen-reactive T lymphocytes (T cells). PMID- 20704972 TI - Immune cells: Actors in pancreas development and regeneration that fail to fulfill their role and lead to diabetes? AB - Extract: Epidemiologists have estimated that, by the year 2025, 250-300 million individuals worldwide will have diabetes mellitus, which consists of variable degrees of insulin-producing beta-cell dysfunction that is responsible for hyperglycemia (high level of sugar in the blood). The predominant form is type 2 diabetes (T2D), also called noninsulin-dependent diabetes mellitus (NIDDM), which is associated with insulin resistance (cells stop responding to insulin) and mainly affects obesity-prone mature adults. By contrast, type 1 diabetes (T1D) or insulin-dependent diabetes mellitus (IDDM), the less common form (characterized by a lack of insulin), also described as autoimmune diabetes, is predominantly observed in children and young adults. However, for several years, the clinical features of diabetes have been changing, as demonstrated by the late appearance of autoimmune signs that are characteristic of T1D, in adults initially diagnosed as having T2D (called latent autoimmune diabetes of adults or LADA), and of T2D in children or young adults. Intriguingly, accumulating evidence indicates that T2D and related obesity are linked to inflammation. PMID- 20704973 TI - "The anatomy of hope: how people prevail in the face of illness". AB - SUMMARY: In "The Anatomy of Hope," Dr. Jerome Groopman, Professor and Chairman of Department of Medicine, Harvard Medical School, tells extraordinary stories of hope in coping with conventionally hopeless diseases and suffering. Biologically, hope may stimulate the release of internal painkiller molecules. PMID- 20704974 TI - Editor's Note. PMID- 20704975 TI - Particulate air pollution and inheritable mutations in mice: Possible health effects? AB - Extract: In a recent study we showed that the particulate fraction of air pollution was capable of increasing the rate at which DNA changes were passed to the next generation (germline mutations) in mice. Here we briefly describe the research that brought us to this experiment, followed by a description of the recent study and its implications. Herring gulls (Larus argentatus) are fish eating water birds that breed throughout the Laurentian Great Lakes and in many other parts of the Northern Hemisphere. In the early to mid 1990's, these birds were used as a sentinel wildlife species in our studies of germline mutations as a function of distance from integrated steel mills. The assay used involved comparison of the DNA profiles (minisatellite DNA -- non-coding sequences) of gull offspring with those of their parents, and identification of novel bands, or mutations, in the DNA profiles of offspring. PMID- 20704976 TI - Mechanisms of bone metastasis. AB - Extract: Cancer frequently spreads to bone, a process termed bone metastasis. Up to 70% of patients with breast cancer or prostate cancer, and 15 to 30% of patients with lung, colon, bladder or kidney cancer develop bone metastasis. Once tumors go to bone, such as in patients with breast cancer or prostate cancer, they are incurable, and only 20% of patients with breast cancer are still alive five years after they are found to have bone metastasis. It is estimated that about 350,000 people die with bone metastasis each year in the United States. Bone metastasis causes severe bone pain and can result in fractures without any injury, as well as other life-threatening conditions. There are two major types of bone metastasis, one in which bone destruction is the predominant feature and the other one in which new bone formation is predominant. Bone metastasis where bone destruction is the predominant feature is known as osteolytic, and that in which new bone formation is the primary feature is called osteoblastic. This classification for metastasis is really two extremes of a continuum because many patients can have both osteolytic and osteoblastic or mixtures of both in their bone metastasis. In fact, patients with prostate cancer who usually have bone metastasis that shows increased new bone formation also have increased bone destruction in the same lesions. PMID- 20704977 TI - Convergence of atherosclerosis and alzheimer's disease: Cholesterol, inflammation, and misfolded proteins. AB - Extract: Alzheimer's disease is a progressive neurodegenerative disease that results initially in memory dysfunction, and is subsequently followed by a more general decline in intellectual function. In western societies, it accounts for the majority (60-70%) of all cases of dementia. Currently, Alzheimer's disease affects over 4 million adults in the United States. With the increase in life expectancy of the general population, more individuals are living longer, exposing them to the increased risk of developing Alzheimer's disease. If current population projections hold true, it is estimated that by 2050 the number of cases of Alzheimer's disease will have quadrupled, and that Alzheimer's disease will begin to rival heart disease, cancer, and stroke as a leading cause of death. This has caused many to observe that Alzheimer's disease represents a new epidemic in medicine. The implications for society, in terms of both human suffering and monetary cost, are far reaching and underscore the urgency in finding effective therapies for the prevention and treatment of the disease. PMID- 20704978 TI - Neurobiology of intelligence: Health implications? AB - Extract: Understanding the neurobiology of intelligence may, in turn, help illuminate the complex relationships between intelligence and health. There is strong evidence that the lateral prefrontal cortex and possibly other brain areas support intelligent behavior. Variations in intelligence and brain structure are heritable, but are also influenced by factors such as education, family environment, and environmental hazards. These exciting scientific advances encourage renewed responsiveness to the social and ethical dimensions of such research, including its health-relevance. PMID- 20704979 TI - Getting advances in science to make a difference: Translation research for improving diabetes care. AB - Extract: By the end of the 20th century the worldwide diabetes pandemic had affected an estimated 171 million individuals. Unfortunately, the future looks even worse. By 2030, approximately 366 million people will have diabetes. This disease accounts for an extraordinary amount of human suffering, it is a major cause of blindness, kidney failure, amputations, and cardiovascular disease, and its complications substantially reduce both the quality and length of life. In addition, diabetes imposes staggering economic costs while lowering productivity and wasting social capital. Fortunately, several efficacious treatments are currently available to reduce or prevent diabetes-related health problems. Blood sugar and blood pressure control can reduce microvascular (retinopathy and nephropathy) complications; eye examinations with timely follow-up and photocoagulation can prevent vision loss; foot care can decrease serious foot disease and amputations; control of blood pressure and lipids as well as aspirin use can prevent or diminish cardiovascular disease events; angiotensin-converting enzyme (ACE) inhibitors can reduce nephropathy and cardiovascular disease; and influenza and pneumococcal vaccines can reduce hospitalizations, respiratory conditions, and death. PMID- 20704980 TI - Cell surface growth factor receptor molecules as targets for cancer therapy. AB - Extract: Molecular communication is essential for the coordinated development and life of multicellular organisms. This process involves sending, receiving and promoting signals by means of elaborate signal transduction networks. Important players for these processes are cell surface receptors which transmit signals across the cell's outer barrier, the cell membrane. The so-called receptor tyrosine kinases (RTKs) play a central role within this group of proteins by controlling a wide array of biological functions such as cell migration, proliferation, survival or differentiation. Concomitantly, deregulated signal transduction leads to aberrant cellular behavior and, as a consequence, can induce or contribute to various pathophysiological disorders such as cancer. Based on this rationale RTKs have been discovered as prime targets for therapeutic intervention and the first drugs that have been approved demonstrate the potential of this approach. A kinase is an enzyme that catalyzes the addition of a phosphoryl group to a molecule, an event called phosphorylation. Tyrosine kinase adds a phosphoryl group to the tyrosine residue of a protein. PMID- 20704981 TI - The cost of new drug discovery and development. AB - Extract: The development of a new drug requires a major investment of capital, human resources, and technological expertise. It also requires strict adherence to regulations on testing and manufacturing standards before a new drug can be used in the general population. All these requirements contribute to the cost increases for a new chemical entities (NCE, i.e., new drug candidate) research and development (R&D). The central question raised by this trend is who will pay for new pharmaceutical R&D? With this question in mind, this article has three objectives: 1) to describe how the environment for pharmaceutical R&D has changed over time and the effect of these changes on the R&D process, 2) to summarize available information on the cost of drug discovery and development for NCEs, and 3) to consider the societal value of new drugs. The focus is on the United States, as the largest pharmaceutical market, and for which the relevant literature is most comprehensive, but many of the issues discussed are similarly important in the other major markets. PMID- 20704982 TI - Rewards wanted: Molecular mechanisms of motivation. AB - Extract: Brain dopamine was first recognized as a neurotransmitter when it was found to be concentrated in a small group of cells that degenerate in Parkinson's disease. Since Parkinson's disease results in tremor, rigidity, and an inability to initiate voluntary movement, and since the cells are localized in the basal ganglia, a region with the primary motor mechanism of the sub-mammalian brain, dopamine was initially identified with motor function. Recent studies indicate, however, that the basal ganglia is much more than simple motor structures. Brain dopamine is now known to play a major role in the ability of rewards to establish learned response habits and preferences. While its importance in reward has caused it to be identified primarily with motivational function, close inspection reveals that one of its primary roles in motivated behavior is a role in the stamping-in of learning and memory. PMID- 20704983 TI - Can we faithfully recall what we remembered? AB - Extract: Fresh memories need time to stabilize. The idea that new long-term memories (LTM) undergo a time-dependent consolidation process after acquisition has received substantial empirical support in over a century of experimental studies. These studies report that recently acquired memories are susceptible to disruption by distracting stimuli, lesions, pharmacological agents and toxins, but over time the memory becomes resistant to these interferences. It is suggested that the formation of new patterns of synaptic connections between neurons are instigated in specific brain regions, such as the hippocampus, during consolidation and these are reactivated during retrieval. Central tenets for this structural view of memory are that only specific synapses that undergo contingent co-activation are modified -- "neurons that fire together, wire together," and that the modifications are permanent. PMID- 20704984 TI - Unfulfilled inflammatory resolution leads to chronic inflammatory diseases. AB - Extract: Inflammatory conditions, particularly those that involve chronic inflammation, represent an area of great interest to the pharmaceutical industry. Regulated as they are by a diverse array of ligand-receptor interactions, inflammatory responses are amenable to small molecule pharmaceutical intervention and a wide variety of anti-histamines and anti-inflammatory treatments. Both steroidal and non-steroidal treatments have been developed to treat pro inflammatory conditions. In their review, Gilroy et al. (2004) present the case for developing novel anti-inflammatory drugs not by finding more effective inhibitors of the inflammatory response, but by developing small molecule drugs that positively regulate the processes and mechanisms by which inflammatory responses are attenuated (i.e., the little known process of inflammatory resolution). PMID- 20704985 TI - Genetically engineered E. coli as a protein delivery vehicle for killing cancer cells. AB - Extract: The beneficial effects of bacteria on rejection of and resistance to tumors have been observed since the 18th century. Physicians have recorded hundreds of cases of spontaneous regression of many types of cancer following bacterial infections, such as staphylococcal or mixed infections, or bacterial vaccines. For example, significantly lower recurrence and number of metastases were recorded in sarcoma patients with concurrent streptococcal infection occurring either spontaneously or by inoculation. More recently, a decreased incidence of malignancy has been recorded in areas or subsets of populations where infectious diseases are endemic. For example, a Swiss study of hospitalized patients over a 20 year period recorded that the previous incidence of acute infections and acute inflammatory episodes was almost nil in groups of cancer patients, compared with a much higher incidence in the non-cancerous groups. Studies in the 1960s with Clostridium showed that this anaerobic bacterium could selectively target and grow inside experimental tumors in mice, leading to tumor regression. However, clinical trials with Clostridium had to be abandoned due to severe toxicities. In the last few years interest in using bacteria as cancer therapies has been reignited. Advances in genetic engineering have enabled modifications of bacteria to reduce toxicity, however, clinical trials with attenuated bacteria such as Salmonella have failed to provide therapeutic benefits that outweigh toxicities in cancer patients. PMID- 20704986 TI - Paralysis research: Promoting nerve fiber protection, growth and functional recovery by cyclic AMP and cell transplantation. AB - Extract: In a recent study we reported that levels of the intracellular signalling molecule, cyclic adenosine monophosphate (cAMP), are important in facilitating spinal cord injury (SCI) repair. Following is a brief summary of previous findings that led us to examine cAMP levels after SCI and to test the hypothesis that elevating the level of cAMP could improve nerve fiber growth and functional outcome. We employed in these experiments an incomplete SCI model, whereby a specific weight is dropped from a consistent height onto the exposed surface of the spinal cord at the thoracic (chest) level to induce a bruising type injury. The elevation of cAMP was used in combination with the transplantation of a type of peripheral nerve cells, called Schwann cells. Lastly, the implications of our findings for human SCI repair are discussed.Regeneration of neurons within the central nervous system following SCI is limited by the presence of inhibitory molecules and a lack of growth supporting molecules at the injury site, by the physical barrier created by a scar that forms around the injury site, and by a reduced intrinsic capacity for growth in neurons that occurs after development and maturation. Transplantation of cells from the peripheral nervous system -- Schwann cells -- can be used to replace lost tissue within the injured spinal cord and form an environment conducive for nerve fiber re-growth. Importantly, Schwann cell transplantation is clinically relevant because of the feasibility of autologous transplantation from harvested peripheral nerves for use in human SCI. However, Schwann cell grafts do not enable regenerated nerve fibers to grow out of the transplant, and they elicit only a weak response from neurons from the brain that are important for voluntary control of walking. These limitations have stimulated the development of combination strategies that will improve the ability of Schwann cells to promote repair of the injured spinal cord and enhance functional recovery. PMID- 20704987 TI - Immunotherapy with enhanced self immune cells. AB - Extract: Immunotherapy with empowered self immune cells, also called adoptive immunotherapy, has emerged as an exciting therapeutic modality for the treatment of cancer and infectious diseases over the past decade. Adoptive immunotherapy can be defined as the ex vivo (outside the body) generation and expansion of antigen-specific T cells over a short time period and infusion back into the patients. Currently, it has been evaluated for the treatment of infections with viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV), along with a variety of malignancies, including malignant melanoma and multiple myeloma. PMID- 20704988 TI - Targeted radiosensitization with DNA topoisomerase I drugs. AB - Extract: Radiation has become a mainstay therapy and currently provides care for approximately one half of the cancer population since its discovery more than a century ago. However, the efficacy of radiotherapy is largely restricted by the radiation-associated side effects, which in a way reflects the lack of tumor specificity of radiation. Drugs targeting DNA topoisomerase I (TOP1) are a novel class of anticancer agents with established activity against many cancers. In addition to their ability to kill cancer cells directly, these drugs are also excellent radiation sensitizers that can enhance the cell-killing effect of radiation. Combining TOP1-targeted drugs and radiotherapy represents a new promising cancer therapy. Here, we briefly review, from basic science to clinical application, the current status of targeted radiosensitization (RS) by combining TOP1 drugs with radiation. PMID- 20704989 TI - Antibody guided precision radiation therapy. AB - Extract: Hybridoma/monoclonal antibody (mAb) technology as described in Kohler and Milstein's work resurrected Ehrlich's century old concept of "magic bullets." This seminal publication described fusion of a plasmacytoma (tumor of activated B lymphocytes) with spleen cells and subsequent isolation of hybrids that secreted mAb with pre-defined specificity. Generation of mouse mAbs against tumor associated antigens became a focus in the 1980's. Pre-clinical studies provided proof-of-concept for the potential of mAbs for therapy although inherent limitations of these models demonstrated discordance in predictability of actual efficacy. Clinical investigations also illustrated deficiencies; foremost, an inevitable immune response, i.e., the production of human anti-murine immunoglobulin antibodies (HAMA). Other limitations included (1) inadequate tumor dose delivery; (2) insufficient activation of effector function(s); (3) slow blood clearance; (4) low affinity and avidity; (5) normal organ targeting; (6) tumor antigen heterogeneity; and (7) insufficient tumor penetration. Most of these were handled with genetic engineering or chemical modification, but some obstacles remained. HAMA production has been addressed by chimerization (combining portions of mouse and human antibodies) or complete humanization (grafting only the key antigen-binding portions of mouse antibody to a human antibody framework) of the mAb. PMID- 20704990 TI - "Brother's Keeper: A Story From the Edge of Medicine". AB - SUMMARY: Jamie Heywood's younger brother Stephen was diagnosed with Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig's disease). Trying to save his brother, Jamie ventured on a roller-coaster ride right on the edge of medicine. PMID- 20704991 TI - EGFR mutants render Iressa more effective in treating lung cancer. PMID- 20704992 TI - Team deCODE led by Dr. Stefansson made a successful run of gene discovery and toward personalized medicine. PMID- 20704993 TI - Industry Trends: Gene discovery by deCODE Genetics. PMID- 20704994 TI - Industry News: Avastin approved for metastatic colorectal cancer. PMID- 20704995 TI - Industry Analysis: Tarceva extends cancer patients survival in a phase III study. PMID- 20704996 TI - "The genome war: how craig venter tried to capture the code of life and save the world". PMID- 20704997 TI - Avastin. PMID- 20704998 TI - Ketek. PMID- 20704999 TI - Sensipar. PMID- 20705000 TI - Fluorescent detection and isolation of DNA variants using stabilized RecA-coated oligonucleotides. AB - Extract: The information generated by the genome sequencing initiatives is being gathered, cataloged and evaluated. These databases will provide fertile ground for the development of new technologies in the areas of functional genomics and molecular diagnostics. Concurrent use of these data sets, however, presents an ethical dilemma. Genomic sequence data reveals a substantial amount of sequence diversity within a population; therefore, confidentiality must be maintained so that an individual is not exposed to the risk of "genetic" discrimination. In addition, as nucleic acid tests enter this diagnostic arena, the obtaining of a high degree of accurate and reliable data from the assays will become essential for decision making in healthcare. Genotyping methodologies, which aim to identify genetic variants in large populations often rely heavily on the use of PCR to amplify the designated template DNA. By its very nature, PCR requires a denaturation step that produces the substrates for primer annealing and template amplification. In some cases, nucleic acid denaturation and the number of processing steps in the PCR reaction can introduce errors into the template, mistakes that are then amplified logarithmically creating a sequence bias. In addition, specimen handling of PCR samples and/or products provides the basis for a certain degree of user contamination. Considering the importance of producing exact genotypic IDs for individuals and its real life implications, new techniques that reduce the potential for mistakes at any stage of the processes resulting in data for analysis should be pursued vigorously. PMID- 20705001 TI - High resolution definition of chromosome abnormalities with probes designed from genome sequences. AB - Extract: Numerical and structural chromosome abnormalities are a common cause of inherited and acquired diseases in humans. Cytogenetic detection of genomic imbalances and rearrangements is standard diagnostic practice, and is used both prognostically and for treatment stratification, especially for neoplastic disorders. Abnormalities are recognized by chromosome banding and by fluorescence in situ hybridization (FISH). FISH permits examination of specific DNA sequences within single or multiple chromosome bands on a metaphase cell or within an interphase cell. Locus-specific FISH probes have traditionally been composed of recombinant DNA segments that span large chromosomal targets of hundreds of thousands of base pairs, about an order of magnitude smaller than the length of a typical chromosomal band. These probes, which contain either repetitive sequences, single copy sequences or combinations of both, have been developed to hybridize to a wide spectrum of chromosomal targets -- encompassing a single gene to an entire chromosome. Commercially available clones are generally useful for detecting more common abnormalities, whereas, detection or characterization of rare chromosomal abnormalities by FISH has relied on clones obtained from research laboratories. PMID- 20705002 TI - Mammalian genome-wide loss-of-function screens using arrayed small interfering RNA expression libraries. AB - Extract: RNA interference (RNAi), first discovered in Caenorhabdtitis elegans and now widely found and applied in a variety of organisms such as Drosophila, zebrafish and mammalian systems, has emerged to revolutionize the field of functional genomics by inducing specific and effective post-transcriptional gene silencing for loss-of-function studies. Mechanistic investigations of RNAi suggest that long double-stranded RNAs (dsRNAs) are first cleaved by the RNase III-like enzyme, Dicer, to 21-23 base pair (bp) small interfering RNAs (siRNAs). These siRNAs are resolved by ATP-dependent RNA helicase, and the resulting single stranded RNAs are then incorporated into the RNA-induced silencing complex (RISC). The antisense strand of the siRNA duplex guides the RISC to the homologous mRNA, where the RISC-associated endoribonuclease cleaves the target mRNA, resulting in silencing of the target gene. The approach of using long dsRNA (up to 1-2 kb) in C. elegans and Drosophila to induce gene silencing cannot be similarly used in mammalian cells, where introduction of long dsRNA activates the dsRNA-dependent protein kinase PKR. PKR phosphorylates and inactivates the translation initiation factor eIF2, resulting in a non-specific gene-silencing effect. Development and implementation of the use of 21 to 23bp siRNAs, which can be prepared by chemical synthesis, in vitro transcription, or expressed in cells using siRNA expression systems, allows specific and effective gene silencing in mammalian cells to occur without activation of PKR. PMID- 20705003 TI - A novel strategy to target lethal peptides against antibiotic resistant bacteria. AB - Extract: One of the major therapeutic challenges that face modern clinicians is the development of bacterial resistance to antibiotics. Currently, antibiotic resistance is a major problem in the treatment of staphylococcal, enterococcal, pneumocystis, helicobacter, and mycobacterial infections, to name a few. While there are several different mechanisms by which this occurs, the common pathway in the development of bacterial resistance has been the widespread use of broad spectrum antibiotics as single agents. In the work summarized here, we devised a novel antibiotic, which could be used to overcome bacterial resistance to standard antibiotics. The concept is based on two principles. 1) Use of a toxin of bacterial origin, as a non-standard antibacterial mechanism of action. For this purpose, colicin Ia of E. coli, a peptide with channel forming properties, was selected in order to produce target cell rupture. 2) To target such a toxin to a particular bacterial organism, we took advantage of a natural mechanism used by these bacteria to communicate with each other, namely, the use of pheromones, which are bacterial peptides secreted and bound by membrane receptors in a species- and strain-specific manner. PMID- 20705004 TI - Combinatorial chemoenzymatic strategies for in vitro glycorandomization: Efforts toward antibiotic optimization. AB - Extract: The natural product pool, which includes many glycosylated secondary metabolites, is the source of over half of the world's drug leads. For example, the antibiotics vancomycin and erythromycin, the antitumor compounds bleomycin and doxorubicin, and the antifungal agents amphotericin and nystatin all contain essential sugar attachments. Carbohydrate groups of natural product-based drugs have long been known to generally influence pharmacokinetic properties and there is an increasing recognition that these carbohydrate appendages also play a key role in drug-target interactions. These findings suggest that the alteration of glycosylation patterns on secondary metabolites is a potential strategy for the generation of novel therapeutics. We postulate that combinatorial chemoenzymatic strategies toward glycorandomized natural products will be able to overcome the limitations associated with total synthesis (time, protecting group manipulations, regio- and stereo-selectivity problems) and with in vivo pathway engineering (structural complexity, pathway bias, toxicity) by combining the advantages of enzymatic catalysis (efficiency, possibility of fermentation-based scale-up) with the power of chemical synthesis (unlimited diversity). We have recently demonstrated the power of in vitro glycorandomization (IVG) using vancomycin as the model. PMID- 20705005 TI - Linking lipid metabolism to immunity: The role of lipid transfer proteins in the selection of iNKT cells. AB - Extract: Since the emergence of the role that CD1d plays in selecting the natural killer T cell population expressing the semi-invariant V-alpha-14 T cell receptor (iNKT cells), a great deal of research has been done to identify the natural lipid antigen involved in this process. This interest has been sparked by the critical role of iNKT cells in the regulation of immune responses and their potential involvement in autoimmunity and the control of carcinogenesis. While iNKT cells show high autoreactivity, the only cellular lipid shown to be presented by CD1d has been phosphatidyl inositol, which does not activate iNKT cells by itself. The only lipid antigens known to activate iNKT cells have been alpha-glycosylceramides. However, alpha-galactosylceramide (alpha-GalCer) is derived from marine sponges and has no known equivalent in mammalian cells, which only synthesize beta-anomers of ceramide. Still, alpha-GalCer has proven to be a valuable tool in defining the role of iNKT cells in host defense, tumor immunity, and homeostatic regulation of anti-self responses. In order to discover the selecting lipid antigen(s), the road that CD1d travels to reach the cell surface and interact with iNKT cells required closer examination. Much work in recent years has shed light on the different pathways undertaken by the various members of the CD1 family to sample the various cellular compartments for lipid antigen presentation. In particular, trafficking of the CD1d molecule to the late endosomal and lysosomal compartments proved essential for selection of the iNKT cell population, suggesting that the natural lipid antigen(s) are sampled in these compartments. PMID- 20705006 TI - Defining the hematopoietic stem cell niche. AB - Extract: Stem cells modulate tissue formation and repair based on a complex interaction of cell autonomous and non-autonomous regulatory mechanisms. While reductionist approaches to understanding stem cell control continue to be extremely productive, understanding the physiological contexts in which stem cells function, will ultimately require definition of the microenvironments in which they live. The location of stem or precursor populations within numerous solid tissues has been described, but delineating specific associated cells and how they participate in regulating stem cell function has generally been lacking for mammalian tissues. However, the use of invertebrate-based models has created particularly productive systems in which to examine the niche context of stem cells. Gonadal tissue from C. elegans and D. melanogaster has permitted the definition and identification of ancillary niche cells, physical interactions and the molecular pathways such as Notch paralogues that govern the interplay between the stem cell and its local environment. We sought to determine a niche component for a mammalian tissue and focused on the hematopoietic system. We focused on hematopoiesis for multiple reasons, but in particular because of the potential for applying the information gained to a medical context. PMID- 20705007 TI - Directed evolution of recombinant serum paraoxonase (PON) variants. AB - Extract: Owing to their detoxifying functions, and roles in drug metabolism as well as the prevention of atherosclerosis, mammalian or serum paraoxonases (PONs) are an intriguing subject of research and a prime therapeutic and engineering target. Initially identified in mammals, PON and PON-related genes have now been found in fowls, zebra fish, and even in invertebrates such as C. elegans. The more closely-related PON genes are divided into three classes or sub-families: PON1, PON2 and PON3, that share 60-70% sequence identity. PONs are calcium dependent hydrolases that catalyze the hydrolysis of a broad range of esters and lactones. PON1, which is by far the most investigated member of this family, also catalyzes, albeit at much lower rates, the hydrolysis and thereby inactivation of various organophosphates (OPs), including the nerve agents sarin and soman. PON1 is also involved in drug metabolism and is used for drug inactivation. In recent years, it has become apparent that PONs also play an important role in the prevention of atherosclerosis. The levels of PON1 in the blood and its catalytic proficiency appear to have a major impact both on the individual's susceptibility to pollutants and insecticides, and to atherosclerosis. Furthermore, mice lacking the PON1 gene are highly susceptible to atherosclerosis and to OP poisoning. PON1 and PON3 reside in the high-density lipoprotein cholesterol-carrying particles known as HDL ("good cholesterol"). HDL has two key roles: mediation of cholesterol efflux, e.g., from macrophage foam cells in atherosclerotic lesions, and limitation of lipid oxidation in LDL. PONs have been implicated in both activities. PMID- 20705008 TI - Dr. Bert Vogelstein, pioneer of cancer genetics and champion of translational research. PMID- 20705009 TI - Industry Trends: Antegren -- Novel drug for autoimmune diseases. PMID- 20705010 TI - Industry Analysis: Erbitux and targeted therapies for cancer. PMID- 20705012 TI - Erbitux. PMID- 20705011 TI - Targeted therapy for cancer. PMID- 20705013 TI - Alimta. PMID- 20705014 TI - Plenaxis. PMID- 20705015 TI - Rescue of the p53 tumor suppressor by a rationally designed molecule. AB - Extract: The tumor suppressor protein p53 is crucial in preventing cancer as well as for achieving the therapeutic effects of both radiotherapy and much of chemotherapy. p53 responds to oncogene activation, DNA damage, hypoxia and other stresses by activating the expression of factors that trigger cell cycle arrest or programmed cell death. Strong evidence that inactivation of p53 is required for cancer cell survival comes from accumulated data that p53 is inactivated by mutations in some 50% of all human tumors, regardless of patient age or tumor type. This makes p53 the most frequently mutated gene in cancer, with more than 18,000 mutations reported so far. Most of the mutations result in a substitution of just one amino acid residue in the core DNA binding domain of p53, which frequently causes the protein to "melt" or denature at body temperature, and thus abolishes its function. Given the high potency of p53 in the induction of cell death, it is expected that small molecules that can refold p53 and rescue its function will efficiently and selectively kill tumor cells, thus providing a powerful new way to combat cancer. Notably, the accumulation of high levels of mutant p53 in tumor cells allows for a selective targeting of tumors. PMID- 20705016 TI - Targeting therapeutic molecules to sites of disease. AB - Extract: The holy grail of drug development is to design a magic bullet that will deliver a therapeutic agent only to the site of disease with minimal side effects. This is of great importance in particular when it refers to biological agents such as cytokines that have pleiotropic actions in different tissues. Cytokines are local mediators of cell-to-cell communication. Their expression is transient and they have a short half-life. Therefore, to overcome the pharmacokinetic limitations of cytokines, they are given subcutaneously to reduce side effects. However, by this route they lose their potency. In order to use cytokines for therapeutic purposes they have to be administered frequently at high doses to achieve biologically active concentrations locally at the required sites of a disease. PMID- 20705017 TI - Combination bacteriolytic cancer therapy: Attacking cancer from inside out. AB - Extract: Problems associated with conventional cancer therapy are numerous, but two stand out: lack of specificity and the inability to totally eradicate all cancerous cells. The former leads to severe, sometimes intolerable, adverse effects, whereas the latter contributes to the dismal prognosis for a variety of cancer types. Effective cancer therapy should consist of components targeting both normoxic and hypoxic tumor tissues. The progression of solid tumors requires a sufficient blood supply to deliver both nutrients and oxygen. However, the growth rate of malignant tumors often outpaces angiogenesis. In addition, the tumor vasculature is often poorly organized and leaky in nature. Consequently, the oxygenation of tumor tissues is not uniform. Well-oxygenated tumor cells lie close to vascular elements, necrotic cells are far away, and a gradient of hypoxia lies in between. Confounding this complexity is the fact that the perfusion of tumors is dynamic, resulting in transiently hypoxic areas. Tumor hypoxia poses major problems for conventional cancer therapies, as radiation therapy and chemotherapy both rely on molecular oxygen and/or active replication of the target cells for their cytotoxic effects. Cancer cells in hypoxic areas are quiescent, making them resistant to such therapies. These cells can escape from the initial assault and start proliferating again once perfusion improves at a subsequent time, leading to relapse. PMID- 20705018 TI - An efficient method for generating human somatic cell gene knockouts. AB - Extract: The Human Genome Project has produced a map detailing a vast genetic frontier that will continue to provide useful insights for the treatment of human diseases. The large number of uncharacterized genes reflects the degree of our progress and the wealth of opportunity. Functional genomics will broadly impact our understanding of disease and illuminate the path to better therapeutics. One of the most definitive ways to determine gene function is to specifically inactivate a gene through knockout approaches, thereby permitting comparisons between genetically matched (i.e., isogenic) knockout and wild-type controls. Gene knockout technologies have been performed in a variety of model organisms, including bacteria, yeast, chickens, and rodents. Though these studies might be useful for inferring human gene function, it is clear that homologues are not always functionally identical. One of the best ways to study gene function in human cells is to generate a human somatic cell gene knockout. However, this approach has historically been inefficient, resulting in the widespread use of "knockdown" approaches employing antisense or RNA interference (siRNA, short interfering RNA) technologies. These approaches reduce, rather than eliminate, the expression of a particular gene and often have non-specific effects that complicate the analysis of gene function. PMID- 20705019 TI - Use of animal models for the treatment of leukemias: Efficacy of DNA vaccination combined with ATRA. AB - Extract: By identifying the proteins (normal or oncogenic), which participate in the development of malignant diseases, we can identify novel targeted therapies to either stabilize or treat the disease. The approach is common to all: identification of targets, establishment of models, definition of pre-requisites for clinical transfer and surrogate markers for evaluation of in vivo efficacy. We have used animal models of myeloid leukemia using a genetic approach in order to understand the biology of leukemogenesis and to develop targeted approaches to therapy. These models are now developed and are ready for testing various different therapeutic strategies. There are good molecular targets for other malignancies and several new drugs are in clinical trials. Our work on the development of DNA vaccines represents, what we hope will be, the beginning of a challenging era in immunotherapy. Our results in the acute promyelocytic leukemia (APL) model, a subtype of acute myelogenous leukemia (AML), show that DNA vaccination combined with all-trans retinoic acid (ATRA) results in a survival advantage. PMID- 20705020 TI - A reusable optical nucleic acid biosensor applied to the rapid detection of single nucleotide polymorphisms associated with Spinal Muscular Atrophy. AB - Extract: Current methodologies for single nucleotide polymorphism (SNP) screening often require amplification, followed by time-consuming enzymatic manipulation (e.g., digestion or extension) and separation of the resultant products. Advancements in real-time PCR methods permit simultaneous amplification and quantification. Unfortunately, the ability to provide quantitative determinations can be made difficult by factors such as non-specific amplification and alterations in amplification efficiency owing to secondary-structure and sample matrix effects. Newer sensor and microarray technologies attempt to facilitate SNP analysis but usually require several hours for hybridization and data analysis. Furthermore, microarrays often cannot be reused as a result of limitations in the chemistries more routinely employed for nucleic acid immobilization. Difficulties associated with control of homogeneity of probe distribution, probe density and fidelity of the probe sequences (particularly when assembled by in-situ synthesis) can result in variations in the binding energetics of interfacial hybridization from spot to spot on an array, or even within individual array elements. Regions on the substrate may therefore exhibit variations in the selectivity, kinetics and dynamic range of response. The biosensor technology developed by our group presents an alternative to such an approach by use of controlled immobilization methodologies in a sensor format that provides for a reusable and quantitative technology where selectivity and kinetics may be more finely tuned. PMID- 20705021 TI - In vitro compartmentalization (IVC): A high-throughput screening technology using emulsions and FACS. AB - Extract: All screening approaches rely on ways of compartmentalizing assay reactions, and means of rapidly screening various molecules imbedded in these compartments. Miniaturization, which has become the hallmark of modern science and technology, has also been applied to screening, thus leading to a variety of high-throughput screening (HTS) technologies that aim at the smallest possible reaction volumes and the most sensitive and rapid means of detection. These demands are general and do not depend on the type of molecules (genes, proteins, small molecules, etc.) or activity (enzymatic, binding, inhibitory, etc.) that are being screened for, nor on the target of screening (functional genomics, directed evolution, drug discovery, etc.). Conventional HTS approaches use either robotic 2D-arrays (e.g., microtitre plates), or living cells. In vitro compartmentalization (IVC) is a newly developed technology that uses the aqueous droplets of water-in-oil (w/o) emulsions as cell-like compartments. PMID- 20705022 TI - Systemic gene therapy by Sindbis vectors: A potentially safe and effective targeted therapy for identifying and killing tumor cells in vivo. AB - Extract: A major obstacle to the development of gene therapy for cancer has been the inability to specifically and systemically deliver gene therapy vectors throughout the body to primary and/or metastasized tumor cells. Although intratumor injections of gene therapy vectors have sometimes been possible, no viral vector has been available that could be administered systemically and would selectively and efficiently target tumors without infection of normal tissues. Furthermore, even when locally injected, many viral vectors end up at high concentrations in the liver, because many cells of the body have low receptor numbers for some of the vectors in current use, whereas the liver has high numbers of such receptors. A number of ingenious approaches have been tried but none so far have fully resolved the problem. For example, tumor-specific promoters have been incorporated into the vectors so that gene expression and/or replication can occur in tumor cells but not normal cells. Unfortunately, only a small fraction of these vectors are typically taken up by the target tumor and expressed. In such cases, tumor cell death is generally insufficient to eradicate or significantly slow tumor growth. PMID- 20705023 TI - An experimental approach for systematic identification of antisense transcripts. AB - Extract: Natural antisense transcripts are endogenous transcripts that contain sequences that are complementary to other transcripts. Such complementary transcripts may be transcribed from opposing DNA strands at the same genomic locus (cis), or from different loci (trans), for example, pseudogenes. Notably, both types of antisense RNAs are genome-encoded and transcribed by DNA-directed RNA polymerases. A third putative source of antisense RNAs is transcription of the sense mRNA by an RNA-dependent RNA polymerase. Although only a few examples have been studied in detail, a significant number of naturally occurring antisense RNAs have been described in most eukaryotes, including mammals. Recent advances in bioinformatics have predicted as many as 2,500 mammalian cis-natural antisense transcripts. In one study, >2,600 human antisense transcripts were identified, of which >1600 were predicted to be true. 8% of the estimated 40,000 human genes were believed to have an antisense partner. Thus, it is likely that gene regulation by antisense transcription might be a common phenomenon in eukaryotic cells. PMID- 20705024 TI - Scientist profile: solomon snyder, m.d. PMID- 20705025 TI - Industry Trends: Pacing discoveries -- traditional lab work vs. high-tech machinery. PMID- 20705026 TI - Industry Analysis: Reversing atherosclerosis -- HDL drugs emerge as "heavy duty plumbing agents". PMID- 20705027 TI - "Better than prozac". AB - Extract: "Better Than Prozac -- Creating the Next Generation of Psychiatric Drugs" is a succinct yet highly informative text devoted to the past, present and future development of psychoactive drugs. Divided into two parts, the first is a historical narrative, which describes the development of psychiatric medications in the 1950s, a time when mental illnesses were very poorly understood, and therapeutic options were limited to say the least. It is a fascinating tale of scientific endeavor, near miraculous clinical effects, and significant amounts of good fortune. Having described the trials and tribulations of developing the first psychotherapeutic drugs, the book goes on to examine the impact that modern day technology is having upon our understanding of mental illnesses, and the rational development of increasingly better treatment options. PMID- 20705028 TI - Lexiva. PMID- 20705029 TI - Namenda. PMID- 20705030 TI - Cialis. PMID- 20705031 TI - Antigen specific tumor immuno-therapy with lentivirus transduced hematopoietic stem cells for transplant. AB - Extract: Immunotherapeutic approaches to tumors have shown generally disappointing clinical results. The goal of the studies presented in this report was to demonstrate a novel approach to tumor immunology in which new techniques were employed to bypass some of the major limitations that have been observed in tumor immunotherapies. Many tumor types express antigens that can be useful targets for the immune system if properly recognized, but tumors have developed means of generating immunological resistance. The studies were designed to generate a potent anti-tumor immune response by manipulating tumor antigen presentation to tumor-reactive T cells such that the immune system would recognize and destroy tumor cells. Towards this end, experiments were designed to address limitations in the previous approaches to tumor vaccines using dendritic cells (DCs) as vehicles. While DCs are potent antigen presenting cells and have been shown to stimulate T cells that are reactive to tumors, efficacy of them in clinical trials as vaccines has left room for improvement. Previous results from trials using ex vivo generated dendritic cells that have been loaded with antigen have shown that while immune responses to antigens can be generated, the ex vivo generated DCs do not efficiently traffic to secondary lymphoid organs. Studies conducted in mouse models suggest that this may be a result of both inefficient trafficking and elimination of the injected DCs by host T cells. A different approach for antigen-loaded DCs, namely, in vivo transfer of antigen has shown that it is difficult to effectively load DCs with antigen in vivo, and in both methods, a small percentage of antigen-loaded DCs were found in the lymph nodes. PMID- 20705032 TI - Modified adeno-associated virus (AAV) vectors: A new generation of targeted gene therapy delivery systems. AB - Extract: Gene therapy in its simplest form is the deliberate transfer of therapeutic genes into a host cell. As a human gene therapy vector, Adeno Associated Virus (AAV) is a promising delivery system. It is able to maintain stable gene expression in host cells, is efficient at gene delivery in vivo, and is non-pathogenic. However, one obstacle facing the advancement of AAV vectors is the natural tropism of the virus. The primary attachment receptor for AAV type-2 (AAV2) is heparan sulfate proteoglycan (HSPG). This receptor is widely expressed on many cell types, which creates a problem when delivering genes that promote cell death, as in anti-cancer gene therapy strategies. Conversely, cells that do not express HSPG cannot be transduced by AAV-2 based vectors. This can cause problems when gene delivery needs to be cell specific. As gene therapy moves forward, it will be imperative to develop AAV vectors that can be targeted to specific cellular receptors and therefore, specific cell types. PMID- 20705033 TI - Receptor-ligand genetics: Inactivation of receptors with a modified viral protein. AB - Extract: The function of a gene can be genetically investigated at the DNA (gene), RNA or protein levels. Homologous recombination or gene targeting has been widely used in mice whose embryonic stem cells can be manipulated to generate mutant offspring. However, it cannot be directly applied to human genetics or primary cells. In addition, it is difficult to generate mice with mutations in multiple genes that are closely linked. Moreover, knockout mice may have cell populations that are able to compensate for the loss of gene function during embryonic development. At the RNA level, anti-sense RNA has been used with limited success. More recently, RNA interference (RNAi) has been employed to knock down gene expression in a number of organisms. Although promising, RNAi has met with various levels of success, especially if the target protein is stable, and it may influence the expression of unrelated genes through unknown mechanisms. At the protein level, one common approach to studying receptor function is through the use of blocking antibodies. However, antibodies have limitations ranging from target specificity to toxicity and in vivo efficacy. The Intrakine and Intrabody system is another method of receptor inhibition in which a cytokine or single chain antibody specific to a receptor is fused to an endoplasmic reticulum (ER) retention signal to sequester the target receptor to the ER. While the Intrakine does reduce receptor function in the target cell, it has been shown to be secreted and to stimulate receptor signaling in surrounding cells. In addition, specific targeting of proteins for degradation is being rapidly developed to investigate protein functions. PMID- 20705034 TI - An improved strategy for constructing "designer" Cys2His2 zinc finger proteins. AB - Extract: The Cys2His2 zinc finger domain (hereafter simply "zinc finger") provides a useful scaffold for creating customized DNA-binding proteins, a technology with potential applications in biological research, molecular medicine, and gene therapy. Using a combination of targeted randomization and selection methodologies (e.g., phage display), many research groups have successfully altered the DNA-binding specificities of single zinc fingers, which typically recognize three to four base pairs of DNA. In these experiments, potential DNA-binding residues in a finger's a-helix (or "recognition helix") were randomized to generate a library of variants and then selection methods were used to identify fingers with desired DNA-binding specificities. To create synthetic multi-finger proteins capable of recognizing longer DNA sequences, various investigators have linked together three or more pre-selected or pre characterized finger domains. This type of strategy, which assumes that individual fingers behave in a modular fashion, permits the rapid assembly of multi-finger proteins directed to bind a wide variety of different DNA sequences. PMID- 20705035 TI - Biothreat agent monitoring using a flow-through polymerase chain reaction instrument. AB - Extract: The 2001 anthrax letter mailings highlighted critical shortfalls in the USA's capabilities for dealing with the threats of bioterrorism: the lack of effective, reliable, low-cost detection systems for use by state and local authorities. During the few months after the letters were received, 17,000 false alarms and hoaxes were reported, and Americans everywhere were terrified to open their mail. Over 200,000 samples were processed by the Center for Disease Control (CDC) and others. In a scenario where the attack was more wide spread, the laboratory processing requirements could be far greater. In light of such statistics, the imperative for high confidence, high throughput, and inexpensive diagnostics is clear. In answer to this technical challenge, nucleic acid-based methodologies are being standardized and documented to provide acceptable mechanisms of detection. Real time PCR (polymerase chain reaction), in particular, allows analysis of aerosolized or environmental samples to occur within minutes, enabling biological defense response architectures that would otherwise be impossible. PCR is a revolutionary technique for amplifying targeted sequences of DNA. The use of a thermostable enzyme (polymerase) allows sequential dissociation, annealing, and hybridization of complimentary DNA to occur very rapidly. A pair of DNA primers, about 20 nucleotides in length, is used to uniquely identify and amplify (over a million fold) the target DNA sequence. PMID- 20705036 TI - Increase of signal-to-noise of more than 10,000 times in liquid state NMR. AB - Extract: Two major applications exist for Nuclear Magnetic Resonance (NMR): spectroscopy and imaging. NMR spectroscopy has gained acceptance as one of the major analytical techniques, due to the detailed information that can be obtained about molecular structure, dynamics and intra- and inter-molecular interactions. Magnetic resonance imaging (MRI) is a non-invasive technique with superior soft tissue contrast and broad diagnostic value. The technique has gained wide clinical acceptance and is of great importance in diagnostic medicine. However, despite significant technological advancements (increasing field strength and cooling of electronics), the application of NMR is limited by an intrinsically low sensitivity, as compared to other analytical methods. Fundamentally, the low sensitivity originates from the low magnetic energy of nuclear spins, compared to the thermal energy at room temperature. At a magnetic field strength of 1.5 Tesla and room temperature, the proton spins are polarized to only 5 parts per million, and an improvement of 200,000 is thus theoretically possible. For other nuclei bearing lower magnetic moments (1/4 for 13C and 1/10 for 15N, respectively, compared to 1H), the theoretical enhancement factor is proportionally greater. The weak nuclear polarization is generally compensated by a high concentration (i.e., a large number of nuclear spins). However, the sensitivity of several other nuclei is further reduced by the low natural abundance of the NMR-active isotope (1.1 % for 13C and 0.36 % for 15N, respectively). PMID- 20705037 TI - Antisense therapy corrects nonsense mutation by exon skipping. AB - Extract: Antisense technology is based on the principle that antisense oligonucleotides (AO) can specifically alter gene expression and the pattern of splicing at the RNA level. The first application of such technology 25 years ago was for knockdown of targeted viral gene expression, which was achieved by targeting mRNA with AO to block the viral gene translation or induce its degradation. Such strategies have now been developed as powerful tools for the functional analysis of targeted genes in the laboratory and are suggested to be of great therapeutic potential against diseases from viral infections to cancers. More recently, antisense technologies have been devised for interference with gene splicing. Such applications target pre-mRNA rather than mRNA and was first established in vitro for correction of altered exon splicing in beta-thalassemia. Mutations in the beta-globin gene activate a cryptic site in the pre-mRNA and as a result the intronic sequences are spliced into the mRNA. This causes disruption of normal protein synthesis. Kole and his colleagues designed specific AO to the cryptic splicing site and successfully blocked its recognition and restored the normal splicing pattern of the gene. The use of AO for selective exon skipping was quickly explored by several laboratories to correct gene mutations for the treatment of Duchenne muscular dystrophy (DMD). PMID- 20705038 TI - Molecular beacons light the way: Imaging native mRNAs in living cells. AB - Extract: In vivo techniques to investigate the pathways that mRNAs undergo from maturation to localization at specific regions within a cell have thus far been the exclusive domain of protein biology as our ability to probe for nucleic acids in vivo have been hindered. In vivo imaging of synthetic transcripts helped dissect such a fundamental cellular process. Yet, in order to fully grasp the diverse organization and behavior of mRNAs in living cells, it is important to visualize the distribution and dynamics of RNA molecules in their living context, much like green fluorescent protein and its variants that fluoresce in diverse colors, have allowed us to image the dynamics of proteins. In 1996, our laboratory described a novel approach for detecting nucleic acids in solution. We have proceeded to make significant adaptations to this technique to facilitate visualization of the distribution and trafficking of mRNAs in living cells. This technique utilizes hybridization probes, called "molecular beacons," that generate fluorescent signals only when hybridized to a complementary nucleic acid target sequence. Molecular beacons are single-stranded oligonucleotides that form a stem-and-loop structure, where the loop portion of the molecule is a probe sequence complementary to a target RNA sequence, and the stem is formed by the annealing of complementary arm sequences which envelope the probe sequence. A fluorophore and a quencher moiety are covalently linked to the end of each arm, respectively. PMID- 20705039 TI - Novel targeting of biotinylated compounds to local tissues with avidin lipoprotein receptor fusion protein. AB - Extract: Targeting of cytotoxic drugs, radionuclides or imaging agents to specific cells or tissues is of great interest for the development of new therapeutic strategies and diagnostic approaches. Targeting should significantly increase efficacy in the desired tissues and reduce side effects elsewhere in the body. Previously, avidin or streptavidin have been used in multistep pretargeting applications either as a fusion protein with a cancer-targeting antibody or as a linker between biotinylated cancer-targeting antibodies and biotinylated radionuclides. However, these three step strategies (i.e., cancer tissue-specific biotinylated antibody; avidin or streptavidin; biotinylated drug) are complicated to use, involve the systemic injection into patients of three different compounds and sometimes only marginally improve the therapeutic window. Also, cancer tissue specific monoclonal antibodies have been difficult to develop and each type of tumor would require the development of different monoclonal antibodies. PMID- 20705040 TI - Gene exchange of thyA for interleukin-10 secures live GMO bacterial therapeutics. AB - Extract: The exponential outburst of knowledge in molecular immunology has provided us with an in depth insight into the biological activity of cytokines. These are small, freely diffusible proteins that, together with numerous growth factors and chemokines, act as messengers by which cells of the immune system communicate with each other and with most other tissues in the body. As such, these molecules are able to regulate many aspects of the immune response in which numerous cells and tissues may be involved at any one time. Most often, cytokines are active in extremely low concentrations. It is for these reasons that they are considered a tempting source of candidate therapeutics for the treatment of immune disorders or of value for boosting prophylactic immune therapies. The field has, however, seen major technical obstacles to the proficient use of many cytokines. Interleukin-10 (IL-10), an anti-inflammatory cytokine, can certainly serve as one of the most prominent examples of this striking combination of high promises -- for targeting immune diseases such as Crohn's disease and asthma -- being blocked in its application by equally high complications such as unacceptable side effects and high clearance. As many of the problems arise from the systemic distribution of IL-10 in the body, targeted delivery could enable the successful use of recombinant IL-10. Here again, however, technical hurdles such as the inherent acid sensitivity of IL-10 alongside the intrinsic high cost of any purified recombinant cytokine probably underlie the non-existence of readily available classical formulations for mucosal application of this cytokine. PMID- 20705041 TI - A novel experimental platform for investigating tumorigenesis and anti-cancer therapy in a human microenvironment derived from embryonic stem cells. AB - Extract: There has been a growing awarenes in recent years that tumorigenesis properties are markedly affected by the surrounding tissue microenvironment at both primary and metastatic sites. Thus, it has been shown that tumor progression is associated with extensive remodeling of adjacent tissues to provide a supportive microenvironment for cancer cell proliferation, migration, invasion, and the formation of blood vessels required for supporting cancer growth. As an example, human prostate carcinoma-associated fibroblasts can promote tumorigenic transformation in initiated human prostate epithelial cells. Appreciation of the importance of the stromal response has led to the development of novel anti cancer therapeutic agents targeted to frustrate stromal response factors, which support progressive tumor growth. Targets for investigation have included proteases, heparanase and other enzymes expressed by cancer cells or by adjacent stromal cells, which degrade extracellular matrix components and facilitate the release of cytokines and growth factors which stimulate angiogenesis, or support the growth and invasion of cancer cells. A great deal of attention has been directed at the development of anti-angiogenic molecules in particular, some of which have reached clinical trials. PMID- 20705042 TI - 25-year mystery unveiled: Hematopoietic stem cell niche is found. AB - Extract: Over the past decade remarkable progress has been made in identifying cytokines that promote the proliferation and differentiation of hematopoietic stem cells (HSCs) and also their co-culture with bone marrow stromal cells in vitro. Thus far, however, the relative inability to expand HSCs in vitro has greatly hindered mechanistic studies of stem cell properties and imposed limitations on the use of these cells in transplantation. This is largely due to a lack of adequate in vivo information regarding how HSCs are maintained, where HSCs reside, and the components of their microenvironment. With recent studies performed by two independent laboratories, the HSC niche is no longer as elusive. The knowledge of where HSCs reside, how stem cells are maintained in vivo, and how the number of HSCs is controlled in homeostasis is fundamentally important. This knowledge is also urgently needed in the application of stem-cell-based bone marrow transplantation for the proper mobilization of HSCs, in vitro expansion of HSCs to satisfy the increasing need for stem cells, and in vitro modification of HSCs such as in stem-cell-mediated gene therapy. PMID- 20705043 TI - PCR-like sensitivity for proteins with bio-bar-code amplification. AB - Extract: The polymerase chain reaction (PCR) made it possible to detect and amplify nucleic acid target sequences of interest when present in extremely dilute quantities. Comparable target detection and signal amplification methods for proteins could dramatically improve medical diagnostics and the developing field of proteomics. In order to improve upon the sensitivity limitations of conventional ELISA assays, researchers turned to oligonucleotide-antibody conjugates where a DNA strand replaced the enzyme as the molecule responsible for the amplification of detection events. The DNA sequence bound to the antibody (Ab) becomes the surrogate for protein detection, and can be amplified with PCR in a process termed immuno-PCR. Although a significant advance in protein detection, this approach and others have several drawbacks: 1) a low ratio of DNA identification sequence to detection Ab, which limits sensitivity; 2) inefficient target capture and slow target binding kinetics because of the heterogeneous nature of the target capture procedure, which increases assay time and decreases assay sensitivity; 3) complex conjugation chemistries that are required to link the Ab and DNA-markers; and 4) they require PCR. PMID- 20705044 TI - von Hippel-Lindau beta-domain-luciferase fusion protein as a bioluminescent hydroxyproline sensor for a hypoxia-inducible factor prolyl hydroxylase assay. AB - Hypoxia-inducible factor prolyl hydroxylases (HPHs) are responsible for hydroxylation of proline residues in hypoxia-inducible factor-alpha (HIF-alpha), resulting in von Hippel-Lindau (VHL)-mediated proteasome degradation of the hydroxylated proteins. Pharmacological inhibition of the enzyme leads to stabilization of HIF-alpha proteins and consequent activation of HIF, which provides therapeutic benefit for a variety of tissues undergoing ischemic stress. In an effort to develop a new assay for measuring HPH activity, we designed a fusion protein, VHL beta-domain-luciferase. Recombinant fusion protein with a glutathione S-transferase (GST) tag was purified from Escherichia coli. GST-VHL beta-domain-luciferase with C-terminal deletion (GVbL-CD) was obtained as a major product and found to have luciferase activity. In a GVbL-CD capture assay using HIF peptide-bound beads, at least a 13-fold increase in luciferase activity was elicited for HIF peptide with hydroxyproline compared with unhydroxylated HIF peptide. HPH inhibitory activities of known HPH inhibitors or HIF-1alpha inducers were assessed using this assay, whose results were in good agreement with those obtained from conventional methods. The competitive effect of 2-ketoglutarate on dimethyloxalylglycine-mediated HPH inhibition was assessed very well in the new assay. Taken together, the VHL beta-domain protein with luciferase activity is of use for HPH activity assay. PMID- 20705045 TI - Blue native electrophoresis to study mitochondrial complex I in C. elegans. AB - Blue native polyacrylamide gel electrophoresis (BN-PAGE) is an essential tool for investigating mitochondrial respiratory chain complexes. However, with current BN PAGE protocols for Caenorhabditis elegans (C. elegans), large worm amounts and high quantities of mitochondrial protein are required to yield clear results. Here, we present an efficient approach to isolate mitochondrial complex I (NADH:ubiquinone oxidoreductase) from C. elegans, grown on agar plates. We demonstrate that considerably lower amounts of mitochondrial protein are sufficient to isolate complex I and to display clear in-gel activity results. Moreover, we present the first complex I assembly profile for C. elegans, obtained by two-dimensional BN/SDS-PAGE. PMID- 20705046 TI - Characterization of azido-NAD+ to assess its potential as a two-dimensional infrared probe of enzyme dynamics. AB - Enzyme active-site dynamics at femtosecond to picosecond time scales are of great biochemical importance, but remain relatively unexplored due to the lack of appropriate analytical methods. Two-dimensional infrared (2D IR) spectroscopy is one of the few methods that can examine chemical biological motions at this time scale, but all the IR probes used so far were specific to a few unique enzymes. The lack of IR probes of broader specificity is a major limitation to further 2D IR studies of enzyme dynamics. Here we describe the synthesis of a general IR probe for nicotinamide-dependent enzymes. This azido analog of the ubiquitous cofactor nicotinamide adenine dinucleotide is found to be stable and bind to several dehydrogenases with dissociation constants similar to that for the native cofactor. The infrared absorption spectra of this probe bound to several enzymes indicate that it has significant potential as a 2D IR probe to investigate femtosecond dynamics of nicotinamide-dependent enzymes. PMID- 20705047 TI - Development of a high-throughput screening assay for cytoprotective agents in rotenone-induced cell death. AB - Parkinson's disease (PD) is a neurodegenerative disease featured by selective loss of substantia nigra neurons. Rotenone administration in animals induces neurodegeneration accompanied by alpha-synuclein-positive Lewy body-like inclusions, recapturing typical histopathological features of PD. In an effort to screen for small-molecule agents to reverse rotenone-induced cytotoxicity, we developed and validated a sensitive and robust assay with neuroblastoma SK-N-SH cells. This assay was amenable to a high-throughput screening format with Z' factor of 0.56. Robotic screening of a bioactive compound library led to the identification of carnosic acid that can effectively protect cells from rotenone treatment. Using a high-content image-based assay and Western blot analysis, we demonstrated that carnosic acid protects cells from rotenone stress by significant induction of HSP70 expression. Therefore, the assay reported here can be used to identify novel cytoprotective agents for clinical therapeutics of PD. PMID- 20705049 TI - Validation of high-performance liquid chromatography-boron-doped diamond detection for assessing hepatic glutathione redox status. AB - Glutathione redox status is a commonly used oxidative stress biomarker. High performance liquid chromatography-ultraviolet (HPLC-UV) and HPLC-electrochemical detection (HPLC-ECD) have been used to assess glutathione status but have potential limitations due to challenging sample preparation procedures or electrochemical signal degradation. Thus, this study aimed to validate an HPLC ECD approach using boron-doped diamond (BDD), a novel electrode material exhibiting excellent electrochemical stability. Liver homogenates from obese (ob/ob) mice and their lean littermates (n=4/genotype) as well as from rats fed high- or low-fat diets (n=8/treatment) were analyzed in parallel by HPLC-BDD and UV. HPLC-BDD responses for reduced glutathione (GSH) and oxidized glutathione (GSSG) were linear over more than four orders of magnitude at 1475 mV, the optimal oxidation potential. Within- and between-day precision values of GSH, GSSG, and GSH/GSSG were 2.1% to 7.9%, and accuracy values of GSH and GSSG were 96% and 105%, respectively. Electrochemical responses were stable up to 48 h of continuous system use. Using HPLC-BDD and -UV, hepatic GSH, GSSG, and GSH/GSSG from mice (r=0.64-0.94) and rats (r=0.79-0.92) were well correlated (P<0.05), and no significant differences in thiol levels were observed between detection methods. Collectively, our findings support HPLC-BDD as a relatively simple, accurate, and validated approach for evaluating hepatic glutathione redox status. PMID- 20705048 TI - A lectin affinity workflow targeting glycosite-specific, cancer-related carbohydrate structures in trypsin-digested human plasma. AB - Glycans are cell-type-specific, posttranslational protein modifications that are modulated during developmental and disease processes. As such, glycoproteins are attractive biomarker candidates. Here, we describe a mass spectrometry-based workflow that incorporates lectin affinity chromatography to enrich for proteins that carry specific glycan structures. As increases in sialylation and fucosylation are prominent among cancer-associated modifications, we focused on Sambucus nigra agglutinin (SNA) and Aleuria aurantia lectin (AAL), lectins which bind sialic acid- and fucose-containing structures, respectively. Fucosylated and sialylated glycopeptides from human lactoferrin served as positive controls, and high-mannose structures from yeast invertase served as negative controls. The standards were spiked into Multiple Affinity Removal System (MARS) 14-depleted, trypsin-digested human plasma from healthy donors. Samples were loaded onto lectin columns, separated by HPLC into flow-through and bound fractions, and treated with peptide: N-glycosidase F to remove N-linked glycans. The deglycosylated peptide fractions were interrogated by ESI HPLC-MS/MS. We identified a total of 122 human plasma glycoproteins containing 247 unique glycosites. Importantly, several of the observed glycoproteins (e.g., cadherin 5 and neutrophil gelatinase-associated lipocalin) typically circulate in plasma at low nanogram per milliliter levels. Together, these results provide mass spectrometry-based evidence of the utility of incorporating lectin-separation platforms into cancer biomarker discovery pipelines. PMID- 20705050 TI - Expression of the carbohydrate recognition domain of FimH and development of a competitive binding assay. AB - Uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infections (UTIs). In the first step of this infective process, the virulence factor FimH located on type 1 pili allows UPEC to specifically adhere to oligosaccharides, which are part of glycoproteins on the urinary bladder mucosa. This initial step prevents the clearance of E. coli from the urinary tract and enables the invasion of the host cells. Because FimH antagonists can block this interaction, they exhibit a promising therapeutic potential as anti-infectives. For the evaluation of their binding properties, a reliable, target-based affinity assay is required. Here, we describe the expression and purification of the carbohydrate recognition domain of FimH (FimH-CRD) as well as the development of a competitive binding assay. FimH-CRD linked with a thrombin cleavage site to a 6His-tag is recombinantly expressed and purified by affinity chromatography. For the evaluation of FimH antagonists, a cell-free binding assay based on the interaction of a biotinylated polyacrylamide glycopolymer with the FimH-CRD was developed. Complexation of the biotinylated glycopolymer with streptavidin coupled to horseradish peroxidase allows the quantification of the binding properties of FimH antagonists. The assay format was optimized and validated by a comparison with affinity data from reported assays. PMID- 20705051 TI - Chondrocyte calcium signaling in response to fluid flow is regulated by matrix adhesion in 3-D alginate scaffolds. AB - The interaction between chondrocytes and their surrounding extracellular matrix plays an important role in regulating cartilage metabolism in response to environmental cues. This study characterized the role of cell adhesion on the calcium signaling response of chondrocytes to fluid flow. Bovine chondrocytes were suspended in alginate hydrogels functionalized with RGD at concentrations of 0-400MUM. The hydrogels were perfused and the calcium signaling response of the cells was measured over a range of fluid velocities from 0 to 68MUm/s. Attachment to RGD-alginate doubled the sensitivity of chondrocytes to flows in the range of 8-13MUm/s, but at higher fluid velocities, the contribution of cell adhesion to the observed calcium signaling response was no longer apparent. The enhanced sensitivity to flow was dependent on the density of RGD-ligand present in the scaffolds. The RGD-enhanced sensitivity to flow was completely inhibited by the addition of soluble RGD which acted as a competitive inhibitor. The results of this study indicate a role for matrix adhesion in regulating chondrocyte response to fluid flow through a calcium dependent mechanism. PMID- 20705052 TI - Characterization of a chromosomal toxin-antitoxin, Rv1102c-Rv1103c system in Mycobacterium tuberculosis. AB - Toxin-antitoxin systems, ubiquitous in prokaryotic genomes, have been proposed to play an important role in several stress responses. While Mycobacterium tuberculosis contains more than 80 putative TA loci, the roles they play in this pathogen are yet to be studied. Here, we characterize a chromosomal Rv1102c Rv1103c TA system in M. tuberculosis. We found that the Rv1102c toxin interacts with the Rv1103c antitoxin in a pull-down assay and the yeast two-hybrid system. Rv1102c cleaved the era mRNA in Escherichia coli, and cleavage was inhibited by co-expression of Rv1103c. Heterologous expression of Rv1102c led to growth arrest in E. coli, which was fully recovered only when Rv1103c was co-expressed in cis with Rv1102c, suggesting that the production and assembly of Rv1102c and Rv1103c are tightly linked. Our additional results indicate that translational coupling of the Rv1102c and Rv1103c genes is important for Rv1102c-Rv1103c binding. Finally, we discovered that the expression of Rv1102c induced growth arrest and increased the level of persister cells in Mycobacterium smegmatis. These results suggest that the Rv1102c-Rv1103c TA system could play a role in M. tuberculosis pathogenesis via generating bacilli that survive in the face of multidrug therapy. PMID- 20705053 TI - The universal mechanism for iron translocation to the ferroxidase site in ferritin, which is mediated by the well conserved transit site. AB - Ferritins are ubiquitous iron storage proteins. Recently, we identified a novel metal-binding site, transit site, in the crystal structure of phytoferritin. To elucidate the function of the transit site in ferritin from other species, we prepared transit-site-deficient mutants of human H ferritin, E140A and E140Q, and their iron oxidation kinetics was analyzed. The initial velocities of iron oxidization were reduced in the variants, especially in E140Q. The crystal structure of E140Q showed that the side chain of the mutated Gln140 was fixed by a hydrogen bond, whereas that of native Glu140 was flexible. These results suggest that the conserved transit site also has a function to assist with the metal ion sequestration to the ferroxidase site in ferritins from vertebrates. PMID- 20705054 TI - SM22alpha-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of gamma-radiation and doxorubicin in HepG2 cells. AB - Smooth muscle protein 22-alpha (SM22alpha) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22alpha overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22alpha overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of gamma-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 MUg/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21(WAF1/Cip1) induction or p16(INK4a)/retinoblastoma protein (pRB) activation. SM22alpha overexpression in HepG2 cells elevated p16(INK4a) followed by pRB activation, but did not activate the p53/p21(WAF1/Cip1) pathway. Moreover, MT-1G, which is induced by SM22alpha overexpression, was involved in the activation of the p16(INK4a)/pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22alpha modulates cellular senescence caused by damaging agents via regulation of the p16(INK4a)/pRB pathway in HepG2 cells and that these effects of SM22alpha are partially mediated by MT-1G. PMID- 20705056 TI - Caenorhabditis elegans TLK-1 controls cytokinesis by localizing AIR-2/Aurora B to midzone microtubules. AB - Defects in chromosome condensation, segregation or cytokinesis during mitosis disrupt genome integrity and cause organismal death or tumorigenesis. The conserved kinase AIR-2/Aurora B is required for normal execution of all these important mitotic events in Caenorhabditis elegans. TLK-1 has been recently shown to be a substrate and activator of AIR-2 in the presence of another AIR-2 activator ICP-1/INCENP, and to cooperate with AIR-2 to ensure proper mitotic chromosome segregation. However, whether TLK-1 may contribute to chromosome condensation or cytokinesis is unclear. A time-lapse microscopy analysis showed that tlk-1 mutants are defective in chromosome condensation and cytokinesis, in addition to chromosome segregation, during mitosis. Our data indicate that TLK-1 contributes to chromosome condensation and segregation, at least in part, in a manner that is distinct from the ICP-1-mediated mechanism and does not involve loading AIR-2 or condensin proteins to mitotic chromosomes. Moreover, TLK-1 functions in cytokinesis by localizing AIR-2 to the midzone microtubules. The localization pattern of TLK-1 is different from those of ICP-1 and AIR-2, revealing differences in dynamic regulation and association of TLK-1 and ICP-1 towards AIR-2 in vivo. Interestingly, human TLK2 could functionally substitute for tlk-1, suggesting that the mitotic roles of TLK members might be evolutionarily conserved. PMID- 20705055 TI - Direct observation to chemokine receptor 5 on T-lymphocyte cell surface using fluorescent metal nanoprobes. AB - Chemokine receptor 5 (CCR5) is a cell surface protein required for HIV-1 infection. It is important to detect the amount and observe the spatial distribution of the CCR5 receptors on the cell surfaces. In this report, we describes the metal nanoparticles which were specially designed as molecular fluorescent probes for imaging of CCR5 receptors on the T-lymphocytic PM1 cell surfaces. These CCR5 monoclonal antibodies (mAbs) metal complexes were prepared by labeling mAbs with Alexa Fluor 680 followed by covalent binding the labeled mAbs on the 20 nm silver nanoparticles. Compared with the labeled mAbs without metal, the mAb-metal complexes were found to display enhanced emission intensity and shortened lifetime due to interactions between fluorophores and metal. The mAb-metal complexes were incubated with the PM1 cell lines. The confocal fluorescent intensity and lifetime cell images were recorded on single cells. It was observed that the mAb-metal complexes could be clearly distinguished from the cellular autofluorescence. By analyzing a pool of cell images, we observed that most CCR5 receptors appeared as clusters on the cell surfaces. The fluorophore metal complexes developed in this report are generally useful for detection of cell surface receptors and provide a new class of probe to study the interaction between the CCR5 receptors with viral gp120 during HIV infections. PMID- 20705057 TI - Silencing of SlFTR-c, the catalytic subunit of ferredoxin:thioredoxin reductase, induces pathogenesis-related genes and pathogen resistance in tomato plants. AB - As a heterodimeric protein, ferredoxin:thioredoxin reductase (FTR) catalyses the light-dependant activation of several photosynthetic enzymes. The active site of the catalytic subunit of FTR contains a redox-active disulfide and a [4Fe-4S] center. We isolated the catalytic subunit gene of FTR, designated SlFTR-c, from tomato (Solanum lycopersicum L.). SlFTR-c transcripts were detected in all tissues examined, including roots, leaves, flowers, fruits, and seeds. Interestingly, virus-induced gene silencing (VIGS) of SlFTR-c resulted in necrotic lesions with typical cell death symptoms and reactive oxygen species (ROS) production in tomato leaves. Moreover, these SlFTR-c-silenced plants displayed enhanced disease resistance against bacterial pathogens, specifically Pseudomonas syringae pv. tomato DC3000, by the induction of defense-related genes (SlPR-1, SlPR-2, SlPR-5, SlGlucA, SlChi3, and SlChi9). Taken together, it seems that SlFTR-c works as a regulator of programmed cell death (PCD) and pathogen resistance in tomato plants. PMID- 20705058 TI - Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma. AB - Glioblastoma multiforme (GBM) are highly proliferative brain tumors characterized by a hypoxic microenvironment which controls GBM stem cell maintenance. Tumor hypoxia promotes also elevated glycolytic rate; thus, limiting glucose metabolism is a potential approach to inhibit tumor growth. Here we investigate the effects mediated by 2-deoxyglucose (2-DG), a glucose analogue, on primary GBM-derived cells maintained under hypoxia. Our results indicate that hypoxia protects GBM cells from the apoptotic effect elicited by 2-DG, which raises succinate dehydrogenase activity thus promoting succinate level decrease. As a consequence hypoxia inducible factor-1alpha (HIF-1alpha) degradation occurs and this induces GBM cells to acquire a neuronal committed phenotype. By adding succinate these effects are reverted, as succinate stabilizes HIF-1alpha and increases GBM stem cell fraction particularly under hypoxia, thus preserving the tumor stem cell niche. 2-DG inhibits anaerobic glycolysis altering GBM cell phenotype by forcing tumor cells into mitochondrial metabolism and by inducing differentiation. PMID- 20705060 TI - Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia. AB - Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low molecular weight kinase inhibitor, AKN-032, targeting the FMS-like tyrosine kinase 3 (FLT3) and discovered in a new type of screening funnel combining the target therapy approach with sequential cellular screens. AKN-032 was identified among 150 selected hits from three different high throughput kinase screens. Further characterization showed inhibitory activity on FLT3 enzyme with an IC(50) of 70 nM. Western blot analysis revealed reduced autophosphorylation of the FLT3-receptor in AML cell line MV4-11 cells after exposure to AKN-032. Flow cytometry disclosed cytotoxic activity against MV4-11, but not against non-malignant 3T3-L1 fibroblast cells. Using a fluorometric microculture cytotoxicity assay, AKN-032 was tested against 15 cell lines and displayed a potent cytotoxic activity in AML cell lines MV4-11 (IC(50)=0.4 MUM) and Kasumi-1 (IC(50)=2.3 MUM). AKN-032 was also highly cytotoxic in tumor cells from AML patients in vitro. Furthermore, AKN-032 demonstrated significant antileukemic effect in a relatively resistant in vivo hollow fiber mouse model. No major toxicity was observed in the animals. In conclusion, AKN-032 is a promising new kinase inhibitor with significant in vivo and in vitro activity in AML. Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML. PMID- 20705059 TI - New insights into tetrahydrobiopterin pharmacodynamics from Pah enu1/2, a mouse model for compound heterozygous tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. AB - Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH(4)) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah(enu1/2) bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH(4) treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH(4) pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using (13)C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pah(enu1/1), and Pah(enu1/2) mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pah(enu1/1) and Pah(enu1/2) indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH(4). In conclusion, our findings show a significant impact of the genotype on the response to BH(4) in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects. PMID- 20705061 TI - PI3K/Akt signaling pathway is required for neuroprotection of thalidomide on hypoxic-ischemic cortical neurons in vitro. AB - Thalidomide, a derivative of glutamic acid, is used for immunomodulatory therapy in various diseases through inhibition of tumor necrotic factor-alpha (TNF-alpha) release. However, the effects of thalidomide in central nervous system (CNS) diseases such as stroke or hypoxic-ischemic encephalopathy (HIE) are unknown. In this study, we aimed to test whether thalidomide protects against hypoxic ischemic neuronal damage and the possible signaling pathway involved in neuroprotection. Primary cultured cortical neurons of rats were treated with oxygen and glucose deprivation (OGD) for 3h to mimic hypoxic-ischemic injury in vivo. Neuronal apoptosis was measured with terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) staining. The expression of total caspase 3 (C3), cleaved caspase-3 (CC3), Akt, phosphorylated-Akt (p-Akt) and Bcl-2 protein were detected by Western blots. We found that OGD treatment increased the expression of CC3 and induced neuronal apoptosis. Both neuronal apoptosis and CC3 expression peaked at 24h after OGD. Furthermore, we found that thalidomide protected neurons against apoptosis by decreasing CC3 and increasing Bcl-2 expression in a dose-dependent manner. Meanwhile, we found that thalidomide induced p-Akt expression, which could be inhibited by PI3K specific inhibitor, LY294002. In addition, inhibition of PI3K increased CC3 but decreased Bcl-2 expression. In summary, thalidomide has anti-apoptotic effects on cortical neurons after OGD by modulating CC3 and Bcl-2 expression through activation of PI3K/Akt pathway. PMID- 20705062 TI - Cerebral expression of neuroglobin and cytoglobin after deep hypothermic circulatory arrest in neonatal piglets. AB - INTRODUCTION: Deep hypothermic circulatory arrest (DHCA) is used in corrective cardiac surgery for complex congenital heart disease. Endogenous protective mechanisms may be responsible for the prevention of brain damage after hypothermic ischemia. Neuroglobin and cytoglobin are expressed in brain cells and appear to modulate hypoxic-ischemic brain injury. However, their neuroprotective potency is still not understood. Thus the aim of this study was to detect the influence exerted by DHCA on their expression. METHODS: The effects of DHCA were analyzed in a neonatal piglet model with cardiopulmonary bypass, DHCA of 60 and 120 min and subsequent reperfusion of 6h. Complete histological analysis and changes in the mRNA expression of neuroglobin and cytoglobin were measured in the brain. RESULTS: In comparison to animals without DHCA, neuroglobin expression was stable after 60 min DHCA and neuronal cell necrosis in the cortex was mild (< 10 %). Neuroglobin expression was significantly reduced after 120 min DHCA, which was accompanied by substantial neuronal cell necrosis (> 50 %). Cytoglobin expression did not differ significantly between animals with neuronal necrosis vs. sham. CONCLUSION: Constitutive expression levels of neuroglobin may explain the mild neuronal injury after 60 min DHCA. Significant neuronal cell death correlates with reduced neuroglobin expression and might reflect a limited capacity to compensate for ischemic injury. Both respiratory cell proteins may constitute attractive targets for therapeutic modulation of gene regulation, but further studies are necessary. PMID- 20705063 TI - Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/Akt pathway. AB - Emerging evidence has demonstrated that postconditioning with sevoflurane provided neuroprotection. In this study, we investigated the neuroprotective effect of different concentrations of sevoflurane in rats with middle cerebral artery occlusion (MCAO). Furthermore, we tested the hypothesis that the neuroprotective effect of postconditioning with sevoflurane is associated with inhibition of apoptosis and mediated by activation of the phosphoinositide-3 kinase/Akt (PI3K/Akt) pathway. Adult male Sprague-Dawley rats were subjected to MCAO for 90 min and then treated with sevoflurane at the beginning of reperfusion. The infarct volume, neurological deficit scores and brain edema were evaluated at 24 hours. Spatial learning and memory was examined by Morris water maze. Apoptosis and apoptosis-related proteins were studied by TUNEL, immunohistochemistry and western blot. The neuroprotective effect and the amount of p-Akt after sevoflurane administration with or without wortmannin were analyzed. Postconditioning with sevoflurane 1.0 minimum alveolar concentration (MAC) and 1.5 MAC significantly decreased neurological deficit scores, infarct volume and brain edema and markedly improved spatial learning and memory. Postconditioning also reduced apoptotic cells, upregulated Bcl-2 and downregulated P53 and Bax. Wortmannin abolished the neuroprotective effect and prevented the increasing of p-Akt. Our data suggest postconditioning with sevoflurane (1.0 MAC and 1.5 MAC) not only reduced infarct volume but also improved learning and memory. Our study further showed that this neuroprotective effect may be partly due to the activation of PI3K/Akt pathway and inhibiting neuronal apoptosis. PMID- 20705064 TI - Role of the lateral preoptic area and the bed nucleus of stria terminalis in the regulation of penile erection. AB - To elucidate the role of the preoptic area (POA) in the regulation of penile erection, we examined the effects of electrical stimulation in and around the POA on penile erection in rats, which was assessed by changes in pressure in the corpus spongiosum of the penis (CSP) and electromyography (EMG) of the bulbospongiosus (BS) muscle. In unanesthetized and anesthetized rats, four types of responses were induced by stimulation in and around the POA; (1) normal type responses, which were similar to spontaneously occurring erections, characterized by slow increase in CSP pressure and sharp peaks concurrent with BS muscle bursting; (2) muscular type responses, which included sharp CSP pressure peaks (muscular component) with almost no vascular component; (3) mixed type responses, which included a sequence of high-frequency CSP peaks followed by low-frequency CSP peaks; and (4) micturition type responses, which had higher-frequency and lower-amplitude CSP peaks than other responses which were identical to those of normal micturition. In unanesthetized condition, erections were evoked by stimulation of the lateral preoptic area (LPOA), medial preoptic area (MPOA), bed nucleus of the stria terminalis (BST), paraventricular nucleus (PVN), reuniens thalamic nucleus (Re) and lateral septum (LS). Lower-intensity stimulation evoked erections from the LPOA, BST, PVN and RE, but not the MPOA. In anesthetized condition, stronger stimuli were required and effective sites were restricted to the LPOA, MPOA and BST. These findings suggest that the lateral and medial subdivisions of the preoptic area play different roles in mediating penile erection. PMID- 20705065 TI - Effect of lipoprotein (a) on annexin A5 binding to cell membrane. AB - BACKGROUND: High blood lipoprotein (a) [Lp(a)] concentration is a risk factor for a thrombotic event. Annexin A5 is involved in anticoagulation on the endothelial surface. How Lp(a) affects the annexin A5 function is not clear. This study investigates annexin A5 binding on the cell membrane in the presence of Lp(a). METHODS: Lp(a) was isolated from human blood plasma by ultracentrifugation and annexin A5 protein was purchased commercially. The cell membrane was prepared from primary human umbilical vein endothelial cells (HUVEC) and cultured cell line HepG2 by sucrose density gradient centrifugation. Enzyme-linked immunosorbent assays (ELISA) were used to examine annexin A5 binding to the cell membrane in the presence of Lp(a). Flow cytometry was used to analyze the binding of fluorescence-labeled annexin A5 to phosphatidylserine (PS)-translocated intact cells in the presence of Lp(a). RESULTS: Annexin A5 binding to the cell membrane was attenuated by a high concentration of Lp(a) in both HUVEC and HepG2 membrane surfaces. The phenomenon was also observed with annexin A5 surface labeling of HepG2 cells and flow cytometry analysis. CONCLUSIONS: The results imply that Lp(a) interferes with annexin A5 binding to the procoagulant PS which translocates to the membrane surface under stress condition and therefore may increase the risk for thrombosis. PMID- 20705066 TI - A multi-target screening analysis in human plasma using fast liquid chromatography-hybrid tandem mass spectrometry (Part II). AB - OBJECTIVES: Perform a comparison of results obtained with a LC-MS/MS method and a Remedi(r) instrument on clinical serum samples. DESIGN AND METHODS: Results obtained on 146 selected plasma samples were compared between the two methods. RESULTS: On the 336 positive identifications, 89% were obtained using the LC MS/MS technique and 57% by the LC-DAD. Benzodiazepines were well recognized by LC MS/MS. For some compounds such as antidepressant agents, sensitivity was improved using LC-MS/MS. Moreover, this method extended the panel of drugs detected in clinical toxicology. CONCLUSION: The new software platform developed for screening and identification of small molecules (SmileMS) allows an easy and reproducible detection of drugs and toxic compounds in blood for general unknown screening. It offers automated generation of reports, which makes the LC-MS/MS easier to use without having specialised skills in mass spectrometry. This LC MS/MS screening method will be a reliable alternative to the Remedi(r) instrument in the global process of screening in emergency clinical toxicology laboratories. PMID- 20705067 TI - When the Smad signaling pathway is impaired, fibroblasts advance open wound contraction. AB - In wound healing transforming growth factor beta1 (TGFbeta1), utilizing the Smad signaling pathway, advances connective tissue deposition, the transformation of fibroblasts into myofibroblasts and wound contraction. The compound SB-505124 disrupts the Smad signaling pathway by blocking activin receptor-like kinase phosphorylation of select Smad signaling proteins. Four full thickness excisional square 2*2 cm wounds were made on the rat dorsum. On day 2, the pair of wounds on the left received 1 MUM SB-505124 in gel, and the pair on the right, controls, received gel alone. Wounds were covered with nonocclusive dressings and treated redressed daily for 4 days. No differences in day 14 wound sizes between treatment groups were found. H&E stained sections revealed increased cell density in SB-505124 treated wounds. Polarized light microscopy showed collagen fiber bundles birefringence intensity and organization were equivalent between treatment groups. Myofibroblast populations, identified by alpha-smooth muscle actin staining, were the norm in controls but absent in SB-505124 treated wounds, which was confirmed by Western blot analysis. Blocking the Smad signaling pathway diminished connective tissue deposition and generated a deficiency in myofibroblast numbers, but wound contraction was unimpaired. The absence of myofibroblasts may be related to the blocking of the Smad signaling pathway or it may be related to the generation of less tension in treated wounds, related to reduce deposited connective tissue. These findings support the notion that wound contraction does not require the generation of myofibroblast contractile forces, but rather the organization of newly deposited collagen fiber bundles by forces related to fibroblast locomotion. PMID- 20705068 TI - Lumican inhibits cell migration through alpha2beta1 integrin. AB - Lumican, an extracellular matrix protein of the small leucine-rich proteoglycan family, has been shown to impede melanoma progression by inhibiting cell migration. In the present study, we show that lumican targets alpha2beta1 integrin thereby inhibiting cell migration. A375 melanoma cells were transfected with siRNA directed against the alpha2 integrin subunit. Compared to A375 control cells, the anti-migratory effect of lumican was abrogated on transfected A375 cells. Moreover, lumican inhibited the chemotactic migration of Chinese hamster ovary (CHO) cells stably transfected with alpha2 integrin subunit (CHO-A2) but not that of wild-type CHO cells (CHO-WT) lacking this subunit. In contrast to CHO WT cells, we observed in time-lapse microscopy a decrease of CHO-A2 cell migration speed in presence of lumican. Focal adhesion kinase phosphorylated at tyrosine-397 (pFAK) and total FAK were analysed in CHO-WT and CHO-A2 cells. A significant decrease of the ratio pFAK/FAK was shown in presence of recombinant human lumican. Using solid phase assays, a direct binding between lumican and the alpha2beta1 integrin was demonstrated. This interaction did not involve the glycan moiety of lumican and was cation independent. Lumican was also able to bind the activated I domain of the alpha2 integrin subunit with a K(d)>=200nM. In conclusion, we demonstrated for the first time that the inhibition of cell migration by lumican depends on a direct binding between the core protein of lumican and the alpha2beta1 integrin. PMID- 20705069 TI - Focus on molecules: collagens V and XI. PMID- 20705070 TI - Trypanosoma cruzi: multiple actin isovariants are observed along different developmental stages. AB - The expression and biological role of actin during the Trypanosoma cruzi life cycle remains largely unknown. Polyclonal antibodies against a recombinant T. cruzi actin protein were used to confirm its expression in epimastigotes, trypomastigotes, and amastigotes. Although the overall levels of expression were similar, clear differences in the subcellular distribution of actin among the developmental stages were identified. The existence of five actin variants in each developmental stage with distinct patterns of expression were uncovered by immunoblotting of protein extracts separated 2D-SDS gels. The isoelectric points of the actin variants in epimastigotes ranged from 4.45 to 4.9, whereas they ranged from 4.9 to 5.24 in trypomastigotes and amastigotes. To determine if the actin variants found could represent previously unidentified actins, we performed a genomic survey of the T.cruzi GeneDB database and found 12 independent loci encoding for a diverse group of actins and actin-like proteins that are conserved among trypanosomatids. PMID- 20705071 TI - Thermoregulation of water foraging honeybees--balancing of endothermic activity with radiative heat gain and functional requirements. AB - Foraging honeybees are subjected to considerable variations of microclimatic conditions challenging their thermoregulatory ability. Solar heat is a gain in the cold but may be a burden in the heat. We investigated the balancing of endothermic activity with radiative heat gain and physiological functions of water foraging Apis mellifera carnica honeybees in the whole range of ambient temperatures (T(a)) and solar radiation they are likely to be exposed in their natural environment in Middle Europe. The mean thorax temperature (T(th)) during foraging stays was regulated at a constantly high level (37.0-38.5 degrees C) in a broad range of T(a) (3-30 degrees C). At warmer conditions (T(a)=30-39 degrees C) T(th) increased to a maximal level of 45.3 degrees C. The endothermic temperature excess (difference of T(body)-T(a) of living and dead bees) was used to assess the endogenously generated temperature elevation as a correlate of energy turnover. Up to a T(a) of ~30 degrees C bees used solar heat gain for a double purpose: to reduce energetic expenditure and to increase T(th) by about 1 3 degrees C to improve force production of flight muscles. At higher T(a) they exhibited cooling efforts to get rid of excess heat. A high T(th) also allowed regulation of the head temperature high enough to guarantee proper function of the bees' suction pump even at low T(a). This shortened the foraging stays and this way reduced energetic costs. With decreasing T(a) bees also reduced arrival body weight and crop loading to do both minimize costs and optimize flight performance. PMID- 20705072 TI - The sense of water in the blowfly Protophormia terraenovae. AB - The gustatory system of the blowfly, Protophormia terraenovae, is a relatively simple biological model for studies on chemosensory input and behavioral output. It appears to have renewed interest as a model for studies on the role of water channels, namely aquaporins or aquaglyceroporins, in water detection. To this end, we investigated the presence of water channels, their role in "water" and "salt" cell responsiveness and the transduction mechanism involved. For the first time our electrophysiological results point to the presence of an aquaglyceroporin in the chemoreceptor membrane of the "water" cell in the blowfly taste chemosensilla whose transduction mechanism ultimately involves an intracellular calcium increase and consequently cell depolarization. This hypothesis is also supported by calcium imaging data following proper stimulation. This mechanism is triggered by "water" cell stimulation with hypotonic solutions and/or solutes such as glycerol which crosses the membrane by way of aquaglyceroporins. Behavioral output indicates that the "sense" of water in blowflies is definitely not dependent on the "water" cell only, but also on the "salt" cell sensitivity. These findings also hypothesize a new role for aquaglyceroporin in spiking cell excitability. PMID- 20705073 TI - Static and dynamic properties of the HCM myocardium. PMID- 20705074 TI - Spatio-temporal calcium dynamics in pacemaking units of the interstitial cells of Cajal. AB - The interstitial cells of Cajal (ICC) are responsible for producing pacemaking signals that stimulate rhythmic contractions in the gastro-intestinal system. The pacemaking signals are generated by membrane depolarizations, which are in turn linked to the integrated transport of calcium between the endoplasmic reticulum (ER), through inositol-trisphosphate receptor (IP(3)R) release, and mitochondria, through the uniporter. A non-specific cation channel (NSCC) is associated with the membrane depolarizations, and is inhibited by intracellular calcium. One theory proposes that the integrated calcium transport occurs within specific regions of the ICC called "pacemaker units," and results in localized calcium concentration reductions within these units, which in turn activate the NSCC and depolarize the membrane. We have constructed a model of the spatio-temporal calcium dynamics within an ICC pacemaker unit to determine under what conditions the local calcium concentrations may reduce below baseline. We obtain reductions of calcium concentrations below baseline but only under certain conditions. Without strong and persistent stimulation of the IP(3)R, reductions of calcium below baseline occur only with a non-physiological, time-dependent uniporter. Alternatively, sufficient IP(3)R release leads to reductions of calcium below baseline, due to depletion of the ER calcium store over the time scale of seconds, although these reductions require strong mitochondrial and ER calcium uptake. PMID- 20705075 TI - Exploration of structure-based drug design opportunities for mGluRs. AB - The metabotropic glutamate receptors (mGluRs) are a subset of the Class C G Protein Coupled Receptors (GPCRs). Recently, an emerging strategy for drug discovery efforts targeting mGluRs has been to develop compounds acting at the so called allosteric site in the 7-transmembrane (7TM) domain, common to all GPCRs, rather than the extracellular (EC) domain containing the orthosteric glutamate binding site. We examine herein some of the intrinsic relative merits of targeting these two domains. Comparisons are made among amino-acid sequences in the two domains and among X-ray structures and homology models of the EC domain. We show that there is greater sequence diversity in the EC domains than in the transmembrane (TM) domains. Thus, contrary to generally accepted descriptions of there being greater evolutionary pressure to preserve the EC domain, it is the 7TM domain that is more highly conserved. Within the EC domain, the glutamate binding site of the Venus flytrap region has hitherto received the most attention as a target site. Analysis of examples of the three-dimensional structures of the EC domains at the glutamate-binding site reveals differences as well, thereby supporting the viability of targeting the EC domain, even at the glutamate binding site, for drug discovery. To exemplify this strategy, we present examples of active compounds identified via high-throughput docking in the EC region. PMID- 20705077 TI - Blocking corticotropin-releasing factor-2 receptors, but not corticotropin releasing factor-1 receptors or glucocorticoid feedback, disrupts the development of conditioned defeat. AB - Several neuroendocrine signals of the hypothalamic-pituitary-adrenal (HPA) axis are released following exposure to stressful events. It has long been proposed that the signals in this cascade each act to modify ongoing and future behavior. In this study we investigated whether blocking glucocorticoid synthesis, corticotropin-releasing factor (CRF)-1 receptors, or CRF-2 receptors during social defeat would alter subsequent behavioral responses. We used a conditioned defeat model in Syrian hamsters in which social defeat results in a dramatic shift from territorial aggression to increased submissive and defensive behavior in future social encounters. We found that intracerebroventricular administration of anti-sauvagine-30, a CRF-2 receptor antagonist, prior to social defeat training reduced the acquisition of conditioned defeat. In contrast, the acquisition of conditioned defeat was not altered by the CRF-1 receptor antagonist CP-154,526 or the glucocorticoid synthesis inhibitor metyrapone. Our results suggest that CRF, and perhaps related neuropeptides such as urocortins, act at CRF-2 receptors to promote the development of defeat-induced changes in social behavior, whereas signaling at CRF-1 and glucocorticoid receptors plays a negligible role in this process. PMID- 20705076 TI - Atypical EEG beta asymmetry in adults with ADHD. AB - BACKGROUND: Abnormal brain laterality (ABL) is well established in ADHD. However, its clinical specificity and association to cognitive and clinical symptoms is not yet understood. Previous studies indicate increased right hemisphere (RH) contribution in both ADHD and reading impaired samples. The current study investigates whether this ABL characteristic occurs in adults with ADHD absent comorbid language impairment. METHODS: EEG beta asymmetry was compared in 35 adult ADHD subjects and 104 controls during rest and active cognition. Group differences in beta asymmetry were then further evaluated for association to linguistic and attentional abilities, as well as association to beta asymmetry measures across different brain regions. RESULTS: Adults with ADHD showed pronounced rightward beta asymmetry (p=.00001) in inferior parietal regions (P8 P7) during a continuous performance task (CPT) that could not be attributed to linguistic ability. Among ADHD subjects only, greater rightward beta asymmetry at this measure was correlated with better CPT performance. Furthermore, this measure showed a lack of normal association (i.e., observed in controls) to left biased processing in temporal-parietal (TP8-TP7) brain regions important for higher order language functions. CONCLUSION: Adult ADHD involves abnormally increased right-biased contribution to CPT processing that could not be attributed to poor language ability. This appears to also involve abnormal recruitment of LH linguistic processing regions and represents an alternative, albeit less effective, CPT processing strategy. These findings suggest different pathophysiologic mechanisms likely underlie RH biased processing in ADHD and reading impaired samples. PMID- 20705078 TI - Over-expression of deltaC-DCLK-short in mouse brain results in a more anxious behavioral phenotype. AB - Products of the Doublecortin-Like Kinase (DCLK) gene are associated with cortical migration and hippocampal maturation during embryogenesis. However, the functions of those DCLK gene transcripts that encode kinases and are expressed during adulthood are incompletely understood. To elucidate potential functions of these DCLK gene splice variants we have generated and analyzed transgenic mice with neuronal over-expression of a truncated, constitutively active form of DCLK short, designated deltaC-DCLK-short. Previously, we have performed an extensive molecular characterization of these transgenic deltaC-DCLK-short mice and established that a specific subunit of the GABA(A) receptor, which is involved in anxiety-related GABAergic neurotransmission, is down-regulated in the hippocampus. Here we show that deltaC-DCLK-short mRNA is highly expressed in the hippocampus, cortex and amygdala of transgenic mice. We provide evidence that the deltaC-DCLK-short protein is expressed and functional. In addition, we examined anxiety-related behavior in deltaC-DCLK-short mice in the elevated plus maze. Interestingly, deltaC-DCLK-short mice spend less time, move less in the open arms of the maze and show a reduction in the number of rim dips. These behaviors indicate that deltaC-DCLK-short mice display a more anxious behavioral phenotype. PMID- 20705079 TI - Tailfin clipping, a painful procedure: Studies on Nile tilapia and common carp. AB - The fish welfare debate is intensifying. Consequently, more research is carried out to further our knowledge on fish welfare in aquaculture. We define here a series of key parameters to substantiate an acute response to a supposedly painful stimulus: a standardized tailfin clip. Ultrastructural analysis of common carp (Cyprinus carpio) tailfin indicates the presence of A-delta and C-type axons, which are typical for transmitting nociceptive signals in (higher) vertebrates. In Nile tilapia (Oreochromis niloticus), responses to a tailfin clip were studied and the unavoidable acute stress associated with the handling required for this procedure. A series of key parameters for further studies was defined. The responses seen in 'classical' stress parameters (e.g., changes in plasma cortisol, glucose and lactate levels) did not allow discrimination between the clipping procedure and the handling stress. However, three parameters indicated a differential, stronger response to the clip stimulus itself: first, swimming activity increased more and clipped fish spent more time in the light (in a tank where half the volume is covered by dark material); second, the gill's mucus cells released their content as observed 1h after the clip, and this response is transient (no longer observed at 6h post clipping). Third, branchial Na(+)/K(+)-ATPase activity assayed in vitro was not affected by the procedures, but a remarkable migration of Na(+)/K(+)-ATPase immunoreactive (chloride) cells into the lamellar epithelium was observed as of 6h post clipping. We conclude that the differential response to clipping supports that this is a painful procedure that evokes a transient specific physiological status. PMID- 20705080 TI - Epigenetic modifications in valproic acid-induced teratogenesis. AB - Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations. PMID- 20705082 TI - Lipid domain formation modulates activities of snake venom phospholipase A(2) enzymes. AB - The goal of the present study is to elucidate the effect of lipid domain formation on activities of Naja naja atra and Bungarus multicinctus phospholipase A(2) (PLA(2)) enzymes. Sphingomyelin inhibited enzymatic activity and membrane damaging activity of PLA(2) against egg yolk phosphatidylcholine (EYPC), while cholesterol and cholesterol sulfate abrogated the inhibitory effect of sphingomyelin. The ability of cholesterol and cholesterol sulfate to abolish the inhibitory effect of sphingomyelin was closely related to their capacity to induce domain formation in EYPC/sphingomyelin vesicles. Laurdan fluorescence measurement revealed that membrane packing of EYPC/sphingomyelin vesicles was differently affected by cholesterol and cholesterol sulfate. Unlike cholesterol, cholesterol sulfate was unable to promote domain formation in dipalmitoylphosphatidylcholine (DPPC) vesicles. Cholesterol increased but cholesterol sulfate reduced PLA(2) activity against DPPC. Self-quenching studies and trinitrophenylation of Lys residues revealed that PLA(2) enzymes adopted different membrane-bound mode upon absorption onto the membrane bilayers comprised of different lipid compositions. Collectively, our data indicate that lipid domain formation regulates PLA(2) activity, and suggest that the physical state of membrane bilayers changes the interactive mode of PLA(2) with phospholipids. PMID- 20705081 TI - Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity. AB - The aim of this study is to investigate the ability of intramuscular and intravenous sulfanegen sodium treatment to reverse cyanide effects in a rabbit model as a potential treatment for mass casualty resulting from cyanide exposure. Cyanide poisoning is a serious chemical threat from accidental or intentional exposures. Current cyanide exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Non-rhodanese mediated sulfur transferase pathways, including 3-mercaptopyruvate sulfurtransferase (3-MPST) catalyze the transfer of sulfur from 3-MP to cyanide, forming pyruvate and less toxic thiocyanate. We developed a water-soluble 3-MP prodrug, 3-mercaptopyruvatedithiane (sulfanegen sodium), with the potential to provide a continuous supply of substrate for CN detoxification. In addition to developing a mass casualty cyanide reversal agent, methods are needed to rapidly and reliably diagnose and monitor cyanide poisoning and reversal. We use non invasive technology, diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS) to monitor physiologic changes associated with cyanide exposure and reversal. A total of 35 animals were studied. Sulfanegen sodium was shown to reverse the effects of cyanide exposure on oxyhemoglobin and deoxyhemoglobin rapidly, significantly faster than control animals when administered by intravenous or intramuscular routes. RBC cyanide levels also returned to normal faster following both intramuscular and intravenous sulfanegen sodium treatment than controls. These studies demonstrate the clinical potential for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for cyanide detoxification. DOS and CWNIRS demonstrated their usefulness in optimizing the dose of sulfanegen sodium treatment. PMID- 20705083 TI - A comparison of monkey and human motion processing mechanisms. AB - Single-cell recording studies have provided vision scientists with a detailed understanding of motion processing at the neuronal level in non-human primates. However, despite the development of brain imaging techniques, it is not known to what extent the response characteristics of motion-sensitive neurons in monkey brain mirror those of human motion-sensitive neurons. Using a motion adaptation paradigm, the direction aftereffect, we recently provided evidence of a strong resemblance in the response functions of motion-sensitive neurons in monkey and human to moving dot patterns differing in dot density. Here we describe a series of experiments in which measurements of the direction aftereffect are used to infer the response characteristics of human motion-sensitive neurons when viewing transparent motion and moving patterns that differ in their signal-to-noise ratio (motion coherence). In the case of transparent motion stimuli, our data suggest suppressed activity of motion-sensitive neurons similar to that reported for macaque monkey. In the case of motion coherence, our results are indicative of a linear relationship between signal intensity (coherence) and neural activity; a pattern of activity which also bears a striking similarity to macaque neural activity. These findings strongly suggest that monkey and human motion-sensitive neurons exhibit similar response and inhibitory characteristics. PMID- 20705084 TI - Lower bounds on the redundancy of natural images. AB - The light intensities of natural images exhibit a high degree of redundancy. Knowing the exact amount of their statistical dependencies is important for biological vision as well as compression and coding applications but estimating the total amount of redundancy, the multi-information, is intrinsically hard. The common approach is to estimate the multi-information for patches of increasing sizes and divide by the number of pixels. Here, we show that the limiting value of this sequence--the multi-information rate--can be better estimated by using another limiting process based on measuring the mutual information between a pixel and a causal neighborhood of increasing size around it. Although in principle this method has been known for decades, its superiority for estimating the multi-information rate of natural images has not been fully exploited yet. Either method provides a lower bound on the multi-information rate, but the mutual information based sequence converges much faster to the multi-information rate than the conventional method does. Using this fact, we provide improved estimates of the multi-information rate of natural images and a better understanding of its underlying spatial structure. PMID- 20705085 TI - Comparison of the antidepressant sertraline on differential depression-like behaviors elicited by restraint stress and repeated corticosterone administration. AB - Depressive disorder involves emotional, cognitive, autonomic and endocrine alterations and also evidences support the role of stress in the development of this disorder. Because the hypothalamic-pituitary-adrenal axis is involved in the stress response with a concomitant rise in plasma corticoids, the present study compares the antidepressant effects of sertraline (10mg/kg, i.p.) on behavioral changes elicited by (i) restraint stress (2.5h/day for 13days) and (ii) corticosterone injections (30mg/kg, s.c., for 13days). Stressed animals, but not corticosterone-treated animals displayed anxiety behavior and a reduction in the acquisition of a conditioned avoidance response to 25% of control levels (8.0+/ 2.2 vs. 31.7+/-3.2), being this effect partly sensitive to sertraline. Stressed, but not corticosterone-treated, animals displayed an increased escape failure compared with the control group (24.6%+/-3.5 vs. 1.6+/-0.7), an effect partly prevented by sertraline treatment (7.3%+/-2.0). Both stressed rats and corticosterone-treated rats showed an increase in immobility in the forced swim test, an effect prevented by sertraline. These results suggest that the altered behaviors elicited by stress and corticosterone can be explained by neural modifications that are sensitive to the sertraline antidepressant. PMID- 20705086 TI - The dopamine D(2) partial agonist and antagonist terguride decreases heroin self administration on fixed- and progressive-ratio schedules. AB - Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D(2) receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction. PMID- 20705087 TI - Concentration regimes and denaturation effects on the conformational changes of alpha-chymotrypsin by viscosity and dynamic light scattering measurements. AB - This work focused on the conformational changes of alpha-chymotrypsin from bovine pancreas for various concentrations as well as the effects of chemical denaturation and organic solvents using both of viscosity and dynamic light scattering techniques. A wide range of concentrations varying between 0.1 and 30 mg/ml is tested to determine the critical concentration c** that separates the extremely dilute regime to the dilute regime and the overlapping concentration c* that separates the dilute regime to the semi-dilute regime. The knowledge of alpha-chymotrypsin folding process is followed for a range of chemical denaturant concentrations varying from 1 to 6 M. We showed that the alpha-chymotrypsin folds through a cooperative two-state transition without detectable kinetic intermediates and the formation of 50% unfolded happens for 5.5 M of urea or guanidinium chloride (GdmCl) concentrations. The action modes of the acetonitrile on the conformational changes of alpha-chymotrypsin are also achieved for concentrations varying between 10 and 50%. PMID- 20705088 TI - Comparative analyses of B cell populations in trout kidney and mouse bone marrow: establishing "B cell signatures". AB - This study aimed to identify the frequency and distribution of developing B cell populations in the kidney of the rainbow trout, using four molecular B cell markers that are highly conserved between species, including two transcription factors, Pax5 and EBF1, recombination-activating gene RAG1, and the immunoglobulin heavy chain mu. Three distinct B cell stages were defined: early developing B cells (CLP, pro-B, and early pre-B cells), late developing B cell (late pre-B, immature B, and mature B cells), and IgM-secreting cells. Developmental stage-specific, combinatorial expression of Pax5, EBF1, RAG1 and immunoglobulin mu was determined in trout anterior kidney cells by flow cytometry. Trout staining patterns were compared to a well-defined primary immune tissue, mouse bone marrow, and using mouse surface markers B220 and CD43. A remarkable level of similarity was uncovered between the primary immune tissues of both species. Subsequent analysis of the entire trout kidney, divided into five contiguous segments K1-K5, revealed a complex pattern of early developing, late developing, and IgM-secreting B cells. Patterns in anterior kidney segment K1 were most similar to those of mouse bone marrow, while the most posterior part of the kidney, K5, had many IgM-secreting cells, but lacked early developing B cells. A potential second B lymphopoiesis site was uncovered in segment K4 of the kidney. The B cell patterns, or "B cell signatures" described here provide information on the relative abundance of distinct developing B cell populations in the trout kidney, and can be used in future studies on B cell development in other vertebrate species. PMID- 20705089 TI - Pharmacological effect of deoxypodophyllotoxin: a medicinal agent of plant origin, on mammalian neurons. AB - Deoxypodophyllotoxin (DOP) is a natural product that can be isolated from a variety of medicinal herb plants. It is well known for its antitumor, antiviral, and anti-inflammatory activities. However, there are few investigations that address neurotoxic effect of DOP in animal nervous system. In this study, whole cell patch clamp and calcium imaging techniques were employed to investigate effects of DOP on electrophysiological properties and calcium regulation of rat dorsal root ganglion (DRG) neurons. DOP inhibited both TTX-S (tetrodotoxin sensitive) and TTX-R (tetrodotoxin-resistant) sodium currents in voltage clamp recording and caused a decrease in the number of action potentials (APs) in current clamp experiment. Suppressive and unfavorable effects of DOP on the kinetics of sodium currents in terms of excitability of DRG neurons may greatly contribute to its antitumor and anti-inflammatory activities. Moreover, DOP evoked increase of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in DRG neurons, and this effect may lead to neuronal cytotoxicity. PMID- 20705091 TI - Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. AB - Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive deficits of relevance to schizophrenia in rodents and their subsequent reversal by first- and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-Choice Serial Reaction Time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of cognitive deficits and negative symptoms in schizophrenia. PMID- 20705092 TI - New therapeutic opportunities in epilepsy: a genetic perspective. AB - Epilepsy is a common and serious neurological disorder. Despite recent advances in drug therapy, treatment for epilepsy is still largely empirical and rational prescribing based on the mechanism of action in an individual patient is generally not possible. Genetic studies have identified an increasing collection of disease-causing genes providing a fundamental molecular foundation on which to build this understanding, at least for some forms of epilepsy. The impact of these genetic discoveries is likely to be wide reaching-from the discovery and validation of new drug targets to the potential to enable rational prescribing based on genetic makeup and even further through animal experimentation to tease out molecular and cellular mechanisms that lead to hyperexcitable neuronal networks causing epilepsy. Here we discuss how we can use knowledge of genetic mechanisms to improve treatment strategies now and into the future. PMID- 20705093 TI - Emerging nanomedicines for early cancer detection and improved treatment: current perspective and future promise. AB - The application of nanotechnology to medicine, commonly referred to as 'nanomedicine', has the potential to transform our approach to human health and disease. Research at the nanoscale level affords the opportunity to address some of the most confounding human diseases at the molecular level, with the potential for significant improvements in disease prevention, diagnosis and treatment. Rapid advances and emerging technologies in nanoscale systems, particularly nanoparticles, are having a profound impact on cancer diagnosis, treatment and monitoring. The development of nanoparticulate systems that offer improved chemotherapeutic delivery through increased solubility and sustained retention times is an area of intense focus in nanomedicine. In addition, active targeting of nanoparticles through conjugation of tumor-specific cell surface markers such as tumor-specific antibodies or ligands can enhance the efficacy of nanoparticle drug delivery systems while significantly reducing toxicity. Perhaps some of the most exciting advances in nanomedicine are multifunctional nanoparticulate systems for simultaneous imaging of tumor mass and drug delivery. In a relatively short period of time, nanomedicine has already begun to have a strong presence in the global market. This review provides a comprehensive summary of recent progress in nanomedicine as it relates specifically to nanoparticles and anticancer drug delivery. Research into different nanoprobes for cancer detection/imaging will also be discussed. Lastly, the future of this growing and dynamic field and its potential impact will be discussed. PMID- 20705094 TI - Sf9 cells: a versatile model system to investigate the pharmacological properties of G protein-coupled receptors. AB - The Sf9 cell/baculovirus expression system is widely used for high-level protein expression, often with the purpose of purification. However, proteins may also be functionally expressed in the defined Sf9 cell environment. According to the literature, the pharmacology of G-protein-coupled receptors (GPCRs) functionally reconstituted in Sf9 cells is similar to the receptor properties in mammalian cells. Sf9 cells express both recombinant GPCRs and G-proteins at much higher levels than mammalian cells. Sf9 cells can be grown in suspension culture, providing an inexpensive way of obtaining large protein amounts. Co-infection with various baculoviruses allows free combination of GPCRs with different G proteins. The absence of constitutively active receptors in Sf9 cells provides an excellent signal-to background ratio in functional assays, allowing the detection of agonist-independent receptor activity and of small ligand-induced signals including partial agonistic and inverse agonistic effects. Insect cell Galpha(i) like proteins mostly do not couple productively to mammalian GPCRs. Thus, unlike in mammalian cells, Sf9 cells do not require pertussis toxin treatment to obtain a Galpha(i)-free environment. Co-expression of GPCRs with Galpha(i1), Galpha(i2), Galpha(i3) or Galpha(o) in Sf9 cells allows the generation of a selectivity profile for these Galpha(i/o)-isoforms. Additionally, GPCR-G-protein combinations can be compared with defined 1:1 stoichiometry by expressing GPCR-Galpha fusion proteins. Sf9 cells can also be employed for ligand screening in medicinal chemistry programs, using radioligand binding assays or functional assays, like the steady-state GTPase- or [(35)S]GTPgammaS binding assay. This review shows that Sf9 cells are a versatile model system to investigate the pharmacological properties of GPCRs. PMID- 20705095 TI - Dynamic control of neuroexocytosis by phosphoinositides in health and disease. AB - Phosphoinositides are a group of phospholipids whose inositol headgroups can be phosphorylated at three distinct positions thereby generating seven different isotypes. The conversion between these lipid species depends on the activity of specific sets of phosphoinositide kinases and phosphatases whose targeting and activity is critical to establish the landscape of phosphoinositides on the cytosol-facing hemi-membrane of all organelles and plasmalemma. Phosphoinositides play pleiotropic roles ranging from signalling and membrane trafficking to modulation of ion channels and survival. In neurons and neurosecretory cells, whose main function is to communicate through the release of neurotransmitter, most of the work has focused on the role played by phosphatidylinositol (4,5) bisphosphate in controlling the mechanism underpinning neurotransmitter release through the fusion of secretory vesicles with the plasmalemma. Emerging evidence supports a multi-faceted regulation of neuroexocytosis by 3-phosphorylated phosphoinositides. In this review, we summarise the molecular mechanism by which these lipids control exocytosis and how minute changes in their metabolism can have devastating effects in the nervous system and lead to neurodegeneration. PMID- 20705096 TI - A FPGA real-time model of single and multiple visual cortex neurons. AB - Using a biologically realistic model of a single neuron can be very beneficial for visual physiologists to test their electrophysiology setups, train students in the laboratory, or conduct classroom-teaching demonstrations. Here we present a Field Programmable Gate Array (FPGA)-based spiking model of visual cortex neurons, which has the ability to simulate three independent neurons and output analog spike waveform signals in four channels. To realistically simulate multi electrode (tetrode) recordings, the independently generated spikes of each simulated neuron has a distinct waveform, and each channel outputs a differentially weighted sum of these waveforms. The model can be easily constructed from a small number of inexpensive commercially available parts, and is straightforward to operate. In response to sinewave grating stimuli, the neurons exhibit biologically realistic simple-cell-like response properties, including highly modulated Poisson spike trains, orientation selectivity, spatial/temporal frequency selectivity, and space-time receptive fields. Users can customize their model neurons by downloading modifications to the FPGA with varying parameter values, particularly desired features, or qualitatively different models of their own design. The source code and documentation are provided to enable users to modify or extend the model's functionality according to their individual needs. PMID- 20705097 TI - Genetically encoded Cl-Sensor as a tool for monitoring of Cl-dependent processes in small neuronal compartments. AB - Chloride (Cl) participates in a variety of physiological functions. To study processes connected with Cl homeostasis we need effective and quantitative probes allowing measurements of intracellular Cl concentration ([Cl(-)](i)) in different cell types, particularly in specialized small cellular compartments such as dendrites and dendritic spines. Of the different tools proposed for monitoring [Cl(-)](i), the genetically encoded Cl-sensitive indicators are the most promising. Recently, a ratiometric CFP-YFP based construct, termed "Cl-Sensor", with a relatively high sensitivity to Cl has been proposed (Markova et al., 2008). In the present study, we have developed conditions for the efficient expression of Cl-Sensor in tiny neuronal compartments including distal dendrites and spines. We also propose a new approach for the calibration of intracellularly expressed probes using a natural triterpenoid saponin, beta-escin. We have mapped [Cl(-)](i) distribution in different neuronal compartments of cultured hippocampal and spinal cord neurons. The maximum Cl concentration was observed in the soma and it had a tendency to decrease gradually along dendritic branches, reaching minimum values in thin distal dendrites. We have also monitored transient increases in intracellular Cl in dendritic spines caused by glutamate application. These results demonstrate that Cl-Sensor enables non-invasive monitoring of the [Cl(-)](i) distribution in different types of neurons with variable morphology. This probe represents an effective tool for the quantitative estimation of [Cl(-)](i) in various cellular compartments including dendritic spines. PMID- 20705098 TI - Detection of input sites in scanning photostimulation data based on spatial correlations. AB - Scanning photostimulation is a well-established method for studying the functional microcircuitry in brain slices. Light-evoked responses are thereby taken as an indicator for a connected presynaptic partner. Such an approach thus requires a clear distinction between the photo-evoked and the spontaneous responses. Here we show that, for a data set from entorhinal cortex layer II with high spontaneous synaptic rates of up to 10Hz, it is possible to identify presynaptic sites. The underlying detection algorithm is based on the finding that a presynaptic cell has several neighboring activation sites, resulting in the clustered appearance of specific photo-evoked inputs. The main idea behind this approach is to identify "hit" locations at which the number of intracellularly recorded synaptic events is significantly larger as expected from the hypothesis of statistical independence. The algorithm works without making use of EPSC amplitude information and for single trials, i.e., each site is stimulated only once. The hit maps are tested upon reliability by repeated stimulations and by blocking synaptically mediated responses via TTX. Furthermore, based on the hit density of surrogate data, we devise a Bayesian formalism to estimate the number of presynaptic partners. In these simulations we find good agreement between estimated and real number of input cells, which shows that the hit density can be used as a reliable measure for afferent connectivity. PMID- 20705100 TI - An experimental paradigm to compare motor performance under laboratory and under everyday-like conditions. AB - Research findings on human motor skills may not necessarily hold in everyday life, since laboratory and everyday scenarios typically differ with respect to the subjects' attention to the skill, their motivation to perform at their best, the goals they try to achieve, and the mode of movement initiation - extrinsic versus intrinsic. Here we present an experimental approach which can be used to substantiate the hypothesized effects of laboratory (L) versus everyday (E) settings on one type of motor skill, i.e., manual prehension. This approach is based on two tasks: In task L, subjects are told that they will participate in an experiment on grasping, and are instructed to seize and move a lever upon appearance of a visual target. In task E, they are told that they will play a computer game, and they have to seize and move the lever in order to proceed from one game level to the next. Both tasks include prehension movements from the same starting position and object to the same terminal position and object; movements differ only in their behavioural context. We exemplify the utility of our approach with a preliminary analysis of kinematic and force data. It shows that the two tasks differ with respect to several performance measures, and that some performance measures make independent contributions to that difference. The existence of independent contributions suggests that behavioural context may influence prehension via several distinct routes. Our approach can be used for comprehensive analyses of the context-dependence of motor skills in various reference groups. PMID- 20705099 TI - Nerve conduction block using combined thermoelectric cooling and high frequency electrical stimulation. AB - Conduction block of peripheral nerves is an important technique for many basic and applied neurophysiology studies. To date, there has not been a technique which provides a quickly initiated and reversible "on-demand" conduction block which is both sustainable for long periods of time and does not generate activity in the nerve at the onset of the conduction block. In this study we evaluated the feasibility of a combined method of nerve block which utilizes two well established nerve blocking techniques in a rat and cat model: nerve cooling and electrical block using high frequency alternating currents (HFAC). This combined method effectively makes use of the contrasting features of both nerve cooling and electrical block using HFAC. The conduction block was initiated using nerve cooling, a technique which does not produce nerve "onset response" firing, a prohibitive drawback of HFAC electrical block. The conduction block was then readily transitioned into an electrical block. A long-term electrical block is likely preferential to a long-term nerve cooling block because nerve cooling block generates large amounts of exhaust heat, does not allow for fiber diameter selectivity and is known to be unsafe for prolonged delivery. PMID- 20705101 TI - Identification of a novel cytotoxic T lymphocyte epitope from CFP21, a secreted protein of Mycobacterium tuberculosis. AB - CFP21 is a major secreted protein of Mycobacterium tuberculosis (Mtb) which is considered as a promising antigen for immunotherapy. To identify CFP21-derived HLA-A*0201 restricted epitopes, a series of native peptides and their analogues were predicted with prediction programs and synthesized. The native peptide, p134 (AVADHVAAV), and its analogues, p134-1Y2L and p134-1Y2L9L, showed potent binding affinity and stability to HLA-A*0201 molecule. In ELISPOT assay, the cytotoxic T lymphocytes (CTLs) induced by these peptides could release IFN-gamma. In cytotoxicity assay, the CTLs induced by p134 and p134-1Y2L9L could specifically lyse peptide-loaded T2 cells. In these two assays, the native peptide, p134, showed the most potent activity. Our results indicated that p134 could be a novel epitope which could serve as a good candidate to develop peptide vaccines against M. tuberculosis. PMID- 20705090 TI - Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. AB - Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. PMID- 20705102 TI - Direct inhibition of human acute myeloid leukemia cell growth by IL-12. AB - Acute myeloid leukemia is a haematopoietic malignancy originating from the transformation of myeloid progenitors that proliferate and accumulate in the bone marrow. In AML patients the survival rate at 5 years is 40-50% highlighting the need for novel therapies. In this study we have asked whether IL-12, an immuno modulatory cytokine with anti-tumor activity, may inhibit directly AML cell growth. We show that the human AML cell lines U937, K562 and THP-1 expressed both chains of the IL-12 receptor (R), i.e. IL-12Rbeta1 and IL-12Rbeta2. IL-12 inhibited the angiogenic potential of AML cells in vitro, but did not affect their survival or proliferation. In vivo experiments were performed using SCID NOD mice injected intraperitoneally (i.p.) with the human U937 AML cell line and subsequently treated with human recombinant IL-12 or PBS i.p. Histological, immunohistochemical and flow cytometric analyses on explanted tumors revealed that IL-12 reduced new vessel formation, induced apoptosis and inhibited tumor cell proliferation. Studies on a panel of angiogenesis related genes in explanted tumors using PCR arrays showed significantly down-regulated expression of numerous pro-angiogenic genes including VEGF-C, IL-6, IL-8, CXCL1, CXCL6 and alanyl aminopeptidase in IL-12 vs PBS treated mice. This study shows for the first time that IL-12 targets directly AML cell growth and paves the way to further investigation of IL-12 as potential drug for AML treatment. PMID- 20705103 TI - Application and expression of HSV gG1 protein from a recombinant strain. AB - According to the homologous sequence of glycoprotein G1 (gG1) genes from different strains of herpes simplex virus type 1 (HSV-1), a pair of primers was designed to amplify the gG1 gene fragment by PCR. Both the PCR product and the pGEX-4T-1 vector were digested with EcoR I and Sal I. The gG1 gene fragment was subcloned into the digested pGEX-4T-1 vector to construct a recombinant plasmid (pGEX-4T-1-gG1). The resultant plasmid was identified by dual-enzyme digestion and sequence analysis, and then transformed into Escherichia coli BL21 for expression under the induction of isopropyl beta-D-1-thiogalactoside (IPTG). The expressed GST-gG1 fragment was detected by SDS-PAGE and purified by affinity chromatography. The properties of GST-gG1 fragment were evaluated by immunoblot analysis. Enzyme-linked immunosorbent assays (ELISAs) based on the GST-gG1 fragment were used for determining IgG or IgM to HSV-1. The GST-gG1 fragment specific ELISA was also compared with ELISA with whole-HSV-1 antigen and commercial ELISA kits. The gG1-specific IgG and IFN-gamma producing CD8+ T cells were induced in mice immunized with the GST-gG1 fragment. These results indicated that the GST-gG1 fragment could be used for replacing whole-virus antigen to detect IgM and IgG to HSV-1 in human sera, which provided a strategy for developing vaccines to protect HSV-1 infection using gG1 fragment. PMID- 20705105 TI - Expression and secretion of Bluetongue virus serotype 8 (BTV-8)VP2 outer capsid protein by mammalian cells. AB - VP2 is the outermost Bluetongue virus (BTV) antigenic protein, forming triskelion motifs on the virion surface. Although VP2 has been expressed successfully through many systems, its paracrine expression as a soluble form by mammalian cells represents a difficult task. In the present paper two fragments of VP2 have been expressed successfully into the medium of transiently transfected mammalian cells through a fusion peptides strategy. The crude conditioned medium containing the secreted peptide could be employed for immunodiagnostic assay development or vaccine purposes. PMID- 20705104 TI - Generation of HIV-1 primary isolates representative of plasma variants using the U87.CD4 cell line. AB - In order to obtain HIV-1 primary isolates in settings with limited access to donor PBMCs, a culture method was developed where patient PBMCs infected with HIV 1 were cultured together with U87.CD4 cells. Using this non-laborious method, it is possible to harvest virus solely on the basis of syncytia formation and circumventing monitoring of viral replication by CA-p24 ELISA. Primary isolates from 23 out of 33 patients (70%) were isolated successfully. From PCR amplification and sequencing of the V1V5 region of the viral gp120 envelope gene, primary isolates were compared with variants obtained from plasma and PBMCs of 13 patients. The primary isolates of seven patients (54%) resembled closely the plasma viral quasispecies, whereas different variants were isolated from the other patients (46%). Three patients harboured a dual infection, while this remained unnoticed from sequencing the plasma or PBMC compartment. The primary isolates were highly infectious for TZM-bl cells and could infect CD4-enriched lymphocytes. This study demonstrates that it is possible to grow viral isolates using a non-laborious and simple method. These isolates may be used in the field for studies on antiretroviral therapy or for vaccine trials. PMID- 20705107 TI - Altered evoked gamma-band responses as a neurophysiological marker of schizophrenia? AB - Evoked gamma-band responses (GBRs) were shown to be involved in different aspects of human cognition and behavior. They have been linked to the integration and processing of incoming information leading to an adequate behavioral outcome. Consequently, altered evoked GBRs have been associated with impaired cognitive and behavioral states present in a variety of psychiatric disorders. However, to the best of our knowledge, there are no reports directly comparing evoked GBRs of different clinical groups in the same experimental setting. Thus, the purpose of the present study was to shed light on the question, whether evoked GBRs, as a kind of a neurophysiological biomarker of pathological states, might serve for characterization and distinguishing of groups suffering from diverse psychiatric disorders. We measured EEG during a passive auditory oddball-paradigm. Participants were patients diagnosed with schizophrenia, mood disorder, and personality disorders as well as a fourth group consisting of healthy participants. Our results indicate that evoked GBRs significantly differed from healthy participants only in schizophrenic patients whereas no difference could be observed for the other clinical groups. Our findings support the notion that early evoked GBRs could be indeed a trait variable of schizophrenia and are not a general marker of pathological brain states. PMID- 20705108 TI - In vitro and in vivo characterisation of a novel peptide delivery system: amphiphilic polyelectrolyte-salmon calcitonin nanocomplexes. AB - The cationic peptide, salmon calcitonin (sCT) was complexed with the cationic amphiphilic polyelectrolyte, poly(allyl)amine, grafted with palmitoyl and quaternary ammonium moieties at pH 5.0 and 7.4 to yield particulates (sCT-QPa). The complexes were approximately 200 nm in diameter, had zeta potentials ranging from +20 to +50 mV, and had narrow polydispersity indices (PDIs). Differential scanning calorimetry revealed the presence of an interaction between sCT and QPa in the complexes. Electron microscopy confirmed the zeta-size data and revealed a vesicular bilayer structure with an aqueous core. Tyrosine- and Nile red fluorescence indicated that the complexes retained gross physical stability for up to 7 days, but that the pH 5.0 complexes were more stable. The complexes were more resistant to peptidases, serum and liver homogenates compared to free sCT. In vitro bioactivity was measured by cAMP production in T47D cells and the complexes had EC50 values in the nM range. While free sCT was unable to generate cAMP following storage for 7 days, the complexes retained approximately 33% activity. When the complexes were injected intravenously to rats, free and complexed sCT (pH 5.0 and 7.4) but not QPa reduced serum calcium over 120 min. Free and complexed sCT but not QPa also reduced serum calcium over 240 min following intra-jejunal administration. In conclusion, sCT-QPa nanocomplexes that have been synthesised are stable, bioactive and resistant to a range of peptidases. These enhanced features suggest that they may have the potential for improved efficacy when formulated for injected and oral delivery. PMID- 20705106 TI - Inhibition of protease-inhibitor-resistant hepatitis C virus replicons and infectious virus by intracellular intrabodies. AB - Hepatitis C virus (HCV) infection is a common cause of chronic liver disease and a serious threat to human health. The HCV NS3/4A serine protease is necessary for viral replication and innate immune evasion, and represents a well-validated target for specific antiviral therapy. We previously reported the isolation of single-chain antibodies (scFvs) that inhibit NS3/4A protease activity in vitro. Expressed intracellularly (intrabodies), these scFvs blocked NS3-mediated proliferation of NS3-transfected cells. Here we show that anti-NS3 scFvs suppress HCV RNA replication when expressed intracellularly in Huh7 hepatoma cells bearing either subgenomic or genome-length HCV RNA replicons. The expression of intrabodies directed against NS3 inhibited the autonomous amplification of HCV replicons resistant to small-molecule inhibitors of the NS3/4A protease, and replicons derived from different HCV genotypes. The combination of intrabodies and interferon-alpha had an additive inhibitory effect on RNA replication in the replicon model. Intrabody expression also inhibited production of infectious HCV in a cell culture system. The NS3 protease activity was inhibited by the intrabodies in NS3-expressing cells. In contrast, cell-free synthesis of HCV RNA by preformed replicase complexes was not inhibited by intrabodies, suggesting that the major mode of inhibition of viral replication is inhibition of NS3/4A protease activity and subsequent suppression of viral polyprotein processing. PMID- 20705109 TI - A carpet-based mechanism for direct antimicrobial peptide activity against vaccinia virus membranes. AB - Antimicrobial peptides have activity against a wide variety of biological membranes and are an important component of innate immunity in vertebrate as well as invertebrate systems. The mechanisms of action of these peptides are incompletely understood and a number of competing but not necessarily mutually exclusive models exist. In this study we examined the virucidal activity of four peptides, the human cathelicidin derived LL37, Xenopus alanine-substituted Magainin-2 amide, uperin-3.1, and a cecropin-LL37 hybrid against vaccinia virus. The peptides were shown to be differentially virucidal but all were shown to attack the viral envelope, with LL37 being the most effective and uperin-3.1 the least. Density gradient analysis of the treated virions indicated the virus outer membrane was efficiently removed by peptide action and suggests a mechanism of direct virus inactivation that is consistent with the carpet model for peptide mediated membrane disruption. Interestingly, the least effective peptide uperin 3.1 was equally effective as the others at inducing susceptibility to neutralizing antibody. This suggests that in addition to direct killing by a carpet-based mechanism, the peptides may simultaneously operate a different mechanism that exposes sequestered antigen without membrane removal. PMID- 20705110 TI - Aquaporin 4 antibody positive central nervous system autoimmunity and multiple sclerosis are characterized by a distinct profile of antibodies to herpes viruses. AB - Viral infections are implicated in the onset and promotion of autoimmunity in genetically predisposed individuals. In this study, immune response patterns to herpes viruses were compared in aquaporin 4 (AQP4) antibody positive central nervous system (CNS) autoimmunity and multiple sclerosis (MS). Serum samples of patients with AQP4 antibody positive CNS autoimmunity (n=52), relapsing-remitting MS (n=55) and controls including non-autoimmune neurological disorders and healthy individuals (n=56) were tested for IgG antibodies to herpes viruses 1-6 (HSV-1, HSV-2, VZV, EBV, CMV, HHV-6) using commercial ELISA kits. AQP4 antibody positive CNS autoimmunity cases most frequently had IgG responses to four viruses (38.5%), while presence of antibodies to three herpes viruses was most common in MS and controls (41.8% and 35.7%, respectively). Compared to MS, AQP4 positive cases had a significantly higher CMV seropositivity rate (P=0.003) and a lower prevalence of EBV antibodies (P=0.01). The analysis of immunoreactivity of samples above the diagnostic threshold revealed that in AQP4 positive CNS autoimmunity the IgG response to EBV (P<0.001) and VZV (P<0.01) was lower than in MS, whereas immununoreactivity to HSV-1 was higher than in controls (P<0.01). The distinct pattern of seroprevalence and immunoreactivity against herpes viruses in AQP4 positive CNS autoimmunity and MS provide further insights to the pathogenetical heterogeneity. Whether these findings reflect an epi-phenomenon of autoimmune disorders or indicate a disease-specific deregulated virus-host interaction needs to be examined in further studies. PMID- 20705111 TI - Association of Omi/HtrA2 with gamma-secretase in mitochondria. AB - Omi/HtrA2, a mitochondrial serine protease with chaperone activity, is involved in varied intracellular processes. Dysfunctional Omi/HtrA2 has thus been implicated in various neurodegenerative disorders. Previously, we have shown that gamma-secretase complexes are present and active in mitochondria. Here, we demonstrate that peptide corresponding to C-terminus of presenilin-1, as previously reported to activate Omi/HtrA2, interacts with Omi/HtrA2 in isolated mitochondria. Moreover, we show that Omi/HtrA2 interacts with presenilin in active gamma-secretase complexes located to mitochondria. Using a biotinylated gamma-secretase inhibitor and confocal microscopy, we could further confirm the association of gamma-secretase complexes with mitochondrial Omi/HtrA2. Furthermore, determination of gamma-secretase complex topology in isolated mitochondria revealed an association of gamma-secretase complexes with the outer membrane of mitochondria with the extreme PS1 C-terminus facing the inter membrane space. We have also studied the impact of Omi/HtrA2 on gamma-secretase activity, measuring APP intracellular domain (AICD) production. We found reduced AICD production in mitochondria isolated from Omi/HtrA2 knockout mouse embryonic fibroblasts, indicating a significant role of Omi/HtrA2 on gamma-secretase activity. Thus, our results provide information for understanding the interplay between mitochondrial Omi/HtrA2 and gamma-secretase complexes in AD. PMID- 20705112 TI - Dendritic cells previously exposed to mannan-binding lectin enhance cytokine production in allogeneic mononuclear cell cultures. AB - Mannan (or mannose)-binding lectin (MBL) can bind to monocytes and dendritic cells, but the significance of such interactions is unknown. We hypothesized that the presence of MBL might prevent the differentiation of monocytes into monocyte derived dendritic cells or interfere with the development of dendritic cells in some way. We therefore investigated the influence of recombinant human MBL on surface antigen expression and on secretion of selected cytokines. By these means, no direct influence of rhMBL on dendritic cell differentiation or maturation was detected. However, mature dendritic cells prepared in the presence of rhMBL and subsequently co-cultured with allogeneic mononuclear cells, markedly promoted production of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in vitro. In most dendritic cell-mononuclear cell combinations, IFN gamma production was also enhanced. This influence required the presence of rhMBL during dendritic cell maturation and was critically dependent on the presence of monocytes. This observation provides evidence that MBL can influence cellular immunity in addition to its established role as an opsonin. PMID- 20705113 TI - Myeloid-derived suppressor cells: natural regulators for transplant tolerance. AB - Myeloid derived suppressor cells (MDSC) contribute to the negative regulation of immune response in cancer patients. This review summarizes results on important issues related to MDSC biology, including expansion and activation of MDSC, phenotype, and subsets as well pathways and different mechanisms by which these cells exert their suppressive effect. Recent observations suggesting that MDSC may have roles in transplant tolerance are presented. Although therapeutic targeting and destruction of MDCS is of primary interest in cancer patients, in transplantation it will instead be necessary to induce, expand, and activate these cells; thus current possibilities for in vitro generation of MDSC are also discussed. PMID- 20705115 TI - Computational analysis of fluorescence induction curves in intact spinach leaves treated at different pH. AB - Effects of change in pH have been investigated on spinach leaf discs by measuring fluorescence induction kinetics using plant efficiency analyzer (PEA). On the basis of computational analysis of the results, we have reported that acidic pH causes a significant inhibition of the donor and the acceptor side of PS II. Energy flux models have been presented using the software Biolyzer HP 3. Effects of pH were investigated on the antenna size heterogeneity of PS II and a relative change in the proportions of alpha, beta, and gamma centers was observed. PMID- 20705114 TI - Toxicity assessment of pramipexole in juvenile rhesus monkeys. AB - Pramipexole (PPX) is a dopamine agonist approved for the treatment of the signs and symptoms of idiopathic Parkinson's disease as well as restless leg syndrome. The objective of this study was to investigate the toxicity of PPX when administered orally to juvenile rhesus monkeys once daily for 30 weeks, and to assess the reversibility of toxicity during a 12-week recovery. Rhesus monkeys (N=4 males and 4 females/group; 22-24 months of age) were orally treated daily for 30 weeks with 0.0, 0.1, 0.5 or 2.0 mg/kg PPX, and subjects were assessed daily using the NCTR Operant Test Battery (OTB). Clinical chemistry, hematology, ophthalmology and other standard postmortem toxicological evaluations, including histopathology and neuropathology as well as toxicokinetics were performed. The systemic exposure to PPX was higher than that at therapeutic doses in man and AUC(0-24 h)-data increased proportionally to dose. Blood pressure significantly decreased over time in all groups including control. Near the end of treatment, there were statistically significant decreases in heart rate for the 0.5 and 2.0 mg/kg/day groups compared to control. After 4 weeks of dosing, serum prolactin was significantly decreased in all treatment groups compared to control. This decrease remained at the end of treatment in the 0.5 and 2.0 mg/kg/day groups. In summary, administration of PPX at doses of up to 2.0 mg/kg/day for 30 weeks to juvenile rhesus monkeys produced adverse findings which were attributable to its pharmacological properties, including hypoprolactinemia. PMID- 20705116 TI - Towards information processing from nonlinear physical chemistry: a synthetic electrochemical cognitive system. AB - It is evident that complex animate materials, which operate far from equilibrium, exhibit sensory responses to the environment through emergent patterns. Formation of such patterns is often the underlying mechanism of an active response to environmental changes and can be interpreted as a result of the distributed parallel information processing taking place within the material. Such emergent patterns are not limited to biological entities; indeed there is a wide range of complex nonlinear dissipative systems which exhibit interesting emergent patterns within a range of parameters. As one example, the present paper describes the detection of emergent phenomena associated with surface electrochemical processes that allow the system to respond to input information through evolving patterns in space and time. Associative mapping of this sort offers the opportunity to devise an electrochemical cognitive system (ECS), where pattern formation can be looked at as a macroscopic phenomenon resulting from the extensive distributive computing that occurs at the microscopic level. PMID- 20705118 TI - The neural process of hazard perception and evaluation for warning signal words: evidence from event-related potentials. AB - Warning signs have been widely applied to industrial production. As an important component of warning signs, warning signal words were mostly studied by using questionnaire. This study used event-related potentials (ERPs) to explore neural temporal features during the processing of warning signal words in human brain, and found that there were two stages involved in processing warning signal words, providing an electrophysiological evidence for a previous warning information processing model, the Communication-Human Information Processing Model (C-HIP). Previous behavioral studies indicated that the subjective hazard perception of participants facilitates their attention to the warning sign, and people can get hazard information from warning words. Our results provided direct evidence for these conclusions. The present findings of significant differences in subjective hazard perception for warning words among individuals showed the importance and necessity of training for people to get the similar understanding of these words. Our results implicated that the warning words reflecting the same hazard level used in the warning sign should be somewhat changed, at the same time, convey equally or similarly hazardous information, to avoid desensitization and habituation due to overuse of them. PMID- 20705117 TI - Cellular localization of genes and proteins for tumor necrosis factor-alpha (TNF), TNF receptor types I and II in bovine endometrium. AB - To determine which cell types produce tumor necrosis factor-alpha (TNF) and its receptors (TNFRI and TNFRII) in bovine endometrium, we investigated the expression and cellular localization of their mRNAs and proteins. TNF transcripts and proteins were co-localized in endometrial epithelial cells, glandular epithelial cells and endothelial cells of microvessels but not in the stromal cells. TNF protein was detected in the lysate and the cultured media of epithelial cells, but was only weakly detected in the stromal cells. Both TNFRI (TNFRSF1A) and TNFRII (TNFRSF1B) transcripts were expressed in the epithelial cells, glandular epithelial cells and the stromal cells, whereas their proteins were weakly expressed in the stroma. TNF mRNA and protein expressions in the cultured epithelial cells were increased by TNF and interleukin-1alpha, and the TNFRII mRNA expressions were stimulated by oxytocin. Together, TNF secreted by the endometrial cells may locally play a role in regulating uterine function throughout the estrous cycle. PMID- 20705119 TI - Contrasting effects of systemic and central sibutramine administration on the intake of a palatable diet in the rat. AB - Sibutramine hydrochloride monohydrate is the only centrally active weight modifying agent currently approved by the FDA for long-term use in the treatment of obesity. Systemic sibutramine treatment has been shown to reduce food intake in humans and rodent models in a manner that is consistent with the enhancement of satiety mechanisms. Although it is generally assumed that the hypophagic effects of the drug are mediated by actions within the brain, the locus or loci of these effects remains unclear. These experiments compared the effects of systemic and intracranial injections of sibutramine on the intake of a palatable diet in non-deprived animals. Consistent with prior reports, systemic injections of sibutramine hydrochloride (at 0, 0.5, 1.0, or 3.0mg/kg sibutramine i.p.) dose dependently reduced feeding on a high fat/high sucrose diet across a 2-h feeding session, but did not alter water intake or locomotor activity. In contrast, bilateral injections of sibutramine (at 0.0, 2.0, 4.0 and 10.0MUg/0.5MUl/side) into either the paraventricular nucleus of the hypothalamus (PVN) or the medial nucleus accumbens shell (ACb) significantly and dose-dependently increased food intake of the sweetened fat diet. ACb treatment also modestly inhibited locomotor behavior; intracranial injections had no effect on water consumption. These experiments are the first to suggest that sibutramine treatment may have distinct actions upon separate neural circuits that modulate food intake behavior in the rat. PMID- 20705120 TI - Nighttime dim light exposure alters the responses of the circadian system. AB - The daily light dark cycle is the most salient entraining factor for the circadian system. However, in modern society, darkness at night is vanishing as light pollution steadily increases. The impact of brighter nights on wild life ecology and human physiology is just now being recognized. In the present study, we tested the possible detrimental effects of dim light exposure on the regulation of circadian rhythms, using CD1 mice housed in light/dim light (LdimL, 300 lux:20 lux) or light/dark (LD, 300 lux:1 lux) conditions. We first examined the expression of clock genes in the suprachiasmatic nucleus (SCN), the locus of the principal brain clock, in the animals of the LD and LdimL groups. Under the entrained condition, there was no difference in PER1 peak expression between the two groups, but at the trough of the PER 1 rhythm, there was an increase in PER1 in the LdimL group, indicating a decrease in the amplitude of the PER1 rhythm. After a brief light exposure (30 min, 300 lux) at night, the light-induced expression of mPer1 and mPer2 genes was attenuated in the SCN of LdimL group. Next, we examined the behavioral rhythms by monitoring wheel-running activity to determine whether the altered responses in the SCN of LdimL group have behavioral consequence. Compared to the LD controls, the LdimL group showed increased daytime activity. After being released into constant darkness, the LdimL group displayed shorter free-running periods. Furthermore, following the light exposure, the phase shifting responses were smaller in the LdimL group. The results indicate that nighttime dim light exposure can cause functional changes of the circadian system, and suggest that altered circadian function could be one of the mechanisms underlying the adverse effects of light pollution on wild life ecology and human physiology. PMID- 20705121 TI - Hippocampal theta rhythm after serotonergic activation of the pedunculopontine tegmental nucleus in anesthetized rats. AB - The pedunculopontine tegmental nucleus (PPN), as a part of reticular formation activating system, is thought to be involved in the sleep/wake cycle regulation, and plays an important role in the generation and regulation of hippocampal rhythmical slow activity. The activity of PPN can be modulated by serotonergic system, mainly through multiple projections from raphe nuclei, which can influence PPN neurons through different classes of 5-HT receptors. In the present study, the effect of intra-PPN injection of two serotonin agonists: 8-OH-DPAT and 5-CT, on hippocampal formation EEG activity was examined in urethane-anesthetized rats. The study found that the microinjections induced prolonged spontaneous theta rhythm in both hippocampi with a short latency. The results obtained suggest that local inhibition of presumably cholinergic neurons in the PPN acts as a trigger for hippocampal theta activity. PMID- 20705122 TI - VEGF and its receptor-2 involved in neuropathic pain transmission mediated by P2X2(/)3 receptor of primary sensory neurons. AB - The pathogenesis of neuropathic pain is complex. P2X2(/)3 receptor plays a crucial role in nociception transduction of chronic pain. VEGF inhibitors are effective for pain relief. The present study investigated the effects of VEGF and VEGF receptor-2 (VEGFR2) on the pain transmission in neuropathic pain states that mediated by P2X2(/)3 receptor in primary sensory neurons. Chronic constriction injury (CCI) model was used as neuropathic pain model. Sprague-Dawley rats had been randomly divided into sham group, CCI group and CCI rats treated with anti rVEGF antibody group. Mechanical withdrawal threshold and thermal withdrawal latency were measured. Expressions of VEGF, VEGFR2 and P2X2(/)3 in L4-6 dorsal root ganglia (DRG) were detected by immunohistochemistry, RT-PCR and western blot analysis. The mechanical withdrawal threshold and thermal withdrawal latency in CCI group were lower than those in sham group and CCI rats treated with anti rVEGF antibody group (p<0.05), while VEGF, VEGFR2 and P2X2(/)3 receptors' expressions of L4-6 DRG in CCI group were higher than those in the other two groups (p<0.05). The expressions of VEGF, VEGFR2 and P2X2(/)3 in L4-6 DRG of CCI rats treated with anti-rVEGF antibody group were decreased compared with those in CCI group (p<0.05). The results show that VEGF and VEGFR2 are involved in the pathogenesis of neuropathic pain and VEGF primarily potentiates pain responses mediated by P2X2(/)3 receptor on DRG neurons. Anti-rVEGF treatment in CCI rats may alleviate chronic neuropathic pain by decreasing the expressions of VEGFR2 and P2X2(/)3 receptors on DRG neurons to inhibit the transmission of neuropathic pain signaling. PMID- 20705123 TI - The effects of serum on the toxicity of manufactured nanoparticles. AB - The aim of the present study was to assess the effects of the presence and absence of serum in NP suspension media in relation to their cytotoxicity, as well as their potential to cause oxidative stress and stimulate pro-inflammatory cytokine release from J774.A1 murine 'macrophage-like' cells. Different sized (20nm and 200nm) carboxylated, fluorescent, model polystyrene beads (PBs) at concentrations from 12.5MUgml(-1) to 100MUgml(-1) were used. Both 20nm and 200nm PBs, independent of the suspension media, were observed to cause limited, yet significant (p<0.05) cytotoxicity over 48h up to 100MUgml(-1). Significant differences (p>0.05) were also found between NP size and serum content of the suspension media used. The smaller sized PBs were found to affect intracellular glutathione (GSH) levels, causing a significant loss (p<0.05) in GSH when suspended in the presence of serum. Subsequent analysis also showed significant (p<0.05) increases in tumour necrosis factor-alpha production after 48h when the 20nm PBs were suspended in both the presence and absence of serum, compared to the affects observed by the larger, 200nm sized PBs. In conclusion, the results of the present study show that the interaction of NPs with serum can significantly affect their resultant toxicity in vitro. PMID- 20705124 TI - Improved dissolution and pharmacokinetic behavior of cyclosporine A using high energy amorphous solid dispersion approach. AB - The aim of the present investigation is to develop solid dispersion (SD) formulations of cyclosporine A (CsA) for improving the oral bioavailability of CsA. Amorphous SDs of CsA with eight hydrophilic polymers were prepared with wet mill employing zirconia beads. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and interaction of CsA with co-existing polymer. Although CsA molecules were found to be amorphous in all wet-milled formulations, some SD formulations failed to improve the dissolution. Of all CsA formulations, SD using polymer with HPC(SSL) exhibited the largest improvement in dissolution behavior. Pharmacokinetic profiling of orally dosed CsA in rats was carried out using UPLC/ESI-MS. After the oral administration of HPC(SSL)-based SD, enhanced CsA exposure was observed with increases in C(max) and AUC of ca. 5-fold, and the variation in AUC was ca. 40% less than that of amorphous CsA. Infrared spectroscopic studies suggested an interaction between CsA and HPC(SSL), as evidenced by the conformational transition of CsA. From the improved dissolution and pharmacokinetic data, the amorphous SD approach using wet-milling technology should lead to consistent and enhanced bioavailability, leading to an improved therapeutic potential of CsA. PMID- 20705125 TI - A statistical approach to the development of a transdermal delivery system for ondansetron. AB - Transdermal delivery of drugs has gained attention as an alternative to intravenous and oral methods of delivery. However, the skin permeation of drugs is generally poor. To overcome this problem, many permeation enhancers have been developed. In this study, ondansetron hydrogels were prepared, and their skin permeation and pharmacological effects were evaluated in mice. To prepare the hydrogels, a Box-Behnken design was introduced. Fifteen formulations of ondansetron hydrogels composed of hydroxyethylcellulose and hydroxypropylcellulose as gel bases, l-menthol as a penetration enhancer and isopropanol (IPA), N-methyl-2-pyrrolidone (NMP) and water as a solvent were prepared. The quantities of IPA (X(1)), l-menthol (X(2)) and NMP (X(3)) were selected as causal factors. We performed an in vitro skin permeation study and an in vivo skin irritation study with the test hydrogels. The flux and the total irritation score were selected as response variables. The optimal formulation, one that has an appropriate penetration and an acceptable skin irritation score, was estimated using a nonlinear response surface method incorporating thin-plate spline interpolation. The optimal formulation also delivered the desired pharmacological activity. These results indicated the feasibility of delivering ondansetron transdermally. PMID- 20705126 TI - Preconditioning with Maillard reaction products improves antioxidant defence leading to increased stress tolerance in cardiac cells. AB - Advanced glycation end products (AGEs) are considered as biomarkers of ageing and are associated with several degenerative diseases. Besides endogenous formation, significant amounts of AGEs are taken up with food. Although nutritional AGEs are considered as undesirable, proinflammatory agents, they may also enclose potentially beneficial antioxidants. We used rodent cardiac cells to evaluate if food AGEs, present in bread crust, can modify the cellular antioxidant defence. Mice were fed with bread crust containing diet to prove the in-vivo relevance for the heart. In mouse cardiac fibroblasts, bread crust extract induced a moderate elevation of ROS production causing an activation of p42/p44(MAPK), p38(MAPK) and NF-kappaB, followed by increased expression of antioxidative enzymes. Preconditioning studies demonstrated that this was sufficient to protect cardiac fibroblasts and rat adult cardiac myocytes against severe oxidative stress. Furthermore, mice, fed a bread crust containing diet, exhibited a similarly improved cardiac expression of antioxidative defence genes. The consumption of AGEs can therefore contribute to an improved antioxidant status of the heart, thus exhibiting cardioprotective effects in case of severe oxidative stress as in ischemia reperfusion injury. Also, these data show that the exclusive interpretation of circulating AGEs as pathophysiological biomarkers of ageing might be misleading. PMID- 20705128 TI - Extracellular polymeric substances (EPS) of microbial aggregates in biological wastewater treatment systems: a review. AB - A review concerning the definition, extraction, characterization, production and functions of extracellular polymeric substances (EPS) of microbial aggregates in biological wastewater treatment reactors is given in this paper. EPS are a complex high-molecular-weight mixture of polymers excreted by microorganisms, produced from cell lysis and adsorbed organic matter from wastewater. They are a major component in microbial aggregates for keeping them together in a three dimensional matrix. Their characteristics (e.g., adsorption abilities, biodegradability and hydrophilicity/hydrophobicity) and the contents of the main components (e.g., carbohydrates, proteins, humic substances and nucleic acids) in EPS are found to crucially affect the properties of microbial aggregates, such as mass transfer, surface characteristics, adsorption ability, stability, the formation of microbial aggregates etc. However, as EPS are very complex, the knowledge regarding EPS is far from complete and much work is still required to fully understand their precise roles in the biological treatment process. PMID- 20705127 TI - Vitamin E and C supplementation reduces oxidative stress, improves antioxidant enzymes and positive muscle work in chronically loaded muscles of aged rats. AB - Aging is associated with increased oxidative stress. Muscle levels of oxidative stress are further elevated with exercise. The purpose of this study was to determine if dietary antioxidant supplementation would improve muscle function and cellular markers of oxidative stress in response to chronic repetitive loading in aging. The dorsiflexors of the left limb of aged and young adult Fischer 344 Brown*Norway rats were loaded 3 times weekly for 4.5 weeks using 80 maximal stretch-shortening contractions per session. The contra-lateral limb served as the intra-animal control. The rats were randomly assigned to a diet supplemented with Vitamin E and Vitamin C or normal non-supplemented rat chow. Biomarkers of oxidative stress were measured in the tibialis anterior muscle. Repetitive loading exercise increased maximal isometric force, negative work and positive work in the dorsiflexors of young adult rats. Only positive work increased in the aged animals that were supplemented with Vitamin E and C. Markers of oxidative stress (H(2)O(2), total GSH, GSH/GSSG ratio, malondialdehyde and 8-OHdG) increased in the tibialis anterior muscles from aged and young adult animals with repetitive loading, but Vitamin E and C supplements attenuated this increase. MnSOD activity increased with supplementation in the young adult animals. CuZnSOD and catalase activity increased with supplementation in young adult and aged animals and GPx activity increased with exercise in the non supplemented young adult and aged animals. The increased levels of endogenous antioxidant enzymes after Vitamin E and C supplementation appear to be regulated by post-transcriptional modifications that are affected differently by age, exercise, and supplementation. These data suggest that antioxidant supplementation improves indices of oxidative stress associated with repetitive loading exercise and aging and improves the positive work output of muscles in aged rodents. PMID- 20705129 TI - Screening of nitrosative stress resistance genes in Coxiella burnetii: Involvement of nucleotide excision repair. AB - Coxiella burnetii, an obligate intracellular Gram-negative bacterium, is the etiological agent of Q fever. This work takes advantage of a hypersensitive Escherichia coli genetic system to identify genes involved in resistance to nitrosative stress imposed by reactive nitrogen intermediates. Among the ten candidate genes identified, the transposase, UvrB and DNA topoisomerase IV are involved in DNA transaction; the sigma-32 factor and the putative DNA-binding protein may be involved in transcriptional regulation; IF-2 is involved in protein translation; malate dehydrogenase and carbamoyl-phosphate synthase are metabolic enzymes; and the ABC transporter is a membrane-bound protein. In addition, a hypothetical protein was identified. The role of the DNA repair gene uvrB in resistance to RNI was further confirmed by investigating the sensitivity of uvrB deletion mutant and complementation by C. burnetii uvrB. Deletion of two other components of the UvrABC nuclease, uvrA and uvrC also renders the cell sensitive to RNI. The relationship between UvrABC and nitrosative stress is discussed. PMID- 20705130 TI - Concepts of evolutionary medicine and energy regulation contribute to the etiology of systemic chronic inflammatory diseases. AB - The etiology of chronic inflammatory diseases (CIDs) is usually based on four criteria: (1) genetic susceptibility, (2) complex environmental priming, (3) exaggerated and continuous immune response against harmless self or foreign antigen, and (4) tissue destruction with a continuous wound response without proper healing but with a fibrotic scarring response. These elements do not include the systemic components of CIDs. Due to improved health care with excellent therapies in CIDs, it becomes more and more clear that many systemic responses need to be future targets of therapies. It is suggested that "the systemic response" should be added to the four etiologic criteria that constitute the full picture of CIDs. As shown in the present review, the systemic response becomes comprehensible in the context of evolutionary medicine and energy regulation. Next to the brain and muscles, the immune system is the third major energy consumer in the body. In the context of long-term activation of the immune system during CIDs, the subsequent stimulation of systemic neuroendocrine pathways is necessary to re-allocate energy-rich fuels to the activated immune system. However, re-allocation of energy-rich fuels is the basis of systemic disease sequelae of CIDs, one of which is the metabolic syndrome. It is suggested that Selye's alarm reaction of the 1930s, which is necessary to re-allocate energy-rich fuels to the body, should be called "energy appeal reaction". In CIDs, a continuous energy appeal reaction triggers systemic detrimental consequences for the rest of the body. PMID- 20705132 TI - Modulation of doxorubicin-induced cardiac dysfunction in dominant-negative p38alpha mitogen-activated protein kinase mice. AB - Doxorubicin (Dox) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Increased expression of p38alpha mitogen activated protein kinase (MAPK) promotes cardiomyocyte apoptosis and is associated with cardiac dysfunction induced by prolonged agonist stimulation. However, the role of p38alpha MAPK is not clear in Dox-induced cardiac injury. Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) mice and transgenic mice with cardiac-specific expression of a dominant-negative mutant form of p38alpha MAPK (TG). Left ventricular (LV) fractional shortening and ejection fraction were higher and the expression levels of phospho-p38 MAPK and phospho-MAPK-activated mitogen kinase 2 were significantly suppressed in TG mouse heart compared to WT mice after Dox injection. Production of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3-positive cells, and phospho-p53 expression were decreased in TG mice after Dox injection. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species was significantly less in TG mice compared to WT mice after Dox injection. These findings suggest that p38alpha MAPK may play a role in the regulation of cardiac function, oxidative stress, and inflammatory and apoptotic mediators in the heart after Dox administration. PMID- 20705131 TI - Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. AB - Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential role for immune dysfunction has been suggested in ASD. To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism (DD). Participants were recruited as part of the population based case-control CHARGE (Childhood Autism Risks from Genetics and Environment) study and included: 97 participants with a confirmed diagnosis of ASD using standard assessments (DSM IV criteria and ADOS, ADI-R), 87 confirmed TD controls, and 39 confirmed DD controls. Plasma was isolated and cytokine production was assessed by multiplex LuminexTM analysis. Observations indicate significant increases in plasma levels of a number of cytokines, including IL 1beta, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls (p<0.04). Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD. PMID- 20705133 TI - Development and in vivo bioavailability study of an oral fondaparinux delivery system. AB - Fondaparinux is an agent of choice for the prevention and initial treatment of venous thromboembolism (VTE) as well as myocardial infarction. Nevertheless, as a negatively charged molecule fondaparinux can pass the intestinal epithelial barrier after oral administration only partially. It was therefore the aim of this study to design a highly efficient small-intestinal-targeted oral delivery system for fondaparinux based on thiolated polycarbophil (PCP-Cys) and glutathione (GSH) combined with sodium decanoate. The formulations were tested in vitro with regard to their release, cytotoxicity profiles and their permeation enhancing properties across small-intestinal mucosa. For the in vivo study, rats were treated with a single oral dose of fondaparinux gels or mini-tablets (5mg/kg) and the subcutaneous and intravenous groups with a dose of 200MUg/kg fondaparinux. The anti-factor Xa activity in the plasma was measured. In the presence of PCP-Cys/GSH/sodium decanoate the uptake of fondaparinux from the intestinal mucosa was 4.1-fold improved. The area under concentration-time curve in rat plasma from 0 to 24h with PCP-Cys/GSH/sodium decanoate gel was 135.3MUgmin/ml and 1.3-fold improved with the tablets. C(max) value of mini tablets was 0.23MUg/ml and the absolute bioavailability of 4.4% was 6.2-fold improved, while the control solution was not absorbed orally. PCP-Cys/GSH/sodium decanoate demonstrated potential for increasing the oral bioavailability of the indirect factor Xa inhibitor as an alternative to currently used subcutaneous delivery. PMID- 20705134 TI - The disintegrin and metalloprotease Meltrin from Drosophila forms oligomers via its protein binding domain and is regulated by the homeobox protein VND during embryonic development. AB - A Disintegrin And Metalloprotease (ADAM) proteins belong to the metzincin superfamily of metalloproteases that are known to play important roles in several physiological and developmental processes including myoblast fusion, tumor necrosis factor-alpha release or fertilization. They are characterized by a typical domain structure with a proteolytically active domain and the protein binding domains both facing the extracellular space. Regulatory mechanisms are largely unknown. Here we report on the potential of the Drosophila ADAM Meltrin to form oligomers via its substrate binding domain. Significantly, oligomerization occurs apparently in a redox-dependent manner. Further analysis revealed that the ACR domain is responsible for aggregation while the disintegrin like and EGF-like domains are not capable of oligomer formation. Stage dependent transcript analysis revealed a constant expression of three different splice variants, two of which were characterized by sequencing. Like many other ADAM proteins, Meltrin shows a highly restricted expression pattern during embryogenesis with at least two of the respective transcripts being present in a subpopulation of neuronal cells in the embryonic central nervous system. Finally, we report on the identification of the first regulator of meltrin: the homeobox protein ventral nervous system defective specifically excludes Meltrin expression from the embryonic ventral neuroectoderm. PMID- 20705135 TI - Sugar transporter genes of the brown planthopper, Nilaparvata lugens: A facilitated glucose/fructose transporter. AB - The brown planthopper (BPH), Nilaparvata lugens, attacks rice plants and feeds on their phloem sap, which contains large amounts of sugars. The main sugar component of phloem sap is sucrose, a disaccharide composed of glucose and fructose. Sugars appear to be incorporated into the planthopper body by sugar transporters in the midgut. A total of 93 expressed sequence tags (ESTs) for putative sugar transporters were obtained from a BPH EST database, and 18 putative sugar transporter genes (Nlst1-18) were identified. The most abundantly expressed of these genes was Nlst1. This gene has previously been identified in the BPH as the glucose transporter gene NlHT1, which belongs to the major facilitator superfamily. Nlst1, 4, 6, 9, 12, 16, and 18 were highly expressed in the midgut, and Nlst2, 7, 8, 10, 15, 17, and 18 were highly expressed during the embryonic stages. Functional analyses were performed using Xenopus oocytes expressing NlST1 or 6. This showed that NlST6 is a facilitative glucose/fructose transporter that mediates sugar uptake from rice phloem sap in the BPH midgut in a manner similar to NlST1. PMID- 20705136 TI - Opposing and synergistic effects of cyclic mechanical stretch and alpha- or beta adrenergic stimulation on the cardiac gap junction protein Cx43. AB - In the heart the most prominent cardiac gap junction protein is connexin43 (Cx43). Increased Cx43 expression has been identified in cardiac hypertrophy and may contribute to arrhythmias. Besides acute effects on gap junction channel function, chronic regulation of Cx43 expression can affect intercellular communication. Since both cyclic mechanical stretch (CMS) and catecholamines play an important role in cardiac physiology and pathophysiology, we wanted to elucidate whether a prolonged beta- or alpha-adrenoceptor stimulation may modulate the effects of CMS on Cx43 expression. Neonatal rat cardiomyocytes were cultured on flexible 6-well plates. Thereafter, cells were kept static without any treatment or stimulated with 0.1MUmol/L isoprenaline or phenylephrine for 24h without or with additional CMS (1Hz; 10% elongation). Isoprenaline and phenylephrine given alone significantly increased Cx43-protein and -mRNA level. Also CMS resulted in a significant Cx43-protein and -mRNA up-regulation. The combined treatment of the cells with either isoprenaline or phenylephrine and stretch also resulted in an up-regulation of Cx43-protein and -mRNA, which did not exceed those of stretch, isoprenaline or phenylephrine alone. However, while CMS reduced the Cx43-protein/mRNA ratio, adrenergic stimulation increased Cx43 protein/mRNA ratio. While isoprenaline and phenylephrine increased Cx43 phosphorylation, additional CMS significantly reduced P-Cx43/Cx43 ratio. For further investigation of the underlying signal transduction pathway, we examined the phosphorylated forms of ERK1/2, GSK3beta and AKT and could demonstrate that these protein kinases are also significantly up-regulated following stretch or adrenoceptor stimulation. Again the combined treatment of cardiomyocytes with CMS and isoprenaline or phenylephrine had no additive effects. Thus, the combination of alpha- or beta-adrenoceptor stimulation and CMS up-regulates Cx43 expression and leads to phosphorylation of ERK1/2 and AKT (=activation) and of GSK3beta (=inactivation). There were no significant additive effects compared to CMS or adrenergic stimulation alone indicating a possible ceiling effect. However, CMS and adrenergic stimulation differentially affected Cx43-protein/mRNA ratio and Cx43-phosphorylation. PMID- 20705137 TI - Differential zinc accumulation and expression of human zinc transporter 1 (hZIP1) in prostate glands. AB - Zinc (Zn) is essential for a very large number and variety of cellular functions but is also potentially toxic. Zn homeostasis is therefore dynamically maintained by a variety of transporters and other proteins distributed in distinct cellular and subcellular compartments. Zn transport is mediated by two major protein families: the Zip family, which mediates Zn influx, and the ZnTs which are primarily linked to Zn sequestration into intracellular compartments and are, thereby, involved in lowering cytoplasmic Zn free ion concentrations. In the prostate epithelial cell, the accumulation of high cellular zinc is a specialized function that is necessary for these cells to carry out the major physiological functions of production and secretion of prostatic fluids. The loss of Zn accumulation is the most consistent and persistent characteristic of prostate malignancy. Currently, there are no direct methods to determine the relative Zn levels in various cell types of prostate gland (i.e. stroma, glandular epithelia, acini, and muscular) and no reliable ways to compare the Zn in normal versus malignant areas of the gland. Here we report a new method to show a differential Zn staining method that correlates with various stages of prostate cancer development in situ and expression of a human Zn transporter1-hZIP1 -in situ by in situ reverse transcriptase-polymerase chain reaction hybridization (ISRTPCR) that correlate with the relative Zn levels determined by the differential Zn staining method. By utilizing these methods, we show for the first time that: (1) the relative Zn levels are very low to absent in the malignant glands, (2) normal glands show high Zn levels in both glandular epithelia as well as in stromal tissues, (3) the Zn levels begin to decrease in pre-malignant glands and precedes the development of malignancy, and (4) the expression of human Zn transporter1 (hZIP1) appears to correlate with the Zn levels in the prostate glands and may be the major Zn regulator in this organ. PMID- 20705138 TI - Conditional RNAi in mice. AB - RNA interference (RNAi)-mediated gene knockdown has developed into a routine method to assess gene function in cultured mammalian cells in a fast and easy manner. For the use of RNAi in mice, short hairpin (sh) RNAs expressed stably from the genome are a fast alternative to conventional knockout approaches. We developed a strategy for complete or conditional gene knockdown in mice, where the Cre/loxP system is used to activate RNAi in a time and tissue dependent manner. Alternatively doxycycline controlled shRNA expression vectors can be used for conditional gene silencing. Single copy RNAi constructs are placed into the Rosa26 locus of ES cells by recombinase mediated cassette exchange and transmitted through the germline of chimeric mice. The shRNA transgenic offspring can be either directly used for phenotypic analysis or are further crossed to a Cre transgenic strain to activate conditional shRNA vectors. The site specific insertion of single copy shRNA vectors allows the expedite and reproducible production of knockdown mice and provides an easy and fast approach to assess gene function in vivo. PMID- 20705139 TI - A systems approach to analyze transcription factors in mammalian cells. AB - Transcription factors (TFs) play a central role in the development of multicellular organisms. The sequential actions of critical TFs direct cells to adopt defined differentiation pathways leading to functional, fully differentiated tissues. Here, we describe a generic experimental pipeline that integrates biochemistry, genetics and next generation sequencing with bioinformatics to characterize TF complexes composition, function and target genes at a genome-wide scale. We show an application of this experimental pipeline which aims to unravel the molecular events taking place during hematopoietic cell differentiation. PMID- 20705140 TI - Zernike phase contrast cryo-electron tomography of sodium-driven flagellar hook basal bodies from Vibrio alginolyticus. AB - Vibrio alginolyticus use flagella to swim. A flagellum consists of a filament, hook and basal body. The basal body is made up of a rod and several ring structures. This study investigates the structure of the T ring which is a unique component of the V. alginolyticus sodium ion-driven flagellar basal body. Using Zernike phase contrast (ZPC) cryo-electron tomography, we compared the 3D structures of purified hook-basal bodies (HBB) from a wild-type strain (KK148) and a deletion mutant lacking MotX and MotY (TH3), which are thought to form the T ring. ZPC images of HBBs had highly improved signal-to-noise ratio compared to conventional phase contrast images. We observed the outline of the HBBs from strains KK148 and TH3, and the TH3 mutant was missing its T ring. In the wild type strain, the T ring was beneath the LP ring and seemed to form a ring shape with diameter of 32 nm. PMID- 20705141 TI - The interstitial crystal-nucleating sheet in molluscan Haliotis rufescens shell: a bio-polymeric composite. AB - The interstitial green sheets in abalone shell nacre are shown to be bifacially differentiated trilaminate polymeric complexes, with glycoprotein layers sandwiching a central core containing chitin. They share some common feature with the organic matrix layers between the aragonite tablets in the nacre and the periostracum, and show similarities to the myostracum. Thus, although the green sheet is reported to be unique to the abalone shell, it represents an interesting model for the study of molluscan shell biomineralization processes. Indeed, during shell formation, prismatic and spherulitic aragonite precedes and follows the deposition of the interstitial green polymeric composite sheets, and there is evidence to suggest that these sheets demark the interruption of nacre synthesis and serve to nucleate the resumption of calcium carbonate crystal growth. The green polymeric interstitial sheet purified from the abalone shell was investigated by spectroscopic and imaging techniques: FTIR, confocal microscopy, scanning and transmission electron microscopy, and by pyrolysis combined with GC MS. Structural and compositional differences are observed between the surfaces of the two sides of the interstitial polymeric composite sheets. Moreover, comparative crystallization experiments on the green sheet sides also reveal asymmetry with respect to the nucleation of calcium carbonate. These findings suggest that these bifacially differentiated interstitial composites may play an active role in the mineral assembly processes, with one of the surfaces acting as a crystal nucleator. PMID- 20705142 TI - Differential effects of the APOE genotype on brain function across the lifespan. AB - Increasing age and carrying an APOE epsilon4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in epsilon4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy epsilon4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 epsilon4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 epsilon4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and epsilon4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older epsilon4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young epsilon4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of epsilon4-carriers to late-life pathology or cognitive decline. PMID- 20705143 TI - Visualization of early infarction in rat brain after ischemia using a translocator protein (18 kDa) PET ligand [11C]DAC with ultra-high specific activity. AB - The aim of this study was to visualize early infarction in the rat brain after ischemia using a translocator protein (TSPO) (18 kDa) PET ligand [(11)C]DAC with ultra-high specific activity (SA) of 3670-4450 GBq/MUmol. An infarction model of rat brain was prepared by ischemic surgery and evaluated 2 days after ischemia using small-animal PET and in vitro autoradiography. Early infarction with a small increase of TSPO expression in the brain was visualized using PET with high SA [(11)C]DAC (average 4060 GBq/MUmol), but was not distinguished clearly with usually reported SA [(11)C]DAC (37 GBq/MUmol). Infarction in the rat brain 4 days after ischemia was visualized using high and usually reported SAs [(11)C]DAC. Displacement experiments with unlabeled TSPO-selective AC-5216 or PK11195 diminished the difference in radioactivity between ipsilateral and contralateral sides, confirming that the increased uptake on the infracted brain was specific to TSPO. In vitro autoradiography with high SA [(11)C]DAC showed that the TSPO expression increased on early infarction in the rat brain. High SA [(11)C]DAC is a useful and sensitive biomarker for the visualization of early infarction and the characterization of TSPO expression which was slightly elevated in the infarcted brain using PET. PMID- 20705144 TI - Increasing taxon sampling using both unidentified environmental sequences and identified cultures improves phylogenetic inference in the Prorodontida (Ciliophora, Prostomatea). AB - Taxon sampling for molecular phylogenetic inferences of microbial eukaryotes is limited because of the difficulties in finding specific taxa and culturing them. By contrast, unidentified sequences are easily collected during environmental diversity surveys. Here taxon sampling within prorodontid ciliates is increased using identified cultured isolates, and complemented with unidentified environmental sequences, with the nuclear small subunit rDNA locus. With identified cultured isolates there is support for the morphologically circumscribed Colepidae. Increasing taxon sampling with unidentified environmental sequences is shown to change both topology and node support in clades that have low sampling for identified cultured isolates. This approach to increasing taxon sampling using unidentified environmental sequences can be used in other ciliate clades in which there is also low taxon sampling. PMID- 20705145 TI - A molecular phylogeny of the pan-tropical pond skater genus Limnogonus Stal 1868 (Hemiptera-Heteroptera: Gerromorpha-Gerridae). AB - We investigated phylogenetic relationships among pond skaters (Heteroptera: Gerridae) of the genus Limnogonus Stal 1868 by performing separate and combined parsimony analyses of DNA sequences from three mitochondrial (COI+II, 16SrRNA) and one nuclear (28SrRNA) gene(s). The taxon sample represented almost two thirds of the known diversity, and with most taxa represented by two or more individuals. A simultaneous analysis of all data showed that L. luctuosus Montrousier 1865 was paraphyletic and suggests that "L. luctuosus" from Australia and possibly also a population from the Society Islands (Moorea) each represents unrecognized species. L. fossarum F. 1775 was strongly supported, but the two subspecies L. f. fossarum F. 1775 and L. f. gilguy Andersen and Weir 1997 were paraphyletic. The two currently recognized subgenera Limnogonus (s. str.) Stal 1868 and L. (Limnogonoides)Andersen 1975 were paraphyletic, and were accordingly broken up in several monophyletic groups, each containing one or more species. From Limnogonus (s. str.) we delimited five clades: I (comprising L. aduncus Drake & Harris 1933, L. recens Drake and Harris 1934, L. profugus Drake & Harris 1930 and L. ignotus Drake and Harris 1934, all from the Neotropical Region), II (comprising L. nitidus Mayr 1865 from the Oriental Region), III (comprising L. franciscanus (Stal 1859) from the New World and L. cereiventris (Signoret 1862) from the Afrotropical Region), IV (comprising L. hungerfordi Andersen 1975 and L. luctuosus Montrousier 1865 from the Oriental and Australasian Regions) and V (comprising L. fossarum F. 1775 from the Oriental and Australasian Regions). From L. (Limnogonoides) we delimited two clades: VI (comprising L. intermedius Poisson 1941 from the Afrotropical Region and L. pectoralis (Mayr 1865) from the Oriental Region) and VII (comprising L. hypoleucus (Gerstaecker 1873), L. nigrescens Poisson 1941, L. poissoni Andersen 1975, and L. capensis China 1925 from the Afrotropical Region). Finally, L. (s. str.) windi Hungerford & Matsuda 1961 from Australia was placed as sister to clades I-VI. A manual optimization of geographical distribution onto the strict consensus tree suggests that Limnogonus is primarily an Old World group with independent transitions to the New World in L. franciscanus and in the common ancestor of Clade I. PMID- 20705146 TI - Genes and environment: multiple pathways to psychopathology. PMID- 20705148 TI - Happy anniversary mifepristone: a decade of promise and challenges. PMID- 20705147 TI - Assessment of the neuropeptide S system in anxiety disorders. AB - BACKGROUND: The G protein-coupled receptor neuropeptide S receptor 1 (NPSR1) and its ligand neuropeptide S (NPS) form a signaling system mainly implicated in susceptibility to asthma and inflammatory disorders in humans and regulation of anxiety and arousal in rodents. We addressed here the role of NPS and NPSR1 as susceptibility genes for human anxiety disorders. METHODS: We performed comprehensive association analysis of genetic variants in NPS and NPSR1 in three independent study samples. We first studied a population-based sample (Health 2000, Finland) of 321 anxiety disorder patients and 1317 control subjects and subsequently a Spanish clinical panic disorder sample consisting of 188 cases and 315 control subjects. In addition, we examined a birth cohort of 2020 children (Barn Allergi Miljo Stockholm Epidemiologi [BAMSE], Sweden). We then tested whether alleles of the most significantly associated single nucleotide polymorphisms alter DNA-protein complex formation in electrophoretic mobility shift assays. Finally, we compared acute stress responses on the gene expression level in wild-type and Npsr1(-/-) mice. RESULTS: We confirmed previously observed epidemiological association between anxiety and asthma in two population-based cohorts. Single nucleotide polymorphisms within NPS and NPSR1 associated with panic disorder diagnosis in the Finnish and Spanish samples and with parent reported anxiety/depression in the BAMSE sample. Moreover, some of the implicated single nucleotide polymorphisms potentially affect transcription factor binding. Expression of neurotrophin-3, a neurotrophic factor connected to stress and panic reaction, was significantly downregulated in brain regions of stressed Npsr1(-/-) mice, whereas interleukin-1 beta, an active stress-related immunotransmitter, was upregulated. CONCLUSIONS: Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety. PMID- 20705149 TI - Factors affecting mortality in a large cohort study with special reference to oral contraceptive use. AB - BACKGROUND: This analysis updates mortality in the Oxford-Family Planning Association (Oxford-FPA) contraceptive study, with emphasis on oral contraceptive (OC) use. STUDY DESIGN: The Oxford-FPA study includes 17,032 women recruited from 1968-1974 at contraceptive clinics, aged 25-39 years, using OCs a diaphragm or an intrauterine device. Follow-up has been to March 2009; by then, 1715 women had died. RESULTS: The rate ratio (RR) for overall mortality was 0.87 (CI 0.79-0.96), comparing ever-users of OCs with never-users. The RR for fatal cervical cancer was increased (7.3), but the CIs were very wide (1.2-305). There was no association between ever-use of OCs and mortality from breast cancer (RR 1.0, CI 0.8-1.2), nor was fatal breast cancer related to duration of OC use. OC use strongly protected against death from other uterine cancer and ovarian cancer; RRs for ever-use of OCs were 0.3 (CI 0.1-0.8) and 0.4 (CI 0.3-0.6), respectively. Protection increased with duration of OC use and persisted more than 20 years after cessation. Circulatory disease mortality was not increased, the RR for ever use of OCs being 0.9 (CI 0.7-1.1). The overall mortality RR for all women smoking 15+ cigarettes daily was 2.25 (CI 1.99-2.53) and, for all women with a body mass index of 28+ kg/m(2), was 1.33 (CI 1.07-1.64). CONCLUSIONS: Long-term follow-up strongly suggests that OC use slightly reduces all cause mortality. PMID- 20705150 TI - Contraceptive sterilization use among married men in the United States: results from the male sample of the National Survey of Family Growth. AB - BACKGROUND: Surgical sterilization has many advantages. Previous information on prevalence and correlates was based on surveys of women. STUDY DESIGN: We estimated the prevalence of vasectomy and tubal ligation of partners for male participants in the 2002 National Survey of Family Growth, a nationally representative survey of US residents aged 15-44 years. We identified factors associated with sterilizations using bivariate and multivariate techniques. RESULTS: The findings revealed that 13.3% of married men reported having had a vasectomy and 13.8% reported tubal sterilization in their partners. Vasectomy increased with older age and greater number of biological children, non-Hispanic white ethnicity, having ever gone to a family planning clinic. Tubal sterilization use was more likely among men who had not attended college, those of older age and those with live births. DISCUSSION: One in eight married men reported having vasectomies. Men who rely on vasectomies have a somewhat different profile than those whose partners have had tubal sterilizations. PMID- 20705151 TI - Sex education and contraceptive use at coital debut in the United States: results from Cycle 6 of the National Survey of Family Growth. AB - BACKGROUND: The study was conducted to characterize the relationship between formal sex education and the use and type of contraceptive method used at coital debut among female adolescents. METHODS: This study employed a cross-sectional, nationally representative database (2002 National Survey of Family Growth). Contraceptive use and type used were compared among sex education groups [abstinence only (AO), birth control methods only (MO) and comprehensive (AM)]. Analyses also evaluated the association between demographic, socioeconomic, behavioral variables and sex education. Multiple logistic regression with adjustment for sampling design was used to measure associations of interest. RESULTS: Of 1150 adolescent females aged 15-19 years, 91% reported formal sex education (AO 20.4%, MO 4.9%, AM 65.1%). The overall use of contraception at coitarche did not differ between groups. Compared to the AO and AM groups, the proportion who used a reliable method in the MO group (37%) was significantly higher (p=.03) (vs. 15.8% and 14.8%, respectively). CONCLUSIONS: Data from the 2002 NSFG do not support an association between type of formal sex education and contraceptive use at coitarche but do support an association between abstinence only messaging and decreased reliable contraceptive method use at coitarche. PMID- 20705152 TI - Clinician satisfaction and insertion characteristics of a new applicator to insert radiopaque Implanon: an open-label, noncontrolled, multicenter trial. AB - BACKGROUND: The etonogestrel (ENG) implant Implanon is a progestin-only contraceptive that provides effective contraception for up to 3 years. A new radiopaque ENG implant has been developed to extend the diagnostic modalities of Implanon and a next-generation applicator (NGA) was designed to facilitate correct subdermal insertion of Implanon. STUDY DESIGN: In this open-label study, 23 investigators, experienced and inexperienced with Implanon, performed 301 insertions of the new radiopaque implant using the NGA. Primary outcome measurements were obtained from clinician satisfaction questionnaires completed after the 4th, 8th and 12th insertions. Additionally, insertion characteristics and X-ray visibility were assessed. RESULTS: Almost all investigators were satisfied with the NGA from the first insertion onward, and all were satisfied or very satisfied after 12 insertions. The most frequently reported advantages included ease of use, one-handed action and fast insertion time; 2% of insertions were considered difficult in skin puncturing and/or sliding the needle subdermally. Three incorrect insertions occurred due to noncompliance with instructions. All assessed implants were visible on plain X-ray imaging. CONCLUSIONS: The NGA was well accepted by investigators with or without prior experience with Implanon. The results stressed the importance of correctly following implant insertion instructions. PMID- 20705153 TI - Vaginal estrogen supplementation during Depo-Provera initiation: a randomized controlled trial. AB - BACKGROUND: Irregular bleeding is often cited as the reason for discontinuation of depot-medroxyprogesterone acetate (DMPA) after the first injection. Estrogen supplementation during DMPA initiation may decrease bleeding and improve continuation. STUDY DESIGN: This prospective, randomized, controlled trial evaluated estrogen supplementation during DMPA initiation. Women initiating DMPA were randomized to receive an estradiol vaginal ring for 3 months versus DMPA alone. Bleeding diaries and questionnaires at three and 6 months assessed bleeding, continuation and ring acceptability. RESULTS: Seventy-one participants enrolled; 49 completed the first follow-up period. The median number of bleeding or spotting days was 16 in the estrogen ring group (n=26) versus 28 in the DMPA alone group (n=23) (p=.19). Seventy-seven percent of the intervention group received a second injection compared with 70% in the DMPA alone group (p=.56). For each additional day of bleeding and/or spotting reported, women were 3% less likely to receive a second injection (OR 0.97, 95% CI 0.94-0.99). Acceptability of the vaginal ring was high among those in the intervention group. CONCLUSIONS: Vaginal estrogen supplementation during DMPA initiation is acceptable to women and may decrease total bleeding. PMID- 20705154 TI - Etonogestrel implant in postpartum adolescents: bleeding pattern, efficacy and discontinuation rate. AB - BACKGROUND: The increasing rate of teenage pregnancies is a challenge to health professionals. New contraceptive methods have been developed to try to improve adherence in this group of patients. The study was conducted to evaluate the bleeding pattern, efficacy and discontinuation rate of etonogestrel implant (68 mg) inserted in postpartum adolescents. STUDY DESIGN: The study population comprised 44 postpartum adolescents managed at the Family Planning Sector of Sao Paulo Federal University. The implant was inserted, on average, 102 days after delivery. Patients were followed prospectively during four 90-day periods. RESULTS: All 44 patients completed the 12 months of follow-up, resulting in a study discontinuation rate of 0%. No implants were removed. There were no pregnancies during the study. After 1 year of use, frequent and prolonged bleeding were reported by less than 5% of the patients and amenorrhea occurred in 38.6% of the users. Laboratory parameters indicated a significant increase in hemoglobin and hematocrit among users. CONCLUSION: These findings suggest that the etonogestrel implant is a safe and effective contraceptive method that is well accepted by adolescents after a pregnancy. PMID- 20705155 TI - Post abortion contraception and its effect on repeat abortions in Auckland, New Zealand. AB - BACKGROUND: Many misconceptions still prevail about the appropriateness of use of the intrauterine device (IUD), particularly for younger women. This study examines the factors associated with post abortion IUD use as compared to the combined oral contraceptive pill (COC). It then examines the effect of type of post abortion contraception with the likelihood of seeking subsequent abortions. STUDY DESIGN: This prospective cohort study followed, for a period of 3 years, 1422 women who had a first trimester surgical abortion between November 2004 and January 2005 in Auckland's public abortion clinic. RESULTS: Compared to women who left the clinic with COC, those leaving with an IUD (OR 0.3) at baseline were less likely to return for a subsequent abortion. Among women who had not had a previous termination, younger women were less likely than older women to have had an IUD inserted post abortion. With every additional live birth, women were three times as likely to have left the abortion clinic with an IUD. Among women who had had a previous termination, age was no longer significantly associated with post abortion IUD insertion. However, parity was still significantly associated, as was having a negative sexually transmitted infection test. CONCLUSIONS: Young and nulliparous women are less likely to use an IUD as a method of contraception following an abortion. However, those women who have an IUD inserted following an abortion are much less likely to return for a subsequent abortion. IUDs are a safe and effective method of contraception that are currently still underused among the younger population. PMID- 20705156 TI - Comparison of two dose regimens of misoprostol for second-trimester pregnancy termination. AB - OBJECTIVE: The study was conducted to compare the efficacy of two different dose regimens of misoprostol administered vaginally in combination with mifepristone for second trimester termination of viable and non-viable pregnancies. DESIGN: Double-blind randomized controlled trial conducted at the University hospital in the Netherlands. One hundred seventy-six women between 14 and 24 weeks gestation with an intrauterine fetal death (n=31), congenital or genetic abnormalities of the fetus (n=116) or requesting a termination of pregnancy for psychosocial reasons (n=29) were studied. Randomization was into one of two groups. Both groups ingested mifepristone 200 mg. Depending on the randomization group, this was followed by either 200 or 400 mcg misoprostol given vaginally beginning 36-48 h later at 4-h intervals (with a maximum of 10 administrations in 48 h) until the fetus was delivered. Randomization, administration of the medication and assessment of the outcome was performed independently from the investigators. Main outcome measures were expulsion rate and the number of incomplete abortions warranting surgical evacuation of retained products of conception. Secondary outcome measures consisted of the time between the first administration of misoprostol to the delivery of the fetus, side-effects, blood loss, live births and changes in hemoglobin level. RESULTS: In the 200-mcg misoprostol group, 66% (57/86) had a complete expulsion of fetus and placenta compared to 73% (66/90) in the 400-mcg group (p=NS). The time between the first administration of misoprostol and delivery of the fetus was significantly longer in the misoprostol 200-mcg group: mean 11.6 h (range: 9.7-13.5 h) versus 9.3 h (range: 8.1-10.5 h) in the 400-mcg group (p=.042). No significant differences between the groups were found for frequency of side-effects like nausea, retching, vomiting, fever, headaches and diarrhea. Blood loss was similar in both groups with a mean of 337 mL in the 200 mcg misoprostol and 296 mL in the 400-mcg misoprostol group (p=NS). Of the women with a viable pregnancy at the beginning of the trial, 18.6% (13/70) in the 200 mcg misoprostol group delivered a live fetus compared to 22.8% (17/75) in the 400 mcg misoprostol group (p=NS). CONCLUSIONS: Both regimens used in this trial proved to be equally effective for termination of both viable and non viable pregnancies during the second trimester. The time between the first administration of misoprostol and delivery of the fetus was significantly longer in the 200-mcg group than in the 400-mcg group. This outcome may be used as the rationale for choosing a 400 mcg misoprostol regimen for termination of pregnancy during the second trimester. PMID- 20705157 TI - Effect of oral contraceptives on markers of hyperandrogenism and SHBG in women with polycystic ovary syndrome. AB - BACKGROUND: This randomized study's aim was to compare the effect of four oral contraceptives (OCs) containing 30 mcg of ethinylestradiol (EE) and different progestogens [drospirenone, (DRSP), chlormadinone acetate (CMA), desogestrel (DSG), gestodene (GSD)] on biochemical and hormonal parameters of hyperandrogenism and sex hormone-binding globulin (SHBG) in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Forty women with PCOS (age 16-35 years) were recruited and randomly assigned to one of four treatment groups of 10 women each, treated, respectively, with 3 mg DRSP/30 mcg EE (Yasmin, Bayer Shering), 2 mg CMA/30 mcg EE (Belara, Grunenthal), 75 mcg GSD/30 mcg EE (Minulet, Wyeth Lederle) and 150 mcg DSG/30 mcg EE (Practil 21, Organon Italia). Blood samples were obtained on day 6-8 of the control cycle and day 6-8 of the third treatment cycle for assay of the following hormones: androsteredione (A), total testosterone (T), free T, SHBG, dehydroepiandrosterone sulphate (DHEAS). RESULTS: In all groups, mean concentrations of free T, total T and A dropped by 40-60%, and concentrations of DHEAS dropped by 20-50%. Formulations with DRSP and CMA caused a greater reduction of androgens and a progressive increase in serum concentrations of SHBG than those with DSG and GSD. CONCLUSIONS: Clinical studies need to be performed to determine effects of these OCs upon clinical signs of hyperandrogenism. PMID- 20705158 TI - The effect of patient gynecologic history on clinician contraceptive counseling. AB - BACKGROUND: Contraceptive providers have an important influence on women's selection of contraception. Previous studies suggest that clinicians inappropriately limit use of intrauterine contraception (IUC). This study investigated the influence of patients' gynecologic histories on recommendations for IUC and other methods of contraception. STUDY DESIGN: Videos of standardized patients varying by history of pelvic inflammatory disease (PID) and parity were shown to clinicians at meetings of national medical societies. Participants indicated their contraceptive recommendations for the patient and whether they would have concerns were the patient to use IUC. RESULTS: Five hundred twenty four providers viewed one video of a standardized patient and completed the survey. Gynecologic history was significantly associated with recommendations for the contraceptive ring, contraceptive patch, and copper IUC. Many clinicians indicated that they had concerns about the use of IUC with respect to risks such as PID, infertility and ectopic pregnancy. Concerns about infertility and pain with use of IUC were related to gynecologic history. CONCLUSIONS: Patient gynecologic characteristics affect recommendations for some reversible contraceptive methods. Clinicians continue to have concerns about IUC use despite evidence supporting its safety. PMID- 20705159 TI - Complication rates and utility of intravenous access for surgical abortion procedures from 12 to 18 weeks of gestation. AB - BACKGROUND: The study was conducted to compare need for intravenous (IV) access and the immediate complication rate in women having an outpatient surgical abortion at 12-1/7 to 15-6/7 weeks gestation (12-15+ weeks) versus 16-0/7 to 18 0/7 weeks of gestation (16-18 weeks). STUDY DESIGN: This retrospective cohort study included 1503 women who underwent a surgical abortion (dilation and curettage or dilation and evacuation) in a free-standing outpatient clinic from April 1, 2001, to April 1, 2008. The primary outcome was IV access used for fluids or emergent medications. RESULTS: Of the procedures, 1216 (81%) were at 12 15+ weeks and 287 (19%) were 16-18 weeks. The incidence of immediate complications that could require IV access was 1.1% and 3.8%, respectively (p=.001). However, most were cervical lacerations that did not require IV fluids or treatments. Major immediate complications (uterine perforation or hospital transfer) occurred in 0.3% and 0.7%, respectively (p=.32). Overall, there were 7 (0.5%, 95% CI 0.1-0.8%) women who required access because of a complication. There were no cases for which IV access was needed emergently and was unable to be obtained. CONCLUSIONS: IV access is rarely medically needed due to an immediate complication from surgical abortion at 12 to 18 weeks gestation. Major complication rates for such procedures are very low. Routine use of IV access at 16-18 weeks solely because of gestational age is not warranted. PMID- 20705160 TI - Vaginal swab specimen processing methods influence performance of rapid semen detection tests: a cautionary tale. AB - BACKGROUND: Detection of semen biomarkers in vaginal fluid can be used to assess women's recent exposure to semen. Quantitative tests for detection of prostate specific antigen (PSA) perform well, but are expensive and require specialized equipment. We assessed two rapid immunochromatographic strip tests for identification of semen in vaginal swabs. STUDY DESIGN: We tested 581 vaginal swabs collected from 492 women. Vaginal secretions were eluted into saline, and PSA was measured using the quantitative IMx (Abbott Laboratories, Abbott Park, IL, USA) assay. Specimens were also tested using the ABAcard p30 test (Abacus Diagnostics, West Hills, CA, USA) for detection of PSA and RSID-Semen test (Independent Forensics, Hillside, IL, USA) for detection of semenogelin (Sg). RESULTS: Vaginal swab extraction using saline was compatible with direct assessment of vaginal swab eluates using ABAcard for PSA detection, but not for Sg detection using RSID. The rapid PSA test detected 91% of specimens containing semen compared to 74% by the rapid Sg test. CONCLUSION: Investigators are urged to optimize vaginal swab specimen preparation methods for performance of RSID or other tests to detect semen components other than PSA. Previously described methods for PSA testing are not uniformly applicable to other tests. PMID- 20705161 TI - Reduced community access to a key contraceptive: public health consequence from false suspicion of HIV-contaminated injectables. AB - BACKGROUND: This study was conducted to investigate a report of positive test results with DMPA on an HIV rapid test. Suspecting HIV contamination, the Zambian Ministry of Health initiated a product withdrawal pending full evaluation. STUDY DESIGN: DMPA was evaluated for compliance to product specifications. Contamination with HIV and blood components was investigated with PCR and human IgG ELISA. The performance of Genie II, Unigold and Determine HIV rapid tests was evaluated using DMPA. RESULTS: DMPA was found compliant with product specifications and negative for HIV and human IgG. DMPA impaired the performance of HIV rapid tests resulting in false-positive/indeterminant results. Rapid test results using polysorbate 80 (formulation component of DMPA) mimicked results obtained with DMPA. CONCLUSIONS: The DMPA sample was negative for HIV and human IgG. Formulation components may have led to the interpretation of false-positive results, reinforcing the need to validate the sample type used in any test. DMPA use was reinstated in Zambia, minimizing the public health impact that resulted from the initial rapid test results. PMID- 20705162 TI - Levonorgestrel inhibits proliferation and induces apoptosis in uterine leiomyoma cells. AB - BACKGROUND: The levonorgestrel intrauterine system (LNG-IUS) is a widely recognized intrauterine anti-fertility system, which can alleviate symptoms of uterine leiomyoma. This study aims to evaluate leimyoma cell growth inhibition induced by high concentrations of LNG. STUDY DESIGN: After treatment with LNG, the growth rate of the cultured primary uterine leiomyoma cells was studied with methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis rate was determined by morphological changes and flow cytometry. Reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were performed to measure the differential mRNA and protein expression levels. RESULTS: The proliferation rate of uterine leiomyoma cells was suppressed after treatment with LNG at a minimum concentration of 10 mcg/mL. The inhibitive effect was positively correlated with the LNG concentration and with the incubation time. Flow cytometry showed that the apoptosis rate was increased with the LNG concentration. The mRNA levels of IGF-1, Bcl-2 and survivin were down-regulated significantly after treatment with 10 mcg/mL LNG. Western blot analysis confirmed that the expression of Bcl-2 and survivin was decreased significantly, and the p38 phosphorylation level was increased and caspase 3 was activated remarkably 72 h after treatment with 10 and 20 mcg/mL LNG. CONCLUSIONS: This study demonstrated that LNG may suppress the proliferation and induce apoptosis of the uterine leiomyoma cells. PMID- 20705163 TI - Cardiac CT. Preface. PMID- 20705164 TI - Cardiac computed tomography technology and dose-reduction strategies. AB - Coronary computed tomography angiography (CCTA) has become an important tool in the assessment of coronary artery disease. It is considered an appropriate test for several indications, including the evaluation of symptomatic patients with low to intermediate probability of obstructive coronary disease. Since its first applications in 1999 using 4-slice CT there have been numerous technological advancements, enabling excellent submillimeter spatial resolution and significant improvements in temporal resolution. This article reviews these advancements in CT technology and the current status and recent developments in cardiac CT with regards to spatial, temporal and contrast resolution and z-axis (volume) coverage. The article also describes the many techniques and new technologies available for dose reduction in cardiac CT. PMID- 20705165 TI - Patient preparation and scanning techniques. AB - Cardiac computed tomographic angiography (CCTA) is a unique diagnostic modality that can provide a comprehensive assessment of cardiac anatomy. Rapid advances in scanner and software technology have resulted in the ability to noninvasively image the coronary arteries. However, careful patient preparation and scanning technique is required to ensure optimal image quality while minimizing radiation dose delivered. Important components of patient preparation include knowledge of the indications and contraindications for CCTA, patient screening, patient premedication, patient positioning, prescan instruction, and electrocardiograph lead placement. Scanning technique should be determined on a patient by patient basis and tailored according to age and radiation risk, body mass index and chest circumference, heart rate and variability, presence of stents, and coronary calcification. PMID- 20705166 TI - Postprocessing techniques for cardiac computed tomographic angiography. AB - Careful protocol design is essential to successfully perform coronary computed tomographic (CT) angiography, from patient preparation, to gating, to contrast infusion, to data acquisition, to data reconstruction parameters. The emergence of newer generation scanners with even larger numbers of detector arrays and dual tubes has further improved dataset quality. However, it is only with tailored interpretation of these datasets that the true value of the newest scanners will be implemented. Unless the user becomes skilled at analyzing CT data, the full potential of new technology will be minimized. This article presents experience based guidance on postprocessing techniques, from axial review to two-dimensional renderings to three dimensional reconstructions, to optimize analysis of cardiac CT data. PMID- 20705167 TI - Computed tomographic evaluation of the normal cardiac anatomy. AB - Accurate interpretation of cardiac computed tomography requires fundamental knowledge of the normal cardiac anatomy and its common variations. This article reviews the normal anatomy of the coronary arteries, cardiac chambers, and cardiac valves. PMID- 20705168 TI - Imaging of coronary artery anomalies. AB - Coronary artery anomalies (CAA) are uncommon congenital variations in coronary anatomy, occurring in 0.2% to 1.2% of the general population, the majority of which are detected incidentally and have little clinical significance. A minority of CAA, primarily due to an interarterial course, is clinically significant, and may present with symptoms of myocardial ischemia, malignant ventricular arrhythmias, and even sudden cardiac death. Until recently, CAA were primarily detected at catheter coronary angiography. With recent advances in multidetector computed tomography (CT) technology and the use of electrocardiographic gating, coronary CT angiography provides an exquisite omnidimensional display of the anomalous coronary arteries and their relation to the adjacent structures noninvasively, and is the diagnostic test of choice. Understanding CAA morphology and clinical significance of CAA is important for establishing a diagnosis, and is essential for appropriate patient management and treatment planning. PMID- 20705169 TI - Evaluation of plaques and stenosis. AB - Cardiac CT scan has emerged from a research tool to a widely used clinical modality in the diagnostic management of coronary artery disease. Based on evidence of numerous clinical studies coronary CT angiography (cCTA) has emerged as a fast, accurate, and noninvasive alternative to conventional angiography in selected patient populations. A major strength of cCTA is its ability to combine information on the coronary artery anatomy, the vessel lumen, and atherosclerotic lesions. Recent investigations on the application of cCTA in myocardial perfusion imaging suggest that cCTA may allow analysis of the hemodynamic relevance of detected stenosis. Data is accumulating that supports its relevance for patient management and outcome. This article examines the role of cCTA for the evaluation of plaques and stenosis. PMID- 20705170 TI - Evaluation of the patient with acute chest pain. AB - The past decade has brought rapid advances in CT technology, which allows increasingly precise application to the study of coronary arteries and acute chest pain. The literature has expanded to lend quantifiable justification to the intuitive appeal of a rapid, reproducible, 3D study of the heart and vasculature. More complete analysis of efficacy and costs on broader populations will further refine our understanding of how best to implement what may become the new gold standard. Meanwhile, evolving technology promises to further challenge radiologists and clinicians to optimize approach and diagnosis to acute chest pain. PMID- 20705171 TI - Evaluation of bypass grafts and stents. AB - Although conventional coronary angiography is used to evaluate the patency of coronary artery bypass grafts, it is invasive and has associated risks. The evolution of the multidetector CT (MDCT) has enabled accurate, noninvasive visualization of graft patency. This article identifies and describes typical MDCT findings in bypass grafts and native coronary arteries. PMID- 20705172 TI - Evaluation of myocardial abnormalities and ischemia. AB - Cardiac computed tomography angiography (CCTA) has emerged as a powerful noninvasive technique for anatomic evaluation of the coronary arteries. Multiple studies have demonstrated very good diagnostic accuracy for detection of coronary artery disease, particularly with 64-slice systems. CCTA allows for accurate assessment of myocardial structure, perfusion, and function comparable to established techniques. CCTA has the potential to be a ''one-stop shop'' because it can be used to assess coronary artery anatomy and myocardial structure, perfusion, and function. In this article, established and emerging CCTA techniques for the evaluation of myocardial structure, perfusion, and function are reviewed. PMID- 20705173 TI - Computed tomography evaluation of cardiac valves: a review. AB - Electrocardiograph (ECG)-gated cardiac computed tomography (CT) angiography has great potential for the evaluation of the cardiac valves, with excellent image quality. The evidence-based, established clinical role of ECG-gated CT coronary angiography provides additional valuable information about valve morphology and function. A wide range of valve pathology, including congenital and acquired conditions, infectious endocarditis, and complications of valve replacement, can be assessed by cardiac CT imaging. Despite recent advances in CT technology, echocardiography remains the gold standard for noninvasive cardiac valve evaluation. Nevertheless, important clinical information about the valves can be obtained with coronary CT angiography examinations. Thus cardiac valve morphology and function should be routinely assessed and reported on coronary CT angiography examinations. PMID- 20705174 TI - Computed tomography of cardiac pseudotumors and neoplasms. AB - Important features of cardiac masses can be clearly delineated on cardiac computed tomography (CT) imaging. This modality is useful in identifying the presence of a mass, its relationship with cardiac and extracardiac structures, and the features that distinguish one type of mass from another. A multimodality approach to the evaluation of cardiac tumors is advocated, with the use of echocardiography, CT imaging and magnetic resonance imaging as appropriately indicated. In this article, various cardiac masses are described, including pseudotumors and true cardiac neoplasms, and the CT imaging findings that may be useful in distinguishing these rare entities are presented. PMID- 20705175 TI - Computed tomography of adult congenital heart disease. AB - Cardiac computed tomography (CT) is a rapidly advancing technology that complements echocardiography in the imaging evaluation of congenital heart disease. CT can play an important role in diagnosis and follow-up via assessment of anatomic features and postoperative complications. An understanding of the pathophysiology and imaging characteristics of various congenital heart lesions is essential for effective implementation and accurate interpretation of the cardiac CT examination. PMID- 20705176 TI - Plant development. Preface. PMID- 20705177 TI - Green beginnings - pattern formation in the early plant embryo. AB - Embryogenesis in plants transforms the zygote into a relatively simple structure, the seedling, which contains all tissues and organs that later form the mature plant body. Despite a profound diversity in cell division patterns among plant species, embryogenesis yields remarkably homologous seedling architectures. In this review, we describe the formative events during plant embryogenesis and discuss the molecular mechanisms that regulate these processes, focusing on Arabidopsis. Even though only a relatively small number of factors are known that regulate each patterning step, a picture emerges where locally acting transcription factors and intercellular signaling contribute to the specification and spatio-temporal coordination of the various cell types in the embryo. Notably, several patterning processes are controlled by the plant hormone auxin. Most regulators that were identified in Arabidopsis have orthologs in other sequenced plant genomes, and several of these are expressed in similar patterns. Therefore, it appears that robust conserved mechanisms may underlie pattern formation in plant embryos. PMID- 20705178 TI - Light-regulated plant growth and development. AB - Plants are sessile and photo-autotrophic; their entire life cycle is thus strongly influenced by the ever-changing light environment. In order to sense and respond to those fluctuating conditions higher plants possess several families of photoreceptors that can monitor light from UV-B to the near infrared (far-red). The molecular nature of UV-B sensors remains unknown, red (R) and far-red (FR) light is sensed by the phytochromes (phyA-phyE in Arabidopsis) while three classes of UV-A/blue photoreceptors have been identified: cryptochromes, phototropins, and members of the Zeitlupe family (cry1, cry2, phot1, phot2, ZTL, FKF1, and LKP2 in Arabidopsis). Functional specialization within photoreceptor families gave rise to members optimized for a wide range of light intensities. Genetic and photobiological studies performed in Arabidopsis have shown that these light sensors mediate numerous adaptive responses (e.g., phototropism and shade avoidance) and developmental transitions (e.g., germination and flowering). Some physiological responses are specifically triggered by a single photoreceptor but in many cases multiple light sensors ensure a coordinated response. Recent studies also provide examples of crosstalk between the responses of Arabidopsis to different external factors, in particular among light, temperature, and pathogens. Although the different photoreceptors are unrelated in structure, in many cases they trigger similar signaling mechanisms including light-regulated protein-protein interactions or light-regulated stability of several transcription factors. The breath and complexity of this topic forced us to concentrate on specific aspects of photomorphogenesis and we point the readers to recent reviews for some aspects of light-mediated signaling (e.g., transition to flowering). PMID- 20705179 TI - Root development-two meristems for the price of one? AB - In this review, we analyze progress in understanding the mechanisms of root meristem development and function. The formation of embryonic and lateral roots, together with the remarkable regenerative ability of roots, seems to be linked to an auxin-dependent patterning mechanism, the "reflux loop," that can act at least partly independently of cellular context. A major feature of root formation is the production of the "structural initials," the center of the developing root. These cells form an organizing center (OC), the quiescent center (QC), which is needed for meristem activity. The exact role of the QC remains somewhat unclear, though it maintains a stem cell (SC) state in adjacent cells and acts as a long term SC pool itself. SCs in the root can be defined on an operational basis, but a molecular definition for SC identity remains elusive. Instead, the behavior of cells in the proximal root might better be understood as the result of a "potential" gradient in the meristem, which confers cellular characteristics with respect to proximity to the QC. This potential gradient also seems to be auxin dependent, possibly as a result of the effect of auxin on the expression of PLETHORA genes, key regulators of meristem function. Only in the root cap (RC) has distinct SC identity been proposed; but increasingly, evidence suggests that regulation of RC development is rather different from that in the proximal meristem; interestingly, a similar dichotomy can also be observed in the shoot meristem. Cell cycle progression must lie at the core of meristematic activity, and recent work has begun to uncover how hormonal regulation feeds forward into various aspects of the cell cycle. The emergent picture is one of coordinate regulation of cell division and elongation by a hormonal signaling network that is integrated by the auxin reflux loop to control root growth. PMID- 20705180 TI - Shoot apical meristem form and function. AB - The shoot apical meristem (SAM) generates above-ground aerial organs throughout the lifespan of higher plants. In order to fulfill this function, the meristem must maintain a balance between the self-renewal of a reservoir of central stem cells and organ initiation from peripheral cells. The activity of the pluripotent stem cell population in the SAM is dynamically controlled by complex, overlapping signaling networks that include the feedback regulation of meristem maintenance genes and the signaling of plant hormones. Organ initiation likewise requires the function of multifactor gene regulatory networks, as well as instructive cues from the plant hormone auxin and reciprocal signals from the shoot meristem. Floral meristems (FMs) are products of the reproductive SAM that sustains a transient stem cell reservoir for flower formation. Regulation of FM activity involves both feedback loops shared with the SAM and floral-specific factors. Recent studies have rapidly advanced our understanding of SAM function by adopting newly developed molecular and computational techniques. These advances are becoming integrated with data from traditional molecular genetics methodologies to develop a framework for understanding the central principles of SAM function. PMID- 20705181 TI - Signaling sides adaxial-abaxial patterning in leaves. AB - Most leaves are dorsiventrally flattened and develop clearly defined upper and lower surfaces. Light capturing is the specialization of the adaxial or upper surface and the abaxial or lower surface is specialized for gas exchange (Fig. 5.1). This division into adaxial and abaxial domains is also key for the outgrowth of the leaf blade or lamina, which occurs along the boundary between the upper and lower sides. How this polarity is set up is not clear but genetic analysis in a range of species suggests that several highly conserved interlocking pathways are involved. Positional information from the meristem is reinforced by signaling through the epidermal layer as the meristem grows away from the leaf primordium. Opposing ta-siRNA and miRNA gradients help refine distinct adaxial and abaxial sides, and mutual inhibition between the genes expressed on each side stabilizes the boundary. In this review we consider how recent work in a range of species is clarifying our understanding of these processes. PMID- 20705182 TI - Evolution of leaf shape: A pattern emerges. AB - Leaf shape is a highly variable trait. Ancestrally, all leaves are proposed to have derived from modifications of branched shoot systems. The formation of blade, smooth margins or serrations on the blade, or distinct leaflets that are the characteristic features of some leaves provides an opportunity to study the generation of morphogenesis in organs that are evolutionarily homologous and yet developmentally distinct in patterning. Intense research in several model species with distinct leaf morphologies has revealed a complex network of genes that interact to pattern the leaf. Several parallels between leaf patterning and shoot patterning exist. The plant growth hormone auxin is emerging as a key player in the specification of both shoot and leaf patterning. The outcome of this underlying auxin pattern may be determined by variation in the two opposing developmental forces of differentiation and indeterminancy. The expanded suite of genetic and physiological factors regulating leaf shape has provided interesting insight into the mechanisms by which morphological innovation is accomplished. PMID- 20705183 TI - Control of tissue and organ growth in plants. AB - Plant organs grow to characteristic, species-specific sizes and shapes. At the cellular level, organ growth is initially characterized by cell proliferation, which gives way to cell expansion at later stages. Using mainly Arabidopsis thaliana as a model species, a number of factors have been isolated in recent years that promote or restrict organ growth, with the altered organ size being associated with changes in cell number, in cell size, or in both. However, cells in an organ do not appear to follow a strictly autonomous program of proliferation and expansion, and their behavior is coordinated in at least three different respects: normally sized organs can be formed consisting of altered numbers of cells with compensatory changes in the size of the individual cells, suggesting that cellular behavior is subject to organ-wide control; the growth of cells derived from more than one clonal origin is coordinated within a plant lateral organ with its different histological layers; and growth of cells in different regions of an organ is coordinated to generate a reasonably flat leaf or floral organ. Organ growth is strongly modulated by environmental factors, and the molecular basis for this regulation is beginning to be understood. Given the complexity of organ growth as a dynamic four-dimensional process, precise quantification of growth parameters and mathematical modeling are increasingly used to understand this fascinating problem of plant biology. PMID- 20705184 TI - Vascular pattern formation in plants. AB - Reticulate tissue systems exist in most multicellular organisms, and the principles underlying the formation of cellular networks have fascinated philosophers, mathematicians, and biologists for centuries. In particular, the beautiful and varied arrangements of vascular tissues in plants have intrigued mankind since antiquity, yet the organizing signals have remained elusive. Plant vascular tissues form systems of interconnected cell files throughout the plant body. Vascular cells are aligned with one another along continuous lines, and vascular tissues differentiate at reproducible positions within organ environments. However, neither the precise path of vascular differentiation nor the exact geometry of vascular networks is fixed or immutable. Several recent advances converge to reconcile the seemingly conflicting predictability and plasticity of vascular tissue patterns. A control mechanism in which an apical basal flow of signal establishes a basic coordinate system for body axis formation and vascular strand differentiation, and in which a superimposed level of radial organizing cues elaborates cell patterns, would generate a reproducible tissue configuration in the context of an underlying robust, self-organizing structure, and account for the simultaneous regularity and flexibility of vascular tissue patterns. PMID- 20705185 TI - Stomatal patterning and development. AB - Stomata are epidermal pores used for water and gas exchange between a plant and the atmosphere. Both the entry of carbon dioxide for photosynthesis and the evaporation of water that drives transpiration and temperature regulation are modulated by the activities of stomata. Each stomatal pore is surrounded by two highly specialized cells called guard cells (GCs), and may also be associated with neighboring subsidiary cells; this entire unit is referred to as the stomatal complex. Generation of GCs requires stereotyped asymmetric and symmetric cell divisions, and the pattern of stomatal complexes in the epidermis follows a "one-cell-spacing rule" (one complex almost never touches another one). Both stomatal formation and patterning are highly regulated by a number of genetic components identified in the last decade, including, but not limited to, secreted peptide ligands, plasma membrane receptors and receptor-like kinases, a MAP kinase module, and a series of transcription factors. This review will elaborate on the current state of knowledge about components in signaling pathways required for cell fate and pattern, with emphasis on (1) a family of extracellular peptide ligands and their relationship to the TOO MANY MOUTHS receptor-like protein and/or members of the ERECTA receptor-like kinase family, (2) three tiers of a MAP kinase module and the kinases that confer novel regulatory effects in specific stomatal cell types, and (3) transcription factors that generate specific stomatal cell types and the regulatory mechanisms for modulating their activities. We will then consider two new proteins (BASL and PAN1, from Arabidopsis and maize, respectively) that regulate stomatal asymmetric divisions by establishing cell polarity. PMID- 20705186 TI - Trichome patterning in Arabidopsis thaliana from genetic to molecular models. AB - The aerial organs of plants typically produce trichomes that may adopt various functions, including light, wind, frost, and herbivore protection. Trichomes are of epidermal origin regularly distributed on the surface. The mechanism by which trichome differentiation is triggered in individual cells in a field of protodermal cells is best studied in Arabidopsis thaliana. The genetic analysis has revealed a number of key genes controlling this patterning process, and further molecular analysis has enabled the in-depth cell-biological and biochemical analysis. The established models explain trichome patterning by the mutual interaction between positive and negative factors. Three activators, a bHLH (helix-loop-helix), a R2R3 MYB-related transcription factor, and a WD40 domain protein, form an active complex. The activity of this complex is counteracted by R3 MYB factors that compete with the R2R3 MYB for binding to the bHLH factor. The R3 MYBs can move between cells and thereby mediate cellular interactions. This general model cannot explain all genetic observations and recent data suggest the existence of several parallel patterning mechanisms. In this chapter we aim to summarize the current data and sketch possible alternative, not mutually exclusive theoretical models. PMID- 20705187 TI - Comparative analysis of flowering in annual and perennial plants. AB - In plants the switch from vegetative growth to flowering involves a major transition in the development of the shoot apex. This transition can occur once, in annual species, or repeatedly, in perennial plants. In annuals, flowering is associated with senescence and death of the whole plant, whereas perennials flower in consecutive years and maintain vegetative development after flowering. The perennial life strategy depends on differential behavior of meristems on a single plant so that some remain in the vegetative state while others undergo the floral transition. A. thaliana provides a powerful model system for understanding the mechanisms of flowering in annuals. Here we review the events that occur in the meristem of A. thaliana during the floral transition and compare these with our understanding of flowering in perennial systems. PMID- 20705188 TI - Sculpting the flower; the role of microRNAs in flower development. AB - microRNAs (miRNAs) are small approximately 21-nucleotide RNAs that function posttranscriptionally to regulate gene activity. miRNAs function by binding to complementary sites in target genes causing mRNA degradation and/or translational repression of the target. Since the discovery of miRNAs in plants in 2002 much has been learned about the function of these small regulatory RNAs. miRNAs function broadly to control many aspects of plant biology and plant development. This review focuses on the role of miRNAs in flower development. miRNAs function throughout flower development, from the earliest stages (floral induction) to very late stages (floral organ cell type specification). miRNAs such as miR156 and miR172 play a key role in vegetative phase change and in the vegetative to reproductive transition in both Arabidopsis and maize. miR172 in Arabidopsis and maize and miR169 in Petunia and Antirrhinum function to control floral organ identity fate during the early stages of flower development by regulating the spatial boundaries of expression of target genes. miR164, miR319, miR159, and miR167 function to specify particular cell types during later stages of flower development. Although much has been learned about the role of miRNAs in flower development in the last 8 years, many challenges remain to fully elucidate the function of these important regulatory molecules. PMID- 20705189 TI - Development of flowering plant gametophytes. AB - Plant reproduction occurs through the production of gametes by a haploid generation, the gametophyte. Flowering plants have highly reduced male and female gametophytes, called pollen grains and embryo sacs, respectively, consisting of only a few cells. Gametophytes are critical for sexual reproduction, but detailed understanding of their development remains poor as compared to the diploid sporophyte. This article reviews recent progress in understanding the mechanisms underlying gametophytic development and function in flowering plants. The focus is on genes and molecules involved in the processes of initiation, growth, cell specification, and fertilization of the male and female gametophytes derived primarily from studies in model systems. PMID- 20705190 TI - Foreword. A primer for primary care: urology. PMID- 20705191 TI - Primary care urology. Preface. PMID- 20705192 TI - Prostate-specific antigen testing and prostate cancer screening. AB - Prostate specific antigen (PSA) screening is an integral part of current screening for prostate cancer. Together with digital rectal examinations, it is recommended annually by the American Cancer Society. PSA screening has resulted in a significant stage migration in the past decades. Different forms of PSA, including free PSA, volume adjusted, complexed, intact, or pro-PSA, are being used in the screening process. Other aspects of the screening process include age at diagnosis, survival, overdiagnosis, and overtreatment. Recent studies have cast doubt on whether PSA screening positively affects mortality and how the quality of life of patients may be affected by screening. Future considerations include the need for more longitudinal studies as well as further study of the PSA components that may become more relevant in the future. PMID- 20705193 TI - Evaluation and management of hematuria. AB - Causes of hematuria can range from benign conditions such as urinary tract infection to serious conditions such as bladder cancer. In evaluating a patient with hematuria, 3 questions must be answered by the primary care physician: (1) Is it really hematuria? (2) Should this patient with hematuria be worked up, and if so, how? (3) Should this patient with hematuria be referred, and if so, to which specialty? This article addresses these questions. Because uniformly high quality studies are lacking, the recommendations included in this article are mostly based on expert consensus. PMID- 20705194 TI - Male sexual dysfunction. AB - Male sexual dysfunction is a common entity in primary care practice. The 3 most common types are erectile dysfunction, premature ejaculation, and decreased libido. Clinicians must be comfortable and skilled in taking a complete sexual, social, and medical history and performing a physical examination in persons complaining of sexual dysfunction. Treatment of male sexual dysfunction may include medications and individual or couples psychotherapy. Treatment should be aimed at reducing emotional and physical morbidity in the patient and his partner. PMID- 20705195 TI - Urinary tract infections. AB - Urinary tract infection (UTI) is the most common urologic disorder and one of the most common conditions for which physicians are consulted. Patients at increased risk for UTI include women; diabetics; the immunocompromised; and those with anatomic abnormalities, impaired mobility, incontinence, advanced age, and instrumentation. Antibiotic therapy aims to relieve symptoms and prevent complications such as pyelonephritis and renal scarring. Distinguishing asymptomatic bacteriuria from a UTI can be difficult, especially in those with comorbidities. Most experts do not recommend screening for UTI, except in the first trimester of pregnancy. PMID- 20705196 TI - Sexually transmitted infections in men. AB - Sexually transmitted infections (STIs) cause tremendous morbidity, great costs, and numerous avoidable deaths in the United States each year. STIs in men can present as discharge, ulcers, papules, infestations, or systemic disease, but most commonly STIs present without any symptoms. Molecular techniques, single dose antibiotics and antivirals, and patient-administered therapies present opportunities for enhanced diagnosis and treatment. Screening for STIs should be part of all primary care practices, specifically targeting high-risk persons and those diagnosed with another STI. PMID- 20705197 TI - Urologic chronic pelvic pain syndrome. AB - Painful bladder syndrome or urologic chronic pelvic pain syndrome is a chronic condition that presents with lower urinary tract symptoms that include dysuria, urgency, frequent urination, and chronic pelvic pain. Diagnoses included in the painful bladder syndrome are interstitial cystitis and prostatodynia. The history, physical examination, and laboratory evaluation of patients with lower urinary tract symptoms are important in ruling out other diagnoses. Treatment options that are US Food and Drug Administration approved and evidence based are limited; however, many symptom-based treatment options can reduce symptoms and improve quality of life. PMID- 20705198 TI - Prostatitis: acute and chronic. AB - Prostatitis, one of the most common urological infections afflicting adult men, has recently been divided into 4 different categories based on the National Institutes of Health consensus classification: acute bacterial prostatitis, chronic bacterial prostatitis, chronic nonbacterial prostatitis and pelvic pain syndrome, and asymptomatic inflammatory prostatitis. Most patients with prostatitis are found to have either nonbacterial prostatitis or prostatodynia. Prostatitis poses an international health problem, with epidemiologic studies suggesting a worldwide prevalence of more than 10%. This article reviews current modes of diagnosis and therapy for acute and chronic prostatitis. PMID- 20705199 TI - Urinary tract stones. AB - Urinary tract stone disease is one of the most common urologic conditions in the US, with a lifetime prevalence of about 13% for men and 7% for women. In this article we review the management of urinary tract stones and discuss when to seek urologic consultation. We cover epidemiologic data, stone types, presenting symptoms, imaging, metabolic evaluation and risk factors, and medical management strategies. We also discuss the indications for surgical intervention and the common operative procedures currently available. PMID- 20705200 TI - Benign prostatic hyperplasia: current clinical practice. AB - Benign prostatic hyperplasia (BPH) is the most common benign adenoma in men, affecting nearly all of them. BPH represents a clinically significant cause of bladder outflow obstruction in up to 40% of men. The growing frequency of diagnosis is due to increasing life expectancy and a trend toward seeking medical advice at earlier stages of the disease. The last decade has witnessed a significant shift in emphasis in the management of BPH, with medical therapies and, to a lesser extent, minimally invasive therapies becoming the predominant active therapy choices. The development of effective therapies such as alpha adrenergic blockers and 5-alpha-reductase inhibitors and the possibility of their combined use represent the most significant advance in the treatment of BPH. PMID- 20705201 TI - Urinary incontinence. AB - Urinary incontinence is a major health problem that becomes more common with increasing age. A thorough history and examination can help determine the type of incontinence: stress, urge, mixed, or other. Initial treatments may include lifestyle and behavioral modifications, pelvic floor exercises, and anticholinergic medications. Urologic referral is appropriate when initial treatment measures fail or in complex cases, such as previous incontinence surgery or irradiation. PMID- 20705202 TI - Common scrotal and testicular problems. AB - Scrotal and testicular problems range from the benign and painless to the malignant and debilitating. The primary care physician should be able to triage these problems and know when to give reassurance and when to initiate a targeted workup that may lead to specialist intervention. This article focuses on scrotal pain and palpable abnormalities. Scrotal pain includes well-defined acute causes such as torsion and infection and the less well-defined chronic orchialgia. Palpable abnormalities covered here include cryptorchidism, hydrocele, spermatocele, varicocele, and testicular cancer. PMID- 20705203 TI - Common penile problems. AB - A variety of penile problems are commonly seen by primary care physicians. This article reviews the diagnosis, evaluation, and management of congenital conditions such as hypospadias, chordee, webbed and buried penis, duplicated urethra, ambiguous genitalia, and micropenis. Acquired emergent conditions, including minor trauma and paraphimosis, are also discussed, with a particular emphasis on initial evaluation and management. Conditions associated with erectile dysfunction, including priapism and Peyronie disease, are reviewed. PMID- 20705204 TI - Male reproductive health and infertility. AB - Primary care physicians have an essential role and opportunity in positively impacting the reproductive health of men. Although men are less likely than women to consistently seek preventive services, an office visit for any reason should be seen as an opportunity to introduce the idea of reproductive health. Additionally, primary care physicians can and should initiate the diagnostic workup for infertile couples in their practices. The initial assessment for the male partner consists of a thorough history and physical examination and appropriate laboratory tests, including a semen analysis. PMID- 20705206 TI - Mandating influenza vaccination for health care workers: putting patients and professional ethics over personal preference. PMID- 20705205 TI - Hospital outbreak caused by Klebsiella pneumoniae producing KPC-2 beta-lactamase resistant to colistin. AB - We describe a hospital outbreak caused by colistin-resistant Klebsiella pneumoniae producing KPC-2 beta-lactamase in two distinct medical centres. Seven clinical isolates of K. pneumoniae exhibiting resistance to carbapenems were collected from patients with hospital-acquired infection. All isolates were phenotypically positive for carbapenemase activity but negative for metallo-beta lactamase production. PCR analysis using specific primers for bla(KPC), bla(SHV), bla(TEM) and bla(CTX-M) demonstrated that all clinical strains of K. pneumoniae from hospital A and one isolate from hospital B were genetically related and carried bla(KPC-2) in addition to bla(SHV-12). In contrast, the remaining isolate carried bla(S)(HV-5) with bla(K)(PC-2) and yielded a different profile. These results indicate the clonal spread of KPC producers between hospitals as well as the acquisition of KPC genes by different K. pneumoniae strains. All isolates were resistant to carbapenems, beta-lactams, ciprofloxacin, aminoglycosides and colistin, but intermediately susceptible to tigecycline and susceptible to gentamicin. The infection was fatal in five cases. The emergence of colistin resistant K. pneumoniae possessing bla(KPC)(-2) underscores the implementation of strict control measures to prevent their dissemination of these organisms in hospitals. PMID- 20705207 TI - [Repair of nose, lips and chin mutilations. The customary repairs versus allografts]. AB - Central-facial mutilations, located within the nose lips and chin triangle, require great quality repairs regarding morphology and function. Plastic surgery history affords the ideas evolution in this field crossing over nose and lips reconstructions, which were the subject of successive reports within our society, in 1994 (nose reconstruction) and 2002 (lips reconstruction). Now a day, following this progress, the plastic surgeon has a large choice of reliable techniques. His choice is dictated by a precise evaluation of the limits of the substance loss to repair, according to a (mapping) classification of the nose-lip and chin triangle. This classification defines three units (nose-labial, bilabial and chin-labial) as reflexion bases to the therapeutic indications. This anatomical and surgical approach was built starting from a retrospective study of 195 central-facial mutilations caused by ballistic damage and dog bites. The results evaluation makes possible to carry out a reflexion on the potential indications regarding allograft as a therapeutic alternative to the traditional reconstructions of this territory. PMID- 20705208 TI - [Treatment indications for hand agenesis or acquired loss: Standard technics versus allotransplantation (CTA)]. AB - The new surgery thinking, in matter of hand loss, is made of two ways: without hand, there is no more functional abilities; homograft or allograft of hand is the best actual treatment. This is not true and we are able to get new functional abilities by other ways: without any treatment, we are able of spontaneous functional recovery. There are other treatments: the old operation of Krukenberg or new bionic prosthesis. This work is a recall of obvious or forgotten facts. PMID- 20705209 TI - [To cure: to become oneself or become different?]. AB - The parallel evolution of lifestyles and medicine calls into question the objectives of the therapeutical relationship. Leading-edge technology, the allotransplant radically questions what curing means: is it about becoming oneself again or another person? This paper studies this dilemma from three standpoints. First, in an aesthetics perspective, the transplant surgery refers to an implicit definition of what is an acceptable body, which introduces a tension between vascular supply, immunology and beauty. How far can we favour one or the other? Secondly, in a religious perspective, transplant contributes to the mimetic desire: how can we regulate this desire in a society that increasingly values the body? Finally, from a philosophical standpoint, allotransplant questions my personal relationship with my body: beyond its technological requirements, we have to determine, in the public and private spheres, if individuals have or are bodies. What responsibility does medicine assume, as an institution and a community of agents, in this anthropological choice? PMID- 20705210 TI - [Anatomy of the artery of the cutaneous posterior nerve of the thigh]. AB - Salmon has described first the vascularisation of the posterior cutaneous nerve in 1936. Since, few articles have described the collaterals of the artery accompanying the posterior cutaneous nerve. The authors conducted an anatomical study on 20 cadaveric dissections with injection in order to define the collaterals of the artery. The findings reveal an artery nourished proximally by fasciocutaneous branches of the profunda perforating arteries and distally by branches from popliteal and genicular arteries. Their association is variable. PMID- 20705211 TI - [Preoperative angiographic CT-scan for perforator flap transfer. Clinical applications in an emergency unit of reconstructive surgery: four clinical cases]. AB - Our experience of the deep inferior epigastric artery perforator flap has led us to perform systematically an abdominal CT-scan for the pretherapeutic checking. This exam gives us a precise vascular mapping of musculocutaneous and septocutaneous perforators artery of the flap, may enable a better orientation in the dissection and reduce the surgery time. We have enlarged the indication of this exam to the members flaps who needs the dissection of a musculocutaneous or a septocutaneous perforators vessels: Nakajima's et al. classification [1]. The mapping of perforating vessels on 3D reconstruction pictures helps us to planify the vascular cutaneous autologous grafts. PMID- 20705212 TI - [Repair of fingertip amputations using composite grafts: nine clinical cases]. AB - PURPOSE: Even if a digital replantation is not possible, we present a series of nine cases of fingertip amputations treated with clinical efficacy by using a composite graft from the amputated finger part. PATIENTS AND METHOD: All of our eight patients (four children and four adults) were traumatically amputated. The level of amputation passed by the bunch of P3 and carried partially or completely the ungula. The reposition was always performed under local anaesthesia. Our evaluation related on the survival of the composite grafts, the functional and the aesthetic result. RESULTS: The composite grafts were revascularised in eight amputations out of nine, with a satisfactory remote result on the function as well as aesthetic level. CONCLUSION: After a short recall of the alternative surgical methods of the treatment of the fingertip amputations, we will insist on the simplicity and the reliability of the repositioning of a composite graft, recommended for us from the start and depending on the traumatic level. In the event of a failure, surgeons still have the possibility of realising the other alternative surgical methods. PMID- 20705213 TI - Health care providers communicate less well with patients with chronic low back pain--a study of encounters at a back pain clinic in Denmark. AB - We aimed to study the quality of communication between health care providers and patients with low back pain with emphasis on information giving in a back pain clinic, including if characteristics of patients could be associated with communication quality. We videotaped 79 encounters in which 21 providers informed patients about the results of magnetic resonance imaging of the back. Background information about the patients was collected by questionnaires and interview after the encounter. Videotapes were analysed with the Four Habits Coding Scheme (4HCS) in which higher scores mean better communication. There were strong negative correlations between 4HCS scores and the duration of back pain, and patient age. The results were significant for all professional subgroups (doctors, physiotherapists, chiropractors). Communication quality in encounters with back pain patients is worse, the longer the patient has suffered pain. Poor communication quality also seems to be associated with patients being older. PMID- 20705214 TI - Brain morphological changes associated with cyclic menstrual pain. AB - Primary dysmenorrhea (PDM) is the most prevalent gynecological disorder for women in the reproductive age. PDM patients suffer from lower abdominal pain that starts with the onset of the menstrual flow. Prolonged nociceptive input to the central nervous system can induce functional and structural alterations throughout the nervous system. In PDM, a chronic viscero-nociceptive drive of cyclic nature, indications of central sensitization and altered brain metabolism suggest a substantial central reorganization. Previously, we hypothesized that disinhibition of orbitofrontal networks could be responsible for increased pain and negative affect in PDM. Here, we further tested this hypothesis. We used an optimized voxel-based morphometry (VBM) approach to compare total and regional gray matter (GM) increases and decreases in 32 PDM patients with 32 healthy age and menstrual cycle matched (peri-ovulatory phase) controls. Abnormal decreases were found in regions involved in pain transmission, higher level sensory processing, and affected regulation while increases were found in regions involved in pain modulation and in regulation of endocrine function. Moreover, GM changes in regions involved in top-down pain modulation and in generation of negative affect were related to the severity of the experienced PDM pain. Our results demonstrate that abnormal GM volume changes are present in PDM patients even in the absence of pain. These changes may underpin a combination of impaired pain inhibition, increased pain facilitation and increased affect. Our findings highlight that longer lasting central changes may occur not only in sustained chronic pain conditions but also in cyclic occurring pain conditions. PMID- 20705215 TI - The evidence for pharmacological treatment of neuropathic pain. AB - Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients. PMID- 20705216 TI - Julia's placebo effect. AB - Placebo analgesia is the occurrence of an analgesic drug effect without drugs. The response is learned through conditioning and mediated by expectancy. It lies on the up-regulation of the pain-modulating areas and the down-regulation of the pain-encoding regions. A further mechanism is the retrieval of the brain circuit activity previously excited by drugs. We describe the case of an infant affected by a tracheal agenesis who underwent a series of operative and diagnostic bronchoscopies for which she received midazolam and fentanyl. After 61 procedures the infant showed a somatosensory response which in our interpretation reflected a placebo effect. Ontogenetic considerations and specific observations indicate that the infant had the appropriate competences in her learning and memory systems and nociceptive and antinociceptive circuits for the placebo effect to take place. Generalizing, the introduction of placebo manipulation in infant pain management may be taken into consideration; its approach through observational and experimental studies is the preliminary target. PMID- 20705217 TI - Adult Bland-White-Garland syndrome presenting as cardiomyopathy characterized by subendocardial fibrosis. PMID- 20705218 TI - Anatomy of the mitral valvular complex and its implications for transcatheter interventions for mitral regurgitation. AB - Mitral regurgitation (MR) poses a significant clinical burden in the adult population, which is expected to increase even more with the ever prolonging life expectancies in developed countries. New technology has brought MR, once exclusively the arena of cardiac surgeons, to the attention of interventional cardiologists. A variety of device-oriented transcatheter strategies have evolved in recent years. A comprehensive understanding of mitral valvular anatomy is crucial for the selection of patients, the implementation of devices, and further refinements of these transcatheter techniques if they are eventually to produce procedural and clinical success. The aim of this review is to elucidate the morphology of the mitral valvular complex, integrating key anatomical features into the developing transcatheter options for the treatment of MR. PMID- 20705219 TI - Earlier intervention in the management of hypercholesterolemia: what are we waiting for? AB - The thesis advanced here is that we are initiating treatment of hypercholesterolemia (and other risk factors) too late in life. Initiating treatment at, for example, age 30 years instead of age 60 years might very well prevent not just 30% of events, as in the 5-year statin trials, but perhaps as many as 60%. PMID- 20705220 TI - Redefining normal low-density lipoprotein cholesterol: a strategy to unseat coronary disease as the nation's leading killer. AB - The new Adult Treatment Panel guidelines will be published in 2011. This paper suggests the consideration of major changes in the existing management guidelines for low-density lipoprotein cholesterol management based on 2 fundamental principles: return the low-density lipoprotein cholesterol level to the normal range and begin treatment closer to disease onset. These principles suggest the value of rethinking all 3 of the principal features of the Adult Treatment Panel III guidelines for low-density lipoprotein cholesterol management: the initiation criteria, the use of variable targets, and the level of the treatment target. Because the principal issue surrounding guideline change is likely to be uncertainty concerning cost and toxicity, the text of new guidelines would have to completely satisfy this concern by strong emphasis on a prudent conservative approach to implementation and would include both cautionary data and caveats concerning the tradeoffs between the potency, cost, and toxicity of statins. The proposed changes in the guidelines, if combined with effective implementation, would likely lead to the displacement of atherosclerotic disease as the nation's number 1 killer. This review provides a logical rationale and discusses the pros and cons for each of the proposed changes. PMID- 20705221 TI - Statin therapy in young adults: ready for prime time? PMID- 20705222 TI - Imaging of vascular inflammation with [11C]-PK11195 and positron emission tomography/computed tomography angiography. AB - OBJECTIVES: We sought to investigate whether positron emission tomography/computed tomography (CT) angiography using [11C]-PK11195, a selective ligand for peripheral benzodiazepine receptors expressed in activated macrophages, can be used to image vascular inflammation. BACKGROUND: Activated macrophages and T lymphocytes are fundamental elements in the pathogenesis of large-vessel vasculitides. METHODS: Fifteen patients (age 52+/-16 years) with systemic inflammatory disorders (6 consecutive symptomatic patients with clinical suspicion of active vasculitis and 9 asymptomatic control patients) underwent positron emission tomography with [11C]-PK11195 and CT angiography. [11C]-PK11195 uptake was measured by calculating target-to-background ratios of activity normalized to venous blood. RESULTS: Coregistration of positron emission tomography with contrast-enhanced CT angiography facilitated localization of [11C]-PK11195 arterial wall uptake. Visual analysis revealed focal [11C]-PK11195 uptake in the arterial wall of all 6 symptomatic patients, but in none of the asymptomatic controls. Although serum inflammatory biomarkers (C-reactive protein, erythrocyte sedimentation rate, white cell count) did not differ significantly between the 2 groups, symptomatic patients had increased [11C] PK11195 vascular uptake (target-to-background ratio 2.41+/-1.59 vs. 0.98+/-0.10; p=0.001). CONCLUSIONS: By binding to activated macrophages in the vessel wall, [11C]-PK11195 enables noninvasive imaging of vascular inflammation. Alternative longer-lived radioligands for probing peripheral benzodiazepine receptors are being tested for wider clinical applications. PMID- 20705224 TI - The year in clinical cardiac electrophysiology. PMID- 20705223 TI - Modest visceral fat gain causes endothelial dysfunction in healthy humans. AB - OBJECTIVES: The aim of this study was to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans. BACKGROUND: Endothelial dysfunction has been identified as an independent predictor of cardiovascular events. Whether fat gain impairs endothelial function is unknown. METHODS: A randomized controlled study was conducted to assess the effects of fat gain on endothelial function. Forty-three normal-weight healthy volunteers were recruited (mean age 29 years; 18 women). Subjects were assigned to gain weight (approximately 4 kg) (n=35) or to maintain weight (n=8). Endothelial function (brachial artery flow-mediated dilation [FMD]) was measured at baseline, after fat gain (8 weeks), and after weight loss (16 weeks) for fat gainers and at baseline and follow-up (8 weeks) for weight maintainers. Body composition was measured by dual-energy X-ray absorptiometry and abdominal computed tomographic scans. RESULTS: After an average weight gain of 4.1 kg, fat gainers significantly increased their total, visceral, and subcutaneous fat. Blood pressure and overnight polysomnography did not change after fat gain or loss. FMD remained unchanged in weight maintainers. FMD decreased in fat gainers (9.1+/-3% vs. 7.8+/ 3.2%, p=0.003) but recovered to baseline when subjects shed the gained weight. There was a significant correlation between the decrease in FMD and the increase in visceral fat gain (rho=-0.42, p=0.004), but not with subcutaneous fat gain (rho=-0.22, p=0.15). CONCLUSIONS: In normal-weight healthy young subjects, modest fat gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after weight loss. Increased visceral rather than subcutaneous fat predicts endothelial dysfunction. (Fat Gain and Cardiovascular Disease Mechanisms; NCT00589498). PMID- 20705225 TI - Giant right coronary artery aneurysm mimicking pericardial mass. PMID- 20705226 TI - Cardiology in India. PMID- 20705228 TI - Statins and altered glucose metabolism: a laboratory curiosity or a new disease? PMID- 20705230 TI - Prognostic factors in patients with implantable cardioverter-defibrillators. PMID- 20705232 TI - Brain death: ethical challenges to palliative care concepts of family care. AB - Brain death is a controversial issue that is often difficult for families to understand or accept. Palliative care interventions can help families to accept the death. However, delaying pronouncement of brain death may be detrimental to the family and lead to financial, ethical, and legal complications, including the potential for insurance fraud. We describe a case of brain death in which the passage of time along with continuation of life support without concomitant testing for brain death led to decreased acceptance of the patient's death by the family. Clinicians should weigh the risks and benefits of harm to the family when deciding how long to keep a brain dead patient on a ventilator. Pronouncement of death, which is good basic medical care regardless of the cause or mechanism of death, should not be delayed for family considerations. Risk management should be involved early in the decision process, if life support is withdrawn without the family's assent. PMID- 20705231 TI - Efficacy of an intervention for fatigue and sleep disturbance during cancer chemotherapy. AB - CONTEXT: Multiple complex symptoms from cancer treatment can interfere with functioning. OBJECTIVES: To evaluate the efficacy of an "energy and sleep enhancement" (EASE) intervention to relieve fatigue and sleep disturbance and improve health-related functional status. METHODS: Individuals receiving chemotherapy (CTX) were randomized to the EASE (n=153) or a control intervention (n=139). The EASE intervention included information and behavioral skills taught by an oncology nurse in three telephone sessions. The primary outcomes of fatigue, sleep disturbance, and functional status were measured before CTX, Day 4 after first treatment (baseline), and 43-46 or 57-60 days later (follow-up), depending on the CTX cycle length. RESULTS: The sample was primarily female (82%) and non-Hispanic white (89%), with mean age of 53.9 years. Fatigue and patient reported sleep disturbance were elevated in both groups at baseline and follow up. Actigraphy revealed that the total sleep time was almost eight hours, and sleep percent was greater than 85% for both groups at both time points (normal range). Physical functioning was diminished and at the same level as a sample with serious illness. Mental functioning was in normal range. A repeated-measures analysis of variance revealed no statistically significant group-by-time effects for fatigue, sleep disturbance, or functional status. Unemployed individuals showed greater benefit from the EASE intervention, reporting less pain and symptom interference. CONCLUSION: Potential explanations include high variability and/or floor effect for fatigue, incorrect timing of measures, insufficient amount or dose of the intervention, and confounding effects of gender. Future research should consider screening for symptom severity and tailoring interventions. PMID- 20705233 TI - SMADs stimulate miRNA processing. AB - MicroRNAs (miRNAs) are potent regulators of gene expression. Consequently, miRNA expression is tightly regulated itself. In this issue, Hata and coworkers provide mechanistic insights into how SMAD proteins regulated the biogenesis of a specific subset of human miRNAs. PMID- 20705234 TI - CBP80 choreographs the NMD two-step. AB - In this issue of Molecular Cell, Hwang et al. (2010) show that the cap-binding protein CBP80 promotes nonsense-mediated decay (NMD) at two steps. In this dual capacity, CBP80 may facilitate essential communication between the premature termination codon (PTC) and the exon-junction complex (EJC) to trigger NMD. PMID- 20705235 TI - A novel effector protein modulates response regulator activity without altering phosphorylation. AB - Genes positively regulated by the global transcriptional response regulator CtrA are not expressed during a life cycle stage of Caulobacter crescentus when the regulator is activated by phosphorylation. Gora et al. (2010), in this issue of Molecular Cell, have discovered a novel effector protein that prevents activation but not repression by the regulator without altering its phosphorylation. PMID- 20705236 TI - Gymnastics of molecular chaperones. AB - Molecular chaperones assist folding processes and conformational changes in many proteins. In order to do so, they progress through complex conformational cycles themselves. In this review, I discuss the diverse conformational dynamics of the ATP-dependent chaperones of the Hsp60, Hsp70, Hsp90, and Hsp100 families. PMID- 20705237 TI - Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. AB - The replication protein A complex (RPA) plays a crucial role in DNA replication and damage response. However, it is not known whether this complex is regulated by the SUMOylation pathway. Here, we show that the 70 kDa subunit of RPA (RPA70) associates with a Sentrin/SUMO-specific protease, SENP6, in the nucleus to maintain RPA70 in a hypoSUMOylated state during S phase. Campothecin (CPT), an inducer of replication stress, dissociates SENP6 from RPA70, allowing RPA70 to be modified by a small ubiquitin-like modifier 2/3 (SUMO-2/3). RPA70 SUMOylation facilitates recruitment of Rad51 to the DNA damage foci to initiate DNA repair through homologous recombination (HR). Cell lines that expressed a RPA70 mutant that cannot be SUMOylated are defective in HR and have a marked increase in sensitivity to CPT. These results demonstrate that SUMOylation status of RPA70 plays a critical role in the regulation of DNA repair through homologous recombination. PMID- 20705238 TI - Homologous recombination restarts blocked replication forks at the expense of genome rearrangements by template exchange. AB - Template switching induced by stalled replication forks has recently been proposed to underlie complex genomic rearrangements. However, the resulting models are not supported by robust physical evidence. Here, we analyzed replication and recombination intermediates in a well-defined fission yeast system that blocks replication forks. We show that, in response to fork arrest, chromosomal rearrangements result from Rad52-dependent nascent strand template exchange occurring during fork restart. This template exchange occurs by both Rad51-dependent and -independent mechanisms. We demonstrate that Rqh1, the BLM homolog, limits Rad51-dependent template exchange without affecting fork restart. In contrast, we report that the Srs2 helicase promotes both fork restart and template exchange. Our data demonstrate that template exchange occurs during recombination-dependent fork restart at the expense of genome rearrangements. PMID- 20705239 TI - The methyltransferase activity of Clr4Suv39h triggers RNAi independently of histone H3K9 methylation. AB - In fission yeast, the pericentromeric dg and dh repeats are transcribed and give rise to small interfering RNAs (siRNAs) by a mechanism that depends on the Clr4(suv39h) histone H3 lysine 9 (H3K9) methyltransferase. Here, we show that Clr4 activity promotes the assembly of a tripartite complex composed of the Clr4 containing CLRC complex and complexes involved in siRNA generation. However, unlike dh siRNAs, dg siRNAs accumulate to near wild-type levels in cells with H3K9 substitutions that cannot be methylated. Thus, Clr4 activity controls siRNA amplification from the different repeat regions by different mechanisms, H3K9 methylation dependent versus independent. Furthermore, artificial tethering of Rik1, a core subunit of the CLRC complex, to a euchromatic RNA mediates RNAi dependent silencing that partially bypasses the requirement for other CLRC subunits. These findings establish Rik1 as a key link between CLRC and RNAi and reveal distinct centromeric siRNA amplification mechanisms that depend on the Clr4 methyltransferase activity. PMID- 20705240 TI - Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. AB - The signal transducers of the transforming growth factor beta (TGFbeta)/bone morphogenetic protein (BMP), the Smads, promote the expression of a subset of miRNAs by facilitating the cleavage reaction by Drosha. The mechanism that limits Smad-mediated processing to a selective group of miRNAs remained hitherto unexplored. In this study, we expand the number of TGFbeta/BMP-regulated miRNAs (T/B-miRs) to 20. Of interest, a majority of T/B-miRs contain a consensus sequence (R-SBE) within the stem region of the primary transcripts of T/B-miRs (pri-T/B-miRs). Here, we demonstrate that Smads directly bind the R-SBE. Mutation of the R-SBE abrogates TGFbeta/BMP-induced recruitment of Smads, Drosha, and DGCR8 to pri-T/B-miRs and impairs their processing, whereas introduction of R-SBE to unregulated pri-miRNAs is sufficient to recruit Smads and to allow regulation by TGFbeta/BMP. Thus, Smads are multifunctional proteins that modulate gene expression transcriptionally through DNA binding and posttranscriptionally through pri-miRNA binding and regulation of miRNA processing. PMID- 20705242 TI - Structural basis for the major role of O-phosphoseryl-tRNA kinase in the UGA specific encoding of selenocysteine. AB - The 21(st) amino acid, selenocysteine (Sec), is assigned to the codon UGA and is biosynthesized on the selenocysteine-specific tRNA (tRNA(Sec)) with the corresponding anticodon. In archaea/eukarya, tRNA(Sec) is ligated with serine by seryl-tRNA synthetase (SerRS), the seryl moiety is phosphorylated by O phosphoseryl-tRNA kinase (PSTK), and the phosphate group is replaced with selenol by Sep-tRNA:Sec-tRNA synthase. PSTK selectively phosphorylates seryl-tRNA(Sec), while SerRS serylates both tRNA(Ser) and tRNA(Sec). In this study, we determined the crystal structures of the archaeal tRNA(Sec).PSTK complex. PSTK consists of two independent linker-connected domains, the N-terminal catalytic domain (NTD) and the C-terminal domain (CTD). The D-arm.CTD binding occurs independently of and much more strongly than the acceptor-arm.NTD binding. PSTK thereby distinguishes the characteristic D arm with the maximal stem and the minimal loop of tRNA(Sec) from the canonical D arm of tRNA(Ser), without interacting with the anticodon. This mechanism is essential for the UGA-specific encoding of selenocysteine. PMID- 20705241 TI - The DEAH box ATPases Prp16 and Prp43 cooperate to proofread 5' splice site cleavage during pre-mRNA splicing. AB - To investigate the mechanisms underlying accurate pre-mRNA splicing, we developed an in vitro assay sensitive to proofreading of 5' splice site cleavage. We inactivated spliceosomes by disrupting a metal-ligand interaction at the catalytic center and discovered that, when the DEAH box ATPase Prp16 was disabled, these spliceosomes catalyzed 5' splice site cleavage but at a reduced rate. Although Prp16 does not promote splicing of a genuine substrate until after 5' splice site cleavage, we found that Prp16 can associate with spliceosomes before 5' splice site cleavage, consistent with a role for Prp16 in proofreading 5' splice site cleavage. We established that Prp16-mediated rejection is reversible, necessitating a downstream discard pathway that we found requires the DEAH box ATPase Prp43, a spliceosome disassembly factor. These data indicate that spliceosomes distinguish slow substrates and that the mechanisms for establishing the fidelity of 5' splice site cleavage and exon ligation share a common ATP dependent framework. PMID- 20705243 TI - Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. AB - Cyclic phosphatidic acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARgamma with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARgamma target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Inhibition of PLD2 by shRNA, a dominant-negative mutant, or a small molecule inhibitor blocks CPA production and relieves PPARgamma inhibition. We conclude that CPA is a second messenger and a physiological inhibitor of PPARgamma, revealing that PPARgamma is regulated by endogenous agonists as well as by antagonists. PMID- 20705244 TI - Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. AB - Mammalian target of rapamycin (mTOR) is an important mediator of phosphoinositol 3-kinase (PI3K) signaling. PI3K signaling regulates B cell development, homeostasis, and immune responses. However, the function and molecular mechanism of mTOR-mediated PI3K signaling in B cells has not been fully elucidated. Here we show that Sin1, an essential component of mTOR complex 2 (mTORC2), regulates B cell development. Sin1 deficiency results in increased IL-7 receptor (il7r) and RAG recombinase (rag1 and rag2) gene expression, leading to enhanced pro-B cell survival and augmented V(D)J recombinase activity. We further show that Akt2 specifically mediates the Sin1-mTORC2 dependent suppression of il7r and rag gene expression in B cells by regulating FoxO1 phosphorylation. Finally, we demonstrate that the mTOR inhibitor rapamycin induces rag expression and promotes V(D)J recombination in B cells. Our study reveals that the Sin1/mTORC2-Akt2 signaling axis is a key regulator of FoxO1 transcriptional activity in B cells. PMID- 20705245 TI - Spindle position is coordinated with cell-cycle progression through establishment of mitotic exit-activating and -inhibitory zones. AB - How spatial information is translated into a chemical signal is a fundamental problem in all organisms. The spindle position checkpoint is a prime example of this problem. This checkpoint senses spindle position and, in budding yeast, inhibits the mitotic exit network (MEN), a signaling pathway that promotes exit from mitosis. We find that spindle position is sensed by a system composed of MEN inhibitory and -activating zones and a sensor that moves between them. The MEN inhibitory zone is located in the mother cell, the MEN-activating zone in the bud, and the spindle pole body (SPB), where the components of the MEN reside, functions as the sensor. Only when an SPB escapes the MEN inhibitor Kin4 in the mother cell and moves into the bud where the MEN activator Lte1 resides can exit from mitosis occur. In this manner, spatial information is sensed and translated into a chemical signal. PMID- 20705246 TI - S-nitrosylation of beta-catenin by eNOS-derived NO promotes VEGF-induced endothelial cell permeability. AB - Disruption of adherens junctions between endothelial cells results in compromised endothelial barrier function and in altered angiogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is essential for increased vascular permeability induced by vascular endothelial growth factor (VEGF). However, the molecular mechanisms by which NO modulates endothelial permeability remain elusive. Here, we show that, within adherens junctions, beta-catenin is a substrate for S-nitrosylation by NO. Stimulation of endothelial cells with VEGF induces S-nitrosylation of beta-catenin, which is dependent on expression and activity of eNOS. Furthermore, VEGF-induced S-nitrosylation of beta-catenin is inhibited in eNOS(-/-) mice. We identify Cys619, located within the VE-cadherin interaction site, as the major S-nitrosylation locus in response to VEGF. Inhibition of S-nitrosylation at Cys619 prevents NO-dependent dissociation of beta-catenin from VE-cadherin and disassembly of adherens junction complexes and inhibits VEGF-stimulated endothelial permeability. Thus, we identify S nitrosylation of beta-catenin as a modulator of intercellular contacts between endothelial cells. PMID- 20705247 TI - Concussion in the adolescent athlete/common lower extremity injuries in the skeletally immature athlete. Foreword. PMID- 20705248 TI - Concussion in the adolescent athlete. AB - Concussion in the adolescent athlete is a common sports and recreation injury. Traditional management of concussion in this age group has focused on sport return-to-play decisions. However, new research on mild traumatic brain injury has dramatically changed the management of concussion. During the acute healing phase, physical and cognitive rest are crucial for healing. In the school-aged athlete, new concepts, such as complete brain rest, have made school management decisions as important as sport return-to-play decisions. Despite tremendous improvements in the understanding of concussion, most of the research has been done in young adults. The lack of prospective studies in early adolescent student athletes limits definitive management recommendations. This article reviews the current understanding of the epidemiology, pathophysiology, and clinical presentation of concussion and discusses the unique factors involved in clinical management of concussion in the adolescent student-athlete. PMID- 20705249 TI - Common lower extremity injuries in the skeletally immature athlete. AB - Lower extremity musculoskeletal pain is a common complaint in the adolescent athlete. During rapid growth, several common biomechanical changes occur that may predispose to overuse injury. Unlike fractures, most of these office-based sports medicine complaints are initially evaluated by the primary care provider. This review discusses several of the most common complaints and briefly discusses some clinically significant conditions that masquerade as common injuries. The article discusses only the injuries unique to the growing athlete. The article's goal is to help develop a framework for the pediatric clinician to evaluate common complaints and formulate a plan that includes simple stretches and physical therapy recommendations. PMID- 20705250 TI - Quality of life and its correlates in patients with obsessive-compulsive disorder. AB - The care of patients with obsessive-compulsive disorder (OCD) has raised quality of life (QOL) issues. The purpose of this study was to compare the level of QOL between patients with and without OCD, and to examine the associations between QOL and sociodemographic data, course of illness, psychopathology, perceived social support, and treatment characteristics. The QOL levels measured with the Taiwan version of the Short Form of the World Health Organization Questionnaire on Quality of Life were compared between 57 subjects with OCD and 106 subjects without OCD. The correlates of QOL were examined among subjects with OCD. The analysis revealed that QOL scores for the general, physical, psychological and social relationship domains were lower in the OCD group than in the control group; however, no difference in the environmental domain was found. Multiple factors were associated with poor QOL in subjects with OCD, including comorbid depression, severe obsession symptoms, perceived low social support, severe adverse effects of medication, combined use of mood stabilizers, and low social status. Different domains of QOL are differently affected by OCD. The QOL of subjects with OCD was correlated to multiple factors that were specific to individual subjects and influenced by interactions with treatment and the social environment. PMID- 20705251 TI - Characteristics of undiagnosed liver abscesses on initial presentation at an emergency department. AB - Liver abscesses often present with nonspecific symptoms and laboratory examination abnormalities, resulting in missed diagnoses at emergency departments (ED). The purpose of this study was to determine if there are differences in presentation and prognosis between patients in whom liver abscess is diagnosed at an ED or once the patient has been transferred to a ward. Patients with a liver abscess who were discharged from our hospital between 2005 and 2007 were retrospectively reviewed. We compared the clinical characteristics between patients with liver abscess diagnosed at an ED or in a ward. Patients with liver abscess diagnosed at an ED had more abdominal pain (73.4%vs. 42.9%, p < 0.001), longer duration of symptoms before hospitalization (5.5 days vs. 3.8 days, p = 0.034) and fewer respiratory tract symptoms (12.5%vs. 24.5%, p = 0.05). Fewer cases with abnormal chest X-rays also existed for these patients (4.7%vs. 14.7%, p = 0.048). Cases not diagnosed at ED had delayed diagnoses for 4.41 +/- 3.16 days. Rates of mortality (6.3%vs. 8.2%, p = 0.740), shock (19.5%vs. 20.4%, p = 0.896), and length of hospital stay (19.6 days vs. 22.4 days, p = 0.173) were not significantly different between the patients diagnosed at an ED and those diagnosed later in a ward. Most information collected at the ED could not be used to aid diagnosis. Only abdominal pain was highly associated with liver abscess diagnosed at the ED. Undiagnosed liver abscess presented less abdominal pain and more symptoms or examination abnormalities related to infection of the respiratory and urinary tracts. Abdominal sonography should be performed more frequently at EDs to exclude liver abscess from differential diagnosis. However, further diagnosis and treatment while the patient with liver abscess is attending a ward does not affect prognosis. PMID- 20705252 TI - Effect of low-flow anesthesia education on knowledge, attitude and behavior of the anesthesia team. AB - The aim of this study was to evaluate the effect of education on the knowledge, attitude and behavior of anesthesiology staff and residents towards low-flow anesthesia. The staff and residents in the Department of Anesthesia and Reanimation, Zonguldak Karaelmas University were given theoretical and practical training in delivering low-flow anesthesia. To evaluate their attitudes and behaviors toward low-flow anesthesia, we collected data during the 6 months before training, during the first 3 months after training, and at 4-6 months after training. Anesthesia follow-up records, operation time, volatile anesthetic agent used, and the amount (in liters) of fresh gas low mid-anesthesia were recorded in all three stages. A total of 3,158 patients received general anesthesia and inhalation anesthesia was used in 3,115 of these patients. Our study group consisted of 2,752 patients who had no absolute or relative contraindications to low-flow anesthesia. While the mean fresh gas flow was 4.00 +/- 0.00 L/min before training, this level dropped to 2.98 L/min in the first 3 months after training, and to 3.26 L/min in the following 3 months. The mean fresh gas flow was significantly lower at the two post-training assessments than before training (p < 0.05). In conclusion, low-flow anesthesia may be used more frequently if educational seminars are provided to anesthetists. The use of low flow anesthesia may increase further by allocating more time to this technique in anesthesia training programs provided at regular intervals. PMID- 20705253 TI - Efficacy of modafinil in 10 Taiwanese patients with narcolepsy: findings using the Multiple Sleep Latency Test and Epworth Sleepiness Scale. AB - This is the first report describing the efficacy of modafinil therapy for narcolepsy in patients in Taiwan. The purpose of this study was to compare the objective Multiple Sleep Latency Test (MSLT) and the subjective Epworth Sleepiness Scale (ESS) for evaluating the efficacy of modafinil in treating excessive daytime sleepiness in patients with narcolepsy in Taiwan. Ten consecutive patients with narcolepsy-with-cataplexy who were treated with 200 mg/day modafinil for more than 6 months at our sleep center between January 2003 and December 2007 were included in this study. This comparative study was prompted by the requirement of the Bureau of National Health Insurance in Taiwan that modafinil users need to be followed up with MSLTs every 6-12 months. The mean age at onset of narcolepsy onset in these 10 patients was 11.8 +/- 3.3 years, and eight (80%) were male. We compared the differences in MSLT and ESS between baseline and follow-up at 6-12 months after starting modafinil therapy using paired t tests. ESS scores (p < 0.001) were considerably more sensitive than MSLT scores (p < 0.05) in documenting efficacy of modafinil and that the improvements in MSLT scores were minimal and remained in the pathologically sleepy range. These findings suggest that the ESS is a more sensitive and clinically meaningful tool to evaluate the efficacy of modafinil in narcolepsy. PMID- 20705254 TI - Clinical, radiologic and pathologic characteristics of the Carney triad: a case report and literature review. AB - This report describes a patient with a gastrointestinal stromal tumor (GIST) and upper gastrointestinal hemorrhage as initial presentations of the Carney triad, a synchronous or metachronous condition involving gastric leiomyosarcoma, extra adrenal paraganglioma and pulmonary chondroma. A 26-year-old woman presented with dizziness and several episodes of melena over 3 days. Physical examination revealed pale conjunctiva but normal hemodynamic status. Gastroendoscopy showed one antral submucosal tumor with evidence of an associated bleeder (the bleeder over the mucosal surface of the gastric tumor). An abdominal computed tomography scan showed an antral submucosal tumor, two secondary lesions over segment II/V of the liver and a retroperitoneal tumor. Surgical removal of the tumor and subsequent recovery were uneventful. The gastric GIST with liver metastasis and retroperitoneal paraganglioma were confirmed by pathologic study. The patient was treated with imatinib mesylate for the GIST with liver metastasis, and continued follow-up treatment at our hospital. An abdominal computed tomography scan at 32 months after surgery showed no change in the liver metastatic lesions and no evidence of local recurrence. Another follow-up visit at 33 months after surgery confirmed the stable condition. Of nearly 100 cases reported in the literature, this case is the first to be reported in Taiwan. This case highlights the possibility of this rare syndrome occurring in young female patients with one of the three components of the triad and the need for further diagnostic studies for early identification of tumors when curative surgery is still possible. PMID- 20705255 TI - Method of retention control for compromised periodontal bone support abutment of conical crown retained denture. AB - Conical crown-retained dentures (CCRD) show a higher survival rate and greater patient satisfaction than transitional removable partial dentures during long term follow-up. However, unsustainable denture retention force on supporting abutments after initial delivery and loss retention are frequently seen in long term follow-up of clinical cases. The main causes are insufficient information concerning denture retention designs and the retention-tolerance of the supporting abutments. Monitoring by dental technicians of the quality of dental prostheses is critical. This case report describes an optimal method for CCRD construction that determines and distributes an optimal denture retention force on the supporting abutments to allow the patient to easily remove the denture while ensuring that the CCRD remains in place during physiologic activities. Oral rehabilitation with CCRD should consider the condition of the abutment periodontal support, the interarch occlusal relationship, supplemental fatigue of the terminal abutment, and patient's estimated bite force. The effects of friction on the abutment's inner crown were based on an optimal a angle. The dental laboratory used these measurements to fabricate a CCRD using a Koni-Meter to adjust the retention of the inner crown. This method protects the abutments and reduces the wear between the inner and outer crowns. The CCRD achieved good esthetic results and physiologic functions. Periodic long-term follow-up of the patient and CCRD after initial placement is recommended. PMID- 20705256 TI - Castleman's disease of the parotid gland: a case report. AB - Castleman's disease (CD) is a very rare disorder characterized by non-neoplastic growths in lymph nodes in any body regions, although over 60% of cases are located in the mediastinum. The head and neck is the second most commonly involved site, with up to 14% of cases. Of these, nearly 85% are located in the neck. These lesions rarely occur in the salivary glands. Clinically, CD can be divided into unicentric and multicentric forms. We report an unusual case with unicentric CD presenting as a parotid tumor in a 34-year-old woman. The lesion was found coincidentally during routine cranial magnetic resonance imaging in the absence of symptoms such as swelling or a mass in the parotid region. PMID- 20705257 TI - Relapsed acute pancreatitis as the initial presentation of pancreatic cancer in a young man: a case report. AB - In this report, we describe a 31-year-old man in whom acute pancreatitis was the initial feature of a subsequently diagnosed pancreatic adenocarcinoma with multiple metastases. He initially presented at our hospital with acute pancreatitis. Abdominal ultrasonography revealed a mildly dilated pancreatic duct and an enlarged pancreatic head. Although a follow-up abdominal ultrasonography revealed a progressively dilated pancreatic duct and a progressively enlarged pancreatic head, he refused further investigation and was lost to follow-up. Four months later, he returned to our hospital with relapsed acute pancreatitis. Obstructive jaundice was noted and drainage was performed. Because choledochoplasty with multiple balloon catheters was not fully effective, biliary tract bypass surgery was carried out. Intraoperative biopsy confirmed pancreatic adenocarcinoma with multiple metastases. The patient died of massive gastrointestinal bleeding a few weeks later. To our knowledge, this is the youngest case of pancreatic cancer with the uncommon initial presentation of acute pancreatitis reported in the literature. For a patient with acute pancreatitis, particularly recurrent episodes, but with no known risk factors for pancreatitis, a pancreatic neoplasm should be considered as a potential underlying cause, even in a young man. PMID- 20705258 TI - Intravascular and extravascular microvessel formation in chronic total occlusions a micro-CT imaging study. AB - OBJECTIVES: The purpose of this study was to characterize the 3-dimensional structure of intravascular and extravascular microvessels during chronic total occlusion (CTO) maturation in a rabbit model. BACKGROUND: Intravascular microchannels are an important component of a CTO and may predict guidewire crossability. However, temporal changes in the structure and geographic localization of these microvessels are poorly understood. METHODS: A total of 39 occlusions were created in a rabbit femoral artery thrombin model. Animals were sacrificed at 2, 6, 12, and 24 weeks (n > or =8 occlusions per time point). The arteries were filled with a low viscosity radio-opaque polymer compound (Microfil) at 150 mm Hg pressure. Samples were scanned in a micro-computed tomography system to obtain high-resolution volumetric images. Analysis was performed in an image processing package that allowed for labeling of multiple materials. RESULTS: Two distinct types of microvessels were observed: circumferentially oriented "extravascular" and longitudinally oriented "intravascular" microvessels. Extravascular microvessels were evident along the entire CTO length and maximal at the 2-week time point. There was a gradual and progressive reduction in extravascular microvessels over time, with very minimal microvessels evident beyond 12 weeks. In contrast, intravascular microvessel formation was delayed, with peak vascular volume at 6 weeks, followed by modest reductions at later time points. Intravascular microvessel formation was more prominent in the body compared with that in the proximal and distal ends of the CTO. Sharply angulated connections between the intravascular and extravascular microvessels were present at all time points, but most prominent at 6 weeks. At later time points, the individual intravascular microvessels became finer and more tortuous, although the continuity of these microvessels remained constant beyond 2 weeks. CONCLUSIONS: Differences are present in the temporal and geographic patterns of intravascular and extravascular microvessel formation during CTO maturation. PMID- 20705259 TI - The differences between neovascularization of chronic total occlusion and intraplaque angiogenesis. PMID- 20705260 TI - Stress and rest dynamic myocardial perfusion imaging by evaluation of complete time-attenuation curves with dual-source CT. AB - OBJECTIVES: This study sought to describe a protocol for myocardial perfusion imaging using dipyridamole stress, with 128-slice dual-source computed tomography (CT), and to assess the ability of CT myocardial perfusion imaging (MPI) to detect abnormal flow reserve and infarction in comparison with nuclear MPI (NMPI). BACKGROUND: CT MPI has not been previously described with the 128-slice dual-source CT scanner, or with the complete evaluation of dynamic time attenuation curves of the myocardium. METHODS: Thirty-five patients underwent a stress CT MPI protocol. Complete time-attenuation curves of the myocardium were acquired using a novel scan mode, which acquires prospectively electrocardiogram (ECG)-triggered axial images at 2 rapidly alternating positions. Myocardial blood flow (MBF) values of fixed and reversible defects obtained were compared between rest and stress. Findings on CT MPI were correlated to NMPI. Perfusion defects detected on CT were correlated to coronary stenoses detected on CT angiography (CTA) and invasive coronary angiography (ICA). RESULTS: There was a 1.5-fold difference between stress (1.21 +/- 0.31 cc/cc/min) and rest (0.82 +/- 0.22 cc/cc/min) MBF in normal tissue. In reversible defects, MBF was 0.65 +/- 0.21 cc/cc/min and 0.63 +/- 0.18 cc/cc/min at stress and rest, respectively. In fixed defects, the MBF was 0.57 +/- 0.22 cc/cc/min at stress and 0.54 +/- 0.23 cc/cc/min at rest. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CT MPI for identifying segments with perfusion defects was 0.83, 0.78, 0.79, and 0.82, respectively. ICA results were available for 30 patients. Sensitivity, specificity, PPV, and NPV of CT MPI compared with ICA were 0.95, 0.65, 0.78, and 0.79, respectively. The radiation dose for CT MPI was 9.15 +/- 1.32 mSv for the stress scan and 9.09 +/- 1.40 mSv for the rest scan. CONCLUSIONS: Vasodilator-stress CT MPI may be feasible in human subjects at a radiation dose similar to NMPI. It identifies areas of abnormal flow reserve and infarction with a high degree of correlation to NMPI as well as to stenoses detected in CTA and ICA. PMID- 20705261 TI - Stress myocardial perfusion imaging by computed tomography a dynamic road is ahead. PMID- 20705262 TI - MR molecular imaging of aortic angiogenesis. AB - OBJECTIVES: The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression. BACKGROUND: The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with alpha(nu)beta(3)-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis. METHODS: Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16. RESULTS: Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with alpha(nu)beta(3)-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05). CONCLUSIONS: Neovascular expansion is a prominent feature of the JCR:LA-cp model. MR imaging with alpha(nu)beta(3) targeted nanoparticles provided a noninvasive assessment of angiogenesis in untreated obese rats, which was suppressed by benfluorex. PMID- 20705263 TI - Prevalence of myocardial scar in patients with cryptogenic cerebral ischemic events and patent foramen ovale. AB - OBJECTIVES: This study sought to evaluate the prevalence of subclinical myocardial infarctions with cardiovascular magnetic resonance imaging (CMRI) in patients with patent foramen ovale (PFO) after cryptogenic cerebral ischemic events. BACKGROUND: A thrombotic mass passing a PFO may embolize in cerebral but also in coronary arteries, resulting in both cerebral and myocardial ischemic events. CMRI with late gadolinium enhancement (LGE) analysis is the most sensitive imaging technique to detect small myocardial infarctions. METHODS: PFO patients (n = 74) with a first cryptogenic cerebral ischemic event without a clinical history for myocardial infarction underwent CMRI and coronary angiography. Right and left ventricular volumes and ejection fractions were measured by CMRI. LGE imaging was performed after administration of gadolinium diethylenetriaminepentaacetic acid. The presence of atrial septal aneurysm (ASA) was evaluated by transesophageal echocardiography. RESULTS: LGE was detected in 8 of 74 (10.8%) patients. LGE pattern was transmural or subendocardial. Patients with LGE and those without did not differ in cardiovascular risk factors, type of ischemic event, presence of ASA, right and left ventricular volumes, and ejection fractions. LGE volume was small and comprised only 7.9 +/- 2.4% of left ventricular muscle mass. Coronary artery disease was ruled out in 7 of 8 patients with LGE. There was a trend towards a larger PFO size in patients with LGE compared with patients without LGE (13.2 +/- 4.1 mm vs. 16.0 +/- 2.8 mm, p = 0.06). CONCLUSIONS: Subclinical myocardial infarctions determined in CMRI were observed in 10.8% of patients with PFO after a first cryptogenic cerebral ischemic event. Our results strengthen the pathophysiologic role of a PFO with paradoxical embolism in patients with cryptogenic cerebral ischemic events. PMID- 20705264 TI - PFO and the heart more than meets the eye! PMID- 20705266 TI - Adipose tissue imaging the potential and the challenge. PMID- 20705265 TI - Increased glucose uptake in visceral versus subcutaneous adipose tissue revealed by PET imaging. AB - OBJECTIVES: The current study tested the hypothesis that glucose utilization differs between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and investigated potential mechanisms for such a finding. BACKGROUND: VAT burden correlates better with cardiovascular risk than does SAT burden. Beyond volumetric measurement, glucose uptake in adipose tissue (AT) might reflect metabolic activity and provide pathophysiologic insight and aid risk stratification. METHODS: We retrospectively studied tissue-specific glucose uptake in vivo in clinically obtained whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) scans in humans. We also assessed glucose uptake in vitro, using stromal vascular cells isolated from SAT and VAT of diet-induced obese C57BL/6 mice. Quantitative polymerase chain reaction (PCR) evaluated the expression of multiple genes involved in cellular glucose metabolism, including glucose transporters (GLUT-1, -3, and -4) and hexokinases (HK-1 and -2) in SAT and VAT of obese C57BL/6 mice. RESULTS: We analyzed whole-body FDG-PET scans from 31 obese and 26 lean patients. VAT exhibited higher FDG uptake compared with SAT (p < 0.0001) independent of age, sex, body mass index, comorbidities, and medications. To investigate mechanisms underlying this observation, we studied glucose uptake in the stromal vascular cell fraction of AT, which is rich in inflammatory cells. Stromal vascular cells from VAT of diet-induced obese C57BL/6 mice exhibited higher glucose uptake than those from SAT (p = 0.01). Evaluation of expression of glucose transporters (GLUT-1, -3, and -4) and hexokinases (HK-1 and -2), revealed increased expression of HK-1 in VAT-derived compared with SAT derived stromal vascular cells, and also in visceral versus subcutaneous unfractionated AT. CONCLUSIONS: In humans in vivo, VAT has increased glucose uptake compared with SAT, as determined noninvasively with FDG PET imaging. Differential stromal metabolic activity may be 1 mechanism underlying differences in metabolic activity of visceral and subcutaneous AT. PMID- 20705268 TI - In-line automated tracking for ventricular function with magnetic resonance imaging. AB - An efficient nonrigid registration algorithm was implemented on the image reconstruction computer to enable in-line automatic tracking of features in steady-state free precession cine images. Four-dimensional left ventricle function analysis was performed with and without use of the in-line automatic tracking result. The method was tested in 30 patients referred for cardiac magnetic resonance imaging for a variety of clinical assessments. The time required for in-line tracking was 10 +/- 2 s per slice using an image reconstructor with dual Advanced Micro Devices single-core Opteron 248 CPUs (2.2 GHz) and 8GB random access memory. The precision of clinical estimates of left ventricular volumes was significantly improved relative to the ground truth research estimates with automatic tracking versus without (6 ml vs. 9 ml in end diastolic volume; 5 ml vs. 10 ml in end-systolic volume; both p < 0.05). In-line automatic tracking of image features shows promise for facilitating clinical analysis of ventricular function. PMID- 20705267 TI - Hemodynamic stress echocardiography in patients supported with a continuous-flow left ventricular assist device. AB - Functional assessment of continuous-flow left ventricular assist devices (LVADs) is usually performed with the patient at rest. This study compared echocardiographic indices of contraction and filling pressure with invasive measures in 12 ambulatory LVAD patients undergoing symptom-limited bicycle exercise. Exercise induced an increase in cardiac output, systolic pulmonary artery pressure, and diastolic pulmonary artery pressure. Although no changes in left ventricular dimensions or fractional shortening were seen on echocardiography, systolic mitral annular motion (S') increased significantly (in parallel with cardiac output) and diastolic E/e' ratio decreased (correlating inversely with diastolic pulmonary artery pressure). These findings emphasize the potential role of exercise echocardiography in studying exercise hemodynamics in LVAD patients. PMID- 20705269 TI - Assessment of subendocardial structure and function. AB - The combination of high energy expenditure and the borderline adequacy of perfusion make the subendocardium uniquely vulnerable to injury. Selective subendocardial involvement is usually a marker of subclinical disease. Technical advances in new noninvasive imaging modalities, especially in spatial resolution, now permit qualitative and quantitative assessment of subendocardial structure, function, and perfusion. Many newer techniques have the potential to provide superior prognostic information to current standard assessment methods. This review describes the contemporary capabilities of multiple imaging modalities for assessment of the subendocardium, and seeks to guide the clinician regarding the information and technical deficiencies of each modality. PMID- 20705270 TI - Multimodality imaging atlas of coronary atherosclerosis. PMID- 20705271 TI - The year in intracoronary imaging. PMID- 20705272 TI - Streptococcal pharyngitis-associated myocarditis mimicking acute STEMI. PMID- 20705273 TI - Lipid-rich obstructive coronary lesions is plaque characterization any important? PMID- 20705274 TI - Intracardiac echocardiographic detection of mobile echodensities adherent to the intracardiac leads. PMID- 20705276 TI - Digging deeper with CT imaging: slice-by-micro slice... PMID- 20705277 TI - Language access and language selection in professional translators. AB - Two experiments were conducted measuring self-paced reading to study language access and language selection in professional translators and bilinguals when they understood sentences randomly presented in their first language (L1, Spanish) and second language (L2, English). These sentences contained a critical cognate word or a control matched word. The effect of cognate words was considered an index of between-language activation while the inhibition of the non-target language was examined with the asymmetrical switching cost. In Experiment 1, participants read and repeated sentences while in Experiment 2 participants read sentences without repeating them after reading. The results indicated that lexical processing depended on the experience of participants in professional translation and the demands imposed by the understanding task (reading and repeating or only reading). PMID- 20705278 TI - Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a degenerative disease of the retina leading to progressive loss of vision and, in many instances, to legal blindness at the end stage. The RP28 locus was assigned in 1999 to the short arm of chromosome 2 by homozygosity mapping in a large Indian family segregating autosomal-recessive RP (arRP). Following a combined approach of chromatin immunoprecipitation and parallel sequencing of genomic DNA, we identified a gene, FAM161A, which was shown to carry a homozygous nonsense mutation (p.Arg229X) in patients from the original RP28 pedigree. Another homozygous FAM161A stop mutation (p.Arg437X) was detected in three subjects from a cohort of 118 apparently unrelated German RP patients. Age at disease onset in these patients was in the second to third decade, with severe visual handicap in the fifth decade and legal blindness in the sixth to seventh decades. FAM161A is a phylogenetically conserved gene, expressed in the retina at relatively high levels and encoding a putative 76 kDa protein of unknown function. In the mouse retina, Fam161a mRNA is developmentally regulated and controlled by the transcription factor Crx, as demonstrated by chromatin immunoprecipitation and organotypic reporter assays on explanted retinas. Fam161a protein localizes to photoreceptor cells during development, and in adult animals it is present in the inner segment as well as the outer plexiform layer of the retina, the synaptic interface between photoreceptors and their efferent neurons. Taken together, our data indicate that null mutations in FAM161A are responsible for the RP28-associated arRP. PMID- 20705280 TI - Photoactivated disinfection of Streptococcus intermedius through dentin disc at clinically relevant intervals: an in vitro study. AB - In this present study we have tested the impact of porfimer sodium (Photofrin, AXCAN PHARMA Inc., Quebec, Canada) photoactivated disinfection (PD) on cells of Streptococcus intermedius in suspension. In order to provide basic data to support future clinical studies of PD in dentistry the study used exposure to Quartz-tungsten-halogen (QTH) dental curing light for clinically relevant time periods to activate Photofrin and measured its effectiveness under a variety of conditions including activation through dentin hard tissue. S. intermedius was grown in planktonic suspension for 48h. Nine groups were formed: three control groups (1-3) and six experimental groups (4-9). Groups 4-6 tested the use of Photofrin treatment combined with QTH light at various intervals of irradiation (5, 15 and 60s). Groups 7-9 were similar to groups 4-6 with the exception that irradiation commenced through a dentin disc. Following treatment, bacteria were plated. Colony counts were measured following 72h incubation at 37 degrees C. Statistical analysis was carried out by one-way ANOVA at a 95% confidence level. A significant reduction in S. intermedius colony counts was observed for all experimental groups and one control group. The reduction in numbers of colonies in the experimental groups varied from 79.28 to 99.40% with an average of 94.61%. Reduction in viable bacterial cells indicated a strong relationship between power density and irradiation interval. When curing light energy density was lower due to the irradiation through the 1mm dentin disc, prolonged irradiation interval enhanced bacterial kill. In conclusion, where direct irradiation is not possible for PD treatment, irradiation through dentin may still be done successfully within a clinically relevant interval. PMID- 20705279 TI - Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal recessive retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 45 genes. Using homozygosity mapping, we identified a ~4 Mb homozygous region on chromosome 2p15 in patients with autosomal-recessive RP (arRP). This region partially overlaps with RP28, a previously identified arRP locus. Sequence analysis of 12 candidate genes revealed three null mutations in FAM161A in 20 families. RT-PCR analysis in 21 human tissues revealed high levels of FAM161A expression in the retina and lower levels in the brain and testis. In the human retina, we identified two alternatively spliced transcripts with an intact open reading frame, the major one lacking a highly conserved exon. During mouse embryonic development, low levels of Fam161a transcripts were detected throughout the optic cup. After birth, Fam161a expression was elevated and confined to the photoreceptor layer. FAM161A encodes a protein of unknown function that is moderately conserved in mammals. Clinical manifestations of patients with FAM161A mutations varied but were largely within the spectrum associated with arRP. On funduscopy, pallor of the optic discs and attenuation of blood vessels were common, but bone-spicule like pigmentation was often mild or lacking. Most patients had nonrecordable electroretinographic responses and constriction of visual fields upon diagnosis. Our data suggest a pivotal role for FAM161A in photoreceptors and reveal that FAM161A loss-of-function mutations are a major cause of arRP, accounting for ~12% of arRP families in our cohort of patients from Israel and the Palestinian territories. PMID- 20705281 TI - Knock, and it will be opened to you? An evaluation of meridian-tapping in obsessive-compulsive disorder (OCD). AB - Meridian-tapping (MT) is a body-oriented therapeutic technique which among other psychological problems targets anxiety disorders. Despite bold claims by some of its advocates that it brings lasting success in the vast majority of patients with anxiety disorders, solid empirical evidence for its effectiveness is scarce and its theoretical foundations are refuted by many scientists. The present study tested the effectiveness of a published MT self-help approach for obsessive compulsive disorder (OCD). Following a baseline assessment over the internet including standard outcome measures for OCD (Y-BOCS, OCI-R) and depression (BDI SF), 70 participants with OCD were randomly allocated to MT or to progressive muscle relaxation (PMR). Four weeks after the dispatch of the self-help manuals (including video demonstrations of the technique), participants were requested to take part in a post assessment. Whereas subjects found MT more helpful than PMR in retrospect (39% versus 19%) and would continue to use it in the future (72% versus 48%) there was no evidence for a stronger decline of OCD symptoms under MT on any of the psychometric measures. Moreover, Y-BOCS scores did not significantly change across time for both interventions. The present study does not support bold claims about the effectiveness of MT as a stand-alone technique. Cognitive-behavioral therapy remains the treatment of choice for OCD. While self help MT may enhance the well-being of a subgroup of participants, its potential for OCD appears to be small. Exaggerated success claims on the effectiveness of MT in conjunction with degrading appraisals of conventional psychotherapy as made by some of its leading figures may in our view foster fatalism in patients not experiencing major symptom relief by MT. PMID- 20705282 TI - Trouble ahead, trouble behind: Narcissism and early maladaptive schemas. AB - Narcissism is a multifaceted construct that is inconsistently defined and assessed between clinical psychology and social-personality psychology. The purpose of the present study was to examine the similarities and differences in the cognitive schemas underlying various forms of narcissism. This was accomplished by examining the associations of normal and pathological forms of narcissism with the early maladaptive schemas. The results showed important similarities in these associations (e.g., all of the narcissism scales were positively associated with the entitlement schema) as well as differences (e.g., vulnerable narcissism was the only form of narcissism that was positively associated with subjugation). Discussion focuses on the implications of these results for the ways in which individuals with these forms of narcissism perceive and navigate their social environments. PMID- 20705283 TI - Simulation studies of the insolubility of cellulose. AB - Molecular dynamics simulations have been used to calculate the potentials of mean force for separating short cellooligomers in aqueous solution as a means of estimating the contributions of hydrophobic stacking and hydrogen bonding to the insolubility of crystalline cellulose. A series of four potential of mean force (pmf) calculations for glucose, cellobiose, cellotriose, and cellotetraose in aqueous solution were performed for situations in which the molecules were initially placed with their hydrophobic faces stacked against one another, and another for the cases where the molecules were initially placed adjacent to one another in a co-planar, hydrogen-bonded arrangement, as they would be in cellulose Ibeta. From these calculations, it was found that hydrophobic association does indeed favor a crystal-like structure over solution, as might be expected. Somewhat more surprisingly, hydrogen bonding also favored the crystal packing, possibly in part because of the high entropic cost for hydrating glucose hydroxyl groups, which significantly restricts the configurational freedom of the hydrogen-bonded waters. The crystal was also favored by the observation that there was no increase in chain configurational entropy upon dissolution, because the free chain adopts only one conformation, as previously observed, but against intuitive expectations, apparently due to the persistence of the intramolecular O3-O5 hydrogen bond. PMID- 20705284 TI - Expression profile of IL-8 and growth factors in breast cancer cells and adipose derived stem cells (ASCs) isolated from breast carcinoma. AB - Adipose-derived stem cells (ASCs) are regarded as a major player of breast cancer microenvironment. By production of various growth factors and expression of regulatory molecules, it is postulated that ASCs protect breast cancer cells from the host immune responses. In this study, the expressions of insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), CXCL8 (IL-8) in breast cancer cells and adipose-derived stem cells isolated from breast tissue of women with breast cancer were investigated. The results were analyzed comparatively in normal ASCs isolated from healthy normal women. In case of breast cancer tissues, results were analyzed between high stage and low stage patients. The expressions of extracted mRNAs were determined using real-time quantitative RT-PCR. As a result, in breast cancer tissues, IGF-1 and IL-8 mRNAs had 28.6 and 56-fold more expressions in high stage compared to low stage patients. In ASCs, relative quantifications (RQ) of VEGF, IL-8, HGF and IGF 1 was about 2-fold higher in patients than controls. Data of this study conclude that presence of resident ASCs within the scaffold of breast tissue may support breast tumor growth and progression through the expressions of tumor promoting factors. PMID- 20705285 TI - [Historic analysis of complex incisional hernia: to an understanding of the double prosthetic repair technique]. AB - The treatment of complex incisional hernias is, on occasions, a real social and professional, and still controversial, challenge. A multitude of techniques have been described over the years in an attempt to solve this problem. The social context and technological development of each period are essential to understand the continuous changes in the way of performing these techniques. This article caries out an historical review of the prosthetic treatment of incisional hernias, trying to understand and apply the basic principles of the treatment of all incisional hernias to the repair with a double mesh. PMID- 20705286 TI - [Laparoscopic transumbilical cholecystectomy. Results with the gel device and literature review]. PMID- 20705287 TI - WITHDRAWN: Corrigendum to "High-sensitive cardiac troponin I (hs-cTnl) values in patients with stable cardiovascular disease: An initial foray" [Clinica Chimica Acta 411 (2010) 812--817]. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20705288 TI - Psychological factors contributing to perceptions pain intensity after acute orthopaedic injury. AB - Psychological factors are capable of influencing an individual's perception of pain and may mediate the evolution from acute to chronic pain. Personality characteristics, such as alexithymia and anxiety sensitivity, can also influence perception of pain by somatising psychological distress associated with acute pain. The aim of this study was to understand if alexithymia and anxiety sensitivity interact with psychological distress at an early stage of recovery from orthopaedic injury, to accentuate perception of pain intensity and potentially mediate the development of chronic pain disorder. 62 patients who had recently suffered orthopaedic injury completed the British Pain Society Pain Rating Scale plus the Hospital Anxiety and Depression Scale, as well as measures of alexithymia and anxiety sensitivity. Pain intensity correlated with each of the psychological measures but a regression analysis found that only depression, in combination with anxiety sensitivity, contributed to a significant amount of the variance in pain scores. The authors suggest that early screening after orthopaedic injury could identify those vulnerable to developing persisting pain disorders. This could lead to effective early intervention using psychological methods of pain management to reduce the risk of acute pain evolving into a chronic pain disorder. PMID- 20705289 TI - Relationship between umbilical artery Doppler waveform analysis and perinatal prognosis in women with intrahepatic cholestasis of pregnancy. PMID- 20705290 TI - One- and two-day mifepristone-misoprostol intervals for second trimester termination of pregnancy between 13 and 16 weeks of gestation. AB - OBJECTIVE: To compare the efficacy of 1-day and 2-day mifepristone and misoprostol intervals for second trimester termination of pregnancy between 13 and 16 weeks. METHODS: A prospective randomized cohort study of 100 women who underwent voluntary termination between 13 and 16 weeks of gestation. Patients were randomly assigned to receive 200mg of oral mifepristone, followed 1 day (group 1) or 2 days (group 2) later by 600 MUg of vaginal misoprostol. All patients received 400 MUg of oral misoprostol every 6 hours for a maximum of 2 doses. Main outcome measure was successful abortion rate at 24 hours after the start of misoprostol treatment. Secondary outcome measures were induction-to abortion interval and frequency of adverse events. RESULTS: The 24-hour successful abortion rate was similar between groups 1 and 2 (47 [94%] vs 50 [100%]; P = 0.241). The mean misoprostol-to-abortion interval was also similar (7.0 +/- 3.0 vs 6.8 +/- 4.3 hours; P = 0.744). Among the 86 patients for whom histological examination of the products of conception was performed, retained chorionic villi rates were higher in the 1-day regimen group compared with the 2 day regimen group (46.2% [18/39] vs 29.8% [14/47]; P<0.001). CONCLUSION: A 2-day mifepristone-misoprostol interval resulted in fewer incomplete abortions than a 1 day interval for second trimester termination of pregnancy between 13 and 16 weeks. PMID- 20705291 TI - The legal status of in vitro embryos. AB - Judicial approaches to stored (cryopreserved) human embryos, in western jurisprudence, tend not to reflect approaches within systems of moral ordering or particular religious traditions, which differ among themselves. The emerging judicial approach is pragmatic, protecting individuals' rights of control and their interests in parenthood. Embryos are approached instrumentally, not by reference to any inherent characteristics that may be attributed to them outside the law. Political legislatures may adopt religious approaches, such as by prohibiting embryo preservation and limiting how many may be created in an IVF treatment cycle. Legislatures may alternatively set time limits on embryo preservation, however, on expiry of which they must be left to natural degeneration. In treating human embryos as property, courts recognize owners' powers of voluntary disposition, for instance by gift, but have held back from making financial assessments of their value, for instance on loss, consistently with legislation prohibiting their exchange for payment. PMID- 20705292 TI - The effect of fenofibrate on lymphocyte cytokine release in patients with impaired fasting glucose and impaired glucose tolerance: a preliminary report. AB - OBJECTIVE: The aim of our study was to investigate the effect of fenofibrate on lymphocyte secretory function in patients with isolated early glucose metabolism abnormalities. METHODS: Fifty-eight patients with impaired fasting glucose (IFG), fifty-six subjects with impaired glucose tolerance (IGT) and fifty-five normolipidemic control subjects with asymptomatic atherosclerosis, were treated for 90 days with either micronized fenofibrate (200 mg/day) or placebo. RESULTS: Compared to control subjects, lymphocytes of both IGF and IGT patients released more amounts of interleukin-2, interferon-gamma and TNF-alpha, and exhibited higher plasma levels of hsCRP. Despite improving glucose metabolism markers in both IFG and IGT subjects, fenofibrate reduced lymphocyte cytokine release only in the latter group of patients. CONCLUSIONS: Our results show for the first time that lymphocyte secretory function is disturbed at early stages of glucose metabolism disturbances and that IGT- but not IFG-induced abnormal function of T cells is corrected by fenofibrate administration. PMID- 20705293 TI - Low-level noise affects balance control differently when applied at different body parts. AB - The main purpose of this study was to determine which body part is the best position to apply noise at so that balance control can be improved most. Twelve young healthy participants were recruited in this study. Balance control was assessed by center of pressure (COP) measures, which were collected when participants were blindfolded and stood upright quietly on a force platform. Low level mechanical noise was separately applied at seven body parts during quiet upright stance, including the forehead, neck, shoulder, finger, abdomen, knee, and ankle. Results showed that dependent COP measures as a whole were not improved when noise was at the finger, shoulder, abdomen, knee, and ankle. In contrast, with the application of noise at the forehead and neck, the dependent COP measures as a whole significantly changed. The forehead appeared to be the better position at which noise should be applied, since the ANOVAs revealed that body sway significantly decreased with the application of noise at the forehead. Findings from this study can aid in the development of noise-based intervention strategies aimed at improving balance. A possible intervention solution might be embedding noise-based devices into head belt. PMID- 20705294 TI - Strain-energy function and three-dimensional stress distribution in esophageal biomechanics. AB - Knowledge of the transmural stress and stretch fields in esophageal wall is necessary to quantify growth and remodeling, and the response to mechanically based clinical interventions or traumatic injury, but there are currently conflicting reports on this issue and the mechanical properties of intact esophagus have not been rigorously addressed. This paper offers multiaxial data on rabbit esophagus, warranted for proper identification of the 3D mechanical properties. The Fung-type strain-energy function was adopted to model our data for esophagus, taken as a thick-walled (1 or 2-layer) tubular structure subjected to inflation and longitudinal extension. Accurate predictions of the pressure radius-force data were obtained using the 1-layer model, covering a broad range of extensions; the calculated material parameters indicated that intact wall was equally stiff as mucosa-submucosa, but stiffer than muscle in both principal axes, and tissue was stiffer longitudinally, concurring our histological findings (Stavropoulou et al., Journal of Biomechanics. 42 (2009) 2654-2663). Employing the material parameters of individual layers, with reference to their zero-stress state, a reasonable fit was obtained to the data for intact wall, modeled as a 2 layer tissue. Different from the stress distributions presented hitherto in the esophagus literature, consideration of residual stresses led to less dramatic homogenization of stresses under loading. Comparison of the 1- and 2-layer models of esophagus demonstrated that heterogeneity induced a more uniform distribution of residual stresses in each layer, a discontinuity in circumferential and longitudinal stresses at the interface among layers, and a considerable rise of stresses in mucosa, with a reduction in muscle. PMID- 20705295 TI - Thermosensitive gels incorporating polythioether units for the selective extraction of class b metal ions. AB - Novel temperature-responsive copolymers of N-isopropylacrylamide and monoaza tetrathioether derivative, were synthesized for the selective extraction of soft metal ions such as silver(I), copper(I), gold(III) and palladium(II) ion. The ratio between N-isopropylacrylamide group and monoaza-tetrathioether group in the copolymer was determined. The ratio between N-isopropylacrylamide group and monoaza-tetrathioether group varied in the range of 66:1-187:1. Each lower critical solution temperature (LCST) of the polymer solution was determined spectrophotometrically by the relative absorbance change at 750 nm via temperature of the polymer solution. Metal ion extraction using the copolymer with appropriate counter anions such as picrate ion, nitrate or perchlorate ion was examined. Soft metal ions such as silver(I), copper(I), gold(III) and palladium(II) ion were extracted selectively into the solid polymer phase. The extraction efficiency of a metal ion such as silver ion increased as the increase of the ratio of the monoaza-tetrathioether group to N-isopropylacrylamide group in the polymer. The quantitative extraction of class b metal ions as well as the liquid-liquid extraction of metal ions with monoaza-tetrathioether molecule was performed. PMID- 20705296 TI - Folding/aggregation of graphene oxide and its application in Cu2+ removal. AB - Graphene oxide (GO) can be aggregated by Cu(2+) in aqueous solution with a huge Cu(2+) absorption capacity. The Cu(2+) causes GO sheets to be folded and also to form large aggregates that were characterized by confocal microscopy and atomic force microscopy. The folding/aggregation is most likely triggered by the coordination between GO and Cu(2+). The equilibrium Cu(2+) concentrations and equilibrium absorption capacity of GO were measured to estimate the maximum absorption capacity of GO for Cu(2+) and the absorption model. GO has a huge absorption capacity for Cu(2+), which is around 10 times of that of active carbon. Representative results are presented and the implication to Cu(2+) removal is discussed. PMID- 20705297 TI - Phase transformation in CaCO3 polymorphs: a spectroscopic, microscopic and diffraction study. AB - This study presents results of the phase transformation from Cm(III) and Eu(III) doped vaterite to calcite. This transformation of one solid solution (An/Ln:vaterite) to another (An/Ln:calcite) was observed by powder X-ray diffraction and scanning electron microscopy. These observations were combined with site-selective time-resolved laser fluorescence spectroscopy (TRLFS), using Eu(3+) and Cm(3+) as atomic probes, which give an internal view of the structure. The transition from vaterite to the thermodynamically stable CaCO(3) polymorph calcite lasts several days. It could be shown that the transformation is taking place in four steps: initial precipitation of low crystalline vaterite, followed by transformation into the crystalline phase, upon suspending the vaterite in CaCO(3) solution the phase transformation to calcite starts. As third step a transition state with again partly hydrated Eu(3+) can be observed before the transformation is completed after 72h. No transition is observed in vaterite kept in vacuum, demonstrating that the transition follows a dissolution/precipitation mechanism. Comparison with Eu(3+)-doped calcite directly synthesized under near equilibrium conditions shows that identical solid solutions are formed, independent of the reaction path. Moreover the trivalent guest cations are fully transferred to the newly formed phase. This is strong evidence for a thermodynamic driving force for the solid solution formation in these systems. PMID- 20705298 TI - Humic acid-inspired hybrid materials as heavy metal absorbents. AB - Three SiO(2)-based materials were prepared via covalent immobilization of carboxyl groups (COOH), phenolic groups (GA), or humic acid on an SiO(2) surface. Their sorbing properties were evaluated for removal of heavy metals (Pb(2+), Cd(2+), Cu(2+), Zn(2+), and Mg(2+)) from aqueous solution. The data show a significant improvement for metal uptake, compared to unmodified silica that can be attributed to the adsorption of metals to the deprotonated form of functional groups (COOH, GA, HA). The metal-uptake capacity of the SiO(2)-HA material was 10 times higher that those of the other two materials. The present data provide direct experimental proof that HA can be viewed and modeled as a combination of COO and R-OH functional groups. PMID- 20705299 TI - Morphology-tunable fibers with Fe3O4 nanocrystals fabricated through assembly. AB - A facile method has been developed to encapsulate Fe(3)O(4) nanocrystals (NCs) in morphology-tunable fibers (belt-like, solid, and tubal) by using a sonochemistry driven synthesis and a subsequent reflux procedure. By adapting the use of tetraethyl orthosilicate, ammonia, Cd(2+), and thiolglycolic acid (TGA) to an ultrasound-driven synthesis, the Fe(3)O(4) NCs were coated with a thin composite shell. Supersonic treatment plays an important role to prevent the agglomeration of the Fe(3)O(4) NCs in an alkaline condition. The composite shell became thicker due to the deposition of SiO(2) monomers, Cd-TGA clusters, Cd(2+), and free TGA molecules during reflux. In addition, these composite shell-coated Fe(3)O(4) NCs were assembled in composite fibers which were created by the growth of Cd-TGA clusters and the deposition of SiO(2) monomers. The Fe(3)O(4) NCs mono-dispersed in fibers revealed superparamagnetic behavior. The magnetic saturation value of tubal fibers is lower than those of belt-like and solid fibers. These fibers with Fe(3)O(4) NCs would be utilizable for further application. The strategy described here should give a useful enlightenment for the design and fabrication of morphology-tunable fibers with functional NCs. PMID- 20705300 TI - Effect of solution chemistry on particle characteristics during metal sulfide precipitation. AB - Metal sulfide precipitation forms an important component of acid mine drainage remediation systems based on bacterial sulfate reduction. The precipitation reaction is thermodynamically favorable, but a number of technical issues remain. In this study the effect of metal to sulfide molar ratio and operating pH on the nature and settling characteristics of copper and zinc sulfide precipitates was studied in a CSTR. A large number of small copper sulfide particles, with highly negatively charged surfaces and poor settling characteristics, were formed in the presence of a stoichiometric excess of sulfide at pH 6. The size and the settling characteristics of the particles were significantly improved, while the number of particles and magnitude of their zeta potential decreased when experiments were conducted at pH values <6. By comparison, for zinc sulfide, a small change in the number and size of the particles was observed for all metal to sulfide molar ratios and tested operating pH values. Precipitates generated at pH 6 had the most negative zeta potential, while operating at pH values <6 reduced the magnitude of the negative surface charge and improved the settling and dewatering characteristics of the precipitate. The data indicated that the amount of reactive sulfide species (HS(-) and S(2-) ions) available in solution during the precipitation process was important in determining the nature and surface characteristics of the particles produced and this was mainly dependent on pH. PMID- 20705301 TI - Synchronized motion of the water surfaces around two fixed camphor disks. AB - The synchronized motion of the water surfaces in contact with two fixed camphor disks was investigated. When the distance between the two camphor disks was greater than 8 mm, the shapes of the water surfaces at the bottoms of the disks oscillated independently. In contrast, synchronized oscillation was observed when the distance was shorter than 7 mm. Depending on the distance, the nature of the Marangoni convection and the difference in the shape of the meniscus changed. The convection was numerically simulated based on the Navier-Stokes equation. The mechanism of synchronization is discussed in relation to the rolling structure of the Marangoni convection. PMID- 20705302 TI - One-step direct reconstitution of biomembranes onto cationic organic polymer bead supports. AB - In this study, we addressed the straightforward reconstitution of red blood cell (RBC) membranes on the surface of cationic organic polymer beads. The RBC membrane-bead complex was obtained by the incubation of white, unsealed rat RBC ghost membranes with a nonporous quaternary ammonium-type anion-exchange polymer bead with a 350-550 microm diameter. Confocal microscopic observations using a fluorescence membrane probe revealed that the RBC membranes were reconstituted on the outer surface of the bead without any remarkable structural gaps in the membrane. The absence of activity of two peripheral enzymes that latently reside on the cytoplasmic face of the RBC membranes demonstrated that the orientation of the RBC membranes immobilized on the beads was asymmetric as well as that in the native state. The RBC membrane-polymer bead complex was incubated with a primary antibody that is directed against the amino-terminal extracellular domain of the integral protein glycophorin A (GPA). The resulting complex was further incubated with a fluorescent secondary antibody and then subjected to confocal microscopic observations. Fluorescence resulting in the binding of the secondary antibody was found on the surface of the complex, which indicates that the amino-terminal extracellular domain of GPA is exposed to the surface of the complex. In addition, the anion uptake function of the most abundant integral protein anion exchanger 1 (AE1) immobilized on the polymer beads was inhibited by pretreatment with its specific inhibitor 4,4'-diisothiocyano-2,2'-stilbene disulfonate, as is observed for the intact RBCs. Based on all these results, the RBC membranes were thought to be reconstituted on the ionic polymer beads by our one-pot procedure while maintaining the orientation and functions of the membrane proteins to some extent. PMID- 20705304 TI - Coastal upwelling, circulation and heat balance around New Caledonia's barrier reef. AB - An outstanding characteristic of New Caledonia upwelling is that most events appear limited to the southern half of the western barrier reef. This north-south difference cannot be explained by alongshore variability of the projected wind stress and no strong evidence for alternative explanations has been proposed. A major objective of this paper is to provide the first dynamical analysis of New Caledonia upwelling and its regional environment, based on numerical simulations. Coastal upwelling around New Caledonia is shown to be modulated by a system of geostrophic currents interacting with the island mass. Upwelling velocities are weaker than expected from the two-dimensional Ekman theory, as Ekman divergence is balanced by "coastal geostrophic convergence". The cooling effect of upwelling is also attenuated by alongshore transport of warm water by the Alis current, reminiscent of the Leeuwin current off Western Australia. Nevertheless, coastal upwelling can locally modify the large-scale surface water heat budget, dominated by meridional advection warming and surface cooling. The upwelled waters appear to be mostly of western origin and are transported below the surface by the Subtropical Counter Current before upwelling off New Caledonia. This appears in sharp contrast with the eastern barrier reef where the general warming by meridional advection of tropical surface waters is accentuated by the vigorous western boundary type Vauban current. PMID- 20705303 TI - Periventricular leucomalacia (PVL)-like lesions in two neonatal cynomolgus monkeys (Macaca fascicularis). AB - Periventricular leucomalacia (PVL) is a lesion of immature cerebral white matter that occurs in the perinatal period. In man, PVL is the predominant form of brain injury and a cause of cerebral palsy and cognitive deficits in premature infants. PVL affects fetuses and newborns, particularly those who have undergone oxygen deprivation as may occur in premature birth. Many clinical and pathological studies of PVL have been performed in man, but there is no clear definition of PVL in animals. A few spontaneous PVL-like cases in puppies or experimental cases in other animal species have been reported. The present study reports the histopathological and immunohistochemical features of PVL-like lesions in two neonatal cynomolgus monkeys. In both cases, there was cerebral white matter necrosis with marked infiltration of lipid-laden phagocytes and a reduction of neurons in the cerebral cortex. In case 1 there was extensive cavitation of the cerebral white matter. In case 2 there was reactive astrocytosis associated with a decrease in oligodendroglial cells and a decrease in cerebral white matter myelin. To our knowledge, this is the first report of PVL-like leucoencephalomalacia in non-human primates. PMID- 20705305 TI - Incidental radiographic findings after injury: dedicated attention results in improved capture, documentation, and management. AB - BACKGROUND: With liberal use of computed tomography in the diagnostic management of trauma patients, incidental findings are common and represent a major patient care and medical-legal concern. Consequently, we began an initiative to capture, notify, and documentadequately incidental finding events with a dedicated incidental finding coordinator. We hypothesized a dedicated incidental finding coordinator would increase incidental finding capture and promote notification, follow-up, and documentation of incidental finding events. METHODS: A quality improvement project to record and follow-up incidental findings postinjury was initiated at our level I trauma center (April 2007-March 2008, prededicated incidental finding). Because of concerns for inadequate documentation of identified incidental finding events, we implemented a dedicated incidental finding coordinator (April 2008-March 2009, postdedicated incidental finding). The dedicated incidental finding coordinator documented incidental findings daily from trauma admission radiology final reads. Incidental findings were divided into 3 groups; category 1: attention prior to discharge; category 2: follow-up with primary doctor within 2 weeks; category 3: no specific follow-up. For category 1 incidental findings, in-hospital consultation of the appropriate service was verified. On discharge, patient notification, follow-up, and documentation of events were confirmed. Certified mail or telephone contact was used to notify either the patient or the primary doctor in those who lacked appropriate notification or documentation. RESULTS: Admission rates and incidental finding categories were similar across the 2 time periods. Implementation of a dedicated incidental finding coordinator resulted in more than a 165% increase in incidental finding capture (n = 802 vs n = 302; P < .001). Patient notification was attempted, and appropriate documentation of events was confirmed in 99.8% of patients. Patient notification was verified, and follow-up was initiated in 95.8% of cases. CONCLUSION: The implementation of a dedicated incidental finding coordinator resulted in more than a 2.5-fold higher capture of incidental findings. Dedicated attention to incidental findings resulted in a near complete initiation of patient notification, follow-up, and hospital record documentation of incidental finding events. Inadequate patient notification and follow-up would delay appropriate care and potentially would result in morbidity or even mortality. A dedicated incidental finding coordinator represents a potential solution to this patient-care and medical-legal dilemma. PMID- 20705306 TI - Verification of proficiency in basic skills for postgraduate year 1 residents. AB - BACKGROUND: The American College of Surgeons and Association of Program Directors in Surgery Phase 1 curriculum involves basic surgical skills instructional modules and Verification of Proficiency. This article is a study and revision of beta versions of the Verification of Proficiency instruments. METHODS: Postgraduate year 1 residents were tested on 11 skills after undergoing lab instruction and practice. Deidentified videotaped performances were scored and data were analyzed to identify correlations between individual checklist items and failure. RESULTS: In all, 23 residents underwent Verification of Proficiency over 2 years; 8 (35%) passed all Verification of Proficiency examinations at the first attempt, 15 (65%) failed at least 1 module, and 11 (48%) failed at least 2 modules. Residents who failed to demonstrate proficiency underwent mandatory remediation and retested until their scores were considered proficient. Scrutiny of the results revealed checklist items that were predictive independently of overall failure. The pass rate was significantly greater in 2009 compared with 2008 after the introduction of rater training and consequences for failure. CONCLUSION: Verification of Proficiency provides a framework to evaluate learner progress toward skills proficiency. That we achieved 100% faculty compliance with more than 250 performances speaks to the feasibility of Verification of Proficiency. This approach should facilitate a more widespread Verification of Proficiency acceptance as a step closer to developing a final proficiency examination for basic surgical skills in postgraduate year 1 residents. PMID- 20705307 TI - Do preclinical background and clerkship experiences impact skills performance in an accelerated internship preparation course for senior medical students? AB - BACKGROUND: Dedicated skills courses may help to prepare 4th-year medical students for surgical internships. The purpose of this study was to analyze the factors that influence the preparedness of 4th-year medical students planning a surgical career, and the role that our skills course plays in that preparedness. METHODS: A comprehensive skills course for senior medical students matching in a surgical specialty was conducted each spring from 2006 through 2009. Students were surveyed for background skills, clerkship experience, and skills confidence levels (1-5 Likert scale). Assessment included 5 suturing and knot-tying tasks pre- and postcourse and a written examination. Data are presented as mean values +/- standard deviations; statistical analyses were by 2-tailed t test, linear regression, and analysis of variance. RESULTS: Sixty-five 4th-year students were enrolled; most common specialties were general surgery (n = 22) and orthopedics (n = 16). Thirty-five students were elite musicians (n = 16) or athletes (n = 19) and 8 regular videogamers. Suturing task times improved significantly from pre- to postcourse for all 5 tasks (total task times pre, 805 +/- 202 versus post, 627 +/- 168 seconds [P < .0001]) as did confidence levels for 8 skills categories, including management of on-call problems (P < .05). Written final examination proficiency (score >=70%) was achieved by 81% of students. Total night call experience 3rd year was 23.3 +/- 10.7 nights (7.3 +/- 4.3 surgical call) and 4th year 10.5 +/- 7.4 nights (7.2 +/- 6.8 surgical call). Precourse background variables significantly associated with outcome measures were athletics with precourse suturing and 1-handed knot tying (P < .05); general surgery specialty and instrument tying (P = .012); suturing confidence levels and precourse suturing and total task times (P = .024); and number of nonsurgical call nights with confidence in managing acute on-call problems (P = .028). No significant correlation was found between these variables and postcourse performance. CONCLUSION: Completion of an accelerated skills course results in comparable levels of student performance postcourse across a variety of preclinical backgrounds and clerkship experiences. PMID- 20705308 TI - Dr John W. Kirklin (1917-2004): a unique surgeon. PMID- 20705309 TI - The persistence in the liver of residual duck hepatitis B virus covalently closed circular DNA is not dependent upon new viral DNA synthesis. AB - Residual hepatitis B virus (HBV) DNA can be detected following the resolution of acute HBV infection. Our previous work using duck hepatitis B virus (DHBV) infected ducks, indicated that ~80% of residual DHBV DNA in the liver is in the covalently closed circular DNA (cccDNA) form, suggesting that viral DNA synthesis is suppressed. The current study asked more directly if maintenance of residual DHBV cccDNA is dependent upon ongoing viral DNA synthesis. Ducks that recovered from acute DHBV infection were divided into 2 groups and treated with the antiviral drug, Entecavir (ETV), or placebo. No major differences in the stability of cccDNA or levels of residual cccDNA were observed in liver biopsy tissues taken 95 days apart from ETV treated and placebo control ducks. The data suggest that residual DHBV cccDNA is highly stable and present in a cell population with a rate of turnover similar to normal, uninfected hepatocytes. PMID- 20705310 TI - Baculoviruses deficient in ie1 gene function abrogate viral gene expression in transduced mammalian cells. AB - One of the newest niches for baculoviruses-based technologies is their use as vectors for mammalian cell transduction and gene therapy applications. However, an outstanding safety issue related to such use is the residual expression of viral genes in infected mammalian cells. Here we show that infectious baculoviruses lacking the major transcriptional regulator, IE1, can be produced in insect host cells stably transformed with IE1 expression constructs lacking targets of homologous recombination that could promote the generation of wt-like revertants. Such ie1-deficient baculoviruses are unable to direct viral gene transcription to any appreciable degree and do not replicate in normal insect host cells. Most importantly, the residual viral gene expression, which occurs in mammalian cells infected with wt baculoviruses is reduced 10 to 100 fold in cells infected with ie1-deficient baculoviruses. Thus, ie1-deficient baculoviruses offer enhanced safety features to baculovirus-based vector systems destined for use in gene therapy applications. PMID- 20705311 TI - Heparin sulphate D-glucosaminyl 3-O-sulfotransferase 3B1 plays a role in HBV replication. AB - Hepatitis B virus infection is a worldwide epidemic and is closely associated with the development of hepatocellular carcinoma. Nevertheless, the molecular mechanisms of HBV infection and carcinogenesis remain elusive. Using a hepatocyte model of HBV infection and comparing the gene expression profiling analysis we found that heparan sulfate D-glucosaminyl 3-O-sulfotransferase 3 B1 (HS3ST3B1,3 OST3-B) is down-regulated in the hepatocytes of chronic HBV infection model. HS3ST3B1 showed potent inhibitory effect on HBV replication. The inhibitory effect of HS3ST3B1 overexpression was lost upon gene silencing of HS3ST3B1 or when a catalytic inactive mutant of HS3ST3B1 was expressed. Our study revealed the anti-viral activity of HS3ST3B1 on HBV replication. It is conceivable that possible therapeutic applications of HBV infection could be devised by manipulating HS3ST3B1 activity. PMID- 20705312 TI - Concentration-dependent response of estrone-degrading bacterial community in activated sludge analyzed by microautoradiography-fluorescence in situ hybridization. AB - Inefficient removal of estrone (E1) in wastewater treatment plants (WWTPs) causes feminizing effects in male aquatic creatures. As E1 is mainly removed by biodegradation, investigation of E1 degradation is important to determine better removal strategies. Using microautoradiography-fluorescence in situ hybridization (MAR-FISH), we demonstrated that the structures of [(3)H]E1-incorporating bacterial communities were different at different E1 concentrations applied to activated sludge. At 200 MUg/L E1, almost all [(3)H]E1-incorporating cells were associated with either Betaproteobacteria or Gammaproteobacteria (60% and 40% of MAR (+) cells, respectively). The proportion of Betaproteobacteria and Gammaproteobacteria in the total number of [(3)H]E1-incorporating cells decreased as the concentration of E1 decreased. In contrast, the proportion of Alphaproteobacteria in the total number of [(3)H]E1-incorporating cells increased as the concentrations of E1 decreased. At the lowest applied concentration (540 ng/L), almost all the [(3)H]E1-incorporating cells were Alphaproteobacteria (96%). The results of MAR-FISH applied to sludge samples collected from various plant locations and activated sludge processes, and during different seasons also demonstrated the high contribution of Alphaproteobacteria to the entire E1 degrading bacterial community (50.4 +/- 11% of the total number of [(3)H]E1 incorporating cells) at 1 MUg/L E1. Since the E1 concentration in domestic wastewater is at sub-MUg/L levels, the key E1 degraders in activated sludge of domestic WWTPs are probably be Alphaproteobacteria. All [(3)H]E1-incorporating Alphaproteobacteria were hybridized with probe ALF968. Few MAR (+) cells were Sphingomonadales. An E1-degrading bacterial community at low E1 concentration appeared to consist of diverse bacterial groups of Alphaproteobacteria. This study suggested that substrate concentration is an essential factor for revealing E1-degrading bacteria in complex communities. PMID- 20705313 TI - Bacteria from drinking water supply and their fate in gastrointestinal tracts of germ-free mice: a phylogenetic comparison study. AB - Microorganisms in drinking water sources may colonize in gastrointestinal (GI) tracts and this phenomenon may pose a potential health risk especially to immunocompromised population. The microbial community diversity of the drinking water was compared with the GI tracts of the mice using phylogenetic and statistical analyses of 16S rRNA gene sequences. A group of germ-free mice were fed with drinking water from public water supply that passed through an automated watering system with documented biofilm accumulation. From drinking water and GI tracts of the germ-free mice, 179 bacteria were isolated and 75 unique 16S rRNA gene phylotypes were sequenced as operational taxonomic unit (OTU, >97% similarity). Three major groups of the genus Acidovorax (21%), Variovorax (42%) and Sphingopyxis (15%) were found in drinking water. Three major groups of the genus Ralstonia (24%), Staphylococcus (20%) and Bosea (22%) were found in GI tracts. Ralstonia (6%, 24%), Sphingopyxis (15%, 2%), Bacillus (3%, 5%), Escherichia coli (3%, 2%) and Mesorhizobium (3%, 5%) were found in both sources - drinking water and GI tract. A lineage-per-time plot shows that the both bacterial communities have convex shape lines, suggesting an excess of closely related ecotypes. A significant F(ST) test (0.00000-0.00901) coupled with an insignificant P test (0.07-0.46) implies that the tree contained several clades of closely related bacteria. Both phylogenetic and statistical results suggest a correlation between the bacterial communities originating in the drinking water and those associated with the GI tracts. The GI tract showed a higher genetic diversity than the drinking water, but a similar lineage-per-time plot was obtained overall. It means a sudden evolutionary transformation and colonization occurred with high selective forces. PMID- 20705314 TI - Identification and quantification of anammox bacteria in eight nitrogen removal reactors. AB - Various studies have revealed anaerobic ammonium oxidation (anammox) as a very attractive alternative process suitable for nitrogen removal from wastewater. Here we investigated anammox bacteria in eight different nitrogen removal reactors. The diversity and abundance of anammox bacteria were determined by the 16S rRNA gene analysis, fluorescence in situ hybridization with specific probes and real-time quantitative PCR (qPCR). In these reactors, at least eight unique near full length anammox 16S rRNA gene sequences were detected, which were distributed over two genera; Candidati Brocadia and Kuenenia. FISH results confirmed that only one anammox bacterium dominated the community in each of the eight reactors investigated in this study. qPCR analysis revealed that anammox bacteria were present in seven of the reactors in the order of 10(9) cells/ml and 10(7) cells/ml in reactor A1. The dominant and divergent Brocadia-like anammox phylotype in one reactor represented a novel species for which we propose the name Candidatus Brocadia sinica. Taken together, these results indicated that a single seeding source could be used to seed anammox reactors designed to treat different types of wastewater, which could lead to a faster start-up of bioreactors. PMID- 20705315 TI - Assessment of the presence and dynamics of fungi in drinking water sources using cultural and molecular methods. AB - A comparison of different isolation techniques and culture media for detection of filamentous fungi and yeasts in the aquatic environment revealed that the use of membrane filtration with the media dichloran rose bengal chloramphenicol (DRBC) optimized fungi detection in terms of abundance and variety in three untreated water sources with very different characteristics (surface water, spring water, and groundwater). The diversity of the fungi population captured by direct DNA extraction of fungi collected by membrane filtration was compared with the isolates obtained after selective growth using different culture media through amplification of the internal transcribed spacer gene and denaturing gradient gel electrophoresis (DGGE). The Czapek-Dox agar, Sabouraud dextrose agar, and DRBC media showed closer similarities to those obtained by the uncultured biomass for the different water sources. Based on these data and the best enumeration results, DRBC is recommended for the assessment of fungi in water sources using culture-based methods. DGGE was also used to monitor temporal variations in the fungal population structure and showed that each water matrix possessed a distinct population profile as well as that changes in the fungal community can be expected in the different matrices throughout the year. PMID- 20705316 TI - A pH-control model for heterotrophic and hydrogen-based autotrophic denitrification. AB - This work presents a model to predict the alkalinity, pH, and Langelier Saturation Index (LSI) in heterotrophic and H(2)-based autotrophic denitrification systems. The model can also be used to estimate the amount of acid, e.g. HCl, added to the influent (method 1) or the pH set point in the reactor (method 2: pH can be maintained stable by CO(2)-sparge using a pH-control loop) to prevent the pH from exceeding the optimal range for denitrification and to prevent precipitation from occurring. The model was tested with two pilot plants carrying out denitrification of groundwater with high hardness: a heterotrophic system using ethanol as the electron donor and an H(2)-based autotrophic system. The measured alkalinity, pH, and LSI were consistent with the model for both systems. This work also quantifies: (1) how the alkalinity and pH in Stage-1 significantly differ from those in Stage-2; (2) how the pH and LSI differ significantly in the two denitrification systems while the alkalinity increase is about the same; and (3) why CO(2) addition is the preferred method for autotrophic system, while HCl addition is the preferred method for the heterotrophic system. PMID- 20705317 TI - Host-specific 16S rRNA gene markers of Bacteroidales for source tracking of fecal pollution in the subtropical coastal seawater of Hong Kong. AB - This study investigated the diversity of Bacteroidales communities in the feces of eight host species in Hong Kong (subtropical Asia), including human (in the form of sewage), cow, pig, horse, cat, dog, rabbit and rat. The analysis of terminal restriction fragment length polymorphism (TRFLP) in the 16S rRNA genes revealed significant differences in Bacteroidales communities among all host species, with the exception of dog and cat. Manual examination of TRFLP profiles resulted in six terminal restriction fragments (TRFs) that were potentially specific to the sewage (one TRF), cow (three TRFs) or pig (two TRFs) samples. All six TRFs were (1) present in 100% of the samples of the respective target host, (2) absent in other hosts or present only in low frequency and low intensity, and (3) verified for sizes using in silico digestion of DNA sequences in clone libraries. The six TRFs could reliably indicate the source of fecal contaminations in natural seawater amended with sewage, cow or pig fecal samples. In field tests conducted for two polluted and one unpolluted coastal site, the sewage-specific TRF was detected in all seawater samples of the sites known to be impacted by raw and treated sewage. However, only two of three cow-specific TRFs were detected for the two polluted sites, which also received fecal input from feral cows. No pig-specific TRF was detected, although one of the coastal sites was chronically polluted by pig farm run-offs. Nevertheless, the total absence of the six potentially host-specific TRFs in the seawater of an unpolluted site demonstrated the specificity of the TRFs as gene markers in indicating actual pollution. PMID- 20705318 TI - Efficiency of phenol biodegradation by planktonic Pseudomonas pseudoalcaligenes (a constructed wetland isolate) vs. root and gravel biofilm. AB - In the last two decades, constructed wetland systems gained increasing interest in wastewater treatment and as such have been intensively studied around the world. While most of the studies showed excellent removal of various pollutants, the exact contribution, in kinetic terms, of its particular components (such as: root, gravel and water) combined with bacteria is almost nonexistent. In the present study, a phenol degrader bacterium identified as Pseudomonas pseudoalcaligenes was isolated from a constructed wetland, and used in an experimental set-up containing: plants and gravel. Phenol removal rate by planktonic and biofilm bacteria (on sterile Zea mays roots and gravel surfaces) was studied. Specific phenol removal rates revealed significant advantage of planktonic cells (1.04 * 10(-9) mg phenol/CFU/h) compared to root and gravel biofilms: 4.59 * 10(-11)-2.04 * 10(-10) and 8.04 * 10(-11)-4.39 * 10(-10) (mg phenol/CFU/h), respectively. In batch cultures, phenol biodegradation kinetic parameters were determined by biomass growth rates and phenol removal as a function of time. Based on Haldane equation, kinetic constants such as MU(max) = 1.15/h, K(s) = 35.4 mg/L and K(i) = 198.6 mg/L fit well phenol removal by P. pseudoalcaligenes. Although P. pseudoalcaligenes planktonic cells showed the highest phenol removal rate, in constructed wetland systems and especially in those with sub-surface flow, it is expected that surface associated microorganisms (biofilms) will provide a much higher contribution in phenol and other organics removal, due to greater bacterial biomass. Factors affecting the performance of planktonic vs. biofilm bacteria in sub-surface flow constructed wetlands are further discussed. PMID- 20705320 TI - Retraction notice to "Effects of organic ligands on fractionation of rare earth elements (REEs) in hydroponic plants: An application to the determination of binding capacities by humic acid for modeling" [Chemosphere 65(11) (2006) 1942 1948]. AB - Reason: This article has been retracted, please see Elsevier Policy on Article Withdrawal:http://www.elsevier.com/locate/withdrawalpolicy This article has been retracted at the request of the editor as the authors have plagiarized part of papers that had already appeared in Chem. Geol. 209 (2004) 271-294, doi:10.1016/j.chemgeo.2004.06.012 and Geochim. Cosmochim. Acta 67 (2003) 2321 2339, doi:10.1016/S0016-7037(02)01413-8. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and we apologize to readers of the journal that this was not detected during the submission process. PMID- 20705321 TI - Biological treatment of thin-film transistor liquid crystal display (TFT-LCD) wastewater using aerobic and anoxic/oxic sequencing batch reactors. AB - The amount of pollutants produced during manufacturing processes of thin-film transistor liquid crystal display (TFT-LCD) substantially increases due to an increasing production of the opto-electronic industry in Taiwan. This study presents the treatment performance of one aerobic and one anoxic/oxic (A/O) sequencing batch reactors (SBRs) treating synthetic TFT-LCD wastewater containing dimethyl sulfoxide (DMSO), monoethanolamine (MEA), and tetra-methyl ammonium hydroxide (TMAH). The long-term monitoring results for the aerobic and A/O SBRs demonstrate that stable biodegradation of DMSO, MEA, and TMAH can be achieved without any considerably adverse impacts. The ammonium released during MEA and TMAH degradation can also be completely oxidized to nitrate through nitrification in both SBRs. Batch studies on biodegradation rates for DMSO, MEA, and TMAH under anaerobic, anoxic, and aerobic conditions indicate that effective MEA degradation can be easily achieved under all three conditions examined, while efficient DMSO and TMAH degradation can be attained only under anaerobic and aerobic conditions, respectively. The potential odor problem caused by the formation of malodorous dimethyl sulfide from DMSO degradation under anaerobic conditions, however, requires insightful consideration in treating DMSO-containing wastewater. PMID- 20705322 TI - Assessing pesticide leaching and desorption in soils with different agricultural activities from Argentina (Pampa and Patagonia). AB - Pesticide distribution in the soil profile depends on soil and pesticide properties as well as on the composition of irrigation water. Water containing surfactants, acids or solvents, may alter pesticide desorption from soil. The distribution of organochlorine pesticides (OCPs) in two Argentinean agricultural areas, Pampa and Patagonia, was evaluated. Furthermore, pesticide desorption from aged and freshly spiked soils was performed by the batch technique, using solutions of sodium oxalate and citrate, dissolved organic carbon (DOC), wastewater and surfactants. Patagonian soil showed the highest OCP levels (46.5 38.1 MUg g(-1) OC) from 0 to 30 cm depth and the predominance of p,p'-DDE residues reflected an extensive and past use of DDT. Pampean soil with lower levels (0.039-0.07 MUg g(-1) OC) was mainly polluted by the currently used insecticide endosulfan. Sodium citrate and oxalate, at levels usually exuded by plant roots, effectively enhanced desorption of p,p'-DDT, p,p'-DDE and alpha cypermethrin, while no effects were observed for alpha-endosulfan and endosulfan sulfate. The non-ionic surfactant Tween 80 behaved similarly to the acids, whereas the anionic sodium dodecyl sulfate enhanced desorption of all pesticides. Increased desorption of the hydrophobic pesticides also occurred when DOC from humic acids but not from sewage sludge or wastewater were used. Soil profile distribution of pesticides was in accordance with results from desorption studies. Data suggest pesticide leaching in Pampean and Patagonian soils, with risk of endosulfan to reach groundwater and that some organic components of wastewaters may enhance the solubilisation and leaching of recalcitrant compounds such as p,p'-DDT and p,p'-DDE. PMID- 20705323 TI - Degradation of organic gases using ultrasonic mist generated from TiO2 suspension. AB - The photocatalytic degradation of organic gases with mist particles that were formed by ultrasonic atomization of a TiO(2) suspension was performed with three different ultraviolet light sources. Three aromatic volatile organic compounds (VOCs; toluene, p-xylene, and styrene) and aldehydes (formaldehyde and acetaldehyde) were chosen as model organic gases for the degradation experiment. Under UV(365) irradiation, toluene was decomposed by a photocatalytic reaction on the surface of mist particles. Under UV(254+185) irradiation, the removal efficiency and mineralization ratio of the VOC gases were higher than those under UV(365) or UV(254) irradiation. Under UV(254+185) irradiation, it was found that VOC gases were immediately degraded and converted to water-soluble intermediates by not only direct photolysis but also oxidation by OH radical, since the removal efficiency of several organic gases depended on the reaction rate with OH radical and the primary effect of generated ozone was to complete the mineralization of the intermediates. On the other hand, water-soluble aldehyde gases were rapidly trapped by mist particles before reaction on their surface. Furthermore, water soluble intermediates that formed via the decomposition of VOC gases were completely trapped in the mist and were not detected at the reactor exit. Therefore, notable secondary particle generation was not observed, even under UV(254+185) irradiation. Based on these results as well as the size distribution of the mist droplets, it was found that primarily submicron-scale droplets contributed to the photocatalytic reaction. Lastly, we propose a mechanism for the degradation of organic gaseous pollutants on the surface of mist particles. PMID- 20705324 TI - Comment on "QSPR/QSAR models for prediction of the physicochemical properties and biological activity of polybrominated diphenyl ethers" by X. Hui-Ying, Z. Jian Wei, Y. Qing-Sen, W. Yan-Hua, Z. Jian-Ying, and J. Hai-Xiao" [Chemosphere 66 (10) (2007) 1998-2010]. PMID- 20705325 TI - In-cloud multiphase behaviour of acetone in the troposphere: gas uptake, Henry's law equilibrium and aqueous phase photooxidation. AB - Acetone is ubiquitous in the troposphere. Several papers have focused in the past on its gas phase reactivity and its impact on tropospheric chemistry. However, acetone is also present in atmospheric water droplets where its behaviour is still relatively unknown. In this work, we present its gas/aqueous phase transfer and its aqueous phase photooxidation. The uptake coefficient of acetone on water droplets was measured between 268 and 281K (gamma=0.7 x 10(-2)-1.4 x 10(-2)), using the droplet train technique coupled to a mass spectrometer. The mass accommodation coefficient alpha (derived from gamma) was found in the range (1.0 3.0+/-0.25) x 10(-2). Henry's law constant of acetone was directly measured between 283 and 298K using a dynamic equilibrium system (H((298K))=(29+/-5)Matm( 1)), with the Van't Hoff expression lnH(T)=(5100+/-1100)/T-(13.4+/-3.9). A recommended value of H was suggested according to comparison with literature. The OH-oxidation of acetone in the aqueous phase was carried out at 298K, under two different pH conditions: at pH=2, and under unbuffered conditions. In both cases, the formation of methylglyoxal, formaldehyde, hydroxyacetone, acetic acid/acetate and formic acid/formate was observed. The formation of small amounts of four hydroperoxides was also detected, and one of them was identified as peroxyacetic acid. A drastic effect of pH was observed on the yields of formaldehyde, one hydroperoxide, and, (to a lesser extent) acetic acid/acetate. Based on the experimental observations, a chemical mechanism of OH-oxidation of acetone in the aqueous phase was proposed and discussed. Atmospheric implications of these findings were finally discussed. PMID- 20705326 TI - Evaluation of an approach for the characterization of reactive and available pools of twenty potentially toxic elements in soils: part I--the role of key soil properties in the variation of contaminants' reactivity. AB - Harmful effects of potentially toxic elements (PTE's) in soils relate to their geochemically reactive fraction. To assess the degree of the reactivity, specific extractions or models are needed. Here we applied a 0.43 M HNO(3) chemical extraction to assess reactive pools of a broad range of PTE's in 136 contaminated and non-contaminated soils. Furthermore we derived Freundlich-type models based on commonly available soil properties (pH, organic carbon and clay) as well as extended models that used other properties such as amorphous Al and Fe oxides and evaluated their possible use in risk assessment. The approach allowed to predict the reactivity of As, Hg, Co, U, Ba, Se, Sb, Mo, Li, Be (r(2): 0.55-0.90) elements not previously included in such studies, as well as that of Cd, Zn, Cu, Pb, Ni and Cr (r(2): 0.73-0.90). The inclusion of pH, organic carbon and clay improved the performance of all models except for Be and Mo, although the role of clay is not completely clear and requires further investigation. The ability of amorphous metal oxides to affect the reactivity of As, Hg, Cu, Ni, Cr, Sb, Mo and Li was expressed by the models in agreement with known geochemical processes leading to the retention of PTE's by the solid matrix. Hence, such approach can be a useful tool to account for regional differences in soil properties during the identification of risk areas and constitute a significantly more powerful tool than the analysis of total pools of PTE's in soils. PMID- 20705327 TI - Triclocarban and triclosan biodegradation at field concentrations and the resulting leaching potentials in three agricultural soils. AB - This study evaluated the leaching potential of the antimicrobials triclocarban (TCC) and triclosan (TCS) in three agricultural soils using a simple model based on biodegradation and adsorption. The antimicrobials were added to the soils at two moisture levels (10% or 15% w/w) to achieve initial concentrations of 0.05, 0.2, or 2 mg kg(-1). The low concentrations (0.05, 0.2 mg kg(-1)) are more representative of field concentrations, important because previous studies have typically focused on higher initial concentrations. After 100 d, significant residuals of both TCC and TCS occurred under all conditions and first-order degradation half-lives indicated TCC was more resistant to biodegradation. The estimated K(d) and K(oc) values were 193-296 L kg(-1) and 18175-33991 L kg(-1) for TCC and 33-55 L kg(-1) and 3968-6310 L kg(-1) for TCS. The resulting leaching models indicated these chemicals have a very low leaching potential and are thus unlikely to contaminate groundwater. PMID- 20705328 TI - Topographic and spatial impacts of temperature inversions on air quality using mobile air pollution surveys. AB - We investigated the spatial and topographic effects of temperature inversions on air quality in the industrial city of Hamilton, located at the western tip of Lake Ontario, Canada. The city is divided by a 90-m high topographic scarp, the Niagara Escarpment, and dissected by valleys which open towards Lake Ontario. Temperature inversions occur frequently in the cooler seasons, exacerbating the impact of emissions from industry and traffic. This study used pollution data gathered from mobile monitoring surveys conducted over a 3-year period, to investigate whether the effects of the inversions varied across the city. Temperature inversions were identified with vertical temperature data from a meteorological tower located within the study area. We divided the study area into an upper and lower zone separated by the Escarpment and further into six zones, based on location with respect to the Escarpment and industrial and residential areas, to explore variations across the city. The results identified clear differences in the responses of nitrogen dioxide (NO(2)) and fine particulate matter (PM2.5) to temperature inversions, based on the topographic and spatial criteria. We found that pollution levels increased as the inversion strengthened, in the lower city. However, the results also suggested that temperature inversions identified in the lower city were not necessarily experienced in the upper city with the same intensity. Further, pollution levels in the upper city appeared to decrease as the inversion deepened in the lower city, probably because of an associated change in prevailing wind direction and lower wind speeds, leading to decreased long-range transport of pollutants. PMID- 20705329 TI - Impact of fugitive emissions in ambient PM levels and composition: a case study in Southeast Spain. AB - The results of this study show the high impact that anthropogenic fugitive emissions of mineral dust have on air quality (levels of PM(10), PM(2.5) and some metals) in a region in SE Spain named L'Alacanti. This could be extensive to other areas of Europe with similar characteristics. Fugitive emissions, such as those arising from large public construction works, cement and ceramic manufacturing, mining, heavy industries, handling and transport of powdered raw materials and road dust, are very often left out of emission monitoring and inspections in Europe. The comparative study of daily PM(10) series in the area shows how the increase of annual average PM(10) concentrations over 40 microg/m(3) is due to extreme episodes occurring in 2006 and 2007, at a regional scale, given the simultaneous recording of PM episodes at distant monitoring sites. The annual average values of the PM(10) concentrations were close to or slightly higher than 40 microg/m(3) (limit value of Directive 2008/50/CE) during 2006-2007 (Alicante-University 39-41, Agost 40-42, Sant Vicent 42-46, Alicante-El Pla 40-42 microg/m(3)). The main PM(10) sources in the zone were identified with the assistance of the PMF receptor model. Six common factors were determined, mineral as a main source (37% at Agost and 32% at Sant Vicent), road traffic, secondary sulfate, petroleum coke, sea spray and industry. Mineralogical studies, with XRD and SEM-EDX techniques, support the hypothesis that the highest PM episodes are associated to fugitive emissions of mineral matter. Despite the fact that L'Alacanti region is a heavily industrialized area with two cement plants and a significant number of ceramic manufacturing plants, the fugitive emissions may have accounted for the exceedances of the PM limit values during these two years, part of them caused by the construction of a highway. These results may contribute to the interpretation of prior studies on source apportionment carried out in Southern Europe, with very high loads of anthropogenic dust in PM(10) and PM(2.5). PMID- 20705330 TI - Long-term trends and variation of acidity, COD(Mn) and colour in coastal rivers of Western Finland in relation to climate and hydrology. AB - High acidity caused by geochemical processes and intensive land use of acid sulphate (AS) soils have continuously degraded the status of water bodies in Western Finland. Despite this, research on the long-term pattern and dynamics of acidification in rivers affected by acid sulphate soils is scarce. This study examined changes in alkalinity and pH value during the period 1913-2007 in nine large Finnish rivers discharging into the Gulf of Bothnia. In addition, patterns of COD(Mn) and colour were analysed during the period 1961-2007. Relationships between pH, alkalinity, COD(Mn) and colour and climate variables were also studied. In four rivers with no AS soil impact (Kokemaenjoki, Kemijoki, Iijoki and Oulujoki), critically low pH levels did not occur during the study period, whereas three rivers exposed to minor or moderate levels of runoff from AS soils (Lestijoki, Kalajoki, and Siikajoki) had all periods with critically low pH and alkalinity. The most severe acidity problems occurred in the rivers Kyronjoki and Lapuanjoki, with extensive drainage of AS soils being the main reason for the low pH status. Maximum discharge was clearly related to the acidity status of many rivers during the autumn-winter runoff period, when a significant negative linear correlation was found between maximum discharge and minimum pH in the rivers affected by AS soils. There was also a more distinct relationship between maximum chemical oxygen demand (COD(Mn)) and minimum pH in autumn runoff than in spring. COD(Mn) levels significantly increased with increasing discharge in the rivers with no or minor AS soil impact. Climate change is predicted to increase river flow in general and winter discharge in particular, and therefore the acidity problems in affected rivers may increase in a future climate. PMID- 20705331 TI - Estimation of the prevalence of rheumatic diseases in Israel. AB - OBJECTIVES: To study the prevalence of rheumatic diseases in Israel by applying the Community Oriented Program for the Control of Rheumatic Diseases core questionnaire (CCQ). METHODS: Representative samples (total of 2520 people) of the Israeli Jewish population aged >=20 were surveyed for rheumatic complaints on 4 separate occasions by the CCQ telephone interview. The findings of the telephone interview were compared with a face-to-face interview and to rheumatologist examination, in 2 separate stages. RESULTS: The telephone applied CCQ had a sensitivity level of 88.6% and specificity of 70.0% when compared with the rheumatologist evaluation (kappa = 0.576) (P < 0.001). A lower prevalence of rheumatic complaints was found in the summer months (17.7%) than in winter months (26.2%, P < 0.01). Prevalence was related to country of origin (0.008 < P < 0.03) (P range in separate surveys) and increasing age (P < 0.001) and was higher in women than in men (0.003 < P < 0.043). Body sites most affected were the lower back (63%) and the knees (47%). Medically related unemployment was more common in those with rheumatic complaints (7.9%) than in those without such complaints (2.9%, P < 0.01). Among those with rheumatic ailments, 12.7% had a related discapacity recognized by the Israeli National Insurance Institute. CONCLUSIONS: The telephone applied CCQ was reliable in screening for rheumatic complaints. Rates for rheumatic complaints in Israel were similar to those in some other countries. Rheumatic complaints were common, age- and gender-related, associated with work discapacity, and with country of origin. This is the first longitudinal prevalence survey of rheumatic complaints in Israel. PMID- 20705332 TI - Reference values for thromboelastometry (ROTEM(r)) in cynomolgus monkeys (Macaca fascicularis). AB - INTRODUCTION: The imbalance in clotting homeostasis, tending towards hypercoagulation, is recognized as the real barrier to the long-term survival of porcine xenografts in pig-to-primate xenotransplatation. The present study aimed to validate in primate blood the applicability of whole blood rotation thromboelastometry, performed by ROTEM(r), which evaluates the characteristics of clot formation by dynamic monitoring. MATERIALS AND METHODS: ROTEM(r) (Pentapharm GmbH, Munich, Germany) was used to investigate native coagulation (NATEM(r)), the intrinsic (INTEM(r)) and extrinsic (EXTEM(r)) pathways, the function of fibrinogen (FIBTEM(r)), and the presence of fibrinolysis in 40 naive cynomolgus monkeys. Using classic validation approaches, the normal thromboelastographic profile was defined and the influence of haematocrit (Hct,%), platelet count (x10(9)/L), fibrinogen (mg/dl), and factor VIII (FVIII,%) was evaluated. RESULTS: In all four (NATEM(r), INTEM(r), EXTEM(r), FIBTEM(r)) assays considered, Clotting Time (CT, sec) and Clot Formation Time (CFT, sec) were shorter in primates than humans. Moreover, alpha-angle ( degrees ), Maximum Clot Firmness (MCF, mm), and MaxVel (mm/min) were also higher in primates than humans. No substantial difference was observed for Hct and platelet count between the two species. On the contrary, FVIII was higher in primates than in humans whereas, interestingly enough, fibrinogen levels were lower in monkeys than in humans. CONCLUSION: ROTEM(r) depicts a hypercoagulable profile in primates as compared to humans. Taken together these data suggest that, with regard to coagulation, xenotransplantation in cynos may represent a much more difficult situation than xenotransplantation in humans. PMID- 20705333 TI - Thrombospondin-1 and ADAMTS13 competitively bind to VWF A2 and A3 domains in vitro. AB - INTRODUCTION: ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeat motif. 13) is the major metalloprotease for VWF degradation. ADAMTS13 deficiency causes the accumulation of uncleaved VWF and might lead to a lethal thrombotic thrombocytopenic purpura (TTP). Thrombospondin 1 (TSP1) is considered as a reductase of VWF (von Willebrand factor) which can mildly downregulate the size of VWF by targeting on disulfide bond between VWF dimers. It was reported that TSP1 might protected VWF from cleaving by ADAMTS13, yet the underlying mechanism of this VWF protection has remained unknown. MATERIALS AND METHODS: Full-length ADAMTS13 and different domains (A1,A2,A3) of human VWF were constructed and expressed respectively. The binding ability of TSP1 or ADAMTS13 with each VWF domain or full-length VWF was investigated by using enzyme linked immunosorbent assay. The inhibition of ADAMTS13 activities by the different concentrations of TSP1 were observed by western blot and residual collagen binding assay (R-CBA) under the denaturing condition. RESULTS: We found that ADAMTS13 interacted with the rVWF A1, A2, A3 domains and full-length VWF, while TSP1 also bound to three A domains, especially to A2 and A3 domains. We observed that TSP1 partially blocked ADAMTS13 binding to A2 domain, A3 domain and full length VWF. The results of our assays showed that TSP1 could restrain ADAMTS13 activity up to 70%. CONCLUSIONS: Our study suggested that TSP1 played competitively inhibitory role in ADAMTS13 binding and cleaving of VWF, and the potential competition might happen within A2 and A3 domains. PMID- 20705334 TI - Associations between high factor VIII and low free protein S levels with traditional arterial thrombotic risk factors and their risk on arterial thrombosis: results from a retrospective family cohort study. AB - INTRODUCTION: Whether high factor (F)VIII and low free protein S levels are risk factors for arterial thrombosis is unclarified. MATERIAL AND METHODS: In a post hoc analysis of a single-centre retrospective family cohort, we determined if these two proteins could increase the risk of arterial thrombosis. In total, 1399 relatives were analysed. RESULTS: Annual incidence in relatives with high FVIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal FVIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Mean FVIII levels adjusted for age and sex were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher in relatives with hypertension, diabetes mellitus, and obesity as compared to relatives without these arterial thrombotic risk factors. Moreover, a dose response relation between increasing FVIII and body mass index was found. None of these associations were shown for free protein S. CONCLUSIONS: High FVIII and low free protein S levels seemed to be mild risk factors for arterial thrombosis. High FVIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors. Free protein S levels were not influenced by these thrombotic risk factors. This assumes that low free protein S levels were genetically determined. PMID- 20705335 TI - Matched-case comparison for the efficacy of neoadjuvant chemotherapy before surgery in FIGO stage IB1-IIA cervical cancer. AB - OBJECTIVE: To evaluate whether neoadjuvant chemotherapy before surgery (NCS) is more efficient than primary surgical treatment (PST) for improving clinical outcomes in FIGO stage IB1-IIA cervical cancer. METHODS: We conducted a matched case comparison where 61 patients treated with NCS were matched to 183 treated with PST. We compared intermediate- and high-risk factors, the need of adjuvant radiotherapy, disease recurrence and survivals between NCS and PST. Patients with >=2 intermediate- or >=1 high-risk factors received adjuvant concurrent chemoradiation using cisplatin-based chemotherapy. RESULTS: NCS reduced more definitely intermediate- and high-risk factors than PST in stage IIA disease in spite of little difference of them in stage IB disease (large tumor size, 25% vs. 52.4%; deep stromal invasion, 57.1% vs. 82.1%; lymphovascular space invasion, 35.7% vs. 65.5%; parametrial invasion, 17.9% vs. 41.7%; p<0.05). Moreover, >=2 intermediate-risk factors were less common in NCS than PST despite no difference of the number of high-risk factors between the 2 treatments, which decreased the need of adjuvant radiotherapy in patients with stage IIA disease who received NCS (46.4% vs. 84.5%, p<0.01). Although there were no differences in progression-free survival and disease recurrence between the 2 treatments, NCS led to poorer overall survival than PST in stage IIA disease with no difference of it in stage IB disease. CONCLUSIONS: The efficacy between NCS and PST may be similar in FIGO stage IB cervical cancer. However, NCS can lead to poor prognosis despite the reduction of intermediate-risk factors and the need of adjuvant radiotherapy in FIGO stage IIA disease. PMID- 20705336 TI - An alternative splicing network links cell-cycle control to apoptosis. AB - Alternative splicing is a vast source of biological regulation and diversity that is misregulated in cancer and other diseases. To investigate global control of alternative splicing in human cells, we analyzed splicing of mRNAs encoding Bcl2 family apoptosis factors in a genome-wide siRNA screen. The screen identified many regulators of Bcl-x and Mcl1 splicing, notably an extensive network of cell cycle factors linked to aurora kinase A. Drugs or siRNAs that induce mitotic arrest promote proapoptotic splicing of Bcl-x, Mcl1, and caspase-9 and alter splicing of other apoptotic transcripts. This response precedes mitotic arrest, indicating coordinated upregulation of prodeath splice variants that promotes apoptosis in arrested cells. These shifts correspond to posttranslational turnover of splicing regulator ASF/SF2, which directly binds and regulates these target mRNAs and globally regulates apoptosis. Broadly, our results reveal an alternative splicing network linking cell-cycle control to apoptosis. PMID- 20705337 TI - Hydrogen bonding-enhanced micelle assemblies for drug delivery. AB - Ring-opening polymerization (ROP) of functionalized cyclic carbonates derived from 2,2-bis(methylol)propionic acid (bis-MPA) allows for incorporation of H bonding urea-functional groups into block copolymers with a potential application of supramolecular drug-delivery systems. The strong H-bonding functionalities of poly(ethylene glycol)-block-poly(ethyl-random-urea carbonate) (PEG-P(E(1-x) U(x))C) block copolymers not only lowered critical micelles concentration (cmc) of the block copolymer (to 1/4x) in aqueous environment compared to conventional PEG-poly(trimethylene carbonate) (PEG-PTMC) block copolymer without the non covalent stabilization, but also improved kinetic stability of micelles and Dox loaded micelles in the presence of a destabilizing agent. It was observed that the incorporation of anticancer drug doxorubicin affected the micellization process of block copolymers in water and caused a sudden increase in sizes of drug-loaded micelles above 200 nm. This phenomenon that can be a significant drawback in drug delivery applications was considerably mitigated in urea-bearing block copolymer/Dox micelles with simultaneously accompanying a significant improvement in drug loading. In vitro drug release profile showed that the increase in urea content led to a slight decrease in Dox release rate. Block copolymer did not have any significant cytotoxicity against HEK293 and HepG2 cells up to 400 mg/L. Importantly, Dox-loaded micelles exerted cytotoxic effect against HepG2 cells. PMID- 20705339 TI - Monitoring exposure to heavy metals among children in Lake Victoria, Kenya: environmental and fish matrix. AB - This study used hair and nails to biomonitor heavy metals (Pb, Cd, Cr and Cu) from geological source and exposure through regular fish consumption among children in Lake Victoria, Kenya. Concentration of Pb and Cu in water reflected anthropogenic pathways, while Cd and Cr reflected accumulation from the catchment basin. Higher concentration of heavy metals in the nails samples than the hair samples suggested longer term exposure. The estimated intake of Cd and Cr from fish in one site associated with high concentration of the metals from geological source was appreciably above the respective recommended daily allowance, signifying possible health risks to humans. Significant correlations between Pb, Cd and Cu in hair, nails and heavy metals from fish consumed suggested fish consumption as possible pathway of heavy metals in humans. Possible health risks from heavy metals were likely due to consumption of higher quantities of fish and from geological basins. PMID- 20705338 TI - The expansion of T-cells and hematopoietic progenitors as a result of overexpression of the lymphoblastic leukemia gene, Lyl1 can support leukemia formation. AB - This study investigates the function of the lymphoblastic leukemia gene, Lyl1 in the hematopoietic system and its oncogenic potential in the development of leukemia. Overexpression of Lyl1 in mouse bone marrow cells caused T-cell increase in the peripheral blood and expansion of the hematopoietic progenitors in culture and in the bone marrow. These observations were the result of increased proliferation and suppressed apoptosis of the progenitor cells caused by the Lyl1-overexpression. Our studies present substantial evidence supporting the secondary, pro-leukemic effect of Lyl1 in early hematopoietic progenitors with the potential to cause expansion of malignant cells with a stem/early progenitor-like phenotype. PMID- 20705340 TI - Drusen with accompanying fluid underneath the sensory retina. AB - PURPOSE: To investigate whether confluent drusen may be accompanied by fluid accumulation underneath the sensory retina and to determine if the detection of subretinal fluid on spectral-domain optical coherence tomography (OCT) in patients with coalescent drusen is indicative of choroidal neovascularization (CNV). DESIGN: Prospective, noncomparative case series. PARTICIPANTS: Seventy four eyes of 57 patients with large, confluent drusen. METHODS: The retinal structure of patients with coalescent drusen was studied by spectral-domain OCT. Optical coherence tomography reflectivity and outer retina topography maps were created and compared with fluorescein angiography (FA) and indocyanine green angiography (ICGA) images as well as with microperimetry. MAIN OUTCOME MEASURES: Optical coherence tomography-derived retinal morphologic features. RESULTS: What appears to be fluid beneath the sensory retina was found on spectral-domain OCT in 8 eyes of 7 patients. The outer retina topography maps demonstrated that fluid accumulates only in the concavity between clustering soft drusen, not on their outward slopes. The maps also revealed a reduced distance between the retinal pigment epithelium (RPE) and the photoreceptor inner/outer segment (IS/OS) junction over large drusen and tiny elevations of the IS/OS junction around drusen of all sizes. Microperimetry showed decreased retinal light sensitivity at the site of diminished distance between the RPE and the IS/OS junction. Seven eyes of 6 patients who were followed up were found to have no retinal changes other than confluent drusen along with subretinal fluid during the entire observational period (12-27 months). There was no evidence of CNV on FA or ICGA in any of the patients. CONCLUSIONS: Large, confluent drusen may be accompanied by subretinal spaces that appear to be filled with fluid. Specific distribution of the fluid limited to the depression between adjacent drusen may indicate that the cluster of coalescent drusen produces mechanical strain to the outer retinal layers that locally pulls the sensory retina away from its normal position. Consequently, the appearance of fluid within subretinal compartment between coalescent drusen in OCT cross-sectional images may not be a reliable marker for the presence of CNV. PMID- 20705341 TI - Association between genetic polymorphisms of adrenergic receptor and diurnal intraocular pressure in Japanese normal-tension glaucoma. AB - PURPOSE: To evaluate the relationship between genetic polymorphisms of the adrenergic receptor (ADR) and diurnal intraocular pressure (IOP) in Japanese normal-tension glaucoma (NTG) patients. DESIGN: Prospective, comparative case series. PARTICIPANTS: Ninety-two untreated NTG patients. METHODS: The IOP of both eyes was measured at 3-hour intervals from 0600 to 2400 hours over 2 consecutive days. We used IOP data from the eye with the greater visual field defect for statistical analysis. The mean IOP over 2 days was used for each time point. Genetic polymorphisms in alpha1A-, alpha2A-, alpha2B-, alpha2C-, beta1-, beta2-, and beta3-ADR were determined mainly by direct DNA sequencing. The relationship between IOP and genetic polymorphisms was analyzed. MAIN OUTCOME MEASURES: The IOP and genotypes of genetic polymorphisms. RESULTS: Diurnal mean IOP of the subjects was 14.8 +/- 2.1 mmHg (mean value +/- standard deviation). For Del 301 303 in alpha2B-ADR, insertion/insertion (I/I) had a significantly higher diurnal mean IOP (P = 0.017), peak IOP (P = 0.038), and trough IOP (P = 0.046) than deletion (D) carriers. For Del 322-325 in alpha2C-ADR, I/I had a significantly lower diurnal mean IOP (P = 0.037) and peak IOP (P = 0.029) than D carriers. For S49G (A/G) in beta1-ADR, A/A had a significantly higher diurnal mean IOP (P = 0.023), peak IOP (P = 0.019), and trough IOP (P = 0.014) than G carriers. For these 3 polymorphisms, repeated measures analysis of variance showed that the major homozygotes and minor carriers had parallel diurnal IOP curves, but significantly different diurnal IOP levels. CONCLUSIONS: Polymorphisms of the ADR gene may alter the untreated IOP level of patients with NTG. PMID- 20705342 TI - Zipper cell endotheliopathy: a new subset of idiopathic corneal edema. AB - PURPOSE: To report the clinical and histologic findings of a new subset of idiopathic corneal edema: zipper cell endotheliopathy. DESIGN: Observational case report. PARTICIPANT: A 55-year-old woman with unilateral bullous keratopathy. METHODS: Clinical observation consisted of slit-lamp examination and in vivo confocal microscopy (IVCM). Aqueous humor samples and the excised corneal button were analyzed for the presence of herpes viruses. The excised cornea was subjected to detailed immunohistochemistry (IHC) and scanning and transmission electron microscopy. MAIN OUTCOME MEASURES: Clinical and pathologic characteristics of zipper cell endotheliopathy. RESULTS: In vivo confocal microscopy revealed unique morphologic alterations of the corneal endothelial layer. Focal areas of denudation were surrounded by endothelial cells with zipper like cell borders and intercellular structures. Besides central corneal edema, no other signs of corneal inflammation were detected. A herpes virus origin for the bullous keratopathy was excluded. The IHC analysis disclosed positive staining for cytokeratin (CK) 7, CK8/18, and CK19, suggesting epithelial metaplasia of the endothelial cells. Ultrastructural examination confirmed the IVCM findings by showing large areas of endothelial denudation and vacuolated endothelial cells with large, broad-based extensions that partially overlapped neighboring cells. Despite extensive complementary research and review of the literature, the endothelial alterations could not be attributed to any known corneal disorder. CONCLUSIONS: To the authors' knowledge, zipper cell endotheliopathy is a new subset of idiopathic corneal edema. The case report presented illustrates the potential use of IVCM to differentiate the spectrum of corneal disorders and to discover new corneal diseases. PMID- 20705343 TI - Fast cleavage of a diselenide induced by a platinum(II)-methionine complex and its biological implications. AB - Platinum-based anticancer drugs such as cisplatin induce increased oxidative stress and oxidative damage of DNA and other cellular components, while selenium plays an important role in the antioxidant defense system. In this study, the interaction between a platinum(II) methionine (Met) complex [Pt(Met)Cl(2)] and a diselenide compound selenocystine [(Sec)(2)] was studied by electrospray ionization mass spectrometry, high performance liquid chromatography mass spectrometry, and (1)H NMR spectroscopy. The results demonstrate that the diselenide bond in (Sec)(2) can readily and quickly be cleaved by the platinum complex. Formation of the selenocysteine (Sec) bridged dinuclear complex [Pt(2)(Met-S,N)(2)(MU-Sec-Se,Cl)](3+) and Sec chelated species [Pt(Met-S,N)(Sec Se,N)](2+) was identified at neutral and acidic media, which seems to result from the intermediate [Pt(Met-S,N)(Sec-Se)Cl](+). An accelerated formation of S-Se and S-S bonds was also observed when (Sec)(2) reacted with excessive glutathione in the presence of [Pt(Met)Cl(2)]. These results imply that the mechanism of activity and toxicity of platinum drugs may be related to their fast reaction with seleno-containing biomolecules, and the chemoprotective property of selenium agents against cisplatin-induced toxicity could also be connected with such reactions. PMID- 20705344 TI - A rapid, Web-based method for obtaining patient views on effects and side-effects of antidepressants. AB - OBJECTIVE: This project was undertaken to develop a rapid method for obtaining a widespread sample of patient views on the efficacy and side-effects of antidepressants. METHOD: A Web-based method is described for rapidly and objectively obtaining patient views on the effects and side-effects of treatment with antidepressants. The method entails a systematized search of many URLs (Uniform Resource Locators, or Web page addresses), using keywords and phrases to extract the named drug and symptom that are reliably relevant to the medication being taken by the individual reporting the experience online. Unwanted medical conditions (e.g., cancer) are excluded. RESULTS: Three successive searches of thousands of Web pages revealed a cumulative total of 835 "mentions" of patient experience on duloxetine, 756 for venlafaxine, 637 for citalopram, 636 for sertraline, 559 for paroxetine, 457 for fluoxetine, 318 for desvenlafaxine, 289 for fluvoxamine, and 210 for mirtazapine, in association with various symptoms. A comparison of the associated symptoms for each of the antidepressants found that the prevalence of the combined factor of fatigue, drowsiness, tiredness or lethargy ranged from 6.4+/-0.8% down to 2.9+/-0.15% of the mentions, where the S.E. was derived from three repeats of the Web-based analysis. The prevalence of dizziness or vertigo ranged from 7.6+/-0.8% down to 1.9+/-0.3% of the mentions. CONCLUSIONS: Given the increasing number of patient narratives about drug experiences on open-access Web forums, this rapid novel method will have increasing utility in post-marketing surveillance and in comparing the effects of psychiatric medications. PMID- 20705345 TI - Ethnicity and symptom expression in patients with acute schizophrenia. AB - Chinese patients have been largely ignored in the literature examining ethnic differences in schizophrenia. This study examined demographics and symptom profiles of Euro-, African-, Chinese-American, and Latino inpatients with schizophrenia. Chinese-American patients had fewer symptoms, hospitalizations, and least amount of education compared to other groups. Cultural and clinical implications are discussed. PMID- 20705346 TI - Motor cortex hyperexcitability in subcortical ischemic vascular dementia. AB - To study whether in subcortical ischemic vascular dementia (SIVD) the changes of motor cortex excitability are due to the dementing process or to the cerebrovascular lesions, we examined 20 SIVD patients, 20 patients with subcortical ischemic disease without dementia (SIDWD) and 20 control subjects who underwent transcranial magnetic stimulation (TMS). Motor threshold (MT), amplitudes of motor evoked potentials (MEPs) and silent period (SP) were considered. MT in SIVD patients (32.7 +/- 2.6%) was significantly lower (p<0.001) than in SIDWD patients (47.9 +/- 3.4%) and in controls (49.1 +/- 4.2%). MEP amplitude was larger in SIVD patients (6.8 +/- 1.7 mV) than in the other groups (5.7 +/- 1.9 mV and 5.2 +/- 1.8 mV, p<0.02). Motor cortex excitability is enhanced in SIVD. Our data, taken together with previous results in Alzheimer disease (AD), indicate that motor cortex hyperexcitability is a common finding in different dementing illnesses. PMID- 20705347 TI - Clinical manifestations of elderly patients with digitalis intoxication in the emergency department. AB - This study aimed to determine the clinical characteristics of elderly patients diagnosed with digitalis intoxication, on the Emergency Department, University Hospital Complex, A Coruna, Spain. During the study period (January-September 2008) cases were included in which digitalis intoxication was confirmed by plasma digoxin levels. We collected data on age, gender, base-line diseases, therapeutic indications for digoxin, functional classification, ejection fraction, plasma digoxin levels, creatinine clearance, ions, gasometry, electrocardiogram, concomitant medication, symptomatology and treatment. The results were: mean age 82.0 +/- 6.6 years, predominantly female subjects (83.7%). The most prevalent pathologies were cardiac valvulopathy (81.0%), hypertension (68.3%) and ischemic cardiopathy (46.3%), 95.1% had a background of cardiac insufficiency, and 52.6% were in functional grade III. The mean digoxin level was 2.7 +/- 0.69 ng/ml, 23.1% of the patients had a creatinine clearance of less than 60 ml/min/1.73 m(2) and 2.6% had a severely reduced glomerular filtration rate (GFR) (clearance<30 ml/min/1.73 m(2)). A negative correlation was found between digoxin levels and clearance (r = -0.22; p = 0.18) and between the levels and cardiac frequency (r = -0.35; p = 0.026). Of the patients, 47.5% presented bradycardia and 87.8% arrhythmias, most frequently auricular fibrillation. The most frequent symptoms were nausea (54.8%), fatigue (42.9%), vomiting (33.3%) and anorexia (28.6%). We conclude that clinical digestive symptoms in elderly women who are taking digitalis, with bradycardia and impaired renal functioning, should lead us to suspect digitalis intoxication. PMID- 20705348 TI - Fatigue and disability in elderly patients with chronic obstructive pulmonary disease (COPD). AB - The purpose of this study was to describe the prevalence and severity of fatigue and to investigate relationships between fatigue, and disability in elderly COPD patients. This descriptive and analytical study was conducted on 98 patients. Three instruments were used: Personal information form (PIF), visual analog scale for fatigue (VAS-F) and brief disability questionnaire (BDQ). The statistical analyses were used in order to evaluate the data: Student's t-test, Kruskall Wallis test, Pearson correlation coefficient calculation and logistic regression analysis. All of patients in the sample experienced fatigue. The level of fatigue and disability experienced by the patients with COPD was high, their energy level was low. It was determined that as COPD patients' fatigue increases their disability also increases, that there are relationships between fatigue and marital status and that there are relationships between disability and gender. Furthermore, in this study significant differences were found in COPD patients' VAS-F and BDQ scores for some symptoms of COPD, such as dyspnea, fatigue, cough and sputum. The results of the study indicated that high levels of fatigue are experienced which impacts on patients' functional condition and needs to be professionally assessed managed. PMID- 20705349 TI - Self-reported problems before and after prosthodontic treatments according to newly created Turkish version of oral health impact profile. AB - The aim of the study was to assess patients' socio-demographic factors with their removable prosthesis in general, as well as to assess their problems with the functional limitation, physical pain, psychological discomfort, physical disability, social disability, and handicap investigate impaired oral health related quality of life (OHRQoL) in patient treated with removable dentures before treatment and at 1 and 12 months after treatment. The first part of the questionnaire was comprised of 20 questions. It was designed in four different sections as: (i) general socio-demographic factors, (ii) general health, (iii) experience and use of dental and denture care, and (iv) anamnestic sign and symptoms of temporomandibular disorders (TMD). A statistical analysis system (SAS) was used for data management and analysis. Patient-reported problems were studied using the item list contained in the Turkish version of the oral health impact profile (OHIP) in a convenience sample of 136 prosthodontic patients before (m(0)), 1 month after (m(1)), and 12 months (m(2)) after treatment were then examined by using two-way ANOVA with repeated measurement. Differences in OHRQoL were present when item-specific prevalence was stratified by time of total scores; gender, residential area, working status, self-reported general health, smoking status, denture type, importance of the convenient dental care, trauma story, self-reported TMD/pain, and self-reported TMD/difficulty opening mouth wide. At baseline, the most prevalent frequently reported problems "difficulties chewing" (49.3%), "digestion worse" (40.4%), "take longer to complete a meal" (36%), "food catching" (30.9%), and "dentures not fitting" (29.4%), and m(2) the most prevalent frequently reported problems were "avoid going out" (25%), "difficulties chewing" (17.6), "sore jaw" (15.5%), and "take longer to complete a meal" (14%). The study confirmed that denture status is by far the strongest predictor of impaired OHRQoL compared to socio-demographic factors. Subjects with strong or moderate values had significantly fewer oral health-related problems (OHIP-extent) of time of total scores. The number of problems decreased substantially after prosthodontic treatment. The profile of pretreatment and post treatment problems differed substantially, but in general, only a few problems remained after adaptation to new dentures. PMID- 20705350 TI - Comparison of epicardial adipose tissue (EAT) thickness and anthropometric measurements in metabolic syndrome (MS) cases above and under the age of 65. AB - EAT is a new index of cardiac and visceral obesity. Waist circumference (WC) measurement is not fully reliable in the determination of visceral adipose tissue (VAT), especially in elderly individuals. Studies on the reflection of the intra abdominal fat mass by the EAT mass surrounding the heart were performed. Our purpose in this study was to determine the relation between the MS criteria and EAT in MS cases and especially to compare anthropometric measures between non geriatric patients under the age of 65, and geriatric ones over the age of 65 years. The study was performed during the years 2008 and 2009 on 120 cases; 66.7% of them were under the age of 65 and 33.3% of the cases were 65-year old or older. All of the patients were diagnosed as MS by the International Diabetes Federation (IDF) criteria. They were randomized as per the application order and included to the study. Each subject underwent transthoracic two-dimensional (2D) guided M-mode echocardiogram. We measured epicardial fat thickness on the 1/3 section close to the ventricle basis adjacent to the free wall of right ventricle from both the parasternal long axis (LA) and parasternal short axis (SA) views. Multiple regression analysis showed that WC, systolic blood pressure (SBP) and age were the strongest independent variables correlated with EAT (p<0.001). We also determined a significant correlation between low-density lipoprotein cholesterol (LDL-C) and EAT (p<0.05). Our data show that EAT-measurement by echocardiography is an efficient method in determination of visceral adiposity and shall be taken into consideration especially when advanced age groups are in question. PMID- 20705351 TI - Updating process of internal model of action as assessed from motor and postural strategies in young adults. AB - Internal models are constantly updated based on the actions and experiences of a person in the world. In the present study, we proposed to assess the updating process of internal models of action by providing new environmental constraints for motor planning, postural control, and execution processes in daily tasks such as STS and BTS. STS and BTS tasks were performed with different inclinations of the support surface on which the participant and the chair were positioned: horizontal support, support tilted 10 degrees to the right, or forward. Twelve healthy adults participated in this experiment. Kinematic characteristics were recorded using an optoelectronic motion analysis system. Movement duration and trunk inclination amplitudes were analyzed for STS and BTS as well as trunk orientation and strategies of head stabilization. Concerning the movement analysis our results showed (1) temporal asymmetry between STS and BTS, attributed mainly to the integration of the mechanical effects of gravity, and (2) a decrease of trunk movements when the support was tilted forward, attesting to an immediate adaptation process. Concerning the postural analysis our study revealed that adults adopted selective head stabilization on space strategy with respect to balance constraints. To conclude, young adults were able to immediately update their internal model of action in order to optimize motor control and vertical body orientation. PMID- 20705352 TI - Sulphur dioxide affects culturability and volatile phenol production by Brettanomyces/Dekkera bruxellensis. AB - The effect of different sulphur dioxide concentrations on culturability and viability of seven strains of Brettanomyces bruxellensis was tested in a synthetic wine medium (SWM) and a different response to molecular SO(2) among strains was detected. Sulphur dioxide induced a viable but non culturable (VBNC) state in all the strains. The greater percentage of VBNC cells were identified for five strains at molecular SO(2) concentrations of 0.2mg/L and for two strains at the concentration of 0.4mg/L. Vinyl phenols were detected in media containing VBNC or not viable B. bruxellensis, suggesting that its spoilage metabolism could be maintained during wine storage. Overall, this study indicates that SO(2) is a chemical stressor inducing VBNC state in B. bruxellensis grown in synthetic wine medium. Further studies are needed to evaluate the effects of SO(2) on the metabolism of this yeast in wine spoilage. PMID- 20705353 TI - Microbial diversity, dynamics and activity throughout manufacturing and ripening of Castelmagno PDO cheese. AB - The diversity, dynamics and activity of Castelmagno PDO cheese microbiota were studied in three batches produced in a floor valley farm, in the Grana Valley (northwest Italy), during the wintertime. Samples of milk, curd and cheese (core and subsurface) at different ripening time were submitted to both culture dependent and -independent analysis. In particular, DNA and RNA directly extracted from the matrices were studied by PCR-Denaturing gradient gel electrophoresis (DGGE) and reverse transcription (RT)-PCR-DGGE. Culture-dependent methods highlighted the initial dominance of a thermophilic streptococcal population with the species Streptococcus thermophilus and S. agalactiae. Then, mesophilic lactococci occurred among isolates during manufacturing, with Lactococcus lactis which was also well represented in the first month of Castelmagno PDO ripening. At this point and throughout the ripening, lactobacilli prevailed in cheese samples, represented from Lactobacillus plantarum and Lb. casei. Culture-independent analysis underlined the undoubted role of L. lactis, actively involved in both Castelmagno PDO manufacturing and ripening. Despite Lb. helveticus was never isolated on selective media, a DGGE band referred to this microorganism was detected, at RNA level, in samples from ripened cheeses. On the other hand, Lb. plantarum was widely isolated from the plates, among lactobacilli, but never detected by direct analysis. Due to the importance of microbiota in the sensory richness and properties of traditional cheeses, new information have been added, in this work, on microbial diversity of Castelmagno PDO cheese. PMID- 20705354 TI - Continuous interstitial glucose monitoring in non-diabetic subjects with end stage renal disease undergoing maintenance haemodialysis. AB - Haemodialysis improves uraemia-induced insulin sensitivity and is therefore likely to induce significant changes in circulating glucose concentrations in end stage renal disease (ESRD). We aimed to assess clinically relevant circulating glucose changes in patients undergoing chronic maintenance haemodialysis using continuous interstitial monitoring. We investigated 14 non-diabetic ESRD subjects aged 40.6+/-2.4 years. Participants were examined 24-h day pre-dialysis, during the index dialysis session and 24-h post-dialysis with simultaneous measurement of capillary blood glucose and continuous interstitial glucose (CGMS). Participants performed five capillary blood glucose measurements the day before dialysis, and 10 during and after dialysis. Mean capillary blood glucose was 128+/-20mg/dl the day before, 93+/-8mg/dl during haemodialysis, and 105+/-13mg/dl after haemodialysis. There was a significant trend towards lower blood glucose during the session from 105+/-16mg/dl to a 3rd hour nadir of 83+/-15mg/dl (Anova F=2.89, p=0.029). No hypoglycaemia was recorded. Interstitial glucose profile was comparable to capillary glucose profile. Glucose concentrations varied significantly from 126+/-13mg/dl before to 112+/-12mg/dl after haemodialysis respectively (p=0.006). This study provides evidence for the use of CGMS in ESRD and haemodialysis, and demonstrates significant changes in glucose concentrations during and after haemodialysis that would guide treatment monitoring and adjustments. PMID- 20705355 TI - Improving children's healthcare through state health insurance programs: an emerging need. AB - OBJECTIVES: State Children's Health Insurance Program (SCHIP) in the USA plays a critical role in healthcare service utilization. This study assesses children's needs for healthcare services among the variations of SCHIP. METHODS: This study applies the PRECEDE-PROCEED behavioral model to analyze the behavior of children with healthcare needs and unmet healthcare needs by using the National Survey of Children with Special Healthcare Needs of the USA. RESULTS: Children who were previously under a Medicaid program are apt to enroll in SCHIP programs. SCHIP children with healthcare needs are more likely than comparable non-SCHIP children to use hospital outpatient departments instead of using doctors' offices and health centers. Children under the SCHIP single and SCHIP combination programs are more likely to use doctors' offices and health centers than those in the Medicaid expansion program. SCHIP combination or SCHIP Medicaid expansion states are significantly less likely to have unmet healthcare needs than children in SCHIP single states. CONCLUSIONS: Medicaid has a significant impact on the SCHIP program. There is a substitution of healthcare service facilities between hospital outpatient departments and either the doctors' offices or health centers. PMID- 20705356 TI - Denial and social and emotional outcomes in lung cancer patients: the protective effect of denial. AB - Denial is a well-known phenomenon in clinical oncology practice. Yet whether the impact of denial on patient well-being is beneficial or harmful remains unknown. The purpose of the current study is to investigate the relationship between denial and social and emotional outcomes in a large sample of lung cancer patients over an extended time period. Denial and social and emotional outcomes were measured in 195 newly diagnosed lung cancer patients. Four assessments were conducted over 8 months. The level of denial was measured using the Denial of Cancer Interview. Patient-reported social and emotional outcomes were measured using the EORTC-QLQ-30 and the HADS. Patients with a moderate or increasing level of denial over time reported better social outcomes (role functioning: p = 0.0036, social functioning: p = 0.027) and less anxiety (p = 0.0001) and depression (p = 0.0019) than patients with a low level of denial. The overall quality of life was better among lung cancer patients who displayed either moderate or increasing levels of denial compared with those who displayed low levels of denial (p < 0.0001). A certain level of denial in lung cancer patients can have a protective effect on social and emotional outcomes. Clinicians should take this into account when providing information about the illness and its prognosis. PMID- 20705357 TI - First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients. AB - The potential differential effect of first-line treatment and molecular mechanisms on survival to second-line chemotherapy or EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) has not been fully investigated. In particular, CHFR is frequently methylated in NSCLC and may influence outcome. We analyzed the outcome of second-line chemotherapy or EGFR TKIs in 179 of 366 patients who had been treated in an ERCC1 mRNA-based customized cisplatin trial and correlated the results with CHFR methylation status. CHFR methylation in circulating DNA was examined by methylation-specific assay. A panel of seven human EGFR wild-type NSCLC cell lines was characterized for their sensitivity to sequential treatment with cisplatin and erlotinib, and the results were correlated with CHFR. Patients who had received first-line docetaxel/cisplatin attained an overall survival of 19.2 months when treated with second-line EGFR TKIs, in comparison with 10.7 months when treated with second line chemotherapy (P = 0.0002). However, for patients who had received first-line docetaxel/gemcitabine, overall survival was 14.8 months with EGFR TKIs and 10.8 months with chemotherapy (P = 0.29). For patients with unmethylated CHFR overall survival to EGFR TKIs was 21.4 months, and 11.2 months for those with treated with chemotherapy (P = 0.0001). In the only lung tumor cell line not expressing CHFR, pretreatment with cisplatin was antagonistic to erlotinib, while it was synergistic in the other six lines. Second-line EGFR TKIs improved survival in patients receiving first-line cisplatin-based treatment. Unmethylated CHFR predicts increased survival to EGFR TKIs. PMID- 20705358 TI - RNA trans-splicing: identification of components of a putative chloroplast spliceosome. AB - Group II introns with highly complex RNA structures have been discovered in both prokaryotes and eukaryotic organelles. Usually, excision of non-coding group II intron sequences occurs by cis-splicing, the intramolecular ligation of exons in the same precursor RNA, but some group II introns are excised by intermolecular ligation. This process is called trans-splicing, and genome sequencing predicted that this type of RNA processing occurs in more than 180 organelle genomes from eukaryotes. A well characterised trans-spliced intron RNA is represented by the chloroplast psaA gene of the model alga Chlamydomonas reinhardtii. The psaA gene is split into three exons, which are widely distributed over the plastome and transcribed independently. PsaA exons are flanked by sequences typical for group II introns and joined by trans-splicing via two transesterification reactions. Although it is known that some group II introns are able to splice autocatalytically, trans-splicing of the psaA RNA depends on several nucleus and chloroplast encoded factors. The phylogenetic relationship between group II introns and nuclear spliceosomal RNA led to the hypothesis that these factors are part of large multiprotein and ribonucleoprotein complexes akin to the nuclear spliceosome. Here, we give a concise overview of experimental strategies to identify novel factors involved in trans-splicing of psaA RNA and review recent results that have elucidated the composition and function of a putative chloroplast spliceosome involved in processing of chloroplast precursor RNAs. PMID- 20705359 TI - Trafficking of galectin-3 through endosomal organelles of polarized and non polarized cells. AB - In epithelial cells, the beta-galactoside-binding lectin galectin-3 mediates the non-raft-dependent glycoprotein targeting to the apical membrane domain. In this study, we aimed to identify intracellular compartments involved in the trafficking of galectin-3. By studying fluorescent fusion proteins in living cells, we could show that galectin-3 accumulates intracellularly in acidified endosomes. Total internal reflection fluorescence microscopy studies of the apical surface of polarized MDCK cells revealed that galectin-3 is enriched in tubular and vesicular Rab11-positive recycling endosomes in the vicinity of the apical cell surface. These endosomal organelles are candidate compartments for the association between galectin-3 and exocytic apical cargo. PMID- 20705360 TI - Cadmium and selenium modulate slow vacuolar channels in rape (Brassica napus) vacuoles. AB - Currents flowing through slow vacuolar SV channels of rape (Brassica napus) growing on media supplemented with Cd2+ (400 MUM), and/or SeO4(2-) (2MUM) were examined. The aim of the study was to investigate the role of Cd2+ in modulation of SV channel activity and to determine whether Se reverses the effect of cadmium. Vacuoles were isolated using a quick surgical method to avoid application of any cell wall-degrading enzymes. Vacuoles of rape exhibited typical SV channel activity with slow activation at positive potentials and strong rectification into the vacuolar lumen. Single-channel conductance in cytoplasm-side-out tonoplast patches ranged between 68.8+/-1.9 pS in the control, 80.1+/-2.5pS, in Cd2+, 74.2+/-2.4 pS in Cd2+/selenate, and 80.1+/-1.8 pS in selenate-pretreated plants. The lack of a clear tendency was likely an effect of equilibration of the pipette solution (without Cd2+/SeO4(2-) with that of the luminal side of the vesicles. In the vacuole-attached configuration, in which natural vacuolar solution was not exchanged, there was a significant reduction in single-channel conductance in the Cd2+ (40.3+/-2.8 pS), Cd2+/selenate (47.1+/-2.8 pS) and selenate-pretreated (42.3+/-1.4 pS) plants, compared to the control (60.2+/-1.7 pS). The reduction in single-channel conductance only partially explained the significant decline in the densities of ion current flowing through the vacuolar membrane in the whole-vacuole configuration in the plants growing on Cd2+ and Cd2+/selenate media. Thus, Cd2+ accumulation in the vacuole reduced the number of active SV channels from 0.28+/-0.05 MUm-2 in the control to 0.021+/ 0.005 and 0.039+/-0.004 MUm-2 in Cd2+ and Cd2+/selenate-pretreated plants, respectively. PMID- 20705361 TI - An aspartic acid protease from common bean is expressed 'on call' during water stress and early recovery. AB - A cDNA encoding a putative aspartic acid protease precursor (PvAP1) was cloned from the leaves of common bean (Phaseolus vulgaris). Sequence analysis showed that PvAP1 presents all the characteristic features of phytepsins, the typical plant APs. PvAP1 gene expression was tightly regulated by water stress, being significantly up-regulated under mild water stress (Psi(w)=-1.0 MPa) for the drought-susceptible cultivar (Carioca) and moderate water stress (Psi(w)=-1.5 MPa) for the more drought-tolerant cultivar (IPA). Protein gel blotting analysis under water stress revealed the presence of two main bands of calculated MW of 46 and 38 kDa, suggesting proteolytic processing of the enzyme precursor form under drought in both cultivars. Taken together, our results suggest that water stress regulates PvAP1 activity both at the transcriptional and post-transcriptional levels, and that the response occurs earlier and is stronger in the drought susceptible cultivar. PMID- 20705362 TI - Metabolic changes of Brassica rapa transformed with a bacterial isochorismate synthase gene. AB - Metabolome analysis by 1-dimensional proton nuclear magnetic resonance (1H NMR) coupled with multivariate data analysis was carried out in Brassica rapa plants transformed with a gene encoding bacterial isochorismate synthase (ICS). Partial least square-discrimination analysis (PLS-DA) on selected signals suggested that the resonances that were dominant in the transgenic plants corresponded to a glucosinolate (neoglucobrassicin), phenylpropanoids (sinapoyl malate, feruloyl malate, caffeoyl malate), organic acids (succinic acid and fumaric acid) and sugars (alpha- and beta-glucose). In contrast, amino acids alanine threonine, valine, leucine were dominant in the untransformed controls. In addition, HPLC data showed that the transgenic plant accumulated salicylic acid (SA) at significantly higher levels than the control plants, whereas the phylloquinone levels were not affected. The results suggest that the expression of the bacterial isochorismate synthase gene in B. rapa does not affect fluxes into pathways to other groups of secondary metabolites through competition for the same precursor. On the contrary, the biosynthesis of isochorismate-derived products (SA) seems to induce the competitive pathways via phenylalanine (phenylpropanoids) and tryptophan (IAA and indole glucosinolates). PMID- 20705363 TI - Communication and adherence to prophylactic antibiotic guidelines in patients with a proximal femoral fracture. PMID- 20705364 TI - Cost and outcomes of nosocomial bloodstream infections complicating major traumatic injury. AB - The objective of this study was to assess the incidence, outcomes, and costs of trauma-related nosocomial bloodstream infection (BSI). This was a 3:1 matched cohort study in patients with severe trauma [defined by an injury severity score (ISS)>=12] admitted to adult or paediatric regional trauma centres over a four year period. Case patients with nosocomial BSI were matched to controls without a BSI based on predetermined criteria. Outcomes of interest included mortality, length of stay (LOS), and cost attributable to nosocomial BSI. Fifty-seven cases were identified, among whom 51 were successfully matched to three controls. The mean ISS among cases was 30.3, and Staphylococcus aureus was the most commonly isolated pathogen (27%). Being a case was accompanied by a 27% relative increase in the hospital LOS (P=0.02). The odds ratio for 30 day mortality associated with being a case was 5.8 (95% confidence interval (CI): 1.1-30.8; P=0.04). Among survivor-matched groups, being a case was associated with 53% relative increase in the geometric mean total hospital cost [$97,993 (95% CI: $70,143-136,899) for cases and $62,297 (95% CI: $52,155-74,411) for controls, P<0.0001]. This is the first study to show that nosocomial BSI complicating severe trauma is associated with a substantial increase in hospital LOS and in total hospital cost. Our data provide justification to support efforts to reduce the adverse impact of BSI in trauma victims. PMID- 20705365 TI - Design, synthesis and pro-apoptotic antitumour properties of indole-based 3,5 disubstituted oxadiazoles. AB - A series of new indole-based 3,5-disubstituted 1,2,4-oxadiazoles has been designed and synthesised as potential pro-apoptotic antitumour agents, via the base-catalysed condensation reaction between substituted amidoximes and indole esters. Evaluation of antiproliferative activity against the human cancer cell lines COLO 320 (colorectal) and MIA PACA-2 (pancreatic) revealed IC(50) values in the low micromolar range. Selected compounds were able to trigger apoptosis in sensitive cell lines, for example via activation of caspase-3/7, demonstrating that indole-based oxadiazoles possess in vitro antitumour and pro-apoptotic activity. PMID- 20705366 TI - Chiral 6-hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: novel antitumor DNA monoalkylating agents. AB - New chiral 1H,3H-pyrrolo[1,2-c]thiazoles were synthesized and screened for their in vitro activity as anti-cancer agents in three human tumor cell lines, colorectal adenocarcinoma, melanoma and breast adenocarcinoma. (R)-6 Hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole and the corresponding benzylcarbamate showed selectivity for breast cancer cell lines with IC(50) values of 2.4 microM and 2.2 microM, respectively. The latter also showed significant activity against colorectal adenocarcinoma cancer cell lines (IC(50) = 8.7 microM). In contrast, the 7-hydroxymethyl-5-methyl-3-phenyl-1H,3H pyrrolo[1,2-c]thiazole gave moderate anti-cancer activity. The performance against breast cancer cell lines (IC(50) = 1.0 microM) of a potential bisalkylating agent, a (3R)-6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazole, wasn't significantly different from the one observed for the monoalkylating derivatives indicating that the main mechanism of action may in fact be the monoalkylation process. PMID- 20705367 TI - E-2-[3-(3,4-dichlorophenyl)-1-oxo-2-propenyl]-3-methylquinoxaline-1,4-dioxide: a lead antitubercular agent which alters mitochondrial respiration in rat liver. AB - A series of 2-(3-aryl-1-oxo-2-propenyl)-3-methylquinoxaline-1,4-dioxides 1a-l and 2-acetyl-3-methylquinoxaline-1,4-dioxide 2 were evaluated against Mycobacterium tuberculosis H(37)Rv. With the exception of the 4-nitro analog 1k, significant antitubercular potencies were observed in series 1 and 2 which have IC(50) values in the range of 1-23 microM. Negative correlations were noted between the IC(50) values of 1a-j, l towards M. tuberculosis and both the sigma and pi constants of the substituents in the benzylidene aryl ring. In particular, 1h emerged as a lead compound having IC(50) and IC(90) figures of 1.03 microM and 1.53 microM, respectively. This molecule affected respiration in rat liver mitochondria which is likely one way that 1h and the bioactive analogs exert their antitubercular properties. The quinoxaline 2, which lacks an alpha,beta-unsaturated group, has no effect on mitochondrial respiration using concentrations which inhibit the growth of M. tuberculosis. PMID- 20705368 TI - Anti-tubercular agents. Part 5: synthesis and biological evaluation of benzothiadiazine 1,1-dioxide based congeners. AB - In an effort to discover new and effective chemotherapeutic agents from this laboratory for the treatment of tuberculosis, here in we describe the synthesis and biological evaluation of a series of novel benzothiadiazine 1,1-dioxide (BTD) based congeners by using rifampicin, streptomycin; ciprofloxacin and amphotericin as positive controls. Further, to understand structural requirements for exploring the structure activity relationship of BTDs, cytotoxicity and in vivo study of recently reported potent molecule 4 (MIC = 1 microg/mL) is also discussed. PMID- 20705369 TI - An alignment independent 3D QSAR study of the antiproliferative activity of 1,2,4,5-tetraoxanes. AB - An alignment-free 3D QSAR study on antiproliferative activity of the thirty-three 1,2,4,5-tetraoxane derivatives toward two human dedifferentiated cell lines was reported. GRIND methodology, where descriptors are derived from GRID molecular interaction fields (MIF), were used. It was found that pharmacophoric pattern attributed to the most potent derivatives include amido NH of the primary or secondary amide, and the acetoxy fragments at positions 7 and 12 of steroid core which are, along with the tetraoxane ring, common for all studied compounds. Independently, simple multiple regression model obtained by using the whole molecular properties, confirmed that the hydrophobicity and the H-bond donor properties are the main parameters influencing potency of compounds toward human cervix carcinoma (HeLa) and human malignant melanoma (FemX) cell lines. Corollary, similar structural motifs are found to be important for the potency toward both examined cell lines. PMID- 20705370 TI - Stereoselective synthesis and biological evaluation of (R)-rugulactone, (6R) ((4R)-hydroxy-6-phenyl-hex-2-enyl)-5,6-dihydro-pyran-2-one and its 4S epimer. AB - A simple and highly efficient synthetic route has been developed for synthesis of (R)-rugulactone (1a), (6R)-((4R)-hydroxy-6-phenyl-hex-2-enyl)-5,6-dihydro-pyran-2 one (1b) and its 4S epimer 1c by employing proline-catalyzed alpha aminooxylation, Sharpless epoxidation, Mitsunobu reaction as chirality introuducing steps. The antibacterial and antifungal activity of the compounds 1a, 1b and 1c were evaluated. 1a and 1b showed better antibacterial activity against Pseudomonas aeroginosa (MIC=12.5 microg/ml for 1a, 25 microg/ml for 1b) Klebsiella pneumonia (MIC=25 microg/ml for 1a). Compounds (1a, 1b, 1c) exhibited good to moderate antifungal activity. PMID- 20705371 TI - Antihypertensive and antiarrhythmic properties of a para-hydroxy[bis(ortho morpholinylmethyl)]phenyl-1,4-DHP compound: comparison with other compounds of the same kind and relationship with logP values. AB - A new para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP substituted compound, (4-(4-hydroxy-3,5-bis(morpholin-4-ylmethyl)phenyl)-2,6-dimethyl-1,4 dihydropyridine-3,5-dicarboxylic acid diethyl ester, LQM300), with antihypertensive and antiarrhythmic properties, has been synthesized. Four pKa values of this compound have been determined with the aid of the program SQUAD, at pseudo-physiological conditions (T = 37 degrees C and I = 0.15 M) by UV spectrophotometry and at T = 25 degrees C and I = 0.05 M by Capillary Zone Electrophoresis (CZE). The logP = 2.7 +/- 0.2 between n-octanol and water, has been estimated by UV spectrophotometry. The antihypertensive and antiarrhythmic efficacies as well as the logP values have been compared with other compounds of the same kind and related with their structure. PMID- 20705372 TI - [Totally implanted access port-related infections: features and management]. AB - Totally implanted access port-related infections are responsible for their own morbidity and mortality. Main risk factors of totally implanted access port related infections are total parenteral nutrition, young age, difficulties during insertion, poor general status and neutropenia. Recent guidelines defined intravascular catheter-related infections. This relies on a strict clinical and microbiological work-up including simultaneous culture of blood drawn from the catheter and a peripheral vein. The search for local or general complications is mandatory: clinical and possibly echographic assessments are therefore needed. Depending on the context and the type of microorganism, this evaluation may include transoesophageal echocardiography and search for suppurative thrombosis in case of catheter-related bloodstream infection caused by Staphylococcus aureus. Indeed, intravascular complications in this setting are frequent. Catheter removal is mandatory in case of local complication (tunnel infection or port pocket abscess), septic thrombosis, infective endocarditis, osteomyelitis, septic shock or infection related to specific pathogens (S. aureus, Candida spp., Pseudomonas aeruginosa). Otherwise, retention of the catheter might be proposed given results from recent studies including antibiotic lock therapy associated with systemic antibiotic. Future studies must focus on defining more precisely the factors associated with salvage therapy failure including host, pathogens virulence factors and biofilm formation. PMID- 20705373 TI - N-3 polyunsaturated fatty acids early supplementation improves ultrasound indices of endothelial function, but not through NO inhibitors in patients with acute myocardial infarction: N-3 PUFA supplementation in acute myocardial infarction. AB - BACKGROUND & AIMS: Our aim was to evaluate early initiated one month n-3 polyunsaturated fatty acids (PUFA) supplementation effects on ultrasound indices of endothelial function and serum asymmetric dimethylarginine (ADMA) levels in patients with acute myocardial infarction (AMI). METHODS: Forty patients with AMI and successful percutaneous coronary intervention (PCI) were recruited into the study and randomized to the study group (group P; n = 20; standard therapy + n-3 PUFA 1 g daily) or the control group (group C; n = 20; standard therapy). Ultrasound indices of endothelial function: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and serum ADMA concentrations (ELISA) were obtained before and after one month (30 +/- 1 days) therapy (presented as means +/- standard deviations). RESULTS: There was a significant difference between both groups in mean delta (baseline/after one month) FMD (P: 8.1 +/- 12.6% vs C: -2.2 +/- 11.8%; p = 0.02) with no difference in mean delta NMD (P: 3.3 +/- 11.9% vs 0.66 +/- 14.3%; p = 0.53). We found also a significant increase in mean FMD (7.4 +/- 6.4 to 15.5 +/- 10.5%; p = 0.02) with a nonsignificant change in mean NMD values (26.9 +/- 12.1 to 30.2 +/- 14.0%; p = 0.24) after 1 month therapy with n-3 PUFA. FMD and NMD mean values did not change in control patients (FMD: 11.6 +/- 6.1% to 9.4 +/- 8.0%; p = 0.5 NMD: 25.1 +/- 11.4% to 25.8 +/- 14.0%; p = 0.84). The comparison of mean delta ADMA values for both groups revealed no differences (P: 6.2 +/- 9.7 MUmol/l vs C: 3.6 +/- 9.5 MUmol/l; p = 0.43). Mean serum ADMA concentrations were significantly increased after 1-month therapy in the group P (P: 2.1 +/- 1.8 to 8.3 +/- 9.7 MUmol/l; p = 0.001; C: 4.5 +/- 7.1 to 8.1 +/- 9.5 MUmol/l; p = 0.09). However, there was a nonsignificant difference in mean baseline serum ADMA levels between both groups (P: 2.1 +/- 1.8 MUmol/l vs C: 4.5 +/- 7.1 MUmol/l; p = 0.32). There were no significant correlations between FMD, NMD, ADMA levels and demographic, clinical or biochemical parameters. CONCLUSIONS: Early and short-term n-3 PUFA supplementation improved ultrasound indices of endothelial function without affecting serum ADMA levels in patients with AMI and successful primary PCI. PMID- 20705374 TI - Effects of dietary glutamine on adhesion molecule expression and oxidative stress in mice with streptozotocin-induced type 1 diabetes. AB - BACKGROUND & AIMS: Glutamine (Gln) is known to have immunomodulatory effects. Previous studies reported that Gln promotes insulin secretion in type 2 diabetes. However, the effects of Gln on insulin-deficient type 1 diabetes are not clear. This study investigated the effects of dietary Gln supplementation on adhesion molecule expression and oxidative damage in type 1 diabetic mice. METHODS: There were 1 normal control (NC) group and 2 diabetic groups in this study. Mice in the NC group were fed a regular chow diet. One diabetic group (DM) was fed a common semipurified diet while the other diabetic group received a diet in which part of the casein was replaced by Gln (DM-Gln), which provided 25% of the total amino acid nitrogen for 6 wk. Diabetes was induced by an intraperitoneal injection of streptozotocin at a dose of 150 mg/kg body weight. Blood samples and the liver and kidneys of the animals were collected at the end of the study for further analysis. RESULTS: Plasma glucose, fructosamine contents and adhesion molecule expressions were significantly higher in the diabetic groups than in the NC group. The DM group had higher leukocyte CD11a/CD18 expression. In diabetic mice, nitrotyrosine concentrations and myeloperoxidase activities were higher and the reduced to oxidized glutathione ratio was lower in liver and/or kidney. These alterations were not found in diabetic mice supplemented with Gln. CONCLUSIONS: These results suggest that supplemental dietary Gln increased the antioxidant potential and consequently decreased leukocyte adhesion molecule expression and oxidative stress in organs of mice with type 1 diabetes. PMID- 20705375 TI - Quantification of sources of PCBs to the atmosphere in urban areas: a comparison of cities in North America, Western Europe and former Yugoslavia. AB - We present estimated emission source strengths of seven polychlorinated biphenyl (PCB) congeners for Banja Luka, a city that was affected by the civil war in Bosnia and Hercegovina (former Yugoslavia) in the 1990s. These emission estimates are compared to PCB emission rates estimated for the cities of Zurich, Switzerland, and Chicago, USA using an approach that combines multimedia mass balance modeling and measurement data. Our modeled per-capita emission estimates for Banja Luka are lower by a factor of ten than those for Zurich and Chicago, which are similar. This indicates that the sources of PCB emissions in Banja Luka are likely to be weaker than in the Western European and North American cities which show relatively high PCB emissions. Our emission rates from the three cities agree within a factor of ten with emission estimates from a global PCB emission inventory derived from production and usage estimates and emission factors. PMID- 20705377 TI - Evidence-based politics: how successful have government reviews been as policy instruments to reduce health inequalities in England? PMID- 20705376 TI - The diagnostic accuracy of the PTSD checklist: a critical review. AB - The PTSD Checklist (PCL) is the most frequently used self-report measure of PTSD symptoms. Although the PCL has been in use for nearly 20 years and over a dozen validation studies have been conducted, this paper provides the first comprehensive review of its diagnostic utility. Eighteen diagnostic accuracy studies of the PCL are presented, followed by an examination of the potential roles of spectrum effects, bias, and prevalence in understanding the variation in sensitivity, specificity, and other operating characteristics across these studies. Two related issues as to the interchangeability of the PCL's three versions (civilian, military, and specific) and various scoring methods are also discussed. Findings indicate that the PCL has several strengths as a PTSD screening test and suggest that it can be a useful tool when followed by a second tier diagnostic test such as a standardized interview. However, the PCL's operating characteristics demonstrate significant variation across populations, settings, and research methods and few studies have examined such factors that may moderate the PCL's utility. Recommendations and cautions regarding the use of the PCL as a clinical screening test, a diagnostic tool in research, and as an estimator of PTSD population prevalence are provided. PMID- 20705378 TI - Anorexia nervosa: a psychiatric illness with gynecological manifestations. A survey of knowledge and practice among Greek gynecologists. AB - OBJECTIVE: Anorexia nervosa (AN) affects a large number of women, usually in their adolescence. One of the primary manifestations of the disease is menstrual irregularity, and the presence of a menstrual cycle is often used as a sign of recovery among patients. Women with AN are likely to seek medical advice from a gynecologist with regards to their period problems. The role of the gynecologist is therefore crucial in identifying and referring these patients promptly to specialised centers. STUDY DESIGN: A brief anonymous questionnaire was completed by 94 gynecologists practising in Athens. RESULTS: Approximately half of the responders felt that the conditions were rarer than it really is, and 25% thought that the disease primarily affects women in their early twenties. Although 56% of gynecologists would not prescribe the combined oral contraceptive in women with AN in order to restore their periods, the remainder of gynecologists were in favour of prescribing hormone replacement with a view to reducing the risk of osteopenia. This is despite the fact that emerging evidence shows there is no benefit. Ten percent of gynecologists never weigh their patients during evaluation of amenorrhoea and 72% felt that their level of knowledge as far as anorexia nervosa is concerned is inadequate. CONCLUSION: More education is required among gynecologists on the subject of anorexia nervosa, in order to identify and refer patients in the early stages of the disease process. PMID- 20705379 TI - Microsatellite instability in endometrial polyps. AB - OBJECTIVE(S): To investigate the prevalence of microsatellite instability (MSI) in endometrial polyps and to evaluate whether there are clinical and histopathological parameters associated with this kind of instability. STUDY DESIGN: Between September 2008 and April 2009, endometrial polyps were collected from 109 patients. MSI was evaluated using the NCI recommended markers BAT25, BAT26, D2S123, D5S346 and D17S250. Histopathological analysis was performed, and clinical information was obtained from patients' records. RESULT(S): MSI low was detected in 6.4% of the validated samples (7/109). Of the seven MSI that were detected, six were positive for instability at D17S250 and one at D5S346. There were no significant differences between polyps with or without MSI with regard to age, BMI, menarche, parity, miscarriage or menopause; however, MSI was more frequent in polyps with simple hyperplasia without atypia (3/20; 15%). Furthermore, patients with multiple polyps had a marginally but statistically insignificant increase in the frequency of MSI (p<0.07). CONCLUSION(S): This is the first prospective study of MSI in endometrial polyps using hysteroscopically obtained samples. In a population of 109 patients, MSI was infrequent in endometrial polyps. Although MSI appears to be more frequent in multiple polyps and polyps with simple hyperplasia without atypia, this was not statistically significant. PMID- 20705380 TI - The effects of acrylamide on sperm parameters and membrane integrity of epididymal spermatozoa in mice. AB - OBJECTIVE: Acrylamide is a chemically reactive substance used in various industries. Recently, the discovery of acrylamide in a variety of human foods including heat-processed starchy foods such as potato chips and bread has been reported. Acrylamide is also known as a carcinogen and cytotoxic material. The aim of this study was to evaluate the detrimental effects of acrylamide on membrane integrity and sperm parameters in mice. STUDY DESIGN: This experimental study was conducted on thirty male NMRI mice, aged 8-10 weeks and weighing 25-30 g. They were randomly allotted into three equal groups. Group I (low dose) and group II (high dose) were fed on water solutions containing acrylamide 5 and 10 mg/kg/day, respectively, for 2 months, while the third group received fresh water as the control group. Sperm analysis was done for parameters as well as evaluation of membrane integrity by Hypoosmotic Swelling Test (HOS-test) for sperm tails and Eosin-Y staining for sperm heads. RESULTS: Total sperm motility and progressive motility (fast and slow) in both groups, I and II, decreased significantly (P = 0.00), but no significant change was observed in non progressive motility (P > 0.05). The total motile sperm percentage decreased significantly only in group II (P = 0.01). Sperm morphology did not significantly change in the experimental groups compared to the controls (P > 0.05). In sperm membrane integrity evaluation, functional intact membrane of sperm tail in both groups I and II had a significant decrease (P = 0.00), but membrane integrity of the sperm head decreased significantly only in group II (P = 0.00). CONCLUSION: These results indicate that acrylamide, through effects on membrane integrity, decreased sperm vitality as well as causing abnormal sperm parameters in progressive motility and total motility. PMID- 20705381 TI - Comparison between transumbilical and transabdominal ports for the laparoscopic retrieval of benign adnexal masses: a randomized trial. AB - OBJECTIVE: To compare the feasibility, operative time, specimen retrieval time, and effect on postoperative pain of laparoscopic retrieval of benign adnexal masses between a 10-mm transumbilical and a 10-mm transabdominal port. STUDY DESIGN: Fifty women with adnexal masses who were scheduled for a laparoscopic procedure between July 2008 and April 2009 were enrolled. The patients were randomized into two groups; these were patients where a transumbilical port was used for specimen retrieval (transumbilical group, n=25) and patients where a transabdominal port was used for specimen retrieval (transabdominal group, n=25). Preoperative suspicion of malignancy and indications suggesting a need for hysterectomy or myomectomy were considered to be exclusion criteria. Randomization was centralized and computer-based. Patients recorded the severity of incisional pain on a visual analog scale (VAS) with 0 meaning no pain and 10 meaning unbearable pain. RESULTS: There were no significant differences in age, body mass index, umbilical thickness, abdominal thickness, cyst size, cyst amount, cyst weight, histology, complications and duration of hospital stay when the two groups were compared. Patients in the transumbilical group had a significantly shorter specimen retrieval time (0.7 +/- 1.8 min vs. 4.9 +/- 12.6 min, p=0.006) and a significantly lower postoperative day (POD) 0 VAS pain score (5.2 +/- 2.1 vs. 6.6 +/- 2.2, p=0.015). Significantly fewer patients in the transumbilical group had a specimen retrieval time of >=10 min (0% vs. 20%, p=0.025) and a POD 0 VAS pain score of >5 (36% vs. 84%, p<0.001). However, the average POD 1 VAS pain score (3.2 +/- 1.8, vs. 3.6 +/- 1.6) and the proportion with a POD 1 VAS pain score >5 (12% vs. 12%) were similar for the two groups. CONCLUSION: When laparoscopic surgery on benign adnexal masses is carried out using a 10-mm incision wound, removal of the specimen via the umbilical port has a shorter retrieval time and produces less postoperative pain than retrieval via a lateral abdominal port. PMID- 20705382 TI - Long non-coding RNAs: Guardians of development. AB - Two decades ago, the existence of long non-coding RNAs (lncRNAs) was discovered. In the following genomics era more transcribed non-coding genomic regions were identified. These were initially regarded as transcriptional noise and did not receive a lot of attention. Emerging data on several of these long non-coding transcripts have refuted this hypothesis by demonstrating that non-coding RNAs (ncRNAs) are important for regulating transcription and cell signaling. A special subset of the lncRNAs affecting gene transcription appears to orchestrate major developmental programs. Here, we discuss the mechanisms by which lncRNAs regulate transcription, and review the evidence that links this class of lncRNAs to a role in development. PMID- 20705383 TI - Nitrogen critical loads and management alternatives for N-impacted ecosystems in California. AB - Empirical critical loads for N deposition effects and maps showing areas projected to be in exceedance of the critical load (CL) are given for seven major vegetation types in California. Thirty-five percent of the land area for these vegetation types (99,639 km(2)) is estimated to be in excess of the N CL. Low CL values (3-8 kg N ha(-1) yr(-1)) were determined for mixed conifer forests, chaparral and oak woodlands due to highly N-sensitive biota (lichens) and N-poor or low biomass vegetation in the case of coastal sage scrub (CSS), annual grassland, and desert scrub vegetation. At these N deposition critical loads the latter three ecosystem types are at risk of major vegetation type change because N enrichment favors invasion by exotic annual grasses. Fifty-four and forty-four percent of the area for CSS and grasslands are in exceedance of the CL for invasive grasses, while 53 and 41% of the chaparral and oak woodland areas are in exceedance of the CL for impacts on epiphytic lichen communities. Approximately 30% of the desert (based on invasive grasses and increased fire risk) and mixed conifer forest (based on lichen community changes) areas are in exceedance of the CL. These ecosystems are generally located further from emissions sources than many grasslands or CSS areas. By comparison, only 3-15% of the forested and chaparral land areas are estimated to be in exceedance of the NO(3)(-) leaching CL. The CL for incipient N saturation in mixed conifer forest catchments was 17 kg N ha(-1) yr(-1). In 10% of the CL exceedance areas for all seven vegetation types combined, the CL is exceeded by at least 10 kg N ha(-1) yr(-1), and in 27% of the exceedance areas the CL is exceeded by at least 5 kg N ha(-1) yr(-1). Management strategies for mitigating the effects of excess N are based on reducing N emissions and reducing site N capital through approaches such as biomass removal and prescribed fire or control of invasive grasses by mowing, selective herbicides, weeding or domestic animal grazing. Ultimately, decreases in N deposition are needed for long-term ecosystem protection and sustainability, and this is the only strategy that will protect epiphytic lichen communities. PMID- 20705384 TI - Application of pig slurry to soils. Effect of air stripping treatment on nitrogen and TOC leaching. AB - The effect of physical-chemical slurry treatment on the mobility and transformation of nitrogen and organic matter from pig slurry after soil application is evaluated. Two different pig slurries (one treated by stripping with air at pH=9 and another non-treated) were applied at the top of a soil column, containing approximately 100 kg of soil. Effluents were monitored measuring concentration values of ammonia, nitrites, nitrates and total organic carbon (TOC). The breakthrough curves were modelled using STANMOD and HYDRUS 1D codes. Low concentrations of ammonia were detected in the effluent recovered at the bottom of the soil profile for both types of slurry. Nitrate concentration in effluent was lower and more homogenous over time when applying stripping treated pig slurry. In N modelling, adsorption of ammonia by soil proved an important process, nitrite and nitrate adsorption being less significant, although not negligible. Transformation from ammonia to nitrite controls the kinetics of the nitrification process. Total organic carbon in the column effluent was higher in the experiment using treated pig slurry, which can be attributed to organic matter solubilisation in the stripping treatment process. PMID- 20705385 TI - An agent-based approach to explore the effect of voluntary mechanisms on land use change: a case in rural Queensland, Australia. AB - In rural regions, land use changes (LUC) are often the result of the decision making of individual farmers. To influence this decision-making, compulsory and voluntary mechanisms are implemented. However, farmers' decision-making is a heterogeneous process that depends on their ability and willingness to take certain decisions. Discrepancies between farmers' ability and willingness and the design of voluntary mechanisms occur frequently. This makes it necessary to understand how farmers' participation in these mechanisms can affect LUC. The aim of this paper was to demonstrate an agent-based approach to analyse and explore how voluntary mechanisms can influence LUC processes in rural regions. This approach was applied to a rural region in Australia, where clearing of native vegetation has occurred for agricultural development. Historical land cover data and semi-structured interviews were used to parameterise an agent-based model. Factors that influence farmers' ability and willingness to participate in these mechanisms were identified. Three scenarios were simulated with the model to explore how the implementation of different voluntary mechanisms can affect the landscape structure of the region. This paper identifies how the diversity of farmers' decision-making can influence the landscape structure in the region. The advantages and limitations of an agent-based approach in relation to LUC research and policy are discussed. PMID- 20705386 TI - The effectiveness of arbuscular-mycorrhizal fungi and Aspergillus niger or Phanerochaete chrysosporium treated organic amendments from olive residues upon plant growth in a semi-arid degraded soil. AB - Arbuscular mycorrhizal (AM) fungi and a residue from dry olive cake (DOC) supplemented with rock phosphate (RP) and treated with either Aspergillus niger (DOC-A) or Phanerochaete chrysosporium (DOC-P), were assayed in a natural, semi arid soil using Trifolium repens or Dorycnium pentaphyllum plants. The effects of the AM fungi and/or DOC-A were compared with P-fertilisation (P) over eleven successive harvests to evaluate the persistence of the effectiveness of the treatments. The biomass of dually-treated plants after four successive harvests was greater than that obtained for non-treated plants or those receiving the AM inoculum or DOC-A treatments after eleven yields. The AM inoculation was critical for obtaining plant growth benefit from the application of fermented DOC-A residue. The abilities of the treatments to prevent plant drought stress were also assayed. Drought-alleviating effects were evaluated in terms of plant growth, proline and total sugars concentration under alternative drought and re watering conditions (8th and 9th harvests). The concentrations of both compounds in plant biomass increased under drought when DOC-A amendment and AM inoculation were employed together: they reinforced the plant drought-avoidance capabilities and anti-oxidative defence. Water stress was less compensated in P-fertilised than in DOC-A-treated plants. DOC-P increased D. pentaphyllum biomass, shoot P content, nodule number and AM colonisation, indicating the greater DOC transforming ability of P. chrysosporium compared to A. niger. The lack of AM colonisation and nodulation in this soil was compensated by the application of DOC-P, particularly with AM inoculum. The management of natural resources (organic amendments and soil microorganisms) represents an important strategy that assured the growth, nutrition and plant establishment in arid, degraded soils, preventing the damage that arises from limited water and nutrient supply. PMID- 20705387 TI - Land-use changes and carbon sequestration through the twentieth century in a Mediterranean mountain ecosystem: implications for land management. AB - Ecosystems in the western Mediterranean basin have undergone intense changes in land use throughout the centuries, resulting in areas with severe alterations. Today, most these areas have become sensitive to human activity, prone to profound changes in land-use configuration and ecosystem services. A consensus exists amongst stakeholders that ecosystem services must be preserved but managerial strategies that help to preserve them while ensuring sustainability are often inadequate. To provide a basis for measuring implications of land-use change on carbon sequestration services, changes in land use and associated carbon sequestration potential throughout the 20th century in a rural area at the foothills of the Sierra Nevada range (SE Spain) were explored. We found that forest systems replaced dryland farming and pastures from the middle of the century onwards as a result of agricultural abandonment and afforestation programs. The area has always acted as a carbon sink with sequestration rates ranging from 28,961 t CO(2) year(-1) in 1921 to 60,635 t CO(2) year(-1) in 1995, mirroring changes in land use. Conversion from pastures to woodland, for example, accounted for an increase in carbon sequestration above 30,000 t CO(2) year(-1) by the end of the century. However, intensive deforestation would imply a decrease of approximately 66% of the bulk CO(2) fixed. In our study area, woodland conservation is essential to maintain the ecosystem services that underlie carbon sequestration. Our essay could inspire policymakers to better achieve goals of increasing carbon sequestration rates and sustainability within protected areas. PMID- 20705388 TI - Reply to Emmanuele A. Jannini's Words of wisdom re: the role of short frenulum and the effects of frenulectomy on premature ejaculation [J Sex Med 2010;7:1269 76]. Eur Urol 2010;57:1119-20. PMID- 20705389 TI - Important considerations in the clinical use of preoperative prostate cancer predictive nomograms. PMID- 20705390 TI - Can robot-assisted radical prostatectomy still be considered a new technology pushed by marketers? The IDEAL evaluation. PMID- 20705391 TI - 20 kHz sonoelectrochemical degradation of perchloroethylene in sodium sulfate aqueous media: influence of the operational variables in batch mode. AB - A preliminary study of the 20 kHz sonoelectrochemical degradation of perchloroethylene in aqueous sodium sulfate has been carried out using controlled current density degradation sonoelectrolyses in batch mode. An important improvement in the viability of the sonochemical process is achieved when the electrochemistry is implemented, but the improvement of the electrochemical treatment is lower when the 20 kHz ultrasound field is simultaneously used. A fractional conversion of 100% and degradation efficiency around 55% are obtained independently of the ultrasound power used. The current efficiency is also enhanced compared to the electrochemical treatment and a higher speciation is also detected; the main volatile compounds produced in the electrochemical and sonochemical treatment, trichloroethylene and dichloroethylene, are not only totally degraded, but also at shorter times than in the sonochemical or electrochemical treatments. PMID- 20705392 TI - Antimicrobial activity of commercial zeolite A on Acinetobacter junii and Saccharomyces cerevisiae. AB - The influence of three samples of commercially produced zeolite A (named A, M and R) in water medium on the bacterium Acinetobacter junii and yeast Saccharomyces cerevisiae was investigated. These microorganisms were used in the bioassay and are not specifically related to the use of zeolite A. All zeolite samples showed the negative influence on the survival and physiological status of A. junii and S. cerevisiae. The EC(50) values for the inhibition of CFU of A. junii were 0.328, 0.138 and 0.139 g l(-1) for zeolite sample A, M and R, respectively. The EC(50) values of tested zeolites for S. cerevisiae, estimated by fermentation and fluorescence microscopy assay, ranged from 2.88 to 5.47 g l(-1). The genotoxic effect of three samples of zeolite to S. cerevisiae was shown by the alkaline comet assay. When assuming all the aspects of zeolite toxicity to bacterium and yeast, the zeolite sample R appeared to be less toxic than the samples A and M. The hydrolysis of zeolite crystals, amorphous aluminosilicate and unreacted gel fraction in water medium and consecutive dissolution and leaching of aluminium and silicon in the form of aluminosilicate molecules (700-1300 Da) was detected. PMID- 20705393 TI - The course of opioid prescribing for a new episode of disabling low back pain: opioid features and dose escalation. AB - Despite utilization concerns, little information is available on opioid prescribing for acute, disabling low back pain (LBP) and how opioid features (purity, strength, and length of action) and dose change over time. This information is important in targeting guideline implementation efforts and identifying risks for inappropriate prescribing. Using 2002-2003 United States' workers compensation claims, a cohort of 2868 cases with a new episode of work related LBP and at least one opioid prescription was followed for 2 years. Opioid prescriptions (timing, dose, and formulation), demographics, and medical data were captured. A longitudinal model of change was used to evaluate factors associated with dosing changes. Opioid prescribing typically began early in the course of care (median=8 days, Inter-Quartile Range (IQR)=3, 43 days) and was often prolonged (median=46 days, IQR=14, 329). At the end of the observation period, 7.1% of non-surgical cases and 30.6% of surgical cases were still receiving opioids. The number of days between the initial LBP report and the first opioid prescription had the greatest association with subsequent dose escalation. Dose escalation was greater with pure formulations, and was not related to clinical severity or surgery. In contrast to previous and current guideline recommendations, opioid prescribing for acute LBP was often prolonged, and longer for surgical cases. These results reinforce recommendations to limit opioid duration, and suggest that consideration of opioid features, purity as an important one, can be part of a strategy to prevent escalating dosages. PMID- 20705394 TI - Noxious heat evokes stronger sharp and annoying sensations in women than men in hairy skin but not in glabrous skin. AB - Brief noxious heat evokes more intense pain in women than in men; however, sex differences in the intensity of pain sensations evoked in hairy and glabrous skins are not clearly understood. Glabrous skin putatively lacks the type of A delta nociceptors that underlie heat-evoked sharp sensation. Therefore, we assessed whether noxious heat-evoked pain qualities differed for hairy and glabrous skins and whether sex differences exist in these evoked pains. We applied a prolonged (30s) ramped noxious heat stimulus to the dorsal and ventral aspects of the feet of 16 males and 16 females. Stimuli were calibrated in each subject to evoke a peak pain magnitude of 50/100. Subjects provided continuous online ratings of pain, annoyance, burning, sharp, stinging and cutting sensations in separate runs. The results indicate that both sex and skin type impact noxious heat-evoked sensations. Specifically, ratings of sharp sensations and annoyance evoked in hairy skin were significantly more intense in women than in men. Sharp, stinging and cutting sensations were evoked in glabrous skin, but the magnitude of these sensations was greater in hairy skin than glabrous skin; an effect only in females. Also, there was no sex difference in sharp sensation and annoyance in glabrous skin. These findings suggest that sharp sensations are evoked more prominently in hairy than in glabrous skin of women and that sharp sensations and annoyance play a prominent role in mediating aspects of pain evoked from hairy skin in women. PMID- 20705395 TI - Babesia canis and Babesia rossi co-infection in an untraveled Nigerian dog. AB - A sexually intact 6-month-old female Alsatian dog was presented to the Veterinary Clinic of the National Veterinary Research Institute, Vom, Plateau State, Nigeria, for the following complaints: anorexia, hemoglobinuria, fever, tick infestation and general malaise. Microscopy revealed piroplasms with a wide range of sizes (1-5 MUm in length) in red blood cells, raising a suspicion of a co infection with two or more Babesia species. Specific PCR assays for canine Babesia spp. and DNA sequencing revealed the presence of Babesia canis and Babesia rossi co-infection. This study constitutes the first report of co infection with B. canis and B. rossi in the West African sub-region and the first report of autochthonous B. canis on the African continent. Practitioners should be aware of potential changes in the species/sub-species of Babesia causing canine babesiosis in this region. PMID- 20705396 TI - Anthelmintic activity of Pistacia lentiscus foliage in two Middle Eastern breeds of goats differing in their propensity to consume tannin-rich browse. AB - The Damascus and Mamber breeds of goats thrive in Middle Eastern Mediterranean regions where the tannin-rich (20% of polyethylene glycol-binding tannins) brush species Pistacia lentiscus L. (lentisk) is ubiquitous. In light of the increasing recognition of the anthelmintic activity of plant tannins, we examined the effect of offering lentisk foliage for 24 days on fecal egg excretion in 5.5-month-old Damascus and Mamber kid goats (n=28) following infection with 10,000 L3 larvae of mixed gastro-intestinal nematodes (GIN). Lentisk foliage was consumed with or without a daily supplement of 20 g polyethylene glycol (PEG; MW 4000). Lentisk tannins showed a strong protein-depletive effect that was totally reversed by the addition of PEG. At the peak of infection, kids of the two breeds lost weight unless they were fed with lentisk without PEG. Fecal egg counts (FEC) were lowest - and did not differ from 0 - in kids fed lentisk without PEG, highest in the controls fed hay as roughage, and intermediate in kids fed lentisk and PEG (241, 1293, and 705 eggs per gram, respectively, SEM 180; P<0.001); therefore, the anthelmintic activity of lentisk was only partly attributable to tannins. The suppressive effect of lentisk on FEC ceased when feeding was discontinued, suggesting that female parasites were not killed but their fertility was reversibly impaired. Damascus kids showed lower FEC than their Mamber counterparts, inferring that the effect of foraging on tannin-rich species is only additive to genetic differences between goat breeds in their sensitivity to GIN infection. On the basis of our results we would expect yearlong lentisk grazing to result in no or very low GIN infection, and Damascus goats to have some advantage over Mamber goats where chemical control of GIN is unfeasible. There appears to be a trade-off between the benefits of lentisk tannin as drug and its side-effects (protein depletion) when given at high level; how goats balance this trade-off requires further elucidation. PMID- 20705397 TI - Advances in the systemic treatment of pancreatic neuroendocrine tumors. AB - Constituting about 1-2% of all tumors of the pancreas, pancreatic neuroendocrine tumors (PNETs) are a subgroup of gastroenetropancreatic neuroendocrine tumors (GEP-NETs) with distinct tumor genetics, biology, and clinicopathological features. Surgical resection is amenable only in a minority of the cases so systemic therapies are considered in most of them. The goals of medical treatment are to control the associated symptoms and signs of the specific tumors and to shrink the tumor mass. Somatostatin analogues can, not only decrease the secretion of peptides and inhibit their functions but also stop tumor growth. Other medical options for limiting tumor growth include interferon, systemic chemotherapy, and targeted therapies including, angiogenesis inhibitors, epidermal growth factor inhibitors, and mTOR inhibitors. Newer agents are tested and the treatment options expected to increase in the near future. Meanwhile optimal use of the available therapeutic strategies is critical. PMID- 20705398 TI - Discrepancy between how children perceive their own alcohol risk and how they perceive alcohol risk for other children longitudinally predicts alcohol use. AB - This paper examined discrepancies between children's self-perceptions of the riskiness of alcohol use versus their perceptions of the riskiness of alcohol use for other children, and whether these discrepancies predicted children's future alcohol use. Participants included 234 children (M=11 years, 45.3% female) who completed baseline and one-year follow-up assessments on self-perceived riskiness of alcohol use, perceived riskiness of alcohol use for other same-age children, and own past year alcohol use. When considering child age and gender, baseline alcohol use, and the individual reports of the riskiness of alcohol use, the interaction between alcohol use riskiness reports prospectively predicted greater odds of alcohol use. The highest percentage of childhood alcohol use at one-year follow-up came from those children with both low self-perceived riskiness of alcohol use and high perceived riskiness of alcohol use for other children. Children's perceptions of multiple people's risk from alcohol use result in identifying important subgroups of children at risk for early-onset alcohol use. PMID- 20705399 TI - Recapture of hepatic apolipoprotein B mRNA editing may be a promising strategy to relieve nephrotic dyslipidemia. AB - A high total plasma cholesterol concentration is the most common abnormality found in patients with kidney disease, which may be associated with the increased hepatic synthesis of apoB containing lipoproteins. ApoB mRNA editing plays an important physiological role in mammalian lipid metabolism by modifying the distribution of apoB-100 and apoB-48. However, it is regretful that apoB mRNA editing cannot be found in human liver because of the absence of apobec-1 expression. In this context, we hypothesize that the recapture of hepatic apoB mRNA editing may be a promising strategy to relieve nephrotic dyslipidemia. The data presented below focus on those which support this hypothesis with regards to evidence in vitro and in vivo. (1) Human wild-type apoB mRNA can be edited only when both apobec-1 and ACF proteins are presented simultaneously in vitro. (2) Adenoviral vectors can produce short-term expression of exogenous apobec-1 in the livers and lower plasma apoB-100 and LDL levels transiently. (3) Apobec-1 transgenic animals exhibit massive hepatic editing of apoB mRNA and fundamental decreased plasma levels of apoB-100 and LDL, but are exposed to high risk of liver dysplasia and hepatocellular carcinomas. In summary, taking into account the therapeutic security, we put forward that apobec-1 recombinant adenoviral vectors can be used for the recapture of hepatic apoB mRNA editing with a transient low-level manner and may achieve satisfactory lipid-lowing effect in nephropathic animals. PMID- 20705400 TI - Adult variant of atypical teratoid/rhabdoid tumor: immunohistochemical and ultrastructural confirmation of a rare tumor in the sella tursica. AB - Atypical teratoid/rhabdoid tumor (AT/RT) is a distinctive neoplasm of young children characterized by diverse histology and fatal course. Adult presentation is rare. We describe the diagnostic problems associated with an AT/RT arising in the sellar region in a 46-year-old female. Vimentin, keratin, synaptophysin, CD34, SMA, PLAP, GFAP, S-100, NSE, desmin, MYF-4, LCA, and CD99 were performed on tissue obtained from the paraffin block. INI1 protein expression was immunohistochemically determined on tumor tissue. Electron microscopy was performed from the tissue block. The tumor was composed of large atypical "rhabdoid" cells having macronucleoli and abundant eosinophilic cytoplasm. Immunohistochemistry showed that the tumor cells were positive for vimentin, CD34, CD99, and reacted variably for keratin, synaptophysin, NSE, and SMA. All were negative for GFAP, S-100, desmin, MYF-4, and LCA. The tumor cells lacked nuclear expression of INI1. Electron microscopy revealed cells with large paranuclear intracytoplasmic collections of intermediate filaments. AT/RT should be considered when dealing with a malignant neoplasm with rhabdoid features, regardless of age. Immunohistochemistry is of importance in differentiating this entity from primitive neuroectodermal tumors (PNET) and carcinosarcomas. Lack of nuclear INI1 protein expression by immunohistochemical methods is required for a reliable diagnosis. PMID- 20705401 TI - Serotonin 6 receptor gene is associated with methamphetamine-induced psychosis in a Japanese population. AB - BACKGROUND: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and d-amphetamine induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by d amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. METHOD: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. RESULTS: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. CONCLUSION: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. PMID- 20705403 TI - Risk factors for bone loss in the hip of 75-year-old women: a 4-year follow-up study. AB - Risk factors for bone loss among the elderly are largely unknown. The objective of the study was to examine longitudinal bone loss in the hip in one-hundred and sixty-two 75-year-old women. Bone mineral density (BMD, g/cm(2)) was measured with dual X-ray absorptiometry (DXA) at baseline and after 4 years. The relationship between changes in BMD during follow-up and the following factors; baseline BMD, baseline weight, weight change, baseline lean and fat body mass (measured with DXA), serum values of biochemical markers and hormones, nutritional and lifestyle factors according to a questionnaire was assessed. The annual mean (SD) change in femoral neck BMD was -0.31% (1.38) in total trochanter -0.35% (1.15) and total hip -0.34% (1.10) and did not differ significantly between measurement sites. Bisphosphonate users had a 2.9%, 1.7% and 1.9% mean adjusted increase in femoral neck, total trochanter and total hip BMD respectively, different from none-users (p<0.05). Subjects with more than three weekly physical activity sessions had less femoral neck bone loss than less active women (p<0.05). The proportion of the variance in BMD changes explained by multivariate models (R(2)) was 12-13%. Women gaining weight had less loss of BMD than those losing weight in the trochanter and the total hip (p<0.001), and in the femoral neck (p=0.055). Elderly women should be advised to maintain their body weight and participate in physical activity. Despite the large number of variables examined in this study, bone loss occurring with increased age is not thoroughly explained. PMID- 20705402 TI - A systematic review of the impact of alcohol use disorders on HIV treatment outcomes, adherence to antiretroviral therapy and health care utilization. AB - BACKGROUND: Alcohol use disorders (AUDs) are highly prevalent and associated with non-adherence to antiretroviral therapy, decreased health care utilization and poor HIV treatment outcomes among HIV-infected individuals. OBJECTIVES: To systematically review studies assessing the impact of AUDs on: (1) medication adherence, (2) health care utilization and (3) biological treatment outcomes among people living with HIV/AIDS (PLWHA). DATA SOURCES: Six electronic databases and Google Scholar were queried for articles published in English, French and Spanish from 1988 to 2010. Selected references from primary articles were also examined. REVIEW METHODS: Selection criteria included: (1) AUD and adherence (N=20); (2) AUD and health services utilization (N=11); or (3) AUD with CD4 count or HIV-1 RNA treatment outcomes (N=10). Reviews, animal studies, non-peer reviewed documents and ongoing studies with unpublished data were excluded. Studies that did not differentiate HIV+ from HIV- status and those that did not distinguish between drug and alcohol use were also excluded. Data were extracted, appraised and summarized. DATA SYNTHESIS AND CONCLUSIONS: Our findings consistently support an association between AUDs and decreased adherence to antiretroviral therapy and poor HIV treatment outcomes among HIV-infected individuals. Their effect on health care utilization, however, was variable. PMID- 20705404 TI - Analysis of mRNA from human heart tissue and putative applications in forensic molecular pathology. AB - The usefulness of post-mortem mRNA analysis and its potential applications in forensic casework is currently of interest, especially because of several factors affecting the quality of RNA samples that are not practically predictable. In fact, post-mortem RNA degradation is a complex process that has not been studied systematically. The purpose of this work is to establish whether RNA analysis from post-mortem heart tissue could be used as a forensic tool to investigate the cause of death, with special regard to those cases where a cardiac disease is suspected as the manner of death. We analysed heart tissue from 16 individuals with normal cardiac function, 9 with long post-mortem intervals (L-PMI) and 7 from organ donors with very short PMIs (S-PMIs). Right ventricle tissue was homogenised, and the RNA was isolated and reverse transcribed. The resulting cDNA was used in real-time PCR reactions to quantify the gene expression of beta glucuronidase (GUSB), Nitric Oxide Synthase 3 (NOS3), Collagen 1 (COL1A1) and Collagen 3 (COL3A1). The percentage of samples with high-quality RNA was higher in samples with S-PMI (7 out of 7) than in samples with L-PMI (4 out of 9, p<0.05). No differences in PMI time or cause of exitus were found between samples with degraded or non-degraded RNA in the L-PMI group. When comparing mRNA levels in samples with non-degraded RNA, we found similar values between the L-PMI and S PMI groups for GUSB, COL1A1 and COL3A1. The NOS3 gene expression in the L-PMI subgroup was less than half that in the S-PMI. These results suggest that high quality mRNA can be extracted from post-mortem human hearts only in some cases. Moreover, our data show that mRNA levels are independent from the PMI, even though there are mRNAs in which the expression levels are very susceptible to ischemia times. Clear knowledge about the relationship between mRNA integrity and expression and PMI could allow the use of several mRNAs as forensic tools to contribute to the determination of the cause of death with special regard to cardiovascular diseases. PMID- 20705405 TI - Forensic entomology in Kuwait: the first case report. AB - To date, entomology has not been used in legal investigations in Kuwait. Indeed, this is true of most Arab countries in the Middle East. There are no known studies on necrophagous species in the region, nor any knowledge of cadaver succession with which to compare case material. Here we report the first case of application of forensic entomology in Kuwait. In Al-Rowdah district, a man was found dead in his bedroom which was air-conditioned and the windows were closed. The temperature of the room was 20 degrees C. The cause of death was morphine overdose. At autopsy, fly larvae were collected from the blanket with which the body was wrapped and were identified as postfeeding 3rd instars of Parasarcophaga (Liopygia) ruficornis using molecular analysis. In addition, the face and neck were extensively and exclusively colonized by different stages of Chrysomya albiceps (secondary fly). Based on the age of P. ruficornis full mature 3rd instars and the location of the body, approximately 7.5-8.5 days postmortem was estimated for the corpse at the time of its discovery. PMID- 20705406 TI - Progressive primary pulmonary tuberculosis presenting as the sudden unexpected death in infancy: a case report. AB - The classification of an unexpected infant death as the sudden infant death syndrome (SIDS) depends upon a complete autopsy and death scene investigation to exclude known causes of death. Here we report the death of a 4-month-old infant in a tuberculosis endemic area that presented as a sudden unexpected death in infancy (SUDI) with no apparent explanation based on the death scene characteristics. The autopsy, however, revealed progressive primary pulmonary tuberculosis with intrathoracicadenopathy, compression of the tracheobronchial tree and miliary lesions in the liver. This case underscores the clinical difficulties in the diagnosis of infantile tuberculosis, as well as the possibility of sudden death as part of its protean manifestations. The pathology and clinical progression of tuberculosis in infants differ from older children and adults due to the immature immune response in infants. This case dramatically highlights the need for complete autopsies in all sudden and unexpected infant deaths, as well as the public health issues in a sentinel infant tuberculosis diagnosis. PMID- 20705407 TI - New technologies in the genetic approach to sudden cardiac death in the young. AB - Sudden cardiac death (SCD) is a major health problem and constitutes one of the most important unsolved challenges in the practice of forensic pathology due to the failure to determine the cause of death. Particularly, an important number of previously healthy young people who have died suddenly and unexpectedly are consequence of genetic heart disorders, either structural cardiomyopathies or arrhythmogenic abnormalities. The technological approach to analyze this type of genetically heterogeneous disorders is far from easy but nowadays the variety of chemistries and methodologies improves choice. This review offers to the reader a state of the art of the available technologies for the study of genetics of sudden cardiac death, including mutation screening approaches, genome wide association studies, and the recently developed next-generation sequencing. PMID- 20705408 TI - Simultaneous determination of seven flavonoids in dog plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to a bioequivalence study of bioactive components in Herba Epimedii and Er-Xian Decoction. AB - In this study, a sensitive and specific ultra-performance liquid chromatography tandem mass method has been developed and validated for the identification and determination of 7 flavonoids in dog plasma for the first time: epimedin A, epimedin B, epimedin C, icariin, sagittatoside B, 2"-O-rhamnosyl icariside II, and baohuoside I. Chromatographic separation was accomplished on an Agilent Zorbax-SB C(18) column (50 mm * 2.1mm, 1.8 MUm) with a gradient elution system composed of 0.3% acetic acid and 0.3% acetic acid in acetonitrile at a flow rate of 0.4 mL/min. Detection was based on a triple quadrupole mass spectrometer using a multiple reaction monitoring mode with an electrospray ionization source. All of the calibration curves showed good linearity (r>0.99) within the tested concentration ranges. The lower limits of quantification of the seven analytes were all lower than 0.0654 ng/mL. The relative standard deviations for intra- and inter-batches of the seven analytes were less than 13.7% and 14.9%, respectively, at four concentration levels of quality control samples, and the recoveries were between 92.8% and 114.5%, respectively. In addition, the seven flavonoids were found to be stable in dog plasma samples under short- and long-term storage and processing conditions. The validated method was successfully applied to a bioequivalence study in dog plasma after the oral administration of extracts of Herba Epimedii and Er-Xian Decoction. PMID- 20705409 TI - Cardiac tamponade as the initial manifestation of systemic lupus erythematosus. PMID- 20705410 TI - Magnetic resonance imaging of cerebral malaria. PMID- 20705411 TI - Development of an ICF-based patient education program. AB - OBJECTIVE: To describe the development of an ICF-based patient education program, to present the results of its pilot test and to present the adaptations and final version of the program. METHODS: The education program was developed in five steps: (1) definition of relevant areas of functioning, (2) development of strategies to enhance self-efficacy in these areas, (3) development of material and instructions, (4) definition of modules and setting and (5) performance of a pilot test targeting acceptability and feasibility of the program. RESULTS: Eleven stroke patients were enrolled in the pilot test. The intervention was well accepted on the part of participants. The developed patient education program is structured in three modules. Module 1 targets to increase patients' understanding of their current level of functioning. Module 2 targets to identify concrete problems and corresponding solutions regarding limited areas. Module 3 is a refresher session. CONCLUSION: Feasibility and acceptability of the intervention were verified and a final version of the patient education program was developed. The effectiveness of the program will be evaluated in a randomized controlled trial. PRACTICE IMPLICATIONS: Due to the universality of the ICF and availability of ICF tools, it is possible to adapt the intervention to different chronic conditions. PMID- 20705412 TI - Chronic condition self-management: expectations of responsibility. AB - OBJECTIVE: While self-management may be beneficial for many patients it assumes and encourages a particular conception of responsibility and self-management that may not fit with all patients' experience of their chronic conditions and their management. It therefore warrants further examination. METHODS: We examine the concept of self-management and responsibility from a range of standpoints, focusing on the Australian context. RESULTS: Attempts to meet people's needs run the risk of imposing specific conceptions of how people should live their lives. While self-management appears to be consistent with placing patients' needs, values and priorities at the heart of healthcare, ill-defined assumptions about responsibility may confound these goals. CONCLUSIONS: Reflection on social determinants of health, the context in which patients seek self-management support from health services, and how their needs and preferences are listened to by health professionals, is critical for the collaborative self-management partnership between them to be effectively realized. PRACTICE IMPLICATIONS: Providing services without reflecting on the meaning of self-management for the person with chronic conditions creates unintended assumptions about responsibility, engagement and care provision which may serve to alienate and further stigmatise some patients. Often, these are the very patients with complex needs who need such service support the most. PMID- 20705413 TI - Measuring cortisol in hair and saliva from dogs: coat color and pigment differences. AB - Cortisol concentrations are frequently measured from a variety of sources including blood, saliva, urine, and feces to quantify stress in dogs. However, a need still exists for less intrusive collection methods in domestic animals and for more efficient means of measuring basal cortisol. The objectives of the present study were to minimize restraint for saliva sampling, to validate hair for basal cortisol measurement in dogs, and to determine concentrations of cortisol within the hair shaft and in relation to hair color. Using food luring, 79% of dogs required no restraint for saliva collection. Salivary and hair cortisol concentrations were positively correlated (P = 0.001), thus validating hair as a medium for basal cortisol quantification. Black dogs had less cortisol than nonblack dogs (P = 0.039) in hair, but not saliva. Across dogs, the average amount of cortisol did not differ between proximal and distal hair sections (P = 0.348). However, for 7 of the 9 dogs, more cortisol was present in the distal portions of the hair. We observed a difference in cortisol concentrations among hairs of different colors from individual dogs (P = 0.001). From the same 7 x 7 cm ischiatic patch from the same dog, black (eumelanin) hairs were consistently lower in cortisol than yellow (pheomelanin) hairs, and cortisol concentrations of agouti hairs were intermediate. This is the first evidence that hair of different colors might sequester cortisol differently. PMID- 20705414 TI - Oxyntomodulin increases the concentrations of insulin and glucose in plasma but does not affect ghrelin secretion in Holstein cattle under normal physiological conditions. AB - Ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS R1a), has been shown to stimulate growth hormone (GH) secretion. Regulation of ghrelin secretion in ruminants is not well studied. We investigated the effects of oxyntomodulin (OXM) and secretin on the secretions of ghrelin, insulin, glucagon, glucose, and nonesterified fatty acids (NEFA) in pre-ruminants (5 wk old) and ruminants (10 wk old) under normal physiological (feeding) conditions. Eight male Holstein calves (pre-ruminants: 52 +/- 1 kg body weight [BW]; and ruminants: 85 +/- 1 kg BW) were injected intravenously with 30 microg of OXM/kg BW, 50 microg of secretin/kg BW, and vehicle (0.1% bovine serum albumin [BSA] in saline as a control) in random order. Blood samples were collected, and plasma hormones and metabolites were analyzed using a double-antibody radioimmunoassay system and commercially available kits, respectively. We found that OXM increased the concentrations of insulin and glucose but did not affect the concentrations of ghrelin in both pre-ruminants and ruminants and that there was no effect of secretin on the concentrations of ghrelin, insulin, and glucose in these calves. We also investigated the dose-response effects of OXM on the secretion of insulin and glucose in 8 Holstein steers (401 +/- 1 d old, 398 +/- 10 kg BW). We found that OXM increased the concentrations of insulin and glucose even at physiological plasma concentrations, with a minimum effective dose of 0.4 microg/kg for the promotion of glucose secretion and 2 microg/kg for the stimulation of insulin secretion. These findings suggest that OXM takes part in glucose metabolism in ruminants. PMID- 20705415 TI - Evidence for the role of oxidative stress in the acetylation of histone H3 by ethanol in rat hepatocytes. AB - The relationship between ethanol-induced oxidative stress and acetylation of histone H3 at lysine 9 (H3AcK9) remains unknown and was therefore investigated in primary cultures of rat hepatocytes. Cells were treated with ethanol, and a select group of pharmacological agents and the status of H3AcK9 and reactive oxygen species (ROS) were monitored. Pretreatment of hepatocytes with N-acetyl cystein (ROS reducer), or dietary antioxidants (quercetin, reserveratrol), or NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase inhibitor apocynin, significantly reduced ethanol (50 mM, 24 h) induced increases in ROS and H3AcK9. In contrast, l-buthionine sulfoximine (ROS inducer) and inhibitor of mitochondrial complexes I (rotenone) and III (antimycin) increased ethanol induced H3AcK9 (P<.01). Oxidative stress also affected ethanol-induced alcohol dehydrogenase 1 mRNA expression. These results demonstrate for the first time that oxidative stress is involved in the ethanol-induced histone H3 acetylation in hepatocytes. PMID- 20705416 TI - Alcohol-induced deterioration in primary antioxidant and glutathione family enzymes reversed by exercise training in the liver of old rats. AB - Chronic alcohol consumption causes severe hepatic oxidative damage, particularly to old subjects by decreasing various antioxidant enzymes. In this study, we test the hypothesis that exercise training can protect the aging liver against alcohol induced oxidative damage. Two different age groups of Wistar albino rats (3 months young, n=24; 18 months old, n=24) were evenly divided into four groups: control (Con), exercise trained (Tr, 23 m/min 30 min/day, 5 days/week for 2 months), ethanol drinking/treated (Et, 2.0 g/kg b.w. orally), and exercise training plus ethanol drinking/treated (Tr+Et). We found significantly (P<.001) lowered hepatic antioxidant enzymes including superoxide dismutase, catalase, selenium (Se)-dependent glutathione peroxidase (Se-GSH-Px), Se-non-dependent glutathione peroxidase (non-Se-GSH-Px), glutathione reductase, and glutathione S transferase activities in aged rats compared with young. Age-related decrease in antioxidant enzyme status was further exacerbated with ethanol drinking, which indicates liver in aged rats is more susceptible to oxidative damage because of decreased free radical scavenging system in aged/old ethanol-drinking rats. However, the decrease in liver antioxidant enzymes status with ethanol consumption was ameliorated by 2 months exercise training in old and young rats. These results demonstrate that age-associated decrease in hepatic free radical scavenging system exacerbated by ethanol drinking. For the first time, we found that this deterioration was significantly reversed by exercise training in aging liver, thus protects against alcohol-induced oxidative damage. PMID- 20705417 TI - An improved method for rapidly quantifying fatty acid ethyl esters in meconium suitable for prenatal alcohol screening. AB - Fatty acid ethyl esters (FAEEs) are nonoxidative metabolites of ethanol, and elevated levels of FAEE in meconium are a useful biomarker for heavy prenatal alcohol exposure. FAEE in meconium has been recommended as useful and cost effective for universal screening for prenatal alcohol exposure. To support an efficient universal screening program, an analytical method to detect and quantify FAEE in meconium needs to be accurate, inexpensive, and rapid. The purpose of this study was to develop an analytical method that would satisfy these criteria and to validate this method using established laboratory guidelines. A method was developed and validated to detect and quantify four FAEEs (ethyl palmitate, ethyl linoleate, ethyl oleate, and ethyl stearate) from 0.5 g of meconium using d(5)-ethyl esters as internal standards. The sample undergoes liquid-liquid extraction with heptane:acetone, the heptane layer is isolated and evaporated, and then, the resulting residue undergoes headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry. The detection limits of the four FAEEs ranged from 0.020 to 0.042 nmol/g and are 6- to 25-fold lower than the individual FAEE threshold concentrations (0.5 nmol/g). This method also has good precision with the coefficient of variation ranging from 2.6 to 19.4% for concentrations of individual FAEE between 0.5 and 2.62 nmol/g meconium (n=4). Calculated concentrations of FAEE that underwent extraction from meconium were 100-101% of the expected concentration, demonstrating the accuracy of the method. The peak shape and retention time of each FAEE were unaffected by the presence of the matrix, and there is no carryover at clinically relevant concentrations. This method was also able to produce clean chromatograms from meconium samples that could not be quantified using a previous method because of high chromatographic background. This method provides an optimal approach to detecting and quantifying FAEE in meconium that could be used in a universal screening program for prenatal alcohol exposure. PMID- 20705418 TI - Fine mapping and expression of candidate genes within the chromosome 10 QTL region of the high and low alcohol-drinking rats. AB - The high and low alcohol-drinking (HAD and LAD) rats were selectively bred for differences in alcohol intake. The HAD/LAD rats originated from the N/Nih heterogeneous stock developed from intercrossing eight inbred rat strains. The HAD*LAD F2 were genotyped, and a powerful analytical approach, using ancestral recombination and F2 recombination, was used to narrow a quantitative trait loci (QTL) for alcohol drinking to a 2-cM region on distal chromosome 10 that was in common in the HAD1/LAD1 and HAD2/LAD2 analyses. Quantitative real-time PCR was used to examine mRNA expression of six candidate genes (Crebbp, Trap1, Gnptg, Clcn7, Fahd1, and Mapk8ip3) located within the narrowed QTL region in the HAD1/LAD1 rats. Expression was examined in five brain regions, including the nucleus accumbens, amygdala, caudate putamen, hippocampus, and prefrontal cortex. All six genes showed differential expression in at least one brain region. Of the genes tested in this study, Crebbp and Mapk8ip3 may be the most promising candidates with regard to alcohol drinking. PMID- 20705419 TI - Lipid-bound sialic acid in alcoholics participates in increased level of total sialic acid. AB - Serum total sialic acid (TSA) concentration is a sensitive marker of excessive alcohol consumption and is the sum of protein-bound sialic acid, lipid-bound sialic acid (LSA), and free sialic acid. The LSA is the fraction of SA attached to gangliosides that are transported in the blood by the lipoproteins. In this article, the effect of chronic alcohol consumption on the serum levels of LSA was evaluated. The objective of the study was to understand the mechanism of elevated serum TSA concentration during alcohol abuse. Additionally, the association of LSA with serum lipid profile was tested. For this purpose, the levels of LSA, TSA, lipids, lipoproteins, and apolipoproteins (apos) in the sera of 106 alcoholics were measured. The serum level of LSA in alcohol abusers was significantly elevated. This increase was because of the elevated level of LSA in patients drinking alcohol up to 2 days before sampling. The elevated level of LSA positively correlated with TSA, and also with biochemical indices of hepatocellular injury such as aspartate aminotransferase and gamma glutamyltransferase, but did not correlate with any lipids, apos, and lipoproteins. The increase in LSA level is not related with the status of serum lipid profile but is related to the liver status estimated by the biochemical markers of liver cell damage. On the basis of our results, we conclude that the elevated level of LSA in alcohol abusers contributes to an increase in the serum concentration of TSA, and contrary to TSA, is affected by the status of liver cells. PMID- 20705420 TI - Effects of prolonged ethanol vapor exposure on forced swim behavior, and neuropeptide Y and corticotropin-releasing factor levels in rat brains. AB - Depressive symptoms in alcohol-dependent individuals are well-recognized and clinically relevant phenomena. The etiology has not been elucidated although it is clear that the depressive symptoms may be alcohol independent or alcohol induced. To contribute to the understanding of the neurobiology of chronic ethanol use, we investigated the effects of chronic intermittent ethanol vapor exposure on behaviors in the forced swim test (FST) and neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) levels in specific brain regions. Adult male Wistar rats were subjected to intermittent ethanol vapor (14 h on/10 h off) or air exposure for 2 weeks and were then tested at three time points corresponding to acute withdrawal (8-12 h into withdrawal) and protracted withdrawal (30 and 60 days of withdrawal) in the FST. The behaviors that were measured in the five-min FST consisted of latency to immobility, swim time, immobility time, and climbing time. The FST results showed that the vapor-exposed animals displayed depressive like behaviors; for instance, decreased latency to immobility in acute withdrawal and decreased latency to immobility, decreased swim time and increased immobility time in protracted withdrawal, with differences between air- and vapor-exposed animals becoming more pronounced over the 60-day withdrawal period. NPY levels in the frontal cortex of the vapor-exposed animals were decreased compared with the control animals, and CRF levels in the amygdala were correlated with increased immobility time. Thus, extended ethanol vapor exposure produced long-lasting changes in FST behavior and NPY levels in the brain. PMID- 20705421 TI - Ethanol exposure during the early first trimester equivalent impairs reflexive motor activity and heightens fearfulness in an avian model. AB - Prenatal alcohol exposure is a leading cause of childhood neurodevelopmental disability. The adverse behavioral effects of alcohol exposure during the second and third trimester are well documented; less clear is whether early first trimester-equivalent exposures also alter behavior. We investigated this question using an established chick model of alcohol exposure. In ovo embryos experienced a single, acute ethanol exposure that spanned gastrulation through neuroectoderm induction and early brain patterning (19-22h incubation). At 7 days posthatch, the chicks were evaluated for reflexive motor function (wingflap extension, righting reflex), fearfulness (tonic immobility [TI]), and fear/social reinstatement (open-field behavior). Chicks exposed to a peak ethanol level of 0.23-0.28% were compared against untreated and saline-treated controls. Birds receiving early ethanol exposure had a normal righting reflex and a significantly reduced wingflap extension in response to a sudden descent. The ethanol-treated chicks also displayed heightened fearfulness, reflected in increased frequency of TI, and they required significantly fewer trials for its induction. In an open field test, ethanol treatment did not affect latency to move, steps taken, vocalizations, defecations, or escape attempts. The current findings demonstrate that early ethanol exposure can increase fearfulness and impair aspects of motor function. Importantly, the observed dysfunctions resulted from an acute ethanol exposure during the period when the major brain components are induced and patterned. The equivalent period in human development is 3-4 weeks postconception. The current findings emphasize that ethanol exposure during the early first trimester equivalent can produce neurodevelopmental disability in the offspring. PMID- 20705423 TI - Ureaplasma urealyticum infection in total hip arthroplasty leading to revision. AB - We describe an infection with Ureaplasma urealyticum causing rapid loosening of a cemented total hip arthroplasty. When reviewing the literature we found that no such case has been reported previously. Taking intraoperative cultures for U urealyticum during revision surgery is not a standard procedure. In cases with rapid, presumed aseptic, loosening of a total hip arthroplasty, an infection with U urealyticum should be considered. PMID- 20705422 TI - Subtle decreases in DNA methylation and gene expression at the mouse Igf2 locus following prenatal alcohol exposure: effects of a methyl-supplemented diet. AB - C57BL/6J (B6) mice are susceptible to in utero growth retardation and a number of morphological malformations following prenatal alcohol exposure, while DBA/2J (D2) mice are relatively resistant. We have previously shown that genomic imprinting may play a role in differential sensitivity between B6 and D2. The best-characterized mechanism mediating genomic imprinting is differential DNA methylation. In the present study we examined DNA methylation and gene expression, in both embryonic and placental tissue, at the mouse Igf2 locus following in utero ethanol exposure. We also examined the effects of a methyl supplemented diet on methylation and ethanol teratogenesis. In embryos from susceptible B6 mice, we found small decreases in DNA methylation at four CpG sites in one of the differentially methylated regions of the Igf2 locus; only one of the four sites showed a statistically significant decrease. We observed no significant decreases in methylation in placentae. All Igf2 transcripts showed approximately 1.5-fold decreases following intrauterine alcohol exposure. Placing dams on a methyl-supplemented diet before pregnancy and throughout gestation brought methylation back up to control levels. Methyl supplementation also resulted in lower prenatal mortality, greater prenatal growth, and decreased digit malformations; it dramatically reduced vertebral malformations. Thus, although prenatal alcohol had only small effects on DNA methylation at the Igf2 locus, placing dams on a methyl-supplemented diet partially ameliorated ethanol teratogenesis. PMID- 20705424 TI - Participation in leisure activities among boys with attention deficit hyperactivity disorder. AB - ADHD is a neural developmental disorder expressed in various life settings. Yet, previous studies have focused mainly on children's function in school and academic achievement. The purpose of the present study was, therefore, to examine participation patterns in outside formal school activities among boys with ADHD compared to typical boys. Participants included 25 boys aged 8-11 years with ADHD and 25 age-matched typical boys. All participants completed the Children's Assessment of Participation and Enjoyment (CAPE). Several aspects of participation were examined: diversity, intensity, enjoyment, place, and partners in 49 extra curricular activities. The findings indicate that boys with ADHD reported significant lower intensity rates of participation in most activity domains. Furthermore, boys with ADHD also reported higher diversity scores and lower enjoyment in 'formal' activities. Yet, no significant differences were found with regard to activity place and partners. These findings enhance the importance of providing therapy that refers to after school activities. Accordingly, CAPE can be useful for assessing boys with ADHD and planning appropriate intervention programs. PMID- 20705425 TI - Estimating prevalence of diabetes in a Congolese town was feasible. AB - OBJECTIVES: To study prevalence, determinants, and complications at diagnosis of diabetes and intermediate hyperglycemia (IH) in Kisantu, a semirural town in Bas Congo province, Democratic Republic of Congo. STUDY DESIGN AND SETTING: A large scale analytical cross-sectional population-based survey was performed in 2007 in Kisantu. After extensive sensitization, the study sample was collected using a modified World Health Organization (WHO) STEPwise strategy, taking subsequently a random sample of streets, households within streets, and inhabitants aged 20 years and older within households. After informed consent, subjects were invited to fixed sites for interview, anthropometry, clinical examination (blood pressure, monofilament, and ophthalmology), and biochemical tests (fasting capillary glucose, serum creatinine, and albuminuria). Fasting glycemia was repeated or 2-hour postload glycemia was measured the next day in subjects with an initial glycemia of 126-199 mg/dL (7.0-11.1 mmol/L) or 100-125 mg/dL (5.6-6.9 mmol/L), respectively. Hence, prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance according to both 2006 WHO/International Diabetes Federation and 2003 American Diabetes Association criteria could be evaluated. Bivariate and multivariate analyses were used for statistical analyses. RESULTS: Response rate was 93.7% (1,898 of 2,025). Complete data were available in 1,866 (92.1%) subjects. CONCLUSION: Estimating the prevalence of diabetes and IH in a small Congolese town was proven to be feasible. PMID- 20705426 TI - Reviews assessing the quality or the reporting of randomized controlled trials are increasing over time but raised questions about how quality is assessed. AB - OBJECTIVE: Many reviews specifically aimed to assess the quality of randomized controlled trials (RCTs). We evaluated the quality of reporting in such reviews. STUDY DESIGN AND SETTING: PubMed and the Cochrane library were searched for all reviews assessing the quality of RCTs between 1987 and 2007, and experts in the field were also contacted. RESULTS: We found 177 reviews published from 1987 to 2007, 58% of which were published after 2002. Of these, 131 (74%) focused on the quality of RCTs, 44 (25%) on quality of reporting, and 2 (1%) assessed both. The search strategy was well reported (92%). The criteria for assessment were reported in 97% of the reviews but were defined in only 38%. Seventy-four different items and 26 different scales were identified. Allocation sequence generation and concealment were reported in 41% and 40%, respectively, but their adequacy was assessed in 20% and 29%, respectively; scales were used in 40% and Consolidated Standards of Reporting Trials (CONSORT) checklist in 12%. CONCLUSION: The number of methodological reviews has dramatically increased in recent years. Despite an improved reporting of the methodology, how quality is assessed still raises important issues. Heterogeneity of criteria used and lack of definition may limit the relevance of these reviews. PMID- 20705427 TI - Systematic review highlights difficulty interpreting diverse clinical outcomes in abnormal uterine bleeding trials. AB - OBJECTIVES: (1) To systematically collect and organize into clinical categories all outcomes reported in trials for abnormal uterine bleeding (AUB); (2) to rank the importance of outcomes for patient decision making; and (3) to improve future comparisons of effects in trials of AUB interventions. STUDY DESIGN AND SETTING: Systematic review of English-language randomized controlled trials of AUB treatments in MEDLINE from 1950 to June 2008. All outcomes and definitions were extracted and organized into major outcome categories by an expert group. Each outcome was ranked "critically important," "important," or "not important" for informing patients' choices. RESULTS: One hundred thirteen articles from 79 trials met the criteria. One hundred fourteen different outcomes were identified, only 15 (13%) of which were ranked as critically important and 29 (25%) as important. Outcomes were grouped into eight categories: (1) bleeding; (2) quality of life; (3) pain; (4) sexual health; (5) patient satisfaction; (6) bulk-related complaints; (7) need for subsequent surgical treatment; and (8) adverse events. CONCLUSION: To improve the quality, consistency, and utility of future AUB trials, we recommend assessing a limited number of clinical outcomes for bleeding, disease-specific quality of life, pain, sexual health, and bulk-related symptoms both before and after treatment and reporting satisfaction and adverse events. Further development of validated patient-based outcome measures and the standardization of outcome reporting are needed. PMID- 20705428 TI - Dietary heme adversely affects experimental colitis in rats, despite heat-shock protein induction. AB - OBJECTIVE: Research on dietary modulation of inflammatory bowel disease is in its infancy. Dietary heme, mimicking red meat, is cytotoxic to colonic epithelium and thus may aggravate colitis. Alternatively, heme-induced colonic stress might also result in potential protective heat-shock proteins (HSPs). Therefore, we investigated the effect of dietary heme on trinitrobenzene sulfonic acid (TNBS) induced colitis in rats. METHODS: Rats were fed a high-fat control diet or a similar diet supplemented with heme. After dietary adaptation, rats were rectally infused with TNBS for colitis induction or saline for sham treatment. Colitis severity was evaluated and several markers were quantified in colonic mucosa isolated 1 wk after colitis induction. Furthermore, cytotoxicity of fecal water and serum alpha-1-acid glycoprotein were measured. RESULTS: Dietary heme increased cytotoxicity of the fecal water. Heme-fed sham-treated rats had higher colonic HSP-25 and heme-oxygenase-1 mRNA levels, which was confirmed by immunohistochemistry. HSP induction by heme was associated with decreased protein levels of myeloperoxidase and interleukin-1beta after subsequent TNBS infusion. However, no dietary effects were observed on histologic colitis score. Furthermore, body weight gain, colon length, and food intake were lower and alpha 1-acid glycoprotein concentrations were higher in heme-fed colitic rats. In addition, somatostatin, involved in mucosal repair, was not changed with TNBS infusion in heme-fed rats. CONCLUSION: Dietary heme adversely affects colitis, despite HSP induction. We speculate that the irritating influence of dietary heme, being continuously present in the colon, impairs recovery after colitis induction. A diet high in red meat might be a risk factor for inflammatory bowel disease development. PMID- 20705429 TI - Usefulness of exchanging a tunneled central venous catheter using a subcutaneous fibrous sheath. AB - OBJECTIVES: The reserve of the venous route to the central veins is important for long-term parenteral nutrition (PN). Frequent catheter-related bloodstream infection (CRBSI) induces occlusion of the venous routes. Therefore, a modified exchange procedure using a tunneled central venous catheter (CVC) with a fibrous sheath was developed to preserve the route to the central veins. METHODS: Seven patients who required long-term PN received the modified exchange procedure and the outcome of exchanged CVC was retrospectively reviewed. RESULTS: The procedure was performed 10 times in seven patients. The venous routes were either the subclavicular or the internal jugular vein in all patients. The exchange of the catheter was due to CRBSI or occlusion in almost all patients. The mean duration of new catheter use was 296.2 days following the exchange. Four catheters continued to be used, and the remaining ones were removed. The reasons for removal were severe CRBSI and occlusion, each of which occurred in two catheterized patients, while the reason for removing the remaining catheters was because the patients no longer needed the catheters. CONCLUSION: The modified catheter exchange using fibrous sheath, even in patients with CRBSI, appears to be an effective procedure for reserving the venous route to the central veins in patients who require either long-term PN or other treatments. PMID- 20705430 TI - Dislocation of the intact mandibular condyle into the middle cranial fossa: a case report. AB - Dislocation of the mandibular condyle into the middle cranial fossa is extremely rare. The authors present a case of superior dislocation of left condyle into the middle cranial fossa. The dislocated condyle was reduced successfully and then a flap of temporal muscle and a thin titanium network were used to repair the defect in the middle cranial fossa. PMID- 20705431 TI - Facial soft tissue response to anterior segmental osteotomies: a systematic review. AB - Bimaxillary protrusion is prevalent among Asians and anterior segmental osteotomies are commonly used for its surgical correction. The objective of this study was to evaluate the soft tissue changes resulting from anterior segmental osteotomies. The electronic databases PubMed, Scopus and ISI Web of knowledge were searched for potentially eligible studies using a set of predetermined keywords. Full texts meeting the inclusion criteria were retrieved and their references were manually searched for additional relevant articles. The study details and outcome data of these reports were extracted using spreadsheets for comparison. The methodological quality of each study was assessed. Eleven studies met the inclusion criteria. Lateral cephalometry was used in all studies. A reduction of the labial prominence with an increase in the nasolabial angle was noted subsequent to anterior segmental osteotomies. The magnitude of the reported soft tissue changes and their ratios corresponding to the osseous movements varied among studies. Long-term, prospective, methodologically sound clinical trials with larger samples and three-dimensional quantification are required to provide sufficient information for predicting the soft tissue response to anterior segmental osteotomies. PMID- 20705432 TI - Prognostic indicators of the outcome of arthrocentesis with and without sodium hyaluronate injection for the treatment of disc displacement without reduction: a magnetic resonance imaging study. AB - This study analysed the prognostic factors for successful arthrocentesis with and without sodium hyaluronate (SH) injection for the treatment of temporomandibular joint (TMJ) disc displacement without reduction (DDwoR) using clinical and radiological results. 29 TMJs in 25 patients with DDwoR were included. Patients were treated with arthrocentesis or arthrocentesis followed by intra-articular (i.a.) injection of SH. Treatment was evaluated for postoperative range of maximum mouth opening and the degree of postoperative pain on a VAS. Prognostic factors analysed were age, sex, duration of locking, trauma history, previous TMJ treatment, depression, bruxism, malocclusion and missing teeth. Degenerative changes were evaluated as probable prognostic factors. After treatment, 24 joints (83%) fulfilled the criteria for success. Duration of locking and present preoperative degenerative changes were the most significant factors for treatment outcome. The results suggest it is sufficient to use only arthrocentesis in patients without preoperative degenerative changes and arthrocentesis with SH in patients with degenerative changes on their preoperative MRIs, but because there were some significant differences between the two groups preventing the authors from comparing them statistically, they cannot come to that conclusion. To clarify the use of SH in such cases, standardized study groups are necessary for future studies. PMID- 20705434 TI - Central pontine demyelinolysis following water intoxication in schizophrenia. PMID- 20705433 TI - Regional prefrontal cortex gray matter volumes in youth at familial risk for schizophrenia from the Harvard Adolescent High Risk Study. AB - BACKGROUND: Regional prefrontal cortex gray matter reductions have been identified in schizophrenia, likely reflecting a combination of genetic vulnerability and disease effects. Few morphometric studies to date have examined regional prefrontal abnormalities in non-psychotic biological relatives who have not passed through the age range of peak risk for onset of psychosis. We conducted a region-of-interest morphometric study of prefrontal subregions in adolescent and young adult relatives of schizophrenia patients. METHODS: Twenty seven familial high-risk (FHR) first-degree relatives of schizophrenia patients and forty-eight control subjects without a family history of psychosis (ages 13 28) underwent high-resolution magnetic resonance imaging at 1.5Tesla. The prefrontal cortex was parcellated into polar, dorsolateral, ventrolateral, ventromedial and orbital subregions. The Chapman scales measured subpsychotic symptoms. General linear models examined associations of prefrontal subregion volumes with familial risk and subpsychotic symptoms. RESULTS: FHR subjects had significantly reduced bilateral ventromedial prefrontal and frontal pole gray matter volumes compared with controls. Ventromedial volume was significantly negatively correlated with magical ideation and anhedonia scores in FHR subjects. CONCLUSIONS: Selective, regional prefrontal gray matter reductions may differentially mark genetic vulnerability and early symptom processes among non psychotic young adults at familial risk for schizophrenia. PMID- 20705435 TI - Global trends in emerging zoonoses. PMID- 20705436 TI - Travellers and viral haemorrhagic fevers: what are the risks? AB - Viral haemorrhagic fevers (VHF) are caused by zoonotic viral infections transmitted to humans directly or by ticks or mosquitoes. The overall risk to travellers is conservatively estimated at <1 in 1 million travel episodes to African countries where infection is present, and febrile patients returning from these countries are at least 1000 times more likely to have malaria than Lassa fever or another VHF. No cases have been reported in fellow travellers exposed to a travelling case and only one asymptomatic seroconversion (to Lassa) has been reported in over 2000 contacts following care of VHF cases in modern Western hospital settings. However, healthcare-associated transmission of infection has been a major problem in some endemic settings. The potential for healthcare associated infection and the threats posed by unrecognised or new agents necessitate a high index of suspicion and a standardised risk assessment approach to febrile travellers. Travel-related hantavirus infections are increasingly being reported from Europe and the Americas. This article summarises the epidemiology and reports of travel-related VHF cases in the past 40 years, together with strategies for their recognition, management and prevention. PMID- 20705437 TI - Discrimination of normal aging, MCI and AD with multimodal imaging measures on the medial temporal lobe. AB - This study aimed to compare the discrimination accuracy of hippocampal volume (HC Vol), parahippocampal cingulum fractional anisotropy (PHC-FA), hippocampal glucose metabolism (HC-Glu), and any combination of the three measurements among normal control (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). Three-dimensional MRI, diffusion tensor imaging, and FDG-PET were applied to age- and gender-matched 17 NC, 17 MCI, and 17 mild AD patients. Subjects also underwent a neuropsychological test battery including three verbal episodic memory tests. Logistic regression analyses were systematically conducted to select the best model for between-group discrimination. PHC-FA plus HC-Vol model, HC-Glu only model, and the model combining all three modalities were finally chosen for NC vs. MCI (discrimination accuracy: 79.4%), MCI vs. AD (73.5%), and NC vs. AD discrimination (94.1%), respectively. All the three imaging measures also showed significant correlation with all three episodic memory tests. These findings support that each imaging measure, respectively, and their combination have a stage-specific potential as a useful neuroimaging marker for detection and progression monitoring of early stage of AD. PMID- 20705438 TI - Biosynthesis of silver nanoparticles by Streptomyces hygroscopicus and antimicrobial activity against medically important pathogenic microorganisms. AB - Biological reduction of aqueous silver ions by extracellular components of Streptomyces hygroscopicus has facilitated the development of industrially viable greener methods for the synthesis of technologically important silver nanoparticles (AgNPs). The synthesized aqueous products showed the characteristic absorption spectra at 420 nm, which confirmed the presence of AgNPs. X-ray diffraction patterns displayed typical peaks of crystalline silver at approximately 38 degrees , approximately 45 degrees and approximately 65 degrees . The AgNPs were determined to be spherical (20-30 nm) with a purity of 70% as determined by FE-SEM, TEM, bio-AFM, XRD, and energy dispersive X-ray analysis. Furthermore, the biosynthesized AgNPs significantly inhibited the growth of medically important pathogenic gram-positive bacteria (Bacillus subtilis and Enterococcus faecalis), gram-negative bacteria (Escherichia coli and Salmonella typhimurium) and yeast (Candida albicans). Thus, bioconversion of silver nanoparticles by S. hygroscopicus could be employed as a potential nanomedicine to eliminate pathogenic microorganisms. PMID- 20705439 TI - Reduction of protein adsorption on well-characterized polymer brush layers with varying chemical structures. AB - To clarify protein adsorption behavior on polymer brush layers, surface characteristics and protein adsorption repellency on polymer brush layers should be precisely determined. Here, we clearly delineated the chemical structure of the polymer brush layers containing various hydrophilic groups, namely, phosphorylcholine, sulfoxybetaine, carboxybetaine (zwitterionic), and hydroxyl group (nonionic) and examined the effects of the chemical structure on initial protein adsorption behavior. Kinetic analysis performed during surface-initiated atom transfer radical polymerization revealed that graft polymerization proceeded in a living manner. The graft density of each type of polymer chain and its surface coverage were high enough to form dense polymer brush structures. The hydroxyl group-bearing polymer brush structure exhibited the highest graft density. Among the zwitterionic polymer brush structures, the graft density and surface coverage of sulfoxybetaine- and carboxybetaine-bearing polymer chains were higher than those of the phosphorylcholine-bearing polymer chains. The amount of protein relative to 100% serum adsorbed on polymer brush layers was quantified using quartz crystal microbalance with dissipation (QCM-D). Protein adsorption on all zwitterionic polymer brush layers apparently decreased with increasing thickness of the grafted polymer layers. Protein adsorption was highly suppressed on thick polymer brush layers bearing phosphorylcholine or sulfoxybetaine groups. However, the amount of proteins adsorbed on thick polymer brush layers bearing hydroxyl groups was 10 times more than that adsorbed on polymer brush layers bearing phosphorylcholine groups. Thus, we concluded that the chemical structure of the polymer brush layer is a significant factor affecting resistance to protein adsorption even for dense polymer brush structures. PMID- 20705440 TI - Chronic inflammation is associated with overweight in Colombian school children. AB - BACKGROUND AND AIMS: To examine the cross-sectional associations of inflammatory markers in plasma including C-reactive protein (CRP) and ferritin, and white blood cell (WBC) count, with overweight, skinfold sum (subscapular + triceps), and skinfold ratio (subscapular/triceps) among children from Bogota, Colombia. METHODS AND RESULTS: The sample (n = 2614) represented low- and middle-income children, aged 5-12 years, from Bogota. We assessed their anthropometry, sociodemographic characteristics, and circulating inflammatory markers. We defined overweight, including obesity, according to the International Obesity Task Force BMI criteria. After adjustment for potential confounders, children in the fourth quartile of the CRP distribution had a 37% higher prevalence of overweight compared to those in the first quartile (P for trend = 0.03); and children in the fourth quartile of ferritin had a 67% greater prevalence of overweight compared to children in the first quartile (P for trend <0.001). Children in the highest 3 quartiles of the WBC distribution had a 35% higher prevalence of overweight than those in the first quartile (P = 0.03). Ferritin was significantly and positively associated with skinfold sum (P for trend < 0.001), while WBC was significantly and positively associated with skinfold ratio (P for trend < 0.001). There was a significant interaction between CRP and ferritin; children in the highest quartiles of CRP and ferritin had twice the prevalence of overweight compared to those below the highest quartiles (P = 0.001). CONCLUSION: Biomarkers of chronic inflammation are positively associated with child overweight. WBC is positively related to skinfold ratio, a proxy for truncal adiposity. PMID- 20705442 TI - Self-reported symptoms and bronchial hyperresponsiveness in elite cross-country skiers. AB - INTRODUCTION: Respiratory symptoms in relationship to exercise, bronchial hyperresponsiveness (BHR), and exercise-induced asthma (EIA) are very common in elite winter athletes. Symptom-based screening for BHR would facilitate selection of athletes with possible EIA. OBJECTIVES: The aim of the present study was to evaluate the diagnostic accuracy of self-reported symptoms as predictors of BHR in an unselected population of adult elite cross-country skiers. METHODS: Forty six Swedish adult skiers competing at national or international level were included. They had a mean (SD) training volume in the past 12 months of 593 (122) hours. Twenty-four subjects had previous physician-diagnosed asthma. The European Community Respiratory Health Survey questionnaire was used to evaluate the presence of respiratory symptoms. BHR was defined as bronchoconstriction to either eucapnic voluntary hyperventilation, dry powder mannitol or methacholine provocation. RESULTS: The "classical" EIA symptom of shortness of breath post exercise was reported by 17% of all skiers. Eight subjects (17%) had BHR. None of the self-reported respiratory symptoms had high positive predictive values. However, symptoms caused by grass or pollen had high negative predictive values. DISCUSSION: EIA in elite winter athletes cannot accurately be based only on self reported symptoms but requires verification with objective testing of BHR. Bronchoprovocation of elite winter athletes reporting respiratory symptoms in rest or because of exercise will probably reveal a high proportion of athletes without BHR. CLINICAL TRIAL: EUDRA-CT number 2006-005822-21. PMID- 20705441 TI - Three-year dispensing patterns with long-acting inhaled drugs in COPD: a database analysis. AB - BACKGROUND: Long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA) and fixed dose combinations (FDC) of inhaled corticosteroids (ICS) and LABA are used as inhaled maintenance therapies for COPD. OBJECTIVE: To estimate persistence rates from dispensing patterns of long-acting inhaled drugs for COPD. METHODS: From the PHARMO-database, COPD patients starting LAMA, LABA or LABA-ICS FDC between 2002 and 2006 were selected. Persistence with the initial as well as with any long-acting inhaled drug was determined, defined as time between start and stop of initial/any therapy, allowing <= 60-days gaps between refills. For patients who did not continue to receive dispensings of the initial therapy for at least one year, the first change in therapy was determined. RESULTS: The study included 2201 LAMA, 1201 LABA and 4146 LABA-ICS FDC users. Persistence rates with initial therapy alone at 1, 2, and 3 years were 25%, 14%, 8% for LAMA, 21%, 10%, 6% for LABA and 27%, 14%, 8% for LABA-ICS FDC. Of patients who did not persist with LAMA alone for one year, 15% added and 13% switched therapy (both mostly LABA-ICS FDC). Of patients not persisting with LABA alone, 9% added therapy (mostly LAMA) and 31% switched therapy (mostly to LABA-ICS FDC). In patients not persisting with LABA-ICS FDC, add-on and switch occurred equally frequent (11%, mostly LAMA). Persistence rates with any long-acting drug at 1, 2 and 3 years were 36%, 23% and 17% respectively. CONCLUSION: Persistence with the initial as well as with any long-acting inhaled drug in COPD is low, with a substantial proportion of patients changing therapy. PMID- 20705443 TI - Enzyme-based choline and L-glutamate biosensor electrodes on silicon microprobe arrays. AB - Brain-implantable microprobe arrays, 6.5 mm shaft-length, incorporating several recessed Pt microelectrodes (50 MUm*150 MUm) and an integrated Ag/AgCl reference electrode fabricated by silicon micromachining dry etching techniques (DRIE) are described. The microelectrodes are coated by an enzyme membrane and a semi permeable m-phenylenediamine layer for the selective detection of the neurotransmitters choline and L-glutamate at physiologically relevant concentrations. The functionalisation is based on electrochemically aided adsorption (EAA) combined with chemical co-cross-linking using glutaraldehyde and electrochemical polymerisation, respectively. These deposition methods are fully compatible with the fabricated microprobe arrays for the simultaneous detection of several analytes in different brain target areas. They are spatially controlled and allow fabricating biosensors on several microelectrodes in parallel or providing a cross-talk-free coating of closely spaced microelectrodes with different enzyme membranes. A sensitivity of 132+/-20 MUA mM(-1) cm(-2) for choline and 95+/-20 MUA mM(-1) cm(-2) for L-glutamate with limits of detections below 0.5 MUM was obtained. The results of in vitro and in vivo experiments confirm the functional viability of the choline and l-glutamate biosensors. PMID- 20705444 TI - Protein immobilisation on micro/nanostructures fabricated by laser microablation. AB - The performance of biomedical microdevices requires the accurate control of the biomolecule concentration on the surface, as well as the preservation of their bioactivity. This desideratum is even more critical for proteins, which present a significant propensity for surface-induced denaturation, and for microarrays, which require high multiplexing. We have previously proposed a method for protein immobilisation on micro/nanostructures fabricated via laser ablation of a thin metal layer deposited on a transparent polymer. This study investigates the relationship between the properties of the micro/nanostructured surface, i.e., topography and physico-chemistry, and protein immobilisation, for five, molecularly different proteins, i.e., lysozyme, myoglobin, alpha-chymotrypsin, human serum albumin, and human immunoglobulin. Protein immobilisation on microstructures has been characterised using quantitative fluorescence measurements and atomic force microscopy. It has been found that the sub micrometer-level, combinatorial nature of the microstructure translates in a 3-10 fold amplification of protein adsorption, as compared to flat, chemically homogenous polymeric surfaces. This amplification is more pronounced for smaller proteins, as they can capitalize better on the newly created surface and variability of the nano-environments. PMID- 20705446 TI - Texting while birthing. PMID- 20705445 TI - Dosimetric evaluation between megavoltage cone-beam computed tomography and body mass index for intracranial, thoracic, and pelvic localization. AB - The aim of this study was to evaluate radiation dose for organs at risk (OAR) within the cranium, thorax, and pelvis from megavoltage cone-beam computed tomography (MV-CBCT). Using a clinical treatment planning system, CBCT doses were calculated from 60 patient datasets using 27.4 * 27.4 cm(2) field size and 200 degrees arc length. The body mass indices (BMIs) for these patients range from 17.2-48.4 kg/m(2). A total of 60 CBCT plans were created and calculated with heterogeneity corrections, with monitor units (MU) that varied from 8, 4, and 2 MU per plan. The isocenters of these plans were placed at defined anatomical structures. The maximum dose, dose to the isocenter, and mean dose to the selected critical organs were analyzed. The study found that maximum and isocenter doses were weakly associated with BMI, but linearly associated with the total MU. Average maximum/isocenter doses in the cranium were 10.0 (+/- 0.18)/7.0 (+/- 0.08) cGy, 5.0 (+/- 0.09)/3.5 (+/- 0.05) cGy, and 2.5 (+/- .04)/1.8 (+/- 0.05) cGy for 8, 4, and 2 MU, respectively. Similar trends but slightly larger maximum/isocenter doses were found in the thoracic and pelvic regions. For the cranial region, the average mean doses with a total of 8 MU to the eye, lens, and brain were 9.7 (+/- 0.12) cGy, 9.1 (+/- 0.16) cGy, and 7.2 (+/- 0.10) cGy, respectively. For the thoracic region, the average mean doses to the lung, heart, and spinal cord were 6.6 (+/- 0.05) cGy, 6.9 (+/- 1.2) cGy, and 4.7 (+/- 0.8) cGy, respectively. For the pelvic region, the average mean dose to the femoral heads was 6.4 (+/- 1.1) cGy. The MV-CBCT doses were linearly associated with the total MU but weakly dependent on patients' BMIs. Daily MV-CBCT has a cumulative effect on the total body dose and critical organs, which should be carefully considered for clinical impacts. PMID- 20705447 TI - Itching to do a TAP block? PMID- 20705449 TI - WITHDRAWN: Remifentanil patient-controlled intravenous analgesia for twin pregnancy. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20705448 TI - Anaesthesia for caesarean section in a patient with Gitelman's syndrome. AB - Gitelman's syndrome is a rare autosomal recessive salt-losing renal tubulopathy characterised by hypomagnesaemia, hypocalciuria and secondary aldosteronism, which results in hypokalaemia and metabolic alkalosis. The syndrome is a variant of a group of renal diseases termed Bartter's syndrome. Diagnosis is based on clinical symptoms and biochemical abnormalities. Sources of information on Gitelman's syndrome in pregnancy are scarce and anaesthetic management is challenging. Close monitoring and supplementation of potassium and magnesium are required to avoid possible obstetric and life threatening complications for both mother and child. PMID- 20705450 TI - The successful use of extra-corporeal membrane oxygenation in the management of a pregnant woman with severe H1N1 2009 influenza complicated by pneumonitis and adult respiratory distress syndrome. AB - We report a case of H1N1 2009 influenza A, in a previously fit woman at 24 weeks of gestation, who presented atypically with abdominal pain. The infection was complicated by severe respiratory failure and acute respiratory distress syndrome, requiring ventilatory support, including extra-corporeal membrane oxygenation (ECMO). This was one of the first cases of severe H1N1 disease presenting in the UK. Use of extra-corporeal membrane oxygenation for the complications of H1N1 resulted in full maternal recovery and subsequent delivery of a healthy infant. PMID- 20705451 TI - Intrauterine resuscitation with fetal cardiocentesis during fetoscopic surgery. PMID- 20705452 TI - Microglia dynamics and function in the CNS. AB - Microglial cells constitute the resident immune cell population of the mammalian central nervous system. One striking feature of these cells is their highly dynamic nature under both normal and pathological brain conditions. The highly branched processes of resting microglia display a constitutive mobility and undergo rapid directional movement towards sites of acute tissue disruption. Microglia can be converted by a large number of different stimuli to a chronically activated state by signaling through both purinergic and Toll-like receptor systems, among others. Recent work has uncovered some of the mechanisms underlying microglia dynamics and shed new light into the functional significance of this enigmatic member of the glial cell family. PMID- 20705453 TI - Structure-based evolutionary relationship of glycosyltransferases: a case study of vertebrate beta1,4-galactosyltransferase, invertebrate beta1,4-N acetylgalactosaminyltransferase and alpha-polypeptidyl-N acetylgalactosaminyltransferase. AB - Cell surface glycans play important cellular functions and are synthesized by glycosyltransferases. Structure and function studies show that the donor sugar specificity of the invertebrate beta1,4-N-acetyl-glactosaminyltransferase (beta4GalNAc-T) and the vertebrate beta1,4-galactosyltransferase I (beta4Gal-T1) are related by a single amino acid residue change. Comparison of the catalytic domain crystal structures of the beta4Gal-T1 and the alpha-polypeptidyl-GalNAc-T (alphappGalNAc-T) shows that their protein structure and sequences are similar. Therefore, it seems that the invertebrate beta4GalNAc-T and the catalytic domain of alphappGalNAc-T might have emerged from a common primordial gene. When vertebrates emerged from invertebrates, the amino acid that determines the donor sugar specificity of the invertebrate beta4GalNAc-T might have mutated, thus converting the enzyme to a beta4Gal-T1 in vertebrates. PMID- 20705454 TI - Reaction mechanisms of DNA photolyase. AB - DNA photolyase uses visible light and a fully reduced flavin cofactor FADH(-) to repair major UV-induced lesions in DNA, the cyclobutane pyrimidine dimers (CPDs). Electron transfer from photoexcited FADH(-) to CPD, splitting of the two intradimer bonds, and back electron transfer to the transiently formed flavin radical FADH degrees occur in overall 1ns. Whereas the kinetics of FADH degrees was resolved, the DNA-based intermediates escaped unambiguous detection yet. Another light reaction, named photoactivation, reduces catalytically inactive FADH degrees to FADH(-) without implication of DNA. It involves electron hopping along a chain of three tryptophan residues in 30ps, as elucidated in detail by transient absorption spectroscopy. The same triple tryptophan chain is found in cryptochrome blue-light photoreceptors and may be involved in their primary photoreaction. PMID- 20705455 TI - Effect of gefitinib on the survival of patients with recurrence of lung adenocarcinoma after surgery: a retrospective case-matching cohort study. AB - BACKGROUND: Patients with lung adenocarcinoma who carry epidermal growth factor receptor (EGFR) gene mutations respond remarkably well to EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, or erlotinib. However, the effect of EGFR-TKI treatment on the prolongation of overall survival (OS) of these patients remains uncertain, although several recent studies have shown prolongation of progression free survival compared with cytotoxic chemotherapy. METHODS: A total of 304 patients with lung adenocarcinoma who had postoperative recurrent disease were studied. To eliminate potential biases as possible, the matching of four potential predictive factors of responsiveness to EGFR-TKI led to the identification of 81 pairs of patients (those who were treated with gefitinib and those who were not). A deletion mutation in exon 19 and a point mutation (L858R) in exon 21 of the EGFR gene were also analyzed. We compared the OS between the two groups. RESULTS: OS in the gefitinib group was significantly longer than in the control group (median, 63 vs. 41 months; p = 0.015). EGFR mutations were detected in 65 out of 129 patients (50%) in the whole sample. EGFR mutational status was not an independent prognostic factor of gefitinib benefit; rather, it was a predictive factor. CONCLUSIONS: This study strongly suggested that gefitinib treatment improved OS of lung adenocarcinoma patients who had postoperative recurrence, especially those carrying EGFR mutations. PMID- 20705456 TI - Selection of stress-tolerant yeasts for simultaneous saccharification and fermentation (SSF) of very high gravity (VHG) potato mash to ethanol. AB - Highly concentrated bioethanol production requires less volume in fermentation tanks and conserves distillery energy. We screened osmotolerant yeasts from a collection of 1699 yeast strains at our institute and found that three strains, NFRI3062, NFRI3213, and NFRI3225, were candidates for use in bioethanol production. All of these strains belonged to Saccharomyces cerevisiae. NFRI3062 produced 15.0% (w/v) of ethanol from YPD medium containing 35% glucose cultivated at 30 degrees C for 60 h, while S. cerevisiae NBRC0224, which has previously been reported suitable for ethanol production, only produced 13.0% (w/v). The thermotolerances of NFRI3213 and NFRI3225 were also superior to those of NBRC0224 and NFRI3062. We also demonstrated the simultaneous saccharification and fermentation (SSF) of very high gravity (VHG) potato mash and sweet-potato mash. NFRI3225 produced ethanol from potato mash at the fastest rate and in the highest volume (13.7% (w/v)) among the tested strains. The maximum productivity and ethanol yields were 9.1g/L/h and 92.3%, respectively. Although the potato mash was not sterilized, bacterial contamination was not observed. This may have been due to the growth inhibition of bacteria by the rapid glucose consumption and ethanol production of NFRI3225 during the VHG-SSF process. PMID- 20705457 TI - Qualitative and quantitative assessment of microbial community in batch anaerobic digestion of secondary sludge. AB - Microbial community shifts were determined by denaturing gradient gel electrophoresis (DGGE) and real-time PCR for an anaerobic batch digester treating secondary sludge. The batch process was successfully operated with an organic removal efficiency of 35% associated with a 91% decrease in the bacterial 16S rRNA gene concentration. The microbial community structures showed continuous shifts within four bacterial phyla and three archaeal orders. Several bacterial species, such as Fusibacter-related, Clostridium-like, and Syntrophus-like organisms, appeared to be responsible for acidogenesis or syntrophic acid degradation. Both hydrogenotrophic and aceticlastic methanogens appear to have been involved in the methanogenesis with the acidogenic products. The quantitative structure of the methanogenic populations varied continuously, with the growth of Methanomicrobiales and Methanosarcinales in series, to result in a Methanomicrobiales-dominant population. The ordination of microbial community structures demonstrated that the quantitative methanogenic structure converged to the seed inoculum while the bacterial and archaeal DGGE band patterns diverged. These results provide an insight into the microbial behavior in the transitional phase (e.g., a start-up period) of anaerobic sludge digestion. PMID- 20705458 TI - Combination of biological pretreatment with mild acid pretreatment for enzymatic hydrolysis and ethanol production from water hyacinth. AB - The mild acid pretreatment and the combination of biological pretreatment by a white rot fungus Echinodontium taxodii or a brown rot fungus Antrodia sp. 5898 with mild acid pretreatment were evaluated under different pretreatment conditions for enzymatic hydrolysis and ethanol production from water hyacinth. The combined pretreatment with E. taxodii (10 days) and 0.25% H(2)SO(4) was proved to be more effective than the sole acid pretreatment. The reducing sugar yield from enzymatic hydrolysis of co-treated water hyacinth increased 1.13-2.11 fold than that of acid-treated water hyacinth at the same conditions. The following study on separate hydrolysis and fermentation with Saccharomyces cerevisiae indicated that the ethanol yield from co-treated water hyacinth achieved 0.192 g/g of dry matter, which increased 1.34-fold than that from acid treated water hyacinth (0.146 g/g of dry matter). This suggested that the combination of biological and mild acid pretreatment is a promising method to improve enzymatic hydrolysis and ethanol production from water hyacinth with low lignin content. PMID- 20705459 TI - Alterations in energy properties of eucalyptus wood and bark subjected to torrefaction: the potential of mass loss as a synthetic indicator. AB - Torrefaction is a mild pyrolysis process (usually up to 300 degrees C) that changes the chemical and physical properties of biomass. This process is a possible pre-treatment prior to further processes (transport, grinding, combustion, gasification, etc) to generate energy or biofuels. In this study, three eucalyptus wood species and bark were subjected to different torrefaction conditions to determine the alterations in their structural and energy properties. The most severe treatment (280 degrees C, 5h) causes mass losses of more than 35%, with severe damage to anatomical structure, and an increase of about 27% in the specific energy content. Bark is more sensitive to heat than wood. Energy yields are always higher than mass yields, thereby demonstrating the benefits of torrefaction in concentrating biomass energy. The overall mass loss is proposed as a relevant parameter to synthesize the effect of torrefaction conditions (temperature and duration). Accordingly, all results are summarised by analytical expressions able to predict the energy properties as a function of the overall mass loss. These expressions are intended to be used in any optimization procedure, from production in the field to the final use. PMID- 20705460 TI - Optimal conditions for bioremediation of oily seawater. AB - To determine the influence of nutrients on the rate of biodegradation, a five level, three-factor central composite design (CCD) was employed for bioremediation of seawater artificially contaminated with crude oil. Removal of total petroleum hydrocarbons (TPH) was the dependent variable. Samples were extracted and analyzed according to US-EPA protocols. A significant (R(2)=0.9645, P<0.0001) quadratic polynomial mathematical model was generated. Removal from samples not subjected to optimization and removal by natural attenuation were 53.3% and 22.6%, respectively. Numerical optimization was carried out based on desirability functions for maximum TPH removal. For an initial crude oil concentration of 1g/L supplemented with 190.21 mg/L nitrogen and 12.71 mg/L phosphorus, the Design-Expert software predicted 60.9% hydrocarbon removal; 58.6% removal was observed in a 28-day experiment. PMID- 20705461 TI - Synthesis and biological activity of N-substituted aminocarbonyl-1,3-dioxolanes as VLA-4 antagonists. AB - A novel set of compounds with a 1,3-dioxolane ring which acts as a proline bioisostere have been successfully designed as VLA-4 receptor antagonists. Compounds (18e), (28j), and (35g) were shown to have high receptor affinities. PMID- 20705462 TI - Synthesis of MRI contrast agents derived from DOTAM-Gly-L-Phe-OH incorporating a disulfide bridge: conjugation to a cell penetrating peptide and preparation of a dimeric agent. AB - A cell penetrating peptide conjugate and dimeric PARACEST MRI contrast agents, based on the DOTAM-Gly-L-Phe-OH scaffold have been prepared in moderate yields using diethyl azodicarboxylate (DEAD) or iodine-mediated disulfide bridge formation as a key step. Magnetic (PARACEST) properties of these agents have been evaluated. PMID- 20705463 TI - Identification of 3',4',5'-trimethoxychalcone analogues as potent inhibitors of Helicobacter pylori-induced inflammation in human gastric epithelial cells. AB - Efforts to identify potent small molecule inhibitors of Helicobacter pylori led to the evaluation of 23 3',4',5'-trimethoxychalcone analogues. Some of the compounds displayed potent antibacterial activity against H. pylori. Three most active and selective compounds 1, 7, and 13 also showed the bactericide activity against the reference as well as multidrug-resistant strains of H. pylori. Additionally, the aforementioned three compounds potentially inhibited the H. pylori adhesion and invasion to human gastric epithelial (AGS) cells. Furthermore, these selective compounds inhibited the H. pylori-induced gastric inflammation by reduced inflammatory mediator's nuclear factor kappa B activation, and the secretion of interleukin-8. PMID- 20705464 TI - Topoisomerase II-alpha as a predictive factor of response to therapy with anthracyclines in locally advanced breast cancer. AB - BACKGROUND: Topoisomerase II-alpha is a molecular target of anthracyclines; several studies have suggested that topoisomerase II-alpha expression is related to response to anthracycline treatment. The objective of this study was to evaluate if topoisomerase II-alpha overexpression predicts response to anthracycline treatment in locally advanced breast cancer patients. MATERIAL AND METHODS: Topoisomerase II-alpha, HER2, estrogen receptor (ER) and progesterone receptor (PR) expression were evaluated by immunohistochemistry in formalin fixed, paraffin-embedded breast tumors from 111 patients presenting with locally advanced breast cancer between 1995 and 2002. The prognostic value of these markers was analyzed using a multivariate proportional hazards regression model and an interaction analysis between topoisomerase II-alpha status and dose intensity. RESULTS: Tumors from 40 patients (36%) showed topoisomerase II-alpha overexpression, 62 patients (56%) for ER, 39 (35%) for PR and 26 (23%) for HER2. There were no significant correlations between topoisomerase II-alpha expression and response to therapy, progression-free survival (PFS) or overall survival (OS). Anthracycline dose intensity had a significant impact on PFS and OS in patients overexpressing topoisomerase II-alpha (P=0.010 and 0.027, respectively). Negative PR (P=0.041), positive HER2 (P=0.013) were identified as risk factors in the multivariate model. The multivariate analysis in patients topoisomerase II alpha negative shown no significance (HR=0.92, IC 95% 0.39-2.15, P=0.839) while the multivariate analysis in topoisomerase II-alpha positive, dose intensity shown to be statistically significant (HR=2.725, IC 95% 1.07-6.95, P=0.036). CONCLUSIONS: Our data do not support a correlation between topoisomerase II-alpha expression in breast cancer patients and improved clinical benefit with anthracycline therapy. However, they do suggest that tumors overexpressing topoisomerase II-alpha may experience better clinical benefit with higher anthracycline dose intensity. PMID- 20705465 TI - Enslavement in the water body by toxic Aphanizomenon ovalisporum, inducing alkaline phosphatase in phytoplanktons. AB - The hepatotoxin cylindrospermopsin (CYN) produced by certain cyanobacteria, including Aphanizomenon ovalisporum (hereafter Aphanizomenon) [1], seriously affects lake water quality [2], but its biological role is not known. Strong correlation between Aphanizomenon abundance in Lake Kinneret, Israel, and alkaline phosphatase (APase) activity suggests that inorganic phosphate (Pi) limitation induces the PHO regulon and APase secretion [3]. Staining lake samples with DAPI [4] revealed a high level of polyphosphate bodies (PPB) in Aphanizomenon. Application of enzyme-labeled fluorescence (ELF-APase) [5] showed APase in various organisms, but not in Aphanizomenon. ELF-APase signals and extracellular APase activity in Aphanizomenon were detected only after exploiting PPB under prolonged Pi deprivation in cultures or toward the end of its autumn bloom. Pi deprivation of Aphanizomenon induces CYN production, high-affinity Pi uptake, and an internal, not external, APase. Addition of Aphanizomenon spent media or CYN to various phytoplanktons, including Chlamydomonas reinhardtii, induced genes typically upregulated under Pi limitation and a rise in extracellular APase activity, despite ample surrounding Pi. Coculturing Aphanizomenon with Chlamydomonas or with Debarya sp. showed positive ELF-APase signals, but not in Aphanizomenon. CYN producers promote Pi supply by inducing APase secretion by other phytoplanktons, possibly explaining their increased abundance despite reduced Pi supply from watersheds. PMID- 20705467 TI - Dosage compensation and demasculinization of X chromosomes in Drosophila. AB - The X chromosome of Drosophila shows a deficiency of genes with male-biased expression, whereas mammalian X chromosomes are enriched for spermatogenesis genes expressed premeiosis and multicopy testis genes. Meiotic X-inactivation and sexual antagonism can only partly account for these patterns. Here, we show that dosage compensation (DC) in Drosophila may contribute substantially to the depletion of male genes on the X. To equalize expression between X-linked and autosomal genes in the two sexes, male Drosophila hypertranscribe their single X, whereas female mammals silence one of their two X chromosomes. We combine fine scale mapping data of dosage compensated regions with genome-wide expression profiles and show that most male-biased genes on the D. melanogaster X are located outside dosage compensated regions. Additionally, X-linked genes that have newly acquired male-biased expression in D. melanogaster are less likely to be dosage compensated, and parental X-linked genes that gave rise to an autosomal male-biased retrocopy are more likely located within compensated regions. This suggests that DC contributes to the observed demasculinization of X chromosomes in Drosophila, both by limiting the emergence of male-biased expression patterns of existing X genes, and by contributing to gene trafficking of male genes off the X. PMID- 20705466 TI - Fimbrin and tropomyosin competition regulates endocytosis and cytokinesis kinetics in fission yeast. AB - BACKGROUND: Tropomyosin is an important actin filament-stabilizing protein that controls the access of other essential proteins to filaments, including myosin motors, Arp2/3 complex, formin, and cofilin. It is therefore critical to establish mechanisms for regulating the actin filament binding of tropomyosin. We examined how the actin filament crosslinking protein fimbrin Fim1p and tropomyosin Cdc8p affect each other's ability to bind filaments, localize to particular cellular structures, and regulate filament severing by cofilin Adf1p in fission yeast Schizosaccharomyces pombe. RESULTS: We discovered a novel mechanism for regulating actin filament dynamics in fission yeast. Fim1p inhibits Cdc8p binding to actin filaments in vitro, which permits Adf1p-mediated severing in the presence of Cdc8p. In cells, the balance between Fim1p and Cdc8p is important for both endocytic actin patch kinetics and contractile ring assembly during cytokinesis. High Fim1p concentrations prevent Cdc8p from associating with actin patches, allowing rapid patch turnover and motility. In the absence of Fim1p, ectopic localization of Cdc8p to actin patches increases patch lifetime while decreasing patch motility. Fim1p and Cdc8p also play antagonistic roles during cytokinesis, in which the deletion of Fim1p rescues the contractile ring assembly defects caused by mutation of Cdc8p. CONCLUSION: Fimbrin Fim1p dissociates tropomyosin Cdc8p from actin filaments, permitting cofilin Adf1p mediated severing. Therefore, we propose that in addition to actin filament crosslinking, Fim1p has a novel role as a positive actin-binding "selector" protein that promotes the access of other proteins to actin filaments by inhibiting Cdc8p. PMID- 20705468 TI - SPATULA links daytime temperature and plant growth rate. AB - Plants exhibit a wide variety of growth rates that are known to be determined by genetic and environmental factors, and different plants grow optimally at different temperatures, indicating that this is a genetically determined character. Moderate decreases in ambient temperature inhibit vegetative growth, but the mechanism is poorly understood, although a decrease in gibberellin (GA) levels is known to be required. Here we demonstrate that the basic helix-loop helix transcription factor SPATULA (SPT), previously known to be a regulator of low temperature-responsive germination, mediates the repression of growth by cool daytime temperatures but has little or no growth-regulating role under warmer conditions. We show that only daytime temperatures affect vegetative growth and that SPT couples morning temperature to growth rate. In seedlings, warm temperatures inhibit the accumulation of the SPT protein, and SPT autoregulates its own transcript abundance in conjunction with diurnal effects. Genetic data show that repression of growth by SPT is independent of GA signaling and phytochrome B, as previously shown for PIF4. Our data suggest that SPT integrates time of day and temperature signaling to control vegetative growth rate. PMID- 20705469 TI - Evolution of a behavioral shift mediated by superficial neuromasts helps cavefish find food in darkness. AB - How cave animals adapt to life in darkness is a poorly understood aspect of evolutionary biology [1]. Here we identify a behavioral shift and its morphological basis in Astyanax mexicanus, a teleost with a sighted surface dwelling form (surface fish) and various blind cave-dwelling forms (cavefish) [2 4]. Vibration attraction behavior (VAB) is the ability of fish to swim toward the source of a water disturbance in darkness. VAB was typically seen in cavefish, rarely in surface fish, and was advantageous for feeding success in the dark. The potential for showing VAB has a genetic component and is linked to the mechanosensory function of the lateral line. VAB was evoked by vibration stimuli peaking at 35 Hz, blocked by lateral line inhibitors, first detected after developmental increases in superficial neuromast (SN) number and size [5-7], and significantly reduced by bilateral ablation of SN. We conclude that VAB and SN enhancement coevolved to compensate for loss of vision and to help blind cavefish find food in darkness. PMID- 20705470 TI - Membrane thickness cue for cold sensing in a bacterium. AB - Thermosensors are ubiquitous integral membrane proteins found in all kinds of life. They are involved in many physiological roles, including membrane remodeling, chemotaxis, touch, and pain [1-3], but, the mechanism by which their transmembrane (TM) domains transmit temperature signals is largely unknown. The histidine kinase DesK from Bacillus subtilis is the paradigmatic example of a membrane-bound thermosensor suited to remodel membrane fluidity when the temperature drops below approximately 30 degrees C [1, 4] providing, thus, a tractable system for investigating the mechanism of TM-mediated input-output control of thermal adaptation. Here we show that the multimembrane-spanning domain from DesK can be simplified into a chimerical single-membrane-spanning minimal sensor (MS) that fully retains, in vivo and in vitro, the sensing properties of the parental system. The MS N terminus contains three hydrophilic amino acids near the lipid-water interface creating an instability hot spot. Mutational analysis of this boundary-sensitive beacon revealed that membrane thickness controls the signaling state of the sensor by dictating the hydration level of the metastable hydrophilic spot. Guided by these results we biochemically demonstrated that the MS signal transmission activity is sensitive to bilayer thickness. Membrane thickness could be a general cue for sensing temperature in many organisms. PMID- 20705471 TI - Differential regulation of unconventional fission yeast myosins via the actin track. AB - BACKGROUND: Fission yeast possesses three unconventional myosins: Myo1p (a class I myosin that functions at endocytic actin patches) and Myo51p and Myo52p (class V myosins that function at contractile rings and actin cables, respectively). Here we used a combination of in vivo and in vitro approaches to investigate how changes in the actin track influence the motor activity and spatial regulation of these myosins. RESULTS: We optimized the isolation of Myo1p, Myo51p, and Myo52p. All three myosins exhibited robust motor activity in ATPase and actin filament gliding assays. However, decoration of actin with tropomyosin differentially regulates the activity of these motors. Tropomyosin inhibits Myo1p by blocking its ability to form productive associations with actin filaments, whereas tropomyosin increases the actin affinity and ATPase activity of Myo51p and Myo52p. The actin filament crosslinking protein fimbrin rescues Myo1p motor activity by displacing tropomyosin from actin filaments. Consistent with our in vitro findings, fimbrin and tropomyosin have opposing effects on Myo1p function at actin patches. Defects in tropomyosin function led to shorter Myo1p patch lifetimes, whereas loss of fimbrin extended Myo1p lifetimes. Furthermore, defects in tropomyosin function decreased the efficiency of Myo52p-directed motility along actin cables in the cell. CONCLUSION: Tropomyosin promotes myosin-V motility along actin cables. Accumulation of fimbrin at actin patches relieves Myo1p from tropomyosin-mediated inhibition, ensuring maximal myosin-I motor activity at these sites. Thus, spatial regulation of myosin motor function is in part controlled by specific changes in the composition of the actin track. PMID- 20705472 TI - Cannabinoid receptor CB1-immunoreactive nerve fibres in painful and non-painful human tooth pulp. AB - The cannabinoid receptor CB1 is involved in modulation of neuronal hypersensitivity and pain. The aim of this study was to evaluate CB1 receptor levels for the first time in dental pain. A total of 19 patients due for molar extraction were divided into two groups, those with existing dental pain (n=9), and those with no history of pain (n=10). Immunohistochemistry and computer image analysis was used to evaluate CB1-positive nerve fibres in tooth pulp, with neurofilament-immunostaining as a structural nerve marker. CB1-immunoreactive nerve fibres were scattered throughout the tooth pulp and often seen in nerve bundles, but the fibres did not penetrate the subodontoblastic layer. There was no statistically significant change in the CB1 nerve fibre percentage area in the painful group compared to the non-painful group (p=0.146); the neurofilament fibres were significantly reduced in the painful group compared to the controls (p=0.028), but there was no difference in the ratio of CB1 to neurofilaments between the two groups. Thus, CB1 expression is maintained by nerve fibres in painful human dental pulp, and peripherally-restricted CB1 agonists currently in development may advance the treatment of dental pain. PMID- 20705473 TI - Assessment of bone healing after Le Fort I osteotomy with 3-dimensional computed tomography. AB - PURPOSE: The purpose of this study was to examine bone healing after Le Fort I osteotomy in Class III patients. PATIENTS AND METHODS: The study group consisted of 18 Japanese patients with mandibular prognathism with and without asymmetry, maxillary retrognathism or open bite. A total of 36 sides were examined. Le Fort I osteotomy was performed without a pterygoid osteotome, with an ultrasonic curette used to remove interference at the pterygomaxillary region. Titanium plates (Universal Mid-face fixation module, Stryker, Freiburg, German) were used for four patients, absorbable plates (poly-L-lactic acid (PLLA): NEOFIX((r)), Gunze, kyoto, Japan) were used for four patients and other absorbable plates (uncalcined and unsintered hydroxyapatite and poly-L-lactic acid (uHA/PLLA): super FIXSORB((r))MX, Takiron Co. Ltd, Osaka, Japan) were used for 10 patients, in the same manner. Postoperative computed tomography (CT) was analyzed for all patients pre-operatively and 1 year postoperative. The anterior and lateral areas between the maxillary segments were measured with 3-dimensional (3D) CT. Bone healing at the pterygomaxillary region was also assessed. RESULTS: There were no significant differences in the area of bone defect healing among the plate types. The areas of bone defect after 1 year were significantly smaller than that immediately after surgery on the right side (p=0.0145) and left side (p=0.0010) in the frontal view and right side in the lateral view (p=0.0118). Bone healing at the pterygomaxillary junction was found in all cases without artificial pterygoid plate fracture. Fourteen of 22 sides with artificial pterygoid plate fracture by an ultrasonic curette showed bone continuity between the pterygoid plate and posterior part of maxilla. CONCLUSION: This study suggested that bony healing could occur in spaces between the segments of maxilla and pterygomaxillary regions as well as the region of the anterior and lateral walls in the maxilla, but it is not always complete within 1 year after Le Fort I osteotomy. PMID- 20705475 TI - Positional occlusion of the right carotid artery in a case of right aortic arch and aneurysm of the thoracic aorta. PMID- 20705477 TI - Sequential use of targeted agents in the treatment of renal cell carcinoma. AB - Sequential use of targeted therapies is a common practice in the treatment of advanced renal cell carcinoma (RCC) that extends disease control beyond the benefit of single therapies. After disease progression on one agent, treatment with a second targeted agent as subsequent-line therapy provides disease control and additional progression-free survival. The most effective sequence of targeted agents has yet to be determined. Results from the only trial of sequenced targeted agents support the use of mammalian target of rapamycin inhibitors after resistance develops to vascular endothelial growth factor (VEGF) inhibitors. Preliminary data suggest an antitumor effect of VEGF-targeted therapy in RCC, despite prior exposure to other VEGF-targeted therapies. The safety and efficacy of sequential therapies are currently under investigation; the optimal sequence may vary among patients to accommodate comorbid conditions or different disease stages. The current evidence supporting sequential use of targeted agents in RCC is presented in this review. PMID- 20705476 TI - Cellular aging and cancer. AB - Aging is manifest in a variety of changes over time, including changes at the cellular level. Cellular aging acts primarily as a tumor suppressor mechanism, but also may enhance cancer development under certain circumstances. One important process of cellular aging is oncogene-induced senescence, which acts as a significant anti-cancer mechanism. Cellular senescence resulting from damage caused by activated oncogenes prevents the growth of potentially neoplastic cells. Moreover, cells that have entered senescence appear to be targets for elimination by the innate immune system. In another aspect of cellular aging, the absence of telomerase activity in normal tissues results in such cells lacking a telomere maintenance mechanism. One consequence is that in aging there is an increase in cells with shortened telomeres. In the presence of active oncogenes that cause expansion of a neoplastic clone, shortening of telomeres, leading to telomere dysfunction, prevents the indefinite expansion of the clone, because the cells enter crisis. Crisis results from chromosome fusions and other defects caused by dysfunctional telomeres and is a terminal state of the neoplastic clone. In this way the absence of telomerase in human cells, while one cause of cellular aging, also acts as an anti-cancer mechanism. PMID- 20705478 TI - Reactions of an aromatic sigma,sigma-biradical with amino acids and dipeptides in the gas phase. AB - Gas-phase reactivity of a positively charged aromatic sigma,sigma-biradical (N methyl-6,8-didehydroquinolinium) was examined toward six aliphatic amino acids and 15 dipeptides by using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR) and laser-induced acoustic desorption (LIAD). While previous studies have revealed that H-atom and NH(2) abstractions dominate the reactions of related monoradicals with aliphatic amino acids and small peptides, several additional, unprecedented reaction pathways were observed for the reactions of the biradical. For amino acids, these are 2H-atom abstraction, H(2)O abstraction, addition - CO(2), addition - HCOOH, and formation of a stable adduct. The biradical reacts with aliphatic dipeptides similarly as with aliphatic amino acids, but undergoes also one additional reaction pathway, addition/C-terminal amino acid elimination (addition - CO - NHCHR(C)). These reactions are initiated by H-atom abstraction by the biradical from the amino acid or peptide, or nucleophilic addition of an NH(2) or a HO group of the amino acid or peptide at the radical site at C-6 in the biradical. Reactions of the unquenched C-8 radical site then yield the products not observed for related monoradicals. The biradical reacts with aromatic dipeptides with an aromatic ring in N-terminus (i.e., Tyr-Leu, Phe-Val, and Phe-Pro) similarly as with aliphatic dipeptides. However, for those aromatic dipeptides that contain an aromatic ring in the C-terminus (i.e., Leu-Tyr and Ala-Phe), one additional pathway, addition/N terminal amino acid elimination (addition - CO - NHCHR(N)), was observed. This reaction is likely initiated by radical addition of the biradical at the aromatic ring in the C-terminus. Related monoradicals add to aromatic amino acids and small peptides, which is followed by Calpha-Cbeta bond cleavage, resulting in side-chain abstraction by the radical. For biradicals, with one unquenched radical site after the initial addition, the reaction ultimately results in the loss of the N-terminal amino acid. Similar to monoradicals, the C-S bond in amino acids and dipeptides was found to be especially susceptible to biradical attack. PMID- 20705479 TI - The long term immunological response of swine after two exposures to a salmon thrombin and fibrinogen hemostatic bandage. AB - Experimental salmon thrombin/fibrinogen dressings have been shown to provide effective hemostasis in severe hemorrhage situations. The hypothesis for this study was that swine would still remain healthy without coagulopathy six months after exposure to salmon thrombin/fibrinogen dressings. Initial exposure was by insertion of the salmon dressing into the peritoneal cavity. Three months after the initial exposure, the same animals were subjected to two full thickness dermal wounds on the dorsal surface. One wound was bandaged with the salmon thrombin/fibrinogen bandage and the other wound was dressed with a standard bandage. The animals were monitored for an additional three months. Blood was drawn every 14 days over the six months for immunological and coagulation function analysis. All of the animals (8 pigs) remained healthy during the six month period and the dermal wounds healed without incidence. Lymph nodes and spleen showed signs of normal immune response and Western blots showed development of antibodies against salmon fibrinogen, but none of the animals made antibodies that recognized any species of thrombin. Coagulation parameters (fibrinogen concentration, thrombin time, PT and aPTT) and hematological parameters remained normal over the course of the study when compared to initial values of the subject swine. PMID- 20705480 TI - Moderate alcohol use and cognitive function in the Guangzhou Biobank Cohort study. AB - PURPOSE: Observational studies in Western settings show moderate alcohol use associated with better cognitive function, but they are vulnerable to contextual bias. Evidence from non-Western settings may be useful to verify causality. We examined such association in southern China where alcohol use is low. METHODS: We used multivariable linear regression in cross-sectional data from the Guangzhou Biobank Cohort Study to assess sex-stratified associations of alcohol use (never, occasional, moderate, heavy and former drinker) with delayed 10-word recall score for all 3 phases (N = 28,537) and Mini-Mental State Examination (MMSE) score in phase 3 (N = 9,571). RESULTS: Delayed 10-word recall scores were higher in moderate drinkers compared with never drinkers among men (0.30 words, 95% confidence interval [CI]: 0.18 to 0.42) but not women (0.02; 95% CI: -0.12 to 0.17), adjusted for sociodemographic factors. Occasional alcohol users also had higher 10-word recall scores among men (0.27; 95% CI: 0.18 to 0.37) and women (0.30; 95% CI: 0.23 to 0.37). These estimates were little altered by further adjustment for cardiovascular risk factors. Results for MMSE scores were similar. CONCLUSIONS: Alcohol may not drive the association between moderate use and better cognitive function, which instead may be due to confounding by general moderation in lifestyle. PMID- 20705481 TI - Reply to Halberstein et al. PMID- 20705483 TI - Multiplicative multi-fractal modeling of electromyography signals for discerning neuropathic conditions. AB - In this paper, we present a new method for multi-scale analysis of electromyography signals based on an interesting fractal process known as multiplicative cascade multi-fractal. Using simulated needle electromyography signals, we show this method provides a means for discrimination of normal and neuropathic electromyography signals. We also present experimental results that show the new parameters, computed using multiplicative cascade multi-fractal modeling, are more robust than the conventional signal parameter, number of turns, in the presence of additive noise. Results of multiplicative cascade multi fractal modeling are consistent with other multi-scale approaches; advantages and differences are high lighted. PMID- 20705482 TI - Regarding "meta-analysis and causal inference: a case study of benzene and non Hodgkin lymphoma": an incomplete analysis. PMID- 20705484 TI - A titanium plug simplifies left ventricular assist device removal after myocardial recovery. PMID- 20705486 TI - Screening for sudden death in the athlete. AB - Sudden death in the athlete is a rare occurrence, yet there is evidence that screening may reduce this tragedy. Pre-participation screening programs differ between the United States and Italy. The causes of sudden death in this young, athletic population are reviewed, as are each program's merits and pitfalls. PMID- 20705485 TI - Transcriptional regulation of heart valve development and disease. AB - Aortic valve disease is estimated to affect 2% of the United States population. There is increasing evidence that aortic valve disease has a basis in development, as congenital valve malformations are prevalent in patients undergoing valve replacement surgery. In fact, a number of genetic mutations have been linked to valve malformations and disease. In the initial stages of aortic valve pathogenesis, the valvular interstitial cells become activated, undergo cell proliferation, and participate in extracellular matrix remodeling. Many of these cell properties are shared with mesenchymal progenitor cells of the normally developing valves and bones. Historically, valve calcification was thought to be a passive process reflecting end-stage disease. However, recent evidence describes the increased expression of transcription factors in diseased AoV that are common to valvulogenic and osteogenic processes. These studies lend support to the idea that a developmental gene program is reactivated in aortic valve disease and may contribute to the molecular mechanisms underlying valve calcification in disease. PMID- 20705487 TI - Sudden cardiac death secondary to demonstrated reperfusion ventricular fibrillation in a woman with Takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy is a left ventricle cardiomyopathy characterized by a reversible dyskinesia responsible for the typical apical ballooning aspect. The disease is considered benignant with a full recovery within a few weeks. We present the case of a 52-year-old woman who presented with angina diagnosed with Takotsubo cardiomyopathy on the basis of both noninvasive (electrocardiography, echocardiography) and invasive (angiography) exams. At discharge, a Holter monitor was fitted to the patient. During the recording the patient faced sudden cardiac death. The analysis of the Holter traces allowed some speculations on the mechanism of this unexpected arrhythmic death. The cause of the fatal ventricular fibrillation appears to be the fast reperfusion following a short occlusion of an epicardial coronary artery. This case highlights the epicardial vasospasm as an important pathogenic mechanism of the syndrome and the possible usefulness of diagnostic tests able to elicit the spasm susceptibility and guide a more targeted pharmacological therapy. Some considerations are also possible on the cellular processes linking the rapid reperfusion and the arrhythmias onset. PMID- 20705488 TI - Open reduction and internal fixation of os acromion fracture-separation as a component of a floating shoulder injury: a case report. PMID- 20705489 TI - Metaversion can reliably predict humeral head version: a computed tomography based validation study. AB - HYPOTHESIS: Circumstances occur when the determination of anatomic humeral head version is difficult. In the setting of irreparable proximal humeral fracture, there are few reliable intraoperative landmarks to determine anatomic humeral head version. This study tested our hypothesis that the metaphyseal version (metaversion) is a landmark that can assist with correct head version and used computed tomography (CT) to evaluate its reliability as a predictor of anatomic version. MATERIALS AND METHODS: CT scans from 50 consecutive patients (20 women, 30 men) were examined using commercial software. Patients were a mean age of 46 years (range, 17-85 years). Exclusion criteria included previous fracture, arthritis, or humeral deformity. The metaversion and humeral head version were measured. Measurements were conducted independently by 2 surgeons blinded to the results of the other. Interobserver and intraobserver reliability was calculated using intraclass correlation. RESULTS: The mean difference between the metaversion and the humeral head version was 2.5 degrees (95% confidence interval [CI], 0.9 degrees -3.9 degrees ). The mean difference between metaversion and humeral head version was 1.8 degrees (95% CI, 0.0 degrees -3.6 degrees ) in women, 2.9 degrees (95% CI, 0.6 degrees -5.1 degrees ) in men, 2.4 degrees (95% CI: 0.6 degrees -4.1 degrees ) in right shoulders, and 2.5 degrees (95% CI, -0.1 degrees to 5.1 degrees ) in left shoulders. Interrater and intrarater reliability was excellent, 0.97 and 0.98, respectively. CONCLUSIONS: Proximal humeral metaphyseal version (metaversion) is an accurate predictor of ipsilateral humeral head version. PMID- 20705490 TI - Psychometric evaluation of the Serbian version of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31). AB - PURPOSE: To evaluate the psychometric properties of the Serbian-language version of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31). METHODS: After undergoing a translation and cultural adaptation of its items in order to create a Serbian-language version of QOLIE-31, we assessed its psychometric properties reliability, construct validity and criterion validity. The sample consisted of 203 adults with epilepsy. Reliability was tested both by assessing the internal consistency and by the test-retest method. Construct validity was assessed by factor analysis, multitrait-scaling analysis and method of known-groups validation. This was achieved by assessing the relationship between scales and external measures (socio-demographic characteristics, seizure severity and etiology of epilepsy). Criterion validity was assessed by correlation analysis between QOLIE-31 and Short form 36 health survey (SF-36) and Neurotoxicity scale II. RESULTS: The domains showed high internal consistency (Cronbach's alpha 0.94). Test-retest reliability for Overall test score was 0.83 (Pearson's coefficient) indicating temporal stability. Seizure severity and etiology of epilepsy significantly influenced all QOLIE-31 domains except the Medication effect domain, with lowest scores in high seizure severity and symptomatic etiology groups. Employment status significantly influenced Overall quality of life, Emotional well-being, Social function and Overall score. Educational level was related to the Emotional well-being domain, with highest scores for students. The QOLIE-31 was highly positively correlated with SF-36 (rho=0.898) and strongly negatively correlated with Neurotoxicity scale-II (rho=-0.783). CONCLUSION: Serbian adaptation of the QOLIE-31 questionnaire is reliable and valid for assessing the quality of life in patients with epilepsy. PMID- 20705492 TI - Carotid artery reconstruction for infected carotid patches. AB - OBJECTIVES: Infected carotid prosthetic patches (ICPP) are a rare but catastrophic complication of carotid endarterectomy (CEA). Prevention and appropriate surgical management is essential. We report our experience of carotid artery reconstruction for ICPP. DESIGN: Single-center retrospective study. METHODS: 10-year review of the surgical treatment of ICPP. RESULTS: Twelve patients presented with patch infection following CEA. Three patients presented acutely with an expanding hematoma, eight with chronic complications (abscess/discharging sinus n = 5, carotid pseudoaneurysm n = 3). Mean age was 75 years. Replacement conduits included superficial femoral artery (n = 6), cadaveric homograft (n = 3), long saphenous vein (n = 2) and one patient had primary closure. Five patients had muscle flaps fashioned for carotid artery protection. Operative complications included hypoglossal nerve injury (1 patient), superficial skin infection (2 patients) and one patient was returned to the operating room for a neck haematoma. Five surgical specimens were culture positive for: Staphylococcus aureus (n = 3), Corynebacterium propionibacterium (n = 1) and Streptococcus anginous (n = 1). There were no 30-day mortalities. Mean hospital stay was 6 days. Median follow-up was 16 months (range 3-108 months). CONCLUSION: Carotid artery reconstruction in a contaminated wound represents a significant surgical challenge. Unlike previous reports that used venous conduits, this is the first series where cadaveric or autologous arterial conduits were preferred. Arterial conduits achieved durable short term follow-up. PMID- 20705491 TI - The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. AB - A20 is a ubiquitin modifying enzyme that restricts NF-kappaB signals and protects cells against tumor necrosis factor (TNF)-induced programmed cell death. Given recent data linking A20 (TNFAIP3) with human B cell lymphomas and systemic lupus erythematosus (SLE), we have generated mice bearing a floxed allele of Tnfaip3 to interrogate A20's roles in regulating B cell functions. A20-deficient B cells are hyperresponsive to multiple stimuli and display exaggerated NF-kappaB responses to CD40-induced signals. Mice expressing absent or hypomorphic amounts of A20 in B cells possess elevated numbers of germinal center B cells, autoantibodies, and glomerular immunoglobulin deposits. A20-deficient B cells are resistant to Fas mediated cell death, probably due to increased expression of NF-kappaB-dependent antiapoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, whereas A20 protects other cells from TNF-induced cell death. Our studies demonstrate how reduced A20 expression predisposes to autoimmunity. PMID- 20705493 TI - Variations in surgical procedures for hind limb ischaemia mouse models result in differences in collateral formation. AB - OBJECTIVE: To identify the optimal mouse model for hind limb ischaemia, which offers a therapeutic window that is large enough to detect improvements of blood flow recovery, for example, using cell therapies. MATERIALS AND METHODS: Different surgical approaches were performed: single coagulation of femoral and iliac artery, total excision of femoral artery and double coagulation of femoral and iliac artery. Blood flow restoration was analysed with laser Doppler perfusion imaging (LDPI). Immuno-histochemical stainings, angiography and micro computed tomography (CT) scans were performed for visualisation of collaterals in the mouse. RESULTS: Significant differences in flow restoration were observed depending on the surgical procedure. After single coagulation, blood flow already restored 100% in 7 days, in contrast to a significant delayed flow restoration after double coagulation (54% after 28 days, P<0.001). After total excision, blood flow was 100% recovered within 28 days. Compared with total excision, double coagulation displayed more pronounced corkscrew phenotype of the vessels typical for collateral arteries on angiographs. CONCLUSION: The extent of the arterial injury is associated with different patterns of perfusion restoration. The double coagulation mouse model is, in our hands, the best model for studying new therapeutic approaches as it offers a therapeutic window in which improvements can be monitored efficiently. PMID- 20705494 TI - In vivo precision of the GE Lunar iDXA densitometer for the measurement of total body, lumbar spine, and femoral bone mineral density in adults. AB - Knowledge of precision is integral to the monitoring of bone mineral density (BMD) changes using dual-energy X-ray absorptiometry (DXA). We evaluated the precision for bone measurements acquired using a GE Lunar iDXA (GE Healthcare, Waukesha, WI) in self-selected men and women, with mean age of 34.8 yr (standard deviation [SD]: 8.4; range: 20.1-50.5), heterogeneous in terms of body mass index (mean: 25.8 kg/m(2); SD: 5.1; range: 16.7-42.7 kg/m(2)). Two consecutive iDXA scans (with repositioning) of the total body, lumbar spine, and femur were conducted within 1h, for each subject. The coefficient of variation (CV), the root-mean-square (RMS) averages of SDs of repeated measurements, and the corresponding 95% least significant change were calculated. Linear regression analyses were also undertaken. We found a high level of precision for BMD measurements, particularly for scans of the total body, lumbar spine, and total hip (RMS: 0.007, 0.004, and 0.007 g/cm(2); CV: 0.63%, 0.41%, and 0.53%, respectively). Precision error for the femoral neck was higher but still represented good reproducibility (RMS: 0.014 g/cm(2); CV: 1.36%). There were associations between body size and total-body BMD and total-hip BMD SD precisions (r=0.534-0.806, p<0.05) in male subjects. Regression parameters showed good association between consecutive measurements for all body sites (r(2)=0.98-0.99). The Lunar iDXA provided excellent precision for BMD measurements of the total body, lumbar spine, femoral neck, and total hip. PMID- 20705495 TI - "Depupylation" of prokaryotic ubiquitin-like protein from mycobacterial proteasome substrates. AB - Ubiquitin (Ub) provides the recognition and specificity required to deliver proteins to the eukaryotic proteasome for destruction. Prokaryotic ubiquitin-like protein (Pup) is functionally analogous to Ub in Mycobacterium tuberculosis (Mtb), as it dooms proteins to the Mtb proteasome. Studies suggest that Pup and Ub do not share similar mechanisms of activation and conjugation to target proteins. Dop (deamidase of Pup; Mtb Rv2112c/MT2172) deamidates the C-terminal glutamine of Pup to glutamate, preparing it for ligation to target proteins by proteasome accessory factor A (PafA). While studies have shed light on the conjugation of Pup to proteins, it was not known if Pup could be removed from substrates in a manner analogous to the deconjugation of Ub from eukaryotic proteins. Here, we show that Mycobacteria have a "depupylase" activity provided by Dop. The discovery of a depupylase strengthens the parallels between the Pup- and Ub-tagging systems of prokaryotes and eukaryotes, respectively. PMID- 20705496 TI - [Physical compatibility of amiodarone in continuous infusion]. AB - OBJECTIVE: To determine the physical compatibility of amiodarone administered in Y-site with other continuous infusion drugs, in order to ensure stability and safe delivery to the patient. METHOD: Experimental in vitro study. We determined the physical compatibility of amiodarone with drugs commonly used in the intensive care unit as a continuous infusion, simulating the same conditions as in daily practice: container, solvent, temperature and fluorescent light. All samples were evaluated by visual observation procedures, looking for colour changes, turbidity, precipitation or gas formation, pH measurement and spectrophotometer absorption at wavelengths: 450 nm and 620 nm to detect colour changes, cloudiness and precipitation, respectively. Compatible mixtures were considered as those that showed no physical changes, variability in pH < 0.50 and the spectral range < 0.010. RESULTS: We analysed 39 samples: 14 single, 13 doubles, 6 triples and 6 quadruples, which were examined at different time intervals: 0, 15, 30, 60 and 120 min. Non-compatible mixtures showed immediate visual changes and higher absorbance values of 0.010 nm. There were no significant changes in pH during the study. CONCLUSIONS: Amiodarone is physically compatible with cisatracurium haloperidol, insulin, midazolam, morphine, nimodipine, nitroglycerin and urapidil and incompatible with bicarbonate, furosemide, heparin and thiopental. PMID- 20705498 TI - Brucellosis serology in HIV-infected patients. AB - BACKGROUND: An accelerated evolution of HIV to AIDS has been reported with brucellosis co-infection. The seroprevalence of brucellosis co-infection with HIV has not been investigated in a brucellosis endemic country like Iran. METHODS: We performed a cross-sectional survey of brucellosis serology in HIV-infected patients attending a university hospital, as well as in healthy controls. A total of 90 HIV-positive patients and 100 healthy age-matched controls were recruited. The clinical characteristics, hemoglobin, and red blood cell, platelet, white blood cell, and CD4+ T cell counts were evaluated. RESULTS: Positive brucellosis serology was significantly higher in HIV-infected patients than in controls (73.3% vs. 30%, respectively, odds ratio 6.42, p<0.001). It was also higher in males than females, p=0.001. Brucellosis-infected patients had significantly lower hemoglobin and white blood cell counts compared with brucellosis-uninfected patients (p<0.001). In HIV-positive patients, white blood cell count was significantly lower in brucellosis-infected than brucellosis-uninfected patients (p<0.05). CONCLUSIONS: Our findings show that brucellosis infection is an important infection in HIV-infected patients. The treatment of brucellosis may be of great clinical importance in the management of HIV infection in a brucellosis endemic country like Iran. PMID- 20705499 TI - [The spinal cord injured patient: semen quality and management by Assisted Reproductive Technology]. AB - Men with spinal cord injury present a unique infertile population. Only 10 % of them can father children without medical assistance, owing to potential impairments in erection, ejaculation and semen quality. The algorithm typically followed is to retrieve semen by Penile Vibratory Stimulation, in case of failure by Electro Ejaculation. Most of these patients have normal sperm concentrations but abnormally low sperm motility and vitality in the ejaculate. The reasons for poor semen quality in spinal cord injured men are reviewed. If semen cannot be obtained by Electro Ejaculation, or if the ejaculate from Penile Vibratory Stimulation or Electro Ejaculation contains an insufficient quantity or quality of sperm for in vitro fertilization with intracytoplasmic sperm injection, then retrieval of sperm from reproductive tissues is attempted. Despite abnormal semen quality, successful pregnancies with sperm from spinal cord injured male partners have occurred by intravaginal insemination, intrauterine insemination, and in vitro fertilization with intracytoplasmic sperm injection. The prevailing pregnancy and fecundity rates in couples with a spinal cord injured male partner are reviewed. PMID- 20705500 TI - Beyond individual neighborhoods: a geography of opportunity perspective for understanding racial/ethnic health disparities. AB - There has been insufficient attention to how and why place and neighborhood context contribute to racial/ethnic health disparities, as well as to policies that can eliminate racial/ethnic health disparities. This article uses a geography of opportunity framework to highlight methodological issues specific for quantitative research examining neighborhoods and racial/ethnic health disparities, including study design, measurement, causation, interpretation, and implications for policy. We argue that failure to consider regional, racialized housing market processes given high US racial residential segregation may introduce bias, restrict generalizability, and/or limit the policy relevance of study findings. We conclude that policies must address the larger geography of opportunity within the region in addition to improving deprived neighborhoods. PMID- 20705501 TI - Fear of movement in pre-operative patients with a lumbar stenosis and or herniated disc: factor structure of the Tampa scale for kinesiophobia. AB - The presence of fear of movement is related to higher disability rates in several patient groups. The purpose of this study was first to analyze fear of movement and the relation with pain and disability in pre-operative patients with low back pain and radiculopathy and secondly to analyze the factor structure of the Dutch version of the Tampa Scale for Kinesiophobia (TSK). The TSK and Pain Disability Index (PDI) were assessed in 128 patients. An explorative factor analysis (EFA) and a confirmatory factor analysis (CFA) of the TSK were performed using Structural Equation Models (SEMs). Fear of movement was significantly related to leg-pain and pain disability. A four-factor model had an explained variance of 49%. After further analyses a solution with three factors (harm, somatic focus, activity avoidance) and nine items (1, 3, 6, 7, 9, 11, 14, 15, 17) had the best fit. Based on the content of this study clinically a factor structure with three subscales with nine items is favorable for usage in pre-operative patients with low back pain and radiculopathy. PMID- 20705502 TI - Causal inference in perception. AB - Until recently, the question of how the brain performs causal inference has been studied primarily in the context of cognitive reasoning. However, this problem is at least equally crucial in perceptual processing. At any given moment, the perceptual system receives multiple sensory signals within and across modalities and, for example, has to determine the source of each of these signals. Recently, a growing number of studies from various fields of cognitive science have started to address this question and have converged to very similar computational models. Therefore, it seems that a common computational strategy, which is highly consistent with a normative model of causal inference, is exploited by the perceptual system in a variety of domains. PMID- 20705503 TI - Experimental and DFT studies on the vibrational and electronic spectra of 1,5 dimethyl-2-phenyl-4-[(pyridin-4-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one. AB - Vibrational spectral measurements were made for 1,5-dimethyl-2-phenyl-4-[(pyridin 4-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one (DPPDP). Optimized geometrical structure and harmonic vibrational frequencies were computed by ab initio RHF and DFT (B-based BP86, BLYP, BPW91, B3-based B3P86, B3LYP, B3PW91 and O3-based O3LYP) methods using 6-311++G(d,p) basis set. Complete assignments of the observed spectra were proposed. The equilibrium geometries computed by all of the methods, were compared with X-ray diffraction results. The absorption spectra of the title compound were computed both in gas phase and in CH(3)CN solution using TD-B3LYP/6 311++G(d,p) and PCM-B3LYP/6-311++G(d,p) approaches and the calculated results provide a good description of positions of the two band maxima in the observed electronic spectrum. PMID- 20705505 TI - Genotypic variation of Pneumocystis jirovecii isolates in India based on sequence diversity at mitochondrial large subunit rRNA. AB - Pneumocystis pneumonia (PCP), a common and serious opportunistic infection in immunocompromised patients, is caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii f. sp. hominis). The aim of the present study was to describe the prevalence and distribution of genotypes of P. jirovecii based on sequence polymorphisms at mitochondrial large subunit ribosomal RNA (mt LSU rRNA) region in both HIV and non-HIV immunocompromised individuals with a positive PCR result for PCP in a tertiary health care centre in northern India. From January 2005 to October 2008, 50 patients [22 HIV-seropositive individuals, 10 post-renal transplant (PRT) recipients, 3 cancer patients, and 15 patients with various other kinds of immunosuppression] were found to be positive for P. jirovecii using PCR at the mt LSU rRNA gene. Genotyping of the positive samples was performed at the mt LSU rRNA locus. Genotype 2 was the most common accounting for 42% of total types. This was followed by the genotypes 3 (24%), 1 (20%), and 4 (8%). Mixed infection was observed in 3 cases (6%). The rates of genotype distribution were similar in HIV-seropositive individuals, cancer patients, and in patients with other kinds of immunosuppression. In the PRT recipients, genotype 1 was the most prevalent type (80%). This is the first study describing the prevalence of genotypes in HIV-infected and HIV-uninfected, immunocompromised patients based on the mt LSU rRNA gene from the Indian subcontinent. The most prevalent genotype observed was type 2 in contrast to many studies from other parts of the world where genotype 1 was the most prevalent type, suggesting geographical variation. PMID- 20705504 TI - Fur is required for the activation of virulence gene expression through the induction of the sae regulatory system in Staphylococcus aureus. AB - Our previous studies showed that both Sae and Fur are required for the induction of eap and emp expression in low iron. In this study, we show that expression of sae is also iron-regulated, as sae expression is activated by Fur in low iron. We also demonstrate that both Fur and Sae are required for full induction of the oxidative stress response and expression of non-covalently bound surface proteins in low-iron growth conditions. In addition, Sae is required for the induced expression of the important virulence factors isdA and isdB in low iron. Our studies also indicate that Fur is required for the induced expression of the global regulators Agr and Rot in low iron and a number of extracellular virulence factors such as the haemolysins which are also Sae- and Agr-regulated. Hence, we show that Fur is central to a complex regulatory network that is required for the induced expression of a number of important S. aureus virulence determinants in low iron. PMID- 20705506 TI - The matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS)-based protein peaks of 4448 and 5302 Da are not associated with the presence of Panton-Valentine leukocidin. AB - The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus plays an important role in the pathogenesis of necrotizing pneumonia and recurrent skin and soft tissue infections. The gene encoding for PVL, lukS/F-PV, is distributed by prophages and can thus spread between isolates. Molecular methods have normally been used to identify lukS/F-PV-positive strains. Recently, however, a matrix assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS)-based method has been described to identify PVL-positive S. aureus strains. The aim of this study was thus to investigate the association of distinct MALDI TOF MS peaks to the toxin profile in molecularly characterized methicillin susceptible (MSSA) and methicillin-resistant S. aureus (MRSA) strains harbouring lukS/F-PV. In contrast to the previous results, the MALDI-TOF MS peaks were detected in all 104 recently described molecularly divergent MRSA irrespective of the presence of PVL. Our result indicates that these described peaks seem to be independent of the presence of PVL. PMID- 20705507 TI - Sugar metabolism, an additional virulence factor in enterobacteria. AB - Enterobacteria display a high level of flexibility in their fermentative metabolism. Biotyping assays have thus been developed to discriminate between clinical isolates. Each biotype uses one or more sugars more efficiently than the others. Recent studies show links between sugar metabolism and virulence in enterobacteria. In particular, mechanisms of carbohydrate utilization differ substantially between pathogenic and commensal E. coli strains. We are now starting to gain insight into the importance of this variability in metabolic function. Studies using various animal models of intestinal colonization showed that the presence of the fos and deoK loci involved in the metabolism of short chain fructoligosaccharides and deoxyribose, respectively, help avian and human pathogenic E. coli to outcompete with the normal flora and colonize the intestine. Both PTS and non-PTS sugar transporters have been found to modulate virulence of extraintestinal pathogenic E. coli strains. The vpe, GimA, and aec35 37 loci contribute to bacterial virulence in vivo during experimental septicemia and urinary tract infection, meningitis, and colibacillosis, respectively. However, in most cases, the sugars metabolized, and the precise role of their utilization in the expression of bacterial virulence is still unknown. The massive development of powerful analytical methods over recent years will allow establishing the knowledge of the metabolic basis of bacterial pathogenesis that appears to be the next challenge in the field of infectious diseases. PMID- 20705508 TI - Dietary intake of lead and cadmium by children and adults - Result calculated from dietary recall and available lead/cadmium level in food in comparison to result from food duplicate diet method. AB - The dietary intakes of lead and cadmium by 30 children and 30 adults living in Jinhu area in China were determined by the duplicate method with a 3-day sampling period. Dietary recall and available lead/cadmium level in food were also used to calculate dietary intakes. Lead intakes based on duplicate method were 15.66MUg(kg(bw))(-1)week(-1) for children and 8.83MUg(kg(bw))(-1)week(-1) for adults. Cadmium intakes were 2.07MUg(kg(bw))(-1)week(-1) for children and 1.49MUg(kg(bw))(-1)week(-1) for adult. The results from the dietary record method were as follows: lead intakes were 11.84MUg(kg(bw))(-1)week(-1) for children and 7.70MUg(kg(bw))(-1)week(-1) for adult. Cadmium intakes were 2.20MUg(kg(bw))( 1)week(-1) for children and 1.44MUg(kg(bw))(-1)week(-1) for adults. Children's dietary intakes were higher than those of adults'. The results of the dietary intakes calculated from two methods did not have significant difference. Compared to the FAO/WHO PTWIs for lead and cadmium, the average lead and cadmium dietary intakes are all below PTWIs. It was concluded that dietary record method can give comparatively accurate result for lead and cadmium dietary intakes compared with duplicate method. The average lead and cadmium dietary intakes for children and adults in Jinhu area are considered safe. However, the high level of dietary lead and cadmium intakes of children in this area deserves our attention. PMID- 20705509 TI - Guiding catheter tip avulsion--an unusual complication of renal artery stenting. AB - A 68-year-old hypertensive male underwent stenting for critical stenosis of the right renal artery through right femoral approach. The stent missed the ostium and repeated attempts at stenting the ostium did not succeed. Brachial approach was resorted to and ostium could be stented successfully. While deploying the stent the balloon was slightly inside the guiding catheter and the catheter tip got partially detached. The whole assembly was withdrawn to the brachial artery and the detached fragment was snared and removed. PMID- 20705510 TI - Innate immune mechanisms for recognition and uptake of Candida species. AB - Candida species are major causes of infections affecting either body surfaces or the deep tissues. Candida is a complex pathogen and the immune system uses various cells, cell surface receptors and signalling pathways to trigger an efficient host defence. Host-Candida interaction can result either in rapid elimination of the pathogen or the persistence of the pathogen in immunocompromised patients, leading to either chronic mucocutanous candidiasis or invasive candidiasis. Here, we discuss the molecular basis of receptor-mediated recognition and uptake of non-opsonized Candida and we describe the relative role of these receptors in initiating inflammation. In addition, the consequence of genetic defects in dectin-1 and dectin-1-mediated signalling and the role of Th17 dependent mechanisms for the mucosal antifungal defence are discussed. PMID- 20705511 TI - Identification of novel missense mutations of GDF9 in Chinese women with polycystic ovary syndrome. AB - The gene for growth differentiation factor 9 (GDF9) is expressed in human oocytes and has an important function in regulating early follicle growth and fertility. Polycystic ovary syndrome (PCOS) is one of the common defects that causes ovary dysfunction and is linked to aberrant processes in folliculogenesis. Previous studies have discovered several mutations in the screening of GDF9 in premature ovarian failure but none in PCOS. This current study focused on the mutational analysis of the coding region of GDF9 among 216 Chinese PCOS patients. Of the 10 different variants found in this study, five novel missense mutations in GDF9 were discovered namely c.15C>G, c.118T>G, c.133A>G, c.1025A>T and c.1275C>A. The above-mentioned mutations indicate GDF9 may be potentially associated with PCOS patients. As far as is known, this study is the first to provide evidence for such an association. PMID- 20705512 TI - Rheohaemapheresis. AB - The rheology of the blood as description of the flow characteristics approves conclusions to the perfusion of the different tissues. Many pathological processes influence the rheological qualities of the blood or the characteristics of the vessels, especially the capillaries. In both cases the perfusion of the tissue can be to a great extent disturbed. The rheological qualities of the blood can be ameliorated in different ways. Rheohaemapheresis is a very effective and save method to reduce high molecular plasma proteins. In the last decades in the meantime rheohaemapheresis was very successfully applied to treat age-related macular degeneration (AMD), idiopathic sudden hearing loss (ISHL), diabetic complications, coronary heart disease, small vessel disease, uveal effusion syndrome, central vein thrombosis of the eye and all other disorders of the microcirculatory system. PMID- 20705513 TI - Schistosomiasis elimination: lessons from the past guide the future. AB - Schistosomiasis is a major neglected tropical disease, with more than 200 million people infected and close to 800 million at risk. The disease burden is estimated to exceed 70 million disability-adjusted life-years. The anthelmintic drug praziquantel is highly effective in killing adult schistosome worms, but it is unable to kill developing schistosomes and so does not prevent reinfection. As a result, current praziquantel-based control programmes in Asia and sub-Saharan Africa are not effective or sustainable in the long term. The control of neglected tropical diseases, including schistosomiasis, is a funding priority for several donor agencies, with over US$350 million committed until 2013. Here we put forward an argument that donor funds would be more effectively spent on the development of a multi-faceted, integrated control programme, which would have a greater and longer lasting effect on disease transmission than the current chemotherapy-based programmes. The development of a transmission-blocking vaccine is also of great importance. A multi-faceted integrated control programme that incorporates a vaccine, even if only partly effective, has the potential to eliminate schistosomiasis. This integrated-approach model has the potential to improve the health of a billion of the world's poorest people and its effect cannot be underestimated. PMID- 20705514 TI - ACTs for schistosomiasis: do they act? PMID- 20705515 TI - The latest threat in the war on antimicrobial resistance. PMID- 20705516 TI - Efficacy of artesunate with sulfalene plus pyrimethamine versus praziquantel for treatment of Schistosoma mansoni in Kenyan children: an open-label randomised controlled trial. AB - BACKGROUND: Schistosomiasis is an important parasitic disease in Kenya. Decreasing susceptibility of schistosomes to praziquantel, the major drug used to reduce disease morbidity, has made assessment of new antischistosomal drugs a priority. We aimed to assess the safety and efficacy of an artesunate-based combination drug in the treatment of schistosomiasis. METHODS: In this open-label randomised trial in Rarieda district of western Kenya, we enrolled school children (aged 6-15 years) who had Schistosoma mansoni infection according to duplicate Kato-Katz thick smears from a stool sample. Computer-generated block randomisation was used to assign children (1:1) to receive artesunate (100 mg) with sulfalene (also known as sulfamethoxypyrazine; 250 mg) plus pyrimethamine (12.5 mg) as one dose every 24 h for 3 days or one dose of praziquantel (40 mg/kg per day). The primary efficacy endpoint was the number of participants cured 28 days after treatment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01054651. RESULTS: Between October and December, 2009, 212 children were enrolled and assigned to receive artesunate with sulfalene plus pyrimethamine (n=106) or praziquantel (n=106). 69 patients (65%) were cured in the praziquantel treatment group compared with 15 (14%) in the artesunate with sulfalene plus pyrimethamine treatment group (p<0.0001). Adverse events were less common in patients taking artesunate with sulfalene plus pyrimethamine than in those taking praziquantel (22% [n=23] vs 49% [n=52], p<0.0001), and no drug-related serious adverse events occurred. INTERPRETATION: The standard treatment with praziquantel is more effective than artesunate with sulfalene plus pyrimethamine in the treatment of children with S mansoni infection in western Kenya. Whether artemisinin-based combination therapy has a role in the treatment of schistosomiasis is unclear. PMID- 20705518 TI - Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. AB - Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this technique only reflects biological activity of the tumour indirectly by detecting the breakdown of the blood-brain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in diffusivity through the interstitial space (diffusion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice. PMID- 20705517 TI - Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. AB - BACKGROUND: Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-beta-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug resistant Enterobacteriaceae in India, Pakistan, and the UK. METHODS: Enterobacteriaceae isolates were studied from two major centres in India--Chennai (south India), Haryana (north India)--and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla(NDM-1) was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. FINDINGS: We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. INTERPRETATION: The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. PMID- 20705519 TI - Increased spontaneous production of VEGF by CD4+ T cells in type 1 diabetes. AB - In the present study we report that CD4(+) T cells from patients with type 1 diabetes produce significantly higher amounts of VEGF than respective cells from the healthy individuals. Among CD4(+) T cells memory subsets were the main source of VEGF. In addition, memory CD4(+) T subsets were the most numerous in patients with diabetic retinopathy (DR). DR was also characterized by significant increase of VEGF concentration in serum and culture supernatants. Hence, these data indicate that there is a sustained spontaneous production of VEGF by CD4(+) T cells in type 1 diabetes, which is additionally exacerbated in DR. In our opinion alterations in the proportions of CD4(+) T cell subsets and their VEGF production may be a useful tool for early assessment of the risk of DR onset and progression. PMID- 20705520 TI - Functional, metabolic, and synaptic changes after seizures as potential targets for antiepileptic therapy. AB - Little is known about how the brain limits seizure duration and terminates seizures. Depending on severity and duration, a single seizure is followed by various functional, metabolic, and synaptic changes that may form targets for novel therapeutic strategies. It is long known that most seizures are followed by a period of postictal refractoriness during which the threshold for induction of additional seizures is increased. The endogenous anticonvulsant mechanisms involved in this phenomenon may be relevant for both spontaneous seizure arrest and increase of seizure threshold after seizure arrest. Postictal refractoriness has been extensively studied in various seizure and epilepsy models, including electrically and chemically induced seizures, kindling, and genetic animal models of epilepsy. During kindling development, two antagonistic processes occur simultaneously, one responsible for kindling-like events and the other for terminating ictus and postictal refractoriness. Frequently occurring seizures may lead to an accumulation of postictal refractoriness that may last weeks. The mechanisms involved in seizure termination and postictal refractoriness include changes in ionic microenvironment, in pH, and in various endogenous neuromodulators such as adenosine and neuropeptides. In animal models, the anticonvulsant efficacy of several antiepileptic drugs (AEDs) is increased during postictal refractoriness, which is a logical consequence of the interaction between endogenous anticonvulsant processes and the mechanism of AEDs. As discussed in this review, enhanced understanding of these endogenous processes may lead to novel targets for AED development. PMID- 20705521 TI - Weakness and focal sensory deficits in the postictal state. AB - Postictal motor deficits may occur in patients following partial and generalized tonic-clonic seizures. Frequency is unclear, epidemiology being hampered by heterogeneous populations and variable methods of detection. Postictal paresis may affect any body part, may be bilateral, and may occur more frequently in seizures involving the sensorimotor cortex. Duration varies depending on the precise mode of testing from a few minutes to 36 hours. Sensory deficits following seizures have been rarely reported but may be missed if not specifically tested for. The lateralizing value of postical paresis is high (>90%), pointing to a seizure origin in the opposite frontal lobe. Postictal paresis often is lesion associated and should encourage MRI, particularly in new onset epilepsy. Etiology is unclear, neuronal exhaustion and hyperinhibition being the main pathophysiological theories discussed. As disability from seizures may be increased, postictal paresis should more systematically be asked and tested for and should also be included when evaluating the success of anticonvulsive treatment. PMID- 20705522 TI - Historical perspectives and definitions of the postictal state. AB - The postictal state and its features were recognized by physicians from Babylonian times through to the advent of modern neurology in the late 19th century. Among varied descriptions and definitions lies one of the best known and still used eponyms in medicine, Todd's paralysis. Despite a relative lack of biological insight, many key observations were made in an era mostly devoid of treatments for epilepsy. PMID- 20705524 TI - Recurrent subconjunctival hemorrhages leading to the discovery of ocular adnexal lymphoma. AB - BACKGROUND: Subconjunctival hemorrhages commonly occur idiopathically or from causes including ocular surgery, trauma, anticoagulation medications, or a Valsalva maneuver. When a hemorrhage persists or recurs, a more extensive list of differential diagnoses must be considered. This report details a case in which persistent subconjunctival hemorrhages led to the discovery of ocular adnexal lymphoma. CASE REPORT: A 68-year-old white man presented with a 7- to 8-month history of a recurrent red left eye. There was no associated pain, discharge, or change in vision over that time. The right eye was never involved. An ocular examination of the left eye found a mild nasal subconjunctival hemorrhage and a salmon-pink-colored lesion involving the superior conjunctiva. Clinical findings, photos, magnetic resonance images, and histopathology results are presented and reviewed. The signs, symptoms, incidence, pathophysiology, treatment, and prognosis of ocular adnexal lymphoma are also discussed. CONCLUSION: Lymphomas can occur in a variety of sites in the body. It is well documented that primary tumors can originate in the ocular adnexa. Although not typical, the first sign in this case was a recurrent subconjunctival hemorrhage. The importance of a thorough ocular examination is paramount for a patient's ocular health and possibly the patient's life. PMID- 20705523 TI - The antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3 beta, in mice. AB - We investigated the antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in mice. A 30-minute pretreatment with AR-A014418 (.1 and 1 mg/kg, intraperitoneal [ip]) inhibited nociception induced by an ip injection of acetic acid. AR-A014418 pretreatment (.1 and .3 mg/kg, ip) also decreased the late (inflammatory) phase of formalin-induced licking, without affecting responses of the first (neurogenic) phase. In a different set of experiments, AR-A014418 (.1-10 MUg/site) coinjected intraplantarly (ipl) with formalin inhibited the late phase of formalin-induced nociception. Furthermore, AR-A014418 administration (1 and 10 ng/site, intrathecal [it]) inhibited both phases of formalin-induced licking. In addition, AR-A014418 coinjection (10 ng/site, it) inhibited nociception induced by glutamate, N-methyl-D-aspartate (NMDA), (+/-)-1-aminocyclopentane-trans-1,3 dicarboxylic acid (trans-ACPD), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) by 47 +/- 12%, 48 +/- 11%, 31 +/- 8%, 46 +/- 13%, and 44 +/- 11%, respectively. In addition, a 30-minute pretreatment with NP031115 (3 and 10 mg/kg, ip), a different GSK-3 beta inhibitor, also attenuated the late phase of formalin-induced nociception. Collectively, these results provide convincing evidence that AR-A014418, given by local, systemic, and central routes, produces antinociception in several mouse models of nociception. The AR A014418-dependent antinociceptive effects were induced by modulation of the glutamatergic system through metabotropic and ionotropic (NMDA) receptors and the inhibition of the cytokine (TNF-alpha and IL-1beta) signaling. PERSPECTIVE: These results suggest that GSK-3beta may be a novel pharmacological target for the treatment of pain. PMID- 20705525 TI - A novel ytterbium-169 brachytherapy source and delivery system for use in conjunction with minimally invasive wedge resection of early-stage lung cancer. AB - PURPOSE: To describe a novel source-delivery system for intraoperative brachytherapy in patients with early-stage lung cancer that is readily adaptable to a video-assisted thoracoscopic surgery approach and can be precisely delivered to achieve optimal dose distribution. METHODS AND MATERIALS: Radioactive ytterbium-169 ((169)Yb) was sealed within a titanium tube 0.28 mm in diameter and then capped and resealed by titanium wires laser welded to the tube to serve as the legs of a tissue-fastening system. Dose simulations were performed using Monte Carlo computer code (Los Alamos National Laboratory, Los Alamos, NM) to mimic the geometric and elemental compositions of the source, fastening apparatus, and surroundings. RESULTS: Five test source capsules were subjected to a tensile load to failure. Failure in each capsule occurred in the wire of the fastener leg; there were no weld failures. Monte Carlo simulations and subsequent dose measurement showed the perturbation by the source legs in the deployed (bent over) position to be small (4-5%) for (169)Yb and much less than that for iodine 125 (32%). CONCLUSION: We have developed a (169)Yb brachytherapy source-delivery system that can be used in conjunction with commercially available surgical stapling instruments, facilitates the precise placement of brachytherapy sources relative to the surgical margin, assures the seeds remain fixed in their precise position for the duration of the treatment, overcomes the technical difficulties of manipulating the seeds through the narrow surgical incision associated with video-assisted thoracoscopic surgery, and reduces the radiation dose to the clinicians. PMID- 20705526 TI - [Diabetic ketoacidosis as the first manifestation of a mixed growth hormone and prolactin-secreting tumor]. PMID- 20705527 TI - [Myofibroblastic tumour, Mycobacterium avium infection and interferon-gamma pathway]. PMID- 20705528 TI - 'Black Salve' and melanomas. PMID- 20705529 TI - Venous malformation associated nerve profiles and pain: an immunohistochemical study. AB - INTRODUCTION: More than 90% of venous malformations (VM) are associated with pain, which is presumed related to phlebolith formation and subsequent nociceptive mediator release. Increasing evidence supports a link between angiogenesis and nerve patterning. Since vascular malformations are aberrations of angiogenesis, it was hypothesised VM pain may be due to differences in nerve profiles associated with these lesions. METHODS: Immunohistochemical staining was performed on retrospective archival paraffin embedded samples of arteriovenous (AVM; n = 9), capillary (CM; n = 4), lymphatic (LM; n = 29) and VM (n = 14). Antibodies to three nerve markers, neurofilament, S100 and protein gene product 9.5 were employed. Light microscopy was used to assess the density of interstitial nerves and nervi vasorum, and assessments were validated by a second investigator. Significance testing was performed using Mann-Whitney U and Fisher's exact tests. RESULTS: There was no significant difference in nerve profile between VM and AVM or CM. LM and normal control skin each exhibited a lower nerve density compared to VM (p < 0.0075). The presence of nervi vasorum was found to be lower in VM than normal cutaneous controls when immunostained with S100 antibody (p = 0.044). CONCLUSION: VM-associated pain is unlikely to be due to simple anatomical differences in nerve structure in this condition. As the nerve profile between VM and normal cutaneous control appears to be distinct, further work may elucidate common neurogenic/angiogenic mediators in the pathogenesis of vascular malformations which could prove targets in treating these conditions. In the meantime, current regimes of compression and non steroidal anti-inflammatory drugs should be continued. PMID- 20705531 TI - Hospitalized wrist fractures in France: Incidence and burden trend changes. AB - INTRODUCTION: The aim of this study was to assess the burden of hospitalized wrist fractures between 2002 and 2006 in France. METHODS: Data were drawn from the French Hospital National Database. The number of admissions and the incidence rates were described as well as the type of entry and discharge from hospital, length of stay, and 2006 in-patients costs. RESULTS: In 2002 and 2006, 38,710 and 38,979 hospitalizations for wrist fractures were registered respectively. The incidence rate of fractures increased with age whatever the year and decreased significantly from 2002 to 2006. Length of stay and mean inpatients costs increased with age. The overall in-patients 2006 costs was 79 millions with an average individual cost of 2100 ? per hospitalized wrist fractures. CONCLUSION: The incidence of hospitalizations for wrist fractures decreased in 2006 compared to 2002. The number of hospitalizations increased, as a consequence of ageing, (except for wrist fracture in men), with a subsequent increase in cost related to these fractures. The increase with age outlines the role of underlying osteoporosis and the relevance of appropriate care of patients at risk of for such fractures. LEVEL OF EVIDENCE: IV. PMID- 20705532 TI - Irreducible Pipkin II femoral head fractures: Is transgluteal approach the best strategy? AB - Femoral head fracture-dislocations (FHFD) are rare, while irreducible cases are even less frequent. Truly irreducible fractures such as the two cases in this report must be differentiated from incomplete reduction due to incarcerated bone or soft tissue interposition. Opinions vary on the surgical approach to be used once the hip is reduced and the fragment of the femoral head yet remains to be stabilized. Reports in the literature do not usually take into account the specificity of irreducible lesions, which in our opinion should be treated by the transgluteal approach (TGA) while reducible forms can be treated by the Hueter approach. The transgluteal approach with the patient in the lateral decubitus position provides a direct anterior view of the antero-infero-medial fracture site as well as dorsal access via the injuries occasioned to dorsal soft tissues by the posterolateral dislocation. A lag screw can be used with this approach, which is the only way to stabilize the ligament teres femoris attachment. LEVEL OF EVIDENCE: Level IV retrospective historical study. PMID- 20705533 TI - The impact of menopausal hormone therapy on the incidence of different breast cancer types--data from the Cancer Registry Hamburg 1991-2006. AB - BACKGROUND: The publication of the Women's Health Initiative Study [1] in 2002 and the Million Women Study [31] in 2003 on the association of menopausal hormone therapy (HT) and breast cancer were followed by a decrease in the prescription of HT to menopausal women in western countries. In the following years several papers from different countries reported declines in breast cancer incidence and discuss whether this decline is related to the decreased use of menopausal hormone therapy. METHODS: We contribute further data by analysing breast cancer incidence rates from the Hamburg Cancer Registry, Germany, for the time period 1991-2006 and HT use data from a large case-control study conducted in the Hamburg region. At first we determined whether there is a decline in breast cancer incidence in 2002/2003. To find supporting evidence for a causal relationship between breast cancer incidence and use of menopausal hormones we addressed the following issues: The decline in incidence should be more pronounced in the age groups, in which HT is used predominantly, i.e. age group 50-69. The decline in incidence should be most pronounced for breast cancer types more strongly associated with HT, i.e. invasive lobular cancer. RESULTS: We observed a statistical significant decline in incidence of all invasive breast cancer in 2002/2003 in Hamburg. The increase in breast cancer incidence as well as the decline was most pronounced in the age group 50-69. Regarding the histological types of tumours in this age group the decline was only pronounced for invasive lobular cancer. The estimated prevalence of HT indicates a decreasing hormone use starting in 2001/2002. We found a strong decrease in prescriptions for menopausal hormone therapy between 2002 and 2005. CONCLUSION: In summary, our data add to the evidence of a relation between breast cancer incidence and menopausal hormone use. PMID- 20705534 TI - Effects of the renin inhibitor MK-8141 (ACT-077825) in patients with hypertension. AB - The renin inhibitor MK-8141 (ACT-077825) demonstrates substantial immunoreactive active renin (ir-AR) increase (sevenfold) without a persistent plasma renin activity (PRA) decrease. The present study assessed the antihypertensive efficacy of MK-8141 in hypertensive patients. In this double-blind, placebo- and active comparator-controlled study, 195 patients with hypertension (trough sitting diastolic blood pressure >=92 to <105 mm Hg, trough sitting systolic blood pressure <170 mm Hg, and 24-hour mean diastolic blood pressure [DBP] >=80 mm Hg) were randomized to one of four treatments (stratified by race, black versus others): MK-8141 250 mg, MK-8141 500 mg, enalapril 20 mg, or placebo. Blood pressure was measured at trough and as 24-hour ambulatory blood pressure monitoring. The primary end point was change from baseline in 24-hour mean ambulatory DBP measured after 4 weeks. At week 4, the change from baseline in 24 hour mean (95% CI) ambulatory DBP compared with placebo was -1.6 mm Hg (-4.2, 1.1), -1.1 mm Hg (-3.9, 1.6), and -4.9 (-7.5, -2.2) for MK-8141 250 mg, MK-8141 500 mg, and enalapril 20 mg, respectively. Only mean ambulatory DBP-lowering with enalapril 20 mg was statistically significant. Enalapril, but not MK-8141, also significantly lowered 24-hour mean ambulatory systolic blood pressure (SBP) compared with placebo (-6.7 mm Hg [-10.5, -2.8]). Neither enalapril nor MK-8141 significantly lowered trough DBP and SBP compared with placebo. MK-8141 was generally well tolerated. In patients with hypertension, MK-8141 (ACT-077825) did not produce significant blood pressure-lowering efficacy despite a demonstrated effect of the drug on ir-AR, in the absence of durable PRA suppression. PMID- 20705535 TI - The distribution and speciation of trace metals in surface sediments from the Pearl River Estuary and the Daya Bay, Southern China. AB - Surface sediments collected from the Pearl River Estuary (PRE) and the Daya Bay (DYB) were analyzed for total metal concentrations and chemical phase partitioning. The total concentrations of Cr, Cu, Ni, Pb, and Zn in the PRE were obviously higher than those in DYB. The maximum concentrations of trace metals in DYB occurred in the four sub-basins, especially in Dapeng Cove, while the concentrations of these metals in the western side of the PRE were higher than those in the east side. Such distribution pattern was primarily due to the different hydraulic conditions and inputs of anthropogenic trace metals. The chemical partitioning of metals analyzed by the BCR sequential extraction method showed that Cr, Ni, and Zn of both areas were present dominantly in the residual fraction, while Pb was found mostly in the non-residual fractions. The partitioning of Cu showed a significant difference between the two areas. PMID- 20705536 TI - Gulf braced for the big clean-up. AB - Earlier oil spills suggest the Gulf may be in for the long haul to recover from this year's disaster. PMID- 20705537 TI - Population in the spotlight. AB - A new inquiry hopes to highlight the issue of population, ignored by most politicians. PMID- 20705538 TI - Cuts spark university rethink. AB - Britain's new government is thinking aloud about radical changes to university funding and other countries are also considering the future. PMID- 20705539 TI - Arctic reality. AB - The threat to the Hudson Bay polar bears highlights the reality of a changing climate under attack from sceptics. PMID- 20705540 TI - Local moulding. AB - New studies suggest the extent to which fungi are local to their indoor habitats. PMID- 20705541 TI - Panama's frog decline. PMID- 20705542 TI - Q&A: Elizabeth C. Raff. PMID- 20705543 TI - XRCC1 deficiency sensitizes human lung epithelial cells to genotoxicity by crocidolite asbestos and Libby amphibole. AB - BACKGROUND: Asbestos induces DNA and chromosomal damage, but the DNA repair pathways protecting human cells against its genotoxicity are largely unknown. Polymorphisms in XRCC1 have been associated with altered susceptibility to asbestos-related diseases. However, it is unclear whether oxidative DNA damage repaired by XRCC1 contributes to asbestos-induced chromosomal damage. OBJECTIVES: We sought to examine the importance of XRCC1 in protection against genotoxic effects of crocidolite and Libby amphibole asbestos. METHODS: We developed a genetic model of XRCC1 deficiency in human lung epithelial H460 cells and evaluated genotoxic responses to carcinogenic fibers (crocidolite asbestos, Libby amphibole) and nongenotoxic materials (wollastonite, titanium dioxide). RESULTS: XRCC1 knockdown sensitized cells to the clastogenic and cytotoxic effects of oxidants [hydrogen peroxide (H2O2), bleomycin] but not to the nonoxidant paclitaxel. XRCC1 knockdown strongly enhanced genotoxicity of amphibole fibers as evidenced by elevated formation of clastogenic micronuclei. Crocidolite induced primarily clastogenic micronuclei, whereas Libby amphibole induced both clastogenic and aneugenic micronuclei. Crocidolite and bleomycin were potent inducers of nuclear buds, which were enhanced by XRCC1 deficiency. Libby amphibole and H2O2 did not induce nuclear buds, irrespective of XRCC1 status. Crocidolite and Libby amphibole similarly activated the p53 pathway. CONCLUSIONS: Oxidative DNA damage repaired by XRCC1 (oxidized bases, single-strand breaks) is a major cause of chromosomal breaks induced by crocidolite and Libby amphibole. Nuclear buds are a novel biomarker of genetic damage induced by exposure to crocidolite asbestos, which we suggest are associated with clustered DNA damage. These results provide mechanistic evidence for the epidemiological association between XRCC1 polymorphisms and susceptibility to asbestos-related disease. PMID- 20705544 TI - Impact of a citywide sanitation program in Northeast Brazil on intestinal parasites infection in young children. AB - BACKGROUND: Sanitation affects health, especially that of young children. Residents of Salvador, in Northeast Brazil, have had a high prevalence of intestinal parasites. A citywide sanitation intervention started in 1996 aimed to raise the level of sewer coverage from 26% to 80% of households. OBJECTIVES: We evaluated the impact of this intervention on the prevalence of Ascaris lumbricoides, Trichuris trichuria, and Giardia duodenalis infections in preschool children. METHODS: The evaluation was composed of two cross-sectional studies (1998 and 2003-2004), each of a sample of 681 and 976 children 1-4 years of age, respectively. Children were sampled from 24 sentinel areas chosen to represent the range of environmental conditions in the study site. Data were collected using an individual/household questionnaire, and an environmental survey was conducted in each area before and after the intervention to assess basic household and neighborhood sanitation conditions. Stool samples were examined for the presence of intestinal parasites. The effect of the intervention was estimated by hierarchical modeling, fitting a sequence of multivariate regression models. FINDINGS: The prevalence ofA. lumbricoides infection was reduced from 24.4% to 12.0%, T. trichuria from 18.0% to 5.0%, and G. duodenalis from 14.1% to 5.3%. Most of this reduction appeared to be explained by the increased coverage in each neighborhood by the sewage system constructed during the intervention. The key explanatory variable was thus an ecological measure of exposure and not household-based, suggesting that the parasite transmission prevented by the program was mainly in the public (vs. the domestic) domain. CONCLUSION: This study, using advanced statistical modeling to control for individual and ecological potential confounders, demonstrates the impact on intestinal parasites of sanitation improvements implemented at the scale of a large population. PMID- 20705545 TI - Can emotion modulate attention? Evidence for reciprocal links in the attentional network test. AB - Evolution theory suggests that adaptive behavior depends on our ability to give preferential attention to emotional information when it is necessary for our survival, and to down-regulate irrelevant emotional influence. However, empirical work has shown that the interaction between emotion and attention varies, based on the attentional network in question. The aim of the current research was to examine the influence of stimulus emotionality on attention in three attentional networks: alerting, orienting, and executive functions. In two studies, using negative and neutral cues in a modified version of the Attention Network Test, it was found that negative cues impaired task performance in the absence of executive conflict, but not when executive processes were activated. Moreover, it was found that the influence of negative cues on task performance in a given trial was attenuated following activation of executive processes in the previous trial. These results suggest that when executive resources are required, inhibitory mechanisms are recruited to decrease the disruptive effect of emotional stimuli. More importantly, these findings indicate that the effect of emotional stimuli on attention is down-regulated both during cognitive conflict and after the conflict has already ended. PMID- 20705546 TI - Representation of categories. AB - In the present study we investigated whether the mental representation of the concept categories is represented by the container image schema (Lakoff & Johnson, 1980). In two experiments participants decided whether two pictures were from the same category (animal or vehicle). Pictures were presented inside or outside a frame that should activate the container schema. We found that performance to pictures was influenced by the frame in congruence with the metaphorical mapping (same category-inside bounded region; different category-not in same bounded region). These results show that the concept categories is metaphorically represented by containers. PMID- 20705547 TI - Across-notation automatic processing of two-digit numbers. AB - The existence of across-notation automatic numerical processing of two-digit (2D) numbers was explored using size comparisons tasks. Participants were Arabic speakers, who use two sets of numerical symbols-Arabic and Indian. They were presented with pairs of 2D numbers in the same or in mixed notations. Responses for a numerical comparison task were affected by decade difference and unit decade compatibility and global distance in both conditions, extending previous findings with Arabic digits (Nuerk, Weger, & Willmes, 2001). Responses for a physical comparison task were affected by congruency with the numerical size, as indicated by the size congruency effect (SiCE). The SiCE was affected by unit decade compatibility but not by global distance, thus suggesting that the units and decades digits of the 2D numbers, but not the whole number value were automatically translated into a common representation of magnitude. The presence of similar results for same- and mixed-notation pairs supports the idea of an abstract representation of magnitude. PMID- 20705548 TI - The interplay of experience-based affective and probabilistic cues in decision making: arousal increases when experience and additional cues conflict. AB - In a study using behavioral and physiological measures we induced experience based affective cues (i.e., differential anticipatory arousal) toward a risky and a safe option by letting participants repeatedly select between two decks of cards with feedback. In later test decisions we presented choice tasks between these trained and new pairs of decks. In some of the trials a low-valid probabilistic cue was provided after stimulus onset but before the decision. Although we were successful in inducing experience-based affective cues these did not influence participants' choices. In decisions without any further cues available people choose the safe and the risky option about equally often. If an additional low-valid probabilistic cue was available people followed this cue. Although experience had no effect on choices it influenced arousal. Anticipatory physiological arousal increased if the probabilistic cue and experience were conflicting. Our results are in line with recent findings indicating diminished loss aversion in experience-based decision making. They are also consistent with parallel constraint satisfaction models and shed light on the interrelation between experience, probabilistic cues, and arousal in decision making. PMID- 20705549 TI - On the decay of distractor-response episodes. AB - Distractor-to-distractor repetition effects can be explained by retrieval and/or inhibitory processes. Interestingly, the two accounts predict different effects from repeated distractors: Inhibition theories always predict benefits, whereas stimulus-response-retrieval theories predict an interaction of response repetition and distractor repetitions, resulting in benefits with response repetitions and costs with response changes. In the present experiment the time course and the temporal separability of a stimulus-response episode on distractor to-distractor repetitions were analyzed. The results showed that the interaction of response repetition and distractor repetitions was affected by a simple decay function. In addition, distractor repetition effects were affected by the temporal separability. In concert, the data yield evidence for retrieval-based explanations of distractor-to-distractor repetitions. PMID- 20705550 TI - Parallel constraint satisfaction in memory-based decisions. AB - Three studies sought to investigate decision strategies in memory-based decisions and to test the predictions of the parallel constraint satisfaction (PCS) model for decision making (Glockner & Betsch, 2008). Time pressure was manipulated and the model was compared against simple heuristics (take the best and equal weight) and a weighted additive strategy. From PCS we predicted that fast intuitive decision making is based on compensatory information integration and that decision time increases and confidence decreases with increasing inconsistency in the decision task. In line with these predictions we observed a predominant usage of compensatory strategies under all time-pressure conditions and even with decision times as short as 1.7 s. For a substantial number of participants, choices and decision times were best explained by PCS, but there was also evidence for use of simple heuristics. The time-pressure manipulation did not significantly affect decision strategies. Overall, the results highlight intuitive, automatic processes in decision making and support the idea that human information-processing capabilities are less severely bounded than often assumed. PMID- 20705551 TI - [Questionnaire for assessing the risk of venous thromboembolism in hospitalized surgical and non-surgical patients in the 4th Hungarian antithrombotic guideline entitled "Risk reduction and treatment of venous thromboembolism"]. AB - A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed. PMID- 20705552 TI - [Genetic background of the efficacy of cholesterol absorption. The role of Niemann-Pick C1-like 1 receptor and its genetic variations in lipid metabolism]. AB - Niemann-Pick C1-like 1 is a sterol sensing domain-containing transmembrane protein that is highly expressed on the apical surface of absorptive enterocytes. Previous studies proved that this protein facilitates the movement of free cholesterol from the gut lumen into enterocytes. Biochemical studies showed that Niemann-Pick C1-like 1 is the target of ezetimibe, a potent cholesterol absorption inhibitor. Recent studies show that genetic variation in Niemann-Pick C1-like 1 may be responsible for the inter-individual variability observed in the rates of intestinal cholesterol absorption and the response to ezetimibe. PMID- 20705553 TI - [Treatment of acromegaly]. AB - Growth hormone (GH) hypersecretion leads to acromegaly which is associated with several co-morbidities and increased mortality. Despite of the typical clinical features and modern diagnostic tools, it often takes years from the onset of the disease until the diagnosis. The aims of the treatment are to reduce or control the tumor growth, inhibit the GH hypersecretion, normalize the insulin-like growth factor-I (IGF-I) levels, treat the co-morbidities and therefore reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonist, somatostatin analogues and GH receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management. PMID- 20705554 TI - [Two hundredth birth anniversary of Frederic Chopin. Was Chopin's illness actually tuberculosis?]. PMID- 20705557 TI - The ongoing debate about nodes. PMID- 20705558 TI - Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer. AB - PURPOSE: The aim of this study was to estimate the cost-effectiveness of adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer from a US health care system perspective. MATERIALS AND METHODS: A Markov model was developed to predict disease progression, mortality, and costs of breast cancer care for premenopausal women with hormone receptor-positive early breast cancer receiving up to 3 years of (1) endocrine therapy (goserelin plus tamoxifen or anastrozole); or (2) endocrine therapy plus zoledronic acid. Model parameters were obtained from ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group Trial-12) and the literature. The incremental cost per quality-adjusted life year (QALY) gained with zoledronic acid was calculated under 2 scenarios: (1) benefits of zoledronic acid persist to maximum (7 years) follow-up in ABCSG-12 ("trial benefits") or (2) benefits persist until death ("lifetime benefits"). RESULTS: Adding zoledronic acid to endocrine therapy was projected to yield a gain of 0.41 life years (LYs) and 0.43 QALYs assuming trial benefits and 1.34 LYs and 1.41 QALYs assuming lifetime benefits. Assuming trial benefits, the incremental cost per QALY gained with zoledronic acid was $9300. Assuming lifetime benefits, zoledronic acid was estimated to increase QALYs and reduce costs. Cost per QALY gained was 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%). CONCLUSION: Weekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent. PMID- 20705561 TI - Effect of trastuzumab on health-related quality of life in patients with HER2 positive metastatic breast cancer: data from three clinical trials. AB - BACKGROUND: Trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) provides clinical benefit when combined with chemotherapy or as monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Given the demonstrated improvement in standard outcomes, it is important to assess this therapy's effect on patients' health-related quality of life (HRQOL). PATIENTS AND METHODS: The QLQ-C30 and BR-23 questionnaires were used to assess global HRQOL; physical, social, and role functioning; and fatigue as secondary endpoints in trials of trastuzumab monotherapy (H0649g and H0650g) or in combination with chemotherapy (H0648g). Patients completed assessments at baseline, week 8 (H0648g only), and at 12-week intervals until disease progression. RESULTS: In H0648g (n = 400), more patients exhibited improved global QOL in the chemotherapy-plus trastuzumab versus chemotherapy arms (51% vs. 36%; P < .05). In the chemotherapy plus-trastuzumab arm, fatigue was significantly improved at week 32 (chemotherapy completed at week 20) compared with baseline in both study arms (P < .05); more patients in the chemotherapy-plus-trastuzumab arm also showed improved physical and role functioning. Subscale scores in H0649g (n = 154) and H0650g (n = 74) were similar at all time points. In H0649g, clinical responders showed meaningful improvements (>or= 10 points) in all 5 subscales by week 12 through week 36. Nonresponders had meaningful decreases in all subscale scores. In H0650g, clinical responders exhibited meaningful increases in social and role functioning and global QOL by week 12; nonresponder scores worsened for all subscales. CONCLUSION: Trastuzumab has a beneficial effect on HRQOL in patients with HER2 positive MBC, particularly those with responsive disease. PMID- 20705562 TI - Breast cancer classification according to immunohistochemistry markers: subtypes and association with clinicopathologic variables in a peruvian hospital database. AB - BACKGROUND: Molecular classification is an excellent prognostic and predictive method in breast cancer (BC). In this study. we evaluated differences in clinicopathologic features and overall survival (OS) in four BC molecular subtypes: luminal A, luminal B, basal cell-like, and HER2/neu. PATIENTS AND METHODS: Immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PgR), and HER2 was performed using a Peruvian hospital database of 1198 BC patients who were diagnosed between 2000 and 2002. Overall survival was calculated. RESULTS: Out of 1198 patients with invasive BC, 49.3% were luminal A; 13.2%, luminal B; 21.3%, basal-like; and 16.2%, HER2. The mean of age at diagnosis was 51.5 years for luminal A; 49.6 for luminal B; 49.5 for basal-like; and 49.4 for HER2. The HER2 subtype showed 63.7% positive lymph nodes, 42.3% stage III and 9.7% stage IV cases. Basal subtypes showed the highest prevalence of a poorly differentiated phenotype (70.3%). Average follow-up was 60 months. Five-year OS was significantly different between all 4 groups (P < .0001); luminal A had the highest OS, followed by luminal B, basal-like; and HER2. Results are compared with other population studies. CONCLUSION: This study shows significant differences between the distribution of molecular subtypes and clinicopathologic features. Immunohistochemistry is useful in the clinical management of BC patients. PMID- 20705563 TI - Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. AB - BACKGROUND: The concept of metronomic chronic administration of low-dose chemotherapy has become relevant for the treatment of cancer in the last several years. This study sought to determine the safety and activity of oral vinorelbine (VNB), using a metronomic schedule of administration, in elderly patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: From October 2004 to March 2007, 34 patients with MBC (median age, 74 years; range, 70-84 years) were treated with oral VNB at 70 mg/m2, fractionated on days 1, 3, and 5, for 3 weeks on and 1 week off, every 4 weeks, for a maximum of 12 cycles. The objective response rate was the primary endpoint. RESULTS: All 34 patients received at least 3 cycles of therapy and were evaluable. Two achieved complete responses (6%), and 11 achieved partial responses (32%). Median progression-free survival and median overall survival entailed 7.7 months (95% confidence interval, 6.9 9.05 months) and 15.9 months (95% CI, 13.1-15.91 months), respectively, for all patients. CONCLUSION: The fractionated administration of oral VNB is well tolerated and presents promising activity in elderly patients with metastatic cancer, warranting further investigation in combination with other chemotherapy agents. PMID- 20705564 TI - A phase II trial of docetaxel with bevacizumab as first-line therapy for HER2 negative metastatic breast cancer (TORI B01). AB - INTRODUCTION: Addition of the antiangiogenic agent bevacizumab to paclitaxel significantly improves response rates and progression-free survival for metastatic breast cancer (MBC). To assess the activity of docetaxel plus bevacizumab, a multicenter phase II trial was conducted. PATIENTS AND METHODS: Patients with measurable first-line HER2/neu-negative MBC were eligible. This trial began as a 2-arm study with a docetaxel-alone arm. When bevacizumab became widely available, it was converted to a 1-arm open-label trial of docetaxel/bevacizumab. Patients enrolled in the docetaxel-alone arm were permitted to cross over to docetaxel/bevacizumab. Patients received bevacizumab 15 mg/kg and docetaxel 75 mg/m2 intravenously (I.V.) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. RESULTS: From March 2005 to September 2006, 76 patients were enrolled. Of the 7 patients who were randomized to docetaxel alone, 6 crossed over to docetaxel/bevacizumab (included in the safety analysis only). Two patients were found to be ineligible before receiving drug. Efficacy data are based on the 67 patients who were originally enrolled in the docetaxel/bevacizumab arm and received at least 1 dose of study medication. The confirmed objective response rate is 51% (34 of 67) with 9% complete responses (6 of 67) and 42% partial responses (28 of 67). Nine additional patients (13%) had stable disease lasting >or= 6 months. With a median follow-up of 21.7 months, the median time to progression is 9.3 months, and median overall survival is 26.3 months. Common grade 3/4 adverse events included neutropenia (33%), leukopenia/lymphopenia (25%), fatigue (22%), infection (17%), pain (16%), and hypertension (9%). CONCLUSION: Docetaxel/bevacizumab was generally well tolerated with manageable toxicity and promising efficacy results. PMID- 20705565 TI - Exemestane and chemotherapy as first-line treatment of metastatic breast cancer: results of a phase II study. AB - BACKGROUND: Metastatic breast cancer remains largely incurable. Strategies involving the combination of the selective estrogen receptor modulator tamoxifen and chemotherapy have been abandoned in view of unacceptable toxicity because of thromboembolic events. The aim of this study was to investigate the safety and efficacy of the third-generation steroidal aromatase inhibitor exemestane plus chemotherapy. PATIENTS AND METHODS: Postmenopausal women with advanced breast cancer received 6 cycles of intravenous chemotherapy (5-fluorouracil [5-FU], epirubicin, and cyclophosphamide) and exemestane 25 mg/day that was continued after chemotherapy was completed. The primary efficacy endpoint was time to progression (TTP), and response rates were also assessed. Safety was assessed from adverse events. RESULTS: Twenty-three patients (median age, 62 years) were included in this study. Twenty patients completed 6 chemotherapy cycles. Median TTP was 13.7 months. Overall response was achieved by 20 patients (73.9%), and the clinical benefit rate was 87%. During the chemotherapy plus exemestane treatments, 50 adverse events were reported in 14 of the 23 patients (60.9%). As expected, the incidence of adverse events decreased during the phase of exemestane treatment alone (19 adverse events in 10 of 20 patients [50%]). There were 2 grade 4 events reported, pulmonary embolism and pneumonia, although pneumonia was not considered to be related. CONCLUSION: Although a small number of patients were included, the combination of exemestane and chemotherapy was well tolerated and only 1 thromboembolic event was reported. Response rates were similar to other comparable series and may encourage further studies to confirm the efficacy of chemotherapy in combination with an aromatase inhibitor. PMID- 20705566 TI - Axillary lymph node involvement in women with breast cancer: does it depend on age? AB - INTRODUCTION: Despite the reduced aggressiveness of breast cancer with older age, elderly patients are diagnosed with larger and more advanced tumors compared with younger patients. We studied the specific relationship between lymph node (LN) involvement and age. PATIENTS AND METHODS: Data were analyzed on 12,152 consecutive breast cancer patients who were operated on between 1995 and 2006 in a single institution. Cubic spline logistic models were used. RESULTS: LN involvement was present in 5409 patients (44.5%). Median age was 52 years; median tumor diameter was 1.7 cm; 83.4% had positive estrogen receptors; and 15.3% had human epidermal growth factor receptor (HER)2/neu overexpression. At the univariate analysis, the probability of LN involvement decreased with increasing age up to approximately 65 years, but it increased thereafter. However, when investigating the relationship in pT strata, after adjusting for other prognostic factors, we observed no increase of LN involvement probability in elderly patients. CONCLUSION: Increasing risk of LN involvement in the elderly can be explained by delayed diagnosis in this age group. Lack of systematic screening programs for this subpopulation and tendency of the elderly to wait longer before consulting a physician might be blamed. Aging per se does not increase the risk of LN involvement. PMID- 20705567 TI - Primary breast lymphoma after mastectomy with reconstruction. AB - Primary breast lymphoma accounts for only 0.05%-1.1% of all breast malignancies, and less than 1% of all cases of non-Hodgkin lymphoma. Although primary breast lymphoma may present clinical similarities to breast carcinoma, the majority of cases lack the typical features of breast malignancy or lymphoma. We describe a case of primary breast lymphoma in a reconstructed breast, 8 years after a mastectomy for breast cancer. To the best of our knowledge, this is the first reported case in the worldwide literature of primary breast lymphoma in a reconstructed breast. We will discuss the diagnostic and treatment strategies involved in the management of primary breast lymphoma, and the effect of breast reconstruction on the detection of recurrent breast cancer. PMID- 20705569 TI - Hormone D deficiency--a serious endocrine disorder. PMID- 20705570 TI - Quantum leap in the AEOH impact factor. PMID- 20705571 TI - Asbestos is still with us: repeat call for a universal ban. AB - All forms of asbestos are proven human carcinogens. All forms of asbestos cause malignant mesothelioma, lung, laryngeal, and ovarian cancers, and may cause gastrointestinal and other cancers. No exposure to asbestos is without risk. Asbestos cancer victims die painful lingering deaths. These deaths are almost entirely preventable. When evidence of the carcinogenicity of asbestos became incontrovertible, concerned parties, including the Collegium Ramazzini, called for a universal ban on the mining, manufacture, and use of asbestos in all countries around the world (J Occup Environ Med. 1999;41:830-832). Asbestos is now banned in 52 countries, and safer products have replaced many materials that once were made with asbestos. Nonetheless, a large number of countries still use, import, and export asbestos and asbestos-containing products. And in many countries that have banned other forms of asbestos, the so-called "controlled use" of chrysotile asbestos is exempted from the ban, an exemption that has no basis in medical science but rather reflects the political and economic influence of the asbestos mining and manufacturing industry. All countries of the world have an obligation to their citizens to join in the international endeavor to ban all forms of asbestos. An international ban on asbestos is urgently needed. PMID- 20705572 TI - Prenatal DDT exposure and testicular cancer: a nested case-control study. AB - The authors examined maternal serum levels of DDT-related compounds in relation to son's risk of testicular cancer 30 years later. Fifteen of 9,744 live-born sons were diagnosed with germ cell testicular cancer and had maternal serum samples. Cases were matched to three controls on race and birth year. Maternal serum DDT-related compounds, measured in the early postpartum, were associated with her son's risk of testicular cancer. Despite low statistical power, we observed that mothers of cases had a significantly higher ratio of p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) to p,p'-DDE (1,1'-dichloro-2,2' bis(p-chlorophenyl)ethylene) and lower o,p'-DDT (1,1,1-tricholoro-2-(p chlororphenyl)-2-(o-chlorophenyl)ethane). These findings are consistent with earlier exposure to DDT and with slower p,p'-DDT elimination among mothers of cases. Whether these associations could be direct, or operate via other pathways is unknown. Further research on interindividual differences in DDT metabolism could provide clues to testicular cancer etiology. PMID- 20705573 TI - Distribution of cardiovascular risk factors in Belgian army men. AB - The objective was to determine the prevalence of cardiovascular risk factors in Belgian army men. Biomedical data and cardiovascular risk factors were obtained by a mailed questionnaire and by data collected from a medical software program (Total Health). The number of responders to the mailing was 1852; 974 of the 1852 responders and 420 of the 3148 nonresponders were registered in Total Health. The prevalence of obesity was 5.6%, 15.0%, and 19.5%, respectively, for officers, noncommissioned officers, and soldiers. There was a strong socioeconomic gradient in the prevalence of smoking: 12.7% of the officers were smokers, compared with 19.7% of the noncommissioned officers and 29.5% of the soldiers (p < .001). Only 8.5% of the officers had a 10-year risk of more than 5% of developing fatal cardiovascular disease, compared with 18% of the lower socioeconomic positions. In conclusion, high-risk groups in Belgian army men are younger than 40 years of age, and smokers. Active prevention should focus on this group with special attention to the specificity of each rank category. PMID- 20705574 TI - Polymorphism of glutathione S-transferase (GST) variants and its effect on distribution of urinary arsenic species in people exposed to low inorganic arsenic in tap water: an exploratory study. AB - Glutathione S-tranferases (GST) are multigenic enzymes that have been associated with arsenic metabolism. The objective of this study was to evaluate the relationship between polymorphic variants of GST and urinary concentration of arsenic species in people exposed to low levels of arsenic. A cross-sectional study among 66 nonoccupationally exposed subjects, living in the city of Antofagasta, Chile. Polymorphic variants were analyzed by polymerase chain reaction (PCR) and arsenic species was determined by atomic absorption spectrometry. The effect of GST variants on arsenic concentration was evaluated using univariate and covariate-adjusted regressions. For both GSTT1 and GSTM1 there were no significant differences in detected arsenic relative species between carriers of the active and null polymorphic variants. There was nondefinitive evidence that polymorphic variants of GST play a role in arsenic metabolism in sample of the Chilean subjects studied. PMID- 20705575 TI - Manganese, arsenic, and infant mortality in Bangladesh: an ecological analysis. AB - Recent studies in Bangladesh indicate that arsenic and manganese in tube-well water may increase the incidence of infant mortality. The study reported here examined whether these findings could be replicated. Data available from some 600 villages under the care of the nongovernmental organization (NGO) Gonoshasthaya Kendra included details of 29744 live births and 934 infant deaths in a 2-year period, with age and cause. These were analyzed by mean well levels of arsenic and manganese as reported by the British Geological Survey for the 12 upazillas. Odds ratios were calculated by age at death and cause. The effect of arsenic on all-cause infant mortality, although small and not significant, was consistent with earlier reports. The previous finding of an increased risk of infant mortality at concentrations of manganese > or =0.4 mg/L was not evident. PMID- 20705577 TI - Effects of leather industry on health and recommendations for improving the situation in Pakistan. AB - The leather industry and its associated sectors contribute significantly to the Pakistani economy. There are around 600 tanneries in Pakistan that are concentrated in 3 major cities (Kasur, Karachi, Sialkot). Waste discharge from tanneries pollutes the air, soil, and water, causing serious health problems. Exposure to such contaminated environmental milieu has been seen to culminate in a multiple array of disease processes such as asthma, dermatitis, hepatic and neurological disorders, and various malignancies. An overall dearth of research on the occupational hazards of employment in the leather industry as well as its effects on pediatric population was observed during literature review with particular reference to Pakistan. It is recommended that research should be conducted about the health hazards in the leather industry in Pakistan as well as globally to gather data that can be translated into effective prevention programs for both adults as well as pediatric populations. PMID- 20705578 TI - Identifying a set of 'core' journals in occupational health, part 2: lists derived by bibliometric techniques. PMID- 20705576 TI - Identification of Iowa live births in the Agricultural Health Study. AB - In the Agricultural Health Study, information on participant live births was largely provided by female partners of male private applicators. At the Iowa site, such information was available for 13,599 (42.9%) of 31,707 applicators. To improve identification of live births among Iowa participants, we used a probabilistic and deterministic approach to link available demographic data from 31,707 households and information on live births from 13,599 households with 1,014,916 Iowa birth certificates. Record linkage identified 16,611 (93.7%) of 17,719 reported live births and 17,883 additional live births, most (14,411 or 80.6%) not reported due to nonresponse by female partners. This record linkage produced an expanded cohort of live-born children among Iowa participants, which will facilitate improved study of the effects of agricultural exposures, including pesticides, on selected birth outcomes and childhood disease. PMID- 20705579 TI - Citation analysis and impact factor trends of 5 core journals in occupational medicine, 1975-1984. PMID- 20705580 TI - The teacher as learner. PMID- 20705581 TI - DNA replication origins, ORC/DNA interaction, and assembly of pre-replication complex in eukaryotes. AB - Chromosomal DNA replication in eukaryotic cells is highly complicated and sophisticatedly regulated. Owing to its large size, a typical eukaryotic genome contains hundreds to tens of thousands of initiation sites called DNA replication origins where DNA synthesis takes place. Multiple initiation sites remove the constraint of a genome size because only a certain amount of DNA can be replicated from a single origin in a limited time. The activation of these multiple origins must be coordinated so that each segment of chromosomal DNA is precisely duplicated only once per cell cycle. Although DNA replication is a vital process for cell growth and its mechanism is highly conserved, recent studies also reveal significant diversity in origin structure, assembly of pre replication complex (pre-RC) and regulation of replication initiation along evolutionary lines. The DNA replication origins in the fission yeast Schizosaccharomyces pombe are found to contain a second essential element that is bound by Sap1 protein besides the essential origin recognition complex-binding site. Sap1 is recently demonstrated to be a novel replication initiation protein that plays an essential role in loading the initiation protein Cdc18 to origins and thus directly participates in pre-RC formation. In this review, we summarize the recent advance in understanding how DNA replication origins are organized, how pre-RC is assembled and how DNA replication is initiated and regulated in yeast and metazoans. PMID- 20705582 TI - DNA binding, cytotoxicity, and apoptotic-inducing activity of ruthenium(II) polypyridyl complex. AB - There is considerable interest in the interactions of ruthenium (Ru)(II) complexes with DNA as well as the biological impact of the interactions. Here, by using isothermal titration calorimetry, viscosity measurement, and circular dichroism, we investigated the interactions of a new Ru(II) complex, [Ru(dmp)(2)PMIP](2+){dmp = 2,9-dimethyl-1,10-phenanthroline, PMIP = 2-(4 methylphenyl)imidazo[4,5-f]1,10-phenanthroline}, with calf thymus DNA (CT DNA). The Ru(II) polypyridyl complex and CT DNA formed a tight 1:1 complex with a binding constant of exceeding 10(6) M(-1) and with a binding mode of intercalation. Cell viability experiments indicated that the Ru(II) complex showed significant dose-dependent cytotoxicity to human lung tumor cell line A549. Further flow cytometry experiments showed that the cytotoxic Ru(II) complex induced apoptosis of human lung cancer cell line A549. Our data demonstrated that the Ru(II) polypyridyl complex binds to DNA and thereby induces apoptosis in tumor cells, suggesting that anti-tumor activity of the Ru(II) complex could be related to its interaction with DNA. PMID- 20705583 TI - NGX6 inhibits cell invasion and adhesion through suppression of Wnt/beta-catenin signal pathway in colon cancer. AB - Colon cancer is a common malignant tumor that is associated with increased morbidity and mortality. Nasopharyngeal carcinoma-associated gene 6 (NGX6) is a novel candidate suppressor gene of tumor metastasis, which is down-regulated in colon cancer. This study was designed to investigate the roles of NGX6 on the growth and invasiveness of human colon cancer cell line, HT-29, and to elucidate the molecular mechanism of their action. Results showed that NGX6 could inhibit the invasiveness and extracellular matrix adhesion of HT-29 cells and restore the gap junctional intercellular communication of cells. Moreover, NGX6 could suppress the translocation of beta-catenin from nucleus and cytoplasm to plasma membrane, inhibit the activity of TCF4 transcript factor, and down-regulate the expression of Wnt-direct-targeted genes c-myc, cyclin D1 and COX-2. We suggested that NGX6 inhibits cell invasion and adhesion through the suppression of Wnt signal pathway in colon cancer. PMID- 20705584 TI - The role of carotenoid isomerase in maintenance of photosynthetic oxygen evolution in rice plant. AB - Carotenoid isomerase (CRTISO) has been suggested to protect photosystem II (PS II) from photodamage, probably through its product lutein. However, the mechanism of the photoprotection still remains to be further elucidated. In this work, we cloned a point mutated gene reported to encode a CRTISO which is responsible for the accumulation of lutein in rice mutant zel1 by a map-based cloning approach. The mutant phenotype was rescued by transformation with the corresponding gene of the wild type (WT). The activity of photosynthetic oxygen evolution was evidently suppressed in zel1. The amount of the core protein of PS II CP47 was much lower in all the PS II complexes especially in the LHCII-PS II supercomplexes and CP43 free PS II of zel1 than that of WT. On the other hand, the amount of another core protein of PS II CP43 of zel1 was decreased in the higher supercomplexes, whereas it was increased in the lower ones and PS II monomer. The immunodetection displayed that CP43, CP47, and the oxygen-evolving extrinsic proteins PsbO and PsbP were reduced, but the amount of reaction center protein D1 did not show significant change in zel1. Northern blot analysis showed that the transcriptional level of CP43 was down-regulated but not that of CP47 or D1 in zel1. In addition, the plastoquinone (PQ) Q(A) was in a reduced state in zel1. On the basis of the results, we suggest that CRTISO might function in regulating the transcription of CP43 and the translation of CP47 by affecting the redox state of the PQ to stabilize the extrinsic proteins of oxygen evolution complexes in the rice plant. PMID- 20705585 TI - Differentiation of murine embryonic stem cells toward renal lineages by conditioned medium from ureteric bud cells in vitro. AB - The kidney is formed from two tissue populations derived from the intermediate mesoderm, the ureteric bud, and the metanephric mesenchyme. Metanephric mesenchyme is a pluripotent renal stem population, and conversion of renal mesenchyme into epithelia depends on the ureteric bud in vivo and in vitro. Embryonic stem (ES) cells have been induced to differentiate into a broad spectrum of specialized cell types in vitro, including hematopoietic, pancreatic, and neuronal cells. Such ES-derived cells can provide a valuable source of progenitor cells. However, whether ES cells can be stimulated by factors secreted from the fetal renal cells to differentiate into renal precursor cells in vitro has not been reported. In this study, we showed that murine ES cells can give rise to embryoid bodies in the absence of leukemia inhibitory factor. Culture conditions were optimized [6 days, 10 ng/ml activin and 10(-7) M retinoic acid (RA)] to generate maximal mesoderm populations specifically expressing Pax2 and brachyury. Results showed that 72% of the cells were brachyury positive by fluorescent activated cell sorter on Day 6 of EB cell differentiation. Conditioned medium collected from cultures of ureteric bud cells from renal cells of a 13-day-old fetus was added to the culture medium. Mesoderm cells were cultured for up to 10 days before showing expression of renal markers, initiation of nephrogenesis (WT-1 and Pax2), and terminally differentiated renal cell types (POD-1 and E-cadherin). This study suggests that ES cells pre-treated by RA and activin can interact with secreted molecules of the fetal renal cells to specifically differentiate into renal precursor cells. Our results provide an experimental basis for the development of in vitro assays to steer differentiation of ES cells toward renal lineages. PMID- 20705586 TI - Connexin 43 hemichannel regulates H9c2 cell proliferation by modulating intracellular ATP and [Ca2+]. AB - Connexin 43 (Cx43), known to be the main protein building blocks of gap junctions and hemichannels in mammalian heart, plays an important role in cardiocytes proliferation. Gap junctional intercellular communication has been suggested to be necessary for cellular proliferation and differentiation. However, the effect of Cx43 hemichannel on cardiocytes proliferation and the mechanism remain unclear. In this study, rat heart cell line H9c2 was used. The Cx43 location, the proliferation rate and hemichannel activity of H9c2 cells and Wnt-3a(+)-H9c2 cells were investigated and the changes of intracellular ATP and [Ca(2+)] were determined. Results showed that the inhibited hemichannel induced by 18beta glycyrrhetinic acid (GA) evoked intracellular ATP and [Ca(2+)] increase and enhanced H9c2 cell proliferation. Wnt-3a(+)-H9c2 cells displayed enhanced hemichannel activity and proliferation rate. Inhibited hemichannel of Wnt-3a(+) H9c2 cells induced by 18beta-GA decreased intracellular ATP, increased [Ca(2+)], and enhanced the proliferation of H9c2 cells. This study validated the role of hemichannel in H9c2 cell proliferation regulation, and showed a mechanism involved in the regulation of H9c2 cell proliferation. The proliferation could be enhanced by Cx43 hemichannel-mediated ATP release accompanying intracellular [Ca(2+)] change. However, different changes of ATP were observed in Wnt-3a(+) H9c2 cells. These findings provided new insights into the molecular mechanisms of proliferation regulation in H9c2 cells and the effect of Wnt-3a on intracellular ATP. PMID- 20705587 TI - Activation of hypoxia-inducible factor-1alpha via nuclear factor-kappa B in rats with chronic obstructive pulmonary disease. AB - Accumulating data suggested that hypoxia inducible factor (HIF)-1alpha plays an important role in the evolution and propagation of the inflammatory process. To characterize the activation of HIF-1alpha in rats with chronic obstructive pulmonary disease (COPD) and examine the possible role of nuclear factor (NF) kappaB in this process, rats were challenged by introtracheal instillation of lipopolysaccharide (LPS) and exposure to cigarette smoke. Pyrrolidine dithiocarbamate (PDTC) was administered via the oral route 1 h before LPS or cigarettes administration. Four weeks later, pulmonary function and histology were tested; bronchoalveolar lavage fluid (BALF) and arterial blood gases were assayed. Activation of pulmonary NF-kappaB was assessed by quantitative PCR, immunoblot analysis, and electrophoretic mobility shift assay, respectively. Results showed that LPS and smog induced the characteristics of COPD seen in human. PDTC alleviated the development of COPD and the levels of cytokines in BALF of PDTC+COPD group were significantly decreased compared with that of COPD group. The activation of pulmonary NF-kappaB was inhibited by PDTC and the accumulation of HIF-1alpha gene expression in the COPD group was attenuated by PDTC pretreatment. Furthermore, the mRNA levels of HIF-1alpha target genes heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were parallel to the attenuation of HIF-1alpha by PDTC. These findings indicated that the activation of HIF-1alpha pathway via NF-kappaB contributes to the development of COPD, and administration of NF-kappaB inhibitor may attenuate the development of COPD. PMID- 20705588 TI - Protective effects of silybin and analogues against X-ray radiation-induced damage. AB - Silybin (SLB) and similar analogues, namely, hesperetin (HESP), naringenin (NAN) and naringin (NAR), are believed to be active constituents of natural flavonoids that have been reported as chemopreventive agents for certain cancers. Moreover, SLB and analogues have been determined to fast repair DNA bases from oxidative damage by pulse radiolysis techniques. The present study was designed to evaluate the protective effects of SLB and analogues on soft X-ray-induced damage to plasmid DNA in vitro. The DNA damage was determined by agarose gel electrophoresis. SLB and analogues were found to protect DNA from radiation damage at micromolar concentrations. Among the compounds tested, HESP and SLB were the most effective in preventing X-ray-induced formation of DNA single strand breaks (SSB). A comparison of these results with other experiments showed that the ability of SLB and analogues to inhibit DNA damage in vitro correlated with the ability of the compounds to scavenge free radicals. Our work revealed that natural flavonoids, SLB and analogues may be used as potent radioprotectors against radiation damage. PMID- 20705589 TI - Inhibition of epithelial to mesenchymal transition in metastatic breast carcinoma cells by c-Src suppression. AB - The aberrant activation of c-Src regulates multiple functions during tumor progression. This study was conducted to investigate the role of c-Src suppression in epithelial to mesenchymal transition (EMT) process in human breast carcinoma cells. c-Src suppression by PP2 (a Src-family kinase inhibitor) or small interfering RNA (siRNA) was carried out in MCF-7 and MDA-MB-231 cells. Cell migration was analyzed by wound-healing assay. The transcription and protein levels of EMT markers and transcription factors were evaluated by reverse transcription-PCR and Western blot analysis, respectively. The changed cell morphology was photographed by light microscope. c-Src suppression by PP2 or siRNA reversed the mesenchymal-like phenotype in MDA-MB-231 cells. E-cadherin was upregulated in MCF-7 and MDA-MB-231 cells after c-Src suppression, whereas vimentin was downregulated in MDA-MB-231 cells. Slug and SIP1 were downregulated after c-Src suppression in MCF-7 and MDA-MB-231 cells, whereas Twist was unchanged. These results suggest that c-Src suppression by PP2 or siRNA may inhibit EMT through regulation of different transcription factors in breast carcinoma cells that have different metastatic potential. PMID- 20705590 TI - Identification of neuropeptide Y-like conopeptides from the venom of Conus betulinus. AB - Neuropeptide Y (NPY) is a ubiquitous endocrine neuropeptide found in vertebrate and invertebrate. In our present work, two NPY-like exocrine conopeptides (designated as cono-NPYs) were first identified in the venom of cone snails. Both cono-NPYs showed sequence characteristics of invertebrate NPYs, suggesting that some exocrine venom peptides are probably evolved from the preexisting endocrine peptides during the evolution of cone snails. PMID- 20705591 TI - Overexpression of P-selectin glycoprotein ligand-1 enhances adhesive properties of endothelial progenitor cells through Syk activation. AB - P-selectin glycoprotein ligand-1 (PSGL-1) not only functions as an anchor molecule to capture monocytes and other leukocytes to endothelial cells in ischemic tissue by its interaction with P-selectin, but also transduces signals to initiate firm adhesion. Endothelial progenitor cells are derived from monocytes and play a very important role in neovascularization. Transplantation of endothelial progenitor cells is a promising therapeutic strategy to improve treatment of ischemic disease such as myocardial and cerebral infarction; however, its efficacy is now limited by the fact that few of the transplanted cells adhere to and accumulate in the ischemic tissue. In this study we aimed to investigate whether the overexpression of PSGL-1 gene promotes endothelial progenitor cells adhesion activity and explore the underlying mechanisms. We found that after transfection with human PSGL-1 gene, endothelial progenitor cells exhibited higher affinity to activated human umbilical vein endothelial cells or recombined P-selectin/ICAM-1 monolayer. The overexpression of PSGL-1 enhanced beta2-integrin expression on endothelial progenitor cells surface, and this effect was Syk dependent. The specific Syk inhibitor abolished the elevating effect of overexpression of PSGL-1 on surface beta2-integrin expression and the adhesive affinity of endothelial progenitor cells. These results suggested that Syk plays a key role in signal transduction downstream of PSGL-1 in endothelial progenitor cells, and the overexpression of PSGL-1 improves endothelial progenitor cells adhesive properties through enhanced activation of Syk and following integrin activation. PMID- 20705592 TI - Expression of HPV6b L1/EBV LMP2 multiepitope and immunogenicity in mice. AB - Human papillomavirus (HPV) major capsid protein L1 is an important vehicle for the delivery of epitopes. To investigate the expression and immunogenicity of hybridized HPV6b L1 containing multiepitope of Epstein-Barr virus (EBV) latency membrane protein 2 (LMP2), a recombinant plasmid pcDNA3.1(+) containing mammalian codon-optimization HPV6b L1 gene and EBV LMP2 multiepitope was constructed. The EBV LMP2 multiepitope containing T- and B-cell epitope-rich peptides was inserted into C-terminal of HPV6b L1-coding sequence. The constructed plasmid after verified by enzyme restriction assay and DNA sequencing was transfected into COS 7 cells. Expression of the chimeric gene in COS-7 cells was confirmed by RT-PCR, western blot analysis and immunofluorescence assay. Results revealed successful expression of the chimeric HPV6b L1/EBV LMP2 multiepitope gene both at the mRNA and protein levels in transfected COS-7 cells. Intramuscular administration in mice was able to elicit not only antibodies against HPV6b L1 virus-like particle and EBV LMP2, but also cytotoxic T lymphocyte activity against the EBV LMP2 epitopes. The present results confirmed that HPV L1 protein is potential to deliver multiepitope of EBV LMP2 as immunogen to the MHC class I and class II pathways, extending the use of HPV L1 as delivery vehicles. PMID- 20705593 TI - Cloning, identification, and expression analysis at the stage of gonadal sex differentiation of chicken miR-363 and 363*. AB - miRNAs (microRNAs) are small, functional, non-coding RNAs and have been proved to implicate in regulation of diverse biological processes ranging from cell differentiation to organism development. With the purpose of exploring the roles of miRNAs on chicken embryo sexual determination and gonadal differentiation, we cloned and identified the stem-loop precursor structure (GenBank accession no. GU597370) of chicken miR-363 and 363* followed by studying their temporal and spatial expression patterns in chicken embryo at the stage of E3.5-6.5 d (embryonic days 3.5-6.5) by semi-quantitative RT-PCR and WISH (whole-mount in situ hybridization) in this study. The results showed that miR-363* located in cloned sequence of unknown segment in chicken genome, and flanking sequence of miR-363 and 363* according to the structural features of miRNAs precursor. Significantly differential expression (P < 0.05) of gga-miR-363 between female and male chicken embryonic gonads was found at E4.5 and 6.5 d, but the differential expression of gga-miR-363* from E3.5 to 6.5 d between both sexes fell short of significant level. The results of WISH indicated that expression signals of gga-miR-363 mainly appeared at limb bud, notochord, ectoderm, brain in E4.5 d chicken embryo, and urogenital systems (UGSs) at E6.5 d, and the expression level of E6.5 d was higher in the female than that in the male. It can be speculated that gga-miR-363 would involve in the gonadal development and gga miR-363* might have transient regulatory functions during the early stages of chicken embryo development. PMID- 20705594 TI - Mitochondrial F1Fo-ATP synthase translocates to cell surface in hepatocytes and has high activity in tumor-like acidic and hypoxic environment. AB - F1Fo-ATP synthase was originally thought to exclusively locate in the inner membrane of the mitochondria. However, recent studies prove the existence of ectopic F1Fo-ATP synthase on the outside of the cell membrane. Ectopic ATP synthase was proposed as a marker for tumor target therapy. Nevertheless, the protein transport mechanism of the ectopic ATP synthase is still unclear. The specificity of the ectopic ATP synthase, with regard to tumors, is questioned because of its widespread expression. In the current study, we constructed green fluorescent protein-ATP5B fusion protein and introduced it into HepG2 cells to study the localization of the ATP synthase. The expression of ATP5B was analyzed in six cell lines with different 'malignancies'. These cells were cultured in both normal and tumor-like acidic and hypoxic conditions. The results suggested that the ectopic expression of ATP synthase is a consequence of translocation from the mitochondria. The expression and catalytic activity of ectopic ATP synthase were similar on the surface of malignant cells as on the surface of less malignant cells. Interestingly, the expression of ectopic ATP synthase was not up regulated in tumor-like acidic and hypoxic microenvironments. However, the catalytic activity of ectopic ATP synthase was up-regulated in tumor-like microenvironments. Therefore, the specificity of ectopic ATP synthase for tumor target therapy relies on the high level of catalytic activity that is observed in acidic and hypoxic microenvironments in tumor tissues. PMID- 20705595 TI - Integrin beta4 was downregulated on the airway epithelia of asthma patients. AB - The shedding of airway epithelial cells and loss of epithelial functional homeostasis are major pathological characteristics of asthma; however, the mechanism underlying these pathologies remains obscure. Our previous work showed that there were three variation sites in 5' flanking region of integrin beta4 in asthma patients, which was correlated with decreased expression of integrin beta4 in peripheral leukocytes. Integrin beta4 is an important structural adhesion molecule on airway epithelia to keep the structural adhesion of epithelial cells. In this work, we further demonstrated that integrin beta4 expression was downregulated in airway epithelia of asthma patients. To probe the relationship between imbalanced expression of integrin beta4 and dysfunction of the airway epithelial cells in asthma, integrin beta4 was silenced in human bronchial epithelium cells (16HBE14O) by integrin beta4 small-interfering RNA lentivirus vector. Upon silencing of integrin beta4, 16HBE14O cells showed reduced proliferation and wound repair. Most cells were shown to be arrested in G1 phase after integrin beta4 silencing, and increased apoptosis was induced in the integrin beta4-silenced cells. In summary, our results provided compelling evidence that integrin beta4 was involved in the structural integrity and functional homeostasis of airway epithelial cells. It is likely that downregulation of integrin beta4 on asthma airway epithelia contributes to the structural disruption and dysfunction of airway epithelial cells. PMID- 20705596 TI - Protective effects of a bacterially expressed NIF-KGF fusion protein against bleomycin-induced acute lung injury in mice. AB - Current evidence suggests that the keratinocyte growth factor (KGF) and the polymorphonuclear leukocyte may play key roles in the development of lung fibrosis. Here we describe the construction, expression, purification, and identification of a novel NIF (neutrophil inhibitory factor)-KGF mutant fusion protein (NKM). The fusion gene was ligated via a flexible octapeptide hinge and expressed as an insoluble protein in Escherichia coli BL21 (DE3). The fusion protein retained the activities of KGF and NIF, as it inhibited both fibroblast proliferation and leukocyte adhesion. Next, the effects of NKM on bleomycin induced lung fibrosis in mice were examined. The mice were divided into the following four groups: (i) saline group; (ii) bleomycin group (instilled with 5 mg/kg bleomycin intratracheally); (iii) bleomycin plus dexamethasone (Dex) group (Dex was given intraperitoneally (i.p.) at 1 mg/kg/day 2 days prior to bleomycin instillation and daily after bleomycin instillation until the end of the treatment); and (iv) bleomycin plus NKM group (NKM was given i.p. at 2 mg/kg/day using the same protocol as the Dex group). NKM significantly improved the survival rates of mice exposed to bleomycin. The marked morphological changes and increased hydroxyproline levels resulted from the instillation of bleomycin (on Day 17) in the lungs were significantly inhibited by NKM. These results revealed that NKM can attenuate bleomycin-induced lung fibrosis, suggesting that NKM could be used to prevent bleomycin-induced lung damage or other interstitial pulmonary fibrosis. PMID- 20705597 TI - Immunogenicity of recombinant F4 (K88) fimbrial adhesin FaeG expressed in tobacco chloroplast. AB - To test the possibility of producing the novel vaccine in plants against diarrhea normally found in neonatal and newly weaned piglets, the faeG gene, encoding a major F4ac fimbrial subunit protein, was introduced into the tobacco chloroplast genome. After two rounds of selection under spectinomycin, we obtained the transgenic plants nearly homoplasmic. RNA gel blot analysis indicated that faeG and the antibiotic selective gene aminoglycoside 3' adenylyltransferase (aadA) were highly transcribed as a dicistron, while the translational level of recombinant FaeG in transplastomic tobacco was about 0.15% of total soluble protein. The immunogenicity of recombinant FaeG produced in tobacco chloroplasts was confirmed by the observation that FaeG-specific antibodies were elicited in mice immunized with total soluble protein of transgenic plants, as well as the result that mouse sera stimulated by chloroplast-derived recombinant FaeG could neutralize F4ac enterotoxigenic Escherichia coli (ETEC) in vivo. This study provides a new alternative for producing the ETEC vaccine using the chloroplast expression system. PMID- 20705598 TI - Identification of genes for normalization of quantitative real-time PCR data in ovarian tissues. AB - Increased attention has been paid to the determination of the potential biomarker and therapeutic target for ovarian cancer in recent years. However, the normalization of quantitative real-time PCR is important to obtain accurate gene expression data. We investigated the stability of 20 reference genes in ovarian tissues under different conditions to determine the most adequate for this application. The study characterized the expression of 20 possible reference genes among 52 ovarian tissue samples involving the normal, non-malignant, and primary ovarian carcinomas. One-way analysis of variance (ANOVA) method was used to compare the candidate gene changes brought about by the disease progression. The stability and suitability of the genes with no statistic difference were further validated employing geNorm and NormFinder softwares. Results showed that the expression levels of the 20 reference genes varied, while the RPL4, RPLP0, HSPCB, TPT1, RPL13A, 18S rRNA, PPIA, TBP, and GUSB kept statistic stability despite different ovarian tissue conditions. RPL4, RPLP0, and HSPCB were demonstrated as the most stable reference genes and the combination of the RPLP0 and RPL4 should be recommended as a much more reliable normalization strategy. PMID- 20705599 TI - A novel strategy for rapid construction of libraries of full-length antibodies highly expressed on mammalian cell surfaces. AB - Development of a versatile mammalian display system is essential for the selection of functional human antibodies with high affinities. Here we described a novel strategy for rapid construction of full-length antibody libraries that could be efficiently expressed on mammalian cell surfaces. The universal vector pDGB-HC-TM was constructed by inserting multiple cloning site unique sequences recognized by restriction endonucleases BsmBI, SfiI, and BstXI for the pop-in and pop-out of genes of interest. Cytomegalovirus promoter, a commonly used promoter for high expression of proteins in a variety of mammalian cells, was used to drive expression of the inserted antibody genes and a transmembrane domain from platelet-derived growth factor receptor was fused in frame to the C-terminus of heavy chain consistent region to anchor the antibody expressed on the mammalian cell surface. Using this strategy, we constructed a full-length human antibody display library. DNA sequence analysis and expression analysis indicated that the library constructed had a combinatory expressible, detectable diversity of 6.58 x 10(10). PMID- 20705600 TI - Cloning and soluble expression of mature alpha-luffin from Luffa cylindrica and its antitumor activities in vitro. AB - Luffin-a, a single-chain Type I ribosome-inactivating protein, which is known to be the most toxic of the luffin family and apparently possesses antitumor activity, was isolated from Luffa cylindrica seeds. In the present study, mature alpha-luffin was cloned from L. cylindrica and it was found that mature alpha luffin shared 96% amino acid similarity with luffin-a. The recombinant mature alpha-luffin was successfully expressed in a partly soluble form in Escherichia coli after optimization of expression conditions. The effects of the recombinant protein on bacterial growth and its in vitro protein synthesis inhibition activity were tested. Then, its antitumor activities against different human cancer cell lines were evaluated by CCK-8 assay and flow cytometry. The results indicated that the recombinant alpha-luffin was slightly toxic to E. coli. It could inhibit protein synthesis in the rabbit reticulocyte lysate system. At the same time, it inhibited the growth of the tumor cell lines in a dose- and time dependent manner. Additionally, recombinant alpha-luffin was able to induce cell death by apoptosis. The cytotoxicity of alpha-luffin towards tumor cells makes it a potential antitumor agent. PMID- 20705601 TI - NADPH oxidase-dependent regulation of T-type Ca2+ channels and ryanodine receptors mediate the augmented exocytosis of catecholamines from intermittent hypoxia-treated neonatal rat chromaffin cells. AB - Nearly 90% of premature infants experience the stress of intermittent hypoxia (IH) as a consequence of recurrent apneas (periodic cessation of breathing). In neonates, catecholamine secretion from the adrenal medulla is critical for maintaining homeostasis under hypoxic stress. We recently reported that IH treatment enhanced hypoxia-evoked catecholamine secretion and [Ca2+]i responses in neonatal rat adrenal chromaffin cells and involves reactive oxygen species (ROS). The purpose of the present study was to identify the source(s) of ROS generation and examine the mechanisms underlying the enhanced catecholamine secretion by IH. Neonatal rats of either sex (postal day 0-5) were exposed to either IH or normoxia. IH treatment increased NADPH oxidase (NOX) activity, upregulated NOX2 and NOX4 transcription in adrenal medullae, and a NOX inhibitor prevented the effects of IH on hypoxia-evoked chromaffin cell secretion. IH upregulated Cav3.1 and Cav3.2 T-type Ca2+ channel mRNAs via NOX/ROS signaling and augmented T-type Ca2+ current in IH-treated chromaffin cells. Mibefradil, a blocker of T-type Ca2+ channels attenuated the effects of hypoxia on [Ca2+]i and catecholamine secretion in IH-treated cells. In Ca2+-free medium, IH-treated cells exhibited higher basal [Ca2+]i levels and more pronounced [Ca2+]i responses to hypoxia compared with controls, and blockade of ryanodine receptors (RyRs) prevented these effects. RyR2 and RyR3 mRNAs were upregulated, RyR2 was S glutathionylated in IH-treated adrenal medullae, and NOX/ROS inhibitors prevented these effects. These results demonstrate that neonatal IH treatment leads to NOX/ROS-dependent recruitment of T-type Ca2+ channels and RyRs, resulting in augmented [Ca2+]i mobilization and catecholamine secretion. PMID- 20705602 TI - Eyes on me: an fMRI study of the effects of social gaze on action control. AB - Previous evidence suggests that 'social gaze' can not only cause shifts in attention, but also can change the perception of objects located in the direction of gaze and how these objects will be manipulated by an observer. These findings implicate differences in the neural networks sub-serving action control driven by social cues as compared with nonsocial cues. Here, we sought to explore this hypothesis by using functional magnetic resonance imaging and a stimulus-response compatibility paradigm in which participants were asked to generate spatially congruent or incongruent motor responses to both social and nonsocial stimuli. Data analysis revealed recruitment of a dorsal frontoparietal network and the locus coeruleus for the generation of incongruent motor responses, areas previously implicated in controlling attention. As a correlate for the effect of 'social gaze' on action control, an interaction effect was observed for incongruent responses to social stimuli in sub-cortical structures, anterior cingulate and inferior frontal cortex. Our results, therefore, suggest that performing actions in a--albeit minimal--social context significantly changes the neural underpinnings of action control and recruits brain regions previously implicated in action monitoring, the reorienting of attention and social cognition. PMID- 20705603 TI - A new role for PTEN in regulating transient receptor potential canonical channel 6-mediated Ca2+ entry, endothelial permeability, and angiogenesis. AB - Phosphatase and tensin homologue (PTEN) is a dual lipid-protein phosphatase that catalyzes the conversion of phosphoinositol 3,4,5-triphosphate to phosphoinositol 4,5-bisphosphate and thereby inhibits PI3K-Akt-dependent cell proliferation, migration, and tumor vascularization. We have uncovered a previously unrecognized role for PTEN in regulating Ca(2+) entry through transient receptor potential canonical channel 6 (TRPC6) that does not require PTEN phosphatase activity. We show that PTEN tail-domain residues 394-403 permit PTEN to associate with TRPC6. The inflammatory mediator thrombin promotes this association. Deletion of PTEN residues 394-403 prevents TRPC6 cell surface expression and Ca(2+) entry. However, PTEN mutant, C124S, which lacks phosphatase activity, did not alter TRPC6 activity. Thrombin failed to increase endothelial monolayer permeability in the endothelial cells, transducing the Delta394-403 PTEN mutant. Paradoxically, we also show that thrombin failed to induce endothelial cell migration and tube formation in cells transducing the Delta394-403 PTEN mutant. Our results demonstrate that PTEN, through residues 394-403, serves as a scaffold for TRPC6, enabling cell surface expression of the channel. Ca(2+) entry through TRPC6 induces an increase in endothelial permeability and directly promotes angiogenesis. Thus, PTEN is indicated to play a role beyond suppressing PI3K signaling. PMID- 20705605 TI - Effect of trehalose on the properties of mutant {gamma}PKC, which causes spinocerebellar ataxia type 14, in neuronal cell lines and cultured Purkinje cells. AB - Several missense mutations in the protein kinase Cgamma (gammaPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant gammaPKC found in SCA14 is susceptible to aggregation, which induces apoptotic cell death. The disaccharide trehalose has been reported to inhibit aggregate formation and to alleviate symptoms in cellular and animal models of Huntington disease, Alzheimer disease, and prion disease. Here, we show that trehalose can be incorporated into SH-SY5Y cells and reduces the aggregation of mutant gammaPKC GFP, thereby inhibiting apoptotic cell death in SH-SY5Y cells and primary cultured Purkinje cells (PCs). Trehalose acts by directly stabilizing the conformation of mutant gammaPKC without affecting protein turnover. Trehalose was also found to alleviate the improper development of dendrites in PCs expressing mutant gammaPKC-GFP without aggregates but not in PCs with aggregates. In PCs without aggregates, trehalose improves the mobility and translocation of mutant gammaPKC-GFP, probably by inhibiting oligomerization and thereby alleviating the improper development of dendrites. These results suggest that trehalose counteracts various cellular dysfunctions that are triggered by mutant gammaPKC in both neuronal cell lines and primary cultured PCs by inhibiting oligomerization and aggregation of mutant gammaPKC. PMID- 20705604 TI - ABCG2 transports and transfers heme to albumin through its large extracellular loop. AB - ABCG2 is an ATP-binding cassette (ABC) transporter preferentially expressed by immature human hematopoietic progenitors. Due to its role in drug resistance, its expression has been correlated with a protection role against protoporhyrin IX (PPIX) accumulation in stem cells under hypoxic conditions. We show here that zinc mesoporphyrin, a validated fluorescent heme analog, is transported by ABCG2. We also show that the ABCG2 large extracellular loop ECL3 constitutes a porphyrin binding domain, which strongly interacts with heme, hemin, PPIX, ZnPPIX, CoPPIX, and much less efficiently with pheophorbide a, but not with vitamin B12. K(d) values are in the range 0.5-3.5 MUm, with heme displaying the highest affinity. Nonporphyrin substrates of ABCG2, such as mitoxantrone, doxo/daunorubicin, and riboflavin, do not bind to ECL3. Single-point mutations H583A and C603A inside ECL3 prevent the binding of hemin but hardly affect that of iron-free PPIX. The extracellular location of ECL3 downstream from the transport sites suggests that, after membrane translocation, hemin is transferred to ECL3, which is strategically positioned to release the bound porphyrin to extracellular partners. We show here that human serum albumin could be one of these possible partners as it removes hemin bound to ECL3 and interacts with ABCG2, with a K(d) of about 3 MUm. PMID- 20705606 TI - Elucidation of a novel extracellular calcium-binding site on metabotropic glutamate receptor 1{alpha} (mGluR1{alpha}) that controls receptor activation. AB - Metabotropic glutamate receptor 1alpha (mGluR1alpha) exerts important effects on numerous neurological processes. Although mGluR1alpha is known to respond to extracellular Ca(2+) ([Ca(2+)](o)) and the crystal structures of the extracellular domains (ECDs) of several mGluRs have been determined, the calcium binding site(s) and structural determinants of Ca(2+)-modulated signaling in the Glu receptor family remain elusive. Here, we identify a novel Ca(2+)-binding site in the mGluR1alpha ECD using a recently developed computational algorithm. This predicted site (comprising Asp-318, Glu-325, and Asp-322 and the carboxylate side chain of the receptor agonist, Glu) is situated in the hinge region in the ECD of mGluR1alpha adjacent to the reported Glu-binding site, with Asp-318 involved in both Glu and calcium binding. Mutagenesis studies indicated that binding of Glu and Ca(2+) to their distinct but partially overlapping binding sites synergistically modulated mGluR1alpha activation of intracellular Ca(2+) ([Ca(2+)](i)) signaling. Mutating the Glu-binding site completely abolished Glu signaling while leaving its Ca(2+)-sensing capability largely intact. Mutating the predicted Ca(2+)-binding residues abolished or significantly reduced the sensitivity of mGluR1alpha not only to [Ca(2+)](o) and [Gd(3+)](o) but also, in some cases, to Glu. The dual activation of mGluR1alpha by [Ca(2+)](o) and Glu has important implications for the activation of other mGluR subtypes and related receptors. It also opens up new avenues for developing allosteric modulators of mGluR function that target specific human diseases. PMID- 20705607 TI - Turning the RING domain protein MdmX into an active ubiquitin-protein ligase. AB - The related RING domain proteins MdmX and Mdm2 are best known for their role as negative regulators of the tumor suppressor p53. However, although Mdm2 functions as a ubiquitin ligase for p53, MdmX does not have appreciable ubiquitin ligase activity. In this study, we performed a mutational analysis of the RING domain of MdmX, and we identified two distinct regions that, when replaced by the respective regions of Mdm2, turn MdmX into an active ubiquitin ligase for p53. Mdm2 and MdmX form homodimers as well as heterodimers with each other. One of the regions identified localizes to the dimer interface indicating that subtle conformational changes in this region either affect dimer stability and/or the interaction with the ubiquitin-conjugating enzyme UbcH5b. The second region contains the cryptic nucleolar localization signal of Mdm2 but is also assumed to be involved in the interaction with UbcH5b. Here, we show that this region has a significant impact on the ability of respective MdmX mutants to functionally interact with UbcH5b in vitro supporting the notion that this region serves two distinct functional purposes, nucleolar localization and ubiquitin ligase activity. Finally, evidence is provided to suggest that the RING domain of Mdm2 not only binds to UbcH5b but also acts as an allosteric activator of UbcH5b. PMID- 20705608 TI - Interfacial kinetic and binding properties of mammalian group IVB phospholipase A2 (cPLA2beta) and comparison with the other cPLA2 isoforms. AB - The cytosolic (group IV) phospholipase A(2) (cPLA(2)s) family contains six members. We have prepared recombinant proteins for human alpha, mouse beta, human gamma, human delta, human epsilon, and mouse zeta cPLA(2)s and have studied their interfacial kinetic and binding properties in vitro. Mouse cPLA(2)beta action on phosphatidylcholine vesicles is activated by anionic phosphoinositides and cardiolipin but displays a requirement for Ca(2+) only in the presence of cardiolipin. This activation pattern is explained by the effects of anionic phospholipids and Ca(2+) on the interfacial binding of mouse cPLA(2)beta and its C2 domain to vesicles. Ca(2+)-dependent binding of mouse cPLA(2)beta to cardiolipin-containing vesicles requires a patch of basic residues near the Ca(2+)-binding surface loops of the C2 domain, but binding to phosphoinositide containing vesicles does not depend on any specific cluster of basic residues. Human cPLA(2)delta also displays Ca(2+)- and cardiolipin-enhanced interfacial binding and activity. The lysophospholipase, phospholipase A(1), and phospholipase A(2) activities of the full set of mammalian cPLA(2)s were quantified. The relative level of these activities is very different among the isoforms, and human cPLA(2)delta stands out as having relatively high phospholipase A(1) activity. We also tested the susceptibility of all cPLA(2) family members to a panel of previously reported inhibitors of human cPLA(2)alpha and analogs of these compounds. This led to the discovery of a potent and selective inhibitor of mouse cPLA(2)beta. These in vitro studies help determine the regulation and function of the cPLA(2) family members. PMID- 20705609 TI - GATA proteins work together with friend of GATA (FOG) and C-terminal binding protein (CTBP) co-regulators to control adipogenesis. AB - GATA transcription factors have been implicated in controlling adipogenesis in Drosophila and in mammals. In mammals, both GATA2 and GATA3 have been shown to be present in preadipocytes, and their silencing allows the onset of adipogenesis. Overexpression of GATA proteins blocks adipogenesis in cellular assays. GATA factors have been found to operate through recruiting cofactors of the Friend of GATA (FOG) family. FOG proteins, in turn, recruit co-regulators, including C terminal binding proteins (CTBPs). We have investigated whether FOGs and CTBPs influence adipogenesis. We found that both FOG1 and FOG2 are expressed in cells prior to adipogenesis but are down-regulated as adipogenesis proceeds. Overexpression of FOG1 or FOG2 interferes with adipogenesis. Mutant versions of FOG2 unable to bind CTBP or GATA proteins are impaired in their inability to inhibit adipogenesis. Finally, a mutant version of GATA2, unable to associate with FOGs, also displays abnormal activity and causes enhanced cell proliferation. These results implicate FOGs and CTBPs as partners of GATA proteins in the control of adipocyte proliferation and differentiation. PMID- 20705610 TI - Raman spectroscopy analysis of botryococcene hydrocarbons from the green microalga Botryococcus braunii. AB - Botryococcus braunii, B race is a unique green microalga that produces large amounts of liquid hydrocarbons known as botryococcenes that can be used as a fuel for internal combustion engines. The simplest botryococcene (C(30)) is metabolized by methylation to give intermediates of C(31), C(32), C(33), and C(34), with C(34) being the predominant botryococcene in some strains. In the present work we have used Raman spectroscopy to characterize the structure of botryococcenes in an attempt to identify and localize botryococcenes within B. braunii cells. The spectral region from 1600-1700 cm(-1) showed nu(C=C) stretching bands specific for botryococcenes. Distinct botryococcene Raman bands at 1640 and 1647 cm(-1) were assigned to the stretching of the C=C bond in the botryococcene branch and the exomethylene C=C bonds produced by the methylations, respectively. A Raman band at 1670 cm(-1) was assigned to the backbone C=C bond stretching. Density function theory calculations were used to determine the Raman spectra of all botryococcenes to compare computed theoretical values with those observed. The analysis showed that the nu(C=C) stretching bands at 1647 and 1670 cm(-1) are actually composed of several closely spaced bands arising from the six individual C=C bonds in the molecule. We also used confocal Raman microspectroscopy to map the presence and location of methylated botryococcenes within a colony of B. braunii cells based on the methylation-specific 1647 cm(-1) botryococcene Raman shift. PMID- 20705611 TI - Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements. AB - Constitutive activation of NFkappaB in estrogen receptor (ER)-positive breast cancer is associated with tumor recurrence and development of anti-estrogen resistance. Furthermore, a gene expression signature containing common targets for ER and NFkappaB has been identified and found to be associated with the more aggressive luminal B intrinsic subtype of ER-positive breast tumors. Here, we describe a novel mechanism by which ER and NFkappaB cooperate to up-regulate expression of one important gene from this signature, ABCG2, which encodes a transporter protein associated with the development of drug-resistant breast cancer. We and others have confirmed that this gene is regulated primarily by estrogen in an ER- and estrogen response element (ERE)-dependent manner. We found that whereas proinflammatory cytokines have little effect on this gene in the absence of 17beta-estradiol, they can potentiate ER activity in an NFkappaB dependent manner. ER allows the NFkappaB family member p65 to access a latent NFkappaB response element located near the ERE in the gene promoter. NFkappaB recruitment to the gene is, in turn, required to stabilize ER occupancy at the functional ERE. The result of this cooperative binding of ER and p65 at adjacent response elements leads to a major increase in both ABCG2 mRNA and protein expression. These findings indicate that estrogen and inflammatory factors can modify each other's activity through modulation of transcription factor accessibility and/or occupancy at adjacent response elements. This novel transcriptional mechanism could have important implications in breast cancer, where both inflammation and estrogen can promote cancer progression. PMID- 20705612 TI - Conversion of mouse epiblast stem cells to an earlier pluripotency state by small molecules. AB - Epiblast stem cells (EpiSCs) are pluripotent cells derived from post-implantation late epiblasts in vitro. EpiSCs are incapable of contributing to chimerism, indicating that EpiSCs are less pluripotent and represent a later developmental pluripotency state compared with inner cell mass stage murine embryonic stem cells (mESCs). Using a chemical approach, we found that blockage of the TGFbeta pathway or inhibition of histone demethylase LSD1 with small molecule inhibitors induced dramatic morphological changes in EpiSCs toward mESC phenotypes with simultaneous activation of inner cell mass-specific gene expression. However, full conversion of EpiSCs to the mESC-like state with chimerism competence could be readily generated only with the combination of LSD1, ALK5, MEK, FGFR, and GSK3 inhibitors. Our results demonstrate that appropriate synergy of epigenetic and signaling modulations could convert cells at the later developmental pluripotency state to the earlier mESC-like pluripotency state, providing new insights into pluripotency regulation. PMID- 20705613 TI - Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. AB - PURPOSE: CD47 plays a variety of roles in intercellular signaling. Herein, we focused on the clinicopathologic significance of CD47 expression in human breast cancer. Our data suggest that the correlation between CD47 and signal regulatory protein alpha (SIRPA) expression may play a key role in the progression of breast cancer. EXPERIMENTAL DESIGN: Quantitative real-time PCR was used to evaluate CD47 mRNA and SIRPA mRNA expression in bone marrow and in peripheral blood from 738 cases of breast cancer. RESULTS: In patients with high levels of CD47 expression in the bone marrow, survival was significantly poorer compared with patients with low levels of CD47 expression [disease-free survival (DFS), P = 0.0035; overall survival (OS), P = 0.015]. Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.024). In the peripheral blood, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis. CD47 expression was strongly correlated with SIRPA expression in both the bone marrow (P < 0.0001) and peripheral blood (P < 0.0001) of breast cancer patients. CONCLUSIONS: This is one of the first studies to show that a host factor in bone marrow confers prognostic importance. CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. Moreover, we suggest that the poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells. PMID- 20705614 TI - Patterns of expression of DNA repair genes and relapse from melanoma. AB - PURPOSE: To use gene expression profiling of formalin-fixed primary melanoma samples to detect expression patterns that are predictive of relapse and response to chemotherapy. EXPERIMENTAL DESIGN: Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer related genes from these studies were combined for analysis. RESULTS: Increased expression of DNA repair genes most strongly predicted relapse and was associated with thicker tumors. Increased expression of RAD51 was the most predictive of relapse-free survival in unadjusted analysis (hazard ratio, 2.98; P = 8.80 * 10( 6)). RAD52 (hazard ratio, 4.73; P = 0.0004) and TOP2A (hazard ratio, 3.06; P = 0.009) were independent predictors of relapse-free survival in multivariable analysis. These associations persisted when the analysis was further adjusted for demographic and histologic features of prognostic importance (RAD52 P = 0.01; TOP2A P = 0.02). Using principal component analysis, expression of DNA repair genes was summarized into one variable. Genes whose expression correlated with this variable were predominantly associated with the cell cycle and DNA repair. In 42 patients treated with chemotherapy, DNA repair gene expression was greater in tumors from patients who progressed on treatment. Further data supportive of a role for increased expression of DNA repair genes as predictive biomarkers are reported, which were generated using multiplex PCR. CONCLUSIONS: Overexpression of DNA repair genes (predominantly those involved in double-strand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability and give insight into mechanisms of melanoma drug resistance and potential therapies. PMID- 20705615 TI - Phase I pharmacokinetic and pharmacodynamic evaluation of combined valproic acid/doxorubicin treatment in dogs with spontaneous cancer. AB - PURPOSE: Histone deacetylase inhibitors (HDACi) are targeted anticancer agents with a well-documented ability to act synergistically with cytotoxic agents. We recently showed that the HDACi valproic acid sensitizes osteosarcoma cells to doxorubicin in vitro and in vivo. As there are no published reports on the clinical utility of HDACi in dogs with spontaneous cancers, we sought to determine a safe and biologically effective dose of valproic acid administered prior to a standard dose of doxorubicin. METHODS: Twenty-one dogs were enrolled into eight cohorts in an accelerated dose-escalation trial consisting of pretreatment with oral valproic acid followed by doxorubicin on a three-week cycle. Blood and tumor tissue were collected for determination of serum valproic acid concentration and evaluation of pharmacodynamic effects by immunofluorescence cytochemistry and immunohistochemistry. Serum and complete blood counts were obtained for determination of changes in doxorubicin pharmacokinetics or hematologic effects. RESULTS: All doses of valproic acid were well tolerated. Serum valproic acid concentrations increased linearly with dose. Doxorubicin pharmacokinetics were comparable with those in dogs receiving doxorubicin alone. A positive correlation was detected between valproic acid dose and histone hyperacetylation in peripheral blood mononuclear cells. No potentiation of doxorubicin-induced myelosuppression was observed. Histone hyperacetylation was documented in tumor and peripheral blood mononuclear cells. Responses included 2 of 21 complete, 3 of 21 partial, 5 of 21 stable disease, and 11 of 21 progressive disease. CONCLUSIONS: Valproic acid can be administered to dogs at doses up to 240 mg/kg/day prior to a standard dose of doxorubicin. In addition, we have developed the pharmacokinetic/pharmacodynamic tools necessary for future studies of novel HDACi in the clinical setting of canine cancer. PMID- 20705618 TI - Something must be done! But is Moore correct that something can be worse than nothing in alcohol control policy? PMID- 20705617 TI - Correlation of femoral intima-media thickness and the severity of coronary artery disease. AB - The carotid artery intima-media thickness (IMT) is an established surrogate marker of vascular risk. We assessed the common femoral artery IMT and its correlation with coronary artery disease (CAD). We also assessed the influence of vascular risk factors on the femoral IMT. Patients (n = 180; mean age 60.4 +/- 10.5 years) who had undergone coronary angiography due to symptoms of CAD were enrolled in this study. We found significantly higher values of femoral IMT in patients with CAD than in those without CAD (P = .0000). A strong positive correlation between femoral IMT and the severity of CAD expressed by the Gensini Score (P = .0000) was observed. There was a positive correlation between femoral IMT and levels of triglycerides (P = .017), body mass index (BMI; P = .036), male gender (P = .0000), and smoking (P = .028). There was a negative correlation between femoral IMT and the level of high-density lipoprotein-cholesterol (P = .001). Femoral IMT could be a novel cardiovascular risk marker. PMID- 20705619 TI - Emerging trends in diabetic foot ulcer management in India. PMID- 20705620 TI - The obesity-diabetes association: what is different in indians? AB - There is a growing epidemic of obesity and type 2 diabetes in the world, more than 75% of the patients are in the developing countries. India is facing a twin burden of under-nutrition and over-nutrition: it figures prominently both in the hunger map of the world as well as being the world's capital of diabetes. Indians are susceptible to diabetes at a younger age and at a relatively lower BMI compared to the white Caucasians. This is partly explained by the fact that the thin-looking Indians are quite adipose (higher body fat percent). Intrauterine epigenetic regulation could explain the thin-fat Indian body composition. A combination of maternal one carbon metabolism derangement (influenced by vitamin B12 and Folate nutrition) and hyperglycemia appear to be major drivers. Persistent micronutrient abnormalities and rapid economic development seem to contribute to the intergenerational amplification of the diabetes-adiposity epidemic in Indians. Effective curtailment of the growing epidemic may lie in the realm of maternal and child health and nutrition. PMID- 20705621 TI - Role of industries in the care of diabetic foot. AB - Diabetic foot disease is a dreaded complication causing severe economic and social burden, mental and physical agony, and severe morbidity and mortality. This complication is largely preventable if the risk factors such as peripheral neuropathy and peripheral arterial disease are detected early and appropriate measures are taken to control glycemia, foot pressure, and chances of foot injury. In the case of ulceration, proper microbial control, pressure offloading by debridement, and use of appropriate footwear are mandatory to save the foot. This article focuses on the need for preventive care for diabetic complications demonstrating potentially helpful roles for industry in India. PMID- 20705622 TI - Epidemiology of diabetic foot and management of foot problems in India. AB - Diabetes the global epidemic is rapidly increasing at an alarming rate. Developing countries like India harbor the majority of diabetic people and by the year 2030 AD India will have the largest number of diabetic patients. Diabetic foot is one of the common diabetic complications found in India. Both aerobic and anaerobic pathogens form the etiology for diabetic foot infection. Members of the Enterobacteriaceae family were the most prominent among the aerobes while members of the Genus Peptostreptococcus and Clostridium were most prominent among the anaerobes. Ulcers infected with anaerobic pathogens showed a longer healing time than ulcers infected with aerobic pathogens. Oxidative stress is one of the major markers of inflammatory response and oxidative stress markers such as lipid peroxidation, thiobarbituric acid reactive substance (TBARS), Superoxide Dismutase (SOD), Catalase, G Peroxidase, G-S Peroxidase and plasma total antioxidant play a major role in the nonhealing of diabetic foot ulcers. Growth factors such as platelet-derived growth factor (PDGF), transforming growth factor (VEGF), and epidermal growth factor (EGF) are needed for normal wound repair, while proteases such as matrix metalloproteinase (MMP) and serine proteases found in chronic wounds delay the healing process. PMID- 20705623 TI - The etiopathogenesis of the diabetic foot: an unrelenting epidemic. AB - Diabetes mellitus is a metabolic disease that is associated with hyperglycemia affecting various organ systems of the body. One of the most dreaded complications of this disease is the diabetic foot. The diabetic foot is the end result of multiple causal pathways, which include peripheral neuropathy and vascular disease. The problem is compounded by the increased incidence of infection. This article deals with the various pathogenic pathways associated with the development of the diabetic foot. PMID- 20705624 TI - Viability and efficacy of coverage of cryopreserved human skin allografts in mice. AB - Human skin allografts are considered one of the best temporary biological coverages for severe burn patients. Human skin allografts can be either viable or nonviable depending on their preservation modalities. However, there is a debate about the use of viable versus nonviable skin for severe burn patients because there is no established correlation between viability and efficacy of coverage. The authors tried to correlate the viability of cryopreserved human skin allografts as assessed by the MTT assay, with efficacy of coverage, intensity of rejection at day 8, and delay of wound healing in a xenograft model using human fresh skin (FS) and cryopreserved skin (CPS) on murine recipients (n = 49). Cryopreserved grafts were less rejectable than fresh grafts, with statistically significant different delays (P = .0008). Mice that had received grafts healed with delays; the delays, whether associated with fresh grafts or cryopreserved grafts, were not statistically significant. On day 8 after the graft, the overall damage score for the tissue's histological architectural integrity was higher for FS. Furthermore, flow cytometry analysis showed a significant increase in the number of CD4 and CD8 T-cells (P = .001) in the spleens of FS-grafted mice. These results confirm that the use of viable CPS does not change the potential for healing. PMID- 20705626 TI - Effects of abscisic acid, ethylene and sugars on the mobilization of storage proteins and carbohydrates in seeds of the tropical tree Sesbania virgata (Leguminosae). AB - BACKGROUND AND AIMS: Endospermic legumes are abundant in tropical forests and their establishment is closely related to the mobilization of cell-wall storage polysaccharides. Endosperm cells also store large numbers of protein bodies that play an important role as a nitrogen reserve in this seed. In this work, a systems approach was adopted to evaluate some of the changes in carbohydrates and hormones during the development of seedlings of the rain forest tree Sesbania virgata during the period of establishment. METHODS: Seeds imbibed abscisic acid (ABA), glucose and sucrose in an atmosphere of ethylene, and the effects of these compounds on the protein contents, alpha-galactosidase activity and endogenous production of ABA and ethylene by the seeds were observed. KEY RESULTS: The presence of exogenous ABA retarded the degradation of storage protein in the endosperm and decreased alpha-galactosidase activity in the same tissue during galactomannan degradation, suggesting that ABA represses enzyme action. On the other hand, exogenous ethylene increased alpha-galactosidase activity in both the endosperm and testa during galactomannan degradation, suggesting an inducing effect of this hormone on the hydrolytic enzymes. Furthermore, the detection of endogenous ABA and ethylene production during the period of storage mobilization and the changes observed in the production of these endogenous hormones in the presence of glucose and sucrose, suggested a correlation between the signalling pathway of these hormones and the sugars. CONCLUSIONS: These findings suggest that ABA, ethylene and sugars play a role in the control of the hydrolytic enzyme activities in seeds of S. virgata, controlling the process of storage degradation. This is thought to ensure a balanced flow of the carbon and nitrogen for seedling development. PMID- 20705627 TI - The use of linezolid in the treatment of paediatric patients with infections caused by enterococci including strains resistant to vancomycin. PMID- 20705628 TI - Metallopharmaceuticals based on silver(I) and silver(II) polydiguanide complexes: activity against burn wound pathogens. AB - OBJECTIVES: The in vitro pharmacodynamics of silver(I) and silver(II) complexes of a polydiguanide ligand, chlorhexidine, were assayed to examine the value of the bactericidal endpoint as an alternative means of evaluating their antibacterial activities against burn wound pathogens. METHODS: Synthesis of silver(I) chlorhexidine [Ag(I)CHX] was accomplished by in situ precipitation of the complex from a feebly acidic or neutral aqueous solution of AgNO(3) and chlorhexidine, whereas silver(II) chlorhexidine [Ag(II)CHX] was synthesized by oxidation of Ag(I), followed by complexation of the oxidized metal with chlorhexidine. Their antibacterial potencies were assessed in vitro by determining the MICs and MBCs for four Gram-positive and four Gram-negative bacteria. Time-kill assays using three different concentrations of these agents were also performed. RESULTS: The MICs of Ag(I)CHX and Ag(II)CHX were much lower than those of chlorhexidine, AgNO(3) and silver sulfadiazine. The time-kill study provided quantitative information on actual times required to reach the bactericidal endpoint using a particular concentration of the active agent. The lethality rates of Ag(I)CHX and Ag(II)CHX against the tested bacteria were 2* to 8* faster than those of chlorhexidine or AgNO(3) at a concentration equal to or 4* MIC. CONCLUSIONS: Ag(I)CHX and Ag(II)CHX showed superior antibacterial activity and faster killing kinetics compared with chlorhexidine and AgNO(3). These complexes may serve as new-generation antibacterial agents in wound care. PMID- 20705630 TI - 3,3'-Dioctadecylindocarbocyanine-low-density lipoprotein uptake and flow patterns in the rabbit aorta-iliac bifurcation under three perfusion flow conditions. AB - The aim of this study was to elucidate which of the following two factors plays a more important role in the localization of atherogenesis: the barrier function of the arterial endothelium modulated by wall shear stress or flow-dependent low density lipoprotein (LDL) concentration at the blood/wall interface. To determine this, the rabbit aorto-iliac bifurcation was perfused with 3,3' dioctadecylindocarbocyanine (DiI)-LDL solution under three different flow conditions: (i) forward flow (perfused in the in vivo flow direction); (ii) backward flow (perfused in a reversed flow direction); and (iii) static group (no flow). The results showed that there was a peak in the curve of DiI-LDL uptake distribution along the lateral wall of the bifurcation for all three groups, which was located in the branching areas where the endothelial cells were round and polygonal with no preferred orientation. Nevertheless, the peak of the forward flow group was much sharper than those of the other two groups. The overall DiI-LDL uptake was the highest for the static group. The present experimental study supports the concept that both the barrier function of the endothelium modulated by wall shear stress and the mass transport phenomenon of LDL concentration polarization are involved in the infiltration/accumulation of atherogenic lipids within the arterial wall. Nevertheless, the latter might play a larger role in the localization of atherogenesis. PMID- 20705629 TI - Regulation of cell proliferation by the opioid growth factor receptor is dependent on karyopherin beta and Ran for nucleocytoplasmic trafficking. AB - The opioid growth factor (OGF; [Met(5)]-enkephalin) and the OGF receptor (OGFr) form an endogenous and tonically active growth-regulating system that modulates cell proliferation by upregulating the cyclin-dependent kinase inhibitory pathway. Previous reports have documented that nucleocytoplasmic trafficking of the OGF-OGFr axis is dependent on nuclear localization signals. This study determined the specific transport factors required for the import of the OGF-OGFr complex from the cytoplasm to the nucleus using a probe of full-length OGFr fused to enhanced green fluorescent protein (eGFP) and knockdown of karyopherin alpha1, alpha2, alpha3, alpha4 or alpha6, karyopherin beta1 or Ran with small interfering RNA (siRNA). A human squamous cell carcinoma of the head and neck cell line (squamous cell carcinoma-1, SCC-1) that was downregulated for karyopherin beta1 or Ran did not have transport of OGFr-eGFP into the nucleus. Moreover, there was an increase of 44% in bromodeoxyuridine (BrdU)-labeled cells in cultures of SCC-1 that were transfected with siRNAs to karyopherin beta1 or Ran compared with cells transfected with scrambled siRNA. No alteration in distribution of OGFr-eGFP or BrdU labeling indexes was recorded in cultures treated with siRNAs to karyopherin alpha1, alpha2, alpha3, alpha4 or alpha6. These results indicate that the regulation of cell proliferation by the OGF-OGFr axis is dependent on nucleocytoplasmic transport by karyopherin beta1 as well as the gradient of RanGTP/RanGDP across the nuclear envelope, but is not reliant on adaptor molecules related to karyopherin alpha. Thus, the passage of the OGF-OGFr complex has controlled entry from the cytoplasm to the nucleus, and the timely and faithful translocation of this cargo across the nuclear envelope is critical to cell proliferation. These hierarchical levels of nuclear import provide multiple pathways for the subtle regulation of OGF-OGFr as it relates to the control of cell proliferative events. PMID- 20705631 TI - Poly(ADP-ribose) polymerase inhibition modulates experimental acute necrotizing pancreatitis-induced oxidative stress, bacterial translocation and neopterin concentrations in rats. AB - Various studies have been performed to find out novel treatment strategies for acute necrotizing pancreatitis (ANP). Inhibition of poly(ADP-ribose) polymerase (PARP) is shown to reduce inflammation in several pathological conditions. We aimed to evaluate the efficacy of benzamide, a PARP inhibitor, in an experimental model of ANP. Thirty Sprague-Dawley rats were divided into three groups: sham operated, ANP and ANP + benzamide groups. All groups except the sham-operated group were subjected to the ANP procedure, induced by infusing of 1 mL/kg of 3% sodium taurocholate into the common biliopancreatic duct. The ANP + benzamide group received 100 mg/kg/day benzamide intraperitoneally for a total of three days after induction of pancreatitis. The surviving animals were killed at the fourth day and the pancreas was harvested for biochemical, microbiological and histological analysis. Blood samples were also obtained from the animals. In the ANP group, a significant increase was observed in concentrations of serum amylase and neopterin and tissue oxidative stress indices (malondialdehyde, superoxide dismutase and glutathione peroxidase). Almost all of these changes were found to be reversed to near their normal values in the ANP + benzamide group. Histological injury scores were significantly higher in the ANP group than in the sham group (P < 0.05, ANP versus sham), and were significantly lower in the ANP + benzamide group than in the ANP group (P < 0.05, ANP + benzamide versus ANP). Evaluation of bacterial translocation identified significantly fewer infected sites in the ANP + benzamide group than in the ANP animals (P < 0.01). We observed that inhibition of PARP with benzamide reduced the severity, the mortality, the bacterial translocation rates and the neopterin concentrations in an experimental ANP model in rats. These findings suggest that it may be possible to improve the outcome of ANP by using PARP inhibitors. PMID- 20705633 TI - Stressful weight loss. AB - This paper describes a patient initially diagnosed with autoimmune thyroiditis who undergoes a diagnostic and investigatory journey. PMID- 20705634 TI - Subregional effects of meniscal tears on cartilage loss over 2 years in knee osteoarthritis. AB - OBJECTIVES: Meniscal tears have been linked to knee osteoarthritis progression, presumably by impaired load attenuation. How meniscal tears affect osteoarthritis is unclear; subregional examination may help to elucidate whether the impact is local. This study examined the association between a tear within a specific meniscal segment and subsequent 2-year cartilage loss in subregions that the torn segment overlies. METHODS: Participants with knee osteoarthritis underwent bilateral knee MRI at baseline and 2 years. Mean cartilage thickness within each subregion was quantified. Logistic regression with generalised estimating equations were used to analyse the relationship between baseline meniscal tear in each segment and baseline to 2-year cartilage loss in each subregion, adjusting for age, gender, body mass index, tear in the other two segments and extrusion. RESULTS: 261 knees were studied in 159 individuals. Medial meniscal body tear was associated with cartilage loss in external subregions and in central and anterior tibial subregions, and posterior horn tear specifically with posterior tibial subregion loss; these relationships were independent of tears in the other segments and persisted in tibial subregions after adjustment for extrusion. Lateral meniscal body and posterior horn tear were also associated with cartilage loss in underlying subregions but not after adjustment for extrusion. Cartilage loss in the internal subregions, not covered by the menisci, was not associated with meniscal tear in any segment. CONCLUSION: These results suggest that the detrimental effect of meniscal tears is not spatially uniform across the tibial and femoral cartilage surfaces and that some of the effect is experienced locally. PMID- 20705635 TI - Elevated serum interleukin-27 levels in patients with systemic sclerosis: association with T cell, B cell and fibroblast activation. AB - OBJECTIVE: To determine serum levels of interleukin 27 (IL-27) in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc. METHODS: Serum levels of IL-27 in 91 patients with SSc and the production of IL 27 by isolated monocytes were examined by ELISA. The expression of IL-27 receptor in the skin fibroblasts, B cells and T cells was quantified by real-time PCR. The effect of IL-27 on immunoglobulin G (IgG) production of B cells, IL-17 production of CD4 T cells and proliferation and collagen synthesis of fibroblasts was also analysed. RESULTS: Serum IL-27 levels were raised in patients with SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fibrosis and immunological abnormalities. IL-27 levels also correlated positively with serum levels of hyaluronan, recently identified as an endogenous ligand for Toll-like receptors. The retrospective longitudinal analysis showed a tendency for serum IL-27 levels to be attenuated during the follow-up period. IL 27 production by cultured monocytes was increased by hyaluronan stimulation. IL 27 receptor expression was upregulated in the affected skin fibroblasts, B cells and CD4 T cells of patients with SSc. Moreover, IL-27 stimulation increased IgG production of B cells, IL-17 production of CD4 T cells and proliferation and collagen synthesis of fibroblasts in patients with SSc compared with those in healthy controls. CONCLUSION: These results suggest that IL-27 and its signalling in B cells, T cells and fibroblasts contributes to disease development in patients with SSc. PMID- 20705636 TI - The pathogenesis of bone erosions in gouty arthritis. AB - The characteristic radiographic hallmarks of chronic gouty arthritis are the presence of macroscopic tophi and erosions with overhanging edges and relative preservation of the joint space. In recent years there has been more insight into the processes underlying the development of bone erosions in gouty arthritis. This review discusses the mechanical, pathological, cellular and immunological factors that may have a role in the pathogenesis of bone erosions in gouty arthritis. It highlights the evidence suggesting that monosodium urate crystal deposition is associated with the presence of underlying osteoarthritis and the important role of osteoclasts and the receptor for activation of nuclear factor kappa B (RANK) and RANK ligand (RANK-RANKL) pathway in the pathogenesis of gouty erosions. Gouty arthritis is primarily driven by interleukin 1beta (IL-1beta). IL 1beta has been implicated in bone destruction and erosions in other inflammatory arthridities. Thus, future IL-1 inhibitors may prevent and treat erosion formation due to tophaceous gouty arthritis. This review discusses imaging modalities and highlights ultrasongraphic evidence suggesting a significant relationship between the presence of the gouty tophus and bone erosions as well as the frequent presence of persistent low-grade inflammation in asymptomatic chronic tophaceous gouty arthritis on high-resolution ultrasonography. It is the tophus eroding the underlying bone that is pivotal for the development of bone erosions in gouty arthritis. PMID- 20705637 TI - Use of TNF blockers and other targeted therapies in rare refractory immune mediated inflammatory diseases: evidence-based or rational? AB - Evidence-based medicine implies that clinical decision making should be based on external research evidence when available. This external evidence includes, but is certainly not restricted to, randomised controlled trials (RCTs). The development of powerful but often expensive targeted therapies for immune mediated inflammatory diseases (IMIDs) is one of the major successes of evidence based medicine but, paradoxically, also threatens the traditional RCT-based approach. Indeed, the increasing availability of these drugs decreases the number of patients available for RCTs, questions the ethical basis for the use of placebo groups and raises the issue of cost-efficacy. These considerations become even more important in rare phenotypically diverse and potentially life- or organ threatening IMIDs such as sarcoidosis, Behcet's disease and uveitis. Using the successful application of tumour necrosis factor blockade in these diseases as an example, this review defends the concept that pathophysiological insights in cellular and molecular disease pathways as well as limited case series are valid sources of external evidence for the rational use of targeted therapies in these rare refractory conditions. If authors fail to redefine their concept of rational therapy along the lines of not only evidence-based but also pathophysiology-based and practice-based medicine, they may underestimate the potential of novel drugs in rare refractory IMIDs and thereby jeopardise the health of their patients. PMID- 20705638 TI - Key lectures from the recent 5th Annual Canadian Cardiac Team Meeting. Introduction. PMID- 20705639 TI - 2009 H1N1 pandemic influenza: An overview. AB - OBJECTIVE: To understand the pathophysiology of influenza A, how seasonal strains behave differently from pandemic strains of the virus, and to summarize published data on the global response to the virus focusing on illness in the critical care setting. PMID- 20705640 TI - The use of ultrasound to guide interventions: from bench to bedside and back again. AB - The ultrasound machine was originally devised as a diagnostic tool to help evaluate heart structure and function. With recent advances in ultrasound, including live 3D ultrasound, its potential to guide interventions within the heart has increasingly been recognized. Cardiologists have adapted this technology and have now published guidelines on the use of ultrasound to guide interventional procedures. Anesthesiologists have also used ultrasound with much success in cardiac operating rooms (ORs) to guide cannula placement and, to a limited extent, interventions. The focus of this article is a review of the author's work on ultrasound and virtual reality-guided cardiac interventions, both in the research laboratory and in the OR. PMID- 20705641 TI - Vasopressin and methylene blue: alternate therapies in vasodilatory shock. AB - Cardiac surgery with cardiopulmonary bypass (CPB) is frequently complicated by vasoplegic syndrome, a vasodilatory shock state. Traditional treatment based on fluid resuscitation and catecholamine drugs is ineffective in a number of patients. Clinical trials investigating both vasopressin and methylene blue as additional rescue or preventative therapy are reviewed. Vasopressin is suggested to retain its vasoconstrictive power in hypoxemia and acidosis, lower pulmonary hypertension, reduce supraventricular arrhythmias, and accelerate intensive care unit (ICU) recovery. Safety concerns include frequent thrombocytopenia and potentially altered mesenteric and renal perfusion. Methylene blue is suggested to facilitate CPB weaning, reduce renal, respiratory, arrhythmic, and septic complications, reduce mortality, and accelerate ICU and hospital recovery. Safety concerns include oximeter interference, pulmonary hypertension, neurotoxicity, arrhythmias, and potentially altered coronary, mesenteric, and renal perfusion. Research on both molecules is ongoing and has yet to confirm on a larger scale their efficacy and safety as treatments for post-CPB vasoplegic syndrome. PMID- 20705642 TI - Pain management after cardiac surgery. AB - Pain levels after cardiac surgery are often severe and undertreated. The effects of undertreatment may be both severe and prolonged. The incidence of chronic pain after cardiac surgery varies between 21% and 55%. Pain syndromes that occur following cardiac surgery may be multiple and may be of visceral, musculoskeletal, or neurogenic origin. Risk factors for acute pain vary depending on the study but generally include younger age, longer duration of surgery, and the location of the surgery. Risk factors for chronic pain include depression and psychological vulnerability, both preoperative and postoperative. Other independent risk factors for chronic pain are more extensive surgery, surgery lasting longer than 3 hours, and ASA grade greater than III. Pain control is achieved with regular and systematic evaluation and the use of multimodal regimens. Treatment strategies that are commonly used include opioids, paracetamol, NSAIDS, and more recently anticonvulsants. PMID- 20705643 TI - Glucose-6-phosphate dehydrogenase deficiency and cardiac surgery. AB - Cardiac surgery involving cardiopulmonary bypass (CPB) in its conventional form involves many processes leading to free radical production, such as perioperative ischemia, reperfusion, circulation of whole body blood through the CPB circuit, hypothermia and acidosis. The red blood cells of a glucose-6-phosphate dehydrogenase (G6PD)-deficient person are unable to scavenge these free radicals, resulting in haemolysis. Here, we describe the successful anaesthetic management of two G6PD-deficient children who underwent cardiac surgery, on and off CPB, without any obvious haemolytic reaction, followed by a discussion of the disorder, with specific consideration of perioperative management of such cases. PMID- 20705644 TI - Early renal damage assessed by the SLICC/ACR damage index is predictor of severe outcome in lupus patients in Pakistan. AB - We investigated patients with systemic lupus erythematosus with the objective of assessing whether early damage accrued in systemic lupus erythematosus as measured by the SLICC/ ACR Damage Index predicts mortality in lupus patients that have been followed prospectively in a single center. Patients with systemic lupus erythematosus from Aga Khan University hospital presenting between 1992 and 2007 were included. This enabled all patients to be potentially followed for at least 10 years. Yearly SLICC/ACR Damage Index scores were determined for each patient. Early damage was defined as a score >=1, and no damage as a score of 0 at the initial assessment. Kaplan-Meier and Log rank tests were used to compare the survival experience between those with and without damage, with all patients being assessed at 10 years. In this inception cohort 198 patients were identified and were followed for 10 years. Of these, 47 (23.7%) patients had a SLICC/ACR Damage Index score of 0 (no damage) while 151 patients (76.3%) had at least one SLICC/ACR Damage Index item scored (early damage). Mean renal damage score at 1, 5 and 10 years was 0.16, 0.34 and 0.67, respectively. Of lupus patients who exhibited renal damage at their first SLICC/ACR Damage Index assessment, 31% died within 10 years of their illness as compared with only 13% who had no early renal damage (p < 0.003). Mean renal damage score at 1 year after diagnosis was a significant predictor of death within 10 years of diagnosis (p < 0.002). PMID- 20705645 TI - Kinetic and functional analysis of the small RNA methyltransferase HEN1: the catalytic domain is essential for preferential modification of duplex RNA. AB - The HEN1 RNA methyltransferase from Arabidopsis thaliana catalyzes S-adenosyl-L methionine (AdoMet)-dependent 2'-O-methylation at the 3'-termini of small double stranded RNAs and is a crucial factor in the biogenesis of plant small noncoding RNAs, such as miRNAs or siRNAs. We performed functional and kinetic studies of the full-length HEN1 methyltransferase and its truncated form comprising the C terminal part of the protein (residues 666-942) with a variety of model RNA substrates. Kinetic parameters obtained with natural RNA substrates indicate that HEN1 is highly catalytically efficient in the absence of any supplementary proteins. We find that the enzyme modifies individual strands in succession leading to complete methylation of an RNA duplex. The rates of methyl group transfer to individual strands of hemimethylated substrates under single turnover conditions are comparable with the multiple turnover rate under steady-state conditions, suggesting that release of reaction products is not a rate-limiting event in the reaction cycle. The truncated protein, which includes conserved motifs characteristic for AdoMet binding, efficiently modifies double-stranded RNA substrates in vitro; however, in contrast to the full-length methyltransferase, it shows weaker interactions with both substrates and is sensitive to base mispairing in the first and second positions of the RNA duplex. Our findings suggest an important role for the N-terminal domains in stabilizing the catalytic complex and indicate that major structural determinants required for selective recognition and methylation of RNA duplexes reside in the C terminal domain. PMID- 20705646 TI - Ubiquitous presence of the hammerhead ribozyme motif along the tree of life. AB - Examples of small self-cleaving RNAs embedded in noncoding regions already have been found to be involved in the control of gene expression, although their origin remains uncertain. In this work, we show the widespread occurrence of the hammerhead ribozyme (HHR) motif among genomes from the Bacteria, Chromalveolata, Plantae, and Metazoa kingdoms. Intergenic HHRs were detected in three different bacterial genomes, whereas metagenomic data from Galapagos Islands showed the occurrence of similar ribozymes that could be regarded as direct relics from the RNA world. Among eukaryotes, HHRs were detected in the genomes of three water molds as well as 20 plant species, ranging from unicellular algae to vascular plants. These HHRs were very similar to those previously described in small RNA plant pathogens and, in some cases, appeared as close tandem repetitions. A parallel situation of tandemly repeated HHR motifs was also detected in the genomes of lower metazoans from cnidarians to invertebrates, with special emphasis among hematophagous and parasitic organisms. Altogether, these findings unveil the HHR as a widespread motif in DNA genomes, which would be involved in new forms of retrotransposable elements. PMID- 20705647 TI - Dissecting functional cooperation among protein subunits in archaeal RNase P, a catalytic ribonucleoprotein complex. AB - RNase P catalyzes the Mg(2)(+)-dependent 5'-maturation of precursor tRNAs. Biochemical studies on the bacterial holoenzyme, composed of one catalytic RNase P RNA (RPR) and one RNase P protein (RPP), have helped understand the pleiotropic roles (including substrate/Mg(2+) binding) by which a protein could facilitate RNA catalysis. As a model for uncovering the functional coordination among multiple proteins that aid an RNA catalyst, we use archaeal RNase P, which comprises one catalytic RPR and at least four RPPs. Exploiting our previous finding that these archaeal RPPs function as two binary RPP complexes (POP5*RPP30 and RPP21*RPP29), we prepared recombinant RPP pairs from three archaea and established interchangeability of subunits through homologous/heterologous assemblies. Our finding that archaeal POP5*RPP30 reconstituted with bacterial and organellar RPRs suggests functional overlap of this binary complex with the bacterial RPP and highlights their shared recognition of a phylogenetically conserved RPR catalytic core, whose minimal attributes we further defined through deletion mutagenesis. Moreover, single-turnover kinetic studies revealed that while POP5*RPP30 is solely responsible for enhancing the RPR's rate of precursor tRNA cleavage (by 60-fold), RPP21*RPP29 contributes to increased substrate affinity (by 16-fold). Collectively, these studies provide new perspectives on the functioning and evolution of an ancient, catalytic ribonucleoprotein. PMID- 20705648 TI - Incorporation of dUTP does not mediate mutation of A:T base pairs in Ig genes in vivo. AB - Activation-induced cytidine deaminase (AID) protein initiates Ig gene mutation by deaminating cytosines, converting them into uracils. Excision of AID-induced uracils by uracil-N-glycosylase is responsible for most transversion mutations at G:C base pairs. On the other hand, processing of AID-induced G:U mismatches by mismatch repair factors is responsible for most mutation at Ig A:T base pairs. Why mismatch processing should be error prone is unknown. One theory proposes that long patch excision in G1-phase leads to dUTP-incorporation opposite adenines as a result of the higher G1-phase ratio of nuclear dUTP to dTTP. Subsequent base excision at the A:U base pairs produced could then create non instructional templates leading to permanent mutations at A:T base pairs (1). This compelling theory has remained untested. We have developed a method to rapidly modify DNA repair pathways in mutating mouse B cells in vivo by transducing Ig knock-in splenic mouse B cells with GFP-tagged retroviruses, then adoptively transferring GFP(+) cells, along with appropriate antigen, into primed congenic hosts. We have used this method to show that dUTP-incorporation is unlikely to be the cause of AID-induced mutation of A:T base pairs, and instead propose that A:T mutations might arise as an indirect consequence of nucleotide paucity during AID-induced DNA repair. PMID- 20705649 TI - Objective sequence-based subfamily classifications of mouse homeodomains reflect their in vitro DNA-binding preferences. AB - Classifying proteins into subgroups with similar molecular function on the basis of sequence is an important step in deriving reliable functional annotations computationally. So far, however, available classification procedures have been evaluated against protein subgroups that are defined by experts using mainly qualitative descriptions of molecular function. Recently, in vitro DNA-binding preferences to all possible 8-nt DNA sequences have been measured for 178 mouse homeodomains using protein-binding microarrays, offering the unprecedented opportunity of evaluating the classification methods against quantitative measures of molecular function. To this end, we automatically derive homeodomain subtypes from the DNA-binding data and independently group the same domains using sequence information alone. We test five sequence-based methods, which use different sequence-similarity measures and algorithms to group sequences. Results show that methods that optimize the classification robustness reflect well the detailed functional specificity revealed by the experimental data. In some of these classifications, 73-83% of the subfamilies exactly correspond to, or are completely contained in, the function-based subtypes. Our findings demonstrate that certain sequence-based classifications are capable of yielding very specific molecular function annotations. The availability of quantitative descriptions of molecular function, such as DNA-binding data, will be a key factor in exploiting this potential in the future. PMID- 20705650 TI - Identifying eIF4E-binding protein translationally-controlled transcripts reveals links to mRNAs bound by specific PUF proteins. AB - eIF4E-binding proteins (4E-BPs) regulate translation of mRNAs in eukaryotes. However the extent to which specific mRNA targets are regulated by 4E-BPs remains unknown. We performed translational profiling by microarray analysis of polysome and monosome associated mRNAs in wild-type and mutant cells to identify mRNAs in yeast regulated by the 4E-BPs Caf20p and Eap1p; the first-global comparison of 4E BP target mRNAs. We find that yeast 4E-BPs modulate the translation of >1000 genes. Most target mRNAs differ between the 4E-BPs revealing mRNA specificity for translational control by each 4E-BP. This is supported by observations that eap1Delta and caf20Delta cells have different nitrogen source utilization defects, implying different mRNA targets. To account for the mRNA specificity shown by each 4E-BP, we found correlations between our data sets and previously determined targets of yeast mRNA-binding proteins. We used affinity chromatography experiments to uncover specific RNA-stabilized complexes formed between Caf20p and Puf4p/Puf5p and between Eap1p and Puf1p/Puf2p. Thus the combined action of each 4E-BP with specific 3'-UTR-binding proteins mediates mRNA specific translational control in yeast, showing that this form of translational control is more widely employed than previously thought. PMID- 20705651 TI - Mapping of the nuclear matrix-bound chromatin hubs by a new M3C experimental procedure. AB - We have developed an experimental procedure to analyze the spatial proximity of nuclear matrix-bound DNA fragments. This protocol, referred to as Matrix 3C (M3C), includes a high salt extraction of nuclei, the removal of distal parts of unfolded DNA loops using restriction enzyme treatment, ligation of the nuclear matrix-bound DNA fragments and a subsequent analysis of ligation frequencies. Using the M3C procedure, we have demonstrated that CpG islands of at least three housekeeping genes that surround the chicken alpha-globin gene domain are assembled into a complex (presumably, a transcription factory) that is stabilized by the nuclear matrix in both erythroid and non-erythroid cells. In erythroid cells, the regulatory elements of the alpha-globin genes are attracted to this complex to form a new assembly: an active chromatin hub that is linked to the pre existing transcription factory. The erythroid-specific part of the assembly is removed by high salt extraction. Based on these observations, we propose that mixed transcription factories that mediate the transcription of both housekeeping and tissue-specific genes are composed of a permanent compartment containing integrated into the nuclear matrix promoters of housekeeping genes and a 'guest' compartment where promoters and regulatory elements of tissue-specific genes can be temporarily recruited. PMID- 20705652 TI - Functional microRNA generated from a cytoplasmic RNA virus. AB - MicroRNAs (miRNAs) are a class of small, non-coding RNAs that play a pivotal role in the regulation of posttranscriptional gene expression in a wide range of eukaryotic organisms. Although DNA viruses have been shown to encode miRNAs and exploit the cellular RNA silencing machinery as a convenient way to regulate viral and host gene expression, it is generally believed that this pathway is not available to RNA viruses that replicate in the cytoplasm of the cell because miRNA biogenesis is initiated in the nucleus. In fact, among the >200 viral miRNAs that have been experimentally verified so far, none is derived from an RNA virus. Here, we show that a cytoplasmic RNA virus can indeed encode and produce a functional miRNA. We introduced a heterologous miRNA-precursor stem-loop sequence element into the RNA genome of the flavivirus tick-borne encephalitis virus, and this led to the production of a functional miRNA during viral infection without impairing viral RNA replication. These findings demonstrate that miRNA biogenesis can be used by cytoplasmic RNA viruses to produce regulatory molecules for the modulation of the transcriptome. PMID- 20705653 TI - RECQ5 helicase associates with the C-terminal repeat domain of RNA polymerase II during productive elongation phase of transcription. AB - It is known that transcription can induce DNA recombination, thus compromising genomic stability. RECQ5 DNA helicase promotes genomic stability by regulating homologous recombination. Recent studies have shown that RECQ5 forms a stable complex with RNA polymerase II (RNAPII) in human cells, but the cellular role of this association is not understood. Here, we provide evidence that RECQ5 specifically binds to the Ser2,5-phosphorylated C-terminal repeat domain (CTD) of the largest subunit of RNAPII, RPB1, by means of a Set2-Rpb1-interacting (SRI) motif located at the C-terminus of RECQ5. We also show that RECQ5 associates with RNAPII-transcribed genes in a manner dependent on the SRI motif. Notably, RECQ5 density on transcribed genes correlates with the density of Ser2-CTD phosphorylation, which is associated with the productive elongation phase of transcription. Furthermore, we show that RECQ5 negatively affects cell viability upon inhibition of spliceosome assembly, which can lead to the formation of mutagenic R-loop structures. These data indicate that RECQ5 binds to the elongating RNAPII complex and support the idea that RECQ5 plays a role in the maintenance of genomic stability during transcription. PMID- 20705654 TI - A flexible loop in yeast ribosomal protein L11 coordinates P-site tRNA binding. AB - High-resolution structures reveal that yeast ribosomal protein L11 and its bacterial/archael homologs called L5 contain a highly conserved, basically charged internal loop that interacts with the peptidyl-transfer RNA (tRNA) T loop. We call this the L11 'P-site loop'. Chemical protection of wild-type ribosome shows that that the P-site loop is inherently flexible, i.e. it is extended into the ribosomal P-site when this is unoccupied by tRNA, while it is retracted into the terminal loop of 25S rRNA Helix 84 when the P-site is occupied. To further analyze the function of this structure, a series of mutants within the P-site loop were created and analyzed. A mutant that favors interaction of the P-site loop with the terminal loop of Helix 84 promoted increased affinity for peptidyl-tRNA, while another that favors its extension into the ribosomal P-site had the opposite effect. The two mutants also had opposing effects on binding of aa-tRNA to the ribosomal A-site, and downstream functional effects were observed on translational fidelity, drug resistance/hypersensitivity, virus maintenance and overall cell growth. These analyses suggest that the L11 P-site loop normally helps to optimize ribosome function by monitoring the occupancy status of the ribosomal P-site. PMID- 20705656 TI - From a cancer drug fund to value based pricing of drugs. PMID- 20705658 TI - Volatile organic compound production by organisms in the genus Ascocoryne and a re-evaluation of myco-diesel production by NRRL 50072. AB - The Patagonian fungal endophyte NRRL 50072 is reported to produce a variety of medium-chain and highly branched volatile organic compounds (VOCs) that have been highlighted for their potential as fuel alternatives and are collectively termed myco-diesel. To assess the novelty of this observation, we determined the extent to which ten closely related Ascocoryne strains from commercial culture collections possess similar VOC production capability. DNA sequencing established a high genetic similarity between NRRL 50072 and each Ascocoryne isolate, consistent with its reassignment as Ascocoryne sarcoides. The Ascocoryne strains did not produce highly branched medium-chain-length alkanes, and efforts to reproduce the branched alkane production of NRRL 50072 were unsuccessful. However, we confirmed the production of 30 other products and expanded the list of VOCs for NRRL 50072 and members of the genus Ascocoryne. VOCs detected from the cultures consisted of short- and medium-chain alkenes, ketones, esters and alcohols and several sesquiterpenes. Ascocoryne strains NRRL 50072 and CBS 309.71 produced a more diverse range of volatiles than the other isolates tested. CBS 309.71 also showed enhanced production compared with other strains when grown on cellulose agar. Collectively, the members of the genus Ascocoryne demonstrated production of over 100 individual compounds, with a third of the short- and medium-chain compounds also produced when cultures were grown on a cellulose substrate. This comparative production analysis could facilitate future studies to identify and manipulate the biosynthetic machinery responsible for production of individual VOCs, including several that have a potential application as biofuels. PMID- 20705659 TI - FSY1, a horizontally transferred gene in the Saccharomyces cerevisiae EC1118 wine yeast strain, encodes a high-affinity fructose/H+ symporter. AB - Transport of glucose and fructose in the yeast Saccharomyces cerevisiae plays a crucial role in controlling the rate of wine fermentation. In S. cerevisiae, hexoses are transported by facilitated diffusion via hexose carriers (Hxt), which prefer glucose to fructose. However, utilization of fructose by wine yeast is critically important at the end of fermentation. Here, we report the characterization of a fructose transporter recently identified by sequencing the genome of the commercial wine yeast strain EC1118 and found in many other wine yeasts. This transporter is designated Fsy1p because of its homology with the Saccharomyces pastorianus fructose/H(+) symporter Fsy1p. A strain obtained by transformation of the V5 hxt1-7Delta mutant with FSY1 grew well on fructose, but to a much lesser extent on glucose as the sole carbon source. Sugar uptake and symport experiments showed that FSY1 encodes a proton-coupled symporter with high affinity for fructose (K(m) 0.24+/-0.04mM). Using real-time RT-PCR, we also investigated the expression pattern of FSY1 in EC1118 growing on various carbon sources. FSY1 was repressed by high concentrations of glucose or fructose and was highly expressed on ethanol as the sole carbon source. The characteristics of this transporter indicate that its acquisition could confer a significant advantage to S. cerevisiae during the wine fermentation process. This transporter is a good example of acquisition of a new function in yeast by horizontal gene transfer. PMID- 20705660 TI - Essential histidine pairs indicate conserved haem binding in epsilonproteobacterial cytochrome c haem lyases. AB - Bacterial cytochrome c maturation occurs at the outside of the cytoplasmic membrane, requires transport of haem b across the membrane, and depends on membrane-bound cytochrome c haem lyase (CCHL), an enzyme that catalyses covalent attachment of haem b to apocytochrome c. Epsilonproteobacteria such as Wolinella succinogenes use the cytochrome c biogenesis system II and contain unusually large CCHL proteins of about 900 amino acid residues that appear to be fusions of the CcsB and CcsA proteins found in other bacteria. CcsBA-type CCHLs have been proposed to act as haem transporters that contain two haem b coordination sites located at different sides of the membrane and formed by histidine pairs. W. succinogenes cells contain three CcsBA-type CCHL isoenzymes (NrfI, CcsA1 and CcsA2) that are known to differ in their specificity for apocytochromes and apparently recognize different haem c binding motifs such as CX(2)CH (by CcsA2), CX(2)CK (by NrfI) and CX(15)CH (by CcsA1). In this study, conserved histidine residues were individually replaced by alanine in each of the W. succinogenes CCHLs. Characterization of NrfI and CcsA1 variants in W. succinogenes demonstrated that a set of four histidines is essential for maturing the dedicated multihaem cytochromes c NrfA and MccA, respectively. The function of W. succinogenes CcsA2 variants produced in Escherichia coli was also found to depend on each of these four conserved histidine residues. The presence of imidazole in the growth medium of both W. succinogenes and E. coli rescued the cytochrome c biogenesis activity of most histidine variants, albeit to different extents, thereby implying the presence of two functionally distinct histidine pairs in each CCHL. The data support a model in which two conserved haem b binding sites are involved in haem transport catalysed by CcsBA-type CCHLs. PMID- 20705661 TI - Long-term impacts of antibiotic exposure on the human intestinal microbiota. AB - Although it is known that antibiotics have short-term impacts on the human microbiome, recent evidence demonstrates that the impacts of some antibiotics remain for extended periods of time. In addition, antibiotic-resistant strains can persist in the human host environment in the absence of selective pressure. Both molecular- and cultivation-based approaches have revealed ecological disturbances in the microbiota after antibiotic administration, in particular for specific members of the bacterial community that are susceptible or alternatively resistant to the antibiotic in question. A disturbing consequence of antibiotic treatment has been the long-term persistence of antibiotic resistance genes, for example in the human gut. These data warrant use of prudence in the administration of antibiotics that could aggravate the growing battle with emerging antibiotic-resistant pathogenic strains. PMID- 20705662 TI - Streptococcal inhibitor of complement-mediated lysis (SIC): an anti-inflammatory virulence determinant. AB - Since the late 1980s, a worldwide increase of severe Streptococcus pyogenes infections has been associated with strains of the M1 serotype, strains which all secrete the streptococcal inhibitor of complement-mediated lysis (SIC). Previous work has shown that SIC blocks complement-mediated haemolysis, inhibits the activity of antibacterial peptides and has affinity for the human plasma proteins clusterin and histidine-rich glycoprotein; the latter is a member of the cystatin protein family. The present work demonstrates that SIC binds to cystatin C, high molecular-mass kininogen (HK) and low-molecular-mass kininogen, which are additional members of this protein family. The binding sites in HK are located in the cystatin-like domain D3 and the endothelial cell-binding domain D5. Immobilization of HK to cellular structures plays a central role in activation of the human contact system. SIC was found to inhibit the binding of HK to endothelial cells, and to reduce contact activation as measured by prolonged blood clotting time and impaired release of bradykinin. These results suggest that SIC modifies host defence systems, which may contribute to the virulence of S. pyogenes strains of the M1 serotype. PMID- 20705663 TI - Heterogeneous distribution of Candida albicans cell-surface antigens demonstrated with an Als1-specific monoclonal antibody. AB - Despite an abundance of data describing expression of genes in the Candida albicans ALS (agglutinin-like sequence) gene family, little is known about the production of Als proteins on individual cells, their spatial localization or stability. Als proteins are most commonly discussed with respect to function in adhesion of C. albicans to host and abiotic surfaces. Development of a mAb specific for Als1, one of the eight large glycoproteins encoded by the ALS family, provided the opportunity to detect Als1 during growth of yeast and hyphae, both in vitro and in vivo, and to demonstrate the utility of the mAb in blocking C. albicans adhesion to host cells. Although most C. albicans yeast cells in a saturated culture are Als1-negative by indirect immunofluorescence, Als1 is detected on the surface of nearly all cells shortly after transfer into fresh growth medium. Als1 covers the yeast cell surface, with the exception of bud scars. Daughters of the inoculum cells, and sometimes granddaughters, also have detectable Als1, but Als1 is not detectable on cells from subsequent generations. On germ tubes and hyphae, most Als1 is localized proximal to the mother yeast. Once deposited on yeasts or hyphae, Als1 persists long after the culture has reached saturation. Growth stage-dependent production of Als1, coupled with its persistence on the cell surface, results in a heterogeneous population of cells within a C. albicans culture. Anti-Als1 immunolabelling patterns vary depending on the source of the C. albicans cells, with obvious differences between cells recovered from culture and those from a murine model of disseminated candidiasis. Results from this work highlight the temporal parallels for ALS1 expression and Als1 production in yeasts and germ tubes, the specialized spatial localization and persistence of Als1 on the C. albicans cell surface, and the differences in Als1 localization that occur in vitro and in vivo. PMID- 20705664 TI - Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. AB - Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that has been associated with aberrant microbiota. This review focuses on the recent molecular insights generated by analysing the intestinal microbiota in subjects suffering from IBS. Special emphasis is given to studies that compare and contrast the microbiota of healthy subjects with that of IBS patients classified into different subgroups based on their predominant bowel pattern as defined by the Rome criteria. The current data available from a limited number of patients do not reveal pronounced and reproducible IBS-related deviations of entire phylogenetic or functional microbial groups, but rather support the concept that IBS patients have alterations in the proportions of commensals with interrelated changes in the metabolic output and overall microbial ecology. The lack of apparent similarities in the taxonomy of microbiota in IBS patients may partially arise from the fact that the applied molecular methods, the nature and location of IBS subjects, and the statistical power of the studies have varied considerably. Most recent advances, especially the finding that several uncharacterized phylotypes show non-random segregation between healthy and IBS subjects, indicate the possibility of discovering bacteria specific for IBS. Moreover, tools are being developed for the functional analysis of the relationship between the intestinal microbiota and IBS. These approaches may be instrumental in the evaluation of the ecological dysbiosis hypothesis in the gut ecosystem. Finally, we discuss the future outlook for research avenues and candidate microbial biomarkers that may eventually be used in IBS diagnosis. PMID- 20705665 TI - A streptococcal effector protein that inhibits Porphyromonas gingivalis biofilm development. AB - Dental plaque formation is a developmental process involving cooperation and competition within a diverse microbial community, approximately 70 % of which is composed of an array of streptococci during the early stages of supragingival plaque formation. In this study, 79 cell-free culture supernatants from a variety of oral streptococci were screened to identify extracellular compounds that inhibit biofilm formation by the oral anaerobe Porphyromonas gingivalis strain 381. The majority of the streptococcal supernatants (61 isolates) resulted in lysis of P. gingivalis cells, and some (17 isolates) had no effect on cell viability, growth or biofilm formation. One strain, however, produced a supernatant that abolished biofilm formation without affecting growth rate. Analysis of this activity led to the discovery that a 48 kDa protein was responsible for the inhibition. Protein sequence identification and enzyme activity assays identified the effector protein as an arginine deiminase. To identify the mechanism(s) by which this protein inhibits biofilm formation, we began by examining the expression levels of genes encoding fimbrial subunits; surface structures known to be involved in biofilm development. Quantitative RT PCR analysis revealed that exposure of P. gingivalis cells to this protein for 1 h resulted in the downregulation of genes encoding proteins that are the major subunits of two distinct types of thin, single-stranded fimbriae (fimA and mfa1). Furthermore, this downregulation occurred in the absence of arginine deiminase enzymic activity. Hence, our data indicate that P. gingivalis can sense this extracellular protein, produced by an oral streptococcus (Streptococcus intermedius), and respond by downregulating expression of cell-surface appendages required for attachment and biofilm development. PMID- 20705666 TI - Revealing the essentiality of multiple archaeal pcna genes using a mutant propagation assay based on an improved knockout method. AB - Organisms belonging to the Crenarchaeota lineage contain three proliferating cell nuclear antigen (PCNA) subunits, while those in the Euryarchaeota have only one, as for Eukarya. To study the mechanism of archaeal sliding clamps, we sought to generate knockouts for each pcna gene in Sulfolobus islandicus, a hyperthermophilic crenarchaeon, but failed with two conventional knockout methods. Then, a new knockout scheme, known as marker insertion and target gene deletion (MID), was developed, with which transformants were obtained for each pMID-pcna plasmid. We found that mutant cells persisted in transformant cultures during incubation of pMID-pcna3 and pMID-araS-pcna1 transformants under counter selection. Studying the propagation of mutant cells by semiquantitative PCR analysis of the deleted target gene allele (Deltapcna1 or Deltapcna3) revealed that mutant cells could no longer be propagated, demonstrating that these pcna genes are absolutely required for host cell viability. Because the only prerequisite for this assay is the generation of a MID transformant, this approach can be applied generally to any micro-organisms proficient in homologous recombination. PMID- 20705667 TI - Candida albicans forms biofilms on the vaginal mucosa. AB - Current understanding of resistance and susceptibility to vulvovaginal candidiasis challenges existing paradigms of host defence against fungal infection. While abiotic biofilm formation has a clearly established role during systemic Candida infections, it is not known whether C. albicans forms biofilms on the vaginal mucosa and the possible role of biofilms in disease. In vivo and ex vivo murine vaginitis models were employed to examine biofilm formation by scanning electron and confocal microscopy. C. albicans strains included 3153A (lab strain), DAY185 (parental control strain), and mutants defective in morphogenesis and/or biofilm formation in vitro (efg1/efg1 and bcr1/bcr1). Both 3153A and DAY815 formed biofilms on the vaginal mucosa in vivo and ex vivo as indicated by high fungal burden and microscopic analysis demonstrating typical biofilm architecture and presence of extracellular matrix (ECM) co-localized with the presence of fungi. In contrast, efg1/efg1 and bcr1/bcr1 mutant strains exhibited weak or no biofilm formation/ECM production in both models compared to wild-type strains and complemented mutants despite comparable colonization levels. These data show for the first time that C. albicans forms biofilms in vivo on vaginal epithelium, and that in vivo biotic biofilm formation requires regulators of biofilm formation (BCR1) and morphogenesis (EFG1). PMID- 20705668 TI - Phenotypic and physiological alterations by heterologous acylhomoserine lactone synthase expression in Pseudomonas putida. AB - Many bacteria harbour an incomplete quorum-sensing (QS) system, whereby they possess LuxR homologues without the QS acylhomoserine lactone (AHL) synthase, which is encoded by a luxI homologue. An artificial AHL-producing plasmid was constructed using a cviI gene encoding the C6-AHL [N-hexanoyl homoserine lactone (HHL)] synthase from Chromobacterium violaceum, and was introduced successfully into both the wild-type and a ppoR (luxR homologue) mutant of Pseudomonas putida. Our data provide evidence to suggest that the PpoR-HHL complex, but neither PpoR nor HHL alone, could attenuate growth, antibiotic resistance and biofilm formation ability. In contrast, swimming motility, siderophore production and indole degradation were enhanced by PpoR-HHL. The addition of exogenous indole increased biofilm formation and reduced swimming motility. Interestingly, indole proved ineffective in the presence of PpoR-HHL, thereby suggesting that the PpoR HHL complex masks the effects of indole. Our data were supported by transcriptome analyses, which showed that the presence of the plasmid-encoded AHL synthase altered the expression of many genes on the chromosome in strain KT2440. Our results showed that heterologous luxI expression that occurs via horizontal gene transfer can regulate a broad range of specific target genes, resulting in alterations of the phenotype and physiology of host cells. PMID- 20705670 TI - Medicare doesn't work as well for younger, disabled beneficiaries as it does for older enrollees. AB - Medicare is not working as well for its eight million disabled beneficiaries under age sixty-five as it is for its older beneficiaries. We report on a 2008 survey that found significant differences between the two Medicare populations, with the younger group experiencing more problems of cost and access. Even with the Medicare Part D prescription drug program, the nonelderly disabled reported greater difficulty in affording medications, and more adverse health consequences as a result. One potential remedy is the Patient Protection and Affordable Care Act. The law includes reforms that could improve access to care and limit out-of pocket expenses for the nonelderly disabled in Medicare-as well as those who are waiting to become eligible for the program. PMID- 20705669 TI - G protein-coupled receptor kinase 2 and arrestin2 regulate arterial smooth muscle P2Y-purinoceptor signalling. AB - AIMS: prolonged P2Y-receptor signalling can cause vasoconstriction leading to hypertension, vascular smooth muscle hypertrophy, and hyperplasia. G protein coupled receptor signalling is negatively regulated by G protein-coupled receptor kinases (GRKs) and arrestin proteins, preventing prolonged or inappropriate signalling. This study investigates whether GRKs and arrestins regulate uridine 5'-triphosphate (UTP)-stimulated contractile signalling in adult Wistar rat mesenteric arterial smooth muscle cells (MSMCs). METHODS AND RESULTS: mesenteric arteries contracted in response to UTP challenge: When an EC(50) UTP concentration (30 uM, 5 min) was added 5 min before (R(1)) and after (R(2)) the addition of a maximal UTP concentration (R(max): 100 uM, 5 min), R(2) responses were decreased relative to R(1), indicating desensitization. UTP-induced P2Y receptor desensitization of phospholipase C signalling was studied in isolated MSMCs transfected with an inositol 1,4,5-trisphosphate biosensor and/or loaded with Ca(2+)-sensitive dyes. A similar protocol (R(1)/R(2) = 10 uM; R(max) = 100 uM, applied for 30 s) revealed markedly reduced R(2) when compared with R(1) responses. MSMCs were transfected with dominant-negative GRKs or siRNAs targeting specific GRK/arrestins to probe their respective roles in P2Y-receptor desensitization. GRK2 inhibition, but not GRK3, GRK5, or GRK6, attenuated P2Y receptor desensitization. siRNA-mediated knockdown of arrestin2 attenuated UTP stimulated P2Y-receptor desensitization, whereas arrestin3 depletion did not. Specific siRNA knockdown of the P2Y(2)-receptor almost completely abolished UTP stimulated IP(3)/Ca(2+) signalling, strongly suggesting that our study is specifically characterizing this purinoceptor subtype. CONCLUSION: these new data highlight roles of GRK2 and arrestin2 as important regulators of UTP-stimulated P2Y(2)-receptor responsiveness in resistance arteries, emphasizing their potential importance in regulating vasoconstrictor signalling pathways implicated in vascular disease. PMID- 20705677 TI - Organized intrapericardial haematoma: a rare cause of heart failure after 2 years of trauma. AB - Intrapericardial organized haematoma secondary to blunt chest trauma is an extremely rare cause of constrictive pericarditis. We report a 30-year-old male who presented with heart failure for 12 months and was found to have an organized intrapericardial haematoma secondary to blunt chest trauma in a road traffic accident 2 years prior. The use of multiple imaging modalities including two dimensional (transthoracic and transoesophageal) echocardiogram and cardiac magnetic resonance imaging established the diagnosis. Surgical excision of the haematoma and removal of the constricting pericardium relieved his symptoms. PMID- 20705678 TI - Extended producer responsibility for packaging wastes and WEEE - a comparison of implementation and the role of local authorities across Europe. AB - A comparison of the implementation of extended producer responsibility (EPR) to packaging waste and waste electrical and electronic equipment (WEEE) is presented for a representative sample of eleven European Union countries based on five indicators: stakeholders and responsibilities; compliance mechanisms; role of local authorities; financing mechanisms and merits and limitations, with four countries selected for more detailed case study analysis. Similarities, trends and differences in national systems are highlighted with particular focus on the role of local authorities and their relationship with obligated producers and the effect on the operation and success of each system. The national systems vary considerably in design, in terms of influence of pre-existing policy and systems, methods of achieving producer compliance (multiple or single collective schemes), fee structures, targets, waste stream prioritization and local authority involvement. Differing approaches are evident across all member states with respect to the role played by local authorities, responsibility apportioned to them, and the evolution of working relationships between obligated producers and municipalities. On the whole, EPR for packaging and WEEE has been successfully implemented throughout Europe in terms of Directive targets. It is, however, clear that the EPR systems currently in application across Europe differ primarily due to contrasting opinion on the legitimacy of local authorities as stakeholders and, in some cases, a fear on the part of industry of associated costs. Where local authorities have been engaged in the design and implementation of national systems, existing infrastructure used and defined roles established for producers and local authorities, results have been significantly more positive than in the cases where local authorities have had limited engagement. PMID- 20705679 TI - Thermal decomposition of pyrometallurgical copper slag by oxidation in synthetic air. AB - The purpose of this study was to investigate the possibility of separating pyrometallurgical copper (fayalite) slag by oxidation in a synthetic air atmosphere into ferrous and silicate phases suitable for resources to be recovered from them. Isothermal oxidation kinetics and the most probable reaction models are studied in the temperature range of 773 to 1173 K using thermogravimetric analysis data and the classical Johnson-Mehl-Avrami-Yerofeev Kolmogorov (JMAYK) equation. Depending on the model applied, the activation energies of fayalite slag oxidation in the temperature range of 773-973 K were: D1: 37.55 kJ mol(-1); D2: 43.27 kJ mol(-1); D3: 50.52 kJ mol(-1); and D4: 45.65 kJ mol(-1). Depending on the model applied, the activation energies of fayalite slag oxidation in the temperature range of 1073-1173 K were: F1: 20.48 kJ mol( 1); R2: 20.45 kJ mol(-1); R3: 20.18 kJ mol(-1); A2: 21.54 kJ mol( -1) and A3: 22.34 kJ mol(-1). The transformation of fayalite to hematite and amorphous silica was completed after 1435, 1350 and 1080 s at temperatures of 1073, 1123 and 1173 K, respectively. The following oxidation products were identified by X-ray diffraction: (1) fayalite, hematite and magnesioferrite (Fe(2)MgO(4)) in the temperature range 773 to 973 K; and (2) hematite and magnesium iron oxide (Mg(1.55)Fe( 1.6)O(4)) in the temperature range of 1073 to 1173 K. PMID- 20705680 TI - miR-200c affects the mRNA expression of E-cadherin by regulating the mRNA level of TCF8 during post-natal epididymal development in juvenile rats. AB - The unique temporal expression pattern of miR-200c in epididymis during post natal development in juvenile rats was revealed by our home-made miRNA microarray in this paper. It was found that miR-200c expressed in the lowest level at Day 7 and then increased to the highest at Day 36 followed by a dramatic decrease. The pattern was exactly inverse to that of mRNA expression of transcription factor 8 (TCF8) revealed by quantitative real-time polymerase chain reaction (qRT-PCR), providing an extra evidence that TCF8 is one degradation target of miR-200c even in epididymis. Moreover, the qRT-PCR study on expression of E-cadherin and interleukin-2 indicated that miR-200c does exert an obvious effect on the mRNA expression of E-cadherin by directly regulating the mRNA level of TCF8, although the effect on interleukin-2 is not obvious as on E-cadherin, which implicates that interleukin-2 may be also regulated by other factors besides TCF8 in rat epididymis. PMID- 20705681 TI - Cancer stem-like cells can be isolated with drug selection in human ovarian cancer cell line SKOV3. AB - One emerging model for the development of drug-resistant tumors utilizes a pool of self-renewing malignant progenitors known as cancer stem cells (CSCs) or cancer-initiating cells (CICs). The purpose of this study was to propagate such CICs from the ovarian cancer cell line SKOV3. The SKOV3 sphere cells were selected using 40.0 micromol/l cisplatin and 10.0 micromol/l paclitaxel in serum free culture system supplemented with epidermal growth factor, basic fibroblast growth factor, leukemia inhibitory factor, and insulin or standard serum containing system. These cells formed non-adherent spheres under drug selection (cisplatin and paclitaxel) and serum-free culture system. The selected sphere cells are more resistant to cisplatin, paclitaxel, adriamycin, and methotrexate. Importantly, the sphere cells have the properties of self-renewal, with high expression of the stem cell genes Nanog, Oct4, sox2, nestin, ABCG2, CD133, and the stem cell factor receptor CD117 (c-kit). Consistently, flow cytometric analysis revealed that the sphere cells have a much higher percentage of CD133(+)/CD117(+)-positive cells (71%) than differentiated cells (33%). Moreover, the SKOV3 sphere cells are more tumorigenic. Furthermore, cDNA microarray and subsequent ontological analyses revealed that a large proportion of the classified genes were related to angiogenesis, extracellular matrix, integrin mediated signaling pathway, cell adhesion, and cell proliferation. The subpopulation isolation from the SKOV3 cell line under this culture system offers a suitable in vitro model for studying ovarian CSCs in terms of their survival, self-renewal, and chemoresistance, and for developing therapeutic drugs that specifically interfere with ovarian CSCs. PMID- 20705683 TI - Improved fall-related efficacy in older adults related to changes in dynamic gait ability. AB - BACKGROUND: Low fall-related efficacy is associated with the number and severity of future falls in older adults with balance disorders. OBJECTIVE: The purpose of this study was to examine whether improvements in clinical measures of balance after an intervention program were associated with changes in efficacy. DESIGN: A prospective, nonexperimental, pretest-posttest design was used. METHODS: Sixty three people (43 men, 20 women; mean [+/-SD] age=76.6+/-4.9 years) with a history of at least 2 falls in the previous 12 months were enrolled between 2004 and 2008 to participate in a 12-week home exercise program. Balance deficits were identified using the Berg Balance Scale (BBS) and the Dynamic Gait Index (DGI), and participants were evaluated monthly. Hierarchical linear regression was used to assess the relationship between measures of balance (BBS and DGI) and efficacy (Falls Efficacy Scale) before intervention. A second model examined the relationship between changes in balance and changes in efficacy after participation in the program. RESULTS: Preintervention scores of efficacy were significantly associated with age, depression, and BBS and DGI scores. After controlling for age, depression, and strength (force-generating capacity), BBS and DGI scores together accounted for 34% of the variance in preintervention efficacy. Significant improvements were noted in efficacy, BBS and DGI scores, and depression after intervention. When controlling for preintervention efficacy and changes in depression, the changes in DGI and BBS scores together explained 11% of the variance in the change in fall-related efficacy; however, only DGI scores contributed uniquely. Limitations These results are tempered by the absence of a control group to examine the role of time on changes in efficacy. CONCLUSIONS: The results suggest that increased emphasis on mobility during rehabilitation leads to improved confidence to perform activities of daily living without falling. PMID- 20705684 TI - Using cluster analysis to interpret the variability of gross motor scores of children with typical development. AB - BACKGROUND: Longitudinal research on gross motor percentile rank scores of children with typical development has documented intra-individual variability of scoring patterns. Clinically, interpreting these fluctuations presents a challenge for therapists. OBJECTIVE: The aim of this study was to determine the utility of cluster analysis as a technique to organize the gross motor scoring patterns of children with typical development into clinically relevant groups. DESIGN: This was a descriptive, exploratory study using data from 2 longitudinal studies. PARTICIPANTS: Sixty-six children with typical development participated in the study. METHODS: The children were assessed on the gross motor subscale of the Peabody Developmental Motor Scales at 9, 11, 13, 16, and 21 months of age and on the gross motor subscale of the Peabody Developmental Motor Scales, 2nd edition, at 4, 4.5, 5, and 5.5 years of age. Demographic and health data were collected. Parents were interviewed when the children were 8 years of age. Cluster analysis was conducted. Demographic and health data were compared across clusters. RESULTS: Four distinct and clinically relevant clusters were identified. A significant difference was found among the clusters for total number of illnesses. LIMITATIONS: The children in these analyses were at low risk for gross motor problems. Further research with a more high-risk sample is needed to validate the clinical utility of the identified clusters. CONCLUSIONS: Cluster analysis techniques may offer a mechanism to explore longitudinal data in physical therapy research. The techniques provided a mechanism to group data without losing the richness of information provided by the intra-individual variability of scoring patterns. Clinically, examination of distinct scoring patterns may lead to improved accuracy in screening for gross motor concerns compared with the traditional use of single-assessment cutoff points. PMID- 20705685 TI - Walking speed threshold for classifying walking independence in hospitalized older adults. AB - BACKGROUND: Walking speed norms and several risk thresholds for poor health outcomes have been published for community-dwelling older adults. It is unclear whether these values apply to hospitalized older adults. OBJECTIVE: The purpose of this study was to determine the in-hospital walking speed threshold that best differentiates walking-independent from walking-dependent older adults. DESIGN: This was a cross-sectional study. METHODS: This study recruited a convenience sample of 174 ambulatory adults aged 65 years and older who had been admitted to a medical-surgical unit of a university hospital. The participants' mean (SD) age was 75 (7) years. Fifty-nine percent were women, 66% were white, and more than 40% were hospitalized for cardiovascular problems. Usual-pace walking speed was assessed over 2.4 m. Walking independence was assessed through self-report. Several methods were used to determine the threshold speed that best differentiated walking-independent patients from walking-dependent patients. Approaches included a receiver operating characteristic (ROC) curve, sensitivity and specificity, and frequency distributions. RESULTS: The participants' mean (SD) walking speed was 0.43 (0.23) m/s, and 62% reported walking independence. Nearly 75% of the patients walked more slowly than the lowest community-based risk threshold, yet 90% were discharged home. Overall, cut-point analyses suggested that 0.30 to 0.35 m/s may be a meaningful threshold for maintaining in hospital walking independence. For simplicity of clinical application, 0.35 m/s was chosen as the optimal cut point for the sample. This threshold yielded a balance between sensitivity and specificity (71% for both). Limitations The limitations of this study were the small size of the convenience sample and the single health outcome measure. CONCLUSIONS: Walking speeds of older adults who are acutely ill are substantially slower than established community-based norms and risk thresholds. The threshold identified, which was approximately 50% lower than the lowest published community-based risk threshold, may serve as an initial risk threshold or target value for maintaining in-hospital walking independence. PMID- 20705686 TI - Exploring the conceptualization of program theories in Dutch community programs: a multiple case study. AB - Our objective was to evaluate whether the limited effectiveness of most community programs intended to prevent disease and promote health should be attributed to the quality of the conceptualization of their program theories. In a retrospective multiple case study we assessed the program theories of 16 community programs (cases) in the Netherlands (1990-2004). Methods were a document analysis, supplemented with member checks (insider information from representatives). We developed a community approach reference framework to guide us in reconstructing and evaluating the program theories. On the whole, programs did not clearly spell out the process theories (enabling the implementation of effective interventions), the program components (interventions) and/or the impact theories (describing pathways from interventions to ultimate effects). Program theories usually turned out to be neither specific nor entirely plausible (complete and valid). The limited effectiveness of most community programs should most probably be attributed to the limited conceptualization of program theories to begin with. Such a failure generally also precludes a thorough examination of the effectiveness of the community approach as such. PMID- 20705687 TI - Gender implications of the teaching of relationships and sexuality education for health-promoting schools. AB - Relationships and sexuality education (RSE) was introduced in Irish schools in 1995 to address pressures on young people specific to relationships and sexuality. RSE is part of a whole school health promotion project. Emphasis is put on personal and social development of students, cross-curricular dimensions, school ethos, school climate and partnership with families and community. However, RSE has become the preserve of female teachers with fewer male teachers attending in-service. This research explored the attitudes, beliefs and needs of male post-primary teachers with regard to RSE in their school. A qualitative design was employed utilizing focus groups. A total of 25 male post-primary teachers took part in five focus groups. Two of the groups consisted of men who had participated in RSE training; the other three groups were with men who had not. The analysis of the data suggested that there was reluctance on the part of male teachers to teach RSE, and that they feel under threat about their personal and professional identity. They felt under threat both from internal personal forces, in the form of mental models assimilated through personal history and upbringing, and from external organisational forces, communicated through the local school and wider social culture. The data indicate the need for professional development and support that is tailored specifically for male teachers. In order to support male teachers to become more involved in school health promotion and in the teaching of health curricula, pre-service education needs to prioritize key issues such as gender roles and identity. PMID- 20705688 TI - The Intermountain Risk Score (including the red cell distribution width) predicts heart failure and other morbidity endpoints. AB - AIMS: The complete blood count (CBC) and basic metabolic profile are common, low cost blood tests, which have previously been used to create and validate the Intermountain Risk Score (IMRS) for mortality prediction. Mortality is the most definitive clinical endpoint, but medical care is more easily applied to modify morbidity and thereby prevent death. This study tested whether IMRS is associated with clinical morbidity endpoints. METHODS AND RESULTS: Patients seen for coronary angiography (n = 3927) were evaluated using a design similar to a genome wide association study. The Bonferroni correction for 102 tests required a P value of <= 4.9 * 10-4 for significance. A second set of angiography patients (n = 10 413) was used to validate significant findings from the first patient sample. In the first patient sample, IMRS predicted heart failure (HF) (P(trend) = 1.6 * 10(-26)), coronary disease (P(trend) = 2.6 * 10(-11)), myocardial infarction (MI) (P(trend) = 3.1 * 10(-25)), atrial fibrillation (P(trend) = 2.5 * 10(-20)), and chronic obstructive pulmonary disease (P(trend) = 4.7 * 10-4). Even more, IMRS predicted HF readmission [hazard ratio (HR) = 2.29/category, P(trend) = 1.2 * 10-6), incident HF (HR = 1.88/category, P(trend) = 0.02), and incident MI (HR = 1.56/category, P(trend) = 4.7 * 10-4). These findings were verified in the second patient sample. CONCLUSION: Intermountain Risk Score, a predictor of mortality, was associated with morbidity endpoints that often lead to mortality. Further research is required to fully characterize its clinical utility, but its low-cost CBC and basic metabolic profile composition may make it ideal for initial risk estimation and prevention of morbidity and mortality. An IMRS web calculator is freely available at http://intermountainhealthcare.org/IMRS. PMID- 20705695 TI - Three-dimensional and two-dimensional quantitative coronary angiography, and their prediction of reduced fractional flow reserve. AB - AIMS: We investigated whether three-dimensional (3D) and two-dimensional quantitative coronary angiography (2D-QCA) measurements differed in their accuracy in predicting reduced fractional flow reserve (FFR), and how this varied with stenosis severity and the FFR cut-off used. METHODS AND RESULTS: Three dimensional and 2D-QCA were compared in their measurements of minimum luminal area (MLA), percentage area stenosis, lesion length, minimum luminal diameter (MLD) and percentage diameter stenosis, and in their prediction of functionally significant FFR. In total, 63 target lesions were interrogated in 63 patients undergoing elective percutaneous coronary intervention. Of all measurements of lesion severity obtained by 3D-QCA, MLA best correlated with FFR (R = 0.63, P < 0.001), and was the most accurate predictor of FFR < 0.75 (C statistic 0.86, P < 0.001). Of 2D-QCA measurements, MLD correlated best with FFR (R = 0.58, P < 0.001), and best predicted FFR < 0.75 (C statistic 0.80, P < 0.001). Overall, 3D QCA showed a non-significant trend towards more accurate prediction of FFR than 2D-QCA, especially in intermediate lesions. The relationship between FFR and apparent stenosis severity was found to be curvilinear. Both 3D- and 2D-QCA were less accurate in intermediate lesions, and in predicting FFR <= 0.80 than in predicting FFR <0.75. CONCLUSIONS: The accuracy of QCA in predicting functionally significant FFR is limited and is dependent on FFR cut-off used and lesion severity. Where FFR is not available or contraindicated, 3D-QCA may assist in the evaluation of coronary lesions of intermediate severity. PMID- 20705694 TI - Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde. AB - AIMS: The present study was designed to examine the mechanism involved in mitochondrial aldehyde dehydrogenase (ALDH2)-induced cardioprotection against ischaemia/reperfusion (I/R) injury with a focus on autophagy. METHODS: Wild-type (WT), ALDH2 overexpression, and knockout (KO) mice (n = 4-6 for each index measured) were subjected to I/R, and myocardial function was assessed using echocardiographic, Langendroff, and edge-detection systems. Western blotting was used to evaluate AMP-dependent protein kinase (AMPK), Akt, autophagy, and the AMPK/Akt upstream signalling LKB1 and PTEN. RESULTS: ALDH2 overexpression and KO significantly attenuated and accentuated, respectively, infarct size, factional shortening, and recovery of post-ischaemic left ventricular function following I/R as well as hypoxia/reoxygenation-induced cardiomyocyte contractile dysfunction. Autophagy was induced during ischaemia and remained elevated during reperfusion. ALDH2 significantly promoted autophagy during ischaemia, which was accompanied by AMPK activation and mammalian target of rapamycin (mTOR) inhibition. On the contrary, ALDH2 overtly inhibited autophagy during reperfusion accompanied by the activation of Akt and mTOR. Inhibition and induction of autophagy mitigated ALDH2-induced protection against cell death in hypoxia and reoxygenation, respectively. In addition, levels of the endogenous toxic aldehyde 4-hydroxy-2-nonenal (4-HNE) were elevated by ischaemia and reperfusion, which was abrogated by ALDH2. Furthermore, ALDH2 ablated 4-HNE-induced cardiomyocyte dysfunction and protein damage, whereas 4-HNE directly decreased pan and phosphorylated LKB1 and PTEN expression. CONCLUSION: Our data suggest a myocardial protective effect of ALDH2 against I/R injury possibly through detoxification of toxic aldehyde and a differential regulation of autophagy through AMPK- and Akt-mTOR signalling during ischaemia and reperfusion, respectively. PMID- 20705696 TI - Cardiac magnetic resonance imaging to guide complex revascularization in stable coronary artery disease. AB - Coronary revascularization has been a cornerstone of the management of patients with coronary artery disease (CAD) for many years. Both coronary artery bypass grafting and percutaneous coronary intervention have evolved and improved over time such that increasingly complex and challenging cases can now be tackled with a high degree of procedural success. In parallel with this, there have been major advances in medical therapy for CAD. Consequently, one of the main decisions in the contemporary management of stable CAD concerns which patients and lesions should be revascularized. This is particularly true for patients with complex disease such as multivessel disease or those with left ventricular impairment. Such patients will potentially benefit the most but are also at highest risk of complications and it is therefore important that they are carefully selected. Recent major trials have challenged the conventional view that consideration of coronary anatomy alone is sufficient in this decision-making. An accumulating body of evidence underscores the importance of functional investigations when assessing the potential benefits of revascularization in these complex patients. In parallel with these developments, cardiac magnetic resonance (CMR) has matured into a robust technology that is able to measure many of the parameters required to accurately characterize these patients. This article will review the importance of myocardial viability and ischaemia when selecting patients with stable CAD for revascularization, the use of CMR imaging for assessing this pathophysiology, and planning complex revascularization, and finally give an outlook on how CMR may help address some important outstanding clinical questions. PMID- 20705693 TI - The different shades of mammalian pluripotent stem cells. AB - BACKGROUND: Pluripotent stem cells have been derived from a variety of sources such as from the inner cell mass of preimplantation embryos, from primordial germ cells, from teratocarcinomas and from male germ cells. The recent development of induced pluripotent stem cells demonstrates that somatic cells can be reprogrammed to a pluripotent state in vitro. METHODS: This review summarizes our current understanding of the origins of mouse and human pluripotent cells. We pay specific attention to transcriptional and epigenetic regulation in pluripotent cells and germ cells. Furthermore, we discuss developmental aspects in the germline that seem to be of importance for the transition of germ cells towards pluripotency. This review is based on literature from the Pubmed database, using Boolean search statements with relevant keywords on the subject. RESULTS: There are distinct molecular mechanisms involved in the generation and maintenance of the various pluripotent cell types. Furthermore, there are important similarities and differences between the different categories of pluripotent cells in terms of phenotype and epigenetic modifications. Pluripotent cell lines from various origins differ in growth characteristics, developmental potential, transcriptional activity and epigenetic regulation. Upon derivation, pluripotent stem cells generally acquire new properties, but they often also retain a 'footprint' of their tissue of origin. CONCLUSIONS: In order to further our knowledge of the mechanisms underlying self-renewal and pluripotency, a thorough comparison between different pluripotent stem cell types is required. This will progress the use of stem cells in basic biology, drug discovery and future clinical applications. PMID- 20705697 TI - Computed angiogram of the upper extremities for diagnosing a rare cause of brachial arterial embolism: the 'Pitcher Syndrome'. PMID- 20705699 TI - Don't you call me desiccated, J. Wellington Wimpy. PMID- 20705698 TI - Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome. AB - BACKGROUND AND PURPOSE: Cerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome. MATERIALS AND METHODS: Intracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities. RESULTS: By study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections. CONCLUSIONS: The arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral. PMID- 20705700 TI - Effect of a prescan patient-radiologist encounter on functional MR image quality. AB - BACKGROUND AND PURPOSE: A substantial number of clinical fMRI examinations inadequately assess language localization or lateralization, usually due to patient movement and suboptimal participation. We hypothesized that a prescan interview of the patient by the radiologist would reduce the fraction of nondiagnostic scans. MATERIALS AND METHODS: A single noise score for each acquisition was produced from time-series data on the basis of a weighted sum of 22 factors. Scores were recorded as the following quartiles: 0-5 = excellent, 5 10 = adequate, 10-15= marginal, and >15 = unacceptable. This measure was evaluated for 202 consecutive fMRI patients: 96 without and 106 with a physician prescan interview. The data were analyzed to compute the fraction of all nondiagnostic sequences and entire studies and were compared between the 2 groups. Image-noise characteristics included the SDs of linear and angular displacements of the head and the number of time-series outliers caused by focal motion. RESULTS: Of 999 sequences acquired, 539 had a prescan interview. The mean noise score significantly decreased for both individual sequence (from 7.9 to 6.3, P = <.001) and study-based (from 7.7 to 6.2, P = .05) methods. The fraction of sequences or studies scored as unacceptable decreased for sequence-based (from 15.2% to 10.9%, P = .04) and study-based (from 9.4% to 1.9%, P = .02) analyses. SDs of head motion decreased for linear (by 12%-14%, P < .01) and angular displacement (by 38%-48%, P < .001). The number of time-series spikes decreased by 10% (P = .004). CONCLUSIONS: We report that a prescan physician-patient interview modestly but significantly reduces fMRI noise scores. These results support the newly added billable costs of professional intervention before fMRI scans. PMID- 20705701 TI - Improvement in angiographic cerebral vasospasm after intra-arterial verapamil administration. AB - BACKGROUND AND PURPOSE: Endovascular options for therapy for patients with vasospasm after SAH include angioplasty and intra-arterial vasodilator infusion. Preliminary studies of the effects of the calcium channel antagonist verapamil on angiographic vasospasm have yielded mixed and/or qualitative results. In this study, improvement in angiographic vasospasm after intra-arterial verapamil administration is demonstrated with quantitative, blinded methods. MATERIALS AND METHODS: This retrospective observational case series includes 12 patients with vasospasm after SAH who collectively received 16 treatments with intra-arterial verapamil during a 2-year period at our institution. The exclusion criterion was concurrent treatment with angioplasty. Blinded reviewers quantitatively evaluated angiograms from each patient and/or treatment after presentation with SAH and before and after intra-arterial treatment of vasospasm. RESULTS: Patients were treated with intra-arterial verapamil for vasospasm 9 +/- 4 days after SAH with a range from 1 to 16 days. For the 34 arterial distributions treated, the segment with the worst angiographic vasospasm from each arterial distribution averaged 51 +/- 13% stenosis, which improved to 29 +/- 18% stenosis (P < .001). There was no significant difference in treatment effect in proximal arterial segments, which may be amenable to angioplasty, compared with distal segments (P > .05). There was no significant difference in treatment effect in arterial segments previously subjected to angioplasty compared with other segments (P > .05). CONCLUSIONS: Intra-arterially administered verapamil improves angiographic vasospasm after SAH when administered at 10 +/- 3 mg per arterial distribution. Optimal dose, infusion rate, and retreatment interval remain to be determined. Randomized controlled trials are needed to prove efficacy in the treatment of clinical vasospasm. PMID- 20705702 TI - White matter microstructure changes in the thalamus in Parkinson disease with depression: A diffusion tensor MR imaging study. AB - BACKGROUND AND PURPOSE: Depression occurs frequently in PD; however the neural basis of depression in PD remains unclear. The aim of this study was to characterize possible depression-related white matter microstructural changes in the thalamus of patients with DPD compared with those with NDPD. MATERIALS AND METHODS: FA and MD maps from DTI were obtained in 14 patients with DPD and 18 patients with NDPD. Region-of-interest-guided VBA was conducted on the FA maps to detect possible microstructural differences in the thalamus between these 2 patient groups. Moreover, mean FA and MD in regions with a detected difference were compared between DPD and NDPD groups, and correlations between diffusion quantities and the severity of depression were analyzed. RESULTS: White matter microstructure differences were found between the patients with DPD and NDPD in the bilateral mediodorsal thalamic regions. In these regions, patients with DPD showed significantly decreased FA values (P < .005) compared with patients with NDPD, and the mean values of FA were negatively correlated with the scores of depression severity (P < .05) for patients with PD. No significant differences of MD were found in the mediodorsal thalamus between these 2 groups. CONCLUSIONS: Our results provide preliminary evidence that the mediodorsal thalamus may play an important role in depression in PD and suggest a relationship between FA in the mediodorsal thalamus and the presence of depressive symptoms in patients with DPD. These findings may be helpful for further understanding the potential mechanisms of depression in PD. PMID- 20705703 TI - HydroCoils, occlusion rates, and outcomes: a large single-center study. AB - BACKGROUND AND PURPOSE: The HydroCoil is an expansile hydrogel coil designed to produce a greater degree of volumetric packing within cerebral aneurysms when compared with bare platinum coils. This increased packing is, in turn, believed to decrease the risk of recurrence within aneurysms and hence the risk of their rupture in the long term. The aim of this work was to assess whether the use of HydroCoils and the proportion of HydroCoil used have any influence on the subsequent occlusion and recurrence rates of treated aneurysms. MATERIALS AND METHODS: A retrospective study was performed of 328 patients during 5 years at a single institution. The initial angiographic and follow-up angiographic occlusion rates were recorded as were any procedural complications. The proportion of HydroCoil used was described as the relative amount of HydroCoil length to the total coil length used during an aneurysm treatment, thus forming 4 groups: 0% 19%, 20%-49%, 50%-69%, 70%-100%, and the subgroups with 100%. RESULTS: Two hundred seventy patients had angiographic follow-up during an average of 13 months. The overall risk of permanent neurologic deficit and death was 3%. The rate of complete occlusion was 31% immediately postcoiling and 64.8% on follow up. At the latest follow-up, 25.6% had residual necks and 9.6% had residual aneurysms. There was a statistically significant trend for HydroCoils to produce greater occlusion rates on follow-up when >70% HydroCoil was used (P = .025). The overall rate of recurrence for all aneurysms as a group was 15.5%. The retreatment rate was 6.6%. There has been 1 rebleed in the 328 patients. CONCLUSIONS: The overall results following the use of HydroCoils to occlude aneurysms compare well with those in other reported series. HydroCoils do produce a statistically significantly greater rate of occlusion when >70% of total aneurysm coil length is HydroCoil compared with coiling with <20% HydroCoil. There was no significant difference, however, in the recurrence or retreatment rate when comparing these groups. PMID- 20705706 TI - Progress in progression? PMID- 20705705 TI - Aberrant regulation of planar cell polarity in polycystic kidney disease. AB - Mutations in PKD1, which encodes polycystin-1 (PC1), contribute to >85% of cases of autosomal dominant polycystic kidney disease (ADPKD). The planar cell polarity (PCP) pathway is necessary for the oriented cell division and convergent extension that establishes and maintains the structure of kidney tubules, but the role of this pathway in the pathophysiology of ADPKD is incompletely understood. Here, we show that inactivation of Pkd1 in postnatal developing mouse kidneys leads to a defect in oriented cell division in precystic kidney tubules. We also observed this defect in precystic Pkd1-inactivated mature kidneys subjected to ischemia-reperfusion injury as a "third hit." Cystic kidneys exhibited striking upregulation and activation of Frizzled 3 (Fz3), a regulator of PCP, and its downstream effector, CDC42. Precystic kidneys demonstrated upregulation of CDC42, but the localization of the polarity proteins Par3 and Par6 was similar to control. Fz3 was expressed on the cilia of cystic kidneys but barely detected on the cilia of normal kidneys. In vitro, PC1 and Fz3 antagonized each other to control CDC42 expression and the rate of cell migration in HEK293T cells. Taken together, our data suggest that PC1 controls oriented cell division and that aberrant PCP signaling contributes to cystogenesis. PMID- 20705707 TI - Cell senescence in the aging kidney. AB - Pedigree genetics and environment modulate the biological process of aging. The permanent and irreversible growth arrest of cell senescence is a central paradigm of aging. Various pathophysiologic pressures such as oxidative stress and mitochondrial injury can also induce senescence. Senescent cells secrete altered levels of growth factors, show increased susceptibility to apoptosis, and associate with delayed repair and regeneration in the aging kidney. Here we discuss new progress in understanding renal aging, focusing on mechanisms of cell senescence and possible interventions to modulate age-related organ damage. PMID- 20705708 TI - Balancing the Wnts in polycystic kidney disease. PMID- 20705709 TI - Dietary fructose and elevated levels of blood pressure. PMID- 20705710 TI - Immature public policy for vascular access. PMID- 20705712 TI - Digitalis and hemodialysis is a bad combination. PMID- 20705711 TI - Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury. AB - Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO 1(-/-) PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild type and HO-1-deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1-deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI. PMID- 20705713 TI - Arteriovenous fistulas among incident hemodialysis patients in Department of Defense and Veterans Affairs facilities. AB - A higher proportion of patients initiate hemodialysis (HD) with an arteriovenous fistula (AVF) in countries with universal health care systems compared with the United States. Because federally sponsored national health care organizations in the United States, such as the Department of Veterans Affairs (DVA) and the Department of Defense (DoD), are similar to a universal health care model, we studied AVF use within these organizations. We used the US Renal Data System database to perform a cross-sectional analysis of patients who initiated HD between 2005 and 2006. Patients who received predialysis nephrology care had 10 fold greater odds of initiating dialysis with an AVF (adjusted odds ratio [aOR] 10.3; 95% confidence interval [CI] 9.6 to 11.1). DVA/DoD insurance also independently associated with initiating HD with an AVF (aOR 1.4; 95% CI 1.2 to 1.5). Fewer patients initiated HD at a DoD facility, but these patients were also approximately twice as likely to use an AVF (aOR 2.3; 95% CI 1.2 to 4.6). In conclusion, patients in DVA/DoD systems are significantly more likely to use an AVF at initiation of HD than patients with other insurance types, including Medicare. Further study of these federal systems may identify practices that could improve processes of care across health care systems to increase the number of patients who initiate HD with an AVF. PMID- 20705715 TI - What type of VEGF do you need? PMID- 20705716 TI - Alcohol misuse, sexual risk behaviour and adverse sexual health outcomes: evidence from Britain's national probability sexual behaviour surveys. AB - BACKGROUND: Evidence for relationships between alcohol misuse, sexual risk behaviour and adverse sexual health outcomes exists from both population-level data and studies undertaken in specific groups. We examine changes in these associations using representative data from two consecutive surveys. METHODS: Probability surveys conducted in 1990/91 and again in 2000/01 involving interviews with British residents aged 16-44. RESULTS: The proportion reporting being drunk as their main reason for first heterosexual intercourse increased from 2.5% among those born in 1946-49 to 6.4% of those born in 1980-84. These respondents were more likely to report intercourse before 16, that sex had occurred too soon, and contraception non-use. Usual alcohol consumption in excess of recommended limits ('heavy drinkers') was more common among those reporting larger partner numbers and unprotected sex with 2+ partners/past year but not with STD clinic attendance/diagnosis. Male heavy drinkers were more likely to report sexual function problems and female heavy drinkers using emergency contraception. The magnitude of these relationships did not significantly increase between 1990/91 and 2000/01. CONCLUSION: In Britain, sexual risk behaviours and some adverse sexual health outcomes continue to be associated with excess alcohol consumption. These findings support addressing the link between alcohol misuse and sexual health in health services and through broader health promotion. PMID- 20705718 TI - Gene expression profile in the endometrium on the day of oocyte retrieval after ovarian stimulation with low-dose hCG in the follicular phase. AB - The past decade has seen growing interest in ovarian stimulation protocols with GnRH antagonists in an effort to reduce the incidence of potential complications, such as cyst formation and ovarian hyperstimulation syndrome, and thus improve the clinical experience for patients. Current assisted reproductive technique programmes also increasingly utilize milder protocols for ovarian stimulation. In a recently published randomized controlled trial, we showed that low-dose hCG can be utilized clinically to replace recombinant FSH (rFSH) during the late follicular phase in a GnRH antagonist protocol. This regimen leads to a significant reduction in rFSH consumption, while the ICSI outcome, in terms of oocyte yield and ongoing pregnancy rate, remains comparable with the control regimen of rFSH plus a GnRH antagonist. In the present study, the influence of the administration of low-dose hCG on the endometrium was assessed. A comparison was made between two protocols for ovarian stimulation with GnRH antagonists, namely the classical protocol with rFSH and the protocol with low-dose hCG in the late follicular phase. We analysed the morphological pattern and gene expression profile of human endometrium on the day of oocyte retrieval. No morphological differences were observed and only a minimal set of 65 differentially expressed probe sets between the treatment groups were identified, enabling a similar efficacy to support implantation. PMID- 20705717 TI - Chorionic gonadotrophin regulates CXCR4 expression in human endometrium via E series prostanoid receptor 2 signalling to PI3K-ERK1/2: implications for fetal maternal crosstalk for embryo implantation. AB - Murine knock-out models and blastocyst co-culture studies have identified prostaglandin-endoperoxide synthase (PTGS) 2, prostaglandin (PG) E receptor 2 (PTGER2) and the chemokine receptor CXCR4 as important regulators of early pregnancy events. In vitro studies and studies in non-human primates have shown that these proteins are regulated in the endometrium by the early embryonic signal, chorionic gonadotrophin (CG). Here we show that expressions of PTGER2 and CXCR4 are elevated during the mid-secretory phase of the menstrual cycle and decidua of early pregnancy in humans. Using first trimester decidua explants, we show that CG induces expression of PTGS2 and biosynthesis of PGE2, and expression of PTGER2. Subsequently, PGE2via PTGER2 induces expression of CXCR4. Using an in vitro model system of Ishikawa endometrial epithelial cells stably expressing PTGER2 and human first trimester decidua explants, we demonstrate that CXCR4 expression is regulated by PTGER2 via the epidermal growth factor receptor (EGFR) phosphatidylinositol-3-kinase (PI3K)-extracellular signal-regulated kinase (ERK1/2) pathway.Taken together, our data suggest that early embryonic signals may regulate fetal-maternal crosstalk in the human endometrium by inducing CXCR4 expression via the PGE2-PTGER2-mediated induction of the EGFR, PI3K and ERK1/2 pathways. PMID- 20705719 TI - The importance of rare diseases: from the gene to society. PMID- 20705721 TI - Correlates of hypertension among urban Asian Indian adolescents. AB - OBJECTIVE: Primary hypertension has become increasingly common in children but remains largely understudied, underdiagnosed and undertreated. This study examines the relationship between hypertension in adolescents and various markers of obesity, serum lipid levels, fasting blood glucose (FBG), haemoglobin A1c (HbA1c) and family history of hypertension. DESIGN/SETTINGS: A cross-sectional population-based study of 1022 students aged 14-19 years in New Delhi, India. MAIN OUTCOME/EXPOSURES: Those with age, gender and height specific blood pressure >95th percentile (derived from study data) or >130/85 mm Hg were considered hypertensive. Various markers of obesity, FBG, HbA1c and serum lipid levels were divided into quartiles and the odds ratios of hypertension calculated for the highest quartiles with reference to the lowest. RESULTS: Hypertension was seen in 65 (6.4%) adolescents (2.7% isolated systolic, 2.0% isolated diastolic and 1.7% both). The odds of having hypertension were higher for those in the highest versus lowest quartiles of various measures of obesity such as body mass index (OR 2.90; 95% CI 1.40 to 6.12) and waist circumference (OR 5.21; 95% CI 2.14 to 12.17). A parental history of hypertension was associated with diastolic hypertension in the child (OR 2.21; 95% CI 1.13 to 4.33); the odds ratio decreased after simultaneous adjustment for salt intake (OR 1.98; 95% CI 1.00 to 3.94). In a multivariable model with backward elimination, waist circumference and triglycerides were the strongest predictors of hypertension, further suggesting that the relationship is stronger with central than peripheral obesity. CONCLUSION: Hypertension in Asian Indian adolescents is associated with obesity, higher serum lipids and a family history of hypertension. PMID- 20705720 TI - The association between birth condition and neuropsychological functioning and educational attainment at school age: a cohort study. AB - OBJECTIVE: Poor condition at birth may impact on IQ, although its effect on other measures of neurodevelopment is unclear. The authors' aim was to determine whether infants receiving resuscitation after birth have reduced scores in measures of attention, memory and language skills or the need for educational support at school even in the absence of clinical encephalopathy. METHODS: Three groups of term infants were identified from the Avon longitudinal study of parents and children: infants resuscitated at birth but asymptomatic for encephalopathy (n=612), infants resuscitated who developed symptoms of encephalopathy (n=40) and the reference infants who were not resuscitated and had no further neonatal care (n=8080). Measures of attention, language, memory and the need for educational support were obtained for children between 8 years and 11 years. Test results (standardised to a mean of 100 and SD of 15) were adjusted for clinical and social covariates. Missing covariate data were imputed using chained equations. RESULTS: Infants asymptomatic after resuscitation had similar scores to those not requiring resuscitation for all measures while infants who developed encephalopathy had lower working memory (-6.65 (-12.34 to -0.96)), reading accuracy (-7.95 (-13.28 to -2.63)) and comprehension (-9.32 (-14.47 to 4.17) scores and increased risk of receiving educational support (OR 6.24 (1.52 to 26.43)) than infants thought to be well at birth, although there was little evidence for an association after excluding infants who developed cerebral palsy. CONCLUSIONS: The authors found no evidence that infants who were resuscitated but remained well afterwards differed from those not requiring resuscitation in the aspects of neuropsychological functioning assessed in this study. Infants who developed neonatal encephalopathy had evidence of worse functioning, particularly in language skills and were more likely to receive educational support at school. PMID- 20705722 TI - Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia. AB - Children treated for acute leukaemia are at increased risk of infection with Streptococcus pneumoniae. The basis for this may include low levels of pneumococcal antibody but this has not been well studied. The authors measured serotype-specific pneumococcal IgG antibody concentrations in children treated for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) >=6 months after completion of standard-dose chemotherapy. Pneumococcal serotype specific IgG antibody concentrations were low. None of the subjects had protective concentrations against all the heptavalent-pneumococcal conjugate vaccine serotypes. There was no significant difference in antibody concentrations between subjects with ALL and AML (p>=0.05). Children treated for ALL and AML generally have non-protective antibody concentrations against S pneumoniae. There is significant morbidity associated with pneumococcal disease in this patient group and strategies for vaccination are required. PMID- 20705723 TI - H pylori infection associated with unspecified abdominal pain in referred children but not with (UAP) in primary care or with recurrent abdominal pain. PMID- 20705727 TI - Chlamydophila psittaci in homing and feral pigeons and zoonotic transmission. AB - Chlamydiosis is a zoonotic disease in birds caused by Chlamydophila psittaci, an obligate intracellular bacterium. There are seven known avian outer-membrane protein A genotypes, A-F and E/B. The importance of genotyping lies in the fact that certain genotypes tend to be associated with certain hosts and a difference in virulence. Genotype B is the most prevalent in pigeons, but the more virulent genotypes A and D have also been discovered. The current study assessed the prevalence of C. psittaci in 32 Belgian homing-pigeon facilities and in 61 feral pigeons captured in the city of Ghent, Belgium. Additionally, zoonotic transmission of C. psittaci was investigated in the homing-pigeon facilities. Homing pigeons were often infected, as at least one of the lofts was positive in 13 of the 32 (40.6 %) pigeon breeding facilities. Genotypes B, C and D were detected. Zoonotic transmission was discovered in 4 of the 32 (12.5 %) pigeon fanciers, revealing genotype D in two of them, whilst genotyping was unsuccessful for the other two human pharyngeal swabs. This study clearly demonstrates the possible risk of C. psittaci zoonotic transmission from homing pigeons. Pigeon fanciers often (37.5 %) used antibiotics for prevention of respiratory disease. Because of the risk of developing drug-resistant strains, regular use of antimicrobial drugs must be avoided. This study is believed to be the first to detect C. psittaci in Belgian feral pigeons. The prevalence rate in the city of Ghent was extremely low, which is beneficial for public health. PMID- 20705728 TI - Campylobacter fetus subspecies fetus spondylodiscitis. AB - Campylobacter spp. are common causes of gastrointestinal infections. Campylobacter fetus is a much rarer pathogen in humans, and usually causes bacteraemia and systemic complications in patients with predisposing conditions. We report a case of spondylodiscitis caused by C. fetus subsp. fetus as revealed by vertebral biopsy culture. This identification was confirmed by sequencing the 16S rRNA gene and by phylogenetic analysis. Treatment consisted of 6 weeks antimicrobial therapy combined with a strict initial immobilization, followed by a re-education program. The patient's recovery was uneventful. PMID- 20705729 TI - Six cases of daptomycin-non-susceptible Staphylococcus aureus bacteraemia in Singapore. AB - We report what we believe to be the first six cases of daptomycin-non-susceptible Staphylococcus aureus infections from Singapore. These strains were rapidly isolated after bacteraemic patients were switched to daptomycin following initial prolonged unsuccessful therapy with vancomycin, despite confirmation of daptomycin susceptibility just prior to initiating daptomycin therapy. The majority of post-vancomycin therapy strains exhibited marked thickening of their cell walls on electron microscopic examination. In patients with persistent S. aureus bacteraemia, therapeutic failure with daptomycin may occur if used as salvage therapy following vancomycin failure, notwithstanding initial susceptibility testing results. PMID- 20705730 TI - Identification of mutants with altered phenazine production in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic human pathogen that causes serious and chronic infections. Many secondary metabolites are secreted throughout its growth, among which phenazine is a known virulence factor and signalling molecule. Phenazine is coordinately controlled by the global regulatory quorum sensing (QS) systems. Despite the detailed understanding of phenazine biosynthesis pathways in P. aeruginosa, the regulatory networks are still not fully clear. In the present study, the regulation of the phzA1B1C1D1E1F1G1 operon (phzA1) has been investigated. Screening of 5000 transposon mutants revealed 14 interrupted genes with altered phzA1 expression, including PA2593 (QteE), which has been identified as a novel regulator of the QS system. Overexpression of qteE in P. aeruginosa significantly reduced the accumulation of homoserine lactone signals and affected the QS-controlled phenotypes such as the production of pyocyanin, rhamnolipids and LasA protease and swarming motility. Indeed, overexpression of qteE in P. aeruginosa attenuated its pathogenicity in the potato and fruit fly infection models. These findings suggest that qteE plays an important role in P. aeruginosa pathogenicity and is part of the regulatory networks controlling phenazine production. PMID- 20705731 TI - Mechanisms behind variation in the Clostridium difficile 16S-23S rRNA intergenic spacer region. AB - Clostridium difficile infection is an increasing problem in hospitals worldwide, mainly due to the recent emergence of a hypervirulent C. difficile strain. C. difficile PCR ribotyping, based on size variation of the 16S-23S rRNA intergenic spacer region (16S-23S ISR), is widely used in Europe for molecular epidemiological investigation. The mechanism underlying the 16S-23S ISR size variations in the genome of C. difficile is currently not completely understood. To elucidate this mechanism, isolates of six different PCR ribotypes were analysed by cloning and sequencing the 16S-23S ISR. A direct repeat, IB, of 9 bp was detected up to five times in the 16S-23S ISR in all 47 clones investigated. Thirty-five clones displayed differences either by ribotype or by nucleotide sequence. The sequences of the 16S-23S ISR of C. difficile showed a uniformly organized structure, composed of a tRNA(Ala) gene and spacers of 33 and 53 bp separated by the 9 bp direct repeat IB. The results of the study support the hypothesis that this composition is responsible for the length variations seen in the 16S-23S ISR, and indicate that these length variations result from slipped-strand mispairing and intra- and possibly interchromosomal homologous recombination. PMID- 20705732 TI - Isolation and genotyping of Acanthamoeba strains from corneal infections in Italy. AB - Acanthamoeba keratitis (AK) is a corneal disease caused by members of a genus of free-living amoebae and is associated predominantly with contact lens (CL) use. This study reports 16 cases of culture-proven AK diagnosed in northern Italy. Genotype identification was carried out with a PCR assay based on sequence analysis of the 18S rRNA gene, and sensitivity and specificity were evaluated in comparison with traditional parasitological techniques. A 405 bp region of the 18S rRNA gene (ASA.S1) including diagnostic fragment 3 (DF3) was amplified using the genus-specific primers JDP1 and JDP2. Genotype assignment was based on phenetic analysis of the ASA.S1 subset of the nuclear small-subunit rRNA gene sequence excluding the highly variable DF3 region. Phylogenetic analysis was also performed on the sequences obtained. All patients complained of monolateral infection; 11 (68.75%) admitted improper CL disinfection. In 14/16 (87.5 %) subjects, corneal scrapings were stained with calcofluor white and haematoxylin and eosin and, in ten cases (62.5 %), microscopy was positive for Acanthamoeba cysts. In vitro culture on 3 % non-nutrient agar plates was obtained in all cases (100 %), whereas cloning and axenic growth were positive for 14 amoebic stocks (87.5 %). PCR analysis had 100 % sensitivity and specificity compared with in vitro axenic culture, showing positive amplification from 15 isolates. All Acanthamoeba strains belonged to the T4 genotype, the main AK-related genotype worldwide. These results confirmed the importance of a complete diagnostic protocol, including a PCR assay, for the clinical diagnosis of AK on biological samples. Genotyping allowed inclusion of all isolates in the T4 group, thus demonstrating the prevalence of this genotype in northern Italy. PMID- 20705733 TI - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. AB - Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ~2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10( 7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population. PMID- 20705734 TI - Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by mutations in the gene coding for the protein dystrophin. Recent work demonstrates that dystrophin is also found in the vasculature and its absence results in vascular deficiency and abnormal blood flow. This induces a state of ischemia further aggravating the muscular dystrophy pathogenesis. For an effective form of therapy of DMD, both the muscle and the vasculature need to be addressed. To reveal the developmental relationship between muscular dystrophy and vasculature, mdx mice, an animal model for DMD, were crossed with Flt-1 gene knockout mice to create a model with increased vasculature. Flt-1 is a decoy receptor for vascular endothelial growth factor, and therefore both homozygous (Flt-1(-/-)) and heterozygous (Flt-1(+/-)) Flt-1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. Here, we show that Flt-1(+/-) and mdx:Flt-1(+/-) adult mice also display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice, respectively. The mdx:Flt-1(+/-) mice show improved muscle histology compared with the mdx mice with decreased fibrosis, calcification and membrane permeability. Functionally, the mdx:Flt-1(+/-) mice have an increase in muscle blood flow and force production, compared with the mdx mice. Consequently, the mdx:utrophin(-/-):Flt-1(+/-) mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin( /-) mice, which show more severe muscle phenotypes than the mdx mice. These data suggest that increasing the vasculature in DMD may ameliorate the histological and functional phenotypes associated with this disease. PMID- 20705735 TI - Transcriptional profiling of fibroblasts from patients with mutations in MCT8 and comparative analysis with the human brain transcriptome. AB - Thyroid hormone (TH) is crucial for normal brain development. TH transporters control TH homeostasis in brain as evidenced by the complex endocrine and neurological phenotype of patients with mutations in monocarboxylate transporter 8 (MCT8). We investigated the mechanisms of disease by analyzing gene expression profiles in fibroblasts from patients with MCT8 mutations. Studying MCT8 and its transcriptional context in different comprehensive spatial and temporal human brain transcriptome data sets revealed distinct region-specific MCT8 expression. Furthermore, MCT8 demonstrated a clear age-dependent decrease, suggesting its importance in early brain development. Performing comparative transcriptome analysis, we linked the genes differentially expressed (DE) in patient fibroblasts to the human brain transcriptome. DE genes in patient fibroblasts were strongly over-represented among genes highly correlated with MCT8 expression in brain. Furthermore, using the same approach we identified which genes in the classical TH signaling pathway are affected in patients. Finally, we provide evidence that the TRalpha2 receptor variant is closely connected to MCT8. The present study provides a molecular basis for understanding which pathways are likely affected in the brains of patients with mutations in MCT8. Our data regarding a functional relationship between MCT8 and TRalpha2 suggest an unanticipated role for TRalpha2 in the (patho)physiology of TH signaling in the brain. This study demonstrates how genome-wide expression data from patient derived non-neuronal tissue related to the human brain transcriptome may be successfully employed to improve our understanding of neurological disease. PMID- 20705736 TI - SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. AB - Reduced expression of the survival motor neuron (SMN) gene causes the childhood motor neuron disease spinal muscular atrophy (SMA). Low levels of ubiquitously expressed SMN protein result in the degeneration of lower motor neurons, but it remains unclear whether other regions of the nervous system are also affected. Here we show that reduced levels of SMN lead to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher SMN levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wild-type littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration and development when SMN levels were reduced. This study reveals novel roles for SMN protein in brain development and maintenance and provides the first insights into cellular and molecular pathways disrupted in the brain in a severe form of SMA. PMID- 20705737 TI - Exome sequencing: the sweet spot before whole genomes. AB - The development of massively parallel sequencing technologies, coupled with new massively parallel DNA enrichment technologies (genomic capture), has allowed the sequencing of targeted regions of the human genome in rapidly increasing numbers of samples. Genomic capture can target specific areas in the genome, including genes of interest and linkage regions, but this limits the study to what is already known. Exome capture allows an unbiased investigation of the complete protein-coding regions in the genome. Researchers can use exome capture to focus on a critical part of the human genome, allowing larger numbers of samples than are currently practical with whole-genome sequencing. In this review, we briefly describe some of the methodologies currently used for genomic and exome capture and highlight recent applications of this technology. PMID- 20705738 TI - A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype. AB - Proximal spinal muscular atrophy (SMA) is a neurodegenerative disease caused by low levels of the survival motor neuron (SMN) protein. In humans, SMN1 and SMN2 encode the SMN protein. In SMA patients, the SMN1 gene is lost and the remaining SMN2 gene only partially compensates. Mediated by a C>T nucleotide transition in SMN2, the inefficient recognition of exon 7 by the splicing machinery results in low levels of SMN. Because the SMN2 gene is capable of expressing SMN protein, correction of SMN2 splicing is an attractive therapeutic option. Although current mouse models of SMA characterized by Smn knock-out alleles in combination with SMN2 transgenes adequately model the disease phenotype, their complex genetics and short lifespan have hindered the development and testing of therapies aimed at SMN2 splicing correction. Here we show that the mouse and human minigenes are regulated similarly by conserved elements within in exon 7 and its downstream intron. Importantly, the C>T mutation is sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C>T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibit exon 7 skipping and mild adult onset SMA characterized by muscle weakness, decreased activity and an alteration of the muscle fibers size. This Smn C>T mouse represents a new model for an adult onset form of SMA (type III/IV) also know as the Kugelberg Welander disease. PMID- 20705739 TI - Object and action naming in children with specific language impairment. AB - PURPOSE: In this study, the authors aimed to examine the accuracy, latency, and errors of noun (object) and verb (action) naming in children with and without specific language impairment (SLI) and to determine whether children with SLI have a particularly large noun-verb performance gap. METHOD: Children with SLI, age-matched peers (AM), and expressive vocabulary-matched peers (VM) named 120 matched object and action pictures in a computerized confrontation naming task. RESULTS: The SLI and VM groups demonstrated comparable naming latency and accuracy; both were slower and less accurate than the AM group. Object naming was more accurate than action naming in the SLI and VM groups; their noun-verb performance gaps were comparable. Object naming was faster than action naming in all children. In comparison with the AM group, the SLI group made proportionally fewer taxonomic errors and more omission errors when naming objects, and fewer misperception errors when naming actions. CONCLUSIONS: The naming abilities of children with SLI, although deficient given their chronological age, are commensurate with their vocabulary level. Their naming errors suggest immaturities in semantic representation. Action naming is significantly more difficult than object naming, but the noun-verb gap that characterizes the performance of children with SLI is appropriate for their vocabulary level. PMID- 20705740 TI - Sentence-position effects on children's perception and production of English third person singular -s. AB - PURPOSE: Two-year-olds produce third person singular -s more accurately on verbs in sentence-final position as compared with verbs in sentence-medial position. This study was designed to determine whether these sentence-position effects can be explained by perceptual factors. METHOD: For this purpose, the authors compared 22- and 27-month-olds' perception and elicited production of third person singular -s in sentence-medial versus-final position. The authors assessed perception by measuring looking/listening times to a 1-screen display of a cartoon paired with a grammatical versus an ungrammatical sentence (e.g., She eats now vs. She eat now). RESULTS: Children at both ages demonstrated sensitivity to the presence/absence of this inflectional morpheme in sentence final, but not sentence-medial, position. Children were also more accurate at producing third person singular -s sentence finally, and production accuracy was predicted by vocabulary measures as well as by performance on the perception task. CONCLUSIONS: These results indicate that children's more accurate production of third person singular -s in sentence-final position cannot be explained by articulatory factors alone but that perceptual factors play an important role in accounting for early patterns of production. The findings also indicate that perception and production of inflectional morphemes may be more closely related than previously thought. PMID- 20705741 TI - Augmented language intervention and the emergence of symbol-infused joint engagement. AB - PURPOSE: This study sought to determine whether the effects of 3 parent-coached language interventions--2 focused on augmented communication using a speech generating device and 1 focused only on speech--for toddlers with developmental delays and fewer than 10 words (M. A. Romski et al., 2010) generalized to children's joint engagement during interactions with parents that took place outside the intervention context. METHOD: Fifty-seven toddlers who participated in one of three parent-coached language interventions were observed both pre- and post-intervention interacting with their parents using a Communication Play Protocol that produced samples of communication related to social interacting, requesting, and commenting. Their engagement states were reliably coded from the videorecords of these interactions. RESULTS: Symbol-infused joint engagement of children in all 3 intervention groups increased significantly from pre- to post intervention. The amount of symbol-infused joint engagement observed post intervention was significantly associated with whether or not the child produced spoken words and, for children in the 2 augmented conditions, the number of augmented words used during the last intervention session. CONCLUSIONS: The effects of parent-coached augmented language interventions generalize to children's engagement in child-parent interactions outside the intervention context in ways that may facilitate additional language acquisition. PMID- 20705742 TI - Observation of classroom social communication: do children with fetal alcohol spectrum disorders spend their time differently than their typically developing peers? AB - PURPOSE: In this research, the authors examined how social communication profiles during classroom activities differed between children with fetal alcohol spectrum disorders (FASD) and typically developing pair-matched peers. METHOD: Twelve pairs of children were observed in their classrooms 20 min a day for 4 days across 2 weeks. Coders documented classroom social communication by recording performance on handheld computers using the Social Communication Coding System (L. B. Olswang, L. Svensson, T. E. Coggins, J. Beilinson, & A. L. Donaldson, 2006). The Social Communication Coding System consists of 6 behavioral dimensions (prosocial/engaged, passive/disengaged, irrelevant, hostile/coercive, assertive, and adult seeking) that account for all verbal and nonverbal productions during a specified timeframe. The frequency of occurrence and duration of each dimension (as measured by proportion of time and average length of time spent performing each dimension) were recorded. RESULTS: Children with FASD had significantly more occurrences of passive/disengaged and irrelevant behavior, and the proportion and average length of time in these behaviors were larger and longer than those of their peers. Further, children with FASD had significantly more occurrences of prosocial/engaged behavior; however, the proportion and average length of time that they spent being prosocial were smaller and shorter than those of their peers. Implications Results suggest children with mild FASD performed differently than their peers in regard to classroom social communication, which was consistent with parent and teacher behavioral reports. PMID- 20705743 TI - Effect of subject types on the production of auxiliary is in young English speaking children. AB - PURPOSE: In this study, the authors tested the unique checking constraint (UCC) hypothesis and the usage-based approach concerning why young children variably use tense and agreement morphemes in obligatory contexts by examining the effect of subject types on the production of auxiliary is. METHOD: Twenty typically developing 3-year-olds were included in this study. The children's production of auxiliary is was elicited in sentences with pronominal subjects, high-frequency lexical noun phrase (NP) subjects (e.g., the dog), and low-frequency lexical NP subjects (e.g., the deer). RESULTS: As a group, children did not use auxiliary is more accurately with pronominal subjects than with lexical NP subjects. Furthermore, individual data revealed that although some children used auxiliary is more accurately with pronominal subjects than with lexical NP subjects, the majority of children did not show this trend. CONCLUSION: The symmetry observed between lexical and pronominal subjects supports the predictions of the UCC hypothesis, although additional mechanisms may be needed to account for the asymmetry between subject types in some individual children. Discrepant results between the present study and previous studies were attributed to differences in task formats and children's developmental levels. PMID- 20705744 TI - Theoretical explanations for preschoolers' lowercase alphabet knowledge. AB - PURPOSE: Letter knowledge is a key aspect of children's language development, yet relatively little research has aimed to understand the nature of lowercase letter knowledge. We considered 4 hypotheses about children's lowercase letter knowledge simultaneously--uppercase familiarity, uppercase-lowercase similarity, own-name advantage, and frequency in printed English--as well as 3 interactions. METHOD: Participants were 461 children ranging in age from 3 to 5 years, all of whom attended public preschool programs serving primarily children from low-income homes, who completed a letter naming task. RESULTS: Uppercase familiarity was the strongest predictor of children's lowercase alphabet knowledge; children were more than 16 times more likely to know a lowercase letter if they knew the corresponding uppercase letter. Uppercase-lowercase similarity and frequency in printed English also predicted children's lowercase letter knowledge, as did the interaction between uppercase familiarity and own-name advantage and the interaction between uppercase familiarity and uppercase-lowercase similarity. CONCLUSIONS: Findings suggest that transference from uppercase letter knowledge may be a primary mechanism for lowercase letter knowledge and that young children's knowledge of the lowercase alphabet letters is multiply determined. PMID- 20705745 TI - Predicting expressive vocabulary acquisition in children with intellectual disabilities: a 2-year longitudinal study. AB - PURPOSE: This study's objectives were to describe expressive vocabulary acquisition in children with intellectual disabilities (ID) and to examine specific pre- and early linguistic behaviors used to request and comment, chronological age, cognitive skills, and vocabulary comprehension as predictors of expressive vocabulary. METHOD: This study included 36 children with ID, age 3;00 (years;months) to 6;05, with an average initial expressive vocabulary of 67 words. Expressive vocabulary acquisition was longitudinally followed over a 2 year period based on 4-monthly administrations of the Dutch version of the MacArthur Communicative Development Inventory/Words and Gestures (I. Zink & M. Lejaegere, 2002). Specific pre- and early linguistic behaviors used to request and comment as well as cognitive skills and vocabulary comprehension were measured at baseline. RESULTS: Individual growth modeling indicated that vocabulary comprehension was the only unique predictor of initial expressive vocabulary. Subsequent vocabulary growth was uniquely predicted by proportion of bimodal gesture + vocalization comments, chronological age, and cognitive skills. CONCLUSIONS: The results of this study underscore the great heterogeneity in expressive vocabulary skills in children with ID. The importance of prelinguistic communication, chronological age, cognitive skills, and vocabulary comprehension for explaining differences in expressive vocabulary skills is discussed. PMID- 20705746 TI - Explaining lexical-semantic deficits in specific language impairment: the role of phonological similarity, phonological working memory, and lexical competition. AB - PURPOSE: In this study, the authors investigated potential explanations for sparse lexical-semantic representations in children with specific language impairment (SLI) and typically developing peers. The role of auditory perception, phonological working memory, and lexical competition were investigated. METHOD: Participants included 32 children (ages 8;5-12;3 [years;months]): Sixteen children with SLI and 16 typically developing age- and nonverbal IQ-matched peers (CA). Children's word definitions were investigated. The words to be defined were manipulated for phonological neighborhood density. Nonword repetition and two lexical competition measures were tested as predictors of word definition abilities. RESULTS: Children with SLI gave word definitions with fewer content details than children in the CA group. Compared with the CA group, the definitions of children in the SLI group were not disproportionately impacted by phonological neighborhood density. Lexical competition was a significant unique predictor of children's word definitions, but nonword repetition was not. CONCLUSIONS: Individual differences in richness of lexical semantic representations as well as differences between children with SLI and typically developing peers may-at least, in part-be explained by processes of competition. However, difficulty with auditory perception or phonological working memory does not fully explain difficulties in lexical semantics. PMID- 20705748 TI - A tutorial on multiblock discriminant correspondence analysis (MUDICA): a new method for analyzing discourse data from clinical populations. AB - PURPOSE: In communication disorders research, clinical groups are frequently described based on patterns of performance, but researchers often study only a few participants described by many quantitative and qualitative variables. These data are difficult to handle with standard inferential tools (e.g., analysis of variance or factor analysis) whose assumptions are unfit for these data. This article presents multiblock discriminant correspondence analysis (MUDICA), which is a recent method that can handle datasets not suited for standard inferential techniques. METHOD: MUDICA is illustrated with clinical data examining conversational trouble-source repair and topic maintenance in dementia of the Alzheimer's type (DAT). Seventeen DAT participant/spouse dyads (6 controls, 5 participants with early DAT, 6 participants with moderate DAT) produced spontaneous conversations analyzed for co-occurrence of trouble-source repair and topic maintenance variables. RESULTS: MUDICA found that trouble-source repair sequences and topic transitions are associated and that patterns of performance in the DAT groups differed significantly from those in the control group. CONCLUSION: MUDICA is ideally suited to analyze language and discourse data in communication disorders because it (a) can identify and predict clinical group membership based on patterns of performance, (b) can accommodate few participants and many variables, (c) can be used with categorical data, and (d) adds the rigor of inferential statistics. PMID- 20705747 TI - Beyond capacity limitations II: effects of lexical processes on word recall in verbal working memory tasks in children with and without specific language impairment. AB - PURPOSE: This study investigated the impact of lexical processes on target word recall in sentence span tasks in children with and without specific language impairment (SLI). METHOD: Participants were 42 children (ages 8;2-12;3 [years;months]): 21 with SLI and 21 typically developing peers matched on age and nonverbal IQ. Children completed a sentence span task in which target words to be recalled varied in word frequency and neighborhood density. Two measures of lexical processes were examined: the number of nontarget competitor words activated during a gating task (lexical cohort competition) and word definitions. RESULTS: Neighborhood density had no effect on word recall for either group. However, both groups recalled significantly more high- than low-frequency words. Lexical cohort competition and specificity of semantic representations accounted for unique variance in the number of target word recalled in the SLI and chronological age-matched (CA) groups combined. CONCLUSIONS: Performance on verbal working memory span tasks for both SLI and CA children is influenced by word frequency, lexical cohorts, and semantic representations. Future studies need to examine the extent to which verbal working memory capacity is a cognitive construct independent of extant language knowledge representations. PMID- 20705750 TI - Understanding expressive speech acts: the role of prosody and situational context in French-speaking 5- to 9-year-olds. AB - PURPOSE: This study was aimed at determining the role of prosody and situational context in children's understanding of expressive utterances. Which one of these 2 cues will help children grasp the speaker's intention? Do children exhibit a "contextual bias" whereby they ignore prosody, such as the "lexical bias" found in other studies (M. Friend & J. Bryant, 2000)? METHOD: In the first experiment, a group of 5- to 9-year-old children and a group of adults performed a computerized judgment task. They had to determine the speaker's intention on the basis of an utterance produced with a particular prosody (positive or negative) in a particular situational context (positive or negative). In the second experiment, the same prosodic utterances were presented to 5- to 9-year-old children without a situational context. RESULTS: The 5- and 7-year-old children relied primarily on situational context, in contrast to adults, who relied on prosody. The 9-year-olds relied on both cues (Experiment 1). When prosody was the sole cue (Experiment 2), all children relied on this cue to infer the speaker's intention. CONCLUSIONS: The results are discussed and integrated into a larger conceptual framework that includes research on lexical bias and sarcasm. PMID- 20705749 TI - The role of phonotactic frequency in sentence repetition by children with specific language impairment. AB - PURPOSE: Recent work suggests that specific language impairment (SLI) results from a primary deficit in phonological processing. This deficit is most striking in nonword repetition tasks, where semantic and syntactic demands are eliminated. Children with SLI repeat nonwords less accurately than do their unimpaired peers, which may reflect difficulty extracting phonological regularities from their lexicons. However, recent evidence suggests that having children with SLI respond to meaningless syllables such as nonwords underestimates their language abilities. Therefore, phonological processing was measured by having children repeat meaningful sentences containing target words differing in phonotactic pattern frequency (PPF). METHOD: Eighteen children with SLI (mean age=9;0 [years;months]) and 18 age-matched controls repeated acoustically degraded sentences containing CVC target words differing in PPF, occurring in either subject position or sentence-final position. RESULTS: Accuracy results revealed significant main effects due to group, PPF, and sentence position (sentence final>subject). Further, the nonsignificant Group*PPF interaction suggests that both groups of children were similarly affected by PPF. CONCLUSION: Children with SLI repeated CVC target words less accurately overall but showed similar sensitivity to PPF as typical controls, suggesting that PPF affects repetition of real words embedded in sentential contexts by both children with SLI and typically developing peers. PMID- 20705751 TI - Lexicality and frequency in specific language impairment: accuracy and error data from two nonword repetition tests. AB - PURPOSE: Deficits in phonological working memory and deficits in phonological processing have both been considered potential explanatory factors in specific language impairment (SLI). Manipulations of the lexicality and phonotactic frequency of nonwords enable contrasting predictions to be derived from these hypotheses. METHOD: Eighteen typically developing (TD) children and 18 children with SLI completed an assessment battery that included tests of language ability, nonverbal intelligence, and two nonword repetition tests that varied in lexicality and frequency. RESULTS: Repetition accuracy showed that children with SLI were unimpaired for short and simple high-lexicality nonwords, whereas clear impairments were shown for all low-lexicality nonwords. For low-lexicality nonwords, greater repetition accuracy was seen for nonwords constructed from high over low-frequency phoneme sequences. Children with SLI made the same proportion of errors that substituted a nonsense syllable for a lexical item as TD children, and this was stable across nonword length. CONCLUSIONS: The data show support for a phonological processing deficit in children with SLI, where long-term lexical and sublexical phonological knowledge mediate the interpretation of nonwords. However, the data also suggest that while phonological processing may provide a key explanation of SLI, a full account is likely to be multifaceted. PMID- 20705752 TI - Dengue virus-induced autophagosomes and changes in endomembrane ultrastructure imaged by electron tomography and whole-mount grid-cell culture techniques. AB - The biogenesis events and formation of dengue virus (DENV) in the infected host cells remain incompletely understood. In the present study, we examined the ultrastructural changes associated with DENV-2 replication in three susceptible host cells, C6/36, Vero and SK Hep1, a cell line of human endothelial origin, using transmission electron microscopy, whole-mount grid-cell culture techniques and electron tomography (ET). The prominent feature in C6/36 cells was the formation of large perinuclear vacuoles with mature DENV particles, and on-grid whole-mount examination of the infected Vero cells showed different forms of DENV core structures associated with cellular membranes within 48 h after infection. Distinct multivesicular structures and prominent autophagic vesicles were seen in the infected SK Hep1 cells when compared with the other two cell lines. ET showed the three-dimensional organization of these vesicles as a continuous system. This is the first report of ET-based analysis of DENV-2 replication in a human endothelial cell line. These results further emphasizes the strong role played by intracellular host membranes-virus interactions in the biogenesis of DENV and strongly argues for the possibility of targeting compounds to block such structure formation as key anti-dengue agents. PMID- 20705753 TI - Implementation of a shared care guideline for back pain: effect on unnecessary referrals. AB - OBJECTIVE: To determine the effect of the implementation of a shared care guideline for the lumbosacral radicular syndrome (LRS) on unnecessary early referrals and the duration of the total diagnostic procedure. DESIGN: Introduction of shared care guideline in November 2005. Pre-test in 2005 (April to October), a first post-test in 2006 (April to October) and a second post-test in 2007 (April to October). SETTING: and INTERVENTION: The introduction of a shared care guideline derived from national guidelines for GPs and several medical/paramedical specialists in two Dutch regions. Three hundred and sixty GPs, 550 physiotherapists and two hospitals (9 neurologists and 18 radiologists) were involved. The essential component of the guideline was a trade-off: if the GP complied with the conservative management approach in the first 6 weeks, the hospital guaranteed a priority appointment with the neurologist after 6 weeks, if still required. MAIN OUTCOME MEASURES: The neurologists in both hospitals registered whether a patient had been unnecessarily referred during the first 6 weeks. The duration of the total diagnostic procedure was defined as the number of days between referral by the GP and the consultation when the neurologist made the final diagnosis. RESULTS: The percentage of patients being unnecessarily referred within 6 weeks fell significantly from 15% in 2005 to 9% in 2006 and 8% in 2007. The duration of the total diagnostic procedure also fell significantly in both the long and short terms. CONCLUSIONS: The introduction of a shared care guideline for all care providers in a region reduces the number of unnecessary early referrals for patients with LRS. PMID- 20705754 TI - Bioinformatics education in India. AB - An account of bioinformatics education in India is presented along with future prospects. Establishment of BTIS network by Department of Biotechnology (DBT), Government of India in the 1980s had been a systematic effort in the development of bioinformatics infrastructure in India to provide services to scientific community. Advances in the field of bioinformatics underpinned the need for well trained professionals with skills in information technology and biotechnology. As a result, programmes for capacity building in terms of human resource development were initiated. Educational programmes gradually evolved from the organisation of short-term workshops to the institution of formal diploma/degree programmes. A case study of the Master's degree course offered at the Bioinformatics Centre, University of Pune is discussed. Currently, many universities and institutes are offering bioinformatics courses at different levels with variations in the course contents and degree of detailing. BioInformatics National Certification (BINC) examination initiated in 2005 by DBT provides a common yardstick to assess the knowledge and skill sets of students passing out of various institutions. The potential for broadening the scope of bioinformatics to transform it into a data intensive discovery discipline is discussed. This necessitates introduction of amendments in the existing curricula to accommodate the upcoming developments. PMID- 20705755 TI - Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. AB - Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age >= 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934). PMID- 20705756 TI - Identification and functional analysis of endothelial tip cell-enriched genes. AB - Sprouting of developing blood vessels is mediated by specialized motile endothelial cells localized at the tips of growing capillaries. Following behind the tip cells, endothelial stalk cells form the capillary lumen and proliferate. Expression of the Notch ligand Delta-like-4 (Dll4) in tip cells suppresses tip cell fate in neighboring stalk cells via Notch signaling. In DLL4(+/-) mouse mutants, most retinal endothelial cells display morphologic features of tip cells. We hypothesized that these mouse mutants could be used to isolate tip cells and so to determine their genetic repertoire. Using transcriptome analysis of retinal endothelial cells isolated from DLL4(+/-) and wild-type mice, we identified 3 clusters of tip cell-enriched genes, encoding extracellular matrix degrading enzymes, basement membrane components, and secreted molecules. Secreted molecules endothelial-specific molecule 1, angiopoietin 2, and apelin bind to cognate receptors on endothelial stalk cells. Knockout mice and zebrafish morpholino knockdown of apelin showed delayed angiogenesis and reduced proliferation of stalk cells expressing the apelin receptor APJ. Thus, tip cells may regulate angiogenesis via matrix remodeling, production of basement membrane, and release of secreted molecules, some of which regulate stalk cell behavior. PMID- 20705757 TI - Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. AB - CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L deficient (Cd40l(-/-)) platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l(-/-) platelets into Apoe(-/-) mice strongly decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wild type platelets. Moreover, Cd40l(-/-) platelets failed to form proinflammatory platelet-leukocyte aggregates. Expression of CD40L on platelets was required for platelet-induced atherosclerosis as injection of Cd40l(-/-) platelets in contrast to Cd40l(+/+) platelets did not promote lesion formation. Remarkably, injection of Cd40l(+/+), but not Cd40l(-/-), platelets transiently decreased the amount of regulatory T cells (Tregs) in blood and spleen. Depletion of Tregs in mice injected with activated Cd40l(-/-) platelets abrogated the athero-protective effect, indicating that CD40L on platelets mediates the reduction of Tregs leading to accelerated atherosclerosis. We conclude that platelet CD40L plays a pivotal role in atherosclerosis, not only by affecting platelet-platelet interactions but especially by activating leukocytes, thereby increasing platelet leukocyte and leukocyte-endothelium interactions. PMID- 20705759 TI - FLT3 as a therapeutic target in AML: still challenging after all these years. AB - Mutations within the FMS-like tyrosine kinase 3 (FLT3) gene on chromosome 13q12 have been detected in up to 35% of acute myeloid leukemia (AML) patients and represent one of the most frequently identified genetic alterations in AML. Over the last years, FLT3 has emerged as a promising molecular target in therapy of AML. Here, we review results of clinical trials and of correlative laboratory studies using small molecule FLT3 tyrosine kinase inhibitors (TKIs) in AML patients. We also review mechanisms of primary and secondary drug resistance to FLT3-TKI, and from the data currently available we summarize lessons learned from FLT3-TKI monotherapy. Finally, for using FLT3 as a molecular target, we discuss novel strategies to overcome treatment failure and to improve FLT3 inhibitor therapy. PMID- 20705758 TI - Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an endogenous trapping mechanism links lymph- and angiogenesis. AB - Angio- and lymphangiogenesis are inherently related processes. However, how blood and lymphatic vessels regulate each other is unknown. This work introduces a novel mechanism explaining the temporal and spatial relation of blood and lymphatic vessels. Vascular endothelial growth factor-A (VEGF-A) surprisingly reduced VEGF-C in the supernatant of blood vessel endothelial cells, suggesting growth factor (GF) clearance by the growing endothelium. The orientation of lymphatic sprouting toward angiogenic vessels and away from exogenous GFs was VEGF-C dependent. In vivo molecular imaging revealed higher VEGF receptor (R)-2 in angiogenic tips compared with normal vessels. Consistently, lymphatic growth was impeded in the angiogenic front. VEGF-C/R-2 complex in the cytoplasm of VEGF A-treated endothelium indicated that receptor-mediated internalization causes GF clearance from the extracellular matrix. GF clearance by receptor-mediated internalization is a new paradigm explaining various characteristics of lymphatics. PMID- 20705760 TI - Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature. AB - Human polymorphonuclear leukocytes adhesion to endothelial cells during the early stage of inflammation leads to cell surface externalization of Annexin A1 (AnxA1), an effector of endogenous anti-inflammation. The antiadhesive properties of AnxA1 become operative to finely tune polymorphonuclear leukocytes transmigration to the site of inflammation. Membrane bound proteinase 3 (PR3) plays a key role in this microenvironment by cleaving the N terminus bioactive domain of AnxA1. In the present study, we generated a PR3-resistant human recombinant AnxA1-named superAnxA1 (SAnxA1)-and tested its in vitro and in vivo properties in comparison to the parental protein. SAnxA1 bound and activated formyl peptide receptor 2 in a similar way as the parental protein, while showing a resistance to cleavage by recombinant PR3. SAnxA1 retained anti-inflammatory activities in the murine inflamed microcirculation (leukocyte adhesion being the readout) and in skin trafficking model. When longer-lasting models of inflammation were applied, SAnxA1 displayed stronger anti-inflammatory effect over time compared with the parental protein. Together these results indicate that AnxA1 cleavage is an important process during neutrophilic inflammation and that controlling the balance between AnxA1/PR3 activities might represent a promising avenue for the discovery of novel therapeutic approaches. PMID- 20705761 TI - Effect of FCGR2A and FCGR3A variants on CLL outcome. AB - Polymorphisms of activating Fc-gamma receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulate antibody-dependent cellular cytotoxicity (ADCC) activity. Whether single-nucleotide polymorphisms of FCGRs correlate with survival of chronic lymphocytic leukemia (CLL) patients treated with a monoclonal antibody containing regimen is unclear. We assessed the FCGR3A and FCGR2A genotype of patients enrolled in the REACH trial, where patients received fludarabine and cyclophosphamide (FC) or rituximab plus FC (R-FC). FCGR3A and FCGR2A polymorphisms did not demonstrate prognostic significance in the FC arm (P = .42 and P = .64, respectively) or R-FC arm (P = .41 and P = .88, respectively) with respect to progression free survival. Patients with intermediate affinity genotypes (FV and HR) benefited significantly from addition of rituximab (hazard ratio = 0.55 [0.37-0.8 CI]; P = .0017 and hazard ratio = 0.63 [0.44-0.9 CI]; P = .011, respectively). Similar benefit was suggested for patients with high- affinity VV and HH (hazard ratio = 0.86 [0.4-1.84 CI]; P = .7 and hazard ratio = 0.7 [0.41-1.18 CI]; P = .18, respectively) and low-affinity FF and RR (hazard ratio = 0.85 [0.56-1.29 CI]; P = .44 and hazard ratio = 0.82 [0.47-1.42 CI]; P = .48, respectively). Overall, our results suggest that FCGR2A and FCGR3A polymorphisms do not significantly influence the outcomes of relapsed or refractory CLL patients treated with FC or the monoclonal antibody regimen R-FC. PMID- 20705762 TI - CLL 17p deletion: more than 'miR'ly p53? PMID- 20705763 TI - The substrate is down: is the IV out? PMID- 20705764 TI - Discovery of Hippo in MCL. PMID- 20705765 TI - Another Lnk to STAT activation. PMID- 20705766 TI - A Munc in the platelet granule works. PMID- 20705767 TI - Enhancing research in regenerative medicine. PMID- 20705768 TI - Population-based analyses in adult acute lymphoblastic leukemia. PMID- 20705770 TI - Independently acquired biallelic JAK2 mutations are present in a minority of patients with essential thrombocythemia. PMID- 20705771 TI - Poor outcome after reintroduction of imatinib in patients with chronic myeloid leukemia who interrupt therapy on account of pregnancy without having achieved an optimal response. PMID- 20705773 TI - Techniques/Databases divided into two separate categories. Editorial. PMID- 20705772 TI - Effects of long-term progesterone exposure on porcine uterine gene expression: progesterone alone does not induce secreted phosphoprotein 1 (osteopontin) in glandular epithelium. AB - Pigs experience significant conceptus loss near mid-gestation, correlating with increasing glandular epithelial (GE) development and secretory activity. Secreted phosphoprotein 1 (SPP1, osteopontin) increases in GE between days 30 and 40 of pregnancy and is expressed in the GE of day 90 pseudopregnant pigs, suggesting that progesterone (P(4)) from corpora lutea is responsible for induction of SPP1 in GE. In this study, pigs were ovariectomized and treated daily with P(4) to assess effects of 40 days of P(4) exposure on SPP1, P(4) receptor (PGR), uteroferrin (ACP5), and fibroblast growth factor 7 (FGF7) expression in porcine endometria. PGR mRNA decreased in pigs injected with P(4) compared with pigs injected with corn oil (CO), and PGRs were downregulated in the luminal epithelium (LE) and GE. ACP5 mRNA increased in pigs injected with P(4) compared with pigs injected with CO, and ACP5 was induced in the GE of P(4)-treated pigs. FGF7 mRNA increased in pigs injected with P(4) compared with pigs injected with CO, and FGF7 was induced in the LE and GE of P(4)-treated pigs. SPP1 mRNA was not different between pigs injected with P(4) compared with pigs injected with CO, and SPP1 was not present in the GE of P(4)-treated pigs. Therefore, long-term P(4), in the absence of ovarian and/or conceptus factors, does not induce SPP1 expression in GE. We hypothesize that a servomechanism involving sequential effects of multiple hormones and cytokines, similar to those for sheep and humans, is required for GE differentiation and function, including the synthesis and secretion of SPP1. PMID- 20705774 TI - Use of a postfall assessment tool to prevent falls. AB - Nursing research in fall prevention should not only identify etiologic risk factors to fall but seek to identify underlying causes, whenever possible. Few studies have investigated the use of a comprehensive postfall assessment tool (PFAT) by nurses as an intervention for the prevention of recurrent falls, especially one that prompts nurses to consider all potential causes through a categorization scheme. This study tested use of a comprehensive PFAT as an intervention, prospectively, facility-wide for 1 year by registered nurses using a pretest-posttest design. A 29.4% reduction in the fall rate (z = 3.89, p < .001), 27.6% decline in total falls experienced by all fallers (p < .001), and a 34.0% decline for recurrent fallers (p = .025) from preintervention to intervention year was observed when trained nurses categorized falls according to perceived causes. These declines are likely due to consistent and rigorous use by trained nursing staff, prompting their critical examination of each fall. PMID- 20705775 TI - An advanced educational program promoting evidence-based practice. AB - Evidence-based practice has led to improved health care quality and safety; greater patient, family, and staff satisfaction; and reduced costs. Despite these promising outcomes, use of evidence-based practice is inconsistent. The purpose of this article is to describe an advanced educational program for nurses in leadership roles responsible for guiding teams and mentoring colleagues through the challenges inherent in the evidence-based practice process. The Advanced Practice Institute: Promoting Adoption of Evidence-Based Practice is an innovative program designed to develop advanced skills essential for completing evidence-based practice projects and building organizational capacity for evidence-based practice programs. Learning is facilitated through group discussion, facilitated work time, networking, and consultation. Content includes finding and synthesizing evidence, learning effective strategies for implementation and evaluation, and discussing techniques for building an EBP program in the nurses' organization. Program evaluations are extremely positive, and the long-term impact is described. PMID- 20705776 TI - Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. AB - The objective of this research is to gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes. Endogenous glucose production is excessive before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin-induced suppression of endogenous glucose production, which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin-induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present. The premise of these studies, as well as those performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future. PMID- 20705777 TI - Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report. AB - OBJECTIVE: We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes. RESEARCH DESIGN AND METHODS: A male patient was diagnosed with diabetes at age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnancy). RESULTS: The genetic screening showed a double heterozygosity for the mutation p.E508K in the HNF1A/MODY3 gene and the novel variant p.R80Q in the HNF4A/MODY1 gene. The genetic testing of the family showed that the father carried the MODY3 mutation while the mother, the sister, and her two children carried the MODY1 mutation. CONCLUSIONS: MODY1 and MODY3 mutations may interact by chance to give a more severe form of diabetes (younger age at presentation and early need of insulin therapy to control hyperglycemia). PMID- 20705778 TI - Estimation and pharmacodynamic consequences of the minimum effective anesthetic volumes for median and ulnar nerve blocks: a randomized, double-blind, controlled comparison between ultrasound and nerve stimulation guidance. AB - BACKGROUND: Nerve stimulation and ultrasound guidance are the most popular techniques for peripheral nerve blocks. However, the minimum effective anesthetic volume (MEAV) in selected nerves for both techniques and the consequences of decreasing the local anesthetic volume on the pharmacodynamic characteristics of nerve block remain unstudied. We designed a randomized, double-blind controlled comparison between neurostimulation and ultrasound guidance to estimate the MEAV of 1.5% mepivacaine and pharmacodynamics in median and ulnar nerve blocks. METHODS: Patients scheduled for carpal tunnel release were randomized to ultrasound guidance (UG) or neurostimulation (NS) groups. A step-up/step-down study model (Dixon method) was used to determine the MEAV with nonprobability sequential dosing based on the outcome of the previous patient. The starting dose of 1.5% mepivacaine was 13 and 11 mL for median and ulnar nerves at the humeral canal. Block success/failure resulted in a decrease/increase of 2 mL. A blinded physician assessed sensory blockade at 2-minute intervals for 20 minutes. Block onset time and duration were noted. RESULTS: The MEAV50 (SD) of the median nerve was lower in the UG group 2 (0.1) mL (95% confidence interval [CI] = [1, 96] to [2, 04]) than in the NS group 4 (3.8) mL (95% CI = [2, 4] to [5, 6]) (P = 0.017). There was no difference for the ulnar nerve between UG group 2 (0.1) mL (95% CI = [1, 96] to [2, 04]) and NS group 2.4 (0.6) mL (95% CI = [2, 1] to [2, 7]). The duration of sensory blockade was significantly correlated to local anesthetic volume, but onset time was not modified. CONCLUSION: Ultrasound guidance selectively provided a 50% reduction in the MEAV of mepivacaine 1.5% for median nerve sensory blockade in comparison with neurostimulation. Decreasing the local anesthetic volume can decrease sensory block duration but not onset time. PMID- 20705779 TI - beta2-adrenergic receptor-coupled phosphoinositide 3-kinase constrains cAMP dependent increases in cardiac inotropy through phosphodiesterase 4 activation. AB - BACKGROUND: Emerging evidence suggests that phosphoinositide 3-kinase (PI3K) may modulate cardiac inotropy; however, the underlying mechanism remains elusive. We hypothesized that beta(2)-adrenergic receptor (AR)-coupled PI3K constrains increases in cardiac inotropy through cyclic adenosine monophosphate (cAMP) dependent phosphodiesterase (PDE) activation. METHODS: We tested the effects of PI3K and PDE4 inhibition on myocardial contractility by using isolated murine cardiac myocytes to study physiologic functions (sarcomere shortening [SS] and intracellular Ca(+) transients), as well as cAMP and PDE activity. RESULTS: PI3K inhibition with the reversible inhibitor LY294002 (LY) resulted in a significant increase in SS and Ca(2+) handling, indicating enhanced contractility. This response depended on G(ialpha) protein activity, because incubation with pertussis toxin (an irreversible G(ialpha) inhibitor) abolished the LY-induced hypercontractility. In addition, PI3K inhibition had no greater effect on SS than both a PDE3,4 inhibitor (milrinone) and LY combined. Furthermore, LY decreased PDE4 activity in a concentration-dependent manner (58.0% of PDE4 activity at LY concentrations of 10 MUM). Notably, PI3K(gamma) coimmunoprecipitated with PDE4D. The beta(2)-AR inverse agonist, ICI 118,551 (ICI), abolished induced increases in contractility. CONCLUSIONS: PI3K modulates myocardial contractility by a cAMP dependent mechanism through the regulation of the catalytic activity of PDE4. Furthermore, basal agonist-independent activity of the beta(2)-AR and its resultant cAMP production and enhancement of the catalytic activity of PDE4 through PI3K represents an example of integrative cellular signaling, which controls cAMP dynamics and thereby contractility in the cardiac myocyte. These results help to explain the mechanism by which milrinone is able to increase myocardial contractility in the absence of direct beta-adrenergic stimulation and why it can further augment contractility in the presence of maximal beta adrenergic stimulation. PMID- 20705780 TI - A long-term clinical evaluation of autoflow during assist-controlled ventilation: a randomized controlled trial. AB - BACKGROUND: Many new mechanical ventilation modes are proposed without any clinical evaluation. "Dual-controlled" modes, such as AutoFlowTM, are supposed to improve patient- ventilator interfacing and could lead to fewer alarms. We performed a long-term clinical evaluation of the efficacy and safety of AutoFlow during assist-controlled ventilation, focusing on ventilator alarms. METHODS: Forty-two adult patients, receiving mechanical ventilation for more than 2 days with a Drager Evita 4 ventilator were randomized to conventional (n = 21) or AutoFlow (n = 21) assist-controlled ventilation. Sedation was given using a nurse driven protocol. Ventilator-generated alarms were exhaustively recorded from the ventilator logbook with a computer. Daily blood gases and ventilation outcome were recorded. RESULTS: A total of 403 days of mechanical ventilation were studied and 45,022 alarms were recorded over a period of 8074 hours. The course of respiratory rate, minute ventilation, Fio(2), positive end-expiratory pressure, Pao(2)/Fio(2), Paco(2), and pH and doses and duration of sedation did not differ between the 2 groups. Outcome (duration of mechanical ventilation, ventilator-associated pneumonia, course of Sequential Organ Failure Assessment score, or death) was not different between the 2 groups. The number of alarms per hour was lower with AutoFlow assist-controlled ventilation: 3.3 [1.5 to 17] versus 9.1 [5 to 19], P < 0.0001 (median [quartile range]). In multivariate analysis, a low alarm rate was associated with activation of AutoFlow and a higher midazolam dose. CONCLUSIONS: This first long-term clinical evaluation of the AutoFlow mode demonstrated its safety with regard to gas exchange and patient outcome. AutoFlow also allowed a very marked reduction in the number of ventilator alarms. PMID- 20705781 TI - Epidural hematoma after neuraxial blockade: a retrospective report from China. AB - We conducted a detailed 54-year retrospective review of patients who developed epidural hematoma after neuraxial blockade in a university hospital and throughout Mainland China. Incidence, risk factors, and outcomes in the Chinese population were identified. The incidence of epidural hematoma after neuraxial blockade was 2.14 of 100,000 (95% confidence interval: 0.44-6.25 of 100,000). Patients who had a bacterial infection and required emergency surgery were at increased risk of developing epidural hematoma. There is a significant correlation between good neurologic recovery and short interval to decompressive surgery. PMID- 20705782 TI - Single versus triple injection ultrasound-guided infraclavicular block: confirmation of the effectiveness of the single injection technique. AB - BACKGROUND: The optimal site for local anesthetic placement during ultrasound guided infraclavicular block remains controversial. METHODS: Patients were randomized to receive lidocaine 2% 30 mL as a single injection posterior to the axillary artery (n = 51) or a triple injection ideally adjacent to each brachial plexus cord (n = 49). Pinprick sensory and motor block (3 = no block, 0 = complete block) were assessed to 20 minutes in the 4 distal nerve territories. RESULTS: The single injection group was not significantly inferior (single versus triple injection median [interquartile range] 20-minute aggregate block score: 5 [2-9] vs 7 [3.5-11]) but also demonstrated superiority (2-tailed test, P = 0.043). The single injection technique was associated with a small reduction in procedural time. CONCLUSIONS: The optimal site for local anesthetic placement during ultrasound-guided infraclavicular block is a single point injection posterior to the axillary artery. PMID- 20705783 TI - Pulse-oximetric measurement of prilocaine-induced methemoglobinemia in regional anesthesia. AB - BACKGROUND: The Masimo Radical 7((r)) is a new pulse CO oximeter designed to measure methemoglobin. The device has not been evaluated in a clinical setting. METHODS: In this prospective observational study we compared the arterial methemoglobin levels and the corresponding pulse CO-oximetric values of the Radical 7((r)) in regional anesthesia with prilocaine. RESULTS: We analyzed 360 data pairs with methemoglobin values up to 6.6%. The mean bias and limits (+/- 1.96 sd) of the device were 0.27% (+/- 1.33%). CONCLUSION: We found a high degree of agreement in measurement of methemoglobin between the 2 methods. PMID- 20705784 TI - The costs and benefits of extending the role of the acute pain service on clinical outcomes after major elective surgery. AB - BACKGROUND: Acute pain services have received widespread acceptance and formal support from institutions and organizations, but available evidence on their costs and benefits is scarce. Although there is good agreement on the provision of acute pain services after many major surgical procedures, there are other procedures for which the benefits are unclear. Data are required to justify any expansion of acute pain services. In this randomized, controlled clinical trial we compared the costs and effects of acute pain service care on clinical outcomes with conventional pain management on the ward. Patients included in the trial were considered by their anesthesiologist to have either arm be suitable for the procedure. METHODS: Four hundred twenty-three patients undergoing major elective surgery were randomized either to an anesthesiologist-led, nurse-based acute pain service group with patient-controlled analgesia or to a control group with IM or IV boluses of opioid analgesia. Both groups were treated with medications to treat opioid-related adverse effects and received the usual care from health professionals assigned to the ward. The main outcome measures were quality of recovery scores, pain intensity measures, global measure of treatment effectiveness, and overall pain treatment cost. Cost-effectiveness acceptability curves were drawn to detect a difference in the joint cost-effect relationship between groups. RESULTS: There was no difference in quality of recovery score on postoperative day 1 between treatment and control groups (mean difference, 0; 95% confidence interval [CI], -0.7 to 0.7; P = 0.94) or in the rate of improvement in quality of recovery score (mean difference, -0.1; 95% CI, -0.4 to 0.1; P = 0.34). The proportion of patients with 1 or more days of highly effective pain management was higher in the acute pain service group than in the control group (86% vs. 75%; P < 0.01). Costs were higher in the acute pain service group (mean difference, US$46; 95% CI, $44 to $48 per patient; P < 0.001). A cost effectiveness acceptability curve showed that the acute pain service was more cost effective than was control for providing highly effective pain management if the decision maker was willing to pay more than US$546 per patient per 1 day with highly effective treatment. CONCLUSION: In extending the role of the acute pain service to a specific group of major surgical procedures, the acute pain service was likely to be cost effective. PMID- 20705785 TI - Goal-directed fluid management based on the pulse oximeter-derived pleth variability index reduces lactate levels and improves fluid management. AB - BACKGROUND: Dynamic variables predict fluid responsiveness and may improve fluid management during surgery. We investigated whether displaying the variability in the pulse oximeter plethysmogram (pleth variability index; PVI) would guide intraoperative fluid management and improve circulation as assessed by lactate levels. METHODS: Eighty-two patients scheduled for major abdominal surgery were randomized into 2 groups to compare intraoperative PVI-directed fluid management (PVI group) versus standard care (control group). After the induction of general anesthesia, the PVI group received a 500-mL crystalloid bolus and a crystalloid infusion of 2 mL . kg(-1) . h(-1). Colloids of 250 mL were administered if the PVI was >13% Vasoactive drug support was given to maintain the mean arterial blood pressure above 65 mm Hg. In the control group, an infusion of 500 mL of crystalloids was followed by fluid management on the basis of fluid challenges and their effects on mean arterial blood and central venous pressure. Perioperative lactate levels, hemodynamic data, and postoperative complications were recorded prospectively. RESULTS: Intraoperative crystalloids and total volume infused were significantly lower in the goal-directed PVI group. Lactate levels were significantly lower in the PVI group during surgery and 48 hours after surgery (P < 0.05). CONCLUSIONS: PVI-based goal-directed fluid management reduced the volume of intraoperative fluid infused and reduced intraoperative and postoperative lactate levels. PMID- 20705786 TI - The effects of carvedilol administration on cardiopulmonary resuscitation in a rat model of cardiac arrest induced by airway obstruction. AB - BACKGROUND: Carvedilol is a nonselective beta-adrenoceptor and selective alpha(1) adrenoceptor blocker and is widely used in the treatment of patients with hypertensive and/or chronic heart failure because, unlike classic beta-blockers, this drug has additional endothelium-dependent vasodilatory effects. We evaluated the effects of oral administration of carvedilol on cardiopulmonary resuscitation (CPR) in a rat model of cardiac arrest (CA) induced by airway obstruction. METHODS: Twenty-four rats were randomly assigned to 2 groups: control group (no medication) and treatment group (oral administration of carvedilol [10 mg/kg/d] for 5 days) (n = 12 per group). All the animals were anesthetized, and CA was induced by obstructing the airway. Three minutes after CA, the animals were revived by administering CPR. The rate of chest compressions (CCs) was 240 to 260 CCs/min and the depth of CCs was adjusted to maintain the diastolic arterial blood pressure between 25 to 30 mm Hg in both groups. Epinephrine (0.02 mg/kg) was administered after 5 minutes of CPR. No other therapy was administered before, during, or after CA. RESULTS: The time interval between airway obstruction and CA in the treatment group was significantly longer than in the control group (230 +/- 27 vs 203 +/- 24 seconds; P < 0.05). The rate of return of spontaneous circulation in the treatment group was significantly higher than in the control group (92% vs 50%; P < 0.05). Acidosis and increased glucose and tumor necrosis factor-alpha concentrations in the treatment group were significantly lower than in the control group. CONCLUSIONS: The results of our study showed that rats that had been administered oral carvedilol for several days were more resistant to CA induced by airway obstruction, and when CA did occur, were more likely to be resuscitated. These findings suggest that carvedilol may prolong the safe ischemic time induced by respiratory failure. PMID- 20705787 TI - Symptomatic axillary hematoma after ultrasound-guided infraclavicular block in a patient with undiagnosed upper extremity mycotic aneurysms. AB - We present a case of axillary hematoma complicating an ultrasound-guided infraclavicular block in a patient with undiagnosed mycotic aneurysms of the peripheral arteries. Mycotic aneurysm is a rare medical condition with well identified risk factors. When performing regional anesthesia in patients with these risk factors, clinicians should have a high degree of suspicion about the possible existence of vascular anomalies. A preprocedure Doppler study of the block area and real-time guidance of the needle using ultrasound may be useful. PMID- 20705788 TI - Dexmedetomidine infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy. AB - BACKGROUND: Dexmedetomidine, a specific alpha(2) agonist, has an analgesic sparing effect and reduces emergence agitation. We compared an intraoperative dexmedetomidine infusion with bolus fentanyl to reduce perioperative opioid use and decrease emergence agitation in children with obstructive sleep apnea syndrome undergoing adenotonsillectomy (T&A). METHODS: One hundred twenty-two patients with obstructive sleep apnea syndrome undergoing T&A, ages 2 to 10 years, completed this prospective, randomized, U.S. Food and Drug Administration approved study. After mask induction with sevoflurane, group D received IV dexmedetomidine 2 MUg . kg(-1) over 10 minutes, followed by 0.7 MUg . kg(-1) . h( 1), and group F received IV fentanyl bolus 1 MUg . kg(-1). Anesthesia was maintained with sevoflurane, oxygen, and nitrous oxide. Fentanyl 0.5 to 1 MUg . kg(-1) was given to subjects in both groups for an increase in heart rate or systolic blood pressure 30% above preincision values that continued for 5 minutes. Observers in the postanesthesia care unit (PACU) were blinded to treatment groups. Pain was evaluated using the objective pain score in the PACU on arrival, at 5 minutes, at 15 minutes, then every 15 minutes for 120 minutes. Emergence agitation was evaluated at the same intervals by 2 scales: the Pediatric Anesthesia Emergence Delirium scale and a 5-point scale described by Cole. Morphine (0.05 to 0.1 mg . kg(-1)) was given for pain (score >4) or severe agitation (score 4 or 5) lasting more than 5 minutes. RESULTS: In group D, 9.8% patients needed intraoperative rescue fentanyl in comparison with 36% in group F (P = 0.001). Mean systolic blood pressure and heart rate were significantly lower in group D (P < 0.05). Minimum alveolar concentration values were significantly different between the 2 groups (P = 0.015). The median objective pain score was 3 for group D and 5 for group F (P = 0.001). In group D, 10 (16.3%) patients required rescue morphine, in comparison with 29 (47.5%) in group F (P = 0.002). The frequency of severe emergence agitation on arrival in the PACU was 18% in group D and 45.9% in group F (P = 0.004); at 5 minutes and at 15 minutes, it was lower in group D (P = 0.028). The duration of agitation on the Cole scale was statistically lower in group D (P = 0.004). In group D, 18% of patients and 40.9% in group F had an episode of Spo(2) below 95% (P = 0.01). CONCLUSIONS: An intraoperative infusion of dexmedetomidine combined with inhalation anesthetics provided satisfactory intraoperative conditions for T&A without adverse hemodynamic effects. Postoperative opioid requirements were significantly reduced, and the incidence and duration of severe emergence agitation was lower with fewer patients having desaturation episodes. PMID- 20705789 TI - The effect of ketamine anesthesia on the immune function of mice with postoperative septicemia. AB - BACKGROUND: It is unknown how ketamine anesthesia immunologically affects the outcome of patients with postoperative septicemia. We investigated the effects of ketamine anesthesia on mice with an Escherichia coli or lipopolysaccharide (LPS) challenge after laparotomy, focusing on phagocytosis by liver macrophages (Kupffer cells) and cytokine production. METHODS: C57BL/6 mice received ketamine or sevoflurane anesthesia during laparotomy, which was followed by an E. coli or LPS challenge; thereafter, mouse survival rates and cytokine secretions were examined. The effects of a beta-adrenoceptor antagonist, nadolol, on ketamine anesthesia were also assessed to clarify the mechanisms of ketamine-induced immunosuppressive effects. RESULTS: Ketamine anesthesia increased the mouse survival rate after LPS challenge after laparotomy compared with sevoflurane anesthesia, whereas such an effect of ketamine was not observed after E. coli challenge. Ketamine suppressed tumor necrosis factor (TNF) and interferon (IFN) gamma secretion after LPS and E. coli challenge. When bacterial growth was inhibited using an antibiotic, ketamine anesthesia effectively improved mouse survival after E. coli challenge compared with sevoflurane anesthesia. Neutralization of TNF also improved survival and decreased IFN-gamma secretion after bacterial challenge in antibiotic-treated mice with sevoflurane anesthesia, suggesting that ketamine's suppression of TNF may improve survival. Ketamine also suppressed in vivo phagocytosis of microspheres by Kupffer cells in LPS challenged mice. Concomitant use of nadolol with an anesthetic dose of ketamine did not restore TNF suppression in LPS-challenged mice, suggesting a mechanism independent of the beta-adrenergic pathway. However, it restored TNF secretion under low-dose ketamine (10% anesthetic dose). In contrast, nadolol restored the decrease in phagocytosis by Kupffer cells, which was induced by the anesthetic dose of ketamine via the beta-adrenergic pathway, suggesting distinct mechanisms. CONCLUSION: Ketamine suppresses TNF production and phagocytosis by Kupffer cells/macrophages. Therefore, unless bacterial growth is well controlled (by an antibiotic), postoperative infection might not improve despite reduction of the inflammatory response. PMID- 20705790 TI - Lung recruitment and positive end-expiratory pressure have different effects on CO2 elimination in healthy and sick lungs. AB - BACKGROUND: We studied the effects that the lung recruitment maneuver (RM) and positive end-expiratory pressure (PEEP) have on the elimination of CO(2) per breath (Vtco(2,br)). METHODS: In 7 healthy and 7 lung-lavaged pigs at constant ventilation, PEEP was increased from 0 to 18 cm H(2)O and then decreased to 0 in steps of 6 cm H(2)O every 10 minutes. Cycling RMs with plateau pressure/PEEP of 40/20 (healthy) and 50/25 (lavaged) cm H(2)O were applied for 2 minutes between 18-PEEP steps. Volumetric capnography, respiratory mechanics, blood gas, and hemodynamic data were recorded. RESULTS: In healthy lungs before the RM, Vtco(2,br) was inversely proportional to PEEP decreasing from 4.0 (3.6-4.4) mL (median and interquartile range) at 0-PEEP to 3.1 (2.8-3.4) mL at 18-PEEP (P < 0.05). After the RM, Vtco(2,br) increased from 3.3 (3-3.6) mL at 18-PEEP to 4.0 (3.5-4.5) mL at 0-PEEP (P < 0.05). In lavaged lungs before the RM, Vtco(2,br) increased initially from 2.0 (1.7-2.3) mL at 0-PEEP to 2.6 (2.2-3) mL at 12-PEEP (P < 0.05) but then decreased to 2.4 (2-2.8) mL when PEEP was increased further to 18 cm H(2)O (P < 0.05). After the RM, the highest Vtco(2,br) of 2.9 (2.1-3.7) mL was observed at 12-PEEP and then decreased to 2.5 (1.9-3.1) mL at 0-PEEP (P < 0.05). Vtco(2,br) was directly related to changes in lung perfusion, the area of gas exchange, and alveolar ventilation but inversely related to changes in dead space. CONCLUSIONS: CO(2) elimination by the lungs was dependent on PEEP and recruitment and showed major differences between healthy and lavaged lungs. PMID- 20705791 TI - Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. AB - The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC(50) of 0.3 MUM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive. PMID- 20705792 TI - Live birth after ICSI of micro-TESE-retrieved spermatozoa into in vitro-matured oocytes. AB - This case report describes a live birth resulting from intracytoplasmic sperm injection (ICSI) of spermatozoa retrieved by microdissection testicular sperm extraction (micro-TESE) into oocytes produced from human chorionic gonadotropin primed in vitro maturation (IVM) cycles. In the IVM treatment, a total of 30 oocytes (1 mature and 29 immature oocytes) were retrieved. Following IVM, 9 oocytes had matured. A total of 4 oocytes were fertilized after ICSI with the husband's micro-TESE spermatozoa and 4 embryos were transferred into the uterus on day 3. A healthy boy weighing 2500 g was born at 35.5 weeks of gestation. PMID- 20705793 TI - Perceived ejaculate volume reduction in patients with erectile dysfunction: psychobiologic correlates. AB - The disorders of orgasm/ejaculation encompass a heterogeneous group of dysfunctions including premature ejaculation, delayed ejaculation, and perceived ejaculate volume reduction (PEVR). The aim of this study was to explore specific associations of PEVR in a consecutive series of 3141 patients (mean age, 51.6 +/- 13.1 years) seeking consultation for erectile dysfunction (ED). Among these, 71 were excluded because they underwent prostate surgery. Different clinical and biochemical factors were evaluated along with parameters derived from the Structured Interview on Erectile Dysfunction evaluating the contribution of organic, relational, and intrapsychic factors to ED. After adjustment for confounders, PEVR was specifically associated with the use of androgen deprivation therapy as well as with different other medications including alpha blockers, serotonergic reuptake inhibitor antidepressants, and angiotensin converting enzyme inhibitors/angiotensin receptor blockers. A higher prevalence of diabetes mellitus and hypogonadism was observed in patients with PEVR compared with the rest of the sample (23.0% vs 14.1% and 9.1% vs 5.3% respectively; both P < .05). In addition, different sexual parameters such as severe ED (hazard ratio [HR] = 1.25 [1.11-1.41]; P < .0001) and patient's (HR = 1.53 [1.38-1.70]; P < .0001) and partner's (HR = 1.21 [1.07-1.36]; P < .005) hypoactive sexual desire (HSD) were also significantly related to PEVR. Furthermore, PEVR was associated with an impairment of both the relational and intrapsychic components of ED. In a multivariate model, adjusting for age, body mass index, smoking habits, and medications, hypogonadism, diabetes mellitus, severe ED, and patient's and partner's HSD were all independently associated with PEVR. Our results indicate that PEVR is important not only for couple reproductive purposes but also appears to have a distinct role in the couple's sexual performance. PMID- 20705794 TI - Functional expression of ropporin in human testis and ejaculated spermatozoa. AB - Asthenozoospermia is a common cause of human male infertility, but the molecular mechanism is not fully understood. With Affymetrix Genechips, ropporin, a component of sperm flagella, was identified by comparing the expression profiles in ejaculated spermatozoa from normozoospermic men and patients with asthenozoospermia. Immunohistochemistry was used to analyze the expression characteristic of ropporin in human testis. Reverse transcription-polymerase chain reaction, Western blotting, and indirect immunofluorescence assay were used to determine the expression of ropporin in ejaculated spermatozoa from normozoospermic and asthenozoospermic men. The results showed that ropporin was predominantly expressed in round spermatids in human testis, and located in the principal piece and the end piece of spermatozoa flagella. The expression level of ropporin was significantly lower in asthenozoospermic men than in normozoospermic controls. These data suggested that ropporin may be involved in sperm motility and its decreased expression may contribute to the low sperm motility in asthenozoospermic patients. PMID- 20705795 TI - Performance of medical residents in sterile techniques during central vein catheterization: randomized trial of efficacy of simulation-based training. AB - BACKGROUND: Catheter-related bloodstream infection (CRBSI) is a preventable cause of a potentially lethal ICU infection. The optimal method to teach health-care providers correct sterile techniques during central vein catheterization (CVC) remains unclear. METHODS: We randomly assigned second- and third-year internal medicine residents trained by a traditional apprenticeship model to simulation based plus video training or video training alone from December 2007 to January 2008, with a follow-up period to examine CRBSI ending in July 2009. During the follow-up period, a simulation-based training program in sterile techniques during CVC was implemented in the medical ICU (MICU). A surgical ICU (SICU) where no residents received study interventions was used for comparison. The primary outcome measures were median residents' scores in sterile techniques and rates of CRBSI per 1,000 catheter-days. RESULTS: Of the 47 enrolled residents, 24 were randomly assigned to the simulation-based plus video training group and 23 to the video training group. Median baseline scores in both groups were equally poor: 12.5 to 13 (52%-54%) out of maximum score of 24 (P = .95; median difference, 0; 95% CI, 0.2-2.0). After training, median score was significantly higher for the simulation-based plus video training group: 22 (92%) vs 18 (75%) for the video training group (P < .001; median difference, 4; 95% CI, 3-6). During the follow up period, there was a significantly lower rate of CRBSI in the MICU (1.0 per 1,000 catheter-days) compared with the SICU (3.4 per 1,000 catheter-days) (P = .03). The incidence rate ratio derived from the Poisson regression (0.30; 95% CI, 0.10-0.91) indicated there was a 70% reduction in the incidence of CRBSI in the postintervention MICU compared with the preintervention MICU and the postintervention SICU. CONCLUSIONS: Simulation-based training in sterile techniques during CVC is superior to traditional training or video training alone and is associated with decreased rate of CRBSI. Simulation-based training in CVC should be routinely used to reduce iatrogenic risk. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00612131; URL: clinicaltrials.gov. PMID- 20705796 TI - Prevalence and recognition of obstructive sleep apnea in Chinese patients with type 2 diabetes mellitus. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with disorders of glucose metabolism. Previous studies revealed a high prevalence of OSA among subjects with type 2 diabetes mellitus (DM). The aims of this study were to determine the prevalence of OSA and associated clinical factors in Chinese patients with DM. METHODS: All records of the DM clinic at a teaching hospital in Hong Kong were screened between January 2007 and June 2008. Inclusion criteria for patients were Chinese, aged 18 to 75 years, with type 2 DM. Patients with unstable medical illnesses, gestational diabetes, or on renal replacement therapy were excluded. RESULTS: Of 3,489 records screened, 1,859 subjects were eligible. A random sample of 663 (mean age, 58.2 +/- 10.8; mean BMI, 26.0 +/- 4.6), except six with known OSA, were invited for polysomnography (PSG). Of 165 subjects on which PSG was performed, OSA was diagnosed (apnea-hypopnea index [AHI] >= 5.0/h) in 89 subjects (53.9%, median Epworth Sleepiness Scale, 6 [interquartile range 3, 10]). Fifty four (32.7%) had moderate/severe OSA (AHI >= 15/h). The estimated OSA prevalence in this diabetic cohort was 17.5% (24.7% in men, 10.3% in women). Regression analysis identified that AHI was associated independently with higher BMI, advanced age, male sex, and higher diastolic BP (R(2) = 29.6%). The adjusted OR of requiring three or more antihypertensive drugs in moderate/severe OSA was 2.48 (95% CI, 1.05-5.87). No association between glycemic control (HbA1c) and sleep was identified. CONCLUSIONS: In conclusion, OSA is more prevalent in Chinese adults with DM than in the general population. A high index of suspicion for OSA in patients with DM is warranted, because they may not have overt daytime sleepiness. PMID- 20705798 TI - Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. AB - BACKGROUND: Ambrisentan is a selective endothelin-receptor antagonist that is approved by the US Food and Drug Administration for the treatment of pulmonary arterial hypertension. We describe hemodynamic responses and clinical outcomes of patients with portopulmonary hypertension (POPH) treated with ambrisentan. METHODS: In this observational study, we prospectively identified and followed consecutive adult patients with POPH who received monotherapy with ambrisentan <= 10 mg daily from January 2007 until December 2009. Liver enzymes were assessed monthly. Pulmonary hemodynamic responses were assessed using echocardiograms and right-sided heart catheterizations. RESULTS: We identified 13 patients (seven men) with POPH and began monotherapy with ambrisentan. The median age was 57 (interquartile range [IQR], 52-60). Patients were followed for a median of 613 days (IQR, 385-1,011). The median model for end-stage liver disease score was 10 (IQR, 8.5-15); eight patients had Child-Turcotte-Pugh A classification. Median time on ambrisentan therapy was 390 days (IQR, 363-611). Two patients died, one of advanced hepatocellular carcinoma and one of septic shock following pneumonia. The mean pulmonary artery pressure decreased from a baseline median of 58 mm Hg (IQR, 37-63) to 41 mm Hg (IQR, 27-48) (P = .004). The pulmonary vascular resistance median was reduced from 445 dynes/s/cm(5) (IQR, 329-834) to 174 dynes/s/cm(5) (IQR, 121-361) (P = .008). There was no difference in the longitudinal analysis of liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) after 12 months of therapy. One patient underwent successful liver transplantation and normalized pulmonary hemodynamic responses after transplantation. CONCLUSIONS: In this small cohort of patients with moderate to severe pulmonary hypertension in the setting of POPH, we have shown that ambrisentan monotherapy can significantly improve pulmonary hemodynamic responses without adverse effect on hepatic function. PMID- 20705797 TI - Smoking-induced upregulation of AKR1B10 expression in the airway epithelium of healthy individuals. AB - BACKGROUND: The aldo-keto reductase (AKR) gene superfamily codes for monomeric, soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that mediate elimination reactions. AKR1B10, an AKR that eliminates retinals, has been observed as upregulated in squamous metaplasia and non-small cell lung cancer and has been suggested as a diagnostic marker specific to tobacco-related carcinogenesis. We hypothesized that upregulation of AKR1B10 expression may be initiated in healthy smokers prior to the development of evidence of lung cancer. METHODS: Expression of AKR1B10 was assessed at the mRNA level using microarrays with TaqMan confirmation in the large airway epithelium (21 healthy nonsmokers, 31 healthy smokers) and small airway epithelium (51 healthy nonsmokers, 58 healthy smokers) obtained by fiberoptic bronchoscopy and brushing. RESULTS: Compared with healthy nonsmokers, AKR1B10 mRNA levels were significantly upregulated in both large and small airway epithelia of healthy smokers. Consistent with the mRNA data, AKR1B10 protein was significantly upregulated in the airway epithelium of healthy smokers as assessed by Western blot analysis and immunohistochemistry, with AKR1B10 expressed in both differentiated and basal cells. Finally, cigarette smoke extract mediated upregulation of AKR1B10 in airway epithelial cells in vitro, and transfection of AKR1B10 into airway epithelial cells enhanced the conversion of retinal to retinol. CONCLUSIONS: Smoking per se mediates upregulation of AKR1B10 expression in the airway epithelia of healthy smokers with no evidence of lung cancer. In the context of these observations and the link of AKR1B10 to the metabolism of retinals and to lung cancer, the smoking-induced upregulation of AKR1B10 may be an early process in the multiple events leading to lung cancer. PMID- 20705799 TI - Increased nitric oxide concentrations in the small airway of older normal subjects. AB - BACKGROUND: There is a paucity of normal-age stratified data for fraction of exhaled nitric oxide (Feno). Our goal was to obtain normal data for large-airway nitric oxide flux (J'awno) and small-airway and/or alveolar nitric oxide concentration (Cano) in nonsmoking, healthy, adult subjects of various ages. METHODS: In 106 normal volunteer subjects (60 women) aged 55 +/- 20 years (mean +/- SD), Feno (parts per billion [ppb]) was measured at 50, 100, 150, and 200 mL/s and J'awno (nL/s) and Cano (ppb) were calculated using a two-compartment model with correction for axial nitric oxide (NO) back diffusion. Fourteen older normal subjects were also treated with inhaled corticosteroid (540 MUg budesonide bid) for 14 days. RESULTS: We studied 34 younger normal subjects (17 women) aged 18 to 39 years (younger), 26 middle-aged normal subjects (22 women) aged 40 to 59 years (middle-aged), and 46 older normal subjects (21 women) aged 60 to 86 years (older). Feno at 50 mL/s in the younger group was 21 (14-28) ppb (median, 1-3 interquartile); in the middle-aged group it was 22 (18-30) ppb, and in the older group it was 27 (21-33) ppb, (analysis of variance [ANOVA]) P = .02. For Feno, the younger vs older groups was (Mann-Whitney) P = .03, and Feno in the combined younger and middle-aged groups was 21 (15-29) ppb vs 27 (21-33) ppb, P = .006 for the older group. Corrected J'awno in the younger group was 1.5 (1.0-2.1) nL/s; in the middle-aged group it was 1.4 (1.0-2.0) nL/s, and in the older group it was 1.8 (1.2-2.4) nL/s, (ANOVA) P = .3. Corrected Cano in the younger group was 1.9 (0.8-3.0) ppb; in the middle-aged group it was 2.8 (0.8-5.1) ppb, and in the older group it was 3.9 (1.4-6.6) ppb, (ANOVA) P = .02. Cano in the younger vs older groups was P = .003, and the combined younger and middle-aged group result was 2.0 (0.8-3.8) vs 3.9 (1.4-6.6), P = .01 in the older group. There was no change in NO gas exchange with inhaled corticosteroids. CONCLUSIONS: In nonsmoking healthy subjects with normal spirometry, Feno at 50 mL/s and Cano increased significantly with age >= 60 years, whereas J'awno did not. We suspect the increase in Cano was due to a decrease in capillary blood volume with reduced NO diffusion, which is also reflected in increased Feno. Inhaled budesonide had no anti-NO-mediated inflammatory effect. Age-matched control subjects will be needed in NO comparative studies. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00576069 and NCT00568347; URL: www.clinicaltrials.gov. PMID- 20705800 TI - Emphysema presence, severity, and distribution has little impact on the clinical presentation of a cohort of patients with mild to moderate COPD. AB - BACKGROUND: Phenotypic characterization of patients with COPD may have potential prognostic and therapeutic implications. Available information on the relationship between emphysema and the clinical presentation in patients with COPD is limited to advanced stages of the disease. The objective of this study was to describe emphysema presence, severity, and distribution and its impact on clinical presentation of patients with mild to moderate COPD. METHODS: One hundred fifteen patients with COPD underwent clinical and chest CT scan evaluation for the presence, severity, and distribution of emphysema. Patients with and without emphysema and with different forms of emphysema distribution (upper/lower/core/peel) were compared. The impact of emphysema severity and distribution on clinical presentation was determined. RESULTS: Fifty percent of the patients had mild homogeneously distributed emphysema (1.84; 0.76%-4.77%). Upper and core zones had the more severe degree of emphysema. Patients with emphysema were older, more frequently men, and had lower FEV(1)%, higher total lung capacity percentage, and lower diffusing capacity of the lung for carbon monoxide. No differences were found between the clinical or physiologic parameters of the different emphysema distributions. CONCLUSIONS: In patients with mild to moderate COPD, although the presence of emphysema has an impact on physiologic presentation, its severity and distribution seem to have little impact on clinical presentation. PMID- 20705801 TI - Lane-Hamilton syndrome: ferritin protects lung macrophages against iron and oxidation. AB - BACKGROUND: Lysosomal disruption and consequent apoptosis have been implicated in lung diseases characterized by iron overload. Free reactive iron in lysosomes sensitizes cells to oxidative stress. Apoptosis is prevented by heavy-chain (H) ferritin, which can incorporate lysosomal iron into ferritin molecules. Tumor necrosis factor (TNF)-alpha stimulates the synthesis of H-ferritin. Idiopathic pulmonary hemosiderosis presents with the accumulation of iron and the upregulation of ferritin synthesis. We therefore analyzed the lysosomal response to oxidants and the role of H-ferritin synthesis in lung macrophages (LMs) harvested from the first Swedish case, to our knowledge, of Lane-Hamilton syndrome. METHODS: Iron-exposed murine macrophages were used as a reference. Both cell types were stimulated with TNF-alpha (or not), then iron was assessed cytochemically and by atomic absorption spectrophotometry. H-ferritin expression was analyzed by Western blot and reduced glutathione (GSH) by spectrofluorometry. Following exposure to hydrogen peroxide, lysosomal membrane integrity and DNA degradation were analyzed by flow cytometry, whereas morphologic signs of apoptosis and necrosis were assessed by light microscopy. RESULTS: GSH levels were approximately equal in LMs and murine macrophages. Although LMs contained much more iron than murine macrophages, lysosomal iron was bound in a harmless unreactive state by ample amounts of ferritin and hemosiderin, its lysosomal degradation product. Therefore, lysosomes of LMs were more oxidant resistant, and these cells were more adept at surviving oxidative stress. In both cell types, TNF-alpha prevented oxidant-induced lysosomal damage and cell death by upregulating synthesis of H-ferritin and GSH. CONCLUSIONS: Iron-overloaded LMs are equipped with an efficient armor of antioxidative mechanisms of which H ferritin and hemosiderin seem to be particularly important. PMID- 20705802 TI - Using voluntary cough to detect penetration and aspiration during oropharyngeal swallowing in patients with Parkinson disease. AB - BACKGROUND: Identification of people with Parkinson disease (PD) who are at risk for aspiration is important, especially because of the high prevalence of aspiration pneumonia. METHODS: Fifty-eight consecutive patients (Hoehn and Yahr stage II-III; average age 72.3) were enrolled in the study. Measures of airflow during voluntary cough production and the degree of penetration/aspiration on a 3 oz oropharyngeal swallow task, derived from videofluorographic images, were examined. RESULTS: To detect at-risk people (those with penetration and/or aspiration on the 3-oz swallow task), four objective measures of voluntary cough (compression phase duration [CPD], expiratory phase rise time [EPRT], expiratory phase peak flow [EPPF], and cough volume acceleration [CVA)]) were collected. CPD, EPRT, EPPF, and CVA measurements produced significant area under the curve (AUC) analyses and likelihood ratios equal to 0.83:2.72, 0.71:2.68, 0.69:1.75, and 0.78:18.42, respectively. CPD, EPRT, EPPF, and CVA measurements demonstrated sensitivities of 95.83%, 70.83%, 87.50%, and 84.53%, and specificities of 64.71%, 73.53%, 50.01%, and 97.06%, respectively. For detection of aspiration, EPPF was significantly associated with an AUC = 0.88 and with an EPPF < 5.24, which had a sensitivity of 57.15% and a specificity of 100%. CONCLUSIONS: The data from this pilot study suggest that in patients with PD, objective airflow measures from voluntary cough production may identify at-risk penetrator/aspirators. To our knowledge, this is the first study to evaluate the discriminative ability of voluntary cough airflow characteristics to model airway compromise in people with PD. PMID- 20705803 TI - Population-level impact of osteoporotic fractures on mortality and trends over time: a nationwide analysis of vital statistics for France, 1968-2004. AB - Osteoporotic fractures are one of the leading causes of death in the elderly population, but mortality may have been reduced by the advances in management and prevention during recent decades. The authors analyzed the population-level impact of these fractures on mortality in France from 1968 to 2004. About 20 million death certificates registered in metropolitan France from 1968 to 2004 were analyzed. Osteoporotic fractures were identified by using a previously developed methodology. Age-specific and standardized mortality rates were calculated by site of fracture and sex, and time trends were evaluated. Associated causes of death were compared between the extreme periods of the study by the observed/expected pairs method; 440,890 (2.2%) death certificates reported an osteoporotic fracture. Osteoporotic fractures overall, particularly hip and skull fractures, declined by half during the study period, exceeding the decline in general mortality and resulting in fracture-deceased subjects being older. However, pelvis, vertebral, and rib fractures became more frequent. Associated causes of death increased with time, except for decubitus ulcers, indicating a change in the pattern of the death process. Despite a 50% decline, osteoporotic fractures still have a significant impact on mortality. The pattern of the death process has changed, with an increased role for comorbidities. PMID- 20705804 TI - Timing of applying electrical stimulation is an important factor deciding the success rate and maturity of regenerating rat sciatic nerves. AB - BACKGROUND: The timing of electrical stimulation (ES) after peripheral nerve transection may enhance axonal regeneration and functional recovery. OBJECTIVE: The authors examined whether percutaneous ES at 1 mA and 2 Hz affects regeneration between the proximal and distal nerve stumps. METHODS: Four groups of adult rats were subjected to sciatic nerve section followed by repair using silicone rubber conduits across a 10-mm gap. All groups received ES for 15 minutes every other day for 2 weeks. Stimulation was initiated on day 1 following the nerve repair for group A, day 8 for group B, and day 15 for group C. The control group D received no ES. RESULTS: At 6 weeks after surgery in groups B and C, histological evaluations showed a significantly higher number of regenerated myelinated fibers in the sciatic nerve, and the electrophysiological results showed higher levels of reinnervation with relatively larger mean values of amplitudes, durations, and areas of compound muscle action potentials compared with A and D. CONCLUSION: A short delay in the onset of ES may improve the recovery of a severe peripheral nerve injury, which should be considered as a way of augmenting rehabilitative approaches. PMID- 20705806 TI - Beta-blocker supplementation of standard drug treatment for schizophrenia. PMID- 20705805 TI - Disorganization/cognitive and negative symptom dimensions in the at-risk mental state predict subsequent transition to psychosis. AB - OBJECTIVE: The at-risk mental state (ARMS) is associated with a very high risk of psychosis, but it is difficult to predict which individuals will later develop psychosis on the basis of their presenting symptoms. We investigated psychopathological dimensions in subjects with an ARMS and examined whether particular symptom dimensions predicted subsequent transition to psychosis. METHOD: The sample comprised 122 subjects (aged 16-35 years) meeting Personal Assessment and Crisis Evaluation clinic criteria for the ARMS recruited through Outreach and Support in South London, a clinical service for people with an ARMS. A principal axis factor analysis was performed on symptom scores, obtained at presentation from the Comprehensive Assessment of the At-Risk Mental State, using Varimax rotation. The relationship between dimension scores and transition to psychosis during the following 24 months was then examined employing Cox regression analysis. RESULTS: Factor analysis gave rise to a 5-factor solution of negative, anxiety, disorganization/cognitive, self-harm, and manic symptom dimensions, accounting for 37% of the total variance. Scores on the negative and on the disorganization/cognitive dimensions were associated with transition to psychosis during the follow-up period (P = 0.044 and P = 0.005, respectively). CONCLUSION: The symptoms of the ARMS have a dimensional structure similar to that evident in patients with schizophrenia except for the positive symptom dimension. The association between scores on the disorganization/cognitive and negative dimensions and later transition is consistent with independent evidence that formal thought disorder, subjective cognitive impairments, and negative symptoms are linked to the subsequent onset of psychosis. PMID- 20705807 TI - NCCN Task Force Report: Specialty Pharmacy. AB - The use of specialty pharmacies is expanding in oncology pharmacy practice. Specialty pharmacies provide a channel for distributing drugs that, from the payor perspective, creates economies of scale and streamlines the delivery of expensive drugs. Proposed goals of specialty pharmacy include optimization of pharmaceutical care outcomes through ensuring appropriate medication use and maximizing adherence, and optimization of economic outcomes through avoiding unwarranted drug expenditure. In oncology practice, specialty pharmacies have become a distribution channel for various agents. The use of a specialty pharmacy, and the addition of the pharmacist from the specialty pharmacy to the health care team, may not only provide benefits for care but also present challenges in oncology practice. The NCCN Specialty Pharmacy Task Force met to identify and examine the impact of specialty pharmacy practice on the care of people with cancer, and to provide recommendations regarding issues discussed. This report provides recommendations within the following categories: education and training of specialty pharmacy practitioners who care for individuals with cancer, coordination of care, and patient safety. Areas for further evaluation are also identified. PMID- 20705808 TI - Effect of salt intensity on ad libitum intake of tomato soup similar in palatability and on salt preference after consumption. AB - Sensory properties of food play an important role in satiation. Studies on the effect of taste intensity on satiation show conflicting results. This may be due to the notion that in these studies taste intensity and palatability were confounded. The objective of this study was to investigate the effect of salt intensity of tomato soup on ad libitum intake (satiation), while controlling for palatability on an individual basis. Forty-eight subjects consumed both a low salt (LS) and high-salt (HS) soup ad libitum from a self-refilling bowl. The results showed no difference between LS and HS soup in ad libitum intake, eating rate, changes in appetite ratings, and changes in hedonic ratings after intake. After intake of HS soup, LS soup was perceived as more bland than before intake of HS soup. After intake of LS soup, HS soup was perceived as more salt intense than before intake of LS soup. In conclusion, this study found no effect of salt intensity on satiation of tomato soups that were similar in palatability. During consumption, subjects adapted quickly to the exposed salt intensity as contrasting salt intensities were rated further from the ideal salt intensity and therefore perceived as less pleasant after consumption. PMID- 20705810 TI - The contraceptive needs for STD protection among women in jail. AB - We assessed the contraceptive needs of women in jails and their sexually transmitted disease (STD) history and risk to determine effective contraceptive methods for this population. A survey of demographics, sexual health, contraceptive use, and preferred method of contraception was completed by participants recruited at jails in a medium-sized metropolitan area. Results from 188 women indicated high rates of STDs, inconsistent contraceptive use, and use of unreliable and user-dependent contraception methods. Intended contraceptive use following release varied depending on women's ability to bear children. Women planning to use condoms after release were more likely to have had an STD and more sexual partners than were women not planning to use condoms. Racial differences were found for participants' sexual health and contraception histories. These women were at high risk for STDs and appeared to need education about contraception methods. Therefore, they might benefit from education on safe sex practices provided prior to release. PMID- 20705809 TI - Cognitive behavioral theories used to explain injection risk behavior among injection drug users: a review and suggestions for the integration of cognitive and environmental models. AB - Injection drug users (IDUs) are at risk for HIV and viral hepatitis, and risky injection behavior persists despite decades of intervention. Cognitive behavioral theories (CBTs) are commonly used to help understand risky injection behavior. The authors review findings from CBT-based studies of injection risk behavior among IDUs. An extensive literature search was conducted in spring 2007. In total, 33 studies were reviewed- 26 epidemiological and 7 intervention studies. Findings suggest that some theoretical constructs have received fairly consistent support (e.g., self-efficacy, social norms), whereas others have yielded inconsistent or null results (e.g., perceived susceptibility, knowledge, behavioral intentions, perceived barriers, perceived benefits, response efficacy, perceived severity). The authors offer some possible explanations for these inconsistent findings, including differences in theoretical constructs and measures across studies and a need to examine the environmental structures that influence risky behaviors. Greater integration of CBT with a risk environment perspective may yield more conclusive findings and more effective interventions in the future. PMID- 20705811 TI - How length of stay for congestive heart failure patients was reduced through six sigma methodology and physician leadership. AB - Unnecessary variation and overuse in care are associated with increased length of stay. Efforts to improve efficiency without physician leadership and buy-in have been unsuccessful. Congestive heart failure (CHF) is the most frequent admitting diagnosis and is associated with increased hospital length of stay. This performance improvement initiative used Six Sigma methodology to reduce CHF length of stay at a community hospital. Daily rounding, prioritization of CHF patients for left-ventricular (LV) assessments, and standardization of orders accounted for improvements in delivery of care. Turnaround time for LV assessments was reduced from a mean of 2.2 days to a mean of 0.78 days. Use of standardized CHF order sets by physicians rose from 25% to 72.6%, and length of stay was reduced from 7 days to 4 days (P = .00). Physician leadership, interdisciplinary team dynamics, and standardization of practice play crucial roles in reducing length of stay. PMID- 20705812 TI - Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. AB - Aurora B is a component of the chromosomal passenger complex (CPC) required for correct spindle-kinetochore attachments during chromosome segregation and for cytokinesis. The chromatin factors that recruit the CPC to centromeres are unknown, however. Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. A nonbinding Survivin-D70A/D71A mutant does not support centromeric CPC concentration, and both Haspin depletion and Survivin-D70A/D71A mutation diminish centromere localization of the kinesin MCAK and the mitotic checkpoint response to taxol. Survivin-D70A/D71A mutation and microinjection of H3T3ph-specific antibody both compromise centromeric Aurora B functions but do not prevent cytokinesis. Therefore, H3T3ph generated by Haspin positions the CPC at centromeres to regulate selected targets of Aurora B during mitosis. PMID- 20705813 TI - Pulsar discovery by global volunteer computing. AB - Einstein@Home aggregates the computer power of hundreds of thousands of volunteers from 192 countries to mine large data sets. It has now found a 40.8 hertz isolated pulsar in radio survey data from the Arecibo Observatory taken in February 2007. Additional timing observations indicate that this pulsar is likely a disrupted recycled pulsar. PSR J2007+2722's pulse profile is remarkably wide with emission over almost the entire spin period; the pulsar likely has closely aligned magnetic and spin axes. The massive computing power provided by volunteers should enable many more such discoveries. PMID- 20705814 TI - Detection of a trailing (L5) Neptune Trojan. AB - The orbits of small Solar System bodies record the history of our Solar System. Here, we report the detection of 2008 LC18, which is a Neptune Trojan in the trailing (L5) Lagrangian region of gravitational equilibrium within Neptune's orbit. We estimate that the leading and trailing Neptune Trojan regions have similarly sized populations and dynamics, with both regions dominated by high inclination objects. Similar populations and dynamics at both Neptune Lagrangian regions indicate that the Trojans were likely captured by a migrating, eccentric Neptune in a dynamically excited planetesimal population. PMID- 20705816 TI - Dendritic discrimination of temporal input sequences in cortical neurons. AB - The detection and discrimination of temporal sequences is fundamental to brain function and underlies perception, cognition, and motor output. By applying patterned, two-photon glutamate uncaging, we found that single dendrites of cortical pyramidal neurons exhibit sensitivity to the sequence of synaptic activation. This sensitivity is encoded by both local dendritic calcium signals and somatic depolarization, leading to sequence-selective spike output. The mechanism involves dendritic impedance gradients and nonlinear synaptic N-methyl D-aspartate receptor activation and is generalizable to dendrites in different neuronal types. This enables discrimination of patterns delivered to a single dendrite, as well as patterns distributed randomly across the dendritic tree. Pyramidal cell dendrites can thus act as processing compartments for the detection of synaptic sequences, thereby implementing a fundamental cortical computation. PMID- 20705817 TI - Beyond petroleum? PMID- 20705815 TI - Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. AB - A hallmark of mitosis is the appearance of high levels of histone phosphorylation, yet the roles of these modifications remain largely unknown. Here, we demonstrate that histone H3 phosphorylated at threonine 3 is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of Survivin, which is a member of the chromosomal passenger complex (CPC). This binding mediates recruitment of the CPC to chromosomes and the resulting activation of its kinase subunit Aurora B. Consistently, modulation of the kinase activity of Haspin, which phosphorylates H3T3, leads to defects in the Aurora B dependent processes of spindle assembly and inhibition of nuclear reformation. These findings establish a direct cellular role for mitotic histone H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division. PMID- 20705818 TI - Gulf Oil Spill. A lot of oil on the loose, not so much to be found. PMID- 20705820 TI - Infectious Diseases. Yellow fever mosquito shows up in Northern Europe. PMID- 20705819 TI - Gulf Oil Spill. An audacious decision in crisis gets cautious praise. PMID- 20705822 TI - Environment. Russia's forest fires ignite concerns about Chornobyl's legacy. PMID- 20705823 TI - Paleoanthropology. Lucy's toolkit? Old bones may show earliest evidence of tool use. PMID- 20705825 TI - Human Evolution. Tracing evolution's recent fingerprints. PMID- 20705826 TI - Profile: Pauline Wiessner. Anthropologist brings worlds together. PMID- 20705827 TI - Paleoclimatology. Climate scientists shine light on cave ice. PMID- 20705828 TI - Science education: poetry. PMID- 20705829 TI - Science education: narrative nonfiction. PMID- 20705830 TI - Science education: neglected. PMID- 20705831 TI - Science education: flouting formality. PMID- 20705833 TI - Science education: learn by listening. PMID- 20705834 TI - Science education: mixed messages. PMID- 20705835 TI - Nuclear waste: knowledge waste? PMID- 20705836 TI - Ecology. Structure and dynamics of ecological networks. PMID- 20705837 TI - Cell Biology. The proteome in balance. PMID- 20705839 TI - Geophysics. Sedimentary basins feeling the heat from below. PMID- 20705838 TI - Immunology. Beta-catenin balances immunity. PMID- 20705840 TI - AIDS/HIV. A boost for HIV vaccine design. PMID- 20705841 TI - Engineering. Concentrating on solar electricity and fuels. PMID- 20705842 TI - Climate Change. The carbon dioxide exchange. PMID- 20705843 TI - Retrospective. Stephen Schneider (1945-2010). PMID- 20705844 TI - Getting better to get bigger. PMID- 20705845 TI - Do we have the energy for the next transition? PMID- 20705846 TI - Sending African sunlight to Europe, special delivery. PMID- 20705847 TI - Is there a road ahead for cellulosic ethanol? PMID- 20705848 TI - Energy's tricky tradeoffs. PMID- 20705849 TI - Out of site. PMID- 20705850 TI - Other siting problems. PMID- 20705851 TI - Feedstocks for lignocellulosic biofuels. AB - In 2008, the world produced approximately 87 gigaliters of liquid biofuels, which is roughly equal to the volume of liquid fuel consumed by Germany that year. Essentially, all of this biofuel was produced from crops developed for food production, raising concerns about the net energy and greenhouse gas effects and potential competition between use of land for production of fuels, food, animal feed, fiber, and ecosystem services. The pending implementation of improved technologies to more effectively convert the nonedible parts of plants (lignocellulose) to liquid fuels opens diverse options to use biofuel feedstocks that reach beyond current crops and the land currently used for food and feed. However, there has been relatively little discussion of what types of plants may be useful as bioenergy crops. PMID- 20705852 TI - Challenges in scaling up biofuels infrastructure. AB - Rapid growth in demand for lignocellulosic bioenergy will require major changes in supply chain infrastructure. Even with densification and preprocessing, transport volumes by mid-century are likely to exceed the combined capacity of current agricultural and energy supply chains, including grain, petroleum, and coal. Efficient supply chains can be achieved through decentralized conversion processes that facilitate local sourcing, satellite preprocessing and densification for long-distance transport, and business models that reward biomass growers both nearby and afar. Integrated systems that are cost-effective and energy-efficient will require new ways of thinking about agriculture, energy infrastructure, and rural economic development. Implementing these integrated systems will require innovation and investment in novel technologies, efficient value chains, and socioeconomic and policy frameworks; all are needed to support an expanded biofuels infrastructure that can meet the challenges of scale. PMID- 20705853 TI - An outlook on microalgal biofuels. AB - Microalgae are considered one of the most promising feedstocks for biofuels. The productivity of these photosynthetic microorganisms in converting carbon dioxide into carbon-rich lipids, only a step or two away from biodiesel, greatly exceeds that of agricultural oleaginous crops, without competing for arable land. Worldwide, research and demonstration programs are being carried out to develop the technology needed to expand algal lipid production from a craft to a major industrial process. Although microalgae are not yet produced at large scale for bulk applications, recent advances-particularly in the methods of systems biology, genetic engineering, and biorefining-present opportunities to develop this process in a sustainable and economical way within the next 10 to 15 years. PMID- 20705854 TI - Generating the option of a two-stage nuclear renaissance. AB - Concerns about climate change, security of supply, and depleting fossil fuel reserves have spurred a revival of interest in nuclear power generation in Europe and North America, while other regions continue or initiate an expansion. We suggest that the first stage of this process will include replacing or extending the life of existing nuclear power plants, with continued incremental improvements in efficiency and reliability. After 2030, a large-scale second period of construction would allow nuclear energy to contribute substantially to the decarbonization of electricity generation. For nuclear energy to be sustainable, new large-scale fuel cycles will be required that may include fuel reprocessing. Here, we explore the opportunities and constraints in both time periods and suggests ways in which measures taken today might, at modest cost, provide more options in the decades to come. Careful long-term planning, along with parallel efforts aimed at containing waste products and avoiding diversion of material into weapons production, can ensure that nuclear power generation remains a carbon-neutral option. PMID- 20705856 TI - In-plane resistivity anisotropy in an underdoped iron arsenide superconductor. AB - High-temperature superconductivity often emerges in the proximity of a symmetry breaking ground state. For superconducting iron arsenides, in addition to the antiferromagnetic ground state, a small structural distortion breaks the crystal's C(4 )rotational symmetry in the underdoped part of the phase diagram. We reveal that the representative iron arsenide Ba(Fe(1)(-x)Co(x))(2)As(2) develops a large electronic anisotropy at this transition via measurements of the in-plane resistivity of detwinned single crystals, with the resistivity along the shorter b axis rho(b) being greater than rho(a). The anisotropy reaches a maximum value of ~2 for compositions in the neighborhood of the beginning of the superconducting dome. For temperatures well above the structural transition, uniaxial stress induces a resistivity anisotropy, indicating a substantial nematic susceptibility. PMID- 20705857 TI - Small-scale mantle convection produces stratigraphic sequences in sedimentary basins. AB - Cyclic sedimentary deposits link stratigraphic sequences that are now geographically distant but were once part of the same depositional environment. Some of these sequences occur at periods of 2 to 20 million years, and eustatic sea-level variations or regional tectonic events are likely causes of their formation. Using numerical modeling, we demonstrate that small-scale mantle convection can also cause the development of stratigraphic sequences through recurrent local and regional vertical surface movements. Small-scale convection driven stratigraphic sequences occur at periods of 2 to 20 million years and correlate only at distances up to a few hundred kilometers. These results suggest that previous sequence stratigraphic analyses may contain erroneous conclusions regarding eustatic sea-level variations. PMID- 20705855 TI - Gamma-ray emission concurrent with the nova in the symbiotic binary V407 Cygni. AB - Novae are thermonuclear explosions on a white dwarf surface fueled by mass accreted from a companion star. Current physical models posit that shocked expanding gas from the nova shell can produce x-ray emission, but emission at higher energies has not been widely expected. Here, we report the Fermi Large Area Telescope detection of variable gamma-ray emission (0.1 to 10 billion electron volts) from the recently detected optical nova of the symbiotic star V407 Cygni. We propose that the material of the nova shell interacts with the dense ambient medium of the red giant primary and that particles can be accelerated effectively to produce pi(0) decay gamma-rays from proton-proton interactions. Emission involving inverse Compton scattering of the red giant radiation is also considered and is not ruled out. PMID- 20705858 TI - Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. AB - Nanoelectronic devices offer substantial potential for interrogating biological systems, although nearly all work has focused on planar device designs. We have overcome this limitation through synthetic integration of a nanoscale field effect transistor (nanoFET) device at the tip of an acute-angle kinked silicon nanowire, where nanoscale connections are made by the arms of the kinked nanostructure, and remote multilayer interconnects allow three-dimensional (3D) probe presentation. The acute-angle probe geometry was designed and synthesized by controlling cis versus trans crystal conformations between adjacent kinks, and the nanoFET was localized through modulation doping. 3D nanoFET probes exhibited conductance and sensitivity in aqueous solution, independent of large mechanical deflections, and demonstrated high pH sensitivity. Additionally, 3D nanoprobes modified with phospholipid bilayers can enter single cells to allow robust recording of intracellular potentials. PMID- 20705859 TI - An allosteric self-splicing ribozyme triggered by a bacterial second messenger. AB - Group I self-splicing ribozymes commonly function as components of selfish mobile genetic elements. We identified an allosteric group I ribozyme, wherein self splicing is regulated by a distinct riboswitch class that senses the bacterial second messenger c-di-GMP. The tandem RNA sensory system resides in the 5' untranslated region of the messenger RNA for a putative virulence gene in the pathogenic bacterium Clostridium difficile. c-di-GMP binding by the riboswitch induces folding changes at atypical splice site junctions to modulate alternative RNA processing. Our findings indicate that some self-splicing ribozymes are not selfish elements but are harnessed by cells as metabolite sensors and genetic regulators. PMID- 20705861 TI - Stability of ecological communities and the architecture of mutualistic and trophic networks. AB - Research on the relationship between the architecture of ecological networks and community stability has mainly focused on one type of interaction at a time, making difficult any comparison between different network types. We used a theoretical approach to show that the network architecture favoring stability fundamentally differs between trophic and mutualistic networks. A highly connected and nested architecture promotes community stability in mutualistic networks, whereas the stability of trophic networks is enhanced in compartmented and weakly connected architectures. These theoretical predictions are supported by a meta-analysis on the architecture of a large series of real pollination (mutualistic) and herbivory (trophic) networks. We conclude that strong variations in the stability of architectural patterns constrain ecological networks toward different architectures, depending on the type of interaction. PMID- 20705860 TI - Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. AB - Dendritic cells (DCs) play a vital role in initiating robust immunity against pathogens as well as maintaining immunological tolerance to self antigens. However, the intracellular signaling networks that program DCs to become tolerogenic remain unknown. We report here that the Wnt-beta-catenin signaling in intestinal dendritic cells regulates the balance between inflammatory versus regulatory responses in the gut. beta-catenin in intestinal dendritic cells was required for the expression of anti-inflammatory mediators such as retinoic acid metabolizing enzymes, interleukin-10, and transforming growth factor-beta, and the stimulation of regulatory T cell induction while suppressing inflammatory effector T cells. Furthermore, ablation of beta-catenin expression in DCs enhanced inflammatory responses and disease in a mouse model of inflammatory bowel disease. Thus, beta-catenin signaling programs DCs to a tolerogenic state, limiting the inflammatory response. PMID- 20705863 TI - Behavioral and psychosocial program needs of young adult cancer survivors. AB - Behavioral interventions for cancer survivors have historically targeted older adults or young adult survivors of childhood cancer. In this study, 18- to 39 year-olds diagnosed with cancer during young adulthood were interviewed to identify the types of behavioral and psychosocial programs needed. These young adult cancer survivors were also asked to identify potential barriers to program utilization. Participants expressed interest in programs targeting physical activity, relaxation, emotional support, provision of cancer-related and other information, and nutrition/weight loss. Emergent themes included the importance of choice, flexibility, convenience, and similarity to other program participants. Barriers to participation included practical barriers (e.g., limited time), lack of awareness of programs, health issues (e.g., fatigue), and psychosocial barriers (e.g., low motivation). Results highlight a range of unmet psychosocial and behavioral needs among young adult cancer survivors. This information can be used to develop interventions for this population. PMID- 20705867 TI - Foreskin management: Survey of Canadian pediatric urologists. AB - OBJECTIVE: To study the approaches to foreskin management of pediatric urologists in Canada. DESIGN: An online questionnaire comprising several survey questions and clinical vignettes. SETTING: Canada. PARTICIPANTS: All members of the Pediatric Urologists of Canada. MAIN OUTCOME MEASURES: Diagnoses and management strategies for common foreskin conditions seen in consultation, including how many pediatric urologists perform neonatal circumcisions, patient costs, and the reasons for performing the surgery. RESULTS: Of the 32 members surveyed, 24 (75%) responded. By far most respondents do not perform neonatal circumcisions; however, many perform circumcisions under general anesthesia for religious and cultural purposes. Typically, patient costs for circumcision range from $500 to $1000. Management of asymptomatic physiologic phimosis is very conservative, with surgeons unlikely to intervene. Neither the presence of ballooning of the foreskin during voiding nor the child's age affects physicians' tendency toward conservative management. Balanitis xerotica obliterans was the only scenario in which most respondents believed there was a need to intervene with either topical steroids or circumcision. CONCLUSION: Our data support the hypothesis that pediatric urologists across Canada are very similar in their conservative approach to the management of common foreskin issues. Our goal is to improve the knowledge base among primary care providers and subsequently decrease patient and family anxieties. PMID- 20705868 TI - Do procedural skills workshops during family practice residency work? AB - OBJECTIVE: To determine if participation in a procedural skills workshop during family practice residency affects future use of these skills in postgraduate clinical practice. DESIGN: Survey involving self-assessment of procedural skills experience and competence. SETTING: British Columbia. PARTICIPANTS: Former University of British Columbia family practice residents who trained in Vancouver, BC, including residents who participated in a procedural skills workshop in 2001 or 2003 and residents graduating in 2000 and 2002 who did not participate in the procedural skills workshop. MAIN OUTCOME MEASURES: Self assessed experience and competence in the 6 office-based procedural skills that were taught during the procedural skills workshops in 2001 and 2003. RESULTS: Participation in a procedural skills workshop had no positive effect on future use of these skills in clinical practice. Participation in the workshop was associated with less reported experience (P = .091) in injection of lateral epicondylitis. As with previous Canadian studies, more women than men reported experience and competence in gynecologic procedures. More women than men reported experience (P = .001) and competence (P = .004) in intrauterine device insertion and experience (P = .091) in endometrial aspiration biopsy. More men than women reported competence (P = .052) in injection of trochanteric bursae. A third year of emergency training was correlated with an increase in reported experience (P = .021) in shoulder injection. CONCLUSION: Participation in a procedural skills workshop during family practice residency did not produce a significant increase in the performance of these skills on the part of participants once they were in clinical practice. The benefit of a skills workshop might be lost when there is no opportunity to practise and perfect these skills. Sex bias in the case of some procedures might represent a needs-based acquisition of skills on the part of practising physicians. Short procedural skills workshops might be better suited to graduated physicians with more clinical experience. PMID- 20705869 TI - Cardiovascular disease in type 2 diabetes: Attributable risk due to modifiable risk factors. AB - OBJECTIVE: To examine the common clinical and behavioural factors that contribute to cardiovascular disease (CVD) risk (ie, attributable risk) among those with type 2 diabetes. DESIGN: Analysis of data from a larger observational study. Using the validated UK Prospective Diabetes Study risk engine, the primary analysis examined the prevalence and attributable risk of CVD for 4 factors. Multivariable models also examined the association between attributable CVD risk and appropriate self-management behaviour. SETTING: Twenty primary health care clinics in the South Texas area of the United States. PARTICIPANTS: A total of 313 patients with type 2 diabetes mellitus currently receiving primary care services for their condition. MAIN OUTCOME MEASURES: Prevalence of elevated CVD risk factors (glycated hemoglobin [HbA(1c)] levels, blood pressure, lipid levels, and smoking status), the attributable risk owing to these factors, and the association between attributable risk of CVD and diet, exercise, and medication adherence. RESULTS: The mean 10-year CVD risk for the study population (N = 313) was 16.2%, with a range of 6.5% to 48.5% across clinics; nearly one-third of this total risk was attributable to modifiable factors. The primary variable driving risk reduction was HbA(1c) levels, followed by smoking status and lipid levels. Patients who were carefully engaged in monitoring their diets and medications reduced their CVD risk by 44% and 39%, respectively (P < .03). CONCLUSION: Patients with diabetes experience a substantial risk of CVD owing to potentially modifiable behavioural factors. High-quality diabetes care requires targeting modifiable patient factors strongly associated with CVD risk, including self management behaviour such as diet and medication adherence, to better tailor clinical interventions and improve the health status of individuals with this chronic condition. PMID- 20705870 TI - Are you SURE?: Assessing patient decisional conflict with a 4-item screening test. AB - OBJECTIVE: To assess the reliability and validity of the 4-item SURE (Sure of myself; Understand information; Risk-benefit ratio; Encouragement) screening test for decisional conflict in patients. DESIGN: Cross-sectional study. SETTING: Four family medicine groups in Quebec and 1 rural academic medical centre in New Hampshire. PARTICIPANTS: One hundred twenty-three French-speaking pregnant women considering prenatal screening for Down syndrome and 1474 English-speaking patients referred to watch condition-specific video decision aids. MAIN OUTCOME MEASURES: Cronbach alpha was used to assess the reliability of SURE. A factorial analysis was performed to assess its unidimensionality. The Pearson correlation coefficient was computed between SURE and the Decisional Conflict Scale to assess concurrent validation. A t test procedure comparing the SURE scores of patients who had made decisions with the scores of those who had not was used to assess construct validation. RESULTS: Among the 123 French-speaking pregnant women, 105 (85%) scored 4 out of 4 (no decisional conflict); 10 (8%) scored 3 ( 100-nm particles. Venous blood and urine samples were collected 8 days before exposure, twice daily during the trial, and 6 days post-exposure. As the first application in nanotechnology studies, stable isotope tracing was used where the ZnO, enriched to > 99% with the stable isotope (68)Zn, allowed dermally absorbed zinc to be distinguished from naturally occurring zinc. The overwhelming majority of applied (68)Zn was not absorbed, although blood and urine samples from all subjects exhibited small increases in levels of tracer (68)Zn. The amount of tracer detected in blood after the 5-day application period was ~1/1000 th that of total Zn in the blood compartment. Tracer levels in blood continued to increase beyond the 5-day application phase in contrast to those in urine. Levels of (68)Zn in blood and urine from females receiving the nano sunscreen appeared to be higher than males receiving the same treatment and higher than all subjects receiving the bulk sunscreen. It is not known whether (68)Zn has been absorbed as ZnO particles or soluble Zn or both. PMID- 20705895 TI - Memory for fear extinction requires mGluR5-mediated activation of infralimbic neurons. AB - Consolidation of fear extinction involves enhancement of N-methyl D aspartate (NMDA) receptor-dependent bursting in the infralimbic region (IL) of the medial prefrontal cortex (mPFC). Previous studies have shown that systemic blockade of metabotropic glutamate receptor type 5 (mGluR5) reduces bursting in the mPFC and mGluR5 agonists enhance NMDA receptor currents in vitro, suggesting that mGluR5 activation in IL may contribute to fear extinction. In the current study, rats injected with the mGluR5 antagonist 2-methyl-6-(phenylethyl)-pyridine (MPEP) systemically, or intra-IL, prior to extinction exhibited normal within-session extinction, but were impaired in their ability to recall extinction the following day. To directly determine whether mGluR5 stimulation enhances the burst firing of IL neurons, we used patch-clamp electrophysiology in prefrontal slices. The mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), increased intrinsic bursting in IL neurons. Increased bursting was correlated with a reduction in the slow after hyperpolarizing potential and was prevented by coapplication of MPEP. CHPG did not increase NMDA currents, suggesting that an NMDA receptor-independent enhancement of IL bursting via stimulation of mGluR5 receptors contributes to fear extinction. Therefore, the mGluR5 receptor could be a suitable target for pharmacological adjuncts to extinction-based therapies for anxiety disorders. PMID- 20705896 TI - Rapid developmental maturation of neocortical FS cell intrinsic excitability. AB - Fast-spiking (FS) cells are a prominent subtype of neocortical gamma-aminobutyric acidergic interneurons that mediate feed-forward inhibition and the temporal sculpting of information transfer in neural circuits, maintain excitation/inhibition balance, and contribute to network oscillations. FS cell dysfunction may be involved in the pathogenesis of disorders such as epilepsy, autism, and schizophrenia. Mature FS cells exhibit coordinated molecular and cellular specializations that facilitate rapid responsiveness, including brief spikes and sustained high-frequency discharge. We show that these features appear during the second and third postnatal weeks driven by upregulation of K(+) channel subunits of the Kv3 subfamily. The low membrane resistance and fast time constant characteristic of FS cells also appears during this time, driven by expression of a K(+) leak current mediated by K(ir)2 subfamily inward rectifier K(+) channels and TASK subfamily 2-pore K(+) channels. Blockade of this leak produces dramatic depolarization of FS cells suggesting the possibility for potent neuromodulation. Finally, the frequency of FS cell membrane potential oscillations increases during development and is markedly slower in TASK-1/3 knockout mice, suggesting that TASK channels regulate FS cell rhythmogenesis. Our findings imply that some of the effects of acidosis and/or anesthetics on brain function may be due to blockade of TASK channels in FS cells. PMID- 20705897 TI - Combined niche and neutral effects in a microbial wastewater treatment community. AB - It has long been assumed that differences in the relative abundance of taxa in microbial communities reflect differences in environmental conditions. Here we show that in the economically and environmentally important microbial communities in a wastewater treatment plant, the population dynamics are consistent with neutral community assembly, where chance and random immigration play an important and predictable role in shaping the communities. Using dynamic observations, we demonstrate a straightforward calibration of a purely neutral model and a parsimonious method to incorporate environmental influence on the reproduction (or birth) rate of individual taxa. The calibrated model parameters are biologically plausible, with the population turnover and diversity in the heterotrophic community being higher than for the ammonia oxidizing bacteria (AOB) and immigration into AOB community being relatively higher. When environmental factors were incorporated more of the variance in the observations could be explained but immigration and random reproduction and deaths remained the dominant driver in determining the relative abundance of the common taxa. Consequently we suggest that neutral community models should be the foundation of any description of an open biological system. PMID- 20705898 TI - Quantitative selection of DNA aptamers through microfluidic selection and high throughput sequencing. AB - We describe the integration of microfluidic selection with high-throughput DNA sequencing technology for rapid and efficient discovery of nucleic acid aptamers. The Quantitative Selection of Aptamers through Sequencing method tracks the copy number and enrichment-fold of more than 10 million individual sequences through multiple selection rounds, enabling the identification of high-affinity aptamers without the need for the pool to fully converge to a small number of sequences. Importantly, this method allows the discrimination of sequences that arise from experimental biases rather than true high-affinity target binding. As a demonstration, we have identified aptamers that specifically bind to PDGF-BB protein with K(d) < 3 nM within 3 rounds. Furthermore, we show that the aptamers identified by Quantitative Selection of Aptamers through Sequencing have approximately 3-8-fold higher affinity and approximately 2-4-fold higher specificity relative to those discovered through conventional cloning methods. Given that many biocombinatorial libraries are encoded with nucleic acids, we extrapolate that our method may be extended to other types of libraries for a range of molecular functions. PMID- 20705899 TI - Fast live simultaneous multiwavelength four-dimensional optical microscopy. AB - Live fluorescence microscopy has the unique capability to probe dynamic processes, linking molecular components and their localization with function. A key goal of microscopy is to increase spatial and temporal resolution while simultaneously permitting identification of multiple specific components. We demonstrate a new microscope platform, OMX, that enables subsecond, multicolor four-dimensional data acquisition and also provides access to subdiffraction structured illumination imaging. Using this platform to image chromosome movement during a complete yeast cell cycle at one 3D image stack per second reveals an unexpected degree of photosensitivity of fluorophore-containing cells. To avoid perturbation of cell division, excitation levels had to be attenuated between 100 and 10,000* below the level normally used for imaging. We show that an image denoising algorithm that exploits redundancy in the image sequence over space and time allows recovery of biological information from the low light level noisy images while maintaining full cell viability with no fading. PMID- 20705900 TI - Lewis base catalysis of bromo- and iodolactonization, and cycloetherification. AB - Lewis base catalyzed bromo- and iodolactonization reactions have been developed and the effects of catalyst structure on rate and cyclization selectivity have been systematically explored. The effects of substrate structure on halolactonization reactions and the interaction of those effects with the effects of catalyst structure have been investigated, leading to synthetically useful improvements in cyclization selectivity. The knowledge acquired was applied to the development of Lewis base catalyzed bromo- and iodocycloetherification reactions. The ability of some of the surveyed catalysts to influence the cyclization selectivity of halolactonization reactions demonstrates their presence in the transition structure of the product-determining cyclization step. This observation implies that chiral derivatives of these catalysts have the potential to provide enantioenriched products regardless of the rates or mechanisms of halonium ion racemization. PMID- 20705901 TI - Age of quantitative proteomics hits voltage-gated calcium channels. PMID- 20705902 TI - The impact of paroxetine coadministration on stereospecific carvedilol pharmacokinetics. AB - STUDY OBJECTIVE: to assess the impact of paroxetine coadministration on the stereoselective pharmacokinetic (PK) properties of carvedilol. DESIGN: prospective, randomized, 2-phase crossover. SETTING: the University of Michigan General Clinical Research Unit and Michigan Clinical Research Unit. PARTICIPANTS: twelve healthy volunteers aged 18 to 45 years, male and female, receiving no treatment with prescription or nonprescription medications. INTERVENTIONS: participants received single dose oral carvedilol (12.5 mg) with and without coadministration of immediate-release paroxetine (10 mg orally twice daily), in random order. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours post-carvedilol dose for determination of R and S carvedilol plasma enantiomer concentrations by high pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: pharmacokinetic (PK) parameters were calculated for each enantiomer by noncompartmental methods and compared between study phases by analysis of variance (ANOVA) controlling for study phase order and subject, with Tukey's studentized range test post hoc. Area under the concentration-time curve (AUC) increased significantly with paroxetine coadministration, approximately 2.5-fold and 1.9-fold for the R and S enantiomers, respectively. R/S AUC ratio increased significantly, from approximately 2.3 to 3.0. Individual increases in enantiomeric AUCs with paroxetine coadministration ranged from 0% to 571% and changes in R/S ratio ranged from -8% to 108%. Heart rate, P-R interval, and blood pressure were monitored and no clinically significant changes in carvedilol effects were noted. CONCLUSION: this study demonstrated a PK drug-drug interaction between paroxetine and carvedilol, with considerable interparticipant variability in carvedilol PK parameters and magnitude of drug interaction. Stereoselectivity of carvedilol metabolism is preserved with paroxetine coadministration, and R/S AUC ratio generally widens. Although this drug interaction could potentially increase adrenergic antagonism and have significant clinical effects in patients, these effects were not seen in our healthy volunteer participants. PMID- 20705903 TI - Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon. AB - Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP 2 (0.1-300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na(+)-channel blocker. GLP-2 inhibitory effect was not affected by N(omega)-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca(2+)-dependent K(+) channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP(7-28) (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a G(i/o) protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by G(i) protein. PMID- 20705904 TI - Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is a devastating intestinal disease of neonates, and clinical studies suggest the beneficial effect of probiotics in NEC prevention. Recently, we have shown that administration of Bifidobacterium bifidum protects against NEC in a rat model. Intestinal apoptosis can be suppressed by activation of cyclooxygenase-2 (COX-2) and increased production of prostaglandin E(2) (PGE(2)). The present study investigates the effect of B. bifidum on intestinal apoptosis in the rat NEC model and in an intestinal epithelial cell line (IEC-6), as a mechanism of protection against mucosal injury. Premature rats were divided into the following three groups: dam fed, hand fed with formula (NEC), or hand fed with formula supplemented with B. bifidum (NEC + B. bifidum). Intestinal Toll-like receptor-2 (TLR-2), COX-2, PGE(2), and apoptotic regulators were measured. The effect of B. bifidum was verified in IEC-6 cells using a model of cytokine-induced apoptosis. Administration of B. bifidum increased expression of TLR-2, COX-2, and PGE(2) and significantly reduced apoptosis in the intestinal epithelium of both in vivo and in vitro models. The Bax-to-Bcl-w ratio was shifted toward cell survival, and the number of cleaved caspase-3 positive cells was markedly decreased in B. bifidum treated rats. Experiments in IEC-6 cells showed anti-apoptotic effect of B. bifidum. Inhibition of COX-2 signaling blocked the protective effect of B. bifidum treatment in both in vivo and in vitro models. In conclusion, oral administration of B. bifidum activates TLR-2 in the intestinal epithelium. B. bifidum increases expression of COX-2, which leads to higher production of PGE(2) in the ileum and protects against intestinal apoptosis associated with NEC. This study indicates the ability of B. bifidum to downregulate apoptosis in the rat NEC model and in IEC-6 cells by a COX-2-dependent matter and suggests a molecular mechanism by which this probiotic reduces mucosal injury and preserves intestinal integrity. PMID- 20705905 TI - Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells. AB - The enteric nervous system may have an important role in modulating gastrointestinal barrier response to disease through activation of enteric glia cells. In vitro studies have shown that enteric glia activation improves intestinal epithelial barrier function by altering the expression of tight junction proteins. We hypothesized that severe injury would increase expression of glial fibrillary acidic protein (GFAP), a marker of enteric glial activation. We also sought to define the effects of vagal nerve stimulation on enteric glia activation and intestinal barrier function using a model of systemic injury and local gut mucosal involvement. Mice with 30% total body surface area steam burn were used as model of severe injury. Vagal nerve stimulation was performed to assess the role of parasympathetic signaling on enteric glia activation. In vivo intestinal permeability was measured to assess barrier function. Intestine was collected to investigate changes in histology; GFAP expression was assessed by quantitative PCR, by confocal microscopy, and in GFAP-luciferase transgenic mice. Stimulation of the vagus nerve prevented injury-induced intestinal barrier injury. Intestinal GFAP expression increased at early time points following burn and returned to baseline by 24 h after injury. Vagal nerve stimulation prior to injury increased GFAP expression to a greater degree than burn alone. Gastrointestinal bioluminescence was imaged in GFAP-luciferase transgenic animals following either severe burn or vagal stimulation and confirmed the increased expression of intestinal GFAP. Injection of S-nitrosoglutathione, a signaling molecule released by activated enteric glia cells, following burn exerts protective effects similar to vagal nerve stimulation. Intestinal expression of GFAP increases following severe burn injury. Stimulation of the vagus nerve increases enteric glia activation, which is associated with improved intestinal barrier function. The vagus nerve may mediate the signaling that occurs from the central nervous system to the enteric nervous system following gastrointestinal injury. PMID- 20705906 TI - Testing founder effect speciation: divergence population genetics of the spoonbills Platalea regia and Pl. minor (Threskiornithidae, Aves). AB - Although founder effect speciation has been a popular theoretical model for the speciation of geographically isolated taxa, its empirical importance has remained difficult to evaluate due to the intractability of past demography, which in a founder effect speciation scenario would involve a speciational bottleneck in the emergent species and the complete cessation of gene flow following divergence. Using regression-weighted approximate Bayesian computation, we tested the validity of these two fundamental conditions of founder effect speciation in a pair of sister species with disjunct distributions: the royal spoonbill Platalea regia in Australasia and the black-faced spoonbill Pl. minor in eastern Asia. When compared with genetic polymorphism observed at 20 nuclear loci in the two species, simulations showed that the founder effect speciation model had an extremely low posterior probability (1.55 * 10(-8)) of producing the extant genetic pattern. In contrast, speciation models that allowed for postdivergence gene flow were much more probable (posterior probabilities were 0.37 and 0.50 for the bottleneck with gene flow and the gene flow models, respectively) and postdivergence gene flow persisted for a considerable period of time (more than 80% of the divergence history in both models) following initial divergence (median = 197,000 generations, 95% credible interval [CI]: 50,000-478,000, for the bottleneck with gene flow model; and 186,000 generations, 95% CI: 45,000 477,000, for the gene flow model). Furthermore, the estimated population size reduction in Pl. regia to 7,000 individuals (median, 95% CI: 487-12,000, according to the bottleneck with gene flow model) was unlikely to have been severe enough to be considered a bottleneck. Therefore, these results do not support founder effect speciation in Pl. regia but indicate instead that the divergence between Pl. regia and Pl. minor was probably driven by selection despite continuous gene flow. In this light, we discuss the potential importance of evolutionarily labile traits with significant fitness consequences, such as migratory behavior and habitat preference, in facilitating divergence of the spoonbills. PMID- 20705907 TI - Random Tree-Puzzle leads to the Yule-Harding distribution. AB - Approaches to reconstruct phylogenies abound and are widely used in the study of molecular evolution. Partially through extensive simulations, we are beginning to understand the potential pitfalls as well as the advantages of different methods. However, little work has been done on possible biases introduced by the methods if the input data are random and do not carry any phylogenetic signal. Although Tree-Puzzle (Strimmer K, von Haeseler A. 1996. Quartet puzzling: a quartet maximum-likelihood method for reconstructing tree topologies. Mol Biol Evol. 13:964-969; Schmidt HA, Strimmer K, Vingron M, von Haeseler A. 2002. Tree-Puzzle: maximum likelihood phylogenetic analysis using quartets and parallel computing. Bioinformatics 18:502-504) has become common in phylogenetics, the resulting distribution of labeled unrooted bifurcating trees when data do not carry any phylogenetic signal has not been investigated. Our note shows that the distribution converges to the well-known Yule-Harding distribution. However, the bias of the Yule-Harding distribution will be diminished by a tiny amount of phylogenetic information. maximum likelihood, phylogenetic reconstruction, Tree Puzzle, tree distribution, Yule-Harding distribution. PMID- 20705908 TI - Role of lysophosphatidic acid acyltransferase 3 for the supply of highly polyunsaturated fatty acids in TM4 Sertoli cells. AB - Sertoli cells supply germ cells with nutrients, including highly polyunsaturated fatty acids (hPUFAs), which are essential for testicular function. We have previously reported high expression of lysophosphatidic acid acyltransferase (LPAAT)3 in mature mouse testis and suggested an arachidonoyl-transferase activity to LPA. To investigate the role of LPAAT3 in the storage and release of PUFAs, TM4 Sertoli cells were stably transfected with LPAAT3-small hairpin (sh)RNA. Arachidonoyl-, eicosapentaenoyl-, and docosapentaenoyl-containing phosphatidylcholine (PC) and linoleoyl-containing phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylglycerol were significantly decreased as determined by liquid chromatography coupled to electrospray ionization mass spectrometry. Expression of murine LPAAT3 in Chinese hamster ovary (CHO)-K1 cells had essentially an opposite effect. The level of polyunsaturated PC correlated with cellular levels of free docosapentaenoic acid and eicosapentaenoic acid in TM4 and CHO-K1 cells, respectively. Activity assays using microsomal preparations as a source of LPAAT3 revealed an excessive PA synthesis from LPA acceptors for docosahexaenoyl-, arachidonoyl- and less pronounced for linoleoyl-CoA. We propose that the efficient incorporation of hPUFAs into PA-the precursor of several phospholipids, including PC-and the selective increase of the polyunsaturated PC pool in TM4 Sertoli cells might be required for the controlled release of hPUFAs and their supply to germ cells. PMID- 20705909 TI - A comparison of global, gene-specific, and relaxed clock methods in a comparative genomics framework: dating the polyploid history of soybean (Glycine max). AB - It is widely recognized that many genes and lineages do not adhere to a molecular clock, yet molecular clocks are commonly used to date divergences in comparative genomic studies. We test the application of a molecular clock across genes and lineages in a phylogenetic framework utilizing 12 genes linked in a 1-Mb region on chromosome 13 of soybean (Glycine max); homoeologous copies of these genes formed by polyploidy in Glycine; and orthologous copies in G. tomentella, Phaseolus vulgaris, and Medicago truncatula. We compare divergence dates estimated by two methods each in three frameworks: a global molecular clock with a single rate across genes and lineages using full and approximate likelihood methods based on synonymous substitutions, a gene-specific clock assuming rate constancy over lineages but allowing a different rate for each gene, and a relaxed molecular clock where rates may vary across genes and lineages estimated under penalized likelihood and Bayesian inference. We use the cumulative variance across genes as a means of quantifying precision. Our results suggest that divergence dating methods produce results that are correlated, but that older nodes are more variable and more difficult to estimate with precision and accuracy. We also find that models incorporating less rate heterogeneity estimate older dates of divergence than more complex models, as node age increases. A mixed model nested analysis of variance testing the effects of framework, method, and gene found that framework had a significant effect on the divergence date estimates but that most variation among dates is due to variation among genes, suggesting a need to further characterize and understand the evolutionary phenomena underlying rate variation within genomes, among genes, and across lineages. PMID- 20705910 TI - Predictors of state-of-the-art management of early breast cancer in Switzerland. AB - BACKGROUND: The aim of this study was to investigate predictors of state-of-the art management of early breast cancer in Switzerland. PATIENTS AND METHODS: The study included 3499 women aged 25-79 years diagnosed with invasive breast cancer stages I-IIIA in 2003-2005. Patients were identified through population-based cancer registries and treated in all kinds of settings. Concordance with national and international recommendations was assessed for 10 items covering surgery, radiotherapy, systemic adjuvant therapy and histopathology reporting. We used multivariate logistic regression to identify independent predictors of high (10 points) and low (<=7 points) concordance. RESULTS: In one-third of the patients, management met guidelines in all items, whereas in about one-fifth, three or more items did not comply. Treatment by a surgeon with caseload in the upper tercile and team involved in clinical research were independent predictors of a high score, whereas treatment by a surgeon with a caseload in the lower tercile was associated with a low score. Socioeconomic characteristics such as income and education were not independent predictors, but patient's place of residence and age independently predicted management according to recommendations. CONCLUSION: Specialization and involvement in clinical research seem to be key elements for enhancing the quality of early breast cancer management at population level. PMID- 20705911 TI - A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. AB - PURPOSE: Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. RESULTS: Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. CONCLUSIONS: Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting. PMID- 20705913 TI - Increased atherosclerosis in mice with vascular ATP-binding cassette transporter G1 deficiency--brief report. AB - OBJECTIVE: The objective of this study was to investigate the role of vascular ATP-binding cassette transporter G1 (ABCG1) in atherogenesis without a confounding difference in macrophage ABCG1 expression. ABCG1 is highly expressed in macrophages and endothelial cells. ABCG1 preserves endothelial function by maintaining endothelial NO synthase activity and by reducing adhesion molecule expression and monocyte adhesion. METHODS AND RESULTS: To investigate the role of vascular ABCG1 in atherosclerosis in vivo Abcg1(-/-)/Ldlr(-/-) and Ldlr(-/-) mice were transplanted with wild-type bone marrow and fed a Western-type diet for 12 or 23 weeks. The atherosclerotic lesion area was similar in both groups after 12 weeks but was increased in Abcg1(-/-)/Ldlr(-/-) recipients after 23 weeks, especially in the aortic arch (2.2-fold; P<0.01). Endothelial NO synthase mediated vascular relaxation was impaired in male Abcg1(-/-)/Ldlr(-/-) recipients. CONCLUSIONS: Our data show an atheroprotective role of vascular ABCG1, especially in the aortic arch, likely related to its role in the preservation of endothelial NO synthase activity. PMID- 20705914 TI - FRNK inhibition of focal adhesion kinase-dependent signaling and migration in vascular smooth muscle cells. AB - OBJECTIVE: To examine whether interference with FRNK targeting to focal adhesions (FAs) affects its inhibitory activity and tyrosine phosphorylation. METHODS AND RESULTS: Focal adhesion kinase and its autonomously expressed C-terminal inhibitor, focal adhesion kinase-related nonkinase (FRNK), regulate vascular smooth muscle cell (VSMC) signaling and migration. FRNK-paxillin binding was reduced by a point mutation in its FA targeting domain (L341S-FRNK). Green fluorescent protein-tagged wild type and L341S-FRNK were then adenovirally expressed in VSMCs. L341S-FRNK targeted to VSMC FAs, despite previous studies in other cell types. L341S-FRNK affected FA binding kinetics (assessed by total internal reflection fluorescnece [TIRF] microscopy and fluorescence recovery after photobleaching [FRAP]) and reduced its steady-state paxillin interaction (determined by coimmunoprecipitation). Both wt-FRNK and L341S-FRNK lowered basal and angiotensin II-stimulated focal adhesion kinase, paxillin, and extracellular signal-regulated kinase 1/2 phosphorylation. However, the degree of inhibition was significantly reduced by L341S-FRNK. L341S-FRNK also demonstrated significantly greater migratory activity compared with wt-FRNK-expressing VSMCs. Angiotensin II-induced Y168 phosphorylation was Src dependent, as evident by a significant reduction in Y168 phosphorylation by the Src family kinase inhibitor PP2 is 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). Surprisingly, Y168 phosphorylation was unaffected by its targeting. Furthermore, Y232 phosphorylation increased approximately 3-fold in L341S-FRNK, which was less sensitive to PP2. CONCLUSIONS: FRNK inhibition of VSMC migration requires both FA targeting and Y168 phosphorylation by Src family kinases. FRNK-Y232 phosphorylation occurs outside of FAs, probably by a PP2-insensitive kinase. PMID- 20705912 TI - Associations of diabetes mellitus with site-specific cancer mortality in the Asia Pacific region. AB - BACKGROUND: Owing to the increasing prevalence of obesity and diabetes in Asia, and the paucity of studies, we examined the influence of raised blood glucose and diabetes on cancer mortality risk. MATERIALS AND METHODS: Thirty-six cohort Asian and Australasian studies provided 367, 361 participants (74% from Asia); 6% had diabetes at baseline. Associations between diabetes and site-specific cancer mortality were estimated using time-dependent Cox models, stratified by study and sex, and adjusted for age. RESULTS: During a median follow-up of 4.0 years, there were 5992 deaths due to cancer (74% Asian; 41% female). Participants with diabetes had 23% greater risk of mortality from all-cause cancer compared with those without: hazard ratio (HR) 1.23 [95% confidence interval (CI) 1.12, 1.35]. Diabetes was associated with mortality due to cancer of the liver (HR 1.51; 95% CI 1.19, 1.91), pancreas (HR 1.78; 95% CI 1.20, 2.65), and, less strongly, colorectum (HR 1.32; 95% CI 0.98, 1.78). There was no evidence of sex- or region specific differences in these associations. The population attributable fractions for cancer mortality due to diabetes were generally higher for Asia compared with non-Asian populations. CONCLUSION: Diabetes is associated with increased mortality from selected cancers in Asian and non-Asian populations. PMID- 20705915 TI - Depletion of intracellular Ca2+ stores stimulates the translocation of vanilloid transient receptor potential 4-c1 heteromeric channels to the plasma membrane. AB - OBJECTIVE: To examine the effect of Ca(2+) store depletion on the translocation of vanilloid transient receptor potential (TRPV) 4-C1 heteromeric channels to the plasma membrane. METHODS AND RESULTS: Vesicular trafficking is a key mechanism for controlling the surface expression of TRP channels in the plasma membrane, where they perform their function. TRP channels in vivo are often composed of heteromeric subunits. Experiments using total internal fluorescence reflection microscopy and biotin surface labeling show that Ca(2+) store depletion enhanced TRPV4-C1 translocation into the plasma membrane in human embryonic kidney 293 cells that were coexpressed with TRPV4 and canonical transient receptor potential 1 (TRPC1). Fluorescent Ca(2+) measurement and patch clamp studies demonstrated that Ca(2+) store depletion enhanced 4alpha-PDD-stimulated Ca(2+) influx and cation current. The translocation required stromal interacting molecule 1 (STIM1). TRPV4-C1 heteromeric channels were more favorably translocated to the plasma membrane than TRPC1 or TRPV4 homomeric channels. Similar results were obtained in native vascular endothelial cells. CONCLUSIONS: Ca(2+) store depletion stimulates the insertion of TRPV4-C1 heteromeric channels into the plasma membrane, resulting in an augmented Ca(2+) influx in response to flow in the human embryonic kidney cell overexpression system and native endothelial cells. PMID- 20705916 TI - Nitric oxide synthase expression and functional response to nitric oxide are both important modulators of circulating angiogenic cell response to angiogenic stimuli. AB - OBJECTIVE: Circulating angiogenic cells (CACs), also termed endothelial progenitor cells, play an integral role in vascular repair and are functionally impaired in coronary artery disease (CAD). The role of nitric oxide (NO) in CAC function is poorly understood. We hypothesized that CAC migration toward angiogenic signals is modulated by both NO synthase (NOS) expression and functional response to NO. METHODS AND RESULTS: Similar to endothelial cells, CAC chemotaxis to vascular endothelial growth factor (VEGF) was blocked by inhibition of NOS, phosphatidylinositol 3-kinase, or guanylyl cyclase or by treatment with an NO scavenger. Addition of an NO donor (S-nitroso-N-acetylpenicillamine) and the NOS substrate l-arginine increased random cell migration (chemokinesis) and enhanced VEGF-dependent chemotaxis. Healthy CACs expressed endothelial NOS, but endothelial NOS was not detected in CAD patient CACs. Both chemokinesis and chemotaxis to VEGF of patient CACs were decreased compared with healthy CACs but were restored to healthy values by S-nitroso-N-acetylpenicillamine. In parallel, CAD patients exhibited lower flow-mediated vasodilation and plasma NO source nitrite than young, healthy subjects, indicating endothelial dysfunction with reduced NO bioavailability. CONCLUSIONS: NOS activity is required for CAC chemotaxis. In CAD patients, impairment of NOS expression and NO bioavailability, rather than response to NO, may contribute to dysfunction of CACs and limit their regenerative capacity. PMID- 20705917 TI - An in vivo murine model of low-magnitude oscillatory wall shear stress to address the molecular mechanisms of mechanotransduction--brief report. AB - OBJECTIVE: Current understanding of shear-sensitive signaling pathways has primarily been studied in vitro largely because of a lack of adequate in vivo models. Our objective was to develop a simple and well-characterized murine aortic coarctation model to acutely alter the hemodynamic environment in vivo and test the hypothesis that endothelial inflammatory protein expression is acutely upregulated in vivo by low-magnitude oscillatory wall shear stress (WSS). METHODS AND RESULTS: Our model uses the shape memory response of nitinol clips to reproducibly induce an aortic coarctation and allow subsequent focal control over WSS in the aorta. We modeled the corresponding hemodynamic environment using computational fluid dynamics and showed that the coarctation produces low magnitude oscillatory WSS distal to the clip. To assess the biological significance of this model, we correlated WSS to inflammatory protein expression and fatty streak formation. Vascular cell adhesion molecule-1 expression and fatty streak formation were both found to increase significantly in regions corresponding to acutely induced low-magnitude oscillatory WSS. CONCLUSIONS: We have developed a novel aortic coarctation model that will be a useful tool for analyzing the in vivo molecular mechanisms of mechanotransduction in various murine models. PMID- 20705918 TI - Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. AB - OBJECTIVE: Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins. METHODS AND RESULTS: Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide (H(2)O(2)), as judged by senescence-associated beta-galactosidase assay and cell morphological appearance. Atorvastatin, pravastatin, and pitavastatin inhibited the oxidative stress induced-endothelial senescence. These statins phosphorylated Akt at Ser473 and subsequently led to increased expression of endothelial nitric oxide synthase (eNOS), SIRT1, and catalase. Treatment with LY294002 or Akt short interfering RNA decreased the eNOS activation, SIRT1 expression, and antisenescent property of atorvastatin. Moreover, in streptozotocin-diabetic mice, administration of pitavastatin increased eNOS, SIRT1, and catalase expression and decreased endothelial senescence, but levels remained unaltered in Sirt1 knockout mice. CONCLUSIONS: Our results indicate that treatment with statins inhibits endothelial senescence and that enhancement of SIRT1 plays a critical role in prevention of endothelial senescence through the Akt pathway, a direct target of statins. PMID- 20705919 TI - Endogenously decreasing tissue n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation. AB - OBJECTIVE: To use the fat-1 transgenic mouse model to determine the role of tissue n-6/n-3 fatty acid ratio in atherosclerotic plaque formation. Although it has been suggested that a low ratio of n-6/n-3 polyunsaturated fatty acids (PUFAs) is more desirable in reducing the risk of atherosclerotic cardiovascular disease, the role of tissue n-6/n-3 fatty acid ratio in atherosclerosis has not been sufficiently tested in a well-controlled experimental system. The fat-1 transgenic mouse model, expressing an n-3 fatty acid desaturase, is capable of producing n-3 PUFAs from n-6 PUFAs and thereby has a ratio of n-6/n-3 fatty acids close to 1:1 in tissues and organs. METHODS AND RESULTS: To generate apolipoprotein E-deficient plus fat-1 transgenic mice (apoE(-/-)/fat-1), we crossed heterozygous fat-1 mice with apoE(-/-) mice. After 14 weeks of a Western type diet rich in n-6 PUFAs, the apoE(-/-)/fat-1 mice showed a lower ratio of n 6/n-3 fatty acids than the apoE(-/-) mice in all organs and tissues tested. The aortic lesion area in apoE(-/-)/fat-1 mice was significantly reduced when compared with that of apoE(-/-) littermates (7.14+/-0.54% versus 13.49+/-1.61%). There were no differences in plasma cholesterol or high- and low-density lipoprotein levels between the 2 groups, except for a higher triglyceride level in the apoE(-/-)/fat-1 mice. A significant reduction of interleukin 6 and prostaglandin E(2) in both plasma and aorta culture medium was observed in apoE( /-)/fat-1 mice. RT-PCR analysis also indicated that the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin 6, and cyclooxygenase-2 was lower in the aortas and the circulating monocytes from apoE(-/-)/fat-1 mice. In addition, the expression of nuclear factor kappaB/p65 in the aorta and the recruitment of macrophages into atherosclerotic plaques were reduced in apoE(-/-)/fat-1 mice, compared with apoE( /-) mice. CONCLUSIONS: To our knowledge, this is the first study to provide direct evidence for the role of tissue n-6/n-3 ratio in atherosclerosis using the fat-1 transgenic mouse model. Our findings demonstrate that a decreased n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apoE(-/-) mice. This protective effect may be attributed to the antiinflammatory properties of n-3 fatty acids, rather than their lipid-lowering effect. PMID- 20705920 TI - Apelin is a crucial factor for hypoxia-induced retinal angiogenesis. AB - OBJECTIVE: To investigate the role of endogenous apelin in pathological retinal angiogenesis. METHODS AND RESULTS: The progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, mainly induced by vascular endothelial growth factor (VEGF) and erythropoietin. Although antiangiogenic therapies using anti-VEGF drugs are effective in treating retinal neovascularization, they show a transient efficacy and cause general adverse effects. New therapeutic target molecules are needed to resolve these issues. It was recently demonstrated that the apelin/APJ system, a newly deorphanized G protein-coupled receptor system, is involved in physiological retinal vascularization. Retinal angiography and mRNA expression were examined during hypoxia-induced retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Compared with age-matched control mice, retinal apelin expression was dramatically increased during the hypoxic phase in oxygen induced retinopathy model mice. APJ was colocalized in proliferative cells, which were probably endothelial cells of the ectopic vessels in the vitreous body. Apelin deficiency hardly induced hypoxia-induced retinal angiogenesis despite the upregulation of VEGF and erythropoietin mRNA in oxygen-induced retinopathy model mice. Apelin small and interfering RNA suppressed the proliferation of endothelial cells independent of the VEGF/VEGF receptor 2 signaling pathway. CONCLUSIONS: These results suggest that apelin is a prerequisite factor for hypoxia-induced retinal angiogenesis. PMID- 20705921 TI - Zyxin mediation of stretch-induced gene expression in human endothelial cells. AB - RATIONALE: Prolonged exposure to enhanced stretch, such as in hypertension, triggers endothelial dysfunction, a hallmark of pathological vascular remodeling processes. Despite its clinical relevance, little is known about stretch-induced gene expression in endothelial cells. OBJECTIVE: Here, we have characterized a new stretch-inducible signaling pathway and the subsequent changes in endothelial gene expression in response to stretch. METHODS AND RESULTS: Using human primary endothelial cells, we observed that the protein zyxin translocates from focal adhesions to the nucleus solely in response to stretch. There, it orchestrates complex changes in gene expression by interacting with a novel cis-acting element found in all zyxin-regulated genes analyzed so far. By way of DNA microarray pathway analyses, stretch-induced changes in endothelial cell gene expression were systematically explored, revealing that zyxin mainly regulates proinflammatory pathways. CONCLUSIONS: Stretch appears to be an important factor in the development of endothelial dysfunction with zyxin as a potential therapeutic target to interfere with these early changes in endothelial cell phenotype. PMID- 20705922 TI - Enhanced fibroblast-myocyte interactions in response to cardiac injury. AB - RATIONALE: A critical event in the development of cardiac fibrosis is the transformation of fibroblasts into myofibroblasts. The electrophysiological consequences of this phenotypic switch remain largely unknown. OBJECTIVE: Determine whether fibroblast activation following cardiac injury results in a distinct electrophysiological phenotype that enhances fibroblast-myocyte interactions. METHODS AND RESULTS: Neonatal rat myocyte monolayers were treated with media (CM) conditioned by fibroblasts isolated from normal (Fb) and infarcted (MI-Fb) hearts. Fb and MI-Fb were also plated on top of myocyte monolayers at 3 densities. Cultures were optically mapped after CM treatment or fibroblast plating to obtain conduction velocity and action potential duration (APD(70)). Intercellular communication and connexin43 expression levels were assessed. Membrane properties of Fb and MI-Fb were evaluated using patch clamp techniques. MI-Fb CM treatment decreased conduction velocity (11.1%) compared to untreated myocyte cultures. APD(70) was reduced by MI-Fb CM treatment compared to homocellular myocyte culture (9.4%) and Fb CM treatment (6.4%). In heterocellular cultures, MI-Fb conduction velocities were different from Fb at all densities (+29.8%, -23.0%, and -16.7% at 200, 400, and 600 cells/mm(2), respectively). APD(70) was reduced (9.6%) in MI-Fb compared to Fb cultures at 200 cells/mm(2). MI-Fb had more hyperpolarized resting membrane potentials and increased outward current densities. Connexin43 was elevated (134%) in MI-Fb compared to Fb. Intercellular coupling evaluated with gap fluorescence recovery after photobleaching was higher between myocytes and MI-Fb compared to Fb. CONCLUSIONS: These data demonstrate cardiac injury results in significant electrophysiological changes that enhance fibroblast-myocyte interactions and could contribute to the greater incidence of arrhythmias observed in fibrotic hearts. PMID- 20705923 TI - Histone deacetylase 3 antagonizes aspirin-stimulated endothelial nitric oxide production by reversing aspirin-induced lysine acetylation of endothelial nitric oxide synthase. AB - RATIONALE: Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular atherothrombosis. Cardiovascular doses of aspirin also reduce systemic blood pressure and improve endothelium-dependent vasorelaxation in patients with atherosclerosis or risk factors for atherosclerosis. Aspirin can acetylate proteins, other than its pharmacological target cyclooxygenase, at lysine residues. The role of lysine acetylation in mediating the effects of low-dose aspirin on the endothelium is not known. OBJECTIVE: To determine the role of lysine acetylation of endothelial nitric oxide synthase (eNOS) in the regulation of endothelial NO production by low-dose aspirin and to examine whether the lysine deacetylase histone deacetylase (HDAC)3 antagonizes the effect of low-dose aspirin on endothelial NO production by reversing acetylation of functionally critical eNOS lysine residues. METHODS AND RESULTS: Low concentrations of aspirin induce lysine acetylation of eNOS, stimulating eNOS enzymatic activity and endothelial NO production in a cyclooxygenase-1-independent fashion. Low-dose aspirin in vivo also increases bioavailable vascular NO in an eNOS-dependent and cyclooxygenase-1-independent manner. Low-dose aspirin promotes the binding of eNOS to calmodulin. Lysine 609 in the calmodulin autoinhibitory domain of bovine eNOS mediates aspirin stimulated binding of eNOS to calmodulin and eNOS-derived NO production. HDAC3 inhibits aspirin-stimulated (1) lysine acetylation of eNOS, (2) eNOS enzymatic activity, (3) eNOS-derived NO, and (4) binding of eNOS to calmodulin. Conversely, downregulation of HDAC3 promotes lysine acetylation of eNOS and endothelial NO generation. CONCLUSIONS: Lysine acetylation of eNOS is a posttranslational protein modification supporting low-dose aspirin-induced vasoprotection. HDAC3, by deacetylating aspirin-acetylated eNOS, antagonizes aspirin-stimulated endothelial production of NO. PMID- 20705924 TI - The transcription factor GATA-6 regulates pathological cardiac hypertrophy. AB - RATIONALE: The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown. OBJECTIVE: To determine the role of GATA-6 in cardiac hypertrophy and homeostasis. METHODS AND RESULTS: Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, whereas deletion with beta-myosin heavy chain-cre (betaMHC cre) produced viable adults with >95% loss of GATA-6 protein in the heart. These latter mice were subjected to pressure overload-induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure, whereas control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes. CONCLUSIONS: These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4. PMID- 20705926 TI - The stability of the blood oxygenation level-dependent functional MRI response to motor tasks is altered in patients with chronic ischemic stroke. AB - BACKGROUND AND PURPOSE: Functional MRI is a powerful tool to investigate recovery of brain function in patients with stroke. An inherent assumption in functional MRI data analysis is that the blood oxygenation level-dependent (BOLD) signal is stable over the course of the examination. In this study, we evaluated the validity of such assumption in patients with chronic stroke. METHODS: Fifteen patients performed a simple motor task with repeated epochs using the paretic and the unaffected hand in separate runs. The corresponding BOLD signal time courses were extracted from the primary and supplementary motor areas of both hemispheres. Statistical maps were obtained by the conventional General Linear Model and by a parametric General Linear Model. RESULTS: Stable BOLD amplitude was observed when the task was executed with the unaffected hand. Conversely, the BOLD signal amplitude in both primary and supplementary motor areas was progressively attenuated in every patient when the task was executed with the paretic hand. The conventional General Linear Model analysis failed to detect brain activation during movement of the paretic hand. However, the proposed parametric General Linear Model corrected the misdetection problem and showed robust activation in both primary and supplementary motor areas. CONCLUSIONS: The use of data analysis tools that are built on the premise of a stable BOLD signal may lead to misdetection of functional regions and underestimation of brain activity in patients with stroke. The present data urge the use of caution when relying on the BOLD response as a marker of brain reorganization in patients with stroke. PMID- 20705925 TI - DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. AB - RATIONALE: DNA damage is present in both genomic and mitochondrial DNA in atherosclerosis. However, whether DNA damage itself promotes atherosclerosis, or is simply a byproduct of the risk factors that promote atherosclerosis, is unknown. OBJECTIVE: To examine the effect of DNA damage on atherosclerosis, we studied apolipoprotein (Apo)E(-/-) mice that were haploinsufficient for the protein kinase ATM (ataxia telangiectasia mutated), which coordinates DNA repair. METHODS AND RESULTS: ATM(+/-)/ApoE(-/-) mice developed accelerated atherosclerosis and multiple features of the metabolic syndrome, including hypertension, hypercholesterolemia, obesity, steatohepatitis, and glucose intolerance. Transplantation with ATM(+/+) bone marrow attenuated atherosclerosis but not the metabolic syndrome. ATM(+/-) smooth muscle cells and macrophages showed increased nuclear DNA damage and defective DNA repair signaling, growth arrest, and apoptosis. Metabolomic screening of ATM(+/-)/ApoE(-/-) mouse tissues identified metabolic changes compatible with mitochondrial defects, with increased beta-hydroxybutyrate but reduced lactate, reduced glucose, and alterations in multiple lipid species. ATM(+/-)/ApoE(-/-) mouse tissues showed an increased frequency of a mouse mitochondrial "common" deletion equivalent and reduced mitochondrial oxidative phosphorylation. CONCLUSIONS: We propose that failure of DNA repair generates defects in cell proliferation, apoptosis, and mitochondrial dysfunction. This in turn leads to ketosis, hyperlipidemia, and increased fat storage, promoting atherosclerosis and the metabolic syndrome. Prevention of mitochondrial dysfunction may represent a novel target in cardiovascular disease. PMID- 20705927 TI - Omega-3 polyunsaturated fatty acid supplementation confers long-term neuroprotection against neonatal hypoxic-ischemic brain injury through anti inflammatory actions. AB - BACKGROUND AND PURPOSE: Current available therapies for neonatal hypoxia/ischemia (H/I) brain injury are rather limited. Here, we investigated the effect of omega 3 polyunsaturated fatty acids on brain damage and long-term neurological function after H/I in neonates. METHODS: Female rats were treated with or without an omega 3 polyunsaturated fatty acids-enriched diet from the second day of pregnancy until 14 days after parturition. Seven-day-old neonates were subjected to H/I and euthanized 5 weeks later for evaluation of tissue loss. Neurological impairment was assessed progressively for 5 weeks after H/I by grid walking, foot fault, and Morris water maze. Activation of microglia and production of inflammatory mediators were examined up to 7 days after H/I. RESULTS: Omega-3 polyunsaturated fatty acid supplementation significantly reduced brain damage and improved long term neurological outcomes up to 5 weeks after neonatal H/I injury. Omega-3 polyunsaturated fatty acids exerted an anti-inflammatory effect in microglia both in an in vivo model of H/I and in in vitro microglial cultures subjected to inflammatory stimuli by inhibiting NF-kappaB activation and subsequent release of inflammatory mediators. CONCLUSIONS: Our results suggest that omega-3 polyunsaturated fatty acids confer potent neuroprotection against neonatal H/I brain injury through, at least partially, suppressing a microglial-mediated inflammatory response. PMID- 20705928 TI - Thrombin mediates severe neurovascular injury during ischemia. AB - BACKGROUND AND PURPOSE: Cerebral ischemia initiates cascades of pathological events such as edema, blood-brain barrier breakdown, and tissue degeneration. Thrombin activation is a key step in coagulation, and thrombin has recently been shown to mediate endothelial permeability and cellular toxicity in vitro. We examined the effect of thrombin on vasculature during ischemia in vivo. METHODS: Focal ischemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery for 4 hours followed by a short period of reperfusion. High-molecular-weight fluorescein isothiocyanate-dextran was injected before surgery to label the severe vascular disruption. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to identify dying cells, which were quantified with manual counts. Intra-arterial thrombin or intravenous thrombin inhibitors were infused during ischemia and reperfusion. RESULTS: Infusion of thrombin (3 U/kg) intra-arterially during ischemia greatly enlarged the volume of severe vascular disruption, as visualized by fluorescein isothiocyanate-dextran extravasation (P<0.05). Thrombin also promoted blood-brain barrier leakage of IgG during ischemia. Vascular disruption was blocked by intravenous infusion of the direct thrombin inhibitor argatroban (1.69 mg/kg, P<0.05). Greater numbers of dying cells were found in regions of severe vascular disruption, and interventions that reduced vascular leakage also reduced the numbers of dying cells. CONCLUSIONS: Thrombin mediates severe vascular disruption during ischemia and thrombin inhibitors may partially ameliorate vascular disruption. Further work is needed to establish whether thrombin, entering parenchyma due to increased vascular permeability, augments neurotoxicity during ischemia. PMID- 20705929 TI - Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. AB - BACKGROUND AND PURPOSE: Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. METHODS: Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. RESULTS: Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65+/-13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5+/-5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. CONCLUSIONS: Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator. PMID- 20705930 TI - Occurence and clinical predictors of spasticity after ischemic stroke. AB - BACKGROUND AND PURPOSE: There is currently no consensus on (1) the percentage of patients who develop spasticity after ischemic stroke, (2) the relation between spasticity and initial clinical findings after acute stroke, and (3) the impact of spasticity on activities of daily living and health-related quality of life. METHODS: In a prospective cohort study, 301 consecutive patients with clinical signs of central paresis due to a first-ever ischemic stroke were examined in the acute stage and 6 months later. At both times, the degree and pattern of paresis and muscle tone, the Barthel Index, and the EQ-5D score, a standardized instrument of health-related quality of life, were evaluated. Spasticity was assessed on the Modified Ashworth Scale and defined as Modified Ashworth Scale >1 in any of the examined joints. RESULTS: Two hundred eleven patients (70.1%) were reassessed after 6 months. Of these, 42.6% (n=90) had developed spasticity. A more severe degree of spasticity (Modified Ashworth Scale >or=3) was observed in 15.6% of all patients. The prevalence of spasticity did not differ between upper and lower limbs, but in the upper limb muscles, higher degrees of spasticity (Modified Ashworth Scale >or=3) were more frequently (18.9%) observed than in the lower limbs (5.5%). Regression analysis used to test the differences between upper and lower limbs showed that patients with more severe paresis in the proximal and distal limb muscles had a higher risk for developing spasticity (Por=4-point drop on the National Institutes of Health Stroke Scale within 72 hours) and its mechanism. Deterioration was attributed to SICH when associated with a PH1 or PH2 hemorrhage on postdeterioration computed tomography scans, to recurrent ischemic stroke when there was clinical and radiologic evidence of a new territorial infarction or new vessel occlusion, and otherwise to evolution of the incident stroke. RESULTS: Of 228 consecutive IV rt-PA-treated patients, 34 (15%) developed early neurologic deterioration, 18 (8%) secondary to incident strokes 10 (4.4%) due to SICH, and 6 (2.6%) due to early recurrent ischemic events, which were significantly associated with atrial fibrillation (present in 5 of 6 patients; 4 paroxysmal, 1 permanent). In 4 patients, sudden clinical deterioration developed during or shortly after IV rt-PA infusion, and in 2, deterioration developed 3 days later. All died 2 days to 2 weeks later. The single case without atrial fibrillation had a recurrent, contralateral, middle cerebral artery stroke during IV rt-PA infusion and multiple high-signal emboli detected by transcranial Doppler. Early recurrent ischemic stroke accounted for 5 of 12 (42%) cases of early neurologic deterioration in patients with atrial fibrillation. CONCLUSIONS: In this single-center series, the incidence of early recurrent ischemic stroke after IV rt-PA was 2.6% and was associated with previous atrial fibrillation. PMID- 20705934 TI - Re: Immediate risk of suicide and cardiovascular death after a prostate cancer diagnosis: cohort study in the United States. PMID- 20705935 TI - Re: Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients. PMID- 20705936 TI - Cancer biomarkers: can we turn recent failures into success? AB - Disease biomarkers are used widely in medicine. But very few biomarkers are useful for cancer diagnosis and monitoring. Over the past 15 years, major investments have been made to discover and validate cancer biomarkers. Despite such investments, no new major cancer biomarkers have been approved for clinical use for at least 25 years. In the last decade, many reports have described new cancer biomarkers that promised to revolutionize the diagnosis of cancer and the management of cancer patients. However, many initially promising biomarkers have not been validated for clinical use. In this commentary, a plethora of parameters before sample analysis, during sample analysis, and after sample analysis that can complicate biomarker discovery and validation and lead to "false discovery" are discussed. Several examples of biomarker discoveries that were published in high-profile journals are also presented, as well as why they were not validated and the lessons learned from these false discoveries, so that similar mistakes can be avoided in the future. PMID- 20705937 TI - Association of insurance and race/ethnicity with disease severity among men diagnosed with prostate cancer, National Cancer Database 2004-2006. AB - BACKGROUND: Previous studies documenting variations in severity of prostate cancer at diagnosis by race/ethnicity and insurance status have been limited to small sample sizes and patients >=65 years of age. This study examines disease severity among patients ages 18 to 99 from the National Cancer Database (NCDB). METHODS: Patients diagnosed between 2004 and 2006 with prostate cancer were selected from the NCDB (n = 312,339). We evaluated the association among three disease severity measures: prostate specific antigen (PSA) level, Gleason score 8 to 10, and clinical T-stage 3/4, by race/ethnicity and insurance while adjusting for sociodemographic and clinical factors. RESULTS: Uninsured and Medicaid insured patients had elevated PSA levels, higher odds of advanced Gleason score [uninsured odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.82-2.12; Medicaid OR, 1.67; 95% CI, 1.55-1.79], and advanced clinical T stage (uninsured OR, 1.85; 95% CI, 1.69-2.03; Medicaid OR, 1.49; 95% CI, 1.35-1.63) compared with privately insured patients. Black (OR, 1.19; 95% CI, 1.15-1.23), Hispanic (OR, 1.16; 95% CI, 1.10-1.23), and Asian patients (OR, 1.22; 95% CI, 1.24-1.43) had higher odds of advanced Gleason score and similar odds of advanced stage of disease relative to whites. CONCLUSION: Insurance status is strongly associated with disease severity among prostate cancer patients. IMPACT: Strong associations between insurance and disease severity may be related to lack of access to preventive services such as PSA screening and barriers to medical evaluation. Although the risks and benefits of PSA screening have not been fully elucidated, it is important that all men have the opportunity to be informed about this option and preventative medical services. PMID- 20705938 TI - Human influenza is more effective than avian influenza at antiviral suppression in airway cells. AB - Airway epithelial cells are the initial site of infection with influenza viruses. The innate immune responses of airway epithelial cells to infection are important in limiting virus replication and spread. However, relatively little is known about the importance of this innate antiviral response to infection. Avian influenza viruses are a potential source of future pandemics; therefore, it is critical to examine the effectiveness of the host antiviral system to different influenza viruses. We used a human influenza (H3N2) and a low-pathogenic avian influenza (H11N9) to assess and compare the antiviral responses of Calu-3 cells. After infection, H3N2 replicated more effectively than the H11N9 in Calu-3 cells. This was not due to differential expression of sialic acid residues on Calu-3 cells, but was attributed to the interference of host antiviral responses by H3N2. H3N2 induced a delayed antiviral signaling and impaired type I and type III IFN induction compared with the H11N9. The gene encoding for nonstructural (NS) 1 protein was transfected into the bronchial epithelial cells (BECs), and the H3N2 NS1 induced a greater inhibition of antiviral responses compared with the H11N9 NS1. Although the low-pathogenic avian influenza virus was capable of infecting BECs, the human influenza virus replicated more effectively than avian influenza virus in BECs, and this was due to a differential ability of the two NS1 proteins to inhibit antiviral responses. This suggests that the subversion of human antiviral responses may be an important requirement for influenza viruses to adapt to the human host and cause disease. PMID- 20705939 TI - Length-dependent modulation of cytoskeletal remodeling and mechanical energetics in airway smooth muscle. AB - Actin cytoskeletal remodeling is an important mechanism of airway smooth muscle (ASM) contraction. We tested the hypothesis that mechanical strain modulates the cholinergic receptor-mediated cytoskeletal recruitment of actin-binding and integrin-binding proteins in intact airway smooth muscle, thereby regulating the mechanical energetics of airway smooth muscle. We found that the carbachol stimulated cytoskeletal recruitment of actin-related protein-3 (Arp3), metavinculin, and talin were up-regulated at short muscle lengths and down regulated at long muscle lengths, suggesting that the actin cytoskeleton- integrin complex becomes enriched in cross-linked and branched actin filaments in shortened ASM. The mechanical energy output/input ratio during sinusoidal length oscillation was dependent on muscle length, oscillatory amplitude, and cholinergic activation. The enhancing effect of cholinergic stimulation on mechanical energy output/input ratio at short and long muscle lengths may be explained by the length-dependent modulation of cytoskeletal recruitment and crossbridge cycling, respectively. We postulate that ASM functions as a hybrid biomaterial, capable of switching between operating as a cytoskeleton-based mechanical energy store at short muscle lengths to operating as an actomyosin powered mechanical energy generator at long muscle lengths. This postulate predicts that targeting the signaling molecules involved in cytoskeletal recruitment may provide a novel approach to dilating collapsed airways in obstructive airway disease. PMID- 20705940 TI - Granulocyte/macrophage colony-stimulating factor causes a paradoxical increase in the BH3-only pro-apoptotic protein Bim in human neutrophils. AB - Neutrophil apoptosis is essential for the resolution of inflammation but is delayed by several inflammatory mediators. In such terminally differentiated cells it has been uncertain whether these agents can inhibit apoptosis through transcriptional regulation of anti-death (Bcl-X(L), Mcl-1, Bcl2A1) or BH3-only (Bim, Bid, Puma) Bcl2-family proteins. We report that granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha prevent the normal time-dependent loss of Mcl-1 and Bcl2A1 in neutrophils, and we demonstrate that they cause an NF-kappaB-dependent increase in Bcl-X(L) transcription/translation. We show that GM-CSF and TNF-alpha increase and/or maintain mRNA levels for the pro-apoptotic BH3-only protein Bid and that GM-CSF has a similar NF-kappaB-dependent effect on Bim transcription and BimEL expression. The in-vivo relevance of these findings was indicated by demonstrating that GM-CSF is the dominant neutrophil survival factor in lung lavage from patients with ventilator-associated pneumonia, confirming an increase in lung neutrophil Bim mRNA. Finally GM-CSF caused mitochondrial location of Bim and a switch in phenotype to a cell that displays accelerated caspase-9-dependent apoptosis. This study demonstrates the capacity of neutrophil survival agents to induce a paradoxical increase in the pro-apoptotic proteins Bid and Bim and suggests that this may function to facilitate rapid apoptosis at the termination of the inflammatory cycle. PMID- 20705941 TI - Transient overexpression of Gremlin results in epithelial activation and reversible fibrosis in rat lungs. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lung parenchyma, without curative treatment. Gremlin is a bone morphogenic protein (BMP) antagonist, its expression being increased in IPF lungs. It has been implicated in promoting myofibroblast accumulation, likely through inhibited fibroblast apoptosis and epithelial-to-mesenchymal transition. In the current study, we examined the effects of selective adenovirus-mediated overexpression of Gremlin in rat lungs. We show that transient Gremlin overexpression results in activation of alveolar epithelial cells with proliferation and apoptosis, as well as partly reversible lung fibrosis. We found myofibroblasts arranged in fibroblastic foci. Fibroblast proliferation occurred delayed as compared with epithelial changes. Fibrotic pathology significantly declined after Day 14, the reversal being associated with an increase of the epithelium-protective element, fibroblast growth factor (FGF)-10. Our data indicate that Gremlin-mediated BMP inhibition results in activation of epithelial cells and transient fibrosis, but also induction of epithelium-protective FGF10. A Gremlin-BMP-FGF10 loop may explain these results, and demonstrate that the interactions between different factors are quite complex in fibrotic lung disease. Increased Gremlin expression in human IPF tissue may be an expression of continuing epithelial injury, and Gremlin may be part of activated repair mechanisms. PMID- 20705942 TI - Asthmatic airway epithelium is intrinsically inflammatory and mitotically dyssynchronous. AB - Asthma is an inflammatory condition for which anti-inflammatory glucocorticoids are the standard of care. However, similar efficacy has not been shown for agents targeting inflammatory cells and pathways. This suggests a noninflammatory cell contributor (e.g., epithelium) to asthmatic inflammation. Herein, we sought to define the intrinsic and glucocorticoid-affected properties of asthmatic airway epithelium compared with normal epithelium. Human primary differentiated normal and asthmatic airway epithelia were cultured in glucocorticoid-free medium beginning at -48 hours. They were pulsed with dexamethasone (20 nM) or vehicle for 2 hours at -26, -2, +22, and +46 hours. Cultures were mechanically scrape wounded at 0 hours and exposed continuously to bromodeoxyuridine (BrdU). Cytokine secretions were analyzed using cytometric bead assays. Wound regeneration/mitosis was analyzed by microscopy and flow cytometry. Quiescent normal (n = 3) and asthmatic (n = 6) epithelia showed similar minimal inflammatory cytokine secretion and mitotic indices. After wounding, asthmatic epithelia secreted more basolateral TGF-beta1, IL-10, IL-13, and IL-1beta (P < 0.05) and regenerated less efficiently than normal epithelia (+48 h wound area reduction = [mean +/- SEM] 50.2 +/- 7.5% versus 78.6 +/- 7.7%; P = 0.02). Asthmatic epithelia showed 40% fewer BrdU(+) cells at +48 hours (0.32 +/- 0.05% versus 0.56 +/- 0.07% of total cells; P = 0.03), and those cells were more dyssynchronously distributed along the cell cycle (52 +/- 10, 25 +/- 4, 23 +/- 7% for G1/G0, S, and G2/M, respectively) than normal epithelia (71 +/- 1, 12 +/- 2, and 17 +/- 2% for G1/G0, S, and G2/M, respectively). Dexamethasone pulses improved asthmatic epithelial inflammation and regeneration/mitosis. In summary, we show that inflammatory/fibrogenic cytokine secretions are correlated with dyssynchronous mitosis upon injury. Intermittent glucocorticoids simultaneously decreased epithelial cytokine secretions and resynchronized mitosis. These data, generated in an airway model lacking inflammatory cells, support the concept that epithelium contributes to asthmatic inflammation. PMID- 20705943 TI - The effect of class II transactivator mutations on bleomycin-induced lung inflammation and fibrosis. AB - IFN-gamma expression increases during the inflammatory response after bleomycin injury in mice. IFN-gamma deficiency attenuates lung inflammation and fibrosis. Because IFN-gamma stimulates class II transactivator (CIITA) expression, which activates major histocompatibility class (MHC) II and represses collagen expression, it was hypothesized that CIITA mediates IFN-gamma action after bleomycin injury. To test this hypothesis, two CIITA mouse lines, one carrying a mutation of the leucine-rich region of CIITA (CIITA C-/-) and one with a deletion extending into the GTP-binding domain (CIITA G-/-), were used. IFN-gamma treatment of lung cells isolated from both strains of mice induced mutant CIITA expression, which did not activate MHC II transcription. Collagen expression was similar in both mutant mouse strains and comparable to C57BL/6 (wild-type) mice. When mice were exposed to intratracheal bleomycin, both strains of CIITA mutant mice retained body weight and altered inflammation at 14 days after bleomycin injury compared with bleomycin-treated wild-type mice. However, there was no difference in fibrosis as judged by histology, mRNA, and protein expression of lungs. Bronchoalveolar lavage cells from CIITA C-/- and C57BL/6 lungs were examined at 3, 7, and 14 days after bleomycin injury. CD4 mRNA expression in bronchoalveolar lavage cells was down-regulated, whereas IL-4 and IL-10 expression was up-regulated, in CIITA C-/- mice, indicating a diminished, skewed Th2 response. The expression of IFN-gamma was the same in all mice tested. Combined, our data suggest that CIITA mutations altered the immune response without affecting fibrosis. PMID- 20705944 TI - Stabilizing function of the diaphragm: dynamic MRI and synchronized spirometric assessment. AB - The aim was to describe diaphragmatic behavior during postural limb activities and examine the ventilatory and stabilizing functions of the diaphragm. Thirty healthy subjects were examined in the supine position using a dynamic MRI system assessed simultaneously with specialized spirometric readings. The diaphragmatic excursions (DEs) were measured at three diaphragmatic points in the sagittal plane; the diaphragm positions (DPs) as related to a reference horizontal baseline were determined. Measurements were taken during tidal breathing (TB) and isometric flexion of upper or lower extremities against external resistance together with TB. Mean DE in both upper and lower postural limb activities was greater compared with the TB condition (P < 0.05), with the effect greater for lower limb activities. Inspiratory DPs in the upper and lower extremity activities were lower compared with TB alone (P < 0.01). Expiratory DP was lower only for lower extremity activities (P < 0.01). DP was most affected at the apex of the crescent and crural (posterior) portion of the diaphragm. DEs correlated strongly with tidal volume (Vt) in all conditions. Changes in DEs relative to the initial value were minimal for upper and lower extremities but were related to lower values of Vt (P < 0.03). Significant involvement of the diaphragm in the limb postural activities was found. Resulting DEs and DPs differed from the TB conditions, especially in lower extremity activities. The differences between the percent changes of DEs vs. Vt found for lower extremity activities were confirmed by both ventilatory and postural diaphragm recruitment in response to postural demands. PMID- 20705945 TI - Skin blood flow and local temperature independently modify sweat rate during passive heat stress in humans. AB - Sweat rate (SR) is reduced in locally cooled skin, which may result from decreased temperature and/or parallel reductions in skin blood flow. The purpose of this study was to test the hypotheses that decreased skin blood flow and decreased local temperature each independently attenuate sweating. In protocols I and II, eight subjects rested supine while wearing a water-perfused suit for the control of whole body skin and internal temperatures. While 34 degrees C water perfused the suit, four microdialysis membranes were placed in posterior forearm skin not covered by the suit to manipulate skin blood flow using vasoactive agents. Each site was instrumented for control of local temperature and measurement of local SR (capacitance hygrometry) and skin blood flow (laser Doppler flowmetry). In protocol I, two sites received norepinephrine to reduce skin blood flow, while two sites received Ringer solution (control). All sites were maintained at 34 degrees C. In protocol II, all sites received 28 mM sodium nitroprusside to equalize skin blood flow between sites before local cooling to 20 degrees C (2 sites) or maintenance at 34 degrees C (2 sites). In both protocols, individuals were then passively heated to increase core temperature ~1 degrees C. Both decreased skin blood flow and decreased local temperature attenuated the slope of the SR to mean body temperature relationship (2.0 +/- 1.2 vs. 1.0 +/- 0.7 mg.cm(-2).min(-1). degrees C(-1) for the effect of decreased skin blood flow, P = 0.01; 1.2 +/- 0.9 vs. 0.07 +/- 0.05 mg.cm(-2).min(-1). degrees C( 1) for the effect of decreased local temperature, P = 0.02). Furthermore, local cooling delayed the onset of sweating (mean body temperature of 37.5 +/- 0.4 vs. 37.6 +/- 0.4 degrees C, P = 0.03). These data demonstrate that local cooling attenuates sweating by independent effects of decreased skin blood flow and decreased local skin temperature. PMID- 20705946 TI - Venous emptying from the foot: influences of weight bearing, toe curls, electrical stimulation, passive compression, and posture. AB - This study investigated the hemodynamic properties of the plantar venous plexus (PVP), a peripheral venous pump in the human foot, with Doppler ultrasound. We investigated how different ways of introducing mechanical changes vary in effectiveness of displacing blood volume from the PVP. The contribution of the PVP was analyzed during both natural and device-elicited compressions. Natural compressions consisted of weight bearing on the foot and toe curl exercises. Device-elicited compressions consisted of intermittent pneumatic compression (IPC) of the foot and electrically elicited foot muscle contractions. Ten healthy participants had their posterior tibial, peroneal, anterior tibial, and popliteal vein blood flow monitored while performing these natural and device-elicited compressions of the PVP supine and in an upright position. Results indicated that 1) natural compression of the PVP, weight bearing and toe curls, expelled a significantly larger volume of blood than device-elicited PVP compression, IPC and electrical stimulation; 2) there was no difference between the venous volume elicited by weight bearing and by toe curls; 3) expelled venous volume recorded at the popliteal vein under all test conditions was significantly greater than that recorded from the posterior tibial and peroneal veins; 4) there was no significant difference between the volume in the posterior tibial and peroneal veins; 5) ejected venous volume recorded in the upright position was significantly higher than that recorded in the supine position. Our study shows that weight bearing and toe curls make similar contributions to venous emptying of the foot. PMID- 20705947 TI - Cardiorespiratory and neural consequences of rats brought past their aerobic dive limit. AB - The mammalian diving response is a dramatic autonomic adjustment to underwater submersion affecting heart rate, arterial blood pressure, and ventilation. The bradycardia is known to be modulated by the parasympathetic nervous system, arterial blood pressure is modulated via the sympathetic system, and still other circuits modulate the respiratory changes. In the present study, we investigate the submergence of rats brought past their aerobic dive limit, defined as the diving duration beyond which blood lactate concentration increases above resting levels. Hemodynamic measurements were made during underwater submergence with biotelemetric transmitters, and blood was drawn from cannulas previously implanted in the rats' carotid arteries. Such prolonged submersion induces radical changes in blood chemistry; mean arterial PCO(2) rose to 62.4 Torr, while mean arterial PO(2) and pH reached nadirs of 21.8 Torr and 7.18, respectively. Despite these radical changes in blood chemistry, the rats neither attempted to gasp nor breathe while underwater. Immunohistochemistry for Fos protein done on their brains revealed numerous Fos-positive profiles. Especially noteworthy were the large number of immunopositive profiles in loci where presumptive chemoreceptors are found. Despite the activation of these presumptive chemoreceptors, the rats did not attempt to breathe. Injections of biotinylated dextran amine were made into ventral parts of the medullary dorsal horn, where central fibers of the anterior ethmoidal nerve terminate. Labeled fibers coursed caudal, ventral, and medial from the injection to neurons on the ventral surface of the medulla, where numerous Fos-labeled profiles were seen in the rats brought past their aerobic dive limit. We propose that this projection inhibits the homeostatic chemoreceptor reflex, despite the gross activation of chemoreceptors. PMID- 20705948 TI - Exercise training restores impaired dilator responses of cerebral arterioles during chronic exposure to nicotine. AB - Our goal was to determine whether exercise training (ExT) alleviates impaired nitric oxide synthase (NOS)-dependent dilation of pial arterioles during chronic exposure to nicotine. We measured dilation of cerebral (pial) arterioles in sedentary and exercised control and nicotine-treated (2 mg.kg(-1).day(-1) for 4 wk via an osmotic minipump) rats to an endothelial NOS (eNOS)-dependent (ADP), a neuronal NOS (nNOS)-dependent [N-methyl-D-aspartic acid (NMDA)], and a NOS independent (nitroglycerin) agonist. In addition, we harvested brain tissue from sedentary and exercised control and nicotine-treated rats to measure the production of superoxide anion and measured superoxide dismutase-1 (SOD-1) protein in cerebral microvessels using Western blot. We found that eNOS-and nNOS dependent, but not NOS-independent, vasodilation was impaired in nicotine-treated compared with control rats. In addition, the production of superoxide anion (lucigenin chemiluminescence) was increased, and SOD-1 protein decreased, in rats treated with nicotine compared with control rats. Further, although ExT did not significantly affect eNOS- or nNOS-dependent vasodilation in control rats, ExT restored impaired eNOS- and nNOS-dependent responses in nicotine-treated rats. In addition, the increase in superoxide anion production observed in nicotine treated rats was reduced by ExT, and SOD-1 protein was increased in nicotine treated rats by ExT. We suggest that ExT restores impaired NOS-dependent dilation of pial arterioles during chronic exposure to nicotine by a mechanism related to the formation of superoxide anion. PMID- 20705950 TI - N-acetylcysteine improves residual renal function in peritoneal dialysis patients: a pilot study. AB - BACKGROUND: Preservation of peritoneal membrane function and residual renal function is important for the optimal care of peritoneal dialysis patients. N Acetylcysteine may ameliorate oxidative stress, which is thought to be involved in peritoneal membrane dysfunction. In addition, N-acetylcysteine may have a positive effect on renal function in the setting of nephrotoxic contrast media administration. The aim of this study was to investigate the effect of N acetylcysteine on peritoneal and residual renal function in peritoneal dialysis patients. METHODS: Ten prevalent peritoneal dialysis patients were administered oral N-acetylcysteine 1200 mg twice daily for 4 weeks. At baseline and at the end of treatment, peritoneal membrane function and residual renal function were assessed using a 4.25% dextrose peritoneal equilibration test and 24-hour dialysate and urine collection for calculation of peritoneal and residual renal Kt/V and mean urea and creatinine residual renal clearance. RESULTS: No significant changes were demonstrated in peritoneal membrane function, including dialysate-to-plasma creatinine ratio, sodium sieving, and net ultrafiltration. Residual renal function improved significantly: urine volume increased from 633 +/- 426 to 925 +/- 552 mL/24 hours (p = 0.022), residual renal Kt/V increased from 0.56 +/- 0.41 to 0.75 +/- 0.47 (p = 0.037), and mean residual urea and creatinine clearance increased from 4.96 +/- 3.96 to 5.95 +/- 4.08 mL/min/1.73 m(2) (p = 0.059). CONCLUSIONS: N-acetylcysteine may improve residual renal function in patients treated with peritoneal dialysis. PMID- 20705949 TI - Effects of sleep on the cardiovascular and thermoregulatory systems: a possible role for hypocretins. AB - Sleep influences the cardiovascular, endocrine, and thermoregulatory systems. Each of these systems may be affected by the activity of hypocretin (orexin) producing neurons, which are involved in the etiology of narcolepsy. We examined sleep in male rats, either hypocretin neuron-ablated orexin/ataxin-3 transgenic (narcoleptic) rats or their wild-type littermates. We simultaneously monitored electroencephalographic and electromyographic activity, core body temperature, tail temperature, blood pressure, electrocardiographic activity, and locomotion. We analyzed the daily patterns of these variables, parsing sleep and circadian components and changes between states of sleep. We also analyzed the baroreceptor reflex. Our results show that while core temperature and heart rate are affected by both sleep and time of day, blood pressure is mostly affected by sleep. As expected, we found that both blood pressure and heart rate were acutely affected by sleep state transitions in both genotypes. Interestingly, hypocretin neuron ablated rats have significantly lower systolic and diastolic blood pressure during all sleep stages (non-rapid eye movement, rapid eye movement) and while awake (quiet, active). Thus, while hypocretins are critical for the normal temporal structure of sleep and wakefulness, they also appear to be important in regulating baseline blood pressure and possibly in modulating the effects of sleep on blood pressure. PMID- 20705951 TI - Coadministration with lopinavir and ritonavir decreases exposure to BILR 355, a nonnucleoside reverse transcriptase inhibitor, in healthy volunteers. AB - The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150 mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r-alone group) were also pooled with group B subjects from 3 similar phase I drug-drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration time curve from 0 to 12 hours (AUC(0-12,ss)) and steady-state maximum measured plasma concentration over a dosing interval (C(max,ss)) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C(12,ss)) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355. PMID- 20705952 TI - Emergence of promising therapies in diabetes mellitus. AB - Diabetes mellitus (DM) results from defects in insulin secretion (type 1) or insulin resistance (type 2). Insulin is used to manage type 1 DM, and oral hypoglycemic agents are used to manage type 2 DM. These therapies are inconsistent in maintaining glycemic control and cause some severe adverse effects such as undue weight gain and hypoglycemia. New and appropriate therapies are needed to overcome these problems. Drugs that are in the pipeline include oral insulins for type 1 DM and incretin mimetics, incretin enhancers, gastric inhibitory peptides, amylin analogues, peroxisome proliferator-activated receptor alpha/gamma ligands, sodium-dependent glucose transporter inhibitors, and fructose 1,6-bisphosphatase inhibitors for type 2 DM. This article describes the mechanisms of action and relative advantages and disadvantages of the promising therapies. PMID- 20705953 TI - Functional impact of cancer-associated mutations in the tumor suppressor protein ING4. AB - Inhibitor of growth 4 (ING4) is a member of the ING family of tumor suppressor proteins. In this study, we have analyzed the impact of two mutations in ING4 associated with human tumors (Y121N and N214D), testing their behavior in a series of functional, biochemical and structural analyses. We report that the N214D mutation dramatically dampened the ability of ING4 to inhibit proliferation, anchorage-independent growth or cell migration or to sensitize to cell death. In turn, the Y121N mutant did not differ significantly from wild-type ING4 in our assays. Neither of the mutations altered the normal subcellular localization of ING4, showing predominantly nuclear accumulation. We investigated the molecular basis of the defect in the activity of the N214D mutant. The folding and ability to bind histone marks of ING4 was not significantly altered by this mutation. Instead, we found that the functional impairment of the N214D mutant correlates with reduced protein stability due to increased proteasome mediated degradation. In summary, our data demonstrates that a point mutation of ING4 associated to human tumors leads to the loss of several essential functions of ING4 pertinent to tumor protection and highlight the importance of ING4 function to prevent tumorigenesis. PMID- 20705954 TI - Unexpected role for the human Cx37 C1019T polymorphism in tumour cell proliferation. AB - Connexins are a large family of proteins that form gap junction channels allowing exchange of ions and small metabolites between neighboring cells. They have been implicated in pathological processes such as tumourigenesis in which they may act as tumour suppressors. A polymorphism in the human connexin37 (Cx37) gene (C1019T), resulting in a non-conservative amino acid change in the regulatory C terminus (CT) of the Cx37 protein (P319S) has been suggested to be implicated in predisposition to angiosarcomas. In this study, we have used communication deficient HeLa and SK-HEP-1 cells transfected with Cx37-319S, Cx37-319P or empty vector. We showed that the expression of Cx37-319P limited proliferation of HeLa and SK-HEP-1 cells, whereas Cx37-319S expression was without effect. Using an in vitro kinase assay, we demonstrated phosphorylation of Cx37 CT by glycogen synthase kinase-3 (GSK-3), a kinase known to be implicated in cell proliferation and cancer. GSK-3-induced phosphorylation was associated with reduced gap junctional intercellular communication (GJIC) as measured by microinjection of the tracer neurobiotin. Inhibition of GSK-3 by LiCl or SB415286 reduced phosphorylation of Cx37-319P and increased GJIC. This latter effect on GJIC involved the beta and not the alpha isoform of GSK-3. In contrast, GSK-3 inhibitors were without effect on HeLa cells expressing Cx37-319S. In conclusion, our data indicate functional effects of the Cx37 C1019T polymorphism on GJIC that might contribute to tumour cell growth. PMID- 20705955 TI - Allele-specific expression of TGFBR1 in colon cancer patients. AB - The genetic component of colorectal cancer (CRC) predisposition has been only partially explained. We recently suggested that a subtle decrease in the expression of one allele of the TGFBR1 gene was a heritable quantitative trait predisposing to CRC. Here, we refined the measurements of allele-specific expression (ASE) of TGFBR1 in a population-based series of CRC patients and controls. Five single-nucleotide polymorphisms (SNPs) in the 3'-untranslated region of the gene were genotyped and used for ASE determination by pyrosequencing. After eliminating non-informative samples and samples with RNA of insufficient quality 109 cases and 125 controls were studied. Allelic ratios ranged between 0.74 and 1.69 without evidence of bimodality or cutoff points for 'ASE' versus 'non-ASE'. Treating ASE as a continuous variable, cases had non significantly different values than controls (P = 0.081 when comparing means by permutation test). However, cases had significantly higher ASE values when comparing medians by permutation test (P = 0.0027) and when using Wilcoxon test (P = 0.0094). We conclude that with the present-day technology, ASE differences between individuals and between cases and controls are too subtle to be used to assess CRC risk. More advanced technology is expected to resolve this issue as well as the low informativity caused by the limited heterozygosity of transcribed SNPs. PMID- 20705960 TI - Questionable increase of childhood leukemia in Basrah, Iraq. PMID- 20705961 TI - Advancing school-based health care policy and practice. PMID- 20705962 TI - The problem that has no name. The Feminine Mystique 1963. PMID- 20705963 TI - Florence Nightingale. Cassandra: an essay. 1979. PMID- 20705964 TI - Influence of age and measure of eGFR on the association between renal function and cardiovascular events. AB - BACKGROUND AND OBJECTIVES: This study investigates whether the association between estimated GFR (eGFR) and cardiovascular (CV) outcome differs for different measures of eGFR and different age groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 1997 and 1998, 8047 participants visited our outpatient clinic for measurement of serum creatinine, serum cystatin C, urinary creatinine, and urinary albumin excretion. GFR was estimated by the Modification of Diet in Renal Disease formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, a cystatin C-based formula, a formula combining serum creatinine and cystatin C, and 24-hour creatinine clearance. Subjects had follow-up on CV events until 2005. RESULTS: During follow up, 530 subjects had a CV event. The association between eGFR and CV events was significantly modified by age, except when GFR was estimated by 24-hour creatinine clearance. In subjects <60 years of age, all measures of eGFR were independently and significantly associated with CV events, whereas in subjects >=60 years of age only 24-hour creatinine clearance had a weak but significant association with CV events. For all measures and all levels of eGFR, subjects with elevated levels of albuminuria were at higher risk of CV events compared with subjects with normoalbuminuria. CONCLUSIONS: In the general population, all measures of eGFR are independently and significantly associated with CV events in individuals <60 years of age, but in subjects >=60 years of age, only 24-hour creatinine clearance is. In general, the association between eGFR and risk of CV events is weaker in elderly subjects than in younger subjects. PMID- 20705965 TI - Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. AB - BACKGROUND AND OBJECTIVES: It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty patients with MN and proteinuria >5 g/24 h received RTX (375 mg/m(2) * 4), with re-treatment at 6 months regardless of proteinuria response. PK analysis was conducted simultaneously with immunological analyses of T and B cells to ascertain the effect of RTX on lymphocyte subpopulations. RESULTS: Baseline proteinuria of 11.9 g/24 h decreased to 4.2 and 2.0 g/24 h at 12 and 24 months, respectively, whereas creatinine clearance increased from 72.4 ml/min per 1.73 m(2) at baseline to 88.4 ml/min per 1.73 m(2) at 24 months. Of 18 patients who completed 24-month follow up, 4 are in complete remission, 12 are in partial remission, 1 has a limited response, and 1 patient relapsed. Serum RTX levels were similar to those obtained with two doses of RTX. CONCLUSIONS: Four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. Baseline quantification of lymphocyte subpopulations did not predict response to RTX therapy. PMID- 20705966 TI - Prevalence and prognostic significance of renal artery calcification in patients with diabetes and proteinuria. AB - BACKGROUND AND OBJECTIVES: Vascular calcification is common and severe in chronic kidney disease. Because the consequences of calcification may differ by vascular beds, we sought to test the hypothesis that patients who have diabetes with proteinuria and have significant renal artery calcification (RAC) have a higher risk for progression to ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using electron-beam computed tomography, RAC was computed as the sum of Agatston scores at each of the two renal ostia and renal arteries. Time-to-event analysis was conducted to compare the risk in individuals with or without significant RAC (total score >10). RESULTS: Of 172 patients with type 2 diabetes and overt proteinuria studied (estimated GFR 56 +/- 25 ml/min per 1.73 m(2)), significant RAC was present in 31%. In 33 +/- 21 months, 41 progressed to ESRD and 65 reached a composite outcome (ESRD or death). Serum phosphorus was a significant predictor of progression to ESRD but was replaced by the significant RAC in multivariate models that included the latter. Individuals with significant RAC had a higher risk for reaching the composite outcome. In contrast, there was no association between coronary artery calcification scores and progression to ESRD. CONCLUSIONS: Significant RAC was an independent predictor of progression to ESRD as well as reaching the composite outcome. Understanding the pathogenesis of RAC would allow determination of whether this risk is potentially modifiable. PMID- 20705968 TI - Anisotropy induced localization of pseudo-relativistic spin states in graphene double quantum wire structures. AB - We study the single-particle properties of Dirac Fermions confined to a double quantum wire system based on graphene. We map out the spatial regions where electrons in a given subband display the largest occupation probability induced by spatial anisotropic effects associated to the interaction strength between the graphene wires and the substrate. Here, the graphene-substrate interaction is considered as an ad hoc parameter which destroys the zero-gap observed in the relativistic Dirac cone characteristic of graphene electronic energy dispersions. Furthermore, the results indicate that the character of quasi-extended spin states, viewed by multisubband probability density function, is highly sensitive to spatial asymmetries and to the graphene-substrate interaction strength. PMID- 20705969 TI - The synthesis of silica nanotubes through chlorosilanization of single wall carbon nanotubes. AB - We demonstrate that single wall carbon nanotubes (SWCNTs) can be coated by a layer of silica through the reaction between chlorosilane and acid-treated SWCNTs. The presence of carboxylic acid groups in the SWCNTs provides the active sites where chlorosilane can be anchored to form the silica coating. Silica nanotubes with diameters ranging from 5 to 23 nm were synthesized after the calcination of silica coated SWCNTs at 900 degrees C in air. It was found that the presence of SWCNT templates and carboxylic acid groups on the SWCNTs' surface is essential to the formation of silica nanotubes. Furthermore, the dependence of the inner diameters of the silica nanotubes on the diameters of bundled or isolated SWCNTs was observed. This novel technique can be applied to the synthesis of other oxide nanotubes if a precursor such as TiCl(4) or ZrCl(4) is used. PMID- 20705967 TI - HIV and proteinuria in an injection drug user population. AB - BACKGROUND AND OBJECTIVES: Proteinuria is a major determinant of chronic kidney disease. We aimed to characterize the prevalence and correlates of proteinuria in a cohort of HIV-infected and uninfected injection drug users. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cross-sectional analysis was performed among 902 injection drug users (273 HIV-infected) in the AIDS Linked to the Intravenous Experience cohort. The primary outcome was proteinuria defined as having a urine protein/creatinine concentration ratio >200 mg/g. Poisson regression with robust variance was used to determine prevalence ratios. RESULTS: Overall, 24.8% of participants had proteinuria; the prevalence was 2.9 times higher among HIV infected participants (45%) compared with HIV-uninfected participants (16%). In addition, age, health insurance, employment status, hepatitis B and C serostatus, diabetes, and high BP were associated with proteinuria. Neither antiretroviral therapy nor features of illicit drug use history were associated with proteinuria. In multivariate analysis, HIV infection, unemployment, increased age, diabetes, hepatitis C infection, and high BP were significantly associated with a higher prevalence of proteinuria. CONCLUSIONS: In an aging, predominantly African-American cohort of injection drug users, we found a striking burden of proteinuria that was strongly associated with HIV status. In addition to being a pathway to ESRD, proteinuria is a potent risk factor for cardiovascular morbidity and mortality. Evaluation of aggressive screening and disease-modification strategies in this high-risk population is warranted. PMID- 20705970 TI - Fast-rate formation of TiO2 nanotube arrays in an organic bath and their applications in photocatalysis. AB - In this work, 18.5 microm titanium oxide (TiO(2)) nanotube arrays were formed by the anodization of titanium (Ti) foil in ethylene glycol containing 1 wt% water and 5 wt% fluoride for 60 min at 60 V. The fast growth rate of the nanotube arrays at 308 nm min(-1) was achieved due to the excess fluoride content and the limited amount of water in ethylene glycol used for anodization. Limited water content and excess fluoride in ethylene glycol inhibited the formation of a thick barrier layer by increasing the dissolution rate at the bottom of the nanotubes. This eased the transport of titanium, fluorine and oxygen ions, and allowed the nanotubes to grow deep into the titanium foil. At the same time, the neutral condition offered a protective environment along the tube wall and pore mouth, which minimized lateral and top dissolution. Results from x-ray photoelectron spectra revealed that the TiO(2) nanotubes prepared in ethylene glycol contained Ti, oxygen (O) and carbon (C) after annealing. The photocatalytic activity of the nanotube arrays produced was evaluated by monitoring the degradation of methyl orange. Results indicate that a nanotube with an average diameter of 140 nm and an optimal tube length of 18.5 microm with a thin tube wall (20 nm) is the optimum structure required to achieve high photocatalytic reaction. In addition, the existence of carbon, high degree of anatase crystallinity, smooth wall and absence of fluorine enhanced the photocatalytic activity of the sample. PMID- 20705971 TI - The thermomutability of single-walled carbon nanotubes by constrained mechanical folding. AB - The thermomutability of single-walled carbon nanotubes (SWCNT) with an ultrahigh aspect ratio has been systematically investigated by molecular dynamics simulations. A constraining matrix is necessary to transform the tube-long Euler instability to a localized cross-section flattening which can effectively hinder phonon transportation at the throttling kinks. A thermal conductivity reduction of approximately 50% was obtained for a 100 nm (5, 5) SWCNT when embedded in a compliant matrix (E approximately 0.4 GPa). An even larger reduction (approximately 80%) can be achieved for a stiffer matrix (40 GPa). The thermal conductivity decreases abruptly at the buckling portion which further develops into folding and connected spirals. The constrained mechanical folding is highly desirable for realizing ultra-sensitive thermal sensors or switches. PMID- 20705972 TI - High-speed cycloid-scan atomic force microscopy. AB - A key hurdle in achieving high scan speeds in atomic force microscopes is that the probe is required to be scanned over the sample in a zig-zag raster pattern. The fast axis of the AFM scanner must track a signal that contains frequencies beyond its mechanical bandwidth. Consequently, fast raster scans generate distortions in the resulting image. We propose a smooth cycloid-like scan pattern that allows us to achieve scan speeds much higher than a raster scan. We illustrate how the proposed method can be implemented on a commercial AFM with minimal modifications. PMID- 20705973 TI - Controlled crystallinity and crystallographic orientation of Cu nanowires fabricated in ion-track templates. AB - The hallmark of materials science is the ability to tailor the structures of a given material to provide a desired response. In this work, the structures involving crystallinity and crystallographic orientation of Cu nanowires electrochemically fabricated in ion-track templates have been investigated as a function of fabrication condition. Both single crystalline and polycrystalline nanowires were obtained by adjusting applied voltages and temperatures of electrochemical deposition. The anti-Hall-Petch effect was experimentally evidenced in the polycrystalline nanowires. The dominant crystallographic orientations of wires along [111], [100], or [110] directions were obtained by selecting electrochemical deposition conditions, i.e., H(2)SO(4) concentration in electrolyte, applied voltage, and electrodeposition temperature. PMID- 20705974 TI - Remarkably enhanced photoluminescence of hexagonal GdPO4.nH2O:Eu with decreasing size. AB - The hexagonal rhabdophane-type GdPO(4) hydrate (GdPO(4).nH(2)O) was synthesized via a simple hydrothermal process. The size and morphology of the products can be tunable by adjusting the pH of reaction systems through the addition of aqueous NaOH. The nanorods with a width of 50-100 nm and a length of about 1 microm were obtained in the absence of NaOH (pH = 2), while a significant reduction of size (width: approximately 10 nm, length: approximately 50 nm) was observed for the product synthesized in the presence of NaOH (pH = 10). Surprisingly, the small sized product exhibits a remarkably enhanced photoluminescence quantum yield and long excited state lifetime in comparison with those of the large-sized product. This abnormal luminescence phenomenon is discussed and explained. The EDS and XPS measurements revealed the presence of Na(+) in the small-sized samples. These Na(+) cations were probably bonded to the surface O(2-) dangling bonds, which thus reduces the number of surface defects that usually serve as the nonradiative energy transfer center channels. A considerable reduction of surface defect centers results in the increase of the emission efficiency and excited state lifetime in a small-sized sample. Obviously, the controlled synthesis of rare earth-doped nanoparticles with a small size, but with relatively strong luminescence, is significant for their applications in the areas of technologies including optoelectronics, sensing and bioimaging. PMID- 20705975 TI - Health implications of lipopolysaccharide endotoxins in domestic container water used by rural households in South Africa. AB - This study assessed the occurrence of endotoxins, cyanobacteria and enterobacteria in untreated drinking water stored in domestic water containers by rural households in South Africa. Endotoxins, cyanobacteria, total coliforms and Escherichia coli were measured in the following numbers and ranges in container water samples: 4-54 microg l(-1), 69-64,505 cells ml(-1), 9,000-280,000 CFU/100 ml and 90-1,100 CFU/100 ml, respectively, in source water and 0.23-24.7 microg l( 1), 1-501,187 cells ml(-1), 25-1,584,893 CFU/100 ml and 1-25,118 CFU/100 ml, respectively, in water from containers. The concentrations of these contaminants in water often exceeded guidelines. Container type, especially those that permit light into the vessel, played a significant role in the occurrence of these contaminants. Limited guidelines, as well as the absence of health evidence, make it uncertain whether the high levels of endotoxins in the containerised drinking water could cause a health effect in healthy persons. Most importantly, in the context of exposure to endotoxins potentially derived from high levels of cyanobacteria and enterobacteria such as coliforms in the water, a case is made for possible health effects in immune-compromised individuals exposed to water containing endotoxins and the bacteria that potentially produce it. PMID- 20705977 TI - Using native riparian barriers to reduce Giardia in agricultural runoff to freshwater ecosystems. AB - Waterway degradation in agricultural settings is caused by direct and diffuse sources of pollution. Waterway fencing focuses on reducing direct faecal contamination, but the extent to which it reduces overland surface runoff of pathogens is unknown. This study evaluated the potential of four riparian treatments to reduce Giardia in saturation excess surface runoff entering the waterway. Treatment 1 comprised exotic pasture grass and weeds that regenerated from bare soil between the fence and the waterway in the absence of cattle grazing and was compared with three others comprising monocultural plantings of New Zealand native grassland plants. Runoff experiments involving Giardia were performed after planting, both prior to and following the summer growing season. Giardia was not detected from any plot prior to cyst addition. In spring the native 'C. secta', 'A. lessoniana' and 'C. richardii' treatments showed significantly greater reductions in Giardia in runoff than the 'exotic grasses' treatment, while in autumn the 'C. richardii' treatment reduced Giardia more than the 'exotic grasses/weeds'. A reduction in public health risk should follow from riparian vegetation, whether exotic or native, but with an added benefit in the case of the native tussock grass C. richardii, due to the associated lower runoff rate. PMID- 20705976 TI - A critical evaluation of two point-of-use water treatment technologies: can they provide water that meets WHO drinking water guidelines? AB - Point-of-use (POU) technologies have been proposed as solutions for meeting the Millennium Development Goal (MDG) for safe water. They reduce the risk of contamination between the water source and the home, by providing treatment at the household level. This study examined two POU technologies commonly used around the world: BioSand and ceramic filters. While the health benefits in terms of diarrhoeal disease reduction have been fairly well documented for both technologies, little research has focused on the ability of these technologies to treat other contaminants that pose health concerns, including the potential for formation of contaminants as a result of POU treatment. These technologies have not been rigorously tested to see if they meet World Health Organization (WHO) drinking water guidelines. A study was developed to evaluate POU BioSand and ceramic filters in terms of microbiological and chemical quality of the treated water. The following parameters were monitored on filters in rural Cambodia over a six-month period: iron, manganese, fluoride, nitrate, nitrite and Escherichia coli. The results revealed that these technologies are not capable of consistently meeting all of the WHO drinking water guidelines for these parameters. PMID- 20705978 TI - Managing waste from confined animal feeding operations in the United States: the need for sanitary reform. AB - Confined food-animal operations in the United States produce more than 40 times the amount of waste than human biosolids generated from US wastewater treatment plants. Unlike biosolids, which must meet regulatory standards for pathogen levels, vector attraction reduction and metal content, no treatment is required of waste from animal agriculture. This omission is of concern based on dramatic changes in livestock production over the past 50 years, which have resulted in large increases in animal waste and a high degree of geographic concentration of waste associated with the regional growth of industrial food-animal production. Regulatory measures have not kept pace with these changes. The purpose of this paper is to: 1) review trends that affect food-animal waste production in the United States, 2) assess risks associated with food-animal wastes, 3) contrast food-animal waste management practices to management practices for biosolids and 4) make recommendations based on existing and potential policy options to improve management of food-animal waste. PMID- 20705979 TI - Differences in water consumption choices in Canada: the role of socio demographics, experiences, and perceptions of health risks. AB - In 2000 and 2001 Canadians were shocked by water contamination events that took place in two provinces. In 2004 we undertook an internet-based survey across Canada that asked respondents to identify in percentage terms their total drinking water consumption according to one of three sources: tap water, bottled water, and home-filtered water (either some type of container or an in-tap filter device). In this paper we investigate the factors that influence these choices and whether choosing to either filter or purchase water is linked to perceptions of health concerns with respect to tap water. A series of one-way analysis of variance (ANOVA) tests suggest that the presence of children in a household and self-reported concern that tap water causes health problems lead to significantly greater consumption of bottled water or filtered water and significantly less tap water consumption. In order to examine these choices in a multivariate framework, we estimate a multinomial logit model. Factors yielding higher probabilities of a respondent being primarily a bottled water drinker (relative to the choice of tap water) include: higher income, unpleasant taste experiences with tap water, non French-speaking, and being a male with children in one's household. Similar factors yield higher probabilities of a respondent being primarily a filtered tap water drinker. An important finding is that two key variables linking a person's health perceptions regarding tap water quality are significant factors leading to the choice of either filtered tap water or bottled water over tap water. They are: a variable showing the degree of health concerns a respondent has with respect to tap water and a second variable indicating whether the respondent believes bottled water is safer than tap water. PMID- 20705980 TI - Water and hygiene interventions to reduce diarrhoea in rural Afghanistan: a randomized controlled study. AB - A randomized controlled trial of four interventions was conducted using tubewells (n=2,486), liquid sodium hypochlorite ('Clorin') distributed with an improved water vessel (n=2,305), hygiene promotion (n=1,877), and a combination of the three (n=2,040) to create an evidence-base for water policy in Afghanistan. A fifth group served as a control (n=2,377). Interventions were randomized across 32 villages in Wardak province. Outcomes were measured through two household surveys separated by one year and twice-weekly household surveillance conducted over 16 months. The households receiving all three interventions showed reduction in diarrhoea compared with the control group, through both longitudinal surveillance data (IRR [95% CI]=0.61 [0.47-0.81]) and cross-sectional survey data (AOR [95% CI]=0.53 [0.30-0.93]). This reduction was significant when all household members were included, but did not reach significance when only children under five were considered. These results suggest multi-barrier methods are necessary where there are many opportunities for water contamination. Surveillance data suggested a greater impact of interventions on reducing diarrhoeal diseases than data from the surveys. Higher economic status as measured through household assets was associated with lower rates of diarrhoea and greater intervention uptake, excepting Clorin. Use of soap was also associated with lower prevalence of diarrhoea. PMID- 20705981 TI - Dynamics of Aeromonas species isolated from wastewater treatment system. AB - Aeromonas are widely distributed in the aquatic environment, and are considered to be emerging organisms that can produce a series of virulence factors. The present study was carried out in a sanitary sewage stabilization pond treatment system, located in Lins, State of Sao Paulo, Brazil. Most probable number was applied for estimation of the genus Aeromonas. Colony isolation was carried out on blood agar ampicillin and confirmed by biochemical characterization. Aeromonas species were isolated in 72.4% of influent samples, and in 55.2 and 48.3% of effluent from anaerobic and facultative lagoons, respectively. Thirteen Aeromonas species were isolated, representing most of the recognized species of these organisms. Even though it was possible to observe a tendency of decrease, total elimination of these organisms from the studied system was not achieved. Understanding of the pathogenic organism's dynamics in wastewater treatment systems with a reuse potential is especially important because of the risk it represents. PMID- 20705982 TI - A preliminary Ames fluctuation assay assessment of the genotoxicity of drinking water that has been solar disinfected in polyethylene terephthalate (PET) bottles. AB - Though microbially safe, concerns have been raised about the genotoxic/mutagenic quality of solar-disinfected drinking water, which might be compromised as a result of photodegradation of polyethylene terephthalate (PET) bottles used as SODIS reactors. This study assessed genotoxic risk associated with the possible release of genotoxic compounds into water from PET bottles during SODIS, using the Ames fluctuation test. Negative genotoxicity results were obtained for water samples that had been in PET bottles and exposed to normal SODIS conditions (strong natural sunlight) over 6 months. Under SODIS conditions, bottles were exposed to 6 h of sunlight, followed by overnight room temperature storage. They were then emptied and refilled the following day and exposed to sunlight again. Genotoxicity was detected after 2 months in water stored in PET bottles and exposed continuously (without refilling) to sunlight for a period ranging from 1 to 6 months. However, similar genotoxicity results were also observed for the dark control (without refill) samples at the same time-point and in no other samples after that time; therefore it is unlikely that this genotoxicity event is related to solar exposure. PMID- 20705983 TI - Alternatives for safe water provision in urban and peri-urban slums. AB - In response to rapid urbanization throughout the global South, urban and peri urban slums are expanding at an alarming rate. Owing to inadequate financial and institutional resources at the municipal level, conventional approaches for safe water provision with centralized treatment and distribution infrastructure have been unable to keep pace with rapidly growing demand. In the absence of alternatives to centralized systems, a global public health emergency of infectious water-related diseases has developed. Alternative decentralized water treatment systems have been promoted in recent years as a means of achieving rapid health gains among vulnerable populations. Though much work with decentralized systems, especially in urban environments, has been at the household level, there is also considerable potential for development at the community level. Both levels of approach have unique sets of advantages and disadvantages that, just as with treatment technologies, may make certain options more appropriate than others in a particular setting. Integrating community, government and other relevant stakeholders into the process of systems development and implementation is essential if the outcome is to be appropriate to local circumstances and sustainable in the long term. PMID- 20705984 TI - Drinking water incidents due to chemical contamination in England and Wales, 2006 2008. AB - Contamination of drinking water by microbiological and chemical agents can lead to adverse health effects. In England and Wales, the Chemicals Hazards and Poisons Division (CHaPD) of the Health Protection Agency provides expert advice on the consequences to public health of chemical contamination incidents affecting drinking water. In this study, we extracted data from the National Database on the type and nature of drinking water contamination events reported to the CHaPD between 2006 and 2008. Eighty-two incidents with confirmed chemical contamination were identified. Among the 70 incidents where data was available, 40% (28/70) of incidents related to contamination of drinking water provided by private suppliers, 31% (22/70) were due to contamination occurring close to the point of consumption (i.e. near consumer) and 29% (20/70) related to incidents where public water supplies were identified as the contaminated source. For the majority of incidents, little or no information was available on the critical exposure variables such as duration of contamination and actual or estimates of the population affected. Reassuringly, the levels of exposure in most incidents were considered unlikely to cause serious immediate or long term ill health effects. Recording of exposure data for reported contamination incidents needs to be improved. PMID- 20705985 TI - 'Hom': a simple point of use water treatment device. AB - This study sought to explore a locally assembled 'Hom' point of use water treatment device by assessing aspects of its performance and possible effects of using it on compliant households and communities. The conceptual framework highlights poverty and environmental degradation as causes and consequences of one another, with ill-health caused by water-borne diseases reinforcing both to form a cycle. Whether or not the device would play a role in interrupting this cycle depends on its capabilities and acceptance, among other factors. Survey results indicated that the device is acceptable to 84% of respondents. Analysed data collected using questionnaires from 60 randomly sampled pilot device users revealed that it is useful to its users. Yield trials results led to the conclusion that one device unit could provide enough drinking water to satisfy the needs of a large representative household. Laboratory tests of water samples filtered with cartridges used for up to 10 years in the device found the water to be safe for drinking. It is concluded that the device is effective, environmentally friendly and useful to compliant households. PMID- 20705986 TI - Catchment process affecting drinking water quality, including the significance of rainfall events, using factor analysis and event mean concentrations. AB - To ensure the protection of drinking water an understanding of the catchment processes which can affect water quality is important as it enables targeted catchment management actions to be implemented. In this study factor analysis (FA) and comparing event mean concentrations (EMCs) with baseline values were techniques used to asses the relationships between water quality parameters and linking those parameters to processes within an agricultural drinking water catchment. FA found that 55% of the variance in the water quality data could be explained by the first factor, which was dominated by parameters usually associated with erosion. Inclusion of pathogenic indicators in an additional FA showed that Enterococcus and Clostridium perfringens (C. perfringens) were also related to the erosion factor. Analysis of the EMCs found that most parameters were significantly higher during periods of rainfall runoff. This study shows that the most dominant processes in an agricultural catchment are surface runoff and erosion. It also shows that it is these processes which mobilise pathogenic indicators and are therefore most likely to influence the transport of pathogens. Catchment management efforts need to focus on reducing the effect of these processes on water quality. PMID- 20705987 TI - Relationship (or its lack) between population and a water and sanitation service: a study of users' perception in Vitoria (ES) Brazil. AB - The objective of this paper is to identify and analyse the perception of groups of dwellers of Vitoria, Espirito Santo, Brazil, regarding their relationship with the water and sanitation service and aspects of water handling. Participants living in four distinct urban districts of the capital city were interviewed in their own houses and the Discourse of the Collective Subject approach was employed to order the data so obtained. The testimonies revealed the health risk to which individuals were exposed by virtue of: (i) inadequate knowledge concerning the water supply offered, (ii) lack of stimulus to exert their citizens' rights and obligations in relation to the water provided for their consumption and (iii) poor channels of communication between the community, the water and sanitation service and the local public health authority. The study concluded that there is a need to rethink the forms of information provided to the population that are presently adopted by these institutions. PMID- 20705988 TI - Health gains from solar water disinfection (SODIS): evaluation of a water quality intervention in Yaounde, Cameroon. AB - In developing countries, the burden of diarrhoea is still enormous. One way to reduce transmission of pathogens is by water quality interventions. Solar water disinfection (SODIS) is a low-cost and simple method to improve drinking water quality on household level. This paper evaluates the implementation of SODIS in slum areas of Yaounde, Cameroon. Promoters trained 2,911 households in the use of SODIS. Two surveys with randomly selected households were conducted before (N=2,193) and after (N=783) the intervention. Using a questionnaire, interviewers collected information on the health status of children under five, on liquid consumption, hygiene and other issues. Prior to the intervention, diarrhoea prevalence amounted to 34.3% among children. After the intervention, it remained stable in the control group (31.8%) but dropped to 22.8% in the intervention group. Households fully complying with the intervention exhibited even less diarrhoea prevalence (18.3%) and diarrhoea risk could be reduced by 42.5%. Multivariate analyses revealed that the intervention effects are also observed when other diarrhoea risk factors, such as hygiene and cleanliness of household surroundings, are considered. According to the data, adoption of the method was associated with marital status. Findings suggest health benefits from SODIS use. Further promotional activities in low-income settings are recommended. PMID- 20705989 TI - Relationships between the occurrence of Giardia and Cryptosporidium and physicochemical properties of marine waters of the Pacific Coast of Mexico. AB - Untreated sewage has adversely affected the quality of marine recreational waters worldwide. Exposure to marine recreational water with poor microbial quality may pose a threat to bathers. The objectives of this study were to assess the effect of physicochemical parameters on Cryptosporidium and Giardia presence in marine recreational water of Sinaloa, Mexico, by Logistic Regression Analyses. Thirty two 10-litre water samples were collected from two tourist beaches, Altata and Mazatlan, between November 2006 and May 2007. Water samples were processed by the EPA 1623 method and pH, temperature, salinity and turbidity were also determined. Cryptosporidium and Giardia were present in 71 and 57% of the samples collected from Altata, respectively. In Mazatlan, Cryptosporidium and Giardia were found in 83 and 72% of the samples, respectively. The overall concentration of Cryptosporidium ranged from 150 to 2,050 oocysts/10 L with an average of 581 oocysts/10 L and Giardia ranged from 10 to 300 cysts/10 L with an average of 73 cysts/10 L. The occurrence of both parasites increased in water with decreasing temperatures and increasing turbidity of the water. PMID- 20705990 TI - Nitrification, denitrification and ammonification in point-of-use biosand filters in rural Cambodia. AB - In order to address the United Nations Millennium Development Goal (MDG) target #7 for water and sanitation, the World Health Organization (WHO) has identified point-of-use (POU) water treatment technologies as an option for providing safe water to households. The BioSand filter (BSF) is a commonly used POU system that has been implemented in Cambodia and over 20 countries worldwide. While the health benefits of using a BSF in terms of reduction of diarrheal disease have been fairly well documented, little research has focused on the ability of this technology to treat for other contaminants that could pose health concerns. To address these concerns, a study was developed to evaluate this technology in rural Cambodia in terms of microbiological and chemical quality of the treated water. The study revealed that simultaneous nitrification and denitrification is occurring inside the BioSand filters. Nitrite concentrations in treated water consistently exceeded WHO guidelines. Seventeen of 20 filters on average did not meet the 3.0 mg l(-1) NO2- guideline and the combined nitrate-nitrite guideline ratio of 1. Denitrification seemed to predominate when BSFs were fed surface water. In addition, nitrate-ammonification occurred in some filters fed surface water, causing increases in ammonia in treated water. PMID- 20705991 TI - Elevated and variable groundwater iron in rural northwestern Bangladesh. AB - Over the past 30 years, tubewells have become a ubiquitous source of potable groundwater in South Asia. Considered safer than surface water, groundwater naturally contains minerals that may impact human health; however, few data exist on tubewell water mineral content or its association with human nutritional or health conditions. We surveyed iron concentration in tubewell water across a 435 km2, contiguous, rural area in northwestern Bangladesh to map and quantify levels of iron in drinking water. One tubewell was randomly sampled from each of 948 adjacent grid cells 675 m2 in size. Water sampling was standardized and iron concentration measured using a field-based colorimetric kit. The median (interquartile range) concentration of iron in tubewell water was 7.6 (1.6, 17.6) mg l(-1). There was high geographic variation (range of 0-46.5 mg l(-1)), and iron in only 3% of surveyed tubewells fell below the WHO aesthetic cut-off of 0.3 mg l(-1) suggesting elevated levels of iron throughout the area. Villagers accurately perceived groundwater iron concentration, based on a 4-point ('none', 'a little', 'medium', 'a lot') scale (p<0.001). Water source iron content can be readily quantified in population settings offering the potential to evaluate the health relevance of groundwater iron exposure in rural communities. PMID- 20705992 TI - Homemade bone charcoal adsorbent for defluoridation of groundwater in Thailand. AB - High levels of fluoride in groundwater are a significant environmental and health problem in Thailand, as in many parts of the world. Small household defluoridators have several advantages over centralized treatment systems. In Thailand, however, use of bone char for water treatment has met resistance because of objectionable taste and odours of the water produced and the social resistance to handling fresh bone. This paper presents a method that uses bone charcoal as an absorbent for removing fluoride from groundwater. The commercially provided boiled bone is burned in a simple homemade furnace that can be constructed, operated and maintained easily by small rural householders. The method to produce the Thai bone char eliminates the odour and objectionable taste and also does not require the user to handle fresh bone, thus eliminating the social resistance. To evaluate the efficacy of the absorbent, batch experiments compare Thai and Indian bone char. Sorption isotherms are fit to the Freundlich and Langmuir equations and the kinetics are modelled using the pseudo first-order Lagergren equation. Results show that the sorption characteristics of Thai bone char compare favourably with the Indian bone char, with approximately 80% of the fluoride removed in both cases. PMID- 20705994 TI - Oxidative degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) in subcritical and supercritical waters. AB - Presence of chlorinated organic compounds in water bodies has become a concern among governments, health authorities and general public. Oxidation of organic compounds in water under high temperature and pressure is considered as a promising technique, but usefulness of the technique to mineralize 2,4 dichlorophenoxyacetic acid (2,4-D) is not well understood. This article aimed to elucidate degradation characteristics of 2,4-D in both subcritical and supercritical waters by laboratory batch experiments. 2,4-D degradation, total organic carbon (TOC) removal and dechlorination increased with increasing reaction time and temperature especially in subcritical waters, while dechlorination was a major step. 2,4-dichlorophenol (2,4-DCP) and acetic acid were the main degradation intermediates both in subcritical and supercritical waters. Though 2,4-D disappeared almost completely in subcritical waters near critical region ( approximately 99%), significant amounts of TOC and organic chlorine still remained as 2,4-DCP and acetic acid. But TOC removal and dechlorination were significantly enhanced ( approximately 95 and 91% respectively) in supercritical waters. Complete mineralization of 2,4-D in subcritical waters required a considerably longer reaction period, while the mineralization was almost complete within a short reaction period in supercritical waters. This is an important information of practical significance for oxidative degradation of chlorinated pesticides similar to 2,4-D. PMID- 20705993 TI - Statistical modelling of the impact of some polyphenols on the efficiency of anaerobic digestion and the co-digestion of the wine distillery wastewater with dairy cattle manure and cheese whey. AB - The objective of this study was to determine the effectiveness of anaerobic digestion in the treatment of polyphenols (PP) present in olive mill wastewater (OMW) and wine distillery wastewater (WDW). Anaerobic Toxicity Assay (ATA) was conducted to assess the impact of the most representative phenolic compounds present in OMW and WDW: catechol, tannins and p-Coumaric acid, on biogas production. The results from this study show that tannins do not present any inhibitory effect on methanogenesis at a concentration level of 1,664 ppm, whereas catechol has an inhibitory effect at 1,664 ppm. In addition, p-Coumaric acid was strongly inhibitory at 50 ppm. The co-digestion of OMW and WDW with other effluents was proposed as a solution for reducing the load of PP in the anaerobic medium. Biochemical methane potential (BMP) tests were carried out for dairy cattle manure and mixtures of five PP. A central composite design was implemented on the BMP tests to model the biogas production response and the degradation kinetics of PP. The co-digestion of WDW with cattle manure and/or whey was also investigated in BMP tests. The results show that the digestion was optimal at a ratio of 16: 64: 20 (WDW: manure: inoculum) with a maximum biogas yield of 172 mL/g of VS and 66% COD removal. PMID- 20705995 TI - DOC and UVA attenuation with soil aquifer treatment in the saturated zone of an artificial coastal sandfill. AB - Results from a direct recharge experiment conducted in the field to investigate DOC and UVA(254) attenuation rates during the direct injection of UF treated wastewater into a artificial coastal sandfill are presented in this paper. Approximately 500 m(3) of ultra-filtered wastewater was injected into the saturated zone, over a period of 9 days. The movement of the plume was tracked over 80 days, during which time samples were obtained from multilevel samplers installed in transects across the drift axis of the plume. An analysis of fluorescein in the samples obtained during the drift of the UF plume showed that DOC and UVA were attenuated beyond rates predicted by conservative mixing, by up to a maximum of 45%. A degradation coefficient of 0.0175 day(-1) was found to be applicable for DOC degradation. After a drift period of 80 days, DOC and UVA reduced to approximately 4.5 mg/l and 0.100 cm(-1), respectively, from initial values of 8.06 mg/l and 0.199 cm(-1). PMID- 20705996 TI - The potential to improve water quality in the middle Rio Grande through effective wetland restoration. AB - The Rio Grande, which forms the United States-Mexico border for much of its course, receives diverse pollutants from both urban and agricultural areas, most notably in the sister cities of El Paso (TX, USA)-Ciudad Juarez (CHI, Mexico). This study aimed to describe regional trends in water quality in waters near the El Paso-Ciudad Juarez metroplex and to examine the potential for water quality improvement through the use of a created wetland. Very few differences in nutrient chemistry were found among drains, canals and the Rio Grande, with the exception of elevated chloride and lower phosphorus levels found in the drains. Overall, chloride concentrations increased with distance downstream, likely due to concentration of salts via evaporation from irrigated agriculture. A wastewater treatment plant (WWTP) contributed substantially to total phosphorus and nitrate levels, which, together with ammonia, tended to exceed state criteria for water quality downstream of the WWTP outflow. The created Rio Bosque wetlands reduced nitrate concentrations in the water, possibly via denitrification enhanced by algae; algae increased in biomass as water flowed through the wetlands. However, the diversion of water for irrigated agriculture, resulting in the absence of water, and thus aquatic plants, in the wetland in the summer has limited the ability of this wetland to improve regional water quality. PMID- 20705997 TI - 2009 Melbourne metropolitan sewerage strategy: a portfolio of decentralised and on-site concept designs. AB - The bulk and retail water companies of the greater Melbourne area are developing the 2009 Metropolitan Sewerage Strategy to provide sustainable sewerage services to 2060. The objective of the strategy is to establish long term principles and near term actions to produce a robust sewage management system for Melbourne. Melbourne's existing sewerage system is largely centralised and discharges to two major treatment plants. Several small satellite treatment plants service local urban areas generally more distant from the centralised system. Decentralised and on-site wastewater systems are options for future sewage management and could play a role in local recycling. A portfolio of 18 on-site and decentralised concept designs was developed, applicable to the full range of urban development types in Melbourne. The concepts can be used in evaluation of metropolitan system configurations as part of future integrated water cycle planning. The options included secondary and tertiary treatment systems incorporating re-use of water for non potable uses, urine separation, black and greywater separation and composting toilets. On-site and cluster treatment systems were analysed. Each option is described by its indicative capital and operating costs, energy use and water and nutrient balances. This paper summarises and compares the portfolio mix of decentralized and on-site options in Melbourne's context. PMID- 20705998 TI - Performance and quality analysis of membrane cartridges used in long-term operation. AB - In this study, operation and maintenance performance in two long-term operating Membrane Bioreactor (MBR) wastewater treatment facilities were investigated. One facility in Japan started its operation in 1999 showed that both effluent BOD and n-hexane extracts were less than 5 mg/L, and a cumulative replacement percentage (CR%) of membrane cartridges was 7.8% as of 2008. Another facility in the United Kingdom (UK) started its operation in 1998 showed that average effluent BOD was less than 5 mg/L and more than 5-log removal of faecal coliforms was maintained. The CR% was 6.4% as of 2008. Amongst 95 facilities in Europe, the CR% was 6.4% after 5-year operation. In order to inspect product quality of membrane cartridges after 10-year operation in the UK facility, clean water flow (CWF) rate and pore size distribution were measured. The CWF rate was approximately 100% of that of new membrane cartridge's, and the pore size distribution was well maintained at less than 0.46 microm. A microscopic observation showed some scratches on the membrane surface. However, they did not lead to deteriorate permeate quality. These data suggested that the membrane cartridges can be used as long as 10 years. PMID- 20705999 TI - Immobilisation of TiO2 for combined photocatalytic-biological azo dye degradation. AB - The biodegradability of the azo dye Remazol Red RR (100 mg/l) was evaluated using unadapted activated sludge and the experiment confirmed the recalcitrance of the dye. Using a combination of photocatalysis and an aerobic biological step, the biodegradability was improved significantly and complete removal of both colour and COD were achieved. Furthermore, TiO2 was successfully immobilised on borosilicate glass slides by calcination, which facilitates reuse of the catalyst. The catalytic activity of the immobilised TiO2 was close to that of suspended TiO2. A reduced activity was however observed when the TiO2 slides were used repeatedly. When comparing NaOH, calcination and UV irradiation for regeneration of the TiO2 slides, immersion in NaOH was shown to be the most efficient method. PMID- 20706000 TI - Analysis of hydrocyclone behaviors in the separation of particulates from highway rainfall runoff. AB - In this study, the separation behaviors of particles in highway rainfall runoff using a O7.5 cm hydrocyclone were examined. The volume fraction and the total suspended solids concentrations in the overflow and underflow from the hydrocyclone were analyzed. The results indicated that the overflow volume fraction increased with increasing operational pressure, but decreased with decreasing ratio of underflow outlet to inlet sizes (D(u)/D(i)), while the underflow volume fraction showed contrary behavior. The TSS concentration ratio between the overflow and inflow (TSS(over)/TSS(in)) decreased as a function of the operational pressure, while the corresponding ratio of underflow to inflow (TSS(under)/TSS(in)) increased. There was no visible difference in the TSS(over)/TSS(in) ratio with increasing D(u)/D(i) ratio but the TSS(under)/TSS(in) decreased sharply. The particle removal efficiency was affected mainly by the particle size. The hydrocyclone can work well using 1.6 m natural water head, and it is more space saving and more efficient in the separation of fine particles than the sedimentation method. PMID- 20706001 TI - Mathematical models for biomass in membrane-BNR process for wastewater treatment. AB - The equation of biomass is related to the mass-balance equation of substrate. This equation of substrate is expressed according to a model using the Monod equation, which indicates some limits for calculating the amounts of VSS in the MBR process. Some degradation of biomass which is caused by long SRT might result in the generation of substrate based on COD. Research was conducted by lab-scale tests with two membrane-BNR (Biological Nutrients Removal) processes. These were composed of multi-reactors as anaerobic, anoxic, aerobic tank and oxygen exhauster. The aerobic tank was also divided into 3 reactors, which were oxic for nitrification, oxic-media containing fluidized sponge typed media for simultaneous nitrification and denitrification, and oxic-membrane for submerged membrane. This membrane-BNR process could remove most of the organics, suspended solids and nutrient substances like nitrogen thus satisfying the reuse guidelines issued by the Korean Ministry of Environment. The value measured of VSS (X(v)) through the experiment with SRT of 35 days was similar to the biomass using the conventional equation while the one with SRT of 60 days was close to the concentration of VSS calculated by a revised equation which considered the biomass degraded with long SRT. PMID- 20706002 TI - The removal of disinfection by-product precursors from water with ceramic membranes. AB - The main objective of this work was to investigate the effectiveness of ceramic ultrafiltration (UF) membranes with different pore sizes in removing natural organic matter (NOM) from model solutions and drinking water sources. A lab scale, cross-flow ceramic membrane test unit was used in all experiments. Two different single-channel tubular ceramic membrane modules were tested with average pore sizes of 4 and 10 nm. The impacts of membrane pore size and pressure on permeate flux and the removals of UV(280 nm) absorbance, specific UV absorbance (SUVA(280 nm)), and dissolved organic carbon (DOC) were determined. Prior to experiments with model solutions and raw waters, clean water flux tests were conducted. UV(280) absorbance reductions ranged between 63 and 83% for all pressures and membranes tested in the raw water. More than 90% of UV(280) absorbance reduction was consistently achieved with both membranes in the model NOM solutions. Such high UV absorbance reductions are advantageous due to the fact that UV absorbing sites of NOM are known to be one of the major precursors to disinfection by-products (DBP) such as trihalomethanes and haloacetic acids. For both UF membranes, the ranges of DOC removals in the raw water and model NOM solutions were 55-73% and 79-91%, respectively. SUVA(280) value of the raw water decreased from 2 to about 1.5 L/mg-m by both membranes. For the model solutions, SUVA(280) values were consistently reduced to < or =1 L/mg-m levels after membrane treatment. As the SUVA(280) value of the NOM source increased, the extent of SUVA(280) reduction and DOC removal by the tested ceramic UF membranes also increased. The results overall indicated that ceramic UF membranes, especially the one with 4 nm average pore size, appear to be effective in removing organic matter and DBP precursors from drinking water sources with relatively high and sustainable permeate flux values. PMID- 20706003 TI - Optimal groundwater contamination monitoring using pumping wells. AB - This study presents a new method for selecting monitoring wells for optimal evaluation of groundwater quality. The basic approach of this work is motivated by difficulties in interpolating groundwater quality from information collected for only few sampled wells. The well selection relies on other existing data relevant to contaminant distribution in the sampling domain, e.g. predictions of models which rely on past measurements. The objective of this study is to develop a method of selecting the optimal wells, from which measurements could best serve some external model, e.g. a kriging system for characterizing the entire plume distribution, a flow-and-transport model for predicting a future distribution, or an inverse model for locating contaminant sources or estimating aquifer parameters. The decision variable at each sampling round determines the specific wells to be sampled. The study objective is accomplished through a spatially continuous utility density function (UDF) which describes the utility of sampling at every point. The entire methodology which utilizes the UDF in conjunction with a sampling algorithm is entitled the UDF method. By applying calculations in steady and unsteady state sampling domains the effectiveness of the UDF method is demonstrated. PMID- 20706004 TI - Sustainable sewerage servicing options for peri-urban areas with failing septic systems. AB - The provision of water and wastewater services to peri-urban areas faces very different challenges to providing services to cities. Sustainable solutions for such areas are increasingly being sought, in order to solve the environmental and health risks posed by failing septic systems. These solutions should have the capability to reduce potable water demand, provide fit for purpose reuse options, and minimise impacts on the local and global environment. A methodology for the selection of sustainable sewerage servicing systems and technologies is presented in this paper. This paper describes the outcomes of applying this methodology to a case study in rural community near Melbourne, Australia, and describes the economic and environmental implications of various sewerage servicing options. Applying this methodology has found that it is possible to deliver environmental improvements at a lower community cost, by choosing servicing configurations not historically used by urban water utilities. The selected solution is currently being implemented, with the aim being to generate further transferable learnings for the water industry. PMID- 20706005 TI - Application of mussels as biosamplers for characterization of faecal pollution in coastal recreational waters. AB - Sources of faecal pollution in coastal recreational waters may be identified by analysing different host associated microorganisms or molecular markers. However, the microbial targets are often present at low numbers in moderately impacted waters, and often exhibit significant temporal and spatial variability in waters with fluctuating faecal loads. This patchy occurrence can limit successful detection of relevant targets in microbial source tracking studies. In this study, we explored the possibility for using the blue mussel (Mytilus edulis) as a biosampler for accumulation of faecal bacteria relevant for microbial source tracking. Non-contaminated blue mussels were transferred to three coastal recreational waters affected by faecal pollution of unknown origin. Molecular markers associated with animal and human waste were targeted by PCR and compared in seawater and mussel samples. The results demonstrated that transplanted mussels in simple enclosures accumulated and retained elevated levels of molecular markers associated with different types of faecal pollution. The targets included a novel putative human associated E. coli subgroup B2 VIII clone, and animal and human associated markers in enterococci (esp, M19, M66, M90, and M91). Human (sewage) associated markers including esp and M66 were sometimes not detectable in seawater samples despite known wastewater contamination, whereas the markers were detectable in mussels. We suggest that transplanted mussels should be considered as potential biosamplers in studies focusing on identifying source of faecal pollution in low or moderately impacted recreational waters. Bioaccumulation of molecular markers in mussels for several days may represent the water quality better than traditional grab samples from the water column. PMID- 20706006 TI - Province-based self-remediation efficiency of the Tha Chin river basin, Thailand. AB - The Tha Chin River Basin located in the great central basin of Thailand is used for water supply, aquaculture, transportation, and recreation as well as a sink for wastewater discharges. Because of gradual deterioration of water quality and fishery resources, this study aimed to explain recent status of the river self remediation efficiency that was influenced by nutrient inputs and outputs from the river system. Field surveys were carried out during May 2007 (early rainy season) and October 2007 (late rainy season) within the Tha Chin River located in 4 provinces; Chainat, Suphan Buri, Nakhon Pathom, and Samut Sakhon. The nutrient budgets in each province section were analyzed. Results indicated that the river was in eutrophic condition all year round. High nitrogen and phosphorus loads from surrounding agricultural land use, agro-industry, and community continuously flew into the river system. Those nutrient concentrations were higher in the early rainy season than the late rainy season. The lowest river zone (in Samut Sakhon province) indicated highest dissolved inorganic nitrogen (DIN) and orthophosphate phosphorus (P) discharges of 145.54 and 36.14 tons/day, respectively. The highest remediation efficiency of the river (ca 60% of the total input) was found in the uppermost area of Suphan Buri province. The lowest remediation efficiency (ca 12%) was found in Samut Sakhon province. From the overall view, long term monitoring of river and estuarine DIN and P should be conducted. To make better condition of aquatic environment and fishery resource in each province-based section, the controls of DIN and P remediation efficiencies (e.g. by effective management of flow speed) at 20 and 50%, respectively, were recommended. PMID- 20706007 TI - On-site treatment of domestic wastewater using a small-scale horizontal subsurface flow constructed wetland. AB - A small-scale horizontal subsurface flow constructed wetland, located in North Greece, was designed and constructed to treat wastewater from a single-family residence. A three-year monitoring program was undertaken to evaluate the performance of this system. The monitoring campaigns were organized every 7 days. Water quality samples were collected at the inlet, at intermediate points (i.e. at the end of each treatment stage) and at the outlet of the system. Temperature, electrical conductivity, pH and DO were measured in-situ with the use of appropriate instruments at the same points of water sample collection. Water samples were analyzed for BOD, COD, TKN, ammonia, nitrate, nitrite, total phosphorus (TP), ortho-phosphate (OP), total suspended solids (TSS) and total coliforms (TC). Mean removal efficiencies for the monitoring period were: 86.5% for BOD, 84.6% for COD, 83.7% for TKN, 82.2% for ammonia, 63.1% for OP, 63.3% for TP, 79.3% for TSS and 99.9% for TC. Furthermore, based on statistical testing, TKN, ammonia and TP removal efficiencies showed dependence on temperature. The paper presents facility description, study details and monitoring results. The study shows that the use of constructed wetlands in wastewater treatment is a good option for single-family residences in rural areas. PMID- 20706008 TI - Performance of pervious pavement parking bays storing rainwater in the north of Spain. AB - Pervious pavements are drainage techniques that improve urban water management in a sustainable manner. An experimental pervious pavement parking area has been constructed in the north of Spain (Santander), with the aim of harvesting good quality rainwater. Forty-five pervious pavement structures have been designed and constructed to measure stored water quantity and quality simultaneously. Ten of these structures are specifically constructed with different geotextile layers for improving water storage within the pavements. Following the confirmation in previous laboratory experiments that the geotextile influenced on water storage, two different geosynthetics (Inbitex and a One Way evaporation control membrane) and control pervious pavements with no geotextile layers were tested in the field. Weather conditions were monitored in order to find correlations with the water storage within the pervious pavement models tested. During one year of monitoring the three different pervious pavement types tested remained at their maximum storage capacity. The heavy rain events which occurred during the experimental period caused evaporation rates within the pervious pavements to be not significant, but allowed the researchers to observe certain trends in the water storage. Temperature was the most closely correlated weather factor with the level of the water stored within the pervious pavements tested. PMID- 20706009 TI - Dynamic stormwater treatment unit model for micropollutants (STUMP) based on substance inherent properties. AB - Modelling the removal of micropollutants (MPs) in stormwater treatment systems is essential in a context that is characterized by a general lack of measurements. This paper presents an innovative dynamic model for the prediction of the removal of MPs in stormwater treatment systems (Stormwater Treatment Unit model for Micro Pollutants--STUMP). The model, based on a conceptual model of two-compartment (water and sediment) serial Continuous Stirred-Tank Reactors (CSTRs), can predict the fate of MPs based on their inherent properties, which are often the only information available regarding this kind of substances. The flexible structure of the model can be applied to a wide range of treatment units and substances. Based on the most relevant removal processes (settling, volatilization, sorption, biodegradation, and abiotic degradation), the model allows the dynamic simulation of the MP behaviour in the different compartments of stormwater treatment systems. The model was tested for heavy metals (copper and zinc) and organic substances (benzene and di(2-ethylhexyl)phthalate). The results show that volatilization plays a big role for removal of benzene while the removal of substances with high sorption capacity is mainly driven by settling. The model was proven to be able to predict the importance of the various fate processes for selected substances with different inherent properties. A thorough assessment of the influence of the various fate process parameters will allow a reliable assessment of the treatment performances for a wide range of MPs. PMID- 20706010 TI - Biodegradable organic matter in domestic wastewaters: comparison of selected fractionation techniques. AB - The first objective of this work was to evaluate the ability of the long-term BOD tests to provide the total biodegradable COD (BCOD) for domestic wastewaters. Results show that the method is repeatable (using two different volume samples, 97 and 164 mL) and that the fractions of BCOD determined were not statistically different from the one obtained by respirometry (at low S/X ratio). Respirometric tests were also repeatable. They were shown to be sensitive to the origin of the sludge. The results obtained are in the range of literature data. But they later indicated that long-term bioassays (>20 days) give higher biodegradable fractions than the other methods (BOD and respirometry). The second objective was to compare soluble fractions obtained with raw and pre-flocculated samples. Flocculated filtered COD is significantly lower than filtered COD, even if a pore size of 0.1 microm is used. The comparison to literature values shows that physicochemical RBCOD fractions are significantly higher than the ones obtained using bioassays. Comparison with the fractions used in calibrated models would help the choice of the more suitable method for modelling purposes. PMID- 20706011 TI - Estimating the costs of collective treatment of wastewater: the case of Walloon Region (Belgium). AB - This paper contributes to a better understanding of costs for collective wastewater treatment in the Walloon Region (Belgium). Based on a large set of data, unit costs to population equivalents are modelled. Considering investment as well as exploitation costs, the model includes not only wastewater treatment plants but also collector and sewage networks in an integrated approach at the technical basin level. Beyond this modelling, each type of process is analyzed independently in order to explore the structure of investment costs and their variation factors. Then, the model was used to forecast the upcoming expenses for 36 areas which are not yet equipped with collective wastewater treatment facilities. In light of these results, strategic choices for decision makers are discussed. PMID- 20706012 TI - Ozonation of estrogenic chemicals in biologically treated sewage. AB - The present study shows that ozonation of effluents from municipal wastewater treatment plants (WWTPs) is likely to be a future treatment solution to remove estrogens and xeno-estrogens. The required ozone dose and electrical energy for producing the ozone were determined in two WWTP effluents for removal of 17 estrogenic chemicals. The estrogenic compounds included parabens, industrial phenols, sunscreen chemicals, and steroid estrogens. The obtained values of Electrical Energy per Order (EEOs) for the treatment of the estrogens were in the range 0.14-1.1 kWh/m(3) corresponding to 1.7-14 g O3/m(3). It is furthermore suggested that UV-absorbance is a useful parameter for online control of the ozone dose in a full scale application since the absorbance of the WWTP effluents and the remaining concentration of the estrogens and xeno-estrogens correlated well with the applied ozone dose. PMID- 20706013 TI - Recovery of proteins from wastewater of tannery beamhouse operations: influence on the main pollution parameters. AB - The recovery of proteins from effluents of beamhouse operations in a hair-pulping process of hides is proposed. Precipitation with sulphuric acid at the isoelectric pH was chosen for protein recovery. The precipitates were characterized in order to study their potential uses. Apart from the protein nitrogen, the precipitate also contained a considerable content of fats resulting from the co-precipitation of natural fat of the hide in the wastewaters. The precipitation of the protein fraction resulted in a reduction of 80-85% of COD, whereas the protein content decreased 68-78%. This diminution of the contamination load led to a notable reduction of the tax on wastewater. The content of protein material in the precipitate varied from 15 to 44%. As expected, the protein in the precipitate did not result from the collagen decomposition of the hide but from soluble proteins such as albumin and globulin and remains of keratin. The precipitates obtained met the maximum limits of heavy metals according to legislation on organic fertilizers. The potential uses of the protein fraction recovered from tannery wastewaters are currently being investigated. PMID- 20706014 TI - Solid-phase extraction and gas chromatography-tandem mass spectrometry method for the simultaneous determination of several pesticides in water. AB - Contamination of surface and groundwater sources with pesticide residues has been of great concern for a long time and it is a major challenge for the preservation and sustainability of the environment. In order to accomplish the requirements of the European Directive 98/83/EC, we developed and validated an analytical method based on the combination of gas chromatography and tandem quadrupole mass spectrometry (GC-MS/MS) using solid-phase extraction as sample preparation. In this work nine pesticides were studied: molinate, simazine, atrazine, terbuthylazine, diazinon, alachlor, metalaxyl, metolachlor and pendimethalin. In order to get the best sensitivity and selectivity for each pesticide, several parameters of the tandem mass spectrometry were optimized using the MRM mode. Good linearity of the detector response was found for all pesticides at concentrations within the tested working range, with linear determination coefficients higher than 0.9988. Recoveries studies in several matrices with different fortification levels were performed, with recoveries between 77 and 115% with RSD lower than 9.5%. The MQLs obtained for these compounds were between 0.013 microg L(-1) and 0.022 microg L(-1), which were much lower than the maximum level established by the European legislation. PMID- 20706015 TI - Evaluation of a BWTK for detection of total coliforms, E. coli and emerging pathogens from drinking water: comparison with standard MPN method. AB - A defined substrate method media in bacteriological water testing kit (BWTK) has been developed to recover and detect the presence/absence of total coliforms and emerging pathogens from drinking water without the need for the confirmatory or complete tests. This method is based on technology that uses a hydrolysable substrate as a specific indicator- nutrient for the target microbes. To perform the test, one only has to add water to the ingredients in the BWTK and incubate at room temperature for a time period of 48 hrs. The target microbes remain viable in the positive kit for at least 10 days and further bacterial isolates from BWTK were characterized phenotypically, molecular identified by sequencing of 16SrRNA gene and antibiotic sensitivity was determined. All of the emerging bacterial isolates were haemolytic and multiple resistant to antibiotics. The epidemiological surveillance of drinking water revealed the occurrence of emerging pathogens responsible for causing acute gastrointestinal illness, soft tissue infections, meningitis, enteritis to acute mesenteric lymphadenitis as Yersinia enterocolitica (94%) and Aeromonas hydrophila (79%). The conventional methods (IS-10500-1991 BIS New Delhi, India) cannot predict the presence of these potentially enteropathogenic microorganisms in drinking water. There are currently no suitable microbiological criteria for the detection of emerging pathogens. In response to these limitations a BWTK has been developed for regularly monitoring of drinking water quality for appraisal to public health officials and take corrective measures regarding health risk when desired. PMID- 20706016 TI - Evaluation of xenobiotic impact on urban receiving waters by means of statistical methods. AB - Xenobiotics in urban receiving waters are an emerging problem. A sound knowledge of xenobiotic input, distribution and fate in the aquatic environment is a prerequisite for risk assessments. Methods to assess the impact of xenobiotics on urban receiving waters should address the diverse characteristics of the target compounds and the spatiotemporal variability of concentrations. Here, we present results from a one-year-monitoring program concerning concentrations of pharmaceuticals, additives from personal care products and industrial chemicals in an urban drainage catchment in untreated and treated wastewater, surface water and groundwater. Univariate and multivariate statistical methods were applied to characterize the xenobiotic concentrations. Correlation and principal component analysis revealed a pronounced pattern of xenobiotics in the surface water samples. The concentrations of several xenobiotics were characterized by a negative proportionality to the water temperature. Therefore, seasonal attenuation is assumed to be a major process influencing the measured concentrations. Moreover, dilution of xenobiotics the surface water was found to significantly influence the concentrations. These two processes control more the xenobiotic occurrence in the surface water than the less pronounced concentration pattern in the wastewater sources. For the groundwater samples, we assume that foremost attenuation processes lead to the found differentiation of xenobiotics. PMID- 20706017 TI - Toxicity assessment of oil field produced water treated by evaporative processes to produce water to irrigation. AB - During the productive life of an oil well, a high quantity of produced water is extracted together with the oil, and it may achieve up to 99% in the end of the well's economical life. Desalination is one of mankind's earliest forms of saline water treatment, and nowadays, it is still a common process used throughout the world. A single-effect mechanical vapor compression (MVC) process was tested. This paper aims to assess the potential toxicity of produced water to be re-used in irrigation. Samples of both produced and distilled water were evaluated by 84 chemical parameters. The distilled produced water presented a reduction up to 97% for the majority of the analyzed parameters, including PAHs. Toxicity bioassays were performed with distilled produced water to evaluate the growth inhibition of Pseudokirchneriella subcapitata algae, the acute toxicity to Danio rerio fish, the germination inhibition of Lactuca sativa vegetable and the severity of toxicity, as well as behavior test with Lumbricid Earthworm Eisenia fetida. The ecotoxicological assays results showed no toxicity, indicating that the referred evaporative process can produce water to be reused in irrigation. PMID- 20706018 TI - Influence of microbial activity on polar xenobiotic degradation in activated sludge systems. AB - The influence of activated sludge quality on the co-metabolic biodegradation of three aminocarboxylic [corrected] acids was investigated for a variety of Luxembourg sewage treatment plants. A combination of biodegradation experiments and respirometric techniques are presented as a reliable approach for the estimation of biokinetics and biological xenobiotic degradation rates that allow for identification of governing parameters such as microbial activity and active biomass. Results showed that biokinetics and degradation rates vary greatly between different plants. The fraction of active biomass on the total suspended solids ranged between 16.9 and 53.7%. Xenobiotic biodegradation rates correlated with microbial activity suggesting a relationship with WWTP performance for carbon and nutrient removal. The biokinetic information can be used to increase the prediction accuracy of xenobiotics removal by individual WWTPs. PMID- 20706019 TI - Technico-economic assessment of groundwater treatment by palladium-on-zeolite catalyst in comparison to GAC fixed bed adsorbers. AB - A technico-economic comparison between palladium-on-zeolite (Pd/Y), and granular activated carbon (GAC) based methods of groundwater clean-up is presented. The treatment concepts are assessed by means of process-based cost functions that can be applied to a broad range of case-specific conditions. The analysis accounts for variability in cost and performance parameters and reduces the interplay of multiple factors to expressive indifference curves that can be used for identifying a favorable technology. The findings for the treatment of halogenated hydrocarbons reveal that the Pd/Y offers advantages compared to GAC use in case of high contaminant concentrations and for the treatment of lower halogenated compounds such as cis-Dichloroethene. PMID- 20706020 TI - Library-dependent and library-independent microbial source tracking to identify spatial variation in faecal contamination sources along a Lake Ontario beach (Ontario, Canada). AB - Multiple microbial source tracking methods were applied to investigate spatial variation in faecal pollution sources impacting a 1.7 km freshwater beach on Lake Ontario (Canada). The highest E. coli concentrations measured in the study area were from interstitial sand pore water at Sunnyside Beach, reaching 2.6 x 10(6) CFU/100 ml. These E. coli concentrations exceeded those in the nearby Humber River and Black Creek, which are impacted by combined sewer overflows containing municipal wastewater and by stormwater conveying washoff from the urban area. Library-independent Bacteroidales HF183 analyses identified the more frequent occurrence of municipal wastewater contamination in the Humber River and at a Sunnyside Beach location closest to the mouth of the river. Library-dependent E. coli antibiotic resistance and rep-PCR DNA fingerprinting analyses identified the more frequent occurrence of bird faecal contamination at Sunnyside Beach locations away from the river mouth. These microbial source tracking results raise caution about managing beaches with multiple sources of contamination as a single entity without considering spatial variability in faecal pollution sources and the need for more localized beach management practices. PMID- 20706021 TI - Influence of the employment of adsorption and coprecipitation agents for the removal of PPCPs in conventional activated sludge (CAS) systems. AB - Three activated sludge reactors were operated to improve the removal of organic micropollutants such as Pharmaceutical and Personal Care Products (PPCPs). Reactor 1 (R1) was operated as a Conventional Activated Sludge reactor (CAS), Reactor 2 (R2) consisted of a CAS unit that was continuously fed with FeCl3 whereas granular activated carbon (GAC) was fed directly into the mixed liquor of Reactor 3 (R3) in order to attain concentrations in the range 100-1,000 mg/L. PPCPs removal rates varied depending on the compound present in each reactor during the entire 220 days of operation. Some substances showed the same behaviour in all reactors, such as the acidic pharmaceuticals naproxen and ibuprofen, which were almost completely removed (> 90%). More hydrophobic organic substances, like musk fragrances, were about 90% removed after 40 days of operation in all of the reactors. The main difference between the three reactors was obtained in R3 when the GAC concentrations in the aeration tank were around 500-1,000 mg/L. Under these conditions, the more recalcitrant compounds like diazepam and carbamazepine could be removed by up to 40%, and diclofenac up to 85%. Adsorption isotherms for PPCPs were obtained with activated carbon, and the results were successfully fitted to the Freundlinch equation. The more recalcitrant compounds (carbamazepine, diazepam and diclofenac) had the highest adsorption capacities onto GAC, which is consistent with the behaviour observed in R3 and helps to identify the removal mechanism (adsorption for these compounds, whereas absorption for fragrances). PMID- 20706022 TI - 3D modelling of transport, deposition and resuspension of highway deposited sediments in wet detention ponds. AB - The paper presents results from an experimental and numerical study of flows and transport of primarily particle bound pollutants in highway wet detention ponds. The study presented here is part of a general investigation on road runoff and pollution in respect to wet detention ponds. The objective is to evaluate the quality of long term simulation based on historical rains series of the pollutant discharges from roads and highways. A three-dimensional hydrodynamic and mud transport model is used for the investigation. The transport model has been calibrated and validated on e.g. experiments in a 30 m long concrete channel with width of 0.8 m and a water depth of approximately 0.8 m and in circular flume experiments in order to reproduce near-bed specific processes such as resuspension and consolidation. With a fairly good agreement with measurements, modelling of hydrodynamics, transport of dissolved pollutants and particles in wet detention ponds is possible with application of a three dimensional RANS model and the advection/dispersion equation taken physical phenomena like wind, waves, deposition, erosion and consolidation of the bottom sediment into account. PMID- 20706023 TI - Distribution and characterization of IL-10-secreting cells in lymphoid tissues of PCV2-infected pigs. AB - Distribution and characterization of interlukin-10 (IL-10)-secreting cells in lymphoid tissues of pigs naturally infected with porcine circovirus type 2 (PCV2) were evaluated in accordance with PCV2 antigen detection. After screening a total of 56 pigs showing the symptoms of postweaning multisystemic wasting syndrome (PMWS), 15 pigs were PCV2 positive and 5 pigs, which showed stronger positive signals over multiples tissues were further investigated. This study showed that in PCV2-infected lymphoid tissues, particularly mandibular lymph node, spleen and tonsil, IL-10 expression was mainly localized in T-cell rich areas but rarely in B cell rich areas. IL-10 was highly expressed in bystander cells but rarely in PCV2-infected cells. Elevated IL-10 expression was predominantly associated with T cells, but rarely with B cells or with macrophages. The results of this study provide evidence for the role of IL-10 in chronic PCV2 infection and its relation to PCV2 antigen in affected tissues. Constantly elevated levels of IL-10 lead to immunosuppression in persistent and chronic viral infections. The increased IL-10 expression observed in PCV2 infection in this study suggests that IL-10-mediated immunosuppression may play an important role in the pathogenesis and maintenance of naturally occurring PCV2 infection. PMID- 20706024 TI - 64-channel multi-detector row CT angiographic evaluation of the micropigs for potential living donor lung transplantation. AB - Micropigs are the most likely source animals for xenotransplantation. However, an appropriate method for evaluating the lung of micropigs had not been established. Therefore, this study was performed to evaluate the feasibility of 64-channel multi-detector row computed tomography (MDCT) to measure the diameter of the pulmonary arteries and the lung volume in micropigs. The mean diameters of the trachea, and left and right bronchi were 1.6 +/- 0.17, 1.18 +/- 0.14, and 1.1 +/- 0.11 cm, respectively. The mean diameters of the main, right, and left pulmonary arteries were 1.38 +/- 0.09, 1.07 +/- 0.26, and 0.98 +/- 0.13 cm and the diameters of right, left, and common inferior pulmonary veins were 0.97 +/- 0.20, 0.76 +/- 0.20, and 1.99 +/- 0.26 cm, respectively. The mean lung volume was 820.3 +/- 77.11 mL. The data presented in this study suggest that the MDCT may be a noninvasive, rapid, and accurate investigational method for pulmonary anatomy in living lung donors. PMID- 20706025 TI - Autoantibodies against thyroid hormones and their influence on thyroxine determination with chemiluminescence immunoassay in dogs. AB - Autoantibodies against thyroxin (T4AA) and triiodothyronine (T3AA) are present in dogs with autoimmune thyroiditis and have been reported to interfere with immunoassays. The objectives of this study were to determine the frequency of autoantibodies and to determine whether interference occurs by T4AA, using a non immunological method (high performance liquid chromatography, HPLC) for thyroxin (T4) measurement. Based on clinical symptoms, T4 and thyroid stimulating hormone (TSH) concentration, 1,339 dogs were divided into six groups: Group 1: hypothyroid (n = 149); Group 2: subclinical thyroiditis (n = 110); Group 3: suspicious for non thyroidal illness (n = 691); Group 4: biochemical euthyroid (n = 138); Group 5: hypothyroid dogs under substitution therapy (n = 141); Group 6: healthy dogs (n = 110). The incidence of T4AA and T3AA, determined using radiometric assay, was low (0.5% and 3.8%) and higher in hypothyroid dogs compared to dogs suspicious for hypothyroidism (Group 2-4) (p < 0.05). T4AA was not detected in dogs with normal T4 and elevated TSH. T4 concentrations of T4AA positive samples determined using HPLC were comparable to results obtained by chemiluminescence immunoassay. These findings indicate that the probability of interference of T4AA leading to falsely elevated T4 concentration in the T4 assay seems to be low. PMID- 20706027 TI - Antigenic and immunogenic investigation of the virulence motif of the Newcastle disease virus fusion protein. AB - Newcastle disease (ND) caused by virulent Newcastle disease virus (NDV) is a highly contagious viral disease of poultry. Virulent NDVs characteristically have a multibasic amino acid sequence (virulence motif) such as (112)RRQKRF(117) at the cleavage site of the precusor fusion (F0) protein. The antigenic and immunogenic characteristics of the virulence motif (112)RRQKRF(117) in the F0 protein of virulent NDVs were investigated. Epitope mapping analysis revealed that a RRQKRF-specific monoclonal antibody 4G2 recognized the KRF section of the motif. A synthetic peptide bearing the RRQKRF motif reacted strongly with sera from virulent NDV (with RRQKRF motif)-infected chickens. These sera also showed reactivity to peptides bearing other virulence motifs ((112)KRQKRF(117), (112)RRQRRF(117) and (112)RRRKRF(117)) but not an avirulence motif ((112)GRQGRL(117)) by ELISA. The synthetic bearing RRQKRF motif reacted with 60% to 91% of sera taken from surviving chickens on ND outbreak farms but not with sera from vaccinated birds, even though most of the sera had antibody to NDV due to vaccination. This indicates that the virulence motif has the potential to differentiate virulent NDV infected birds from vaccinated birds. PMID- 20706026 TI - Prevalence of tick-borne encephalitis virus in ticks from southern Korea. AB - The prevalence of tick-borne encephalitis virus (TBEV) in southern Korea was determined by collecting ticks using tick drags. A total of 4,077 of 6,788 ticks collected were pooled (649 pools) according to collection site, species, and developmental stage and assayed for TBEV. The TBEV protein E and NS5 gene fragments were detected using RT-nested PCR in six pools of nymphs collected from Jeju Island (2,491 ticks). The minimum field detection rates for TBEV were 0.17% and 0.14% for Haemaphysalis longicornis and Haemayphysalis. flava nymphs, respectively. The 252 bp NS5 and 477 bp protein E gene amplicons were sequenced. Phylogenetic analysis showed that the NS5 and protein E genes of the Jeju strain were clustered with Western subtype (98.0% and 99.4% identity, respectively). The Western subtype of TBEV is endemic in Korea, including Jeju Island. The study of vector and zoonotic host susceptibility to TBEV is required to better understand its potential impact on public health. PMID- 20706028 TI - Inhibitory effects of interleukin-10 plasmid DNA on the development of atopic dermatitis-like skin lesions in NC/Nga mice. AB - Interleukin (IL)-10 exerts potent anti-inflammatory effects by suppression of both T-help (Th) 1 and Th2 cells. Previous studies have reported that IL-10 can ameliorate various inflammatory disorders. The present study was performed to examine whether IL-10 plasmid DNA could suppress development of atopic dermatitis (AD)-like skin lesions in NC/Nga mice, as an initial step towards the development of an appliance for use in dogs with AD. Intradermal injection of IL-10 plasmid DNA markedly inhibited the development of AD-like skin lesions, as evidenced by a marked decrease in skin symptoms and reduced inflammation within the skin lesions. Efficacy was confirmed by significant decreases in eosinophil ratio and serum IgE concentration, and a reduction in the number of Staphylococcus aureus recovered from the ear. Moreover, relative mRNA expression levels of IL-4 and interferon-gamma in the skin lesions of mice injected with IL-10 plasmid DNA were also decreased compared with those of control mice. Of note, higher serum IL-10 levels in mice injected with IL-10 plasmid DNA were maintained compared with those in control mice. Taken together, the results indicate that IL-10 plasmid DNA can suppress the development of AD-like skin lesions by suppressing both Th1 and Th2 cell responses. Beneficial effects of IL-10 plasmid DNA may be expected in dogs with AD. PMID- 20706029 TI - Detection of Helicobacter spp. in gastric, fecal and saliva samples from swine affected by gastric ulceration. AB - The aim of this study was to evaluate the presence of Helicobacter (H.) spp. in swine affected by gastric ulceration. Stomachs from 400 regularly slaughtered swine were subjected to gross pathological examination to evaluate the presence of gastric ulcers. Sixty-five samples collected from ulcerated pars esophagea and 15 samples from non-ulcerated pyloric portions were submitted to histopathological and molecular analyses, to detect Helicobacter spp., H. suis and H. pylori by PCR. Feces and saliva swabs were also collected from 25 animals in order to detect in vivo the presence of Helicobacter spp.. Gastric ulcers were detected in 373 cases (93%). The presence of ulcers in association with inflammatory processes was further confirmed by histological examination. Forty nine percent (32/65) of the ulcerated esophageal portions as well as 53% (8/15) of the non-ulcerated pyloric portions were positive for Helicobacter spp. by PCR. The Helicobacter spp. positive samples were also positive for H. suis, while H. pylori was not detected. These results were confirmed by restriction enzyme analysis. With regard to feces and saliva samples, 15/25 (60%) and 16/25 (64%) were positive for Helicobacter spp. PCR, respectively but all were negative in H. suis and H. pylori specific PCR. PMID- 20706030 TI - Molecular heterogeneity of plpE gene in Indian isolates of Pasteurella multocida and expression of recombinant PlpE in vaccine strain of P. multocida serotype B: 2. AB - Outer membrane proteins of Pasteurella (P.) multocida have been known to be protective immunogens. Pasteurella lipoprotein E (PlpE) has been reported to be an important cross reactive outer membrane protein in P. multocida. The gene encoding the PlpE of P. multocida serotypes A: 3, B: 2 and D: 1 was amplified from the genomic DNA. The amplified products were cloned and the nucleotide sequence was determined. Sequence analysis of the recombinant clones revealed a single open reading frame of 1,011 bp, 1,008 bp and 1,017 bp encoding a protein with a calculated molecular mass of 37.829 kDa, 37.389 kDa and 37.965 kDa for serotypes A: 3, B: 2 and D: 1 respectively. The comparison of the plpE sequence in different capsular types revealed a high degree (> 90%) of homology. Furthermore, the plpE gene of Haemorhhagic septicaemia causing serotype (B: 2) was expressed in E. coli and recombinant PlpE was strongly immunostained by antiserum against whole cell antigen, indicating that the protein is expressed in vivo. PMID- 20706031 TI - Development and evaluation of a multiplex PCR assay for simultaneous detection of Flavobacterium psychrophilum, Yersinia ruckeri and Aeromonas salmonicida subsp. salmonicida in culture fisheries. AB - Bacterial cold water disease, enteric red mouth disease and frunculosis are the common bacterial diseases of fish worldwide. The etiologic agents of these diseases are Flavobacterium (F.) psychrophilum, Yersinia (Y.) ruckeri and Aeromonas (A.) salmonicida subsp. salmonicida, respectively. In this study, a multiplex polymerase chain reaction (m-PCR) method with YER8/10-Fer3/4-FP1/3 primer pairs which can identify these fish pathogens simultaneously was developed and optimized. In optimized conditions, neither false specific nor nonspecific amplification occurred. The detection limits of the m-PCR method using DNA extracts from dilutions of pure cultures of bacteria were 35 pg for Y. ruckeri and F. psychrophilum and 70 pg for A. salmonicida subsp. salmonicida. It was determined that 15 CFU Y. ruckeri and F. psychrophilum and 30 CFU A. salmonicida subsp. salmonicida could be detected by m-PCR developed using genomic DNA extracted from dilutions of the suspensions. The detection limits in the presence of tissue debris were 125 CFU for Y. ruckeri and F. psychrophilum and 250 CFU for A. salmonicida subsp. salmonicida. In conclusion, we submit that the m-PCR method developed and optimized in this study can be used for accurate and rapid identification of these bacteria. PMID- 20706032 TI - Sequence and phylogenetic analysis of the non-structural 3A and 3B protein-coding regions of foot-and-mouth disease virus subtype A Iran 05. AB - The A Iran 05 foot-and-mouth disease virus (FMDV) subtype was detected in Iran during 2005 and has proven to be highly virulent. This study was undertaken to focus on molecular and phylogenetic analysis of 3A and 3B coding-regions in the A Iran 05 field isolate. To assess the genetic relatedness of A Iran 05 isolate the nucleotide and predicted amino acid sequences of the 3AB region of type A FMDV isolates were compared with twenty previously described type A FMDV isolates. The phylogenetic tree based on the 672 bp 3AB gene sequences of type A FMDV from thirteen different locations clustered them into five distinct lineages. The A Iran 05 isolate clustered in lineage A along with four type A variants and was closely matched with viruses isolated in Turkey and Pakistan during 2005~2006. The number of protein sequence differences exhibited by each of the isolates revealed that A Iran 05 isolate contains three amino acid substitutions at positions 47 and 119 of 3A and 27 of the 3B coding region. The nucleotide identity between A Iran 05 and the other four isolates of lineage A was estimated to be 98%. PMID- 20706033 TI - Clinical findings, rhinoscopy and histological evaluation of 54 dogs with chronic nasal disease. AB - Nasal diseases are very common in dogs and rhinoscopy is often required for a definitive diagnosis. Rhinoscopy, while superficial in nature, can guide the clinician to the final diagnosis. In this study, rhinoscopy was performed on 54 dogs with symptoms of chronic nasopharyngeal disease. The endoscopic diagnosis of neoplasia or chronic nasal inflammation was validated with histological examination of pathological samples, in order to evaluate the degree of concordance between endoscopic findings and histological diagnosis. The agreement between endoscopy and histology was tested by application of Cohen's kappa coefficient. We conclude that correlation between endoscopic results and histological diagnosis, expressed by a Cohen's kappa coefficient of 0.73, is only possible with a constant cooperation between the clinician and the pathologist. PMID- 20706034 TI - Pre- and post-operative cardiac evaluation of dogs undergoing lobectomy and pneumonectomy. AB - This study aimed to assess the influence of lobectomy and pneumonectomy on cardiac rhythm and on the dimensions and function of the right-side of the heart. Twelve dogs undergoing lobectomy and eight dogs undergoing pneumonectomy were evaluated preoperatively and one month postoperatively with electrocardiography and Doppler echocardiography at rest. Pulmonary artery systolic pressure (PASP) was estimated by the tricuspid regurgitation jet (TRJ) via the pulse wave Doppler velocity method. Systemic inflammatory response syndrome criteria (SIRS) were also evaluated based on the clinical and hematological findings in response to lobectomy and pneumonectomy. Following lobectomy and pneumonectomy, we predominantly detected atrial fibrillation and varying degrees of atrioventricular block (AVB). Dogs that died within seven days of the lobectomy (n = 2) or pneumonectomy (n = 1) had complete AVB. Preoperative right atrial, right ventricular, and pulmonary artery dimensions increased gradually during the 30 days (p < 0.05) following pneumonectomy, but did not undergo significant changes during that same period after lobectomy. Mean PASP was 56.0 +/- 4.5 mmHg in dogs having significant TRJ after pneumonectomy. Pneumonectomy, but not lobectomy, could lead to increases (p < 0.01) in the SIRS score within the first day post-surgery. In brief, it is important to conduct pre- and postoperative cardiac evaluation of dogs undergoing lung resections because cardiac problems are a common postoperative complication after such surgeries. In particular, complete AVB should be considered a lifethreatening complication after pneumonectomy and lobectomy. In addition, pneumonectomy appears to increase the likelihood of pulmonary hypertension development in dogs. PMID- 20706035 TI - Identification of Arcanobacterium pyogenes isolated by post mortem examinations of a bearded dragon and a gecko by phenotypic and genotypic properties. AB - The present study was designed to identify phenotypically and genotypically two Arcanobacterium (A.) pyogenes strains isolated by post mortem examinations of a bearded dragon and a gecko. The A. pyogenes strains showed the typical biochemical properties and displayed CAMP-like synergistic hemolytic activities with various indicator strains. The species identity could be confirmed genotypically by amplification and sequencing of the 16S rDNA gene and, as novel target gene, by sequencing of the beta subunit of RNA polymerase encoding gene rpoB, of both strains and of reference strains representing nine species of the genus Arcanobacterium. The species identity of the two A. pyogenes strains could additionally be confirmed by PCR mediated amplification of species specific parts of the 16S-23S rDNA intergenic spacer region, the pyolysin encoding gene plo and by amplification of the collagen-binding protein encoding gene cbpA. All these molecular targets might help to improve the future identification and further characterization of A. pyogenes which, as demonstrated in the present study, could also be isolated from reptile specimens. PMID- 20706036 TI - Simultaneous detection and subtyping of porcine endogenous retroviruses proviral DNA using the dual priming oligonucleotide system. AB - The purpose of this study was to develop a multiplex PCR that can detect porcine endogenous retrovirus (PERV) proviral genes (pol, envA, envB, envC) and porcine mitochondrial DNA, using a dual priming oligonucleotide (DPO) system. The primer specifically detected the PERV proviral genes pol, envA, envB, envC, and porcine mitochondrial DNA only in samples of pig origin. The sensitivity of the primer was demonstrated by simultaneous amplification of all 5 target genes in as little as 10 pg of pig DNA containing PERV proviral genes and mitochondrial DNA. The multiplex PCR, when applied to field samples, simultaneously and successfully amplified PERV proviral genes from liver, blood and hair root samples. Thus, the multiplex PCR developed in the current study using DPO-based primers is a rapid, sensitive and specific assay for the detection and subtyping of PERV proviral genes. PMID- 20706037 TI - Anti-inflammatory effects of a Houttuynia cordata supercritical extract. AB - Anti-inflammatory effects of Houttuynia cordata supercritical extract (HSE) were investigated in a carrageenan-air pouch model. HSE (200 mg/kg, oral) suppressed exudation and albumin leakage, as well as inflammatory cell infiltration. Dexamethasone (2 mg/kg, i.p.) only decreased exudation and cell infiltration, while indomethacin (2 mg/kg, i.p.) reduced exudate volume and albumin content. HSE lowered tumor-necrosis factor (TNF)-alpha and nitric oxide (NO), as well as prostaglandin E(2) (PGE(2)). Dexamethasone only reduced TNF-alpha and NO, while indomethacin decreased TNF-alpha and PGE(2). The suppressive activity of HSE on NO and PGE(2) production was confirmed in RAW 264.7. These results demonstrate that HSE exerts anti-inflammatory effects by inhibiting both TNF-alpha-NO and cyclooxygenase II-PGE(2) pathways. PMID- 20706038 TI - Tc-99m MIBI scintigraphy in multiple myeloma: prognostic value of different Tc 99m MIBI uptake patterns. AB - PURPOSE: Technetium-99m 2 methoxyisobutylisonitrile (Tc-99m MIBI) scintigraphy has been used to identify biologic activity and extent of multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS). The examination could also serve both as a prognostic tool and an examination for monitoring the disease course in MM patients. The purpose of this study was to evaluate the prognostic value of different Tc-99m MIBI uptake patterns. MATERIALS AND METHODS: Ninety-nine consecutive patients with newly diagnosed symptomatic MM and 18 patients with MGUS underwent baseline Tc-99m MIBI scintigraphy before applying any kind of therapy. The Tc-99m MIBI scans were classified as showing normal, diffuse, and focal or combined (diffuse and focal) patterns of tracer uptake. To evaluate the prognostic value of different Tc-99m MIBI uptake patterns, overall survival (OS) was chosen as an end point. Median of follow-up period was 84 months. Survival according to patterns of Tc-99m MIBI uptake was calculated using the Kaplan-Meier plots. RESULTS: Statistically significant correlation between the baseline patterns of Tc-99m MIBI uptake and OS was found (P < 0.0001). Focal or combined patterns of Tc-99m MIBI uptake indicated significantly worse prognosis with shorter OS than normal or diffuse tracer patterns. CONCLUSIONS: Tc 99m MIBI scintigraphy plays the predictive role in the follow-up of patients with MM. Baseline scintigraphic pattern of Tc-99m MIBI uptake seems to be a useful prognostic indicator of OS in MM patients and Tc-99m MIBI scintigraphy could be used as an additional tool for the initial examination in patients with newly diagnosed MM. PMID- 20706039 TI - Role of Tc-99m pertechnetate for remnant scintigraphy post-thyroidectomy. AB - PURPOSE OF THE REPORT: Current surgical techniques in patients with differentiated thyroid cancer can leave little or no remnant tissue. Coupled with favorable prognostic factors, this subgroup of patients might not require radioablative remnant ablation with Iodine-131 (I-131). Postoperative scanning may help to identify this subgroup, however low dose I-131 can lead to stunning and suboptimal response to ablative therapy. Iodine-123 (I-123) can be used but is expensive and supply can be limited. We investigate technetium-99m pertechnetate (pertechnetate) as a potential alternative for remnant scintigraphy post-thyroidectomy. MATERIALS AND METHODS: Seventy consecutive post-total thyroidectomy patients were evaluated retrospectively. Preablative pertechnetate scans of the thyroid bed were viewed blindly then directly compared with postablative I-131 scans. RESULTS: For patients with unequivocally positive pertechnetate uptake, the sensitivity was 81% (patients), 61% (sites), and the PPV was high (100% patients, 95% sites). In patients with either definite or equivocal pertechnetate uptake, the sensitivity was 90% (patients), 68% (sites), and the PPV was also high (100% patients, 81% sites). CONCLUSIONS: Pertechnetate had reasonable correlation with postablative I-131 scans with a moderately high sensitivity and a very high PPV. A positive pertechnetate scan is therefore sufficient to guide progression to I-131 ablation in most patients. When the scan is equivocal or negative, diagnostic imaging with radioiodine may be required. Pertechnetate scintigraphy may be of particular benefit if it is considered desirable to avoid I-131 in post-thyroidectomy remnant imaging. PMID- 20706040 TI - A correlative study of FDG PET, MRI/CT, electroencephalography, and clinical features in subacute sclerosing panencephalitis. AB - OBJECTIVE: To describe F-18 fluorodeoxyglucose positron emission tomography (FDG PET) profile in patients with subacute sclerosing panencephalitis (SSPE) and to investigate its possible correlation with clinical, electroencephalography (EEG) or magnetic resonance imaging/computed tomography (MRI/CT) findings. METHODS: EEG recording, MRI/CT and FDG PET imaging were performed in 16 patients with SSPE (1.9-15.6 years). FDG PET scans were assessed visually and in standardized uptake values. Finally, all the findings including clinical data were compared. RESULTS: MRI was abnormal in 10 patients. It was normal in 6 of 10 patients in earlier clinical stages. Nonspecific T2-weighted white matter findings were the most consistent MRI finding (10 patients). No thalamic lesion was detected in MRI/CT. FDG PET imaging was abnormal in 14 patients (8/10 patients in earlier stages). Glucose metabolism was decreased in thalamus, cerebellum or cerebral cortex in 12, 12, and 9 patients, respectively. Frontal cortex metabolism was preserved in earlier clinical stages. FDG PET imaging revealed putaminal hypermetabolism in 7 patients. However, MRI indicated striatal abnormality only in 2 patients with prolonged disease and later clinical stage. Three patients with putaminal hypermetabolism experienced a more rapid clinical deterioration. Onset age of SSPE, age of measles infection and EEG findings were not correlated with the imaging findings. CONCLUSIONS: Our findings suggest that FDG PET imaging can indicate affected brain regions in SSPE more confidently and earlier than MRI. FDG PET imaging would provide new insights into the pathogenesis of SSPE and help to develop new approaches to the patients with SSPE. PMID- 20706041 TI - Brain single photon emission computed tomography with Tc-99m MIBI or Tc-99m ECD in comparison to MRI in multiple sclerosis. AB - PURPOSE: To evaluate whether or not brain single photon emission computed tomography (SPECT) with Tc-99m MIBI or Tc-99m ECD (ethyl cysteinate dimer) can detect any abnormality in patients with definite multiple sclerosis (MS). We then compared these values with the results of T1, T2, and fluid-attenuated inversion recovery in magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 16 patients with proved MS were enrolled in the study, and the MRI with and without gadolinium contrast and also brain SPECT with Tc-99m MIBI (8 cases) or Tc 99m ECD (8 other cases) were performed. RESULTS: MRI studies was performed in 16 patients (13 women and 3 men, aged 16-38 years) and an average of 10.47, 3.7, 5.3, 1.7, and 0.9 lesions was found in respect in periventricular white matter, juxtacortical white matter, corpus callosum, cerebellar peduncles, and brainstem, whereas brain SPECT with Tc-99m MIBI or Tc-99m ECD detected no abnormality. In addition, 6 cases had some degree of contrast enhancement. CONCLUSIONS: It seems that brain SPECT with Tc-99m MIBI or Tc-99m ECD would not improve this insufficiency. The small sizes of some plaques, particularly in chronic atrophic form of lesions, and the possibility of deeper anatomic positions of plaques can explain to some extent why the MS lesions were impossible to delineate on brain scan, although additional studies are needed. PMID- 20706042 TI - Utility of bone scintigraphy to determine the appropriate vertebral augmentation levels. AB - PURPOSE OF THE REPORT: Vertebral augmentation procedures have been used as an effective treatment for back pain due to vertebral compression fracture from different causes, including metastatic disease and osteoporosis. However, diagnosis and localization of the causative vertebral level(s) may be difficult using any single imaging modality. In this retrospective study, we assessed the ability of preprocedural bone scans to determine the appropriate level(s) of subsequent vertebroplasty. MATERIALS AND METHODS: The study consisted of a retrospective chart review of 44 patients who underwent bone scintigraphs and vertebroplasties at Montefiore Medical Center from 2002 to 2008. Online medical records and reports were used to determine the level of vertebroplasty and the preprocedure bone scan levels. The data was reviewed by a panel consisting of a neuroradiologist and nuclear medicine physician for agreement. RESULTS AND CONCLUSIONS: Our retrospective study assessed the utility of bone scans as a diagnostic tool to identify candidate vertebral levels for vertebroplasty and determined that bone scans were positive in 78.3% of all fractures that subsequently underwent vertebral augmentation procedures. Although no significant difference was seen in the positivity of bone scans to subsequent vertebroplasty levels between benign or metastatic compression fractures (79% vs. 76%), a difference was observed when single level vertebroplasty patients were compared with multiple-level vertebroplasty patients (87% vs. 69%). Our results support the use of whole body bone scintigraphy as a diagnostic tool prior to vertebroplasty, especially in cases where a single vertebral level is involved or MRI might be contraindicated. PMID- 20706043 TI - Pulmonary metastasis of struma ovarii: a case report. AB - We report the case of a 42-year-old woman who presented with multiple pulmonary nodules. Surgical resection of 3 nodules revealed differentiated thyroid carcinoma. Thyroid and neck ultrasound was normal. A review of her history revealed that this patient underwent an ovarian cyst resection 15 years ago. Reexamination of pathology samples, with the help of immunohistochemical markers, concluded to a struma ovarii. Pelvic ultrasound was normal; F-18 FDG PET scan was negative. She had total thyroidectomy, with negative histology, followed by first I-131 therapy (3.9 GBq). Thyroglobuline (Tg) was elevated (3230 microg/L in hypothyroidism). The whole-body scan showed multiple foci of pulmonary I-131 uptake, a bone metastasis of third rib, and I-131 uptake in an abdominal para aortic lymph node. At second I-131 therapy (3.8 GBq), Tg level had decreased to 14 microg/L and there was a decrease in the number of pulmonary nodular I-131 uptake, and resolution of the bone and para-aortic lymph node metastasis. At third I-131 therapy (4.9 GBq), thyroglobuline was undetectable and the whole-body scan showed no I-131 uptake. Struma ovarii is a rare ovarian tumor mostly benign. Metastasis of malignant struma ovarii are rare. Most frequent localizations are liver and peritoneum. Treatment of the malignant struma ovarii implies ovarian surgical resection, total thyroidectomy, and I-131 therapy. PMID- 20706044 TI - Health care reform: a short summary. AB - The Health Care Reform legislation has many provisions of importance to the nuclear medicine community. This article is not a complete summary of the thousands of pages in the legislation, but emphasizes some relevant aspects of the bills. When the plan is fully implemented, about 32 million more Americans will have health insurance. Pre-existing medical conditions will no longer result in insurance denials. There are many initiatives to slow the growth of spending on health care in various ways, such as by setting up the new Medicare Advisory Board. There are also new fees, taxes, penalties, subsidies, and tax deduction changes. PMID- 20706045 TI - F-18 FDG PET/CT findings in pulmonary necrotizing sarcoid granulomatosis. AB - Necrotizing sarcoid granulomatosis (NSG) is a rare systemic disease that was described by Liebow in 1973. Dyspnea and chest pain may be present, as in our first patient; however, 25% of patients are asymptomatic, as our second patient. The typical radiographic findings are nonspecific: single or multiple lung opacities, with common involvement of the pleura. To the best of our knowledge, fluorodeoxyglucose (FDG) PET has only been reported in one case of NSG, which was atypical as it occurred in an adolescent. We report 2 cases, confirming that the lesions of NSG are FDG positive, showing a typical pattern of multiple bilateral lung nodules (imaged with PET/CT in 1 case). FDG imaging has a potential role when this distribution is observed on CT, to guide the surgical biopsy and show the actual extent of the disease. PMID- 20706046 TI - Response assessment of hormonal therapy in prostate cancer by [11C] choline PET/CT. AB - A 57-year-old man with an adenocarcinoma of the prostate, presented with multiple lymph nodes in the para-aortic and right iliac region on computer tomography (CT). However, since the radiologic images were taken 3 weeks following an urosepsis, the differentiation between inflamed and metastatic lymph nodes is difficult. Thus, an integrated [C] choline positron emission tomography and computer tomography (PET/CT) was performed, showing multiple lymph nodes. The patient was staged as cT3N1M0 and treated with hormonal therapy. The choline PET/CT performed after hormonal treatment showed no more hypermetabolic lymph nodes. This case substantiate the hypothesis that choline PET/CT could be used to evaluate therapy response in prostate cancer patients. PMID- 20706047 TI - Hodgkin lymphoma post-transplant lymphoproliferative disorder following pediatric renal transplant: serial imaging with F-18 FDG PET/CT. AB - Post-transplant lymphoproliferative disorder (PTLD) occurs in 1.2% of pediatric renal transplant patients, and is frequently Epstein-Barr Virus mediated. Hodgkin Lymphoma PTLD is the rarest of the 4 types of PTLDs recognized by the World Health Organization, with an incidence of <4% of all PTLD patients. It has a distinct clinical course and treatment from all other types of PTLD. This is a case of a 16-year-old girl who had a renal transplant in 2000 due to Moya Moya disease. Her first F-18 FDG PET/CT done in 2006 showed mildly FDG-avid mediastinal adenopathy (histologically nonspecific reactive nodes), however in 2009, after presenting with fevers, a repeat PET/CT showed extensive intensely FDG-avid disease. Biopsy of a supraclavicular node identified Hodgkin Lymphoma PTLD. The patient was treated with chemotherapy and reimaged, showing excellent response to therapy. In contrast, classic PTLD is treated by withdrawal of immunosuppression and administration of Rituximab. F-18 FDG PET/CT is known to be very useful in the staging and monitoring of response to therapy in the setting of classic PTLD. In this case, serial F-18 FDG PET/CT scans proved very useful in the evaluation and follow-up of the rare and distinct Hodgkin Lymphoma PTLD subtype. PMID- 20706048 TI - Myeloid sarcoma presenting as an anterior mediastinal mass invading the pericardium: Serial Imaging With F-18 FDG PET/CT. AB - Myeloid sarcoma is a tumor formed by extramedullary accumulation of myeloblasts or immature myeloid cells. These tumors can develop in lymphoid organs, bone, skin, soft tissue, and other organs, and may precede or occur concurrently with acute myeloid leukemia. This is a case of a 42-year-old man who presented with a 2-week history of cough and shortness of breath on exertion. A computed tomography (CT) scan showed a large mediastinal mass and pericardial effusion. An F-18 fluorodeoxyglucose positron emission tomography-CT scan showed intense fluorodeoxyglucose (FDG) uptake in the mediastinal mass with invasion of the parietal pericardium. Biopsy of the mediastinal mass and pericardium revealed myeloid sarcoma. The pericardial effusion was drained and the patient was treated with high-dose cytosine arabinoside (HiDAC) chemotherapy. A follow-up positron emission tomography-CT was done 2 months after the last cycle, showing poor response to therapy and significant progression of disease with invasion through the anterior chest wall. Myeloid sarcoma can be added to the differential diagnosis of F-18 FDG avid anterior mediastinal masses, as well as F-18 FDG uptake in the pericardium. PMID- 20706049 TI - F-18 FDG PET/CT in primary tonsillar lymphoma. AB - Non-Hodgkin lymphomas quite often present in the head and neck but primary tonsillar lymphomas of extranodal non-Hodgkin lymphomas are far less than 1% of head and neck malignancies. Reports of F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET/CT) related to primary tonsillar lymphoma are seldom. A 59-year-old man suffered from painful swelling of the bilateral tonsil. Biopsy diagnosed diffuse large B-cell lymphoma. F-18 FDG PET/CT was performed for disease staging. Whole-body F-18 FDG PET/CT revealed the intense FDG uptake of bilateral tonsil with an additional small lymph node in the right side of the neck. This case also highlights the usefulness of staging and assessing therapy response in rare types of lymphoma. PMID- 20706050 TI - A focal pulmonary F-18 FDG uptake without pulmonary CT abnormality in PET/CT probably due to mislocation of the urine F-18 FDG in the left upper renal calyx. AB - We experienced a case of a focal pulmonary F-18 fluoro-2-deoxy-D-glucose (FDG) uptake without pulmonary computed tomography (CT) abnormality probably due to the urine FDG in the upper pole calyx of the left kidney. A 76-year-old male patient was referred for evaluation of the postoperative right lung cancer. Positron emission tomography/CT was performed 1 hour after intravenous injection of FDG and showed a small focus of increased uptake in the left lower lung field accompanying no abnormality in the corresponding lung CT images. The lung uptake was not noted in repeated positron emission tomography/CT images taken after 1 hour, suggesting misplacement of the left renal upper calyx into the lower lung. PMID- 20706051 TI - Pleomorphic carcinoma of the lung with intrapulmonary aerogenic metastases on FDG PET. AB - A 59-year-old man presented with hemoptysis. Chest x-ray and computed tomography showed a cavitating mass and ground glass opacities in the right lower lobe. Positron emission tomography showed large regions of markedly increased fluorodeoxyglucose uptake in the right lower lobe consistent with primary cancer and intrapulmonary metastases, and several foci of high fluorodeoxyglucose uptake in the mediastinum and left neck consistent with lymph node metastases. We concluded that ground glass opacities were not aspiration of blood but intrapulmonary aerogenic metastases. Continuous active bleeding from the right bronchus (B6) was confirmed by bronchoscopy, and the right lower lobe was resected to remove the bleeding source. Pathologic findings showed pleomorphic carcinoma of the lung with intrapulmonary aerogenic metastases. PMID- 20706052 TI - Pericholecystic rim sign on PET/CT secondary to locally invasive gallbladder carcinoma. AB - A variety of gallbladder pathology (eg, carcinoma, acute and chronic cholecystitis, adenomyomatosis, cholestasis) has been imaged with F-18 fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography. The pericholecystic rim sign seen on conventional Tc-99m hepatobiliary scintigraphy is a marker of acute cholecystitis, possibly complicated by perforation or gangrene. A case of increased fluorodeoxyglucose uptake within the gallbladder fossa secondary to locally invasive gallbladder carcinoma reminiscent of a classic rim sign is presented. PMID- 20706053 TI - Inflammatory pseudotumor of the lung with high FDG uptake. AB - We present the case of a 23-year-old woman with 2 episodes of hemoptysis. Computed tomography showed a small mass lesion with an adjacent cyst in the left lower lobe. On whole-body fluorodeoxyglucose positron emission tomography/computed tomography, the lesion had a high focal fluorodeoxyglucose uptake (SUVmax 21.0). Differential diagnosis included tuberculosis, fungal infection, and tumors such as bronchial carcinoma, sarcoma, or rare entities like endometriosis. Bronchoscopy with transbronchial biopsies failed to deliver a conclusive diagnosis. Lobectomy was performed, and histopathology presented an inflammatory myofibroblastic pseudotumor. PMID- 20706054 TI - Solitary necrotic nodule with larval infestation in the liver on F-18 FDG PET/CT. AB - We present the case of a 64-year-old woman who suffered from occasional right upper abdominal pain for several months. Both abdominal ultrasonography and magnetic resonance imaging showed a hepatic mass of indeterminate nature. F-18 FDG PET/CT showed a solitary hypermetabolic mass in the liver; a malignancy was therefore suspected. Her hepatic tumor was resected; it was a solitary necrotic nodule with larval infestation but no evidence of malignancy. PMID- 20706055 TI - Hepatic paragonimiasis revealed by FDG PET/CT. AB - A 72-year-old asymptomatic man with a hepatic lesion incidentally detected by ultrasonography in routine examination undertook fluorodeoxyglucose (FDG) positron emission tomography/computed tomography for further evaluation. The images revealed increased FDG activity in the lesion, which was suggestive of malignancy. However, the pathologic examination demonstrated that the lesion was a granuloma caused by Paragonimus westermani, a lung fluke. Although increased FDG activity in the lung due to P. westermani infection is expected and reported previously, such lesion identified in the liver by FDG positron emission tomography/computed tomography is unusual. PMID- 20706056 TI - Chest wall and axillary lymph node FDG uptake associated with cancer vaccine therapy for lung cancer. AB - Cancer vaccines are now undergoing clinical investigations, and clinical trials of therapeutic cancer vaccines have been conducted mainly for advanced cancer patients. We experienced 2 cases of multifocal F-18 fluoro-2-deoxy-D-glucose uptake in the chest wall and axillary lymph nodes associated with personalized peptide vaccine therapy for recurrent lung cancer. In this article, we report fluoro-2-deoxy-D-glucose -positron emission tomography and positron emission tomography/computed tomography findings. PMID- 20706057 TI - Unusual case of adrenal and renal metastases from papillary carcinoma of thyroid. AB - We report a rare case of adrenal and renal metastases from papillary thyroid carcinoma (PTC). A 30-year-old man underwent total thyroidectomy with left neck dissection for cytology proven nodal metastases from PTC. This was followed by high-dose radioiodine therapy with a dose of 265 mCi (9.805 GBq). Thereafter, patient was lost to follow-up. He presented 2 decades later with low backache radiating to both the lower limbs. Magnetic resonance imaging examination of spine detected left SI joint, dorsal and lumbar vertebral metastases. A whole body radioiodine scan showed extensive iodine avid foci in thyroid bed, mediastinum, bilateral lungs, liver, bones, and in bilateral lumbar regions. An abdominal single photon emission computed tomography-computed tomography (CT) revealed the lumbar lesions to be within bilateral adrenal glands. Contrast enhanced CT of abdomen revealed lesions in bilateral adrenals and renal regions suggestive of metastases. A CT-guided biopsy of left adrenal focus confirmed metastasis from the carcinoma of thyroid. A high degree of suspicion with further radiologic and cytologic correlation clinched the diagnosis of both adrenal and renal metastases from PTC, which has been rarely reported. Fortunately, radioiodine concentration in adrenal metastases made them amenable to high-dose radioiodine therapy. Therefore, 225 mCi (8.325 GBq) of radioiodine was administered to this patient. This case is a strong reminder of the fact that regular and long-term follow-up is imperative in the management of thyroid cancer patients. PMID- 20706058 TI - Incidental vesicocolic fistula on routine bone scintigraphy: Value of additional delayed images and direct radionuclide cystography. AB - An unexpected vesicocolic fistula can be detected incidentally on routine bone scintigraphy. A 55-year-old man who had a radical colectomy for carcinoma of the sigmoid colon 1 year previously underwent bone scintigraphy to evaluate bone metastasis. Whole-body images showed an abnormal accumulation of radioactivity in the right lower quadrant of the abdomen, but the radioactivity did not precisely define a structure. Additional delayed images obtained after 15 and 24 hours of the initial image localized a vesicocolic fistula. Subsequent radionuclide cystography confirmed leakage of the radioactivity from the bladder. PMID- 20706059 TI - Scintigraphic findings of growth arrest lines after bisphosphonate administration in a steroid-induced osteoporosis patient: a case study. AB - Bisphosphonates inhibit bone resorption, and are used to treat patients who have low bone mineral density. This treatment results in the development of growth arrest lines, which typically appear parallel sclerotic lines to the growth plate on radiographs. We describe the case of a 14-year-old boy with steroid-induced osteoporosis, who was treated by pamidronate. This patient exhibited linearly increased bilateral uptake in the shafts of his femora, tibiae, radii, and ulnae that were parallel to the growth plates. A simple radiograph corresponding bone scan demonstrated linear sclerotic lines at the same sites. PMID- 20706060 TI - False-positive MIBG uptake in pneumonia in a patient with stage IV neuroblastoma. AB - A 32-month-old female child with a history of stage IV favorable biology neuroblastoma with a 123-I MIBG (metaiodobenzylguanidine scan) avid adrenal mass, with retroperitoneal nodal extension and bony metastasis, was in complete remission after intense multimodal therapy. Seventeen months after diagnosis a surveillance 123-I MIBG scan showed abnormal tracer uptake in the midzone of the right thorax. Chest x-ray and CT scan confirmed right upper lobe consolidation corresponding to the tracer uptake. Chest x-ray after antibiotics showed resolution of the abnormality. 123-I MIBG scan 3 months later showed no abnormal uptake. False-positive MIBG uptake in pneumonia has not been previously reported. PMID- 20706061 TI - Lung morphology-perfusion correlation on perfusion SPECT-CT fusion images in two cases of septic pulmonary embolism. AB - Septic pulmonary embolism (SPE) is a critical disorder which requires fast diagnosis for treatment, while SPE continues to pose a diagnostic challenge in radiologic imaging. We describe detailed findings on breath-hold perfusion SPECT CT fusion images in 2 patients with SPE. Regardless of absence or nonspecific morphologic abnormality in these patients, the fusion images showed multiple wedge-shaped segmental/subsegmental perfusion defects along specific pulmonary arteries, highly suggesting embolic event. Follow-up fusion images after treatment showed changes in lung perfusion defects and morphology. Assessment of lung morphology-perfusion correlation on reliable fusion images contributes to correct diagnosis of SPE and monitoring of treatment effect. PMID- 20706062 TI - Incidental detection of a pulmonary adenocarcinoma on low-dose computed tomography used for attenuation correction in myocardial perfusion imaging with SPECT. AB - A 68-year-old patient with known 3-vessel coronary artery disease, a history of aortocoronary bypass surgery, and presently without chest pain, was referred to myocardial perfusion imaging for preoperative risk assessment as infrarenal aortic aneurysm repair was planned. Single photon emission computed tomography (CT) revealed normal myocardial perfusion at adenosine-stress and at rest. However, the CT scan used for attenuation correction (AC) demonstrated a large tumor in the right upper lung as an incidental finding, and the patient was referred for staging with F-18 fluorodeoxyglucose positron emission tomography/CT and subsequently to thoracic surgery. The lesion was resected and diagnosed to be an adenocarcinoma (stage pT2, cN0, cM0). When last seen, the patient was recovering well from surgery. PMID- 20706063 TI - Current readings in nuclear medicine. PMID- 20706064 TI - Local excision of T1 rectal cancer: where are we now? PMID- 20706065 TI - Treatment of recurrence after transanal endoscopic microsurgery (TEM) for T1 rectal cancer. AB - PURPOSE: The aim of this study was to evaluate the management and outcome of local recurrences after transanal endoscopic microsurgery for T1 rectal cancer. METHODS: Consecutive patients who underwent transanal endoscopic microsurgery for pT1 rectal cancer at a Dutch referral center (IJsselland Hospital) were registered in a prospective database. Follow-up was according to Dutch guidelines on rectal cancer, with additional rigid rectoscopy and endorectal ultrasound examinations every 3 months for the first 2 years, and every 6 months thereafter. Annual MRI of the lesser pelvis was added during the last 2 years of the study. Patients with local recurrence during follow-up were selected for individual analysis of outcome. RESULTS: Of a total of 88 patients who underwent transanal endoscopic microsurgery for pT1 rectal cancer, 18 patients (20.5%) had a local recurrence. Median time to local recurrence was 10 (range, 4-50) months. Median age at diagnosis of recurrence was 74 (range, 56-84) years. Of the 18 patients, 2 did not undergo further surgery because of concomitant metastatic disease, and 16 underwent salvage surgery, without need for multivisceral resections. No postoperative mortality was observed. In 15 patients (94%), a microscopically negative excision margin was obtained; in 1 patient, the excision margin was microscopically positive. Median follow-up after salvage surgery was 20 (range, 2 112) months. One patient had a local renewal of recurrence, and 7 patients (39%) had distant metastases. At 3 years, overall survival was 31%; cancer-related survival was 58%. CONCLUSIONS: Recurrent disease after transanal endoscopic microsurgery for T1 rectal cancer is a major problem. Although salvage surgery for achieving local control is feasible in most patients, survival is limited, mainly because of distant metastases. Tailoring selection of T1 rectal cancers and exploring possible adjuvant treatment strategies following salvage procedures should be the next steps toward improving survival. PMID- 20706066 TI - Are there predictors of outcome following rectovaginal fistula repair? AB - BACKGROUND: Rectovaginal fistula is a distressing condition for patients and for physicians who are continuously challenged in providing durable treatment options. The aim of this study is to assess the results of rectovaginal fistula repair and identify predictive factors for poor outcome. METHODS: Retrospective analysis of patients who underwent rectovaginal fistula repair from 1988 to 2008 was performed. chi tests and logistical regression analysis were used to study treatment outcomes according to the following fistula characteristics: etiology, size, location, and number of prior attempts at fistula repair. In addition, patient factors such as age, body mass index, smoking history, comorbid condition of diabetes, use of steroid and immunosuppressive medications, number of prior vaginal deliveries, and presence of a diverting stoma were analyzed. RESULTS: A total of 184 procedures were performed in 125 patients. Inflammatory bowel disease was the most common indication for surgery (45.6%), followed by obstetric injury (24%) and surgical trauma (16%). The mean duration of fistula presence was 31.2 months. The procedures performed included endorectal advancement flap (35.3%), gracilis muscle interposition (13.6%), seton placement (13.6%), and transperineal (8.7%) and transvaginal repair (8.1%). The overall success rate per procedure was 60%, with no difference in recurrence rates based on the type of repair. Patients with Crohn's disease had more recurrent fistulas (44.2% success per procedure; P < .01), although 78% eventually healed after an average of 1.8 procedures. Patients with obstetric injuries had an 89% success rate after an average of 1.3 procedures per patient, which is similar to the success rate for traumatic fistulas. Pouch vaginal fistulas had a 91% success rate after an average of 1.6 procedures per patient. The overall success rate per patient was 88% after multiple procedures with a mean follow-up of 16.3 months. Age, body mass index, diabetes, use of steroids and immunosuppressive agents, size and location of the fistula, number of vaginal deliveries, time interval between a recurrent episode and subsequent repair, and the presence of fecal diversion did not affect outcomes. The presence of Crohn's disease and a smoking history are strongly associated with rectovaginal fistula recurrence (P = .02). CONCLUSIONS: Despite a relatively low initial success rate (60%), most rectovaginal fistulas can be successfully repaired with subsequent operations. Crohn's disease and smoking are associated with adverse outcomes. PMID- 20706067 TI - Clinical algorithms for the surgical management of locally recurrent rectal cancer. AB - PURPOSE: Advances in surgical practice have helped expand the options for patients with locally recurrent rectal cancer through improvements in reconstructive options, management of operative complications, addition of intraoperative adjuvant therapies, and postoperative care. This review outlines the presentation and management of patients with locally recurrent rectal cancer, and it describes easy-to-apply clinical algorithms to aid management. METHODS: The electronic literature was searched for studies reporting outcomes for locally recurrent rectal cancer limited to the English language. RESULTS: Prospective and retrospective case series and single-center experiences were identified. A total of 106 articles were selected for full-text review of which 82 fulfilled the inclusion criteria. No randomized studies were identified. We found that multimodality treatment of locally recurrent rectal cancer can improve 5-year survival from 0% to over 40%, and selected patients may survive up to 10 years. A mixture of imaging modalities is used in patient selection for surgery. An R0 resection is consistently a favorable prognostic factor. R1 resection and surgery in the setting of oligometastases compare favorably with nonoperative palliation. Although mortality figures remain low, morbidity is significant and mostly wound related. CONCLUSIONS: Improvements in radiological imaging modalities and technical improvements in surgical and reconstructive options have facilitated more accurate staging, better selection of patients for surgery, reduced morbidity and mortality, and higher R0 resections. Optimal management is in specialist units with a multidisciplinary approach with the use of multimodal therapy. PMID- 20706068 TI - Mesenteric embolization for lower gastrointestinal bleeding. AB - PURPOSE: Mesenteric embolization is an established treatment for lower gastrointestinal bleeding. The aim of this study was to determine the outcome of angiography and embolization and its influencing factors. METHODS: A prospective database of all mesenteric angiograms performed for lower gastrointestinal bleeding at a tertiary center between 1998 and 2008 was analyzed in combination with chart review. RESULTS: There were 107 angiograms performed during 83 episodes of lower gastrointestinal bleeding in 78 patients. Active bleeding was identified in 40 episodes (48%), and embolizations were performed in 37 (45%). One patient without active bleeding on angiogram also underwent embolization, making a total of 38 embolizations. Overall mortality was 7% with 4 deaths due to rebleeding and 2 deaths due to a medical comorbidity (respiratory failure, pneumonia). Short-term complications of angiography were false aneurysm (1 patient) and Enterobacter sepsis (1 patient). Long-term complications were groin lymphocele (1 patient) and late rebleed from collateralization (1 patient). In 43 episodes, angiography did not demonstrate active bleeding. Twelve (28%) of these patients continued to bleed, 9 of whom had successful surgery. Of the 38 patients who had embolizations, all had immediate cessation of bleeding. Nine patients (24%) later rebled; 5 of these patients required surgery and 3 had reembolizations. Of the 3 patients who underwent reembolization, 2 developed ischemic bowel and 1 stopped bleeding; surgery was required in 1 patient. CONCLUSIONS: Mesenteric angiography for lower gastrointestinal bleeding effectively identifies the site of bleeding in 48% of patients and allows embolization in 45%. Embolization achieves clinical success in 76% of patients but repeat embolization is associated with a high rate of complications. PMID- 20706069 TI - Benefits of perineal colostomy on perineal morbidity after abdominoperineal resection. AB - PURPOSE: Abdominoperineal resection has a high rate of postoperative morbidity of the perineal wound. This study aimed to determine the effects of perineal colostomy on perineal morbidity after abdominoperineal resection. METHODS: All patients who underwent an abdominoperineal resection for rectal adenocarcinoma between 1993 and 2007 were studied. Two groups were identified and compared who had undergone either an iliac colostomy or a perineal colostomy. RESULTS: The analysis included 110 patients (iliac colostomy group, n = 41; perineal colostomy group, n = 69). There were fewer instances of pelviperineal morbidity (P = .008) and fewer instances of wound dehiscence (P = .02) in the perineal colostomy group, which resulted in a shorter time to healing (35.3 vs 45.1 d, respectively; P = .04). There was no specific postoperative morbidity in any patient and no difference between the 2 groups regarding long-term perineal morbidity. The benefits from perineal colostomy were statistically significant in patients who received radiation therapy in terms of pelviperineal morbidity (P = .01) and healing time (50.8 vs 35.9 days, respectively; P = .02), whereas no difference was found in patients who had not received radiation therapy. CONCLUSION: Perineal colostomy is a safe and functionally acceptable procedure for perineal reconstruction after abdominoperineal resection for rectal adenocarcinoma. In the present study, there was no additional morbidity related to perineal colostomy, and this procedure was associated with a decrease in perineal morbidity and healing time compared with primary perineal closure, in particular, after radiotherapy treatment. PMID- 20706070 TI - Perineal colostomy with spiral smooth muscle graft for neosphincter reconstruction following abdominoperineal resection of very low rectal cancer: long-term outcome. AB - BACKGROUND: To avoid abdominal colostomy and improve quality of life, several types of anorectal reconstruction following abdominoperineal resection have been proposed. The aim of this study was to assess functional results and the quality of life of patients with very low rectal cancer after abdominoperineal resection and neosphincter reconstruction by perineal colostomy with a colonic muscular cuff. PATIENTS AND METHODS: Twenty-seven patients who had undergone neosphincter reconstruction with a perineal spiral cuff plasty after abdominoperineal resection were included in a retrospective study to evaluate long-term outcome. The functional results were analyzed using anal manometry and the continence score. The quality of life was measured with the global and disease-specific questionnaires European Organization for Research and Treatment of Cancer QLQ-C30 and C38. RESULTS: Median follow-up time was 105 months (range, 18-185 mo). The median Holschneider continence score of the study sample was 13 (continent), with a range of 10 (partially continent) to 16 (continent), thus demonstrating satisfactory functional results. The functional assessment was completed by neosphincter manometry which revealed a median resting vs compression pressure of 40 vs 96 cmH2O with a range of 5 to 81 cmH2O vs 49 to 364 cmH2O. The quality-of life analyses showed an above-average score for both global health and disease specific status. CONCLUSION: Spiral cuff colostomy with reconstruction after abdominoperineal resection of very low distal rectal cancer offers a surgical option for a selective group of patients with reasonable functional long-term results and an improved quality of life. PMID- 20706071 TI - Histopathology predictors of medically refractory ulcerative colitis. AB - PURPOSE: The ability of ulcerative colitis histology to predict medically refractory disease was evaluated. METHODS: Twenty patients who underwent colectomy for medically refractory disease were compared with 48 medically managed patients. All patients were followed up for > or =6 months. The study design was a retrospective longitudinal observational chart review to determine whether specific histologic parameters were predictive of a later colectomy for medically refractory disease. RESULTS: On initial biopsy, medically refractory patients were more likely to have severe cryptitis, 75% vs 49%; lymphoid follicles, 78% vs 48%; and erosions, 35% vs 11%. There was no significant difference in the prevalence of crypt abscesses, mucin depletion, crypt distortion, or mucosal ulceration between medically refractory and medically managed patients. Active inflammation on endoscopy was not statistically different between groups (P = .192). In a recursive partition model, the strongest predictors of future colectomy were age dependent. Among older patients (>38 y), severe cryptitis was the strongest determinant of refractory disease. Only 1 of 21 (5%) of the patients who initially did not have severe cryptitis progressed to colectomy. In younger patients (< or =38 y), the presence of lymphoid follicles was the strongest predictor of future colectomy; 9 of 14 (64%) patients with lymphoid follicles progressed to colectomy. CONCLUSIONS: Medically refractory ulcerative colitis was associated with initial biopsy findings of severe cryptitis, lymphoid follicles, and erosions. Refractory disease was not predicted by the severity or extent of endoscopic findings. In younger patients, the presence of lymphoid follicles, and in older patients, severe cryptitis, were the most important predictors of medically refractory disease. PMID- 20706072 TI - Development and validation of a novel prognostic scoring model for ischemic colitis. AB - PURPOSE: This study was conducted to identify prognostic factors affecting the course of ischemic colitis and to develop a prognostic scoring model. METHODS: We analyzed medical records of consecutive patients with ischemic colitis treated between October 2002 and September 2008 at Severance Hospital, Seoul, Republic of Korea. Patients were excluded if results of endoscopy were unavailable. Patients were classified as having severe ischemic colitis on the basis of outcome (improvement delayed for more than 2 weeks, complications requiring surgery, or death). Univariate analyses and multivariate logistic regression analyses with backward stepwise selection were used to identify clinical, endoscopic, and laboratory variables associated with severe ischemic colitis. A novel prognostic scoring model was derived from the data, with probability of severe ischemic colitis and risk index determined for 8 risk groups based on independent risk factors identified by multivariate analyses. Predictive power was tested by means of 10-fold cross-validation, with area under the receiver operating characteristic curve representing discrimination accuracy. RESULTS: Analyzable data were available for 153 of 173 consecutive patients. Ischemic colitis was classified as severe in 20 patients. Multivariate analyses showed the following significant independent predictors of severe ischemic colitis: tachycardia (adjusted odds ratio = 4.6; 95% CI, 1.4-14.7), shock within 24 hours after admission (adjusted odds ratio = 6.5; 95% CI, 2.0-21.2), and endoscopic evidence of ulceration (adjusted odds ratio = 9.9; 95% CI, 2.0-48.8). Probability of severe ischemic colitis and risk index were 74 times higher for patients with all 3 risk factors (group 8) than for patients with none (group 1). Internal validation showed the area under the receiver operating characteristic curve to be 0.91 (95% confidence interval, 0.86-0.96). CONCLUSIONS: Endoscopic findings and instability of vital signs were associated with the disease course of ischemic colitis. A novel scoring model based on presence of tachycardia, shock within 24 hours after admission, and endoscopic evidence of ulceration provides a method of assessing patient prognosis and should be further validated. PMID- 20706073 TI - Impact of narcotic use on the requirement for colectomy in inpatients with ulcerative colitis. AB - BACKGROUND: The effect of narcotic use in the disease course of ulcerative colitis has not been studied. The aim of the study was to evaluate the impact of narcotic use on the requirement for colectomy in inpatients with ulcerative colitis. METHODS: All eligible patients with ulcerative colitis admitted to gastroenterology service for disease flare-ups between 2002 and 2008 were included. Excluded were patients with ulcerative colitis admitted to the colorectal surgery service for emergent or elective colectomy and patients with Crohn's disease. Demographic, clinical, and laboratory data were reviewed. The definition of narcotics use was oral or intravenous administration of the agents during hospital admission or at hospital transfer. Multivariable analysis was performed. RESULTS: A total of 223 patients were included. One hundred six patients were males. The mean age was 38.7 +/- 18.1 years. Forty-four patients (19.7%) were on oral or intravenous narcotics during the hospitalization. Sixty seven patients (30%) had colectomy during the hospitalization and the colectomy rate was similar between narcotic user and nonnarcotic users (29.5% vs 30.2%, P = .9). In multivariable analysis, only the serum albumin level remained in the model as an independent risk factor associated with colectomy (OR = 0.4; 95% CI, 0.2-0.9; P = .03). Narcotic use was not an independent risk factor for colectomy in this study (P = .5). CONCLUSION: Narcotics were commonly prescribed to patients with ulcerative colitis who were admitted to the gastroenterology service. However, narcotic use appeared not to have a significant negative impact on the colectomy rate in inpatients with ulcerative colitis. In contrast, the low albumin level at flare was associated with an increased risk for colectomy. PMID- 20706074 TI - Effectiveness of a multimedia-based educational intervention for improving colon cancer literacy in screening colonoscopy patients. AB - PURPOSE: Limited data exist regarding colon cancer literacy in screening colonoscopy patients. We aimed to prospectively assess baseline colon cancer literacy and to determine whether a multimedia educational intervention was associated with improved colon cancer literacy. METHODS: Colon cancer literacy was assessed in a convenience sample of colonoscopy patients before and after educational intervention. Statistically significant associations with colon cancer literacy scores were assessed by use of multivariate logistic regression analysis. Results are frequency (proportion), mean +/- SD, and odds ratio (OR (95% CI)). RESULTS: Seventy-three subjects participated: mean age, 57 +/- 12 years, 35 (48%) were women, 41 (57%) had a college degree, 43 (59%) had prior colonoscopy, 21 (29%) were accompanying family, and 16 (22%) were health care employees. Multivariate factors associated with a higher baseline colon cancer literacy score included health care employee status (7.9 (95% CI, 1.6-63); P = .02) and family colon cancer history (5.3 (95% CI, 1.3-25); P = .02). After multimedia education, mean scores improved from 53% +/- 23% to 88% +/- 12% (Delta = 35%; P < .0001). On univariate analysis, college-educated subjects had higher final scores (91% vs 83%; P = .007), but this association was not significant on multivariate regression (P = .07). Only baseline score was associated with higher postintervention score (1.7 (95% CI, 1.2-2.6); P = .005). Sixty-two subjects (86%) were very satisfied, and 70 (97%) would recommend the module to friends and family. CONCLUSION: A knowledge deficit of colon cancer-related concepts is frequently observed in patients undergoing screening colonoscopy. Multimedia based educational intervention was an effective, satisfying strategy for addressing cancer-specific knowledge deficit in laypersons. PMID- 20706075 TI - Rectal motility in patients with idiopathic fecal incontinence: a study with impedance planimetry. AB - INTRODUCTION: Most patients with fecal incontinence have poor anal sphincter function. In patients with idiopathic fecal incontinence no structural abnormality can be identified. The aim of the present study was to compare rectal motility patterns in patients with idiopathic fecal incontinence and in healthy controls. METHODS: Rectal impedance planimetry provides simultaneous measurement of rectal pressure, anal pressure, and rectal cross-sectional area at 5 levels. This allows highly detailed description of rectoanal motility. In 12 female patients with idiopathic fecal incontinence (mean age, 64.5) and 12 healthy controls (mean age, 47; 12 females) rectal phasic activity and tone were studied at a distension pressure 10 cm H2O above basic rectal pressure for one hour during fast and one hour after the meal. RESULTS: The median rectal cross sectional area during fast was 3178 mm2 (range, 1905-4095) in patients with fecal incontinence and 2907 mm2 (range, 1832-4195) in the control group (P = .42). The postprandial decrease in rectal cross-sectional area was significantly more pronounced in patients (median postprandial reduction 462 mm2 (range, 3124 reduction to 7 increase)) than in the control group (median postprandial change 33 mm2 (range, 844 reduction to 974 increase)) (P = .007). The number of anal sampling reflexes during fast was reduced in patients (P = .03) and rectal wall tension during anal sampling reflexes also tended to be lower (P = .07). No differences in other phasic rectal motility patterns were found. CONCLUSION: Idiopathic fecal incontinence is associated with enhanced postprandial increase in rectal tone and a reduced frequency of anal sampling reflexes. PMID- 20706076 TI - Perirectal fascia and spaces: annular distribution pattern around the mesorectum. AB - PURPOSE: In view of debate on the optimal surgical planes for total mesorectal excision, this study was designed to explore the regional anatomy of the perirectal fascia and spaces. METHODS: Twenty-one cadavers (15 male and 6 female) were embalmed and their vessels visualized by injection with color dye. From the cadavers, 30 hemipelves and 6 three-quarter pelves were harvested. The perirectal fascia and spaces and the pelvic autonomic nerves were dissected and examined. RESULTS: Three tissue layers were dissected from the inside to the periphery: the proper rectal fascia enveloping the mesorectum, the presacral fascia, and the piriformis fascia fused with the sacral periosteum. The mesorectum comprised 2 parts: posterior, with the classical posterolateral fat covered by the proper rectal fascia; and anterior, with the anterior fat covered by the posterior layer of Denonvilliers fascia. Extending anteriorly to the anterior layer of Denonvilliers fascia, the presacral fascia bisected the space between the mesorectum and the piriformis fascia into the retrorectal space and the presacral space. The retrorectal space extended cranially to the left Toldt's space, anterior to the space between the 2 layers of Denonvilliers fascia. CONCLUSIONS: From the inside to the periphery, the proper rectal fascia, the presacral fascia, and the muscular fascia are distributed in an annular pattern around the mesorectum. The presacral fascia divides the perirectal space into 2 annular parts: the central retrorectal space and the peripheral presacral space. The retrorectal space is the ideal surgical plane for the total mesorectal excision. PMID- 20706077 TI - Assessment of comparative skills between hand-assisted and straight laparoscopic colorectal training on an augmented reality simulator. AB - PURPOSE: The aim of this study was to compare skills sets during a hand-assisted and straight laparoscopic colectomy on an augmented reality simulator. METHODS: Twenty-nine surgeons, assigned randomly in 2 groups, performed laparoscopic sigmoid colectomies on a simulator: group A (n = 15) performed hand-assisted then straight procedures; group B (n = 14) performed straight then hand-assisted procedures. Groups were compared according to prior laparoscopic colorectal experience, performance (time, instrument path length, and instrument velocity changes), technical skills, and operative error. RESULTS: Prior laparoscopic colorectal experience was similar in both groups. Both groups had better performances with the hand-assisted approach, although technical skill scores were similar between approaches. The error rate was higher with the hand-assisted approach in group A, but similar between both approaches in group B. CONCLUSIONS: These data define the metrics of performance for hand-assisted and straight laparoscopic colectomy on an augmented reality simulator. The improved scores with the hand-assisted approach suggest that with this simulator a hand-assisted model may be technically easier to perform, although it is associated with increased intraoperative errors. PMID- 20706078 TI - Impact of lifestyle factors on colorectal polyp detection in the screening setting. AB - BACKGROUND: Awareness of risk factors for colorectal neoplasia could address risk reduction strategies in asymptomatic subjects. METHODS: This is a post hoc analysis of a prospective, cross-sectional study of 1321 asymptomatic adults. All the subjects underwent same-day CT colonography and colonoscopy to determine the prevalence of colorectal neoplasia. The variables examined included body mass index, smoking, alcohol consumption, age, and gender. Univariate and logistic regression analyses were performed for detection of colorectal neoplasia and hyperplastic polyps. Odds ratios with 95% confidence intervals were calculated. RESULTS: Colorectal adenomas and hyperplastic polyps were detected in 378 (28.6%) and 157 (11.9%) participants, respectively. In both univariate and multivariate analysis, increasing age, male gender, and body mass index > or =25 were significantly associated with the detection of colorectal adenomas, with an odds ratio of 1.22 (95% CI,1.09-1.36), 1.28 (95% CI, 1.06-1.45), and 1.34 (95% CI, 1.02-1.77), respectively. A history of smoking was the only identifiable risk factor for hyperplastic polyps (odds ratio, 1.98; 95% CI, 1.41-2.78). CONCLUSIONS: Body mass index > or =25, increasing age, and male gender were all associated with an increased likelihood of colorectal adenomas at screening, whereas smoking was strongly associated with hyperplastic polyps. PMID- 20706079 TI - Laparoscopic parastomal hernia repair. AB - Parastomal hernia is a common complication after stoma formation. Its reported incidence varies from 30% to 50%. Loop ileostomy has the lowest risk (0%-6.2%), followed by end ileostomy, and loop colostomy with a similar risk of 28% to 30%. End colostomy carries the highest risk for parastomal hernia of 48%. Even though most hernias occur within the first 2 years after stoma construction, the risk of herniation extends up to 20 years. Theoretically, parastomal hernia occurs as a result of mechanical factors, an intrinsic defect in collagen metabolism, and wound repair. Parastomal hernia is asymptomatic most of the time, but it may be associated with serious complications such as strangulation and perforation; hence, elective repair is mandatory for carefully selected cases and surgical approaches. Primary closure of the aponeurosis at the hernia site, either via peristomal approach or through midline incision, is a simple procedure, but it carries a recurrence rate of 38% to 100%. Stoma relocation may result in a zero recurrence rate at the same hernia site, but the risk of a parastomal hernia after new stoma formation is still expected. In addition, an incisional hernia at the previous colostomy site closure may also occur. Similar to other sites of hernia repair, prosthetic mesh has been used to reinforce the hernia defect intraperitoneally through open incision and recently via the laparoscopic approach. Mesh repair has demonstrated the lowest risk of recurrence for parastomal hernia of 0% to 33%. PMID- 20706082 TI - Just because it can be done, should it? PMID- 20706083 TI - Bioprosthetics in parastomal hernia repair. PMID- 20706087 TI - Garden walking for depression: a research report. AB - This study was designed to determine the effect of garden walking and reflective journaling on adults who are 65 years old and older with depression. The Geriatric Depression Scale measured depression. Four themes emerged from the interview data collected from each participant. PMID- 20706088 TI - The Touchstone Process: an ongoing critical evaluation of reiki in the scientific literature. AB - BACKGROUND: Reiki is used by a growing number of people but little is known about the scientific basis for its use. PURPOSE: The Touchstone Process was developed as an ongoing process to systematically analyze published, peer-reviewed studies of Reiki, the results being made accessible to the public online. METHOD: Thirteen scientifically qualified experts in the field of Reiki were assembled into 3 teams to retrieve, evaluate, and summarize articles using standardized, piloted evaluation forms. RESULTS: Summaries of 26 Reiki articles, including strengths and weaknesses, were posted on a newly developed Web site (www.centerforreikiresearch.org), together with an overall summary of the status of Reiki research and guidelines for future research: The Touchstone Process determined that only 12 articles were based on a robust experimental design and utilized well-established outcome parameters. Of these articles, 2 provided no support, 5 provided some support, and 5 demonstrated strong evidence for the use of Reiki as a healing modality. CONCLUSION: There is a need for further high quality studies in this area. PMID- 20706089 TI - The effect of mindfulness meditation on painful diabetic peripheral neuropathy in adults older than 50 years. AB - This pilot study explored the effect of mindfulness meditation for diabetic neuropathy. Twenty participants (10 in each group) completed the study. No significant differences were found between the groups. However, differences between the means were found on 2 constructs: pain quality of life and symptom related quality of life. Further studies may show efficacy. PMID- 20706090 TI - Lifestyle strategies for the prevention of vision loss. AB - As the baby boom generation ages, it is anticipated that half a million cases per year will be added to the 19 to 21 million Americans not living in institutions or serving in the military who have low vision or blindness. The 4 major causes of vision loss and blindness in the United States are cataract, diabetic retinopathy, glaucoma, and age-related macular degeneration. All 4 diseases involve change in the microcirculation in eye structures. Holistic approaches to health incorporate attention to individuals' lifestyle choices. Relevant research literature was reviewed to identify strategies for lifestyle modification that nurses can use to prevent or slow progression of these diseases. Prevention strategies in general are those that promote avoidance of cardiovascular disease and diabetes. Because vision loss has been shown to be associated with diminished quality of life and increased mortality, lifestyle changes that prevent or moderate the impact of these diseases are an important focus of nursing care. PMID- 20706092 TI - Self-care essential extras: an integration of holistic nursing, functional medicine, and health coaching to promote therapeutic lifestyle change and decrease chronic disease. AB - The Essential Vitality Program blends holistic nursing, functional medicine, and health coaching to promote lifestyle changes that modify risk factors of costly chronic disease. Karl is a client who experienced enhanced vitality, decreased chronic pain and medications use, and improved meaningful functioning, by partnering with a holistic nurse coach. PMID- 20706093 TI - Social networking, holistic nursing, and self-care. PMID- 20706094 TI - Should pregnant women be able to choose elective cesarean as a birth option? PMID- 20706096 TI - Respectful disposition in early pregnancy loss. AB - This article discusses an issue rarely seen in the professional literature: the tangible ways nurses can respect a woman's needs following miscarriage by ensuring the safe handling and disposition of fetal tissue or remains. Concepts of personhood, place, and protection are important for nurses to understand within the context of a woman's response to miscarriage. Hospitals or clinics that foster a culture of respectful fetal disposition should have a system in place to bury tissue or fetal remains in a designated area; in fact, several states have enacted laws that regulate what hospitals and clinics must do, or what women must be offered, after a miscarriage or ectopic pregnancy. Barriers may exist to creating a culture of respectful disposition, including staff attitudes, perceived time and financial constraints, lack of knowledge, and inefficient communication between departments. Nurses can begin implementing change in this regard through conducting a needs assessment using guiding questions contained in this article. In addition, through communication, education, and implementation of respectful disposition, nurses can promote safe processes that will honor women's preferences and wishes for care following a miscarriage. PMID- 20706098 TI - Screening and counseling for postpartum depression by nurses: the women's views. AB - PURPOSE: In this part 2 article of research examining a model of care in which nurses screen and counsel postpartum women for postpartum depression, acceptability of such a model to postpartum patients was evaluated with a diverse sample of American women. STUDY DESIGN AND METHODS: Descriptive survey of two groups: 691 predominately white postpartum women with relatively high annual incomes (Sample 1) and 132 low-income women, some of whom were ethnic minorities (Sample 2). The surveys were distributed and needed to be mailed back to the investigators. The response rate was 72% in Sample 1 and 30% in Sample 2. RESULTS: The overwhelming majority in both groups (>90%) felt that it was acceptable for nurses to perform screening for postpartum depression and for nurses to do the necessary counseling. More than half in each sample were "definitely willing" to see a nurse for counseling. Although women in both samples had positive views, when compared with each other, women with higher incomes (Sample 1) had more positive views of nurse-delivered mental healthcare. More than half in each sample were "definitely willing" to see a nurse for counseling. For Sample 1, 15% reported having taken medications for postpartum depression; in Sample 2 this number was 22.3%. CLINICAL IMPLICATIONS: Nurses have frequent contact with postpartum women; as such, they are well positioned to provide depression screening and counseling. Nurse-delivered mental healthcare has the potential to obviate many barriers that prevent the detection and treatment of depression, and ultimately improve outcomes for infant and children. PMID- 20706099 TI - NNP education in neonatal end-of-life care: a needs assessment. AB - PURPOSE: To determine from practicing neonatal nurse practitioners (NNPs) their perceived end-of-life (EOL) care learning needs. DESIGN AND METHOD: A needs assessment-based evaluation methodology was used to answer the research questions. A neonatal EOL needs assessment survey was developed, pilot tested, and then mailed to 260 NNPs across the United States. RESULTS: NNPs in clinical practice regarded their education on EOL for neonates and their families as inadequate. Twenty-three percent ranked "delivery room decisions to resuscitate infants considered at edge of viability" as the item for which they most wanted more training. The other top-ranked EOL items included balance between giving parents false hopes and removing all hopes, and communicating and giving bad news to families. CLINICAL IMPLICATIONS: Based on these findings, specific neonatal EOL education and communication skill workshops are warranted for graduate nursing core and advance practice continuing education courses. Additionally, there needs to be a mechanism to provide EOL content and support for the NNP already in clinical practice; it is suggested that learning about EOL issues can be integrated into existing (continuing nursing education CNE) educational activities. Further research is needed on what issues, tools, and methods in CNE programs make a difference in the experience of NNPs. PMID- 20706100 TI - Assessing mandated breastfeeding education in Istanbul. AB - PURPOSE: To assess the implementation of a breastfeeding education program for women in Istanbul against the backdrop of the relevant policies adopted by the country of Turkey. METHODS: Descriptive and cross-sectional survey of mothers of 801 infants, ages 0 to 12 months, who presented at the vaccination and neonatal follow-up unit of the Yenibosna Mother and Child Health and Family Planning Center in Istanbul. Mothers were interviewed using a questionnaire developed by the investigators. Frequency distributions and chi-square analyses were used for the data. RESULTS: Forty-six percent of the women in the sample had received breastfeeding education either when they gave birth or right afterward; 63.8% had initiated breastfeeding in the first hour after birth. The rate of exclusive breastfeeding was 81.1% in the first month, 51.5% in the fourth month, 19.8% in the sixth month, and 1% in the twelfth month. The average duration of exclusive breastfeeding was 3.45 months (+/-2.1). Introduction to a supplementary food started at an average of 4.4 months (+/-2.1), usually with tea, water, fruit juice, or yogurt. CLINICAL IMPLICATIONS: Despite a government mandate to educate every new mother about the advantages of breastfeeding, less than one-half of the women in this study actually reported receiving the education. Nurses who work with pregnant and postpartum women can use this study to help guide implementation of interventions to increase breastfeeding programs. It is clear that more effort needs to go into teaching women not only about initiating breastfeeding, but also about exclusive breastfeeding until at least 6 months of age. PMID- 20706101 TI - The scoop on salt. PMID- 20706102 TI - What is the HIT systems life cycle? PMID- 20706105 TI - e-Iatrogenesis. PMID- 20706106 TI - Embracing telemedicine in wound care. PMID- 20706107 TI - Efficacy of human papillomavirus-based screen-and-treat for cervical cancer prevention among HIV-infected women. AB - BACKGROUND: Cervical cancer prevention should be provided as part of primary healthcare services for HIV-infected women but conventional screening programs are difficult to implement in low-resource settings. Here, we evaluate the efficacy among HIV-infected women of a simpler, screen-and-treat strategy in which all women with a positive screening test are treated with cryotherapy. METHODS: We conducted a randomized clinical trial of two screen-and-treat strategies among 6555 women in Cape Town, South Africa, among whom 956 were HIV positive. Women were randomized to screen-and-treat utilizing either human papillomavirus DNA testing or visual inspection with acetic acid as the screening method or to a control group. Women were followed for up to 36 months after randomization with colposcopy and biopsy to determine the study endpoint of cervical intraepithelial neoplasia grade 2 or higher. RESULTS: In the control group, HIV-positive women had higher rates of cervical intraepithelial neoplasia grade 2 or higher detected by 36 months (14.9%) than HIV-negative women (4.6%) (P = 0.0006). Screen-and-treat utilizing human papillomavirus DNA testing significantly reduced cervical intraepithelial neoplasia grade 2 or higher through 36 months in both HIV-positive (relative risk = 0.20, 95% confidence interval 0.06-0.69) and HIV-negative women (relative risk = 0.31, 95% confidence interval 0.20-0.50). Reductions in the visual inspection with acetic acid-and treat group were less marked. Complications of cryotherapy were mostly minor and did not differ in frequency between HIV-positive and HIV-negative women. CONCLUSION: Screen-and-treat using human papillomavirus testing is a simple and effective method to reduce high-grade cervical cancer precursors in HIV-infected women. PMID- 20706108 TI - Activation of Notch signaling pathway in HIV-associated nephropathy. AB - OBJECTIVE: HIV-associated nephropathy (HIVAN) is characterized by the development of glomerulosclerosis and is associated with glomerular epithelial cell proliferation. It has recently been shown that activation of the Notch signaling pathway in podocytes results in glomerulosclerosis and podocyte proliferation. To determine whether Notch signaling is involved in renal disorder associated with HIVAN, we evaluated the expression of Notch receptors in HIVAN. DESIGN: We evaluated the expression of the Notch signaling pathway using an HIV-transgenic (HIV-Tg) rat model of HIVAN, and biopsy samples from HIVAN and normal controls. METHODS: Paraffin sections and kidney lysates were used for immunohistochemistry, immunofluorescence and western blot analysis. RESULTS: A collapsing variant of glomerulosclerosis and focal segmental sclerosis was observed in HIV-Tg rats. Glomeruli of HIV-Tg rats demonstrated activation of Notch1 and Notch4, as determined by the presence of the intracellular domains. In addition, we observed increased expression of the Notch target protein, hairy enhancer of split homolog 1 in glomeruli of these animals. The expression of the Groucho homolog transducin like enhancer protein 4, a Notch effector protein, and the homeodomain protein cut homeobox 1 were also significantly increased in glomeruli of HIV-Tg rats, and this was associated with decreased expression of the cyclin kinase inhibitor p27. Intriguingly, renal biopsy samples from HIVAN patients also showed upregulation of cleaved Notch1 and Notch4 in the glomeruli compared with the expression in normal kidneys. CONCLUSION: Our results demonstrate activation of Notch signaling pathway in HIVAN, thereby underscoring its role in disease pathogenesis. PMID- 20706109 TI - Episomal and integrated human papillomavirus type 16 loads and anal intraepithelial neoplasia in HIV-seropositive men. AB - OBJECTIVES: To assess levels of episomal and integrated human papillomavirus type 16 (HPV-16) loads in HIV-seropositive men who have sex with men (MSM) in anal infection and to study the association between episomal and integrated HPV-16 loads and anal intraepithelial neoplasia (AIN). STUDY DESIGN: A cohort study of 247 HIV-positive MSM followed each 6 months for 3 years. Overall, 135 (54.7%) men provided 665 HPV-16-positive anal samples. METHODS: Episomal and integrated HPV 16 loads were measured with quantitative real-time PCR assays. HPV-16 integration was confirmed in samples with a HPV-16 E6/E2 of 1.5 or more with PCR sequencing to demonstrate the presence of viral-cellular junctions. RESULTS: The HPV-16 DNA forms in anal samples were characterized as episomal only in 627 samples (94.3%), mixed in 22 samples (3.3%) and integrated only in nine samples (1.4%). HPV-16 episomal load [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.1], number of HPV types (OR = 1.4, 95% CI 1.1-1.8) and current smoking (OR = 4.8, 95% CI 1.3-18.6) were associated with high-grade AIN (AIN-2,3) after adjusting for age and CD4 cell counts. Integrated HPV-16 load was not associated with AIN-2,3 (OR = 0.7, 95% CI 0.4-1.1). Considering men with AIN-1 at baseline, four (16.7%) of the 24 men who progressed to AIN-2,3 had at least one sample with integrated HPV-16 DNA compared with three (23.1%) of 13 men who did not progress (OR = 0.7, 95% CI 0.2-3.8; P = 0.64). Integration was detected in similar proportions in samples from men without AIN, with AIN-1 or AIN-2,3. CONCLUSION: High episomal HPV-16 load but not HPV-16 integration load measured by real-time PCR was associated with AIN-2,3. PMID- 20706111 TI - Forensic aspect of cause of subendocardial hemorrhage in cardiopulmonary resuscitation cases: chest compression or adrenaline. AB - Subendocardial hemorrhage (SEH) is a striking feature seen in many forensic autopsy cases. It was believed earlier to represent an agonal phenomenon without any particular reference to the cause of death. However, the latest study showed that even minor SEH might have an influence on cardiac function and might be involved in the mechanism of death. To rule out the possible cause of SEH from defibrillation, autopsies were performed in 240 adults admitted to Department of Forensic Medicine, Faculty of Medicine, Srinakarinwirot University and Department of Forensic Medicine, Faculty of Medicine, Chulalongkorn University between July 2006 and June 2008. All the subjects were subdivided into 2 groups: one group receiving resuscitation and the other group receiving no resuscitation. In the former group, 76 patients had attempted cardiopulmonary resuscitation with adrenaline and 44 patients without adrenaline. While in the latter group, 120 patients received no resuscitation attempt. Approximately, 43.4% of resuscitation with adrenaline cases (33/76) demonstrated SEH in contrast to 4 cases of resuscitation without adrenaline (9.1%, P < 0.05). This demonstrates an increasing trend of SEH in cases with prolonged resuscitation and higher level of adrenaline utilizations. PMID- 20706110 TI - A randomized controlled trial of intermittent compared with daily cotrimoxazole preventive therapy in HIV-infected children. AB - OBJECTIVE: Cotrimoxazole preventive therapy (CPT) reduces morbidity and mortality in HIV-infected children. The WHO recommends prolonged daily CPT for HIV-infected infants and children. In adults, intermittent CPT has been associated with less adverse events than daily, with increased tolerability and equal efficacy. We investigated the efficacy and tolerability of intermittent CPT compared with daily CPT in HIV-infected children over a 5-year period. DESIGN: A prospective randomized controlled study. METHODS: HIV-infected children aged at least 8 weeks were randomized to thrice weekly or daily CPT. Outcome measures were mortality, bacterial infections, hospitalizations and adverse events. RESULTS: Three hundred and twenty-four children (median age 23 months) were followed for 672 child years; 165 (51%) were randomized to intermittent CPT. Most children (287, 89%) were Centers for Disease Control and Prevention clinical category B or C; 207 (64%) received HAART during the study. Mortality (53 deaths, 16%) was similar in the intermittent CPT compared with the daily CPT group {24 (14%) vs. 29 (18%), hazard ratio 0.75 [95% confidence interval (CI) 0.44-1.29]}. The predominant causes of death in both groups were sepsis (17, 32%), pneumonia (13, 25%) or diarrhoea (8, 15%). Intermittent CPT was associated with more bacteraemias [incidence rate ratio 2.36 (95% CI 1.21-4.86)]. Children receiving intermittent CPT also spent more days in hospital [incidence rate ratio 1.15 (95% CI 1.04 1.28)]. The rate of serious adverse events was similar between groups [incidence rate ratio 1.07 (95% CI 0.58-2.02)]. CONCLUSION: Intermittent CPT was associated with more invasive bacterial disease than daily CPT, but survival was similar. Both regimens were well tolerated. On balance, daily CPT remains preferable to intermittent therapy for HIV-infected children. PMID- 20706112 TI - A pilot study to examine the feasibility and effects of a home-based aerobic program on reducing fatigue in children with acute lymphoblastic leukemia. AB - BACKGROUND: Fatigue is one of the most frequent symptoms experienced by children with cancer during treatment. Effective management of fatigue is essential for improving children's quality of life. OBJECTIVE: The aim of this study was to examine the feasibility of a home-based aerobic exercise intervention to reduce fatigue in children with acute lymphoblastic leukemia (ALL). METHODS: A 6-week home-based aerobic exercise intervention was implemented for children who were in the intervention group, whereas patients in the control group received routine care. Multivariate analysis was used to examine the effects of the aerobic exercise intervention on the children's self-reported levels of fatigue at posttest and 1-month follow-up. Two types of analysis were used: intent-to-treat analysis and per-protocol analysis. RESULTS: This study was conducted with 22 children with ALL: 12 in the intervention group and 10 in the control group who were matched by age and sex. For per-protocol analysis, the finding indicated that children who received the exercise intervention reported significantly lower "general fatigue" subscale than those in the control group at the 1-month follow up measurement. For intent-to-treat analysis, the findings indicated that there were no intervention and time effect for any of the 3 fatigue subscales at either posttest or 1-month follow-up. CONCLUSION: The finding indicated that the exercise program is feasible and warrants being tested in a clinical trial with a much larger sample of children for ALL. IMPLICATIONS FOR PRACTICE: It suggests that a home-based exercise program may reduce fatigue for ALL children who are undergoing maintenance chemotherapy. PMID- 20706113 TI - Coronary artery bypass graft surgery (CABG) for patients with diabetes and multivessel coronary artery disease: identifying patients who would benefit with CABG and understanding the potential mechanisms involved. AB - Treatment of diabetic patients with multivessel coronary artery disease is controversial. This paper reviews pertinent literature on surgical revascularization with emphasis on which patients benefit from therapy. Recent studies of medical, percutaneous, and surgical therapies have added greatly to our understanding of the treatment of diabetic patients with coronary artery disease. Randomized trials show no advantage with prophylactic percutaneous coronary intervention over medical therapy. However, in patients with more severe three-vessel disease, coronary artery bypass graft surgery (CABG) improved outcomes with respect to reduced myocardial infarction events and cardiac death as compared with medical therapy. In addition, rates of late myocardial infarction and mortality were significantly lower in patients treated with CABG compared with those who received drug-eluting stents. Although the need for subsequent revascularization with drug-eluting stents is reduced compared with angioplasty and bare-metal stents, the rate is still higher than that associated with CABG. CABG reduces risks of myocardial infarction, cardiac death, and need for repeat revascularization in diabetic patients with severe, multivessel coronary artery disease. PMID- 20706114 TI - Neurogenic inflammation of the ocular surface. AB - PURPOSE OF REVIEW: The purpose of the present review is to describe the involvement of neurogenic inflammation in ocular surface diseases and to outline recent advances in understanding the complex interaction of neuromediators and inflammatory cells in the conjunctiva. RECENT FINDINGS: Evidence indicates that all clinical forms of ocular surface disease, including allergic and autoimmune, share the involvement of a neurogenic inflammation triggered by nociceptive stimuli and resulting in plasma extravasation and local activation of immune cells. Players of this complex mechanism are neuropeptides, including substance P, calcitonine gene-related peptide, neuropeptide Y, and vasoactive intestinal peptide. These neuropeptides are, however, only a minor component of a complex neuroimmune cross-talk capable of modulating local inflammation. SUMMARY: As already shown in other mucosal surfaces, neurogenic inflammation and innate immunity may work together to protect the ocular surface. In this review, we present the most recent advances in the understanding of the roles played by nerve endings and neuropeptides in local inflammatory processes of the ocular surface, in order to better clarify their function in physiologic and pathologic conditions and to open new research, diagnostic, and therapeutic perspectives. PMID- 20706115 TI - Update in drug allergy: novel drugs with novel reaction patterns. AB - PURPOSE OF REVIEW: In the last years, many novel drugs have been introduced, generating new patterns of drug hypersensitivity. There are also novel clinical and biologic techniques that have enabled us to understand the mechanisms and diagnosis of reactions to old used drugs. This review summarizes current knowledge on the epidemiology, mechanisms, and clinical and in-vitro diagnosis of these reactions. RECENT FINDINGS: Traditional and complementary alternate medicines are also causes of adverse drug reactions, and many of them are cataloged as allergy. Research in the field of skin and drug provocation test to antibiotics such as beta-lactams and carbapenems, and iodinated and gadolinium contrast media has allowed the understanding of cross-reactivity reactions and permitted the use of well tolerated alternate drugs in cases of proper negative drug allergy work-up. Many unique cases have been reported, including diverse drugs as infliximab, succinylcholine, hydroxychloroquine, that widen the spectrum of clinical manifestations of drug hypersensitivity to various drugs. Several studies have been published in the field of in-vitro diagnosis, including basophil activation tests, radioallergosorbent test, Immuno-Cap, ELISA, enzyme linked immunospot assays, and T-cell proliferation tests allowing novel approaches to assess drug allergy. SUMMARY: As new and old drugs continue to be used, new reports regarding new and known drug hypersensitivity manifestations are made. Advances in mechanisms are enhanced by the use of new in-vitro techniques to detect specific antibodies or T cells. Research in the field of skin and provocation tests has allowed the use of well tolerated alternate drugs in individuals with proven drug allergy. PMID- 20706116 TI - Genome-wide approaches to the etiology of eczema. AB - PURPOSE OF REVIEW: The present review summarizes the new discoveries in the genetics of eczema, focusing on the results from the recently published first genome-wide association study. RECENT FINDINGS: The first genome-wide association study for eczema included 10 000 individuals and provided strong evidence for a new susceptibility locus for eczema in chromosome 11q13.5 (P = 7.6 x 10). Importantly, this finding has been confirmed by an independent research group. Homozygous carriers of the risk allele rs7927894[A] represent 11% of the population and their risk of developing eczema is 1.47 times higher than in no carriers. This polymorphism also confers risk to Crohn's disease, suggesting the locus may be related to epithelial immunity or differentiation. This study also detected association with the epidermal differentiation complex in 1q21 and suggests that additional risk factors exist in this region apart from the well established mutations in the filaggrin gene. SUMMARY: The first genome-wide association study for eczema has convincingly identified a new susceptibility locus for eczema. However, the exit from this study was limited, as only one new locus was identified. Complementary strategies aiming to distinguish the 'true association' signals from the false positive results, together with larger sample sizes are required in order to achieve the full potential of this promising approach. PMID- 20706117 TI - Neurogenic aspects of stress urinary incontinence. AB - PURPOSE OF REVIEW: Vaginal childbirth is a significant risk factor for stress urinary incontinence (SUI). Women with SUI demonstrate dysfunction of the pelvic floor and pudendal nerve. Animal models of SUI have been developed to investigate its pathophysiology and for preclinical testing of potential treatments. RECENT FINDINGS: Vaginal distension, a method of simulating childbirth injury in animals, produces a reliable decrease in leak point pressure (LPP), a measure of urethral resistance to leakage and quantification of SUI severity in animals. In addition to ischemia and direct tissue damage, vaginal distension causes denervation of the external urethral sphincter (EUS). Pudendal nerve crush produces a similar decrease in LPP, whereas combined PNC and vaginal distension injury delays recovery of LPP compared with either single injury alone. Neurophysiologic studies have elucidated the results of each injury and their combination on pudendal nerve and EUS function. Urethrolysis, electrocautery, and pudendal nerve transection produce more durable functional impairment via both structural damage and denervation. Pubourethral ligament injury eliminates the structural support of the urethra, but its neurologic effects are unknown. SUMMARY: Animal models demonstrate a complex interplay between tissue damage and pudendal nerve dysfunction, and provide insight into the importance of neuroregeneration in the recovery of continence. PMID- 20706118 TI - Effect of prolapse repair on voiding and bladder overactivity. AB - PURPOSE OF REVIEW: To determine the effects of repair of pelvic organ prolapse (POP) on detrusor overactivity, overactive bladder (OAB) symptoms and voiding function. Understanding the cause of OAB in women with prolapse gives us more insight into the cause of detrusor overactivity and OAB in general. Understanding the different causes involved in OAB will allow us to target our treatments more effectively. This review discusses the evidence linking OAB and prolapse. Relevant studies or review articles were identified by performing a literature search using PubMed and MEDLINE. RECENT FINDINGS: Prolapse and OAB may occur by chance together, but epidemiological studies support a link between OAB and prolapse. Also, POP repair (surgical correction or a ring pessary placement) is associated with improvement or resolution of OAB symptoms and detrusor overactivity. For these reasons, there seems to be a causal link between prolapse and OAB. The cause of OAB and detrusor overactivity is not fully understood, but theories relate to myogenic, neurogenic and obstructive elements. The most commonly accepted pathophysiology when prolapse is involved is that of increased bladder outlet obstruction or resistance. This is supported when the correction of POP improves voiding function, which is associated with a reduction in OAB. SUMMARY: POP repair (surgery/ring pessary) has a positive effect on the resolution of OAB, detrusor overactivity and voiding dysfunction, providing a theory for a causal effect between the conditions. Larger prospective observational studies are needed. PMID- 20706119 TI - Female sexual dysfunction and adolescents. AB - PURPOSE OF REVIEW: To review recent publications in the area of sexual dysfunction in females including the adolescent age group. RECENT FINDINGS: Though as many as 40% of adult females have a sexual dysfunction, the incidence among adolescent females is unknown. Though over half of adolescents are sexually active, sexual dysfunction is not a term universally accepted among the general public as well as researchers. Research on sexual dysfunction in females typically starts with age 18 years or over. Causes of sexual dysfunction include medical disorders, gynecological problems, which started from the adolescent age, psychiatric disorders, and complications of medications such as selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and others. Management includes identification of the specific sexual dysfunction and treatment of the underlying condition, including surgical treatment in such cases as absent vagina or obstetrics fistula. Psychological therapy is helpful when psychological factors are contributory to the dysfunction. Pharmacologic principles of management cases can, for example, include treatment of gynecological problems such as pelvic inflammatory disease (PID) or endometriosis as a cause of sexual dysfunction or include removal of the offending drug, use of glutamatergic strategies or trazodone in SSRI-association dysfunction, and addition of bupropion or other medications in select cases. No medication is FDA-approved for sexual dysfunction in females. SUMMARY: Sexual dysfunction in females includes lack of sexual desire, sexual pain disorders (as dyspareunia), anorgasmia, and sexual arousal dysfunction. Acceptance of the high incidence of sexual dysfunction in all female populations is necessary to appreciate this phenomenon in the adolescent cohort, because some gynecological disease can arise from the adolescent age and can cause sexual dysfunction. Some sexual dysfunctions require immediate treatment, including surgical in the case of congenital anomaly, ovarian cyst, or tumor. Current understanding is based on extrapolation of research in the adult population. Management principles include removal of offending drugs and treatment of underlying disorders. Research in the adolescent population is recommended for more understanding and acceptance of this phenomenon in this age group. PMID- 20706120 TI - Supportive care in neurooncology. AB - PURPOSE OF REVIEW: Malignant brain tumors have a very poor prognosis and the natural history of disease is very short, usually less than 1 year. Brain tumor patients often present peculiar symptoms of disease that require appropriate supportive treatment, namely, peritumoral brain edema, venous thromboembolism, seizures and opportunistic infections. On the other hand, some important problems such as rehabilitation, depression, psychological support/communication and end of-life issues/treatment decisions have been poorly investigated so far. RECENT FINDINGS: This review focuses on the most recent findings for the management of the most relevant symptoms of brain tumor patients, also discussing the complexity of palliative measures that should be adopted in patients approaching the end of life. SUMMARY: In recent years, there has been some progress in the medical management of brain tumor patients. Nevertheless, much still needs to be done for further improvement, especially focusing on the unmet need for education in supportive care and end-of-life issues. PMID- 20706121 TI - Epilepsy and brain tumors. AB - PURPOSE OF REVIEW: To present an overview of the recent findings in pathophysiology and management of epileptic seizures in patients with brain tumors. RECENT FINDINGS: Low-grade gliomas are the most epileptogenic brain tumors. Regarding pathophysiology, the role of peritumoral changes [hypoxia and acidosis, blood-brain barrier (BBB) disruption, increase or decrease of neurotransmitters and receptors] are of increasing importance. Tumor-associated epilepsy and tumor growth could have some common molecular pathways. Total/subtotal surgical resection (with or without epilepsy surgery) allows a seizure control in a high percentage of patients. Radiotherapy and chemotherapy as well have a role. New antiepileptic drugs are promising, both in terms of efficacy and tolerability. The resistance to antiepileptic drugs is still a major problem: new insights into pathogenesis are needed to develop strategies to manipulate the pharmakoresistance. SUMMARY: Epileptic seizures in brain tumors have been definitely recognized as one of the major problems in patients with brain tumors, and need specific and multidisciplinary approaches. PMID- 20706122 TI - Circulating tumor cells and emerging blood biomarkers in breast cancer. AB - PURPOSE OF REVIEW: To critically review the latest findings concerning the role of circulating tumor cells (CTCs) and other blood biomarkers in breast cancer. RECENT FINDINGS: CTCs are epithelial tumor cells detected in the peripheral blood of patients with solid tumors using mainly cytometric/antibody-based and molecular approaches. Most technologies for CTC detection, including the FDA approved CellSearch, are only detecting epithelial cell adhesion molecule (EpCAM) positive CTCs and may miss clinically relevant subpopulations of CTCs. The value of CTC detection by CellSearch in metastatic breast cancer (MBC) may depend on the clinical setting and regimen used. In a retrospective analysis of 516 patients with MBC, CTC detection did not predict clinical outcome in chemo-naive women with HER2-positive MBC treated with anti-HER2 therapy, but had prognostic value in other breast cancer subtypes. Similarly, changes in CTCs during treatment did not predict outcome in 67 women treated with first-line bevacizumab/chemotherapy. CTC detection by CellSearch before or after adjuvant chemotherapy was associated with worse disease-free survival in 1489 patients with early breast cancer. Circulating nucleic acids, microRNAs and genomic rearrangements have been suggested as promising blood biomarkers. SUMMARY: Currently, there is no role for CTCs in clinical practice. The clinical utility of CTCs and other blood biomarkers should be prospectively tested. PMID- 20706123 TI - Individual cancer risk as a function of current age and risk profile. AB - Behavioural changes are an important partner in the fight against cancer (primary prevention or the choice to participate in secondary prevention). To make such behavioural changes, people need to have a correct assessment of their own risk, which is often underestimated or overestimated. These risk estimates depend, among others, on the calculation method that is used. Currently, the method that is used most often is 'indirect cumulative risk' (ICR). We discuss several drawbacks of using ICR in individual counselling and therefore use an alternative method. In this alternative (life table method) we calculated 10-year risks for a whole range of cancers as a function of the current age and risk profile, while taking into account other causes of death. These estimates can easily be used to give an individualized assessment of the risk of cancer. Regardless of the risk estimation method used, the risk needs to be broken down for 'risk factors'. If only the risk for an average person of the population is given, this means a small overestimation for the non-risk group, but a significant underestimation for the at-risk group. When we compare the life table risk as a function of risk factors to the more commonly used ICR, large differences are found, especially in prostate, breast and lung carcinomas. The life table method, although it has certain limitations, has advantages over the ICR method for individual counselling. To our knowledge this is the first overview in which 10-year risks as a function of the current risk profile are given for multiple cancers. The calculated risks are primarily intended to better inform people who are considering preventive measures. For example, for a 40-year-old woman without familial risk who is considering the pros and cons of breast cancer mammographic screening, it is more interesting to know that she has a 0.7% chance of getting breast cancer in the next 5 years, rather than being told that 11% of women get breast cancer during their lives (ICR 0-74). Current smokers can now be given absolute risk reduction estimates of smoking cessation. To keep the life table risk estimates up to date, they must be repeated every couple of years, using up to-date incidence and mortality data. PMID- 20706124 TI - A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. AB - PURPOSE: To evaluate the role of complex alleles, with two or more mutations in cis position, of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the definition of the genotype-phenotype relationship in cystic fibrosis (CF), and to evaluate the functional significance of the highly controversial L997F CFTR mutation. METHODS: We evaluated the diagnosis of CF or CFTR-related disorders in 12 unrelated subjects with highly variable phenotypes. According to a first CFTR mutational analysis, subjects appeared to be compound heterozygotes for a classic mutation and the L997F mutation. A further CFTR mutational analysis was conducted by means of a protocol of extended sequencing, particularly suited to the detection of complex alleles. RESULTS: We detected a new [R117L; L997F] CFTR complex allele in the four subjects with the highest sweat test values and CF. The eight subjects without the complex allele showed the most varied biochemical and clinical outcome and were diagnosed as having mild CF, CFTR related disorders, or even no disease. CONCLUSIONS: The new complex allele partially explains the variable phenotype in CF subjects with the L997F mutation. CFTR complex alleles are likely to have a role in the definition of the genotype phenotype relationship in CF. Whenever apparently identical CFTR-mutated genotypes are found in subjects with divergent phenotypes, an extensive mutational search is mandatory. PMID- 20706125 TI - Initial duloxetine prescription dose and treatment adherence and persistence in patients with major depressive disorder. AB - Adherence and persistence with medication therapy are important in the management of major depressive disorder. This study examined the association between initial prescription dosage of duloxetine and its adherence and persistence. In a large commercial managed-care claims database, 6132 patients with major depressive disorder were initiated on duloxetine between 1 July 2005 and 30 June 2006 at low dose (<60 mg/day, n=1989), mid dose (60 mg/day, n=3733), or high dose (>60 mg/day, n=410). Adherence was defined as medication possession ratio more than or equal to 0.8, and persistence was defined as the length of therapy without exceeding a 15-day gap. Over a 6-month period after duloxetine initiation, mid dose initiated patients had a higher adherence rate (42.2%) than low-dose (35.6%, P<0.001) or high-dose initiated patients (36.1%, P<0.001). Mid-dose duloxetine initiated patients stayed significantly longer with the medication (107.3 days) compared with low-dose (95.8 days, P<0.01) or high-dose patients (95.4 days, P<0.01). After adjustment for baseline demographics, comorbid conditions, and prior medications, mid-dose initiated patients remained to have better adherence and longer persistence than low-dose or high-dose initiators. The findings suggest that patients initiated with a dose of 60 mg/day of duloxetine seem to be more adherent to and persistent with the medication than those initiated with less or more than 60 mg/day. PMID- 20706126 TI - Tolerability of paliperidone: a meta-analysis of randomized, controlled trials. AB - Balancing tolerability and efficacy of medications can be problematic for clinicians when assessing appropriate therapy for patients. For antipsychotic therapy, this can be especially challenging because of the hazardous movement and metabolic effects associated with them. Paliperidone is an atypical antipsychotic used for the treatment of schizophrenia and schizoaffective disorder. A systematic review of the literature for the tolerability of the drug, paliperidone, was performed. A total of 15 articles met the criteria for inclusion representing a total of 3779 patients. Data combination was conducted using the Mantel-Haenszel method, random effects model at 95% confidence. Adverse events with the greatest incidence in the paliperidone population were any treatment emergent adverse event (68%), extra-pyramidal symptoms (23%), headache (14%), insomnia (11%), somnolence (9%), tachycardia (9%) and weight gain (8%). Reported events most likely related to paliperidone [largest attributable risks (AR)] were extra-pyramidal symptoms (AR=10), reduction in acute psychosis (AR=8), any treatment emergent adverse event (AR=6), tachycardia (AR=4), and weight gain (AR=4). Events where incidence was entirely because of paliperidone (incidence equals AR) were hypersalivation (3), dysarthria (2), and sexual dysfunction (1). Reported events totally unrelated to paliperidone (AR=0) included anxiety, asthenia, constipation, depression, dyspepsia, glucose related events, and vomiting. Overall, a 50% reduction in treatment emergent psychosis was seen in schizophrenic patients treated with paliperidone, however the reduction of a psychotic event is about equal to the occurrence of an adverse event with paliperidone. PMID- 20706127 TI - Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients. AB - OBJECTIVE: To determine maraviroc (MVC) concentrations in cerebrospinal fluid (CSF) in HIV-infected patients. METHODS: Twelve CCR5+ HIV-1 adult antiretroviral experienced patients receiving MVC-containing regimens for at least 1 month were enrolled. Both CSF and blood samples were taken around 12 hours after the last MVC dose. liquid chromatography tandem mass spectrometry was used to determine MVC concentrations, and HIV-1 viral load was determined by real-time polymerase chain reaction, (LOD, 40 copies/mL). RESULTS: Twelve blood and 12 CSF samples were collected. Median CD4 count was 281(120-759) cells per microliter, and median HIV-1 viral load was <40 copies per milliliter. Median time on MVC was 13.5 weeks (4-60). Nucleoside analogues (tenofovir/didanosine) were given in only 1 case. Median MVC concentrations in plasma were 124.75 (7.3-517) ng/mL. In all except one, CSF sample-receiving an erroneous MVC dose while taking concomitantly nevirapine-MVC concentrations [2.58 (<0.5-7.22) ng/mL] were within the EC(90) range (0.06-10.70). Median MVC CSF: plasma ratio was 0.022 (0.004-0.17), and when the free MVC plasma concentration was used, 0.094 (2.58-27.44). CSF viral load was <40 copies per milliliter in all 9 patients with undetectable plasma viral load. CONCLUSIONS: MVC achieves concentrations within the EC(90) range in CSF. All patients with undetectable plasma viral load although receiving nucleoside sparing regimens including new drugs showed viral suppression in CSF. PMID- 20706128 TI - On the epidemiologic and economic importance of the National AIDS Strategy for the United States. PMID- 20706129 TI - The Gordian knot linking left ventricular hypertrophy and kidney disease. PMID- 20706130 TI - Can we trust automatic sphygmomanometer validations? AB - Hypertension is a leading risk factor for mortality. Detecting, treating and monitoring hypertensive patients require accurate blood pressure measurements. Protocols for validation of automatic sphygmomanometers exist, but quality control of validations is limited to peer review of published reports, which has severe limitations. An extensive international measurement framework provides quality assurance, traceability and laboratory accreditation for many measurements that are important to society, including industrial, scientific and trade measurements, medical imaging and medical laboratory testing. An important part of this quality assurance is external accreditation of laboratories that perform testing and calibration to the international standard ISO 17025 General requirements for the competence of testing and calibration laboratories. Automatic sphygmomanometer validation is a form of calibration and deserves quality control at least as good as other tests and calibrations that are important to society. It is suggested that laboratories that perform automatic sphygmomanometer validations should participate in the international measurement framework and be externally accredited by accrediting agencies that are members of the International Laboratory Accreditation Cooperation. PMID- 20706131 TI - Reliability of palpation of the radial artery compared with auscultation of the brachial artery in measuring SBP. AB - BACKGROUND: Systolic blood pressure contributes more to cardiovascular disease than DBP, especially in elderly persons. Palpation of the radial artery to assess SBP - Riva-Rocci's technique - may be an attractive alternative for auscultatory SBP in these patients. Therefore, we investigated the difference between SBP determined by palpation of the radial artery (pSBP) and SBP assessed by auscultation of the brachial artery (aSBP). METHODS: Patients were included from the waiting room of a hypertension outpatient clinic. In each patient eight simultaneous pSBP and aSBP measurements were assessed by two observers in the same arm. After every two readings the observers switched between pSBP and aSBP. RESULTS: Forty patients were included, 25 men (62.5%), mean age 55.3 years (range 24-78). From a total of 320 measurements, mean difference between pSBP and aSBP was -5.2 mmHg (range -12-26 mmHg) (P < 0.01). This difference correlated significantly with BMI (r = 0.51, P < 0.01), but not with age (r = 0.15, P = 0.35), pulse rate (r = 0.29, P = 0.09) or mean SBP (r = 0.03, P = 0.85). After averaging the first three comparisons, reproducibility did not improve when increasing the number of comparisons. When correcting for the underestimation of 6 mmHg over the first three comparisons, Riva-Rocci's technique estimates SBP with an acceptable accuracy. CONCLUSION: In clinical practice, Riva-Rocci's palpatory technique offers an acceptable alternative for auscultatory SBP measurement. It is recommended to take three measurements and then correct for the average underestimation of 6 mmHg. PMID- 20706132 TI - Is periodontal inflammation associated with raised blood pressure? Evidence from a National US survey. AB - There is incomplete and inconclusive evidence for the association between periodontal disease markers and arterial blood pressure, particularly from large national epidemiological studies. This study assessed the relationship between different markers of periodontal inflammation and disease with arterial blood pressure in people aged 17 years and over in USA. We analysed data from the Third National Health and Nutrition Examination Survey on 6617 men and 7377 women who received a periodontal examination. Blood pressure was analysed in both a continuous format and a binary variable for case definition of hypertension. Periodontal disease markers (extent of gingival bleeding, pocket depth, and loss of attachment, and a case definition of periodontitis) were associated on the arterial blood pressure outcomes through a series of regression models, incrementally adjusting for confounders (demographic, inflammation markers, chronic conditions, smoking, BMI, socio-economic status). All periodontal measures had significant crude associations with SBP and hypertension. Gingival bleeding, a marker of current periodontal inflammation, was the only measure consistently and significantly associated with raised SBP and an increased odds of hypertension in the US adult population throughout the adjustment process. For a 10% greater extent of gingival bleeding, the average SBP was higher by 0.5 (0.3, 0.6) mmHg in the fully adjusted model. By referring to the general population and the whole distribution of blood pressure, not only to those at higher risk for hypertension, this association might have some important implications for clinical practice and public health strategies. PMID- 20706133 TI - Regression of superficial glomerular podocyte injury in type 2 diabetic rats with overt albuminuria: effect of angiotensin II blockade. AB - OBJECTIVE: Clinical studies indicate that the remission, regression or both of nephrotic-range albuminuria are exerted by angiotensin II receptor blockers (ARBs) in diabetes. The current study was performed to test the hypothesis that these effects of ARBs are associated with regression of glomerular podocyte injury. METHODS: We examined the effects of an ARB, olmesartan, on glomerular podocyte injury in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty rats with overt albuminuria. RESULTS: At baseline (55-week-old), diabetic Otsuka-Long-Evans Tokushima-Fatty rats showed severe albuminuria with desmin-positive areas (an index of podocyte injury) in both superficial and juxtamedullary glomeruli, and podocyte injury was much greater in juxtamedullary than in superficial glomeruli. At 75-week-old, Otsuka-Long-Evans-Tokushima-Fatty rats had developed more severe albuminuria and superficial glomerular podocyte injury, whereas juxtamedullary glomerular podocyte injury did not advance further. Olmesartan (10 mg/kg per day) decreased albuminuria and superficial glomerular desmin staining to levels that were lower than those at baseline, whereas advanced juxtamedullary glomerular podocyte injury was not changed. CONCLUSION: The current study demonstrates for the first time that juxtamedullary glomerular podocyte injury reaches a severe condition at an earlier time than superficial glomerular podocyte injury during the progression of overt albuminuria in type 2 diabetic rats. Our data also support the hypothesis that the antialbuminuric effects of ARBs are associated with regression of superficial glomerular podocyte injury in type 2 diabetes with nephrotic-range albuminuria. PMID- 20706134 TI - Left ventricular hypertrophy as a determinant of renal outcome in patients with high cardiovascular risk. AB - OBJECTIVE: The prognostic importance of left ventricular hypertrophy (LVH) on renal impairment has not been addressed previously. We investigated whether LVH determines renal outcomes in patients with high cardiovascular risk. METHODS: We retrospectively studied 6163 men with high cardiovascular risk (68 +/- 13 years, 23% with coronary artery disease, 34% with diabetes, 83% with hypertension and 30% smokers) followed for a period of 14 years. Left ventricular mass index was assessed at baseline, whereas kidney function and blood pressure levels were determined at both baseline and the end of the follow-up period. Renal outcomes were doubling of serum creatinine, estimated glomerular filtration rate (eGFR) below 30 ml/min per 1.73 m and incident hemodialysis. RESULTS: During the follow up, 5.8% (n = 356), 7% (n = 429) and 2.7% (n = 165) of men fulfilled the above mentioned three outcomes, respectively. After adjustment, for each 42 g/m (1 SD) increase in left ventricular mass index, there was a rise in risk of all renal outcomes by 45.7% (95% confidence interval 28.5-58.3) for doubling of serum creatinine, 51.9% (95% confidence interval 39.7-65%) for eGFR below 30 ml/min per 1.73 m and 58.3% (95% confidence interval 39.7-79.3) for hemodialysis (P < 0.001 for all). Severe LVH (160 < left ventricular mass index <= 180 g/m) compared with non-LVH predicted a significant increase in: doubling of serum creatinine by 103.8%, eGFR-guided outcome by 109.1% and hemodialysis by 74.1%. In those with LVH and impaired kidney function at baseline (GFR <60 ml/min per 1.73 m) compared with those without such entities, serum creatinine, eGFR and hemodialysis-guided outcomes were increased by four-fold, 15-fold and 16-fold, respectively. CONCLUSION: Increased left ventricular mass is a predictor of subsequent kidney dysfunction and should be considered in renal risk stratification in a broad spectrum of men with high cardiovascular risk. PMID- 20706135 TI - Impact of 6-year body weight change on cardiac geometry and function in ageing adults: the SUpplementation en Vitamines et Mineraux AntioXydants -2 (SU.VI.MAX 2) cardiovascular ultrasound substudy. AB - BACKGROUND AND OBJECTIVE: Although the relationships between BMI and cardiac geometry and function have been established, information remains limited on the impact of BMI, waist circumference and body composition variations over time on echocardiographic changes in ageing adults. METHODS AND RESULTS: Multiple linear regressions were used to correlate cardiac echographic parameters and baseline anthropometric data and their changes over 6 years in 280 participants of the SU.VI.MAX 2 cohort study. During the follow-up, BMI increased by 0.6 (95% confidence interval: 0.3-0.8) kg/m, waist circumference by 2.3 (1.6-3.0) cm and percentage body fat mass (%BFM) by 4.0 (3.4-4.6) %. A 6-year change (2001-2007) by 1 kg/m in BMI or 1 cm in waist circumference was associated with an increase in indexed left ventricular mass by 2.3 g/m (1.3-3.3, P < 0.001) and 0.4 g/m (0.06-0.6, P < 0.017), respectively, and an increase in left atrial area by 0.3 cm (0.1-0.5, P < 0.001) and 0.05 cm (0.003-0.10, P < 0.037), respectively. Follow up left ventricular mass and left atrial area were not impacted by changes in percentage body fat mass. A significant correlation was observed between E-wave transmitral flow deceleration time and baseline BMI and waist circumference, but not with their changes over time. CONCLUSION: Changes in anthropometric markers over time are associated with increased left ventricular mass and left atrial size. These findings reinforce the potential benefit of a healthy diet and lifestyle to maintain body weight and, in turn, cardiac geometry and function in ageing adults. PMID- 20706136 TI - Association of blood pressure and heart rate response during exercise with cardiovascular events in the Heart and Soul Study. AB - BACKGROUND: We sought to evaluate the association of blood pressure and heart rate response during exercise with myocardial infarction (MI), heart failure, stroke, transient ischemic attack (TIA) and death in ambulatory adults with coronary artery disease. METHODS: A study population of 937 patients with stable coronary artery disease underwent treadmill exercise stress testing and was followed for 5 years. Participants were divided into quartiles based on peak SBP change, peak SBP and heart rate. We used multivariable Cox proportional hazards models to evaluate the association of change in SBP and heart rate with subsequent cardiovascular events. RESULTS: The participants with SBP increases in the highest quartile had a decreased rate of hospitalization for heart failure [hazard ratio 0.38, 95% confidence interval (CI), 0.21-0.7; P = 0.002], MI (hazard ratio 0.3, 95% CI 0.15-0.58; P = 0.0004), stroke or TIA (hazard ratio 0.39, 95% CI 0.15-0.98; P = 0.04), and all cause mortality (hazard ratio 0.5, 95% CI 0.33-0.76; P = 0.001). After adjusting for age, history of MI and HTN, use of beta blockers, statins and calcium channel blockers, resting heart rate, and SBP, participants with SBP change in the highest quartile remained at lowest risk of MI (hazard ratio 0.31, 95% CI 0.15-0.66, P = 0.002), hospitalization for heart failure (hazard ratio 0.46, 95% CI 0.22-0.97, P = 0.04) and death (hazard ratio 0.52, 95% CI 0.32-0.86, P = 0.01). This association was largely explained by greater exercise capacity in those with the highest SBP change. Change in heart rate had a similar association with cardiovascular events. CONCLUSION: In ambulatory patients with coronary artery disease, the group with the greatest blood pressure and heart rate increase had the lowest risk of MI, heart failure, stroke or TIA and death. These findings support the notion that a robust blood pressure response predicts favorable outcomes. PMID- 20706137 TI - Contributory role of endothelium and voltage-gated potassium channels in apocynin induced vasorelaxations. AB - OBJECTIVE: Although apocynin, the nicotinamide adenine dinucleotide phosphate oxidase inhibitor improves vascular function in hypertension, its specificity has been questioned. The present study examined whether apocynin-induced vasorelaxations involve endothelium and/or K channels in vascular cells. METHODS: Aortas from Sprague-Dawley rats were suspended in organ baths for functional studies. Changes in intracellular calcium ([Ca]i) and nitric oxide ([NO]i) in rat endothelial cells were detected by fluorescence imaging. Whole-cell voltage-gated K (Kv) currents were recorded in vascular smooth muscle cells. RESULTS: Apocynin induced aortic relaxations were attenuated by the absence of endothelium, endothelial nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester, or nitric oxide-dependent soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one. 4-Aminopyridine (4-AP, voltage-gated potassium channels blocker) attenuated apocynin-induced relaxations, its combined treatment with 1H [1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) did not cause further inhibition. Apocynin increased [Ca]i and [NO]i in endothelial cells, which were abolished by 4-AP, indicating the involvement of voltage-gated potassium channels in endothelial cells. In addition, apocynin-stimulated increase in endothelial nitric oxide synthase phosphorylation at Ser depended on the presence of extracellular Ca. Notably, 4-AP also reduced apocynin-induced relaxations in the absence of endothelium and apocynin increased 4-AP-sensitive voltage-gated potassium channel currents in vascular smooth muscle cells. CONCLUSION: This study provides novel data showing that apocynin-induced relaxations of rat aortas are mediated by 4-AP-sensitive stimulation of [Ca]i and [NO]i increases in endothelium and by activation of voltage-gated potassium channels in vascular smooth muscle cells. PMID- 20706138 TI - Adenosine-induced transient asystole for intracranial aneurysm surgery: a retrospective review. AB - BRIEF SUMMARY: We describe the use of adenosine-induced cardiac arrest to facilitate intracranial aneurysm clip ligation. BACKGROUND: Cerebral aneurysms are highly variable which may result in difficult surgical exposure for clip ligation in select cases. Secure clip placement is often not feasible without temporarily decompressing the aneurysm. This can be accomplished with temporary clip ligation of proximal vessels, or with deep hypothermic circulatory arrest on cardiopulmonary bypass, although these methods have their own inherent risks. Here we describe an alternate method of decompressing the aneurysm via adenosine induced transient asystole. METHODS: We examined the records of 27 patients who underwent craniotomy for cerebral aneurysm clipping in which adenosine was used to induce transient asystole to facilitate clip ligation. Duration of adenosine induced bradycardia (heart rate <40) and hypotension (SBP < 60) recorded on the electronic anesthesia record and outcome data including incidence of successful clipping, intraoperative and postoperative complications, and mortality were recorded. RESULTS: Satisfactory aneurysm decompression was achieved in all cases, and all aneurysms were clipped successfully. The median dose of intravenous adenosine resulting in bradycardia greater than 30 seconds was 30 mg. The median dose of adenosine resulting in hypotension greater than 30 seconds was 15 mg, and greater than 60 seconds was 30 mg. One case of prolonged hypotension after rapid redosing of adenosine required brief closed chest compressions before circulation was spontaneously restored. No other adverse events were observed. CONCLUSIONS: Adenosine cardiac arrest is a relatively novel method for decompression of intracranial aneurysms to facilitate clip application. With appropriate safety precautions, it is a reasonable alternative method when temporary clipping of proximal vessels is not desirable or not possible. PMID- 20706139 TI - Urinary retention as the cause of acute brain bulge during pediatric neurosurgery in prone position. PMID- 20706140 TI - Intracranial hemorrhage surgery on patients on mechanical circulatory support: a case series. AB - BACKGROUND: Cardiac disease is the leading cause of death in the United States and late-stage heart failure is associated with a high level of morbidity and mortality. The ventricular assist devices and extracorporeal membrane oxygenators are the mainstay of mechanical circulatory support devices for the patients with extremely low cardiac output. However, they come at a price of significant risk factors, including intracranial hemorrhage. The incidence of intracranial hemorrhage on extracorporeal membrane oxygenators and on ventricular assist devices is 37% and 13% to 14%, respectively. METHODS/RESULTS: The cases in this series focus on the risks of ICH and the decompressive craniotomies that were carried out on patients while they were on mechanical circulatory support. The intraoperative anesthetic management for patients on mechanical circulatory support for the noncardiothoracic anesthesiologist is highlighted. CONCLUSIONS: The results of recent cardiothoracic surgery trials have led to an increase of surgical management instead of medical management in the treatment of heart failure. Although most agree with the immediate reversal of anticoagulation and antiplatelet therapy, there is no standard protocol for restarting anticoagulation or antiplatelet therapy after craniotomy in this population. The standard practices of resuscitation and ACLS including inotropes, vasopressors, and vasodilators (with the exception of chest compressions that can dislodge the devices), can be used as needed. The identification of cardiothoracic surgeons and perfusionists who are available for immediate assistance as and when required during the surgery and transportation is an important factor. PMID- 20706141 TI - Comparison of A-line autoregressive index and observer assessment of alertness/sedation scale for monitored anesthesia care with target-controlled infusion of propofol in patients undergoing percutaneous vertebroplasty. AB - BACKGROUND: Percutaneous vertebroplasty (PV) with monitored anesthesia care (MAC) is a growing trend. Without adequate sedation, patient movement can affect and even interrupt the procedure during MAC. The aim of this study was to compare the performance of the auditory-evoked potential (AEP) index and the Observer Assessment of Alertness/Sedation (OAA/S) scale as indicators of depth of sedation in patients undergoing PV. METHODS: Two hundred and twenty patients in ASA II to III, aged 43 to 92 years, undergoing elective PV with MAC, were randomly allocated to the AEP or the OAA/S group (n = 110 each). Initially, all patients received 1 MUg/kg of fentanyl and 0.02 mg/kg of midazolam intravenously and sedation with a target-controlled infusion (TCI) of propofol at a target concentration of 1.2 MUg/mL. The concentration for the propofol TCI was adjusted in 0.2 MUg/mL increments or decrements according to the A-Line autoregressive index (AAI) or the OAA/S scale. A blinded study nurse recorded the measured parameters. RESULTS: Some parameters were significantly different in the AEP group compared with the OAA/S group: lower AAI, lower OAA/S score, lower respiratory rates, and higher end-tidal carbon dioxide pressure were noted from local anesthetic infiltration to bone cement implantation, fewer patients whose movements affected the procedure (10 vs. 36, respectively, P < 0.001), and more adjustments of TCI (twice vs. once, respectively, P < 0.006). The surgeons' satisfaction was greater for the AEP group than for the OAA/S group. CONCLUSIONS: TCI propofol with AEP monitoring can provide less patient movement, better sedation, and higher surgeon satisfaction in patients during prone-position PV procedures than can TCI propofol with OAA/S monitoring. PMID- 20706142 TI - Development of a safe and pragmatic awake craniotomy program at Maine Medical Center. AB - BACKGROUND: Awake craniotomy offers an excellent means of performing intraoperative mapping and optimizing surgical resection of brain tumors. Awake craniotomy relies on a strong collaboration between anesthesiologists, neurosurgeons, and operating room staff. The authors recently introduced awake craniotomy for tumor resection at the Maine Medical Center and propose that it can be performed safely, effectively, and efficiently in a high-volume community hospital. METHODS: We describe a practical approach to performing awake craniotomy involving streamlined anesthetic protocols and simplified intraoperative testing parameters in a carefully selected group of patients. Our first 25 patients are retrospectively reviewed with particular attention to the anesthetic protocol, the extent of resection, the operative time, post-operative complications, the length of hospitalization, and their functional status at follow-up. RESULTS: The authors established an anesthetic protocol based primarily on midazolam, fentanyl, propofol, and local anesthetic. The authors note that all but one patient was able to tolerate the awake procedure. Gross total resection was achieved in nearly 80% of patients with a glial tumor. Operative time was short, averaging 159 minutes of entire anesthesia care. Length of stay averaged 3.7 days. Persistent new post-operative deficits were noted in 2 of 25 patients. There was no substantial difference in total hospital charges for patients undergoing awake craniotomy when compared to a matched historical control. CONCLUSIONS: With attention focused on patient selection and a streamlined anesthetic protocol, the authors were able to successfully implement an awake craniotomy protocol in a community setting with satisfying results, including low operative morbidity, short operative times, low anesthetic complications, and excellent patient tolerance. PMID- 20706143 TI - Intraoperative brainstem auditory evoked potential observations after trigeminocardiac reflex during cerebellopontine angle surgery. AB - BACKGROUND: The occurrence of trigeminocardiac reflex (TCR) is known to be a negative prognostic factor for hearing preservation in cerebellopontine angle tumor surgery. Our study was conducted to investigate brainstem auditory evoked potential (BAEP) changes after this reflex in cerebellopontine angle tumor surgery and to evaluate their impact on postoperative hearing function. METHODS: Five of 102 consecutive patients had an intraoperative TCR (4.9%) and were retrospectively evaluated for the intraoperative BAEP changes after TCR and postoperative auditory function (7 to 10 d after surgery). One of the 5 patients was preoperatively deaf and therefore excluded from this analysis. RESULTS: Four patients with preoperative functional hearing developed one or more episodes of TCR. Intraoperative BAEP was maintained in 1 patient, whereas in 3 cases an acute intraoperative BAEP deterioration occurred within 2:04 to 3:27 minutes (mean 2:44 min) after TCR with increased wave latency, decreased wave amplitude, and even wave loss. Two patients had deteriorated BAEP waves until the surgical completion and were postoperatively deaf. CONCLUSIONS: Although no direct cause-effect relationship has yet been shown, we suggest TCR as an additional event that may cause BAEP changes. The observed BAEP alterations occurred minutes rather than seconds after the TCR incident leading to both temporary and permanent wave deterioration. This association of BAEP deterioration and TCR occurrence, however, remains yet to be proven justifying further study in the field. PMID- 20706144 TI - Effects of nursing care and staff skill mix on patient outcomes within acute care nursing units. AB - This article presents the findings from a study that evaluates the relationships between staffing indicators and patient outcomes at the hospital unit level. Nursing administrators should not only evaluate the impact staffing decisions have on patient outcomes at the hospital level but also examine these relationships at the unit level. The findings from this study have implications for nursing practice in the areas of staff orientation, education, and patient outcome monitoring. PMID- 20706145 TI - Aplastic anemia following hepatitis associated with human herpesvirus 6. PMID- 20706146 TI - Interaction of Saccharomyces boulardii with intestinal brush border membranes: key to probiotic effects? AB - The probiotic Saccharomyces boulardii exerts beneficial effects in humans, which include trophic effects, anti-inflammatory effects, antisecretory effects, inhibition of toxins, immunostimulatory effects, and resistance to bacterial overgrowth. This short communication discusses the interactions of the probiotic with brush border membrane (BBM) constituents because most of these effects are BBM mediated. The use of bacterial and yeast probiotics has increased dramatically in more and more clinical states, but their exact mechanisms of action remain largely unknown. The present communication focuses on the interactions of a confirmed yeast probiotic (S boulardii) on the constituents of BBMs. PMID- 20706147 TI - Seasonal variation of enteropathogens in infants and preschoolers with acute diarrhea in western Mexico. AB - The present study estimates the prevalence of some enteropathogens in infants and preschoolers with acute diarrhea. From 2006 to 2007, 5459 consecutive stool samples were evaluated. Cryptosporidium parvum was the parasite identified with the higher frequency (5.1%), followed by Giardia lamblia (1.2%). Campylobacter jejuni was isolated in 858 cases (15.7%) and was the most frequent enteropathogen overall. The rates of C parvum, Shigella, and Salmonella were higher in the summer. Rotavirus had the expected winter peak and it was the third enteropathogen because of its frequency. Overall frequency of stool-reducing substances was 15.6% and was associated with a rotavirus-positive test. PMID- 20706148 TI - Families' perspectives on the effect of constipation and fecal incontinence on quality of life. AB - OBJECTIVES: Understanding families' quality of life can be important for interdisciplinary treatment planning. The present study examined child and parent perspectives about how constipation and fecal incontinence affect families' quality of life. PATIENTS AND METHODS: Semistructured interviews were conducted with 8 children/adolescents and 8 caregivers. All of the children met Rome II criteria for functional constipation. Interviews were analyzed by an interdisciplinary team using a content analysis approach, which included developing a coding manual that described emergent themes from the interview transcripts. RESULTS: Qualitative and quantitative responses revealed the varied experiences of participating families. Child and parent views may be misaligned, which can affect treatment planning and effectiveness. Families described variable satisfaction with the treatment recommendations they had been offered and experienced difficulty finding appropriate care. Children's social and family functioning were significantly affected by constipation and fecal incontinence difficulties. Both children and parents described the challenges of discussing the problems with others. CONCLUSIONS: Multiple domains of individual and family functioning are affected by children's constipation and fecal incontinence difficulties, thereby affecting the quality of life of both children and their parents. The findings underscore the need for providers to consider the influence of symptoms on adjustment to both the medical condition and treatment adherence and discuss concerns with children and parents. The results provide the foundation for developing a standardized tool for quantitative assessment of quality of life for children with constipation. PMID- 20706149 TI - A million-dollar work-up for abdominal pain: is it worth it? AB - BACKGROUND AND AIM: Pain-predominant-functional gastrointestinal disorders (PP FGIDs) are common. The diagnosis is clinical and there are no biological markers to characterize these conditions. Despite limited evidence, investigations are commonly performed. The aim of the study was to investigate diagnostic practices, yield, and costs in children with PP-FGIDs. PATIENTS AND METHODS: Charts of all of the children older than 4 years diagnosed as having abdominal pain were reviewed. Results and costs of diagnostic investigations were analyzed. RESULTS: Of 243 children with abdominal pain, 122 (50.2%) had PP-FGIDs (79 girls, mean age 12.7 years). All of the children underwent diagnostic work-up. Complete blood cell count was done in 91.8% of patients. None had elevated white blood cells, platelets, and low albumin. Six had either elevated erythrocyte sedimentation rate or C-reactive protein, but none had elevation of both; 4 of these 6 cases underwent endoscopies with normal results in 3 cases; Helicobacter pylori was found in 1 case. One child had elevated tissue transglutaminase 1 only antibodies with normal endoscopy. Amylase, lipase, direct bilirubin, stool cultures, and ova or parasites were always normal. One child had intermittent elevation of aspartate aminotransferase and alanine transaminase. There were no significant abnormalities in urinalysis or electrolytes. Abdominal x-rays were done in 38.5%, showing only retained stools in 13% of these patients. Abdominal ultrasound and computed tomography scan were done in 23.7% and 9% of cases, respectively, but were of no clinical value; 33.6% patients had esophagogastroduodenoscopy (9.7% abnormal: Helicobacter pylori, chemical gastritis, esophagitis) and 17.2% had colonoscopy (9.5% abnormal: rare fork crypts, lymphoid hyperplasia). Total costs: $744,726. Average cost per patient: $6104.30. CONCLUSIONS: In children with PP FGIDs, investigations are common, costs are substantial, and yield is minimal. PMID- 20706150 TI - Healing of erosive esophagitis and improvement of symptoms of gastroesophageal reflux disease after esomeprazole treatment in children 12 to 36 months old. AB - OBJECTIVES: The aim of the study was to evaluate erosive esophagitis healing and symptom improvement with once-daily esomeprazole in children ages 12 to 36 months with endoscopically or histologically proven gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: Data from children ages 12 to 36 months were included in a post-hoc analysis of an 8-week, multicenter, randomized, and double blind by dose strata study of patients ages 1 to 11 years with endoscopically or histologically confirmed GERD. Children were randomized to receive esomeprazole 5 or 10 mg once daily. Patients underwent endoscopy and, if required, mucosal biopsy at baseline. Patients who had erosive esophagitis (graded using the Los Angeles classification system) at baseline underwent a follow-up endoscopy at final study visit to assess healing of erosive esophagitis. Investigators scored severity of GERD symptoms at baseline and every 2 weeks using the Physician Global Assessment. RESULTS: Thirty-one of 109 primary study patients ages 12 to 36 months were included in the post hoc analysis. At baseline, 15 patients (48.4%) had erosive esophagitis, underwent follow-up endoscopy, and were healed after 8 weeks of esomeprazole treatment. Of the 19 patients with moderate-to severe baseline Physician Global Assessment symptom scores, 84.2% had lower scores by the final visit. Following esomeprazole treatment, GERD symptoms were significantly improved from baseline to final visit (P <= 0.0018). CONCLUSIONS: Esomeprazole 5 or 10 mg may be used to successfully treat erosive esophagitis and symptoms of GERD in children as young as 1 year. Moreover, although not yet validated in pediatric patients, the Los Angeles classification system was useful in grading erosive esophagitis in children ages 12 to 36 months. PMID- 20706151 TI - Does laparoscopy lower the threshold for the surgical treatment of gastroesophageal reflux disease in children? AB - OBJECTIVE: To assess whether laparoscopic surgery lowers the threshold for surgical intervention, we examined whether the introduction of the laparoscopic technique at our institution in 1997 has resulted in an increase in antireflux surgery in children at our clinic. PATIENTS AND METHODS: The number of annual fundoplications between 1997 and 2008 at a single institution was assessed in children younger than 18 years. The number of fundoplications was compared with the number of pyloromyotomies and appendicectomies per year in the same period of time to prove or exclude a general increase in the referral of children. RESULTS: Since 1997, the proportion of laparoscopic fundoplications increased from 60% in 1997 to 100% in 2008. During this period, 109 laparoscopic fundoplications were performed: 31 in the period from 1997 to 2002 and 78 from 2003 to 2008. Regression analysis shows a significant increase in the number of performed fundoplications (slope: 1.03 +/- 0.28, P = 0.0043), whereas both the number of pyloromyotomies and appendicectomies remained stable (slopes: -0.14 +/- 0.40, P = 0.73, and -0.75 +/- 0.47, P = 0.14, respectively). CONCLUSIONS: Since the introduction of minimally invasive surgery at our tertiary referral center in 1997, the number of patients referred for an antireflux operation has increased. This cannot be explained by an increase of referrals from outside the region or a change in the indication for surgery. We conclude that laparoscopy lowers the threshold for the surgical treatment of gastroesophageal reflux disease in children. PMID- 20706152 TI - Reduction of interstitial cells of Cajal in esophageal atresia. AB - OBJECTIVES: Postrepair esophageal dysmotility and gastroesophageal reflux are well-known consequences in patients with congenital esophageal atresia (EA) with or without distal tracheoesophageal fistula (TEF). The interstitial cells of Cajal (ICC), considered the intestinal pacemaker, are altered in congenital diseases with abnormal peristalsis, but no data are available for EA. Therefore, presence and maturation of ICC was verified in EA-TEF newborns. PATIENTS AND METHODS: Fifteen full-term neonates underwent repair of EA-TEF. Control specimens were from 10 newborns who died of nonesophageal diseases. Specimens from upper pouch, fistula, proximal, and distal esophagus were processed for hematoxylin and eosin, c-kit immunohistochemistry for ICC identification, and transmission electron microscopy. Frequency of c-kit-positive cells was evaluated in 20 fields per slide using a visual score (absent, very low, low, medium, high, very high). Morphocytometry and statistical analysis were also performed. RESULTS: In the proximal normal esophagus, ICC frequency was very high (3 cases), high (5), and medium (2); distally, it was high (4) and medium (6). In EA-TEF upper pouch, it was high (2) and medium (13); in the fistula, it was medium (5), low (6), very low (3), and absent (1). Morphocytometry confirmed these results. Comparison between pouch and fistula versus proximal and lower esophagus, respectively, showed statistically significant differences. Transmission electron microscopy demonstrated ICC immaturity in EA-TEF. CONCLUSIONS: The significant lower ICC density in EA-TEF is in favor for the pathogenesis of esophageal dysmotility frequently observed in such patients. PMID- 20706153 TI - Butyrate and type 1 diabetes mellitus: can we fix the intestinal leak? AB - OBJECTIVES: An intestinal permeability defect precedes type 1 diabetes mellitus and may be a permissive factor in its pathogenesis. Butyrate strengthens the intestinal tight junctions. We hypothesized that enteral administration of sodium butyrate (NaB) in preweaned rats would result in differences in the development of diabetes associated with decreased inflammation and pancreatic beta-cell destruction. MATERIALS AND METHODS: Using biobreeding diabetes-prone rat pups, oral NaB or saline was administered twice per day via micropipette from postnatal days 10 to 23. Rat pups were randomly assigned to 1 of 4 groups for the first experiment (control group, n = 7) and 3 different doses of butyrate groups (n = 8 for each group) and 2 groups for the second and third experiments (control n = 23; NaB at 400 mg . kg(-1) . day(-1), n = 20). Animals were studied into adulthood (up to day 140) for development of diabetes. RESULTS: The results showed that the survival rates were 28% versus 20% (butyrate vs control). No significant differences in survival were seen; however, there was a trend of delaying of onset of diabetes in the butyrate group. There were no differences of pancreatic histology score of islet inflammation between the 2 groups. Cytokine induced neutrophil chemoattractant-1 was lower in the butyrate group at a dose of 400 mg . kg(-1) . day(-1) in the distal small intestine (P = 0.008) and in the liver (P = 0.01). There were no significant differences in the tracer flux measurements across the distal ileum and colon between the 2 animal groups. CONCLUSIONS: Oral NaB given during the preweaning period did not significantly decrease the subsequent development of death from diabetes in biobreeding diabetes-prone rats. PMID- 20706154 TI - A single-center experience with methotrexate after thiopurine therapy in pediatric Crohn disease. AB - BACKGROUND AND AIM: Thiopurines are a common, effective means of maintaining remission in pediatric Crohn disease (CD). Methotrexate (MTX) may be considered for those intolerant of or unresponsive to thiopurines. The purpose of this study was to examine the effectiveness of MTX as maintenance therapy in patients previously treated with thiopurines. PATIENTS AND METHODS: All of the patients at Nationwide Children's Hospital from 1998 to 2007 with an International Classification of Diseases code indicative of CD were identified. Patients with a diagnosis of CD, a history of prior thiopurine use, no current infliximab therapy, and at least 6 months of follow-up after MTX initiation were included. The primary outcome was defined as steroid-/infliximab-free remission determined by the physician global assessment at 6 and 12 months. Secondary outcomes included subsequent treatment with infliximab and/or corticosteroids, rate of discontinuation of MTX, and adverse events (AEs). RESULTS: Twenty-seven patients (17 boys, 63%) with a mean age at diagnosis of 12.3 +/- 0.7 years and mean disease duration of 1.49 +/- 0.3 years were identified. Indications for MTX included nonresponse to thiopurines, AE, and poor adherence to thiopurines. At 6 and 12 months, 13 of 27 patients (48.1%) and 9 of 27 patients (33.3%), respectively, were in steroid-/infliximab-free remission. A total of 10 patients (37.0%) required infliximab therapy during the 12-month period and 5 patients discontinued MTX. Nausea was the most commonly reported AE. Transient transaminase elevation occurred in 4 patients and transient leukopenia in 2 patients. CONCLUSIONS: MTX can be effective as maintenance therapy for patients with pediatric CD previously intolerant of or unresponsive to thiopurines; however, greater than one third of this cohort required escalation to antitumor necrosis factor therapy within 12 months following MTX initiation. MTX was well tolerated. PMID- 20706155 TI - The effect of heavy- vs. moderate-load training on the development of strength, power, and throwing ball velocity in male handball players. AB - The aim was to compare the effect of 2 differing 10-week resistance training programs on the peak power (PP) output, muscle volume, strength, and throwing velocity of the upper limbs in handball players during the competitive season. The subjects were 26 men (age 20.0 +/- 0.6 years, body mass 85.0 +/- 13.2 kg, height 1.86 +/- 0.06 m, and body fat 13.7 +/- 2.4%). They were randomly assigned to 1 of 3 groups: control (C; n = 8), heavy resistance (n = 9), or moderate resistance (MR; n = 9) training, performed twice a week. A force-velocity test on an appropriately modified Monark cycle ergometer determined PP. Muscle volumes were estimated using a standard anthropometric kit. One-repetition maximum (1RM) bench press (1RMBP) and 1RM pull-over (1RMPO) scores assessed arm strength. Handball throwing velocity was measured with (TR) and without run-up (TW). Both training programs enhanced absolute PP relative to controls (p < 0.05), although differences disappeared if PP was expressed per unit of muscle volume. Heavy resistance-enhanced 1RMBP and 1RMPO compared to both MR (p < 0.01 and p < 0.05, respectively) and C (p < 0.001 for both tests). Heavy resistance also increased TR and TW compared to C (p < 0.01 and p < 0.05, respectively). Moderate resistance increased only TR compared to C (p < 0.01). Thus, during the competitive season, the PP, 1RMBP, 1RMPO, and TW of male handball players were increased more by 10 weeks of bench press and pull-over training with suitably adapted heavy loads than with moderate loads. It would seem advantageous to add such resistance exercise before customary technical and tactical handball training sessions. PMID- 20706156 TI - Structural and functional predictors of drop vertical jump. AB - This investigation was designed to determine if relatively small manipulations of squat load and the inclusion of selected morphologic variables might augment the explained variance in vertical jump (VJ) displacement. Fifty-two university students (27 women and 25 men) with weight training experience served as subjects. All were assessed for body fat percentage (BF%), height, body weight (BW), leg length (LL), ankle range of motion, and quadriceps angle (Q-angle). Additionally, subjects performed drop vertical jumps (DVJs) and both countermovement jump (CMJ) squats and static jump (SJ) squats at 20, 30, and 40% of their back squat 1 repetition maximum (1RM). A preliminary analysis revealed that DVJcm for all subjects (28.1 +/- 6.64; mean +/- SD) was most highly correlated with both CMJ @ 30% 1RM (CMJ30PP) and SJ @ 20% 1RM (SJ20PP) (r = 0.84, p < 0.001). Forced multiple regression was then used to determine which variables contributed to VJ displacement. The greatest variability explained (83%) used a CMJ: DVJcm = 20.311 + (0.008) (CMJ30PP) - (0.346) (BW). When the same variables were used to calculate separate gender-based regressions, the explained variance in DVJcm (men = 33.0 +/- 5.34 cm; women = 23.4 +/- 3.79 cm) was 68% for men and 64% for women. These findings suggest that jump squat peak power at a light load is a good predictor of VJ and that its training-induced augmentation would likely improve VJ. The addition of BW to the equation explained slightly more variability in DVJcm than in BF%. Because excess amounts of either would be an additional load to be moved against gravity (fat in general or skeletal muscle in the upper torso), it follows that relatively high levels of either might be expected to attenuate VJ performance. PMID- 20706157 TI - Vertical jump biomechanics after plyometric, weight lifting, and combined (weight lifting + plyometric) training. AB - The purpose of this study was to compare the effects of an Olympic weight lifting (OL), a plyometric (PL), and combined weight lifting + plyometric (WP) training program on vertical jump (VJ) biomechanics. Thirty-six men were assigned randomly to 4 groups: PL group (n = 9), OL group (n = 9), WP group (), and control (C) group (n = 8). The experimental groups trained 3 d.wk, for 8 weeks. Sagital kinematics, VJ height, power, and electromyographic (EMG) activity from rectus femoris (RF) and medial gastrocnemius (GAS) were collected during squat jumping and countermovement jumping (CMJ) before and after training. The results showed that all experimental groups improved VJ height (p < 0.05). The OL training improved power and muscle activation during the concentric phase of the CMJ while the subjects used a technique with wider hip and knee angles after training (p < 0.05). The PL group subjects did not change their CMJ technique although there was an increase in RF activation and a decrease of GAS activity after training (p < 0.05). The WP group displayed a decline in maximal hip angle and a lower activation during the CMJ after training (p < 0.05). These results indicate that all training programs are adequate for improving VJ performance. However, the mechanisms for these improvements differ between the 3 training protocols. Olympic weight lifting training might be more appropriate to achieve changes in VJ performance and power in the precompetition period of the training season. Emphasis on the PL exercises should be given when the competition period approaches, whereas the combination of OL and PL exercises may be used in the transition phases from precompetition to the competition period. PMID- 20706158 TI - High turnover stays for pediatric asthma in the United States: analysis of the 2006 Kids' Inpatient Database. AB - BACKGROUND: Pediatric observation units provide an alternative to traditional hospitalization. The extent to which observation units could replace inpatient care for asthmatic children is unknown. OBJECTIVE: To describe brief inpatient ("high-turnover," HTO) stays for US children hospitalized with a principal discharge diagnosis of asthma, to characterize cases that may be appropriate for observation. DESIGN: We analyzed the 2006 Kids' Inpatient Database, a nationally representative sample of hospital discharges. HTO stays were defined as hospitalizations of 0 or 1 night in duration. We conducted descriptive statistics and case-mix adjusted, sample-weighted regression analysis of HTO stays, and associated hospital charges. SUBJECTS: Discharges among children aged 2 to 20 years with a principal discharge diagnosis of asthma. MEASURES: HTO stays and total charges. RESULTS: Overall, 34,592 (34%) pediatric asthma hospitalizations were HTO, accounting for 66,278 hospital days in 2006. HTO stays were associated with younger age, uncomplicated asthma, and private insurance. Freestanding children's hospitals had the highest proportion of HTO stays, 38% (95% CI: 34% 42%) compared with 32% (95% CI: 28%-36%) for children's units and 33% (95% CI: 31%-34%) for general hospitals. In multivariate regression analyses, charges were significantly higher across hospital types when HTO stays begin in the emergency department. CONCLUSIONS: The presence of a large number of HTO stays for children hospitalized for asthma suggests the need to explore opportunities to restructure care for this condition, perhaps through the development of physically or operationally distinct observation units. PMID- 20706159 TI - Provision of potentially teratogenic medications to female veterans of childbearing age. AB - BACKGROUND: Certain medications increase the risk of birth defects whether used during pregnancy or immediately preconception. OBJECTIVES: To describe dispensing of potentially teratogenic medications (Food and Drug Administration classes D or X) to female Veterans treated by the Veterans Affairs (VA) Healthcare System, and assess whether documented provision of family planning services is more common when potentially teratogenic medications are prescribed. RESEARCH DESIGN: We examined all 2,634,441 prescriptions filled in fiscal year 2007 or 2008 by 78,232 female Veterans, aged 18 to 45, who made >or=2 visits to VA clinics within the year prior to medication dispensing from VA pharmacies. MEASURES: : Medications dispensed, contraceptive counseling, and pregnancy testing. RESULTS: Prescriptions for potentially teratogenic medications were filled by 48.8% of female Veterans who received medications from a VA pharmacy. Women who filled prescriptions for potentially teratogenic medications were only slightly more likely to have documented family planning services (eg, contraception, contraceptive counseling, or pregnancy testing) than women who filled class C, but not class D or X, prescriptions (55.7% vs. 51.8%). Women filling only class A or B prescriptions were least likely to have documented family planning services (35.9%). Among women dispensed potentially teratogenic medications, family planning services were significantly more likely to be documented for women who were >or=25 years (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.57 3.11), unmarried (OR, 1.30; 95% CI, 1.23-1.35), non-White (OR, 1.17; 95% CI, 1.09 1.26), seen at a women's clinic (OR, 1.96; 95% CI, 1.88-2.05), received a retinoid medication (OR, 7.72; 95% CI, 3.02-19.7), or had serious mental illness (OR, 1.26; 95% CI, 1.18-1.34). CONCLUSIONS: Medications that may cause birth defects if used during pregnancy are dispensed frequently to female Veterans by VA pharmacies without documented receipt of contraceptive counseling or pregnancy testing. PMID- 20706160 TI - Initiation of Primary Care-Mental Health Integration programs in the VA Health System: associations with psychiatric diagnoses in primary care. AB - BACKGROUND: Providing collaborative mental health treatment within primary care settings improves depression outcomes and may improve detection of mental disorders. Few studies have assessed the effect of collaborative mental health treatment programs on diagnosis of mental disorders in primary care populations. In 2008, many Department of Veterans Affairs (VA) facilities implemented collaborative care programs, as part of the VA's Primary Care-Mental Health Integration (PC-MHI) program. OBJECTIVES: To assess the prevalence of diagnosed mental health conditions among primary care patient populations in association with PC-MHI programs, overall and for patient subpopulations that may be less likely to receive mental health treatment. RESEARCH DESIGN: Using a difference-in differences analysis, we evaluated whether the rates of psychiatric diagnoses among primary care patient populations at 294 VA facilities changed from fiscal year (FY)07 to FY08, and whether trends differed at facilities with PC-MHI encounters in FY08. Subgroup analyses examined whether trends differed by patient age and race/ethnicity. SUBJECTS, MEASURES, AND RESULTS: From FY07 to FY08, the prevalence of diagnosed depression, anxiety, post-traumatic stress disorder, and alcohol abuse increased more in the 137 facilities with PC-MHI program encounters than in the 157 facilities without these encounters. Increases were more likely among patients who were younger (18-64) and white. CONCLUSIONS: Initiation of PC MHI programs was associated with elevated diagnosis patterns, which may enhance recognition of mental health needs among primary care patients. Increases in diagnosis prevalence were not uniform across patient subgroups. Further research is needed on treatment processes and outcomes for individuals receiving services in PC-MHI programs. PMID- 20706161 TI - Cost of breast-related care in the year following false positive screening mammograms. AB - OBJECTIVE: We sought to estimate the direct cost, from the perspective of the health insurer or purchaser, of breast-care services in the year following a false positive screening mammogram compared with a true negative examination. DESIGN: We identified 21,125 women aged 40 to 80 years enrolled in an integrated healthcare delivery system in Washington State, who participated in screening mammography between January 1, 1998 and July 30, 2002. Pathology and cancer registry data were used to identify breast cancer diagnoses in the year following the screening mammogram. A positive examination was defined as a Breast Imaging Reporting and Data System assessment of 0, 4, or 5. Women with a positive screening mammogram but no breast cancer diagnosed within 1 year were classified as false positives. We used diagnostic and procedure codes in automated health plan data to identify services received in the year following the screening mammogram. Medicare reimbursement rates were applied to all services. We used ordinary least-squares linear regression to estimate the difference in costs following a false positive versus true negative screening mammogram. RESULTS: False positive results occurred in 9.9% of women; most false positives (87.3%) were followed by breast imaging only. The mean cost of breast-care following a false positive mammogram was $527. This was $503 (95% confidence interval, $490 $515) more than the cost of breast-care services for true negative women. CONCLUSIONS: The direct costs for breast-related procedures following false positive screening mammograms may contribute substantially to US healthcare spending. PMID- 20706162 TI - Mental health, frequency of healthcare visits, and colorectal cancer screening. AB - BACKGROUND: Research regarding the association between mental health and colorectal cancer (CRC) screening has produced mixed results. Variations may be explained by methodology, including whether potential confounders such as frequency of healthcare visits are considered. OBJECTIVE: We examined the association between mental health and CRC screening, before and after controlling for demographics, comorbidities, and outpatient visit frequency. DESIGN: Observational study based on a retrospective cohort. SUBJECTS: A total of 855 veterans receiving care at a Veterans Affairs Medical Center. MEASURES: Medical record data were used to assess CRC screening rates and mental health status (number of diagnoses and the presence of depression, anxiety, posttraumatic stress disorder, substance, or psychotic disorders). Logistic regression was used to estimate the association between mental health diagnoses and CRC screening, before and after controlling for covariates. RESULTS: Bivariate analyses suggested that CRC screening rates were higher for patients with a history of one or more mental health diagnoses (57% vs. 47%, P < 0.01). However, adjusting for timing of mental health diagnosis and outpatient visit frequency resulted in significant negative associations between CRC screening and all measures of mental health except posttraumatic stress disorder. CONCLUSIONS: Estimates of the association between mental health and CRC screening that do not adjust for outpatient visit frequency may be misleading. Veterans with mental health diagnoses were significantly less likely to be screened for CRC than their counterparts with no mental health diagnoses and an equal number of outpatient visits. PMID- 20706163 TI - The role of ethics committees and ethics consultation in allocation decisions: a 4-stage process. AB - BACKGROUND: Decisions about the allocation and rationing of medical interventions likely occur in all health care systems worldwide. So far very little attention has been given to the question of what role ethics consultation and ethics committees could or should play in questions of allocation at the hospital level. OBJECTIVES AND METHODS: This article argues for the need for ethics consultation in rationing decisions using empirical data about the status quo and the inherent nature of bedside rationing. Subsequently, it introduces a 4-stage process for establishing and conducting ethics consultation in rationing questions with systematic reference to core elements of procedural justice. RESULTS: Qualitative and quantitative findings show a significant demand for ethics consultation expressed directly by doctors, as well as additional indirect evidence of such a need as indicated by ethically challenging circumstances of inconsistent and structurally disadvantaging rationing decisions. To address this need, we suggest 4 stages for establishing and conducting ethics consultation in rationing questions we recommend: (1) training, (2) identifying actual scarcity-related problems at clinics, (3) supporting decision-making, and (4) evaluation. CONCLUSION: This process of ethics consultation regarding rationing decisions would facilitate the achievement of several practical goals: (i) encouragement of an awareness and understanding of ethical problems in bedside rationing, (ii) encouragement of achieving efficiency along with rationing, (iii) reinforcement of consistency in inter- and intraindividual decision-making, (iv) encouragement of explicit reflection and justification of the prioritization criteria taken into consideration, (v) improvement in internal (in-house) and external transparency, and (vi) prevention of the misuse of the corresponding consulting structures. PMID- 20706164 TI - Impact of restricted reimbursement on the use of statins in Finland: a register based study. AB - OBJECTIVES: New and expensive medicines are a driving force behind growth in medicine costs, and policies promoting use of less expensive products have been widely introduced. This study investigated the short-term consequences of the restricted reimbursement of expensive statins (atorvastatin and rosuvastatin) on the use of statins in Finland. METHODS: Data on patients purchasing atorvastatin, rosuvastatin, or simvastatin in 2002-2007 were retrieved from the nationwide Prescription Register. Outcome measures included the time trend in the numbers of purchasers and initiators of different statins, the morbidities of new users before and after the new policy, and the proportion of users of expensive statins switching to other statins. RESULTS: After the restriction, the numbers of purchasers of atorvastatin and rosuvastatin dropped, and atorvastatin and rosuvastatin were seldom prescribed as first-line therapy. Before the restriction, 20.9% of new users of atorvastatin and 18.4% of those of rosuvastatin had either coronary artery disease or familial hyperlipidemia. After the restriction the corresponding figures were 28.7% and 26.8%. After the restriction new users of atorvastatin and rosuvastatin were also more likely to use other cardiovascular medicines or antidiabetics or to have previous statin purchases. A total of 57.6% of those using atorvastatin and 49.2% of those using rosuvastatin before the restriction switched to a less expensive statin. CONCLUSIONS: Restricted reimbursement of expensive statins decreased their use. It seems that after the policy new statin treatments have channeled appropriately. Although it is likely that the cost-containment aim of the policy was reached, health and long-term effects are not known. PMID- 20706165 TI - Impact of knee osteoarthritis on health care resource utilization in a US population-based national sample. AB - OBJECTIVE: We sought to estimate the impact of knee osteoarthritis (OA) on health care utilization. RESEARCH DESIGN: Using the 2003 Medicare Current Beneficiary Survey, a population-based survey of Medicare beneficiaries linked to Medicare claims, we selected a national cohort of community-dwelling persons aged 65 and older with knee OA and a sex- and age-matched comparison cohort without any form of OA. We distinguished following 4 components of health care utilization: physician (MD) office visits, non-MD office visits, inpatient hospital stays, and emergency department visits. We built multiple regression models to determine whether knee OA affects utilization, controlling for comorbidity count, obesity, functional limitation, education, race, and working status. RESULTS: A total of 545 Medicare Current Beneficiary Survey participants with knee OA were matched with 1090 OA-free individuals. Mean age in both cohorts was 76 years; approximately 70% were female. Knee OA and OA-free subjects differed significantly in obesity (Knee OA: 37%, OA-free: 20%), % with >or=2 comorbidities (Knee OA: 69%, OA-free: 43%), and functional limitation (Knee OA: 42%, OA-free: 26%). In multivariable regression models, the knee OA cohort had on average 6.0 more annual MD visits (95% confidence interval [CI]: 4.7, 7.4) and 3.8 more non MD visits (95% CI: 2.8, 4.7) than the OA-free cohort. The knee OA cohort also had 28% more hospital stays (odds ratio [OR] = 1.3, 95% CI: 1.0, 1.6), a difference attributable to total joint replacements. CONCLUSIONS: This first national, population-based study of health care utilization in persons with knee OA documents considerable excess utilization attributable to knee OA, independent of comorbidity, and other patient characteristics. PMID- 20706166 TI - Outcomes and costs of community health worker interventions: a systematic review. AB - OBJECTIVES: We conducted a systematic review on outcomes and costs of community health worker (CHW) interventions. CHWs are increasingly expected to improve health outcomes cost-effectively for the underserved. RESEARCH DESIGN: We searched Medline, Cochrane Collaboration resources, and the Cumulative Index to Nursing and Allied Health Literature for studies conducted in the United States and published in English from 1980 through November 2008. We dually reviewed abstracts, full-text articles, data abstractions, quality ratings, and strength of evidence grades and resolved disagreements by consensus. RESULTS: We included 53 studies on outcomes of CHW interventions and 6 on cost or cost-effectiveness. For outcomes, limited evidence (5 studies) suggests that CHW interventions can improve participant knowledge compared with alternative approaches or no intervention. We found mixed evidence for participant behavior change (22 studies) and health outcomes (27 studies). Some studies suggested that CHW interventions can result in greater improvements in participant behavior and health outcomes compared with various alternatives, but other studies suggested that CHW interventions provide no statistically different benefits than alternatives. We found low or moderate strength of evidence suggesting that CHWs can increase appropriate health care utilization for some interventions (30 studies). Six studies with economic information yielded insufficient data to evaluate the cost-effectiveness of CHW interventions relative to other interventions. CONCLUSIONS: CHWs can improve outcomes for underserved populations for some health conditions. The effectiveness of CHWs in many health care areas requires further research that addresses the methodologic limitations of prior studies and that contributes to translating research into practice. PMID- 20706167 TI - Medicare spending and outcomes after postacute care for stroke and hip fracture. AB - BACKGROUND: Elderly patients who leave an acute care hospital after a stroke or a hip fracture may be discharged home, or undergo postacute rehabilitative care in an inpatient rehabilitation facility (IRF) or skilled nursing facility (SNF). Because 15% of Medicare expenditures are for these types of postacute care, it is important to understand their relative costs and the health outcomes they produce. OBJECTIVE: To assess Medicare payments for and outcomes of patients discharged from acute care to an IRF, a SNF, or home after an inpatient diagnosis of stroke or hip fracture between January 2002 and June 2003. RESEARCH DESIGN: This is an observational study based on Medicare administrative data. We adjust for observable differences in patient severity across postacute care sites, and we use instrumental variables estimation to account for unobserved patient selection. STUDY OUTCOMES: Mortality, return to community residence, and total Medicare postacute payments by 120 days after acute care discharge. RESULTS: Relative to discharge home, IRFs improve health outcomes for hip fracture patients. SNFs reduce mortality for hip fracture patients, but increase rates of institutionalization for stroke patients. Both sites of care are far more expensive than discharge to home. CONCLUSIONS: When there is a choice between IRF and SNF care for stroke and hip fracture patients, the marginal patient is better off going to an IRF for postacute care. However, given the marginal cost of an IRF stay compared with returning home, the gains to these patients should be considered in light of the additional costs. PMID- 20706168 TI - Factors associated with variation in estimates of the cost of resistant infections. AB - BACKGROUND: Existing estimates of the costs of antimicrobial resistance exhibit broad variability, and the contributing factors are not well understood. This study examines factors that contribute to variation in these estimates. METHODS: Studies of the costs of resistant infections (1995-2009) were identified, abstracted, and stated in comparable terms (eg, converted to 2007 U.S. dollars). Linear regressions were conducted to assess how costs incurred by patients with resistant infections versus those incurred by uninfected or susceptible-organism infected controls varied according to (1) costs incurred by control subjects; (2) study population characteristics; (3) methodological factors (eg, matching); and (4) length of stay. RESULTS: Estimates of difference in costs incurred by patients with resistant infections versus patients without resistant infections varied between $-27,609 (control costs exceeded case costs) and $126,856. Differences were greater when the costs incurred by control subjects were higher (ie, when the underlying cost of care was high). Study-adjusted cost differences were greater for bloodstream infections (vs. any other infection site), for studies that reported median (vs. mean) costs, for studies that reported total (vs. postinfection or infection-associated) costs, for studies that used uninfected (vs. susceptible-organism-infected) controls, and for studies that did not match or adjust for length of stay before infection. CONCLUSION: The cost of antimicrobial resistance seems to vary with the underlying cost of care. Increased costs of resistance are partially explained by longer length of stay for patients with resistant infections. Further research is needed to assess whether interventions should be differentially targeted at the highest cost cases. PMID- 20706169 TI - Referral practices for spinal surgery are poorly predicted by clinical guidelines and opinions of primary care physicians. AB - BACKGROUND: Degenerative disease of the lumbar spine is common. Although surgery can benefit selected patients, variation in surgical referrals reduces overall access to care. OBJECTIVES: To compare the actual referral practices for patients with degenerative disease of the lumbar spine with recommendations for surgical referral based on clinical practice guidelines (CPGs) and family physician (FP) opinions. RESEARCH DESIGN: An expert panel of primary and specialist physicians, using a Delphi process, came to a consensus on referral recommendations from CPGs based on a series of clinical vignettes. The vignettes were also presented to practicing FPs in Ontario, Canada, to determine their preferences for (or likelihood of) referral. SUBJECTS: We assembled a 10-member multispecialty expert panel. Practicing FPs were randomly sampled, stratified by county, and their patients were sampled purposefully by the FP. MEASURES: Respondents, both panelists and FPs, were asked to rate the appropriateness of surgical referral for a series of clinical vignettes. Patients reported their clinical symptoms and whether they had been referred to a surgeon. Using random-effects probit regression, predictions were compared with actual referral. Receiver operating characteristic curves were constructed and area under the curve (AUC) was measured. RESULTS: Consensus of the panel on recommendations for referral was achieved after 2 iterations (Cronbach alpha = 0.96). Based on responses from 107 patients and 61 FPs, we found poor concordance of both predicted FP preferences (AUC 0.57) and CPG recommendations (AUC 0.64) with actual referral. CONCLUSIONS: Referral practices are poorly predicted by CPG recommendations and individual FP opinions, based on clinical factors. Understanding other nonclinical factors may be more important in reducing variation in referrals and improving access. PMID- 20706170 TI - Disproportionate share hospital subsidies for treating the uninsured. AB - BACKGROUND: Federal, state, and local governments provide substantial subsidies to so-called "safety-net" hospitals, in part, to offset the loss in revenue associated with providing a disproportionate share (DSH) of care to low-income and uninsured patients, with the goal to improve access to care for uninsured and ensure affordable care for them. OBJECTIVES: We investigate the targeting of DSH subsidies and their impact on pricing to uninsured patients in acute care for profit and nonprofit hospitals. METHODS: The study sample includes all California acute care private hospitals that report comparable financial data to the State and covers 2001 through 2006 time period. Relative price to uninsured is measured as the percent difference of uninsured payments from Medicare payments, by comparing percent of charges paid by uninsured as a group to percent of charges paid by Medicare within each hospital. RESULTS: Sixty-five percent of all uninsured care among private hospitals is provided by nonprofit hospitals that are non-DSH. Although, uninsured patients still pay lower prices at DSH hospitals compared with non-DSH hospitals of the same ownership category, this difference reduced substantially over time. For-profit DSH hospitals serve a smaller share of uninsured patients and charge higher uninsured prices than nonprofit non-DSH hospitals but receive the highest DSH subsidy as a percent of their revenues. CONCLUSIONS: In California, DSH subsidies do not target highest providers of care to uninsured and in 2005-2006 have had very small potential as a mechanism of reducing prices to uninsured. PMID- 20706171 TI - Selected summaries from the XVII World Congress of Psychiatric Genetics, San Diego, California, USA, 4-8 November 2009. AB - The XVII World Congress of Psychiatric Genetics, sponsored by The International Society of Psychiatric Genetics (ISPG) took place in San Diego, California from 4 to 8 November 2009. Approximately 550 participants gathered to discuss the latest molecular genetic findings relevant to serious mental illness, including schizophrenia, mood disorders, substance abuse, autism, and attention deficit disorder. Recent advances in the field were discussed, including the genome-wide association studies results, copy number variation (CNV) in the genome, genomic imaging, and large multicenter collaborations. The following report, written by junior travel awardees who were assigned sessions as rapporteurs represents some of the areas covered in oral presentation during the conference, and reports on some of the notable major new findings described at this 2009 World Congress of Psychiatric Genetics. PMID- 20706172 TI - Intraocular and serum levels of vascular endothelial growth factor in acute retinal necrosis and ocular toxoplasmosis. AB - PURPOSE: To determine the intraocular and serum vascular endothelial growth factor (VEGF) levels in patients with acute retinal necrosis (ARN) and compare those with VEGF levels found in patients with ocular toxoplasmosis (OT). METHODS: Paired intraocular fluid and serum samples of 17 patients with ARN and of 16 patients with OT were analyzed by ELISA for VEGF levels, and the clinical records were reviewed. RESULTS: The mean intraocular VEGF levels in patients with ARN were higher than in patients with OT (P = 0.005), whereas the serum levels did not differ. Intraocular VEGF levels exceeded the serum levels in 8 of 17 patients (47%) with ARN compared with 1 of 16 patients (6%) with OT (P = 0.009). The group with high intraocular VEGF was associated with a more extensive retinitis and lower visual acuity at 3-month follow-up (P < 0.001 and P = 0.031, respectively). CONCLUSION: Intraocular VEGF levels were elevated in patients with ARN compared with OT patients. Our results suggest strong intraocular VEGF production in ARN, which might be of importance for the treatment of these patients. PMID- 20706173 TI - Association of fluorescein angiographic features with visual acuity and with optical coherence tomographic and stereoscopic color fundus photographic features of diabetic macular edema in a randomized clinical trial. AB - BACKGROUND: Fluorescein angiography (FA) has been performed as part of the management of diabetic macular edema for many years. Its current role relative to the role of optical coherence tomography (OCT) is not well defined. PURPOSE: To evaluate the associations of FA features with visual acuity (VA) and with OCT and fundus photographic characteristics in eyes with diabetic macular edema. METHODS: In a clinical trial, conducted by the Diabetic Retinopathy Clinical Research Network to compare two methods of laser photocoagulation to treat diabetic macular edema, FA (film and digital), color photographs, OCT, and VA measurements were obtained at baseline and at 1 year. Grading of morphologic features was performed at a reading center. Reproducibility of FAs was assessed, and the correlations of FA features with VA, OCT, and color photograph features were computed. RESULTS: From 79 clinical sites, data of 323 study eyes and 203 fellow nonstudy eyes were analyzed. Fluorescein leakage area at baseline was associated with reduced VA, increased OCT measures of retinal thickness and volume, and color photographic measurements of retinal thickening (r = 0.33-0.58). No important associations were found with changes from baseline to 12 months in these parameters or with any of the other variables analyzed. CONCLUSION: Fluorescein leakage is associated with VA and some OCT and color photographic variables. We did not identify any unique FA variables that had a stronger association with VA than OCT measures of retinal thickness. These data may be useful to investigators planning future diabetic macular edema clinical trials. PMID- 20706174 TI - Central retinal vessel blood flow after surgical treatment for central retinal vein occlusion. AB - PURPOSE: The purpose of this study was to determine the effect of radial optic neurotomy and retinal endovascular surgery on retinal blood flow velocity in patients with central retinal vein occlusion. METHODS: A prospective interventional case series. RESULTS: Six patients with a central retinal vein occlusion of <12 months' duration were included. Three patients were treated with radial optic neurotomy and three with retinal endovascular surgery. Five patients had decreased central venous blood flow velocity compared with the fellow eye, and one patient had similar central venous blood flow in both eyes at baseline. All study eyes had decreased central venous blood flow velocity compared with the fellow eye at 24 weeks after treatment. Two patients had a further decrease in central venous blood flow during the study. Three patients had no minimal change in central venous blood flow, and 1 patient showed a minimal increase from 3 cm/s at baseline to 4 cm/s 24 weeks after surgery. CONCLUSION: Radial optic neurotomy and retinal endovascular surgery do not alter central retinal blood flow velocity. The place of these therapies in the treatment for central retinal vein occlusion should be questioned. PMID- 20706175 TI - Performance of commercial herpes simplex virus type-2 antibody tests using serum samples from Sub-Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: Several commercial type-specific serologic tests are available for herpes simplex virus type 2 (HSV-2). Poor specificity of some tests has been reported on samples from sub-Saharan Africa. METHODS: To summarize the performance of the tests using samples from sub-Saharan Africa, we conducted a systematic review of publications reporting performance of commercially available HSV-2 tests against a gold standard (Western Blot or monoclonal antibody-blocking EIA). We used random-effects meta-analyses to summarize sensitivity and specificity of the 2 most commonly evaluated tests, Kalon gG2 enzyme-linked immunosorbent assay (ELISA), and Focus HerpeSelect HSV-2 ELISA. RESULTS: We identified 10 eligible articles that included 21 studies of the performance of Focus, and 12 of Kalon. The primary analyses included studies using the manufacturers' cut-offs (index value = 1.1). Focus had high sensitivity (random effects summary estimate 99%, 95% confidence interval [CI]: 99%-100%) but low specificity (69%, 95% CI: 59%-80%). Kalon had sensitivity of 95% (95% CI: 93% 97%) and specificity of 91% (95% CI: 86%-95%). Specificity of Focus was significantly lower (P = 0.002) among HIV-positive (54%, 95% CI: 40%-68%) than HIV-negative individuals (69%, 95% CI: 56%-82%). When the cut-off optical density index was increased above the recommended value of 1.1 to between 2.2 and 3.5, the specificity of Focus increased to 85% (95% CI: 77%-92%). CONCLUSIONS: Sensitivity and specificity of HSV-2 tests used in sub-Saharan Africa vary by setting, and are lower than reported from studies in the United States and Europe. Increasing the cut-off optical density index may improve test performance. Evaluation of test performance in a given setting may help deciding which test is most appropriate. PMID- 20706176 TI - The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassay: a case-study from the Greater Toronto Area. AB - BACKGROUND: In 2005, syphilis screening in the Greater Toronto Area of Canada moved from the rapid plasma reagin (RPR) to a treponemal enzyme immunoassay (EIA). We sought to understand the consequences of this change on laboratory results and testing patterns with a population-based retrospective study of laboratory-based diagnoses of syphilis. METHODS: Samples positive under RPR (1998 2005) and EIA (2005-2008) screening were confirmed with an alternate treponemal test, and during the latter period underwent RPR testing. We compared monthly rates and the forecasting relationship between positives and future submissions with time-series methods, and assessed risk factors for EIA(+)/RPR(-) results using Poisson regression. RESULTS: A total of 3,092,938 submissions were included. Following EIA implementation, confirmed positive rates increased by 10.3 per 100,000 population (P<0.001). 0.59% of EIA(+)/RPR(-) individuals converted to RPR(+) within 2 months. EIA(+)/RPR(-) patients were more likely to be male (incidence rate ratio [IRR]: 2.3, 95% confidence interval [CI]: 1.6-2.5), asymptomatic (IRR: 1.8, 95% CI: 1.3-2.8), and aged>50 years (IRR: 2.4, 95% CI: 1.6-3.5) than those with EIA(+)/RPR(+) results. We detected a significant positive feedback loop between positive tests and subsequent submissions. This relationship was only transiently evident for EIA(+)/RPR(-) results up to 1 year following the changeover. CONCLUSIONS: EIA screening facilitates identification of probable latent syphilis and earlier serological detection of infectious syphilis, but may transiently cause increases in testing and indirectly suggests that physicians' interpretation of RPR(-) serology may lead to partner testing. In the absence of a true gold standard, implementation of EIA screening warrants careful communication regarding serological interpretation. PMID- 20706177 TI - Sexual transmission of hepatitis C virus in human immunodeficiency virus-negative men who have sex with men: a series of case reports. AB - Hepatitis C Virus (HCV) has recently emerged as sexual transmitted infection among (human immunodeficiency virus) HIV-positive but not HIV-negative men who have sex with men (MSM). We present 4 case reports showing that HIV-infection is not an absolute prerequisite for sexual HCV transmission in MSM. HIV-negative MSM with ulcerative sexual transmitted infection, those who engage in rough sexual practices or report a HCV-positive sexual partner, should be regularly screened for HCV. PMID- 20706179 TI - The future of cell transplant therapies: a need for tissue grafting. AB - Current methodologies of solid organ-derived cell transplant therapies introduce donor cells into hosts through a vascular route, a strategy modeled after hematopoietic therapies. These strategies fail because of inefficient engraftment, poor survival of the cells, and propensity for formation of life threatening emboli. Transplant success necessitates grafting methods, requiring a mixture of appropriate cell sources embedded into or onto precise mixes of extracellular matrix components and then localized to the diseased or dysfunctional tissue, promoting necessary proliferation, engraftment, and vascularization. Grafting technologies are rapidly translatable to therapeutic uses in patients and provide alternative treatments for regenerative medicine. PMID- 20706178 TI - Physician awareness of sexual orientation and preventive health recommendations to men who have sex with men. AB - BACKGROUND: Men who have sex with men (MSM) have unique health risks and needs. Providers who assume patients to be heterosexual may be providing suboptimal care. This study sought (1) to describe primary care provider (PCP) knowledge of patients' sexual orientation and the demographic and provider-related factors associated with such knowledge; and, (2) to assess whether PCP knowledge of sexual orientation was associated with appropriate recommendations for preventive and diagnostic health care services. METHODS: A total of 271 MSM completed a cross-sectional survey. We measured MSMs' disclosure of their sexual orientation and demographic information, and PCP recommendations for preventive health services. RESULTS: Most participants' PCPs (72%) knew the participants' sexual orientation. Participants with female, gay, and/or younger PCPs were more likely to have disclosed their sexual orientation. Black men, men from rural areas, and men with incomes under $15,000 per year were less likely to have disclosed their sexual orientation. PCP knowledge of sexual orientation was associated with a higher likelihood that PCPs recommended disease screening and preventive health measures: 59% versus 13% for human immunodeficiency virus testing, 32% versus 16% for hepatitis A or B vaccination. Inconsistencies were found between participants' self-reported risk behaviors and PCP recommendations. CONCLUSIONS: Disclosure of sexual orientation is associated with several patient-related and provider-related characteristics. Lack of disclosure to providers significantly decreased the likelihood that appropriate health services were recommended to participants. Efforts to promote discussion of sexual orientation within the primary health care setting should be directed toward both PCPs and MSM. PMID- 20706180 TI - Care for end-of-life cancer patients should be 24/7. PMID- 20706181 TI - Faecal incontinence in older people: delivering effective, dignified care. AB - Incontinence of faeces may effect up to 10% of adults in the community but people are reluctant to seek help owing to the stigma of this debilitating and distressing condition. There are multiple risk factors associated with the development of faecal incontinence that community nurses are well placed to identify. These risk factors range from reduced dietary and fluid intake to the complex symptoms found in patients with long-term conditions. Community continence services are historically nurse led and are delivered at the patient interface by community nurses, in collaboration with other disciplines and agencies. The ongoing drive to increase productivity sets a challenge for nursing to demonstrate the value of investing in a proactive approach to preventing faecal incontinence in older people or to improve the quality of life for those with intractable symptoms. A range of proven and emerging interventions are able to achieve more positive outcomes for patients. PMID- 20706182 TI - Sense of coherence and health among home-dwelling older people. AB - Sense of coherence (SOC) is important for maintaining health. The aim of this study was to investigate if the SOC experience among home-dwelling physically active older people differs from that of hospital patients with the same age and sex. Data were collected with questionnaires and structured interviews containing Antonovsky's SOC scale in an age- and sex-matched study group (n=160). Non parametric statistical analyses were performed. No differences were found in SOC between home-dwelling individuals and patients. Ninety-five percent of the home dwelling individuals perceived themselves as being in good health and 42.5% among the patients (p<0.001). SOC and disease were predictors for health in the total study group. Among the home-dwelling individuals, SOC, disease and being single were predictors for health and among the patients solely SOC. When using the components of the SOC concept, comprehensibility and disease predicted health for the home-dwelling individuals and meaningfulness predicted health for the patients. PMID- 20706183 TI - Stroke awareness among British ethnic minorities. AB - Stroke is the third common cause of death in the UK. It is also a leading cause of disability. The recent National Stroke Strategy (Department of Health, 2007) has provided major impetus behind changes in the ways in which stroke is prevented and treated (National Audit Office, 2010). Stroke awareness sits as a significant part of the Strategy, but there are some concerns that the Government's centrepiece campaign to increase public knowledge is not reaching some of the most vulnerable sections of our population, people from black and minority ethnic communities, despite clear evidence of increased risk among some ethnic communities. This paper describes some of the literature, mainly from the United States, which can help nurses working in community settings consider strategies for raising awareness about both stroke knowledge and risk. The paper points to three important themes: initial and prolonged engagement with local communities; self-management and cultural sensitivity. PMID- 20706184 TI - Preparing for future incapacity. AB - A recent inquest in South Wales heard of the tragic case of a husband who killed himself and his wife through carbon monoxide poisoning because he could not bear to see her continued suffering. His wife had spent two years in a persistent vegetative state and attempts to obtain a court order allowing the withholding of her artificial nutrition and hydration had been subject to lengthy delays. This article discusses how this case highlights the importance of making preparations for possible future incapacity by creating an advance decision refusing treatment and a health and welfare power of attorney under the Mental Capacity Act 2005. These provisions will ensure that the wishes of the patient are respected without the need to go to court and so avoid delay. PMID- 20706185 TI - IA (the ileostomy and internal pouch Support Group). PMID- 20706186 TI - General practitioner commissioning: dialogue is key. PMID- 20706187 TI - Community nurses working in piloted primary care teams: Irish Republic. AB - Primary care health services in the Irish Republic have undergone fundamental transformation with the establishment of multidisciplinary primary care teams nationwide. Primary care teams provide a community-based health service delivered through a range of health professionals in an integrated way. As part of this initiative ten pilot teams were established in 2003. This research was undertaken in order to gain an understanding of nurse's experiences of working in a piloted primary care team. The methodology used was a focus group approach. The findings from this study illustrated how community nurse's roles and responsibilities have expanded within the team. The findings also highlighted the benefits and challenges of working as a team with various other community-based health-care disciplines. PMID- 20706188 TI - Thinking falls - taking action: a guide to action for falls prevention. AB - Clinical guidelines and research papers help clinicians measure and understand the risk of falling in their older clients but very few provide the assessor with recommendations as to which interventions they can use to reduce the risk of a fall. The Guide to Action for Falls Prevention tool (GtA) was developed to help professionals from a broad range of organizations to recognize factors that might increase falls risk and know which actions to take to lessen that risk. Twenty four professionals tested the GtA in a clinical setting and found it quick (15 minutes) and easy to complete. The GtA needs further evaluation to test whether it is a practical way of delivering a falls prevention intervention. PMID- 20706189 TI - Public services: a new era? PMID- 20706190 TI - Expressive vocabulary of children with hearing loss in the first 2 years of life: impact of early intervention. AB - OBJECTIVE: The aim of this study was to determine the expressive vocabulary of children with hearing loss (HL) enrolled in early intervention (EI) <= 3 vs >3 months in the first 24 months and to compare with hearing controls. It was hypothesized that the number of words produced would be higher for children with HL enrolled in EI <= 3 vs >3 months. STUDY DESIGN: This is a prospective longitudinal matched cohort study. RESULT: The children with HL produced fewer words than the children with hearing. In addition, children with HL enrolled in EI <= 3 months had a larger expressive vocabulary percentile score compared with children with HL enrolled >3 months. Children with mild HL enrolled in EI <= 3 months had the greatest growth in vocabulary between 12 to 16 and 18 to 24 months. CONCLUSION: Although multiple factors are associated with expressive vocabulary growth of children with HL, enrollment in EI <= 3 months has sustained beneficial effects on expressive vocabulary at 18 to 24 months. PMID- 20706191 TI - An interdisciplinary, family-focused approach to relational learning in neonatal intensive care. AB - OBJECTIVE: The aim of this study is to show the efficacy of the Program to Enhance Relational and Communication Skills-Neonatal Intensive Care Unit (PERCS NICU). STUDY DESIGN: In this study, 74 practitioners attended workshops and completed baseline, post-training and follow-up questionnaires. RESULT: On yes/no questions, 93 to 100% reported improved preparation, communication skills and confidence post-training and follow-up. A total of 94 and 83% improved their ability to establish relationships, and 76 and 83% reported reduced anxiety post training and follow-up, respectively. On Likert items, 59 and 64% improved preparation, 45 and 60% improved communication skills and confidence, 25 and 53% decreased anxiety and 16 and 32% improved relationships post-training and follow up, respectively. Qualitative themes included integrating new communication and relational abilities, honoring the family perspective, appreciating interdisciplinary collaboration, personal/human connection and valuing the learning. In total, 93% applied skills learned, three-quarters transformed practice and 100% recommended PERCS-NICU. CONCLUSION: After PERCS-NICU, clinicians improved preparation, communication and relational abilities, confidence and reduced anxiety when holding difficult neonatal conversations. PMID- 20706192 TI - Genetic variation of vascular endothelial growth factor pathway does not correlate with the severity of retinopathy of prematurity. AB - OBJECTIVE: The aim of this study was to assess the genetic effects of the vascular endothelial growth factor (VEGF) pathway on retinopathy of prematurity (ROP). STUDY DESIGN: A prospective study from a tertiary center that enrolled 204 Japanese infants (<35 weeks of gestational age (GA)) having no anomalies. ROP developed in 127, but not in 77 infants. The relative severity was defined as non severe, moderate and severe ROP for GA, based on the staging criteria. VEGF (g. 634G>C, g.+13553C>T) and VEGF-receptor (KDR g.+4422(AC)11 to 14, Flt-1 c.+6724(TG)13 to 23) gene polymorphisms and clinical variables were assessed by uni/multivariate analyses. RESULT: The frequency of polymorphisms did not differ between ROP and non-ROP patients. The TT genotype of g.+13553 showed a higher odds ratio for non-severe ROP than CC genotype (P=0.006). Multivariate analyses indicated that low birth weight, blood transfusion and respiratory distress syndrome, but not polymorphisms, were the risk factors of advanced ROP (>= stage 3). CONCLUSION: A genotype of the VEGF pathway weakly affects the severity of ROP compared with other clinical factors. PMID- 20706193 TI - High salt intake delayed angiotensin II-induced hypertension in mice with a genetic variant of NADPH oxidase. AB - BACKGROUND: gp91(PHOX), a catalytic subunit of NAD(P)H oxidase, is involved in angiotensin II (Ang II)-induced superoxide (O2-) generation. This study was designed to examine the hypothesis that an enhancement in O2- generation due to elevated Ang II induces salt-sensitivity, which contributes to the development of hypertension. METHODS: Assessment of blood pressure and renal excretory responses to Ang II infusion (2.2 ng.min/g) for 2 weeks via osmotic minipump was made in knockout (KO; n = 20) mice lacking the gene for gp91(PHOX) which were fed on either normal-salt (NS; 0.04% NaCl) or high-salt (HS, 4% NaCl) diet and compared these responses with those in wild-type (WT; n = 23) mice. RESULTS: Ang II induced increase in systolic blood pressure (SBP) was started within the 4th day in all groups except in HS fed KO mice in which SBP increased after the 10(th) day of Ang II infusion. The increases in SBP were lower in KO than WT mice at the end of 2-week infusion period. In Ang II + HS fed KO mice, the urinary excretion rate of nitrite/nitrate (U(NOx)V) markedly increased but 8-isoprostane excretion rate remained unchanged. These findings indicate that an increase in nitric oxide (NO) with a lack of O2- formation was involved in the delayed hypertension in Ang II + HS fed KO mice. CONCLUSION: These data suggest that an enhanced O2- activity and its interaction with NO contribute to the early developmental phase of Ang II induced salt-sensitive hypertension.American Journal of Hypertension (2011). doi:10.1038/ajh.2010.173. PMID- 20706194 TI - Serum magnesium, ambulatory blood pressure, and carotid artery alteration: the Ohasama study. AB - BACKGROUND: To investigate the associations of 24-h ambulatory blood pressure (ABP) and serum magnesium level (sMg) with risk of carotid artery alteration in a general population. METHODS: sMg and ABP, monitored every 30 min, were measured in 728 subjects (mean age, 67 years) from the Japanese general population. The extent of carotid artery alteration was evaluated according to mean common carotid intima-media thickness (IMT) and the presence of focal carotid plaque. To determine the association of sMg and carotid artery alteration, analysis of covariance (ANCOVA) (for adjusted mean IMT) or multiple logistic regression analysis (for odds ratio (OR) for the presence of carotid plaques) was used. RESULTS: Lower sMg was significantly associated with mean IMT (P = 0.004) and risk of >=2 carotid plaques (P = 0.03) after adjusting for possible confounding factors, including 24-h ABP (systolic), creatinine clearance (Ccr) (estimated using the Cockcroft-Gault equation), and serum minerals (sodium, potassium, calcium, and inorganic phosphorus). Even when 24-h ABP values were within normal range (<130/80 mm Hg), lower sMg levels (<2.2 mg/dl) were significantly associated with mean IMT (P = 0.007) and risk of >=2 carotid plaques (OR, 2.14; 95% confidence interval, 1.18-3.85; P = 0.01). CONCLUSIONS: Both 24-h ABP and lower sMg were closely and independently associated with risk of carotid artery alteration. Further investigations are needed to examine the relationship between sMg levels and the incidence of cardiovascular disease. PMID- 20706195 TI - Cardiovascular and renal damage in primary aldosteronism: outcomes after treatment. AB - Primary aldosteronism (PA) is one of the common forms of curable hypertension. Recent views have suggested that PA is far from being relatively benign, as it was previously thought, but it is associated with a variety of cardiovascular and renal sequelae that reflect the capability of inappropriately elevated aldosterone to induce tissue damage over that induced by hypertension itself. The evidence supporting these views has been obtained from experiments conducted in hypertensive animal models and studies involving patients with PA. Preclinical studies have also indicated that aldosterone causes cardiovascular and renal tissue damage only in the context of inappropriate salt status. It has been suggested that untoward effects of high-salt intake are dependent on activation of mineralocorticoid receptors (MRs) that might result from increased oxidative stress and changes in the intracellular redox potential. Unilateral adrenalectomy or treatment with MR antagonists are the current options for treating an aldosterone-producing adenoma (APA) or idiopathic adrenal hyperplasia (IHA). Treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent cardiovascular events and deterioration of renal function indicates that surgery and medical treatment are equally beneficial in the long term. PMID- 20706196 TI - Obesity-related hypertension: epidemiology, pathophysiology, and clinical management. AB - The prevalence of obesity, including childhood obesity, is increasing worldwide. Weight gain is associated with increases in arterial pressure, and it has been estimated that 60-70% of hypertension in adults is attributable to adiposity. Centrally located body fat, associated with insulin resistance and dyslipidemia, is a more potent determinant of blood pressure elevation than peripheral body fat. Obesity-related hypertension may be a distinct hypertensive phenotype with distinct genetic determinants. Mechanisms of obesity-related hypertension include insulin resistance, sodium retention, increased sympathetic nervous system activity, activation of renin-angiotensin-aldosterone, and altered vascular function. In overweight individuals, weight loss results in a reduction of blood pressure, however, this effect may be attenuated in the long term. An increasing number of community-based programs (including school programs and worksite programs) are being developed for the prevention and treatment of obesity. Assessment and treatment of the obese hypertensive patient should address overall cardiovascular disease (CVD) risk. There are no compelling clinical trial data to indicate that any one class of antihypertensive agents is superior to others, and in general the principles of pharmacotherapy for obese hypertensive patients are not different from nonobese patients. Future research directions might include: (i) development of effective, culturally sensitive strategies for the prevention and treatment of obesity; (ii) clinical trials to identify the most effective drug therapies for reducing CVD in obese, hypertensive patients; (iii) continued search for the genetic determinants of the obese, hypertensive phenotype. PMID- 20706197 TI - Vascular structure and oxidative stress in salt-loaded spontaneously hypertensive rats: effects of losartan and atenolol. AB - BACKGROUND: Renin-angiotensin system (RAS) modulation by high dietary sodium may contribute to salt-induced hypertension, oxidative stress, and target organ damage. We investigated whether angiotensin II (Ang-II) type 1 (AT1)-receptor blockade (losartan) could protect the aorta and renal arteries from combined hypertension- and high dietary salt-related oxidative stress. METHODS: Spontaneously hypertensive rats (3-month-old, n = 10/group) received tap water (SHR), water containing 1.5% NaCl (SHR+S), 1.5% NaCl and 30 mg losartan/kg/day (SHR+S+L), or 50 mg atenolol/kg/day (SHR+S+A). Atenolol was used for comparison. Ten Wistar-Kyoto rats (WKY) were controls. Systolic blood pressure (SBP) was determined by tail plethysmography. After 5 months of treatment, vascular remodeling and oxidative stress (superoxide production and NAD(P)H-oxidase activity (chemiluminescence), malondialdehyde (MDA) content (high-performance liquid chromatography), endothelial nitric oxide synthase (eNOS) activity [(14)C arginine to (14)C citrulline], CuZn-SOD activity (spectrophotometry)) were studied. RESULTS: In SHR, salt-loading significantly aggravated hypertension, urinary protein excretion, intraparenchymal renal artery (IPRArt) perivascular fibrosis, aortic and renal artery oxidative stress, and induced endothelial cell loss in IPRArts. In salt-loaded SHR, 5-month losartan and atenolol treatments similarly reduced SBP, but only losartan significantly prevented (i) urinary protein excretion increase, (ii) or attenuated hypertension-related vascular remodeling, (iii) aortic MDA accumulation, (iv) renal artery eNOS activity lowering, and (v) aortic and renal artery superoxide dismutase (SOD) activity reduction. In SHR+S, the contributions to aortic superoxide production were as follows: uncoupled eNOS > xanthine oxidase (XO) > NAD(P)H oxidase. CONCLUSIONS: In this salt-sensitive genetic hypertension model, losartan protects from hypertension- and high dietary salt-related vascular oxidative stress, exceeding the benefits of BP reduction. Also, during salt overload, BP-independent factors contribute to vascular remodeling, at least part of which derive from AT1 receptor activation. PMID- 20706198 TI - Age-dependent association between sleep duration and hypertension in the adult Korean population. AB - BACKGROUND: In Western countries, sleep deprivation has been reported to elevate blood pressure. Here, we examined whether this association is true also for an Asian population. METHODS: The study sample comprised 5,393 Korean adults aged 19 99 years who had participated in the 2005 Korean National Health and Nutrition Examination Survey. Hypertension was defined as a systolic blood pressure (SBP) >=140 mm Hg or a diastolic blood pressure (DBP) >=90 mm Hg, or regular use of antihypertensive medication. RESULTS: Among the participants, 1,345 subjects (24.9%) displayed hypertension. The median sleep duration was 7 h/day. In the young and middle-aged adults aged <65 years, the unadjusted odds ratio (OR) for hypertension was 1.5-fold greater in those with a sleep duration of <=5 h (OR 1.52; 95% confidence interval (CI) 1.19, 1.94) as compared to those who slept 7 h. This trend did not significantly change after adjustments for putative risk factors for hypertension such as gender, obesity, smoking status, alcohol consumption, physical activity, depressive symptom, diabetes mellitus, and stroke (OR 1.31; 95% CI 1.01, 1.71). However, in the older adults aged >=65 years, no association was found between sleep duration and the risk of hypertension. Long sleep duration (>=8 h) was not associated with hypertension in either the younger or older adults in this study. CONCLUSION: Short sleep duration (<=5 h) is independently associated with hypertension in young and middle-aged Korean adults. PMID- 20706199 TI - Tyrosine hydroxylase polymorphism (C-824T) and hypertension: a population-based study. AB - BACKGROUND: Sympathetic nervous system (SNS) overactivity is present in a large proportion of the hypertensive population and precedes the development of established hypertension. Variations in the proximal promoter of the tyrosine hydroxylase (TH) gene have been shown to influence biochemical and physiological traits in the SNS as well as hypertension. METHODS: We investigated the relationship between a common single-nucleotide polymorphism (SNP) in the proximal TH promoter (C-824T) and blood pressure (BP) in a large general population sample, characterized by 24-h ambulatory BP (ABP) monitoring and office BP measurement. RESULTS: The study population consisted of 1,221 women and 1,182 men, ages 41-71 years, without major cardiovascular diseases. Regarding the C-824T SNP, 32.4% had the C/C genotype, 50.0% the C/T genotype, and 17.6% the T/T genotype. The T/T genotype conferred an ~45% increase in relative risk of hypertension, defined by conventional criteria, compared with the C/C genotype, and participants with the T/T genotype had significantly higher mean (95% confidence interval (CI)) systolic BP (SBP) (138 (136-140) mm Hg vs. 135 (133 136)), diastolic BP (DBP) (88 (86-89) mm Hg vs. 85 (84-86)), and heart rate (68 (67-69) beats/min vs. 66 (65-67)) than participants with the C/C genotype (P < 0.05). BP, heart rate, and prevalence of hypertension were intermediate in participants with the C/T genotype. These effects were the same in women and men and whether BP was measured in the office or by 24-h ambulatory monitoring. CONCLUSION: The C-824T SNP in the proximal TH promoter influences BP and prevalence of hypertension in the general population. PMID- 20706200 TI - Association of prescription H1 antihistamine use with obesity: results from the National Health and Nutrition Examination Survey. AB - The incidence of obesity in the United States has reached epidemic proportions. Previous research has shown several medications exert noticeable effects on body weight regulation. Histamine-1 (H1) receptor blockers commonly used to alleviate allergy symptoms are known to report weight gain as a possible side effect. Therefore, we investigated the association between prescription H1 antihistamine use and obesity in adults using data from the 2005-2006 National Health and Nutrition Examination Survey (NHANES). Adults taking prescription H1 antihistamines were matched by age and gender with controls and compared on the basis of body measurements, plasma glucose, insulin concentrations, and lipid levels. Prescription H1 antihistamine users had a significantly higher weight, waist circumference, and insulin concentration than matched controls. The odds ratio (OR) for being overweight was increased in prescription H1 antihistamine users. H1 antihistamine use may contribute to the increased prevalence of obesity and the metabolic syndrome in adults given these medications are also commonly used as over-the-counter remedies. PMID- 20706201 TI - Influence of psychosocial factors on postpartum weight retention. AB - For some women, pregnancy may increase the risk of future obesity with consequences for health and well-being. Psychosocial factors may be partly responsible for this. The aim of this study was to examine the association between psychosocial factors during pregnancy and postpartum weight retention (PPWR) at 6 and 18 months. A total of 37,127 women in The Danish National Birth Cohort (DNBC; 1996-2002) participated in four telephone interviews before and after delivery. They gave information about their experience of distress, depression and anxiety, social support, and psychosocial burdens during pregnancy. PPWR was defined as retention >= 5 kg at 6 and 18 months postpartum according to a woman's prepregnancy weight. The associations were examined by use of logistic regression and presented as odds radios with 95% confidence intervals. Women who were more likely to feel depressed/anxious or distressed during pregnancy had a higher risk of PPWR at 6 months (1.35 (1.27; 1.44) and 1.30 (1.22; 1.38)) and 18 months (1.34 (1.24; 1.45) and 1.32 (1.23; 1.42)). Likewise, women who felt burdened by their economy or working situation had a higher risk of PPWR as did women with the lowest incomes or less education. Women who reported a high level of distress or depression/anxiety both during pregnancy and in the first 6 months of motherhood had the highest risk of PPWR 18 months postpartum (1.54 (1.39; 1.71) and 1.49 (1.32; 1.69), respectively). Feeling distressed, depressed, or anxious during pregnancy was associated with higher PPWR as was personal and economical burdens. Adverse psychosocial characteristics may be a common determinant of weight retention after childbirth. PMID- 20706202 TI - The prevalence of metabolically healthy obese subjects defined by BMI and dual energy X-ray absorptiometry. AB - Nearly one-third of obese (OB) people are reported to be metabolically healthy based on BMI criteria. It is unknown whether this holds true when more accurate adiposity measurements are applied such as dual-energy X-ray absorptiometry (DXA). We compared differences in the prevalence of cardiometabolic abnormalities among adiposity groups classified using BMI vs. DXA criteria. A total of 1,907 adult volunteers from Newfoundland and Labrador participated. BMI and body fat percentage (%BF; measured using DXA) were measured following a 12-h fasting period. Subjects were categorized as normal weight (NW), overweight (OW), or OB based on BMI and %BF criteria. Cardiometabolic abnormalities considered included elevated triglyceride, glucose, and high-sensitivity C-reactive protein (hsCRP) levels, decreased high-density lipoprotein (HDL) cholesterol levels, insulin resistance, and hypertension. Subjects were classified as metabolically healthy (0 or 1 cardiometabolic abnormality) or abnormal (>= 2 cardiometabolic abnormalities). We found low agreement in the prevalence of cardiometabolic abnormalities between BMI and %BF classifications (kappa = 0.373, P < 0.001). Among NW and OW subjects, the prevalence of metabolically healthy individuals was similar between BMI and %BF (77.6 vs. 75.7% and 58.8 vs. 62.5%, respectively) however, there was a pronounced difference among OB subjects (34.0 vs. 47.7%, P < 0.05). Similar trends were evident using three additional definitions to characterize metabolically healthy individuals. Our findings indicate that approximately one-half of OB people are metabolically healthy when classified using %BF criteria which is significantly higher than previously reported using BMI. Caution should therefore be taken when making inferences about the metabolic health of an OB population depending on the method used to measure adiposity. PMID- 20706203 TI - Different impacts of neck circumference and visceral obesity on the severity of obstructive sleep apnea syndrome. AB - Our aim was to investigate the significance of neck circumference (NC) on the presence and severity of obstructive sleep apnea (OSA) syndrome independent of visceral fat (VF) obesity. A total of 219 subjects with suspected OSA underwent a complete polysomnography (PSG) study, along with the measurement of NC, and total body fat (TF) and VF levels (VFLs) measured by bioelectrical impedance analysis. We proposed NC divided by height (NC/H) as the simple index for height-corrected NC in Japanese subjects. NC/H exhibited a significantly stronger correlation than NC per se with BMI (r = 0.781 vs. 0.675, P = 0.0178), TF (r = 0.531 vs. 0.156, P < 0.0001), and VF (r = 0.819 vs. 0.731, P = 0.0203), indicating that NC/H is a better indicator of visceral obesity than NC per se. Interestingly, despite the strong correlation between NC/H and VFL, VFL was significantly associated with the apnea-hypopnea index (AHI) >= 5, >= 15, and >= 30, but not with >= 40 or >= 50, whereas NC/H was significantly associated with higher AHI values, i.e., AHI >= 50 but not with lower AHI value. Furthermore, multiple regression analyses revealed that VFL and NC/H were independently associated with the square root of AHI (AHI(0.5)) levels in obese and nonobese patients, respectively. In conclusion, NC is associated with the severity of OSA independently of visceral obesity, especially in nonobese patients. PMID- 20706204 TI - Obesity-induced diabetes in mouse strains treated with gold thioglucose: a novel animal model for studying beta-cell dysfunction. AB - An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic beta-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic beta-cells to secrete insulin. PMID- 20706205 TI - Insulin resistance and oxidative stress influence colony-forming unit-endothelial cells capacity in obese patients. AB - The aim of this study was to investigate the relationship between a sub population of endothelial progenitor cells (EPC), namely colony-forming unit endothelial cells (CFU-EC), their colony-forming capacity and variable clinical parameters, including insulin resistance and oxidative stress, in obese individuals. Thirty-eight obese adults (aged 42.5 +/- 12.7), with BMI 32.3 +/- 4.0 and 13 normal-weight controls (aged 48.2 +/- 12.9; BMI 23.2 +/- 2.3) were studied. CFU-EC colony-forming capacity was impaired in the group of obese individuals compared to the normal-weight controls (P = 0.001). The inverse correlation between homeostasis model assessment-insulin resistance (HOMA(IR)) index and CFU-EC number (r = -0.558, P < 0.0001) as well as positive total antioxidant status of plasma (TAS)/CFU-EC relation were noticed during the study. Additionally, correlations between the concentration of triglycerides (TG), high density lipoproteins (HDLs), and body composition parameters in the obese participants were established. Our results demonstrate that insulin resistance and oxidative stress have a significant impact on the CFU-EC colony formation in obesity. Moreover, in multivariate regression analysis, in both studied groups, the HOMA(IR) index and HDL concentration were independent predictors of the number of CFU-EC. Endothelium dysfunction, which can be present in obesity, may in part be caused by EPC function impairment in this condition. PMID- 20706206 TI - Association between body composition and pulmonary function in elderly people: the Korean Longitudinal Study on Health and Aging. AB - The age-related increase in body fat and decrease in muscle mass are associated with increased morbidity in elderly populations. Pulmonary function also decreases with age, but no study has investigated whether regional body composition is associated with pulmonary function in an older population. The Korean Longitudinal Study on Health and Aging is a community-based cohort study of people aged > 65 years selected by random stratified sampling. Anthropometrics, biochemical factors, and lung function by spirometry were evaluated in 439 men (mean age of 75.9 +/- 8.6 years) and 561 women (mean age of 76.0 +/- 8.8 years). Dual-energy X-ray absorptiometry (DXA) was performed to assess the whole and regional body composition. Computed tomography (CT) was also used to measure fat or muscle distribution at the abdominal and mid-thigh levels. Although pulmonary function and muscle mass were inversely related to age, fat mass was not. After adjusting for age, height, BMI, smoking and exercise status, and high sensitivity C-reactive protein (hsCRP), fat mass in trunk or central area was inversely associated with lung function in both sexes (P < 0.01). Men with more muscle in trunk and mid-thigh level had better lung function (P < 0.01). The results of this community-based study show that regional body composition is significantly associated with lung function. Augmentation of muscle in the trunk and low extremity in men, and reduction of fat in the trunk and upper body in men and women may be helpful in maintaining lung function in the elderly population. PMID- 20706208 TI - Cooperation and Hamilton's rule in a simple synthetic microbial system. AB - A fundamental problem in biology is understanding the evolutionary emergence and maintenance of altruistic behaviors. A well-recognized conceptual insight is provided by a general mathematical relation, Hamilton's rule. This rule can in principle be invoked to explain natural examples of cooperation, but measuring the variables that it involves is a particularly challenging problem and controlling these variables experimentally an even more daunting task. Here, we overcome these difficulties by using a simple synthetic microbial system of producers and nonproducers of an extracellular growth-enhancing molecule, which acts as a 'common good.' For this system, we are able to manipulate the intrinsic growth difference between producers and nonproducers, as well as the impact of the common good on the growth rate of its recipients. Our synthetic system is thus uniquely suited for studying the relation between the parameters entering Hamilton's rule and the quantities governing the systems' behavior. The experimental results highlight a crucial effect of nonlinearities in the response to the common good, which in general tend to limit the predictive value of Hamilton's rule. PMID- 20706207 TI - Targeted interactomics reveals a complex core cell cycle machinery in Arabidopsis thaliana. AB - Cell proliferation is the main driving force for plant growth. Although genome sequence analysis revealed a high number of cell cycle genes in plants, little is known about the molecular complexes steering cell division. In a targeted proteomics approach, we mapped the core complex machinery at the heart of the Arabidopsis thaliana cell cycle control. Besides a central regulatory network of core complexes, we distinguished a peripheral network that links the core machinery to up- and downstream pathways. Over 100 new candidate cell cycle proteins were predicted and an in-depth biological interpretation demonstrated the hypothesis-generating power of the interaction data. The data set provided a comprehensive view on heterodimeric cyclin-dependent kinase (CDK)-cyclin complexes in plants. For the first time, inhibitory proteins of plant-specific B type CDKs were discovered and the anaphase-promoting complex was characterized and extended. Important conclusions were that mitotic A- and B-type cyclins form complexes with the plant-specific B-type CDKs and not with CDKA;1, and that D type cyclins and S-phase-specific A-type cyclins seem to be associated exclusively with CDKA;1. Furthermore, we could show that plants have evolved a combinatorial toolkit consisting of at least 92 different CDK-cyclin complex variants, which strongly underscores the functional diversification among the large family of cyclins and reflects the pivotal role of cell cycle regulation in the developmental plasticity of plants. PMID- 20706213 TI - Journal club. Endothelin 1 from the vascular endothelium contributes to blood pressure control. PMID- 20706209 TI - DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO. AB - Insulin/IGF-1 signaling controls metabolism, stress resistance and aging in Caenorhabditis elegans by regulating the activity of the DAF-16/FoxO transcription factor (TF). However, the function of DAF-16 and the topology of the transcriptional network that it crowns remain unclear. Using chromatin profiling by DNA adenine methyltransferase identification (DamID), we identified 907 genes that are bound by DAF-16. These were enriched for genes showing DAF-16 dependent upregulation in long-lived daf-2 insulin/IGF-1 receptor mutants (P=1.4e(-11)). Cross-referencing DAF-16 targets with these upregulated genes (daf 2 versus daf-16; daf-2) identified 65 genes that were DAF-16 regulatory targets. These 65 were enriched for signaling genes, including known determinants of longevity, but not for genes specifying somatic maintenance functions (e.g. detoxification, repair). This suggests that DAF-16 acts within a relatively small transcriptional subnetwork activating (but not suppressing) other regulators of stress resistance and aging, rather than directly regulating terminal effectors of longevity. For most genes bound by DAF-16::DAM, transcriptional regulation by DAF-16 was not detected, perhaps reflecting transcriptionally non-functional TF 'parking sites'. This study demonstrates the efficacy of DamID for chromatin profiling in C. elegans. PMID- 20706214 TI - Susceptible mice: identifying a diabetic nephropathy disease locus using a murine model. AB - Diabetic nephropathy is a common, complex disease with a clear genetic predisposition. Human gene association studies are beginning to bear fruit by identifying gene loci that increase diabetic nephropathy risk. Chua et al. report a similar study in diabetic mice that reveals a major nephropathy locus on chromosome 8. Could this be a human nephropathy gene? Time will tell, but such findings will at least improve the use of mouse models of human kidney disease. PMID- 20706215 TI - Urinary kidney injury biomarkers and urine creatinine normalization: a false premise or not? AB - Substantial research has focused on the discovery of urinary biomarkers to detect acute kidney injury (AKI) before a rise in serum creatinine. As in chronic kidney diseases, the concentrations of urinary AKI biomarkers have been normalized to urine creatinine concentration to account for creatinine clearance and urine flow. Waikar et al. challenge the assumption that normalization to creatinine clearance in a chronic disease state can be extrapolated to an acute state, in which creatinine clearance is, by definition, changing acutely. PMID- 20706216 TI - Toward a B-cell signature of tolerance? AB - Operational tolerance is a rare and still unexplained phenomenon in organ transplantation. Pallier et al. analyzed the peripheral B-cell compartment of 12 renal transplant patients with drug-free long-term graft function and found a peculiar blood B-cell phenotype, with an expansion of memory activated B cells and increased expression of inhibitory molecules, suggesting a role of B cells in maintaining graft tolerance. PMID- 20706217 TI - Peritoneo-scrotal shunting diagnosed by Tc-99m DTPA SPECT/CT imaging. PMID- 20706218 TI - Make your diagnosis: adynamic ileus after insertion of peritoneal dialysis catheter. PMID- 20706220 TI - Who needs a greener revolution? PMID- 20706219 TI - The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer? AB - Epithelial-to-mesenchymal transition (EMT) is a fundamental process in development and disease. Zinc-finger enhancer binding (ZEB) transcription factors (ZEB1 and ZEB2) are crucial EMT activators, whereas members of the miR-200 family induce epithelial differentiation. They are reciprocally linked in a feedback loop, each strictly controlling the expression of the other. Now data show that EMT not only confers cellular motility, but also induces stem-cell properties and prevents apoptosis and senescence. Thus the balanced expression of ZEB factors and miR-200 controls all these processes. We therefore propose that the ZEB/miR 200 feedback loop is the molecular motor of cellular plasticity in development and disease, and in particular is a driving force for cancer progression towards metastasis by controlling the state of cancer stem cells. PMID- 20706221 TI - Histone Sin mutations promote nucleosome traversal and histone displacement by RNA polymerase II. AB - Nucleosome traversal by RNA polymerase II (pol II) and recovery of chromatin structure after transcription are essential for proper gene expression. In this paper we show that nucleosomes assembled with Sin mutant histones present a much weaker barrier to traversal by pol II and are less likely to survive transcription. Increases in traversal from incorporation of Sin mutant histones and histones lacking H2A/H2B amino-terminal tails were in most cases additive, indicating that traversal can be facilitated by distinct mechanisms. We had identified a key intermediate in traversal, the zero (slashed circle)-loop, which mediates nucleosome survival during transcription. Sin mutations probably destabilize these intermediates and thus increase the likelihood of nucleosome disassociation. PMID- 20706223 TI - Pretransplant cardiovascular evaluation and posttransplant cardiovascular risk. AB - Modern immunosuppression has expanded access to kidney transplantation by limiting the risk of rejection. However, cardiovascular disease (CVD) remains the principal cause of death with a functioning graft, threatening the long-term survival of transplant recipients. The article reviews the leading risk factors for cardiovascular morbidity both before and after kidney transplantation. Evidence linking poor renal function to CVD is discussed. The function of immunosuppression in exacerbating the risk of both nephrotoxicity and CVD is explored through means of a clinical case study. Underlying kidney disease, hypertension, hyperlipidemia, and diabetes are recognized risk factors for CVD both before and after kidney transplantation. Worsening kidney function and posttransplant immunosuppression exacerbate the risk. Although underlying medical conditions and demographic factors are not easily modifiable, immunosuppression has been recognized as a suitable target. Multiple risk factors converge to increase the risk of cardiovascular events and cardiovascular mortality after kidney transplantation. Clinicians are charged with isolating and treating modifiable risk factors to reduce the risk to long-term survival. PMID- 20706224 TI - Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile. AB - Currently used immunosuppressants exacerbate cardiovascular risk. However, attempts to limit the use of these agents increase the risk of allograft rejection. Immunosuppressants targeting signal 2 and signal 3 lymphocyte activation pathways are under clinical development. Clinical data from trials of the Janus family protein tyrosine kinase-3 inhibitor tasocitinib and the costimulation blocker belatacept are presented. Additional pipeline agents are described. Results from two phase III clinical trials of belatacept revealed efficacy that is not inferior to that provided by cyclosporine (CsA). In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial enrolling recipients of standard criteria living or deceased donor organs, the risk of rejection was higher among patients treated with a more intensive treatment regimen. Increased risk of posttransplant lymphoproliferative disorder, particularly among Epstein-Barr virus-patients, was a notable adverse event. Data from a phase II trial of tasocitinib suggested good prophylaxis of rejection. Safety signals included increased risk of infection and potential myelosuppression, leading to anemia, neutropenia, and leukopenia. Both belatacept and tasocitinib were associated with a low cardiovascular risk profile and improved renal function compared with CsA. New immunosuppressive regimens should maintain the effectiveness provided by current agents while preserving renal function and cardiovascular health. Surveillance for new adverse events must be an integral part of the long-term management strategy. PMID- 20706225 TI - The metabolic syndrome following kidney transplantation. AB - The metabolic syndrome is a constellation of defined cardiovascular risk factors occurring simultaneously in a single individual. The result of dysregulated glucose and vascular metabolism, the syndrome has been identified as a significant risk factor for cardiovascular morbidity in the general population. More recently, a relatively high prevalence of the metabolic syndrome has been recognized among kidney transplant recipients. The prevalence, risk factors, pathophysiology, and potential consequences of the metabolic syndrome in the general population and in kidney transplant recipients are reviewed. The definitions and clinical utility of the metabolic syndrome as a medical condition continue to be debated. Nevertheless, the burden of risk increases with the presence of multiple components, including insulin resistance, abdominal obesity, and dysregulated lipid metabolism. Risk factors specific to transplant recipients include the duration of pretransplant dialysis and posttransplant immunosuppression and weight gain. The metabolic syndrome is emerging as a significant surveillance target following kidney transplantation. Control of body mass index, blood glucose and lipid levels, as well as blood pressure, is required to prevent the consequences of the metabolic syndrome, including cardiovascular events and cardiovascular death. Immunosuppressive regimens should be designed to limit exacerbation of components of the metabolic syndrome. PMID- 20706226 TI - Targeting dental resources to reduce inequalities in oral health in the North East of England - a health equity audit methodology to evaluate the effects of practice location, practice population and deprivation. AB - AIM: To use nationally available data sets to undertake an equity audit to support the targeting of resources to meet the needs of patients from deprived communities, in areas where levels of poor oral health remain higher than the rest of the population as a whole. METHODS: Postcodes of 224,107 patients in County Durham were matched to Lower Super Output Areas (LSOA) for each practice. Deprivation scores were identified for each LSOA. The postcode of dental practices (59) was matched to the LSOA and the practice population divided into quintiles from the most to the least deprived areas. RESULTS: Results indicated that the more deprived the area in which a dental practice was located, the greater the proportion of the practice population accessing care from the most deprived quintile. The size of the practice alone was not directly related to meeting the needs of a more deprived population. CONCLUSIONS: The methodology used in this study can be used to identify inequalities and inequities in oral health in different areas. In the audit area improving access to dental services for those in most need, was best tackled by targeted investment into dental practices located in deprived communities. Audits are recommended to insure a fare distribution of resources to meet local population needs. PMID- 20706228 TI - Dentist 50533. Does dentistry. PMID- 20706227 TI - The influence of varying maxillary incisal edge embrasure space and interproximal contact area dimensions on perceived smile aesthetics. AB - OBJECTIVE: The aim of this study was to determine the influence of incisal edge embrasure space and interproximal contact area dimensions on perceived smile aesthetics. DESIGN: Cross-sectional study. SETTING: Postgraduate dental teaching hospital. METHODS: A photograph of a smiling female, displaying only the lips and maxillary teeth was digitally altered. First, the proportions of the incisal edge embrasure spaces were modified to produce five different images. Secondly, the lengths of the interproximal contact areas were altered to produce five different images. The two sets of photographs were ranked from 'most attractive' to 'least attractive' by 35 dentists, 35 dental technicians and 35 patients. RESULTS: An embrasure space arrangement where the size of the embrasures increases progressively distally from the midline was deemed most attractive; absence of embrasure spaces was deemed least attractive. In assessing the interproximal contact areas, all groups assessed an arrangement where the areas between the teeth were equal (and 50% the length of the central incisor) as most attractive, and where the contact areas increased in length progressively distally from the midline as least attractive. There were few statistically significant differences between the groups in these perceptions. CONCLUSION: Whilst there is broad agreement in what the participant groups deem to be aesthetic, our findings do not wholly correspond to the 'ideals' that have been previously suggested in the dental literature. PMID- 20706229 TI - A unique resource. PMID- 20706230 TI - Anonymity rights. PMID- 20706231 TI - Hard to swallow. PMID- 20706232 TI - NHS responsibility. PMID- 20706233 TI - Lip seals. PMID- 20706234 TI - Diagnosis tosh. PMID- 20706244 TI - Coronectomy - oral surgery's answer to modern day conservative dentistry. AB - Removal of mandibular third molars is a common oral surgery procedure which is associated with a significant risk of injury to the inferior dental nerve (IDN). In an era of conservative dentistry the technique of coronectomy, which is conservative in terms of surgery and successful in minimising the incidence of IDN injury, has been met with some resistance and has been deemed non-ideal and controversial by many oral surgeons. This article outlines the benefits of coronectomy and highlights some examples from other dental specialities that have embraced conservative principles, despite their detractors. PMID- 20706245 TI - Risk management in clinical practice. Part 3. Crowns and bridges. AB - Provision of indirect restorations is associated with more complaints and litigation than any other area of dentistry. In the third part of this series we identify possible causes of such complaints. We explore each of the stages from clinical assessment to treatment, highlighting areas which may trigger litigation when they are not addressed carefully - particularly in relation to cosmetic dentistry. The article is illustrated with clinical examples drawn from the authors' personal experience. With patients' ever-increasing expectations, the pressure to deliver quality dentistry has never been higher and will not diminish. PMID- 20706250 TI - Summary of: targeting dental resources to reduce inequalities in oral health in the North East of England - a health equity audit methodology to evaluate the effects of practice location, practice population and deprivation. AB - AIM: To use nationally available data sets to undertake an equity audit to support the targeting of resources to meet the needs of patients from deprived communities, in areas where levels of poor oral health remain higher than the rest of the population as a whole. METHODS: Postcodes of 224,107 patients in County Durham were matched to Lower Super Output Areas (LSOA) for each practice. Deprivation scores were identified for each LSOA. The postcode of dental practices (59) was matched to the LSOA and the practice population divided into quintiles from the most to the least deprived areas. RESULTS: Results indicated that the more deprived the area in which a dental practice was located, the greater the proportion of the practice population accessing care from the most deprived quintile. The size of the practice alone was not directly related to meeting the needs of a more deprived population. CONCLUSIONS: The methodology used in this study can be used to identify inequalities and inequities in oral health in different areas. In the audit area improving access to dental services for those in most need, was best tackled by targeted investment into dental practices located in deprived communities. Audits are recommended to insure a fare distribution of resources to meet local population needs. PMID- 20706251 TI - Summary of: the influence of varying maxillary incisal edge embrasure space and interproximal contact area dimensions on perceived smile aesthetics. AB - OBJECTIVE: The aim of this study was to determine the influence of incisal edge embrasure space and interproximal contact area dimensions on perceived smile aesthetics. DESIGN: Cross-sectional study. SETTING: Postgraduate dental teaching hospital. METHODS: A photograph of a smiling female, displaying only the lips and maxillary teeth was digitally altered. First, the proportions of the incisal edge embrasure spaces were modified to produce five different images. Secondly, the lengths of the interproximal contact areas were altered to produce five different images. The two sets of photographs were ranked from 'most attractive' to 'least attractive' by 35 dentists, 35 dental technicians and 35 patients. RESULTS: An embrasure space arrangement where the size of the embrasures increases progressively distally from the midline was deemed most attractive; absence of embrasure spaces was deemed least attractive. In assessing the interproximal contact areas, all groups assessed an arrangement where the areas between the teeth were equal (and 50% the length of the central incisor) as most attractive, and where the contact areas increased in length progressively distally from the midline as least attractive. There were few statistically significant differences between the groups in these perceptions. CONCLUSION: Whilst there is broad agreement in what the participant groups deem to be aesthetic, our findings do not wholly correspond to the 'ideals' that have been previously suggested in the dental literature. PMID- 20706252 TI - State-of-the-art techniques in operative dentistry: contemporary teaching of posterior composites in UK and Irish dental schools. AB - AIM: Advances of composite systems and their application have revolutionised the management of posterior teeth affected by caries, facilitating a minimally invasive approach. Previous surveys have indicated that the teaching of posterior composites within dental schools was developing, albeit not keeping pace with clinical evidence and the development of increasingly predictable techniques and materials. Concurrently, surveys of dental practice indicate that dental amalgam still predominates as the 'material of choice' for the restoration of posterior teeth within UK general dental practice. In light of such considerations, the aim of this study was to investigate current teaching of posterior composites in Irish and UK dental schools. METHODS: An online questionnaire which sought information in relation to the current teaching of posterior composites was developed and distributed to the 17 established Irish and UK dental schools with undergraduate teaching programmes in late 2009. RESULTS: Completed responses were received from all 17 schools (response rate = 100%). All 17 schools taught the placement of occlusal and two-surface occlusoproximal composites in premolar and permanent molar teeth. Two schools did not teach placement of three-surface occlusoproximal composites in either premolars or molars. In their preclinical courses, ten schools taught posterior composites before teaching dental amalgams. Fifty-five percent of posterior restorations placed by dental students were of composite (range = 10-90%) and 44% amalgam (range = 10-90%), indicating an increase of 180% in the numbers of posterior composites placed over the past five years. Diversity was noted in the teaching of clinical techniques and students at different schools are trained with different composites and bonding systems. Some cause for concern was noted in the teaching of certain techniques that were not in keeping with existing best evidence, such as the teaching of transparent matrix bands and light-transmitting wedges for occluso-proximal composites (eight schools) and the teaching of bevels on the cavosurface enamel margins of both the occlusal and proximal box margins (three schools). CONCLUSION: The teaching of posterior composites in the Irish and UK dental schools has substantially increased over the last five years. Dental students in these schools often gain more experience in the placement of posterior composites than amalgam. However, practice trends indicate that a majority of GDPs continue to place amalgam in preference to composite, thereby suggesting a source of tension as current dental students emerge into the dental workforce over the coming years. There is, as a consequence, a challenge to the dental profession and its funding agencies in the UK to encourage more of a shift towards the minimally interventive use of composite systems in the restoration of posterior teeth, in particular among established practitioners. PMID- 20706273 TI - Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies. AB - Apoptosis is a mode of cell death through which cells are dismantled and cell remains are packed into small, membrane-bound, sealed vesicles called apoptotic bodies, which are easy to erase by phagocytosis by neighbouring and immune system cells. The end point of the process is to cleanly eliminate damaged or unnecessary cells without disrupting the surrounding tissue or eliciting an inflammatory response. The apoptotic process involves a series of specific events including deoxyribonucleic acid and nuclear fragmentation, protease-driven cleavage of specific substrates, which inhibits key survival functions and reorganizes the cell's structure, externalization of molecules involved in phagocytosis, membrane blebbing and cell shrinkage. Apoptotic volume decrease (AVD) leading to cell shrinkage is a core event in the course of apoptosis, the biological meaning of which has not been clearly ascertained. In this article we argue that volume loss is a geometrical requisite for cell dismantling into apoptotic bodies. This is derived from the cell's volume-to-surface ratio. Indeed, package of the original cell volume into smaller membrane-sealed vesicles requires that either cell membrane surface increase or cell volume decrease. In this sense, AVD provides a reservoir of membrane surface for apoptotic body formation. The strategic situation of AVD in the time course of apoptosis is also discussed in the context of apoptotic body formation. PMID- 20706274 TI - Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression. AB - The human T-cell leukemia virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL) is incurable by currently known therapies. ATL samples and cell lines derived from ATL patients show restricted sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 ligand (CD95L). We have recently shown that HTLV-1-infected cells express elevated levels of cellular caspase-8 FLICE-inhibitory protein (c-FLIP) conferring resistance to receptor-mediated apoptosis. This finding underscores the demand to develop new strategies for treatment of ATL. In this study, we show that the naturally occurring herbal compound Rocaglamide (Roc) sensitizes CD95L- and TRAIL induced apoptosis in HTLV-1-infected cells by downregulation of c-FLIP expression. Investigation of the molecular mechanism of Roc-mediated downregulation of c-FLIP revealed that it inhibits phosphorylation of the translation initiation factor 4E (eIF4E), a key factor that controls the rate limiting step of translation, through inhibition of the MEK-ERK-MNK1 signaling pathway. This event prevents de novo synthesis of short-lived proteins such as c FLIP in HTLV-1-infected cells. Our data suggest that Roc may serve as an adjuvant for TRAIL-based anticancer therapy. PMID- 20706275 TI - Specific disintegration of complex II succinate:ubiquinone oxidoreductase links pH changes to oxidative stress for apoptosis induction. AB - The formation of reactive oxygen species (ROS) and the change of the intracellular pH (pH(i)) are common phenomena during apoptosis. How they are interconnected, however, is poorly understood. Here we show that numerous anticancer drugs and cytokines such as Fas ligand and tumour necrosis factor alpha provoke intracellular acidification and cause the formation of mitochondrial ROS. In parallel, we found that the succinate:ubiquinone oxidoreductase (SQR) activity of the mitochondrial respiratory complex II is specifically impaired without affecting the second enzymatic activity of this complex as a succinate dehydrogenase (SDH). Only in this configuration is complex II an apoptosis mediator and generates superoxides for cell death. This is achieved by the pH(i) decline that leads to the specific dissociation of the SDHA/SDHB subunits, which encompass the SDH activity, from the membrane-bound components of complex II that are required for the SQR activity. PMID- 20706276 TI - BH3-only protein Bmf mediates apoptosis upon inhibition of CAP-dependent protein synthesis. AB - Tight transcriptional regulation, alternative splicing and/or post-translational modifications of BH3-only proteins fine-tune their proapoptotic function. In this study, we characterize the gene locus of the BH3-only protein Bmf (Bcl-2 modifying factor) and describe the generation of two major isoforms from a common transcript in which initiation of protein synthesis involves leucine-coding CUG. Bmf(CUG) and the originally described isoform, Bmf-short, display comparable binding affinities to prosurvival Bcl-2 family members, localize preferentially to the outer mitochondrial membrane and induce rapid Bcl-2-blockable apoptosis. Notably, endogenous Bmf expression is induced on forms of cell stress known to cause repression of the CAP-dependent translation machinery such as serum deprivation, hypoxia, inhibition of the PI3K/AKT pathway or mTOR, as well as direct pharmacological inhibition of the eukaryotic translation initiation factor eIF-4E. Knock down or deletion of Bmf reduces apoptosis under some of these conditions, demonstrating that Bmf can act as a sentinel for stress-impaired CAP dependent protein translation machinery. PMID- 20706279 TI - Plant killers on the spot. PMID- 20706277 TI - New insights into the development of lymphoid tissues. AB - Secondary lymphoid organs are important locations for the initiation of adaptive immune responses. They develop before birth, and their formation requires interaction between lymphotoxin-alpha1beta2-expressing lymphoid-tissue inducer cells and lymphotoxin-beta receptor-expressing stromal organizer cells. Here, we discuss new insights into the earliest phases of peripheral lymph node and Peyer's patch formation that occur before lymphotoxin-beta receptor signalling and suggest a role for the developing nervous system. In addition, we discuss the differing requirements for the postnatal formation of mucosa-associated lymphoid tissues and tertiary lymphoid structures that develop at sites of chronic inflammation. PMID- 20706278 TI - RNA-based antiviral immunity. AB - In eukaryotic RNA-based antiviral immunity, viral double-stranded RNA is recognized as a pathogen-associated molecular pattern and processed into small interfering RNAs (siRNAs) by the host ribonuclease Dicer. After amplification by host RNA-dependent RNA polymerases in some cases, these virus-derived siRNAs guide specific antiviral immunity through RNA interference and related RNA silencing effector mechanisms. Here, I review recent studies on the features of viral siRNAs and other virus-derived small RNAs from virus-infected fungi, plants, insects, nematodes and vertebrates and discuss the innate and adaptive properties of RNA-based antiviral immunity. PMID- 20706280 TI - Moving in and renovating: exporting proteins from Plasmodium into host erythrocytes. AB - Malaria parasites live within erythrocytes in the host bloodstream and induce crucial changes to these cells. By so doing, they can obtain the nutrients that they require for growth and can effect the evasion and perturbation of host defences. In order to accomplish this extensive host cell remodelling, the intracellular parasite exports hundreds of proteins to commander the erythrocyte for its own purposes. An export motif, a processing enzyme that specifies protein targeting and a translocon that mediates the export of proteins from the parasite into the host erythrocyte have been identified. However, important questions remain regarding the secretory pathway and the function of the translocon. In addition, this export pathway provides potentially useful targets for the development of inhibitors to interfere with functions that are vital for the virulence and survival programmes of the parasite. PMID- 20706282 TI - Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs. AB - PURPOSE: To report a new phenotype with additional data on the oculo-dental syndrome of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) caused by mutations on CNNM4, a metal transporter, with linkage at achromatopsia locus 2q11 (Jalili syndrome). METHODS: Three siblings aged 5, 6, and 10 years from a six generation Arab family in Gaza City underwent full systemic, ophthalmic, and dental examinations, investigations and detailed genealogy. RESULTS: Subjects presented at early childhood with visual impairment and abnormal dentition together with photophobia and fine nystagmus increasing under photopic conditions, in the presence of normal fundi. Electrophysiologically, photopic flicker responses were impaired; scotopic responses were extinguished at the age of 10 years. Anterior open bite accompanied AI in all siblings. The syndrome formed 83% of CRD cases in the Gaza Strip, which has a prevalence of 1 : 10,000. CONCLUSION: On the basis of clinical features and electrophysiology, two phenotypes exist: an infancy onset form with progressive macular lesion and an early childhood onset form with normal fundi. More prevalent than previously thought, Jalili syndrome presents a model of the effect of different mutations of the same genetic defect, observations of the same phenotype at different stages of the natural history of the disease, and the influence of epigenetic and tissue specific factors as causes of phenotypic variability. The paper calls for action to tackle consanguinity in endogamous communities, addresses the possible role of high fluoride levels in groundwater as a trigger for genetic mutations, and the use of red-tinted filter in cone disorders. PMID- 20706283 TI - Pitfalls in the management of TB-associated uveitis. AB - AIM: The aim of this study is to highlight the pitfalls in the diagnosis and management of tuberculosis (TB)-associated uveitis. METHODS: This is a retrospective review of case records of four patients with TB-associated uveitis. RESULTS: In cases 1 and 2, failure to treat tubercular uveitis with anti tubercular therapy (ATT) and unopposed steroid therapy led to a serious systemic consequence--development of intra-cranial tuberculoma. In case 4, similar failure to initiate ATT caused recurrent disease (focal choroiditis) in the eye. All four cases showed appearance of new lesions or worsening of existing lesions in the eye, following initiation of ATT. Such paradoxical reactions resolved by adding/increasing corticosteroid therapy. CONCLUSION: TB-associated uveitis needs a strong index of suspicion for diagnosis and a combined anti-tubercular plus anti-inflammatory therapy for successful outcome. PMID- 20706281 TI - A hitchhiker's guide to the nervous system: the complex journey of viruses and toxins. AB - To reach the central nervous system (CNS), pathogens have to circumvent the wall of tightly sealed endothelial cells that compose the blood-brain barrier. Neuronal projections that connect to peripheral cells and organs are the Achilles heels in CNS isolation. Some viruses and bacterial toxins interact with membrane receptors that are present at nerve terminals to enter the axoplasm. Pathogens can then be mistaken for cargo and recruit trafficking components, allowing them to undergo long-range axonal transport to neuronal cell bodies. In this Review, we highlight the strategies used by pathogens to exploit axonal transport during CNS invasion. PMID- 20706284 TI - Combination intravitreal rituximab and methotrexate for massive subretinal lymphoma. PMID- 20706285 TI - Subretinal migration of trypan blue during macular hole and epiretinal membrane peel: an observational case series. Is there a safer method? AB - PURPOSE: To report the inadvertent subretinal migration and effect of trypan blue (TB) during staining of the epiretinal membrane (ERM) for macular pucker, and internal limiting membrane during macular hole (MH) surgery, and to suggest alternative safe methods of injecting TB. METHODS: Three cases in which TB migrated to the subretinal space were followed up on day 1, day 7, day 21, and at 3 months following the initial operation. Two of the cases were operated for MH and one patient had ERM peel. Colour fundus and optical coherence tomography (OCT) were performed on day 1 and on each subsequent visit. RESULTS: In both cases of MH the hole was closed postoperatively. The patient with ERM had the membrane peeled successfully as documented by OCT. Clinically, all patients demonstrated chorioretinal atrophy in the area of TB migration. There was thinning of the retina as noted by OCT. CONCLUSION: It is difficult to prove whether the chorioretinal atrophy was caused by the subretinal TB or by the accidental forceful dye injection, but subretinal TB and contact of TB with the retinal pigment epithelium should be avoided, and precautions should be taken during intravitreal injection. We suggest a more controlled method of dye injection in such cases using the flute needle rather than the syringe technique that is conventionally used. PMID- 20706286 TI - Plasmid injection and application of electric pulses alter endogenous mRNA and protein expression in B16.F10 mouse melanomas. AB - The application of electric pulses to tissues causes cell membrane destabilization, allowing exogenous molecules to enter the cells. This delivery technique can be used for plasmid gene therapy. Reporter gene expression after plasmid delivery with eight representative published protocols was compared in B16.F10 mouse melanoma tumors. This expression varied significantly based on the pulse parameters utilized for delivery. To observe the possible influence of plasmid injection and/or pulse application on endogenous gene expression, levels of stress-related mRNAs 4 and 24 h after delivery were determined by PCR array. Increases in mRNA levels for several inflammatory chemokines and cytokines were observed in response to plasmid injection, electric pulses alone or the combination. This upregulation was confirmed by individual real-time reverse transcription TaqMan PCR assays. Proteins were extracted at the same time points from identically treated tumors and inflammatory protein levels were assayed by enzyme-linked immunosorbent assay and by a custom multiplex bead array. Increases in inflammatory protein levels generally paralleled mRNA levels. Some differences were observed, which may have been due to differing expression kinetics. The observed upregulated expression of these cytokines and chemokines may aid or inhibit the therapeutic effectiveness of immune-based cancer gene therapies. PMID- 20706287 TI - Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients. AB - Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the occurrence of tumors of parathyroids, neuroendocrine cells of the gastro enteropancreatic tract and anterior pituitary. MEN1 gene encodes menin oncosuppressor protein. Loss of heterozygosity at 11q13 is typical of MEN1 tumors. We have analyzed the MEN1 mRNA and menin expression in fibroblasts from normal skin biopsies and from MEN1 patients (two with a frameshift 738del4 (exon 3) mutation, introducing a premature stop codon, and an individual with an R460X (exon 10) nonsense mutation). The expression of full-length menin protein did not differ between MEN1 and normal fibroblasts. Wild-type alleles mRNAs were expressed in MEN1 patients, whereas mutant alleles were partially degraded by nonsense-mediated mRNA decay pathway, suggesting a mechanism of compensation for allelic loss by the up-regulation of wild-type menin expression at a post transcriptional level. Small-interfering RNA silencing of the wild-type mRNA allele abolished menin compensation, whereas the ribozyme silencing of the MEN1 mutated mRNA allele resulted in strongly enhanced wild-type menin expression. Gel retardation analysis showed that in vitro-specific RNA-protein complexes bound to MEN1 mRNA. These findings contribute to the understanding of tumorigenesis in MEN1, offering the basis for the development of RNA-based therapies in MEN1 gene mutation carriers. PMID- 20706289 TI - [Just ask!]. PMID- 20706288 TI - Enhanced tumor suppression in vitro and in vivo by co-expression of survivin specific siRNA and wild-type p53 protein. AB - The development of malignant prostate cancer involves multiple genetic alterations. For example, alterations in both survivin and p53 are reported to have crucial roles in prostate cancer progression. However, little is known regarding the interrelationships between p53 and survivin in prostate cancer. Our data demonstrate that the expression of survivin is inversely correlated with that of wtp53 protein (r(s)=0.548) in prostate cancer and in normal prostate tissues. We have developed a therapeutic strategy, in which two antitumor factors, small interfering RNA-survivin and p53 protein, are co-expressed from the same plasmid, and have examined their effects on the growth of PC3, an androgen-independent prostate cancer cell line. When p53 was expressed along with a survivin-specific short hairpin RNA (shRNA), tumor cell proliferation was significantly suppressed and apoptosis occurred. In addition, this combination also abrogated the expression of downstream target molecules such as cyclin dependent kinase 4 and c-Myc, while enhancing the expression of GRIM19. These changes in gene expression occurred distinctly in the presence of survivin shRNA/wtp53 compared with control or single treatment groups. Intratumoral injection of the co-expressed construct inhibited the growth and survival of tumor xenografts in a nude mouse model. These studies revealed evidence of an interaction between p53 and survivin proteins plus a complex signaling network operating downstream of the wtp53-survivin pathway that actively controls tumor cell proliferation, survival and apoptosis. PMID- 20706290 TI - [Multiple trauma and trauma centers]. PMID- 20706291 TI - [Rationed treatment of expensive premature infants?]. PMID- 20706292 TI - [Cynicism and profit chase]. PMID- 20706293 TI - [Of respect for the deceased]. PMID- 20706295 TI - [Just use of costs data]. PMID- 20706296 TI - [Cover picture--what's happening?]. PMID- 20706297 TI - [Strange scientific concepts]. PMID- 20706298 TI - [Perioperative treatment: in the track of the anesthesiologists]. PMID- 20706301 TI - [Leadership challenges in a radiology department]. PMID- 20706302 TI - [Systematic off-label use of drugs]. PMID- 20706303 TI - [Immigrants are not a homogenous groups]. PMID- 20706304 TI - [Seriously injured patients transferred from local hospitals to a university hospital]. AB - BACKGROUND: We studied diagnostics and stabilizing surgery in severely injured patients transferred from local hospitals to a university hospital. The purpose was to identify a potential for improvement of regional trauma care. MATERIAL AND METHODS: The material comprises all severely injured patients (Injury Severity [ISS] Score > 15) transferred from local hospitals to the University Hospital of Northern Norway in the period 01.01.2006 - 31.12.2007. Information about diagnostics, extent of injury and treatment during the first 24 hours after transferral was recorded by retrospective chart review. Emergency surgical interventions are defined according to plans for a national trauma system. RESULTS: 6/74 patients underwent emergency surgery at the local hospital (chest tube insertion, external fracture fixation); eight after arrival at the university hospital (chest tube insertion, hemostatic packing of the abdomen and pelvis, external fracture fixation). 66/74 were CT-scanned locally; 37 with a CT multitrauma series (CT caput, neck, thorax, abdomen and pelvis). Of the 62 who had head CT scans performed at a local hospital, the cervical spine was not imaged for 10. For eight of 55 patients who had CT scans of the thorax/abdomen/pelvis intravenous contrast agent was not administered. INTERPRETATION: Trauma care at local hospitals may be improved by more systematic imaging, a lower threshold for emergency surgery, and early communication with the university hospital. PMID- 20706305 TI - [Health and function after occupational injury]. AB - BACKGROUND: Available statistics provide relatively reliable information on the number of occupational injuries, their causes and mechanisms, but less is known about long-term health impact. MATERIAL AND METHODS: A group of workers, who had been referred to a specialist for medico-legal assessment after seeking compensation because of occupational injury, were asked to complete a questionnaire approximately three years (median) after the injury. Perceived health and function was assessed through the Short Form Questionnaire (SF-36) and a 100 mm visual analogue scale for physical and psychological health. The injuries were scored according to the Abbreviated Injury Scale (AIS). Information on outcome of the insurance claims was obtained from the Norwegian Labour and Welfare Administration (NAV). RESULTS: Of 314 distributed questionnaires, 191 (62 %) were returned. 83 % of the respondents had injuries with an AIS score < 2; mostly sprains, strains and contusions. Compared to Norwegian population norms, the claimants reported substantially reduced health and functioning; this was especially pronounced among those with soft-tissue injuries, age at injury < 45 years, and < 12 years of education. 33 % of the respondents worked full time, while 55 % were recipients of insurance benefits. 30 % had been granted workers' compensation by NAV. INTERPRETATION: The reported health deterioration in this selected injury group seems to be at odds with a biologically based disease model. Medico-legal considerations should take into account that prognosis after occupational injury may be influenced by factors other than the actual injury. PMID- 20706306 TI - [Use of glucosamine does not reduce the need for other pain-relieving drugs]. AB - BACKGROUND: Since 2004, glucosamine has been available as a prescription drug for symptomatic treatment of mild to moderate osteoarthritis. The aim of this study was to characterize glucosamine utilization patterns, and patients' concomitant use of other analgesics, as well as the prescribers' medical specialty. MATERIAL AND METHODS: We searched the Norwegian Prescription Database for all glucosamine prescriptions dispensed during the years 2004, 2005 and 2006, and prescriptions for analgesics with codeine, and non-steroidal anti-inflammatory drugs (NSAIDs) reimbursed for arthrosis for the same patients. RESULTS: In the three-year period, 91,107 patients received 297,558 prescriptions for glucosamine corresponding to a total cost for patients of 70 mill. NOK. 86 % of patients were more than 50 years old, 69 % were women. Among physicians with a known specialty, 84 % of prescribers were specialists in general practice. 33.3 % of patients used glucosamine all three years. Among the patients who used glucosamine regularly 19 % were prescribed NSAIDs, while 22 % of them used analgesics containing codeine. Patients who started taking glucosamine did not reduce their use of analgetics containing codeine. A positive correlation was seen between use of glucosamine and use of NSAIDs. INTERPRETATION: Glucosamine use is not associated with use of less other pain-relieving drugs. This may reflect insufficient clinical effect of glucosamine. PMID- 20706307 TI - [Magnetic navigation for ablation of cardiac arrhythmias]. AB - BACKGROUND: The first use of magnetic navigation for radiofrequency ablation of supraventricular tachycardias, was published in 2004. Subsequently, the method has been used for treatment of most types of tachyarrhythmias. This paper provides an overview of the method, with special emphasis on usefulness of a new remote-controlled magnetic navigation system. MATERIAL AND METHODS: The paper is based on our own scientific experience and literature identified through a non systematic search in PubMed. RESULTS: The magnetic navigation system consists of two external electromagnets (to be placed on opposite sides of the patient), which guide an ablation catheter (with a small magnet at the tip of the catheter) to the target area in the heart. The accuracy of this procedure is higher than that with manual navigation. Personnel can be quickly trained to use remote magnetic navigation, but the procedure itself is time-consuming, particularly for patients with atrial fibrillation. The major advantage is a considerably lower radiation burden to both patient and operator, in some studies more than 50 %, and a corresponding reduction in physical strain on the operator. The incidence of procedure-related complications seems to be lower than that observed with use of manually operated ablation catheters. Work is ongoing to improve magnetic ablation catheters and methods that can simplify mapping procedures and improve efficacy of arrhythmia ablation. The basic cost for installing a complete magnetic navigation laboratory may be three times that of a conventional electrophysiological laboratory. INTERPRETATION: The new magnetic navigation system has proved to be applicable during ablation for a variety of tachyarrhythmias, but is still under development. PMID- 20706308 TI - [Acid-base disturbances in intensive-care patients]. AB - BACKGROUND: Acid-base disturbances may cause a variety of symptoms, multi-organ failure and compromised immune defense. The aim of this paper is to provide an overview of acid-base disturbances in intensive-care patients. MATERIAL AND METHOD: The article is based on a non-systematic search in Pub Med, a textbook on intensive care and the authors' clinical experience. RESULTS: The Henderson Hasselbalch equation describes acid-base status by changes in pCO2 and bicarbonate. Changes in pCO2 reflect the respiratory and bicarbonate the metabolic status. Standard base excess describes the metabolic part more exactly. Anion gap is calculated as a supplement. The Stewart method, describes acid-base status through three independent variables (pCO2, weak acids and strong ion difference [SID]) that regulate the dependent variables pH and bicarbonate concentration. INTERPRETATION: The Henderson-Hasselbalch equation and standard base excess do not consider which acids or bases that are involved, The anion gap may disclose unmeasured anions and distinguish hyperchloremic acidosis from other types of metabolic acidosis, but the calculation is associated with uncertainty. The Stewart method describes the involved ions, but complicated equations makes it unsuitable in clinical practice. A combination of standard base excess and anion gap corrected for albumin levels provide a good description of acid-base status. PMID- 20706309 TI - [Screening for intellectual disability among adults]. AB - BACKGROUND: Instigation of proper measures in case of intellectual disability is often conditioned by a diagnosis. Our aim was to assess whether the Hayes Ability Screening Index (HASI) is a suitable screening instrument for intellectual disability among adults. MATERIAL AND METHODS: The article is based on three former studies aimed at validating HASI for use among patients referred for neuropsychological examination, prison inmates and psychiatric inpatients in community mental health centres. RESULTS: The sample consisted of 264 persons. The HASI correlated with the more comprehensive scales of assessing intellectual functioning (Wechsler tests) (r = 0.73, p < 0.001). With a cut-off value of 85, HASI had a sensitivity of 0.97 and a specificity of 0.61 in relation to an IQ < 70. INTERPRETATION: HASI is associated with few false negatives, but a large number of false positives. This implies that an intellectual disability is concluded in too many cases; a positive screening should be followed up with a more thorough assessment. PMID- 20706310 TI - [Morphine or oxycodone tablets for pain?]. AB - The opioids morphine and oxycodone are potent analgesics that are available as extended-release and immediate-release tablets. Indications are the same for both; i.e. severe acute pain and chronic pain (non-malignant or malignant). Few clinical studies have compared morphine and oxycodone directly. There is no evidence to support that one is superior over the other. PMID- 20706311 TI - ["Look to Norway"--but for how long?]. AB - Internationally, Norway receives positive attention mainly in the context of Winter Olympics or peace initiatives. However, an Associated Press article recently suggested that the Norwegian health care system had "found the Solution to Killer Superbug". Furthermore, Norway was proclaimed "The Most Infection Free Country in the World". What my be the reality behind such headlines, and how shall we as a nation maintain a favourable situation? Physicians in Scandinavian countries and the Netherlands have a long tradition for modest prescription of antibiotics, and are trained to use agents with a narrow antimicrobial spectre whenever possible. This is probably the main reason why these countries have had less antibiotic resistance than others. The number of antibiotics marketed in a country correlates positively with total drug consumption. Until 1992, Norwegian authorities could reject marketing of new compounds if national experts found no medical need for them. The foresight of senior colleagues has led to the number of marketed antibiotics in Norway, even today, being 10-fold lower than in some other European countries. The national surveillance programme, NORM, reports antimicrobial resistance in human pathogens on an annual basis. For example, national levels of MRSA and ESBL-producing Enterobacteriaceae are still very low whereas ampicillin and ciprofloxacin resistance in E coli and high- level gentamicin resistance in enterococci cause some concern. Norway has well established epidemiological surveillance systems in the fields of microbiology and infectious diseases. Nevertheless, more knowledge is needed on how antibiotics are used in hospitals. Two national strategic plans (since 2003) have emphasized the explicit importance of antibiotic surveillance to counteract future antibiotic resistance problems. To fulfil national ambitions, there is an urgent need for economic grants to this field; the human resources are there and as eager to start as Olympic performers! PMID- 20706312 TI - [Must we exercise for good health?]. PMID- 20706313 TI - [Children with neurodegenerative disease]. PMID- 20706315 TI - [General practitioner in New Zealand]. PMID- 20706318 TI - Optically efficient free-space folded perfect shuffle network. AB - A light-efficient folded perfect shuffle network is described. Two-dimensional (2 D) raster encoding of the processing element nodes is used to accommodate large arrays with simple imaging optics. The network uses 2-D arrays of lenslets and prisms to correct for magnification and replication losses. Simulation results show the required prism arrays to be of low complexity and suggest that the network is tolerant to imperfections in the prism parameters. PMID- 20706317 TI - Holographic function/interconnection module. AB - Optical logic circuits using function/interconnection modules are needed for the construction of optical digital computers. Construction of function/interconnection modules by holographic techniques is proposed. Holographic function/interconnection modules do not require the complementary inputs that were needed for modules proposed previously. Moreover, a number of modules can be constructed in one filtering system by our holographic technique. Experiments describing this kind of implementation are described. Potential integration of the modules into one filtering system and the power efficiency of proposed modules are also discussed. PMID- 20706319 TI - Cascaded operation of arrays of symmetric self-electro-optic effect devices. AB - Two identical optical modules were used to demonstrate the cascaded operation of 32-element arrays of symmetric self-electro-optic effect devices. The devices had 5 microm x 10 microm optical windows spaced on a square grid with a 20-microm spacing. They were operated as optically interconnected inverters at 1.1 MHz. The optical power was provided by two current modulated laser diodes per array, each with a maximum output power of 9 mW. The operation of the devices as logic gates is optically implemented but not demonstrated. PMID- 20706320 TI - Photorefractive adaptive filter structure with 40-dB interference rejection. AB - A new architecture for photorefractive adaptive filtering is introduced. This architecture is based on the principle of time-integrating correlator with a photorefractive material as the time-integrating photosensor. A compact and rugged system is achieved by using the same Bragg cell as both the delay line for computing correlation values and the delay to which the tap weights are applied. In this way a self-aligning structure is achieved. Semiconductor photorefractive materials are used with 1.2-1.3-microm wavelength injection lasers to achieve fast response, low power, and a compact structure. Tests of an experimental system demonstrated >40-dB rejection of narrow-band interference with a transient response time constant of 70micros. PMID- 20706321 TI - Reconstructing volume holograms without image field losses. AB - The reconstruction of volume holograms at wavelengths different from that of hologram formation suffers from the degradation of image quality and thus of an incomplete retrieval of the stored information. The major source of information loss is due to image field reduction. It is shown that these image field losses result from the local violation of Bragg's law induced by spherical recording waves. The evaluation of the spatially varying Bragg condition yields a spherical readout wave necessary for a complete image field reconstruction at an arbitrary wavelength. The effects on resolution are examined qualitatively by visual inspection of test targets. PMID- 20706322 TI - Polarization holographic characterization of organic azo dyes/PVA films for real time applications. AB - Two azo dyes were introduced in polyvinyl alcohol matrices giving thin solid colored films on which they can record polarization volume holograms in real time. These new azo dye polymer photosensitive systems have been holographically studied. Holographic characterization was investigated to determine its optimal and dynamical recording application conditions. Under a light exposure of 300 mJ/cm(2), polarization volume real time holograms having 0.27% diffraction were produced. We present three simple uses based on the facts that these photosensitive films are erasable and reusable for many thousand write/read/erase cycles and that they may show a memory effect in specific conditions. PMID- 20706323 TI - Performance characteristics of an optically addressed ferroelectric liquid crystal spatial light modulator. AB - Key performance characteristics of an optically addressed ferroelectric liquid crystal spatial light modulator have been measured and compare favorably with those of other commercially available spatial light modulators. Several characteristics that are important for optical pattern recognition, including imaging resolution, visibility, and response time, are discussed. Maximum resolution was measured to be 40 line pairs/mm at an imaging rate of 60 Hz. This differs from previously published results [Appl. Phys. Lett. 55, 537 (1989)], primarily because the device was operated so that good sensitivity was obtained with moderate illumination while the high resolution of the device was retained. PMID- 20706324 TI - Influence of speckle on laser range finders. AB - Speckle noise is shown to constitute a fundamental limit to laser range finders based on triangulation. A model is derived that relates the magnitude of this noise to the optical geometry used. Synchronized laser scanners are shown to have inherent speckle noise reduction properties. Experimental results are presented. PMID- 20706325 TI - Use of electron trapping materials in optical signal processing. 2: two dimensional associative memory. AB - The application of electron trapping materials to new optical architectures of associative memory based on space- and Fourier-domain inner products is described. Experimental results are presented. PMID- 20706326 TI - Spatial light rebroadcaster bit-slice word-addressable holographic memory. AB - A heteroassociative memory is proposed that allows a key word in a dictionary of key words to be used to recall an associated holographic image in a database of images. A novel bit-slice search approach finds the word sought in a dictionary of key words and generates a beam that selects the corresponding holographic image from a directory of images. Spatial light rebroadcasters are proposed for the key-word database. Optical experimental results demonstrate that spatial light rebroadcasters may be used in loops with image intensifiers and optically addressable liquid-crystal light valves and that the approach can be used to select holograms based on key-word matching. In the case considered, a holographic image having more than 40,000 bits is selected from 8 by using a key word from a dictionary of 8 words. PMID- 20706327 TI - Hole burning, Stark effect, and data storage: 2: holographic recording and detection of spectral holes. AB - The properties of holographic recording and detection of spectral holes in the frequency and electric-field dimension are investigated. To optimize the storage properties of optical memory devices, based on spectral hole burning and holography, cross-talk effects between adjacent holograms have to be minimized. These interactions depend on the relative phases of the holograms chosen during the recording stage. Using free-base chlorin (2,3-dihydroporphyrin) in polyvinyl butyral as host at a temperature of 1.7 K, the influence of the relative phase difference between holograms is demonstrated in both the frequency and the electric-field dimension. Experimental results are presented for rows and columns of holograms stored either in the laser frequency or the electric-field dimension and compared to transmission data. Using both dimensions a 10 x 10 matrix of holograms has been stored within the range of a single wave number. PMID- 20706328 TI - Extracting input-line position from Hough transform data. AB - The Hough transform (HT) detects lines in an input but not their location. We describe a new way to determine the position of a line from HT data. The line position information is extracted from the shape of the HT pattern around the HT peak. Results are shown illustrating this algorithm on single- and multiple-line input images. PMID- 20706329 TI - Image restoration using multigrid methods. AB - In this paper, we discuss several iterative methods for solving the system of linear equations that arises in the process of solving a Fredholm integral equation of the first kind. When applied to the very large systems that arise in connection with two- or three-dimension signal reconstructions, direct methods based on the singular-value decomposition require too much computation and conventional single grid iterative schemes may converge too slowly. We have developed a multigrid scheme in which the solution is sought on a fine grid, but discretizations on a set of coarser grids are used for intermediate calculations to reduce the overall computation effort. Although the quality of the reconstruction obtained using such methods is typically not as good as that achieved using a singular-value decomposition based method, computational considerations should make multigrid methods appealing for large systems of equations. PMID- 20706331 TI - Dual-modulation laser line-locking scheme. AB - Dual modulation laser line locking, useful for long-term trace species monitoring, achieves wavelength stability <0.1 ppm and rejects baseline drift in the measured absorbance3000-fold. PMID- 20706330 TI - Photoresponse of ion-damaged germanium. AB - Ion implantation was used to create predetermined defect densities to examine photoresponse for optoelectronic switch applications. Ion-damaged germanium shows a significant decrease in photoresponsivity with implant dose, particularly with doses exceeding the critical amorphizing dose (D(c) approximately 1 x 10(14) cm( 2)). PMID- 20706332 TI - Instabilities in retrieval of atmospheric trace gas profiles caused by the use of atmospheric level models. AB - When inverse radiative transfer algorithms are applied to atmospheric level models rather than to layer models, the stability of retrieval may significantly deteriorate. PMID- 20706333 TI - Optical properties of several Pacific fishes. AB - Reflectivity and depolarization of six species of fishes were measured using blue and green light. In general, the fish were between 15% and 25% reflective. PMID- 20706334 TI - Measurements of air-, N(2)-, and O(2)-broadened halfwidths and pressure-induced line shifts in the v(3) band of (13)CH(4): errata. PMID- 20706335 TI - Infrared continuum water vapor absorption coefficients derived from satellite data. AB - In a recent paper W. B. Grant ["Water Vapor Absorption Coefficients in the 8-13 microm Spectral Region: a Critical Review," Appl. Opt. 29, 451-462 (1990)] reviewed experimental measurements of the water vapor continuum absorption coefficients in the 8-13-microm spectral region. In comparing three different groundbased techniques he concluded that the absorption coefficients used in the HITRAN and LOWTRAN-7 codes are in reasonable agreement with the measurements. These coefficients are approximately 20% lower than those used in the LOWTRAN-6 code. A fourth method of experimentally determining the water vapor absorption coefficients is described which suggests an opposite result. A comparison between sets of satellite measured infrared radiances and ship measurements of sea surface temperature using a model of infrared transmission through the atmosphere gives coefficients that are 20-40% larger than those used in LOWTRAN-6. Agreement between the four different measurement techniques is only posible if a much stronger negative temperature dependence of the continuum absorption coefficients is adopted. This results in significant increases in the coefficients at temperatures below 270 K. PMID- 20706336 TI - Surface-plasma-enhanced quantum efficiency of a Ag-Ti-n-GaAs grating photodiode. AB - An array of Ag-Ti-n-GaAs grating photodiodes was designed and fabricated, with each diode having an active area with a diameter of 400 microm. Both electrical and optical characterizations were performed. We have made two experimental observations concerning (1) the surface-plasma-enhanced detectivity as a function of wavelength for 30 degrees angle of incidence and (2) the offset in angle between the reflectivity minimum and the current maximum at the surface-plasma resonance. PMID- 20706337 TI - Fiber optic temperature sensor using sampled homodyne detection. AB - A method of homodyne detection using laser emission frequency modulation and sampling of the interferometer output signal is described for a temperature sensor using a Mach-Zehnder all-fiber interferometer configuration. Both ac and dc signal detection are possible with this scheme. Temperature changes over the 5 80 degrees C range are measurable with a resolution of 1.4 mK by fringe counting and electronically determining the slope of the phase change. PMID- 20706338 TI - Adapting the mode profile of planar waveguides to single-mode fibers: a novel method. AB - A novel method for coupling single-mode fibers to planar optical circuits with small waveguide dimensions is proposed. The method eliminates the need to apply microoptics or to adapt the waveguide dimensions within the planar circuit to the fiber dimensions. Alignment tolerances are comparable to those of fiber- fiber coupling. The low loss potential of the method is experimentally demonstrated for A1(2) O(3) waveguides on silicon substrates. PMID- 20706339 TI - Fiber-optic sensor for simultaneous and independent measurement of vibration and temperature in electric generators. AB - A fiber-optic sensor designed to operate inside high-power electric plants is presented. The probe is based on a fiber-optic proximity sensor that detects the light intensity modulation induced by an elastic transducer. The nonlinear response of the optical head is exploited in an original manner to obtain the simultaneous and ndependent measurement of temperature and vibration at 100 Hz. The particular working principle provides an intrinsically lead-insensitive response. PMID- 20706340 TI - Polarization dependence of 4 x 4 optical fiber couplers. AB - The performance of monolithic 4 x 4 couplers is calculated as a function of arbitrary input polarization. By assuming polarization-independent diagonal coupling, an analytic result is obtained that is shown to agree with experiment. The effects of polarization-dependent diagonal coupling are calculated numerically. The measured polarization dependence of 4 x 4 fused fiber couplers is presented as a function of the degree of fusion of the fibers and is shown to be +/-0.5% for a medium fused device. PMID- 20706341 TI - Phase-matched second harmonic generation in poled dye/polymer waveguide. AB - Poled film of 2-methyl-4-nitroaniline (MNA) and poly(methyl methacrylate) is prepared. Poling effects of MNA molecular alignments are observed by reducing the absorption spectrum and increasing the refractive index of the film. Phase matched second harmonic generation (SHG) is achieved using the mode dispersion relation of the optical waveguide with an estimated SHG conversion efficiency of 7.4 x 10(-3) % in the waveguide. PMID- 20706342 TI - Use and misuse of end-facet reflections in the characterization of optical waveguide directional couplers. AB - From an analysis of the effects of end facet reflections on measurements of the characteristics of optical waveguide directional couplers, we show that these reflections can result in uncertainties of almost 6 dB in measurements of coupler extinction ratios. We present methods for estimating and minimizing these uncertainties. We also show that the Fabry-Perot loss measurement technique, which is widely used for measurements of single waveguides, can be used for loss measurements on directional couplers, but only for high extinction ratio devices. PMID- 20706343 TI - Analytic design of an achromatic double grating coupler. AB - A method for designing a double grating for coupling a polychromatic wave out of a waveguide with negligible angular dispersion is presented. It is based on calculating analytically two different grating functions, such that the chromatic dispersion of the first grating function is compensated by the second grating function. It is shown that the usable wavelength range can be increased by more than 2 orders of magnitude relative to conventional grating couplers for typical angular tolerance. PMID- 20706344 TI - Absolute optical ranging using low coherence interferometry. AB - We describe a method for measuring submicrometer distances with an asymmetric fiber Michelson interferometer having an LED as a source of radiation. By measuring the phase slope of the Fourier components in the frequency domain, it is possible to locate the position of reflections with nanometer precision even in the presence of sample dispersion. The method is compatible with time domain sampling at the Nyquist rate which assures efficiency in data acquisition and processing. PMID- 20706345 TI - Fluorescent angular scattering emissions from dye-filled fibers. AB - Fluorescent angular scattering from laser dye-filled small-core-diameter fibers shows increased backscattered fluorescent emissions as the core diameter decreases below 23 microm. The fluorescent angular scattering from Coumarin 7 laser dye-filled hollow-core quartz fibers were measured at three different fluorescent wavelengths and compared with the elastic scattered incident radiation at 442 nm. PMID- 20706346 TI - Approximate solution to the scalar wave equation for optical waveguides. AB - We consider an approximate solution to the wave equation appropriate to the optical waveguides encountered in practice. The refractive-index profile may be arbitrary, and the geometry may be two or three dimensional. A circular or a planar waveguide could thus be treated by this method. The technique is more accurate and more useful than the WKB method, which is often used in problems of this type, because the technique is valid even at the turning points, where the WKB solution fails. The fields and the propagation constants of the lowest-order modes for two profiles are calculated, and they compare well with the exact solutions. The solutions that we proposed are, in fact, not new. However, insofar as we know, they are unknown and unused by the optics community. PMID- 20706347 TI - Detection of nitrogen atoms in flames using two-photon laser-induced fluorescence and investigations of photochemical effects. AB - Nitrogen atoms, in a flame or produced by photodissociation of nitrogen containing molecules, were excited through a two-photon absorption process at 211 nm, and the near IR fluorescence was detected. Both in flame and in photodissociation experiments of cold gases, fluorescence, which was resonantly enhanced at the atomic nitrogen wavelength but which originated from excited oxygen atoms, was also identified. This phenomenon, the photochemical effects and those of molecular absorption, stimulated emission, and the mixing of gases are discussed in connection with the detection of atomic nitrogen in flames. PMID- 20706348 TI - Laser Rayleigh scattering for flame thermometry in a toroidal jet stirred combustor. AB - Pulsed laser Rayleigh scattering is used to obtain instantaneous flame temperatures in a turbulent flow combustor with poor optical access, a background of black body radiation, and laser induced glare. A novel method based on polarization is used for the extraction of the Rayleigh scattering. Probability density functions (PDFs) of the fluctuating temperature are obtained for fuel lean ethylene-air combustion. The smearing effects of shot noise are removed from the observed PDFs to obtain the actual fluctuating temperature PDF. PMID- 20706349 TI - Rapid tuning cw laser technique for measurements of gas velocity, temperature, pressure, density, and mass flux using NO. AB - An intracavity-doubled rapid-tuning cw ring dye laser was used to acquire fully resolved absorption profiles of NO line pairs in the A ? X band at 225 nm at a rate of 4 kHz. These profiles were utilized for simultaneous measurements of flow parameters in the high speed 1-D flows generated in a shock tube. Velocity was determined from the Doppler shift measured using a pair of profiles simultaneously acquired at different angles with respect to the flow direction. Temperature was determined from the intensity ratio of the adjacent lines. Pressure and density were found both from the collisional broadening and the fractional absorption. From this information the mass flux was determined. The results compare well to 1-D shock calculations. PMID- 20706350 TI - Low temperature hydrogen broadened linewidths of ammonia in the (0,1,0,0)?(0,0,0,0) band at 200 K. AB - Fourier transform spectra of the (0,1,0,0)?(0,0,0,0) band of ammonia have been measured for values of the hydrogen broadened linewidth parameters at a temperature of 200 K. The halfwidths for >200 lines have been determined with an average RMS of 5% in the interval between 750 and 1250 cm(-1). No measurements of the widths in the (s)R branch, and only 12 widths in the (s)Q branch, were obtained because of severe lending of the J-K manifolds. The broadening coefficients vary between 0.06 and 0.14 cm(-1)/atm. for (J,K) < (12,12). PMID- 20706351 TI - Time-delayed statistics for a bistatic coherent lidar operating in atmospheric turbulence. AB - Analytical expressions are derived for the time-delayed statistics and the heterodyne signal power as a function of the transmitter-receiver spacing for the general case of a bistatic coherent lidar. The effect of the turbulence-induced correlation between the outgoing and return paths was included and the 5/3 law form of the wave structure function was used. PMID- 20706352 TI - Fluorescent particle image velocimetry: application to flow measurement in refractive index-matched porous media. AB - This paper presents results in which particle image velocimetry (PIV) is used in conjunction with refractive index matching to measure fluid flow velocities within complex, multiphase systems. This application required the adaptation of PIV for use with fluorescent, rather than scattering, seed particles; we refer to the technique as fluorescent PIV (FPIV). We applied index-matched FPIV to the measurement of low flow velocities (tens of microns per second) at high spatial resolution (tens of microns) in a porous medium. We produced clear images of flowing particles in heterogeneous porous media and obtained reliable velocity vectors by a point-by-point interrogation of these images. We also found evidence of the intrapore mixing of porous media flow. PMID- 20706353 TI - Cloud hole boring with long pulse CO(2) lasers: theory and experiment. AB - Chemically generated CO(2) laser pulses at 10.6 microm have been used to clear a 5-cm diameter hole through a stratus-like cloud in a laboratory cloud chamber. The results show that 100% clearing can be achieved. The mechanism is shown to be droplet shattering followed by evaporation. In the experimental conditions, the channel closure is effected by turbulent mixing and droplet recondensation. PMID- 20706354 TI - Urban light pollution: the effect of atmospheric aerosols on astronomical observations at night. AB - The transfer of diffuse city light from a localized source through a dust-laden atmosphere with optical depth <0.5 has been analyzed in the source-observer plane on the basis of an approximate treatment. The effect on several types of astronomical observation at night has been studied, considering different size distributions and amounts as well as particle shapes of the aerosols. The analysis is made not as a function of the absolute aerosol amount but in terms of the signal-to-noise ratios for a given amount of aerosol. The model is applied to conditions at the Wise Astronomical Observatory in the Negev desert and limiting backgrounds for spectroscopy, photometry, and photography of stars and extended objects have been calculated for a variety of signal-to-noise ratios. Applications to observations with different equipment at various distances from an rban area of any size are possible. Due to the use of signal-to-noise ratios, the conclusions are different for the different experimental techniques used in astronomy. PMID- 20706356 TI - Patents. AB - 4,906,070; 4,906,087; 4,913,524; 4,917,447; 4,921,338; 4,953,922; 4,962,311; 4,974,944; 4,979,819; 4,979,821. PMID- 20706355 TI - Relationship between backscattering and extinction coefficients of aerosols with application to turbid atmosphere. AB - The relationship between backscattering beta(a), and extinction alpha(a) coefficients of aerosols at a ruby laser wavelength of 694.3 nm is studied using Mie scattering theory. A simple relationship of the form beta(a) = C(a)alpha(ka)(a) is assumed, and the dependence of k(a) and C(a) on different aerosol characteristics such as size distribution and refractive index is studied. The validity of a similar relationship is examined for a turbid atmosphere (troposphere and lower stratosphere) containing both aerosols and air molecules. PMID- 20706357 TI - Formula for the future. AB - This three-part article, reprinted by permission from The Los Angeles Times, discusses solutions to the science education crisis. The first section surveys how a post-Sputnik experiment in teaching the brightest students leftmost of a generation bored. Part 2 looks at minority schools with hands-on techniques that help students grasp abstract concepts. And the last section urges a national strategy to reformulate mathematics and science. PMID- 20706358 TI - Delayed elastic effects in the glass ceramics Zerodur and ULE at room temperature. AB - The time-dependent phenomenon of delayed elasticity was studied at room temperature and is presented here for Zerodur and ULE. The effect is believed to be related to the alkali oxide content of the glass and to the rearrangement of the ion groups within the structure during stress. PMID- 20706359 TI - Fourteen-decade photocurrent measurements with large-area silicon photodiodes at room temperature. AB - Recent improvements in commercial silicon photodiodes and operational amplifiers permit electrical noise to be reduced to an equivalent of 0.1 fA of photocurrent when a measurement time of 400 s is used. This is equivalent to a photocurrent resulting from fewer than 800 photons/s, and it implies a dynamic range of 14 orders of magnitude for a detector circuit. We explain the circuit theory, paying particular attention to the measurement bandwidth, the causes of noise and drift, and the proper selection of circuit components. These optical radiation detectors complement the primary radiometric standards. These detectors may replace photomultiplier tubes that have been used traditionally and or that were too costly to be used. PMID- 20706360 TI - Image plane detector for Fabry-Perot interferometers: physical model and improvement with anticoincidence detection. AB - Modern Fabry-Perot interferometers use image plane array detection to obtain the multiplex advantage. The imaging quality of these image plane detectors (IPD's) limits their ultimate resolution and usefulness. The influence of pulse spreading on photon-counting IPD's is investigated, first theoretically and then experimentally on real devices. The model developed in our study is in good agreement with laboratory measurements and suggests a more reliable technique to measure the blurring of the Fabry-Perot fringe caused by the IPD. Based on the model, an anticoincidence detection circuit is designed; the circuit is simple, greatly reduces the blurring, and increases the resolution of the IPD. PMID- 20706361 TI - Multiplex Fabry-Perot interferometer. AB - The Fabry-Perot interferometer (FPI) traditionally has been used to examine either small spectral ranges or relatively imple spectra. Recently, however, studies have shown that the FPI can be competitive with the Michelson interferometer ver extended spectral ranges. This paper describes a relatively new FPI technique in which one of the etalon plates is moved over a large optical distance while the other remains fixed, thus exploiting the multiplex advantage of the instrument. we have chosen to call this instrument the multiplex Fabry Perot interferometer (MFPI). It is shown that this technique could be useful for the remote sensing of minor atmospheric species because the MFPI, like a Michelson interferometer, has the ability to examine large spectral regions at high resolution but retains the small size of the FPI. PMID- 20706362 TI - High-resolution spectrometry with a masked Fabry-Perot interferometer. AB - Features of a real Fabry-Perot interferometer are severely affected by surface irregularities. A new configuration, based on appropriately masking the plates, is proposed. Theoretical results show an increase in the finesse of as much as a factor of 10 as well as an increase in the contrast factor of as much as a factor of 100, while the luminosity-finesse product is preserved. The case of nonnormal incidence is also considered, and the differences arising from that case are discussed. PMID- 20706363 TI - Influence of spherical aberration of an interferometric system on the measurement error in the case of a finite fringe observation field. AB - The propagation of the interfering waves through the aberrated optical system of an interferometer is analyzed. The general formula describing the measurement error is found. The role of different parameters is described. A Fizeau interferometer is used as a model for the analysis. PMID- 20706364 TI - Influence of aberrations of Fizeau interferometer elements on measurement errors. AB - The propagation of interfering waves through the whole optical system of the Fizeau interferometer is analyzed. A general formula is found that describes the measurement errors introduced by optical elements of the system. In particular, we studied the influence of the position of the beam splitter and the objective of the imaging system of the interferometer. PMID- 20706365 TI - Prototype Michelson interferometer with Fabry-Perot cavities. AB - We describe a rigid, internally modulated Michelson interferometer with Fabry Perot cavities in the interferometer arms. The high contrast (0.986) and the small cavity losses (2.7%) permit efficient use of the light power available. The measured shot-noise-limited displacement sensitivity for 35mW of light power is 2.5 x 10(-17) m radicalHz, in good agreement with the calculated signal-to-noise ratio. PMID- 20706366 TI - Two-wavelength double heterodyne interferometry using a matched grating technique. AB - Two-wavelength double heterodyne interferometry is applied for topographic measurements on optically rough target surfaces. A two-wavelength He-Ne laser and a matched grating technique are used to improve system stability and to simplify heterodyne frequency generation. PMID- 20706367 TI - Estimation of optical parameters in a living tissue by solving the inverse problem of the multiflux radiative transfer. AB - Calculations of radiative transfer require knowledge of the absorption and scattering coefficients and the asymmetry factor of scattering in the medium. A method is presented for estimating these coefficients in living plant leaves from fiber-optic measurements. We consider the plant leaf as consisting of two layers of different refractive indices and with reflecting surfaces. Light intensities at the boundaries of these layers in several irradiated plant leaves have been measured using a thin (70-microm) glass fiber connected to a photomultiplier. The diffuse reflection and transmission were measured with an integrating sphere. From these values we derive an estimation of the scattering and absorption coefficients and the asymmetry factor of scattering applying an inversion of the multiflux theory of light propagation in turbid media. In addition, we compare these coefficients with those obtained by using the Kubelka-Munk theory. PMID- 20706368 TI - Effects of high-numerical-aperture focusing on the state of polarization in optical and magneto-optic data storage systems. AB - Using vector diffraction theory and an exact method for computing reflection coefficients for multilayer structures, we analyze the effects of high-numerical aperture focusing on the state of polarization in optical data storage systems. The focused incident beam is decomposed into a spectrum of plane waves, and the reflected beam is obtained by the superposition of these plane waves after they are independently reflected from the multilayer. Plots of polarization rotation angle and ellipticity for several disk structures are presented. PMID- 20706369 TI - Procedure for computer-controlled milling of accurate surfaces of revolution for millimeter and far-infrared mirrors. AB - We discuss a simple method for milling accurate off-axis parabolic mirrors with a computer-controlled milling machine. For machines with a built-in circle-cutting routine, an exact paraboloid can be milled with few computer commands and without the use of the spherical or linear approximations that have been discussed in other mirror-cutting procedures in the literature. The method given here can be adapted easily to cut offaxis sections of elliptical or spherical mirrors. PMID- 20706370 TI - Properties of chemical-vapor-deposited silicon carbide for optics applications in severe environments. AB - Important data on chemical-vapor-deposited (CVD) SiC concerning the elastic modulus, polishability, scattering measurement, thermal and cryogenic stability, and degradation owing to the effects of atomic oxygen and electron beams have been obtained with the aim of assessing the suitability of SiC as an optical substrate for severe environments. These measurements show that CVD SiC substrates exhibit excellent polishability (<0.1 nm rms) with low scatter, good retention of mechanical properties up to 1500 degrees C, superior thermal and cryogenic stability (-190 degrees to 1350 degrees C) and high resistance to atomic-oxygen and electron-beam degradation. These results suggest that CVD SiC optical substrates will perform extremely well in severe environments such as outer space, and when used in lasers, combustion, and synchrotron x rays. PMID- 20706371 TI - Attenuated-total-reflection technique for the determination of optical constants. AB - In a glass-metal-dielectric system, it is normally impossible to determine simultaneously the complex dielectric constant, the thickness of the metal, and the corresponding parameters of a dielectric overlayer. We propose the use of the pseudo-Brewster or Abeles angle as an additional parameter to characterize simultaneously a dielectric thin-film overcoating and the metal surface parameters. We use a Kretschmann attenuated-total-reflection configuration. An admittance diagram is used to illustrate graphically the role of an absentee layer at this angle. A study of the limitations of the method is also presented. PMID- 20706372 TI - Absolute measurements of diffuse reflectance in the alpha degrees /d configuration. AB - An improved theory for data reduction of absolute reflectance measurements using the third Taylor method in the alpha degrees / d configuration is presented. A brief description is given of an absolute reflectometer operating in the 0.8-2.5 microm region. The reflectometer is operated according to the improved theory. Experimental data for some widely used samples are given, as well as data showing agreement between the current measurements and those made by the U.S. National Institute of Standards and Technology. PMID- 20706373 TI - Infrared optical constants and roughness factor functions determination: the H(T)H(R)TR method. AB - This method was developed to determine the complex infrared optical constant of a single free-standing partially absorbing plate as wellas a thin solid film eposited on it. The method is based on exact formulas for normal transmittance T and near-normal reflectance R of the substrate as well as the film-substrate double layer. Coherent multiple reflections throughout the film and incoherent multiple reflections in the substrate as well as the intensity losses on the rough surface are taken into account. The influence of various data on the solution of the inverse problem is discussed by a contour map study. The method is explained using examples of both- and single-side-polished silicon wafers where the transmission and reflection roughness factor functions H(T),H(R) are determined for the rough surface. The thin-film example has been the silicon oxide film formed on the single-side-polished silicon substrate by chemical vapor deposition. PMID- 20706374 TI - Measurement of angular velocity using speckle photography. AB - A new speckle photographic technique to find the angular velocity of rotating diffuse objects has been proposed. This technique employs a simple experimental setup and minimum theory. Also, this equipment sets an upper limit for the in plane rotational speckle correlation. PMID- 20706375 TI - Profile measurement of an aspheric cylindrical surface from retroreflection. AB - A new algorithm for measuring the profile of an aspheric cylindrical surface is developed in which directions of the surface normal and slopes at various locations are found with the aid of a retroreflected beam. The locations of retroreflection can be found with the simple algorithm developed in this paper, and the surface profile is integrated from the slope. The accuracy of the new algorithm is determined mostly by the algorithm's ability to find the true range of the surface being integrated. In the measurement of the surface sagitta over the range of 5000 microm, the accumulated error from the integration is less than 30microm. PMID- 20706376 TI - Profile measuring method based on reflection characteristics at a critical angle in a right-angle prism. AB - A new method is proposed for profile measurements using a right-angle prism. With this method, the distance to an object surface is measured by using triangulation based on a change of the critical angle of total reflection. An object surface is illuminated by a scanning laser beam and the incident angle of the scattered light into the prism is measured using the change in the critical angle. Three dimensional profiles of objects with rough surfaces can be measured with high accuracy. PMID- 20706377 TI - Roughness measurements of Si and Al by variable angle spectroscopic ellipsometry. AB - Rough surfaces of silicon and aluminum have been studied by rotating analyzer spectroscopic ellipsometry (RASE). The roughness of a silicon sample similar to that used for the RASE measurements was also studied by cross-sectional transmission electron microscopy. Total integrated scattering was measured on the aluminum specimens to obtain numerical estimates of the rms roughness. The ellipsometry measurements on these specimens were carried out at a number of angles of incidence in the 30-80 degrees range and at a number of discrete wavelengths in the 300-650-nm spectral range. The RASE results were hen analyzed using the Bruggeman effective-medium theory for the Si sample and scalar diffraction theory for the Al samples. This study shows that 70 degrees is the optimum angle of incidence for characterizing the roughness of these Al surfaces using RASE. It also demonstrates the self-consistency of the Bruggeman theory with angular variation for the Si sample. The need for a vector diffraction theory for the retation of the rms roughness using ellipsometric angles Delta and Psi is discussed. PMID- 20706378 TI - Light-scattering measurement of the rms slopes of rough surfaces. AB - Angle-resolved light scattering (ARLS) is used to estimate the root-mean-square (rms) slopes of rough surfaces having a well-defined lay, and the effect on slope measurements caused by changing the angles of incidence and scattering is investigated. The ARLS patterns are taken with the Detector Array for Laser Light Angular Scattering (Dallas) research instrument, and the rms slopes are obtained from the angular widths of these patterns. In general, it was found that the angular width, and thus the estimated rms slope, is surprisingly insensitive to relatively large changes in both the incident and scattering angles of light. These results are independent of surface material and are valid for both sinusoidal and random rough surfaces with lay. The principles, experiments, analyses, and conclusions involved in using ARLS to estimate rms surface slopes are described. PMID- 20706379 TI - Optical methods for thickness measurements on thin metal films. AB - The thickness and the dielectric constants of thin metal films on glass substrates are determined by two different methods. The first method is a combination of transmission and ellipsometer measurements (TELL method) and the second is based on attenuated total reflection (ATR method in the Kretschmann arrangement). For comparison, both methods are applied to gold films within a thickness range of 20-80 nm. Furthermore, the TELL method was applied to chromium films of thicknesses up to 150 nm. All experiments are done with a He-Ne laser at 633-nm wavelength. PMID- 20706380 TI - TiO(2)-SiO(2) mixed films prepared by the fast alternating sputter method. AB - We introduced the fast alternating sputter method and its application on deposition of TiO(2)-SiO(2) mixed films. By using fast alternating sputter, the TiO(2) and SiO(2) were completely mixed in the film, and no thinpair structure could be found by x-ray diffraction. The structure of the mixed films was amorphous in a wide composition range. The optical properties of the mixed films in the visible and near infrared changed from SiO(2)-dominant to TiO(2)-dominant as TiO(2) content in the film increased. PMID- 20706381 TI - Adaptation of the refractive indices of antireflection coatings to other surrounding media. AB - The design of various types of antireflection coating is extensively described in the literature. In practice, however, such designs must often be adapted to other surrounding media or angles of incidence. For such cases, a method is presented in which, starting from a known antireflection coating, a useful reflectance characteristic is obtained for changed situations. PMID- 20706382 TI - Sidelobe suppression of the point-spread function in annular-pupil optical systems. AB - New optical configurations suppressing sidelobes of point-spread functions in annular-pupil transmission optical systems are proposed for both one- and two dimensional suppressions. In both optics, a point source and a one-dimensionally apodized pupil are combined. For two-dimensional suppression, the source and the pupil are rotated synchronously and its point-spread function is synthesized with time accumulation. The optical transfer functions of the two optics are theoretically derived. PMID- 20706383 TI - Singly reflected skew rays inside a hollow tube: an exact cardiold solution for incident rim rays. AB - Diffuse light entering a hollow cylindrical tube forms a manifold of concentric bright bands as a result of multiple internal reflections. A circular occulting stop, filling the entrance aperture except for a narrow rim annulus, converts these successive bands into sharply bounded rings, the first of which is produced solely by singly reflected skew and meridional rays. The exact geometrical optics of all rays emitted by any point on the rim are considered, and it is shown that after a single reflection all such rays appear to arise from a single cardioid curve. When rotated about the optic axis, this cardioid predicts the flaring ring intensity distribution observed. (Any departure of this first ring from concentricity around the direct image of the rim annulus provides a quantitative measure of nonstraightness of the tube.). PMID- 20706384 TI - Direct imaging of nonsolar planets with infrared telescopes using apodized coronagraphs. AB - This research examines the use of modified Lyot coronagraphs with monolithic and segmented infrared telescopic systems for imaging nonsolar planets. These systems are investigated with the aim of reducing the effects of stellar diffracted energy on the planet image in the final image plane. A square telescope objective is best for this purpose. The associated coronagraph is composed of a cross shaped apodizer in the first focal plane and either a square Lyot stop or circular corner Lyot stops in the corners of the pupil plane. We examine the consequences of segmenting the aperture and the effects of various segment spacings and random piston and tilt errors of the individual segments. A system to correct for the misalignments is proposed. PMID- 20706385 TI - Applied optics of optics and opticists. PMID- 20706387 TI - Cyclic matrix representation for sequential multiplication of complex matrices. AB - A cyclic matrix representation for complex numbers is proposed for sequential multiplication of complex matrices. The related optical implementation is discussed. PMID- 20706388 TI - Two-dimensional multichannel optical switch. AB - We propose a new type of two-dimensional multichannel optical switch that uses polarization controllers and birefringent plates. This switch is small in size and has lowdriving- power characteristics. An 8 X 8 optical switch is described as an example. PMID- 20706389 TI - Synthetic discriminants and egenvector decompositions. PMID- 20706390 TI - New algorithm for analog optical matrix inversion. AB - A new matrix inversion algorithm is described. It provides a meaningful estimate of the inverse A(-1) of a matrix A on an analog optical processor in a reduced calculation time (compared to other methods). The new nested iterative algorithm has no convergence conditions on the matrix and requires fewer operations than prior iterative neural net and other algorithms. PMID- 20706391 TI - Free-space optical collinear crossover interconnects. AB - Two new optical free-space collinear cross-over interconnect schemes are suggested. The first optical implementation uses mirrors and beam splitters, while the second uses a Fresnel zone plate and lens combination. Some proof-of principle experimental results are also presented. PMID- 20706392 TI - Acousto-optic signal processors for transmission and reception of phased-array antenna signals. AB - Novel acousto-optic processors for control and signal processing in phased-array antennas are presented. These processors can operate in both the antenna transmit and receive modes. An experimental acousto-optic processor is demonstrated in the laboratory. This optical technique replaces all the phase-shifting devices required in electronically controlled phased-array antennas. PMID- 20706393 TI - New method of one-step rainbow holography of diffuse three-dimensional objects with no slit. AB - A new method of one-step rainbow holography of diffuse three-dimensional objects with no slit is proposed. Diffuse three-dimensional objects are translated uniformly along the direction of the y(0) axis. A coherent plane wave illuminates the objects and its propagation direction is situated on the x(0)-z(0) plane. As a result of this process, a sinc function modulating the complex amplitude distribution of the objects is produced in the back focal plane of the lens. Therefore, rainbow holography is achieved. Theoretical analysis and some experimental results are presented. PMID- 20706394 TI - Signal synthesis for diffractive optical elements in hybrid systems. AB - Generally, a diffractive optical element/digital hologram is used as a component in a system. For a specific system output, an appropriate signal must be realized as a diffraction pattern. We present methods to determine such signals, whereby the characteristics of the system are considered. In particular, we calculate signals and corresponding digital amplitude holograms for the generation of a special binary data set in a holographic storage system and a special binary surface relief in a microlithographic production process. PMID- 20706395 TI - High-gain, low-noise signal beam amplification in photorefractive BaTiO(3). AB - We describe a pulse readout technique for high gain and a high signal-to-noise ratio (SNR) in signal beam amplification by two-beam coupling in a photorefractive BaTiO(3) crystal. The basic idea behind the technique is the formation of photorefractive gratings using a low-intensity pump beam and subsequent readout of this grating with a strong pulse for a duration that is less than the time constant for noise development or beam fanning. Large values ( approximately 11,000) of the signal beam gain and SNR's of approximately 1300 are achieved. A noise-free image amplification is the main achievement of this technique. PMID- 20706396 TI - One-way imaging through an aberrator with spatially incoherent light by using an optically addressed spatial light modulator. AB - A real-time holographic technique employing an optically addressed spatial light modulator was used to correct an incoherently illuminated image that had made a single pass through an aberrator. Aberrations that change slowly compared with the integration time of the spatial light modulator are fully corrected. PMID- 20706397 TI - Effect of spatial noise on the minimum resolvable temperature of a staring sensor. AB - The development of staring infrared focal plane arrays has forced potential users to consider the effect of spatial noise on the performance of infrared sensors. We varied the amount of spatial noise present in infrared imagery and measured its effect on the value of the minimum resolvable temperature (MRT). A mathematical model for including the effects of spatial noise on image quality is presented and compared to experimental data. The effect of both the spatial and temporal power spectral density on the MRT is discussed. Excess low-frequency noise in the temporal domain is shown to be a source of spatial noise. PMID- 20706398 TI - Image synthesis from nonimaged laser-speckle patterns: comparison of theory, computer simulation, and laboratory results. AB - The performance of an imaging technique relying on the spatial correlation of laser-speckle intensity measurements is evaluated on the basis of theoretical analysis, computer simulation, and laboratory results. A theoretical expression for the signal-to-noise ratio of the recovered imaging target's power spectrum is used to estimate the imaging performance expected in the computer simulation and laboratory experiment. Power-spectrum estimates for an imaging target, obtained both in the laboratory and through simulation, are compared with the theoretical results and with the true spectrum of the target. Images recovered from the simulation data and the laboratory data are also compared. Our results suggest that the signal-to-noise ratio expression provides an accurate means for estimating the recoverable frequency content of a simple target. PMID- 20706399 TI - Use of synthetic discriminant functions for handwritten-signature verification. AB - Handwritten-signature verification is treated as a two-class synthetic discriminant function (SDF) problem. Images of valid and casually forged signatures are collected and binarized, using an electronic digitizing camera. Performance of this approach with a small number of valid signatures in the training set is examined, and substantial improvement is demonstrated when forgeries are included in the set. In particular, the equal-error rate for the SDF classifier with forgeries included is shown to average approximately 4% across nine different subjects. The effects of image preprocessing on false acceptance and true rejection rates are examined. The use of alternatives to forged signatures in the training matrix is explored. Finally, SDF performance is shown to deteriorate when the tested forgeries are produced with some a priori knowledge of the target signature. PMID- 20706400 TI - Use of the biased estimator in the interpretation of spectroscopic ellipsometry data. AB - The use of the biased estimator in the fitting of spectroscopic ellipsometry data is examined and applied to data from two-channel polarization modulation ellipsometry experiments. It is pointed out that the use of the biased estimator, as opposed to the unbiased estimator that is usually found in the literature, allows the experimentalist to weight properly the more accurate parts of the spectrum, to switch among different representations of the data, and to calculate a goodness of fit. The fit to data taken on a 59-nm SiO(2) film on Si is examined with both the biased and the unbiased estimators. PMID- 20706401 TI - Nasa patter. PMID- 20706402 TI - Light and color in the open air: introduction by the feature editor. PMID- 20706403 TI - Polarimetry of a 22 degrees halo. AB - The linear polarization and intensity of a 22 degrees halo has been measured simultaneously at seven wavelengths as a function of scattering angle. The polarization pattern is found to be dominated by a narrow peak centered at the halo angle. The amount of polarization in this peak is much higher than expected from Fresnel refraction alone. The observations are explained with a birefringence-diffraction halo polarization model. The effective diameter of the hexagonal face of the halo-generating crystals is found to be 41 and 54 microm for two separate scans. An independent single-wavelength parhelion observation indicates a stronger birefringence peak concentrated in an even smaller angular scattering range and a crystal diameter of 220 microm. Crystal sizes derived from the halo intensity distributions are found to be consistent with those obtained from polarization. The data demonstrate the power of halo polarimetry as a tool for detection and identification of birefringent crystals in terrestrial or extraterrestrial atmospheres. PMID- 20706404 TI - What are "all the colors of the rainbow"? AB - Both folklore and theory imply that naturally occurring rainbows display a wide range of nearly pure colors. However, digital image analysis of color slides shows that the natural rainbow's colors are not especially pure and that the bow's background causes much of this desaturation. PMID- 20706405 TI - Mie theory model of the corona. AB - We performed a calculation of the corona colors that employed Mie theory to obtain the scattered light intensity. The scattered intensity was integrated over the visible spectrum for a number of different cloud droplet size distriubtions. The results were converted to chromaticity coordinates, convolved with the angular size of the sun, and plotted on the 1931 CIE chromaticity diagram. The results were compared to observations of multiple-ring coronas. It was found that, when using Mie theory to estimate cloud droplet sizes, water droplets with diameters in the 7-microm less, similar D less, similar 15-microm range produced the 13 multiple-ring coronas that were observed. PMID- 20706406 TI - Rainbows and fogbows. AB - The optics of rainbows and fogbows is investigated theoretically for monodisperse drops using Mie theory. Included in the calculations are a realistic solar illumination spectrum and the finite size of the sun. Drop sizes range from 3 to 300 microm (3800 > X > 38). Results are presented on the location, width, contrast, polarization, and color of both primary and secondary rainbows. Particular attention is given to rainbows formed in small drops (fogbows). PMID- 20706407 TI - Corona-producing cirrus cloud properties derived from polarization lidar and photographic analyses. AB - Polarization lidar data are used to demonstrate that clouds composed of hexagonal ice crystals can generate multiple-ringed colored coronas. Although relatively uncommon in our mid-latitude cirrus sample (derived from Project FIRE extended time observations), the coronas are associated with unusual cloud conditions that appear to be effective in generating the displays. Invariably, the cirrus cloud tops are located at or slightly above elevated tropopauses (12.7-km MSL average height) at temperatures between -60 degrees and -70 degrees C. The cloud top region also generates relatively strong laser backscattering and unusually high 0.5-0.7 linear depolarization ratios. Color photograph analysis of corona ring angles indicates crystals with mean diameters of from 12 to 30 microm. The cirrus cloud types were mainly subvisual to thin (i.e., bluish-colored) cirrostratus, but also included fibrous cirrus. Estimated cloud optical thicknesses at the 0.694-microm laser wavelength ranged from 0.001 to 0.2, where the upper limit reflects the effects of multiple scattering and/or unfavorable changes in particle characteristics in deep cirrus clouds. PMID- 20706408 TI - Unfolded optical glory of spheroids: backscattering of laser light from freely rising spheroidal air bubbles in water. AB - Enhancement in backscattering known as glory scattering results from geometric and material properties of spherically symmetric scatterers. The wave-front shape near the spherical scatterer is locally a circular torus. Radiation from a toroidal wave front is axially focused on the backward-directed axis. It is shown that the axial point caustic unfolds to an astroid caustic as the scatterer's shape changes from spherical to slightly spheroidal. The wave front pertinent for slightly spheroidal scatterers was modeled as a toroidal wave front with a superimposed harmonic angular perturbation. Experimental observations are displayed for cross-polarized backscattering by freely vertical rising, slightly oblate spheroidal air bubbles in water illuminated by a horizontally propagating laser beam. These patterns were recorded with a camera for two different incident beam polarization directions relative to the axis of rotational symmetry of the bubble. Angular scattering patterns were also computed using a perturbation analysis based on use of the harmonically perturbed toroidal wave front and physical optics. Bubble oblateness was estimated from features of the angular scattering pattern and from hydrodynamic relations. PMID- 20706409 TI - Opening rate of the transverse cusp diffraction catastrophe in light scattered by oblate spheroidal drops. AB - Light scattered by an oblate drop of water has been observed to produce cusp caustics in the general vicinity of the rainbow region [P. L. Marston and E. H. Trinh, Nature London 312, 529-531 (1984)]. The principal curvatures of the generic local wave front that produces the far-field transverse cusp are examined. This wave front is shown to generate a transverse cusp curve (U - U(c))(3) = - d(infinity)V(2), where U and V are horizontal and vertical scattering angles and U(c) is the cusp point direction. The far-field opening rate d(infinity) is calculated for the transverse cusp. It is shown that d(infinity) has a simple dependence on the parameters of the generic wave front. We define the aspect ratio of the drop q = D/H, where H is the height and D is the equatorial width for the scattering drop. The method of generalized ray tracing is used to relate q to principal curvatures and shape parameters of the outgoing wave front and hence to d(infinity). Measurements of d(infinity) for scattering laser light from acoustically levitated drops appear to support the calculation. As q goes to q(4) approximately 1.31, the critical value for generation of a hyperbolic-umbilic focal section, the predicted d(infinity) goes to infinity. The nature of the divergence was numerically investigated as was the rate at which d(infinity) vanishes as q approaches critical values for lips and transition events. PMID- 20706410 TI - Forward glory scattering from bubbles. AB - The scattering enhancement known as the glory was observed in forward scattering from bubbles in liquids. A physical-optics model of the forward glory is detailed, based on transmitted waves reflected within the bubble. Some aspects of the model are compared with the Mie theory and with features in the cross polarized light from single bubbles. Clouds of small bubbles rising in water show an angular structure in the forward glory light that is useful for estimating the bubble size. PMID- 20706411 TI - Rainbow-enhanced forward and backward glory scattering. AB - When the refractive index m of a sphere is such that rainbows occur in the forward or backward direction, the glory scattering becomes exceptionally strong. A number of these refractive-index values have been determined from the geometry of ray paths. A physical-optics model of the scattering leads to an a(2)x(4/3) dependence in the scattered irradiance, where a is the radius of the sphere, and x = ka is the size parameter. Normal glory scattering gives an irradiance proportional to x. Mie theory computations illustrate the presence of rainbow glories at predicted m values and the x(4/3) irradiance factor. As in normal glory scattering, the rainbow-enhanced glory light contains a strong cross polarized component. Experiments using single glass spheres immersed in liquids show the predicted cross-polarized scattering with a sensitive dependence on m. PMID- 20706412 TI - Scattering of white light from levitated oblate water drops near rainbows and other diffraction catastrophes. AB - Oblate drops of water illuminated perpendicular to their symmetry axis generate a hyperbolic-umbilic diffraction catastrophe near the primary rainbow [P. L. Marston and E. H. Trinh, Nature London 312, 529-531 (1984)]. Observations were made of this diffraction catastrophe generated by white-light illumination of acoustically levitated drops of water in air. The observations suggest what generalized rainbows would look like if they were produced in nature when sunlight illuminates large raindrops. Unlike the usual rainbow arc, the transverse cusp of the unfolded catastrophe is not distinctly colored. The hyperbolic-umbilic focal section is distinctly colored as is another diffraction catastrophe generated in the rainbow region when the drop is highly oblate. PMID- 20706413 TI - On the gamut of colors seen through birefringent airplane windows. AB - Colors in birefringent airplane windows seen through polarizing filters are not especially pure nor are all colors equally probable. This is a consequence of the shape of transmission vs wavelength for a retarder-polarizer combination illuminated by partially polarized skylight. Although transmission can have a single peak in the blue or green, a peak in the red is accompanied by one in the blue. This and the general blueness of skylight are why the purest colors seen in airplane windows are greens, yellowish-greens, and purples (mixtures of red and blue). Purer colors and a wider gamut are obtained for birefringent sheets interposed between dichroic polarizing filters and illuminated by tungsten light. PMID- 20706414 TI - Colors observed when sunlight is scattered by bubble clouds in seawater. AB - Colored bands photographed in sunlit subsurface bubble clouds are described. The colors are found to be associated with the transition from partial-to-total reflection by the bubbles. The most pronounced band is a red-yellow band located near the transition region. Theoretical evidence is also summarized that the colored bands observed are only weakly affected by thin coatings and the oblate shape of freely rising bubbles. PMID- 20706415 TI - Investigation into the scattering of light by human hair. AB - We describe a general investigation into the scattering of light by human hair. The main features of the intensity distribution produced by light scattered by an individual hair are identified. Qualitative explanations for the features are advanced in terms of the arrangement of the outer structure of the hair and its level of pigmentation. Contrast gloss values are calculated in an attempt to quantify the appearance of hair. These values are found to depend not only on the properties of hair, such as color and condition, but also on the direction and polarization state of the incident light. In assessing the effects of cosmetic treatments on hair, gloss values are shown to be useful where readings from treated hairs are compared with those from a control sample investigated in the same conditions. PMID- 20706416 TI - Light and color on the wing: structural colors in butterflies and moths. AB - All butterfly and moth scales share the same basic architecture, but various elements of this architecture are particularly complex in those scales that exhibit structural colors. These elements include the scales' ridges and their associated lamellae and microribs, and the trabeculae, the pillars normally that act as spacers within scales. The additional ornamentation produces thin film, Tyndall blue or diffraction colors and represents a particularly striking example of precision in biological pattern formation. PMID- 20706417 TI - Can normal outdoor activities be carried out during civil twilight? AB - Ambient illumination during civil twilight, which occurs approximately a half hour before sunrise and after sunset, has traditionally been characterized as posing no restriction on normal visual activities. However, consideration of the selective degradation of visual-recognition functions and the concurrent sparing of visual-guidance functions at the prevailing (relevant) luminance levels suggests that this characterization of civil twilight is no longer appropriate, particularly in light of the visual demands of industrialized society. Rather, special notice should be taken of the implications of selective degradation of visual recognition during civil twilight for traffic safety and other visually demanding hazardous tasks. PMID- 20706418 TI - Toying with the moon illusion. AB - We propose that the correct interpretation of the moon illusion is that the zenith moon appears small, not that the horizon moon appears large. This illusion is caused by the visual gap between the observer and the overhead moon. Because of the gap, the observer has no or little optical information about the distance of the moon. This results in empty field myopia where the moon is neurally, although not necessarily cognitively, processed as being at about arm's length. When the moon is seen on the horizon, there usually is optical information about distance. That results in reduced accommodation, and so the moon is processed as at a greater distance. Consistent with the size-distance-invariance hypothesis, the moon is then judged as large. This is a specific example of the more general fact that all distant objects appear small in the absence of a stimulus for accommodation to be distant. This outcome produces the toy illusion. PMID- 20706419 TI - Step brightness changes of distant mountain ridges and their perception. AB - When successive ridges of distant mountains are seen, observers often report that, near the ridge where the brightness changes abruptly, the upper part of the nearer ridge appears darker than at its lower portions. Similarly, they report that the base of the more distant mountain seems brighter adjacent to the nearer ridge than on its upper portions. The explanation of this phenomenon, known as the step contrast effect, is a special case of Mach bands. It is usually attributed to a visual illusion involving lateral inhibition in the eye, which is most apparent in the vicinity of step brightness changes. Using analytic techniques and numerical integrations to simulate the airlight-induced brightness distributions of such scenes, we show that in many cases the perceived brightness distribution is qualitatively similar to the true brightness distribution and thus is not a visual illusion. PMID- 20706420 TI - Atmospheric optics in art. AB - A brief historical overview of the atmospheric optical phenomena that appear in works of fine art is presented. It is shown that artists have recorded many features of the color and brightness of the sky and clouds, aerial perspective and visibility effects, and phenomena, including crepuscular rays, rainbows, halos, and coronas. Artistic biases resulting from prevailing styles and societal influences are noted. Attention is drawn to a number of phenomena recorded by artists that have not yet been explained or modeled. PMID- 20706421 TI - Rainbows in the Indian rock art of desert western America. AB - For thousands of years the image of the rainbow was pecked and painted by native Americans onto the rocks of the Great Basin and the Southwest. This long-lived tradition, which transcended major developments in lifestyles and cultures, underscores the important symbolic significance of the rainbow to the inhabitants of this arid region. The rainbow rock art depictions were usually associated with humanlike ceremonial figures, snakes, clouds, rain, and lightning bolts, suggesting that the rainbow symbol was employed as part of an elaborate sacred tradition. Although such ceremonial usage of the rainbow image tends to lead to abstraction and symbolic representation, there are examples, including a properly colorized rainbow painting from central Utah (approximately a thousand years old), that indicate observationally based rainbow reproductions of relatively great antiquity. PMID- 20706422 TI - Ulloa's observations of the glory, fogbow, and an unidentified phenomenon. AB - Ulloa's complete print of the glories and fogbows on Mt. Pambamarca in Peru (now Ecuador) is presented. It shows two other phenomena, an erupting volcano and an as yet unidentified optical effect. The glories and fogbow are analyzed to obtain the drop size of the fog, and the unidentified features are discussed. PMID- 20706423 TI - Finnish Halo Observing Network: search for rare halo phenomena. AB - The Finnish Halo Observing Network obtains information about rare halos through literature study and amateur network observations. Recent photographs and historical drawings of some yet unexplained halo effects are presented. PMID- 20706424 TI - High-finesse measurements at low temperatures. AB - High-reflectivity supermirrors were used to produce a Fabry-Perot cavity that operated at cryogenic temperatures. The best finesse below 80 K was found to be 19,000 and remained constant down to 4.2 K. PMID- 20706425 TI - Arm-length measurement of an interferometer using the optical-frequency-scanning technique. AB - The long-arm-length difference of an interferometer is measured by changing the optical frequency of a YAG laser used with a resolution of millimeters. PMID- 20706426 TI - Aberration compensation in confocal microscopy. AB - In confocal microscopy, spherical aberration is introduced when one is focusing deep within the specimen. This can be compensated for by altering the effective tube length at which the objective is operated. The limitations of this approach are investigated. PMID- 20706427 TI - Ensquared power for obscured circular pupils with off-center imaging. AB - Power incident upon square detectors in the focal plane of diffraction-limited optical systems with obscured circular pupils is computed as a function of the line-of-sight position on the detector. The results are applied to an analysis of the dependence of the signal-to-noise ratio on detector size for obscuration ratios of 0, 0.25, and 0.5 and for line-of-sight position on the detector. PMID- 20706428 TI - Position offsets in curved-channel microchannel plate detectors. AB - Microchannel plate detectors are widely used for ultraviolet (UV) and extreme ultraviolet (EUV) observations. Curved-channel microchannel plates, or C plates, provide an electron gain of approximately 10(6) in a single plate because the curved channels prevent ion feedback. However, offsets between input and output in curved-channel microchannel plates produce slight distortions in the spatial or spectral scale of thedetector, complicating the use of such detectors for high resolution imaging and spectroscopy. We have examined the image distortion caused by nonconstant curvature of the channels by (a) observing spectral nonlinearities in an EUV spectrometer, (b) measuring the positions of several plugged channels of a typical plate and comparing the positions of the channels on both the input and the output sides, and (c) mapping input versus output of typical plates, using a mechanically scanned spot of UV light. We find that a typical C plate with 25-microm-diameter pores exhibits +/-25-microm image distortion across the plate. Calibration of this image distortion as reflected in the spectral nonlinearity of our EUV spectrograph improves the spectral line positions by a factor of 4, permitting solar-emission-line Doppler shift determination of +/- 2 microm (+/- 1 km/s). PMID- 20706429 TI - Absolute standardless calibration of photodetectors based on quantum two-photon fields. AB - A new method of absolute calibration of photodetectors based on a nonclassical effect in nonlinear optics is discussed. The combined influence of a monochromatic flux of pump photons and quantum vacuum noise on a nonlinear crystal with no center of symmetry results in the appearance of rigorously correlated pairs of photons with continuous spectral distribution in the spontaneous parametric scattering of light (spontaneous parametric downconversion) process. The presence of an optical field in a broad spectral range created by the two-photon states (biphotons) makes it possible to develop a new method of measuring the spectral distribution of the absolute value of the quantum efficiency of photodetectors, both in photon counting and in analog regimes, that does not use any calibrated standard light sources (etalons). The feasibility of the method is demonstrated on different types of photomultiplier tube. PMID- 20706430 TI - Aberration properties of a Czerny-Turner spectrograph using plane-holographic diffraction grating. AB - In this paper I discuss the construction and the aberration properties of plane holographic diffraction gratings in a Czerny-Turner mounting. A ray-tracing scheme has been formulated for computing the aberrations of the system. It has been found that in the area near the recording wavelength for the holographic grating, the system has better resolution than does a conventional grating system. The design parameters of a medium-sized holographic grating spectrograph are specified. The performance of the spectrograph is evaluated by plotting spot diagrams, which show that astigmatic defects are much reduced. PMID- 20706431 TI - Holographic diffraction gratings generated by aberrated wave fronts: application to a high-resolution far-ultraviolet spectrograph. AB - We investigated the ability of aberration-corrected concave holographic gratings used in the Rowland mount at normal diffraction to provide high spectral resolution in the far-ultraviolet region. By assuming that astigmatism and spherical aberration are geometrically corrected by an ellipsoid, we show that holography can be used to correct the remaining prominent second-type coma. Stigmatic sources require a laser wavelength that is too far in the ultraviolet for current recording technology. However, at 3336 A a simple compact symmetric mount, which involves two spherical mirrors, can generate aberrated wave fronts that can be used to record a coma-corrected holographic grating. When compared with the equivalent equally spaced straight-groove grating, which requires a modified ellipsoid substrate, holography cancels the additional asymmetrical term of deformation that permits the use of a simpler surface for the substrate. Some areas of potential difficulty in the holographic mounting are briefly analyzed. PMID- 20706432 TI - Nd:YAG laser machining with multilevel resist kinoforms. AB - We demonstrate that resist kinoforms can be used for laser micromachining. A 10 level resist kinoform, manufactured by electron-beam lithography, was shown to have a diffraction efficiency of 68%. Nine diffraction-limited holes were simultaneously drilled in 0.10-mm-thick stainless steel. Marking in a silicon wafer is also demonstrated. PMID- 20706433 TI - Use of holographic optical elements in speckle metrology. Part 3: application to fracture mechanics. AB - In this work a two-hololens imaging system has been used to measure crack-mouth opening displacement and crack-tip opening displacement to determine the stress intensity factor K(1), the crack-tip plastic zone size r(p)(*) and the rotational factor r in a beam specimen having the central edge crack subjected to three point bending using focused plane speckle photography. Experimental results are in good agreement with theoretical predictions. Current experimental investigations establish that low-cost holographic optics can be advantageously used in speckle metrology to solve complex problems of fracture mechanics. PMID- 20706434 TI - Three-color laser-diode interferometer. AB - The combined optical spectrum of a pair of multimode laser diodes is composed of a large number of welldefined wavelengths. This work reports the use of three of these wavelengths in a phase-modulated interferometer to measure absolute distance over 360-microm intervals with a resolution of 0.5 nm. The laboratory demonstration system is composed of a three-wavelength source coupled by single mode fiber to a compact interferometric probe. This system has been used for displacement measurement and profiling of optical surfaces. PMID- 20706435 TI - Double sinusoidal phase-modulating laser diode interferometer for distance measurement. AB - Sinusoidal phase-modulating interferometry is used to detect exactly the sinusoidal phase variation of an interference signal even when the amplitude of the interference signal is varied by modulation of the injection current. We can easily provide a sinusoidal phase-modulating interferometer with a feedback control system that eliminates the phase fluctuations caused by mechanical vibrations. The methods using sinusoidal phase-modulating interferometry improve the resolution of distance measurements. Experimental results show that the thickness of gauge blocks is measured with a resolution of approximately 0.5 microm. PMID- 20706436 TI - Phase-locked laser diode interferometer: high-speed feedback control system. AB - We have previously proposed a phase-locked laser diode interferometer. In that previous interferometer, however, there was substantial room for improvement in the reduction of measurement time. This reduction is achieved by using a different process for generation of the feedback signal in which the output of a chargecoupled device image sensor is used effectively. We analyze the feedback control system of the interferometer as a discrete-time system and discuss the characteristics of the interferometer. It is shown that the measurement time is much shorter than that of the interferometer proposed previously. PMID- 20706437 TI - Fourier fringe analysis: the two-dimensional phase unwrapping problem. AB - A new phase unwrapping algorithm is described that uses local phase information to mask out those parts of the field that cause inconsistencies in the unwrapping. Unlike earlier techniques, which produce only a consistent unwrapping of the phase in the presence of discontinuities, this technique can produce an approximately correct unwrapping. The technique is tolerant of discontinuities and noise in the phase and is fast, efficient, and simple to implement. In the absence of discontinuities an rms signal-to-noise ratio in the wrapped phase of <2:1 can be tolerated. PMID- 20706438 TI - Imaging and radiometric properties of microlens arrays. AB - The imaging and radiometric properties of erect lens arrays made up of small biconvex microlenses are derived from a ray analysis. The lens arrays provide erect, unit magnification images. The relationship between the radii of curvature, the lens thickness, and the one-to-one conjugate distance is derived for both the single-layer case and a double-layer structure, which contains field lenses. Radiometric properties of the microlens and the array are derived for both structures. The results are compared to experimentally measured values obtained from arrays fabricated by a photothermal process. PMID- 20706439 TI - Diffraction-limited blazed reflection diffractive microlenses for oblique incidence fabricated by electron-beam lithography. AB - Blazed reflection diffractive microlenses potentially have many uses. The fabrication accuracy and the optical characteristics of these microlenses can be greatly improved compared with transmission diffractive microlenses. The reflection microlenses for oblique incidence can be flexibly used without a beam splitter. The functions of the electron-beam writing system that we developed have been expanded so that the diffraction-limited microlenses for oblique incidence can be fabricated. It is demonstrated that the fabricated microlens exhibits diffraction-limited focusing characteristics with 78% high efficiency at a large oblique angle of 30 degrees . These microlenses could be used as key devices in planar optics and optical interconnections. PMID- 20706440 TI - Analysis of miniature FLIR test targets. AB - Hughes Aircraft Company has developed a miniature forward-looking infrared test target that uses differential emissivity to simulate differential temperature. This paper provides a theoretical analysis for the emissivity target. The analysis leads to a semiempirical formula that gives a reasonably good prediction of apparent temperature differences. The formula is useful for designing future emissivity targets. PMID- 20706441 TI - Interferometric method for concurrent measurement of thermo-optic and thermal expansion coefficients. AB - A Fabry-Perot-type interferometer is described that permits the concurrent measurement of the coefficient of thermal expansion (alpha) and the thermooptic coefficient (dn/dT) of transparent materials. Measurements of the a and the dn/dT of vitreous silica and a heavy-metal fluoride glass show that the technique is accurate, reproducible, and easily performed. In addition, the technique is used to show that the dn/dT of heavy-metal fluoride glasses is negative and temperature dependent. The magnitude of dn/dT is found to increase with increasing temperature. PMID- 20706442 TI - Optical properties of sol-gel spin-coated TiO(2) films and comparison of the properties with ion-beam-sputtered films. AB - Transparent and optical-grade TiO(2) coatings were prepared by sol-gel spinning and ion-beam sputtering techniques. We investigate process parameters for the fabrication of sol-gel spin-coated TiO(2) films exhibiting high optical quality comparable with that of ion-beam-sputtered TiO( 2) films. X-ray diffraction studies showed the sol-gel-deposited films to be amorphous for heat treatments below 350 degrees C, whereas the ion-beam-sputtered films were slightly crystalline and exhibited the anatase structure. The refractive index and the extinction coefficient were evaluated from transmittance characteristics in the ultraviolet, visible, and nearinfrared regions. Transmission spectra and ellipsometric measurements showed that spin-coated films were essentially optically equivalent to those prepared by ion-beam sputter deposition. PMID- 20706443 TI - Electron micrography and x-ray study of dip-lacquered LiF (220). AB - It has been proposed to use the 220 reflection of LiF with a multilayer deposited upon the top for simultaneous spectroscopy near Fe-k and O-k and below the C-k absorption edge (284 eV) in x-ray astronomy. We demonstrate that a substantial reduction of surface roughness is obtained by dip lacquering state-of-the-art polished LiF(220) surfaces. Using a microdensitometer analysis of electron micrographs of surface replicas and x-ray reflection, we have measured approximately 10-A rms roughness of Au-coated dip-lacquered LiF(220) crystals, as opposed to approximately 60 A measured on the bare LiF(220) crystal surface. PMID- 20706444 TI - Ophthalmic lenses: accurately characterizing transmittance of photochromic and other common lens materials. AB - Ophthalmic lens materials are characterized by their spectral transmittance and by derived luminous and average UV-B and UV-A transmittances. Photochromic materials, whose transmittances depend on previous and immediate radiant exposure and other environmental conditions, require special methods of spectrophotometry, which are described here. Nonphotochromic materials are characterized by customary spectrophotometry. Transmittances of seven common ophthalmic lens materials are reported (white crown glass, allyldiglycol carbonate and polycarbonate plastics, and four photochromic glasses). The transmittance spectra of sunlight-darkened photochromics are determined by extrapolation to the instant of removal from exposure by using a sequence of rapidly scanned spectra recorded at precisely timed intervals after removal. Luminous transmittances and average UV-B and UV-A transmittance of all materials tested agree well with published values. PMID- 20706445 TI - Wavelength dependence of the large lattice constant magneto-optic spatial light modulator. AB - Faraday rotation and optical absorption coefficients are reported at laser wavelengths for the large lattice constant magneto-optic spatial light modulator. Optimum operation occurs at yellow-green wavelengths. PMID- 20706446 TI - Applications of optical Boolean matrix operations to graph theory. AB - The transition from optical numerical matrix algebra to optical Boolean matrix algebra is explored in detail. All important Boolean matrix algebra tasks can be performed optically. Quantitative measurement is replaced by a simple light-or-no light decision, something optics can do well. The parallelism advantage of optics becomes greater as the matrix size increases. As an illustration of utility, we consider graph theory. PMID- 20706447 TI - Role of photon statistics in energy-efficient optical computers. AB - One of the limiting factors in the operation of highly energy-efficient optical computers is the fluctuation in the rate of photon detection events. Squeezed light technology, which appeared to be a possible way to mitigate this fluctuation, is shown to be of limited utility in this field. PMID- 20706448 TI - Comparison of error diffusion methods for computer-generated holograms. AB - Error diffusion (ED) is a powerful tool for the generation of binary computer generated holograms (CGH's). Several modifications of the original ED algorithm have been proposed to incorporate special requirements and assumptions present in CGH's. This paper compares different versions of the algorithm for their pplication to computer-generated holography with respect to reconstruction errors and the overall brightness of the reconstruction. PMID- 20706449 TI - Hybrid kinoform fanout holograms in dichromated gelatin. AB - The technique for fabricating hybrid holograms, introduced by Bartelt and Case [Appl. Opt. 21, 2886 (1982)], is applied here to record extremely high-efficiency (>90%) space-invariant fanout holograms in dichromated gelatin. The object wave front corresponding to that produced by a kinoform with a continuous-phase profile is derived by appropriate spatial filtering from a binary computer generated hologram fabricated using electron-beam lithography. PMID- 20706450 TI - Self-routing crossbar packet switch employing free-space optics for chip-to-chip Interconnections. AB - A nonblocking crossbar network that employs free-space optical interconnections between optoelectronic switching nodes is proposed. The architecture can be implemented using standard electronic technologies for the switching logic, systematic self-electro-optic effect devices for modulators and detectors, and fairly simple optics to connect adjacent chips in the network. Since optical interconnections are only required between adjacent chips, this architecture may have advantages compared with other architectures that have been proposed using optical interconnections between electronic chips. In addition, a simple routing scheme is discussed that permits the optical crossbar network to be operated as a self-routing packet switch. This packet switch provides for contention resolution, priority routing, and automatic increases in the priority of blocked packets. An example illustrating one implementation of the network is then described and analyzed. PMID- 20706451 TI - Restoration of moving binary images degraded owing to phosphor persistence. AB - The degraded images of dynamic objects obtained by using a phosphor-based electro optical display are analyzed in terms of dynamic modulation transfer function (DMTF) and temporal characteristics of the display system. The direct correspondence between the DMTF and image smear is used in developing real-time techniques for the restoration of degraded images. PMID- 20706452 TI - Image reconstruction methods for the PBX-M pinhole camera. AB - We describe two methods that have been used to reconstruct the soft x-ray emission profile of the PBX-M tokamak from the projected images recorded by the PBX-M pinhole camera [Proc. Soc. Photo-Opt. Instrum. Eng. 691, 111 (1986)]. Both methods must accurately represent the shape of the reconstructed profile while also providing a degree of immunity to noise in the data. The first method is a simple least-squares fit to the data. This has the advantage of being fast and small and thus easily implemented on the PDP-11 computer used to control the video digitizer for the pinhole camera. The second method involves the application of a maximum entropy algorithm to an overdetermined system. This has the advantage of allowing the use of a default profile. This profile contains additional knowledge about the plasma shape that can be obtained from equilibrium fits to the external magnetic measurements. Additionally the reconstruction is guaranteed positive, and the fit to the data can be relaxed by specifying both the amount and distribution of noise in the image. The algorithm described has the advantage of being considerably faster for an overdetermined system than the usual Lagrange multiplier approach to finding the maximum entropy solution [J. Opt. Soc. Am. 62, 511 (1972); Rev. Sci. Instrum. 57, 1557 (1986)]. PMID- 20706453 TI - Centroid fluctuations of speckled targets. AB - We present a statistical description of the centroid fluctuations of imaged targets under coherent illumination. We derive analytic expressions that take into account the illumination and imaging geometries. The fluctuations are shown to be insensitive to linear filtering and constitute a physical limitation to remote sensing devices making use of lasers. PMID- 20706454 TI - Noise and sensitivity characteristics of Bi(12)SiO(20) crystals for optimization of a real-time self-diffraction holographic interferometer. AB - The optimization of a real-time holographic interferometer that uses photorefractive Bi(12)SiO(20) crystals as the recording media through anisotropic self-diffraction is considered with regard to the optical noise and sensitivity characteristics of two particular crystals. A simple theoretical treatment is given to describe the factors influencing the maximum area of an object that can be viewed interferometrically by using these crystals. Experimental values of the noise distribution and sensitivity of the crystals are presented and used to obtain a value for the maximum observable object area of the order of 1 m(2). PMID- 20706455 TI - High-speed optical signal processing potential of grating-coupled waveguide filters. AB - The application of grating-coupled waveguides to spread spectrum fiber-optic communications systems is described. It is first shown that such a device can act as its own matched filter for impulsive excitation, which allows its use as an encoder and decoder of ultrashort pulses. This is true even in the case of strong coupling, although considerable pulse distortion occurs. A typical performance that might be expected from existing technology is then outlined, and a number of numerical examples are presented to illustrate typical signal processing operations. PMID- 20706456 TI - Read/write performance and reliability of a flying optical head using a monolithically integrated LD-PD. AB - A flying head using the switching characteristics of an optically switched laser diode is shown to have an excellent read/write performance and head-disk interface. This head consists of an aluminum nitride slider and a 1.3-microm wavelength InGaAsP laser diode monolithically integrated with a photodetector (LD PD). A ridged waveguide is fabricated on top of the LD facet to converge the light beam. The lensless flying head has a minimum power of 18 mW for writing information (at 1 MHz) at a medium velocity of 7 m/s. The disk has a SiN protective layer over a SbTeGe phase-change recording medium. The head signal remains good after more than 5 x 10(4) contact start/stop cycles and 4.4 x 10(8) passes in an experimental room environment. PMID- 20706457 TI - Core-radius dependency of mode transition and attenuation constants in circular hollow waveguides for the infrared. AB - Attenuation constants in circular hollow waveguides are numerically evaluated based on the exact characteristic equation. Mode transition takes place when waveguides become thinner. PMID- 20706458 TI - Laser action from 2,6,8-trisubstituted-1,3,5,7-tetramethyl-pyrromethene-BF(2) complexes: part 2. AB - In laser activity 1,3,5,7-tetramethyl-2,6-dicarboethoxy-8- cyanopyrromethene BF(2)complex 5 under flash-lamp excitation was approximately 1.8 times more energy efficient than Rhodamine-B; about the same efficiency of Rhodamine-575 was found for 1,3,5, 7-tetramethyl-2,6,8-triethylpyrromethene- BF(2) complex 2. PMID- 20706459 TI - Patents. AB - 4,971,412; 4,974,230; 4,984,863; 4,939,742; 4,925,302. PMID- 20706460 TI - First-order sources in first-order systems: second-order correlations: errata. PMID- 20706461 TI - Effective non-linear second-order coefficient d(eff) for the type II interaction in KTP crystal. AB - An expression for the nonlinear coefficient of the biaxial crystal KTiOPO(4) (KTP) for frequency doubling of irradiation at lambda = 1.064 .microm is presented. This expression is compared with those published recently. PMID- 20706462 TI - Measurements of the refractive-index variations with temperature of a photomonomer. AB - The temperature dependence of the index of refraction of CIBATOOL XB5081, a commercial photomonomer commonly used for stereolithographic part building, is measured at wavelengths of 632.8, 514.5, and 488.0 nm. PMID- 20706463 TI - Near-infrared diode laser spectrometer with frequency calibration using internal second harmonics. AB - Frequency calibration of a 1.3-microm diode laser spectrometer was carried out with a simultaneously recording spectrum of the iodine molecule in the visible region using internal second harmonics from the diode laser itself. An absolute accuracy of 0.002 cm(-1) was achieved with the frequency standard spectrum of the iodine molecule in the visible region and frequency markers from an etalon. Several atomic and molecular transitions in the near-infrared region were remeasured using this new frequency reference. PMID- 20706464 TI - Determination of radio-frequency phase in harmonic frequency modulation spectroscopy. AB - We have devised two useful schemes to determine the rf phase of the modulation waveforms in harmonic FM spectroscopy, a novel technique that we reported recently for the removal of residual amplitude modulation. The first method is based on the study of the signal line shapes as a function of the relative rf phase of the two modulating signals. By comparing the experimental results with the theoretical ones, the rf phase can be accurately inferred. The second method requires an analysis of the laser FM sideband spectrum. Since the two harmonic rf waveforms are coherently generated and applied simultaneously to the modulator, the frequency-modulated sideband spectrum should show an interference pattern that reveals the rf phase relationship. With the rf phase information available, a suitable feedback control may then be easily incorporated into the spectroscopic detection system. PMID- 20706465 TI - Simple method to determine the gain and saturation irradiance of a laser. AB - A new method is proposed to determine the gain parameter and the saturation irradiance of a partially homogeneously broadened gaseous laser medium in a unidirectional ring cavity. The proposed method is applied to a He-Xe 3.5-microm line, and the gain parameter and the saturation irradiance are then determined to be 0.0665 cm(-1) and 4.69 microW/mm(2), respectively. The method developed here is expected to be more accurate than conventional methods such as that using more than one laser and that with frequency detuning because less ambiguity is involved in the experiments and the theoretical treatment. PMID- 20706466 TI - Two-dimensional optical grating produced on a poly-p-phenylene vinylene/V(2)O(5) gel film by ultrashort pulsed laser radiation. AB - A two-dimensional permanent transmission grating was formed on a novel polymer gel composite film by ultrashort ( approximately 0.5-ps) and visible ( approximately 602-nm) pulsed laser radiation. With an arrangement of three noncoplanar coherent laser beams, we used two approaches to produce direct formation of a two-dimensional grating on the film. One approach is to expose the sample twice to different combinations of two beams, and the other is to expose the sample to three laser beams simultaneously. The diffraction patterns and the relative intensity distributions for different order diffraction of the two dimensional gratings formed on the poly-p-phenylene vinylene/V(2)O(5)-gel films are analyzed for the different two-beam combinations and relative orientations among the three laser beams. The total diffraction efficiency for the incident probe laser beam into all the non-zero-order diffraction beams reaches 48%. PMID- 20706467 TI - Approximate analytical method of gain saturation analysis of hollow waveguide lasers. AB - A simple analytical expression is derived relating the waveguide laser output power to the distributed loss, the mirror reflectances, the waveguide dimensions, and the small-signal gain coefficient. In our model the transverse-mode distributions are taken into account and the longitudinal field distribution is approximated by the threshold field distribution. PMID- 20706468 TI - Longitudinal-mode selectivity and perturbation sensitivity of multimirror laser cavities. AB - Some relevant features of a particular type of multimirror laser cavity, i.e., those cavities terminating in highfinesse reflective multipass interferometers, are theoretically investigated with the aim of highlighting the dependence of the level of spectral control achievable with these cavities on their geometrical and optical characteristics. It is shown that cavities equipped with suitably designed reflective multipass interferometers are not only capable of forcing a laser operation on a single longitudinal mode but can act at the same time as effective emission frequency stabilizers because of their inherently low sensitivity to any perturbation affecting the cavity optical length. This feature is particularly attractive for intrapulse and pulse-to-pulse stabilization of high power pulsed lasers. Criteria are given also for the design of optimized cavities that could simultaneously provide narrow linewidth laser emission and minimize the effects of perturbations. PMID- 20706469 TI - Control of intrapulse frequency chirping in long-pulse CO(2) lasers employing perturbation-insensitive optical cavities. AB - We present the results of intrapulse frequency chirping measurements that were carried out on a TEA CO(2) laser equipped with various conventional and unconventional frequency-selective optical cavities. We experimentally demonstrate that there is a close relationship between the causes and the extent of intrapulse frequency chirping on the one hand and the type of optical configuration that is used for controlling the laser mode behavior on the other. In particular, it is shown that intrapulse chirping of the emitted frequency can be significantly reduced by employing laser cavities terminating in high-finesse reflective multipass interferometers for single-mode selection. In fact, this type of cavity can be designed in such a way to minimize the effects on the emitted frequency of perturbations affecting the cavity optical length. PMID- 20706470 TI - CO(2) laser frequency stabilization using the radio-frequency optogalvanic Lamb dip. AB - The Lamb dip of the CO(2) saturation signal in an extracavity low-pressure CO(2) N(2) rf glow discharge is detected optogalvanically and used to stabilize the frequency of a CO(2) laser. The frequency stability is estimated to be better than 100 kHz. PMID- 20706471 TI - Semiconductor laser far-field shaping by means of an angle-selective facet coating. AB - An optical short-wave pass filter, applied as a coating on a semiconductor laser facet, is observed to decrease the far-field width perpendicular to the active layer. The resulting far field has a higher coupling efficiency to circular optics. Combination of this coating with a highly reflective coating on the rear facet gives an improvement of the available external differential efficiency and maintains the threshold current of the uncoated laser. The experimental results obtained can be explained in the framework of a simple model. PMID- 20706472 TI - High-order stimulated Raman scattering and nonlinear red-shifted broadening in benzyl alcohol core optical fiber. AB - Six orders of Stokes lines and the first-order anti-Stokes line were observed we believe for the first time, in a benzyl alcohol liquid core optical fiber. All the Stokes lines were asymmetrically broadened favoring the lower frequencies. The blue-shifted broadening was only a few percent of the amount of the red shifted broadening, and the broadening of the fifty-order Stokes line was so broadened to exceed the characteristic Raman frequency shift, 1000 cm(-1), to connect with the sixth-order Stokes line. The asymmetric broadening was discussed to be mainly due to the effect of the stimulated Rayleigh wing scattering. PMID- 20706473 TI - Raman shifting of picosecond light pulses in hydrogen gas. AB - Picosecond light pulses are used to generate multiple wavelengths by means of stimulated Raman scattering. A review of the processes involved is presented, followed by a discussion of the experimental apparatus. Stokes and anti-Stokes Raman-shifted lines arising from vibrational and rotational transitions are observed. The polarization of the incident pump laser considerably affects which wavelengths are observed. Some vibrational Raman lines exhibit a splitting that is due to scattering from different initial H(2) rotational states. PMID- 20706474 TI - Green function for the three-dimensional analysis of electro-optic modulators. AB - The Green function for an electro-optic modulator structure is derived in three dimensions. This Green function, the kernel of the integral equation, gives the potential in the entire structure and provides a powerful tool in the design of electro-optic modulators of arbitrary geometry. Numerical examples, based on this formulation, are shown. PMID- 20706475 TI - Precise length measurements in multimode optical fibers. AB - Selective optical excitation permits both the group index and the group delay of on-axis modes of multimode fibers to be determined with high precision. The group index of several types of fiber was measured at 1310 nm in a fiber Michelson interferometer, and the values were tabulated. Group delays were obtained from the transit time of short-duration optical pulses. From these data the length of reference fibers approximately 2 km long was calculated. Length-measurement accuracy was limited by group-index uncertainties to approximately 0.04%. Also, a technique that uses these reference fibers to minimize uncertainties in distance measurements made with multimode optical-time-domain reflectometers is described. PMID- 20706476 TI - Pulse distortion characteristic of multimode optical fibers. AB - A fast and accurate numerical algorithm for calculating fiber group delay is described. This algorithm allows one to evaluate time and frequency responses. An example of a response obtained in such a way for real fiber is compared to the corresponding experimental data. These confirm that this approach has some advantages and can be easily applied in practice. PMID- 20706477 TI - Simple numerical technique for the analysis of cylindrically symmetric refractive index profile optical fibers. AB - We extend an earlier proposed matrix method for the analysis of cylindrically symmetric arbitrary refractive-index profile optical fibers to calculate the propagation constant and leakage/absorption loss of modes. This method involves only straightforward multiplications of 2 x 2 matrices and is highly attractive, since no complex plane iterations are performed even to obtain leakage or absorption losses. Thus the method is ideally suited for implementation on desktop computers. The applicability of the method has been shown through calculations of propagation constants and leakage loss of the LP(01) mode in depressed inner clad fibers. PMID- 20706478 TI - Light-scattering Mueller matrix from a fiber as a function of MgO contamination. AB - The light-scattering Mueller matrix for an r = 0.345-microm-radius quartz fiber, illuminated at lambda = 0.4416 microm, is examined as a function of contamination with MgO crystals. When the MgO contamination is low, the matrix elements resemble those of a fiber of slightly larger radius. The MgO contamination creates higher-frequency, smaller-amplitude oscillations in the matrix elements that mask the lower-frequency oscillations indicative of a perfect cylinder. The contamination also causes scatter outside the plane of incidence. PMID- 20706479 TI - Recursive design of a holographic focusing grating coupler. AB - A method for designing and recording a holographic optical element that is used as a waveguide focusing grating coupler is presented. It is based on recording the holographic coupler with two predistorted wave fronts, derived from interim holograms, whose readout and recording geometries are different. The corrected holographic coupler has almost aberration-free performance even for couplers with very small f/numbers or with large wavelength shift between recording and readout. PMID- 20706480 TI - Nonlinear refractive-index changes induced by carrier injection in an InSb etalon. AB - We report the bistable switching of an InSb etalon in a novel mode of operation where the necessary changes in refractive index are induced by minority carrier injection through a p-n junction. Refractive-index changes of approximately 10( 5) are achieved using 3-V pulses. Switch ON and switch OFF characteristics and projected performance are discussed. PMID- 20706481 TI - Characterization of an AlGaAs rib waveguide using a grating in a Fabry-Perot etalon configuration. AB - We characterize an AlGaAs rib waveguide using a structure based on a third-order Bragg reflector fabricated by electron-beam lithography. The grating forms a resonant cavity with the sample's uncoated output facet, and we observe a Fabry Perot etalon behavior superimposed on the Bragg reflector characteristics. We present transmitted intensity measurements as a function of wavelength and temperature. We derive results for waveguide refractive-index profile, loss coefficient, group effective index, effective-index wavelength dispersion, and effective-index temperature dispersion. An auxiliary prism on top of the grating allows us to couple light out of the waveguide into the air. Angular measurements of the outcoupled orders at different wavelengths confirm the wavelength dispersion measurements made on the Fabry-Perot etalon formed by the grating and the cleaved mirror. PMID- 20706482 TI - Formulas for Fabry-Perot velocimeter performance using both stripe and multifrequency techniques. AB - New stripe and multifrequency techniques for Fabry-Perot velocimetry are incorporated into an analytical model for the entire system. Properties of striped interferometers (FP's) are derived. An understanding of energy flow in both striped and unstriped FP's is presented. Nine contributions to the velocity resolution are examined, and analytical approximations are provided for each of them. Formulas for the overall velocity and time resolution of each fringe are derived. Using brightness arguments to limit the maximum usable light acceptable by the system, we also derived analytical limits on the photographic writing speed of each fringe. PMID- 20706483 TI - Restoration of turbulence-degraded images by the most-common method. AB - A method for improving turbulence-degraded pictures is proposed and demonstrated. The algorithm is based on a study of the time distribution of the gray-level values of each pixel in a series of short-exposure video frames. PMID- 20706484 TI - Double-pulse dual-wavelength alexandrite laser for atmospheric water vapor measurement. AB - We describe a new alexandrite laser source arrangement designed to measure atmospheric water vapor using the differential absorption lidar technique. This laser is capable of emitting two pulses at two appropriately selected wavelengths within a single flash lamp discharge. A narrow spectral linewidth of Deltalambda < 1 pm is obtained for each pulse by intracavity filtering with a birefringent filter and two Fabry-Perot interferometers. Wavelength commutation between the two pulses is performed by electro-optically tuning the birefringent filter. The temporal separation between the two pulses can be chosen between 50 and 70 micros and each pulse duration is <250-ns (full width at half-maximum). Typical output energies of 50 mJ/pulse at each wavelength are obtained with this laser system at a 10-Hz repetition rate for a 1.3-kW input electrical power. PMID- 20706485 TI - Tunable 2.1-,microm Ho lidar for simultaneous range-resolved measurements of atmospheric water vapor and aerosol backscatter profiles. AB - An eye-safe, tunable differential-absorption lidar system has been developed for the range-resolved measurement of aerosol backscatter and water vapor in the atmosphere. The lidar uses a flash-lamp-pumped, qswitched, 10-mJ solid-state Ho:YSGG laser that is continuously tunable over a 20cm(-1) wavelength range near 2.084 microm. Both path-averaged and range-resolved measurements were performed with the Ho differential-absorption lidar system. Preliminary measurements have been made of the temporal variation of atmospheric aerosol backscatter and water vapor profiles at ranges out to 1 km. These results indicate that the Ho lidar has the potential for the eye-safe remote sensing of atmospheric water vapor and backscatter profiles at longer ranges if suitably enhanced in laser power and laser linewidth. PMID- 20706486 TI - Remote fiber-optic chemical sensing using evanescent-wave interactions in chalcogenide glass fibers. AB - An infrared-transmitting chalcogenide fiber was used as an optical probe to analyze qualitatively and quantitatively various chemical substances in aqueous solutions. An unclad fiber with 380-microm diameter was combined with a Fourier transform infrared spectrometer to monitor the concentration of the analytes in solutions by measuring the changes in the absorbance of their fundamental vibration peaks. A linear relationship was observed between the absorption by the vanescent field and concentrations of various analytes. For this study low concentrations of acetone, ethyl alcohol, and sulfuric acid were detected in aqueous solutions. The minimum detection limit for these three chemical substances was 5, 3, and 2 vol. %, respectively, with a sensor length of 15 cm. It was also demonstrated that the same sensor design is capable of monitoring gaseous species such as dichlorodifluoromethane. PMID- 20706487 TI - CO(2) laser for lidar applications, producing two narrowly spaced independently wavelength-selectable Q-switched output pulses. AB - In this research directed toward using lidar methods for mapping concentrations of a variety of hazardous gases and vapors in an indoor workplace, a need was identified for a CO(2) laser that would meet certain special requirements, including an ability to produce 50-100-ns FWHM pulses in pulse pairs having interpulse spacings of 5-100 mus with each pulse of the pair being independently wavelength selectable. A laser was constructed with a low-pressure CO(2) amplifier section because of CO(2)'s long upper lasing level lifetime (>60 micros). This permitted the Q switching of two output pulses from a single laser amplifier electrical transverse discharge pulse, while allowing several microseconds for wavelength changing between pulses. An intracavity beam telescope was employed to use the amplifier discharge cavity cross section efficiently with the small CdTe Q-switch crystals available. A 1200-Hz oscillating grating with a high-resolution grating position sensor was used to change and reprogram wavelengths rapidly. Programming of wavelengths was accomplished by selecting appropriate delay times from the grating position reference signal for triggering the laser amplifier and the Q switch. Most of the basic performance goals of the device were achieved in the laboratory prototype. PMID- 20706488 TI - Nondestructive measurement of chlorophyll pigment content in plant leaves from three-color reflectance and transmittance. AB - We propose a nondestructive or optical method of measuring the chlorophyll content in a leaf after constructing a mathematical model of reflectance and transmittance of plant leaves as a function of their chlorophyll pigment content. The model is based on the Kubelka-Munk theory and involves the modeling of the multiple reflection of light in a leaf that is assumed to be composed of a stack of four layers. It also includes the assumption that the scattering coefficient and the absorption coefficient of the Kubelka-Munk theory can be expressed as a linear function of the pigment content of a plant leaf. In the proposed method, the chlorophyll content is calculated from reflectances and transmittances at three bands whose center wavelengths are 880,720, and 700 nm. Experiments were performed to confirm the applicability of the model and the method. Reflectance and transmittance calculated with the model showed good agreement with measured values. Furthermore, several unmeasurable constants necessary in the calculation were determined by a least-squares fit. We also confirmed that these results were consistent with several well-known facts in the botanical field. The method proposed here showed a small estimation error of 6.6 microg/cm (2) over the 0-80 microg/cm(2) chlorophyll content range for all kinds of plant tested. PMID- 20706489 TI - Precision of light scattering techniques for measuring optical parameters of microspheres. AB - This experimental and theoretical study of light scattering techniques addresses the questions of deconvolution of light scattering data (phase functions and optical resonance spectra) from droplets and the uniqueness of that deconvolution for the measurement of size and refractive index of microspheres. Theory and experiment are compared for single component and multicomponent microdroplets and for layered microspheres levitated in electrodynamic balances. Size changes of the order of 1 A have been measured by tracking resonance shifts of slowly evaporating single component droplets. For multicomponent droplet evaporation, which involves simultaneous size and refractive index changes, and for rapid evaporation, precision is reduced to approximately 1 part in 10(4) for each parameter. PMID- 20706490 TI - Scattering of a CO(2) laser beam at 10.6 microm by bare soils: experimental study of the polarized bidirectional scattering coefficient; model and comparison with directional emissivity measurements. AB - The bistatic polarized scattering by bare soil samples of a CO(2) laser beam at 10.6 microm has been experimentally studied. Large differences between HH and VV curves are usually observed, particularly in the forward plane. A simple phenomenological parameterization is proposed, based on the assumption of totally incoherent scattering by a rough medium. The normalized function F(theta)/F(0) accounting for slope distribution and shadowing is found from angular backscatter to be of the form cos(m)(theta), with m = 5.24 for all samples. This result is generalized to account for the bistatic case. The index of refraction of the medium is obtained from the ratio of HH and VV curves in the forward plane. Good agreement is found between experimental and calculated curves in the case of sand. The directional reflectivity and emissivity are calculated and compare well with experimental data. The calculated emissivity at nadir, for lambda = 10.6 microm, is within 0.5% of the value directly measured from emitted radiation. The backscattered peak has not yet been addressed in detail, therefore preventing relating in a semiquantitative manner the intensity of the backscattered light and the emissivity. PMID- 20706491 TI - Two-dimensional mapping of temperature in a lame by enerate four-wave mixing in OH. AB - Phase conjugate images are produced by resonant degenerate four-wave mixing from rotationally excited OH molecules in a premixed, laminar methane/air flame. By comparing signal intensities in the images produced using transitions from different rotational levels, the temperature map of a planar section of the flame is derived. PMID- 20706492 TI - Patents. AB - 4,986,619; 4,986,640; 4,988,153; 4,988,157; 4,993,788; 4,993,790; 5,002,395. PMID- 20706494 TI - Charge-coupled device polarimetry and its measurement of the Stokes vector of light transmitted by a polymer plate. AB - The Stokes vector of light transmitted by a polycarbonate plate is studied by a modified charge-coupled device polarimeter. A sheet polarizer is measured for comparison. PMID- 20706493 TI - Extreme-ultraviolet optical constant determination near an absorption edge. AB - The determination of optical constants from the reflectance versus angle of incidence data in the extreme ultraviolet region near an absorption edge may be affected by instrument spectral resolution. PMID- 20706495 TI - Cryogenic refractive indices of ZnSe, Ge, and Si at 10.6 microm. AB - Refractive-indexm easurementsa s a function of temperature have been made for zinc selenide, germanium, and silicon at 10.6 jlm over a temperature range of 20 300 K. Each measurement was made by finding the deviation angle of a beam perpendicularly incident on a right triangle prism. The curves for index of refraction versus temperature have been fitted to polynomials, and values for the change in index with temperature are given as a function of temperature. PMID- 20706496 TI - Roof-angle error effect on modulation transfer function. II. PMID- 20706497 TI - Simple approach to reflectance analysis of birefringent stratified films. AB - A simple analysis is presented of reflectance from a stratified uniaxial media with the optic axes parallel or perpendicular to the plane of incidence. PMID- 20706498 TI - Third-generation Rowland holographic mounting. AB - Holographic gratings using aspheric blanks and/or aberrated laser recording sources are most often required to achieve high spectral resolution over a large spectral range. We propose a configuration derived from the optimized holographic Rowland mounting, where the grating is recorded by the interference of two aberrated wave fronts diffracted from concave holographic gratings. These two auxiliary gratings are recorded with laser point sources, and the three blanks are spherical, which is well suited to the severe far-UV constraints on shape and polishing. In addition to the correction of astigmatism, coma C(1), and spherical aberration S(1) given by the optimized Rowland mounting, this mounting cancels, at least at one point of the spectrum, coma C(2) and spherical aberrations S(2) and S(3). PMID- 20706499 TI - Synthetic wavelength stabilization for two-color laser-diode interferometry. AB - The phase ambiguity in conventional interferometers can be removed by using two laser diodes of different optical frequencies to generate a synthetic wavelength. However, the stability requirements for a two-color interferometric laser gauge that must provide unambiguous determination of the optical fringe order over a large distance can be severe. We derive upper limits on the optical wavelength uncertainty and express them as a function of optical path difference between the object and reference beams, phase measurement errors, and the synthetic wavelength. A simple stabilization arrangement is proposed, involving simultaneous servo control of both lasers with a single Fabry-Perot etalon. The experimental implementation of the proposed system demonstrates its effectiveness for long-term (16-h) stabilized two-color interferometry over a distance of 250 mm, with a 15-mm synthetic wavelength and a repeatability of 40 nm. For periods of < 1000 s, the repeatability was 8 nm. PMID- 20706500 TI - Dual-beam interferometer for the accurate determination of surface-wave velocity. AB - A novel dual-beam interferometer has been designed and constructed that enables two beams from a He-Ne laser to probe remotely the surface of a material. The separation of the two He-Ne beams is adjustable in the 15-to- 40-mm range with a spatial resolution of 2 microm. Surface-acoustic-wave measurements have been performed with two different probe separations so that the travel time for the surface waves over a known distance can be determined accurately. With the aid of autocorrelation algorithms, the Rayleigh pulse velocity on 7075-T651 aluminum has been measured to be 2888 +/- 4 m/s. The current precision of the system is limited mainly by the 10-ns sampling rate of the digital oscilloscope used. Rayleigh pulse interactions with a surface-breaking slot, machined to a nominal depth of 0.5 mm, have also been examined and the depth estimated ultrasonically to be 0.49 +/- 0.02 mm. The system may also provide a technique for direct quantitative studies of surface-wave attenuation. PMID- 20706501 TI - Two-wavelength sinusoidal phase/modulating laser-diode interferometer insensitive to external disturbances. AB - We describe a two-wavelength laser-diode interferometer that is insensitive to external disturbances such as fluctuations in the wavelength of the laser diode and mechanical vibrations of the optical components. In sinusoidal phase modulating interferometry this insensitivity is easily obtained by controlling the injection current of the laser diode with a feedback control system. Using an equivalent wavelength of 152 microm provided by two single-frequency laser diodes, we can measure the distance, rotation angle, and surface profile measurements with great accuracy. PMID- 20706502 TI - Wavelength-shift interferometry for distance measurements using the Fourier transform technique for fringe analysis. AB - The Fourier transform technique, originally developed for spatial fringe pattern analysis, has been applied to the analysis of a temporal fringe signal obtained by a wavelength-shift interferometer used for absolute distance measurements. It has been shown that the error caused by the nonlinear and time-varying current wavelength characteristic of the laser diode can be removed by combining the Fourier transform technique with the reference technique. A novel technique for distance measurement based on multiple-beam interferometry has been proposed, and an experimental demonstration is given for a three-beam interferometer that includes a reference reflector as an integral part of the system. Error sources and the limitation of the technique are discussed. PMID- 20706503 TI - Fiber-optic refractive-index sensor for use in fresh concrete. AB - We describe the development of a portable fiber-optic refractive-index sensor for detecting the air-bubble content in fresh concrete. The sensor uses a low-power visible laser diode as the light source. Data processing is performed in real time by a lap-top microcomputer. We introduce a new digital image-processing methodology for the interpretation of reflected-light intensity signals. Sensor performance is examined through laboratory and field studies on concrete poured at actual highway sites. PMID- 20706504 TI - Optical proximity sensor that uses a laser-scanning system. AB - An optical-sensor scheme that uses a conically scanned laser-beam spot is proposed and discussed. An algorithm for distance and orientation measurements is used together with numerical-analysis techniques to measure distance to an accuracy of +/- 1 mm and orientation to +/- 1.50 degrees . The system's applications for robotic arm manipulators are discussed. PMID- 20706505 TI - Prediction of the bandwidth of an all-dielectric bandpass filter. AB - The bandwidth between adjacent stop bands is useful in the design of a multilayer all-dielectric bandpass with a prescribed bandwidth. PMID- 20706506 TI - Surface-mounted optical fiber strain sensor design. AB - We develop the theory of surface-mounted interferometric optical fiber strain sensor design for arbitrarily configured fiber paths and present design techniques to select the path of a curved fiber-optic sensor required to isolate predetermined strain components. Several of these gauges are combined to form a rosette that directly measures the state of strain without the need to solve a set of simultaneous equations. We also use the design procedures to develop an optical fiber sensor that measures a single arbitrary stress component in an isotropic body. The design process is guided by a fundamental relationship among path, strain, and phase change for an arbitrarily configured optical fiber. The design theory is restricted to small strains and flat surfaces. All fiber sensor designs are validated with experiments. PMID- 20706507 TI - Infrared optical properties of orthorhombic sulfur. AB - Because of recent developments in planetary astronomy, there has been a resurgence of interest in the optical and thermodynamic properties of elemental sulfur. An encounter between the space probe Galileo and the Jovian moons, particularly Io, is expected to contribute further to this interest. A thorough investigation of the optical properties of orthorhombic sulfur from 2 to 56 microm (5000-180 cm(-1)) is presented. Since less care was taken in many past studies of this element than was warranted, a critical review of some of the relevant literature is included. The near-normal specular reflectance of the (111) face of an orthorhombic sulfur crystal has been measured in both polarized and unpolarized radiation at room temperature. The reflectance of a cryptocrystalline melt freeze has also been obtained. Associated optical constants are determined from a Kramers-Kronig phase shift analysis of the reflectance data. The average reflectance and absolute refractive index n were found to vary with polarization from 0.100 to 0.125 and from 1.92 to 2.09, respectively. Between eight and eleven mostly weak absorption bands of the cyclo S(8) molecule were discernible, but the attenuation index k remains small throughout most of the region studied. The crystal spectra were found to be quite sensitive to polarization in the neighborhood of the v(4) fundamental. Extrapolation of n to other temperatures and to the liquid phase through the use of the Lorentz-Lorenz relation is discussed. PMID- 20706508 TI - Enhanced transmission through rough-metal surfaces. AB - The enhanced-transmission effect, manifested as a narrow peak in the angular distribution of the intensity of diffuse scattered light in the antispecular direction, was experimentally investigated by passage of a p-polarized laser beam through a metal film deposited upon a glass substrate. The peak is the analog of enhanced backscattering in the reflection of light from a randomly rough-metal surface. A fully automated, bidirectional reflectometer was used to measure the enhanced transmission of surfaces coated with gold and silver under illumination by a He-Ne laser. The experimental results are compared with those obtained recently by a perturbation theory of the localization of surface polaritons. PMID- 20706509 TI - Photofabrication of one-dimensional rough surfaces for light-scattering experiments. AB - An optical method of fabricating randomly rough one-dimensional surfaces is described. The variations in the surface profile are produced by exposing photoresist-coated plates to a narrow line of light and scanning them under computer control. A theoretical analysis of the basic statistical properties of the fabricated surfaces is presented. These surfaces are in general non-Gaussian, but their statistics can be easily calculated, making them attractive for experimental and theoretical work. Several such surfaces have been fabricated and characterized with a stylus profilometer. The estimated statistical properties are in agreement with the theoretical predictions. PMID- 20706510 TI - Surface-roughness effects on the determination of optical properties of materials by the reflection method. AB - The effects of surface roughness on the determination of the optical properties of materials by the reflection method were investigated. We showed that the refractive indices of a material with a moderately rough surface can be obtained by the reflection method, provided that the radio of the angular reflectances at both states of polarization is known. Specifically, we showed that for a nonspecular surface with specularity index as low as 0.07 the real and imaginary parts of the complex refractive index can be determined with an average deviation from its actual value of 2.9% and 5.0%, respectively. PMID- 20706511 TI - Improved VO(2) thin films for infrared switching. AB - Vanadium dioxide (VO(2),) undergoes a thermally induced phase transition from a semiconductor to a metal near 68 degrees C. The deposition of VO(2), thin films by using a process of activated-reactive evaporation provides high-quality VO(2) film material; specifically, the semiconducting phase-extinction coefficient in the infrared is reduced by an order of magnitude without detrimental effect on the corresponding metal phase coefficient. The materials improvement significantly enhances accessible performance limits for optical switching devices, as compared with VO(2) thin films deposited by both standard reactive and ion-assisted reactive evaporation. PMID- 20706512 TI - Infrared thin-film totally reflecting quarter-wave retarders. AB - Double-layer ThF(4)-ZnS coatings on a prism of KCl, KBr, and KI are optimized to give totally reflecting quarter-wave retarders at a wavelength of 10.6 microm. The influence on the design parameters of the light absorption occurring at high temperatures is described. PMID- 20706513 TI - Influence of coating thickness on the performance of a Fabry-Perot interferometer. AB - The effects of the coating thickness on the physical performance of a Fabry-erot interferometer (FP) are investigated. The FP is modeled as three media separated by two thin films and not merely by two interfaces. We show that the transmitted intensity obeys an Airy function, but not the reflected intensity because of the appearance of a complex factor accounting for the coupling between the reflected waves in the coatings. The Stokes relations are generalized for this model. We study the dependence of the phase lag of reflection in the coatings on the angle of incidence, which causes a shift in the position of the intensity maxima. We discuss as well the properties of the FP with an absorbing medium in the cavity, defining a merit function that optimizes the compromise between peak transmission and finesse. PMID- 20706514 TI - Large-range refractive-index control of silicon monoxide antireflection coatings using oblique incident thermal evaporation. AB - With silicon monoxide films thermally evaporated at various angles between the substrate normal and the vapor stream, we obtain a refractive-index change ranging from 2.04 to 1.27, with evaporation angles ranging from 0 to 80 deg, respectively. This method provides an alternative to evaporating with a partial pressure of oxygen, which is now used to control the refractive index. Also, the selectivity of the lower range of refractive-index values may satisfy the needs of special applications that require a value lower than what is available from common bulk materials. PMID- 20706515 TI - Corneal lens goggles and visual space perception. AB - Night vision goggles are head-mounted, unity-power systems designed to allow the human operator to see and operate at night. Field experience and experimental studies have revealed many drawbacks in conventional designs that impair performance. One major drawback is the poor space perception provided by the goggles. The Hadani et al. [J. Opt. Soc. Am. 70, 60-65 (1980)] model for space perception attributes this drawback to the fact that the conventional designs shift the observer's effective center of perspective approximately 15 cm ahead and also predicts the resulting impairments. An innovative redesign is presented in this paper-the corneal lens goggles (CLG)-which brings the effective center of perspective of the goggles to coincide with the center of perspective of the eyes, thus annulling the optical length of the device. Qualitative and quantitative laboratory studies have compared the performance of the CLG and conventional goggles (type AN/PVS-5). These studies have revealed better visual and visual-motor performance with the CLG. The implications to optical design of the Hadani et al. theory and the CLG concept are discussed. PMID- 20706516 TI - Comparison of three-dimensional retinal imaging methods: the method of scanning laser triangulation. AB - Three methods of three-dimensional imaging of the vitreous and the fundus of the human eye are compared. Equations are derived for the theoretical depth resolution of stereophotogrammetry, scanning laser tomography, and scanning laser triangulation. Scanning laser triangulation provides superior depth resolution without requiring axial scanning. A description of a prototype scanning laser triangulator is given. PMID- 20706518 TI - Patents. AB - 4,926,696; 4,930,352; 4,946,280; 4,949,367; 4,968,117; 4,974,943; 4,978,182; 4,979,176; 4,979,828; 4,983,024; 4,988,169; 4,988,170. PMID- 20706517 TI - Efficiency of grazing incidence optics: the spiral collimator. AB - Geometric properties and construction of the spiral collimator are discussed. The expression for the efficiency of power conversion of a divergent soft x-ray point source into a parallel beam is obtained. The efficiency of the spiral collimator is shown to be up to 30-90% in the whole soft x-ray spectral range. This efficiency is limited only by the fundamental reason: x-ray radiation absorption in the mirror coating of the spiral collimator. In this sense, the spiral collimator is more effective than any known x-ray optical collimation system with one or manifold reflections. PMID- 20706519 TI - Reduced coherence, stability, and temporal overlap requirements for holography. AB - We demonstrate that the conventional requirements for hologram formation can be substantially relaxed by interfering two independent local reference beam holograms in a photorefractive medium. PMID- 20706520 TI - Simplified processing method of dichromated gelatin holographic recording material. AB - We are concerned with new simplified procedures for obtaining sufficient initial bias hardness of dichromated gelatin film by inserting the dehydration process before exposure. PMID- 20706521 TI - Illumination-independent high-efficiency joint transform correlator. AB - A novel polarization-encoded two-channel joint transform correlator is described that can produce unity interference modulation, independent of the illumination of the target and the reference. PMID- 20706522 TI - Rotation-invariant correlation with incoherent light. AB - We have incorporated an algorithm for rotation invariance, based on circular harmonic expansion, into a pattern recognition system that uses incoherent light. Simulations and experimental results reveal that the algorithm can provide adequate peak-to-background ratios regardless of the input rotation. PMID- 20706523 TI - Digital optical counter using directional coupler switches. AB - We describe the design and implementation of a bit-serial, four-bit, binary optical counter. The counter was designed and simulated using a digital optical simulation program developed for this purpose. It consists of five switches, a 4 bit fiber loop memory to store the count, four splitters, and fibers to interconnect the components. The counter is presently limited to a clock rate of 50 MHz because of the propagation delay in the single-bit time feedback loop. As designed, the same hardware may be used to count any even number of bits simply by changing the lengths of two fiber loops. The counter is unique in that it does not employ latches or other synchronizing memory elements, rather relying on a time-of-flight architecture. We describe the system issues involved in construction of the counter as well as the novel requirements on the switch drive electronics. We then outline the issues still to be addressed for the current counter and conclude with suggested design alternatives to improve its operation and increase its clock rate. PMID- 20706524 TI - Color-reflection holography: theory and experiment. AB - We present a theoretical and experimental analysis of color-reflection holography. Full parallax three-dimensional color images are obtained by the superposition of wavelength-selective reflection holograms recorded at eight combinations of three laser wavelengths. The test object used was a set of eight Munsell color chips recommended by the Commission Internationale de l'Eclairage (CIE) for color-rendering analysis. The spectral power distributions of all the holographic images are measured using a telespectroradiometer and corresponding points are calculated and plotted on a color diagram. The holograms are modeled by a combination of sinc functions for the diffracted replay signal and an empirically determined function for the replay scatter noise. A new definition of signal-to-noise ratio for color holograms is described. The model is matched to a spectral power distribution by choosing values for relative diffraction efficiencies, bandwidth, signal-to-noise ratio, and wavelength shift components. One spectral power distribution having been matched, theoretical predictions of the remaining colors in the holographic images are obtained. The predictions mapped on the CIE 1976 diagram are shown to agree with experimental results: the average distance between theoretical and experimental points on the CIE diagram for all eight Munsell chips on all eight holograms is 0.0001 CIE 1976 chromaticity diagram unit; the discrepancy of the average gamut area between theoretical and experimental points on the CIE diagrams was < 10%. Good agreement between theory and experiment having been shown, a synthesis of holographic color reproduction at any combination of wavelengths predicts optimum recording wavelengths of 460, 530, and 615 nm for typical replay by a color-reflection hologram. PMID- 20706525 TI - Electronic holography and speckle methods for imaging through tissue using femtosecond gated pulses. AB - Electronic holography and speckle interferometry are combined with femtosecond gating techniques to form images of absorbing structures embedded in organic tissue. The method takes advantage of the inherent instability of living tissue. PMID- 20706526 TI - Image processing of human corneal endothelium based on a learning network. AB - We applied a learning network to a cell's boundary detection of human corneal endothelium photomicrographs measured by specular microscopy. Interconnections between units in our model are constrained to be locally space invariant to meet space-invariant processing. The neural network was trained to extract the cell's boundary by showing part of the photomicrograph and its subjective boundary image, which is an outline drawing made by hand. After training, the network showed good performance with the microphotograph that was not trained. Internal representations of the network were also studied. PMID- 20706527 TI - Three-dimensional image reconstruction using interferometric data from a limited field of view with noise. AB - A reconstruction of phase objects using an algebraic reconstruction technique in an unconfined environment from multidirectional interferometric data is presented. The effect of noise on the data from the interference patterns is studied. It is shown that in the presence of noise the number of iterations need to be critically evaluated; otherwise the solution tends to diverge. Criteria used to quantify the noise are presented. Also shown is a relationship between noise and the required number of iterations, which yields the least error in reconstruction. This procedure is applied to experimentally obtained interferometric data. PMID- 20706528 TI - Limited degree-of-freedom adaptive optics and image reconstruction. AB - The use of limited degree-of-freedom adaptive optics in conjunction with statistical averaging and a linear image reconstruction algorithm is addressed. Image reconstruction is traded for full predetection compensation. It is shown through analytic calculations that the average optical transfer function (OTF) is significant for high spatial frequencies in the case of imaging through atmospheric turbulence with an adaptive optics system composed of a Hartmann-type wave-front sensor and a deformable mirror possessing far fewer actuators than one per atmospheric coherence diameter (r(0)). Statistical averaging is used to overcome the effects of measurement noise and randomness in individual realizations of the OTF. The imaging concept and signal-to-noise considerations are presented. PMID- 20706529 TI - Multiple-object binary joint transform correlation using multiple-level threshold crossing. AB - We investigate the performance of the binary joint transform correlator (JTC) in the presence of multiple objects for two types of thresholding that are used to binarize the joint power spectrum. The first method uses the median of the joint power spectrum of the reference image and the input scene as the threshold value. The second method is a two-dimensional thresholding technique used to maximize the light intensity of the correlation peak, and it eliminates the even-order harmonic terms. The correlation performance of the binary JTC is determined for both thresholding methods. The binary JTC output is determined analytically in terms of multiple input targets. The separation requirements of the binary JTC and the conventional JTC in the presence of multiple targets are computed. Computer simulation and experiments are presented for a limited number of multiple-target images to determine the correlation peak-to-sidelobe ratio and the correlation width for both thresholding techniques. In the experiments, a hybrid optical processor with an optically addressed spatial light modulator is used to implement the binary JTC. The results indicate that, using both thresholding methods, the binary JTC produces a large peak-to-sidelobe ratio and a narrow peak for the multiple-target images used in the tests. The two dimensional threshold function produces better correlation performance compared with the median thresholding. PMID- 20706530 TI - Multichannel acousto-optic crossbar switch. AB - We analyze an acousto-optic crossbar switch architecture that can be used to implement an N x N point-to-point switch with just N hardware complexity. In our analysis, we determine that insertion loss and cross talk are minimized if we place the output ports in the diffraction far field of the acousto-optic cell. Using this result, we develop an optimum switch design based on Fourier optics: a Fourier transform lens is used both to scale the output beams for efficient coupling to the output ports and to provide a necessary optical fan-in from input to output ports. We demonstrate the performance of switch configurations using single-mode fiber input ports in conjunction with single-mode fiber, multimode fiber, and photodiode output ports. PMID- 20706532 TI - New Diagnostic Real-Time PCR for Specific Detection of Mycoplasma hominis DNA. AB - Mycoplasma hominis is a fastidious micro-organism causing genital and extragenital infections. We developed a specific real-time PCR that exhibits high sensitivity and low intrarun and interrun variabilities. When applied to clinical samples, this quantitative PCR allowed to confirm the role of M. hominis in three patients with severe extragenital infections. PMID- 20706531 TI - Proteomic analysis of Pichinde virus infection identifies differential expression of prothymosin-alpha. AB - The arenaviruses include a number of important pathogens including Lassa virus and Junin virus. Presently, the only treatment is supportive care and the antiviral Ribavirin. In the event of an epidemic, patient triage may be required to more effectively manage resources; the development of prognostic biomarker signatures, correlating with disease severity, would allow rational triage. Using a pair of arenaviruses, which cause mild or severe disease, we analyzed extracts from infected cells using SELDI mass spectrometry to characterize potential biomarker profiles. EDGE analysis was used to analyze longitudinal expression differences. Extracts from infected guinea pigs revealed protein peaks which could discriminate between mild or severe infection, and between times post infection. Tandem mass-spectrometry identified several peaks, including the transcriptional regulator prothymosin-alpha. Further investigation revealed differences in secretion of this peptide. These data show proof of concept that proteomic profiling of host markers could be used as prognostic markers of infectious disease. PMID- 20706533 TI - Cardiovascular Diseases among Suiciders: A Population-Based Study in Northern Finland Population. AB - Objective. Depression has been found to be an independent risk factor with cardiovascular diseases (CVDs) and also associated with increased mortality among these patients. Method. We used a comprehensive database of all suicides (n = 2, 283) committed in Northern Finland with information on all hospital-treated cardiovascular diseases and psychiatric disorders. Results. Coronary artery disease (CAD) had been present in 7.7% and other cardiovascular diseases (CVDs) in 11.6% of the suiciders. The likelihood of suicide for patients with hospital treated CAD was estimated to be two-fold compared to the general population while likelihood for suicide was not elevated among those with other CVDs. Males with CAD and females with CAD or any CVD had been hospitalized significantly more often with depression compared to reference group. Conclusions. Suicidality among patients with cardiovascular diseases has been suggested to associate with depression. Psychiatric consultation is highly recommended in clinical practice for cardiac patients with depression or alcohol-related disorders. PMID- 20706535 TI - Development of 3D CAD/FEM Analysis System for Natural Teeth and Jaw Bone Constructed from X-Ray CT Images. AB - A three-dimensional finite element model of the lower first premolar, with the three layers of enamel, dentin, and pulp, and the mandible, with the two layers of cortical and cancellous bones, was directly constructed from noninvasively acquired CT images. This model was used to develop a system to analyze the stresses on the teeth and supporting bone structure during occlusion based on the finite element method and to examine the possibility of mechanical simulation. PMID- 20706536 TI - The Caries Phenomenon: A Timeline from Witchcraft and Superstition to Opinions of the 1500s to Today's Science. AB - This historical treatise follows the documented timeline of tooth decay into today's understanding, treatment, and teaching of caries biology. Caries has been attributed to many different causes for several millennia, however, only since the late 1900s has research revealed its complex multifactorial nature. European writers of the 1600s to 1700s held views that general health, mechanical injuries, trauma, and sudden temperature changes all caused caries-holding a common belief that decay was due to chemical agents, faulty saliva, and food particles. Until the early 1800s most writers believed that caries was due to inflammation from surrounding diseased alveolar bone. Today's science has demonstrated that caries is caused by indigenous oral microorganisms becoming a dynamic biofilm, that in the presence of fermentable sugars produce organic acids capable of dissolving inorganic enamel and dentin followed by the proteolytic destruction of collagen leaving soft infected dentin. As bacteria enter the pulp, infection follows. PMID- 20706534 TI - Brain aging in the oldest-old. AB - Nonagenarians and centenarians represent a quickly growing age group worldwide. In parallel, the prevalence of dementia increases substantially, but how to define dementia in this oldest-old age segment remains unclear. Although the idea that the risk of Alzheimer's disease (AD) decreases after age 90 has now been questioned, the oldest-old still represent a population relatively resistant to degenerative brain processes. Brain aging is characterised by the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs) as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In nondemented cases NFTs are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is little correlation between the quantitative distribution of SP and AD severity. The pattern of lesion distribution and neuronal loss changes in extreme aging relative to the younger-old. In contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared. This pattern suggests that both the extent of NFT development in the hippocampus as well as a displacement of subregional NFT distribution within the Cornu ammonis (CA) fields may be key determinants of dementia in the very old. Cortical association areas are relatively preserved. The progression of NFT formation across increasing cognitive impairment was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and entorhinal cortex. The total amount of amyloid and the neuronal loss in these regions were also significantly lower than those reported in younger AD cases. Overall, there is evidence that pathological substrates of cognitive deterioration in the oldest-old are different from those observed in the younger old. Microvascular parameters such as mean capillary diameters may be key factors to consider for the prediction of cognitive decline in the oldest-old. Neuropathological particularities of the oldest-old may be related to "longevity enabling" genes although little or nothing is known in this promising field of future research. PMID- 20706537 TI - Agreement of immunoassay and tandem mass spectrometry in the analysis of cortisol and free t4: interpretation and implications for clinicians. AB - Objective. To quantify differences in results obtained by immunoassays (IAs) and tandem mass spectrometry (MSMS) for cortisol and free thyroxine (FT4). Design & Patients. Cortisol was measured over 60 minutes following a standard ACTH stimulation test (n = 80); FT4 was measured over time in two cohorts of pregnant (n = 57), and nonpregnant (n = 28) women. Measurements. Samples were analyzed with both IA and MSMS. Results. Results for cortisol by the two methods tended to agree, but agreement weakened over the 60-minute test and was worse for higher (more extreme) concentrations. The results for FT4 depended on the method. IA measurements tended to agree with MSMS measurements when values fell within "normal levels", but agreement was not constant across trimester in pregnant women and was poorest for the extreme (low/high) concentrations. Correlations between MSMS measurements and the difference between MSMS and IA results were strong and positive (0.411 < r < 0.823; all P < .05). Conclusions. IA and MSMS provide different measures of cortisol and FT4 at extreme levels, where clinical decision making requires the greatest precision. Agreement between the methods is inconsistent over time, is nonlinear, and varies with the analyte and concentrations. IA-based measurements may lead to erroneous clinical decisions. PMID- 20706538 TI - Elevated levels of IL-10 and G-CSF associated with asymptomatic malaria in pregnant women. AB - In sub-Saharan Africa, approximately 30 million pregnant women are at risk of contracting malaria annually. Nearly 36% of healthy pregnant women receiving routine antenatal care tested positive for Plasmodium falciparum HRP-II antigen in Ghana. We tested the hypothesis that asymptomatic HRP II positive pregnant women expressed a unique Th1 and Th2 phenotype that differs from healthy controls. Plasma from healthy (n = 15) and asymptomatic (n = 25) pregnant women were evaluated for 27 biomarkers (IL-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL 8, IL-9, IL-10, IL-12, IL-13, IL-15, IL- 17, Eotaxin, bFGF-2, G-CSF, GM-CSF, IFN gamma, IP-10, MCP-1, MIP-1alpha, MIP-1beta, PDGF-bb, RANTES, TNF, and VEGF) associated with Th1 and Th2 cytokine homeostasis. IL-10 and G-CSF levels were elevated in the asymptomatic group when compared with the healthy group (P = .031 and .041, resp.). The median ratios of IL-1beta:5, IL-1beta:10, IL-1beta:G-CSF, IL-1beta:Eotaxin, IL-12:G-CSF, IL-15:10, IL-17:G-CSF, IL-17:Eotaxin, TNF:IL-4, TNF:IL-5, and TNF:G-CSF were significantly different among the two groups. Thus, asymptomatic malaria carriage may be linked to circulating levels of IL-10 and G CSF. PMID- 20706539 TI - Hepatic haemangioma masquerading as the gallbladder in a case of gallbladder agenesis: a case report and literature review. AB - Gallbladder agenesis is uncommon. In contrast, liver haemangiomas are the most common type of benign liver lesions. We describe the first documented case of gallbladder agenesis where the clinical presentation was consistent with biliary colic, and radiological investigation suggested the presence of gallstones. Subsequent operative findings revealed a solitary haemangioma of the liver sited in the normal position of the gallbladder fossa but with absence of the gallbladder. It is important that clinicians should keep gallbladder agenesis in mind when the gallbladder appears abnormal on preoperative imaging studies and cannot be found at laparoscopy. As symptoms will improve in 98% of cases, it is very important to avoid unnecessary intervention in patients who have a negative laparoscopy. The clinical presentation, investigations, and operative findings are discussed with a review of other relevant reported cases in the literature. PMID- 20706541 TI - Learning arm/hand coordination with an altered visual input. AB - The focus of this study was to test a novel tool for the analysis of motor coordination with an altered visual input. The altered visual input was created using special glasses that presented the view as recorded by a video camera placed at various positions around the subject. The camera was positioned at a frontal (F), lateral (L), or top (T) position with respect to the subject. We studied the differences between the arm-end (wrist) trajectories while grasping an object between altered vision (F, L, and T conditions) and normal vision (N) in ten subjects. The outcome measures from the analysis were the trajectory errors, the movement parameters, and the time of execution. We found substantial trajectory errors and an increased execution time at the baseline of the study. We also found that trajectory errors decreased in all conditions after three days of practice with the altered vision in the F condition only for 20 minutes per day, suggesting that recalibration of the visual systems occurred relatively quickly. These results indicate that this recalibration occurs via movement training in an altered condition. The results also suggest that recalibration is more difficult to achieve for altered vision in the F and L conditions compared to the T condition. This study has direct implications on the design of new rehabilitation systems. PMID- 20706540 TI - Potential role of sugar transporters in cancer and their relationship with anticancer therapy. AB - Sugars, primarily glucose and fructose, are the main energy source of cells. Because of their hydrophilic nature, cells use a number of transporter proteins to introduce sugars through their plasma membrane. Cancer cells are well known to display an enhanced sugar uptake and consumption. In fact, sugar transporters are deregulated in cancer cells so they incorporate higher amounts of sugar than normal cells. In this paper, we compile the most significant data available about biochemical and biological properties of sugar transporters in normal tissues and we review the available information about sugar carrier expression in different types of cancer. Moreover, we describe the possible pharmacological interactions between drugs currently used in anticancer therapy and the expression or function of facilitative sugar transporters. Finally, we also go into the insights about the future design of drugs targeted against sugar utilization in cancer cells. PMID- 20706542 TI - Early primary biliary cirrhosis: a new association with erythema nodosum of unknown origin. AB - Primary biliary cirrhosis (PBC) is associated with immune-mediated dermatologic disorders. The association of PBC with erythema nodosum (EN) seems rare. We report two females (42 and 44 years old) with low-grade fever, arthralgias, and elevated cholestatic enzymes in the first and fatigue in the second. Patients were also suffering from typical EN lesions characterized by multiple erythematous, painful nodules over the anterior portions of their lower extremities. Clinical and extensive laboratory work up excluded all known EN causes. PBC diagnosis was established according to the cholestatic biochemical profile, anti-mitochondrial antibodies (AMA) positivity and liver histology (first), and AMA and antinuclear (ANA) PBC-specific antibodies (second). Our report may suggest that PBC could be kept in mind in EN patients of unknown aetiology and particularly, when middle-aged female patients are affected. In such cases a thorough evaluation for AMA and/or ANA PBC-specific antibodies could be helpful to achieve a correct and timely diagnosis. PMID- 20706543 TI - Collet-sicard syndrome from thrombosis of the sigmoid-jugular complex: a case report and review of the literature. AB - Purpose. Collet-Sicard syndrome is a very rare condition characterised by unilateral palsy of the IX-XII cranial nerves. It is distinguished from Villaret syndrome by lack of presence of sympathetic involvement. Current literature contains only two cases of Collet-Sicard syndrome due to idiopathic internal jugular vein thrombosis. Method and Results. We report the case of Collet-Sicard syndrome in a 30-year-old man who presented with delayed development of XIth nerve dysfunction, due to internal jugular vein-sigmoid sinus thrombosis. A multidisciplinary team approach was employed in the management of this patient. At three-month followup, he had significantly improved swallowing, and repeat computed tomography neck scan showed partial recanalisation of the right internal jugular vein. Conclusion. In suspected Collet-Sicard syndrome, a focal primary lesion or metastasis to the temporal bone must be excluded, and sigmoid-jugular complex thrombosis should be considered in the differential diagnosis. Early recognition and treatment may result in significant functional recovery. PMID- 20706544 TI - Dermoscopic features of a black hairy tongue in 2 Japanese patients. AB - Dermoscopic features of a black hairy tongue have never been reported. Dermoscopy might be useful in speculating pathologic features of oral lesions. The objective was to identify additional dermoscopic criteria. Two Japanese patients who were clinically given a diagnosis of "black hairy tongue" were evaluated for dermoscopic features. We have shown characteristic dermoscopic features of brownish hair-like elongation of filiform papillae with whitish lingual papillae. Dermoscopic examination seemed useful as an adjunct to the diagnosis of this benign disorder of the tongue, demonstrating exact changes in shape and color of filiform papillae. It might also be helpful in more objective observation of the therapeutic efficacy. PMID- 20706545 TI - On the v-line radon transform and its imaging applications. AB - Radon transforms defined on smooth curves are well known and extensively studied in the literature. In this paper, we consider a Radon transform defined on a discontinuous curve formed by a pair of half-lines forming the vertical letter V. If the classical two-dimensional Radon transform has served as a work horse for tomographic transmission and/or emission imaging, we show that this V-line Radon transform is the backbone of scattered radiation imaging in two dimensions. We establish its analytic inverse formula as well as a corresponding filtered back projection reconstruction procedure. These theoretical results allow the reconstruction of two-dimensional images from Compton scattered radiation collected on a one-dimensional collimated camera. We illustrate the working principles of this imaging modality by presenting numerical simulation results. PMID- 20706546 TI - Increased range of motion and function in an individual with breast cancer and necrotizing fasciitis-manual therapy and pulsed short-wave diathermy treatment. AB - Necrotizing fasciitis is a severe soft tissue infection of the subcutaneous tissue and fascia affecting those predisposed to immune system compromise. It is a life threatening condition; mortality can be reduced by rapid diagnosis, adequate early surgical debridement and antibiotic ointment. In this case report we present the use of manual therapy (MT) techniques, joint and soft tissue mobilization, following a regimen of pulsed short wave diathermy (PSWD) in the treatment of a woman 3 years post necrotizing fasciitis developed during chemotherapy treatment for breast cancer. During her course of chemotherapy, she developed necrotizing fasciitis which was treated with extensive surgical debridement (8 linear feet of incisions) followed by debridement to both hips and the pelvis area. When we started working with her, we put her on a course of PSWD/MT. After six weeks of following this regimen, she gained 25 degrees of external rotation in both her left and right hips, 15 degrees of left hip flexion and 17 degrees of right hip flexion. The patient gained 10 degrees of right hip extension, yet there was no improvement in left hip extension. The treatments led to a dramatic reduction in pain and scarring from previous surgeries. The patient also returned to running. PMID- 20706548 TI - Reply to Narra. PMID- 20706547 TI - Sedation and analgesia in children with developmental disabilities and neurologic disorders. AB - Sedation and analgesia performed by the pediatrician and pediatric subspecialists are becoming increasingly common for diagnostic and therapeutic purposes in children with developmental disabilities and neurologic disorders (autism, epilepsy, stroke, obstructive hydrocephalus, traumatic brain injury, intracranial hemorrhage, and hypoxic-ischemic encephalopathy). The overall objectives of this paper are (1) to provide an overview on recent studies that highlight the increased risk for respiratory complications following sedation and analgesia in children with developmental disabilities and neurologic disorders, (2) to provide a better understanding of sedatives and analgesic medications which are commonly used in children with developmental disabilities and neurologic disorders on the central nervous system. PMID- 20706549 TI - Reading Minds and Telling Tales in a Cultural Borderland. AB - In this article I consider "narrative mind reading," the practical capability of inferring the motives that precipitate and underlie the actions of others. Following Jerome Bruner, I argue that this everyday capacity depends on our ability to place action within unfolding narrative contexts. While Bruner has focused on narrative mind reading as a within-culture affair, I look to border situations that cross race and class lines where there is a strong presumption among participants that they do not, in fact, share a cultural framework. Instead, interactions often reinforce actors' perceptions of mutual misunderstanding and cultural difference. Drawing on a longitudinal study of African American families who have children with severe illnesses, I examine narrative mind reading and misreading in one mother's interactions with the clinicians who treat her child. I further explore how narrative misreadings are supported through chart notes and "familiar stranger" stories. The focus on miscommunication grounds a theory of the reproduction of cultural difference in interactive dynamics and brings Bruner's emphasis on narrative into dialogue with contemporary anthropology of cultural borderlands. PMID- 20706551 TI - Bruner's Search for Meaning: A Conversation between Psychology and Anthropology. AB - We introduce a special issue of Ethos devoted to the work of Jerome Bruner and his careerlong attempts to seek innovative ways to foster a dialogue between psychology and anthropology. The articles in this special issue situate Bruner's meaning-centered approach to psychology and his groundbreaking work on narrative in the broader context of the developmental trajectory of both of fields of inquiry. Bruner's work has been enormously influential in the subfields of cultural psychology and psychological anthropology, especially because of his important contributions to our understanding of the intimate relationship between culture and mind. We examine Bruner's past and ongoing engagement with such luminary figures as Lev Vygotsky, Jean Piaget, Alfred Kroeber, Claude Levi Strauss, and Clifford Geertz to highlight points of convergence and tension between his version of cultural psychology and contemporary theorizing and practice in psychological anthropology. We also review his practical and theoretical contributions to the fields of medicine, law, and education. PMID- 20706550 TI - RIP1 kinase mediates arachidonic acid-induced oxidative death of oligodendrocyte precursors. AB - Oxidative damage is implicated in many neurological disorders including ischemic cerebral white matter injury. Oligodendrocyte precursors (preOLs) are intrinsically highly susceptible to various forms of oxidative stress. Here we report the identification of RIP1 kinase as a signaling molecule that mediates arachidonic acid- and glu-tathione depletion-induced oxidative death of preOLs. Blockade of RIP1 kinase activity with the specific allosteric inhibitor, necrostatin-1, rescued preOLs from arachidonic acid, cystine deprivation, and buthionine sulfoximine, but not hydrogen peroxide, induced necrosis. Arachidonic acid triggered robust production of reactive oxygen species (ROS) and sustained activation of the JNK pathway in preOLs, whereas inhibition of JNK significantly prevented cell death. Treatment of cells with necrostatin-1 efficiently abolished arachidonic acid-induced ROS production and JNK activation, indicating that RIP1 kinase activation is an upstream event. This study provides the first evidence that RIP1 kinase may play an active role in arachidonic acid- and glutathione depletion-mediated oxidative damage and suggests the therapeutic potential of necrostatin-1 in protecting undifferentiated OLs against oxidative injury. PMID- 20706552 TI - The use of aluminum nanostructures as platforms for metal enhanced fluorescence of the intrinsic emission of biomolecules in the ultra-violet. AB - We consider the possibility of using aluminum nanostructures for enhancing the intrinsic emission of biomolecules. We used the finite-difference time-domain (FDTD) method to calculate the effects of aluminum nanoparticles on nearby fluorophores that emit in the ultra-violet (UV). We find that the radiated power of UV fluorophores is significantly increased when they are in close proximity to aluminum nanostructures. We show that there will be increased localized excitation near aluminum particles at wavelengths used to excite intrinsic biomolecule emission. We also examine the effect of excited-state fluorophores on the near-field around the nanoparticles. Finally we present experimental evidence showing that a thin film of amino acids and nucleotides display enhanced emission when in close proximity to aluminum nanostructured surfaces. Our results suggest that biomolecules can be detected and identified using aluminum nanostructures that enhance their intrinsic emission. We hope this study will ignite interest in the broader scientific community to take advantage of the plasmonic properties of aluminum and the potential benefits of its interaction with biomolecules to generate momentum towards implementing fluorescence-based bioassays using their intrinsic emission. PMID- 20706553 TI - Least Squares Congealing for Unsupervised Alignment of Images. AB - In this paper, we present an approach we refer to as "least squares congealing" which provides a solution to the problem of aligning an ensemble of images in an unsupervised manner. Our approach circumvents many of the limitations existing in the canonical "congealing" algorithm. Specifically, we present an algorithm that: (i) is able to simultaneously, rather than sequentially, estimate warp parameter updates, (ii) exhibits fast convergence and (iii) requires no pre-defined step size. We present alignment results which show an improvement in performance for the removal of unwanted spatial variation when compared with the related work of Learned-Miller on two datasets, the MNIST hand written digit database and the MultiPIE face database. PMID- 20706554 TI - Canonical Correlation Analysis for Data Fusion and Group Inferences: Examining applications of medical imaging data. PMID- 20706556 TI - Phase-alignment of delayed sensory signals by adaptive filters. AB - Correction of sensory transmission delays is an intractable problem because there is no absolute reference for calibration. Phase alignment is a practical alternative solution and can be realized by adaptive filters that operate locally with simple error signals. PMID- 20706555 TI - Autobiographical Memory Phenomenology and Content Mediate Attachment Style and Psychological Distress. AB - In two studies, the present research tested the phenomenology and content of autobiographical memory as distinct mediators between attachment avoidance and anxiety and depressive symptoms. In Study 1, participants (N = 454) completed measures of attachment and depressive symptoms in one session, and retrieved and rated two self-defining memories of romantic relationships in a separate session. In Study 2, participants (N = 534) were primed with attachment security, attachment insecurity, or a control prime and then retrieved and rated a self defining relationship memory. Memory phenomenology, specifically memory coherence and emotional intensity, mediated the association between attachment avoidance and depressive symptoms, whereas the negative affective content of the memory mediated the association between attachment anxiety and depressive symptoms. Priming attachment security led to retrieval of a more coherent relationship memory, whereas insecurity led to the retrieval of a more incoherent relationship memory. Discussion focuses on the construction and recollection of memories as underlying mechanisms of adult attachment and psychological distress, the importance of memory coherence, and the implications for counseling research and practice. PMID- 20706557 TI - Targeting Angiogenesis in Rheumatoid Arthritis. AB - Angiogenesis, the development of new capillaries, is a crucial process in health and disease. The perpetuation of neovascularization in rheumatoid arthritis is highly involved in leukocyte extravasation into the synovium and pannus formation. Numerous soluble and cell surface-bound angiogenic mediators, including growth factors, cytokines, proteases, matrix macromolecules, cell adhesion receptors, chemokines and chemokine receptors, have been implicated in the process of neovascularization. Endogenous angiostatic factors, primarily angiostatin, endostatin, IL-4, IL-13, some angiostatic chemokines may be used to downregulate neovascularization. In addition, angiogenesis might be targeted by several specific approaches against VEGF, angiopoietin, alpha(v)beta(3) integrin or by exogenously administered compounds including DMARDs, anti-TNF agents, fumagillin analogues or thalidomide. Potentially all anti-angiogenic could be tried in order to control synovitis. PMID- 20706559 TI - AN IMPROVED UNBIASED METHOD FOR DIFFSPECT QUANTIFICATION IN EPILEPSY. AB - Determining the region of seizure onset is of critical importance for treating medically intractable epilepsy. Comparisons between an ictal and interictal Single Photon Emission Computed Tomography (SPECT) images have been shown to be successful in localizing focal epilepsy. The Ictal-Interictal Subtraction Analysis by Statistical Parametric Mapping (ISAS) algorithm remains one the more successful algorithms for comparing these images. However ISAS is limited by its statistical design. This design introduces a scan order bias in the estimation of the normal variance of sequential SPECT images. We have corrected this bias by estimating the normal variance with a half-normal distribution. In this paper we present an updated algorithm (ISAS HN) based on the original ISAS algorithm with a corrected estimate of the normal variance and an open-source utility for ISAS HN. PMID- 20706558 TI - Resistance to integrase inhibitors. AB - Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding sequence appear to confer cross-resistance. The characterization of those mutations is critical for the development of second generation IN inhibitors to overcome resistance. This review focuses on IN resistance based on structural and biochemical data, and on the role of the IN flexible loop i.e., between residues G140-G149 in drug action and resistance. PMID- 20706560 TI - Targeting Rb mutant cancers by inactivating TSC2. AB - Retinoblastoma (Rb), a tumor suppressor gene, is inactivated in many types of cancer. However little is known about how the loss of Rb function can be targeted in cancer therapies. We have identified that inactivation of TSC2 in Rb mutant cancer cells will induce a synergistic cell death. The synergistic cell death is due to an increase in cellular stress including metabolic, ER, and oxidative stress. Therefore, inactivation of TSC2 and chemothereputics that result in induction of cellular stress may be a novel and effective way to treat cancers containing inactivated Rb. PMID- 20706561 TI - Mediation and moderation: Testing relationships between symptom status, functional health, and quality of life in HIV patients. AB - We extended Wilson and Cleary's (1995) health-related quality of life model to examine the relationships among symptoms status (Symptoms), functional health (Disability), and quality of life (QOL). Using a community sample (N = 956) of male HIV positive patients, we tested a mediation model in which the relationship between Symptoms and QOL is partially mediated by Disability. Common and unique ideas from three approaches to examining moderation of effects in mediational models (Edwards & Lambert, 2007; Preacher, Rucker, & Hayes, 2007; MacKinnon, 2008) were used to test whether (a) the direct relationship of Symptoms to QOL and (b) the relationship of Disability to QOL are moderated by age. In the mediation model, both the direct and the indirect (mediated) effects were significant. The direct relationship of Symptoms to QOL was significantly moderated by age, but the relationship of Disability to QOL was not. High Symptoms were associated with lower QOL at all ages, but that this relationship became stronger at older ages. We compare the three approaches and consider their advantages over traditional approaches to combining mediation and moderation. PMID- 20706562 TI - Pocahontas Goes to the Clinic: Popular Culture as Lingua Franca in a Cultural Borderland. AB - Urban hospitals constitute an example of what is arguably the most visible site in anthropology these days-the border zone. Negotiating health care requires trafficking in tricky spaces where patients and their families must pay vigilant attention about when to submit, when to resist, and how to collaborate. Drawing from ethnographic research carried out over the past nine years among African American families who have children with severe illnesses and disabilities, I examine how children's popular culture operates in the fraught borderland that constitutes the urban clinic. Global icons like a Disneyfied Pocahantas can function as a lingua franca, offering a language of publicly available symbols on which families, health professionals, and children can draw to create a shared imaginative space across race and class divides and across the sometimes even more radical divide between sufferer and healer. PMID- 20706564 TI - A Class of Semiparametric Mixture Cure Survival Models with Dependent Censoring. AB - Modern cancer treatments have substantially improved cure rates and have generated a great interest in and need for proper statistical tools to analyze survival data with non-negligible cure fractions. Data with cure fractions are often complicated by dependent censoring, and the analysis of this type of data typically involves untestable parametric assumptions on the dependence of the censoring mechanism and the true survival times. Motivated by the analysis of prostate cancer survival trends, we propose a class of semiparametric transformation cure models that allows for dependent censoring without making parametric assumptions on the dependence relationship. The proposed class of models encompasses a number of common models for the latency survival function, including the proportional hazards model and the proportional odds model, and also allows for time-dependent covariates. An inverse censoring probability reweighting scheme is used to derive unbiased estimating equations. We validate small sample properties with simulations and demonstrate the method with a data application. PMID- 20706565 TI - Harm or Mere Inconvenience? Denying Women Emergency Contraception. AB - This paper addresses the likely impact on women of being denied emergency contraception (EC) by pharmacists who conscientiously refuse to provide it. A common view-defended by Elizabeth Fenton and Loren Lomasky, among others-is that these refusals inconvenience rather than harm women so long as the women can easily get EC somewhere else close by. I argue from a feminist perspective that the refusals harm women even when they can easily get EC somewhere else close by. PMID- 20706566 TI - Preliminary clinical experience with waon therapy in Korea: safety and effect. AB - BACKGROUND: Waon therapy has beneficial effects on chronic heart failure (CHF), peripheral arterial disease, and other various diseases. This was to assess the safety and effect of Waon therapy by echocardiography for the first time in Korea. METHODS: Ten patients with CHF were enrolled. The patients with a light gown were placed in a sitting-position in an evenly maintained 60 dry sauna system for 15 minutes, and then after leaving the sauna, they underwent bed rest with a blanket to keep them warm for an additional 30 minutes. Waon therapy was performed once a day, 5 days a week. RESULTS: Four of the 5 patients who had been treated for more than 2 weeks as protocol noted improvement of heart failure (HF) symptoms and decrease in left ventricular (LV) volume. There were trends in improvement of LV ejection fraction and parameters of diastolic function after the therapy although statistical significance was lack. No one complained of worsening of HF symptoms. In each session, body weight (61.8+/-10.2 kg vs. 61.6+/ 10.3 kg, p=0.008) and blood pressure (systolic, 119+/-28 vs. 111+/-27 mmHg, p=0.005; diastolic, 69+/-12 mmHg vs. 63+/-10 mmHg, p=0.005) were significantly decreased, oral temperature (35.9+/-0.4 vs. 37.0+/-0.9, p=0.017) was increased by 1.0 at the end of sauna bathing, but the heart rate (71+/-10/min vs. 72+/-8/min, p=0.8) was not changed. CONCLUSION: We have experienced Waon therapy which was safe and well tolerated and some beneficial effects for patients with CHF. Large scale randomized study is needed to apply Waon therapy as a promising therapy in Korean HF patients. PMID- 20706567 TI - Waon therapy, can it be new therapeutic modality in heart failure patients? PMID- 20706568 TI - Comparison of myocardial contrast echocardiography versus rest sestamibi myocardial perfusion imaging in the early diagnosis of acute coronary syndrome. AB - BACKGROUND: It remains unclear whether myocardial contrast echocardiography (MCE) is as accurate as myocardial perfusion imaging with technetium-99m sestamibi (MPI) for the diagnosis of acute coronary syndrome (ACS). We sought to directly compare the diagnostic accuracy of MCE with resting MPI in a head-to-head fashion. METHODS: We prospectively enrolled 98 consecutive patients (mean age; 59+/-9 years, 68 males) who presented to the emergency department with chest pain suggestive of acute myocardial ischemia. Early MCE was performed by using continuous infusion of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) during intermittent power Doppler harmonic imaging. Myocardial perfusion defects observed in at least one coronary territory were considered positive. Sestamibi was injected immediately after MCE and MPI was obtained within 6 hours of tracer injection. RESULTS: ACS was confirmed in 67 patients. There were 32 patients with acute myocardial infarction (AMI) and 35 patients with unstable angina requiring urgent revascularization. The sensitivities of MCE and MPI for the diagnosis of ACS were 72% and 61%, respectively, which were significantly higher than those of ST segment change (24%, p<0.001 vs. MCE and vs. MPI) and troponin I (27%, p<0.001 vs. MCE and vs. MPI), with similar specificities of 90% to 100%. On a receiveroperating characteristics curve demonstrating diagnostic accuracy for ACS, the area under the curve of MCE was significantly larger than that of MPI (0.86 vs. 0.77, respectively; p=0.019). CONCLUSION: MCE and MPI overcome the low sensitivity of routine triage tests for detecting ACS, and MCE is more accurate than MPI for the diagnosis of ACS in the emergency department. PMID- 20706569 TI - Secondary subaortic stenosis after patch closure of subarterial ventricular septal defect. AB - Subaortic stenosis usually occurs without a previous heart operation, however, it can occur after heart surgery as well, with a condition known as a secondary subaortic stenosis (SSS). SSS has been reported after surgical repair of several congenital heart defects. There are only a few recorded cases of SSS after repair of ventricular septal defect (VSD). Here we report a rare case of SSS that occurred 3 years after surgical repair of subarterial VSD. A follow-up echocardiogram is essential for detecting SSS caused by the newly developed subaortic membrane in patients who had cardiac surgery. PMID- 20706570 TI - A rare case of unruptured sinus of valsalva aneurysm obstructing the right ventricular outflow tract. AB - An unruptured sinus of Valsalva aneurysm is rare and is usually asymptomatic until a symptom associated with its complication develops. Hence, an unruptured sinus of Valsalva aneurysm is not infrequently missed unless echocardiogram is performed with other indications. An unruptured sinus of Valsalva aneurysm rarely protrudes into the right ventricular outflow tract, causing the right ventricular outflow tract obstruction. In this report, I describe a rare case of unruptured sinus of Valsalva aneurysm producing the right ventricular outflow tract obstruction, which was incidentally detected by echocardiography. PMID- 20706571 TI - A case of a right atrial and inferior vena caval thrombus resembling a right atrial myxoma. AB - A right atrial and inferior vena caval thrombus in a structurally normal heart is a very rare condition. We report a case of such a thrombus in a 66-year-old woman. She was admitted to our hospital with recent onset dyspnea. Based on echocardiography, we suspected that she had myxoma. We performed an excision of a mass, which was found, by pathologic examination, to be an organized mural thrombus. PMID- 20706572 TI - A case of right ventricular dysfunction caused by pectus excavatum. AB - Pectus excavatum compresses the underlying right side of the heart, which might lead to right ventricular dysfunction as illustrated in this case report. PMID- 20706573 TI - Papillary fibroelastoma presenting as a left ventricular mass. AB - Cardiac papillary fibroelastoma (CPF) is a benign cardiac tumor that usually affects cardiac valves. It is usually discovered incidentally on routine echocardiography. However, left ventricular CPF is rare. This report describes the case of a 73-year-old female, referred to a cardiology department for evaluation of a mass of the left ventricle. The mass was found routine echocardiography. The transthoracic echocardiography revealed a 2.2x1.3 cm highly oscillating mass, attached by stalk on the inferior wall of the left ventricle. Cardiac magnetic resonance imaging demonstrated a non-enhanced, 1.8x1.0 cm mass on the inferior wall of the left ventricle. The patient underwent surgical resection of the mass, histopathologic examination of the mass confirmed the diagnosis of a CPF. PMID- 20706574 TI - A case of quadricuspid aortic valve with aortic regurgitation. PMID- 20706575 TI - Insights in 17beta-HSD1 enzyme kinetics and ligand binding by dynamic motion investigation. AB - BACKGROUND: Bisubstrate enzymes, such as 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), exist in solution as an ensemble of conformations. 17beta-HSD1 catalyzes the last step of the biosynthesis of estradiol and, thus, it is a potentially attractive target for breast cancer treatment. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the conformational transitions of its catalytic cycle, a structural analysis of all available crystal structures was performed and representative conformations were assigned to each step of the putative kinetic mechanism. To cover most of the conformational space, all-atom molecular dynamic simulations were performed using the four crystallographic structures best describing apoform, opened, occluded and closed state of 17beta-HSD1 as starting structures. With three of them, binary and ternary complexes were built with NADPH and NADPH-estrone, respectively, while two were investigated as apoform. Free energy calculations were performed in order to judge more accurately which of the MD complexes describes a specific kinetic step. CONCLUSIONS/SIGNIFICANCE: Remarkably, the analysis of the eight long range trajectories resulting from this multi-trajectory/-complex approach revealed an essential role played by the backbone and side chain motions, especially of the betaF alphaG'-loop, in cofactor and substrate binding. Thus, a selected-fit mechanism is suggested for 17beta-HSD1, where ligand-binding induced concerted motions of the FG-segment and the C-terminal part guide the enzyme along its preferred catalytic pathway. Overall, we could assign different enzyme conformations to the five steps of the random bi-bi kinetic cycle of 17beta-HSD1 and we could postulate a preferred pathway for it. This study lays the basis for more-targeted biochemical studies on 17beta-HSD1, as well as for the design of specific inhibitors of this enzyme. Moreover, it provides a useful guideline for other enzymes, also characterized by a rigid core and a flexible region directing their catalysis. PMID- 20706576 TI - Invasive predators deplete genetic diversity of island lizards. AB - Invasive species can dramatically impact natural populations, especially those living on islands. Though numerous examples illustrate the ecological impact of invasive predators, no study has examined the genetic consequences for native populations subject to invasion. Here we capitalize on a natural experiment in which a long-term study of the brown anole lizard (Anolis sagrei) was interrupted by rat invasion. An island population that was devastated by rats recovered numerically following rat extermination. However, population genetic analyses at six microsatellite loci suggested a possible loss of genetic diversity due to invasion when compared to an uninvaded island studied over the same time frame. Our results provide partial support for the hypothesis that invasive predators can impact the genetic diversity of resident island populations. PMID- 20706577 TI - Capric acid secreted by S. boulardii inhibits C. albicans filamentous growth, adhesion and biofilm formation. AB - Candidiasis are life-threatening systemic fungal diseases, especially of gastro intestinal track, skin and mucous membranes lining various body cavities like the nostrils, the mouth, the lips, the eyelids, the ears or the genital area. Due to increasing resistance of candidiasis to existing drugs, it is very important to look for new strategies helping the treatment of such fungal diseases. One promising strategy is the use of the probiotic microorganisms, which when administered in adequate amounts confer a health benefit. Such a probiotic microorganism is yeast Saccharomyces boulardii, a close relative of baker yeast. Saccharomyces boulardii cells and their extract affect the virulence factors of the important human fungal pathogen C. albicans, its hyphae formation, adhesion and biofilm development. Extract prepared from S. boulardii culture filtrate was fractionated and GC-MS analysis showed that the active fraction contained, apart from 2-phenylethanol, caproic, caprylic and capric acid whose presence was confirmed by ESI-MS analysis. Biological activity was tested on C. albicans using extract and pure identified compounds. Our study demonstrated that this probiotic yeast secretes into the medium active compounds reducing candidal virulence factors. The chief compound inhibiting filamentous C. albicans growth comparably to S. boulardii extract was capric acid, which is thus responsible for inhibition of hyphae formation. It also reduced candidal adhesion and biofilm formation, though three times less than the extract, which thus contains other factors suppressing C. albicans adherence. The expression profile of selected genes associated with C. albicans virulence by real-time PCR showed a reduced expression of HWP1, INO1 and CSH1 genes in C. albicans cells treated with capric acid and S. boulardii extract. Hence capric acid secreted by S. boulardii is responsible for inhibition of C. albicans filamentation and partially also adhesion and biofilm formation. PMID- 20706578 TI - A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase. AB - BACKGROUND: The protozoan parasite Cryptosporidium parvum is responsible for significant disease burden among children in developing countries. In addition Cryptosporidiosis can result in chronic and life-threatening enteritis in AIDS patients, and the currently available drugs lack efficacy in treating these severe conditions. The discovery and development of novel anti-cryptosporidial therapeutics has been hampered by the poor experimental tractability of this pathogen. While the genome sequencing effort has identified several intriguing new targets including a unique inosine monophosphate dehydrogenase (IMPDH), pursuing these targets and testing inhibitors has been frustratingly difficult. METHODOLOGY AND PRINCIPAL FINDINGS: Here we have developed a pipeline of tools to accelerate the in vivo screening of inhibitors of C. parvum IMPDH. We have genetically engineered the related parasite Toxoplasma gondii to serve as a model of C. parvum infection as the first screen. This assay provides crucial target validation and a large signal window that is currently not possible in assays involving C. parvum. To further develop compounds that pass this first filter, we established a fluorescence-based assay of host cell proliferation, and a C. parvum growth assay that utilizes automated high-content imaging analysis for enhanced throughput. CONCLUSIONS AND SIGNIFICANCE: We have used these assays to evaluate C. parvum IMPDH inhibitors emerging from our ongoing medicinal chemistry effort and have identified a subset of 1,2,3-triazole ethers that exhibit excellent in vivo selectivity in the T. gondii model and improved anti cryptosporidial activity. PMID- 20706579 TI - Dietary modulation of Drosophila sleep-wake behaviour. AB - BACKGROUND: A complex relationship exists between diet and sleep but despite its impact on human health, this relationship remains uncharacterized and poorly understood. Drosophila melanogaster is an important model for the study of metabolism and behaviour, however the effect of diet upon Drosophila sleep remains largely unaddressed. METHODOLOGY/PRINCIPAL FINDINGS: Using automated behavioural monitoring, a capillary feeding assay and pharmacological treatments, we examined the effect of dietary yeast and sucrose upon Drosophila sleep-wake behaviour for three consecutive days. We found that dietary yeast deconsolidated the sleep-wake behaviour of flies by promoting arousal from sleep in males and shortening periods of locomotor activity in females. We also demonstrate that arousal from nocturnal sleep exhibits a significant ultradian rhythmicity with a periodicity of 85 minutes. Increasing the dietary sucrose concentration from 5% to 35% had no effect on total sucrose ingestion per day nor any affect on arousal, however it did lengthen the time that males and females remained active. Higher dietary sucrose led to reduced total sleep by male but not female flies. Locomotor activity was reduced by feeding flies Metformin, a drug that inhibits oxidative phosphorylation, however Metformin did not affect any aspects of sleep. CONCLUSIONS: We conclude that arousal from sleep is under ultradian control and regulated in a sex-dependent manner by dietary yeast and that dietary sucrose regulates the length of time that flies sustain periods of wakefulness. These findings highlight Drosophila as an important model with which to understand how diet impacts upon sleep and wakefulness in mammals and humans. PMID- 20706580 TI - Comparison of microscopy and Alamar blue reduction in a larval based assay for schistosome drug screening. AB - BACKGROUND: In view of the current widespread use of and reliance on a single schistosomicide, praziquantel, there is a pressing need to discover and develop alternative drugs for schistosomiasis. One approach to this is to develop High Throughput in vitro whole organism screens (HTS) to identify hits amongst large compound libraries. METHODOLOGY/PRINCIPAL FINDINGS: We have been carrying out low throughput (24-well plate) in vitro testing based on microscopic evaluation of killing of ex-vivo adult S. mansoni worms using selected compound collections mainly provided through the WHO-TDR Helminth Drug Initiative. To increase throughput, we introduced a similar but higher throughput 96-well primary in vitro assay using the schistosomula stage which can be readily produced in vitro in large quantities. In addition to morphological readout of viability we have investigated using fluorometric determination of the reduction of Alamar blue (AB), a redox indicator of enzyme activity widely used in whole organism screening. A panel of 7 known schistosome active compounds including praziquantel, produced diverse effects on larval morphology within 3 days of culture although only two induced marked larval death within 7 days. The AB assay was very effective in detecting these lethal compounds but proved more inconsistent in detecting compounds which damaged but did not kill. The utility of the AB assay in detecting compounds which cause severe morbidity and/or death of schistosomula was confirmed in testing a panel of compounds previously selected in library screening as having activity against the adult worms. Furthermore, in prospective library screening, the AB assay was able to detect all compounds which induced killing and also the majority of compounds designated as hits based on morphological changes. CONCLUSION: We conclude that an HTS combining AB readout and image-based analysis would provide an efficient and stringent primary assay for schistosome drug discovery. PMID- 20706581 TI - Lack of detection of XMRV in seminal plasma from HIV-1 infected men in The Netherlands. AB - BACKGROUND: Xenotropic murine leukaemia virus-related virus (XMRV) is a recently discovered human gammaretrovirus with yet unknown prevalence and transmission route(s). Its presence in prostate stromal fibroblasts and prostatic secretions suggests that XMRV might be sexually transmitted. We chose to study a compartment closely connected to the prostate, a location where XMRV was detected in independent studies. Seminal plasma samples from HIV-1 infected men were examined as they have an increased probability of acquiring sexually transmitted pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We studied the prevalence of XMRV in 93 seminal plasma samples of 54 HIV-1 infected men living in The Netherlands with a nested PCR amplification specifically targeting the XMRV gag gene. As a control for the presence and integrity of retrovirus particles, HIV-1 was amplified from the same samples with a PCR amplification targeting the env gene of the virus, or HIV-1 was quantified with a real-time PCR amplifying part of the pol gene. CONCLUSIONS/SIGNIFICANCE: Although HIV-1 was amplified from 25% of the seminal plasma samples, no XMRV was detected, suggesting that either the prevalence of XMRV is very low in The Netherlands, or that XMRV is not naturally present in the seminal plasma. PMID- 20706582 TI - Transcription profiling of Epstein-Barr virus nuclear antigen (EBNA)-1 expressing cells suggests targeting of chromatin remodeling complexes. AB - The Epstein-Barr virus (EBV) encoded nuclear antigen (EBNA)-1 regulates virus replication and transcription, and participates in the remodeling of the cellular environment that accompanies EBV induced B-cell immortalization and malignant transformation. The putative cellular targets of these effects of EBNA-1 are largely unknown. To address this issue we have profiled the transcriptional changes induced by short- and long-term expression of EBNA-1 in the EBV negative B-cell lymphoma BJAB. Three hundred and nineteen cellular genes were regulated in a conditional transfectant shortly after EBNA-1 induction while a ten fold higher number of genes was regulated upon continuous EBNA-1 expression. Promoter analysis of the differentially regulated genes demonstrated a significant enrichment of putative EBNA-1 binding sites suggesting that EBNA-1 may directly influence the transcription of a subset of genes. Gene ontology analysis of forty seven genes that were consistently regulated independently on the time of EBNA-1 expression revealed an unexpected enrichment of genes involved in the maintenance of chromatin architecture. The interaction network of the affected gene products suggests that EBNA-1 may promote a broad rearrangement of the cellular transcription landscape by altering the expression of key components of chromatin remodeling complexes. PMID- 20706584 TI - Enhanced in vivo activity of cefditoren in pre-immunized mice against penicillin resistant S. pneumoniae (serotypes 6B, 19F and 23F) in a sepsis model. AB - BACKGROUND: Specific antibodies are likely to be present before S. pneumoniae infection. We explored cefditoren (CDN) total and free values of serum concentrations exceeding the MIC (t>MIC) related to efficacy in a mice sepsis model, and the effect of specific gammaglobulins on in-vitro phagocytosis and in vivo efficacy. METHODOLOGY/PRINCIPAL FINDINGS: We used three pneumococcal isolates (serotype, MIC OF CDN): Strain 1 (6B, 1 microg/ml), Strain 2 (19F, 2 microg/ml) and Strain 3 (23F, 4 microg/ml). Hyperimmune serum (HS) was obtained from mice immunized with heat-inactivated strains. In-vitro, phagocytosis by HS diluted 1/10 in presence/absence of sub-inhibitory concentrations was measured by flow cytometry including fluorescent bacteria and a neutrophil cell line. In-vivo dose-ranging experiments with HS (dilutions 1/2-1/16) and CDN (6.25 mg/kg-100 mg/kg tid for 48 h) were performed to determine the minimal protective dilution/dose (highest survival) and the non-protective highest dilution/dose (highest mortality: HS-np dilution and CDN-np dose) over 7 days. Efficacy of CDN np in animals pre-immunized with HS-np (combined strategy) was explored and blood bacterial clearance determined. The CDN measured protein binding was 86.9%. In vitro, CDN significantly increased phagocytosis (vs. HS 1/10). In non pre immunized animals, t>MIC values for CDN of approximately 35% (total) and approximately 19% (free) were associated with 100% survival. Significant differences in survival were found between HS-np alone (< or = 20%) or CDN-np alone (< or = 20%) vs. the combined strategy (90%, 60% and 60% for Stains 1, 2 and 3), with t>MIC (total/free) of 22.8%/14.3%, 26.8%/16.0%, and 22.4%/12.7% for Strains 1, 2 and 3, respectively. Prior to the second dose (8 h), median bacterial counts were significantly lower in animals surviving vs. dead at day 7. CONCLUSIONS/SIGNIFICANCE: In mice (CDN protein binding similar to humans) total t>MIC values of approximately 35% (approximately 19% free) were efficacious, with a decrease in the required values in pre-immunized animals. This reinforces that immunoprotection to overcome resistance may provide lifesaving strategies. PMID- 20706583 TI - Purification and functional characterisation of rhiminopeptidase A, a novel aminopeptidase from the venom of Bitis gabonica rhinoceros. AB - BACKGROUND: Snake bite is a major neglected public health issue within poor communities living in the rural areas of several countries throughout the world. An estimated 2.5 million people are bitten by snakes each year and the cost and lack of efficacy of current anti-venom therapy, together with the lack of detailed knowledge about toxic components of venom and their modes of action, and the unavailability of treatments in rural areas mean that annually there are around 125,000 deaths worldwide. In order to develop cheaper and more effective therapeutics, the toxic components of snake venom and their modes of action need to be clearly understood. One particularly poorly understood component of snake venom is aminopeptidases. These are exo-metalloproteases, which, in mammals, are involved in important physiological functions such as the maintenance of blood pressure and brain function. Although aminopeptidase activities have been reported in some snake venoms, no detailed analysis of any individual snake venom aminopeptidases has been performed so far. As is the case for mammals, snake venom aminopeptidases may also play important roles in altering the physiological functions of victims during envenomation. In order to further understand this important group of snake venom enzymes we have isolated, functionally characterised and analysed the sequence-structure relationships of an aminopeptidase from the venom of the large, highly venomous West African gaboon viper, Bitis gabonica rhinoceros. METHODOLOGY AND PRINCIPAL FINDINGS: The venom of B. g. rhinoceros was fractionated by size exclusion chromatography and fractions with aminopeptidase activities were isolated. Fractions with aminopeptidase activities showed a pure protein with a molecular weight of 150 kDa on SDS-PAGE. In the absence of calcium, this purified protein had broad aminopeptidase activities against acidic, basic and neutral amino acids but in the presence of calcium, it had only acidic aminopeptidase activity (APA). Together with the functional data, mass spectrometry analysis of the purified protein confirmed this as an aminopeptidase A and thus this has been named as rhiminopeptidase A. The complete gene sequence of rhiminopeptidase A was obtained by sequencing the PCR amplified aminopeptidase A gene from the venom gland cDNA of B. g. rhinoceros. The gene codes for a predicted protein of 955 amino acids (110 kDa), which contains the key amino acids necessary for functioning as an aminopeptidase A. A structural model of rhiminopeptidase A shows the structure to consist of 4 domains: an N-terminal saddle-shaped beta domain, a mixed alpha and beta catalytic domain, a beta-sandwich domain and a C-terminal alpha helical domain. CONCLUSIONS: This study describes the discovery and characterisation of a novel aminopeptidase A from the venom of B. g. rhinoceros and highlights its potential biological importance. Similar to mammalian aminopeptidases, rhiminopeptidase A might be capable of playing roles in altering the blood pressure and brain function of victims. Furthermore, it could have additional effects on the biological functions of other host proteins by cleaving their N terminal amino acids. This study points towards the importance of complete analysis of individual components of snake venom in order to develop effective therapies for snake bites. PMID- 20706585 TI - Virus-induced gene silencing as a tool for comparative functional studies in Thalictrum. AB - Perennial woodland herbs in the genus Thalictrum exhibit high diversity of floral morphology, including four breeding and two pollination systems. Their phylogenetic position, in the early-diverging eudicots, makes them especially suitable for exploring the evolution of floral traits and the fate of gene paralogs that may have shaped the radiation of the eudicots. A current limitation in evolution of plant development studies is the lack of genetic tools for conducting functional assays in key taxa spanning the angiosperm phylogeny. We first show that virus-induced gene silencing (VIGS) of a PHYTOENE DESATURASE ortholog (TdPDS) can be achieved in Thalictrum dioicum with an efficiency of 42% and a survival rate of 97%, using tobacco rattle virus (TRV) vectors. The photobleached leaf phenotype of silenced plants significantly correlates with the down-regulation of endogenous TdPDS (P<0.05), as compared to controls. Floral silencing of PDS was achieved in the faster flowering spring ephemeral T. thalictroides. In its close relative, T. clavatum, silencing of the floral MADS box gene AGAMOUS (AG) resulted in strong homeotic conversions of floral organs. In conclusion, we set forth our optimized protocol for VIGS by vacuum infiltration of Thalictrum seedlings or dormant tubers as a reference for the research community. The three species reported here span the range of floral morphologies and pollination syndromes present in Thalictrum. The evidence presented on floral silencing of orthologs of the marker gene PDS and the floral homeotic gene AG will enable a comparative approach to the study of the evolution of flower development in this group. PMID- 20706586 TI - Prophylactic efficacy of TcVac2 against Trypanosoma cruzi in mice. AB - BACKGROUND: Chagas disease is a major health problem in Latin America, and an emerging infectious disease in the US. Previously, we have screened the Trypanosoma cruzi sequence database by a computational/bioinformatics approach, and identified antigens that exhibited the characteristics of vaccine candidates. METHODOLOGY: We investigated the protective efficacy of a multi-component DNA prime/protein-boost vaccine (TcVac2) constituted of the selected candidates and cytokine (IL-12 and GM-CSF) expression plasmids in a murine model. C57BL/6 mice were immunized with antigen-encoding plasmids plus cytokine adjuvants, followed by recombinant proteins; and two-weeks later, challenged with T. cruzi trypomastigotes. ELISA and flow cytometry were employed to measure humoral (antibody isotypes) and cellular (lymphocyte proliferation, CD4(+) and CD8(+) T cell phenotype and cytokines) responses. Myocardial pathology was evaluated by H&E and Masson's trichrome staining. PRINCIPAL FINDINGS: TcVac2 induced a strong antigen-specific antibody response (IgG2b>IgG1) and a moderate level of lymphocyte proliferation in mice. Upon challenge infection, TcVac2-vaccinated mice expanded the IgG2b/IgG1 antibodies and elicited a substantial CD8(+) T cell response associated with type 1 cytokines (IFN-gamma and TNF-alpha) that resulted in control of acute parasite burden. During chronic phase, antibody response persisted, splenic activation of CD8(+) T cells and IFN-gamma/TNF-alpha cytokines subsided, and IL-4/IL-10 cytokines became dominant in vaccinated mice. The tissue parasitism, inflammation, and fibrosis in heart and skeletal muscle of TcVac2 vaccinated chronic mice were undetectable by histological techniques. In comparison, mice injected with vector or cytokines only responded to T. cruzi by elicitation of a mixed (type 1/type 2) antibody, T cell and cytokine response, and exhibited persistent parasite burden and immunopathology in the myocardium. CONCLUSION: TcVac2-induced activation of type 1 antibody and lymphocyte responses provided resistance to acute T. cruzi infection, and consequently, prevented the evolution of chronic immunopathology associated with parasite persistence in chagasic hearts. PMID- 20706587 TI - Characterization of major histocompatibility complex (MHC) DRB exon 2 and DRA exon 3 fragments in a primary terrestrial rabies vector (Procyon lotor). AB - The major histocompatibility complex (MHC) presents a unique system to explore links between genetic diversity and pathogens, as diversity within MHC is maintained in part by pathogen driven selection. While the majority of wildlife MHC studies have investigated species that are of conservation concern, here we characterize MHC variation in a common and broadly distributed species, the North American raccoon (Procyon lotor). Raccoons host an array of broadly distributed wildlife diseases (e.g., canine distemper, parvovirus and raccoon rabies virus) and present important human health risks as they persist in high densities and in close proximity to humans and livestock. To further explore how genetic variation influences the spread and maintenance of disease in raccoons we characterized a fragment of MHC class II DRA exon 3 (250 bp) and DRB exon 2 (228 bp). MHC DRA was found to be functionally monomorphic in the 32 individuals screened; whereas DRB exon 2 revealed 66 unique alleles among the 246 individuals screened. Between two and four alleles were observed in each individual suggesting we were amplifying a duplicated DRB locus. Nucleotide differences between DRB alleles ranged from 1 to 36 bp (0.4-15.8% divergence) and translated into 1 to 21 (1.3-27.6% divergence) amino acid differences. We detected a significant excess of nonsynonymous substitutions at the peptide binding region (P = 0.005), indicating that DRB exon 2 in raccoons has been influenced by positive selection. These data will form the basis of continued analyses into the spatial and temporal relationship of the raccoon rabies virus and the immunogenetic response in its primary host. PMID- 20706588 TI - The expression of vasoactive intestinal peptide receptor 1 is negatively modulated by microRNA 525-5p. AB - BACKGROUND: The human Vasoactive Intestinal Peptide (VIP) is a neurokine with effects on the immune system where it is involved in promoting tolerance. In this context, one of its receptors, VPAC1, has been found to be down-modulated in cells of the immune network in response to activating stimuli. In particular, the bacterial liposaccharide (LPS), a strong activator of the innate immune system, induces a rapid decrease of VPAC1 expression in monocytes and this event correlates with polymorphisms in the 3'-UTR of the gene. METHODOLOGY/PRINCIPAL FINDINGS: MicroRNA 525-5p, having as putative target the 3'-UTR region of VPAC1, has been analysed for its expression in monocytes and for its role in down modulating VPAC1 expression. We report here that miR-525-5p is promptly up regulated in LPS-treated monocytes. This microRNA, when co-transfected in 293T cells together with a construct containing the 3'-UTR of the VPAC1 gene, significantly reduced the luciferase activity in a standard expression assay. The U937 cell line as well as primary monocytes enforced to express miR-525-5p, both down-modulate VPAC1 expression at similar extent. CONCLUSIONS/SIGNIFICANCE: Our results show that the response to an inflammatory stimulus elicits in monocytes a rapid increase of miR-525-5p that targets a signaling pathway involved in the control of the immune homeostasis. PMID- 20706589 TI - Ketogenic essential amino acids modulate lipid synthetic pathways and prevent hepatic steatosis in mice. AB - BACKGROUND: Although dietary ketogenic essential amino acid (KAA) content modifies accumulation of hepatic lipids, the molecular interactions between KAAs and lipid metabolism are yet to be fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We designed a diet with a high ratio (E/N) of essential amino acids (EAAs) to non-EAAs by partially replacing dietary protein with 5 major free KAAs (Leu, Ile, Val, Lys and Thr) without altering carbohydrate and fat content. This high-KAA diet was assessed for its preventive effects on diet-induced hepatic steatosis and whole-animal insulin resistance. C57B6 mice were fed with a high fat diet, and hyperinsulinemic ob/ob mice were fed with a high-fat or high sucrose diet. The high-KAA diet improved hepatic steatosis with decreased de novo lipogenesis (DNL) fluxes as well as reduced expressions of lipogenic genes. In C57B6 mice, the high-KAA diet lowered postprandial insulin secretion and improved glucose tolerance, in association with restored expression of muscle insulin signaling proteins repressed by the high-fat diet. Lipotoxic metabolites and their synthetic fluxes were also evaluated with reference to insulin resistance. The high-KAA diet lowered muscle and liver ceramides, both by reducing dietary lipid incorporation into muscular ceramides and preventing incorporation of DNL derived fatty acids into hepatic ceramides. CONCLUSION: Our results indicate that dietary KAA intake improves hepatic steatosis and insulin resistance by modulating lipid synthetic pathways. PMID- 20706590 TI - Cost-effectiveness of "golden mustard" for treating vitamin A deficiency in India. AB - BACKGROUND: Vitamin A deficiency (VAD) is an important nutritional problem in India, resulting in an increased risk of severe morbidity and mortality. Periodic, high-dose vitamin A supplementation is the WHO-recommended method to prevent VAD, since a single dose can compensate for reduced dietary intake or increased need over a period of several months. However, in India only 34 percent of targeted children currently receive the two doses per year, and new strategies are urgently needed. METHODOLOGY: Recent advancements in biotechnology permit alternative strategies for increasing the vitamin A content of common foods. Mustard (Brassica juncea), which is consumed widely in the form of oil by VAD populations, can be genetically modified to express high levels of beta-carotene, a precursor to vitamin A. Using estimates for consumption, we compare predicted costs and benefits of genetically modified (GM) fortification of mustard seed with high-dose vitamin A supplementation and industrial fortification of mustard oil during processing to alleviate VAD by calculating the avertable health burden in terms of disability-adjusted life years (DALY). PRINCIPAL FINDINGS: We found that all three interventions potentially avert significant numbers of DALYs and deaths. Expanding vitamin A supplementation to all areas was the least costly intervention, at $23-$50 per DALY averted and $1,000-$6,100 per death averted, though cost-effectiveness varied with prevailing health subcenter coverage. GM fortification could avert 5 million-6 million more DALYs and 8,000-46,000 more deaths, mainly because it would benefit the entire population and not just children. However, the costs associated with GM fortification were nearly five times those of supplementation. Industrial fortification was dominated by both GM fortification and supplementation. The cost-effectiveness ratio of each intervention decreased with the prevalence of VAD and was sensitive to the efficacy rate of averted mortality. CONCLUSIONS: Although supplementation is the least costly intervention, our findings also indicate that GM fortification could reduce the VAD disease burden to a substantially greater degree because of its wider reach. Given the difficulties in expanding supplementation to areas without health subcenters, GM fortification of mustard seed is an attractive alternative, and further exploration of this technology is warranted. PMID- 20706591 TI - SAW: a method to identify splicing events from RNA-Seq data based on splicing fingerprints. AB - Splicing event identification is one of the most important issues in the comprehensive analysis of transcription profile. Recent development of next generation sequencing technology has generated an extensive profile of alternative splicing. However, while many of these splicing events are between exons that are relatively close on genome sequences, reads generated by RNA-Seq are not limited to alternative splicing between close exons but occur in virtually all splicing events. In this work, a novel method, SAW, was proposed for the identification of all splicing events based on short reads from RNA-Seq. It was observed that short reads not in known gene models are actually absent words from known gene sequences. An efficient method to filter and cluster these short reads by fingerprint fragments of splicing events without aligning short reads to genome sequences was developed. Additionally, the possible splicing sites were also determined without alignment against genome sequences. A consensus sequence was then generated for each short read cluster, which was then aligned to the genome sequences. Results demonstrated that this method could identify more than 90% of the known splicing events with a very low false discovery rate, as well as accurately identify, a number of novel splicing events between distant exons. PMID- 20706592 TI - A major role for mammals in the ecology of Mycobacterium ulcerans. AB - BACKGROUND: Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), a destructive skin disease found predominantly in sub-Saharan Africa and south eastern Australia. The precise mode(s) of transmission and environmental reservoir(s) remain unknown, but several studies have explored the role of aquatic invertebrate species. The purpose of this study was to investigate the environmental distribution of M. ulcerans in south-eastern Australia. METHODOLOGY/PRINCIPAL FINDINGS: A range of environmental samples was collected from Point Lonsdale (a small coastal town southwest of Melbourne, Australia, endemic for BU) and from areas with fewer or no reported incident cases of BU. Mycobacterium ulcerans DNA was detected at low levels by real-time PCR in soil, sediment, water residue, aquatic plant biofilm and terrestrial vegetation collected in Point Lonsdale. Higher levels of M. ulcerans DNA were detected in the faeces of common ringtail (Pseudocheirus peregrinus) and common brushtail (Trichosurus vulpecula) possums. Systematic testing of possum faeces revealed that M. ulcerans DNA could be detected in 41% of faecal samples collected in Point Lonsdale compared with less than 1% of faecal samples collected from non endemic areas (p<0.0001). Capture and clinical examination of live possums in Point Lonsdale validated the accuracy of the predictive value of the faecal surveys by revealing that 38% of ringtail possums and 24% of brushtail possums had laboratory-confirmed M. ulcerans skin lesions and/or M. ulcerans PCR positive faeces. Whole genome sequencing revealed an extremely close genetic relationship between human and possum M. ulcerans isolates. CONCLUSIONS/SIGNIFICANCE: The prevailing wisdom is that M. ulcerans is an aquatic pathogen and that BU is acquired by contact with certain aquatic environments (swamps, slow-flowing water). Now, after 70 years of research, we propose a transmission model for BU in which terrestrial mammals are implicated as reservoirs for M. ulcerans. PMID- 20706593 TI - The Mutyh base excision repair gene influences the inflammatory response in a mouse model of ulcerative colitis. AB - BACKGROUND: The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: The severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh(-/-) phenotype was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh(-/-) mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh(-/-) mice. Lymphoid hyperplasia and a significant reduction in Foxp3(+) regulatory T cells were observed only in Mutyh( /-) mice. CONCLUSIONS: The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response. PMID- 20706594 TI - Different oxidative stress response in keratinocytes and fibroblasts of reconstructed skin exposed to non extreme daily-ultraviolet radiation. AB - Experiments characterizing the biological effects of sun exposure have usually involved solar simulators. However, they addressed the worst case scenario i.e. zenithal sun, rarely found in common outdoor activities. A non-extreme ultraviolet radiation (UV) spectrum referred as "daily UV radiation" (DUVR) with a higher UVA (320-400 nm) to UVB (280-320 nm) irradiance ratio has therefore been defined. In this study, the biological impact of an acute exposure to low physiological doses of DUVR (corresponding to 10 and 20% of the dose received per day in Paris mid-April) on a 3 dimensional reconstructed skin model, was analysed. In such conditions, epidermal and dermal morphological alterations could only be detected after the highest dose of DUVR. We then focused on oxidative stress response induced by DUVR, by analyzing the modulation of mRNA level of 24 markers in parallel in fibroblasts and keratinocytes. DUVR significantly modulated mRNA levels of these markers in both cell types. A cell type differential response was noticed: it was faster in fibroblasts, with a majority of inductions and high levels of modulation in contrast to keratinocyte response. Our results thus revealed a higher sensitivity in response to oxidative stress of dermal fibroblasts although located deeper in the skin, giving new insights into the skin biological events occurring in everyday UV exposure. PMID- 20706596 TI - Small-Signal Performance and Modeling of sub-50nm nMOSFETs with f above 460-GHz. AB - We have fabricated and tested the performance of sub-50nm gate nMOSFETs to assess their suitability for mixed signal applications in the super high frequency (SHF) band, i.e. 3-30GHz. For a 30nm*40 MUm*2 device, we found f(T) =465GHz at V(ds)=2V, V(g)=0.67V, which is the highest cut-off frequency reported for a MOSFET produced on bulk silicon substrate so far. However, our measurements of f(max) and noise figure indicate that parasitics impose limitations on SHF operation. We also present a high-frequency ac model appropriate to sub-50nm gate length nanotransistors, which incorporates the effects of the parasitics. The model accurately accounts for measurements of the S and Y parameters in the frequency range from 1 to 50GHz. PMID- 20706595 TI - Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. I. Parasitological, hematological and pathological parameters. AB - African trypanosomiasis is a severe parasitic disease that affects both humans and livestock. Several different species may cause animal trypanosomosis and although Trypanosoma vivax (sub-genus Duttonella) is currently responsible for the vast majority of debilitating cases causing great economic hardship in West Africa and South America, little is known about its biology and interaction with its hosts. Relatively speaking, T. vivax has been more than neglected despite an urgent need to develop efficient control strategies. Some pioneering rodent models were developed to circumvent the difficulties of working with livestock, but disappointedly were for the most part discontinued decades ago. To gain more insight into the biology of T. vivax, its interactions with the host and consequently its pathogenesis, we have developed a number of reproducible murine models using a parasite isolate that is infectious for rodents. Firstly, we analyzed the parasitical characteristics of the infection using inbred and outbred mouse strains to compare the impact of host genetic background on the infection and on survival rates. Hematological studies showed that the infection gave rise to severe anemia, and histopathological investigations in various organs showed multifocal inflammatory infiltrates associated with extramedullary hematopoiesis in the liver, and cerebral edema. The models developed are consistent with field observations and pave the way for subsequent in-depth studies into the pathogenesis of T. vivax - trypanosomosis. PMID- 20706597 TI - UNSUSPECTED FATAL DRUG-RESISTANT TUBERCULOSIS IN A CLOSELY MONITORED CHILD: A PLEA FOR IMPROVED SOURCE-CASE TRACING AND DRUG SUSCEPTIBILITY TESTING. AB - We report a case of rapidly progressive miliary tuberculosis in a 21-month old HIV-infected girl exposed to tuberculosis, despite early access to highly active antiretroviral therapy and proven adherence to isoniazid chemoprophylaxis. Post mortem revealed multidrug-resistant tuberculosis. This case report illustrates the consequences of inadequate programmatic management of children exposed to an adult case of sputum smear-positive multidrug-resistant tuberculosis. Drug susceptibility testing of the adult source case should become standard of care for all children who have been in close contact with a case of sputum smear positive tuberculosis, and the choice of chemoprophylactic agents should be based on the sensitivities of the source case organism. PMID- 20706598 TI - LIPODYSTROPHY SYNDROME IN HIV-INFECTED CHILDREN ON HAART. AB - Lipodystrophy syndrome (LD) is common in HIV-infected children, particularly those taking didanosine, stavudine or zidovudine. Lipo-atrophy in particular causes major stigmatisation and interferes with adherence. In addition, LD may have significant long-term health consequences, particularly cardiovascular. Since the stigmatising fat distribution changes of LD are largely permanent, the focus of management remains on early detection and arresting progression. Practical guidelines for surveillance and avoidance of LD in routine clinical practice are presented. The diagnosis of LD is described and therapeutic options are reviewed. The most important therapeutic intervention is to switch the most likely offending antiretroviral to a non-LD-inducing agent as soon as LD is recognised. Typically, when lipoatrophy or lipohypertrophy is diagnosed the thymidine nucleoside reverse transcriptase inhibitor (NRTI) is switched to a non thymidine agent such as abacavir (or tenofovir in adults). Where dyslipidaemia is predominant, a dietician review is helpful, and the clinician may consider switching to a protease inhibitor-sparing regimen or to atazanavir. PMID- 20706599 TI - Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining. AB - In mammalian cells, DNA double-strand breaks (DSBs) are primarily repaired by nonhomologous end joining (NHEJ). The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PK(cs) to form the active DNA dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that mediate DSB end joining. However, recent studies show that additional DNA-PK-independent NHEJ pathways also exist. Unfortunately, the presence of DNA-PK(cs) appears to inhibit DNA-PK-independent NHEJ, and in vitro analysis of DNA-PK-independent NHEJ in the presence of the DNA-PK(cs) protein remains problematic. We have developed an in vitro assay that is preferentially active for DNA-PK-independent DSB repair based solely on its reaction conditions, facilitating coincident differential biochemical analysis of the two pathways. The results indicate the biochemically distinct nature of the end-joining mechanisms represented by the DNA-PK-dependent and -independent NHEJ assays as well as functional differences between the two pathways. PMID- 20706600 TI - Transport vesicle uncoating: it's later than you think. AB - Transport vesicle coat proteins play active roles in vesicle cargo sorting as well as membrane deformation and fission during vesicle biogenesis. For years, it was assumed that this was the extent of the coats' function and that the coats depolymerized immediately after vesicle budding, leaving the exposed fusion machinery free to find, dock, and fuse with the proper target membrane. Recently, however, it has become increasingly clear that the coat remains on transport vesicles during their post-budding life and in fact helps properly pair up the vesicle with its intended target membrane. These data have brought up urgent questions about exactly when vesicles do uncoat and how uncoating is regulated. Here, we summarize the latest round of evidence for post-budding roles for coats, including a few hints about how the uncoating process may be coupled to docking and fusion. We also speculate about the possibility of post-fusion functions for residual coats. PMID- 20706601 TI - Response to letter to the editor E08-5236A. PMID- 20706602 TI - Narrating September 11: Race, Gender, and the Play of Cultural Identities. AB - This article considers the September 11 tragedy as an event that has created a powerful experience-an astonishing and unthinkable "breach" from the expected and routine-that has riveted the American public and provoked personal storytelling. September 11 and its aftermath have provided an occasion for rethinking and reworking cultural identity. We explore how September 11 and subsequent events have been experienced, constructed, and narrated by African American women, primarily from working-class and low-income backgrounds. These stories, and the commentaries and discussions that surround them, provide vehicles for these women to ponder what sort of social contexts they inhabit, within what sort of subject positions they are placed, and how these may be shifting in light of the attacks and America's "War on Terrorism. PMID- 20706603 TI - TREATING DEPRESSION IN PATIENTS WITH HEART DISEASE: Is the Glass Half Empty or Half Full? PMID- 20706606 TI - Evaluation of the Antimicrobial Properties of the Essential Oil of Myrtus communis L. against Clinical Strains of Mycobacterium spp. AB - Mycobacterium tuberculosis is the etiological agent of tuberculosis. The World Health Organization has estimated that 8 million of people develop active TB every year and the situation is complicated by an increase of Mycobacterium tuberculosis strains resistant to drugs used in antitubercular therapy: MDR and XDR-TB. Myrtle leaf extracts, used as an antiseptic in Sardinian traditional medicine, have strong antibacterial activity as several investigations showed. In this study we investigated the antimicrobial properties of the essential oil of Myrtus communis against clinical strains of M. tuberculosis and M. paratuberculosis. PMID- 20706604 TI - Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. AB - Human fatty acid synthase (FASN) is a 270-kDa cytosolic dimeric enzyme that is responsible for palmitate synthesis. FASN is slowly emerging and rediscovered as a marker for diagnosis and prognosis of human cancers. Recent studies showed that FASN is an oncogene and inhibition of FASN effectively and selectively kill cancer cells. With recent publications of the FASN crystal structure and the new development of FASN inhibitors, targeting FASN opens a new window of opportunity for metabolically combating cancers. In this article, we will review critically the recent progresses in understanding the structure, function, and the role of FASN in cancers and pharmacologically targeting FASN for human cancer treatment. PMID- 20706607 TI - Acute, multiple-dose dermal and genetic toxicity of Nu-3: a novel antimicrobial agent. AB - Nu-3 [butyl-phosphate-5'-thymidine-3'-phosphate-butyl] is a modified nucleotide that has been shown to have antimicrobial activity against a range of bacteria including Pseudomonas aeruginosa. However, data on the toxicological profile of Nu-3 are still lacking. In the present study, the toxicity of Nu-3 was evaluated by the following studies: acute oral toxicity, dermal and mucous membrane irritation, multiple-dose toxicity and genotoxicity in vivo and vitro. The acute oral toxicity test in mice showed that Nu-3 had an LD(50) of 2001 mg/kg body weight. The irritation tests on rats revealed that Nu-3 was not irritant, with an irritation scoring of 0. The multiple-dose toxicity study in rats showed that Nu 3 did not cause significant changes in histology, selected serum chemistry, and hematological parameters compared to the controls. Rats administrated with multiple-doses of Nu-3 showed no visible toxic symptoms. Both in vitro and in vivo, Nu-3 exhibited no notable genetic toxicity. Overall, the data suggest that Nu-3 is hypotoxic or nontoxic antimicrobial compound that warrants being further developed for treating Pseudomonas aeruginosa infection. PMID- 20706605 TI - Lipid disturbances in psoriasis: an update. AB - Psoriasis is a common disease with the population prevalence ranging from 2% to 3%. Its prevalence in the population is affected by genetic, environmental, viral, infectious, immunological, biochemical, endocrinological, and psychological factors, as well as alcohol and drug abuse. In the recent years, psoriasis has been recognised as a systemic disease associated with numerous multiorgan abnormalities and complications. Dyslipidemia is one of comorbidities in psoriatic patients. Lipid metabolism studies in psoriasis have been started at the beginning of the 20th century and are concentrated on skin surface lipids, stratum corneum lipids and epidermal phospholipids, serum lipids, dermal low density lipoproteins in the psoriatic skin, lipid metabolism, oxidative stress and correlations between inflammatory parameters, lipid parameters and clinical symptoms of the disease. On the basis of the literature data, psoriasis can be described as an immunometabolic disease. PMID- 20706609 TI - Optimal fluxes, reaction replaceability, and response to enzymopathies in the human red blood cell. AB - Characterizing the capabilities, key dependencies, and response to perturbations of genome-scale metabolic networks is a basic problem with important applications. A key question concerns the identification of the potentially most harmful reaction knockouts. The integration of combinatorial methods with sampling techniques to explore the space of viable flux states may provide crucial insights on this issue. We assess the replaceability of every metabolic conversion in the human red blood cell by enumerating the alternative paths from substrate to product, obtaining a complete map of he potential damage of single enzymopathies. Sampling the space of optimal steady state fluxes in the healthy and in the mutated cell reveals both correlations and complementarity between topologic and dynamical aspects. PMID- 20706610 TI - Computational method for estimating DNA copy numbers in normal samples, cancer cell lines, and solid tumors using array comparative genomic hybridization. AB - Genomic copy number variations are a typical feature of cancer. These variations may influence cancer outcomes as well as effectiveness of treatment. There are many computational methods developed to detect regions with deletions and amplifications without estimating actual copy numbers (CN) in these regions. We have developed a computational method capable of detecting regions with deletions and amplifications as well as estimating actual copy numbers in these regions. The method is based on determining how signal intensity from different probes is related to CN, taking into account changes in the total genome size, and incorporating into analysis contamination of the solid tumors with benign tissue. Hidden Markov Model is used to obtain the most likely CN solution. The method has been implemented for Affymetrix 500K GeneChip arrays and Agilent 244K oligonucleotide arrays. The results of CN analysis for normal cell lines, cancer cell lines, and tumor samples are presented. The method is capable of detecting copy number alterations in tumor samples with up to 80% contamination with benign tissue. Analysis of 178 cancer cell lines reveals multiple regions of common homozygous deletions and strong amplifications encompassing known tumor suppressor genes and oncogenes as well as novel cancer related genes. PMID- 20706608 TI - The role of genetic variation near interferon-kappa in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin. PMID- 20706611 TI - Dual effect of neutrophils on pIgR/secretory component in human bronchial epithelial cells: role of TGF-beta. AB - Neutrophils have a dual affect on epithelial pIgR/SC, the critical receptor for transcellular routing of mucosal IgA, but mechanisms of pIgR/SC upregulation remain elusive. Requirements of cytokine, redox, and signalling pathways for pIgR/SC production were assessed in human bronchial epithelial (Calu-3) cells cocultured with increasing numbers of blood neutrophils. Increased SC production was observed after incubation for 48 hrs with intermediate neutrophil numbers (1.25 to 2.5 x 10(6)), was favoured by the elastase inhibitor SLPI, and correlated with increased TGF-beta production. Exogenous TGF-beta stimulated SC production with a maximal effect at 48 hrs and both TGF-beta- and neutrophil driven SC upregulation were dependent on redox balance and p38 MAP-kinase activation. This paper shows that activated neutrophils could upregulate epithelial pIgR/SC production through TGF-beta-mediated activation of a redox sensitive and p38 MAPK-dependent pathway. An imbalance between the two neutrophil driven opposite mechanisms (SC upregulation and SC degradation) could lead to downregulation of pIgR/SC, as observed in severe COPD. PMID- 20706612 TI - Strategies for cancer vaccine development. AB - Treating cancer with vaccines has been a challenging field of investigation since the 1950s. Over the years, the lack of effective active immunotherapies has led to the development of numerous novel strategies. However, the use of therapeutic cancer vaccines may be on the verge of becoming an effective modality. Recent phase II/III clinical trials have achieved hopeful results in terms of overall survival. Yet despite these encouraging successes, in general, very little is known about the basic immunological mechanisms involved in vaccine immunotherapy. Gaining a better understanding of the mechanisms that govern the specific immune responses (i.e., cytotoxic T lymphocytes, CD4 T helper cells, T regulatory cells, cells of innate immunity, tumor escape mechanisms) elicited by each of the various vaccine platforms should be a concern of cancer vaccine clinical trials, along with clinical benefits. This review focuses on current strategies employed by recent clinical trials of therapeutic cancer vaccines and analyzes them both clinically and immunologically. PMID- 20706613 TI - A method for individualizing the prediction of immunogenicity of protein vaccines and biologic therapeutics: individualized T cell epitope measure (iTEM). AB - The promise of pharmacogenomics depends on advancing predictive medicine. To address this need in the area of immunology, we developed the individualized T cell epitope measure (iTEM) tool to estimate an individual's T cell response to a protein antigen based on HLA binding predictions. In this study, we validated prospective iTEM predictions using data from in vitro and in vivo studies. We used a mathematical formula that converts DRB1* allele binding predictions generated by EpiMatrix, an epitope-mapping tool, into an allele-specific scoring system. We then demonstrated that iTEM can be used to define an HLA binding threshold above which immune response is likely and below which immune response is likely to be absent. iTEM's predictive power was strongest when the immune response is focused, such as in subunit vaccination and administration of protein therapeutics. iTEM may be a useful tool for clinical trial design and preclinical evaluation of vaccines and protein therapeutics. PMID- 20706614 TI - The Formation and Stability of Alkylthiol Monolayers on Carbon Substrates. AB - The formation and stability of alkylthiol monolayers on amorphous carbon thin films are investigated. Alkylthiol monolayers were prepared via a two-step, wet chemical process in which the carbon surface was first halogenated and then incubated with (4-(trifluoromethyl)phenyl)methanethiol (4tBM). The 4tBM covalently attaches to the surface in a substitution reaction in which the 4tBM thiol replaces the surface halogen. Studies of the substitution mechanism showed that monolayer formation is affected by the nature of the surface-bound halogen as well as the concentration and nucleophilicity of the 4tBM sulfur atom, consistent with a bimolecular (S(N)2) substitution reaction mechanism. The alkylthiol monolayers are stable over a wide range of solvent, pH, and temperature conditions. PMID- 20706615 TI - Chemical signal amplification in two-dimensional paper networks. AB - Two-dimensional paper networks (2DPNs) hold great potential for extending the utility of paper-based chemical and biochemical diagnostics at a cost and ease-of use that is comparable to conventional lateral flow strips. 2DPNs enable the automated sequential delivery of multiple reagents to a detection region with a single user activation step, and therefore have the potential to extend the processing capabilities of inexpensive paper-based assays with comparable ease of use to conventional lateral flow tests. In this communication, we used a simple 3 inlet 2DPN to perform signal amplification of a colloidal gold label using a gold enhancement solution, thus demonstrating the capability of 2DPNs to perform processes that can improve limits of detection. PMID- 20706616 TI - Two step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines. AB - A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6 quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide. PMID- 20706617 TI - Towards A Fully Automated High-Throughput Phototransfection System. AB - We have designed and implemented a framework for creating a fully automated high throughput phototransfection system. Integrated image processing, laser target position calculation, and stage movements show a throughput increase of > 23X over the current manual phototransfection method while the potential for even greater throughput improvements (> 110X) is described. A software tool for automated off-line single cell morphological measurements, as well as real-time image segmentation analysis, has also been constructed and shown to be able quantify changes in the cell before and after the process, successfully characterizing them, using metrics such as cell perimeter, area, major and minor axis length, and eccentricity values. PMID- 20706618 TI - A Wafer-Scale Etching Technique for High Aspect Ratio Implantable MEMS Structures. AB - Microsystem technology is well suited to batch fabricate microelectrode arrays, such as the Utah electrode array (UEA), intended for recording and stimulating neural tissue. Fabrication of the UEA is primarily based on the use of dicing and wet etching to achieve high aspect ratio (15:1) penetrating electrodes. An important step in the array fabrication is the etching of electrodes to produce needle-shape electrodes with sharp tips. Traditional etching processes are performed on a single array, and the etching conditions are not optimized. As a result, the process leads to variable geometries of electrodes within an array. Furthermore, the process is not only time consuming but also labor-intensive. This report presents a wafer-scale etching method for the UEA. The method offers several advantages, such as substantial reduction in the processing time, higher throughput and lower cost. More importantly, the method increases the geometrical uniformity from electrode to electrode within an array (1.5 +/- 0.5 % non uniformity), and from array to array within a wafer (2 +/- 0.3 % non-uniformity). Also, the etching rate of silicon columns, produced by dicing, are studied as a function of temperature, etching time and stirring rate in a nitric acid rich HF HNO(3) solution. These parameters were found to be related to the etching rates over the ranges studied and more-importantly affect the uniformity of the etched silicon columns. An optimum etching condition was established to achieve uniform shape electrode arrays on wafer-scale. PMID- 20706619 TI - Rough set soft computing cancer classification and network: one stone, two birds. AB - Gene expression profiling provides tremendous information to help unravel the complexity of cancer. The selection of the most informative genes from huge noise for cancer classification has taken centre stage, along with predicting the function of such identified genes and the construction of direct gene regulatory networks at different system levels with a tuneable parameter. A new study by Wang and Gotoh described a novel Variable Precision Rough Sets-rooted robust soft computing method to successfully address these problems and has yielded some new insights. The significance of this progress and its perspectives will be discussed in this article. PMID- 20706620 TI - Clinical omics analysis of colorectal cancer incorporating copy number aberrations and gene expression data. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC) and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an "omics" study by integrating many kinds of analysis into a single comprehensive investigation. In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers. Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC. This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC. MATERIALS AND METHODS: Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language. RESULT: We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene expression analysis, together with the clinical information, suggested UGT2B28, LOC440995, CXCL6, SULT1B1, RALBP1, TYMS, RAB12, RNMT, ARHGDIB, S1000A2, ABHD2, OIT3 and ABHD12 as genes that are possibly associated with CRC. Some of these genes have already been reported as being related to CRC. TYMS has been reported as being associated with resistance to the anti-cancer drug 5 fluorouracil, and we observed a copy number increase for this gene. RALBP1, ARHGDIB and S100A2 have been reported as oncogenes, and we observed copy number increases in each. ARHGDIB has been reported as a metastasis-related gene, and our data also showed copy number increases of this gene in cases with metastasis. CONCLUSION: The combination of CNA analysis and gene expression analysis was a more effective method for finding genes associated with the clinicopathological classification of CRC than either analysis alone. Using this combination of methods, we were able to detect genes that have already been associated with CRC. We also identified additional candidate genes that may be new markers or targets for this form of cancer. PMID- 20706621 TI - A picture of the healthful food environment in two diverse urban cities. AB - BACKGROUND: Local food environments influence fresh produce purchase and consumption, and previous research has found disparities in local food environments by income and ethnicity. Other existing studies have begun to quantify the distribution of food sources, but there has been limited attention to important features or types of healthful food that are available or their quality or cost. Two studies assessed the type, quantity, quality and cost of healthful food from two diverse urban cities, Kansas City, Kansas and Missouri and Honolulu, Hawaii, and evaluated differences by neighborhood income and ethnic composition. METHOD: A total of 343 food stores in urban neighborhoods were assessed using the one-page Understanding Neighborhood Determinants of Obesity (UNDO) Food Stores Assessment (FSA) measuring healthful foods. US Census data were used to define median household income and ethnic minority concentration. RESULTS: In Study 1, most low socioeconomic status (SES), high ethnic minority neighborhoods had primarily convenience, liquor or small grocery stores. Quality of produce was typically lower, and prices of some foods were more than in comparison neighborhoods. In Study 2, low SES neighborhoods had more convenience and grocery stores. Farmers' markets and supermarkets had the best produce availability and quality, and farmers' markets and pharmacies had the lowest prices. CONCLUSIONS: Messages emphasizing eating more fruits and vegetables are not realistic in urban, low SES, high ethnic concentration neighborhoods. Farmers' markets and supermarkets provided the best opportunities for fresh produce. Increasing access to farmers' markets and supermarkets or reducing prices could improve the local food environment. PMID- 20706622 TI - QSPR Modeling of Bioconcentration Factors of Nonionic Organic Compounds. AB - The terms bioaccumulation and bioconcentration refer to the uptake and build-up of chemicals that can occur in living organisms. Experimental measurement of bioconcentration is time-consuming and expensive, and is not feasible for a large number of chemicals of potential regulatory concern. A highly effective tool depending on a quantitative structure-property relationship (QSPR) can be utilized to describe the tendency of chemical concentration organisms represented by, the important ecotoxicological parameter, the logarithm of Bio Concentration Factor (log BCF) with molecular descriptors for a large set of non-ionic organic compounds. QSPR models were developed using multiple linear regression, partial least squares and neural networks analyses. Linear and non-linear QSPR models to predict log BCF of the compounds developed for the relevant descriptors. The results obtained offer good regression models having good prediction ability. The descriptors used in these models depend on the volume, connectivity, molar refractivity, surface tension and the presence of atoms accepting H-bonds. PMID- 20706623 TI - Purification and characterization of a sperm motility inhibiting factor from caprine epididymal plasma. AB - Several studies have been reported on the occurrence of sperm motility inhibiting factors in the male reproductive fluids of different mammalian species, but these proteins have not been adequately purified and characterized. A novel sperm motility inhibiting factor (MIF-II) has been purified from caprine epididymal plasma (EP) by Hydroxylapatite gel adsorption chromatography, DEAE-Cellulose ion exchange chromatography and chromatofocusing. The MIF-II has been purified to apparent homogeneity and the molecular weight estimated by Sephacryl S-300 gel filtration is 160 kDa. MIF-II is a dimeric protein, made up of two subunits each having a molecular mass of 80 kDa as shown by SDS-PAGE. The isoelectric point of MIF-II is 5.1 as determined by chromatofocusing and isoelectric focusing. It is a heat labile protein and maximal active at the pH 6.9 to 7.5. The sperm motility inhibiting protein factor at 2 microg/ml (12.5 nM) level showed maximal motility inhibiting activity. The observation that the epididymal plasma factor lowered the intracellular cAMP level of spermatozoa in a concentration-dependent manner suggests that it may block the motility of caprine cauda spermatozoa by interfering the cAMP dependent motility function. The results revealed that the purified protein factor has the potential of sperm motility inhibition and may serve as a vaginal contraceptive. The antibody raised against the MIF-II has the potential for enhancement of forward motility of cauda-spermatozoa. This antibody may thus be useful for solving some of the problems of male infertility due to low sperm motility. PMID- 20706624 TI - Targeted Therapy Database (TTD): a model to match patient's molecular profile with current knowledge on cancer biology. AB - BACKGROUND: The efficacy of current anticancer treatments is far from satisfactory and many patients still die of their disease. A general agreement exists on the urgency of developing molecularly targeted therapies, although their implementation in the clinical setting is in its infancy. In fact, despite the wealth of preclinical studies addressing these issues, the difficulty of testing each targeted therapy hypothesis in the clinical arena represents an intrinsic obstacle. As a consequence, we are witnessing a paradoxical situation where most hypotheses about the molecular and cellular biology of cancer remain clinically untested and therefore do not translate into a therapeutic benefit for patients. OBJECTIVE: To present a computational method aimed to comprehensively exploit the scientific knowledge in order to foster the development of personalized cancer treatment by matching the patient's molecular profile with the available evidence on targeted therapy. METHODS: To this aim we focused on melanoma, an increasingly diagnosed malignancy for which the need for novel therapeutic approaches is paradigmatic since no effective treatment is available in the advanced setting. Relevant data were manually extracted from peer-reviewed full-text original articles describing any type of anti-melanoma targeted therapy tested in any type of experimental or clinical model. To this purpose, Medline, Embase, Cancerlit and the Cochrane databases were searched. RESULTS AND CONCLUSIONS: We created a manually annotated database (Targeted Therapy Database, TTD) where the relevant data are gathered in a formal representation that can be computationally analyzed. Dedicated algorithms were set up for the identification of the prevalent therapeutic hypotheses based on the available evidence and for ranking treatments based on the molecular profile of individual patients. In this essay we describe the principles and computational algorithms of an original method developed to fully exploit the available knowledge on cancer biology with the ultimate goal of fruitfully driving both preclinical and clinical research on anticancer targeted therapy. In the light of its theoretical nature, the prediction performance of this model must be validated before it can be implemented in the clinical setting. PMID- 20706625 TI - The Echinococcus granulosus antigen B gene family comprises at least 10 unique genes in five subclasses which are differentially expressed. AB - BACKGROUND: Antigen B (EgAgB) is a major protein produced by the metacestode cyst of Echinococcus granulosus, the causative agent of cystic hydatid disease. This protein has been shown to play an important role in modulating host immune responses, although its precise biological function still remains unknown. It is generally accepted that EgAgB is comprised of a gene family of five subfamilies which are highly polymorphic, but the actual number of genes present is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Based on published sequences for the family, we designed specific primers for each subfamily and used PCR to amplify them from genomic DNA isolated from individual mature adult worms (MAW) taken from an experimentally infected dog in China and individual larval protoscoleces (PSC) excised from a single hydatid cyst taken from an Australian kangaroo. We then used real-time PCR to measure expression of each of the genes comprising the five EgAgB subfamilies in all life-cycle stages including the oncosphere (ONC). CONCLUSIONS/SIGNIFICANCE: Based on sequence alignment analysis, we found that the EgAgB gene family comprises at least ten unique genes. Each of the genes was identical in both larval and adult E. granulosus isolates collected from two geographical areas (different continents). DNA alignment comparisons with EgAgB sequences deposited in GenBank databases showed that each gene in the gene family is highly conserved within E. granulosus, which contradicts previous studies claiming significant variation and polymorphism in EgAgB. Quantitative PCR analysis revealed that the genes were differentially expressed in different life cycle stages of E. granulosus with EgAgB3 expressed predominantly in all stages. These findings are fundamental for determining the expression and the biological function of antigen B. PMID- 20706626 TI - A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. AB - BACKGROUND: There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro. METHODS AND FINDINGS: A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting. CONCLUSIONS: CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue. TRIAL REGISTRATION: Current Controlled Trials number ISRCTN38002730. PMID- 20706627 TI - A nuclear family A DNA polymerase from Entamoeba histolytica bypasses thymine glycol. AB - BACKGROUND: Eukaryotic family A DNA polymerases are involved in mitochondrial DNA replication or translesion DNA synthesis. Here, we present evidence that the sole family A DNA polymerase from the parasite protozoan E. histolytica (EhDNApolA) localizes to the nucleus and that its biochemical properties indicate that this DNA polymerase may be involved in translesion DNA synthesis. METHODOLOGY AND RESULTS: EhDNApolA is the sole family A DNA polymerase in E. histolytica. An in silico analysis places family A DNA polymerases from the genus Entamoeba in a separate branch of a family A DNA polymerases phylogenetic tree. Biochemical studies of a purified recombinant EhDNApolA demonstrated that this polymerase is active in primer elongation, is poorly processive, displays moderate strand displacement, and does not contain 3'-5' exonuclease or editing activity. Importantly, EhDNApolA bypasses thymine glycol lesions with high fidelity, and confocal microscopy demonstrates that this polymerase is translocated into the nucleus. These data suggest a putative role of EhDNApolA in translesion DNA synthesis in E. histolytica. CONCLUSION: This is the first report of the biochemical characterization of a DNA polymerase from E. histolytica. EhDNApolA is a family A DNA polymerase that is grouped into a new subfamily of DNA polymerases with translesion DNA synthesis capabilities similar to DNA polymerases from subfamily nu. PMID- 20706629 TI - Spatiotemporal trends and climatic factors of hemorrhagic fever with renal syndrome epidemic in Shandong Province, China. AB - BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by Hantaviruses. It is endemic in all 31 provinces, autonomous regions, and metropolitan areas in mainland China where human cases account for 90% of the total global cases. Shandong Province is among the most serious endemic areas. HFRS cases in Shandong Province were first reported in Yutai County in 1968. Since then, the disease has spread across the province, and as of 2005, all 111 counties were reported to have local human infections. However, causes underlying such rapid spread and wide distribution remain less well understood. METHODS AND FINDINGS: Here we report a spatiotemporal analysis of human HFRS cases in Shandong using data spanning 1973 to 2005. Seasonal incidence maps and velocity vector maps were produced to analyze the spread of HFRS over time in Shandong Province, and a panel data analysis was conducted to explore the association between HFRS incidence and climatic factors. Results show a rapid spread of HFRS from its epicenter in Rizhao, Linyi, Weifang Regions in southern Shandong to north, east, and west parts of the province. Based on seasonal shifts of epidemics, three epidemic phases were identified over the 33-year period. The first phase occurred between 1973 and 1982 during which the foci of HFRS was located in the south Shandong and the epidemic peak occurred in the fall and winter, presenting a seasonal characteristic of Hantaan virus (HTNV) transmission. The second phase between 1983 and 1985 was characterized by northward and westward spread of HFRS foci, and increases in incidence of HFRS in both fall-winter and spring seasons. The human infections in the spring reflected a characteristic pattern of Seoul virus (SEOV) transmission. The third phase between 1986 and 2005 was characterized by the northeast spread of the HFRS foci until it covered all counties, and the HFRS incidence in the fall-winter season decreased while it remained high in the spring. In addition, our findings suggest that precipitation, humidity, and temperature are major environmental variables that are associated with the seasonal variation of HFRS incidence in Shandong Province. CONCLUSIONS: The spread of HFRS in Shandong Province may have been accompanied by seasonal shifts of HTNV-dominated transmission to SEOV-dominated transmission over the past three decades. The variations in HFRS incidence were significantly associated with local precipitation, humidity, and temperature. PMID- 20706630 TI - FMRFamide-like peptides (FLPs) enhance voltage-gated calcium currents to elicit muscle contraction in the human parasite Schistosoma mansoni. AB - Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca(2+) influx through sarcolemmal voltage operated Ca(2+) channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 microM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31-8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 microM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca(2+) influx through VOCC currents using a PKC-dependent pathway. PMID- 20706628 TI - Arboviral etiologies of acute febrile illnesses in Western South America, 2000 2007. AB - BACKGROUND: Arthropod-borne viruses (arboviruses) are among the most common agents of human febrile illness worldwide and the most important emerging pathogens, causing multiple notable epidemics of human disease over recent decades. Despite the public health relevance, little is know about the geographic distribution, relative impact, and risk factors for arbovirus infection in many regions of the world. Our objectives were to describe the arboviruses associated with acute undifferentiated febrile illness in participating clinics in four countries in South America and to provide detailed epidemiological analysis of arbovirus infection in Iquitos, Peru, where more extensive monitoring was conducted. METHODOLOGY/FINDINGS: A clinic-based syndromic surveillance system was implemented in 13 locations in Ecuador, Peru, Bolivia, and Paraguay. Serum samples and demographic information were collected from febrile participants reporting to local health clinics or hospitals. Acute-phase sera were tested for viral infection by immunofluorescence assay or RT-PCR, while acute- and convalescent-phase sera were tested for pathogen-specific IgM by ELISA. Between May 2000 and December 2007, 20,880 participants were included in the study, with evidence for recent arbovirus infection detected for 6,793 (32.5%). Dengue viruses (Flavivirus) were the most common arbovirus infections, totaling 26.0% of febrile episodes, with DENV-3 as the most common serotype. Alphavirus (Venezuelan equine encephalitis virus [VEEV] and Mayaro virus [MAYV]) and Orthobunyavirus (Oropouche virus [OROV], Group C viruses, and Guaroa virus) infections were both observed in approximately 3% of febrile episodes. In Iquitos, risk factors for VEEV and MAYV infection included being male and reporting to a rural (vs urban) clinic. In contrast, OROV infection was similar between sexes and type of clinic. CONCLUSIONS/SIGNIFICANCE: Our data provide a better understanding of the geographic range of arboviruses in South America and highlight the diversity of pathogens in circulation. These arboviruses are currently significant causes of human illness in endemic regions but also have potential for further expansion. Our data provide a basis for analyzing changes in their ecology and epidemiology. PMID- 20706631 TI - Gene expression programs of mouse endothelial cells in kidney development and disease. AB - Endothelial cells are remarkably heterogeneous in both morphology and function, and they play critical roles in the formation of multiple organ systems. In addition endothelial cell dysfunction can contribute to disease processes, including diabetic nephropathy, which is a leading cause of end stage renal disease. In this report we define the comprehensive gene expression programs of multiple types of kidney endothelial cells, and analyze the differences that distinguish them. Endothelial cells were purified from Tie2-GFP mice by cell dissociation and fluorescent activated cell sorting. Microarrays were then used to provide a global, quantitative and sensitive measure of gene expression levels. We examined renal endothelial cells from the embryo and from the adult glomerulus, cortex and medulla compartments, as well as the glomerular endothelial cells of the db/db mutant mouse, which represents a model for human diabetic nephropathy. The results identified the growth factors, receptors and transcription factors expressed by these multiple endothelial cell types. Biological processes and molecular pathways were characterized in exquisite detail. Cell type specific gene expression patterns were defined, finding novel molecular markers and providing a better understanding of compartmental distinctions. Further, analysis of enriched, evolutionarily conserved transcription factor binding sites in the promoters of co-activated genes begins to define the genetic regulatory network of renal endothelial cell formation. Finally, the gene expression differences associated with diabetic nephropathy were defined, providing a global view of both the pathogenic and protective pathways activated. These studies provide a rich resource to facilitate further investigations of endothelial cell functions in kidney development, adult compartments, and disease. PMID- 20706632 TI - Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity. AB - BACKGROUND: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). METHODS: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. RESULTS: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. CONCLUSIONS: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000886. PMID- 20706633 TI - Podocalyxin is a novel polysialylated neural adhesion protein with multiple roles in neural development and synapse formation. AB - Neural development and plasticity are regulated by neural adhesion proteins, including the polysialylated form of NCAM (PSA-NCAM). Podocalyxin (PC) is a renal PSA-containing protein that has been reported to function as an anti-adhesin in kidney podocytes. Here we show that PC is widely expressed in neurons during neural development. Neural PC interacts with the ERM protein family, and with NHERF1/2 and RhoA/G. Experiments in vitro and phenotypic analyses of podxl deficient mice indicate that PC is involved in neurite growth, branching and axonal fasciculation, and that PC loss-of-function reduces the number of synapses in the CNS and in the neuromuscular system. We also show that whereas some of the brain PC functions require PSA, others depend on PC per se. Our results show that PC, the second highly sialylated neural adhesion protein, plays multiple roles in neural development. PMID- 20706636 TI - Late simultaneous metastasis of renal cell carcinoma to the submandibular and thyroid glands seven years after radical nephrectomy. AB - Background. Renal cell carcinoma (RCC) metastasis to the salivary glands is extremely rare. Most cases reported previously have involved the parotid gland and only six cases involving the submandibular gland exist in the current literature. Metastasis of RCC to thyroid gland is also rare but appears to be more common than to salivary glands. Methods and Results. We present the first case of simultaneous metastasis to the submandibular and thyroid glands from clear cell RCC in a 61-year-old woman who presented seven years after the primary treatment. The submandibular and thyroid glands were excised completely with preservation of the marginal mandibular and recurrent laryngeal nerves, respectively. Conclusion. Metastatic disease should always be considered in the differential diagnosis for patients who present with painless salivary or thyroid gland swelling with a previous history of RCC. If metastatic disease is confined only to these glands, prompt surgical excision can be curative. PMID- 20706635 TI - Human genetics of diabetic retinopathy: current perspectives. AB - Diabetic retinopathy (DR) is a most severe microvascular complication which, if left unchecked, can be sight-threatening. With the global prevalence of diabetes being relentlessly projected to rise to 438 million subjects by 2030, DR will undoubtedly pose a major public health concern. Efforts to unravel the human genetics of DR have been undertaken using the candidate gene and linkage approaches, while GWAS efforts are still lacking. Aside from evidence for a few genes including aldose reductase and vascular endothelial growth factor, the genetics of DR remain poorly elucidated. Nevertheless, the promise of impactful scientific discoveries may be realized if concerted and collaborative efforts are mounted to identify the genes for DR. Harnessing new genetic technologies and resources such as the upcoming 1000 Genomes Project will help advance this field of research, and potentially lead to a rich harvest of insights into the biological mechanisms underlying this debilitating complication. PMID- 20706634 TI - Hypoxia-inducible factor 1alpha determines gastric cancer chemosensitivity via modulation of p53 and NF-kappaB. AB - BACKGROUND: Reduced chemosensitivity of solid cancer cells represents a pivotal obstacle in clinical oncology. Hence, the molecular characterization of pathways regulating chemosensitivity is a central prerequisite to improve cancer therapy. The hypoxia-inducible factor HIF-1alpha has been linked to chemosensitivity while the underlying molecular mechanisms remain largely elusive. Therefore, we comprehensively analysed HIF-1alpha's role in determining chemosensitivity focussing on responsible molecular pathways. METHODOLOGY AND PRINCIPAL FINDINGS: RNA interference was applied to inactivate HIF-1alpha or p53 in the human gastric cancer cell lines AGS and MKN28. The chemotherapeutic agents 5-fluorouracil and cisplatin were used and chemosensitivity was assessed by cell proliferation assays as well as determination of cell cycle distribution and apoptosis. Expression of p53 and p53 target proteins was analyzed by western blot. NF-kappaB activity was characterized by means of electrophoretic mobility shift assay. Inactivation of HIF-1alpha in gastric cancer cells resulted in robust elevation of chemosensitivity. Accordingly, HIF-1alpha-competent cells displayed a significant reduction of chemotherapy-induced senescence and apoptosis. Remarkably, this phenotype was completely absent in p53 mutant cells while inactivation of p53 per se did not affect chemosensitivity. HIF-1alpha markedly suppressed chemotherapy-induced activation of p53 and p21 as well as the retinoblastoma protein, eventually resulting in cell cycle arrest. Reduced formation of reactive oxygen species in HIF-1alpha-competent cells was identified as the molecular mechanism of HIF-1alpha-mediated inhibition of p53. Furthermore, loss of HIF-1alpha abrogated, in a p53-dependent manner, chemotherapy-induced DNA binding of NF-kappaB and expression of anti-apoptotic NF-kappaB target genes. Accordingly, reconstitution of the NF-kappaB subunit p65 reversed the increased chemosensitivity of HIF-1alpha-deficient cells. CONCLUSION AND SIGNIFICANCE: In summary, we identified HIF-1alpha as a potent regulator of p53 and NF-kappaB activity under conditions of genotoxic stress. We conclude that p53 mutations in human tumors hold the potential to confound the efficacy of HIF-1-inhibitors in cancer therapy. PMID- 20706637 TI - Dermoscopic Features of CD8-Positive Solitary Pagetoid Reticulosis on the Left Leg. AB - Solitary pagetoid reticulosis, also known as Woringer-Kolopp disease, is a rare subtype of cutaneous T-cell lymphoma. The typical clinical presentation is a solitary, localized psoriasiform or hyperkeratotic plaque or tumor located on the extremities. It primarily affects middle-aged males. Because the clinical features of pagetoid reticulosis are indistinctive, pagetoid reticulosis may progress for years before accurate diagnosis. We reported a 57-year-old Japanese woman who presented with a 1-year history of a solitary erythematous plaque on the left leg. Dermoscopic features simulated Bowen's disease showing dotted and glomerular vessels, whitish scaly areas, and a broad negative network. Dermoscopic features of pagetoid reticulosis have never been reported. We have discussed the diagnostic significance of the observed dermoscopic findings. PMID- 20706638 TI - A case report exploring activity intensity in inpatient rehabilitation after stroke. AB - Background and Purpose. Inpatient rehabilitation in countries other than the United States (US) has been described as a time where patients are often not engaged in intensive physical activity. The purpose of this case report is to explore the amount and intensity of physical activity provided in inpatient rehabilitation after stroke in the US. Methods. This study presents a case report of a person admitted to an inpatient rehabilitation unit after sustaining a first stroke. A customized data collection tracked type of activity, activity intensity and social interaction every 5 minutes during the rehabilitation day. Results. 74 percent of the day was spent in low intensity, often seated, physical activity; 14% of the day was spent resting or sleeping. Only 2.91% the day was spent in moderate or high intensity activity with a mobility focus. Conclusions. Consistent with other studies, this case report suggests a relatively low physical demand to rehabilitation delivered in inpatient stroke rehabilitation. This case begins to raise questions about optimized rehabilitation parameters for acute stroke rehabilitation. PMID- 20706639 TI - High-Speed Burring with and without the Use of Surgical Adjuvants in the Intralesional Management of Giant Cell Tumor of Bone: A Systematic Review and Meta-Analysis. AB - Local control rates for Giant Cell Tumor of Bone (GCT) have been reported in a large number of retrospective series. However, there remains a lack of consensus with respect to the need for a surgical adjuvant when intralesional curettage is performed. We have systematically reviewed the literature and identified six studies in which two groups from the same patient cohort were treated with intralesional curettage and high-speed burring with or without a chemical or thermal adjuvant. Studies were evaluated for quality and pooled data was analyzed using the fixed effects model. Data from 387 patients did not indicate improved local control with the use of surgical adjuvants. Given the available data, we conclude that surgical adjuvants are not required when meticulous tumor removal is performed. PMID- 20706640 TI - Pain in children: assessment and nonpharmacological management. AB - Pain perception in children is complex, and is often difficult to assess. In addition, pain management in children is not always optimized in various healthcare settings, including emergency departments. A review of pain assessment scales that can be used in children across all ages, and a discussion of the importance of pain in control and distraction techniques during painful procedures are presented. Age specific nonpharmacological interventions used to manage pain in children are most effective when adapted to the developmental level of the child. Distraction techniques are often provided by nurses, parents or child life specialists and help in pain alleviation during procedures. PMID- 20706641 TI - Peroxisome proliferator-activated receptors alpha, Beta, and gamma mRNA and protein expression in human fetal tissues. AB - Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study examines expression of PPARalpha, beta, and gamma mRNA and protein in human fetal tissues. With increasing fetal age, mRNA expression of PPARalpha and beta increased in liver, but PPARbeta decreased in heart and intestine, and PPARgamma decreased in adrenal. Adult and fetal mean expression of PPARalpha, beta, and gamma mRNA did not differ in intestine, but expression was lower in fetal stomach and heart. PPARalpha and beta mRNA in kidney and spleen, and PPARgamma mRNA in lung and adrenal were lower in fetal versus adult. PPARgamma in liver and PPARbeta mRNA in thymus were higher in fetal versus adult. PPARalpha protein increased with fetal age in intestine and decreased in lung, kidney, and adrenal. PPARbeta protein in adrenal and PPARgamma in kidney decreased with fetal age. This study provides new information on expression of PPAR subtypes during human development and will be important in evaluating the potential for the developing human to respond to PPAR environmental or pharmaceutical agonists. PMID- 20706643 TI - Assessment of the Efficacy of L-Lysine Sulfate vis-a-vis L-Lysine Hydrochloride as Sources of Supplemental Lysine in Broiler Chickens. AB - In this study the effects of L-lysine hydrochloride (containing 78.8% available lysine as crystalline lysine) and L-lysine sulfate (containing 51% available lysine in bacterial cell mass) as source of supplemental lysine in broiler chickens was assessed. The basal diet was supplemented with either L-lysine hydrochloride or L-lysine sulfate to meet lysine requirement. Lysine supplementation irrespective of source improved (P < .05) live weight and food conversion. Live weight and food conversion ratio of the L-lysine sulfate group was superior (P < .05) to the L-lysine hydrochloride group. Supplementation of lysine to the basal diet improved breast meat yield (P < .05). Meat protein content and protein accretion increased (P < .01) when L-lysine sulfate was supplemented. Nutrient metabolizability, N retention, protein utilization efficiency and live weight gain : lysine intake ratio also improved (P < .01) with L-lysine sulfate. A fasting trial conducted after the completion of the feeding trial indicated that the birds receiving L-lysine sulfate retained more of their live weight than the control and the L-lysine hydrochloride dietary groups (P < .05). It was concluded that due to the retained bacterial cell mass, L-lysine sulfate may be a superior source of supplemental lysine than L-lysine hydrochloride for broiler chickens. PMID- 20706642 TI - Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application. AB - Toll-like receptors (TLRs) are known to be expressed by innate immune response cells and to play a critical role in their activation against foreign pathogens. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system (CNS). TLR signaling was reported to be associated with a yin-yang effect in the CNS. While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases. This paper will focus on TLR signaling in glial cells in neurodegenerative diseases such as Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis, and Parkinson's disease. Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application. PMID- 20706644 TI - Trisomy 9 mosaicism diagnosed in utero. AB - We present three cases of trisomy 9 mosaicism diagnosed by amniocentesis with ongoing pregnancies after referral to our center due to fetal abnormalities. Two cases were associated with severe fetal growth restriction (FGR), each of which resulted in an intrauterine fetal demise (IUFD) in the third trimester. The other case involved mild FGR with a congenital diaphragmatic hernia and resulted in a live birth with severe development delay. A major prenatal finding of trisomy 9 mosaicism is FGR. Fetuses with trisomy 9 mosaicism can rarely survive in the case of severe FGR. PMID- 20706645 TI - Paraneoplastic pemphigus presenting as mild cutaneous features of pemphigus foliaceus and lichenoid stomatitis with antidesmoglein 1 antibodies. AB - Herein, we report a case of paraneoplastic pemphigus with mild skin features of pemphigus foliaceus and lichenoid stomatitis associated with B-cell lymphoma. A 49-year-old man presented with scattered blisters and erosions on the trunk along with mucosal blisters and erosions. Skin biopsy showed subcorneal acantholytic bulla and oral mucosal biopsy demonstrated lichenoid dermatitis. Direct immunofluorescence showed cell surface deposits of IgG and C3. Indirect immunofluorescence identified circulating IgG autoantibodies to the cell surfaces of normal human skin and also on the transitional epithelium of rat bladder. Enzyme-linked immunosorbent assay using recombinant baculoproteins showed positive antidesmoglein 1 autoantibodies (index 46) but negative antidesmoglein 3 autoantibodies (index 8). Immunoblot analysis using normal human epidermal extract detected BP230 and the 190 kDa periplakin, while immunoprecipitation using radiolabeled cultured keratinocyte immunoprecipitated BP230 and the 210 kDa envoplakin. We consider that the skin lesion was produced by humoral immunity whereas the oral lesion was produced by cellular immunity. PMID- 20706646 TI - Therapeutic effect of oral bisphosphonates on choroidal neovascularization in the human eye. AB - Purpose. Choroidal neovascularization (CNV) is often associated with age-related macular degeneration (AMD) and pathological myopia (PM). Bisphosphonates, the drug of choice to treat osteoporosis, have been recently reported to have anti angiogenic effects. The purpose of this study is to investigate the therapeutic effects of oral bisphosphonates for CNV in humans. Methods. Thirty-six consecutive cases with CNV due to AMD or PM who declined anti-VEGF therapy were recruited. The patients were prescribed 5 mg of oral alendronates daily for 6 months. The best-corrected visual-acuity (BCVA), the lesion size in fundus photographs and fluorescein angiography, foveal thickness and total macular volume in optical coherence tomography were compared between pre- and post treatment. Results. The mean BCVA of the patients was significantly improved after a months with the treatment in the AMD group. In the PM group, the mean BCVA was maintained up to 6 months with the treatment. The mean lesion size was significantly decreased by 3 months in both groups. The averages of foveal thickness and total macular volume were significantly reduced after 1 month of treatment in the AMD group.Conclusions. Oral bisphosphonate should be further investigated as a possible therapeutic and preventive drug for CNV due to AMD and PM. PMID- 20706648 TI - Primary small bowel liposarcoma (atypical lipomatous tumour) with myogenic differentiation. AB - Primary small intestinal liposarcomas originating in the small bowel are uncommon with a generally poor prognosis due to the advanced stage at the time of diagnosis. We describe a case of primary small bowel dedifferentiated liposarcoma presenting as a solid mass in the right iliac fossa. The current case is unusual as the tumour seemingly originated from the bowel and the well-differentiated component was seen extensively infiltrating the bowel wall including the small bowel submucosa. PMID- 20706647 TI - Electrodelivery of drugs into cancer cells in the presence of poloxamer 188. AB - In the present study it is shown that poloxamer 188, added before or immediately after an electrical pulse used for electroporation, decreases the number of dead cells and at the same time does not reduce the number of reversible electropores through which small molecules (cisplatin, bleomycin, or propidium iodide) can pass/diffuse. It was suggested that hydrophobic sections of poloxamer 188 molecules are incorporated into the edges of pores and that their hydrophilic parts act as brushy pore structures. The formation of brushy pores may reduce the expansion of pores and delay the irreversible electropermeability. Tumors were implanted subcutaneously in both flanks of nude mice using HeLa cells, transfected with genes for red fluorescent protein and luciferase. The volume of tumors stopped to grow after electrochemotherapy and the use of poloxamer 188 reduced the edema near the electrode and around the subcutaneously growing tumors. PMID- 20706649 TI - Objectively measured physical activity and body mass index in preschool children. AB - Aim. To examine the association between objectively measured physical activity (PA) and body mass index (BMI) in preschool children. Methods. The study comprised 281 children (55.9% boys) aged from 4 to 6 years. PA was measured by accelerometer. Children were categorized as non-overweight (NOW) and overweight/obese (OW) according to the sex-adjusted BMI z-score (<1 and >/=1, resp.). Results. Total and moderate intensity PA were not associated with BMI. We observed that a higher proportion of OW children were classified as low-vigorous PA compared to their NOW peers (43.9 versus 32.1%, resp., P > .05). Logistic regression analysis showed that children with low-vigorous PA had higher odds ratio (OR) to be classified as OW compared to those with high-vigorous PA (OR = 4.4; 95% CI: 1.4-13.4; P = .008) after adjusting for BMI at first and second years of life and other potential confounders. Conclusion. The data suggests that vigorous PA may play a key role in the obesity development already at pre-school age. PMID- 20706651 TI - Identification of C-kit-positive interstitial cells in the dog lower urinary tract and relationship with smooth muscle and nerves. Hypotheses for a likely pacemaker role. AB - The aim of this work was to give an evidence of the likely presence of interstitial cells in the canine lower urinary tract and to study their possible interactions with the musculature and the intramural innervation. Cryosections of normal canine bladder and urethra were immunofluorescently labelled with c-kit, a transmembrane, tyrosine kinase growth factor receptor, known to be expressed on the interstitial cells of Cajal (ICCs) of the gut. The relationship with antiactin positive smooth muscle cells and PGP9.5-positive intramural innervation was also investigated by confocal microscopy. Anti-c-kit labelling demonstrated a network of elongated and branched c-kit positive cells, which were located in interstitial spaces, oriented in parallel to the smooth muscle bundles that form the bladder muscular layer, irrespective of dog sex. Cells with a similar localization were also PAS- and NADPH-diaphorase-positive. A contact between c kit immunofluorescent cells and intramural innervation was demonstrated, too. The roles of interstitial cells might include regulation of smooth muscle activity of the bladder detrusor, integrating neuronal signals during urine storage and voiding. PMID- 20706650 TI - PPARs, Cardiovascular Metabolism, and Function: Near- or Far-from-Equilibrium Pathways. AB - Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta and gamma) play a key role in metabolic regulatory processes and gene regulation of cellular metabolism, particularly in the cardiovascular system. Moreover, PPARs have various extra metabolic roles, in circadian rhythms, inflammation and oxidative stress. In this review, we focus mainly on the effects of PPARs on some thermodynamic processes, which can behave either near equilibrium, or far-from equilibrium. New functions of PPARs are reported in the arrhythmogenic right ventricular cardiomyopathy, a human genetic heart disease. It is now possible to link the genetic desmosomal abnormalitiy to the presence of fat in the right ventricle, partly due to an overexpression of PPARgamma. Moreover, PPARs are directly or indirectly involved in cellular oscillatory processes such as the Wnt b-catenin pathway, circadian rhythms of arterial blood pressure and cardiac frequency and glycolysis metabolic pathway. Dysfunction of clock genes and PPARgamma may lead to hyperphagia, obesity, metabolic syndrome, myocardial infarction and sudden cardiac death, In pathological conditions, regulatory processes of the cardiovascular system may bifurcate towards new states, such as those encountered in hypertension, type 2 diabetes, and heart failure. Numerous of these oscillatory mechanisms, organized in time and space, behave far from equilibrium and are "dissipative structures". PMID- 20706652 TI - Differences between Goldmann Applanation Tonometry and Dynamic Contour Tonometry following Trabeculectomy. AB - Background. To evaluate differences between Goldmann Applanation Tonometry (GAT) and Dynamic Controur Tonometry (DCT) following trabeculectomy. Methods. Thirty eight glaucomatous eyes with a history of trabeculectomy (Trabeculectomy group, TG), 20 eyes without a history of trabeculectomy but with a history of latanoprost use (Latanoprost group, LG), and 19 nonglaucomatous eyes (Control group, CG) were included. GAT-IOP, DCT-IOP, the difference between them (dIOP), the central corneal thickness (CCT), the axial length (AL), and the depth of the anterior chamber (ACD) were measured. Results. dIOP was significantly higher in TG (5.19 mmHg) than in LG (4.01 mmHg) and CG (1.98 mmHg). Correlations between AL and dIOP were statistically significant in both TG and LG but not in CG whereas correlations between dIOP and other clinical parameters examined were statistically not significant in all groups. Conclusions. The significantly higher dIOP in TG implies that the bio-mechanical properties of the ocular walls are altered following trabeculectomy. PMID- 20706653 TI - Effects of assisted reproduction technology on placental imprinted gene expression. AB - We used placental tissue to compare the imprinted gene expression of IGF2, H19, KCNQ1OT1, and CDKN1C of singletons conceived via assisted reproduction technology (ART) with that of spontaneously conceived (SC) singletons. Of 989 singletons examined (ART n = 65; SC n = 924), neonatal weight was significantly lower (P < .001) in the ART group than in the SC group, but placental weight showed no significant difference. Gene expression analyzed by real-time PCR was similar for both groups with appropriate-for-date (AFD) birth weight. H19 expression was suppressed in fetal growth retardation (FGR) cases in the ART and SC groups compared with AFD cases (P < .02 and P < .05, resp.). In contrast, CDKN1C expression was suppressed in FGR cases in the ART group (P < .01), while KCNQ1OT1 expression was hyperexpressed in FGR cases in the SC group (P < .05). As imprinted gene expression patterns differed between the ART and SC groups, we speculate that ART modifies epigenetic status even though the possibilities always exist. PMID- 20706654 TI - The LH/hCG Axis in Endometrial Cancer: A New Target in the Treatment of Recurrent or Metastatic Disease. AB - Endometrial cancer (EC) is a hormone-dependent cancer that currently represents the most frequent malignancy of the female reproductive tract. The involvement of steroid hormones in EC etiology and progression has been reported. More recently, gonadotropins, and, in particular LH/hCG, are emerging as novel regulators of tumor progression. In the present review, we discuss the role of the LH/hCG axis (i.e. LH/hCG and its receptors, LH/hCG-R) in both gonadal and nongonadal tissues, in physiological and neoplastic conditions. In cancer cells, LH/hCG mainly controls cell proliferation and apoptosis. In particular, in EC LH/hCG improves cell invasiveness, through a mechanism which involves the LH/hCG-R, which in turn activate protein kinase A and modulate integrin adhesion receptors. Indeed, the LH/hCG-R mRNA is expressed in primary ECs and this expression correlates with LH/hCG-induced cell invasiveness in vitro. These results lead to hypothesize that recurrent and metastatic ECs, which express LH/hCG-R, could benefit from therapies aimed at decreasing LH levels, through Gn-RH analogues. Hence, the LH/hCG axis could represent a prognostic factor and a new therapeutic target in EC. PMID- 20706655 TI - Sleep Health Issues for Children with FASD: Clinical Considerations. AB - This article describes the combined clinical experience of a multidisciplinary group of professionals on the sleep disturbances of children with fetal alcohol spectrum disorders (FASD) focusing on sleep hygiene interventions. Such practical and comprehensive information is not available in the literature. Severe, persistent sleep difficulties are frequently associated with this condition but few health professionals are familiar with both FASD and sleep disorders. The sleep promotion techniques used for typical children are less suitable for children with FASD who need individually designed interventions. The types, causes, and adverse effects of sleep disorders, the modification of environment, scheduling and preparation for sleep, and sleep health for their caregivers are discussed. It is our hope that parents and also researchers, who are interested in the sleep disorders of children with FASD, will benefit from this presentation and that this discussion will stimulate much needed evidence-based research. PMID- 20706657 TI - A rare association of congenital diaphragmatic hernia with lower esophageal atresia and perforation. AB - Congenital diaphragmatic hernia is known to be associated with esophageal atresia, which is a rare association. We report a rare occurrence of congenital diaphragmatic hernia and lower esophageal atresia. PMID- 20706658 TI - Association of Toll-like receptor signaling and reactive oxygen species: a potential therapeutic target for posttrauma acute lung injury. AB - Acute lung injury (ALI) frequently occurs in traumatic patients and serves as an important component of systemic inflammatory response syndrome (SIRS). Hemorrhagic shock (HS) that results from major trauma promotes the development of SIRS and ALI by priming the innate immune system for an exaggerated inflammatory response. Recent studies have reported that the mechanism underlying the priming of pulmonary inflammation involves the complicated cross-talk between Toll-like receptors (TLRs) and interactions between neutrophils (PMNs) and alveolar macrophages (AMvarphi) as well as endothelial cells (ECs), in which reactive oxygen species (ROS) are the key mediator. This paper summarizes some novel mechanisms underlying HS-primed lung inflammation focusing on the role of TLRs and ROS, and therefore suggests a new therapeutic target for posttrauma ALI. PMID- 20706659 TI - Regulatory effect of melatonin on cytokine disturbances in the pristane-induced lupus mice. AB - Systemic lupus erythematosus (SLE) develops in relation to many environmental factors. In our opinion, it is more important to investigate the effect of melatonin on the environmental- related SLE. In the present study, 0.5 ml pristane were used to induce SLE in female BALB/c mice. Melatonin (0.01, 0.1, 1.0 mg/kg) was orally administered immediately after pristane-injection for 24 weeks. IgM anti ssDNA and histone antibodies were detected after 0, 1, 2, 4, 8 weeks pristane injection. The levels of IL-2, IL-6 and IL-13 were detected after 24 weeks. Renal lesions were also observed. The results showed that melatonin antagonized the increasing levels of IgM anti ssDNA and histone autoantibodies. Melatonin could also decrease the IL-6 and IL-13 production and increase the IL-2 production. Besides, melatonin could lessen the renal lesions caused by pristane. These results suggested that melatonin has a beneficial effect on pristane induced lupus through regulating the cytokines disturbances. PMID- 20706656 TI - DAMPening inflammation by modulating TLR signalling. AB - Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system. PMID- 20706660 TI - 20 Years of Research on Socioeconomic Inequality and Children's-Unintentional Injuries Understanding the Cause-Specific Evidence at Hand. AB - Injuries are one of the major causes of both death and social inequalities in health in children. This paper reviews and reflects on two decades of empirical studies (1990 to 2009) published in the peer-reviewed medical and public health literature on socioeconomic disparities as regards the five main causes of childhood unintentional injuries (i.e., traffic, drowning, poisoning, burns, falls). Studies have been conducted at both area and individual levels, the bulk of which deal with road traffic, burn, and fall injuries. As a whole and for each injury cause separately, their results support the notion that low socioeconomic status is greatly detrimental to child safety but not in all instances and settings. In light of variations between causes and, within causes, between settings and countries, it is emphasized that the prevention of inequities in child safety requires not only that proximal risk factors of injuries be tackled but also remote and fundamental ones inherent to poverty. PMID- 20706661 TI - Lethal Clostridium difficile Colitis Associated with Paclitaxel and Carboplatin Chemotherapy in Ovarian Carcinoma: Case Report and Review of the Literature. AB - Clostridium difficile colitis, although rare, could represent a serious complication following chemotherapy. Prior antibiotic use has been considered the single most important risk factor in the development of C. difficile infection. Recently, the association between antineoplastic therapy and C. difficile associated diarrhea in the absence of a prior antibiotic therapy has become more apparent. A 75-year-old woman with serous adenocarcinoma of the ovary developed lethal pancolitis caused by C. difficile after five cycles of paclitaxel- and carboplatin-based chemotherapy. She presented with diarrhea, coffee-ground emesis, and oliguria and was hospitalized immediately for aggressive treatment. Despite all the medical efforts, her condition worsened and she died after twenty days. We describe the second case reported of a patient developing a severe C. difficile colitis following chemotherapy without any recent antibiotic use and review the data of the literature, emphasizing the need to a prompt diagnosis and management that can significantly decrease the morbidity and life-threatening complications associated with this infection. PMID- 20706662 TI - The matrix metalloproteases and endothelin-1 in infection-associated preterm birth. AB - Preterm birth (PTB) is clinically defined as any delivery which occurs before the completion of 37 weeks of gestation, and is currently the most important problem in obstetrics. In the United States, PTB accounts for 12-13% of all live births, and, with the exception of fetuses suffering from anomalies, is the primary cause of perinatal mortality. While the risk factors for PTB are numerous, the single most common cause is intrauterine infection. As there is currently no FDA approved therapy for infection-associated PTB, understanding the pathogenesis of preterm labor (PTL) and delivery should be given high priority. The matrix metalloproteinases (MMPs) are a family of enzymes that have been implicated in normal parturition as well as infection-triggered rupture of membranes and preterm birth. Several lines of evidence also suggest a role for endothelin-1 (ET 1) in infection-associated preterm delivery. This paper focuses on the evidence that the MMPs and ET-1 act in the same molecular pathway in preterm birth. PMID- 20706663 TI - Analysis of horse myostatin gene and identification of single nucleotide polymorphisms in breeds of different morphological types. AB - Myostatin (MSTN) is a negative modulator of muscle mass. We characterized the horse (Equus caballus) MSTN gene and identified and analysed single nucleotide polymorphisms (SNPs) in breeds of different morphological types. Sequencing of coding, untranslated, intronic, and regulatory regions of MSTN gene in 12 horses from 10 breeds revealed seven SNPs: two in the promoter, four in intron 1, and one in intron 2. The SNPs of the promoter (GQ183900:g.26T>C and GQ183900:g.156T>C, the latter located within a conserved TATA-box like motif) were screened in 396 horses from 16 breeds. The g.26C and the g.156C alleles presented higher frequency in heavy (brachymorphic type) than in light breeds (dolichomorphic type such as Italian Trotter breed). The significant difference of allele frequencies for the SNPs at the promoter and analysis of molecular variance (AMOVA) on haplotypes indicates that these polymorphisms could be associated with variability of morphology traits in horse breeds. PMID- 20706664 TI - Novel method of cell-free in vitro synthesis of the human fibroblast growth factor 1 gene. AB - Recombinant DNA projects generally involve cell-based gene cloning. However, because template DNA is not always readily available, in vitro chemical synthesis of complete genes from DNA oligonucleotides is becoming the preferred method for cloning. This article describes a new, rapid procedure based on Taq polymerase for the precise assembly of DNA oligonucleotides to yield the complete human fibroblast growth factor 1 (FGF1) gene, which is 468 bp long and has a G+C content of 51.5%. The new method involved two steps: (1) the design of the DNA oligonucleotides to be assembled and (2) the assembly of multiple oligonucleotides by PCR to generate the whole FGF1 gene. The procedure lasted a total of only 2 days, compared with 2 weeks for the conventional procedure. This method of gene synthesis is expected to facilitate various kinds of complex genetic engineering projects that require rapid gene amplification, such as cell free whole-DNA library construction, as well as the construction of new genes or genes that contain any mutation, restriction site, or DNA tag. PMID- 20706665 TI - 63 years and 715 days to the "boxed warning": unmasking of the propylthiouracil problem. AB - 715 days after potential problems related to PTU use in children were presented in a debate in front of the Lawson Wilkins Pediatric Endocrine Society (LWPES), the US Food and Drug Administration issued a "black-box" warning about the hepatotoxicity risk of the antithyroid drug propylthiouracil (PTU). This safety advisory followed the collective actions of academic societies, medical publishers, the National Institutes of Health, and the FDA. Considering that surgery and radioactive iodine are the legitimate treatment options for Grave Disease (GD), and are now the preferred alternative therapy in individuals who developed toxic reactions to MMI, the use of PTU should now be limited to exceptional circumstances and pregnancy. Long-term PTU therapy, especially in children, is not justifiable. The current advisory comes 63 years after the introduction of PTU for clinical use in 1947. PMID- 20706666 TI - Frequency of drug resistance gene amplification in clinical leishmania strains. AB - Experimental studies about Leishmania resistance to metal and antifolates have pointed out that gene amplification is one of the main mechanisms of drug detoxification. Amplified genes code for adenosine triphosphate-dependent transporters (multidrug resistance and P-glycoproteins P), enzymes involved in trypanothione pathway, particularly gamma glutamyl cysteine synthase, and others involved in folates metabolism, such as dihydrofolate reductase and pterine reductase. The aim of this study was to detect and quantify the amplification of these genes in clinical strains of visceral leishmaniasis agents: Leishmania infantum, L. donovani, and L. archibaldi. Relative quantification experiments by means of real-time polymerase chain reaction showed that multidrug resistance gene amplification is the more frequent event. For P-glycoproteins P and dihydrofolate reductase genes, level of amplification was comparable to the level observed after in vitro selection of resistant clones. Gene amplification is therefore a common phenomenon in wild strains concurring to Leishmania genomic plasticity. This finding, which corroborates results of experimental studies, supports a better understanding of metal resistance selection and spreading in endemic areas. PMID- 20706667 TI - Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up. AB - Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term. PMID- 20706668 TI - Causes of mortality and diseases in farmed deer in Switzerland. AB - To investigate diseases and causes of mortality in Swiss farmed deer, deer found dead or shot due to diseased condition between March 2003 and December 2004 were requested for a complete postmortem examination. One hundred and sixty-two animals were submitted. Perinatal mortality, necrobacillosis in 3 week to 6 month old deer, and endoparasitosis in 6 month to 2 year old deer were identified as the most important causes of loss, followed by ruminal acidosis, which was diagnosed in 22% of deer older than 1 year. Congenital malformations were observed in 15% of deer less than 6 months old. Reportable infectious diseases known as major problems in deer farming in other countries were rare (yersiniosis, malignant catarrhal fever) or not observed (tuberculosis, chronic wasting disease). Overall, the results indicate that the Swiss deer population does not present major health problems of concern for domestic animals. PMID- 20706670 TI - PPAR-gamma Signaling Crosstalk in Mesenchymal Stem Cells. AB - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcriptional factors. Among other functions, PPAR-gamma acts as a key regulator of the adipogenesis. Since several cytokines (IL-1, TNF-alpha, TGF-beta) had been known to inhibit adipocyte differentiation in mesenchymal stem cells (MSCs), we examined the effect of these cytokines on the transactivation function of PPAR-gamma. We found that the TNF-alpha/IL-1-activated TAK1/TAB1/NIK (NFkappaB-inducible kinase) signaling cascade inhibited both the adipogenesis and Tro-induced transactivation by PPAR-gamma by blocking the receptor binding to the cognate DNA response elements. Furthermore, it has been shown that the noncanonical Wnts are expressed in MSCs and that Wnt-5a was capable to inhibit transactivation by PPAR-gamma. Treatment with Wnt5a-activated NLK (nemo-like kinase) induced physical association of the endogenous NLK and H3K9 histone methyltransferase (SETDB1) protein complexes with PPAR-gamma. This resulted in histoneH3K9 tri-methylation at PPAR-gamma target gene promoters. Overall, our data show that cytokines and noncanonical Wnts play a crucial role in modulation of PPAR-gamma regulatory function in its target cells and tissues. PMID- 20706671 TI - Integration of services for victims of child sexual abuse at the university teaching hospital one-stop centre. AB - Objective. To improve care of sexually abused children by establishment of a "One Stop Centre" at the University Teaching Hospital. Methodology. Prior to opening of the One Stop Centre, a management team comprising of clinical departmental heads and a technical group of professionals (health workers, police, psychosocial counselors lawyers and media) were put in place. The team evaluated and identified gaps and weaknesses on the management of sexually abused children prevailing in Zambia. A manual was produced which would be used to train all professionals manning a One Stop Centre. A team of consultants from abroad were identified to offer need based training activities and a database was developed. Results. A multidisciplinary team comprising of health workers, police and psychosocial counselors now man the centre. The centre is assisted by lawyers as and when required. UTH is offering training to other areas of the country to establish similar services by using a Trainer of Trainers model. A comprehensive database has been established for Lusaka province. Conclusion. For establishment of a One Stop Centre, there needs to be a core group comprising of managers as well as a technical team committed to the management and protection of sexually abused children. PMID- 20706672 TI - Examining the genomic influence of skin antioxidants in vitro. AB - A series of well-known, purified antioxidants including: Resveratrol, Epigallocatechin Gallate (EGCG), Genistein, Rosavin, Puerarin, Chlorogenic Acid, Propolis and two newer unexplored isoflavonoids isolated from Maclura pomifera (Osage Orange) including Pomiferin and Osajin, were applied to Normal Human Dermal Fibroblasts (NHDF) and Normal Human Dermal Keratinocytes (NHEK) for 24 hours. The resulting treated cells were then examined using human gene microarrays supplied by Agilent. These chips typically have somewhere on the order of 30,000 individual genes which are expressed in the human genome. For our study, this large list of genes was reduced to 205 principal genes thought to be important for skin and each individual ingredient was examined for its influence on the culled list of genes. Working on a hypothesis that there may be some common genes which are either upregulated or downregulated by all or most of these ingredients, a short list of genes for each cell line was developed. What appears to emerge from these studies is that several genes in the gene pool that was screened are influenced by most or all of the molecules of interest. Genes that appear to be upregulated in both cell lines by all the ingredients include: ACLY, AQP3, COX1, NOS3, and PLOD3. Genes that appear to be downregulated in both cell lines by all ingredients include only PGR. PMID- 20706673 TI - Rank Protein Immunolabeling during Bone-Implant Interface Healing Process. AB - The purpose of this paper was to evaluate the expression of RANK protein during bone-healing process around machined surface implants. Twenty male Wistar rats, 90 days old, after having had a 2 mm diameter and 6 mm long implant inserted in their right tibias, were evaluated at 7, 14, 21, and 42 days after healing. After obtaining the histological samples, slides were subjected to RANK immunostaining reaction. Results were quantitatively evaluated. Results. Immunolabeling analysis showed expressions of RANK in osteoclast and osteoblast lineage cells. The statistical analysis showed an increase in the expression of RANK in osteoblasts at 7 postoperative days and a gradual decrease during the chronology of the healing process demonstrated by mild cellular activity in the final stage (P < .05). Conclusion. RANK immunolabeling was observed especially in osteoclast and osteoblast cells in primary bone during the initial periods of bone healing/implant interface. PMID- 20706674 TI - Statistical analysis aiming at predicting respiratory tract disease hospital admissions from environmental variables in the city of Sao Paulo. AB - This study is aimed at creating a stochastic model, named Brazilian Climate and Health Model (BCHM), through Poisson regression, in order to predict the occurrence of hospital respiratory admissions (for children under thirteen years of age) as a function of air pollutants, meteorological variables, and thermal comfort indices (effective temperatures, ET). The data used in this study were obtained from the city of Sao Paulo, Brazil, between 1997 and 2000. The respiratory tract diseases were divided into three categories: URI (Upper Respiratory tract diseases), LRI (Lower Respiratory tract diseases), and IP (Influenza and Pneumonia). The overall results of URI, LRI, and IP show clear correlation with SO2 and CO, PM10 and O3, and PM10, respectively, and the ETw4 (Effective Temperature) for all the three disease groups. It is extremely important to warn the government of the most populated city in Brazil about the outcome of this study, providing it with valuable information in order to help it better manage its resources on behalf of the whole population of the city of Sao Paulo, especially those with low incomes. PMID- 20706669 TI - Global distribution, public health and clinical impact of the protozoan pathogen cryptosporidium. AB - Cryptosporidium spp. are coccidians, oocysts-forming apicomplexan protozoa, which complete their life cycle both in humans and animals, through zoonotic and anthroponotic transmission, causing cryptosporidiosis. The global burden of this disease is still underascertained, due to a conundrum transmission modality, only partially unveiled, and on a plethora of detection systems still inadequate or only partially applied for worldwide surveillance. In children, cryptosporidiosis encumber is even less recorded and often misidentified due to physiological reasons such as early-age unpaired immunological response. Furthermore, malnutrition in underdeveloped countries or clinical underestimation of protozoan etiology in developed countries contribute to the underestimation of the worldwide burden. Principal key indicators of the parasite distribution were associated to environmental (e.g., geographic and temporal clusters, etc.) and host determinants of the infection (e.g., age, immunological status, travels, community behaviours). The distribution was geographically mapped to provide an updated picture of the global parasite ecosystems. The present paper aims to provide, by a critical analysis of existing literature, a link between observational epidemiological records and new insights on public health, and diagnostic and clinical impact of cryptosporidiosis. PMID- 20706675 TI - Mycoplasma, Ureaplasma, and adverse pregnancy outcomes: a fresh look. AB - Recent work on the Molicutes that associate with genital tract tissues focuses on four species that may be of interest in potential maternal, fetal, and neonatal infection and in contributing to adverse pregnancy outcomes. Mycoplasma hominis and Ureaplasma urealyticum have historically been the subject of attention, but Mycoplasma genitalis which causes male urethritis in addition to colonizing the female genital tract and the division of Ureaplasma into two species, urealyticum and parvum, has also added new taxonomic clarity. The role of these genital tract inhabitants in infection during pregnancy and their ability to invade and infect placental and fetal tissue is discussed. In particular, the role of some of these organisms in prematurity may be mechanistically related to their ability to induce inflammatory cytokines, thereby triggering pathways leading to preterm labor. A review of this intensifying exploration of the mycoplasmas in relation to pregnancy yields several questions which will be important to examine in future research. PMID- 20706676 TI - Alterations in Lipids and Adipocyte Hormones in Female-to-Male Transsexuals. AB - Testosterone therapy in men and women results in decreased high-density lipoprotein cholesterol (HDL) and increased low-density lipoprotein cholesterol (LDL). We sought to determine whether testosterone therapy has this same effect on lipid parameters and adipocyte hormones in female-to-male (FTM) transsexuals. Twelve FTM transsexuals provided a fasting lipid profile including serum total cholesterol, HDL, LDL, and triglycerides prior to and after 1 year of testosterone therapy (testosterone enanthate or cypionate 50-125 mg IM every two weeks). Subjects experienced a significant decrease in mean serum HDL (52 +/- 11 to 40 +/- 7 mg/dL) (P < .001). The mean LDL (P = .316), triglyceride (P = .910), and total cholesterol (P = .769) levels remained unchanged. In a subset of subjects, we measured serum leptin levels which were reduced by 25% but did not reach statistical significance (P = .181) while resistin levels remained unchanged. We conclude that testosterone therapy in FTM transsexuals can promote an increased atherogenic lipid profile by lowering HDL and possibly reduce serum leptin levels. However, long-term studies are needed to determine whether decreases in HDL result in adverse cardiovascular outcomes. PMID- 20706677 TI - Toll-like receptor signaling and liver fibrosis. AB - Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis. PMID- 20706678 TI - Sexual assault: a report on human immunodeficiency virus postexposure prophylaxis. AB - The objective of this report is to describe an urban county hospital human immunodeficiency virus (HIV) infection prevention protocol offering prophylactic combination antiretroviral medications to female victims of sexual assault. A retrospective chart review was conducted from June, 2007 through June, 2008 of 151 women who were prescribed antiretroviral prophylaxis by protocol. All women receiving HIV prophylaxis initially screened HIV seronegative. Of the 58 women who reported taking any HIV prophylaxis, 36 (62%) were HIV screened at 12 and/or 24 weeks and none had HIV seroconverted. Although the initiation of an HIV post exposure prophylaxis protocol for sexual assault in a county hospital population is feasible, patient follow-up for counseling and HIV serostatus evaluation is an identified barrier. PMID- 20706679 TI - Intravitreal Ampicillin Sodium for Antibiotic-Resistant Endophthalmitis: Streptococcus uberis First Human Intraocular Infection Report. AB - Purpose. To describe the clinical characteristics, diagnosis, and treatment with intravitreal ampicillin sodium of a postoperative endophthalmitis case due to Streptococcus uberis; an environmental pathogen commonly seen in mastitis cases of lactating cows. Methods. Case Report. A 52-year-old, Hispanic diabetic patient who suddenly developed severe pain and severe loss of vision, following vitrectomy. Results. The patient was diagnosed with postoperative endophthalmitis secondary to a highly resistant strain of Streptococcus uberis that did not respond to intravitreal antibiotics. He was treated with an air-fluid interchange, anterior chamber washout, intravitreal ampicillin sodium (5 mg/0.1 mL), and silicon oil tamponade (5000 ck). The eye was anatomically stabilized, though there was no functional recovery. Conclusion. Streptococcus uberis is an uncommon pathogen to the human eye, which has unique features that help the strain in developing resistance to antibiotics. While treatment with intravitreal ampicillin is feasible, there are still concerns about its possible toxicity. PMID- 20706680 TI - Upregulation of endogenous HMOX1 expression by a computer-designed artificial transcription factor. AB - Heme oxygenase-1 (HO-1) is well known as a cytoprotective factor. Research has revealed that it is a promising therapeutic target for cardiovascular diseases. In the current study, an HMOX1 (HO-1 gene) enhancer-specific artificial zinc finger protein (AZP) was designed using bioinformatical methods. Then, an artificial transcription factor (ATF) was constructed based on the AZP. In the ATF, the p65 functional domain was used as the effector domain (ED), and a nuclear localization sequence (NLS) was also included. We next analyzed the affinity of the ATF to the HMOX1 enhancer and the effect of the ATF on endogenous HMOX1 expression. The results suggest that the ATF could effectively upregulate endogenous HMOX1 expression in ECV304 cells. With further research, the ATF could be developed as a potential drug for cardiovascular diseases. PMID- 20706681 TI - Extramedullary plasmacytoma of the tonsil with nodal involvement. AB - We present a rare case of extramedullary plasmacytoma of the palatine tonsil with cervical lymph node involvement treated by surgical resection. A 58-year-old Caucasian male presented with a solitary 3 cm x 3 cm jugulodigastric lymph node and was found to have an ipsilateral tonsillar swelling. The involved tonsil and lymph node were surgically resected after two inconclusive fine-needle aspirates, and plasmacytoma was confirmed histologically and by immunocytochemistry. Adjuvant radiotherapy was not indicated as adequate resection was achieved at surgery. We also highlight the challenges of diagnosis when fine-needle aspiration is inconclusive and the need for careful planning before surgery. PMID- 20706682 TI - 2D Fast Vessel Visualization Using a Vessel Wall Mask Guiding Fine Vessel Detection. AB - The paper addresses the fine retinal-vessel's detection issue that is faced in diagnostic applications and aims at assisting in better recognizing fine vessel anomalies in 2D. Our innovation relies in separating key visual features vessels exhibit in order to make the diagnosis of eventual retinopathologies easier to detect. This allows focusing on vessel segments which present fine changes detectable at different sampling scales. We advocate that these changes can be addressed as subsequent stages of the same vessel detection procedure. We first carry out an initial estimate of the basic vessel-wall's network, define the main wall-body, and then try to approach the ridges and branches of the vasculature's using fine detection. Fine vessel screening looks into local structural inconsistencies in vessels properties, into noise, or into not expected intensity variations observed inside pre-known vessel-body areas. The vessels are first modelled sufficiently but not precisely by their walls with a tubular model structure that is the result of an initial segmentation. This provides a chart of likely Vessel Wall Pixels (VWPs) yielding a form of a likelihood vessel map mainly based on gradient filter's intensity and spatial arrangement parameters (e.g., linear consistency). Specific vessel parameters (centerline, width, location, fall-away rate, main orientation) are post-computed by convolving the image with a set of pre-tuned spatial filters called Matched Filters (MFs). These are easily computed as Gaussian-like 2D forms that use a limited range sub optimal parameters adjusted to the dominant vessel characteristics obtained by Spatial Grey Level Difference statistics limiting the range of search into vessel widths of 16, 32, and 64 pixels. Sparse pixels are effectively eliminated by applying a limited range Hough Transform (HT) or region growing. Major benefits are limiting the range of parameters, reducing the search-space for post convolution to only masked regions, representing almost 2% of the 2D volume, good speed versus accuracy/time trade-off. Results show the potentials of our approach in terms of time for detection ROC analysis and accuracy of vessel pixel (VP) detection. PMID- 20706683 TI - Evaluation of acne quality of life and clinical severity in acne female adults. AB - Acne is a common disease especially among teenagers. It has a considerable psychological impact on affected individuals. The aim of this paper was to assess if the effect of acne on acne-related quality of life is correlated to acne clinical severity. 112 university female students attending the university medical clinics with acne complaints were examined. Cardiff Acne Disability Index (CADI) was used to assess acne-related quality of life, and global acne grading system (GAGS) was used to assess clinical severity of acne. There was no correlation between acne severity (GAGS scoring system) and quality of life impairment as assessed by CADI score (r = 0.145, P = .127). Additionally, CADI score did not correlate with disease duration or age of patients. We therefore conclude that acne clinical severity alone does not affect acne-related quality of life changes. Many other factors might play a role. PMID- 20706684 TI - CMV enteritis causing massive intestinal hemorrhage in an elderly patient. AB - Background. Cytomegalovirus (CMV) disease is rare in previously immunocompetent patients. We report a case of CMV enteritis complicated by massive intestinal bleeding. Case History. A 72-year-old immunocompetent patient was admitted for diarrhea and abdominal pain. Aspecific pattern of duodenitis was found at abdomen computed tomography and on biopsies during endoscopy. A diagnosis of vasculitis was suspected on the basis of the clinical and biological course (skin lesions, arthralgias, proteinuria, low complement C3 and C4 fractions, etc.) and pulse steroid therapy was prescribed. The patient developed multiple episodes of intestinal bleeding with shock and required urgent laparotomy. Jejunitis due to CMV vasculitis was proven by histological examination of the operative specimen. Treatment with ganciclovir was initiated. No bleeding recurrence was noted. No other lesions from CMV infection were observed. The patient died from unrelated complications. Discussion. CMV enteritis is a rare cause of intestinal bleeding particularly in previously immunocompetent patients. Aging could be accompanied by a relative immune weakness and specific antiviral therapy seems to be indicated. PMID- 20706685 TI - Clinical features of sarcomatoid carcinoma (carcinosarcoma) of the urinary bladder: analysis of 221 cases. AB - Background. Urinary bladder sarcomatoid carcinoma (carcinosarcoma) is rare. The objective of this study was to examine the epidemiology, natural history, and prognostic factors of urinary bladder carcinosarcoma using population-based registry. Methods. The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify cases by tumor site and histology codes. The association between clinical and demographic characteristics and long-term survival was examined. Results. A total of 221 histology confirmed cases were identified between 1973 and 2004, this accounted for approximately 0.11% of all primary bladder tumors during the study period. Median age of the patients was 75 years (range 41-96). Of the patients with a known tumor stage (N = 204), 72.5% had a regional or distant stage; 98.4% of patients with known histology grade (N = 127), had poorly or undifferentiated histology. Multiple primary tumors were indentified in about 40% of study subjects. The majority of patients (95.9%) received cancer directed surgery, 35.8% had radical or partial cystectomy, 15.8% of patients received radiation therapy combination with surgery. The median overall survival was 14 months (95% CI 7-21 months). 1-, 5-, and 10-year cancer specific survival rate were 53.9%, 28.4% and 25.8%. In a multivariate analysis, only tumor stage was found to be a significant prognostic factor for disease specific survival. Conclusions. Urinary bladder carcinosarcoma commonly presented as high grade, advanced stage and aggressive behavior with a poor prognosis. Emphasis on early detection, including identification of risk factors is needed to improve the outcome for patients with this malignancy. PMID- 20706686 TI - Exercise stress testing in children with metabolic or neuromuscular disorders. AB - The role of exercise as a diagnostic or therapeutic tool in patients with a metabolic disease (MD) or neuromuscular disorder (NMD) is relatively underresearched. In this paper we describe the metabolic profiles during exercise in 13 children (9 boys, 4 girls, age 5-15 yrs) with a diagnosed MD or NMD. Graded cardiopulmonary exercise tests and/or a 90-min prolonged submaximal exercise test were performed. During exercise, respiratory gas-exchange and heart rate were monitored; blood and urine samples were collected for biochemical analysis at set time points. Several characteristics in our patient group were observed, which reflected the differences in pathophysiology of the various disorders. Metabolic profiles during exercises CPET and PXT seem helpful in the evaluation of patients with a MD or NMD. PMID- 20706687 TI - Using the electronic medical record to improve education in patients at risk for adrenal insufficiency. AB - Background. Adrenal insufficiency is a life-threatening event. It is recommended that patients with known adrenal insufficiency and their families receive careful and repeated education on sick-day glucocorticoid management. We hypothesized that the electronic medical record (EMR) can be used to improve patient education through automated provider notification. Methods. We established an automated electronic alert in the EMR that triggered in the outpatient endocrine clinic. The alert asked if stress dose education was reviewed at the visit. The response to this alert was evaluated between July 15, 2009 and February 19, 2010. Results. 128 unique patients had visits both prior to and following the implementation of the EMR alert. The alert was acknowledged in 58 unique patient visits. After the alert was implemented, 87/128 (68%) of the patients had documentation in their record that stress dosing was reviewed. In the visit just prior to implementation of the alert, 48/128 (38%) of the patient encounters showed written documentation of stress dose review. Conclusion. This report documents that an automated alert in the EMR can promote improved provider adherence to recommendations regarding ongoing education of patients for stress dosing of glucocorticoids. Whether this translates into better outcomes for patients remains to be seen. PMID- 20706688 TI - The Role of Peroxisome Proliferator-Activated Receptor beta/delta on the Inflammatory Basis of Metabolic Disease. AB - The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects. PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPARbeta/delta ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPARbeta/delta ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases. PMID- 20706690 TI - Electrodiagnostic examination of the tibial nerve in clinically normal ferrets. AB - Tibial nerves of 10 normal domestic ferrets (Mustela putorius furo) were evaluated by means of electrodiagnostic tests: motor nerve conduction studies (MNCSs), supramaximal repetitive nerve stimulation (SRNS), F waves, and cord dorsum potentials (CDPs). Values of conduction velocity, proximal and distal compound muscular action potentials, and amplitudes of MNCS were, respectively, 63.25 +/- 7.56 m/sec, 10.79 +/- 2.75 mV, and 13.02 +/- 3.41 mV. Mean decrements in amplitude and area of compound muscular action potentials of wave 9 with low frequency SRNS were 0.3 +/- 3.83% and 0.1 +/- 3.51%. The minimum latency of the F waves and the F ratio were, respectively, 8.49 +/- 0.65 ms and 1.92 +/- 0.17. Onset latency of CDP was 1.99 +/- 0.03 ms. These tests may help in diagnosing neuromuscular disorders and in better characterizing the hindlimb paresis reported in many ferrets with systemic illnesses. PMID- 20706689 TI - Chronic inflammation in obesity and the metabolic syndrome. AB - The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks. PMID- 20706691 TI - Prevalence and risk factors of sexually transmitted infections and cervical neoplasia in women from a rural area of southern Mozambique. AB - There is limited information on the prevalence of sexually transmitted infections and the prevalence of cervical neoplasia in rural sub-Saharan Africa. This study describes the prevalence and the etiology of STIs and the prevalence of cervical neoplasia among women in southern Mozambique. An age-stratified cross-sectional study was performed where 262 women aged 14 to 61 years were recruited at the antenatal clinic (59%), the family-planning clinic (7%), and from the community (34%). At least one active STI was diagnosed in 79% of women. Trichomonas vaginalis was present in 31% of all study participants. The prevalence of Neisseria gonorrhea and Chlamydia trachomatis were 14% and 8%, respectively, and Syphilis was diagnosed in 12% of women. HPV DNA was detected in 40% of women and cervical neoplasia was diagnosed in 12% of all women. Risk factors associated with the presence of some of the STIs were being divorced or widowed, having more than one sexual partner and having the partner living in another area. A higher prevalence was observed in the reproductive age group and some of the STIs were more frequently diagnosed in pregnant women. STI control programs are a priority to reduce the STIs burden, including HIV and cervical neoplasia. PMID- 20706693 TI - A road map for the global elimination of congenital syphilis. AB - Congenital syphilis is the oldest recognized congenital infection, and continues to account for extensive global perinatal morbidity and mortality today. Serious adverse pregnancy outcomes caused by maternal syphilis infection are prevented with screening early in pregnancy and prompt treatment of women testing positive. Intramuscular penicillin, an inexpensive antibiotic on the essential medicine list of nations all over the world, effectively cures infection and prevents congenital syphilis. In fact, at a cost of $11-15 per disability adjusted life year (DALY) averted, maternal syphilis screening and treatment is among the most cost-effective public health interventions in existence. Yet implementation of this basic public health intervention is sporadic in countries with highest congenital syphilis burden. We discuss the global burden of this devastating disease, current progress and ongoing challenges for its elimination in countries with highest prevalence, and next steps in ensuring a world free of preventable perinatal deaths caused by syphilis. PMID- 20706692 TI - Contribution of gut bacteria to liver pathobiology. AB - Emerging evidence suggests a strong interaction between the gut microbiota and health and disease. The interactions of the gut microbiota and the liver have only recently been investigated in detail. Receiving approximately 70% of its blood supply from the intestinal venous outflow, the liver represents the first line of defense against gut-derived antigens and is equipped with a broad array of immune cells (i.e., macrophages, lymphocytes, natural killer cells, and dendritic cells) to accomplish this function. In the setting of tissue injury, whereby the liver is otherwise damaged (e.g., viral infection, toxin exposure, ischemic tissue damage, etc.), these same immune cell populations and their interactions with the infiltrating gut bacteria likely contribute to and promote these pathologies. The following paper will highlight recent studies investigating the relationship between the gut microbiota, liver biology, and pathobiology. Defining these connections will likely provide new targets for therapy or prevention of a wide variety of acute and chronic liver pathologies. PMID- 20706694 TI - Assessment of DNA damage by RAPD in Paracentrotus lividus embryos exposed to amniotic fluid from residents living close to waste landfill sites. AB - The aim of this study was to assess the genotoxic effects of environmental chemicals on residents living near landfills. The study was based on samples of amniotic fluid from women living in the intensely polluted areas around the Campania region of Italy compared to a nonexposed control group. We evaluated the genetic effects that this amniotic fluids collected in contaminated sites had on Paracentrotus lividus embryos. DNA damage was detected through changes in RAPD (Random Amplified Polymorphism DNA) profiles. The absence of the amplified DNA fragments indicated deletions in Paracentrotus lividus DNA exposed to the contaminated amniotic fluids when compared to equal exposure to uncontaminated fluids. These results show the ability of RAPD-PCR to detect and isolate DNA sequences representing genetic alterations induced in P. lividus embryos. Using this method, we identified two candidate target regions for DNA alterations in the genome of P. lividus. Our research indicates that RAPD-PCR in P. lividus embryo DNA can provide a molecular approach for studying DNA damage from pollutants that can impact human health. To our knowledge, this is the first time that assessment of DNA damage in P. lividus embryos has been tested using the RAPD strategy after exposure to amniotic fluid from residents near waste landfill sites. PMID- 20706700 TI - [Current state of laparoscopic hepatic surgery: results of a survey of DGAV members]. AB - BACKGROUND: To date laparoscopic hepatic surgery is only common in a few centres for a specific selected patient group. The intention of this survey was to estimate the current state of affairs for laparoscopic hepatic surgery in Germany at 2008. MATERIALS AND METHODS: A questionnaire was prepared and sent out by e mail in May 2009 to the members of the DGAV (German Society of General and Visceral Surgery). The feedback was evaluated anonymously. RESULTS: A total of 181 answers were received by 31st July 2009 (return rate of 15.9%). The return rate of basic and standard care hospitals was 9.2%, specialized hospitals 23.6%, hospitals with maximum care 50% and university hospitals had a return rate of 71.9%. The question whether laparoscopic hepatic surgery had been performed in 2008 was answered with YES by 125 (69.1%) and NO by 54 (29.8%) members. The number of laparoscopic hepatic surgery interventions (laparoscopic ultrasound, laparoscopic radiofrequency ablation and resection) in 2008 was given as more than 50 by 4 (2.2%) hospitals, between 20 and 50 by 11 (6.1%) hospitals, between 10 and 20 by 23 (12.7%) hospitals, between 5 and 10 by 45 (24.9%) hospitals and between 0 and 5 by 54 (29.8%) hospitals. In 2008 the frequency of laparoscopic ultrasound during intraoperative staging to confirm the diagnosis ranged from 2 to 250, whereby 96.4% of the hospitals had less than 50 and only 2 hospitals (2.7%) had 211 and 250 examinations, respectively. 50 hospitals carried out laparoscopic radiofrequency ablation (RFA). 69 (38.1%) of the interviewed hospitals reported hepatic laparoscopic resections (n=551). CONCLUSION: Laparoscopic liver surgery has been done in Germany in patients with benign or malignant liver lesions. Pure laparoscopy is the most common access. Atypical resections are the primarily indication followed by left lateral resections. All further types of resection have been done in a very small number. Laparoscopic liver surgery has been performed in all types of hospitals. PMID- 20706701 TI - [Urticaria update]. PMID- 20706702 TI - [Infections and chronic spontaneous urticaria. A review]. AB - Urticaria represents a common skin reaction pattern that can be induced by different factors. Triggering by infections has been discussed for many years but the exact role and mechanism of mast cell activation by infectious processes is unclear. In acute spontaneous urticaria, there is no doubt about a causal relationship to infections and all chronic urticaria must start as acute. Remission of annoying spontaneous chronic urticaria has been reported after successful treatment of persistent infections. Summarizing available studies evaluating the course after proven Helicobacter eradication demonstrates a statistically significant benefit compared to not-eradicated or Helicobacter negative patients. The licensed treatment with a standard dose of H1 antihistamines is not effective in a significant number of patients and infections can be easily treated. Therefore, appropriate diagnostic procedures should be included in the routine work-up, especially the search for Helicobacter pylori. PMID- 20706703 TI - Intracellular ROS level is increased in fibroblasts of triple A syndrome patients. AB - Triple A syndrome is named after the main symptoms of alacrima, achalasia, and adrenal insufficiency but also presents with a variety of neurological impairments. To investigate the causes of progressive neurodegeneration, we examined the oxidative status of fibroblast cultures derived from triple A syndrome patients in comparison to control cells. Patient cells showed a 2.1-fold increased basal level of reactive oxygen species (ROS) and a massive boost after induction of artificial oxidative stress by paraquat. We examined the expression of the ROS-detoxifying enzymes superoxide dismutase 1 and 2 (SOD1, SOD2), catalase, and glutathione reductase. The basal expression of SOD1 was significantly (1.3-fold) increased, and the expression of catalase was 0.7-fold decreased in patient cells after induction of artificial oxidative stress. We show that the mitochondrial network is 1.8-fold more extensive in patient cells compared to control fibroblasts although the maximal ATP synthesis was unchanged. Despite having the same energy potential as the controls, the patient cells showed a 1.4-fold increase in doubling time. We conclude that fibroblasts of triple A patients have a higher basal ROS level and an increased response to artificially induced oxidative stress and undergo "stress-induced premature senescence". The increased sensitivity to oxidative stress may be a major mechanism for the neurodegeneration in triple A syndrome. PMID- 20706704 TI - Sexual dimorphism in immune function changes during the annual cycle in house sparrows. AB - Difference between sexes in parasitism is a common phenomenon among birds, which may be related to differences between males and females in their investment into immune functions or as a consequence of differential exposure to parasites. Because life-history strategies change sex specifically during the annual cycle, immunological responses of the host aiming to reduce the impact of parasites may be sexually dimorphic. Despite the great complexity of the immune system, studies on immunoecology generally characterise the immune status through a few variables, often overlooking potentially important seasonal and gender effects. However, because of the differences in physiological and defence mechanisms among different arms of the immune system, we expect divergent responses of immune components to environmental seasonality. In male and female house sparrows (Passer domesticus), we measured the major components of the immune system (innate, acquired, cellular and humoral) during four important life-history stages across the year: (1) mating, (2) breeding, (3) moulting and (4) during the winter capture and also following introduction to captivity in aviary. Different individuals were sampled from the same population during the four life cycle stages. We found that three out of eight immune variables showed a significant life cycle stage * sex interaction. The difference in immune response between the sexes was significant in five immune variables during the mating stage, when females had consistently stronger immune function than males, while variables varied generally non-significantly with sex during the remaining three life cycle stages. Our results show that the immune system is highly variable between life cycle stages and sexes, highlighting the potential fine tuning of the immune system to specific physiological states and environmental conditions. PMID- 20706705 TI - [Male breast cancer: a challenge for urologists]. AB - Male breast cancer (male BC) accounts for <1% of all cancers in men, showing an increasing incidence with a peak in the sixth decade. Overall, men experience a worse prognosis than women, probably due to an advanced stage together with the higher age at diagnosis of male patients. Major risk factors for developing male BC include clinical disorders involving hormonal imbalances (excess of estrogen or a deficiency of testosterone as seen in patients with Klinefelter syndrome) and a positive family history for breast cancer. About 90% of male BC are invasive ductal carcinomas. Standard treatment for localized cancer is surgical removal. Adjuvant radiation and systemic therapy are the same as in women with breast cancer. Male BC expresses hormone receptors in about 90% of cases; therefore, tamoxifen is a therapeutic option. A future challenge for the urologist or andrologist is to diagnose the disease at an early stage to improve prognosis. PMID- 20706706 TI - QTL mapping for yield and lodging resistance in an enhanced SSR-based map for tef. AB - Tef is a cereal crop of cultural and economic importance in Ethiopia. It is grown primarily for its grain though it is also an important source of fodder. Tef suffers from lodging that reduces both grain yield and quality. As a first step toward executing a marker-assisted breeding program for lodging resistance and grain yield improvement, a linkage map was constructed using 151 F(9) recombinant inbred lines obtained by single-seed-descent from a cross between Eragrostis tef and its wild relative Eragrostis pilosa. The map was primarily based on microsatellite (SSR) markers that were developed from SSR-enriched genomic libraries. The map consisted of 30 linkage groups and spanned a total length of 1,277.4 cM (78.7% of the genome) with an average distance of 5.7 cM between markers. This is the most saturated map for tef to date, and for the first time, all of the markers are PCR-based. Using agronomic data from 11 environments and marker data, it was possible to map quantitative trait loci (QTL) controlling lodging, grain yield and 15 other related traits. The positive effects of the QTL identified from the wild parent were mainly for earliness, reduced culm length and lodging resistance. In this population, it is now possible to combine lodging resistance and grain yield using a marker-assisted selection program targeting the QTL identified for both traits. The newly developed SSR markers will play a key role in germplasm organization, fingerprinting and monitoring the success of the hybridization process in intra-specific crosses lacking distinctive morphological markers. PMID- 20706707 TI - Arthroscopic treatment of symptomatic bipartite patella. AB - Successful arthroscopic treatment of symptomatic bipartite patella in a 23-year old female professional volleyball player is reported. PMID- 20706709 TI - Coronary artery dilatation in toxic shock-like syndrome: the Kawasaki disease shock syndrome. AB - Kawasaki disease is a common systemic vasculitis of childhood that may result in life-threatening coronary artery abnormalities. Despite an overlap of clinical features with toxic shock syndrome, children with Kawasaki disease generally do not develop shock. We report two cases of older children who presented with a toxic shock-like illness, and were diagnosed with Kawasaki disease when coronary artery abnormalities were found on echocardiography, in keeping with the recently described 'Kawasaki disease shock syndrome'. Clinicians should consider Kawasaki disease in all children presenting with toxic shock and assess for coronary artery damage. PMID- 20706711 TI - Uncontrolled hypertension in a child with Hurler syndrome. PMID- 20706708 TI - Putative biological mechanisms for the association between early life adversity and the subsequent development of PTSD. AB - RATIONALE: Early Life Stress (ELS) increases risk for both adult traumatization and posttraumatic stress disorder (PTSD). Adult PTSD may also reflect a continuation of a response to an earlier exposure to adversity. Given similarities between neuroendocrine aspects of PTSD and ELS, such as in reduced cortisol signaling and glucocorticoid receptor (GR) responsiveness, some aspects of the biology of PTSD may reflect biological correlates of risk. OBJECTIVES: This paper will examine how empirical findings regarding the biological basis of ELS can inform our understanding of the neuroendocrinology of PTSD. This paper will also propose a hypothetical model to guide future research that integrates genetic, epigenetic, neuroendocrine, and psychological observations to understand the contribution of ELS neurobiology to PTSD. RESULTS: Recent genetic findings demonstrate heritable aspects of at least some of these cortisol-related disturbances. Furthermore, ELS may produce at least some of the PTSD-associated changes in glucocorticoid responsiveness through epigenetic mechanisms such as developmental programming. These, then, may contribute to enduring changes in stress responsiveness as well as enhanced risk for adult exposure and PTSD. CONCLUSION: Molecular mechanisms associated with gene x environment interactions or GR programming are essential in explaining current observations in the neuroendocrinology of PTSD that have been difficult to understand through the lens of contemporary stress theory. PMID- 20706712 TI - Sirenomelia--sympus unipus (mermaid deformity). PMID- 20706713 TI - Estimated cumulative radiation dose from PET/CT in children with malignancies. PMID- 20706714 TI - Acute inversion injury of the ankle without radiological abnormalities: assessment with high-field MR imaging and correlation of findings with clinical outcome. AB - BACKGROUND: Acute inversion injuries of the ankle are the most common sports accidents, accounting for approximately 10% of emergency room admissions. In up to 85%, an injury of the lateral collateral ligaments is observed. Classically, the assessment of these injuries has relied on clinical examination and radiographs, including stress views. The aim of our study was to correlate prospectively the findings of high-field 3 T MRI in acute ankle distortion with clinical outcome. METHODS: During a 6-month period, 38 patients were prospectively included. MRI was performed within 48 h of trauma and clinical examination using a protocol consisting of axial T2-weighted and coronal and sagittal T1-weighted images and a sagittal proton density (PDw) sequence. Each ligament injury was graded on a three-point scale. Functional outcome was evaluated using the AOFAS ankle-hindfoot scale. RESULTS: In 24/38 patients (63.12%), ligament injury was observed. In 22/24 cases, this was an injury of the lateral ligaments and in 2/24 cases of the medial ligaments. Injury of the syndesmosis occurred in three patients, a bone bruise in four, and an osteochondral lesion in three cases. Patients with an injury of two or more ligaments or a bone bruise had a lower AOFAS score and returned to sports activities and full weight-bearing later (P < 0.01). CONCLUSION: MR imaging at 3 Tesla is an independent predictor for clinical outcome. Therefore MRI may be beneficial in those cases where the findings influence further treatment. PMID- 20706715 TI - Human papillomavirus type 16 E6-specific antitumor immunity is induced by oral administration of HPV16 E6-expressing Lactobacillus casei in C57BL/6 mice. AB - Given that local cell-mediated immunity (CMI) against the human papillomavirus type 16 E6 (HPV16 E6) protein is important for eradication of HPV16 E6-expressing cancer cells in the cervical mucosa, the HPV16 E6 protein may be a target for the mucosal immunotherapy of cervical cancer. Here, we expressed the HPV16 E6 antigen on Lactobacillus casei (L. casei) and investigated E6-specific CMI following oral administration of the L. casei-PgsA-E6 to mice. Surface expression of HPV16 E6 antigens was confirmed and mice were orally inoculated with the L. casei-PgsA or the L. casei-PgsA-E6. Compared to the L. casei-PgsA-treated mice, significantly higher levels of serum IgG and mucosal IgA were observed in L. casei-PgsA-E6 immunized mice; these differences were significantly enhanced after boost. Consistent with this, systemic and local CMI were significantly increased after the boost, as shown by increased counts of IFN-gamma-secreting cells in splenocytes, mesenteric lymph nodes (MLN), and vaginal samples. Furthermore, in the TC-1 tumor model, animals receiving the orally administered L. casei-PgsA-E6 showed reduced tumor size and increased survival rate versus mice receiving control (L. casei-PgsA) immunization. We also found that L. casei-PgsA-E6-induced antitumor effect was decreased by in vivo depletion of CD4(+) or CD8(+) T cells. Collectively, these results indicate that the oral administration of lactobacilli bearing the surface-displayed E6 protein induces T cell-mediated cellular immunity and antitumor effects in mice. PMID- 20706716 TI - Integrating individual functional moieties of CXCL10 and CXCL11 into a novel chimeric chemokine leads to synergistic antitumor effects: a strategy for chemokine-based multi-target-directed cancer therapy. AB - The complexity of tumor biology necessitates a multimodality approach that targets different aspects of tumor environment in order to generate the greatest benefit. IFN-inducible T cell alpha chemoattractant (ITAC)/CXCL11 and IFN inducible protein 10 (IP10)/CXCL10 could exert antitumor effects with functional specificity and thus emerge as attractive candidates for combinatorial strategy. Disappointedly, a synergistic antitumor effect could not be observed when CXCL10 and CXCL11 were pooled together. In this regard, we seek to improve antitumor efficacy by integrating their individual functional moieties into a chemokine chimeric molecule, designated ITIP, which was engineered by substituting the N terminal and N-loop region of CXCL10 with those of CXCL11. The functional properties of ITIP were determined by chemotaxis and angiogenesis assays. The antitumor efficacy was tested in murine CT26 colon carcinoma, 4T1 mammary carcinoma and 3LL lung carcinoma. Here we showed that ITIP not only exhibited respective functional superiority but strikingly promoted regression of established tumors and remarkably prolonged survival of mice compared with its parent chemokines, either alone or in combination. The chemokine chimera induced an augmented anti-tumor immunity and a marked decrease in tumor vasculature. Antibody neutralization studies indicated that CXCL10 and CXCL11 moieties of ITIP were responsible for anti-angiogenesis and chemotaxis in antitumor response, respectively. These results indicated that integrating individual functional moieties of CXCL10 and CXCL11 into a chimeric chemokine could lead to a synergistic antitumor effect. Thus, this integration strategy holds promise for chemokine-based multiple targeted therapy of cancer. PMID- 20706717 TI - Factors influencing success of marine protected areas in the Visayas, Philippines as related to increasing protected area coverage. AB - Throughout the world there is a general consensus among environmentalists that there should be an increase in the amount of marine area that should be reserved in marine protected areas (MPAs). In fact, the 1998 Philippines Fishery Code indicates a need for designation of at least 15% of municipal waters for fish refuges or sanctuaries. Such an increase in area would take productive fishing areas away from fishing communities that can ill-afford the loss. The larger the protected area, there will be a greater number of people impacted. This article examines the relationship between factors that influence the success of Community Based MPA (CBMPA) performance in the Visayas, Philippines and their significance in efforts to increase the size of protected areas. PMID- 20706718 TI - Integrating environmental and socio-economic indicators of a linked catchment coastal system using variable environmental intensity. AB - Can we develop land use policy that balances the conflicting views of stakeholders in a catchment while moving toward long term sustainability? Adaptive management provides a strategy for this whereby measures of catchment performance are compared against performance goals in order to progressively improve policy. However, the feedback loop of adaptive management is often slow and irreversible impacts may result before policy has been adapted. In contrast, integrated modelling of future land use policy provides rapid feedback and potentially improves the chance of avoiding unwanted collapse events. Replacing measures of catchment performance with modelled catchment performance has usually required the dynamic linking of many models, both biophysical and socio-economic and this requires much effort in software development. As an alternative, we propose the use of variable environmental intensity (defined as the ratio of environmental impact over economic output) in a loose coupling of models to provide a sufficient level of integration while avoiding significant effort required for software development. This model construct was applied to the Motueka Catchment of New Zealand where several biophysical (riverine water quantity, sediment, E. coli faecal bacteria, trout numbers, nitrogen transport, marine productivity) models, a socio-economic (gross output, gross margin, job numbers) model, and an agent-based model were linked. An extreme set of land use scenarios (historic, present, and intensive) were applied to this modelling framework. Results suggest that the catchment is presently in a near optimal land use configuration that is unlikely to benefit from further intensification. This would quickly put stress on water quantity (at low flow) and water quality (E. coli). To date, this model evaluation is based on a theoretical test that explores the logical implications of intensification at an unlikely extreme in order to assess the implications of likely growth trajectories from present use. While this has largely been a desktop exercise, it would also be possible to use this framework to model and explore the biophysical and economic impacts of individual or collective catchment visions. We are currently investigating the use of the model in this type of application. PMID- 20706719 TI - Temporal bone imaging using digital volume tomography and computed tomography: a comparative cadaveric radiological study. AB - PURPOSE: The aim of the present study was to analyze the diagnostic value of some temporal bone structures, e.g., ossicular chain, with digital volume tomography (DVT) compared with computed tomography (CT). METHODS: Radiological imaging for presentation structures of the temporal bone were performed by DVT and CT. Axial and coronal scans in vitro examinations were performed in 38 human temporal bones. 43 structures were defined. The frequency of visualization of these anatomic structures were studied and statistically analyzed. RESULTS: In the present study there was a higher significance of identified structures in DVT. In 15 (34.9%) temporal bone specimens defined structures were found equally in DVT and CT scans of axial images and 12 (27.9%) of coronal images. However, 9 structures (20.1%) of axial scans and 5 structures (11.6%) of coronal scans could be identified statistically significantly (P < 0.05) more often in DVT than in CT. CONCLUSION: Anatomical structures of the temporal bone can be identified in higher significance in DVT than in CT scans. PMID- 20706720 TI - Predictors for splenectomy among patients with primary chronic immune thrombocytopenia: a population-based cohort study from Denmark. AB - We conducted a nationwide cohort study of adult Danish patients with primary chronic immune thrombocytopenia (cITP) to examine selected patient and clinical characteristics as predictors for splenectomy. We analyzed data from the Danish National Patient Registry and patient medical records from 1996 to 2007. Using Cox regression analyses, we calculated incidence rate ratios (IRRs) and associated 95% confidence intervals (CI) for splenectomy. We included 371 adult cITP patients. Of these, 87 patients (23%) underwent a splenectomy during a median of 3.6 years of follow-up. The majority (84%) of cITP patients who underwent splenectomy had splenectomy within the first year after cITP diagnosis. Predictors for splenectomy included age <= 75 years (adjusted 1-year IRR = 6.79 (95% CI, 2.10-21.90)) at least one platelet count <= 30 * 10(9)/L (i.e., high disease activity; adjusted 1-year IRR = 2.67 (95% CI, 1.37-5.22)) during follow up and year of cITP diagnosis in early period (1996-2001; adjusted 1 year IRR = 2.37 (95% CI, 1.46-3.85)). Presence of chronic comorbidity was associated with lower rates of splenectomy (adjusted 1 year IRR = 0.58 (95% CI, 0.33-1.05)). Our findings suggest that high disease activity and absence of chronic comorbidity may be associated with higher rates of splenectomy, and that contraindications for splenectomy (i.e., patients' perceived frailty) cause the physicians to use the procedure cautiously. PMID- 20706721 TI - The role of routine imaging procedures in the detection of relapse of patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma. AB - Despite improved initial therapies, a subgroup of patients with aggressive non Hodgkin (A-NHL) and Hodgkin lymphomas (HL) will relapse after first remission. The optimal follow-up strategy for the detection of relapse has not been clarified and periodic imaging is not recommended in most written guidelines. We identified 125 patients with HL and A-NHL diagnosed between January 1993 and September 2008 who relapsed at least 1 month after the end of initial therapy. We assessed whether relapse was detected based on clinical signs or periodic computed tomography (CT), [(18)F] fluorodeoxyglucose positron emission tomography (PET), or combined PET/CT and whether the mode of detection influenced the pattern and outcome of relapsed disease. Overall, most relapses (62%) were diagnosed clinically especially in A-NHL and in patients with extranodal involvement at diagnosis (p < 0.05); however, relapses of HL occurring after 2001 when PET/CT became available were more commonly detected by routine imaging (p < 0.05). Imaging-detected relapse was not associated with improved survival. While clinical exam remains the most common mode of detecting relapse, our results suggest a potential role for routine PET/CT surveillance in HL patients; however, survival does not appear to be affected by mode of detection. PMID- 20706722 TI - Pegfilgrastim reduces the length of hospitalization and the time to engraftment in multiple myeloma patients treated with melphalan 200 and auto-SCT compared with filgrastim. AB - To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim (n = 46; 50%), or daily filgrastim (n = 46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p = 0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p = 0.024). Pegfilgrastim-treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10) versus 0.5 transfusions (range, 0-9), p = 0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim (p = 0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT. PMID- 20706723 TI - GSEA-SNP identifies genes associated with Johne's disease in cattle. AB - SNP-based gene-set enrichment analysis from single nucleotide polymorphisms, or GSEA-SNP, is a tool to identify candidate genes based on enrichment analysis of sets of genes rather than single SNP associations. The objective of this study was to identify modest-effect genes associated with Mycobacterium avium subsp. paratuberculosis (Map) tissue infection or fecal shedding using GSEA-SNP applied to KEGG pathways or Gene Ontology (GO) gene sets. The Illumina Bovine SNP50 BeadChip was used to genotype 209 Holstein cows for the GSEA-SNP analyses. For each of 13,744 annotated genes genome-wide located within 50 kb of a Bovine SNP50 SNP, the single SNP with the highest Cochran-Armitage Max statistic was used as a proxy statistic for that gene's strength of affiliation with Map. Gene-set enrichment was tested using a weighted Kolmogorov-Smirnov-like running sum statistic with data permutation to adjust for multiple testing. For tissue infection and fecal shedding, no gene sets in KEGG pathways or in GO sets for molecular function or cellular component were enriched for signal. The GO biological process gene set for positive regulation of cell motion (GO:0051272, q = 0.039, 5/11 genes contributing to the core enrichment) was enriched for Map tissue infection, while no GO biological process gene sets were enriched for fecal shedding. GSEA-SNP complements traditional SNP association approaches to identify genes of modest effects as well as genes with larger effects as demonstrated by the identification of one locus that we previously found to be associated with Map tissue infection using a SNP-by-SNP genome-wide association study. PMID- 20706724 TI - [Surgical management of entropion]. AB - Entropion is an inward folding malposition of the eyelid margin. As a result of persistent entropion and trichiasis severe complications of the conjunctiva and the cornea can occur, which can lead to loss of visual acuity. Conservative forms of therapy mostly provide only a temporary solution and are generally used in preoperative care or if surgical intervention is unfeasible. The main therapeutic means is surgery. Normally congenital entropion recedes throughout the first 12 months of life, so that surgery is not needed immediately. Spastic inflammatory entropion disappears with successful treatment of the inflammation. Senile entropion is caused by three different pathological mechanisms: loss of lid laxity, loss of tension of lower lid retractors and alterations to the musculus orbicularis. These can be corrected with the procedures developed by Wies and also by Quickert and Jones. The surgeon should be careful to avoid an overcorrection with iatrogenic ectropion. Finally, cicatricial entropion can occur as a consequence of persistent inflammation or injuries. In this case free mucosa grafts may be necessary. PMID- 20706725 TI - [Surgical management of ectropion]. AB - In view of demographic changes in the population pyramid age structure an increase in eyelid malpositions such as ectropion is likely to occur. The surgical correction of ectropion requires a detailed knowledge of anatomical and pathophysiological factors to be able to effectively evaluate changes of the anterior and posterior lamellae with shortening, weakness, dehiscence and paralytic components. The choice of surgical procedure considering the age of the patient, genesis and the exact localization of the pathological change is of utmost importance in order to achieve ideal cosmetic and functional results. PMID- 20706726 TI - How did the surgeons treat neonates with imperforate anus in the eighteenth century? AB - Anorectal malformations (ARMS) are one of those challenging topics of pediatric surgery. The developments in assessing and approaching patients with these anomalies have been made in the last decades and the methods described in older textbooks functioned as a guide in planning these attempts (Kiely and Pena in Pediatric surgery, Mosby, Missouri, pp 1425-1449, 1998; Grosfeld in Anorectal malformations in children, Springer-Verlag, Berlin, pp 3-15, 2006). The aim of this study is to present the attitude of a surgeon of eighteenth century to the treatment of anorectal malformations, and the evolution in the history of the anomaly. The part about imperforate anus in a textbook of surgery, found in a second-hand bookstore, was translated. The description and the classification of the anomaly, the methods of approaching these cases together with some case reports were presented and compared with today's practice. The historical background of the anomaly was evaluated not only with regard to the book of Heister specifically but also to the other data obtained in the literature. The anomaly was reported to be "not rarely" observed. The obstetricians were warned to examine a newborn baby completely for early diagnosis. The classification of the anomaly was made according to the properties of the membrane covering the anus but prompt treatment, initiating with its simple excision, was suggested in all types. Better results in cases whose anus was covered with a thin, delicate membrane were reported. The results show that routine neonatal examination for all babies was recommended in this Textbook of Surgery which had been published 260 years ago. The physical deterioration due to delay was well described. A broad classification of imperforate anus was made and successful outcome in low type anomalies of today was reported with some case samples. It is clear that all the efforts starting from Soranus until today improved the understanding of the anomaly. Combining previous information with today's practice in the meetings focused totally on anorectal malformations, where the leading surgeons shared their experiences and re-evaluated the problems encountered, enlightened the future status of this interesting topic of pediatric surgery. PMID- 20706727 TI - Integration of genetic signature and TNM staging system for predicting the relapse of locally advanced colorectal cancer. AB - PURPOSE: To identify potential genetic markers in treated stage II-III colorectal cancer patients and predict 3-year tumor relapse using statistical models based on important clinical factors and significant genetic markers. METHODS: Gene expression profiling by cDNA-mediated Annealing, Selection, extension and Ligation assay was performed in a prospectively collected 95 stage II-III colorectal cancer patients with Fluorouracil-based adjuvant chemotherapy. We studied the gene expression level of 502 genes for patients with different outcomes. The prognostic effect of genetic signature was evaluated in multivariate analysis. We further integrated the genetic signature to clinical Classification of Malignant Tumors (TNM) staging system for predicting of 3-year tumor relapse. RESULTS: An 8-gene signature was identified to well discriminate patients with different treatment outcomes. An integrated risk factor, which including 8-gene signature and TNM staging has been developed. ROC curve revealed that our integrated risk factor was better than genetic signature or current sixth edition TNM staging system alone. CONCLUSIONS: Our 8-gene signature was promising in predicting 3-year disease-free survival rate for locally advanced colorectal cancer. The integrated risk factor, which combining genetic signature with clinical TNM staging system may further improve the outcome prediction. PMID- 20706728 TI - Omega-3 fatty acids and lipoprotein associated phospholipase A(2) in healthy older adult males and females. AB - PURPOSE: Lipoprotein associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammatory factor that has been independently associated with stroke and cardiovascular disease (CVD). Omega-3 fats have been implicated in reducing inflammation associated with CVD. The aim of this study was to determine if an 8 week isocaloric diet supplemented with eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) in the form of fish oil or alpha-linolenic acid (ALA) in the form of flaxseed oil would alter Lp-PLA(2) among healthy adults ages 50 years and older. METHODS: Fifty-nine healthy adults (~75% female, average age 61 years) were randomized to one of three groups with equal amounts of total fat intake. All capsules contained ~1 g of fat. The control group (n = 19) consumed olive oil capsules (~11 g/day); the ALA group (n = 20) consumed flaxseed oil capsules (~11 g/day) and the EPA/DHA group (n = 20) consumed fish oil capsules (~2 g/day + 9 g/day of olive oil). Fasting blood samples were obtained before and after the 8 week intervention for determination of Lp-PLA(2) mass and activity as well as lipid values. RESULTS: We did not find any significant changes in Lp-PLA(2) mass or activity after the intervention in any of the groups; however, change in oxidized LDL was associated with change in Lp-PLA(2) mass (r = 0.37, p < 0.01). CONCLUSION: Supplementing the diet with omega-3 fatty acids for 8-weeks did not influence Lp-PLA(2) activity or mass among older adults; altering oxidized LDL may be necessary to see changes in Lp-PLA(2) levels. PMID- 20706729 TI - Transfer of radionuclides to ants, mosses and lichens in semi-natural ecosystems. AB - There is a scarcity of data on transfer of both natural and anthropogenic radionuclides to detritivorous invertebrates for use in the assessment of radiation exposure. Although mosses and lichens have been extensively used in biomonitoring programs, the data on transfer of radionuclides to these species are limited, particularly for natural radionuclides. To enhance the available data, activity concentrations of (137)Cs, (226)Ra and (228)Ra were measured in ants, mosses and lichens and corresponding undisturbed soil collected from semi natural ecosystems in Serbia and Montenegro and biota/soil concentration ratios (CR) calculated. Since the majority of internal dose to biota is expected to come from (40)K, the activity concentrations of this radionuclide were also determined. The mean CR values for (137)Cs, (226)Ra and (228)Ra in ants analyzed in this study were found to be 0.02, 0.06 and 0.02, respectively. The mean CR values of radionuclides in mosses were found to be 2.84 for (137)Cs, 0.19 for (226)Ra and 0.16 for (228)Ra, while those in lichens were found to be 1.08 for (137)Cs, 0.15 for (226)Ra and 0.13 for (228)Ra. The CR values obtained in this study were compared with default CR values used in the ERICA Tool database and also with those reported in other studies. PMID- 20706730 TI - Non-homologous chromosome pairing and crossover formation in haploid rice meiosis. AB - While many studies have provided significant insight into homolog pairing during meiosis, information on non-homologous pairing is much less abundant. In the present study, fluorescence in situ hybridization (FISH) was used to investigate non-homologous pairing in haploid rice during meiosis. At pachytene, non homologous chromosomes paired and formed synaptonemal complexes. FISH analysis data indicated that chromosome pairing could be grouped into three major types: (1) single chromosome paired fold-back as the univalent structure, (2) two non homologous chromosomes paired as the bivalent structure, and (3) three or more non-homologous chromosomes paired as the multivalent structure. In the survey of 70 cells, 65 contained univalents, 45 contained bivalents, and 49 contained multivalent. Moreover, chromosomes 9 and 10 as well as chromosomes 11 and 12 formed non-homologous bivalents at a higher frequency than the other chromosomes. However, chiasma was always detected in the bivalent only between chromosomes 11 and 12 at diakinesis or metaphase I, indicating the pairing between these two chromosomes leads non-homologous recombination during meiosis. The synaptonemal complex formation between non-homologs was further proved by immunodetection of RCE8, PAIR2, and ZEP1. Especially, ZEP1 only loaded onto the paired chromosomes other than the un-paired chromosomes at pachytene in haploid. PMID- 20706731 TI - The effect of caffeine on intraocular pressure: a systematic review and meta analysis. AB - BACKGROUND: Caffeine is widely consumed, and its effect on intraocular pressure (IOP) has been reported in conflicting data. The aim of this meta-analysis was to quantitatively summarize the effect of caffeine on IOP in normal individuals and in patients with glaucoma or ocular hypertension (OHT). METHODS: A comprehensive literature search was performed using the Cochrane Collaboration methodology to identify pertinent randomized controlled trials (RCTs) from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and EMBASE. A systematic review and meta-analysis was performed. IOP at 0.5 hour (h), 1 h and 1.5 h after caffeine ingestion was the main outcome measurement. RESULTS: Six RCTs (two parallel-designed and four crossover-designed) evaluating 144 participants fulfilled inclusion criteria. The risk of bias for these studies was uncertain. Among the participants, 103 were normal individuals and 41 were patients with glaucoma or OHT. In normal individuals, the IOPs measured at 0.5 h, 1 h and 1.5 h post-intervention were not affected by ingestion of caffeine. The weighted mean difference (WMD) with 95% confidence intervals (95%CI) for each measurement point were -0.740 (-2.454, 0.974), 0.522 (-0.568, 1.613) and 0.580 (-1.524, 2.684). However, in patients with glaucoma or OHT, IOP increased at each measurement point, with the WMD and 95%CI being 0.347 (0.078, 0.616), 2.395 (1.741,3.049) and 1.998 (1.522,2.474) respectively. No publication bias was detected by either Begg's or Egger's test. CONCLUSION: Available evidences showed that caffeine had different effects on IOP in different groups of individuals. For normal individuals, IOP was not changed by ingestion of caffeine, while for patients with glaucoma or OHT, IOP increased significantly. More high-quality RCTs are warranted to confirm this. The mechanisms underlying this phenomenon and the clinical significance are to be explored. PMID- 20706732 TI - Effects of eccentric exercise-induced muscle damage on intramyocellular lipid concentration and high energy phosphates. AB - Eccentric exercise is known to cause changes to the ultrastructure of skeletal muscle and, in turn, may alter the ability of the muscle to store and utilise intracellular substrates such as intramyocellular lipid (IMCL). The purpose of this study was to test the hypothesis that exercise-induced muscle damage (EIMD) results in IMCL accumulation. Six males (31 +/- 6 years; mean +/- SD, and 72.3 +/ 9.7 kg body mass) performed 300 unilateral, maximal, isokinetic, eccentric contractions (Ecc) (30 degrees s(-1)) of the quadriceps on an isokinetic dynamometer, followed immediately by an equal amount of work by the contralateral leg but with concentric action (Con). Phosphate compounds and IMCL content of the vastus lateralis of both legs were measured using (31)P and (1)H magnetic resonance spectroscopy. IMCL content was higher in Ecc than Con 24 h post but the reverse was evident 48 h post-exercise (P = 0.046). A significant time * trial interaction for resting [P(i)] (P = 0.045), showed increases in Ecc across time but no change in Con. A significant main effect of trial (P = 0.002) was apparent indicating the Ecc leg had marked metabolic dysfunction. The P(i)/PCr ratio showed a significant effect of trial (P = 0.001) with an increase evident in Ecc leg, primarily due to increases in [P(i)]. The present study highlights changes in IMCL content of skeletal muscle following EIMD. PMID- 20706733 TI - Effects of a single habituation session on neuromuscular isokinetic profile at different movement velocities. AB - Single training session (STS) may increase the power output (i.e., maximal torque) in different contraction types; however, little is known about the neuromuscular adaptations to reach this enhancement. In this way, the present study examined the differences between knee extensors EMG, kinematics, and dynamometry at 60 and 180 degrees s(-1) before (PRE) and after (POST) a STS. Seventeen healthy males completed three different tasks: (1) 5-maximal isokinetic knee extensions, without previous habituation (PRE) at 60 and 180 degrees s(-1); (2) in the same day and after a proper rest, two bouts of 5-maximal isokinetic contractions (STS) at 60 and 180 degrees s(-1); and (3) in a new visit, POST consisted in new 5-maximal isokinetic contractions at 60 and 180 degrees s(-1). The main parameters examined were: knee extensors peak torque (PT), total work (TW), EMG (prior to the movement onset, agonist and antagonist activation), rate of force (RFD), and velocity development (RVD). There was significant increase in PT [12% (60 degrees s(-1)) and 8.7% (180 degrees s(-1))] and TW [13.5% (60 degrees s(-1)) and 10.7% (180 degrees s(-1))] from PRE to POST sessions. Increases in RFD were found for both velocities (p < 0.05); however, RVD and vastus lateralis EMG prior to the movement onset were significantly higher for POST only at 60 degrees s(-1). The RFD percentage of change (%change) was significantly correlated to %change for PT at 60 degrees s(-1) (r(2) = 0.53) and 180 degrees s(-1) (r(2) = 0.45). In conclusion, STS improves neural strategies to contract muscles stronger and faster at the slowest velocity, while higher velocities present different adaptations and might need more practice to further adaptations. PMID- 20706734 TI - Regulation of the gibberellin pathway by auxin and DELLA proteins. AB - The synthesis and deactivation of bioactive gibberellins (GA) are regulated by auxin and by GA signalling. The effect of GA on its own pathway is mediated by DELLA proteins. Like auxin, the DELLAs promote GA synthesis and inhibit its deactivation. Here, we investigate the relationships between auxin and DELLA regulation of the GA pathway in stems, using a pea double mutant that is deficient in DELLA proteins. In general terms our results demonstrate that auxin and DELLAs independently regulate the GA pathway, contrary to some previous suggestions. The extent to which DELLA regulation was able to counteract the effects of auxin regulation varied from gene to gene. For Mendel's LE gene (PsGA3ox1) no counteraction was observed. However, for another synthesis gene, a GA 20-oxidase, the effect of auxin was weak and in WT plants appeared to be completely over-ridden by DELLA regulation. For a key GA deactivation (2-oxidase) gene, PsGA2ox1, the up-regulation induced by auxin deficiency was reduced to some extent by DELLA regulation. A second pea 2-oxidase gene, PsGA2ox2, was up regulated by auxin, in a DELLA-independent manner. In Arabidopsis also, one 2 oxidase gene was down-regulated by auxin while another was up-regulated. Monitoring the metabolism pattern of GA(20) showed that in Arabidopsis, as in pea, auxin can promote the accumulation of bioactive GA. PMID- 20706735 TI - The 3' untranslated region of the two cytosolic glutamine synthetase (GS(1)) genes in alfalfa (Medicago sativa) regulates transcript stability in response to glutamine. AB - Glutamine synthetase (GS) catalyzes the ATP-dependent condensation of ammonia with glutamate to produce glutamine. The GS enzyme is located either in the chloroplast (GS(2)) or in the cytoplasm (GS(1)). GS(1) is encoded by a small gene family and the members exhibit differential expression pattern mostly attributed to transcriptional regulation. Based on our recent finding that a soybean GS(1) gene, Gmglnbeta ( 1 ) is subject to its 3'UTR-mediated post-transcriptional regulation as a transgene in alfalfa (Medicago sativa) we have raised the question of whether the 3'UTR-mediated transcript destabilization is a more universal phenomenon. Gene constructs consisting of the CaMV35S promoter driving the reporter gene, GUS, followed by the 3'UTRs of the two alfalfa GS(1) genes, MsGSa and MsGSb, were introduced into alfalfa and tobacco. The analysis of these transformants suggests that while both the 3'UTRs promote transcript turnover, the MsGSb 3'UTR is more effective than the MsGSa 3'UTR. However, both the 3'UTRs along with Gmglnbeta ( 1 ) 3'UTR respond to nitrate as a trigger in transcript turnover. More detailed analysis points to glutamine rather than nitrate as the mediator of transcript turnover. Our data suggests that the 3'UTR-mediated regulation of GS(1) genes at the level of transcript turnover is probably universal and is used for fine-tuning the expression in keeping with the availability of the substrates. PMID- 20706736 TI - Efficacy of a combination of imidacloprid 10%/moxidectin 2.5% spot-on (Advocate(r) for dogs) in the prevention of canine spirocercosis (Spirocerca lupi). AB - The nematode Spirocerca lupi is a major canine parasite in warm regions of the world, classically causing parasitic nodules in the esophagus, aortic aneurysms, and spondylitis. This study evaluated the preventive efficacy of monthly treatment with imidacloprid 10%/moxidectin 2.5% spot-on (Advocate(r) for dogs) administered over a period of 9 months in young dogs naturally exposed to S. lupi on Reunion island. One hundred and twelve puppies, aged from 2.0 to 4.0 months and with a negative spirocerca fecal examination at inclusion, completed the study. They were randomly allocated to two groups. Group A puppies (n=58) received nine spot-on treatments with Advocate(r) at the minimum dose of 2.5 mg moxidectin/kg bw at monthly intervals. Control group B puppies (n=54) received no treatment for S. lupi. During the study, regular clinical and fecal examinations were performed, as was final upper gastrointestinal endoscopy. Endoscopy showed that 19 dogs from group B had spirocerca nodules, corresponding to a prevalence of 35.2% in dogs aged 12 to 14 months. In contrast, only one dog from group A had a nodule, corresponding to a preventive efficacy of 94.7% (p<0.0001). None of the 378 fecal examinations were positive for spirocerca. This study confirms a high prevalence of canine spirocercosis on Reunion and shows that infestation occurs in very young puppies. Furthermore, it demonstrates that monthly spot-on administration of a combination of imidacloprid 10%/moxidectin 2.5% (Advocate(r) for dogs) in puppies starting at the age of 2 to 4 months achieves effective and safe prevention of canine spirocercosis. PMID- 20706737 TI - Decrease of peritoneal inflammatory CD4(+), CD8(+), CD19(+) lymphocytes and apoptosis of eosinophils in a murine Taenia crassiceps infection. AB - After an intraperitoneal infection of mice with Taenia crassiceps metacestodes, peritoneal inflammatory cells labeled with fluoresceinated MoAb anti-mouse were analyzed by flow cytometry. Apoptosis was studied by annexin A/PI, TUNEL assays, DNA laddering, caspase-3 activity, and electron microscopy. An important continuous decrease of CD4+, CD8+ and CD19+ lymphocytes, and an increase of eosinophils and macrophages throughout the observation time were found. Apoptosis of eosinophils was quantified during the observation period with a peak at 6 days post-infection (67.27%). In an additional experiment at 12 days post-infection using TUNEL staining, a high level of apoptosis of eosinophil (92.3%) and a significant decrease of CD4+, CD8+, and CD19+ lymphocytes were confirmed. Caspase 3 activity in peritoneal fluid, peritoneal cells' DNA fragmentation, and apoptosis of eosinophils and monocytes were found. The dramatic decrease of peritoneal inflammatory T and B cells and the high level of apoptosis of inflammatory eosinophils induced in mice by infection with T. crassiceps cysticerci may be important factors of the immunosuppression observed in cysticercosis. PMID- 20706738 TI - Identification of an autosomal recessive stuttering locus on chromosome 3q13.2 3q13.33. AB - Stuttering is a common speech disorder with substantial genetic contributions. To better understand the genetic factors involved in stuttering, we performed a genome-wide linkage study in a newly-ascertained consanguineous stuttering family from Pakistan. A linkage scan in this family using parametric linkage analysis revealed significant linkage only on chromosome 3q13.2-3q13.33, with a maximum two-point LOD score of 4.23 under an autosomal recessive model of inheritance. PMID- 20706740 TI - [Analgesic efficacy of TENS therapy in patients with gonarthrosis. A prospective, randomised, placebo-controlled, double-blind study]. AB - BACKGROUND: The goal of the study was to substantiate the influence of TENS on pain development and medication needs of patients with proven gonarthrosis and chronic pain. The study included a 3-week stimulation period and 2-week observation period after the end of stimulation. MATERIALS AND METHODS: Patients (at least 20 per group) were assigned to either an active treatment group or placebo group in a randomised, double-blind, placebo-controlled trial. For the active treatment group the TENS therapy device with HAN stimulation (alternating phase of stimulation) was used (TENStem eco).Total length of time: 30 min at least two times a day. The length of therapy was 3 weeks (therapy), followed by an observation period of 2 weeks (follow-up). The total length of the study was 5 weeks, whereby at the beginning and at the end of weeks 1, 3 and 5 the SF-36, WOMAC score and Lysholm score were documented; the pain score was documented daily. RESULTS: There are no significant demographic differences between the groups. In the active treatment group there was clear relief in pain intensity in the morning, midday and evening over the 3-week period of therapy. The Lysholm score in the active treatment group was 53.4 at the beginning, 90 after 1 week, 94.5 after the third week and 91 by the fifth week (significant difference). There were no side effects. CONCLUSION: TENS therapy with HAN stimulation resulted in pain relief in patients with gonarthrosis during the therapy period with TENS, but the pain relief did not last beyond the end of the TENS therapy. There was an improvement in the Lysholm score and the WOMAC score during the therapy. This improvement remained over the following 2-week period of observation without further TENS therapy. TENS therapy is a simple and effective method to treat gonarthrosis with very few side effects. PMID- 20706741 TI - Effects of precipitation and temperature on crop production variability in northeast Iran. AB - Climate variability adversely impacts crop production and imposes a major constraint on farming planning, mostly under rainfed conditions, across the world. Considering the recent advances in climate science, many studies are trying to provide a reliable basis for climate, and subsequently agricultural production, forecasts. The El Nino-Southern Oscillation phenomenon (ENSO) is one of the principle sources of interannual climatic variability. In Iran, primarily in the northeast, rainfed cereal yield shows a high annual variability. This study investigated the role played by precipitation, temperature and three climate indices [Arctic Oscillation (AO), North Atlantic Oscillation (NAO) and NINO 3.4] in historically observed rainfed crop yields (1983-2005) of both barley and wheat in the northeast of Iran. The results revealed differences in the association between crop yield and climatic factors at different locations. The south of the study area is a very hot location, and the maximum temperature proved to be the limiting and determining factor for crop yields; temperature variability resulted in crop yield variability. For the north of the study area, NINO 3.4 exhibited a clear association trend with crop yields. In central locations, NAO provided a solid basis for the relationship between crop yields and climate factors. PMID- 20706742 TI - Severe methemoglobinemia after dental anesthesia: a warning about propitocaine induced methemoglobinemia in neonates. AB - Methemoglobinemia is a fatal complication of local anesthesia. We describe a case report of female neonate who developed severe methemoglobinemia after extraction of neonatal teeth conducted with general anesthesia plus local injection of Citanest-Octapressin((r)) (propitocaine of approximately 10 mg/kg). Central cyanosis appeared within an hour after surgery. The percentage of methemoglobin reached up to 43.9%. Not only pediatric dentists but also anesthesiologists generally agree with the idea that local anesthesia provides various benefits in painful procedures in neonates. However, this case may serve as a warning when using Citanest-Octapressin((r)), which is still commercially available for neonatal patients. PMID- 20706739 TI - SAGES guidelines for the clinical application of laparoscopic biliary tract surgery. PMID- 20706744 TI - Heparanase expression in term placentas of diabetic patients and healthy controls. AB - PURPOSE: The prevalence of diabetic disorders in pregnancy is rising, which goes along with increased risks for maternal and foetal complications during pregnancy and delivery. The expression of the endo-beta-D: -glucuronidase, heparanase (HPSE), may increase under hyperglycaemic conditions, is believed to play an important role in diabetes associated morbidity outside the female reproductive tract and is expressed in the placenta throughout gestation. However, the placental expression of HPSE has not been investigated in diabetic patients. MATERIALS AND METHODS: Placental biopsies of 30 patients with pre-existing or gestational diabetes and 30 healthy controls were analysed by real-time PCR and immunohistochemistry with regard to the presence of HPSE at term. RESULTS: Patients and controls were comparable with respect to foetal outcome and maternal characteristics except for maternal body mass index. We were unable to show significant differences in placental HPSE expression between diabetic patients and healthy controls. DISCUSSION: This study suggests that HPSE expression in term placentas is not affected by maternal diabetes and thus does not contribute to pathological processes in diabetic pregnancies with deliveries at term. PMID- 20706745 TI - Attitudes of graduating medical doctors toward using sex selection techniques in Jordan in 2009. AB - OBJECTIVES: The aim of this study was to describe the attitude of graduating medical doctors toward the use of sex selection techniques in Jordan in 2009. MATERIALS AND METHODS (DESIGN): A self-administered questionnaire was used to assess attitude toward using sex selection. Demographic variables, gender preference of future children, and score on attitude toward using technology scale were used as independent variables. RESULTS: A total of 254 doctors (178 males, 76 females) completed the questionnaire. Forty-one (16.1%) doctors thought that sex selection as PGD should be strictly prohibited and 45 (17.7%) thought it should be allowed freely. More than half (54.7%) of them thought it should only be available for medical reason. Only 59 (23.2%) reported that they may consider the use of sex selection technology to choose their future children. Participants who preferred their firstborn child to be a boy or those who preferred their first born child to be a girl were more likely to use sex selection than those without preference. Christian participants were more likely to use sex selection technology than Muslim participants, 9 (47.4%) versus 50 (21.3%). For each one point increase in Attitude score, the odds of using sex selection increased by 20%. CONCLUSIONS: The majority of graduating medical doctors believed that sex selection should be restricted and they were not willing to use it. PMID- 20706746 TI - Cystic hamartoma of the tuber cinereum. PMID- 20706747 TI - Environmental enrichment increases the in vivo extracellular concentration of dopamine in the nucleus accumbens: a microdialysis study. AB - The present study was designed to elucidate the effects of environmental enrichment in adulthood (EE) on the in vivo basal and stimulated extracellular concentration of dopamine in the nucleus accumbens of awake rats. The effects of EE on novelty-induced motor activity in an open field and on the levels of brain derived neurotrophic factor (BDNF) in the nucleus accumbens and striatum were also analysed. Male Wistar rats (3 months of age) were housed in enriched or control conditions during 12 months. After behavioural testing, animals were subdivided in two groups. In one of the groups, BDNF protein levels were determined. In the second group of rats, microdialysis experiments were performed to monitor dialysate concentrations of dopamine in the nucleus accumbens after the perfusion of the glutamatergic agonist alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid (AMPA; 100 MUM) or potassium (100 mM). Both basal and potassium stimulated dialysate concentrations of dopamine were higher in EE than in control rats (basal: 80%; potassium: 210%). EE did not significantly change the increases of dialysate concentrations of dopamine induced by AMPA although there was a trend towards an enhancement of the effects of AMPA. EE decreased novelty-induced locomotor activity but did not modify the levels of BDNF in the nucleus accumbens or in the striatum. These results suggest that the in vivo activity of the mesolimbic dopamine system is enhanced by housing rats in an enriched environment and that this effect is not mediated by BDNF. These findings may be relevant for the understanding of the effects of EE on motor behaviour. PMID- 20706748 TI - Synthesis of C5-tetrazole derivatives of 2-amino-adipic acid displaying NMDA glutamate receptor antagonism. AB - Five derivatives of 2-amino-adipic acid bearing a tetrazole-substituted in C5 position were synthesized. These compounds displayed selective antagonism towards N-methyl-D: -aspartate (NMDA) receptors compared with AMPA receptors, and they were devoid of any neurotoxicity. Among these five analogues, one exhibited a higher affinity for synaptic NMDA responses than the other four. Therefore, C5 tetrazole-substituted of 2-amino-adipic acid represent an interesting series of new NMDA receptor antagonists. This approach may be considered as a new strategy to develop ligands specifically targeted to synaptic or extra-synaptic NMDA receptors. PMID- 20706749 TI - Mapping O-GlcNAc modification sites on tau and generation of a site-specific O GlcNAc tau antibody. AB - The microtubule-associated protein tau is known to be post-translationally modified by the addition of N-acetyl-D: -glucosamine monosaccharides to certain serine and threonine residues. These O-GlcNAc modification sites on tau have been challenging to identify due to the inherent complexity of tau from mammalian brains and the fact that the O-GlcNAc modification typically has substoichiometric occupancy. Here, we describe a method for the production of recombinant O-GlcNAc modified tau and, using this tau, we have mapped sites of O GlcNAc on tau at Thr-123 and Ser-400 using mass spectrometry. We have also detected the presence of a third O-GlcNAc site on either Ser-409, Ser-412, or Ser 413. Using this information we have raised a rabbit polyclonal IgG antibody (3925) that detects tau O-GlcNAc modified at Ser-400. Further, using this antibody we have detected the Ser-400 tau O-GlcNAc modification in rat brain, which confirms the validity of this in vitro mapping approach. The identification of these O-GlcNAc sites on tau and this antibody will enable both in vivo and in vitro experiments designed to understand the possible functional roles of O GlcNAc on tau. PMID- 20706750 TI - Bone metabolism and the muscle-bone relationship in children, adolescents and young adults with phenylketonuria. AB - The aim of the study was to assess body composition in subjects with phenylketonuria (PKU). Forty-five patients aged 13.8 +/- 5.2 years were evaluated. Among them, 15 patients had not reached sexual maturity, showing normal serum values of phenylalanine (Phe) (subgroup 1), and 30 subjects were sexually mature (Tanner 5 stage), showing either normal serum Phe (18 cases; subgroup 2a) or increased serum Phe (12 cases; subgroup 2b). DXA-assessed spine and total body (TB) measurements [bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and the calculated ratios BMC/LBM] as well as laboratory parameters (serum carboxyterminal telopeptide of type I collagen, bone alkaline phosphatase, osteocalcin, parathormone, calcitonin, total and ionized calcium) were analyzed. Statistically significant differences were revealed between subgroup 1 versus 2a for TB BMC/LBM ratio SD scores and between subgroup 2a versus 2b for TB BMD, spine BMD, TB BMC/LBM ratio and spine BMC/LBM ratio SD scores. Stepwise multiple regression analysis revealed that serum Phe negatively affected bone status. The skeletal status in children with PKU is impaired by the disease. Applying body composition parameters instead of BMD alone may reflect the level of impairment in a new, different way. PMID- 20706752 TI - Extramasticatory dental wear reflecting habitual behavior and health in past populations. AB - In skeletal remains, teeth are valuable sources of information regarding age, diet, and health. Dental wear is especially helpful in reconstructions of dietary patterns in populations of varying subsistence. In past societies, teeth have also been used as "a third hand" or as a "tool." The present article examines this type of dental wear and traits attributed to habitual behavior during prehistoric and historic times. Terminology and classification of habitual dental wear are described mainly by appearance, for instance, notching, grooving, cuts, scrapes, and polished surfaces, and their characteristics are illuminated by different case studies. Secondary health effects caused by the extramasticatory use of teeth, such as periapical lesions, tilting, skeletal changes at the temporomandibular joint, chipping, and antemortem tooth loss are also examined. During the examination of extramasticatory dental wear, information should be recorded on morphology, size, frequency, intensity, and location within the dental arch, as well as descriptions and detailed photographic documentation. The advantage of using a low- to medium-resolution microscope in all dental examination is emphasized. By categorizing the wear marks, characteristics are emphasized rather than an exact causing agent. In this way, tentative analogies for the origin of different extramasticatory wear, and consequently for human behavior in the past, can be avoided. PMID- 20706751 TI - Effect of three radicular dentine treatments and two luting cements on the regional bond strength of quartz fibre posts. AB - The purpose was to investigate by push-out tests and scanning electron microscopy (SEM)/energy-dispersive spectroscopy (EDS) the effect, after first acid etching the post space walls, of three radicular dentine treatments on the regional bond strength of quartz fibre posts placed using two heavily filled resin luting cements. The crowns of 39 extracted maxillary central incisors were sectioned transversely 2 mm coronal to the labial cement-enamel junction and the roots endodontically treated. After standardized post space preparations and etching 15 s with 32% phosphoric acid, 36 roots were randomly divided into six equal groups. Quartz fibre posts (D.T. LIGHT-POST) were placed using three radicular dentine treatments (0.9% sodium chloride (NaCl) for 60 s, 10% sodium hypochlorite (NaOCl) for 60 s, 17% ethylenediaminetetraacetic acid (EDTA) for 60 s followed by 5.25% NaOCl for 60 s) and two resin composite luting cements (ONE-STEP PLUS/DUO-LINK; ONE-STEP PLUS/LuxaCore Dual). Transverse segments (S1-S7), 1.00 mm (SD = 0.05 mm) thick, were sectioned from the coronal 8 mm of each root. Push-out bond strength tests were performed on coronal, middle and apical post space segments (S2, S4, S6) at a crosshead speed of 0.5 mm/min. Data were recorded and analyzed using a two-way mixed ANOVA design (a = 0.05). Three segments (S1, S5, S7) from roots in each group were examined using SEM/EDS. After post space preparation, acid etching and using each of the three radicular dentine treatments, the three remaining roots were sectioned longitudinally for SEM observation of the post space walls. At all root segment sites, the mean bond strengths from using 0.9% NaCl were significantly lower than for the other two radicular dentine treatments (P <= 0.02), and DUO-LINK cement had significantly higher mean bond strengths than LuxaCore Dual cement (P <= 0.01). There was a significant linear trend for reduced bond strengths from coronal to apical post space segments (P < 0.001), which was supported by the SEM/EDS observations of dentine tubule appearance and resin tag formation. Acid etching followed by either 10% NaOCl or 17% EDTA and 5.25% NaOCl dentine treatments of the post spaces provided good adhesion and resin luting cement tag infiltration of dentinal tubules in the coronal and middle segments in particular. PMID- 20706753 TI - Pyogenic sacroiliitis in children-a diagnostic challenge. AB - Osteoarticular infections in paediatric patients are associated with significant morbidity. Pyogenic sacroiliitis is rare and accounts for approximately 1-2% of osteoarticular infections in children. Diagnosis of this disease has been difficult in the past due to its deep location and may be delayed due to the lack of specific clinical signs and symptoms. We identified 11 paediatric patients with clinical-radiological signs of pyogenic sacroiliitis during an 8-year period and observed an unusual cluster of four cases during the last 11 months. Early diagnosis was possible due to a reproducible clinical pattern as well as radiological evidences of infection using magnetic resonance imaging and/or bone scintigraphy; most patients having predisposing factors. Staphylococcus aureus was the sole causative agent identified. All patients including two children with associated muscle abscesses were managed conservatively with antibiotic therapy only and showed good clinical response with no sequelae during follow-up. An algorithm for the correct and prompt diagnosis of this pathology is proposed. Standardised optimal therapy remains to be defined. PMID- 20706754 TI - Sialidosis type I with neoplasms in siblings: the first clinical cases. PMID- 20706755 TI - Far from rare: revisiting the relevance of idiopathic basal ganglia calcifications. PMID- 20706756 TI - The effect of lentivirus-mediated TH and GDNF genetic engineering mesenchymal stem cells on Parkinson's disease rat model. AB - This study was designed to assess the potential therapeutic efficacy of gene modified mesenchymal stem cells (MSCs), MSCs-TH and MSCs-GDNF, in PD rats. Fifty nine PD rat models were divided into five groups and then the gene-modified MSCs were transplanted into the striatum of rats according to the design. Apomorphine induced rotational behavior in rats was observed weekly; rats which received both MSCs-TH and MSCs-GDNF showed the most significant improvement compared with those in other groups (P < 0.01). Three weeks later, immunohistochemistry analysis found TH-positive cells and GDNF-positive cells in striatal. Eight weeks later, PD rats were killed. HPLC and ELISA results showed DA and GDNF content in striatum of rats which received both MSCs-TH, and MSCs-GDNF was considerably higher compared with those of other groups (P < 0.01),respectively. In conclusion, our results suggest that combined transplantation of MSCs expressing TH and GDNF can lead to remarkable therapeutic effects in a rat model of PD. PMID- 20706758 TI - Prior uterine perforation resulting in intestinal obstruction in a subsequent pregnancy. PMID- 20706757 TI - First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience. AB - Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. But these studies and subsequent non-phase III studies have also shown risks associated with local chemotherapy within the central nervous system. The introduction of concomitant radiochemotherapy with temozolomide (TMZ) has later demonstrated a survival benefit in a phase III trial and has become the current treatment standard for newly diagnosed malignant glioma patients. Lately, this has resulted in clinical protocols combining local chemotherapy with BCNU wafers and concomitant radiochemotherapy with TMZ although this may carry the risk of increased toxicity. We have compiled the treatment experience of seven neurosurgical centers using implantation of carmustine wafers at primary surgery followed by 6 weeks of radiation therapy (59-60 Gy) and 75 mg/m(2)/day TMZ in patients with newly diagnosed glioblastoma followed by TMZ monochemotherapy. We have retrospectively analyzed the postoperative clinical course, occurrence and severity of adverse events, progression-free interval, and overall survival in 44 patients with newly diagnosed glioblastoma multiforme. All patients received multimodal treatment including tumor resection, BCNU wafer implantation, and concomitant radiochemotherapy. Of 44 patients (mean age 59 +/- 10.8 years) with glioblastoma who received Gliadel wafer at primary surgery, 28 patients (64%) had died, 16 patients (36%) were alive, and 15 patients showed no evidence of clinical or radiographic progression after a median follow-up of 15.6 months. At time of analysis of adverse events in this patient population, the median overall survival was 12.7 months and median progression-free survival was 7.0 months. Surgical, neurological, and medical adverse events were analyzed. Twenty-three patients (52%) experienced adverse events of any kind including complications that did not require treatment. Nineteen patients (43%) experienced grade 3 or grade 4 adverse events. Surgical complications included cerebral edema, healing abnormalities, cerebral spinal fluid leakage, meningitis, intracranial abscess, and hydrocephalus. Neurological adverse events included newly diagnosed seizures, alteration of mental status, and new neurological deficits. Medical complications were thromboembolic events (thrombosis, pulmonary embolism) and hematotoxicity. Combination of both treatment strategies, local chemotherapy with BCNU wafer and concomitant radiochemotherapy, appears attractive in aggressive multimodal treatment schedules and may utilize the sensitizing effect of TMZ and carmustine on MGMT and AGT on their respective drug resistance genes. Our data demonstrate that combination of local chemotherapy and concomitant radiochemotherapy carries a significant risk of toxicity that currently appears underestimated. Adverse events observed in this study appear similar to complication rates published in the phase III trials for BCNU wafer implantation followed by radiation therapy alone, but further add the toxicity of concomitant radiochemotherapy with systemic TMZ. Save use of a combined approach will require specific prevention strategies for multimodal treatments. PMID- 20706759 TI - Laparoscopic resection of colorectal cancer: matched comparison in elderly and younger patients. AB - BACKGROUND: Several studies have addressed the issue of the feasibility of laparoscopic colorectal surgery in elderly patients, usually by choosing an arbitrary cut-off age limit, and retrospectively evaluating patient outcomes. The aim of this study was to assess the effects of age on the outcome of laparoscopic colorectal surgery for cancer in a single department, by comparing younger and older patients, matched by ASA score and type of operation. METHODS: The perioperative outcome of patients >=75 years old who underwent laparoscopic colorectal surgery for cancer between June 2005 and January 2009 were compared with findings in younger patients, matched by ASA score and type of operation. RESULTS: The study included 100 patients, fifty <75 years old (Group A) and fifty >=75 (Group B) years old. There were 18 right hemicolectomies, 16 left hemicolectomies, 4 anterior resections, 9 low anterior resections, 2 Miles' operations and 1 segmental resection in each group. We observed a significantly higher overall morbidity rate among elderly patients than among younger patients (24 vs. 8%). CONCLUSIONS: Short-term results after laparoscopic colorectal surgery for cancer in patients >=75 years old reveal that they have higher postoperative risk compared to their younger counterparts, even when matched by ASA score and type of operation. It suggests that although advanced age, per se, is not a contraindication, it is a risk for patients who undergo laparoscopic colorectal surgery for cancer. This surgery in elderly patients should be performed by experienced surgeons in specialized centers to keep postoperative risk to a minimum. PMID- 20706760 TI - Defunctioning ileostomy closure following low anterior resection by chemotherapy. AB - AIM: The aim of this study is to review the time between formation and closure of loop ileostomies following total mesorectal excision in patients with rectal cancer. PATIENTS AND METHODS: A retrospective study of 170 patients who underwent low anterior resection for rectal cancer, between 1990 and 2009. Loop ileostomies were created in 8 patients. RESULTS: Of the 8 patients with defunctioning loop ileostomies, 4 received adjuvant chemo-radiotherapy, 3 received neo-adjuvant chemo-radiotherapy and 1 did not receive anything. There was 12.5% morbidity. The time from formation to closure for the patient with no adjuvant therapy was 3 months and for those with adjuvant therapy was 7 months. This was a significant delay. CONCLUSION: Time between formation and closure of loop ileostomy following anterior resection of rectum is significantly delayed by adjuvant chemotherapy. PMID- 20706761 TI - Garenoxacin-induced increase of CD11b expression on human polymorphonuclear neutrophils does not affect phagocytosis and killing of Staphylococcus aureus. AB - Garenoxacin is considered to be the most active quinolone against Staphylococcus aureus. Quinolones are believed to alter the function of human polymorphonuclear leukocytes (PMN) and garenoxacin is known to be the only quinolone which alters the expression of the beta-chain (CD11b) of the complement receptor 3 (CR3) which is known to be important in the phagocytosis of S. aureus by PMN. Therefore, the effect of this altered CD11b expression on phagocytosis, oxidative burst, and killing of S. aureus was addressed and compared with that of standard quinolones. Phagocytosis and oxidative burst were determined by flow cytometry, and killing was measured by a colony-count method. Garenoxacin at therapeutic concentrations affected neither phagocytosis nor killing of Staphylococcus aureus NMS54. At supratherapeutic concentrations (1,500 mg/l) garenoxacin reduced and delayed phagocytosis like all other quinolones tested except norfloxacin. This decrease seems to be a result of inhibition of the oxidative burst of PMN and reduced CD11b expression at this supratherapeutic concentration. In conclusion, the alteration of CD11b expression of PMN caused by garenoxacin at 0.5, 5.0, and 100.0 mg/l is not considered to hamper the function of these first-line-defense phagocytes. PMID- 20706762 TI - Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: the minimal effect of raltegravir and atazanavir. AB - Antiretroviral therapy for HIV infection is associated with lipodystrophy. However, raltegravir (RAL), a new integrase inhibitor, and atazanavir (ATV), a new generation of protease inhibitor (PI), have not been reported to significantly induce metabolic abnormalities in some clinical studies. The aim of this study was to investigate the influence and molecular mechanisms of RAL and compared it with the other three classes of ARVs (nucleoside reverse transcriptase inhibitors; NRTI, nonnucleoside reverse-transcriptase inhibitor; NNRTI, and PI) on adipogenesis using 3T3-L1 cells. RAL and ATV had minimal effects on the lipid metabolism of 3T3-L1 cells. NRTI induced a moderate change, and NNRTI and some PIs induced a severe reduction in cell lipid content. These ARVs induced a decrease in the expression of genes associated with lipogenic transcription factors (sterol regulatory-element-binding protein-1c, CAAT box enhancer-binding protein-alpha, and peroxisome proliferator-activated receptor gamma). The differentiated 3T3-L1 cells were less sensitive to ARV-induced metabolic disturbance than were predifferentiated cells. RAL and ATV did not significantly affect the lipid metabolism in our in vitro study. The other ARVs had a direct influence on adipocytes. Degree and underlying mechanisms of metabolic disturbance differed among different ARVs. These data suggest that the distinct metabolic side-effect profiles of ARVs are a consequences of their differential effects on the adipocyte physiology. A better understanding of the mechanism of ARV-induced metabolic abnormalities could lead to safer use of ARVs or selection of alternative agents for further clinical development. PMID- 20706763 TI - A case of uterine endometritis caused by Atopobium vaginae. AB - Although Atopobium vaginae has been reported as a causative organisms in patients with bacterial vaginosis and/or tubo-ovarian abscess, clinical significance of Atopobium species has not been defined to date. Here we report the case of uterine endometritis caused by A. vaginae. PMID- 20706764 TI - A mechanobiological investigation of platelets. AB - Understanding mechanotransduction pathways leading to thrombosis will require progressive steps, including determination of the mechanical behavior of the platelet membrane in response to applied loads. The platelet membrane deformation capacity, as quantified by membrane progression into a borosilicate glass micropipette of defined internal diameter, was probed in murine platelets using a controlled range of negative pressure (0-7 cm H(2)O). Based on our observations that the platelet portion outside the micropipette was mostly spherical and that the platelet volume did not change upon aspiration, a novel continuum mechanics based model of the platelet micropipette aspiration experiment was created, and a new hyperelastic isotropic material model including membrane residual tension was proposed for the platelet membrane. Murine platelet membranes maintained an average linear deformation behavior: L (p)/R (p) = 146,100p (i) * R (p) + 19.923, where L (p) is the platelet length aspirated in the micropipette (m), R (p) is micropipette radius (m) and p (i) is the aspiration pressure (Pa). The theoretical model was used to generate material constants for the murine platelet membrane that allowed for an accurate simulation of the micropipette aspiration experiments. From published results, another set of material constants was established for the human platelet membrane. Limited cases of platelet lysis upon aspiration were analyzed using the theoretical model to determine preliminary membrane tension strength values. PMID- 20706765 TI - DNA amplification on chromosome 13q31.1 correlated with poor prognosis in colorectal cancer. AB - Colorectal cancer is a leading cause of cancer deaths worldwide. Genetic markers involved in prognosis of colorectal cancer are still being elucidated. In this study, genetic alterations associated with prognosis of colorectal cancer were determined using arbitrarily primed polymerase chain reaction (AP-PCR) and analyzed quantitatively by real-time PCR. Seven different DNA sequences, mapped on chromosomes 13q31.1, 9q31.1, 1q24, 4q31.3, 10q21, 11q13.4, and 13q13.3, were identified. Among these sequences, seven cases (23%) harbored DNA amplification in chromosome 13q31.1, and 9 (29%) and 7 (23%) presented genetic alterations in chromosome 1q24 and 11q13.4, respectively. Multivariate analysis showed that only DNA amplification in chromosome 13q31.1 was associated with poor survival among patients with colorectal cancer, with median survival time for chromosome 13q31.1 amplification versus no amplification of 64 versus 268 weeks (P = 0.001). This genetic alteration may have a prognostic role in colorectal cancer. PMID- 20706767 TI - Targeting DNA repair proteins for cancer treatment. PMID- 20706766 TI - Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment. AB - The apurinic endonuclease 1/redox factor-1 (APE1) has a crucial function in DNA repair and in redox signaling in mammals, and recent studies identify it as an excellent target for sensitizing tumor cells to chemotherapy. APE1 is an essential enzyme in the base excision repair pathway of DNA lesions caused by oxidation and alkylation. As importantly, APE1 also functions as a redox agent maintaining transcription factors involved in cancer promotion and progression in an active reduced state. Very recently, a new unsuspected function of APE1 in RNA metabolism was discovered, opening new perspectives for this multifunctional protein. These observations underline the necessity to understand the molecular mechanisms responsible for fine-tuning its different biological functions. This survey intends to give an overview of the multifunctional roles of APE1 and their regulation in the context of considering this protein a promising tool for anticancer therapy. PMID- 20706768 TI - Protein arginine deiminase 4: a target for an epigenetic cancer therapy. AB - The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines (NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4 inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic agents for this disease. PMID- 20706769 TI - Serum complement C3 has a stronger association with insulin resistance than high sensitive C-reactive protein in non-diabetic Chinese. AB - OBJECTIVE: To compare association of complement C3 (C3) and high sensitive C reactive protein (hs-CRP) with insulin resistance. SUBJECTS: A total of 587 non diabetic Chinese aged 20-80 years were recruited. METHODS: Complement C3 and hs CRP were measured by the rate nephelometry method and the particle enhanced immunoturbidimetric method, respectively, and their relationship to insulin resistance was assessed. Insulin resistance was defined as the upper quartile of HOMA2-IR. RESULTS: Complement C3 and hs-CRP were significantly higher in subjects with insulin resistance than those without. Complement C3 was the second strongest determinant of insulin in the study (beta = 0.34, P < 0.001). By regression analysis, C3 was significantly associated with insulin resistance (OR = 3.78, P < 0.05), independent of waist circumference and other metabolic risk factors; however, hs-CRP was not. Receiver operating characteristic curve analysis indicated the best model predicting insulin resistance was one that included C3 and waist circumference (AUC = 0.741, P < 0.05). CONCLUSION: Compared to hs-CRP, serum C3 might be a better inflammatory marker of insulin resistance in the non-diabetic Chinese population. PMID- 20706770 TI - (1)H-MRS of brain metabolites in migraine without aura: absolute quantification using the phantom replacement technique. AB - OBJECTIVE: Several studies have demonstrated differences in migraine patients when performing (1)H-MRS; however, no studies have performed (1)H-MRS in migraine without aura (MwoA), the most common migraine subtype. The aim of this (1)H-MRS study was to elucidate whether any differences could be found between MwoA patients and controls by performing absolute quantification. MATERIALS AND METHODS: (1)H-MRS was performed in 22 MwoA patients and 25 control subjects. Absolute quantification was based on the phantom replacement technique. Corrections were made for T (1) and T (2) relaxation effects, CSF content, coil loading and temperature. The method was validated by phantom measurements and in vivo measurements in the occipital visual cortex. RESULTS: After calibration of the quantification procedure and the implementation of the required correction factors, measured absolute concentrations in the visual cortex of MwoA patients showed no significant differences compared to controls, in contrast to relative results obtained in earlier studies. CONCLUSION: In this study, we demonstrate the implementation of quantitative in vivo (1)H-MRS spectroscopy in migraine patients. Despite rigorous quantification, no spectroscopic abnormalities could be found in patients with migraine without aura. PMID- 20706771 TI - Intracranial ependymomas treated with radiotherapy: long-term results from a single institution. AB - The purpose of the study is to report long-term outcomes following surgery and radiotherapy for intracranial ependymoma. We retrospectively reviewed the medical records of patients treated with radiotherapy for localized intracranial ependymomas from 1964 to 2006. Patients with subependymomas and ependymoblastomas, and those undergoing re-irradiation, were excluded. Our study population is 44 patients: 37 infratentorial lesions, 7 supratentorial. All patients had postoperative radiotherapy; most received sub-total resection and one-third received gross total resection. Most patients received local radiotherapy alone (median tumor dose 55 Gy); one-quarter received craniospinal irradiation (median dose 35 Gy). The 5- and 10-year local-control rates for all patients were 60 and 46%, respectively; 23% of local recurrences occurred after 5 years. Ninety-five percent of the patients recurred at the primary site; 5% had spinal seeding with no evidence of disease at the primary site. No patient who received craniospinal irradiation recurred in the spine. The 5- and 10-year disease-free survival and overall-survival rates for all patients were 60 and 42% and 57 and 43%, respectively. On multivariate analysis, age >=18 years, gross total resection and infratentorial site were associated with improved local control. No patient with continuous local control had grade 4 or 5 toxicities; 27% of patients had grade 2 or 3 toxicities. One patient developed a radiation induced meningioma >20 years after radiotherapy. Maximal safe resection followed by adjuvant radiotherapy provided local control in one-half of patients at 10 years. Age, extent of surgery, and location were identified as major independent prognostic factors in patients with intracranial ependymomas. PMID- 20706773 TI - Demography and diffusion in epidemics: malaria and black death spread. AB - The classical models of epidemics dynamics by Ross and McKendrick have to be revisited in order to incorporate elements coming from the demography (fecundity, mortality and migration) both of host and vector populations and from the diffusion and mutation of infectious agents. The classical approach is indeed dealing with populations supposed to be constant during the epidemic wave, but the presently observed pandemics show duration of their spread during years imposing to take into account the host and vector population changes as well as the transient or permanent migration and diffusion of hosts (susceptible or infected), as well as vectors and infectious agents. Two examples are presented, one concerning the malaria in Mali and the other the plague at the middle-age. PMID- 20706772 TI - Association of matrix metalloproteinase-1 gene polymorphism with glioblastoma multiforme in a northern Indian population. AB - Matrix metalloproteinase-1 (MMP-1) is known to be involved in the pathogenesis of glioma. It damages the extra-cellular matrix to produce invasiveness in cancer tissue, and hence has a direct effect in cancer invasion. The study aims to explore the association of single nucleotide polymorphism of -1607 MMP-1 gene with susceptibility to glioblastoma multiforme (GBM) in northern Indian subjects. One hundred and ten GBM patients and 150 healthy controls were included in this study. 1607 MMP-1 gene was studied by PCR-RFLP; different genotypes being combinations of 1G and 2G allele (1G/1G, 1G/2G and 2G/2G). 2G/2G genotype was significantly associated with GBM patients (OR, 2.24; P = 0.016; 95% CI, 1.16 4.30) as compared to controls. Prevalence of the 2G allele of -1607 MMP-1 polymorphism was significantly greater in GBM patients as compared to controls (62.3 vs 48.3%, OR, 1.76; P = 0.002; 95% CI, 1.23-2.52). This study suggests that the 2G/2G genotype and 2G allele of -1607 MMP-1 polymorphism are associated with an increased susceptibility for developing GBM. PMID- 20706775 TI - A web of controversies: complexity in the burgess shale debate. AB - Using the Burgess Shale controversies as a case-study, this paper argues that controversies within different domains may interact as to create a situation of "com- plicated intricacies," where the practicing scientist has to navigate through a context of multiple thought collectives. To some extent each of these collectives has its own dynamic complete with fairly negotiated standards for investigation and explanation, theoretical background assumptions and certain peculiarities of practice. But the intellectual development in one of these collectives may "spill over" having far reaching consequences for the treatment of apparently independent epistemic problems that are subject of investigation in other thought collectives. For the practicing scientist it is necessary to take this complex web of interactions into account in order to be able to navigate in such a situation. So far most studies of academic science have had a tendency to treat the practicing scientist as members of a single (enclosed) thought collective that stands intellectually isolated from other similar entities unless the discipline was in a state of crisis of paradigmatic proportions. The richness and complexity of Burgess Shale debate shows that this encapsulated kind of analysis is not enough. PMID- 20706774 TI - Activation tagging of an Arabidopsis SHI-RELATED SEQUENCE gene produces abnormal anther dehiscence and floral development. AB - The tapetum is a layer of cells covering the inner surface of pollen sac wall. It contributes to anther development by providing enzymes and materials for pollen coat biosynthesis and nutrients for pollen development. At the end of anther development, the tapetum is degenerated, and the anther is dehisced, releasing mature pollen grains. In Arabidopsis, several genes are known to regulate tapetum formation and pollen development. However, little is known about how tapetum degeneration and anther dehiscence are regulated. Here, we show that an activation-tagged mutant of the S HI-R ELATED S EQUENCE 7 (SRS7) gene exhibits disrupted anther dehiscence and abnormal floral organ development in addition to its dwarfed growth with small, curled leaves. In the mutant hypocotyls, cell elongation was reduced, and gibberellic acid sensitivity was diminished. Whereas anther development was normal, its dehiscence was suppressed in the dominant srs7 1D mutant. In wild-type anthers, the tapetum disappeared at anther development stages 11 and 12. In contrast, tapetum degeneration was not completed at these stages, and anther dehiscence was inhibited, causing male sterility in the mutant. The SRS7 gene was expressed mainly in the filaments of flowers, where the DEFECTIVE-IN-ANTHER-DEHISCENCE 1 (DAD1) enzyme catalyzing jasmonic acid (JA) biosynthesis is accumulated immediately before flower opening. The DAD1 gene was induced in the srs7-1D floral buds. In fully open flowers, the SRS7 gene was also expressed in pollen grains. It is therefore possible that the abnormal anther dehiscence and floral development of the srs7-1D mutant would be related with JA. PMID- 20706776 TI - Immunohistochemical localization of LIM mineralization protein 1 during mouse molar development. AB - LIM mineralization protein 1 (LMP-1) is an essential positive regulator of osteoblast differentiation, maturation and bone formation. Our previous investigations on the distribution of LMP-1 in mature human teeth indicated that LMP-1 might play a role in the odontoblast differentiation and dentin matrix mineralization. The aim of the present study was to use immunohistochemistry to determine the expression of LMP-1 during tooth development in mouse molars. In embryonic and postnatal Kunming mice, LMP-1 protein was expressed during molar development, but the expression levels and patterns differed at various developmental stages. At embryonic day 13.5 (E13.5), LMP-1 was found in the enamel organ. At E14.5, LMP-1 was detected in the entire enamel organ and in the underlying mesenchyme. At E16.5, LMP-1 was observed in the inner and outer enamel epithelium and the stratum intermedium. The expression also converged at the cusps in the dental papilla. At E18.5 and postnatal day 2.5 (P2.5), LMP-1 was restricted to the stratum intermedium, in differentiating dental papilla cells at cusps, while it disappeared in terminal differentiated ameloblasts and odontoblasts. At P13.5, no positive staining was detected in the odontoblasts or in the dental pulp cells. Therefore, LMP-1 showed spatiotemporal expression patterns during molar development and might participate in molar crown morphogenesis and odontoblast differentiation at late molar development. PMID- 20706777 TI - The mammary gland vasculature revisited. AB - Concomitant with the extensive growth and differentiation of the mammary epithelium during pregnancy and lactation, and epithelial involution after weaning, the vasculature of the mammary gland undergoes repeated cycles of expansion and regression. Vascular expansion is effected by sprouting angiogenesis, intussusception and conceivably also vasculogenesis. The capacity of the epithelial cells to stimulate vascular growth and differentiation is dependent on the constellation of systemic and local hormones and growth factors as well as the changing demands for oxygenation and nutrient supply. This results in the release of angiogenic factors which stimulate endothelial cell growth and regulate vascular architecture. In contrast to the angiogenic phase of the mammary gland cycle, little is known about the control of vascular regression although this would possibly offer new insights into therapeutic possibilities against breast cancer. In this review we summarize knowledge regarding the mechanisms regulating the vasculature of the mammary gland and delineate the importance of the vasculature in the attainment of organ function. In addition, we discuss the angiogenic mechanisms observed during mammary carcinogenesis and their consequences for breast cancer therapy. PMID- 20706779 TI - The relationship between school engagement and delinquency in late childhood and early adolescence. AB - Engagement in school is crucial for academic success and school completion. Surprisingly little research has focused on the relationship between student engagement and delinquency. This study examines whether engagement predicts subsequent school and general misconduct among 4,890 inner-city Chicago elementary school students (mean age: 11 years and 4 months; 43.3% boys; 66.5% black; 28.8% Latino). To improve upon prior research in this area, we distinguish three types of engagement (emotional, behavioral, and cognitive), examine whether the relationship between engagement and misconduct is bidirectional (misconduct also impairs engagement), and control for possible common causes of low engagement and misconduct, including peer and family relationships and relatively stable indicators of risk-proneness. Emotional and behavioral engagement predict decreases in school and general delinquency. However, cognitive engagement is associated with increases in these outcomes. School and general delinquency predict decreased engagement only in the cognitive domain. Suggestions for future research and implications for policy are discussed. PMID- 20706778 TI - Novel automatic endotracheal position confirmation system: mannequin model algorithm evaluation. AB - OBJECTIVE: A novel endotracheal intubation accurate positioning confirmation system based on image classification algorithm is introduced and evaluated using a mannequin model. METHODS: The system comprises a miniature complementary metal oxide silicon sensor (CMOS) attached to the tip of a semi rigid stylet and connected to a digital signal processor (DSP) with an integrated video acquisition component. Video signals acquired and processed by an algorithm implemented on the processor. During mannequin intubations, video signals were continuously recorded. A total of 10 videos were recorded. From each video, 7 images of esophageal intubation and 8 images of endotracheal intubation (in which the carina could be clearly seen) were extracted, yielding a total of 150 images taken from arbitrary positions and angles which were processed by the confirmation algorithm. RESULTS: The performance of the confirmation algorithm was evaluated using a leave-one-out method: in each iteration, 149 images were used to train the system and estimate the models, and the remaining image was used to test the system. This process was repeated 150 times such that each image participated once in testing. The system correctly identified 80 out of 80 endotracheal intubations and 70 out of 70 esophageal intubations. CONCLUSIONS: This fully automatic image recognition system was used successfully to discriminate airway carina and non-carina endotracheal tube positioning. The system had a 100% success rate using a mannequin model and therefore further investigation including live tissue model and human research should follow. PMID- 20706780 TI - Inhibitory effect of farnesylthiosalicylic acid on mediators release by mast cells: preferential inhibition of prostaglandin D(2) and tumor necrosis factor alpha release. AB - There is substantial evidence suggesting that the Ras inhibitor farnesylthiosalicylic acid (FTS) may modulate various aspects of immune function and inflammation in addition to its well known anti-cancer activity. In this regard, we have recently shown that FTS suppresses T lymphocyte-mediated immune responses. Mast cells (MC), the main effector cells in the elicitation of the allergic response, are known to secrete granule-associated mediators and to release prostaglandins and cytokines on FCepsilonRI-cross-linking, thereby contributing to the pathogenesis of allergic diseases. We hypothesized that MC act as an additional target for FTS. In the present work we analyze the effects of FTS on MC degranulation, prostaglandin release, and cytokine release in vitro, and on the elicitation of IgE-mediated MC dependent cutaneous allergic inflammation in vivo. First we have established that FTS inhibited Ras activation in MC. Next, we have shown that FTS preferentially inhibited prostaglandin (PG) D(2) and tumor necrosis factor (TNF)-alpha release without having any significant effect on MC beta-hexosaminidase secretion. In vivo administration of FTS inhibited the late phase of passive cutaneous anaphylaxis reaction. The time course of FTS-induced inhibition in vivo correlated with mediators release and not with degranulation. This data suggests that FTS may have an inhibitory effect on MC mediated allergic inflammation, and thus may be considered as a possible therapeutic modality. PMID- 20706781 TI - Transfer entropy--a model-free measure of effective connectivity for the neurosciences. AB - Understanding causal relationships, or effective connectivity, between parts of the brain is of utmost importance because a large part of the brain's activity is thought to be internally generated and, hence, quantifying stimulus response relationships alone does not fully describe brain dynamics. Past efforts to determine effective connectivity mostly relied on model based approaches such as Granger causality or dynamic causal modeling. Transfer entropy (TE) is an alternative measure of effective connectivity based on information theory. TE does not require a model of the interaction and is inherently non-linear. We investigated the applicability of TE as a metric in a test for effective connectivity to electrophysiological data based on simulations and magnetoencephalography (MEG) recordings in a simple motor task. In particular, we demonstrate that TE improved the detectability of effective connectivity for non linear interactions, and for sensor level MEG signals where linear methods are hampered by signal-cross-talk due to volume conduction. PMID- 20706782 TI - Induction of apoptosis by melamine in differentiated PC12 cells. AB - Melamine (2, 4, 6-triamino-1, 3, 5-triazine) was found in milk powder as an additive to raise the measured protein content in 2008 and thereby resulted in the outbreak of renal failure in infants in China. Previous studies focused on the renal toxicity in dogs and in cats. However, the toxicity of melamine in the central nervous system (CNS) is of little concern. The purpose of this study was to assess the possibility of melamine toxicity in differentiated PC12 cells. MTT assay indicated that melamine (above 33 MUg/ml and 12 h) inhibited the proliferation of differentiated PC12 cells in a concentration- and time-dependent manner. Hoechst 33258 staining and flow cytometry assay showed that melamine induced the apoptotic cell death rather than necrosis in a dose-dependent manner. Reduced superoxide dismutase activity indirectly indicated that melamine could cause oxidative damage in differentiated PC12 cells. These results suggest that melamine is able to cause cytotoxicity in differentiated PC12 cells with involvement of oxidative damage and will provide evidence for further research on the potential toxicity in CNS. PMID- 20706783 TI - Anti-angiogenic potential of small molecular inhibitors of cyclin dependent kinases in vitro. AB - Small molecular kinase inhibitors are promising novel drugs. Initially, they were designed for the highest possible specificity. Recently, this concept has been challenged by multikinase inhibitors, which are clinically more potent. This change of paradigm calls for re-examination of already known compounds in different functional contexts. We have compared 6 reported structurally different inhibitors of cyclin-dependent kinases (Cdks) regarding their functional effects on endothelial cells (proliferation, cell cycle, apoptosis, migration, tube formation), as well as their actions on some kinases (AKT, p38, ERK1/2, c-src, GSK3beta). Only some of these compounds had anti-angiogenic effects in concentrations up to 10 MUM (aminopurvalanol, indirubin-3'-monoxime, and alsterpaullone), depending on their kinase profile. Interestingly, the impact of the compounds on Cdks seemed to be of minor importance, as compared to other mechanisms. Aminopurvalanol, indirubin-3'-monoxime, and alsterpaullone might turn out as interesting scaffolds for the development of novel anti-angiogenic drugs. PMID- 20706784 TI - Comments on: Sluiter MD and van Rensburg EJ, Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. PMID- 20706785 TI - Comparative nutrient utilization, growth, and rumen enzyme profile of mithun (Bos frontalis) and Tho-tho cattle (Bos indicus) fed on tree-leaves-based ration. AB - A study was conducted to compare the nutrient utilization, growth, and rumen enzyme profile of mithun (Bos frontalis) and Tho-tho cattle (Bos indicus) reared in the same feeding and managemental conditions. For the purpose, male mithun (n = 8) and male Tho-tho cattle (n = 8) of 1.5 years age, selected from the farm of National Research Centre on Mithun, Nagaland, India, were fed on mixed-tree leaves-based ration as per the requirement of NRC (2001) for cattle for 12 months. Average daily gain (ADG), average dry matter intake (DMI), and feed conversion ratio (FCR) for all animals were recorded. A metabolic trial was conducted at 6 months of the experiment to assess the digestibility coefficient of different nutrients and nutritive value of ration. At 12 months of the experiment, rumen liquor was collected from all animals and analyzed for rumen enzyme profiles, viz., carboxymethylcellulase, xylanase, alpha-amylase, beta glucosidase, alpha-glucosidase, urease, and protease. It was found that ADG (507.8 g vs 392.8 g), DM intake (6.59 vs 5.85 kg/day) and DMI/W(0.75) (98.75 g vs 91.00 g/day), crude protein intake (780 vs 700 g/day), and total digestible nutrient intake (3.65 vs 3.32 kg/day) were higher (p < 0.05) in mithun than cattle. The nitrogen balance was higher and FCR was better (p < 0.05) in mithun compared with cattle. The digestibility coefficient of different nutrients was similar (p > 0.05) between the species. The microbial enzyme profiles of mithun and cattle were not different (p > 0.05). The better growth performance of mithun than cattle as found in the present study clearly indicates that the mithun has higher genetic potential for growth than Tho-tho cattle of north-eastern hilly region of India. PMID- 20706786 TI - The incidence of low eGFR and proteinuria in a large tertiary referral lipid clinic. AB - INTRODUCTION: The prevalence of chronic kidney disease (CKD) stages 3 to 5, defined as eGFR <60 ml/min/1.73 m(2) for more than three months, in the United Kingdom (UK) is 8%. We investigated the incidence of low eGFR and proteinuria in patients attending our large tertiary referral lipid clinic in 2008. METHODS: In 2008, 1,283 patients were seen, of which 1,029 had complete serum lipid and renal profiles. Estimated glomerular filtration rate (eGFR) was calculated for these patients using the 4-variable MDRD formula. The prevalence of low eGFR (eGFR < 60 ml/min/1.73 m(2)) and proteinuria (albumin/creatinine ratio >2.4 mg/mmol or urinary protein excretion >0.06 g/l) was calculated. RESULTS: The prevalence of low eGFR and proteinuria was 11.2 and 19.4%, respectively. The percentage of patients with serum lipid levels within the target range suggested by international guidelines was lower among those with low eGFR and proteinuria than in the entire study population, despite similar proportions being treated with statins across all groups. CONCLUSIONS: The prevalences of low eGFR and proteinuria in a group of 1,029 dyslipidaemic patients attending a large tertiary referral lipid clinic were 11.18 and 19.42%, respectively. These levels are much higher than in the general UK population. PMID- 20706787 TI - Nucleotide binding to noncatalytic sites is essential for ATP-dependent stimulation and ADP-dependent inactivation of the chloroplast ATP synthase. AB - Light-dependent binding of labeled ADP and ATP to noncatalytic sites of chloroplast ATP synthase and the effect of light-exposed thylakoid membrane preincubation with ADP or ATP on ATPase activity were studied. ADP binding during the preincubation was shown to inactivate the chloroplast ATPase, whereas ATP binding caused its activation. The rate and equilibrium constants of ATPase inactivation and activation were close to those of ADP and ATP binding to a noncatalytic site, with K (d) values of 38 and 33 MUM, respectively. It is suggested that ADP- or ATP-binding to one of the noncatalytic sites affects the ATPase activity of chloroplast ATP synthase through a mechanism that modulates tightness of ADP binding to a catalytic site. PMID- 20706788 TI - Eukaryotic algae: where lies the diversity of oxygenic photosynthesis. PMID- 20706789 TI - Secondary ketocarotenoid astaxanthin biosynthesis in algae: a multifunctional response to stress. AB - Under stressful environments, many green algae such as Haematococcus pluvialis accumulate secondary ketocarotenoids such as canthaxanthin and astaxanthin. The carotenogenesis, responsible for natural phenomena such as red snows, generally accompanies larger metabolic changes as well as morphological modifications, i.e., the conversion of the green flagellated macrozoids into large red cysts. Astaxanthin accumulation constitutes a convenient way to store energy and carbon, which will be used for further synthesis under less stressful conditions. Besides this, the presence of high amount of astaxanthin enhances the cell resistance to oxidative stress generated by unfavorable environmental conditions including excess light, UV-B irradiation, and nutrition stress and, therefore, confers a higher survival capacity to the cells. This better resistance results from the quenching of oxygen atoms for the synthesis itself as well as from the antioxidant properties of the astaxanthin molecules. Therefore, astaxanthin synthesis corresponds to a multifunctional response to stress. In this contribution, the various biochemical, genetic, and molecular data related to the biosynthesis of ketocarotenoids by Haematococcus pluvialis and other taxa are reviewed and compared. A tentative regulatory model of the biochemical network driving astaxanthin production is proposed. PMID- 20706790 TI - Dietary broccoli sprouts protect against myocardial oxidative damage and cell death during ischemia-reperfusion. AB - Cruciferous vegetables are known for antioxidant and anti-carcinogenic effects. In the current study we asked whether dietary broccoli sprouts can protect the heart from ischemia-reperfusion. Rats were fed either control diet (sham and control groups) or a diet mixed with 2% dried broccoli sprouts for 10 days. After 10 days the isolated hearts were subjected to ischemia for 20 min and reperfusion for 2 h, and evaluated for cell death, oxidative damage, and Nrf2-regulated phase 2 enzyme activities. Broccoli sprouts feeding inhibited markers of necrosis (lactate dehydrogenase release) and apoptosis (caspase-3 activity) by 78-86%, and decreased indices of oxidative stress (thiobarbituric acid reactive substances and aconitase inactivation) by 82-116%. While broccoli sprouts increased total glutathione and activities of the phase 2 enzymes glutamate cysteine ligase and quinone reductase in liver, they did not affect these in ischemic-reperfused heart. While the mechanism is not clear, the results show that a relatively short dietary treatment with broccoli sprouts can strongly protect the heart against oxidative stress and cell death caused by ischemia-reperfusion. PMID- 20706791 TI - Philosophy on steroids: a reply. AB - Brent Kious has recently attacked several arguments generally adduced to support anti-doping in sports, which are widely supported by the sports medicine fraternity, international sports federations, and international governments. We show that his attack does not succeed for a variety of reasons. First, it uses an overly inclusive definition of doping at odds with the WADA definition, which has global, if somewhat contentious, currency. Second, it seriously misconstrues the position it attacks, rendering the attack without force against a more balanced construal of an anti-doping position. Third, it makes unwarranted appeals to matters Kious considers morally 'clear', while simultaneously attacking a position many others take to be equally morally 'clear', namely that of anti doping. Such an inconsistency, attacking and appealing to the moral status quo as befits one's argument, is not acceptable without further qualification. Fourth, his position suffers from a general methodological flaw of over-reliance upon argumentation by analogy. Moreover, it is argued that the analogies, being poorly selected and developed, fail to justify his conclusion that the anti-doping lobby lacks philosophical and moral authority for its stance. These issues are symptomatic of a more fundamental problem: any attempt at providing a blanket solution to the question of whether doping is morally acceptable or not is bound to run up against problems when applied to highly specific contexts. Thus, rather than reaching any particular conclusion for or against doping products or processes in this article, we conclude that an increased context-sensitivity will result in a more evenhanded appraisal of arguments on the matter. PMID- 20706792 TI - Technical feasibility of laparoscopic lateral pelvic lymph node dissection for patients with low rectal cancer after concurrent chemoradiation therapy. AB - AIM: To test the technical feasibility of laparoscopic lateral pelvic lymph node dissection for patients with clinically positive lateral node(s) after preoperative concurrent chemoradiation therapy for lower rectal cancer. METHODS: The operation procedures are detailed in the attached video. RESULTS: Forty-five procedures of laparoscopic lateral pelvic lymphadenectomy were performed in 34 patients, with dissection over bilateral lateral node foci in 11 patients and dissection over unilateral lateral node station in 23. There were four procedures in which the metastatic node was very close to or even encased the adjacent iliac vessel and therefore the lymphadenectomy was done with a surgical margin of less than 1 mm. The median (range) number of lymph nodes harvested in each lateral station was 6 (2-14). Lympho-adipose tissues from 32 (71.1%, 32/45) lateral node dissections were confirmed by histopathology to harbor metastatic adenocarcinoma. For unilateral lateral pelvic lymph node dissection, median (range) blood loss was 44 (20-240) ml and median (range) operation time was 58 (42-94) min. There was one (2.9%) operative mortality and seven (20.6%) postoperative complications. Postoperatively, most patients presented with mild postoperative pain and quick convalescence. During follow-up (mean 24 months), nine patients (27.3%) developed recurrent disease. Remarkably, all four patients with surgical margin less than 1 mm developed cancer recurrence. CONCLUSIONS: Laparoscopic lateral pelvic lymphadenectomy is technically feasible for some selected patients. To date, laparoscopic approach is still underdeveloped to treat the complex clinical condition in which the metastatic node involves the iliac vessel and combined resection of the vessel is required to obtain sufficient margin. PMID- 20706793 TI - Evaluation of the association of urokinase plasminogen activator system gene polymorphisms with susceptibility and pathological development of hepatocellular carcinoma. AB - BACKGROUND: The urokinase plasminogen activator (uPA) system is a serine proteinase system involved in extracellular matrix (ECM) degradation. The levels of uPA system components in tumor tissues are implicated as prognostic biomarkers in a wide range of malignancies. Although the contributions of uPA system components to the formation of many types of cancer are well known, their possible association with the prediction of risk and prognosis of hepatocellular carcinoma (HCC) remains poorly investigated. METHODS: A total of 102 HCC patients and 344 controls were recruited. Genetic polymorphisms of uPA system genes, including uPA, uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1, were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping analysis. RESULTS: When individuals were classified into male and female subgroups to estimate adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) of each uPA system gene, the HCC risks of males and females with PAI-1 5G/5G genotype were 6.06-fold (95% CI = 1.39 26.36) and 0.04-fold (95% CI = 0.003-0.69), respectively, as compared with those with PAI-1 4G/4G genotype. High risk for hepatitis B surface antigen (HBsAg) positive clinical status and significantly higher serum aspartate aminotransferase (AST) concentration were exhibited in HCC patients with PAI-1 4G/5G and 5G/5G genotypes as compared with 4G/4G homozygotes. CONCLUSIONS: The results suggest that PAI-1 genotypes could be an important factor contributing to increased susceptibility and pathological development of HCC in Taiwanese population. PMID- 20706794 TI - A novel sequence-based method of predicting protein DNA-binding residues, using a machine learning approach. AB - Protein-DNA interactions play an essential role in transcriptional regulation, DNA repair, and many vital biological processes. The mechanism of protein-DNA binding, however, remains unclear. For the study of many diseases, researchers must improve their understanding of the amino acid motifs that recognize DNA. Because identifying these motifs experimentally is expensive and time-consuming, it is necessary to devise an approach for computational prediction. Some in silico methods have been developed, but there are still considerable limitations. In this study, we used a machine learning approach to develop a new sequence based method of predicting protein-DNA binding residues. To make these predictions, we used the properties of the micro-environment of each amino acid from the AAIndex as well as conservation scores. Testing by the cross-validation method, we obtained an overall accuracy of 94.89%. Our method shows that the amino acid micro-environment is important for DNA binding, and that it is possible to identify the protein-DNA binding sites with it. PMID- 20706795 TI - Non-carcinogenic risks induced by metals in drinking source water of Jiangsu Province, China. AB - In this study, we investigated the levels of eight metallic elements in source water of 40 tap water treatment plants (TWTPs) located along Yangtze River, Taihu Lake and Huaihe River in the section of Jiangsu Province, China during 2007-2009 and assessed the non-carcinogenic risks induced by the metals. Among the metals, Fe had the highest concentration (121.5 MUg L( - 1)) and Pb contributed most (32.4%) to the average hazard index (HI) of 40 TWTPs, followed by Cd (24.7%) and Cr (21.6%). The average concentration of each metal was below the permissible limit of China and USA except for Pb. Both hazard quotients of individual metals and HI of total non-carcinogenic risk in each TWTP were lower than 1.0, suggesting that these pollutants posed negligible hazards to public health of local residents. Temporal and spatial comparisons showed that high HIs occurred more frequently in low water seasons, and the three TWTPs located along Huaihe River (Dongtai, Jinhu and Yishuichang) had relatively higher HIs. PMID- 20706796 TI - Structure-activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells. AB - The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C(20)-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p nitrobenzoate (39), exhibited cytotoxic activity, and 11,15 dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC(50) values against A549 cells ranged from 1.72 to 5.44 MUM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest. PMID- 20706797 TI - Single-chain variable fragment antibody against ginsenoside Re as an effective tool for the determination of ginsenosides in various ginsengs. AB - A single-chain variable fragment antibody (scFv) against ginsenoside Re (G-Re) was constructed and applied to an enzyme-linked immunosorbent assay (ELISA) for determining the total concentration of ginsenosides in various ginsengs. The variable heavy and light chain genes were cloned directly from the cDNA of the 4G10 hybridoma cell line and assembled by means of splicing by overlapping extension PCR (SOE-PCR) using specific primers designed to have flexible peptide (Gly(4)Ser)(3) between the variable heavy chain and light chain domains. The constructed scFv gene was ligated into the pET28a expression vector and transformed into E. coli BL21 (DE3). The recombinant scFv against G-Re (GRe-scFv) was expressed as a chimera protein containing the His6-tag at its N-termini, purified by immobilized metal ion affinity chromatography (IMAC), and refolded by a stepwise dialysis method. The yield of GRe-scFv after purification was 1.7 mg per liter of culture medium. Characterization of GRe-scFv revealed that it retained the characteristics of the parental monoclonal antibody (MAb) against G Re (MAb-4G10) which has wide cross-reactivity with 20(S)-protopanaxadiol- and 20(S)-protopanaxatriol-type ginsenosides. The detectable range for G-Re in ELISA using scFv antibody was 0.02-10 ug/ml. Based on validation analysis, the use of GRe-scFv in ELISA is a precise, accurate, and sensitive method. In light of the time-consuming and labor-intensive procedures for the preparation of MAb, speedy bacterial expression of GRe-scFv is a powerful alternative tool for producing MAb to use in ELISA for quantitative analysis of total ginsenoside concentrations. PMID- 20706798 TI - Phytosterol ester constituents affect micellar cholesterol solubility in model bile. AB - Plant sterols and stanols (phytosterols) and their esters are nutraceuticals that lower LDL cholesterol, but the mechanisms of action are not fully understood. We hypothesized that intact esters and simulated hydrolysis products of esters (phytosterols and fatty acids in equal ratios) would differentially affect the solubility of cholesterol in model bile mixed micelles in vitro. Sodium salts of glycine- and taurine-conjugated bile acids were sonicated with phosphatidylcholine and either sterol esters or combinations of sterols and fatty acids to determine the amount of cholesterol solubilized into micelles. Intact sterol esters did not solubilize into micelles, nor did they alter cholesterol solubility. However, free sterols and fatty acids altered cholesterol solubility independently (no interaction effect). Equal contents of cholesterol and either campesterol, stigmasterol, sitosterol, or stigmastanol (sitostanol) decreased cholesterol solubility in micelles by approximately 50% compared to no phytosterol present, with stigmasterol performing slightly better than sitosterol. Phytosterols competed with cholesterol in a dose-dependent manner, demonstrating a 1:1 M substitution of phytosterol for cholesterol in micelle preparations. Unsaturated fatty acids increased the micelle solubility of sterols as compared with saturated or no fatty acids. No differences were detected in the size of the model micelles. Together, these data indicate that stigmasterol combined with saturated fatty acids may be more effective at lowering cholesterol micelle solubility in vivo. PMID- 20706799 TI - Recurrent bilateral varicose veins secondary to tricuspid regurgitation. AB - BACKGROUND: Varicose veins are a common condition. We present a case of recurrent veins due to tricuspid regurgitation. CASE HISTORY: A 55-year-old female presented with large bilateral varicosities. On examination these were extensive and pulsatile in nature over both legs. Three and 5 years previously she presented with similar signs and had undergone bilateral venous surgery including Trendelenburg procedure. Past medical history included successful atrial septal defect repair in 1995. Severe tricuspid regurgitation and right heart failure was diagnosed in 2000, followed by annuloplasty 2 years later. Prior to attempting venous surgery the third time an echocardiogram was performed. This demonstrated severe tricuspid regurgitation again and therefore surgery was not undertaken at this time. DISCUSSION: Concurrent valvular disease should be fully investigated and optimised before consideration is given to surgery, with a multidisciplinary approach being essential in its management. PMID- 20706801 TI - Abstracts of the Annual Meeting of the Royal Academy of Medicine in Ireland Section of Biomedical Sciences. June 23-24, 2010. Dublin, Ireland. PMID- 20706800 TI - A practical guide to using the World Federation for Medical Education (WFME) standards. WFME 1: mission and objectives. AB - Preparing a medical school for institutional review can be a challenging undertaking for any institution requiring an understanding of the international standards being used and adequate preparation and planning (MacCarrick et al. in Med Teach 32(5):e227-e232, 2010). This series examines each of the nine standards developed by the World Federation for Medical Education (WFME in Basic Medical Education: Global Standards for Quality Improvement, University of Copenhagen Denmark, 2003) with practical advice on their use in both self-review and independent accreditation processes. The WFME standards and their purpose are described and the use of these standards to 'drive' the quality improvement agenda in undergraduate medical education is also discussed. PMID- 20706802 TI - Abstracts of the 2010 Summer Scientific Meeting of the Faculty of Public Health Medicine of the Royal College of Physicians of Ireland. May 24-25, 2010. Dublin, Ireland. PMID- 20706803 TI - Distension-induced gastric contraction is attenuated in an experimental model of gastric restraint. AB - BACKGROUND: Gastric distension has important implications for motility and satiety. The hypothesis of this study was that distension affects the amplitude and duration of gastric contraction and that these parameters are largely mediated by efferent vagus stimulation. METHODS: A novel isovolumic myograph was introduced to test these hypotheses. The isovolumic myograph isolates the stomach and records the pressure generated by the gastric contraction under isovolumic conditions. Accordingly, the phasic changes of gastric contractility can be documented. A group of 12 rats were used under in vivo conditions and isolated ex vivo conditions and with two different gastric restraints (small and large) to determine the effect of degree of restraint. RESULTS: The comparison of the in vivo and ex vivo contractility provided information on the efferent vagus mediation of gastric contraction, i.e., the in vivo amplitude and duration reached maximum of 12.6 +/- 2.7 mmHg and 19.8 +/- 5.6 s in contrast to maximum of 5.7 +/- 0.9 mmHg and 7.3 +/- 1.3 s in ex vivo amplitude and duration, respectively. The comparison of gastric restraint and control groups highlights the role of distension on in vivo gastric contractility. The limitation of gastric distension by restraint drastically reduced the maximal amplitude to below 2.9 +/- 0.2 mmHg. CONCLUSIONS: The results show that distension-induced gastric contractility is regulated by both central nervous system and local mechanisms with the former being more substantial. Furthermore, the gastric restraint significantly attenuates gastric contractility (decreased amplitude and shortened duration of contraction) which is mediated by the efferent vagus activation. These findings have important implications for gastric motility and physiology and may improve our understanding of satiety. PMID- 20706805 TI - Novel treatment for lead exposure in children with autism. PMID- 20706804 TI - Zinc deficiency: a frequent and underestimated complication after bariatric surgery. AB - BACKGROUND: Although zinc deficiency is common after bariatric surgery, its incidence is underestimated. The objective was to monitor zinc and nutritional status before and 6, 12 and 24 months (M6, M12 and M24) after gastric bypass (Roux-en-Y gastric bypass), sleeve gastrectomy and biliopancreatic diversion with duodenal switch (DS) in patients receiving systematised nutritional care. METHODS: Data for 324 morbidly obese patients (mean body mass index 46.2 +/- 7.3 kg/m(2)) were reviewed retrospectively. The follow-up period was 6 months for 272 patients, 12 months for 175, and 24 months for 70. Anthropometric, dietary and serum albumin, prealbumin, zinc, iron and transferrin saturation measures were determined at each timepoint. RESULTS: Nine percent of patients had zinc deficiency pre-operatively. Zinc deficiency was present in 42.5% of the population at M12 and then remained stable. Zinc deficiency was significantly more frequent after DS, with a prevalence of 91.7% at M12. Between M0 and M6, variation in plasma prealbumin, surgery type and zinc supplementation explained 27.2% of the variance in plasma zinc concentration. Surgery type explained 22.1% of this variance between M0 and M24. Mean supplemental zinc intake was low (22 mg/day). The percentage of patients taking zinc supplementation at M6, M12 and M24 was 8.9%, 20.6% and 29%, respectively. CONCLUSIONS: Reduced protein intake, impaired zinc absorption and worsening compensatory mechanisms contribute to zinc deficiency. The mechanisms involved differ according to the type of surgery and time since surgery. Zinc supplementation is necessary early after bariatric surgery, but this requirement is often underestimated or is inadequate. PMID- 20706806 TI - Sampling of the intestinal microbiota by epithelial M cells. AB - Sampling of intestinal pathogens and commensals is an important aspect of the gut immune system, and is accomplished through the action of specialized epithelial M cells. Although their sampling abilities have been appreciated for decades, few molecular details of their development or function are known. This review discusses several recent advances in our understanding of these cells, including signals controlling their development, the mechanisms they use for taking up microbes, and their exploitation by certain pathogens. Future research directions are discussed, including development of oral vaccines. PMID- 20706807 TI - Numerous aggregates of "tiny" micromegakaryocytes in the bone marrow. PMID- 20706808 TI - Technical challenges of total knee arthroplasty in skeletal dysplasia. AB - BACKGROUND: Total knee arthroplasty (TKA) in patients with skeletal dysplasias is particularly challenging as a result of the anatomic variances and substantial bony deformities. Little has been written regarding technical considerations that should be made when performing TKA in skeletal dysplasia. QUESTIONS/PURPOSES: We describe special operative considerations that must be made when performing TKA on patients with skeletal dysplasia, including implant selection and ligamentous balancing. PATIENTS AND METHODS: We retrospectively reviewed 12 TKAs in eight patients with varying degrees of deformity (ranging from 30 degrees of varus to 45 degrees of valgus) secondary to three types of skeletal dysplasias: multiple hereditary exostosis, achondroplasia, and osteogenesis imperfecta. Clinical notes, operative records, and radiographic data were reviewed. Minimum followup was 1 year (average, 4 years; range, 1-10 years). RESULTS: We used customized implants in three of the 12 knees. Constrained tibial inserts were used in five knees. All 12 knees underwent releases (soft tissue or epicondylar osteotomy) to address gap balancing or patellar tracking. Average Knee Society scores improved from 35.9 preoperatively to 82.9 postoperatively and average function scores improved from 47.9 preoperatively to 96.7 postoperatively. Complications included two transient peroneal nerve palsies. CONCLUSIONS: Special considerations must be made with regard to implant selection and ligamentous balancing as a result of the unusual anatomy and deformities that accompany skeletal dysplasia, but the short-term clinical results reveal consistent improvements in pain and function. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20706809 TI - Highlights of the ISOLS/MSTS 2009 meeting: editorial comment. PMID- 20706810 TI - Outcomes after scarf osteotomy for treatment of adult hallux valgus deformity. AB - BACKGROUND: Many procedures have been developed to correct hallux valgus deformity using distal soft tissue realignment, metatarsal osteotomy, and periodically, a proximal phalanx osteotomy (Akin). The ideal metatarsal osteotomy allows for varying degrees of correction with reliable improvement in deformity and patient satisfaction. QUESTIONS/PURPOSES: We evaluated the results after scarf osteotomy with respect to American Orthopaedic Foot and Ankle Society (AOFAS) scores, patient satisfaction, radiographic results, and complications. PATIENTS AND METHODS: We evaluated 29 patients (34 feet) during an 18-month period who underwent a unilateral scarf osteotomy combined with distal soft tissue realignment. Preoperative and postoperative AOFAS scores, patient satisfaction, and radiographic data were used to evaluate the effectiveness of the procedure. Complications were recorded. Minimal followup was 12 months (average, 26.4 months; range, 12-48 months). RESULTS: The mean AOFAS scores improved from 61.5 to 90.3. At final followup, 94% of patients were satisfied with the surgery. The hallux valgus angle improved from 34.6 degrees to 14.9 degrees and the intermetatarsal angle improved from 15.8 degrees to 7.2 degrees postoperatively. A combined Akin osteotomy was performed in only four cases. Complications included superficial wound infection (one), recurrence (two), and troughing (three). CONCLUSIONS: Our results suggest the scarf osteotomy produces improved AOFAS scores, high percentage of patient satisfaction, and effective correction of hallux valgus deformities. Using our scarf technique of rotation combined with translation minimizes the need for an Akin osteotomy while still obtaining good correction and avoids associated complications described in the literature. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20706811 TI - A second decade lifetable survival analysis of the Oxford unicompartmental knee arthroplasty. AB - BACKGROUND: The role of unicompartmental arthroplasty in managing osteoarthritis of the knee remains controversial. The Oxford medial unicompartmental arthroplasty employs a fully congruent mobile bearing intended to reduce wear and increase the lifespan of the implant. Long-term second decade results are required to establish if the design aim can be met. QUESTIONS/PURPOSES: We report the (1) 20-year survivorship for the Oxford mobile bearing medial unicompartmental knee arthroplasty; (2) reasons for the revisions; and (3) time to revision. METHODS: We reviewed a series of 543 patients who underwent 682 medial Oxford meniscal bearing unicompartmental knee arthroplasties performed between 1983 and January 2005. The mean age at implantation was 69.7 years (range, 48-94 years). The median followup was 5.9 years (range, 0.5 to 22 years). One hundred and forty-one patients (172 knees) died. None were lost to followup. The primary outcome was 20-year survival, a key variable in assessing the longevity of arthroplasty. RESULTS: The 16-year all cause revision cumulative survival rate was 91.0% (CI 6.4, 71 at risk) and survival was maintained to 20 years (91.0%, CI 36.2, 14 at risk). There had been 29 revision procedures: 10 for lateral arthrosis, nine for component loosening, five for infection, two bearing dislocations, and three for unexplained pain. In addition, five patients had undergone bearing exchange, four for dislocation and one for bearing fracture. The mean time to revision was 3.3 years (range, 0.3-8.9 years). CONCLUSIONS: Mobile bearing unicompartmental knee arthroplasty is durable during the second decade after implantation. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 20706812 TI - Giant cell tumor of bone: risk factors for recurrence. AB - BACKGROUND: Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial. QUESTIONS/PURPOSES: We evaluated the recurrence-free survival after surgical treatment of GCT to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence. METHODS: We retrospectively reviewed 118 patients treated for benign GCT of bone between 1985 and 2005. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum followup was 36 months (mean, 108.4 +/- 43.7; range, 36 233 months). RESULTS: Wide resection had a lower recurrence rate than intralesional surgery (5% versus 25%). Application of polymethylmethacrylate decreased the risk of local recurrence after intralesional surgery compared with bone grafting; phenol application alone had no effect on the risk of recurrence. Pulmonary metastases occurred in 4%; multidisciplinary treatment including wedge resection, chemotherapy, and radiotherapy achieved disease-free survival or stable disease in all of these patients. CONCLUSION: We recommend intralesional surgery with polymethylmethacrylate for the majority of primary GCTs. Because pulmonary metastases are rare and aggressive treatment of pulmonary metastases is usually successful, we believe the potential for metastases should not by itself create an indication for wide resection of primary tumors. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20706813 TI - The John Insall Award: control-matched evaluation of painful patellar Crepitus after total knee arthroplasty. AB - BACKGROUND: Patellar crepitus (PC) is reported in up to 14% of subjects implanted with cruciate-substituting total knee arthroplasty (TKA). Numerous etiologies of PC have been proposed. QUESTIONS/PURPOSES: We determined when painful PC typically occurs postoperatively and compared patients undergoing primary TKA who developed painful PC requiring subsequent surgery with a matched group without this complication to identify clinical, radiographic, and surgical variables associated with this complication. METHODS: From the databases of two institutions (greater than 4000 TKAs), we identified 60 patients who required surgery for painful PC from 2002 to 2008. This group was then compared with an identified control group of 60 TKA subjects without PC who were matched for the key variables of age, gender, and body mass index to determine clinical, radiographic, and surgical factors associated with the development of PC. RESULTS: The mean time to presentation of PC was 10.9 months. The incidence of PC correlated with a greater number of previous knee surgeries, decreased patellar component size, decreased composite patellar thickness, shorter preoperative and postoperative patellar tendon length, increased posterior femoral condylar offset, use of smaller femoral components and thicker tibial polyethylene inserts, and placement of the femoral component in a flexed posture. CONCLUSIONS: Many of the factors associated with an increased incidence of postoperative PC such as shortened patellar tendon length, use of smaller patellar components, decreased patellar composite thickness, and increased posterior femoral condylar offset may all increase quadriceps tendon contact forces against the superior aspect of the intercondylar box, increasing the risk of fibrosynovial proliferation and entrapment within the intercondylar region of the femoral component. Based on these findings, the authors recommend use of larger patellar components when possible, avoid oversection of the patella or increasing posterior femoral condylar offset, and advising patients preoperatively who have had previous knee surgery or demonstrate a shortened patellar tendon length of an increased risk of development of postoperative patellar crepitus. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20706814 TI - The Repicci II(r) unicondylar knee arthroplasty: 9-year survivorship and function. AB - BACKGROUND: Unicompartmental knee arthroplasty (UKA) is a recognized procedure for treatment of medial compartment osteoarthritis. UKA using minimally invasive surgery (MIS) has the theoretical advantage of less bone resection and quicker rehabilitation. Whether the function of patients with UKA compares with that of patients with conventional TKA is unclear. QUESTIONS/PURPOSES: We determined (1) the length of stay and complications associated with a short-stay MIS protocol; (2) whether MIS techniques allow for accurate positioning of the implant and alignment of the limb; (3) the change in functional scores; (4) the revision rate, reasons for revision, and survival of this implant. PATIENTS AND METHODS: We prospectively followed 100 patients who had 114 UKAs. All completed an International Knee Society (IKS) score preoperatively, at 1 year, and at last followup. We determined survivorship. Minimum followup was 5.2 years (mean, 7.4 years; range, 5.2-9 years). RESULTS: Mean length of stay was 1.2 days, with 41% discharged the same day. The perioperative complication rate was 6%. The mean IKS score improved from 77 to 93 and was 86 at last followup. The mean hip-knee-ankle axis changed from 6 degrees varus to 1.7 degrees varus. Twenty-two patients underwent a revision procedure at a mean 6.2 years after the index procedure. Survivorship of the prosthesis was 78% at 9 years. CONCLUSIONS: The short-stay protocol was not associated with a high perioperative complication rate. This technique is associated with improvement in function and restoration of limb alignment, allowing accurate positioning of the implant. Compared with other reports of survival of UKA, this implant had a lower survivorship and increased revision rate. PMID- 20706815 TI - Expression of hsp90 mediates cytoprotective effects in the gastrodermis of planarians. AB - Heat shock proteins (HSPs) play a crucial role in the protection of cells. In the present study, we have identified an hsp90-related gene (Djhsp90) encoding a cytosolic form of HSP90 that is primarily expressed in gastrodermis of the planarian Dugesia japonica. Djhsp90 becomes significantly induced after traumatic amputation or other stress stimuli, such as exposure to X-ray or ultraviolet radiations, heat shock, or prolonged starvation. When Djhsp90 is silenced by ribonucleic acid interference (RNAi), planarians dramatically decrease in size, becoming unable to eat, and die in a few weeks. Our results indicate that this gene plays an essential cytoprotective role in the gastrodermis of planarians and suggest that this chaperone can be involved in autophagic processes that are activated by this tissue. PMID- 20706817 TI - Childhood obesity in developing countries. PMID- 20706816 TI - Applications of grayscale and radiofrequency intravascular ultrasound to image atherosclerotic plaque. PMID- 20706818 TI - Medication compliance among children. PMID- 20706819 TI - The genetics of inflammatory bowel disease: diagnostic and therapeutic implications. AB - BACKGROUND: The genetics of inflammatory bowel diseases (IBD) has brought new insight into the spectrum of disease phenotypes that are collectively labeled as either Crohn's disease or ulcerative colitis. In concert with the pharmacogenomics of drug therapy, it has led clinicians to develop the notion of a more tailored approach to therapy. DATA SOURCES: Articles were searched from PubMed (1995-2010) with key words "inflammatory bowel diseases", "Genetics", "pharmacogenomics". RESULTS: Among all the putative susceptibility loci, the NOD2 gene has been the most studied and linked to an aggressive form of stricturing and perforating disease of the ileum. Other potential gene polymorphisms, including those encoding for the interleukin-23 receptor, have lent themselves to the recent development of potential novel immunosuppressive therapies. While the linkage of a number of autophagy genes with either Crohn's disease or ulcerative colitis has provided insight into the innate adaptive immune pathway's response to commensual intestinal bacteria. Pharmacogenetic polymorphisms of azathioprine metabolism have been shown to predict toxicity to anti-metabolite therapy. Patients with absent thiopurine methyl transferase enzyme activity are at risk for irreversible bone marrow suppression, and are not considered good candidates for either 6-mercaptopurine (6-MP) or azathioprine therapy. CONCLUSIONS: Ultimately, the correlation between these genotypes and clinical phenotype of disease will inevitably lead to an improved understanding of disease natural history and a more tailored approach to therapy. Although there is ongoing debate as to whether these inherent differences in enzyme activity can predict responsiveness to anti-metabolite therapy, some gastroenterologists do find value in 6-MP metabolite testing as a means of monitoring patient compliance and tailoring the dose of anti-metabolite therapy based on a perceived therapeutic window. In the future, patients with IBD will ultimately be categorized based on their genomic imprint to allow for a better delineation of disease phenotype. Furthermore, the application pharmacogenomics of drug therapy into clinical practice will be pivotal in maximizing treatment response while avoiding untoward side-effects. PMID- 20706820 TI - Liver abscess in children: an overview. AB - BACKGROUND: Liver abscess (LA) in the pediatric population has become relatively uncommon in developed countries but it continues to have a high incidence among children in developing countries. This article aims to review the trends in all aspects of LA in children, both temporally and geographically. DATA SOURCES: The PubMed and Google Scholar database were searched with the keywords "liver abscess", "children", "predisposing causes", "clinical signs and symptoms", "treatment" from 1975 to 2009 and all kinds of retrospective and prospective studies, reviews, case series were included. RESULTS: Pyogenic LA constitutes the majority of cases, followed by amebic and fungal LA. Staphylococcus aureus is the most common pathogen worldwide. Ultrasonography (US) and computed tomography (CT) are widely used as diagnostic tools. There are varying opinions regarding the treatment of LA in children. The general trend is towards less invasive modalities of treatment like percutaneous drainage along with antimicrobial drug therapy. However, in selected patients, open surgical drainage still plays an important role. The mortality rate for pyogenic LA has shown a decline from about 40% before the 1980s to less than 15% in the recent years. At the same time, the mortality rate of amebic LA cases reported to be around 11%-14% before 1984 has reduced to less than 1% at present. CONCLUSIONS: Etiological pattern of LA in children has remained the same over the years, and in most regions, it is associated with Staphylococcus aureus and amebic LA is quite uncommon. US or CT scan is the most frequently employed diagnostic modality for LA, and follow-up is usually performed by serial US scans. Antimicrobial therapy along with, if necessary, drainage of the abscess by either percutaneous or open surgical route remains the treatment of choice. PMID- 20706821 TI - Iodine nutritional status and goiter prevalence in 6-12 years primary school children of Saurashtra region, India. AB - BACKGROUND: Iodine deficiency disorder (IDD) or goiter is the cause of preventable brain damage, mental retardation, and stunted growth and development in children. This study aimed to detect the prevalence of IDD in Rajkot district, India by testing urinary iodine excretion levels and iodine salt intake of school children. METHODS: A cross-sectional study was conducted in 2940 school children of both sexes aged 6-12 years from 14 talukas subdivisions of the district. Thirty clusters were selected by using cluster sampling technique. Goiter was assessed in all the studied children along with biochemical analysis of iodine in 420 urine samples and iodine content in 840 edible salt samples in the studied area. RESULTS: Goiter was reported from all talukas subdivisions of the studied area. Goiter prevalence ranged from 1% to 35%, and the overall prevalence was 8.8% (grade 1: 7.6%; grade 2: 1.2%), indicating a mild public health problem. In the study areas, 18.1% of the population showed a level of urinary iodine excretion <50 microg/L. The median level of urinary iodine in the studied areas was 110 microg/L (range 10-415 microg/L). The iodine level of more than 15 ppm was found in 81% of salt samples tested at the household level. CONCLUSION: There is mild goiter prevalence in primary school children of Rajkot district, which is due to the inadequate iodine intake or content from salt at the household level. PMID- 20706823 TI - Risk profiles of progression in primary focal segmental glomerulosclerosis. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a component of childhood nephrotic syndrome occurring in 10%-20% of all cases. Over time, 25%-50% of children with FSGS develop kidney failure disease. We followed a cohort of children with FSGS in order to delineate the risk profile of progression to kidney failure (KF). METHODS: We evaluated patient data collected from 1977 to 2002 at a regional mid-Atlantic nephrology center in the United States. KF was defined primarily for those patients whose serum creatinine (SCr) value doubled compared with the SCr value from a previous visit. Patients who received dialysis or a kidney transplant were also defined as having KF. We analyzed patient data for those who had at least two visits with SCr values recorded. Various baseline characteristics of patients who had developed KF and those with no kidney failure (NKF) were compared. Hazard ratios and correlation were used to further investigate potential risk factors of the kidney failure. We also compared the inverse SCr trend for KF and NKF patients using weighted linear regression. RESULTS: Thirty-four of 43 FSGS patients had adequate follow-up data. About 60% of the patients developed KF over the study period. The average age of the KF patients at diagnosis of FSGS was 9 years, and that of NKF patients 12 years (P=0.05). FSGS patients with KF had a significantly higher mean diastolic blood pressure (DBP) at baseline, compared to those with NKF (P<0.0001). Other baseline characteristics including race, body mass index (BMI), systolic blood pressure, total cholesterol, urinary protein/creatinine ratio and calculated glomerular filtration rate (cGFR) were not significantly different. Baseline DBP was a significant risk factor in progression to KF (HR: 1.03; 95%CI: 1.01-1.06). Inverse SCr values were significantly decreased over time in KF patients (P=0.01). CONCLUSIONS: The data of this study indicate that children diagnosed with FSGS who are younger than 10 years and have elevated baseline DBP are more likely to develop kidney failure. The non-significant hazard ratios for other baseline characteristics including gender, race, and BMI are not instrumental risk factors. These results may help understand what may affect progression towards kidney failure in children with FSGS. PMID- 20706822 TI - A cross-sectional survey of participation of asthmatic children in physical activity. AB - BACKGROUND: Physical exercise has been proven to be beneficial to children with asthma, but the traditional view in China is that asthmatic children should not take part in sports. This study was undertaken to investigate the current status of children with asthma taking part in exercise in China. METHODS: One hundred and twenty-three asthmatic children (7-14 years old) who had visited our asthma control center between February 2009 and June 2009 were enrolled in this cross sectional study. Each child had a pulmonary function test and his/her health related quality of life was assessed. The children also finished a questionnaire about their physical activity. As a control group, 109 nonasthmatic children from a primary school were surveyed about their level of activity. RESULTS: Asthmatic children took part in less exercise than their healthy peers, and 62.6% (77/123) of the children with asthma never reached the criteria of exercise prescription for patients with asthma advised by the American College of Sports Medicine. The asthmatic children were divided into two groups based on the level of activity; compared with the group with a higher physical activity level, more children in the group with lower activity believed that exercise could make asthma worse, more parents and teachers restricted the children's exercise, and fewer doctors approved them participating in exercise. All of the parameters of basic lung function were higher in the group with higher activity level. Moreover, the children with a higher exercise level had a higher score on all parts of the pediatric asthma quality-of-life questionnaire. About 78.5% (96/123) of children ever experienced coughing, chest distress, dyspnea, or gasping during exercise, but 49.6% (61/123) had these symptoms occasionally. CONCLUSIONS: Our study reveals that children with asthma do not have enough exercise in China. The concept that children, parents, teachers and doctors have about exercise for patients with asthma is urgent to be updated. We need to prescribe appropriate exercise for children with asthma. PMID- 20706824 TI - High prevalence of vitamin D and calcium deficiency among pregnant women and their newborns in Chengdu, China. AB - BACKGROUND: Vitamin D and calcium deficiency is common in pregnant women and newborn infants. There are few data about the prevalence of hypovitaminosis D during pregnancy and infancy in China. We assessed vitamin D status of pregnant women and their neonates in Chengdu, Sichuan province, China. METHODS: Maternal serum and cord blood levels of calcium, 25-hydroxyvitamin D [25(OH)D], alkaline phosphatase, and parathyroid hormone (PTH) were studied in 77 urban and rural mother-neonate pairs at term. RESULTS: The mean level of maternal serum 25(OH)D was 35.95+/-19.7 nmol/L, and that of cord blood 25(OH)D was 40.98+/-18.89 nmol/L. The intake of calcium and vitamin D was uniformly low, although it was higher in urban (1010+/-450 mg/d, 237+/-169 IU/d) than in rural (320+/-210 mg/d, 62+/-66 IU/d) women. Maternal serum 25(OH)D was correlated positively with cord blood 25(OH)D (r=0.94, P<0.01). CONCLUSIONS: There is a high prevalence of vitamin D and calcium insufficiency in pregnant women and neonates in Chengdu even when mothers are compliant with prenatal vitamin supplementation. Supplementation is needed to improve maternal and neonatal vitamin D and calcium nutrition. PMID- 20706825 TI - One day hospitalization after open, double-J stented pyeloplasty. AB - BACKGROUND: This study was undertaken to assess the effect of antegrade placement of internal double-J catheters for patients who underwent open pyeloplasty for ureteropelvic junction (UPJ) obstruction. METHODS: Medical records of unilateral dismembered pyeloplasties of 71 patients with UPJ obstruction treated between 1998 and 2008 were reviewed retrospectively. In all patients, a double-J catheter was placed in an antegrade fashion during the operation. The patients were reviewed in terms of age, sex, postoperative complications and length of hospital stay. RESULTS: All children but one using double-J catheter were discharged within 24 hours after the operation. Neither urinary leak nor re-obstruction occurred in the operated kidneys during a follow-up. CONCLUSION: Transanastomotic stenting with double-J catheter is recommended as the reasonable mode of drainage in open pyeloplasty in pediatric patients. PMID- 20706826 TI - A Chinese girl molecularly diagnosed with Alagille syndrome. AB - BACKGROUND: Alagille syndrome (AGS) is a rare or fatal disease affecting multiple systems including the liver, heart, eyes, skeleton and face. It has been considered a genetically heterogeneous disorder of the Notch signaling pathway. METHODS: A 28-month-old Chinese girl with congenital heart disease and jaundice was diagnosed with Alagille syndrome by liver biopsy showing a paucity of the intrahepatic bile ducts. Variants of the JAG1 gene were detected by DNA sequencing in the patient and her unaffected father. RESULTS: A heterozygous missense mutation was identified in exon 2 of the JAG1 gene in the proband but not in exon 2, 4, 6, 9, 17, 23, 24 by DNA sequencing in her father. The mutation G-->T change was seen at position 133 in the cDNA sequence (c.133 G-->T), causing a substitution of a leucine for a valine (V45L) residue in the N terminus between signal peptide and DSL domain of the Notch ligand. This mutation, however, was absent in her father. CONCLUSION: Genes in the Notch signaling pathway should be further studied in AGS, and used to confirm clinical or prenatal diagnosis and facilitate genetic counseling. PMID- 20706827 TI - SPECT-CT image fusion could enhance Meckel scan. PMID- 20706828 TI - Kaposi's varicelliform eruption (eczema herpeticum) in an infant. PMID- 20706829 TI - [Increasing efficiency and patient satisfaction by structured clinical processes in presurgical visits]. AB - BACKGROUND: In clinical routine the process of presurgical visit and signed informed consent is imperfectly realized in surgical patients. MATERIAL AND METHODS: A total of 450 consecutive patients were interviewed after a presurgical visit for informed consent using a questionnaire. The aim of the study was to investigate the amount of knowledge gained by informed consent. Patient satisfaction with medical treatment and logistic workflow was correlated with real waiting times and process times. RESULTS: Mean information duration was 36.1+/-0.8 min. In patients with no appointed time, waiting times and overall stay was shorter. Patient's satisfaction with medical treatment and time process was significantly higher in the elderly. Longer conversation with the surgeon was associated with a higher assessment of surgeons' medical experience irrespective of his specialist's state. Real waiting times did not affect patient's satisfaction. CONCLUSION: A walk-in clinic for presurgical visit and signed informed consent can improve patient satisfaction. It allows an excellent patients information in an appropriate time-frame. Clinical pathways can improve patient satisfaction and information concerning the lining up operation and disease pattern. PMID- 20706830 TI - Leisure-time physical activity and type 2 diabetes during a 28 year follow-up in twins. AB - AIMS/HYPOTHESIS: The study aimed to investigate whether baseline physical activity protects against the occurrence of type 2 diabetes during a 28 year follow-up, after controlling for childhood environment and genetic predisposition. METHODS: At baseline in 1975 same-sex twin pairs born in Finland before 1958 were sent a questionnaire including questions on physical activity. The participants (20,487 individuals, including 8,182 complete twin pairs) were divided into quintiles by leisure-time physical activity metabolic equivalent (MET) index (MET h/day). Type 2 diabetes was determined from nationwide registers for the follow-up period (1 January 1976-31 December 2004). Individual and pairwise Cox proportional hazard models were used. RESULTS: During follow-up, 1,082 type 2 diabetes cases were observed. Among all individuals, participants in MET quintiles (Q) III-V had significantly decreased risk for type 2 diabetes compared with sedentary individuals (QI). The pairwise analysis on pairs discordant for physical activity showed that participants in MET QII to V had significantly lower hazard ratios (0.61, 0.59, 0.61, 0.61) compared with sedentary participants. These findings from the pairwise analysis persisted after adjusting for BMI. In the pairwise analysis, the BMI-adjusted hazard ratio for type 2 diabetes was lower for physically active members of twin pairs (combined QII-V) than for inactive co-twins (HR 0.54; 95% CI 0.37-0.78). Similar results were obtained for both dizygotic and monozygotic pairs, as well as for the subgroup of twin pairs defined as free of co-morbidities in 1981 (HR 0.36; 95% CI 0.17-0.76). CONCLUSIONS/INTERPRETATION: Leisure-time physical activity protects from type 2 diabetes after taking familial and genetic effects into account. PMID- 20706831 TI - The increasing importance of carbon nanotubes and nanostructured conducting polymers in biosensors. AB - The growing need for analytical devices requiring smaller sample volumes, decreased power consumption and improved performance have been driving forces behind the rapid growth in nanomaterials research. Due to their dimensions, nanostructured materials display unique properties not traditionally observed in bulk materials. Characteristics such as increased surface area along with enhanced electrical/optical properties make them suitable for numerous applications such as nanoelectronics, photovoltaics and chemical/biological sensing. In this review we examine the potential that exists to use nanostructured materials for biosensor devices. By incorporating nanomaterials, it is possible to achieve enhanced sensitivity, improved response time and smaller size. Here we report some of the success that has been achieved in this area. Many nanoparticle and nanofibre geometries are particularly relevant, but in this paper we specifically focus on organic nanostructures, reviewing conducting polymer nanostructures and carbon nanotubes. PMID- 20706833 TI - CD spectroscopy of peptides and proteins bound to large unilamellar vesicles. AB - Circular dichroism (CD) spectroscopy is an essential tool for determining the conformation of proteins and peptides in membranes. It can be particularly useful for measuring the free energy of partitioning of peptides into lipid vesicles. The belief is broadly held that such CD measurements can only be made using sonicated small unilamellar vesicles (SUVs) because light scattering associated with extruded large unilamellar vesicles (LUVs) is unacceptably high. We have examined this issue using several experimental approaches in which a chiral object (i.e., peptide or protein) is placed both on the membrane and outside the membrane. We show that accurate CD spectra can be collected in the presence of LUVs. This is important because SUVs, unlike LUVs, are metastable and consequently unsuitable for equilibrium thermodynamic measurements. Our data reveal that undistorted CD spectra of peptides can be measured at wavelengths above 200 nm in the presence of up to 3 mM LUVs and above 215 nm in the presence of up to 7 mM LUVs. We introduce a simple way of characterizing the effect on CD spectra of light scattering and absorption arising from suspensions of vesicles of any diameter. Using melittin as an example, we show that CD spectroscopy can be used to determine the fractional helical content of peptides in LUVs and to measure their free energy of partitioning of into LUVs. PMID- 20706834 TI - Physiology and biochemistry of reduction of azo compounds by Shewanella strains relevant to electron transport chain. AB - Azo dyes are toxic, highly persistent, and ubiquitously distributed in the environments. The large-scale production and application of azo dyes result in serious environmental pollution of water and sediments. Bacterial azo reduction is an important process for removing this group of contaminants. Recent advances in this area of research reveal that azo reduction by Shewanella strains is coupled to the oxidation of electron donors and linked to the electron transport and energy conservation in the cell membrane. Up to date, several key molecular components involved in this reaction have been identified and the primary electron transportation system has been proposed. These new discoveries on the respiration pathways and electron transfer for bacterial azo reduction has potential biotechnological implications in cleaning up contaminated sites. PMID- 20706835 TI - Cadmium effects on transcriptional expression of rhlB/rhlC genes and congener distribution of monorhamnolipid and dirhamnolipid in Pseudomonas aeruginosa IGB83. AB - While variable production of the biosurfactant, rhamnolipid, by Pseudomonas aeruginosa has been shown to be dependent on growth conditions, no research has evaluated potential relationships between rhamnolipid production and the presence of heavy metals. The current investigation evaluates the influence of Cd(2+) on rhamnolipid synthesis. Cultures grown in the presence of 0.45 and 0.89 mM Cd(2+) were monitored for rhlB/rhlC expression, rhamnolipid yield, and the ratio of monorhamnolipid (RL1) and dirhamnolipid (RL2) produced. Results show a Cd-induced enhancement of rhlB expression in mid-stationary phase (53 h). In addition, sustained production of rhamnolipid through late stationary growth phase (96 h) was observed for Cd-amended cultures, unlike Cd-free control cultures that ceased rhamnolipid production by mid-stationary growth phase. Most significant was an observed increase in the ratio of RL2 to RL1 congeners produced by cultures grown in the presence of Cd(2+). Previous results have shown that the complexation constant for RL2-Cd is several orders of magnitude larger than that of RL1-Cd thus the preferential production of RL2 in the presence of Cd(2+) impacts its bioavailability and toxicity both for the cell and in the surrounding environment. PMID- 20706836 TI - Permanent stoma not only affects patients' quality of life but also that of their spouses. AB - BACKGROUND: Living with a permanent colostomy can significantly diminish a patient's quality of life. However, little is known about the effects on the patient's spouse. Therefore, the aim of the present study was to evaluate the quality of life of spouses whose partners had undergone sphincter-sacrificing surgery for rectal carcinoma. METHODS: We studied 56 couples after one partner underwent sphincter-sacrificing surgery for rectal carcinoma: female spouses (n = 30) and male spouses (n = 26). To identify how surgery affected the life standards of the spousal population, questionnaires were constructed by the Department of Public Health, General Surgery and Psychology at the University of Ankara. RESULTS: Sixteen of 26 male spouses increased time spent at home, whereas 10 of 30 female spouses increased time spent at home (p < 0.05, male spouses versus female spouses). All of the spouses had been sexually active before their partners' operation; however 20 of 26 male spouses and 10 of 30 female spouses were sexually inactive afterward (p < 0.05, male spouses versus female spouses). Ten male patients and 3 female patients wanted their colostomy care to be managed by their spouses (p < 0.01, female spouses versus male spouses). CONCLUSIONS: In a patient with a colostomy, the social and sexual aspects of the life of the patient's spouse are affected. This observation needs to be taken into account when patients are preoperatively counseled. Therefore, preoperative counseling regarding the possible problems after surgery should not only include the patient but also the spouse. PMID- 20706837 TI - The influence on outcome of indications for antireflux surgery. AB - BACKGROUND: Patients with gastroesophageal reflux referred for fundoplication present with different symptom patterns. Previous studies have not analyzed the clinical outcome after fundoplication in patients stratified according to symptom patterns. METHODS: Five hundred eighteen patients undergoing laparoscopic fundoplication were stratified according to reflux symptom patterns: group 1, regurgitation; group 2, poorly controlled reflux; group 3, regurgitation and poor reflux control (combination of 1 and 2); and group 4, symptoms well controlled but patient does not want to continue taking medication. Clinical outcomes (heartburn control, dysphagia, satisfaction) were assessed prospectively using a standardized questionnaire at early (6 months to 2 years) and late (3-5 years) follow-up intervals. RESULTS: Preoperative demographic data for the four groups were similar, except for age and the frequency of esophagitis (patients in group 4 were younger and more likely to have esophagitis). Perioperative morbidity was similar for the four groups. Eighty-seven percent of the overall study group was satisfied at early follow-up and 88% at late follow-up. Early clinical outcomes were similar for all subgroups, except dysphagia scores were higher in early follow-up in groups 1 and 3 (P = 0.001). At late clinical follow-up, there were no significant differences in clinical outcome between any groups. CONCLUSIONS: At early follow-up (6 months to 2 years), patients who had reported regurgitation as the primary indication for surgery had a less favorable clinical outcome for the side effect dysphagia. However, at later follow-up, the type of preoperative reflux symptoms did not influence the clinical outcome. PMID- 20706839 TI - Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101). AB - PURPOSE: The primary objective of this sub-study, undertaken as an extension to the previously reported phase-I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary pharmacodynamic (PD) studies were also performed to enable comparison of the biological effects of the oral and intravenous formulations. PATIENTS AND METHODS: Oral belinostat was administered in a range of doses and schedules (once, twice or thrice daily), on either day 1 or days 1 5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase-I trial of intravenous belinostat. Serial blood samples were collected for PK and PD (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. RESULTS: A total mean daily AUC of 2,767 +/- 1,453 ng h/ml (8.7 +/- 4.6 MUM h) resulted from a dose of 1,000 mg/m(2) once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid); however, a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half-life (T1/2) of a single dose of 1,000 mg/m(2) was 1.5 h (+/- 0.3 h) and peak levels were reached in an average of 1.9 h (+/- 0.3 h). The half-life was found to be independent of dose, but a trend towards increasing half-life following multiple dosing was observed. Histone H4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. CONCLUSIONS: High doses of oral belinostat, up to 1,000 mg/m(2) bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat. PMID- 20706840 TI - High-resolution 3D non-contrast-enhanced, ECG-gated, multi-step MR angiography of the lower extremities: comparison with contrast-enhanced MR angiography. AB - OBJECTIVE: To determine the diagnostic value of non-contrast-enhanced, 3D-high resolution, ECG-gated, multi-step MR angiography (non-ceMRA) of the lower extremities using a modified turbo-spin-echo technique in comparison to 1.0-molar contrast-enhanced MR angiography (ceMRA) in patients with suspected peripheral vascular disease (PVD). METHODS: Fifty consecutive patients underwent non-ceMRA before ceMRA within the same session. We assessed examination time, image quality, localisation and severity of stenosis. RESULTS: Examination time was shorter for ceMRA (12 +/- 4 min) compared with non-ceMRA (28 +/- 6 min, p < 0.001). The image quality of the aorta-iliac, femoral and combined popliteal and lower leg arteries was inferior for non-ceMRA (2.8 +/- 0.8/3.3 +/- 0.8/3.3 +/- 0.9) versus ceMRA (4.7 +/- 0.8/4.8 +/- 0.6/4.8 +/- 0.7) on a 5-point scale with 5 for maximum quality (p < 0.01). CeMRA offered more assessable data sets than non ceMRA (98% vs. 90%). For detecting stenosis >50% or occlusions of pelvic and femoral arteries using non-ceMRA the sensitivity, specificity, positive and negative predictive values were 94%, 86%, 67% and 98% and for popliteal and lower leg arteries 93%, 87%, 69% and 98%, respectively. CONCLUSION: We demonstrated that 3D non-ceMRA represents a very promising technique in patients with lower extremities PVD and could be used as an alternative if gadolinium-based contrast agents cannot be administered. PMID- 20706841 TI - Malpractice and medical litigation. PMID- 20706842 TI - Photodynamic therapy of early stage oral cavity and oropharynx neoplasms: an outcome analysis of 170 patients. AB - The indications of photodynamic therapy (PDT) of oral cavity and oropharynx neoplasms are not well defined. The main reason is that the success rates are not well established. The current paper analyzes our institutional experience of early stage oral cavity and oropharynx neoplasms (Tis-T2) to identify the success rates for each subgroup according to T stage, primary or non-primary treatment and subsites. In total, 170 patients with 226 lesions are treated with PDT. From these lesions, 95 are primary neoplasms, 131 were non-primaries (recurrences and multiple primaries). The overall response rate is 90.7% with a complete response rate of 70.8%. Subgroup analysis identified oral tongue, floor of mouth sites with more favorable outcome. PDT has more favorable results with certain subsites and with previously untreated lesions. However, PDT can find its place for treating lesions in previously treated areas with acceptable results. PMID- 20706844 TI - Less can be more, less can be better. PMID- 20706843 TI - When, how and why to treat the neck in patients with esthesioneuroblastoma: a review. AB - Esthesioneuroblastoma is an uncommon tumor that presents in the sinonasal cavity and anterior skull base. Cervical metastases are not frequently found on initial presentation but eventually occur in 20-25% of these patients. This presents the treating physician with the difficult decision as to how and when to treat the neck in this disease. The aims of this study were to provide a comprehensive review of the incidence of N+ disease at presentation, make recommendations about the optimal treatment strategy of patients with N+ disease, explain the role of elective neck treatment in patients with N0 disease, and comment on treatment of patients with late cervical metastases that require salvage therapy, using the literature review of the incidence and treatment of neck disease in patients with esthesioneuroblastoma. This review revealed an approximately 5-8% incidence of cervical nodal metastasis at the time of presentation. Combined modality therapy with surgery and radiotherapy is recommended to treat the N+ neck at the time of diagnosis and later. Chemotherapy may have a role combined with radiation treatment, but there are little data to support this. There is limited evidence to substantiate the use of elective neck dissection or elective radiotherapy in the clinically and radiologically N0 neck. Patients who have late cervical metastases have a clear survival advantage (59 vs. 14%) when treated with combined surgery and radiotherapy relative to single modality methods alone. The results indicate that the management of the neck in esthesioneuroblastoma continues to be a significant challenge in the treatment algorithm of these complex patients. PMID- 20706845 TI - Intracranial hypertension following intrathecal administration of liposomal cytarabine. PMID- 20706846 TI - Unusual association of seronegative, nonparaneoplastic limbic encephalitis and relapsing polychondritis in a patient with history of thymectomy for myasthenia: a case study. PMID- 20706847 TI - Seroprevalence of human T-cell lymphotropic virus type 1 and 2 in blood donors from the regional hospital of Valdivia, Chile. AB - It is estimated that 15-20 millions of people are infected with human T-cell lymphotropic virus 1/2 (HTLV-1/2) worldwide, and 20-30% of them are Latin Americans. The seroprevalence rates vary according to geographic area, socio demographic composition and individual risk behaviors. The impact of HTLV-1 associated diseases on the community, as well as the increasing concerns about blood transfusion safety due to infectious transmitted agents, has required mandatory screening assays of blood donors as an effective preventive strategy in HTLV-1 transmission. The aim of this study was to estimate the seroprevalence of HTLV-1/2 in blood donors from Valdivia, southern Chile during the first year of mandatory screening of HTLV by Chilean government. Blood samples were collected from blood donors between May 2009 and 2010 at the Regional Hospital of Valdivia, Chile. Serum samples were screened for antibodies against HTLV-1/2 by enzyme linked immunosorbent assay MUREX HTLV I + II Abbott. Among 6,237 samples tested by serological assay, 28 samples were reactive; nevertheless, confirmatory techniques indicate that only 15 samples were positive to HTLV-1. Our study shows HTLV-1 seroprevalence of 0.24%, indicating a similar seroprevalence associated with blood donors than previous reports for our country. PMID- 20706848 TI - Does investment into "expensive" tissue compromise anti-parasitic defence? Testes size, brain size and parasite diversity in rodent hosts. AB - Species richness of parasite assemblages varies among host species. Earlier studies that searched for host-related determinants of parasite diversity mainly considered host traits that affect the probability of host encounter with parasites, whereas host traits related to defensibility against parasites have rarely been investigated. From the latter perspective, evolutionary investment in "expensive" tissue or organs (like testes or brain) may trade off against energetically costly anti-parasitic defences. If so, richer parasite assemblages are expected in hosts with larger testes and brains. We studied the relationships between testes and brain size and diversity of parasites (fleas, gamasid mites and helminths) in 55 rodent species using a comparative approach and application of two methods, namely the method of independent contrasts and generalized least squares (GLS) analysis. Both phylogenetically correct methods produced similar results for flea and helminth species richness. Testes size positively correlated with flea and helminth species richness but not gamasid mite species richness. No correlation between brain size and species richness of any parasite group was found by the method of independent contrasts. However, GLS analysis indicated negative correlation between brain size and mite species richness. Our results cast doubt on the validity of the expensive tissue hypothesis, but suggest instead that larger testes are associated with higher parasite diversity via their effect on mobility and/or testosterone-mediated immunosuppression. PMID- 20706849 TI - Masting in ponderosa pine: comparisons of pollen and seed over space and time. AB - Many plant species exhibit variable and synchronized reproduction, or masting, but less is known of the spatial scale of synchrony, effects of climate, or differences between patterns of pollen and seed production. We monitored pollen and seed cone production for seven Pinus ponderosa populations (607 trees) separated by up to 28 km and 1,350 m in elevation in Boulder County, Colorado, USA for periods of 4-31 years for a mean per site of 8.7 years for pollen and 12.1 for seed cone production. We also analyzed climate data and a published dataset on 21 years of seed production for an eighth population (Manitou) 100 km away. Individual trees showed high inter-annual variation in reproduction. Synchrony was high within populations, but quickly became asynchronous among populations with a combination of increasing distance and elevational difference. Inter-annual variation in temperature and precipitation had differing influences on seed production for Boulder County and Manitou. We speculate that geographically variable effects of climate on reproduction arise from environmental heterogeneity and population genetic differentiation, which in turn result in localized synchrony. Although individual pines produce pollen and seed, only one-third of the covariation within trees was shared. As compared to seed cones, pollen had lower inter-annual variation at the level of the individual tree and was more synchronous. However, pollen and seed production were similar with respect to inter-annual variation at the population level, spatial scales of synchrony and associations with climate. Our results show that strong masting can occur at a localized scale, and that reproductive patterns can differ between pollen and seed cone production in a hermaphroditic plant. PMID- 20706850 TI - Self-reported fatigue: one dimension or more? Lessons from the Functional Assessment of Chronic Illness Therapy--Fatigue (FACIT-F) questionnaire. AB - Across two general population (total n=1,878) and two cancer (total n=3,140) samples, we evaluated the dimensionality of self-reported fatigue as measured by the Functional Assessment of Chronic Illness Therapy--Fatigue (FACIT-F) instrument. After evaluating dimensionality of the FACIT-F, we compared the conceptually distinct fatigue experience versus fatigue impact scores in each sample. Confirmatory factor analysis of the 13-item scale showed very good fit to a single dimension ("unidimensional") model for each sample (comparative fit index range=0.92-0.97). Using a bifactor model to compare the loading of each item with the general fatigue factor versus the identified sub-domain (experience or impact), we found the item-general loading to be higher than that of the item sub-domain factor in 52 of 52 comparisons (13 items; four samples). When scored separately, experience and impact scores were correlated highly (range=0.80 0.88), yet their difference relative to one another was significant (p<0.001). Consistently across samples, experience scores were systematically higher (more endorsement) than impact scores, by a margin of 0.21-0.46 SD units. This suggests that the fatigue experience and the impact of fatigue upon function are reported along a single dimensional continuum, but that experience is more likely than impact upon function to be endorsed at lower levels of fatigue. Fatigue as an outcome or trial endpoint can be expressed as a single number, and the experience of the symptom is more likely to be endorsed at mild levels of fatigue, presumably before the symptom exerts an adverse impact upon function. PMID- 20706851 TI - Oral symptoms and functional outcome related to oral and oropharyngeal cancer. AB - PURPOSE: This study aimed to assess: (1) oral symptoms of patients treated for oral or oropharyngeal cancer; (2) how patients rank the burden of oral symptoms; (3) the impact of the tumor, the treatment, and oral symptoms on functional outcome. METHODS: Eighty-nine patients treated for oral or oropharyngeal cancer were asked about their oral symptoms related to mouth opening, dental status, oral sensory function, tongue mobility, salivary function, and pain. They were asked to rank these oral symptoms according to the degree of burden experienced. The Mandibular Function Impairment Questionnaire (MFIQ) was used to assess functional outcome. In a multivariate linear regression analyses, variables related to MFIQ scores (p<=0.10) were entered as predictors with MFIQ score as the outcome. RESULTS: Lack of saliva (52%), restricted mouth opening (48%), and restricted tongue mobility (46%) were the most frequently reported oral symptoms. Lack of saliva was most frequently (32%) ranked as the most burdensome oral symptom. For radiated patients, an inability to wear a dental prosthesis, a T3 or T4 stage, and a higher age were predictive of MFIQ scores. For non-radiated patients, a restricted mouth opening, an inability to wear a dental prosthesis, restricted tongue mobility, and surgery of the mandible were predictive of MFIQ scores. CONCLUSIONS: Lack of saliva was not only the most frequently reported oral symptom after treatment for oral or oropharyngeal cancer, but also the most burdensome. Functional outcome is strongly influenced by an inability to wear a dental prosthesis in both radiated and non-radiated patients. PMID- 20706852 TI - Study of coronary artery calcification risk in Egyptian adolescents with type-1 diabetes. AB - The objective of the study is to assess coronary artery calcification (CAC) among adolescents with type-1 diabetes and to determine its relation with high sensitivity C-reactive protein (hs-CRP), dyslipidaemia, glycaemic control and microvascular complications. The study included sixty patients with type-1 diabetes. Their ages ranged from 12 to 18 years and their diabetes duration ranged between 10 and 15 years. Patients were compared with 60 healthy subjects who served as controls. Clinical examination and laboratory investigations were done for evaluation of glycaemic control and presence of microvascular complications. Lipid profile, hs-CRP and multislice spiral computed tomography were done. Hs-CRP, total cholesterol, triglycerides and low-density lipoproteins levels were significantly higher in patients with diabetes compared to controls (P < 0.001). Twelve patients with diabetes (20%) had positive CAC. The mean calcium score was significantly higher in patients with diabetes compared to controls (P < 0.05). Smoking significantly affects CAC as 50% of smokers with diabetes had evidence of CAC compared to 9.1% of non-smokers with diabetes (P < 0.001). Fifty percent of patients with diabetes on angiotensin-converting enzyme inhibitor (ACEI) had evidence of CAC compared to 0% of patients without history of ACEI therapy (P < 0.001). Diabetics with CAC had significantly elder age, longer disease duration and higher mean glycosylated hemoglobin compared to diabetics without CAC (P < 0.05). Blood pressure percentiles, albumin creatinine ratio and serum lipids were significantly higher in patients with CAC compared to those without CAC (P < 0.001). All diabetics with severe retinopathy had positive CAC compared to 0% with normal Fundus (P < 0.001). All diabetics with overt nephropathy had positive CAC compared to 13.3% and 0% in micro- and normo albuminuric patients (P < 0.001). Young patients with diabetes have evidence of CAC. Smoking, microvascular complications and dyslipidaemia might contribute to this risk. PMID- 20706853 TI - Identification of a novel functional nuclear localization signal in the protein encoded by open reading frame 47 of Bombyx mori nucleopolyhedrovirus. AB - BM47 is encoded by open reading frame 47 of Bombyx mori nucleopolyhedrovirus (BmNPV). BM47 was localized in the nucleus of BmNPV-infected cells. In the present study, we investigated a novel nuclear localization signal (NLS) for BM47 transport and accumulation in the nucleus. By expressing various regions of BM47 fused to enhanced green fluorescent protein (EGFP), we demonstrated that residues 117-148 are necessary for mediating nuclear localization of BM47. Site-directed mutation analysis showed that the two basic residue clusters at positions 117-120 (117RKRR) and 144-148 (144RKR-K) constitute an authentic NLS for BM47 localization. Finally, we observed that two clusters of basic residues were conserved in BM47 homologues of group-I nucleopolyhedroviruses. PMID- 20706854 TI - Electronic structure and conformational properties of 1H-indole-3-acetic acid. AB - The conformational space of 1H-Indole-3-Acetic Acid (IAA) was scanned using molecular dynamics at semiempirical level, and complemented with functional density calculations at B3LYP/6-31G** level, 14 conformers of lowest energy were obtained. Electronic distributions were analyzed at a higher calculation level, thus improving the basis set (B3LYP/6-311++G**). A topological study based on Bader's theory ( AIM: atoms in molecules) and natural bond orbital (NBO) framework performed with the aim to analyze the stability and reactivity of the conformers allowed the understanding of electronic aspects relevant in the study of the antioxidant properties of IAA. Intramolecular hydrogen bonds were found and were characterized as blue-shifting hydrogen bonding interactions. Furthermore, molecular electrostatic potential maps (MEPs) were obtained and analyzed in the light of AIM and NBO results, thus showing subtle but essential features related not only to reactivity but also with intramolecular weak interactions, charge delocalization and structure stabilization. PMID- 20706855 TI - Antimicrobial resistance in colonizing group B Streptococci before the implementation of a Swedish intrapartum antibiotic prophylaxis program. AB - The prevalence of antibiotic resistance and their genetic determinants in colonizing group B streptococci (GBS) sampled in a Swedish nationwide survey was examined. In five GBS isolates (1.3%), kanamycin/amikacin resistance and the presence of the aphA-3 gene was identified. Three of these isolates carried the aad-6 gene and were streptomycin-resistant. Screening with kanamycin and streptomycin 1,000-MUg disks enabled a rapid and easy detection of these isolates. In all, 312/396 (79%) GBS were tetracycline-resistant and 95% of the examined isolates harbored the tetM gene. Among the 22 (5.5%) GBS resistant to erythromycin and/or clindamycin, the ermB gene was detected in nine isolates (41%) and erm(A/TR) in ten isolates (45%). A high level of erythromycin and clindamycin resistance with minimum inhibitory concentrations (MICs) >256 mg/L was found in four serotype V isolates that harbored ermB. The erythromycin/clindamycin resistance was distributed among all of the common serotypes Ia, Ib, II, III, IV, and V, but was not present in any of the 44 serotype III isolates associated to clonal complex 17. Screening for penicillin resistance with 1-MUg oxacillin disks showed a homogenous population with a mean inhibition zone of 20 mm. A change in the present oxacillin breakpoints for GBS is suggested. PMID- 20706856 TI - Stronger correlation between antibiotic use and the incidence of Clostridium difficile determined by culture results instead of faecal toxin detection only. AB - The detection of Clostridium difficile in previous studies evaluating antibiotic use as a risk factor was limited to toxin assay tests. The reported associations may have been misleading due to the low sensitivity of toxin assay tests compared to culture results. Antibiotic use and the incidence of C. difficile of 19 units (wards) over 5 years were analysed. Stool samples were tested for toxin A/B and cultured. The correlation of antibiotic use with the incidence of C. difficile determined by culture results was compared to the correlation determined by toxin assay results. Additionally, single antibiotics were analysed as risk factors. Of 5,772 faecal samples tested for C. difficile, 154 single-first cases were detected by the toxin assay and 251 additional single-first cases by culture. Antibiotic use was a significantly stronger risk factor in the correlation based on the culture results (R2 = 0.63) versus toxin assay results (R2 = 0.40). Multivariate analysis did not improve the correlation significantly and only the group of broad-spectrum beta-lactams was identified as an independent risk factor. The correlation between antibiotic use and C. difficile incidence rates significantly improves if detection is not limited to faecal toxin assays. Therefore, antibiotic pressure was previously underestimated as a risk factor. PMID- 20706858 TI - Tools for multi-media presentations and publications. PMID- 20706859 TI - Automatic monitoring of localized skin dose with fluoroscopic and interventional procedures. AB - This software tool locates and computes the intensity of radiation skin dose resulting from fluoroscopically guided interventional procedures. It is comprised of multiple modules. Using standardized body specific geometric values, a software module defines a set of male and female patients arbitarily positioned on a fluoroscopy table. Simulated X-ray angiographic (XA) equipment includes XRII and digital detectors with or without bi-plane configurations and left and right facing tables. Skin dose estimates are localized by computing the exposure to each 0.01 * 0.01 m(2) on the surface of a patient irradiated by the X-ray beam. Digital Imaging and Communications in Medicine (DICOM) Structured Report Dose data sent to a modular dosimetry database automatically extracts the 11 XA tags necessary for peak skin dose computation. Skin dose calculation software uses these tags (gantry angles, air kerma at the patient entrance reference point, etc.) and applies appropriate corrections of exposure and beam location based on each irradiation event (fluoroscopy and acquistions). A physicist screen records the initial validation of the accuracy, patient and equipment geometry, DICOM compliance, exposure output calibration, backscatter factor, and table and pad attenuation once per system. A technologist screen specifies patient positioning, patient height and weight, and physician user. Peak skin dose is computed and localized; additionally, fluoroscopy duration and kerma area product values are electronically recorded and sent to the XA database. This approach fully addresses current limitations in meeting accreditation criteria, eliminates the need for paper logs at a XA console, and provides a method where automated ALARA montoring is possible including email and pager alerts. PMID- 20706857 TI - Divergent aging characteristics in CBA/J and CBA/CaJ mouse cochleae. AB - Two inbred mouse strains, CBA/J and CBA/CaJ, have been used nearly interchangeably as 'good hearing' standards for research in hearing and deafness. We recently reported, however, that these two strains diverge after 1 year of age, such that CBA/CaJ mice show more rapid elevation of compound action potential (CAP) thresholds at high frequencies (Ohlemiller, Brain Res. 1277: 70 83, 2009). One contributor is progressive decline in endocochlear potential (EP) that appears only in CBA/CaJ. Here, we explore the cellular bases of threshold and EP disparities in old CBA/J and CBA/CaJ mice. Among the major findings, both strains exhibit a characteristic age (~18 months in CBA/J and 24 months in CBA/CaJ) when females overtake males in sensitivity decline. Strain differences in progression of hearing loss are not due to greater hair cell loss in CBA/CaJ, but instead appear to reflect greater neuronal loss, plus more pronounced changes in the lateral wall, leading to EP decline. While both male and female CBA/CaJ show these pathologies, they are more pronounced in females. A novel feature that differed sharply by strain was moderate loss of outer sulcus cells (or 'root' cells) in spiral ligament of the upper basal turn in old CBA/CaJ mice, giving rise to deep indentations and void spaces in the ligament. We conclude that CBA/CaJ mice differ both quantitatively and qualitatively from CBA/J in age related cochlear pathology, and model different types of presbycusis. PMID- 20706860 TI - Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. AB - Sorafenib, an orally active multi-kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC), is primarily metabolized both via cytochrome P450 3A4 isoform (CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways, sorafenib is considered to be less susceptible than other agents to CYP3A4 drug-drug interactions. This report discusses a clinically relevant pharmacokinetic CYP3A4 drug-drug interaction between sorafenib and felodipine in an 80-year-old Caucasian patient with HCC. On day 15, after the introduction of sorafenib (400 mg bid), sorafenib plasma concentration was at 3.6 mg/L. Felodipine (5 mg bid), an anti-hypertensive agent that is exclusively CYP3A4 substrate, was then introduced due to grade 2 sorafenib-related hypertension. On day 30, hypertension was well controlled. However, sorafenib plasma concentration was 3-fold greater (11.4 mg/L) and the patient experienced grade-3 anorexia. Since neither diarrhea nor cutaneous side effects were noticed at this time, sorafenib treatment was continued at the same daily dosage. On day 45, sorafenib plasma concentration was stable (10.8 mg/L) before declining on days 60 and 75 (7.0 mg/L and 7.4 mg/L, respectively), which was probably related to an occurrence of grade-2 diarrhea. This observation suggests a pharmacokinetic interaction involving CYP3A4 inhibition by felodipine. According to the Drug Interaction Probability Scale, this interaction was possible. Since hypertension is a common toxicity of sorafenib, clinicians should be aware of this possible interaction. The clinical relevance of pharmacokinetic interactions involving CYP3A4 inhibition in HCC patients receiving sorafenib is analyzed in this case report. PMID- 20706861 TI - A phase II study of S-1 and oxaliplatin (SOx) combination chemotherapy as a first line therapy for patients with advanced gastric cancer. AB - BACKGROUND: Palliative chemotherapy has been shown to have a survival benefit for patients with recurrent or metastatic gastric cancer. 5-fluorouracil (5-FU) and cisplatin have been widely used in a variety of combinations. We conducted a phase II study of combination chemotherapy with new agents, S-1 and oxaliplatin (SOx), in advanced gastric cancer patients in an effort to evaluate the efficacy and toxicity of this regimen. METHOD: Histologically confirmed recurrent or metastatic gastric cancer were treated by the oral administration of S-1 80 mg/m(2)/day on days 1-28, and oxaliplatin 85 mg/m(2) administered as a 90-min intravenous infusion on days 1, 15, and 29. Treatment courses were repeated every 6 weeks. Patients received a maximum of four cycles. RESULTS: From Feb 2006 to May 2008, 41 patients were enrolled in this study. The ratio of males to females was 28 to 13. The median patient age was 61 years (range, 36-74 years), and 85.4% (35/41) of the patients had a performance status (ECOG) of 1. The median number of chemotherapy cycles administered was 3 (range, 1-4). According to the results of our Intent-to-Treat analysis, 22 patients (53.7%) achieved a partial response (95% CI, 38-70%). 15 patients (36.6%) evidenced a stable disease, and 1 patient (2.4%) progressed during the course of the treatment. 3 patients were lost to follow-up prior to evaluation. The median time to progression and overall survival time were 4.6 months (95% CI, 3.4-5.8 months) and 7.8 months (95% CI, 6.9-8.7 months) from the start of the chemotherapy, respectively. A total of 114 cycles were assessed for toxicity. The major hematologic toxicities included grade 2 anemia (41.2%), grade 1-2 neutropenia (28.1%), and grade 1 thrombocytopenia (23.7%). Only 1 cycle of neutropenic fever occurred. The non hematological toxicities observed were grade 3 vomiting (12.2%) and grade 3 diarrhea (4.9%). No treatment-related deaths occurred in our patient population during the study period. CONCLUSION: The SOx regimen evidenced a relatively high response rate and was well tolerated as a first-line therapy for advanced gastric cancer. PMID- 20706862 TI - A comparative study on arsenic and humic substances in alluvial aquifers of Bengal delta plain (NW Bangladesh), Chianan plain (SW Taiwan) and Lanyang plain (NE Taiwan): implication of arsenic mobilization mechanisms. AB - Humic substances in groundwater and aquifer sediments from the arsenicosis and Blackfoot disease (BFD) affected areas in Bangladesh (Bengal delta plain) and Taiwan (Lanyang plain and Chianan plain) were characterized using fluorescence spectrophotometry and Fourier transform infrared (FT-IR) spectroscopy. The results demonstrate that the mean concentration of As and relative intensity of fluorescent humic substances are higher in the Chianan plain groundwater than those in the Lanyang plain and Bengal delta plain groundwater. The mean As concentrations in Bengal delta plain, Chianan plain, and Lanyang plain are 50.65 MUg/l (2.8-170.8 MUg/l, n=20), 393 MUg/l (9-704 MUg/l, n=5), and 104.5 MUg/l (2.51-543 MUg/l, n = 6), respectively. Average concentrations and relative fluorescent intensity of humic substances in groundwater are 25.381 QSU (quinine standard unit) and 17.78 in the Bengal delta plain, 184.032 QSU and 128.41 in the Chianan plain, and 77.56 QSU and 53.43 in the Lanyang plain. Moreover, FT-IR analysis shows that the humic substances extracted from the Chianan plain groundwater contain phenolic, alkanes, aromatic ring and amine groups, which tend to form metal carbon bonds with As and other trace elements. By contrast, the spectra show that humic substances are largely absent from sediments and groundwater in the Bengal delta plain and Lanyang plain. The data suggest that the reductive dissolution of As-adsorbed Mn oxyhydroxides is the most probable mechanism for mobilization of As in the Bengal delta plain. However, in the Chianan plain and Lanyang plain, microbially mediated reductive dissolution of As adsorbed amorphous/crystalline Fe oxyhydroxides in organic-rich sediments is the primary mechanism for releasing As to groundwater. High levels of As and humic substances possibly play a critical role in causing the unique BFD in the Chianan plain of SW Taiwan. PMID- 20706863 TI - Investigation of changes in skeletal muscle alpha-actin expression in normal and pathological human and mouse hearts. AB - We have developed a quantitative antibody-based assay to measure the content of skeletal muscle alpha-actin relative to cardiac alpha-actin. We found 21 +/- 2% skeletal muscle alpha-actin content in normal heart muscle of adult man and mouse. In end stage failing heart 53 +/- 5% of striated actin was skeletal muscle alpha-actin and in samples of inter-ventricular septum from patients with hypertrophic obstructive cardiomyopathy (HOCM) skeletal muscle alpha-actin was 72 +/- 2% of sarcomeric actin. Thin filaments containing actin isolated from normal and HOCM heart muscle were functionally indistinguishable when studied by quantitative in vitro motility assay. We also found elevated skeletal muscle alpha-actin (60 +/- 7%) in a mouse model of dilated cardiomyopathy. PMID- 20706864 TI - Low-intensity electrical stimulation ameliorates disruption of transverse tubules and neuromuscular junctional architecture in denervated rat skeletal muscle fibers. AB - We determine the effects of direct electrical stimulation (ES) on the histological profiles in atrophied skeletal muscle fibers after denervation caused by nerve freezing. Direct ES was performed on the tibialis anterior (TA) muscle after denervation in 7-week-old rats divided into groups as follows: control (CON), denervation (DN), or denervation with direct ES (subdivided into a 4 mA (ES4), an 8 mA (ES8), or a 16 mA stimulus (ES16). The stimulation frequency was set at 10 Hz, and the voltage was set at 40 V (30 min/day, 6 days/week, for 3 weeks). Ultrastructural profiles of the membrane systems involved in excitation contraction coupling, and four kinds of mRNA expression profiles were evaluated. Morphological disruptions occurred in transverse (t)-tubule networks following denervation: an apparent disruption of the transverse networks, and an increase in the longitudinal t-tubules spanning the gap between the two transverse networks, with the appearance of pentads and heptads. These membrane disruptions seemed to be ameliorated by relatively low intensity ES (4 mA and 8 mA), and the area of longitudinally oriented t-tubules and the number of pentads and heptads decreased significantly (P < 0.01) in ES4 and ES8 compared to the DN. The highest intensity (16 mA) did not improve the disruption of membrane systems. There were no significant differences in the (alpha1s)DHPR and RyR1 mRNA expression among CON, DN, and all ES groups. After 3 weeks of denervation all nerve terminals had disappeared from the neuromuscular junctions (NMJs) in the CON and ES16 groups. However, in the ES4 and ES8 groups, modified nerve terminals were seen in the NMJs. The relatively low-intensity ES ameliorates disruption of membrane system architecture in denervated skeletal muscle fibers, but that it is necessary to select the optimal stimulus intensities to preserve the structural integrity of denervated muscle fibers. PMID- 20706865 TI - CT-GalNAc transferase overexpression in adult mice is associated with extrasynaptic utrophin in skeletal muscle fibres. AB - Duchenne muscular dystrophy is a genetic muscle disease characterized by the absence of sub-sarcolemmal dystrophin that results in muscle fibre necrosis, progressive muscle wasting and is fatal. Numerous experimental studies with dystrophin-deficient mdx mice, an animal model for the disease, have demonstrated that extrasynaptic upregulation of utrophin, an analogue of dystrophin, can prevent muscle fibre deterioration and reduce or negate the dystrophic phenotype. A different approach for ectopic expression of utrophin relies on augmentation of CT-GalNAc transferase in muscle fibre. We investigated whether CT-GalNAc transferase overexpression in adult mice influence appearance of utrophin in the extrasynaptic sarcolemma. After electrotransfer of plasmid DNA carrying an expression cassette of CT-GalNAc transferase into tibialis anterior muscle of wild type and dystrophic mice, muscle sections were examined by immunofluorescence. CT-GalNAc transgene expression augmented sarcolemmal carbohydrate glycosylation and was accompanied by extrasynaptic utrophin. A 6 week time course study showed that the highest efficiency of utrophin overexpression in a plasmid harboured muscle fibres was 32.2% in CD-1 and 52% in mdx mice, 2 and 4 weeks after CT-GalNAc gene transfer, respectively. The study provides evidence that postnatal CT-GalNAc transferase overexpression stimulates utrophin upregulation that is inherently beneficial for muscle structure and strength restoration. Thus CT-GalNAc may provide an important therapeutic molecule for treatment of dystrophin deficiency in Duchenne muscular dystrophy. PMID- 20706867 TI - Making time for well-baby care: the role of maternal employment. AB - The American Academy of Pediatrics recommends children receive six well-baby visits between ages 1 month and 1 year, yet by age 14 months less than 10% of infants have received all six visits. Cost sharing under public and private insurance is very low. Low compliance rates despite the low cost of care suggest other factors, such as time costs, may be important. This paper examines the relationship between maternal employment and receipt of well-baby care. The Medical Expenditure Panel Survey contains rich information on use of preventive care, maternal employment, and other economic and non-economic factors that may influence care decisions. Several approaches, including a proxy variable strategy and instrumental variables analysis, are used to attempt to address the potential endogeneity of maternal employment and examine the sensitivity of findings. Findings indicate mothers who work full-time take their children to 0.18 fewer visits (or 9% fewer at the mean) than those who have quit their jobs. Mothers with employer provided paid vacation leave take their children to 0.20 more visits (or 9% more at the mean) than other working mothers. Time appears to be an important factor in determining well-baby care receipt. Policies that extend paid leave to more employed women may improve compliance with preventive care recommendations. PMID- 20706866 TI - Self-efficacy as a mediator between maternal depression and child hospitalizations in low-income urban families. AB - The objective of this study is to examine the role of maternal self-efficacy as a potential mediator between maternal depression and child hospitalizations in low income families. We analyzed data from 432 mother-child pairs who were part of the control-group for the Nurse-Family Partnership trial in Memphis, TN. Low income urban, mostly minority women were interviewed 12 and 24 months after their first child's birth and their child's medical records were collected from birth to 24 months. We fit linear and ordered logistic regression models to test for mediation. We also tested non-linear relationships between the dependent variable (child hospitalization) and covariates (depressive symptoms and self-efficacy). Elevated depressive symptoms (OR: 1.70; 90% CI: 1.05, 2.74) and lower maternal self-efficacy (OR: 0.674; 90% CI: 0.469, 0.970) were each associated with increased child hospitalizations. When both maternal self-efficacy and depressive symptoms were included in a single model, the depressive symptoms coefficient decreased significantly (OR decreased by 0.13, P = 0.069), supporting the hypothesis that self-efficacy serves as a mediator. A non-linear, inverse-U shaped relationship between maternal self-efficacy and child hospitalizations was supported: lower compared to higher self-efficacy was associated with more child hospitalizations (P = 0.039), but very low self-efficacy was associated with fewer hospitalizations than low self-efficacy (P = 0.028). In this study, maternal self-efficacy appears to be a mediator between maternal depression and child hospitalizations. Further research is needed to determine if interventions specifically targeting self-efficacy in depressed mothers might decrease child hospitalizations. PMID- 20706868 TI - Early intervention for substance abuse among youth and young adults with mental health conditions: an exploration of community mental health practices. AB - This mixed method study examined current practices and barriers for screening and assessing substance use among youth/young adults in community mental health systems. Substance use rates remain high among youth/young adults in the general population and substance use disorders are prevalent among young people involved in public service systems such as mental health. In an effort to understand the dynamics for early intervention, 64 case managers and/or clinical directors from children's mental health systems in two states participated in an online survey or focus group in fall 2008. Quantitative survey questions and qualitative focus group questions explored attitudes and perspectives about screening and early intervention for substance use among youth/young adults involved in the mental health system and current agency practices. Mixed method results suggest a number of barriers to substance use screening and early intervention and point to innovations that could be more effectively supported. PMID- 20706869 TI - Effect of starvation on activities and mRNA expression of lipoprotein lipase and hormone-sensitive lipase in tilapia (Oreochromis niloticus x O. areus). AB - A 4-week study was conducted to determine the effect of starvation on activities and mRNA expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) in hybrid tilapia (Oreochromis niloticus x O. areus). The tissue samples were sampled once a week. Results showed that body weight (BW) and hepatosomatic index (HSI) were decreased significantly (P < 0.05) during starvation. The percentages of crude fat and crude protein in the whole body and the fat content in muscle decreased significantly (P < 0.05), while the rate of moisture and crude ash increased significantly (P < 0.05). The response of LPL, HSL activities and mRNA expression in tissues was tissue dependent. The activities of LPL and HSL in muscle at day 7 were elevated by 2.5 times (P < 0.05) and 11.8 times (P < 0.05) of the value at day 0, respectively, and both then decreased to pre starvation levels at day 14 and finally stabilized at a certain level afterward. LPL and HSL mRNA abundance in muscle remained relatively stable between 0 and 14 day; then, a significant increase was seen after 14 days. In the liver, LPL activity maintained a significantly increasing trend during starvation, while HSL activity rose dramatically at day 7 of starvation by 2.35 times (P < 0.05) and finally stabilized at a certain level. The mRNA abundance of liver LPL increased significantly during the whole process of starvation (P < 0.05), whereas the mRNA abundance of liver HSL decreased significantly at day 7 of starvation, elevating significantly afterward (P < 0.05). PMID- 20706870 TI - Inference of the phylogenetic position of the phylum Deferribacteres from gene order comparison. AB - The phylogenetic placement of the phylum Deferribacteres was investigated on the basis of gene order comparisons of completely sequenced bacterial genomes. Two completely sequenced Deferribacteres species share five sets of gene arrangements with a group of phyla, Proteobacteria, Aquificae, Planctomycetes, Spirochaetes, Bacteroidetes, Chlorobi, Acidobacteria, Verrucomicrobia, Elusimicrobia and Nitrospirae, while the other group of phyla, Synergistetes, Firmicutes, Actinobacteria, Thermotogae, Chloroflexi and Deinococcus-Thermus, Fusobacteria, shares alternative sets of gene arrangements, suggesting that the Deferribacteres is classified in the former group of phyla. Gene transfers that are thought to have occurred in a common ancestor of the Deferribacteres, Deltaproteobacteria and Nitrospirae exclusive of virtually all other phyla were identified, which suggests that the Deferribacteres is phylogenetically proximal to the Proteobacteria and Nitrospirae. PMID- 20706871 TI - Pichia anomala: cell physiology and biotechnology relative to other yeasts. AB - Pichia anomala is a most interesting yeast species, from a number of environmental, industrial and medical aspects. This yeast has been isolated from very diverse natural habitats (e.g. in foods, insects, wastewaters etc.) and it also exhibits wide metabolic and physiological diversity. Some of the activities of P. anomala, particularly its antimicrobial action, make it a very attractive organism for biological control applications in the agri-food sectors of industry. Being a 'robust' organism, it additionally has potential to be exploited in bioremediation of environmental pollutants. This paper provides an overview of cell physiological characteristics (growth, metabolism, stress responses) and biotechnological potential (e.g. as a novel biocontrol agent) of P. anomala and compares such properties with other yeast species, notably Saccharomyces cerevisiae, which remains the most exploited industrial microorganism. We await further basic knowledge of P. anomala cell physiology and genetics prior to its fuller commercial exploitation, but the exciting biotechnological potential of this yeast is highlighted in this paper. PMID- 20706873 TI - [Not Available]. PMID- 20706875 TI - Placebo adherence and its association with morbidity and mortality in the studies of left ventricular dysfunction. AB - BACKGROUND: A provocative finding from several double-blind clinical trials has been the association between greater adherence to placebo study medication and better health outcomes. We used data from the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial (SOLVD-TT) and the SOLVD Prevention Trial (SOLVD-PT) to examine whether such associations could be validated and to examine several sources of bias and potential confounding. METHODS: Survival analytic methods were used to estimate the association between placebo adherence and several health outcomes, employing a number of modeling techniques to test for the existence of alternative explanations for the association. Higher adherence was defined as having taken >=75% of prescribed study medication. RESULTS: Higher placebo adherence was associated with improved overall survival in both SOLVD-TT and SOLVD-PT [hazard ratio (HR) = 0.52, 95% confidence interval (CI): 0.35 to 0.79 and HR = 0.52, 95%CI: 0.38 to 0.71, respectively]. Associations were similar for fatal or non-fatal cardiovascular or coronary heart disease events. Adjustment for both modifiable and non-modifiable cardiac risk factors (including age, gender, diabetes, blood pressure, smoking, weight, alcohol use, and levels of education) had minimal effect on the strength of the association. Little evidence of bias was found as an explanation for this relationship. CONCLUSIONS: In these two trials, better adherence to placebo was associated with markedly superior health outcomes, including total in-study mortality and incident cardiovascular events. No important confounders were identified. These data suggest there may exist strong but unrecognized determinants of health outcomes for which placebo adherence is a marker. PMID- 20706876 TI - No association of the eNOS gene polymorphisms with survival in patients with colorectal cancer. AB - Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) is involved in numerous physiologic and pathophysiologic process including tumor angiogenesis and apoptosis. Accordingly, the present study analyzed polymorphisms of eNOS gene and their impact on the prognosis for patients with colorectal cancer. Four hundred and forty-four consecutive patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 2 polymorphisms of eNOS gene (eNOS T786C and eNOS G894T) determined using a real-time PCR genotyping assay. The 2 eNOS gene polymorphisms were successfully amplified, and the frequencies of each genotype are as follows [T786C: TT (82.2%), TC (16.9%), CC (0.9%); G894T: GG (82.0%), GT (17.3%), TT (0.7%)]. Multivariate survival analysis including stage, age, site of disease, and CEA level showed that these polymorphisms were not associated with survival. For the clinicopathologic parameters, CEA level and TNM stage were significant prognostic factors in a Cox model for survival. The eNOS gene polymorphisms investigated in this study were not found to be an independent prognostic marker for Korean patients with surgically resected colorectal cancer. However, further studies are warranted to clarify the role of the eNOS gene polymorphisms as a prognostic biomarker for colorectal patients with cancer. PMID- 20706877 TI - Effect of adhesive layer thickness and drug loading on estradiol crystallization in a transdermal drug delivery system. AB - The effects of adhesive layer thickness and drug loading on estradiol crystallization were studied in a drug-in-adhesive patch. Patches containing different estradiol loadings (1.1% and 1.6% w/w) in different thicknesses (45, 60, and 90 MUm) were prepared by coating of a homogenous mixture of adhesive solution and the drug on a siliconized release liner by a film applicator. After drying, the film was laminated on a Poly(ethylene terephthalate) backing layer and cut into appropriate size. Release tests were performed using thermostated Chien-type diffusion cells. Cross-section of the patches was observed by optical microscopy. Scanning electron microscopy was done for surface analysis of the patches after drug release test. Crystal formation was not expected in the adhesive layer based on the linear free-energy relationship formalisms however; crystalline regions were observed in different locations through the thickness of the patches. These regions were significantly more discontinuous in 45 MUm samples which elucidated the effective role of adhesive layer thickness in drug crystallization. Extensive crystallization observed for thicker patches was attributed to the strong crosslinking capability of estradiol hemihydrate. Drug release study confirmed some of the crystallization results. No significant increase was observed in the burst release with increasing in thickness from 45 to 60 MUm which can be attributed to the severe increase in the crystallization extent. Also, formation of a crystalline layer near the releasing surface and more discontinuous pattern of the crystals in some samples was confirmed by investigation of the drug release curves. PMID- 20706878 TI - A statistical approach to optimize the spray drying of starch particles: application to dry powder coating. AB - This article describes the preparation of starch particles, by spray drying, for possible application to a dry powder coating process. Dry powder coating consists of spraying a fine powder and a plasticizer on particles. The efficiency of the coating is linked to the powder morphological and dimensional characteristics. Different experimental parameters of the spray-drying process were analyzed, including type of solvent, starch concentration, rate of polymer feeding, pressure of the atomizing air, drying air flow, and temperature of drying air. An optimization and screening of the experimental parameters by a design of the experiment (DOE) approach have been done. Finally, the produced spray-dried starch particles were conveniently tested in a dry coating process, in comparison to the commercial initial starch. The obtained results, in terms of coating efficiency, demonstrated that the spray-dried particles led to a sharp increase of coating efficiency value. PMID- 20706879 TI - Should ancillary brain blood flow analyses play a larger role in the neurological determination of death? AB - PURPOSE: We present two patients who regained spontaneous respiration following clinical neurological determination of death (NDD) while ancillary radiological imaging demonstrated brain blood flow. CLINICAL FEATURES: A 26-yr-old male with chronic otitis media presented with a Glasgow Coma Scale (GCS) score of 3 and fixed 7-mm pupils. Computed tomography demonstrated right-sided mastoiditis and a temporal lobe abscess associated with uncal herniation. The patient was diagnosed brain dead seven-hr later when motor responses and brainstem reflexes were absent and his apnea test was positive. Approximately 28-hr after NDD, during post declaration organ resuscitation, the patient regained spontaneous respiration and magnetic resonance imaging revealed brain blood flow. Spontaneous respirations persisted for five-days before cardiovascular collapse occurred. In the second case, a 50-yr-old female presented with a GCS score of 3 and fixed 6-mm pupils following a traumatic brain injury and a five-minute cardiac arrest. The patient was deemed clinically brain dead six-hr later when physical examination revealed absent motor responses and brainstem reflexes and her apnea test was positive. As confirmation of brain death, a cerebral radionuclide angiogram was performed, which surprisingly revealed intracranial arterial flow. During organ resuscitation, 11-hr after NDD, the patient regained spontaneous respiration. She expired hours after family decision to withdraw treatment. CONCLUSION: For both patients, several unrecognized confounding factors for NDD were present. These cases illustrate the difficulties encountered by experienced clinicians in determining brain death using clinical criteria alone, and they suggest that more routine use of ancillary brain blood flow analyses should be recommended. PMID- 20706880 TI - An outbreak of gangrenous dermatitis in commercial broiler chickens. AB - The present report describes an outbreak of gangrenous dermatitis (GD) infection in a commercial poultry farm in Delaware involving 34-day-old broiler chickens. In addition to obvious clinical signs, some GD-affected broilers also showed severe fibrino-necrotic enteritis and large numbers of Gram-positive rods in the necrotic tissue. Histopathological findings included haemorrhage, degeneration and necrosis of parenchymatous cells, especially of skin, muscle, and intestine. Immunofluorescence staining revealed Clostridium-like bacilli in the skin and the intestine. Both Clostridium perfringens and Clostridium septicum genomic sequences were identified by polymerase chain reaction in bacterial cultures isolated from the skin, muscle, and intestine, and in the frozen tissues from the GD-affected birds. Serological analysis demonstrated that both affected and clinically healthy birds from the same house had high serum antibody titres against C. perfringens, C. septicum, Eimeria, chick anaemia virus, and infectious bursal disease virus. These results are discussed in the context of the relationship between the different Clostridium spp. and the pathogenesis of GD. PMID- 20706881 TI - Immunopathology and cytokine responses in commercial broiler chickens with gangrenous dermatitis. AB - Gangrenous dermatitis (GD) is an emerging disease of increasing economic importance in poultry resulting from infection by Clostridium septicum and Clostridium perfringens type A. Lack of a reproducible disease model has been a major obstacle in understanding the immunopathology of GD. To gain better understanding of host-pathogen interactions in GD infection, we evaluated various immune parameters in two groups of birds from a recent commercial outbreak of GD, the first showing typical disease signs and pathological lesions (GD-like birds) and the second lacking clinical signs (GD-free birds). Our results revealed that GD-like birds showed: reduced T-cell and B-cell mitogen-stimulated lymphoproliferation; higher levels of serum nitric oxide and alpha-1-acid glycoprotein; greater numbers of K55(+), K1(+), CD8(+), and MHC class II(+) intradermal lymphocytes, and increased K55(+), K1(+), CD8(+), TCR1(+), TCR2(+), Bu1(+), and MHC class II(+) intestinal intraepithelial lymphocytes; and increased levels of mRNAs encoding proinflammatory cytokines and chemokines in skin compared with GD-free chickens. These results provide the first evidence of altered systemic and local (skin and intestine) immune responses in GD pathogenesis in chickens. PMID- 20706882 TI - Infection dynamics of highly pathogenic avian influenza and virulent avian paramyxovirus type 1 viruses in chickens, turkeys and ducks. AB - A range of virus doses were used to infect 3-week-old chickens, turkeys and ducks intranasally/intraocularly, and infection was confirmed by the detection of virus shedding from the buccal or cloacal route by analysis of swabs collected using real-time reverse transcriptase-polymerase chain reaction assays. The median infectious dose (ID(50)) and the median lethal dose (LD(50)) values for two highly pathogenic avian influenza (HPAI) viruses of H5N1 and H7N1 subtypes and one virulent Newcastle disease virus (NDV) were determined for each virus and host combination. For both HPAI viruses, turkeys were >100-fold more susceptible to infection than chickens, while both these hosts were >10-fold more susceptible to H5N1 virus than the H7N1 virus. All infected chickens and turkeys died. Ducks were also much more readily infected with the H5N1 virus (ID(50)< or =10(1) median embryo infective dose [EID(50)]) than the H7N1 virus (ID(50)=10(4.2) EID(50)). However, the most notable difference between the two viruses was their virulence for ducks, with a LD(50) of 10(3) EID(50) for the H5N1 virus, but no deaths in ducks being attributed to infection with H7N1 virus even at the highest dose (10(6) EID(50)). For both HPAI virus infections of ducks, the ID(50) was lower than the LD(50), indicating that infected birds were able to survive and thus excrete virus over a longer period than chickens and turkeys. The NDV strain used did not appear to establish infection in ducks even at the highest dose used (10(6) EID(50)). Some turkeys challenged with 10(6) EID(50), but not other doses, of NDV excreted virus for a number of days (ID(50)=10(4.6) EID(50)), but none died. In marked contrast, chickens were shown to be extremely susceptible to infection and all infected chickens died (ID(50)/LD(50)=10(1.9) EID(50)). PMID- 20706883 TI - Combined hepatocellular-cholangiocarcinoma in a lesser flamingo (Phoenicopterus minor). AB - A case of combined hepatocellular-cholangiocarcinoma (CHCC) in an adult male lesser flamingo (Phoenicopterus minor) that was part of a breeding programme at a private facility is reported. Grossly, the liver was markedly enlarged with multifocal, well-circumscribed, pinpoint to 2 cm diameter pale tan nodular masses. Histologically, the hepatic parenchyma was replaced by neoplastic cells that demonstrated hepatocellular and, less frequently, biliary epithelial cell differentiation. Positive pan-cytokeratin (AE1/AE3/PCK26) immunolabelling of the neoplastic cells forming bile ducts with the scattered immunoreactivity of cells forming glandular structures within the areas of hepatocellular differentiation supported the diagnosis. No metastases were detected. CHCC is a rare neoplasm in mammals and birds. This is the first report where gross, histological, and immunohistochemical characteristics of CHCC in a bird are described, and the first report of CHCC in a lesser flamingo. PMID- 20706884 TI - The role of selected cytochrome P450 enzymes on the bioactivation of aflatoxin B1 by duck liver microsomes. AB - A study was conducted to determine the cytochrome (CYP) P450 enzymes responsible for the bioactivation of aflatoxin B1 (AFB1) into its epoxide form (AFBO) in duck liver microsomes. Six male and six female 6-week-old Pekin ducks were used. The biochemical toxicology strategies applied included the use of selective inhibitors, prototype substrate activity for specific human P450s, correlation between aflatoxin bioactivation and enzymatic activity of prototype substrates, and the expression of specific CYP450 enzymes using antibodies against human CYP450s. Enzymatic activity was detected for the duck orthologues CYP1A1/2, CYP2A6 and CYP3A4 but not for the CYP2D6 orthologue. Immunoreactive proteins for CYP1A1, CYP2A6 and CYP3A4 were also detected. Inhibition studies suggested that the duck turkey CYP2A6 orthologue and, to a lesser extent, the CYP1A1 orthologue are involved in the bioactivation of AFB1. Correlation studies, however, suggest that CYP3A4, CYP2A6 and CYP1A1/2 are all involved in AFBO formation. The finding that four CYP enzymes may be involved in AFB1 bioactivation in ducks could explain the high sensitivity of this species to AFB1. Further studies are needed to fully elucidate the phase I hepatic metabolism of AFB1 in ducks, the only poultry species that develops hepatic cancer from AFB1 exposure. PMID- 20706885 TI - Impact of Escherichia coli vaccine on parent stock mortality, first week mortality of broilers and population diversity of E. coli in vaccinated flocks. AB - In the present investigation 20,000 broiler parents were vaccinated during rearing with Nobilis Escherichia coli vaccine and were placed in two out of four identical houses, with the remaining two houses on the same farm accommodating 20,000 unvaccinated control birds. During the production period a total of 335 dead birds (including 171 vaccinated and 164 control birds) randomly selected from the four houses were subjected to post-mortem examination. Although the overall mortality between the vaccinated and control flocks did not differ, mortality due to E. coli infections made up only 8.2% in vaccinated birds compared with 24.6% in unvaccinated birds. All E. coli isolates recovered from internal organs were assigned to the same phylogenetic group (B2), but a major genetic diversity was outlined by multilocus sequence typing. Only a single isolate was demonstrated to harbour a gene encoding the P-fimbriae variant F11, a key component of the Nobilis vaccine. Significant differences in average first week mortality, calculated average weight at 38 days and food conversion rate among broiler flocks originating from vaccinated and control birds, respectively, were not found. Further investigations are needed to explain the protection observed and the impact on the genetic diversity of E. coli. PMID- 20706886 TI - Distribution of serotypes and virulence-associated genes in pathogenic Escherichia coli isolated from ducks. AB - The objective of the present study was to investigate the serotypes and virulence associated genes of avian pathogenic Escherichia coli (APEC) isolated from duck colibacillosis cases. Two hundred and fifty-four APEC isolates from duck colibacillosis cases were serotyped and amplified for 12 known virulence associated genes and the betA gene (encoding choline dehydrogenase) by polymerase chain reaction assays. One hundred and forty-three E. coli isolates from cloacal swabs of healthy ducks were also amplified for the same genes. A total of 53 O serogroups were found in 254 APEC isolates, among which O93, O78 and O92 were predominant serogroups. Polymerase chain reaction results showed that Shiga-toxin producing E. coli distributed in only 2.4% of ducks compared with 49.2% of the APEC isolates harbouring the irp2 gene, and 44.9% the fyuA gene, respectively. The ibeA gene was only present in 27 APEC isolates and was not found in healthy ducks. The rfaH gene was detected in 20.5% of APEC isolates, whereas 5.6% was found in healthy ducks. A total 79.5% of APEC isolates harboured the betA gene, which was significantly higher than in healthy ducks (16.1%), suggesting that betA may be associated with virulence. PMID- 20706890 TI - In vitro and in vivo antibiofilm activity of a coral associated actinomycete against drug resistant Staphylococcus aureus biofilms. AB - Staphylococcus aureus is now amongst the most important pathogenic bacteria responsible for bloodstream nosocomial infections and for biofilm formation on indwelling medical devices. Its increasing resistance to common antibiotics, partly attributed to its ability to form biofilms, is a challenge for the development of new antimicrobial agents. Accordingly, the goal of this study was to evaluate the effect of a coral associated actinomycete (CAA)-3 on S. aureus biofilms both in vitro and in vivo. Methanolic extracts of CAA-3 showed a reduction in in vitro biofilm formation by S. aureus ATCC 11632, methicillin resistant S. aureus ATCC 33591 and clinical isolates of S. aureus at the biofilm inhibitory concentration (BIC) of 0.1 mg ml(-1). Furthermore, confocal laser scanning microscope (CLSM) studies provide evidence of CAA-3 inhibiting intestinal colonisation of S. aureus in the nematode Caenorhabditis elegans. To conclude, this study for the first time, reports CAA as a promising source of anti-biofilm compounds, for developing novel drugs against highly resistant staphylococcal biofilms. PMID- 20706891 TI - Engineered antifouling microtopographies: the role of Reynolds number in a model that predicts attachment of zoospores of Ulva and cells of Cobetia marina. AB - A correlation between the attachment density of cells from two phylogenetic groups (prokaryotic Bacteria and eukaryotic Plantae), with surface roughness is reported for the first time. The results represent a paradigm shift in the understanding of cell attachment, which is a critical step in the biofouling process. The model predicts that the attachment densities of zoospores of the green alga, Ulva, and cells of the marine bacterium, Cobetia marina, scale inversely with surface roughness. The size and motility of the bacterial cells and algal spores were incorporated into the attachment model by multiplying the engineered roughness index (ERI(II)), which is a representation of surface energy, by the Reynolds number (Re) of the cells. The results showed a negative linear correlation of normalized, transformed attachment density for both organisms with ERI(II) x Re (R(2) = 0.77). These studies demonstrate for the first time that organisms respond in a uniform manner to a model, which incorporates surface energy and the Reynolds number of the organism. PMID- 20706892 TI - Building long-term patient-physician relationships. AB - We provide a framework for physician-controlled preconditions that impact patient trust and commitment and uncover the influence that trust and commitment have on three central patient outcomes: retention, referral behavior, and ease of voice. Based on survey data from a sample of obstetric patients, we find that though the proposed preconditions have a significant effect on both patient trust and commitment, the predominance of trust on desirable outcomes such as retention, referral behavior, and ease of voice has profound implications for physicians and other health care providers in the development of patient relationship strategy. PMID- 20706893 TI - Exploration of fairness in health services: a qualitative analysis. AB - A content analysis of fair and unfair experiences described by students as customers of health care services was made. The way customers had been treated by the staff during the implementation of procedures, along with the information exchange between client and service providers turned out to have a strong impact on justice perception. An outstanding point is the reciprocity on the treatment. The clients' comments about waiting times and the physical and emotional consequences of patients' encounters with health services also played a major role in fairness perception and the patients' assessment of their experience. These matters should be considered in the management of health care services. PMID- 20706894 TI - Optimal nonverbal communications strategies physicians should engage in to promote positive clinical outcomes. AB - This article discusses the importance of physician management of their nonverbal communication behavior during physician-patient interactions. This management is important because certain nonverbal behaviors are associated with clinical outcomes. The article outlines research findings involving various physicians' nonverbal behaviors, such as gaze orientation, head nodding, facial expressiveness, body orientation, proxemics, and paralinguistics. It also highlights the need to train physicians in nonverbal communications skills and provides a taxonomy of best practices or optimal nonverbal communications strategies that a physician should engage while interacting with patients. PMID- 20706895 TI - The message development tool: a case for effective operationalization of messaging in social marketing practice. AB - That messages are essential, if not the most critical component of any communicative process, seems like an obvious claim. More so when the communication is about health--one of the most vital and elemental of human experiences (Babrow & Mattson, 2003). Any communication campaign that aims to change a target audience's health behaviors needs to centralize messages. Even though messaging strategies are an essential component of social marketing and are a widely used campaign model, health campaigns based on this framework have not always been able to effectively operationalize this key component, leading to cases where initiating and sustaining prescribed health behavior has been difficult (MacStravic, 2000). Based on an examination of the VERB campaign and an Australian breastfeeding promotion campaign, we propose a message development tool within the ambit of the social marketing framework that aims to extend the framework and ensure that the messaging component of the model is contextualized at the core of planning, implementation, and evaluation efforts. PMID- 20706896 TI - Marketing nursing as a profession: integrated marketing strategies to address the nursing shortage. AB - The nursing shortage in the United States is at a crisis level characterized by critical shortages of highly trained nurses and of nursing faculty. Key issues in addressing these shortages include awareness and image-building, along with enhanced outreach programs. Although these issues are related to marketing theory, most studies in this area are based on a vocational choice model. This study was grounded in marketing theory and the results offer a new perspective for addressing the nursing shortage. In-depth interviews conducted with 31 first year nursing students indicated that there were two distinct segments among nursing students: traditionals and instrumentals. Traditionals were attracted to nursing as a helping profession while instrumentals were interested in career related rewards such as variety, mobility, and compensation. These findings were discussed in terms of building awareness and marketing programs for nursing students that are integrated across schools of nursing, private foundations and public agencies. PMID- 20706897 TI - Impact of diazotrophy on N stable isotope signatures of nitrate and particulate organic nitrogen: case studies in the north-eastern tropical Atlantic Ocean. AB - During two independent cruises in the north-eastern tropical Atlantic Ocean, we applied two different approaches to investigate the impact of diazotrophy on nitrogen stable isotope signatures in nitrate and particulate organic nitrogen (PON) of the food-web constituents. The first approach, used during the Poseidon cruise 348 in the Mauritanian upwelling, investigated the long-term influence of diazotrophy on the natural abundance of delta(15)N-NO(-)(3) and PON. The second approach, adopted during the Cape Verde field cruise, applied stable isotope tracer addition experiments. These served to determine the instantaneous transfer of diazotrophic N to the higher trophic level. Both approaches showed that N(2) fixation was compatible with the pattern and the magnitude of the isotopic depletion of dissolved NO(-)(3) during the Mauritanian upwelling cruise, as well as PON in zooplankton and phytoplankton during the Cape Verde cruises. An N budget using (15)N incorporation rates and diazotrophic N(2) fixation rates showed that 6 % of the daily N(2) fixation was potentially taken up by the mesozooplankton community. Direct grazing accounted for 56 % of gross mesozooplanktonic N incorporation, while 46 % occurred due to channelling through the microbial loop. PMID- 20706898 TI - Identification and quantification of the active component quercetin 3-O rutinoside from Barringtonia racemosa, targets mitochondrial apoptotic pathway in acute lymphoblastic leukemia. AB - Barringtonia racemosa has been used as a traditional medicine for the treatment of various diseases. The antitumor property of the seed extract of this plant in mice model promotes us to search for the active component present in the fruit extract. Quercetin 3-O-rutinoside (QOR) has been isolated from the fruits of this plant for the first time and quantified by HPLC method. The compound was identified by IR, mass, and NMR (1D, 2D) spectral data analysis. QOR showed dose- and time-dependent anti-proliferative activity in several leukemic cell lines with negligible effect on normal human peripheral blood mononuclear cell (PBMC). A representative T-lineage acute lymphoblastic leukemia cell line (MOLT-3) showed phosphatidyl serine externalization and DNA fragmentation, indicating QOR-induced programmed cell death. We established that QOR-induced apoptosis occurred preferentially on accumulation of cells in the sub-G(0) phase and genomic DNA fragmentation through the activation of mitochondria-dependent caspase cascade for the first time in T-lineage ALL cell line. PMID- 20706899 TI - Two new secoiridoid glycosides from Verbena officinalis. AB - Two new secoiridoid glycosides, verbenoside A (1) and verbenoside B (2), have been isolated from the ethanol extract of the aerial parts of Verbena officinalis L. Their structures were elucidated on the basis of spectroscopic evidences, especially 1D, 2D NMR, and MS experiments. PMID- 20706900 TI - Further polyoxypregnane glycosides from Marsdenia tenacissima. AB - Three new polyoxypregnane glycosides, tenacigenosides F-H (1-3), were isolated from the stems of Marsdenia tenacissima. The structures of these new compounds were elucidated from 1D and 2D NMR spectra, as well as from HR-MS and acid hydrolysis. PMID- 20706901 TI - Structural determination of crotamides A and B, the new amides from Croton sparsiflorus. AB - Two new amides crotamides A and B, have been isolated from the n-hexane soluble fraction of Croton sparsiflorus in addition to salisomide and N-(4 hydroxyphenethyl)-octacosanamide reported for the first time from this species. Their structures were assigned from spectral data including 1D and 2D NMR spectroscopic data. PMID- 20706902 TI - Two new triterpenoids from Lycopodium obscurum L. AB - Two new onoceranoid triterpenoids, (3 alpha,8 beta,14 alpha,21 beta)-26,27 dinoronocerane-3,8,14,21-tetrol (1) and 26-nor-8 beta-hydroxy-alpha-onocerin (2), were isolated from Lycopodium obscurum L. Their structures were elucidated on the basis of spectroscopic analyses. PMID- 20706903 TI - Antifungal activity of the osthol derivative JS-B against Phytophthora capsici. AB - JS-B (C(12)H(10)O(3)) is a derivative compound of osthol. The antifungal properties of JS-B were tested against 10 economically important plant pathogens. JS-B was effective in inhibiting the mycelial growth of Phytophthora capsici, and its inhibition on different stages of the life cycle of P. capsici was observed. The 50% effective concentration (EC(50)) of JS-B on mycelial dry weight and zoospore germination of P. capsici was 43.74 and 86.03 microg/ml, respectively. The rupture of released zoospores induced by JS-B was reduced by the addition of 100 mM glucose. The ultrastructural study showed that JS-B caused destruction of most of the mitochondrions, the concentration of cell nuclear, and the existing vesicles. When compared with dimethomorph, the activity of JS-B on P. capsici was determined under pot conditions. The result showed that JS-B has a curative effect on pepper blight. PMID- 20706904 TI - Three new flavane glucosides from the leaves of Morus wittiorum. AB - Three new flavane glucosides (1-3) were isolated from the leaves of Morus wittiorum. The structures with absolute configuration were determined on the basis of hydrolysis and spectroscopic methods including UV, IR, HR-ESI-MS, 1D, and 2D NMR. PMID- 20706905 TI - Two new dimeric secoiridoid glycosides from the fruits of Ligustrum lucidum. AB - Two new secoiridoid glycosides, ligusides A and B (1 and 2), as well as seven known compounds (3-9), were isolated from the fruits of Ligustrum lucidum. Their structures were elucidated on the basis of spectroscopic and chemical analysis. PMID- 20706906 TI - Antinociceptive activity of steroid alkaloids isolated from Solanum trilobatum Linn. AB - Solasodine (1) was isolated for the first time from the roots of Solanum trilobatum Linn., a member of the Solanaceae, and assessed for its presumed antinociceptive activity using several experimental murine models, viz. the writhing, formalin, and hot plate tests. When used at doses of 2, 4, and 8 mg/kg, this steroidal alkaloid caused a significant and dose-dependent decrease in the nociception induced by an intraperitoneal injection of acetic acid (p < 0.001). It also led to a significant reduction of the painful sensation caused by formalin in both phases of the formalin test (p < 0.001). Furthermore, the alkaloid produced a significant increase in the reaction time in the hot plate test (p < 0.001). These results suggest that solasodine elicited antinociceptive activity through both central and peripheral mechanisms. PMID- 20706907 TI - Three polyoxygenated cyclohexenes from Uvaria calamistrata. AB - Three new polyoxygenated cyclohexenes, named uvacanols F, G, H (1-3), were isolated from the roots of Uvaria calamistrata (Annonaceae). Their structures were determined to be 2-acetoxyl-5-chlorine-benzoyloxymethylcyclohex-1 (6)-ene-4 ol-3-benzoate (1), benzoyloxy-methylcyclohex-1 (6)-ene-2,3,4-triols-5-benzoate (2), 3-acetoxyl-benzoyloxymethylcyclohex-1 (6)-ene-4,5-diols-2-benzoate (3) by spectroscopic methods and chemical derivatization. PMID- 20706908 TI - Chemical constituents of Citrus sinensis var. Shukri from Pakistan. AB - The variety 'Shukri' is a new hybrid of Citrus sinensis and is frequently grown for its sweet edible fruits in the southern part of Pakistan. The leaves of this hybrid variety have been investigated in search of secondary metabolites for the first time. As a result of chromatographic analysis of the methanolic extract, a new ceramide along with a flavonone glycoside and two steroids has been isolated, which were spectroscopically characterized as (E)-N-(1,3,4,5 tetrahydroxyhexadecan-2-yl)dec-4-enamide (1), atripliside B (2), beta-sitosterol (3), and beta-sitosterol-3-O-beta-D-glucopyranoside (4), respectively. Compound 1 was found to be a new addition in the list of natural products, whereas, to the best of our knowledge, compounds 2-4 have been isolated for the first time from this source. PMID- 20706910 TI - Structure of barlericin, the neolignan diglycoside from Barleria acanthoides. AB - Barlericin, the new neolignan diglycoside, has been isolated from the n-butanol soluble sub-fraction of Barleria acanthoides along with dehydrodiconiferyl alcohol 12-O-beta-D-glucopyranoside (2), reported for the first time from the genus Barleria. Their structures have been assigned on the basis of spectral studies. PMID- 20706909 TI - Immunosuppressive constituents from Urtica dentata Hand. AB - A novel biscoumarin, 6,6',7,7'-tetramethoxyl-8,8'-biscoumarin (1), was isolated from the ethyl acetate extract of Urtica dentata Hand, together with five known compounds named as 7,7'-dihydroxy-6,6'-dimethoxy-8,8'-biscoumarin (2), 7,7' dimethoxy-6,6'-biscoumarin (3), scoparone (4), vanillic acid (5), and daucosterol (6). Structures of the isolated compounds were elucidated on the basis of spectroscopic analysis including 2D NMR experiments. Compounds 1 and 2 were confirmed to be a rare carbon-carbon linked symmetrical biscoumarin. Compounds 1 4, especially 1 (IC(50) = 8.18 x 10(- 5) mol/l), showed potent immunosuppressive activities as determined by the Cell Counting Kit-8 assay for lymphocyte proliferation. Also, in the FACS analysis, 1 (IC(50) = 5.19 x 10(- 4) mol/l) promoted the differentiation of CD4(+)CD25(+)Foxp3(+) T regulatory cells distinctly compared to the normal control. Thus, 1 possessed specific immunosuppressive property by eliciting T regulatory cells, which may provide a potential treatment strategy for autoimmune diseases. PMID- 20706911 TI - A new compound from Hypericum reptans. AB - A new compound, 2,7,4a-trimethoxy-1,4,4a,8b-tetrahydrodibenzo-p-dioxin-4-one (1), was isolated from the aerial parts of the Hypericum reptans. The structure of the new compound was elucidated on the basis of extensive analysis of 1D and 2D NMR spectroscopic data and further confirmed by single-crystal X-ray diffraction. PMID- 20706912 TI - A new isoprenyl phenyl ether riboside from the culture of basidiomycete Laccaria amethystea. AB - A new isoprenyl phenyl ether riboside, 3-(3-methylbut-2-enyloxy)-4-O-alpha-D ribofuranose benzoic acid methyl ester (1), was isolated from the culture of basidiomycete Laccaria amethystea. The structure of 1 was elucidated on the basis of extensive spectroscopic analysis. PMID- 20706913 TI - A new ganoderic acid from Ganoderma lucidum mycelia. AB - A new ganoderic acid (GA), 7-O-ethyl ganoderic acid O (GA-O) (1), together with two known compounds, GA-T (2) and GA-Me (3), was isolated and purified from fermented mycelia of Ganoderma lucidum. The structure of the new triterpenoid was elucidated on the basis of the interpretation of extensive spectroscopic data (HR MS, IR, UV, 1D and 2D NMR) as 3 alpha,15 alpha,22-triacetoxy-7 alpha-ethoxy-5 alpha-lanost-8,24E-dien-26-oic acid. The new compound was found to contain a rare ethoxyl group at C-7. In addition, its cytotoxicity against 95D and HeLa human cancer cell lines was also evaluated. PMID- 20706914 TI - Perceived social competence, negative social interactions, and negative cognitive style predict depressive symptoms during adolescence. AB - The current study examined whether negative interactions with parents and peers would mediate the longitudinal association between perceived social competence and depressive symptoms and whether a negative cognitive style would moderate the longitudinal association between negative interactions with parents and increases in depressive symptoms. Youth (N = 350; 6th-10th graders) completed self-report measures of perceived social competence, negative interactions with parents and peers, negative cognitive style, and depressive symptoms at three time points. Results indicated that the relationship between perceived social competence and depressive symptoms was partially mediated by negative interactions with parents but not peers. Further, baseline negative cognitive style interacted with greater negative parent interactions to predict later depressive symptoms. PMID- 20706916 TI - Facial attractiveness and self-esteem in adolescence. AB - Facial attractiveness has been associated with many (social) advantages in life, like greater popularity, acceptance, and social competence. Because social evaluations and acceptance are important factors contributing to self-esteem (SE), we hypothesized that high levels of attractiveness would be related to increased levels of SE. To test this assumption, 230 adolescents from two age groups (13 and 15 years) were surveyed annually for 5 years. A latent growth curve model was used to model the influence of facial attractiveness on the development of SE over time. Results showed that younger adolescents with higher levels of attractiveness had lower levels of SE at baseline. Attractiveness was not found to be a significant predictor in explaining the development of SE over time. These findings indicate that attractive children are more likely to have lower levels of SE when they enter early adolescence compared to their less attractive counterparts. PMID- 20706915 TI - Clinical and cognitive correlates of depressive symptoms among youth with obsessive compulsive disorder. AB - Depression is the most common comorbidity among adults with obsessive compulsive disorder (OCD), yet little is known about depressive symptoms in childhood OCD. This study examined clinical and cognitive variables associated with depressive symptomatology in 71 youths (62% male, M age = 12.7 years) with primary OCD. Youths presented with a range of depressive symptoms, with 21% scoring at or above the clinical cutoff on the self-report measure of depression. Higher levels of depressive symptoms were associated with higher levels of cognitive distortions assessed on measures of insight, perceived control, competence, and contingencies. Depressive symptoms were also linked to older age and more severe OCD. Low perceived control and self-competence and high OCD severity independently predicted depression scores. PMID- 20706917 TI - Cognitive-behavioral treatment of panic disorder in adolescence. AB - This investigation represents the first randomized controlled trial to evaluate the feasibility and efficacy of Panic Control Treatment for Adolescents (PCT-A). Thirteen adolescents, ages 14 to 17, were randomized to 11 weekly sessions of PCT A treatment, whereas 13 were randomized to a self-monitoring control group. Results indicate that adolescents receiving immediate PCT-A showed a significant reduction in clinician-rated severity of panic disorder and in self-reported anxiety, anxiety sensitivity, and depression, in comparison to control group participants. These treatment gains were maintained at 3- and 6-month follow-up. Clinical severity of panic continued to improve from posttreatment to 3-month follow-up and then remained stable at 6-month follow-up. In light of study limitations, these findings suggest that cognitive-behavioral treatment for panic disorder in adolescence is a feasible and potentially efficacious intervention for this debilitating condition in youth. PMID- 20706918 TI - Incremental validity of test session and classroom observations in a multimethod assessment of attention deficit/hyperactivity disorder. AB - This study tested the incremental validity of behavioral observations, over and above parent and teacher reports, for assessing symptoms of Attention Deficit/Hyperactivity Disorder (ADHD) in children ages 6 to 12, using the Test Observation Form (TOF) and Direct Observation Form (DOF) from the Achenbach System of Empirically Based Assessment. The TOF Attention Problems and DOF Intrusive scales contributed significant unique variance, over and above parent and teacher ratings, to predicting parent and teacher ratings of hyperactivity and impulsivity and predicting categorical diagnoses of ADHD-Combined type versus Non-ADHD and ADHD-Combined type versus ADHD-Predominantly Inattentive type. The TOF Oppositional and Attention Deficit/Hyperactivity Problems scales contributed unique variance to predicting parent ratings of hyperactivity and impulsivity and the DOF Oppositional and Attention Deficit/Hyperactivity Problems scales contributed unique variance to predicting teacher ratings of hyperactivity and impulsivity. PMID- 20706920 TI - Parental maltreatment, bullying, and adolescent depression: evidence for the mediating role of perceived social support. AB - The support deterioration model of depression states that stress deteriorates the perceived availability and/or effectiveness of social support, which then leads to depression. The present study examined this model in adolescent depression following parent-perpetrated maltreatment and peer-perpetrated bullying, as assessed by a rigorous contextual interview and rating system. In 101 depressed and nondepressed community adolescents between the ages of 13 and 18 (M = 15.51, SD = 1.27), peer bullying and father-perpetrated maltreatment were associated with lower perceptions of tangible support and of belonging in a social network. These forms of support mediated the association of bullying and father perpetrated maltreatment with greater depression severity. In contrast, mother perpetrated maltreatment was associated with higher perceptions of tangible support. PMID- 20706919 TI - Trajectories of childhood sexual abuse and early adolescent HIV/AIDS risk behaviors: the role of other maltreatment, witnessed violence, and child gender. AB - Childhood sexual abuse (CSA) has been associated with HIV/AIDS risk behavior; however, much of this work is retrospective and focuses on women. The current study used semi-parametric mixture modeling with youth (n = 844; 48.8% boys) from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) to examine the link between trajectories of CSA (2 to 12 years old) and HIV/AIDS risk behavior at age 14 (i.e., sexual intercourse & alcohol use). Trajectory analyses revealed a link between a history of CSA and the development of risky behavior. In addition, trajectories for physical and emotional abuse, but not neglect or witnessed violence, contributed to risky behavior over and above the role of CSA. Child gender did not moderate the findings. Findings highlight the significance of CSA histories, as well as the broader context of maltreatment, for better understanding the development of risk behaviors in both girls and boys. PMID- 20706921 TI - Longitudinal associations between clique membership status and internalizing and externalizing problems during late childhood. AB - This study examined the longitudinal link between clique membership status and the development of psychopathology in 451 children followed annually from age 9 to 12 years. Classroom clique membership status was identified through social network analysis, and internalizing and externalizing problems were assessed using peer nominations. Controlling for concurrent experiences of social preference and dyadic friendships, a high clique membership probability was found to be related to low levels of internalizing problems and to an increase in externalizing problems across 4 years. This link between clique membership and an increase in externalizing problems was found for boys only. PMID- 20706922 TI - The effects of incentives on families' long-term outcome in a parenting program. AB - To examine the impact of paying for participation in a preventive parenting program on treatment outcomes, 197 families with preschool-aged children were randomized to paid or unpaid conditions. Although both groups improved on nearly all measures, paid families showed less improvement on 3 of 10 variables, including father-reported child prosocial behavior and parenting skills and maternal distress. The interaction between payment and treatment format (individual vs. group) was examined. Compared to unpaid group participants, paid group intervention participants had significantly worse mother and father parenting skills posttreatment, whereas paid individual intervention mothers had significantly better skills. These findings suggest payment may lead to smaller treatment effects, although the bulk of the data point to no impact on outcomes. Given that payment attracts families who would not otherwise receive treatment, this appears to be a viable strategy to recruit families without appreciably impacting outcomes. PMID- 20706923 TI - Implementing trauma-focused CBT with fidelity and flexibility: a family case study. AB - Effective approaches for the treatment of childhood posttraumatic stress disorder and traumatic grief are needed given the prevalence of trauma and its impact on children's lives. To effectively treat posttraumatic stress disorder in children, evidence-based practices should be implemented with flexibility and responsiveness to culture, developmental level, and the specific needs of the family. This case study illustrates flexibility with fidelity in the use of a manualized treatment, describing the implementation of Trauma Focused-Cognitive Behavior Therapy with three traumatized family members-a caregiver and two children. Particular attention is paid to the use of creative strategies to tailor interventions to the individual clients while maintaining fidelity to the principles and components of this evidence-based treatment. PMID- 20706924 TI - Conceptualization of children's interpersonal relatedness with the Rorschach: a qualitative multiple case study. AB - In this in-depth, qualitative, multiple case study, we examined Rorschach data as they relate to the interpersonal behavior, experience, and perceptions of an individual. In this study, we addressed the following question: How are the correspondences between Rorschach variables and children's interpersonal behavior revealed? We conducted an examination of the Rorschach variables and criterion data regarding the children's interpersonal functioning through a qualitative analysis of 6 nonpatient girls between the ages of 8 and 11 years old. The results reveal individualized correspondences between Rorschach variables and interpersonal functioning in which some variables proved more fruitful in describing expressed interpersonal behavior than others. Specifically, the variables utilizing human images, such as the HRV and the thematic descriptions, corresponded most highly to real life interpersonal behavior. PMID- 20706925 TI - Reference group effects in the measurement of personality and attitudes. AB - Reference-group effects (discovered in cross-cultural settings) occur when responses to self-report items are based not on respondents' absolute level of a construct but rather on their level relative to a salient comparison group. In this article, we examine the impact of reference-group effects on the assessment of self-reported personality and attitudes. Two studies illustrate that a reference-group effect can be induced by small changes to instruction sets, changes that mirror the instruction sets of commonly used measures of personality. Scales that specified different reference groups showed substantial reductions in criterion-related validities for academic performance, self reported counterproductive behaviors, and self-reported health outcomes relative to reference-group-free versions of those scales. PMID- 20706926 TI - The comprehensive alcohol expectancy questionnaire: confirmatory factor analysis, scale refinement, and further validation. AB - The Comprehensive Alcohol Expectancy Questionnaire (CAEQ; Demmel & Hagen, 2003a, 2003b) is a self-report measure designed to assess an individual's alcohol expectancies. In this study, we examined the CAEQ in a student sample (N= 932) and in a clinical sample of alcohol-dependent inpatients (N= 744). The Five factor structure was confirmed by means of confirmatory factor analysis. Convergent validity of the revised CAEQ was supported by showing significant relationships to quantity and frequency of drinking. The results of this study suggest that the revised CAEQ appears to be a psychometrically sound tool for the assessment of alcohol expectancies among both students and alcohol-dependent inpatients. PMID- 20706927 TI - Demand effects on positive response distortion by police officer applicants on the Revised NEO Personality Inventory. AB - Understanding and detecting response distortion is important in the high-demand circumstances of personnel selection. In this article, we describe positive response distortion on the Revised NEO Personality Inventory (NEO PI-R; Costa & McCrae, 1992) among police officer applicants under high and low demand conditions. Positive response distortion primarily reflected denial/minimization of Neuroticism and accentuation of traits associated with moralistic bias (Agreeableness and Conscientiousness). Validity of the NEO PI-R research validity scale, Positive Presentation Management, was weakly supported with respect to the Neuroticism domain only. Results will be useful in interpreting personality inventory results in the police personnel selection process. PMID- 20706928 TI - Development of the Zuckerman-Kuhlman-Aluja Personality Questionnaire (ZKA-PQ): a factor/facet version of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). AB - The development of a new 200-item questionnaire based on the theoretical constructs of the alternative Five-factor model of personality is described. We developed the Zuckerman-Kuhlman-Aluja Personality Questionnaire (ZKA-PQ) from an initial pool of 537 items. Its final version includes 5 factors with 4 facets per factor and 10 items per facet. Internal consistencies were adequate particularly for the factors. The 1 factor confirmatory factor analyses showed satisfactory goodness-of-fit indexes, but not for the 5 factor simple structure. When incorporating the secondary loadings and the correlated error terms, the model fit improved. A multigroup analysis showed gender differences for the factors Sensation Seeking, Neuroticism, Aggressiveness, and Activity for the Spanish speaking sample but only for Aggressiveness in the English-speaking sample. We assessed the convergent and discriminant validity of the ZKA-PQ by inspecting correlations with shortened versions of the Revised NEO Personality Inventory (Costa & McCrae, 1992) and Temperament and Character Inventory-Revised (Cloninger, 1999) in 2 independent and additional samples. This new instrument may be useful for basic and applied research, including normal personality, psychobiology of personality, personality and clinical disorders, and industrial organizational psychology. PMID- 20706929 TI - Convergent validity of the Defense Mechanisms Manual and the Defensive Functioning Scale. AB - We examined the convergent validity of Cramer's Defense Mechanisms Manual (DMM; Cramer, 1991b) by comparing it to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) Defensive Functioning Scale (DFS). A total of 60 low income urban women from a primary care medical facility responded to four Thematic Apperception Test (TAT; Murray, 1943) cards and an interview of early memories and descriptions of significant others. We scored the TAT narratives with the DMM, and we coded the interview narratives with the DFS. DMM Denial and Projection scales were negatively correlated with the DFS Overall Defensive Functioning scale (r = -.28, p< .01 and r = -.22, p< .10, respectively) and were positively correlated with a DFS pathological composite score (r = .36, p< .01 and r = .32, p< .05, respectively). These findings support the convergent validity of the DMM Denial and Projection scales. PMID- 20706930 TI - Assessing values at an early age: the Picture-Based Value Survey for Children (PBVS-C). AB - In this article, we introduce the Picture-Based Value Survey for Children (PBVS C): a new assessment instrument that was developed within the conceptual framework of Schwartz's (1994) theory of universal human values. In the article, we describe the development of the PBVS-C with a specific focus on children's cognitive-developmental background (Harter, 1999; La Greca, 1990) and first applications. Multidimensional Scaling analyses in 2 samples of 8- to 12-year-old children (N= 267, N= 421, respectively) revealed highly differentiated structural patterns that closely correspond to Schwartz's theory. We discuss these findings and the potentials and limitations of the new instrument with respect to future directions of values research. PMID- 20706931 TI - A psychometric analysis of the Trait Emotional Intelligence Questionnaire-Short Form (TEIQue-SF) using item response theory. AB - Trait emotional intelligence refers to a constellation of emotional self perceptions located at the lower levels of personality hierarchies. In 2 studies, we sought to examine the psychometric properties of the Trait Emotional Intelligence Questionnaire-Short Form (TEIQue-SF; Petrides, 2009) using item response theory (IRT). Study 1 (N= 1,119, 455 men) showed that most items had good discrimination and threshold parameters and high item information values. At the global level, the TEIQue-SF showed very good precision across most of the latent trait range. Study 2 (N= 866, 432 men) used similar IRT techniques in a new sample based on the latest version of the TEIQue-SF (version 1.50). Results replicated Study 1, with the instrument showing good psychometric properties at the item and global level. Overall, the 2 studies suggest the TEIQue-SF can be recommended when a rapid assessment of trait emotional intelligence is required. PMID- 20706932 TI - Validation of the Spanish SIRS with monolingual Hispanic outpatients. AB - Psychologists are faced with formidable challenges in making their assessment methods relevant to growing numbers of Hispanic clients for whom English is not the primary or preferred language. Among other clinical issues, the determination of malingering has profound consequences for clients. In this investigation, we evaluated a Spanish translation of the Structured Interview of Reported Symptoms (SIRS; Rogers, Bagby, & Dickens, 1992) with 80 Spanish-speaking Hispanic American outpatients. Using a between-subjects simulation design, the Spanish SIRS was found to produce reliable results with small standard errors of measurement. Regarding validity, very large effect sizes (mean Cohen's d= 2.00) were observed between feigners and honest responders for the SIRS primary scales. We consider the potential role of the Spanish SIRS with reference to Spanish translations for other assessment instruments. PMID- 20706935 TI - Environmental determinants of participation in tourism and recreation of people with varying degrees of disability. AB - Environmental determinants for participation of disabled subjects in tourism and recreation comprise an important social problem. The amount and use of free time for individuals with disabilities in daily life, holidays, and vacation leave and the location for tourism and recreation were examined. Seven hundred and fifty individuals, aged 16-75 yr, with varying degrees of disability, from three eastern provinces of Poland: Podlaskie, Lubelskie and Podkarpackie were investigated. In these studies, a diagnostic survey method with the use of questionnaire, interviews, and analysis of data was carried out. It was found that individuals with disabilities have a significant amount of free time, which is usually spent with family and friends. Among the specific benefits of participation in physical activities are well-being, health improvement, and making new acquaintances. The main factors determining participation in tourism and recreation were price, a friendly group, and doctor recommendations. PMID- 20706936 TI - Natural compounds in the human diet and their ability to bind mutagens prevents DNA-mutagen intercalation. AB - Human diet may contain many mutagenic or carcinogenic aromatic compounds as well as some beneficial physiologically active dietary components, especially plant food phytochemicals, which act as mutagenesis or carcinogenesis inhibitors. This study compared the binding properties of natural compounds in the human diet (caffeine, theophylline, theobromine, and resveratrol) with a water-soluble derivative of chlorophyll to bind to acridine orange, a known mutagen. An analysis was conducted to determine which substances were effective binding agents and may thus be useful in prevention of chemical-induced mutagenesis and carcinogenesis. Data indicated that in order to bind 50% of the mutagen in a complex, less than twice the concentration of chlorophyllin was needed, the resveratrol concentration was 20-fold higher, while a 1000-fold or even 10,000 fold excess of xanthines were required to bind acridine orange. PMID- 20706937 TI - Calcium availability from yogurt by itself or yogurt-cereal-containing products. AB - Dairy products are the basic source of calcium (Ca) for many nations. The aim of this study was to determine the influence of addition of cereal products to yogurt on the ability of subsequent release of Ca present in yogurt. This was conducted in vitro by the process of enzymatic digestion simulating digestion in the human gastrointestinal tract (GIT). Calcium content was determined in commercial yogurts containing cereal and in yogurt meals with subsequent addition of cereal products or bread. Only 3 samples contained more Ca than 100 mg/100 g. Only about 45% (from 28.5 to 77.9%) of Ca was released from the samples with cereals. Innovations in yogurt production technologies actually result in less Ca being released to humans, which may be a problem for individuals with low daily Ca intake. PMID- 20706938 TI - Cornelian cherry (cornus MAS L.) juices as a source of minerals in human diet. AB - The aim of this study was to determine the mineral content of Cornelian cherry (Cornus mas L.), as this fruit and its preservatives may be considered as important nutritional supplements. Potassium (K), calcium (Ca), sodium (Na), iron (Fe), zinc (Zn), manganese (Mn), and copper (Cu) were present in Cornelian cherry juice as measured by atomic absorption. Compared to other juices obtained from plum, pear, and apple, Cornelian cherry juice contained high levels of Ca, reaching 10-fold higher (323 mg/L) levels than other juices (14-77 mg/L). With respect to the remaining elements, K, Na, Fe, Zn, and Mn, the levels noted for Cornus mas juice were also higher than in other juices studied. The reverse was true for Cu, for which levels were lower. Data indicate that Cornelian cherry juices are rich in various essential elements and might be considered as an important dietary mineral supplementation for individuals deficient in nutritional elements. PMID- 20706939 TI - The influence of intracerebral streptozotocin and/or cadmium on memory processes in mice exposed to transient cerebral oligemia. AB - The aim of the study was to examine the effects of simultaneous acute exposure to cadmium (Cd) and in the presence of streptozotozin (STZ) on the central nervous system (CNS) memory processes in mice subjected to transient brain ischemia. In order to obtain transient brain ischemia, operative occlusion of common carotid arteries for 30 min was performed. Cadmium chloride was administered intraperitoneally (ip) after the surgery at a single dose of 0.1 LD(50) (LD(50) = 14 mg/kg). Disturbances in glucose metabolism in the brain tissue were induced by bilateral intracerebral administration of STZ, a drug that inhibits the function of a neuronal insulin receptor. Long-term memory was evaluated by means of a step through passive avoidance task. Spatial working memory expressed as spontaneous alternations was tested in the Y-maze test. Coexposure to brain oligemia and STZ on the CNS produced significant impairment of long-term memory processes in mice. An additional exposure to Cd exacerbated the deficits of these processes. These results indicate that brain oligemia, Cd, and altered glucose metabolism may aggravate adverse effects on memory. PMID- 20706940 TI - Influence of fenpropathrin on memory and movement in mice after transient incomplete cerebral ischemia. AB - Fenpropathrin, a synthetic pyrethroid widely used as an insecticide, is known to affect locomotion and memory in mammals. It is possible that exposure to pyrethroids may occur in an elderly population where transient ischemic attacks are a higher risk for occurrence with consequent changes in memory and control of movement. Thus, the aim of this study was to determine whether bilateral clamping of carotid arteries (BCCA), a model for ischemia, together with fenpropathrin affected memory in tests such as the passive avoidance task and fresh spatial memory in a Y-maze, as well as movement activity and movement coordination on a rotarod in mice. BCCA together with fenpropathrin significantly reduced latency in a passive avoidance task compared to controls. There were no significant differences among the groups with respect to the Y-maze, movement activity, or movement coordination. In conclusion, fenpropathrin needs to be used with caution in the presence of an elderly population at risk for ischemia, as there appears to be evidence of some memory loss in mice. PMID- 20706941 TI - Dietary dried egg white protein influences accumulation and distribution of cadmium in rats. AB - The effect of a dried egg white dietary supplement (2%) on cadmium distribution was examined within 32 d post dosing in the carcass, liver, kidneys, testes, and thigh muscles of male Wistar rats administered cadmium chloride daily, orally for 28 d at a dose corresponding to 10 mg/Cd/kg of feed. Rats fed the egg white protein-supplemented diet displayed markedly higher carcass Cd retention than animals given a standard diet. Further, the protein-supplemented diet increased significantly hepatic Cd retention at 12 h and 4 d, and renal metal retention at 12 h until d 16. In contrast, testicular and thigh-muscle Cd retention was significantly lower in the rats fed the egg white protein supplemented diet compared to rats on a standard diet. Higher carcass, hepatic, and renal Cd concentrations were accompanied by greater body weight gains. Taken together, the results of this study showed that increased egg white dietary protein levels enhanced Cd retention in carcass, liver, and kidneys but lowered the metal concentrations in thigh muscles and testes. Data indicate that body weight gains in rats supplemented with egg white proteins exerted tissue-specific effects with respect to Cd accumulation. The potential toxic risk of Cd burden in testes was diminished due to lower metal levels in rats on a protein-supplemented diet. However, this may not be the case in liver and kidneys, as Cd concentrations rose in presence of protein supplementation. PMID- 20706942 TI - Mercury content in the trophic chain of the Tanew River, Poland, ecosystem. AB - Mercury (Hg) is a highly toxic metal posing a hazard to water ecosystems. This investigation was aimed at determining Hg content in the Tanew River, Poland, and subsequent transfer to fish inhabiting this lake. The area studied included approximately a 50-km distance of the river, with 5 sampling locations selected. Samples of water and bottom sediments were collected from 10 sites along the river-bank zone for each location. At the same location, fish were caught and samples of coastal water plants were collected. Fish that were caught included the following species: chub (Leuciscus cephalus), pike (Esox lucius), ide (Leuciscus idus), and roach (Rutilus rutilus). Dominanting species of water plants included reed-mace (Typha angustifolia), rigid hornwort (Ceratophyllum demersum), and water knotweed (Polygonum amphibium). Mercury content in samples of water, bottom sediments, water plants, and fish tissues (muscles and gills) were determined by using a Mercury/MA-2000 system (NIC, Japan). The average Hg content in the waters of Tanew ranged between 1 and 5 microg/L, and in the bottom sediments ranged between 17 and 214 microg/kg dry weight, which are characteristic values for typical unpolluted areas. The highest Hg contamination of waters and bottom sediments was found where the Tanew estuary enters the San River. Mercury levels in fish from the Tanew delta appeared to be higher compared to other sampling sites. Data indicated that even if water environment is contaminated with Hg to a limited extent, fish accumulate this metal at higher levels, probably due to a bioaccumulation or bioconcentration factor. PMID- 20706943 TI - Bioaccumulation and temporal trends of trace elements in flounder from the southern Baltic Sea for the 1996-2003 period. AB - This study determined the concentrations of copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb), mercury (Hg), and arsenic (As) in flounder from the southern Baltic for the 1996-2003 period. Analysis of more than 200 samples was used to determine the following: (1) concentrations of Hg and As in muscle tissue of flounder from different regions of the southern Baltic; (2) concentrations of Hg in the muscle tissue of flounder of different sizes; and (3) temporal trends in the concentrations of trace metals during the 1996-2003 period. A positive correlation between fish length and Hg concentration was noted. Further, the concentrations of Hg and As in flounder were correlated with sampling site. The most heavily polluted region of the Polish Baltic zone was the eastern region of the Baltic Sea. The temporal trend analyses showed significant downward trends in concentrations of Cd, Hg, and Pb in the flounder from the 1996-2003 period. Data suggest a decrease in the concentration of these elements in the environment of the Polish zone of the Baltic. It is noteworthy that no upward trends were noted in the concentrations of trace metals in the fish studied. If the flounder selected for the study are recognized as bioindicators of environmental pollution, then it is possible to conclude that the changes in trace metals concentrations in the Polish zone of the Baltic Sea are being reduced. PMID- 20706944 TI - Microbiological hazards resulting from application of dairy sewage sludge: effects on occurrence of pathogenic microorganisms in soil. AB - The aims of this study were to (1) examine the extent of bacterial contamination of soils subjected to exposure to dairy sewage sludge applied to soils as measured by determination of number of bacteria from the Escherichia coli family and (2) determine the effects of dairy sewage sludge and straw on populations of other microbial species present in gray-brown podzolic soil. The gray-brown podzolic soil was formed from heavy loamy sand, which is characterized by the following granulometric composition: a sand fraction, 65%; a silt fraction, 19%; and a silt and clay fraction; 16%. The brown soil was formed from silt-loam and characterized by the following granulometric composition of silty-clay deposit: sand fraction, 8%; silt fraction, 48%; and clay and silt fraction, 46%. In dairy sewage sludge the total bacteria number as defined by Alef and Nannipieri (1995) was 51 x 10(4) colony-forming units (cfu)/ kg dry matter (dm), fungi total number 10 x 10(3) cfu/ kg dm, and E. coli bacteria 9.5 x 10(3) most probable number (MPN)/kg dm. In dairy sewage sludge mixed with straw, total number of bacteria and total number of fungi decreased to 10(3) and 10(2), respectively. Competition for nitrogen, glucose, and lactose and organic acids such as acetic and succinic with soil microorganisms, as well as soil conditions such as lack of oxygen, lower soil pH, and temperature, may account for the reduction in the number of E. coli bacteria in soils to which dairy sewage sludge was applied. Dairy sewage sludge may provide a beneficial impact on soil environment and adversely affect microorganisms such that dairy sewage sludge may be used as a safe organic fertilizer. PMID- 20706945 TI - Activity of soil dehydrogenases, urease, and acid and alkaline phosphatases in soil polluted with petroleum. AB - This study was undertaken to (1) determine the effects of petroleum pollution on changes in the biochemical properties of soil and (2) demonstrate whether the application of compost, bentonite, and calcium oxide is likely to restore biological balance. Petroleum soil pollution at a dose ranging from 2.5 to 10 cm(3)/kg disturbed the biochemical balance as evidenced by inhibition of the activities of soil dehydrogenases (SDH), urease (URE), and acid phosphatase (ACP). The greatest change was noted in the activity of SDH, whereas the least change occurred in URE. Petroleum significantly increased the activity of soil alkaline phosphatase (ALP) in soil used for spring rape, whereas in soil used for oat harvest there was decreased ALP activity. The application of compost, bentonite, and calcium oxide to soil proved effective in mitigating the adverse effects of petroleum on the activities of soil enzymes. Soil enrichment with compost, bentonite, and calcium oxide was found to stimulate the activities of URE and ALP and inhibit the activity of ACP. The influence of bentonite and calcium oxide was greater than that of compost. Calcium oxide and, to a lesser extent, compost were found to increase the activity of SDH, whereas bentonite exerted the opposite effect, especially in the case of the main crop, spring rape. The activities of SDH, URE, and ACP were higher in soil used for rape than that for oats. In contrast the activity of ALP was higher in soil used for oats. Data thus indicate that compost and especially bentonite and calcium oxide exerted a positive effect on activities of some enzymes in soil polluted with petroleum. Application of neutralizing additives to soil restored soil biological balance by counteracting the negative influence of petroleum on activities of URE and ALP. PMID- 20706946 TI - Relationship between selenium accumulation and mycelial cell composition in Lentinula edodes (Berk.) cultures. AB - It was postulated that fractions enriched in selenium (Se) isolated from Lentinula edodes mycelium polysaccharide might possess higher biological activity than the non-enriched fractions currently used to treat cancer. In order to obtain Se-enriched mycelial preparations, L. edodes cultures were cultivated in media enriched with sodium selenite. In order to determine whether the concentration of Se in the culture medium affected the biosynthesis and composition of cell wall and cell membrane, concentrations of the exopolysaccharide (EPS), chitin, and sterol (ergosterol) were measured in harvested mycelia. In addition, the relationship between Se accumulation and content of polyphenols and vitamin D(2) in L. edodes mycelium was examined. The effects of Se levels on the mycelium cell composition were determined in culture media enriched with Se at concentrations ranging from 0 to 30 microg/ml. In each culture mycelial growth, total Se and Se distribution were determined between mycelial fractions of different polarity. The EPS, polyphenolics, and ergosterol content in harvested mycelia rose in proportion to Se concentration in the culture medium. The chitin content in mycelia increased with Se concentrations in the range 0-5 microg/ml, but at higher concentrations chitin levels decreased. Data showed that Se in culture medium exerted potent effects on the composition of the mushroom cell wall and semipermeable membrane, and on the content of polyphenolics that are involved in detoxification processes. Our findings indicate the optimal concentration of Se required in the culture medium for maximal yield of immunostimulatory-active selenated exopolysaccharides. PMID- 20706947 TI - Phytotoxicity of sulfamethazine soil pollutant to six legume plant species. AB - The effect of traces of sulfamethazine (SMZ) in soil (0.01, 0.1, 0.25, 1, 5, 15, and 20 mM) on cellular distribution of cytochrome c oxidase activity, shoot and root growth, and leachate electroconductivity was analyzed in germinating seeds of yellow lupin, pea, lentil, soybean, adzuki bean, and alfalfa. Results showed that a high activity of cytochrome c oxidase in mitochondria correlated with high seed vigor and viability. The appearance of necroses and root decay was associated with a decrease in the activity of mitochondrial cytochrome c oxidase but was accompanied by an increase in cytosolic cytochrome c oxidase activity. A short exposure period of seeds (3 and 6 d) to sulfamethazine did not influence germination. Elongation of roots and stems was more sensitive than germination rate as an indicator of soil contamination by sulfamethazine. Among all tested leguminous plants, yellow lupin was the most reliable bioindicator of SMZ contaminated soil. PMID- 20706948 TI - Populations of selected microbial and fungal species growing on the surface of rape seeds following treatment with desiccants or plant growth regulators. AB - The aim of this study was to determine the effects of desiccants and plant growth regulators on selected microbial species affecting rape seeds, with special emphasis on the growth of fungi and identification of the genus and species composition. The experimental material in the study was seeds of winter rape cv. Californium that were collected from the field during combine harvest. The chemical agents applied, both desiccants and growth regulators, generally decreased the populations of bacteria occurring on the surface of rape seeds. The responses of fungi depended upon the type of agent applied and were manifested as either stimulation or inhibition of the growth of the fungal species. The fungi isolated from the surface of rape seeds were characteristic of those found in the field environment (Cladosporium and Penicillium) and typical for those present on the surface of rape seeds (Alternaria). PMID- 20706949 TI - Determination of lead, cadmium, and persistent organic pollutants in wild and orchard-farm-grown fruit in northeastern Poland. AB - The concentrations of the heavy metals lead (Pb) and cadmium (Cd) were determined in berries (blackberry, raspberry, bilberry, wild strawberry), and hazelnuts picked from plants in the wild as well as in fruit (blackberry, raspberry, blueberry) and hazelnuts picked from orchard-farmed plants in northeastern Poland. The levels of seven congeners of polychlorinated biphenyls (PCB(7)), gamma isomer of hexachlorocyclohexane (gamma-HCH), and sum of dichlorodiphenyl trichloroethane and its metabolites (SigmaDDT) were also measured in plants and nuts. In addition, the concentrations of Pb, Cd, PCB(7,) gamma-HCH, and SigmaDDT were determined in the surface samples of soil from the sites of fruit picking. The highest acceptable concentrations based upon Polish standards for Pb and Cd were not exceeded in forest fruit. In wild berries, Pb occurred at a level below the detection limit, whereas the concentration of Cd ranged from 6 to 49 microg/kg fresh weight. The levels were Cd 72 microg/kg fresh weight and Pb 290 microg/kg fresh weight in raspberries from orchard plants and exceeded the maximal acceptable limit of 50 microg/kg for Cd and 200 microg/kg for Pb. The level of Pb at 210 microg/kg fresh weight in hazelnuts from orchard plants also exceeded maximal acceptable limits. Individual samples of fruit, regardless of their origin, were found to contain trace amounts of organic pollutants such as 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p'-DDE) and PCB congeners 101 and 118. All soil samples contained from 3.2 to 14.9 mg/kg dry weight concentrations of Pb and most soil samples also contained Cd. Further, individual soil samples were found to contain high levels of SigmaDDT (145 microg/kg), including p,p'-DDT at a concentration of 67 microg/kg. The concentrations of persistent organic pollutants (POP) in wild and orchard-farm-grown fruit in northeastern Poland were generally below threshold permissible limits, and no correlation was found between levels of contaminants in soils and POP concentrations in fruit. PMID- 20706950 TI - Herbicide residues and nitrate concentration in tubers of table potatoes. AB - This study examined Wiking-cultivar table potato tubers in a field experiment conducted between 2002 and 2004 using a rye complex soil. The experimental factors included (a) two methods of tillage, including traditional and simplified, as well as (b) seven methods of cultivation with the use of herbicides as follows: 1, control without herbicides; 2, Plateen 41.5 WG; 3, Plateen 41.5 WG + Fusilade Forte 150 EC; 4, Plateen 41.5 WG + Fusilade Forte 150 EC + adjuvant Atpolan 80 EC; 5, Barox 460 SL; 6, Barox 460 SL + Fusilade Forte 150 EC; and 7, Barox 460 SL + Fusilade Forte 150 EC + adjuvant Atpolan 80 EC. Determination of residues was performed using high-performance liquid and gas chromatography. Only trace quantities of bentazone (Barox 460 SL) were found in potato tubers, amounts that fell below the maximum residue limit (MRL). The nitrate content of potato tubers was determined using a nitrate ion-selective electrode and silver chloride reference electrode. The nitrate content in fresh matter of unpeeled and peeled tubers depended significantly only on weather conditions in the years of study. In contrast, agrotechnical procedures such as methods of tillage and cultivation did not significantly affect potato tuber nitrate content. PMID- 20706951 TI - Polycylic aromatic hydrocarbons in rape seeds with relation to their growing site and thermal treatment. AB - A significant source of polycyclic aromatic hydrocarbons (PAH) in human diet is vegetable oils, especially those produced from plants grown in regions where the soil and the atmosphere are contaminated with these chemicals. Contamination with PAH of vegetable oils may also occur in the process of plant material drying with smoke or exhaust fumes, or in the course of extraction of that material with solvents containing trace amounts of PAH. The objective of this study was to determine the relationship between the levels of PAH present in rape seeds and the occurrence of these compounds in cultivation region and the relationship of the levels of PAH in rape seeds to thermal treatment after harvest. Rape seeds and pods from experimental fields and rape seeds subjected to thermal treatment in dryers obtained from suppliers of the raw material were examined and compared. Cleanup of extracts was performed with high-resolution size exclusion chromatography (SEC) and final determinations were by Trace Ultra/PolarisQ gas chromatography-mass spectroscopy (GC-MS). The results obtained indicated that during thermal treatment of rape seeds the concentration of PAH increased, but the levels of benzo[a]pyrene did not exceed threshold permissible levels. Data demonstrate that rapeseed cultivation in the presence of PAH results in higher levels of contaminants; however, the PAH levels still did not exceed the maximal allowable levels in Poland. PMID- 20706952 TI - Growth and mineral composition of nickel-stressed plants under conditions of supplementation with excessive amounts of calcium and iron. AB - This study investigated the effectiveness of excessive calcium (Ca) and iron (Fe) supplement nutrition in spinach Markiza F(1) cv. and sweet corn Zlota Karlowa cv. to alleviate nickel (Ni)-induced phytotoxicity. The following doses of the pollutant Ni were introduced: 0 (control), 40, or 60 mg Ni/kg growth medium. Two levels of calcium (Ca), 270 (basic) and 400 mg/kg (intensive), as well as two levels of iron (Fe), 10 (basic) and 20 mg/kg (intensive), respectively, were used. Intensive nutrition supplementation of Ni-stressed test plants species with Ca or Fe was beneficial as manifested by significantly increased maize shoots and roots biomass, lowered content of Ni in spinach and maize in above-ground parts, and decreased concentration of the pollutant in roots of intensive Ca-supplied maize plants grown in the environment containing 60 mg Ni/kg. Moreover there was significantly elevated Fe content in highly fertilized with iron spinach plants grown in the presence of 60 mg Ni/kg and in shoots of Ni-treated maize plants intensively supplied with Ca or Fe. Generally, high content of Ca or Fe in the growth medium significantly raised the content of free and bound Ca in shoots of Ni-stressed spinach plants. The same phenomenon was found in roots, but only in the presence of 60 mg Ni. Intensive nutrition supplementation of Ni-treated maize plants with Fe or Ca generally did not change the concentration of free Ca in plant organs, but elevated bound Ca levels in roots was observed. Increased bound Ca content was also found in leaves of maize plants intensive supplied with Ca. Thus, intensive Ca or Fe nutrition presents a promising potential for use in the conditions of Ni contamination by increasing plant growth, reducing Ni translocation from roots to shoots and raising the nutritive value of above ground parts of spinach and maize plants. PMID- 20706953 TI - Effects of chromium(III and VI) on spring barley and maize biomass yield and content of nitrogenous compounds. AB - The aim of this study was to (1) determine the effects of trivalent Cr(III) or hexavalent chromium Cr(VI) soil contamination on biomass yield and nitrogenous compound content of spring barley (Hordeum vulgare L.) as the main crop and subsequently maize (Zea mays L.) grown successively, and (2) examine whether the neutralizing additives applied (compost, zeolite, and calcium oxide) may be effective in reducing adverse impact of chromium (Cr) on crops. Spring barley yield was markedly decreased by Cr compounds, particularly Cr(VI). In contrast, maize yield was significantly increased by Cr(VI). Hexavalent Cr exerted a greater effect than the Cr(III) form on nitrogen levels in spring barley. Chromium significantly increased ammonia nitrogen content in maize. The accumulation of NO(3)(-)-N in plants treated with Cr(VI) was lower than in controls. The application of compost, zeolite, and calcium oxide onto the soil increased yield of maize only in pots containing Cr(III). Neutralizing additives exerted a positive, increased effect on the N-total content of maize but not spring barley, which was apparent with calcium oxide. Accumulation of NH(4)(+)-N in maize in pots with Cr(VI) was increased by all additives applied. The content of nitrate nitrogen in spring barley was predominantly affected by addition of compost and calcium oxide into the soil, producing a significant rise in NO(3)(-) N content. Chromium, especially Cr(VI), used at doses of 100 and 150 mg/kg soil exerted adverse effects in treated plants, particularly spring barley. PMID- 20706954 TI - Memory for pitch in congenital amusia: beyond a fine-grained pitch discrimination problem. AB - Congenital amusia is a disorder that affects the perception and production of music. While amusia has been associated with deficits in pitch discrimination, several reports suggest that memory deficits also play a role. The present study investigated short-term memory span for pitch-based and verbal information in 14 individuals with amusia and matched controls. Analogous adaptive-tracking procedures were used to generate tone and digit spans using stimuli that exceeded psychophysically measured pitch perception thresholds. Individuals with amusia had significantly smaller tone spans, whereas their digits spans were a similar size to those of controls. An automated operation span task was used to determine working memory capacity. Working memory deficits were seen in only a small subgroup of individuals with amusia. These findings support the existence of a pitch-specific component within short-term memory and suggest that congenital amusia is more than a disorder of fine-grained pitch discrimination. PMID- 20706955 TI - Memory and the Moses illusion: failures to detect contradictions with stored knowledge yield negative memorial consequences. AB - Although contradictions with stored knowledge are common in daily life, people often fail to notice them. For example, in the Moses illusion, participants fail to notice errors in questions such as "How many animals of each kind did Moses take on the Ark?" despite later showing knowledge that the Biblical reference is to Noah, not Moses. We examined whether error prevalence affected participants' ability to detect distortions in questions, and whether this in turn had memorial consequences. Many of the errors were overlooked, but participants were better able to catch them when they were more common. More generally, the failure to detect errors had negative memorial consequences, increasing the likelihood that the errors were used to answer later general knowledge questions. Methodological implications of this finding are discussed, as it suggests that typical analyses likely underestimate the size of the Moses illusion. Overall, answering distorted questions can yield errors in the knowledge base; most importantly, prior knowledge does not protect against these negative memorial consequences. PMID- 20706956 TI - Extracellular-purine metabolism in blood vessels (part I). Extracellular-purine level in blood of patients with abdominal aortic aneurysm. AB - Adenosine and adenosine derivatives are the main regulators of purinoceptors (P1 and P2) mediated hemostasis and blood pressure. Since impaired hemostasis and high blood pressure lead to atherosclerosis and to the development of aneurysm, in this study we tested and compared the concentration of extracellular purines (e-purines) in the blood in of patients having abdominal aortic aneurysm with that from healthy volunteers. Whereas adenine nucleosides and nucleotides level in human blood plasma was analysed using reverse phase high performance liquid chromatography (HPLC), cholesterol concentration was estimated by an enzymatic assay. We did not find any correlation between e-purines concentration and the age of healthy volunteers. Furthermore, the sum level of e-purines (ATP, ADP, AMP, adenosine, and inosine) in the control group did not exceed 70 microM, while it was nearly two-fold higher in the blood of patients having abdominal aortic aneurysm, (123 microM). In a special case of people with Leriche Syndrome, a disease characterized by deep atherosclerotic changes, the e-purines level had further increased. Additionally, we also report typical atherosclerotic changes in the aorta using histological assays as well as total cholesterol rise. The significant rise in cholesterol concentration in the blood of the patients with abdominal aortas aneurysm, compared with the control groups, was not unique since 23% of the healthy people also exceeded the normal level of cholesterol. Therefore, our results strongly indicate that the estimation of e-purines concentration in the blood may serve as another indicator of atherosclerosis and warrant further consideration as a futuristic diagnostic tool. PMID- 20706957 TI - Antimicrobial and DNA-cleavage studies of 22-membered N4 tetraaza macrocyclic triazoles: template synthesis and physicochemical characterization. AB - A novel series of 22-membered macrocyclic complexes of the type [MLCl(2)] (M=Co(2+), Ni(2+) and Cu(2+)) have been synthesized with newly derived biologically active ligands (L(1)-L(IV)). These ligands were synthesized by the condensation of ortho-phthalaldehyde and bis-(4-amino-5-mercapto-1, 2, 4-triazole 3-yl)alkanes. The mode of bonding and overall geometry of the complexes have been inferred through IR, EPR, electronic spectral studies, conductivity, magnetic, thermal, and electrochemical studies. All these complexes have been screened for their antibacterial (Escherichia coli, Staphylococus aureus, Salmonella typhi, Pseudomonas aeruginosa) and antifungal activities (Aspergillus niger, Aspergillus flavus, and Cladosporium) by the minimal inhibitory concentration (MIC) method. The DNA cleavage study was done by agarose gel electrophoresis technique. PMID- 20706958 TI - Design of fMet-tRNA and calculation of its bonding properties by quantum mechanics. AB - It is generally accepted that initiation of protein synthesis in Escherichia coli starts with formyl-methionine, directed by the codons of AUG or GUG. In one case, reinitiating on the mRNA of amber mutants of UUG is used as the initiation codon. Early studies indeed showed that the triplets AUG, GUG, and UUG are the most effective in stimulating fMet-tRNA binding to ribosomes in vitro. We study the bonding properties of fMet-tRNA. The structure was optimized at the Hartree-Fock (HF) level of theory. We performed nonempirical quantum mechanical calculations at the HF and BLYP and B3LYP/3-21G, 6-31G, and 6-31G* levels of theory in the gas phase and water solvent at temperature of 310 K. Finally, we employed the density functional theory (DFT) and HF to calculate nuclear magnetic resonance spectra and infrared spectra. PMID- 20706959 TI - The spontaneous rearrangement of 2,4-dinitrophenyl substituent in ribonucleosides under neutral conditions. AB - In the cytidine and adenosine derivatives an isomerization of a 2,4-dinitrophenyl group between the 2'- and 3'-positions of the ribose was observed under neutral conditions. Moreover, it was shown that isomerization of the 2,4-dinitrophenyl group in conditions required to synthesize phosphoramidites and lability in aqueous ammonia make chemical synthesis of 2'-O-(2,4-dinitrophenyl) oligonucleotides impossible. PMID- 20706960 TI - Revisit to the reaction of o-phenylene diamine with thiosemicarbazide to give benzimidazole-2-thione rather than benzotriazine-2-thione and its glycosylation. AB - Reaction of o-phenylene diamine with thiosemicarbazide did not give benzotriazine 2-thione 2 as reported, although the product was found to be benzimidazole-2 thione 3. Glycosylation of 3 with acetobromo sugars 4a-4b gave the respective thioglycosides 7a-7d in addition to minor products of the nucleosides 8a and 8b, in the case of the gluco- and galacto-analogs, respectively. The regioselectivity of glycosylation reaction has been investigated. PMID- 20706961 TI - Synthesis of novel acyclic nucleoside analogues with anti-retroviral activity. AB - A series of novel acyclic thymine nucleoside analogues were prepared by the Mitsunobu reaction from appropriately protected chiral triols. The enantiomeric triols were obtained from substituted gamma-lactone acids, prepared by asymmetric oxidation of 3-substituted-1,2-cyclopentanediones. The cytotoxic activity of new analogues was evaluated on MCF-7 human breast cancer and HeLa cells, and antiviral activities on human immunodeficiency virus type 1 and hepatitis C virus models. The synthesized compounds revealed specific anti-retroviral activity and no cytotoxic side effects. PMID- 20706962 TI - Does higher general trust serve as a psychosocial buffer against social pain? An NIRS study of social exclusion. AB - Social exclusion evokes social pain in excluded individuals. Neuroimaging studies suggest that this social pain is associated with activation of the dorsal anterior cingulate cortex (dACC), with further regulation of social pain being reflected in activation of the right ventrolateral prefrontal cortex (rVLPFC). The present study focused on factors that influence activation of the rVLPFC during social exclusion. We conducted a near-infrared spectroscopy (NIRS) experiment to investigate whether two psychosocial resources (general trust and trait self-esteem) increase rVLPFC activity during social exclusion, thereby buffering against social pain. Thirty-seven undergraduates participated in an NIRS session in which they were socially rejected during an online ball-tossing game. Levels of general trust and trait self-esteem were negatively correlated with self-reported social pain in the exclusion conditions. Furthermore, general trust was positively correlated with rVLPFC activity, although there was no such relationship with self-esteem. rVLPFC activity mediated the relationship between general trust levels and social pain. The rVLPFC appears to be critical for the regulation of social pain. Taken together, these findings suggest that general trust and trait self-esteem probably have different impacts at different times over the course of a series of adaptive processes, all geared toward the modulation of social pain. PMID- 20706963 TI - The role of social cognition in moral judgment in frontotemporal dementia. AB - Patients with behavioral variant frontotemporal dementia (bvFTD) exhibit a set of behavioral disturbances that have been strongly associated with involvement of the prefrontal cortex (PFC). Many such disturbances have been linked to impaired moral behavior, especially in regard to "personal" or "emotionally driven" moral dilemmatic judgment, which has been demonstrated to also depend on the integrity of the PFC. In this study, we administered a personal moral dilemma (the footbridge dilemma) and social cognition measures to patients with early bvFTD, who were also assessed with an extensive neuropsychological battery, including moral knowledge, cognitive and emotional empathy, and affective decision-making. BvFTD patients who would push a man off a footbridge (knowing this would kill him) to save the life of five workers who would have been otherwise killed by the train showed significantly lower scores on affective Theory of Mind (ToM) relative to those bvFTD patients who responded negatively. No significant differences were found on other sociodemographic, neuropsychological or social cognition variables. This study reveals that altered dilemmatic judgment may be related to impaired affective ToM, which has important clinical and theoretical implications. PMID- 20706964 TI - [Detection and evaluation of OCT findings in macular diseases]. PMID- 20706965 TI - ["Is there a future for non-English scientific journals?"]. PMID- 20706966 TI - [New aspects for cataract surgery and intraocular lens implantation]. PMID- 20706967 TI - [Topical anaesthesia in cataract surgery]. AB - Topical anaesthesia was introduced together with the establishment of modern cataract surgery as an operation in a closed system. Superficial anaesthesia by itself leads to a good analgesia in most cases. However, up to 30% of the patients feel uncomfortable or even experience pain during surgery. Superficial anaesthesia can be intensified with subconjunctival infiltration or by modifying the application forms such as sponges or gel. With the introduction of the intracameral anaesthesia in the 1990 s primarily with unpreserved lidocaine 1%, the efficacy of the topical anaesthesia was improved significantly. The combined topical anaesthesia plus intracameral lidocaine administration can be used as a routine method. A general anaesthesia care for premedication and monitoring during cataract surgery is useful since most cataract patients are of advanced age and frequently suffer from cardiovascular diseases. In almost 10% of the patients changes in cardiopulmonal comorbidities were observed and in 2.6% anaesthesia intervention was required. PMID- 20706968 TI - [Assessment of centration and position stability of modern intraocular lenses after cataract surgery]. AB - Centration and positional stability of intraocular lenses (IOLs) are crucial factors for optical quality and predictability of the result after IOL implantation. Continuous improvements of IOL design and materials, surgical techniques and measurement methods have contributed to an optimised correction of the presudophakic eye and to a better unterstanding of the effects of IOL positioning. With modern IOLs implanted into the capsular bag, positioning and stability comparable to the natural crystalline lens can be achieved. PMID- 20706969 TI - [Blue Light-Filtering IOLs - Currently available data]. AB - Data from both experimental and epidemiological trials have suggested a potential correlation between extraction of the natural lens associated with exposure to photo-oxidative stress to the retina and a progression of diseases such as AMD. A fundamental factor could be the unchecked exposure to blue light. This is why in the past years so-called blue light-filtering intraocular lenses have been implanted to serve as a protection to the retina. The following contribution is based on a data base research (Pub Med, National Library of Medicine, USA) and summarises information currently available on the use of blue light-filtering lenses. Experimental modeling has shown that, compared to regular UV lenses, blue light-filtering lenses block a considerable part of blue light transmission to the retina and reduce damage to retinal cells and production of inflammatory markers such as VEGF. The majority of the clinical data demonstrate that blue light-filtering lenses are compatible in terms of visual acuity, contrast sensitivity and colour perception as well as patient-rated quality of vision. But a few additional studies report reduced contrast sensitivity and limitations in mesopic vision.This is also true for the circadian rhythm. However, the evaluation of this parameter in connection with blue light-filtering lenses has only been done on a theoretical basis. Long-term data showing that blue light filtering lenses actually do reduce the incidence of retinal diseases such as AMD are currently not available. PMID- 20706970 TI - [IOL power calculation after refractive surgery]. AB - Cataract surgery is evolving more and more into a refractive procedure with high expectations in terms of visual rehabilitation. Especially patients presenting after previous Excimer laser corneal surgery are used to being independent from glasses. Unfortunately, some of these patients showed unexpected hyperopic surprises after cataract surgery in the past. The changes of corneal radii and keratometer index as well as the inaccurate prediction of the postoperative intraocular lens (IOL) position using different formulas were determined as error sources which led to a reduced IOL power calculation in dioptres. Several methods have been proposed to solve this problem which can be divided in two groups. On the one hand, there are methods that depend on refraction and biometry values before the initial treatment (e. g., clinical history, Feiz-Mannis, double-K, adjusted effective refractive power [EffRadj]-, cornea bypass/Wake Forest methods as well as correction factors to adjust K-values) and on the other hand procedures that only need current pre-cataract surgery measurements (e. g., contact lens method, corneal topography systems, ray tracing, aphakic refraction technique, correction factors to adjust K-values and new formulas including Haigis-L or BESSt and recently a novel pachymetry method). This review describes these procedures and analyses their strengths and weaknesses. The number of presented methods emphasises already that no perfect solution has been determined so far that would be valid for every patient. Some methods do provide a good predictability; however, individual deviations can occur. In general, it is advisable to inform the patient about the higher risk for an inaccurate IOL power calculation. It can be helpful to compare the results of different methods indicating the importance to provide all required individual data by the refractive surgeon already. PMID- 20706971 TI - [Combined cataract and vitreoretinal surgery]. AB - Both cataract and many vitreoretinal diseases occur more frequently and often at the same time in the elderly population. Therefore, one has to consider whether to combine cataract surgery and vitrectomy or to plan a sequential approach. The aim of the present survey - based on a thorough review of the current literature is to point out the advantages and disadvantages of a combined versus a sequential approach. Furthermore, practically oriented guidelines have been compiled for finding the right indication for a combined procedure with regard to the underlying vitreoretinal disease. PMID- 20706972 TI - [Psychosomatic symptoms in somatic diseases - open-angle glaucoma for example]. AB - Psychological aspects exist in somatic diseases like tumours and even fractures, not only in the beginning but also in the management of disease. Somatic diseases give rise to signs of a special constellation of life and management of these diseases is important for the psychological constellation of the individual. Studies on open-angle glaucoma have shown that many patients suffering from this disease are anxious, hypochondric, perfectionist and emotional instable. Chronic diseases are demanding processes of flexibility and defense, and define how the individual can deal with the diseases and what place in life the disease will occupy in the future. In the holistic view of medicine even psychological conflicts should be treated. In many situations, these conflicts are not consciously experienced by the individual. Therapeutically, 2 different tools can be used: symbolic stories can bring forces to manage the conflict and to solve the conflict (2 examples in the text). The method of positive psychotherapy describes the reasons for psychosomatic diseases in three parts: psychosomatic in the traditional understanding, in further and comprehensive understanding. Especially the psychosomatic effects in comprehensive understanding are embedded in the individual's sociocultural environment and provide tips on reasons for the diseases in those parts of life. The "positive balance model" gives an example of life-management and conflict-therapy. In ophthalmology, fear is often more important for the patient than pain. To avoid this, the patients develop techniques to deny, to cover or to suppress the fear. In the article questions are presented like those the ophthalmologist should be able to ask patients in the office concerning open-angle glaucoma. Tips for the therapy and management for neurotic stress are offered and some special anamnestic questions for the ophthalmologist are presented. Unsolved conflicts and denied desires as neurotic symptoms can be focused in symptoms of eye diseases. Macrotraumata and microtraumata may be reason for changes of the hormonal situation and subsequent destabilisation of the metabolism, hypertonic disease and variation of the intraocular pressure. This article gives an example of the therapeutic possibilities in somatic diseases, to discuss the psychic situation with the patient and to be able to give tips for self-help. Finally, the therapeutic procedere in patients with somatic and psychosomatic diseases is discussed and a 5-step model is presented. PMID- 20706973 TI - [Implantation of multifocal add-on IOLs simultaneously with cataract surgery: results of a prospective study]. AB - BACKGROUND: A prospective study was carried out to evaluate postoperative visual acuity and patients satisfaction after implantation of a multifocal add-on IOL. PATIENTS AND METHODS: In 50 eyes of 25 patients operated by two surgeons "group A (MK) = 15 patients; group B (MWR) = 10 patients" with age-related cataract after "normal" cataract surgery, sulcus-fixated multifocal add-on IOLs (MS 714 PB Diff., Dr. Schmidt Intraocularlinsen, Sankt Augustin) were implanted. 12 weeks after surgery in both groups the following parameters were evaluated: far visual acuity; intermediate visual acuity (1 meter) and near visual acuity (33 centimeter). In addition, the patients satisfaction was measured in three steps (1 = excellent; 2 = satisfied; 3 = not satisfied) ermittelt. In group A also contrast sensitivity was measured using the Ginsberg box. RESULTS: Surgery was performed in all cases without complications. No postoperative complications were observed. After 12 weeks the results in both groups were comparable. Median distance visual acuity was 0.05 +/- 0.02 (LogMar) uncorrected and 0 +/- 0.05 (LogMar) with correction. Intermediate visual acuity was 0.25 +/- 0.06 (LogMar) uncorrected (0.1 +/- 0.09 (LogMar) with correction. Near visual acuity was 0.2 +/ 0.07 (LogMar) and 0.15 +/- 0.02 (LogMar), respectively. Patients satisfaction was 80 - 90%. CONCLUSIONS: Sulcus-fixated add-on IOLs are a useful addition to our refractive surgical armamentarium. The present results encourage us to use this method as a standard procedure. PMID- 20706974 TI - [Non-response and change of anti-VEGF agent in exsudative age-related macular degeneration]. PMID- 20706975 TI - [By the 130th birthday and the 65th return of the date of death: the editor of the "Monatsblatter" Aurel von Szily, and his unpublished scientific treatise about the congenital optic disc anomalies]. PMID- 20706976 TI - Why were the results of randomized trials on the clinical utility of fetal fibronectin negative? A systematic review of their study designs. AB - Randomized trials on the clinical utility of fetal fibronectin in women with symptoms of preterm labor have thus far failed to demonstrate benefits. We systematically reviewed the methodology of these trials to assess if these negative results may be related to their study designs. We searched the literature for randomized trials that evaluated fibronectin testing in women with symptoms of preterm labor. Study results were evaluated and five methodological criteria were assessed: (1) randomization of discordant test results, (2) use of a fixed management protocol, (3) description of interventions in relation to the test result, (4) evaluation of a learning curve, and (5) sample size calculation in agreement with the prevalence of the test results. We detected four randomized trials that met inclusion criteria. All trials allocated women to a strategy with or without availability of fibronectin results without using a discordancy design or a fixed management protocol. One study reported the given treatment in relation to the test results. Learning curves were evaluated in one study. Two studies used transport sample size calculations. The negative results of randomized trials on fetal fibronectin may be due to particular choices in their study design. PMID- 20706977 TI - [The use of the German APHAB for quality control in hearing aid fitting in an ENT office. Comparison of our results with the given US-norm]. AB - OBJECTIVE: ISO 9001 recommends a customer survey both pre and post hearing aid fitting. A lot of different German questionnaires are in use, but most of them have not been investigated by a large number of patients. The APHAB is well evaluated in the US. We want to compare our APHAB (German) outcome with the US norm given by the HARL, to be able to answer the question if the German-APHAB can be used for quality control in hearing aid fitting done in a German ENT-office. Furthermore we want to discuss some special aspects of the benefit of the APHAB in quality control of hearing aid fitting. MATERIAL AND METHODS: We collected the APHAB data of 224 patients in 9 ENT-offices. The scores were measured pre and post fitting. We compared APHAB mean score for EC-, RV-, BN-, and AV-subscale and performed a wider outlook by statistical methods. RESULTS: We tested the null hypothesis: "There is no difference between the percentiles given by HARL and ours". All probabilities by using the Wilcoxon rank sum test are greater than 0.025, so we have to accept this with a p < 2.5%. By using the sign test we got a probability of a positive benefit for hearing aid fitting of about 75-78% in the EC-, BN-, RV- and 28% in the AV-subscale (confidence interval 95%). CONCLUSIONS: The trial shows, that we can well use the German-APHAB for quality control in hearing aid fitting done in an ENT-office. Patients fitted in a German ENT-office score the same as patients fitted by US-audiologists. We will continue using the APHAB forms, analyse the scoring and use it for technical adjustments to increase the coaching for negative scoring patients. PMID- 20706978 TI - Popliteal artery branching patterns detected by digital subtraction angiography. AB - PURPOSE: To describe the popliteal and distal branching patterns detected by digital subtraction angiography. MATERIALS AND METHODS: The popliteal branching patterns were analyzed in 535 extremities (270 right, 265 left). Of these, 226 limbs were evaluated bilaterally, while 83 were evaluated unilaterally. The branching patterns were classified according to the level of branching and the presence of hypoplasia or aplasia of the distal branches. RESULTS: Four hundred and seventy-two (88.1%) limbs had a normal level of popliteal artery branching. Type IA was the most frequently encountered pattern. High division of the popliteal artery was seen in 30 (5.6%) limbs. Type IIA was the most frequently encountered pattern among these limbs. Type IIC was not seen. We encountered a new pattern characterized by high division of the peroneal artery with a trifurcation pattern and an anterior tibial artery with a proximal medial course and a distal lateral course. We called this pattern Type IID. Thirty-three (6.1%) limbs exhibited hypoplasia/aplasia of the distal branches. Type IIIA was the most frequently encountered pattern among these limbs. CONCLUSION: Variations that occur in nearly 10% of patients should be understood because they may affect the choice of management strategy. PMID- 20706979 TI - Invasive lobular carcinoma of the breast: mammographic and sonographic evaluation. AB - PURPOSE: To evaluate the efficacy of mammography and sonography together in the assessment of patients with pure invasive lobular carcinomas (ILCs) of the breast. MATERIALS AND METHODS: We retrospectively reviewed 38 cases of pure invasive lobular carcinomas of the breast. The tumors were evaluated both mammographically and sonographically. The mammographic images were reviewed by two experienced mammographers. All patients underwent surgical management. Histopathologic assessments were made by experienced breast pathologists. RESULTS: On physical examination, six tumors (15.7%) showed no clinical findings. The most common mammographic result was a spiculated mass or architectural distortion (42%). Eleven lesions (29%) were mammographically negative. Five cases (13%) showed pleomorphic or heterogeneous calcifications that were compatible with Breast Imaging Reporting and Data System (BI-RADS) 4 or 5. The most common sonographic result was a hypoechoic mass with or without shadowing (60.5%). Four tumors (10.5%) were sonographically invisible. Two cases (5%) were negative, and 25 cases (65.8%) were positive in both modalities. The overall sensitivity was 71.05% for mammography and 89.47% for sonography. The number of tumors detected by either of these two modalities was 36, and the overall sensitivity was 94.73%. CONCLUSION: Mammography and ultrasonography are useful imaging methods in the evaluation of invasive lobular carcinoma. Because of the low rate of suspicious calcifications and low density of lesions, the false-negative rate tends to be high for these tumors. With the use of sonography and mammography together, invasive lobular carcinomas can be detected with a sensitivity of 94.73%. We recommend additional sonographic evaluations for all patients, especially those with dense breast tissue with or without positive mammographic findings. PMID- 20706980 TI - Assessment of downstream effectors of BCR/ABL protein tyrosine kinase using combined proteomic approaches. AB - Leukaemic transformation is frequently associated with the aberrant activity of a protein tyrosine kinase (PTK). As such it is of clinical relevance to be able to map the effects of these leukaemogenic PTKs on haemopoietic cells at the level of phosphorylation modulation. In this paradigm study we have employed a range of proteomic approaches to analyse the effects of one such PTK, BCR/ABL. We have employed phosphoproteome enrichment techniques allied to peptide and protein quantification to identify proteins and pathways involved in cellular transformation. Amongst the proteins shown to be regulated at the post translational level were cofilin, an actin-severing protein thus linked to altered motility and Cbl an E3 ubiquitin ligase integrally linked to the control of tyrosine kinase signalling (regulated by 5 and 6 PTKs respectively). The major class of proteins identified however were molecular chaperones. We also showed that HSP90 phosphorylation is altered by BCR/ABL action and that HSP90 plays a crucial role in oncogene stability. Further investigation with another six leukaemogenic PTKs demonstrates that this HSP90 role in oncogene stability appears to be a common phenomenon in a range of leukaemias. This opens up the potential opportunity to treat different leukaemias with HSP90 inhibitors. PMID- 20706981 TI - Differential effect of YidC depletion on the membrane proteome of Escherichia coli under aerobic and anaerobic growth conditions. AB - YidC of Escherichia coli belongs to the evolutionarily conserved Oxa1/Alb3/YidC family. Members of the family have all been implicated in membrane protein biogenesis of respiratory and energy transducing proteins. The number of proteins identified thus far to require YidC for their membrane biogenesis remains limited and the identification of new substrates may allow the elucidation of properties that define the YidC specificity. To this end we investigated changes in the membrane proteome of E. coli upon YidC depletion using metabolic labeling of proteins with 15N/14N combined with a MS-centered proteomics approach and compared the effects of YidC depletion under aerobic and anaerobic growth conditions. We found that YidC depletion resulted in protein aggregation/misfolding in the cytoplasm as well as in the inner membrane of E. coli. A dramatic increase was observed in the chaperone-mediated stress response upon YidC depletion and this response was limited to aerobically grown cells. A number of transporter proteins were identified as possible candidates for the YidC-dependent insertion and/or folding pathway. These included the small metal ion transporter CorA, numerous ABC transporters, as well as the MFS transporters KgtP and ProP, providing a new subset of proteins potentially requiring YidC for membrane biogenesis. PMID- 20706982 TI - The stromal-vascular fraction of adipose tissue contributes to major differences between subcutaneous and visceral fat depots. AB - Adipose tissue represents a complex tissue both in terms of its cellular composition, as it includes mature adipocytes and the various cell types comprising the stromal-vascular fraction (SVF), and in relation to the distinct biochemical, morphological and functional characteristics according to its anatomical location. Herein, we have characterized the proteomic profile of both mature adipocyte and SVF from human visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) fat depots in order to unveil differences in the expression of proteins which may underlie the distinct association of VAT and SAT to several pathologies. Specifically, 24 proteins were observed to be differentially expressed between SAT SVF versus VAT SVF from lean individuals. Immunoblotting and RT-PCR analysis confirmed the differential regulation of the nuclear envelope proteins lamin A/C, the membrane-cytoskeletal linker ezrin and the enzyme involved in retinoic acid production, aldehyde dehydrogenase 1A2, in the two fat depots. In sum, the observation that proteins with important cell functions are differentially distributed between VAT and SAT and their characterization as components of SVF or mature adipocytes pave the way for future research on the molecular basis underlying diverse adipose tissue-related pathologies such as metabolic syndrome or lipodystrophy. PMID- 20706983 TI - Graphene and graphene oxide: synthesis, properties, and applications. AB - There is intense interest in graphene in fields such as physics, chemistry, and materials science, among others. Interest in graphene's exceptional physical properties, chemical tunability, and potential for applications has generated thousands of publications and an accelerating pace of research, making review of such research timely. Here is an overview of the synthesis, properties, and applications of graphene and related materials (primarily, graphite oxide and its colloidal suspensions and materials made from them), from a materials science perspective. PMID- 20706984 TI - Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis. AB - Th17 cells and Th1 cells coordinate to play a critical role in the formation of inflammatory bowel diseases. To examine how Th17 and Th1 cells are regulated at inflammatory sites, we used Th1-dominant CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) and Th1/Th17-mixed IL-10(-/-) mice. Interestingly, not only did colitic RAG-2(-/-) mice that were parabiosed with WT mice show significant amelioration of colitis, but amelioration of disease was also observed in those parabiosed with colitic IL-10(-/-) mice. To assess the interference between Th1 and Th17 colitogenic T cells, we co-transferred colitogenic CD4(+) T cells from the lamina propria (LP) of CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice into RAG-2(-/-) mice. Surprisingly, the co-transferred RAG-2( /-) mice showed a vast cellular infiltration of LP CD4(+) T cells similar to that seen in RAG-2(-/-) mice re-transferred with the cells from colitic RAG-2(-/-) mice alone, but the co-transferred RAG-2(-/-) mice did not have the wasting symptoms, which are also absent in RAG-2(-/-) mice transferred with cells from colitic IL-10(-/-) mice alone. Furthermore, the percentages of Th1 and Th17 cells originating from IL-10(-/-) mice and those of Th1 cells originating from colitic RAG-2(-/-) mice were all significantly decreased in the co-transferred mice as compared with the singly-transferred paired RAG-2(-/-) mice, suggesting that Th1 and Th17 cells are in competition, and that their orchestration results in a merged clinical phenotype of the two types of murine colitis. PMID- 20706985 TI - Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL 22 and IL-17 production by human T helper cells. AB - Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-gamma, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4(+) T cells. The specific AHR inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naive CD4(+) T cells to produce IL-22 without IL-17 and IFN-gamma. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161(+) Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4(+) T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. PMID- 20706986 TI - The sequential activity of Gata3 and Thpok is required for the differentiation of CD1d-restricted CD4+ NKT cells. AB - While most CD4(+) T cells are MHC class II-restricted, a small subset, including the CD1d-restricted 'invariant' NKT (iNKT) cells, are selected on non-classical MHC-I or MHC-I-like molecules. We previously showed that the sequential activity of two zinc finger transcription factors, Gata3 and Thpok, promotes the differentiation of conventional, MHC II-restricted thymocytes into CD4(+) T cells. In the current study, we show that a Gata3-Thpok cascade is required for the differentiation of CD4(+) iNKT cells. Gata3 is required for iNKT cells to express Thpok, whereas Thpok is needed for proper NKT cell differentiation, and notably for NKT cells to maintain CD4 and terminate CD8 expression. These findings identify the sequential activity of Gata3 and Thpok as a hallmark of CD4(+) T-cell differentiation, regardless of MHC restriction. PMID- 20706987 TI - Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis. AB - The role of STAT3 in infectious diseases remains undetermined, in part because unphosphorylated STAT3 has been considered an inactive protein. Here, we report that unphosphorylated STAT3 contributes to cholinergic anti-inflammation, prevents systemic inflammation, and improves survival in sepsis. Bacterial endotoxin induced STAT3 tyrosine phosphorylation in macrophages. Both alpha 7 nicotinic receptor (alpha 7nAChR) activation and inhibition of JAK2 blunt STAT3 phosphorylation. Inhibition of STAT3 phosphorylation mimicked the alpha 7nAChR signaling, inhibiting NF-kappaB and cytokine production in macrophages. Transfection of macrophages with the dominant-negative mutant STAT3F, to prevent its tyrosine phosphorylation, reduced TNF production but did not prevent the alpha 7nAChR signaling. However, inhibition of STAT3 protein expression enhanced cytokine production and abrogated alpha 7nAChR signaling. Alpha 7nAChR controls TNF production in macrophages through a mechanism that requires STAT3 protein expression, but not its tyrosine phosphorylation. In vivo, inhibition of STAT3 tyrosine phosphorylation by stattic prevented systemic inflammation and improved survival in experimental sepsis. Stattic also prevented the production of late mediators of sepsis and improved survival in established sepsis. These results reveal the immunological implications of tyrosine-unphosphorylated STAT3 in infectious diseases. PMID- 20706988 TI - Interferon-induced TRAIL-independent cell death in DNase II-/- embryos. AB - The chromosomal DNA of apoptotic cells and the nuclear DNA expelled from erythroid precursors is cleaved by DNase II in lysosomes after the cells or nuclei are engulfed by macrophages. DNase II(-/-) embryos suffer from lethal anemia due to IFN-beta produced in the macrophages carrying undigested DNA. Here, we show that Type I IFN induced a caspase-dependent cell death in human epithelial cells that were transformed to express a high level of IFN type I receptor. During this death process, a set of genes was strongly activated, one of which encoded TRAIL, a death ligand. A high level of TRAIL mRNA was also found in the fetal liver of the lethally anemic DNase II(-/-) embryos, and a lack of IFN type I receptor in the DNase II(-/-) IFN-IR(-/-) embryos blocked the expression of TRAIL mRNA. However, a null mutation in TRAIL did not rescue the lethal anemia of the DNase II(-/-) embryos, indicating that TRAIL is dispensable for inducing the apoptosis of erythroid cells in DNase II(-/-) embryos, and therefore, that there is a TRAIL-independent mechanism for the IFN-induced apoptosis. PMID- 20706989 TI - The story of DNase II: a stifled death-wish leads to self-harm. AB - DNase II is an endonuclease which plays a fundamental role in the degradation of DNA from both apoptotic cells, and nuclei extruded from red blood cells during erythropoiesis: important tasks, considering that everyday 10(8)-10(9) cells undergo apoptosis, and 10(11) red blood cells are produced in the adult human. The DNase II-null mouse demonstrates embryonic lethality due to type I interferon mediated erythroid precursor cell death triggered by undegraded nucleic acids. However, the mechanisms leading to such cytotoxicity are poorly understood. A study in the current issue of the European Journal of Immunology investigates the role of the death ligand TRAIL in this process. Although TRAIL is shown to be dispensable for the interferon-induced apoptosis of erythroid cells in DNAse II( /-) embryos, the authors have developed a useful strategy for further exploring this question in future studies. Interestingly, earlier studies by the same group showed that crossing the DNase II-null mouse with a mouse deficient for the type I interferon receptor can rescue the lethal anaemia observed in the DNase II-null embryos, but only at the cost of developing autoimmunity. PMID- 20706990 TI - Biosimilar epoetins and other "follow-on" biologics: update on the European experiences. AB - After the patents of biopharmaceuticals have expired, based on specific regulatory approval pathways copied products ("biosimilars" or "follow-on biologics") have been launched in the EU. This article summarizes experiences with hematopoietic medicines, namely the epoetins (two biosimilars traded under five different brand names) and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists should be familiar with the legal and pharmacological specialities of biosimilars: The production process can differ from that of the original, clinical indications can be extrapolated, glycoproteins contain varying isoforms, the formulation may differ from the original, and biopharmaceuticals are potentially immunogenic. Only on proof of quality, efficacy and safety, biosimilars are a viable option because of their lower costs. PMID- 20706991 TI - Hyaluronan inhibits matrix metalloproteinase-13 in human arthritic chondrocytes via CD44 and P38. AB - We investigated the effects of hyaluronan (HA) on interleukin-1beta (IL-1beta) stimulated matrix metalloproteinase (MMP)-13 production in human chondrocytes from patients with osteoarthritis (OA) or rheumatoid arthritis (RA). Secreted levels of MMP-13 in conditioned media were detected by immunoblotting, while intracellular MMP-13 synthesis in articular cartilage was evaluated by immunofluorescence microscopic analysis. Mitogen-activated protein kinases (MAPKs), p38, extracellular signal-regulated kinases (ERK), and c-jun NH2 terminal kinase (JNK) were assessed by Western blotting. IL-1beta (2 ng/ml) stimulates the secretion of MMP-13 in both OA and RA chondrocytes. Inhibition studies using specific MAPK inhibitors revealed that IL-1beta induced MMP-13 via p38 in both OA and RA chondrocytes. HA down-regulates IL-1beta-stimulated MMP-13 and phosphorylated p38 (p-p38) in a dose-dependent manner (0.1, 1, 2, and 4 mg/ml). When used at 4 mg/ml, HA inhibits p-p38 phosphorylation by more than 60%. In response to IL-1beta, RA chondrocytes express a higher level of p-p38 than that of OA chondrocytes. Inhibition of CD44, using a blocking antibody, significantly reversed the inhibitory effect of HA on both MMP-13 and p-p38. Our study clearly shows that HA inhibits IL-1beta-induced MMP-13 via its principal receptor, CD44, and subsequent intracellular p38 MAPK signaling in OA and RA chondrocytes. PMID- 20706992 TI - Maternal-infant biomonitoring of environmental chemicals: the epidemiologic challenges. AB - There is growing concern about the potential health effects of exposure to various environmental chemicals during pregnancy and infancy. One of the key limitations of past epidemiologic research in this field has been the potential for exposure misclassification to lead to biases in the health risk estimate. The use of biomarkers in pregnancy cohort or case-control studies has significantly advanced the field; however, this is true only if the biomarker is a true measurement of exposure for the relevant time period of interest. There are a number of theoretical and practical constraints to their use, including difficulty interpreting biomonitoring data, high analytical and collection costs, potential participant selection biases, and ethical challenges in reporting results to study subjects. Identifying a representative sample and collecting biospecimens in the developmental window of interest can be problematic. Various strategies for identifying pregnant women range from the more representative but least efficient sampling of the general population to recruitment through early ultrasound clinics and local advertising. Whereas measurement of xenobiotic chemicals in cord blood, amniotic fluid, or meconium provides unequivocal evidence that the chemical has entered the fetal environment, analysis of maternal blood and urine can be used as a surrogate for fetal exposure. Use of stored midpregnancy serum collected for fetal screening and of large-cohort biobanks offer unique opportunities for biomonitoring data for birth defects studies. Future research is needed to explore less invasive matrices for biomonitoring of infants and to develop less costly analytical methods that require smaller sample volumes. PMID- 20706993 TI - The principles of teratology: are they still true? AB - James Wilson originally proposed a set of "Principles of Teratology" in 1959, the year before he helped to found the Teratology Society. By 1977, when these Principles were presented in a more definitive form in Wilson and Fraser's Handbook of Teratology, they had become a standard formulation of the basic tenets of the field. Wilson's Principles have continued to guide scientific research in teratology, and they are widely used in teaching. Recent advances in our knowledge of the molecular and cellular bases of embryogenesis serve only to provide a deeper understanding of the fundamental developmental mechanisms that underlie Wilson's Principles of Teratology. PMID- 20706994 TI - Maternal diabetes and renal agenesis/dysgenesis. AB - BACKGROUND: Renal agenesis and dysgenesis are potentially lethal congenital malformations affecting 2 to 5 infants per 10,000 live births annually in the United States. The low prevalence of these malformations has complicated understanding of potential risk factors. Maternal diabetes (type 1, type 2, and gestational) has been evaluated extensively as a risk factor for other congenital malformations, but only a limited number of studies have assessed the association between diabetes and renal agenesis. METHODS: We conducted a population-based case-control study of deliveries after 20 weeks gestation in Texas Health Service Region 6 (Houston/Galveston area) from January 1, 2000 to December 31, 2002. Cases of renal agenesis/dysgenesis (n = 89) were ascertained from the Texas Birth Defects Registry. Cumulative incidence sampling was used to randomly select, from birth and fetal death records, 356 controls frequency matched to cases by delivery year and vital status. Maternal diabetes and other covariates were collected from vital records. RESULTS: The odds of renal agenesis/dysgenesis were 3.1 (95% confidence interval [CI], 1.1-9.3) times greater among deliveries of mothers with diabetes compared to deliveries of mothers without diabetes, controlling for matching factors. CONCLUSIONS: Our results are consistent with prior, but limited, research identifying diabetes as a risk factor for renal agenesis/dysgenesis. While these data did not differentiate diabetes diagnoses by type, the results suggest that maternal diabetes may be associated with renal malformations. Further study is warranted. PMID- 20706995 TI - Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats. AB - BACKGROUND: Prenatal alcohol exposure can alter physical and behavioral development, leading to a range of fetal alcohol spectrum disorders. Despite warning labels, pregnant women continue to drink alcohol, creating a need to identify effective interventions to reduce the severity of alcohol's teratogenic effects. Choline is an essential nutrient that influences brain and behavioral development. Recent studies indicate that choline supplementation can reduce the teratogenic effects of developmental alcohol exposure. The present study examined whether choline supplementation during prenatal ethanol treatment could mitigate the adverse effects of ethanol on behavioral development. METHODS: Pregnant Sprague-Dawley rats were intubated with 6 g/kg/day ethanol in a binge-like manner from gestational days 5-20; pair-fed and ad libitum chow controls were included. During treatment, subjects from each group were intubated with either 250 mg/kg/day choline chloride or vehicle. Spontaneous alternation, parallel bar motor coordination, Morris water maze, and spatial working memory were assessed in male and female offspring. RESULTS: Subjects prenatally exposed to alcohol exhibited delayed development of spontaneous alternation behavior and deficits on the working memory version of the Morris water maze during adulthood, effects that were mitigated with prenatal choline supplementation. Neither alcohol nor choline influenced performance on the motor coordination task. CONCLUSIONS: These data indicate that choline supplementation during prenatal alcohol exposure may reduce the severity of fetal alcohol effects, particularly on alterations in tasks that require behavioral flexibility. These findings have important implications for children of women who drink alcohol during pregnancy. PMID- 20706997 TI - Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders. AB - To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. PMID- 20706998 TI - Genetic and pathologic aspects of retinoic acid-induced limb malformations in the mouse. AB - Because all-trans retinoic acid (atRA) is teratogenic in all species tested and many of the specific defects induced are common across the phylogenetic spectrum, it would be logical to predict that murine strain differences in teratology to this agent are minimal. However, for specific defects, strain susceptibilities are vastly different. Studies with atRA have shown stark differences between C57BL/6 and SWV mouse strains in susceptibility to postaxial forelimb ectrodactyly and ectopic hindlimb formation, with the C57 strain being more susceptible for both defects. Various approaches were used to determine why these strains differ in susceptibility, but the mechanisms remain unknown. Hindlimb duplications were hypothesized to be caused by the formation of ectopic posterior body axes. For forelimb ectrodactyly, a locus on chromosome 11, Rafar, has linkage to the strain difference, and mRNA localization has shown that specific genes (Fgf8, Dlx3, Bmp4, and Sp8) in the postaxial preAER (prior to formation of the apical ectodermal ridge) of the developing limb bud (the site of the defect) were downregulated hours after atRA administration more in the susceptible C57 than in the SWV strain. Because both atRA and divalent cadmium induce postaxial forelimb ectrodactyly (right-sided predominance) at a high rate in C57BL/6 and low in the SWV strain, there is debate as to whether they share a common mechanism. These teratogens cause a greater-than-additive level of forelimb ectrodactyly when coadministered at low doses, but cadmium does not induce ectopic hindlimb formation. The hypothesis is that these agents have separate molecular pathologic pathways that converge to perturb a common anatomic structure. PMID- 20706999 TI - Cytoskeletal scaffolding proteins interact with Lynch-Syndrome associated mismatch repair protein MLH1. AB - The involvement of MLH1 in several mismatch repair-independent cellular processes has been reported. In an attempt to gain further insight into the protein's cellular functions, we screened for novel interacting partners of MLH1 utilizing a bacterial two-hybrid system. Numerous unknown interacting proteins were identified, suggesting novel biological roles of MLH1. The network of MLH1 and its partner proteins involves a multitude of cellular processes. Integration of our data with the "General Repository for Interaction Datasets" highlighted that MLH1 exhibits relationships to three interacting pairs of proteins involved in cytoskeletal and filament organization: Thymosin beta 4 and Actin gamma, Cathepsin B and Annexin A2 as well as Spectrin alpha and Desmin. Coimmunoprecipitation and colocalization experiments validated the interaction of MLH1 with these proteins. Differential mRNA levels of many of the identified proteins, detected by microarray analysis comparing MLH1-deficient and proficient cell lines, support the assumed interplay of MLH1 and the identified candidate proteins. By siRNA knock down of MLH1, we demonstrated the functional impact of MLH1-Actin interaction on filament organization and propose that dysregulation of MLH1 plays an essential role in cytoskeleton dynamics. Our data suggest novel roles of MLH1 in cellular organization and colorectal cancerogenesis. PMID- 20707000 TI - A proteomics approach to study synergistic and antagonistic interactions of the fungal-bacterial consortium Fusarium oxysporum wild-type MSA 35. AB - Fusarium oxysporum is an important plant pathogen that causes severe damage of many economically important crop species. Various microorganisms have been shown to inhibit this soil-borne plant pathogen, including non-pathogenic F. oxysporum strains. In this study, F. oxysporum wild-type (WT) MSA 35, a biocontrol multispecies consortium that consists of a fungus and numerous rhizobacteria mainly belonging to gamma-proteobacteria, was analyzed by two complementary metaproteomic approaches (2-DE combined with MALDI-Tof/Tof MS and 1-D PAGE combined with LC-ESI-MS/MS) to identify fungal or bacterial factors potentially involved in antagonistic or synergistic interactions between the consortium members. Moreover, the proteome profiles of F. oxysporum WT MSA 35 and its cured counter-part CU MSA 35 (WT treated with antibiotics) were compared with unravel the bacterial impact on consortium functioning. Our study presents the first proteome mapping of an antagonistic F. oxysporum strain and proposes candidate proteins that might play an important role for the biocontrol activity and the close interrelationship between the fungus and its bacterial partners. PMID- 20706996 TI - Understanding diabetic teratogenesis: where are we now and where are we going? AB - Maternal pregestational diabetes (type 1 or type 2) poses an increased risk for a broad spectrum of birth defects. To our knowledge, this problem first came to the attention of the Teratology Society at the 14th Annual Meeting in Vancouver, B.C. in 1974, with a presentation by Lewis Holmes, "Etiologic heterogeneity of neural tube defects". Although advances in the control of diabetes in the decades since the discovery of insulin in the 1920's have reduced the risk for birth defects during diabetic pregnancy, the increasing incidence of diabetes among women of childbearing years indicates that this cause of birth defects is a growing public health concern. Major advances in understanding how a disease of maternal fuel metabolism can interfere with embryogenesis of multiple organ systems have been made in recent years. In this review, we trace the history of the study of diabetic teratogenesis and discuss a model in which tissue-specific developmental control genes are regulated at specific times in embryonic development by glucose metabolism. The major function of such genes is to suppress apoptosis, perhaps to preserve proliferative capability, and inhibit premature senescence. PMID- 20707001 TI - Protein Information and Knowledge Extractor: Discovering biological information from proteomics data. AB - One of the main goals in proteomics is to solve biological and molecular questions regarding a set of identified proteins. In order to achieve this goal, one has to extract and collect the existing biological data from public repositories for every protein and afterward, analyze and organize the collected data. Due to the complexity of this task and the huge amount of data available, it is not possible to gather this information by hand, making it necessary to find automatic methods of data collection. Within a proteomic context, we have developed Protein Information and Knowledge Extractor (PIKE) which solves this problem by automatically accessing several public information systems and databases across the Internet. PIKE bioinformatics tool starts with a set of identified proteins, listed as the most common protein databases accession codes, and retrieves all relevant and updated information from the most relevant databases. Once the search is complete, PIKE summarizes the information for every single protein using several file formats that share and exchange the information with other software tools. It is our opinion that PIKE represents a great step forward for information procurement and drastically reduces manual database validation for large proteomic studies. It is available at http://proteo.cnb.csic.es/pike. PMID- 20707002 TI - A proteomic approach towards the identification of the matrix protein content of the two types of microbodies in Neurospora crassa. AB - Microbodies (peroxisomes) comprise a class of organelles with a similar biogenesis but remarkable biochemical heterogeneity. Here, we purified the two distinct microbody family members of filamentous fungi, glyoxysomes and Woronin bodies, from Neurospora crassa and analyzed their protein content by HPLC/ESI MS/MS. In the purified Woronin bodies, we unambiguously identified only hexagonal 1 (HEX1), suggesting that the matrix is probably exclusively filled with the HEX1 hexagonal crystal. The proteomic analysis of highly purified glyoxysomes allowed the identification of 191 proteins. Among them were 16 proteins with a peroxisomal targeting signal type 1 (PTS1) and three with a PTS2. The collection also contained the previously described N. crassa glyoxysomal matrix proteins FOX2 and ICL1 that lack a typical PTS. Three PTS1 proteins were identified that likely represent the long sought glyoxysomal acyl-CoA dehydrogenases of filamentous fungi. Two of them were demonstrated by subcellular localization studies to be indeed glyoxysomal. Furthermore, two PTS proteins were identified that are suggested to be involved in the detoxification of nitroalkanes. Since the glyoxysomal localization was experimentally demonstrated for one of these enzymes, a new biochemical reaction is expected to be associated with microbody function. PMID- 20707003 TI - A well-characterised peak identification list of MALDI MS profile peaks for human blood serum. AB - MALDI MS profiling, using easily available body fluids such as blood serum, has attracted considerable interest for its potential in clinical applications. Despite the numerous reports on MALDI MS profiling of human serum, there is only scarce information on the identity of the species making up these profiles, particularly in the mass range of larger peptides. Here, we provide a list of more than 90 entries of MALDI MS profile peak identities up to 10 kDa obtained from human blood serum. Various modifications such as phosphorylation were detected among the peptide identifications. The overlap with the few other MALDI MS peak lists published so far was found to be limited and hence our list significantly extends the number of identified peaks commonly found in MALDI MS profiling of human blood serum. PMID- 20707005 TI - Illuminating the molecular basis of diabetic arteriopathy: a proteomic comparison of aortic tissue from diabetic and healthy rats. AB - Arterial disease is a major diabetic complication, yet the component molecular mechanisms of diabetic arteriopathy remain poorly understood. In order to identify major proteins/pathways implicated in diabetic arteriopathy, we studied the effect of 16-wk untreated streptozotocin-induced diabetes on the rat aortic proteome. Specific protein levels in isolated aortas were compared in six discrete, pair-wise (streptozotocin-diabetic and non-diabetic age-matched controls) experiments in which individual proteins were identified and quantified by iTRAQ combined with LC-MS/MS. A total of 398 unique non-redundant proteins were identified in at least one experiment and 208 were detected in three or more. Between-group comparisons revealed significant changes or trends towards changes in relative abundance of 51 proteins (25 increased, 26 decreased). Differences in levels of selected proteins were supported by Western blotting and/or enzyme assays. The most prominent diabetes-associated changes were in groups of proteins linked to oxidative stress responses and the structure/function of myofibrils and microfilaments. Indexes of mitochondrial content were measurably lower in aortic tissue from diabetic animals. Functional cluster analysis also showed decreased levels of glycolytic enzymes and mitochondrial electron transport system-complex components. These findings newly implicate several proteins/functional pathways in the pathogenesis of arteriosclerosis/diabetic arteriopathy. PMID- 20707004 TI - Upregulation of plasma C9 protein in gastric cancer patients. AB - Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Current biomarkers used in the clinic do not have sufficient sensitivity for gastric cancer detection. To discover new and better biomarkers, protein profiling on plasma samples from 25 normal, 15 early-stage and 21 late-stage cancer was performed using an iTRAQ-LC-MS/MS approach. The level of C9 protein was found to be significantly higher in gastric cancer compared with normal subjects. Immunoblotting data revealed a congruent trend with iTRAQ results. The discriminatory power of C9 between normal and cancer states was not due to inter patient variations and was independent from gastritis and Helicobacter pylori status of the patients. C9 overexpression could also be detected in a panel of gastric cancer cell lines and their conditioned media compared with normal cells, implying that higher C9 levels in plasma of cancer patients could be attributed to the presence of gastric tumor. A subsequent blind test study on a total of 119 plasma samples showed that the sensitivity of C9 could be as high as 90% at a specificity of 74%. Hence, C9 is a potentially useful biomarker for gastric cancer detection. PMID- 20707006 TI - Modern proteomic methodologies for the characterization of lactosylation protein targets in milk. AB - Heat treatment of milk induces the Maillard reaction between lactose and proteins; in this context, beta-lactoglobulin and alpha-lactalbumin adducts have been used as markers to monitor milk quality. Since some milk proteins have been reported as essential for the delivery of microelements and, being resistant against proteolysis in the gastrointestinal tract, also contributing to the acquired immune response against pathogens and the stimulation of cellular proliferation, it is crucial to systematically determine the milk subproteome affected by the Maillard reaction for a careful evaluation of aliment functional properties. This is more important when milk is the unique nutritional source, as in infant diet. To this purpose, a combination of proteomic procedures based on analyte capture by combinatorial peptide ligand libraries, selective trapping of lactosylated peptides by m-aminophenylboronic acid-agarose chromatography and collision-induced dissociation and electron transfer dissociation MS was used for systematic identification of the lactosylated proteins in milk samples subjected to different thermal treatments. An exhaustive modification of proteins was observed in milk powdered preparations for infant nutrition. Globally, this approach allowed the identification of 271 non-redundant modification sites in 33 milk proteins, which also included low-abundance components involved in nutrient delivery, defence response against virus/microorganisms and cellular proliferative events. A comparison of the modified peptide identification percentages resulting from electron transfer dissociation or collision-induced dissociation fragmentation spectra confirmed the first activation mode as most advantageous for the analysis of lactosylated proteins. Nutritional, biological and toxicological consequences of these findings are discussed on the basis of the recent literature on this subject, emphasizing their impact on newborn diet. PMID- 20707007 TI - Editor's introduction: the impact of the Violence Against Women Act. PMID- 20707008 TI - A simple method for the evaluation of microfluidic architecture using flow quantitation via a multiplexed fluidic resistance measurement. AB - Quality control of microdevices adds significant costs, in time and money, to any fabrication process. A simple, rapid quantitative method for the post-fabrication characterization of microchannel architecture using the measurement of flow with volumes relevant to microfluidics is presented. By measuring the mass of a dye solution passed through the device, it circumvents traditional gravimetric and interface-tracking methods that suffer from variable evaporation rates and the increased error associated with smaller volumes. The multiplexed fluidic resistance (MFR) measurement method measures flow via stable visible-wavelength dyes, a standard spectrophotometer and common laboratory glassware. Individual dyes are used as molecular markers of flow for individual channels, and in channel architectures where multiple channels terminate at a common reservoir, spectral deconvolution reveals the individual flow contributions. On-chip, this method was found to maintain accurate flow measurement at lower flow rates than the gravimetric approach. Multiple dyes are shown to allow for independent measurement of multiple flows on the same device simultaneously. We demonstrate that this technique is applicable for measuring the fluidic resistance, which is dependent on channel dimensions, in four fluidically connected channels simultaneously, ultimately determining that one chip was partially collapsed and, therefore, unusable for its intended purpose. This method is thus shown to be widely useful in troubleshooting microfluidic flow characteristics. PMID- 20707009 TI - Community acquired pneumonia. PMID- 20707010 TI - Fluid assets and liabilities. PMID- 20707011 TI - Understanding the 'Swiss watch' function of Switzerland's health system. [Interview by Tsung-Mei Cheng]. PMID- 20707012 TI - Obtaining accurate hemodynamics from echocardiography: achieving independence from right heart catheterization. AB - PURPOSE OF REVIEW: Accurate noninvasive evaluation of right heart hemodynamics is an essential component of the comprehensive cardiac examination. We aim to highlight recent advances in echocardiography allowing integration of measurements to obtain diagnostic accuracy. RECENT FINDINGS: Reports have advocated different imaging methods to describe right ventricular function and pulmonary artery pressure. Recent review articles provide comprehensive resources for the physician or technologist, and other articles compare echocardiography techniques, including strain imaging and three-dimensional echocardiography. We discuss the descriptions of the accuracy of Doppler echocardiography in comparison with cardiac catheterization. SUMMARY: Several measurements should be taken together for an accurate interpretation of right heart hemodynamics. We advocate the measurement of the tricuspid regurgitation gradient, pulmonary regurgitation gradient, pulmonary artery stroke distance (velocity time integral; VTI), evaluation of right ventricular function, and right atrial pressure. PMID- 20707013 TI - Poultry veterinarians' perspectives on antimicrobial resistance. PMID- 20707014 TI - Bridging the gap between education and the needs of the profession. PMID- 20707015 TI - Expectations and rewards of veterinary practice. PMID- 20707016 TI - FDA seeks comments on draft antimicrobial use guide, feed directive process. Document addresses judicious use, antimicrobial resistance. PMID- 20707017 TI - [The ideal city: utopias and projects: a historical sketch]. PMID- 20707018 TI - Play up, but don't play the game: English amateur athletic elitism, 1863-1910. PMID- 20707019 TI - Questions of consent: women's recruitment for Assam tea gardens, 1859-1900. PMID- 20707020 TI - "A sufficiency of clothing": dress and domesticity in Victorian Britain. PMID- 20707021 TI - U.S. dental school applicants and enrollees, 2008 entering class. PMID- 20707022 TI - Heat-sensitive lysis mutants of Bacillus subtilis 168 blocked at three different stages of peptidoglycan synthesis. AB - Three heat-sensitive mutants of Bacillus subtilis 168, which lysed at the non permissive temperature, have been shown under these conditions to be defective in the synthesis of peptidoglycan. This was caused by lesions in three different stages of peptidoglycan synthesis.In one mutant (ddl), D-alanine: D-alanine ligase was defective, leading to the accumulation of UDP-MurAc-L-Ala-D-Glu-meso A,pm ; the ddl mutation was closely linked(87 yo cotransducible) with dal, specifying alanine racemase. In a second mutant (dapE),the lesion was in N-acetyl L-diaminopimelate deacylase, resulting in UDP-MurAc-L-Ala-D-Glu being accumulated, whilst in a third mutant (ptg-1435), UDP-MurAc-L-Ala-D-Glumeso-A,pm D-Ala-D-Ala was the peptidoglycan precursor accumulated although the enzyme defect has not been ascertained. Both dapE and ptg-1435 were located between metC and pyr(AD), dapE being 25% cotransducible and ptg-1435 were located between metC and pyr(AD), dapE being 25% cotransducible with pyr(AD). PMID- 20707023 TI - "The burial-place of the fashions": the representation of the dress of the poor in illustrated serial prose by Dickens and Hardy. PMID- 20707025 TI - "Murillo-like rags or clean pinafores": artistic and social preferences in the representation of the dress of the rural poor. PMID- 20707024 TI - Welsh peasant dress - workwear or national costume? PMID- 20707026 TI - Educating boys to be queer: Braddon's Lady Audley's secret. PMID- 20707027 TI - Quaker dress, sexuality, and the domestication of reform in the Victorian novel. PMID- 20707029 TI - Elegant Amazons: Victorian riding habits and the fashionable horsewoman. PMID- 20707030 TI - Widowhood-related mortality in Scania, Sweden during the 19th century. PMID- 20707031 TI - Allogeneic somatic cell therapy: process development challenges and future opportunities. AB - Cell-replacement therapy has emerged during the past decade as a potential solution for many diseases. However, for this promise to be fulfilled, numerous process development challenges specific to these products need to be overcome. This editorial overview highlights some key observations derived from research on an allogeneic somatic cell therapy product for the treatment of Parkinson's disease. PMID- 20707032 TI - [Lin Zexu's ideas on and practice of famine relief]. PMID- 20707033 TI - Gene transfer and cell-based therapies. PMID- 20707034 TI - [The reasons behind the rise of cotton production in the Lake Tai area from the Song dynasty]. PMID- 20707035 TI - From horses to humans: species crossovers in the origin of modern sports training. PMID- 20707037 TI - Incest, cousin marriage, and the origin of the human sciences in nineteenth century England. PMID- 20707038 TI - Those horrible iron cages: the Sisters of the Church and the care of orphans in late Victorian England. PMID- 20707039 TI - Widows and their living arrangements in preindustrial France. PMID- 20707041 TI - Iran and cholera in the nineteenth century. PMID- 20707042 TI - Report from the 2009 Inter-American Conference on Onchocerciasis: progress towards eliminating river blindness in the Region of the Americas. PMID- 20707044 TI - Monthly report on dracunculiasis cases, January-June 2010. PMID- 20707043 TI - Who was who? Race and Jews in turn-of-the-century Britain. PMID- 20707045 TI - [Varicella complications: is it time to consider a routine varicella vaccination?]. AB - BACKGROUND/AIM: Varicella is a common and benign disease of childhood. Complications are rare, but in some patients, even without risk factors, severe, life treathening complications could be seen. The aim of this study was to establish the type and frequency of varicella complications among hospitalised patients over an 8-year period. METHODS: This retrospective analysis included medical charts of the patients hospitalised in the Infectious Disease Clinic, Belgrade, Serbia, from 2001-2008 (4.85% of all registered patients with varicella in Belgrade, 2001-2008). Among hospitalised patients dermografic characteristics were analysed: hospitalisation lenght, presence and type of complications, presence of immunocompromising conditions and outcome of the disease. The diagnosis of varicella was made on clinical grounds, and in persons >40 years, with negative epidemiological data of contacts, serological confirmation (ELISA VZV IgM/IgG BioRad) and avidity of IgG antibodies were done to exclude the possibility of disseminated herpes zoster. RESULTS: A total of 474 patient were hospitalised over an 8-year period. The age of patients was from 5 months to 75 years (mean 22.4 +/- 16.1, median 23.5 years). The majority of patients were adults (n=279; 58.9%) and 195 (41.1%) patients were < or =15 years old. Complications were found in 321/474 (67.7%) patients. The registered complications were: varicella pneumonia (n=198; 41.38%), bacterial skin infections (n=40; 8.4%), cerebelitis (n=28; 5.9%), bacterial respiratory infection (n=21; 4.4%), viral meningitis (n=10; 2.31%), encephalitis (n=9; 1.9%), thrombocytopenia (n=2; 0.4%); 11 (2.3%) patients had more than one complication, among them were sepsis, myopericarditis and retinal hemorrhages. When complications were analysed according to the age, there were no statistical significance, but when type of complication was analysed statistical significance was found (p < 0.05). In adults, pneumonia was the most common complication: 173/279 (62%), followed by skin infections (2.9%), bacterial respiratory infections (2.2%), and more than one complication (2.3%). Pneumonia was more common in adults than in children (7:1). In children skin infections were the most common complications (16.4%), followed by cerebelitis (13.3%), viral pneumonia (12.8%), bacterial respiratory infections (7.7%), encephalitis (3.6%), and more than one complication (4.1%). Neuroinfections were more common in children than in adults (6:1), as well as bacterial skin infections (4:1). Two patients died (0.4%). CONCLUSION: There was no difference in the incidence of varicella complication in children and adults, but the type of complication differed. In children the most common complications were skin and neurological infections, while in adults it was varicella pneumonia. These data provide a baseline for estimating the burden of varicella in Belgrade and support the inclusion of varicella vaccine in childhood immunisation program in Serbia. PMID- 20707046 TI - [Psychiatric syndromes associated with atypical chest pain]. AB - BACKGROUND/AIM: Chest pain often indicates coronary disease, but in 25% of patients there is no evidence of ischemic heart disease using standard diagnostic tests. Beside that, cardiologic examinations are repeated several times for months. If other medical causes could not be found, there is a possibility that chest pain is a symptom of psychiatric disorder. The aim of this study was to determine the presence of psychiatric syndromes, increased somatization, anxiety, stress life events exposure and characteristic of chest pain expression in persons with atypical chest pain and coronary patients, as well as to define predictive parameters for atypical chest pain. METHOD: We compared 30 patients with atypical chest pain (E group) to 30 coronary patients (K group), after cardiological and psychiatric evaluation. We have applied: Mini International Neuropsychiatric Interiview (MINI), The Symptom Checklist 90-R (SCL-90 R), Beck Anxiety Invetory (BAI), Holms-Rahe Scale of stress life events (H-R), Questionnaire for pain expression Pain-O-Meter (POM). Significant differences between groups and predictive value of the parameters for atypical chest pain were determined. RESULTS: The E group participants compared to the group K were younger (33.4 +/- 5.4: 48.3 +/- 6,4 years, p < 0.001), had a moderate anxiety level (20.4 +/- 11.9: 9.6 +/- 3.8, p < 0.001), panic and somatiform disorders were present in the half of the E group, as well as eleveted somatization score (SOM > or = 63-50%: 10%, p < 0.01) and a higher H-R score level (102.0 +/- 52.2: 46.5 +/- 55.0, p < 0.001). Pain was mild, accompanied with panic. The half of the E group subjects had somatoform and panic disorders. CONCLUSION: Somatoform and panic disorders are associated with atypical chest pain. Pain expression is mild, accompained with panic. Predictive factors for atypical chest pain are: age under 40, anxiety level >20, somatization > or =63, presence of panic and somatoform disorders, H-R score >102, and a lack of positive diagnostic test of coronary disease. Defining of these parameters could be useful for early psychiatric evaluation of persons with atypical chest pain. PMID- 20707047 TI - Serum Fas/FasL levels in dependence on clinical presentations of coronary disease and their relationship with risk factors. AB - BACKGROUND/AIM: Ischemic heart disease is mostly a consequence of atherosclerosis. Besides the inflammation, the Fas/Fas ligand (FasL)/caspase death pathway is documented to be activated in atherosclerotic lesions. The aim of this study was to compare the values of soluble forms of Fas and FasL in patients with different presentations of coronary disease and to correlate Fas/FasL with risk factors. METHODS: We studied 30 patients with chronic stable angina pectoris (SAP), 27 with non-stable angina pectoris (NSAP), and 39 with acute ST-elevation myocardial infarction (STEMI) and 27 age-matched healthy volunteers (the control group). Serum Fas/APO1 and FasL concentrations were determined using a commercially available enzyme-linked immunoassays (ELISA). RESULTS: Fas/APO-1 levels in the STEMI patients (6.981 +/- 2.689 ng/mL) were significantly higher than Fas levels in the controls (5.092 +/- 1.252 ng/mL, p < 0.01), but not significantly higher than Fas values in the SAP (5.952 +/- 2.069 ng/mL) and the USAP patients (5.627 +/- 2.270 ng/ml). Levels of FasL did not show any significant difference among the studied groups. In the SAP patients Fas/APO1 showed a significant positive correlation with high sensitivity C-reactive protein (hsCRP) (p < 0.05) and a negative correlation with high-density lipoprotein cholesterol (HDL-C) (p < 0.05), while FasL showed a significant positive correlation with low-density lipoprotein cholesterol (LDL-C) (p < 0.05). Fas levels between the patients having cholesterol within normal range and those whose cholesterol was above the normal range showed a significant difference (p < 0.05) only in the NSAP patients. Fas and FasL levels between the patients with hsCRP lower than 3.0 mg/L and those with hsCRP higher than 3.0 mg/L of the SAP group showed a significant differences (p < 0.001, p < 0.05, respectively). Strong correlation between Fas concentration and diabetes mellitus (p < 0.05) and FasL concentrations and both cholesterol (p < 0.01) and triglycerides (p < 0.01) in the NSAP patients was observed. The patients in the SAP group showed no strong correlation between Fas and FasL concentration and risk factors. CONCLUSIONS: The obtained results showed that apoptotic process is dysregulated in the patients with ischemic heart disease. Interdependence between Fas and FasL and inflammatory and lipid markers as well as with cardiovascular risk factors was established. PMID- 20707048 TI - [Importance of D-dimer testing in ambulatory detection of atypical and "silent" phlebothrombosis]. AB - BACKGROUND/AIM: Deep venous thrombosis (DVT) is a life-threatening condition, which could be manifested with discrete symptoms (silent DVT). High mortality and disability of patients with DVT indicate the importance of early diagnosis, especially of "silent" DVT. The aim of this paper was to evaluate of reliability of early detection model for diagnosing DVT in ambulatory patients by using clinical probability of DVT presence, D-dimmer test (DD) and ultrasound evaluation (US). METHODS: Ambulatory patients with suspected DVT were classified as "unlikely" and "likely" DVT by the Wells clinical model. The patients were randomly divided into the control and DD group. In the control group (629 patients) only US examination of lower limbs deep vein was done. All patients in the DD group (643 patients), with "unlikely" TDV, had DD, and in the positive patients US examination was done. In the "likely" patients US examination was done and negative US finding indicated DD test. Positive DD test was an indication for US examination after 7 days. The patients with initially excluded DVT were evaluated during 3 months. RESULTS: A total number of 1 272 patients were examined; 117 (9.19%) patients were with DVT--62 (9.640%) in the DD and 55 (8.74%) in the control group. During the follow-up periods in the DD group (with 582 initially excluded DVT) we registered DVT in only one patient (0.17%). It was significantly lower (p < 0.05) compared to the control group where we registered 7 (1.10%) DVT (a group with 581 initially excluded DVT). The applied DD diagnostic strategy for 70.7% (p < 0.001) reduced the need for US examination. CONCLUSION: The applied DD strategy in the diagnostic of DVT reduces the need for US examinations and reduces frequency of false negative results, with direct impact on cost and efficacy of procedures. DD diagnostic model should replace serial US examination in patients with suspect DVT. PMID- 20707049 TI - [Soldiers suicides risk factors in the Serbian Army Forces]. AB - BACKGROUND/AIM: Analyses of suicide risk factors enable to undertake appropriate preventive measures within the Suicide Prevention Program in Military Environment, which was fully applied in 2003 in the Serbian Army Forces. The aim of our study was to identify the most important suicide risk factors in soldiers within the period from 1998 to 2007. METHODS: Analysis of suicide risk factors was carried out on the basis of data obtained by psychological suicide autopsy. The control group was matched with adapted soldiers by socio-demographic factors. A descriptive statistical analysis was used. Comparison of groups of soldiers was done by the t-test and Pearson's chi2-test. RESULTS: A total of 35 soldiers aged 22-49 years (21.76 +/- 1.76 years on average) committed suicide within the period 1999-2007, the 2/3 within, and 1/3 out of a military compound. More than one half soldiers committed suicide after transferring to a different post. Soldiers who committed suicide had come from uncompleted, dysfunctional families (p < 0.05). In comparison with the adapted soldiers, in premilitary period they had more interpersonal problems with their comrades (p < 0.001) and problems with law (p < 0.05). During military service, alcohol consumption was less presented; they used to have fewer separation problems (p < 0.05) and to be rarely awarded (p < 0.001) in comparison with the adapted soldiers. A soldier who committed suicide was emotionally and socially immature persons. The commonest motives for suicide were: decreased capacity of adaptation to military service, actual psychic disturbance, emotional interruption, fear of environment judgment, actual family problems, but in the one fifth, motive stayed unrecognized. CONCLUSION: Suicide risk factors in soldiers are primary in their immature personality organization, its relation with family and military environment factors which, in coexistence with actual life accidents, result in suicide as a consequence. A suicide prevention program in Serbian Army Forces should be designed to prevent multiple suicide risk factors. PMID- 20707050 TI - [Post-voiding residual urine and capacity increase in orthotopic urinary diversion--standard vs. modified technique]. AB - BACKGROUND/AIM: Ever since the time when the first orthotopic urinary diversion (pouch) was performed there has been a constant improvement and modification of surgical techniques. The aim has been to create a urinary reservoir similar to normal bladder, to decrease incidence of postoperative complications and provide an improved life quality. The aim of this study was to compare post-voiding residual urine (PVR) and capacity of the pouch constructed by standard or modified technique. METHODS: In this prospective and partially retrospective clinical study we included 79 patients. In the group of 41 patients (group ST) pouch was constructed using 50-70 cm of the ileum (standard technique). In the group of 38 patients (group MT) pouch was constructed using 25-35 cm of the ileum (modified technique). Postoperatively, PVR and pouch capacity were measured using ultrasound in a 3-, 6- and 12-month period. RESULTS: Postoperatively, an increase in PVR and pouch capacity was noticed in both groups. Twelve months postoperatively, PVR was significantly smaller in the group MT than in the group ST [23 (0-90) mL vs. 109 (0-570) mL, p < 0.001]. In the same period the pouch capacity was significantly smaller in the MT group than in the ST group [460 (290 710) mL vs. 892 (480-2 050) mL, p < 0.001]. CONCLUSION: Postoperatively, an increase in PVR and pouch capacity was noticed during a 12-month period. A year following the operation the pouch created from a shorter ileal segment reached capacity of the "normal" bladder with small PVR. The pouch created by standard technique developed an unnecessary large PVR and capacity. PMID- 20707051 TI - [Chronic low-grade inflammation, lipid risk factors and mortality in functionally dependent elderly]. AB - BACKGROUND/AIM: It has been proved that a highly sensitive C-reactive protein (hsCRP) can be used as an established marker of chronic inflammation for cardiovascular risk assessment. Since mean values of both low-density cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) decrease during aging, the knowledge that increased hsCRP concentration predicts mortality (Mt) would influence therapy and treatment outcome. The aim of this study was to examine importance of chronic low grade inflammation and its association with lipid risk factors for all-cause Mt in functionally dependent elderly. METHODS: The participants of this longitudinal prospective study were 257 functionally dependent elderly aged 65-99 years. Baseline measurements: anthropometric measurements, blood pressure, fasting plasma total cholesterol (TC), triglyceride (TG), HDL-C, LDL-C, non-HDL-C, hemoglobin Alc (HbA1c) were recorded and different lipid ratios were calculated. Inflammation was assessed by the levels of white blood cells, fibrinogen and hsCRP. The participants with hsCRP grater than 10 mg/L were excluded from the study. The residual participants (77.4% women) were divided into three groups according to their hsCRP levels: a low (< 1 mg/L, n=70), average (1 to 3 mg/L, n=69), and high (3-10 mg/L, n=69) hsCRP group. Associations of all-cause Mt with different risk factors were examined using logistic regression analysis. RESULTS: The hsCRP level showed a significant positive correlation with waist (r = 0.199, p = 0.004) and hip (r = 0.187, p = 0.007) circumferences, body mass index (r = 0.143, p = 0.040) and serum triglyceride level (r = 0.139, p = 0.045) and significant negative correlation with HDL-C (r = -0.164, p = 0.018). Ratios TC/HDL-C and TG/HDL-C were significantly smaller in the low hsCRP group compared to the average hsCRP group (p = 0.019,p = 0.045, respectively) and without significant differences compared with the high hsCRP group. Two years after the baseline examination 22.1% participants died from all-cause Mt. After adjustment for other risk factors, a TC was significantly associated with all-cause Mt only in high hsCRP group: Odds ratio (OR) = 3.71 (95% confidence interval-CI: 1.09-12.63). CONCLUSIONS: In this study a high hsCRP was an important factor to identify functionally dependent elderly at high risk who may have more benefit from agressive lipid lowering treatment. PMID- 20707052 TI - [Exogenous luteinizing hormone for assisted reproduction techniques in poor response patients]. AB - BACKGROUND/AIM: Two gonadotrophins, two cell theory refers to necessity of both gonadotrophin activities for theca and granulose cells steroidogenesis of dominant follicle. The aim of this study was to determine the influence of recombinant LH in women qualified as poor responders in the first assisted reproduction procedure (IVF), on fertility results, expressed as percentage of clinical pregnancies. METHOD: The study included 12 women, 35 years and older who were their own controls. The next trial of IVF was with the same dose of recombinant FSH and GnRH agonist, and with the same, long protocol. Recombinant LH was added in the dose of 75 IU from the 2nd to 7th day of the cycle, and 150 IU from the 8th day of the cycle to the aspiration of oocytes. RESULTS: Within the two different protocols: there was no significant difference between LH concentration in 8th and 12th day of cycle; there was no significant difference between E2 concentration on day 2nd and day 8th; there was a significant difference between E2 concentrations on day 12th; endometrial thickness was not significantly different on the day of aspiration, neither was the number of follicles and embryos. In the two patients, clinical pregnancy was detected (pregnancy rate 17%), and they delivered in term. So, a statistically significant difference between the two protocols was in the rate of clinical pregnancies. CONCLUSION: The patients with low response to a long protocol in IVF procedures had significantly better results according to the clinical pregnancy rate when the recombinant LH was added to recombinant FSH in the stimulation protocol. PMID- 20707053 TI - Oxidative stress, hemoglobin content, superoxide dismutase and catalase activity influenced by sulphur baths and mud packs in patients with osteoarthritis. AB - BACKGROUND/AIM: It is weel-known that sulphur baths and mud paks demonstrate beneficial effects on patients suffering from degenerative knee and hip osteoarthritis (OA) through the increased activity of protective antioxidant enzymes. The aim of this study was to assess lipid peroxidation level, i.e., malondialdehyde concetration, in individuals with knee and/or hip osteoarthritis (OA), as well as to determine the influence of sulphur baths and mud packs application on the activity of superoxide dismutase (SOD) and catalase (CAT) in order to minimize or eliminate excessive free radical species production (oxidative stress). METHODS: Thirty one patiens with knee and/or hip OA of both sexes were included in the study. All OA patients received mud pack and sulphur bath for 20 minutes a day, for 6 consecutive days a week, over 3 weeks. Blood lipid peroxidation, i.e., malondialdehyde concentration, superoxide dismutase and catalase activity were measured spectrophotometrically, before, on day 5 during the treatment and at the end of spa cure. Healthy volunteers (n=31) were the controls. RESULTS: The sulphur baths and mud packs treatment of OA patients caused a significant decrease in plasma malondialdehyde concentration compared to the controls (p < 0.001). The mean SOD activity before the terapy was 1836.24 U/gHb, on day 5 it rose to 1942.15 U/gHb and after the spa cure dropped to 1745.98 U/gHb. Catalase activity before the therapy was 20.56 kU/gHb and at the end of the terapy decreased to 16.16 kU/gHb. The difference in catalase activity before and after the therapy was significant (p < 0.001), and also significant as compared to control (p < 0.001). At the end of the treatment significant increase of hemoglobin level and significant decrease of pain intensity were noticed. CONCLUSION: A combined 3-week treatment by sulphur bath and mud packs led to a significant decrease of lipid peroxidation in plasma, as well as pain intensity in the patients with OA. These changes were associated with changes in plasma activity of SOD and CAT and a significant increase of hemoglobin level suggesting their role in beneficial effect of spa therapy in the patients with OA. PMID- 20707054 TI - Sexual rehabilitation after myocardial infarction and coronary bypass surgery: why do we not perform our job? AB - BACKGROUND/AIM: There is a perception that in patients with heart diseases in Serbia sexual rehabilitation does not exist. Why do we not perform our job? A kind of resistance to sexual rehabilitation is common for heart disease patients. Prejudices regarding patients' sexuality, fear and limited knowledge are not rare among the members of medical staff. The aim of this study was to assess knowledge on sexual rehabilitation, inner sense during conversation on sexual rehabilitation and quality of sexual life in patients with myocardial infarction (MI) and bypass surgery (BPS). Also, we wanted to assess an opinion of the medical staff members about that. METHODS: We performed a prospective nonrandomized clinical study, which involved 40 participants: ten patients, six partners and twenty four medical staff members. All participants were tested by the self-created questionnaires. The main issues of observation were: knowledge about sexual rehabilitation, quality of sexual life and inner sense during conversation on sexual rehabilitation. The data were analyzed by the Shapiro-Wilk test, Kolmogorov Smirnov test, Mann Whitney Exact test and Fishers Exact test. Statistical significance was set up to p < 0.05. RESULTS: There was a statistically significant difference among the participants regarding an attitude when sexual activity should be resumed after MI or BPS. The members of medical staff had a significantly different opinion about the most important team members responsible for sexual rehabilitation performance. There was a statistically significant difference (p = 0.01) in quality of patient's sexual life after MI or BPS (score: 14.2 +/- 5.5) in relation to conditions before them (score: 21.3 +/- 3.1). The members of medical staff had significantly (P = 0.05) worse inner sense (score: 3.8 +/- 0.7) during and after fulfilling the questionnaires than the patients (score: 4.6 +/- 0.5). CONCLUSION: Ignorance and prejudices are reasons why we do not perform our job. PMID- 20707055 TI - The effects of arterial hypertension on aortic valve stenosis. PMID- 20707056 TI - Reconstruction of the penile skin loss due to "radical" circumcision with a full thickness skin graft. AB - BACKGROUND: Excessive resection of penile skin is a rare but important complication of circumcision. Penis "trapping" under the skin and consequent sexual dysfunction occur as a result. CASE REPORT: Excessive circumcision with complete resection of the penile skin is shown. Penis, trapped under the skin, was deliberated and skin defect was substituted with the full thickness skin graft. One year after the surgery penis has a good cosmetic appearance, adequate size and sexual function. CONCLUSION: Full thickness skin graft is a good option for augmentation of the penile skin loss in cases with intact hypodermal tissue and extensive skin loss, for the reconstruction in a single act. PMID- 20707057 TI - [Rare extracranial localizations of the head and neck schwannomas]. AB - INTRODUCTION: Schwannomas are tumors of neurogenic origin, that arise from Schwann cells which surround peripheral, cranial and autonomic nerves. Schwannomas account for only 5% of all benign soft tissue tumors, and 25-45% of extracranial schwannomas are present in the head and neck region. They are usually classified according to the nerve of origin and the site within the head and neck. CASE REPORT: We presented extremely rare extracranial localizations of schwannomas and discussed about diagnosis and management of these tumors. CONCLUSION: Schwannomas are slow-growing tumors and late symptoms appearance may cause a delay in diagnosis and treatment of patients with these tumors. An appropriate diagnostic protocol is indispensable tool in performing a differential diagnosis of malignant from benign lesions. Choice of surgical approach depends on schwannomas localization. PMID- 20707058 TI - [Effects of heavy metal on Astragalus membranaceus seeds germination and physiological target]. AB - OBJECTIVE: To study the effects of heavy metals on germination and antioxidant systems of the seeds of Astragalus membranaceus. METHOD: The seeds were treated with three different heavy metals (Cu, Pb, Cd) and the germination rate, germination energy, germination index, seedling root length, seedling fresh weight, soluble protein, antioxidant enzyme systems, electrical conductivity were detected and analyzed. RESULT: The results indicated that all of the three kinds of heavy metals had a significant effect on the seed germination index at different levels of concentrations except germinating ability. Different kinds of heavy metals could also enhance the vitality of POD and CAT, increase the electrical conductivity and the concentration of soluble protein. CONCLUSION: It can be concluded that heavy metals have a significant effect on the growth and antioxidant system of the seed. PMID- 20707059 TI - [Residuals of organochlorine pesticides and heavy metals in Radix Ophiopogonis and Ophiopogon japonicus growing soil]. AB - OBJECTIVE: To determine the residues of organochlorine pesticides and heavy metals in Radix Ophiopogonis and Ophiopogon japonicus. METHOD: The residues of 4 isomers of benzene hexa chloride (BHC) and 4 isomers of dichloro dipheny trichloroethane (DDT) were determined by gas chromatography. The contents of Pb, Cd, Cu, Cr, Hg and As were determined by ICP. RESULT: The residues of organochlorine pesticides in Radix Ophiopogonis were lower than the permissible maximum limits of the Chinese national standard except hexachloride (BHC) in Radix Ophiopogonis from Cixi as well as Cu in soil of Luojiang. CONCLUSION: The enrichment capacity of Radix Ophiopogonis for (BHC) and Hg is higher. It is suggested that we should try to select herbs-growing soil for O. japonicus with a particular emphasis on the pesticides residues in soil. PMID- 20707060 TI - [Variations of flavanoid contents in vine tips among different varieties, parts and time of topping of sweetpotato for vegetable-use]. AB - OBJECTIVE: To study the variations of flavonoids contents in vine tips of sweetpotato (Ipomoea batatas) among different varieties, parts and the time of topping. METHOD: The flavonoid contents in leaf, petiole and stem of vine tips at 6 different topping time of 3 varieties for vegetable-use Pushu 53, Guangcaishu No. 2 and Fushu 7-6, which were collected from Chongqing were determined by UV spectrophotometry with rutin as a standard substance. RESULT: The results showed that the flavonoid content of Guangcaishu No. 2 was higher than that of Pusu 53, so was that of Pusu 53 than that of Fushu 7-6. The average flavonoid contents in leaf of 3 varieties were between 3.66 mg x L(-1) and 11.09 mg x L(-1) during 6 topping time, and those in petiole, stem were between 2.20-5.26 mg x L(-1) and 4.03-7.79 mg x L(-1), respectively. The rations of average flavonoid contents in leaf, petiole and stem to the total contents of vine tips among 3 varieties during their whole topping periods were 46.71%, 20.65% and 32.63%, respectively. The contents during earlier topping time were higher than those of later periods. The variance analysis of flavonoid contents revealed that there was significant difference between different varieties, parts and time of topping and significant interactions among varieties, parts and time of topping. CONCLUSION: The results of the study indicate that the contents of flavonoid should be considered for the breeding, cultivation and industrialization of sweetpotato for vegetable-use. PMID- 20707061 TI - [Effects of Pinellia ternata extracts on inhibiting of oviposition and ovicidal action against Plutella xylostella]. AB - OBJECTIVE: To study the bioactivities of the extracts from Pinellia ternata against Plutella xylostella. METHOD: The active material in P. ternata was Soxhlet extracted with petroleum ether, ethyl acetate, ethanol successively. The bioactivities of the extracts were determined. RESULT: Results indicated that all extracts using three solvents showed inhibition of oviposition and ovicidal action activities, but the activity of ethanol extract was the strongest. The higher concentration, the more obviously the effect on the pest was. 24 h after treatment with 100 g x L(-1) ethanol extract in no-choice tests and choice tests, the deterrent rates were 85.13%, 73.38%, respectively. Furthermore, treatment with 100 g x L(-1) ethanol extract after 5 d could effectively reduced the percentage of eggs incubation, ovicidal rate could reach 62.40%. CONCLUSION: These results suggest that extracts of P. ternata could be used to control pest. PMID- 20707062 TI - [Ecological environment of cultivated Astragali radix and market specification of prepared slices]. AB - Astragali Radix is derived from roots of Astragalus membranaceus var. mongholicus and A. membranaceus. The exhaustion of wild Astragali Radix has made cultivated Astragali Radix possess the commercial market of Astragali Radix. So the ecological environment of cultivated Astragali Radix should be investigated through field survey. Through investigation, we found that A. membranaceus var. mongholicus are cultivated in Hengshan mountain of Shanxi province, Longnan of Gansu province, south of Inner Mongolia and Qinghai provinces. A. membranaceus var. mongholicus is almost planted on the plain, except in Shanxi province it grows on the sunny side of the mountain. What is more, soil type, elevation, annual temperature and annual rainfall of these locations are different. So the ecological environments of cultivated location of Astragali Radix are different from each other. A. membranaceus is wild in Heilongjiang and northeast of Inner Mongolia, but the resource is drying up. It is also planted in few places of the provinces of Shanxi, Shandong, Hebei, Gansu, but cultivated scope of A. membranaceus is smaller than A. membranaceus var. mongholicus.. So A. membranaceus var. mongholicus possesses large part of Astragali Radix market. In market, there exists no unified specification fro slices of Astragali Radix, and specification of prepared slices will influence the contents of chemical components. Through investigation, different kind of prepared slices can be collected and compared, this provides evidences for quality control of prepared slices. Through investigation, five different specifications of prepared slices were found in market. The distributions of some specification of prepared slices are specified, like transverseprepared slices prepared from A. membranaceus only found in Heilongjiang province. Transverse prepared slices possess half part of prepared slice market, and can be used to identify original plant of Astragali Radix. So transverse prepared slices should be the unified specification of Astragali Radix. PMID- 20707063 TI - [Self-microemulsifying drug delivery system increasing solubility and intestinal absorption in situ of tanshinones]. AB - OBJECTIVE: Study the effect of self-microemulsifying drug delivery system(SMEDDS) on the solubility and absorption of tanshinones to guide the selection of composition of tanshinone SMEDDS. METHOD: The solubility of tanshinones in the solution of SMEDDS was determined by UV-spectrometer and the absorption of tanshinone SMEDDS was determined by HPLC as the detection method. RESULT: The solubility of tanshinones in solution of SMEDDS was 10 times in water and 2.5 times in micelle solution. The solubility of tanshinones in solution of SMEDDS was increased with the increasing of oil (MCT) in composition of tanshinone SMEDDS. The absorption constants (Ka) in SMEDDS and micelle solution was 0.479 h( 1) and 0.326 h(-1) respectively, and the absorption half life (t1/2) was 1.44 h and 2.12 h respectively. The absorption was increased with the oil increasing in composition of tanshinone SMEDDS. CONCLUSION: SMEDDS can increase the solubility and absorption of tanshinones significantly and the increasing of oil content (MCT) in SMEDDS composition promote the dissolution and absorption of tanshinones. PMID- 20707064 TI - [Preparation technology of effective fraction of Catharsius molossus based on determination of effective composition and characterization of physico-chemical property]. AB - OBJECTIVE: To optimize the preparation technology of effective fraction of Catharsius molossus, and investigate the feasibility of process control by the physical and chemical characterization of extracts. METHOD: Used single-factor test method, choosed the main effective components of peptides and amino acids as indexes, combined with theology, chemistry, electricity, and other characterization, the study researched the prepared technology of effective fraction of C. molossus including extraction, concentration, separation, purification, drying and so on. RESULT: The optimal preparation technology of effective fraction of C. molossus was that soaked an amount of crude drugs with three times of 85% ethanol for 48 h, added 10 times of 85% ethanol, percolated in 4 mL x min(-1) x kg(-1), collected percolation liquid, concentrated to 1:1 at 50 55 degrees C, removed fat by frozen, adopted DA201-C macroporous resin, used 1 BV of water and 4 BV of 70% ethanol as eluting agent, collected eluant respectively. The water part was concentrated and dried, then washed twice with 85% ethanol, collected washing liquid and mixed with 70% ethanol eluant. The product was obtained by concentrating and dring. At the same time, the liquid-phase system of each link was characterized in preparation of effective fraction of C. molossus, which showed that the surface tension related to polypeptide was essentially unchanged, and the conductivity related to salt decreased by about 90% with ineffective substances closely related to salt The results showed that the preparation technology maximumly retained the effective information, and removed the invalid information. CONCLUSION: The preparation technology of effective fraction of C. molossus is stable and reliable, and the process control in physico-chemical characterization of extracts is feasible. PMID- 20707065 TI - [Extraction of ginkgolides from Ginkgo biloba]. AB - OBJECTIVE: To establish the technology for extraction of ginkgolides from Ginkgo Biloba with alcohol-water. METHOD: The parameters such as alcohol concentration, pH of extracting solution, ratio of dosage liquor, temperature and time, the extraction of ginkgolides from G. biloba was investigated, and its parameters were optimized. RESULT: The optimized parameters were alcohol concentration 30%, extracting temperature 50 degrees C, extracting time 2 h, pH 5 solid-liquid ratio 1:15. CONCLUSION: This method has the merits of low cost and simple operation. PMID- 20707066 TI - [Optimization of extraction process for compund kaliziran gel with orthogonal design]. AB - OBJECTIVE: To optimize the extraction process of compund kaliziran gel. METHOD: Orthogonal design was used to optimize the extracting process of eight herb medicines with the extract yield, the content of psoralen, isopsoralen and osthole as indexes, and to optimize the extracting process of Polygonum multflorumi and Seman sinapis albae with the extract yield and the content of 2,3,5,4'-tetrehydroxy-stilbene glucoside as indexes. RESULT: The optimum extraction progress was as follows:eight herb medicines were extract 2 times for 1 hour with 8 times of 60% alcohol; P. multflorumi and S. sinapis albae were extract 2 times for 1 hour with 8 times of 40% alcohol. CONCLUSION: The optimum extraction processes are stable and feasible. PMID- 20707067 TI - [O-methylnotopterol, a new natural product from the roots and rhizomes of Notopterygium incisum]. AB - OBJECTIVE: To study the chemical constituents of ethyl acetate-soluble fraction from methanolic extract of the roots and rhizomes of Notopterygium incisum . METHOD: The chemical constituents were isolated and purified by various chromatographic methods, and their structures were identified by NMR and MS data analysis. RESULT: Five compounds were obtained and identified as falcarindiol (1), 8-hydroxy-l-methoxy-( Z) -9-heptadecene-4, 6-diyn-3-one (2) angenomalin (3), scopoletin (4), O-methylnotopterol (5). CONCLUSION: Compound 5 was a new natural product and compounds 2-4 were isolated from the roots and rhizomes of N. incisum for the first time. PMID- 20707068 TI - [Ethyl acetate-soluble chemical constituents from whole plants of Senecio chrysanthemoides]. AB - OBJECTIVE: To investigate the chemical constituents from the whole plants of Senecio chrysanthemoides. METHOD: The chemical constituents were isolated and purified by chromatographic techniques over silica gel, Sephadex LH-20, preparative TLC and preparative HPLC. Structures of the compounds were identified by NMR and MS spectroscopic methods. RESULT: Twenty five compounds were obtained and their structures were elucidated as seneciphyline (1), senecionine (2) , 1,2 dihydrocacalohastine (3) , eu-desm-4( 15)-ene-1beta,6alpha-diol (4), 7,11,15 trimethyl- 3methylidenehexadecane-1,2-diol (5), faradiol 3-O-palmitate (6),maniladiol 3-O-palmitate (7), faradiol (8), maniladiol (9), beta-amyrin (10), alpha-amyrin (11), betulin (12), loranthol (13), (+)-syringaresinol (14) , 1 hydroxy-4-oxo-cyclohexane-1-acetate (15), 2, 6-dimethoxy-p-benzoquinone (16), stigmasta-5, 22-dien-3beta-hydroxy-7-one (17) , stigmasta-5, 22-dien-7-one (18) , stigmasta-4-en-3-one (19), stigmasta-4,22-dien-3-one (20), beta-sitosterol (21), stigmasterol (22), daucosterol (23), glycerol 1-hendecanoate (24), and methyl hendecanoate (25). CONCLUSION: Compounds 5-9,13, 17-20 and 24 were obtained from the genus Senecio for the first time. PMID- 20707069 TI - [Flavonoids and phenolic acid derivatives from flos farfarae]. AB - OBJECTIVE: To investigate the chemical constituents of the flower buds of Tussilago farfara. METHOD: The chemical constituents were isolated by silica gel and Sephadex LH-20 column chromatography, and structurally elucidated by spectral evidence together with physiochemical properties. RESULT: Seven flavonoids, quercetin (1), quercetin-3-O-beta-D-glucopyranoside (2), quercetin-4'-O-beta-D glucopyranoside (3), hyperoside (4), rutin (5), kaempferol (6), kaempferol-3-O alpha-L-rhamnopyranosyl-(1-6)-beta-D-glucopyranoside (7), together with eight phenolic acid derivatives, caffeic acid (8), methyl caffeate (9), ethyl caffeate (10), (E)-2,5-dihydroxycinnamic acid (11), 3,4-di-O-caffeoylquinic acid (12), 4,5 di-O-caffeoylquinic acid (13), methyl4,5-di-O-caffeoylquinate (14) and chlorogenic acid (15) were isolated from the flower buds of Tussilago farfara. CONCLUSION: Compounds 7, 9-14 are isolated from this plant, also from this genus, for the first time. PMID- 20707070 TI - [Chemical constituents from Excoecaria acerifclia and their bioactivites]. AB - OBJECTIVE: To investigate the chemical constituents of Excoecaria acerifclia and their antitumor activities. METHOD: The constituents were isolated and purified by column chromatography. Their structures were identified by their physicochemical properties and spectral features. Cytotoxicities of the purified compounds were evaluated by MTI method against human cancer cell lines HepG2. RESULT: Eight compounds were isolated and identified as: 7-hydroxy-6-methoxy coumarin (1), 8-hydroxy-6,7-methoxy-coumarin (2), kaempferol (3), kaempferol-3-O beta-D-glucoside (4), quercetin-3-O-beta-D galactoside (5), kaempferol-3-O-beta-D glucoside-2"-gallate (6), beta-sitosterol (7), daucosterol (8). CONCLUSION: All compounds were isolated from this plant for the first time. Compounds 5 showed inhibitory activity towards HepG2 with IC50 values of 7.13 mol x L(-1). PMID- 20707071 TI - [Determination of indirubin in serum by HPLC and its application to pharmacokinetics in rats]. AB - OBJECTIVE: To improve the method of indirubin in serum by HPLC and apply to pharmacokinetics in rats. METHOD: Chromatographic separation was conducted on an C18 column (4.6 mm x 250 mm, 5 microm), using a mixture of methanol-water (75:25) as mobile phase at a flow rate of 1.0 mL min(-1) with UV detection at 289 nm, the column temperature was at 35 degrees C and ethinyl estradiol was used as an internal standard. Rats were administered i. v. bolus of indirubin in doses of 2.0 and 4.0 mg x kg(-1) through a jugular vein catheter, respectively. Serial blood samples (about 100 microL) were individually collected at 2, 5, 10, 20, 30, 60, 90, 120, 180 min after administration, and the concentrations of indirubin determined were in rat serum by HPLC. The pharmacokinetic parameters were calculated with the Winnonlin 5.0 software. RESULT: The calibration curve for indirubin was linear ( R2 = 0.9996) in the range of 0.031-2.48 mg x L(-1) and the limit of detection (LOD) was 31 microg x L(-1). The average recovery of indirubin in rat serum was more than 98% and the relative standard deviations of intra-day and inter-day were both less than 10%. The pharmacokinetics of Indirubin in rats was fitted to two-compartment model. CONCLUSION: The method is simple and accurate with a high sensitivity and a good repeatability, and it can be applied to the evaluation of pharmacokinetic parameters of indirubin in rats and blood concentration of indirubin in clinical controlling. PMID- 20707072 TI - [Comparisons of crystal form of raphides to toxicity raphides in four poisonous herbs of Araceae family]. AB - OBJECTIVE: To compare the crystal form with the toxicity intensitity of raphides in four poisonous herbs of Araceae family. METHOD: The four kinds of raphides were extracted and isolated from Pinellia ternate, P. pedatisecta, Arisaema amurense and Typhonium giganteum. These raphides were observed with scanning electron microscopy (SEM), and the elements were analyzed with X-ray photoelectron spectroscopy. Infrared spectrum was used for detecting the functional groups. Toxic intensities of the four kinds of raphides were detected by mice acute toxicity experiment, and the value of LD0 were from caculated by Bliss rule. RESULT: The raphides in the four plants have the similar crystal form. Observation with SEM showed a pointed and blunt end, and a long groove and barbs on a raphide. The raphides in P. ternate and P. pedatisecta were sharper than that in other two, respectively. The results of X-ray diffraction, photoelectric spectra showed that the major component of raphides was calcium oxalate monohydrate, and also showed the elements of N and S existing. Infrared spectra showed the raphides contained functional groups of -COOH and -NH2. These results illustrated that the calcium oxalate monohydrate was not the only component of the raphide. The raphides could produce severe toxic reactions. LD50 values of P. ternate, P. pedatisecta, A. amurense and T. giganteum were 14.78, 14.11, 16.02 and 18.90 mg x kg(-1) (ip), respectively. The corresponding LD50 values of crude drugs were all above 3000 mg x kg(-1) (ip). The toxicity of raphides was 200 times of crude drugs'. CONCLUSION: The raphides in P. ternate and P. pedatisecta, A. amurense and T. giganteum were their common poisonous factor. PMID- 20707073 TI - [Alpha-glucosidase inhibitors from leaves of Forsythia suspense in Henan province]. AB - OBJECTIVE: The alpha-glucosidase inhibitory compounds were searched from Forsythia suspense. METHOD: The active compounds were isolated by the method of bioassay-guided in vitro and column chromatographic techniques. The structures of compounds were identified by MS and NMR spectroscopy. The inhibitory kinetics of the isolated compounds were investigated. RESULT: The ethyl acetate extract showed the strongest inhibitory activity, and five active compounds were isolated from this extract. The IC50 value of compound 1-5 were all lower than that of acarbose as positive control. Compound 1, the mixture of 1, 2 and 4 all showed noncompetitive type model on alpha-glucosidase. CONCLUSION: Compound 1-3 as the inhibitors of alpha-glucosidase were reported for the first time. Compound 3 was isolated from the genus for the first time. PMID- 20707074 TI - [Determination of chlorogenic acid, caffeic acid and linarin in Flos Chrysanthemi Indici from different places by RP-hPLC]. AB - OBJECTIVE: To evaluate the quality of Flos Chrysanthemi Indici which produced in twenty-two different producing places. METHOD: Chlorogenic acid and caffeic acid were analyzed on a Shim-pack C8 colunm (4.6 mm x 250 mm, 5 microm) eluted with the mobile phase consisted of acetonitrile-0.5% phosphoric acid( 19:81). The detection wavelength was set at 326 nm. Linarin were eluted with the mobile phase consisted of methanol-water-acetic acid(26: 23: 1). The detection wavelength was set at 334 nm. The column temperature was 25 degrees C. The flow rate was 1.0 mL x min . RESULT: The linear response ranged within 2.5-50 microg for chlorogenic acid (r = 0.998), 2.5-25 microg for caffeic acid (r = 0.998) and 4.97-41.47 microg for linarin (r = 0.999), respectively. Recoveries were 100.8% with RSD 2.1% for chlorogenic acid, 96.2% with RSD 2.3% for caffeic acid and 103.7% with RSD 1.8% for linarin. CONCLUSION: There was a significant difference in the content of chlorogenic acid, caffeic acid, linarin among the samples. The content of chlorogenic in the sample from Fengdou Chongqing city was the highest in those from other places. The content of caffeic acid in the all samples is very low. The content of linarin in the samples from Jiangsu province and Anhui province almost reached the national standard in pharmacopoeia. PMID- 20707075 TI - [Effects of Wuji pill compound with different compatibility on cytochrome P450 CYP3A1/3A2 in rat liver microsomes in vitro]. AB - OBJECTIVE: Wuji pill is a prescription of traditional Chinese medicine(TCM) and was composed of Rhizoma Coptidis, Fructus Evodiae Rutaecarpae and Radix Paeoniae Alba. The aim of this research is to investigate the effects of Wuji pill compound with different compatibility on the levels of enzymic activity of cytochrome P450 CYP3A1/3A2 in rat liver microsomes in vitro, and to confirm the compatibility mechanism of Wuji pill from the point of relationships between compound prescription of TCM and metabolism. METHOD: With testosterone being a probe, the levels of enzymic activity of CYP3A1/3A2 were detected by HPLC, which were suppressed by Wuji pill with different compatibility in vitro. RESULT: The IC50 of Rhizoma Coptidis, Fructus Evodiae Rutaecarpae, Radix Paeoniae Alba and 1" 9" of different level Wuji pill is: 38.96, 871.96, 15 519.17, 43.17, 60. 47, 276.12, 133.40, 118.08, 88. 47, 64. 36, 35. 13 and 39. 91 mg x L -', respectively. Rhizoma Coptidis and 1-9" of Wuji pill can suppress the enzymic activity of CYP3A1/3A2 significantly, and the capability of Rhizoma Coptidis in Wuji pill of action on CYP3A1/3A2 can be modified by different composition of Fructus Evodiae Rutaecarpae and Radix Paeoniae in Wuji pill, and there are statistical differences among the IC50 of 1#-9# of Wuji pill. While the ratio of Rhizoma Coptidis raises up in Wuji pill, Wuji pill may suppress the enzymic activity of CYP1A2 largely. CONCLUSION: The reason why Wuji pill with different compatibility has different pharmacodynamics and pharmacokinetics characteristics is likely to lie in the difference of the capability of Wuji pill with different compatibility on CYP3A1/3A2. [Key words] Wuji pill; CYP3A1/3A2; testosterone; HPLC; different compatibility prescription of traditional Chinese medi-cine PMID- 20707076 TI - [Effect of oxysophoridine on electric activities and its power spectrum of reticular formation in rats]. AB - OBJECTIVE: To observe the effect of oxysophoridine (OSR) on the EEG and its power spectrum of reticulum formation in mesencephalon of anaesthetized rat. METHOD: Utilizing the technique of brain stereotactic apparatus, electrodes were implanted into reticulum formation of mesencephalon. Monopolar lead and computerized FFT technique were employed to record and analyse the index of EEG, power spectrum and frequency distribution in order to study the effect of oxysophoridine on the bioelectricity change of mesencephalon reticulum formation in rats. RESULT: After administrating(icy) with oxysophoridine at the dose of 2.5,5, 10 mg/rat, the EEG of mesencephalon reticulum formation mainly characterized with low amplitude and slow waves accompanied by spindle-formed sleeping waves with a significant decrease of total power of EEG (P < 0.05) while the ratio of theta, alpha waves increased in total frequency of rats (P < 0.05). CONCLUSION: Oxysophoridine possesses central inhibitory effects and its inhibitory mechanism may associate with the reduction of bioelectricity in mesencephalon reticulum formation. Mesencephalon reticulum formation may serve as one part of the structure serving as the circuit conducting the central inhibitory effect of oxysophoridine. [Key words] oxysophoridine; reticulum formation; electroencephalogram (EEG) ; rats PMID- 20707077 TI - [Antitumor effects and the mechanism of two kinds of bromophenols from marine algae]. AB - OBJECTIVE: To investigate the antitumor effects of two kinds of bromophenols isolated from marine algae Rhodomela confervoides on three tumor cells of Hela, MGC and BGC-823 and their antitumor mechanism in vitro. METHOD: MTT method was employed to assay the inhibitory effects of marine bromphenols with various concentrations. Flow cytometry (FCM) was used to study the cell cycle and aneuploid induction. RESULT: Both of two bromophenols showed cytotoxic activities on the tested tumor cells. Hela cells were proved to be the most sensitive to the marine bromophenols. Although they couldn't cause apoptosis of the tumor cells, the aneuploid and cell cycle inhibition were detected. For Hela and MGC cells, hypoploid was observed under low drug concentrations, while G1 phase block was caused by higher drug concentrations. For BGC-823 cells, G1 phase inhibition was observed for different drug concentrations, and the inhibitiory effect showed dose-dependent. CONCLUSION: Marine bromophenol can inhibit the proliferation of three tumor cells, and the mechanism was probably aneuploid induction and cell cycle inhibition. PMID- 20707078 TI - [Effects of total alkaloid of Sophora alopecuroides on serum IL-1beta and IL-4 expression in mice with acute ulcerative colitis]. AB - OBJECTIVE: To investigate the effects of total alkaloid of Sophora alopecuroides (TASA) on expression of serum IL-1beta and IL-4 in mice with DSS-induced acute ulcerative colitis. METHOD: C57BL/C mice were randomly divided into six groups: normal group, model group, SASP group, low, middle and high dosage TASA group. Acute ulcerative colitis was induced by administrating 5% dextran sulfate sodium (DSS) solution as drinking water freely for 8 days. Mice were given drug by stomach at the same time and sacrificed after 8 days. The general morphological and histopathological changes were observed during the experiments. Daily disease activity index (DAI) was assessed. The serum levels of IL-1beta and IL-4 were detected by ELISA. RESULT: In UC mice, the expression of serum IL-1beta was significantly increased whereas IL-4 was decreased when compared with the normal group (P < 0.01). In all treatment groups, TASA could reduce the expression of IL 1beta (P < 0. 01) , increase the level of IL-4 and alleviate the symptom of UC and decrease the DAI. CONCLUSION: TASA can effectively attenuate DSS-induced acute ulcerative colitis through the decreasing the over-expression of pro inflammatory cytokine levels. PMID- 20707079 TI - [Study on sensitization and mechanism of CGA-BSA]. AB - OBJECTIVE: To investigate the sensitization and mechanism of artificial antigen of chlorogenic acid (CGA-BSA). METHOD: Using intensive immunization to establish allergy animal model on guinea pig and preparing antiserum and tissue for further test. Using HE staining to observe pathology change of lungs, trachea, liver. Using passive mast cell (PMC) degranulation test to observe the immunogenicity of CGA-BSA and using ELISA to detect IgE and histamine in plasma. RESULT: There established allergy animal model on guinea pig, which include a increase cell degranulation by a ratio (63.58 +/- 10.23)% in PMC test, increase of specific antibody IgE and increase of histamine in plasma after provocation by ELISA. CONCLUSION: Allergen CGA-BSA could provoke allergenic response in guinea pig, and the allergic response belongs to type I allergy. PMID- 20707080 TI - [Effects of Coptis chinensis and Evodia rutaecarpa water extract on DMH-induced precancerous lesion of colon]. AB - OBJECTIVE: To investigate the effects of Coptis chinensis and Evodia rutaecarpa water extract on precancerous lesion of colon induced by DMH and proliferation and apoptosis changes of colon mucosa crypts. METHOD: Precancerous lesion of colon was induced by DMH. The changes of proliferation and apoptosis of colon mucosa crypts were detected by morphological analysis. The numbers of aberrant crypt foci (ACF) were measured by feulgen staining. RESULT: C. chinensis and E. rutaecarpa water extract could significantly inhibit the formation of ACF in model animals. The proliferative crypts were increased obviously in middle and distal colon, and decreased by C. chinensis and E. rutaecarpa water extract. The apoptosis crypts were increased in distal colon but not middle colon. C. chinensis and E. rutaecarpa water extract could promote apoptosis of both middle and distal colon. CONCLUSION: C. chinensis and E. rutaecarpa water extract could significantly inhibit the formation of ACF in model animals. These results indicated that C. chinensis and E. rutaecarpa water extract maybe have an inhibitory and clinically therapeutic effect on colon cancer, which were partly resulted from inhibiting proliferation and promoting apoptosis of crypts in middle and distal colon. PMID- 20707081 TI - [Antitumor effect of phlomio1 in vivo and in vitro]. AB - To study the antitumor effect of phlomiol extracted from Phlomis younghusbandii in vivo and in vitro. The inhibitory effect of phlomiol on two kinds of human tumor cells proliferation was assayed by MTT method. Transplant tumor models of S180 and H22 were used. After transplantation, different doses of phlomiol were given to the mice for 14 days. The inhibitory rates were calculated. MTT method was used to assess the proliferation of T spleen lymphocyte cells and the activity of NK cells in tumor-bearing mice with S180. Phlomiol (50-100 mg x L( 1)) inhibited the proliferation of three kinds of tumor cells in vitro, antitumor effect of phlomiol was in a dose-dependent manner (r = 0.989, P < 0.05). The inhibitory rates of phlomiol (2.5, 5, 10 mg x kg(-1)) were 28.5%-65.0% and 35.0% 74.5% in tumor-bearing mice with S180 and H22 respectively, It could stimulate the spleen T-cells in tumor-bearing mice with S180 and increase the activity of the NK cells. Phlomiol could inhibit the proliferation of three kinds of tumor cells in vitro, present antitumor effect on the tumor-bearing mice, and improve the immunological function. PMID- 20707082 TI - [Pharmacokinetics study on paeoniflorin in radix paeoniae alba extract by LC-MS]. AB - OBJECTIVE: To develop a LC-MS method to determine paeoniflorin concentration in rats plasma. The method was applied to investigate pharmacokinetics of paeoniflorin in rats in vivo. METHOD: Blood samples were collected at different time after oral administration of Radix Paeoniae Alba extract at doses of 0.2, 0.4, 0.8 g x kg(-1). The paeoniflorin concentration in plasma was determined by LC-MS method. Pharmacokinetic parameters were fitted by WinNonlin 5.1 software package. RESULT: The linear range and the average recovery of paeoniflorin were 2.5-500 microg x L(-1) (r = 999 4) and more than 80% (n = 5) , respectively. The inner- and inter-days precision were both less than 15%. The T1/2 was similar. The relationship between dose and AUC showed good linearity. CONCLUSION: The method described in this report has high sensitivity and selectivity, and was suitable for pharmacokinetic study of paeoniflorin. The kinetic process of paeoniflorin in palsma showed two-compartment model after oral administration of Radix Paeoniae Alba extract at doses of 0.2, 0.4, 0.8 g x kg(-1) to rats. PMID- 20707083 TI - [Thinking of current situation about decreasing, abolishing and substitution of Chinese medicine species in Shanghanlun]. AB - Currently, some Chinese medicine species in Shanghan Zabing Lun have been abolished or substituted, or the use frequency has decreased. In this article, the reason of these phenomenons has been analyzed. It might be connected with the intensive toxicity of the herb, deficiency of some valuable species and indefinite pharmacodynamic action mechanism. Even more, some species usage deviate from clinical ethics. Further more, the solution of the problem resulted by above phenomena was proposed. To propose solutions from successive dynasty documents, clinical therapeutic effect verification and pharmaceutical research, the enlargement of the use frequency for some species will come true. And some abolished species will be waken up to use in clinical. Those substituted herbs will be suitable for the practice better. PMID- 20707084 TI - [Advances in studies of renal adverse reactions of Leonurus heterophyllus]. AB - Motherwort (Herb of Leonurus heterophyllus) was a traditional Chinese medicine used for the treatment of various kinds of gynaecological diseases, which was considered as non-toxic medicine since ancient times. However, adverse effects such as kidney damage, uterus damage, allergy and diarrhea were frequently reported recently. This paper reviews the possible target site, toxic dosage, chemical substance and other related factors of these kidney damage caused by motherwort from both the clinic and animal experiment view. PMID- 20707085 TI - [Dynamic characteristics of forest landscape in Chengdu City in last 20 years]. AB - Based on the remote sensing data of Landsat TM (1985, 1995, and 2000) and CBERS (2006), and by using landscape pattern method and index model of regional land use change in combining with eco-function regionalization, this paper analyzed the dynamic characteristics of forest landscape in Chengdu City in 1985-2006. In the study period, over 17,000 hm2 of forest land lost, and the number and area of small- and medium-size patches changed significantly, indicating the apparent conversion and fragmentation of forest land. Forest land was mainly distributed in mountainous area, accounting for 70% of the total. In contrast, more number of patches was found in plain region, amounting to 70% of the total. The most rapid change of forest land area occurred in 1985-1995, especially in mountainous region. The relative change rate of forest land area in different eco-function regions also varied in different periods. Forest land, converted to or converted from, was mainly related to cropland and grassland. In 2000-2006, forest land was quite stable. Survival-oriented economic welfare, environmental security, and fast urbanization process were the main driving forces of the temporal dynamic change of forest landscape, whereas geographical division and socio-economic layout were the main constraints to the spatial dynamic change of forest landscape. PMID- 20707086 TI - [Long-term effects of Dendrolimus superans Bulter disturbance on forest landscape in Huzhong Forest Bureau of Great xing' an Mountains: a simulation study]. AB - A spatially explicit landscape model LANDIS was applied to simulate the long-term effects of Dendrolimus superans Bulter disturbance on the forest landscape in Huzhong Forest Bureau of Great Xing' an Mountains. The statistical software pakage APACK was used to calculate the distribution area of D. superans and representative tree species, the aggregation index reflecting the spatial pattern, and the average area of forest patchs. The dynamics of forest landscape in the study region was simulated under two scenarios, i.e., with and without D. superans disturbance for 300 years (from 1990 to 2290). In the region, the distribution area of D. superans showed a trend of increased first and decreased then. Under D. superans disturbance scenario, the distribution area and the average patch size of Larix gmelinii in 0-150 years and the aggregation index of L. gmelinii in 0-190 years, the distribution area and the average patch size of Betula platyphylla and its aggregation index in 80-190 years, as well as the distribution area, average patch size, and aggregation index of Pinus sylvestris var. mongolica were lower or slightly lower than those under no disturbance scenario. D. superans disturbance led to the fragmentation of forest landscape to some extent. PMID- 20707087 TI - [Soil respiration of degraded Korean pine forest ecosystem in Changbai Mountains]. AB - Taking the broad-leaved Korean pine forest area in Changbai Mountains, a typical eastern forest belt of Northeast China for global change as test object, and by using the approaches of trenching-plot and infrared gas exchange analyzer, this paper analyzed the soil respiration in a selected series of degraded Korean pine forest ecosystem, i.e., broad-leaved Korean pine forest (CK), poplar-birch forest (Y), hardwood forest (S), Mongolian oak forest (M), and bare land (L). In the growth season of the forests, soil respiration showed a clear single peak curve, with the maximum in July or August. The soil respiration decreased in the sequence of Y>M>CK>S>L. The amount of CO2 release in Y and M was about 0.4 and 0.3 times higher than that in CK; and that in S and L accounted for 88% and 78% of CK, respectively. PMID- 20707088 TI - [Spatiotemporal dynamics of vegetation cover based on trajectory change detection: a case study in Dapeng Peninsula of Shenzhen]. AB - By using the second-time developed ArcEngine component at pixel level, this paper studied the spatiotemporal dynamics of vegetation cover in the Dapeng Peninsula of Shenzhen, China in 1986-2007, and analyzed the characters and causes of the dynamics. To quantify this dynamics, the NDVI changes in 1986-2007 were extracted from 10 time-series TM/ETM+ remote sensing images, and the results showed that from 1986 to 2007, there were four trajectories of vegetation cover change in the Peninsula, including stable (a), stable-rising-stable (aba), stable-descending stable (aca), and stable-descending-stable-rising-stable (acaba). The area with these four types occupied 71.54% of the total. Among the four types, type "a" was most common, occupying 1/3 of the study area, mainly in the mountains; and type "acaba" was the typical one, which was closely related to the deforestation and reforestation after the human disturbances of original vegetation. The areas at higher elevation or steeper slopes exhibited smaller vegetation change, mainly because of the constrained human disturbances. Timing of the vegetation cover change showed a relative stability in the mid-90s of 20th century, but a dramatic change after 2003, coinciding with the growth of Shenzhen City. PMID- 20707089 TI - [Effect zone of forest road on plant species diversity in Great Hing 'an Mountains]. AB - Forest road has far-reaching effects on plant species diversity across varying scales, and the estimation of its effect distance and effect zone is a key issue to integrate the road effect and ecological processes in forest area. In this paper, ten transects, 2 m wide and extending 50 m from varying grade roads including main road, main line for wood transportation, and secondary line for wood transportation in Huzhong forest area of Great Hing' an Mountains were set. The plant composition was investigated in twenty-five 2 m x 2 m plots of each transect. The road-effect distance on plant species diversity identified by moving window analysis in terms of the important value of each plot. The results showed that in study area, the effect distance reached up to 20-34 m, regardless of the roads grade. The plant species diversity of shrub stratum and herb stratum within the effect zone was greater than that in adjacent habitat, with the Shannon-Weiner index increased by 21% and 60%, respectively. The response of shrub stratum to the road effect was more stable than herb stratum, but no significant change was observed in tree stratum. Chamaenerion angustifolium was the indicative species of road-effect zone communities. Based on the estimation of road-effect distance, the road area in Huzhong Forestry Bureau and Great Hing' an Mountains occupied about 0.10%, and its effect zone on vegetation occupied 1.79% and 1.53%, respectively. PMID- 20707090 TI - [Dynamic changes of landscape pattern and eco-disturbance degree in Shuangtai estuary wetland of Liaoning Province, China]. AB - The main objective of establishing natural reserve is to protect its natural resources from human disturbances and maintain its critical ecological service values. This paper introduced the concept of hemeroby, and by using remote sensing technology, systematically assessed the dynamic changes of landscape pattern and eco-disturbance degree in Shuangtai estuary wetland of Liaoning Province, China. Firstly, a knowledge-based expert system was used to classify the landscape into three first-level types based on eco-disturbance degree, i.e., undisturbed, partially disturbed, or completely disturbed, which were further classified into 30 second-level categories. Secondly, questionnaire and experts knowledge were adopted to determine the hemeroby index for each landscape type and to formulate a landscape classification system. Finally, the landscape classification maps and hemeroby indices were derived by using the Landsat Thematic Mapper (TM)/Enhanced Thematic Mapper Plus (ETM+) data acquired on 30 April 1987, 7 June 1995, 12 June 2000, and 11 October 2006. The results indicated that from 1987 to 2006, the landscape patches in the study area became more fragmented, being most obvious for reed marsh. Undisturbed landscape type decreased in area, while partially and completely disturbed types were in adverse. The overall characteristics of the spatial distribution of hemeroby index were of most variable in the areas along the river and surrounding the estuary and being the highest in the areas surrounding the city, largely due to the rapid urbanization and the blooming fishery in the study area. PMID- 20707091 TI - [Markov process of vegetation cover change in arid area of northwest China based on FVC index]. AB - Based on the fractional vegetation cover (FVC) data of 1982-2000 NOAA/AVHRR (National Oceanic and Atmospheric Administration/ the Advanced Very High Resolution Radiometer) images, the whole arid area of Northwest China was divided into three sub-areas, and then, the vegetation cover in each sub-area was classified by altitude. Furthermore, the Markov process of vegetation cover change was analyzed and tested through calculating the limit probability of any two years and the continuous and interval mean transition matrixes of vegetation cover change with 8 km x 8 km spatial resolution. By this method, the Markov process of vegetation cover change and its indicative significance were approached. The results showed that the vegetation cover change in the study area was controlled by some random processes and affected by long-term stable driving factors, and the transitional change of vegetation cover was a multiple Markov process. Therefore, only using two term image data, no matter they were successive or intervallic, Markov process could not accurately estimate the trend of vegetation cover change. As for the arid area of Northwest China, more than 10 years successive data could basically reflect all the factors affecting regional vegetation cover change, and using long term average transition matrix data could reliably simulate and predict the vegetation cover change. Vegetation cover change was a long term dynamic balance. Once the balance was broken down, it should be a long time process to establish a new balance. PMID- 20707092 TI - [Disturbance assessment of urban wetland ecosystem services: a case study in Pingshan watershed of Shenzhen City]. AB - To understand the wetland ecosystem services in urbanizing area is much needed in wetland assessment. Currently, the dominant approach in assessing wetland value is the assessment model using environmental economic analysis. However, this approach can not reflect the impact of human disturbance. This paper introduced the connotation of wetland ecosystem services and the patterns of human disturbance, established an evaluation index system which could characterize the disturbance impact, and determined the weight of each index by using analytic hierarchy process. Moreover, a dual-grade fuzzy comprehensive evaluation model was applied to analyze the spatial heterogeneity of human disturbance. Our case study in Pingshan River Basin, a typical urbanizing area of Shenzhen, showed that geographic condition was the primary factor in determining the intensity of human disturbance on wetland ecosystem services. The main disturbance pattern in the south hilly area was vegetation degeneration, but the disturbance intensity was low. Even so, the vegetation protection and management in this area shouldn't be ignored though. The disturbance pattern in north valley area was diverse, and the disturbance intensity was much higher than that south hilly area. From the upper reach to the lower reach of the main stream, the impact of human disturbance increased first and decreased then, being accorded with the characteristics of land use pattern, but the disturbance pattern didn't have a continuous distribution. Our study showed that fuzzy comprehensive evaluation model had good performance in the disturbance assessment of wetland ecosystem services. PMID- 20707093 TI - [Assessment of freshwater ecosystem services in Beijing based on demand and supply]. AB - Freshwater ecosystem provides a variety of services to humanity, and in return, human activities give strong stress on the services, particularly in urban area. It is of significance to study the impact of human occupation and stress on freshwater ecosystem. In this paper, a water equivalent method was used to calculate the human occupation on the freshwater ecosystem services in Beijing from 1998 to 2007, and assessed the human stress effect on the freshwater ecosystem, based on the total amount of water resources. In the past 10 years, the water equivalent of human activities in Beijing was about 5 to 17 times larger than the supply of the freshwater ecosystem. The water equivalent of the ecosystem services was decreased in the order of water environment purification > water resources supply > water habitat maintenance > water safety regulation. The gap between the consumption and the supply of freshwater ecosystem services had a trend of increasing to decreasing from 1998 to 2007, with the largest gap occurred in 1999. This study revealed that there was a huge gap between the consumption and the supply of freshwater ecosystem services in Beijing, which would inevitably result in the overloading occupation of the water resources in the City and give stress to the other regions. PMID- 20707094 TI - [Application of regression tree in analyzing the effects of climate factors on NDVI in loess hilly area of Shaanxi Province]. AB - Based on the 10-day SPOT VEGETATION NDVI data and the daily meteorological data from 1998 to 2007 in Yan' an City, the main meteorological variables affecting the annual and interannual variations of NDVI were determined by using regression tree. It was found that the effects of test meteorological variables on the variability of NDVI differed with seasons and time lags. Temperature and precipitation were the most important meteorological variables affecting the annual variation of NDVI, and the average highest temperature was the most important meteorological variable affecting the inter-annual variation of NDVI. Regression tree was very powerful in determining the key meteorological variables affecting NDVI variation, but could not build quantitative relations between NDVI and meteorological variables, which limited its further and wider application. PMID- 20707095 TI - [Grain effect of landscape pattern indices in a gully catchment of Loess Plateau, China]. AB - By using landscape pattern analysis based on GIS, this paper studied the grain effect of landscape pattern indices with a scale 1-50 m in a gully catchment of the Loess Plateau, China from 1975 to 2007. In the catchment, the grain effect was obvious, and differed significantly with year. The grain effect had five types, i.e., stable, stable decreasing, undulatory decreasing, amplitude accreting, and anomalistic changing. With increasing grain, the stable grain effect showed a stable patch richness density, the stable decreasing grain effect showed a decreasing trend of total edge, edge density, landscape shape index, aggregation index, and contagion index, the undulatory decreasing grain effect showed an undulatory decreasing trend of perimeter-area fractal dimension, the amplitude-accreting grain effect showed an amplitude increasing trend of total area, Shannon's diversity index, and evenness index, and the anomalistic changing grain effect showed an anomalistic change of patch number, patch density, mean patch area, largest patch index, splitting index, and landscape division index. In 1975, the grain effect of all the indices differed significantly from that in other years, and even, was in opposite. PMID- 20707096 TI - [Effects of grain size change on landscape pattern indices of Hefei City]. AB - Based on the land use map of Hefei in 2002, and by using ArcView software and Fragstats 3.3 spatial analysis program, this paper studied the change characteristics of selected 22 landscape pattern indices of Hefei under effects of different grain size, and analyzed the fitting functions and variation coefficients of partial landscape indices. The results showed that with the grain size increased from 10 to 100 m, the selected indices displayed different change trend, illustrating that the change of grain size had obvious effects on landscape indices. The effects of the grain size could be classified as 4 kinds of situation, i.e., overall rise, overall drop, less change, and no regulation change. The response curves of landscape pattern indices to grain size were fitted by quadratic function, cubic function, power function, and linear function, respectively. For the 1:50000 land use map of Hefei, the suitable range of grain size for computing and analyzing landscape indices was 15-35 m. PMID- 20707097 TI - [Responses of ecosystem service values to landscape pattern change in typical Karst area of northwest Guangxi, China]. AB - Based on 3S technique, this paper examined the responses of ecosystem service values (ESVs) to the landscape pattern change in the typical Karst area of northwest Guangxi, China in 1985, 1990, 2000 and 2005. The ESVs in the study area had close relations to landscape area, fragmentation degree, complexity of patch shape, areas of critical type, patch connectivity, and patch richness. It was linearly positively correlated with landscape area and had curvilinear positive correlations with patch index (LPI), contagion index (CONTAG), aggregative index (AI), effective mesh (MESH), proportion of like adjacencies (PLADJ), and tended to be increased with increasing patch area and patch connectivity of critical landscape type. The ESVs had curvilinear negative correlations with division index (DIVISION), split index (SPLIT), and patch richness (PRD), and decreased with increasing patch fragmentation and shrinking patch size. Therefore, it would be important to protect the critical landscape types such as woodland, shrub, and grassland, and to increase the patch size and connectivity to 'avoid further fragmentation. Moreover, it would be necessary to reduce the frequency and severity of disturbances to ensure the ESVs growth and the sustainable development of the study area. PMID- 20707098 TI - [Dynamic changes of forest landscape pattern in Lushuihe Forest Bureau of Changbai Mountains, northeast China]. AB - Based on the forest management inventories in Lushihe Forest Bureau of Changbai Mountains in 1987, 1995 and 2003, and by using ArcGIS and Fragstats spatial analysis software, this paper analyzed the relationships between landscape pattern change and forest management mechanism in the study area at landscape and patch scales. During the study period, the landscape fragmentation degree and heterogeneity in the study area increased. From 1987 to 2003, the patch number increased by 979, while the proportion of the largest patch area decreased from 28. 7% to 12.7%. With the change of management strategy, the landscape matrix changed from mixed broad-leaved forest matrix in 1987 to compound matrix in 1995. The extent of landscape fragmentation in 1995-2003 was somewhat reduced, compared with that in 1987-1995. During the study period, the mean patch area and edge density of broadleaved mixed forest decreased most, suggesting that natural secondary forest suffered most from human disturbances. PMID- 20707099 TI - [Estimation of topographical factors in revised universal soil loss model based on maximum up-stream flow path]. AB - By using maximum upstream flow path, a self-developed new method for calculating slope length value based on Arc Macro Language (AML), five groups of DEM data for different regions in Bijie Prefecture of Guizhou Province were extracted to compute the slope length and topographical factors in the Prefecture. The time cost for calculating the slope length and the values of the topographical factors were analyzed, and compared with those by iterative slope length method based on AML (ISLA) and on C++ (ISLC). The results showed that the new method was feasible to calculate the slope length and topographical factors in revised universal soil loss model, and had the same effect as iterative slope length method. Comparing with ISLA, the new method had a high computing efficiency and greatly decreased the time consumption, and could be applied to a large area to estimate the slope length and topographical factors based on AML. Comparing with ISLC, the new method had the similar computing efficiency, but its coding was easily to be written, modified, and debugged by using AML. Therefore, the new method could be more broadly used by GIS users. PMID- 20707100 TI - [Extraction of buildings three-dimensional information from high-resolution satellite imagery based on Barista software]. AB - The demand for accurate and up-to-date spatial information of urban buildings is becoming more and more important for urban planning, environmental protection, and other vocations. Today's commercial high-resolution satellite imagery offers the potential to extract the three-dimensional information of urban buildings. This paper extracted the three-dimensional information of urban buildings from QuickBird imagery, and validated the precision of the extraction based on Barista software. It was shown that the extraction of three-dimensional information of the buildings from high-resolution satellite imagery based on Barista software had the advantages of low professional level demand, powerful universality, simple operation, and high precision. One pixel level of point positioning and height determination accuracy could be achieved if the digital elevation model (DEM) and sensor orientation model had higher precision and the off-Nadir View Angle was relatively perfect. PMID- 20707101 TI - [Reform of collective forest property in Liaoning Province: a discussion]. AB - The reform of collective forest property has increased the farmers' income, and brought new development to forestry. On the basis of expatiating the conception of collective forest property and related management system, this paper introduced in detail the course, main ways, and effects of the reform in Liaoning Province, analyzed the research progress of the reform and existing problems, and made appraisement and exceptions to the reform of collective forest property in Liaoning Province, aimed to give comments to the development and orientation of forward reform. In this province, the reform of collective forest property had the characteristics of classified reform, different reform types in different areas, and the main and affiliated reform being carried out at the same time. By the end of 2009, the main task had turned into affiliated reform. In the future, the reform should be focused on the optimal forestry management model to improve the forest economic, ecological, and social benefits, and using multi disciplinary methods to strengthen the researches on the relationships between forestry management and forest ecological functions to provide scientific bases for the reform of collective forest property in Liaoning Province. PMID- 20707102 TI - [Effects of CO2 storage flux on carbon budget of forest ecosystem]. AB - Carbon dioxide (CO2) storage flux in the air space below measurement height of eddy covariance is very important to correctly evaluate net ecosystem exchange of CO2 (NEE) between forest ecosystem and atmosphere. This study analyzed the dynamic variation of CO2 storage flux and its effects on the carbon budget of a temperate broad-leaved Korean pine mixed forest at Changbai Mountains, based on the eddy covariance flux data and the vertical profile of CO2 concentration data. The CO2 storage flux in this forest ecosystem had typical diurnal variation, with the maximum variation appeared during the transition from stable atmospheric layer to unstable atmospheric layer. The CO2 storage flux calculated by the change in CO2 concentration throughout a vertical profile was not significantly different from that calculated by the change in CO2 concentration at the measurement height of eddy covariance. The NEE of this forest ecosystem was underestimated by 25% and 19% at night and at daytime, respectively, without calculating the CO2 storage flux at half-hour scale, and was underestimated by 10% and 25% at daily scale and annual scale, respectively. Without calculating the CO2 storage flux in this forest ecosystem, the parameters of Michaelis-Menten equation and Lloyd-Taylor equation were underestimated, and the ecosystem apparent quantum yield (alpha) and the ecosystem respiration rate (Rref) at the reference temperature were mostly affected. The gross primary productivity (GPP) and ecosystem respiration (Re) of this forest ecosystem were underestimated about 20% without calculating the CO2 storage flux at half-hour, daily scale, and annual scale. PMID- 20707103 TI - [Effects of precipitation intensity on soil organic carbon fractions and their distribution under subtropical forests of South China]. AB - From December 2006 to June 2008, a field experiment was conducted to study the effects of natural precipitation, doubled precipitation, and no precipitation on the soil organic carbon fractions and their distribution under a successional series of monsoon evergreen broad-leaf forest, pine and broad-leaf mixed forest, and pine forest in Dinghushan Mountain of Southern China. Different precipitation treatments had no significant effects on the total organic carbon (TOC) concentration in the same soil layer under the same forest type (P > 0.05). In treatment no precipitation, particulate organic carbon (POC) and light fraction organic carbon (LFOC) were mainly accumulated in surface soil layer (0-10 cm); but in treatments natural precipitation and doubled precipitation, the two fractions were infiltrated to deeper soil layers. Under pine forest, soil readily oxidizable organic carbon (ROC) was significantly higher in treatment no precipitation than in treatments natural precipitation and doubled precipitation (P < 0.05). The percentage of soil POC, ROC, and LFOC to soil TOC was much greater under the forests at early successional stage than at climax stage, suggesting that the forest at early successional stage might not be an ideal place for soil organic carbon storage. Precipitation intensity less affected TOC, but had greater effects on the labile components POC, ROC, and LFOC. PMID- 20707104 TI - [Macropore characteristics and its relationships with the preferential flow in broadleaved forest soils of Simian Mountains]. AB - Brilliant blue dyeing and water breakthrough curve were applied to study the number and distribution of macropores and their relations to the preferential flow in typical sub-tropic broad-leaved forest soils of Simian Mountains. The radii of the macropores were mainly between 0. 3 and 3.0 mm, with the macroporosities in the range of 6.3% to 10.5%, and the macropores were always distributed in aggregation with increasing soil depth. The number of the macropores in each radius interval of dye-stained areas was tenfold increase than that of blank areas. The number of the macropores with radius larger than 0.3 mm, especially larger than 1.5 mm, was the most important factor affecting the occurrence of preferential flow. Significant correlations were found between the number of macropores and the water steady effluent volume, with the highest correlation coefficients of 0.842 and 0.879 for the radii intervals of 0.7-1.5 mm and 1.5-3.0 mm, respectively. Macro-pore continuity in dye-stained areas was better than that in blank areas, especially in the radius interval of 1.5-3.0 mm, with the biggest difference of 78.31%. In dye-stained areas, the number of macropores decreased gradually with soil depth. The filler-like distribution of macropores formed an effective water pressure gradient, which resulted in the preferential transport of water. PMID- 20707105 TI - [Effects of different pruning modes on the light distribution characters and fruit yield and quality in densely planted 'Red Fuji' apple orchard]. AB - This paper studied the effects of different pruning modes on the light distribution at different positions of canopy and the fruit yield and quality in different layers in a densely planted 'Red Fuji' apple orchard. Comparing with no pruning, both light and heavy pruning improved the light distribution in the canopy. Under light pruning, the canopy volume with a relative light intensity less than 30% occupied 14. 6% of the total, and that with a relative light intensity more than 80% accounted for 11.2%. Under heavy pruning, the two values were 12.8% and 28.8%, respectively. The fruit yield under light pruning increased in the first year, but that under heavy pruning decreased, with the fruit quality being both improved. The mean fruit mass, firmness, and soluble solid matter content decreased in the order of light pruning > heavy pruning > no pruning, the titratable acid content was in adverse, and the anthocyanin content was in the order of heavy pruning > light pruning > no pruning. From the viewpoint of fruit yield and quality, light pruning was the best modification mode for densely planted orchards. PMID- 20707106 TI - [Impact of atmospheric total suspended particulate pollution on photosynthetic parameters of street mango trees in Xiamen City]. AB - With the development of urbanization, total suspended particulate (TSP) pollution is getting serious, and the normal physiological processes of urban vegetation are profoundly affected while adsorbing and purifying the particulates. In this study, four areas were selected, i.e., Tingxi reservoir (clean control area), Xiamen University (cultural and educational area), Xianyue (business area), and Haicang (industrial area), with their atmospheric TSP concentrations and the photosynthetic parameters of street Mango (Mangifera indica) trees monitored in April and May, 2009. The daily average concentration of TSP in Tingxi, Xiamen University, Xianyue, and Haicang was 0.061, 0.113, 0.120 and 0.205 mg x m(-3), respectively, and the impact of TSP stress on M. indica was in the sequence of Haicang > Xianyue > Xiamen University > Tingxi. TSP pollution negatively affected the net photosynthetic rate, stomatal conductance, and transpiration rate of M. indica, and induced intercellular CO2 concentration changed significantly. High TSP concentration could cause the decline of net photosynthetic rate via stomatal limitation. PMID- 20707107 TI - [Seasonal variations of wild apricot seed dispersal and hoarding by rodents in rehabilitated land]. AB - Rodents feed with and disperse plant seeds, which may thereby affect the seed spatiotemporal distribution, germination, and seedling establishment, and eventually play an important role in the restoration of deforested area. Taking the State-owned Yugong Forest Farm in Jiyuan of Henan, China as study site, the tagged seeds of wild apricot (Prunus armeniaca) were artificially released in rehabilitated land in the spring, summer, and autumn 2008, aimed to investigate their dispersal and hoarding by rodents in different seasons. It was found that Apodemus peninsulae, Niviventer confucianus, and Apodemus agrarius were the main rodent species acting on the seed dispersal and hoarding. The dispersal rate of the seeds was significantly lower in spring than in summer, and also, lower in summer than in autumn. The amount of removed seeds was affected by the interaction of season and seed status, being significantly lesser in spring than in summer, and lesser in summer than in autumn. The mean transportation distance differed with seasons, which was longer in autumn than in spring and summer. The cache size in majority caches was 1 seed, but in a few caches, each cache contained 2 or 3 seeds. The cache number was affected by the interaction of season and seed status, i.e., one seed cache was lesser in spring than in summer and autumn, while the caches containing 2 or 3 seeds were more in summer and autumn. Among the 1800 seeds released, there were five seeds hoarded in summer and autumn respectively established seedlings in the next year of the experiment. PMID- 20707108 TI - [Climatic risk zoning for banana and litchi's chilling injury in South China]. AB - Based on the 1951-2006 climatic observation data from 224 meteorological stations in South China (Guangdong Province, Guangxi Autonomous Region, and Fujian Province) and the historical information about the chilling injury losses of banana and litchi, the accumulated harmful chilling for the processes with minimum daily temperature < or = 5.0 degrees C and more than 3 days was used to indicate the climatic risk of chilling injury during the whole growth season, and an integrated climatic index with the background of climate change was constructed. The maps of geographical distribution of climatic risk probability for each grade chilling injury, and of integrated climatic risk zoning for banana and litchi's chilling injury were drawn, and the spatial variation of climatic risk for banana and litchi's chilling injury was commented. The results indicated that in the study area, climate warming might lead to the decrease of cold resistance of banana and litchi, which could increase the disaster risk of chilling injury. The geographical distribution of climatic risk probability for banana and litchi's chilling injury showed a zonal pattern. According to the integrated climatic risk index, the banana and litchi's chilling injury region was divided into three risk types, i.e., high risk, moderate risk, and low risk, which provided an important basis for the adjustment of agricultural production structure. PMID- 20707109 TI - [Critical tidal level for Kandelia candel forestation in strong tidal range area]. AB - Taking Ximen island of Yueqing bay, the biggest tidal range area among the coasts of China, as study site, an investigation was made on the survival rate, growth characteristics, and attached barnacles of 1- and 3-year-old Kandelia candel seedlings at the elevations 1.96, 1.66, 1.35, and 1.03 m above the zero tidal level of Yellow Sea. Significant differences were observed in the survival rate and growth situation of the seedlings among the elevations. There were two barnacle species, Balanus albicostatus and Balanus amphitrite amphitrite, and B. albicostatus was the major species which attached K. candel most seriously at elevation 1.35 m. The critical tidal level for K. candel in the site was 1.66 m above the zero tidal level, i.e., at least 1.29 m higher than the local mean sea level, and the flooding time per tide cycle being less than 3.65 h. Barnacle, strong tide, and extreme weather event were the main reasons for the higher critical tidal level. PMID- 20707110 TI - [Influence of soil factors on species diversity of arbuscular mycorrhizal (AM) fungi in Stipa steppe of Tibet Plateau]. AB - This study was based on the isolation and identification of arbuscular mycorrhizal (AM) fungi collected from the alpine Stipa steppe of north Tibet, and focused on the influence of soil texture, pH, organic matter, and available P on the spore density, isolation frequency, relative abundance, importance value, species diversity, and species evenness of the AM fungi. In the rhizosphere soil of the steppe, a total of 15 species AM fungi were isolated and identified, including 9 species of Glomus, 6 species of Acaulospora, and 1 species of Scutellospora. Among them, Glomus and Acaulospora were the dominant genera, and Glomus claroideum and Acaulospora laevis were the dominant species. In the soils with different texture, the spore density, isolation frequency, relative abundance, and importance value of the AM fungi all showed a trend of Glomus > Acaulospora > Scutellospora. Soil pH value had no significant effects on the species composition of AM fungi. However, the isolation frequency, relative abundance, and importance value of Glomus and Acaulospora showed an increasing trend with increasing soil pH, while Scutellospora showed the contrary trend. In the soils with different organic matter content, the spore density of AM fungi all showed a trend of Glomus > Acaulospora > Scutellospora, while the distribution of AM fungi had no definite pattern. The species richness and spore density of AM fungi were less affected by the soil available P content, but the species diversity and evenness showed an increasing trend with the increasing content of soil available P. PMID- 20707111 TI - [Sustainability of crop yields in China under long-term fertilization and different ecological conditions]. AB - By using sustainable yield index (SYI), this paper analyzed the sustainability of maize, rice, and wheat yields at 20 long-term fertilization experiment sites in China under different fertilization system and ecological conditions. The SYI value of test crops varied significantly with fertilization system, crop kind, effective accumulated temperature, and sunshine hour. Irrespective of fertilization, the SYI value of rice was generally higher than that of maize and wheat. Under long-term no fertilization, the SYI values of rice, wheat, and maize were lower, being 0.55, 0.44, and 0.43, respectively. Fertilization, especially a combined application of NPK and manure, promoted the sustainability of crop yields, with the SYI values of rice, wheat, and maize being 0.66, 0.58, and 0.57, respectively. Under the application of N and NK, the SYI values ranged in 0. 36 0. 47. SYI value > 0.55 represented the better sustainability of crop yields, while SYI < 0.45 represented a worse one. Longitude, altitude, and weather factors also affected the SYI values, especially that of maize. Under no fertilization, maize had the largest variation of SYI value, followed by wheat, and rice. Our results indicated that a combined application of chemical fertilizers with manure benefited high and stable yielding, being the optimal fertilization mode for maintaining the sustainability of grain yield. PMID- 20707112 TI - [Influence of light and temperature factors on biomass accumulation of winter wheat in field]. AB - To explore the influence of light and temperature factors on the biomass accumulation of winter wheat at its development stages and in different organs, this paper analyzed the variation patterns of the biomass accumulation and the influence of TEP (thermal effectiveness photosynthetically active radiation) on the accumulation at each development stage, based on the observation data from the Xifen Agrometeorological Experiment Station in Gansu Province, including winter wheat phenophase and yield factors in 1981-2008, biomass at three-leaf, over-wintering, jointing, heading, milky maturity, and maturity stages in 1995 2008, and meteorological data in 1995-2008. The biomass accumulation of winter wheat in its whole growth period presented "S" curve, with the maximum value at heading-milky maturity stage. Since 1981, the TEP at heading-milky maturity stage increased with a rate of 3. 314 MJ x m(-2) x a(-1), and the TEP at other stages varied as parable curves. The TEP at turning green-jointing and milky maturity maturity stages had a higher value in the 1990s and a lower value in the 1980s and early 21st century, while that at jointing-heading stage had a lower value in the 1990s but a higher value in the 1980s and early 21st century. There was a significant correlation between the TEP at each development stage and the actual yield. The LAI (leaf area index) at each development stage also had a significant correlation with the utilization rate of TEP at corresponding stage. When the LAI at jointing and heading stages was increased by 1, the utilization rate of TEP was correspondingly increased by 0.049 and 0.259 g x MJ(-1), respectively. PMID- 20707113 TI - [Effects of low nitrogen stress on source-sink characters and grain-filling traits of different genotypes summer maize]. AB - This paper studied the source-sink characters and grain-filling traits of six genotype summer maize varieties under 2 years (from 2007 to 2008) application of low dosage (105 kg x hm(-2)) and normal dosage (337.5 kg x hm(-2)) fertilizer nitrogen. Under low nitrogen stress, the population yield, leaf area index (LAI), source-sink characters, and grain-filling traits of test varieties differed significantly. The varieties tolerant to low nitrogen, e.g., Xianyu 335 and Zhengdan 958, had longer active grain-filling stage, higher maximum filling rate, longer duration of maximum LAI, and more harmonious sink-source relation; while less tolerant species, e.g., Shaandan 902 and Yuyu 22, had shorter active grain filling hours, lower maximum filling rate, lower mass increment and LAI under maximum grain-filling rate after silking, and significantly decreased source supply capacity. Low nitrogen stress increased the yield difference among the test varieties significantly. PMID- 20707114 TI - [Plant transpiration in a maize/soybean intercropping system measured with heat balance method]. AB - In an experimental field with maize/soybean strip intercropping, the transpiration of maize and soybean plants was measured with sap flow gauge based on heat balance method. In the intercropping system, the diurnal change of the sap flow rates of the plants fitted single-peak curve in sunny day and multi-peak curve in cloudy day. The plant sap flow rates were affected by many environmental factors, among which, solar radiation was the most important meteorological factor. The daily sap flow per maize or soybean plant showed significant correlations with solar radiation, air temperature, relative humidity, wind speed, and soil heat flux. During the observation period (June 1-30, 2008), the mean daily transpiration of maize plant (1.44 mm x d(-1)) was about 1.8 times of that of soybean plant (0.79 mm x d(-1)). Maize transpiration and soybean transpiration contributed 64% and 36% to the total transpiration of the intercropping system, respectively. Due to the spatial variation of stem diameter and leaf area, it would be necessary to install more sap flow gauges to accurately measure the sap flow of maize and soybean plants. PMID- 20707115 TI - [Effects of graft on lipid peroxidation and antioxidative enzyme activities of Capsicum annum seedlings under low temperature and weak light intensity]. AB - Taking 'Chifengtexuan' as scion and 'Weishi' as rootstock, this paper studied the changes in the electrolyte leakage (EL), malondialdehyde (MDA) content, antioxidative enzyme activities, and root activity of own-rooted and grafted Capsicum annuum seedlings under 1-7 days low temperature (8 degrees C/ 5 degrees C) and weak light intensity (100 micromol x m(-2) x s(-1) stress and after 1-3 d recovery. During the early stress days, the EL, MDA content, and activities of superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX) and glutathione reductase (GR) in both own-rooted and grafted seedlings leaves and roots increased, but the root activity decreased significantly. 1-3 days later, grafted seedlings showed a stable state in EL and MDA content, a decrease in SOD, POD, APX, and GR activities, and an increasing trend in root activity. After 3 days recovery, the EL, MDA content, antioxidative enzyme activities, and root activity of grafted seedlings reached or exceeded their original levels, except for the MDA content in roots, while the EL and MDA content of own-rooted seedlings were still significantly higher than those before the stress. Comparing with own-rooted seedlings, grafted seedlings showed lower EL and MDA content, higher activities of SOD, POD, APX and GR, and higher root activity during stress and recovery days. These data suggested that graft could effectively decrease the lipid peroxidation, and alleviate the damage of low temperature and weak light intensity to Capsicum annuum seedlings. PMID- 20707116 TI - [Effects of exogenous melatonin on active oxygen metabolism of cucumber seedlings under high temperature stress]. AB - Taking the seedlings of cucumber cultivar 'Jinchun 4' as test material, this paper studied the effects of foliar application of exogenous melatonin (MT) on the active oxygen metabolism of the seedlings under high temperature stress. Under the stress, the exogenous MT could significantly decrease the leaf superoxide radical (O2-*) production rate, hydrogen peroxide (H2O2) content, cell membrane permeability (electrolyte leakage), and malonaldehyde (MDA) content, but increase the activities of superoxide radical (SOD), peroxidase (POD), and catalase (CAT), and the contents of ascorbic acid (AsA), glutathione (GSH), and soluble proteins, illustrating that pretreatment with MT could inhibit the reactive oxygen species (ROS) production, raise the antioxidative enzyme activities and antioxidant contents, and decrease the membrane lipid peroxidation and electrolyte leakage to protect the integrity of lipid membranes, being able to alleviate the damage of high temperature stress to the seedlings. PMID- 20707117 TI - [Interactive effects of P deficiency and Al toxicity on soybean growth: a pot experiment with acid soil]. AB - Taking seven soybean genotypes differing in P efficiency as test materials, a pot experiment with acid soil was conducted to study the interactive effects of P deficiency and Al toxicity on the growth of the genotypes under liming and P fertilization. The results showed that P deficiency and Al toxicity were the limiting factors for the soybean growth on acid soil, and the impact of Al toxicity was more severe. There existed interactive effects between P deficiency and Al toxicity. Comparing with liming or P fertilization alone, their combination could greatly promote soybean growth. The impact of P deficiency and Al toxicity on the P uptake by soybean was far greater than that on N and K uptake. A reasonable planting system for soybean would be helpful for the amelioration of acid soil. The combined application of 1.103 g Ca(OH)2 x kg(-1) soil and 2.018 g KH2PO4 x kg(-1) soil) could increase the acid soil pH by 38.4% and the available P content by 3223.8%, and decreased the soil exchangeable Al content by 96.3%. Planting P-efficient soybean genotypes rather than P in efficient soybean genotypes had better effect in acid soil amelioration. PMID- 20707118 TI - [Responses of soil properties to ecosystem degradation in Karst region of northwest Guangxi, China]. AB - Four typical ecosystems, i.e., maize-sweet potato rotational cultivated land (KMS), grazing grassland burned annually in winter (KGB), natural restoration land (KNR), and primary forest land (KPF), in Karst region of northwest Guangxi were selected to investigate the responses of soil nutrients (C, N and P), soil microbial biomass, and soil structure to the degradation of ecosystem. The contents of soil organic C, total N and P, and soil microbial biomass C, N, and P were significantly higher in KPF than in KMS, KGB, and KNR (P < 0.01). In the latter three degraded ecosystems, the contents of soil organic C and total N were in the sequence of KNR>KGB> KMS but the difference was not significant, soil total P content in KMS (0.87 g x kg(-1)) was 2.07 and 9.67 times of that in KNR and KGB, respectively (P < 0.01), and soil microbial biomass C, N and P contents were significantly higher in KGB and KNR than in KMS (P < 0.05). The soil microbial biomass C was significantly higher in KGB than in KNR (P < 0.05), but there were no significant differences in soil microbial biomass N and P between the two ecosystems. These results illustrated that the reduction of human activity could induce a slight increase of soil organic C in Karst degraded ecosystems, and proper grazing and natural restoration could be the feasible modes for the restoration of degraded ecosystem. Soil microbial biomass was more sensitive in response to the change of ecosystem, being able to be used as a sensitive indicator to reflect the change of degraded ecosystem in Karst region. In KPF, KNR, and KGB, soil water-stable macro-aggregates (> 0.25 mm) accounted for more than 70%, and dominated by >2 mm aggregates; while in KMS, soil water stable macro-aggregates only occupied 40.34%, and dominated by 2-0.25 mm aggregates. The destruction rate of soil structure in KMS, KGB, KNR, and KPF was 51.62%, 23.48%, 9.09%, and 9.46%, respectively (P < 0.05), indicating that human disturbance or farming practice destroyed soil macro-aggregates, and made the destruction rate of soil structure increased. To reduce human disturbance and implement natural rehabilitation would be the suitable ecological restoration strategy in Karst region. PMID- 20707119 TI - [Application of niche theory in evaluation of main tourism scenic areas in Zhangjiajie City]. AB - Five tourism scenic areas in Zhangjiajie City were selected as research objects, and fifty kinds of resource conditions affecting the development of tourism scenic area were taken as evaluation indices. Through disposing and consolidating the indices level by level, an analysis was made on the niche breadth and niche overlap of the five tourism scenic areas at three levels (I, II, and III). In the five scenic areas, index level had significant effects on the niche breadth (F = 10.278, P = 0.006), but less effects on the relative niche breadth, suggesting that in the evaluation of the development potential of tourism scenic area, relative niche breadth was more reasonable than absolute niche breadth. From level III to level I, the niche overlap of the five scenic areas was increasing, indicating that level choice would affect the evaluation of the actual niche overlap of the scenic areas. With the progressive refinement of the indices to certain level, and when the difference between observed and Monte Carlo-simulated Pianka indices achieved to significant level, this index level could be used as the minimum standard of the refinement, and the simulated niche overlap could be taken as an important reference in the competition evaluation of tourism scenic area. PMID- 20707120 TI - [Effects of several ecological factors on the hatching of Sepiella maindroni wild and cultured eggs]. AB - This paper compared the differences between Sepiella maindroni wild and cultured eggs, and studied the effects of temperature, salinity, hatching density, and egg type on the hatching rate and hatching time of the eggs. Wild eggs had better quality than cultured eggs. Among cultured eggs, small and black eggs had the best quality. For wild eggs, the optimum hatching temperature was 27 degrees C - 29 degrees C, and the optimum hatching salinity was 24.5-32.0. Hatching density had no significant effects on the hatching rate of wild eggs. For culturd Fol eggs, their hatching rate was 6.7% 30.0% when the temperature was 19 degrees C - 29 degrees C. No cultured eggs were hatched when the temperature was higher than 33 degrees C or lower than 17 degrees C. When the salinity was 19.5-32.0, the hatching rate of cultured eggs was 18.3%-25.0%. No hatching was observed when the salinity was below 17.0. Hatching density had no significant effects on the hatching rate of cultured eggs when air was provided, but the hatching rate was significantly affected when no air was provided. PMID- 20707121 TI - [Comparison of the methods for extracting and purifying microbial total DNA from an aeolian sandy soil]. AB - In order to select and establish an appropriate method for extracting and purifying the microbial total DNA from an aeolian sandy soil, six extraction methods (five direct methods and one indirect method) and two purification methods were examined, with the quantity and quality of extracted and purified total DNA compared. All the six extraction methods could extract the total DNA with a length of approximately 23 kb, among which, the improved SDS high salt extraction method (using 40% PEG8000 and 4 mol x L(-1) NaCl to precipitate DNA) was the best. This method could have a yield slightly less than that obtained by using kits, and the extracted DNA had the highest purity after purification, being available in 16S rDNA PCR amplification. Among the purification methods, the effect of agarose gel electrophoresis plus minicolumn was satisfactory, with most of the purified total DNA being able to be PCR-amplified and meet the requirements of the purity of DNA in the follow-up molecular operations. PMID- 20707122 TI - [Isolation, identification, and degrading characteristics of a high-efficient pyrene-degrading bacterial strain]. AB - By using selective enrichment culture with pyrene as the sole carbon source, a pyrene-degrading bacterial strain ZQ5 was isolated from the oil-contaminated soil in Shenfu Irrigation Area. The strain was identified as Stenotrophomonas sp., based on its morphological, physiological, and biochemical characteristics, and similarity identification of 16S rDNA sequence. The pyrene-degrading characteristics and the effects of culture condition on the degrading efficiency of the strain were investigated by shaking flask culture. After shaking culture with the initial concentration of pyrene being 100 mg x L(-1) at 30 degrees C for 10 days, the degradation rate of pyrene was 91.2%. Adding 100 mg x L(-1) of alicylic acid into culture medium could enhance the degrading efficiency of the strain. For the degradation of pyrene by ZQ5, the optimal medium pH was 7-8, and the optimal salt concentration was lower than 2%. PMID- 20707123 TI - [Effects of transgenic Bt crops on non-target soil animals]. AB - Transgenic Bt crops are widely planted around the world. With the quick development and extension of genetically modified crops, it is needed to make a deep study on the effects of Bt crops on soil ecosystem. This paper reviewed the research progress on the effects of transgenic Bt crops on the population dynamics and community structure of soil animals, e.g., earthworm, nematode, springtail, mite, and beetle, etc. The development history of Bt crops was introduced, the passway the Bt protein comes into soil as well as the residual and degradation of Bt protein in soil were analyzed, and the critical research fields about the ecological risk analysis of transgenic Bt crops on non-target soil animals in the future were approached, which would provide a reference for the research of the effects of transgenic Bt crops on non-target soil animals. PMID- 20707124 TI - [Effects of sewage sludge vermicompost on the growth of marigold]. AB - The 1:1, 2:1, 3:1, 4:1, 5:1, and 1:0 mixtures of sewage sludge and cattle dung were treated with earthworm Eisenia foetida, and then, mixed with black soil in the proportions of 10%, 20%, and 30% (dry mass) to investigate the effects of the vermicompost on the marigold plant height, stem diameter, leaf number, branch number, aboveground biomass, underground biomass, ratio of root to shoot, flower bud number, flower yield, flower diameter, and flower biomass. An obvious promotion effect of the vermicompost was observed on the growth of marigold. The smaller the ratio of sewage sludge to cattle dung, the better the growth of marigold; while a higher proportion of the vermicompost to soil would inhibit the marigold growth. In this study, a proportion of 20% vermicompost to soil was the best for the growth of marigold. PMID- 20707125 TI - [Synthesis, spectroscopy and antibacterial activity of charge transfer complexes of heteropolytungstate containing sulfanilamide]. AB - Two charge transfer complexes of heteropolytungstate with Keggin structure, (C6 H9 N2 O2S) 3PW12 O40 x 6H2O (SPW12) and (C6 H9 N2 O2S)4 SiW12 O40 x 5H2O (SSiW12) were synthesized with 12-tungstophosphoric (silicic) acid and sulfanilamide in aqueous phase. The title complexes were characterized by means of elementary analysis, FTIR, UV, 1H NMR, XRD and TG-DSC. The results indicate that the title complexes are new heteropoly compounds, and the UV results reveal that there is a charge transfer interaction between sulfanilamide and heteropoly anion. Thermal analysis shows that the process of mass loss of the title complexes is carried out in four stages, and the two complexes begin to decompose at 272.8 degrees C and 330.4 degrees C, respectively. The intermediates of the thermal decomposition were identified by FTIR Antibacterial test results show that the title complexes both have good antibacterial activity, and the inhibition rate of SPW12 to Escherichia coli, Staphylococcus aurous is 73.28% and 99.36%, respectively. PMID- 20707126 TI - [Study of the microwave emissivity characteristics over different land cover types]. AB - The microwave emissivity over land is very important for describing the characteristics of the lands, and it is also a key factor for retrieving the parameters of land and atmosphere. Different land covers have their emission behavior as a function of structure, water content, and surface roughness. In the present study the global land surface emissivities were calculated using six month (June, 2003-August, 2003, Dec, 2003-Feb, 2004) AMSR-E L2A brightness temperature, MODIS land surface temperature and the layered atmosphere temperature, and humidity and pressure profiles data retrieved from MODIS/Aqua under clear sky conditions. With the information of IGBP land cover types, "pure" pixels were used, which are defined when the fraction cover of each land type is larger than 85%. Then, the emissivity of sixteen land covers at different frequencies, polarization and their seasonal variation were analyzed respectively. The results show that the emissivity of vegetation including forests, grasslands and croplands is higher than that over bare soil, and the polarization difference of vegetation is smaller than that of bare soil. In summer, the emissivity of vegetation is relatively stable because it is in bloom, therefore the authors can use it as its emissivity in our microwave emissivity database over different land cover types. Furthermore, snow cover can heavily impact the change in land cover emissivity, especially in winter. PMID- 20707127 TI - [The enhancement of electric field distribution in one-dimensional metallic dielectric photonic crystals]. AB - The authors theoretically study the transmission properties and electric filed distribution in one-dimensional metallic-dielectric photonic crystals with the transfer matrix method. The results show that the physical properties can be improved considerably after the introduction of antireflection layer and optimizing structural parameters, e. g., 77% electric file distribution in metal layers can be obtained under 19% transmittance, and 72% transmittance can be obtained with 28% electric field distribution in metal layers. These photonic crystal structures, whose transmission properties and electric field in metal layers are tunable, could be widely used in nonlinear photon device based on the enhancement of electric field in metal layers. PMID- 20707128 TI - [The upconversion luminescence characteristics of Ho3+/Yb3+ codoped ZrO2-ZnO]. AB - Samples of Ho3+/Yb3+ codoped ZrO2-ZnO powder were prepared by a solid-state reaction. Upconversion luminescence of Ho3+ /Yb3+ codoped ZrO2-ZnO powders was reported in the present paper. The excitation spectrum detected at room temperature suggests three excitation peaks centered at 540, 671 and 762 nm respectively, corresponding to 5S2/5F4 --> I8, 5 Fs --> 5 I8, and 5S2/5 F4 --> 5 I7 or 5 I4 --> 5 I8 of Ho3+ ions. The contents of rare-earth ions could influence the property of upconversion lumunescence. When the Ho3+ content was 0.1 mol%, with the increase in Yb3+ content, the intensity of red luminescence and green luminescence decreased first and then increased, but the intensity of infrared luminescence increased first and then decreased. Furthermore, the ratio of the intensity of green emission to red emission decreased. When the Yb3+ content was 4.7 mol%, with the increase in Ho3+ content, the intensity of all emission decreased, but the ratio of the intensity of green emission to red emission was almost constant. The logI - logP curve shows that all the upconversion luminescence is double-photon processes. And the upconversion mechanisms of the samples were introduced. It is shown from the XRD spectrum that the powder of samples is uniform. PMID- 20707129 TI - [Effects of white organic light-emitting devices using color conversion films on electroluminescence spectra]. AB - The authors report a novel white organic light-emitting device (WOLED), which uses a strategy of exciting organic/ inorganic color conversion film with a blue organic light-emitting diode (OLED). The luminescent layer of the blue OLED was prepared by use of CBP host blended with a blue highly fluorescent dye N-BDAVBi. The organic/inorganic color conversion film was prepared by dispersing a mixture of red pigment VQ-D25 and YAG : Ce3+ phosphor in PMMA. The authors have achieved a novel WOLED with the high color stability by optimizing the thickness and fluorescent pigment concentration of the color conversion film. When the driving voltage varied between 6 and 14 V, the color coordinates (CIE) varied slightly from (0.354, 0.304) to (0.357, 0.312) and the maximum current efficiency is about 5.8 cd x A(-1) (4.35 mA x cm(-2)), the maximum brightness is 16 800 cd x m(-2) at the operating voltage of 14 V. PMID- 20707130 TI - [Mid-infrared emission and multiphonon relaxation in Tm3+-doped Ge-Ga-Se glasses]. AB - A series of chalcogenide glasses based on the composition Ge30 Ga5 Se65 (at. %) doped with the different Tm3+ ions were synthesized by melt-quenching technique. The refractive indexes, Raman spectra, absorption spectra, near-and mid-infrared fluorescence, and lifetimes of glass samples under 800 nm laser excitation were measured. The intensity parameters omega(i) (i = 2, 4, 6), transition probabilities, branching ratios and radiative lifetimes have been predicted for Tm3+ ions in samples by using the Judd-Ofelt theory. The near-infrared emission spectra at 1.23, 1.48 and 1.8 microm were observed and their quantum efficiencies were evaluated respectively in glass doped with 1 Wt% Tm(3+)-ions under 800 nm excitation. The mid-infrared fluorescence spectra were investigated with the different Tm3+ ion concentration under 800 nm excitation. The multiphonon relaxation rate of Tm3+ : 3 H5 --> 3F4 by the measured and calculated lifetimes, and the relative parameters of W(0) and a in Ge30 Ga5 Se65 glass were evaluated. Results show that the multiphonon relaxation rates were significantly lower than other glasses due to the lower maximum phonon energy, so the selenide glasses are promising as host materials for doping by rare earth ions and for preparation of mid-infrared optical elements. PMID- 20707131 TI - [Spectra analysis of lignin small molecular guaiacyl coniferyl alcohol biological modification treated by laccase]. AB - The enzymatic modification mechanism of lignin small molecular lignin guaiacyl coniferyl alcohol existing in softwood and hardwood treated by laccase was studied. Gas chromatography-mass spectrometry (GC-MS), gel permeation chromatography (GPC), FTIR spectrum and PCD(particle charge detector) etc were used for the measurement. GC-MS could not detect the coniferyl alcohol monomer after treated by laccase, so it was speculated that coniferyl alcohol participated in the reaction totally, and the structure of coniferyl alcohol was changed. GPC demonstrated that the molecular weight of coniferyl alcohol increased when it was treated by laccase, and coniferyl alcohol was polymerized. FTIR spectrum determined the reaction point of coniferyl alcohol when treated by laccase, and it is mainly phenolic hydroxyl, aromatic ring side chain substituent such as methoxy, double bound in side chain, beta-carbonyl groups, and gamma carbonyl groups. PCD gave a result that the cationic demandv(CD) decreased by 88.38%. PMID- 20707132 TI - [New progress in noninvasive method of blood glucose measurement using FT-mid-IR spectroscopy]. AB - The blood glucose concentrations of volunteers from diabetes patients and healthy adults (all patients and volunteers who joined this experiment gave their consents) were measured by using a modified WQF-200 FTIR spectrometer with a newly designed ATR accessory from the Beijing Rayleigh Analytical Instrument Corp. The determination basis for this technique from the physiological point of view is also discussed based on the experimental results, which indicated that the glucose measured by the FT-Mid-IR ATR instrument is from the secretions on the skin and glucose components within the body. The secreted glucose components will increase with the time increasing. The authors' previous study demonstrated 1 120 cm(-1) band as an index to characterize the blood glucose. During the experiments, the authors used the band of 1 455 cm(-1) as internal standard because of its stability, and because the relative intensity of I1 120/I1 455 band possesses the higher sensitivity. Meanwhile, from the spectra, the relative intensity of I1 120/I1 455 band of the glucose in both sources exhibits a linear relationship with blood glucose concentration within the body. The dried blood has the similar spectra as fingers'. The fingers' spectra will exhibit higher sensitivity if the time of measurement is longer after washing hand, and the results showed that when measured 10 minutes after washing hand, the sensitivity will be higher than that when measured 4 minutes after washing hand. All the results can be used in promoting a convenient, rapid and noninvasive way to monitor the continuous variation of blood glucose concentration of diabetes patients in real time. PMID- 20707133 TI - [Application of SOF-FTIR method to measuring ammonia emission flux of chemical plant]. AB - In the present paper, a new method is introduced for real-time monitoring polluted gas emission flux of chemical plant, which is called FTIR based on the solar occultation flux technique (SOF-FTIR). The model to obtain background spectrum, measured spectrum and atmospheric penetration rate surrounding polluted gas under complicated conditions is also proposed. Continuous measurements were preformed at a closed loop surrounding the contaminated areas that need to be mornitored to obtain measured spectrum, and finally column concentration of polluted gas was retrieved by using the nonlinear least squares fitting algorithm (NLLS). Then the flux information combined with the meteorological data and GPS information of the time was obtained when the experiments were done. Using this method, remote sensing experiment of ammonia emission around a chemical plant was done, and the concentration distribution and its emission flux was quantitatively analyzed. Compared with traditional FTIR methods of monitoring, this method is featured by convenient operation and high maneuverability, so it has a good application prospect in pollution monitoring and other applications in regional air pollution contingency monitoring. PMID- 20707134 TI - [Near infrared reflectance spectroscopy (NIRS) and its application in the determination for the quality of animal feed and products]. AB - Near-infrared reflectance spectroscopy (NIRS) has been the most rapidly developing and noticeable spectrographic analytical technique in recent years. The determining principle and progresses of near-infrared reflectance spectroscopy are presented briefly. It mainly includes the progresses in pre processing technique and analyzing model of near-infrared reflectance spectroscopy. Two pre-processing techniques, including differential coefficient dealt with technique, the signal-smoothing technique, and four analyzing models of near-infrared spectroscopy, including the multiplied lined regression (MLR), principal component analysis (PCA), partial least squares (PLS), and artificial nerve network (ANN). The application of near-infrared reflectance spectroscopy to the first time. The investigation of reviewed papers shows that the near-infrared reflectance spectroscopy is widely applied in feed analysis and animal products analysis because of its rapidness, non-destruction and non-pollution. The near infrared reflectance spectroscopy has been used to determine the feed common ingredient, such as dry matter, crude protein, crude fiber, crude fat and so on, micro-components including amino acid, vitamin, and noxious components, and to determine the physical and chemical properties of animal products which including egg, mutton, beef and pork. Details of the analytical characteristics of feed and animal products described in the reviewed papers are given. New trends and limits to the application of near-infrared reflectance spectroscopy in these fields are also discussed. PMID- 20707135 TI - [Study on rapid determination of active ingredient of agrochemicals by near infrared spectroscopy]. AB - The main problem of disqualification of the agrochemicals is the insufficiency and abuse of its active ingredient, but lacking of the rapid and on the site analysis method. In the present thesis, the content of haloxyfop-r-methyl in the emulsifiable concentration was analyzed quantitatively by the FT-NIR spectroscopy combined with partial least square (PLS) method. The calibration models of haloxyfop-r-methyl were developed, the determination coefficients (R2) of the calibration models were no less than 0.999 9, the SEC were less than 0.019, and the SEP were less than 0.030. Meanwhile, the factors affecting the calibration model were studied and the validation was done by the actual sample. The result indicated that the method of near-infrared spectroscopy can predict the content of the active ingredient in emulsifiable concentration accurately; while the resolution of the instrument and the content of addition agent will not affect the prediction precision of the calibration model remarkably. Therefore, it is a feasible, convenient and quick method to analyze the active ingredient in the commodity agrochemicals by near-infrared spectroscopy, which has an important significance in the on-line determination, analysis on site in the enterprise and the rapid quantitative analysis of agrichemicals in the department of quality monitoring. PMID- 20707136 TI - [Study on Chinese herb Astragalus membranceus by FTIR fingerprint]. AB - The aim of the study is to find new approach to identifying different growth years and different producing areas of astragalus membranceus simply and rapidly. The FTIR spectrometry, which is accurate, simple and efficient and has high resolution, was used to obtain the sample's FTIR spectrometry. After simple separation and extraction, the drying powder of the sample was detected. In 22 samples, there were 9 common peaks for identifying the authenticity of astragalus membranceus and 5 different peaks. According to the number, shape, and relative intensity of the peak, different growth years and different producing areas of astragalus membranceus can be distinguished. CONCLUSION: It is convenient and fast to identify different growth years and different producing areas of astragalus membranceus by FTIR fingerprint. PMID- 20707137 TI - [Study on the prediction of soil heavy metal elements content based on mid infrared diffuse reflectance spectra]. AB - The present paper analyzed the possibility of mid-infrared diffuse reflectance spectra for quick assessment of heavy metal element content in soil quickly. Soil samples were collected from Jiangning District and Baguazhou Island, and the numbers of sample were 103 and 58 separately. Jiangning District samples were used as calibration set while Baguazhou Island samples as validation set. To assess the utility of different pre-treatment process of MIR spectroscopy for soil heavy metal element content analysis, we used PLSR method to develop the calibration between spectral data and soil elements content. Three spectral pretreating techniques such as smooth, log(1/N), baseline correction, multiplicative scatter correction were used for promotion of predicting performance. The result showed that the progress of (log-BC-MSC) in turn achieved optimal calibration of MIR spectra and better prediction for ex-situ soils. Though the calibration data were treated by different pre-treating schema, the R2 of the 8 elements followed the same law: Ni > 0.8 > Cr, Cu, Zn, Pb, Hg > 0.6 > As, Cd. When we applied these calibrations to Baguazhou Island soils, (log-BC MSC) treated data results in the smallest RMSEp-BGZ. We used the same calibration method to compare the predictive ability of MIR spectra to VNIR spectra. The R2 of 8 elements developed by VNIR spectral calibration are sometime larger than MIR's, but after we applied these calibrations to validation set, the RSME of MIR data for prediction of BGZ soil samples is 21% to 73% of VNIR's. This result showed us that for predicting ex-situ soils, MIR analysis substantially outperformed VNIR These results indicated that MIR spectra can be used to predict soil heavy metal content quickly and non-destructively. PMID- 20707138 TI - [Measurement of methane and carbon dioxide emissions from ruminants based on the NDIR technique]. AB - Methane (CH4) production in the rumen represents a loss of energy for the host animal; in addition, methane eructated by ruminants may contribute to a greenhouse effect or global warming. The dinumal CH4 and carbon dioxide (CO2) emissions from sheep were continuously recorded using the flow-through chamber method. A type new type of non-disperse infrared (NDIR) gas sensors based on pulse IR source was introduced, and by using the high performance pyroelectric IR sensor with built in interference filter and the "single light and two wavelengths" technology, CH4 and CO2 measurement from ruminants was achieved. Animals were given dry oat hay as the basic diet and supplemented concentrate with the ratio of 7 : 3. The results showed that the recovery was 96.7% and 96.2% for CH4 and CO2, respectively. Methane and carbon dioxide output from sheep respectively averaged 15.6 g per day and 184.7 g per day, equivalent to 6.8 and 71.1 kg per animal. Diurnal fluctuations in hourly rates of CH4 and CO2 production in hourly of methane increased during day light to reach a peak at or near sunset and then declined towards sunrise, and consideration was given to the dry matter intake of the animals used in these studies and its possible effects on CH4 production. PMID- 20707139 TI - [High temperature Raman spectra and structure study of stolzite-structured PbWO4 crystals and its melt]. AB - Raman spectra of stolzite-structured PbWO4 crystal were recorded from 298 to 1 473 K. All the appearing vibrational modes were interpreted and assigned. The most intense mode at 902.7 cm(-1), which is identified as the internal mode upsilon1(Ag) of symmetrical stretching attributed to the vibration of [WO4]2- tetrahedron. Temperature dependent characteristics of the Raman spectra of the crystal were investigated. Band half-widths widened accompanied by the relative intensity decreased, and the lattice became more disorder with the increase in temperature. As being heated up to 1 398 K, PbWO4 crystals began to be melting and have completely transformed to liquid state at 1 473 K, while the internal vibrational modes of isolated [WO4]2- tetrahedron have appeared and the symmetry of vibrational modes transformed from S4 in crystal into Td of [WO4]2- in melt. It suggested that the isolated [WO4]2- structure unit exists in the melt. PMID- 20707140 TI - [Raman micro spectroscopic analysis of relationship between DNA degradation in tissue cells and postmortem interval]. AB - The present work is to study the relationship between DNA degradation in tissue cells and estimation of postmortem interval, and to provide a new way for the estimation of postmortem interval (PMI). The tissue cells of kidney and liver in vitro obtained at different time points were kept in a controlled environment. The kidney tissue and liver tissue were taken out every 4 h, during 48-72 h after death at 25 degrees C. The DNA content in different tissue cells was examined by means of confocal Raman micro spectroscopy with an excitation wavelength of 532 nm. Results show that the relative peak intensities (I1 094/I2 923) of confocal Raman microscopy for the tissue cells decreased gradually with the prolongation of postmortem interval from 48 to 72 h after death, while the peak intensity at 1 094 cm(-1) was reduced obviously; and the peak intensity at 1 454 and 2 923 cm( 1) did not change significantly. It is concluded that the DNA content in tissue cells decreased gradually with the prolongation of postmortem interval from 48 to 72 h after death. There is a linear relationship between the degradation rate of DNA in the tissue cells and postmortem interval. This investigation shows that Raman micro spectroscopy is useful to the estimation of postmortem interval (PMI). PMID- 20707141 TI - [Rapid estimate of the depth of single point fluorescence source for fluorescence molecular tomography]. AB - Fluorescence molecular tomography (FMT) supports monitoring molecular events non invasively in vivo over a span of long time, and meets the demands of monitoring a process of life. Priori information can be applied to speed the complex and time-consuming reconstruction process and to enhance the quality of the reconstructed images for FMT. A method was proposed in the present paper to estimate rapidly the depth of fluorescence source. The estimation process was accomplished with an optimization algorithm, particle swarm optimization (PSO). Firstly the fluorescence intensity ratio Rf of two positions on the boundary of tissue was derived under extrapolated boundary condition and a diffusion model for the propagation of near-infrared photons in biological tissue. Then a PSO algorithm was applied to minimize the difference between the theoretical ratio Rf(T) and the measured ratio Rf(M). The depth of fluorescence source was estimated after the rapid PSO optimization process. Two phantoms indicated that the proposed method can estimate the depth of single fluorescence source rapidly and easily without the time-consuming mesh generation and reconstruction process. PMID- 20707143 TI - [Fluorescence properties of lake water]. AB - Fluorescence spectrum technique has advantages of high sensitivity, high selectivity and quick-and-easy detection, and excitation-emission matrix (EEM) can provide abundant information. Fluorescence spectrum is unique for each water sample and is named as "fluorescence fingerprint". In the present paper, excitation-emission matrix was used to study the variability of water quality from spring to winter of two neighboring lakes in an urban park in Beijing. There was typical protein-like and humic-like fluorescence in the EEMs of the two lakes and the intensity of the protein-like fluorescence was significantly stronger. The close relationships between the fluorescence intensities and natural/anthropogenic activities showed that the water quality changed obviously with the season: the water quality in spring and summer was better than in autumn and winter. Natural factor like the growth of algae and plants etc was the major impact factor for the lake for pleasure boats, and anthropogenic factor such as planting was significantly important for the lake with ornamental plants. So the variability of water quality of lake is determined by the function of lake. To remove the remains of algae and plants in spring and autumn benefits the water quality of the lakes. PMID- 20707142 TI - [A fluorescent-probe detecting CYP2C9 * 3 DNA]. AB - The mismatched CYP2C9 * 3 DNA was detected by a exciplex fluorescent-probe system. The exciplex fluorescent-probe model system comprises of two 12-mer oligonucleotides fluorescent-probes, complementary to neighbouring sites of a 24 (47) -mer DNA target and plasmid target, each equipped with moieties able to form an exciplex on correct, contiguous hybridization. Very similar results were obtained between the 24-mer target and the 47-mer target when WT and MT systems were detected by the exciplex fluorescent-probe. Exciplex bands at 505 nm were found for both 24(47)-mer WT and 24(47)-mer MT-targets at 5 degrees C, but were not distinctive enough to distinguish 24(47)-mer WT-target and 24(47)-mer MT target. However the experiments were carried out at Tm, the exciplex band disappeared almost completely for 24(47)-mer MT-target system like control system, and there was still a strong exciplex band for the 24(47)-mer WT target system. Exciplex peaks at 505 nm were seen for the WT circular plasmids system, but not for MT circular plasmids. Therefore, mismatches of CYP2C9 * 3 DNA can be effectively detected by this exciplex construct, giving potential for single nucleotide polymorphism detection. PMID- 20707144 TI - [Fluorescence spectroscopy characterization of asphaltene liquefied from coal and study of its association structure]. AB - Structure and association of asphaltenes from coal direct hydroliquefaction were studied by fluorescence spectrometry and UV-Vis absorption spectrometry in this paper. The results indicate that asphaltene is aromatic mixtures mainly containing naphthalene nucleus and shows strong fluorescent characteristic. The forming of exciplex between asphaltene and solvent results in the red shift of fluorescence peak and fluorescence quenching of asphaltene that increases with the polarity and electron acceptability. The self-aggregation of asphaltene is formed by non-covalent bond interaction, so that the asphaltene liquefied at higher temperture that shows high aromaticity has stronger association than that liquefied at lower temperature. Aggregation of asphaltene has been found to be a gradual process, in which there is no critical aggregation constant observed, and the inflection point of the plot of apparent fluorescence intensity as a function of asphaltene concentration varies with the excitation wavelength. PMID- 20707145 TI - [Spectral properties and energy transfer of Ce3+ and Tb3+ ions co-doped Ca2SrAl2O6 phosphor]. AB - Ce3+, Tb3+ co-doped green phosphor Ca2SrAl2O6 was synthesized by solid state method and its excitation and emission spectra were measured and studied. The results showed that the emission spectrum is composed of four groups of narrow bands and the peaks are located at 497, 545, 595 and 623 nm. The strongest emission peak islocated at 545 nm and chromaticity coordinate (x, y) is (0.300 5, 0.500 2) at 4 mol% Ce3+ and Tb3+ doping, which indicate that Ca2SrAl2O6 : Ce3+, Tb3+ was a good green phosphor. The excitation spectrum for 545 nm was in the region of 320-400 nm, which indicated that this phosphor could be effectively excited by UVLED. Duo to the overlap of the Ce3+ emission bands and the Tb3+ excitation bands, the energy transfer between Ce3+ and Tb3+ is expected to be very efficient. The emission intensity of co-doped Ca2SrAl2O6 phosphor was stronger than that of Tb3+ doped phosphor. The luminescence intensity reached the maximum when the concentration of Ce3+ and Tb3+ was 4 mol%. PMID- 20707146 TI - [Fluorescence excitation-emission matrix spectroscopy of CDOM from Yundang Lagoon and its indication for organic pollution]. AB - Fluorescence excitation-emission matrix spectroscopy (EEMs) combined with absorption spectroscopy were applied to study the optical properties of CDOM samples from highly-polluted Yundang Lagoon in Xiamen in order to demonstrate the feasibility of using these spectral properties as a tracer of the degree of organic pollution in similar polluted coastal waters. Surface water samples were collected from 13 stations 4 times during April and May, 2008. Parallel factor analysis (PARAFAC) model was used to resolve the EEMs of CDOM. Five separate fluorescent components were identified, including two humic-like components (C1: 240, 325/422 nm; C5: 260, 380/474 nm), two protein-like components (C2: 225, 275/350 nm; C4: 240, 300/354 nm) and one xenobiotic-like component (C3: 225/342 nm), which could be used as a good tracer for the input of the anthropogenic organic, pollutants. The concentrations of component C3 and dissolved organic carbon (DOC) are much higher near the inlet of sewage discharge, demonstrating that the discharge of surrounding sewage is a major source of organic pollutants in Yundang Lagoon. CDOM absorption coefficient alpha (280) and the score of humic like component C1 showed significant linear relationships with COD(Mn), and a strong positive correlation was also found between the score of protein-like component C2 and BOD5. This suggested that the optical properties of CDOM may provide a fast in-situ way to monitor the variation of the water quality in Yundang Lagoon and that of similar polluted coastal waters. PMID- 20707147 TI - [Fluorescence research on reaction mechanism of nucleic acid with small organic molecules]. AB - The interaction mechanism of nucleic acid with small organic molecules plays an important role in the recognition of the structure and function of nucleic acids, which can also reveal the biological function of nucleic acids and the mechanism of some drugs. Research on the interaction between nucleic acid and small organic molecules plays an important part in simulating the life process and exploring the essence of life. In the present article, detailed description of the fluorescence spectroscopy research methods used in this field is presented. The fluorescence quenching types of the interaction between nucleic acid and small organic molecules (including dyes and drugs) are discussed. There are many factors influencing the fluorescence quenching type, including the temperature, the rate constant of bimolecular quenching process, the fluorescence lifetime, changes of the absorption spectra and so on. So according to different affecting factors, the fluorescence quenching type can be determined based on corresponding theories. Many different kinds of calculation methods are also summarized, including the calculations of the binding constant, the distance between fluorescence donor and receptor, the interaction force type and the binding mode of nucleic acid with small organic molecules. Furthermore, the formation constant of nucleic acid with small organic molecules is studied with different binding numbers. These conclusions have guiding significance for studying the interaction between nucleic acid and small organic molecules. These results can also provide guidance for the development of new nucleic acid probe, and the design of new drug molecules, of which nucleic acid is the important target. PMID- 20707148 TI - [Experimental studies on three-dimensional fluorescence spectral of mineral oil in ethanol]. AB - Three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy was applied to characterize the mineral oil in ethanol. In the paper, a simple way of treating the first-order Rayleigh, Raman and second-order Rayleigh scatter is used involving subtracting an EEM of a solvent blank, and removing and replacing the values with zeros. The corrected results showed that the characteristic three dimensional fluorescence spectra of mineral oil were as follows: there was one mainly peak in the fluorescence spectrum of the kerosene, and the peak was identified at excitation/emission wavelengths (Ex/Em) of 270/290 nm; there were two intense fluorescence peaks in the fluorescence spectrum of 0 # diesel, located at (Ex/Em) of 240/344 nm and 270/362 nm respectively; there were several fluorescence peaks in the fluorescence spectrum of lubricating oil, with the two intense peaks located at (Ex/Em) of 240/348 nm and 258/358 nm respectively. Furthermore, the relation between the relative fluorescence intensity and the concentration of mineral oil was studied, and the sensitivity and the limitation of detection of the method were also analyzed. The results of this study show that the method of three-dimensional fluorescence can be used to detect the low concentration of oil. PMID- 20707149 TI - [Quantitative fluorescence characterization of organic matter stability during chicken manure composting]. AB - Due to its high sensitivity, good selectivity and nondestructive nature, fluorescence spectroscopy was widely applied to characterize the nature of dissolved organic matter (DOM) from different source since the last decade. In the present study, dissolved organic matter (DOM) extracted from chicken manure samples during composting progress was quantitatively characterized by fluorescence analysis techniques and mathematical analysis methods. The results showed that, the ratio between the fluorescence intensities at 330 nm (humic-like matter) and 280 nm(protein-like matter) (I330/I280) in synchronous-scan excitation mode spectra, the area of a fluorescence spectrum obtained by excitation at the blue wavelength of 465 nm(A470-640), and the ratio between the area of the last quarter (435-480 nm) and the area of the first quarter (300-345 nm) of the emission spectrum (A435-480 nm/A300-345 nm) by exciting the sample with ultraviolet radiation of 240 nm, all increased during composting, and the humification degree of compost increased as well. Three-dimensional excitation emission matrix fluorescence spectroscopy showed that the intensity of protein like matter decreased during composting progress and diminished at the end, while that of fulvic-like matter increased all the time. The ratio between the intensity of the ultraviolet fulvic-like fluorescence (Peak A) and that of the visible fulvic-like fluorescence gamma (A, C) showed an overall significant downward trend during composting, but fluctuated in the progress. The correlation analysis showed that, I330/I280, A470-640 and A435-480 nm/A300-345 nm were all significant correlative, while gamma (A, C) was not correlative with the above mentioned three parameters at 0. 05 level due to effect by other factors. The results show that, I330/I280, A470-640 and A435-480 nm/A300-345 nm can be effectively used in the process of the evaluation of humification degree during composting. PMID- 20707150 TI - [A study of developing fingermarks by nano-titanium dioxide shielding ultraviolet ray]. AB - In view of the difficulty in developing fingermarks on the color or strong fluorescence surface, the present paper reported a novel method to develop fingermark by shielding ultraviolet-ray. Nano-titanium dioxide with rutile phase had extremely high shielding ability of ultraviolet-ray. The TEM indicated that the average particle size of rutile titanium dioxide in experiment was about 30 nm, and they were mostly sphericity. The UV-Vis spectra indicated that the rutile nanoparticles shield UV with wavelength less than 400 nm. The rutile nanoparticles were physically adsorbed on the ridges of fingermarks on the color or strong fluorescence surface adequately and were not or a little adsorbed on the object surface by dusting or shaking. The ridges of the developed fingermarks were dark and the background was light under irradiation of 365 nm. We could obtain good images, and the contrast of lightness between the ridge and the background was obvious. In contrast to traditional developing technique-superglue fuming-Rhodamine 6G (or BBD) dyeing strengthening technique, the effect of nano titanium dioxide shielding ultraviolet-ray detection technique was better. By the new detection technique, the ridges of the developed fingermarks were smooth and the detail characteristics of the developed fingermarkes were clear. The research results indicate that the nano-titanium dioxide particle is an effective and convenient developer of fingermark on the color or strong-fluorescence or color strong fluorescence surface under irradiation of 365 nm with its shielding ultraviolet-ray property. Especially, the developer also has quite satisfactory effect on old fingermarks on the non-porous objects in contrast to traditional methods. The new detection technique is convenient, efficient, fast, and economical and has a wide application foreground in the field of fingermark developing. PMID- 20707151 TI - [UV/Visible spectroscopic study of the beta-diketonate zirconium active species for olefin polymerization]. AB - The method of UV/Visible absorption spectroscopy for olefin catalytic system was introduced in this paper, whose testing condition was much closer to the polymerization conditions. The actions of olefin polymerization catalyst (dbm)2 ZrCl2 with cocatalyst AlEt2 Cl (or MAO) were investigated by UV/visible absorption spectroscopy at atmosphere temperature. It was shown that the UV/Visible main absorption band of the zirconocenium, which can be related to the ligand to metal charge transfer bands (LMCT), varies greatly upon incremental addition of AlEt2 Cl or MAO. For the low molar ratios of Al/Zr in the catalytic system, there was the substitution of an electron withdrawing chlorine atom by a donating alkyl group. Then a hypsochromic shift of the initial catalyst absorption band, corresponding to the monomethylation of the catalyst, was observed in each catalytic system (dbm)2 ZrCl2/AlEt2 Cl (or (dbm)2 ZrCl2/MAO). On the contrary, further addition of AlEt2 Cl (or MAO) was accompanied by a continuous bathochromic shift of the maximal wavelength, which corresponding to the formation of more dissociated ionic active species. Then, there would be a coordination of monomer to the ionic active species. PMID- 20707152 TI - [Vegetation change of Yamzho Yumco Basin in southern Tibet based on SPOT-VGT NDVI]. AB - The area we studied is Lake Yamzho Yumco Basin (28 degrees 27'-29 degrees 12'N, 90 degrees 08'-91 degrees 45'E), the largest inland lake basin in southern Tibetan Plateau, China. Using the SPOT-VGT NDVI vegetation index from 1998 to 2007 in the basin, the temporal and spatial variation characteristics of NDVI and its correlation with the major climatic factors (air temperature, precipitation) were analyzed. The results show that the average NDVI of the lake basin ranges from 0.12 to 0.31 and its seasonal change is obvious; the NDVI begins to rise rapidly in May and reaches the maximum value in early September. The average NDVI of the basin shows the slow increasing trend during 1998 to 2007, and it indicates that the eco-environment of the basin is recovering. The high value of NDVI has close relationships with water supply, altitude and vegetation types, so NDVI is relatively high near water sources and is the highest in meadow grassland. The summer air temperature and precipitation are the important climate elements that influence the vegetation in the basin, and the linear correlation coefficients between NDVI and air temperature and precipitation are 0.7 and 0.71, respectively. In recent years, warm and humid trend of the local climate is prevailing to improve the ecological environment in Yamzho Yumco Basin. PMID- 20707153 TI - [Evaluation of complex diet dry matter digestibility of sheep using spectra difference]. AB - The present study aimed to predict the dry matter digestibility (DMD) of animals fed complex diet using the spectra difference between diets and feces by near infrared reflectance spectroscopy (NIRS). Four indoor experiments were carried out with artificial mixed complex diets in the state field observatory stations located at Hebei province. The sheep were used as tested animals. One hundred and four parts of "diet-feces" were obtained and divided into a calibration sample set (70 samples) and a validation sample set (34 samples). The spectra difference between diets and feces, and the partial least square (PLS) were used to calibrate the models of DMD of sheep. The results indicated that the optimum range of spectrum was 8 656-4 310 cm(-1). The optimum proceeding method was multivariate scattering correction + first derivative + Norris smoothing. The optimum number of factors was 7. The root mean square error of prediction (RMSEP) was 2.46%, and the RPD value of validation was above 2.5. The coefficient of correlation between the actual and predicted DMD using the NIRS was 0.8339, indicating that the NIRS could be used to evaluate dry matter digestibility of sheep fed complex diets. PMID- 20707154 TI - [Monitoring of winter wheat stripe rust based on the spectral knowledge base for TM images]. AB - In most cases, the reversion model for monitoring the severity degree of stripe rust based on the hyperspectral information can not be directly applied by the satellite images with relatively broad bandwidth, while the airborne hyperspectral images can not be applied for large-scale monitoring either, due to the scale limitation of its data and high cost. For resolving this dilemma, we developed a monitoring method based on PHI images, which relies on the construction of spectral knowledge base of winter wheat stripe rust. Three PHI images corresponding to the winter wheat experimental field that included different severity degree of stripe rust were used as a medium to establish the spectral knowledge base of relationships between disease index (DI) and the simulated reflectance of TM bands by using the empirical reversion model of DI(%) and the relative spectral response (RSR) function of TM-5 sensor. Based on this, we can monitor and identify the winter wheat stripe rust by matching the spectral information of an untested pixel to the spectral knowledge base via Mahalanobis distance or spectral angle mapping (SAM). The precision of monitoring was validated by simulated TM pixels, while the effectiveness of identification was tested by pixels from TM images. The results showed that the method can provide high precision for monitoring and reasonable accuracy for identification in some certain growth stages of winter wheat. Based on the simulated TM pixels, the model performed best in the pustulation period, yielded a coefficient of determination R2 = 0.93, while the precision of estimates dropped in the milk stage, and performed worst in the jointing stage, which is basically inappropriate for monitoring. Moreover, by using the pixels from TM images, the infected pixels could be identified accurately in pustulation and milk stages, while failed to be identified in jointing stage. For matching algorithms, the Mahalanobis distance method produced a slightly better result than SAM method. PMID- 20707155 TI - [Study on fault diagnosis of power-shift steering transmission based on spectrometric analysis and SVM]. AB - Spectrometric oil analysis is an important method to study the running state of Power-Shift Steering Transmission (PSST). A method of multiple out least squares support vector regression was developed using spectrometric oil analysis data and SVM (Support Vector Machine). The spectrometric oil analysis data were studied using multiple out least squares support vector regression. It has been proved that the regression data are good in approximation effect for No. 1 PSST. And the predictive values for No. 2 PSST are highly veracious with the test data. The fault information was found and the fault position was determined through compar4tive analysis. This method has been proved to have practice significance for finding fault-hidden dangers and judging fault positions. PMID- 20707156 TI - [Standardization of technical methods for apple fluorescence canopy spectral detection]. AB - Aiming at spectral detection of apple fluorescence canopy, the present paper carried out spectral detection tests under different weather conditions, different detection times, and different detection heights and angles to apple canopy in the two years of 2008 and 2009, so as to analyze impacts of these factors on apple canopy spectral characteristics and explore standardized spectral detection methods for apple fluorescence canopy. The results indicated the regularity in spectral reflectance of apple fluorescence canopy to a certain degree under different conditions, especially in the 760-1 350 nm near-infrared bands. The authors found that canopy spectral reflectance declined along with the decrease in sunshine and it is appropriate to detect canopy spectrum in sunny days with few clouds. In addition, spectral reflectance tended to be stable when the wind scale was below grade 2. The discrepancy of canopy spectra is small during the time period from 10:00 to 15:00 of a day compared to that of other times. For maintaining stable spectral curves, the height of detector to apple canopy needed to be adjusted to cover the whole canopy within the field of view according to detection angle of the detector. The vertical or approximately vertical detection was the best for canopy spectral reflectance acquisition. The standardization of technical methods of spectral detection for apple fluorescence canopy was proposed accordingly, which provided theoretical references for spectral detection and information extraction of apple tree canopy. PMID- 20707157 TI - [Spectral analysis of cyanobacteria chlorophyll in polluted water]. AB - The polluted water with abundant nourishment cause phytoplankton, such as cyanobacteria, to grow rapidly, which brings great harm to environment. In the present paper, the absorption spectrum of cyanobacteria was measured and analyzed in order to estimate the content of the chlorophyll accurately. The same amount of cyanobacteria was separately cultured in pure water and lake water for different time. The chlorophyll was extracted from the cyanobacteria for the same time by 95% of ethanol. Then the ethanol extract was tested by ultraviolet visible spectrometry. The results show that the absorption spectrum of the chlorophyll has three absorption peaks at 279.5, 436.0 and 664.5 nm respectively. However, the absorbency at 279.5 nm cannot reflect the content of the chlorophyll. The absorbencies at 436.0 and 664.5 nm have linear relationship with the content of chlorophyll. Moreover, the dispersion between the absorbency at 436.0 nm and the absorbency at 664. 5 nm can reflect the content of chlorophyll more accurately. The research provides the experimental and theoretical basis for the highly accurate detection of the water quality. PMID- 20707158 TI - [Analysis of directional characteristics of winter wheat canopy spectra]. AB - The bidirectional reflectance factors vary as the incidence directions and the view angles change. At present the remote sensing is almost at nadir, therefore it is possible to improve the accuracy of remote sensing application by reasonably selecting the looking angle, solar zenith angle, and so on. Based on the multidirectional spectra of winter wheat canopy at several critical growth stages, the paper quantitatively analyzed the sensitivity of narrowband bidirectional reflectance to view planes, view zenith angle, solar zenith angle, growth stage, and band by using anisotropy factor (ANIF) and anisotropy index (ANIX). The change of NDVI with view zenith angle, solar zenith angle and growth stage was also studied. The results show that the anisotropy characteristics of bidirectional reflectance factors at solar principal plane was stronger than that at the other planes, and orthogonal principal plane was the weakest. The ANIX at solar principal plane was the biggest. The reason was that the shadow of canopy changed more dramatically at solar principal plane than at the other planes. The sensitivity of bidirectional reflectance factor at visible bands to zenith angles was stronger than in near infrared regions, the reason for which was that the shadow effect in visible regions was stronger than in near infrared regions. The ANIX in visible regions was bigger than in near infrared regions. The sensitivity of bidirectional reflectance factor to solar zenith angles increased as the view zenith angle increased. The NDVIs at every looking zenith angle all increased with the leaf area index increasing. The NDVIs at forward direction were larger than at backward direction, which resulted from that the shadow effect in visible regions was stronger than in near infrared regions. The solar principal plane implies rich internal structure information on object. In order to reduce the uncertainty from the observing method, the near infrared bands and small solar zenith angle should be chosen. The retrieve of structure parameters ought to select solar principal plane, and avoid hot spot region when inversing biological parameters using NDVI. PMID- 20707159 TI - [Synthesis and spectroscopic study of polyamine-type cellulose-based chelating fiber]. AB - The graft copolymer (CPGMA) made from bleached chemical eucalyptus pulp (BCEP) and glycidyl methacrylate (GMA) was reacted with ethylenediamine (EDA) to synthesize the polyamine-type cellulose-based chelating fiber CPGMA-EDA. The chelating fiber was characterized by means of Fourier transform infrared spectroscopy (FTIR), 13C cross polarization magic angle spinning NMR spectra (13C CP/MAS NMR) and X-ray diffraction (XRD). The results of FTIR and 13C CP/MAS NMR show that the characteristic absorption peak (904 cm(-1) of epoxy group in CPGMA disappeared, and the absorption peak around 3 200-3 500 cm(-1) broadened due to the vibration of new formed N-H bond while the CPGMA reacted with EDA. Both of these indicate that amino group was grafted onto CPGMA through the ring-opening reaction. The XRD results indicate that the crystallinity of CPGMA-EDA was 48.1%, and decreased by 31.1% compared to that of BECP, indicating that the reaction not only takes place in the noncrystal regions, but also in the crystal regions of cellulose. PMID- 20707160 TI - [Design and application of hyperspectral radiation system for sea ice observation]. AB - Sea ice plays an important role in the global climate systems. In the present article, a hyperspectral radiation system for the observation of optical properties of sea ice was designed. The system consists of three optical channels, which can operate simultaneously. Two kinds of optical detectors were designed, and the problem relevant to the water-tightness was resolved. The system can be used to measure the solar radiation beneath the sea ice by an "L" bracket. Another bracket for detecting bidirectional reflectance was designed, which can fix the optical detector at any angle ranging over 0-180 measured with an angle detector. In order to make a most suitable and automatic integrated time, the system can adjust the integrated time intelligently by itself. The system can work stably under extremely low temperature. Furthermore, the system was equipped with four thermistors and one GPS. The system was validated showing a good stability and veracity in situ in the Liaodong Bay. PMID- 20707161 TI - [Using the distance between hyperspectral red edge position and yellow edge position to identify wheat yellow rust disease]. AB - The objective of the present paper is to identify healthy wheat and disease wheat by using hyeprspectral remote sensing as soon as possible. The canopy spectral reflectance of winter wheat infected by different severity yellow rust was measured and the disease indices (DI) were investigated in the field respectively. Smoothing the canopy spectra and calculating the first derivative values, the two methods were used to calculate the red edge position (REP) and yellow edge position (YEP) of the first derivative values: (a) maximum of the first derivative value; (b) Cho and Skidmore method. The result showed that REP gradually shifted to short-wave band, and the YEP gradually shifted to long-wave band with disease severity increasing, however, REP-YEP quickly became smaller. Analyzing and comparing the prediction precision of REP, YEP and REP-YEP for DI, the result indicated that the model REP-YEP as variable has the best estimation precision for DI than REP and YEP, the model estimation error is 6.22, and relative error is 14.3%, and it could identify healthy and disease wheat 12 days before the disease symptom apparently appeared. Therefore, this study not only can provide theory and technology for large areas monitoring of wheat disease by using hyperspectral remote sensing in the future, but also has the important meaning and practical application value for implementing precision agriculture. PMID- 20707162 TI - [Special decorrelation technique used for DWT-based hyperspectral image compression]. AB - Hyperspectral images are massive data consisting of hundreds of spectral bands and have been used in a large number of applications. With growth of spectral resolution and spatial resolution of hyperspectral data, data size increases rapidly. How to effectively compress hyperspectral image becomes a key problem that affects the development and popularization of hyperspectral image. Recently, DWT-based methods have been proved promising for hyperspectral image. But their performances are restricted because it is difficult for them to efficiently take advantage of the various properties of hyperspectral image. For the traditional wavelet transform, the specific properties of hyperspectral images are basically utilized by corresponding to characteristics of wavelet coefficients. So the present paper proposes a new DWT-based method using decorrelation technique according to the spectral characters of hyperspectral image. Block predictive coding is designed to remove the spectral correlation as well as spatial correlation simultaneously and is applied into the DWT-based method. Firstly, hyperspectral image is divided into several image blocks. The bands in a single block possess high spectral correlation. Afterwards, it is deduced that bands of a single block tend to be proportional in altitudes. Bands prediction, which is done in the range of each block respectively, is designed according to this and others characteristics of hyperspectral images. Finally, reference bands of block prediction and the deviation data obtained after block prediction are compressed by 2D-DWT algorithm and 3D-DWT algorithm respectively. Experiment results indicate that compared with the well known techniques the proposed method can significantly improve SNR and PSNR performance, even to 4.2 dB (compared with AT 3DSPIHT algorithm). And the code efficiency at low bit rates is also competitive. PMID- 20707163 TI - [An object-oriented remote sensing image segmentation approach based on edge detection]. AB - Satellite sensor technology endorsed better discrimination of various landscape objects. Image segmentation approaches to extracting conceptual objects and patterns hence have been explored and a wide variety of such algorithms abound. To this end, in order to effectively utilize edge and topological information in high resolution remote sensing imagery, an object-oriented algorithm combining edge detection and region merging is proposed. Susan edge filter is firstly applied to the panchromatic band of Quickbird imagery with spatial resolution of 0.61 m to obtain the edge map. Thanks to the resulting edge map, a two-phrase region-based segmentation method operates on the fusion image from panchromatic and multispectral Quickbird images to get the final partition result. In the first phase, a quad tree grid consisting of squares with sides parallel to the image left and top borders agglomerates the square subsets recursively where the uniform measure is satisfied to derive image object primitives. Before the merger of the second phrase, the contextual and spatial information, (e. g., neighbor relationship, boundary coding) of the resulting squares are retrieved efficiently by means of the quad tree structure. Then a region merging operation is performed with those primitives, during which the criterion for region merging integrates edge map and region-based features. This approach has been tested on the QuickBird images of some site in Sanxia area and the result is compared with those of ENVI Zoom Definiens. In addition, quantitative evaluation of the quality of segmentation results is also presented. Experiment results demonstrate stable convergence and efficiency. PMID- 20707164 TI - [Independent component analysis for spectral unmixing in hyperspectral remote sensing image]. AB - Hyperspectral remote sensing plays an important role in earth observation on land, ocean and atmosphere. A key issue in hyperspectral data exploitation is to extract the spectra of the constituent materials (endmembers) as well as their proportions (fractional abundances) from each measured spectrum of mixed pixel in hyperspectral remote sensing image, called spectral un-mixing. Linear spectral mixture model (LSMM) provides an effective analytical model for spectral unmixing, which assumes that there is a linear relationship among the fractional abundances of the substances within a mixed pixel. To be physically meaningful, LSMM is subject to two constraints: the first constraint requires all abundances to be nonnegative and the second one requires all abundances to be summed to one. Independent component analysis (ICA) has been proposed as an advanced tool to un mix hyperspectral image. However, ICA is based on the assumption of mutually independent sources, which violates the constraint conditions in LSMM. This embarrassment compromises ICA applicability to hyperspectral data. To overcome this problem, the present paper introduces a solution of minimization of total correlation of the components. Interestingly, with the minimization of total correlation of the components, the angle of the direction between each components is invariable. A Parallel oblique-ICA (Pob-ICA) algorithm is proposed to correct the angle of the searching direction between the components. Two novelties result from our proposed Pob-ICA algorithm. First, the algorithm completely satisfies the physical constraint conditions in LSMM and overcomes the limitation of statistical independency assumed by ICA. Second, the last component, which is missed in other existing ICA algorithms, can be estimated by our proposed algorithm. In experiments, Pob-ICA algorithm demonstrates excellent performance in the simulative and real hyperspectral images. PMID- 20707165 TI - [Comparisons and analysis of the spectral response functions' difference between FY-2E's and FY2C's split window channels]. AB - Remote sensors' channel spectral response function (SRF) was one of the key factors to influence the quantitative products' inversion algorithm, accuracy and the geophysical characteristics. Aiming at the adjustments of FY-2E's split window channels' SRF, detailed comparisons between the FY-2E and FY-2C corresponding channels' SRF differences were carried out based on three data collections: the NOAA AVHRR corresponding channels' calibration look up tables, field measured water surface radiance and atmospheric profiles at Lake Qinghai and radiance calculated from the PLANK function within all dynamic range of FY 2E/C. The results showed that the adjustments of FY-2E's split window channels' SRF would result in the spectral range's movements and influence the inversion algorithms of some ground quantitative products. On the other hand, these adjustments of FY-2E SRFs would increase the brightness temperature differences between FY-2E's two split window channels within all dynamic range relative to FY 2C's. This would improve the inversion ability of FY-2E's split window channels. PMID- 20707167 TI - The active conformation of allophycocyanin from Spirulina platensis studied with spectroscopic analysis. AB - Allophycocyanin (APC) was purified from Spirulina platensis using hydroxylapatite chromatography and ion-exchange chromatography. Effects of solution pH on spectra of APC were studied. APC has an absorption maximum at 650 nm, and a shoulder at 620 nm. The fluorescence emission peak is at 660 nm. The efficiency of energy absorbing and transfer in APC could be reflected by the absorption spectra and fluorescence spectra, respectively. Structural variations of APC could be monitored by means of circular dichroism spectra. APC showed good absorbance and fluorescence stability at varying pH with only minor changes between pH 4-10. The trimeric structure of APC was maintained while local variations of protein peptides were allowed in response to the environmental disturbance. Beyond this pH range, secondary structure as well as overall conformation of APC dramatically changed, and the energy absorption and transfer ability were also disrupted. PMID- 20707166 TI - [Progress in retrieving vegetation water content under different vegetation coverage condition based on remote sensing spectral information]. AB - The present paper reviews the progress in the methods of retrieving vegetation water content using remote sensing spectral information, including vegetation spectral reflectance information (VIR, SWIR, and NIR) to directly extract vegetation water content and establish vegetation water indices (WI), i. e. NDWI = (R860 - R1 240)/(R860 + R1 240) and PWI = R970/R900; and using radiation transfer (RT) model such as PROSPAIL to detect plant water content information. The authors analyze the method of retrieving vegetation water content under low crop coverage condition. The plant water can be estimated by using canopy physiological parameters firstly, and using vegetation indices and radiation transfer model secondly, which can eliminate soil background effect. The estimated agricultural drought and vegetation water content by using multi-angle polarized reflectance and bi-directional reflectance (BRDF) was discussed in this paper. In the end, the possible development trend of retrieval methods for plant water information under plant low coverage conditions was discussed. PMID- 20707168 TI - [Decoloration and degradation of direct pink 12B by microwave-promoted heterogeneous Fenton-like reaction]. AB - Microwave-promoted heterogeneous Fenton-like reaction, the combination of Fenton like reagent with microwave, is an efficient method for waste water treatment. In the present paper, the degradation of direct pink 12B (a kind of organic dye) was studied using this method was studied. Through numerous experiments, the influences of various parameters including the initial pH value, dosage of Fe-Ni Mn/AlO3, dosage of H2O2 and microwave were investigated intensively. The characteristic curve of direct pink12B, the concentration-absorbency curve of direct pink12B, the orthogonal optimization tests and comparative tests were given. In this paper, the mechanisms of this reaction were also been probed. It is concluded from the experiments that the microwave can accelerate the process of degradation effectively. Under optimal conditions, the overall color removal was more than 99.0% within 10 min. In the study, all the characterization was carried out using UV-Vis spectral-analysis. PMID- 20707169 TI - [Investigation on rapid detection of lead by LIBS based on common spectrograph]. AB - In the present paper, the lead concentrations of samples including glass, soldering tin and so on were determined by LIBS based on a Nd : YAG Q-switched pulse laser with wavelength 1 064 nm as an exciting source and CCD in common spectrograph as the detector. The pulse energy on the surface of samples is about 95 mJ and the pulse width is 12 ns. By the detection of different samples, the detection limit of lead in samples was found to be 0.007 4% and the maximum relative standard deviation of quantitative analysis was about 4.0% based on the LIBS system of the instruments all made in China. The quantitative analysis can be done in two or three minutes and will spend one minute finishing the process by software in the future. The results suggest that the accuracy of determination of lead meets the challenge of quantitative analysis and the CCD can displace the very expensive ICCD as detector. The feasibility and low cost of the method, which uses common spectrometer and CCD to realize the LIBS detection, is proved by the result and our investigation will be beneficial to the LIBS application. PMID- 20707170 TI - [Characteristic study of plasma plume produced by nanosecond pulsed laser ablation of silicon using optical emission spectroscopy]. AB - The 355 nm laser pulse from THG (Third Harmonic Generation) of a Qswitched Nd3+ : YAG laser was used to ablate silicon mounted in air. The time-and space-resolved optical emission spectra were measured for different pulse energy in the wavelength range of 380-420 nm, the emission spectra of N+ was found for impact ionization of air near target surface on the early stage of plasma plume expansion. Under the model of local thermodynamic equilibrium, the electronic temperature of plasma was deduced to be in the range of 18 000-40 000 K using the Saha equation by the relative line intensities, and the electron density was deduced to be in the 10(17) cm(-3) scale by FWHM (the full width at half maximum) of Si spectral lines, the temporal and spatial evolution of the electronic temperature and electron density was given, showing that the electronic temperature and electron density exhibited second order exponential decreasing with laser delay time and a Lorentz distribution in space. The reason for the spatial position deviation of the maximum electron density from the maximum spectral intensity was analyzed. The relationship between the plasma plume parameters and laser pulse energy was discussed. PMID- 20707171 TI - [Application of AAS to detecting the influence of railway on the soil of navel orange garden]. AB - Railway transportation has boosted the economy of railway road area, meanwhile it brings some undesirable impacts on the environment of the railway road area. The quality of the fruits is directly related with the elements of the soil, so understanding the element contents of soil in navel oranges garden in the vicinity of railway is meaningful to the security of agriculture products and ecological conditions in the areas surrounding the railways. As a favorite fruit, navel orange is widely planted around the railway in the south China, especially in Sichuan, Chongqing, Hubei, Jiangxi and Guizhou. The present paper studied the contents of Pb, Cd, Mn, Cu, Zn etc in the soil planting navel orange in the vicinity of Chengdu-Dazhou railway by AAS. The railway was built in 1997 and the research area was sited in Jintang county, Sichuan. The results showed that the contents of Pb and Mn in soil planting navel orange were significantly higher than those in the control soil, but the contents of Cd, Cu and Zn showed no significant difference. PMID- 20707172 TI - [Studies on cold resistance of hazel determined and analyzed by atomic absorption spectrometry]. AB - Using annual branch of hazel as the experimental materials, the K(+)-leakage and relative electric conductivity of three hazel species (six hazel clones) which had been treated with different low temperature were determined by electro conductivity gauge and atomic absorption spectrometry. Regression models were established for low temperature to the K(+)-leakage or the relative electric conductivity of six hazel clones. The results showed that there was the same result of cold resistance for all clones using the two methods of comprehensive evaluation, and the indicator of K(+)-leakage rate determined by atomic absorption spectrometry can be used as a means of early identification of cold resistance of hazel clones. There were obvious differences among the clones in the ability of cold resistance. The order of the ability of cold resistance for the six hazel clones was C7R7 > Z-9-40 > C6R1 > CS2R1 > Z-9-22 > Z-9-30, and the order of the ability of cold resistance for the three hazel species was C. heterophylla > C. heterophyllax X (C. heterophylla X C. avellana) > C. heterophylla X C. avellana. The median lethal temperature of tissue for all clones is -26(-)-40 degrees "C. PMID- 20707173 TI - [Thickness measurement of ultrathin SiO2 layer on Si by using XPS standard curve]. AB - A new method of standard curve analysis associated with X-ray photoelectron spectroscopy (XPS) is presented for measuring the thickness of ultrathin SiO2 layer on Si substrate. In this method, XPS spectra of series SiO2/Si standard samples with different known thicknesses of silicon oxides are firstly recorded, and then the ratios of Si2p peak heights corresponding to SiO2 and Si, viz. R = H(SiO2/H(Si), are calculated. The known thicknesses of silicon oxides are plotted against the peak height ratios and an XPS standard curve is derived. Under the same experimental conditions, the samples with unknown thicknesses are measured by using XPS technique and then their thicknesses can be obtained from the XPS standard curve. The SiO2 /Si standard samples were provided by authoritative lab with the advanced analytical equipments and rich experiences, and the oxide thicknesses were measured by multiple techniques. The present results show that the standard curve, plotted in terms of accuracy of the oxide thickness from the standard samples, can be used for the thickness measurement for ultrathin SiO2 on Si, and this method is valuable in practice owing to the swiftness, convenience and accuracy. PMID- 20707174 TI - [Analysis of decayed wood by fungi with X-ray diffractometry and Fourier transform infrared spectroscopy]. AB - In order to make clear the changes in the micro crystal structures of celluloses and the functional group of main components including cellulose, hemicelluloses and lignin in wood decayed by fungi, the crystallinity, layer spacing d in crystalline unit cell, width of crystallite and functional group of main components of Populus tomentosa Carr wood, which was decayed by Phanerochaete Chysosporium (white-rot) and Postia Placenta (brown-rot) with various durations, for two weeks, four weeks, six weeks, eight weeks and ten weeks, respectively, were investigated by means of X-ray diffraction and FTIR spectroscopy methods. It was concluded that the lattice structures of crystallite in wood cellulose were not destroyed by PC and PP, and the two theta angles and layer spacing d in crystallite were constant, although the decaying treatment times were different for each other when decayed by the same fungi. However, the crystallinity and width of crystallite decreased with the decaying treatment times increasing, and the decaying effects by PP were more significantly than those by PC, which showed that the damage extent of celluloses decayed by PP was greater than that by PC. It was estimated that the xylan in hemicelluloses had been degraded to various extents with the process of decaying in wood, resulting in the carbonyl content increasing, and the effects of degradation on hemicelluloses and celluloses by PC and PP were almost the same. Furthermore, benzene rings in lignin, which had no remarkable changes by PP, were oxidized into chain hydrocarbon after decaying by PC. PMID- 20707175 TI - [Comparison of correction methods for nonlinear optic path difference of reflecting rotating Fourier transform spectrometer]. AB - The principle of reflecting rotating Fourier transform spectrometer was introduced in the present paper. The nonlinear problem of optical path difference (OPD) of rotating Fourier transform spectrometer universally exists, produced by the rotation of rotating mirror. The nonlinear OPD will lead to fictitious recovery spectrum, so it is necessary to compensate the nonlinear OPD. Three methods of correction for the nonlinear OPD were described and compared in this paper, namely NUFFT method, OPD replace method and interferograms fitting method. The result indicates that NUFFT was the best method for the compensation of nonlinear OPD, OPD replace method was better, its precision was almost the same as NUFFT method, and their relative error are superior to 0.13%, but the computation efficiency of OPD replace method is slower than NUFFT method, while the precision and computation efficiency of interferograms fitting method are not so satisfied, because the interferograms are rapid fluctuant especially around the zero optical path difference, so it is unsuitable for polynomial fitting, and because this method needs piecewise fitting, its computation efficiency is the slowest, thus the NUFFT method is the most suited method for the nonlinear OPD compensation of reflecting rotating Fourier transform spectrometer. PMID- 20707176 TI - [Study on calibration method of spatial heterodyne spectrometer]. AB - Spatial heterodyne spectroscopy (SHS) is a novel method for hyperspectral analysis, but the calibration methods have not been thoroughly studied. The present paper gives some basic theories of SHS, and investigates the laboratory calibration methods, including spectral calibration and radiometric calibration. According to emission lines and the relation between detector size and system bandwidth, we designed the spectral calibration plan for SHS, which uses tunable laser and halogen lamp. Experiments show that the actual spectral range and resolution of our instrument is the same as it was designed, and the spectral shift is less by stability testing. For radiometric calibration, we measured the system's stability by using integrating sphere, and its responses were also calibrated by using standard lamp and diffuser. The experimental results, after validation, proved that our method can be used for SHS calibration. This is a fundamental work for quantified retrieval. PMID- 20707177 TI - [Baseline correction method for spectrum signal of SF6 insulating air with optimum wavelet basis]. AB - SF6 gas has been widely used in the power equipments as an excellent electric insulating and arc-quenching medium. In the present paper, a baseline correction method based on the optimum wavelet basis for spectrum detection is proposed to measure the composition content of the SF6 insulating gas to secure the power safety. In this method, the optimum wavelet basis is selected in the wavelet packet according to constructor function on the energy concentration criterion to express the spectrum signal in the time-frequency domain. Then the strong spectrum composition is removed from the spectrum signal with the threshold method to eliminate the interference with the continuous spectrum fitting. Finally we remove the continuous spectrum which is fitting result from the origin spectrum and obtain the useful signal of line spectrum. The intensities of spectral line processed with the proposed algorithm could reflect the concentration of the conponents to be measured in SF6 gas. Experiments to analyze the absorption spectrum of the SF6 insulating gas mixture show that the proposed algorithm can estimate and correct the drifting baseline accurately, and its performance is better than the algorithm based on iterative wavelet. PMID- 20707178 TI - [Coma and resolution in wide spectral region Czerny-Turner spectrometer]. AB - The Czerny-Turner layout, which is most frequently used in miniature spectrometers, should follow Shafer's coma-free condition and Fastie's flat-field principal to eliminate the central wave's primary coma and maximize its resolution. However, the design process does not take the comas and resolutions at non-central waves into consideration. Based on the theory of primary coma in reflection optical system, the present paper points out that in the crossed beam design, the resolutions at wide 'spectral region present a "V" shape, while in the M design, the resolutions change little over the whole region, and present an approximately straight line shape, so the latter kind of spectrometer maintains a far more consistent resolution than the former one. Accordingly, this paper designs two kinds of spectrometers with spectrum regions from 400 to 600 nm, and carries out theoretical simulation and contrast experiment. The result demonstrates that for the two designs the resolutions at the fringe wavelength are 3.8 times and 1.5 times respectively that at the central wavelength, which accords with the conclusion of the theoretical simulation. PMID- 20707179 TI - [Analysis and experimental validation of signal-to-noise for limb imaging spectrometer]. AB - Limb imaging spectrometer is an important new remote sensor for research and application. Signal-to-noise ratio (SNR) is one of the key parameters to quantitatively evaluate the image quality and radiometric performance of an imaging spectrometer. The estimation and testing of SNR are very important for developing an imaging spectrometer. From the perspectives of radiative transmission and energy conversion, the SNR model is proposed, and the SNR equation of dispersive-type limb imaging spectrometer is derived, and the SNR values under several observing conditions for an limb imaging spectrometer prototype developed are theoretically evaluated based on atmospheric radiative transfer code MODTRAN 4.0. The results show that the SNR of the prototype under typical viewing geometry is not less than 8. As experimental validation, SNR testing was performed using an internally illuminated integrating sphere, and the experimental results have proved the correctness of this theoretical model. PMID- 20707180 TI - [Thermal spectral property of prism in hyper spectral imager]. AB - Prism is one of the most key parts in the hyper spectral imager (HSI). Consequently, to set thermal control target and make thermal control design, the thermal spectral property of prism in the HSI was studied. The working principle of the HSI and the definition of its thermal spectral property were introduced. The working environment of prism and its thermal effect were analyzed; also the study contents and technical route of the prism's thermal spectral property were discussed. The effects of different uniform temperature field on deflexion angle and angular dispersion of the prism in the HSI were deduced, and the changes in displacement of the spectra and the spectral bandwidth under different uniform temperature were obtained. For one instance, the thermal spectral property of the K9 prism and the fused silica prism were compared based on FEM and combined experiments, furthermore, its thermal control target was ascertained and a thermal spectral property test was carried out to validate the rationality of the thermal spectral property analysis. The results of analysis indicated that the changes in spectral bandwidth and spectrum resolution brought by thermal distortions can be ignored according to current fixing mode, and the displacement of the spectra is mainly determined by thermal coefficient of material refractive index; because of it's the lower thermal coefficient of material refractive index, the displacement of the spectra of the K9 prism is smaller under the same temperature changes; the material deflexion changes (dn/dlambda) of prism are not sensitive to the temperature, so the changes in spectral bandwidth caused by them are not obvious. And the results of test proved that the studied method of thermal spectral property is reasonable and essential, and the results are authentic and credible. So it can provide some guidance for setting thermal control target and optimizing thermal control design. PMID- 20707181 TI - [Galaxy spectrum subtraction of a mixed spectrum based on two class PCA eigen spectra]. AB - The authors present a new method called two class PCA for decomposing the mixed spectra, namely, for subtracting the host galaxy contamination from each SN spectrum. The authors improved the quality of reconstructed galaxy spectrum and computational efficiency, and these improvements were realized because we used both the PCA eigen spectra of galaxy templates library and SN templates library to model the mixed spectrum. The method includes mainly three steps described as follows. The first step is calculating two class PCA eigen spectra of galaxy templates and SN templates respectively. The second step is determining all reconstructed coefficients by the SVD matrix decomposition or orthogonal transformation. And the third step is computing a reconstructed galaxy spectrum and subtracting it from each mixed spectrum. Experiments show that this method can obtain an accurate decomposition of a mixed synthetic spectrum, and is a method with low time-consumption to get the reliable SN spectrum without galaxy contamination and can be used for spectral analysis of large amount of spectra. The time consumption using our method is much lower than that using chi2-template fitting for a spectrum. PMID- 20707182 TI - [Techniques for pixel response nonuniformity correction of CCD in interferential imaging spectrometer]. AB - Based on in-depth analysis of the relative radiation scaling theorem and acquired scaling data of pixel response nonuniformity correction of CCD (charge-coupled device) in spaceborne visible interferential imaging spectrometer, a pixel response nonuniformity correction method of CCD adapted to visible and infrared interferential imaging spectrometer system was studied out, and it availably resolved the engineering technical problem of nonuniformity correction in detector arrays for interferential imaging spectrometer system. The quantitative impact of CCD nonuniformity on interferogram correction and recovery spectrum accuracy was given simultaneously. Furthermore, an improved method with calibration and nonuniformity correction done after the instrument is successfully assembled was proposed. The method can save time and manpower. It can correct nonuniformity caused by other reasons in spectrometer system besides CCD itself's nonuniformity, can acquire recalibration data when working environment is changed, and can also more effectively improve the nonuniformity calibration accuracy of interferential imaging PMID- 20707183 TI - [Research on laser spectrum detecting technology based on the bilateral-wedges Fourier interferometer]. AB - To increase the spectrum resolution without changing the size of static Fourier interferometer, the bilateral-wedges Fourier transform interferometer was designed and the methods of stretching interference fringes in the same optical path difference were proposed. Through analyzing the optical path difference function between the bilateral-wedges Fourier transform interferometer and static Fourier transform interferometer, the spectrum resolution was enhanced to 9.1 cm( 1) with the same size, and the enhancement was nearly 8 times. It will not bring about being unable to collect the interference fringes due to fringe aliasing. In the experiments, the bilateral-wedges Fourier transform interferometer was made by the BK7, using laser with six different wavelengths to show analysis of interference fringes. The experimental result demonstrated the interference fringes to be longer than normal with the augmentation of the reflection position. Of course, the kind of this error can be calibrated, because it is linear augmentation by wavelength. According to the calculation, it is known that each 1 nm of the laser wavelength change causes 0.021 1 nm increase in the error. After the spectrum calibration, the system can detect the correct spectrum data, raising the spectrum resolution with the same size. PMID- 20707184 TI - [Fiber monitoring network of methane concentration based on space division multiplexing in coal mine]. AB - Methane explosion accidents occur frequently, and accurate and real-time detection and early warning of methane concentration are the effective means of preventing these accidents. The research was based on the spectrum absorption properties of methane, and a near-infrared tunable DFB laser diode of 1.65 microm wave band was used. With the mode-hopping features of laser diode, a differential absorption of double-wavelength and single-fiber optical sensor network was designed. Sixteen methane sensors were multiplexed in this system with space division multiple access technology and optical switch, and the key technologies of anti-dust in gas absorption cell were researched. All signals were gathered by the PCI data acquisition card, and information of each way was analyzed and displayed with virtual instrument. The results of experiment show that the method can reach the sensitivity of 0.05% even without using a phase-locked amplifier and the absorption light path is only 10 centimeters. Long-time accuracy and stability of all sensors could meet the practical demands, and the response time of each sensor was less than 1 seconds. With the replacement of lasers, the network can be used for the real-time detection of other gases. PMID- 20707185 TI - [Determination of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucopyranoside and anthraquinon simultaneously in Polygonum multiflori of different growing stage and gathering periods by HPLC]. AB - OBJECTIVE: A HPLC method was established for the determination of 2, 3, 5, 4' tetrahydroxystilbene-2-O-beta-D-glucopyranoside and anthraquinon simultaneously in Polygonum multiflori. The contents variation from different growing stages in P. multiflori were observed. METHOD: The HPLC method was used to measure the contents of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-beta-D-glucopyranoside and anthraquinon simultaneously in 14 years old P. multiflori which were harvested in July to December. Chromatographic conditions: The chromatography column was C18 with a mobile phase composed of methanol-0.1% water phosphoric acid. The detection wavelength was 320 nm and 254 nm respectively, and the flow rate was 1.0 mL x min(-1). RESULT: In a certain range, 2, 3, 5, 4'-tetrahydroxystilbene-2 O-beta-D-glucopyranoside, emodin and physcion showed good linearity, precision, reproducibility, stability and average recovery. CONCLUSION: The developed method is sensitive, accurate. The contents of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-beta D-glucopyranoside and anthraquinon in P. multiflorum rapidly accumulated in one to two years, and in three year that was the highest. The samples collected in November accumulate much higher amounts of 2, 3, 5, 4'-tetrahydroxystilbene-2-O beta-D-glucopyranoside and anthraquinon than those which were collected in other months. PMID- 20707186 TI - [Determination and principal components analyze of mineral elements in different population of Thesium chinense]. AB - OBJECTIVE: To determine the concentration of mineral elements and analyze the principal components in Thesium chinense. METHOD: Mineral elements were determined by ICP-DES. Principal components analysis (PCA) was used toanalyze and evaluate the characteristic elements. RESULT: T. chinense contained more than 17 mineral elements, Fe, Zn, Cu, Mn, Cr, Co, Ni, Sr, B, Ca, P, K, Na, Mg, Mg, Mn, Zn and Cu were abundance in T. chinense. The concentration of Mn and Zn were about 100 microg x g(-1), Mg was from 1 898.0 to 3 137.73 micro x g(-1), Fe > 500 microg x g(-1). PCA concluded that four factors (F1, F2, F3, F4 ) could be used to evaluate the quality of T. chinense. The function is following: F = 0.444 77F1 + 0.237 71F2 + 0.167 28F3 + 0.150 24F4. The scores of different populations of T. chinens were from 0.627 to 0.189. Zn,Cu,Mg,P, K, Al, Fe, Cr, Na, Co, Pb, Mn, B and Ca were the characteristic elements of T. chinense. CONCLUSION: T. chinense contain more than 17 mineral elements. Zn, Cu, Mg, P, K, Al, Fe, Cr, Na, Co, Pb, Mn, B and Ca were the characteristic elements of T. chinense. PMID- 20707187 TI - [Effects of continuous cropping obstacle on growth of Angelica sinensis and its mechanism]. AB - OBJECTIVE: To study the effects of continuous cropping obstacles on growth of Angelica sinensis. METHOD: The growth indexes, photosynthetic characteristic, activity of leaf protective enzymes, and the yield, essential oil content and extract content were determined. RESULT: Continuous cropping decreased the growth and the yield, essential oil content, extract content of A. sinensis. Photosynthetic pigment, which include Chla and Chlb, and photosynthetic rate of A. sinensis leaves decreased. Activity of leaf SOD, POD and CAT were also inhibited. The content of proline, soluble sugar and MDA increased. CONCLUSION: Through decreasing the activity of protective enzymes and their ability of cleaning free radical, continuous cropping made free radical remain in plant so that induced membrane lipid peroxidization, electrolytic leakage became heavier, content of proline and soluble sugar increased. The external manifestation of this influences were that plant growth was inhibited, content of photosynthetic pigments decreased, so did the intensity of photosynthesis and respiration, content of dry mass. PMID- 20707188 TI - [Differences in shapes and properties and microscopic frameworks of wild and cultivated Radix Salviae Miltiorrhizae from different regions]. AB - OBJECTIVE: To compare the differences in shapes and properties and the microscopic frameworks of the wild and cultivated Radix Salviae Miltiorrhizae from different regions. METHOD: The differences in the shapes and properties, the characters of transverse sections, the powder and disintegrated tissue of roots were compared using microscopic measurement and statistics analysis. RESULT: The wild Radix Salviae Miltiorrhizae had several long cylinder roots with rough flaky squama skin and brown red or wine culour, the cultivated had root of many branch with cling skin and brick-red or chestnut culour. The difference of microscopic histological structure was that the xylem vessel of wild Radix Salviae Miltiorrhizae had bunched vessel with the rank form of big diameter alternating with small diameter, and had stone cell on samples from some producing region, the xylem vessel of the cultivated had no bunched vessel and no stone cell with the rank form of tangential radial. Radix Salviae Miltiorrhizae cultivated in Sichuan Province is called original-region medicinal materials and named Chuandanshen. Chuandanshen had the differences with the Salviae Miltiorrhizae Radix cultivated in other region. The root of Chuandanshen had 1.2 cm diameter, and was bulky and fat with solid fabric and the fracture with brownish yellow color and cutin-alikeness, its xylem vessel of transverse section of root was thin with the rank form of tangential radial, and 19-24 vascular bundle and a few wood fiber. CONCLUSION: Salviae Miltiorrhizae Radix of the wild and the cultivated, of the original-region (Chuandanshen) and the other-region, have the differences in the shapes and properties, and the microscopic frameworks. The character can be identified by the differences in the shapes of medicinal materials, and the rank form of vascular bundle of transverse section of root. PMID- 20707189 TI - [Lethal effects of entomopathogenic nematodes on larvae of Dorysthenes hydropicus in laboratory experiment]. AB - In order to explore the environmental pest management method of Dorysthenes hydropicus, three strains of entomopathogenic nematodes, viz. Heterorhabditis bacteriphora (H06), Steinernema scapterisci (SS), S. carpocapsae (All) were used on larvae of Dorysthenes hydropicus, with treatments of 0, 5 000 and 10 000 nematodes each larva. The result showed that these three strains viz. All, H06 and SS had high lethal effects on the larvae. Lethal rates had dose-effects relationship with inoculation amounts. High dose treatments resulted in high mortalities and led to quick death, especially in the treatment of H06. Treatment of H06 with 10 000 nematodes per larva resulted in 100% mortality after inoculated 4 days. Different strains of these nematodes had various lethal characters, H06 with only one peak mortality, the larvae died quickly after inoculated, while All and SS with 2 peak mortalities, there was a stable stage with low mortality between the 2 peak mortalities. Entomopathogenic nematodes could be used as a hopeful method for controlling of Dorysthenes hydropicus in fields. PMID- 20707190 TI - [Pharmacognostical and chemical studies of Lysinotus wilsonii]. AB - OBJECTIVE: To provide evidences for the pharmacognostical and chemical identification and the further development of Lysinotus wilsonii. METHOD: The paraffin section method was used for the microscopic identifications of stems and leaves. The slide with chloral hydrate was applied for the microscopic identifications of the powder of stems and leaves. The HPLC was used for the identification of the phenylpropanoids. RESULT: An obvious periderm consisted of a line of inseparable cells, lots of stone cells existed in the periderm and cortex, narrow ring of xylem and broad pith could be easily observed in the stem transaction of L. wilsonii. Epidermis was composed of one lines of parenchyma, three lines of epithelial cells in the side of above epidermis, palisade tissue was composed of 2-3 lines of square and thin cells and amphicribral vascular bundle in transaction of midrib also could be observed in the leaf transaction of L. wilsonii. Long xylem fibers, lots of pitted vessels, stone cells and anomocytic type stomas existed in the powder of L. wilsonii. Acteosidel and caleolarioside B were detected in L wilsonii. CONCLUSION: The pharmacognostic and chemical characteristics of L. wilsonii can be used for authentication of the plant. PMID- 20707191 TI - [Evaluation on SMEDDS of effective parts from Jiaotai pills in vitro and in vivo]. AB - OBJECTIVE: To investigate the properties of self-microemulsifying drug delivery system (SMEDDS) of effective parts from Jiaotai pills, and evaluate the character on improving intestinal absorption in rat. METHOD: The appearance, the morphology, the particle size, tape, the time of formulating micro emulsion, the content and the stability were investigated; Taken total alkaloid as index, the intestinal absorption were investigated by using in situ recirculation model and comparing the micro emulsion solution and reference solution, The T (relative percentage remained) and K(a) (absorption rate constant) were calculated. RESULT: After self-microemulsified, the average diameter of microemulsion was 34.12 nm and the time of self-microemulsifying was less than 3 min. SMEDDS was stable in room temperature in 3 months. The microemulsion were stable in 0.1 mol x L(-1) HCl at 37 degrees C for 8 h. T and K(a) of total alkaloid in SMEDDS were much higher than in that of its reference (P < 0.01), and the former K(a) was 152.6% of versus reference. CONCLUSION: SMEDDS might significantly improve the absorption of both poorly soluble and low biological availability drugs in the intestinal tract, and increase drug stability, which will be suitable for compound Chinese medicine. PMID- 20707192 TI - [Separation of gamma linolenic acid from evening primrose oil with urea inclusion -orthogonal experiment of optimizing technological parameters and observation of urea inclusion compound I]. AB - OBJECTIVE: The influence on the urea inclusion compound under different conditions (allocated proportion, time of inclusion, temperature of inclusion) were studied through the orthogonal test, and theoretical reference of urea inclusion process for further optimization wound be offered. METHOD: The orthogonal experiment was adopted, and microscope was used to observe the shape, aperture size of the urea inclusion compound under different technological parameters, the GC was employed to inspect the purity of GLA. RESULT: The results indicated that the ratio of fatty acids and urea, inclusion of temperature, time of inclusion had great effect on urea inclusion compound. The three factors and its interactions significantly affected the purity of GLA. The results also showed that the best process was that the ratio of fatty acids and urea was 1 : 3, temperature of inclusion was--15 degrees C, time of inclusion was 24 h. CONCLUSION: Under the best condition, the purity of GLA reach up to 95.575 9%; and it is feasible to observe the shape and the amount of the urea inclusion compound to reflect and guide the urea inclusion technology. PMID- 20707193 TI - [Optimization of combination modes of medical materials in extract of Huanglian Jiedu decoction by semi-bionic extraction]. AB - OBJECTIVE: To optimize the combination modes of medical materials in extract of Huanglian Jiedu decoction. METHOD: Divided the medical materials of Huanglian Jiedu decotion into 15 groups and extracted by semi-bionic estraction (SBE), the contents of berberine, baicalin, geniposide, total alkaloid, total flavonoid, total integral calculus area of HPLC and extract of 1 000 were determined, standardized, weighted and evaluated, respectively. RESULT: The maximum evaluated value Y for the extracting technique was AD + BC. CONCLUSION: The optimal combination mode of the perscription is that Rhizoma Coptidis and Fructus Gardeniae, Radix Scutellariae and Cortex Phellodendri Amurensis are decocted together respectively then the two decoctions are merged. PMID- 20707194 TI - [Chemical constituents of stems and branches of Adina polycephala]. AB - OBJECTIVE: To investigate chemical constituents of the stems and branches of Adina polycephala and their pharmacological activities. METHOD: The constituents were isolated by a combination of various chromatographic techniques including column chromatography on silica gel, Sephadex LH-20, and C-18, as well as reversed-phase HPLC. Structures of the isolates were identified by spectroscopic data analysis. In vitro cytotoxic, anti-inflammatory, anti-oxidant, anti-HIV, neuroprotective and anti-diabetic activities were screened by using cell-based models. RESULT: Twenty-eight constituents were isolated. Their structures were identified as clemochinenoside B (1), kelampayoside A (2), osmanthuside H (3), 4 hydroxy-3-methoxyphenol-beta-D-[6-O-(4-hydroxy-3,5-dimethoxylbenzoate)] glucopyranoside (4), and syringic acid beta-D-glucopyranosyl ester (5). Ten iridoidal glycosides: geniposidic acid (6), geniposide (7), 6beta hydroxygeniposide (8), 6beta-hydroxygeniposide (9), ixoside (10), ixoside 11 methyl ester (11), 11-methyl forsythide (12), 7beta-hydroxysplendoside (13), gardoside (14) and mussaenosidic acid (15), (+) -pinoresinol (16), (+) medioresinol (17), (+) -syringaresinol (18), (-)-lariciresinol (19), evofolin-B (20), alpha-hydroxyacetovaillone (21), syringic acid (22), vanillin (23), 3, 4, 5 trimethoxyphenol (24), and 2,6-dimethoxy-1, 4-benzoquinone (25), beta-sitosterol (26), mannitol (27), and daucosterol (28). At a concentration of 1.0 x 10(-5) mol x L(-1), these compounds were inactive in the assays, including cytotoxicity against human tumor cell lines (HCT-8, Bel-7402, BGC-823, A549 and A2780), anti inflammatory activity against the release of beta-glucuronidase in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor (PAF), antioxidant activity in Fe(2+)-cystine-induced rat liver microsomal lipid peroxidation, anti-HIV activity against HIV-1 replication, neuroprotective activity against serum deprivation or glutamate induced neurotoxicity in cultures of PC12 cells, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). CONCLUSION: Compounds 1-20 were obtained from the genus Adina for the first time. The 13C-NMR data of compounds 10 and 11 were reassigned. A further evaluation of pharmacological activity of these compounds is expected. PMID- 20707195 TI - [Alkaloids in stems and leaves of Stephania cepharantha]. AB - OBJECTIVE: To study the alkaloids in the stems and leaves of Stephania cepharantha. METHOD: The dried stems and leaves of S. cepharantha were percolated with 95% ethanol and the solvent was removed by rotary evaporation to give a concentrate, and the concentrate was extracted by petroleum ether and chloroform. Column chromatograghy on MCI CHP 20P, silica gel, Rp-18, Sephadex LH-20 and polyamide were applied for the isolation and purification of the chloroform fraction. The structures were elucidated by their physicochemical properties and spectral data. RESULT: Eleven alkaloids were obtained and identified as lysicamine (1), tetrahadropalmatine (2), palmatine (3), isocorydione (4), corydalmine (5), corypalmine (6), sinoracutine (7), sinoacutine (8), cepharamine (9), isocorydine (10) and corydine (11). CONCLUSION: Compounds 2-7 were isolated from S. cepharantha for the first time, and compound 7 was isolated from the genus Stephania for the first time, compound 4 was isolated from the Menispermaceae family for the first time. PMID- 20707196 TI - [Determination of five active constituents in aerial part of Tibetan medicine Gentiana straminea by HPLC]. AB - A new RP-HPLC method was developed for the simultaneous determination of 5 active constituents, including loganic acid, swertiamarin, gentiopicroside, sweroside, isoorientin in aerial part of Gentiana straminea. Analysis was achieved on a Hypersil ODS analytical column (4.6 mm x 250 mm, 5 microm) eluted with methanol and water containing 0.02% phosphoric acid in gradient elution. The flow rate was 1 mL x min(-1), the column temperature was set at 35 degrees C and detection wavelength was set at 254 nm. The results showed that 5 active components were separated well and showed good linearity. The corelation coefficints and concentration ranges of the calibration curves were as follow: r = 0.999 9, 0.364 2.18 microg for loganic acid. r = 0.999 9, 0.275-1.65 (microg for swertiamarin. r = 0.999 9, 0.614-3.68 microg for gentiopicroside. r = 0.999 9, 0.065 6-0.394 microg for sweroside. r = 0.999 9, 0.089 9-0.539 microg for isoorientin. The contents of loganic acid and gentiopicroside far exceed that of the other 3 active components, and made up 60% in the total contents. The developed method was proved to be rapid, sensitive, accurate, credible and repeatable. It can be applied to quality control of aerial part of Tibetan medicine Gentiana straminea. PMID- 20707197 TI - [Comparation study on quality of different population of wild and breeding Whitmania pigra]. AB - OBJECTIVE: To examine the quality of Whitmania pigra from the different populations to provide the basis for new species selection. METHOD: The contents of the moisture, alcohol extractive, total ash, acid-insoluble ash, and the activity of antiplatelet aggregation enzyme of wild and the breeding W. pigra were determined by the methods were determined in Chinese Pharmacopoeia (2005 edition). The contents xanthine and hypoxanthine by HPLC. RESULT: It showed that the contents of the alcohol extractive, total ash, acid-insoluble ash, antiplatelet aggregation enzyme, and xanthine and hypoxanthine content of the breeding population in Nanjing are lations. Many quality indexes of the breeding in Zhejiang Tongxiang base were beffer than the wild. CONCLUSION: The breeding W. pigra are good in quality, It suggested large-scale promotion of aquaculture. PMID- 20707198 TI - [Determination of quercetin-3-O-alpha-L-arabinopyranoside in Periploca forrestii by RP-HPLC]. AB - The aim of the paper was to develop a HPLC method for the quality control of Periploca forrestii Schltr. The 18 samples were analyzed on a Hypersil C18 column. The mobile phase was methanol-water (33:67) and the flow rate was 1 mL x min(-1). The detection wavelength was at 370 nm and column temperature was 25 degrees C. The linear relationship was good (r = 0.999 9) in the range of 0.204 4 2.044 microg for quercetin-3-O-alpha-L-arabinopyranoside. The average recovery was 97.78% (RSD 0.8%, n = 9). The contents of 18 samples varied from 0.171% to 0.264%. The method showed high precision, good repeatability and stability, so it can be used to assess the quality of P. forrestii. PMID- 20707199 TI - [ROS is not involved in induction of cell death by Ent-11 alpha-hydroxy-15-oxo kaur-16-en-19-oic-acid in HepG2 cells]. AB - OBJECTIVE: To identify the role of reactive oxygen species (ROS) formation on cell death induced by Ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) in HepG2 cells. METHOD: MTT assay was used to determine the effect of 5F on proliferation of HepG2 cells, and apoptotic morphological changes were assessed using Hoechst/PI assay. To evaluate intracellular ROS levels, a GENMED kit was used. HepG2 cells were treated with 5F for 24 h or with 1 mmol x L(-1) GSH for 1 h prior to treatment with 5F for 24 h, then cytoplasmic mono- and oligonucleosomes were assessed with Cell Death Detection ELISA kit. RESULT: The cytotoxicity of 5F on HepG2 cells was elevated with increasing 5F concentrations, as evidenced by the cell viability assay, and the apoptotic changes such as chromatin condensation were confirmed by Hoechst/PI staining. The decrease in ROS generation was observed in HepG2 cells following treatment with 5F. Cytoplasmic mono- and oligonucleosomes induced by 5F were not changed by decreasing basal level of ROS-mediated signaling with GSH. Further more, induction of ROS production by cisplatinum (CDDP) was canceled by treatment with 5F and 5F revealed a additive effect to cell killing by CDDP. CONCLUSION: 5F can not only induce apoptosis through non-ROS-depandent pathway, and can abate oxidant stress. PMID- 20707200 TI - [Cigu Xiaozhi pills's influence on lipid peroxidation and TNF-alpha expression in liver tissues of rats with nonalcoholic steatohepatitis]. AB - OBJECTIVE: To investigate the effect of Cigu Xiaozhi pills on expression of tumor necrosis factor alpha (TNF-alpha) in rat with nonalcoholic steatoheptatitis (NASH). METHOD: Fifty male SD rats were divided randomly into five groups: the normal group (n = 10), the model group (n = 10), the high dosage group (n = 10) and the little dosage group of the treatment (n = 10), Dongbao Gantai group (n = 10). Rats in normal control group were fed with standard diet. Rats in other four groups were established models of nonalcoholic steatohepatitis and were treated simultaneously with traditional Chinese medicine and positive medicine. Histopathological changes in the liver were observed. The serum ALT, AST, TG, TC and hepatic MDA, SOD, GPX were detected histologically. The expression of TNF alpha in the liver was determined using the immunohistochemical technique and RT PCR. RESULT: In model group, extensive adipose degeneration and inflammatory cell infiltration were found in the liver. In treatment groups steatohepatitis were markedly alleviated. Compared with model group, TG, TC, ALT, AST of the serum and MDA of liver tissue were reduced significantly, and SOD, GPX were increased significantly in treatment groups and positive control group (P < 0.05). TNF alpha was not expressed almost in normal rat liver and was expressed highly in model rat liver. Compared with model group, the TNF-alpha mRNA and protein expression were significantly lower in liver of treatment groups and positive control group (P < 0.05). And the effects of high dosage group surpass than those of Dongbao Gantai group (P < 0.05). CONCLUSION: TNF-alpha plays an important role in NASH pathogenesis. Cigu Xiaozhi pills can effectively treat experimental nonalcoholic steatohepatitis in rats, and its mechanism may be associated with ameliorating hepatocellular steatosis, removing the free radicals and enhancing the capability of anti-oxidation and anti-inflammatory. PMID- 20707201 TI - [Effect and mechanism of total flavonoids of orange peel on rat adjuvant arthritis]. AB - OBJECTIVE: To investigate the effect of the total flavonoids of orange peel (TFO) against adjuvant arthritis (AA) and the underlying mechanism. METHOD: AA model was induced in male Wistar (correction of SD) rats by immunization with Freund's complete adjuvant Pad thickness was assayed by caliper. Pathological impairment of ankle joint was analysised by hematoxylin and eosin (H&E) staining. Levels of tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1beta and prostaglandin (PG) E2 in serum was detected by radioimmunoassay method. Cyclooxygenase (COX)-2 expression in synovium tissues was measured by Western blot assay. RESULT: The 75 mg x kg(-1) and 150 mg x kg(-1) TFO treatment obviously decreased the pad thickness and improve the pathological impairment of ankle joint of AA rats. In addition, abnormal elevation of TNF-alpha, IL-1beta and PGE2 in serum and COX-2 expression in synovium tissues of AA rats were markedly repressed by TFO treatment. CONCLUSION: TFO can inhibit the development of AA in rats, and the mechanism were likely due to depressing inflammatory mediators production. PMID- 20707202 TI - [Effects of Chuankezhi injection on airway inflammation in mouse model of asthma and isolated guinea-pig airway smooth muscle]. AB - OBJECTIVE: To observe the effects of inhaled Chuankezhi injection (CKZ) on airway inflammation in a mouse model of asthma and dilation of isolated guinea-pig airway smooth muscle in vitro, which can provide pharmacodynamic evidence for CKZ treating acute attack of asthma. METHOD: BALB/c mice were sensitized with ovalbumin (OVA) on Days 1, 15, and then were inhaled with OVA aerosol on Days 22 28. The sensitized mice were administered with inhalation of aerosolized CKZ injection (0.2, 0.4, 0.8 mL x kg(-1), bid), or intraperitoneal injection of CKZ (0.4 mL x kg(-1), bid), dexamethsone (0.5 mg x kg(-1) x d(-1)) and saline (control) on Days 22-28. Airway inflammation was evaluated by counting cells in bronchoalveolar lavage fluid (BALF) and by lung histology. The influences of CKZ on the dilation of tracheal smooth muscle in guinea-pig and the contraction induced by carbamylcholine (CCH)/histamine in vitro were also observed. RESULT: In vivo, OVA-sensitized mice developed a significant airway inflammatory response that was significant inhibited by inhalation of CKZ (0.8 mL x kg(-1), bid), and intraperitoneal injection of CKZ (0.4 mL x kg(-1), bid) and dexamethasone (0.5 mg x kg(-1) x d(-1)). in vitro, CKZ did not dilate tracheal smooth muscles in guinea pigs, and did not attenuate the contraction induced by carbamylcholine (CCH)/histamine. CONCLUSION: CKZ can modulate airway inflammation in asthma, but has no dilation effect on the tracheal smooth muscle in guinea-pig in vitro. These results demonstrate that inhaled CKZ is not a preferred administration. PMID- 20707203 TI - [Neuroprotective effects of serum with Tongqiao Huoxue decoction (TQHXD) against glutamate-induced neurotoxicity in PC12 cells]. AB - OBJECTIVE: To observe the protective effect of serum with Tongqiao Huoxue decoction (TQHXD) on PC12 cells damaged by glutamate(Glu) and provide clinical proof of the formulae. METHOD: Sprague Dawley rats underwent intragastric administration of Tongqiao Huoxue decoction twice a day for five days, the administration dose for rats was 4 g x kg(-1). Thus the serum containing TQHXD was prepared. The model of neurocytes damaged by Glu had been established by adding 12.5 mmol x L(-1) Glu to culture medium of PC12 cells. Photic microscope had been used to observe the morphologic changes of cells, the proliferation and activity of PC12 cells had been detected by MTT. Cell membrane permeability had been investigated by the methods of the coloration of trypan blue and AO/EB, the activities of LDH and the contents of NO in the supernatant of PC12 cells had been detected after 5%, 10%, 20% TQHXD being added to the culture medium of PC12 cells damaged by Glu. RESULT: The morphologic changes in cells were observed under the inverted microscope. Normal PC12 cells in control group were full and bright, but the cells exposed to Glu were shrank; moreover, some cells were disrupted, configuration of the cells in the TQHXD group was closed to that of normal group. Compared with model group, the ratio of living cells in the group being treated by TQHXD after trypan blue staining had a significant increase. After AO/EB staining, cells in TQHXD groups were less being stained by EB. The absorbance (A) values of TQHXD group increased largely. LDH and NO in cell culture supernatant had decreased, it had shown the marked difference. CONCLUSION: TQHXD showed an apparent protective effect on neurocytes damaged by Glu on proliferation activity and membrane permeability. PMID- 20707204 TI - [Effect of magnesium isoglycyrrhizinate on allergy contact dermatitis (ACD) in mice]. AB - OBJECTIVE: To investigate the effect of magnesium isoglycyrrhizinate (MgIG) on allergy contact dermatitis (ACD) in mice. METHOD: The model of ACD was sensitized and challenged by 1% dinitrofluorobenzene(DNFB).48 SPF grade mice were divided into 6 groups randomly: a control group, a model group, three dosage groups and a positive group. The drug was injected through vena caudalis. The change of ear's swelling and the scores of ear's thickness and erythema of each mouse was observed. The level of INF-gamma, IgE, IL-4 in serum was detected by ELISA method. Then the pathologic change of mice ears was using HE staining examined under light microscope. RESULT: MgIG could decrease (P < 0.05) the ear's swelling, the scores of ear's thickness and erythema, and INF-gamma and IgE level in mice serum. It was observed that MgIG could significantly alleviate the infiltrate of inflam cell and the hemangiectasis in ear tissue. CONCLUSION: Certain concentration of MgIG has significant therapeutic effect on ACD in mice. Therapeutic mechanism of MgIG may be relevant with the suppression of INF-gamma and IgE. PMID- 20707205 TI - [Study on pharmacokinetics of matrine by intramuscular administration in rat]. AB - OBJECTIVE: To study the pharmacokinetics of matrine (MT) intramuscular administration in rat. METHOD: Plasma concentration of matrine was determined by HPLC under the following conditions: column (Shim-pack VP-ODS, 4. 6 mm x 150 mm, 5 m); eluent (acetonitrile-0.02 mol ammonium acetate buffer-triethylamine 30: 70: 0.04); flow rate was 1 mL x min(-1) and ultraviolet detection wavelength was set at 220 nm; column temperature 40 degrees C; aliquot injected 20 microL. All data of concentration-time of matrine were treated with pharmacokinetics program DAS 2. 1. 1. RESULT: A simple, sensitive and reliable method for determining matrine in rat plasma by HPLC was established. The plasma concentration time profiles of MT fitted in with two-compartment models well, and the main pharmacokinetic parameters found for MT after i. m. infusion were as follows: C(max) = 21.113 9 mg x L(-1), t(max) = 0.75 h, t1/2alpha 1.34 h, t1/2beta = 3.509 h, AUC(0-t) = 90.984 mg x h(-1) x L(-1), AUC(0-infinity) = 100.346 mg x h(-1) x L(-1). CONCLUSION: Compare with oral administration, the matrine is absorbed well and distributes fast with intramuscular administration; the absolute bioavailability of matrine is higher. According to this, the pharmacological action is also stronger and duration is longer. PMID- 20707206 TI - [Analgesic effects and mechanism of Yuanhuzhentong capsule]. AB - OBJECTIVE: To study the analgesic effects and mechanism of Yuanhuzhentong capsule. METHOD: The rats trigeminal nerve headache model, the migraine model caused by nitroglycerim, and the mice hot plate test. The rat formalin test were used to evaluate the analgesic effects. The effects on mice automative activities, the content of monoamine neurotansmitters in rats trigeminal nerve headache model and the hemorrheology in model of blood stasis were investigated to analyze the analgesic effects. RESULT: Yuanhuzhentong capsule can prolong the latency of the rats trigeminal nerve headache model and reduce the durante dolors. It can relieve the reaction caused by nitroglycerim in different times and increase the threshold in mice hot plate test. It can decrease obviously the response time of the chronicity pain model rat caused by formalin in second phase and also decrease the counts of automative activities in 5 min. It can increase the content of 5-HT and decrease blood viscosity in blood stasis model rats. CONCLUSION: The results indicated that Yuanhuzhentong capsule has obvious analgesic effects, and the mechanism concernes with the sedation, adjusting the secretion of NT in brain and improving the blood circulation. PMID- 20707207 TI - [Mechanism study of beta-elemene derivative (ET) in NB4 cell on apoptosis induction]. AB - OBJECTIVE: beta-Elemene is an active component of herb medicine Curcuma wenyujin, N-(beta-elemene-13-yl)tryptophan (ET) was synthesized to increase the activity. The antiproliferative and apoptotic effects of ET were investigated with NB4 cell. METHOD: The mechanism of ET were studied with the technology of cell culture in vitro using MTT assay, flow cytometry and Western blot analysis. RESULT: ET inhibited cell growth and induced apoptosis in NB4 cell at concentrations less than 40 micromol x L(-1). The apoptosis induction of ET in NB4 cell was associated with the generation of hydrogen peroxide (H2O2) and activation of caspase-3. Catalase pretreatment blocked ET-induced apoptosis in NB4 cells. CONCLUSION: ET induces apoptosis through generation of H2O2 in NB4 cell. PMID- 20707208 TI - [Protective activity of different concentration of tea polyphenols and its major compound EGCG against whole body irradiation-induced injury in mice]. AB - OBJECTIVE: To evaluate the different concentrate of tea polyphenols (TP) and its compound for irradiation-protection and investigate its mechanism. METHOD: To evaluate the radioprotective activity, mice were exposed to whole body gamma irradiation. TP 80 and TP 50 (50, 10 mg x kg(-1)) and its major constituent epigallocatechin gallate (EGCG) (50, 10 mg x kg(-1)) were administered after irradiation to examine its inhibition against irradiation-induced injury. RESULT: This study indicate that in comparison with non-irradiated controls, irradiation resulted in a significant reduction the spleen index (spleen weight/body weight 100), haematological parameters (RBC, WBC and PLT), activity of superoxide dismutase (SOD), and increase of malondialdehde (MDA) level in 28 days. Oral administration of TP (50 mg x kg(-1)) shown the best effect on reducing the irradiation-induced injury on mice studied, and showed a protective effect against irradiation-induced haematological parameters (RBC, WBC and PLT), the spleen index and MDA level significant reduction, and antioxidase activity (SOD) decrease. CONCLUSION: The results suggest that TP 50 mg x kg(-1) and EGCG have in vivo antioxidant potential and radioprotective activity against whole body gamma irradiation in mice. It may be concluded that TP (50% EGCG) possess good irradiation-protective and antioxidant effect. PMID- 20707209 TI - [Research of coptis effect on incidence of neonatal jaundice based on Cox model]. AB - OBJECTIVE: To learn the effects of coptis in treating neonatal jaundice and to find the index that guides the clinical administration of the medicine. METHOD: Clinical data of 412 cases of neonatal jaundice were studied retrospectively, and univariate and multivariate analysis were made to the factors affecting the incidence according to the Cox model which led to the establishment of the predictive equation. According to the regression coefficients, the relative risk, wald value, the coptis effects were evaluated on the incidence of neonatal jaundice. RESULT: Single-factor Cox model analysis shows that there are five main factors affecting the incidence of neonatal jaundice, Multivariate Cox model analysis indicates that the five main factors are also independent factors that affect the incidence, the roles of which, ranking from minor to major are, in turn, age, applied coptis, ethnic, G6PD deficiency and cesarean section. Among them, the regression coefficient is -0.259, relative risk 0.772, wald value 6.832. It sugguests that coptis may reduce the incidence of neonatal jaundice, and that it is a protective factor. The prediction equation, by regression coefficients, which has been used to establish the incidence of neonatal jaundice, is as following: h(t, x) = h0 (t) exp (- 0.022 x2 - 0.494x3 + 0.344x8 + 0.226x9 - 0.259x10). CONCLUSION: Coptis is one of the important factors that affect the occurrence of neonatal jaundice, and it has a protective effect in preventing neonatal jaundice from occurrence. PMID- 20707210 TI - [Changes of plasma fibrinogen level among acute ischemic stroke subtypes according to TOAST criteria and effects of Songling Xuemaikang]. AB - OBJECTIVE: To investigate the changes of plasma fibrinogen level among acute ischemic stroke (ACI) subtypes according to Trial of Org10172 in Acute Stroke Treatment (TOAST) criteria and effects of Songling Xuemaikang. METHOD: The 160 patients with acute ischemic stroke were divided into two groups randomly: treatment group 85 cases (Songling Xuemaikang + Shuxuetong + Aspirin enterie coated tablets), control group 75 cases (Shuxuetong + Aspirin enterie ccoated tablets). The plasma fibrinogen was detected before and after treatment. RESULT: Compared with OC subtype, Fbg was higher in LAA, CE and SAO subtypes (P < 0.05). Compared with UE subtype, Fbg was higher in LAA, CE and SAO subtypes (P < 0.05). There was a significantly difference between LAA and SAO (P < 0.05). In LAA, SAO, CE of treatment group,the Fbg level were lowered significantly at the 15th day compared with pretherapy (P < 0.05). There was a significantly difference of Fbg between treatment group and control group In LAA, SAO and CE subtypes at the 15th day (P < 0.05). CONCLUSION: Fbg produces a marked effect at the pathomechanism of LAA, SAO and CE subtypes. Songling Xuemaikang can depress the plasma fibrinogen level of ACI, and be an effective adjunctive therapy on ACI. PMID- 20707211 TI - [Retrospective study of adverse reactions of Niuhuang Jiedu tablet (pill) and risk control based on literature analysis]. AB - In this retrospective study, 56 cases of adverse reactions caused by Niuhuang Jiedu tablet (pill) were statistically analyzed in respects of genders, ages, routes of administration, clinical manifestations, etc. We pinpointed that the main factors related to safety problems of Niuhuang Jiedu tablet (pill) are irrational drug use and drug quality, and put forward suggestions for strengthening the surveillance and administration of Niuhuang Jiedu tablet (pill) and improving clinical rational use. PMID- 20707212 TI - [Elucidation of compatibility principle and scientific value of Chinese medical formulae based on pharmacometabolomics]. AB - By using UPLC coupled with MS, the analysis of the constituents absorbed into blood after oral administration of Yinchenhao decotion with different combination had been carried out, the body fate of constituents detected in the blood was elucidated also; At the same time, the overall body respones after multi-input of the medical formule were evaluated by metabolomic analysis. These data explained the scientific values in both drug metabolisim and metabonomics, the results had given some new evidences for the potentialities of pharmacometabonomics to elucidate the compatibility principle of Chinese medical formule. As a conclusion, concept of "Pharmacometabolomics of Chinmediformulae" has been defined. PMID- 20707213 TI - [Thought and method of treating dyslipidemia]. AB - The formation of dyslipidemia is related to phlegm-blood stasis and Spleen-Kidney Deficiency in traditional Chinese medicine, the former of which is Biao and the latter is Ben of the disease. The therapeutic method is utilizing syndrome differentiation, specially get sick the special medicine and replenishing kidney. Long-term usage of lipid-regulating western medicine may cause Kidney Deficiency and Qi Deficiency, the phenomenon of which we should pay great attention to. PMID- 20707214 TI - [Current situation, problem analyses and its countermeasure of formulae of traditional Chinese medicine (FTCM) preventing and curing tumor angiogenesis]. AB - Malignant tumor is the common disease that threaten severely to people's health. Formulae of traditional Chinese medicine (FTCM), as the major component of traditional drugs, has played more important role on the prevention and cure to tumor. The Folkman's theory that tumorous growth depends on tumor neovascularization has been confirmed so many years, so to inhibit the tumor angiogenesis, is an important path to treat tumor. The research of FTCM to antagonizing tumor angiogenesis in our country has been started more lately. Since it has been reported some FTCMs can inhibit angiogenesis, and it also exists many problems. The article summarized the correlated research of FTCM to antagonize tumor angiogenesis for the past several years, and according this, analyzed, stated and commented to the problems, countermeasures, development and direction of PTCM to antagonize tumor angiogenesis. PMID- 20707215 TI - [Rising attention to the market to ratio meet demand of improving efficiency of pharmaceutical circulation--based on complicated variety and specification of drugs]. AB - Analyzing the complicated variety and specification of drugs and the objective demand of pharmaceutical circulation, to seek out the key factors in improving the efficiency of pharmaceutical circulation, for putting forward suggestions to promote the development of pharmaceutical circulation in China. The conclusion is drawed from industrial organization theory and successful experience of foreign countries, high market attention met with the demand of complicated variety and specification of drugs in pharmaceutical circulation. PMID- 20707216 TI - [Mitochondrial DNA: properties and applications]. AB - Mitochondria are the intracellular organelle responsible for the production of cellular energy. They play an important role in the regulation of cellular metabolism, apoptosis and oxydative stress control. Mitochondrial DNA (mtDNA) has many special features such as a high copy number in cell, maternal inheritance, and a high mutation rate which have made it attractive to scientists from many fields. In anthropological genetics, mtDNA is useful to trace geographic distribution of genetic variation, for the investigation of expansions, migrations and other pattern of gene flow. mtDNA is widely applicated in forensic science. It is a powerful implement to identify human remains. mtDNA is characterized by the high rate of polymorphisms and mutations. Some of which are increasingly recognized as an important cause of human pathology such as oxidative phosphorylation (OXPHOS) disorders, maternally inherited diabetes and deafness (MIDD), Type 2 diabetes mellitus, neurodegenerative disorders, heart failure and cancer. PMID- 20707217 TI - [Apoptosis induced by bleomycin: influence of cellular models]. AB - Bleomycins are a family of glycopeptides isolated from streptomyces verticillus and exhibiting antibiotic properties. They are commonly included in chemotherapy regimens used to treat patients with Hodgkin's or non Hodgkin's malignant lymphoma, squamous-cell carcinoma or germ-cell tumor. The chemical structure and action mode of bleomycin have been extensively studied, in contrast, the molecular mechanisms of the cytotoxic effects of bleomycin, in vivo, remain poorly understood. Recently, the apoptotics signaling pathway induce by bleomycin was the object of study, of many groups. In this sense, some studies suggested that bleomycin induce in some cells different apoptotic pathway in dose and time depending manner. The sensibility or the resistance to apoptosis induced by bleomycin may explain the sensibility or the resistance of tumor cells to bleomycin. The aim of this review was to describe the machinery of apoptosis induced by bleomycin in tumor cells. PMID- 20707218 TI - [HLA-G: an immunoregulatory non classical class I HLA molecule]. AB - HLA-G is a particular non classical HLA class I molecule. Despite its tissue restricted expression and low polymorphism, this molecule plays an important role in innate and adaptative immunity. The tolerogenic propriety of HLA-G makes it an immunomodulatory molecule acting in the early phases of conception, protecting fetal tissues from the maternal immune system. Immunomodulatory functions of HLA G and the associations of this molecule with some pathological states are reported in this review. So, little amounts of soluble HLA-G or particular allelic expression of this molecule are associated with some pregnancy complications. HLA-G expression on tumor cells by preventing antitumor responses via a trogocytosis mechanism and regulatory T cells induction is associated with invasiveness and clinical evolution of some tumor types. HLA-G is also involved in the protection of the transplanted tissues from rejection. Revealing of new more functional homomultimeric isoforms of this molecule offers new insight in a better understanding of clinical and biological role of HLA-G. PMID- 20707219 TI - [Immuno-modulating effects of eukaryotic expressing vectors of IL-12 and GM-CSF associated to DNA-based vaccination against experimental cutaneous leishmaniasis in BALB/c mouse]. AB - Different works of DNA based vaccination against leishmaniasis highlight the complexity of the induced immune responses to fight against the disease. In this work, we exploited the capacity of IL-12 and GMC-SF to activate immune cell mediators and effectors to induce a Th1 response, more capable of clearing the parasite. To generate these immunomodulating activities, we associated eukaryotic expressing vectors of murine IL-12 and GMC-SF to several DNA based vaccine candidates encoding to several L. (L.) major antigens, in the BALB/c mouse. When mice were challenged with a high parasitic load in the hind footpad, no additional protective effect could be generated. However, when the challenge was carried out in the inner face of the ear with a small parasitic load, the association of plasmids encoding to IL-12 and GMC-SF to DNA based vaccination, the protective effects were increased. PMID- 20707220 TI - Functional polymorphisms of PTPN22 and FcgR genes in Tunisian patients with rheumatoid arthritis. AB - To investigate a possible association between functional polymorphisms of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22-R620W) and receptors for the Fc fragment of IgG (FcgRIIa-H131R, FcgRIIIa-F158V FcgRIIIb-NA1/NA2), and rheumatoid arthritis (RA), 133 Tunisian patients with RA and 100 controls were genotyped. We found strong evidence of an association of PTPN22 620W allele and RA. However, analysis does not detect an association between auto-antibodies seropositivity, presence of nodules or erosions and this allele. No significant skewing of any of the three FcgR polymorphisms was seen in this RA group. Nevertheless, we identified FcgRIIIa-V/V158 as the most important FcgR genotype for severe disease subset with joint erosions and observed that patients with FcgRIIIb-NA2/NA2 genotype had an earlier incidence of clinical symptoms. In conclusion, we have confirmed that PTPN22 620W allele is associated with Tunisian RA but does not constitute a factor influencing clinical manifestations. Conversely, this study supports that the FcgRIIa/IIIa and IIIb polymorphisms could influence the course and the severity of this disease. A large number of samples are required to provide independent confirmation of these findings. PMID- 20707221 TI - Prevalence of autoantibodies in a Tunisian cohort of hepatitis C virus infected dialysis patients. AB - The hepatitis C virus (HCV) is the principal agent of viral chronic hepatitis. Cirrhosis and hepatocellular carcinoma are the major complications of this chronic infection. In haemodialysis, HCV infection remains a very frequent problem. Several autoimmune phenomena have been described during this infection. Two hundred haemodialysis patients, all of them anti-HCV (+), were included in this study to evaluate the frequency of Anti-Nuclear Autoantibodies (ANA), anti cardiolipine antibodies (ACL), anti-smooth muscle antibodies (ASMA), anti mitochondria antibodies (AMA), anti-thyroperoxydase antibodies (ATPO) and Rheumatoid Factor (RF) comparing them to healthy controls. Sixty eight serums (34%) patients were positive to at least one of the auto-antibodies tested. The difference between patients and controls was statistically significant. These markers were dominated by RF of the IgM isotype and ACL of the IgG isotype. Nevertheless, the positivity of ANA, ASMA, AMA and ATPO was not statistically different comparing to the controls. In addition, an association between the presence of the auto-antibodies and the viral replication was found suggesting that HCV is responsible for inducing these autoimmune phenomena. PMID- 20707222 TI - Comparison of hepatitis A seroprevalence in blood donors in South Tunisia between 2000 and 2007. AB - The aim of the study was to assess hepatitis A virus (HAV) seroprevalence in blood donors from South Tunisia in two periods 2000 and 2007. Serum samples collected from 376 blood donors in each period aged 18 to 30 years from different regions of South Tunisia were analysed for anti-HAV IgG. The global seroprevalence of HAV infection was 85.9% in 2007 as compared with 94.9% in 2000. The seroprevalence in the 18-20 years age group was 91.9% in 2000 vs 80.6% in 2007, and increased to 99% in 2000 and 92% in 2007 in the subjects over 26. Taking account of geographic area, the HAV seroprevalence in Sfax city decreased from 88.9% in 2000 to 62.7% in 2007 (p < 0.001), but it is still approximatively the same in rural areas (98.4% and 96%) and in the governorates of South Tunisia (97.6% and 99.2%). In conclusion, the number of adults in the city of Sfax which are not immunized against HAV is increasing. Thus, adolescents and young adults are at risk to develop symptomatic and potentially severe hepatitis A. PMID- 20707223 TI - [Avian infectious bronchitis disease in Tunisia: seroprevalence, pathogenicity and compatibility studies of vaccine-field isolates]. AB - A sero-epidemiological study was carried out on 5660 sera collected, between 2006 and 2008, from different flocks in different regions of the country. The ELISA results showed low levels of antibodies indicating vaccination failures. 45 to 69% of the flocks showed positive levels of antibodies and only 5 to 15% of these were protected. The pathogenicity studies of the Tunisian field isolates TN20/00 and TN335/01 demonstrated high clinical and lesion scores indicating the pathogenic effect of the two isolates. The challenge experiments conducted to evaluate the cross-protection between the H120 vaccine and the field isolates showed low protection rate, especially against the TN20/00 virus. The overall results allowed the determination of the pathogenic nature of the field isolates and a vaccination program based on the use of the only Massachusetts H120 strain did not reduce tracheal and kidney lesions. To better control the disease, adapting the vaccination program by using vaccine allowing better protection against variant strains, is recommended. PMID- 20707224 TI - Concordance with selected population recommendations for cancer prevention among third- and fourth-grade schoolchildren in Quetzaltenango, Guatemala. AB - BACKGROUND: The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 1997 recommendations for cancer prevention were meant to apply to children as well as adults. OBJECTIVE: To assess the concordance of behaviors and body composition of urban Guatemalan schoolchildren with the tenets of the WCRF/AICR 1997 recommendations. METHODS: A survey was conducted involving determination of 24-hour consumption of foods and beverages by a pictorial registry and height and weight measurements in 355 third- and fourth-grade schoolchildren in the western highland city of Quetzaltenango, Guatemala. Based on a previous, exhaustive parsing of the population goal recommendations of the WCRF/AICR 1997 report, 25 subcomponents were identified. Eleven could be evaluated with the survey data collected. Adult population criteria could be applied in seven, whereas four components had unique criteria adapted to this juvenile survey setting. RESULTS: The study sample was concordant on seven components-nutrient adequacy, total variety of foods consumed, plant-based diets, body mass index, vegetable and fruit intake, limitation of red meat consumption, and limitation of total fat consumption, and nonconcordant on four-variety of fruits and vegetables consumed, variety of starchy foods consumed, total intake of starchy foods, and limitation of sugar consumption. CONCLUSIONS: Educational and public health actions need to be conceived and implemented to further improve the rate of concordance of these 11 components with the WCRF/AICR 1997 recommendations for cancer prevention. PMID- 20707225 TI - Vitamin A fortification in Uganda: comparing the feasibility, coverage, costs, and cost-effectiveness of fortifying vegetable oil and sugar. AB - BACKGROUND: Twenty-eight percent of Ugandan preschool children suffer from vitamin A deficiency. With vitamin A supplementation covering only a third of children under 5 years of age, fortification is essential to reduce their vitamin A deficiency-related disease burden. At present, the only widely consumed food in Uganda that is fortified with vitamin A is vegetable oil. OBJECTIVE: To compare the feasibility, coverage, costs, and cost-effectiveness of fortifying vegetable oil and sugar with vitamin A in order to assess, from a public health policy perspective, whether sugar should also be fortified. METHODS: The 2005/6 Uganda Household Budget Survey was used to analyze households' apparent consumption levels of sugar and vegetable oil and to model the additional intake of vitamin A, assuming the sugar and oil fortification levels are those set by the Uganda Bureau of Standards. RESULTS: The annual incremental private sector cost of vitamin fortification is US $555,668 for oil and US $2,644,765 for sugar. Assuming that oil and sugar fortification are both effective in reducing vitamin A deficiency by 30% among those who consume these foods, the estimated cost per disability-adjusted life year (DALY) averted is US $82 for sugar and US $18 for oil. Vitamin Afortification of vegetable oil is 4.6 times more cost-effective than vitamin A fortification of sugar. If sugar were to be fortified, the 17% of Ugandans who purchase sugar but do not purchase oil would become new beneficiaries of vitamin A fortification. This would increase the coverage of vitamin A-fortified foods by 31% and reduce the percentage of Ugandans without any coverage to 25%. Those most at risk for vitamin A deficiency-members of rural, poor households-would benefit disproportionately from the introduction of sugar fortification. CONCLUSIONS: Although the lack of information on the vitamin A deficiency status of consumers of oil and sugar precludes making definitive conclusions, the increased coverage and cost per DALY averted due to sugar fortification suggests-based on World Health Organization guidelines-that the Government of Uganda should pursue sugar fortification. PMID- 20707227 TI - Iodine status and availability of iodized salt: an across-country analysis. AB - BACKGROUND: Iodine deficiency has serious consequences, and the Universal Salt iodization initiative has attempted to reduce the extent of deficiency. OBJECTIVE: We aim to see how far across-country variations in urinary iodine in school-age children can be explained by environmental factors, particularly soil iodine and the availability of iodized salt. METHODS: We use simple multivariate regression for two separate datasets, one for 30 developing countries, and one for 13 developed countries, using data on availability of iodized salt and soil iodine levels. RESULTS: Median urinary iodine excretion is significantly and positively related to household availability of iodized salt (elasticity, 0.73) for developing countries, but the soil coefficient is not significant, probably because the dummy variable is not well measured. For the developed countries, there is a positive and significant effect of salt penetration rates (elasticity, 0.83) and a positive and significant effect of soil iodine (elasticity, 0.77). There is also a suggestion that countries with more serious soil deficits are more likely to iodize salt, so that univariate regressions of urinary iodine excretion on salt availability or penetration rates underestimate the beneficial effects of iodized salt availability on iodine nutrition. CONCLUSIONS: There are limitations to cross-sectional (ecologic) studies such as this, and the data are not perfect. Nevertheless, the results provide support for policies to iodize salt, given the widespread deficiency of iodine in diets worldwide. PMID- 20707226 TI - Protein and amino acid intakes in a rural area of Bangladesh. AB - BACKGROUND: Few studies have described protein and amino acid intakes in rural Bangladesh, a country with considerable undernutrition. OBJECTIVE: The purpose of this population-based study was to assess and describe protein and amino acid intakes in Araihazar, Bangladesh. METHODS: The study participants were 11,170 adult men and women who participated in the Health Effects of Arsenic Longitudinal Study (HEALS), which had a 98% participation rate. Dietary exposures were assessed by a food-frequency questionnaire that had been designed and validated for the HEALS study population. RESULTS: The mean body mass index (BMI) was 19.7 among all participants, and 34.9% of women and 44.4% of men had a BMI below 18.5. The average caloric intake was 2142 and 2394 kcal/day among women and men, respectively, and the mean protein intake was 67.5 and 78.2 g/day. The largest sources of protein were from rice and fish. Greater protein intake was related to younger age and several socioeconomic measures, including more years of education, land and television ownership, and employment in business, farming, or as a laborer (for men) or as a homemaker (for women). CONCLUSIONS: This study found a high prevalence of underweight among study participants. Nonetheless, most participants had adequate protein intake according to Food and Agriculture Organization standards for body weight. PMID- 20707228 TI - Nutritional status of primary schoolchildren in Garhwali Himalayan villages of India. AB - BACKGROUND: Anemia and micronutrient deficiencies are common among Indian schoolchildren. However, past studies have narrowly focused on only a few micronutrients and have not carefully evaluated the association between sociodemographic factors and nutritional status of schoolchildren. OBJECTIVE: To assess the nutritional status of schoolchildren in Himalayan villages of India and to determine the relationships between their nutritional status, intestinal helminth infection, and sociodemographic characteristics. METHODS: A random sample of 499 children 6 to 10 years of age from 20 public primary schools was selected. Household sociodemographic data and morbidity data on children were collected through interviews with their caretakers. Height and weight were measured, and venous blood was drawn for assessment of hemoglobin, serum ferritin, soluble transferrin receptor, retinol, zinc, folic acid, vitamin B12, and C-reactive protein. Stool samples were analyzed for parasitic infections. Results. Underweight, stunting, and wasting were present in 60.9%, 56.1%, and 12.2% of schoolchildren, respectively. Anemia, iron-deficiency anemia, and low serum concentrations of ferritin, zinc, retinol, folate, and vitamin B12 were found in 36.7%, 10.2%, 24.1%, 57.1%, 56.1%, 67.9%, and 17.4% of the children, respectively. One-fifth of the children had intestinal parasites. Being underweight was associated with lower household wealth (p < .05). Helminth infection was associated with stunting, anemia, and low serum retinol (p < .05). Living at higher altitude was associated with low serum levels of ferritin, retinol, and vitamin B12. There were no associations between any sociodemographic variables and serum zinc orfolate. CONCLUSIONS: Growth impairment and micronutrient deficiencies are prevalent among schoolchildren in Himalayan villages of India. PMID- 20707229 TI - Magnitude and distribution of vitamin A deficiency in Ethiopia. AB - BACKGROUND: Several surveys conducted over a period of 40 years have shown that vitamin A deficiency is a serious public health problem in Ethiopia. To address the problem effectively, up-to-date, comprehensive information on the magnitude and distribution of vitamin A deficiency is needed. OBJECTIVE: A national vitamin A survey was conducted to assess the national and regional prevalence rates of vitamin A deficiency in Ethiopia. METHODS: The survey employed a multistage, cluster-sampling approach and a cross-sectional study design. A total of 23,148 children aged 6 to 71 months and their respective mothers were examined for clinical signs and symptoms, and blood samples were collected from 1200 systematically selected children for serum retinol analysis. RESULTS: The findings indicated national prevalence rates of 1.7% for Bitot's spots among children. 0.8% for night-blindness among children, and 1.8% for night-blindness among mothers. Nationally, 37.7% of children (95% CI, 35.6% to 39.9%) had deficient serum retinol levels, 50.7% had been sick in the previous 15 days, and 22.6% had received vitamin A supplements in the previous 6 months. The prevalence of clinical vitamin A deficiency was significantly (p < .05) higher among children who were male, older, or rural residents. CONCLUSIONS: The study confirmed that vitamin A deficiency is a serious public health problem in Ethiopia. Intensification of the ongoing vitamin A supplementation program, postpartum vitamin A supplementation for mothers, intensifying efforts to improve the health status of preschool age children, and promotion of production and consumption of fruits and vegetables are recommended. PMID- 20707230 TI - Stunting associated with poor socioeconomic and maternal nutrition status and respiratory morbidity in Colombian schoolchildren. AB - BACKGROUND: There are few recent reports on the prevalence and risk factors of stunting and thinness among schoolchildren in Latin America. OBJECTIVE: To determine the prevalence and sociodemographic correlates of stunting and thinness among school-age children in Bogota, Colombia, and to examine whether these nutritional indices are associated with the risk of respiratory and diarrheal morbidity symptoms, visits to the doctor, and school absenteeism during the school year in a prospective study. METHODS: We obtained information on anthropometric and maternal sociodemographic characteristics of 3100 children 5 to 12 years of age who attended public primary schools in 2006 and who came from low- and middle-income households. Data on the incidence of common gastrointestinal and respiratory symptoms were collected prospectively on morbidity diaries throughout the year. RESULTS: The prevalence rates of stunting and thinness were 9.9% and 8.7%, respectively. There were inverse, statistically significant trends in the prevalence of stunting by categories of child's birth and current weight; maternal education level, height, and body mass index (BMI); and household socioeconomic stratum. A strong positive association was found with maternal parity (p for trend < .0001). Thinness was positively associated with the child's and the mother's age and inversely associated with birthweight and maternal BMI. Stunting was associated with a 44% increase in the incidence of cough with fever during the school year (p = .04). CONCLUSIONS: Child stunting in Bogota is associated with poor socioeconomic and maternal nutritional status and predicts symptoms of respiratory infection. PMID- 20707231 TI - Recommendations for improving Guatemala's food fortification program based on household income and expenditure survey (HIES) data. AB - BACKGROUND: Fortification offers great potential for reducing the enormous disease burden of micronutrient deficiencies. The lack of information on food consumption patterns has been a major impediment to the development of fortification programs. In some countries, the absence of this information has been an obstacle to the introduction of fortification. In countries that have fortification, governments are increasingly being challenged to provide evidence that programs are well designed and effective. OBJECTIVE: To examine the usefulness of household income and expenditure surveys (HIES) as a means for addressing this information gap and making fortification programs more evidence based and more accountable. METHODS: Data from Guatemala's 2005/6 Living Standards Measurement Survey are used to develop a measure of "apparent food consumption". The measure is used to assess Guatemala's fortification program by analyzing the coverage and the additional micronutrient intake attributable to different food vehicles, combinations of food vehicles, and fortification formulations. RESULTS: There are three key findings. The impact of the wheat flour fortification program is considerably greater than had previously been estimated; the level at which sugar is currently fortified with vitamin A may be excessive and should be reviewed; and fortifying semolina flour (used to make pasta) would extend the benefits of wheat flour fortification to 60,000 households that currently do not benefit from it and would increase the amount of fortified food consumed by 68% of the population. Beneficiaries would include 63% of the extreme poor, and the greatest benefits would go to those wheat flour consumers who currently benefit the least from consuming fortified wheat flour products. CONCLUSIONS: HIES data should be used more routinely as a tool in the designing, monitoring, and assessing of fortification programs. PMID- 20707232 TI - WHO/UNICEF/WFP/UNHCR consultation on the management of moderate malnutrition in children under 5 years of age. PMID- 20707233 TI - When the children smile: a tribute to the nutrition leaders of the early years at international organizations. PMID- 20707234 TI - The South Asia Infant Feeding Research Network (SAIFRN). Introduction. AB - The South Asia Infant Feeding Research Network (SAIFRN) was established in 2007 to foster and coordinate a research partnership among South Asian and international research groups interested in infant and young child feeding. SAIFRN has brought together a mix of researchers and program managers from Bangladesh, India, Nepal, Pakistan, and Sri Lanka together with international partners from Australia. As the first activity, SAIFRN conducted a series of analyses using Demographic and Health Surveys of Bangladesh, Nepal, and Sri Lanka and the National Family Health Survey of India. The results highlight that most indicators of infant and young child feeding in these four countries have not reached the targeted levels. The rates vary considerably by country, and the factors associated with poor feeding practices were not always consistent across countries. Driven by the ultimate goal of improved child survival in the region, SAIFRN wishes to expand its partnerships with governmental and nongovernmental organizations that share common interests both within and outside the South Asia region. In the future, SAIFRN hopes to provide more opportunities to researchers in the region to improve their skills by participating in capacity-building programs in collaboration with international partner institutions, and looks forward to liaising with potential donors to support such activities. PMID- 20707235 TI - Determinants of infant and young child feeding practices in Bangladesh: secondary data analysis of Demographic and Health Survey 2004. AB - BACKGROUND: In Bangladesh, poor infant and young child feeding practices are contributing to the burden of infectious diseases and malnutrition. Objective. To estimate the determinants of selected feeding practices and key indicators of breastfeeding and complementary feeding in Bangladesh. METHODS: The sample included 2482 children aged 0 to 23 months from the Bangladesh Demographic and Health Survey of 2004. The World Health Organization (WHO)-recommended infant and young child feeding indicators were estimated, and selected feeding indicators were examined against a set of individual-, household-, and community-level variables using univariate and multivariate analyses. RESULTS: Only 27.5% of mothers initiated breastfeeding within the first hour after birth, 99.9% had ever breastfed their infants, 97.3% were currently breastfeeding, and 22.4% were currently bottle-feeding. Among infants under 6 months of age, 42.5% were exclusively breastfed, and among those aged 6 to 9 months, 62.3% received complementary foods in addition to breastmilk. Among the risk factors for an infant not being exclusively breastfed were higher socioeconomic status, higher maternal education, and living in the Dhaka region. Higher birth order and female sex were associated with increased rates of exclusive breastfeeding of infants under 6 months of age. The risk factors for bottle-feeding were similar and included having a partner with a higher educational level (OR = 2.17), older maternal age (OR for age > or = 35 years = 2.32), and being in the upper wealth quintiles (OR for the richest = 3.43). Urban mothers were at higher risk for not initiating breastfeeding within the first hour after birth (OR = 1.61). Those who made three to six visits to the antenatal clinic were at lower risk for not initiating breastfeeding within the first hour (OR = 0.61). The rate of initiating breastfeeding within the first hour was higher in mothers from richer households (OR = 0.37). CONCLUSIONS: Most breastfeeding indicators in Bangladesh were below acceptable levels. Breastfeeding promotion programs in Bangladesh need nationwide application because of the low rates of appropriate infant feeding indicators, but they should also target women who have the main risk factors, i.e., working mothers living in urban areas (particularly in Dhaka). PMID- 20707236 TI - Infant and young child feeding indicators and determinants of poor feeding practices in India: secondary data analysis of National Family Health Survey 2005 06. AB - BACKGROUND: In India, poor feeding practices in early childhood contribute to the burden of malnutrition and infant and child mortality. OBJECTIVE: To estimate infant and young child feeding indicators and determinants of selected feeding practices in India. METHODS: The sample consisted of 20,108 children aged 0 to 23 months from the National Family Health Survey India 2005-06. Selected indicators were examined against a set of variables using univariate and multivariate analyses. RESULTS: Only 23.5% of mothers initiated breastfeeding within the first hour after birth, 99.2% had ever breastfed their infant, 89.8% were currently breastfeeding, and 14.8% were currently bottle-feeding. Among infants under 6 months of age, 46.4% were exclusively breastfed, and 56.7% of those aged 6 to 9 months received complementary foods. The risk factors for not exclusively breastfeeding were higher household wealth index quintiles (OR for richest = 2.03), delivery in a health facility (OR = 1.35), and living in the Northern region. Higher numbers of antenatal care visits were associated with increased rates of exclusive breastfeeding (OR for 2 7 antenatal visits = 0.58). The rates of timely initiation of breastfeeding were higher among women who were better educated (OR for secondary education or above = 0.79), were working (OR = 0.79), made more antenatal clinic visits (OR for 2 7 antenatal visits = 0.48), and were exposed to the radio (OR = 0.76). The rates were lower in women who were delivered by cesarean section (OR = 2.52). The risk factors for bottle-feeding included cesarean delivery (OR = 1.44), higher household wealth index quintiles (OR = 3.06), working by the mother (OR = 1.29), higher maternal education level (OR = 1.32), urban residence (OR = 1.46), and absence of postnatal examination (OR = 1.24). The rates of timely complementary feeding were higher for mothers who had more antenatal visits (OR = 0.57), and for those who watched television (OR = 0.75). CONCLUSIONS: Revitalization of the Baby Friendly Hospital Initiative in health facilities is recommended. Targeted interventions may be necessary to improve infant feeding practices in mothers who reside in urban areas, are more educated, and are from wealthier households. PMID- 20707237 TI - Determinants of infant and young child feeding practices in Nepal: secondary data analysis of Demographic and Health Survey 2006. AB - BACKGROUND: Childhood undernutrition and mortality are high in Nepal, and therefore interventions on infant and young child feeding practices deserve high priority. OBJECTIVE: To estimate infant and young child feeding indicators and the determinants of selected feeding practices. METHODS: The sample consisted of 1906 children aged O to 23 months from the Demographic and Health Survey 2006. Selected indicators were examined against a set of variables using univariate and multivariate analyses. RESULTS: Breastfeeding was initiated within the first hour after birth in 35.4% of children, 99.5% were ever breastfed, 98.1% were currently breastfed, and 3.5% were bottle-fed. The rate of exclusive breastfeeding among infants under 6 months of age was 53.1%, and the rate of timely complementary feeding among those 6 to 9 months of age was 74.7%. Mothers who made antenatal clinic visits were at a higher risk for no exclusive breastfeeding than those who made no visits. Mothers who lived in the mountains were more likely to initiate breastfeeding within 1 hour after birth and to introduce complementary feeding at 6 to 9 months of age, but less likely to exclusively breastfeed. Cesarean deliveries were associated with delay in timely initiation of breastfeeding. Higher rates of complementary feeding at 6 to 9 months were also associated with mothers with better education and those above 35 years of age. Risk factors for bottle-feeding included living in urban areas and births attended by trained health personnel. CONCLUSIONS: Most breastfeeding indicators in Nepal are below the expected levels to achieve a substantial reduction in child mortality. Breastfeeding promotion strategies should specifically target mothers who have more contact with the health care delivery system, while programs targeting the entire community should be continued. PMID- 20707238 TI - Determinants of infant and young child feeding practices in Sri Lanka: secondary data analysis of Demographic and Health Survey 2000. AB - BACKGROUND: Poor feeding practices in early childhood contribute to the burden of childhood malnutrition and morbidity. OBJECTIVE: To estimate the key indicators of breastfeeding and complementary feeding and the determinants of selected feeding practices in Sri Lanka. METHODS: The sample consisted of 1127 children aged 0 to 23 months from the Sri Lanka Demographic and Health Survey 2000. The key infant feeding indicators were estimated and selected indicators were examined against a set of individual-, household-, and community-level variables using univariate and multivariate analyses. RESULTS: Breastfeeding was initiated within the first hour after birth in 56.3% of infants, 99.7% had ever been breastfed, 85.0% were currently being breastfed, and 27.2% were being bottle-fed. Of infants under 6 months of age, 60.6% were fully breastfed, and of those aged 6 to 9 months, 93.4% received complementary foods. The likelihood of not initiating breastfeeding within the first hour after birth was higher for mothers who underwent cesarean delivery (OR = 3.23) and those who were not visited by a Public Health Midwife at home during pregnancy (OR = 1.81). The rate of full breastfeeding was significantly lower among mothers who did not receive postnatal home visits by a Public Health Midwife. Bottlefeeding rates were higher among infants whose mothers had ever been employed (OR = 1.86), lived in a metropolitan area (OR = 3.99), or lived in the South-Central Hill country (OR = 3.11) and were lower among infants of mothers with secondary education (OR = 0.27). Infants from the urban (OR = 8.06) and tea estate (OR = 12.63) sectors were less likely to receive timely complementary feeding than rural infants. CONCLUSIONS: Antenatal and postnatal contacts with Public Health Midwives were associated with improved breastfeeding practices. Breastfeeding promotion strategies should specifically focus on the estate and urban or metropolitan communities. PMID- 20707239 TI - Across-country comparisons of selected infant and young child feeding indicators and associated factors in four South Asian countries. AB - BACKGROUND: Information on infant and young child feeding is widely available in Demographic and Health Surveys and National Family Health Surveys for countries in South Asia; however, infant and young child feeding indicators from these surveys have not been compared between countries in the region. OBJECTIVE: To compare the key indicators of breastfeeding and complementary feeding and their determinants in children under 24 months of age between four South Asian countries. METHODS: We selected data sets from the Bangladesh Demographic and Health Survey 2004, the India National Family Health Survey (NFHS-03) 2005-06, the Nepal Demographic and Health Survey 2006, and the Sri Lanka 2000 Demographic and Health Survey. Infant feeding indicators were estimated according to the key World Health Organization indicators. RESULTS: Exclusive breastfeeding rates were 42.5% in Bangladesh, 46.4% in India, and 53.1% in Nepal. The rate of full breastfeeding ranged between 60.6% and 73.9%. There were no factors consistently associated with the rate of no exclusive breastfeeding across countries. Utilization of health services (more antenatal clinic visits) was associated with higher rates of exclusive breastfeeding in India but lower rates in Nepal. Delivery at a health facility was a negative determinant of exclusive breastfeeding in India. Postnatal contacts by Public Health Midwives were a positive factor in Sri Lanka. A considerable proportion of infants under 6 months of age had been given plain water, juices, or other nonmilk liquids. The rate of timely first suckling ranged from 23.5% in India to 56.3% in Sri Lanka. Delivery by cesarean section was found to be a consistent negative factor that delayed initiation of breastfeeding. Nepal reported the lowest bottle-feeding rate of 3.5%. Socioeconomically privileged mothers were found to have higher bottlefeeding rates in most countries. CONCLUSIONS: Infant and young child feeding practices in the South Asia region have not reached the expected levels that are required to achieve a substantial reduction in child mortality. The countries with lower rates of exclusive breastfeeding have a great potential to improve the rates by preventing infants from receiving water and water-based or other nonmilk liquids during the first 6 months of life. PMID- 20707240 TI - Vitamin D. What is its role in diabetes? PMID- 20707241 TI - Frugal cooking. Using leftovers. PMID- 20707242 TI - Diabetes alert dogs. PMID- 20707243 TI - How much do you know about metformin? PMID- 20707244 TI - Managing your medicines. Tips and tools that can help. PMID- 20707246 TI - Supermarket smarts. Frozen desserts. PMID- 20707245 TI - Diagnosing diabetes. How--and why--standards change. PMID- 20707247 TI - Neuroendocrine tumors and their association with rare tumors: observation of 4 cases. AB - PURPOSE: Neuroendocrine tumors are rare neoplasms, with an incidence of about 1/100,000/year. The association between digestive neuroendocrine tumors and epithelial tumors is known, accounting for about 10% of cases, whilst in a very small number of other cases an association with other low incidence tumors has been observed. METHODS: During the past 19 years the Rare Hormonal Tumors Group of the Istituti Ospitalieri in Cremona, Italy has observed 300 patients affected by neuroendocrine tumors. We report here on four cases in which there was an unusual association with other rare neoplasms. RESULTS: Overall, four of the 300 observed cases (1.3%) showed an unusual association with rare nonepithelial neoplasms: (1) gastric carcinoid and glioblastoma multiforme; (2) Merkel cell tumor and squamous cell carcinoma of the skin; (3) medullary thyroid carcinoma, yolk sac tumor of the testis and gastrointestinal stromal tumor (GIST); (4) gastric carcinoid and gastrointestinal stromal tumor (GIST). DISCUSSION: There cases are of interest not only from an epidemiological point of view, but also offer insight into possible geno-phenotypical implications. The c-kit expression, typical of GISTs but observed also in other epithelial and neuroendocrine tumors, not only broadens the possibility to gain insight into the carcinogenesis of these neoplasms, but also opens the field to possible new therapeutic opportunities using multitargeted molecules. The contemporaneous presence of other lesions, such as the Merkel cell tumor and the squamous cell carcinoma of the skin can be interpreted as an answer by the cell to the same mutagenic stimulus. In other cases, where a possible link is not yet found which could explain the synchronism or metachronism of low incidence neoplasms, it remains possible that the associations are entirely coincidental. We await for new instruments which could help us demonstrate the possible relationships between low incidence neoplasms. PMID- 20707249 TI - Strange formation of N-hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one and its oxime derivative--synthesis, stereochemistry, antibacterial and antifungal activity. AB - OBJECTIVES AND METHODS: A collection of novel N-hydroxy-3,3-dimethyl-2,6 diarylpiperidin-4-one oximes 28-32 are synthesized, characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR (1H & 13C) and two dimensional Noesy spectroscopic data and evaluate for their in vitro antibacterial and antifungal activities. RESULTS AND CONCLUSION: Compound 32, exerted a wide range of antibacterial activities against the entire tested gram positive and gram-negative bacterial strains except Escherichia coli, besides compound 30, which is more active against Klebsiella pneumoniae, a gram-negative coccus. Compound 29 exerted strong antifungal activities against Aspergillus flavus and Microsporum gypseum. In addition, compound 32 is more potent against Rhizopus. PMID- 20707248 TI - Post-operative analgesia following total knee arthroplasty: comparison of low dose intrathecal morphine and single-shot ultrasound-guided femoral nerve block: a randomized, single blinded, controlled study. AB - BACKGROUND AND OBJECTIVES: Total knee arthroplasty often results in marked postoperative pain. A recent meta-analysis supports the use of femoral nerve block or alternatively spinal injection of morphine plus local anaesthetic for post-operative analgesia. On the other hand, the use of intrathecal morphine may be associated with a large number of distressing side effects (itching, urinary retention, nausea and vomiting, delayed respiratory depression). The aim of this study was to compare the effectiveness of femoral nerve block and low dose intrathecal morphine in post-operative analgesia after primary unilateral total knee arthroplasty. MATERIAL AND METHODS: Fifty-two consecutive patients scheduled for primary unilateral total knee arthroplasty were allocated to the intrathecal morphine group (ITM group) or to the femoral nerve block group (FNB group). In ITM group a subarachnoid puncture was performed at the L3-L4 inter-vertebral space with hyperbaric bupivacaine 15 mg plus 100 mcg of preservative-free morphine. Patients allocated to the FNB group received a single-injection ultrasound-assisted femoral nerve block with ropivacaine 0.75% 25 ml before the spinal injection of hyperbaric bupivacaine 15 mg. All patients received postoperative patient-controlled-analgesia (PCA) morphine, using a 1-mg bolus and a 5-minute lockout period. Data were analyzed using Student t test or two-way analysis of variance (ANOVA) for repeated measures with time and treatment as the 2 factors. Post hoc comparisons were performed by Bonferroni test. Statistical significance for all test was a p value < 0.05. RESULTS: Patient characteristics were similar between the 2 groups. We found a statistically significant differences in postoperative pain between the two groups: ITM group had the lower visual analogic pain score (VAS) values. Morphine consumption was lower in the ITM group: average consumption within the first 6 hours was 0.9 mg in IT group compared to 3.1 mg in FNB group; at 12 h 4.2 mg vs 6.3 mg; at 24 h 6.9 mg vs 10.3 mg; at 48 h 9.7 mg vs 13.6 mg. However, the difference in the opiate consumption was not statistically different (p value = 0.06). Thirteen patients in ITM group experienced itching, only 5 in FNB group. We did not find any difference in the two treatment groups in the use of antiemetic and antipruritic medication. No cases of respiratory depression was recorded. CONCLUSIONS: Our results show that low dose of intrathecal morphine may be safe and more efficient than single-shot femoral nerve block for post-operative analgesia after total knee arthroplasty. PMID- 20707250 TI - Effect of mangosteen (Garcinia mangostana L.) extracts as a feed additive on growth and hematological parameters of African catfish (Clarias gariepinus) fingerlings. AB - AIM: The efficacy of dietary inclusion of various parts of mangosteen (Garcinia mangostana L.) extract on growth and hematological parameters of African catfish (Clarias gariepinus) fingerlings were investigated. MATERIAL AND METHODS: Ninety six fingerlings were randomly distributed into each of ten 20L plastic aquaria. Each treatment groups consists of three replicates. Four experimental diets were prepared: controls, leaf extract, shoot extract and rind extract. The 0.5% of various parts (leaf, rind and shoot extract) of mangosteen were included in the experimental diets at the expense of 0.5% rice bran. The fingerlings were fed with experimental diets at satiation for five weeks. RESULTS: The results showed that no significant difference on growth, specific growth rate, average daily growth, feed conversion ratio and condition factors of the dietary inclusion of the different mangosteen extract treatment when compared to control groups except leaf extract. Significantly higher red blood cells (RBC) count and white blood cells (WBC) count were recorded in fish fed with shoot extract incorporated diet fed groups than the other groups. However, no significant impact on hemoglobin content between the experimental groups and control groups. CONCLUSIONS: Based on the results of the present study, it is suggested that feeding fish with 0.5 % of mangosteen extracts for 35 days has no adverse effect on growth and enhanced the hematological parameters of African catfish fingerlings. PMID- 20707251 TI - Myocardial ischemia in cocaine-user with anomalous origin of the left circumflex coronary artery. AB - The prevalence of anomalous coronary artery is approximately 0.6-1.7% in patients who undergo coronary angiography. These anomalies may cause angina, acute myocardial infarction, syncope and sudden death. Cocaine abuse is now a major health hazard: more than 5 million of Americans are current users. Cocaine abuse can result in coronary artery vasocostriction and the association between cocaine abuse, myocardial ischemia and infarction in the absence of coronary artery disease has been reported. We report the case of a patient with a story of nasally inhaled cocaine abuse presented with exertional chest pain and a perfusion defect of the anterior and inferior-lateral walls of the left ventricle during myocardial perfusion SPECT. The anomalous origin of the left circumflex coronary artery from the righ sinus of Valsalva was detected during coronary angiography and confirmed by the multislice computed tomography (MSCT). Although the coronary angiography is the gold standard of cardiac imaging technique for the diagnosis of coronary artery disease the identification of anomalous coronary arteries is frequently difficult with conventional coronary angiography because of the lack of 3-dimensional (3D) information related to the course of the coronary arteries to the great vessels. The MSCT provides a high spatial resolution, which allows a successful identification of the congenital coronary artery anomalies. This case report provides further a supportive evidence for the role of MSCT in the detection of the coronary artery anomalies. PMID- 20707252 TI - Proposal for a new self-compiled questionnaire in patients affected by temporo mandibular joint disorders (TMD). AB - In this work, we propose a self-compiled questionnaire, for those patients showing dysfunctions of the temporomandibular joint. The questionnaire, composed by 33 closed multiple-choice questions, represents one of the steps in the diagnostic procedure, together with the clinical notes compiled by the medical specialist and with the other necessary diagnostic researches. It also has the purpose to make easier anamnesis and clinic procedure and gathering of all informations useful for a right clinical diagnosis, and so for an appropriate therapy. PMID- 20707254 TI - Acute mastoiditis complicated with bezold abscess, sigmoid sinus thrombosis and occipital osteomyelitis in a child. AB - Acute otitis media complications are relative rare since the introduction of antibiotics. Still many controversies exist on the diagnosis and treatment of some of them. In this report we describe a pediatric case of upper cervical abscess (bezold abscess), sigmoid sinus thrombosis and occipital osteomyelitis following mastoiditis, presenting with persistent fever and otorrhea. The patient responded well to intravenous antibiotics and wall-intact mastoidectomy. We discuss methods of early diagnosis and appropriate treatment options. PMID- 20707253 TI - Acetaminophen plus codeine compared to ketorolac in polytrauma patients. AB - INTRODUCTION: The management of pain in polytrauma patients is mandatory. While non-steroidal anti-inflammatory drugs (NSAIDs) represent the most used drugs in polytrauma patients, their use may be associated with an increased risk of haemorrhage. Opioids may represent a valid alternative to NSAIDs either alone or in combination with acetaminophen. Whether their efficacy is comparable to that produced by NSAIDs in polytrauma patients has never been studied. PATIENTS AND METHODS: 60 polytrauma patients were enrolled for this study. 30 patients were treated with acetaminophen 1000 mg plus codeine 60 mg tid for 24 hours (Group A), while the remaining 30 with ketorolac 10 mg qid for 24 hours (Group B). Pain intensity has been evaluated using an analogical visual scale (VAS) ranging from 0 (no pain) to 10 (very severe pain). The level of pain was valuated at enrolment (TO) as well as after 2 (T2), 12 (T12) and 24 (T24) hours from the starting of the analgesic therapy. Results obtained by the group A were compared with those reported by the group B. RESULTS: T0: Group A mean score was 6.4 +/- 1.5 compared with 6.6 +/- 1.5 of Group B (p= ns); T2: Group A mean score was 3.4 +/- 2.8, compared with 3.5 +/- 2.4 of group B (p = ns); T12: Group A mean score was 3.4 +/ 3.4, compared with 3.5 +/- 3 of Gorup B (p = ns); T24: Group A mean score was 2.9 +/- 1.5, compared to 3.0 +/- 1.6 of Group B (p = ns). All those drugs determined a significant reduction of pain intensity during the course of therapy. CONCLUSIONS: Acetaminophen plus codeine is effective in pain control in polytrauma patients at least in our series. It may represent a valid alternative to NSAIDs, especially in patients with a documented haemorrhage or with a high hemorrhagic risk. PMID- 20707256 TI - Compartment syndrome of the hand with acute bullous eruption due to extravasation of computed tomography contrast material. AB - This article presents a case of an 80-year-old woman with severe hematoma and consequently a compartmental syndrome of the hand complicated with acute bullous eruption due to extravasation of contrast material. Compartment syndrome of the hand has been linked to a number of various etiologies. Failure to adequately diagnose and treat compartment syndromes of the hand can lead to irreparable functional loss. In the majority of the cases extravasation results only in minimal swelling or erythema. However, severe skin necrosis, ulceration and compartment syndrome may occur with extravasation of large volumes. Compartment syndrome was diagnosed, and the patient underwent immediately fasciotomy. After fasciotomy we weekly followed up our patient with medications and after she regained the full use of the hand. We report this case to assess the importance of a careful evaluation of the intravenous administration site and close monitoring of the patient during contrast material injection to obtain minimal or prevent every kind of extravasation injuries. PMID- 20707255 TI - Melkersson-Rosenthal syndrome associated with Down syndrome. AB - We present a clinical case of Melkersson-Rosenthal (M-R) syndrome associated with Down syndrome. No evidence of this association is described in the literature. We also present a technique for the macrocheilia treatment of lower lip caused by M R syndrome in a patient with Down syndrome. This patient during pediatric age had many events of facial nerve paralysis and edematous episodes of lower lip with unknown etiology. This technique is based on a wedge full thickness central excision of the lower lip and on a transversal lozenge excision in the vermilion portion with orbicular muscle to reverse the chin-labial corner. The results are an agreeable aspect of the lip and physiological digestive and phonetic processes. The technique is safe and simple and the aesthetic functional result is very good. In our case, the postoperative complication is caused by an insufficient collaboration of the patient and it is solved in three weeks. PMID- 20707257 TI - Will red ink cause IDSs to self-destruct? AB - Faced with mounting losses associated with owned medical practices, leaders of integrated systems can be tempted to allow their concerns about the situation to goad them to act too hastily to remedy it. IDS leaders require a process for examining the causes of medical practice underperformance that focuses simply on clarifying the facts. As part of this process, they should examine five areas: accounting methodology, structural decisions, post-integration changes, accounts receivable, and productivity of physicians and nonphysician practitioners. PMID- 20707258 TI - 5 things to look for in a next-generation revenue cycle management system. AB - Healthcare leaders should look for five key attributes in a next-generation revenue cycle management system: The ability to provide real-time information. Exception-based workflow. Features that support financially aware care. Virtual business office functionality. Functionality that supports an enhanced consumer experience. PMID- 20707259 TI - Top 10 things hospitals need to know about health reform ... but were afraid to ask. AB - The top 10 critical areas of reform that are of concern to hospitals include: Understand financial implications. Do more with less. Optimize revenue cycle, labor productivity, and supply chain. Move patients from self-pay to coverage. Make quality job No.1. Prepare for transparency. Deal with infections. Implement physician alignment. Move from volume to value: accountable care organizations. Obtain HITECH funding. PMID- 20707260 TI - ACOs: preparing for Medicare's shared savings program. AB - Organizations that qualify as accountable care organizations under Medicare's Shared Savings Program will be required to participate for at least three years. Among the benefits of participation are those resulting from healthcare delivery system innovation, enhanced community benefit and reputation, improved payer relations, organizational and management development, systems enhancements, and financial gains to the participants. There are also risks to providers that participate, including legal risks and risks associated with the uncertainty surrounding HHS's implementation approach, the high cost of participation, inevitable game change, and the possibility of being disqualified. PMID- 20707261 TI - Tax exemption and community benefit: key questions for addressing a critical concern. PMID- 20707262 TI - Accountable care the journey begins. AB - In healthcare reform legislation, the concept of accountable care organizations (ACOs) has been deliberately broad. Providers' efforts to develop ACOs are likely to proceed on different paths and at different paces in various parts of the country, and some organizations will move faster than others. In deciding which approach to use, a provider should choose a target market, a service area, and a reimbursement methodology; identify the provider structure; design, develop, enhance, and modify core support elements; and identify patient-related and organizational strategies for improvement. PMID- 20707263 TI - Moving quality and cost to the top of the hospital agenda. AB - Award-winning healthcare organizations have used the following four tactics to move quality to the top of the hospital agenda: Leverage the strategic plan to support the organization's quality and safety goals. Use "budget-like" tactics to set quality and safety goals. Emulate the finance model of reporting and accountability to meet quality goals. Base a portion of incentive compensation, salary adjustments, and annual performance reviews on the achievement of quality related goals. PMID- 20707264 TI - Protocols, prompters, bundles, checklists, and triggers: synopsis of a preventable mortality reduction strategy. AB - An improvement strategy focused on preventing avoidable patient mortality should target the following leverage points: The Joint Commission's National Patient Safety Goals. CMS's core measures. Prevention of healthcare-associated infections, CMS's "never events," and adverse drug events. PMID- 20707265 TI - Funding a hospitalist program: which approach will you take? AB - Hospitals that take a care-team approach to their hospitalist program can increase the hospital's long-term value. Funding the program in terms of its cost reduction, revenue generation, and cost avoidance abilities creates value for hospitals. Hospitals should organize their hospitalist program so it supports the organization's goals. PMID- 20707266 TI - How to avoid a HIPAA horror story. AB - The Health Information Technology for Economic and Clinical Health Act of 2009 significantly expands the financial risk of violations of the Health Insurance Portability and Accountability Act (HIPAA) and extends HIPAA procedures and penalties to business associates. Hospitals, physicians, and their business associates should ensure that HIPAA privacy and security provisions are adopted. Compliance efforts should focus on high-risk areas, including information access management, access control, and impermissible disclosures of protected health information. PMID- 20707267 TI - Using labor metrics to achieve value-driven health care. AB - Four strategies that hospitals should consider to reduce nursing labor costs without jeopardizing quality of care are the following: Use net cost variances to drive authorized FTEs by skill level. Manage supplemental labor. Control distribution of nonproductive time throughout the year. Monitor rate and efficiency variances. PMID- 20707268 TI - What would you do? How should this IDS develop and thrive? PMID- 20707269 TI - Margin of U.S. not-for-profit and public hospitals. PMID- 20707270 TI - [DNA degradation in nucleolus of skeletal muscle, heart, liver, kidney and brain in mice after death]. AB - OBJECTIVE: To study the change of DNA degradation in nucleolus of mice organs and its relationship with the postmortem interval, and to investigate a new accurate method to estimate the postmortem interval. METHODS: Eight parameters of cell nuclei were chosen, including the head DNA level, the tail DNA level, the head radius, the tail length, the tail moment, the Olive moment, the head area and the tail area. The changes of DNA degradation were analyzed in skeletal muscle, myocardium, liver, kidney and brain in mice at different intervals (0-72 h postmortem) by using single-cell gel electrophoresis and fluorescent microscope connected with auto-analysis-image system. RESULTS: The tail DNA level, the tail length, the tail moment, the Olive moment and the tail area showed an increasing tendency. The head DNA level, the head radius and the head area showed a decreasing tendency within 72h postmortem in mice. A quadratic regression equation (P < 0.001) and multiple regression equation of DNA degradation tendency were established (P < 0.000 1). CONCLUSION: The regression equations established can be used as a new method for estimating postmortem interval in forensic practice. PMID- 20707271 TI - [Expression of M3 subtype of muscarinic receptor during the skin incised wound healing in mice]. AB - OBJECTIVE: To investigate the expression of M3 subtype of muscarinic receptors (M3R) during the incised wound healing of the skin in mice and the characteristics of its time-dependent. METHODS: The change of M3R in skin incised wound was detected by immunohistochemical staining and Western blot. RESULTS: M3R positive cells were detected in epidermis, hair follicle, sebaceous glands, sweat glands, dermomuscular layer in normal mouse skin. Expression of M3R was mainly detectable in polymorphonuclear cells (PMNs) in the wound specimens aged from 6h to 12h after injury. Afterwards, the M3R-positive cells were mostly mononuclear cells (MNCs) and fibroblastic cells (FBCs) at 1 d to 3d post-injury, whereas the M3R-positive cells were mostly FBCs aged from 5 d to 14d. Morphometrically, the ratio of the M3R-positive cells increased aged from 6h to 12h after injury, with a peak at 12h. The ratios kept a high relatively level aged from 1 d to 5 d, but significantly that lowered as compared with aged 12h after injury. The ratio reached the peak at 7 d again after injury, and then decreased gradually. The M3R protein also revealed a time-dependent tendency with double peaks at 12h and 7 d after injury as detected by Western blotting. CONCLUSION: M3R is time-dependently expression in PMNs, MNCs and FBCs suggesting that it may play roles during the skin incised wound healing, and M3R may be used as a marker for wound age determination. PMID- 20707272 TI - [The relationship between eyeball structure and visual acuity in high myopia]. AB - OBJECTIVE: To explore the relationship between eyeball structure and visual acuity in high myopia. METHODS: Totally, 152 people (283 eyeballs) with different levels of myopia were tested for visual acuity, axial length, and fundus. All cases were classified according to diopter, axial length, and fundus. The relationships between diopter, axial length, fundus and visual acuity were studied. The mathematical models were established for visual acuity and eyeball structure markers. RESULTS: The visual acuity showed a moderate correlation with fundus class, comus, axial length and diopter ([r] > 0.4, P < 0.000 1). The visual acuity in people with the axial length longer than 30.00 mm, diopter above -20.00 D and fundus in 4th class were mostly below 0.5. The mathematical models were established by visual acuity and eyeball structure markers. CONCLUSION: The visual acuity should decline with axial length extension, diopter deepening and pathological deterioration of fundus. To detect the structure changes by combining different kinds of objective methods can help to assess and to judge the vision in high myopia. PMID- 20707273 TI - [Morphological classification of frontal sinuses on digital X-ray films and its forensic identification indexes]. AB - OBJECTIVE: To explore morphological classification of the Caldwell view of frontal sinuses in computer radiography (CR) for forensic identification and to construct a forensic identification system with digital X-ray films with assistance of identification indexes coding. METHODS: Four hundred CR films of the Caldwell view of frontal sinus were selected from Sichuan Han ethnic Chinese. The frontal sinuses were classified according to the relationship between the tangential line above the upper edge of the bilateral orbits and the location of the frontal sinus. Then to code the identification indexes for the frontal sinus. RESULTS: The Caldwell view of frontal sinuses were classified into 6 categories. Eight identification indexes for the frontal sinus were identified, including degree of asymmetry, superiority of side, ratio of the left frontal sinus area and orbit area (A(LFS)/A(LOR)), ratio of the right frontal sinus area and orbit area ((RFS)/A(ROR)), outline of the left upper border, outline of the right upper border, occurrence of partial septa and location of frontal median margin. CONCLUSION: Initial identification by the Caldwell view classification of frontal sinuses followed with coding the frontal sinuses with 8 indexes is likely a novel approach for forensic identification of the frontal sinuses in CR. PMID- 20707274 TI - [Measurement of intracranial hematoma using the improved cubature formula]. AB - OBJECTIVE: The more accurate calculate method was investigated according to the improved formula of intracranial hematoma using segment deducing. METHODS: The improved formula was deduced to calculate the intracranial hematoma using the volume formula of the solid geometry. The volume of intracranial hematoma was measured as a related accurate standards using software. The volumes of intracranial hematoma calculated by the improved formula, Tada's formula and the software were compared. RESULTS: The measure accuracy of the improved formula was higher than that of Tada's formula, and showed a similarity with that by using software method. CONCLUSION: The improved formula method shows a more accurate result than Tada's formula, and can be used in forensic practice. PMID- 20707275 TI - [Comparison among three standards of TW2 to skeletal age determination in children with central precocious puberty]. AB - OBJECTIVE: To discuss the diagnostic value of English, Chinese and Japanese standards of TW2 to skeletal age assessment of children with central precocious puberty (CPP), then to confirm the normal thresholds. METHODS: Sixty one children as patient group were definitely assured CPP. The control group had 67 children. Among them, 61 were normal children, another 6 children as a special control group. Left hand-wrist X-ray radiographs were retrospectively analyzed by two doctors separately and their skeletal ages were assessed with the three standards of TW2 method. The differences between skeletal age and chronological age were analyzed with ROC in SPSS 13.0. RESULTS: (1) The skeletal age results showed kappa value is 0.776 deduced by two clinical doctors(u = 16.128, P < 0.05). (2) There were no statistic differences for the areas under ROC curves among three methods. (3) d > or = 1.15 years in TW2, d > or = 1.25 years in TW2-CHN and d > or = 0.65 years in TW2-JP were more susceptive and specific points. CONCLUSION: TW2, TW2-CHN and TW2-JP provided a higher value for the diagnosis of skeletal age in unhealthy children, and TW2-CHN is highest value for Chinese children. PMID- 20707276 TI - [Identification of sibling sisters using STR and SNP]. AB - OBJECTIVE: The methods for identification of sibling sisters were explored with detection of genetic markers on autochromosome and X-chromosome. METHODS: Genomic DNA of the sibling sisters were extracted, and 15 STRs on autochromosome and 17 STRs on X-chromosome were genotyped by Sinofiler kit, Mentype Argus X-8 kit and in-house kit of X-STRs, respectively. 11 X-SNPs were genotyped with TaqMan technology. RESULTS: Full sibling relationship of the test samples were confirmed by calculating full sibling index of STRs in autochromosome, which were also supported by the detection of 1-2 same alleles at each locus on X-chromosome. CONCLUSION: In identification of full sibling sister, not only STRs on autochromosome but also polymorphism genetic markers in X-chromosome can be utilized. PMID- 20707277 TI - [Simultaneous determination of opioid compounds in human urine by UPLC-MS/MS]. AB - OBJECTIVE: To propose a method for simultaneous determination of codeine(COD), 6 monoacetyl-morphine (6-MAM), morphine (MOR), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in human urine by ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). METHODS: After precipitation of protein by acetonitrile, the urine samples, with added the morphine-d3 (MOR-d3) and morphine-3-Glucuronide-d3 (M3G-d3) as internal standards, were pre-treated by Sirocco protein precipitation plate, and then analyzed by UPLC-MS/MS. RESULTS: The limit of detection was 0.2 ng/mL for both COD and MAM, the limit of quantitation was 0.5 ng/mL for both COD and MAM. The limit of detection was 0.5 ng/mL for MOR, M3G and M6G, the limit of quantitation was 1 ng/mL for them. The linear correlation coefficients were not less than 0.9997, both the inter-day and intra-day precisions were less than 10%, the recoveries were in the range of 70.0% to 98.3%, the matrix effects were about 50.5% to 99.0%. CONCLUSION: This proposed method is simple, rapid and accurate, it could be applied in forensic toxicological analysis. PMID- 20707278 TI - [Forensic analysis of 74 tumor related medical malpractice cases]. AB - OBJECTIVE: To analyze the causes of medical malpractice in patients with tumor, to determine the medical responsibility, and to recommend the related preventions. METHODS: Seventy four medical malpractice cases, which were involved in tumor and collected from 2000 to 2009 in medicolegal expertise center of west China, were analyzed retrospectively. RESULTS: The medical malpractice cases in the patients with tumor showed an increasing tendency in recent years. The main causes are missed diagnosis, misdiagnosis, improper chemotherapy and neglect of complications. The causes of medical malpractice were different in the different levels of medical services. The occurrence of medical malpractice in surgery and OB-GYN showed more frequent than the others. CONCLUSION: Forensic pathology autopsy is important to resolve medical malpractice of tumor patients by finding out the cause of death and clarifying the medical responsibility. The occurrence of medical malpractice could be reduced by the clinical doctors through improving serve consciousness, obtaining the patients' trust, improving the medical treatment, following related laws and rules, fulfiling duty of medical careness. PMID- 20707279 TI - [The identification and analysis of cleaver traces on human bone]. AB - OBJECTIVE: The injury instruments were identified and studied according to the cleaver traces on bone. METHODS: The bone and fresh shrub branches were cut with the same part of the same cleaver respectively. To visualize the traces on the bone by histological processing and to match the traces on bone and branch by the comparison microscope. Then to analyze the character of traces on the bone. RESULTS: Cutting-line traces made by cleaver on the bone can be fully matched with those in the shrub branch sample. CONCLUSION: Cleaver traces on the bone can be displayed clearly and shown at micro level. It will provide a new method for the identification of suspected weapon. PMID- 20707280 TI - [Review on estimation of postmortem interval using FTIR spectroscopy]. AB - Estimation of the postmortem interval (PMI) is a practical task in daily forensic casework. Researches on PMI is an important practical project in forensic field. Estimation of the time since death is influenced by internal and external, antemortem and postmortem factors, thus the old methods have limitations. Fourier transform infrared (FTIR) spectroscopy has been applied to study the pure protein, nucleic acid and carbohydrate and to detect the changes in complex cells and tissues. At present because the powerful software has could be used to achieve the spectrum transformation, smoothing, baseline correction and normalization, it is possible to analyze the samples quantitatively with the FTIR which has been applied in the biology and clinical medicine. This paper has reviewed the mechanism of FTIR and its application in biomedicine. The postmortem FTIR spectral changes were also discussed, which showed its potential for estimating PMI. PMID- 20707281 TI - [The analysis of pericardial fluid in forensic practice]. AB - Pericardial fluid is a kind of serous fluid in pericardial cavity. Because blood undergoes postmortem changes such as autolysis and putrefaction, vitreous humor is limited,cerebrospinal fluid is easily mixed with blood, pericardial fluid, on the other hand, exists in a closed cavity and can be hardly contaminated by postmortem changes, and also is easily obtained. Pericardial fluid not only plays an important role in clinic practice, but also is widely applicable in forensic practice. This paper briefly presented the properties of pericardial fluid and its clinical significance. It reviewed biochemical changes in decedents died of heart diseases, drowning and asphyxia, and explored the significance in medico legal investigation. Moreover, application of pericardial fluid in forensic serology, forensic toxicological analysis and other fields were also discussed. Pericardial fluid analysis may provide important information for determination of the cause of death with further investigation concerning forensic applicability of pericardial fluid. PMID- 20707282 TI - [Advance of neurogenic erectile dysfunction therapy by stem cells]. AB - Neurogenic erectile dysfunction (NED) commonly results from erectile nerve damage. Recent researches have focused on the preclinical study of stem cell based therapies targeted at repairing and protecting nervi erigentes. In this paper, researches of NESCs, MDSCs, ASCs and MSCs in NED are reviewed. Early studies have demonstrated that stem cells and gene modified stem cells were effective to the therapy of ED, even likely to cure ED. Stem cells are expected to be applied in the clinical therapy of NED. Stem cells as a new therapy technique will bring up a new challenge in forensic clinical medicine. PMID- 20707283 TI - [The application of evaluation tools for criminal responsibility in forensic psychiatric expertise]. AB - Criminal responsibility is divided into three types: full criminal responsibility, diminished criminal responsibility and criminal irresponsibility in China. In forensic psychiatric expertise, doctors often have different opinions about the responsibility in a given case because of lacking objective criteria. The evaluation of criminal responsibility is always unresolved problem in forensic psychiatric expertise. Application of these evaluation tools in forensic psychiatric expertise were reviewed in this article. The value of the tools were still controversial in the reliability and validity, but it is clear that these tools have the positive roles in ensuring the standardization and the uniformity of the forensic investigation. PMID- 20707284 TI - Synthesis of novel naphthyl substituted fused indazolonols as potent anticandidal agents. AB - OBJECTIVES: A new series of naphthyl substituted indazolonols 15-21 were synthesized and characterized by their melting point, elemental analysis, MS, FT IR, one-dimensional 1H, D2O exchanged 1H and 13C NMR spectroscopic data. METHODS: All the synthesized compounds 15-21 were tested for their in vitro antifungal activities against Candida sp. namely Candida albicans, Candida glabrata, Candida tropicalis and Candida parapsilosis. RESULTS: A close inspection of the in vitro anticandidal activity profile in differently electron donating (CH3 and OCH3) and electron withdrawing (-F, -Cl, Br and -NO2) functional group substituted phenyl rings of novel naphthyl substituted indazolonols 15-21 exerted strong anticandidal activity against all the tested Candida species. CONCLUSIONS: Compounds 17, 19-21 exhibit MIC value in the range of 6.25-200 microg/mL against all the tested candida species. PMID- 20707285 TI - In vitro antioxidant and antimicrobial assays of acetone extracts from Nepeta meyeri Bentham. AB - BACKGROUND AND OBJECTIVIES: Nepeta species are used as diuretic, diaphoretic, antitussive, antispasmodic, antiasthmatic, febrifuge, emmenagogue, sedative agents, insecticidal, acaricidal, antiviral, anti-inflammatory and antioxidant. Acetone extract of Nepeta meyeri (Labiatae) was screened for antioxidant and antimicrobial activities. MATERIALS AND METHODS: The antioxidant prop erties of the extract were investigated by using various methods established in vitro systems such as 1,1-diphenyl-2-picrylhydrazyl (DPPH)/nitric oxide (NO) radical scavenging activity. Reducing power and total phenolic substance analysis and also antimicrobial activity of acetone extract of Nepeta meyeri were tested against six gram negative, seven gram positive bacteria and the yeast strain using the disc diffusion method. RESULTS AND DISCUSSION: Acetone extract of the plant examined exhibited a significant concentration-dependent inhibition of DPPH and NO* radical. Furthermore, Nepeta meyeri showed very high reducing power. In DPPH radical and NO* scavenging assays the IC50 value of extract was 672.2 microg/ml and 165.32 microg/ml, respectively. The amounts of total phenolic compounds were also determined and 12.86 microg pyrocatechol equivalents of phenols were detected in the extract. The data obtained from these in vitro models clearly demonstrated antioxidant potential of acetone extract of Nepeta meyeri. The extract revealed antibacterial activity against all gram positive bacteria but not was active against gram negative bacteria. PMID- 20707286 TI - Anticancer activity of Sargassum oligocystum water extract against human cancer cell lines. AB - BACKGROUND AND OBJECTIVES: Antitumor drug resistance and side effects of antitumor compounds are the most common problems in medicine. Therefore, finding new antitumor agents with low side effects could be interesting. This study was designed to assay antitumor activity of the extract from brown alga Sargassum oligocystum, gathered from Persian Gulf seashore, against K562 and Daudi human cancer cell lines. MATERIALS AND METHODS: The research was performed as an in vitro study. The effect of the alga extract on proliferation of cell lines were measured by two methods: MTT assay and trypan blue exclusion test. RESULTS AND CONCLUSION: The most effective antitumor activity has been shown at concentrations 500 microg/ml and 400 microg/ml of the alga extract against Daudi and K562 cell lines, respectively. The results showed that the extracts of brown alga Sargassum oligocystum have remarkable antitumor activity against K562 and Daudi cell lines. It is justified to be suggested for further research such as algal extract fractionation and purification and in vivo studies in order to formulate natural compounds with antitumor activities. PMID- 20707287 TI - Screening of antibacterial activity of mucus extract of snakehead fish, Channa striatus (Bloch). AB - AIM: The objective of this study is to gain a better understanding of the antimicrobial properties of the mucus extract of snakehead fish, Channa striatus against selected human and fish pathogenic microbes. MATERIALS AND METHODS: The fish mucus samples were extracted with crude, acidic and aqueous solvents to identify potential antimicrobial agents including aqueous and acid soluble compounds. The study also determined the protein content of the three different mucus extracts. The highest protein content (0.589 mg/ml) was noticed in the crude extract followed by aqueous mucus extract (0.291 mg/ml) and acidic extract (0.267 mg/ml). Preliminary screening for antimicrobial activity of all three mucus extracts were tested against 5 human pathogens (Bacillus subtilis, Klebsiella pneumoniae, Salmonella enteritidis, Proteus vulgaris and Pseudomonas aeruginosa) and fish pathogen (Aeromonas hydrophila) using the British Society for Antimicrobial Chemotherapy (BSAC) standardized disc susceptibility test method. The activity was measured in terms of zone of inhibition in mm. RESULTS: The acidic mucus extracts exhibited a bactericidal activity and inhibited the growth of Klebsiella pneumoniae, Pseudomonas aeruginosa and Bacillus subtilis while aqueous and crude extract showed no bactericidal activity for any of the human pathogens tested. Further test against fish pathogen Aeromonas hydrophila showed that the aqueous and crude extracts are capable of inhibiting the growth of the pathogen, demonstrating the presence of antimicrobial agents and the role of fish mucus in antimicrobial protection. CONCLUSIONS: The present results suggest that the mucus extracts of snakehead fish Channa striatus may be a potential source of antimicrobial agents for human and fish pathogens. PMID- 20707288 TI - Biofilms and infections of the upper respiratory tract. AB - Biofilms are microbial communities consisting of bacteria that either are self reproducing on biological surfaces or are present in the lifeless environment. Biofilms are quite diffuse entities frequently found in human pathological conditions. The formation of bacterial biofilms involves mainly the contamination of artificial medical devices, such as valves and catheters, and their direct implant on mucous membranes, with subsequent development of chronic or recurrent infections. Bacterial biofilms show a complex organization consisting of bacterial cells adherent to a surface and surrounded by a large extracellular matrix mostly made up of polysaccharides and proteins. The resistance observed in biofilms does not appear to be genotypic; instead, it is due to multicellular strategies and/or to the ability of each cell, contained inside the biofilm, to differentiate into a protected phenotypic state which tolerates the antibiotic action. In fact, biofilms are subject to changes following their recurrent exposure to antimicrobial agents, thus incrementing their resistance. Biofilms play an important role in otitis media, sinusitis, chronic cholesteatomatous otitis media, tonsillitis and adenoiditis, thus demonstrating that adenoidectomy may be helpful to children suffering from such a morbid conditions. It is presently estimated that biofilm formation is involved in at least 60% of all chronic and/or recurrent infections. In addition, 30% of the exudates developing in the course of otitis media has shown to be positive for the presence of biofilms; likewise biofilms have been found in tonsillar crypts and in odontostomatologic infections as well. Studies have been carried out on both the use and the efficacy of N-acetylcysteine (NAC) in biofilm breakdown. It has been shown that NAC, used at different concentrations, is able to reduce bacterial adhesion in several anatomical districts. PMID- 20707289 TI - Treatment of stable vitiligo hands by ReCell system: a preliminary report. AB - BACKGROUND: The aim of this report was to analyze the results obtained with the ReCell system for the surgical treatment of stable vitiligo hands. MATERIALS AND METHODS: One patient with stable vitiligo of the hands was admitted at the Department of Plastic and Reconstructive Surgery, University of Rome Tor Vergata. The patient underwent to ReCell system for the treatment of stable vitiligo hands. RESULTS: The repigmentation was assessed using the Vitiligo Area Scoring index (VASI). The extent of pigmentation was scored as excellent, good, fair, and poor depending on the percentage of the repigmentation in the previously depigmented site. The color of the repigmented area was compared with the adjacent normally pigmented area. The patient had an excellent repigmentation. CONCLUSIONS: ReCell system is a simple, safe and feasible technique. The method that uses noncultured autologous epidermal suspension is simpler, cheaper, less time consuming and does not require sophisticated laboratory facilities, when compared with methods employing cultured melanocytes. PMID- 20707290 TI - Predictors of survival in idiopathic interstitial pneumonia. AB - AIM: To evaluate the ability of newly identified clinical factors to predict prognosis and survival in idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). METHODS: Seventy-eight patients referred to the University of Genoa and the Regional Hospital of Aosta between January 1995 and December 2006 were evaluated prospectively. Fifty-nine patients were diagnosed with IPF and 19 with NSIP on the basis of surgical lung biopsy specimens. Gender, age at diagnosis, smoking, New York Heart Association class (NYHA), systolic pulmonary artery pressure (sPAP), Octreoscan uptake index (UI), and therapy were the chosen variables. Primary end-point was survival. RESULTS: With the exception of gender and smoking history, all baseline patient characteristics correlated significantly with the diagnosis (IPF vs. NSIP). Median survival for the entire study group was 52.7 months. Univariate analysis showed poorer survival for the IPF group versus the NSIP group, and survival was significantly lower for older patients (p < 0.001). Multivariate analysis confirmed the negative prognostic effect of age (p < 0.001) on survival with a risk of death for older patients ( > OR =66 years old) being more than 4 times higher than that for younger patients (<58 yr.). NYHA class and pulmonary artery pressure were also significant predictors of survival, and all patients with a sPAP < OR = 35-mm Hg were alive at the end of the follow-up period. There was a good correlation between Octreoscan uptake index and the diagnosis. CONCLUSION: Diagnosis (IPF vs. NSIP), NYHA class, sPAP, and especially age appear to represent important prognostic indicators in the two most prevalent forms of idiopathic pulmonary fibrosis (IPF and NSIP). Lower Octreoscan uptake values were found in all patients with IPF, suggesting that this test may have a role as a new predictor of survival for differentiating IPF from NSIP. PMID- 20707291 TI - Decline in FEV1 related to genetic polymorphisms (+138insA/delA and Lys198Asn) of the endothelin-1 gene in COPD. A pilot study. AB - BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor and bronchoconstrictor but it has been shown to have also proinflammatory properties. Its ability to attract inflammatory cells in its site of production, upregulates the synthesis of adhesion molecules and stimulates the release of cytokines. The fact that cytokines have the ability to induce its synthesis and release, creates a dynamic loop for self-preservation and augmentation of the airway inflammation in Chronic Obstructive Pulmonary Disease (COPD), even after the ceasing of the noxious stimulus, i.e., cigarette smoke. Therefore, functional polymorphisms that may lead to increased levels of ET-1 may also cause an increased susceptibility to COPD development. MATERIALS AND METHODS: We analyzed the longitudinal effect on lung function of two ET-1 gene polymorphisms in a population of 190 smokers (95 non-COPD and 95 COPD smokers). The two polymorphisms involved an insertion polymorphism (+138 adenine insertion 3A/4A, 138bp downstream from the transcription start site, exon 1) and a single nucleotide transversion polymorphism on exon 5 (G/T, Lys198Asn). A total of 190 subjects were enrolled in the study for each polymorphism and were followed for 3 years by annual spirometry sessions. RESULTS: The adjusted annual decline of forced expiratory volume in 1 second (dFEV1) was greater for those having at least one copy of the mutated gene ins/delA compared to those with the wild type allele both in the non COPD smokers group (mean difference in dFEV, of 19.4 ml/year, p = 0.004) and COPD smokers (mean difference in dFEV1 of 11.15 ml/year, p = 0.003). On the contrary, those heterozygous for the Lys198Asn polymorphism were found to have a slower decline in FEV1 compared to those homozygous for the wild type allele. The non COPD smokers group had a gain-in-loss of 11,24 ml/year (p < 0.001) while the COPD smokers group had a slower decline of 11.42 ml/year (p = 0.002). Those homozygous for the polymorphisms examined show an even greater deviation from those with the wild type allele but due to the small number comprising their group, the results don't have enough statistical power. Though, they still show the trend of the effect the polymorphisms have on annual FEV1 decline. CONCLUSIONS: The present data shows that ET-1 and its functional polymorphisms may be implicated in COPD phenotype and severity. PMID- 20707292 TI - Magnetic resonance cholangiography: past, present and future: a review. AB - INTRODUCTION: Magnetic resonance cholangio-pancreatography (MRCP) is a valuable method for the evaluation of biliary and pancreatic diseases and a valuable alternative to endoscopic retrograde cholangiopancreatography (ERCP). It is noninvasive and does not require the use of contrast material or ionizing radiation. Since its introduction in 1991, this technique has significantly improved in spatial resolution, now allowing the accurate assessment of the major bilio-pancreatic diseases. STATE OF THE ART: MRCP is commonly performed with heavily T2-weighted sequences in order to highlight static fluids, as those contained in dilated pancreatic and biliary ducts. Newest MR equipments allow to perform MRCP within 10-15 minutes, due to the availability of ultra-fast sequences. Currently, MRCP is widely performed as a primary imaging modality for the assessment of obstructive jaundice and other benign or malignant bilio pancreatic ducts abnormalities. The primary MRCP application is the evaluation of biliary obstructions due to choledocholithiasis, iatrogenic strictures, cholangiocarcinoma or pancreatic carcinoma. Other MRCP applications include the assessment of the exocrine pancreatic function, following secretin stimulation. Whenever needed, the MRCP may be completed with a conventional contrast-enhanced magnetic resonance imaging (MRI) of the upper abdomen and functional studies as well, thus providing an all-in-one mophological and functional study of the pancreas and biliary system. More recent applications include the possibility of 3D reconstructions and the use of hepato-biliary contrast agents, that provide a higher definition of the biliary tree, both in pathologic and normal conditions. The introduction of 3Tesla magnets could provide higher anatomic detail. CONCLUSIONS: In the next years the role of MRCP will further expand, due to the availability of faster sequences, 3D imaging and functional studies. PMID- 20707293 TI - The neo-adjuvant treatment in gastrointestinal stromal tumor. AB - Gastrointestinal Stromal Tumor (GIST) is a rare intra-abdominal tumor, characterized by a specific histological and immunohistochemical pattern. These tumors affect with higher frequency stomach and small bowel and occur at a median age of 60 years with a slight male predominance. An early stage of GIST often don't cause any symptoms, so most GISTs are diagnosed in later stages of the disease. We report a case of GIST diagnosed only with clinical data and positron emission tomography (PET). We demonstrate the usefulness of neoadjuvant treatment with Imatinib mesylate, a newly developed tyrosine kinase receptor inhibitor. The neoadjuvant treatment with Imatinib reduced the mass size and vascularization, making possible a surgical approach. PMID- 20707294 TI - [From piroplasmosis to babesiosis--problems with classification of Babesia protozoa isolated from dogs]. AB - Babesia and Theileria are the tick-borne parasites belonging to the order Piroplasmida. Both of them cause a severe disease with symptoms of hemolytic anemia. The main etiological factors of canine piroplasmosis are protozoa Babesia. There are two species of this pathogen infective for dogs: Babesia canis and Babesia gibsoni. Based on the results of molecular biology techniques it is possible to distinguish them as well as many subspecies or strains. It is known since quite some time that there are substantial differences in vector specificity, cross-immunity and pathogenicity between isolates of this species. Also the results of molecular analysis of these protozoa indicate that their genetic structure is diversified. On the basis of analysis of Babesia DNA sequences, the new variants of protozoa in dogs were detected. It is possible that, these new variants of Babesia are characterized by high virulence for dogs and resistance to drugs used in babesiosis therapy. PMID- 20707295 TI - [The spread of nematodes from Toxocara genus in the world]. AB - Twenty seven species belong to the genus Toxocara. Most of the species infect Carnivora from families: Canidae, Felidae, Viverridae, Procyonidae, Mustelidae and Herpestidae. The most widespread species are: T. canis, T. cati and T. vitulorum. The life cycle of Toxocara spp. is connected with young animals and adults with the lowered immune response. Three of the Toxocara species: T. canis, T. cati and T. pteropodis are the aetiological agents of human toxocariasis. PMID- 20707296 TI - [Biology, epidemiology and diagnostics of pathogenic waterborne protozoan parasites]. AB - Cryptosporidium, Giardia intestinalis, Cyclospora cayetanensis, Isosopra belli and micropsoridia are the most important and common pathogens found in humans and many other species of vertebrates. In humans, mainly in immunocompromised patients, children, pregnant women and elderly people, they are the most frequently identified protozoan parasites causing gastrointestinal disease worldwide. These pathogens have several transmission routes, including anthroponotic and zoonotic transmission. What is more, in many cases of epidemics caused by mentioned pathogens the major cause of infection was contaminated with these organisms water and food. In spite of many existing regulations of clearing and making use of drinking water supplies and recreational water, cosmopolitan protozoan parasites are still the danger of public health. These organisms are responsible for many waterborne outbreaks worldwide. Light microscopy and immunofluorescence assay have been used to identify these organisms in most laboratories. However, these traditional techniques have major limitations in the specific diagnosis, these methods are not sensitive enough to detect cysts or oocysts in environmental samples, so the new molecular tools must be applied. Recently, PCR-based techniques have been developed for detection and genetic characterization of the different species and population variants of protozoan parasites is central to the prevention, surveillance and control of gastrointestinal diseases. In this review were characterized biology, epidemiology and the progress in technology for detection and surveillance of the most important waterborne protozoan parasites. PMID- 20707297 TI - [Achievements and perspectives of research into development of a vaccine against malaria]. AB - Malaria is caused by parasites of the genus Plasmodium. Every year from 350 to 500 million of malaria cases are recorded with an estimated annual death toll of over 1.1 million deaths, making malaria the global health problem. Malaria deepens the poverty, limits the education and causes absences at schools and workplaces--what makes the progress of civilization and economy slower. This is why beside the classical methods of malaria prevention, such as the elimination of the places of mosquito breeding and, application of insecticides or chemoprophylaxis, the elaboration of effective malaria vaccine is a necessity. Despite considerably high financial investments for long term malaria research, so far it has not been possible to develop an efficient vaccine against this disease. This is why the main topic of the present review is presenting of achievements and perspectives of research on development of vaccine against malaria with special consideration of tested antigens. Our review also contains an attempt to typify the most prospective vaccine. Currently developed and tested vaccines against malaria may be divided in three groups depending on the parasite living stage which the vaccine influences: pre-erythrocytic stage vaccines, blood stage vaccines and transmission blocking vaccines. At the moment it seems that the most promising vaccine against malaria is RTS,S/ASO2A which represent the pre erythrocytic stage vaccines. However developing a completely safe, efficient and budget-friendly vaccine still remains the far-reaching goal and requires further years of research. PMID- 20707298 TI - [Occurrence of Toxocara spp. eggs in household environment of children with diagnosed toxocariasis in Lodz voivodeship]. AB - Toxocariasis is a zoonosis due to infection of humans by dog or cat roundworm (Toxocara canis, T. cati). Humans become infected by ingestion of infective eggs either from soil, dirty hands, raw fruits and vegetables or larvae from undercooked meat of paratenic hosts. The aim of the study was to evaluate the level of contamination of soil samples from households of children with diagnosed toxocariasis in rural and urban areas of Lodz voivodeship. In the years 2004-2007 toxocariasis was confirmed in 178 patients of the Polish Memorial Hospital in Lodz. The soil samples were collected from 53 courtyards of patients' domiciles. Toxocara spp. eggs were isolated from the samples using flotation technique (Dada 1979). The examinations revealed the high prevalence of ground contamination with Toxocara eggs in both, rural (30.4%) and urban areas (23.3%). The presence of Toxocara eggs in households enlarges the risk of re-infection for children with diagnosed toxocariasis, especially in rural areas where the high level of contamination was detected. PMID- 20707299 TI - [The utility of MTT and XTT colorimetric tests in the studies conducted in vitro with Toxoplasma gondii tachyzoites]. AB - Tetrazolium salts are widely used as indicators of metabolic activity for both eukaryotic and prokaryotic cells. Live cells reduce the tetrazole ring in MTT or XTT salts and then a colored formazane formed can be assessed spectrophotometrically. Despite widespread use of MTT/XTT reduction tests biochemical mechanisms of the reaction are still unknown, and each test application case requires standardization of experimental conditions. In the present study we tested in vitro the utility of both MTT and XTT salts to determine the influence of selected extracellular agents for T. gondii tachyzoites and their host cells (i.e. mouse L929 fibroblasts). The results showed that MTT is reduced more intensively than XTT by host and parasite cells. The attenuation of T. gondii tachyzoites resulted in a decrease of reduction level of both tetrazolium salts, particularly of XTT. Using MTT we found also that T. gondii is not susceptible to extremely toxic substance, sodium azide. Our results confirmed a high usefulness of MTT reduction tests in numerous studies on eukaryotic cells. PMID- 20707300 TI - Trichodina shitalakshyae sp. n. and Trichodina acuta Lom, 1961 (Ciliophora: Trichodinidae) from the freshwater fishes in the Shitalakshya River, Bangladesh. AB - Two trichodinid species were identified from freshwater fishes, Mystus bleekeri and Glossogobius giuris, in the Shitalakshya River of Gazipur district, Bangladesh. Trichodina acuta Lom, 1961 is found for the first time in Bangladesh. Trichodina shitalakshyae sp. n. is characterized by having an undivided clear central area in the adhesive disc with a rounded or slightly undulated perimeter containing a few dark granules which form patches; elongated and rectangular blade with large interblade space and blunt tangent point; indistinct anterior blade apophysis and a shallow apex at the base of blade that never extends beyond the Y+1 axis; moderately wide and triangular central part with blunt point; and space between tip of ray and central clear area forms a wide impregnated ring. Based on these characters and the unique shape and absence of variability of the denticles among the silver impregnated specimens of the present species, it resembles Trichodina porocephalusi Asmat, 2001. PMID- 20707301 TI - [The influence of Taenia taeniaeformis larval infection on morphometrical parameters of muskrat (Ondatra zibethicus)]. AB - An investigation aimed to check the influence of Taenia taeniaeformis larvae on morphometrical parameters of muskrat (Ondatra zibethicus) was carried. A total of 30 animals were hunted down in upper Vistula river basin in south Poland, then measured, weighed and dissected. Statistical comparison were done using U Mann Whitney test. T. taeniaeformis larvae--cysticercus fasciolaris was found in the liver of 24 muskrats (80%). Significant differences between infected and non infected animals are reported, as regards their body mass, total length, abdomen circumference (p < 0.01) and also in body length (total minus tail length), head length, or chest and neck circumference (p < 0.05). The effect of infection on both muskrat condition and the presence of adult cestodes in definitive hosts are discussed. PMID- 20707302 TI - Drug susceptibility of 64 strains of Rhodotorula sp. AB - Rhodotorula sp. have emerged as opportunistic pathogens, particularly in immunocompromised patients. Knowledge about the susceptibility of Rhodotorula strains to the common antifungal drugs is essential for the treatment of such new infections. The 68 isolates identified as: Rhodotorula mucilaginosa (47 strains; 69%), R. minuta (14; 21%) and R. glutinis (7; 10%) obtained from various sources (feces, skin and nails, vagina and hospital environment) were tested for susceptibility to 5-fluorocytosine (5FC), amphotericin B (AMB), fluconazole (FLC) and itraconazole (ITR). All of the isolates had low MICs for AMB and 5FC. For ITR, the R. minuta isolates had the lowest MICs within a range 0.125-0.25 mg/l and for FLC all isolates affected within the range 2-64 mg/l. The majority of R. mucilaginosa isolates (82.2%) had MICs in the range 64-128 mg/l for FLC and 95.6% of isolates had MICs above or equal to 2 mg/1 for ITR. PMID- 20707303 TI - [Genotype analysis of Giardia duodenalis isolates obtained from humans in west central Poland]. AB - Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a cosmopolitan flagellate organism belonging to the most common intestinal protozoan parasites of humans and animals. Great genetic heterogeneity has been found within G. duodenalis, where only genotypes representing assemblages A and B have zoonotic potential. Fecal samples (447 specimens) obtained from 232 humans in West-central region of Poland were examined by microscopy and PCR. The total prevalence of Giardia in humans was 1.3%. DNA was extracted from three positive fecal samples and PCR products were obtained after amplification using the beta-giardin primers G7 and G759. Sequence and phylogenetic analyses showed that G. duodenalis isolates from humans belonged to A and B genotypes. Moreover, three subgenotypes, including a cosmopolitan subgenotype A2 and two new subgenotypes A and B were detected. PMID- 20707304 TI - Coproscopical investigations of the European otter (Lutra lutra) from Bialowieza Primeval Forest. AB - The parasitofauna of the European otter (Lutra lutra) remains poorly known in Poland. In the presented study 106 fecal samples from otters living in the Bialowieza Primeval Forest were examined, using standard flotation and sedimentation methods. We found that the overall prevalence of parasitic infections was 30.1%. Eggs of Alaria alata (0.9%), Opistorchis or Metorchis sp. (5.7%), Diphyllobothrium latum (1.9%) and Aonchotheca putori (1.9%) were identified, but in other cases the species of parasite could not be reliably determined. Parasitological dissections should give better results in future studies. PMID- 20707305 TI - Nanoencapsulation of insulin into zirconium phosphate for oral delivery applications. AB - The encapsulation of insulin into different kinds of materials for noninvasive delivery is an important field of study because of the many drawbacks of painful needle and syringe delivery such as physiological stress, infection, and local hypertrophy, among others (Khafagy, E.-S.; et al. Adv. Drug Delivery Rev. 2007, 59 (15), 1521-1546). A stable, robust, nontoxic, and viable noninvasive carrier for insulin delivery is needed. We present a new approach for protein nanoencapsulation using layered zirconium phosphate (ZrP) nanoparticles produced without any preintercalator present. The use of ZrP without preintercalators produces a highly pure material, without any kinds of contaminants, such as the preintercalator, which can be noxious. Cytotoxicity cell viability in vitro experiments for the ZrP nanoparticles show that ZrP is not toxic, or harmful, in a biological environment, as previously reported for rats (Zhu, Z. Y.; et al. Mater. Sci. Forum 2009, 620-622, 307-310). Contrary to previous preintercalator based methods, we show that insulin can be nanoencapsulated in ZrP if a highly hydrate phase of ZrP with an interlayer distance of 10.3 A (10.3 A-ZrP or theta ZrP) is used as a precursor. The intercalation of insulin into ZrP produced a new insulin-intercalated ZrP phase with about a 27 A interlayer distance, as determined by X-ray powder diffraction, demonstrating a successful nanoencapsulation of the hormone. The in vitro release profile of the hormone after the intercalation was determined and circular dichroism was used to study the hormone stability upon intercalation and release. The insulin remains stable in the layered material, at room temperature, for a considerable amount of time, improving the shell life of the peptidic hormone. This type of material represents a strong candidate to developing a noninvasive insulin carrier for the treatment of diabetes mellitus. PMID- 20707306 TI - Protein substitution affects glass transition temperature and thermal stability. AB - When proteins are removed from their native state they suffer from two deficiencies: (1) glassy behavior with glass transition temperatures (Tg) well above room temperature and (2) thermal instability. The glassy behavior originates in multiple hydrogen bonds between amino acids on adjacent protein molecules. Proteins, like most biopolymers, are thermally unstable. Substituting ovalbumin with linear and cyclic substituents using a facile nucleophilic addition reaction can affect Tg and thermal stability. More hydrophobic linear substituents lowered Tg by interrupting intermolecular interactions and increasing free volume. More hydrophilic and cyclic substituents increased thermal stability by increasing intermolecular interactions. In some cases, substituents instituted cross-linking between protein chains that enhanced thermal stability. Internal plasticization using covalent substitution and external plasticization using low molecular weight polar liquids show the same protein structural changes and a signature of plasticization is identified. PMID- 20707307 TI - Determination of amino acids in Chinese rice wine by fourier transform near infrared spectroscopy. AB - Chinese rice wine is abundant in amino acids. The possibility of quantitative detection of 16 free amino acids (aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, and arginine) in Chinese rice wine by Fourier transform near-infrared (NIR) spectroscopy was investigated for the first time in this study. A total of 98 samples from vintage 2007 rice wines with different aging times were analyzed by NIR spectroscopy in transmission mode. Calibration models were developed using partial least-squares regression (PLSR) with high-performance liquid chromatography (HPLC) by postcolumn derivatization and diode array detection as a reference method. To validate the calibration models, full cross (leave-one-out) validation was employed. The results showed that the calibration statistics were good (rcal>0.94) for all amino acids except proline, histidine, and arginine. The correlation coefficient in cross validation (rcv) was >0.81 for 12 amino acids. The residual predictive deviation (RPD) value obtained was >1.5 in all amino acids except proline and arginine, and it was >2.0 in 6 amino acids. The results obtained in this study indicated that NIR spectroscopy could be used as an easy, rapid, and novel tool to quantitatively predict free amino acids in Chinese rice wine without sophisticated methods. PMID- 20707308 TI - Impact of electrostatic deposition of anionic polysaccharides on the stability of oil droplets coated by lactoferrin. AB - The purpose of this study was to investigate the effects of three anionic polysaccharides (low methoxyl pectin (LMP), high methoxyl pectin (HMP) and alginate) on the physicochemical properties and stability of lactoferrin (LF) coated lipid droplets. LMP, HMP and alginate were shown to adsorb to the surfaces of LF-coated droplets at neutral pH, which was primarily attributed to electrostatic attraction between anionic groups on the polysaccharide molecules and cationic patches on the protein surfaces. In the absence of polysaccharide, the LF-coated droplets were highly unstable to aggregation when heated above about 60 degrees C at pH 7, presumably because thermal denaturation of the adsorbed proteins increased droplet attraction. The addition of either LMP or HMP prior to heating greatly improved the thermal stability of the emulsions, with no aggregation being observed from 30 to 90 degrees C. On the other hand, the presence of anionic polysaccharides had little effect on emulsion stability or even promoted emulsion instability when 0 to 200 mM NaCl or CaCl2 was added. This study shows that the stability of LF-coated lipid droplets can be improved by careful selection of an appropriate type and amount of anionic polysaccharide to incorporate. PMID- 20707309 TI - Correlation of 3-isobutyl-2-methoxypyrazine to 3-isobutyl-2-hydroxypyrazine during maturation of bell pepper (Capsicum annuum) and wine grapes (Vitis vinifera). AB - Environmental factors affecting degradation of 3-isobutyl-2-methoxypyrazine (IBMP, "green pepper aroma") in wine grapes (V. vinifera) are widely studied, but the degradation pathway is not defined. We hypothesized that IBMP is demethylated to 3-isobutyl-2-hydroxypyrazine (IBHP) during fruit maturation effectively reversing the final putative step of IBMP biosynthesis. A quantification method for IBHP was developed using solid-phase extraction coupled to one- or two dimensional gas chromatography-mass spectrometry with a recovery of ca. 80%. IBMP and IBHP in bell peppers (Capsicum annuum) and V. vinifera (cv. 'Cabernet Franc', 'Riesling', 'Pinot noir') were then measured at different maturities. IBMP and IBHP were inversely correlated in both bell peppers (R2=0.958) and Cabernet Franc grapes (R2=0.998) over a range of maturities. In bell peppers, we observed a significant decline in IBMP (125 to 15 ng/mL) and increase in IBHP (undetectable to 42 ng/mL) during ripening. In grapes, all cultivars had comparable IBHP concentrations preveraison (64 to 88 pg/mL) but differed in IBHP concentration by 2 orders of magnitude at the final sampling point (undetectable to 235 pg/mL). Higher preveraison IBMP was correlated with higher final IBHP across the three grape cultivars, with the order Cabernet Franc>Riesling>Pinot noir for both IBMP and IBHP. Acid hydrolysis resulted in a significant increase (33%) in IBHP in Cabernet Franc, indicating that IBHP exists partially in a bound form in grapes. PMID- 20707310 TI - Physico-chemical and chromatic characterization of malvidin 3-glucoside vinylcatechol and malvidin 3-glucoside-vinylguaiacol wine pigments. AB - The physicochemical and chromatic features of malvidin 3-glucoside-vinylcatechol (PA1) and malvidin 3-glucoside-vinylguaiacol (PA2) adducts were investigated. Important differences between both pigments were observed. In the investigated pH range (2.0-4.5), our results suggest that PA1 could be considered as a noncovalent dimer of two pyranoflavylium ions (AH)2 which undergo a hydration reaction in two successive steps, with no proton transfer. In contrast, only proton transfer equilibrium between the pyranoflavylium ion and the quinonoid bases was observed for PA2. The hydration and acidity thermodynamic constants of both pyranoanathocyanins were determined by UV-vis spectroscopy. Pigment PA1 was shown to be less sensitive to bisulfite addition than to water addition, and PA2 seems to be largely insensitive to both water and bisulfite additions. The binding constants for the interaction between the pigments and (+)-catechin in aqueous solution and the changes in the CIELAB parameters that it provoked were also determined. The huge increase in the absorption of the pyranoflavylium ion of PA2 when it binds catechin has no equivalent for anthocyanins and nicely outlines the potential of pyranoanthocyanins in the expression of natural colors. PMID- 20707311 TI - Structural insight into methyl-coenzyme M reductase chemistry using coenzyme B analogues . AB - Methyl-coenzyme M reductase (MCR) catalyzes the final and rate-limiting step in methane biogenesis: the reduction of methyl-coenzyme M (methyl-SCoM) by coenzyme B (CoBSH) to methane and a heterodisulfide (CoBS-SCoM). Crystallographic studies show that the active site is deeply buried within the enzyme and contains a highly reduced nickel-tetrapyrrole, coenzyme F(430). Methyl-SCoM must enter the active site prior to CoBSH, as species derived from methyl-SCoM are always observed bound to the F(430) nickel in the deepest part of the 30 A long substrate channel that leads from the protein surface to the active site. The seven-carbon mercaptoalkanoyl chain of CoBSH binds within a 16 A predominantly hydrophobic part of the channel close to F(430), with the CoBSH thiolate lying closest to the nickel at a distance of 8.8 A. It has previously been suggested that binding of CoBSH initiates catalysis by inducing a conformational change that moves methyl-SCoM closer to the nickel promoting cleavage of the C-S bond of methyl-SCoM. In order to better understand the structural role of CoBSH early in the MCR mechanism, we have determined crystal structures of MCR in complex with four different CoBSH analogues: pentanoyl, hexanoyl, octanoyl, and nonanoyl derivatives of CoBSH (CoB(5)SH, CoB(6)SH, CoB(8)SH, and CoB(9)SH, respectively). The data presented here reveal that the shorter CoB(5)SH mercaptoalkanoyl chain overlays with that of CoBSH but terminates two units short of the CoBSH thiolate position. In contrast, the mercaptoalkanoyl chain of CoB(6)SH adopts a different conformation, such that its thiolate is coincident with the position of the CoBSH thiolate. This is consistent with the observation that CoB(6)SH is a slow substrate. A labile water in the substrate channel was found to be a sensitive indicator for the presence of CoBSH and HSCoM. The longer CoB(8)SH and CoB(9)SH analogues can be accommodated in the active site through exclusion of this water. These analogues react with Ni(III)-methyl, a proposed MCR catalytic intermediate of methanogenesis. The CoB(8)SH thiolate is 2.6 A closer to the nickel than that of CoBSH, but the additional carbon of CoB(9)SH only decreases the nickel thiolate distance a further 0.3 A. Although the analogues do not induce any structural changes in the substrate channel, the thiolates appear to preferentially bind at two distinct positions in the channel, one being the previously observed CoBSH thiolate position and the other being at a hydrophobic annulus of residues that lines the channel proximal to the nickel. PMID- 20707312 TI - Cytotoxicity of Monascus pigments and their derivatives to human cancer cells. AB - Six pigments were separated from Monascus product, and some derivatives were chemically synthesized. The cytotoxicity of different Monascus pigments to various human cancer cells (SH-SY5Y, HepG2, HT-29, BGC-823, AGS, and MKN45) was evaluated. Rubropunctatin showed the greatest anticancer effect within the tested compounds. The inhibition effect of rubropunctatin was higher than that of taxol on the growth of the human gastric cancer cell SH-SY5Y (P<0.05), BGC-823 (P<0.01), AGS (P<0.01), and MKN45 (P<0.05). On the other hand, its cytotoxicity to the normal human gastric epithelial cell GES-1 was less than that of taxol (P<0.01). The experimental data demonstrated that rubropunctatin was a valuable compound with high anticancer activity, which could offer better therapeutic benefits than taxol. Cell apoptosis stages were assayed by annexin V-EGFP/PI staining experiments using flow cytometry. The data showed that 87.63% of tested BGC-823 cells entered the early phase of apoptosis when treated with 5 microM rubropunctatin for 24 h. A drug concentration-dependent cell apoptosis was observed. The analysis of the relationship between pharmaceutical activity and the chemical structure of the tested compounds led to the conclusion that 6 internal ether, 4-carbonyl, and conjugated double bonds in the tricyclic structure of rubropunctatin were necessary to the anticancer effect, whereas the difference of C2H4 in the side chain showed little influence. Rubropunctatin could be supplied as a precursor compound in the development of a new natural anticancer reagent. PMID- 20707314 TI - Functional analysis, overexpression, and kinetic characterization of pyruvate kinase from methicillin-resistant Staphylococcus aureus. AB - Novel antimicrobial targets are urgently needed to overcome rising antibiotic resistance of important human pathogens including methicillin-resistant Staphylococcus aureus (MRSA). Here we report the essentiality and kinetic properties of MRSA pyruvate kinase (PK). Targetron-mediated gene disruption demonstrated PK is essential for S. aureus growth and survival, suggesting that this protein may be a potential drug target. The presence of the pfk (6 phosphofructokinase)-pyk operon in MRSA252, and the nonessential nature of PFK shown by targetron, further emphasized the essential role of PK in cell viability. The importance of PK in bacterial growth was confirmed by showing that its enzymatic activity peaked during the logarithmic phase of S. aureus growth. PK from Staphylococcus and several other species of bacteria have an extra C terminal domain (CT) containing a phosphoenolpyruvate (PEP) binding motif. To elucidate the possible structure and function of this sequence, the quaternary structures and kinetic properties of the full-length MRSA PK and truncated MRSA PK lacking the CT domain were characterized. Our results showed that (1) MRSA PK is an allosteric enzyme with homotetramer architecture activated by AMP or ribose 5-phosphate (R5P), but not by fructose 1,6-bisphosphate (FBP), which suggests a different mode of allosteric regulation when compared with human isozymes, (2) the CT domain is not required for the tetramerization of the enzyme; homotetramerization occurred in a truncated PK lacking the domain, (3) truncated enzyme exhibited high affinity toward both PEP and ADP and exhibited hyperbolic kinetics toward PEP in the presence of activators (AMP and R5P) consistent with kinetic properties of full-length enzyme, indicating that the CT domain is not required for substrate binding or allosteric regulation observed in the holoenzyme, (4) the kinetic efficiency (k(cat)/S(0.5)) of truncated enzyme was decreased by 24- and 16-fold, in ligand-free state, toward PEP and ADP, respectively, but was restored by 3-fold in AMP-bound state, suggesting that the sequence containing the CT domain (Gly(473)-Leu(585)) plays a substantial role in enzyme activity and comformational stability, and (5) full-length MRSA PK activity was stimulated at low concentrations of ATP (e.g., 1 mM) and inhibited by inorganic phosphate and high concentrations of FBP (10 mM) and ATP (e.g., >2.5 mM), whereas for truncated enzyme, stimulation at low concentrations of ATP was lost. These findings suggest that the CT domain is involved in maintaining the specificity of allosteric regulation of MRSA PK by AMP, R5P, and ATP. The CT extension also encodes a protein domain with homology to enzyme I of the Escherichia coli sugar-PTS system, suggesting that MRSA PK may also exert an important regulatory role in sugar transport metabolism. These findings yield new insights into MRSA PK function and mode of allosteric regulation which may aid in the development of clinically important drugs targeting this enzyme and further define the role of the extra C-terminal domain in modulating the enzyme's activity. PMID- 20707313 TI - High-resolution MAS NMR analysis of PI3-SH3 amyloid fibrils: backbone conformation and implications for protofilament assembly and structure . AB - The SH3 domain of the PI3 kinase (PI3-SH3 or PI3K-SH3) readily aggregates into fibrils in vitro and has served as an important model system in the investigation of the molecular properties and mechanism of formation of amyloid fibrils. We describe the molecular conformation of PI3-SH3 in amyloid fibril form as revealed by magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopy. The MAS NMR spectra of these fibrils display excellent resolution, with narrow (13)C and (15)N line widths, representing a high degree of structural order and the absence of extensive molecular motion for the majority of the polypeptide chain. We have identified the spin systems of 82 of the 86 residues in the protein and obtained sequential resonance assignments for 75 of them. Chemical shift analysis indicates that the protein subunits making up the fibril adopt a compact conformation consisting of four well-defined beta-sheet regions and four random-coil elements with varying degrees of local dynamics or disorder. The backbone conformation of PI3-SH3 in fibril form differs significantly from that of the native state of the protein, both in secondary structure and in the location of dynamic or disordered segments. The site-specific MAS NMR analysis of PI3-SH3 fibrils we report here is compared with previously published mechanistic and structural data, resulting in a detailed interpretation of the factors that mediate fibril formation by PI3-SH3 and allowing us to propose a possible model of the core structure of the fibrils. Our results confirm the structural similarities between PI3-SH3 fibrils and amyloid assemblies directly related to degenerative and infectious diseases. PMID- 20707315 TI - Enhanced uptake of porous silica microparticles by bifunctional surface modification with a targeting antibody and a biocompatible polymer. AB - Strategies were developed by which mesoporous microparticles were modified on their external surfaces with tetraethylene glycol (TEG), a protein, or both, leaving the pore surfaces available for modification with a separate moiety, such as a dye. Only particles bifunctionally modified with both TEG and a cell specific antibody were taken up specifically by a targeted cancer cell line. In contrast to similarly functionalized nanoparticles, endocytosed microparticles were not contained within a lysosome. PMID- 20707316 TI - Preliminary assessment of avian stomach oils: a vector of contaminants to chicks and potential for diet analysis and biomonitoring. AB - Bird species from the order Procellariiformes or petrels, including the northern fulmar (Fulmarus glacialis), produce high lipid and high energy content stomach oils from the prey they consume, which enables them to exploit distant marine food sources. Stomach oils are also used as a food source for chicks and for defensive purposes. Samples of stomach oils from two Arctic colonies, St. George Island Alaska, USA and Cape Vera, Devon Island Nunavut, Canada, were collected and analyzed for organochlorine contaminants. SigmaPCB concentrations ranged from 13 to 236 ng g(-1) wet weight (ww) and SigmaDDT concentrations from 5 to 158 ng g(-1) ww and were similar in both sites, though differences in chemical signatures were apparent. Stomach oils are a rich energy source; however, they may also provide a higher dose of contaminants per unit energy than the direct consumption of prey items, as illustrated using mass and energy balance calculations to estimate chick exposure to SigmaDDT for hypothetical stomach oil and whole prey diets. The results of this study suggest that stomach oils are an important vector of organochlorine contaminants to chicks and should be considered in future risk assessments of northern fulmars and other species of petrels. To our knowledge this is the first study of stomach oils as an overlooked vector of organochlorine contaminants to chicks and as a potentially valuable medium for dietary analysis and noninvasive biomonitoring both of petrel dietary exposure and of marine contaminant concentrations. PMID- 20707317 TI - Fullerene/porphyrin multicomponent nanostructures on Ag(110): from supramolecular self-assembly to extended copolymers. AB - A novel two-step bottom-up approach to construct a 2D long-range ordered, covalently bonded fullerene/porphyrin binary nanostructure is presented: in the first place, reversible supramolecular interactions between C60 and 5,15-bis(4 aminophenyl)-10,20-diphenylporphyrin are exploited to obtain large domains of an ordered binary network, subsequently a reaction between fullerene molecules and the amino-groups residing on porphyrin units, triggered by thermal treatment, is used to freeze the supramolecular nanostructure with covalent bonds. The resulting nanostructure resists high temperature treatments as expected for an extended covalent network, whereas very similar fullerene/porphyrin nanostructures held together only by weak interactions are disrupted upon annealing at the same or at lower temperatures. PMID- 20707318 TI - Smaller is faster and more sensitive: the effect of wire size on the detection of hydrogen by single palladium nanowires. AB - Palladium nanowires prepared using the lithographically patterned nanowire electrodeposition (LPNE) method are used to detect hydrogen gas (H2). These palladium nanowires are prepared by electrodepositing palladium from EDTA containing solutions under conditions favoring the formation of beta-phase PdHx. The Pd nanowires produced by this procedure are characterized by X-ray diffraction, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. These nanowires have a mean grain diameter of 15 nm and are composed of pure Pd with no XPS detectable bulk carbon. The four-point resistance of 50-100 MUm segments of individual nanowires is used to detect H2 in N2 and air at concentrations ranging from 2 ppm to 10%. For low [H2] < 1%, the response amplitude increases by a factor of 2-3 with a reduction in the lateral dimensions of the nanowire. Smaller nanowires show accelerated response and recovery rates at all H2 concentrations from, 5 ppm to 10%. For 12 devices, response and recovery times are correlated with the surface area/volume ratio of the palladium detection element. We conclude that the kinetics of hydrogen adsorption limits the observed response rate seen for the nanowire, and that hydrogen desorption from the nanowire limits the observed recovery rate; proton diffusion within PdHx does not limit the rates of either of these processes. PMID- 20707319 TI - Size differentiation and absolute quantification of gold nanoparticles via single particle detection with a laboratory-built high-sensitivity flow cytometer. AB - Employing single nanoparticle detection with a laboratory-built high-sensitivity flow cytometer, we developed a simple and versatile platform that is capable of detecting the surface plasmon resonance scattering of gold nanoparticles (GNPs) as small as 24 nm, differentiating GNPs of different sizes, and providing accurate quantification of GNPs. Low-concentration samples (fM to pM) in small volumes (microL) can be measured in minutes with an analysis rate of up to 100 200 GNPs per second. Among these features, absolute quantification provides a distinct advantage because it does not require standard samples. PMID- 20707320 TI - Dinitrogen complexation and extent of N[triple bond]N activation within the group 6 "end-on-bridged" dinuclear complexes, {(eta5-C5Me5)M[N(i-Pr)C(Me)N(i-Pr)]}2(mu eta1:eta1-N2) (M = Mo and W). AB - Chemical reduction of Cp*M[N(i-Pr)C(Me)N(i-Pr)]Cl(3) (Cp* = eta(5)-C(5)Me(5)) (1, M = Mo) and (2, M = W) using 0.5% NaHg in THF provided excellent yields of the diamagnetic dinuclear end-on-bridged dinitrogen complexes {Cp*M[N(i-Pr)C(Me)N(i Pr)]}(2)(mu-eta(1):eta(1)-N(2)) (6, M = Mo) and (8, M = W), respectively. Chemical reduction of Cp*Mo[N(i-Pr)C(NMe(2))N(i-Pr)]Cl(2) (4) with 3 equiv of KC(8) in THF similarly yielded diamagnetic {Cp*Mo[N(i-Pr)C(NMe(2))N(i-Pr)]}(2)(mu eta(1):eta(1)-N(2)) (7). Single-crystal X-ray analyses of 7 and 8 confirmed the dinuclear end-on-bridged mu-eta(1):eta(1)-N(2) coordination mode and the solid state molecular structures of these compounds provided d(NN) values of 1.267(2) and 1.277(8) A for 7 and 8, respectively. Based on a comparison of (15)N NMR spectra for (15)N(2) (99%)-labeled 6 and (15)N(2) (99%)-labeled 8, as well as similarities in chemical reactivity, a dinuclear mu-eta(1):eta(1)-N(2) structure for 6 is further proposed. For comparison with a first-row metal derivative, chemical reduction of Cp*Ti[N(i-Pr)C(Me)N(i-Pr)]Cl(2) (9) with KC(8) in THF was conducted to provide {Cp*Ti[N(i-Pr)C(Me)N(i-Pr)]}(2)(mu-eta(1):eta(1)-N(2)) (10) for which a d(NN) value of 1.270(2) A was obtained through X-ray crystallography. Compounds 6-8 were all found to be thermally robust in toluene solution up to temperatures of at least 100 degrees C, and 6 and 8 were determined to be inert toward the addition of H(2) or H(3)SiPh under a variety of conditions. Single crystal X-ray analysis of meso-{Cp*Mo(H)[N(i-Pr)C(Me)N(i-Pr)]}(2)(mu eta(1):eta(1)-N(2)) (meso-11), which was serendipitously isolated as a product of attempted alkylation of Cp*Mo[N(i-Pr)C(Me)N(i-Pr)]Cl(2) (3) with 2 equiv of n butyllithium, revealed a smaller d(NN) value of 1.189(4) A that is consistent with two Mo(IV,d(2)) centers connected by a bridging diazenido, [mu-N(2)](2-), moiety. Moreover, meso-11 was found to undergo clean dehydrogenation in solution at 50 degrees C to provide 6 via a first-order process. Chemical oxidation of 8 with an excess of PbCl(2) in toluene solution at 25 degrees C provided a 1:1 mixture of rac- and meso-{Cp*W(Cl)[N(i-Pr)C(Me)N(i-Pr)]}(2)(mu-eta(1):eta(1) N(2)) (12); both isomers of which provided solid-state structures through X-ray analyses that are consistent with an electronic configuration comprised of two W(IV,d(2)) centers linked through a bridging [N(2)](2-) group [cf. for rac-12, d(NN) = 1.206(9) A, and for meso-12, d(NN) = 1.192(3) A]. Finally, treatment of 6 and 8 with either 4 equiv of CNAr (Ar = 3,5-Me(2)C(6)H(3)) or an excess of CO in toluene provided excellent yields of Cp*M[N(i-Pr)C(Me)N(i-Pr)](CNAr)(2) (13, M = Mo and 14, M = W) and Cp*M[N(i-Pr)C(Me)N(i-Pr)](CO)(2) (15, M = Mo and 16, M = W), respectively. Single-crystal X-ray analyses of 13-16, along with observation of reduced IR vibrational nu(CN) or nu(CO) bond-stretching frequencies, provide strong support for the electron-rich character of the Cp*M[N(i-Pr)C(Me)N(i-Pr)] fragment that can engage in a high degree of back-donation with moderate to strong pi-acceptors, such as N(2), CNR, and CO. The collective results of this work are analyzed in terms of the possible steric and electronic factors that contribute to preferred mode of mu-N(2) coordination and the extent of N[triple bond]N activation, including complete N-N bond scission, within the now completed experimentally-derived ligand-centered isostructural series of {Cp*M[N(i Pr)C(Me)N(i-Pr)]}(2)(mu-N(2)) compounds where M = Ti, Zr, Hf, Ta, Mo, and W. PMID- 20707321 TI - Dual-switchable bioelectrocatalysis synergistically controlled by pH and perchlorate concentration based on poly(4-vinylpyridine) films. AB - Poly(4-vinylpyridine) (P4VP) films were electropolymerized on a pyrolytic graphite (PG) electrode surface. The cyclic voltammetric (CV) response of ferrocenedicarboxylic acid (Fc(COOH)(2)) at P4VP film electrodes was very sensitive to the pH and perchlorate (ClO(4)(-)) concentration in testing solutions. Fc(COOH)(2) was at the "on" state with a relatively large CV oxidation peak current for the films at pH 4.0 but showed the "off" state with significantly suppressed CV response at pH 7.0. The reversible ClO(4)(-) concentration-sensitive on-off property of P4VP films toward Fc(COOH)(2) at pH 4.0 was also observed. In particular, the influence of pH and ClO(4)(-) concentration on the on-off behavior of the system is not independent or separate but synergetic or cooperative, and the electrostatic interaction between the films and the probe plays a predominant role in deciding the pH- and/or ClO(4)(-) concentration-dependent behavior for the system. The dual-responsive property of the P4VP films toward Fc(COOH)(2) could also be used to control the bioelectrocatalysis of glucose by glucose oxidase. This synergetic-triggered bioelectrocatalysis on the basis of the intelligent interface system may establish a foundation for fabricating novel multiple factor-controllable biosensors based on enzymatic electrocatalysis. PMID- 20707322 TI - Annealing-induced changes in double-brush Langmuir-Blodgett films of alpha helical diblock copolypeptides. AB - The effect of annealing on the structure and the helix orientation in Langmuir Blodgett (LB) monolayers of diblock copolymers (PLGA-b-PMLGSLGs) of poly(alpha-L glutamic acid) (PLGA) and poly(gamma-methyl-L-glutamate-ran-gamma-stearyl-L glutamate) with 30 mol % of stearyl substituents (PMLGSLG) with unidirectional helix orientation deposited on hydrophilic silicon substrates was characterized by means of small-angle X-ray reflectivity, transmission Fourier transform infrared spectroscopy, and atomic force microscopy. Upon annealing at 100 degrees C for 24 h, the alpha-helices became less tilted toward the substrate surface normal. Surface area shrinkage accompanied the change in tilt, indicated by an increase in both film thickness and electron density, resulting in more compact and uniform films. The enhancement of the helix orientation by thermal annealing was greater for the PMLGSLG block and for the diblock copolymers with the shorter block lengths. For these diblock copolymers, annealing resulted in postorientation of the PMLGSLG block helices almost perpendicular to the substrate surface. This effect originates from a considerable increase in intermolecular packing of the PLGA block caused by hydrogen bonds between the carboxylic groups upon annealing, as well as the high mobility of the PMLGSLG block helices for rearrangement favored by the melted side chain mantle at elevated temperatures. PMID- 20707323 TI - Tailored distribution of single-wall carbon nanotubes from arc plasma synthesis using magnetic fields. AB - We report a method for tuning the distribution of single-wall carbon nanotubes (SWCNTs) produced by the anodic arc production method via the application of nonuniform magnetic fields to the gap region during synthesis. Raman, ultraviolet visible-near-infrared absorbance and near-infrared fluorescence spectroscopies were used to characterize samples together with scanning electron microscopy. Application of the nonuniform magnetic field 0.2-2 kG results in a broadening of the diameter range of SWCNTs produced toward decreased diameters, with substantial fractions of produced SWCNTs being of small diameter, less than ~1.3 nm, at the highest field. The ability to tune production of the arc production method may allow for improvement in achievable SWCNT properties. PMID- 20707324 TI - Effect of surface charge distribution on the adsorption orientation of proteins to lipid monolayers. AB - The adsorption orientation of the proteins lysozyme and ribonuclease A (RNase A) to a neutral 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and a negatively charged stearic acid lipid film was investigated by means of X-ray reflectivity. Both proteins adsorbed to the negatively charged lipid monolayer, whereas at the neutral monolayer, no adsorption was observed. For acquiring comprehensive information on the proteins' adsorption, X-ray reflectivity data were combined with electron densities obtained from crystallographic data. With this method, it is possible to determine the orientation of adsorbed proteins in solution underneath lipid monolayers. While RNase A specifically coupled with its positively charged active site to the negatively charged lipid monolayer, lysozyme prefers an orientation with its long axis parallel to the Langmuir film. In comparison to the electrostatic maps of the proteins, our results can be explained by the discriminative surface charge distribution of lysozyme and RNase A. PMID- 20707325 TI - Zwitterion modulation of O(2)-evolving activity of cyanobacterial photosystem II. AB - Photosystem II (PSII) is the only enzyme in nature that can catalyze the challenging catalytic photooxidation of H(2)O into four protons, four electrons, and O(2). Slowing down turnover of the O(2)-evolving complex (OEC) is a plausible approach to gain mechanistic information on the reaction. However, modulating the kinetics of the reaction without perturbing the active site is a challenge. In this study, it is shown that the steady-state activity of cyanobacterial PSII is inhibited by small zwitterions, such as glycine betaine and beta-alanine. We show that the binding of zwitterions is nondenaturing, is highly reversible, and results in the decrease of the rate of catalytic turnover by ~50% in the presence of excess zwitterion. Control measurements of photoinduced electron transfer in O(2)-inactive PSII show that the inhibition by zwitterions is the result of a specific decrease in the rate of catalytic turnover of the OEC. Recovery of activity upon addition of an exogenous proton carrier (HCO(3)(-)) provides evidence that proton-transfer pathways, thought to be essential for the relay of protons from the OEC to the lumen, are affected. Interestingly, no inhibition is observed for spinach PSII, suggesting that zwitterions act specifically by binding to the extrinsic proteins on the lumenal side of PSII, which differ significantly between plants and cyanobacteria, to slow proton transfer on the electron donor side of PSII. PMID- 20707326 TI - Friction and adhesion of hierarchical carbon nanotube structures for biomimetic dry adhesives: multiscale modeling. AB - With unique hierarchical fibrillar structures on their feet, gecko lizards can walk on vertical walls or even ceilings. Recent experiments have shown that strong binding along the shear direction and easy lifting in the normal direction can be achieved by forming unidirectional carbon nanotube array with laterally distributed tips similar to gecko's feet. In this study, a multiscale modeling approach was developed to analyze friction and adhesion behaviors of this hierarchical fibrillar system. Vertically aligned carbon nanotube array with laterally distributed segments at the end was simulated by coarse grained molecular dynamics. The effects of the laterally distributed segments on friction and adhesion strengths were analyzed, and further adopted as cohesive laws used in finite element analysis at device scale. The results show that the laterally distributed segments play an essential role in achieving high force anisotropy between normal and shear directions in the adhesives. Finite element analysis reveals a new friction-enhanced adhesion mechanism of the carbon nanotube array, which also exists in gecko adhesive system. The multiscale modeling provides an approach to bridge the microlevel structures of the carbon nanotube array with its macrolevel adhesive behaviors, and the predictions from this modeling give an insight into the mechanisms of gecko-mimicking dry adhesives. PMID- 20707327 TI - High current, low voltage carbon nanotube enabled vertical organic field effect transistors. AB - State-of-the-art performance is demonstrated from a carbon nanotube enabled vertical field effect transistor using an organic channel material. The device exhibits an on/off current ratio >10(5) for a gate voltage range of 4 V with a current density output exceeding 50 mA/cm(2). The architecture enables submicrometer channel lengths while avoiding high-resolution patterning. The ability to drive high currents and inexpensive fabrication may provide the solution for the so-called OLED backplane problem. PMID- 20707328 TI - Virus-enabled silicon anode for lithium-ion batteries. AB - A novel three-dimensional Tobacco mosaic virus assembled silicon anode is reported. This electrode combines genetically modified virus templates for the production of high aspect ratio nanofeatured surfaces with electroless deposition to produce an integrated nickel current collector followed by physical vapor deposition of a silicon layer to form a high capacity silicon anode. This composite silicon anode produced high capacities (3300 mAh/g), excellent charge discharge cycling stability (0.20% loss per cycle at 1C), and consistent rate capabilities (46.4% at 4C) between 0 and 1.5 V. The biological templated nanocomposite electrode architecture displays a nearly 10-fold increase in capacity over currently available graphite anodes with remarkable cycling stability. PMID- 20707329 TI - Thermocurable hyperbranched polystyrenes for ultrathin polymer dielectrics. AB - Thermocurable hyperbranched polystyrenes were successfully synthesized using atom transfer radical polymerization and exhibited superior ultrathin film formation capabilities in comparison with the linear analogues, as assessed by the minimal film thickness attainable by spin-coating without dewetting. They were suitable as ultrathin film organic dielectrics, with parallel plate specific capacitances as high as ~680 nF/cm2. Similar to high performance inorganic dielectrics, capacitance measurements pointed to the presence of "dead" interfacial capacitance, which could be accounted for by considering the geometric effect of roughness "incommensurability" between metal electrode and polymer film. PMID- 20707330 TI - Clathrate hydrates for ozone preservation. AB - We report the experimental evidence for the preservation of ozone (O(3)) encaged in a clathrate hydrate. Although ozone is an unstable substance and is apt to decay to oxygen (O(2)), it may be preserved for a prolonged time if it is encaged in hydrate cavities in the form of isolated molecules. This possibility was assessed using a hydrate formed from an ozone + oxygen gas mixture coexisting with carbon tetrachloride or xenon. Each hydrate sample was stored in an air filled container at atmospheric pressure and a constant temperature in the range between -20 and 2 degrees C and was continually subjected to iodometric measurements of its fractional ozone content. Such chronological measurements and structure analysis using powder X-ray diffraction have revealed that ozone can be preserved in a hydrate-lattice structure for more than 20 days at a concentration on the order of 0.1% (hydrate-mass basis). PMID- 20707331 TI - Solid-state (2)H NMR and MD simulations of positional isomers of a monounsaturated phospholipid membrane: structural implications of double bond location. AB - The impact that the position of double bonds has upon the properties of membranes is investigated using solid-state (2)H NMR and MD simulations to compare positional isomers of 1-palmitoyl-2-octadecenoylphosphatidylcholine (16:0-18:1PC) bilayers that are otherwise identical apart from the location of a single cis double bond at the Delta(6), Delta(9), Delta(12), or Delta(15) position in the 18:1 sn-2 chain. Moment analysis of (2)H NMR spectra recorded for isomers perdeuterated in the 16:0 sn-1 chain reveals that average order parameters S(CD) change by more than 35% and that the temperature for chain melting T(m) varies by 40 degrees C. At equal temperature, the S(CD) values exhibit a minimum, as do T(m) values, when the double bond is in the middle of the 18:1 sn-2 chain and increase as it is shifted toward each end. Order parameter profiles generated from depaked ("dePaked") spectra for the 16:0 sn-1 chain all possess the same shape with a characteristic "plateau" region of slowly decreasing order in the upper portion before progressively decreasing more in the lower portion. The NMR results are interpreted on the basis of MD simulation results obtained on each of the four systems. The simulations support the idea that the order parameter changes reflect differences in molecular surface areas, and furthermore that the molecular areas are a function of the strength of the acyl chain attractions. PMID- 20707332 TI - Electric-field-induced fluorescence quenching in polyfluorene, ladder-type polymers, and MEH-PPV: evidence for field effects on internal conversion rates in the low concentration limit. AB - Electric field-induced fluorescence quenching has been measured for a series of conjugated polymers with applications in organic light-emitting diodes. Electrofluorescence measurements on isolated chains in a glassy matrix at 77 K show that the quenching efficiency for poly[2-methoxy-5-(2-ethylhexyloxy)-p phenylenevinylene] (MEH-PPV) is an order of magnitude larger than that for either a ladder-type polymer (MeLPPP) or polyfluorene (PFH). This effect is explained in terms of the relatively high probability of field-enhanced internal conversion deactivation in MEH-PPV relative to either MeLPPP or PFH. These data, obtained under dilute sample conditions such that chain-chain interactions are minimal, are contrasted with the much higher quenching efficiencies observed in the corresponding polymer films, and several explanations for the differences are considered. In addition, the values of the change in dipole moment and change in polarizability on excitation (|DeltaMU| and tr(Deltaalpha), respectively) are reported, and trends in these values as a function of molecular structure and chain length are discussed. PMID- 20707333 TI - Development and validation of a ReaxFF reactive force field for Cu cation/water interactions and copper metal/metal oxide/metal hydroxide condensed phases. AB - To enable large-scale reactive dynamic simulations of copper oxide/water and copper ion/water interactions we have extended the ReaxFF reactive force field framework to Cu/O/H interactions. To this end, we employed a multistage force field development strategy, where the initial training set (containing metal/metal oxide/metal hydroxide condensed phase data and [Cu(H(2)O)(n)](2+) cluster structures and energies) is augmented by single-point quantum mechanices (QM) energies from [Cu(H(2)O)(n)](2+) clusters abstracted from a ReaxFF molecular dynamics simulation. This provides a convenient strategy to both enrich the training set and to validate the final force field. To further validate the force field description we performed molecular dynamics simulations on Cu(2+)/water systems. We found good agreement between our results and earlier experimental and QM-based molecular dynamics work for the average Cu/water coordination, Jahn Teller distortion, and inversion in [Cu(H(2)O)(6)](2+) clusters and first- and second-shell O-Cu-O angular distributions, indicating that this force field gives a satisfactory description of the Cu-cation/water interactions. We believe that this force field provides a computationally convenient method for studying the solution and surface chemistry of metal cations and metal oxides and, as such, has applications for studying protein/metal cation complexes, pH-dependent crystal growth/dissolution, and surface catalysis. PMID- 20707334 TI - Peptide hydrogel as an intraocular drug delivery system for inhibition of postoperative scarring formation. AB - A biocompatible hydrogel self-assembled from a peptide comprised of a peptide backbone containing Arg-Gly-Asp (RGD) sequence and a hydrophobic N-fluorenyl-9 methoxycarbonyl (FMOC) tail was designed and prepared to load antiproliferative model drug (5-fluorouracil, 5-Fu). After administering this 5-Fu-loaded peptide hydrogel in the filtering surgery of rabbit eyes, because of the sustained release of 5-Fu from the hydrogel to inhibit the scleral flap fibrosis efficiently, the pathology and immunohistochemistry demonstrate that the filtration fistula is patent without postoperative scarring formation, resulting in the significantly low intraocular pressure (IOP) of the rabbit eyes within postoperative 28 days. In a comparison with the conventional 5-Fu exposure, the strategy demonstrated here presents several advantages including providing convenience and preventing the toxicity of 5-Fu to the surrounding ocular tissues efficiently, suggesting a feasibility of this peptide hydrogel as a potential implanted drug delivery system for the inhibition of postoperative scarring formation. PMID- 20707335 TI - Au(I)-catalyzed cascade reaction involving formal double hydroamination of alkynes bearing tethered carboxylic groups: an easy access to fused dihydrobenzimidazoles and tetrahydroquinazolines. AB - A process involving gold(I)-catalyzed formal double hydroamination of alkynes, bearing a tethered carboxylic group, for the synthesis of fused dihydrobenzimidazoles and tetrahydroquinazolines has been developed. A series of transition metal catalysts have been screened for this transformation, and a catalyst system consisting of Ph(3)PAuCl (1 mol %) and AgOTf (1 mol %) was found to be the best. The procedure entails the reaction of easily accessible starting materials such as alkynoic acids and 1,2-diaminobenzenes/2-aminobenzylamines in the presence of the catalyst in 1,2-dichloroethane at 100 degrees C. In the case of alpha-substituted alkynoic acids, the corresponding products were obtained in high diastereoselectivities; the structure of the diastereomers has been unambiguously characterized by NMR techniques. The mechanism of the reaction is discussed, and the origin of the diastereoselectivities is addressed. It was observed that under the microwave irradiation conditions, the reaction time is significantly shortened (0.5 h). PMID- 20707336 TI - Effects of oxygen content on Bi3Mn3O(11+delta): from 45 K antiferromagnetism to room-temperature true ferromagnetism. AB - The effects of oxygen content on the structural, physical, and chemical properties of Bi(3)Mn(3)O(11) with KSbO(3)-type structure have been investigated. It was found that the oxygen content in Bi(3)Mn(3)O(11+delta) can vary over a wide delta range, keeping the same cubic structure (space group Pn3, a = 9.12172(5) A for delta = -0.5, a = 9.13784(8) A for delta = 0, and a = 9.09863(7) A for delta = 0.6) and semiconducting properties of the material. At the same time, magnetic properties change from true antiferromagnetic with T(N) = 45 K for delta = -0.5 to true ferromagnetic with T(C) = 307 K for delta = +0.6. Bi(3)Mn(3)O(11) (delta = 0) shows ferrimagnetic-like properties with T(C) = 150 K and features typical for a re-entrant spin-glass below 30 K. Noticeable changes of the magnetic transition temperature and magnetism in Bi(3)Mn(3)O(11+delta) with delta can be compared with changes of the magnetic and electronic properties of LaMnO(3+delta), BiMnO(3+delta), high-temperature copper superconductors (e.g., YBa(2)Cu(3)O(7+delta)), and other cuprates. Bi(3)Mn(3)O(11.6) shows a new record high T(C) among insulating/semiconducting true ferromagnets. Our results demonstrate that the oxygen content can vary for the same cation composition in KSbO(3)-type materials, and the oxygen content can be increased up to BiMnO(3.867) (Bi(3)Mn(3)O(11.6)). PMID- 20707337 TI - Self-assembled inverted micelles stabilize ionic liquid domains in supercritical CO2. AB - Molecular aggregation is a complex phenomenon that is difficult to study in detail experimentally. Here, we elucidate the formation of ionic liquid-in-carbon dioxide (IL-in-CO(2)) microemulsions via a computer simulation technique that demonstrates the entire process of self-aggregation at the atomic level. Our study reveals direct evidence of the existence of stable IL droplets within a continuous CO(2) phase through amphiphilic surfactants. The microstructure of the nanodroplets matches very well with the small-angle neutron scattering data. A detailed investigation of the structural and energetic properties explains why guanidium acetate-based IL-in-CO(2) microemulsions showed a greater stability than imidazolium hexafluorophosphate-based microemulsions in recent spectroscopic experiments. In contrast to the existing hypothesis in literature, the study reveals that the stability of the microemulsions mainly pertains to the IL anion headgroup interactions, while the cations play a secondary role. The detailed atomic level understanding provides a deeper insight that could help in designing new surfactants for improved IL uptake in CO(2). PMID- 20707338 TI - Distribution and in vitro availability of selenium in selenium-containing storage protein from selenium-enriched rice utilizing optimized extraction. AB - Selenium (Se) distribution in Se-enriched rice and optimization of extraction for Se-containing protein were studied. Se availability in Se-containing protein product was simulated using an in vitro gastrointestinal digestion. The results showed that Se was predominately found as organic Se, whereas inorganic Se comprised only 2.85% of the total Se. The glutelin fraction contained the largest amount of Se, approximately 31.3% of the total Se in the rice gain. Utilizing orthogonal analysis, the optimum extraction conditions were selected at a volume to weight of 20:1, 0.08 M NaOH, an extraction time of 3 h, and at a temperature of 35 degrees C. A Se-containing rice protein product with 83.5% protein and 9.09 microg g(-1) Se was sequestered using the optimal extraction method. This rice protein product with high molecular weight Se-containing protein can readily be digested to low molecular weight peptides and selenomethionine (52.3% of total Se in protein extract). PMID- 20707339 TI - Characterization and differentiation of monovarietal grape pomace distillate from native varieties of Galicia. AB - Monovarietal grape pomace distillates (orujo) of six native varieties of Vitis vinifera L. from Galicia (Albarino, Treixadura, Godello, Loureira, Dona Branca, and Torrontes) have been thoroughly analyzed considering esters, alcohols, major aldehydes, monoterpenes, sesquiterpenes, norisoprenoids, and diterpenes. Albarino and Loureira distillates showed similar profiles of terpenic compounds, with the Loureira products having higher contents of monoterpenols. Native Torrontes distillate from Galicia is principally characterized by marked levels of some sesquiterpenes such as cadinene isomers and epizonarene. On the other hand, Treixadura, Godello, and Dona Branca grape pomace distillates seem not to have any marked terpenic content, and their single separation is difficult. PCA data treatments showed a good separation among the terpenic-rich varieties. Also, the p-menthen-9-al isomers, typical flavors in honey citrus and dill herb (derived from 8-hydroxylinalool), are reported for the first time in grape pomace distillate. PMID- 20707340 TI - Range of validity of drop shape techniques for surface tension measurement. AB - Drop shape techniques are widely used for surface tension measurement. As the shape becomes close to spherical, the performance of drop shape techniques deteriorates. A quantitative criterion called shape parameter was previously introduced to quantify the meaning of "well-deformed" drops and "close to spherical" drops. In this paper, a modified definition of the shape parameter that does not depend on the radius of curvature at the drop apex is proposed. Such definition is applicable to different constellations of pendant and sessile drops/bubbles. Dimensional analysis is used to describe similarity in constrained sessile drop shapes and to express the problem using appropriate dimensionless groups. The proposed shape parameter is found to depend only on two dimensionless groups: the dimensionless volume (drop volume normalized by the cube of the holder radius) and the Bond number (using the drop holder's radius as the length scale). A critical shape parameter (minimum value of the shape parameter that guarantees a specified accuracy) is shown to depend only on Bond number. A set of experiments were performed with pure liquids to illustrate the change of the critical shape parameter with the Bond number. PMID- 20707341 TI - Photoprotection by plant extracts: a new ecological means to reduce pesticide photodegradation. AB - A pesticide's reactivity toward light at the leaf surface after crop treatment is rarely considered, although such degradation reactions directly affect the pesticide's effectiveness. To overcome these limitations, the use of plant pigments was proposed as a new class of photoprotecting agent. The photoprotecting properties of seven plant pigments were tested under controlled conditions over herbicide sulcotrione. Grape wine extracts were tested over a panel of pesticides from distinct chemical families. The addition of plant extracts almost systematically reduced the pesticide's photoreactivity. The grape wine extracts improve at least by 38% the half-life of photolysis of almost all of the active ingredients tested, except for the herbicide triclopyr. Fustictree extract increases by 82% the photostability of the herbicide sulcotrione. Plant extracts mainly act as sunscreens; that is, the photostabilization of the active ingredient is due to the competitive energy absorption of UV photon. The use of natural plant extracts is a promising strategy to limit pesticide photodegradation. It is a way to develop sustainable and innovative technology for the plant protection industry, being beneficial from both economic and ecological points of view. PMID- 20707342 TI - CO2/H2O adsorption equilibrium and rates on metal-organic frameworks: HKUST-1 and Ni/DOBDC. AB - Metal-organic frameworks (MOFs) have recently attracted intense research interest because of their permanent porous structures, huge surface areas, and potential applications as novel adsorbents and catalysts. In order to provide a basis for consideration of MOFs for removal of carbon dioxide from gases containing water vapor, such as flue gas, we have studied adsorption equilibrium of CO(2), H(2)O vapor, and their mixtures and also rates of CO(2) adsorption in two MOFs: HKUST-1 (CuBTC) and Ni/DOBDC (CPO-27-Ni or Ni/MOF-74). The MOFs were synthesized via solvothermal methods, and the as-synthesized products were solvent exchanged and regenerated before experiments. Pure component adsorption equilibria and CO(2)/H(2)O binary adsorption equilibria were studied using a volumetric system. The effects of H(2)O adsorption on CO(2) adsorption for both MOF samples were determined, and the results for 5A and NaX zeolites were included for comparison. The hydrothermal stabilities for the two MOFs over the course of repetitive measurements of H(2)O and CO(2)/H(2)O mixture equilibria were also studied. CO(2) adsorption rates from helium for the MOF samples were investigated by using a unique concentration-swing frequency response (CSFR) system. Mass transfer into the MOFs is rapid with the controlling resistance found to be macropore diffusion, and rate parameters were established for the mechanism. PMID- 20707343 TI - Light-emitting color barcode nanowires using polymers: nanoscale optical characteristics. AB - We report on the light-emitting color barcode nanowires (LECB-NWs), which were fabricated by alternating the electrochemical polymerization of light-emitting polymers with various luminescence colors and efficiencies. The nanoscale photoluminescence characteristics of LECB-NWs were investigated using a laser confocal microscope with a high spatial resolution. The alternating light emissions of the LECB-NWs showed orange-yellow, red, and green colors due to the serial combination of poly(3-butylthiophene), poly(3-methylthiophene), and poly(3,4-ethylenedioxythiophene), respectively, with distinct luminescence intensities. The optical detection sensitivity and stability of LECB-NWs have been enhanced through a nanoscale Cu metal coating onto the NWs, based on surface plasmon resonance coupling and protection against oxidation. The flexibility of the LECB-NWs has been investigated through the folding and unfolding of the NWs by an applied nanotip impetus. The flexible LECB-NWs can be used as highly sensitive optical identification nanosystems for nanoscale or microscale products with complex physical shapes. PMID- 20707344 TI - Lycopersicon esculentum seeds: an industrial byproduct as an antimicrobial agent. AB - Lycopersicon esculentum (tomato) fruit is a widely studied matrix. However, only few works focus their attention on its seeds, which constitute a major byproduct of the tomato processing industry. In this study the antimicrobial potential of ten different tomato seed extracts from "Bull's heart" and "Cherry" varieties were analyzed against Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Enterococcus faecalis and Bacillus cereus) and Gram-negative (Proteus mirabilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhimurium) bacteria and fungi (Candida albicans, Aspergillus fumigatus and Trichophyton rubrum). Regarding antibacterial capacity, the different extracts were revealed to be active only against Gram-positive bacteria, E. faecalis being the most susceptible one (MIC: 2.5-10 mg/mL). Concerning antifungal activity, "Bull's heart" extracts were the most active. In a general way C. albicans was the most susceptible species (MIC: 5-10 mg/mL). The chemical composition of the extracts was also pursued, concerning organic acids, phenolics and fatty acids, in order to establish a possible relationship with the observed antimicrobial effect. PMID- 20707345 TI - Profiles of phytoestrogens in human urine from several Asian countries. AB - Intake of a diet rich in phytoestrogens has been associated with a decreased risk for hormone-dependent cancers in humans. Biomonitoring of phytoestrogens in human urine has been used to assess the intake of phytoestrogens. Although studies have reported phytoestrogen levels in urine specimens from the United States and Japan, little is known of human intake of phytoestrogens in other Asian countries. In this study we determined the concentrations of seven phytoestrogens, namely, enterolactone, enterodiol, daidzein, equol, O desmethylangolensin (O-DMA), genistein, and coumestrol, in 199 human urine samples from three Asian countries, Vietnam (Hanoi and Ho Chi Minh), Cambodia (Phnom Penh), and India (Chennai and Kolkata), using a simple, sensitive, and reliable liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method. The residue levels of phytoestrogens in urine samples from the three Asian countries were compared with the concentrations in 26 urine samples from Japan (Ehime) and 16 urine samples from the United States (Albany), analyzed in this study. Among the phytoestrogens analyzed, isoflavones such as daidzein and genistein were predominant in urine samples from Vietnam; samples from Cambodia and India contained higher concentrations of enterolactone than isoflavones. Urinary concentrations of isoflavones in samples from Hanoi, Vietnam, were notably higher than the concentrations in samples from Cambodia, India, and the United States and similar to the concentrations in samples from Japan. The lowest concentrations of daidzein and the highest concentrations of enterolactone were found in urine samples from India. Concentrations of equol and O-DMA, which are microbial transformation products of daidzein (produced by gut microflora), were notably high in urine samples from Hanoi, Vietnam. The ratios of the concentration of equol or O-DMA to that of daidzein were significantly higher in samples from Hanoi than from Japan, indicating high biotransformation efficiency of daidzein by the population in Hanoi. High concentrations of equol, in addition to isoflavones, in urine have been linked to reduced breast cancer risk in previous studies, and, thus, the Vietnamese population may have potential protective effect against breast cancer. This study suggests that the dietary intake and profiles of phytoestrogens vary considerably, even among Asian countries. PMID- 20707346 TI - Enhanced seed carotenoid levels and branching in transgenic Brassica napus expressing the Arabidopsis miR156b gene. AB - The Arabidopsis AtmiR156b gene was expressed in Brassica napus under the control of the cauliflower mosaic virus (CaMV) 35S promoter and the seed-specific napin promoter. Seed carotenoid levels, branching habit, seed yield, and seed weight were examined in the transgenic B. napus. Our results demonstrated that constitutive expression of AtmiR156b in B. napus resulted in enhanced levels of seed lutein and beta-carotene and a 2-fold increase in the number of flowering shoots, whereas AtmiR156b driven by the napin promoter did not affect these traits. This suggested that enhancement of seed quality and shoot branching are both related to AtmiR156b expression patterns. Seed yield and seed weight varied significantly within the transgenic lines. However, one line was found to have enhanced seed carotenoid levels but unchanged seed weight or yield. These data suggest that AtmiR156b gene expression could be applied in plant breeding initiatives for enhancing carotenoid production in canola and other crop species. PMID- 20707347 TI - Heterogeneities in fullerene nanoparticle aggregates affecting reactivity, bioactivity, and transport. AB - Properties of nanomaterial suspensions are typically summarized by average values for the purposes of characterizing these materials and interpreting experimental results. We show in this work that the heterogeneity in aqueous suspensions of fullerene C(60) aggregates (nC(60)) must be taken into account for the purposes of predicting nanomaterial transport, exposure, and biological activity. The production of reactive oxygen species (ROS), microbial inactivation, and the mobility of the aggregates of the nC(60) in a silicate porous medium all increased as suspensions were fractionated to enrich with smaller aggregates by progressive membrane filtration. These size-dependent differences are attributed to an increasing degree of hydroxylation of nC(60) aggregates with decreasing size. As the quantity and influence of these more reactive fractions may increase with time, experiments evaluating fullerene transport and toxicity end points must take into account the evolution and heterogeneity of fullerene suspensions. PMID- 20707348 TI - Conformations of silica-bound (pentafluorophenyl)propyl groups determined by solid-state NMR spectroscopy and theoretical calculations. AB - The conformations of (pentafluorophenyl)propyl groups (-CH(2)-CH(2)-CH(2) C(6)F(5), abbreviated as PFP), covalently bound to the surface of mesoporous silica nanoparticles (MSNs), were determined by solid-state NMR spectroscopy and further refined by theoretical modeling. Two types of PFP groups were described, including molecules in the prone position with the perfluorinated aromatic rings located above the siloxane bridges (PFP-p) and the PFP groups denoted as upright (PFP-u), whose aromatic rings do not interact with the silica surface. Two dimensional (2D) (13)C-(1)H, (13)C-(19)F and (19)F-(29)Si heteronuclear correlation (HETCOR) spectra were obtained with high sensitivity on natural abundance samples using fast magic angle spinning (MAS), indirect detection of low-gamma nuclei and signal enhancement by Carr-Purcell-Meiboom-Gill (CPMG) spin echo sequence. 2D double-quantum (DQ) (19)F MAS NMR spectra and spin-echo measurements provided additional information about the structure and mobility of the pentafluorophenyl rings. Optimization of the PFP geometry, as well as calculations of the interaction energies and (19)F chemical shifts, proved very useful in refining the structural features of PFP-p and PFP-u functional groups on the silica surface. The prospects of using the PFP-functionalized surface to modify its properties (e.g., the interaction with solvents, especially water) and design new types of the heterogeneous catalytic system are discussed. PMID- 20707349 TI - The catalytic role of N-heterocyclic carbene in a metal-free conversion of carbon dioxide into methanol: a computational mechanism study. AB - A density functional theory study at the M05-2X(IEFPCM, THF)/6-311+G**//M05-2X/6 31G* level has been conducted to gain insight into the catalytic mechanism of the first metal-free N-heterocyclic carbene (NHC)-catalyzed conversion of carbon dioxide into methanol. Among the various examined reaction pathways, we found that the most favorable leads to the experimentally detected intermediates, including formoxysilane (FOS), bis(silyl)acetal (BSA), silylmethoxide (SMO), and disiloxane (DSO). However, our study also revealed that formaldehyde (CH(2)O), generated from the dissociation of BSA into DSO and CH(2)O via a mechanism somewhat similar to the Brook rearrangement, should be an inevitable intermediate, although it was not reported by the experimentalists. When NHC catalyzes the reactions of CO(2)/FOS/CH(2)O with silane, there are two activation modes. It was found that NHC prefers to activate Si-H bonds of silane and push electron density to the H atoms of the Si-H bonds in favor of transferring a hydridic atom of silane to the electrophilic C center of CO(2)/FOS/CH(2)O. This holds true in particular for the NHC-catalyzed reactions of silane with FOS/CH(2)O to produce BSA/SMO. The preferred activation mode can operate by first passing an energetically unfavorable NHC-silane local minimum via pi-pi interactions or by directly crossing a transition state involving three components simultaneously. The activation mode involving initial coordination of NHC with the electrophilic C atom of CO(2)/FOS/CH(2)O is less favorable or inoperable. The predicted catalytic mechanism provides a successful interpretation of the experimental observation that phenylsilane is more efficient than diphenylsilane in performing the conversion. PMID- 20707350 TI - Small molecule-capped gold nanoparticles as potent antibacterial agents that target Gram-negative bacteria. AB - This report illustrates a new strategy in designing antibacterial agents--a series of commercially available compounds, amino-substituted pyrimidines (themselves completely inactive as antibiotics), when presented on gold nanoparticles (NPs), show antibacterial activities against multidrug-resistant clinical isolates, without external sources of energy such as IR. These pyrimidine-capped gold NPs exert their antibiotic actions via sequestration of magnesium or calcium ions to disrupt the bacterial cell membrane, resulting in leakage of cytoplasmic contents including nucleic acids from compromised cell membranes, and via interaction with DNA and inhibition of protein synthesis by internalized NPs. These amino-substituted pyrimidine-capped gold NPs induce bacterial resistance more slowly compared with conventional, small-molecule antibiotics and appear harmless to human cells; these NPs may hence be useful for clinical applications. PMID- 20707351 TI - SmI2-mediated 3-exo-trig cyclization of beta,gamma-unsaturated carbonyl compounds: diastereoselective synthesis of cyclopropanols. AB - SmI(2)-mediated 3-exo-trig cyclizations of beta,gamma-unsaturated carbonyl compounds to generate cyclopropanols are not generally observed processes. The reported examples are limited to beta,gamma-unsaturated carbonyl compounds that possess ester groups conjugated with the alkene unit. The results of the current study show that this cyclization also occurs when other substitution patterns are present on the alkene moiety, affording (E)-cyclopropanols in good to excellent yields and in most cases with high degrees of diastereoselectivity. PMID- 20707352 TI - Gold(III)-catalyzed tandem reaction of O-arylhydroxylamines with 1,3-dicarbonyl compounds: highly selective synthesis of 3-carbonylated benzofuran derivatives. AB - A highly regioselective protocol for the synthesis of 3-carbonylated benzofuran derivatives has been developed involving the gold(III)-catalyzed tandem condensation/rearrangement/cyclization reaction of O-arylhydroxylamines with 1,3 dicarbonyl compounds. PMID- 20707353 TI - A new strategy for ring modification of metallocenes: carbodiimide Insertion into the eta(5)-Y-C5H5 bond and subsequent isomerization. AB - Unusual insertion of carbodiimide into the Y-Cp (Cp = C(5)H(5)) bond and isomerization of the resulting cyclopentadienyl (Cp)-substituted amidinate complex to the amidino-substituted Cp complex have been established, representing an efficient and simple method for ring modification of sensitive metallocenes. All products, including the rare four-center interaction precursor of the insertion, have been characterized by X-ray structural analyses. PMID- 20707354 TI - Comparison of isotopic substitution methods for equilibrium and t-jump infrared studies of beta-hairpin peptide conformation. AB - Laser induced temperature jump (T-jump) relaxation kinetics were measured with infrared absorbance (IR) detection for a set of beta-hairpin peptides, related to the Trpzip2 hairpin, but containing single isotopic labels, (13)C on the amide C horizontal lineO of selected residues both in the center of the strands and at the terminal regions of the hairpin. Variations in the behavior of single labeled peptides are compared to those previously reported for double labeled variants. Although single labels do not result in spectral intensity enhancement, as seen for cross-strand labeling, the IR frequency shifts are still diagnostic of hairpin unfolding. If C horizontal lineO's in the beta-strand portion of the hairpin (between the Trp residues) are labeled, the dynamic behavior of the local modes is similar to the results obtained with double labels in terms of relaxation time and activation energy and closely tracks the kinetics of the beta strand components. This implies that either property, local secondary structure (change of varphi,psi), or cross-strand coupling enabled by strand formation and H-bonding relaxes with the same kinetic mechanism. Single labeled residues on the terminal positions have a different behavior and are less able to be detected due to overlap with the (12)C components, in contrast to double labels involving these positions, which are enhanced due to coupling. DFT-based spectral simulations that use the NMR structure of Trpzip2C indicate that the single labeled peptides should have roughly equivalent (12)C bands but the (13)C mode frequencies will vary with sequence position. Effective solvent corrections using COSMO yield significant changes in the frequencies but not in the relative isotope shifts obtained in our calculated spectra. Sequence positional dependence of labels is shown to be more discriminatory for kinetics changes than for thermodynamic variations. PMID- 20707355 TI - Intramolecular hydrogen bond-controlled prolyl amide isomerization in glucosyl 3(S)-hydroxy-5-hydroxymethylproline hybrids: a computational study. AB - Peptide mimics containing spirocyclic glucosyl-(3(S)-hydroxy-5(S) hydroxymethyl)proline (1) and glucosyl-(3(S)-hydroxy-5(R)-hydroxymethyl)proline (2) hybrids differing in the stereochemistry of the polar hydroxymethyl substitutent at the C-5- or (C(delta))-position have been investigated computationally. A computational "build and search" protocol of molecular mechanics systematic search/Monte Carlo search, followed by density functional theory (DFT), has been developed to ensure complete coverage of the large conformational space. Gas-phase DFT optimizations at the B3LYP level of theory lead to a strong preference for the cis conformation in the prolyl amide bond for both compounds 1 and 2. However, inclusion of the solvent water by means of continuum solvation (PCM) results in a reduction of the prolyl amide cis population in both compounds, leading to good agreement with previous experimental observations. Intramolecular hydrogen bonding involving the C-5 hydroxymethyl substitutent is seen to play a crucial role to tune the thermodynamics of prolyl amide cis/trans isomerization and is responsible for the high cis prolyl amide population in compound 2. Our results indicate that H-bond forming substituents like the hydroxymethyl group at the C-5-position in proline can be used to control cis/trans prolyl amide isomerization. High cis prolyl amide conformer populations can be achieved by proper choice of the stereochemistry at the C-5-position. PMID- 20707356 TI - In vivo monitoring of quantum dots in the extracellular space using push-pull perfusion sampling, online in-tube solid phase extraction, and inductively coupled plasma mass spectrometry. AB - To monitor the dynamic changes of extracellular quantum dots (QDs) in vivo in the livers of anesthetized rats, we developed an automatic online analytical system comprising push-pull perfusion (PPP) sampling, the established in-tube solid phase extraction (SPE) procedure, and inductively coupled plasma mass spectrometry (ICPMS). The method takes advantage of the retention of QDs onto the interior surface of a polytetrafluoroethylene (PTFE) tube as a means of extracting the QDs from complicated push-pull perfusates. For the injected QDs present in the liver extracellular fluid (ECF) at low picomolar levels, a temporal resolution of 10 min was required to collect sufficient amounts of QDs to meet the sensitivity requirements of the ICPMS system. To the best of our knowledge, this study is the first to exploit the PPP technique for the collection of QDs from living animals and PTFE tubing as a SPE adsorbent for the online extraction of QDs and the removal of biological matrix prior to ICPMS analysis of cadmium-containing inorganic nanocrystal. We confirmed the analytical reliability of this method from measurements of the spike recoveries of saline samples; in addition, we demonstrated the systems' applicability through in vivo monitoring of the time-dependent concentration profile of liver extracellular QDs in living rats after intravenous administration. PMID- 20707357 TI - Single-cell MALDI-MS as an analytical tool for studying intrapopulation metabolic heterogeneity of unicellular organisms. AB - Heterogeneity is a characteristic feature of all populations of living organisms. Here we make an attempt to validate a single-cell mass spectrometric method for detection of changes in metabolite levels occurring in populations of unicellular organisms. Selected metabolites involved in central metabolism (ADP, ATP, GTP, and UDP-Glucose) could readily be detected in single cells of Closterium acerosum by means of negative-mode matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The analytical capabilities of this approach were characterized using standard compounds. The method was then used to study populations of individual cells with different levels of the chosen metabolites. With principal component analysis and support vector machine algorithms, it was possible to achieve a clear separation of individual C. acerosum cells in different metabolic states. This study demonstrates the suitability of mass spectrometric analysis of metabolites in single cells to measure cell-population heterogeneity. PMID- 20707358 TI - Total synthesis of (-)-apicularen A. AB - A convergent total synthesis of (-)-apicularen A, a highly cytostatic 12-membered macrolide, has been accomplished. The key steps include assembling of iodoalkene 8 and aldehyde 9 by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3 chirality transfer reaction, and Yamaguchi macrolactonization. Introduction of the (2Z,4Z)-heptadienamide moiety in the side chain by an efficient Cu(I) mediated coupling completed the total synthesis. PMID- 20707360 TI - Density scaling of supercooled simple liquids near the glass transition. AB - In this work, we show that two competing equations of state, the first one derived from some effective approximation of intermolecular potential suspected to be responsible for so-called "thermodynamic scaling" and the second one following from the definition of isothermal bulk modulus, are able to describe very well experimental volumetric data of supercooled van der Waals liquids in the thermodynamic scaling regime. The values of the exponent gamma(EOS) experimentally established from both these equations of state are numerically very close, and moreover they enable us to achieve a high quality of the specific volume or density linear scaling suggested by these equations. However, the found density scaling requires a distinctly different value of gamma(EOS) than that leading to the scaling of dynamic quantities. The discrepancy can be explained by our modification of the Avramov model which assumes the density scaling of the maximal energy barrier with the scaling exponent gamma(EOS). PMID- 20707361 TI - Crystal phase engineering in single InAs nanowires. AB - Achieving phase purity and control in III-V nanowires is a necessity for future nanowire-based device applications. Many works have focused on cleaning specific crystal phases of defects such as twin planes and stacking faults, using parameters such as diameter, temperature, and impurity incorporation. Here we demonstrate an improved method for crystal phase control, where crystal structure variations in single InAs nanowires are designed with alternating wurtzite (WZ) and zinc blende (ZB) segments of precisely controlled length and perfect interfaces. We also demonstrate the inclusion of single twin planes and stacking faults with atomic precision in their placement, designed ZB quantum dots separated by thin segments of WZ, acting as tunnel barriers for electrons, and structural superlattices (polytypic and twin plane). Finally, we present electrical data to demonstrate the applicability of these designed structures to investigation of fundamental properties. From electrical measurements we observe clear signatures of controlled structural quantum dots in nanowires. This method will be directly applicable to a wide range of nanowire systems. PMID- 20707362 TI - Phospholipid diffusion at the oil-water interface. AB - Fluorescence recovery after photobleaching was used to characterize the diffusion of fluorescently labeled phospholipids at the oil/water interface for oil viscosities that varied over four orders of magnitude. Measurements were performed over a range of surface concentrations corresponding to molecular areas of 40-130 A(2)/molecule. As expected, the interfacial diffusion coefficient increased with molecular area, saturating at an area of approximately 100 A(2)/molecule. At molecular areas below approximately 80 A(2)/molecule, macroscopic domains of a condensed monolayer phase were observed; the diffusion of these domains was characterized by direct tracking and trajectory analysis. For oils with viscosity BF(3)C(3)F(7)(-) > BF(3)C(4)F(9)(-), which is well reproduced by the molecular dynamic simulations. The analysis of the rotational relaxation of emim(+) suggests that the translational diffusion of cations and anions is associated with the rotational diffusion of emim(+). PMID- 20707369 TI - Ultrafast dynamics of 1-ethynylpyrene-modified RNA: a photophysical probe of intercalation. AB - The photophysics of pyrene attached to an adenine base within RNA single strands and duplexes is examined with respect to the position of the pyrene within the strand and the number of pyrenes attached to one duplex. Compounds with pyrenes intercalating sequence specifically are examined, as well as a doubly modified compound, where the two pyrenes are located close enough to each other for significant excimer interaction. Femtosecond transient absorption measurements and time correlated single photon counting measurements allow a thorough examination of the local influences on the pyrene photophysics. Our results suggest that optical excitation establishes an equilibration between two molecular states of different spectroscopic properties and lifetimes that are coupled only via the excited state as a gateway. One of them is a neutral pyrene adenine excited state, S*, while the second one is connected to an excited charge transfer state, S*(CT). In all compounds, an ultrafast sub-ps decay from a higher excited state into the lowest excited state S* occurs, and an excited charge transfer species S*(CT) is formed within picoseconds. The fluorescence behavior of the pyrene-modified adenine, however, is strongly dependent on RNA conformation. Both S* and S*(CT) states are fluorescent, and decay within hundreds of picoseconds and approximately 2 ns, respectively. The ratio between S* and S*(CT) fluorescence depends strongly on pyrene intercalation, and it is found that the S* state is quenched selectively upon intercalation of the pyrene into RNA. The doubly modified duplex exhibits an additional fluorescent state with a lifetime of 18.7 ns, which is associated with the pyrene excimer state. This state coexists with a significant population of the pyrene monomer, since the characteristic features of the latter can still be observed. Formation of the excimer occurs on femtosecond time scales. The pyrene label thus provides a sensitive tool to monitor the local structural dynamics of RNA with the chromophore acting as a molecular beacon. PMID- 20707370 TI - Structural and dynamical properties and vibrational spectra of bisulfate ion in water: a study by Ab initio quantum mechanical charge field molecular dynamics. AB - The ab initio quantum mechanical charge field molecular dynamics (QMCF MD) formalism was applied to simulate the bisulfate ion, HSO4-, in aqueous solution. The averaged geometry of bisulfate ion supports the separation of six normal modes of the O*-SO3 unit with C3v symmetry from three modes of the OH group in the evaluation of vibrational spectra obtained from the velocity autocorrelation functions (VACFs) with subsequent normal coordinate analyses. The calculated frequencies are in good agreement with the observations in Raman and IR experiments. The difference of the averaged coordination number obtained for the whole molecule (8.0) and the summation over coordinating sites (10.9) indicates some water molecules to be located in the overlapping volumes of individual hydration spheres. The averaged number of hydrogen bonds (H-bonds) during the simulation period (5.8) indicates that some water molecules are situated in the molecular hydration shell with an unsuitable orientation to form a hydrogen bond with the ion. The mean residence time in the surroundings of the bisulfate ion classify it generally as a weak structure-making ion, but the analysis of the individual sites reveals a more complex behavior of them, in particular a strong interaction with a water molecule at the hydrogen site. PMID- 20707371 TI - Surfactant-mediated ion exchange and charge reversal at ionic liquid interfaces. AB - Room-temperature ionic liquids (ILs) exhibit a unique set of properties due to their charged character, presenting opportunities for numerous applications. Here, we show that the combination of charged surfactants with ILs leads to rich interfacial behavior due to the interplay between electrostatic and surface forces. Using traditional measures of surface activity and X-ray photoelectron spectroscopy (XPS), we find that sodium alkyl sulfates and alkyl trimethylammonium bromides are, indeed, surface-active at the air-IL interfaces of both [EMIM][EtSO(4)] and [BHEDMA][MeSO(3)]. XPS also reveals that surfactant counterions readily dissociate into the bulk, which when combined with the surfactant surface activity has striking consequences. We find that ion exchange occurs between surfactants and like-charged IL ions, with the greatest exchange for short surfactant alkyl chains. The initial negative surface charge of neat [EMIM][EtSO(4)] can be switched to positive by the addition of alkyl trimethylammonium bromides, with the effect most pronounced at short chain lengths. By contrast, the surface charge of [BHEDMA][MeSO(3)] is largely unaffected by the added surfactants, suggesting a key role for the strength of ion-pairing within the IL. The results here illustrate a simple but effective means of manipulating IL interfacial properties. PMID- 20707372 TI - Facile formation of N-acyl-oxazolidinone derivatives using acid fluorides. AB - A mild method is presented for the formation of N-acylated oxazolidinones that employs acid fluorides and mild bases, such as (i)Pr(2)NEt and NEt(3). Optimized reaction conditions for two types of substrates have been developed utilizing either the oxazolidinone itself or the corresponding in situ generated O silyloxazolidinones resulting in the formation of the desired N-acylated products in high yields of up to 98%. PMID- 20707373 TI - Effects of nonionic surfactant addition on populations of polycyclic aromatic hydrocarbon-degrading bacteria in a bioreactor treating contaminated soil. AB - We studied the effects of two polyethoxylated nonionic surfactants, Brij 30 and C(12)E(8), on populations of polycyclic aromatic hydrocarbon- (PAH-) degrading bacteria from a bioreactor treating PAH-contaminated soil. Each surfactant was evaluated at doses that corresponded to aqueous-phase concentrations both above and below the critical micelle concentration (CMC) after mixing with reactor slurry. Real-time quantitative PCR was used to quantify 16S rRNA (rRNA) gene sequences representing degraders of salicylate, naphthalene, phenanthrene, or pyrene previously identified in the bioreactor community by stable-isotope probing. Sequences representing two groups of organisms associated with degradation of naphthalene and/or salicylate in the bioreactor increased in abundance by more than an order of magnitude after incubation with either surfactant at each dose tested. In contrast, the abundance of a group of uncultivated pyrene-degrading bacteria, whose relative abundance in the soil without surfactant addition was up to 9% of the total 16S rRNA genes, decreased by an order of magnitude or more in the presence of each surfactant at each dose. These results indicate that surfactant addition can have substantial, differential effects on populations of organisms responsible for contaminant degradation within a microbial community. PMID- 20707375 TI - Slow magnetic relaxation in an octanuclear manganese chain. AB - A one-dimensional chain containing a mixed-valence octanuclear manganese(II,III) building unit, (NEt(4))(2n)[Mn(8)O(2)(salox)(6)(N(3))(8)(MeOH)(3)](n) (H(2)salox = salicylaldoxime), was synthesized and characterized structurally and magnetically. Each building unit contains a [Mn(II)(2)Mn(III)(6)O(2)](18+) structural topology. The frequency dependence of the out-of-phase component in alternating current magnetic susceptibilities and hysteresis loops for the complex indicates single-chain-magnet-like behavior. PMID- 20707374 TI - Genetic interception and structural characterization of thiopeptide cyclization precursors from Bacillus cereus. AB - The pyridine core of the thiocillins has long been postulated to arise from a late-stage tail-to-tail condensation of two dehydroalanines. Genetic disruption of tclM, a proposed "Diels-Alderase", allowed isolation of acyclic precursors to this pyridine ring. The isolated products possess the full cohort of post translational modifications that are normally displayed by the thiocillins, including dehydrobutyrines, thiazoles, C-terminal decarboxylation, and the two previously unconfirmed dehydroalanines. Additionally, leader peptides have undergone extensive N-terminal degradation and the remaining leader peptide residues have been N-succinylated. These results identify TclM and its homologues in other thiazolyl peptide producing strains as the enzymes responsible for the trans-annular heteroannulation at core of this class of molecules. PMID- 20707376 TI - Membrane-induced conformational changes of kyotorphin revealed by molecular dynamics simulations. AB - The analgesic dipeptide kyotorphin (l-Tyr-l-Arg) was studied in the two most relevant protonation states at physiological pH, both in water and in a membrane model, using molecular dynamics simulations. Kyotorphin is found to exhibit a remarkable conformational freedom even when strongly interacting with the bilayer. Nevertheless, we observe a strong decrease in the population of the tyrosine's chi(1) torsion angle around 60 degrees that could be correlated with the dipeptide biological function. We employed a linear response approximation methodology to determine the N-terminus pK(a) values of kyotorphin and obtained 7.80 and 7.94 for aqueous and lipidic systems, respectively. Our results also indicate that the interaction of kyotorphin with a biological membrane model is consistent with the "membrane catalyst" hypothesis, and that even after the reduction of conformational freedom due to membrane insertion, this peptide fulfils most of the known constraints present in the opioid-like receptors. PMID- 20707377 TI - Debye process in Ibuprofen glass-forming liquid: insights from molecular dynamics simulation. AB - By means of molecular dynamics simulations, dynamical properties of racemic ibuprofen glass-forming liquid are investigated at different temperatures from 360 to 500 K. The origin of the peculiar low amplitude Debye-type relaxation observed experimentally by dielectric relaxation spectroscopy is addressed (Bras, A. R.; Noronha, J. P.; Antunes, A. M. M.; Cardoso, M. M.; Schonhals, A.; Affouard, F.; Dionisio, M.; Correia, N. T. J. Phys. Chem. B 2008, 112, 11087). Single and total dipolar autocorrelation functions are calculated. It is found that the behavior of the total dipole correlation is dominated at short and long times by the single function. It mainly originates from the antiparallel dipoles correlations in agreement with a value of the Kirkwood correlation factor slightly smaller than unity. The simulation suggests that the long time Debye type decay of the dipole-dipole correlation is dominated by the internal cis trans conversion of the O=C-O-H group coupled to the change of the intermolecular linear/cyclic HB structures. The overall rotation of the molecules is about 1-2 decades faster than the cis to trans transformation, so all the O=C-O-H group environments are equal on average. The effective rotational potential energy barriers of the O=C-O-H groups due to the surroundings are thus averaged and dipolar relaxation follows a simple Debye law. It is found that cyclic dimers inhibit the cis to trans conversion unlike the linear dimers and trimers which favor this conversion and stabilize the trans isomer. It is well in line with the very low amplitude of the dielectric strength associated with the Debye relaxation observed experimentally and its increase when the liquid is maintained isothermally above the melting temperature since this amplitude mainly relates to the low fraction of ibuprofen molecules in the trans conformation. A comparison is made with the Debye-type relaxation found in microstructured monohydroxy alcohols. PMID- 20707378 TI - Estimating the hydrogen bond energy. AB - First, different approaches to detect hydrogen bonds and to evaluate their energies are introduced newly or are extended. Supermolecular interaction energies of 256 dimers, each containing one single hydrogen bond, were correlated to various descriptors by a fit function depending both on the donor and acceptor atoms of the hydrogen bond. On the one hand, descriptors were orbital-based parameters as the two-center or three-center shared electron number, products of ionization potentials and shared electron numbers, and the natural bond orbital interaction energy. On the other hand, integral descriptors examined were the acceptor-proton distance, the hydrogen bond angle, and the IR frequency shift of the donor-proton stretching vibration. Whereas an interaction energy dependence on 1/r(3.8) was established, no correlation was found for the angle. Second, the fit functions are applied to hydrogen bonds in polypeptides, amino acid dimers, and water cluster, thus their reliability is demonstrated. Employing the fit functions to assign intramolecular hydrogen bond energies in polypeptides, several side chain CH...O and CH...N hydrogen bonds were detected on the fly. Also, the fit functions describe rather well intermolecular hydrogen bonds in amino acid dimers and the cooperativity of hydrogen bond energies in water clusters. PMID- 20707379 TI - Lateral spin injection in germanium nanowires. AB - Electrical injection of spin-polarized electrons into a semiconductor, large spin diffusion length, and an integration friendly platform are desirable ingredients for spin-based devices. Here we demonstrate lateral spin injection and detection in germanium nanowires, by using ferromagnetic metal contacts and tunnel barriers for contact resistance engineering. Using data measured from over 80 samples, we map out the contact resistance window for which lateral spin transport is observed, manifestly showing the conductivity matching required for spin injection. Our analysis, based on the spin diffusion theory, indicates that the spin diffusion length is larger than 100 mum in germanium nanowires at 4.2 K. PMID- 20707380 TI - Bleach-imaged plasmon propagation (BlIPP) in single gold nanowires. AB - Here, we present a novel approach to visualize propagating surface plasmon polaritons through plasmon-exciton interactions between single gold nanowires and a thin film of a fluorescent polymer. A plasmon polariton was launched by exciting one end of a single gold nanowire with a 532 nm laser. The local near field of the propagating plasmon modes caused bleaching of the polymer emission. The degree of photobleaching along the nanowire could be correlated with the propagation distance of the surface plasmon polaritons. Using this method of bleach-imaged plasmon propagation (BlIPP), we determined a plasmon propagation distance of 1.8 +/- 0.4 mum at 532 nm for chemically grown gold nanowires. Our results are supported by finite difference time domain electromagnetic simulations. PMID- 20707381 TI - Fluorescent, superparamagnetic nanospheres for drug storage, targeting, and imaging: a multifunctional nanocarrier system for cancer diagnosis and treatment. AB - For early cancer diagnosis and treatment, a nanocarrier system is designed and developed with key components uniquely structured at nanoscale according to medical requirements. For imaging, quantum dots with emissions in the near infrared range (~800 nm) are conjugated onto the surface of a nanocomposite consisting of a spherical polystyrene matrix (~150 nm) and the internally embedded, high fraction of superparamagnetic Fe(3)O(4) nanoparticles (~10 nm). For drug storage, the chemotherapeutic agent paclitaxel (PTX) is loaded onto the surfaces of these composite multifunctional nanocarriers by using a layer of biodegradable poly(lactic-co-glycolic acid) (PLGA). A cell-based cytotoxicity assay is employed to verify successful loading of pharmacologically active drug. Cell viability of human, metastatic PC3mm2 prostate cancer cells is assessed in the presence and absence of various multifunctional nanocarrier populations using the MTT assay. PTX-loaded composite nanocarriers are synthesized by conjugating anti-prostate specific membrane antigen (anti-PSMA) for targeting. Specific detection studies of anti-PSMA-conjugated nanocarrier binding activity in LNCaP prostate cancer cells are carried out. LNCaP cells are targeted successfully in vitro by the conjugation of anti-PSMA on the nanocarrier surfaces. To further explore targeting, the nanocarriers conjugated with anti-PSMA are intravenously injected into tumor-bearing nude mice. Substantial differences in fluorescent signals are observed ex vivo between tumor regions treated with the targeted nanocarrier system and the nontargeted nanocarrier system, indicating considerable targeting effects due to anti-PSMA functionalization of the nanocarriers. PMID- 20707382 TI - Formation and instability of silver nanofilament in Ag-based programmable metallization cells. AB - In this paper, we report on the formation and rupture of Ag nanofilament on planar Ag/TiO2/Pt cells using visual observation. During the forming process, the filament tends to stay very thin. Specifically, it is so thin that it breaks up into a chain of nanospheres (according to Rayleigh instability) right after the formation has been completed. Similar mechanical breakup may also impact vertically stacked cells, causing reliability concerns. PMID- 20707383 TI - Electrical contact tunable direct printing route for a ZnO nanowire Schottky diode. AB - Although writing was the first human process for communication, it may now become the main process in the electronics industry, because in the industry the programmability as an inherent property is a necessary requirement for next generation electronics. As an effort to open the era of writing electronics, here we show the feasibility of the direct printing of a high-performance inorganic single crystalline semiconductor nanowire (NW) Schottky diode (SD), including Schottky and Ohmic contacts in series, using premetallization and wrapping with metallic nanofoil. To verify the feasibility of our process, SDs made of Al premetalized ZnO NWs and plain ZnO NWs were compared with each other. Even with cold direct printing, the Al-premetalized ZnO NW SD showed higher performance, specifically 1.52 in the ideality factor and 1.58 x 10(5) in its rectification ratio. PMID- 20707384 TI - Lewis acid catalyzed highly stereoselective domino-ring-opening cyclization of activated aziridines with enolates: synthesis of functionalized chiral gamma lactams. AB - A highly enantio- and diastereoselective Lewis acid catalyzed S(N)2-type ring opening followed by cyclization of aziridines with active methylene carbon nucleophiles to functionalized chiral gamma-lactams in a domino fashion has been developed. gamma-Lactams have been desulfonated and decarboxylated, providing pyrrolidone-3-carboxylate and N-tosylpyrrolidinone derivatives, respectively, in good yields. PMID- 20707385 TI - Synthesis, X-ray structure, and anion-binding properties of a cryptand-like hybrid calixpyrrole. AB - The novel cryptand in/out-3, containing two tripyrrolemethane units bridged by three 1,3- diisopropylidenbenzene arms, was readily synthesized by a convergent three-step synthesis. It binds fluoride by inclusion with excellent selectivity with respect to a number of other tested anions. The structure of the free receptor and that of its fluoride complex were investigated in solution by NMR spectroscopy. The solid-state X-ray structure of the free cryptand 3 was also determined. PMID- 20707387 TI - Transition state models for probing stereoinduction in Evans chiral auxiliary based asymmetric aldol reactions. AB - The use of chiral auxiliaries is one of the most fundamental protocols employed in asymmetric synthesis. In the present study, stereoselectivity-determining factors in a chiral auxiliary-based asymmetric aldol reaction promoted by TiCl(4) are investigated by using density functional theory methods. The aldol reaction between chiral titanium enolate [derived from Evans propionyl oxazolidinone (1a) and its variants oxazolidinethione (1b) and thiazolidinethione (1c)] and benzaldehyde is examined by using transition-state modeling. Different stereochemical possibilities for the addition of titanium enolates to aldehyde are compared. On the basis of the coordination of the carbonyl/thiocarbonyl group of the chiral auxiliary with titanium, both pathways involving nonchelated and chelated transition states (TSs) are considered. The computed relative energies of the stereoselectivity-determining C-C bond formation TSs in the nonchelated pathway, for both 1a and 1c, indicate a preference toward Evans syn aldol product. The presence of a ring carbonyl or thiocarbonyl group in the chiral auxiliary renders the formation of neutral TiCl(3)-enolate, which otherwise is energetically less favored as compared to the anionic TiCl(4)-enolate. Hence, under suitable conditions, the reaction between titanium enolate and aldehyde is expected to be viable through chelated TSs leading to the selective formation of non-Evans syn aldol product. Experimentally known high stereoselectivity toward Evans syn aldol product is effectively rationalized by using the larger energy differences between the corresponding diastereomeric TSs. In both chelated and nonchelated pathways, the attack by the less hindered face of the enolate on aldehyde through a chair-like TS with an equatorial disposition of the aldehydic substituent is identified as the preferred mode. The steric hindrance offered by the isopropyl group and the possible chelation are identified as the key reasons behind the interesting stereodivergence between Evans and non-Evans products normally reported for the title reaction. The application of an activation strain model on the critical TSs has been effective toward rationalizing the origin of stereoselectivity. Improved interaction energy between the reactants is found to be the key stabilizing factor for the lowest energy TS in both chelated and nonchelated pathways. The present study provides newer insights on the role of titanium(IV) toward modulating stereoselectivity in aldol reactions. PMID- 20707386 TI - Enhanced gene delivery and siRNA silencing by gold nanoparticles coated with charge-reversal polyelectrolyte. AB - Charge-reversal functional gold nanoparticles first prepared by layer-by-layer technique were employed to deliver small interfering RNA (siRNA) and plasmid DNA into cancer cells. Polyacrylamide gel electrophoresis measurements of siRNA confirmed the occurrence of the charge-reversal property of functional gold nanoparticles. The expression efficiency of enhanced green fluorescent protein (EGFP) was improved by adjuvant transfection with charge-reversal functional gold nanoparticles, which also had much lower toxicity to cell proliferation. Lamin A/C, an important nuclear envelope protein, was effectively silenced by lamin A/C siRNA delivered by charge-reversal functional gold nanoparticles, whose knockdown efficiency was better than that of commercial Lipofectamine 2000. Confocal laser scanning microscopic images indicated that there was more cy5-siRNA distributed throughout the cytoplasm for cyanine 5-siRNA/polyethyleneimine/cis-aconitic anhydride-functionalized poly(allylamine)/ polyethyleneimine/11 mercaptoundecanoic acid-gold nanoparticle (cy5-siRNA/PEI/PAH-Cit/PEI/MUA-AuNP) complexes. These results demonstrate the feasibility of using charge-reversal functional gold nanoparticles as a means of improving the nucleic acid delivery efficiency. PMID- 20707390 TI - Ultra-high performance liquid chromatography-mass spectrometry for the fast profiling of histone post-translational modifications. AB - Histones are subjected to extensive post-translational modifications (PTMs) that are known to play key roles in many biological processes. In this study, we report a fast, efficient, highly reproducible, and easily automated method involving ultra-high performance liquid chromatography (UHPLC) coupled to a high resolution/high mass accuracy LTQ-Orbitrap mass spectrometer to profile core histone modifications/variants from WI-38 primary human fibroblasts. The whole analysis was performed on intact unfractionated histones within 19 min, which is ~3-fold faster than previously published procedures. High mass accuracy measurements combined with top-down tandem mass spectrometry (MS) experiments enable accurate histone identification. Experimental and biological variations were thoroughly assessed and were 8% and 16% on average, respectively. With a sample preparation reduced to the minimum, characterization of the most abundant histones can be achieved in a single experiment. Semi-quantitative information can be obtained with respect to the relative abundances of the detected isoforms through a label-free approach. Isoform identities and relative distributions were further confirmed by the LC-MS/MS analysis of tryptic digests. Overall, our UHPLC MS approach for histone profiling offers a sensitive and reproducible tool that will be of great value for exploring PTMs and variants and can readily be applied to clinical or pharmaceutical studies. PMID- 20707389 TI - Analysis of low abundance membrane-associated proteins from rat pancreatic zymogen granules. AB - Zymogen granules (ZG) are specialized storage organelles in the exocrine pancreas that allow the sorting, packaging, and regulated apical secretion of digestive enzymes. As there is a critical need for further understanding of the key processes in regulated secretion to develop new therapeutic options in medicine, we applied a suborganellar proteomics approach to identify peripheral membrane associated ZG proteins. We focused on the analysis of a "basic" group (pH range 6.2-11) with about 46 spots among which 44 were identified by tandem mass spectrometry. These spots corresponded to 16 unique proteins, including rat mast cell chymase (RMCP-1) and peptidyl-prolyl cis-trans isomerase B (PpiB; cyclophilin B), an ER-resident protein. To confirm that these proteins were specific to zymogen granules and not contaminants of the preparation, we conducted a series of validation experiments. Immunoblotting of ZG subfractions revealed that chymase and PpiB behaved like bona fide peripheral membrane proteins. Their expression in rat pancreas was regulated by feeding behavior. Ultrastructural and immunofluorescence studies confirmed their ZG localization. Furthermore, a chymase-YFP fusion protein was properly targeted to ZG in pancreatic AR42J cells. Interestingly, for both proteins, proteoglycan-binding properties have been reported. The importance of our findings for sorting and packaging during ZG formation is discussed. PMID- 20707388 TI - The flavanol (-)-epigallocatechin 3-gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity. AB - Islet amyloid polypeptide (IAPP, amylin) is the major protein component of the islet amyloid deposits associated with type 2 diabetes. The polypeptide lacks a well-defined structure in its monomeric state but readily assembles to form amyloid. Amyloid fibrils formed from IAPP, intermediates generated in the assembly of IAPP amyloid, or both are toxic to beta-cells, suggesting that islet amyloid formation may contribute to the pathology of type 2 diabetes. There are relatively few reported inhibitors of amyloid formation by IAPP. Here we show that the tea-derived flavanol, (-)-epigallocatechin 3-gallate [(2R,3R)-5,7 dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5 trihydroxybenzoate] (EGCG), is an effective inhibitor of in vitro IAPP amyloid formation and disaggregates preformed amyloid fibrils derived from IAPP. The compound is thus one of a very small set of molecules which have been shown to disaggregate IAPP amyloid fibrils. Fluorescence-detected thioflavin-T binding assays and transmission electron microscopy confirm that the compound inhibits unseeded amyloid fibril formation as well as disaggregates IAPP amyloid. Seeding studies show that the complex formed by IAPP and EGCG does not seed amyloid formation by IAPP. In this regard, the behavior of IAPP is similar to the reported interactions of Abeta and alpha-synuclein with EGCG. Alamar blue assays and light microscopy indicate that the compound protects cultured rat INS-1 cells against IAPP-induced toxicity. Thus, EGCG offers an interesting lead structure for further development of inhibitors of IAPP amyloid formation and compounds that disaggregate IAPP amyloid. PMID- 20707392 TI - Iridoids. A review. AB - Tre review presents a glossary of the iridoid glycosides, secoiridoids, bis iridoids, and non-glycosidic iridoids. The following information is present for each compound, when available: structural formula, molecular formula, molecular weight, mp and [alpha]D values, uv, ir, 1H-nmr, 13C-nmr, and ms data, as well as mp and [alpha]D values for the correspondent acetate derivative. The natural source, the family and generic name, is given as well as the reference. A cross index and molecular weight tables are presented. PMID- 20707391 TI - Temporal profiling of the secretome during adipogenesis in humans. AB - Adipose tissue plays a key role as a fat-storage depot and as an endocrine organ. Although mouse adipogenesis has been studied extensively, limited studies have been conducted to characterize this process in humans. We carried out a temporal proteomic analysis to interrogate the dynamic changes in the secretome of primary human preadipocytes as they differentiate into mature adipocytes. Using iTRAQ based quantitative proteomics, we identified and quantified 420 proteins from the secretome of differentiated human adipocytes. Our results revealed that the majority of proteins showed differential expression during the course of differentiation. In addition to adipokines known to be differentially secreted in the course of adipocyte differentiation, we identified a number of proteins whose dynamic expression in this process has not been previously documented. They include collagen triple helix repeat containing 1, cytokine receptor-like factor 1, glypican-1, hepatoma-derived growth factor, SPARC related modular calcium binding protein 1, SPOCK 1, and sushi repeat-containing protein. A bioinformatics analysis using Human Protein Reference Database and Human Proteinpedia revealed that of the 420 proteins identified, 164 proteins possess signal peptides and 148 proteins are localized to the extracellular compartment. Additionally, we employed antibody arrays to quantify changes in the levels of 182 adipokines during human adipogenesis. This is the first large-scale quantitative proteomic study that combines two platforms, mass spectrometry and antibody arrays, to analyze the changes in the secretome during the course of adipogenesis in humans. PMID- 20707393 TI - The flavonoids of Parthenium L. AB - The distribution of 34 flavonoids detected in the North American species of Parthenium L. is presented. Of the 27 flavonoids identified (some tentatively) all are flavonols: eight are based on kaempferol, seven on quercetin, four on 6 hydroxykaempferol and eight on the quercetagetin skeleton. Of the 34 flavonoids detected, 19 are glycosides and 15 are aglycones, primarily highly methylated compounds. PMID- 20707394 TI - Valepotriates in tissue cultures of nine different Valerianaceae species in comparison to literature data of the intact plants. PMID- 20707395 TI - Alkyl and phenylalkyl anacardic acids from Knema elegans seed oil. PMID- 20707396 TI - Biosynthesis of opium alkaloids. Substrate specificity and aberrant biosynthesis: attempted detection of oripavine in Papaver somniferum. PMID- 20707397 TI - Biosynthesis of unnatural papaverine derivatives in Papaver somniferum. AB - The unnatural thebaine analog, oripavine 3-ethyl ether, was efficiently metabolized to morphine 3-ethyl ether and morphine in the opium poppy. An attempt to detect oripavine hy an isotope dilution experiment based on its presumed biosynthesis from reticuline was unsuccessful. PMID- 20707398 TI - Flavonoids from the leaves of Kalmia latifolia. PMID- 20707399 TI - The isolation of loliolide from an Indian Ocean opisthobranch mollusc. PMID- 20707400 TI - Fixed and volatile constituents of Croton aff. nepetifolius. PMID- 20707402 TI - A proteomics-based translational approach reveals an antifolate resistance inherent in human plasma derived from blood donation. AB - The inhibition of dihydrofolate reductase (DHFR) by antifolates is a common practice both in cell culture and in chemotherapy. Surprisingly, antifolate resistance was also observed in cultured murine myeloma cells (SP2/0) in the presence of human plasma (HP); thus, we used a proteomic approach to identify novel plasma biomarker(s) for this condition. In contrast to the in vitro antifolate response, metabolic enzymes and translation machinery proteins were found to be up-regulated in the presence of HP. The antifolate resistance inherent in HP may be explained by a simultaneous promotion of cell proliferation and the maintenance of DNA integrity. Furthermore, the factor(s) was found to be extrinsic, heat stable and very small in size. Adenine, a supplemented additive in erythrocyte preservation, was subsequently identified as the contributing factor and exogenous addition in cultures reversed the cytotoxicity induced by antifolates. Importantly, adenine-containing blood components, which may provide enhanced survival to otherwise sensitive antifolate-targeted cells, showed a dose dependent adverse effect in transfusion recipients receiving antifolate (methotrexate) medications. These findings not only highlight a previously unnoticed role of adenine, but also emphasize a novel mechanistic link between transfusion and subsequently reduced survival in patients taking methotrexate. PMID- 20707403 TI - Transgelin promotes migration and invasion of cancer stem cells. AB - Recent studies have suggested the existence of a small subset of cancer cells called cancer stem cells (CSCs), which possess the ability to initiate malignancies, promote tumor formation, drive metastasis, and evade conventional chemotherapies. Elucidation of the specific signaling pathway and mechanism underlying the action of CSCs might improve the efficacy of cancer treatments. In this study, we analyzed differentially expressed proteins between tumerigenic and nontumorigenic cells isolated from the human hepatocellular carcinoma (HCC) cell line, Huh7, via proteomic analysis to identify proteins correlated with specific features of CSCs. The expression level of Transgelin was 25-fold higher in tumorigenic cells than nontumorigenic cells. Similar results were also observed in tumorigenic cells derived from colorectal adenocarcinoma and prostate carcinoma. More importantly, the elevated levels of Transgelin significantly increased the invasiveness of tumorigenic cells, whereas reduced levels decreased the invasive potential. Moreover, in tumors derived from Huh7-induced xenografts, Transgelin was also co-expressed with CXCR4, which is responsible for tumor invasion. Taken together, these results indicate that the metastatic potential of CSCs arises from highly expressed Transgelin. PMID- 20707404 TI - In this issue. Estrogen double whammy. PMID- 20707406 TI - Sensitization of non-small cell lung cancer cells to cisplatin by naturally occurring isothiocyanates. AB - We show that naturally occurring isothiocyanates (ITCs) sensitize human non-small cell lung cancer cells to cisplatin. Moreover, the structure of the ITC side chain moiety is important for sensitization. In NCI-H596 cells, 20 microM benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) enhance the efficacy of various concentrations of cisplatin, but sulforaphane (SFN) does not. Reducing the concentration of BITC and PEITC to 10 microM still allows for the sensitization of cells to cisplatin. Neither cellular platinum accumulation nor DNA platination account for this increased cytotoxicity. BITC and PEITC deplete beta-tubulin, but SFN does not; this correlates with and may be important for sensitization. PMID- 20707407 TI - Cloning, expression and functional characterization of cytochrome P450 3A37 from turkey liver with high aflatoxin B1 epoxidation activity. AB - Cytochrome P450s (P450) play an important role in the formation of carcinogenic and mutagenic electrophilic intermediates from a wide range of xenobiotics, including naturally occurring dietary compounds. The pathogenesis of hepatotoxic and hepatocarcinogenic action of the mycotoxin aflatoxin B(1) (AFB(1)) involves initial bioactivation by P450s to a reactive and electrophilic intermediate exo aflatoxin B(1)-8,9-epoxide (exo-AFBO). Poultry, especially turkeys are extremely sensitive to AFB(1), a condition due, in part, to efficient epoxidation by P450 1A and 3A enzymes. We previously reported the discovery of P450 1A5 from turkey liver, which like its human homologue, 1A2, bioactivated AFB(1) to exo-AFBO and aflatoxin M(1) (AFM(1)). Here, we describe P450 3A37, the 3A4 homologue from turkey liver. This gene has an open reading frame (ORF) of 1512 bp, and the protein is predicted to be 504 amino acids with 97% identity to chicken P450 3A37. A truncated construct of the turkey P450 3A37 gene with 11 amino acids deleted from the hydrophobic N-terminal region was heterologously expressed in Escherichia coli, the protein from which exhibited a CO difference spectrum typical of P450s. Like human P450 3A4, 3A37 biotransformed AFB(1) to exo-AFBO and aflatoxin Q(1) (AFQ(1)) and possessed nifedipine oxidation activity, both of which were inhibited by the P450 3A4 inhibitor 17alpha-ethynylestradiol. Oxidation of AFB(1) to exo-AFBO and AFQ(1) by P450 3A37 followed sigmoidal Hill kinetics, suggestive of an allosteric interaction between the enzyme and AFB(1). The Hill coefficient (n) value was 1.9 for exo-AFBO and 1.6 for AFQ(1), indicative of positive cooperativity. The calculated K(m) and V(max) values for the formation of exo-AFBO were 287 +/- 21 muM and 1.45 +/- 0.07 nmol/min/nmol P450, respectively, whereas those of AFQ(1) formation were 302 +/- 51 muM and 7.86 +/- 0.75 nmol/min/nmol P450, respectively. These data strongly suggest that P450 3A37, along with P450 1A5, plays an important role in AFB(1) epoxidation in turkey liver. PMID- 20707409 TI - Estrogenic activity of anthraquinone derivatives: in vitro and in silico studies. AB - Comprehension of the ligand-receptor interactions is a prerequisite for constructing mechanism based quantitative structure-activity relationship (QSAR) models on xenoestrogenic activity. Molecular docking was performed to simulate the interactions between anthraquinone derivative (AQs) molecules and the estrogen receptor alpha (ERalpha). Hydrogen bonding, hydrophobic, and pi-pi interactions were found to be the dominant interactions between AQs and the receptor, which implied the estrogenic activities of the compounds. The recombinant yeast-based assay was employed to determine the estrogenic activities of 20 AQs. On the basis of the observed interactions between the AQs and ERalpha, appropriate molecular structural parameters were computed to develop a QSAR model. The polarizability term, the binding energy, the average molecular polarizability, the most negative formal charge in the molecule, and the average of the negative potentials on the molecular surface were significant parameters explaining the estrogenicity. The developed QSAR model had good robustness, predictive ability, and mechanism interpretability. The interactions between the AQs and ERalpha and the partition ability of the AQs into the biophase are main factors governing the estrogenic activities. Moreover, the applicability domain of the model was described. PMID- 20707408 TI - Malondialdehyde-deoxyguanosine adduct formation in workers of pathology wards: the role of air formaldehyde exposure. AB - Formaldehyde is an ubiquitous pollutant to which humans are exposed. Pathologists can experience high formaldehyde exposure levels. Formaldehyde-among other properties-induce oxidative stress and free radicals, which react with DNA and lipids, leading to oxidative damage and lipid peroxidation, respectively. We measured the levels of air-formaldehyde exposure in a group of Italian pathologists and controls. We analyzed the effect of formaldehyde exposure on leukocyte malondialdehyde-deoxyguanosine adducts (M(1)-dG), a biomarker of oxidative stress and lipid peroxidation. We studied the relationship between air formaldehyde and M(1)-dG adducts. Air-formaldehyde levels were measured by personal air samplers. M(1)-dG adducts were analyzed by a (32)P-postlabeling assay. Reduction room pathologists were significantly exposed to air-formaldehyde with respect to controls and to the pathologists working in other laboratory areas (p < 0.001). A significant difference for M(1)-dG adducts between exposed pathologists and controls was found (p = 0.045). The effect becomes stronger when the evaluation of air-formaldehyde exposure was based on personal samplers (p = 0.018). Increased M(1)dG adduct levels were only found in individuals exposed to air-formaldehyde concentrations higher than 66 microg/m(3). When the exposed workers and controls were subgrouped according to smoking, M(1)-dG tended to increase in all of the subjects, but a significant association between M(1)-dG and air-formaldehyde was only found in nonsmokers (p = 0.009). Air-formaldehyde played a role positive but not significant (r = 0.355, p = 0.075, Pearson correlation) in the formation of M(1)-dG, only in nonsmokers. Working in the reduction rooms and exposure to air-formaldehyde concentrations higher than 66 microg/m(3) are associated with increased levels of M(1)-dG adducts. PMID- 20707410 TI - The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 enzyme. AB - Inhaled glucocorticoid (GC) therapy is a vital part of the management of chronic asthma. GCs are metabolized by members of the cytochrome P450 3A family in both liver and lung, but the enzymes are differentially expressed. Selective inhibition of one or more P450 3A enzymes could substantially modify target and systemic concentrations of GCs. In this study, we have evaluated the mechanism based inactivation of P450 3A4, 3A5, and 3A7 enzymes by GCs. Among the five major inhaled GCs approved for clinical use in the United States, fluticasone propionate (FLT) was the most potent mechanism-based inactivator of P450 3A5, the predominant P450 enzyme in the lung. FLT inactivated P450 3A5 in a time- and concentration-dependent manner with K(I), k(inact), and partition ratio of 16 muM, 0.027 min(-1), and 3, respectively. In contrast, FLT minimally inactivated P450 3A4 and did not inactivate 3A7, even with a concentration of 100 muM. The inactivation of P450 3A5 by FLT was irreversible because dialysis did not restore enzyme activity. In addition, the exogenous nucleophilic scavenger GSH did not attenuate inactivation. The prosthetic heme of P450 3A5 was not modified by FLT. The loss of P450 3A5 activity in lung cells could substantially decrease the metabolism of FLT, which would increase the effective FLT concentration at its target site, the respiratory epithelium. Also, inactivation of lung P450 3A5 could increase the absorption of inhaled FLT, which could lead to high systemic concentrations and adverse effects, such as life-threatening adrenal crises or cataracts that have been documented in children receiving high doses of inhaled GCs. PMID- 20707411 TI - Teratogenic effects of blue cohosh (Caulophyllum thalictroides) in Japanese medaka (Oryzias latipes) are probably mediated through GATA2/EDN1 signaling pathway. AB - Blue cohosh (Caulophyllum thalictroides) (BC) has been used widely to induce labor and to treat other uterine conditions. However, the safety and effectiveness of this herbal product has not yet been evaluated by the US Food and Drug Administration (FDA). Several conflicting reports indicated that the root extract of BC is a teratogen and, by some unknown mechanisms, is able to induce cardiovascular malfunctions in new-born babies. To understand the mechanism, we have used Japanese medaka (Oryzias latipes) embryo-larval development as the experimental model and the methanolic extract of BC root as the teratogen. The embryo mortality, hatching efficiency, and morphological abnormalities in craniofacial and cardiovascular systems are considered for the evaluation of BC toxicity. Our results indicate that BC is able to disrupt cardiovascular and craniofacial cartilage development in medaka embryo in a dose and developmental stage-specific manner. Moreover, embryos in precirculation are to some extent more resistant to BC than ones with circulation. By using subtractive hybridization, we have observed that gata2 mRNA was differentially expressed in the circulating embryos after BC treatment. As GATA-binding sequences are required for the expression of the endothelin1 (edn1) gene and edn1 expressed in blood vessels and craniofacial cartilages, we have extended our investigations to edn1 gene expression regulation by BC. We found that edn1, furin1, and endothelin receptor A (ednrA) genes are developmentally regulated; endothelin converting enzyme mRNA (ece1) maintained a steady-state level throughout development. Circulating medaka embryos (3 days post fertilization, dpf) exposed to BC (10 microg/mL) for 48 h have increased levels of gata2, ece1, and preproenodthelin (preproedn1) mRNA contents; however, other mRNAs (furin and ednrA) remained unaltered. Therefore, the enhanced expression of gata2 mRNA followed by ece1 and preproedn1 mRNA by BC might be able to induce vasoconstriction and cardiovascular defects and disrupt craniofacial cartilages in medaka embryos. We conclude that cardiovascular and craniofacial defects in medaka embryogenesis by BC are probably mediated through a GATA2-EDN1 signaling pathway. PMID- 20707413 TI - Evidence of reactive aromatics as a major source of peroxy acetyl nitrate over China. AB - We analyze the observations of near-surface peroxy acetyl nitrate (PAN) and its precursors in Beijing, China in August of 2007. The levels of PAN are remarkably high (up to 14 ppbv), surpassing those measured over other urban regions in recent years. Analyses employing a 1-D version of a chemical transport model (Regional chEmical and trAnsport Model, REAM) indicate that aromatic non-methane hydrocarbons (NMHCs) are the dominant (55-75%) PAN source. The major oxidation product of aromatics that produces acetyl peroxy radicals is methylglyoxal (MGLY). PAN and O(3) in the observations are correlated at daytime; aromatic NMHCs appear to play an important role in O(3) photochemistry. Previous NMHC measurements indicate the presence of reactive aromatics at high levels over broad polluted regions of China. Aromatics are often ignored in global and (to a lesser degree) regional 3D photochemical transport models; their emissions over China as well as photochemistry are quite uncertain. Our findings suggest that critical assessments of aromatics emissions and chemistry (such as the yields of MGLY) are necessary to understand and assess ozone photochemistry and regional pollution export in China. PMID- 20707412 TI - Quantitative proteomics reveals a "poised quiescence" cellular state after triggering the DNA replication origin activation checkpoint. AB - An origin activation checkpoint has recently been discovered in the G1 phase of the mitotic cell cycle, which can be triggered by loss of DNA replication initiation factors such as the Cdc7 kinase. Insufficient levels of Cdc7 activate cell cycle arrest in normal cells, whereas cancer cells appear to lack this checkpoint response, do not arrest, and proceed with an abortive S phase, leading to cell death. The differential response between normal and tumor cells at this checkpoint has led to widespread interest in the development of pharmacological Cdc7 inhibitors as novel anticancer agents. We have used RNAi against Cdc7 in combination with SILAC-based high resolution MS proteomics to investigate the cellular mechanisms underlying the maintenance of the origin activation checkpoint in normal human diploid fibroblasts. Bioinformatics analysis identified clear changes in wide-ranging biological processes including altered cellular energetic flux, moderate stress response, reduced proliferative capacity, and a spatially distributed response across the mitochondria, lysosomes, and the cell surface. These results provide a quantitative overview of the processes involved in maintenance of the arrested state, show that this phenotype involves active rather than passive cellular adaptation, and highlight a diverse set of proteins responsible for cell cycle arrest and ultimately for promotion of cellular survival. We propose that the Cdc7-depleted proteome maintains cellular arrest by initiating a dynamic quiescence-like response and that the complexities of this phenotype will have important implications for the continued development of promising Cdc7-targeted cancer therapies. PMID- 20707414 TI - Chemical sinks of organic aerosol: kinetics and products of the heterogeneous oxidation of erythritol and levoglucosan. AB - The heterogeneous oxidation of pure erythritol (C(4)H(10)O(4)) and levoglucosan (C(6)H(10)O(5)) particles was studied in order to evaluate the effects of atmospheric aging on the mass and chemical composition of atmospheric organic aerosol. In contrast to what is generally observed for the heterogeneous oxidation of reduced organics, substantial volatilization is observed in both systems. However, the ratio of the decrease in particle mass to the decrease in the concentration of the parent species is about three times higher for erythritol than for levoglucosan, indicating that details of chemical structure (such as carbon number, cyclic moieties, and oxygen-containing functional groups) play a governing role in the importance of volatilization reactions. The kinetics of the reaction indicate that while both compounds react at approximately the same rate, reactions of their oxidation products appear to be slowed substantially. Estimates of volatilities of organic species based on elemental composition measurements suggest that the heterogeneous oxidation of oxygenated organics may be an important loss mechanism of organic aerosol. PMID- 20707415 TI - Selective determination of volatile sulfur compounds in wine by gas chromatography with sulfur chemiluminescence detection. AB - Volatile sulfur compounds can be formed at various stages during wine production and storage, and some may impart unpleasant "reduced" aromas to wine when present at sensorially significant concentrations. Quantitative data are necessary to understand factors that influence the formation of volatile sulfur compounds, but their analysis is not a trivial undertaking. A rapid and selective method for determining 10 volatile sulfur-containing aroma compounds in wine that have been linked to "off-odors" has been developed. The method utilizes static headspace injection and cool-on-column gas chromatography coupled with sulfur chemiluminescence detection (GC-SCD). Validation demonstrated that the method is accurate, precise, robust, and sensitive, with limits of quantitation around 1 microg/L or better, which is below the aroma detection thresholds for the analytes. Importantly, the method does not form artifacts, such as disulfides, during sample preparation or analysis. To study the contribution of volatile sulfur compounds, the GC-SCD method was applied to 68 commercial wines that had reductive sensory evaluations. The analytes implicated as contributors to reductive characters were hydrogen sulfide, methanethiol, and dimethyl sulfide, whereas carbon disulfide played an uncertain role. PMID- 20707416 TI - Theoretical study of the low lying states of Ga(2)X (X = P, As). AB - Since the low lying electronic states of Ga(2)X (X = P, As) are nearly degenerate, an accurate determination of the electronic structure of these states was incomplete in the previous works. In this study, the geometry optimization and vibrational frequency calculation have been performed at the various levels of theory, using the effective core pseudopotentials of the Ga and As atoms and the associated cc-pVTZ basis sets. The ground state of Ga(2)P is found to be the (2)A' state correlating with the (2)B(2) state in C(2v) structure, which lies 0.031 eV above the global minimum at the RCCSD(T) level. The equilibrium of the (2)A(1) state is optimized above that of the (2)B(2) state, and the (2)B(1) state, predicted previously as the ground state, has a stable minimum above the optimized geometries of the former states. Concerning the low lying states of Ga(2)As, our results confirm in general the previous studies. Because all the states of both compounds can be considered monoconfigurational around their equilibrium, the RCCSD(T) method is well adapted to acurrately describe both systems. In turn, we have applied our obtained information to analyze the Ga(2)P( ) and Ga(2)As(-) anion photoelectron spectra, to which it remains difficult to appropriately assign the low lying states of Ga(2)P and Ga(2)As. As a consequence, our analysis supports the previous assignment for Ga(2)P, but contrasts partially to that for Ga(2)As. PMID- 20707417 TI - Near-field vector intensity measurements of a small solid rocket motor. AB - Near-field vector intensity measurements have been made of a 12.7-cm diameter nozzle solid rocket motor. The measurements utilized a test rig comprised of four probes each with four low-sensitivity 6.35-mm pressure microphones in a tetrahedral arrangement. Measurements were made with the rig at nine positions (36 probe locations) within six nozzle diameters of the plume shear layer. Overall levels at these locations range from 135 to 157 dB re 20 microPa. Vector intensity maps reveal that, as frequency increases, the dominant source region contracts and moves upstream with peak directivity at greater angles from the plume axis. PMID- 20707418 TI - Ultrasonic output from the excised rat larynx. AB - The source of ultrasonic vocalizations (USVs) produced by rats is thought to be within the larynx. The purpose of this investigation was to determine if the rat larynx is capable of producing ultrasounds with the full range of frequencies reported in vivo. Acoustic output of excised rat larynges with and without vocal fold constriction was measured. At biologically-reasonable airflow rates and pressures, only larynges with a constriction produced the full range of ultrasounds reported in vivo, providing support for the hypothesis that a constriction within the larynx is likely the source of rat USVs. PMID- 20707419 TI - Perceptual assimilation of American English vowels by inexperienced Russian listeners. AB - In a perceptual assimilation task, 16 Russian speakers categorized American English (AE) vowels [i[see text], I, epsilon, ae[see tedxt], a[see text], u[see text]] in /Vp/ disyllables into Russian (RU) response categories and rated their perceived goodness on a 9-point Likert scale. Cross-language discriminant analysis established acoustic similarities to Russian vowels. For all but AE [epsilon], acoustic similarity predicted modal assimilation responses. Russian listeners consistently assimilated AE point vowels to their Russian counterparts, whereas assimilation of the remaining vowels was less consistent. These acoustic and perceptual similarity patterns provide a baseline for future studies of AE vowel discrimination by Russian learners of English. PMID- 20707420 TI - Possible relation of noise levels in streets to the population of the municipalities in which they are located. AB - A preview of the results of applying a categorization method to twenty towns with populations between 2200 and 700 000 inhabitants and areas between 0.57 km(2) and 59 km(2) is presented. This represents a significant expansion of the population size and area of urban sites studied by this method, with variations of two to three orders of magnitude, including the fourth most populous town in Spain. It is found that there is a relationship between urban noise and inhabitants, and also between urban noise and inhabited area, reflecting the urban structure defined in the strata of the categorization method. PMID- 20707421 TI - On advantages of derivation of exact dynamical stiffness matrices from boundary integral equations. AB - Dynamical stiffness matrices are broadly used for solving problems in wave propagation in elastic structures. For elastic waveguides that support both propagating and evanescent waves, the standard use of transfer matrices to obtain their dynamical stiffness matrix may cause problems in computations. In this letter to the editor, an advanced way to derive dynamical stiffness matrices is proposed and exemplified in the classical Bernoulli-Euler beam theory. PMID- 20707422 TI - Impact of source depth on coherent underwater acoustic communications. AB - A recent paper [Song et al., J. Acoust. Soc. Am. 123, 856-865 (2008)] investigated ocean variability impact on coherent underwater acoustic communications (8-16 kHz) for a single near-seafloor transmitter in shallow water during an extended period (27 h). This letter extends that investigation to various source depths and receiver subarrays. Specifically, the middle water column source, which is either in or out of the thermocline, experiences performance variability of 6-7 dB in terms of output signal-to-noise ratio. Further, the source below the thermocline consistently outperforms the source above the thermocline when the receiver subarray is located below the thermocline. PMID- 20707423 TI - Vestibular evoked myogenic responses to amplitude modulated sounds. AB - Auditory steady state responses (ASSR) allow objective assessment of hearing thresholds. At high stimulation levels artifactual responses have been reported in subjects with severe to profound deafness. Relatively large amplitude 'steady state' responses to amplitude modulated tones were measured from the Sternocleidomastoid muscle at 500 Hz. Response thresholds were similar to those of vestibular evoked myogenic potentials and scaled with neck muscle tension. 'Steady-state' myogenic responses showed broad tuning to modulation frequency. Reduced amplitude responses were measured at the inion indicating volume conduction from the SCM. While dependant on neck tension, such responses are a potential source of artifacts when recording ASSR. PMID- 20707424 TI - Echolocation clicks of free-ranging Chilean dolphins (Cephalorhynchus eutropia). AB - In this paper, evidence is provided that Chilean dolphins (Cephalorhynchus eutropia) produce ultrasonic echolocation clicks of the narrow-band high frequency category. Echolocation clicks emitted during approaches of the hydrophones consisted only of narrow-band (rms-BW: 12.0 kHz) single pulses with mean centroid frequencies of about 126 kHz, peak frequencies of 126 kHz, and a 20 dB duration of 82.6 micros. The maximum received level measured exceeded 165 dB re 1 microPa. In addition, high repetition-rate buzzes were recorded during foraging behavior (click interval: 2 ms), but no whistles or calls with tonal components were detected. PMID- 20707425 TI - Frequency-dependent and longitudinal changes in noise-induced hearing loss in a bottlenose dolphin (Tursiops truncatus). AB - Temporary threshold shift (TTS) was measured in a bottlenose dolphin (Tursiops truncatus) after exposure to 16-s tones at 3 and 20 kHz to examine the effects of exposure frequency on the onset and growth of TTS. Thresholds were measured approximately one-half octave above the exposure frequency using a behavioral response paradigm featuring an adaptive staircase procedure. Preliminary data provide evidence of frequency-specific differences in TTS onset and growth, and increased susceptibility to auditory fatigue after exposure to 3-kHz tones compared to data obtained two years earlier. PMID- 20707426 TI - Estimating the dynamic effective mass density of random composites. AB - The effective mass density of an inhomogeneous medium is discussed. Random configurations of circular cylindrical scatterers are considered, in various physical contexts: fluid cylinders in another fluid, elastic cylinders in a fluid or in another solid, and movable rigid cylinders in a fluid. In each case, time harmonic waves are scattered, and an expression for the effective wavenumber due to Linton and Martin [J. Acoust. Soc. Am. 117, 3413-3423 (2005)] is used to derive the effective density in the low frequency limit, correct to second order in the area fraction occupied by the scatterers. Expressions are recovered that agree with either the Ament formula or the effective static mass density, depending upon the physical context. PMID- 20707427 TI - Low-frequency sound speed and attenuation in sandy seabottom from long-range broadband acoustic measurements. AB - A joint China-U.S. underwater acoustics experiment was conducted in the Yellow Sea with a very flat bottom and a strong and sharp thermocline. Broadband explosive sources were deployed both above and below the thermocline along two radial lines up to 57.2 km and a quarter circle with a radius of 34 km. Two inversion schemes are used to obtain the seabottom sound speed. One is based on extracting normal mode depth functions from the cross-spectral density matrix. The other is based on the best match between the calculated and measured modal arrival times for different frequencies. The inverted seabottom sound speed is used as a constraint condition to extract the seabottom sound attenuation by three methods. The first method involves measuring the attenuation coefficients of normal modes. In the second method, the seabottom sound attenuation is estimated by minimizing the difference between the theoretical and measured modal amplitude ratios. The third method is based on finding the best match between the measured and modeled transmission losses (TLs). The resultant seabottom attenuation, averaged over three independent methods, can be expressed as alpha=(0.33+/-0.02)f(1.86+/-0.04)(dB/m kHz) over a frequency range of 80-1000 Hz. PMID- 20707428 TI - Proof of principle for inversion of vector sensor array data. AB - Acoustic data collected from a 22 m long horizontal line array with elements comprised of omni-directional hydrophone sensors co-located with acceleration vector sensor triplets are analyzed for seabed geo-acoustic information. Broadband and continuous wave tone data were recorded from the passage of a surface vessel source, the R/V Montague, in an August 2006 experiment conducted in Monterey Bay. The water depth at the array and along the source track was approximately 85 m. Simultaneous inversions for source track and geo-acoustic parameters were performed with 18 tones from the 62-415 Hz tone data for source ranges 0.5-2.0 km. The efficacy of inversions with vector sensor data is demonstrated by the fact that data from vector sensor acceleration components parallel to the array line of bearing produced inversion solutions approximately identical to the solutions obtained from the inversion of data for the same tones from the hydrophone array components. In addition the source spectra derived from these inversions are in nominal agreement with the source spectra obtained from an independent measurement. PMID- 20707429 TI - Cross-correlation function of acoustic fields generated by random high-frequency sources. AB - Long-range correlations of noise fields in arbitrary inhomogeneous, moving or motionless fluids are studied in the ray approximation. Using the stationary phase method, two-point cross-correlation function of noise is shown to approximate the sum of the deterministic Green's functions describing sound propagation in opposite directions between the two points. Explicit relations between amplitudes of respective ray arrivals in the noise cross-correlation function and the Green's functions are obtained and verified against specific problems allowing an exact solution. Earlier results are extended by simultaneously accounting for sound absorption, arbitrary distribution of noise sources in a volume and on surfaces, and fluid inhomogeneity and motion. The information content of the noise cross-correlation function is discussed from the viewpoint of passive acoustic characterization of inhomogeneous flows. PMID- 20707430 TI - Experimental observations of active invariance striations in a tank environment. AB - The waveguide invariant in shallow water environments has been widely studied in the context of passive sonar. The invariant provides a relationship between the frequency content of a moving broadband source and the distance to the receiver, and this relationship is not strongly affected by small perturbations in environment parameters such as sound speed or bottom features. Recent experiments in shallow water suggest that a similar range-frequency structure manifested as striations in the spectrogram exists for active sonar, and this property has the potential to enhance the performance of target tracking algorithms. Nevertheless, field experiments with active sonar have not been conclusive on how the invariant is affected by the scattering kernel of the target and the sonar configuration (monostatic vs bistatic). The experimental work presented in this paper addresses those issues by showing the active invariance for known scatterers under controlled conditions of bathymetry, sound speed profile and high SNR. Quantification of the results is achieved by introducing an automatic image processing approach inspired on the Hough transform for extraction of the invariant from spectrograms. Normal mode simulations are shown to be in agreement with the experimental results. PMID- 20707431 TI - Design and analysis of a recoil-type vibrotactile transducer. AB - This article describes the design of a high-bandwidth, iron-less, recoil-based electromagnetic vibrotactile actuator. Its working principle, the theoretical analysis, the method used to determine its transfer function, its scaling properties and its design constraints are discussed along with its fabrication and possible improvements. PMID- 20707432 TI - A re-expansion method for determining the acoustical impedance and the scattering matrix for the waveguide discontinuity problem. AB - The paper gives a new method for analyzing planar discontinuities in rectangular waveguides. The method consists of a re-expansion of the normal modes in the two ducts at the junction plane into a system of functions accounting for the velocity singularities at the corner points. As the new expansion has an exponential convergence, only a few terms have to be considered for obtaining the solution of most practical problems. To see how the method works some closed form solutions, obtained by the conformal mapping method, are used to discuss the convergence of the re-expanded series when the number of retained terms increases. The equivalent impedance accounting for nonplanar waves into a plane wave analysis is determined. Finally, the paper yields the scattering matrix which describes the coupling of arbitrary modes at each side of the discontinuity valid in the case of many propagating modes in both parts of the duct. PMID- 20707433 TI - An electromechanical low frequency panel sound absorber. AB - The sound absorbing properties of a thin micro-perforated plate (MPP) coated with piezoelectric material with shunt damping technology is investigated. First a theoretical model is presented to predict the sound absorption coefficients of a thin plate attached with a piezoelectric patch and electrical circuits. Then the model is extended to analyze the sound absorption for a thin plate with micro perforations and piezoelectric material. Measurements are also carried out in an impedance tube and found to be in good agreements with the theoretical model. The sound absorption of the constructions can be much improved by tuning the electrical circuits. PMID- 20707434 TI - MP3 player listening habits of 17 to 23 year old university students. AB - This study evaluated the potential risk to hearing associated with the use of portable digital audio players. Twenty-eight university students (12 males, 16 females; aged 17-23) completed a 49-item questionnaire assessing user listening habits and subjective measures of hearing health. Sound level measurements of participants' self-identified typical and 'worst case' volume levels were taken in different classrooms with background sound levels between 43 and 52 dBA. The median frequency and duration of use was 2 h per day, 6.5 days a week. The median sound levels and interquartile ranges (IQR) at typical and 'worst case' volume settings were 71 dBA (IQR=12) and 79 dBA (IQR=9), respectively. When typical sound levels were considered with self-reported duration of daily use, none of the participants surpassed Leq(8) 85 dBA. On the questionnaire, 19 students reported experiencing at least one symptom of possible noise-induced hearing loss. Significant differences in MP3 user listening patterns were found between respondents who had experienced tinnitus and those who had not. The findings add to a growing body of literature that collectively supports a need for further research investigating MP3 player user listening habits in order to assess their potential risk to hearing health. PMID- 20707435 TI - The just noticeable difference of center time and clarity index in large reverberant spaces. AB - Just noticeable difference (JND) values are available for most acoustical parameters currently used in practice. However, they have been determined with reference to conditions typically encountered in concert halls and in rooms for speech, covering a range of reverberation times (T) spanning from 0.5 s to 2 s. When reverberation gets longer, the relationship between measured parameters describing acoustic clarity may change significantly and subjective perception might also be different. The proposed research investigates the influence of reverberation time on JND for clarity measures taking into account three reference cases having T values varying from 2 s to 6 s. Measured B-format impulse responses were properly modified to introduce the desired changes and then auralized with two music motifs for presentation on a 4-channel playback system. Listening tests based on paired comparisons were carried out to determine subjective limens. The results proved to be independent of music motifs and showed that JND in the clarity index is almost independent of T, while JND in the center time is significantly related to T and can be assumed as the 8.5% of the reference T(S) value. PMID- 20707436 TI - Acoustic contributions of a sound absorbing blanket placed in a double panel structure: absorption versus transmission. AB - The objective of this paper is to propose a simple tool to estimate the absorption vs. transmission loss contributions of a multilayered blanket unbounded in a double panel structure and thus guide its optimization. The normal incidence airborne sound transmission loss of the double panel structure, without structure-borne connections, is written in terms of three main contributions; (i) sound transmission loss of the panels, (ii) sound transmission loss of the blanket and (iii) sound absorption due to multiple reflections inside the cavity. The method is applied to four different blankets frequently used in automotive and aeronautic applications: a non-symmetric multilayer made of a screen in sandwich between two porous layers and three symmetric porous layers having different pore geometries. It is shown that the absorption behavior of the blanket controls the acoustic behavior of the treatment at low and medium frequencies and its transmission loss at high frequencies. Acoustic treatment having poor sound absorption behavior can affect the performance of the double panel structure. PMID- 20707437 TI - A phase comparison technique for sound velocity measurement in strongly dissipative liquids under pressure. AB - An accurate technique for the sound velocity measurement in strongly dissipative liquids is elaborated. This technique is based upon high sensitive phase detection. Each medium, at a given temperature and pressure, is characterized by a specific phase shift due to the propagation of the ultrasonic wave within the analyzed medium. By tuning the insonation frequency of the ultrasonic signal, a succession of consecutive nulls of the output dc voltage generated by the phase detector is observed. Thus from the obtained series of frequency values, the sound velocity is computed. Numerous organic liquids, such as alcohols and alkanes, have been used to validate this experimental procedure. As the developed method is well suited for the sound velocity measurement in strongly dissipative liquids, measurements of compressional wave velocity in heavy oil are also carried out over the temperature range 10 degrees C to 50 degrees C. The experimental results agree well with those found in the literature. The accuracy of the developed method is estimated at about +/-0.3%. PMID- 20707438 TI - Fast inverse scattering solutions using the distorted Born iterative method and the multilevel fast multipole algorithm. AB - The distorted Born iterative method (DBIM) computes iterative solutions to nonlinear inverse scattering problems through successive linear approximations. By decomposing the scattered field into a superposition of scattering by an inhomogeneous background and by a material perturbation, large or high-contrast variations in medium properties can be imaged through iterations that are each subject to the distorted Born approximation. However, the need to repeatedly compute forward solutions still imposes a very heavy computational burden. To ameliorate this problem, the multilevel fast multipole algorithm (MLFMA) has been applied as a forward solver within the DBIM. The MLFMA computes forward solutions in linear time for volumetric scatterers. The typically regular distribution and shape of scattering elements in the inverse scattering problem allow the method to take advantage of data redundancy and reduce the computational demands of the normally expensive MLFMA setup. Additional benefits are gained by employing Kaczmarz-like iterations, where partial measurements are used to accelerate convergence. Numerical results demonstrate both the efficiency of the forward solver and the successful application of the inverse method to imaging problems with dimensions in the neighborhood of ten wavelengths. PMID- 20707439 TI - The synthesis of robust broadband beamformers for equally-spaced linear arrays. AB - Broadband beamforming applied to superdirective arrays is known to be highly sensitive to transducers characteristics errors. Recently, an effective method to synthesize a robust, broadband, data-independent, filter-and-sum beamformer, which considers the probability distributions of errors, has been proposed. It considers an array with arbitrary lay-out and provides a spatial directivity pattern close to the desired one. Unfortunately, the evaluation of the cost function requires a computational load and an amount of memory that increases very quickly with the transducers and the filter coefficients. As the synthesis process requires an iterative minimization, it may become unacceptably long. In this paper, an alternative procedure for evaluating the same cost function is presented, drastically reducing such problems and without introducing any approximation. The only additional constraint is on the antenna which must be an equally-spaced linear array. This procedure makes it much easier to apply the above-mentioned synthesis method to a wide panorama of practical situations. PMID- 20707440 TI - Geoacoustic inversion with two source-receiver arrays in shallow water. AB - A geoacoustic inversion scheme based on a double beamforming algorithm in shallow water is proposed and tested. Double beamforming allows identification of multi reverberated eigenrays propagating between two vertical transducer arrays according to their emission and reception angles and arrival times. Analysis of eigenray intensities yields the bottom reflection coefficient as a function of angle of incidence. By fitting the experimental reflection coefficient with a theoretical prediction, values of the acoustic parameters of the waveguide bottom can be extracted. The procedure was initially tested in a small-scale tank experiment for a waveguide with a Plexiglas bottom. Inversion results for the speed of shear waves in Plexiglas are in good agreement with the table values. A similar analysis was applied to data collected during an at-sea experiment in shallow coastal waters of the Mediterranean. Bottom reflection coefficient was fitted with the theory in which bottom sediments are modeled as a multi-layered system. Retrieved bottom parameters are in quantitative agreement with those determined from a prior inversion scheme performed in the same area. The present study confirms the interest in processing source-receiver array data through the double beamforming algorithm, and indicates the potential for application of eigenray intensity analysis to geoacoustic inversion problems. PMID- 20707441 TI - Underwater imaging using a hybrid Kirchhoff migration: direction of arrival method and a sparse surface sensor array. AB - This paper considers the problem of imaging a complex object submerged in shallow waters using a sparse surface sensor array and a hybrid signal processing method. This method is constructed by refining the Kirchhoff migration technique to incorporate a zoning of the sensors and an analysis of multiple reflections, and combining it with the direction of arrival estimation method. Its performance is assessed and analyzed with the shape identification of a mockup submarine by numerical simulation. The obtained numerical results highlight the potential of this approach for identifying underwater intruders. PMID- 20707442 TI - Estimation of modal group velocities with a single receiver for geoacoustic inversion in shallow water. AB - Due to the expense associated with at-sea sensor deployments, a challenge in underwater acoustics has been to develop methods requiring a minimal number of sensors. This paper introduces an adaptive time-frequency signal processing method designed for application to a single source-receiver sensor pair. The method involves the application of conjugate time-frequency warping transforms to improve the SNR and resolution of the time-frequency distribution (TFD) of the measured field. Such refined knowledge of the TFD facilitates efforts to extract tomographic information about the propagation medium. Here the method is applied to the case of modal propagation in a shallow ocean range independent environment to extract a refined TFD. Given knowledge of the source-receiver separation, the refined TFD is used to extract the frequency dependent group velocities of the individual modal components. The extracted group velocities are then incorporated into a computationally light tomographic inversion method. Simulated and experimental results are discussed. PMID- 20707443 TI - Locating arbitrarily time-dependent sound sources in three dimensional space in real time. AB - This paper presents a method for locating arbitrarily time-dependent acoustic sources in a free field in real time by using only four microphones. This method is capable of handling a wide variety of acoustic signals, including broadband, narrowband, impulsive, and continuous sound over the entire audible frequency range, produced by multiple sources in three dimensional (3D) space. Locations of acoustic sources are indicated by the Cartesian coordinates. The underlying principle of this method is a hybrid approach that consists of modeling of acoustic radiation from a point source in a free field, triangulation, and de noising to enhance the signal to noise ratio (SNR). Numerical simulations are conducted to study the impacts of SNR, microphone spacing, source distance and frequency on spatial resolution and accuracy of source localizations. Based on these results, a simple device that consists of four microphones mounted on three mutually orthogonal axes at an optimal distance, a four-channel signal conditioner, and a camera is fabricated. Experiments are conducted in different environments to assess its effectiveness in locating sources that produce arbitrarily time-dependent acoustic signals, regardless whether a sound source is stationary or moves in space, even toward behind measurement microphones. Practical limitations on this method are discussed. PMID- 20707444 TI - Effort variation regularization in sound field reproduction. AB - In this paper, active control is used in order to reproduce a given sound field in an extended spatial region. A method is proposed which minimizes the reproduction error at a number of control positions with the reproduction sources holding a certain relation within their complex strengths. Specifically, it is suggested that the phase differential of the source driving signals should be in agreement with the phase differential of the desired sound pressure field. The performance of the suggested method is compared with that of conventional effort regularization, wave field synthesis (WFS), and adaptive wave field synthesis (AWFS), both under free-field conditions and in reverberant rooms. It is shown that effort variation regularization overcomes the problems associated with small spaces and with a low ratio of direct to reverberant energy, improving thus the reproduction accuracy in the listening room. PMID- 20707445 TI - Hearing one's own voice during phoneme vocalization--transmission by air and bone conduction. AB - The relationship between the bone conduction (BC) part and the air conduction (AC) part of one's own voice has previously not been well determined. This relation is important for hearing impaired subjects as a hearing aid affects these two parts differently and thereby changes the perception of one's own voice. A large ear-muff that minimized the occlusion effect while still attenuating AC sound was designed. During vocalization and wearing the ear muff the ear-canal sound pressure could be related to the BC component of a person's own voice while the AC component was derived from the sound pressure at the entrance of an open ear-canal. The BC relative to AC sensitivity of one's own voice was defined as the ratio between these two components related to the ear canal sound pressure at hearing thresholds for BC and AC stimulation. The results of ten phonemes showed that the BC part of one's own voice dominated at frequencies between 1 and 2 kHz for most of the phonemes. The different phonemes gave slightly different results caused by differences during vocalization. However, similarities were seen for phonemes with comparable vocalization. PMID- 20707446 TI - Subjective quantification of earplug occlusion effect using external acoustical excitation of the mouth cavity. AB - Occlusion of the ear canal by hearing aids or hearing protectors often results in an occlusion effect, which creates a discomfort to wearers in that it changes their perception of their own voice. As no account was found in the literature on the quantification of this subjective voice occlusion effect, an experimental method is proposed based on the use of an artificial sound source emitting within the subject's mouth to replace his own voice. A block diagram is constructed to identify the different internal sound path components involved in the perception of one's own voice and is used to show that the subjective voice occlusion effect is the weighted energy summation of two components. The first component, the voice air and body conduction occlusion effect for which data is obtained from the experiments reported in the present paper, constitute the lower limit of the subjective voice occlusion effect. The second component, the voice body conduction occlusion effect for which data is available in the literature, constitutes the upper limit. From these limits, order of magnitudes for subjective voice occlusion effect intervals are estimated to be [+5+20] dB below 2000 Hz and [-10+5] dB above 2000 Hz. PMID- 20707447 TI - On- and off-frequency compression estimated using a new version of the additivity of forward masking technique. AB - On- and off-frequency compression at the 4000- and 8000-Hz cochlear places were estimated using a new version of the additivity of forward masking (AFM) technique, that measures the effects of combining two non-overlapping forward maskers. Instead of measuring signal thresholds to estimate compression of the signal as in the original AFM technique, the decrease in masker threshold in the combined-masker condition compared to the individual-masker conditions is used to estimate compression of the masker at the signal place. By varying masker frequency it is possible to estimate off-frequency compression. The maskers were 500-Hz-wide bands of noise, and the signal was a brief pure tone. Compression at different levels was estimated using different overall signal levels, or different masker-signal intervals. It was shown that the new AFM technique and the original AFM technique produce consistent results. Considerable compression was observed for maskers well below the signal frequency, suggesting that the assumption of off-frequency linearity used in other techniques may not be valid. Reducing the duration of the first masker from 200 to 20 ms reduced the compression exponent in some cases, suggesting a possible influence of olivocochlear efferent activity. PMID- 20707449 TI - Auditory frequency focusing is very rapid. AB - The present experiments examine the effect of a weak 40-ms tone burst (cue) on the detection of a closely following 40-ms signal at the same frequency. Detection becomes more difficult as the temporal separation (onset to onset) between them shortens from around 300 ms to under 52 ms. The threshold increase or proximal interference is similar whether signal frequency is constant from trial to trial--frequency certainty--or changing--frequency uncertainty. The increase is also similar whether the cue goes to the same ear as the signal or to the opposite ear. This contralateral interference by such weak cues, only 4 dB SL against a continuous broadband noise, appears to exclude a role for forward masking by the cues. When the preceding tone burst differs in frequency from the signal, threshold increases little at any temporal separation. Combined with earlier results on frequency uncertainty (Scharf, B., et al., 2007, J. Acoust. Soc. Am. 121, 2149-2157), the present results show that a listener can shift focusing to an unexpected signal frequency in less than 52 ms. However, the rapidity of focusing is usually obscured by proximal interference, which possibly occurs whenever cue and signal share the same period (approximately 200 ms) of temporal integration. PMID- 20707448 TI - The auditory brainstem response in two lizard species. AB - Although lizards have highly sensitive ears, it is difficult to condition them to sound, making standard psychophysical assays of hearing sensitivity impractical. This paper describes non-invasive measurements of the auditory brainstem response (ABR) in both Tokay geckos (Gekko gecko; nocturnal animals, known for their loud vocalizations) and the green anole (Anolis carolinensis, diurnal, non-vocal animals). Hearing sensitivity was measured in 5 geckos and 7 anoles. The lizards were sedated with isoflurane, and ABRs were measured at levels of 1 and 3% isoflurane. The typical ABR waveform in response to click stimulation showed one prominent and several smaller peaks occurring within 10 ms of the stimulus onset. ABRs to brief tone bursts revealed that geckos and anoles were most sensitive between 1.6-2 kHz and had similar hearing sensitivity up to about 5 kHz (thresholds typically 20-50 dB SPL). Above 5 kHz, however, anoles were more than 20 dB more sensitive than geckos and showed a wider range of sensitivity (1-7 kHz). Generally, thresholds from ABR audiograms were comparable to those of small birds. Best hearing sensitivity, however, extended over a larger frequency range in lizards than in most bird species. PMID- 20707450 TI - The perceptual organization of sine-wave speech under competitive conditions. AB - Speech comprises dynamic and heterogeneous acoustic elements, yet it is heard as a single perceptual stream even when accompanied by other sounds. The relative contributions of grouping "primitives" and of speech-specific grouping factors to the perceptual coherence of speech are unclear, and the acoustical correlates of the latter remain unspecified. The parametric manipulations possible with simplified speech signals, such as sine-wave analogues, make them attractive stimuli to explore these issues. Given that the factors governing perceptual organization are generally revealed only where competition operates, the second formant competitor (F2C) paradigm was used, in which the listener must resist competition to optimize recognition [Remez, R. E., et al. (1994). Psychol. Rev. 101, 129-156]. Three-formant (F1+F2+F3) sine-wave analogues were derived from natural sentences and presented dichotically (one ear=F1+F2C+F3; opposite ear=F2). Different versions of F2C were derived from F2 using separate manipulations of its amplitude and frequency contours. F2Cs with time-varying frequency contours were highly effective competitors, regardless of their amplitude characteristics. In contrast, F2Cs with constant frequency contours were completely ineffective. Competitor efficacy was not due to energetic masking of F3 by F2C. These findings indicate that modulation of the frequency, but not the amplitude, contour is critical for across-formant grouping. PMID- 20707451 TI - A computational study of the effect of vocal-fold asymmetry on phonation. AB - Unilateral laryngeal paralysis leads to tension imbalance and hence to asynchronous movements between the two vocal folds during phonation. In the current study, a computational model of phonation that couples a two-mass model of the vocal folds with a Navier-Stokes model of the glottal airflow, has been used to examine the dynamics of vocal fold configurations with tension imbalance and its implications for phonation. The simulations show that tension imbalance influences phonation onset, intensity as well as the fundamental phonation frequency. Distinct non-linear effects such as period-doubling bifurcation and preferential frequency selection are also observed. PMID- 20707452 TI - Intraglottal pressures in a three-dimensional model with a non-rectangular glottal shape. AB - This study used a symmetric, three-dimensional, physical model of the larynx called M6 in which the transverse plane of the glottis is formed by sinusoidal arcs for each medial vocal fold surface, creating a maximum glottal width of 0.16 cm at the location of the minimal glottal area. Three glottal angles were studied: convergent 10 degrees, uniform (0 degrees), and divergent 10 degrees. Fourteen pressure taps were incorporated in the upstream-downstream direction on the vocal fold surface at three coronal locations, at the one-fourth, one-half, and three-fourths distances in the anterior-posterior direction of the glottis. The computational software FLUENT was used to compare and augment the data for these cases. Near the glottal entrance, the pressures were similar across the three locations for the uniform case; however, for the convergent case the middle pressure distribution was lower by 4% of the transglottal pressure, and lower by about 2% for the divergent case. Also, there were significant secondary velocities toward the center from both the anterior commissure and vocal process regions (of as much as approximately 10% of the axial velocities). Thus, the three dimensionality created relatively small pressure gradients and significant secondary velocities anteriorly-posteriorly within the glottis. PMID- 20707453 TI - Between-speaker and within-speaker variation in speech tempo of American English. AB - This study characterizes the speech tempo (articulation rate, excluding pauses) of two distinct varieties of American English taking into account both between speaker and within-speaker variation. Each of 192 speakers from Wisconsin (the northern variety) and from North Carolina (the southern variety), men and women, ranging in age from children to old adults, read a set of sentences and produced a spontaneous unconstrained talk. Articulation rate in spontaneous speech was modeled using fixed-mixed effects analyses. The models explored the effects of the between-speaker factors dialect, age and gender and included each phrase and its length as a source of both between- and within-speaker variation. The major findings are: (1) Wisconsin speakers speak significantly faster and produce shorter phrases than North Carolina speakers; (2) speech tempo changes across the lifespan, being fastest for individuals in their 40s; (3) men speak faster than women and this effect is not related to the length of phrases they produce. Articulation rate in reading was slower than in speaking and the effects of gender and age also differed in reading and spontaneous speech. The effects of dialect in reading remained the same, showing again that Wisconsin speakers had faster articulation rates than did North Carolina speakers. PMID- 20707454 TI - The effects of prosodic prominence and serial position on duration perception. AB - This study addresses how prosodic expectations affect perceptual discrimination. Prosodic expectations were created using natural recordings of six-syllable sentences in dactylic, iambic, and trochaic metrical patterns at two speech rates, slow and quick. PSOLA resynthesis was used to lengthen target syllables located in three different serial positions in each of the three patterns. Subjects made forced-choice comparisons of durational structure in an AX task. Lengthening was detected significantly better for strong syllables than for weak ones in all metrical patterns, serial positions, and at speech rates. The result obtains even when absolute duration is eliminated as a potential confound. Results are interpreted in the light of prior research showing that prosodically strong syllables offer perceptual advantages in recognition and identification tasks, even when prosodic strength is cued only by the prior context (and not by any acoustic phonetic properties of the target syllables). In conclusion, metrical expectations cause listeners to focus their attention on metrically prominent syllables, with attentional focus leading to better performance in tasks tapping multiple levels of processing. PMID- 20707455 TI - Speech-on-speech masking with variable access to the linguistic content of the masker speech. AB - It has been reported that listeners can benefit from a release in masking when the masker speech is spoken in a language that differs from the target speech compared to when the target and masker speech are spoken in the same language [Freyman, R. L. et al. (1999). J. Acoust. Soc. Am. 106, 3578-3588; Van Engen, K., and Bradlow, A. (2007), J. Acoust. Soc. Am. 121, 519-526]. It is unclear whether listeners benefit from this release in masking due to the lack of linguistic interference of the masker speech, from acoustic and phonetic differences between the target and masker languages, or a combination of these differences. In the following series of experiments, listeners' sentence recognition was evaluated using speech and noise maskers that varied in the amount of linguistic content, including native-English, Mandarin-accented English, and Mandarin speech. Results from three experiments indicated that the majority of differences observed between the linguistic maskers could be explained by spectral differences between the masker conditions. However, when the recognition task increased in difficulty, i.e., at a more challenging signal-to-noise ratio, a greater decrease in performance was observed for the maskers with more linguistically relevant information than what could be explained by spectral differences alone. PMID- 20707456 TI - Simulations of cochlear-implant speech perception in modulated and unmodulated noise. AB - Experiment 1 replicated the finding that normal-hearing listeners identify speech better in modulated than in unmodulated noise. This modulated-unmodulated difference ("MUD") has been previously shown to be reduced or absent for cochlear implant listeners and for normal-hearing listeners presented with noise-vocoded speech. Experiments 2-3 presented normal-hearing listeners with noise-vocoded speech in unmodulated or 16-Hz-square-wave modulated noise, and investigated whether the introduction of simple binaural differences between target and masker could restore the masking release. Stimuli were presented over headphones. When the target and masker were presented to one ear, adding a copy of the masker to the other ear ("diotic configuration") aided performance but did so to a similar degree for modulated and unmodulated maskers, thereby failing to improve the modulation masking release. Presenting an uncorrelated noise to the opposite ear ("dichotic configuration") had no effect, either for modulated or unmodulated maskers, consistent with the improved performance in the diotic configuration being due to interaural decorrelation processing. For noise-vocoded speech, the provision of simple spatial differences did not allow listeners to take greater advantage of the dips present in a modulated masker. PMID- 20707457 TI - Interrupted speech perception: the effects of hearing sensitivity and frequency resolution. AB - Jin & Nelson (2006) found that although amplified speech recognition performance of hearing-impaired (HI) listeners was equal to that of normal-hearing (NH) listeners in quiet and in steady noise, nevertheless HI listeners' performance was significantly poorer in modulated noise. As a follow-up, the current study investigated whether three factors, auditory integration, low-mid frequency audibility and auditory filter bandwidths, might contribute to reduced sentence recognition of HI listeners in the presence of modulated interference. Three findings emerged. First, sentence recognition in modulated noise found in Jin & Nelson (2006) was highly correlated with perception of sentences interrupted by silent gaps. This suggests that understanding speech interrupted by either noise or silent gaps require similar perceptual integration of speech fragments available either in the dips of a gated noise or across silent gaps of an interrupted speech signal. Second, those listeners with greatest hearing losses in the low frequencies were poorest at understanding interrupted sentences. Third, low-to mid-frequency hearing thresholds accounted for most of the variability in Masking Release (MR) for HI listeners. As suggested by Oxenham and his colleagues (2003 and 2009), low-frequency information within speech plays an important role in the perceptual segregation of speech from competing background noise. PMID- 20707458 TI - Absolute pitch correlates with high performance on musical dictation. AB - Absolute pitch (AP)--the ability to name a musical note in the absence of a reference note--is a rare ability whose relevance to musical proficiency has so far been unclear. Sixty trained musicians--thirty who self-reported AP and thirty with equivalent age of onset and duration of musical training--were administered a test for AP and also a musical dictation test not requiring AP. Performance on both types of test were highly correlated (r=.81, p<.001). When subjects were divided into three groups based on their performance on the AP test, highly significant differences between the groups emerged. Those who clearly possessed AP showed remarkably high performance on the musical dictation test, the scores of those without AP varied widely, and the performance of the intermediate group of borderline AP possessors fell between that of clear AP possessors and clear nonpossessors. The findings support the hypothesis that AP is associated with proficiency in performing other musical tasks, and run counter to the claim that it confers a disadvantage in the processing of relative pitch. PMID- 20707459 TI - The measurement of ultrasound scattering from individual micron-sized objects and its application in single cell scattering. AB - The measurement of the ultrasound backscatter from individual micron-sized objects such as cells is required for various applications such as tissue characterization. However, performing such a measurement remains a challenge. For example, the presence of air bubbles in a suspension of cells during the measurements may lead to the incorrect interpretation of the acoustic signals. This work introduces a technique for measuring the ultrasound backscatter from individual micron-sized objects by combining a microinjection system with a co registered optical microscope and an ultrasound imaging device. This allowed the measurement of the ultrasound backscatter response from a single object under optical microscope guidance. The optical and ultrasonic data were used to determine the size of the object and to deduce its backscatter responses, respectively. In order to calibrate the system, the backscatter frequency responses from polystyrene microspheres were measured and compared to theoretical predictions. A very good agreement was found between the measured backscatter responses of individual microspheres and theoretical predictions of an elastic sphere. The backscatter responses from single OCI-AML-5 cells were also investigated. It was found that the backscatter responses from AML cells are best modeled using the fluid sphere model. The advantages, limitations, and future applications of the developed technique are discussed. PMID- 20707460 TI - Ultrasonic backscatter coefficients for weakly scattering, agar spheres in agar phantoms. AB - Applicability of ultrasound phantoms to biological tissue has been limited because most phantoms have generally used strong scatterers. The objective was to develop very weakly scattering phantoms, whose acoustic scattering properties are likely closer to those of tissues and then compare theoretical simulations and experimental backscatter coefficient (BSC) results. The phantoms consisted of agar spheres of various diameters (nominally between 90 and 212 microm), containing ultrafiltered milk, suspended in an agar background. BSC estimates were performed at two institutions over the frequency range 1-13 MHz, and compared to three models. Excellent agreement was shown between the two laboratory results as well as with the three models. PMID- 20707461 TI - Analytical model of internally coupled ears. AB - Lizards and many birds possess a specialized hearing mechanism: internally coupled ears where the tympanic membranes connect through a large mouth cavity so that the vibrations of the tympanic membranes influence each other. This coupling enhances the phase differences and creates amplitude differences in the tympanic membrane vibrations. Both cues show strong directionality. The work presented herein sets out the derivation of a three dimensional analytical model of internally coupled ears that allows for calculation of a complete vibration profile of the membranes. The analytical model additionally provides the opportunity to incorporate the effect of the asymmetrically attached columella, which leads to the activation of higher membrane vibration modes. Incorporating this effect, the analytical model can explain measurements taken from the tympanic membrane of a living lizard, for example, data demonstrating an asymmetrical spatial pattern of membrane vibration. As the analytical calculations show, the internally coupled ears increase the directional response, appearing in large directional internal amplitude differences (iAD) and in large internal time differences (iTD). Numerical simulations of the eigenfunctions in an exemplary, realistically reconstructed mouth cavity further estimate the effects of its complex geometry. PMID- 20707462 TI - Communication calls of little brown bats display individual-specific characteristics. AB - Bats' echolocation signals have been shown to be situation-, colony-, and individual-specific, but whether or not these findings apply to bats' communication signals is not fully understood. The primary goal of this study was to test the hypothesis that the communication calls of adult little brown bats (Myotis lucifugus) are individual specific. Bats were paired to form focal pairs from June 2007 to August 2008. Each bat's vocalizations were recorded on a PC based digital recorder with a custom made ultrasonic microphone. The vocal signals were first classified using a previously established classification scheme. Three acoustic parameters (the minimum and maximum frequencies, and the call duration) of two of the dominant call-types, the steep-FM and broadband noise bursts, of individual bats were further analyzed. Discriminant function analysis, and multi- and univariate analyses of variance of these parameters revealed that these vocal signals were individually distinct and likely contain individual signatures to allow bats to identify individuals acoustically. PMID- 20707463 TI - Geographic variations in the whistles of bottlenose dolphins (Tursiops aduncus) along the east and west coasts of Australia. AB - Macrogeographic variations in the structure and repertoire of whistles from four geographically separated bottlenose dolphin (Tursiops aduncus) populations from the east and west coasts of Australia were investigated. Microgeographic variations were examined from two adjacent social groups from the same east coast population. Whistles were divided into five different tonal classes; sine, rise, down-sweep, flat and concave. The acoustic parameters of whistles; start, end, low, high and carrier frequencies and the number of inflection points and harmonics were measured and compared. These features were used to identify and define distinct whistle types. Differences in acoustic parameters of whistles between populations varied with the tonal class and the acoustic parameter being tested and were likely to be driven by localized environmental conditions. There were few differences in the acoustic parameters of whistles between social groups which was likely a result of vocal learning and mimicry from intermixing of individuals. There were small percentages of distinct whistle types that were shared between the both intermixing social groups and geographically separated populations, however, the majority of the whistle repertoires were unique. The development of the unique whistle repertoires may be primarily driven by the complex social organization of the bottlenose dolphin. PMID- 20707519 TI - Communication: The influence of line tension on the formation of liquid bridges. AB - The formation of liquid bridges between planar and conical substrates is analyzed macroscopically taking into account the line tension. Depending on the value of the line tension coefficient tau and geometric parameters of the system one observes two different scenarios of liquid bridge formation upon changing the fluid state along the bulk liquid-vapor coexistence. For tau > tau* (tau* < 0) there is a first-order transition to a state with infinitely thick liquid bridge. For tau < tau* the scenario consists of two steps: First there is a first-order transition to a state with liquid bridge of finite thickness, which upon further increase of temperature is followed by continuous growth of the thickness of the bridge to infinity. In addition to constructing the relevant phase diagram we examine the dependence of the width of the bridge on thermodynamic and geometric parameters of the system. PMID- 20707520 TI - A semiclassical correction for quantum mechanical energy levels. AB - We propose a semiclassical method for correcting molecular energy levels obtained from a quantum mechanical variational calculation. A variational calculation gives the energy level (i.e., eigenvalue) as the expectation value of the molecular Hamiltonian , where /phi> is the trial wave function. The true (i.e., exact) eigenvalue E can thus be expressed as this variational result plus a correction, i.e., E=+DeltaE, the correction being due to the lack of exactness of the trial wave function. A formally exact expression for DeltaE is usually given (via Lowdin partitioning methodology) in terms of the Greens function of the Hamiltonian projected onto the orthogonal complement of /phi>. Formal treatment of this expression (using Brillouin-Wigner perturbation theory to infinite order) leads to an expression for DeltaE that involves matrix elements of the Greens function for the unprojected, i.e., full molecular Hamiltonian, which can then be approximated semiclassically. (Specifically, the Greens function is expressed as the Fourier transform of the quantum mechanical time evolution operator, e(-iHt/variant Planck's over 2pi), which in turn is approximated by using an initial value representation of semiclassical theory.) Calculations for several test problems (a one dimensional quartic potential, and vibrational energy levels of H(2)O and H(2)CO) clearly support our proposition that the error in the total eigenvalue E arises solely due to the semiclassical error in approximating DeltaE, which is usually a small fraction of the total energy E itself. PMID- 20707464 TI - Effects of filtering of harmonics from biosonar echoes on delay acuity by big brown bats (Eptesicus fuscus). AB - Big brown bats emit FM biosonar sounds containing two principal harmonics (FM1 approximately 55-22 kHz;FM2 approximately 105-45 kHz). To examine the role of harmonics, they were selectively filtered from stimuli in electronic-echo delay discrimination experiments. Positive stimuli were delayed by 3.16 ms (55 cm simulated target range); negative stimuli were by delayed by 3.96 ms (68 cm). This large 800-micros delay difference (nearly 14 cm) was easily discriminated for echoes containing equal-strength FM1 and FM2. Performance gradually decreased as highpass filters removed progressively larger segments from FM1. For echoes with FM2 alone, performance collapsed to chance, but performance remained good for lowpass echoes containing FM1 alone. Attenuation of FM2 by 3 dB relative to FM1 also decreased performance, but shortening electronic delay of the attenuated FM2 by 48 micros counteracted amplitude-latency trading and restored performance. Bats require the auditory representations of FM1 and FM2 to be in temporal register for high delay acuity. Misalignment of neuronal responses degrades acuity, but outright removal of FM2, leaving only FM1, causes little loss of acuity. Functional asymmetry of harmonics reflects lowpass effects from beaming and atmospheric propagation, which leave FM1 intact. It may cooperate with latency shifts to aid in suppression of clutter. PMID- 20707521 TI - Unidirectional hopping transport of interacting particles on a finite chain. AB - Particle transport through an open, discrete one-dimensional channel against a mechanical or chemical bias is analyzed within a master equation approach. The channel, externally driven by time-dependent site energies, allows multiple occupation due to the coupling to reservoirs. Performance criteria and optimization of active transport in a two-site channel are discussed as a function of reservoir chemical potentials, the load potential, interparticle interaction strength, driving mode, and driving period. Our results, derived from exact rate equations, are used in addition to test a previously developed time dependent density functional theory, suggesting a wider applicability of that method in investigations of many particle systems far from equilibrium. PMID- 20707522 TI - Theoretical studies of surface enhanced hyper-Raman spectroscopy: the chemical enhancement mechanism. AB - Hyper-Raman spectra for pyridine and pyridine on the surface of a tetrahedral 20 silver atom cluster are calculated using static hyperpolarizability derivatives obtained from time dependent density functional theory. The stability of the results with respect to choice of exchange-correlation functional and basis set is verified by comparison with experiment and with Raman spectra calculated for the same systems using the same methods. Calculated Raman spectra were found to match well with experiment and previous theoretical calculations. The calculated normal and surface enhanced hyper-Raman spectra closely match experimental results. The chemical enhancement factors for hyper-Raman are generally larger than for Raman (10(2)-10(4) versus 10(1)-10(2)). Integrated hyper-Raman chemical enhancement factors are presented for a set of substituted pyridines. A two-state model is developed to predict these chemical enhancement factors and this was found to work well for the majority of the molecules considered, providing a rationalization for the difference between hyper-Raman and Raman enhancement factors. PMID- 20707523 TI - Link atom bond length effect in ONIOM excited state calculations. AB - We investigate how the choice of the link atom bond length affects an electronic transition energy calculation with the so-called our own N-layer integrated molecular orbital molecular mechanics (ONIOM) hybrid method. This follows our previous paper [M. Caricato et al., J. Chem. Phys. 131, 134105 (2009)], where we showed that ONIOM is able to accurately approximate electronic transition energies computed at a high level of theory such as the equation of motion coupled cluster singles and doubles (EOM-CCSD) method. In this study we show that the same guidelines used in ONIOM ground state calculations can also be followed in excited state calculations, and that the link atom bond length has little effect on the ONIOM energy when a sensible model system is chosen. We also suggest further guidelines for excited state calculations which can help in checking the effectiveness of the definition of the model system and controlling the noise in the calculation. PMID- 20707524 TI - Steady-state current transfer and scattering theory. AB - The correspondence between the steady-state theory of current transfer and scattering theory in a system of coupled tight-binding models of one-dimensional wires is explored. For weak interwire coupling both calculations give nearly identical results, except at singular points associated with band edges. The effect of decoherence in each of these models is studied using a generalization of the Liouville-von Neuman equation suitable for steady-state situations. An example of a single impurity model is studied in detail, leading to a lattice model of scattering off target that affects both potential scattering and decoherence. For an impurity level lying inside the energy band, the transmission coefficient diminishes with increasing dephasing rate, while the opposite holds for impurity energy outside the band. The efficiency of current transfer in the coupled wire system decreases with increasing dephasing. PMID- 20707525 TI - Optimal design strategies for electrostatic energy storage in quantum multiwell heterostructures. AB - We study physical principles of optimal design of a nanoscale multiwell heterostructure functioning as an electrostatic energy storage device. We performed numerical optimization of the multiwell trapping potential for electrons in the nanostructure with the goal to obtain the maximum possible static polarizability of the system. The response of the heterostructure is modeled microscopically using nonlocal linear response theory within the random phase approximation. Three main design strategies are identified which lead to the maximization of the stored energy. We found that the efficiency of each strategy crucially depends on the temperature and the broadening of electron levels. The stored energy for optimized heterostructures can exceed the nonoptimized ones by a factor of 450. These findings provide a theoretical basis for the development of new nanoscale capacitors with high energy density storage capabilities. PMID- 20707526 TI - About the collapse of the 3.3 microm CH stretching band with ionization in polycyclic aromatic hydrocarbons: configuration interaction and quantum Monte Carlo studies of the CH fragment. AB - The puzzling difference between the IR spectra of polycyclic aromatic hydrocarbons (PAHs) and those of the corresponding positive ions (PAHs(+)) is a well documented fact, although the basic reason for it is far from clear. In this report, the CH fragment, in its neutral and ionized forms is taken as a case study for investigating the collapse of the CH stretching vibration with ionization. A comprehensive study of the dipole moment function around the equilibrium geometries of the fragments using large scale configuration interaction and quantum Monte Carlo methods shows very different variations with the CH distance: a marked decrease for neutral CH((2)Pi) and a perfect stability for ionized CH(+)((1)Sigma(+)). These results are consistent with strong/weak intensities of the CH vibrations in the neutral/ionized PAHs, the key point being the presence, or not, of a hole in the pi shell. A topological analysis of the electronic densities shows that the collapse of the CH stretching with ionization is directly linked to the compensation between the internal charge transfer contribution and the distortion of the electronic density within the CH bond. PMID- 20707527 TI - State-to-state quantum dynamics of the O(3P)+OH(2Pi)-->H(2S)+O2(3Sigma(g)-) reaction. AB - The authors report a detailed quantum mechanical study of the state-to-state dynamics of the O+OH(v(i)=0, j(i)=0)-->H+O(2)(v(f),j(f)) reaction on an accurate HO(2)(X(2)A") potential energy surface. The scattering dynamics was treated using a reactant coordinate based Chebyshev real wavepacket method with full Coriolis coupling. A total of 84 partial waves were calculated in order to achieve convergence up to the collision energy of 0.17 eV. The differential cross section is near forward-backward symmetric, consistent with the complex-forming mechanism. The O(2) product was found to have a monotonically decaying vibrational distribution and highly excited and inverted rotational distributions, also consistent with the formation of the HO(2) intermediate. These quantum mechanical results were compared with those obtained in earlier quasiclassical trajectory and statistical studies and it is shown that the statistical theory gives a reasonably good description of the product state distributions despite its inability to predict the total reaction cross section. PMID- 20707528 TI - Toward a realistic density functional theory potential energy surface for the H5+ cluster. AB - The potential energy surface of H(5)(+) is characterized using density functional theory. The hypersurface is evaluated at selected configurations employing different functionals, and compared with results obtained from ab initio CCSD(T) calculations. The lowest ten stationary points (minima and saddle-points) on the surface are located, and the features of the short-, intermediate-, and long range intermolecular interactions are also investigated. A detailed analysis of the surface's topology, and comparisons with extensive CCSD(T) results, as well as a recent ab initio analytical surface, shows that density functional theory calculations using the B3(H) functional represent very well all aspects studied on the H(5)(+) potential. These include the tiny energy difference between the minimum at 1-C(2v) configuration and the 2-D(2d) one corresponding to the transition state for the proton transfer between the two equivalent C(2v) minima, and also the correct asymptotic behavior of the long-range interactions. The calculated binding energy and dissociation enthalpies compare very well with previous benchmark coupled-cluster ab initio data, and with experimental data available. Based on these results the use of such approach to perform first principles molecular dynamics simulations could provide reliable information regarding the dynamics of protonated hydrogen clusters. PMID- 20707529 TI - A-band methyl halide dissociation via electronic curve crossing as studied by electron energy loss spectroscopy. AB - Excitation of the A-band low-lying electronic states in the methyl halides, CH(3)I, CH(3)Br, CH(3)Cl, and CH(3)F, has been investigated for the (n-->sigma*) transitions, using electron energy loss spectroscopy (EELS) in the range of 3.5 7.5 eV. For the methyl halides, CH(3)I, CH(3)Br, and CH(3)Cl, three components of the Q complex ((3)Q(1), (3)Q(0), and (1)Q(1)) were directly observed, with the exception of methyl fluoride, in the optically forbidden EELS experimental conditions of this investigation. The effect of electronic-state curve crossing emerged in the transition probabilities for the (3)Q(0) and (1)Q(1) states, with spin-orbit splitting observed and quantified against results from recent ab initio studies. PMID- 20707530 TI - H2 production from reactions between water and small molybdenum suboxide cluster anions. AB - Reactions between molybdenum suboxide cluster anions, Mo(x)O(y)(-) (x=1-4; y < or = 3x), and water (H(2)O and D(2)O) have been studied using mass spectrometric analysis of products formed in a high-pressure, fast-flow reactor. Product distributions vary with the number of metal atoms in the cluster. Within the MoO(y)(-) oxide series, product masses correspond to the addition of one water molecule, as well as a H/D exchange with MoO(4)H(-). Within the Mo(2)O(y)(-) oxide series, product evolution and distribution suggest sequential oxidation via Mo(2)O(y)(-)+H(2)O/D(2)O-->Mo(2)O(y+1)(-)+H(2)/D(2) reactions for y<5, while for Mo(2)O(5)(-), Mo(2)O(6)H(2)/D(2)(-) is produced. Mo(2)O(6)(-) does not appear to be reactive toward water. For the Mo(3)O(y)(-) oxide series, sequential oxidation similarly is suggested for y<5, while Mo(3)O(5)(-) reactions result in Mo(3)O(6)H(2)/D(2)(-) formation. Mo(3)O(6)(-) appears uniquely unreactive. Mo(3)O(7)(-) and Mo(3)O(8)(-) react to form Mo(3)O(8)H(2)/D(2)(-) and Mo(3)O(9)H(2)/D(2)(-), respectively. Lower mass resolution in the Mo(4)O(y)(-) mass range prevents unambiguous mass analysis, but intensity changes in the mass spectra do suggest that sequential oxidation with H(2)/D(2) evolution occurs for y<6, while Mo(4)O(y+1)H(2)/D(2)(-) addition products are formed in Mo(4)O(6)(-) and Mo(4)O(7)(-) reactions with water. The relative rate constants for sequential oxidation and H(2)O/D(2)O addition for the x=2 series were determined. There is no evidence of a kinetic isotope effect when comparing reaction rates of H(2)O with D(2)O, suggesting that the H(2) and D(2) losses from the lower oxide/hydroxide intermediates are very fast relative to initial reaction complex formation with H(2)O or D(2)O. The rate constants determined here are two times higher than those determined in identical reactions between W(2)O(y)( )+H(2)O/D(2)O. PMID- 20707531 TI - A perfectly matched layer applied to a reactive scattering problem. AB - The perfectly matched layer (PML) technique is applied to a reactive scattering problem for accurate domain truncation. A two-dimensional model for dissociative adsorbtion and associative desorption of H(2) from a flat surface is considered, using a finite difference spatial discretization and the Arnoldi method for time propagation. We compare the performance of the PML to that of a monomial complex absorbing potential, a transmission-free complex absorbing potential, and to exterior complex scaling. In particular, the reflection properties due to the numerical treatment are investigated. We conclude that the PML is accurate and efficient, especially if high accuracy is of significance. Moreover, we demonstrate that the errors from the PML can be controlled at a desired accuracy, enabling efficient numerical simulations. PMID- 20707532 TI - Dynamics of highly excited barium atoms deposited on large argon clusters. I. General trends. AB - Ba(Ar)(approximately 750) clusters were generated by associating the supersonic expansion and the pick-up techniques. A femtosecond pump (266.3 nm)-probe (792 or 399.2 nm) experiment was performed to document the dynamics of electronically excited barium within the very multidimensional environment of the argon cluster. Barium was excited in the vicinity of the 6s9p (1)P state and probed by ionization. The velocity imaging technique was used to monitor the energy distribution of photoelectrons and photoions as a function of the delay time between the pump and the probe pulses. A complex dynamics was revealed, which can be interpreted as a sequence/superposition of elementary processes, one of which is the ejection of barium out of the cluster. The latter has an efficiency, which starts increasing 5 ps after the pump pulse, the largest ejection probability being at 10 ps. The ejection process lasts at a very long time, up to 60 ps. A competing process is the partial solvation of barium in low lying electronic states. Both processes are preceded by a complex electronic relaxation, which is not fully unraveled here, the present paper being the first one in a series. PMID- 20707533 TI - Optimized basis sets for the calculation of indirect nuclear spin-spin coupling constants involving the atoms B, Al, Si, P, and Cl. AB - The aug-cc-pVTZ-J series of basis sets for indirect nuclear spin-spin coupling constants has been extended to the atoms B, Al, Si, P, and Cl. The basis sets were obtained according to the scheme previously described by Provasi et al. [J. Chem. Phys. 115, 1324 (2001)]. First, the completely uncontracted correlation consistent aug-cc-pVTZ basis sets were extended with four tight s and three tight d functions. Second, the s and p basis functions were contracted with the molecular orbital coefficients of self-consistent-field calculations performed with the uncontracted basis sets on the simplest hydrides of each atom. As a first illustration, we have calculated the one-bond indirect spin-spin coupling constants in BH(4)(-), BF, AlH, AlF, SiH(4), SiF(4), PH(3), PF(3), H(2)S, SF(6), HCl, and ClF at the level of density functional theory using the Becke three parameter Lee-Yang-Parr and the second order polarization propagator approximation with coupled cluster singles and doubles amplitudes. PMID- 20707534 TI - Resonant two-photon ionization spectroscopy of jet-cooled tantalum carbide, TaC. AB - The optical spectrum of diatomic TaC has been investigated for the first time, with transitions recorded in the range from 17,850 to 20,000 cm(-1). Six bands were rotationally resolved and analyzed to obtain ground and excited state parameters, including band origins, upper and lower state rotational constants and bond lengths, Fermi contact parameter b(F) for the ground state, and lambda doubling parameters for the excited states. The ground state of TaC was found to be X (2)Sigma(+), originating from the 1sigma(2)2sigma(2)1pi(4)3sigma(1) electronic configuration, in which only the valence orbitals arising from the Ta(5d+6s) and C(2s+2p) orbitals are listed. All of the rotationally resolved and analyzed bands were found to originate from the ground state, giving B(0)"=0.489 683(83) cm(-1), r(0)"=1.749 01(15) A, and b(F)"=0.131 20(36) cm(-1) (1sigma error limits) for (181)Ta (12)C. Comparison of the Fermi contact parameter to the atomic value shows that the 3sigma orbital is approximately 75% Ta 6s in character. The other group 5 transition metal carbides, VC and NbC, have long been known to have 1sigma(2)2sigma(2)1pi(4)1delta(1), (2)Delta ground states, with low-lying 1sigma(2)2sigma(2)1pi(4)3sigma(1), (2)Sigma(+) excited states. The emergence of a different ground state in TaC, as compared to VC and NbC, is due to the relativistic stabilization of the 6s orbital in Ta. This lowers the energy of the 6s-like 3sigma orbital in TaC, causing the 1sigma(2)2sigma(2)1pi(4)3sigma(1), (2)Sigma(+) state to fall below the 1sigma(2)2sigma(2)1pi(4)1delta(1), (2)Delta state. PMID- 20707535 TI - Rovibronically selected and resolved two-color laser photoionization and photoelectron study of nickel carbide cation. AB - We have performed a two-color laser photoionization and photoelectron study of nickel carbide (NiC) and its cation (NiC(+)). By preparing NiC in a single rovibronic level of an intermediate vibronic state via visible laser excitation prior to ultraviolet laser photoionization, we have measured the photoionization efficiency spectrum of NiC near its ionization threshold, covering the formation of NiC(+)(X (2)Sigma(+);v(+)=0-3). We have also obtained well-resolved rotational transitions for the v(+)=0 and 1 vibrational bands of the NiC(+)(X (2)Sigma(+)) ground state. The assignment of rotational transitions observed between the neutral NiC intermediate state and the NiC(+) ion ground state has allowed the direct determination of a highly precise value for the ionization energy of NiC, IE(NiC)=67,525.1+/-0.5 cm(-1) (8.372 05+/-0.000 06 eV). This experiment also provides reliable values for the vibrational spacing [DeltaG(1/2)=859.5+/-0.5 cm( 1)], rotational constants (B(e)(+)=0.6395+/-0.0018 cm(-1) and alpha(e)(+)=0.0097+/-0.0009 cm(-1)), and equilibrium bond distance (r(e)(+)=1.628 A) for the NiC(+)(X (2)Sigma(+)) ground state. The experimental results presented here are valuable for benchmarking the development of more reliable ab initio quantum computation procedures for energetic and spectroscopic calculations of transition metal-containing molecules. PMID- 20707536 TI - Trading sensitivity for information: Carr-Purcell-Meiboom-Gill acquisition in solid-state NMR. AB - The Carr-Purcell-Meiboom-Gill (CPMG) experiment has gained popularity in solid state NMR as a method for enhancing sensitivity for anisotropically broadened spectra of both spin 1/2 and half integer quadrupolar nuclei. Most commonly, the train of CPMG echoes is Fourier transformed directly, which causes the NMR powder pattern to break up into a series of sidebands, sometimes called "spikelets." Larger sensitivity enhancements are observed as the delay between the pi pulses is shortened. As the duration between the pi pulses is shortened, however, the echoes become truncated and information about the nuclear spin interactions is lost. We explored the relationship between enhanced sensitivity and loss of information as a function of the product Omega 2tau, where Omega is the span of the anisotropic lineshape and 2tau is the pi pulse spacing. For a lineshape dominated by the nuclear shielding anisotropy, we found that the minimum uncertainty in the tensor values is obtained using Omega 2tau values in the range Omega 2tau approximately 12(-1)(+6) and Omega 2tau approximately 9(-3)(+3) for eta(s)=0 and eta(s)=1, respectively. For an anisotropic second-order quadrupolar central transition lineshape under magic-angle spinning (MAS), the optimum range of Omega 2tau approximately 9(-2)(+3) was found. Additionally, we show how the Two-dimensional One Pulse (TOP) like processing approach can be used to eliminate the cumbersome sideband pattern lineshape and recover a more familiar lineshape that is easily analyzed with conventional lineshape simulation algorithms. PMID- 20707537 TI - On the paradoxical relation between the melting temperature and forbidden energy gap of nanoparticles. AB - We comment on the paradox that seems to exist about a correlation between the size-dependent melting temperature and the forbidden energy gap of nanoparticles. By analyzing the reported expressions for the melting temperature and the band gap of nanoparticles, we conclude that there exists a relation between these two physical quantities. However, the variations of these two quantities with size for semiconductors are different from that of metals. PMID- 20707538 TI - Two-photon resonances in femtosecond time-resolved four-wave mixing spectroscopy: beta-carotene. AB - Femtosecond time-resolved pump-degenerate four-wave mixing (pump-DFWM) spectroscopy has been used to study the ultrafast dynamics of beta-carotene involving several electronic and vibrational states. An initial pump pulse, resonant with the S(0)-to-S(2) transition, excites the molecular system and a DFWM process, resonant with the S(1)-to-S(n) transition, is used to probe the relaxation pathways. The transient shows a peculiar decay behavior, which is due to the contributions of resonant DFWM signal of the excited S(1) state, nonresonant DFWM signal of the ground S(0) state and vibrational hot S(0)* state, and the two-photon resonant DFWM signal of the ground S(0) state. We have used a kinetic model including all the signal contributions to successfully fit the transient. The time constants extracted are in very good agreement with the known values for beta-carotene. For comparison, a two-pulse pump-probe experiment was performed measuring the transient absorption at the wavelength of the DFWM experiment. PMID- 20707539 TI - Mesoscale spatial distribution of electron spins studied by time-resolved small angle and ultrasmall-angle neutron scattering with dynamic nuclear polarization: a case of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) doped in high-density polyethylene. AB - We carried out time-resolved small-angle neutron scattering (SANS) and ultrasmall angle neutron scattering (USANS) studies of dynamically polarized high-density polyethylene (HDPE) doped with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) persistent free radicals. We observed a remarkable enhancement of the scattering intensity shortly after a switching of microwave frequency from positive (negative) to negative (positive) dynamic nuclear polarization (DNP). The enhancement was found to be due to spatially heterogeneous proton-spin polarization generated as a result of heterogeneously distributed TEMPO in the HDPE sample. The spatial fluctuation of the polarization ranged up to the length scale of > or = 100 nm. This result strongly suggests that the TEMPO free radicals are localized more in nonfibrils but less in fibrils of HDPE. In this way, we propose that the time-resolved DNP-SANS and DNP-USANS be general techniques to determine mesoscale spatial distribution of electron spins in dielectric materials. PMID- 20707540 TI - Hydrogen vibrational modes on graphene and relaxation of the C-H stretch excitation from first-principles calculations. AB - Density functional theory (DFT) calculations are used to determine the vibrational modes of hydrogen adsorbed on graphene in the low-coverage limit. Both the calculated adsorption energy of a H atom of 0.8 eV and calculated C-H stretch vibrational frequency of 2552 cm(-1) are unusually low for hydrocarbons, but in agreement with data from electron energy loss spectroscopy on hydrogenated graphite. The clustering of two adsorbed H atoms observed in scanning tunneling microscopy images shows its fingerprint also in our calculated spectra. The energetically preferred adsorption on different sublattices correlates with a blueshift of the C-H stretch vibrational modes in H adatom clusters. The C-H bending modes are calculated to be in the 1100 cm(-1) range, resonant with the graphene phonons. Moreover, we use our previously developed methods to calculate the relaxation of the C-H stretch mode via vibration-phonon interaction, using the Born-Oppenheimer surface for all local modes as obtained from the DFT calculations. The total decay rate of the H stretch into other H vibrations, thereby creating or annihilating one graphene phonon, is determined from Fermi's golden rule. Our calculations using the matrix elements derived from DFT calculations show that the lifetime of the H stretch mode on graphene is only several picoseconds, much shorter than on other semiconductor surfaces such as Ge(001) and Si(001). PMID- 20707541 TI - Dynamically skewed lines: rotations in superfluid helium. AB - Dynamically skewed spectral lines arise for chirped damped oscillators. We extend this to the chirped damped rotor and apply it to treat the rovibrational line shapes of small molecules isolated in superfluid helium. The simple analysis generates valuable physical insights on the prevailing dynamics of a rotor coupled to its environment. PMID- 20707542 TI - The covariant dissipation function for transient nonequilibrium states. AB - It has recently become apparent that the dissipation function, first defined by Evans and Searles [J. Chem. Phys. 113, 3503 (2000)], is one of the most important functions in classical nonequilibrium statistical mechanics. It is the argument of the Evans-Searles fluctuation theorem, the dissipation theorem, and the relaxation theorems. It is a function of both the initial distribution and the dynamics. We pose the following question: How does the dissipation function change if we define that function with respect to the time evolving phase space distribution as one relaxes from the initial equilibrium distribution toward the nonequilibrium steady state distribution? We prove that this covariant dissipation function has a rather simple fixed relationship to the dissipation function defined with respect to the initial distribution function. We also show that there is no exact, time-local, Evans-Searles nonequilibrium steady state fluctuation relation for deterministic systems. Only an asymptotic version exists. PMID- 20707543 TI - Multiple coherent states semiclassical initial value representation spectra calculations of lateral interactions for CO on Cu(100). AB - Lateral interactions between carbon monoxide molecules adsorbed on a copper Cu(100) surface are investigated via semiclassical initial value representation (SC-IVR) molecular dynamics. A previous analytical potential is extended to include long-range dipole interactions between coadsorbed molecules and preliminary classical simulations were performed to tune the potential parameters. Then, the spectra for several coadsorbed molecules are calculated using the multiple coherent states approximation of the time-averaging representation of the SC-IVR propagator. Results show strong resonances between coadsorbed molecules as observed by past experiments. Resonances turn into dephasing when isotopical substitutions are performed. PMID- 20707544 TI - Multiplexed polarization spectroscopy: measuring surface hyperpolarizability orientation. AB - Infrared-visible sum frequency generation (SFG) has seen increasing usage as a surface probe, particularly for liquid interfaces since they are amenable to few alternate probes. Interpreting the SFG data to arrive at a molecular-level configuration on the surface, however, remains a challenge. This paper reports a technique for analyzing and interpreting SFG data--called polarization-angle null or PAN-SFG. PAN-SFG enables ready identification of the ratio of the surface tangential and longitudinal hyperpolarizabilities--the hyperpolarizability direction--as well as the phase relationship between these components separated from the optical factors due to the substrate and experimental geometry. Separation of the surface optical factors results in an immediate connection between the null angle and the surface species polarization. If the Raman polarizability is also known, then PAN-SFG analysis, like the previously reported null techniques, provides a very accurate orientation. In addition, the reported polarization-angle, phase-shift analysis enables facile separation of the nonresonant background polarization from that of the resonant signal. Beyond orientation, PAN-SFG can be used to deconvolute overlapping resonances and identify components beyond a dipole response. This paper reports PAN-SFG for two systems providing deeper insight into both. An acetonitrile-water mixture was previously reported to undergo a phase transition at 7 mol %, attributed to a sudden change in orientation. PAN-SFG demonstrates that acetonitrile generates a classic dipole response and provides compelling evidence that the acetonitrile configuration remains constant as a function of concentration. An alternate model for the phase transition is presented. Like many aqueous systems, the SFG spectrum of the hydrogen-bonded region of ice consists of broad and overlapping features; features previously identified with PAN-SFG. Here PAN-SFG analysis is used to show that the reddest of these, the feature at 3098 cm(-1), contains a significant quadrupole contribution that grows as the temperature is lowered. The quadrupole and its temperature dependence are used to assign the 3098 cm(-1) feature to bilayer-stitching-hydrogen bonds. This is the first definitive assignment in the hydrogen-bonded region of water. PMID- 20707545 TI - Assignment of near-edge x-ray absorption fine structure spectra of metalloporphyrins by means of time-dependent density-functional calculations. AB - The C 1s and N 1s near-edge x-ray absorption fine structure (NEXAFS) spectra of three prototype tetraphenyl porphyrin (TPP) molecules are discussed in the framework of a combined experimental and theoretical study. We employ time dependent density-functional theory (TDDFT) to compute the NEXAFS spectra of the open- and closed-shell metalloporphyrins CoTPP and ZnTPP as well as the free-base 2HTPP in realistic nonplanar conformations. Using Becke's well-known half-and half hybrid functional, the computed core excitation spectra are mostly in good agreement with the experimental data in the low-energy region below the appropriate ionization threshold. To make these calculations feasible, we apply a new, simple scheme based on TDDFT using a modified single-particle input spectrum. This scheme is very easy to implement in standard codes and allows one to compute core excitation spectra at a similar cost as ordinary UV/vis spectra even for larger molecules. We employ these calculations for a detailed assignment of the NEXAFS spectra including subtle shifts in certain peaks of the N 1s spectra, which depend on the central coordination of the TPP ligand. We furthermore assign the observed NEXAFS resonances to the individual molecular subunits of the investigated TPP molecules. PMID- 20707546 TI - Interaction of fluids with physically patterned solid surfaces. AB - We derive coarse-grained potentials for the interaction of a fluid atom with a solid substrate patterned with cylindrical or rectangular pillars, as well as with rectangular grooves. These potentials rely on the assumption of pairwise Lennard-Jones (LJ) (12-6) interactions of a fluid atom with a surface that has a uniform density of solid atoms. In the limit of a flat, semi-infinite surface, this potential becomes the LJ 9-3 potential. Simplified forms of the potentials are presented that are valid for sufficiently large pillars or grooves. The potentials can be truncated for greater computational efficiency while retaining similar accuracy to the full form. Both the full and simplified potentials exhibit the same features as a full summation of LJ (12-6) interactions, and these may be used in simulation studies to resolve phenomena associated with the interaction of fluids with patterned surfaces. PMID- 20707547 TI - Vibrational characterization of ethylene adsorption and its thermal evolution on Si(001)-(2 x 1): identification of majority and minority species. AB - The vibrational and structural properties of a single-domain Si(001)-(2 x 1) surface upon ethylene adsorption have been studied by density functional cluster calculations and high-resolution electron energy loss spectroscopy. The detailed analysis of the theoretically and the experimentally determined vibrational frequencies reveals two coexisting adsorbate configurations. The majority species consist of ethylene molecules which are di-sigma bonded to the two Si atoms of a single Si-Si dimer. The local symmetry of this adsorption complex is reduced to C(2) for ethylene saturation coverage as determined by surface selection rules for the vibrational excitation process. The symmetry reduction includes the rotation of the C-C bond around the surface normal and the twist of the methylene groups around the C-C axis. Experimentally, 17 ethylene-derived modes are found and assigned for the majority and the minority species based on a comparison with calculated vibrational frequencies. The minority species which can account up to 14% of the total ethylene coverage is spectroscopically identified for the first time. It is assigned to ethylene molecules di-sigma bonded to two adjacent Si-Si dimers (in an end-bridge configuration). One part of the minority species desorbs molecularly at 665 K, about 50 K higher than the majority species, whereas the remaining part dissociates to adsorbed acetylene at temperatures around 630 K. For the latter, a di-sigma end-bridge like bonding configuration is proposed based on a comparison with vibrational data for adsorbed acetylene on Si(100)-(2 x 1). PMID- 20707548 TI - Hydrodynamic interactions suppress deformation of suspension drops in Poiseuille flow. AB - Evolution of a suspension drop entrained by Poiseuille flow is studied numerically at a low Reynolds number. A suspension drop is modeled by a cloud of many nontouching particles, initially randomly distributed inside a spherical volume of a viscous fluid which is identical to the host fluid outside the drop. Evolution of particle positions and velocities is evaluated by the accurate multipole method corrected for lubrication, implemented in the HYDROMULTIPOLE numerical code. Deformation of the drop is shown to be smaller for a larger volume fraction. At high concentrations, hydrodynamic interactions between close particles significantly decrease elongation of the suspension drop along the flow in comparison to the corresponding elongation of the pure-fluid drop. Owing to hydrodynamic interactions, the particles inside a dense-suspension drop tend to stay for a long time together in the central part of the drop; later on, small clusters occasionally separate out from the drop, and are stabilized by quasiperiodic orbits of the constituent nontouching particles. Both effects significantly reduce the drop spreading along the flow. At large volume fractions, suspension drops destabilize by fragmentation, and at low volume fractions, by dispersing into single particles. PMID- 20707549 TI - Solubilization of aromatic and hydrophobic moieties by arginine in aqueous solutions. AB - Experiments hold intriguing, circumstantial clues to the mechanisms behind arginine-mediated solubilization of small organic drugs and suppression of protein aggregation driven by hydrophobic or aromatic associations, but how exactly arginine's molecular structure and interactions contribute to its function remains unclear since attention has focused so far on the thermodynamics of the preferential exclusion or binding of arginine. Here, we examine, through molecular dynamics simulations, how arginine solubilizes nanoscale particles with hydrophobic surfaces or aromatic-ring-type surface interactions. We show that preferential, hydrophobic, and dispersion interactions of arginine's guanidinium group with the particles lead to a surfactant-like behavior of arginine around the particles and to a solvation layer with a protective polar mask creating a hydrophilic shell. Additionally, arginine-arginine association around the solvation layer further prevents aggregative contacts. The results shed some light on the mechanistic basis of arginine's function as a suppressant of protein aggregation, although the complex energy landscapes and kinetic pathways of aggregation are protein-dependent and pose formidable challenges to developing comprehensive mechanistic pictures. Our results suggest arginine's mode of interaction with hydrophobic patches and aromatic residues could reduce aggregation-prone intermediate states of proteins and shield protein-protein aggregative contacts. The approach used here offers a systematic way of exploring implications of other amino acid/excipient interactions by studying interactions of the excipient with particles grafted with amino acids. PMID- 20707550 TI - Notes: Kinetic unfreezing of a binary alloy and configurational entropy. PMID- 20707552 TI - Communication: Ionization and Coulomb explosion of xenon clusters by intense, few cycle laser pulses. AB - Intense, ultrashort pulses of 800 nm laser light (12 fs, approximately 4 optical cycles) of peak intensity 5x10(14) W cm(-2) have been used to irradiate gas-phase Xe(n) clusters (n=500-25,000) so as to induce multiple ionization and subsequent Coulomb explosion. Energy distributions of exploding ions are measured in the few cycle domain that does not allow sufficient time for the cluster to undergo expansion due to Coulombic and hydrodynamic pressures. This results in overall dynamics that appear to be significantly different to those in the many-cycle regime. One manifestation is that the maximum ion energies are measured to be much lower than those obtained when longer pulses of the same intensity are used. Ion yields are cluster-size independent but polarization dependent in that they are significantly larger when the polarization is perpendicular to the detection axis than along it. This unexpected behavior is qualitatively rationalized in terms of a spatially anisotropic shielding effect induced by the electronic charge cloud within the cluster. PMID- 20707553 TI - Communication: Conical intersections using constrained density functional theory configuration interaction. AB - The constrained density functional theory-configuration interaction (CDFT-CI) method has previously been used to calculate ground-state energies and barrier heights. In this work, it is examined for use in computing electronic excited states, for the challenging case of conical intersections. Conical intersections are a prevalent feature of excited electronic surfaces, but conventional time dependent density functional theory calculations are found to be entirely unsatisfactory at describing them, for two small systems. CDFT-CI calculations on those systems are found to be in qualitative agreement with reference CAS surfaces. These results suggest that with a suitable definition of atomic populations and a careful choice of constrained states, CDFT-CI could be the basis for a seamless description of electronic degeneracy. PMID- 20707554 TI - Communication: Molecular dynamics simulations of the interfacial structure of alkali metal fluoride solutions. AB - Molecular dynamics simulations are carried out to study the interfacial profiles of alkali metal fluoride solutions (NaF, KF, RbF, and CsF) at 1 atm and 300 K. For these solutions, we find that the occupancy of the cations in the interfacial region is comparable to or greater than that of the F(-) anion. Cations that have weaker hydration abilities have higher concentrations at the interface. The order of enhanced concentrations of cations at the interface is Na(+)100 micros, and independent of binding energy. The lifetimes of strongly bound (>30 meV) K(+)..CN(-) ion pairs are found to be similarly long but begin to decrease markedly as the binding energy is reduced below this value. This behavior is attributed to conversion of rotational energy in the CN(-) ion into translational energy of the ion pair. No long-lived K(+)..SF(6)(-) ion pairs are observed, their lifetimes decreasing with increasing binding energy. This behavior suggests that ion-pair loss is associated with mutual neutralization as a result of charge transfer. PMID- 20707565 TI - Ultrafast deactivation processes in the 2-aminopyridine dimer and the adenine thymine base pair: similarities and differences. AB - 2-Aminopyridine dimer has frequently been used as a model system for studying photochemistry of DNA base pairs. We examine here the relevance of 2 aminopyridine dimer for a Watson-Crick adenine-thymine base pair by studying UV light induced photodynamics along two main hydrogen bridges after the excitation to the localized (1)pi pi(*) excited-state. The respective two-dimensional potential-energy surfaces have been determined by time-dependent density functional theory with Coulomb-attenuated hybrid exchange-correlation functional (CAM-B3LYP). Different mechanistic aspects of the deactivation pathway have been analyzed and compared in detail for both systems, while the related reaction rates have also be obtained from Monte Carlo kinetic simulations. The limitations of the 2-aminopyridine dimer as a model system for the adenine-thymine base pair are discussed. PMID- 20707566 TI - Imaging the radical channel in acetaldehyde photodissociation: competing mechanisms at energies close to the triplet exit barrier. AB - The photodissociation of acetaldehyde in the radical channel has been studied at wavelengths between 315 and 325 nm using the velocity-map imaging technique. Upon one-photon absorption at 315 nm, the molecule is excited to the first singlet excited state S(1), which, in turn, undergoes intersystem crossing to the first excited triplet state T(1). On the triplet surface, the molecule dissociates into CH(3) and HCO radicals with large kinetic energy release (KER), in accordance with the well characterized exit barrier on T(1). However, at longer wavelengths (>320 nm), which correspond to excitation energies just below the triplet barrier, a sudden change in KER is observed. At these photolysis wavelengths, there is not enough energy to surpass the exit barrier on the triplet state, which leaves the possibility of unimolecular dissociation on S(0) after internal conversion from S(1). We have characterized the fragments' KER at these wavelengths, as well as determined the energy partitioning for the radical fragments. A new accurate estimate of the barrier height on T(1) is presented. PMID- 20707567 TI - Giant Renner-Teller vibronic coupling in the BF2 radical: an ab initio study of the X (2)A1 and A (2)Pi electronic states. AB - The potential energy surfaces (PESs) of the ground X (2)A(1) and the first excited A (2)Pi (1 (2)B(1), 2 (2)A(1)) electronic states of the BF(2) radical have been studied ab initio, using a large basis set and CCSD(T) and EOM-CCSD techniques. The calculated PESs were used to variationally calculate the energy levels up to approximately 36,000 cm(-1) above the ground state. The Renner Teller splitting parameter (epsilon=0.928) found for the A (2)Pi state of this radical is very large which results in an unusual excited state energy level structure. PMID- 20707568 TI - The electronic structure of the triiodide ion from relativistic correlated calculations: a comparison of different methodologies. AB - The triiodide ion I(3)(-) exhibits a complex photodissociation behavior, the dynamics of which are not yet fully understood. As a first step toward determining the full potential energy surfaces of this species for subsequent simulations of its dissociation processes, we investigate the performance of different electronic structure methods [time-dependent density functional theory, complete active space perturbation theory to second order (CASPT2), Fock-space coupled cluster and multireference configuration interaction] in describing the ground and excited states of the triiodide ion along the symmetrical dissociation path. All methods apart from CASPT2 include scalar relativity and spin-orbit coupling in the orbital optimization, providing useful benchmark data for the more common two-step approaches in which spin-orbit coupling is introduced in the configuration interaction. Time-dependent density functional theory with the statistical averaging of model orbital potential functional is off the mark for this system. Another choice of functional may improve performance with respect to vertical excitation energies and spectroscopic constants, but all functionals are likely to face instability problems away from the equilibrium region. The Fock space coupled cluster method was shown to perform clearly best in regions not too far from equilibrium but is plagued by convergence problems toward the dissociation limit due to intruder states. CASPT2 shows good performance at significantly lower computational cost, but is quite sensitive to symmetry breaking. We furthermore observe spikes in the CASPT2 potential curves away from equilibrium, signaling intruder state problems that we were unable to curb through the use of level shifts. Multireference configuration interaction is, in principle, a viable option, but its computational cost in the present case prohibits use other than for benchmarking purposes. PMID- 20707569 TI - Recoupling of native homonuclear dipolar couplings in magic-angle-spinning solid state NMR by the double-oscillating field technique. AB - A new solid-state NMR method, the double-oscillating field technique (DUO), that under magic-angle-spinning conditions produces an effective Hamiltonian proportional to the native high-field homonuclear dipole-dipole coupling operator is presented. The method exploits one part of the radio frequency (rf) field to recouple the dipolar coupling interaction with a relatively high scaling factor and to eliminate offset effects over a reasonable bandwidth while in the recoupling frame, the other part gives rise to a sufficiently large longitudinal component of the residual rf field that averages nonsecular terms and in addition ensures stability toward rf inhomogeneity and rf miscalibration. The capability of the DUO experiment to mediate transfer of polarization is described theoretically and compared numerically and experimentally with finite pulse rf driven recoupling and experimentally with dipolar-assisted rotational resonance. Two-dimensional recoupling experiments were performed on antiparallel amyloid fibrils of the decapeptide SNNFGAILSS with the FGAIL fragment uniformly labeled with (13)C and (15)N. PMID- 20707570 TI - Monte Carlo study of structural ordering of Lennard-Jones fluids confined in nanochannels. AB - We investigate quantitatively the ordering of Lennard-Jones fluids confined in a thin and infinitely long nanochannel with square cross section. The most probable spatial configurations of the atoms were examined by Monte Carlo simulations, and the order parameter was calculated. The effect of the various parameters, such as the wall-fluid attractive interaction, the size of constriction, and the temperature, was studied. The results indicate that for strong wall-fluid interactions and small constrictions, the ordering of the fluid particles is almost perfect. Geometrical mismatch, as well as increasing the system's temperature, deteriorates the ordering phenomenon, even for very small openings. We observe a nontrivial trend in the dependence of the order parameter on the size of the opening of the channel with a linear size smaller than five atomic layers. We also examined the rearrangements of the fluid's atoms in more symmetrical pores--slitlike pores and cylindrical nanopores--and discuss their similarities and differences with the square channels. PMID- 20707571 TI - A generalized reactive force field for nonlinear hydrogen bonds: hydrogen dynamics and transfer in malonaldehyde. AB - Using molecular dynamics (MD) simulations, the spectroscopy and dynamics of malonaldehyde is investigated. To this end, the recently proposed molecular mechanics with proton transfer (MMPT) potential is generalized to nonlinear hydrogen bonds. The calculated properties for malonaldehyde in both gas and condensed phases, including equilibrium geometries, infrared spectra, tunneling splittings, and hydrogen transfer rates, compare well with previous experimental and computational works. In particular, by using a harmonic bath averaged (HBA) Hamiltonian, which is based on a reaction path Hamiltonian, it is possible to estimate the tunneling splitting in an efficient manner. It is found that a zero point corrected barrier of 6.7 kcal/mol and effective masses of 1.234 (i.e., 23.4% larger than the mass of a physical H-atom) and 1.117 (for the physical D atom) are consistent with the measured splittings of 21.6 and 2.9 cm(-1), respectively. The HBA Hamiltonian also yields a pair of hydrogen transfer fundamentals at 1573 and 1267 cm(-1), similar to results obtained with a reaction surface Hamiltonian on a MP2/6-31G(**) potential energy surface. This amounts to a substantial redshift of more than 1000 cm(-1) which can be rationalized by comparison with weakly (HCO(+): rare gas) and strongly (H(2)O-H(+)-OH(2)) proton bound systems. Hydrogen transfer rates in vacuum and water were determined from the validated MMPT potential and it is found that the solvent enhances the rate by a factor of 5 at 300 K. The rates of 2.4/ns and 10/ns are commensurate with previous density functional tight binding ab initio MD studies. PMID- 20707572 TI - The distorted close-packed crystal structure of methane A. AB - We have determined the full crystal structure of the high-pressure phase methane A. X-ray single-crystal diffraction data were used to determine the carbon-atom arrangement, and neutron powder diffraction data from a deuterated sample allowed the deuterium atoms to be located. It was then possible to refine all the hydrogen positions from the single-crystal x-ray data. The structure has 21 molecules in a rhombohedral unit cell, and is quite strongly distorted from the cubic close-packed structure of methane I, although some structural similarities remain. Full knowledge of this structure is important for modeling of methane at higher pressures, including in relation to the mineralogy of the outer solar system. We discuss interesting structural parallels with the carbon tetrahalides. PMID- 20707573 TI - Why are para-hydrogen clusters superfluid? A quantum theorem of corresponding states study. AB - The quantum theorem of corresponding states is applied to N=13 and N=26 cold quantum fluid clusters to establish where para-hydrogen clusters lie in relation to more and less quantum delocalized systems. Path integral Monte Carlo calculations of the energies, densities, radial and pair distributions, and superfluid fractions are reported at T=0.5 K for a Lennard-Jones (LJ) (12,6) potential using six different de Boer parameters including the accepted value for hydrogen. The results indicate that the hydrogen clusters are on the borderline to being a nonsuperfluid solid but that the molecules are sufficiently delocalized to be superfluid. A general phase diagram for the total and kinetic energies of LJ (12,6) clusters encompassing all sizes from N=2 to N=infinity and for the entire range of de Boer parameters is presented. Finally the limiting de Boer parameters for quantum delocalization induced unbinding ("quantum unbinding") are estimated and the new results are found to agree with previous calculations for the bulk and smaller clusters. PMID- 20707574 TI - Three pulse UV photon echo studies of molecules in solution: effect of the chirp. AB - We report on the electronic dephasing times of the nonpolar chromophore diphenylacetylene (DPA) in ethanol and in cyclohexane (polar and nonpolar solvents respectively) by photon echo measurements in the ultraviolet. Contrary to previous reports, we observed sub-100-fs electronic dephasing times for DPA in both solvents. We identify fast dynamics of tau=40+/-10 fs on the photon echo peak shift (PEPS) traces of DPA in ethanol. In addition, we observed a dependence of the PEPS asymptotic value on the temporal chirp of the pulses. We propose a model to describe it in terms of phase-matching condition and beam geometry. PMID- 20707575 TI - Determining the three-phase coexistence line in methane hydrates using computer simulations. AB - Molecular dynamics simulations have been performed to estimate the three-phase (solid hydrate-liquid water-gaseous methane) coexistence line for the water methane binary mixture. The temperature at which the three phases are in equilibrium was determined for three different pressures, namely, 40, 100, and 400 bar by using direct coexistence simulations. In the simulations water was described by using either TIP4P, TIP4P/2005, or TIP4P/Ice models and methane was described as simple Lennard-Jones interaction site. Lorentz-Berthelot combining rules were used to obtain the parameters of the cross interactions. For the TIP4P/2005 model positive deviations from the energetic Lorentz-Berthelot rule were also considered to indirectly account for the polarization of methane when introduced in liquid water. To locate the three-phase coexistence point, two different global compositions were used, which yielded (to within statistical uncertainty) the same predictions for the three-phase coexistence temperatures, although with a somewhat different time evolution. The three-phase coexistence temperatures obtained at different pressures when using the TIP4P/Ice model of water were in agreement with the experimental results. The main reason for this is that the TIP4P/Ice model reproduces the melting point of ice I(h). PMID- 20707576 TI - Theory and simulation of the dynamic heat capacity of the east Ising model. AB - A recently developed methodology for the calculation of the dynamic heat capacity from simulation is applied to the east Ising model. Results show stretched exponential relaxation with the stretching exponent, beta, decreasing with decreasing temperature. For low temperatures, the logarithm of the relaxation time is approximately proportional to the inverse of the temperature squared, which is the theoretical limiting behavior predicted by theories of facilitated dynamics. In addition, an analytical approach is employed where the overall relaxation is a composite of relaxation processes of subdomains, each with their own characteristic time. Using a Markov chain method, these times are computed both numerically and in closed form. The Markov chain results are seen to match the simulations at low temperatures and high frequencies. The dynamics of the east model are tracked very well by this analytic procedure, and it is possible to associate features of the spectrum of the dynamic heat capacity with specific domain relaxation events. PMID- 20707577 TI - Concerted electron and proton transfer in ionic crystals mapped by femtosecond x ray powder diffraction. AB - X-ray powder diffraction, a fundamental technique of structure research in physics, chemistry, and biology, is extended into the femtosecond time domain of atomic motions. This allows for mapping (macro)molecular structure generated by basic chemical and biological processes and for deriving transient electronic charge density maps. In the experiments, the transient intensity and angular positions of up to 20 Debye Scherrer reflections from a polycrystalline powder are measured and atomic positions and charge density maps are determined with a combined spatial and temporal resolutions of 30 pm and 100 fs. We present evidence for the so far unknown concerted transfer of electrons and protons in a prototype material, the hydrogen-bonded ionic ammonium sulfate [(NH(4))(2)SO(4)]. Photoexcitation of ammonium sulfate induces a sub-100 fs electron transfer from the sulfate groups into a highly confined electron channel along the c-axis of the unit cell. The latter geometry is stabilized by transferring protons from the adjacent ammonium groups into the channel. Time-dependent charge density maps derived from the diffraction data display a periodic modulation of the channel's charge density by low-frequency lattice motions with a concerted electron and proton motion between the channel and the initial proton binding site. Our results set the stage for femtosecond structure studies in a wide class of (bio)molecular materials. PMID- 20707578 TI - Quantum oscillatory exciton migration in photosynthetic reaction centers. AB - The harvesting of solar energy and its conversion to chemical energy is essential for all forms of life. The primary photon absorption, transport, and charge separation events, which trigger a chain of chemical reactions, take place in membrane-bound photosynthetic complexes. Whether quantum effects, stemming from entanglement of chromophores, persist in the energy transport at room temperature, despite the rapid decoherence effects caused by environment fluctuations, is under current active debate. If confirmed, these may explain the high efficiency of light harvesting and open up numerous applications to quantum computing and information processing. We present simulations of the photosynthetic reaction center of photosystem II that clearly establish oscillatory energy transport at room temperature originating from interference of quantum pathways. These signatures of quantum transport may be observed by two dimensional coherent optical spectroscopy. PMID- 20707579 TI - Self-assembly in binary mixtures of dipolar colloids: molecular dynamics simulations. AB - Dipolar colloid particles tend to align end-to-end and self-assemble into micro- and nanostructures, including gels and cocrystals depending on external conditions. We use molecular dynamics computer simulation to explore the phase behavior including formation, structure, crystallization, and/or gelation of binary systems of colloid particles with permanent dipole moments. Particle particle interactions are modeled with a discontinuous potential. The phase diagrams of an equimolar binary mixture of dipolar colloid particles with different diameter ratios and different dipole moment ratios are calculated in the temperature-volume fraction plane. Several types of phases are found in our simulations: ordered phases including face centered cubic (fcc), hexagonal-close packed (hcp), and body-centered tetragonal (bct) at high volume fractions, and fluid, string-fluid, and gel phases at low volume fractions. We also find several coexistence regions containing ordered phases including fcc(a)+fcc(b), fcc(a)+hcp(b), hcp(a)+hcp(b), bct(a)+bct(b), and bct(a)+bct(b)+large voids where a and b are the two species. Two novel aspects of our results are the appearance of a bicontinuous gel consisting of two interpenetrating networks--one formed by chains of particles with high dipole moment and the other formed by chains of particles with low dipole moment, and cocrystals of large and small dipolar colloid particles. PMID- 20707580 TI - The effect of dopant at the Zr site on the proton conduction pathways of SrZrO3: an orthorhombic perovskite. AB - Doping orthorhombic SrZrO(3) at 12.5% of the Zr sites with Al(3+) leads to a local squaring of the lattice, while doping with larger Y(3+) increases local octahedral distortions. Proton activation energy barriers and transition state theory prefactors are calculated. The wide range of intra-, inter-, and rotational barriers suggest that a comprehensive pathway analysis is needed to find the limiting conduction barriers. Simple seven to ten step periodic pathways leading to system wide conduction are enumerated using vertex coding. At 900-1300 K, the average limiting barriers to long range conduction are 0.6 and 0.4 eV in Al/SrZrO(3) and Y/SrZrO(3), respectively, in reasonable agreement with the experiment. Path analysis gives the added insight that conduction pathways in Al/SrZrO(3) avoid doped regions, while conduction pathways in Y/SrZrO(3) traverse them. PMID- 20707581 TI - Identifying configuration and orientation of adsorbed molecules by inelastic electron tunneling spectra. AB - Scanning tunneling microscopy (STM) topographical images and inelastic electron tunneling spectra (IETS) of a cis-2-butene molecule adsorbed on a Pd(110) surface have been simulated by first-principles calculations. Calculations have eliminated the ambiguity between the STM image and the adsorption orientation caused by the symmetry of the system and local chemical environment. A combination of STM images and IETS spectra has been shown to be particularly useful in determining the configuration of the molecule on the surface. PMID- 20707582 TI - Kohn's localization in the insulating state: one-dimensional lattices, crystalline versus disordered. AB - The qualitative difference between insulators and metals stems from the nature of the low-lying excitations, but also--according to Kohn's theory [W. Kohn, Phys. Rev. 133, A171 (1964)]--from a different organization of the electrons in their ground state: electrons are localized in insulators and delocalized in metals. We adopt a quantitative measure of such localization, by means of a "localization length" lambda, finite in insulators and divergent in metals. We perform simulations over a one-dimensional binary alloy model, in a tight-binding scheme. In the ordered case the model is either a band insulator or a band metal, whereas in the disordered case it is an Anderson insulator. The results show indeed a localized/delocalized ground state in the insulating/metallic cases, as expected. More interestingly, we find a significant difference between the two insulating cases: band versus Anderson. The insulating behavior is due to two very different scattering mechanisms; we show that the corresponding values of lambda differ by a large factor for the same alloy composition. We also investigate the organization of the electrons in the many body ground state from the viewpoint of the density matrices and of Boys' theory of localization. PMID- 20707583 TI - Insights from Monte Carlo simulations on charge inversion of planar electric double layers in mixtures of asymmetric electrolytes. AB - Monte Carlo simulations of a planar negatively charged dielectric interface in contact with a mixture of 1:1 and 3:1 electrolytes are carried out using the unrestricted primitive model under more realistic hydrated ion sizes. Two typical surface charge densities are chosen to represent the systems from the weak to strong coupling regimes. Our goal is to determine the dependence of the degree of charge inversion on increasing concentration of both mono- and trivalent salts and to provide a systematic study on this peculiar effect between short-range and electrostatic correlations. The numerical results show that addition of monovalent salt diminishes the condensation of trivalent counterions due to either the favorable solvation energy or the available space constraints. As the concentration of trivalent salt increases, on the other hand, the inclusion of the ionic size and size asymmetry results in a damped oscillatory charge inversion at low enough surface charge and another counterintuitive surface charge amplification. It is proposed that both of the anomalous events in the weak coupling regime are thought to be entropic in origin which is completely different from the electrostatic driven charge inversion in the strong coupling regime. In addition, the electrostatic images arising from the dielectric mismatch lead to a decaying depletion effect on the structure of double layer with growing salt concentration in the case of low charged interface but have no effect at high surface charge values. The microscopic information obtained here points to the need for a more quantitative theoretical treatment in describing the charge inversion phenomenon of real colloidal systems. PMID- 20707584 TI - The absorption of oxygenated silicon carbide nanoparticles. AB - We have investigated the absorption of 0.9-1.4 nm silicon carbide nanoparticles (SiC NPs) by time-dependent density functional calculations, focusing on the effect of various oxygen adsorbates of the surface. We have found that Si-O and C O single bonds result in relatively large optical gaps in the ultraviolet region while Si=O and C=O double bonds will dramatically lower the optical gap into the visible blue and red regions, respectively. Our findings can help interpret recent experiments on colloidal SiC NPs and their utilization in biological applications. PMID- 20707585 TI - Monte Carlo simulation of a single ring among linear chains: structural and dynamic heterogeneity. AB - We perform lattice Monte Carlo simulation using the bond-fluctuation model to examine the conformation and dynamic properties of a single small flexible ring polymer in the matrix of linear chains as functions of the degree of polymerization of the linear chains. The average conformation properties as gauged by the mean-square radius of gyration and asphericity parameter are insensitive to the chain length for all the chain lengths examined (30, 100, 300, and 1000). However, in the longer chain (300 and 1000) samples, there is an increased spread in the distribution of the value of these quantities, suggesting structural heterogeneity. The center-of-mass diffusion of the ring shows a rapid decrease with increasing chain length followed by a more gradual change for the two longer chain systems. In these longer chain systems, a wide spread in the value of the apparent self-diffusion coefficient is also observed, as well as qualitatively different square displacement trajectories among the different samples, suggesting heterogeneity in the dynamics. A primitive path analysis reveals that in these long chain systems, the ring can exist in topologically distinct states with respect to threading by the linear chains. Threading by the linear chain can dramatically slow down and in some cases stall the diffusive motion of the ring. We argue that the life times for these topological conformers can be longer than the disentanglement time of the linear chain matrix, so that the ring exhibits nonergodic behavior on time scales less or comparable to the life time of these conformers. Our results suggest a picture of the ring diffusion as one where the diffusion path consists of distinctive segments, each corresponding to a different conformer, with slow interconversion between the different conformers. PMID- 20707586 TI - Parametrization of the Gay-Berne potential for conjugated oligomer with a high aspect ratio. AB - The Gay-Berne (GB) potential has been a popular semiempirical model for describing the short-range intermolecular forces for a wide variety of aspherical molecules, including liquid crystals and anisotropic colloids, with generally small molecular dimensions and low aspect ratios (<5). This study evaluates the parametrization of the GB potential for a high-aspect-ratio (=10) oligomer belonging to a model conjugated polymer. We elaborate that the semiflexibility associated with a large oligomer species demands a variant umbrella-sampling scheme in establishing the potentials of mean force (PMFs) for four pair ellipsoid arrangements typically utilized to parametrize the GB potential. The model ellipsoid so constructed is shown to capture the PMFs of essential intermediate arrangements as well, and, according to the results of simplex optimizations, recommendations are given for the minimum set of parameters to be included in the optimization of a large oligomer or particulate species. To further attest the parametrized GB potential, the coarse-grained (CG) Monte Carlo simulations employing the GB potential and the back-mapped, full-atom atomistic molecular dynamics (AMD) simulations were performed for a dense oligomer system at two representative system temperatures. The results indicated that the CG simulations can capture, with exceptional computational efficiency, the AMD predictions with good thermal transferability. In future perspectives, we remark on potential applications to construct efficient, parameter-free CG models for capturing fundamental material properties of large oligomer/particulate species as well as long-chain conjugated polymers. PMID- 20707587 TI - Dynamics of pressure propulsion of a sphere in a viscous compressible fluid. AB - A mechanical model of pressure propulsion of a sphere in a viscous compressible fluid is studied on the basis of the linearized Navier-Stokes equations. It is assumed that chemical reactions in the neighborhood of the sphere cause pressure waves which push the sphere. A simple expression is derived for the displacement after a single pulse on the basis of a generalized Faxen theorem. The cooperation of many pulses leads to stochastic behavior of the sphere displacement due to randomness in position of the pulses relative to the sphere surface and due to randomness in time of expansion events. PMID- 20707588 TI - Real-space self-consistent mean-field theory study of ABC star triblock copolymers. AB - The phase behavior of ABC star triblock copolymers is examined using real-space self-consistent mean-field theory. The central part of the triangular phase diagram for ABC triblock copolymers with equal A/B, B/C, and C/A interactions is determined by comparing the free energy of a number of candidate ordered phases. In this region of the phase diagram, the dominant microstructures are cylinders with polygonal cross sections or two-dimensional polygon-tiling patterns. Most of the known polygon-tiling patterns observed in experiments and simulations, plus some neighboring morphologies, are considered in the construction of the phase diagram. The resulting phase behavior is consistent with experiments and computer simulations. PMID- 20707589 TI - Numerical simulation of Gaussian chains near hard surfaces. AB - We present a coarse grain representation for Gaussian chains in the presence of hard surfaces. Whereas a Gaussian chain in the bulk can be represented by a bead spring model with a quadratic potential between adjacent beads, the presence of a surface reduces the number of allowed chain configurations and modifies the effective potential between the beads. We derive the corrected potentials for several surface geometries: a single wall, two parallel walls (slit), and a spherical or cylindrical object (nanoparticle). Those potentials can be used in any model that includes a Gaussian chain, regardless of the simulation method. As an illustration, we consider a coarse grain model of a polymeric melt and, using Monte Carlo simulations, we compute the density profiles for (i) a melt confined in a slit and (ii) a melt in the vicinity of a nanoparticle. The case of a polymeric solution confined within a slit is also addressed, and the proposed approach is shown to yield results in qualitative agreement with those obtained with field-theoretic simulations. PMID- 20707590 TI - Pathways of mechanical unfolding of FnIII(10): low force intermediates. AB - We study the mechanical unfolding pathways of the FnIII(10) domain of fibronectin by means of an Ising-like model, using both constant force and constant velocity protocols. At high forces and high velocities our results are consistent with experiments and previous computational studies. Moreover, the simplicity of the model allows us to probe the biologically relevant low force regime, where we predict the existence of two intermediates with very close elongations. The unfolding pathway is characterized by stochastic transitions between these two intermediates. PMID- 20707591 TI - Obstacles faced by general practitioners in Loreto Department, Peru in pursuing residency training. AB - INTRODUCTION: The Department of Loreto, one of the poorest regions of Peru, has an insufficient number of physicians, particularly specialists, needed to provide adequate health care for its population. The majority of Loreto physicians are GPs who have completed a one-year internship after medical school, followed by a mandatory year of rural service, with no subsequent training. Currently there are no residency training programs available in Loreto. The Loreto Ministry of Health recognizes the value in retaining its own medical school graduates and is, therefore, considering building residency programs in the 4 'basic specialties': internal medicine, pediatrics, general surgery, and obstetrics/gynecology. The objectives of this study were to: (1) characterize the population of currently practicing GPs in Iquitos and Requena in terms of demographics, current medical practice, and educational goals; (2) determine the obstacles faced by general physicians in Loreto, Peru in pursuing residency training; (3) provide baseline information to be used by medical academic institutions to develop specialization programs in Loreto. METHODS: A survey of 55 questions was created in Spanish encompassing demographics, current medical practice, education, training, and professional goals. Of the total 416 GPs in Loreto, 55 were identified in 2 locations: Iquitos and Requena. The goal was to administer the survey to each of these 55 physicians. Consent was given verbally, and 49 surveys were self administered. Survey responses were translated into English, data were entered in EpiData and analyzed using SPSS software (SPSS Inc; Chicago, IL, USA). RESULTS: A total of 49 surveys were completed by GPs in Iquitos and Requena. Of the respondents, 84% were male, the majority were either married or in common-law relationships, with at least one child. Their average age was 37.6 years. Sixty five percent were born in Loreto and most currently lived in Iquitos. Almost all respondents reported that they intended to pursue further training, the majority (59%) intending to pursue residency. Of those intending to complete a residency in the future, 40% specified a desired specialty from among the basic four, 22% a more specialized residency, and 37% did not specify any. The location of training sites, cost of moving to and living in Lima, and/or personal or family reasons were each identified by approximately 50% of respondents as obstacles to their pursuit of residency. Less common obstacles were: not passing the entrance exam, lack of job stability, and not knowing English. Fifty percent of the respondents only identified one obstacle, while 35% identified two and 15% identified three. CONCLUSION: Cost and location were the most significant factors preventing physicians from pursuing residency; overall, 83% of the physicians surveyed identified one or both of these as a factor that prevented them from pursuing residency. This suggests that there would be interest among the local physician population in residency programs established in Loreto. PMID- 20707592 TI - 'Closing the Gap': how maternity services can contribute to reducing poor maternal infant health outcomes for Aboriginal and Torres Strait Islander women. AB - CONTEXT: The reproductive health outcomes for Aboriginal and Torres Strait Islander mothers and infants are significantly poorer than they are for other Australians; they worsen with increasing remoteness where the provision of services becomes more challenging. Australia has committed to 'Overcoming Indigenous Disadvantage' and 'Closing the Gap' in health outcomes. ISSUES: Fifty five per cent of Aboriginal and Torres Strait Islander birthing women live in outer regional and remote areas and suffer some of the worst health outcomes in the country. Not all of these women are receiving care from a skilled provider, antenatally, in birth or postnatally while the role of midwives in reducing maternal and newborn mortality and morbidity is under-utilised. The practice of relocating women for birth does not address their cultural needs or self identified risks and is contributing to these outcomes. An evidence based approach for the provision of maternity services in these areas is required. Australian maternal mortality data collection, analysis and reporting is currently insufficient to measure progress yet it should be used as an indicator for 'Closing the Gap' in Australia. LESSONS LEARNED: A more intensive, coordinated strategy to improve maternal infant health in rural and remote Australia must be adopted. Care needs to address social, emotional and cultural health needs, and be as close to home as possible. The role of midwives can be enabled to provide comprehensive, quality care within a collaborative team that includes women, community and medical colleagues. Service provision should be reorganised to match activity to need through the provision of caseload midwives and midwifery group practices across the country. Funding to embed student midwives and support Aboriginal and Torres Strait Islander women in this role must be realised. An evidence base must be developed to inform the provision of services in these areas; this could be through the testing of the Rural Birth Index in Australia. The provision of primary birthing services in remote areas, as has occurred in some Inuit and New Zealand settings, should be established. 'Birthing on Country' that incorporates local knowledge, on-site midwifery training and a research and evaluation framework, must be supported. PMID- 20707593 TI - 11beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes. AB - IMPORTANCE OF THE FIELD: The prevalence of obesity and type 2 diabetes is rising and reaching pandemic proportions. For this reason, identification of novel therapeutic targets is urgently needed. AREAS COVERED IN THIS REVIEW: The endoluminal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes glucocorticoid activation in key metabolic tissues including skeletal muscle, liver and adipose tissue, and is strongly implicated in the pathogenesis of obesity, type 2 diabetes and the metabolic syndrome. Selective 11beta-HSD1 inhibitors limit local glucocorticoid availability and improve insulin sensitivity, glucose tolerance, lipid profiles and atherosclerosis. To date, there is a paucity of clinical studies using selective 11beta-HSD1 inhibitors; however, early indications show that these compounds have great therapeutic potential. WHAT THE READER WILL GAIN: We present a comprehensive overview of the background to the development of selective 11beta-HSD1 inhibitors, the preclinical data supporting 11beta-HSD1 as a therapeutic target, and the current status of clinical trials of these agents. TAKE HOME MESSAGE: Selective 11beta HSD1 inhibitors have the potential to improve insulin sensitivity and may ultimately add to the treatment options available for patients with type 2 diabetes. However, further clinical studies are urgently required. PMID- 20707595 TI - Sixth issue of the year 2010. PMID- 20707594 TI - Novel integrase inhibitors for HIV. AB - IMPORTANCE OF THE FIELD: Integrase inhibitors are the newest class of antiretroviral agents developed to treat HIV-1 infection. Raltegravir (RAL), the only integrase inhibitor (INI) currently approved for the treatment of HIV infected patients, has proven to be a potent and well-tolerated antiretroviral (ARV) agent. It is currently approved and used for the treatment of both ARV experienced and ARV-naive patients. Nevertheless, the relatively low genetic barrier for resistance of RAL encourages the search for new INIs with different mechanisms of actions and resistance profiles. AREAS COVERED IN THIS REVIEW: Here we review the data available about INI that are currently being tested in clinical trials or are in preclinical development: elvitegravir (EVG), S/GSK1349572, S/GSK1265744 and LEDGINs. We focus on their clinical efficacy, pharmacokinetic, safety and resistance profiles. WHAT THE READER WILL GAIN: Up-to date overview on the currently available, clinically relevant INIs and promising preclinical inhibitors at all phases of development. TAKE HOME MESSAGE: Integrase inhibitors represent the newest therapeutic class available to treat HIV-1 infection. There are a variety of compounds either available in the clinic (RAL), advancing to Phase III trials (EVG), or in earlier phases of development. Taken together, this class offers new treatment options for the HIV-infected individual. PMID- 20707596 TI - Evaluation of activity limitation and social participation, and the effects of reconstructive surgery in people with disability due to leprosy: a prospective cohort study. AB - PURPOSE: To assess how activity limitation and social participation of individuals with leprosy-related disability change over time, and to quantify the effect of reconstructive surgery. METHOD: Individuals with disability due to leprosy who accepted invitations for assessment at a leprosy clinic between March and July 2007 were interviewed using the SALSA Scale (measuring activity limitation) and the Participation Scale (assessing social participation). All participants were offered reconstructive surgery. Follow-up interviews were done 1 year after the first interview or 1 year after surgery. The main outcomes were changes in SALSA score and Participation score. We used analysis of variance to identify the effects of independent factors on mean SALSA and Participation scores. RESULTS: We interviewed 222 participants, 15 of whom took up the offer of surgery and 207 who did not. Comparison of SALSA Scale scores at baseline and 1 year revealed that activity limitation did not significantly change over time in individuals who declined surgery; however, participants who had surgery showed a significant improvement at 1 year (p < 0.001). Social participation improved over time in both groups, but the difference was significant only in the non-surgery group (p < 0.001). CONCLUSIONS: The findings suggest that reconstructive surgery has beneficial effects on functioning. Evaluation of the need for, and effect of, surgery in larger studies is recommended. PMID- 20707597 TI - Alpha-2 agonists in acute pain management. AB - IMPORTANCE OF THE FIELD: This review explores the significance of alpha-2 agonists used clinically in acute pain management. AREAS COVERED IN THIS REVIEW: Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords 'alpha-2 agonist', 'clonidine', 'dexmedetomidine', 'fadolmidine', 'pharmacokinetics', 'pharmacodynamics', 'postoperative analgesia', 'epidural', 'intrathecal', 'peripheral nerve block' and various combinations with these keywords. The years 1977 - 2009 have been included, with particular focus on clinical studies from between 1990 and 2009. WHAT THE READER WILL GAIN: This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-to-date evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail. TAKE HOME MESSAGE: Alpha 2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control. PMID- 20707598 TI - Facing up to toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) is a rare but life-threatening mucocutaneous adverse drug reaction. The disease is characterized by a specific and extensive destruction of the epidermis and mucosal epithelia, particularly of the mouth, genitalia and eyes. The TEN pathomechanism is probably initiated by a toxic drug metabolism inside keratinocytes, leading to a self-activation of apoptosis and necrosis. These events are boosted by additional effects of T lymphocytes and macrophages. At present there is still a lack of validated mainstay treatment for TEN. However, a few treatment modalities have been reported to halt TEN progression in some patients. PMID- 20707599 TI - Zonation of heme synthesis enzymes in mouse liver and their regulation by beta catenin and Ha-ras. AB - Cytochrome P450 (CYP) hemoproteins play an important role in hepatic biotransformation. Recently, beta-catenin and Ha-ras signaling have been identified as players controlling transcription of various CYP genes in mouse liver. The aim of the present study was to analyze the role of beta-catenin and Ha-ras in the regulation of heme synthesis. Heme synthesis-related gene expression was analyzed in normal liver, in transgenic mice expressing activated beta-catenin or Ha-ras, and in hepatomas. Regulation of the aminolevulinate dehydratase promoter was studied in vitro. Elevated expression of mRNAs and proteins involved in heme biosynthesis was linked to beta-catenin activation in perivenous hepatocytes, in transgenic hepatocytes, and in hepatocellular tumors. Stimulation of the aminolevulinate dehydratase promoter by beta-catenin was independent of the beta-catenin/T-cell-specific transcription factor dimer. By contrast, activation of Ha-ras repressed heme synthesis-related gene expression. The present data suggest that beta-catenin enhances the expression of both CYPs and heme synthesis-related genes, thus coordinating the availability of CYP apoprotein and its prosthetic group heme. The reciprocal regulation of heme synthesis by beta-catenin and Ha-ras-dependent signaling supports our previous hypothesis that antagonistic action of these pathways plays a major role in the control of zonal gene expression in healthy mouse liver and aberrant expression patterns in hepatocellular tumors. PMID- 20707600 TI - Amino acid residues modulating the activities of staphylococcal glutamyl endopeptidases. AB - The glutamyl endopeptidase family of enzymes from staphylococci has been shown to be important virulence determinants of pathogenic family members, such as Staphylococcus aureus. Previous studies have identified the N-terminus and residues from positions 185-195 as potentially important regions that determine the activity of three members of the family. Cloning and sequencing of the new family members from Staphylococcus caprae (GluScpr) and Staphylococcus cohnii (GluScoh) revealed that the N-terminal Val residue is maintained in all family members. Mutants of the GluV8 enzyme from S. aureus with altered N-terminal residues, including amino acids with similar properties, were inactive, indicating that the Val residue is specifically required at the N-terminus of this enzyme family in order for them to function correctly. Recombinant GluScpr was found to have peptidase activity intermediate between GluV8 and GluSE from Staphylococcus epidermis and to be somewhat less specific in its substrate requirements than other family members. The 185-195 region was found to contribute to the activity of GluScpr, although other regions of the enzyme must also play a role in defining the activity. Our results strongly indicate the importance of the N-terminal and the 185-195 region in the activity of the glutamyl endopeptidases of staphylococci. PMID- 20707601 TI - Mipomersen as a potential adjunctive therapy for hypercholesterolemia. AB - Mipomersen, an antisense oligonucleotide directed against apolipoprotein B-100 (apoB), was investigated for its safety and efficacy in reducing low-density lipoprotein (LDL) cholesterol (C) as adjunctive treatment for patients with homozygous familial hypercholesterolemia (HoFH) in a Phase III, double-blind, randomized, controlled trial. HoFH patients are very rare in the general population (~ 1:1,000,000) and have very high risk for cardiovascular events. HoFH patients respond poorly to statins and most other existing lipid-lowering therapies. Mipomersen (200 or 160 mg) administered subcutaneously to 34 HoFH patients for 26 weeks significantly reduced LDL-C by 24.7% from baseline. In addition, mipomersen lowered plasma lipoprotein (a). In most patients, mipomersen administration was most associated with injection-site reactions; influenza-like symptoms were also more common in mipomersen-treated patients. Four patients had elevated serum alanine aminotransferase (ALT) concentrations, one of whom also had a significant increase in intrahepatic triglyceride content. Another patient met the stopping rules for increased ALT concentrations. No patient developed steatohepatitis during the study. Thus, so far short-term data indicate that mipomersen is safe and effective as an adjunctive drug for lowering LDL-C. Despite these promising results, the longer-term safety and efficacy of mipomersen still needs to be determined. PMID- 20707602 TI - Role of the second disulfide bridge (Cys(18)-Cys(274)) in stabilizing the inactive AT1 receptor. AB - Previous research showed that disruption of the Cys(18)-Cys(274) bond in the angiotensin II (AngII) AT1 receptor mutant (C18S), expressed in CHO cells, causes an increase in the basal activity and attenuation of the maximum response to AngII. In addition, this mutant was mostly intracellularly distributed. Our aim was to investigate whether the intracellular presence of the mutant was due to a constitutive internalization or to a defective maturation of the receptor. The first hypothesis was assessed by pretreating the cells with losartan or [Sar1Leu8]-AngII, specific AT1 receptor antagonists, a maneuver to revert the receptor internalization. The second hypothesis was tested using calnexin, an endoplasmic reticulum marker. We found that treatment with AT1 receptor antagonists causes an increase in the binding ability of the mutant to AngII. Furthermore, whereas the maximum effect is increased, it reduces the enhanced basal levels of IP3. The hypothesis for a lack of maturation of the mutant receptor was ruled out because calnexin was poorly colocalized with the intracellular C18S receptor. Our results suggest that the mutation of the AT1 receptor leads to a conformational structure similar to that of the active mode of the AT1 receptor, favoring its internalization in the absence of the agonist. PMID- 20707603 TI - The neuronal proteins CIPP, Cypin and IRSp53 form a tripartite complex mediated by PDZ and SH3 domains. AB - Here we report the dissection of a tripartite complex formed by CIPP (channel interacting PDZ protein), IRSp53 (insulin receptor tyrosine kinase substrate protein) and Cypin (cytosolic PSD-95 interactor) in cultured cells. The three proteins are expressed in similar neuronal districts, where CIPP binds to different membrane channels and receptors, IRSp53 regulates the morphogenesis of actin-rich dendritic spines, and Cypin promotes dendrite branching and patterning by binding to tubulin heterodimers. We observed that the interaction among the three proteins is mediated by small binding domains: CIPP works as a bridge, linking the carboxy-termini of IRSp53 and Cypin with its PDZ domains; IRSp53 connects Cypin, through an unusual SH3-mediated association, which can be impaired by substituting two crucial positively charged residues of Cypin. The observation that the three engineered proteins co-localize in the cytoplasm, and at the tip of induced neurites in neuronal cells, raises the interesting possibility that they work together in the formation of neuronal protrusions. PMID- 20707604 TI - Expression and role of the cell surface protease seprase/fibroblast activation protein-alpha (FAP-alpha) in astroglial tumors. AB - Seprase or fibroblast activation protein-alpha (FAP-alpha) is a cell-surface serine protease that was previously described nearly exclusively on reactive and tumor stromal fibroblasts and thought to be involved in tissue remodeling. We investigated the expression and significance of FAP-alpha in astrocytomas/glioblastomas. As shown by quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, FAP-alpha was elevated in whole glioblastoma tissues and in particular in most glioma cells in situ and in vitro. In glioma stem-like cells (gliospheres), FAP-alpha was detected at low levels; however, FAP-alpha was considerably induced upon differentiation with 10% fetal calf serum. To explore its functional role, FAP alpha was silenced by siRNA transfection. In Boyden chamber assays, FAP-alpha silenced cells migrated similar as control cells through non-coated or Matrigel (basal lamina)-coated porous membranes, but significantly slower through membranes coated with gelatin or brevican, a major component of brain extracellular matrix. Furthermore, FAP-alpha-silenced glioma cells migrated through murine brain slices much slower under the conditions tested than differentially fluorescent-labeled control cells. Thus, FAP-alpha is highly expressed on the surface of glioma cells and contributes to diffuse glioma invasion through extracellular matrix components. PMID- 20707605 TI - E. coli hypoxia-inducible factor ArcA mediates lifespan extension in a lipoic acid synthase mutant by suppressing acetyl-CoA synthetase. AB - We have previously shown that both the hypoxia-inducible transcription factor ArcA and the PoxB/Acs bypass of the pyruvate dehydrogenase complex contribute to extended lifespan in Escherichia coli. In agreement with studies in higher eukaryotes, we also demonstrated that long-lived E. coli mutants, including LipA deficient cells, are stress resistant. Here, we show that ArcA contributes to the enhanced lifespan and heat shock resistance of the lipA mutant by suppressing expression of the acetyl-CoA synthetase (acs) gene. The deletion of acs reversed the reduced lifespan of the lipA arcA mutant and promoted the accumulation of extracellular acetate, indicating that inhibition of carbon source uptake contributes to survival extension. However, Acs also sensitized cells lacking ArcA to heat shock, in the absence of extracellular acetate. These results provide evidence for the role of Acs in regulating lifespan and/or stress resistance by both carbon source uptake-dependent and -independent mechanisms. PMID- 20707606 TI - Demonstration of protein absorption in the intestinal epithelium of fish and mice by laser scanning confocal microscopy. AB - Selective permeability for small proteins and oligopeptides occurs in the intestinal epithelium of many animal species and humans. Whole proteins are sometimes endocytosed and undergo partial hydrolysis in intestinal epithelial cells with the probable release of essential oligopeptides into the bloodstream. Increased permeability to certain proteins can cause asthma and other metabolic disorders. Permeable proteins have also been successfully used to deliver vaccines or drugs via oral consumption. Protein absorption has been inferred in many cases and demonstrated in some cases by histochemical, tracer, and analytical techniques. However, the nature and importance of protein absorption remains largely unknown. Here, we demonstrate the movement of two lumenal proteins (GFP: 26 kDa and OFP: 23 kDa) across the intestinal epithelium of fish and mice using laser scanning confocal microscopy. The results provide evidence that small proteins can be taken up intact by intestinal epithelial cells, even though large proteins are digested to single amino acids or protein fragments before they are absorbed. Our results suggest that it is possible to orally administer some small proteinous medicines for therapeutic purposes. PMID- 20707607 TI - New structural aspects of FKBP38 activation. AB - The human FK506-binding protein 38 (FKBP38) regulates Bcl-2 in neuronal apoptosis. To control Bcl-2 activity, FKBP38 requires a prior interaction with the Ca(2+)-sensor calmodulin (CaM). The resulting FKBP38/CaM complex is unique within the FKBP family. Here, we present novel insights into the structural arrangement of this complex. Chemical shift perturbation analyses of the individual protein domains revealed two separate interaction sites between FKBP38 and CaM. On the one hand, residues Glu303, Tyr307 and Leu311, belonging to the predicted CaM-binding site at the C-terminal end of FKBP38, become embedded in the hydrophobic target protein-binding cleft of the C-terminal CaM lobe. On the other hand, in a second binding interaction, the N-terminal end of the catalytic FKBP38 domain shows surface contacts to the AB and CD loops of CaM as well as the adjacent helices. Furthermore, a Glu-rich region at the non-structured FKBP38 N terminus features additional contacts to CaM helix A. In combination with previous results, we thus conclude that the FKBP38/CaM complex is constituted by (i) a Ca(2+)-dependent interaction of the CaM-binding motif at the C-terminal end of FKBP38 with the C-terminal CaM lobe and (ii) a Ca(2+)-independent interaction between the N-terminal CaM lobe and the N-terminal region of the catalytic FKBP38 domain. PMID- 20707608 TI - The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging. AB - In the past year and a half, five studies have independently established a direct connection between the hypoxic response transcription factor, HIF-1, and aging in Caenorhabditis elegans. These studies demonstrated that HIF-1 can both promote and limit longevity via pathways that are mechanistically distinct. Here, we review the current state of knowledge regarding modulation of aging by HIF-1 and speculate on potential aspects of HIF-1 function that could be relevant for mammalian longevity and healthspan. PMID- 20707609 TI - Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis. AB - In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging. PMID- 20707611 TI - Pharmacokinetic and pharmacodynamic evaluation of sitagliptin plus metformin. AB - IMPORTANCE OF THE FIELD: Type 2 diabetes is an increasingly prevalent disease resulting from various complex combinations of defects in insulin secretion and insulin action. Adequate blood glucose control is necessary to minimize complications. DPP IV inhibitors (sitagliptin, vildagliptin, saxagliptin) offer new options for combined pharmacological therapy. AREAS COVERED IN THIS REVIEW: An extensive literature search was performed to analyze the potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between metformin (first-line drug for the management of type 2 diabetes) and sitagliptin (first commercialized DPP IV inhibitor). Metformin and sitagliptin may be administered together, either separately or in fixed-dose combination. WHAT THE READER WILL GAIN: Updated information about PK/PD data on metformin alone, sitagliptin alone and sitagliptin plus metformin. Metformin and sitagliptin are not prone to PK drug-drug interactions. Their co-administration, either separately or in a fixed dose combination, improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin related gastrointestinal side effects. TAKE HOME MESSAGE: The combination sitagliptin plus metformin may be used as a first- or second-line therapy in the management of type 2 diabetes. PMID- 20707610 TI - Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants. AB - The mitochondrial DNA (mtDNA) encompasses two classes of functionally important sequence variants: recent pathogenic mutations and ancient adaptive polymorphisms. To rapidly and cheaply evaluate both classes of single nucleotide variants (SNVs), we have developed an integrated system in which mtDNA SNVs are analyzed by multiplex primer extension using the SNaPshot system. A multiplex PCR amplification strategy was used to amplify the entire mtDNA, a computer program identifies optimal extension primers, and a complete global haplotyping system is also proposed. This system genotypes SNVs on multiplexed mtDNA PCR products or directly from enriched mtDNA samples and can quantify heteroplasmic variants down to 0.8% using a standard curve. With this system, we have developed assays for testing the common pathogenic mutations in four multiplex panels: two genotype the 13 most common pathogenic mtDNA mutations and two genotype the 10 most common Leber Hereditary Optic Neuropathy mutations along with haplogroups J and T. We use a hierarchal system of 140 SNVs to delineate the major global mtDNA haplogroups based on a global phylogenetic tree of coding region polymorphisms. This system should permit rapid and inexpensive genotyping of pathogenic and lineage-specific mtDNA SNVs by clinical and research laboratories. PMID- 20707612 TI - Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J mice. AB - To assess the significance of the non-genomic signaling of TCDD (=dioxin) on liver of C57BL/6 mice and HepG2 human hepatoma cells, we first determined the group of markers that are susceptible to inhibition by parthenolide, a compound known to specifically suppress NF-kappaB-mediated inflammation. Of those, the most consistent marker turned out to be SOCS3 (a suppressor of cytokine signaling) known to respond to inflammation. An early diagnostic test on the action of TCDD on HepG2 cells in vitro within 3-6 h indicated that Cox-2 and SOCS3 are mainly induced via a non-genomic route, whereas PAI-2 appears to be induced through the classical action route. More detailed diagnostic tests at later stages of action of TCDD in HepG2 cells revealed that induction of IL 1beta, BAFF, and iNOS are largely mediated by the protein kinase-dependent non genomic route. An in vivo study on the 7 day action of TCDD on liver of AhR(NLS) mice showed that several early markers (e.g., Cox-2, MCP-1 and SOCS3) are induced, but not late markers such as IL-1beta. Together, these results show that the non-genomic pathway contributes significantly to the early stress response reactions to TCDD that includes inflammation in hepatoma cells as well as in the liver. PMID- 20707613 TI - Does very advanced maternal age, with or without egg donation, really increase obstetric risk in a large tertiary center? AB - OBJECTIVE: to assess complications of very advanced maternal age (VAMA) pregnancies >= 45 years with and without egg donation (ED). STUDY DESIGN: obstetric and neonatal complications were studied in 20,659 singleton pregnancies according to three maternal age groups: 20-39, 40-44 [advanced maternal age (AMA)] and >= 45 years (VAMA). Twenty pregnancies within the AMA/LAMA group that were achieved with ED were compared with age-matched controls. RESULTS: AMA mothers were more likely to have higher rates of preterm deliveries (OR 1.25), cesarean sections (OR 1.84) hypertension (OR 1.71) and diabetes (OR 2.45). Their newborns were more frequently small for gestational age (OR 1.30), and were more likely to have high rates of respiratory distress syndrome (OR 1.66), neonatal intensive care admission (OR 1.40) and perinatal/neonatal mortality (OR 1.83). VAMA pregnancies had >50% cesarean section rate and a high rate of diabetes (OR 2.29), hypertension (OR 1.54) and postpartum hemorrhage (OR 5.38). Congenital anomalies were more common among ED pregnancies. CONCLUSIONS: the higher rate of pregnancy complications for women >= 40 years is not further increased after 45 years of age. PMID- 20707614 TI - The role of melatonin in post-partum psychosis and depression associated with bipolar disorder. AB - Recent data has highlighted the association of a bipolar disorder (BD) with an increased risk of post-partum psychosis and depression. It is suggested that genetic- and environmental-induced decrease in the levels of melatonin in BD contributes to post-partum disorders. Melatonin may also have some efficacy in the treatment of BD, especially in decreasing the side-effects associated with lithium and the neuroleptics. It is proposed that the optimization of melatonin levels, perhaps in conjunction with optimized vitamin D3 level, would decrease post-partum psychosis and depression associated with BD. PMID- 20707615 TI - Serial changes of lung morphology and biochemical profiles in a rat model of bronchopulmonary dysplasia induced by intra-amniotic lipopolysaccharide and postnatal hyperoxia. AB - AIM: to investigate serial changes of lung morphology and biochemical profiles in a rat model of bronchopulmonary dysplasia (BPD) induced by intra-amniotic lipopolysaccharide (LPS) administration and postnatal hyperoxia (85%). METHODS: we evaluated histological changes of the lungs and compared the levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and protein carbonyl in lung tissue on days 1, 7, and 14 after birth in a rat model of BPD. RESULTS: the inhibition of alveolarization was sustained in the LPS plus hyperoxia group from day 7 to 14, whereas alveolarization resumed in the hyperoxia group after oxygen exposure was withdrawn at day 7. Administration of LPS alone did not adversely affect lung morphometry. IL-6 levels showed transient overexpression at day 1 in the LPS-treated groups, but decreased at days 7 and 14. VEGF protein levels were elevated in the LPS-treated groups, but not in the hyper-oxia and control groups at days 1, 7, and 14. Exposure to hyperoxia affected protein carbonyl levels in the hyperoxia group at days 7 and 14. CONCLUSION: lung injury induced by intra-amniotic inflammation and postnatal hyperoxia may be due to inhibition of alveolarization without recovery even after withdrawal of oxygen. PMID- 20707616 TI - Endoscopic transventricular third ventriculostomy through the lamina terminalis. AB - OBJECT: Endoscopic third ventriculostomy (ETV) has become a well-accepted option for obstructive hydrocephalus. However, standard ventriculostomy at the floor of the third ventricle might not be feasible under certain conditions. Here, the authors report in detail on their initial experience with an alternative option of endoscopic ventriculostomy through the lamina terminalis via a transventricular route. METHODS: Endoscopic third ventriculostomy through the lamina terminalis from a transventricular transforaminal route was evaluated in 4 cadaveric human heads and in 4 clinical cases. RESULTS: In all 4 human cadavers, an opening of the lamina terminalis via a transventricular approach could be achieved without injury to either the optic chiasm or the anterior cerebral arteries. In the 4 clinical cases, an accurate and reliable ventriculostomy was performed at the lamina terminalis. The bur hole was placed directly at the coronal suture 2 cm lateral from the midline. After identifying the optic chiasm and the anterior cerebral arteries, a blunt perforation was made just anterior to the optic chiasm by using perforation forceps and a balloon catheter. After the opening, the stoma was inspected with a 0 degrees and 30 degrees rod lens endoscope, and its patency as well as the preservation of vessels and optic nerves was checked. No complications occurred, although all patients suffered from a clinically silent fornical contusion at the foramen of Monro. CONCLUSIONS: Endoscopic opening of the lamina terminalis via a transventricular transforaminal route appears to be feasible. No complications were observed. Although no conclusions on the clinical success rate can be drawn, the reliable anatomical opening and known success rate for anterior subfrontal approaches suggest that the technique represents an alternative in a small subgroup of patients in whom a standard ETV cannot be performed. PMID- 20707617 TI - Anterior third ventriculostomy: an endoscopic variation on a theme. PMID- 20707618 TI - Non-watertight dural reconstruction in meningioma surgery: results in 439 consecutive patients and a review of the literature. Clinical article. AB - OBJECT: There are various schools of thought when it comes to dural reconstruction following meningioma surgery, which are largely based on the personal experience of the individual surgeons. The authors' aim in this study was to review different dural reconstruction techniques, with an emphasis on their experience with the synthetic onlay dural graft technique. METHODS: The medical records of 439 consecutive patients who were surgically treated for an intracranial meningioma over a period of 7 years, and for whom dural reconstruction was performed using the onlay dural graft DuraGen (Integra Neurosciences) were reviewed retrospectively. The most common tumor location was the convexity (27.6%), and 12% of the patients had undergone previous surgery. Complications related to the closure technique and/or closure material, such as CSF leakage from the incision, rhinorrhea, or infectious or chemical meningitis were reviewed. RESULTS: A CSF leak was encountered in 2 patients (0.4%), and 10 patients (2.3%) experienced graft-related complications in the form of chemical meningitis, cerebritis, and accumulation of extraaxial fluid. Infectious complications were seen in 4 patients (0.9%; bacterial meningitis, osteomyelitis, epidural abscess). None of the patients had pseudomeningocele that required a second intervention. CONCLUSIONS: In the authors' experience, the incidence of CSF leakage following non-watertight reconstruction of the dura mater in meningioma surgery performed using dural onlay graft was 0.4%. Graft-related complications occurred in 2.3%. These figures compare favorably to the majority of the series in which watertight dural closure is described and emphasized. PMID- 20707619 TI - Incorporating a parenchymal thermal diffusion cerebral blood flow probe in bedside assessment of cerebral autoregulation and vasoreactivity in patients with severe traumatic brain injury. AB - OBJECT: Cerebral autoregulation may be altered after traumatic brain injury (TBI). Recent evidence suggests that patients' autoregulatory status following severe TBI may influence cerebral perfusion pressure management. The authors evaluated the utility of incorporating a recently upgraded parenchymal thermal diffusion probe for the measurement of cerebral blood flow (CBF) in the neurointensive care unit for assessing cerebral autoregulation and vasoreactivity at bedside. METHODS: The authors evaluated 20 patients with severe TBI admitted to San Francisco General Hospital who underwent advanced neuromonitoring. Patients had a parenchymal thermal diffusion probe placed for continuous bedside monitoring of local CBF ((loc)CBF) in addition to the standard intracranial pressure and brain tissue oxygen tension (P(bt)O(2)) monitoring. The CBF probes were placed in the white matter using a separate cranial bolt. A pressure challenge, whereby mean arterial pressure (MAP) was increased by about 10 mm Hg, was performed in all patients to assess autoregulation. Cerebral CO(2) vasoreactivity was assessed with a hyperventilation challenge. Local cerebral vascular resistance ((loc)CVR) was calculated by dividing cerebral perfusion pressure by (loc)CBF. Local cerebral vascular resistance normalized to baseline ((loc)CVR(normalized)) was also calculated for the MAP and hyperventilation challenges. RESULTS: In all cases, bedside measurement of (loc)CBF using a cranial bolt in patients with severe TBI resulted in correct placement in the white matter with a low rate of complications. Mean (loc)CBF decreased substantially with hyperventilation challenge (-7 +/- 8 ml/100 g/min, p = 0.0002) and increased slightly with MAP challenge (1 +/- 7 ml/100 g/min, p = 0.17). Measurements of (loc)CBF following MAP and hyperventilation challenges can be used to calculate (loc)CVR. In 83% of cases, (loc)CVR increased during a hyperventilation challenge (mean change +3.5 +/- 3.8 mm Hg/ml/100 g/min, p = 0.0002), indicating preserved cerebral CO(2) vasoreactivity. In contrast, we observed a more variable response of (loc)CVR to MAP challenge, with increased (loc)CVR in only 53% of cases during a MAP challenge (mean change -0.17 +/- 3.9 mm Hg/ml/100 g/min, p = 0.64) indicating that in many cases autoregulation was impaired following severe TBI. CONCLUSIONS: Use of the Hemedex thermal diffusion probe appears to be a safe and feasible method that enables continuous monitoring of CBF at the bedside. Cerebral autoregulation and CO(2) vasoreactivity can be assessed in patients with severe TBI using the CBF probe by calculating (loc)CVR in response to MAP and hyperventilation challenges. Determining whether CVR increases or decreases with a MAP challenge ((loc)CVR(normalized)) may be a simple provocative test to determine patients' autoregulatory status following severe TBI and helping to optimize CPP management. PMID- 20707620 TI - Low maternal serum matrix metalloproteinase (MMP)-2 concentrations are associated with preterm labor and fetal inflammatory response. AB - OBJECTIVES: to assess the relationship between maternal and umbilical serum concentrations of matrix metalloproteinases (MMP)-2,8,9, the soluble receptor for advanced glycation end products (sRAGE) and IL-10 and premature delivery and fetal inflammation. METHODS: maternal serum levels of MMPs, sRAGE, IL-10 and C reactive protein (CRP) were determined in 67 women with preterm labor and in 38 healthy pregnant women of similar gestational age (GA). In the group with preterm labor we also determined umbilical concentrations of MMPs, IL-6 and sRAGE. The group with preterm labor was additionally divided based on the presence of funisitis and elevations of fetal umbilical IL-6 concentrations. RESULTS: maternal serum levels of MMP-2 and sRAGE were significantly lower in women with preterm labor compared to women with normal pregnancy. Additionally, within the group of women with preterm labor, maternal serum MMP-2 concentrations were significantly lower in the subgroup with funisitis and in the subgroup with elevated umbilical concentration of IL-6. CONCLUSION: our results demonstrate significantly different serum concentrations of MMP-2 and sRAGE in women with preterm labor compared to healthy pregnant patients of the same GA. PMID- 20707621 TI - The expression pattern of two novel cytokines (IL-24 and IL-29) in human fetal membranes. AB - OBJECTIVE: interleukin (IL)-24 and -29 are novel cytokines, produced by immune cells in response to microbial antigens. The functions of these cytokines in the reproductive system are unknown. We examined the expression pattern of IL-24 and IL-29 in human fetal membranes from preterm and term births and in in vitro in response to microbial antigens. METHODS: fetal membranes collected from cesarean sections at term (normal, not in labor) were placed in culture for 48 h. These membranes were then stimulated with bacterial lipopolysaccharide (LPS) or viral antigen poly-inosinic and cytidylic acid (polyIC) for an additional 24 h. Amniotic fluids (AF) and fetal membranes were also collected from preterm and term deliveries. IL-24 and IL-29 expressions were studied by RT-PCR. ELISA documented culture media and AF cytokine concentrations. RESULTS: IL-24 and IL-29 expressions were seen in cultured fetal membranes regardless of stimulation. Expressions were also found in preterm and term labor membranes, but not in non labor tissues at term. IL-24 concentrations were higher after LPS stimulation whereas IL-29 concentrations were higher after polyIC-stimulation. AF analysis did not detect either of the cytokines either preterm or term. CONCLUSION: this is the first study to report IL-24 and IL-29 expressions in human fetal membranes. Higher concentrations of these cytokines in response to distinct infectious stimuli suggest different pathways for fetal immune response during infection. PMID- 20707622 TI - Mediastinal tumor during pregnancy: a multidisciplinary approach. PMID- 20707623 TI - Comparative analysis of insulin-like growth factor binding protein-1 (IGFBP-1), placental alpha-microglobulin-1 (PAMG-1) and nitrazine test to diagnose premature rupture of membranes in pregnancy. AB - PURPOSE: to compare insulin-like growth factor binding protein-1 (IGFBP-1) (non phosphorylated), placental alpha-microglobulin-1 (PAMG-1) and nitrazine test to diagnose premature rupture of membrane to allow gestation-specific management. METHODS: we recruited 100 women with signs or symptoms of premature rupture of membranes (PROM), between 17 and 37 weeks at a tertiary referral center. RESULTS: in 100 women in whom PAMG-1 was performed, sensitivity was 92.7%, specificity was 100%, positive predictive value (PPV) was 100% and negative predictive value (NPV) was 95.2%. IGFBP-1 was performed in 94 women, the sensitivity was 87.5%, specificity was 94.4%, PPV was 92.1% and NPV was 91.1%. In 98 women in whom nitrazine test was performed, the sensitivity was 85%, specificity was 39.7%, PPV was 49.3% and NPV was 79.3%. CONCLUSION: PAMG-1 was the most accurate test in diagnosing rupture of membranes and had the highest sensitivity, specificity, PPVs and NPVs. PMID- 20707624 TI - Prenatal tobacco exposure and cortisol levels in infants of teen mothers. AB - AIMS: prenatal tobacco exposure (PTE) is an important public health concern for the offspring of teen mothers. We examined whether PTE is associated with baseline cortisol levels in four-month-old infants of teenage mothers. METHODS: we assessed salivary cortisol levels of 212 infants. PTE was measured by using self-reports of cigarette smoking during pregnancy. We used a propensity scores matching analysis to compare infants with PTE and those without. RESULTS: of 212 mothers, 151 smoked during pregnancy. However, there was no association between PTE and infant cortisol levels. CONCLUSIONS: we could not support a relation between PTE and cortisol levels in a sample of four-month-old infants of teenage mothers. PMID- 20707625 TI - Effect of prenatal tobacco smoke exposure on fetal growth potential. AB - AIM: to determine the independent effect of prenatal tobacco smoke exposure on fetal growth using customized birthweight norms. METHODS: demographic characteristics and data on exposure to tobacco smoke during pregnancy were obtained from singleton neonates >= 34 weeks' gestation. Centile Calculator software v62.2 (www.gestation.net) was used for calculating customized birthweight percentiles. RESULTS: of the 3227 neonates studied, 30.9% were exposed to maternal smoking during pregnancy, whereas involuntary maternal exposure was reported in 20.1%. Growth restriction was noted in 350 (10.8%). The odds ratio (OR) for fetal growth restriction was 1.49 (1.10-1.91) in passive smokers, and 2.34 (1.81-2.96) in smokers. A decrease in birthweight and an increase in the prevalence of growth restriction with the increasing number of cigarette consumption was observed. This effect was evident even in cases of a "minimal" consumption of 1-5 cigarettes per day. CONCLUSION: an essential adverse effect of tobacco smoke exposure on fetal growth in pregnancies exposed to passive smoking, as well as in those with "minimal" maternal cigarette consumption, was found. Since approximately 30% of growth restricted neonates could be independently attributed to active or passive maternal exposure, these findings reinforce the need for smoking preventive strategies in pregnant women and their environment. PMID- 20707626 TI - Neonatal abstinence syndrome (NAS) after intrauterine exposure to tramadol. PMID- 20707627 TI - A great lack of knowledge regarding umbilical cord blood banking among pregnant women in Berlin, Germany. AB - OBJECTIVE: we evaluated what German-speaking women in Berlin know about umbilical cord blood banking (UCBB) and whether a correlation exists between women's knowledge about UCBB and level of education. METHOD: we used the anonymous questionnaire given to German-speaking women in Berlin, Germany. RESULTS: a total of 300 questionnaires could be evaluated. Although three quarters of our population heard of UCBB, most had no further knowledge about the method. Only about one-third of the interviewed women were informed about whether certain diseases had been treated with umbilical cord blood (UCB) by the time the survey was being conducted, whereas 50-65% did not know how to answer these questions. CONCLUSION: women in Berlin were poorly educated about the usefulness, the costs and the methods of cryopreservation. To some extent there is a correlation between women's level of education and their knowledge regarding UCB. PMID- 20707628 TI - The source of error in the estimation of intertwin birth weight discordance. AB - OBJECTIVE: to assess the accuracy of paired estimated fetal weights (EFWs) to predict three levels of twin birth weight discordance (>15%, >20% and >25%). METHOD: a cohort of twin pairs underwent ultrasound examinations within 2 weeks from birth. We calculated the frequency of under- and overestimation of the actual birth weight (< or >10%, respectively) in the entire cohort as well in the subset of mono- and dichorionic pairs. RESULTS: discordance was largely underestimated (observed 10.4 +/- 0.8% compared to actual 19.2 +/- 1.1%, P=0.001) because the larger twin was more frequently underestimated [30.6 vs. 17.7%, odds ratio (OR) 2.0, 95% confidence interval (CI) 1.1, 3.9 in the entire cohort, and 34.2 vs. 13.1%, OR 3.4, 95% CI 1.4, 8.4 in the dichorionic pairs]. Overall, the specificity for detecting the three levels of discordance was adequate (91.5 94.2%) but the sensitivity was poor (11.1-17.8%) and tended to decrease with increasing discordance level. CONCLUSION: the poor ability of paired EFWs to diagnose birth weight discordance results from underestimation of the larger twin. PMID- 20707629 TI - Comparison of complications in second trimester amniocentesis performed with 20G, 21G and 22G needles. AB - AIM: to compare short- and long-term complications of amniocentesis performed with 20G, 21G, and 22G needles. METHODS: this observational study included 793 pregnant women who underwent amniocentesis in the Perinatology Department of Cerrahpasa Medical Faculty, Istanbul University, Turkey. The patients were divided into three groups according to the needle size used for the procedure: 20G (Group 1), 21G (Group 2), and 22G (Group 3). The incidences of early and late complications were compared among groups. RESULTS: fetal loss rates did not differ among groups (Group 1=1.57%, Group 2=1.47%, Group 3=1.61%). Rates of vaginal bleeding (1.57%, 1.10%, and 0.81%, respectively), bloody amniotic fluid (2.32%, 6.23%, and 2.67%, respectively) and amniotic fluid leakage (1.57%, 1.10%, and 1.61%, respectively) were also similar among the three groups. CONCLUSION: short- and long-term complications did not differ among amniocenteses performed with 20G, 21G, and 22G needles. PMID- 20707630 TI - Evidence of the escape of antithrombin from the blood into the interstitial space in pregnant women. AB - OBJECTIVE: we investigated whether ascites samples obtained from pregnant women during cesarean sections contained antithrombin because it is unknown whether antithrombin escapes from the blood and passes into the interstitial space during pregnancy. METHODS: the concentration and activity levels of antithrombin were determined in six ascites samples obtained from six consecutive women who exhibited generalized edema, ascites, and a gradual decline in antithrombin activity. RESULTS: all six ascites samples contained antithrombin (mean +/- SD, 4.9 +/- 2.2 mg/dL; range, 2.7-8.8 mg/dL) and exhibited an antithrombin activity level of 15.5 +/- 6.0% (range, 10-24%). CONCLUSIONS: antithrombin escapes from the blood into the interstitial space in pregnant women. This phenomenon partially explains the gradual decline in antithrombin activity observed in these six pregnant women with generalized edema and large volumes of ascites. PMID- 20707631 TI - Fetoscopic laser photocoagulation and uterine wall defects. PMID- 20707632 TI - Melatonin: pharmacological aspects and clinical trends. AB - Melatonin, N-acetyl-5-methoxytryptamine, the major hormone produced by the pineal gland under the influence of the dark/light cycle, has been shown to have a large number of therapeutic possibilities. It has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep-wake cycle disturbances in blind people, and shift workers. In our mechanism of act, the G(i) protein-coupled metabotropic melatonin receptors MT1 and MT2 are the primary mediators of the physiological actions of melatonin. This hormone plays an important role in the regulation of physiological and neuroendocrine functions, such as synchronization of seasonal reproductive rhythms and entrainment of circadian cycles. In addition to its chronobiological role, several pharmacological effects of melatonin have been reported in mammals including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities. There is some evidence from clinical trials that melatonin can be helpful in that event. Current trends of pharmacological functions of melatonin pointed out its use in the treatment of neurodegenerative and neoplastic diseases. These effects and uses of melatonin are mentioned but further confirmatory studies are needed in most of them. PMID- 20707633 TI - Hypothesis on the relationship between the change in intracellular pH and incidence of sporadic Alzheimer's disease or vascular dementia. AB - In order to perform their normal physiological functions, it is important that cells maintain the intracellular pH within the physiological range. Intracellular enzyme activity, cytoskeleton component integration, and cellular growth and differentiation rates are all closely associated with the intracellular pH. It has been demonstrated that in nervous system diseases, such as ischemic stroke, traumatic brain injury, epilepsy, Parkinson's disease, and Alzheimer's disease (AD), the common characteristics are decreased pH or acidosis at both tissular and cellular levels. Particularly, some AD-associated enzymes will have altered activities under acidic conditions. We inferred that aging or ischemia may cause intracellular acidification. This acidification not only induces apoptosis but also substantially alters enzyme activities and promotes the development of AD or vascular dementia. The hypothesis of an intracellular pH role in sporadic AD or vascular dementia will be discussed in this paper. If confirmed, this hypothesis may lead to the formulation of new pathogenesis and new therapeutic approaches to AD or vascular dementia. PMID- 20707634 TI - 1H-MR spectroscopy changes in transient ischemic attack patients and their correlation with perfusion-weighted imaging. AB - PURPOSE: We investigated whether patients with transient ischemic attack (TIA) have metabolic changes in the brain. METHODS: 35 patients with clinically diagnosed TIA were prospectively included in our study. Clinical and neurological data were compiled. 1H-MR spectroscopy and perfusion-weighted imaging were performed in all patients within 3 days of the onset of symptoms. RESULTS: In TIA patients, the N-acetylaspartate (NAA)/choline (Cho) ratio in noninfarcted regions was significantly decreased in the symptomatic hemisphere (1.33 +/- 0.38) compared with the asymptomatic hemisphere (1.51 +/- 0.41, p < .05). Patients with a history of prior TIA had a significantly decreased NAA/Cho ratio in both the symptomatic (p < .05) and asymptomatic (p < .05) hemispheres compared with TIA patients without a prior TIA. TIA patients with diffusion-weighted imaging lesions had a significantly increased lactate/NAA ratio in both the symptomatic (p < .05) and asymptomatic (p < .05) hemispheres compared with TIA patients without lesions. The relative cerebral blood flow (rCBF) value was directly related to the symptomatic Cho/creatine (Cr) value (r = 0.81, p < .01). The higher the rCBF value, the higher the symptomatic Cho/Cr value. CONCLUSIONS: TIA patients have neurological deficits that are transient; however, metabolic damage to the brain is present up to 3 days after the onset of the symptoms. These metabolic changes are not restricted to the symptomatic hemisphere or to areas close to ischemic lesions and the changes are related in the CBF. PMID- 20707635 TI - Analysis of neuronal nitric oxide synthase expression and increasing astrogliosis in the brain of senescence-accelerated-prone 8 mice. AB - The senescence-accelerated mouse (SAM) is an autogenic senile murine model characterized by early cognitive impairment and age-related deterioration of learning and memory. The present study investigated the alternations of neuronal nitric oxide synthase (nNOS) expression in frontal cortex and hippocampus in the aging process of SAM-prone 8 (SAMP8) and SAM-resistant 1 (SAMR1) mice. The results demonstrated that the expression of nNOS was upregulated in the frontal cortex, but downregulated in the hippocampus in SAMP8. Further, age-related increases of astrogliosis were seen in the cortex and hippocampi of aged SAMP8 and SAMR1, as revealed by the expression of the astrocyte specific marker, glial fibrillary acidic protein (GFAP). Indeed, astrogliosis in aged SAMP8 was significantly greater than that of aged SAMR1. Our results suggest the possibility of a correlation between the downregulation of nitric oxide (NO) in the hippocampus and reported learning and memory deficits in SAMP8. However, the toxic effects of NO and age-related increases of astrogliosis, may have contributed to abnormal alterations in metabolism and neurochemical mechanisms in aged SAMP8. PMID- 20707636 TI - Quantitative evaluation of the effects of subthalamic stimulation on gait in Parkinson's disease patients using principal component analysis. AB - BACKGROUND: Principal component analysis (PCA) was applied to the ground reaction force (GRF) for evaluating the deep brain stimulation of the subthalamic nucleus (DBS-STN) effects in Parkinson's disease (PD) subjects with and without medication. METHODS: Ten subjects who underwent DBS-STN were evaluated under the following four conditions: without treatment (mof-sof), with stimulation (mof son), with medication (mon-sof), and with both treatments (mon-son). A control group of 30 subjects was also evaluated. PCA was applied separately on each GRF component. Broken stick criterion selected eight principal components (PC) from vertical GRF and one from each horizontal GRF. A standard distance was calculated using these 10 PCs and the gait speed to measure how far the PD group's gait was from the normal pattern. RESULTS: The standard distance allowed classifying normal and PD subjects in the mof-sof condition with 100% accuracy, sensitivity, and specificity. The same distance was calculated for mon-sof, mof-son, and mon son conditions. The smallest mean standard distance was found in the mon-son condition, which was significantly different from mof-sof (Friedman test with Dunn post-hoc, p < .05). CONCLUSION: PCA allowed the quantitative evaluation of treatment effects, indicating that DBS-STN improves the GRF pattern in PD subjects, primarily in the medication on state. PMID- 20707637 TI - Addition of an anabolic steroid to strength training promotes muscle strength in the nonparetic lower limb of poststroke hemiplegia patients. AB - In this prospective observer-blinded open-label nonrandomized controlled trial, 25 inpatients with hemiplegia 1-8 months after stroke were assigned to an anabolic androgenic steroid (AAS; n = 14) or a control (n = 11) group: the former received 100 mg metenolone enanthate by intramuscular injection once a week for 6 weeks along with rehabilitation therapy including muscle strength training of the nonparetic lower limb, which consisted of 100 repetitions of isokinetic reciprocal knee extension/flexion (60 degrees /s) on a dynamometer once a day for 5 days a week over 6 weeks, and the latter received rehabilitation therapy alone. The maximal peak torque of the nonparetic lower limb, including the isokinetic (60 degrees /s, 120 degrees /s, and 180 degrees /s), isotonic, and isometric muscle strength of knee extension/flexion, measured every 2 weeks, was compared with the baseline values. Significant increases in peak torque were seen at 2 weeks in 9 of the 10 conditions and at 6 weeks in 8 of the 10 conditions tested for the AAS group but in only 1 and 5 conditions for the control group, respectively. While no contraindications for AAS were encountered, the combination of AAS and muscle strength training tended to have a positive effect on muscle strength after stroke. PMID- 20707638 TI - Intradural neurenteric cyst--two case reports of surgical treatment. AB - Intradural neurenteric cysts are rare congenital lesions and arise from incomplete separation of the developing notochord and foregut in the embryo. Neurenteric cysts are often seen in conjunction with other forms of occult spinal dysraphism. The cases of a 48-year-old male with pain in the right shoulder and numbness in both hands and a 7-year-old girl with subacute muscle weakness of the lower extremities are presented. Both patients underwent surgery. One lesion was completely excised, while the other could be only partially removed because of negative monitoring potential during the operation. Histological examination, showing pseudostratified ciliated columnar epithelium, confirmed the diagnosis of neurenteric cyst. The symptoms in both patients nearly disappeared after surgery. Recurrence of cyst was observed in the girl, though without neurological symptoms. In conclusion, two cases of intradural extramedullary cysts are reported. Clinical presentations, intraoperative findings, and histological features are discussed with a review of the literature. PMID- 20707640 TI - The detection of in vivo and in vitro HIV type 1 B/F profiles in Brazil using a real-time PCR assay for five HIV type 1 genomic regions. AB - We sought to determine the frequency and profile of HIV-1 BF recombinants in vitro and in vivo. Laboratory HIV-1 strains from subtypes B and F were cocultured and evaluated. Clinical samples from the city of Santos, Brazil, where the first HIV-1 B/F circulating recombinant forms (CRF) were described, were also assessed. Five real-time PCR assays were developed to equally amplify subtypes B and F, and subtype-specific probes were developed and optimized. To validate the PCR systems, clinical samples from Santos were sequenced and phylogenetically analyzed. The real-time PCR assays were performed on these samples and on the supernatant of an in vitro competition assay to assess emergent recombinant strains. Out of 157 clinical samples, 62.1% were defined as subtype B, 3.0% were subtype F, 16.7% presented the CRF28_BF profile, and 13.6% of the samples presented the CRF29_BF profile. The specificity and sensitivity in the discrimination assay for this sample panel were 93% and 92%, respectively. The HIV that emerged from the coinfected cell culture closely resembled the CRF28_BF profile. The first-described CRFs are still fixed in this geographic region of Brazil, and the in vitro emerging strains detected by real-time PCR suggest that in addition to the shaping of recombinant strains by immune selection, viral structures may also play an important role in emerging CRFs. PMID- 20707642 TI - ELF noise fields: a review. AB - The debate as to whether low-level electromagnetic fields can affect biological systems and in the long term cause health effects has been going on for a long time. Yet the interaction of weak electromagnetic fields (EMF) with living cells, undoubtedly a most important phenomenon, is still not well understood. The exact mechanisms by which the effects are produced have not been identified. Furthermore, it is not possible to clearly define which aspects of an EMF exposure that constitute the "dose." One of the groups that contributed to solving this problem is the Bioelectromagnetics group at Catholic University of America (CUA), Washington, D.C. Their work has been devoted to investigating the physical parameters that are needed to obtain an effect of EMF exposure on biological systems, and also how to inhibit the effect. This is a review of their work on bioeffects caused by low-level EMF, their dependence on coherence time, constancy, spatial averaging, and also how the effects can be modified by an applied ELF noise magnetic field. The group has been using early chick embryos, and L929 and Daudi cells as their main experimental systems. The review also covers the work of other groups on low-level effects and the inhibition of the effects with an applied noise field. The group at CUA has shown that biological effects can be found after exposure to low-level ELF and RF electromagnetic fields, and when effects are observed, applying an ELF magnetic noise field inhibits the effects. Also, other research groups have tried to replicate the studies from the CUA group, or to apply EMF noise to suppress EMF-induced effects. Replications of the CUA effects have not always been successful. However, in all cases where the noise field has been applied to prevent an observed effect, it has been successful in eliminating the effect. PMID- 20707641 TI - Calcium ion cyclotron resonance (ICR), 7.0 Hz, 9.2 microT magnetic field exposure initiates differentiation of pituitary corticotrope-derived AtT20 D16V cells. AB - The aim of this work is the study of the effect of electromagnetic radiations (ELF-EMF) tuned to the calcium cyclotron resonance condition of 7.0 Hz, 9.2 microT on the differentiation process of pituitary corticotrope-derived AtT20 D16V cells. These cells respond to nerve growth factor by extending neurite-like processes. To establish whether exposure to the field could influence the molecular biology of the pituitary gland, a corticotrope-derived cells line (AtT20 D16V) was exposed to ELF-EMF at a frequency of 7.0 Hz, 9.2 microT electromagnetic field by a Vega Select 719 power supply. Significant evidence was obtained to conclude that as little as 36 h exposure to the Ca(2+) ICR condition results in enhanced neurite outgrowth, with early expression and aggregation of the neuronal differentiation protein NF-200 into neurite structures. PMID- 20707643 TI - Is there any possible genotoxic effect in exfoliated bladder cells of rat under the exposure of 1800 MHz GSM-like modulated radio frequency radiation (RFR)? AB - People are exposed to many carcinogenic and mutagenic chemicals in their everyday lives. These include antineoplastic drugs, Polycyclic aromatic hydrocarbons (PAH)s, aromatic amines, nitrosamines, metals, and electromagnetic radiation. Based on the state of knowledge acquired during the last 50 years of research on possible biological effects of electromagnetic fields (EMF), the majority of the scientific community is convinced that exposure to EMF below the existing security limits does not cause a risk to the health of the general public. However, this position is questioned by others, who are of the opinion that the available research data are contradictory or inconsistent and, therefore, unreliable. In this study, we aimed to investigate if there is any effect of 1800 MHz GSM modulated radio frequency radiation (RFR) on the number of micronucleus in exfoliated bladder cells of rat which will be informative about the genotoxic damage. Exposure period was 20 min/day, 5 days/week during a month. Six female Wistar rats were used for two groups: Group I (n=6): controls; Group II (n=6): 1.8 GHz exposed animals. 1800 MHz RFR did not showed a significant MN frequencies in rat bladder cells when compared with the control group (p>0.05). 1800 MHz RFR exposed animals did not produce any genotoxic effect when compared with the control group ( p>0.05). Kinetic studies are important for any biomarker, especially those in which tissue differentiation and maturation processes will heavily influence the time between induction of damage and collection of damaged cells for micronucleus analysis. PMID- 20707644 TI - A role for the geomagnetic field in cell regulation. AB - We advance the hypothesis that biological systems utilize the geomagnetic field (GMF) for functional purposes by means of ion cyclotron resonance-like (ICR) mechanisms. Numerous ICR-designed experiments have demonstrated that living things are sensitive, in varying degrees, to magnetic fields that are equivalent to both changes in the general magnetostatic intensity of the GMF, as well as its temporal perturbations. We propose the existence of ICR-like cell regulation processes, homologous to the way that biochemical messengers alter the net biological state through competing processes of enhancement and inhibition. In like manner, combinations of different resonance frequencies all coupled to the same local magnetic field provide a unique means for cell regulation. Recent work on ultraweak ICR magnetic fields by Zhadin and others fits into our proposed framework if one assumes that cellular systems generate time-varying electric fields of the order 100 mV/cm with bandwidths that include relevant ICR frequencies. PMID- 20707645 TI - Magnetic stimulation influences injury-induced migration of white matter astrocytes. AB - This study investigates the effects and underlying mechanism of magnetic stimulation on injury-induced migration of white matter astrocytes. Twenty-four adult healthy SD rats were selected to inject 0.5 ml of 1% ethidium bromide (EB) in PBS into the dorsal spinal cord funiculus on the left side at the T10-11 level to make located spinal cord injury models. Then they were randomly divided into four groups (A, B, C, and D). Groups A, B, C, and D were exposed to 1 Hz pulsed magnetic stimulation underwent 5-min sessions on 14 consecutive days at the following levels: 0T (Group A) 1.9x40% T (Group B); 1.9x80% T (Group C); 1.9x100% T (Group D). On day 14 after stimulation, the rats were killed and the expression of glial fibrillary acidic protein (GFAP), microtubule associated protein-2 (MAP 2), extracellular signal-regulated kinase1/2 (ERK1/2), and the volume of holes were detected with immunohistochemistry. Quantitative analysis of the expression of GFAP, MAP-2, and ERK1/2 were performed with the image analysis system. With the increase of magnetic stimulation intensity, the volume of hole decreased at day 14 (P<0.05). In lesion areas, the expression of GFAP and ERK1/2 could be seen, while that of MAP-2 did not change before and after magnetic stimulation. Significant difference was revealed in the expression of GFAP, ERK1/2 among the four groups. It was significantly higher in the magnetic stimulation groups than that in the control group (P<0.05). After magnetic stimulation, astrocytes migrated into the hole. U0126, a potent and selective MEK1/2 inhibitor, inhibited up-regulation of pERK1/2 which was stimulated by magnetic stimulation. These data indicate that magnetic stimulation increases the migratory capacity of reactive white matter astrocytes in the injured center nervous system, which may be associated with activation of MEK1,2/ERK mitogenic pathway. PMID- 20707646 TI - Differentiation of K562 cells under ELF-EMF applied at different time courses. AB - The time-course of ELF-EMF application to biological systems is thought to be an important parameter determining the physiological outcome. This study investigated the effect of ELF-EMF on the differentiation of K562 cells at different time courses. ELF-EMF (50 Hz, 5 mT, 1 h) was applied at two different time-courses; first at the onset of hemin induction for 1 h, and second, daily 1 h for four days. While single exposure to ELF-EMF resulted in a decrease in differentiation, ELF-EMF applied everyday for 1 h caused an increase in differentiation. The effect of co-stressors, magnesium, and heat-shock was also determined and similar results were obtained. ELF-EMF increased ROS levels in K562 cells not treated with hemin, however did not change ROS levels of hemin treated cells indicating that ROS was not the cause. Overall, these results imply that the time-course of application is an important parameter determining the physiological response of cells to ELF-EMF. PMID- 20707647 TI - Short communication: Biological and genetic characterization of HIV type 1 subtype B and nonsubtype B transmitted viruses: usefulness for vaccine candidate assessment. AB - Due to the extraordinary degree of genetic diversity of HIV-1 and the structural complexity of its envelope glycoproteins, designing an effective vaccine is difficult, requiring the development of viral reagents to assess vaccine-elicited neutralizing antibodies. The aim of this study was to improve on our previously developed panel of HIV-1 strains of different genetic forms, focusing on strains from acute and recently acquired infections as the most representative of the transmitted viruses. HIV-1 primary isolates were expanded in peripheral blood mononuclear cells. Viral stocks of 40 ml each were produced. Syncytium-inducing (SI) phenotype, coreceptor use, and TCID(50)/ml were determined. Near full-length HIV-1 genomes were amplified by RT-nested PCR in four overlapping segments. Phylogenetic analyses were performed with neighbor-joining trees and bootscanning. Forty-four HIV-1 strains were included in the panel. Twenty-four (54.1%) strains were from early infections (16 acute and 8 recent); of them, 21 (87%) were sexually transmitted. NSI/R5 phenotype was detected in 37 (84.1%) viruses and SI/R5,X4 in another 7 (15.9%). TCID(50)/ml ranged between 10(4) and 10(6.6). Twelve different genetic forms constituted this panel: subtypes A1, B, C, F1, and G; circulating recombinant forms CRF02_AG, CRF14_BG, and CRF24_BG; and unique recombinant forms CRF02_AG/A3, BF1, CRF12_BF/B, and DF1G. In conclusion, in this study, we report the development of a comprehensive and well characterized panel of HIV-1 isolates for assessing neutralization in HIV vaccine research. This panel is available for distribution through the Programme EVA Centre for AIDS Reagents, National Institute for Biological Standard and Control (NIBSC). PMID- 20707648 TI - Impacts of leuprolide acetate on quality of life in patients with prostate cancer: a prospective multicenter study. AB - OBJECTIVE: To investigate the impacts of leuprolide acetate on the quality of life (QoL) of patients with prostate cancer. MATERIAL AND METHODS: A total of 104 patients was enrolled in this prospective multicenter study. All patients received subcutaneous injections of 3.75 mg leuprolide acetate at 4 week intervals for a total of 12 weeks. QoL was assessed before treatment and at 12 weeks using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and an accompanying prostate cancer-specific module (QLQ-PR25). RESULTS: Eighty-nine of 104 patients (85.6%) completed the 12 week study. Eighty-six of 89 patients (96.6%) achieved and maintained medical castration. The results of the EORTC QLQ-C30 indicated that patients experienced an improvement in global health status/QoL (p < 0.001), despite a deterioration in physical and role functioning (p = 0.012 and p = 0.007, respectively). The symptom scales indicated a statistically significant improvement in appetite (p = 0.003). The results of the QLQ-PR25 revealed that patients experienced an increase in hot flushes (p < 0.001) and erection problems and uncomfortable sexual intimacy among the sexual functioning items (p = 0.030 and p = 0.023, respectively), but day-time urinary frequency was improved (p = 0.004). CONCLUSION: The results of this prospective study indicate that leuprolide acetate treatment was accompanied by improvements in global health status/QoL, despite a deterioration in physical, role and sexual function. PMID- 20707649 TI - Involvement of ERK1/2 signalling and growth-related molecules' expression in response to heat stress-induced damage in rat jejunum and IEC-6 cells. AB - Our previous studies found small intestine epithelial tissues from several different animals (including rats, pigs and chickens) became significantly damaged following exposure to extreme heat. However, damaged tissue was rapidly repaired or regenerated in the following few days. Growth-related molecules are critical for cellular survival and promote endothelial cell proliferation and migration. The ERK1/2 signalling pathway is reported to regulate the growth and adaptation of endothelial cells to both physiological and pathological stimuli. However, little information is available concerning both growth-related molecules and ERK1/2 in response to heat stress. Herein, we employed both live rats and rat IEC-6 cells to investigate growth-related molecule expression and ERK1/2 activation in heat stress. Heat stress caused significant morphological damage to rat intestinal tissue and IEC-6 cells, reduced cell growth and proliferation, induced apoptosis, altered growth-related molecule mRNA expression and increased ERK1/2 phosphorylation. Addition of U0126 (a selective inhibitor of MEK kinase responsible for ERK phosphorylation) combined with heat stress exacerbated the morphological damage and apoptosis. With the addition of U0126, further up- or down-regulation of Egfr, Ctgf, Tgif, Vegfa, Okl38 and Gdf15 in response to heat stress was observed. In conclusion, extreme heat stress caused obvious damage to rat jejunum and IEC-6 cells. Both growth-related molecule expression and ERK1/2 phosphorylation were involved in response to heat stress. ERK1/2 inhibition exacerbated apoptosis and affected growth factor mRNA expression in heat stress. PMID- 20707650 TI - Apoptotic and necrotic effects of tumour necrosis factor-alpha potentiated with hyperthermia on L929 and tumour necrosis factor-alpha-resistant L929. AB - PURPOSE: The cytotoxic effect of the combination treatment of TNF-alpha and hyperthermia on L929 and TNF-alpha-resistant L929 (rL929) cells was investigated. MATERIALS AND METHODS: L929 cells were treated with TNF-alpha (5 ng/mL), heating at 43 degrees C or the combination of TNF-alpha and heating. The cells were harvested at different time within the 24-hour period. The viability and the type of cell death of the harvested cells were examined. RESULTS: When L929 cells were treated with a combination of TNF-alpha and heating the cells died quickly and apoptosis increased to an overwhelming extent, especially in the group pre treated with TNF-alpha for 1 h prior to heating. Although rL929 cells were resistant to TNF-alpha alone, the cells became sensitive to TNF-alpha treatment when combined with heating. Similar to the L929 cell, the cells also died rapidly and exhibited apoptosis to a higher extent. Using an Annexin-V-FITC kit and flow cytometer, we found that both necrosis and apoptosis occurred. Agarose gel electrophoresis of DNA extracted from treated cells showed that the DNA fragments were multiples of approximately 200 bp. Furthermore, by studying the kinetics of cell death and apoptosis, we found that the loss of cell membrane integrity preceded the DNA fragmentation in both L929 and rL929 cells. CONCLUSION: The results suggested that hyperthermia may enhance the necrotic and apoptotic effects of TNF-alpha on some tumour cells and overcome the resistance of some tumour cells to TNF-alpha. PMID- 20707651 TI - Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model. AB - PURPOSE: Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity. MATERIALS AND METHODS: The effect of mild heat (40 degrees C) on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumour cell line. In vivo oxaliplatin was administered at various doses and times before, during and after fever-range thermal therapy (6 h at 40 degrees C) to rats bearing an MTLn3 mammary adenocarcinoma. Tumour growth, survival, and toxicity were measured to determine treatment outcome. RESULTS: Heating halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24 h before thermal therapy were completely immunologically cured, while a further 11% regressed their primary tumour but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumour efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 h before fever-range whole body thermal therapy. CONCLUSIONS: When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumours in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life. PMID- 20707652 TI - The effect of hot-tub therapy on serum Hsp70 level and its benefit on diabetic rats: a preliminary report. AB - PURPOSE: To carry out a preliminary study examining the efficacy of long-term hot tub therapy (HTT) in the improvement of diabetic complications on streptozotocin induced diabetic rats. MATERIALS AND METHODS: Male Wistar rats were immersed mid sternum in a circulating water bath (42 degrees C for 30 min) to obtain a core body temperature of 41 degrees C; this process was repeated three times a week for 5 months. The blood was collected every month. Multiple parameters were examined for all rats including heat shock protein (Hsp70) level, serum glucose and insulin concentrations, advanced glycation end product (AGE) and glycated haemoglobin (HbA1c) formation, lipid profile and antioxidant defence system. Additionally, the chaperoning capacity of glycated Hsp70 was evaluated based on in vitro studies in which the refolding of denatured luciferase was compared to refolding by native Hsp70. RESULTS: HTT-treated diabetic rats showed a significant improvement in lipid profile, antioxidant capacity, insulin secretion and serum Hsp70 level and a significant decrease in AGE formation compared to the untreated diabetic rats. However, HTT had a borderline significant effect on weight and fasting blood glucose. Glycated Hsp70 lost its chaperoning ability to reactivate the denatured luciferase. CONCLUSION: A decrease in complications in diabetic rats after hot-tub therapy is shown here. An increase in the extracellular Hsp70 level due to HTT was observed. This increase may serve to protect the structure of proteins (e.g. preventing AGE formation), and the observed beneficial effects may be related to it. PMID- 20707653 TI - The potential role of dynamic MRI in assessing the effectiveness of high intensity focused ultrasound ablation of breast cancer. AB - PURPOSE: To retrospectively evaluate magnetic resonance imaging (MRI) features of breast cancer after high-intensity focused ultrasound (HIFU) ablation. MATERIALS AND METHODS: Six patients with invasive ductal carcinomas underwent HIFU ablation. In all patients, dynamic MRI was performed prior to and two weeks after HIFU. Serial follow-up studies were performed. Changes in signal intensity and size of the index tumour in addition to peripheral enhancement patterns were evaluated. Histopathological results were compared with MRI findings. RESULTS: All patients had a single index tumour with a mean size 25.6 mm (range 12 to 37 mm) at the ablation time. In three of six patients, thin rim enhancement around the ablation zone was seen on the subtraction image after first ablation, which showed no change on follow-up MRI. Complete ablation was confirmed by the histopathology (biopsy in two and surgery in one). In the remaining three patients, nodular or irregular thick enhancement was shown on the subtraction image and viable tumour was confirmed by surgery and biopsy in two patients. CONCLUSION: The MR characteristics of successfully ablated breast cancers included central dark signal intensities with thin rim enhancement on subtraction images. Nodular or irregular thick enhancements should raise concern of partial ablation. We propose MRI plays a critical role in assessing the effectiveness of HIFU treatment. PMID- 20707654 TI - Electromagnetic thermal surgery system for liver resection: an animal study. AB - PURPOSE: Electromagnetic thermal surgery is a new technique. It applies an electrical current through coils to generate a high frequency magnetic field to heat up magnetic materials in the targeted area. Using this technique, we aim to perform liver resection without bleeding in rats and rabbits. MATERIALS AND METHODS: The electromagnetic machine can produce a high frequency magnetic field, with an input of 220 V-55 A-60 Hz, an output frequency of 62.1 kHz, and a power of 2.2 kW. The magnetic materials used in this study were fine needles made of stainless steel. For ex vivo experiments, we used porcine liver explants; in the animal model, sixteen Sprague-Dawley rats and seven New Zealand White rabbits were used. We inserted one needle array along the attempted resection lines and then used the magnetic coils to heat up the needles for three min. After heating, we resected the designated liver portions using surgical scalpels. RESULTS: In the ex vivo test, the fine needles were heated up effectively to achieve tissue coagulation (more than 90 degrees C). In the animal model the liver resection was performed without bleeding and no bile peritonitis was observed after the surgery. All animals were alive after the surgery until the end of the experiment (30 days). CONCLUSIONS: The experiments showed that our thermal surgery system is very effective in performing bloodless liver resection without further ligation or embolisation needed. Our technique is new and the system has great potential to develop into clinical practice. PMID- 20707655 TI - Do Japanese children with high-functioning autism spectrum disorder respond differently to Wh-questions and Yes/No-questions? AB - The present study compared 12 Japanese children with high-functioning autism spectrum disorder (HFASD), ranging in age from 7.3-14.8 years, with 12 typically developing (TD) children matched for age, gender, and vocabulary. The means of full-scale IQ and verbal-IQ of the children with HFASD were 95.92 (SD = 15.30) and 98.00 (SD = 18.44), respectively. Children responded to questions from their mothers in conversations collected under a semi-structured setting, and the responses of both groups were examined from the viewpoint of adequacy. Compared to TD children, HFASD children produced more inadequate responses to Wh-questions than to Yes/No questions. To both types of questions, HFASD children produced more inappropriate responses than TD children. The findings suggest that parents of HFASD children should consider the influence of the question format on these children's response inadequacies. PMID- 20707656 TI - Breast MRI as an adjunct to mammography: Does it really suffer from low specificity? A retrospective analysis stratified by mammographic BI-RADS classes. AB - BACKGROUND: Reports on the specificity of breast MRI are heterogeneous, depending on the respective setting of the performed study. PURPOSE: To retrospectively estimate the sensitivity and especially the specificity of breast MRI in the non screening setting as an adjunct to mammography sorted by breast density and to estimate the accuracy of breast MRI in cases rated BI-RADS 0 and 3 mammographically. MATERIAL AND METHODS: A total of 216 consecutive patients with referral to breast MRI and previously acquired mammography were enrolled in this analysis. Negative findings were followed up with a mean time of 26.7 months. The loss to follow-up was 10.8%. The single breast was regarded as the study subject (n=399, 364 cases were eligible for calculation of diagnostic accuracy). BI-RADS 1 and 2 were rated as benign, 4 and 5 as malignant. BI-RADS 0 and 3 were analyzed separately. The 95% confidence intervals (CIs) were calculated from the normally approximated binomial distribution and taken to represent significant differences for the two imaging modalities if they did not overlap. RESULTS: Among the study population, 62 malignant neoplasms were detected. For cases rated BI-RADS 1, 2, 4, and 5 (n=251), the sensitivity of breast MRI was 95.7% (95% CI 89.9-100.0%) and 74.5% (95% CI 62.0-87.0%) for mammography, respectively. The specificity of breast MRI was 96.1% (95% CI 93.4-98.8%) and 92.2% (95% CI 88.5-95.9%) for mammography, respectively. The diagnostic accuracy of breast MRI did not depend on breast density. In cases rated BI-RADS 0, n=57 (3, n=56), breast MRI achieved a sensitivity of 100% (90.9%) and a specificity of 98.1% (88.9%). There was a significant (P< 0.01) accumulation of dense breast tissue (ACR IV) in breasts rated BI-RADS 0 in mammography. Breast MRI missed three malignant lesions, two of them being smaller than 3 mm. CONCLUSION: There is no rationale to criticize the low specificity of breast MRI when used as an adjunct to mammography. The independency of the diagnostic accuracy of breast MRI from breast density makes it a worthwhile choice in mammographic BI-RADS 0 cases. PMID- 20707657 TI - Diagnostic accuracy of dual-source CT coronary angiography: The effect of average heart rate, heart rate variability, and calcium score in a clinical perspective. AB - BACKGROUND: Dual-source CT coronary angiography (CTCA) has been used to detect coronary artery disease; however, the factors with potential to affect its diagnostic accuracy remain to be defined. PURPOSE: To prospectively evaluate the accuracy of dual-source CTCA in diagnosing coronary artery stenosis according to conventional coronary angiography (CAG), and the effect of average heart rate, heart rate variability, and calcium score on the accuracy of CTCA. MATERIAL AND METHODS: A total of 113 patients underwent both dual-source CTCA and CAG. The results were used to evaluate the findings in dual-source CTCA to assess the accuracy in the diagnosis of > or =50% (significant stenosis) and >75% (severe stenosis) of coronary artery according to those by CAG. Patients were divided into subgroups according to their heart rate (HR), HR variability (HRV), and calcium score, and the accuracy of CTCA was further evaluated. The chi-square test was used to analyze the difference in sensitivity and specificity for the detection of > or =50% and >75% coronary stenosis among subgroups. The generalized estimation equation method was used in per-vessel analysis to adjust for within-patient correlation. RESULTS: In all, 113 patients had 338 vessels and 1661 segments evaluated by CAG. Dual-source CTCA displayed 1527 segments (91.9%). Among them, 1468 segments (calcium score by CAG score 1, n=1018; score 2, n=270; score 3, n=180) were assessable in CTCA. On a per-patient analysis, the sensitivity and specificity of CTCA were 93.9% and 93.5% for significant stenosis and 86.9% and 98.1% for severe stenosis. On a per-vessel basis, the sensitivity and specificity were 90.2% and 97.1% for significant and 83.3% and 98.1% for severe stenosis. On a per-segment analysis, the sensitivity and specificity were 90.2% and 97.1% for significant and 83.3% and 98.1% for severe stenosis. Average HR had no effect on the sensitivity and specificity of CTCA (P>0.05); whereas HRV and calcium score had some effect on the sensitivity and specificity of CTCA (P<0.05). CONCLUSION: On a per-patient, per-vessel, and per-segment basis, dual source CTCA has a high sensitivity and specificity for the diagnosis of coronary artery stenosis. Average HR has no effect on the diagnostic accuracy of CTCA, while HRV and calcium score have a statistically significant effect on the sensitivity and specificity of CTCA. PMID- 20707658 TI - Contrast-induced nephropathy in patients undergoing computed tomography (CONNECT) - a clinical problem in daily practice? A multicenter observational study. AB - BACKGROUND: Although several studies have examined contrast-induced nephropathy (CIN) following computed tomography (CT) procedures under closely controlled clinical trial conditions, less is known about the incidence of CIN (or its key predictive factors) in a "real world" clinical setting. PURPOSE: A multicenter, observational registry study was undertaken in Italian hospital radiology departments to retrospectively assess the incidence of CIN in at-risk patients undergoing iodixanol-enhanced CT procedures. MATERIAL AND METHODS: Each department used center-specific (nonstandardized) CT protocols. Data were available from 493 at-risk patients; most (76.4%) had 1 risk factor for CIN, 19.8% had 2, and 3.4% had 3. In all, 169 patients (34.3%) had reduced renal function (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m(2)). Prophylactic volume expansion was not used in 70.6% of the study population. RESULTS: The overall incidence of CIN (defined as a > or =44.2 micromol/l [0.5 mg/dl] increase in serum creatinine from baseline 72 h postprocedure) was 2.6%; in the subpopulation of patients with renal impairment (with or without other risk factors), CIN incidence was 4.7%. Multivariate analysis identified renal insufficiency as the only risk factor predictive of CIN (relative risk, 3.850; 95% confidence interval, 1.200-12.348; P=0.023). CONCLUSION: In the clinical setting of hospital CT radiology practice, where guideline-recommended strategies for CIN prevention may not be consistently followed, use of the iso-osmolar agent iodixanol appears to be associated with a low incidence of CIN in at-risk patients. PMID- 20707660 TI - Management of tracheal obstruction caused by benign or malignant thyroid disease using covered retrievable self-expandable nitinol stents. AB - BACKGROUND: Curative resection is often contraindicated in patients with airway obstruction by aggressive thyroid disease. PURPOSE: To evaluate the safety and clinical effectiveness of covered retrievable self-expandable nitinol stents placed in patients with airway obstruction caused by benign or malignant thyroid disease. MATERIAL AND METHODS: From 1996 to 2009, covered retrievable self expandable nitinol stents were placed in nine symptomatic patients with malignant (n=7) or benign (n=2) thyroid disease. Improvement in patient respiratory status, complications and their management, and survival data were evaluated. Stents were removed if stent-related complications occurred or the stents were no longer necessary. RESULTS: A total of 11 stents were successfully placed without procedure-related complications. Improvement of more than one dyspnea grade was seen in eight of nine patients (89%), while the ninth patient underwent intubation due to upper airway swelling. Stent migration, sputum retention, and tumor overgrowth occurred in 27.3% (n=3), 9.1% (n=1), and 9.1% (n=1) of the stents, respectively. A total of six stents were successfully removed because of stent-related complications (n=4) or after total thyroidectomy (n=2). In two patients with benign thyroid goiters, a stable airway was maintained until total thyroidectomy. CONCLUSION: Placement of covered retrievable self-expandable nitinol stents was safe and effective in patients with airway obstruction caused by benign or malignant thyroid disease. Stent retrievability was very useful in cases of stent-related complications. In patients with benign thyroid disease, stent placement can serve as an effective bridge to surgery. PMID- 20707661 TI - Parenchymal and pleural findings in pulmonary embolism visualized by multi channel detector computed tomography. AB - BACKGROUND: A normal computed tomography (CT) scan of the pulmonary arteries in the presence of parenchymal and pleural abnormalities may indicate a false negative diagnosis of pulmonary embolism (PE). Multi-channel detector CT (MDCT) with thinner collimation may improve the detection of small peripheral PEs causing such abnormalities. PURPOSE: To investigate parenchymal and pleural findings visualized by contrast-enhanced MDCT in patients with and without PE, and to identify possible predictors of PE. MATERIAL AND METHODS: 129 patients with clinical signs of PE were included. In all patients an iopromide-enhanced 64 MDCT (64x0.625 mm collimation, pitch 1.375, overlapping reconstruction with a slice thickness of 0.625 mm, increment of overlapping slice reconstruction 0.43) was performed within 24 h after the onset of the symptoms. RESULTS: MDCT detected PE in 45 of the 129 patients (35%). PE and parenchymal/pleural findings were localized predominantly within the lower lobes. Wedge-shaped opacities were significantly associated with PE (OR =3.00; 95% confidence interval 1.13-7.91). Vascular signs were only visualized in patients with PE. Nodules, consolidations, atelectasis, or effusions were not predictive of PE. CONCLUSION: The present MDCT study verified that parenchymal and pleural findings can be found in patients with or without PE. Wedge-shaped opacities and vascular signs were significantly associated with PE and therefore can be potential predictors of PE. PMID- 20707663 TI - Interobserver variability among measurements of the maximum and mean standardized uptake values on (18)F-FDG PET/CT and measurements of tumor size on diagnostic CT in patients with pulmonary tumors. AB - BACKGROUND: (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG PET) imaging has been shown to be an accurate method for diagnosing pulmonary lesions, and the standardized uptake value (SUV) has been shown to be useful in differentiating benign from malignant lesions. PURPOSE: To survey the interobserver variability of SUV(max) and SUV(mean) measurements on (18)F-FDG PET/CT scans and compare them with tumor size measurements on diagnostic CT scans in the same group of patients with focal pulmonary lesions. MATERIAL AND METHODS: Forty-three pulmonary nodules were measured on both (18)F-FDG PET/CT and diagnostic chest CT examinations. Four independent readers measured the SUV(max) and SUV(mean) of the (18)F-FDG PET images, and the unidimensional nodule size of the diagnostic CT scans (UD(CT)) in all nodules. The region of interest (ROI) for the SUV measurements was drawn manually around each tumor on all consecutive slices that contained the nodule. The interobserver reliability and variability, represented by the intraclass correlation coefficient (ICC) and coefficient of variation (COV), respectively, were compared among the three parameters. The correlation between the SUV(max) and SUV(mean) was also analyzed. RESULTS: There was 100% agreement in the SUV(max) measurements among the 4 readers in the 43 pulmonary tumors. The ICCs for the SUV(max), SUV(mean), and UD(CT) by the four readers were 1.00, 0.97, and 0.97, respectively. The root-mean-square values of the COVs for the SUV(max), SUV(mean), and UD(CT) by the four readers were 0%, 13.56%, and 11.03%, respectively. There was a high correlation observed between the SUV(max) and SUV(mean) (Pearson's r=0.958; P <0.01). CONCLUSION: This study has shown that the SUV(max) of lung nodules can be calculated without any interobserver variation. These findings indicate that SUV(max) is a more valuable parameter than the SUV(mean) or UD(CT) for the evaluation of therapeutic effects of chemotherapy or radiation therapy on serial studies. PMID- 20707664 TI - Diffusion tensor imaging of the brain in a healthy adult population: Normative values and measurement reproducibility at 3 T and 1.5 T. AB - BACKGROUND: Diffusion tensor imaging (DTI) is an increasingly used method for investigation of brain white matter integrity in both research and clinical applications. Familiarity with normal variation of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and measurement reproducibility is essential when DTI measurements are interpreted in clinical patients. PURPOSE: To establish normal values for FA and ADC in a healthy adult population at 1.5 T and 3 T MRI based on region of interest (ROI) analysis, and to study the inter- and intra-observer reproducibility of the measurements. MATERIAL AND METHODS: Forty healthy volunteers (26 women, 14 men, mean age 38.3, SD 11.6 years) underwent conventional MRI and DTI of the brain, 30 with 3 T and 10 with 1.5 T clinical scanners. ROI-based measurements for FA and ADC values were performed in five different anatomic locations of each hemisphere and in three locations within the corpus callosum. Mean values for FA and ADC for each region were calculated. Inter-observer variation of ROI measurements was evaluated by comparing the results of the two observers, intra-observer variation by repeated measurement of 10 subjects by both observers. RESULTS: The FA values varied considerably between different regions. The highest values were found in the genu and splenium of the corpus callosum and the lowest in the corona radiata, respectively. In general, ADC values showed less variation; the highest values were found in the body of the corpus callosum and the lowest in the corona radiata. The reproducibility of both inter- and intra-observer measurements also varied regionally. The highest agreement was found for the corpus callosum and the lowest for the corona radiata and centrum semiovale. CONCLUSION: In a normal adult population FA and ADC values of the brain white matter show regional variation. The repeatability of the ROI measurements also varies regionally. This regional variability must be acknowledged when these measurements are interpreted in clinical patients. PMID- 20707665 TI - Ultrasound-guided percutaneous radiofrequency ablation of small renal tumors: Clinical results and radiological evolution during follow-up. AB - BACKGROUND: Treatment of small renal masses with percutaneous radiofrequency ablation (RFA) is under development. Data are limited regarding the oncologic efficacy and complication rates of ultrasound (US)-guided RFA. PURPOSE: To retrospectively analyze results and factors predictive of incomplete ablation and local recurrence in patients treated for small renal tumors with US-guided percutaneous RFA. MATERIAL AND METHODS: Forty-one consecutive patients (27 males), mean 70 (40-86) years, with 44 tumors were included. Core biopsies were obtained before treatment. Follow-up was performed with CT or MRI. Tumor diameter, tumor volume, volume of the ablation zone, necrosis index, tumor location, distance from tumor to skin, and BMI were analyzed. RESULTS: Biopsies showed malignancy in 72%, 10% were benign, and 18% were inconclusive. Thirty-six tumors (82%) were completely ablated after first RFA and 40 tumors (91%) after a second treatment. Mean follow-up was 27 months. Nine completely ablated tumors (23%) showed local recurrence during follow-up, six of them were retreated. Tumor size was significantly larger and mean necrosis index lower in tumors with incomplete ablation compared with those completely ablated initially. In tumors <30 mm, the initial complete ablation rate was 93% and the local recurrence rate during follow-up was 16% (4/25). CONCLUSION: US guidance is feasible for RFA of small renal tumors. However, thorough long-term follow-up appears mandatory, as a substantial proportion of the patients will develop late local recurrence and will need more than one RFA treatment session. Large tumor diameter and volume and a low necrosis index were predictive indicators of incomplete ablation after the first treatment. PMID- 20707666 TI - Application of artificial neural networks for the prediction of lymph node metastases to the ipsilateral axilla - initial experience in 194 patients using magnetic resonance mammography. AB - BACKGROUND: In breast MRI (bMRI), prediction of lymph node metastases (N+) on the basis of dynamic and morphologic descriptors of breast cancers remains a complex task. PURPOSE: To predict N+ using an artificial neural network (ANN) on the basis of 17 previously published descriptors of breast lesions in bMRI. MATERIAL AND METHODS: Standardized protocol and study design were applied in this study (T1w-FLASH; 0.1 mmol/kg body weight Gd-DTPA; T2w-TSE; histological verification after bMRI). All lesions were evaluated by two experienced radiologists in consensus. In every lesion 17 previously published descriptors were assessed. Matched subgroups with (N+; n=97) and without N+ were created (N-; n=97), forming the dataset of this study (n=194). An ANN was constructed ("Multilayer Perceptron"; training: "Batch"; activation function of hidden/output layer: "Hyperbolic Tangent"/"Softmax") to predict N+ using all descriptors in combination on a randomly chosen training sample (n=123/194) and optimized on the corresponding test sample (n=71/194) using dedicated software. The discrimination power of this ANN was quantified by area under the curve (AUC) comparison (vs AUC=0.5). Training and testing cycles were repeated 20 times to quantify the robustness of the ANN (median-AUC; confidence intervals, CIs). RESULTS: The ANN demonstrated highly significant discrimination power to classify N+ vs N- (P<0.001). Diagnostic accuracy reached "moderate" AUC (median-AUC=0.74; CI 0.70 0.76). CONCLUSION: Application of ANNs for the prediction of lymph node metastases in breast MRI is feasible. Future studies should evaluate the clinical impact of the presented model. PMID- 20707667 TI - Impact of early childhood air pollution on respiratory status of school children. AB - INTRODUCTION: In previous papers we analysed the incidence of wheezing in young children living near the iron and steel factory in Calarasi, and in a control region (Roseti) without industrial air pollution. RESEARCH QUESTION: Is industrial air pollution exposure during the first years of life a risk factor for the presence of asthmatic symptoms in children at school age? METHODS: We assessed the prevalence of asthma symptoms using the ISAAC short form questionnaire for children aged 6-7 years, and measured the FEV1 and PEF in the children of both municipalities (297 children in Calarasi, i.e. the exposed cohort, and 237 in Roseti, i.e. the non-exposed cohort). RESULTS: We found an OR of 7.2 (95% CI: 3.6-14.3) for affirmative answers to at least one of ISAAC questions for children living in Calarasi compared to the children in Roseti. The numbers of affirmative answers to all but one of the ISAAC questions were significantly higher in Calarasi. The main result remained robust after adjusting for a series of co-variables using multiple logistic regression analysis (OR 14.8; 95% CI: 4.8-46.1). There was a strong relation between early life wheezing and asthma symptoms at school age (OR 9.0; 95%CI: 3.4-23.5). CONCLUSION: Children, who had been living near an iron and steel factory during their early years, are still at increased risk for asthma symptoms at school age. PMID- 20707668 TI - Successful and unsuccessful users of bilateral amplification: differences and similarities in binaural performance. AB - Bilateral amplification seems to be the best solution for bilaterally hearing impaired persons. Nevertheless, some individuals are unsuccessful with this strategy. The goals of the present study were to develop tests to improve the diagnostic test battery before rehabilitation of hearing-impaired persons with bilateral or unilateral amplification, and to evaluate the tests with normally hearing subjects and with two groups of hearing-impaired persons. The latter two groups contained 11 successful and 11 unsuccessful users of bilateral amplification respectively. Hearing thresholds, speech recognition in noise, signal analysis ability, binaural abilities, and dichotic tests were used in the investigation. The subjects answered a questionnaire and hearing aid gain curves were measured. The results for the two groups were similar for peripheral hearing functions and binaural performance. The unilateral amplification group showed significantly worse results in speech-in-noise and dichotic tests. Spatial aspects within the questionnaire were correlated to amplification preference. We therefore suggest the inclusion of speech-in-noise, dichotic tests, and questions on spatial orientation into the diagnostic scheme before rehabilitation with hearing aids. PMID- 20707669 TI - Studying tinnitus in the ICF framework. AB - Activity limitation and participation restriction (AL/PR) on account of tinnitus was studied in the ICF framework in order to understand how tinnitus restricts individuals from fulfilling social and economic obligations. The objective of the study was to study the impact of tinnitus in the framework of ICF. Twenty-one adults in the age range of 20-60 years with chronic tinnitus (>3 months) and with normal hearing sensitivity were included in the study. THI was mapped to the framework of ICF. Twenty out of twenty-five items belonged to the domains under body function and five items addressed AL/PR. Five more AL/PR items applicable to tinnitus were added to THI. The THI+ICF questionnaire tested well on test reliability (0.987) and internal consistency (0.873). Body function was significantly more affected than AL/PR (P = 0.0005). These results suggest that tinnitus does not result in significant AL/PR from the ICF perspective. Further, psycho-acoustic characteristics such as intensity, frequency of tinnitus, and time since onset of tinnitus have only minimal if any impact on AL/PR. PMID- 20707670 TI - Influenza vaccination and intention to receive the pandemic H1N1 influenza vaccine among healthcare workers of British Columbia, Canada: a cross-sectional study. AB - OBJECTIVE: To assess healthcare workers' attitudes and concerns regarding seasonal and pandemic influenza vaccines in order to improve vaccination campaign communications. DESIGN: Cross-sectional survey. SETTING: All 6 health authorities in British Columbia, Canada. METHODS: An anonymous, self-administered online survey was conducted from August 30 through September 30, 2009. Question topics included demographic characteristics, factors influencing acceptance of seasonal influenza vaccine, factors influencing intentions to accept pandemic H1N1 influenza vaccine, and knowledge and concerns regarding the effect of the influenza pandemic. PARTICIPANTS: All 96,217 British Columbia healthcare workers were eligible to participate. RESULTS: A volunteer sample of 4,046 healthcare workers returned the survey; 3,563 (88%) were women, 58% were under 50 years old (mean age + or - standard deviation, 45.3 + or - 10.9 years), 3,152 of 4,023 (79%) had 5 or more years of experience in their profession, 1,853 of 4,023 (46%) were nurses, and 2,833 (70%) had been vaccinated against seasonal influenza the previous year. Two thousand eight hundred (69%) respondents reported intending to receive the pandemic H1N1 vaccine. The most important predictor of this intention was having received the seasonal vaccine the previous year (odds ratio [OR], 6.25 [95% confidence interval {CI}, 5.39-7.26]). Worry about making loved ones ill was the only attitude associated with intention to receive the pandemic H1N1 vaccine (adjusted OR, 1.38 [95% CI, 1.27-1.50]). Concerns with vaccine safety (adjusted OR, 0.31 [95% CI, 0.25-0.39]) and belief "that H1N1 is not severe enough" (adjusted OR, 0.29 [95% CI, 0.26-0.32]) were independently associated with the intention to reject the pandemic H1N1 vaccine. CONCLUSIONS: Vaccination campaigns for pandemic H1N1 vaccine should use messages that emphasize the risk of illness among younger people and the opportunity to protect loved ones by getting the vaccine and should address concerns about the safety and effectiveness of the vaccine. PMID- 20707671 TI - Evaluation of a method for fibroblast growth factor-23: a novel biomarker of adverse outcomes in patients with renal disease. AB - Abstract Background: Fibroblast growth factor 23 (FGF-23), a phosphaturic peptide hormone secreted by the osteoblasts, is an important regulator of phosphorus and vitamin D metabolism. In chronic kidney disease, FGF-23 levels rise with declining kidney function. Increasing FGF-23 levels are associated with increasing risk of mortality in dialysis patients. Two assays for FGF-23 have been reported. One assay detects only full-length/intact FGF-23. In contrast, the carboxy-terminal assay recognizes both intact and carboxy-terminal FGF-23. AIM/METHODS: The aim of this study was to evaluate both assays for FGF-23. Test samples were analyzed with both the intact and carboxy-terminal FGF-23 enzyme linked immunosorbent assay (ELISA) kits according to manufacturers' instructions. RESULTS: Carboxy-terminal FGF-23 showed very good precision with coefficients of variation (CV) ranging from 4% to 10.5%, whereas the CVs for intact FGF-23 were not very good (6-37.5%). The carboxy-terminal assay was linear, stable in plasma samples, and was not affected by common interferents. Also, the carboxy-terminal FGF-23 assay appeared to correlate better with worsening of kidney function as assessed by plasma creatinine and calculated estimated glomerular filtration rate (eGFR). CONCLUSION: Thus, the carboxy-terminal FGF-23 assay is robust and can be used in prospective trials to validate its utility as a biomarker of adverse outcomes in patients with renal disease. PMID- 20707672 TI - Integrons. AB - Integrons are genetic elements able to acquire and rearrange open reading frames (ORFs) embedded in gene cassette units and convert them to functional genes by ensuring their correct expression. They were originally identified as a mechanism used by Gram-negative bacteria to collect antibiotic resistance genes and express multiple resistance phenotypes in synergy with transposons. More recently, their role has been broadened with the discovery of chromosomal integron (CI) structures in the genomes of hundreds of bacterial species. This review focuses on the resources carried in these elements, on their unique recombination mechanisms, and on the different mechanisms controlling the cassette dynamics. We discuss the role of the toxin/antitoxin (TA) cassettes for the stabilization of the large cassette arrays carried in the larger CIs, known as superintegrons. Finally, we explore the central role played by single-stranded DNA in the integron cassette dynamics in light of the recent discovery that the integron integrase expression is controlled by the SOS response. PMID- 20707673 TI - Bacterial antisense RNAs: how many are there, and what are they doing? AB - Antisense RNAs encoded on the DNA strand opposite another gene have the potential to form extensive base-pairing interactions with the corresponding sense RNA. Unlike other smaller regulatory RNAs in bacteria, antisense RNAs range in size from tens to thousands of nucleotides. The numbers of antisense RNAs reported for different bacteria vary extensively, but hundreds have been suggested in some species. If all of these reported antisense RNAs are expressed at levels sufficient to regulate the genes encoded opposite them, antisense RNAs could significantly impact gene expression in bacteria. Here, we review the evidence for these RNA regulators and describe what is known about the functions and mechanisms of action for some of these RNAs. Important considerations for future research as well as potential applications are also discussed. PMID- 20707674 TI - Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. AB - Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease. PMID- 20707676 TI - Clostridium difficile and methicillin-resistant Staphylococcus aureus: emerging concepts in vaccine development. AB - Both Clostridium difficile and Staphylococcus aureus asymptomatically colonize a significant percentage of humans, particularly during the first year of life. The epidemiology of both has been and continues to be quite dynamic; presently, we are in the midst of epidemics of infections by C. difficile and S. aureus. These ancient microbes are now armed with more potent virulence factors, which have extended their reach from the hospital into community settings, and from the elderly and debilitated hosts into the younger and otherwise healthy population. This review presents some emerging concepts that will likely shape efforts to develop active and passive immunization interventions in response to the reemergence of these bacterial pathogens. PMID- 20707675 TI - Stress- and allostasis-induced brain plasticity. AB - The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prevent and treat chronic and prevalent health conditions via allodynamic brain mechanisms. PMID- 20707678 TI - Brucellosis of the spine affecting multiple non-contiguous levels. AB - Brucellosis is a systemic, endemic infection with spondylitis constituting a severe form of the disease, posing a risk of neurological sequelae. It most commonly affects the lumbar spine. This article presents a case of a patient with brucellar spondylodiscitis, affecting simultaneously the cervical, thoracic and lumbar spine, who had responded well to conservative management. PMID- 20707679 TI - New applicator improves waterjet dissection quality. AB - OBJECTIVE: Waterjet dissection is accomplished with Helix Hydro-Jet, but a new device with improved operative handling and potentially superior dissection qualities has been developed. MATERIALS AND METHODS: Eighty-four fresh cadaveric pig brains were simultaneously cut with Helix Hydro-Jet and Erbejet 2. A commonly used applicator and a new applicator for the Helix Hydro-Jet were directly compared to the new Erbejet 2. Under standardised conditions, different pressure levels were applied to the brain surface without arachnoids. Technical features, cutting depth, tissue damage and differences of applicators were examined. RESULTS: Microscopic analysis of cutting depth revealed different dissection characteristics of both the devices. With the standard applicators, waterjet cutting depth was shown to be deeper and with more foaming using the Helix Hydro Jet compared to that of the Erbejet 2. With the new applicators, less foaming and a lower and more linear increased cutting depth were observed with the Helix Hydro-Jet, very similar to the superior qualities shown by the Erbejet 2. CONCLUSIONS: The new developed applicator of the Erbejet 2 also improves the intraoperative results of the so far applied Helix Hydro-Jet. The new Erbejet 2 provides some advantages for practicability; but in combination with the new applicator, the Helix Hydro-Jet accomplished almost identical superior dissection qualities of the Erbejet 2. PMID- 20707680 TI - Pneumorrhachis with pneumocranium: an unusual complication of intra-abdominal sepsis. AB - We present this unusual case of a 60-year-old gentleman who presented with meningism and reduced conscious level. Imaging demonstrated a perforated sigmoid colon with retroperitoneal air associated with pneumorrhachis and pneumocranium. He required a Hartmann's procedure and broad spectrum intra-thecal antibiotics which led to resolution of the pneumorrhachis and pneumocranium. PMID- 20707681 TI - The value of intraoperative ultrasound in oblique corpectomy for cervical spondylotic myelopathy and ossified posterior longitudinal ligament. AB - Intraoperative ultrasound (IOUS) has been described to be useful during central corpectomy for compressive cervical myelopathy. This study aimed at documenting the utility of IOUS in oblique cervical corpectomy (OCC). Prospective data from 24 patients undergoing OCC for cervical spondylotic myelopathy and ossified posterior longitudinal ligament (OPLL) were collected. Patients had a preoperative cervical spine magnetic resonance (MR) image, IOUS and a postoperative cervical CT scan. Retrospective data from 16 historical controls that underwent OCC without IOUS were analysed to compare the incidence of residual compression between the two groups. IOUS identified the vertebral artery in all cases, detected residual cord compression in six (27%) and missed compression in two cases (9%). In another two cases with OPLL, IOUS was sub optimal due to shadowing. IOUS measurement of the corpectomy width correlated well with these measurements on the postoperative CT. The extent of cord expansion noted on IOUS after decompression showed no correlation with immediate or 6-month postoperative neurological recovery. No significant difference in residual compression was noted in the retrospective and prospective groups of the study. Craniocaudal spinal cord motion was noted after the completion of the corpectomy. IOUS is an inexpensive and simple real-time imaging modality that may be used during OCC for cervical spondylotic myelopathy. It is helpful in identifying the vertebral artery and determining the trajectory of approach, however, it has limited utility in patients with OPLL due to artifacts from residual ossification. PMID- 20707682 TI - The use of danaparoid to manage coagulopathy in a neurosurgical patient with heparin-induced thrombocytopenia type II and intracerebral haemorrhage. AB - This study presents a case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred. PMID- 20707683 TI - Gunshot wound to the clivus. AB - A 14 year old boy presents with a gunshot wound into the roof of his mouth to lodge into the clivus, and miraculously he is neurologically intact. PMID- 20707684 TI - In vitro photodynamic therapy on human U251 glioma cells with a novel photosensitiser ZnPcS4-BSA. AB - This article reports the phototoxicity effects of a novel photosensitiser ZnPcS4 BSA on human U251 glioma cells in vitro. The cellular uptake of ZnPcS4-BSA by U251 glioma cells was quantified by UV-spectra, and the optimal incubation time was determined. Human U251 glioma cells were incubated in ZnPcS4-BSA of various concentrations, and received laser irradiation of different energy densities. Cell survival rates were measured by CCK-8 assay. Flow cytometer was used to detect apoptosis. Expression of vascular endothelial growth factor (VEGF) gene was detected by real-time PCR in U251 cells after photodynamic therapy (PDT), and beta-actin was used as an internal standard. The normal U251 cells severed as controls. Results indicate that the uptake of ZnPcS4-BSA by U251 glioma cells reaches maximum after incubation for 4 hours. ZnPcS4-BSA with different concentrations without light irradiation has no significant effects on cell survival rates. Without ZnPcS4-BSA incubation, cell survival rate of high-dose group (400 J/cm(2)) is the lowest, whereas no significant difference has been found between any other two groups. At laser irradiation of 150 J/cm(2), inhibition rates of the cells increase with ZnPcS4-BSA concentration, and half inhibitory concentration (IC50) is 0.16 MUmol/L. Apoptosis rate of the cells after PDT is significantly higher than that of the control group (p < 0.01). The VEGF expression in the cells increases 5.616 times after PDT. The novel ZnPcS4 BSA is a good photosensitiser for PDT towards U251 glioma cells. The ZnPcS4-BSA based PDT can induce effective apoptosis. PMID- 20707685 TI - Extrusion of a ventriculoperitoneal shunt catheter through an appendicovesicostomy. AB - Migration of a ventriculoperitoneal shunt catheter is a rare but well-recognised complication in hydrocephalus treatment. Perforation into different organs or through natural or artificial orifices has been described. In this case, the shunt catheter has extruded through a Mitrofanoff appendicovesicostomy. PMID- 20707686 TI - Delayed and spontaneous intracranial foreign body migration. AB - We present a case of spontaneous migration of a metal rod into the brain. No causative factor was identified but possible mechanisms for this occurrence are considered, and the importance of correct early management of this unusual injury emphasised. PMID- 20707687 TI - Myxopapillary ependymoma of the cerebellopontine angle: retrograde metastasis or primary tumour? AB - Myxopapillary ependyoma (MPE) is a rare variant of ependymoma and represents a distinct subentity of tumour. It is almost exclusively restricted to the conus medullaris or filum terminale region. Here we present a case of a presumed primary MPE occurring in the cerebellopontine angle. PMID- 20707688 TI - Nonimmune hydrops fetalis in the stillborn. PMID- 20707689 TI - Cultural adaptation of a U.S. evidence-based parenting intervention for rural Western Kenya: from parents matter! To families matter! AB - Evidence-based interventions (EBIs) are critical for effective HIV prevention, but time and resources required to develop and evaluate new interventions are limited. Alternatively, existing EBIs can be adapted for new settings if core elements remain intact. We describe the process of adapting the Parents Matter! Program, an EBI originally developed for African American parents to promote effective parent-child communication about sexual risk reduction and parenting skills, for use in rural Kenya. A systematic process was used to assess the community's needs, identify potential EBIs, identify and make adaptations, pilot test the adapted intervention, and implement and monitor the adapted EBI. Evaluation results showed the adapted EBI retained its effectiveness, successfully increasing parent-child sexual communication and parenting skills. Our experience suggests an EBI can be successfully adapted for a new context if it is relevant to local needs, the process is led by a multidisciplinary team with community representation, and pilot-testing and early implementation are well monitored. PMID- 20707690 TI - Harassment, discrimination, violence, and illicit drug use among young men who have sex with men. AB - We examined the relationship among social discrimination, violence, and illicit drug use among an ethnically diverse cohort of young men who have sex with men (YMSM) residing in Los Angeles. Five Hundred twenty-six YMSM (aged 18-24 years) were recruited using a venue-based, stratified probability sampling design. Surveys assessed childhood financial hardship, violence (physical assault, sexual assault, intimate partner violence), social discrimination (homophobia and racism), and illicit drug use in the past 3 months. Analyses examined main and interaction effects of key variables on drug use. Experiences of financial hardship, physical intimate partner violence and homophobia predicted drug use. Although African American participants were less likely to report drug use than their Caucasian peers, those who experienced greater sexual racism were at significantly greater risk for drug use. Racial/ethnic minority YMSM were at increased risk for experiencing various forms of social discrimination and violence that place them at increased risk for drug use. PMID- 20707691 TI - Examining HIV infection among male sex workers in Bangkok, Thailand: a comparison of participants recruited at entertainment and street venues. AB - HIV prevalence and associated factors were examined among male sex workers (MSWs, N = 414) in Bangkok, Thailand. Cross-sectional venue-day-time sampling was used to collect data in entertainment and street venues. Chi-square and logistic regression were used to identify HIV risk factors. HIV prevalence was 18.8% overall, but differences were found between MSW recruited in entertainment and street venues. Significant relationships were found between several demographic, behavioral, exposure to HIV prevention, and other characteristics, and recruitment location. In multivariate analyses, being sexually attracted to men was significantly associated with HIV infection among both groups of sex workers. In addition, among street-based sex workers, not having had sex with a woman in the past 3 months, having ever had a sexually transmitted disease symptom, and not having a friend to talk to about personal problems were significantly associated with HIV infection. PMID- 20707692 TI - CDC HIV testing guidelines and the rapid and conventional testing practices of homeless youth. AB - The study's aims were to describe rapid and conventional HIV testing practices and referrals/linkages to services posttest among homeless youth in New York City. We also examined variation among service-involved youth, street youth, and "nomads." Respondent-driven sampling was used to recruit 217 homeless youth who participated in structured interviews. Almost all youth were tested in the past year (82%). Most received pretest/posttest counseling (> 77%). Rapid testing was common and conducted in diverse settings. However, youth reported that rates of referral/linkage to services posttest were low (< 44.4%). Service-involved youth were significantly more likely to receive rapid testing, be tested in the past year, and be tested at a high frequency. Street youth and nomads, those at highest risk for poor health outcomes, had less access to testing and may require creative, low-threshold services. Further, a better understanding of barriers to the use of referrals/linkages to services posttest is needed. PMID- 20707693 TI - Evaluation of a U.S. evidence-based parenting intervention in rural Western Kenya: from parents matter! To families matter! AB - We evaluated Families Matter! Program (FMP), an intervention designed to improve parent-child communication about sexual risk reduction and parenting skills. Parents of 10- to 12-year-olds were recruited in western Kenya. We aimed to assess community acceptability and FMP's effect on parenting practices and effective parent-child communication. Data were collected from parents and their children at baseline and 1 year postintervention. The intervention's effect was measured on six parenting and parent-child communication composite scores reported separately for parents and children. Of 375 parents, 351 (94%) attended all five intervention sessions. Parents' attitudes regarding sexuality education changed positively. Five of the six composite parenting scores reported by parents, and six of six reported by children, increased significantly at 1 year postintervention. Through careful adaptation of this U.S. intervention, FMP was well accepted in rural Kenya and enhanced parenting skills and parent-child sexuality communication. Parents are in a unique position to deliver primary prevention to youth before their sexual debut as shown in this Kenyan program. PMID- 20707694 TI - Theory-based HIV-related sexual risk reduction prevention for chinese female rural-to-urban migrants. AB - BACKGROUND: The objective of this pilot study was to evaluate the initial efficacy of a protection motivation theory-based behavioral HIV prevention intervention in increasing HIV knowledge, condom use perception, condom use intention and consistent condom use among female rural-to-urban migrants in Beijing, China. Three hundred female migrants were assigned to the intervention group (N = 200) and control group (N = 100). Data were collected at baseline and a 4-month follow-up. The results suggest that HIV-related knowledge, condom use perceptions, condom use intention and condom use skills at the follow-up were significantly improved among female migrants in the intervention group compared with those in the control group. Moreover, a significantly higher rate of consistent condom use at post intervention was found compared with that at baseline in the intervention group (17.0% vs. 32.0%, p < .05) but not in the control group (23.8% vs. 29.2%, ns). The current study suggests that the theory based intervention can be efficacious in increasing HIV knowledge, condom use perceptions and skills, and consistent condom use among female rural-to-urban migrants in China. PMID- 20707695 TI - HIV testing among bisexual men in the United States. AB - Little is known about HIV testing among bisexual men in the United States. Existing studies lack adequate representation, multivariate analytical strategies, and measurement of bisexuality indicators. To address these limitations, this study used the National Survey of Family Growth (N = 3,875). Sexual behavior and identity measures compared bisexual and other men along HIV testing history, reasons for testing, and recency of testing. Multivariate analyses adjusted for sociodemographic and risk factors that covary with testing. Bisexually active men were significantly less likely than homosexually active men to ever test, and they tested less often to know their HIV serostatuses. Bisexual identification decreased the odds of testing among bisexually active men but not others. Findings suggest that bisexual behavior and identity interact to decrease men's likelihoods of HIV testing. Interventions must recognize the potentially mediating roles of bisexual identity and behavior as well as risk factors that increase bisexual men's susceptibility to HIV infection. PMID- 20707696 TI - Reducing sexual risk among Filipina female bar workers: effects of a CBPR developed structural and network intervention. AB - The effects of three interventions designed to reduce sexual risk among Filipina female bar workers (FBWs) were compared with each other and with usual care (nonintervention). The interventions were developed iteratively by a community based participatory research (CBPR) partnership comprising lay community members, organizational representatives (including nongovernmental organizations), and academic researchers from the United States and the Philippines. Peer educators and bar managers from 110 different establishments in three southern regions were recruited and trained to increase knowledge of HIV and of condom use rules and regulations within establishments, as well as to change attitudes about risk reduction, provide HIV and sexually transmitted infection (STI) testing referrals, and build condom use skills among FBWs. Compared with the control community, all three interventions increased HIV and STI testing; however, only FBWs in the combination peer-educator and manager-training intervention significantly increased condom use from baseline to 2-year follow-up. Condom use was significantly associated with higher HIV knowledge, attendance of a prevention class, and being taught how to use condoms properly. Given these findings, research is warranted to further explore and understand various forms of commercial sex work and to test adapted peer-educator and manger-training interventions within HIV epicenters. PMID- 20707697 TI - Pregnancy-associated progenitor cells differentiate and mature into neurons in the maternal brain. AB - Bidirectional cell trafficking between fetus and mother during pregnancy is a well-established phenomenon observed in placental vertebrates including humans. Although studies have shown that transmigratory fetal cells, also termed pregnancy-associated progenitor cells (PAPCs), can integrate into multiple maternal organs, the integration, long-term survival, and differentiation of PAPCs in the brain has not been extensively studied. Using a murine model of fetomaternal microchimerism, we show that PAPCs integrated and persisted in several areas of the maternal brain for up to 7 months postpartum. Besides expressing neural stem cell or immature neuronal markers, PAPCs were observed to express mature neuronal markers, indicating that PAPCs adopted a neuronal fate. Further, PAPCs also displayed morphologically neuronal maturation by an increasing axonal/dendritic complexity over time. Therefore, PAPCs seem to undergo a molecular and morphological maturation program similar to that observed during adult neurogenesis. We provide evidence that neuronal gene expression of PAPCs was not a consequence of cell fusion with maternal neurons. In addition, in mothers with experimentally induced Parkinson's disease (PD), the frequency of PAPCs within the hippocampus initially increased whereas long-term presence of PAPCs was compromised. Also, the spatial distribution of PAPCs within the hippocampus was altered in mothers with PD. Thus, the disease context influenced the initial attraction, long-term survival, and spatial distribution of PAPCs, which may have wider implications on cell replacement strategies in human neurodegenerative diseases such as PD. PMID- 20707699 TI - A child with an FGFR3 mutation, a laterality disorder and an hepatoblastoma: novel associations and possible gene-environment interactions. AB - We report on a 3-year-old girl, from a 3-generation family with an FGFR3 Pro250Arg mutation, who in addition to craniosynostosis, had a laterality disorder and hepatoblastoma, following a pregnancy complicated by maternal insulin-dependent diabetes. The clinical features possibly result from the combined effects of the maternal diabetes and the familial FGFR3 mutation, thus representing a unique gene-environment interaction that may have implications for the understanding of the phenotypes described in this child. PMID- 20707698 TI - Rethinking prevention of HIV type 1 infection. AB - Research on the prevention of human immunodeficiency virus (HIV)-1 infection is at a critical juncture. Major methodological challenges to performing prevention trials have emerged, and one after another promising biomedical interventions have failed to reduce the incidence of HIV-1 infection. Nevertheless, there is growing optimism that progress can be achieved in the near term. Mathematical modeling indicates that 2 new strategies, "test and treat" and preexposure prophylaxis, could have a major impact on the incidence of HIV-1 infection. Will our hopes be justified? We review the potential strengths and limitations of these antiretroviral "treatment as prevention" strategies and outline other new options for reducing the incidence of HIV-1 infection in the near term. By maximizing the potential of existing interventions, developing other effective strategies, and combining them in an optimal manner, we have the opportunity to bring the HIV-1 epidemic under control. PMID- 20707700 TI - A General Factor of Personality (GFP) in the personality disorders: three studies of the Dimensional Assessment of Personality Pathology - Basic Questionnaire (DAPP-BQ). AB - We used structural equation modeling to test the hypothesis that a General Factor of Personality (GFP) occupies the apex of the hierarchy of personality disorders in three validation samples of the Dimensional Assessment of Personality Pathology - Basic Questionnaire (DAPP-BQ). In a general population sample (N = 942), we found a GFP explained 34% of the variance in four first-order factors and 33% of the variance in all 18 scales. In a twin sample (N = 1,346), a GFP explained 35% of the variance in four first-order factors and 34% of the variance in all 18 scales. In a clinical sample (N = 656), a GFP explained 34% of the variance in four first-order factors and 30% of the variance in all 18 scales. PMID- 20707701 TI - Mates and marriage matter: genetic and environmental influences on subjective wellbeing across marital status. AB - Specific environments and social relationships may alter the impact of genes. Previous studies have shown marriage to moderate heritability for depressive symptoms in females, suggesting that marriage provides protection or compensation against genetic risks. Similar mechanisms may be relevant for subjective wellbeing (SWB), which is considerably influenced by genes and almost universally associated with marital status. Questionnaire data on SWB from a population-based sample of 1250 monozygotic (MZ) and 981 dizygotic (DZ) male and female twin pairs (n = 4462) were analyzed using structural equation modeling by means of Mx to investigate genetic and environmental influences on SWB across marital status. Resemblance for SWB in MZ twins exceeded that of DZ twins, but the magnitude of this difference varied across marital status. Genetic factors explained 51% and 54% of the variance in SWB among unmarried males and females, and 41% and 39% in married or cohabitating respondents. Remaining variance was attributable to the nonshared environment. The genetic influences were partly different (r(g) = 0.64) across marital status in females, but overlapping in married and single males. Our findings show that marriage moderates the magnitude of genetic influences on SWB in both males and females, with a smaller estimate of genetic influences for those with a marital or equivalent partner. The genetic influences on SWB are thus clearly contingent on the environmental context. PMID- 20707702 TI - Sex differences in the genetic architecture of optimism and health and their interrelation: a study of Australian and Swedish twins. AB - Optimism has a positive influence on mental and somatic health throughout lifetime and into old age. This association is mainly due to shared genetic influences, with some indication of sex differences in the heritability of these and related traits (e.g., depression and subjective wellbeing). Here we extend our initial study of Australian twins by combining with data available from Swedish twins, in order to increase the power to explore potential sex differences in the genetic architecture of optimism, mental and self-rated health and their covariation. Optimism, mental, and self-rated health were measured in 3053 Australian (501 identical female (MZf), 153 identical male (MZm), 274 non identical female (DZf), 77 non-identical male (DZm), and 242 non-identical opposite-sex twin pairs, and 561 single twins; mean age 60.97 +/- 8.76), and 812 Swedish (71 MZf, 53 MZm, 93 DZf and 67 DZm twin pairs, and 244 single twins; mean age 60 +/- 14.3) twin individuals using the Life Orientation Test (LOT), the General Health Questionnaire (GHQ) and a single-item self-rating of overall health, respectively. In females all three traits were moderately heritable (.27 .47), whereas in males heritability was substantially lower (.08-.19), but genetic modeling showed that sex differences were not significant. The absence of significant sex differences, despite the consistent trend across the two cohorts, is likely due to a lack of power, raising the importance for future studies, on the same or similar traits, to utilize large samples and to keep the possibility of sex differences in mind when conducting their analyses. PMID- 20707703 TI - Are attitudes towards economic risk heritable? Analyses using the Australian twin study of gambling. AB - Abstract This study employs multiple regression models based on DeFries and Fulker (1985), and a large sample of twins, to assess heritability in attitudes towards economic risk, and the extent to which this heritability differs between males and females. Consistent with Cesarini et al. (2009), it is found that attitudes towards risk are moderately heritable, with about 20 percent of the variation in these attitudes across individuals being linked to genetic differences. This value is less than one-half the estimates reported by Zyphur et al. (2009) and Zhong et al. (2009). While females are more risk averse than males, there is no evidence that heritability in attitudes towards risk differs between males and females. Even though heritability is shown to be important to economic risk-taking, the analyses suggest that multivariate studies of the determinants of attitudes towards risk which to not take heritability into consideration still provide reliable estimates of the partial effects of other key variables, such as gender and educational attainment. PMID- 20707704 TI - The family history method in disordered gambling research: a comparison of reports obtained from discordant twin pairs. AB - The purpose of this study was to examine potential biases in family history reports of problem gambling and gambling frequency. Same-sex twin pairs discordant for a history of problem (n = 230 pairs) and pathological gambling (n = 48 pairs) and for three indexes of gambling frequency (ever gambling, monthly gambling, and weekly gambling; n = 44-517 pairs) were identified from a large Australian national twin study. The problem gambling affected twin was significantly more likely to endorse paternal problem gambling than the problem gambling unaffected cotwin (OR = 5.5), and similar findings were obtained for family history reports of gambling frequency (OR = 2.0-2.8). These results could not be explained by differences between the discordant pairs in whether they had spent time gambling with the parents; there was no association between a history of problem, monthly or weekly gambling and having gambled with the parents among discordant twin pairs. The results of this study suggest that relying solely on family history assessments of disordered gambling and gambling involvement can lead to incorrect estimates of the strength of the family history effect. PMID- 20707705 TI - Major depression and the metabolic syndrome. AB - The aim of this study is to characterize the relationship between major depression and the metabolic syndrome in a large community based sample of Australian men and women aged 26-90 years. A lifetime history of major depression was assessed by telephone interview following the DSM-III-R. A current history of metabolic syndrome was assessed following the United States National Cholesterol Education Program Adult Treatment Panel III (NCEP AP-III) guidelines 1 to 3 years later. Logistic regression was used to estimate the association between depression and the metabolic syndrome, and its component criteria, controlling for age, sex and alcohol dependence. There was no association between a lifetime history of major depression and the presence of the metabolic syndrome. There was a weak association between depression and low high-density lipoprotein cholesterol but not with other component criteria of the metabolic syndrome. Despite calls for interventions directed at depression to reduce the onset of the metabolic syndrome there are important failures to replicate in large samples such as this, no consensus regarding the threshold at which depression may pose a significant risk even allowing for heterogeneity across populations, and no consensus regarding confounders that may explain inter-study differences. The absence of any dosage effect of depression on the associated risk for the metabolic syndrome in other unselected samples does not support a direct causal relationship. The call for intervention studies on the basis of the currently published evidence base is unwarranted. PMID- 20707707 TI - Heritability of head size in Dutch and Australian twin families at ages 0-50 years. AB - We assessed the heritability of head circumference, an approximation of brain size, in twin-sib families of different ages. Data from the youngest participants were collected a few weeks after birth and from the oldest participants around age 50 years. In nearly all age groups the largest part of the variation in head circumference was explained by genetic differences. Heritability estimates were 90% in young infants (4 to 5 months), 85-88% in early childhood, 83-87% in adolescence, 75% in young and mid adulthood. In infants younger than 3 months, heritability was very low or absent. Quantitative sex differences in heritability were observed in 15- and 18-year-olds, but there was no evidence for qualitative sex differences, that is, the same genes were expressed in both males and females. Longitudinal analysis of the data between 5, 7, and 18 years of age showed high genetic stability (.78 > R(G) > .98). These results indicate that head circumference is a highly heritable biometric trait and a valid target for future GWA studies. PMID- 20707708 TI - The sex ratios of monozygotic and dizygotic twins. AB - Fellman and Eriksson (2010) cited my suggestion that the sex ratio (proportion male) of monozygotic (MZ) twins is lower than that of dizygotic (DZ) twins (James 1975). Here I offer elaborations on and potential explanations for this. PMID- 20707706 TI - Nicotine withdrawal symptoms in adolescent and adult twins. AB - We examined the variation and heritability of DSM-IV nicotine withdrawal (NW) in adult and adolescent male and female twin cigarette smokers (who reported smoking 100 or more cigarettes lifetime). Telephone diagnostic interviews were completed with 3,112 Australian adult male and female smokers (53% women; age: 24-36) and 702 Missouri adolescent male and female smokers (59% girls; age: 15-21). No gender or cohort differences emerged in rates of meeting criteria for NW (44%). Latent class analyses found that NW symptoms were best conceptualized as a severity continuum (three levels in adults and two levels in adolescents). Across all groups, increasing NW severity was associated with difficulty quitting, impairment following cessation, heavy smoking, depression, anxiety, conduct disorder and problems with alcohol use. NW was also associated with seeking smoking cessation treatment and with smoking persistence in adults. The latent class structure of NW was equally heritable across adult and adolescent smokers with additive genetic influences accounting for 49% of the variance and the remaining 51% of variance accounted for by unique environmental influences. Overall, findings suggest remarkable similarity in the pattern and heritability of NW across adult and adolescent smokers, and highlight the important role of NW in psychiatric comorbidity and the process of smoking cessation across both age groups. PMID- 20707709 TI - Sexual behaviour of women with twin pregnancies. AB - It has been assumed that sexual activity during pregnancy would lead to an increased risk for miscarriage and other complications of pregnancy. Various studies showed no association of sexual behavior and pregnancy complications in single pregnancies. The aim of our study was to evaluate changes in sexual activity in women with twin pregnancies and whether a higher frequency of sexual intercourse was associated with an increased risk for pregnancy complications. We report on 50 women with twin pregnancies who answered a questionnaire on sexual behavior during pregnancy. At the time of delivery, patients were aged 31.0 +/- 4.8 years. All women reported to have had sexual intercourse during pregnancy. In contrast to the first trimester in the vast majority of patients (41/50, 82.0%) the coital frequency decreased in the last month of pregnancy. Patients who had become pregnant after in-vitro fertilization were significantly less likely to have regular sexual intercourse than patients after spontaneous conception during early pregnancy (p = .002). No statistical significances were found when the rates of preterm delivery before the 37th gestational week were compared to the frequencies of sexual intercourse during early pregnancy and during late pregnancy (p >.05). In conclusion, our study demonstrates a decrease in frequency of sexual intercourse from early to late pregnancy in the specific collective of women with twin pregnancies, especially in women after in-vitro fertilization. There was no association between sexual activity and preterm delivery. PMID- 20707710 TI - Association between twin discordance at 6-9 weeks' of gestation and birthweight complications. AB - Twins achieved through in-vitro fertilisation often undergo a viability ultrasound at 6-9 weeks of gestation. The presence of inter-twin crown-rump length discordance at this stage is not an uncommon finding; however the clinical significance of this is unknown. We analyzed 218 dichorionic twin pregnancies, producing two live fetuses > 24 weeks gestation, to determine whether inter-twin discordance (> or = 85th centile) in the mid-first trimester was associated with birthweight discordance (> 20%), or small for gestational age (< 10th centile). The incidence of birthweight discordance and small for gestational age infants were determined, with no increased risk found for the discordant population. This may provide some reassurance to treating clinicians. PMID- 20707711 TI - Influence of gestational diabetes mellitus on weight discrepancy in twin pregnancies. AB - OBJECTIVE: To evaluate the influence of gestational diabetes mellitus on weight discrepancy in twin pregnancies. METHODS: 200 twin pregnancies were included in the study. 157 nondiabetic pregnant women with twin gestations and 43 twin pregnancies with gestational diabetes mellitus (GDM) with viable fetuses born after 24 weeks of gestation were enrolled. Influence of maternal age, body-mass index at the time of the oral glucose tolerance test, parity, smoking, chorionicity, gestational age at delivery and diagnosis of GDM on weight discrepancy of the twins was evaluated. RESULTS: Mean weight discrepancy of all analyzed twin pregnancies was 285 grams (+/- 231), relative weight discrepancy was 11.3% (+/- 8.6). Univariate regression analyses showed that GDM, chorionicity and gestational age at delivery were significantly associated with weight discrepancy. In the multivariate model only diagnosis of GDM was significantly associated with weight discrepancy. CONCLUSION: Twin pregnancies with insulin requiring gestational diabetes seem to have less birth weight discrepancy than twin pregnancies with normal glucose tolerance. PMID- 20707712 TI - A genome-wide association study of self-rated health. AB - Self-rated health questions have been proven to be a highly reliable and valid measure of overall health as measured by other indicators in many population groups. It also has been shown to be a very good predictor of mortality, chronic or severe diseases, and the need for services, and is positively correlated with clinical assessments. Genetic factors have been estimated to account for 25-64% of the variance in the liability of self-rated health. The aim of the present study was to identify Single Nucleotide Polymorphisms (SNPs) underlying the heritability of self-rated health by conducting a genome-wide association analysis in a large sample of 6,706 Australian individuals aged 18-92. No genome wide significant SNPs associated with self-rated health could be identified, indicating that self-rated health may be influenced by a large number of SNPs with very small effect size. A very large sample will be needed to identify these SNPs. PMID- 20707714 TI - Acinetobacter baumannii 2002-2008: increase of carbapenem-associated multiclass resistance in the United States. AB - The study consisted of data for 55,330 U.S. Acinetobacter baumannii isolates from The Surveillance Network((r)) database for the period 2002-2008. Risk factors were time, age, sex, census region, location (Ward or ICU), and isolate source. Antimicrobial susceptibility data were available for carbapenems, cephalosporins, aminoglycosides, fluoroquinolones, and beta-lactam/beta-lactamase inhibitor combinations. Multiclass resistance was defined as nonsusceptibility to carbapenems and two or more additional classes. Odds of resistance were obtained using a logistic regression model with cubic splines. Carbapenem-associated multiclass resistance has had a 3.7-fold (95% confidence interval [CI] 3.4-4.3) increase from 20.6% in 2002 to 49.2% in 2008. Among blood isolates the increase was by 2.2 times (95% CI 1.7-2.9). Subjects <18 years old had significantly (p < 0.001) lower rates in 2002 (6.9%) than those 65 years or older (21.5%), but by 2008 this difference diminished as rates increased to 44.2% and 54.2%, respectively. A similar divergence was also observed between ICU and Ward, with no differences in 2002, whereas in 2008 ICU isolates had significantly higher rates (55.2%, 95% CI 53.6%-56.9%) than Ward isolates (45.6%, 95% CI 44.2%-47.0%). Over half of all A. baumannii-resistant isolates were carbapenem and multiclass resistant in 2008. Rates among subjects <18 years old have increased faster than those of the elderly, and in the ICU as compared to Ward. PMID- 20707715 TI - Treatment with Qing'E, a kidney-invigorating Chinese herbal formula, antagonizes the estrogen decline in ovariectomized mice. AB - A Chinese herbal preparation, Qing'E formula (QEF), has been used clinically for treating osteoporosis in postmenopausal women by virtue of its kidney invigorating function; however, no evidence base links QEF to estrogen replacement therapy. In this study, we undertake a characterization of estrogenic activity of QEF using an in vivo model of ovariectomized (OVX) mice together with in vitro studies with the MCF-7 cells for further molecular characterization. OVX mice were treated intragastrically with QEF at doses of 0.85, 1.7, and 3.4 g/kg per day for 4 weeks. QEF treatments restored the estrus cycle and demonstrated significant estrogenic activity, as indicated by reversal of uterine atrophy (six fold increase in uterine weight), reduction in rectal temperature, and increased expression (1.6-fold) of estrogen receptors (ERs) in the uterus. Notably, the largest changes in these three parameters were found at the lowest dose. At the highest dose of QEF, significant changes were found in adrenal gland weight (30% increase), serum estradiol (E(2)) (60% increase), and luteinizing hormone (LH) (17% decrease) compared with untreated OVX controls. The data suggest estrogenic responses induced by QEF show tissue variation that reflects different affinities of ERs for QEF components. QEF could significantly induce luciferase expression (2.7-fold compared with control) from an estrogen response element luciferase reporter and induced expression of ERalpha and ERbeta (1.2-fold and 1.7-fold respectively) in MCF-7 cells. Both activities were inhibited 80-90% by the estrogen antagonist ICI 182,780. This study demonstrates that QEF activity is mediated through estrogenic components and provides an evidence base for QEF treatment of postmenopausal symptoms. PMID- 20707716 TI - Immuno-positron emission tomography: shedding light on clinical antibody therapy. AB - Summation Monoclonal antibodies (mAbs) have been approved for therapeutic use in a broad range of medical indications, especially in oncology, and are forming the most rapidly expanding category of pharmaceuticals. Although engineered mAb fragments and nontraditional antibody-like scaffolds are receiving increasingly more attention, most of the mAb candidates evaluated in past and ongoing clinical trials are full-length mAbs. Immuno-positron emission tomography (PET), the tracking and quantification of mAbs with PET in vivo at superior imaging quality, is an exciting novel option for better understanding the in vivo behavior and efficacy of mAbs in individual patients. This review focuses on immuno-PET with full-length mAbs, and the associated use of the long-lived positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I). Very recently, crucial achievements have been obtained to allow broad-scale application of (89)Zr- and (124)I-immuno-PET in clinical mAb development and applications. (89)Zr and (124)I became commercially available worldwide for clinical use. A chelate for facile coupling of (89)Zr to mAbs became commercially available, and generic procedures for labeling of mAbs with (89)Zr and (124)I in a current good manufacturing practice compliant way were established. In this review, critical aspects for the translation of immuno-PET from preclinical investigations to clinical trials will be discussed, as well as the potential clinical applications of immuno-PET. An overview of the results of the first clinical immuno-PET studies will be provided. PMID- 20707717 TI - Localization of complexed anticytokeratin 8 scFv TS1-218 to HeLa HEp-2 multicellular tumor spheroids and experimental tumors. AB - Recombinant single-chain fragment variable (scFv) antibodies with specificity to tumor antigens can be used to target tumors in vivo. The approach to use administration of complexes of idiotypic-anti-idiotypic scFvs when targeting tumors has not been tested earlier, and from a theoretical point it could contribute to longer in vivo circulation and improved targeting efficiency by dissociation, when in contact with the target antigen. In this study two models to evaluate the targeting efficiency of such complexes were used. HeLa HEp-2 tumor cells were grown as multicellular tumor spheroids (MCTS) and exposed to the antibody constructs in vitro. The behavior in vivo was tested in an in vivo tumor xenograft model. To increase the size of the anticytokeratin 8 scFv, TS1-218, complexes were formed between TS1-218 and its anti-idiotype, alphaTS1 scFv. The functionality of (125)I-labeled TS1-218 alone and in complex was studied in both models. The uptake patterns were similar in both models. The idiotypic TS1-218 was able to localize to the MCTS and xenografted tumors, both alone and in complex with alphaTS1 scFv. TS1-218 in complex, however, demonstrated a significantly higher uptake than the monomeric TS1-218 in both models (p < 0.0005 and p < 0.0089, respectively). When complexes were administered in vivo, a slower clearance and an increased tumor half-life could be observed. The present investigation indicates that administration of targeting antibodies, with initially blocked antigen-binding sites by complex formation with their anti idiotypes, may improve targeting efficiency. PMID- 20707718 TI - A pretherapy biodistribution and dosimetry study of indium-111-radiolabeled trastuzumab in patients with human epidermal growth factor receptor 2 overexpressing breast cancer. AB - PURPOSE: The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of (111)Indium ((111)In) MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether (90)Y-MxDTPA trastuzumab should be evaluated in subsequent clinical therapy trials. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4-8 mg/kg IV), followed 4 hours later by 5 mCi (111)In-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days. RESULTS: Eight (8) patients received (111)In-MxDTPA-trastuzumab, which was well tolerated with no adverse side-effects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No antiantibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with (90)Y were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi. CONCLUSIONS: In summary, results from this study indicate that (90)Y-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to (111)In-MxDTPA trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other (90)Y-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose limiting cardiotoxicity. PMID- 20707719 TI - Tumor-suppressive effect of adenovirus-mediated inhibitor of growth 4 gene transfer in breast carcinoma cells in vitro and in vivo. AB - The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential suppressive effect on different tumors via multiple pathways. However, the role of adenovirus mediated ING4 (Ad-ING4) gene therapy for human breast carcinoma remains unknown. This study investigates the therapeutic effect of Ad-ING4 on human breast cancers in vitro and in vivo in an athymic nude mouse model, using two human breast carcinoma cell lines MDA-MB-231 (mutant p53) and MCF-7 (wild-type p53) and elucidated its underlying mechanism. It was found that Ad-ING4 treatment could induce in vitro significant growth suppression in both mutant p53 MDA-MB-231 and wild-type p53 MCF-7 breast carcinoma cells despite p53 status. This study further demonstrates that Ad-ING4 gene transfer resulted in G2/M phase arrest and apoptosis, upregulated P21, P27, and Bax, downregulated Bcl-2, IL-8, and Ang-1, promoted cytochrome c release from mitochondria into cytosol, and activated caspase-9, caspase-3, and PARP in mutant p53 MDA-MB-231 breast carcinoma cells. Moreover, intratumoral injections of Ad-ING4 in nude mice bearing mutant p53 MDA MB-231 breast tumors remarkably inhibited the human breast xenografted tumor growth and reduced CD34 expression of tumor vessels and microvessel density. This retarded MDA-MB-231 breast carcinoma growth in vitro and in vivo elicited by Ad ING4 closely correlated with the upregulation of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to proapoptotic molecules Bcl-2/Bax, release of cytochrome c from mitochondria into cytosol followed by caspase-9 and 3 activation leading to apoptosis via intrinsic apoptotic pathway, and the reduced expression of proangiogenic factors IL-8 and Ang-1 involved in the inhibition of tumor angiogenesis. Thus, the results indicate that Ad-ING4 is a potential candidate for breast cancer gene therapy. PMID- 20707720 TI - Radiolabeling of morphine with (131)i and its biodistribution in rats. AB - This study was conducted to determine the possible radiopharmaceutical potential of morphin labeled with (131)I. Morphine was extracted from dry capsules of the opium poppy (Papaver somniferum L.), purified by high-performance liquid chromatography, and characterized with nuclear magnetic resonance and infrared spectroscopy. The purified compound was labeled with (131)I. Male Albino Wistar rats (18) were used for receptor blockage and unblockage biodistribution studies. Tissue distribution studies showed that radiolabeled morphine had higher uptake in lung, liver, small intestines, large intestines, and stomach than the other tissues. The highest uptake of radiolabeled compounds in rats' brain was found to be in the midbrain and hypothalamus. After receptor blockage with morphine, uptake of (131)I-morphine decreased in the lungs, liver, kidney, testis, prostate, spinal cord, cerebellum, hippocampus, striatum, and temporal cortex with respect to receptor unblockage studies of rats. This study concludes that the labeling yield of (131)I-morphine was high, high amount of (131)I-morphine was found in the hypothalamus, and (131)I-morphine has enough stability for diagnostic scanning. PMID- 20707721 TI - Static magnetic fields enhanced the potency of cisplatin on k562 cells. AB - PURPOSE: This study investigates whether 8.8 mT static magnetic fields (SMFs) can enhance the killing potency of cisplatin (DDP) on human leukemic cells (K562). METHODS: The cell proliferation, cell cycle distribution, DNA damage, and the change in cell surface ultrastructure after K562 cells were exposed to 8.8 mT SMFs with or without DDP were analyzed. RESULTS: The results show that SMFs enhanced the killing effect of DDP on K562 cells, reducing the efficient killing concentration of DDP on K562 cells from 20 to 10 microg/mL. Atomic force microscope observation showed that the cell surface ultrastructure was altered. The results of fluorescence-activated cell sorting analysis indicated that K562 cells treated with SMF plus DDP were arrested at the S phase. The SMF exposure induced DNA to become thicker than controls, and breakage of DNA occurred in the DDP group; however, DNA breakage was increased in the SMF + DDP group. CONCLUSIONS: The results show that SMFs enhanced the anticancer effect of DDP on K562 cells. The mechanism correlated with the DNA damage model. This study also shows the potentiality of SMFs as an adjunctive treatment method for chemotherapy. PMID- 20707722 TI - Environmental enrichment improves age-related immune system impairment: long-term exposure since adulthood increases life span in mice. AB - Age-related changes in immunity have been shown to highly influence morbidity and mortality. The aim of the present work was to study the effects of environmental enrichment (EE) (8-16 weeks) on several functions and oxidative stress parameters of peritoneal leukocytes, previously described as health and longevity markers, in mice at different ages, namely adult (44 +/- 4 weeks), old (69 +/- 4 weeks), and very old (92 +/- 4 weeks). Mortality rates were monitored in control and enriched animals, and effects on survival of long-term exposure to EE until natural death were determined. The results showed that exposure to EE was efficient in improving the function (i.e., macrophage chemotaxis and phagocytosis, lymphocyte chemotaxis and proliferation, natural killer cell activity, interleukin-2 and tumor necrosis factor-alpha levels) and decreasing the oxidative-inflammatory stress (i.e., lowered oxidized glutathione content, xanthine oxidase activity, expression of Toll-like receptors 2 and 4 on CD4 and CD8 cells, and increased reduced glutathione and glutathione peroxidase and catalase activities) of immune cells. These positive effects of EE were especially remarkable in animals at older ages. Importantly, long-term exposure to EE from adult age and until natural death stands out as a useful strategy to extend longevity. Thus, the present work confirms the importance of maintaining active mental and/or physical activity aiming to improve quality of life in terms of immunity, and demonstrates that this active life must be initiated at early stages of the aging process and preserved until death to improve life span. PMID- 20707724 TI - CTX-M-type extended-spectrum beta-lactamases present in Escherichia coli from the feces of cattle in Ohio, United States. AB - CTX-M extended-spectrum beta-lactamases are enzymes produced by bacteria that are capable of inhibiting the antimicrobial effects of cephalosporin drugs. Recently, the first domestically acquired Salmonella in the United States expressing bla(CTX-M) was reported. This is a concern because expanded-spectrum cephalosporins are the treatment of choice for invasive Gram-negative infections, including salmonellosis in children. Because Salmonella transmission is primarily foodborne, there is also concern that resistant enteric bacteria from livestock can be transferred through the food supply chain to consumers. bla(CTX-M) has not been previously identified in bacterial isolates from food animal populations in the United States. We report the recovery of CTX-M-type extended-spectrum beta lactamases from fecal Escherichia coli of sick and healthy dairy cattle in Ohio. Four individual fecal samples yielded E. coli isolates representing three clonal strains that carried bla(CTX-M) on transferable plasmids. Two distinguishable plasmids were identified, each encoding bla(CTX-M-1) or bla(CTX-M-79). Transferrable bla(CTX-M) genes in bovine E. coli have the potential to serve as a reservoir of resistance for pathogens and may represent a public health concern. PMID- 20707723 TI - Salt stress phenotypes in Listeria monocytogenes vary by genetic lineage and temperature. AB - Listeria monocytogenes can survive and grow under wide-ranging environmental stress conditions encountered both in foods and in the host. The ability of certain L. monocytogenes subtypes to thrive under stress conditions present in specific niches was hypothesized to reflect genetic characteristics and phenotypic capabilities conserved among strains within a subtype. To quantify variations in salt stress phenotypes among 40 strains selected to represent the diversity of the three major L. monocytogenes genetic lineages and to determine if salt stress phenotypes were associated with genetic relatedness, we measured growth under salt stress at both 7 degrees C and 37 degrees C. At 7 degrees C, in brain-heart infusion with 6% NaCl, average growth rates among the lineages were similar. A comparison of doubling times after exposure to salt stress at 7 degrees C or 37 degrees C indicated that growth at 7 degrees C provided crossprotection to subsequent salt stress for strains in lineages I and II. At 37 degrees C, in brain-heart infusion with 6% NaCl, lineage I and III strains grew significantly faster (p<0.0001) than lineage II strains. Under salt stress at 37 degrees C, differences in growth parameters were significantly (p<0.005) associated with genetic relatedness of the strains. Compatible solute uptake is part of the L. monocytogenes salt stress response, but growth differences between the lineages were not related to differences in transcript levels of osmolyte transporter-encoding genes betL, gbuA, oppA, and opuCA. The combination of phylogenetic and phenotypic data suggests that L. monocytogenes lineage I and III strains, which are most commonly associated with human and animal disease, may be better adapted to osmotic stress at 37 degrees C, conditions that are present in the host gastrointestinal tract. PMID- 20707725 TI - Vaccinia virus is not inactivated after thermal treatment and cheese production using experimentally contaminated milk. AB - Bovine vaccinia is an emergent zoonosis caused by the Vaccinia virus (VACV). The disease is characterized by the appearance of exanthematic lesions that occur in humans and dairy cows. Previous studies have revealed the presence of infectious viral particles in milk samples during an outbreak of bovine vaccinia in Brazil, indicating the possibility of disease transmission through raw milk. To assess the viability of the virus in milk after thermal treatment and processing procedures, milk samples were experimentally contaminated with 10(3) plaque forming units (PFU)/mL (group I) and 10(5) PFU/mL (group II) VACV Guarani P2 virus, and the third group was not contaminated and served as a control. The samples were submitted to storage temperatures in a cold chamber, freezer for 48 hours, and to low temperature long-time treatment. Moreover, the viral viability was evaluated in cheese produced with contaminated milk using 10(4) PFU/mL VACV Guarani P2. Notably, the virus remained viable in milk after storage for 48 hours in both the cold chamber and the freezer, with a reduction in viral titer of 14.49% and 25.86%, respectively. Group II showed a viral reduction in titer of 61.88% and 75.98%, respectively. Thermal treatment 65 degrees C for 30 minutes showed a reduction of viral titer of 94.83% and 99.99%, respectively, in group I and group II, but still showed remaining viable virus particles. In addition, it was possible to recover infectious viral particles from both the solid curds and the whey of the cheese produced with experimentally contaminated milk. The cheese shows a reduction in viral titer of 84.87% after storage at 4 degrees C for 24 hours. The presence of viable viral particles in milk after both thermal treatment and cheese production indicates a potential public health risk. PMID- 20707726 TI - Quantitative risk from fluoroquinolone-resistant Salmonella and Campylobacter due to treatment of dairy heifers with enrofloxacin for bovine respiratory disease. AB - The objective of this study was to evaluate the human health impact of using fluoroquinolones to treat bovine respiratory disease (BRD) in dairy heifers less than 20 months of age. Specifically, this study quantified the probability of persistent symptoms in humans treated with a fluoroquinolone, for a fluoroquinolone-resistant Campylobacter, Salmonella, or multidrug-resistant (MDR) Salmonella infection acquired following the consumption of ground beef. To comply with a Food and Drug Administration requirement for approval of enrofloxacin use in dairy heifers, a binomial event tree was constructed following Food and Drug Administration guidance 152. Release was estimated from the slaughter of dairy cattle carrying fluoroquinolone-resistant bacteria attributed to the proposed use in dairy heifers. For exposure, human foodborne exposure to Campylobacter, Salmonella, and MDR Salmonella after consumption of ground beef was estimated. The consequence assessment included illness, fluoroquinolone treatment, and persistent symptoms in patients treated with a fluoroquinolone. Using best available data to estimate the parameters and probabilities of each event, stochastic simulation was used to represent uncertainty and variability in many of the parameters. A scenario analysis was performed to evaluate the uncertainty of the following parameters: (1) probability of resistance development in treated animals, (2) portion of illnesses attributable to ground beef, and (3) probability of persistent symptoms in patients 18 years of age and over treated with a fluoroquinolone. The population at risk was restricted to people 18 years of age and over, as fluoroquinolones are not labeled for treatment of gastroenteritis in children. The mean annual increased risk of cases in the U.S. population (18 years of age and over) where compromised fluoroquinolone treatment resulted in persistent symptoms was estimated to be 1 in 61 billion (one case every 293 years) for Salmonella, 1 in 33 billion (one case every 158 years) for MDR Salmonella, and 1 in 2.8 billion (one case every 13 years) for Campylobacter. PMID- 20707727 TI - Evaluation of narrow-band imaging as a complementary method for the detection of bladder cancer. AB - PURPOSE: We evaluated the use of narrow-band imaging (NBI) cystoscopy for the detection of bladder cancer and analyzed its diagnostic efficacy in cases of carcinoma in situ (CIS) and in cases with known urine cytology results. PATIENTS AND METHODS: A prospective controlled study of NBI was conducted in 104 consecutive patients with definite or suspected bladder cancer. Transurethral targeted biopsies were performed after white light imaging (WLI) and NBI cystoscopy, and the histologic outcomes were compared. RESULTS: A total of 313 biopsies were taken, including 161 from sites identified as potentially abnormal by NBI and/or WLI cystoscopy, and 152 from apparently normal sites. The percentage of malignancies in the sites identified only by NBI was 55.7% (39/70 places). In 26.9% of patients (28/104), bladder tumors were detected only by NBI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio of a negative test (NLR) for the detection of bladder tumors using NBI in all patients were 92.7%, 70.9%, 63.4%, 94.7%, and 0.10, respectively. The sensitivity, specificity, PPV, NPV, and NLR for the detection of CIS using NBI were 89.7%, 74.5%, 78.8%, 87.2%, and 0.14, respectively. The sensitivity, specificity, PPV, NPV, and NLR for the detection of bladder tumors using NBI in patients with positive vs negative urine cytology were 85.4% vs 98.4%, 75.7% vs 66.3%, 61.2% vs 64.5%, 92.0% vs 98.5%, and 0.19 vs 0.02, respectively. CONCLUSIONS: NBI is a simple and effective method for identifying bladder tumors including CIS without the need for dyes because of its high sensitivity, high NPV, and low NLR. PMID- 20707728 TI - Short communication: Severe symptomatic hyperlactatemia among HIV type 1-infected adults on antiretroviral therapy in Cote d'Ivoire. AB - Stavudine is no longer recommended for use in first-line antiretroviral therapy (ART), but it remains in high demand worldwide because it is affordable. We report the clinical presentation and incidence of severe hyperlactatemia (SL) in HIV-infected adults who initiated ART between April 2005 and May 2009 in Cote d'Ivoire, West Africa. In a prospective cohort study at the HIV care center affiliated with the National Centre for Blood Transfusion, we used standardized forms to record baseline and follow-up data. We measured serum lactate levels for all adults on ART who showed signs of hyperlactatemia. SL was defined as serum lactate >2.5 mmol/liter. Overall, 806 adults initiated ART. Among the 591 patients (73%) on stavudine-containing regimens, 394 were women (67%); the median pre-ART CD4 count was 150/mm3 and the median body mass index was 20.9 kg/m2. These patients were followed for a median of 28 months. We detected SL only among patients taking stavudine. The incidence of SL was 0.55/100 person-years (PY) (95% CI 0.47-0.63) overall and 0.85/100 PY among women (95% CI 0.75-0.95). Among the eight patients with SL, 100% lost >9% of body weight before diagnosis, 100% had serum lactate >4 mmol/liter (range 4.2-12.1), 50% had pre-ART BMI >25 kg/m2, and three patients died (38%), accounting for 6.4% of deaths among patients taking stavudine. As long as HIV clinicians continue to use stavudine in sub Saharan Africa, they should watch out for acute unexplained weight loss in patients taking ART, particularly among women and patients with high pre-ART BMI. PMID- 20707729 TI - Frequency of prothrombotic risk factors in patients with deep venous thrombosis and controls: their implications for thrombophilia screening in Chilean subjects. AB - In this work, we evaluated the frequency of prothrombotic defects associated with deep venous thrombosis (DVT) in southern Chilean subjects. A total of 261 individuals, 87 patients with DVT confirmed by Doppler ultrasonography and 174 controls, were included in this study. Factor V and factor VIII levels, activated protein C (APC) resistance, and lupus anticoagulant detection were assayed by clotting methods. Basal homocysteine was quantified by immunoassay, and the polymorphisms in factor V (F5), methylenetetrahydrofolate reductase (MTHFR), and cystathionine beta-synthase (CBS) genes were genotyped by molecular methods. The most frequent defects were APC resistance, hyperhomocysteinemia, and increased levels of factor VIII. We observed a complete absence of the F5 G1691A variant in the studied population, and the frequency of MTHFR C677T polymorphism was significantly different between patients and controls (odds ratio = 3.2; 95% confidence interval, 1.513-6.735; p = 0.016). In addition, subjects carrying the homozygous MTHFR 677TT genotype exhibited higher levels of plasma homocysteine. Our data suggest that the APC resistance is the most important defect in Chilean patients with DVT. However, this phenotype is not associated with the presence of the F5 G1691A variant. In addition, only MTHFR C677T polymorphism constituted a molecular biomarker of DVT in Chilean population. PMID- 20707730 TI - Thrombophilic gene mutations in women with repeated spontaneous miscarriage. AB - AIM: One of the main problems concerning repeated spontaneous miscarriage (RSM) is the etiological diagnosis. The relation of thrombophilia to RSM is a matter of debate. In this case-control study, we determined the percentages of three thrombophilic mutations (factor V leiden, prothrombin, and methylenetetrahydrofolate reductase) amongst 20 cases with RSM and 20 control normal parous women. RESULTS: There were high statistically significant increases in the number of cases with factor V, prothrombin, and methylenetetrahydrofolate reductase gene mutations compared with normal control and the percentage of multiple gene mutations was higher than single gene mutation. CONCLUSION: The prevalence of thrombophilic mutations is higher in cases of RSM than control. PMID- 20707732 TI - Evolution of mitochondrial DNA content after planned interruption of HAART in HIV infected pediatric patients. AB - HAART-related long-term toxicities, many of them ascribed to mitochondrial (mt) toxicity of the nucleoside analogues, are being increasingly reported in HIV infected children. HIV infection can also cause mt damage. Case series include 13 vertically HIV-infected pediatric patients (9 girls, median age 10.5 years) with optimal long-term response to a first-line HAART regimen who underwent planned treatment interruption (PTI). MtDNA content from peripheral blood mononuclear cells was assessed by means of a real-time PCR technique at PTI and 12 months later and expressed as an mtDNA/nuclear DNA ratio, together with lactate levels. At PTI, patients had remained a median time of 4.7 years on HAART and 4.3 years with complete suppression of viral replication. The main reason leading to PTI was treatment fatigue. One month after PTI, HIV plasmatic viral load had increased to 4.8 log copies/ml and stabilized thereafter. During the 12-month study period, all children remained free from any HIV-related clinical event. A progressive and significant decrease in median CD4 cell counts and percentages was observed 12 months after PTI. One year after PTI, the median mtDNA/nuclear DNA ratios had increased from 0.76 to 1.08 (p = 0.002) and lactate levels had decreased (from 1.12 to 0.73 mmol/liter; p = 0.019). Changes in mtDNA did not correlate with changes in lactate levels. No relationship was found between the evolution in mt toxicity markers and the rest of the clinical, immunological, and virological variables. In this series, PTI led to a partial restoration of mtDNA levels and a significant decrease in lactate values. PMID- 20707731 TI - Directly observed therapy (DOT) for nonadherent HIV-infected youth: lessons learned, challenges ahead. AB - Adherence to medications is critical to optimizing HIV care and is a major challenge in youth. The utility of directly observed therapy (DOT) to improve adherence in youth with HIV remains undefined and prompted this pilot study. Four U.S. sites were selected for this 24-week cooperative group study to assess feasibility and to identify the logistics of providing DOT to HIV-infected youth with demonstrated adherence problems. Once-a-day DOT was provided by DOT facilitators at the participant's choice of a community-based location and DOT tapered over 12 weeks to self-administered therapy based on ongoing adherence assessments. Twenty participants, median age 21 years and median CD4 227 cells/microl, were enrolled. Participants chose their homes for 82% of DOT visits. Compliance with recommended DOT visits was (median) 91%, 91%, and 83% at weeks 4, 8, and 12, respectively. Six participants completed >90% of the study specified DOT visits and successfully progressed to self-administered therapy (DOT success); only half sustained >90% medication adherence 12 weeks after discontinuing DOT. Participants considered DOT successes were more likely to have higher baseline depression scores (p = 0.046). Via exit surveys participants reported that meeting with the facilitator was easy, DOT increased their motivation to take medications, they felt sad when DOT ended, and 100% would recommend DOT to a friend. In conclusion, this study shows that while community based DOT is safe, feasible, and as per participant feedback, acceptable to youth, DOT is not for all and the benefits appear short-lived. Depressed youth appear to be one subgroup that would benefit from this intervention. Study findings should help inform the design of larger community-based DOT intervention studies in youth. PMID- 20707733 TI - Transmission of drug-resistant HIV type 1 strains in HAART-naive patients: a 5 year retrospective study in Sicily, Italy. AB - The transmission of drug-resistant HIV-1 strains might compromise the efficacy of current first-line antiretroviral (ARV) regimens. Between 2004 and 2008, HIV-1 reverse transcriptase (RT) and protease (PR) genes of 108 ARV-naive Sicilian patients were amplified and sequenced to describe the prevalence of ARV resistance mutations among HAART-naive HIV-1-infected individuals. The frequency of transmitted drug resistance mutations (DRAMs) was determined by using genotypic interpretation algorithms. The proportion of HAART-naive HIV-1-infected patients in Sicily increased from 18.4% to 23.5% during 2004-2008. Among naive patients, the overall prevalence of DRAMs was 15.7% [17/108; 95% CI: 9.4-24.0]. DRAMs to nonnucleoside reverse transcriptase inhibitors (nNRTI) were detected most frequently [11/108 (10.2%)], of which K103N was the most prevalent (4.6%), whereas the prevalence of DRAMs was lowest for protease inhibitors (PI) [3/108 (2.8%)]. Drug resistance substitutions associated with two or three drug classes were rarely observed. The prevalence of HIV-1 DRAMs in Sicily was relatively higher than that observed in Italy and other European geographic areas and much higher than in resource-limited countries. However, the possible clinical role played by DRAMs in HAART-naive HIV-1-infected individuals will require further assessment. PMID- 20707734 TI - Enumeration and strain characterization of fecal Escherichia coli associated with feeding triticale dried distillers grain with solubles in beef cattle diets. AB - Triticale dried distillers grain with solubles (TDDGS), a major by-product of the bioethanol industry, has potential for utilization in animal feed. This study investigated the changes in generic fecal Escherichia coli strains associated with inclusion of TDDGS in cattle diets. Within this study, a longitudinal experiment (112 days) examined the effect of step-up increasing TDDGS inclusion from control to a final diet containing 30% TDDGS among cattle (n = 4), and a short-term experiment (28 days) compared animals (n = 16) fed control, 20%, 25%, or 30% TDDGS diets. We found that incorporation of either 20%, 25%, or 30% TDDGS did not have any effect on the amount of total E. coli shedding over either the longitudinal (p = 0.06) or the short-term (p = 0. 87) study. In both the experiments, 67% of the total E. coli isolates were found to be resistant to one or more of the 17 antimicrobials tested. Among the resistant isolates, cephalothin was the most prevalent resistance (44% isolates). Over the duration of the study, tet(C) was a commonly detected resistance gene in tetracycline resistant E. coli. Significant diversity was observed among isolates with 33 and 31 pulsed-field gel electrophoresis patterns clustering into 11 and 10 restriction endonuclease digestion pattern clusters for the longitudinal and short-term studies, respectively. Neither the duration of feeding nor increasing the proportion of TDDGS within the diet affected the diversity of E. coli resistance phenotypes or the clonal relatedness of the observed strains. Individual animals retained similar or closely related strains. Based on this study, inclusion of TDDGS as a protein and fiber source in cattle diets is not associated with increased maintenance, shedding, or proliferation of resistant strains of generic E. coli, which is an important reservoir of antimicrobial resistance among cattle. PMID- 20707736 TI - Production of monoclonal antibodies in a mouse model via lipopolysaccharide conjugates with synthetic polymers specific to Salmonella Enteritidis O antigen. AB - Monoclonal antibodies (Mabs) specific for lipopolysaccharide (LPS) of Salmonella Enteritidis were evaluated in a model of LPS conjugated synthetic polymer immunization of Balb/c mice by conventional hybridoma method. Nine hybridoma cell lines were determined as antibody positive against LPS. The clone 5A8 secreting the highest antibody was selected for further characterization. Evaluated results indicate that the synthetic polymer can be used as an effective adjuvant in immunization with LPS, because the 5A8 Mab were obtained using synthetic polymer as an adjuvant. 5A8 Mab was classified as IgG2a isotype by antibody capture enzyme-linked immunosorbent assay. The reactivity of the Mab against lipid A and different LPS of Salmonella were investigated using an indirect enzyme-linked immunosorbent assay. Mab presented a wide spectrum of reactivity, coupling with antigens against Salmonella. The hybridoma 5A8 determined in this study has a great potential to be used in the development of diagnostic, prophylactic, and therapeutic agents specific for Salmonella Enteritidis and Salmonella LPS. PMID- 20707735 TI - Growth temperature-dependent contributions of response regulators, sigmaB, PrfA, and motility factors to Listeria monocytogenes invasion of Caco-2 cells. AB - Foodborne pathogens encounter rapidly changing environmental conditions during transmission, including exposure to temperatures below 37 degrees C. The goal of this study was to develop a better understanding of the effects of growth temperatures and temperature shifts on regulation of invasion phenotypes and invasion-associated genes in Listeria monocytogenes. We specifically characterized the effects of L. monocytogenes growth at different temperatures (30 degrees C vs. 37 degrees C) on (i) the contributions to Caco-2 invasion of different regulators (including sigma(B), PrfA, and 14 response regulators [RRs]) and invasion proteins (i.e., InlA and FlaA), and on (ii) gadA, plcA, inlA, and flaA transcript levels and their regulation. Overall, Caco-2 invasion efficiency was higher for L. monocytogenes grown at 30 degrees C than for bacteria grown at 37 degrees C (p = 0.0051 for the effect of temperature on invasion efficiency; analysis of variance); the increased invasion efficiency of the parent strain 10403S (serotype 1/2a) observed after growth at 30 degrees C persisted for 2.5 h exposure to 37 degrees C. For L. monocytogenes grown at 30 degrees C, the motility RRs DegU and CheY and sigma(B), but not PrfA, significantly contributed to Caco-2 invasion efficiency. For L. monocytogenes grown at 37 degrees C, none of the 14 RRs tested significantly contributed to Caco-2 invasion, whereas sigma(B) and PrfA contributed synergistically to invasion efficiency. At both growth temperatures there was significant synergism between the contributions to invasion of FlaA and InlA; this synergism was more pronounced after growth at 30 degrees C than at 37 degrees C. Our data show that growth temperature affects invasion efficiency and regulation of virulence-associated genes in L. monocytogenes. These data support increasing evidence that a number of environmental conditions can modulate virulence-associated phenotypes of foodborne bacterial pathogens, including L. monocytogenes. PMID- 20707737 TI - Biochemical correlates of bariatric-responsive diabetes. AB - OBJECTIVE: In a prospective observational cohort study, the biochemical profile of bariatrically managed diabetes was documented, aiming to assess its association with clinical outcome. METHODS: The population (n = 82; age, 50.7 +/- 10.3 years; 92.7% women; followed up for 93 +/- 34 months) was stratified as responsive diabetes (Group I) (36.6%, 30 of 82) and controls without diabetes (Group II) (57.3%, 47 of 82). A few refractory subjects were identified in this cohort (Group III [refractory diabetes], 6.3%, five of 82). Nonbariatric overweight and obese diabetes subjects with similar follow-up (n = 21) were documented as well. Main outcome measures were diabetes regression, body mass index (BMI), glucose, glycosylated hemoglobin A1c (HbA1c), serum lipids, and white blood cell count (WBC) count. RESULTS: Preoperative BMI was somewhat discrepant among operated groups but leveled off from 2 years on. Baseline WBC count, total cholesterol, low-density lipoprotein-cholesterol, blood glucose, and HbA1c were higher in responsive subjects, but a downward shift occurred, without differences regarding controls, in the subsequent period. Conservatively managed diabetes displayed favorable changes of some lipid fractions, but not glucose, HbA1c, total cholesterol, or WBC count. CONCLUSIONS: Diabetes regression rate was 94.3% at 5 years and 84.7% at around 8 years. In responsive patients, both BMI and biochemical indices normalized in the first 2 years and followed a stable path thereafter. Nonoperative treatment was unable to reduce HbA1c, glucose, or WBC count, and HbA1c was a clear prognostic marker of persistent disease in surgical cases. Further studies emphasizing the metabolic and inflammatory signature of obesity-related diabetes are worthwhile. PMID- 20707738 TI - Obesity and metabolic abnormalities in offspring of subjects with diabetes mellitus. AB - BACKGROUND: Some recent studies observed that a number of obese children had family members with type 2 diabetes. The aim of the present study was to assess prevalence of obesity and metabolic abnormalities among offspring of subjects with type 2 diabetes mellitus. METHODS: Children of patients with type 2 diabetes mellitus were studied. Detailed medical history, physical examination, hemogram, renal and liver function tests, lipid profile, body composition, and oral glucose tolerance tests were done for all subjects. Plasma insulin was also done in addition to glucose at 0, 30, 60, and 120 min after oral glucose. RESULTS: A total of 355 subjects from 208 families (194 males [55%] and 161 females [45%], mean age 23 +/- 11 years) were studied. Among them, 209 (58.9%) were lean, 91 (25.6%) were overweight, and 55 (15.5%) were obese. Seventeen (4.8%) subjects had impaired fasting glucose, 29 (8.2%) had impaired glucose tolerance, and 10 (2.8) had diabetes mellitus. Twenty (35.7%) of 56 with abnormal glucose tolerance were lean. One hundred six (29.8%) subjects had triglyceride levels greater than 150 mg/dL, 137 (38.6%) had low levels of high-density lipoprotein-cholesterol, and 67 (18.9%) had high total cholesterol levels. Prevalence of obesity, elevated plasma triglyceride, and glucose intolerance was higher among older subjects and subjects both of whose parents had diabetes. CONCLUSIONS: Children from families with type 2 diabetes are at increased risk for obesity. Risk increases by fivefold when both parents have diabetes. PMID- 20707739 TI - Screening people with type 2 diabetes at risk for foot ulceration in Iran. AB - BACKGROUND: Foot screening is one of the most effective means of preventing foot complications in diabetes. Therefore the aim of this study was to perform a screening program for people with type 2 diabetes at risk of foot complications. METHODS: Physical examinations consisting of vascular, neurological, musculoskeletal, and dermatologic examinations were performed. We used a Semmes Weinstein monofilament and a 128-Hz tuning fork to test peripheral neuropathy. The study population was categorized based on Scottish Intercollegiate Guidelines into three groups of low, medium, and high risk for diabetes foot disease. RESULTS: Of a total of 148 people with type 2 diabetes, 4.7% had an active foot ulcer, and 41.9% were classed as low risk, 40.6% as medium risk, and 12.8% as high risk. CONCLUSIONS: Considering the potential of developing risk of foot disease in people with diabetes, it is recommended that foot screening should be performed by primary care practitioners and specialists to detect foot disease in an early stage. Foot screening program for people with diabetes should also be taken into account by health policy makers in national guidelines. PMID- 20707743 TI - What is your diagnosis? Foreign body. PMID- 20707740 TI - Chitosan/short hairpin RNA complexes for vascular endothelial growth factor suppression invasive breast carcinoma. AB - Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis. The aim of this study was to use chitosan/short hairpin VEGF (shVEGF) [short hairpin RNA (shRNA)-expressing pDNA targeting VEGF-A] complexes in the treatment of rat breast cancer model. Therefore, chitosan/shVEGF complexes were prepared in (2/1) ratio and injected to the breast-tumor bearing Sprague-Dawley rats. Intratumoral and intraperitoneal injections were applied and compared. Tumor volumes were measured during the 36 days. To investigate the effect of complexes on the VEGF expression, VEGF were analyzed by immunohistochemistry and western blotting. The mRNA levels of VEGF were determined by real-time polymerase chain reaction. Tumor volume decreased at the end of experiments after shRNA treatment. The highest suppression in the tumor volume was observed after intratumoral complex injection to rats (96%). Compared with intratumoral and intraperitoneal injection, higher tumor inhibition was obtained with intratumoral injection. Free shRNA injection indicated lower tumor suppression. The immunohistochemistry and western blotting results correlated with the real-time polymerase chain reaction and tumor volume measurements. The data suggest that chitosan/shVEGF complexes can be used to inhibit tumor growth in breast carcinoma model of rats. PMID- 20707744 TI - What is your diagnosis? Pneumopericardium. PMID- 20707745 TI - Pathology in practice. Superficial necrolytic dermatitis. PMID- 20707746 TI - Comparison of long-term financial implications for five veterinary career tracks. AB - OBJECTIVE: To compare present values of expected income streams for 5 distinct veterinary medical career tracks. DESIGN: Present value model. SAMPLE POPULATION: AVMA survey data. PROCEDURES: Present values of expected income streams (net of debt repayment) were created and ranked. Sensitivity to each independent variable was assessed. RESULTS: Career present value at 34 years after graduation (CPV(34)) was highest for board-certified specialist (SP; $2,272,877), followed by practice owner (PO; $2,119,596), practice owner buying into practice after 10 years (PO-10; $1,736,333), SP working three-fourths time (SP3/4; $1,702,744), and general practitioner (GP; $1,221,131). Compared with CPV(34) for SP, other career tracks yielded values of 93.3% (PO), 76.4% (PO-10), 74.9% (SP3/4), and 53.7% (GP). The model was robust to debt, interest rate, loan term, and discount rate but was sensitive to mean starting incomes and mean incomes. CONCLUSIONS AND CLINICAL RELEVANCE: Greatest return on time and money invested by a veterinary student is through practicing full-time as an SP or through being a PO. Being an SP or SP3/4 was substantially more lucrative than being a GP and was comparable to being a PO. Practice ownership and working as an SP3/4 may be options for balancing financial gain with free time. Specialty training and practice ownership may be career tracks with the best potential repayment options for veterinarians with a large educational debt. Regardless of the amount of debt, the type of practice, mean incomes in a particular field, personal lifestyle, and professional interests are important factors when deciding among career tracks. PMID- 20707747 TI - In vivo effects of adjunctive tetracycline treatment on refractory corneal ulcers in dogs. AB - OBJECTIVE: To evaluate effect of adjunctive treatment with tetracycline analogues on time to complete corneal reepithelialization in dogs with nonhealing (ie, refractory) corneal ulcers. DESIGN: Randomized controlled clinical trial. ANIMALS: 89 dogs with refractory corneal ulcers. PROCEDURES: Corneal ulcers were treated via debridement and grid keratotomy. Dogs were assigned to receive 1 of 3 treatment regimens for up to 6 weeks: doxycycline (5 mg/kg [2.27 mg/lb], PO, q 12 h) with topically applied ophthalmic ointment containing neomycin, polymyxin B, and bacitracin (ie, triple antibiotic ointment; q 8 h); cephalexin (22 mg/kg [10 mg/lb], PO, q 12 h) with topically applied oxytetracycline ophthalmic ointment (q 8 h); or a control treatment of cephalexin (22 mg/kg, PO, q 12 h) with topically applied triple antibiotic ointment (q 8 h). Healing was monitored via measurements of the wound with calipers and evaluation of photographs obtained every 2 weeks. Treatment effectiveness was evaluated by wound healing and decreased signs of pain. RESULTS: The Boxer breed was overrepresented in all groups. At the 2-week time point, wound healing was significantly more common in small-breed dogs, compared with large-breed dogs. Dogs treated with oxytetracycline ophthalmic ointment had a significantly shorter healing time than did dogs receiving the control treatment. Corneal ulcers in dogs that received doxycycline PO healed more rapidly than did ulcers in dogs in the control treatment group; however, this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE: Topical tetracycline ophthalmic ointment was a safe, inexpensive, and effective adjunctive treatment for refractory corneal ulcers in dogs. PMID- 20707748 TI - Evaluation of collars and microchips for visual and permanent identification of pet cats. AB - OBJECTIVE: To determine the percentage of pet cats still wearing collars and having functional microchips 6 months after application. DESIGN: Randomized controlled clinical trial. ANIMALS: 538 client-owned cats. PROCEDURES: Cats were randomly assigned to wear 1 of 3 types of collars: plastic buckle, breakaway plastic buckle safety, and elastic stretch safety. Each cat was fitted with the assigned collar, and a microchip was inserted SC between the scapulae. Owners completed questionnaires about their experiences and expectations of collars at enrollment and at the conclusion of the study. RESULTS: 391 of the 538 (72.7%) cats successfully wore their collars for the entire 6-month study period. Owners' initial expectations of the cats' tolerance of the collar and the number of times the collar was reapplied on the cats' necks were the most important factors predicting success. Type of collar likely influenced how often collars needed to be reapplied. Eighteen (3.3%) cats caught a forelimb in their collar or caught their collar on an object or in their mouth. Of the 478 microchips that were scanned at the conclusion of the study, 477 (99.8%) were functional. CONCLUSIONS AND CLINICAL RELEVANCE: Most cats successfully wore their collars. Because even house cats can become lost, veterinarians should recommend that all cats wear identification collars since they are the most obvious means of identifying an owned pet. For some cats, collars may frequently come off and become lost; therefore, microchips are an important form of backup identification. Owners should select a collar that their cat will tolerate and should check it often to ensure a proper fit. PMID- 20707749 TI - Effects of infiltration of the incision site with bupivacaine on postoperative pain and incisional healing in dogs undergoing ovariohysterectomy. AB - OBJECTIVE: To determine the effects of infiltration of the incision site with bupivacaine hydrochloride as part of a multimodal analgesia protocol (incisional block) on postoperative analgesia and incisional healing. DESIGN: Randomized controlled clinical trial. ANIMALS: 92 shelter-owned female dogs undergoing routine ovariohysterectomy. PROCEDURES: As part of a multimodal analgesic protocol for ovariohysterectomy, dogs received 1 of the following treatments at the incision site: no injection (26 dogs), preincisional infiltration with saline (0.9% NaCl) solution (12 dogs) or bupivacaine (21 dogs), or postincisional infiltration with bupivacaine (33 dogs). Postoperative pain was assessed with the Glasgow pain scale and response to mechanical stimulation with von Frey filaments. Incisions were monitored for signs of inflammation (edema, erythema, and discharge) and complications in wound healing. RESULTS: There was no difference in pain scores or response to mechanical stimulation over time among treatments. There were no significant differences in incisional edema or discharge among treatments. There was significantly more erythema in dogs that received preincisional infiltration with saline solution at 4 hours after surgery and less erythema in dogs that received postincisional infiltration with bupivacaine at 24 hours after surgery, compared with other treatments. The number of complications for dogs that had preincisional infiltration of bupivacaine was higher than for dogs that had other treatments; complications included excessive inflammation, splenic laceration, and herniation. CONCLUSIONS AND CLINICAL RELEVANCE: No additional analgesic benefit was found in dogs that underwent local bupivacaine infiltration as part of a multimodal analgesic protocol for ovariohysterectomy. PMID- 20707750 TI - Agreement between directly measured blood pressure and pressures obtained with three veterinary-specific oscillometric units in cats. AB - OBJECTIVE: To determine whether veterinary-specific oscillometric blood pressure units yield measurements that are in good agreement with directly measured blood pressures in cats. DESIGN: Evaluation study. ANIMALS: 21 cats undergoing routine spaying or neutering. PROCEDURES: A 24-gauge catheter was inserted in a dorsal pedal artery, and systolic, diastolic, and mean arterial pressures were directly measured with a validated pressure measurement system. Values were compared with indirect blood pressure measurements obtained with 3 veterinary-specific oscillometric blood pressure units. RESULTS: There was poor agreement between indirectly and directly measured blood pressures. For unit 1, bias between indirectly and directly measured values was -14.9 mm Hg (95% limits of agreement [LOA], -52.2 to 22.4 mm Hg), 4.4 mm Hg (95% LOA, -26.0 to 34.8 mm Hg), and -1.3 mm Hg (95% LOA, -26.7 to 24.1 mm Hg) for systolic, diastolic, and mean arterial pressures, respectively. For unit 2, bias was -10.3 mm Hg (95% LOA, -52.9 to 32.2 mm Hg), 13.0 mm Hg (95% LOA, -32.1 to 58.0 mm Hg), and 9.1 mm Hg (95% LOA, -32.9 to 51.2 mm Hg) for systolic, diastolic, and mean arterial pressures, respectively. For unit 3, bias was -13.4 mm Hg (95% LOA, -51.8 to 25.1 mm Hg), 8.0 mm Hg (95% LOA, -25.5 to 41.6 mm Hg), and -3.6 mm Hg (95% LOA, -31.6 to 24.5 mm Hg) for systolic, diastolic, and mean arterial pressures, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that none of the 3 veterinary-specific oscillometric blood pressure units could be recommended for indirect measurement of blood pressure in cats. PMID- 20707751 TI - Diagnosis and treatment of myelo-osteolytic plasmablastic lymphoma of the femur in a domestic ferret. AB - CASE DESCRIPTION: A 6-year-old 0.82-kg (1.8-lb) spayed female domestic ferret was evaluated because of a 1-month history of decreased activity that had progressively worsened over the past week. The ferret had previously been determined to have adrenocortical disease and was undergoing medical management for the associated clinical signs. CLINICAL FINDINGS: Physical examination revealed lameness of the right hind limb with evidence of pain elicited during palpation of the right femur. Results of a CBC suggested mild anemia, and those of a serum biochemical analysis indicated a high blood glucose concentration. Radiography of the limb revealed extensive lysis of the right femur. Cytologic evaluation of a fine-needle aspirate of the bone lesion revealed a dominant plasma cell component. Plasma cell neoplasia was suspected on the basis of these findings. TREATMENT AND OUTCOME: Radical right hind limb amputation with mid to caudal hemipelvectomy was performed. Histologic evaluation of the lesion allowed a diagnosis of lymphoma with plasmablastic features, and immunohistochemical testing revealed a few CD79alpha-positive neoplastic cells and rare BLA36 positive cells. Adjunctive antineoplastic treatment with systemically administered multidrug chemotherapy was initiated. Six months after surgery, the ferret was reevaluated, and chemotherapy was discontinued when results of clinicopathologic tests, whole body survey radiography, and abdominal ultrasonography suggested no recurrence of the disease. CLINICAL RELEVANCE: The ferret appeared to cope well with radical hind limb amputation, and the chemotherapeutic protocol used was easy to administer. This treatment approach might lead to better owner and patient compliance in other cases of lymphoma in ferrets. PMID- 20707752 TI - Central diabetes insipidus in an African Grey parrot. AB - CASE DESCRIPTION: A 5.5-year-old sexually intact female African Grey parrot (Psittacus erithacus) was evaluated for a 1-year history of pronounced polyuria and polydipsia. The bird also had a 1-month history of signs of mild depression and mydriasis. CLINICAL FINDINGS: Physical examination revealed a thin body condition and incomplete bilateral mydriasis. Other examination findings as well as CBC and screening radiography results were unremarkable. Plasma biochemical analysis revealed mild hypernatremia. The bird had a 3.3% loss in body weight over 170 minutes during a water deprivation test, and urine osmolality remained low. After IM administration of 0.9 microg of desmopressin, the rate of weight loss decreased substantially and urine osmolality increased 300% over the following 200 minutes. TREATMENT AND OUTCOME: Initial attempts to treat the bird with orally administered desmopressin failed to correct the polydipsia and polyuria. Ultimately, IM administration of 24 microg of desmopressin/kg (10.9 microg/lb) every 12 hours yielded a noticeable reduction in water consumption and urine production over a 6- to 8-hour period. Eight months later, the bird was returned for a recheck examination, at which time it was in good health and continued to respond to the medication. Despite continued response to the medication, right-sided internal ophthalmoparesis was detected 16 months after the initial diagnosis. CLINICAL RELEVANCE: To the authors' knowledge, central diabetes insipidus in birds has not been reported. The condition should be considered in birds with clinical signs of disease similar to those in mammals. Long-term IM administration of desmopressin may be a viable treatment option. PMID- 20707753 TI - Effect of colostral volume, interval between calving and first milking, and photoperiod on colostral IgG concentrations in dairy cows. AB - OBJECTIVE: To identify cow and management factors associated with colostral IgG concentration in dairy cows. DESIGN: Prospective observational study. ANIMALS: 81 multiparous Holstein-Friesian cows from a single herd. PROCEDURES: Serum was obtained at the start of the nonlactating period, and cows were assigned to 1 of 4 photoperiod groups: natural day length (n = 22 cows), long days (16 h of light/d [21]) or short days (8 h of light/d [20]) for the entire nonlactating period, or natural day length followed by short days for the last 21 days of the nonlactating period (18). Serum and colostrum were collected at the first milking after calving. Regression analysis was used to investigate associations between colostral IgG concentration and the interval between calving and first milking, colostral volume, photoperiod, length of the nonlactating period, and season of calving. RESULTS: Colostral IgG concentration decreased by 3.7% during each subsequent hour after calving because of postparturient secretion by the mammary glands. The interval between calving and first milking and the colostral volume were significantly and negatively associated with colostral IgG concentration, with the former effect predominating. Photoperiod had no effect on colostral IgG concentration or volume. Serum protein concentration at calving correlated poorly with colostral IgG concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Dairy producers should harvest colostrum as soon as possible after calving to optimize transfer of passive immunity in neonatal calves. Photoperiod can be manipulated without adversely affecting colostral IgG concentration. PMID- 20707754 TI - Risk factors associated with cataracts and lens luxations in captive pinnipeds in the United States and the Bahamas. AB - OBJECTIVE: To determine risk factors for lens luxation and cataracts in captive pinnipeds in the United States and the Bahamas. DESIGN: Cross-sectional study. ANIMALS: 111 pinnipeds (99 California sea lions [Zalophus californianus], 10 harbor seals [Phoca vitulina], and 2 walruses [Odobenus rosmarus]) from 9 facilities. PROCEDURES: Eyes of each pinniped were examined by a veterinary ophthalmologist for the presence of cataracts or lens luxations and photographed. Information detailing husbandry practices, history, and facilities was collected with a questionnaire, and descriptive statistical analyses were performed for continuous and categorical variables. Odds ratios and associated 95% confidence intervals were estimated from the final model. RESULTS: Risk factors for lens luxation, cataracts, or both included age >or= 15 years, history of fighting, history of ocular disease, and insufficient access to shade. CONCLUSIONS AND CLINICAL RELEVANCE: Diseases of the lens commonly affect captive pinnipeds. Access to UV-protective shade, early identification and medical management of ocular diseases, and prevention of fighting can limit the frequency or severity of lens-related disease in this population. An extended life span may result from captivity, but this also allows development of pathological changes associated with aging, including cataracts. PMID- 20707755 TI - Pharmacotherapy and psychotherapy of pediatric depression. AB - IMPORTANCE OF THE FIELD: Depressive disorders in children and adolescents are prevalent and impairing. Current available treatments of childhood depression have advanced over the years but still leave many patients with residual symptoms. AREAS COVERED IN THIS REVIEW: We here review the pharmacotherapy and psychoptherapy of pediatric major depressive disorder. We conducted a Pubmed review on this topic covering the last 30 years. WHAT THE READER WILL GAIN: The reader will learn about the current evidence on the efficacy and safety of the different pediatric depression treatment modalities. We review evidence-based treatments, namely cognitive behavioral therapy, interpersonal therapy, and antidepressant treatments. We critically review the extant clinical trials for these treatments, and discuss both antidepressants efficacy and adverse events, including risk for suicidal events. TAKE HOME MESSAGE: Current treatments lead to a sustained response rate of up to 80% and a remission rate of 60% by 6 months, but we are in need of more personalized treatment to optimize treatment response. The identification of biomarkers of response may be the first step towards personalized treatment development. PMID- 20707756 TI - Management of idiopathic membranous nephropathy. AB - IMPORTANCE OF THE FIELD: Idiopathic membranous nephropathy (IMN) can have a variable natural course. Treatments able to induce remission can improve the long term prognosis. However, the optimal therapy for IMN remains controversial. AREA COVERED IN THIS REVIEW: We reviewed the historical and current literature from 1979 to 2010 regarding the natural course of IMN and the possible treatments giving special emphasis to randomized controlled trials and to more recent approaches. WHAT THE READER WILL GAIN: The reader will gain a comprehensive review of the available treatments of IMN. A personal therapeutic algorithm for nephrotic patients with IMN is also provided. TAKE HOME MESSAGE: At least five different treatments showed efficacy in many (but not all) patients with IMN. PMID- 20707757 TI - Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib. AB - IMPORTANCE OF THE FIELD: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC. AREAS COVERED IN THIS REVIEW: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor. WHAT THE READER WILL GAIN: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC. TAKE HOME MESSAGE: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention. PMID- 20707758 TI - Combination therapy for hypertension: focus on high-dose olmesartan medoxomil (40 mg) plus hydrochlorothiazide. AB - IMPORTANCE OF THE FIELD: Cardiovascular disease is a major cause of premature death and disability worldwide, and effective blood pressure (BP) control is crucial for the reduction of cardiovascular risk in patients with hypertension. Despite this, many will fail to attain recommended BP goals. A reappraisal of European guidelines led to revised recommendations for BP reduction to values within the SBP/DBP range of 130 - 139/80 - 85 mmHg in all patients with hypertension, including higher-risk groups such as those with diabetes. AREAS COVERED IN THIS REVIEW: The majority of hypertensive patients will require the enhanced blood-pressure-lowering effects of at least two antihypertensive drugs with complementary mechanisms of action to achieve these goals. WHAT THE READER WILL GAIN: The angiotensin II receptor blocker (ARB) olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide (HCTZ) provide greater antihypertensive efficacy when used in combination than as monotherapy with either component, with a similar tolerability profile. In addition, there is evidence that higher doses of olmesartan may prolong the antihypertensive effect of this ARB, and a number of US 'treat-to-target' and European add-on clinical trials have been conducted to assess the efficacy and safety of high-dose olmesartan plus HCTZ in a wide range of patients with mild-to-severe hypertension. TAKE HOME MESSAGE: Combination therapy with olmesartan, including the high 40-mg dose, plus HCTZ is an effective and safe treatment option for controlling BP in patients with mild to-severe hypertension, particularly those who fail to achieve recommended BP goals with monotherapy. PMID- 20707759 TI - Ticagrelor for the treatment of arterial thrombosis. AB - IMPORTANCE OF THE FIELD: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y(12) blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y(12) receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y(12) receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor. AREAS COVERED IN THIS REVIEW: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y(12) receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about 'AZD6140' and 'ticagrelor' in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings. WHAT THE READER WILL GAIN: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y(12) receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers. TAKE HOME MESSAGE: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use. PMID- 20707760 TI - Safinamide in the treatment of Parkinson's disease. AB - IMPORTANCE OF THE FIELD: Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non dopaminergic actions could offer a significant advantage. AREAS COVERED IN THIS REVIEW: This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound - safinamide, which has both dopaminergic and non-dopaminergic actions - might address these. WHAT THE READER WILL GAIN: The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced 'OFF' time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD. TAKE HOME MESSAGE: safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials. PMID- 20707762 TI - Association between obesity and periodontal risk indicators in adolescents. AB - OBJECTIVE: In a cross-sectional study design we test the hypothesis of whether obesity in adolescence is associated with periodontal risk indicators or disease. STUDY DESIGN: Obese adolescents (n=52) and normal weight subjects (n=52) with a mean age of 14.5 years were clinically examined with respect to dental plaque, gingival inflammation, periodontal pockets and incipient alveolar bone loss. The subjects answered a questionnaire concerning medical conditions, oral hygiene habits, smoking habits and sociodemographic background. Body mass index (BMI) was calculated and adjusted for age and gender (BMI-SDS). Samples of gingival crevicular fluid (GCF) were analyzed for the levels of adiponectin, plasminogen activator inhibitor-1 (PAI-1), interleukin-1beta (IL-beta), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha). RESULTS: Obese subjects exhibited more gingival inflammation (P<0.001) and more pathological periodontal pockets (>4 mm) (P<0.001) but not incipient alveolar bone loss compared with the normal weight subjects. Higher levels of IL-1beta (P<0.001) and IL-8 (P=0.002) were measured in GCF from obese subjects compared with the controls. In a multivariate logistic regression analysis, adjusted BMI-SDS (P=0.03; Odds Ratio [OR]=1.87) was significantly associated with the occurrence of pathological periodontal pockets. CONCLUSION: The study demonstrates an association between obesity and periodontal risk indicators in adolescents that in the long term may lead to oral morbidity. This result further strengthens obesity's negative effect on teenagers' periodontal health and highlights the importance of a close collaboration between dentists and pediatricians in the prevention and treatment of obesity. PMID- 20707763 TI - Association of childhood obesity with atopic and nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999-2006. AB - BACKGROUND: Obesity and asthma prevalence have both risen among children over the last several decades, and research efforts increasingly suggest that obesity is associated with asthma. Some, but not all, studies have shown that the effect of obesity on asthma is stronger among nonatopic individuals than among those with atopy. Systemic inflammation may be a factor in this relationship. OBJECTIVE: To examine the association of obesity with atopic and nonatopic asthma among U.S. children and to assess the role of C-reactive protein. DESIGN: Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) were used to examine the relationship of weight to current asthma using logistic regression. Overweight was defined as >= 85th percentile of body mass index (BMI)-for-age and obesity was defined as >= 95th percentile of BMI-for-age. The presence of at least one positive allergen-specific immunoglobulin E (IgE) was used to stratify the relationship by atopic status in 2005-2006 data (n = 3387). Setting and Participants. Stratified, multistage probability sampling was used to identify survey participants. This analysis includes children ages 2-19 (n = 16,074) from the 1999-2006 NHANES who have information on BMI and current asthma. MAIN OUTCOME MEASURE: Self-report of doctor-diagnosed current asthma. RESULTS: Obesity was significantly related to current asthma among children and adolescents (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.33, 2.12). The association was stronger in nonatopic children (OR: 2.46, 95% CI: 1.21, 5.02) than in atopic children (OR: 1.34, 95% CI: 0.70, 2.57) (interaction p value = .09). C-reactive protein levels were associated with current asthma in nonatopic children, but not after adjusting for BMI. CONCLUSION: Excess weight in children is associated with higher rates of asthma, especially asthma that is not accompanied by allergic disease. PMID- 20707764 TI - Annual change of respiratory functions in adult patients with asthma: the potential of antiasthma treatments for many years to repair irreversible changes of the airway. AB - BACKGROUND: Little is known regarding annual changes of respiratory functions among patients with asthma after asthma symptoms enter remission. OBJECTIVE: Annual changes of respiratory function and influence of patient characteristics and treatment variables on these changes were assessed in patients with adult asthma. METHODS: Respiratory function (pre- and postbronchodilator forced expiratory volume in one second [FEV1] and reversibility by short-acting beta2 agonist) and their changes were retrospectively investigated and relationships between these changes, after symptomatic remission, and patient characteristics and treatments were analyzed in adult outpatients with asthma who had undergone spirometry (including a reversibility test) >=5 times in >5 years. RESULTS: In patients >=40 years old, or with disease duration >=10 years or receiving treatment for severe asthma (steps 4-5, high-dose inhaled glucocorticosteroids, or addition of other medications), both pre- and postbronchodilator FEV1 values were significantly lower (p < .05). Mean annual change of prebronchodilator FEV1 (Deltapre-FEV1), annual change of postbronchodilator FEV1 (Deltapost-FEV1), and annual change of reversibility (Delta reversibility) were -13.8 +/- 59.7 ml/year, -25.9 +/- 51.0 ml/year, and -0.56% +/- 1.89%/year, respectively. Multivariate analysis after stepwise selection for variables in patient characteristics or treatments showed that disease duration >=10 years contributed to annual improvement of respiratory functions (Deltapre-FEV1: odds ratio [OR] 1.57, 95% confidence interval [CI] 1.01-2.46; Deltapost-FEV1: OR 2.13, 95% CI 1.25-3.66), treatment with long-acting beta2-agonists (LABAs) contributed to annual improvement of respiratory function (Deltapre-FEV1: OR 2.05, 95% CI 1.23-3.16; Deltapost-FEV1: OR 1.78, 95% CI 1.11-2.87), and poor compliance contributed to annual worsening of respiratory functions (Deltapre-FEV1: OR 0.43, 95% CI 0.24 0.76; Deltapost-FEV1: OR 0.39, 95% CI 0.22-0.70). In addition, duration of disease >=10 years and severe treatment (steps 4-5) from the beginning contributed to decreasing Deltareversibility (OR 0.55, 95% CI 0.34-0.87 and OR 0.50, 95% CI 0.29-0.83, respectively). CONCLUSIONS: Long-term treatments for asthma are expected to normalize respiratory dysfunction, which cannot be repaired in the short term. Treatment with LABAs and patient compliance may be the most important factors associated with annual improvement of respiratory functions. PMID- 20707766 TI - Nutritional evaluation of outer fleshy coat of Terminalia catappa fruit in two varieties. AB - The nutritional potential of outer (50-55%) fleshy edible cover of Terminalia catappa fruit was selected for investigation in search of a new source of nutrients. Two different varieties, red and yellow in their ripe and unripe stages, were analyzed for proximate and mineral composition along with phytochemicals. In the results (per 100 g sample), the red variety has shown to be a rich source of protein (1.95 g vs. 1.65 g) while the yellow variety has shown a high content of carbohydrate and ash (12.03 g vs. 6.14 g and 1.21 g vs. 0.70 g). Of the phytochemicals, beta-carotene and vitamin C were found to be present in high amount in the red variety (2,090 MUg vs. 754 MUg and 138.6 mg vs. 105.4 mg), wherein the former increased while the latter decreased with ripening of the fruit. The results of the study show that the edible outer cover of tropical almond can contribute significantly to the nutrient intake. PMID- 20707765 TI - Phentermine, topiramate and their combination for the treatment of adiposopathy ('sick fat') and metabolic disease. AB - Positive caloric balance often causes pathologic adipocyte and adipose tissue anatomical and functional changes (termed adiposopathy or 'sick fat'), which may lead to pathogenic adipocyte and adipose tissue responses and metabolic disease. Fat weight loss may improve adiposopathy, and thus improve metabolic disease in overweight patients. Unfortunately, the efficacy of non-surgical weight loss therapies is often limited due to redundant physiological systems that help 'protect' against starvation and/or negative caloric balance. One strategy to overcome these limitations is to combine weight loss drug therapies having complementary mechanisms of action, thereby affecting more than one physiologic process influencing body fat accumulation. Phentermine is a noradrenergic sympathomimetic amine approved for short-term treatment of obesity. Topiramate is a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide D-fructose approved as a treatment for migraine headaches and seizure disorders. Although known to facilitate weight loss since its approval, topiramate monotherapy does not have a regulatory indication as an anti obesity agent. Phentermine HCl/topiramate controlled-release (PHEN/TPM CR) is a combination agent containing immediate-release phentermine and controlled-release topiramate. Clinical trials involving thousands of patients demonstrate PHEN/TPM CR to be effective in improving the weight of patients, and also effective in improving adiposopathy-associated metabolic diseases. This review examines the pathophysiology of adiposopathy as a contributor to metabolic disease, the data supporting phentermine monotherapy, topiramate monotherapy and their combination as anti-obesity and anti-adiposopathy agents, and the preliminary evidence supporting PHEN/TPM CR as a generally well-tolerated and effective agent to improve metabolic disease. PMID- 20707767 TI - Impact of solifenacin on diary-recorded and patient-reported urgency in patients with severe overactive bladder (OAB) symptoms. AB - OBJECTIVE: It is widely recognized that patient perception of overactive bladder (OAB) symptoms can vary considerably from mild to severe bother. This post hoc analysis reports outcomes in patients with severe OAB symptoms at baseline taken from the VESIcare Efficacy and Safety in PatieNts with Urgency Study (VENUS). METHODS: VENUS was a 12-week, randomized, double-blind, placebo-controlled trial of solifenacin (5 or 10 mg/day, flexibly dosed) in OAB patients. The primary endpoint in VENUS was mean change from baseline to study end in urgency episodes/day using 3-day bladder diaries. Secondary endpoints included other diary endpoints (frequency, incontinence, and nocturia), warning time (WT; time between first sensation of urgency to voiding), and patient-reported outcome (PRO) measures of urgency (the Indevus Urgency Severity Scale [IUSS] and Urgency Perception Scale [UPS]) and of symptom bother and health-related quality of life (HRQL) (the Patient Perception of Bladder Condition [PPBC] and Overactive Bladder Questionnaire). For this analysis, severe OAB was defined as baseline PPBC score >=5 (1 = no problems, 6 = many severe problems). TRIAL REGISTRATION: NCT00454896. RESULTS: In total, 158/707 (22.3%) patients in the full analysis set (FAS) reported severe OAB symptoms. Solifenacin reduced mean urgency episodes/day versus placebo in the severe subgroup (-4.6 vs. -3.1, p = 0.1150), similar to the significant reduction observed in the FAS (-3.9 vs. -2.7, p < 0.0001). Solifenacin also improved the other diary endpoints and PRO measures in the severe subgroup; these changes were consistent with the significant solifenacin- versus placebo-related improvements for the FAS. Treatment-emergent adverse events were mostly mild/moderate, and few patients taking solifenacin or placebo discontinued treatment in the severe subgroup (4.5% vs. 6.5%) or FAS (6.5% vs. 4.6%). Key limitations are that VENUS was not powered to detect treatment differences in subgroups, and that the lack of a standardized definition of OAB symptom severity may limit the generalizability of the findings. CONCLUSIONS: Patients with severe OAB symptoms showed objective and subjective improvements in symptoms, symptom bother, HRQL, and urgency severity with solifenacin similar to the FAS. Solifenacin was also well-tolerated in this subgroup. PMID- 20707768 TI - Health economic evaluation of a vaccine for the prevention of herpes zoster (shingles) and post-herpetic neuralgia in adults in Belgium. AB - OBJECTIVE: To determine the cost-effectiveness of vaccination against herpes zoster (HZ) and post-herpetic neuralgia (PHN) in individuals aged 60 years and older in Belgium. METHODS: A Markov model was developed to compare the cost effectiveness of vaccination with that of a policy of no vaccination. The model estimated the lifetime incidence and consequences of HZ and PHN using inputs derived from Belgian data, literature sources, and expert opinion. Cost effectiveness was measured by the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life-year (QALY) gained. RESULTS: Vaccination in individuals aged 60 years and older resulted in ICERs of ?6,799 (third party payer perspective), ?7,168 (healthcare perspective), and ?7,137 (societal perspective). The number needed to vaccinate to prevent one case was 12 for HZ, and 35 or 36 for PHN depending on the definition used. Univariate sensitivity analyses produced ICERs of ?4,959-19,052/QALY; duration of vaccine efficacy had the greatest impact on cost-effectiveness. Probabilistic sensitivity analysis showed at least a 94% probability of ICERs remaining below the unofficial ?30,000 threshold. DISCUSSION: Key strengths of the model are the combination of efficacy data from a pivotal clinical trial with country-specific epidemiological data and complete sensitivity analysis performed. Main limitations are the use of non country-specific PHN proportion and non Belgian disease-specific utilities. Results are comparable with those recently published. CONCLUSIONS: HZ vaccination in individuals aged 60 years and older would represent a cost-effective strategy in Belgium. PMID- 20707769 TI - Recent progress on fabrication of calcium-based inorganic biodegradable nanomaterials. AB - Calcium-based inorganic biodegradable nanomaterials (CIBNs) including calcium phosphate, hydroxyapatite (HA), calcium silicate, calcium carbonate, and calcium sulfate, are important materials and have been widely used in biomedical field. Although CIBNs have been intensively studied, there are only a few synthesis methods that showed promising characteristics for practical applications. Here, we intend to review recent progress in the synthesis of the CIBNs including both patents and papers. In addition, the mechanisms of CIBNs are introduced. Finally, the current and future developments are put forward. In summary, we briefly review the patents and the patent-interrelated papers concerning the fabrication, mechanism, and future development of CIBNs in this mini-review. The paper provides an overview about the potential application of nanotechnology in biomedical field. PMID- 20707770 TI - Domain structure elucidation of human decorin glycosaminoglycans. AB - The structure of the GAG (glycosaminoglycan) chain of recombinantly expressed decorin proteoglycan was examined using a combination of intact-chain analysis and domain compositional analysis. The GAG had a number-average molecular mass of 22 kDa as determined by PAGE. NMR spectroscopic analysis using two-dimensional correlation spectroscopy indicated that the ratio of glucuronic acid to iduronic acid in decorin peptidoglycan was 5 to 1. GAG domains terminated with a specific disaccharide obtained by enzymatic degradation of decorin GAG with highly specific endolytic and exolytic lyases were analysed by PAGE and further depolymerized with the enzymes. The disaccharide compositional profiles of the resulting domains were obtained using LC with mass spectrometric and photometric detection and compared with that of the polysaccharide. The information obtained through the disaccharide compositional profiling was combined with the NMR and PAGE data to construct a map of the decorin GAG sequence motifs. PMID- 20707771 TI - Prevalence and correlates of DSM-IV alcohol abuse and dependence in Australia: findings of the 2007 National Survey of Mental Health and Wellbeing. AB - AIMS: To report nationally representative data on the prevalence and correlates (including psychiatric comorbidity and treatment) of DSM-IV alcohol abuse and dependence in Australian adults. DESIGN: The 2007 National Survey of Mental Health and Wellbeing (NSMHWB). SETTING: Australian nationally representative household survey. PARTICIPANTS: 8841 Australian adults (16-85 years). MEASUREMENTS: Interview schedule that assessed symptoms of the most prevalent DSM IV mental disorders in the life-time and the past 12 months. FINDINGS: Prevalence of life-time and 12-month disorders was 18.3% and 2.9% for alcohol abuse and 3.9% and 1.4% for alcohol dependence. Current alcohol abuse and dependence was significantly more common in males and younger adults. There were significant associations between current alcohol use and other drug use disorders (OR 18.2) and between anxiety disorders and alcohol use disorders (OR 2.6). Only 22.4% of those with alcohol use disorders were treated for their alcohol disorder. CONCLUSIONS: Alcohol use disorders are highly prevalent, especially among young adult males. Comorbidity between anxiety and other drug use disorders is common and remains a significant challenge for the delivery of effective health-care services and treatment. The low rate of effective interventions for alcohol problems is a significant public health concern. PMID- 20707772 TI - Contingency management treatments: controversies and challenges. PMID- 20707773 TI - Towards a self-change-friendly treatment and policy for addictive behaviours. PMID- 20707774 TI - Why is natural recovery so common for addictive disorders? PMID- 20707775 TI - What do marshmallows and golf tell us about natural recovery research? PMID- 20707776 TI - What does self-change mean for how we deliver treatment? PMID- 20707778 TI - Commentary on Merrall et al. (2010): understanding mortality and health outcomes for ex-prisoners - first steps on a long road. PMID- 20707779 TI - Commentary on Norstrom & Pape (2010): unleashing the beast within? Suppressed anger and changes in drinking and fighting. PMID- 20707780 TI - Commentary on Nelson et al. (2010): the many sources of survey under-coverage. PMID- 20707781 TI - Challenges to antagonist blockade during sustained-release naltrexone treatment. AB - AIMS: Naltrexone is a competitive opioid antagonist that effectively blocks the action of heroin and other opioid agonists. Sustained-release naltrexone formulations are now available that provide long-acting opioid blockade. This study investigates the use of heroin and other opioids among opioid-dependent patients receiving treatment with long-acting naltrexone implants, their subjective experience of drug 'high' after opioid use, and factors associated with opioid use. METHODS: Participants (n = 60) were opioid-dependent patients receiving treatment with naltrexone implants. Outcome data on substance use, drug 'high', depression and criminal activity were collected over a 6-month period. Blood samples were taken to monitor naltrexone plasma levels, and hair samples to verify self-reported opioid use. FINDINGS: More than half [n = 34 or 56%; 95% confidence interval (CI) 44-68%)] the patients challenged the blockade with illicit opioids during the 6-month treatment period; 44% (n = 26; 95% CI 32-56%) were abstinent from opioids. Mean opioid use was reduced from 18 [standard deviation (SD)13] days during the month preceding treatment to 6 days (SD 11) after 6 months. Of the respondents questioned on opioid 'high' (n = 31), nine patients (30%; 95% CI 16-47%) reported partial drug 'high' following illicit opioid use, and three (12%; 95% CI 3-26%) reported full 'high'. Opioid use was associated with use of non-opioid drugs and criminal behaviour. CONCLUSIONS: Challenging naltrexone blockade with heroin on at least one occasion is common among sustained-release naltrexone patients, but only a minority of patients use opioids regularly. Challenges represent a warning sign for poor outcomes and often occur in the context of polydrug use and social adjustment problems. PMID- 20707782 TI - Commentary on Joossens et al. (2010): eliminating the global illicit cigarette trade - what do we really know? PMID- 20707783 TI - Association of adolescent symptoms of depression and anxiety with daily smoking and nicotine dependence in young adulthood: findings from a 10-year longitudinal study. AB - AIMS: To examine the association of adolescent depression and anxiety symptoms with daily smoking and nicotine dependence in young adulthood. DESIGN: A prospective cohort study of adolescent and young adult health (n = 1943). Teen assessments occurred at 6-monthly intervals, with two follow-up assessments in young adulthood (wave 7, 1998; wave 8, 2001-03). SETTING: Victoria, Australia. Participants Students who participated at least once during the first six (adolescent) waves of the cohort study. MEASUREMENTS: Adolescent depression and anxiety symptoms were assessed using the Revised Clinical Interview Schedule (CIS R). Young adult tobacco use was defined as: daily use (6 or 7 days per week) and dependent use (> or =4 on the Fagerstrom Test for Nicotine Dependence). FINDINGS: Among adolescent 'less than daily' smokers, those with high levels of depression and anxiety symptoms had an increased risk of reporting nicotine dependence in young adulthood [odds ratio (OR) 3.3, 95% confidence interval (CI) 1.2-9.1] compared to young adults who had low levels of adolescent depression and anxiety symptoms, after adjusting for potential confounding factors. Similarly, in the adjusted model (OR 1.9, 95% CI 1.0-3.4), among adolescent 'daily' smokers, those with high levels of depression and anxiety symptoms had an almost two-fold increase in the odds of reporting nicotine dependence in young adulthood compared to young adults with low levels of adolescent depression and anxiety symptoms. CONCLUSIONS: Adolescent smokers with depression and anxiety symptoms are at increased risk for nicotine dependence into young adulthood. They warrant vigilance from primary care providers in relation to tobacco use well into adulthood. PMID- 20707786 TI - Use of the Ambu((r)) aScopeTM in 10 patients with predicted difficult intubation. AB - Fibreoptic intubation is the gold standard for patients with predicted difficult intubation. The Ambu((r)) aScopeTM is a single-use device for fibreoptic tracheal intubation. We assessed its performance in 10 patients with predicted difficult tracheal intubation. The procedure was easy and successful in nine patients. However, the limited time of use did not permit intubation in one patient who required three attempts with different size tracheal tubes. The limited image resolution that can be expected of a single-use fibreoptic system and the absence of a suction channel are other potential limitations. On the other hand, being single-use this device has the advantage of avoiding the risk of infectious disease transmission and is always ready to use. PMID- 20707784 TI - Failure to improve cigarette smoking abstinence with transdermal selegiline + cognitive behavior therapy. AB - AIMS: To examine the effectiveness of transdermal selegiline for producing cigarette smoking abstinence. DESIGN: Adult smokers were randomly assigned to receive selegiline transdermal system (STS) or placebo given for 8 weeks. All participants received cognitive behavior therapy (CBT). Follow-ups were conducted at 25 and 52 weeks. SETTING: Community smoking cessation clinic. PARTICIPANTS: 243 adult smokers (> or =18 years of age; > or =10 cigarettes/day). MEASURES: Expired-air carbon monoxide confirmed 7-day point prevalence abstinence. FINDINGS: STS was not superior to placebo. More women than men were abstinent at 52 week follow-up (28% vs 16%, P < 0.05). Behavioral activation (BAS) moderated treatment response (P = 0.01). The survival rate through week 52 for those with high 'drive' scores on the BAS was 47% if assigned to selegiline and 34% if assigned to placebo. The survival rate for those with low 'drive scores' on the BAS was 35% if assigned to selegiline compared to 53% if assigned to placebo. CONCLUSION: Transdermal selegiline does not appear generally effective in aiding smoking cessation though there may be a selective effect in those smokers with low 'behavioral activation'. PMID- 20707787 TI - Association of ABCB1 polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting. AB - We investigated whether the 2677G>T/A and 3435C>T polymorphisms of adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) affect the efficacy of ondansetron to prevent postoperative nausea and vomiting. One hundred and ninety eight patients undergoing general anaesthesia were enrolled. Thirty minutes before the end of surgery, 0.1 mg.kg-1 ondansetron was administered intravenously. The incidence of postoperative nausea and vomiting was compared between genotypes in the 2677G>T/A and 3435C>T polymorphisms of ABCB1. The incidence of postoperative nausea and vomiting was lower in patients with the 2677TT genotype (TT vs Non-TT = 25.9% vs 53.0%, p = 0.01) and 3435TT genotype (CC + CT vs TT = 52.6% vs 21.7%, p = 0.01) during the first 2 h after surgery. There were no significant differences in the incidence of postoperative nausea and vomiting between the different genotype groupings during period between 2 and 24 h after surgery. In conclusion, ABCB1 genotypes may be a clinical predictor of responsiveness for ondansetron. PMID- 20707788 TI - Allele-sharing statistics using information on family history. AB - When conducting genetic studies for complex traits, large samples are commonly required to detect new genetic factors. A possible strategy to decrease the sample size is to reduce heterogeneity using available information. In this paper we propose a new class of model-free linkage analysis statistics which takes into account the information given by the ungenotyped affected relatives (positive family history). This information is included into the scoring function of classical allele-sharing statistics. We studied pedigrees of affected sibling pairs with one ungenotyped affected relative. We show that, for rare allele common complex diseases, the proposed method increases the expected power to detect linkage. Allele-sharing methods were applied to the symptomatic osteoarthritis GARP study where taking into account the family-history increased considerably the evidence of linkage in the region of the DIO2 susceptibility locus. PMID- 20707789 TI - Reduced bladder tumour recurrence rate associated with narrow-band imaging surveillance cystoscopy. AB - OBJECTIVE: To evaluate frequency of recurrences among patients with papillary bladder tumours followed sequentially with conventional white-light (WLI) cystoscopy and narrow-band imaging (NBI) cystoscopy. PATIENTS AND METHODS: A cohort of 126 patients with recurrent low-grade papillary bladder tumours were followed every 6 months for 3 years by conventional WLI cystoscopy, and then over the next 3 consecutive years by NBI cystoscopy. Recurrent tumours detected were treated by outpatient fulguration or transurethral resection. We compared the tumour recurrence rate during follow-up with WLI and NBI cystoscopy, using patients as their own controls. RESULTS: Of the 126 patients, 94% had tumour recurrences during WLI cystoscopy vs 62% during NBI cystoscopy. The mean number of recurrent tumours was 5.2 with WLI cystoscopy vs 2.8 with NBI cystoscopy, and the median recurrence-free survival time was 13 vs 29 months (P= 0.001). CONCLUSION: Compared with follow-up with WLI cystoscopy, NBI cystoscopy was associated with fewer patients having tumour recurrences, fewer numbers of recurrent tumours, and a longer recurrence-free survival time. PMID- 20707790 TI - Trospium chloride once-daily extended release is efficacious and tolerated in elderly subjects (aged >= 75 years) with overactive bladder syndrome. AB - OBJECTIVE: * To evaluate the safety and efficacy of once-daily trospium chloride extended release (ER) in overactive bladder syndrome (OAB) in subjects aged >= 75 years. SUBJECTS AND METHODS: * The analysis included subjects >= 75 years of age with OAB. * A subgroup analysis of pooled data was performed for subjects aged >= 75 years from two randomized, double-blind, multicenter studies of subjects with OAB receiving once-daily trospium 60 mg extended release (ER) or placebo for 12 weeks, followed by 9-month open-label extension periods during which all subjects received trospium ER. A total of 143 of the 1165 subjects from two phase III registration trials who were aged >= 75 years (85 trospium ER, 58 placebo; mean age 79 years and ranging up to 90 years; 73% female) were evaluated. * Dual primary efficacy variables were the changes from baseline in the average number of toilet voids per day and urge urinary incontinence episodes per day. RESULTS: * At week 12 of the double-blind period, trospium ER produced greater improvements from baseline than placebo in voiding diary parameters, OAB Patient Global Assessment, and quality of life. * Efficacy and tolerability persisted among subjects receiving open-label trospium ER for up to 1 year. CONCLUSIONS: * Once-daily trospium chloride 60 mg ER demonstrated efficacy vs placebo and was tolerated in subjects aged >= 75 years with OAB. * For subjects who continued into the open-label treatment period, efficacy and tolerability were observed for up to 1 year. PMID- 20707791 TI - The WHO classification of 1973 is more suitable than the WHO classification of 2004 for predicting survival in pT1 urothelial bladder cancer. AB - OBJECTIVE: To ascertain which of the currently defined World Health Organization (WHO) grading classifications of pT1 urothelial bladder cancer (BC), published in 1973 and 2004, is more suitable for predicting outcome. PATIENTS AND METHODS: Transurethral resection of the bladder (TURB) specimens of 310 patients with first diagnosis of initial pT1 BC were reassessed by three urological pathologists according to the WHO classifications of 1973 and 2004. The TURB procedure was followed by either immediate cystectomy or adjuvant bacille Calmette-Guerin (BCG) instillations. Kaplan-Meier analysis was used to compare survival rates of the different tumour grades (mean follow-up was 57 months). RESULTS: According to the 1973 WHO classification, none of the pT1 BC specimens were graded as G1, while 36% were graded as G2 and 64% were graded as G3. Histological reassessment according to the 2004 WHO classification highlighted only 4% low-grade and 96% high-grade tumours. The 10-year cancer-specific survival rates of high-grade tumours (85%) were intermediate between G2 (96%) and G3 (78%). CONCLUSIONS: The results of the present study support the presumption that the 1973 WHO classification is more suitable for predicting outcome for pT1 tumours, by defining at least two prognostic groups. A new classification should revise the definition of low- and high-grade pT1 BC to preserve the prognostic value of tumour grading. PMID- 20707792 TI - Evidence-based urology in practice: randomized controlled trials stopped early for benefit. PMID- 20707793 TI - Continence, potency and oncological outcomes after robotic-assisted radical prostatectomy: early trifecta results of a high-volume surgeon. AB - OBJECTIVE: * To evaluate early trifecta outcomes after robotic-assisted radical prostatectomy (RARP) performed by a high-volume surgeon. PATIENTS AND METHODS: * We evaluated prospectively 1100 consecutive patients who underwent RARP performed by one surgeon. In all, 541 men were considered potent before RARP; of these 404 underwent bilateral full nerve sparing and were included in this analysis. * Baseline and postoperative urinary and sexual functions were assessed using self administered validated questionnaires. * Postoperative continence was defined as the use of no pads; potency was defined as the ability to achieve and maintain satisfactory erections for sexual intercourse >50% of times, with or without the use of oral phosphodiesterase type 5 inhibitors; Biochemical recurrence (BCR) was defined as two consecutive PSA levels of >0.2 ng/mL after RARP. * Results were compared between three age groups: Group 1, <= 55 years, Group 2, 56-65 years and Group 3, >65 years. RESULTS: * The trifecta rates at 6 weeks, 3, 6, 12, and 18 months after RARP were 42.8%, 65.3%, 80.3%, 86% and 91%, respectively. * There were no statistically significant differences in the continence and BCR-free rates between the three age groups at all postoperative intervals analysed. * Nevertheless, younger men had higher potency rates and shorter time to recovery of sexual function when compared with older men at 6 weeks, 3, 6 and 12 months after RARP (P < 0.01 at all time points). * Similarly, younger men had higher trifecta rates at 6 weeks, 3 and 6 months after RARP compared with older men (P < 0.01 at all time points). CONCLUSION: * RARP offers excellent short-term trifecta outcomes when performed by an experienced surgeon. * Younger men had higher overall trifecta rates when compared with older men at 6 weeks, 3 and 6 months after RARP. PMID- 20707794 TI - Confocal laser endomicroscopy for the diagnosis of urothelial bladder neoplasia: a technology of the future? AB - OBJECTIVE: To evaluate bladder urothelium by confocal laser endomicroscopy (CLE) and correlate microscopic findings with standard histopathology. PATIENTS AND METHODS: Fresh bladder urothelium tissue specimens were topically stained with acriflavine for instantaneous microscopic imaging. A single-line laser in a handheld CLE probe delivered an excitation wavelength of 488 nm providing a high resolution of 0.7 um and an adjustable imaging depth of 0-250 um. Resection specimens of 18 patients were investigated with 1000-fold magnification and ex vivo findings were compared with targeted histopathology (haematoxylin and eosin staining). RESULTS: Typical tumour growth patterns such as altered nuclear to cytoplasmic ratio, pseudopapillar tissue stratification and neoangiogenesis were readily visible. Nuclear and subnuclear architecture of healthy bladder tissue could be discriminated against neoplastic tissue. CONCLUSIONS: In addition to white light cystoscopy, CLE is a promising novel tool for the in vivo microscopic visualization of bladder cancer; first results of the present study show its potential to define microscopic characteristics of bladder cancer tissue. Further in vivo studies are necessary to determine sensitivity and specificity of the technique. PMID- 20707795 TI - A post-radical-prostatectomy nomogram incorporating new pathological variables and interaction terms for improved prognosis. AB - OBJECTIVE: To evaluate new variables in prostate pathology reporting including, the per cent of Gleason patterns 4 and/or 5 (% 4/5), presence or absence of intraductal carcinoma of the prostate (IDCP), tumour volume and the prostatic zone of tumour origin as predictors of post-radical-prostatectomy (RP) biochemical recurrence (BCR). To develop an optimal postoperative nomogram for patients with prostate cancer. PATIENTS AND METHODS: Our study cohort was 1939 eligible patients from the Abbott West Australian Prostatectomy Database. Multivariate Cox proportional hazard regression models were developed to predict BCR which was defined as prostate-specific antigen (PSA) >= 0.2 ng/mL. Our models and the 2009 Kattan postoperative nomogram were compared in terms of discrimination and calibration, with internal validation of our final model performed using bootstrapping methods. Our final model is presented as a nomogram. RESULTS: The Kattan nomogram was accurate in discriminating our patients according to risk (concordance index: 0.791) but calibration analysis indicated underestimation of patient risk, particularly for high-risk disease. Our nomogram incorporates % 4/5, IDCP and prostate weight plus interaction terms between % 4/5, positive surgical margins and extracapsular extension, giving improved predictive accuracy (concordance index: 0.828) and calibration. CONCLUSIONS: Nomograms that predict risk of BCR defined as PSA >= 0.4 ng/mL may not be optimal for patient cohorts where BCR is defined as PSA >= 0.2 ng/mL. If our findings are validated in other populations, current post-RP nomograms may be improved to a modest degree by incorporating the new variables prostate weight, IDCP and % 4/5, and by considering interactions between predictive variables. PMID- 20707796 TI - Life and death of spare (selective bladder preservation against radical excision): reflections on why the spare trial closed. PMID- 20707797 TI - Hypoxia-inducible factor and mammalian target of rapamycin pathway markers in urothelial carcinoma of the bladder: possible therapeutic implications. AB - OBJECTIVE: To investigate the rationale for using targeted therapies against hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways in urothelial carcinoma of the bladder, by studying the immunohistochemical expression of molecules of these pathways in urothelial carcinoma, as recent pre clinical studies and clinical trials have shown the potential utility of such targeted therapies. PATIENTS AND METHODS: Immunohistochemical stains were performed on a tissue microarray prepared from 92 cases of >= pT2 urothelial (transitional cell) carcinoma of bladder, using antibodies against HIF-1alpha and VEGF-R2, and phospho-S6 and phospho-4E BP1, molecules of HIF and activated mTOR pathways, respectively. Immunoreactivity was graded from 0 to 3+ (0, 0-5%; 1+, 6 25%; 2+, 26-50%; 3+, > 50% tumour cells positive). RESULTS: In all, 58, 34, 35 and 17% of the tumours showed grade 2-3+ expression of phospho-4E BP1, phospho S6, HIF-1alpha and VEGF-R2, respectively. Moderate correlation for immunoreactivity was observed between molecules within the same pathway [(phospho 4E BP1 with phospho-S6 (rho = 0.411), and HIF-1alpha with VEGF-R2 (rho = 0.265)], but not between molecules across pathways. CONCLUSIONS: Urothelial carcinomas of the bladder express molecules of the HIF and mTOR pathways, providing a rationale for clinical trials evaluating agents targeting these pathways. Correlation between molecules within the same pathway, and not across pathways, suggests that investigating the usefulness of a specific targeted agent might benefit from pre treatment evaluation of pathway marker expression. PMID- 20707798 TI - Perioperative morbidity and renal function in young and elderly patients undergoing elective nephron-sparing surgery or radical nephrectomy for renal tumours larger than 4 cm. AB - OBJECTIVE: To analyse renal function, perioperative morbidity and overall survival (OS) in patients aged <55 years compared with patients aged > 65 years treated by radical nephrectomy (RN) or elective nephron-sparing surgery (NSS) for renal tumours > 4 cm. PATIENTS AND METHODS: From our database, we identified 829 patients with renal tumours > 4 cm treated by either RN (n = 641) or NSS (n= 188) at our institution between 1981 and 2007. After excluding patients with imperative indication and metastases, we identified retrospectively 81 patients aged < 55 years (young patients) and 85 patients aged > 65 years (elderly patients) treated for renal tumours > 4 cm. In all, 36 and 33 patients underwent NSS and 45 and 52 patients underwent RN in the young and elderly group, respectively. Preoperative and periodically postoperative serum creatinin values were used to estimate glomerular filtration rate (GFR). Chronic kidney disease (CKD) was defined as GFR < 60 mL/min/1.73 m2. Clinical characteristics, complications and renal function were compared between age groups and surgical approaches, and OS was estimated using the Kaplan-Meier method. RESULTS: The median (range) tumour size in young patients was larger compared with that of elderly patients, i.e. 6 (4.2-14.0) cm vs 5 (4.2-16.0) cm, with P < 0.001 considered to be statistically significant. The complication rates did not differ between the age groups (P = 0.656) or between NSS and RN in young (P = 0.095) or elderly patients (P = 0.277). Chronic kidney disease after RN or NSS occurred in 31.1% and 15.5% for young patients, respectively and in 50.9% and 24.2% in elderly patients, respectively, until last available follow-up which was obtained after a median (range) of 5.69 (0.1-19.2) years for young patients and 5.48 (0.8 18.1) years for elderly patients. Overall survival did not significantly differ between NSS vs RN in young (P = 0.655) and elderly patients (P = 0.058). CONCLUSION: Our findings suggest that performing NSS for tumours > 4 cm when feasible in young and carefully selected elderly patients is more beneficial for maintaining long-term renal function. Regardless of age, patients undergoing RN for renal tumours > 4 cm developed more new onsets of CKD than patients treated by elective NSS. The complication rate did not differ between the age groups or between types of surgery. PMID- 20707799 TI - Predictors of prolonged operative time during robot-assisted laparoscopic radical prostatectomy. AB - OBJECTIVE: To determine risk factors for prolonged operative time (OT) during robot-assisted laparoscopic radical prostatectomy (RALP). Being able to predict prolonged OT is of pivotal importance both to the physician for patient counseling and to the hospital management. PATIENTS AND METHODS: Retrospective review of patient records undergoing RALP between 2003 and 2009 at a tertiary academic center with a structured teaching program. The following variables were recorded: age, race, body-mass index (BMI), previous abdominal surgery (yes/no), nerve-sparing technique (yes/no), lymph nodes dissection (yes/no), pathological stage (organ-confined versus non), cumulative surgical experience with RALP (expressed as number of years since introduction of RALP at our center), prostate weight and OT calculated skin-to-skin by the anesthesiologists. Prolonged OT was defined as the upper quintile (20%) according to the distribution. Multivariate regression model was generated to assess potential predictors of prolonged OT. RESULTS: A total of 523 records were retrieved. Caucasians accounted for 77.8% of the cohort. Median age was 60.3 years (interquartile range, IQR, 55.0-64.6 years), median BMI 28.1 (25.8-30.7 kg/m2), prostate weight 46.0 g (37.0-57.8 g). Eighty-six (16.4%) patients had previous abdominal surgery, lymph nodes dissection was performed in 341 (65.2%) and nerve-sparing technique was done in 310 (59.3%) cases. Median OT was 175 min (IQR 146-220 min). Prolonged OT was set at > 230 min, thereby 105 (20.1%) records were classified as such. On multivariate analysis, cumulative surgical experience with RALP (P < 0.001), nerve sparing (P = 0.023) and prostate weight (P < 0.001) were independent predictors of prolonged OT. CONCLUSIONS: Larger prostates are associated with longer OT and this effect is maintained independently of cumulative robotic experience that represents another independent factor in determining OT. PMID- 20707800 TI - Effects of bariatric surgery on urinary and sexual function. AB - OBJECTIVE: To investigate the effects of weight loss and time post laparoscopic gastric banding surgery (LGB) on urinary and sexual function. MATERIALS AND METHODS: 653 females and 145 males who underwent LGB over the last 10 years at a single centre in Australia were contacted by post and asked to complete validated questionnaires. RESULTS: The pre-surgery body-mass index (BMI) was higher in males than females (47.3 vs 43.5); 65% of the females and 24% of males previously had some degree of urinary incontinence (UI). There were significant weight and BMI losses in males and females (23.2 kg and 7.51 vs 22.7 kg and 8.28; P < 0.0001). In females there were significant improvements in the ICIQ-SF (P= 0.0008) and Quality of Life (P < 0.0001) scores. For each kilogram lost there was a 0.05 improvement in the ICIQ score (P= 0.03) in females. There were also postoperative improvements in all symptoms of UI and stress incontinence in females but urge incontinence worsened, when adjusted for weight loss. In males there was no improvement in UI with weight loss after LGB. There was no relationship with time and UI in either gender; 83.3% of males reported a degree of ED before LGB. There was improvement in the IIEF score in males post LGB but there was worsening of erectile index (P= 0.005) and orgasmic function (P= 0.002) when adjusted for time. More males had started using phosphodiesterase type 5 inhibitors, post-LGB. CONCLUSIONS: Surgically induced weight loss by LGB improved overall UI, quality of life and stress incontinence in females but urge incontinence worsened. There was no improvement in UI with weight-loss or overall sexual function after LGB in males. However, erectile index and orgasmic function worsened when adjusted for time. Further evaluation is required by means of larger prospective studies involving urodynamic testing. PMID- 20707801 TI - Prostate cancer death is unlikely in high-risk patients following quality permanent interstitial brachytherapy. AB - OBJECTIVE: To evaluate cause-specific survival (CSS), biochemical progression free survival (bPFS) and overall survival (OS) in high-risk prostate cancer brachytherapy patients. PATIENTS AND METHODS: From April 1995 to June 2005, 284 patients with high-risk prostate cancer (Gleason score >= 8 or prostate-specific antigen > 20 ng/mL or clinical stage >= T2 c) underwent brachytherapy. Supplemental external beam radiation therapy was given to 257 (90.5%) patients and 179 (63.0%) received androgen deprivation therapy (ADT). Median follow up was 7.8 years. The median post-implant day 0 D90 was 118.9% of prescription dose. Patients with metastatic prostate cancer or castrate-resistant disease without obvious metastases who died of any cause were classified as dead from prostate cancer. Multiple parameters were evaluated for impact on survival. RESULTS: Twelve-year CSS, bPFS and OS were 94.2%, 89.0% and 69.7%. On multivariate analysis, bPFS was best predicted by percent positive biopsies and ADT. The analysis failed to identify any predictors for CSS, while OS was highly correlated with patient age, percent positive biopsies and diabetes. Fourteen percent of patients died from diseases of the heart, while 8%, 8% and 6% of patients died from non-prostate cancer, other causes and prostate cancer, respectively. When OS was stratified by patients with 0-3 vs >= 4 comorbidities, the 12-year OS was 73.0% and 52.7% (P = 0.036). CONCLUSIONS: High-quality brachytherapy results in favourable bPFS and CSS for high-risk patients. Death from diseases of the heart is more than twice as likely as death from prostate cancer. Strategies to improve cardiovascular health may positively impact OS. PMID- 20707803 TI - Development of urological cancers in renal transplant recipients: 30-year experience at the Frankfurt Transplant Center. AB - Fatal post-transplant malignancies with a high proportion of genitourinary neoplasms represent a serious long-term challenge. With continuous improvement of the allograft and patient survival, cancer development after renal transplantation may soon turn to the leading morbidity cause. In a retrospective single-center study of 1990 renal transplant recipients between November 1979 and November 2009, records of patients with urological neoplasms including epidemiological, clinical and survival parameters were accessed. Sixty-six de novo urological malignancies in 58 recipients were recorded in the study period, being most common after skin cancers (15.6% of enregistered tumors). From these, 29 were renal cell cancers, including five neoplasms of transplanted kidney, 24 transitional cell carcinomas, 11 prostate carcinomas, and two germ cell carcinomas with incidence rates of 1.5%, 1.2%, 0.9% and 0.2%, respectively. The patient follow up was virtually complete. Tumor-related death was found in 44% of cases. By multivariate analysis, no influence of either duration of dialysis, mode or duration of immunosuppression, gender or age at transplantation on overall patient survival could be demonstrated. This study, documenting a 30-year single center experience, emphasizes the increased risk for urological neoplasms occuring after renal transplantation. Screening strategies for urological cancers should be optimized. PMID- 20707804 TI - WASP and WAVE family proteins: friends or foes in cancer invasion? AB - Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE) family proteins activate cells' major actin nucleating machinery, the actin-related protein 2/3 (Arp2/3) complex, leading to the formation and remodeling of cortical actin filament networks. Cortical actin regulation is critical in many aspects of cell physiology including cell-cell adhesion and cell motility, whose dysregulation is directly associated with cancer invasion and metastasis. In line with this association, the WASP and WAVE family proteins have been reported to be involved in cancer malignancies. What is puzzling, however, is that they can act as either enhancers or suppressors of cancer malignancies depending on the type of cancer and its pathological stage. We are still far from understanding the roles of the WASP and WAVE family proteins in cancer progression. Here, we summarize the recent advances of studies of the WASP and WAVE family proteins with respect to cancer invasion and we offer a model that can account for the diverse outcomes originating from dysregulated WASP and WAVE family proteins in cancer development. PMID- 20707805 TI - Characterization of the epithelial cell adhesion molecule (EpCAM)+ cell population in hepatocellular carcinoma cell lines. AB - Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM(+) subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM(-) subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra-immunodeficient NOD/scid/gammac(null) (NOG) mice, revealed that a smaller number of EpCAM(+) cells (minimum 100) than EpCAM(-) cells was necessary for tumor formation. The bifurcated differentiation of EpCAM(+) cell clones into both EpCAM(+) and EpCAM(-) cells was obvious both in vitro and in vivo, but EpCAM(-) clones sustained their phenotype. These clonal analyses suggested that EpCAM(+) cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM(+) clones, but not into EpCAM(-) clones, markedly enhanced their tumor-forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor-forming ability between EpCAM(+) and EpCAM(-) cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM(+) population is biologically quite different from the EpCAM(-) population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC. PMID- 20707806 TI - Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors. AB - Enzastaurin is an oral serine/threonine kinase inhibitor that targets the protein kinase C (PKC) and phosphoinositide 3-kinase/AKT pathways to induce apoptosis and suppress proliferation of various cancer cell lines. This phase I study evaluated the tolerability and pharmacokinetics of enzastaurin in Japanese patients with advanced solid tumors and determined the recommended dose for phase II. Eligible patients had advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received enzastaurin orally once daily until disease progression (PD) or unacceptable toxicity occurred. Enzastaurin was started at 250 mg/day followed by stepwise dose increases based on the incidence of dose-limiting toxicities (DLT). Twenty-three patients (seven patients: 250 mg; six patients: 375 mg; six patients: 500 mg; four patients: 750 mg) were enrolled and received enzastaurin. The major tumor types were non-small-cell lung cancer (n = 5) and breast cancer (n = 3). No DLT was reported at doses of 500 mg or less. Because two DLT (grade 2 QTc prolongation lasting for a week) were observed at 750 mg enzastaurin, this was determined as the maximum tolerated dose. Multiple daily doses at 500 mg achieved the target plasma concentration to inhibit PKC activity (1400 nmol/L). Enzastaurin was well tolerated up to 500 mg in Japanese patients with advanced solid tumors. The recommended dose for phase II was determined to be 500 mg daily for a 28-day cycle on the basis of safety and plasma exposures. PMID- 20707809 TI - Climate predictors of late quaternary extinctions. AB - Between 50,000 and 3,000 years before present (BP) 65% of mammal genera weighing over 44 kg went extinct, together with a lower proportion of small mammals. Why species went extinct in such large numbers is hotly debated. One of the arguments proposes that climate changes underlie Late Quaternary extinctions, but global quantitative evidence for this hypothesis is still lacking. We test the potential role of global climate change on the extinction of mammals during the Late Quaternary. Our results suggest that continents with the highest climate footprint values, in other words, with climate changes of greater magnitudes during the Late Quaternary, witnessed more extinctions than continents with lower climate footprint values, with the exception of South America. Our results are consistent across species with different body masses, reinforcing the view that past climate changes contributed to global extinctions. Our model outputs, the climate change footprint dataset, provide a new research venue to test hypotheses about biodiversity dynamics during the Late Quaternary from the genetic to the species richness level. PMID- 20707810 TI - Diagnostic value and prognostic significance of plasmatic proteasome level in patients with melanoma. AB - Plasmatic proteasome (p-proteasome) also called circulating proteasome has recently been described as a tumor marker. We investigated the diagnostic and prognostic accuracies of p-proteasome levels in a melanoma population classified according to the American Joint Committee on Cancer staging system. Using an ELISA test, we measured p-proteasome levels in 90 patients and 40 controls between March 2003 and March 2008. The subunit composition of p-proteasomes was determined in metastatic melanoma by proteomic analysis. The mean p-proteasome levels were correlated with stages (P < 0.0001; r(S) = 0.664). They were significantly higher in patients with stage IV and stage III with lymph node metastasis (9187 +/- 1294 and 5091 +/- 454 ng/ml, respectively) compared to controls (2535 +/- 187 ng/ml; P < 0.001), to stage I/II (2864 +/- 166 ng/ml; P < 0.001) and to stage III after curative lymphadenectomy (2859 +/- 271 ng/ml; P < 0.001). The diagnostic accuracy of p-proteasome was evaluated by receiver operating characteristic analysis. With a cut-off of 4300 ng/ml, diagnostic specificity and sensitivity of p-proteasome for regional or visceral metastases were respectively 96.3% and 72.2%. In univariate analysis, high p-proteasome levels (>4300 ng/ml) were significantly correlated with an increased risk of progression [hazard ratio (HR) = 7.34; 95% CI 3.54-15.21, P < 0.0001] and a risk of death (HR = 5.92; 95% CI 2.84-12.33, P < 0.0001). In multivariate analysis, high p-proteasome levels were correlated with a poorer clinical outcome in the subgroup analysis limited to patients with disease stages I, II and III. Proteomic analysis confirmed the presence of all proteasome and immunoproteasome subunits. Taken together, these results indicate that p-proteasomes are a new marker for metastatic dissemination in patients with melanoma. PMID- 20707811 TI - Human primary dendritic cell subsets differ in their IL-12 release in response to Leishmania major infection. AB - Immunity against leishmaniasis has primarily been studied in experimental infections of mice. It was shown that infected skin dendritic cells (DC) are critical for the induction of protection against this pathogen, and targeting skin DC in vaccination approaches in mice has proven to be successful. However, little is known about the contribution of human DC subsets from the skin to primary immunity against this pathogen. In this study, we have analysed the interaction between different human DC subsets and Leishmania major. Primary human myeloid and monocyte-derived DC ingested the parasite comparable to that of murine skin DC, and this resulted in DC activation and IL-12 release, a cytokine essential for the induction of Th1/Tc1-dependent protection. Interestingly, both Langerhans cells and plasmacytoid DC did not appear to contribute to protection in humans. Thus, in leishmaniasis, both murine and human data suggest that dermal inflammatory DC appear to be superior in promoting protection. PMID- 20707812 TI - Self-renewal capacity of human epidermal Langerhans cells: observations made on a composite tissue allograft. AB - Epidermal Langerhans cells (LC) are dendritic, antigen-presenting cells residing within mammalian epidermis and mucosal epithelia. When massively depleted, they are replaced by cells of bone-marrow origin. However, their renewal within normal skin under steady-state conditions is not precisely known. We observed that epidermal LC within a human hand allograft remain stable in the long term (10 years) and are not replaced by cells of recipient's origin; furthermore, we observed a Langerhans cell in mitosis within the epidermis 8 years postgraft. These results show that under almost physiological conditions, human LC renew in the epidermis by local mitoses of preexisting cells. PMID- 20707813 TI - A novel in vitro assay for electrophysiological research on human skin fibroblasts: degenerate electrical waves downregulate collagen I expression in keloid fibroblasts. AB - Electrical stimulation (ES) has been used for the treatment of wounds and has been shown to alter gene expression and protein synthesis in skin fibroblasts in vitro. Here, we have developed a new in vitro model system for testing the effects of precisely defined, different types of ES on the collagen expression of normal and keloid human skin fibroblasts. Keloid fibroblasts were studied because they show excessive collagen production. Both types of fibroblasts were electrically stimulated with alternating current (AC), direct current (DC) or degenerate waves (DW). Cells were subjected to 20, 75 and 150mV/mm electric field strengths at 10 and 60Hz frequencies. At lower electric fields, all types of ES upregulated collagen I in both cell types compared to controls. However, at higher electric field strength (150mV/mm) and frequency (60Hz), DW maximally downregulated collagen I in keloid fibroblasts, yet had significantly lower cytotoxic effects on normal fibroblasts than AC and DC. Compared to unstimulated cells, both normal skin and keloid fibroblasts showed a significant decrease in collagen I expression after 12h of DW and AC stimulation. In contrast, increasing amplitude of DC upregulated collagen I and PAI-1 gene transcription in normal and keloid fibroblasts, along with increased cytotoxicity effects. Thus, our new preclinical assay system shows highly differential effects of specific types of ES on human fibroblast collagen expression and cytotoxicity and identifies DW of electrical current (DW) as a promising, novel therapeutic strategy for suppressing excessive collagen I formation in keloid disease. PMID- 20707814 TI - Resource quantity and seasonal background alter warming effects on communities of biofilm ciliates. AB - The impacts of experimental warming on field-related communities of biofilm ciliates were studied in contrasting seasons (winter vs. summer), which incorporated both different species sets and environmental background conditions. The biofilms for the experiments were cultivated in river bypass systems that were exposed to increasing temperatures based on the ambient river temperature. Opposing effects of warming were observed for ciliate 'summer' and 'winter' communities. While winter warming resulted in both stimulation (abundance and biomass) of the ciliate communities and significant shifts in the community structure, summer warming induced a significant decline in the ciliate biomass, but did not affect the relative community composition. By the simultaneous manipulation of temperature and resource density in summer, it was demonstrated that negative warming effects on the ciliate quantity during summer could be compensated by increasing the availability of food. Taken together, our results indicate that the responses of ciliate communities towards warming are strongly coupled to the availability of resources, and that the strongest impacts of environmental warming should thus be expected in resource-rich environments. PMID- 20707815 TI - Postbiostimulation microbial community structure changes that control the reoxidation of uranium. AB - This study evaluated the influence of changes in the microbial community structure on reoxidation of reduced uranium during a postbiostimulation period. Effluent groundwater from acetate-stimulated sediment flow-through columns was analyzed over 60 days after acetate amendment was discontinued. Only a small reoxidation of iron or uranium (17%) occurred in the presence of 1-2 mg L(-1) O(2) influent groundwater for the 2-month period. Most uranium reoxidation occurred during the first 2 weeks after biostimulation with acetate was discontinued. Groundwater and sediment microbial community compositions suggested that two processes played important roles immediately after the cessation of acetate addition. The first process was characterized by a predominance of both sediment-bound and planktonic microorganisms most closely related to Hydrogenophaga sp., Thiobacillus sp., and Gallionella sp., which could oxidize a variety of reduced compounds. The second process was characterized by organisms closely related to Lysobacter sp. and Sterolibacterium sp., with the potential to feed on complex organic compounds from biomass turnover. The presence of these bacteria and the lack of uranium oxidation implied that after acetate addition was stopped, reduced inorganic compounds and dead biomass became electron donors for a microbial community capable of using low ambient oxygen as a terminal electron acceptor, contributing to the preservation, at least temporarily, of biogenic U(IV). PMID- 20707816 TI - Influence of the papiliocin peptide derived from Papilio xuthus on the perturbation of fungal cell membranes. AB - Papiliocin is a 37-residue peptide isolated from the swallowtail butterfly Papilio xuthus. In this study, the antifungal effects and the mechanism of actions of papiliocin were investigated. First of all, papiliocin was shown to exert fungicidal activity. To understand the antifungal mechanism(s), propidium iodide influx into Candida albicans cells, induced by papiliocin, was examined. The result indicated that papiliocin perturbed and disrupted the fungal plasma membrane. Furthermore, calcein leakage from large unilamellar vesicles and rhodamine leakage from giant unilamellar vesicles further confirmed and visualized the membrane-disruptive action of papiliocin in the fungal model membrane, respectively. In summary, the present study suggests that papiliocin exerts its antifungal activity by a membrane-active mechanism and that this peptide can be developed into novel potent antifungal agents. PMID- 20707817 TI - Analysis of plasmid diversity in 96 Rhodococcus equi strains isolated in Normandy (France) and sequencing of the 87-kb type I virulence plasmid. AB - To characterize the potential epidemiological relationship between the origin of Rhodococcus equi strains and the type of their virulence plasmids, we performed a comparative analysis of virulence plasmid types encountered in 96 R. equi strains isolated from (1) autopsied horses, (2) organic samples (horse faeces, manure and straw) and (3) environmental samples. Our results revealed no clear epidemiological link between virulence plasmid type and the origin of R. equi strains isolated from horse-related environments. To understand this result, we determined the nucleotide sequence of the second most frequently isolated virulence plasmid type: a 87-kb type I (pVAPA116) plasmid and compared it with the previously sequenced (and most commonly encountered) 85-kb type I (pVAPA1037) plasmid. Our results show that the divergence between these two plasmids is mainly due to the presence of three allelic exchange loci, resulting in the deletion of two genes and the insertion of three genes in pVAPA116 compared with pVAPA1037. In conclusion, it appears that the divergence between the two sequenced rhodococcal virulence plasmids is not associated with the vap pathogenicity island and may result from an evolutionary process driven by a mobility-related invertase/resolvase invA-like gene. PMID- 20707818 TI - The combination of minocycline and fluconazole causes synergistic growth inhibition against Candida albicans: an in vitro interaction of antifungal and antibacterial agents. AB - Combination therapy can be used for the treatment of fungal infections, especially for those caused by antifungal-resistant fungi. In the present study, in vitro interactions and mechanisms between fluconazole and minocycline against Candida albicans were evaluated. The nature of the interactions determined by spectrophotometric method in a checkerboard assay was interpreted using nonparametric models of fractional inhibitory concentration index (FICI) and percentages of growth difference (DeltaE). In the mechanism study, we evaluated the potential activity of minocycline on fluconazole penetrating the C. albicans biofilm. Furthermore, the effect of fluconazole and minocycline alone and in combination on the cellular calcium balance, as well as on the uptake and efflux of fluconazole were evaluated. It was found that fluconazole can work synergistically with minocycline against fluconazole-resistant C. albicans; the minimum inhibitory concentration of fluconazole decreased from 512 to 2 microgmL( 1) when fluconazole and minocycline were given in combination, with an FICI of 0.035 and 0.064 and high-percentage synergistic interactions of 1250% and 988% for the two resistant strains. The mechanism of action was suggested to be the enhancement of minocycline on fluconazole penetrating biofilm, and inducing the intracellular calcium release, instead of impacting on the uptake and efflux of fluconazole. Our results suggest that the combination of fluconazole and minocycline can reduce the fluconazole resistance of C. albicans in vitro. PMID- 20707819 TI - Coexpression of fungal phytase and xylanase utilizing the cis-acting hydrolase element in Pichia pastoris. AB - Plant-based animal feed contains antinutritive agents, necessitating the addition of digestive enzymes in commercial feeds. Enzyme additives are costly because they are currently produced separately from recombinant sources. The coexpression of digestive enzymes in a single recombinant cell system would thus be advantageous. A coexpression system for the extracellular production of phytase and xylanase was established in Pichia pastoris yeast. The genes for each enzyme were fused in-frame with the alpha-factor secretion signal and linked by the 2A peptide-encoding sequence. Each enzyme was expressed extracellularly as individual functional proteins. The specific activities of 2A-expressed phytase (PhyA-2A) and 2A-expressed xylanase (XylB-2A) were 9.3 and 97.3 U mg(-1) , respectively. Optimal PhyA-2A activity was observed at 55 degreesC and pH 5.0. PhyA-2A also exhibited broad pH stability from 2.5 to 7.0 and retained approximately 70% activity after heating at 90 degreesC for 5 min. Meanwhile, XylB-2A exhibited optimal activity at 50 degreesC and pH 5.5 and showed pH stability from 5.0 to 8.0. It retained >50% activity after incubation at 50 degreesC for 10 min. These enzyme properties are similar to those of individually expressed recombinant enzymes. In vitro digestibility test showed that PhyA-2A and XylB-2A are as efficient as individually expressed enzymes for hydrolyzing phytate and crude fiber in feedstuff, respectively. PMID- 20707820 TI - Vaccines based on whole recombinant Saccharomyces cerevisiae cells. AB - The ultimate goal of therapeutic vaccines is to activate and exploit the patient's own immune system to vigorously and dynamically seek and eradicate established malignant or virally infected cells. Therapeutic vaccines also offer the potential for preventing disease recurrence. Saccharomyces cerevisiae-based vaccines, where the yeast is engineered to express viral or tumor antigens, represent an ideal therapeutic approach due to their ability to stimulate tumor- or viral-specific CD4(+) and CD8(+) T-cell responses that are capable of reducing disease burden. This review describes preclinical and clinical studies supporting the development of S. cerevisiae-based therapeutic vaccines for the treatment of cancer and viral diseases, as well as multimodal strategies in which therapeutic vaccines are combined with cytotoxic drugs to achieve a greater clinical response. PMID- 20707821 TI - Unnoticed ingestion of dislodged fixed prosthesis in an elderly patient. PMID- 20707822 TI - Implementation of antiretroviral therapy adherence interventions: a realist synthesis of evidence. AB - AIM: This paper is a report of a synthesis of evidence on implementation of interventions to improve adherence to antiretroviral therapy. BACKGROUND: Evidence on efficacy must be supplemented with evidence on how interventions were implemented in practice and on how that implementation varied across populations and settings. DATA SOURCES: Sixty-one reports were reviewed of studies conducted in the United States of America in the period 2001 to December 2008. Fifty-two reports were included in the final analysis: 37 reporting the effects of interventions and 15 reporting intervention feasibility, acceptability, or fidelity. REVIEW METHODS: An adaptation of Pawson's realist synthesis method was used, whereby a provisional explanatory model and associated list of propositions are developed from an initial review of literature. This model is successively refined to the point at which it best explains empirical findings from the reports reviewed. RESULTS: The final explanatory model suggests that individuals with HIV will be more likely to enroll in interventions that protect their confidentiality, to attend when scheduling is responsive to their needs, and both to attend and continue with an intervention when they develop a strong, one-to one relationship with the intervener. Participants who have limited prior experience with antiretroviral therapy will be more likely to continue with an intervention than those who are more experienced. Dropout rates are likely to be higher when interventions are integrated into existing delivery systems than when offered as stand-alone interventions. CONCLUSION: The explanatory model developed in this study is intended to provide guidance to clinicians and researchers on the points in the implementation chain that require strengthening. PMID- 20707824 TI - Movement behaviour within and beyond perceptual ranges in three small mammals: effects of matrix type and body mass. AB - 1. For animal species inhabiting heterogeneous landscapes, the tortuosity of the dispersal path is a key determinant of the success in locating habitat patches. Path tortuosity within and beyond perceptual range must differ, and may be differently affected by intrinsic attributes of individuals and extrinsic environmental factors. Understanding how these factors interact to determine path tortuosity allows more accurate inference of successful movements between habitat patches. 2. We experimentally determined the effects of intrinsic (body mass and species identity) and extrinsic factors (distance to nearest forest fragment and matrix type) on the tortuosity of movements of three forest-dwelling didelphid marsupials, in a fragmented landscape of the Atlantic Forest, Brazil. 3. A total of 202 individuals were captured in forest fragments and released in three unsuitable matrix types (mowed pasture, abandoned pasture and manioc plantation), carrying spool-and-line devices. 4. Twenty-four models were formulated representing a priori hypotheses of major determinants of path tortuosity, grouped in three scenarios (only intrinsic factors, only extrinsic factors and models with combinations of both), and compared using a model selection approach. Models were tested separately for individuals released within the perceptual range of the species, and for individuals released beyond the perceptual range. 5. Matrix type strongly affected path tortuosity, with more obstructed matrix types hampering displacement of animals. Body mass was more important than species identity to determine path tortuosity, with larger animals moving more linearly. Increased distance to the fragment resulted in more tortuous paths, but actually reflects a threshold in perceptual range: linear paths within perceptual range, tortuous paths beyond. 6. The variables tested explained successfully path tortuosity, but only for animals released within the perceptual range. Other factors, such as wind intensity and direction of plantation rows, may be more important for individuals beyond their perceptual range. 7. Simplistic scenarios considering only intrinsic or extrinsic factors are inadequate to predict path tortuosity, and to infer dispersal success in heterogeneous landscapes. Perceptual range represents a fundamental threshold where the effects of matrix type, body mass and individual behaviour change drastically. PMID- 20707825 TI - Partial migration in tropical birds: the frontier of movement ecology. AB - Partial migration, in which only some individuals of a species migrate, might be central to the evolution of migratory behaviour and is likely to represent an evolutionary transition between sedentariness and complete migration. In one of the few detailed, individual-based migration studies of tropical birds, Jahn et al. study the partial migration system of a South American bird species for the first time. Food limitation forces the large adult males and small, young females to migrate, contrary to the expectations of the body size and dominance hypotheses. This study confirms the importance of food variability as the primary driver of migratory behaviour. There is urgent need for similar studies on the movement ecology of understudied tropical bird species, whose diversity of migratory behaviour can shed light on the evolution of bird migration. PMID- 20707826 TI - Long-term effects of a home-visiting intervention for depressed mothers and their infants. AB - BACKGROUND: Whereas preventive interventions for depressed mothers and their infants have yielded positive short-term outcomes, few studies have examined their long-term effectiveness. The present follow-up of a randomised controlled trial (RCT) is one of the first to examine the longer-term effects of an intervention for mothers with postpartum depression and their infants at school age. In early infancy, the intervention was found effective in improving mother infant interaction and the child's attachment to its mother. METHODS: Twenty-nine mother-child pairs who completed the intervention are compared with 29 untreated mother-child dyads as to the quality of maternal interactive behaviour and the child outcomes of attachment security to the mother, self-esteem, ego-resiliency, verbal intelligence, prosocial behaviour, school adjustment, and behaviour problems at age 5 (M=68 months). RESULTS: In the total sample no lasting treatment benefits were found, but in families reporting a higher number of stressful life events, children in the intervention group had fewer externalising behaviour problems as rated by their mothers than children in the control group. CONCLUSIONS: In the context of multiple stressful life events the intervention served as a buffer by preventing the development of externalising problems in the child. The results warrant cautious interpretation because of the relatively small sample size and differential attrition revealing the mothers that completed the follow-up assessment to have improved less on maternal sensitivity following the intervention than the mothers who did not participate in the follow-up. PMID- 20707827 TI - Periacineta mexicana n. sp. (Ciliophora, Suctoria, Discophryida), epizoic on Mexican backswimmers of the genus Buenoa (Insecta, Hemiptera, Notonectidae). AB - A new species of suctorian in the genus Periacineta, epibiotic on aquatic bugs (Hemiptera, Heteroptera, Nepomorpha), is described on the basis of morphological characteristics of the cell body, lorica, tentacular placement, and stalk, and its 18S rRNA partial sequence gene. Periacineta mexicana n. sp. is a loricate suctorian with elongate body and rounded apical region; tentacles are distributed randomly over apical region and not grouped into fascicles. Macronucleus in adult is elongate and located centrally. The suctorian usually forms closely aggregated pseudocolonies. We provide morphological data based on optical and scanning electron microscopy. A comparison with similar congeners, and emended diagnosis of the genus Periacineta also are provided. The ciliates were found attached to the first two pairs of legs of Mexican notonectids Buenoa pallens and Buenoa spp. (backswimmers). PMID- 20707828 TI - Evidence for rosettes as an unrecognized stage in the life cycle of Leishmania parasites. AB - Leishmania parasites, which afflict 12 million people in 88 countries, exist as promastigotes transmitted by insect vectors and as amastigotes residing in mammalian macrophages. Promastigote cells arranged in rosettes have also been described but universally disregarded as a distinct stage in the life cycle. We present evidence that only rosettes of Leishmania major promastigotes express cell surface poly-alpha2,8 N-acetyl neuraminic acid (PSA) and PSA containing de-N acetyl neuraminic acid (NeuPSA). Expression of rosette-specific PSA antigens was mosaic, with individual promastigotes expressing PSA, NeuPSA or both. A 50 kDa protein was detected by Western blot analysis of a detergent-insoluble cell fraction with both PSA and NeuPSA-reactive antibodies. Frequencies of rosette formation as well as cell surface PSA/NeuPSA expression were temperature dependent. Rosettes also engaged in an unusual swarming behavior, congregating into extended clusters. Distinct structures resembling cellular fusion bodies were formed in and released from rosettes. The results indicate that rosettes are an unrecognized stage in the life cycle of Leishmania. We hypothesize that rosettes initiate mating in Leishmania during which PSA/NeuPSA expression plays an important role. Recognizing rosettes as a distinct form of the Leishmania life cycle opens new possibilities for treatment or prevention of disease and, possibly, in vitro genetic recombination without passage of cells through insect vectors. PMID- 20707829 TI - Infliximab efficacy in nail psoriasis. A retrospective study in 48 patients. AB - BACKGROUND: Nail psoriasis occurs in up to half of psoriatic patients and can lead to significant physical impairment and pain. To date, patients and clinicians are actually dissatisfied by current therapeutic approaches. OBJECTIVE: Our main aim is to evaluate Infliximab efficacy in nail psoriasis. METHODS: We performed an open-label and uncontrolled retrospective study considering all psoriatic patients presenting recalcitrant nail involvement and receiving Infliximab in our Department during the period between January 2008 and March 2009. We calculated nail psoriasis severity index (NAPSI) score at 0, 14, 22 and 38 weeks and percentage of patients achieving NAPSI-50,-75,-90 at 14, 22 and 38 weeks. RESULTS: We observed a rapid nail improvement in most cases after 22 weeks of Infliximab therapy, but a complete nail clearing was reached in only five (10.4%) patients. We don't have a follow-up longer than 38 weeks to assess long-term efficacy of this treatment in nail psoriasis. CONCLUSIONS: Infliximab, in our experience, has proved to be effective in reducing nail lesions and, in some cases, even clearing them. Our data demonstrate long-term efficacy of this biological agent in nail psoriasis. PMID- 20707830 TI - The role of fantasy in a serial sexual offender: a brief review of the literature and a case report. AB - Extensive research has attempted to elucidate the role of fantasy in sexual offending. In this paper, the authors summarize the main results of the literature, especially the contents, themes, dynamics, etiopathogenesis, and potential functions of fantasy in sexual offending. Further, the authors analyze the case of a serial sexual offender who assaulted 39 women. The forensic psychiatric assessment revealed that his fantasies of forced sex, sexual coercion, and dominance, which were linked to narcissistic personality organization and functioning, were the primary drive mechanism in his crimes, because he imagined himself in the role of the aggressor, identified with the power associated with the role of perpetrator, and was sexually aroused by such images of omnipotent control of the victim. In conclusions, the authors suggest that fantasies of sexual aggression, coercion, and dominance of women may stimulate grandiosity and omnipotence and, in a minority of cases, may lead to sexual offending. PMID- 20707831 TI - Testing discriminant functions for sex determination from deciduous teeth. AB - Three studies have proposed discriminant functions for sex determination from deciduous tooth crown dimensions, and this study tests the existing functions on a sample of 46 Portuguese immature skeletons of known sex, aged from birth to 10 years. Deciduous teeth were measured in their mesiodistal and faciolingual crown dimensions, and percentage of correct allocation accuracy in determining sex using each specific function was determined. Discriminant functions were also calculated from data collected for this study and tested using cross-validation. Results show poor overall accuracy (33.3-75%) and poor cross-validation (46.2 60.0%). This is related to low sexual dimorphism in deciduous tooth crown size, as well as differences in degree of sexual dimorphism and in overall tooth size between different samples. For these reasons, deciduous crown size does not seem to show significant forensic value as discriminator of sex, particularly when methods developed on one population are applied to individuals of another population. PMID- 20707832 TI - Validation of a DNA quantitation method on the Biomek(r) 3000. AB - Laboratory automation has the ability to increase the throughput and efficiency of laboratory processes to keep pace with current backlogs and requests for analysis. This paper addresses the specific studies employed to properly evaluate an automated method for DNA quantitation setup using Applied Biosystems QuantifilerTM Human DNA Quantification kit on a Biomek(r) 3000. The calibration of robotic pipetting as well as comparison with manually performed steps confirmed the accuracy of the automated methods used. Reproducibility studies evaluated differences between robotic and manually prepared human DNA standard curves. Additional studies examined DNA samples of known quantities, extract storage formats, sensitivity, and an assessment of contamination. The Biomek(r) 3000 not only demonstrated reproducibility and accuracy that equaled or surpassed the manual method but also revealed a contamination-free method to replace the multiple pipetting steps required during quantitation setup. PMID- 20707833 TI - Application of postmortem 3D-CT facial reconstruction for personal identification. AB - Postmortem computed tomography (CT) images can show internal findings related to the cause of death, and it can be a useful method for forensic diagnosis. In this study, we scanned a ready-made box by helical CT on 2-mm slices in a mobile CT scanner and measured each side of the box to assess whether reconstructed images are useful for superimposition. The mean difference between the actual measurements and the measurements on the three-dimensional (3D) reconstructed images (3D-CT images) is 0.9 mm; we regarded it as having no effect on reconstruction for the superimposition method. Furthermore, we could get 3D-CT images of the skull, which were consistent with the actual skull, indicating that CT images can be applied to superimposition for identification. This study suggested that postmortem CT images can be applied as superimpositions for unidentified cases, and thinner slices or cone beam CT can be a more precise tool. PMID- 20707834 TI - Forensic approach to an archaeological casework of "vampire" skeletal remains in Venice: odontological and anthropological prospectus. AB - During the years 2006-2007, the Archeological Superintendent of Veneto (Italy) promoted a research project on mass graves located on Nuovo Lazzaretto in Venice, where the corpses of plague deaths were buried during the 16th and 17th centuries. The burials were of different stages and are believed to be the remains of plague victims from the numerous outbreaks of pestilence, which occurred between the 15th and 17th centuries. Among the fragmented and commingled human bones, an unusual burial was found. The body was laid supine, with the top half of the thorax intact, arms parallel to the rachis axis, the articulations were anatomically unaltered. Both the skull morphology and the dimensions of the caput omeris suggest the body was a woman. A brick of moderate size was found inside the oral cavity, keeping the mandible wide open. The data collected by the anthropologist were used to generate a taphonomic profile, which precluded the positioning of the brick being accidental. Likewise, the probability of the brick having come from the surrounding burial sediment was rejected, as the only other inclusions found were bone fragments from previous burials in the same area. The data collected by the odontologist were employed for age estimation and radiological dental assessment. The forensic profile was based conceptually on the "circumstances of death" and concluded that the positioning of the brick was intentional, and attributed to a symbolic burial ritual. This ritual confirms the intimate belief held at those times, between the plague and the mythological character of the vampire. PMID- 20707835 TI - Initial results on the composition of fingerprints and its evolution as a function of time by GC/MS analysis. AB - Determining the time since deposition of fingermarks may prove necessary to assess their relevance to criminal investigations. The crucial factor is the initial composition of fingermarks, because it represents the starting point of any aging model. This study mainly aimed to characterize the initial composition of fingerprints, which show a high variability between donors (inter variability), but also to investigate the variations among fingerprints from the same donor (intra-variability). Solutions to reduce this initial variability using squalene and cholesterol as target compounds are proposed and should be further investigated. The influence of substrates was also evaluated, and the initial composition was observed to be larger on porous surface than nonporous surfaces. Preliminary aging of fingerprints over 30 days was finally studied on a porous and a nonporous substrate to evaluate the potential for dating of fingermarks. Squalene was observed to decrease in a faster rate on a nonporous substrate. PMID- 20707836 TI - Sudden and unexpected death in three cases of Ehlers-Danlos syndrome type IV. AB - Ehlers-Danlos syndrome (EDS) type IV is a connective tissue disorder characterized by the inability to produce sufficient amounts of collagen or a defect in the structure of collagen. The most serious complications include a rupture of a viscus or vascular rupture with or without mural dissection. Death may result from internal hemorrhage. This report describes three cases of sudden and unexpected death caused by EDS type IV. Two cases involved hemothorax as a result of dissection of the subclavian artery and aorta, respectively. The third case represented spontaneous pulmonary rupture and hemorrhage. A detailed family history should be sought, and additional specimens collected to confirm the diagnosis, including skin fibroblasts for collagen testing and blood for DNA testing. The forensic pathologist should consider the possibility of EDS type IV upon discovery of spontaneous visceral or arterial rupture and should alert the family members of this hereditary and potentially fatal condition. PMID- 20707837 TI - The recovery and persistence of salivary DNA on human skin. AB - Salivary DNA is encountered in many crimes, such as sexual assaults and murders. In this study, saliva from three male donors was deposited on the skin of three female recipients. The amount of male salivary DNA remaining on the female skin was measured over a 96-h period using the QuantifilerTM Y Human Male DNA Quantification Kit. In eight of the nine experiments, a full male DNA profile matching the donor was obtained even after 96 h. In addition, the study showed that the concentration of salivary DNA varied from donor to donor and from day to day. The efficiency of two recovery methods, wet and dry swabbing and minitaping, was compared. The results indicate the tapelift method gave higher DNA recovery. This study also examined the secondary transfer of salivary DNA from skin to fabrics. Cotton and polyester give higher DNA transfer than leather. PMID- 20707838 TI - The role of bronchoscopy in foreign body removal in dogs and cats: 37 cases (2000 2008). AB - BACKGROUND: Foreign body aspiration is a differential diagnosis for acute or chronic cough that requires medical or surgical management in animals. HYPOTHESIS: Success of bronchoscopy in airway foreign body removal is dependent on the size of the animal, duration of clinical signs, and location of the foreign body. ANIMALS: Thirty-two dogs and 5 cats with airway foreign bodies identified at the UC Davis Veterinary Medical Teaching Hospital. METHODS: Retrospective case study evaluating the role of duration of clinical signs and body size in successful bronchoscopic removal of foreign bodies. In addition, radiographic localization of disease was compared with bronchoscopic identification. Bronchoalveolar lavage (BAL) culture and cytologic findings are reported. RESULTS: Bronchoscopy was successful for removal of airway foreign bodies in 76% of animals (24/28 dogs and 2/5 cats), and in dogs was independent of duration of clinical signs or body size. One-third of thoracic radiographs lacked distinctive features of an airway foreign body, and therefore radiography was unable to predict the affected site. BAL fluid at the site of the foreign body contained more neutrophils and more often had intracellular bacteria than lavage fluid from a separate site. CONCLUSIONS AND CLINICAL IMPORTANCE: Bronchoscopy was successful in removing airway foreign bodies regardless of animal size or long duration of clinical signs. Results of this study confirm the utility of bronchoscopy with lavage in management of suspected foreign bodies, even in the absence of localizing radiographic findings. PMID- 20707839 TI - Evaluation of a quality-of-life tool for cats with diabetes mellitus. AB - BACKGROUND: Success in management of diabetes mellitus (DM) is defined as improvement of blood glucose concentrations and clinical signs. However, the psychological and social impact of DM and its daily treatment regimen on quality of life (QoL) of both animal and owner is uncertain. HYPOTHESIS/OBJECTIVES: To design, validate, and apply a diabetic pet and owner-centered, individualized measure of impact of DM (DIAQoL-pet). ANIMALS/SUBJECTS: Two hundred and twenty one owners of insulin-treated diabetic cats were recruited to complete the DIAQoL pet. METHODS: Discussions and pilot surveys with clinicians and owners of diabetic cats led to the design of 29 specific DM-associated QoL questions. Owners of diabetic cats completed the finalized survey. Each item was scored according to impact frequency and perceived importance. An item-weighted impact score (IWIS) for each item was calculated, as was an average-weighted impact score (AWIS) by averaging all IWISs. Principal component analysis and Cronbach's alpha calculation assessed the measure's reliability. Two overview questions measured overall QoL and diabetes-dependent QoL. RESULTS: The DIAQoL-pet showed high reliability (Cronbach alpha 0.83). The AWIS was -1.76 +/- 2.4 (mean +/- SD). Areas reported as most negatively impacting QoL included: "boarding difficulties" (IWIS +/- SD: -4.67 +/- 5.3), "owner wanting more control" (-4.34 +/- 4.7), "difficulties leaving cat with friends or family" (-4.21 +/- 4.7), "worry" (-4.10 +/- 3.9), "worry hypo" (-3.67 +/- 3.5), "social life" (-3.48 +/- 3.9), "costs" ( 3.04 +/- 3.8), and "work life" (-3.03 +/- 3.7). Forty-one percent of owners believed their cat's life would be "a little better" without DM. CONCLUSIONS AND CLINICAL IMPORTANCE: The DIAQoL-pet proved robust and identified specific areas most negatively impacting on diabetic cats and their owners' QoL. This tool warrants further investigation for use in clinical or research settings. PMID- 20707840 TI - Urinary catecholamine and metanephrine to creatinine ratios in dogs with hyperadrenocorticism or pheochromocytoma, and in healthy dogs. AB - BACKGROUND: Urinary catecholamines and metanephrines are used for the diagnosis of pheochromocytoma (PHEO) in dogs. Hyperadrenocorticism (HAC) is an important differential diagnosis for PHEO. OBJECTIVES: To measure urinary catecholamines and metanephrines in dogs with HAC. ANIMALS: Fourteen dogs with HAC, 7 dogs with PHEO, and 10 healthy dogs. METHODS: Prospective clinical trial. Urine was collected during initial work-up in the hospital; in dogs with HAC an additional sample was taken at home 1 week after discharge. Parameters were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. RESULTS: Dogs with HAC had significantly higher urinary epinephrine, norepinephrine and normetanephrine to creatinine ratios than healthy dogs. Urinary epinephrine, norepinephrine, and metanephrine to creatinine ratios did not differ between dogs with HAC and dogs with PHEO, whereas the urinary normetanephrine to creatinine ratio was significantly higher (P= .011) in dogs with PHEO (414, 157.0-925.0, median, range versus (117.5, 53.0-323.0). Using a cut-off ratio of 4 times the highest normetanephrine to creatinine ratio measured in controls, there was no overlap between dogs with HAC and dogs with PHEO. The variables determined in urine samples collected at home did not differ from those collected in the hospital. CONCLUSION AND CLINICAL IMPORTANCE: Dogs with HAC might have increased concentrations of urinary catecholamines and normetanephrine. A high concentration of urinary normetanephrine (4 times normal), is highly suggestive of PHEO. PMID- 20707841 TI - Utility of 2 immunological tests for antemortem diagnosis of equine protozoal myeloencephalitis (Sarcocystis neurona Infection) in naturally occurring cases. AB - BACKGROUND: Antemortem diagnosis of equine protozoal myeloencephalitis (EPM) is challenging. Limited information is available regarding a commercial test (surface antigen 1 [SAG-1] ELISA). Performance of another commercial test (indirect fluorescent antibody test [IFAT]) using samples from an independent group has not been well described. HYPOTHESIS/OBJECTIVES: The primary goal was to evaluate the SAG-1 ELISA and IFAT using naturally occurring EPM cases. A secondary goal was to obtain more information regarding clinical presentation. ANIMALS: Hospital cases were admitted over 20 months and classified into 4 groups. Confirmed positive cases (n = 9) had asymmetric or multifocal neurologic deficits or both and postmortem lesions consistent with EPM. Confirmed negative cases (n = 17) had variable clinical signs and postmortem lesions consistent with another neurologic disease (or no lesions). Suspected positive cases (n = 10) had asymmetric or multifocal deficits or both, marked improvement after treatment for EPM, and other likely diseases excluded. Suspected negative cases (n = 29) had orthopedic disease and no neurologic deficits. METHODS: Results of immunological testing (SAG-1 ELISA and IFAT on serum or cerebrospinal fluid [CSF] or both), neurologic examinations, CSF analyses, and postmortem examinations were analyzed retrospectively. RESULTS: SAG-1 ELISA sensitivity was 12.5% (95% CI, 1.6-38.4) and specificity was 97.1% (95% CI, 84.7-99.9) using serum. IFAT sensitivity was 94.4% (95% CI, 72.7-99.9) and specificity was 85.2% (95% CI, 66.3-95.8) using serum; sensitivity was 92.3% (95% CI, 64.0-99.8) and specificity was 89.7% (95% CI, 72.7-97.8) using CSF. CONCLUSIONS AND CLINICAL IMPORTANCE: Low sensitivity of the SAG-1 ELISA limited its usefulness for antemortem diagnosis of EPM in this patient population. PMID- 20707842 TI - Use of Simpson's method of disc to detect early echocardiographic changes in Doberman Pinschers with dilated cardiomyopathy. AB - BACKGROUND: M-mode is the echocardiographic gold standard to diagnose dilated cardiomyopathy (DCM) in dogs, whereas Simpson's method of discs (SMOD) is the preferred method to detect echocardiographic evidence of disease in humans. OBJECTIVES: To establish reference values for SMOD and to compare those with M mode measurements. ANIMALS: Nine hundred and sixty-nine examinations of 471 Doberman Pinschers. METHODS: Using a prospective longitudinal study design. Reference values for SMOD were established using 75 healthy Doberman Pinschers >8 years old with <50 ventricular premature contractions (VPCs) in 24 hours. The ability of the new SMOD cut-off values, normalized to body surface area (BSA), for left ventricular end-diastolic volume (LVEDV/BSA >95mL/m(2) ) and end systolic volume (LVESV/BSA > 55mL/m(2) ) to detect echocardiographic changes in Doberman Pinschers with DCM was compared with currently recommended M-mode values. Dogs with elevated SMOD values but normal M-mode measurements were followed-up using a prospective longitudinal study design. RESULTS: At the final examination 175 dogs were diagnosed with DCM according to both methods (M-mode and SMOD). At previous examinations, M-mode values were abnormal in 142 examinations only, whereas all 175 SMOD already had detected changes. Additionally, 19 of 154 dogs with >100 VPCs/24 hours and normal M-mode values had abnormal SMOD measurement. Six dogs with increased SMOD measurements remained healthy at several follow-up examinations (classified as false positive); in 24 dogs with increased SMOD measurements, no follow-up examinations were available (classified as unclear). CONCLUSIONS AND CLINICAL IMPORTANCE: SMOD measurements are superior to M-mode to detect early echocardiographic changes in Dobermans with occult DCM. PMID- 20707843 TI - The effects of pentoxifylline on equine platelet aggregation. AB - BACKGROUND: Pentoxifylline (PTX) possesses a number of vasomotor, immunomodulatory, and hemorheologic properties. Based upon the hypothesis that equine laminitis and navicular disease result from microthrombosis, the inhibitory effects of PTX on inflammatory cytokines, and its inhibitory effects on human platelet aggregation, PTX has been widely used to treat equine endotoxemia, navicular disease, and laminitis. Despite this, the effects of PTX on equine platelet aggregation have not been investigated previously. HYPOTHESIS: PTX decreases platelet aggregation in equine whole blood at concentrations approximating those achieved in horses given clinically relevant doses of PTX. ANIMALS: Seven healthy adult horses from a research herd. METHODS: Whole blood impedance aggregometry using whole equine blood incubated with varying concentrations of PTX. Adenosine diphosphate (ADP) and collagen were used to initiate aggregation. RESULTS: The onset time of collagen-induced equine platelet aggregation was significantly shortened by PTX. The maximum slope of resistance change (dR/dt) and total resistance change of collagen-induced platelet aggregation were unaffected by PTX. No effects of PTX on ADP-induced onset time of aggregation, dR/dt, or total resistance change were observed. CONCLUSIONS AND CLINICAL IMPORTANCE: Our hypothesis is not supported by the results. PTX hastens the onset of collagen-induced platelet aggregation in equine whole blood, but has no effect on the rate of collagen-induced aggregation. PTX does not affect ADP dependent equine platelet aggregation. Given these findings, PTX may not be a reasonable therapeutic option to decrease platelet aggregation in horses. PMID- 20707844 TI - Clinical features and prognostic variables in 109 horses with esophageal obstruction (1992-2009). AB - BACKGROUND: Esophageal obstruction is common in horses and can result in life threatening complications. Previous studies have described clinical findings in horses with esophageal obstruction, but there are no reports that attempt to make correlations of clinical findings with outcome. HYPOTHESIS: Specific clinical features of horses with esophageal obstruction are associated with increased likelihood of complications. ANIMALS: One hundred and nine horses with esophageal obstruction. METHODS: Retrospective cross-sectional study. All clinical records of horses admitted between April 1992 and February 2009 for esophageal obstruction were reviewed. The association among 24 clinical, hematological, biochemical, therapeutic variables and the likelihood of complications was investigated by a univariable logistic regression model, followed by multivariable analysis. RESULTS: Multiple logistic regression analysis revealed that intact males (P= .02), age >15 years (P < .01), and a need for general anesthesia (P < .01) were associated with the development of complications after an episode of esophageal obstruction. Increased respiratory rate (>22 breaths/min) and moderate or severe tracheal contamination, although not associated with complications as a whole, significantly increased the risk of developing aspiration pneumonia (P<= .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Signalment, clinical variables, and endoscopic findings were confirmed as important tools in assessing the severity of the esophageal lesion and pulmonary involvement. Knowledge of risk factors for the development of complications will aid in making informed decisions to optimize treatment and assist in the assessment of prognosis. PMID- 20707845 TI - Dose-titration effects of fish oil in osteoarthritic dogs. AB - BACKGROUND: Food supplemented with fish oil improves clinical signs and weight bearing in dogs with osteoarthritis (OA). OBJECTIVE: Determine whether increasing the amount of fish oil in food provides additional symptomatic improvements in OA. ANIMALS: One hundred and seventy-seven client-owned dogs with stable chronic OA of the hip or stifle. METHODS: Prospective, randomized clinical trial using pet dogs. Dogs were randomly assigned to receive the baseline therapeutic food (0.8% eicosopentanoic acid [EPA] + docosahexaenoic acid [DHA]) or experimental foods containing approximately 2- and 3-fold higher EPA+DHA concentrations. Both veterinarians and owners were blinded as to which food the dog received. On days 0, 21, 45, and 90, serum fatty acid concentrations were measured and veterinarians assessed the severity of 5 clinical signs of OA. At the end of the study (day 90), veterinarians scored overall arthritic condition and progression of arthritis based on their clinical signs and an owner interview. RESULTS: Serum concentrations of EPA and DHA rose in parallel with food concentrations. For 2 of 5 clinical signs (lameness and weight bearing) and for overall arthritic condition and progression of arthritis, there was a significant improvement between the baseline and 3X EPA+DHA foods (P=.04, .03, .001, .0008, respectively) but not between the baseline and the 2X EPA+DHA foods. CONCLUSIONS AND CLINICAL IMPORTANCE: Increasing the amount of fish oil beyond that in the baseline food results in dose-dependent increases in serum EPA and DHA concentrations and modest improvements in the clinical signs of OA in pet dogs. PMID- 20707846 TI - Immunohistochemical detection of retinoid receptors in tumors from 30 dogs diagnosed with cutaneous lymphoma. AB - BACKGROUND: Retinoids exert their effects by binding to retinoid receptors. Two types of retinoid receptors have been described: retinoic acid receptor (RAR) and retinoid X receptor (RXR), and their subtypes alpha, beta, and gamma. The expression of subtypes varies depending on the disease process. This study intended to detect the pattern of retinoid receptor expression in cutaneous lymphomas in dogs. HYPOTHESIS: Cutaneous lymphomas in dogs have variable expression of retinoid and retinoid X receptors. ANIMALS: Biopsy specimens from 30 dogs with cutaneous lymphoma. METHODS: Tissues of dogs with cutaneous lymphoma were evaluated by immunohistochemistry for expression of retinoid receptors. The tissues were tested for the presence of 3 RAR and RXR subtypes (alpha, beta, and gamma). Lymphoma immunophenotype was determined by the use of the immunohistochemical markers CD79a (B-cell) and CD3 (T-cell) in all cases. RESULTS: Twenty-nine of 30 dogs were CD3 positive. The retinoid receptors expressed with the greatest frequency were RARbeta (87% of cases), and RXRalpha and RXRgamma (77% of cases). The expression of RARgamma was not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Retinoid and rexinoid receptor binding drugs may have an impact on the treatment of dogs with cutaneous lymphoma. PMID- 20707847 TI - Cutaneous and tendon sheath mastocytomas with eosinophilic joint and tendon sheath effusions in a horse. PMID- 20707848 TI - Is age a risk factor for Candida glabrata colonisation? AB - Studies have reported that Candida glabrata infections are more common in older adults. We sought to determine colonisation rates of C. glabrata in the oral cavity and its relationship with age, comorbid illnesses and hospital or extended care facility stay. Samples were obtained from four sites in the oral cavity and from dentures, when available, from 408 subjects from the community (136), hospital (126) or an extended care facility (146). Overall, 219 (53.7%) subjects were colonised with yeast; the predominant species was Candida albicans. Sixty two patients (15.2%) were colonised with C. glabrata. None of the subjects <40 years was colonised with C. glabrata; in those from the community, only nine persons, all of whom were >60 years, were colonised with C. glabrata. By multivariate analysis, increasing age, dentures and use of psychotropic medications were independently associated with C. glabrata colonisation; residing in the community, rather than hospital or extended care, was strongly protective against colonisation. Candida glabrata colonisation is multifactorial; age, and hospitalisation/extended care stay contribute to colonisation. Dentures are strongly associated with colonisation with any yeast and with C. glabrata. Further study is needed to evaluate the relationship of these findings to increasing C. glabrata infections in older adults. PMID- 20707849 TI - Parlez-vous effectors? PMID- 20707850 TI - Mining for nutrients - regulatory aspects of cluster root function and development. PMID- 20707851 TI - The right stuff: evidence for an 'optimal' genome size in a wild grass population. PMID- 20707852 TI - What is the speed of link between aboveground and belowground processes? PMID- 20707854 TI - Ecology and evolution on the banks of the St Lawrence. PMID- 20707855 TI - Towards population genomics of effector-effector target interactions. AB - Pathogen-plant host coevolutionary interactions exert strong natural selection on both organisms, specifically on the genes coding for effectors (pathogens), as well as on those coding for effector targets and R proteins (plant hosts). Natural selection leaves behind DNA sequence signatures on such genes and on linked genomic regions. These signatures can readily be detected by studying the patterns of intraspecies polymorphisms and interspecies divergence of the DNA sequences. Recent developments in DNA sequencing technology have made whole genome studies on patterns of DNA polymorphisms : divergence possible. This type of analysis, called 'population genomics', appears to be powerful enough to identify novel effector-effector target genes. Here, we provide an overview of the statistical tools used for population genomics and their applications. This is followed by a brief review of evolutionary studies on plant genes involved in host-pathogen interactions. Finally we provide an example from our study on Magnaporthe oryzae. PMID- 20707856 TI - Care managers' view of family influence on needs assessment of older people. AB - Research has shown that families experience poor involvement in needs assessment of older people while little is known about municipal care managers' views of family participation. The aim was to explore how municipal care managers view families' participation in and influence on needs assessment of older people receiving public home help. Individual interviews (n=26) were conducted with care managers (n=5) about their previously conducted needs assessments (n=5-6). As a complement, a focus group interview with care managers (n=9) from nine different municipalities was conducted. All interviews were analysed using a qualitative content analysis. The results revealed the overarching category, 'Having to establish boundaries towards family influence and at the same time use them as a resource', which encompassed five principal categories. How family participation was viewed and handled during the needs assessment process seemed determined by the way care managers set boundaries for their professional responsibility. Their views revealed both distancing and strengthening attitudes. The distancing attitude dominated, in particular towards family members who were not perceived as having any legal rights to be considered, even though their participation was an important resource. To follow legislation and municipal guidelines of allocation of public home help to avoid reprimands caused a need for self protection. The care managers seemed pressed by demands from organizations and families, and in this competition, the family lost out. Adherence to organizational developed patterns of handling legislation and guidelines were prioritized. Because family members often are older and assist in providing care, family participation in the needs assessment of older help recipients needs further societal support. PMID- 20707857 TI - Professional autonomy of nurses in hospital settings--a review of the literature. AB - Autonomy is regarded as an essential element of professional status. Especially nurse managers have an important role in searching for ways to empower nurses and to provide conditions that promote autonomous practice. This article provides an overview of the empirical research literature on the professional autonomy of nurses in hospital settings. The aim is to clarify the concept and to give information on how the autonomy of nurses has been studied through the decades. The definitions of autonomy and the results of empirical research are reviewed. Further, the article offers a description of the methodologies used in the studies of the autonomy of nurses over the years: data collection methods, samples and research contexts. The review focuses on empirical articles published between 1966 and December 2009 retrieved from the CINAHL and MEDLINE databases. The studies were classified based on a content analysis. This review draws attention to the complexity of the concept of autonomy and its various definitions. Moreover, the data for studies have been collected primarily by questionnaires; the sampling methods have been nonrandomized and the samples varying. It would be necessary to study autonomy in different countries using the same instrument. PMID- 20707858 TI - Refinement of a viral transmission risk model for blood donations in seroconversion window phase screened by nucleic acid testing in different pool sizes and repeat test algorithms. AB - BACKGROUND: In minipool nucleic acid test (MP-NAT) screening protocols, the donations implicated in reactive test pools are released for transfusion when they are nonreactive in a repeat test on the individual samples, but in individual-donation (ID)-NAT screening algorithms the release of nonrepeatable reactive (NRR) donations is under discussion. STUDY DESIGN AND METHODS: A previously developed window phase (WP) transmission risk model for NAT-screened blood transfusions has been refined to take the effect of repeat tests of initially reactive (IR) MP- or ID-NAT results into account. The model has then been applied to simulate the effect of different screening algorithms with ULTRIO and the new-generation ULTRIO Plus assay (Novartis Diagnostics) on transmission risk for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). RESULTS: We calculated WP risk-day equivalents for MP16-, MP8-, and ID-NAT with and without duplicate retesting of IR results of 3.1, 2.7, 1.5, and 1.3 days for HCV; 6.3, 5.5, 3.3, and 2.9 days for HIV; and 24.4, 22.2, 15.6, and 14.1 days for HBV, respectively. These latter infectious HBV WPs reduced to 20.4, 18.2, 11.6, and 10.3 days, respectively, with the more sensitive ULTRIO Plus assay. CONCLUSION: ULTRIO Plus ID-NAT screening reduces the virus transmission risk in the WP by 54% to 58% compared to ULTRIO MP16-NAT, while the incremental risk caused by releasing donations with duplicate ID-NAT NRR results is 5% to 6%. To achieve maximum safety and specificity a similar repeat test algorithm can be applied to ID-NAT as used for serologic assays. PMID- 20707859 TI - Blood group genotyping by high-throughput DNA analysis applied to 356 reagent red blood cell samples. AB - BACKGROUND: DNA analysis for the prediction of blood group antigen expression has broad implications in transfusion medicine. It may be of particular interest especially to detect variants, when antigen expression is weak or altered. The use of high-throughput DNA analysis has never been applied to donors whose red blood cells (RBCs) are selected for reagent RBCs. The aim of this study was to analyze the concordance between the serologic phenotype and that predicted from DNA analysis in panel donors, to determine the benefit of the use of DNA analysis in reagent RBC selection strategy. STUDY DESIGN AND METHODS: The "Panel National de Reference du Centre National de Reference sur les Groupes Sanguins" is a reference reagent mainly used for antibody identification. DNA genotyping of 356 panel donors was performed with BeadChips (human erythrocyte antigen v1.2 BeadChips, BioArray Solutions). The comparison between serologic phenotype and that predicted from DNA analysis held on 8876 paired results obtained from 10 blood group systems and 25 antigens. RESULTS: A 99.95% concordance was observed. Discrepancies in four cases (RH, KEL, LU, and DO systems) were analyzed. Genotyping precisions on the Duffy system were of particular interest. No new rare blood group was observed. CONCLUSION: Systematic DNA analysis of panel donors should unquestionably change the management of reagent RBC selection. The notion of "antigens in double dose" should evolve regarding data obtained from DNA analysis, allowing an improved quality of reagent RBCs for antibody screening and identification. PMID- 20707860 TI - A case-control study of the risk factors for canine juvenile-onset generalized demodicosis in the USA. AB - Canine juvenile-onset generalized demodicosis (JOGD) is a common skin disorder suspected to be associated with multiple risk factors, including breed predispositions. These risk factors have not been well documented in a large population. A retrospective case-control study was conducted by searching the electronic medical records of 1,189,906 dogs examined at 600 hospitals during 2006 in order to assess the risk factors associated with JOGD in the USA. Multivariate analyses were conducted using logistic regression to estimate the relative risk with the odds ratio for variables hypothesized to influence the risk for canine demodicosis. Breeds (odds ratio) found to have the greatest association with a diagnosis of JOGD were American Staffordshire terrier (35.6), Staffordshire bull terrier (17.1) and Chinese shar-pei (7.2). Nonbreed risk factors (odds ratio) significantly associated with a diagnosis of JOGD were the diagnosis of pyoderma (5.5), coccidiosis (2.7) or hookworms (1.5), short coat (1.9) and nonenrollment in a preventative care wellness plan (1.5). Documenting these risk factors may help veterinarians to prioritize differential diagnoses and will aid in the design of prospective studies to elucidate the pathogenesis of demodicosis in dogs. PMID- 20707861 TI - Serological survey of Toxoplasma gondii infection in the domestic goose (Anser domestica) in southern China. AB - In the present study, the antibodies to Toxoplasma gondii in 191 farm-bred and 83 house-bred geese (Anser domestica) were assessed for the prevalence of T. gondii infection in southern China with the modified agglutination test. Antibodies to T. gondii (MAT >= 1 : 5) were found in 27 (14.14%) of farm-bred geese and 14 (16.87%) of house-bred geese. Geese infected with T. gondii may be a source of T. gondii infection for humans and cats. PMID- 20707862 TI - Factors associated with the risk of West Nile virus among crows in New York State. AB - West Nile virus (WNV) is transmitted between avian hosts in enzootic cycles by a mosquito vector. The virus has significant disease effects on humans and equines when it bridges into an epizootic cycle. As the initial epidemic of WNV in 1999, perennial outbreaks in New York State suggest the local establishment of natural foci with perpetuation of the virus among susceptible hosts rather than reintroduction of the virus. The factors that play a role in the perpetuation of the virus are not fully understood. American crows (Corvus brachyrhynchos) are known to be highly susceptible to infection with the virus. We investigate the factors that put crows at risk of infection in Tompkins County, New York during the period of 2000-2008 in a case-control study. Cases were crow carcasses that were found dead and tested positive for WNV using real time reverse transcription or VecTest. Data on putative risk factors were collected and assessed for significance of association with the presence of WNV using logistic regression analysis to evaluate the significance of each factor while simultaneously controlling for the effect of others. The risk of a crow carcass testing WNV positive varied with age, season of the year and ecological area where the carcass was found. Crows that were more than 1-year-old were four times more likely to be WNV positive in comparison to birds that were less than 1 year of age. It was three times more likely to find WNV positive carcasses in residential areas in comparison to rural areas. The risk of testing WNV positive did not vary by sex of the crow carcasses. PMID- 20707863 TI - Persistence of Mycobacterium bovis Bacillus Calmette-Guerin in white-tailed deer (Odocoileus virginianus) after oral or parenteral vaccination. AB - Mycobacterium bovis is the cause of tuberculosis in cattle and a serious zoonotic pathogen, most commonly contracted through consumption of unpasteurized dairy products. To control this zoonosis, many countries have developed bovine tuberculosis eradication programmes. Although relatively successful, efforts are hindered in many regions by spillover from wildlife reservoirs of M. bovis to cattle. Such is the case in the United States where spillover of M. bovis from free-ranging white-tailed deer to cattle occurs. One approach to control such inter-species transmission is vaccination of wildlife. The live, attenuated human vaccine M. bovis Bacillus Calmette-Guerin (BCG) has been shown to reduce disease severity in white-tailed deer; however, vaccine persistence within tissues has also been noted. Consumption of venison containing BCG by hunters may present a public health concern as BCG exposure, although unlikely to cause disease, could cause false positive tuberculin skin test results. To examine BCG persistence further, 42 white-tailed deer were vaccinated orally or subcutaneously (SC) with BCG Danish. Three deer from each group were killed and examined at periods ranging from 2 weeks to 11 months after vaccination. BCG was recovered from orally vaccinated deer as late as 3 months after vaccination, while BCG persisted in SC vaccinated deer for as long as 9 months. At no time was BCG isolated from meat; however, prolonged persistence was seen in lymphoid organs. Although vaccine persistence was noted, especially in SC vaccinated deer, the distribution of culture-positive tissues makes human exposure through consumption unlikely. PMID- 20707864 TI - Mexico's methamphetamine precursor chemical interventions: impacts on drug treatment admissions. AB - AIMS: To help counter problems related to methamphetamine, Mexico has implemented interventions targeting pseudoephedrine and ephedrine, the precursor chemicals commonly used in the drug's synthesis. This study examines whether the interventions impacted methamphetamine treatment admissions-an indicator of methamphetamine consequences. DESIGN: Quasi-experiment: autoregressive integrated moving average (ARIMA)-based intervention time-series analysis. INTERVENTIONS: precursor chemical restrictions implemented beginning November 2005; major rogue precursor chemical company closed (including possibly the largest single drug cash seizure in history) March 2007; precursor chemicals banned from Mexico (North America's first precursor ban) August 2008. SETTINGS: Mexico and Texas (1996-2008). MEASUREMENTS: Monthly treatment admissions for methamphetamine (intervention series) and cocaine, heroin and alcohol (quasi-control series). FINDINGS: The precursor restriction was associated with temporary methamphetamine admissions decreases of 12% in Mexico and 11% in Texas. The company closure was associated with decreases of 56% in Mexico and 48% in Texas; these decreases generally remained to the end of the study period. Neither intervention was associated with significant changes in the Mexico or Texas quasi-control series. The analysis of Mexico's ban was indeterminate due largely to a short post-ban series. CONCLUSIONS: This study, one of the first quasi-experimental analyses of an illicit-drug policy in Mexico, indicates that the country's precursor interventions were associated with positive impacts domestically and in one of the Unites States' most populous states--Texas. These interventions, coupled with previous US and Canadian interventions, amount to a new, relatively cohesive level of methamphetamine precursor control across North America's largest nations, raising the possibility that the impacts found here could continue for an extended period. PMID- 20707866 TI - Modulation of white adipose tissue proteome by aging and calorie restriction. AB - Aging is associated with an accrual of body fat, progressive development of insulin resistance and other obesity comorbidities that contribute to decrease life span. Caloric restriction (CR), which primarily affects energy stores in adipose tissue, is known to extend life span and retard the aging process in animal models. In this study, a proteomic approach combining 2-DE and MS was used to identify proteins modulated by aging and CR in rat white adipose tissue proteome. Proteomic analysis revealed 133 differentially expressed spots, 57 of which were unambiguously identified by MS. Although CR opposed part of the age associated protein expression patterns, many effects of CR were on proteins unaltered by age, suggesting that the effects of CR on adipose tissue are only weakly related to those of aging. Particularly, CR and aging altered glucose, intermediate and lipid metabolism, with CR enhancing the expression of enzymes involved in oxalacetate and NADPH production, lipid biosynthesis and lipolysis. Consistently, insulin-beta and beta3-adrenergic receptors were also increased by CR, which denotes improved sensitivity to lipogenic/lipolytic stimuli. Other beneficial outcomes of CR were an improvement in oxidative stress, preventing the age-associated decrease in several antioxidant enzymes. Proteins involved in cytoskeleton, iron storage, energy metabolism and several proteins with novel or unknown functions in adipose tissue were also modulated by age and/or CR. Such orchestrated changes in expression of multiple proteins provide insights into the mechanism underlying CR effects, ultimately allowing the discovery of new markers of aging and targets for the development of CR-mimetics. PMID- 20707865 TI - Genome-wide screen identifies Escherichia coli TCA-cycle-related mutants with extended chronological lifespan dependent on acetate metabolism and the hypoxia inducible transcription factor ArcA. AB - Single-gene mutants with extended lifespan have been described in several model organisms. We performed a genome-wide screen for long-lived mutants in Escherichia coli, which revealed strains lacking tricarboxylic acid (TCA)-cycle related genes that exhibit longer stationary-phase survival and increased resistance to heat stress compared to wild-type. Extended lifespan in the sdhA mutant, lacking subunit A of succinate dehydrogenase, is associated with the reduced production of superoxide and increased stress resistance. On the other hand, the longer lifespan of the lipoic acid synthase mutant (lipA) is associated with reduced oxygen consumption and requires the acetate-producing enzyme pyruvate oxidase, as well as acetyl-CoA synthetase, the enzyme that converts extracellular acetate to acetyl-CoA. The hypoxia-inducible transcription factor ArcA, acting independently of acetate metabolism, is also required for maximum lifespan extension in the lipA and lpdA mutants, indicating that these mutations promote entry into a mode normally associated with a low-oxygen environment. Because analogous changes from respiration to fermentation have been observed in long-lived Saccharomyces cerevisiae and Caenorhabditis elegans strains, such metabolic alterations may represent an evolutionarily conserved strategy to extend lifespan. PMID- 20707867 TI - Moderately elevated body mass index is associated with metabolic variables and cardiovascular risk factors in Swedish children. AB - AIM: To evaluate associations between anthropometrics and metabolic variables as well as cardiovascular risk factors among children. METHODS: Subjects were recruited from a cohort of 274 healthy children in Umea, Sweden. Anthropometric measures, blood pressure and venous blood samples were collected at age 10 years and simultaneously from parents. RESULTS: Altogether 144 children (53%), 142 mothers and 123 fathers participated. The prevalence of overweight and obesity among the children was 18 and 2%, respectively. Overweight children (above age- and sex-specific cut offs corresponding adult BMI >= 25 kg/m(2) ), compared to normal weight children, had significantly higher BMI already during infancy and higher S-insulin and Homeostatic Model Assessment (HOMA) index at 10 years. The children's BMI was positively associated with waist (boys' r = 0.67, girls' r = 0.81), hip (r = 0.68), waist/hip ratio (girls' r = 0.37), waist/height ratio (boys' r = 0.59, girls' r = 0.80), sagittal abdominal diameter (r = 0.75), S insulin (r = 0.45), HOMA index (r = 0.49), systolic blood pressure (r = 0.24), mothers' BMI (girls' r = 0.42) and mothers' waist (girls' r = 0.42). CONCLUSION: Children at 10 years of age with moderately elevated BMI had higher levels of some metabolic variables and cardiovascular risk factors than did normal weight children, and there was a correlation between BMI and some metabolic variables as well as cardiovascular risk factors. PMID- 20707868 TI - Frailty-based competing risks model for multivariate survival data. AB - In this work, we provide a new class of frailty-based competing risks models for clustered failure times data. This class is based on expanding the competing risks model of Prentice et al. (1978, Biometrics 34, 541-554) to incorporate frailty variates, with the use of cause-specific proportional hazards frailty models for all the causes. Parametric and nonparametric maximum likelihood estimators are proposed. The main advantages of the proposed class of models, in contrast to the existing models, are: (1) the inclusion of covariates; (2) the flexible structure of the dependency among the various types of failure times within a cluster; and (3) the unspecified within-subject dependency structure. The proposed estimation procedures produce the most efficient parametric and semiparametric estimators and are easy to implement. Simulation studies show that the proposed methods perform very well in practical situations. PMID- 20707869 TI - Hierarchical modeling for estimating relative risks of rare genetic variants: properties of the pseudo-likelihood method. AB - Many major genes have been identified that strongly influence the risk of cancer. However, there are typically many different mutations that can occur in the gene, each of which may or may not confer increased risk. It is critical to identify which specific mutations are harmful, and which ones are harmless, so that individuals who learn from genetic testing that they have a mutation can be appropriately counseled. This is a challenging task, since new mutations are continually being identified, and there is typically relatively little evidence available about each individual mutation. In an earlier article, we employed hierarchical modeling (Capanu et al., 2008, Statistics in Medicine 27, 1973-1992) using the pseudo-likelihood and Gibbs sampling methods to estimate the relative risks of individual rare variants using data from a case-control study and showed that one can draw strength from the aggregating power of hierarchical models to distinguish the variants that contribute to cancer risk. However, further research is needed to validate the application of asymptotic methods to such sparse data. In this article, we use simulations to study in detail the properties of the pseudo-likelihood method for this purpose. We also explore two alternative approaches: pseudo-likelihood with correction for the variance component estimate as proposed by Lin and Breslow (1996, Journal of the American Statistical Association 91, 1007-1016) and a hybrid pseudo-likelihood approach with Bayesian estimation of the variance component. We investigate the validity of these hierarchical modeling techniques by looking at the bias and coverage properties of the estimators as well as at the efficiency of the hierarchical modeling estimates relative to that of the maximum likelihood estimates. The results indicate that the estimates of the relative risks of very sparse variants have small bias, and that the estimated 95% confidence intervals are typically anti-conservative, though the actual coverage rates are generally above 90%. The widths of the confidence intervals narrow as the residual variance in the second stage model is reduced. The results also show that the hierarchical modeling estimates have shorter confidence intervals relative to estimates obtained from conventional logistic regression, and that these relative improvements increase as the variants become more rare. PMID- 20707870 TI - A mixture model for quantum dot images of kinesin motor assays. AB - We introduce a nearly automatic procedure to locate and count the quantum dots in images of kinesin motor assays. Our procedure employs an approximate likelihood estimator based on a two-component mixture model for the image data; the first component has a normal distribution, and the other component is distributed as a normal random variable plus an exponential random variable. The normal component has an unknown variance, which we model as a function of the mean. We use B splines to estimate the variance function during a training run on a suitable image, and the estimate is used to process subsequent images. Parameter estimates are generated for each image along with estimates of standard errors, and the number of dots in the image is determined using an information criterion and likelihood ratio tests. Realistic simulations show that our procedure is robust and that it leads to accurate estimates, both of parameters and of standard errors. PMID- 20707871 TI - High-dimensional variable selection in meta-analysis for censored data. AB - This article considers the problem of selecting predictors of time to an event from a high-dimensional set of candidate predictors using data from multiple studies. As an alternative to the current multistage testing approaches, we propose to model the study-to-study heterogeneity explicitly using a hierarchical model to borrow strength. Our method incorporates censored data through an accelerated failure time model. Using a carefully formulated prior specification, we develop a fast approach to predictor selection and shrinkage estimation for high-dimensional predictors. For model fitting, we develop a Monte Carlo expectation maximization (MC-EM) algorithm to accommodate censored data. The proposed approach, which is related to the relevance vector machine (RVM), relies on maximum a posteriori estimation to rapidly obtain a sparse estimate. As for the typical RVM, there is an intrinsic thresholding property in which unimportant predictors tend to have their coefficients shrunk to zero. We compare our method with some commonly used procedures through simulation studies. We also illustrate the method using the gene expression barcode data from three breast cancer studies. PMID- 20707872 TI - Effect of health promotion and fluoride varnish on dental caries among Australian Aboriginal children: results from a community-randomized controlled trial. AB - OBJECTIVES: We tested a dental health program in remote Aboriginal communities of Australia's Northern Territory, hypothesizing that it would reduce dental caries in preschool children. METHODS: In this 2-year, prospective, cluster-randomized, concurrent controlled, open trial of the dental health program compared to no such program, 30 communities were allocated at random to intervention and control groups. All residents aged 18-47 months were invited to participate. Twice per year for 2 years in the 15 intervention communities, fluoride varnish was applied to children's teeth, water consumption and daily tooth cleaning with toothpaste were advocated, dental health was promoted in community settings, and primary health care workers were trained in preventive dental care. Data from dental examinations at baseline and after 2 years were used to compute net dental caries increment per child (d3mfs). A multi-level statistical model compared d3mfs between intervention and control groups with adjustment for the clustered randomization design; four other models used additional variables for adjustment. RESULTS: At baseline, 666 children were examined; 543 of them (82%) were re examined 2 years later. The adjusted d3mfs increment was significantly lower in the intervention group compared to the control group by an average of 3.0 surfaces per child (95% CI = 1.2, 4.9), a prevented fraction of 31%. Adjustment for additional variables yielded caries reductions ranging from 2.3 to 3.5 surfaces per child and prevented fractions of 24-36%. CONCLUSIONS: These results corroborate findings from other studies where fluoride varnish was efficacious in preventing dental caries in young children. PMID- 20707873 TI - Association of glycoprotein gp130 with hereditary catalepsy in mice. AB - Glycoprotein gp130 is involved in the interleukin-6 (IL-6) and related cytokines' signaling. Linkage between the gp130 coding gene and freezing reaction (catalepsy) was shown. Here, we compared the expression and function of the gp130 in male mice of catalepsy-resistant AKR/J strain and catalepsy-prone congenic AKR.CBA-D13Mit76 strain created by transferring the gp130 gene allele from catalepsy-prone CBA/Lac to the genome of AKR/J strain. No difference in the gp130 expression in the frontal cortex, hippocampus and midbrain between AKR and AKR.CBA-D13Mit76 mice was found. However, AKR.CBA-D13Mit76 mice were more sensitive to bacterial lipopolysaccharide (LPS). The administration of LPS (50 ug/kg, ip) significantly increased mRNA level of the gene coding IL-6-regulated glial fibrillary acidic protein (GFAP) in the midbrain, induced catalepsy and decreased locomotion in the open field and social investigation tests in AKR.CBA D13Mit76, but not in AKR mice. The result indicates (1) the association between gp130 and hereditary catalepsy, (2) increased functional activity rather than expression of gp130 in AKR.CBA-D13Mit76 mice and (3) the involvement of gp130 in the mechanism of LPS-induced alteration of behavior. PMID- 20707875 TI - Which plant for which skin disease? Part 1: Atopic dermatitis, psoriasis, acne, condyloma and herpes simplex. AB - Plant extracts and isolated compounds are increasingly used in cosmetics and food supplements to improve skin conditions. We first introduce the positive plant monographs with dermatological relevance of the former German Commission E. Subsequently clinical studies with botanicals for atopic dermatitis, psoriasis, acne, condylomata acuminata and herpes simplex are discussed. The best studies have been conducted with atopic dermatitis and psoriasis patients. Mahonia aquifolium, Hypericum perforatum, Glycyrrhiza glabra and certain traditional Chinese therapies have been shown to be effective in the treatment of atopic dermatitis. Mahonia aquifolium, Indigo naturalis and Capsicum frutescens are effective treatments for psoriasis. Green tea extract and tea tree oil have been investigated in the treatment of acne. Podophyllin and green tea extract are effective treatments for condylomata acuminata. Balm mint and a combination of sage and rhubarb have been shown to be effective in the treatment of herpes simplex in proof of concept studies. PMID- 20707874 TI - Resistance to change and vulnerability to stress: autistic-like features of GAP43 deficient mice. AB - There is an urgent need for animal models of autism spectrum disorder (ASD) to understand the underlying pathology and facilitate development and testing of new treatments. The synaptic growth-associated protein-43 (GAP43) has recently been identified as an autism candidate gene of interest. Our previous studies show many brain abnormalities in mice lacking one allele for GAP43 [GAP43 (+/-)] that are consistent with the disordered connectivity theory of ASD. Thus, we hypothesized that GAP43 (+/-) mice would show at least some autistic-like behaviors. We found that GAP43 (+/-) mice, relative to wild-type (+/+) littermates, displayed resistance to change, consistent with one of the diagnostic criteria for ASD. GAP43 (+/-) mice also displayed stress-induced behavioral withdrawal and anxiety, as seen in many autistic individuals. In addition, both GAP43 (+/-) mice and (+/+) littermates showed low social approach and lack of preference for social novelty, consistent with another diagnostic criterion for ASD. This low sociability is likely because of the mixed C57BL/6J 129S3/SvImJ background. We conclude that GAP43 deficiency leads to the development of a subset of autistic-like behaviors. As these behaviors occur in a mouse that displays disordered connectivity, we propose that future anatomical and functional studies in this mouse may help uncover underlying mechanisms for these specific behaviors. Strain-specific low sociability may be advantageous in these studies, creating a more autistic-like environment for study of the GAP43 mediated deficits of resistance to change and vulnerability to stress. PMID- 20707876 TI - Research in practice: More than skin deep -aging of subcutaneous fat tissue. AB - Mitochondria, responsible for the generation of energy in our cells, contain their own genome, mitochondrial (mt)DNA. It is known that mutations of mtDNA accumulate during normal aging and that this can be accelerated by oxidative stress, i.e. induced by ultraviolet radiation. These mutations are functionally relevant and they play a causative role in normal aging as well as premature aging induced by ultraviolet radiation. While the focus of scientific research was more on epidermis and dermis within the last years, alterations of subcutaneous fat tissue were not investigated thus far. Cockayne syndrome (CS) A and B are two proteins known to repair oxidatively induced DNA damage via nucleotide excision repair (NER) in the nucleus. We could show that these two proteins enrich in mitochondria upon oxidative stress, directly interact with mtDNA and the two repair-associated proteins mtSSBP-1 and mtOGG-1 and protect from deletions of mtDNA. If CSA or CSB are lacking, mtDNA mutations accumulate particularly in the cells of subcutaneous fat tissue which appears to mediate loss of adipocytes via apoptosis. Therefore, the two NER-associated proteins CSA and CSB appear to play a direct role in protection from mutations which in turn are causative in aging-associated loss of subcutaneous fat tissue. PMID- 20707877 TI - Which plant for which skin disease? Part 2: Dermatophytes, chronic venous insufficiency, photoprotection, actinic keratoses, vitiligo, hair loss, cosmetic indications. AB - This paper continues our review of scientifically evaluated plant extracts in dermatology. After plants effective against dermatophytes, botanicals with anti edema effects in chronic venous insufficiency are discussed. There is good evidence from randomized clinical studies that plant extracts from grape vine leaves (Vitis vinifera), horse chestnut (Aesculus hippocastanum), sea pine (Pinus maritima) and butcher's broom (Ruscus aculeatus) can reduce edema in chronic venous insufficiency. Plant extracts from witch hazel (Hamamelis virginiana), green tea (Camellia sinensis), the fern Polypodium leucotomos and others contain antioxidant polyphenolic compounds that may protect the skin from sunburn and photoaging when administered topically or systemically. Extracts from the garden spurge (Euphorbia peplus) and from birch bark (Betula alba) have been shown to be effective in the treatment of actinic keratoses in phase II studies. Some plant extracts have also been investigated in the treatment of vitiligo, various forms of hair loss and pigmentation disorders, and in aesthetic dermatology. PMID- 20707878 TI - Expanded phylogenetic representation of genera Opercularia and Epistylis sheds light on the evolution and higher-level taxonomy of peritrich ciliates (Ciliophora: Peritrichia). AB - We have generated 18S rRNA sequences for peritrichs collected in Brazil, including four Opercularia species, two different populations of Epistylis plicatilis (one epibiont and another free-living), and one additional Epistylis species. Our Opercularia species clustered with the previously available Opercularia microdiscum, corroborating the monophyly of this genus. The Epistylis sampled here clustered with previously sequenced species of this genus. The two populations of E. plicatilis collected in Brazil clustered closely together despite their different ecological contexts, whereas both were very divergent from the sample assigned to the same species previously sampled in China. If affirmed by additional morphological corroboration of species assignment, this observation would indicate that samples from different continents morphologically allocated in the same species may in fact belong to distant evolutionary lineages. More broadly, our results support the recognition of two major clades within Peritrichia. Given the robustness of their support, we suggest that these two clades should be formally recognized as orders, and propose the names Vorticellida and Operculariida to designate them. Furthermore, Epistylis species occurred in both orders, tending to occupy basal positions. This suggests that characters used to define this genus may be plesiomorphic for Peritrichia, so that Epistylis may in fact represent an assemblage of basal species retaining ancestral features. PMID- 20707879 TI - Noninvasive prediction of oesophageal varices: as simple as blood count? PMID- 20707881 TI - Polymorphism between HLA-A*0301 and A*0302 located outside the pocket F alters the POmega peptide motif. AB - The human leukocyte antigen (HLA)-A*03 group has more than 90 known members and is one of the largest families of HLA class I alleles, with the most common variant being HLA-A*0301. In this study, we determined the peptide-binding motif of the highly frequent Sudanese allele A*0302 and compared it with the previously published peptide-binding motif of A*0301. The two alleles differ only at two distinct residues Glu152Val and Leu156Gln, which are predicted to be part of specificity pockets D, C and E and thus in contact with the peptide. Soluble recombinant A*0302 was expressed, affinity purified and the bound peptides were then eluted and analysed by mass spectrometry. The peptide-binding motif of A*0302 differs significantly from the previously published HLA-A*0301 and the Glu152Val/Leu156Gln mismatches appear to have a significant impact on the peptide binding features of A*0302 and A*0301. PMID- 20707882 TI - Q&A: Single-molecule localization microscopy for biological imaging. PMID- 20707884 TI - Assessing the potential effects and cost-effectiveness of programmatic herpes zoster vaccination of elderly in the Netherlands. AB - BACKGROUND: Herpes zoster (HZ) is a painful disease affecting a considerable part of the elderly. Programmatic HZ vaccination of elderly people may considerably reduce HZ morbidity and its related costs, but the extent of these effects is unknown. In this article, the potential effects and cost-effectiveness of programmatic HZ vaccination of elderly in the Netherlands have been assessed according to a framework that was developed to support evidence-based decision making regarding inclusion of new vaccines in the Dutch National Immunization Program. METHODS: An analytical framework was used combining a checklist, which structured relevant data on the vaccine, pathogen and disease, and a cost effectiveness analysis. The cost-effectiveness analysis was performed from a societal perspective, using a Markov-cohort-model. Simultaneous vaccination with influenza was assumed. RESULTS: Due to the combination of waning immunity after vaccination and a reduced efficacy of vaccination at high ages, the most optimal cost-effectiveness ratio (21716 euro per QALY) for HZ vaccination in the Netherlands was found for 70-year olds. This estimated ratio is just above the socially accepted threshold in the Netherlands of 20000 euro per QALY. If additional reduction of postherpetic neuralgia was included, the cost effectiveness ratio improved (approximately 10000 euro per QALY) but uncertainty for this scenario is high. CONCLUSIONS: Vaccination against HZ at the age of 70 years seems marginally cost-effective in the Netherlands. Due to limited vaccine efficacy a considerable part of the disease burden caused by HZ will remain, even with optimal acceptance of programmatic vaccination. PMID- 20707885 TI - SICTIN: Rapid footprinting of massively parallel sequencing data. AB - BACKGROUND: Massively parallel sequencing allows for genome-wide hypothesis-free investigation of for instance transcription factor binding sites or histone modifications. Although nucleotide resolution detailed information can easily be generated, biological insight often requires a more general view of patterns (footprints) over distinct genomic features such as transcription start sites, exons or repetitive regions. The construction of these footprints is however a time consuming task. METHODS: The presented software generates a binary representation of the signals enabling fast and scalable lookup. This representation allows for footprint generation in mere minutes on a desktop computer. Several different input formats are accepted, e.g. the SAM format, bed files and the UCSC wiggle track. CONCLUSIONS: Hypothesis-free investigation of genome wide interactions allows for biological data mining at a scale never before seen. Until recently, the main focus of analysis of sequencing data has been targeted on signal patterns around transcriptional start sites which are in manageable numbers. Today, focus is shifting to a wider perspective and numerous genomic features are being studied. To this end, we provide a system allowing for fast querying in the order of hundreds of thousands of features. PMID- 20707883 TI - Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study. AB - BACKGROUND: Excitotoxicity is involved in the pathogenesis of a number neurodegenerative diseases, and axonopathy is an early feature in several of these disorders. In models of excitotoxicity-associated neurological disease, an excitotoxin delivered to the central nervous system (CNS), could trigger neuronal death not only in the somatodendritic region, but also in the axonal region, via oligodendrocyte N-methyl-D-aspartate (NMDA) receptors. The retina and optic nerve, as approachable regions of the brain, provide a unique anatomical substrate to investigate the "downstream" effect of isolated excitotoxic perikaryal injury on central nervous system (CNS) axons, potentially providing information about the pathogenesis of the axonopathy in clinical neurological disorders.Herein, we provide ultrastructural information about the retinal ganglion cell (RGC) somata and their axons, both unmyelinated and myelinated, after NMDA-induced retinal injury. Male Sprague-Dawley rats were killed at 0 h, 24 h, 72 h and 7 days after injecting 20 nM NMDA into the vitreous chamber of the left eye (n = 8 in each group). Saline-injected right eyes served as controls. After perfusion fixation, dissection, resin-embedding and staining, ultrathin sections of eyes and proximal (intraorbital) and distal (intracranial) optic nerve segments were evaluated by transmission electron tomography (TEM). RESULTS: TEM demonstrated features of necrosis in RGCs: mitochondrial and endoplasmic reticulum swelling, disintegration of polyribosomes, rupture of membranous organelle and formation of myelin bodies. Ultrastructural damage in the optic nerve mimicked the changes of Wallerian degeneration; early nodal/paranodal disturbances were followed by the appearance of three major morphological variants: dark degeneration, watery degeneration and demyelination. CONCLUSION: NMDA-induced excitotoxic retinal injury causes mainly necrotic RGC somal death with Wallerian-like degeneration of the optic nerve. Since axonal degeneration associated with perikaryal excitotoxic injury is an active, regulated process, it may be amenable to therapeutic intervention. PMID- 20707886 TI - A robotic wheelchair trainer: design overview and a feasibility study. AB - BACKGROUND: Experiencing independent mobility is important for children with a severe movement disability, but learning to drive a powered wheelchair can be labor intensive, requiring hand-over-hand assistance from a skilled therapist. METHODS: To improve accessibility to training, we developed a robotic wheelchair trainer that steers itself along a course marked by a line on the floor using computer vision, haptically guiding the driver's hand in appropriate steering motions using a force feedback joystick, as the driver tries to catch a mobile robot in a game of "robot tag". This paper provides a detailed design description of the computer vision and control system. In addition, we present data from a pilot study in which we used the chair to teach children without motor impairment aged 4-9 (n = 22) to drive the wheelchair in a single training session, in order to verify that the wheelchair could enable learning by the non-impaired motor system, and to establish normative values of learning rates. RESULTS AND DISCUSSION: Training with haptic guidance from the robotic wheelchair trainer improved the steering ability of children without motor impairment significantly more than training without guidance. We also report the results of a case study with one 8-year-old child with a severe motor impairment due to cerebral palsy, who replicated the single-session training protocol that the non-disabled children participated in. This child also improved steering ability after training with guidance from the joystick by an amount even greater than the children without motor impairment. CONCLUSIONS: The system not only provided a safe, fun context for automating driver's training, but also enhanced motor learning by the non-impaired motor system, presumably by demonstrating through intuitive movement and force of the joystick itself exemplary control to follow the course. The case study indicates that a child with a motor system impaired by CP can also gain a short-term benefit from driver's training with haptic guidance. PMID- 20707887 TI - Relationship between blood glucose and carotid intima media thickness: A meta analysis. AB - BACKGROUND: Increased coronary intima media thickness (CIMT) has been associated with adverse cardiovascular outcomes, as have increased glucose levels. The link has not been established between glucose and CIMT; therefore, we sought to assess the relationship between glucose and CIMT. METHODS: Medline, EMBASE, Scopus, and Cochrane databases were searched from inception through 2009 for original research reporting both postprandial glucose levels and CIMT measurements. Glucose was classified as normal, impaired, or diabetic. Outputs included inverse variance weighted effect size and also average correlation (using the Wang and Bushman approach). Data were combined using a random effects meta-analytic model. Heterogeneity as assessed using chi(2) and I(2); bias was examined using Egger plots and Begg-Mazumdar tau. Polynomial functions (i.e., linear, quadratic, cubic, quartic) were fit to the data and the Akaike Information Criteria were used to select the optimal model. RESULTS: We identified 172 papers; 161 were rejected (19 inappropriate design, 8 had selected patients, 101 inappropriate outcomes) leaving 11 accepted. We used data from 15,592 patients (8250 normals, 3013 impaired glucose, 4329 diabetics). There was no evidence of heterogeneity or publication bias. The overall correlation was 0.082 (CI95%:0.066-0.098); the overall effect size was 0.294 (0.245-0.343) between diabetics and normals and 0.137 (0.072-0.202) between normals and those with impaired glucose. The equation of best fit was linear (CIMT = 0.828 + 0.009*glucose). CONCLUSIONS: There is a small but significant relationship between postprandial glucose levels and CIMT, which have both been associated with adverse cardiovascular outcomes. PMID- 20707888 TI - Pitfalls with the "chest compression-only" approach: the challenge of an unusual cause. AB - Chest compression-only (CC-only) is now incorporated in the Norwegian protocol for dispatch guided CPR (cardiopulmonary resuscitation) in cardiac arrest of presumed cardiac aetiology.We present a case that is unique and instructive as well as unusual. It reminds us of the challenges that face bystanders, dispatch centres and ambulance services when faced with possible cardiac arrest.This case report describes a 50 year old man in a rural community. He had suffered a heart attack 8 months previously, and was found unconscious with respiratory arrest in his garden one morning. Due to the proximity to the ambulance station, the paramedics were on the scene within three minutes. A chain-saw was lying beside him, but no external injuries were seen. The patient had no radial pulse, central cyanosis and respiratory gasps approximately every 30 seconds. Ventilation with bag and mask was given, and soon a femoral pulse could be palpated. Blood sugar was elevated and ECG (electrocardiogram) was normal. GCS (Glasgow Coma Scale) was 3. Upon arrival of the physician staffed air ambulance, further examination revealed bilateral miosis of the pupils and continuing bradypnoea. Naloxone was given with an immediate effect and the patient woke up. The patient denied intake of narcotics, but additional information from the dispatch centre revealed that he was hepatitis C positive. After a few hours, the patient admitted to have obtained a fentanyl transdermal patch from an acquaintance, having chewed it before falling unconscious. This case report shows the importance as well as the challenges of identifying a non-cardiac cause of possible cardiac arrest, and the value of providing causal therapy. PMID- 20707889 TI - Hydroxysafflor Yellow A protects spinal cords from ischemia/reperfusion injury in rabbits. AB - BACKGROUND: Hydroxysafflor Yellow A (HSYA), which is one of the most important active ingredients of the Chinese herb Carthamus tinctorius L, is widely used in the treatment of cerebrovascular and cardiovascular diseases. However, the potential protective effect of HSYA in spinal cord ischemia/reperfusion (I/R) injury is still unknown. METHODS: Thirty-nine rabbits were randomly divided into three groups: sham group, I/R group and HSYA group. All animals were sacrificed after neurological evaluation with modified Tarlov criteria at the 48th hour after reperfusion, and the spinal cord segments (L4-6) were harvested for histopathological examination, biochemical analysis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. RESULTS: Neurological outcomes in HSYA group were slightly improved compared with those in I/R group. Histopathological analysis revealed that HSYA treatment attenuated I/R induced necrosis in spinal cords. Similarly, alleviated oxidative stress was indicated by decreased malondialdehyde (MDA) level and increased superoxide dismutase (SOD) activity after HSYA treatment. Moreover, as seen from TUNEL results, HSYA also protected neurons from I/R-induced apoptosis in rabbits. CONCLUSIONS: These findings suggest that HSYA may protect spinal cords from I/R injury by alleviating oxidative stress and reducing neuronal apoptosis in rabbits. PMID- 20707890 TI - Association of measured physical performance and demographic and health characteristics with self-reported physical function: implications for the interpretation of self-reported limitations. AB - BACKGROUND: Self-reported limitations in physical function often have only weak associations with measured performance on physical tests, suggesting that factors other than performance commonly influence self-reports. We tested if personal or health characteristics influenced self-reported limitations in three tasks, controlling for measured performance on these tasks. METHODS: We used cross sectional data on adults aged >/= 60 years (N = 5396) from the Third National Health and Nutrition Examination Survey to examine the association between the repeated chair rise test and self-reported difficulty rising from a chair. We then tested if personal characteristics, health indicators, body composition, and performance on unrelated tasks were associated with self-reported limitations in this task. We used the same approach to examine associations between personal and health characteristics and self-reported difficulty walking between rooms, controlling for timed 8-foot walk, and self-reported difficulty getting out of bed, controlling for repeated chair rise test results. RESULTS: In multivariate analyses, participants who performed worse on the repeated chair rise test were more likely to report difficulty with chair rise. However, older age, lower education level, lower serum albumin, comorbidities, knee pain, and being underweight were also significantly associated with self-reported limitations with chair rise. Results were similar for difficulty walking between rooms and getting out of bed. CONCLUSIONS: Self-reports of limitations in physical function are influenced by personal and health characteristics that reflect frailty, and should not be interpreted solely as measured difficulty performing the task. PMID- 20707891 TI - Redo-redo aortic root replacement with a mechanical valved conduit in a patient with von Willebrand's disease: Case report. AB - A 40 year-old female, with a history of cardiac surgery for congenital aortic valve stenosis and von Willebrand's disease (VWD) presented with increasing shortness of breath due to mixed aortic valve dysfunction. With a paucity of such cases in the literature, we describe the successful outcome of a patient with VWD who underwent elective redo-redo aortic root replacement with a mechanical valved conduit. She was given a three-month trial of warfarin pre-operatively to evaluate the extent of bleeding risk. Her post-operative course was uneventful and she was discharged home after six days. PMID- 20707893 TI - Ashaninka medicinal plants: a case study from the native community of Bajo Quimiriki, Junin, Peru. AB - BACKGROUND: The Ashaninka Native Community Bajo Quimiriki, District Pichanaki, Junin, Peru, is located only 4 km from a larger urban area and is dissected by a major road. Therefore the loss of traditional knowledge is a main concern of the local headman and inhabitants. The present study assesses the state of traditional medicinal plant knowledge in the community and compares the local pharmacopoeia with the one from a related ethnic group. METHODS: Fieldwork was conducted between July and September 2007. Data were collected through semi structured interviews, collection of medicinal plants in the homegardens, forest walks, a walk along the river banks, participant observation, informal conversation, cross check through voucher specimens and a focus group interview with children. RESULTS: Four-hundred and two medicinal plants, mainly herbs, were indicated by the informants. The most important families in terms of taxa were Asteraceae, Araceae, Rubiaceae, Euphorbiaceae, Solanaceae and Piperaceae. Eighty four percent of the medicinal plants were wild and 63% were collected from the forest. Exotics accounted to only 2% of the medicinal plants. Problems related to the dermal system, digestive system, and cultural belief system represented 57% of all the medicinal applications. Some traditional healers received non indigenous customers, using their knowledge as a source of income. Age and gender were significantly correlated to medicinal plant knowledge. Children knew the medicinal plants almost exclusively by their Spanish names. Sixteen percent of the medicinal plants found in this community were also reported among the Yanesha of the Pasco Region. CONCLUSIONS: Despite the vicinity to a city, knowledge on medicinal plants and cultural beliefs are still abundant in this Ashaninka Native Community and the medicinal plants are still available in the surroundings. Nevertheless, the use of Spanish names for the medicinal plants and the shift of healing practices towards a source of income with mainly non-indigenous customers, are signs of acculturation. Future studies on quantification of the use of medicinal plants, dynamics of transmission of ethno-medicinal knowledge to the young generations and comparison with available pharmacological data on the most promising medicinal plants are suggested. PMID- 20707892 TI - Experimental traumatic brain injury. AB - Traumatic brain injury, a leading cause of death and disability, is a result of an outside force causing mechanical disruption of brain tissue and delayed pathogenic events which collectively exacerbate the injury. These pathogenic injury processes are poorly understood and accordingly no effective neuroprotective treatment is available so far. Experimental models are essential for further clarification of the highly complex pathology of traumatic brain injury towards the development of novel treatments. Among the rodent models of traumatic brain injury the most commonly used are the weight-drop, the fluid percussion, and the cortical contusion injury models. As the entire spectrum of events that might occur in traumatic brain injury cannot be covered by one single rodent model, the design and choice of a specific model represents a major challenge for neuroscientists. This review summarizes and evaluates the strengths and weaknesses of the currently available rodent models for traumatic brain injury. PMID- 20707894 TI - Atorvastatin pretreatment diminishes the levels of myocardial ischemia markers early after CABG operation: an observational study. AB - BACKGROUND: Statin pretreatment has been associated with a decrease in myocardial ischemia markers after various procedures and cardiovascular events. This study examined the potential beneficial effects of preoperative atorvastatin treatment among patients undergoing on-pump CABG operation. METHODS: Twenty patients that had received atorvastatin treatment for at least 15 days prior to the operation and 20 patients who had not received any antihyperlipidemic agent prior to surgery were included in this study. CK-MB and troponin I levels were measured at baseline and 24 hours after the operation. Perioperative variables were also recorded. RESULTS: Twenty-four hours after the operation, troponin I and CK-MB levels were significantly lower in the atorvastatin group: for CK-MB levels, 12.9 +/- 4.3 versus 18.7 +/- 7.4 ng/ml, p = 0.004; for troponin I levels, 1.7 +/- 0.3 versus 2.7 +/- 0.7 ng/ml, p < 0.001. In addition, atorvastatin use was associated with a decrease in the duration of ICU stay. CONCLUSIONS: Preoperative atorvastatin treatment results in significant reductions in the levels of myocardial injury markers early after on-pump CABG operation, suggesting a reduction in perioperative ischemia in this group of patients. Further studies are needed to elucidate the mechanisms of these potential benefits of statin pretreatment. PMID- 20707895 TI - An interactive problem-solving approach to teach traumatology for medical students. AB - AIM: We aimed to evaluate an interactive problem-solving approach for teaching traumatology from perspectives of students and consider its implications on Faculty development. METHODS: A two hour problem-solving, interactive tutorial on traumatology was structured to cover main topics in trauma management. The tutorial was based on real cases covering specific topics and objectives. Seven tutorials (5-9 students in each) were given by the same tutor with the same format for fourth and fifth year medical students in Auckland and UAE Universities (n = 50). A 16 item questionnaire, on a 7 point Likert-type scale, focusing on educational tools, tutor-based skills, and student-centered skills were answered by the students followed by open ended comments. RESULTS: The tutorials were highly ranked by the students. The mean values of educational tools was the highest followed by tutor-centered skills and finally student centered skills. There was a significant increase of the rating of studied attributes over time (F = 3.9, p = 0.004, ANOVA). Students' open ended comments were highly supportive of the interactive problem-solving approach for teaching traumatology. CONCLUSIONS: The interactive problem-solving approach for tutorials can be an effective enjoyable alternative or supplement to traditional instruction for teaching traumatology to medical students. Training for this approach should be encouraged for Faculty development. PMID- 20707896 TI - Co-localization and regulation of basic fibroblast growth factor and arginine vasopressin in neuroendocrine cells of the rat and human brain. AB - BACKGROUND: Adult rat hypothalamo-pituitary axis and choroid plexus are rich in basic fibroblast growth factor (FGF2) which likely has a role in fluid homeostasis. Towards this end, we characterized the distribution and modulation of FGF2 in the human and rat central nervous system. To ascertain a functional link between arginine vasopressin (AVP) and FGF2, a rat model of chronic dehydration was used to test the hypothesis that FGF2 expression, like that of AVP, is altered by perturbed fluid balance. METHODS: Immunohistochemistry and confocal microscopy were used to examine the distribution of FGF2 and AVP neuropeptides in the normal human brain. In order to assess effects of chronic dehydration, Sprague-Dawley rats were water deprived for 3 days. AVP neuropeptide expression and changes in FGF2 distribution in the brain, neural lobe of the pituitary and kidney were assessed by immunohistochemistry, and western blotting (FGF2 isoforms). RESULTS: In human hypothalamus, FGF2 and AVP were co-localized in the cytoplasm of supraoptic and paraventricular magnocellular neurons and axonal processes. Immunoreactive FGF2 was associated with small granular structures distributed throughout neuronal cytoplasm. Neurohypophysial FGF2 immunostaining was found in axonal processes, pituicytes and Herring bodies. Following chronic dehydration in rats, there was substantially-enhanced FGF2 staining in basement membranes underlying blood vessels, pituicytes and other glia. This accompanied remodeling of extracellular matrix. Western blot data revealed that dehydration increased expression of the hypothalamic FGF2 isoforms of ca. 18, 23 and 24 kDa. In lateral ventricle choroid plexus of dehydrated rats, FGF2 expression was augmented in the epithelium (Ab773 as immunomarker) but reduced interstitially (Ab106 immunostaining). CONCLUSIONS: Dehydration altered FGF2 expression patterns in AVP-containing magnocellular neurons and neurohypophysis, as well as in choroid plexus epithelium. This supports the involvement of centrally-synthesized FGF2, putatively coupled to that of AVP, in homeostatic mechanisms that regulate fluid balance. PMID- 20707897 TI - Determinants of tick-borne encephalitis in counties of southern Germany, 2001 2008. AB - BACKGROUND: Tick-borne encephalitis (TBE) virus can cause severe symptoms in humans. The incidence of this vector-borne pathogen in humans is characterised by spatial and temporal heterogeneity. To explain the variation in reported human TBE cases per county in southern Germany, we designed a time-lagged, spatially explicit model that incorporates ecological, environmental, and climatic factors. RESULTS: We fitted a logistic regression model to the annual counts of reported human TBE cases in each of 140 counties over an eight year period. The model controlled for spatial autocorrelation and unexplained temporal variation. The occurrence of human TBE was found to be positively correlated with the proportions of broad-leafed, mixed and coniferous forest cover. An index of forest fragmentation was negatively correlated with TBE incidence, suggesting that infection risk is higher in fragmented landscapes. The results contradict previous evidence regarding the relevance of a specific spring-time temperature regime for TBE epidemiology. Hunting bag data of roe deer (Capreolus capreolus) in the previous year was positively correlated with human TBE incidence, and hunting bag density of red fox (Vulpes vulpes) and red deer (Cervus elaphus) in the previous year were negatively correlated with human TBE incidence. CONCLUSIONS: Our approach suggests that a combination of landscape and climatic variables as well as host-species dynamics influence TBE infection risk in humans. The model was unable to explain some of the temporal variation, specifically the high counts in 2005 and 2006. Factors such as the exposure of humans to infected ticks and forest rodent population dynamics, for which we have no data, are likely to be explanatory factors. Such information is required to identify the determinants of TBE more reliably. Having records of TBE infection sites at a finer scale would also be necessary. PMID- 20707898 TI - Harm perception among Swedish daily smokers regarding nicotine, NRT-products and Swedish Snus. AB - BACKGROUND: In Sweden NRT-products and Snus, are easily available and used as smoking cessation aids. However, most quit attempts are made without any cessation aids. The limited use of these products as cessation aids may be influenced by the way smokers perceive the harmfulness of NRT-products and Snus compared to smoking. The present study examines these perceptions and their association with perceptions of the harmfulness of nicotine itself. METHODS: The study is based on the Swedish part of a two-nation web-based survey of daily smokers in Sweden (n = 1016) and Norway (n = 1000). Questionnaire items addressed perceptions of NRT-products' and Snus' harmfulness and nicotine's part of the health risks of smoking. Data analyses included cross-tabulations and logistic regressions. RESULTS: A majority, 59% of the answers to the question about harmfulness of NRT-products, and 75% of the answers about harmfulness of Snus, were inconsistent with the scientific evidence by demonstrating exaggerated perceptions of harmfulness. The strongest predictor of consistent answers was the perception of the harmfulness of nicotine. There were also significant associations with own experience of successful use of the products in question. Overall the perceptions of the harmfulness of nicotine were considerably exaggerated. This pattern was more pronounced among women than men. Prevailing misperceptions may be related to the way that different tobacco and nicotine products are presented in the media and other publicly available information sources. CONCLUSIONS: Public information about smoking and health should be expanded to include objective and unambiguous information regarding nicotine's part in the harmfulness of smoking and the harmfulness of different nicotine containing products compared to smoking.This is essential in order to preclude that misperceptions regarding these matters could discourage smokers from adopting effective cessation practices with use of nicotine-containing aids. PMID- 20707899 TI - Modeling the volume-effectiveness relationship in the case of hip fracture treatment in Finland. AB - BACKGROUND: A common argument in the recent health policy debate is that treatment is more effective among care providers with large volumes. It is challenging, however, to examine the volume-effectiveness relationship empirically. Several suggestions have recently been made for methodological improvements in the examination of the volume-effectiveness relationship. The aim of this study is to develop an extended methodology for examining the volume effectiveness relationship and demonstrate it for the case of hip fracture treatment. METHODS: Data consisting of 22,857 hip fracture patients from 52 hospitals in Finland in 1998-2001 were extracted from the administrative registers. The relationship between hospital and rehabilitation unit volumes and effectiveness was examined using a statistical model that allowed risk adjustments and hierarchical modeling of volume trends, developed for the purposes of this study. Four-month mortality and the alternative register-based measure of maintainability were used as effectiveness indicators. RESULTS: No clear relationship was found between hospital volume and the effectiveness of hip fracture treatment, but a novel result showing an association between the rehabilitation unit volume and effectiveness was detected. The face validity of the maintainability indicator seemed to be acceptable. CONCLUSIONS: The methodological ideas presented allow for improved examination of the volume effectiveness relationship. There are no indications that patients with hip fractures should only be treated in high-volume hospitals, though it may be beneficial to centralize the rehabilitation of hip fracture patients to specialized units. PMID- 20707900 TI - Dual role of nNOS in ischemic injury and preconditioning. AB - BACKGROUND: Nitric oxide (NO) is cardioprotective and a mediator of ischemic preconditioning (IP). Endothelial nitric oxide synthase (eNOS) is protective against myocardial ischemic injury and a component of IP but the role and location of neuronal nitric oxide synthase (nNOS) remains unclear. Therefore, the aims of these studies were to: (i) investigate the role of nNOS in ischemia/reoxygenation-induced injury and IP, (ii) determine whether its effect is species-dependent, and (iii) elucidate the relationship of nNOS with mitoKATP channels and p38MAPK, two key components of IP transduction pathway. RESULTS: Ventricular myocardial slices from rats and wild and nNOS knockout mice, and right atrial myocardial slices from human were subjected to 90 min ischemia and 120 min reoxygenation (37 degrees C). Specimens were randomized to receive various treatments (n = 6/group). Both the provision of exogenous NO and the inhibition of endogenous NO production significantly reduced tissue injury (creatine kinase release, cell necrosis and apoptosis), an effect that was species-independent. The cardioprotection seen with nNOS inhibition was as potent as that of IP, however, in nNOS knockout mice the cardioprotective effect of non selective NOS (L-NAME) and selective nNOS inhibition and also that of IP was blocked while the benefit of exogenous NO remained intact. Additional studies revealed that the cardioprotection afforded by exogenous NO and by inhibition of nNOS were unaffected by the mitoKATP channel blocker 5-HD, although it was abrogated by p38MAPK blocker SB203580. CONCLUSIONS: nNOS plays a dual role in ischemia/reoxygenation in that its presence is necessary to afford cardioprotection by IP and its inhibition reduces myocardial ischemic injury. The role of nNOS is species-independent and exerted downstream of the mitoKATP channels and upstream of p38MAPK. PMID- 20707901 TI - Primary resistance to clarithromycin, metronidazole and amoxicillin of Helicobacter pylori isolated from Tunisian patients with peptic ulcers and gastritis: a prospective multicentre study. AB - BACKGROUND: The frequency of primary resistance to antibiotics in H. pylori isolates is increasing worldwide. In Tunisia, there are limited data regarding the pattern of H. pylori antibiotic primary resistance. AIM: To evaluate the primary resistance of H. pylori to clarithromycin, metronidazole and amoxicillin and to detect the mutations involved in clarithromycin resistance. MATERIALS AND METHODS: 273 strains isolated from adults and children were enrolled. The primary resistance to clarithromycin, metronidazole and amoxicillin was evaluated by means of E-test minimal inhibitory concentration (MIC). The real-time PCR using Scorpion primers was performed in all cases to assess clarithromycin primary resistance and point mutations involved. RESULTS: No resistance to amoxicillin was detected. For adults, resistance to clarithromycin and metronidazole was found respectively in 14.6% and 56.8%, and respectively in 18.8% and 25% in children. Overall, the rates of global primary resistance to clarithromycin and metronidazole in Tunisia were respectively determined in 15.4% and 51.3%.By the use of Scorpion PCR, the A2143G was the most frequent point mutation observed (88.1%), followed by the A2142G (11.9%); the A2142C was not found and 18 of 42 patients (42.8%) were infected by both the resistant and the susceptible genotype.The association of clarithromycin resistance with gender was not statistically significant, but metronidazole resistant strains were isolated more frequently in females (67.8%) than in males (32.2%) and the difference was significant. As for gastroduodenal diseases, the difference between strains isolated from patients with peptic ulceration and those with non peptic ulceration was not statistically significant. When about the distribution of resistant strains to clarithromycin and metronidazole between the three Tunisian cities (Tunis, Menzel Bourguiba and Mahdia), the difference was not statistically significant. CONCLUSION: Local data regarding the primary resistance of H. pylori to clarithromycin, metronidazole and amoxicillin and the main genetic mutation involved in clarithromycin resistance in vivo (A2143G) are necessary to prove a clear need for a periodic evaluation of antibiotic consumption and new therapeutic strategies in Tunisia in order to avoid the emergence of resistant strains. PMID- 20707902 TI - Cognitive testing of physical activity and acculturation questions in recent and long-term Latino immigrants. AB - BACKGROUND: We ascertained the degree to which language (English versus Spanish), and residence time in the US influence responses to survey questions concerning two topics: self-reported acculturation status, and recent physical activity (PA). This topic is likely to be of general interest because of growing numbers of immigrants in countries worldwide. METHODS: We carried out qualitative (cognitive) interviews of survey items on acculturation and physical activity on 27 Latino subjects from three groups: (a) In Spanish, of those of low residence time (less than five years living in the U.S.) (n = 9); (b) In Spanish, of those of high residence time (15 or more years in the U.S) (n = 9); and (c) in English, of those of high residence time (n = 9). RESULTS: There were very few language translation problems; general question design defects and socio-cultural challenges to survey responses were more common. Problems were found for both acculturation and PA questions, with distinct problem types for the two question areas. Residence time/language group was weakly associated with overall frequency of problems observed: low residence time/Spanish (86%), high residence time/Spanish (67%), and English speaking groups (62%). CONCLUSIONS: Standardized survey questions related to acculturation and physical activity present somewhat different cognitive challenges. For PA related questions, problems with such questions were similar regardless of subject residence time or language preference. For acculturation related questions, residence time/language or education level influenced responses to such questions. These observations should help in the interpretation of survey results for culturally diverse populations. PMID- 20707903 TI - Optimization strategies for metabolic networks. AB - BACKGROUND: The increasing availability of models and data for metabolic networks poses new challenges in what concerns optimization for biological systems. Due to the high level of complexity and uncertainty associated to these networks the suggested models often lack detail and liability, required to determine the proper optimization strategies. A possible approach to overcome this limitation is the combination of both kinetic and stoichiometric models. In this paper three control optimization methods, with different levels of complexity and assuming various degrees of process information, are presented and their results compared using a prototype network. RESULTS: The results obtained show that Bi-Level optimization lead to a good approximation of the optimum attainable with the full information on the original network. Furthermore, using Pontryagin's Maximum Principle it is shown that the optimal control for the network in question, can only assume values on the extremes of the interval of its possible values. CONCLUSIONS: It is shown that, for a class of networks in which the product that favors cell growth competes with the desired product yield, the optimal control that explores this trade-off assumes only extreme values. The proposed Bi-Level optimization led to a good approximation of the original network, allowing to overcome the limitation on the available information, often present in metabolic network models. Although the prototype network considered, it is stressed that the results obtained concern methods, and provide guidelines that are valid in a wider context. PMID- 20707904 TI - Unique features of the rice blast resistance Pish locus revealed by large scale retrotransposon-tagging. AB - BACKGROUND: R gene-mediated resistance is one of the most effective mechanisms of immunity against pathogens in plants. To date some components that regulate the primary steps of plant immunity have been isolated, however, the molecular dissection of defense signaling downstream of the R proteins remains to be completed. In addition, R genes are known to be highly variable, however, the molecular mechanisms responsible for this variability remain obscure. RESULTS: To identify novel factors required for R gene-mediated resistance in rice, we used rice insertional mutant lines, induced by the endogenous retrotransposon Tos17, in a genetic screening involving the rice blast fungus Magnaporthe oryzae. We inoculated 41,119 mutant lines with the fungus using a high throughput procedure, and identified 86 mutant lines with diminished resistance. A genome analysis revealed that 72 of the 86 lines contained mutations in a gene encoding a nucleotide binding site (NBS) and leucine rich repeat (LRR) domain-containing (NBS-LRR) protein. A genetic complementation analysis and a pathogenesis assay demonstrated that this NBS-LRR gene encodes Pish, which confers resistance against races of M. oryzae containing avrPish. The other 14 lines have intact copies of the Pish gene, suggesting that they may contain mutations in the signaling components downstream of Pish. The genome analysis indicated that Pish and its neighboring three NBS-LRR genes are high similar to one another and are tandemly located. An in silico analysis of a Tos17 flanking sequence database revealed that this region is a "hot spot" for insertion. Intriguingly, the insertion sites are not distributed evenly among these four NBS-LRR genes, despite their similarity at the sequence and expression levels. CONCLUSIONS: In this work we isolated the R gene Pish, and identified several other mutants involved in the signal transduction required for Pish-mediated resistance. These results indicate that our genetic approach is efficient and useful for unveiling novel aspects of defense signaling in rice. Furthermore, our data provide experimental evidence that R gene clusters have the potential to be highly preferred targets for transposable element insertions in plant genomes. Based on this finding, a possible mechanism underlying the high variability of R genes is discussed. PMID- 20707905 TI - Interaction of magnetite-based receptors in the beak with the visual system underlying 'fixed direction' responses in birds. AB - BACKGROUND: European robins, Erithacus rubecula, show two types of directional responses to the magnetic field: (1) compass orientation that is based on radical pair processes and lateralized in favor of the right eye and (2) so-called 'fixed direction' responses that originate in the magnetite-based receptors in the upper beak. Both responses are light-dependent. Lateralization of the 'fixed direction' responses would suggest an interaction between the two magnetoreception systems. RESULTS: Robins were tested with either the right or the left eye covered or with both eyes uncovered for their orientation under different light conditions. With 502 nm turquoise light, the birds showed normal compass orientation, whereas they displayed an easterly 'fixed direction' response under a combination of 502 nm turquoise with 590 nm yellow light. Monocularly right-eyed birds with their left eye covered were oriented just as they were binocularly as controls: under turquoise in their northerly migratory direction, under turquoise-and-yellow towards east. The response of monocularly left-eyed birds differed: under turquoise light, they were disoriented, reflecting a lateralization of the magnetic compass system in favor of the right eye, whereas they continued to head eastward under turquoise-and-yellow light. CONCLUSION: 'Fixed direction' responses are not lateralized. Hence the interactions between the magnetite receptors in the beak and the visual system do not seem to involve the magnetoreception system based on radical pair processes, but rather other, non lateralized components of the visual system. PMID- 20707906 TI - Intelligence and ambition are distributed equally around the globe. AB - The impact of freely accessible knowledge distribution platforms is briefly discussed. PMID- 20707907 TI - Retraction: Influenza or not influenza: analysis of a case of high fever that happened 2000 years ago in Biblical time. PMID- 20707908 TI - Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study. AB - BACKGROUND: We are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals. As an initial test of this strategy, we conducted a pilot study with human colorectal cancer (CRC) and its mouse model C57BL/6J ApcMin/+, focusing on human 5q22.2 and 18q21.1-q21.2. METHODS: We first performed bioinformatics analysis on the evolution of 5q22.2 and 18q21.1-q21.2 regions. Then, we performed exon-targeted sequencing, real time quantitative polymerase chain reaction (qPCR), and real time quantitative reverse transcriptase PCR (qRT-PCR) analyses on a number of genes of both regions with both human and mouse colon tumors. RESULTS: These two regions (5q22.2 and 18q21.1-q21.2) are frequently deleted in human CRCs and encode genuine colorectal tumor suppressors APC and SMAD4. They also encode genes such as MCC (mutated in colorectal cancer) with their role in CRC etiology unknown. We have discovered that both regions are evolutionarily unstable, resulting in genes that are clustered in each human region being found scattered at several distinct loci in the genome of many other species. For instance, APC and MCC are within 200 kb apart in human 5q22.2 but are 10 Mb apart in the mouse genome. Importantly, our analyses revealed that, while known CRC driver genes APC and SMAD4 were disrupted in both human colorectal tumors and tumors from ApcMin/+ mice, the questionable MCC gene was disrupted in human tumors but appeared to be intact in mouse tumors. CONCLUSIONS: These results indicate that MCC may not actually play any causative role in early colorectal tumorigenesis. We also hypothesize that its disruption in human CRCs is likely a mere result of its close proximity to APC in the human genome. Expanding this pilot study to the entire genome may identify more questionable genes like MCC, facilitating the discovery of new CRC driver gene candidates. PMID- 20707909 TI - Deep sequencing-based transcriptome profiling analysis of bacteria-challenged Lateolabrax japonicus reveals insight into the immune-relevant genes in marine fish. AB - BACKGROUND: Systematic research on fish immunogenetics is indispensable in understanding the origin and evolution of immune systems. This has long been a challenging task because of the limited number of deep sequencing technologies and genome backgrounds of non-model fish available. The newly developed Solexa/Illumina RNA-seq and Digital gene expression (DGE) are high-throughput sequencing approaches and are powerful tools for genomic studies at the transcriptome level. This study reports the transcriptome profiling analysis of bacteria-challenged Lateolabrax japonicus using RNA-seq and DGE in an attempt to gain insights into the immunogenetics of marine fish. RESULTS: RNA-seq analysis generated 169,950 non-redundant consensus sequences, among which 48,987 functional transcripts with complete or various length encoding regions were identified. More than 52% of these transcripts are possibly involved in approximately 219 known metabolic or signalling pathways, while 2,673 transcripts were associated with immune-relevant genes. In addition, approximately 8% of the transcripts appeared to be fish-specific genes that have never been described before. DGE analysis revealed that the host transcriptome profile of Vibrio harveyi-challenged L. japonicus is considerably altered, as indicated by the significant up- or down-regulation of 1,224 strong infection-responsive transcripts. Results indicated an overall conservation of the components and transcriptome alterations underlying innate and adaptive immunity in fish and other vertebrate models. Analysis suggested the acquisition of numerous fish specific immune system components during early vertebrate evolution. CONCLUSION: This study provided a global survey of host defence gene activities against bacterial challenge in a non-model marine fish. Results can contribute to the in depth study of candidate genes in marine fish immunity, and help improve current understanding of host-pathogen interactions and evolutionary history of immunogenetics from fish to mammals. PMID- 20707910 TI - Homologous illegitimate random integration of foreign DNA into the X chromosome of a transgenic mouse line. AB - BACKGROUND: It is not clear how foreign DNA molecules insert into the host genome. Recently, we have produced transgenic mice to investigate the role of the fad2 gene in the conversion of oleic acid to linoleic acid. Here we describe an integration mechanism of fad2 transgene by homologous illegitimate random integration. RESULTS: We confirmed that one fad2 line had a sole integration site on the X chromosome according to the inheritance patterns. Mapping of insertion sequences with thermal asymmetric interlaced and conventional PCR revealed that the foreign DNA was inserted into the XC1 region of the X chromosome by a homologous illegitimate replacement of an entire 45,556-bp endogenous genomic region, including the ovarian granulosa cell tumourigenesis-4 allele. For 5' and 3' junction sequences, there were very short (3-7 bp) common sequences in the AT rich domains, which may mediate the recognition of the homologous arms between the transgene and the host genome. In addition, analysis of gene transcription indicated that the transgene was expressed in all tested fad2 tissues and that its transcription level in homozygous female tissues was about twice as high as in the heterozygous female (p < 0.05). CONCLUSIONS: Taken together, the results indicated that the foreign fad2 behaved like an X-linked gene and that foreign DNA molecules were inserted into the eukaryotic genome through a homologous illegitimate random integration. PMID- 20707911 TI - Factors associated with dental caries among institutionalized residents with schizophrenia in Taiwan: a cross-sectional study. AB - BACKGROUND: Little research has been done on the relationship between dental caries and the personal characteristics of institutionalized residents diagnosed with schizophrenia. This study investigates the individual and treatment factors associated with the dental caries among institutionalized residents with schizophrenia in Taiwan. METHODS: An oral health survey of institutionalized residents with schizophrenia in the largest public psychiatric hospital was conducted in Taiwan in 2006. Based on this data, multiple logistic analyses were used to determine the relationship between some explanatory variables and the outcome variables of dental caries among subjects with schizophrenia. RESULTS: Among the 1,108 subjects with schizophrenia, age was the only variable independently associated with DMFT > 8 (OR = 7.74, 95% CI = 3.86-15.55, p < 0.001 in comparison to residents aged 65 + years vs. 20-44 years; OR = 3.06, 95% CI = 2.03-4.61, p < 0.001 in comparison to residents aged 55-64 years vs. 20-44 years) after making adjustments for other explanatory variables. In addition, those with an education of only elementary school (OR = 1.67, 95% CI = 1.08-2.56, p = 0.021), low income (OR = 1.58, 95% CI = 1.02-2.44, p = 0.039), and length of stay (LOS) of > 10 years (OR = 2.09, 95% CI = 1.30-3.37, p = 0.002) were associated with a care index < 54.7%. Older age, lower educational level, and longer hospital stays were associated with number of remaining teeth being < 24. CONCLUSIONS: Aging was the most important factor related to a high level of dental caries. Low educational level, low income, and LOS were also associated with the indicators of dental caries among institutionalized subjects with schizophrenia. It is necessary to address the treatment factors such as prolonged stay in institutions when decision-makers are planning for preventive strategies of oral health for institutionalized residents with schizophrenia. PMID- 20707912 TI - Genetic validation of whole-transcriptome sequencing for mapping expression affected by cis-regulatory variation. AB - BACKGROUND: Identifying associations between genotypes and gene expression levels using microarrays has enabled systematic interrogation of regulatory variation underlying complex phenotypes. This approach has vast potential for functional characterization of disease states, but its prohibitive cost, given hundreds to thousands of individual samples from populations have to be genotyped and expression profiled, has limited its widespread application. RESULTS: Here we demonstrate that genomic regions with allele-specific expression (ASE) detected by sequencing cDNA are highly enriched for cis-acting expression quantitative trait loci (cis-eQTL) identified by profiling of 500 animals in parallel, with up to 90% agreement on the allele that is preferentially expressed. We also observed widespread noncoding and antisense ASE and identified several allele-specific alternative splicing variants. CONCLUSION: Monitoring ASE by sequencing cDNA from as little as one sample is a practical alternative to expression genetics for mapping cis-acting variation that regulates RNA transcription and processing. PMID- 20707913 TI - Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts. AB - BACKGROUND: Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-O-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth in vivo. METHODS: We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. In vitro studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using in vivo xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. In vivo studies were statistically analyzed using Student's t test. RESULTS: In vitro, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular density within the tumors. By contrast, transient exogenous treatment of MDA-MB-231 xenografts with rhSulf2 was not sufficient to inhibit or reverse tumor growth. CONCLUSION: These data indicate that in vivo progression of human breast cancer xenografts can be inhibited with sulfatase expression, and therapeutic effect requires constant delivery at the tumor site. Our results support a direct effect of sulfatases on tumor growth or invasion, rather than an effect in the stromal compartment. PMID- 20707914 TI - Identification of Staphylococcus aureus: DNase and Mannitol salt agar improve the efficiency of the tube coagulase test. AB - BACKGROUND: The ideal identification of Staphylococcus aureus clinical isolates requires a battery of tests and this is costly in resource limited settings. In many developing countries, the tube coagulase test is usually confirmatory for S. aureus and is routinely done using either human or sheep plasma. This study evaluated Mannitol salt agar and the deoxyribonuclease (DNase) test for improving the efficiency of the tube coagulase test in resource limited settings. The efficiency of human and sheep plasma with tube coagulase tests was also evaluated. METHODS: One hundred and eighty Gram positive, Catalase positive cocci occurring in pairs, short chains or clusters were subjected to growth on Mannitol salt agar, deoxyribonuclease and tube coagulase tests. Of these, isolates that were positive for at least two of the three tests (n = 60) were used to evaluate the performance of the tube coagulase test for identification of S. aureus, using PCR-amplification of the nuc gene as a gold standard. RESULTS: Human plasma was more sensitive than sheep plasma for the tube coagulase test (sensitivity of 91% vs. 81% respectively), but both plasmas had very low specificity (11% and 7% respectively). The sensitivity and specificity of the tube coagulase test (human plasma) was markedly improved when Mannitol salt agar and DNase were introduced as a tri-combination test for routine identification of Staphylococcus aureus (100% specificity and 75% sensitivity). The specificity and sensitivity of Mannitol salt agar/DNase/tube coagulase (sheep plasma) combination was 100% and 67%, respectively. CONCLUSION: The efficiency of the tube coagulase test can be markedly improved by sequel testing of the isolates with Mannitol salt agar, DNase and Tube coagulase. There is no single phenotypic test (including tube coagulase) that can guarantee reliable results in the identification of Staphylococcus aureus. PMID- 20707915 TI - Associations between genetic variations in the FURIN gene and hypertension. AB - BACKGROUND: Hypertension is a complex disease influenced by multiple genetic and environmental factors. The Kazakh ethnic group is characterized by a relatively high prevalence of hypertension. Previous research indicates that the FURIN gene may play a pivotal role in the renin-angiotensin system and maintaining the sodium-electrolyte balance. Because these systems influence blood pressure regulation, we considered FURIN as a candidate gene for hypertension. The purpose of this study was to systematically investigate the association between genetic variations in the FURIN gene and essential hypertension in a Xinjiang Kazakh population. METHODS: We sequenced all exons and the promoter regions of the FURIN gene in 94 hypertensive individuals to identify genetic variations associated with the disorder. Genotyping was performed using the TaqMan polymerase chain reaction method for four representative common single nucleotide polymorphisms (SNPs, -7315C > T, 1970C > G, 5604C > G, 6262C > T) in 934 Kazakh Chinese people. One SNP (1970C > G) was replicated in 1,219 Uygur Chinese people. RESULTS: Nine novel and seven known single nucleotide polymorphisms were identified in the FURIN gene. The results suggest that 1970C > G was associated with a hypertension phenotype in Kazakh Chinese (additive model, P = 0.091; dominant model, P = 0.031, allele model, P = 0.030), and after adjustment with logistic regression analysis, ORs were 1.451 (95%CI 1.106-1.905, P = 0.008) and 1.496 (95% 1.103 2.028, P = 0.01) in additive and dominant models, respectively. In addition, the association between 1970C > G and hypertension was replicated in Uygur subjects (additive model, P = 0.042; dominant model, P = 0.102; allele model, P = 0.027) after adjustment in additive and dominant models, ORs were 1.327 (95% 1.07 1.646), P = 0.01 and 1.307 (95%CI 1.015-1.681, P = 0.038), respectively. G allele carriers exhibited significant lower urinary Na+ excretion rate than non-carriers in the Kazakh Chinese population (152.45 +/- 76.04 uM/min vs 173.33 +/- 90.02 uM/min, P = 0.007). CONCLUSION: Our results suggest that the FURIN gene may be a candidate gene involved in human hypertension, and that the G allele of 1970C > G may be a modest risk factor for hypertension in Xinjiang Kazakh and Uygur populations. PMID- 20707916 TI - Genomic comparisons of Brucella spp. and closely related bacteria using base compositional and proteome based methods. AB - BACKGROUND: Classification of bacteria within the genus Brucella has been difficult due in part to considerable genomic homogeneity between the different species and biovars, in spite of clear differences in phenotypes. Therefore, many different methods have been used to assess Brucella taxonomy. In the current work, we examine 32 sequenced genomes from genus Brucella representing the six classical species, as well as more recently described species, using bioinformatical methods. Comparisons were made at the level of genomic DNA using oligonucleotide based methods (Markov chain based genomic signatures, genomic codon and amino acid frequencies based comparisons) and proteomes (all-against all BLAST protein comparisons and pan-genomic analyses). RESULTS: We found that the oligonucleotide based methods gave different results compared to that of the proteome based methods. Differences were also found between the oligonucleotide based methods used. Whilst the Markov chain based genomic signatures grouped the different species in genus Brucella according to host preference, the codon and amino acid frequencies based methods reflected small differences between the Brucella species. Only minor differences could be detected between all genera included in this study using the codon and amino acid frequencies based methods. Proteome comparisons were found to be in strong accordance with current Brucella taxonomy indicating a remarkable association between gene gain or loss on one hand and mutations in marker genes on the other. The proteome based methods found greater similarity between Brucella species and Ochrobactrum species than between species within genus Agrobacterium compared to each other. In other words, proteome comparisons of species within genus Agrobacterium were found to be more diverse than proteome comparisons between species in genus Brucella and genus Ochrobactrum. Pan-genomic analyses indicated that uptake of DNA from outside genus Brucella appears to be limited. CONCLUSIONS: While both the proteome based methods and the Markov chain based genomic signatures were able to reflect environmental diversity between the different species and strains of genus Brucella, the genomic codon and amino acid frequencies based comparisons were not found adequate for such comparisons. The proteome comparison based phylogenies of the species in genus Brucella showed a surprising consistency with current Brucella taxonomy. PMID- 20707917 TI - 3D collagen type I matrix inhibits the antimigratory effect of doxorubicin. AB - BACKGROUND: The cell microenvironment, especially extracellular matrix proteins, plays an important role in tumor cell response to chemotherapeutic drugs. The present study was designed to investigate whether this microenvironment can influence the antimigratory effect of an anthracycline drug, doxorubicin, when tumor cells are grown in a matrix of type I collagen, a three-dimensional (3D) context which simulates a natural microenvironment. METHODS: To this purpose, we studied the migratory parameters, the integrin expression, and the activation state of focal adhesion kinase (FAK) and GTPase RhoA involved in the formation of focal adhesions and cell movement. These parameters were evaluated at non toxic concentrations which did not affect HT1080 cell proliferation. RESULTS: We show that while doxorubicin decreased cell migration properties by 70% in conventional two-dimensional (2D) culture, this effect was completely abolished in a 3D one. Regarding the impact of doxorubicin on the focal adhesion complexes, unlike in 2D systems, the data indicated that the drug neither affected beta1 integrin expression nor the state of phosphorylation of FAK and RhoA. CONCLUSION: This study suggests the lack of antiinvasive effect of doxorubicin in a 3D environment which is generally considered to better mimic the phenotypic behaviour of cells in vivo. Consistent with the previously shown resistance to the cytotoxic effect in a 3D context, our results highlight the importance of the matrix configuration on the tumor cell response to antiinvasive drugs. PMID- 20707918 TI - Infection with HIV and HCV enhances the release of fatty acid synthase into circulation: evidence for a novel indicator of viral infection. AB - BACKGROUND: Fatty acid synthase (FASN) is an enzyme synthesized by the liver and plays an important role in lipogenesis. The present study aimed to investigate whether serum FASN concentration may provide a direct link between HIV and/or HCV viral infections and lipid metabolic disorders commonly observed in HIV/HCV infected patients. METHODS: We evaluated serum FASN concentration in 191 consecutive HIV-infected patients in the absence or presence of HCV co-infection. For comparison, 102 uninfected controls were included. Metabolic and inflammatory phenotype was also compared with respect to the presence of HCV co-infection. RESULTS: Serum FASN concentration was significantly higher in HIV-infected patients than in healthy participants and HCV co-infected patients showed higher levels than those without co-infection. Levels were also affected by treatment regimen, but marginally influenced by virological variables. Insulin concentration was the sole variable among metabolic parameters that demonstrated a significant correlation with serum FASN concentrations. Serum alanine aminotransferase (ALT) values correlated significantly with serum FASN concentration and provided the best discrimination with respect to the presence or absence of HCV co-infection. In multivariate analysis, only ALT, monocyte chemoattractant protein-1 (MCP-1) and the presence of antiretroviral treatment regimen significantly contributed to explain serum FASN concentration in HIV/HCV co-infected patients. CONCLUSION: Serum FASN concentration is significantly increased in HIV-infected individuals. The release of FASN into the circulation is further enhanced in patients who are co-infected with HCV. Subsequent studies should explore the usefulness of this indicator to monitor the effect of viral infections on disease progression and survival. PMID- 20707919 TI - Fabrication of PLGA nanoparticles with a fluidic nanoprecipitation system. AB - Particle size is a key feature in determining performance of nanoparticles as drug carriers because it influences circulating half-life, cellular uptake and biodistribution. Because the size of particles has such a major impact on their performance, the uniformity of the particle population is also a significant factor. Particles comprised of the polymer poly(lactic-co-glycolic acid) (PLGA) are widely studied as therapeutic delivery vehicles because they are biodegradable and biocompatible. In fact, microparticles comprised of PLGA are already approved for drug delivery. Unfortunately, PLGA nanoparticles prepared by conventional methods usually lack uniformity. We developed a novel Fluidic NanoPrecipitation System (FNPS) to fabricate highly uniform PLGA particles. Several parameters can be fine-tuned to generate particles of various sizes. PMID- 20707920 TI - Contextual and individual assessment of dental pain period prevalence in adolescents: a multilevel approach. AB - BACKGROUND: Despite evidence that health and disease occur in social contexts, the vast majority of studies addressing dental pain exclusively assessed information gathered at individual level. OBJECTIVES: To assess the association between dental pain and contextual and individual characteristics in Brazilian adolescents. In addition, we aimed to test whether contextual Human Development Index is independently associated with dental pain after adjusting for individual level variables of socio-demographics and dental characteristics. METHODS: The study used data from an oral health survey carried out in Sao Paulo, Brazil, which included dental pain, dental exams, individual socioeconomic and demographic conditions, and Human Development Index at area level of 4,249 12 year-old and 1,566 15-year-old schoolchildren. The Poisson multilevel analysis was performed. RESULTS: Dental pain was found among 25.6% (95%CI = 24.5-26.7) of the adolescents and was 33% less prevalent among those living in more developed areas of the city than among those living in less developed areas. Girls, blacks, those whose parents earn low income and have low schooling, those studying at public schools, and those with dental treatment needs presented higher dental pain prevalence than their counterparts. Area HDI remained associated with dental pain after adjusting for individual level variables of socio demographic and dental characteristics. CONCLUSIONS: Girls, students whose parents have low schooling, those with low per capita income, those classified as having black skin color and those with dental treatment needs had higher dental pain prevalence than their counterparts. Students from areas with low Human Development Index had higher prevalence of dental pain than those from the more developed areas regardless of individual characteristics. PMID- 20707921 TI - The role of spectrophotometry in the diagnosis of melanoma. AB - BACKGROUND: Spectrophotometry (SPT) could represent a promising technique for the diagnosis of cutaneous melanoma (CM) at earlier stages of the disease. Starting from our experience, we further assessed the role of SPT in CM early detection. METHODS: During a health campaign for malignant melanoma at National Cancer Institute of Naples, we identified a subset of 54 lesions to be addressed to surgical excision and histological examination. Before surgery, all patients were investigated by clinical and epiluminescence microscopy (ELM) screenings; selected lesions underwent spectrophotometer analysis. For SPT, we used a video spectrophotometer imaging system (Spectroshade MHT S.p.A., Verona, Italy). RESULTS: Among the 54 patients harbouring cutaneous pigmented lesions, we performed comparison between results from the SPT screening and the histological diagnoses as well as evaluation of both sensitivity and specificity in detecting CM using either SPT or conventional approaches. For all pigmented lesions, agreement between histology and SPT classification was 57.4%. The sensitivity and specificity of SPT in detecting melanoma were 66.6% and 76.2%, respectively. CONCLUSIONS: Although SPT is still considered as a valuable diagnostic tool for CM, its low accuracy, sensitivity, and specificity represent the main hamper for the introduction of such a methodology in clinical practice. Dermoscopy remains the best diagnostic tool for the preoperative diagnosis of pigmented skin lesions. PMID- 20707922 TI - The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. AB - BACKGROUND: Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out. METHODS: Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI50 data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested in vitro for the ability to influence tumor susceptibility to arsenic trioxide. RESULTS: A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down. CONCLUSIONS: In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment. PMID- 20707923 TI - Matrix metalloproteinase-3 promoter polymorphisms but not dupA-H. pylori correlate to duodenal ulcers in H. pylori-infected females. AB - BACKGROUND: This study investigated if the H. pylori dupA genotype and certain host single nucleotide polymorphisms (SNPs) of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), including MMP-3, MMP-7, MMP-9, TIMP-1 and TIMP-2, might correlate with ulcer risk of H. pylori-infected Taiwanese patients. RESULTS: Of the 549 H. pylori-infected patients enrolled, 470 patients (265 with gastritis, 118 with duodenal ulcer, and 87 with gastric ulcer) received SNPs analysis of MMP-3-1612 6A > 5A, MMP-7-181 A > G, MMP-9exon 6 A > G, TIMP-1372 T > C and TIMP-2-418 G > C by PCR-RFLP. The 181 collected H. pylori isolates were detected for the dupA genotype by PCR. The rates of dupA-positive H. pylori infection were similar among patients with duodenal ulcer (22.8%), gastric ulcer (20.0%), and gastritis (25.5%) (p > 0.05). Males had higher rates of duodenal ulcer and gastric ulcer than females (p < 0.01). Of H. pylori-infected patients, the MMP-3 6A6A genotype were more common in patients with duodenal ulcers than in those with gastritis (87.7% vs. 74.9%, p < 0.05) in females. This genotype had a 2.4-fold (95% CI: 1.02-5.66) increased risk of duodenal ulcer, compared to those with the 5A carrier. Combining the MMP-3/TIMP-1 genotype as 6A6A/CC, the risk of duodenal ulcer increased up to 3.6 fold (p < 0.05) in H. pylori-infected females. CONCLUSIONS: The MMP-3 promoter polymorphism, but not the dupA-status, may correlate with susceptibility to duodenal ulcer after H. pylori infection in Taiwanese females. PMID- 20707924 TI - Central odontogenic fibroma: a case report with long-term follow-up. AB - An osteolytic tumour of the mandible with prominent expansive growth on the alveolar ridge and displacement of the involved teeth is described in a 28-year old man. The lesion was diagnosed as a central odontogenic fibroma, an uncommon benign neoplasm derived from dental apparatus, and was removed by curettage. The patient remains asymptomatic after thirteen years of follow-up, which supports the claimed indolent behavior of this poorly documented disease and the adequacy of a conservative surgical treatment. PMID- 20707925 TI - Encoding the states of interacting proteins to facilitate biological pathways reconstruction. AB - BACKGROUND: In a systems biology perspective, protein-protein interactions (PPI) are encoded in machine-readable formats to avoid issues encountered in their retrieval for the reconstruction of comprehensive interaction maps and biological pathways. However, the information stored in electronic formats currently used doesn't allow a valid automatic reconstruction of biological pathways. RESULTS: We propose a logical model of PPI that takes into account the "state" of proteins before and after the interaction. This information is necessary for proper reconstruction of the pathway. CONCLUSIONS: The adoption of the proposed model, which can be easily integrated into existing machine-readable formats used to store the PPI data, would facilitate the automatic or semi-automated reconstruction of biological pathways. REVIEWERS: This article was reviewed by Dr. Wen-Yu Chung (nominated by Kateryna Makova), Dr. Carl Herrmann (nominated by Dr. Purificacion Lopez-Garcia) and Dr. Arcady Mushegian. PMID- 20707926 TI - Non-polypoidal, synchronous mantle-cell lymphoma of small intestine: a rare case. AB - Herein is reported the case of a mantle cell lymphoma (MCL) with synchronous double intestinal location. A 74-year old male presented with mild abdominal pain. CT scan imaging indicated invasion of lateral intestinal cavity by large mass formation. Exploratory laparotomy was performed and two solid extra-mural masses were isolated and excised. Histology revealed non-polypoid double synchronous lymphoma of mantle cell origin, an unusual presentation of the disease. PMID- 20707927 TI - Modulation of the maternal immune system by the pre-implantation embryo. AB - BACKGROUND: A large proportion of pregnancy losses occur during the pre implantation period, when the developing embryo is elongating rapidly and signalling its presence to the maternal system. The molecular mechanisms that prevent luteolysis and support embryo survival within the maternal environment are not well understood. To gain a more complete picture of these molecular events, genome-wide transcriptional profiles of reproductive day 17 endometrial tissue were determined in pregnant and cyclic Holstein-Friesian dairy cattle. RESULTS: Microarray analyses revealed 1,839 and 1,189 differentially expressed transcripts between pregnant and cyclic animals (with > or = 1.5 fold change in expression; P-value < 0.05, MTC Benjamini-Hochberg) in caruncular and intercaruncular endometrium respectively. Gene ontology and biological pathway analysis of differentially expressed genes revealed enrichment for genes involved in interferon signalling and modulation of the immune response in pregnant animals. CONCLUSION: The maternal immune system actively surveys the uterine environment during early pregnancy. The embryo modulates this response inducing the expression of endometrial molecules that suppress the immune response and promote maternal tolerance to the embryo. During this period of local immune suppression, genes of the innate immune response (in particular, antimicrobial genes) may function to protect the uterus against infection. PMID- 20707928 TI - ReCGiP, a database of reproduction candidate genes in pigs based on bibliomics. AB - BACKGROUND: Reproduction in pigs is one of the most economically important traits. To improve the reproductive performances, numerous studies have focused on the identification of candidate genes. However, it is hard for one to read all literatures thoroughly to get information. So we have developed a database providing candidate genes for reproductive researches in pig by mining and processing existing biological literatures in human and pigs, named as ReCGiP. DESCRIPTION: Based on text-mining and comparative genomics, ReCGiP presents diverse information of reproduction-relevant genes in human and pig. The genes were sorted by the degree of relevance with the reproduction topics and were visualized in a gene's co-occurrence network where two genes were connected if they were co-cited in a PubMed abstract. The 'hub' genes which had more 'neighbors' were thought to be have more important functions and could be identified by the user in their web browser. In addition, ReCGiP provided integrated GO annotation, OMIM and biological pathway information collected from the Internet. Both pig and human gene information can be found in the database, which is now available. CONCLUSIONS: ReCGiP is a unique database providing information on reproduction related genes for pig. It can be used in the area of the molecular genetics, the genetic linkage map, and the breeding of the pig and other livestock. Moreover, it can be used as a reference for human reproduction research. PMID- 20707929 TI - Effect of experimental treatment on GAPDH mRNA expression as a housekeeping gene in human diploid fibroblasts. AB - BACKGROUND: Several genes have been used as housekeeping genes and choosing an appropriate reference gene is important for accurate quantitative RNA expression in real time RT-PCR technique. The expression levels of reference genes should remain constant between the cells of different tissues and under different experimental conditions. The purpose of this study was to determine the effect of different experimental treatments on the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA so that the reliability of GAPDH as reference gene for quantitative real time RT-PCR in human diploid fibroblasts (HDFs) can be validated. HDFs in 4 different treatment groups viz; young (passage 4), senescent (passage 30), H2O2-induced oxidative stress and gamma-tocotrienol (GTT)-treated groups were harvested for total RNA extraction. Total RNA concentration and purity were determined prior to GAPDH mRNA quantification. Standard curve of GAPDH expression in serial diluted total RNA, melting curve analysis and agarose gel electrophoresis were used to determine the reliability of GAPDH as reference gene. RESULTS: HDFs with different experimental treatments exhibited diverse cell morphology with different expression of senescence-associated beta-galactosidase (SA beta-gal) activity. However the expression level of GAPDH was consistent in all treatment groups. CONCLUSION: The study demonstrated that GAPDH is reliable as reference gene for quantitative gene expression analysis in HDFs. Therefore it can be used as housekeeping gene for quantitative real time RT-PCR technique in human diploid fibroblasts particularly in studying cellular senescence. PMID- 20707930 TI - Endotoxin tolerance and cross-tolerance in mast cells involves TLR4, TLR2 and FcepsilonR1 interactions and SOCS expression: perspectives on immunomodulation in infectious and allergic diseases. AB - BACKGROUND: The study of the endotoxin tolerance phenomenon in light of the recently defined roles of mast cells and toll-like receptors as essential components of the innate immune response and as orchestrators of acquired immunity may reveal potentially useful mechanisms of immunomodulation of infectious and allergic inflammatory responses, such as sepsis or asthma. Here we evaluated the phenomenon of direct tolerance of endotoxins, as well as the induction of cross-tolerance and synergism by stimulation with toll-like receptor 2 (TLR2) and FcepsilonR1 agonists, in murine mast cells prestimulated with lipopolysaccharide (LPS). Additionally, we evaluated some stimulatory and inhibitory signaling molecules potentially involved in these phenomena. METHODS: MC/9 cells and primary bone marrow-derived mast cells obtained from C57BL/6 and TLR4-/- knock-out mice were sensitized to DNP-HSA (antigen) by incubation with DNP-IgE and were prestimulated with LPS for 18 hr prior to stimulation. Cultures were stimulated with LPS or Pam3Cys-Ser-(Lys)4 3HCl (P3C), a TLR2 agonist, individually or in combination with antigen. The production of IL-6 and TNFalpha, the phosphorylation of NFkappaB and p38 MAPK, and the expression of TLR4 and SOCS 1 and -3 were analyzed. RESULTS: We found that production of TNFalpha and IL-6 in murine mast cells that have been pretreated with LPS and challenged with TLR4 (LPS) or -2 (P3C) agonists was reduced, phenomena described as endotoxin tolerance (LPS) and cross-tolerance (P3C), respectively. The expression of TLR4 was not affected by LPS pretreatment. Our results show that the FcepsilonR1 agonist DNP-HSA (antigen) interacts synergistically with LPS or P3C to markedly enhance production of cytokines (TNFalpha and IL-6). This synergistic effect with LPS and P3C was also attenuated by LPS pretreatment and was mediated by TLR4. These results may be attributed to the reduction in phosphorylation of the mitogen-activated protein kinase (MAPK), p38, and the transcription factor NFkappaB, as well as to an increase in the expression of the suppressors of cytokine signaling (SOCS)-1 and -3 proteins in LPS-pretreated mast cells. CONCLUSIONS: These findings can be explored with respect to the modulation of inflammatory responses associated with infectious and allergic processes in future studies. PMID- 20707931 TI - Comparative cost assessment of the Kato-Katz and FLOTAC techniques for soil transmitted helminth diagnosis in epidemiological surveys. AB - BACKGROUND: The Kato-Katz technique is widely used for the diagnosis of soil transmitted helminthiasis in epidemiological surveys and is believed to be an inexpensive method. The FLOTAC technique shows a higher sensitivity for the diagnosis of light-intensity soil-transmitted helminth infections but is reported to be more complex and expensive. We assessed the costs related to the collection, processing and microscopic examination of stool samples using the Kato-Katz and FLOTAC techniques in an epidemiological survey carried out in Zanzibar, Tanzania. METHODS: We measured the time for the collection of a single stool specimen in the field, transfer to a laboratory, preparation and microscopic examination using standard protocols for the Kato-Katz and FLOTAC techniques. Salaries of health workers, life expectancy and asset costs of materials, and infrastructure costs were determined. The average cost for a single or duplicate Kato-Katz thick smears and the FLOTAC dual or double technique were calculated. RESULTS: The average time needed to collect a stool specimen and perform a single or duplicate Kato-Katz thick smears or the FLOTAC dual or double technique was 20 min and 34 sec (20:34 min), 27:21 min, 28:14 min and 36:44 min, respectively. The total costs for a single and duplicate Kato-Katz thick smears were US$ 1.73 and US$ 2.06, respectively, and for the FLOTAC double and dual technique US$ 2.35 and US$ 2.83, respectively. Salaries impacted most on the total costs of either method. CONCLUSIONS: The time and cost for soil transmitted helminth diagnosis using either the Kato-Katz or FLOTAC method in epidemiological surveys are considerable. Our results can help to guide healthcare decision makers and scientists in budget planning and funding for epidemiological surveys, anthelminthic drug efficacy trials and monitoring of control interventions. PMID- 20707932 TI - Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report. AB - BACKGROUND: Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. CASE PRESENTATION: We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. CONCLUSIONS: This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important. PMID- 20707933 TI - A population-based survey of the epidemiology of symptom-defined gastroesophageal reflux disease: the Systematic Investigation of Gastrointestinal Diseases in China. AB - BACKGROUND: The epidemiology of gastroesophageal reflux disease (GERD) has yet to be investigated using the symptomatic threshold criteria recommended by the Montreal Definition. This study aimed to determine the prevalence of symptom defined GERD across five regions of China, and to investigate variables associated with GERD. METHODS: A representative sample of 18 000 adults (aged 18 80 years) were selected equally from rural and urban areas in each region (n = 1800). According to the Montreal Definition, GERD is present when mild symptoms of heartburn and/or regurgitation occur on >or=2 days a week, or moderate-to severe symptoms of heartburn and/or regurgitation occur on >or=1 day a week. RESULTS: In total, 16 091 participants completed the survey (response rate: 89.4%) and 16 078 responses were suitable for analysis. Applying the Montreal criteria, the prevalence of symptom-defined GERD was 3.1% and varied significantly (p < 0.001) among the five regions (from 1.7% in Guangzhou to 5.1% in Wuhan) and between rural and urban populations (3.8% vs 2.4%). Factors significantly associated with GERD included living in a rural area and a family history of gastrointestinal diseases. CONCLUSIONS: This population-based survey found that the prevalence of symptom-defined GERD in China was 3.1%, which is lower than that found in Western countries. PMID- 20707934 TI - Environmental exposures and mutational patterns of cancer genomes. AB - The etiology of most human cancers is unknown. Genetic inheritance and environmental factors are thought to have major roles, and for some types of cancer, exposure to carcinogens is a proven mechanism leading to tumorigenesis. Sequencing of entire cancer genomes has not only begun to provide clues regarding functionally relevant mutations, but has also paved the way towards understanding the initial exposures leading to DNA damage, repair and eventually to mutation of specific sequences within a cancer genome. Two recent studies of melanoma and small cell lung cancer exemplify what type of information can be gained from cancer genome sequencing. PMID- 20707935 TI - Activated protein C in severe acute pancreatitis without sepsis? Not just yet ... AB - Severe acute pancreatitis (SAP) is characterized by an unregulated systemic proinflammatory response secondary to activation of trypsin within the pancreatic tissue, resulting in multiple organ failure. This dysregulated inflammation leading to organ dysfunction also characterizes severe sepsis. Activated protein C (APC) has pleotropic effects on the immune, coagulation, inflammatory and apoptotic pathways, and has been postulated to benefit acute pancreatitis- although concerns of possible retroperitoneal bleeding remain. Currently, experimental studies and subgroup data on patients with pancreatitis from a randomized controlled trial of APC in severe sepsis form the literature on the possible role of APC in SAP. We review the first randomized controlled trial of APC in acute pancreatitis published in the present issue of Critical Care. PMID- 20707936 TI - Induced pluripotent stem cells--alchemist's tale or clinical reality? AB - Following Shinya Yamanaka's first report describing the reprogramming of fibroblasts into stem cells over three years ago, some sceptics initially drew analogies between this new field of research and the quasi-mystical practice of 'alchemy'. Unlike the alchemist, however, stem cell researchers have rigorously tested and repeated experiments, proving their very own brand of cellular 'alchemy' to be a reality, with potentially massive implications for the study of human biology and clinical medicine. These investigations have resulted in an explosion of related publications and initiated the field of stem cell research known as 'induced pluripotency'. In this review, we give an account of the historical development, current technologies and potential clinical applications of induced pluripotency and conclude with a perspective on the possible future directions for this dynamic field. PMID- 20707937 TI - Aging with long-term physical impairments: the significance of social support. AB - This article examines the living situations and access to social support for community-dwelling people between the ages of 50 and 65, and who have lived with significant physical impairment for more than 15 years. Data were gathered through in-depth, semi-structured interviews with eight men and women. Findings suggest that coping with long-term impairment may be a lonely experience when the individual lacks a strong network of family and/or friends to offer emotional support. Participants felt their experiences of aging with significant long-term impairment were improved when they shared thoughts, feelings, and problems with others. Findings also show the significance of gender regarding access to social support and point towards the importance of using subjective understanding when ascertaining the level of social support available to individuals. More generally, findings underscore the broader point that individuals aging with impairments are immersed in and wish to maintain reciprocal relationships. PMID- 20707938 TI - Flow experience in the daily lives of older adults: an analysis of the interaction between flow, individual differences, serious leisure, location, and social context. AB - This study examined how serious leisure, individual differences, social context, and location contribute to older adults' experiences of flow - an intense psychological state - in their daily lives. The Experience Sampling Method was used with 19 older adults in a Midwestern city in the United States. Experience of flow was the outcome measure, and the data were analyzed using hierarchical linear modeling. Results indicated that location and employment status influenced the subjects' flow experience. Furthermore, the findings revealed that retirement was negatively related to experiencing flow, and there was a significant association between home and the flow experience. The results of this study enhance the understanding of flow experiences in the everyday lives of older adults. PMID- 20707939 TI - The dwelling-type choices of older Canadians and future housing demand: an investigation using the Aging and Social Support Survey (GSS16). AB - Using the 2002 Aging and Social Support Survey (GSS16), multinomial logit regression, and cohort-component projection techniques, this study explored how social support networks, health, and economic characteristics have shaped the residential choices of older Canadians, and predicts how they are likely to do so in the future. It focused on the distribution of 55-to-75-year-olds across three private-dwelling types: general community living, age-restricted housing, and age restricted housing with nursing care. The analysis shows that social support characteristics are the strongest predictors of dwelling type, meaning that individuals appear to choose their dwellings largely on the basis of their social needs and wants, rather than on their economic or health characteristics. The analysis also indicates an increased age-specific demand for all dwelling types in the future, but with a reduction of over 2 million older Canadians living in dwellings in the general community between 2002 and 2022. PMID- 20707940 TI - Minimalist models for proteins: a comparative analysis. AB - The last decade has witnessed a renewed interest in the coarse-grained (CG) models for biopolymers, also stimulated by the needs of modern molecular biology, dealing with nano- to micro-sized bio-molecular systems and larger than microsecond timescale. This combination of size and timescale is, in fact, hard to access by atomic-based simulations. Coarse graining the system is a route to be followed to overcome these limits, but the ways of practically implementing it are many and different, making the landscape of CG models very vast and complex. In this paper, the CG models are reviewed and their features, applications and performances compared. This analysis, restricted to proteins, focuses on the minimalist models, namely those reducing at minimum the number of degrees of freedom without losing the possibility of explicitly describing the secondary structures. This class includes models using a single or a few interacting centers (beads) for each amino acid. From this analysis several issues emerge. The difficulty in building these models resides in the need for combining transferability/predictive power with the capability of accurately reproducing the structures. It is shown that these aspects could be optimized by accurately choosing the force field (FF) terms and functional forms, and combining different parameterization procedures. In addition, in spite of the variety of the minimalist models, regularities can be found in the parameters values and in FF terms. These are outlined and schematically presented with the aid of a generic phase diagram of the polypeptide in the parameter space and, hopefully, could serve as guidelines for the development of minimalist models incorporating the maximum possible level of predictive power and structural accuracy. PMID- 20707942 TI - Multilevel modelling of the prevalence of hospitalized patients infected with Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is one of the leading nosocomial pathogens. The question of the respective contribution of endogenous and exogenous sources remains controversial. In this study, we shed new light on this issue by means of a multilevel logistic regression analysis which allowed a simultaneous investigation of factors associated with prevalence of patients infected with P. aeruginosa at two levels: patient and healthcare facility (HCF) in the eastern regions of France. A total of 25 533 in-patients from 51 HCFs were included in the analysis. The overall prevalence was 0.37% (range 0-1.65%). Multilevel modelling estimated that <14% of total variability of the outcome variable was explained by differences between HCFs and that after adjusting for patient-level variables, which explained 52% of HCF-level variance, the latter became non significantly different from zero. A compositional effect (patient factors), rather than a contextual effect (ecological factors), explains heterogeneity of the prevalence of patients infected with P. aeruginosa in the eastern HCFs of France. PMID- 20707943 TI - The effects of vitamin C supplementation on incident and progressive knee osteoarthritis: a longitudinal study. AB - OBJECTIVE: To evaluate the association between vitamin C supplementation and the incidence and progression of radiographic knee osteoarthritis (OA). DESIGN: Prospective cohort study. SETTING: Clearwater Osteoarthritis Study (COS): (1988 to the present) a longitudinal study. SUBJECTS: Male and female COS participants aged 40 years and above (n 1023). The study exposure was the participants' self reported history of vitamin C supplementation. The participants underwent biennial, sequential knee radiographs, which were assessed using the Kellgren Lawrence ordinal scale to determine evidence of the study 2 outcomes: incident radiographic knee OA (RKOA) and progression of RKOA. RESULTS: Individuals without baseline knee OA who self-reported vitamin C supplement usage were 11% less likely to develop knee OA than were those individuals who self-reported no vitamin C supplement usage (risk ratio (RR)=0.89, 95% CI 0.85, 0.93). Among those participants with RKOA at baseline, vitamin C supplement usage did not demonstrate an association with RKOA progression (RR=0.94, 95% CI 0.79, 1.22). CONCLUSIONS: In the present prospective cohort study, we found no evidence to support a protective role of vitamin C in the progression of knee OA. However, after controlling for confounding variables, these data suggest that vitamin C supplementation may indeed be beneficial in preventing incident knee OA. Given the massive public health burden of OA, the use of a simple, widely available and inexpensive supplement to potentially reduce the impact of this disease merits further consideration. PMID- 20707941 TI - Rotavirus genotypes co-circulating in Europe between 2006 and 2009 as determined by EuroRotaNet, a pan-European collaborative strain surveillance network. AB - EuroRotaNet, a laboratory network, was established in order to determine the diversity of co-circulating rotavirus strains in Europe over three or more rotavirus seasons from 2006/2007 and currently includes 16 countries. This report highlights the tremendous diversity of rotavirus strains co-circulating in the European population during three years of surveillance since 2006/2007 and points to the possible origins of these strains including genetic reassortment and interspecies transmission. Furthermore, the ability of the network to identify strains circulating with an incidence of >=1% allowed the identification of possible emerging strains such as G8 and G12 since the beginning of the study; analysis of recent data indicates their increased incidence. The introduction of universal rotavirus vaccination in at least two of the participating countries, and partial vaccine coverage in some others may provide data on diversity driven by vaccine introduction and possible strain replacement in Europe. PMID- 20707944 TI - Sociodemographic, lifestyle, mental health and dietary factors associated with direction of misreporting of energy intake. AB - OBJECTIVE: To estimate the extent of under- and over-reporting, to examine associations with misreporting and sociodemographic and lifestyle characteristics and mental health status and to identify differential reporting in micro- and macronutrient intake and quality of diet. DESIGN: A health and lifestyle questionnaire and a semi-quantitative FFQ were completed as part of the 2007 Survey of Lifestyle, Attitudes and Nutrition. Energy intake (EI) and intake of micro- and macronutrients were determined by applying locally adapted conversion software. A dietary score was constructed to identify healthier diets. Accuracy of reported EI was estimated using the Goldberg method. ANOVA, chi2 tests and logistic regression were used to examine associations. SETTING: Residential households in Ireland. SUBJECTS: A nationally representative sample of 7521 adults aged 18 years or older. RESULTS: Overall, 33.2 % of participants were under-reporters while 11.9 % were over-reporters. After adjustment, there was an increased odds of under-reporting among obese men (OR = 2.01, 95 % CI 1.46, 2.77) and women (OR = 1.68, 95 % CI 1.23, 2.30) compared to participants with a healthy BMI. Older age, low socio-economic status and overweight/obesity reduced the odds of over-reporting. Among under-reporters, the percentage of EI from fat was lower and overall diet was healthier compared to accurate and over-reporters. The reported usage of salt, fried food consumption and snacking varied significantly by levels of misreporting. CONCLUSIONS: Patterns in differential reporting were evident across sociodemographic, lifestyle and mental health factors and diet quality. Consideration should be given to how misreporting affects nutrient analysis to ensure sound nutritional policy. PMID- 20707945 TI - CHD risk in relation to alcohol intake from categorical and open-ended dietary instruments. AB - OBJECTIVE: To examine the risk of CHD in relation to alcohol intake from three different instruments. DESIGN: In the European Prospective Investigation into Cancer in Norfolk study, weekly alcohol intake was estimated from a single question in a mail-in health and lifestyle questionnaire (HLQ), a semi quantitative FFQ, and a 7 d diet diary (7DD). Information on smoking status, physical activity, disease history, social class and medication use was reported in the HLQ. Height, weight, blood pressure and blood lipids were measured at a health check-up. The average length of follow-up was 11 years. The association between alcohol intake and incident fatal and non-fatal CHD in a nested case control sample was calculated using logistic regression. SETTING: Norfolk, England. SUBJECTS: A total of 2151 cases of incident fatal and non-fatal CHD and 5354 controls. RESULTS: The Spearman correlation values between the 7DD, FFQ and HLQ alcohol estimates ranged from r = 0.70 to 0.82 (P < 0.0001 for all r values). Alcohol intake from all instruments was inversely associated with the risk of CHD in age- and multivariate-adjusted models. The relationships between the risk of CHD and alcohol intake from the 7DD, HLQ or FFQ were not significantly different from each other (P >0.10). A marginal difference between men and women was detected for the risk of CHD in relation to HLQ alcohol intake (P = 0.065). CONCLUSIONS: In conclusion, while the instruments were not uniform in their assessment of alcohol intake levels, the 7DD, HLQ and FFQ yielded similar inverse associations between alcohol intake and risk of CHD. PMID- 20707947 TI - Developing a timeline for evaluating public health nutrition policy interventions. What are the outcomes and when should we expect to see them? AB - OBJECTIVE: To develop a timeline for evaluating public health nutrition policy interventions. DESIGN: Concept mapping, a stakeholder-driven approach for developing an evaluation framework to estimate the 'time to impact' for policy interventions. The Schools (Health Promotion and Nutrition) (Scotland) Act 2007 was used as the model to develop the evaluation timeline as it had typical characteristics of government policy. Concept mapping requires stakeholders to generate a list of the potential outcomes, sort and rate the outcomes. Multidimensional scaling and hierarchical cluster data analysis were used to develop an anticipated timeline to impact for the policy. SETTING: United Kingdom. SUBJECTS: One hundred and eleven stakeholders representing nutrition, public health, medicine, education and catering in a range of sectors: research, policy, local government, National Health Service and schools. RESULTS: Eighty five possible outcomes were identified and grouped into thirteen clusters describing higher-level themes (e.g. long-term health, food literacy, economics, behaviour, diet, education). Negative and unintended consequences were anticipated relatively soon after implementation of the policy, whereas positive outcomes (e.g. dietary changes, health benefits) were thought likely to take longer to emerge. Stakeholders responsible for implementing the legislation anticipated that it would take longer to observe changes than those from policy or research. CONCLUSIONS: Developing an anticipated timeline provides a realistic framework upon which to base an outcome evaluation for policy interventions and identifies positive and negative outcomes as well as considering possible unintended consequences. It offers benefit to both policy makers and researchers in mapping the progress expected towards long-term health goals and outcomes. PMID- 20707946 TI - The global context for public health nutrition taxation. AB - OBJECTIVE: To assess critically the scope for public health nutrition taxation within the framework of the global tax reform agenda. DESIGN: Review of the tax policy literature for global policy priorities relevant to public health nutrition taxation; critical analysis of proposals for public health nutrition taxation judged against the global agenda for tax reform. SETTING: The global tax reform agenda shapes decisions of tax policy makers in all countries. By understanding this agenda, public health nutritionists can make feasible taxation proposals and thus improve the development, uptake and implementation of recommendations for nutrition-related taxation. RESULTS: The priorities of the global tax reform agenda relevant to public health nutrition taxation are streamlining of taxes, adoption of value-added tax (VAT), minimisation of excise taxes (except to correct for externalities) and removal of import taxes in line with trade liberalisation policies. Proposals consistent with the global tax reform agenda have included excise taxes, extension of VAT to currently exempted (unhealthy) foods and tariff reductions for healthy foods. CONCLUSIONS: Proposals for public health nutrition taxation should (i) use existing types and rates of taxes where possible, (ii) use excise taxes that specifically address externalities, (iii) avoid differential VAT on foods and (iv) use import taxes in ways that comply with trade liberalisation priorities. PMID- 20707948 TI - Factors associated with exclusive breast-feeding and breast-feeding in Norway. AB - OBJECTIVE: To identify factors associated with exclusive breast-feeding and breast-feeding during the first year of life among Norwegian infants. DESIGN: Data on breast-feeding practices were collected by a semi-quantitative FFQ. SETTING: In 2006-2007 about 3000 infants were invited to participate in a population-based prospective cohort study in Norway. SUBJECTS: A total of 1490 mothers/infants participated at both 6 and 12 months of age. RESULTS: Exclusive breast-feeding at 4 months was associated with parental education, parity and geographical region, while exclusive breast-feeding at 5.5 months was associated only with maternal age. At both ages, a negative association with exclusive breast-feeding was observed for maternal smoking. Breast-feeding at 6 months was associated with parental education, maternal age and marital status. Breast feeding at 12 months was associated with maternal education, maternal age and number of children. At both ages, negative associations with breast-feeding were observed for maternal smoking and descending birth weight. At 12 months, a negative association was also observed for having day care by other than the parents. CONCLUSIONS: Even though Norway has an extensive and positive breast feeding tradition and a maternal leave system that supports the possibility to breast-feed, factors like maternal education, maternal age and maternal smoking are strongly associated with duration of exclusive breast-feeding and breast feeding. Research to better understand the reasons for inequalities in breast feeding is needed to facilitate the development of more effective breast-feeding promotion strategies. This again may improve compliance with recommendations and reduce inequalities in infant feeding practices. PMID- 20707950 TI - Robotic-assisted salpingostomy for ectopic pregnancy. PMID- 20707949 TI - Validation of an FFQ and options for data processing using the doubly labelled water method in children. AB - OBJECTIVE: To validate an FFQ designed to estimate energy intake in children against doubly labelled water (DLW). To investigate how quality control and standard beverage portion sizes affect the validity of the FFQ. DESIGN: Thirty healthy children, aged 4-6 years, participated. Total energy expenditure (EE) was measured by the DLW method during an observation period of 15 d. At the end of this period parents filled out an FFQ designed to assess the child's habitual energy intake (EI) of the preceding four weeks. SETTING: Validation study in The Netherlands. SUBJECTS: Thirty healthy children (fifteen boys and fifteen girls), aged 4-6 years. RESULTS: Mean EI (6117 (sd 1025) kJ/d) did not differ significantly from mean EE (6286 (sd 971) kJ/d; P = 0.15); the mean EI:EE ratio was 0.98. The Pearson correlation coefficient between EI and EE was 0.62. The Bland-Altman plot showed no systematic bias and a constant bias close to zero. Less intensive quality control of the FFQ maintained the mean EI:EE ratio and decreased the correlation slightly. Using standard instead of individually measured beverage portion sizes decreased the mean EI:EE ratio, but maintained the correlation. CONCLUSIONS: It can be concluded that the developed FFQ is a valid instrument to estimate mean energy intake in a group of 4- to 6-year-old children and performs reasonably well to rank the subjects with respect to energy intake. It is therefore a useful instrument to estimate energy intake in children in surveys and epidemiological studies in The Netherlands. PMID- 20707951 TI - Contribution of select maternal groups to temporal trends in rates of caesarean section. AB - OBJECTIVE: To estimate the contribution of select maternal groups to temporal trends in Caesarean section (CS) rates. METHODS: Using the Nova Scotia Atlee Perinatal Database, all deliveries by CS during the 24-year period from 1984 to 2007, at the Women's Hospital, IWK Health Centre were identified. Deliveries by CS were classified into groups using parity (nullipara/multipara), plurality (singleton/multiple), presentation (cephalic/breech/transverse), gestational age (term/preterm), history of previous CS (previous CS/no previous CS), and labour (spontaneous/induced/no labour). CS rates in each group and the contribution of each group to the overall CS rate was determined for three eight-year epochs. The risk of CS in each group over time, accounting for identified maternal, fetal, and obstetric practice factors, was evaluated using logistic regression. RESULTS: Of 113,016 deliveries, 23,232 (20.6%) were identified as deliveries by CS meeting the inclusion and exclusion criteria. The CS rate rose from 16.8% in 1984 to 1991 to 26.8% in 2000 to 2007 (P < 0.001). The biggest contributors to the overall CS rate in the last study epoch (2000-2007) were nulliparous women with singleton, cephalic, term pregnancies with spontaneous or induced labour; women with singleton, cephalic, term pregnancies with previous CS; and women with breech presentation. Adjusted analyses explained some increases in the rate of CS and demonstrated reduced risks in others. CONCLUSION: Only some temporally increased CS rates in select maternal groups remain increased after adjusting for confounding variables. The identification of potentially modifiable maternal risk factors, re-evaluation of the indications and techniques for induction of labour in nulliparous women, provision of clinical services for vaginal birth after Caesarean section, and external cephalic version for selected breech presentation are important clinical management areas to consider for safely lowering the Caesarean section rate. PMID- 20707952 TI - The life of a Canadian doula: successes, confusion, and conflict. AB - OBJECTIVE: Despite evidence that doulas improve maternal and newborn outcomes, some maternity care professionals have had difficulty both in understanding the role of doulas and in accepting doulas as collaborators. We sought to examine the backgrounds, practices, and professional motivations of doulas and to understand their role and interactions with other maternity care providers. METHODS: We conducted a postal survey of 212 Canadian doulas whose contact information was provided by DONA International. The main outcome measures of the survey were demographics, practices, motivations, perception of working environment, interactions with and acceptance by other maternity care providers, and overall work satisfaction. RESULTS: The most common reasons for becoming a doula were the desire to support women in childbirth, personal interest, and a wish to share their own positive birth experience with others. Only 21.7% described the doula role as a means of achieving personal financial support. Most respondents intended to continue doula work in the next five years. Doulas felt more accepted by midwives than other care providers. Most doulas reported no conflict with other maternity care providers, but on rare occasions, doulas had been excluded from attending birth by maternity care providers, hospital and/or administrative regulations, and rarely by a client. Almost all doulas (98.5%) rated their overall professional experience as good or excellent. CONCLUSION: Better recognition and respect from other providers significantly influenced doulas' satisfaction. This study helps clarify areas of possible conflict and obstacles that doulas may face in their work environment and in their interactions with other maternity care providers. PMID- 20707953 TI - Comparison of costs and associated outcomes between women choosing newly integrated autonomous midwifery care and matched controls: a pilot study. AB - OBJECTIVE: In response to consumer demand and a critical shortage of Canadian maternity care providers, provinces have integrated or are in the process of integrating midwives into their health care systems. We compared the costs and outcomes of newly integrated, autonomous midwifery care with existing health care services in the province of Alberta. METHODS: Alberta Health and Wellness cost data from (1) physician fee-for-service, (2) outpatient, and (3) inpatient records, as well as outcome data from vital statistics records, were compared between participants in a midwifery integration project and individually matched women who received standard perinatal care during the same time period. Records of births occurring within the same time frame were matched according to risk score, maternal age, parity, and postal code. RESULTS: For women who chose midwifery care, an average saving of $1172 per course of care was realized without adversely affecting maternal or neonatal outcomes. Cost reductions are partially realized through provision of out-of-hospital health services. Women who chose midwifery care had more prenatal visits (P < 0.01) and fewer inductions of labour (P < 0.01); their babies had greater gestational ages (P < 0.05) and higher birth weights (P < 0.05) than controls. The sample size was insufficient to compare events associated with extremely high costs, or rare or catastrophic outcomes. CONCLUSION: Regulated and publicly funded midwifery care appears to be an effective intervention for low-risk women who make this choice. When compared with existing care, autonomous care by newly integrated midwives does not increase health care costs. PMID- 20707954 TI - The Ottawa hospital quality incident notification system for capturing adverse events in obstetrics. AB - OBJECTIVE: To describe the design and implementation of a Quality Incident Notification (QIN) system in an obstetrical unit and provide an analysis of the frequency and nature of events captured by the system. METHODS: We implemented a system to capture quality events, consisting of an on-line form that was easily accessible to all levels of staff. A list of quality indicators was developed to indicate potential safety concerns, near misses, or poor outcomes that required closer scrutiny. We retrospectively analyzed the cases reported in the first year following introduction of the QIN for the presence, severity, and avoidability of harm. RESULTS: During the 12-month study period there were 6752 deliveries, and 578 QINs were generated, a rate of one QIN for every 11.7 deliveries (8.5%). The most frequent indicators reported were "neonatal near miss" (15.4%), "records/results" (14.5%), and "staff communication" (10.0%). Out of the 497 QINs with complete data, 67 (13.4%) showed minor harm to the mother, the baby, or both, and 37 (7.4%) QINs showed major harm. Only 28 of the 110 cases of actual harm were considered to be caused by the medical care (0.4% of all deliveries), and 14 patients were judged to have experienced avoidable actual harm due to medical care (0.2% of all deliveries). CONCLUSION: The QIN system captured a relatively low rate of adverse events, with about half of these being avoidable. Used consistently, this type of system can be an effective tool for risk management and improvement of practices. PMID- 20707955 TI - Family history screening: use of the three generation pedigree in clinical practice. AB - With a growing understanding of genetic disorders in the scientific and lay literature, it is becoming increasingly important to consider risk factors based on family history and ethnicity for identifying individuals for whom genetic testing is indicated and will be most beneficial. A pedigree helps to identify patients and families who have an increased risk for genetic disorders, to optimize counselling, screening, and diagnostic testing, with the goal of disease prevention or early diagnosis and management of the disease. Information should be updated periodically as new information regarding family history is acquired. This review was designed to provide a rationale for and an approach to obtaining a three-generation pedigree for patients who are seen as new assessments or those under ongoing care by primary care or specialist physicians, as well to summarize some resources available for constructing a useful pedigree. PMID- 20707956 TI - Natural family planning: physicians' knowledge, attitudes, and practice. AB - OBJECTIVE: To assess physicians' knowledge, attitudes, and practice with respect to four evidence-based natural family planning (NFP) methods: Standard Days, cervical mucus, basal body temperature, and the lactational amenorrhea method. METHODS: We undertook a cross-sectional survey of a random sample of family physicians and all gynaecologists in British Columbia (n = 460) who have women of reproductive age in their practice, as well as all affiliated residents (n = 239). Main outcome measures were (1) physicians' attitudes towards NFP and their perceptions of its effectiveness; (2) the relationship between physicians' demographic factors, their personal experience or beliefs, and their attitudes and knowledge; and (3) how these factors affect the counselling physicians offer their patients. RESULTS: The survey response rate was 44%. Only 3% to 6% of physicians had correct knowledge of the effectiveness in perfect use of the NFP methods cited in this study. Fifty percent of physicians who responded mention NFP to their patients as an option for contraception, and 77% of physicians mention NFP as an option to couples trying to conceive. Family physicians and residents were much more likely than gynaecologists or gynaecology residents to mention NFP during counselling. Older physicians were more likely to mention NFP than younger physicians and also had more personal experience with NFP. CONCLUSION: Most physicians in our study underestimated the effectiveness of NFP methods, and only a small proportion of physicians provide information about NFP during contraceptive counselling. Physicians need better understanding of modern methods of NFP to provide evidence-based contraceptive counselling to selected highly motivated patients who prefer NFP as a contraceptive choice. PMID- 20707957 TI - The acceptability of HPV vaccination among women attending the University of Saskatchewan Student Health Services. AB - OBJECTIVE: Women attending the University of Saskatchewan Student Health Services are being offered human papillomavirus (HPV) vaccination but are not filling their prescriptions. We sought to identify gaps in knowledge of the link between HPV infection, cervical dysplasia, and cervical cancer among women attending the Student Health Services, and to identify barriers to HPV vaccination among this cohort of women. METHODS: Women attending the University of Saskatchewan Student Health Services for any reason were invited to complete an 18-question survey. The survey included questions regarding knowledge of the purpose of Pap smears, the role of HPV infection in cervical dysplasia and cancer, and HPV vaccination. The questions were designed to elicit both quantitative and qualitative data. Data analysis included basic descriptive analysis and summarization of qualitative data. RESULTS: Four hundred surveys were distributed, and 371 (91%) were returned. Eighty-two percent of participants were aware of the HPV vaccine, and 40% ranked their knowledge of HPV as good or very good; however, only 6% correctly answered questions about methods of preventing HPV infection. Participants identified cost (62%), concerns over adverse effects (43%), and lack of knowledge (36%) as barriers to undergoing vaccination. Comments about the HPV vaccine reflected frustration with cost and concerns about adverse effects. When participants were asked if they would undergo vaccination if it were free, 60% responded "yes," 31% responded "maybe," and 8% responded "no." CONCLUSION: The young women in our survey had significant gaps in knowledge of HPV infection and prevention, and educational programs must be structured to address these deficits. Institutions promoting vaccination must deal with the barriers of cost and fear of adverse effects. PMID- 20707958 TI - Effect of obesity on parameters of ovarian reserve in premenopausal women. AB - OBJECTIVE: To study the relationship between obesity and serum and ultrasound markers of ovarian reserve in premenopausal women. METHODS: We performed a cross sectional comparative study of two age-matched groups of premenopausal participants (early transition phase): 50 participants ("non-obese") had a BMI < 30 kg/m2, and the other 50 participants ("obese") had a BMI of 30 to 35 kg/m2. The obese women had a mean age of 46.2 years and the non-obese women had a mean age of 46.1 years. Blood samples were collected from all participants, anthropometric measurements were calculated, and transvaginal ultrasonography was performed to measure the antral follicle count (AFC) and ovarian volume during the early follicular phase. The blood samples were assayed for antimullerian hormone (AMH), follicle-stimulating hormone (FSH), fasting blood glucose (FBG) and two-hour postprandial blood glucose (2h PP). RESULTS: There was no significant difference between the two groups in mean age, levels of serum AMH, serum FSH, FBG, 2 hr PP, or AFC. Ovarian volume was significantly lower in obese women (3.7 +/- 0.8 mL) than in non-obese women (6.6 +/- 0.4 mL) (P = 0.03). There was no significant correlation between BMI and serum AMH, serum FSH, FBS, or 2 hr PP. CONCLUSION: Obesity has no association with levels of serum FSH, AMH, blood glucose, or AFC indicating that obesity is unlikely to affect ovarian reserve in the perimenopausal age group. PMID- 20707959 TI - The Coffin-Lowry syndrome: a case report and review of the literature. AB - BACKGROUND: Prenatal ultrasound has afforded insights into many structural and syndromic fetal disorders. In this report, the ultrasound findings were of assistance when counselling a patient who presented with a history of Coffin Lowry syndrome (CLS). CASE: A 39-year-old woman presented in the third trimester of pregnancy asking whether CLS could be diagnosed in utero. Three of her male offspring had been found to have this syndrome in childhood. Ultrasound assessment of the fetus was able to confirm female sex, which provided direction for counselling. An additional finding was of short and stubby digits, which have been well described as part of this syndrome. This information provided direction for pediatric management. CONCLUSION: CLS is a rare syndrome that is typically diagnosed in childhood. To our knowledge, this is the first report of a case in which prenatal ultrasound provided assistance for counselling before delivery. PMID- 20707960 TI - A case of severe preeclampsia leading to the diagnosis of de novo abnormal fatty acid metabolism and ACE gene deletion. AB - BACKGROUND: Enzymes involved in the metabolism of free fatty acids are essential for the proper use of caloric intake. Abnormal enzymes unable to degrade fatty acids will result in an accumulation of fatty acids in organs like the liver, impairing its function. CASE: A 28-year-old primigravid woman underwent induction of labour because of severe preeclampsia. She was subsequently found to be a carrier for mutations in several fatty acid enzymes as well as the angiotensin converting enzyme. CONCLUSION: During pregnancy, the increased need for fatty acid degradation will expose women who are carriers of mutations in these enzymes. The clinical manifestations in such women include acute fatty liver of pregnancy that may mimic severe preeclampsia. Strict metabolic control to avoid excess fatty acid degradation may allow for better pregnancy outcomes and newborn assessment. PMID- 20707961 TI - Choriocarcinoma arising in a serous carcinoma of ovary: an example of histopathology driving treatment. AB - BACKGROUND: Choriocarcinoma within an ovarian carcinoma is exceptionally rare. Nevertheless, recognition of this mixed tumour is important for administration of appropriate chemotherapy. CASE: A 65-year-old woman underwent resection of an ovarian mass after presenting with a pelvic mass and breast tenderness. On pathologic examination the mass showed a choriocarcinoma in association with a serous carcinoma. This pathologic diagnosis led to a specific chemotherapy regimen with cisplatin, etoposide, and bleomycin, suitable for both types of malignancy. CONCLUSION: Both gynaecologists and pathologists should be aware that the histopathologic classification of ovarian epithelial carcinoma and its variants, such as this one, may have an increasing role in the management of this disease. PMID- 20707962 TI - Wait times for women with abnormal uterine bleeding in South-Western Ontario. AB - OBJECTIVE: Women referred to an obstetrician-gynaecologist because of abnormal uterine bleeding (AUB) should be seen within 12 weeks, according to the benchmarks recommended for medically acceptable wait times established by the Society of Obstetricians and Gynaecologists of Canada. Our study aimed to determine the proportion of patients having wait times that meet this recommendation, and to understand patient-level sources of variation in these waits. METHODS: We performed a secondary analysis of data from the Delivering Primary Healthcare Information (DELPHI) project database. Electronic medical record data from 10 family practices across south-western Ontario were used to study AUB wait times. RESULTS: Over a 30-month period, 223 referrals were made to obstetrician-gynaecologists because of AUB. The mean wait time for initial assessment was 70.4 days (median = 51 days); the range among referring practices varied from 36 to 111 days. Seventy-one percent of women were seen by the obstetrician-gynaecologist within the recommended time of 12 weeks or less. Multi level regression analysis indicated that older patients were more likely to have shorter waits. The intraclass correlation was 0.256, indicating that nearly a quarter of the variation in wait time was explained at the practice level. CONCLUSION: Nearly 30% of women referred to specialists because of AUB wait longer than the period of time recommended by the SOGC, with younger women more likely to wait longer. This difference may be due to the perception of an increased risk of malignancy in older women. Future research on correlates of AUB wait times should take factors such as severity and prior family physician work up into account. PMID- 20707973 TI - [Rationalisation, prioritisation and rationing: approaches to future health care delivery]. AB - Complex developments are increasing the gap between the financial feasibility of the German health care system and new possibilities in diagnosis and therapy. Influencing factors, inter alia, include rapid medical progress, demographic and epidemiological trends and changing perceptions of health and illness. This raises the question of how a just allocation of scarce resources can be developed and implemented. Concepts such as rationalisation, rationing and prioritisation are being intensively discussed. In this paper definitions of and differentiations between these terms will be presented, which are often missing from the current debate. Furthermore, the need for action implying ethical and structural-political challenges will be outlined. In this regard, a sustainable process should focus on transparency, responsibility and public involvement. PMID- 20707974 TI - [Dealing with bottlenecks in health care--ethical issues]. AB - Due to the ageing of our society and the enduring progress of medicine it will no longer be possible to provide universal access to everything health care providers could potentially offer. Therefore, we need a debate on legitimate health care claims and fair distribution of medical resources under conditions of scarcity - hence on matters of social justice. This paper will look at some general ethical aspects and some specific proposals for fair criteria of rationing in health care. PMID- 20707975 TI - [Dealing with bottlenecks in ambulatory patient care: a judge's perspective]. AB - In ambulatory care diagnostic and therapeutic procedures may only be applied if they have a positive recommendation from the Federal Joint Committee. Both physicians and patients are bound by this rule. Limitations of ambulatory care cannot be attributed to the existing rules applicable to the funding for ambulatory care services; they only affect the pecuniary interests of Statutory Health Insurance (SHI) accredited physicians which are beyond the control of the insured. The prescription of medical drugs, supplements and health aids is subject to stronger restrictions, which can pose a dilemma for physicians: on the one hand, they are allowed by law to prescribe even the most costly medical drugs to every insured patient, if required, but on the other hand, they will have to prepare themselves for drug recourse claims. This situation can be relieved by appropriately handling reviews of so-called average prescription limits. Physicians should support the exertion of indirect influence over their prescription behaviour through measures like substitution ("aut idem" principle) and discount contracts and also, they should actively commit themselves to this approach when facing their patients. Otherwise financial viability, especially with respect to the supply with medical drugs, of the statutory health insurance system will be at risk. PMID- 20707976 TI - [Summary of Discussion Ii]. PMID- 20707977 TI - [Summary of Discussion III]. PMID- 20707978 TI - [Triage: a military physician's perspective]. AB - The treatment of patients in mass casualties generally requires a high level of organisational understanding. The delivery of medical care to one patient should not cause delays in helping all other patients. Therefore triage and a prioritisation of treatment and transport is necessary. Military triage has developed over centuries and forms the basis of civilian triage. The differences between both systems include established military triage performed by paramedics and care under fire. These characteristics have led to the development of separate algorithms. PMID- 20707979 TI - [Triage--and the management of mass casualty incidents]. AB - Triage ("sorting") will only be necessary in the setting of mass casualties and lack of sufficient paramedical and medical specialists as well as equipment. Triage means that the victims will be divided into four categories denoting urgency of treatment and chance of survival. The most experienced medical doctor or officer is responsible for the triage. PMID- 20707980 TI - An outbreak of peste des petits ruminants (PPR) in camels in the Sudan. AB - In mid-August 2004, an outbreak of a previously unknown fatal disease of camels was reported to Kassala State veterinary authorities. Several areas in the state were visited during August-October 2004 to collect epidemiological data and specimens for diagnosis. Clinically the disease was characterized by sudden death of apparently healthy animals and yellowish and later bloody diarrhea and abortion. The disease outbreaks coincided with the seasonal movement of animals towards autumn green pasture. Death was always sudden and proceeded with colic and difficulty in respiration. Mortality rate ranged between 0% and 50% and vary in accordance with the area with a mean of 7.4%. More than 80% of deaths were in pregnant and recently-delivered she-camels. All age, sex and breed groups were affected but more than 50% of deaths were reported in adult animals in comparison to calves and young camels. The main post-mortem findings include lung congestion and consolidation, paleness and fragility of liver, enlarged lymph nodes and congestion and hemorrhage of small intestine and stomach. Agar gel diffusion test (AGDT), RT-PCR and virus isolation in cell culture gave positive results for peste des petits ruminants virus (PPRV), a virus belonging to the Morbillivirus, Genus, member of the family Paramyxoviridae. The effect of this new devastating disease on camel production in the affected area was discussed as well as proposals for future research. PMID- 20707981 TI - Antioxidant, larvicidal and antiacetylcholinesterase activities of cashew nut shell liquid constituents. AB - Anacardic acid, cardanol and cardol, the main constituents of natural cashew nut shell liquid (CNSL), were obtained by solvent extraction and assayed for antioxidant, larvicidal and antiacetylcholinesterase activity. Their relative percent composition was obtained by HPLC analysis. Antioxidant activity was assessed using the DPPH and ABTS(+) tests, which showed cardanol as the most active, followed by cardol and anacardic acid. The three CNSL components demonstrated good larvicidal activity against Aedes aegypti (LC(50)=12.40 for anacardic acid, 10.22 for cardol and 14.45 for cardanol) and exhibited inhibition zones for acetylcholinesterase enzymes in the TLC test similar to carbachol, which was used as standard. Based on the results, these multipotent compounds represent promising agents in the control of Ae. aegypti, the main dengue vector in Brazil. PMID- 20707982 TI - Steady-state and time-resolved fluorescence quenching with transition metal ions as short-distance probes for protein conformation. AB - A series of model dye-labeled histidine-containing peptides was used to investigate the nature of the quenching mechanism with Cu(2+) and Ni(2+). The strong reduction in steady-state fluorescence was found to be unaccompanied by any noticeable changes in lifetime kinetics. This static nature of quenching is not consistent with the dynamic Forster resonance energy transfer (FRET) phenomenon, which was assumed to dominate the quenching mechanism, and is likely caused by shorter range orbital coupling. Our results indicate that the FRET-like sixth power of distance dependence of quenching cannot be automatically assumed for transition metal ions and that time-resolved measurements should be used to distinguish various quenching mechanisms. PMID- 20707983 TI - T3 affects expression of collagen I and collagen cross-linking in bone cell cultures. AB - Thyroid hormones (T3,T4) have a broad range of effects on bone, however, its role in determining the quality of bone matrix is poorly understood. In-vitro, the immortalized mouse osteoblast-like cell line MC3T3-E1 forms a tissue like structure, consisting of several cell layers, whose formation is affected by T3 significantly. In this culture system, we investigated the effects of T3 on cell multiplication, collagen synthesis, expression of genes related to the collagen cross-linking process and on the formation of cross-links. T3 compared to controls modulated cell multiplication, up-regulated collagen synthesis time and dose dependently, and stimulated protein synthesis. T3 increased mRNA expressions of procollagen-lysine-1,2-oxoglutarate 5-dioxygenase 2 (Plod2) and of lysyloxidase (Lox), both genes involved in post-translational modification of collagen. Moreover, it stimulated mRNA expression of bone morphogenetic protein 1 (Bmp1), the processing enzyme of the lysyloxidase-precursor and of procollagen. An increase in the collagen cross-link-ratio Pyr/deDHLNL indicates, that T3 modulated cross-link maturation in the MC3T3-E1 culture system. These results demonstrate that T3 directly regulates collagen synthesis and collagen cross linking by up-regulating gene expression of the specific cross-link related enzymes, and underlines the importance of a well-balanced concentration of thyroid hormones for maintenance of bone quality. PMID- 20707984 TI - Scn1a missense mutation impairs GABAA receptor-mediated synaptic transmission in the rat hippocampus. AB - Mutations of the Na(v)1.1 channel subunit SCN1A have been implicated in the pathogenesis of human febrile seizures (FS). We have recently developed hyperthermia-induced seizure-susceptible (Hiss) rat, a novel rat model of FS, which carries a missense mutation (N1417H) in Scn1a[1]. Here, we conducted electrophysiological studies to clarify the influences of the Scn1a mutation on the hippocampal synaptic transmission, specifically focusing on the GABAergic system. Hippocampal slices were prepared from Hiss or F344 (control) rats and maintained in artificial cerebrospinal fluid saturated with 95% O(2) and 5% CO(2)in vitro. Single neuron activity was recorded from CA1 pyramidal neurons and their responses to the test (unconditioned) or paired pulse (PP) stimulation of the Schaffer collateral/commissural fibers were evaluated. Hiss rats were first tested for pentylenetetrazole-induced seizures and confirmed to show high seizure susceptibility to the blockade of GAGA(A) receptors. The Scn1a mutation in Hiss rats did not directly affect spike generation (i.e., number of evoked spikes and firing threshold) of the CA1 pyramidal neurons elicited by the Schaffer collateral/commissural stimulation. However, GABA(A) receptor-mediated inhibition of pyramidal neurons by the PP stimulation was significantly disrupted in Hiss rats, yielding a significant increase in the number of PP-induced firings at PP intervals of 32-256ms. The present study shows that the Scn1a missense mutation preferentially impairs GABA(A) receptor-mediated synaptic transmission without directly altering the excitability of the pyramidal neurons in the hippocampus, which may be linked to the pathogenesis of FS. PMID- 20707985 TI - Assessment of chronological lifespan dependent molecular damages in yeast lacking mitochondrial antioxidant genes. AB - The free radical theory of aging states that oxidative damage to biomolecules causes aging and that antioxidants neutralize free radicals and thus decelerate aging. Mitochondria produce most of the reactive oxygen species, but at the same time have many antioxidant enzymes providing protection from these oxidants. Expecting that cells without mitochondrial antioxidant genes would accumulate higher levels of oxidative damage and, therefore, will have a shorter lifespan, we analyzed oxidative damages to biomolecules in young and chronologically aged mutants lacking the mitochondrial antioxidant genes: GRX2, CCP1, SOD1, GLO4, TRR2, TRX3, CCS1, SOD2, GRX5, and PRX1. Among these mutants, ccp1Delta, trx3Delta, grx5Delta, prx1Delta, mutants were sensitive to diamide, and ccs1Delta and sod2Delta were sensitive to both diamide and menadione. Most of the mutants were less viable in stationary phase. Chronologically aged cells produced higher amount of superoxide radical and accumulated higher levels of oxidative damages. Even though our results support the findings that old cells harbor higher amount of molecular damages, no significant difference was observed between wild type and mutant cells in terms of their damage content. PMID- 20707986 TI - Effects of selective serotonin reuptake inhibitors on GABAergic inhibition in the hippocampus of normal and pilocarpine induced epileptic rats. AB - Selective serotonin reuptake inhibitors (SSRIs) acting on the serotonin (5-HT) receptors may affect gamma-aminobutyric acid (GABA)-ergic transmission. The role of 5-HT in the epileptic hippocampus remains controversial since 5-HT has both convulsive and anticonvulsive effects. We investigated the effects of fluoxetine, paroxetine and citalopram on the GABAergic transmission in the normal and pilocarpine-induced epileptic rat hippocampus using electroencephalogram (EEG), paired-pulse inhibition (PPI) and vesicular GABA transporter (VGAT) immunoreactivity. EEG showed spontaneous spike activities in normal rats treated with citalopram, fluoxetine, or paroxetine. PPIs were reduced in normal rats treated with citalopram or fluoxetine, and this reduction was especially prominent in normal rats treated with citalopram. PPIs were markedly reduced in the epileptic rats treated with citalopram, but not in the epileptic rats treated with paroxetine. Normal rats treated with citalopram or paroxetine showed a greater reduction in the relative density of VGAT immunoreactivity in the hippocampus than the normal control rats. Similarly, epileptic rats treated with citalopram or fluoxetine also showed a greater reduction in the relative density of VGAT immunoreactivity in the hippocampus than the epileptic control rats. These findings suggest that SSRI treatment has a slight influence on GABAergic transmission in the hippocampus. SSRI treatment may increase seizure susceptibility in the normal hippocampus and increase the frequency and intensity of seizures in the epileptic hippocampus. However, whether these differential effects result from a direct effect on GABAergic interneurons or via 5-HT subtype receptors remains to be elucidated. PMID- 20707987 TI - Lack of association between PCDH11X genetic variation and late-onset Alzheimer's disease in a Han Chinese population. AB - Protocadherin 11X (Pcdh11X) has been suspected to be associated with Alzheimer's disease through participating in the metabolism of PP1alpha and beta-catenin or by altering the synaptic functions. A recent genome-wide association study reported that a common single nucleotide polymorphism (SNP, rs5984894) in the gene encoding Pcdh11X was associated with susceptibility to late-onset Alzheimer's disease (LOAD) in Caucasians. In order to assess the involvement of the PCDH11X polymorphism in the risk of developing AD in Chinese, we analyzed the genotype and allele distributions of the PCDH11X rs5984894 polymorphism in a Han Chinese population (355 LOAD cases and 399 healthy controls). Our results failed to find any significant association between the tested SNP and LOAD, indicating that PCDH11X gene polymorphism does not play a major role in the genetic predisposition to LOAD in this Han Chinese population. PMID- 20707988 TI - The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats. AB - Transient cerebral ischemia may result in neuronal apoptosis. During this process, several apoptosis-regulatory genes are induced in apoptotic cells. Among these genes, cysteinyl aspartate-specific protease-3 (caspase-3) and B-cell leukemia-2 (Bcl-2) are the most effective apoptotic regulators because they play a decisive role in the occurrence of apoptosis. Research has shown that propofol, which is an intravenous anesthetic agent, exhibits neuroprotective effects against cerebral ischemia-reperfusion injury, although the neuroprotective mechanism is still unclear. In this study, we examined the effects of propofol in rats after forebrain ischemia-reperfusion. We assessed the expression of hippocampal caspase-3, which acts as an apoptotic activator, and Bcl-2, which acts as an apoptotic suppressor. Forebrain ischemia was induced in hypotensive rats by clamping the bilateral common carotid arteries for 10 min. Propofol was administered via a lateral cerebral ventricle injection using a microsyringe after the induction of ischemia. Neuronal damage was determined by histological examination of brain sections at the level of the dorsal hippocampus. Caspase-3 and Bcl-2 expression in the hippocampus were detected using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We also used an immunohistochemical method after ischemia-reperfusion. In the hippocampus, caspase-3 and Bcl-2 mRNA were dramatically increased at 24h after forebrain ischemia. Following 6-24h of reperfusion, forebrain ischemia for 10 min induced a gradual increase in the expression of caspase-3 and Bcl-2 protein in the rat hippocampus, which peaked at 24h. In the propofol (1.0mg/kg) intervention group, the hippocampal expression of caspase-3 mRNA decreased significantly in rats 24h after ischemia; Bcl-2 mRNA was increased at the same time point. During the 24-h reperfusion period and after treatment with propofol, the level of caspase-3 protein expression was low, while the level of Bcl-2 was high. Thus, our results suggest that the neuroprotective effects of propofol against neuronal apoptosis may be mediated by the inhibition of caspase-3 expression and an increase in Bcl-2 expression. PMID- 20707989 TI - Origin and timing of voltage-sensitive dye signals within layers of the turtle cerebellar cortex. AB - Optical recording techniques were applied to the turtle cerebellum to localize synchronous responses to microstimulation of its cortical layers and reveal the cerebellum's three-dimensional processing. The in vitro yet intact cerebellum was first immersed in voltage-sensitive dye and its responses while intact were compared to those measured in thick cerebellar slices. Each slice is stained throughout its depth, even though the pial half appeared darker during epi illumination and lighter during trans-illumination. Optical responses were shown to be mediated by the voltage-sensitive dye because the evoked signals had opposite polarity for 540- and 710-nm light, but no response to 850-nm light. Molecular layer stimulation of the intact cerebellum evoked slow transverse beams. Similar beams were observed in the molecular layer of thick transverse slices but not sagittal slices. With low currents, beams in transverse slices were restricted to sublayers within the molecular layer, conducting slowly away from the stimulus site. These excitatory beams were observed nearly all the way across the turtle cerebellum, distances of 4-6mm. Microstimulation of the granule cell layer of both transverse or sagittal slices evoked a local membrane depolarization restricted to a radial wedge, but these radial responses did not activate measurable molecular layer beams in transverse slices. White matter microstimulation in sagittal slices (near the ventricular surface of the turtle cerebellum) activated the granule cell and Purkinje cell layers, but not the molecular layer. These responses were nearly synchronous, were primarily caudal to the stimulation, and were blocked by cobalt ions. Therefore, synaptic responses in all cerebellar layers contribute to optical signals recorded in intact cerebellum in vitro (Brown and Ariel, 2009). Rapid radial signaling connects a sagittally-oriented, fast-conduction system of the deep layers with the transverse-oriented, slow-conducting molecular layer, thereby permitting complex temporal processing between two tangential but orthogonal paths in the cerebellar cortex. PMID- 20707990 TI - Involvement of peripheral opioid receptors in electroacupuncture analgesia for carrageenan-induced hyperalgesia. AB - Acupuncture is widely used to relieve pain; however, the mechanism underlying electroacupuncture analgesia (EAA) during inflammatory pain is unclear. We investigated whether endogenous peripheral opioid receptors participated in EAA during hyperalgesia elicited by carrageenan-induced inflammation. Moreover, we investigated which subtype of opioid receptor was involved in EAA. Carrageenan was subcutaneously administered by intraplanter (i.pl.) injection into the left hind paw. Nociceptive thresholds were measured using the paw pressure threshold (PPT). Rats received 3Hz electroacupuncture (EA) for 1h after carrageenan injection. The nonselective peripheral opioid receptor antagonist, naloxone methiodide, was administered by i.pl. injection of the inflamed paw 5min before EA. Also, animals received i.pl. or intravenous (i.v.) injection of selective antagonists against MU(D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), delta(naltrindole, NTI), or kappa (nor-Binaltorphimine, nor-BNI) opioid receptors 1h before EA. PPT decreased significantly 3h after carrageenan injection. EA resulted in significant increases of PPT, moreover, PPT elevations persisted for 9h after carrageenan injection. PPT elevations produced by EA were antagonized by local i.pl. injection of naloxone methiodide at 3 and 5h after cessation of EA. NTI, nor-BNI and CTOP blocked EAA from immediately, 1h, and 3h after EA cessation, respectively. The EAA in the inflamed paw could not be blocked by i.v. injection of NTI, nor-BNI and CTOP. These findings suggest that peripheral MU, delta and kappa receptors on peripheral nerve terminals are activated by EA, although there is a time difference among these activations. PMID- 20707991 TI - Tandem mass spectrometric identification of dextrose markers in dried-blood spots from infants receiving total parenteral nutrition. AB - BACKGROUND: The false positive rate for the newborn screening of disorders of amino acid metabolism for premature infants is higher than full term infants. This may be due to very low birth weight infants receiving high concentrations of amino acids from total parenteral nutrition (TPN) administration and/or immature metabolism. An investigation of the possible influence of TPN on screening of premature infants resulted in the detection of three unusual peaks in the tandem mass spectrometry (MS/MS) acylcarnitine profile. These markers were closely correlated with the detection of very high multiple amino acid increases in the profiles of newborns administered with TPN and who were ultimately found to be normal and free of inherited metabolic disorders. METHODS: TPN solutions contain a concentrated mixture of amino acids and dextrose and other nutrients in saline. Due to its high concentration and suggestion of a carbohydrate, it was hypothesized that dextrose (D-glucose) was the contaminant and source of the markers detected. Dextrose, stable isotope-labeled 13C6-dextrose and various TPN solutions were analyzed directly or after enrichment in whole blood by multiple MS/MS acquisition modes including MS-only, product and precursor ion and neutral loss scans. RESULTS: Analysis of dried-blood spots (DBS) prepared from whole blood spiked with TPN solutions containing 12.5% dextrose and amino acid formulations designed to deliver 2.5 gm/kg/day of an amino acid mixture had moderate increases of all 3 dextrose markers detected at m/z 325, 399 and 473 as compared to controls. MS-only scans, product and precursor ion scans of dextrose and 13C6-dextrose in positive ion mode confirmed that these 3 peaks are derived from dextrose. Mass spectral analysis of labeled and unlabeled dextrose suggested that these peaks were dimers derived from dextrose. CONCLUSION: The identification of dextrose markers in DBS indicates that high concentrations of dextrose were present in blood and the likely source was contamination by TPN solutions most likely occurring during a sample collection process. PMID- 20707992 TI - Matrix metalloproteinase 9 gene haplotypes affect left ventricular hypertrophy in hypertensive patients. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are involved in cardiac remodeling and are encoded by genes showing genetic polymorphisms that have functional implications. We examined whether MMP-9 genetic polymorphisms are associated with hypertension and with left ventricular (LV) remodeling in hypertensive patients. METHODS: We studied 173 hypertensive patients and 137 age, race and gender matched healthy controls. Heart echocardiography was performed in all patients and the following MMP-9 genetic polymorphisms were analyzed: C(-1562)T (rs3918242), -90 (CA)(14-24) (rs2234681) and Q279R (rs17576). Haplo.stats analysis was used to assess whether MMP-9 haplotypes are associated with hypertension. Linear regression analysis was performed to assess whether MMP-9 haplotypes affect LV mass index (LVMI) and other echocardiography parameters. RESULTS: MMP-9 -90 (CA)(14-24) "HH" genotype (H allele defined by number of CA repeats >=21) was associated with hypertension (P=0.0085; OR=2.321, 95% confidence interval=1.250 to 4.309). While one MMP-9 haplotype ("C, H, Q") protects against LVMI and end-diastolic diameter increases due to remodeling (P=0.0490 and P=0.0367), another MMP-9 haplotype apparently has detrimental effects over both parameters in hypertensive patients ("T, H, Q", P=0.0015 and P=0.0057, respectively). CONCLUSION: Genetic polymorphisms in MMP-9 gene may modify the susceptibility of hypertensive patients to LV remodeling. Further studies are necessary to examine whether these polymorphisms affect clinical events in hypertensive patients. PMID- 20707993 TI - New testicular mechanisms involved in the prevention of fetal meiotic initiation in mice. AB - In mammals, early fetal germ cells are unique in their ability to initiate the spermatogenesis or oogenesis programs dependent of their somatic environment. In mice, female germ cells enter into meiosis at 13.5 dpc whereas in the male, germ cells undergo mitotic arrest. Recent findings indicate that Cyp26b1, a RA degrading enzyme, is a key factor preventing initiation of meiosis in the fetal testis. Here, we report evidence for additional testicular pathways involved in the prevention of fetal meiosis. Using a co-culture model in which an undifferentiated XX gonad is cultured with a fetal or neonatal testis, we demonstrated that the testis prevented the initiation of meiosis and induced male germ cell differentiation in the XX gonad. This testicular effect disappeared when male meiosis starts in the neonatal testis and was not directly due to Cyp26b1 expression. Moreover, neither RA nor ketoconazole, an inhibitor of Cyp26b1, completely prevented testicular inhibition of meiosis in co-cultured ovary. We found that secreted factor(s), with molecular weight greater than 10 kDa contained in conditioned media from cultured fetal testes, inhibited meiosis in the XX gonad. Lastly, although both Sertoli and interstitial cells inhibited meiosis in XX germ cells, only interstitial cells induced mitotic arrest in germ cell. In conclusion, our results demonstrate that male germ cell determination is supported by additional non-retinoid secreted factors inhibiting both meiosis and mitosis and produced by the testicular somatic cells during fetal and neonatal life. PMID- 20707994 TI - The retinal pigment epithelium of the eye regulates the development of scleral cartilage. AB - The majority of vertebrate species have a layer of hyaline cartilage within the fibrous sclera giving an extra degree of support to the eyeball. In chicks, this is seen as a cuplike structure throughout the scleral layer. However, the mechanisms that control the development of scleral cartilage are largely unknown. Here we have studied the phases of scleral cartilage development and characterised expression profiles of genes activated during the cartilage differentiation programme. CART1 and SOX9, the earliest markers of pre-committed cartilage, are expressed in the mesenchyme surrounding the optic cup. Later AGGRECAN, a matrix protein expressed during chondrocyte differentiation, is also expressed. The expression of these genes is lost following early removal of the optic cup, suggesting a role for this tissue in inducing scleral cartilage. By grafting young retinal pigment epithelium (RPE) and retina into cranial mesenchyme in vivo, it was found that RPE alone has the ability to induce cartilage formation. There are some exceptions within the vertebrates where scleral cartilage is not present; one such example is the placental mammals. However, we found that the cartilage differentiation pathway is initiated in mice as seen by the expression of Cart1 and Sox9, but expression of the later cartilage marker Aggrecan is weak. Furthermore, cartilage forms in mouse peri ocular mesenchyme micromass culture. This suggests that the process halts in vivo before full differentiation into cartilage, but that murine scleral mesenchyme has retained the potential to make cartilage in vitro. RA, Wnts and Bmps have been linked to the cartilage development process and are expressed within the developing RPE. We find that RA may have a role in early scleral cartilage development but is not likely to be the main factor involved. These data reveal the course of scleral cartilage formation and highlight the key role that the optic cup plays in this process. The driving element within the optic cup is almost certainly the retinal pigmented epithelium. PMID- 20707995 TI - Hematopoietic progenitors and hemocyte lineages in the Drosophila lymph gland. AB - The Drosophila lymph gland (LG) is a model system for studying hematopoiesis and blood cell homeostasis. Here, we investigated the patterns of division and differentiation of pro-hemocytes in normal developmental conditions and response to wasp parasitism, by combining lineage analyses and molecular markers for each of the three hemocyte types. Our results show that the embryonic LG contains primordial hematopoietic cells which actively divide to give rise to a pool of pro-hemocytes. We found no evidence for the existence of bona fide stem cells and rather suggest that Drosophila pro-hemocytes are regulated as a group of cells, rather than individual stem cells. The fate-restriction of plasmatocyte and crystal cell progenitors occurs between the end of embryogenesis and the end of the first larval instar, while Notch activity is required for the differentiation of crystal cells in third instar larvae only. Upon parasitism, lamellocyte differentiation prevents crystal cell differentiation and lowers plasmatocyte production. We also found that a new population of intermediate progenitors appears at the onset of hemocyte differentiation and accounts for the increasing number of differentiated hemocytes in the third larval instar. These findings provide a new framework to identify parameters of developmental plasticity of the Drosophila lymph gland and hemocyte homeostasis in physiological conditions and in response to immunological cues. PMID- 20707996 TI - FLN-1/filamin is required for maintenance of actin and exit of fertilized oocytes from the spermatheca in C. elegans. AB - Filamin, known primarily for its actin cross-linking function, is a stretch sensitive structural and signaling scaffold that binds transmembrane receptors and a wide variety of intracellular signaling proteins. The Caenorhabditis elegans filamin ortholog, FLN-1, has a well conserved overall structure, including an N-terminal actin-binding domain, and a series of 20 immunoglobulin (Ig)-like repeats. FLN-1 partially colocalizes with actin filaments in spermathecal and uterine cells. Analysis of phenotypes resulting from a deletion allele and RNAi depletion indicates FLN-1 is required to maintain the actin cytoskeleton in the spermatheca and uterus, and to allow the exit of embryos from the spermatheca. FLN-1 deficient animals accumulate embryos in the spermatheca, lay damaged and unfertilized eggs, and consequently exhibit dramatically reduced brood sizes. The phospholipase PLC-1 is also required for the exit of embryos from the spermatheca, and analysis of doubly mutant animals suggests that PLC-1 and FLN-1 act in the same pathway to promote proper transit of embryos from the spermatheca to the uterus. Given the modular protein structure, subcellular localization, genetic interaction with PLC-1, and known mechanosensory functions of filamin, we postulate that FLN-1 may be required to convert mechanical information about the presence of the oocyte into a biochemical signal, thereby allowing timely exit of the embryo from the spermatheca. PMID- 20707998 TI - Dynein axonemal intermediate chain 2 is required for formation of the left-right body axis and kidney in medaka. AB - Ciliary defects lead to various diseases, such as primary ciliary dyskinesia (PCD) and polycystic kidney disease (PKD). We isolated a medaka mutant mii, which exhibits defects in the left-right (LR) polarity of organs, and found that mii encodes dynein axonemal intermediate chain 2a (dnai2a). Ortholog mutations were recently reported to cause PCD in humans. mii mutant embryos exhibited loss of nodal flow in Kupffer's Vesicle (KV), which is equivalent to the mammalian node, and abnormal expression of the left-specific gene. KV cilia in the mii mutant were defective in their outer dynein arms (ODAs), indicating that Dnai2a is required for ODA formation in KV cilia. While the mii mutant retained motility of the renal cilia and failed to show PKD, the loss of dnai2a and another dnai2 ortholog dnai2b led to PKD. These findings demonstrate that Dnai2 proteins control LR polarity and kidney formation through regulation of ciliary motility. PMID- 20707997 TI - Expression of secreted Wnt pathway components reveals unexpected complexity of the planarian amputation response. AB - Regeneration is widespread throughout the animal kingdom, but our molecular understanding of this process in adult animals remains poorly understood. Wnt/beta-catenin signaling plays crucial roles throughout animal life from early development to adulthood. In intact and regenerating planarians, the regulation of Wnt/beta-catenin signaling functions to maintain and specify anterior/posterior (A/P) identity. Here, we explore the expression kinetics and RNAi phenotypes for secreted members of the Wnt signaling pathway in the planarian Schmidtea mediterranea. Smed-wnt and sFRP expression during regeneration is surprisingly dynamic and reveals fundamental aspects of planarian biology that have been previously unappreciated. We show that after amputation, a wounding response precedes rapid re-organization of the A/P axis. Furthermore, cells throughout the body plan can mount this response and reassess their new A/P location in the complete absence of stem cells. While initial stages of the amputation response are stem cell independent, tissue remodeling and the integration of a new A/P address with anatomy are stem cell dependent. We also show that WNT5 functions in a reciprocal manner with SLIT to pattern the planarian mediolateral axis, while WNT11-2 patterns the posterior midline. Moreover, we perform an extensive phylogenetic analysis on the Smed-wnt genes using a method that combines and integrates both sequence and structural alignments, enabling us to place all nine genes into Wnt subfamilies for the first time. PMID- 20707999 TI - Developing in vivo biophysics by fishing for single molecules. AB - Single-molecule techniques (SMT) provide the possibility to quantitatively analyze the action of single molecules. SMTs can resolve the distribution of states of an ensemble of molecules, collecting information that is otherwise not accessible by typical ensemble techniques. Until now, the application of SMTs in developmental biology was limited. Several recent studies illustrate the possibility to investigate the behavior of single biological molecules in invertebrates such as Caenorhabditis elegans and transparent embryos of model teleosts. These studies have paved the way for the application of fluorescence based SMTs, e.g. fluorescence correlation spectroscopy, fluorescent energy transfer, or single particle tracking, in developmental biology. This review aims to define SMTs applicable in developmental biology, and discuss properties of an ideal animal model. PMID- 20708000 TI - Pathophysiology of human glaucomatous optic nerve damage: insights from rodent models of glaucoma. AB - Understanding mechanisms of glaucomatous optic nerve damage is essential for developing effective therapies to augment conventional pressure-lowering treatments. This requires that we understand not only the physical forces in play, but the cellular responses that translate these forces into axonal injury. The former are best understood by using primate models, in which a well-developed lamina cribrosa, peripapillary sclera and blood supply are most like that of the human optic nerve head. However, determining cellular responses to elevated intraocular pressure (IOP) and relating their contribution to axonal injury require cell biology techniques, using animals in numbers sufficient to perform reliable statistical analyses and draw meaningful conclusions. Over the years, models of chronically elevated IOP in laboratory rats and mice have proven increasingly useful for these purposes. While lacking a distinct collagenous lamina cribrosa, the rodent optic nerve head (ONH) possesses a cellular arrangement of astrocytes, or glial lamina, that ultrastructurally closely resembles that of the primate. Using these tools, major insights have been gained into ONH and the retinal cellular responses to elevated IOP that, in time, can be applied to the primate model and, ultimately, human glaucoma. PMID- 20708002 TI - Dysregulation of microRNAs in cancer: playing with fire. AB - MicroRNAs have emerged as key post-transcriptional regulators of gene expression, involved in various physiological and pathological processes. It was found that several miRNAs are directly involved in human cancers, including lung, breast, brain, liver, colon cancer and leukemia. In addition, some miRNAs may function as oncogenes or tumor suppressors in tumor development. Furthermore, a widespread down-regulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites, frequently amplified or deleted in human cancer, suggesting an important role in malignant transformation. A better understanding of the miRNA regulation and misexpression in cancer may ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies may arise against cancer. Here, we discuss the occurrence of the deregulated expression of miRNAs in human cancers and their importance in the tumorigenic process. PMID- 20708001 TI - Glaucomatous cupping of the lamina cribrosa: a review of the evidence for active progressive remodeling as a mechanism. AB - The purpose of this review is to examine the literature in an attempt to elucidate a biomechanical basis for glaucomatous cupping. In particular, this work focuses on the role of biomechanics in driving connective tissue remodeling in the progression of laminar morphology from a normal state to that of an excavated glaucomatous state. While there are multiple contributing factors to the pathogenesis of glaucoma, we focus on laminar extracellular matrix (ECM) remodeling in glaucoma and the feedback mechanisms and signals that may guide progressive laminar cupping. We review the literature on the potential mechanisms of glaucomatous changes in the laminar ECM at the anatomic, structural, cellular and subcellular levels in the context of the biomechanical paradigm of glaucomatous onset and progression. Several conclusions can be drawn from this review. First, extensive remodeling of the lamina cribrosa ECM occurs in primary open angle glaucoma. Second, there is surprisingly little evidence to support acute mechanical damage to the lamina as the principal mechanism of cupping. Third, ONH astrocytes and lamina cribrosa cells can sense their mechanical environment and respond to mechanical stimuli by remodeling the ECM. Fourth, there is evidence suggesting that chronic remodeling of the lamina results in a progressive posterior migration of the laminar insertion into the canal wall, which eventually results in the posterior lamina inserting into the pia mater. Finally, modeling studies suggest that laminar remodeling may be a biomechanical feedback mechanism through which cells modify their environment in an attempt to return to a homeostatic mechanical environment. It is plausible that biomechanics driven connective tissue remodeling is a mechanism in the progression of laminar morphology from a normal state to that of a cupped, excavated glaucomatous state. PMID- 20708003 TI - Consistency of knee pain: correlates and association with function. AB - OBJECTIVE: The extent and factors associated with knee pain fluctuation are not well-known. We evaluated the prevalence, correlates, and association with function of consistency of knee pain. DESIGN: Participants of the Multicenter Osteoarthritis (MOST) Study, a cohort of individuals with or at high risk of knee osteoarthritis (OA) had baseline knee X-rays, questionnaires, and a question about frequent knee pain (FKnP) (pain on most of the past 30 days) at two time points: a telephone screen and a later clinic visit. We computed the prevalence of inconsistent knee pain (positive answer to FKnP question at only one time point) and consistent knee pain (positive answer to FKnP question at both time points). We evaluated the association of consistency of FKnP with a number of sociodemographic factors, pain severity, and function. RESULTS: There were 2940 participants with complete data (5867 knees) [mean age 62, mean body mass index (BMI) 30.7, 60% female]. Of those, 2977 knees had pain, with 43% having inconsistent and 57% having consistent knee pain. Those with radiographic OA [odds ratio (OR) 0.46], depressive symptoms (OR 0.73), and widespread pain (OR 0.68) (all P<0.05) were less likely to have inconsistent compared with consistent knee pain. Pain, function, and strength were significantly better in persons with two knees that had inconsistent compared with consistent pain. CONCLUSIONS: A substantial proportion of persons with knee pain have inconsistent knee pain, associated with better physical function and strength (adjusting for pain severity). Such pain may be suggestive of an earlier stage of disease. PMID- 20708004 TI - The multidimensionality of sleep quality and its relationship to fatigue in older adults with painful osteoarthritis. AB - OBJECTIVE: To evaluate subjective sleep quality and its relationship to fatigue in older adults with osteoarthritis (OA). METHOD: In a community cohort with hip/knee OA, subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and fatigue was measured by the Profile of Mood States - Fatigue subscale (POMS-F). Correlates of sleep quality and fatigue were determined by standardized interviews including socio-demographics, OA severity (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) summary score), comorbidity, depression (Center for Epidemiologic Studies Depression Scale, CES-D), stressful life events, daytime napping, symptoms of restless legs syndrome (RLS) and prior sleep disorder diagnoses. Logistic regression examined correlates of poor sleep (PSQI score>5). Linear regression evaluated the relationship between poor sleep and fatigue, and the effect of napping on this relationship. RESULTS: In 613 respondents, mean age was 78 years, 78% were female, 11% had concomitant fibromyalgia, and 26% had 3+ comorbid conditions. Responses indicated moderate OA severity. Seventy percent reported poor sleep; 25% met criteria for RLS and 6.5% reported a diagnosed sleep disorder. Independent correlates of poor sleep were: greater arthritis severity (adjusted odds ratio (OR) per unit increase in WOMAC score=1.03, P<0.0001), 3+ comorbid conditions (adjusted OR=1.88; P=0.03), depressed mood (adjusted OR per unit increase in CES-D score=1.09, P<0.0001), and RLS (adjusted OR=1.87; P=0.02). Controlling for previously reported fatigue correlates, poor sleep was significantly associated with greater fatigue (parameter estimate=1.63, P=0.0003) and napping did not moderate this relationship (P=0.55 for the interaction between napping and poor sleep). CONCLUSIONS: Among older people with OA, poor sleep is highly prevalent and significantly linked with fatigue. Identifying the nature of sleep disturbances in OA is important as treatment of sleep disturbances may reduce OA-related fatigue. PMID- 20708005 TI - Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. AB - BACKGROUND & AIMS: Little data are available from genome-wide association studies (GWASs) of liver histology in patients with nonalcoholic fatty liver disease (NAFLD). We conducted a pilot GWAS in patients with NAFLD, characterized by histology, who were enrolled in the NASH Clinical Research Network (CRN) Database Study. METHODS: We studied clinical, laboratory, and histologic data from 236 non Hispanic white women with NAFLD. We analyzed 324,623 single nucleotide polymorphisms (SNPs) from the 22 autosomal chromosomes. Multivariate-adjusted logistic regression analyses were conducted for binary outcomes, and linear regression analysis was applied for quantitative traits. A P value < 1 * 10(-6) was considered to be significant. RESULTS: In multivariate models adjusted for age, body mass index, diabetes, waist/hip ratios, and levels of glycated hemoglobin, the NAFLD activity score was associated with the SNP rs2645424 on chromosome 8 in farnesyl diphosphate farnesyl transferase 1 (FDFT1) (P = 6.8 * 10(-7)). The degree of fibrosis was associated with the SNP rs343062 on chromosome 7 (P = 2.7 * 10(-8)). SNPs associated with lobular inflammation included SNP rs1227756 on chromosome 10 in COL13A1 (P = 2.0 * 10(-7)), rs6591182 on chromosome 11 (P = 8.6 * 10(-7)), and rs887304 on chromosome 12 in EFCAB4B (P = 7.7 * 10(-7)). SNPs associated with serum levels of alanine aminotransferase included rs2499604 on chromosome 1 (P = 2.2 * 10(-6)), rs6487679 on chromosome 12 in PZP (P = 1.3 * 10(-6)), rs1421201 on chromosome 18 (P = 1.0 * 10(-5)), and rs2710833 on chromosome 4 (P = 6.3 * 10(-7)). No significant associations were observed between genotypes and steatosis, ballooning degeneration, portal inflammation, or other features of NAFLD. CONCLUSIONS: A GWAS significantly associated genetic variants with features of hepatic histology in patients with NAFLD. These findings should be validated in larger and more diverse cohorts. PMID- 20708006 TI - Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. AB - BACKGROUND & AIMS: Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients. Pegylated alpha-interferon can effectively treat chronic HEV infection after liver transplantation but is contraindicated for kidney transplantation. We assessed the antiviral effect of ribavirin monotherapy in patients with chronic HEV infection following kidney transplantation. METHODS: In a pilot study performed at Toulouse University Hospital, 6 patients that received kidney transplants who were positive for HEV RNA (infected with HEV for 36.5 months; [range, 11-46 months]) were given ribavirin monotherapy for 3 months. Ribavirin was given at 600-800 mg/day in 2 separate doses, based on the patient's ability to clear creatinine. RESULTS: Median serum concentration of HEV RNA at baseline was 5.77 log copies/mL (range, 4.35-7.35 log copies/mL). Three months after ribavirin therapy commenced, HEV RNA was undetectable in serum samples from all patients. A sustained virologic response was observed in 4 patients; the other 2 patients relapsed at 1 and 2 months after ribavirin therapy ended. At the end of the study, all patients had normal levels of alanine and aspartate aminotransferase. Anemia was the main side effect caused by ribavirin therapy. CONCLUSIONS: Ribavirin monotherapy inhibits the replication of HEV in vivo and might induce a sustained virological response in patients with chronic HEV infections. Further studies are required to determine the optimal duration of ribavirin therapy. PMID- 20708007 TI - Bowel disturbances are the most important risk factors for late onset fecal incontinence: a population-based case-control study in women. AB - BACKGROUND & AIMS: Age, diarrhea, and certain chronic illnesses are risk factors for fecal incontinence (FI). However, the contribution of obstetric injury to the development of FI later in life is unclear. We sought to better understand the risk factors for FI. METHODS: Through the Rochester Epidemiology Project, a nested case-control study of 176 randomly selected women with FI (cases; mean age, 58 years) and 176 age-matched community controls was conducted in a population-based cohort from Olmsted County, Minnesota. Risk factors for FI were evaluated by reviewing inpatient and outpatient medical (including original obstetric) records. Analyses focused on conditions that preceded the index date (incidence date of FI for case in each matched pair). RESULTS: In 88% of cases, FI began at age >=40 years; severity was mild (37%), moderate (58%), or severe (5%). By multivariable analysis, current smoking (odds ratio [OR], 4.7; 95% confidence interval [CI], 1.4-15), body mass index (OR per unit, 1.1; 95% CI, 1.004-1.1), diarrhea (OR, 53; 95% CI, 6.1-471), irritable bowel syndrome (OR, 4.8; 95% CI, 1.6-14), cholecystectomy (OR, 4.2; 95% CI, 1.2-15), rectocele (OR, 4.9; 95% CI, 1.3-19), and stress urinary incontinence (OR, 3.1; 95% CI, 1.4-6.5), but not obstetric events, were independent risk factors for FI. CONCLUSIONS: Bowel disturbances rather than prior obstetric injury are the main risk factors for FI. Measures to ameliorate bowel disturbances and other potentially reversible risk factors should be implemented before anal imaging is performed on women with FI. PMID- 20708008 TI - Maternal deprivation has sexually dimorphic long-term effects on hypothalamic cell-turnover, body weight and circulating hormone levels. AB - Maternal deprivation (MD) has numerous outcomes, including modulation of neuroendocrine functions. We previously reported that circulating leptin levels are reduced and hypothalamic cell-turnover is affected during MD, with some of these effects being sexually dimorphic. As leptin modulates the development of hypothalamic circuits involved in metabolic control, we asked whether MD has long term consequences on body weight, leptin levels and the expression of neuropeptides involved in metabolism. Rats were separated from their mother for 24h starting on postnatal day (PND) 9 and sacrificed at PNDs 13, 35 and 75. In both sexes MD reduced body weight, but only until puberty, while leptin levels were unchanged at PND 35 and significantly reduced at PND 75. Adiponectin levels were also reduced at PND 75 in females, while testosterone levels were reduced in males. At PND 13, MD modulated cell-turnover markers in the hypothalamus of males, but not females and increased nestin, a marker of immature neurons, in both sexes, with males having higher levels than females and a significantly greater rise in response to MD. There was no effect of MD on hypothalamic mRNA levels of the leptin receptor or metabolic neuropeptides or the mRNA levels of leptin and adiponectin in adipose tissue. Thus, MD has long-term effects on the levels of circulating hormones that are not correlated with changes in body weight. Furthermore, these endocrine outcomes are different between males and females, which could be due to the fact that MD may have sexually dimorphic effects on hypothalamic development. PMID- 20708009 TI - Short-term exposure to a synthetic estrogen disrupts mating dynamics in a pipefish. AB - Sexual selection is responsible for the evolution of some of the most elaborate traits occurring in nature, many of which play a vital role in competition over access to mates and individual reproductive fitness. Because expression of these traits is typically regulated by sex-steroids there is a significant potential for their expression to be affected by the presence of certain pollutants, such as endocrine disrupting compounds. Endocrine disruptors have been shown to alter primary sexual traits and impact reproduction, but few studies have investigated how these compounds affect secondary sexual trait expression and how that may, in turn, impact mating dynamics. In this study we examine how short-term exposure to a synthetic estrogen impacts secondary sexual trait expression and mating dynamics in the Gulf pipefish, a species displaying sex-role reversal. Our results show that only 10days of exposure to 17alpha-ethinylestradiol results in adult male pipefish developing female-like secondary sexual traits. While these males are capable of reproduction, females discriminate against exposed males in mate choice trials. In natural populations, this type of discrimination would reduce male mating opportunities, thus potentially reducing their long-term reproductive success. Importantly, the effects of these compounds on mating dynamics and mating opportunity would not be observed using the current standard methods of assessing environmental contamination. However, disrupting these processes could have profound effects on the viability of exposed populations. PMID- 20708011 TI - Integrin beta1 subunit from Ostrinia furnacalis hemocytes: molecular characterization, expression, and effects on the spreading of plasmatocytes. AB - When lepidopteran larvae are infected by a large quantity of pathogens or parasitized by nonadaptive parasitoids, hemocytes in the hemocoel will encapsulate these foreign invaders. Cellular encapsulation requires hemocytes, particularly plasmatocytes, to change their states from nonadhesive, spherical cells into adhesive, spreading cells. However, it is unclear how the changes of plasmatocytes are regulated. Here we report that the integrin beta1 subunit from hemocytes of Ostrinia furnacalis (Ofint beta1) plays an important role in regulating the spreading of plasmatocytes. The full length cDNA sequence (4477 bp) of Ofint beta1 was cloned from hemocytes. Phylogenetic analysis showed that Ofint beta1 belonged to the integrin betaPS family of Drosophila melanogaster with highest sequence identity (78.7%) to the beta-integrin of Pseudoplusia includens. Structural analysis of the deduced amino acid sequence indicated that Ofint beta1 had similar functional domains to known beta-integrins in other lepidopteran insects. RT-PCR, Northern blotting, Western blotting and immunohistochemical analyses showed that OfINT beta1 was expressed mainly in hemocytes, especially in plasmatocytes, and weakly in fat body, Malpighian tubes and epidermis. After hemocytes had spread onto slides, fewer antibodies to OfINT beta1 bound to the surface of plasmatocytes. Furthermore, anti-OfINT beta1 serum clearly inhibited the spreading of plasmatocytes. Together these results indicate that OfINT beta1 may play an important role in regulating the spreading of plasmatocytes. PMID- 20708010 TI - Human disturbance alters endocrine and immune responses in the Galapagos marine iguana (Amblyrhynchus cristatus). AB - Anthropogenic disturbance is a relevant and widespread facilitator of environmental change and there is clear evidence that it impacts natural populations. While population-level responses to major anthropogenic changes have been well studied, individual physiological responses to mild disturbance can be equally critical to the long-term survival of a species, yet they remain largely unexamined. The current study investigated the impact of seemingly low-level anthropogenic disturbance (ecotourism) on stress responsiveness and specific fitness-related immune measures in different breeding stages of the marine iguana (Amblyrhynchus cristatus). Specifically, we found stress-induced elevations in plasma corticosterone among tourist-exposed populations relative to undisturbed populations. We also found changes in multiple immunological responses associated with stress-related effects of human disturbance, including bacterial killing ability, cutaneous wound healing, and hemolytic complement activity, and the responses varied according to reproductive state. By identifying health-related consequences of human disturbance, this study provides critical insight into the conservation of a well-known species that has a very distinct ecology. The study also broadens the foundation of knowledge needed to understand the global significance of various levels of human disturbance. PMID- 20708012 TI - Inhibition of melanization by a Nasonia defensin-like peptide: implications for host immune suppression. AB - The parasitic wasp Nasonia vitripennis suppresses host immune mechanisms that include melanization reactions. Melanization is an important immune response of hosts induced by wasp infection and thus its inhibition represents a successful strategy for parasitism. However, the molecular basis associated with such inhibition is largely unknown in N. vitripennis. Here, we report recombinant expression, structural and functional characterization of a Nasonia-derived defensin-like peptide (called nasonin-3) whose recombinant product exerts inhibitory effect on host melanization. The possible role of nasonin-3 in immune suppression is also discussed. PMID- 20708013 TI - CD117, adult cardiac stem cell marker, is transiently expressed in methothelial epicardial cells. PMID- 20708014 TI - Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte death. AB - Among the identified microRNAs (miRs) thus far, ~50% of mammalian miRs are clustered in the genome and transcribed as polycistronic primary transcripts. However, whether clustered miRs mediate non-redundant and cooperative functions remains poorly understood. In this study, we first identified activation of the promoter of miR-144/451 by GATA-4, a critical transcription factor in the heart. Next, we observed that ectopic expression of miR-144 and -451 individually augmented cardiomyocyte survival, which was further improved by overexpression of miR-144/451, compared to control cells in response to simulated ischemia/reperfusion. In contrast, knockdown of endogenous miR-144 and -451 revealed opposite effects. Using luciferase reporter assay and western blot analysis, we also validated that both miR-144 and miR-451 target CUG triplet repeat-binding protein 2 (CUGBP2), a ubiquitously expressed RNA-binding protein, known to interact with COX-2 3'UTR and inhibit its translation. Accordingly, protein levels of CUGBP2 were greatly reduced and COX-2 activity was markedly increased in miR-144-, miR-451-, and miR-144/451-overexpressing cardiomyocytes, compared to GFP cells. Furthermore, inhibition of COX-2 activity by either NS-398 or DUP-697 partially offset protective effects of the miR-144/451 cluster. Together, these data indicate that both partners of the miR-144/451 cluster confer protection against simulated I/R-induced cardiomyocyte death via targeting CUGBP2-COX-2 pathway, at least in part. Thus, both miR-144 and miR-451 may represent new therapeutic agents for the treatment of ischemic heart disease. PMID- 20708015 TI - Digitalis and Na/Ca exchange: old dog learns new mitochondrial tricks. PMID- 20708016 TI - Conformation changes in E. coli Rho monitored by hydrogen/deuterium exchange and mass spectrometry: response to ligand binding. AB - Escherichia coli Rho is a doughnut-shaped homohexameric ATP-dependent RNA-DNA helicase that releases newly synthesized RNA molecules from transcription complexes. Rho binds 60-80 bases of RNA among six primary RNA binding sites around the inside of its N-terminal crown; the RNA then passes through the central hole of the hexamer. Here it triggers ATP hydrolysis and is moved with respect to the protein. We study protein conformation changes upon ligand binding using amide proton hydrogen/deuterium exchange and mass spectrometry. Global exchange studies indicate net mass differences of about 15 Da after 1 h of exchange in the presence--versus in the absence--of the ligand MgATP or the RNA poly(C). Sites of ligand-dependent exchange differences were localized by mass determination of the peptic peptides of Rho. A peptide of the N-terminal domain near the known primary RNA sites (aa 56-63) was protected from amide proton exchange in the presence of poly(C), as was a novel N-terminal domain peptide that is not near RNA in the crystal structures or in NMR structures with RNA oligomers (aa 37-46). This result may further define the primary interaction site of RNA with Rho. The Q-loop-containing peptide in the central hole of the protein that interacts with RNA was also protected by RNA (aa 271-286). The exchange rate of one peptide near the ATPase active site (aa 206-218) slowed in the presence of MgATP and increased in the presence of RNA. Overall, the results show changes in a few protein segments rather than a different overall conformation. PMID- 20708017 TI - Structure of the AML1-ETO NHR3-PKA(RIIalpha) complex and its contribution to AML1 ETO activity. AB - AML1-ETO is the chimeric protein product of t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the nervy homology region (NHR) 3 domain, which shares homology with A-kinase anchoring proteins and interacts with the regulatory subunit of type II cAMP-dependent protein kinase A (PKA(RIIalpha)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RIIalpha). Based on this structure, a key residue in AML1-ETO for PKA(RIIalpha) association was mutated. This mutation did not disrupt AML1-ETO's ability to enhance the clonogenic capacity of primary mouse bone marrow cells or its ability to repress proliferation or granulocyte differentiation. Introduction of the mutation into AML1-ETO had minimal impact on in vivo leukemogenesis. Therefore, the NHR3-PKA(RIIalpha) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia. PMID- 20708018 TI - Replicator dynamics of reward & reputation in public goods games. AB - Public goods games have become the mathematical metaphor for game theoretical investigations of cooperative behavior in groups of interacting individuals. Cooperation is a conundrum because cooperators make a sacrifice to benefit others at some cost to themselves. Exploiters or defectors reap the benefits and forgo costs. Despite the fact that groups of cooperators outperform groups of defectors, Darwinian selection or utilitarian principles based on rational choice should favor defectors. In order to overcome this social dilemma, much effort has been expended for investigations pertaining to punishment and sanctioning measures against defectors. Interestingly, the complementary approach to create positive incentives and to reward cooperation has received considerably less attention-despite being heavily advocated in education and social sciences for increasing productivity or preventing conflicts. Here we show that rewards can indeed stimulate cooperation in interaction groups of arbitrary size but, in contrast to punishment, fail to stabilize it. In both cases, however, reputation is essential. The combination of reward and reputation result in complex dynamics dominated by unpredictable oscillations. PMID- 20708019 TI - A study of entropy/clarity of genetic sequences using metric spaces and fuzzy sets. AB - The study of genetic sequences is of great importance in biology and medicine. Sequence analysis and taxonomy are two major fields of application of bioinformatics. In the present paper we extend the notion of entropy and clarity to the use of different metrics and apply them in the case of the Fuzzy Polynuclotide Space (FPS). Applications of these notions on selected polynucleotides and complete genomes both in the I(12*k) space, but also using their representation in FPS are presented. Our results show that the values of fuzzy entropy/clarity are indicative of the degree of complexity necessary for the description of the polynucleotides in the FPS, although in the latter case the interpretation is slightly different than in the case of the I(12*k) hypercube. Fuzzy entropy/clarity along with the use of appropriate metrics can contribute to sequence analysis and taxonomy. PMID- 20708020 TI - Investigation of the performance of fermentation processes using a mathematical model including effects of metabolic bottleneck and toxic product on cells. AB - A number of recent research studies have focused on theoretical and experimental investigation of a bottleneck in a metabolic reaction network. However, there is no study on how the bottleneck affects the performance of a fermentation process when a product is highly toxic and remarkably influences the growth and death of cells. The present work therefore studies the effect of bottleneck on product concentrations under different product toxicity conditions. A generalized bottleneck model in a fed-batch fermentation is constructed including both the bottleneck and the product influences on cell growth and death. The simulation result reveals that when the toxic product strongly influences the cell growth and death, the final product concentration is hardly changed even if the bottleneck is removed, whereas it is markedly changed by the degree of product toxicity. The performance of an ethanol fermentation process is also discussed as a case example to validate this result. In conclusion, when the product is highly toxic, one cannot expect a significant increase in the final product concentration even if removing the bottleneck; rather, it may be more effective to somehow protect the cells so that they can continuously produce the product. PMID- 20708021 TI - Majority-rule (+) consensus trees. AB - The construction of a consensus tree to summarize the information of a given set of phylogenetic trees is now routinely a part of many studies in systematic biology. One popular method is the majority-rule consensus tree. In this paper we introduce and characterize a new consensus method that refines the majority-rule tree by adding certain compatible clusters satisfying a simple criterion. PMID- 20708023 TI - Chemosensory signals of competition increase the skin conductance response in humans. AB - In vertebrates, chemosensory signals of competition are communicated between conspecifics, eliciting behavioral and physiological adaptations in the perceiving animal. The current study investigates, whether chemosensory signals of competition are also communicated between humans, and whether they elicit physiological changes in the perceiver. It is further investigated whether personality traits alter this physiological responding. Axillary sweat was collected from six male donors during a competition (badminton match) and a sport control condition (running). The donors' testosterone rose stronger during the competition as compared to the sport control condition. The chemosensory stimuli were presented to 18 (9 male) participants through a constant-flow olfactometer, while the skin conductance response (SCR) was measured. Results reveal that the SCR was larger in response to chemosensory signals collected during the competition condition as compared to those collected during the sport control condition. Furthermore, regression analyses showed, that higher scores on trait social anxiety were related to larger SCRs towards the chemosensory signals of competition. The current result suggests that chemosensory signals of competition can be communicated between humans, and that they elicit orienting in the perceiving individual. These data are consistent with current research, suggesting that high socially anxious individuals process threatening social information preferentially. The current results add to the growing body of research into human chemosensory communication of social information, and extend previous research on the chemosensory communication of anxiety. PMID- 20708024 TI - Seasonal variation in tissue estrogen-2/4-hydroxylases (EH) and in vitro effects of steroids on ovarian EH activity in the catfish Heteropneustes fossilis. AB - A radiometric assay was used to measure microsomal EH activity from tritiated H(2)O formed during the conversion of [2,4 (3)H] estradiol-17beta into catecholestrogens in the microsomal fractions of liver, brain and ovary of the catfish Heteropneustes fossilis. The validation data show that enzyme activity increased with incubation time, and substrate and cofactor (NADPH) concentrations, elicited temperature optima of 30-37 degrees C and pH optima of 6.8-7.8. EH activity was strongly NADPH-dependent and in its absence only 13.48% activity was recorded. Liver recorded the highest enzyme activity, followed by brain and ovary. EH activity showed a significant seasonal variation with the peak activity in spawning phase and the lowest activity in resting phase. In the ovary, the follicular layer (theca and granulosa) elicited the highest activity over that of the denuded oocytes. Modulatory effects of steroids on ovarian enzyme activity were further demonstrated. The incubation of postvitellogenic follicles with 1, 10 or 100 nM concentrations of various steroids for 24 h produced varied effects on EH activity. Progesterone and 2-hydroxyestradiol 17beta elicited strong suppressive effects on enzyme activity. Estrogens (E(1), E(2) and E(3)) suppressed the activity in a concentration-dependent manner. Among the progestins tested, 17,20alpha-dihydroxy-4-pregnen-3-one, the isomer of 17,20beta-dihydroxy-4-pregnen-3-one (a teleost maturation-inducing steroid) showed the lowest depressing effect. Among androgens, the testosterone metabolite 11-ketotestosterone (functional teleost androgen) showed a high suppressing effect. Corticosteroids elicited low activity with cortisol suppressed the activity at higher concentrations. The study will form a basis to understand the physiological role of catecholestrogens in ovarian functions. PMID- 20708022 TI - A quantitative model of thermal injury-induced acute inflammation. AB - Severe burns are among the most common causes of death from unintentional injury. The induction and resolution of the burn-induced systemic inflammatory response are mediated by a network of factors and regulatory proteins. Numerous mechanisms operate simultaneously, thus requiring a systems level approach to characterize their overall impact. Towards this goal, we propose an in silico semi-mechanistic model of burn-induced systemic inflammation using liver-specific gene expression from a rat burn model. Transcriptional responses are coupled with extracellular signals through a receptor mediated indirect response (IDR) and transit compartment model. The activation of the innate immune system in response to the burn stimulus involves the interaction between extracellular signals and critical receptors which triggers downstream signal transduction cascades leading to transcriptional changes. The resulting model consists of fifteen (15) coupled ordinary differential equations capturing key aspects of inflammation such as pro inflammation, anti-inflammation and hypermetabolism. The model was then evaluated through a series of biologically relevant scenarios aiming at revealing the non linear behavior of acute inflammation including: investigating the implication of effect of different severity of thermal injury; examining possible mechanistic dysregulation of IKK-NF-kappaB system which may reflect secondary effects that lead to potential malfunction of the response; and exploring the outcome of administration of receptor antagonist or anti-body to significant cytokines. PMID- 20708025 TI - Head and neck cancer due to heavy metal exposure via tobacco smoking and professional exposure: a review. AB - Chronic exposures to heavy metals via tobacco smoking and professional exposure may increase the risk of head and neck cancer, although the epidemiologic evidence is limited by problems of low study power and inadequate adjustment for tobacco and professional exposure use. Numerous scientific reviews have examined the association of various heavy metals exposure with respiratory cancer as well as other cancer types, but few have been published on head and neck cancer. The purpose of this paper, therefore, is to review the head and neck tract cancer related data on exposure to heavy metals via smoking and working exposure and to study the major mechanisms underlying some toxic metals carcinogenesis. PMID- 20708026 TI - Latrotoxin-induced exocytosis in mast cells transfected with latrophilin. AB - alpha-Latrotoxin (alpha-LTX) is known to cause massive exocytosis from presynaptic nerve terminals. We investigated the effects of alpha-LTX on exocytotic release from mast cells, typical non-neuronal secretory cells. When we transfected mast cells with latrophilin, a specific receptor for alpha-LTX, alpha LTX caused intracellular Ca(2+) to increase and led to exocytosis in the presence of extracellular Ca(2+). On the other hand, neither Ca(2+) increase nor exocytosis was observed in the absence of extracellular Ca(2+). These results indicate that alpha-LTX, together with latrophilin, works as a Ca(2+) ionophore. However, alpha-LTX had additional effects on signal transduction in mast cells. We found that inhibitors of protein kinase C (PKC) partially suppressed exocytosis. Furthermore, several soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, including SNAP-23, were phosphorylated by alpha-LTX. These results suggest that exocytosis induced by alpha-LTX can be explained by (1) elevation of intracellular Ca(2+), (2) phosphorylation of SNARE proteins including SNAP-23, syntaxin-4 and VAMP-8 through PKC-dependent and -independent pathways. Our study may provide a new system to investigate the action of alpha-LTX and the mechanism of exocytosis in mast cells. PMID- 20708027 TI - Preparation and metal uptake studies of modified forms of chitin. AB - Chitin (C), a biopolymer which showed moderate sorption capacity (SC) towards Cu(II) and Fe(III) was suitably modified to enhance the SC. Three types of modifications viz., protonated chitin (PC), carboxylated chitin (CC) and grafted chitin (GC) were carried out to increase the SC. The modified forms of chitin showed enhanced SC for both Cu(II) and Fe(III) than the raw chitin. These sorbents were characterized by the FTIR and SEM with EDAX analysis. The various influencing parameters viz., contact time, pH and the interference of common anions during the sorption have been investigated. The sorption data was reasonably explained using Freundlich and Langmuir isotherms. The calculated values of thermodynamic parameters indicated that, the sorption is spontaneous and endothermic in nature. The order of selectivity of Cu(II) and Fe(III) on modified chitin was found to be Fe(III)>Cu(II). The suitability of modified chitin has been tested with the field samples collected in a near by industrial area. The suitable mechanism for the respective metal removal has been established. PMID- 20708028 TI - The effect of nitric oxide and hydrogen peroxide in the activation of the systemic immune response of Anopheles albimanus infected with Plasmodium berghei. AB - The expression of genes encoding the antimicrobial peptides (AMPs) attacin, cecropin and gambicin, as well as the effects of NO and H(2)O(2) on their expression was investigated in midguts and fat bodies of Anopheles albimanus during the midgut infection with Plasmodium berghei. Midgut infection induced an increase in the expression of the three AMPs in both tissues; while NO and H(2)O(2) were present in haemolymph. Treatment with L-NAME and vitamin C reduced the effect of P. berghei infection on the AMP's expression, and exogenous NO and H(2)O(2) induced their expression in the mosquito fat body. The induction of AMPs in abdominal tissues, while the malaria parasites are in the mosquito midgut, suggests communication between the midgut epithelial cells and the abdominal tissue which has not yet had direct contact with the parasites. Free radical production in mosquito midgut and haemolymph during Plasmodium infection and their inductive effect on AMPs in abdominal tissues indicates the possible participation of these radicals in mediating a systemic immune response in this mosquito. PMID- 20708030 TI - Pandemic (H1N1) 2009 influenza in HIV-infected adults: clinical features, severity, and outcome. PMID- 20708031 TI - High direct healthcare costs of patients hospitalised with pandemic (H1N1) 2009 influenza in Malaysia. PMID- 20708029 TI - Relationship between blood harmane and harmine concentrations in familial essential tremor, sporadic essential tremor and controls. AB - INTRODUCTION: Harmane, a potent tremor-producing beta-carboline alkaloid, may play a role in the etiology of essential tremor (ET). Blood harmane concentrations are elevated in ET cases compared with controls yet the basis for this elevation remains unknown. Decreased metabolic conversion (harmane to harmine) is one possible explanation. Using a sample of >500 individuals, we hypothesized that defective metabolic conversion of harmane to harmine might underlie the observed elevated harmane concentration in ET, and therefore expected to find a higher harmane to harmine ratio in familial ET than in sporadic ET or controls. METHODS: Blood harmane and harmine concentrations were quantified by high performance liquid chromatography. RESULTS: There were 78 familial ET cases, 187 sporadic ET cases, and 276 controls. Blood harmane and harmine concentrations were correlated with one another (Spearman's r=0.24, p<0.001). The mean (+/-SD) harmane/harmine ratio=23.4+/-90.9 (range=0.1-987.5). The harmane/harmine ratio was highest in familial ET (46.7+/-140.4), intermediate in sporadic ET (28.3+/-108.1), and lowest in controls (13.5+/-50.3) (p=0.03). In familial ET cases, there was no association between this ratio and tremor severity (Spearman's r=0.08, p=0.48) or tremor duration (Spearman's r=0.14, p=0.24). CONCLUSION: The basis for the elevated blood harmane concentration, particularly in familial ET, is not known, although the current findings (highest harmane/harmine ratio in familial ET cases) lends support to the possibility that it could be the result of a genetically-driven reduction in harmane metabolism. PMID- 20708033 TI - Measuring torsional eye movements by tracking stable iris features. AB - We propose a new method to measure torsional eye movements from videos taken of the eye. In this method, we track iris features that have been identified as Maximally Stable Volumes. These features, which are stable over time, are dark regions with bright borders that are steep in intensity. The advantage of Maximally Stable Volumes is that they are robust to nonuniform illumination and to large changes in eye and camera position. The method performs well even when the iris is partially occluded by reflections or eyelids, and is faster than cross-correlation. In addition, it is possible to use the method on videos of macaque eyes taken in the infrared, where the iris appears almost featureless. PMID- 20708032 TI - The therapeutic potential of G-protein coupled receptors in Huntington's disease. AB - Huntington's disease is a late-onset autosomal dominant inherited neurodegenerative disease characterised by increased symptom severity over time and ultimately premature death. An expanded CAG repeat sequence in the huntingtin gene leads to a polyglutamine expansion in the expressed protein, resulting in complex dysfunctions including cellular excitotoxicity and transcriptional dysregulation. Symptoms include cognitive deficits, psychiatric changes and a movement disorder often referred to as Huntington's chorea, which involves characteristic involuntary dance-like writhing movements. Neuropathologically Huntington's disease is characterised by neuronal dysfunction and death in the striatum and cortex with an overall decrease in cerebral volume (Ho et al., 2001). Neuronal dysfunction begins prior to symptom presentation, and cells of particular vulnerability include the striatal medium spiny neurons. Huntington's is a devastating disease for patients and their families and there is currently no cure, or even an effective therapy for disease symptoms. G-protein coupled receptors are the most abundant receptor type in the central nervous system and are linked to complex downstream pathways, manipulation of which may have therapeutic application in many neurological diseases. This review will highlight the potential of G-protein coupled receptor drug targets as emerging therapies for Huntington's disease. PMID- 20708034 TI - Seizure logging: A new approach to synchronized cable-free EEG and video recordings of seizure activity in mice. AB - We describe a new cable-free, non-telemetric method for synchronized electrophysiological and video recordings of seizure activity in freely moving mice. The electrophysiological recordings were made by a head-mounted 4-channel data-logging device, allowing the mouse to move freely in its cage, and even to be moved from cage to cage under ongoing recording. Seizures were studied in Synapsin I/II double knock-out (SynDKO) mice, a genetically engineered mouse line that shows seizures upon daily handling procedures such as tail lifting during cage changes, much in resemblance to the more studied El mouse. The ability to elicit seizures through daily handling in SynDKO mice undergoing electrophysiological recording is a significant improvement in comparison to the traditional cable-based set-up. Furthermore, with its four channels and a sample rate of up to 500Hz, the data-logging device opens for more varied electrophysiological studies than other available cable-free systems. PMID- 20708035 TI - A pseudo-plaque method for infectious particle assay and clonal isolation of adeno-associated virus. AB - A colorimetric method has been developed for the detection of adeno-associated virus (AAV) infectious centers in cell culture monolayers. Due to its non cytopathic nature, AAV has not been amenable to the traditional plaque assay, involving an agar overlay and cellular stains. As a result, an alternate method was required. The pseudo-plaque assay is based on enzyme-catalyzed color development after a fixed cell monolayer is probed with anti-AAV monoclonal antibodies. In spite of chemical fixation, expected to damage the viral genomes and particles, infectious particles can be recovered and amplified for the propagation of viral clones. PMID- 20708036 TI - Rapid prediction of sustained virological response in patients chronically infected with HCV by evaluation of RNA decay 48h after the start of treatment with pegylated interferon and ribavirin. AB - The combination of pegylated interferons (PEG-IFNs) and ribavirin represents the standard of care for the treatment of chronic HCV-infected patients, yet with a success rate around 50% in genotypes 1 and 4, high costs and side effects. Therefore, early prediction of sustained virological response (SVR) is a relevant issue for HCV-patients. We evaluated the association between SVR and decline of HCV-RNA at 48h in a prospective cohort of 145 HCV-patients treated with PEG-IFNs and ribavirin (males=69.1%; genotypes 1/4=51.0%; HIV-1 coinfected=6.7%). SVR was obtained in 65.5% of patients, while 16.6% experienced relapse and 17.9% no response. The first-phase of HCV-RNA decline clearly differentiated patients with SVR from relapsers and non-responders, independently of genotype (P<0.001). In univariate and multivariate analyses, different infralogaritmic thresholds of HCV RNA decay at 48h were tested, observing the highest predictive potential at 0.5log: decays above this threshold showed a 76.2% negative predictive value for SVR, whereas decays >0.5log indicated a 6.8 odds ratio (95% C.I.: 2.0-23.2) for SVR after controlling for genotype, baseline viremia, adherence to therapy and HIV coinfection. Decays beyond the 0.5log threshold were also strongly associated with and highly predictive of early virological response (95.0% positive predictive value, P<0.001). PMID- 20708037 TI - Inhibition of adenovirus infections by siRNA-mediated silencing of early and late adenoviral gene functions. AB - Adenoviruses are pathological agents inducing mild respiratory and gastrointestinal infections. Under certain circumstances, for example in immunosuppressed patients, they induce severe infections of the liver, heart and lung, sometimes leading to death. Currently, adenoviral infections are treated by palliative care with no curative antiviral therapy yet available. Gene silencing by RNA interference (RNAi) has been shown to be a potent new therapeutic option for antiviral therapy. In the present study, we examined the potential of RNAi mediated inhibition of adenovirus 5 infection by the use of small interfering (si)RNAs targeting both early (E1A) and late (hexon, IVa2) adenoviral genes. Several of the initially analyzed siRNAs directed against E1A, hexon and IVa2 showed a distinct antiviral activity. Among them, one siRNA for each gene was selected and used for the further comparative investigations of their efficiency to silence adenoviruses. Silencing of the late genes was more efficient in inhibiting adenoviral replication than comparable silencing of the E1A early gene. A combination strategy involving down-regulation of any two or all three of the targeted genes did not result in an enhanced inhibition of viral replication as compared to the single siRNA approaches targeting the late genes. However, protection against adenovirus-mediated cytotoxicity was substantially improved by combining siRNAs against either of the two late genes with the siRNA against the E1A early gene. Thus, an enhanced anti-adenoviral efficiency of RNAi-based inhibition strategies can be achieved by co-silencing of early and late adenoviral genes, with down regulation of the E1A as a crucial factor. PMID- 20708039 TI - gamma2-Adaptin is functioning in the late endosomal sorting pathway and interacts with ESCRT-I and -III subunits. AB - gamma2-Adaptin is a clathrin adaptor-related protein with unclear physiological function. Previous studies indicated that gamma2-adaptin might act within the multivesicular body (MVB) protein-sorting pathway that is central to receptor down-regulation, lysosome biogenesis, and budding of enveloped viruses. Here, we have analyzed the effects of excess and deficit gamma2-adaptin on exogenous and endogenous MVB cargoes and on the MVB machinery itself. Foreign cargoes, like retroviral Gags, are entrapped by overexpressed gamma2-adaptin in detergent insoluble polymers and blocked in budding. When viral budding involves MVB/endosomal structures, excess gamma2-adaptin acts by accelerating lysosomal Gag destruction. Consistently, depletion of gamma2-adaptin avoids Gag routing to the lysosome and increases viral production. Functional studies with natural MVB cargoes support a role of gamma2-adaptin in MVB-to-lysosome transition. Furthermore, we show that different members of the endosomal sorting complex required for transport (ESCRT) that drive sorting from endosomes to lysosomes are sequestered upon gamma2-adaptin overexpression. If sequestered irreversibly, they are targeted to enhanced lysosomal degradation. The participation of gamma2 adaptin in MVB sorting is further suggested by our finding that it specifically interacts with the ESCRT subunits Vps28 and CHMP2A. These observations identify gamma2-adaptin as a critical factor in MVB trafficking, which likely is involved in endosome-to-lysosome maturation. PMID- 20708038 TI - Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons. AB - Homeostatic response is an endowed self-correcting/maintaining property for living units, ranging from subcellular domains, single cells, and organs to the whole organism. Homeostatic responses maintain stable function through the ever changing internal and external environments. In central neurons, several forms of homeostatic regulation have been identified, all of which tend to stabilize the functional output of neurons toward their prior "set-point." Medium spiny neurons (MSNs) within the forebrain region the nucleus accumbens (NAc) play a central role in gating/regulating emotional and motivational behaviors including craving and seeking drugs of abuse. Exposure to highly salient stimuli such as cocaine administration not only acutely activates a certain population of NAc MSNs, but also induces long-lasting changes in these neurons. It is these long-lasting cellular alterations that are speculated to mediate the increasingly strong cocaine-craving and cocaine-seeking behaviors. Why do the potentially powerful homeostatic mechanisms fail to correct or compensate for these drug-induced maladaptations in neurons? Based on recent experimental results, this review proposes a hypothesis of homeostatic dysregulation induced by exposure to cocaine. Specifically, we hypothesize that exposure to cocaine generates false molecular signals which misleads the homeostatic regulation process, resulting in maladaptive changes in NAc MSNs. Thus, many molecular and cellular alterations observed in the addicted brain may indeed result from homeostatic dysregulation. This review is among the first to introduce the concept of homeostatic neuroplasticity to understanding the molecular and cellular maladaptations following exposure to drugs of abuse. PMID- 20708040 TI - Codon-improved fluorescent proteins in investigation of Staphylococcus aureus host pathogen interactions. AB - Here we present the use of three fluorescent proteins in Staphylococcus aureus, Cerulean, PA-GFP, and mRFPmars. All molecules have an improved codon adaptation for expression in the A + T rich organisms and extend the fluorescent protein portfolio in staphylococcal research. PMID- 20708041 TI - The effect of aging on movement related cortical potentials during a face naming task. AB - In the present study a face naming reaction time task was employed in order to evaluate the effect of age on performance and on movement related cortical potentials (MRCPs). In addition, the effect of three response categories with different cognitive demands (DON'T KNOW-don't know the name-, KNOW-correct naming and TOT-tip-of the-tongue state) on performance and on MRCPs in a sample of older adults was evaluated. The same MRCPs found in a previous study in a sample of young adults were identified in older adults. The results indicated that older participants were generally slower at providing responses than young adults, and that both age groups showed longer reaction time in TOT than in DON'T KNOW and KNOW categories. The first component of readiness potential (1st-RP) showed larger amplitude and longer duration in older than in young adults, especially in the TOT category, which would explain the generally slower responses provided by older participants. In addition, in older adults, the 1st-RP was larger in TOT than in the DON'T KNOW category, but a slope reduction and stabilization were observed in TOT from the more demanding stages of stimulus processing. These results may reflect a lengthening in the preparation period in the TOT category, which probably explains the behavioural slowing in this category. The data of the present study suggest differences in the allocation of processing resources between groups, indicating that the sensoriomotor performance should be compromised more in older than in young adults in tasks with high cognitive load. PMID- 20708042 TI - Investigation of neuronal progenitor cell origin after transient focal cerebral ischemia in mice. AB - Following cerebral ischemia both neuronal precursors and hematogenous cells migrate along chemokine gradients towards the injured tissue. Bone marrow derived cells are involved in the stroke related inflammatory and restaurative processes and newly born neurons are known to proliferate and migrate from the subventricular zone to the ischemic lesion. In the present study, we investigated whether hematogenous cells contribute to subpopulations of neuronal precursors using green fluorescent protein-transgenic bone marrow chimeric mice. In our experiments we found no blood-borne neuronal precursors within the ischemic site indicating that detected neuronal progenitor cells are only of brain parenchymal origin. PMID- 20708043 TI - Protein quality control mechanisms and neurodegenerative disorders: Checks, balances and deadlocks. AB - Neurodegenerative disorders are a group of hereditary and sporadic conditions that are characterized by progressive nervous system dysfunctions. These disorders are often associated with neuronal atrophy and are characterized by the presence of intra- or extra-neuronal inclusions in the central or peripheral nervous system. The emerging understanding on these apparently diverse set of disorders suggest that they share a few key pathomechanisms, one of which could be the abnormality in the protein quality control pathways. Recent studies have shown that either an overload on the proteolytic pathways - the ubiquitin proteasome system and the autophagosome-lysosome system - or defects in the critical components of these pathways might underlie the neuropathology. Here, we review the recent advances in our understanding on the role of protein quality control systems in the pathomechanisms of neurodegenerative disorders, highlight the interdependence between the two pathways and their involvement in neuronal survival. PMID- 20708044 TI - 13-Cis-retinoic acid decreases hypothalamic cell number in vitro. AB - 13-Cis-retinoic acid (13-cis-RA) causes depression-related behavior in mice. Hypothalamic dysregulation has been implicated in clinical depression. In fact, apoptosis of hypothalamic neurons may lead to depression after myocardial infarction. Our objective was to determine if 13-cis-RA affects cultured hypothalamic cell number. Treatment of GT1-7 hypothalamic cells with 10MUM 13-cis RA for 48h decreased cell growth to 45.6+/-13% of control. To determine if this decrease in cell number was due to 13-cis-RA acting as an oxidant, cells were treated with 13-cis-RA and ascorbic acid or butylated hydroxyanisole (BHA) for 24 or 48h. Neither antioxidant alleviated the inhibitory affects of 13-cis-RA. In addition, 13-cis-RA treatment did not increase superoxide anion production, indicating 13-cis-RA was not acting as an oxidant. To determine if 13-cis-RA was acting via retinoic acid receptors (RARs) to decrease cell number, GT1-7 cells were treated with 13-cis-RA and the RAR pan-antagonist, AGN 193109. Treatment with the RAR-antagonist blocked the ability of 13-cis-RA to decrease cell number, indicating this phenomenon was a RAR-independent mechanism. We hypothesize that the ability of 13-cis-RA to decrease hypothalamic cell number may contribute to the increased depression-related behaviors observed in mice. PMID- 20708045 TI - (+)-Cholesten-3-one induces differentiation of neural stem cells into dopaminergic neurons through BMP signaling. AB - To identify small molecules that induce dopaminergic neurons from neural stem cells (NSCs) is promising for therapy of Parkinson's disease. Here we report the results of analyzing structurally related steroids in traditional Chinese medicine to identify agents that enhance dopaminergic differentiation of NSCs. Using P19 cells transfected by tyrosine hydroxylase (TH) promoter reporter construct, (+)-Cholesten-3-one with carbonyl, but not cholesterol and cholesterol myristate can effectively promote the activity of TH promoter. This effect depends on bone morphogenetic protein (BMP) signaling. Phenotypic cellular analysis indicated that (+)-Cholesten-3-one induces differentiation of NSCs to dopaminergic neurons with increased expression of specific dopaminergic markers including TH, dopamine transporter, dopa decarboxylase and higher level of dopamine secretion. (+)-Cholesten-3-one significantly increases the expression of BMPR IB, but not BMPR IA or BMPR II; p-Smad1/5/8 positive nuclei and expression of p-Smad1/5/8 were detected in NSCs treated with (+)-Cholesten-3-one, indicating that (+)-Cholesten-3-one may activate the BMP signaling. Moreover, overexpression of BMP4 or inhibition of BMP affects the effect of (+)-Cholesten-3-one on the dopaminergic phenotype. These findings may contribute to efficient production of dopaminergic neurons from NSCs culture for many applications and raise interesting questions about the role of (+)-Cholesten-3-one in neurogenesis. PMID- 20708046 TI - Influence of culture parameters on ear mesenchymal stem cells expanded on microcarriers. AB - Mesenchymal stem cells (MSCs) have an accrued potential as a tool for cell-based therapies, thanks largely to their trophic properties. The significant amounts of cells needed for this goal should be attainable through optimized bioreactor expansion of MSCs. However, because of the specific properties of these cell populations, there is a need to investigate novel cell culture strategies adapted from established bioreactor cultivation practices. Among these, stirred culture on microcarriers appears as an appropriate approach for the expansion of MSCs but its optimization requires the identification of key limiting parameters to achieve a further increase in growth span. In this work, among the physico chemical and physiological parameters affecting the expansion of ear-derived MSCs (E-MSCs) on porous microcarriers, supply of growth factors was important in controlling their growth span. The apparent growth rate of E-MSCs was found to be correlated with the percentage of cells in the S phase of the cell cycle. Moreover, this percentage was directly linked with the fraction of growth factor/receptor complexes. Thus, controlling the percentage of E-MSCs in S phase with suitable growth factor feeds led to an increase of their growth span. Finally, in response to these adapted feeds the cells maintained the key properties defining their MSC phenotype in terms of expression of markers and in vitro differentiation potential. PMID- 20708047 TI - The 126- and/or 183-kDa replicases or their coding regions are responsible both for inefficient local and for systemic movements of Paprika mild mottle virus Japanese strain in tomato plants. AB - Paprika mild mottle virus Japanese strain (PaMMV-J), a member of the genus Tobamovirus, was originally isolated from sweet pepper plants (Capsicum annuum L.). In experimental conditions, PaMMV-J spread more slowly in inoculated leaves of tomato plants and moved to uninoculated upper leaves at a lower frequency than Tomato mosaic virus (ToMV). In this study, we aimed to identify the viral factors responsible for the low efficiency of local and systemic movement of PaMMV-J in tomato plants. Using several viruses formed as chimeras between PaMMV-J and ToMV, we observed that a chimeric virus (Pa-RepL) having the 126- and 183-kDa replicase genes of ToMV could move systemically in tomato plants, similar to ToMV. Furthermore, analysis of a PaMMV-J mutant (PaMMV-1483C) showed that a single nucleotide substitution in 126- and 183-kDa replicase genes of PaMMV-J enhanced the efficiency of local movement of the virus in inoculated leaves to an extent similar to that of ToMV. However, PaMMV-1483C did not spread over the uninoculated upper leaves. In addition, viral RNA accumulation levels in tomato protoplasts inoculated with Pa-RepL and PaMMV-1483C were lower and similar to those of parental PaMMV-J. These results suggest that the 126- and/or 183-kDa replicases or their coding regions are responsible both for inefficient local and for systemic movements of PaMMV-J in tomato plants. PMID- 20708048 TI - The capsid protein of Grapevine rupestris stem pitting-associated virus contains a typical nuclear localization signal and targets to the nucleus. AB - Grapevine rupestris stem pitting-associated virus (GRSPaV) is a positive strand, ssRNA virus of the genus Foveavirus (family Betaflexiviridae; order Tymovirales). GRSPaV is distributed in table and wine grapes worldwide and comprises a large family of sequence variants. As a newly discovered virus, mechanisms of virus replication and movement of GRSPaV have not been elucidated. We recently revealed the subcellular localization of the proteins encoded by the triple gene block of GRSPaV (Rebelo et al., 2008). However, the subcellular localization and interaction of its capsid protein (CP) have not been explored. We report here that GRSPaV CP contains a nuclear localization signal "KRKR" near its N-terminus, which is conserved among all five strains whose genomes are completely sequenced. Similar sequences were also detected in the CP of two other viruses of the same family: African oil palm ringspot virus and Cherry green ring mottle virus. Using fluorescent protein tagging, we demonstrate that the CP targets to the nucleus in tobacco protoplasts. Mutation to this nuclear localization signal abolished the nuclear localization. Using bi-molecular fluorescence complementation, we show that the capsid protein of GRSPaV engages in homologous interaction. To our knowledge, this is the first report on the nuclear localization of a CP encoded by a RNA plant virus. PMID- 20708049 TI - Complementations and exclusions between mutated versions of a potato virus Y genotype during mixed infections of Nicotiana hosts. AB - Understanding the processes that have led to the recent prevalence of necrotic genotypes in PVY populations is an important challenge for research programs studying this virus. Non-necrotic PVY(O)-139, necrotic PVY(N)-605 and point mutated versions of PVY(N)-605 (PVY(KRED), PVY(KR) and PVY(ED)), were used in mixtures to inoculate two Nicotiana hosts which express (N. tabacum cv. Xanthi) or not (N. clevelandii) necrosis symptoms in response to infection by PVY(N) group members. The comparison during serial passage experiments of proportions of PVY genotypes produced in mixed infected plants with those of the inocula was used to describe: (i) complementation between PVY(KR) and PVY(N) and between PVY(KRED) and PVY(O) genotypes; (ii) exclusion of the PVY(KRED) genotype, previously described as fitter, during mixed infections in the presence of one of the less fit PVY(N), PVY(ED) and PVY(KR) genotypes and (iii) the prevalence of the non-necrotic PVY(KR) genotype in the presence of PVY(N) parental sequence. These results indicate that the role of both A/G(2213) and A/C(2271) nucleotides in the fitness of PVY genotypes depends on other genetic information in the viral genome that has not yet been identified. Moreover, the collected data indicate that mutation of the nucleotide 2213 in the PVY(N)-605 sequence could lead to the prevalence, both in N. tabacum cv. Xanthi and in N. clevelandii, of the non necrotic PVY(KR) genotype. PMID- 20708050 TI - Selectively targeting estrogen receptors for cancer treatment. AB - Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ERalpha and ERbeta, which mediate proliferation and differentiation of cells. For decades, ERalpha mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most notably with the selective estrogen receptor modulator (SERM) tamoxifen. Selectively targeting ERs occurs at two levels: tissue selectivity and receptor subtype selectivity. SERMs have been developed with emphasis on tissue selectivity to target ER signaling for breast cancer treatment. Additionally, new approaches to selectively target the action of ERalpha going beyond ligand-dependent activity are under current investigation. As evidence of the anti-proliferative role of ERbeta accumulates, selectively targeting ERbeta is an attractive approach for designing new cancer therapies with the emphasis shifted to designing ligands with subtype selectivity. This review will present the mechanistic and structural features of ERs that determine tissue and subtype selectivity with an emphasis on current approaches to selectively target ERalpha and ERbeta for cancer treatment. PMID- 20708052 TI - Antimicrobial cyclic decapeptides with anticancer activity. AB - Antimicrobial peptides have been considered as potential candidates for cancer therapy. We report here the cytotoxicity of a library of 66 antibacterial cyclodecapeptides on human carcinoma cell lines, and their effects on apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase (PARP)] and cell signaling proteins (p53 and ERK1/2) in cultured human cervical carcinoma cells. A design of experiments approach permitted to analyze the results of a subset of 16 peptides and define rules for high anticancer activity against MDA-MB-231 breast carcinoma cells. Eight peptides were identified with IC(50) values ranging from 18.5 to 57.5 MUM against the five cell lines tested, being HeLa cells the most sensitive. Among these sequences, BPC88, BPC96, BPC98, and BPC194 displayed specificity and high cytotoxicity against HeLa cells (IC(50) of 22.5-38.5 MUM), showed low hemolytic activity and low cytotoxicity to non-malignant fibroblasts, and were stable to proteases in human serum. Induction of apoptosis by these peptides was observed and the apoptotic effect of BPC88 and BPC96 caused a marked decrease on the activated form of ERK1/2 kinase and an induction of p53. We further showed that BPC96 at low doses synergized the cytotoxic effect of cisplatin. These findings suggest that cyclic decapeptides may represent novel anticancer agents providing a new strategy in cancer therapy. PMID- 20708053 TI - Effects of post-mortem intervals on regional brain protein profiles in rats using SELDI-TOF-MS analysis. AB - Identification of disease-associated proteins is critical for elucidating CNS disease mechanisms and elaborating novel treatment strategies. It requires post mortem tissue analysis which can be significantly affected by the collection process, post-mortem intervals (PMIs), and storage conditions. To assess the effect of time and storage conditions on brain protein stability, SELDI-TOF-MS protein profiles were assessed in rat frontal cortex, caudate-putamen, hippocampus and medulla samples collected after various PMIs (0, 6, 12, 24, 48, and 72 h) at 4 degrees C or at room temperature (RT) storage. Regions of interest were isolated from cryosections (tissue apposition, TA), or micropunched from cryosections apposed on filter paper (paper apposition, PA), and applied onto an NP20 ProteinChip array. Protein alterations, while greater at RT than at 4 degrees C, were detected at 6h then differentially evolved in the various brain regions, with greater alterations in the caudate-putamen (60%) and the cortex (48%). Overall, our sensitive analytical method allowed unveiling of different patterns of protein susceptibility to PMI and to storage temperature in the various brain regions. Some protein peaks were altered in all brain regions and may potentially serve as markers of the PMI status of the brain, or for reference values when studying new proteins. Changes in disease-related proteins within post-mortem samples can be greatly affected by PMI and storage conditions, particularly when studying fragile and/or low abundant protein/peptides in tissues sampled from the caudate-putamen and neocortex. PMID- 20708051 TI - Nuclear receptors in stem cells and their therapeutic potential. AB - The core transcriptional regulatory circuitries are important for controlling stem cell self-renewal and differentiation. Nuclear receptors provide an ideal model to regulate gene expression in both ligand-dependent and ligand-independent manners. Recent studies of regulatory events by nuclear receptors in neural stem cells, embryonic stem cells, and induced pluripotent stem cells (iPSCs) provided unique insights into mechanisms of stem cell regulation and provided invaluable resources for regenerative medicine. Nuclear receptors have been shown to be key players in stem cell self-renewal, pluripotency, and reprogramming. We summarize recent progress of studies on nuclear receptors in stem cell field as well as the potential therapeutic implications of these nuclear receptors and their cognate ligands. These studies not only uncover molecular mechanisms of stem cell regulation, but also provide unique opportunities for drug discovery. PMID- 20708054 TI - Isoquercitrin is the most effective antioxidant in the plant Thuja orientalis and able to counteract oxidative-induced damage to a transformed cell line (RGC-5 cells). AB - The shrub Thuja orientalis is extensively used as a herbal medicine in Korea and China. In the present study extracts of the plant were subjected to fractionation and purification, with seven compounds (myricitrin, isoquercitrin, hypoletin-7-O beta-D-xylopyranoside, quercitrin, kaempferin, kaempferol, and amentoflavone) being isolated. Of these seven compounds, isoquercitrin was found to be the most effective at attenuating the death of RGC-5 cells in culture caused by exposure to hydrogen peroxide (H(2)O(2)). It was found that an insult of H(2)O(2) to RGC-5 cells caused them to die by apoptosis, demonstrated not only by staining dead cells for phosphatidylserine but also by the up-regulation (cleaved PARP, AIF, p53) and down-regulation (Bcl-2) of proteins associated with apoptosis and survival. Subsequent studies showed that isoquercitrin acts as a powerful antioxidant. It scavenges ROS generally as demonstrated by staining of cultures as well as the generation of individual radical species (H(2)O(2), OH* and O(2)(* )). Moreover, isoquercitrin reduced the depletion of glutathione (GSH) caused by elevation of specific radical species (H(2)O(2), OH* and O(2)(*-)) in RGC-5 cells in culture and blunted the decrease in catalase and glutathione peroxidase 1 (Gpx 1) caused by exposure of RGC-5 cells to H(2)O(2). Furthermore, isoquercitrin potently attenuated the lipid peroxidation of rat brain homogenates initiated by nitric oxide, with an IC(50) value of 1.04 MUM. Since isoquercitrin can be tolerated when taken orally it is suggested that this substance might reach the retina and therefore be potentially useful for treating glaucoma, in which oxidative stress is thought to play a major role in the demise of retinal ganglion cells. PMID- 20708055 TI - Chrysotoxine, a novel bibenzyl compound, inhibits 6-hydroxydopamine induced apoptosis in SH-SY5Y cells via mitochondria protection and NF-kappaB modulation. AB - Some naturally occurring bibenzyl compounds have been reported as free radical scavengers. The present study tested our hypothesis that bibenzyl compounds may be neuroprotective against apoptosis induced by the neurotoxins. Five structurally similar bibenzyl derivatives were tested for their protective effect against 6-hydroxydopamine (6-OHDA) induced toxicity in the human neuroblastoma cell line SH-SY5Y. The results showed that one bibenzyl compound, namely chrysotoxine, significantly attenuated 6-OHDA-induced cell death. The subsequent mechanism study demonstrated that chrysotoxine significantly attenuated 6-OHDA induced apoptosis characterized by DNA fragmentation and nuclear condensation in a dose-dependent manner. 6-OHDA-induced intracellular generation of reactive oxygen species (ROS), activation of p38 MAPK and ERK1/2, and mitochondrial dysfunctions, including the decrease of membrane potential, increase of intracellular free Ca2+, release of cytochrome c, imbalance of Bax/Bcl-2 ratio and activation of caspase-3 were strikingly attenuated by chrysotoxine pretreatment. Meanwhile, chrysotoxine counteracted NF-kappaB activation by blocking its translocation to the nucleus, thereby preventing up-regulation of inducible nitric oxide synthase (iNOS) and intracellular NO release. The data provide the first evidence that chrysotoxine protects SH-SY5Y cells against 6 OHDA toxicity possibly through mitochondria protection and NF-kappaB modulation. Chrysotoxine is thus a candidate for further evaluation of its protection against neurodegeneration in Parkinson's disease. PMID- 20708056 TI - The high-affinity nAChR partial agonists varenicline and sazetidine-A exhibit reinforcing properties in rats. AB - Varenicline (Chantix(r), Champix(r)) is a nicotinic acetylcholine receptor (nAChR) partial agonist clinically approved for smoking cessation, yet its potential abuse liability properties have not been fully characterized. The nAChR ligand sazetidine-A has been reported as a selective full or partial agonist at alpha4beta2* nAChR subtypes in in vitro studies. In the present studies, varenicline, sazetidine-A and nicotine exhibited inverted U-shaped dose-response functions under fixed-ratio (peak responding at 30, 60 and 10-30 MUg/kg/inf, respectively) or progressive-ratio (peak responding at 30-60, 30-100 and 30 MUg/kg/inf, respectively) schedules in rats trained to self-administer nicotine. Varenicline (ED(50) 0.2 mg/kg) and sazetidine-A (ED(50) 0.44 mg/kg) fully substituted for nicotine (ED(50) 0.09 mg/kg) in rats trained to discriminate nicotine (0.4 mg/kg, i.p.) from saline. The reinforcing and discriminative stimulus (DS) properties of sazetidine-A, varenicline and nicotine were attenuated by acute pretreatment with the non-selective neuronal non-competitive nAChR antagonist mecamylamine or the alpha4* nAChR-selective antagonist dihydro beta-erythroidine, but not by the alpha7 nAChR subtype antagonist methyllycaconitine. Drug-naive rats acquired stable self-administration of varenicline (30 MUg/kg/inf), and sazetidine-A (60 MUg/kg/inf), at doses that supported peak responding under a fixed-ratio 3 schedule in nicotine-trained rats. Nonetheless, self-administration and re-acquisition of varenicline and sazetidine-A were less robust than nicotine. Thus, partial activation of alpha4beta2* nAChRs by varenicline or sazetidine-A is sufficient to mimic the DS and reinforcing properties of nicotine in nicotine-experienced rats, although the reinforcing properties of partial agonists are diminished in nicotine-naive rats. Future studies should assess nicotine withdrawal measures in animals chronically exposed to varenicline or sazetidine-A. PMID- 20708057 TI - Effect of antidepressants on brain-derived neurotrophic factor (BDNF) release from platelets in the rats. AB - Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family, and enhances the growth and maintenance of several neuronal systems. In addition, BDNF may promote neurogenesis and protect against hippocampal volume loss in depressive disorders. Although first detected in brain, BDNF also exists in peripheral tissues and is mainly stored in platelets and circulates in blood. Recent reports indicate that serum BDNF levels in depressive patients are lower than in control subjects, and antidepressant treatment increases serum BDNF levels in responders. A single report suggests that decreased serum BDNF in major depression is related to mechanisms of platelet BDNF release; however, the mechanisms of changes in BDNF blood levels are still poorly understood. In the present study, we investigated the direct influence of antidepressants on BDNF release from platelets and their effects on serum levels. We used samples of washed platelets prepared from rat blood, and investigated the platelet BDNF release and serum BDNF concentration changes in response to adding antidepressants. We found that BDNF was dose-dependently released from platelets by direct treatment with various kinds of antidepressants in vitro, and serum BDNF concentration was also increased by intravenous antidepressant treatment. These results confirm that BDNF release from platelets is affected by antidepressants, which may relate to the circulating BDNF level change in peripheral blood. The response of BDNF release differs depending on the type and amount of antidepressants, making BDNF a serious candidate as a predictor of antidepressant treatment response. PMID- 20708058 TI - Potential peripheral biological predictors of suicidal behavior in major depressive disorder. AB - Previous studies have shown that dysfunctions in the serotonin system and hypothalamic-pituitary-adrenal axis (HPA) are associated strongly with suicidal behavior and suicide, especially among individuals with major depressive disorder. Suicidal behavior has been explained using both the stress-diathesis model and the state-trait interaction model. Specifically, diatheses, or trait dependent risk factors, are associated with dysfunctions in the serotonin system; however, stress responses, or state-dependent factors, are associated with HPA hyperactivity. Decreases in cholesterol and brain-derived neurotrophic factor (BDNF) levels have been associated with impaired brain plasticity among individuals with suicidal behavior. Decreased serotonin functioning has been measured using cerebral spinal fluid (CSF) 5-HIAA, fenfluramine challenge studies, and platelet 5-HT2A receptors. HPA axis dysfunction has been evaluated with the dexamethasone suppression test. Cholesterol and BDNF levels have been measured in blood serum or plasma. Nevertheless, challenges to finding promising and accessible neurobiological predictors of suicide and suicidal behavior remain. As suicide behavior is a complex phenomenon, a combined or multidimensional approach, including each of the aforementioned methods, may be required to predict suicide risk among individuals with major depressive disorder. PMID- 20708059 TI - Effects of caffeic acid phenethyl ester on thioacetamide-induced hepatic encephalopathy in rats. AB - Hepatic encephalopathy (HE) is a major neurological complication secondary to severe liver failure. The aim of the present study was to examine the possible neuroprotective effects of caffeic acid phenethyl ester (CAPE) with or without laxative treatment against thioacetamide-induced HE by investigating behavioral and motor activities in rats as well as blood ammonia level and oxidant antioxidant parameters of cortex, brain stem and cerebellum. After induction of HE by thioacetamide, the rats were treated with lactulose, CAPE (CAPE treatment was started one day before the first dose of thioacetamide) or CAPE plus lactulose. The behavioral and motor scales were measured at the 54th hour after the first thioacetamide injection, the blood samples and brains were taken under anesthesia at the 60th hour for biochemical analysis. The survival rates were 37.5% in HE group, 70% in HE+lactulose group, 80% in HE+CAPE group, and 100% in HE+CAPE+lactulose group. Increased ammonia, ALT and AST levels in blood along with impaired sensory-motor behavior tests were reversed to proximate control values in CAPE+lactulose treated group. There were increased lipid peroxidation and protein oxidation and decreased antioxidant enzyme activities in almost all brain parts of HE group. CAPE or lactulose treatment alone ameliorated those oxidant and antioxidant parameters; however, CAPE treatment together with lactulose reversed them to almost control level. In conclusion, thioacetamide induced HE injury in rats was reversed almost fully by CAPE and laxative combination. There was no death in CAPE and laxative treated group animals and it may be due to the direct neuroprotective effect of CAPE together with the prevention of the body from ammonia production. PMID- 20708060 TI - Pramipexole for stage 2 treatment-resistant major depression: an open study. AB - OBJECTIVE: To examine the effectiveness and safety of adjunctive pramipexole in the treatment of stage 2 treatment-resistant major depressive disorder. METHODS: This study included patients with moderate or non-psychotic severe major depressive disorder according to DSM-IV-TR criteria despite at least two adequate treatment trials with antidepressants from different pharmacological classes. Pramipexole 0.25 to 2 mg daily was added to antidepressant therapy. Previous treatments were continued unchanged, but no new treatments were allowed. We conducted assessments at baseline and at weeks 2, 4, 6, and 8. We defined response as a 50% or greater reduction on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Ten patients (4 men, 6 women) aged 43.7+/-11.4 years received pramipexole at mean dose of 1.3+/-0.6 mg/d. Mean MADRS scores improved significantly from baseline to endpoint (mean differences=11.4, 95% CI [4.1, 18.7], P=0.0064). At the endpoint, six of 10 (60%) were responders on MADRS (>=50% reduction). Two patients (20%) terminated early due to mild somatic and psychiatric adverse effects. CONCLUSION: These preliminary data suggest that the addition of pramipexole to antidepressant treatment may be effective and well tolerated in patients with stage 2 treatment-resistant major depressive disorder. PMID- 20708061 TI - Relationship between brain and plasma carbaryl levels and cholinesterase inhibition. AB - Carbaryl is a N-methylcarbamate pesticide and, like others in this class, is a reversible inhibitor of cholinesterase (ChE) enzymes. Although studied for many years, there is a surprising lack of information relating tissue levels of carbaryl with ChE activity in the same animals. The present studies were undertaken to describe the dose-response relationship about 40 min (approximate time of maximal ChE inhibition) after oral treatment in adult, post-natal day (PND) 17, and PND11 rats. Additionally, the time-course of plasma ChE activity and carbaryl levels in adult rats was determined after a 30 mg/kg dosage of carbaryl. The time-course study found that carbaryl levels could be detected in plasma 1 h after dosing, but rapidly decreased below the level of quantitation by the 2 h time point. In the dose-response studies, treatment-related increases in plasma and brain carbaryl levels were observed 40 min after dosing. Plasma levels of carbaryl increased linearly, while brain levels appeared to asymptote after 75 mg/kg carbaryl. Plasma and brain levels of carbaryl appeared to be linearly related with a slope close to 1 after various dosages (range: 1-75 mg/kg) of carbaryl at the 40 min time point. Finally, the dose-related relationship between tissue levels of carbaryl and ChE activity was described using a first order exponential decay function with an asymptote. The parameters of this function did not appear to differ between adult, PND17, or PND11 rats. This indicates that age related differences in brain ChE inhibition by carbaryl are unlikely to be the result of greater tissue levels of the pesticide in PND11 animals. These are the first studies to report the relationship between brain and plasma tissue levels of carbaryl and ChE activity on an individual animal basis. The results of these experiments will be useful to extend physiologically-based pharmacokinetic models for carbaryl and their application in risk assessment. PMID- 20708062 TI - Does mandibular edentulous bone height affect prosthetic treatment success? AB - OBJECTIVES: The aim of this study is to determine whether mandibular bone height affects patients' ratings of satisfaction and function with mandibular 2-implant overdentures (IODs) and conventional dentures (CDs). METHODS: 214 edentulous elders were randomly allocated into 2 groups and treated with maxillary CDs and either mandibular CDs or IODs. Classifications of mandibular bone height were carried out on panoramic radiographs using 4 published methods. At baseline and 6 months after delivery, all participants rated their satisfaction with their prostheses using the McGill Denture Satisfaction Instrument. Independent t-tests and a linear multivariable regression model were used for statistical analyses. RESULTS: Mandibular bone height has no effect on patients' ratings of general satisfaction, nor on ratings of ability to chew, stability, comfort, aesthetics and ability to speak at 6 months (p>0.05, linear regression). There were significant between treatment differences in ratings of general satisfaction, comfort, stability and ability to chew from all mandibular bone height categories, with higher ratings assigned to IODs (p<0.01, t-tests). Linear regression analyses confirmed that, for general satisfaction, as well as ability to chew, stability, comfort, aesthetics and ability to speak, treatment with IODs contributes to higher satisfaction ratings (p<0.001), while mandibular bone height does not. CONCLUSIONS: The evidence demonstrates that mandibular bone height has no effect on patients' satisfaction with the function, chewing ability and comfort of their prostheses. Furthermore, no matter how much mandibular bone, these results suggest that edentulous elders will benefit more from mandibular IODs than from CDs. PMID- 20708063 TI - Mathematical modelling of immune regulation of type 1 diabetes. AB - Type 1 diabetes is a disease characterized by progressive loss of beta cell function due to an autoimmune reaction affecting the islets of Langerhans. Two types of T cells are involved in diabetes: turncoat auto-reactive T cells, or T cells gone bad, that kill the insulin-producing cells, and regulatory T cells that are unable to control the auto-reactive T cells. We formulate a mathematical model that incorporates the role of cytotoxic T cells and regulatory T cells in type 1 diabetes. This study shows that onset of type 1 diabetes is due to a collective, dynamical instability, rather than being caused by a single etiological factor. It is also a numbers game between regulatory T cells and auto reactive T cells. The problem in the onset of this disease is that there are not enough of the regulatory cells that suppress the immune response against the body's insulin-producing pancreatic islet cells. PMID- 20708064 TI - The role of low-grade inflammation in the polycystic ovary syndrome. AB - PCOS is not only the most frequent cause of oligomenorrhea in young women, but also a metabolic disorder characterized by insulin resistance, glucose intolerance, dyslipidemia, and obesity, especially the visceral phenotype. PCOS represents a broad spectrum of endocrine and metabolic alterations which change with age and with increasing adiposity. In fact, during adolescence and youth the predominant clinical manifestations of PCOS are menstrual abnormalities, hirsutism and acne, whereas in peri-menopausal and post-menopausal periods metabolic disorders and an increased risk for cardiovascular diseases prevail. The pathogenetic links between PCOS and metabolic or cardiovascular complications are still debated. However, recent evidence has been focused on a condition of low-grade chronic inflammation as a potential cause of the long-term consequence of the syndrome. In this review we describe the state of low-grade inflammation observed in PCOS. In addition, we hypothesize the potential mechanisms responsible for the generation of this inflammatory state and the role played by low-grade inflammation in linking hyperandrogenism and insulin resistance with the metabolic and cardiovascular long-term complications of the syndrome. PMID- 20708065 TI - Apamin, a selective blocker of SK(Ca) channels, inhibits posthypoxic hyperexcitability but does not affect rapid hypoxic preconditioning in hippocampal CA1 pyramidal neurons in vitro. AB - The aim of this study was to investigate the effects of apamin, a selective blocker of SK(Ca) channels, on the repeated brief hypoxia-induced posthypoxic hyperexcitability and rapid hypoxic preconditioning in hippocampal CA1 pyramidal neurons in vitro. The method of field potentials measurement in CA1 region of the rat hippocampal slices was used. Application of apamin (50nM) to the hippocampal slices during hypoxic episodes significantly abolished posthypoxic hyperexcitability induced by brief hypoxic episodes. However, in contrast to our previous results with iberiotoxin, a selective blocker of BK(Ca) channels, apamin significantly enhanced the depressive effect of brief hypoxia on the PS amplitude during hypoxic episode and did not abolish the rapid hypoxic preconditioning in CA1 pyramidal neurons. Present results indicate that SK(Ca) channels, along with previously implicated BK(Ca) channels, play an important role in the development of posthypoxic hyperexcitability induced by brief hypoxic episodes in CA1 pyramidal neurons. However, SK(Ca) channels, in contrast to the BK(Ca) channels, are not involved in the rapid hypoxic preconditioning in CA1 hippocampal region in vitro. PMID- 20708066 TI - Novel 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine 2(3H)-thione as selective adenosine A(2A) receptor antagonist. AB - Adenosine A(2A) receptor (A(2A)R) antagonists have emerged as potential drug candidates to alleviate progression and symptoms of Parkinson's disease (PD), and reduce the dopaminergic side effects. The synthesis of novel compound 8-(furan-2 yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2-(3H)-thione (BTTP) was carried out to evaluate the potential of BTTP as A(2A)R antagonist using SCH58261, a standard A(2A)R antagonist. The strong interaction of BTTP with A(2A)R (DeltaG=-12.46kcal/mol and K(i)=0.6nM) in silico analysis was confirmed by radioligand receptor binding studies showing high affinity (K(i)=0.004nM) and selectivity with A(2A)R (A(2A)/A(1)=1155-fold). The effect of CGS21680 (selective A(2A)R agonist) induced cAMP concentration (0.1pmol/ml) in HEK293 cells was antagonized with BTTP (0.065pmol/ml) and SCH58261 (0.075pmol/ml). Furthermore, BTTP pre-treated (5, 10 and 20mg/kg) haloperidol-induced mice demonstrated significant attenuation in catalepsy and akinesia. BTTP induced elevation in the striatal dopamine concentration (2.90MUM/mg of tissue) was comparable to SCH58261 (2.92MUM/mg of tissue) at the dose of 10mg/kg. The results firmly articulate that BTTP possesses potential A(2A)R antagonist activity and can be further explored for the treatment of PD. PMID- 20708067 TI - Expression of organic anion transporters 1 and 3 in the ovine fetal brain during the latter half of gestation. AB - Development and maturation of the fetal brain is critical for homeostasis in utero, responsiveness to fetal stress and, in ruminants, control of the timing of birth. In the sheep, as in the human, the placenta secretes estrogen and other signaling molecules into both the fetal and maternal blood, molecules whose entry or exit across the blood-brain barrier is likely to be facilitated by transporters. The purpose of this study was to test the hypothesis that the ovine fetal brain expresses organic anion transporters, and that the expression of these transporters varies as a function of brain region and fetal gestational age. Brains and pituitaries were collected at the time of sacrifice from fetal and newborn sheep at 80, 100, 120, 130, 145 days gestation and on the first day of postnatal life (parturition in sheep is at approximately 147 days gestation). Hypothalamus, medullary brainstem, cerebellum, and pituitary were processed for mRNA extraction and synthesis of cDNA (4-5/group). Real-time PCR analysis of OAT1 and OAT3 expression revealed significant expression of both genes in all of the tissues tested. In hypothalamus and cerebellum, there were statistically significant increases in the expression of one or both genes towards the end of gestation. In medullary brainstem and pituitary, the levels of expression were relatively unchanged as there were no statistically significant changes with developmental age. We conclude that the ovine fetal brain expresses both OAT1 and OAT3, that the pattern of expression suggests an increasing role for these transporters in the physiology of the developing fetal brain as the fetus nears the time of spontaneous parturition. PMID- 20708068 TI - Modulators of BK and SK channels alter electrical activity in vitro in single vasopressin neurons isolated from the rat supraoptic nucleus. AB - Release of arginine vasopressin (AVP) from magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) is controlled by the electrical activities of the MNCs. Ca(2+)-activated K(+) channels, such as the BK and SK channels, are K(+)-selective ion channels that are activated in response to increased intracellular calcium concentrations. Intrinsic affinities for Ca(2+) permit these channels to exert a negative feedback effect on cellular excitability. In the present study, we used the whole-cell patch-clamp technique to examine the effects of BK or SK channel modulators on neuronal activity in single isolated rat SON MNCs that express an AVP-enhanced green fluorescent protein (eGFP) transgene. Application of BK or SK channel activators abolished the action potentials and induced hyperpolarization. In contrast, the number of action potentials was significantly increased after application of BK or SK channel blockers. Our results suggest that BK and SK channels in AVP neurons may play a role in the regulatory mechanisms of neural activity. PMID- 20708069 TI - Processing in prefrontal cortex underlies tactile direction discrimination: An fMRI study of a patient with a traumatic spinal cord lesion. AB - We have investigated cortical processing of tactile direction discrimination (TDD) in a patient with unilateral tactile disturbance due to spinal cord lesion. The patient R.A. (male, 45 years old), suffers from a traumatic dorsal column lesion at the level of Th XI-XII on the right side. He was instructed to report the direction of 2mm long skin pull stimulations applied in a proximal or distal direction on his right or left lower legs during functional magnetic resonance imaging (fMRI). Although R.A. considered himself to have nearly normal tactile sensibility, testing showed severely disturbed TDD on his right leg whereas results were within the range of healthy subjects on his left leg. For both legs TDD activated an extensive cortical network that included opercular parietal area 1 (OP1) of the second somatosensory cortex (S2), as has previously been observed in healthy subjects. However, dorsolateral prefrontal cortex (DLPFC) and anterior insular cortex (AIC) were only activated for the unaffected (left) leg where TDD was normal. A revisit of previously published data showed that healthy subjects consistently had TDD-related activations in DLPFC and AIC. However, in several healthy subjects AIC, but not DLPFC, was also activated for skin pull stimulations per se without the TDD task. Thus, the patient's data, in conjunction with the previous results from healthy subjects, suggest that DLPFC processing is important for tactile decision making based on proper tactile input. PMID- 20708070 TI - Elevation of oxidized DJ-1 in the brain and erythrocytes of Parkinson disease model animals. AB - DJ-1, the causative gene of a familial form of Parkinson's disease (PD), has been reported undergo oxidation preferentially at the 106th cysteine residue (Cys-106) under oxidative stress. Recently, it has been found that the levels of oxidized DJ-1 in erythrocytes of unmedicated PD patients are markedly higher than those in medicated PD patients and healthy subjects. In the present study, we examined the changes in oxidized DJ-1 levels in the brain and erythrocytes of PD animal models using specific antibodies against Cys-106-oxidized DJ-1. Treatment with PD model compounds such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6 hydroxydopamine significantly elevated the levels of oxidized DJ-1 in erythrocytes. Immunohistochemical analysis also revealed that the number of oxidized DJ-1 antibody-positive cells in the substantia nigra of MPTP-treated mouse increased in a dose-dependent manner. These results suggest that the oxidative modification of DJ-1 in the brain and erythrocytes is involved in the pathogenesis of PD in animal models. PMID- 20708071 TI - A new abietane diterpene from Glyptostrobus pensilis. AB - A new abietane diterpene, glypensin A (1) and four known compounds, 12-acetoxy ent-labda-8(17), 13E-dien-15-oic acid (2), quercetin 3-O-alpha-L arabinofuranoside (3), quercetin 3-O-beta-D-galactopyranoside (4), beta sitosterol (5) were isolated from the branches and leaves of Glyptostrobus pensilis (Staut.) Koch. Their structures were determined by MS, 1D- and 2D-NMR means. Compound 1 showed cytotoxicity on human chronic myeloid leukemia cell line K562 (IC(50) = 21.2MUM). PMID- 20708072 TI - Molecular phylogenetic study in genus Hydra. AB - Among 8000-9000 species of Cnidaria, only several dozens of species of Hydrozoa have been found in the fresh water. Hydra is such a fresh water polyp and has been used as a good material for research in developmental biology, regeneration and pattern formation. Although the genus Hydra has only a few ten species, its distribution is cosmopolitan. The phylogenetic relationship between hydra species is fascinating from the aspect of evolutionary biology and biogeography. However, only a few molecular phylogenetic studies have been reported on hydra. Therefore, we conducted a molecular phylogenetic study of the genus Hydra based on mitochondrial and nuclear nucleotide sequences using a hydra collection that has been kept in the National Institute of Genetics (NIG) of Japan. The results support the idea that four species groups comprise the genus Hydra. Within the viridissima group (green hydra) and braueri group, genetic distances between strains were relatively large. In contrast, genetic distances between strains among the vulgaris and oligactis groups were small irrespective of their geographic distribution. The vulgaris group strains were classified at least (as far as our investigated samples) into three sub-groups, vulgaris sub-group, carnea sub-group, and H. sp. (K5 and K6) sub-group. All of the vulgaris sub-group and H. sp. (K5 and K6) sub-group strains were collected in Eurasia. The carnea sub-group strains in NIG collection were all collected in North America. A few newly collected samples in Japan, however, suggested belonging to the carnea sub group according to the molecular phylogenic analysis. This suggests a trans Pacific distribution of the carnea sub-group hydra. PMID- 20708073 TI - Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. AB - Widely used conazole antifungals were tested for endocrine disruptive effects using a panel of in vitro assays. They all showed endocrine disrupting potential and ability to act via several different mechanisms. Overall the imidazoles (econazole, ketoconazole, miconazole, prochloraz) were more potent than the triazoles (epoxiconazole, propiconazole, tebuconazole). The critical mechanism seems to be disturbance of steroid biosynthesis. In the H295R cell assay, the conazoles decreased the formation of estradiol and testosterone, and increased the concentration of progesterone, indicating inhibition of enzymes involved in the conversion of progesterone to testosterone. Prochloraz was most potent followed by econazole~miconazole>ketoconazole>tebuconazole>epoxiconazole>propiconazole. In the MCF-7 cell proliferation assay, the conazoles showed anti-estrogenic effect, including aromatase inhibition, since they inhibited the response induced by both 17beta-estradiol (miconazole>econazole~ketoconazole>prochloraz>tebuconazole>epoxiconazole>propicon zole) and testosterone (econazole>miconazole>prochloraz>ketoconazole>tebuconazole>epoxiconazole>propicon zole). The triazoles were anti-androgenic in an androgen receptor reporter gene assay (epoxiconazole~tebuconazole>propiconazole). This effect could not be evaluated for the pharmaceutical imidazoles due to cytotoxicity. PMID- 20708074 TI - Juvenile toxicity study of faropenem medoxomil in beagle puppies. AB - We determined the toxicity of faropenem medoxomil (FPM) in neonatal/juvenile dogs following 28 days of administration. The puppies received vehicle or FPM beginning on Postnatal Day (PND) 22 at respective dose levels of 0, 100, 300, 600, or 1400 mg/kg-d (four daily doses (QID) of 25, 75, 150, or 350 mg/kg/dose), respectively, at a dose volume of 5 mL/kg/dose. Body weight, food consumption, clinical observation, clinical pathology, urine analysis and TK were evaluated. Body weight in males and kidney findings at 1400 mg/kg-d were considered adverse. Comparison of Day 27 TK values with Day 1 parameters showed a change in FPM pharmacokinetic behavior over time with an apparent increase in the rate of clearance characterized by a decrease in AUC(0-6) and T(max) values on Day 27 with little to no change in C(max) values. Based on these results, the No Observed Adverse Effect Level was 600 mg/kg-d. PMID- 20708075 TI - Comparative embryotoxicity of different antimalarial peroxides: in vitro study using the rat whole embryo culture model (WEC). AB - Three groups of compounds: (i) active peroxides (artemisinin and arterolene), (ii) inactive non-peroxidic derivatives (deoxyartemisinin and carbaOZ277) and (iii) inactive peroxide (OZ381) were tested by WEC system to provide insights into the relationship between chemical structure and embryotoxic potential, and to assess the relationship between embryotoxicity and antimalarial activity. Deoxyartemisinin, OZ381 and carbaOZ277 did not affect rat embryonic development. Artemisinin and arterolane affected primarily nucleated red blood cells (RBCs), inducing anemia and subsequent tissue damage in rat embryos, with NOELs for RBC damage at 0.1 and 0.175MUg/mL, respectively. These data support the idea that only active antimalarial peroxides are able to interfere with normal embryonic development. In an attempt to establish whether and to what extent activity as antimalarials and embryotoxicity can be divorced, IC(50)s for activity in Plasmodium falciparum strains and the NOELs for RBCs were compared. From this comparison, arterolane showed a better safety margin than artemisinin. PMID- 20708076 TI - A new mucoadhesive dosage form for the management of oral lichen planus: formulation study and clinical study. AB - The work aimed at studying a new mucoadhesive prolonged release tablet containing 24 MUg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl2. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n=16) who received three applications-a-day over 4 weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123 MUg/application) extemporary mixed with OrabaseTM (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n=2) and taste alteration (n=4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24 MUg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment. PMID- 20708077 TI - The effect of network charge on the immobilization and release of proteins from chemically crosslinked dextran hydrogels. AB - Size is the main protein characteristic that determines its release from non degrading neutral hydrogels. The effect of network charge on the release of proteins has not been studied systematically so far. Therefore, we investigated the release of proteins from charged hydrogels that were obtained by co polymerization of methacrylated dextran (Dex-MA) with either methacrylic acid (MA) or 2-N,N-dimethylaminoethyl methacrylate (DMAEMA). These hydrogels are stable under physiological conditions. The effect of incorporation of the charged monomers on hydrogel charge, equilibrium swelling, and release of model proteins was assessed at both low (10mM HEPES) and physiological ionic strength (HEPES buffered saline, HBS). Model proteins were chosen on the basis of their charge at physiological pH; bovine serum albumin (BSA, negatively charged), myoglobin (neutral), and cytochrome C (positively charged). Interestingly, as opposed to myoglobin, both charged proteins were fully immobilized in the networks with opposite charge by electrostatic interaction at low ionic strength. On the other hand, at physiological ionic strength, the percentage of immobilized protein depended on the charge density of the hydrogel. For all proteins, the diffusion coefficient of the mobile fractions was not affected by opposite network charge. However, the release rate of BSA from similarly (negatively) charged networks significantly increased when a relatively high amount of charged monomers was incorporated. We conclude that incorporation of charge in a hydrogel network is suited as a tool for the immobilization of proteins and triggered release by increasing ionic strength. PMID- 20708078 TI - Cryptic domains of tenascin-C differentially control fibronectin fibrillogenesis. AB - The three-dimensional organization of the ubiquitous extracellular matrix glycoprotein fibronectin regulates cell fate and morphogenesis during development; in particular tubule formation that constitutes the vasculature, lung and kidney. Tenascin-C is a matrix protein with a restricted expression pattern; it is specifically up-regulated at sites of fibronectin fibril assembly during development and in remodeling adult tissues. Here we demonstrate that specific domains of tenascin-C inhibit fibronectin matrix assembly whereas full length tenascin-C does not. These domains act via distinct mechanisms: TNfn1-8 blocks fibrillogenesis by binding to fibronectin fibrils and preventing intermolecular fibronectin interactions whilst FBG acts independently of binding to fibronectin and instead is internalized and causes cytoskeletal re organization. We also show that TNfn1-8 disrupts epithelial cell tubulogenesis. Our data demonstrate that tenascin-C contains cryptic sites which can control tissue levels of fibrillar fibronectin either by preventing de novo fibril assembly or reducing levels of deposited fibronectin. Exposure of these domains during tissue remodeling may provide a novel means of controlling fibronectin assembly and tubulogenic processes dependent on the assembly of this matrix. PMID- 20708079 TI - Expression in SPARC-null mice of collagen type I lacking the globular domain of the alpha1(I) N-propeptide results in abdominal hernias and loss of dermal collagen. AB - The sequence encoding the N-propeptide of collagen I is characterized by significant conservation of amino acids across species; however, the function of the N-propeptide remains poorly defined. Studies in vitro have suggested that one activity of this propeptide might be to act as a feedback inhibitor of collagen I synthesis. To determine whether the N-propeptide contributed to decreased collagen content in SPARC-null mice, mice carrying a deletion of exon 2, which encodes the globular domain of the N-propeptide of collagen I, were crossed to SPARC-null animals. Mice lacking SPARC and expressing collagen I without the globular domain of the N-propeptide were viable and fertile. However, a significant number of animals developed abdominal hernias within the first 2 months of life with an approximate 20% penetrance (~35% of males). The dermis of SPARC-null/exon 2-deleted mice was thinner and contained fewer large collagen fibers in comparison with wild-type or in either single transgenic animal. The average collagen fibril diameter of exon 2-deleted mice did not significantly differ from wild-type mice (WT: 87.9 nm versus exon 2-deleted: 88.2 nm), whereas SPARC-null/exon 2-deleted fibrils were smaller than that of SPARC-null dermis (SPARC-null: 60.2 nm, SPARC-null/exon 2-deleted: 40.8 nm). As measured by hydroxyproline analysis, double transgenic skin biopsies contained significantly less collagen than those of wild-type, those of exon 2-deleted, and those of SPARC-null biopsies. Acetic acid extraction of collagen from skin biopsies revealed an increase in the proportion of soluble collagen in the SPARC-null/exon 2-deleted mice. These results support a function of the N-propeptide of collagen I in facilitating incorporation and stabilization of collagen I into the insoluble ECM and argue against a primary function of the N-propeptide as a negative regulator of collagen synthesis. PMID- 20708081 TI - Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress. AB - Depression is potentially life-threatening. The most important neuroendocrine abnormality in this disorder is hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. Recent findings suggest that all depression treatments may boost the neurotrophin production especially brain-derived neurotrophic factor (BDNF). Moreover, BDNF is highly involved in the regulation of HPA axis activity. The aim of this study was to determine the impact of chronic stress (restraint 3h/day for 3 weeks) on animal behavior and HPA axis activity in parallel with hippocampus, hypothalamus and pituitary BDNF levels. Chronic stress induced changes in anxiety (light/dark box test) and anhedonic states (sucrose preference test) and in depressive-like behavior (forced swimming test); general locomotor activity and body temperature were modified and animal body weight gain was reduced by 17%. HPA axis activity was highly modified by chronic stress, since basal levels of mRNA and peptide hypothalamic contents in CRH and AVP and plasma concentrations in ACTH and corticosterone were significantly increased. The HPA axis response to novel acute stress was also modified in chronically stressed rats, suggesting adaptive mechanisms. Basal BDNF contents were increased in the hippocampus, hypothalamus and pituitary in chronically stressed rats and the BDNF response to novel acute stress was also modified. This multiparametric study showed that chronic restraint stress induced a depressive-like state that was sustained by mechanisms associated with BDNF regulation. PMID- 20708080 TI - Hippocampal phenotypes in kalirin-deficient mice. AB - Regulation of forebrain cellular structure and function by small GTPase pathways is crucial for normal and pathological brain development and function. Kalirin is a brain-specific activator of Rho-like small GTPases implicated in neuropsychiatric disorders. We have recently demonstrated key roles for kalirin in cortical synaptic transmission, dendrite branching, spine density, and working memory. However, little is known about the impact of the complete absence of kalirin on the hippocampus in mice. We thus investigated hippocampal function, structure, and associated behavioral phenotypes in KALRN knockout (KO) mice we have recently generated. Here we show that KALRN KO mice had modest impairments in hippocampal LTP, but normal hippocampal synaptic transmission. In these mice, both context and cue-dependent fear conditioning were impaired. Spine density and dendrite morphology in hippocampal pyramidal neurons were not significantly affected in the KALRN KO mice, but small alterations in the gross morphology of the hippocampus were detected. These data suggest that hippocampal structure and function are more resilient to the complete loss of kalirin, and reveal impairments in fear learning. These studies allow the comparison of the phenotypes of different kalirin mutant mice and shed light on the brain region specific functions of small GTPase signaling. PMID- 20708082 TI - Characterisation of an immunodominant, high molecular weight glycoprotein on the surface of infectious Neoparamoeba spp., causative agent of amoebic gill disease (AGD) in Atlantic salmon. AB - Amoebic gill disease can be experimentally induced by the exposure of salmonids to Neoparamoeba spp. freshly isolated from infected fish, while cultured amoebae are non-infective. Results from our previous work suggested that one key difference between infectious and non-infectious Neoparamoeba were the highly glycosylated molecules in the glycocalyx. To characterise these surface glycans or glycoproteins we used a monoclonal antibody (mAb 44C12) specific to a surface molecule unique to infective parasites. This mAb recognised a carbohydrate epitope on a high molecular weight antigen (HMWA) that make up 15-19% of the total protein in a soluble extract of infectious parasites. The HMWA consisted of at least four glycoprotein subunits of molecular weight (MW) greater than 150 kDa that form disulfide-linked complexes of MW greater than 600 kDa. Chemical deglycosylation yielded at least four protein bands of approximate MW 46, 34, 28 and 18 kDA. While a similar HMWA complex was present in non-infective parasites, the glycoprotein subunits were of lower MW and exhibited differences in glycosylation. The four glycoproteins subunits recognised by mAb 44C12 were resistant to degradation by PNGase F, PNGase A, O-glycosidase plus beta-1, 4 galactosidase, beta-N-acetylglucosaminidase and neuraminidase. The major monosaccharides in the HMWA from infectious parasites were rhamnose, fucose, galactose, and mannose while sialic acids were absent. The carbohydrate portion constituted more than 90% of the total weight of the HMWA from infectious Neoparamoeba spp. Preliminary results indicate that immunisation of salmon with HMWA does not lead to protection against challenge infection; rather it may even have an immunosuppressive effect. PMID- 20708083 TI - Simultaneous intracranial EEG and fMRI of interictal epileptic discharges in humans. AB - Simultaneous scalp EEG-fMRI measurements allow the study of epileptic networks and more generally, of the coupling between neuronal activity and haemodynamic changes in the brain. Intracranial EEG (icEEG) has greater sensitivity and spatial specificity than scalp EEG but limited spatial sampling. We performed simultaneous icEEG and functional MRI recordings in epileptic patients to study the haemodynamic correlates of intracranial interictal epileptic discharges (IED). Two patients undergoing icEEG with subdural and depth electrodes as part of the presurgical assessment of their pharmaco-resistant epilepsy participated in the study. They were scanned on a 1.5 T MR scanner following a strict safety protocol. Simultaneous recordings of fMRI and icEEG were obtained at rest. IED were subsequently visually identified on icEEG and their fMRI correlates were mapped using a general linear model (GLM). On scalp EEG-fMRI recordings performed prior to the implantation, no IED were detected. icEEG-fMRI was well tolerated and no adverse health effect was observed. intra-MR icEEG was comparable to that obtained outside the scanner. In both cases, significant haemodynamic changes were revealed in relation to IED, both close to the most active electrode contacts and at distant sites. In one case, results showed an epileptic network including regions that could not be sampled by icEEG, in agreement with findings from magneto-encephalography, offering some explanation for the persistence of seizures after surgery. Hence, icEEG-fMRI allows the study of whole-brain human epileptic networks with unprecedented sensitivity and specificity. This could help improve our understanding of epileptic networks with possible implications for epilepsy surgery. PMID- 20708084 TI - Novel H1N1 influenza in hematopoietic stem cell transplantation recipients: two centers' experiences. AB - Respiratory virus infections, such as influenza A, cause significant morbidity in hematopoietic stem cell transplantation (HSCT) recipients. The clinical characteristics and impact of infection with the novel H1N1 virus in this patient population is not yet well defined, however. HSCT recipients diagnosed with proven or probable H1N1 during the 2009 pandemic were identified and charts were retrospectively reviewed with analysis of clinical descriptions, risk factors, diagnosis, treatments, and outcomes. Twenty-seven patients from two medical centers were identified. Fever and cough were the most common presenting symptoms. The incidence of influenza lower respiratory tract infection (LRTI) was 52% (14/27). Compared with patients with LRTI, those with influenza upper respiratory tract infection (URTI) were more likely to have a classic influenza like syndrome. Compared to patients with URTI, those with LRTI were started on antiviral therapy significantly later after symptom onset (3.0 days vs 6.58 days after onset of symptoms; P = .03; 95% confidence interval [CI], 0.29-6.8). Overall influenza-related 30-day mortality was 22% (6/27), and that in patients with LRTI was 43% (6/14). Chronic steroid use (>=20 mg/day of prednisone equivalent) at the time of presentation was associated with LRTI (P = .006) and mortality (P = .003) on univariate analysis. Five cases were hospital-acquired. In this first season of the novel H1N1 pandemic, infection in HSCT often presented as an atypical severe illness with a high incidence of LRTI and high mortality. PMID- 20708085 TI - Humoral and cellular immunity to primary H1N1 infection in patients with hematologic malignancies following stem cell transplantation. AB - Limited data are available on immunologic responses to primary H1N1 infection in patients with hematologic malignancies. We present a prospective, case surveillance study of such patients with real-time polymerase chain reaction (RT PCR) confirmed H1N1-influenza who presented to our institution between September 2009 and January 2010. Ninety-two patients presented with influenza-like symptoms, and 13 had H1N1 infection confirmed by RT-PCR, including 4 allogeneic stem cell transplant recipients (1 with acute myelogenous leukemia, 1 with chronic lymphoblastic leukemia [CLL], 1 with non-Hodgkin lymphoma, and 1 with chronic myelogenous leukemia), 5 patients with multiple myeloma following autologous stem cell transplantation, 1 patient with multiple myeloma perimobilization, 2 patients with NHL post chemotherapy, and 1 patient with CLL. All 13 patients required hospitalization. Six (43%) were admitted to the intensive care unit (ICU), of whom 4 (67%) died. We evaluated B cell and T cell responses to H1N1 infection prospectively in these patients compared with those in 4 otherwise healthy controls. Within 12 weeks of diagnosis, only 6 of 11 patients developed seropositive antibody titers as measured by hemagglutination inhibition or microneutralization assays, compared with 4 of 4 controls. H1N1 specific T cells were detected in only 2 of 8 evaluable patients compared with 4 of 4 controls. H1N1-specific T cells were functional, capable of producing interferon gamma, tumor necrosis factor alpha, and CD107a mobilization. Furthermore, CD154 was up-regulated on CD4(+) T cells in 3 of 4 controls and 2 of 2 patients who had both B cell and T cell responses to H1N1. Post-H1N1 infection, 5 of 8 patients developed seasonal influenza-specific T cells, suggesting cross reactivity induced by H1N1 infection. These data offer novel insights into humoral and cell-mediated immunologic responses to primary H1N1 infection. PMID- 20708086 TI - Acute kidney injury in patients with systemic sclerosis participating in hematopoietic cell transplantation trials in the United States. AB - Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury (AKI), and this risk may be increased in patients who undergo transplantation for severe systemic sclerosis (SSc) due to underlying scleroderma renal disease. AKI after transplantation can increase treatment-related mortality. To better define these risks, we analyzed 91 patients with SSc who were enrolled in 3 clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation (HCT). Eleven (12%) of the 91 patients with SSc in these studies (8 undergoing autologous HCT, 1 undergoing allogeneic HCT, 1 pretransplantation, 1 given i.v. cyclophosphamide on a transplantation trial) experienced AKI, of whom 8 required dialysis and/or therapeutic plasma exchange. AKI injury in the 9 HCT recipients developed a median of 35 days (range, 0-90 days) after transplantation. Ten of 11 patients with AKI received angiotensin-converting enzyme inhibitor (ACE-I) therapy. The etiology of AKI was attributed to scleroderma renal crisis in 6 patients (including 2 with normotensive renal crisis), to AKI of uncertain etiology in 2 patients, and to AKI superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died, one each because of progression of SSc, multiorgan failure, gastrointestinal and pulmonary bleeding, pericardial tamponade and pulmonary complications, diffuse alveolar hemorrhage, pulmonary embolism, graft versus-host disease, and malignancy. Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure, and aggressive use of ACE-Is may be of importance in preventing renal complications after HCT for SSc. PMID- 20708087 TI - Cytokinetic abscission in animal cells. AB - Cytokinesis leads to the separation of dividing cells, which in animal cells involves the contraction of an actin-myosin ring and subsequent fission during abscission. Abscission requires a series of dynamic events, including midbody targeted vesicle secretion, specialization of plasma membrane domains, disassembly of midbody-associated microtubule bundles and plasma membrane fission. A large number of molecular factors required for abscission have been identified through localization, loss-of-function and proteomics studies, but their coordinate function in abscission is still poorly understood. Here, we review the structural elements and molecular factors known to contribute to abscission, and discuss their potential role in the context of proposed models for the abscission mechanism. PMID- 20708089 TI - Mechanisms controlling division-plane positioning. AB - A critical and irreversible step in the cell division cycle is cytokinesis which physically separates the two daughter cells. This event is consequently subject to tight spatial and temporal regulation. This review focuses on the spatial regulatory mechanisms controlling the position of the division plane. Studies performed in prokaryotic and eukaryotic systems have revealed that various signal emitting spatial cues - mitotic spindle, nucleus, nucleoid or cell tips - can favour or inhibit the assembly of the cytokinetic apparatus in their vicinity. Most often, several mechanisms operate in parallel to integrate spatial information and promote faithful genome segregation as well as proper cytoplasmic division. We primarily describe the spatial regulatory mechanisms operating in the fission yeast model system, where a detailed molecular understanding of cytokinesis has been achieved. In this system, spatial regulations target a major factor controlling the position of the division plane, the anillin-like protein Mid1. These mechanisms are then compared to spatial regulatory mechanisms prevailing in animal cells and rod-shaped bacteria. PMID- 20708088 TI - Mechanisms of contractile-ring assembly in fission yeast and beyond. AB - Most eukaryotes including fungi, amoebas, and animal cells assemble an actin/myosin-based contractile ring during cytokinesis. The majority of proteins implied in ring formation, maturation, and constriction are evolutionarily conserved, suggesting that common mechanisms exist among these divergent eukaryotes. Here, we review the recent advances in positioning and assembly of the actomyosin ring in the fission yeast Schizosaccharomyces pombe, the budding yeast Saccharomyces cerevisiae, and animal cells. In particular, major findings have been made recently in understanding ring formation in genetically tractable S. pombe, revealing a dynamic and robust search, capture, pull, and release mechanism. PMID- 20708090 TI - Toxoplasma IgG and IgA, but not IgM, antibody titers increase in sera of immunocompetent mice in association with proliferation of tachyzoites in the brain during the chronic stage of infection. AB - Toxoplasma IgG and IgA, but not IgM, antibody titers were significantly higher in immunocompetent mice with cerebral proliferation of tachyzoites during the chronic stage of infection than those treated with sulfadiazine to inhibit the parasite growth. Their IgG and IgA antibody titers correlated significantly with the amounts of tachyzoite-specific SAG1 mRNA in their brains. In contrast, neither IgG, IgA, nor IgM antibody titers increased following two different doses of challenge infection in chronically infected mice. Increased antibody titers in IgG and IgA but not IgM may be a useful indicator suggesting an occurrence of cerebral tachyzoite growth in immunocompetent individuals chronically infected with Toxoplasma gondii. PMID- 20708091 TI - New insights into Whipple's disease and Tropheryma whipplei infections. AB - Whipple's disease is a rare multi-systemic disease associated with the ubiquitous environmental bacterium Tropheryma whipplei. Over the last 10 years, since the isolation of the bacterium, recent advances in medical microbiology, epidemiology and cellular biology have provided major insights into the understanding of the pathophysiology of T. whipplei infections that may result in Whipple's disease. PMID- 20708093 TI - Surfactant protein A: an immunoregulatory molecule involved in female reproductive biology. AB - Surfactant protein A (SP-A), a member of the collectin family originally described as a major component of lung surfactant, plays an important role in the modulation of lung host defense. A new interest in SP-A is provided by the link between fetal lung development and the timing of labor in the mouse. In the present review, we discuss some of the known features of SP-A such as biological functions, signaling pathways involved and the recent developments showing that SP-A bind and serve as a signal in the female genital tract. Therefore, such reports support a new paradigm involving SP-A as a multifunctional protein in the parturition process. PMID- 20708092 TI - Inactivation of p38 MAPK during liver regeneration. AB - There is increasing evidence that p38 MAPK, which is classified as a stress activated kinase, also participates in cell cycle regulation, functioning as a suppressor of cell proliferation and tumorigenesis. We conducted a study of p38 MAPK phosphorylation during liver regeneration in mice to determine whether p38 MAPK activation or inactivation may correlate with events that lead to DNA replication after partial hepatectomy (PH), and whether p38 MAPK activation may be required for hepatocyte DNA replication in vivo and in culture. We report that active p38 (Pi-p38 MAPK) is present in normal liver, is rapidly inactivated starting 30 min after PH, and is re-activated by 12h. Although levels of Pi-MKK 3/6, the upstream kinases that activate p38 MAPK increase after PH, the expression of the dual protein phosphatase 1 is also elevated, and may be responsible for Pi-p38 MAPK dephosphorylation after PH. Inactivation and re activation of p38 MAPK inversely correlates with the stimulation of protein synthesis and translation pathways, as indicated by activation of p70S6 kinase, increases in the phosphorylation of initiation factor elF-4E and translational repressor, 4E-BP. The activity of a p38 MAPK downstream substrate, MAPKAPK2 (MK2), did not reflect the changing levels of Pi-p38 MAPK during liver regeneration. Pi-p38 MAPK may be involved in TNF-stimulated DNA replication of murine hepatocytes in culture, but is not necessary for hepatocyte DNA replication after PH. Our results suggest that p38 MAPK inactivation plays a permissible role in DNA replication during liver regeneration and is consistent with a role for p38 MAPK in the maintenance of hepatocyte cell cycle arrest in adult liver. PMID- 20708094 TI - Arginine vasopressin receptor antagonists (vaptans): pharmacological tools and potential therapeutic agents. AB - Arginine vasopressin (AVP) attracted attention as a potentially important neurohormonal mediator of the heart failure (HF) syndrome and hyponatremic states in humans because AVP influences renal handling of free water, vasoconstriction and myocyte biology through activation of V2 and V1(a) receptors. Current research is exploring V2- and dual V1(a)/V2 receptor antagonism for the treatment of hyponatremia, as well as for the congestion and edema associated with chronic HF, because vasopressin receptor antagonists might offer benefits in comparison with conventional loop diuretics. The purpose of this review is to update the current status of experimental and clinical studies with available vasopressin receptor antagonists (conivaptan and tolvaptan) and their potential role in the treatment of HF and hyponatremia of multiple causes. PMID- 20708095 TI - Biotransformation pathway maps in WikiPathways enable direct visualization of drug metabolism related expression changes. AB - In recent decades, our knowledge of the genetics and functional genomics of drug metabolizing enzymes has increased and a wealth of data on drug-related 'omics' has become available. Despite the availability of large amounts of biological information on xenobiotic biotransformation, the number of available biotransformation pathway maps that can easily be used for visualization of multiple omics data is limited. Here, we created integrated biotransformation pathway maps suitable for multiple omics analysis using PathVisio. The ease of visualizing data on these maps was demonstrated by using published microarray data from human hepatocyte-like cell models, exemplifying - where a sufficient capacity for metabolizing chemicals is a prerequisite for a suited model - how the biotransformation pathway maps can be used for model selection. PMID- 20708096 TI - The future of toxicity testing: a focus on in vitro methods using a quantitative high-throughput screening platform. AB - The US Tox21 collaborative program represents a paradigm shift in toxicity testing of chemical compounds from traditional in vivo tests to less expensive and higher throughput in vitro methods to prioritize compounds for further study, identify mechanisms of action and ultimately develop predictive models for adverse health effects in humans. The NIH Chemical Genomics Center (NCGC) is an integral component of the Tox21 collaboration owing to its quantitative high throughput screening (qHTS) paradigm, in which titration-based screening is used to profile hundreds of thousands of compounds per week. Here, we describe the Tox21 collaboration, qHTS-based compound testing and the various Tox21 screening assays that have been validated and tested at the NCGC to date. PMID- 20708097 TI - Fit-for-purpose biomarker method validation in anticancer drug development. AB - The introduction of new anticancer drugs into the clinic is often hampered by a lack of qualified biomarkers. Method validation is indispensable to successful biomarker qualification and is also a regulatory requirement. Recently, the fit for-purpose approach has been developed to promote flexible yet rigorous biomarker method validation, although its full implications are often overlooked. This review aims to clarify many of the scientific and regulatory issues surrounding biomarker method validation and the analysis of samples collected from clinical trial subjects. It also strives to provide clear guidance on validation strategies for each of the five categories that define the majority of biomarker assays, citing specific examples. PMID- 20708098 TI - Broad spectrum antimutagenic activity of antioxidant active fraction of punica granatum L. peel extracts. AB - Over the past few decades, scientific research has indicated a credible basis for some of the traditional ethnomedicinal uses of pomegranate. This study aims to evaluate the broad spectrum antioxidant and antimutagenic activities of peel extracts of pomegranate. The sequentially extracted Punica granatum peel fractions were tested for their antioxidant activity by DPPH free radical scavenging, phosphomolybdenum, FRAP (Fe(3+) reducing power) and CUPRAC (cupric ions (Cu(2+)) reducing ability) assays. The methanol fraction showed highest antioxidant activity by all the four in vitro assays comparable to ascorbic acid and butylated hydroxy toluene (BHT) followed by activity in ethanol, acetone, and ethyl acetate fractions. Based on the promising antioxidant activities, the methanol fraction was evaluated for antimutagenic activity by Ames Salmonella/microsome assay against sodium azide (NaN(3)), methyl methane sulphonate (MMS), 2-aminofluorene (2-AF) and benzo(a)pyrene (B(a)P) induced mutagenicity in Salmonella typhimurium (TA97a, TA98, TA100 and TA102) tester strains. The methanol fraction showed no sign of mutagenicity at tested concentration of 10-80MUg/mL. This fraction showed antimutagenic activity against NaN(3) and MMS with percent inhibition of mutagenicity ranging from 66.76% to 91.86% in a concentration-dependent manner. Similar trend of inhibition of mutagenicity (81.2-88.58%) against indirect mutagens (2-AF and B(a)P) was also recorded. Phytochemical analysis by HPLC, LC-MS and total phenolic content revealed high content of ellagitannins which might be responsible for promising antioxidant and antimutagenic activities of P. granatum peel extract. Further, contribution of bioactive compounds detected in this study is to be explored to understand the exact mechanism of action as well as their therapeutic efficacy. PMID- 20708100 TI - Mesenchymal stem cells stimulate angiogenesis in a murine xenograft model of A549 human adenocarcinoma through an LPA1 receptor-dependent mechanism. AB - Carcinoma-associated fibroblasts play a key role in tumorigenesis and metastasis by providing a tumor-supportive microenvironment. In the present study, we demonstrate that conditioned medium from A549 human lung adenocarcinoma cells induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to carcinoma-associated fibroblasts expressing alpha-smooth muscle actin, vascular endothelial growth factor, and stromal cell-derived factor-1. A549 conditioned medium-induced differentiation of hASCs to carcinoma-associated fibroblasts was completely abrogated by treatment of hASCs with Ki16425, a lysophosphatidic acid receptor antagonist, or knockdown of lysophosphatidic acid receptor 1 (LPA(1)) expression in hASCs with small interfering RNA or lentiviral short hairpin RNA. Using a murine xenograft transplantation model of A549 cells, we showed that co-transplantation of hASCs with A549 cells stimulated growth of A549 xenograft tumor, angiogenesis, and differentiation of hASCs to carcinoma associated fibroblasts in vivo. Knockdown of LPA(1) expression in hASCs abrogated hASCs-stimulated growth of A549 xenograft tumor, angiogenesis, and differentiation of hASCs to carcinoma-associated fibroblasts. Moreover, A549 conditioned medium-treated hASCs stimulated tube formation of human umbilical vein endothelial cells by LPA(1)-dependent secretion of vascular endothelial growth factor. These results suggest that A549 cells induce in vivo differentiation of hASCs to carcinoma-associated fibroblasts, which play a key role in tumor angiogenesis within tumor microenvironment, through an LPA-LPA(1) mediated paracrine mechanism. PMID- 20708099 TI - Specialized pro-resolving lipid mediators in the inflammatory response: An update. AB - A new genus of specialized pro-resolving mediators (SPM) which include several families of distinct local mediators (lipoxins, resolvins, protectins, and maresins) are actively involved in the clearance and regulation of inflammatory exudates to permit restoration of tissue homeostasis. Classic lipid mediators that are temporally regulated are formed from arachidonic acid, and novel local mediators were uncovered that are biosynthesized from omega-3 poly-unsaturated fatty acids, such as eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid. The biosynthetic pathways for resolvins are constituted by fatty acid lipoxygenases and cyclooxygenase-2 via transcellular interactions established by innate immune effector cells which migrate from the vasculature to inflamed tissue sites. SPM provide local control over the execution of an inflammatory response towards resolution, and include recently recognized actions of SPM such as tissue protection and host defense. The structural families of the SPM do not resemble classic eicosanoids (PG or LT) and are novel structures that function uniquely via pro-resolving cellular and molecular targets. The extravasation of inflammatory cells expressing SPM biosynthetic routes are matched by the temporal provision of essential fatty acids from circulation needed as substrate for the formation of SPM. The present review provides an update and overview of the biosynthetic pathways and actions of SPM, and examines resolution as an integrated component of the inflammatory response and its return to homeostasis via biochemically active resolution mechanisms. PMID- 20708102 TI - Endocardial and epicardial substrates of ventricular tachycardia in a patient with Fabry disease. PMID- 20708101 TI - Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? AB - BACKGROUND: The diagnosis of arrhythmogenic right ventricular cardiomyopathy can be challenging. Disease-causing mutations in desmosomal genes have been identified. A novel diagnostic feature, loss of immunoreactivity for plakoglobin from the intercalated disks, recently was proposed. OBJECTIVE: The purpose of this study was to identify two novel mutations in the intracellular cadherin segment of desmoglein-2 (G812S and C813R in exon 15). Co-segregation of the G812S mutation with disease expression was established in a large Caucasian family. Endomyocardial biopsies of two individuals showed reduced plakoglobin signal at the intercalated disk. METHODS: To understand the pathologic changes occurring in the diseased myocardium, functional studies on three mutations in exon 15 of desmoglein-2 (G812C, G812S, C813R) were performed. RESULTS: Localization studies failed to detect any differences in targeting or stability of the mutant proteins, suggesting that they act via a dominant negative mechanism. Binding assays were performed to probe for altered binding affinities toward other desmosomal proteins, such as plakoglobin and plakophilin-2. Although no differences were observed for the mutated proteins in comparison to wild-type desmoglein-2, binding to plakophilin-2 depended on the expression system (i.e., bacterial vs mammalian protein expression). In addition, abnormal migration of the C813R mutant protein was observed in gel electrophoresis. CONCLUSION: Loss of plakoglobin immunoreactivity from the intercalated disks appears to be the endpoint of complex pathologic changes, and our functional data suggest that yet unknown posttranslational modifications of desmoglein-2 might be involved. PMID- 20708103 TI - Biological pacemakers in canines exhibit positive chronotropic response to emotional arousal. AB - BACKGROUND: Biological pacemakers based on the HCN2 channel isoform respond to beta-adrenergic and muscarinic stimulation, suggesting a capacity to respond to autonomic input. OBJECTIVE: The purpose of this study was to investigate autonomic response to emotional arousal in canines implanted with murine HCN2 based biological pacemakers using gene therapy. METHODS: An electronic pacemaker was implanted with its lead in the right ventricular apical endocardium (VVI 35 bpm). An adenoviral HCN2/GFP construct (Ad-HCN2, n = 7) or saline (control, n = 5) was injected into the left bundle branch on day 2 after radiofrequency ablation of the atrioventricular node to induce complete atrioventricular block. Emotional arousal was achieved by presenting food following an overnight fast. Autonomic control was evaluated with Poincare plots of R-R(N) against R-R(N+1) intervals to characterize heart rate variability (HRV) and with continuous RR interval assessment via 24-hour ambulatory ECG. The 24-hour ECG and Poincare plot shape were analyzed. RESULTS: During day 1 after biological pacemaker implantation, Poincare HRV parameters and RR intervals were unchanged with food presentation. However, on day 7, food presentation was accompanied by an increase in HRV (SD1, p < 0.07, and SD2, p < 0.05) and shortening of RR interval (P < .05) in dogs with Ad-HCN2 but not in controls. CONCLUSION: This is the first demonstration that biological pacemakers are capable of responding to natural arousal stimuli to elicit appropriate chronotropic responses, a potential advantage over electronic pacemakers. PMID- 20708104 TI - Nucleosome occupancy at transcription start sites in the human malaria parasite: a hard-wired evolution of virulence? AB - Almost a decade after the publication of the complete sequence of the genome of the human malaria parasite Plasmodium falciparum, the mechanisms involved in gene regulation remain poorly understood. Like other eukaryotic organisms, P. falciparum's genomic DNA organizes into nucleosomes. Nucleosomes are the basic structural units of eukaryotic chromatin and their regulation is known to play a key role in regulation of gene expression. Despite its importance, the relationship between nucleosome positioning and gene regulation in the malaria parasite has only been investigated recently. Using two independent and complementary techniques followed by next-generation high-throughput sequencing, our laboratory recently generated a dynamic atlas of nucleosome-bound and nucleosome-free regions (NFRs) at single-nucleotide resolution throughout the parasite erythrocytic cycle. We have found evidences that genome-wide changes in nucleosome occupancy play a critical role in controlling the rigorous parasite replication in infected red blood cells. However, the role of nucleosome positioning at remarkable locations such as transcriptional start sites (TSS) was not investigated. Here we show that a study of NFR in experimentally determined TSS and in silico-predicted promoters can provide deeper insights of how a transcriptionally permissive organization of chromatin can control the parasite's progression through its life cycle. We find that NFRs found at TSS and core promoters are strongly associated with high levels of gene expression in asexual erythrocytic stages, whereas nucleosome-bound TSSs and promoters are associated with silent genes preferentially expressed in sexual stages. The implications in terms of regulatory evolution, adaptation of gene expression and their impact in the design of antimalarial strategies are discussed. PMID- 20708105 TI - Molecular diversity of Trichobilharzia franki in two intermediate hosts (Radix auricularia and Radix peregra): a complex of species. AB - Recently, the systematic use of the molecular approach as a complement to the other approaches (morphology, biology, life cycle) has brought help for the identification of species considered as different in the past to be regrouped and synonymised, and distinctions to be drawn between species similar at the morphological level. Among these species, we tried to clarify the situation of Trichobilharzia frankiMuller and Kimmig, 1994, species that today include more than 50 haplotypes notably coming from larval stages isolated from intermediate hosts belonging to gastropods of the Radix genus. Cercariae were isolated in France and Iceland from various molluscs, before being analyzed, with their hosts, by molecular analysis of various fields such as the D2 and ITS of the ribosomal DNA and the COX1 of mitochondrial DNA. We thus show the presence of two clades depending on the specificity of their intermediate host in which they were isolated (Radix auricularia or Radix peregra), thus allowing separation of the species T. franki that had been described in the past as a probable new species. PMID- 20708106 TI - Mitochondrial complex III: an essential component of universal oxygen sensing machinery? AB - Oxygen is necessary for the survival of mammalian cells. In order to maintain adequate cellular oxygenation, mammals have evolved multiple acute and long-term adaptive responses to hypoxia. These include hypoxic increases in erythropoiesis, pulmonary vasoconstriction and carotid body neurosecretion. Collectively, these responses help maintain oxygen homeostasis as oxygen levels remain scarce. There are multiple effectors proposed to underlie these diverse responses to hypoxia including PHD2, AMPK, NADPH oxidases, and mitochondrial complex III. Here I propose a model wherein complex III is integral to oxygen sensing in regulating diverse response to hypoxia. PMID- 20708108 TI - Quantitative determination of un-derivatised amino acids in artistic mural paintings using high-performance liquid chromatography/electrospray ionization triple quadrupole mass spectrometry. AB - The tempera painting technique is one of the most common methods used throughout art history. Tempera is defined by the type of binders used and in this work we study protein-based temperas. Proteinaceous binders can be characterized by the chromatographic determination of the amino acids present where techniques are either based on gas chromatography or high-performance liquid chromatography (HPLC) coupled to mass spectrometry. The objective of this work was to develop a derivatisation-free HPLC method with triple quadrupole tandem mass spectrometric detection (HPLC/ESI-MS/MS) of 21 amino acids contained in the protein-based binders of tempera paints. The analytical method identifies the painting techniques of two contemporary artists: Sironi and DeLuigi. The sample data are compared to painting material standards. The results show that the samples from works by DeLuigi contain mainly animal glue binders, while the samples from Sironi paintings contain binders that are an amino acid mixture with an overall composition between that of eggs and casein. PMID- 20708107 TI - Modulation of cardiorespiratory function mediated by the paraventricular nucleus. AB - The hypothalamic paraventricular nucleus (PVN) coordinates autonomic and neuroendocrine systems to maintain homeostasis and to respond to stress. Neuroanatomic and neurophysiologic experiments have provided insight into the mechanisms by which the PVN acts. The PVN projects directly to the spinal cord and brainstem and, specifically, to sites that control cardio-respiratory function: the intermediolateral cell columns and phrenic motor nuclei in the spinal cord and rostral ventrolateral medulla (RVLM) and the rostral nuclei in the ventral respiratory column (rVRC) in the brainstem. Activation of the PVN increases ventilation (both tidal volume and frequency) and blood pressure (both heart rate and sympathetic nerve activity). Excitatory and inhibitory neurotransmitters including glutamate and GABA converge in the PVN to influence its neuronal activity. However, a tonic GABAergic input to the PVN directly modulates excitatory outflow from the PVN. Further, even within the PVN, microinjection of GABA(A) receptor blockers increases glutamate release suggesting an indirect mechanism by which GABA control contributes to PVN functions. PVN activity alters blood pressure and ventilation during various stresses, such as maternal separation, chronic intermittent hypoxia (CIH), dehydration and hemorrhage. Among the several PVN neurotransmitters and neurohormones, vasopressin and oxytocin modulate ventilation and blood pressure. Here, we review our data indicating that increases in vasopressin and vasopressin type 1A (V(1A)) receptor signalling in the RVLM and rVRC are mechanisms increasing blood pressure and ventilation after exposure to CIH. That blockade of V(1A) receptors in the medulla normalizes baseline blood pressure as well as blunts PVN-evoked blood pressure and ventilatory responses in CIH-conditioned animals indicate the role of vasopressin in cardiorespiratory control. In summary, morphological and functional studies have found that the PVN integrates sensory input and projects to the sympathetic and respiratory control systems with descending projections to the medulla and spinal cord. PMID- 20708109 TI - Comparison of multivariate preprocessing techniques as applied to electronic tongue based pattern classification for black tea. AB - In an electronic tongue, preprocessing on raw data precedes pattern analysis and choice of the appropriate preprocessing technique is crucial for the performance of the pattern classifier. While attempting to classify different grades of black tea using a voltammetric electronic tongue, different preprocessing techniques have been explored and a comparison of their performances is presented in this paper. The preprocessing techniques are compared first by a quantitative measurement of separability followed by principle component analysis; and then two different supervised pattern recognition models based on neural networks are used to evaluate the performance of the preprocessing techniques. PMID- 20708110 TI - Development of near infrared sensors: detection of influential factors by the AComDim method. AB - The development of near infrared (NIR) sensors has to go through different steps of testing. Once a prototype is ready to be used, it is necessary to evaluate and optimize the experimental conditions and the data collection, in terms of accuracy, repeatability, reproducibility and speed. This paper studies the effects of controllable experimental factors on the quality of the spectral response, to determine the influence of each instrumental parameter and to improve the predictions obtained from the collected data. The AComDim method, based on the multi-block analysis of ANOVA matrices, was used here to evaluate the impact of experimental factors on the responses from the different sensors tested. PMID- 20708111 TI - Electrochemical sensing of melamine with 3,4-dihydroxyphenylacetic acid as recognition element. AB - A new electrochemical sensor for melamine with 3,4-dihydroxyphenylacetic acid as the recognition element is established. The results of Fourier Transform Infrared (FT-IR) spectra demonstrate that melamine may interact with 3,4 dihydroxyphenylacetic acid to form a complex mainly through the hydrogen-bonding interaction. The electrochemical behavior of 3,4-dihydroxyphenylacetic acid in the presence of melamine was studied. The anodic peak currents of 3,4 dihydroxyphenylacetic acid obtained by differential pulse voltammetry are linear with the logarithm of melamine concentrations in the range from 1.0 x 10(-8) to 5.0 x 10(-6) M with a linear coefficiency of 0.997. The detection limit is 3.0 x 10(-9) M. The proposed method displayed an excellent sensitivity and was successfully applied to the determination of melamine in milk products. PMID- 20708113 TI - Flower-like tungsten oxide particles: synthesis, characterization and dimethyl methylphosphonate sensing properties. AB - Flower-like WO(3) particles with high specific surface area were synthesized via a template/surfactant-free way. Scanning and transmission microscopies and X-ray diffraction were applied to investigate the formation mechanism of the morphology. Gas sensing characterization showed an enhanced sensitivity (70 Hz/ppm) to dimethyl methylphosphonate (DMMP) as compared with previously reported WO(3) nanoflakes (38 Hz/ppm) at a DMMP concentration of 4ppm. Cross-sensitivity results revealed that flower-like WO(3) still showed sound sensitivity in presence of interfering agents, which benefited from its intrinsic high sensitivity. The mechanism of DMMP adsorption on the flower-like WO(3) particle was studied by in situ diffuse reflectance infrared Fourier transform spectroscopy. PMID- 20708112 TI - A sensitive amperometric sensor for hydrazine and hydrogen peroxide based on palladium nanoparticles/onion-like mesoporous carbon vesicle. AB - Onion-like mesoporous carbon vesicle (MCV) with multilayer lamellar structure was synthesized by a simply aqueous emulsion co-assembly approach. Palladium (Pd) nanoparticles were deposited on the MCV matrix (Pd/MCV) by chemical reduction of H(2)PdCl(4) with NaBH(4) in aqueous media. Pd(X)/MCV (X wt.% indicates the Pd loading amount) nanocomposites with different Pd loading amount were obtained by adjusting the ratio of precursors. The particular structure of the MCV results in efficient mass transport and the onion-like layers of MCV allows for the obtainment of highly dispersed Pd nanoparticles. The introduction of Pd nanoparticles on the MCV matrix facilitates hydrazine oxidation at more negative potential and delivers higher oxidation current in comparison with MCV. A linear range from 2.0 x 10(-8) to 7.1 x 10(-5) M and a low detection limit of 14.9 nM for hydrazine are obtained at Pd(25)/MCV nanocomposite modified glassy carbon (GC) electrode. A nonenzymatic amperometric sensor for hydrogen peroxide based on the Pd(25)/MCV nanocomposite modified GC electrode is also developed. Compared with MCV modified GC electrode, the Pd(25)/MCV nanocomposite modified GC electrode displays enhanced amperometric responses towards hydrogen peroxide and gives a linear range from 1.0 x 10(-7) to 6.1 x 10(-3) M. The Pd(25)/MCV nanocomposite modified GC electrode achieves 95% of the steady-current for hydrogen peroxide within 1s. The combination of the unique properties of Pd nanoparticles and the porous mesostructure of MCV matrix guarantees the improved analytical performance for hydrazine and hydrogen peroxide. PMID- 20708114 TI - Microtiterplate phosphate assay based on luminescence quenching of a terbium complex amenable to decay time detection. AB - We describe a terbium-ligand complex (TbL) for a microtiterplate assay for phosphate (P) in the 0.3-100 micromol L(-1) range based on luminescence quenching. As the pH optimum is at neutral pH (7.4) the probe is quenched by both, primary (H(2)PO(4)(-)) and secondary phosphate (HPO(4)(2-)). The LOD is 110 nmol L(-1). A Stern-Volmer study revealed that quenching is mostly static. Due to the ms-decay time of TbL, the first luminescence lifetime assay for phosphate could also be developed. The lifetime-based calibration plot is linear between 0.5 and 5 micromol L(-1) of P. The effect of various surfactants on assay performance and a study on interferents are presented. The probe was successfully applied to determination of P in commercial plant fertilizers and validated against the molybdenum blue test. The probe is the most sensitive lanthanide based probe for phosphate. PMID- 20708116 TI - Imprinted sol-gel materials for monitoring degradation products in automotive oils by shear transverse wave. AB - Titania sol-gel layers imprinted with capric acid have been used as synthetic receptors for highly sensitive detection of oxidized products resulting from degradation of automotive engine oil. These layers have been applied as sensitive coating material on shear transverse wave (STW) resonators of frequencies ranging from 100 MHz to 430 MHz. A relatively small size of STW resonators, i.e. about 2 mm for 430 MHz makes these devices extremely useful while considering the concept of miniaturization. It has been proved experimentally that by increasing fundamental resonance frequency of these devices, a very high sensor response i.e. 22 kHz up to 460 kHz can be generated. The geometry of long chain capric acid fits best as recognition element in the synthesis of imprinted TiO(2) network. The thin titania layers coated on transducer surface provide excellent diffusion pathways to oxidized products of waste engine oil for selective and reversible re-inclusion i.e. recovery time of 30 min. Viscosity effects of oxidized engine oil can be minimized by shear waves which do not dissipate considerable amount of energy that ensure smooth liquid phase operation. Different oxidized products i.e. carbonic acids and esters can be characterized in lubricant via infra-red (IR) spectroscopy. The increasing IR absorbance of different waste oil samples is a clear indication of increasing concentration of carbonyl group. The IR absorbance of carbonyl groups is directly correlated to the age of respective waste engine oil samples and a quantitative relationship between sensor responses from STWs and IR absorbance was also developed. PMID- 20708115 TI - Enhancement in fluorescence response by a quencher for amiloride upon binding to thymine opposite an abasic site in a DNA duplex. AB - By using iodide (I(-)) as a quencher, we successfully improve the fluorescence response of amiloride when binding to thymine opposite an AP site in a 21-meric DNA duplex. From fluorescence measurements, as compared to the NaCl solutions, the addition of NaI as a quencher as well as salt to adjust the ionic strength effectively suppresses the background fluorescence from unbound amiloride in a solution. The Stern-Volmer analysis shows that the bound amiloride to the nucleobase at the AP site is unexposed to NaI quencher. Therefore the high signal to-background fluorescence response of amiloride is obtained. Such enhancement in fluorescence response of amiloride by using the quencher can provide the significant improvement of the detection limit for DNA duplexes carrying T target base. The method presented in this study is simple and effective. The present method could be applicable to other detection system where microenvironment of fluorophores changes at a recognition event. PMID- 20708118 TI - Preparation of chlorogenic acid surface-imprinted magnetic nanoparticles and their usage in separation of traditional Chinese medicine. AB - The chlorogenic acid (CGA) surface-imprinted magnetic polymer nanoparticles have been prepared via water-in-oil-in-water multiple emulsions suspension polymerization. This kind of molecularly imprinted polymer nanoparticles (MIPs) had the core-shell structure with the size of about 50 nm. Magnetic susceptibility was given by the successful encapsulation of Fe(3)O(4) nanoparticles with a high encapsulation efficiency of 19.3 wt%. MIPs showed an excellent recognition and selection properties for the imprinted molecule CGA. The recognition capacity of MIPs was near three times than that of non-imprinted polymer nanoparticles (NIPs). Compared with the competitive molecule caffeic acid (CFA), the selectivity of MIPs for CGA was 6.06 times as high as that of NIPs. MIPs could be reused and regenerated, and their rebinding amount in the fifth use was up to 78.85% of that in the first use. The MIPs prepared were successfully applied to the separation of CGA from the extract of Traditional Chinese Medicine Honeysuckle. PMID- 20708117 TI - Construction of a simple optical sensor based on air stable lipid film with incorporated urease for the rapid detection of urea in milk. AB - This work describes the construction of a simple optical sensor for the rapid, selective and sensitive detection of urea in milk using air stable lipid films with incorporated urease. The lipid film is stabilized on a glass filter by polymerization using UV (ultra-violet) radiation prior its use. Methacrylic acid was the functional monomer, ethylene glycol dimethacrylate was the crosslinker and 2,2'-azobis-(2-methylpropionitrile) was the initiator. Urease is incorporated within this mixture prior to the polymerization. The presence of the enzyme in these films quenched this fluorescence and the colour became similar to that of the filters without the lipid films. A drop of aqueous solution of urea provided a "switching on" of the fluorescence which allows the rapid detection of this compound at the levels of 10(-8) M concentrations. The investigation of the effect of potent interferences included a wide range of compounds usually found in foods and also of proteins and lipids. These lipid membranes were used for the rapid detection of urea in milk. PMID- 20708119 TI - Complementary chromatography separation combined with hydride generation inductively coupled plasma mass spectrometry for arsenic speciation in human urine. AB - This study aimed to establish complementary high performance liquid chromatography (HPLC) methods including three modes of separation: ion pairing, cation exchange, and anion exchange chromatography, with detection by inductively coupled plasma mass spectrometry (ICPMS). The ion pairing mode enabled the separation of inorganic arsenate (As(V)), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)). However, the ion pair mode was unable to differentiate inorganic arsenite (As(III)) from arsenobetaine (AsB); instead, cation exchange chromatography was used to isolate and quantify AsB. Anion exchange chromatography was able to speciate all of the aforementioned arsenic species. Potential inaccurate quantification problem with urine sample containing elevated concentration of AsB, which eluted immediately after As(III) in anion exchange or ion pairing mode, was overcame by introducing a post-column hydride generation (HG) derivatization step. Incorporating HG between HPLC and ICPMS improved sensitivity and specificity by differentiating AsB from hydride-forming arsenic species. This paper emphasizes the usefulness of complementary chromatographic separations in combination with HG-ICPMS to quantitatively determine concentrations of As(III), DMA(V), MMA(V), As(V), and AsB in the sub microgram per liter range in human urine. PMID- 20708120 TI - High-performance liquid chromatography with post-column 2,2'-diphenyl-1 picrylhydrazyl radical scavenging assay: methodological considerations and application to complex samples. AB - An improved post-column 2,2'-diphenyl-1-picrylhydrazyl (DPPH*) radical scavenging assay for the screening of antioxidants in complex matrices was developed. Experimental parameters believed to be influential to DPPH* response were studied in a univariate approach. Optimum conditions were found to be: 5 x 10(-5) M DPPH* reagent prepared in a 75% methanol: 25% 40 mM citric acid-sodium citrate buffer (pH 6) solution, degassed with nitrogen; reaction coil of 2 m x 0.25 mm i.d. PEEK tubing; detection at 521 nm; analysis at room temperature. The analytical utility of this protocol was evaluated by screening for antioxidants in thyme and green tea, in comparison with two commonly employed methodologies. PMID- 20708121 TI - Application of a validated stability-indicating chromatographic method to evaluate the reproducibility between batches of small peptides in solution. AB - A stability-indicating reversed-phase high-performance liquid chromatographic method was developed and validated as per the International Conference on Harmonization (ICH) guidelines to evaluate the reproducibility of batches of synthetic peptides included in a stability program, in particular cholecystokinin (CCK-4) peptide. Both isothermal and nonisothermal approaches were used to determine stability under experimental conditions and the resulting degradation products were identified by liquid chromatography-mass spectrometry (LC-MS). The principal degradation product was the cyclic dimer, although another two products derived from it were also detected, due to the loss of one or two Phe-NH(2) residues. The dimerization follows first-order kinetics, whereas the hydrolytic cleavage implies both consecutive and in-parallel processes. The linear Arrhenius plot indicates that the degradation mechanism and kinetics do not change with temperature or the batch, but the degradation rate does depend on the batch, for example, the shelf-life at 25 degrees C was 2.54 days for batch 3, which is 13 times lower than batch 2. This variability is caused by a change in the synthesis process introduced by the manufacturer. The combination of these two elements: the analytical and stability-evaluating methods provide enough data to establish a stability-indicating profile, as required by the guideline ICH-Q6B for biotechnological/biological products. PMID- 20708122 TI - Preparation of a reference mussel tissue material for polycyclic aromatic hydrocarbons and trace metals determination. AB - Due to high cost of certified reference materials (CRMs), reference materials (RMs) are preferred to check the method performance in environmental analysis. In this work, a laboratory reference material (LRM) was prepared and characterised to carry out the quality control in monitoring analysis of eight polycyclic aromatic hydrocarbons (PAHs) and nine trace metals in mussel tissue. Mussels were collected in a naturally polluted area. Before the reference material was bottled, the mussel tissue was stabilised by freeze-drying, ground and sieved. For the material characterisation, several statistical tests were applied to check the homogeneity of the analytes in the tissue, and a stability test was performed to study the effect of the storage temperature in the analyte concentration. Other characteristics such as specific density, moisture and lipid contents as well as particle size distribution of the material were determined. Although the LRM had a homogeneous distribution for all PAHs and almost all metals, the stability study showed different results at both storage temperatures studied. For both PAHs and trace metals, the material was suitable to assure the quality control of the analysis. PMID- 20708123 TI - Evaluation of four rapid tests for diagnosis and differentiation of HIV-1 and HIV 2 infections in Guinea-Conakry, West Africa. AB - With both HIV-1 and HV-2 prevalent in Guinea-Conakry, accurate diagnosis and differentiation is crucial for treatment purposes. Thus, four rapid HIV tests were evaluated for their HIV-1 and HIV-2 diagnostic and discriminative capacity for use in Guinea-Conakry. These included SD Bioline HIV 1/2 3.0 (Standard Diagnostics Inc.), Genie II HIV1/HIV2 (Bio-Rad), First Response HIV Card Test 1 2.0 (PMC Medical) and Immunoflow HIV1-HIV2 (Core Diagnostics). Results were compared with gold standard tests (INNO-LIA HIV-I/II Score) and NEW LAV BLOT II (Bio-Rad). Four hundred and forty three sequential stored HIV-positive serum samples, of known HIV-type, were evaluated. Genie II HIV1/HIV2, Immunoflow HIV1 HIV2 and SD Bioline HIV 1/2 3.0 had 100% sensitivity (95% CI, 98.9-100%) while for First Response HIV Card Test 1-2.0 this was 99.5% (95% CI, 98.2%-99.9%). In terms of discriminatory capacity, Genie II HIV1/HIV2 identified 382/ 384(99.5%) HIV-1 samples, 49/ 52(95%) HIV-2 and 7/7(100%) HIV-positive untypable samples. Immunoflow HIV1-HIV2 identified 99% HIV-1, 67% HIV-2 and all HIV-positive untypable samples. First Response HIV Card Test 1-2.0 identified 94% HIV-1, 64% HIV-2 and 57% HIV-positive untypable samples. SD-Bioline HIV 1/2 3.0 was the worst overall performer identifying 65% HIV-1, 69% HIV-2 and all HIV-positive untypable samples. The use of SD Bioline HIV 1/2 3.0 (the current standard in Guinea-Conakry) as a discriminatory HIV test is poor and may be best replaced by Immunoflow HIV1-HIV2. PMID- 20708124 TI - Snake bite envenomation in Ecuador. AB - The aim of this study was to evaluate the burden of snake bite in Ecuador and to identify the difficulties of snake bite management in Ecuadorian health facilities. A survey based on national health statistics was carried out in Ecuador to estimate the overall incidence and mortality due to snake bites. During the period 1998-2007, the average annual incidence and mortality was respectively 11 and 0.5 per 100 000 inhabitants. The at-risk population was represented mainly by males aged 10-54 years. Snake bite incidence increased during the rainy season and El Nino. According to one data source, the majority of snake bites occurred in the coastal region (56%) compared with the Amazonian rainforest (11%) and the highlands (33%). This geographical variation in snake bite incidence may reflect the distribution of venomous snakes and human population densities and activities. This preliminary national survey on the incidence of the envenomings due to snake bite in Ecuador showed a stable incidence over the time period studied but was heterogeneous in the three geographical regions of Ecuador. The incidence and mortality were higher in the lowland humid regions where Bothrops species are abundant. PMID- 20708125 TI - Monitoring of poliovirus neutralizing antibodies in Sao Paulo State, Brazil. AB - As the world envisions poliomyelitis eradication, objective parameters are needed to ascertain whether immunocompetence against the virus provided by vaccine campaigns has been attained. The presence of neutralizing antibodies is considered a surrogate marker of protective immune response to the agent. Neutralization of three poliovirus serotypes were evaluated in a total of 411 sera samples collected from 1999 to 2005 in Sao Paulo State, Brazil. Antibody titres >/=1:8 were presented at 88.1% (362/411), 88.8% (365/411) and 61.6% (253/411) of samples for 1, 2 and 3 serotypes, respectively. Evaluation of poliovirus immune status may be a useful tool to support decisions concerning polio vaccine policy. PMID- 20708127 TI - Derivation of cat embryonic stem-like cells from in vitro-produced blastocysts on homologous and heterologous feeder cells. AB - The domestic cat is a focal mammalian species that is used as a model for developing assisted reproductive technologies for preserving endangered cats and for studying human diseases. The generation of stable characterized cat embryonic stem cells (ESC) lines to use as donor nuclei may help to improve the efficiency of interspecies somatic cell nuclear transfer for preserving endangered cats and allow the creation of knockout cell lines to generate knockout cats for studying function of specific genes related to human diseases. It will also enable the possibility of producing gametes in vitro from ESC of endangered cats. In the present study, we report the generation of cat embryonic stem-like (cESL) cells from blastocysts derived entirely in vitro. We generated 32 cESL cell lines from 331 in vitro derived blastocysts from which inner cell masses were isolated by immunosurgery or by a mechanical method. Inhibition of cat dermal fibroblast (CDF) proliferation after exposure to mitomycin-C was both dose and time dependent, where doses of 30 to 40 microg/mL for 5 h were most efficient. These dosages were higher than that required to inhibit cell proliferation of mouse fetal fibroblasts (MFF; 10 microg/mL for 2.5 h). Mitomycin-C did not significantly increase necrosis of cells from either species, and had an anti proliferative effect at concentrations below cytotoxicity. A clear species specific relationship between feeder layers and derivation of cESL cell lines was observed, where higher numbers of cESL cell lines were generated on homologous cat feeder layers (n = 26) than from those derived on heterologous mouse feeder layers (n = 6). Three cESL cell lines generated from immunosurgery and cultured on CDF maintained self-renewal and were morphologically undifferentiated for nine and twelve passages (69-102 days). These lines showed a tightly packed dome shaped morphology, exhibited alkaline phosphatase activity and immuno-expression of the pluripotent marker OCT-4 and surface marker SSEA-1. Primary colonies at P0 to P3 and cat blastocysts expressed transcription factors OCT-4, NANOG and SOX-2 and the proto-oncogene C-MYC. However, expression was at levels significantly lower than in vitro produced blastocysts. During culture, cESL colonies spontaneously differentiated into fibroblasts, cardiomyocytes, and embryoid bodies. Development of techniques to prevent differentiation of cESL cells will be essential for maintaining defined cell lines. PMID- 20708128 TI - A review of malpractice cases after tonsillectomy and adenoidectomy. AB - OBJECTIVE: To examine sources of litigation following tonsillectomy and/or adenoidectomy. STUDY DESIGN: Analysis of malpractice claims filed after tonsillectomy or adenoidectomy provided by 16 medical liability insurance companies. SETTING: Not applicable. SUBJECTS AND METHODS: Data was obtained from 16 members of the Physician Insurers Association of America. All claims were either filed or closed between 1985 and 2006. Claims were evaluated and categorized according to the type of complication. RESULTS: One hundred and fifty four claims were identified between 1985 and 2006. Six categories were created based on frequency of claims (bleeding complication n=27 [17.5%], airway fire n=2 [1.5%], burns n=28 [18.2%], consent related n=9 [5.8%], medication related n=9 [5.8%] and residual tissue/recurrence n=9 [5.8%]). Other less frequent claims were grouped as miscellaneous n=70 [45.5%]. CONCLUSIONS: A significant portion of malpractice claims following tonsillectomy or adenoidectomy are related to complications not commonly discussed in the literature. PMID- 20708130 TI - Is it necessary to accompany probing with endoscopy in cases of congenital nasolacrimal canal obstruction? AB - OBJECTIVE: To compare the results of probing with and without endoscopy in cases of congenital nasolacrimal duct obstruction who had previously not undergone probing. METHODS: Fifty-one children with congenital nasolacrimal duct obstruction who underwent surgical intervention between June 2007 and April 2009 in our hospital were included in the study. Patients who had had previous probings were excluded from the study. Conventional probing was performed in 37 eyes of 25 patients, and probing with intranasal endoscopic visualization in 36 eyes of 26 patients. Diagnosis was based on history of epiphora since birth or shortly after, and fluorescein dye disappearance test. RESULTS: Thirty-two of 37 eyes (86.48%) were cured by probing. Of the 5 cases with complaints, 1 had lacrimal sac fistula. Thirty-four of 36 eyes (94.44%) were cured by probing guided by endoscope observation. Thirty-two cases had stenosis at the lower end of the nasolacrimal duct which required probing. In two cases the probe passed submucosally to the floor of the nose. In two cases a false passage was made at the upper end of the inferior meatus. In these cases, the operation was continued by repeating the process until the distal end of the nasolacrimal canal was seen to have been passed. CONCLUSION: Probing with endoscopy may be excessive in primary cases but in cases which have undergone unsuccessful probing, it is useful for visualization of anomalies in the lower nasolacrimal canal and to obtain the correct anatomic position for the probe. PMID- 20708129 TI - Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of c.35delG and p.M34T mutations in the GJB2 gene among children with early onset hearing loss and within a general population of Estonia. METHODS: Using an arrayed primer extension assay, we screened 233 probands with early childhood onset hearing loss for 107 different mutations in the GJB2 gene. We then looked for the two most common mutations, c.35delG and p.M34T, in a population of 998 consecutively born Estonian neonates to determine the frequency of these mutations in the general population. RESULTS: In 115 (49%) of the patients with early onset hearing loss, we found a mutation in at least one allele of the GJB2 gene. Seventy-three (31%) were homozygous for the c.35delG mutation, seven (3%) were homozygous for the p.M34T mutation, and five (2%) had c35delG/p.M34T compound heterozygosity. Other six identified mutations in GJB2 gene occurred rarely. Among the 998 anonymous newborn samples, we detected 45 who were heterozygous for c.35delG, 2 individuals homozygous for c.35delG, and 58 who were heterozygous for p.M34T. Additionally, we detected two c.35delG/p.M34T compound heterozygotes. CONCLUSION: The most common GJB2 gene mutations in Estonian children with early onset hearing loss were c.35delG and p.M34T, with c.35delG accounting for 75% of GJB2 alleles. The carrier frequency for c.35delG and p.M34T in a general population of Estonia was 1 in 22 and 1 in 17, respectively, and was higher than in most other countries. PMID- 20708131 TI - Serial intralesional steroid injection combined with balloon dilation as an alternative to open repair of subglottic stenosis. AB - This article will describe successful use of serial balloon dilations and steroid injections to help a child with acute SGS avoid tracheotomy or major reconstructive procedures. An 11-month infant presented with subglottic ulcerations that developed after intubation for acute laryngotracheitis. Over the next 4 months, the child developed SGS, requiring three balloon dilations consisting of triamcinalone injection into the scar tissue followed by outpatient balloon dilation without intraoperative intubation. Twelve months after initial presentation and 8 months follow-up from the third and final dilation, the patient is thriving. This report illustrates the potential safety and efficacy of serial intralesional steroids combined with balloon dilation as an alternative to more invasive treatments. The technique is novel in the number of attempts at balloon dilation, highlighting that serial dilations can succeed after initial failure. Issues for further investigation include optimal timing and number of dilations. PMID- 20708132 TI - Healing the wounds: 2010 National EMS Memorial Service. PMID- 20708133 TI - Better standardization. PMID- 20708134 TI - Miracle or luxury? PMID- 20708135 TI - Pain protocols. PMID- 20708136 TI - Miracle or luxury? PMID- 20708137 TI - 'S' is for ... Implement these seven 's' components to transform your agency. PMID- 20708138 TI - Leading the pack: correctly interpreting ECG data. PMID- 20708139 TI - 'We've got ya': getting people past their fear. PMID- 20708140 TI - Toxic temptations: treating pediatric patients with hydrocarbon poisoning. PMID- 20708141 TI - The trauma "A" team: advanced trauma life support training enhances ED & hospital trauma decisions and care. PMID- 20708142 TI - Pay back time: health-care reform to boost transport reimbursements. PMID- 20708143 TI - Alternate route: the humerus bone - a viable option for IO access. PMID- 20708144 TI - On the same page: making transitions between EMS & urgent care centers smooth. AB - Medic 25 is called to a local urgent care center to a chief complaint of a possible heart attack at 8:45 p.m. On their way there, one of the medics tells his partner they've been getting multiple calls to this facility at about the same time each evening, so they can "unload" their patients before it closes at 9 p.m. He says it's usually for minor complaints and seems to be more for the convenience of the urgent care center staff than for any true emergencies. PMID- 20708145 TI - Lethal detonation: responding to scenes involving blast injuries. PMID- 20708146 TI - Playing ball: nothin' soft about it. PMID- 20708147 TI - [Homebirths' safety: data, interpretation, and unanswered questions... but for who?]. PMID- 20708148 TI - Mediterranean diet and coronary heart disease: is obesity a link? - A systematic review. AB - AIMS: Adherence to a healthy dietary pattern, such as the Mediterranean diet, exerts a beneficial role regarding the development of coronary heart disease. In addition, several studies support the protective role of the Mediterranean diet as far as obesity is concerned. This review, examining results from prospective cohort and cross-sectional studies, as well as clinical trials, aims to clarify whether the beneficial effect of the Mediterranean dietary pattern on coronary heart disease is due to the impact of this diet on weight loss and obesity status or an independent effect. DATA SYNTHESIS: 35 original-research studies that were published in English until 2009, selected through a computer-assisted literature search are discussed, from which 3 were prospective, 11 were cross-sectional studies, and 21 were clinical trials. CONCLUSION: Although not all studies show a protective effect of the Mediterranean diet on body weight and obesity, the evidence suggests a possible beneficial role of this dietary pattern. Thus the Mediterranean diet protects against the development of coronary heart disease not only because of its beneficial role regarding cardiovascular risk factors, but also due to a possible effect on body weight and obesity. PMID- 20708149 TI - A centrosome kinase modulates antitumor drug sensitivity. AB - In this issue of Cancer Cell, Ahmed and coworkers identify SIK2 as a centrosome kinase and show that it controls the localization of the centriole linker protein C-Nap1. Interference with SIK2 function results in loss of normal mitotic spindle function and increased sensitivity to antitumor drugs. PMID- 20708150 TI - Her 2 in 1. AB - In this issue of Cancer Cell, Park et al. demonstrate that anti-erbB2 antibody primes adaptive immunity for increased tumor clearance and suggest that chemotherapy may in fact interfere with this process. PMID- 20708153 TI - SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. AB - Regulators of mitosis have been successfully targeted to enhance response to taxane chemotherapy. Here, we show that the salt inducible kinase 2 (SIK2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation. Interference with the known SIK2 inhibitor PKA induced SIK2-dependent centrosome splitting in interphase while SIK2 depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers. We believe these data identify SIK2 as a plausible target for therapy in ovarian cancers. PMID- 20708154 TI - Che-1 promotes tumor cell survival by sustaining mutant p53 transcription and inhibiting DNA damage response activation. AB - Che-1 is a RNA polymerase II binding protein involved in the regulation of gene transcription and, in response to DNA damage, promotes p53 transcription. In this study, we investigated whether Che-1 regulates mutant p53 expression. We found that Che-1 is required for sustaining mutant p53 expression in several cancer cell lines, and that Che-1 depletion by siRNA induces apoptosis both in vitro and in vivo. Notably, loss of Che-1 activates DNA damage checkpoint response and induces transactivation of p73. Therefore, these findings underline the important role that Che-1 has in survival of cells expressing mutant p53. PMID- 20708155 TI - Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. AB - Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. We demonstrate that intestinal epithelial cell specific expression of oncogenic K-ras(G12D) in mice induces serrated hyperplasia, which is characterized by p16(ink4a) overexpression and induction of senescence. Deletion of Ink4a/Arf in K-ras(G12D) expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras represents a key player during an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development. PMID- 20708156 TI - Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. AB - Mdm2 is the major negative regulator of the p53 pathway. Here, we report that Mdm2 is rapidly degraded after DNA damage and that phosphorylation of Mdm2 by casein kinase I (CKI) at multiple sites triggers its interaction with, and subsequent ubiquitination and destruction, by SCF(beta-TRCP). Inactivation of either beta-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCF(beta-TRCP)-dependent Mdm2 turnover also contributes to the control of repeated p53 pulses in response to persistent DNA damage. Our results provide insight into the signaling pathways controlling Mdm2 destruction and further suggest that compromised regulation of Mdm2 results in attenuated p53 activity, thereby facilitating tumor progression. PMID- 20708157 TI - The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. AB - Anti-HER2/neu antibody therapy is reported to mediate tumor regression by interrupting oncogenic signals and/or inducing FcR-mediated cytotoxicity. Here, we demonstrate that the mechanisms of tumor regression by this therapy also require the adaptive immune response. Activation of innate immunity and T cells, initiated by antibody treatment, was necessary. Intriguingly, the addition of chemotherapeutic drugs, although capable of enhancing the reduction of tumor burden, could abrogate antibody-initiated immunity leading to decreased resistance to rechallenge or earlier relapse. Increased influx of both innate and adaptive immune cells into the tumor microenvironment by a selected immunotherapy further enhanced subsequent antibody-induced immunity, leading to increased tumor eradication and resistance to rechallenge. This study proposes a model and strategy for anti-HER2/neu antibody-mediated tumor clearance. PMID- 20708158 TI - Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage. AB - Two vascular growth factor families, VEGF and the angiopoietins, play critical and coordinate roles in tumor progression and metastasis. A single inhibitor targeting both VEGF and angiopoietins is not available. Here, we developed a chimeric decoy receptor, namely double anti-angiogenic protein (DAAP), which can simultaneously bind VEGF-A and angiopoietins, blocking their actions. Compared to VEGF-Trap or Tie2-Fc, which block either VEGF-A or angiopoietins alone, we believe DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumors; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage. PMID- 20708160 TI - Polycystic ovary syndrome: challenges in adolescence. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age. PCOS typically develops during adolescence and is a heterogeneous syndrome classically characterized by features of anovulation combined with signs of androgen excess (hirsutism, acne). Increasing obesity in adolescents probably exacerbates signs of PCOS, contributing to its earlier recognition. Recognizing the features of this syndrome can be very challenging in adolescence. Although adolescents' concerns are often cosmetic, if left untreated these girls are at risk for diabetes, metabolic syndrome, and infertility as they mature. Efforts should be made to diagnose and treat PCOS to minimize the development of symptoms and prevent the onset of cardiovascular and metabolic disturbances. PMID- 20708162 TI - Keeping Simon simple: examining the relationship between sequential modulations and feature repetitions with two stimuli, two locations and two responses. AB - The present study examined performance across three two-choice tasks that used the same two stimuli, the same two stimulus locations, and the same two responses to determine how task demands can alter the Simon Effect, its distribution across reaction time, and its sequential modulation. In two of the tasks, repetitions of stimulus features were not confounded with sequences of congruent and incongruent trials. This attribute allowed us to investigate the sequential modulation of the Simon Effect in a two-choice task while equalizing the occurrence of feature repetitions. All tasks showed a similar sequential modulation, suggesting that it is not driven by feature repetitions. Moreover, distributional analyses revealed that the advantage for congruent trials decreased as reaction time increased similarly following congruent and incongruent trials. Finally, a large increase in RT was observed when repeated responses were made to novel stimuli and when novel responses were made to repeated stimuli. This effect also showed a sequential modulation regardless of whether the stimulus repeated. The findings suggest that, even in two-choice tasks, response selection is mediated by complex, dynamic representations that encode abstract properties of the task rather than just simple features. PMID- 20708159 TI - Regulation of tumor angiogenesis by EZH2. AB - Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach. PMID- 20708163 TI - Dendrimer templated construction of silver nanoparticles. AB - Silver nanoparticles continue to evoke great current interest due to their tremendous potential in designing smart materials for a wide variety of applications. Much emphasis has been placed lately in developing methodologies that could modulate the size and shape of these metal particles. Dendrimers that are monodisperse in nature with a regular and highly branched three-dimensional architecture, provide a useful platform to accomplish this goal. These hyperbranched macromolecules have been widely explored as templates in the construction of silver metal nanoparticles, and this review aims to provide a detailed overview of dendrimer-assisted synthesis of silver nanoparticles. PMID- 20708164 TI - Weight gain prevention interventions in obese pregnant women. PMID- 20708165 TI - Partial contributions of developmental hypoxia and undernutrition to prenatal alterations in somatic growth and cardiovascular structure and function. AB - OBJECTIVE: The objective of the study was to compare and contrast the effects of developmental hypoxia vs undernutrition on fetal growth, cardiovascular morphology, and function. STUDY DESIGN: On day 15 of gestation, Wistar dams were divided into control, hypoxic (10% O(2)), or undernourished (35% reduction in food intake) pregnancy. On day 20, fetal thoraces were fixed, and the fetal heart and aorta underwent quantitative histological analysis. In a separate group, fetal aortic vascular reactivity was determined via wire myography. RESULTS: Both hypoxic and undernourished pregnancy was associated with asymmetric fetal growth restriction. Pregnancy complicated by hypoxia promoted fetal aortic thickening without changes in cardiac volumes when expressed as a percentage of total heart volume. In contrast, maternal undernutrition affected fetal cardiac morphology without changes in aortic structure. Fetal aortic vascular reactivity was also differentially affected by hypoxia or undernutrition. CONCLUSION: Developmental hypoxia or undernutrition in late gestation has differential effects on fetal cardiovascular morphology and function. PMID- 20708166 TI - Contemporary cesarean delivery practice in the United States. AB - OBJECTIVE: To describe contemporary cesarean delivery practice in the United States. STUDY DESIGN: Consortium on Safe Labor collected detailed labor and delivery information from 228,668 electronic medical records from 19 hospitals across the United States, 2002-2008. RESULTS: The overall cesarean delivery rate was 30.5%. The 31.2% of nulliparous women were delivered by cesarean section. Prelabor repeat cesarean delivery due to a previous uterine scar contributed 30.9% of all cesarean sections. The 28.8% of women with a uterine scar had a trial of labor and the success rate was 57.1%. The 43.8% women attempting vaginal delivery had induction. Half of cesarean for dystocia in induced labor were performed before 6 cm of cervical dilation. CONCLUSION: To decrease cesarean delivery rate in the United States, reducing primary cesarean delivery is the key. Increasing vaginal birth after previous cesarean rate is urgently needed. Cesarean section for dystocia should be avoided before the active phase is established, particularly in nulliparous women and in induced labor. PMID- 20708167 TI - Preimplantation factor promotes first trimester trophoblast invasion. AB - OBJECTIVE: Preimplantation factor is a novel embryo-derived peptide that influences key processes in early pregnancy implantation, including immunity, adhesion, remodeling, and apoptosis. Herein, we explore the effects of synthetic preimplantation factor on trophoblast invasion. STUDY DESIGN: Invasion patterns of immortalized cultured HTR-8 trophoblast cells were analyzed through Matrigel extracellular matrix +/- synthetic preimplantation factor (25-100 nM) in a transwell assay. Effects were compared with epidermal growth factor 10 MUg/mL, scrambled aminoacid sequence of preimplantation factor, or media alone as controls. RESULTS: Synthetic preimplantation factor enhances trophoblast invasion at physiologic doses (at 50 nM, 260%; 95% confidence interval [CI], 174-346%; P = .05; 100 nM ,178%; 95% CI, 170-184%; P < .02), compared with scrambled amnioacid sequence preimplantation factor or control media. Epidermal growth factor added to synthetic preimplantation factor does not further enhance trophoblast invasion (synthetic preimplantation factor 50 nM + epidermal growth factor, 238%; 95% CI, 237-239%; P < .03; synthetic preimplantation factor 100 nM + epidermal growth factor 269%; 95% CI, 265-273%; P < .04). CONCLUSION: Preimplantation factor should be further investigated as it shows a potential preventative or therapeutic role for pregnancy complications associated with inadequate trophoblast invasion. PMID- 20708170 TI - Quadricuspid morphology of the aortic valve. AB - Quadricuspid aortic valve is a rare congenital heart defect. It may be isolated or associated to other cardiac anomalies. It may cause aortic valve dysfunction, commonly aortic regurgitation. Management of patients with quadricuspid aortic valve is represented by strict follow-up, because they may require aortic valve replacement in later life. We report the case of a 37-year old male patient, occasionally diagnosed to have quadricuspid aortic valve. Diagnosis and management are discussed. PMID- 20708169 TI - Does midtrimester cervical length >=25 mm predict preterm birth in high-risk women? AB - OBJECTIVE: We sought to assess pregnancy outcome along a continuum of cervical lengths (CLs) >=25 mm. STUDY DESIGN: We conducted planned secondary analysis of a randomized cerclage trial of women with prior spontaneous preterm birth 17(0) 34(6/7) weeks. Outcomes of women who maintained CLs >=25 mm were analyzed. Women with CLs <25 mm randomized to no cerclage comprised an internal comparison group. RESULTS: Of 1014 screened, 153 had CL <25 mm, and 672 had CL >=25 mm. Birth <35 weeks occurred in 16% of the >=25 mm cohort. The relationship between CLs >=25 mm and birth gestational age was null (P = .15). In the <25 mm group, progressively shorter CLs predicted birth <35 weeks (P < .001); this relationship was null in the >=25 mm group (P = .17). CONCLUSION: The continuum of CLs >=25 mm measured between 16(0/7)-22(6/7) weeks does not predict gestational length in women with prior spontaneous preterm birth. PMID- 20708171 TI - [Drug-eluting stents: do we respect the on-label use in our daily practice?]. AB - Drug-eluting stents (DES) are known to dramatically reduce restenosis. However, they are more expansive than bare-metal stents (BMS) and they require prolonged dual antiplatelet therapy. In France, the French Society of Cardiology and the "Haute Autorite de sante" have defined recommendations for the use of DES (restricted to patients in high-risk group). The aim of this work was to evaluate our practice (whether these recommendations were well respected or not in our center). Between November 2007 and January 2008 then November 2008 and January 2009 we evaluated all Percutaneous Coronary Interventions (PCI). Two hundred and sixteen (216) patients (mean age 65 +/- 13 years, 164 (76 %) were males and, 41 (19 %) were diabetics) had a PCI for stable angina or silent ischemia (47 %), unstable angina or acute coronary syndrome (ACS) ST- (26 %), ACS ST+<48 hours (24 %) or ACS ST+>48 hours-1 month (3 %). Two hundred and seventy six (276) stents were used, including 35 % of DES. The recommendations were well respected in 82 % of cases. However, 27 % of BMS were implanted in patients in whom DES were indicated. The French recommendations for DES are a reference to help practitioners, but they require to be adapted to each patient, depending on clinical state and their ability to be treated with prolonged dual antiplatelet therapy. PMID- 20708172 TI - The role of the corpus callosum in transcranial magnetic stimulation induced interhemispheric signal propagation. AB - BACKGROUND: The corpus callosum, the main interhemispheric connection in the brain, may serve to preserve functional asymmetry between homologous cortical regions. METHODS: To test this hypothesis, 30 healthy adult subjects underwent combined transcranial magnetic stimulation (TMS)-electroencephalography procedures. Nineteen of these subjects also completed diffusion tensor imaging and tractography procedures. We examined the relationship between microstructural integrity of subdivisions of the corpus callosum with TMS-induced interhemispheric signal propagation. RESULTS: We found a significant inverse relationship between microstructural integrity of callosal motor fibers with TMS induced interhemispheric signal propagation from left to right motor cortex. We also found a significant inverse relationship between microstructural integrity of genu fibers of the corpus callosum and TMS-induced interhemispheric signal propagation from left to right dorsolateral prefrontal cortex (DLPFC). We then demonstrated neuroanatomic specificity of these relationships. CONCLUSIONS: Taken together, our findings suggest that TMS-induced interhemispheric signal propagation is transcallosally mediated and neuroanatomically specific and support a role for the corpus callosum in preservation of functional asymmetry between homologous cortical regions. Delineation of the relationship between corpus callosum microstructure and interhemispheric signal propagation in neuropsychiatric disorders, such as schizophrenia, may reveal novel mechanisms of pathophysiology. PMID- 20708173 TI - Synthesis of the monoterpenoid esters cypellocarpin C and cuniloside B and evidence for their widespread occurrence in Eucalyptus. AB - Short syntheses of cuniloside B and cypellocarpin C, (+)-(R)-oleuropeic acid containing carbohydrates, are reported. Also disclosed are syntheses of the noreugenin glycosides, undulatoside A and corymbosins K(1) and K(2). Leaf extracts of 28 diverse eucalypts revealed cuniloside B to be present in all, and cypellocarpin C to be present in most, of the species examined. The widespread occurrence of these carbohydrate monoterpenoid esters supports their roles in essential oil biosynthesis or mobilization from sites of synthesis to secretory cavity lumena. PMID- 20708175 TI - Traumatic foot amputation in young children secondary to all-terrain vehicles: a case series. PMID- 20708174 TI - Poly(ethylene glycol)-carboxymethyl chitosan-based pH-responsive hydrogels: photo induced synthesis, characterization, swelling, and in vitro evaluation as potential drug carriers. AB - In this study, carboxymethyl chitosan was prepared, characterized, and then photo induced graft copolymerized with poly(ethylene glycol) under a nitrogen atmosphere in aqueous solution using 2,2-dimethoxy-2-phenyl acetophenone (DMPA) as the photo-initiator. The grafting copolymerization process was confirmed and the resulting copolymers were characterized using differential scanning calorimetry (DSC), FTIR spectroscopy, 2D-X ray diffraction, and elemental analysis. The kinetics of the grafting reactions was also studied. Under the applied experimental conditions, the optimum grafting values were obtained at: CMCs=0.2 g, PEGA=249 mM, DMPA=10.4 mM at a 2 h reaction time. Some of the resulting copolymers were selected and used in the presence of methylene bisacrylamide (MBA) as a crosslinking agent to develop pH-responsive hydrogel matrices. The swelling characteristics and the in vitro release profiles of 5 fluorouracil (5-FU), as a model drug, from the hydrogels were investigated. The results revealed that the hydrogel matrices developed in this study can be customized to act as good candidates in drug delivery systems. PMID- 20708177 TI - Improving quality and safety of maternity care. PMID- 20708178 TI - Leukocytosis as an initial sign of aggressive growth of granulocyte colony stimulating factor-producing cervical cancer. PMID- 20708179 TI - Acute abdomen due to vaginal impalement. PMID- 20708180 TI - Frequency of asthma as the cause of dyspnea in pregnancy. AB - OBJECTIVE: To estimate the prevalence of asthma among pregnant women with dyspnea. METHODS: Pregnant women referred for prenatal care visits who had complaints of dyspnea were included. All pregnant women were evaluated by a respiratory specialist. Spirometry was performed by a single trained physician. RESULTS: Asthma was diagnosed in 38.8% of participants. Dyspnea was diagnosed as being physiologic in 36.4% of cases, but 24.8% of cases were of probable asthma (spirometric values were within normal range but symptoms and signs were suggestive of asthma). Cough, wheezing, and post-exercise symptoms were significantly more prevalent in asthmatic and probable-asthmatic women than in women without asthma. CONCLUSION: Dyspnea in pregnancy can be physiologic, but when it is accompanied by other symptoms such as cough or wheezing it is likely to be caused by asthma. Because of the high prevalence of asthma during pregnancy, it seems logical to evaluate dyspnea via physical examination and response to bronchodilators. PMID- 20708181 TI - Pattern of hepatitis virus infection among pregnant women and their newborns at the Women's Health Center of Assiut University, Upper Egypt. AB - OBJECTIVE: To determine the prevalence, risk factors, and rate of vertical transmission of HBV and/or HCV infection among pregnant women in Upper Egypt, and assess the preventive efficacy of administering hepatitis B immunoglobulin and vaccine to newborns on their carrier status at 8 months. METHODS: Five hundred pregnant women were screened for HCV and HBV serum markers by enzyme-linked immunoassay. Those testing positive had their status confirmed by polymerase chain reaction and their levels of liver enzymes and interferon gamma were evaluated. The newborns of HBV-positive women received hepatitis B immunoglobulin and vaccine and were followed up to assess the rates of vertical transmission and carrier status among the newborns. RESULTS: Of the 500 pregnant women, 6.4% were HCV positive, 4.0% were HBV positive, and 1.0% were both. The vertical transmission rate was 3.1% for HCV, 30.0% for HBV, and 20.0% for a combined infection. The carrier rate of the infants at the end of their eighth month was 10.8% for those with HCV and 8% for those with HBV. CONCLUSION: Infection with HBV and/or HCV is highly prevalent among pregnant women in Upper Egypt. The rate of vertical transmission was also high. Administering hepatitis B vaccine and immunoglobulin resulted in a 92% reduction in carrier status among newborns. PMID- 20708182 TI - Partner, workplace, and stranger abuse during pregnancy in Germany. AB - OBJECTIVE: To investigate the prevalence, perpetrators, sociodemographic correlates, and health impacts of psychological, physical, and sexual abuse during pregnancy among women attending a maternity ward in Germany. METHODS: A written questionnaire was given to pregnant women in a maternity ward of a university hospital in Munich. Abuse during pregnancy was assessed using the Abuse Assessment Screen. RESULTS: Of 552 women, 401 completed the questionnaire for a response rate of 72.6%. The prevalence of psychological, physical, or sexual abuse during pregnancy by any perpetrator was 6.7% (n = 27); the main perpetrators were women's partners and work colleagues. After controlling for the effect of age, psychological, physical, or sexual abuse during pregnancy was significantly associated with a history of abuse, low education level of the woman and the father of her child, short relationship duration, unintended pregnancy, financial problems caused by the pregnancy, having more than 3 children, and insufficient social support. Women who reported abuse during pregnancy were significantly more likely to smoke and to have adverse maternal health outcomes. CONCLUSION: Psychological, physical, or sexual abuse during pregnancy was experienced by 1 in 15 women who attended a maternity ward in Munich and adversely affected maternal health outcomes. PMID- 20708183 TI - Urodynamic findings in women with pelvic organ prolapse and obstructive voiding symptoms. AB - OBJECTIVE: To determine whether obstructive voiding symptoms in women with advanced pelvic organ prolapse (POP) were associated with objective bladder outflow tract obstruction. METHODS: We reviewed preoperative data from patients with advanced POP who underwent surgical correction at the Department of Obstetrics and Gynecology, Carmel Medical Center, Haifa, Israel, between December 1, 2005, and November 30, 2007. Obstructive voiding symptoms were recorded from Pelvic Floor Distress Inventory-20 questionnaires. RESULTS: Of the 81 women aged 44-80 years who were included in the study, 40 (49.4%) reported incomplete bladder emptying preoperatively. There was no significant difference between these women and asymptomatic women in terms of demographic and clinical parameters such as age, parity, and stage of prolapse. Furthermore, there was no significant difference with regard to postvoid residual bladder volume (52.8 +/- 65.8 vs 41.6 +/- 41.2 mL), maximal (23.8 +/- 11 vs 21.9 +/- 9.6 mL/second) and average (10.3 +/- 6.2 vs 9.3 +/- 4 mL/second) urinary flow velocities, prevalence of increased postvoid residual volume (10.0% vs 4.8%), or obstructive urinary flow (17.5% vs 7.3%). CONCLUSION: Almost half of all women with advanced POP experienced incomplete bladder emptying; however, this symptom did not correlate with objective urodynamic bladder outflow tract obstruction. PMID- 20708184 TI - Adoption of HPV testing as an adjunct to conventional cytology in cervical cancer screening in Japan. AB - OBJECTIVE: To assess the effectiveness of including HPV testing as an adjunct to conventional cytology in cervical cancer screening. METHODS: Atypical epithelial cells (ATC) were classified according to the 2001 Bethesda classification system. The study ran for 6 years from May 2004 to November 2009 in conjunction with public cervical cancer screening for Kanazawa City residents. Patients with ATC (ASC-US, ASC-H, and AGC) underwent parallel testing for high-risk HPV types with the Hybrid Capture II system; HPV positive and cytology-ATC cases were recalled for colposcopic examination and biopsied if necessary. Results were compared with those obtained before HPV screening was initiated. RESULTS: A total of 62645 women underwent screening over the 6-year period; of these, 3622 (5.8%) were ATC positive, among whom 527 (14.5%) tested HPV-positive. These 527 women (0.8% of the screened population) were recalled for colposcopic examination. The resulting 426 biopsies were diagnosed as CIN 1 (n = 187), CIN 2 (n = 53), CIN 3 (n = 11), and invasive cervical cancer (n = 2). CONCLUSION: HPV testing as an adjunct to conventional cytology in cervical cancer screening seems to increase detection sensitivity with proven cost-effectiveness. PMID- 20708185 TI - Nursing staff attitudes of hip protector use in long-term care, and differences in characteristics between adherent and non-adherent residents: a survey and observational study. AB - BACKGROUND: Hip fractures represent an increasing public health burden with a simple fall to the floor as the most common cause. Because nursing home residents are particularly at risk, nursing homes should implement a broad range of fall prevention strategies. However, not all fall incidents can be avoided and external hip protectors may contribute to prevent hip fractures. A major problem in studying the effectiveness of hip protectors is residents' poor adherence. In nursing homes, adherence is dependent not only on the resident, but also on staff knowledge of and attitudes about hip protectors. OBJECTIVES: To describe (1) attitudes of day versus night shift caregivers towards the use of a soft hip protector, (2) residents' adherence about the use of such protectors, and (3) differences in characteristics between adherent and non-adherent residents. DESIGN: Survey and observational study. SETTING: Nursing home. PARTICIPANTS/METHODS: : Survey of care staff (n=37) in a nursing home after 8 months of continued application of a soft hip protector policy in residents (n=68). Adherence to wearing the hip protector, measured by weekly unannounced, randomly determined checks during day and night in the 8 months after the start of the study. RESULTS: Overall, 85% agreed to wear a hip protector. At 8 months, only 29% was still wearing their hip protector; with significant differences between day and night shifts. Although virtually all caregivers (97%) considered a hip protector policy in residential care as feasible, the attitude towards hip protectors was found to be significantly different between day and night caregivers. Pain and discomfort, patient insight in the usefulness of these devices, interference with incontinence materials, and the overall resident mix and care acuity were reported as major barriers. CONCLUSION: Implementing a hip protector policy for injury prevention in long-term care is not an issue of whether or not to use the devices. Rather, it is a continued clinical nursing decision process about when and when not, by whom and by whom not, why and why not, for how long, and to what clinical benefit--considering both the needs of the individual resident and the feasibility of such a policy in the context of resident mix and nursing staff. PMID- 20708187 TI - LDL apheresis improves deranged cardiovagal modulation in hypercholesterolemic patients. AB - OBJECTIVE: Hypotensive episodes are relatively frequent adverse effects during LDL apheresis. To evaluate the impact of LDL apheresis on autonomic cardiovascular control we investigated hypercholesterolemic patients before and after a single LDL apheresis in comparison to an age-matched control group. METHODS: We continuously recorded systemic arterial blood pressure, electrocardiogram and respiration in 21 hypercholesterolemic patients (57 +/- 15 years) on regular LDL apheresis treatment and 22 healthy control subjects (56 +/- 4 years) during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt). Baroreflex sensitivity and frequency spectra of R-R intervals and systolic blood pressure were evaluated by trigonometric regressive spectral analysis. RESULTS: Hypercholesterolemic patients had reduced resting baroreflex sensitivity and high-frequency power of heart rate variability compared to controls. Consequently, there was a sympathetic predominance of heart rate modulation reflected by increased ratio of low-to-high frequency power of R R intervals. Cardiovascular stimulation failed to adequately activate baroreflex mechanisms before LDL apheresis. After LDL apheresis, the parasympathetic response to cardiovascular stimulation improved and sympathetic outflow to peripheral vasculature was reduced. Baroreflex sensitivity remained low. CONCLUSION: Hypercholesterolemic patients on regular LDL apheresis treatment have significant autonomic dysfunction. A single LDL apheresis does not evoke sympathetic overactivation but improved deranged cardiovagal heart rate modulation in hypercholesterolemia. PMID- 20708186 TI - Patients' self-estimated likelihood of taking a statin as prescribed after different types of prognostic information. AB - BACKGROUND: Statins are frequently used in cardiovascular prevention, however medication adherence is suboptimal. AIMS: To examine if different types of prognostic information associated with prescription of a statin by physicians, can influence the self-estimated likelihood of taking the drug as prescribed, and to investigate whether patients want this type of information. METHODS: A survey was performed in 313 patients diagnosed with CVD. Patients were presented to facts with relative risk reduction and absolute risk reduction figures associated with the use of a statin and the self-estimated likelihood of taking the drug as prescribed was registered after each given fact. RESULTS: Self-estimated likelihood of taking the statin as prescribed was highest when the cardiologist recommended the drug without presenting absolute and relative risk reduction figures. Presenting relative risk reduction figures for the patients gave significantly higher self-estimated likelihood to take the statin as prescribed compared to giving the patients absolute risk reduction figures (p<0.001). A vast majority of the patients (84%) wanted to achieve information about risk reduction associated with the statin treatment. CONCLUSION: The patients wanted information about the CV risk reduction associated with the prescribed statin; however, the best self-estimated medication adherence was achieved when the cardiologist recommended the drug without presenting risk reduction figures. PMID- 20708188 TI - Regulation of the patellofemoral contact area: an essential mechanism in patellofemoral joint mechanics? AB - Although the relationship between contact area and pressure under physiological loading has been described in the feline patellofemoral joint, this interaction has only been examined under simplified loading conditions and/or considerably lower forces than those occurring during demanding activities in humans. We hypothesized that patellofemoral contact area increases non-linearly under an increasing joint reaction force to regulate patellofemoral pressure. Eight human cadaveric knees were ramp loaded with muscle forces representative of the stance phase of stair climbing at 30 degrees knee flexion. Continuous pressure data were acquired with a pressure sensitive film that was positioned within the patellofemoral joint. While pressure was linearly dependent upon the resulting joint reaction force, contact area asymptotically approached a maximum value and reached 95% of this maximum at patellofemoral forces of 349-723N (95% CI). Our findings indicate that the regulatory influence of increasing contact area to protect against high patellofemoral pressure is exhausted at relatively low loads. PMID- 20708189 TI - Influence of simulated neuromuscular noise on movement variability and fall risk in a 3D dynamic walking model. AB - People at risk of falling exhibit increased gait variability, which may predict future falls. However, the causal mechanisms underlying these correlations are not well known. Increased neuronal noise associated with aging likely leads to increased gait variability, which could in turn lead to increased fall risk. This paper presents a model of how changes in neuromuscular noise independently affect gait variability and probability of falling, and aims to determine the extent to which changes in gait variability directly predict fall risk. We used a dynamic walking model that incorporates a lateral step controller to maintain lateral stability. Noise was applied to this controller to approximate neuromuscular noise in humans. Noise amplitude was varied between low amplitudes that did not induce falls and high amplitudes for which the model always fell. With increases in noise amplitude, the model fell more often and after fewer steps. Gait variability increased with noise amplitude and predicted increased probability of falling. Importantly, these relationships were not linear. At either low gait variability or very high gait variability, small increases in noise and variability affected probability of falling very little. Conversely, at intermediate noise and/or variability levels, the same small increases resulted in large increases in probability of falling. Our results validate the idea that age-related increases in neuromuscular noise likely play a direct contributing role in increasing fall risk. However, neuromuscular noise remains only one of many important factors that need to be considered. These findings have important implications for fall prevention research and practice. PMID- 20708190 TI - Determination of alkylphenols and 17beta-estradiol in fish homogenate. Extraction and clean-up strategies. AB - The determination of target analytes such as nonyl- and octylphenols and 17beta estradiol in fish homogenate require of solid-liquid extraction step. In this work microwave-assisted extraction (MAE) and focused-ultrasound liquid extraction (FUSLE) were studied as two different alternatives for extraction of the target compounds in zebrafish (Danio rerio) homogenate. In this work solid phase extraction (SPE) using 5-g and 10-g Florisil cartridges and gel permeation chromatography (GPC) were studied for the clean-up of the MAE and FUSLE extracts due to the non-selective extraction step. Although good recoveries were obtained both for SPE (106% and 126% range) and GPC (79% and 100% range) clean-up procedures, cleaner chromatograms were obtained after SPE and finally 5-g Florisil cartridges were tested since no improvement was observed when 10-g Florisil cartridges were used. Under optimized clean-up conditions, MAE and FUSLE provided comparable results for 4nOP and NP, while more accurate results were obtained for 4tOP and E2 after FUSLE. Finally, the method was applied to the determination of alkylphenols and 17beta-estradiol in zebrafish homogenate that had been exposed to known concentrations of the target analytes. In the case of alkylphenols two different isomers of nonyl- and octylphenol (4-(3',6'-dimethyl 3'-hepthyl)phenol, 363-NP, and 4-(3'-methyl-3'-hepthyl)phenol, 33-OP) were studied. PMID- 20708191 TI - Analysis of polysulfides in drinking water distribution systems using headspace solid-phase microextraction and gas chromatography-mass spectrometry. AB - Sulfide and polysulfides are strong nucleophiles and reducing agents that participate in many environmentally significant processes such as the formation of sulfide minerals and volatile organic sulfur compounds. Their presence in drinking water distribution systems are of particular concern and need to be assessed, since these species consume disinfectants and dissolved oxygen, react with metal ions to produce insoluble metal sulfides, and cause taste and odour problems. The analysis of sulfide and polysulfides in drinking water distribution systems is challenging due to their low concentrations, thermal instability and their susceptibility to undergo oxidation and disproportionation reactions. This paper reports on the development and optimisation of a rapid, simple, and sensitive method for the determination of sulfide and polysulfides in drinking water distribution systems. The method uses methyl iodide to derivatize sulfide and polysulfides into their corresponding dimethyl(poly)sulfides, which are then extracted using solid-phase microextraction in the headspace mode and analysed by gas chromatography-mass spectrometry. Good sensitivity was achieved for the analysis of dimethyl(poly)sulfides, with detection limits ranging from 50 to 240 ng L(-1). The method also demonstrated good precision (repeatability: 3-7%) and good linearity over two orders of magnitude. Matrix effects from raw drinking water containing organic carbon (3.8 mg L(-1)) and from sediment material from a drinking water distribution system were shown to have no interferences in the analysis of dimethyl(poly)sulfides. The method provides a rapid, robust, and reliable mean to analyse trace levels of sulfides and polysulfides in aqueous systems. The new method described here is more accessible and user-friendly than methods based on closed-loop stripping analysis, which have been traditionally used for the analysis of these compounds. The optimised method was used to analyse samples collected from various locations in a drinking water distribution system. Some of the samples were shown to contain inorganic polysulfides, and their presence was associated with high sediment density in the system and the absence of disinfectant residual in the bulk water. PMID- 20708192 TI - Matrix-assisted refolding of autoprotease fusion proteins on an ion exchange column: a kinetic investigation. AB - Matrix-assisted refolding is an excellent technique for performing refolding of recombinant proteins at high concentration because aggregation during refolding is partially suppressed. The autoprotease N(pro) and its engineered mutant EDDIE can be efficiently refolded on cation-exchangers. In the current work, denatured fusion proteins were loaded at different column saturations (5 and 50 mg mL(-1) gel), and refolding and self-cleavage were initiated during elution. The contact time of the protein with the matrix significantly influenced the refolding rate and yield. On POROS 50 HS, the refolding rate was comparable to a batch refolding process, but yield was substantially higher; at a protein concentration of 1.55 mg mL(-1), an almost complete conversion was observed. With Capto S, the rate of self-cleavage increased by a factor of 20 while yield was slightly reduced. Processing the autoprotease fusion protein on Capto S at a high protein loading of 50 mg mL(-1) gel and short contact time (0.5h) yielded the highest productivity. PMID- 20708193 TI - Temperature-controlled headspace liquid-phase microextraction device using volatile solvents. AB - A novel temperature-controlled headspace liquid-phase microextraction (TC-HS LPME) device was established in which volatile solvents could be used as extractant. In this device, a PTFE vial cap with a cylindrical cavity was used as the holder of the extraction solvent. Up to 40 microl of extraction solvent could be suspended in the cavity over the headspace of aqueous sample in the vial. A cooling system based on thermoelectric cooler (TEC) was used to lower the temperature of extractant in PTFE vial cap to reduce the loss of volatile solvent during extraction process and increase the extraction efficiency. The selection of solvents for HS-LPME was then extended to volatile solvents, such as dichloromethane, ethyl acetate and acetone. The use of volatile extraction solvents instead of semi-volatile solvent reduced the interference of the large solvent peak to the analytes peaks, and enhanced the compatibility of HS-LPME with gas chromatograph (GC). Moreover, the use of larger volume of extractant solvent increases the extraction capacity and the injection volume of GC after extraction, thus improving detection limits. Several critical parameters of this technique were investigated by using chlorobenzenes (CBs) as the model analytes. High enrichment factors (498-915), low limits of detection (0.004-0.008 microg/L) and precision (3.93-5.27%) were obtained by using TC-HS-LPME/GC-FID. Relative recoveries for real samples were more than 83%. PMID- 20708194 TI - Electrophoresis of neutral oil in water. AB - Negative electrophoretic mobilities of oil in water are widely interpreted in terms of adsorption of hydroxide leading to negative surface charge. Challenging this traditional view, an increasing body of evidence suggests surface depletion of hydroxide and surface accumulation of hydronium leading to a positive surface charge. We present results from molecular dynamics (MD) simulations showing electrophoretic mobilities of oil in water with the same sign and magnitude as in experiment but in the absence of ions. The underlying mechanism involves interfacial roughness leading to gradients in dielectric permittivity in field direction and, thus, local elevation of the applied electric field. Although all molecules have zero net charge, their partial charges are distributed non uniformly such that oil exhibits negative and water positive excess charge in regions of high field intensities; this induces a net force on the oil or the water against or in field direction, respectively. Our results indicate that deducing net charges from electrophoretic mobilities as widely done can be misleading. Our findings suggest that pH dependent electrophoretic mobilities in experiment being negative above and positive below pH 2.5 arise from a competition between the negative mobility of the ion-free interface and the positive mobility from adsorbed hydronium ions. PMID- 20708195 TI - The construction, fouling and enzymatic cleaning of a textile dye surface. AB - The enzymatic cleaning of a rubisco protein stain bound onto Surface Plasmon Resonance (SPR) biosensor chips having a dye-bound upper layer is investigated. This novel method allowed, for the first time, a detailed kinetic study of rubisco cleanability (defined as fraction of adsorbed protein removed from a surface) from dyed surfaces (mimicking fabrics) at different enzyme concentrations. Analysis of kinetic data using an established mathematical model able to decouple enzyme transfer and reaction processes [Onaizi, He, Middelberg, Chem. Eng. Sci. 64 (2008) 3868] revealed a striking effect of dyeing on enzymatic cleaning performance. Specifically, the absolute rate constants for enzyme transfer to and from a dye-bound rubisco stain were significantly higher than reported previously for un-dyed surfaces. These increased transfer rates resulted in higher surface cleanability. Higher enzyme mobility (i.e., higher enzyme adsorption and desorption rates) at the liquid-dye interface was observed, consistent with previous suggestions that enzyme surface mobility is likely correlated with overall enzyme cleaning performance. Our results show that reaction engineering models of enzymatic action at surfaces may provide insight able to guide the design of better stain-resistant surfaces, and may also guide efforts to improve cleaning formulations. PMID- 20708197 TI - Comparison of isolates of Mycoplasma mycoides subspecies capri from asymptomatic and septicaemic goats. AB - Strains of Mycoplasma mycoides subspecies capri (Mmc) are frequently isolated from goats with contagious agalactia, but they can also be recovered from herds that have shown no clinical signs of mycoplasmosis for several years. The present study was conducted in order to explore the potential genetic and antigenic differences existing between an Mmc strain isolated from an outbreak (septicaemic) and a strain isolated from the ear canal of a goat belonging to a herd with no recent episode of mycoplasmosis (carriage strain). The genomes of the two strains, compared by suppression subtractive hybridization, were shown to be poorly divergent. The two strains were inoculated into goats to produce specific antisera, but both induced fatal mycoplasmosis. These results indicate that septicaemic and carriage strains cannot be distinguished by their genetic background or by their pathogenic capacity under experimental conditions. PMID- 20708196 TI - Undifferentiated high-grade pleomorphic sarcoma in a California sea lion (Zalophus californianus). AB - A tumour located in the pectoral region and the left front flipper was observed in a 29-year-old female California sea lion (Zalophus californianus) that died following signs of respiratory disease and inappetence. Metastases were present in the lung and adrenal gland. The histological pattern of the tumour was variable. In some areas the tumour consisted of pleomorphic fibroblast-like cells arranged in a storiform pattern, while in other areas it comprised oval or polygonal cells with round to oval nuclei and some bizarre cells arranged in an alveolar pattern. Occasionally, multinucleated giant cells were observed. Immunohistochemically, the neoplastic cells only expressed vimentin. On the basis of the microscopical and immunohistochemical features the tumour was diagnosed as an undifferentiated high-grade pleomorphic sarcoma. This type of neoplasm with disseminated involvement of other organs is rare in all species and has never been reported in California sea lions. PMID- 20708198 TI - Fronto-temporal disconnectivity and clinical short-term outcome in first episode psychosis: a DTI-tractography study. AB - Determining reliable markers of clinical outcome for psychosis is essential to adjust intervention efforts. White matter alterations exist prior to psychosis onset but its association with clinical outcome in the very early phase of psychosis is currently unknown. In the present study, white matter was assessed by diffusion tensor imaging (DTI) in patients with first episode psychosis (FEP) and healthy controls. Forty-four FEP patients and 30 matched healthy controls completed a DTI scan. The patient group was split in poor (n = 24) and good (n = 20) outcome subgroups based on 6-month clinical data. DTI tractography was used to estimate fractional anisotropy (FA) in the three main tracts connecting frontal and temporal regions (i.e. the cingulum, the superior longitudinal fasciculus and the uncinate fasciculus). The analyses showed selective FA reductions in both the uncinate and the superior longitudinal fasciculi, but not in the cingulum, when comparing FEP patients to healthy controls. FEP subgroup analyses revealed greater white matter changes in these tracts in patients with poor outcome as compared to patients with good outcome. These findings confirm that abnormal fronto-temporal connectivity contributes to the physiopathology of FEP and constitutes an early marker of clinical short-term outcome. PMID- 20708200 TI - The prominent expression of plasma matrix metalloproteinase-8 in acute thoracic aortic dissection. AB - BACKGROUND: The relationship between elastolytic matrix metalloproteinases (MMPs) (such as MMP-2, MMP-9) and thoracic aortic dissection (TAD) has been described, but little is known regarding the role of collagenolytic MMPs in thoracic aortic dissection. The aim of this study was to determine the role of MMP-8 in acute thoracic aortic dissection. MATERIALS AND METHODS: Forty-five patients affected by TAD and 40 with acute myocardial infarction (AMI) were recruited into this study. Blood samples within 72 h of the onset of symptoms were available for all the 85 patients. Healthy individuals were selected from the out-patients who complained of chest pain but in whom no cardiovascular diseases were found. Plasma levels of MMP-1, -8, -13 were measured by enzyme-linked immunosorbent assay (ELISA) technique in all subjects. Aortic tissue samples obtained during surgery were evaluated by Western blot for MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. RESULTS: Plasma MMP-8 levels in patients affected by TAD and AMI were both higher than that in healthy subjects (284.35 +/ 96.32 ng/mL and 88.57 +/- 26.71 ng/mL versus 75.39 +/- 23.36 ng/mL). The difference of the MMP-8 level between TAD patients and healthy subjects was significant (P = 0.000). No significant differences were found in MMP-1 and MMP 13 plasma levels among the three groups. CONCLUSIONS: The acute phase of TAD is characterized by a prominent increase of MMP-8 plasma level, which may play a key role in the occurrence of TAD. MMP-8 could be involved in the acute inflammatory reaction and may be a useful marker for the diagnosis of acute TAD. PMID- 20708199 TI - Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics. AB - Approximately 60-70 percent of women with premenstrual dysphoric disorder (PMDD) show symptomatic improvement in response to the GnRH agonist leuprolide acetate, which suppresses ovarian function. However, it has been very difficult to either predict or understand why some women respond, while others do not. We applied several complementary statistical methods to the dynamics of pre-treatment mood rating data to determine possible predictors of response for women with PMDD. We compared responders (n = 33) to nonresponders (n = 12) in clinical trials of leuprolide (three months in duration) as a treatment for PMDD, on the basis of pre-trial daily self-ratings of sadness, anxiety, and irritability. We analyzed both sequential irregularity (approximate entropy, ApEn) and a quantification of spikiness of these series, as well as a composite measure that equally weighted these two statistics. Both ApEn and Spikiness were significantly smaller for responders than nonresponders (P <= 0.005); the composite measure was smaller for responders compared with nonresponders (P <= 0.002) and discriminated between the subgroups with high sensitivity and specificity. In contrast, mean symptom levels were indistinct between the subgroups. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to leuprolide by women with PMDD with high probability, moreover based on typically less than 3 months of daily records. The statistical measures may have broad and direct applicability to behavioral studies for many psychiatric disorders, facilitating both accurate diagnosis and the prediction of response to treatment. PMID- 20708201 TI - 3T deep gray matter T2 hypointensity correlates with disability over time in stable relapsing-remitting multiple sclerosis: a 3-year pilot study. AB - Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients. PMID- 20708202 TI - Weather regimes and orographic circulation around New Caledonia. AB - The local climate and island-scale circulation around New Caledonia is investigated using a 4-km resolution mesoscale atmospheric model in concert with QuikSCAT scatterometer winds at 12.5-km resolution. The mesoscale atmospheric weather regimes are first examined through an objective classification applied to the remote sensed winds for nine warm seasons from 1999 to 2008. Four main weather types are identified. Their corresponding synoptic-scale circulation reveals that they are strongly discernable through the position and intensity of the South Pacific Convergence zone (SPCZ), the mid-latitude systems, and the subtropical jet stream. The link between the mesoscale weather types and the two dominant large-scale modes of variability, namely the Madden-Julian Oscillation (MJO) and the El Nino-Southern Oscillation (ENSO), is also described in terms of their influence on the occurrence of each weather type. It shows that their occurrence is significantly controlled by both MJO and ENSO, through modulation of the SPCZ. The large-scale modes of variability are scaled down to island-scale circulation through synoptic and mesoscale regimes, and are eventually modulated by orographic and thermal control. The island-scale circulation is inferred in this study by applying the compositing method to both observed and simulated winds. Their comparison clearly shows the ability of the mesoscale model to capture the local circulation and its spatial and temporal variability. A scaling analysis conducted from the simulated atmospheric parameters shows that the mountain range of New Caledonia is hydrodynamically steep. As a result of trade wind obstruction by the mountainous island, the flow is shaped by coastally trapped mesoscale responses, i.e., blocking, flow splitting and corner winds, with a spatial scale of about 150 km. Two main obstacles, Mont Panie and Mont Humboldt play a significant role on the dynamical behavior of the low-level flow, while the diurnal heating cycle in the vicinity of the Mainland strongly modulates the local circulation. Moreover, nocturnal drainage flow of cold air occurs on the leeside slope of Mont Humboldt and inhibits vertical mixing over the ocean, which results in a deceleration of surface winds. PMID- 20708203 TI - Serum levels of the adipokine zinc-alpha2-glycoprotein are increased in chronic hemodialysis. AB - Zinc-alpha2-glycoprotein (ZAG) has recently been proposed as a new adipokine involved in body weight control. In the current study, we investigated renal elimination of this adipokine by comparing circulating ZAG levels in patients on chronic hemodialysis (CD) with controls. Sixty CD patients and 60 controls with a glomerular filtration rate greater than 50 mL/min were included. Serum concentrations of ZAG were determined by enzyme-linked immunosorbent assay; and its relationship with renal function, glucose and lipid metabolism, as well as inflammation was studied in both groups. Median ZAG serum levels were almost 2 fold higher in CD patients (94.4 +/- 29.4 mg/L) as compared with controls (48.3 +/- 23.5 mg/L) (P < .001). Furthermore, circulating ZAG was negatively correlated with fasting insulin, homeostasis model assessment of insulin resistance, and leptin in controls in univariate analysis. Moreover, CD independently predicted ZAG concentrations in multiple regression analysis. Renal filtration appears to be an important route of ZAG elimination, and markers of renal function should be included in studies on ZAG physiology. PMID- 20708204 TI - Fuel oxidation at the walk-to-run-transition in humans. AB - Multiple factors (including anthropometric, kinetic, mechanical, kinematic, perceptual, and energetic factors) are likely to play a role in the walk-to-run transition in humans. The primary purpose of the present study was to consider an additional factor, the metabolic fuel source. Indirect calorimetry was used to measure fuel oxidation, and perception of effort was recorded as 10 overnight fasted adults locomoted on a level treadmill at speeds progressing from 1.56 to 2.46 m s(-1) in increments of 0.11 m s(-1) and 10.0 minutes under 3 conditions: (1) unconstrained choice of gait, (2) walking at all speeds, and (3) running at all speeds. The preferred transition speed was 2.08 +/- 0.03 m s(-1). Gait transition from walking to running increased oxygen consumption rate, decreased the perception of effort, and decreased the rate of carbohydrate oxidation. We propose that, in an evolutionary context, gait transition, guided by the perception of effort, can be viewed as a carbohydrate-sparing strategy. PMID- 20708205 TI - [Dosimetric stereotactic radiosurgical accident: Study of 33 patients treated for brain metastases]. AB - The consequences of a dosimetric radiosurgery accident are not the same as a conventional radiotherapy accident. The objective of this study was to estimate the clinical and radiological outcome of patients treated by radiosurgery for metastasis during the period of the overexposure accident that occurred in the Toulouse Radiosurgery Unit. Between April 2006 and March 2007, 33 patients with 57 metastases were treated in the Toulouse Radiosurgery Unit (Novalis((r)), BrainLab). An initial error in the estimation of the scatter factors led to an overexposure to radiation. The median age was 55 years [range, 35-85]. Twenty-one patients (64%) harbored a single metastasis. The primary tumor location was lung (16 cases), kidney (nine cases), breast (four cases), and others (four cases). The mean tumoral volume was 3.2cm(3) [0.04-14.07]. The mean prescribed dose at the isocenter was 20 Gy [range, 10-23], the mean delivered dose was 31.5 Gy [range, 13-52], and the mean overdose was 61.2% [range, 5.6-226.8]. In order to evaluate the consequences of the overdose, three parameters were analyzed: a risk index using dose and volume, the volume of parenchyma that received more than 12 Gy, and the mean dose in a sphere of 20cm(3) surrounding the target volume. Median actuarial survival was 14.1 months, the survival rate was 79.4 % at six months, 59.1% at 12 months, and 27.2% at 24 months. The rate of tumor control was 80.7%. No morbidity was observed. There was no correlation between death and the parameters studied. The survival rates and times observed in our study of the patients treated for brain metastases by radiosurgery and overexposed were among the good results of the international literature. Deaths were not related to the overdose and no side effect was noted. This dosimetric accident has not had worse consequences in this population. PMID- 20708206 TI - Nitric oxide synthase-like dependent NO production enhances heme oxygenase up regulation in ultraviolet-B-irradiated soybean plants. AB - Heme oxygenase (HO) has antioxidant properties and is up-regulated by reactive oxygen species (ROS) in ultraviolet-B-irradiated soybean plants. This study shows that nitric oxide (NO) protects against oxidative damage and that nitric oxide synthase (NOS)-like activity is also required for HO-1 induction under UV-B radiation. Pre-treatments with sodium nitroprussiate (SNP), a NO-donor, prevented chlorophyll loss, H(2)O(2) and O(2)(*-) accumulation, and ion leakage in UV-B treated plants. HO activity was significantly enhanced by NO and showed a positive correlation with HO-1 transcript levels. In fact, HO-1 mRNA levels were increased 2.1-fold in 0.8 mM SNP-treated plants, whereas subsequent UV-B irradiation augmented this expression up to 3.5-fold with respect to controls. This response was not observed using ferrocyanide, a SNP inactive analog, and was effectively blocked by 2-(4-carboxyphenil)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (cPTIO), a specific NO-scavenger. In addition, experiments carried out in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) or tungsten, well known inhibitors of NOS and nitrate reductase, showed that NOS is the endogenous source of NO that mediates HO-1 expression. In summary, we found that NO is involved in the signaling pathway leading to HO-1 up-regulation under UV-B, and that a balance between NO and ROS is important to trigger the antioxidant response against oxidative stress. PMID- 20708207 TI - Time-action profiles of insulin detemir in normal and diabetic dogs. AB - Insulin detemir is the first member of a new class of long-acting soluble insulin analogues capable of maintaining the basal level of insulin in humans. In this preliminary study, we investigated the time-action profiles of insulin detemir in normal and diabetic dogs since the use of insulin detemir in canines has yet to be determined. Eight animals were used in our study (three normal and five insulin dependent diabetic dogs). Time-action profiles of insulin detemir were monitored in normal dogs using an artificial pancreas apparatus under euglycemic condition. Blood sampling was performed at 2h intervals post feeding, with insulin administration, in insulin dependent diabetic dogs. Time-action profiles of insulin detemir, in normal dogs, demonstrated that insulin detemir is a long lasting preparation similar to what has been observed in humans. A pronounced peak was detected at 8-10h while the glucose-lowering effect lasted for over 24h after insulin injection, thus illustrating its longer prolonged peak activity time. Furthermore, intensive glycemic control was achieved with insulin detemir in insulin dependent diabetic dogs, using a lower dosage than NPH insulin and insulin glargine therapeutic doses. Our results indicate that insulin detemir has a greater effect than either NPH insulin or insulin glargine in canines, requiring a lower dose than either insulin preparation. However, using insulin detemir also carries a higher risk of inducing hypoglycemia as compared to either NPH insulin or insulin glargine. PMID- 20708208 TI - Insertion of host DNA into PVL-encoding phages of the Staphylococcus aureus lineage ST80 by intra-chromosomal recombination. AB - Temperate bacteriophages play a critical role in the pathogenicity of the human pathogen Staphylococcus aureus by mediating positive lysogenic conversion for different virulence factors such as Panton-Valentine leukocidin (PVL) or by interrupting chromosomal virulence genes. PVL-encoding phages are integrated in the S. aureus genome within a conserved ORF which is surrounded by a cluster of tandemly repeated genes. Here we demonstrate that in S. aureus clonal complex ST80 strains PVL-phage induction led to the acquisition of host DNA into the phage genome probably due to a homologous recombination event between direct repeats of the two paralogous genes adjacent to the phage integration site. Phage excision was accompanied by an additional chromosomal deletion in this region. This so far unrecognized mechanism of DNA uptake into the phage genome may play an important role in the co-evolution of phages and bacteria. PMID- 20708209 TI - Properties of HTLV-I transformed CD8+ T-cells in response to HIV-1 infection. AB - HIV-1 infection studies of primary CD8(+) T-cells are hampered by difficulty in obtaining a significant number of targets for infection and low levels of productive infection. Further, there exists a paucity of CD8-expressing T-cell lines to address questions pertaining to the study of CD8(+) T-cells in the context of HIV-1 infection. In this study, a set of CD8(+) T-cell clones were originated through HTLV-I transformation in vitro, and the properties of these cells were examined. The clones were susceptible to T-cell tropic strains of the virus and exhibited HIV-1 production 20-fold greater than primary CD4(+) T-cells. Productive infection resulted in a decrease in expression of CD8 and CXCR4 molecules on the surface of the CD8(+) T-cell clones and antibodies to these molecules abrogated viral binding and replication. These transformed cells provide an important tool in the study of CD8(+) T-cells and may provide important insights into the mechanism(s) behind HIV-1 induced CD8(+) T-cell dysfunction. PMID- 20708210 TI - BST-2 mediated restriction of simian-human immunodeficiency virus. AB - Pathogenic simian-human immunodeficiency viruses (SHIV) contain HIV-1 Vpu and SIV Nef, both shown to counteract BST-2 (HM1.24; CD317; tetherin) inhibition of virus release in a species-specific manner. We show that human and pig-tailed BST-2 (ptBST-2) restrict SHIV. We found that sequential "humanization" of the transmembrane domain (TMD) of the pig-tailed BST-2 (ptBST-2) protein resulted in a fluctuation in sensitivity to HIV-1 Vpu. Our results also show that the length of the TMD in human and ptBST-2 proteins is important for BST-2 restriction and susceptibility to Vpu. Taken together, our results emphasize the importance of tertiary structure in BST-2 antagonism and suggests that the HIV-1 Vpu transmembrane domain may have additional functions in vivo unrelated to BST-2 antagonism. PMID- 20708211 TI - Oxidation of fluoroquinolone antibiotics and structurally related amines by chlorine dioxide: Reaction kinetics, product and pathway evaluation. AB - Fluoroquinolones (FQs) are a group of widely prescribed antibiotics and have been frequently detected in the aquatic environment. The reaction kinetics and transformation of seven FQs (ciprofloxacin (CIP), enrofloxacin (ENR), norfloxacin (NOR), ofloxacin (OFL), lomefloxacin (LOM), pipemidic acid (PIP) and flumequine (FLU)) and three structurally related amines (1-phenylpiperazine (PP), N phenylmorpholine (PM) and 4-phenylpiperidine (PD)) toward chlorine dioxide (ClO(2)) were investigated to elucidate the behavior of FQs during ClO(2) disinfection processes. The reaction kinetics are highly pH-dependent, can be well described by a second-order kinetic model incorporating speciation of FQs, and follow the trend of OFL > ENR > CIP ~ NOR ~ LOM > > PIP in reactivity. Comparison among FQs and related amines and product characterization indicate that FQs' piperazine ring is the primary reactive center toward ClO(2). ClO(2) likely attacks FQ's piperazinyl N4 atom followed by concerted fragmentation involving piperazinyl N1 atom, leading to dealkylation, hydroxylation and intramolecular ring closure at the piperazine moiety. While FQs with tertiary N4 react faster with ClO(2) than FQs with secondary N4, the overall reactivity of the piperazine moiety also depends strongly on the quinolone ring through electronic effects. The reaction rate constants obtained in clean water matrix can be used to model the decay of CIP by ClO(2) in surface water samples, but overestimate the decay in wastewater samples. Overall, transformation of FQs, particularly for those with tertiary N4 amines, could be expected under typical ClO(2) disinfection conditions. However, the transformation may not eliminate antibacterial activity because of little destruction at the quinolone ring. PMID- 20708212 TI - Silage supports sulfate reduction in the treatment of metals- and sulfate containing waste waters. AB - Silage was used as source of carbon and electrons for enrichment of silage degrading and sulfate reducing bacteria (SRB) from boreal, acidic, metals containing peat-bog samples and to support their use in batch and semi-batch systems in treatment of synthetic waste water. Sulfidogenic silage utilization resulted in a rapid decrease in lactate concentrations; concentrations of acetate, butyrate and propionate increased concomitantly. Synthetic waste water consisting of Mn, Mg and Fe (II) ions inhibited sulfate reduction at concentrations of 6 g/l, 8 g/l and 1 g/l respectively. During treatment, Mn and Mg ions remained in solution while Fe ions partially precipitated. Up to 87 mg sulfate was reduced per gram of silage. Sulfate reduction rates of 34, 22 and 6 mg/l/day were obtained at temperatures of 30, 20 and 9 degrees C respectively. In semi-batch reactors operated at low pH, the iron precipitation capacity was controlled by sulfate reduction rates and by partial loss of hydrogen sulfide to the gas phase. Passive reactor systems should, therefore, be operated at neutral pH. Metals tolerant, silage-fermenting (predominantly species belonging to genus Clostridium) and sulfate reducing bacteria (including a species similar to the psychrotolerant Desulfovibrio arcticus) were obtained from the peat bog samples. This work demonstrates that silage supports sulfate reduction and can be used as a low cost carbon and electron source for SRB in treatment of metals-containing waste water. PMID- 20708213 TI - Identification of hydroxylated metabolites of 3,3',4,4'-tetrachlorobiphenyl and metabolic pathway in whole poplar plants. AB - Polychlorinated biphenyls (PCBs) can be metabolized to hydroxylated polychlorinated biphenyls (OH-PCBs) as reported in a number of animal studies. However, there are few studies on OH-PCBs in vivo in whole plants. In order to explore the formation of OH-PCBs in whole plants in detail, poplars (Populus deltoides*nigra, DN34) were exposed to 3,3',4,4'-tetrachlorobiphenyl (CB77) in hydroponic solution. Poplars are widely used in phytoremediation applications and the complete genome has been sequenced. In this research, a HPLC-MS method was developed to directly determine the hydroxylated metabolites of CB77 (OH-CB77s), avoiding the experimental errors introduced by derivatization pretreatments required by gas chromatography-based methods. Three potential hydroxylated metabolites of CB77, including 6-hydroxy-3,3',4,4'-tetrachlorobiphenyl (6OH CB77), 5-hydroxy-3,3',4,4'-tetrachlorobiphenyl (5OH-CB77) and 4'-hydroxy 3,3',4,5'-tetrachlorobiphenyl (4'OH-CB79), were determined in poplar tissues. The major product, 6OH-CB77, was detected in the roots, bottom bark, bottom wood, middle bark and middle wood for the whole poplar plants, but the minor product, 5OH-CB77, was detected only in the poplar roots. The concentration of 6OH-CB77 was about 10 times greater than that of 5OH-CB77 in the roots. However, the major mammalian metabolite, 4'OH-CB79 was not detected in any of the samples. The results suggest that the hydroxylated metabolic pathway of CB77 is via an epoxide intermediate in poplar. PMID- 20708214 TI - Noise, sleep and poor health: Modeling the relationship between road traffic noise and cardiovascular problems. AB - Several adverse effects have been associated with exposure to traffic noise. Studies supporting a noise-stress-health model have suggested links between noise level and increased noradrenalin concentrations in urine, hypertension and myocardial infarction. Among the more commonly documented effects, sleep disturbances have been regarded as being the most serious. Both noise annoyance and sleep disturbance have been proposed as important mediators of the impact of noise on health. The present paper investigates the relationships among long-term noise exposure, annoyance, sleeping problems and subjective health complaints by the use of a structural equation model. Further, it aims at giving insight into how noise sensitivity is related to sleep disturbances from road traffic noise. Finally, it examines whether any effect of noise exposure or response to noise can be detected on prevalence of cardiovascular problems, when information on sleep disturbances is included in a model. Data from a questionnaire survey conducted among a population sample in Oslo (N=2786) are combined with nighttime noise levels calculated from outside each respondents dwelling, at the bedroom facade. The results of the analysis showed significant relationships between noise annoyance at night and sleeping problems. The model also showed strong links among pseudoneurological complaints, annoyance and sleeping problems, thus pointing to the importance of including information on psychosomatic disorders and mild psychological problems in future studies looking at potential health effects of noise. The analysis showed no relationship between neither noise exposure nor response to noise and cardiovascular problems. PMID- 20708215 TI - Cell type specificity of lung cancer associated with nitric oxide. AB - We aimed to explore whether lung cancer associated with air pollutants, specifically nitric oxide (NO), has cell type specificity. Both Spearman correlation and multiple linear regression between the air quality indices (SO(2), CO, O(3), NO, and NO(2)) and age-standardized incidence rate (ASR) of lung cancer by two major pathological types were calculated for both genders. We conducted 4 levels of analyses based on different NO concentrations. We also used Poisson regression to estimate the relative risk of lung cancer. Regardless of gender, the influences of SO(2), CO, O(3), and NO(2) were not statistically significant. There was a dose-response relationship between NO concentrations and adenocarcinoma (AC) incidence rates. On the other hand, none of the air pollutants had a significant impact on the squamous cell carcinoma (SCC) incidence rates for both males and females. The Poisson regression results showed that with the NO concentration < or = 5.59 ppb as the baseline, the risk for AC among males at 5.59 < NO < or = 8.55 ppb was 1.32 times of that at the baseline level (95% CI, 1.11-1.59), 1.33 times at 8.55 < NO < or = 13.54 ppb (95% CI, 1.11 1.61), 1.66 times when NO > 13.54 ppb (95% CI, 1.36-2.01). The test for trend was statistically significant at P<0.001. Similar results were observed among females. On the contrary, for SCC, we found NO did not pose any significant danger to males and females. CONCLUSION: Our results showed that there was a dose response relationship between gaseous NO concentrations and lung AC incidence rates. PMID- 20708216 TI - Brain acetylcholinesterase, malondialdehyde and reduced glutathione as biomarkers of continuous exposure of tench, Tinca tinca, to carbofuran or deltamethrin. AB - In this study, the chronic effect of the insecticides carbofuran and deltamethrin on acetylcholinesterase (AChE) activity and malondialdehyde (MDA) and reduced glutathione (GSH) levels were examined in the brain of tench. Both pesticides were evaluated in two separate experiments, and animals were exposed in a continuous flow-system to three different concentrations of carbofuran (0, 10 and 100 microg/L) and deltamethrin (0, 0.0039 and 0.039 microg/L) for 60 days. After that period, animals were kept into pesticide-free water for other 30 days. In all cases, animals were sampled every 10 days all along the experience. AChE activity was significantly inhibited in fish exposed to 100 microg/L of carbofuran, during the first 30 days of exposition, returning to basal levels after this initial period. With respect to deltamethrin exposure, AChE activity was not significantly affected. When considering MDA levels, significant changes could only be detected during the recovery period for both pesticides, with a maximum of induction at 70 and 80 days, respectively associated to the highest dose of carbofuran and deltamethrin. Similarly, GSH levels varied all along the experience, with a maximum of significant increase at day 80 of exposition to the highest dose of both pesticides. This study shows that changes in AChE brain activity in tench can be used as a biomarker of early pesticide exposition in environmental monitoring programs, whereas MDA and GSH levels could be more associated to long-term expositions. The above results confirm and broaden former observations, suggesting that more investigations are needed before these biochemical parameters can be used as biomarkers. PMID- 20708217 TI - Gene expression programming for total bed material load estimation--a case study. AB - This paper presents Gene-Expression Programming (GEP), which is an extension to the genetic programming (GP) approach to predict the total bed material load for three Malaysian rivers. The GEP is employed without any restriction to an extensive database compiled from measurements in the Muda, Langat, and Kurau rivers. The GEP approach demonstrated a superior performance compared to other traditional sediment load methods. The coefficient of determination, R(2) (=0.97) and the mean square error, MSE (=0.057) of the GEP method are higher than those of the traditional method. The performance of the GEP method demonstrates its predictive capability and the possibility of the generalization of the model to nonlinear problems for river engineering applications. PMID- 20708218 TI - Platelet apoptosis resistance and increased CXCR4 expression in pediatric patients with chronic immune thrombocytopenic purpura. AB - The pathogenesis of childhood chronic immune thrombocytopenic purpura (ITP) is mainly mediated by antiplatelet autoantibodies, which have been shown to induce platelet apoptosis in murine models. Decreased CXCR4 expression, which can regulate apoptotic pathway, has been described in platelet disorders. The present study aims to determine whether platelet apoptosis is increased in pediatric patients with chronic ITP and whether there is any involvement of the CXCR4 chemokines axis. Twenty-one patients and 12 controls were studied. Using flow cytometry, we investigated apoptotic markers of platelets including annexin V, caspase 3, and mitochondrial inner transmembrane potential depolarization. The percentage of the platelets with apoptosis-positive markers was not increased in chronic ITP patients. CXCR4 expression was higher in the patients as detected by flow cytometric (P=0.001) and western blotting analysis (P=0.013). The results also revealed that CXCR4 downstream proteins, Akt phosphorylation was more frequent in chronic ITP patients than controls. Plasma stromal cell-derived factor 1 levels analyzed by enzyme-linked immunosorbent assay were decreased in patients (P=0.001) and inversely correlated to CXCR4 expression (r=-0.62, P<0.001). In conclusion, the study shows platelet apoptosis resistance existing in pediatric patients with chronic ITP. It may be associated with enhanced CXCR4 expression and Akt activation. PMID- 20708219 TI - Plasma levels of microparticle-associated tissue factor activity in patients with clinically suspected pulmonary embolism. AB - INTRODUCTION: Microparticles (MPs) carrying active tissue factor (TF) have been detected in the plasma of cancer patients in particular in those presenting with acute deep vein thrombosis (DVT) or pulmonary embolism (PE). Experimental studies in mice have revealed that circulating MPs carrying TF contribute to thrombus formation. AIM: To study whether unselected patients with an acute confirmed PE have elevated TF activity in the MP fraction (MP-TF activity). MATERIALS AND METHODS: Plasma MP-TF activity was measured in 159 non-selected patients with clinically suspected PE and in 48 healthy controls as previously described. Blood was collected at time of inclusion. The diagnosis of acute PE was confirmed in 54 patients and excluded in 105 patients. RESULTS: Median MP-TF activity in 159 patients with clinically suspected PE was 72 fM Xa/min [range 32-6657] fM Xa/min and higher than in healthy controls (66 [range 28-183] fM Xa/min; P<0.05). There was no significant difference (P=0.169) in MP-TF activity between patients with confirmed PE (median 84.5 fM Xa/min [range 36-2149]) and patients without PE (72 fM Xa/min [range 32-6657]) fM Xa/min). In the 159 patients with clinically suspected PE we observed in an exploratory analysis higher MP-TF activity levels in patients with active cancer (median 137 fM Xa/min [range 36-6657]) and cardiovascular disease (median 131.5 fM Xa/min [range 45-2149]) than in patients without these disorders (P=0.0004 and P=0.014, respectively). CONCLUSION: In patients presenting with clinically suspected PE plasma MP-TF activity was not associated with confirmed PE. PMID- 20708220 TI - Use of adult criteria for slice imaging may limit unnecessary radiation exposure in children presenting with hematuria and blunt abdominal trauma. AB - OBJECTIVE: To examine whether it would be safe to use adult criteria for imaging in pediatric blunt renal trauma and hematuria. MATERIAL AND METHODS: From 1999 to 2007, 46 consecutive children were admitted for renal trauma and hematuria. All had abdominal computed tomography (CT) scan. Patients were divided into 2 groups: microhematuria and macrohematuria. Outcomes analyzed were presence of renal injury per CT, grade of renal injury, and indication for and details of surgical intervention. RESULTS: Twenty-seven patients (59%) had microhematuria. Nineteen (41%) had macrohematuria. On abdominal CT scan, no injury was found in 18 patients with microhematuria (67%) and 3 (16%) with macrohematuria. Two microhematuria patients required surgical intervention. In both cases, no actual renal intervention was performed during surgery. Three macrohematuria patients required surgical intervention; all had renal relevant procedures. The performance of the macro-microhematuria distinction in the prediction of renal injury on CT scan is relatively poor: sensitivity 59%, specificity 14%, positive predictive value (PPV) 84%, and negative predictive value (NPV) 62%, whereas the performance of macrohematuria criteria in the prediction of renal-relevant injury is sensitivity 100%, specificity 61%, PPV 18%, and NPV 93%. CONCLUSIONS: The yield of abdominal CT in pediatric renal trauma is low in patients presenting with microhematuria. Our data suggest that it may be possible that adult criteria for renal imaging are sufficient for children with abdominal blunt trauma and microhematuria. Adopting such strategy will result in substantial reduction in exposure to radiation, supposedly without increasing the patient's risk. PMID- 20708221 TI - Immunohistochemical expression of Hsp60 correlates with tumor progression and hormone resistance in prostate cancer. AB - OBJECTIVES: To investigate the expression of Hsp60 protein in prostate cancer biopsy samples, and its association with prognostic clinical parameters and hormone resistance and survival. Molecular chaperones are involved in protein folding, protein degradation, and protein trafficking among subcellular compartments. METHODS: We selected 107 patients with localized and locally advanced prostate cancer at our hospital from 1999 through 2004. We performed an analysis by western blot and immunohistochemistry on paraffin-embedded tissue sections. Clinical data were used to determine associations between immunohistochemical expression of Hsp60 and tumor behavior. RESULTS: The expression level of Hsp60 was significantly increased in tumors with high Gleason score (P < .001). Hsp60 expression was also significantly associated with initial serum PSA levels (P < .01) and with the presence of lymph node metastasis (P < .003). In 50 locally advanced cancers treated by androgen ablation we found an association between high Hsp60-expressing tumors and an early onset of hormone refractory disease (P < .02) and reduced cancer-specific survival (P < .05). CONCLUSIONS: Hsp60 protein is overexpressed in poorly differentiated prostate cancers. Hsp60 expression is strongly associated with prognostic clinical parameters, such as Gleason score, initial serum PSA levels, and lymph node metastasis and with the onset of hormone-refractory disease and reduced cancer specific survival. Identification of such markers could be of relevance in the clinical management of prostate cancer. PMID- 20708222 TI - Vesico-acetabular cutaneous fistula: a delayed complication of hip surgery. AB - Vesico-acetabular cutaneous fistula is an uncommon but important postoperative complication of prosthetic hip surgery. We present a case and images involving a 70-year-old woman who presented with a chronically discharging gluteal wound, 5 years after a complex composite hip replacement. PMID- 20708223 TI - Penile fracture: diagnosis, treatment and outcomes of 150 patients. AB - OBJECTIVE: To report the diagnosis, treatment options, and outcomes of 150 patients with suspicion of penile fracture. MATERIALS AND METHODS: We analyzed 150 patients with clinically suspected penile fracture (PF). The patients were divided into two groups: group 1 (G1) with low suspicion of penile fracture (n = 25), and group 2 (G2) with high suspicion of penile fracture (n = 125). Complementary image methods were conducted on 59 patients (39.3%), with ultrasonography (USG) performed on 37 (24.6%) patients and magnetic resonance imaging on only one (0.6%). Retrograde urethrocystogram was performed when urethral injury was suspected (21 patients, 14%). In G1, all patients underwent USG to complement diagnosis. In G2, 12 patients underwent USG owing to a doubtful diagnosis. Mean follow-up was 34.6 months. RESULTS: All patients in G1 were able to achieve erection after the initial traumatic event and immediate penile detumescence did not occur in any of the cases. Of the 125 patients evaluated in G2, 110 (92%) presented with disruption of the tunica albuginea and 15 (8%) showed injury of the dorsal vein of the penis. Urethral injury was found in 20 (16%) patients and was always associated with corpus cavernosum injury. Among 110 cases of PF, 95 (86.3%) presented with unilateral and 15 (13.7%) presented with bilateral lesions. CONCLUSIONS: Patients with high suspicion of PF should be treated surgically. However, in cases of low suspicion of corpora cavernosum injury, based on clinical criteria and imaging methods, conservative treatment is a feasible and safe option. PMID- 20708224 TI - Retroperitoneoscopic nephrectomy with a modified hand-assisted approach. AB - OBJECTIVES: To present the first experience with a 3-port technique for retroperitoneoscopic (HARP) radical nephrectomy, radical nephroureterectomy, and total and live donor nephrectomy. We believe that the retroperitoneoscopic (RP) approach to nephrectomy is advantageous, as it avoids mobilization of intraperitoneal organs and provides direct access to the renal artery. Nonetheless, this approach is not as popular as the transperitoneal approach, likely because of the steeper learning curve. We believe that hand-assistance reduces the learning curve because of the tactile feedback and similarity to open surgery. METHODS: Over a 4-year period, 133 HARP nephrectomies were performed, including 92 radical nephrectomies, 19 radical nephroureterectomies, 12 total nephrectomies, and 10 live donor nephrectomies. Mean patient age was 62 years and mean body mass index was 30; 42% of patients had abdominal scars. Our technique uses a 7-cm muscle-sparing Gibson incision for the hand-port with 2 endoscopic ports. RESULTS: Mean operative time, including ureterectomy, was 109 minutes, with a mean operative blood loss of 167 mL. Average hospitalization was 3.8 days. Two cases (1.5%) required open conversion. The complication rate was limited to 3.8% for blood transfusion, 3.8% for cardiac issues, 1.5% for pulmonary embolism, 2.3% for wound infection, and 1.5% for urinary retention. CONCLUSIONS: Based on our results, we conclude that HARP nephrectomy is safe and effective and can be expeditiously performed. It is a versatile approach that is applicable for both neoplastic and non-neoplastic indications. In addition, HARP provides a minimally invasive alternative to open conversion in difficult cases of simple nephrectomy. PMID- 20708225 TI - Postoperative intra-abdominal collections using a sodium hyaluronate carboxymethylcellulose (HA-CMC) barrier at the time of laparotomy for uterine or cervical cancers. AB - OBJECTIVES: A prior analysis of patients undergoing laparotomy for ovarian malignancies at our institution revealed an increased rate of intra-abdominal collections using HA-CMC film during debulking surgery. The primary objective of the current study was to determine whether the use of HA-CMC is associated with the development of postoperative intra-abdominal collections in patients undergoing laparotomy for uterine or cervical malignancies. METHODS: We retrospectively identified all laparotomies performed for these malignancies from 3/1/05 to 12/31/07. We identified cases involving the use of HA-CMC via billing records and operative reports. Intra-abdominal collections were defined as localized intraperitoneal fluid accumulations in the absence of re-accumulating ascites. We noted incidences of intra-abdominal collections, as well as other complications. Appropriate statistical tests were applied using SPSS 15.0. RESULTS: We identified 169 laparotomies in which HA-CMC was used and 347 in which HA-CMC was not used. The following were statistically similar in both cohorts: age, body mass index (BMI), primary site, surgery for recurrent disease, prior intraperitoneal surgery, and extent of current surgery. Intra-abdominal collections were seen in 6 (3.6%) of 169 HA-CMC cases compared to 10 (2.9%) of 347 non-HA-CMC cases (p=0.7). The rate of infected collections was similar in both groups (1.2% vs. 1.4%). In the subgroup that underwent tumor debulking, intra-abdominal collections were seen in 3 (11.5%) of 26 HA-CMC cases compared to 2 (5.4%) of 37 non-HA-CMC cases (p=0.6). CONCLUSIONS: HA-CMC use does not appear to be associated with postoperative intra-abdominal collections in patients undergoing laparotomy for uterine or cervical cancer. PMID- 20708226 TI - Lymphadenectomy during endometrial cancer staging: practice patterns among gynecologic oncologists. AB - OBJECTIVES: Several controversies surround lymphadenectomy for endometrial cancer; surgical approach, who to stage, and the anatomic borders of the lymphadenectomy. The purpose of this study was to identify practice patterns among gynecologic oncologists when performing a lymph node evaluation during staging for endometrial cancer. METHODS: A self-administered survey was sent via email to all SGO members on 3 occasions between 2/09 and 4/09. The survey addressed surgical approach, algorithms used to determine staging, and anatomic landmarks defining lymphadenectomy. RESULTS: Four hundred and six members (40%) responded. Eighty-two percent completed fellowship and 14% were fellows. Thirty four percent finished fellowship in 2000 or later. Eighty-five percent educate fellows/residents in either academic (65%) or private practice settings (20%). For a majority of cases 40% prefer laparotomy, 31% perform robotic surgery, and 29% use laparoscopy. Minimally invasive surgery was associated with university based practice (p=0.048). Most (53%) never/rarely use frozen section to determine whether or not to perform lymphadenectomy. A majority perform staging on all grade 2 and grade 3 cancers (66% and 90%, respectively). When performing paraaortic lymphadenectomy, 50% of respondents use the IMA as the upper border and 11% take the dissection to the renal vessels. Participants who completed fellowship in 2000 or later were less likely to go to the renal vessels (p=0.002). CONCLUSION: Current controversies in surgical staging for endometrial cancer are reflected in the practice patterns among gynecologic oncologists. At this point it is unclear if standardizing surgical practice patterns will improve outcomes for patients with endometrial cancer. PMID- 20708230 TI - Sperm ultrastructure, morphometry, and abnormal morphology in American black bears (Ursus americanus). AB - The objective of this study was to describe sperm ultrastructure, morphometry, and abnormal morphology in American black bears. Electroejaculation was successful in 53.8% (7/13) of the attempts, but urine contamination was common. Epididymal sperm samples were also obtained from five bears. Sperm had a paddle like head shape and the ultrastructure was similar to that of most other mammals. The most striking particularity of black bear sperm ultrastructure was a tightening of the nucleus in the equatorial region. Although the differences were not significant in all bears, the overall decrease in sperm nucleus dimensions during transport from the caput epididymis to the cauda suggested increasing compaction of the nucleus during maturation. For ejaculated sperm, nucleus length, width, and base width were 4.9, 3.7, and 1.8 MUm, respectively, whereas sperm head length, width, and base width were 6.6, 4.8, and 2.3 MUm, and midpiece, tail (including midpiece), and total sperm lengths were 9.8, 68.8, and 75.3 MUm. Evaluation of sperm cytoplasmic droplets in the epididymis revealed that proximal droplets start migrating toward a distal position in the caput epididymis and that the process was mostly completed by the time sperm reached the cauda epididymis. The proportion of morphologically normal sperm in the ejaculate was 35.6%; the most prevalent sperm defects were distal cytoplasmic droplets and bent/coiled tails. The morphology of abnormal sperm and the underlying ultrastructural defects were similar to that in other large domestic animals thus suggesting similar underlying pathogenesis of specific sperm defects and similar effects on fertility. PMID- 20708227 TI - Conservative surgery in early-stage cervical cancer: what percentage of patients may be eligible for conization and lymphadenectomy? AB - OBJECTIVE: To determine the proportion of young patients with early-stage invasive cervical cancer treated with radical hysterectomy who may have been eligible for fertility-sparing surgery consisting of cervical conization with pelvic lymph node dissection. METHODS: We retrospectively identified all patients with early-stage cervical cancer (stages IA1-IB1) who underwent a radical hysterectomy at The University of Texas M. D. Anderson Cancer Center between 1990 and 2009. We reviewed these patients' records to identify patients who were <40 years who had not previously undergone tubal ligation and who would have been considered candidates for cold-knife conization with pelvic lymph node dissection i.e., women with tumors smaller than 2 cm, low-risk histology (squamous, adenocarcinoma, or adenosquamous), and no lymphovascular space invasion (LVSI). RESULTS: A total of 507 patients with early-stage cervical cancer were identified who underwent radical hysterectomy during the review period. Of these women, 277 (55%) were 40 years or younger. Of these 277 patients, 75 (27%) had had a previous tubal ligation and 202 (73%) had not. Of these 202 patients potentially interested in fertility preserving surgery, 53 (26%) had favorable pathologic characteristics including low-risk histology, tumors <=2 cm in size and no LVSI present. Of these 53 patients, none had parametrial involvement or positive lymph nodes. CONCLUSION: Among 202 women with age younger than 40 years and no previous tubal ligation who underwent radical hysterectomy, 53 (26%) may have been eligible for fertility-sparing surgery such as cold-knife conization with pelvic lymph node dissection. PMID- 20708229 TI - Fertility of swamp buffalo following the synchronization of ovulation by the sequential administration of GnRH and PGF2alpha combined with fixed-timed artificial insemination. AB - This study evaluated fertility in swamp buffalo after synchronization of ovulation combined with fixed time artificial insemination. At the start of the study, designated day 0, from a group of 98 female Thai swamp buffalo, 55 buffalo (heifers n degrees = 20 and cows n degrees = 35) were selected to be synchronized with GnRH (Day 0) followed by PGF2alpha (Day 7) and a second treatment with GnRH (Day 9). All buffalo were inseminated at two fixed times 12 h and 24 h after the second injection of GnRH (Ovsynch+TAI group); a second group of 43 buffalo (heifers n degrees = 19 and cows n degrees = 24) were not treated and were artificially inseminated (AI) at natural estrus (AI group). Blood samples were taken 22 days after insemination to evaluate progesterone plasma levels. In the Ovsynch+TAI group, overall conception rate (CR; i.e. the number of cows with progesterone >4.0 ng/ml on day 22 after AI divided by the number of animals inseminated), was 38.1% and overall pregnancy rate (PR; i.e. the number of cows that were pregnant at day 50-60 after insemination divided by the number of animals inseminated), was 32.7%. In the AI group overall CR and PR was 34.9%. Within the Ovsynch+TAI group, CR and PR were reduced (P < 0.05) in heifers compared with cows (CR 15.0% vs. 51.4% for heifers and cows, respectively; PR 15.0% vs. 42.9% for heifers and cows, respectively). Within the AI group the efficacy of treatment was similar between heifers and cows (CR and PR 31.6% for heifers and 37.5% for cows). In conclusion, this study indicates that in swamp buffalo it is possible to synchronize ovulation and use timed artificial insemination with the Ovsynch+TAI protocol. PMID- 20708232 TI - Enhanced histone acetylation in somatic cells induced by a histone deacetylase inhibitor improved inter-generic cloned leopard cat blastocysts. AB - The objective was to determine whether alterations of histone acetylation status in donor cells affected inter-generic SCNT (igSCNT)-cloned embryo development. Leopard cat cells were treated with trichostatin A (TSA; a histone deacetylase inhibitor) for 48 h, and then donor cells were transferred into enucleated oocytes from domestic cats. Compared to non-treated cells, the acetylated histone 3 at lysine 9 (AcH3K9) and histone 4 at lysine 5 (AcH4K5) in the TSA group increased for up to 48 h (P < 0.05). The AcH3K9 signal ratios of igSCNT group was higher than control group 3 h after activation (P < 0.05). Treatment with TSA significantly increased total cell number of blastocysts (109.1 +/- 6.9 vs. 71.8 +/- 2.9, mean +/- SEM), with no significant effects on rates of cleavage or blastocyst development (71.1 +/- 2.8 vs. 67.6 +/- 2.9 and 12.2 +/- 2.6 vs. 11.0 +/- 2.6, respectively). When igSCNT cloned embryos were transferred into a domestic cat oviduct and recovered after 8 d, blastocyst development rates and total cell numbers were greater in the TSA-igSCNT group (20.7 +/- 3.0% and 2847.6 +/- 37.2) than in the control igSCNT group (5.7 +/- 2.2% and 652.1 +/- 17.6, P < 0.05). Average total cell numbers of blastocysts were approximately 4.4-fold higher in the TSA-igSCNT group (2847.6 +/- 37.2, n = 10) than in the control group (652.1 +/- 17.6, n = 8; P < 0.05), but were ~2.9-fold lower than in vivo cat blastocysts produced by intrauterine insemination (8203.8 +/- 29.6, n = 5; P < 0.001). Enhanced histone acetylation levels of donor cells improved in vivo developmental competence and quality of inter-generic cloned embryos; however, fewer cells in blastocysts derived from igSCNT than blastocysts produced by insemination may reduce development potential following intergeneric cloning (none of the cloned embryos were maintained to term). PMID- 20708231 TI - In vitro comparison of myometrial contractility induced by aglepristone-oxytocin and aglepristone-PGF2alpha combinations at different stages of the estrus cycle in the bitch. AB - The aim of this in vitro study was to compare the uterokinetic activity of oxytocin and dinoprost, the natural PGF2alpha, with or without aglepristone, in canine myometrial fibers. Thirty-three bitches were allocated into one of four groups, depending on their estrous stage and whether or not they had received a treatment with aglepristone (metestrus aglepristone, n = 5; metestrus without treatment, n = 9; anestrus aglepristone, n = 9; anestrus without treatment, n = 10). After hysterectomy, longitudinal and circular uterine strips were mounted in organ baths. Oxytocin or PGF2alpha (10 nmol/l to 10 micromol/l) were applied non cumulatively. A linear mixed effects models theory was used to compare the fiber effect, the aglepristone effect, and the treatment effect, from the area under the curves calculated from the contractile effect/concentration curves for each drug. Oxytocin and PGF2alpha induced concentration-dependent myometrial contractions in longitudinal (LF) and circular myometrial fibers (CF), indicating the presence of functional contractile oxytocin- and PGF2alpha-receptors in metestrus and anestrus. The contractile response to oxytocin was greater in LF than in CF in all of the groups; the response to PGF2alpha was greater in LF than in CF in non-treated bitches in anestrus and in treated bitches in metestrus. These results suggest that there is a difference in sensitivity or a heterogeneous distribution of oxytocin and PGF2alpha-receptors in the myometrial layers, which is independent of hormonal impregnation. The contractile response to oxytocin and PGF2alpha was significantly increased after aglepristone treatment in LF during metestrus, suggesting that the progesterone withdrawal induced by aglepristone has a role to play. The longitudinal myometrial layer also appeared to be the target for the two drugs at this stage. This study provides new information about canine uterine contractile activity, notably the differing behavior of myometrial CF and LF; in vivo studies are required to test the use of a combination of aglepristone and oxytocin in the treatment of canine pyometra. PMID- 20708233 TI - Dextran vitrification media prevents mucin coat and zona pellucida damage in rabbit embryo. AB - Vitrification of embryos is being increasingly important for cryopreservation in mammals. However, damage and toxicity has to be reduced even more. The composition of cryoprotective medium used to immerse the embryos affects viability and developmental potential. The aim of this work was to assess the effect of the Polyvinylalcohol-PVA- and Dextran addition to vitrification media on the in vitro development of rabbit embryos from superovulated and non superovulated females. Superovulation group were treated intramuscularly with 25 IU rhFSH. The vitrification media contained the same permeable cryoprotectans (Ethylene Glycol-ET- and Dimethyl Sulfoxide-Me2SO-) and different macromolecules (PVA and Dextran) in different combinations. There was a significantly higher proportion of embryos without damages in mucin coat or zona pellucida after warming (undamaged embryos) in the control than in the superovulation group (95.8% vs. 83.2%, respectively). The proportion of undamaged embryos was significantly affected by the vitrification solution composition. The rate of undamaged embryos after warming in media containing 20% Me2SO was significantly lower in media supplemented with PVA than in media with dextran (67.3 vs. 93.8, respectively). However, the proportion of undamaged embryos for the medium supplemented with dextran was similar for media with 15 or 20% Me2SO. In conclusion, the addition of dextran to the vitrification media improve the preservation of rabbit embryos and permits to reduce the amount of Me2SO for vitrification. Additionally, in vitro developmental ability of undamaged embryos were not affected by superovulation treatment nor vitrification media. PMID- 20708234 TI - Embryo production and possible species preservation by nuclear transfer of somatic cells isolated from bovine semen. AB - Somatic cells in semen are a potential source of nuclei for nuclear transfer to produce genetically identical animals; this is especially important when an animal has died and the only viable genetic material available is frozen semen. Usefulness of somatic cells obtained from fresh (cultured) and frozen (isolated, not cultured) bovine semen for nuclear transfer was evaluated. Twelve ejaculates were collected from nine bulls representing three breeds: Charolais, Brahman, and crossbred Rodeo bull. All samples were processed immediately and cell growth was obtained from seven of the twelve ejaculates (58.3%). Cells from three bulls (with the best growth rates) were evaluated by optical microscopy and used in cloning experiments. In culture, these cells exhibited classic epithelial morphology and expressed cytokeratin and vimentin, indicating they were of epithelial origin. When cells from the three bulls were used as donor cells, 15.9% (18/113), 34.5% (29/84), and 14.4% (13/90) of the fused embryos developed into blastocysts, respectively. Of the blastocyst stage embryos, 38.9% (7/18), 72.4% (21/29), and 61.5% (8/13) hatched, respectively. Somatic cells isolated (not cultured) from frozen bovine semen were also used in the cloning experiments. Although cleavage occurred, no compact morulae or blastocysts were obtained. In conclusion, epithelial cell growth was obtained from fresh bovine ejaculates with relatively high efficiency. Somatic cells from semen can be used as nucleus donors to produce cloned blastocyst-stage embryos. PMID- 20708235 TI - Effect of genotype at the MTNR1A locus and melatonin treatment on first conception in Sarda ewe lambs. AB - A sample of 423 Sarda ewe lambs from three different farms was used to evaluate the effect of one or two melatonin implants on the time of first conception. On each farm, 141 animals were divided into three groups. On June 30 these animals received either no treatment (Group C), 18 mg melatonin (Group M1, one implant), or 18 + 18 mg melatonin (Group M2, two implants). Thirty-five days after treatment, rams were introduced in the ewe lambs flock and subsequently removed after 40 days. Lambing dates were recorded between 150 and 190 days from the first day of male introduction. Genotyping and sequencing of the MT1 exon 2 were carried out to analyze the structure and the possible influence of the MT1 receptor gene on reproductive response to melatonin treatment. Melatonin-treated animals had a higher rate of pregnancy (P < 0.05) and lambed earlier (P < 0.05) compared with untreated animals. Single nucleotide polymorphisms were found in exon II of MT1 gene at positions C606T and G612A leading to genotypes C/C, C/T or T/T and +/+, +/- and -/-, respectively. Melatonin-treated animals of +/+ genotype showed a higher number of pregnancies (P < 0.05) and lambed earlier (P < 0.05) compared to untreated animals of the same genotype. Melatonin treatment did not affect reproductive activity in any other genotype analyzed. No correlation between genotype and the time of first conception was found in untreated animals. Concluding data revealed the positive effect of melatonin treatment on the time of first conception in ewe lambs and highlighted that +/+ genotype is able to influence reproductive response to melatonin treatment. PMID- 20708236 TI - Oxytocin treatment immediately after calving does not reduce the incidence of retained fetal membranes or improve reproductive performance in crossbred Zebu cows. AB - The objective was to determine the effect of oxytocin treatments after calving on the incidence of RFM and reproductive performance in dual purpose cows under tropical conditions. Five hundred thirty six pluriparous, crossbred Zebu cows were randomly assigned to two groups: Oxy (n = 280): cows were given 30 IU of oxytocin im immediately after normal unassisted calving, and again 6 h later; C (n = 256): control. Expulsion of fetal membranes was evaluated 24 h after delivery. After a 30-d voluntary waiting period, AI was done 12 h after cows were detected in estrus. Oxytocin had no effect on the incidence of RFM (4.6 vs. 3.1% for Oxy and C, respectively, P > 0.05). Cows in Oxy and C had similar first service and overall pregnancy rates (54.0 vs. 47.8% and 75.4 vs. 73.4%; respectively, P > 0.05). There were no differences between Oxy and C for calving to first estrus (83.6 +/- 3.7 vs. 77.2 +/- 3.8 d) and calving to conception intervals (113.6 +/- 5.0 vs. 110.5 +/- 5.2 d), as well as rates of anestrus (13.6 vs. 13.7%), repeat breeding (21.8 vs. 20.7%), and culling (15.7 vs. 16.4%). In conclusion, oxytocin treatment after normal unassisted calving did not significantly reduce the incidence of RFM or improve reproductive performance in crossbred Zebu cows under tropical conditions. PMID- 20708237 TI - Effect of feeding a docosahexaenoic acid-enriched nutriceutical on the quality of fresh and frozen-thawed semen in Holstein bulls. AB - The aim of the current study was to investigate the effect of feeding a DHA enriched nutriceutical on the in vitro quality and sperm motility parameters of fresh and frozen-thawed bull semen assessed by CASA. Samples were obtained from nineteen Holstein bulls used for semen collection at Semen Production Center, Karaj, Iran. Control group (n = 10) were fed a standard concentrate feed while treatment group bulls (n = 9) had this standard feed top dressed with 100 g of a commercially available DHA-enriched nutriceutical. Semen quality was assessed on ejaculates collected at the baseline and after 5, 9, and 12 weeks of supplementation. Classical semen evaluation, assessment of sperm motility (subjective and computer-assisted), viability (eosin-nigrosin), and hypo-osmotic swelling test (HOST) were conducted. Semen volume, sperm concentration, and consequently total sperm output were not affected by dietary treatment (P > 0.05). Feeding the nutriceutical was indeed found to affect sperm motility parameters assessed by CASA after 9 weeks of trial. The treatment has improved total motility (P < 0.01), progressive motility (P < 0.05), average path velocity (P < 0.05), HOST-positive (P < 0.01), and proportion of rapid spermatozoa (P < 0.01) in the fresh semen of bulls. Moreover, the proportion of viable spermatozoa increased (P < 0.05) in the ejaculates collected from nutriceutical-fed bulls compared to the control after 12 weeks of feeding trial. The post-thawed HOST and sperm motility data obtained by CASA did not differ between two groups (P > 0.05). On the other hand, dietary supplementation did not affect body weight, BCS and scrotal circumference. Consequently, it can be concluded that dietary DHA supplementation or its precursors, improve in vitro quality and motility parameters of fresh semen assessed by CASA in Holstein bulls. However, this effect was not pronounced in frozen-thawed semen. PMID- 20708238 TI - Large scale in vivo risk assessment of bovine viral diarrhea virus (BVDV) transmission through transfer of bovine embryos produced via somatic cell nuclear transfer (SCNT). AB - The objective was to use the bovine viral diarrhea virus (BVDV) as a model to assess the risk of infectious disease transmission in the system of in vitro embryo production and transfer via somatic cell nuclear transfer (SCNT) technology. The risks of BVDV transmission in the SCNT embryo production were previously evaluated. In that in vitro study, following standard operating procedures (SOP), including pre-nuclear transfer donor cell testing, oocyte decontamination and virus-free cell and embryo culture conditions, SCNT embryos produced were free of detectable viral RNA. The current study focused on the evaluation of the potential risk of disease transmission from SCNT embryos to recipients, and the risk of producing persistently infected animals via SCNT embryo transfer. Blood samples were collected from 553 recipients of SCNT embryos and 438 cloned calves and tested for the presence of BVDV viral RNA via a sensitive real time PCR method. All samples tested were negative. These results, in conjunction with the previous in vitro study, confirmed that the established SCNT embryo production and transfer system is safe and presents no detectable risk of disease transmission. PMID- 20708240 TI - Social behavior and kin discrimination in a mixed group of cloned and non cloned heifers (Bos taurus). AB - For more than ten years, reproductive biotechnologies using somatic cell nuclear transfer have made possible the production of cloned animals in various domestic and laboratory species. The influence of the cloning process on offspring characteristics has been studied in various developmental aspects, however, it has not yet been documented in detail for behavioral traits. Behavioral studies of cloned animals have failed to show clear inter-individual differences associated with the cloning process. Preliminary results showed that clones favor each other's company. Preferential social interactions were observed among cloned heifers from the same donor in a mixed herd that also included cloned heifers and control heifers produced by artificial insemination (AI). These results suggest behavioral differences between cloned and non-cloned animals and similarities between clones from the same donor. The aim of the present study was to replicate and to extend these previous results and to study behavioral and cognitive mechanisms of this preferential grouping. We studied a group composed of five cloned heifers derived from the same donor cow, two cloned heifers derived from another donor cow, and AI heifers. Cloned heifers from the same donor were more spatially associated and interacted more between themselves than with heifers derived from another donor or with the AI individuals. This pattern indicates a possible kin discrimination in clones. To study this process, we performed an experiment (using an instrumental conditioning procedure with food reward) of visual discrimination between images of heads of familiar heifers, either related to the subjects or not. The results showed that all subjects (AI and cloned heifers) discriminated between images of familiar cloned heifers produced from the same donor and images of familiar unrelated heifers. Cattle discriminated well between images and used morphological similarities characteristic of cloned related heifers. Our results suggest similar cognitive capacities of kin and non kin discrimination in AI and cloned animals. Kinship may be a common factor in determining the social grouping within a herd. PMID- 20708239 TI - Detection of nerve growth factor (NGF) and its specific receptor (TrkA) in ejaculated bovine sperm, and the effects of NGF on sperm function. AB - The objective was to confirm the presence of nerve growth factor (NGF) and its specific receptor, TrkA, in ejaculated bovine sperm, and to investigate the effects of NGF on specific aspects of bovine sperm function. Both TrkA transcripts and immunoreactivity typical of the translated protein were detected by RT-PCR and western blotting. However, only the NGF protein was detected in bovine sperm using western blotting, and there was no RT-PCR evidence for NGF transcripts in sperm. Using an immunofluorescent technique, NGF-immunoreactivity was localized to the sperm head and tail, whereas that of TrkA was detected in the acrosomal cap, nucleus, and tail regions When sperm were treated with exogenous NGF, both leptin secretion and sperm viability were increased (P < 0.05); moreover, the percentages of late apoptotic and dead sperm were increased (P < 0.05). However, NGF had no effects on insulin secretion, mitochondrial activity, intracellular calcium levels, or the acrosome reaction of sperm (P > 0.05). In conclusion, the presence of TrkA transcript, as well as NGF and TrkA immunoreactivity were confirmed in bovine sperm. Furthermore, exogenous NGF had significant effects on the secretion of leptin, cell viability, and sperm apoptosis. This study provided strong evidence that NGF/TrkA may have roles in regulation of sperm physiology and perhaps male fertility and infertility. PMID- 20708241 TI - Directional freezing as an alternative method for cryopreserving rhesus macaque (Macaca mulatta) sperm. AB - The objective was to develop a freezing protocol using a directional freezing (DF) technique for cryopreservation of rhesus macaque sperm and achieve a survival rate comparable to that achieved with a conventional freezing (CF) technique. Rhesus macaque sperm frozen with a DF technique, with cooling rates of 12 or 16 degrees C/min, had higher post-thaw motility (P < 0.05) than those cooled at 7 degrees C/min (59.3, 61.1, and 50.3%, respectively). Furthermore, sperm cryopreserved with 5% glycerol and a DF technique had similar frozen-thawed sperm motility to those cryopreserved by a CF technique (63.7 vs. 53.9%, P > 0.05). The function of sperm cryopreserved at the optimized cooling rate using a DF technique was evaluated by in vitro fertilization of oocytes collected from gonadotropin-stimulated rhesus macaques. Of the 38 mature oocytes collected, 78.9% were fertilized and 71.1, 47.4, and 42.1% of the oocytes developed to the 2 cell, morulae, and blastocyst stages, respectively. In conclusion, rhesus macaque sperm was effectively cryopreserved using a DF technique, providing a new and effective method for genetic preservation in this important species. PMID- 20708242 TI - Dietary omega-3 fatty acids (fish oils) have limited effects on boar semen stored at 17 degrees C or cryopreserved. AB - To evaluate the influence of dietary supplementation of omega-3 polyunsaturated fatty acids (n-3 PUFA) on storage of boar semen, three experiments were conducted: two involved long-term, fresh semen storage (Exp. 1 and Exp. 2), whereas the other involved cryopreservation (Exp. 3). Boars were allocated randomly to three dietary treatments (for 6-7 mo). In addition to a daily allowance of 2.5 kg of a basal diet, they received: 1) 62 g of hydrogenated animal fat (AF); 2) 60 g of menhaden oil (MO), containing 18% docosahexanoic acid (DHA) and 15% eicosapentanoic acid (EPA); or 3) 60 g of tuna oil (TO), containing 33% DHA and 6.5% EPA. In Experiment 1 (n = 26) and Experiment 2 (n = 18), semen was cooled and stored in vitro for several days at 17 degrees C before assessment, whereas in Experiment 3 (n = 18), viability, motility, acrosomal integrity, susceptibility to peroxidation (LPO), and DNA fragmentation were determined in fresh and frozen-thawed sperm. In Experiment 1, sperm from boars fed TO had better resistance to fresh storage; even after 7 or 9 d of storage at 17 degrees C, there were more (P = 0.03) motile sperm in boars fed TO (>60%) than in those fed AF or MO. In Experiment 2, fish oil supplementation did not influence any aspect of sperm quality during semen storage (P > 0.10). In Experiment 3, cryopreservation decreased the proportion of motile and viable frozen-thawed sperm as well as acrosomal integrity and increased DNA fragmentation and LPO (P < 0.01) relative to fresh semen, although sperm quality was unaffected by treatments (P > 0.09). In conclusion, although adding fish oil to the diet failed to significantly improve the quality of cryopreserved boar sperm, inconsistent responses of long-term storage of cooled sperm to dietary n-3 PUFA supplementation warrant further investigation. PMID- 20708243 TI - Influence of synthetic lamprey GnRH-III on gonadotropin release and steroid hormone levels in gilts. AB - Based on the supposition that lamprey GnRH-III (lGnRH-III) elicits FSH releasing activity in swine, synthetic lGnRH-III (peforelin, Maprelin(r) XP10) was used in puberal estrus synchronized gilts. The secretion of reproductive hormones FSH, LH, estradiol and progesterone was analyzed, and follicle growth and ovulation recorded. Altogether, 24 German Landrace gilts were treated after an 18-day long synchronization of the estrus cycle with Regumate(r) as follows: 48 h after the last Regumate(r) feeding they received im either 150 MUg Maprelin(r) XP10 (lGnRH III, group Maprelin, n = 6), 50 MUg Gonavet Veyx(r) (GnRH-I agonist, group GnRH, n = 6), 850 IE Pregmagon(r) (eCG, group eCG, n = 6) or saline (group Control, n = 6). Additionally, in eight gilts the concentrations of FSH and LH were analyzed after treatment with 150 MUg Maprelin(r) XP10 (n = 3), 50 MUg Gonavet Veyx(r) (n = 3) or saline (n = 2) at mid-cycle (day 10 of the estrus cycle). Blood samples were collected via implanted jugular vein catheters. Ovarian features were judged endoscopically at the end of the Regumate(r) feeding and on days 5 and 6 after treatment. Maprelin(r) XP10 had no effect on FSH release in gilts; neither at the pre-ovulatory period or at mid-cycle. Furthermore, LH levels were unaffected. In contrast, GnRH-I agonist stimulates FSH release, however less compared to LH secretion. LH secretion was induced by GnRH-I both during the follicular phase and at mid-cycle. Equine CG did not stimulate the release of pituitary hormones FSH and LH due to its direct action on the ovary. Increased estradiol concentrations during days 2 to 5 after Regumate(r) in all treatment groups indicated pre-ovulatory follicle growth in gilts. Equine CG stimulated a higher (P < 0.01) number of ovulatory follicles compared to the other treatment groups. All together, 83 to 100 % of gilts ovulated by day 6 post treatment. In summary, results of our study on reproductive hormone secretion do not provide evidence that synthetic lGnRH-III (Maprelin(r) XP10) selectively releases FSH in estrus synchronized gilts. PMID- 20708244 TI - Differential thermal sensitivity between the recipient ooplasm and the donor nucleus in Holstein and Taiwan native yellow cattle. AB - The objective of this study was to compare thermal sensitivity of recipient ooplasm and donor nucleus from Holstein and Taiwan native yellow (TY) cows. Oocytes and cumulus cells from each breed were incubated at 43 degrees C (heat shock) or 38.5 degrees C (control) for 1 h prior to nucleus transplantation. Reconstructed embryos cloned by transfer of non-heated Holstein donor cells to heat-shocked Holstein ooplasm (Ho(+)-Hd-) had a lower (P < 0.05) blastocyst rate than those cloned from non-heated Holstein ooplasm receiving heated (Ho--Hd(+)) or non-heated (Ho--Hd-) Holstein donor cells (11.3 vs. 34.3 or 36.8%). Heat shocked donor cells from either Holstein or TY cows did not significantly affect blastocyst rates of reconstructed embryos produced from Holstein ooplasm (30.6 32.9%). In contrast, blastocyst rates of reconstructed embryos generated with heat-shocked Holstein ooplasm were lower (P < 0.05) than that with heat-shocked TY ooplasm (11.2 vs 45.2%). Without heat shock, embryos reconstructed by transferring donor cells to ooplasm of Holstein or TY cows had similar (P > 0.05) blastocyst rates (28.9-33.3%). Transplantation of reconstructed embryos (n = 30) to recipients (n = 23) resulted in three live calves, derived from embryos cloned with TY ooplasm and donor nuclei from either Holstein (n = 2) or TY cows (n = 1). In conclusion, ooplasm of TY cattle was more resistant to heat stress than that derived from Holsteins; therefore, ooplasm may be a major determinant for thermal sensitivity in bovine oocytes and embryos. PMID- 20708245 TI - Large-scale in vitro embryo production and pregnancy rates from Bos taurus, Bos indicus, and indicus-taurus dairy cows using sexed sperm. AB - Herein we describe a large-scale commercial program for in vitro production of embryos from dairy Bos taurus, Bos indicus, and indicus-taurus donors, using sexed sperm. From 5,407 OPU, we compared the number of recovered oocytes (n = 90,086), viable oocytes (n = 64,826), and embryos produced in vitro from Gir (Bos indicus, n = 617), Holstein (Bos taurus, n = 180), 1/4 Holstein * 3/4 Gir (n = 44), and 1/2 Holstein-Gir (n = 37) crossbred cows, and the pregnancy rate of recipient cows. Viable oocytes were in vitro matured (24 h at 38.8 degrees C, 5% CO(2) in air) and fertilized by incubating them for 18 to 20 h with frozen-thawed sexed sperm (X-chromosome bearing) from Gir (n = 8) or Holstein (n = 7) sires (2 * 10(6) sperm/dose). Embryos were cultured in similar conditions of temperature and atmosphere as for IVM, with variable intervals of culture (between Days 2 and 5) completed in a portable incubator. All embryos were transferred fresh, after 24 to 72 h of transportation (up to 2,000 km). On average, 16.7 +/- 6.3 oocytes (mean +/- SEM) were obtained per OPU procedure and 72.0% were considered viable. Total and viable oocytes per OPU procedure were 17.1 +/- 4.5 and 12.1 +/- 3.9 for Gir cows, 11.4 +/- 3.9 and 8.0 +/- 2.7 for Holstein cows, 20.4 +/- 5.8 and 16.8 +/- 5.0 for 1/4 Holstein * 3/4 Gir, and 31.4 +/- 5.6 and 24.3 +/- 4.7 for 1/2 Holstein-Gir crossbred females (P < 0.01). The mean number of embryos produced by OPU/IVF and the pregnancy rates were 3.2 (12,243/ 3,778) and 40% for Gir cows, 2.1 (2,426/1,138) and 36% for Holstein cows, 3.9 (1,033/267) and 37% for 1/4 Holstein * 3/4 Gir, and 5.5 (1,222/224), and 37% for 1/2 Holstein-Gir. In conclusion, we compared oocyte yield from two levels of indicus-taurus breeds and demonstrated the efficiency of sexed sperm for in vitro embryo production. Culturing embryos during long distance transportation was successful, with potential for international movement of embryos. PMID- 20708246 TI - Effect of extender supplementation with various antimicrobial agents on viability of Brucella ovis and Actinobacillus seminis in cryopreserved ovine semen. AB - The objective was to determine the effectiveness of various antimicrobial agents added to semen extender for inactivation of B. ovis or A. seminis in ovine semen after cryopreservation. In Experiment 1, 20 ejaculates from a crossbred ram infected with B. ovis were cryopreserved in Tris-based extenders with various antimicrobial agents: (I) control without antibiotics, (II) with penicillin and streptomycin (1000 IU/mL and 1 mg/mL, respectively), (III) lincomycin (0.15 mg/mL), (IV) sulphadiazine (0.60 mg/mL), and (V) gentamicin sulphate (0.25 mg/mL). Semen was stored in 0.25 mL straws at a final concentration of 150 * 10(6) spermatozoa/mL. After thawing (37 degrees C for 30 s), sperm total motility (TM), sperm morphology, integrity of sperm membranes, and bacterial growth were assessed. In Experiment 2, six B. ovis isolates were separately inoculated into aliquots of a fresh ejaculate from a B. ovis-free ram. Mock inoculated semen was processed for cryopreservation using the five extenders described above, and bacteriologically evaluated after thawing. In Experiment 3, sensitivity of A. seminis to the same antimicrobial agents was evaluated by inoculating an ejaculate from an A. seminis and B. ovis-free ram. There were no significant differences among treatments in post-thawing sperm parameters. B. ovis was isolated from 100% (20/20), 0% (0/20), 95% (19/20), 100% (20/20), and 5% (1/20) of semen samples diluted in tris-based extender of untreated (I) and treated semen samples with antimicrobial agents II, III, IV, and V, respectively. Frequencies of isolation from samples treated with antimicrobial agent II and V were significantly lower than untreated ones (P < 0.05). There were no significant differences in the profile of antimicrobial resistance of different B. ovis isolates. A. seminis had a similar sensitivity to the antimicrobial agents. We concluded that addition of a combination of penicillin and streptomycin or gentamicin alone to ram semen cryo-extenders inactivated B. ovis and A. seminis. PMID- 20708247 TI - Spermatogonia-specific proteins expressed in prepubertal buffalo (Bubalus bubalis) testis and their utilization for isolation and in vitro cultivation of spermatogonia. AB - Buffalo is an economically important livestock species in Asia. Little is known about male germ line technology owing to lack of sufficient understanding regarding expression of germ- and somatic-cell specific-proteins in the testis. In this study, we identified UCHL-1 (PGP 9.5) and lectin- Dolichos biflorus agglutinin (DBA) as specific markers for spermatogonia in buffalo testis. Expression of germ-cell and pluripotency-specific proteins such as DDX4 (VASA) and POU5F1 (OCT3/4) were also present in spermatogonia. Interestingly, the expression of somatic cell-specific proteins such as VIMENTIN and GATA4 were also detected in germ cells. Using two-step enzymatic digestion followed by differential plating and Percoll density-gradient centrifugation, an approximately 55% spermatogonia-enriched cell population could be obtained from the prepubertal buffalo testis. Isolated spermatogonia could survive and proliferate in vitro in DMEM/F12 medium containing 10% fetal bovine serum in the absence of any specific growth factors for a week. Cultured spermatogonia showed DBA affinity and expressed DDX4 and POU5F1. These results may help to establish a long-term culture system for buffalo spermatogonia. PMID- 20708248 TI - Improved in vitro development of OPU-derived bovine (Bos taurus) embryos by group culture with agarose-embedded helper embryos. AB - The average number of oocytes collected by ovum pick up (OPU) from Bos taurus cattle is <8 per live donor. The objective was to determine whether development of small numbers of cattle embryos (produced by OPU and IVF), was enhanced by including "helper" embryos, produced from abbatoir-derived oocytes and embedded in agarose. Oocytes were from abbatoir-derived ovaries (Experiments 1 and 2) or OPU of elite donors (Experiment 3). In Experiment 1, cleaved embryos (2-8 cells), were randomly allocated. Controls were groups of 1, 3, 5, 10, and 20 cleaved embryos cultured in 50 MUL serum-free SOF, whereas treatments were groups of 1, 3, and 5 embryos freely cultured along with helpers in groups of either 9, 7 or 5 embedded in agarose per droplet. Therefore, there were 10 cleaved embryos per droplet in combinations of 1 + 9, 3 + 7 or 5 + 5 (free + helper), respectively. There was an increase in the progression to blastocyst for 1-5 embryos per droplet, compared to 10 and 20 (6.6-24.2% vs. 39.2-43.3%, P < 0.05). For the tested free embryos, those cultured with helpers had increased blastocyst development over their control counterparts (39.3-49.5% vs. 6.6-24.2%, P < 0.05). When the number of embryos per droplet was 10 or 20, blastocyst percentage was similar (39.2-49.5%, P > 0.05). In Experiment 2, addition of an agarose chip to the culture medium did not significantly affect development to the blastocyst stage. In Experiment 3, after fertilizing OPU oocytes with sorted X-sperm, a group of three cleaved embryos were cultured in a droplet with either seven helpers (3 + 7) or alone (3 + 0). Blastocyst development of OPU oocytes in the 3 + 7 group was 37.1%, higher than that in the 3 + 0 group (11.8%, P < 0.05). In conclusion, limited numbers of OPU/IVF oocytes had competent development when cultured with helpers (embedded in agarose to provide physical separation). PMID- 20708249 TI - Diurnal variation in LH and temporal relationships between oscillations in LH and progesterone during the luteal phase in heifers. AB - Diurnal variation in progesterone and LH during the luteal phase and the temporal relationships between oscillations of the two hormones were studied in 10 heifers by collection of blood samples at 0100, 0700, 1300, and 1900 h each day, beginning on Day 1 (Day 0 = ovulation). Concentration of LH on Days 5-9, but not on Days 10-14, was lower (P < 0.05) at 0700 h (0.25 +/- 0.02 ng/mL) than at each of the other three hours (combined, 0.32 +/- 0.02 ng/mL). An oscillation was defined as an uninterrupted increase and decrease in concentrations. The number of LH oscillations/heifer with the peak at 1900 h (6.1 +/- 0.7) throughout the luteal phase was greater (P < 0.01) than for each of the other hours (combined, 4.0 +/- 0.2). Diurnal variation in progesterone was not detected. Only statistically defined LH oscillations were used to determine the temporal association between the peak of an LH oscillation and various components of a progesterone oscillation. On Days 5-14, the frequency of the peak of an LH oscillation occurring at the same hour as the peak of a progesterone oscillation (26/48, 54%) was greater (P < 0.0001) than at the progesterone nadir (3/48, 6%). The frequency of the LH peak occurring during increasing (11/34, 32%) and decreasing (8/25, 32%) progesterone concentrations was intermediate (P < 0.05). Results indicated the following: 1) diurnal variation occurred in LH as determined by concentration and by the hour of the peak of an oscillation; and 2) LH oscillations were temporally and positively related to progesterone oscillations. PMID- 20708250 TI - The effect on preimplantation embryo development of non-specific inflammation localized outside the reproductive tract. AB - The aim of this study was to evaluate the possible effect of non-specific acute inflammation localized outside the reproductive tract on the quality of preimplantation embryos. In fertilized female mice two experimental models of inflammation were used-trinitrobenzene sulfonic acid colitis and carrageenan paw oedema. Inflammation was induced during the cleavage period of embryo development and embryos were collected at 92 h post hormonal synchronization. Stereomicroscopical evaluation of in vivo derived embryos showed that the presence of inflammation in the maternal body did not affect their basic developmental abilities, i.e. there were no significant differences in the proportion of early blastocysts, morulas, slowly developing embryos and degenerates between embryonic pools obtained from mothers with induced inflammation and control mothers. In the next step, non-degenerated embryos from all mothers were cultured in vitro under standard conditions for another 24 h, and the average cell number (fluorescence DNA staining) and the incidence of cell death (fluorescence viability staining combined with TUNEL assay) were evaluated. The majority of cultured embryos reached expanded blastocyst stage. There were no significant differences in the average cell numbers of blastocysts, but blastocysts derived from mothers with induced inflammation showed a significantly higher incidence of dead cells in both experiments. The majority of dead cells were of apoptotic origin. These results show that non-specific inflammation localized outside the reproductive tract has no detrimental effect on the preimplantation embryo growth; however it can affect the embryo quality. PMID- 20708251 TI - Noninvasive bovine oocyte quality assessment: possibilities of a single oocyte culture. AB - Although bovine embryos are routinely produced in vitro for several decades, there still exists a critical need for techniques to accurately predict the oocyte's developmental competence in a noninvasive way, before the in vitro embryo production procedure. In this review, several noninvasive methods to evaluate oocyte quality are discussed, such as morphological assessment of the cumulus oocyte complex and the use of brilliant cresyl blue. Because an individual oocyte and embryo culture method can possibly generate additional insights into the factors that determine oocyte quality, the second part of this review summarizes the state of the art of bovine single oocyte culture. The optimization of individual in vitro embryo production can obviously accelerate the quest for better noninvasive oocyte quality markers, because more information about the oocyte's requirements and intrinsic quality will be revealed. Although each step of in vitro culture has to be re-examined in light of the hampered production of single embryos, the reward at the end will be substantial. Individual scored oocytes will be traceable along the in vitro embryo production procedure and the final blastocyst outcome can be linked to the original oocyte quality and follicular environment without the bias caused by simultaneously developing embryos. PMID- 20708252 TI - Variation in sexual behaviors in a group of captive male Yangtze finless porpoises (Neophocaena phocaenoides asiaeorientalis): motivated by physiological changes? AB - Most male mammals in temperate regions demonstrate seasonal sexual behaviors that coincide with seasonal variations in gonadal activities and androgen hormones. The Yangtze finless porpoise is a temperate freshwater cetacean species and an obvious seasonal breeder. To investigate the relationship between sexual behavior and gonadal activity in this animal, testicular size (volume) and structure (ultrasonogram pixel intensity) of two adult male porpoises (AF, AB) and one sub adult male (TT) were longitudinally monitored from November 2008 to November 2009. Serum testosterone concentration was also monitored during the same period. Variations in the frequency of sexual behavior in AF and AB had similar, but seasonal trends. Their testicular size and pixel intensity also varied seasonally. Testicular size increased in March, peaked from April through June, and decreased gradually from August through September, whereas testicular pixel intensity started to increase in early February. The frequency of sexual behavior was positively correlated with testicular volume and pixel intensity (P = 0.000018 and P = 0.00012, respectively) in AF. Serum testosterone concentrations also varied. The sub-adult male porpoise, TT, was undergoing puberty, as evidenced by its marked increase in testicular volume, testicular pixel intensity, and serum testosterone concentrations from the beginning of 2009. Interestingly, TT exhibited the highest frequency of sexual behavior, most of which was same-sex pairing. However, its oversexed behavior neither quantitatively correlated with its smaller testicular volume (P = 0.61) nor with its testicular pixel intensity (P = 0.69). PMID- 20708253 TI - Fluoride releasing restorative materials: Effects of pH on mechanical properties and ion release. AB - OBJECTIVES: Secondary caries and restorative fracture are the two main reasons for restoration failures. Fluoride ion (F) release can help inhibit caries. Plaque pH after a sucrose rinse can decrease to a cariogenic pH of 4-4.5. The objective of this study was to investigate the effects of solution pH and immersion time on the mechanical properties and F release of restorative materials. METHODS: Three resin-modified glass ionomers (Viremer, Fuji II LC, Ketac Nano), one compomer (Dyract Flow), and one composite (Heliomolar), were tested. Flexural strength and elastic modulus were measured before and after 84d of immersion in solutions of pH 4, 5.5, and 7. F release was measured as a function of pH and immersion time. RESULTS: Immersion and material type had significant effects on mechanical properties. Vitremer had a flexural strength (mean+/-sd; n=6) of 99+/-25MPa before immersion; it decreased to 32+/-9MPa after 84d of immersion (p<0.05). In comparison, Heliomolar had a smaller strength loss, decreasing from 99+/-9MPa to 65+/-7MPa (p<0.05). Solution pH had little effect on mechanical properties. For example, Fuji II LC had a strength of 63+/-15MPa at pH 4, similar to 61+/-30MPa at pH 5.5, and 56+/-22MPa at pH 7 (p>0.1). In contrast, solution pH had a significant effect on F release. F release at 84d for Fuji was 609+/-25MUg/cm(2) at pH 4, much higher than 258+/-36MUg/cm(2) at pH 5.5, and 188+/-9MUg/cm(2) at pH 7. SIGNIFICANCE: The restoratives tested were able to greatly increase the F release at acidic, cariogenic pH, when these ions are most needed to inhibit caries. However, mechanical properties of these F-releasing restoratives degraded significantly in immersion. Efforts are needed to develop F releasing restoratives with high levels of sustained F release, as well as improved durability of mechanical properties for large stress-bearing restorations. PMID- 20708255 TI - Effect of specialist retrieval teams on outcomes in children admitted to paediatric intensive care units in England and Wales: a retrospective cohort study. AB - BACKGROUND: Intensive care services for children have undergone substantial centralisation in the UK. Along with the establishment of regional paediatric intensive care units (PICUs), specialist retrieval teams were set up to transport critically ill children from other hospitals. We studied the outcome of children transferred from local hospitals to PICUs. METHODS: We analysed data that were gathered for a cohort of children ( 900ng/ml at diagnosis have demonstrated to be a good predictor for OS and PFS in this cohort of patients. PMID- 20708264 TI - Evaluation of beauvericin genotoxicity with the chromosomal aberrations, sister chromatid exchanges and micronucleus assays. AB - Beauvericin, a naturally occurring contaminants of food and feeds, has been implicated in several mycotoxicoses; however, there is little information on its genotoxicity. Therefore, the genotoxic and cytotoxic effects of beauvericin in in vitro cultures of human lymphocytes were investigated with chromosome aberrations (CAs), sister-chromatid exchanges (SCEs), micronuclei (MN) as well as mitotic, proliferative and nuclear division indices. Beauvericin caused a significant concentration-dependent increase in chromosomal aberrations, sister-chromatid exchanges and micronuclei. It also significantly decreased the mitotic index at the two highest concentrations. However, no significant change in the proliferative and nuclear division indices was found. The results indicated that BEA is genotoxic to human lymphocytes in vitro. PMID- 20708265 TI - Minerals as additives for decreasing the toxicity of Mediterranean contaminated dredged sediments. AB - The management of dredged sediments is a priority issue in the Mediterranean sea where sediments are historically polluted. The aims of this study were to evaluate the toxicity of port sediment samples and the effect of three mineral additives (hematite, zerovalent iron (ZVI) and natural zeolite (NZ)) on sediment elutriate toxicity. Four sediments (A, B, C and D) were provided by port authorities after composting procedure; particle size, particulate organic carbon, metals and organic pollutants (TBT, PAHs, PCBs) were determined in whole sediments. Elutriates from these composted sediments were analyzed by determining toxicity level using oyster (Crassostrea gigas) larvae bioassay, metal and dissolved organic carbon concentrations. Toxicity, measured on undiluted elutriates (250 g/L), decreased as follows: A>=B>C~D. The treatment of sediments with mineral additives (5%) revealed that hematite tends to decrease the elutriate toxicity in all samples, particularly in samples B and C. This effect may be related to metal concentration decrease in elutriates, in particular Cu and Zn, that have a significant toxic effect on oyster larvae. ZVI and NZ have a variable influence on elutriate toxicity. Results suggest that hematite may be a possible candidate for decreasing chemical concentration and improving the quality of elutriates. Hematite could be used for sediment stabilization prior to the deposit in a specific site or landfill. PMID- 20708266 TI - Joint action of binary mixtures of cetyltrimethyl ammonium chloride and aromatic hydrocarbons on Chlorella vulgaris. AB - The joint action of binary mixtures of cetyltrimethyl ammonium chloride (CTAC), a cationic surfactant, and six aromatic hydrocarbons (AHs) on green algae Chlorella vulgaris was investigated. In single systems, inhibition efficiency of CTAC on the growth of algae was much higher than that of AHs (benzene, toluene, phenol, nitrobenzene, phenanthrene and fluoranthene). In combined systems, the toxicity of CTAC was enhanced by low concentrations of AHs. 96 h EC(50) value of CTAC varied from 145+/-13.35-56+/-8.27 to 56+/-8.27-226+/-8.22 MUg/L when exposed to 0 1.13 and 1.13-100.84 MUg/L fluoranthene, respectively. Zeta potential of algae initially increased and then decreased with the increase of fluoranthene concentration, whereas residual CTAC concentration displayed an opposite trend in the combined system. These results of this investigation showed that fluoranthene influenced the sorption of CTAC by C. vulgaris. The above results indicated that cationic surfactants and AHs have synergetic toxic effects on aquatic biota. PMID- 20708267 TI - Validation of a refined short-term adult fish reproductive test with improved power for mummichog (Fundulus heteroclitus) to test complex effluents. AB - Short-term adult fish reproductive tests are widely used to assess the toxicity of chemicals and waste streams. However, these tests often have low power to detect differences in egg production among treatments, due to high variance and small sample sizes, limiting their effectiveness for informing regulatory decisions. A protocol for a fish reproductive test using mummichog (Fundulus heteroclitus) was refined to increase statistical power. Three studies using the original protocol were compared with three studies using the refined protocol. Tank pre-selection and sample size increased the a priori power from 11.2% to 85.7%. After exposure, average power levels were 62.0%, a more than five-fold increase compared to studies that used the original protocol (power of 15.0%). There was a high level of consistency compared to the original protocol; differences >33% in female and male gonad size and egg production could be detected among treatments. This study demonstrates that a refinement process can address shortcomings in short-term adult fish reproductive protocols, creating a solid foundation for further standardization and possible regulatory use. PMID- 20708268 TI - Factors affecting members' evaluation of agri-business ventures' effectiveness. AB - This paper presents work to identify factors affecting effectiveness of agri business ventures (A-BVs) on the side of providers as perceived by their members. A survey was conducted among 95 members of A-BVs in Zanjan province, Iran. To collect data, a questionnaire was designed. Two distinct groups of A-BVs with low (group 1) and high (group 2) perceived (evaluated) levels of effectiveness were revealed. The study showed that there were significant differences between the two groups on important characteristics of A-BVs and their members. The study also found that there were statistically significant relationships between A-BVs' governance structure and capacity, management and organization characteristics and the perceived effectiveness, whereas there were no statistically significant relationships between A-BVs' advisory methods characteristic applied by members and the perceived effectiveness. Logistic regression results also showed that level of application of rules encouraging members' active participation in important decision makings, clear terms of reference to guide contracting procedures, roles, and responsibilities of parties involved, type of people served and geographical area of program coverage, and members' ability to use Information and Communication Technologies (ICTs) were predictors of the perceived (evaluated) effectiveness of A-BVs. The study showed that evaluation of members of effectiveness of A-BVs would not be the same. It is suggested that Iranian public agricultural extension organization, as responsible organization for monitoring and evaluating services conducted by A-BVs, considered these differences between members with different levels of some important variables. PMID- 20708270 TI - Visual information and object size in infant reaching. AB - It has been suggested that the onset of successful reaching in infants is mediated by the onset of an ability to use sight of the hand to make corrective reaches. However, removing vision of the hand in infants younger than 6 months has not been shown to have an effect on reaching onset or kinematics. We investigated the use of vision of the hand by testing 6-, 9-, and 12-month-old infants reaching for objects in the light and in the dark. We found that infants reached faster in the dark at 6 months, and faster in the light at 1 year. Parallel effects were observed in the movement times. Consistent effects of altering target object size on average speed were seen at 12 months. The data support the hypothesis that vision is used by older infants around 6 months-of age, and that reach and grasp planning differentiate with object size at about 9 and 12 months-of-age. At younger ages reaches are corrected on the basis of proprioceptive information and sight of the target object. PMID- 20708269 TI - Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. AB - PURPOSE: To compare the efficacy of intravitreal injection of clindamycin and dexamethasone with classic treatment for ocular toxoplasmosis. DESIGN: Prospective, randomized single-masked clinical trial. PARTICIPANTS: A total of 68 patients with active ocular toxoplasmosis were assigned randomly to 2 treatment groups: 34 in the intravitreal clindamycin plus dexamethasone (IVCD) group and 34 in the classic treatment (CT) group. INTERVENTION: The IVCD group received 1 to 3 injection(s) of 1 mg intravitreal clindamycin and 400 MUg dexamethasone, and the CT group received 6 weeks of treatment with pyrimethamine and sulfadiazine plus prednisolone. Antitoxoplasmosis antibodies (immunoglobulin [Ig] M and IgG) were measured using an enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Changes in retinochoroidal lesion size, measured by a computer program written in the MATLAB environment, 6 weeks after initiation of treatment. Visual acuity (VA) changes, vitreous inflammatory response, adverse drug reactions, and rate of recurrence were secondary outcome measures. RESULTS: The mean number of injections in the IVCD group was 1.6. The lesion size reduction was statistically significant after treatment in both IVCD and CT groups (P < 0.001 and P = 0.009, respectively). However, the difference in mean percentage of reduction at 6 weeks was not significant: 57.0 +/- 27.8% in the IVCD group versus 58.4 +/- 29.3% in the CT group (P = 0.569). In relation to the baseline, VA increased by 0.44 +/- 0.24 and 0.29 +/- 0.19 logarithm of the minimum angle of resolution units in the IVCD and CT groups, respectively (P < 0.001); however, the difference of VA improvement between the groups was not significant. The interaction effect of IgM and treatment group on lesion size reduction was significant (P = 0.002); this indicated that IgM-positive cases responded better to CT and IgM-negative cases responded better to IVCD treatment. Vitreous inflammation reduction was insignificant between the groups. Within 2 years, 4 eyes (2 in each group) had 1 episode of recurrence. Adverse drug reactions occurred in 2 patients in the CT group. No major injection-related complication was encountered in the IVCD group. CONCLUSIONS: Intravitreal injection of clindamycin and dexamethasone may be an acceptable alternative to the classic treatment in ocular toxoplasmosis. It may offer the patient more convenience, a safer systemic side effect profile, greater availability, and fewer follow-up visits and hematologic evaluations. PMID- 20708271 TI - Object retrieval through observational learning in 8- to 18-month-old infants. AB - Observational learning was studied in 8-, 10-, 12-, 15- and 18-month-old infants. Using object-retrieval tasks of relatively comparable difficulty for each age group, we showed that between 10 and 12 months there is a change in the capacity to learn a new skill by observation. PMID- 20708272 TI - Parents, parenting and toddler adaptation: evidence from a national longitudinal study of Australian children. AB - Because infants and toddlers are particularly susceptible to parents' socialization efforts, the purpose of this 2-year longitudinal study (N=4271 infants) was to forecast toddlers' competence and problems (adaptational outcomes, age M=30 months) from parenting experiences when they were infants (age M=9 months). Using structural equation modeling and data from a nationally representative sample, parenting during infancy was important to toddlers' adaptational outcomes, with parenting warmth most strongly connected to toddler competence and parenting hostility most strongly connected to toddler problems. Additionally, toddlers' outcomes were associated with their parents' mental health symptoms, life difficulty, coping and self-efficacy when measured 2 years earlier (parent context), and parenting warmth and hostility mediated some of these associations. These pathways indicated that the infant parenting context had some spill over effect on toddlers via parental warmth and hostility. However, mediational paths were not as common as expected, suggesting that the parent context had more direct than indirect effects on toddlers. Conclusions were similar even after accounting for infant temperament, family demographic characteristics and infant birthweight, with substantial reductions in effects only found for associations of parenting self-efficacy with toddlers' outcomes. PMID- 20708273 TI - Knowledge of and attitudes towards depression and adherence to treatment: the Antidepressant Adherence Scale (AAS). AB - BACKGROUND: Non-adherence to treatment can result from forgetting, carelessness, stopping the drug when feeling worse, or stopping the drug when feeling better. OBJECTIVE: To develop and psychometrically assess a brief instrument that can be easily used in clinical practice to measure adherence to antidepressants. METHOD: We developed the Antidepressants Adherence Scale (AAS); a self report rating scale including four items to assess the degree to which forgetting, carelessness, and stopping due to feeling worse or feeling better interfere with adherence in the last 4 weeks. Our proposed four-item adherence instrument was developed based on previous research and theory. PARTICIPANTS: Experts in mood disorders (n=12) participated in the formal validity assessment of the instrument, and the developed instrument was administered to patients who were prescribed antidepressants (n=63). All patients also completed a multiple choice question instrument to measure knowledge of depression, and a Likert self report questionnaire to assess attitudes towards depression and its treatment. RESULTS: There was 90% agreement among experts that the items were highly relevant providing strong evidence for content validity. Also, there was empirical evidence for validity. There were significant correlations (p<0.05) between knowledge and attitude subscales and adherence items. The internal consistency reliability (Cronbach's alpha) was 0.66 for the instrument. CONCLUSION AND SIGNIFICANCE: Knowledge of and attitudes to depression and its treatment may have significant impact on the adherence to antidepressants. The AAS can be used in clinical settings (2-3 min to administer) to evaluate patients' adherence to antidepressants. PMID- 20708274 TI - Can general practitioners identify people with distress and mild depression? A meta-analysis of clinical accuracy. AB - BACKGROUND: There is increasing emphasis on distress and mild depression but uncertainty regarding how well general practitioners (GPs) identify these conditions. Further, the proportion of attendees suffering distress is also unclear. AIM: To quantify the rate of distress in primary care and to clarify the ability of GPs to identify distressed and/or mildly depressed individuals using their clinical skills. METHODS: Meta-analysis of clinical recognition of distress and mild depression defined on a continuum (severity scale) or categorically (semi-structured interview). RESULTS: From 157 studies that examined the ability of GPs to diagnose any emotional or mental disorder, we identified 23 that focused on defined distress and 9 that reported on mild depression. The prevalence of broadly defined distress was 37.4% (n=23, 95% CI=29.5% to 45.5) although it was 47.3% (n=14, 95% CI=38.0% to 56.7%) using self-report methods. GPs correctly identified distressed individuals in 48.4% (n=21, 95% CI=42.6% to 54.2%) of presentations and identified non-distressed people in 79.4% (n=21, 95% CI=74.3% to 84.1%) of presentations without distress. GPs correctly identified 33.8% (95% CI=27.3% to 40.7%) of people with mild depression and had a detection specificity of 80.6% (95% CI=66.4% to 91.6%) for the non-depressed. Clinicians' ability to recognize mild depression was significantly lower than their ability to recognize moderate-severe depression. Out of 100 consecutive presentations, a typical GP making a single assessment would correctly identify 19 out of 39 people with distress, missing 20. He or she would correctly re-assure 48 out of 61 people without distress, falsely label 13 people as distressed. For mild depression, out of 100 consecutive presentations, a typical GP would correctly identify 4 out of 11 people with mild depression, missing 7. GPs would correctly re-assure 72 out of 89 people without distress, falsely diagnosing 19. CONCLUSIONS: Clinicians have considerable difficulty accurately identifying distress and mild depression in primary care with only one in three people correctly diagnosed. Clinicians are better able to identify distress than mild depression but success remains limited. However not all such individuals want professional help, and some people who are overlooked get help elsewhere, or improve spontaneously, therefore the implications of these detection problems are not yet clear. PMID- 20708275 TI - Changes in sleep quality, but not hormones predict time to postpartum depression recurrence. AB - BACKGROUND: Poor sleep quality, dysregulation of hormones and increased inflammatory cytokines are all associated with the risk for postpartum major depression (PPMD). We evaluated change over time in sleep quality and hormones during the first 17 weeks postpartum, as well as a single cytokine measure, and their association with PPMD recurrence. METHODS: Participants were pregnant women (N=56), with past histories of MDD/PPMD but not depressed in their current pregnancy. The Pittsburgh Sleep Quality Index (PSQI) and blood samples were collected 8 times during the first 17 weeks postpartum. Estradiol, prolactin and cortisol, and a single measure of IL-6 were assayed. Recurrence was determined by two consecutive 21-item Hamilton Rating Scale for Depression (HRSD) scores>=15 and clinician interview. RESULTS: In the analyses of time to PPMD recurrence, poor sleep quality, but none of the hormones, was associated with PPMD recurrence (p<.05) after controlling for medication assignment. With every one point increase in PSQI scores across time, a woman's risk for recurrence increased by approximately 25% There was no significant association between PSQI scores and IL 6 concentrations in early postpartum (chi(2)=0.98, p=.32). CONCLUSIONS: Poor sleep quality across the first 17 weeks post-delivery increases the risk for recurrent PPMD among women with a history of MDD. Changes in the hormonal milieu were not associated with recurrence. Further exploration of the degree to which poor sleep contributes to hormonal and cytokine dysregulation and how they are involved in the pathophysiology of PPMD is warranted. PMID- 20708276 TI - Affective temperamental profiles are associated with white matter hyperintensity and suicidal risk in patients with mood disorders. AB - BACKGROUND: Patients with white matter hyperintensities (WMH) may be at higher risk for affective disorders and suicide. Affective temperaments may play a significant role in mood disorders. This study aimed to evaluate the eventual association between WMH, affective temperaments and suicidal behaviour in major affective disorder. METHODS: A total of 318 patients with major affective disorders were consecutively admitted as psychiatric inpatient. A total of 247 were included and given, brain magnetic resonance imaging (MRI) and assessed with the Mini International Neuropsychiatric Interview (MINI), the Beck Hopelessness Scale (BHS), the Hamilton Depression Rating Scale (HDRS(17)), the Young Mania Rating Scale (YMRS) and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A). RESULTS: A total of 48% of patients had periventricular WMH (PWMH) and 39% of them had deep WMH (DWMH). Patients with higher dysthymia and lower hyperthymia (H-DCIA group) were more likely to have higher BHS scores (BHS>=9=77% vs. 52%; p>0.001), more WMH (46% vs. 29%; chi(2)(n=3)=9.90; p<0.05), higher MINI suicidal risk (54% vs. 42%; p<0.05), and more recent suicide attempts (24% vs. 14%; p<0.05), than patients with higher hyperthymia and lower dysthymia (H-H group). LIMITATIONS: The small sample size did not allow the generalization of the present findings. CONCLUSIONS: Differences among temperament groups measured by the TEMPS-A are associated with differences in their MRIs, indicating that different temperament profiles are associated with differences in the subcortical structures of the brain. The implications of the results were discussed. PMID- 20708277 TI - Discriminant and convergent validity of TEMPS-A[P] correlation with MMPI and the emotional-affective state following a stressful situation. AB - BACKGROUND: The temperament evaluation of the Memphis, Pisa, Paris and San Diego questionnaire (TEMPS), in its rater-wise and its self-evaluation forms, has been designed to evaluate temperamental characteristics in clinical and non-clinical populations. The validation process is currently in progress in various countries. In order to improve this validation process we have extended the area of correlations of its self-evaluation form (TEMPS-A[P]) to MMPI, and to a special RS that allows assessment of the emotional-affective state following a stressful situation. METHODS: In 693 candidates applying to become cadets in the Italian Air Force we have assessed the correlation between the TEMPS-A[P] and the MMPI validity and clinical scales, and administered an emotional-affective state questionnaire (EAS-RS) after they had gone through the stressful challenge of taking an academy entrance examination. RESULTS: As regards MMPI validity scales, TEMPS-A[P] depressive candidates tend to report their symptoms sincerely. Hyperthymic candidates tend to give false answers so that others will see them in a good light. Cyclothymic and irritable candidates tend to exaggerate symptoms. As regards the MMPI clinical scales, a low level of linkage between affective temperaments and abnormal personality traits was found. As regards EAS-RS: hyperthymic temperament on one hand, and cyclothymic and depressive temperaments on the other, are characterized by counter-polar emotional states following the test; these are desirable in the first case and undesirable in the other two. CONCLUSIONS: The convergent and discriminant validity of TEMPS-A[P] was confirmed. From a personalistic point of view, temperaments seem to belong to the realm of normality rather than to that of pathology, in line with their putative adaptive role. PMID- 20708278 TI - Involvement of IFN-gamma and perforin, but not Fas/FasL interactions in regulatory T cell-mediated suppression of experimental autoimmune encephalomyelitis. AB - Autoaggressive, myelin-reactive T cells are involved in multiple sclerosis and its prototype experimental autoimmune encephalomyelitis (EAE) in mice. A peripheral negative feedback mechanism involving regulatory CD4+ and CD8+T cells (Treg) operates to suppress disease-mediating T cell responses. We have recently characterized a novel population of Qa-1a-restricted, TCR-peptide-reactive CD8alphaalpha+TCRalphabeta+ Treg that induce apoptotic depletion of the encephalitogenic Vbeta8.2 cells in vivo and provide protection from EAE. Here we have used mice deficient in perforin, Fas/FasL and IFN-gamma molecules to investigate their role in Treg-mediated regulation of EAE. Data show that Fas/FasL interactions are not involved, but regulation mediated by Treg is dependent on the presence of IFN-gamma and the perforin pathway. These data provide a molecular mechanism of Treg-mediated killing of the pathogenic T cells and have important implications in the design of immune interventions for demyelinating disease. PMID- 20708280 TI - Bladder management and the functional outcome of elderly ischemic stroke patients. AB - The purpose of this study was to investigate how bladder management, rather than urinary incontinence, may affect the functional outcome of ischemic stroke patients. We studied 919 consecutive patients admitted for ischemic stroke rehabilitation. Level of bladder management was determined by Functional Independence Measurement (FIM TM) sub-scale scores relevant to bladder control. FIM scores less than 5 points was determined as low-bladder management score (Low BMS) while FIM scores greater than 5 was determined as high-bladder management score (High-BMS). Data were analyzed by t-test, Pearson correlation, and chi square test as well as by multiple linear regression analysis. There were 594 low bladder score patients (Low-BMS) and 325 high-bladder score patients (High-BMS), at admission. Compared with High-BMS, Low-BMS patients were slightly older (p = 0.002), had longer rehabilitation stays (p < 0.001) and lower mini-mental state examination (MMSE) scores (p < 0.001). Total FIM at admission and discharge were lower in Low-BMS, yet their total FIM gain upon discharge was higher, compared with High-BMS (19.5 +/- 16.46 vs. 17.59 +/- 12.55, p = 0.07). Multiple linear regression analyses showed that total FIM at discharge was inversely associated with Low-BMS at admission (beta = -0.407; p<0.001) and age (beta = -0.127; p < 0.001). A high MMSE score (beta = 0.334; p < 0.001) emerged as predicting higher total FIM scores upon discharge. Low-BMS was independently predictive for total FIM gain at discharge (beta = 0.166; p < 0.001). The findings suggest that Low BMS should be held as adversely affecting the rehabilitation outcomes of elderly stroke patients. However, Low-BMS patients do obtain significant gains and should not be deprived of rehabilitation. PMID- 20708279 TI - Intracellular uptake and associated toxicity of silver nanoparticles in Caenorhabditis elegans. AB - Silver nanoparticles (AgNPs) are frequently used as antimicrobials. While the mechanism(s) by which AgNPs are toxic are unclear, their increasing use raises the concern that release into the environment could lead to environmental toxicity. We characterized the physicochemical behavior, uptake, toxicity (growth inhibition), and mechanism of toxicity of three AgNPs with different sizes and polyvinylpyrrolidone (PVP) or citrate coatings to the nematode Caenorhabditis elegans. We used wild-type (N2) C. elegans and strains expected to be sensitive to oxidative stress (nth-1, sod-2 and mev-1), genotoxins (xpa-1 and nth-1), and metals (mtl-2). Using traditional and novel analytical methods, we observed significant aggregation and extra-organismal dissolution of silver, organismal uptake and, in one case, transgenerational transfer of AgNPs. We also observed growth inhibition by all tested AgNPs at concentrations in the low mg/L levels. A metallothionein-deficient (mtl-2) strain was the only mutant tested that exhibited consistently greater AgNP sensitivity than wild-type. Although all tested AgNPs were internalized (passed cell membranes) in C. elegans, at least part of the toxicity observed was mediated by ionic silver. Finally, we describe a modified growth assay that permits differentiation between direct growth inhibitory effects and indirect inhibition mediated by toxicity to the food source. PMID- 20708282 TI - Competition in general practice: prescriptions to the elderly in a list patient system. AB - Income motivation among general practitioners (GPs) is frequently discussed in the health economics literature. The question addressed in the present study on reimbursement drugs and addictive drugs is whether increased competition among GPs, which is part of a declared health policy to improve efficiency, contributes to more prescriptions for the elderly. The dataset comprises registered data of all prescribed drugs dispensed at pharmacies from the Norwegian Prescription Database merged with data on GPs. In choosing a method, particular attention is given to the fact that patients tend to be attracted to GPs who fit their preferences. Hence, we treat the composition of the patient list as endogenous. The results indicate that the stronger competition a GP faces, the more drugs are prescribed, which implies that GPs' prescription style may conflict with their role as gatekeepers, and even worse, it may be a hazard to patients' health. PMID- 20708281 TI - Population-based reference values of handgrip strength and functional tests of muscle strength and balance in men aged 70-80 years. AB - With aging, the incidence of falls and fractures increases. There has during the last decades been secular changes in demographics so that the proportion of elderly increases in society. Hence, there is an increasing need for clinicians to be able to make a solid appraisal of the elderly patient's functional capacity, as to identify individuals with an increased risk to fall. If high risk individuals could be targeted fall preventive strategies might be implemented in specific risk cohorts. This would require reference values for muscle strength tests and functional tests, in order to defined high risk individuals performing inferior. From the MrOS Sweden cohort, 999 subjects aged 70-80 years were evaluated. Muscle strength and functional performance was tested by timed-stands test, 6-m and 20-cm narrow walk tests and Jamar handgrip strength test. Normative data is presented. With increasing age, there was a 10-18% successively decline in performance throughout the entire age span. This study provides reference values for handgrip strength and functional muscle tests in 70-80 years old men. The decline in the test values with increasing age, infer the use of age-specific normative data when using these tests both in clinical and research settings. PMID- 20708283 TI - Body weight and smoking initiation: evidence from Add Health. AB - In volume 23, issue 2 of this journal, Cawley, Markowitz and Tauras used data from the National Longitudinal Survey of Youth 1997 Cohort to estimate the relationship between body weight and smoking initiation. Using maternal obesity status as an instrument, they found strong evidence that overweight females between the ages of 12 and 21 were more likely to initiate smoking. Drawing on data from the National Longitudinal Study of Adolescent Health, we reexamine the relationship between body weight and smoking initiation. Our results are generally consistent with those of Cawley, Markowitz and Tauras. PMID- 20708284 TI - High-dose preoperative chemoradiotherapy in esophageal cancer patients does not increase postoperative pulmonary complications: correlation with dose-volume histogram parameters. AB - PURPOSE: To investigate the association of high-dose preoperative chemoradiotherapy (CRT) and dose-volume histogram (DVH) parameters of lungs with incidence of postoperative pulmonary complications and to identify predictive clinical factors of pulmonary complications. METHODS: Data of 65 patients were collected retrospectively. Thirty-five patients underwent transthoracic esophagectomy (TTE) alone and 30 received cisplatin and 5-fluorouracil, concomitant with radiotherapy, median dose 66Gy, and followed by TTE. From the DVH for each lung alone and for both lungs together as one organ we generated total lung volume, mean radiotherapy dose, relative and absolute volumes receiving more than a threshold dose, and relative and absolute volumes receiving less than a threshold dose. Postoperative pulmonary complications were defined as pneumonia or respiratory failure. RESULTS: Sixty percent of the patients in the TTE alone group had postoperative pulmonary complications versus 63% in the CRT+TTE group. Postoperative mortality was 8.6% and 16.7% in the respective patient groups (p=NS). None of the DVH parameters was associated with postoperative pulmonary complications. Squamous cell carcinoma was an adverse factor related to increased postoperative pulmonary complications. CONCLUSION: High-dose preoperative CRT was not associated with increased postoperative pulmonary complications in this cohort of esophageal cancer patients. PMID- 20708285 TI - Tools for consensus analysis of experts' contours for radiotherapy structure definitions. AB - BACKGROUND AND PURPOSE: To demonstrate and examine the ability of a newly developed software tool to estimate and analyze consensus contours from manually created contours by expert radiation oncologists. MATERIAL AND METHODS: Several statistical methods and a graphical user interface were developed. For evaluation purposes, we used three breast cancer CT scans from the RTOG Breast Cancer Atlas Project. Specific structures were contoured before and after the experts' consensus panel meeting. Differences in the contours were evaluated qualitatively and quantitatively by the consensus software tool. Estimates of consensus contours were analyzed for the different structures and Dice-similarity and Dice Jaccard coefficients were used for comparative evaluation. RESULTS: Based on kappa statistics, highest levels of agreement were seen in the left-breast, lumpectomy, and heart. Significant improvements between pre- and post-consensus contours were seen in delineation of the chestwall and breasts while significant variations were noticed in the supraclavicular and internal mammary nodes. Dice calculations for all pre-consensus STAPLE estimations and final consensus panel structures reached 0.80 or greater for the heart, left/right-breast, case-A lumpectomy, and chestwall. CONCLUSIONS: Using the consensus software tool incorporating STAPLE estimates provided the ability to create contours similar to the ones generated by expert physicians. PMID- 20708286 TI - Segmentation of positron emission tomography images: some recommendations for target delineation in radiation oncology. AB - Positron emission tomography can be used in radiation oncology for the delineation of target volumes in the treatment planning stage. Numerous publications deal with this topic and the scientific community has investigated many methodologies, ranging from simple uptake thresholding to very elaborate probabilistic models. Nevertheless, no consensus seems to emerge. This paper reviews delineation techniques that are popular in the literature. Special attention is paid to threshold-based techniques and the caveats of this methodology are pointed out by formal analysis. Next, a simple model of positron emission tomography is suggested in order to shed some light on the difficulties of target delineation and how they might be eventually overcome. Validation aspects are considered as well. Finally, a few recommendations are gathered in the conclusion. PMID- 20708287 TI - The effect of a non-steroidal anti-inflammatory drug on two important predictors for accidental falls: postural balance and manual reaction time. A randomized, controlled pilot study. AB - Accidental falls in older individuals are a major health and research topic. Increased reaction time and impaired postural balance have been determined as reliable predictors for those at risk of falling and are important functions of the central nervous system (CNS). An essential risk factor for falls is medication exposure. Amongst the medications related to accidental falls are the non-steroidal anti-inflammatory drugs (NSAIDs). About 1-10% of all users experience CNS side effects. These side effects, such as dizziness, headaches, drowsiness, mood alteration, and confusion, seem to be more common during treatment with indomethacin. Hence, it is possible that maintenance of (static) postural balance and swift reactions to stimuli are affected by exposure to NSAIDs, indomethacin in particular, consequently putting older individuals at a greater risk for accidental falls. The present study investigated the effect of a high indomethacin dose in healthy middle-aged individuals on two important predictors of falls: postural balance and reaction time. Twenty-two healthy middle-aged individuals (59.5 +/- 4.7 years) participated in this double-blind, placebo-controlled, randomized crossover trial. Three measurements were conducted with a week interval each. A measurement consisted of postural balance as a single task and while concurrently performing a secondary cognitive task and reaction time tasks. For the first measurement indomethacin 75 mg (slow-release) or a visually identical placebo was randomly assigned. In total, five capsules were taken orally in the 2.5 days preceding assessment. The second measurement was without intervention, for the final one the first placebo group got indomethacin and vice versa. Repeated measures GLM revealed no significant differences between indomethacin, placebo, and baseline in any of the balance tasks. No differences in postural balance were found between the single and dual task conditions, or on the performance of the dual task itself. Similarly, no differences were found on the manual reaction time tasks. The present study showed that a high indomethacin dose does not negatively affect postural balance and manual reaction time in this healthy middle-aged population. Although the relatively small and young sample limits the direct ability to generalize the results to a population at risk of falling, the results indicate that indomethacin alone is not likely to increase fall risk, as far as this risk is related to above mentioned important functions of the CNS, and not affected by comorbidities. PMID- 20708288 TI - Mycotoxin production of selected Fusarium species at different culture conditions. AB - The toxin producing capacity of seven Fusarium species (F. langsethiae, F. sporotrichioides, F. poae, F. avenaceum, F. tricinctum, F. graminearum and F. culmorum) and the effect of culture conditions on the toxin production were studied. The strains were isolated from Finnish grains and cultivated on a grain mixture at three different water activity/temperature combinations (i.e. 0.994/15 degrees C; 0.994/25 degrees C; 0.960/25 degrees C). The mycotoxins produced were analyzed with a multi-toxin method based on liquid chromatography-tandem mass spectrometry enabling the simultaneous determination of 18 different Fusarium toxins. The general toxin profiles revealed F. langsethiae and F. sporotrichioides as producers of diacetoxyscirpenol, neosolaniol, HT-2 and T-2 toxins. F. sporotrichioides produced additionally beauvericin. In the F. poae cultures, only beauvericin was detected. F. avenaceum and F. tricinctum were capable of producing enniatins, moniliformin and antibiotic Y, and F. graminearum and F. culmorum produced zearalenone, deoxynivalenol and 3-acetyl deoxynivalenol. Differences existed in the quantitative toxin production between the individual strains representing the same species. Additionally, the culture conditions affected the range and amounts of toxins produced. In general, a(w) 0.994 and temperature of 15 degrees C favoured the type-A trichothecene production of F. langsethiae and F. sporotrichioides. The beauvericin production of F. sporotrichioides occurred more favourably at a(w) 0.960 and 25 degrees C. F. poae produced the highest concentrations of beauvericin under two different conditions, namely at a(w) 0.994/15 degrees C and a(w) 0.960/25 degrees C. None of the combinations particularly favoured toxin production of F. avenaceum, with all three toxins being produced extensively at all culture conditions. F. tricinctum produced enniatins most efficiently at a(w) 0.994/25 degrees C. The moniliformin production of both these two species occurred readily at a(w) 0.960/25 degrees C. F. culmorum and F. graminearum produced the highest concentrations and variety of mycotoxins at a(w) 0.960/25 degrees C. The results give valuable information on the toxigenicity of some important Fusarium species. Additionally, this is the first in-depth study to investigate the influence of environmental conditions on the toxin production by F. langsethiae, F. poae, F. avenaceum and F. tricinctum. PMID- 20708289 TI - Bacteriocins produced by wild Lactococcus lactis strains isolated from traditional, starter-free cheeses made of raw milk. AB - Sixty bacterial strains were encountered by random amplification of polymorphic DNA (RAPD) and repetitive extragenic palindromic (REP) typing in a series of 306 Lactococcus lactis isolates collected during the manufacturing and ripening stages of five traditional, starter-free cheeses made from raw milk. Among the 60 strains, 17 were shown to produce bacteriocin-like compounds in both solid and liquid media. At a genotypic level, 16 of the strains were identified by molecular methods as belonging to L. lactis subsp. lactis and one to L. lactis subsp. cremoris. Among the L. lactis subsp. lactis strains, phenotypic and genetic data determined that eleven produced either nisin A (nine strains) or nisin Z (two strains), and that five produced lactococcin 972. Variable levels of the two bacteriocins were produced by different strains. In addition, nisin was shown to be produced in inexpensive, dairy- and meat-based media, which will allow the practical application of its producing strains in industrial processes. Specific PCR and nucleotide and deduced amino acid sequence analysis identified the inhibitor produced by the single L. lactis subsp. cremoris isolate as a lactococcin G-like bacteriocin. Beyond the use of bacteriocins as functional ingredients for the biopreservation of foods, the newly identified bacteriocin producing L. lactis strains from traditional cheeses may also be useful for designing starter cultures with protective properties and/or adjunct cultures for accelerating cheese ripening. PMID- 20708290 TI - Production of folate by bacteria isolated from oat bran. AB - Twenty bacteria isolated from three commercial oat bran products were tested for their folate production capability. The bacteria as well as some reference organisms were grown until early stationary phase on a rich medium (YPD), and the amount of total folate in the separated cell mass and the culture medium (supernatant) was determined by microbiological assay. Folate vitamer distribution was determined for eight bacteria including one isolated from rye flakes. For seven bacteria the effect of temperature and pH on folate production was studied in more detail. Relatively large amount of folate was both produced in the cell biomass (up to 20.8microg/g) and released to the culture medium (up to 0.38microg/g) by studied bacteria. The best producers were characterized as Bacillus subtilis ON4, Chryseobacterium sp. NR7, Janthinobacterium sp. RB4, Pantoea agglomerans ON2, and Pseudomonas sp ON8. The level of folate released in culture medium was the highest for B. subtilis ON5, Chryseobacterium sp. NR7, Curtobacterium sp. ON7, Enterococcus durans ON9, Janthinobacterium sp. RB4, Paenibacillus sp. ON10, Propionibacterium sp. RB9, and Staphylococcus kloosii RB7. Marked differences in the distribution of folate vitamers among the bacterial strains were revealed by the HPLC analysis. The main vitamers were tetrahydrofolate, 5,10-methenyltetrahydrofolate, 5-methyltetrahydrofolate, and 5 formyltetrahydrofolate. Increase in the folate content during bacterial growth was accompanied by proportional increase in the 5-methyltetrahydrofolate content and decrease of 5-formyltetrahydrofolate. 10-Formylfolic acid dominated in the culture media of four bacteria, and Janthinobacterium sp. RB4 was also found to excrete 5-methyltetrahydrofolate. Intracellular folate content was higher when the bacteria were grown at 28 degrees C than at 18 degrees C or 37 degrees C and also higher at pH 7 than at pH 5.5. PMID- 20708291 TI - Maintenance of duplicate genes and their functional redundancy by reduced expression. AB - Although evolutionary theories predict functional divergence between duplicate genes, many old duplicates still maintain a high degree of functional similarity and are synthetically lethal or sick, an observation that has puzzled many geneticists. We propose that expression reduction, a special type of subfunctionalization, facilitates the retention of duplicates and the conservation of their ancestral functions. Consistent with this hypothesis, gene expression data from both yeasts and mammals show a substantial decrease in the level of gene expression after duplication. Whereas the majority of the expression reductions are likely to be neutral, some are apparently beneficial to rebalancing gene dosage after duplication. PMID- 20708292 TI - Scaling analysis of baseline dual-axis cervical accelerometry signals. AB - Dual-axis cervical accelerometry is an emerging approach for the assessment of swallowing difficulties. However, the baseline signals, i.e., vibration signals with only quiet breathing or apnea but without swallowing, are not well understood. In particular, to comprehend the contaminant effects of head motion on cervical accelerometry, we need to study the scaling behavior of these baseline signals. Dual-axis accelerometry data were collected from 50 healthy adult participants under conditions of quiet breathing, apnea and selected head motions, all in the absence of swallowing. The denoised cervical vibrations were subjected to detrended fluctuation analysis with empirically determined first order detrending. Strong persistence was identified in cervical vibration signals in both anterior-posterior (A-P) and superior-inferior (S-I) directions, under all the above experimental conditions. Vibrations in the A-P axes exhibited stronger correlations than those in the S-I axes, possibly as a result of axis specific effects of vasomotion. In both axes, stronger correlations were found in the presence of head motion than without, suggesting that head movement significantly impacts baseline cervical accelerometry. No gender or age effects were found on statistical persistence of either vibration axes. Future developments of cervical accelerometry-based medical devices should actively mitigate the effects of head movement. PMID- 20708293 TI - Uptake and tolerance of adjuvant chemotherapy in early stage NSCLC patients in Alberta, Canada. AB - Adjuvant chemotherapy for early stage non-small cell lung cancer was approved for provincial insurance coverage in Alberta, Canada in 2004. The purpose of this study was to measure factors related to uptake of chemotherapy in eligible patients and compare toxicity and survival outcomes in the Alberta population with those found in clinical trials. All Alberta residents diagnosed with stage IB-IIB NSCLC from 2004 to 2006 who had surgery and a consultation with an oncologist to discuss initial treatment were included in the study. Diagnostic, demographic, and vital statistics data were obtained from the Alberta Cancer Registry; chart reviews were conducted to identify details related to treatments discussed, refused, co-morbidities, and toxicity. Analyses were conducted to identify factors associated with discussion and receipt of chemotherapy and toxicity. Toxicity and survival were calculated and compared to clinical trial results. 226 patients were included in the study. Adjuvant chemotherapy was not recommended to 57 patients (25%) and 30 patients (13%) refused chemotherapy. Primary reasons for not recommending chemotherapy were co-morbidities and/or frailty (24 patients). Of the 139 patients who began chemotherapy, 47 (34%) stopped treatment early. Stage II patients who received adjuvant chemotherapy had over a 2-fold decrease in risk of death compared to those who did not receive chemotherapy after adjusting for age and co-morbidities. Efforts to improve uptake of adjuvant chemotherapy in patients with stage II NSCLC should be made as the survival advantage appears to be comparable to that found in clinical trials. PMID- 20708294 TI - Multidisciplinary approach for advanced stage thymic tumors: long-term outcome. AB - BACKGROUND: In advanced stage thymic tumors complete surgical resection is not always achievable. Although surgery remains the cornerstone of therapy, there is growing evidence that multimodality treatment increases resectability and reduces the incidence of local and systemic relapses. METHODS: Between 1980 and 2008, 75 patients with stages III (n = 51), IVA (n = 18) and IVB (n = 6) thymic tumors were treated. Twenty-six patients had A-AB-B1 and 49 B2-B3-C histotype. Thirty eight (50.6%) patients considered not radically resectable at preoperative workup, received induction chemotherapy; postoperatively 37 (49.3%) had radiotherapy, 25 (33.3%) chemoradiotherapy and 4 (5.3%) chemotherapy. RESULTS: No perioperative mortality was recorded. Sixty-one (81.3%) had complete resection (CR) and 14 (18.7%) incomplete resection (IR). CR was lower in patients who received induction chemotherapy (73.7% vs 89.2%, p = 0.02). In 11 (14.7%) cases a vascular procedure was carried out. Overall 5- and 10-year survivals were 70% and 57%, respectively. Five and 10-year tumor-related survival was 78% and 70%. Ten year survival was better for CR vs IR resection (62% vs 28%; p = 0.003) and for type A-AB-B1 vs B2-B3-C (60% vs 53%; p = 0.03). No statistical difference was found between stage III and IV (10-year survival: 63% and 43%; p = 0.42) and induction vs no induction chemotherapy (10-year survival: 52% vs 56%; p = 0.54). At multivariate analysis CR (p = 0.001) and type A-AB-B1 (p = 0.04) were independent predictors of better survival. During follow-up, 34.4% of CR developed tumor recurrence. CONCLUSIONS: Multimodality treatment of stages III and IV thymic tumors guarantees good disease control and provides high survival and acceptable recurrence rates. PMID- 20708295 TI - Obesity abrogates the concentration-dependent effect of leptin on endogenous cholesterol synthesis in human monocytes. AB - Leptin the cytokine-like hormone is involved not only in local inflammations, but it regulates cholesterol biosynthesis in human monocytes. Since, monocyte membrane composition in obesity shows considerable difference from control cells, our aim was to elucidate the concentration dependence of the effect of leptin in OW monocytes, and the downstream signaling of high and low leptin concentrations. Control and OW monocytes were stimulated with leptin in the presence or absence of different inhibitors. Our results are as follows: a concentration-dependent biphasic effect could only be detected in control monocytes whereas in OW cells only elevated cholesterol synthesis was found. The signal pathway of 50 ng/mL leptin stimulation involves Ca(2+) signal, activation of PI3K, MAPK and HMG CoA reductase. In the 500 ng/mL leptin-stimulated control monocytes the suppression of cholesterol synthesis was dependent on the Ca(2+) signal, the H-7 sensitive cPKC and PI3K activation, whereas in OW monocytes only PI3K was involved in increased cholesterol synthesis. We conclude that leptin-signaling in OW monocytes is characterized by Ca(2+) influx, abrogation of H-7 sensitive cPKC activation, and by PI3K mediated PKC activation. PMID- 20708296 TI - TIP47 confers resistance to taxol-induced cell death by preventing the nuclear translocation of AIF and Endonuclease G. AB - Tail-interacting protein (TIP47, also named PP17) has been implicated in lipid droplet metabolism and in the development of late endosomes, to date however, no data about its possible role in regulating cell death processes has been available. Here, we provide evidence for the role of TIP47 in the regulation of mitochondrial membrane stability and cell death. Overexpression of TIP47 protected NIH3T3 cells from taxol-induced cell death, while suppression of TIP47 by siRNA facilitated cell death. TIP47, but not its truncated form, t-TIP47, decreased taxol-induced cell death as determined by propidium iodide and fluorescent Annexin V staining. Recombinant TIP47, but not t-TIP47, partially prevented taxol-induced depolarization of mitochondria in vitro. Overexpression of TIP47, but not its truncated form, prevented the taxol-induced nuclear and cytoplasmic translocation of AIF and Endonuclease G, as well as the taxol-induced depolarization of mitochondria in NIH3T3 cells. Furthermore, overexpression of TIP47 facilitated Bcl-2 expression and suppressed Bax expression in taxol-treated cells. These data show that besides its previously known functions, TIP47 is involved in the regulation of mitochondria-related cell death by directly stabilizing the mitochondrial membrane system and by favorably affecting the expression of Bcl-2 homologues. Since TIP47 is overexpressed in certain tumors, it is possible that TIP47 contributes to the development of cytostatic resistance. PMID- 20708297 TI - Engineering the K+ uptake regulatory pathway by MultiRound Gateway. AB - In a previous study, we described improved versions of MultiRound Gateway vectors. Here, we engineered a calcineurin B-like (CBL) pathway for potassium (K+) nutrition to demonstrate their effectiveness. Using the two improved entry vectors pL12R34H-Ap and pL34R12-Cm, and through 2-4 rounds of Gateway recombination reactions, we generated five pMDC99-derived binary vectors [pK21 (CIPK23+CBL1), pK29 (CIPK23+CBL9), pK31 (CIPK23+CBL1+AKT1), pK39 (CIPK23+CBL9+AKT1), and pK4 (CIPK23+CBL1+AKT1+CBL9)], in which all four genes have the same pSuper promoter and tNos terminator. pK31, pK39 and pK4 were transformed into Arabidopsis. PCR analysis confirmed that all transgenes usually co-existed in the K31, K39 or K4 transgenic plants, and qRT-PCR analysis indicated that the transgenes were expressed at reasonably high levels. The eight overexpression lines, except K31-1, displayed significantly tolerant phenotypes to low-K+ and low-K+ combined with low-Ca2+ compared to the wild type. Significant differences between the K31, K39 and K4 lines were not observed. These results indicate that the improved MultiRound Gateway vectors efficiently assembled multiple transgenes, which were stably inherited and expressed in transformed plants, even with the same promoter and terminator. PMID- 20708298 TI - Enhanced polyamine accumulation alters carotenoid metabolism at the transcriptional level in tomato fruit over-expressing spermidine synthase. AB - Polyamines are involved in crucial plant physiological events, but their roles in fruit development remain unclear. We generated transgenic tomato plants that show a 1.5- to 2-fold increase in polyamine content by over-expressing the spermidine synthase gene, which encodes a key enzyme for polyamine biosynthesis. Pericarp columella and placental tissue from transgenic tomato fruits were subjected to (1)H-nuclear magnetic resonance (NMR) for untargeted metabolic profiling and high performance liquid chromatography-diode array detection for carotenoid profiling to determine the effects of high levels of polyamine accumulation on tomato fruit metabolism. A principal component analysis of the quantitative (1)H NMR data from immature green to red ripe fruit showed a clear discrimination between developmental stages, especially during ripening. Quantification of 37 metabolites in pericarp-columella and 41 metabolites in placenta tissues revealed distinct metabolic profiles between the wild type and transgenic lines, particularly at the late ripening stages. Notably, the transgenic tomato fruits also showed an increase in carotenoid accumulation, especially in lycopene (1.3- to 2.2-fold), and increased ethylene production (1.2- to 1.6-fold) compared to wild-type fruits. Genes responsible for lycopene biosynthesis, including phytoene synthase, phytoene desaturase, and deoxy-d-xylulose 5-phosphate synthase, were significantly up-regulated in ripe transgenic fruits, whereas genes involved in lycopene degradation, including lycopene-epsilon cyclase and lycopene beta cyclase, were down-regulated in the transgenic fruits compared to the wild type. These results suggest that a high level of accumulation of polyamines in the tomato regulates the steady-state level of transcription of genes responsible for the lycopene metabolic pathway, which results in a higher accumulation of lycopene in the fruit. PMID- 20708299 TI - Possible role of hypercoagulability in calciphylaxis: review of the literature. AB - BACKGROUND: The role of a hypercoagulable state in the pathogenesis of calciphylaxis has yet to be determined. OBJECTIVE: We sought to find evidence of an association between hypercoagulability and calciphylaxis. METHODS: We reviewed the primary literature for review articles, studies, and case reports that discussed or demonstrated a possible relationship between calciphylaxis and a hypercoagulable state. RESULTS: Review of the primary literature showed that in cases of calciphylaxis with reported levels of protein C and S, 38% of the patients had decreased protein C levels and 43% had decreased levels of protein S. From review of case reports, 3 cases of improvement of skin lesions with low molecular weight heparin treatment, and a fourth case of healing of skin lesions with tissue plasminogen activator treatment, were found. Calciphylaxis was also found in a patient with antiphospholipid antibody syndrome, and a patient with cryofibrinogenemia had clinical and histologic findings consistent with possible calciphylaxis. LIMITATIONS: A limited number of reports were available for review. CONCLUSION: Our review of the literature found sufficient evidence to suggest a possible role of a hypercoagulable state in the pathogenesis of calciphylaxis. A prospective study with serial testing of all relevant clotting factors in patients with calciphylaxis is needed to more definitively establish this role. PMID- 20708300 TI - An analysis of health system reform for dermatologists: elements and implications of the Patient Protection and Affordable Care Act. AB - The Patient Protection and Affordable Care Act will have substantial effects on the US health care system. Physicians hold varied opinions regarding the overall merits or drawbacks of the health system reform law, but it is critical that we understand its components and the implications for our practices and our patients. This article describes the provisions most relevant to dermatology, analyzes the political and economic landscapes that shaped the legislation, and examines both opportunities and challenges that lie ahead. Physician leadership will be critical in future years as the regulations are written, the law is implemented, and legislative changes are considered. PMID- 20708301 TI - Device-associated nosocomial infection in the intensive care units of a tertiary care hospital in northern India. PMID- 20708302 TI - Evaluation of quality control procedures in an oesophageal cancer cohort study in Anyang, China. AB - We wished to evaluate the efficiency of internal quality control procedures of a cohort study investigating human papilloma virus (HPV) infection as a key exposure factor in oesophageal cancer in Anyang, China. This was done by testing 2395 environmental/equipment swab and mock quality control samples from 14 loci on sample collection equipment for human beta-globin and HPV DNA. Human beta globin was present in 3.88% of these samples but no HPV DNA was detected. There was no evidence of HPV DNA contamination in the sample collection or processing under the rigorous quality control in our ongoing cohort study. The study results indicated that use of disposable appliances, rigorous environmental cleaning and a high standard of sterilisation of reusable instruments are important in contamination prevention. PMID- 20708303 TI - Bacteraemia caused by non-freundii, non-koseri Citrobacter species in Taiwan. AB - This study analysed the clinical characteristics of bacteraemia due to unusual Citrobacter species. All non-freundii and non-koseri Citrobacter isolates were identified to species level by two commercial identification methods and 16S rRNA gene sequence analysis. A total of 306 patients with Citrobacter spp. bacteraemia were identified from January 2000 through December 2009. Four patients (1.3%) had C. braakii bacteraemia, and one had C. amalonaticus and C. sedlakii sepsis, respectively. Misidentification as non-freundii and non-koseri Citrobacter spp., which occurred in eight isolates with the Phoenix automated system PMIC/ID-30 and three with the Vitek II system, occurred in five of six infection episodes. Among the six patients with bacteraemia caused by non-freundii and non-koseri Citrobacter spp., five (83.3%) had healthcare-associated infection and five (83.3%) infections were secondary to intra-abdominal infection. Cancer and liver cirrhosis were the commonest underlying diseases. An attributable mortality was 33.3%. Antimicrobial susceptibility testing showed that the resistance patterns varied among different Citrobacter species. Non-freundii and non-koseri Citrobacter species are difficult to identify and are a rare cause of intra abdominal infections with secondary healthcare-associated bacteraemia in immunocompromised patients. PMID- 20708304 TI - Chemometric modeling, docking and in silico design of triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors as antimalarials. AB - In the present work, QSAR and molecular docking studies have been performed on triazolopyrimidine-based dihydroorotate dehydrogenase (DHODH) inhibitors as antimalarial agents. The QSAR studies have been carried out using classical QSAR (physicochemical) approach using linear free energy related (LFER) model and molecular shape analysis using shape, spatial, electronic, thermodynamic and structural descriptors. Docking studies suggest that the 2 methyltriazolopyrimidine ring interacts with some polar and some nonpolar amino acids whereas the substituted phenyl ring binds with a hydrophobic pocket of the enzyme formed by some nonpolar amino acid residues. According to QSAR and molecular docking studies, we have designed some new compounds which showed good in silico predicted activity as per the developed QSAR models. PMID- 20708305 TI - Synthesis and biological property of some novel 1,3,4-oxadiazoles. AB - A series of biphenyl-1,3,4-oxadiazoles namely 5-[substituted-(1,1'-biphenyl)-3 yl]-1,3,4-oxadiazole-2(3H)-thiones and its S-alkyl derivatives have been synthesized by multi step organic synthesis involving Suzuki-Miyaura coupling using palladium catalyst. The synthesized compounds were characterized by (1)H NMR, (13)C NMR, (19)F NMR, IR and LCMS spectroscopic properties. They were tested for their antimicrobial and analgesic activities. Some of them showed significant activity. PMID- 20708306 TI - Synthesis of new series of quinoxaline based MAO-inhibitors and docking studies. AB - A series of 2-benzyl-3-(2-arylidenehydrazinyl)quinoxalines 3, 4-benzyl-1-aryl [1,2,4]triazolo[4,3-a]quinoxalines 4 and phenyl(1-aryl-[1,2,4]triazolo[4,3 a]quinoxalin-4-yl)methanones 5 analogues were synthesized and investigated for their monoamine oxidase (MAO) inhibitory property. The inhibition profile was found to be competitive for compounds 3k, 3m, 5f and 5n with MAO-A selectivity. Observation of the docked positions of these compounds revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. The structural features of the new compounds have been determined from the microanalytical, IR, (1)H, (13)C NMR spectral studies and X-ray crystalography. PMID- 20708307 TI - [Chorea revealing a polycytemia vera]. AB - Neurological manifestations in polycytemia vera are common. However, chorea is an exceptionally revealing feature of this disease. We report a 78-year-old man who presented with headache and an abnormal movement disorder corresponding to chorea. Laboratory findings showed increased levels of hemoglobin at 20 g/dl and hematocrit at 62.3%. An elevated erythrocyte mass to twice the normal value demonstrated the absolute erythrocytosis. A JAK2 V617F gene mutation was identified. A diagnosis of polycytemia vera-associated chorea was obtained. Clinical and biological outcomes were favorable after therapeutic phlebotomy and treatment with hydroxyurea. We recommend a complete blood cell count in elderly patient presenting with chorea to eliminate a diagnosis of polycytemia vera. PMID- 20708308 TI - Nutrient intake and serum level of gamma-glutamyltransferase, MCP-1 and homocysteine in early stages of heart failure. AB - BACKGROUND & AIMS: Dietary quality probably may impact heart failure outcomes. The aim of the study was to determine the potential effects of nutrient intake on homocysteine, MCP-1 and GGT levels in patients with heart failure. METHODS: The study group comprised 55 patients with diagnosed HF with coronary artery disease origin, below 65y, with NYHA class I/II. The patients had received standard treatment. The control comprised 55 patients with mild hyperlipidemia, not treated. Diet was evaluated on the basis of a dietary questionnaire and a 24-h dietary recall. The serum lipid profile, folic acid, homocysteine, GGT and MCP-1 were determined. RESULTS: In the HF group significantly higher concentration of homocysteine (32%), MCP-1 (58%) and GGT (100%) are found as compared to the control group (p < 0.00001). Patients with HF had greater cholesterol consumption, with less folates, vitamin C and dietary fiber as compared to the control group (p < 0.05). CONCLUSION: High consumption of total fat and dietary cholesterol accompanied by a low folate, antioxidant vitamin, a special vitamin C and dietary fiber intake, contributes to elevated Hcy, GGT and MCP-1 levels and in consequence, could lead to intense inflammatory process and atherosclerosis in HF patients. PMID- 20708309 TI - Aggregate prediction of resting energy expenditure may perform better than individual estimates. PMID- 20708310 TI - Complementarity of Subjective Global Assessment (SGA) and Nutritional Risk Screening 2002 (NRS 2002) for predicting poor clinical outcomes in hospitalized patients. AB - BACKGROUND & AIMS: We evaluated the ability of Nutritional Risk Screening 2002 (NRS 2002) and Subjective Global Assessment (SGA) to predict malnutrition related to poor clinical outcomes. METHODS: We assessed 705 patients at a public university hospital within 48 h of admission. Logistic regression and number needed to screen (NNS) were calculated to test the complementarity between the tools and their ability to predict very long length of hospital stay (VLLOS), complications, and death. RESULTS: Of the patients screened, 27.9% were at nutritional risk (NRS+) and 38.9% were malnourished (SGA B or C). Compared to those patients not at nutritional risk, NRS+, SGA B or C patients were at increased risk for complications (p=0.03, 0.02, and 0.003, respectively). NRS+ patients had an increased risk of death (p=0.03), and SGA B and C patients had an increased likelihood of VLLOS (p=0.008 and p<0.0001, respectively). Patients who were both NRS+ and SGA C had lower estimates of NNS than patients who were NRS+ or SGA C only, though their confidence intervals did overlap. CONCLUSIONS: The concurrent application of SGA in NRS+ patients might enhance the ability to predict poor clinical outcomes in hospitalized patients in Brazil. PMID- 20708311 TI - Midwives of India: missing in action. AB - India had well-trained European and indigenous midwives during the time of British rule. The strong midwifery profession lost its importance after independence for various reasons. As a result maternal mortality remains high in India. This paper analyses reasons for the dilution in the midwifery profession, which include amended regulations, lack of social or political priorities, and change in health programme directions. This paper also presents a framework for midwifery-based maternal health services. This analysis shows that there are local as well as internationally supported efforts to improve midwifery in India. PMID- 20708312 TI - Improving the maternal mortality ratio in Zhejiang Province, China, 1988-2008. AB - OBJECTIVE: maternal mortality remains a major public health problem in many countries. The aim of this paper is to describe the progress made in maternal health care in Zhejiang Province, China over 20 years in reducing the maternal mortality ratio (MMR). SETTING: Zhejiang Province is located on the mid-east coast of China, approximately 180km south of Shanghai, and has a population of 49 million. Almost all mothers give birth in hospitals or maternal and infant health institutes. METHOD: the annual maternal death audit reports from 1988 to 2008 were analysed. These reports were prepared annually by the Zhejiang Prenatal Health Committee after auditing each individual case. MEASUREMENTS AND FINDINGS: China has made considerable progress in reducing the MMR. Zhejiang has one of fastest developing economies in China, and since the 86 economic reforms of 1978, health care has improved rapidly and the MMR has declined. During the 1988-2008 period, 2258 maternal deaths were reported from 8,880,457 live births. During these two decades, the MMR decreased dramatically from 48.50 in 1988 to 6.57 per 100,000 in 2008. The MMR in migrant women dropped from 66.87 in 2003 to 21.67 per 100,000 in 2008. The rate of decline was more rapid in rural areas than in the city. There has been a decline in the proportion of deaths with direct obstetric causes and a corresponding increase in the proportion of indirect causes. The proportion of deaths classified as preventable has declined in the past two decades. Social factors are important in maternal safety, and on average 26.8% of maternal deaths were influenced by these factors. CONCLUSION: as the economy was developing, maternal safety was made a priority health issue by the Government and health workers. The provincial MMR has dropped rapidly and is now similar to the rates in developed countries and lower than that in the USA. However, more work is still needed to ensure that all mothers, including migrant workers, continue to have these low rates. PMID- 20708313 TI - Plasma vitellogenin in male teleost fish from 43 rivers worldwide is correlated with upstream human population size. AB - It has been previously demonstrated that vitellogenin (VTG)--a precursor egg yolk protein--is produced in male fish exposed to estrogenic compounds in wastewater treatment plant (WWTP) effluent. However, little attention has been given to examine whether any patterns of male VTG production exists across fish species on a global scale. We hypothesized that a composite measure of human population size over river discharge would best explain variations of protein levels in male fish. We compiled VTG data in 13 fish species from 43 rivers receiving municipal WWTP effluent on 3 continents. We found that human population size explained 28% of the variation in male VTG concentrations, whereas population/flow rate failed to significantly correlate with VTG. We suggest this result may be explained by the low solubility of estrogenic compounds, resulting in localized contamination near WWTP outfalls, rather than dilution by river water. PMID- 20708314 TI - Enrichment of polycyclic aromatic hydrocarbons (PAHs) in mariculture sediments of Hong Kong. AB - Surface and core sediments collected from six fish farms in Hong Kong and from reference sites were investigated for the enrichment and sources of polycyclic aromatic hydrocarbons (PAHs). Moderately high SigmaPAH16 levels (123-947 ng g( 1), mean: 450 ng g(-1)) were found in the surface aquaculture sediments. In comparison with the sediments from the reference sites, the average enrichment percentage of total organic carbon (TOC) and PAHs in surface sediments were 21.4 and 43.8%, respectively, and in the core sediments, 24.6 and 73.7%, respectively. Mathematical source apportionment analyses (i.e. isomer ratios, hierarchical cluster analysis, principal components analysis with multiple linear regression analysis) suggested a higher percentage of petrogenic sources in aquaculture sediments. The fish feeds might be the main source of the enriched PAHs in the aquaculture sediments. To our knowledge, this is the first study showing that PAHs in aquaculture sediments could be attributed to human aquaculture activities. PMID- 20708315 TI - Internalized homophobia and internalizing mental health problems: a meta-analytic review. AB - Research on internalized homophobia (IH) has linked it to both mental and physical health outcomes. Extant research indicates that IH and mental health are related in a variety of different subgroups of lesbian, gay and bisexual (LGB) persons. However, much of this research has suffered from methodological issues. Studies have frequently substituted distress-related constructs (e.g., self esteem and general well-being) for measures of internalizing mental health problems. Furthermore, many studies have misapplied measures of IH designed for gay men with lesbian samples. The current study used Hierarchical Linear Modeling to perform meta-analysis. Effect sizes were combined across multiple studies that used dimensional measures of internalizing mental health problems (i.e., depression and anxiety). The use of multilevel modeling techniques allowed for the evaluation of moderating effects on these relationships, including those of gender, year of data collection, mean age of the sample, publication type, and type of symptomatology measured. Thirty-one studies were meta-analyzed for the relationship between IH and mental health (N=5831), revealing a small to moderate overall effect size for the relationship between the two variables. Higher levels of IH were associated with higher scores on dimensional measures of internalizing mental health problems. Significant moderating effects were also found for mean age of the sample and the type of symptomatology measured in each study. The relationship between IH and internalizing mental health problems was stronger in studies with a higher mean age. The relationship between IH and depressive symptomatology was stronger than the relationship between IH and symptoms of anxiety. Limitations and future research directions are discussed as well as implications for clinical practice. PMID- 20708316 TI - The "aid contract" and its compensation scheme: a case study of the performance of the Ugandan health sector. AB - Current literature on aid effectiveness describes increasing use of a more contractual approach to the relationship between donor and recipient government in which a system of rewards and penalties for good and bad performance operates. The purpose of this case study of the Ugandan health sector was to understand the extent to which this approach is influencing processes and effectiveness. This qualitative study used a conceptual framework based on agency theory and 'realistic evaluation'. Our results showed that the main official mechanism to assess and reward performance established through the Sector Wide Approach lacked objective criteria and was based on an unstructured system of discussions and agreements among donors. The achievement of a satisfactory performance rating was facilitated by the agreeing to undertakings that were under-demanding, vaguely formulated and lacking quantitative benchmarks against which progress could be measured. However, even when poor performance was readily observable, penalties failed to be applied by donors. This was always the case in relation to health sector performance and mostly so in relation to general governance and accountability. Funds continued to be disbursed despite the lack of progress made in achieving targets and undertakings and other evident performance problems (e.g. in the area of governance). A series of explanations of the failure to penalise were put forward by donor representatives in relation to this behaviour including the need to maintain long-term relationships based on trust and not to undermine health sector performance by withdrawing aid. Thus there are likely to be incentives to disburse funds and report success, irrespective of the realities of aid programmes in the context of large foreign aid volumes associated with increased political visibility of aid in donor countries. PMID- 20708317 TI - Biomechanical stress distribution on fixation screws used in bilateral sagittal split ramus osteotomy: assessment of 9 methods via finite element method. AB - PURPOSE: The aim of this study was to assess the biomechanical stress tolerance of screws used in 9 fixation methods after bilateral sagittal split ramus osteotomy to determine which configuration leads to lesser force load on the cortical bone at fixation points. MATERIALS AND METHODS: A 3-dimensional computerized model of a human mandible with posterior teeth was generated. The bilateral sagittal split ramus osteotomy was virtually performed on this model. The separated model was assembled with 9 fixation methods: single screw, 2 screws one behind the other, 2 screws one below the other, 3 screws in an L configuration, 3 screws in an inverted backward L configuration, miniplate with 2 screws, miniplate with 4 screws, 2 parallel plates (upper + lower border), and square miniplate with 4 screws. Then, 75-, 135-, and 600-N vertical loads were applied on the posterior teeth of these models. The stress distribution on the screw sites on the buccal cortex was measured by the finite element method. RESULTS: In this model all the fixation methods withstood forces between 75 and 135 N. However, the single-screw and the 2-hole miniplate models showed that the stress distributions in the configurations were intolerable when 600 N of posterior force was applied. The results of this study indicated that the inverted backward L configuration with 3 bicortical screws was the most stable. CONCLUSION: Although this study indicated that the inverted backward L configuration with 3 bicortical screws was the most stable pattern, most of the patterns had adequate stability for clinical applications (mean, 125 N). PMID- 20708318 TI - Registration of 3-dimensional facial photographs for clinical use. AB - PURPOSE: To objectively evaluate treatment outcomes in oral and maxillofacial surgery, pre- and post-treatment 3-dimensional (3D) photographs of the patient's face can be registered. For clinical use, it is of great importance that this registration process is accurate (< 1 mm). The purpose of this study was to determine the accuracy of different registration procedures. MATERIALS AND METHODS: Fifteen volunteers (7 males, 8 females; mean age, 23.6 years; range, 21 to 26 years) were invited to participate in this study. Three-dimensional photographs were captured at 3 different times: baseline (T(0)), after 1 minute (T(1)), and 3 weeks later (T(2)). Furthermore, a 3D photograph of the volunteer laughing (T(L)) was acquired to investigate the effect of facial expression. Two different registration methods were used to register the photographs acquired at all different times: surface-based registration and reference-based registration. Within the surface-based registration, 2 different software packages (Maxilim [Medicim NV, Mechelen, Belgium] and 3dMD Patient [3dMD LLC, Atlanta, GA]) were used to register the 3D photographs acquired at the various times. The surface based registration process was repeated with the preprocessed photographs. Reference-based registration (Maxilim) was performed twice by 2 observers investigating the inter- and intraobserver error. RESULTS: The mean registration errors are small for the 3D photographs at rest (0.39 mm for T(0)-T(1) and 0.52 mm for T(0)-T(2)). The mean registration error increased to 1.2 mm for the registration between the 3D photographs acquired at T(0) and T(L). The mean registration error for the reference-based method was 1.0 mm for T(0)-T(1), 1.1 mm for T(0)-T(2), and 1.5 mm for T(0) and T(L). The mean registration errors for the preprocessed photographs were even smaller (0.30 mm for T(0)-T(1), 0.42 mm for T(0)-T(2), and 1.2 mm for T(0) and T(L)). Furthermore, a strong correlation between the results of both software packages used for surface-based registration was found. The intra- and interobserver error for the reference-based registration method was found to be 1.2 and 1.0 mm, respectively. CONCLUSION: Surface-based registration is an accurate method to compare 3D photographs of the same individual at different times. When performing the registration procedure with the preprocessed photographs, the registration error decreases. No significant difference could be found between both software packages that were used to perform surface-based registration. PMID- 20708319 TI - Use of temporalis fascia as an interpositional arthroplasty in temporomandibular joint ankylosis: analysis of 8 cases. AB - PURPOSE: Different interpositional materials have been used to prevent recurrence after gap arthroplasty in temporomandibular joint ankylosis. In this study, the versatility of the temporalis fascia as an interpositional arthroplasty was evaluated. MATERIALS AND METHODS: Eight cases of unilateral temporomandibular joint ankylosis were evaluated, with a follow-up of 11 months to 6 years. RESULTS: Patients had a preoperative maximal interincisal opening of 1 to 9 mm (mean, 2.75 mm). During the last follow-up observation after surgery, patients had a maximum interincisal opening of 32 to 40 mm (mean, 36.5 mm). Deviation to the affected side was observed in all cases. Paresthesia or anesthesia of the temporal branch of facial nerve was absent in all cases. Periodic panoramic radiographs showed that the intra-articular space was well maintained because of interposed tissue, without signs of relapse. There were no signs of reankylosis in any patient. CONCLUSION: The findings of this study show that the temporalis fascia is a good alternative for interpositional arthroplasty. PMID- 20708320 TI - Musical intervention reduces patients' anxiety in surgical extraction of an impacted mandibular third molar. AB - PURPOSE: Patients undergoing impacted mandibular third molar (IMTM) extraction often have severe perioperative anxiety, which may lead to increased perceptions of pain and vital sign instability throughout surgery. Intraoperational musical interventions have been used during operations to decrease patient anxiety levels. We investigated the anxiolytic effects of musical intervention during surgical extraction of an IMTM. We tested the hypothesis that musical intervention would have positive effects on patients' vital signs, anxiety levels, and perceptions of pain. PATIENTS AND METHODS: We recruited 219 patients with IMTM surgery to participate in this study. Participants were randomly assigned to a music-treated group (106 subjects) or a control group (113 subjects). In a preoperative meeting, patient demographic data were collected, and the patients' favorite songs were selected. For the music-treated group, their selected music was played from the time of arrival to the operating room until the end of the operation. Perioperative anxiety and perceptions of pain were assessed using the Dental Anxiety Scale and the Visual Analog Scale, respectively. Patients' vital signs (blood pressure, heart rate, and respiratory rate) were monitored throughout the surgery. One-way analysis of covariance using perioperative anxiety as a covariant was performed to compare intraoperative anxiety levels and perioperative perceptions of pain between the 2 groups. Repeated measures analysis of variance was used to compare changes in vital signs across surgical stages between the 2 groups. RESULTS: Vital signs changed significantly throughout surgery according to the stage of the procedure. For both groups, vital signs increased from baseline and reached peak values at the time of the initial incision and then decreased quickly and plateaued within normal limits. There were no significant differences between groups in blood pressure; however, the music-treated group showed a significantly smaller change in heart rate than the control group. The music-treated group reported significantly less intraoperative anxiety than the nonmusic-treated control group when controlling for preoperative anxiety levels (F = 4.226, P < .05). CONCLUSION: These results support the hypothesis that the use of patient-chosen music during surgical extraction of an IMTM significantly lowers patient intraoperative anxiety levels. PMID- 20708321 TI - Soft tissue profile changes after bilateral sagittal split osteotomy for mandibular setback: a systematic review. AB - PURPOSE: To evaluate the ratio of soft tissue to hard tissue in bilateral sagittal split setback osteotomy with rigid internal fixation or wire fixation. MATERIALS AND METHODS: A literature search was performed using PubMed, Medline, CINAHL, Web of Science, the Cochrane Library, and Google Scholar Beta. From the original 766 articles identified, 8 articles were included. Two articles were prospective and 6 retrospective. The follow-up period ranged from 1 year to 12.7 years for rigid internal fixation. Two articles on wire fixation were found to be appropriate for inclusion. RESULTS: The differences between short- and long-term ratios of the lower lip to lower incisors for bilateral sagittal split setback osteotomy with rigid internal fixation or wire fixation were quite small. The ratio was 1:1 in the long term and by trend slightly lower in the short term. No distinction was seen between the short- and long-term ratios for mentolabial fold. The ratio was found to be 1:1 for the mentolabial fold to point B. In the short term, the ratio of the soft tissue pogonion to the pogonion showed a 1:1 ratio, with a trend to be lower in the long term. The upper lip showed mainly protrusion, but the amount was highly variable. CONCLUSIONS: This systematic review shows that evidence-based conclusions on soft tissue changes are difficult to draw. This is mostly because of inherent problems of retrospective studies, inferior study designs, and the lack of standardized outcome measurements. Well designed prospective studies with sufficient samples and excluding additional surgery, ie, genioplasty or maxillary surgery, are needed. PMID- 20708322 TI - Aggressive central giant cell granuloma of the mandible. PMID- 20708323 TI - Improving esthetic results in benign parotid surgery: statistical evaluation of facelift approach, sternocleidomastoid flap, and superficial musculoaponeurotic system flap application. AB - PURPOSE: The purpose of this article was to analyze the efficacy of facelift incision, sternocleidomastoid muscle flap, and superficial musculoaponeurotic system flap for improving the esthetic results in patients undergoing partial parotidectomy for benign parotid tumor resection. The usefulness of partial parotidectomy is discussed, and a statistical evaluation of the esthetic results was performed. PATIENT AND METHODS: From January 1, 1996, to January 1, 2007, 274 patients treated for benign parotid tumors were studied. Of these, 172 underwent partial parotidectomy. The 172 patients were divided into 4 groups: partial parotidectomy with classic or modified Blair incision without reconstruction (group 1), partial parotidectomy with facelift incision and without reconstruction (group 2), partial parotidectomy with facelift incision associated with sternocleidomastoid muscle flap (group 3), and partial parotidectomy with facelift incision associated with superficial musculoaponeurotic system flap (group 4). Patients were considered, after a follow-up of at least 18 months, for functional and esthetic evaluation. The functional outcome was assessed considering the facial nerve function, Frey syndrome, and recurrence. The esthetic evaluation was performed by inviting the patients and a blind panel of 1 surgeon and 2 secretaries of the department to give a score of 1 to 10 to assess the final cosmetic outcome. The statistical analysis was finally performed using the Mann-Whitney U test for nonparametric data to compare the different group results. P less than .05 was considered significant. RESULTS: No recurrence developed in any of the 4 groups or in any of the 274 patients during the follow up period. The statistical analysis, comparing group 1 and the other groups, revealed a highly significant statistical difference (P < .0001) for all groups. Also, when group 2 was compared with groups 3 and 4, the difference was highly significantly different statistically (P = .0018 for group 3 and P = .0005 for group 4). Finally, when groups 3 and 4 were compared, the difference was not statistically significant (P = .3467). CONCLUSION: Partial parotidectomy is the real key point for improving esthetic results in benign parotid surgery. The evaluation of functional complications and the recurrence rate in this series of patients has confirmed that this technique can be safely used for parotid benign tumor resection. The use of a facelift incision alone led to a high statistically significant improvement in the esthetic outcome. When the facelift incision was used with reconstructive techniques, such as the sternocleidomastoid muscle flap or the superficial musculoaponeurotic system flap, the esthetic results improved further. Finally, no statistically significant difference resulted comparing the use of the superficial musculoaponeurotic system and the sternocleidomastoid muscle flap. PMID- 20708324 TI - Oral mucoceles: a clinicopathologic review of 1,824 cases, including unusual variants. AB - PURPOSE: To review the clinicopathologic features of oral mucoceles, with special consideration given to unusual variants and exclusion of salivary duct cysts. MATERIALS AND METHODS: This was a retrospective consecutive case review of all oral mucoceles diagnosed by the Medical University of South Carolina, Oral Pathology Biopsy Laboratory, from 1997 to 2006. The following data were recorded: patient demographics, clinical features (anatomic location, color, size, and consistency), clinical impression, history of trauma, history of periodic rupture, and occurrence of unusual mucocele variants. RESULTS: During the study period, 1,824 oral mucoceles were diagnosed. Of these cases, 1,715 represented histopathologically confirmed cases that were not recurrences. There was no significant gender predilection, and the average age was 24.9 years. The most common locations were the lower labial mucosa (81.9%), floor of mouth (5.8%), ventral tongue (5.0%), and buccal mucosa (4.8%); infrequent sites included the palate (1.3%) and retromolar area (0.5%). The lesions most often were described as blue/purple/gray or normal in color. The mean maximum diameter was 0.8 cm (range, 0.1 to 4.0 cm). In 456 cases, a history of trauma was reported, and in 366 cases a history of periodic rupture was reported. Unusual variants included superficial mucoceles (n = 3), mucoceles with myxoglobulosis (n = 6), and mucoceles with papillary synovial metaplasialike change (n = 2). CONCLUSIONS: Our results confirm the findings of previous investigators regarding the major clinicopathologic features of oral mucoceles. Special variants of oral mucoceles occur infrequently, although it is important to recognize these variants to avoid misdiagnosis. PMID- 20708325 TI - Alveolar ridge augmentation using lingual tori. PMID- 20708326 TI - Castleman's disease of the neck: report of 4 cases with unusual presentations. PMID- 20708327 TI - Thirty-day mortality in critical care outreach patients with cancer: an investigative study of predictive factors related to outreach referral episodes. AB - AIM: To establish factors that predict outcome in critically ill, deteriorating cancer patients through critical care outreach referral episodes, characteristics and care reviews. METHODS: A population-based prospective and retrospective study was undertaken with analysis exploring predictive factors regarding critically ill cancer patients referred to a critical care outreach team. Data collected included: diagnosis; presenting problem; early warning scores at referral and at deterioration; physiological and observation data; admission to critical care, length of stay; 30-day mortality; limitation of care including precipitating DNAR orders and documentation of not for CCU admission/intervention). RESULTS: Data were collected on 407 episodes from 318 patients over a period of 8 months from 2006 to 2007. Outreach initiated decisions to limit care with medical teams in 32.2% (n=103/318) of all patients. Early warning scores were not predictive of outcome. A high heart rate at referral (HR), a high potassium, low SpO2 at time of deterioration were independently predictive of 30-day mortality. The logistic regression (LR) model, using these three variables correctly predicts the 30-day outcome of 71% of the patients, demonstrating a relatively high predictability in this patient population. The odds of mortality increase with a higher potassium, heart rate and as the oxygen saturation at deterioration (DSpO(2)) worsen. Management factors included limitation of care, which is highly associated with 30-day mortality. Cancer patients recently receiving chemotherapy may have an increased mortality once admitted to critical care. Being a haemato-oncology patient, or the timeliness of critical care outreach referral does not appear to affect 30-day mortality. CONCLUSION: The LR model was able to predict 30-day outcome of 71% of the patients, demonstrating a reasonably high predictability in this cancer patient population. Critical care outreach initiated discussions on limiting treatment which had an effect on mortality. PMID- 20708328 TI - Clinical predictors of survival in patients treated with therapeutic hypothermia following cardiac arrest. AB - INTRODUCTION: Therapeutic hypothermia has been shown to provide neuroprotection and improved survival in patients suffering a cardiac arrest. We report outcomes of consecutive patients receiving therapeutic hypothermia for cardiac arrest and describe predictors of short and long-term survival. METHODS: Eighty patients receiving therapeutic hypothermia between January 2005 and December 2008 were identified and categorized as those who survived and died. Outcomes and predictors of survival were determined. RESULTS: Forty-five patients (56%) survived to hospital discharge and were alive at 30 days and among survivors 41 (91%) were alive 1 year after discharge. Survivors were younger, were more likely to present with VF, required less epinephrine during resuscitation, were more likely to have preserved renal function, and were less likely to be taking beta blockers and ACE inhibitors. Predictors of survival included VF on presentation (OR 14.9, CI 2.7-83.2, p=0.002), pre-cardiac arrest aspirin use (OR 9.7, CI 1.6 61.1, p=0.02), return of spontaneous circulation <20 min (OR 9.4, CI 2.2-41.1, p=0.003), absence of coronary artery disease (OR 5.3, CI 1.1-24.7, p=0.002) and preserved renal function. CONCLUSION: Therapeutic hypothermia is useful in the treatment of patients suffering a cardiac arrest. Several clinical factors may aid in predicting patients who are likely to survive after a cardiac arrest. PMID- 20708329 TI - Thrombophilic risk factors for placental stillbirth. AB - OBJECTIVES: To define the characteristics of placental stillbirth and the possible contribution of thrombophilic risk factors. STUDY DESIGN: A prospective cohort study was performed. Women diagnosed with antenatal stillbirth (>20 weeks) of singleton pregnancies between 2006 and 2008 were referred postpartum for evaluation. Maternal risk factors, fetal, placental and cord abnormalities, and a detailed thrombophilia screening, including inherited and acquired thrombophilia, were evaluated. Fetal autopsy and placental pathology were encouraged. Placental stillbirth was defined as death of a normally-formed fetus with evidence of intrauterine fetal growth restriction, oligohydramnios, placental abruption and/or histological evidence of placental contribution to fetal death. Pregnancy characteristics and thrombophilia profiles were compared between placental and non-placental stillbirth cases. RESULTS: Sixty-seven women with stillbirth comprised the study group. Placental stillbirth was evident in 33/67 (49.3%). Significantly more women with placental stillbirth were nulliparous, when compared with non-placental stillbirth women (21/33 vs. 9/34, p=0.002). Mean gestational age was lower for placental, compared with non-placental stillbirth (31.1 +/- 6.1 weeks vs. 33.9 +/- 4.8 weeks, p=0.04), as was birth weight. Thirty six of the 67 women (53.7%) tested positive for at least one thrombophilia. The prevalence of maternal thrombophilia was higher for placental stillbirth women (63.6%), and even higher (69.6%) for women after preterm (<37 weeks) placental stillbirth. Factor V Leiden and/or prothrombin G20210A mutation were much more prevalent in placental versus non-placental stillbirth women (OR 3.06, 95% CI 1.07-8.7). CONCLUSIONS: Placental stillbirth comprises a unique subgroup with specific maternal characteristics. Maternal thrombophilia is highly prevalent, especially in preterm placental stillbirth. This may have implications for the management strategy in future pregnancies in this subgroup. PMID- 20708330 TI - Mercury uptake by Silene vulgaris grown on contaminated spiked soils. AB - Mercury is a highly toxic pollutant with expensive clean up, because of its accumulative and persistent character in the biota. The objective of this work was to evaluate the effectiveness of Silene vulgaris, facultative metallophyte which have populations on both non-contaminated and metalliferous soils, to uptake Hg from artificially polluted soils. A pot experiment was carried out in a rain shelter for a full growth period. Two soils (C pH = 8.55 O.M. 0.63% and A pH = 7.07 O.M. 0.16%) were used, previously contaminated with Hg as HgCl(2) (0.6 and 5.5 mg Hg kg(-1) soil). Plants grew healthy and showed good appearance throughout the study without significantly decreasing biomass production. Mercury uptake by plants increased with the mercury concentration found in both soils. Differences were statistically significant between high dosage and untreated soil. The fact that S. vulgaris retains more mercury in root than in shoot and also, the well known effectiveness of these plants in the recovering of contaminated soils makes S. vulgaris a good candidate to phytostabilization technologies. PMID- 20708331 TI - Randomized controlled trial of barbed polyglyconate versus polyglactin suture for robot-assisted laparoscopic prostatectomy anastomosis: technique and outcomes. AB - BACKGROUND: Transperitoneal robot-assisted laparoscopic prostatectomy (RALP) urethrovesical anastomosis is a critical step. Although the prevalence of urine leaks ranges from 4.5% to 7.5% at high-volume RALP centers, urine leaks prolong catheterization and may lead to ileus, peritonitis, and require intervention. Barbed polyglyconate sutures maintain running suture line tension and may be advantageous in RALP anastomosis for reducing this complication. OBJECTIVE: To compare barbed polyglyconate and polyglactin 910 (Vicryl, Ethicon, Somerville, NJ, USA) running sutures for RALP anastomosis. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, randomized, controlled, single-surgeon study comparing RALP anastomosis using either barbed polyglyconate (n = 45) or polyglactin 910 (n = 36) sutures. SURGICAL PROCEDURE: RALP anastomosis using either barbed polyglyconate or polyglactin 910 sutures was studied. MEASUREMENTS: Operative time, cost differential, perioperative complications, and cystogram contrast extravasation by anastomosis suture type were measured. RESULTS AND LIMITATIONS: Although baseline characteristics and overall operative times were similar, barbed polyglyconate sutures were associated with shorter mean anastomosis times of 9.7 min versus 9.8 min (p = 0.014). In addition, anastomosis with barbed polyglyconate rather than polyglactin 910 sutures was associated with more frequent cystogram extravasation 8 d postoperatively (20.0% vs 2.8%; p = 0.019), longer mean catheterization times (11.1 d vs 8.3 d; p = 0.048), and greater suture costs per case ($51.52 vs $8.44; p < 0.001). After 8 of 29 (27.6%) barbed polyglyconate anastomosis sites demonstrated postoperative day 8 cystogram extravasation, we modified our technique to avoid overtightening, reducing cystogram extravasation to 1 (6.3%) of 16 subsequent barbed polyglyconate anastomosis sites. Potential limitations include small sample size and the single surgeon study design. CONCLUSIONS: Compared to traditional sutures, barbed polyglyconate is more costly and requires technical modification to avoid overtightening, delayed healing, and longer catheterization time following RALP. PMID- 20708332 TI - Familial early onset frontotemporal dementia caused by a novel S356T MAPT mutation, initially diagnosed as schizophrenia. AB - Autosomal dominant frontotemporal dementia (FTD) due to mutations in the MAPT gene is referred to as FTD with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). Typically the disease begins in the sixth decade of life. We report a novel exon 12 mutation in MAPT (S356T), in a family with an exceptionally early age at onset (27 and 29 years), causing familial behavioural variant frontotemporal dementia. Both the proband and the proband's father were initially diagnosed as having schizophrenia. Pathological examination showed frontotemporal lobar degeneration with extensive neuronal and glial tau deposition. This mutation is one of a small group of MAPT mutations (including P301S, G335V and S352L) that cause very early onset FTDP-17T. It is likely that the early age at onset reflects a marked pathogenic effect of the mutation involving a disturbance of microtubule binding, tau phosphorylation or a major acceleration of tau aggregation. PMID- 20708333 TI - Pretreatment methods to improve sludge anaerobic degradability: a review. AB - This paper presents a review of the main sludge treatment techniques used as a pretreatment to anaerobic digestion. These processes include biological (largely thermal phased anaerobic), thermal hydrolysis, mechanical (such as ultrasound, high pressure and lysis), chemical with oxidation (mainly ozonation), and alkali treatments. The first three are the most widespread. Emphasis is put on their impact on the resulting sludge properties, on the potential biogas (renewable energy) production and on their application at industrial scale. Thermal biological provides a moderate performance increase over mesophilic digestion, with moderate energetic input. Mechanical treatment methods are comparable, and provide moderate performance improvements with moderate electrical input. Thermal hydrolysis provides substantial performance increases, with a substantial consumption of thermal energy. It is likely that low impact pretreatment methods such as mechanical and thermal phased improve speed of degradation, while high impact methods such as thermal hydrolysis or oxidation improve both speed and extent of degradation. While increased nutrient release can be a substantial cost in enhanced sludge destruction, it also offers opportunities to recover nutrients from a concentrated water stream as mineral fertiliser. PMID- 20708334 TI - Selenium removal from drinking water by adsorption to chitosan-clay composites and oxides: batch and columns tests. AB - Polymer-clay composites were designed to adsorb selenium from water. The highest adsorption efficiency was obtained for chitosan-montmorillonite composites. These composites were characterized by XRD, zeta potential, and FTIR measurements. Adsorption isotherms of selenate on the composite, on Al-oxide and on Fe-oxide were in good agreement with the Langmuir model, yielding a somewhat higher capacity for the composite, 18.4, 17.2 and 8.2 mg/g, respectively. In addition, adsorption by the composite was not pH dependent while its adsorption by the oxides decreased at high pH. Selenium removal from well water (closed due to high selenium concentrations, 0.1 mg/L) by the composite, brought levels to below the WHO limit (0.01 mg/L) and was selective for selenium even in the presence of sulfur (13 mg/L). Selenium adsorption by the composite was higher than by the Al oxide due to high adsorption of sulfur by the later. Unlike employment in batch Al-oxide is more suitable for employment in filtration columns due to its high hydraulic conductivity. A semi-pilot columns experiment demonstrated selenium removal from the well water below the recommended limit (first 400 pore volumes) by Al-oxide columns. Regeneration of Al-oxide and of the composite was studied and readsorption of selenium was demonstrated. PMID- 20708335 TI - Comparative study of Pb-phytoextraction potential in Sesuvium portulacastrum and Brassica juncea: tolerance and accumulation. AB - Lead phytoextraction from salty soils is a difficult task because this process needs the use of plants which are able to tolerate salt and accumulate Pb(2+) within in their shoots. It has recently been suggested that salt-tolerant plants are more suitable for heavy metals extraction than salt-sensitive ones commonly used in this approach. The aim of this study was to investigate Pb phytoextraction potential of the halophyte Sesuvium portulacastrum in comparison with Brassica juncea commonly used in Pb-phytoextraction. Seedlings of both species were exposed in nutrient solution to 0, 200, 400, 800 and 1000 MUM Pb(2+) for 21 days. Lead strongly inhibited growth in B. juncea but had no impact on S. portulacastrum. Exogenous Pb(2+) reduced nutrients uptake mainly in B. juncea as compared to S. portulacastrum. Lead was preferentially accumulated in roots in both species. S. portulacastrum accumulated more Pb(2+) in the shoot than B. juncea. Hence, the amounts of Pb(2+) translocated at 1000 MUM Pb(2+) were 3400 MUg g(-1) DW and 2200 MUg g(-1) DW in S. portulacastrum and B. juncea, respectively. These results suggest that S. portulacastrum is more efficient to extract Pb(2+) than B. juncea. PMID- 20708336 TI - Adsorption of paraquat on goethite and humic acid-coated goethite. AB - Adsorption of cationic pesticides in soils is generally attributed to mineral clays and organic matter components. However, iron oxides may also contribute to such adsorption or affect it by associating with other components. Using goethite and humic acid as models for iron oxides and organic matter respectively, we studied the adsorption of the cationic pesticide paraquat on goethite and humic acid-coated goethite. At pH 4.0 the adsorption on goethite was not significant, and at pH 10.0, although the surface of the oxide was negatively charged, much less pesticide was adsorbed than on mineral clays. At this pH the adsorption of paraquat decreased as the ionic strength increased, and application of the charge distribution multisite complexation model (CD-MUSIC model) enabled interpretation of the results. At pH 4, the adsorption of paraquat on the humic acid-coated goethite was similar to the adsorption on mineral clays, but was considerably less than the adsorption on humic acid in solution. The lower adsorption on solid organic matter is attributed to a decrease in the number of "active" binding sites on the humic acid as a result of the binding to iron oxide. PMID- 20708337 TI - Air ambulance transfer of adult patients to a UK regional burns centre: Who needs to fly? AB - INTRODUCTION: Helicopter emergency medical services play a valuable role in the transfer of critically ill patients. This paper reviews the role of air ambulance services in the provision of regional burns care and suggests guidelines for their use. METHODS: A retrospective review of patients treated at the Midlands Adult Burns Centre over a 3-year period. RESULTS: 27 adult burns patients were transported by air ambulance during the study period. Patients were aged 19-89 years (average 41.3 years) with an estimated burn size of 5-70% TBSA. Distance travelled was 11-79 miles (average 41.2 miles). All patients were appropriately referred to the burns centre according to national referral guidelines but in 7 cases (26%) it was felt that transport by air ambulance was not clinically indicated and land transfer would have been safe and appropriate. CONCLUSION: Air ambulances offer a fast and effective means of transferring patients to a regional burns centre in selected cases. There is limited data for the beneficial effects of helicopters and survival benefit is seen only in the most severely injured patients. We suggest criteria for the use of air ambulances in burns patients in order to maximise the benefit and reduce unnecessary flights. PMID- 20708339 TI - The distribution of the parasitic fauna dictates the distribution of the haemochromatosis genes. AB - No satisfactory explanation has been offered, to date, to account for the prevalence of the haemochromatosis genes in the European population and yet relative paucity of the gene in the tropics. Traditional wisdom suggests that, in antiquity, the haemochromatosis gene, which promotes iron absorption, would have protected ancient man from iron loss resulting from injury either during hunting or through war. However, such an advantage would be equally desirable for other populations where the incidence of the alleles is negligible. Others have tackled the polemic from the another view, postulating that the paucity of the haemochromatosis alleles in populations outside of Europe may be explained by the fact that iron load predisposes to infection and that iron deficiency anaemia is protective against this by limiting parasitic access to host stores of iron. This explanation alone is equally unsatisfactory as European populations are exposed to pathogens and would benefit from any protection afforded by mild anaemia. Others have mooted genetic drift as another alternative explanation. Yet this would be unexpected for a gene which is deleterious. We propose here that the driving force for the propagation of the haemochromatosis alleles was not infection per se but the nature of the parasitic fauna which sojourned with mankind. The tropics are inhabited with multicellular parasitic and highly pathogenic organisms, which consequently have a high demand for iron. The organisms have developed aggressive means of iron extraction from their hosts. Where there is iron in abundance such organisms would have a licence to multiply in an unbridled fashion at the expense of the host. Such a host, due to their increased iron load, would be able to harbour a high parasitic load which would be harmful to the population as a whole, not just the individual with the haemochromatosis allele. As man migrated from the tropics many of the larger pathogens disappeared and man had only to contend with traditional unicellular adversaries. Iron is a critical micronutrient that the host attempts to withhold for invading pathogens. We also advance the theory that the tropical anaemias including sickle cell trait, thalassaemia, glucose-6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency are an ingenious evolutionary means by the host of withholding iron from tropical pathogens while simultaneously avoiding the deleterious effects of frank iron deficiency and/or iron deficiency anaemia. The mechanism is essentially an immunological passive aggressive orchestrated by man kind. PMID- 20708338 TI - Traumatic canal stenosis should not be an indication for surgical decompression in thoracolumbar burst fracture. AB - Thoracolumbar burst fracture (TLBF) is a common type of spinal injuries and frequently causes spinal cord injury. The frequency of neurological deficits in all TLBF can reach up to 50-60%. The typical TLBF images seen on axial computerized tomography are the bone fragment projected into the spinal canal, which always persuade surgeons that the narrowed canal must compress the neural content and therefore is responsible for neurological deficits, with the corollary that surgical decompression of spinal canal is an essential therapeutic strategy for functional recovery. We hypothesize that in TLBF, traumatic canal stenosis is a predictive factor for neurological dysfunction and the surgical decompression is vital to the recovery of neurological function. After a review of the available evidences, we conclude that spinal canal stenosis is poorly correlated with neurological dysfunction in TLBF, and surgical decompression is not vital to the neurological recovery. Therefore, traumatic canal stenosis should not be an isolated indication for surgical decompression in TLBF. PMID- 20708340 TI - Bupropion as the treatment of choice in depression associated with Parkinson's disease and it's various treatments. AB - Parkinson disease (PD) is a chronic progressive degenerative disorder that affects over 6 million people worldwide. It is manifested by motor and psychiatric signs. The latter inflicts up to 88% of PD patients. With the prolongation of life expectancy, it is presumed that the prevalence of PD will further rise, together with comorbid depression. As a result, the need for an adequate therapeutic answer for compounded PD with depression is called for urgently. Several theories try to explain the trigger of depression in PD patients by impaired activity in dopamine, norepinephrine and serotonin systems. Various treatment to combat depressive symptoms in PD patients were proposed and are in use, with ambiguous results and disturbing side effects. These anti depressive modalities include SSRI's, SNRI, TCA, NRI and ECT. Dopamine agonists showed some anti-depressant activity in several studies in depressive PD, but may cause side effects such as dizziness, somnolence, confusion and even hallucinations. The role of dopamine agonists in the treatment of depression is still being explored because of no sufficient number of controlled studies in this area. Our hypothesis is to suggest NDRI - Bupropion - as the first line of treatment in PD patients with depression, in PD induced depression and/or in depression triggered by one of the treatments given for PD. Dual norepinephrine and dopamine reuptake inhibition is associated with unique clinical profile that compounds together anti-depressant efficacy without serotonin associated side effects such as weight gain, sedation, sexual dysfunction. Bupropion, as mainly dopaminergic and noradrenergic anti-depressant can alleviate therapeutically depressive symptoms associated with PD. Clinical controlled studies on Bupropion use in PD depressed patients are required to support this hypothesis. PMID- 20708341 TI - Follicular occlusion due to hyperkeratosis: a new hypothesis on the pathogenesis of mammillary fistula. AB - Mammary fistula (MF) is a disease characterised by recurrent draining abscesses around the areola. The aetiology of MF remains unclear. The most common cause is duct obstruction by squamous metaplasia. The clinical aspects and histological findings of MF are very similar to those observed in hidradenitis suppurativa (HS). We propose a new hypothesis on the pathogenesis of MF and suggest that occlusion of hair follicles by keratinous plugging may relevantly contribute to the development of MF. PMID- 20708342 TI - Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? AB - As sulfur containing thiols, alpha lipoic acid (ALA) and its reduced form dihydrolipoic acid (DHLA) are powerful antioxidants and free radical scavengers capable of performing many of the same functions as glutathione (GSH). ALA supplementation may help protect mitochondria from oxidative stress, a possible mechanism contributing to certain forms of brain diseases called schizophrenia. Shortly before the advent of antipsychotic medications, two small studies found ALA relieved psychiatric symptoms in schizophrenia. More recently, animal studies have shown ALA augmentation improves mitochondrial function. At pharmaceutical levels, niacinamide helps preserve mitochondrial membrane integrity and acts as an antioxidant. ALA is a precursor for lipoamide, an essential mitochondrial coenzyme and niacinamide is a component of niacinamide adenine dinucleotide (NAD). NADH, the reduced form of NAD, is involved in the reduction of ALA to DHLA within the mitochondria. This is relevant to contemporary research because DHLA increases GSH and low GSH levels contribute to mitochondrial dysfunction and oxidative stress which have been implicated in the pathophysiology of schizophrenia. PMID- 20708343 TI - Monitoring the effects of high pressure processing and temperature on selected beef quality attributes. AB - The combined effects of high pressure processing (HPP) and temperature on meat quality attributes were assessed in bovine M. pectoralis profundus, with particular focus on lipid oxidation and fatty acid composition. Beef samples were pressurised at 200, 300 and 400 MPa at two different temperatures 20 degrees C and 40 degrees C. Both pressure and temperature regimes had significant effects on colour, cook loss and lipid oxidation. Pressurisation at 200 MPa had a lower impact on colour parameters than higher pressurisation levels. Cook loss also increased when higher levels of pressure were applied. Across all pressure conditions, lower cook loss was observed at 40 degrees C compared to 20 degrees C. An increase in TBARS values was observed at the higher pressure levels (300, 400 MPa). While some alterations of individual fatty acids were observed, high pressure had no effect on polyunsaturated/saturated fatty acid (PUFA/SFA) or omega 6/omega 3 (n6/n3) ratio. The temperature at which HPP was applied had a significant effect on the sum of saturated (SFA), monounsaturated (MONO) and polyunsaturated (PUFA) fatty acids. HPP at 40 degrees C showed higher SFA and PUFA and lower MONO compared to HPP at 20 degrees C. These results show that high pressure at low or moderate temperatures improves the microbiological quality of the meat with minimal affects on meat quality. PMID- 20708344 TI - Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients. AB - PURPOSE: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12 6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage detoxification GSTM1 and GSTT1 genes (allele deletion). METHODS AND MATERIALS: Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. RESULTS: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1 Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52). CONCLUSIONS: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings. PMID- 20708345 TI - Development of a porcine delayed wound-healing model and its use in testing a novel cell-based therapy. AB - PURPOSE: A delayed full-thickness wound-healing model was developed and used for examining the capacity of adipose-derived stem cells (ASCs), either alone or in platelet-rich fibrin gels, to promote healing. METHODS AND MATERIALS: Four pigs received electron beam radiation to the dorsal skin surface. Five weeks after radiation, subcutaneous fat was harvested from nonirradiated areas and processed to yield ASCs. Two weeks later, 28 to 30 full-thickness 1.5-cm(2) wounds were made in irradiated and nonirradiated skin. Wounds were treated with either saline solution, ASCs in saline solution, platelet-rich plasma (PRP) fibrin gel, ASCs in PRP, or non-autologous green fluorescence protein-labeled ASCs. RESULTS: The single radiation dose produced a significant loss of dermal microvasculature density (75%) by 7 weeks. There was a significant difference in the rate of healing between irradiated and nonirradiated skin treated with saline solution. The ASCs in PRP-treated wounds exhibited a significant 11.2% improvement in wound healing compared with saline solution. Enhancement was dependent on the combination of ASCs and PRP, because neither ASCs nor PRP alone had an effect. CONCLUSIONS: We have created a model that simulates the clinically relevant late radiation effects of delayed wound healing. Using this model, we showed that a combination of ASCs and PRP improves the healing rates of perfusion-depleted tissues, possibly through enhancing local levels of growth factors. PMID- 20708348 TI - Changes at drug and alcohol dependence. PMID- 20708346 TI - Clinical outcomes of intensity-modulated pelvic radiation therapy for carcinoma of the cervix. AB - PURPOSE: To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: We included all patients with Stage I-IVA cervical carcinoma treated with IMRT at three different institutions from 2000-2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions. RESULTS: The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I-IIA disease and 48 had Stage IIB-IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68-88%) and 69% (95% CI, 59-81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6-22%) and 17% (95% CI, 8-25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0-7%) and 7% (95% CI, 2-13%), respectively. CONCLUSIONS: Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques. PMID- 20708349 TI - Benzodiazepine use among patients in heroin-assisted vs. methadone maintenance treatment: findings of the German randomized controlled trial. AB - Benzodiazepine (BZD) use has been found to be associated with poorer psychosocial adjustment, higher levels of polydrug use and more risk-taking behaviors among opioid dependent patients. The aim of this paper is to analyze the correlation between BZD use, BZD prescription and treatment outcome among participants in the German trial on heroin-assisted treatment. 1015 patients who participated in the study comparing heroin-assisted and methadone maintenance treatment (HAT & MMT) for 12 months were included in the analysis. Analyses were carried out to assess the association of treatment outcome with baseline BZD use, with ongoing BZD use and with different patterns of BZD prescription. Baseline BZD use correlated with lower retention rates but not with poorer outcome. Ongoing BZD use correlated with poorer outcomes. Significantly better outcomes were found in the course of phobic anxiety symptomatology for those with regular prescription of BZD. The percentage of BZD positive urine tests decreased more in HAT than in MMT. Poorer outcome for benzodiazepine users may be mediated by a higher severity of addiction. Cautious prescribing of benzodiazepines may be beneficial due to the reduction of overall illicit use. PMID- 20708351 TI - A novel spatial and stochastic model to evaluate the within- and between-farm transmission of classical swine fever virus. I. General concepts and description of the model. AB - A new stochastic and spatial model was developed to evaluate the potential spread of classical swine fever virus (CSFV) within- and between-farms, and considering the specific farm-to-farm contact network. Within-farm transmission was simulated using a modified SI model. Between-farm transmission was assumed to occur by direct contacts (i.e. animal movement) and indirect contacts (i.e. local spread, vehicle and person contacts) and considering the spatial location of farms. Control measures dictated by the European legislation (i.e. depopulation of infected farms, movement restriction, zoning, surveillance, contact tracing) were also implemented into the model. Model experimentation was performed using real data from Segovia, one of the provinces with highest density of pigs in Spain, and results were presented using the mean, 95% probability intervals [95% PI] and risk maps. The estimated mean [95% PI] number of infected, quarantined and depopulated farms were 3 [1,17], 23 [0,76] and 115 [0,318], respectively. The duration of the epidemic was 63 [26,177] days and the most important way of transmission was associated with local spread (61.4% of the infections). Results were consistent with the spread of previous CSFV introductions into the study region. The model and results presented here may be useful for the decision making process and for the improvement of the prevention and control programmes for CSFV. PMID- 20708352 TI - Isolation and genetic analysis of a novel triple-reassortant H1N1 influenza virus from a pig in China. AB - Influenza A viruses of subtype H1N1 have been reported widely in pigs in China, associated with clinical disease. These mainly include classical swine H1N1, avian-like H1N1, and human-like H1N1 viruses. In this study, we reported a novel triple-reassortant H1N1 virus (A/swine/Guangdong/1/2010) containing genes from the classical swine (NP, NS), human (PB1) and avian (HA, NA, M, PB2, PA) lineages, which was for the first time reported in China. Also, phylogenetic analysis further confirmed that five genes segments (NS, NP, PB2, PB1, PA) of the isolate were closely related to the novel reassortant H1N2 viruses isolated in China in 2006, while the other three (HA, NA, M) were closely related to avian like H1N1 viruses in China. The isolation of triple-reassortant H1N1 influenza virus provides further evidence that pigs serve as emergence hosts or "mixing vessels", and swine influenza virus (SIV) surveillance in China should be given a high priority. PMID- 20708350 TI - Construction of an infectious cDNA clone of avian hepatitis E virus (avian HEV) recovered from a clinically healthy chicken in the United States and characterization of its pathogenicity in specific-pathogen-free chickens. AB - A genetically distinct strain of avian hepatitis E virus (avian HEV-VA strain) was isolated from a healthy chicken in Virginia, and thus it is important to characterize and compare its pathogenicity with the prototype strain (avian HEV prototype) isolated from a diseased chicken. Here we first constructed an infectious clone of the avian HEV-VA strain. Capped RNA transcripts from the avian HEV-VA clone were replication-competent after transfection of LMH chicken liver cells. Chickens inoculated intrahepatically with RNA transcripts of avian HEV-VA clone developed active infection as evidenced by fecal virus shedding, viremia, and seroconversion. To characterize the pathogenicity, RNA transcripts of both avian HEV-VA and avian HEV-prototype clones were intrahepatically inoculated into the livers of chickens. Avian HEV RNA was detected in feces, serum and bile samples from 10/10 avian HEV-VA-inoculated and 9/9 avian HEV prototype-inoculated chickens although seroconversion occurred only in some chickens during the experimental period. The histopathological lesion scores were lower for avian HEV-VA group than avian HEV-prototype group in the liver at 3 and 5 weeks post-inoculation (wpi) and in the spleen at 3 wpi, although the differences were not statistically significant. The liver/body weight ratio, indicative of liver enlargement, of both avian HEV-VA and avian HEV-prototype groups were significantly higher than that of the control group at 5 wpi. Overall, the avian HEV-VA strain still induces histological liver lesions even though it was isolated from a healthy chicken. The results also showed that intrahepatic inoculation of chickens with RNA transcripts of avian HEV infectious clone may serve as an alternative for live virus in animal pathogenicity studies. PMID- 20708353 TI - The extra-intestinal avian pathogenic Escherichia coli strain BEN2908 invades avian and human epithelial cells and survives intracellularly. AB - Extra-intestinal pathogenic Escherichia coli (ExPEC) strains are responsible for a wide range of diseases in humans and animals. Using in vitro invasion assays and transmission electron microscopy, we showed that BEN2908, an ExPEC strain of avian origin (also termed APEC for Avian Pathogenic E. coli), is able to usurp cellular endocytic pathways to invade A549 human type II pneumocytes and LMH avian hepatocytes where it is able to survive over several days. Although type 1 fimbriae are the major adhesin of BEN2908, proportions of adherent fimbriated or afimbriated bacteria that entered cells were comparable. Internalization of BEN2908 into human pneumocytes reinforces previous studies indicating that APEC strains could represent a zoonotic risk. PMID- 20708355 TI - Serodiagnosis of sporotrichosis infection in cats by enzyme-linked immunosorbent assay using a specific antigen, SsCBF, and crude exoantigens. AB - The main objective of this study is to standardize an ELISA for the diagnosis of feline sporotrichosis. Sporothrix schenckii is the etiological agent of human and animal sporotrichosis. Cats may act as reservoirs for S. schenckii and can transmit the infection to humans by a bite or scratch. There are few methods for the serological diagnosis of fungal diseases in animals. In this paper, an ELISA test for the diagnosis of cat sporotrichosis is proposed, which detects S. schenckii-specific antibodies in feline sera. Two different kinds of antigens were used: "SsCBF", a specific molecule from S. schenckii that consists of a Con A-binding fraction derived from a peptido-rhamnomannan component of the cell wall, and a S. schenckii crude exoantigen preparation. The ELISA was developed, optimized, and evaluated using sera from 30 cats with proven sporotrichosis (by culture isolation); 22 sera from healthy feral cats from a zoonosis center were used as negative controls. SsCBF showed 90% sensitivity and 96% specificity in ELISA; while crude exoantigens demonstrated 96% sensitivity and 98% specificity. The ELISA assay described here would be a valuable screening tool for the detection of specific S. schenckii antibodies in cats with sporotrichosis. The assay is inexpensive, quick to perform, easy to interpret, and permits the diagnosis of feline sporotrichosis. PMID- 20708354 TI - Quorum sensing in Aeromonas salmonicida subsp. achromogenes and the effect of the autoinducer synthase AsaI on bacterial virulence. AB - The Gram-negative fish pathogenic bacterium Aeromonas salmonicida possesses the LuxIR-type quorum sensing (QS) system, termed AsaIR. In this study the role of QS in A. salmonicida subsp. achromogenes virulence and pigment production was investigated. Five wild-type Asa strains induced the N-acyl-homoserinelactone (AHL) monitor bacteria. HPLC-HR-MS analysis identified only one type of AHL, N butanoyl-L-homoserine lactone (C4-HSL). A knock out mutant of AsaI, constructed by allelic exchange, did not produce a detectable QS signal and its virulence in fish was significantly impaired, as LD(50) of the AsaI-deficient mutant was 20 fold higher than that of the isogenic wt strain and the mean day to death of the mutant was significantly prolonged. Furthermore, the expression of two virulence factors (a toxic protease, AsaP1, and a cytotoxic factor) and a brown pigment were reduced in the mutant. AsaP1 production was inhibited by synthetic QS inhibitors (N-(propylsulfanylacetyl)-L-homoserine lactone; N (pentylsulfanylacetyl)-L-homoserine lactone; and N-(heptylsulfanylacetyl)-L homoserine lactone) at concentrations that did not affect bacterial growth. It is a new finding that the AHL synthase of Aeromonas affects virulence in fish and QS has not previously been associated with A. salmonicida infections in fish. Furthermore, AsaP1 production has not previously been shown to be QS regulated. The simplicity of the A. salmonicida subsp. achromogenes LuxIR-type QS system and the observation that synthetic QSI can inhibit an important virulence factor, AsaP1, without affecting bacterial growth, makes A. salmonicida subsp. achromogenes an interesting target organism to study the effects of QS in disease development and QSI in disease control. PMID- 20708356 TI - Sepsis-associated electroencephalographic changes in extremely low gestational age neonates. AB - BACKGROUND: Sepsis in premature infants is associated with adverse neurodevelopmental outcomes. No previous studies have assessed acute changes in brain function during sepsis that might precede these adverse outcomes. METHODS: We performed amplitude-integrated electroencephalography (aEEG) monthly, from 28 weeks until 36 weeks of postmenstrual age, on 108 premature infants born before 28 weeks of gestation. Additional aEEG recordings were performed during infants' first episode of sepsis. Two independent readers who were blinded to the infant's gestational age at birth and chronologic age, as well as to whether the infant had sepsis, evaluated aEEG recordings for the presence of burst suppression and assigned a maturation score. RESULTS: Burst supression was found in 22% of aEEG recordings from infants without sepsis and 57% of recordings from infants with sepsis at the time of the recording (odds ratio=4.2; 95% confidence limits=2.4, 7.2; p<0.001). After adjustment for postmenstrual age at the time of the recording, the association between sepsis and burst suppression persisted (odds ratio=2.4; 95% confidence limits=1.2, 4.8; p=0.01). No statistically significant difference was found in the rate of increase in aEEG maturation score between infants with sepsis and those without. CONCLUSION: Sepsis is associated with acute electroencephalographic changes, as indicated by burst supression, but not with a decreased rate of brain wave maturation. PMID- 20708357 TI - Prevalence of fibromyalgia and chronic widespread pain in community-dwelling elderly subjects living in Sao Paulo, Brazil. AB - OBJECTIVES: To estimate the prevalence of fibromyalgia (FM) and chronic widespread pain (CWP) in community-dwelling elderly individuals living in Sao Paulo, to assess the spectrum of problems related to these diseases using the Fibromyalgia Impact Questionnaire (FIQ) and to correlate the FIQ with the number of tender points and with pain threshold. METHODS: Our sample consisted of 361 individuals (64% women, 36% men, mean age of 73.3+/-5.7 years). Individuals were classified into four groups: FM (according to American College of Rheumatology criteria), CWP, regional pain (RP) and no pain (NP). Pain characteristics and dolorimetry for 18 tender points and the FIQ were assessed. RESULTS: The prevalence of FM was 5.5% [95% confidence interval (CI)=5.4-5.7], and the prevalence of CWP was 14.1% (95% CI: 10.5-17.7%). The frequency of RP was 52.6% and the prevalence of NP was 27.7%. FIQ scores were higher in people with FM (44.5), followed by CWP (31.4), RP (18.1) and NP (5.5) (p<0.001). There was a positive correlation between the domains of the FIQ and the number of tender points (p<0.05), and a negative correlation between FIQ score and pain threshold (p<0.05). CONCLUSION: In our elderly subjects, the prevalence of FM was slightly higher compared to previously reported studies, and CWP was around 14%. The spectrum of problems related to chronic pain was more severe in FM followed by CWP, strongly suggesting that these conditions should be diagnosed and adequately treated in older individuals. PMID- 20708359 TI - Determination of acidic and neutral therapeutic drugs in human blood by liquid chromatography-electrospray tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method using pneumatically assisted electrospray ionisation (LC-ESI-MS/MS) was developed for the simultaneous determination of paracetamol, naproxen, ibuprofen, etodolac, diclofenac, salicylic acid, lamotrigine, carbamazepine, 10-OH-carbazepine, phenytoin, phenobarbital, barbital, cyclobarbital, pentobarbital, amobarbital and caffeine in human live and post-mortem whole blood. The blood proteins were precipitated in a mixture of methanol and acetonitrile, and the extract was purified by ultrafiltration. The separation was performed on an ether-linked phenyl column with polar endcapping, and both negative and positive ESI were applied. Matrix-matched standards were used for calibration. The relative intra laboratory reproducibility standard deviations were, in general, better than 8% at concentrations in the therapeutic range. The mean true recoveries were in the range 92-101% for the live blood and 84-101% for the post-mortem blood. PMID- 20708358 TI - Women lose patella cartilage at a faster rate than men: a 4.5-year cohort study of subjects with knee OA. AB - OBJECTIVES: Patellofemoral knee osteoarthritis (OA) is a common disease, and a significant cause of knee pain, however few data have examined longitudinal change at the patellofemoral joint. The aim of this study was to examine factors affecting change in patella cartilage over a longer time period than previously examined. STUDY DESIGN: Longitudinal study of 77 subjects (58% female) with knee OA underwent magnetic resonance imaging (MRI), with a repeat MRI of the same knee obtained approximately 4.5 years later. MAIN OUTCOME MEASURES: Annual change in patella cartilage volume, and annual percentage change over 4.5 years. RESULTS: After adjusting for age, gender, BMI and patella bone volume at baseline, cartilage change was observed at the rate of 2.5% (95% confidence interval, 2.0, 3.0) per annum over 4.5 years. Cartilage was lost at a higher rate in women compared to men after accounting for age, BMI or bone volume at baseline (3.3% vs. 1.4%, respectively, p=0.03). Increased patella bone volume was associated with increased patella cartilage loss (p=0.02). No measures of radiographic severity of disease affected change in cartilage volume. CONCLUSIONS: The increased rate of cartilage loss in women may contribute to the increased prevalence of disease, although the underlying mechanism requires further study. Increased patella bone volume was also associated with increased patella cartilage loss. Whether this is due to biomechanical factors will need to be determined. PMID- 20708360 TI - Autistic regression with and without EEG abnormalities followed by favourable outcome. AB - OBJECTIVES: To explore the relationship between autistic regression (AR) with and without EEG abnormalities and favourable outcome. METHODS: Follow up data on children with favourable outcome in a series of 534 cases aged below 5 years and diagnosed as ASD. RESULTS: Cases with regression were 167 (31.8%), usually with persistent ASD, intellectual disabilities and EEG abnormalities. Thirty nine children (7.3%) went off autism and recovered entirely their intellectual and social abilities. Few of them included examples of pharmacologically treated Landau and Kleffner syndrome and other similar complex cases with abnormal EEG. The majority was represented by 36 (6.7%) children, mostly males, with a dysmaturational syndrome: their development was initially normal up to 18 months when an autistic regression occurred accompanied by the appearance of motor and vocal tics. Relational therapies were followed by rapid improvement. By 6 years all children had lost features of ASD and their I.Q. was in most cases between 90 and 110. Convulsions were absent and EEG was normal in all cases except one. In a few of them recovery was spontaneous. Seventeen children were followed after 5 years 6 months: 12 (70%) had ADHD, 10 (56%) persistent tics. Tics were often present in parents and relatives, ASD absent, suggesting a genetic background different from cases with persistent ASD. With one exception all "off autism" children had a previous autistic regression. CONCLUSIONS: In this series "off autism" children had either early onset epilepsy and/or EEG abnormalities or cases of dysmaturational syndrome. Autistic regression was present in almost all. PMID- 20708361 TI - Value of pelvic embolization in the management of severe postpartum hemorrhage due to placenta accreta, increta or percreta. AB - OBJECTIVES: To evaluate the role, efficacy and safety of pelvic embolization in the management of severe postpartum hemorrhage in women with placenta accreta, increta or percreta. METHODS: The clinical files and angiographic examinations of 12 consecutive women with placenta accreta (n=4), increta (n=2) or percreta (n=6) who were treated with pelvic embolization because of severe primary (n=10) or secondary (n=2) postpartum hemorrhage were reviewed. Before embolization, four women had complete placental conservation, four had partial placental conservation, three had an extirpative approach and one had hysterectomy after failed partial conservative approach. RESULTS: In 10 women, pelvic embolization was successful and stopped the bleeding, after one (n=7) or two sessions (n=3). Emergency hysterectomy was needed in two women with persistent bleeding after embolization, both with placenta percreta and bladder involvement first treated by extirpation. One case of regressive hematoma at the puncture site was the single complication of embolization. CONCLUSIONS: In women with severe postpartum hemorrhage due to placenta accreta, increta or percreta, pelvic embolization is effective for stopping the bleeding in most cases, thus allowing uterine conservation and future fertility. Further studies, however, should be done to evaluate the potential of pelvic embolization in women with placenta percreta with bladder involvement. PMID- 20708362 TI - Coronary artery disease: which degree of coronary artery stenosis is indicative of ischemia? AB - PURPOSE: To prospectively determine the best cut-off value of stenosis degree for low-dose computed tomography coronary angiography (CTCA) to predict the hemodynamic significance of coronary artery stenoses compared to catheter angiography (CA) using a cardiac magnetic resonance based approach as standard of reference. MATERIALS AND METHODS: Fifty-two patients (mean age, 64+/-10 years) scheduled for CA underwent cardiac magnetic resonance (CMR) at 1.5-T and dual source CTCA using prospective ECG-triggering the same day. Diagnostic performance of CTCA and CA to detect myocardial ischemia was evaluated with CMR as the standard of reference. The diagnostic performance and best cut-off values to predict the hemodynamic significance of coronary were determined from receiver operating characteristics analysis (ROC). RESULTS: CA revealed >50% stenoses in 131/832 segments (15.7%) in 78/156 (50.0%) coronary arteries in 32/52 (62%) patients. CTCA revealed >50% stenoses in 148/807 (18.3%) segments, corresponding to 83/156 (53.2%) coronary arteries in 34/52 (65.4%) patients. CMR revealed ischemia in 118/832 (14.2%) myocardial segments corresponding to the territories of 60/156 (38.5%) coronary arteries in 29/52 (56%) patients. ROC analysis showed equal diagnostic performance for low-dose CTCA and CA with areas under the curve (AUC) of 0.82 and 0.83 (P=0.64). The optimal cut-off value was determined at stenosis of >60% for the prediction of hemodynamically significant coronary stenosis by CTCA. Using this cut-off value, sensitivity, specificity, NPV and PPV to predict hemodynamic significance by CTCA were 100%, 83%, 100%, and 88% on a per-patient basis and 88%, 73%, 83% and 81% on a per-artery analysis, respectively. CONCLUSION: By considering coronary stenosis >60%, diagnostic performance for predicting the hemodynamic significance of coronary stenosis by CTCA is optimal and equals that of CA. PMID- 20708363 TI - Analyzing diffusion tensor images with ghosting artifacts: the effects of direct and indirect normalization. AB - The current study aims to assess the applicability of direct or indirect normalization for the analysis of fractional anisotropy (FA) maps in the context of diffusion-weighted images (DWIs) contaminated by ghosting artifacts. We found that FA maps acquired by direct normalization showed generally higher anisotropy than indirect normalization, and the disparities were aggravated by the presence of ghosting artifacts in DWIs. The voxel-wise statistical comparisons demonstrated that indirect normalization reduced the influence of artifacts and enhanced the sensitivity of detecting anisotropy differences between groups. This suggested that images contaminated with ghosting artifacts can be sensibly analyzed using indirect normalization. PMID- 20708364 TI - Rapid assay of rufinamide in dried blood spots by a new liquid chromatography tandem mass spectrometric method. AB - Rufinamide (RUF) is a new antiepileptic drug with efficacy in several types of seizures. The aim of this study was to evaluate the use of dried blood spot (DBS) specimens to determinate RUF levels during treatment. Therapeutic drug monitoring of RUF could be useful in routine clinical practice. Advantages of DBS include short collection time, low invasiveness, ease and low cost of sample collection, transport and storage. The analysis was performed in selected reaction monitoring (SRM) mode. The calibration curve in matrix was linear in the concentration range of 0.008-0.8 mg/L (0.48-47.60 mg/L in DBS) of rufinamide with correlation coefficient value of 0.996. In the concentration range of 0.48-47.6 mg/L, the coefficients of variation in DBS were in the range 1.58-4.67% and the accuracy ranged from 89.73% to 107.32%. The sensitivity and specificity of tandem mass spectrometry allow now high throughput rufinamide analysis. This new assay has favourable characteristics being highly precise and accurate. The published HPLC UV methods also proved to be precise and accurate, but required not less than 0.2 0.5 mL of plasma and are therefore unsuitable for sample collection in neonates in whom obtaining larger blood samples is not convenient or possible. PMID- 20708365 TI - Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism. AB - OBJECTIVES: We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2 loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes. BACKGROUND: CYP2C19*2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention. METHOD: A prospective multicenter study enrolling 411 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of >= 50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%. RESULTS: One hundred thirty-four patients (35.3%) carried at least one 2C19*2 allele (11 homozygotes [2.7%] and 123 heterozygotes [32.6%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild type alleles (61.7 +/- 18.4% vs. 49.2 +/- 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 +/- 10.1% vs. 50.6 +/- 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19*2 carriers exhibiting HTPR to reach a VASP index <50%. CONCLUSIONS: Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19*2 polymorphism. PMID- 20708366 TI - Case report: Delayed subclavian vein injury secondary to clavicular malunion. AB - BACKGROUND: Fractures of the clavicle are extremely common, representing 2.6-12% of all fractures and 35-44% of all shoulder girdle injuries; 69-82% of these fractures occur in the middle third of the clavicle. Vascular injuries relating to clavicle fracture are usually due to extreme force applied to the clavicle in an acute setting. No other reports of delayed subclavian vein laceration were found on literature search. OBJECTIVES: We present this case to increase awareness among emergency physicians of the potential delayed presentation of this rare condition. CASE REPORT: A 21-year-old man presented to the Emergency Department with acute swelling of the base of the neck after carrying a heavy load on his left shoulder the night before. He had been recovering from a clavicle fracture for 2 months. Malunion of his left midshaft clavicle fracture led to subclavian vein injury and formation of a large hematoma secondary to reinjury that occurred at work the night before presentation. Computed tomography revealed a 9-cm hematoma at the fracture site. The patient was found to have a subclavian vein injury without evidence of arterial injury or nervous system involvement. The patient was admitted for observation and subsequently discharged without need for surgical intervention. CONCLUSION: Subclavian vein laceration is a rare complication of clavicle fracture. Patient education at discharge after conservative management is important due to the risk of vascular complications from malunion and reinjury. PMID- 20708367 TI - Breaking through. PMID- 20708368 TI - Improving hemodialysis in patient care: critical areas. PMID- 20708369 TI - The effects of ethanol administration on brush border membrane glycolipids in rat intestine. AB - Ethanol ingestion is well known to induce morphological and biochemical changes in intestine and is responsible for intestinal dysfunctions. Luminal surface of enterocytes is rich in glycolipids, but the effects of ethanol ingestion on membrane glycolipids are not well characterized. In the present study, rats were given 1 mL of 30% ethanol daily for 15, 25, 35, and 56 days. Ethanol feeding for 15 days did not affect glycolipid pattern in microvillus membranes, but the levels of cerebrosides (glucosylceramide, lactosylceramide, globotriasyloceramide) were enhanced in rats fed with ethanol for 35 or 56 days compared with controls. In contrast, the content of fucolipids and gangliosides was reduced in rats on ethanol ingestion for 35 or 56 days. The observed changes in membrane glycolipids were substantiated using biotinylated lectins Jacalin (affinity for N-acetylgalactosamine) and Aleuria aurantia (affinity for alpha-l fucose). The incorporation of [(14)C]-mannose and [(14)C]-glucosamine revealed an increase (P<.01) in glucosamination and reduction (P<.01) in mannosylation of glycolipids from ethanol-fed rats for 45 days compared with controls. These findings were further characterized by autoradiography of the glycolipids separated on thin layer chromatograms. These findings indicate that ethanol ingestion modulates the glycolipids composition of brush borders, resulting in generalized aberration of intestinal glycosylation in chronic alcoholism in rats. PMID- 20708370 TI - AFP and hepatoma staging. PMID- 20708371 TI - Modified core wash cytology (CWC), an asset in the diagnostic work-up of breast lesions. AB - AIM: A quick and reliable preliminary diagnosis is essential in the management of a same-day breast clinic. In a preclinical study we developed an alternative method of core wash cytology (CWC). This study is an evaluation of this new CWC method introduced into the clinical setting. METHODS: From April 2008 to April 2009, biopsies were taken from lesions in the breast. CWC was obtained from core needle biopsy (CNB) with a modified technique and classified into the categories: malignant, suspicious for malignancy, atypical, benign and inadequate. CWC and CNB diagnoses were correlated with the histopathology of subsequently obtained resection specimens. The sensitivity and specificity were calculated. RESULTS: CWC was obtained from 226 breast lesions. In 167 of these cases subsequent resection of the lesion was performed revealing 149 carcinomas and 18 benign lesions. Of the 149 malignant cases, 136 were considered as either malignant or suspicious for malignancy by CWC, 7 as atypical, 4 as benign and 2 as inadequate. None of the 18 benign lesions were classified as suspicious or malignant on CWC. Eight out of 149 resected carcinomas were not recognized as malignant by histological analysis of the CNB, while 7 of these cases the CWC was considered malignant. The sensitivity and specificity were 97% and 100%, respectively. CONCLUSIONS: In the vast majority of patients the modified CWC technique can provide a quick and reliable diagnosis of malignant breast lesions. Furthermore, combining CWC with CNB histology can improve adequate, preoperative recognition of the malignant character of breast lesions. PMID- 20708372 TI - [Ignaz Semmelweis]. PMID- 20708373 TI - [Oral vitamin B12: Efficacy and safety data in 31 patients with pernicious anemia and food-cobalamin malabsorption]. AB - OBJECTIVE: The aim of this study is to validate the efficacy and safety of oral cobalamin therapy in the treatment of cobalamin deficiency related to various causes. PATIENT AND METHOD: It's a retrospective study, including 31 patients with documented cobalamin deficiency related to food-cobalamin malabsorption (n=20) and pernicious anemia (n=11). These patients were treated at least for 3 months with oral cyanocobalamin, between 125 to 1000microg per day. Serum cobalamin levels and hematological parameters were compared before and after the therapy and in relation with the nature of cobalamin deficiency. Safety data were also recorded. RESULTS: After 3 months of therapy, the serum cobalamin levels have significantly increased in all the patients, with a mean of +161.6+/ 79.3pg/mL in the food-cobalamin malabsorption group (P<0,00005) and +136.7+/ 67.4pg/mL in the pernicious anemia group (P<0,0001). Hematological parameters have been normalized in 90 % of the patients, independently of the cause of the cobalamin deficiency. Only 1 patient presented an urticarial reaction. CONCLUSION: This study confirms the efficacy and safety of oral cobalamin therapy in food-cobalamin malabsorption and also in case of pernicious anemia. PMID- 20708374 TI - Acute aortic regurgitation secondary to disk embolization of a Bjork-Shiley prosthetic aortic valve. AB - Having passed the 30th anniversary of the first implantation of a Bjork-Shiley convexo-concave tilting mechanical valve, recognition of the life-threatening complication of strut fracture is not widespread. The authors report the case of a 48-year-old man with acute-onset chest pain and dyspnea found to have strut fracture and disk embolization of a 26-year-old Bjork-Shiley prosthetic aortic valve. The value of echocardiography in the diagnosis of this condition is discussed. PMID- 20708375 TI - Uncommon Doppler echocardiographic findings of severe pulmonic insufficiency. AB - BACKGROUND: Two-dimensional and Doppler echocardiography are standard methods to assess the severity of pulmonic insufficiency (PI). However, methods to define severity of PI - including the current published guidelines - remain qualitative and unvalidated. METHODS: We reviewed all the electronic reports of echocardiographic studies performed at our institution since the publication of the 2003 American Society of Echocardiography guidelines on native valvular regurgitation. There were 8,279 instances of severe valvular insufficiency among 100,167 echocardiographic studies (approximately 90% transthoracic and 10% transesophageal). We also searched for uncommon findings of severe PI. RESULTS: Of all forms of severe valvular insufficiency, PI was least common. There were 135 instances of severe PI as defined by the existing guidelines; they accounted for only 1.6% of all instances of severe valvular insufficiency. Premature closure of the tricuspid valve was seen in 6.6%, holodiastolic flow reversal in 3.7%, premature opening of the pulmonic valve in 1.5%, PI with laminar retrograde flow in 1.5%, very low peak velocity of the PI jet in 1.5% of patients with severe PI. CONCLUSIONS: The published criteria do not include in detail the subtle signs of severe PI such as (1) holodiastolic flow reversal in the pulmonary artery, (2) PI with laminar retrograde flow, (3) premature opening of the pulmonic valve, (4) very low peak velocity of the PI jet, and (5) premature closure of the tricuspid valve. These signs should be considered in the grading of PI severity in addition to the existing guidelines criteria. PMID- 20708376 TI - Multi-modality imaging of an adult parachute mitral valve. AB - A parachute abnormality of the mitral valve is an extremely rare finding in adults. It is usually seen as part of Shone's complex. The authors present multimodality imaging from a case of adult parachute abnormality of the mitral valve to illustrate and explain features such as the characteristic "pear" shape of the valve and "doming" of the subvalvular apparatus. The solitary papillary muscle that defines the condition may be difficult to identify on transthoracic echocardiography, but redundancy of the chordae is a key echocardiographic feature in the adult form of the condition. PMID- 20708378 TI - Antioxidant activity and hepatoprotective effects of whey protein and Spirulina in rats. AB - OBJECTIVES: The aims of the present study were to evaluate the antioxidant, radical scavenging, and metal-chelating activity of whey protein concentrate (WPC) and Spirulina alone or in combination in vitro and to evaluate their hepatoprotective effects against CCl(4) in vivo. METHODS: Five concentrations (20, 40, 60, 80, and 100 mg/100 mL) of WPC, Spirulina, and their combination were tested in vitro. In the in vivo study, eight groups of male rats comprised the control group and the groups treated with WPC, Spirulina alone, or in combination with or without CCl(4) were used. RESULTS: The in vitro study showed that WPC and Spirulina showed antioxidant, radical scavenging, and metal-chelating activities in dose-dependent manner. The in vivo study showed that both agents succeeded in preventing liver damage induced by CCl(4). This prevention was more pronounced in rats receiving the combination of WPC and Spirulina. CONCLUSION: Whey protein concentrate and Spirulina have free radical scavenging properties and antioxidant activity. PMID- 20708377 TI - A gel-based proteomic analysis of the effects of green tea polyphenols on ovariectomized rats. AB - OBJECTIVE: Our recent study demonstrated the protective action of green tea polyphenols (GTPs) against bone loss in ovariectomized (OVX) rats through their antioxidant capacities to scavenge reactive oxygen species. The objective of the present study was to evaluate the alterations of liver protein profiles in estrogen-deficient middle-aged rats after GTP treatment by a gel-based proteomic approach. This may lead to understanding the mechanisms of GTPs in promoting bone health. METHODS: Liver samples were obtained from 14-mo-old female OVX rats treated with no GTPs (OVX) or 0.5% (w/v) GTPs (OVX + GTP) in drinking water for 16 wk (n = 10/group). Two-dimensional difference gel electrophoresis combined with mass spectrometry was used to compare the liver protein profiles of pooled samples from the OVX and OVX + GTP groups. Liver proteins were labeled in duplicate by reversing the fluorescent dyes. RESULTS: Approximately 800 protein spots were detected. The expression levels of superoxide dismutase-1 and adenosine triphosphate synthase were 2.0-fold and 1.5-fold higher in the OVX + GTP group versus the OVX group, respectively, whereas the expression level of catechol-O-methyltransferase was 1.5-fold lower in the OVX + GTP group versus the OVX group. The changes of superoxide dismutase-1 and catechol-O-methyltransferase in individual liver samples were confirmed by western blots. CONCLUSION: Our data provide further evidence for the antioxidant role of GTPs by increasing superoxide dismutase-1 and adenosine triphosphate synthase and the estrogen associated effect of GTPs by decreasing catechol-O-methyltransferase. PMID- 20708379 TI - Anti-diabetic effects including diabetic nephropathy of anti-osteoporotic trace minerals on diabetic mice. AB - OBJECTIVE: In our previous study to evaluate the effects of soluble silicon (Si) on bone metabolism, Si and coral sand (CS) as a natural Si-containing material suppressed peroxisome proliferator-activated receptor gamma (PPARgamma), which regulates both glucose and bone metabolism and increases adipogenesis at the expense of osteogenesis, leading to bone loss. In this study, we investigated the anti-diabetic effects of bone-seeking elements, Si and stable strontium (Sr), and CS as a natural material containing these elements using obese diabetic KKAy mice. METHODS: Weanling male mice were fed diets containing 1% Ca supplemented with CaCO(3) as the control and CS, and diets supplemented with 50 ppm Si or 750 ppm Sr to control diet for 56 d. The mRNA expressions related to energy expenditure in the pancreas and kidney were quantified by real-time polymerase chain reaction. RESULTS: At the end of feeding, plasma glucose, insulin, leptin, and adiponectin levels decreased significantly in three test groups, while pancreatic PPARgamma and adiponectin mRNA expression levels increased significantly toward the normal level, improving the glucose sensitivity of beta cells and inducing a significant decrease in insulin expression. The renal PPARgamma, PPARalpha, and adiponectin expression levels, histologic indices of diabetic glomerulopathy, and plasma indices of renal function were also improved significantly in the test groups. CONCLUSION: Taken together, anti-osteoporotic trace minerals, Si and Sr, and CS containing them showed novel anti-diabetic effects of lowering blood glucose level, improving the tolerance to insulin, leptin, and adiponectin, and reducing the risk of glomerulopathy through modulation of related gene expression in the pancreas and kidney. PMID- 20708380 TI - Malnutrition in pediatric hospital patients: current issues. AB - Malnutrition in hospitalized children is still very prevalent, especially in children with underlying disease and clinical conditions. The purpose of this review is to describe current issues that have to be taken into account when interpreting prevalence data. Weight-for-height and height-for-age standard deviation scores are used for classification for acute and chronic malnutrition, respectively. Body mass index for age can also be used for the definition of acute malnutrition but has a few advantages in the general pediatric population. The new World Health Organization child-growth charts can be used as reference but there is a risk of over- and underestimation of malnutrition rates compared with country-specific growth references. For children with specific medical conditions and syndromes, specific growth references should be used for appropriate interpretation of nutritional status. New screening tools are available to identify children at risk for developing malnutrition during admission. Because of the diversity of medical conditions and syndromes in hospitalized children, assessment of nutritional status and interpretation of anthropometric data need a tailored approach. PMID- 20708381 TI - Time course of vitamin C distribution and absorption after oral administration in SMP30/GNL knockout mice. AB - OBJECTIVE: Because vitamin C (VC) has multiple metabolic and antioxidant functions, we investigated the movement of VC throughout the tissues of senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice. METHODS: SMP30/GNL KO mice, which cannot synthesize VC in vivo, were divided into two groups: VC sufficient and VC deficient. Starting at 2 mo of age, both groups had free access to water containing 1.5 and 0.0375 g/L of VC for 1 mo. RESULTS: The average rate of VC retention in 20 tissues of VC-deficient SMP30/GNL KO mice was only 13.7% of that in VC-sufficient mice. Tissues that retained over 20% of VC were the cerebellum, white fat, testes, eyeballs, and pancreas, and those with less than 5% VC were the kidneys and heart. These results clearly indicate the different VC retention capacities among tissues. Next, we examined the time course of VC distribution and absorption in VC-deficient SMP30/GNL KO mice. After oral VC administration, VC content in the liver and kidney peaked at 3 h and then decreased. VC content in the lungs, adrenal glands, skin, white fat, and pancreas peaked at 6 h and in the cerebellum, cerebrum, skeletal muscles, eyeballs, thyroid gland, and testes at 12 h. CONCLUSION: In this study, we found that exogenous VC administered orally in VC-deficient SMP30/GNL KO mice was distributed at distinctly different rates within individual tissues. The SMP30/GNL KO mice used in this study are a useful animal model that provides unique opportunities for investigating VC movement and metabolism in the entire body. PMID- 20708383 TI - Fatal status epilepticus: a clinico-pathological analysis among 100 patients: from a developing country perspective. AB - PURPOSE: We evaluated the neuropathological features associated with fatal SE with emphasis on neuroanatomy and etiology, and attempted to correlate with the clinical observations. MATERIALS AND METHODS: Details of 100 (n=100; M:F=64:36) autopsied cases of status epilepticus were studied retrospectively with emphasis on clinico-pathological characteristics. RESULTS: Sixty-five percent of patients presented for the first time as SE. Patients with prior history of epilepsy (35%), had discontinued treatment in 71.4% of cases, resulting in SE. Majority of patients with SE had generalized convulsive seizures (75%). The mean GCS score at admission was 4.4. Median delay in initiating the treatment following seizure was 23.5h (mean: 29.5+/-32.8h). The etiological factors could be identified in two thirds of cases, neuroinfection (n=34) and stroke (n=16) being the commonest. Frontal lobe was the most commonly involved area (38.6%), in both localized and multilobar pathology. Dual pathology was observed in seven patients. Clinico pathological concordance was noted in 58%. The discordance observed in 42 patients was either due to low index of suspicion for additional etiologies, inaccurate neuroimaging interpretation or non-availability of extensive diagnostic modalities prior to referring to this centre. CONCLUSIONS: This is one of the largest cohort of fatal SE with pathological correlation in the literature. Clinico-pathological concordance was observed in 58% of patients. Neuroinfection and cerebral stroke were observed in two-thirds of patients as the etiological factor. Prolonged duration of SE, long delay in initiating treatment, poor GCS score at admission, poor drug compliance and symptomatic etiologies were common in this cohort of fatal SE from a developing country, most of which could have been preventable. PMID- 20708382 TI - Anti-inflammatory activities of red curry paste extract on lipopolysaccharide activated murine macrophage cell line. AB - OBJECTIVE: This study investigated anti-inflammatory and antioxidant activities of an ethanol extract from Thai red curry paste. METHODS: The RAW264.7 murine macrophage cell line was incubated with the extract (65-260 MUg/mL) with or without lipopolysaccharide. The anti-inflammatory activities of the extract were examined by measuring inducible nitric oxide synthase, cyclo-oxygenase-2, tumor necrosis factor-alpha, and interleukin-6 mRNA and protein level by reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay, respectively. Nitric oxide production and intracellular reactive oxygen species generation were determined by the Griess method and fluorescence intensity. The activation of mitogen-activated protein kinases and inhibitor kappaB were determined by western blot. RESULTS: Exposure of cells with the extract significantly suppressed lipopolysaccharide-induced nitric oxide production and inducible nitric oxide synthase, cyclo-oxygenase-2, tumor necrosis factor-alpha, and interleukin-6 expressions (P < 0.05) by dose-dependently without cytotoxic effect. Intracellular reactive oxygen species significantly decreased (P < 0.05) in lipopolysaccharide-induced RAW264.7 cells. The inhibitory effect was mediated partly by inhibiting activation of inhibitor kappaB-alpha and mitogen-activated protein kinases. CONCLUSION: These results suggest that the anti-inflammatory and antioxidant properties of Thai red curry paste stem from bioactive compounds present in the spice and herb constituents. The health benefits of Thai red curry paste warrant further investigations in vivo. PMID- 20708384 TI - Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey. AB - PURPOSE: Fatigue represents a frequent complaint in epileptic patients (EP). This study attempted to evaluate fatigue in both conditions (inter-ictally and post ictally) and to investigate the relative contribution of depression, sleepiness and epilepsy characteristics. METHODS: Consecutive EP were enrolled prospectively during a 3-month period, providing they were aged over 15 and able to fill auto questionnaires. Age, gender, co-morbidities, seizure frequency, treatment, epilepsy syndrome, seizure lateralization and localization and last seizure occurrence were collected. Fatigue, depression and sleepiness were evaluated in both groups using the Fatigue Impact Scale (FIS), the Beck Depression Inventory (BDI), and the Epworth Sleepiness Scale (ESS). Furthermore, FIS was prospectively scored by patients post-ictally (within 24h after an incident seizure). RESULTS: 122 EP filled inclusion criteria (65 women, mean age 39+/-15). Among them, 82% presented with non-idiopathic partial epilepsy and 18% idiopathic generalized epilepsy. EP exhibit high chronic fatigue scores (62/160) irrespective of the type of epilepsy, seizure frequency, and number of antiepileptic drugs. FIS score was higher in post-ictally (79/160) than inter-ictally. FIS positively correlated with BDI and ESS. DISCUSSION: Chronic inter-ictal and post-ictal fatigue could represent a further complication of epilepsy, associated with depression. The impact of fatigue should be considered with the aim of improving quality of life and care of patients with epilepsy. PMID- 20708385 TI - Capacity building for zoonotic and foodborne diseases in the Mediterranean and Middle East regions (an intersectoral WHO/MZCP proposed strategy). AB - Epidemics and threats of epidemics are events of national and international public health importance. Zoonotic and foodborne disease management in the Mediterranean and the Middle East regions suffers from the inconsistent availability of accurate data at national and regional levels as well as difficulties in the timely recognition and containment of disease events. This situation mostly results from weak intersectoral national policies, strategies and programmes, together with a lack of education for professionals in crucial technical posts to help them provide effective management. There is urgent need for the development of a capacity-building strategy among human resources through specialised training in fields of major importance. The adoption of an expanded training strategy at national and inter-country level targeted at increasing the capability of professionals in sectors involved in zoonoses, foodborne diseases, food safety, the environment, emergencies, public health education and promoting intersectoral collaboration and coordination is proposed. Such a capacity building strategy will need sustained political commitment for support and reform, together with sustained technical contributions and funds mobilisation by international organisations. PMID- 20708386 TI - Alkali, thermo and halo tolerant fungal isolate for the removal of textile dyes. AB - In the present study potential of a fungal isolate Aspergillus lentulusFJ172995, was investigated for the removal of textile dyes. The removal percentages of dyes such as Acid Navy Blue, Orange-HF, Fast Red A, Acid Sulphone Blue and Acid Magenta were determined as 99.43, 98.82, 98.75, 97.67 and 69.98, respectively. None of the dyes inhibited the growth of A. lentulus. Detailed studies on growth kinetics, mechanism of dye removal and effect of different parameters on dye removal were conducted using Acid Navy Blue dye. It was observed that A. lentulus could completely remove Acid Navy Blue even at high initial dye concentrations, up to 900 mg/L. Highest uptake capacity of 212.92 mg/g was observed at an initial dye concentration of 900 mg/L. Dye removing efficiency was not altered with the variation of pH; and biomass production as well as dye removal was favored at higher temperatures. Dye removal was also efficient even at high salt concentration. Through growth kinetics studies it was observed that the initial exponential growth phase coincided with the phase of maximal dye removal. Microscopic studies suggest that bioaccumulation along with biosorption is the principle mechanism involved in dye removal by A. lentulus. Thus, it is concluded that being alkali, thermo and halo tolerant, A. lentulus isolate has a great potential to be utilized for the treatment of dye bearing effluents which are usually alkaline, hot and saline. PMID- 20708387 TI - Electrochemical behavior of rutin on a multi-walled carbon nanotube and ionic liquid composite film modified electrode. AB - In this paper, the electrochemical behaviors of rutin at the MWNTs-IL-Gel/glassy carbon electrode (GCE) were investigated. Good electrocatalysis behavior towards the oxidation of rutin with enhancement of the redox peak current and decrease of the peak-to-peak separation was demonstrated. The electrochemical parameters of rutin were calculated giving values of the charge-transfer coefficient (alpha) and the electrode reaction standard rate constant (k(s)) as 0.47 and 0.2s(-1), respectively. In addition, the MWNTs-IL-Gel/GCE was characterized by different methods including electrochemical impedance spectroscopy (EIS), scanning electron microscope (SEM), clay film thickness, and UV-vis spectra. The oxidation peak currents of rutin in such modified electrode increased linearly with the concentration of rutin in the range from 7.2 x 10(-8) to 6.0 x 10(-6) mol L(-1) with a detection limit of 2.0 x 10(-8) mol L(-1). These results suggest that the proposed electrode can be used for sensitive, simple and rapid determination of rutin. PMID- 20708388 TI - The influence of surfactants on cell surface properties of Aeromonas hydrophila during diesel oil biodegradation. AB - In this study the capacity of the newly isolated environmental strain Aeromonas hydrophila was evaluated. The influence of three surfactants: rhamnolipides, saponins and Triton X-100 on cell surface properties of the A. hydrophila environmental strain and the biodegradation process of diesel oil was studied. The surface activities in water, a mineral salts medium and in the biological system of all considered surfactants were estimated by means of equilibrium surface tension experiments. The obtained results indicated that critical micellar concentration in the biological system is twice higher for saponins and Triton X-100, and three times higher for rhamnolipides. Our results indicated also, that cell surface hydrophobicity (CSH) of bacteria is correlated with carbon sources in broth medium. The mechanism of surfactant action seems to be dependent on the type and concentration of surfactant used in the studies. The best effect of saponins on diesel oil biodegradation was observed using the A. hydrophila strain, diesel oil biodegradation after 21 days was 78%. PMID- 20708389 TI - Non-cholesterol sterols in different forms of primary hyperlipemias. AB - BACKGROUND AND AIMS: We investigated the behaviour of non-cholesterol sterols, surrogate markers of cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol), in primary hyperlipemias. METHODS AND RESULTS: We studied 53 patients with polygenic hypercholesterolemia (PH), 38 patients with familial combined hyperlipemia (FCH), and 19 age- and sex-matched healthy control subjects. In all participants, plasma sitosterol, campesterol and lathosterol were determined by gas chromatography coupled to mass spectrometry. To correct for the effect of plasma lipid levels, non-cholesterol sterol concentrations were adjusted for plasma cholesterol (102 MUmol/mmol cholesterol). Patients with FCH were more frequently men, and had higher body mass index (BMI), fasting glucose, insulin and HOMA-IR. Lathosterol was higher in FCH than in pH or controls (p < 0.05). Campesterol was significantly lower in FCH (p < 0.05), while no differences were found between pH and controls. Sitosterol displayed higher values in pH compared to FCH (p < 0.001) and controls (p < 0.05). Spearman's rank correlations showed positive correlations of lathosterol with BMI, waist circumference, HOMA-IR, triglycerides, apoprotein B, and a negative one with HDL cholesterol. Sitosterol had a negative correlation with BMI, waist circumference, HOMA-IR, triglycerides, and a positive one with HDL-cholesterol and apoprotein AI. Multivariate regression analyses showed that cholesterol absorption markers predicted higher HDL-cholesterol levels, while HOMA-IR was a negative predictor of sitosterol and BMI a positive predictor of lathosterol. CONCLUSIONS: Our findings suggest the occurrence of an increased cholesterol synthesis in FCH, and an increased cholesterol absorption in pH. Markers of cholesterol synthesis cluster with clinical and laboratory markers of obesity and insulin resistance. PMID- 20708390 TI - Racial/ethnic discrepancies in the metabolic syndrome begin in childhood and persist after adjustment for environmental factors. AB - BACKGROUND AND AIMS: Evaluation of metabolic syndrome (MetS) characteristics across an age spectrum from childhood to adulthood has been limited by a lack of consistent MetS criteria for children and adults and by a lack of adjustment for environmental factors. We used the pediatric and adult International Diabetes Federation (IDF) criteria to determine whether gender-specific and race-specific differences in MetS and its components are present in adolescents as in adults after adjustment for socio-economic status (SES) and lifestyle factors. METHODS AND RESULTS: Waist circumference, blood pressure, triglycerides, HDL cholesterol, and fasting glucose measures were obtained from 3100 adolescent (12-19 years) and 3419 adult (20-69 years) non-Hispanic white, non-Hispanic black, and Mexican American participants of the 1999-2006 National Health and Nutrition Examination Surveys. We compared odds of having MetS and its components across racial/ethnic groups by age group, while adjusting for income, education, physical activity and diet quality. After adjusting for possible confounding influences of SES and lifestyle, non-Hispanic-black adolescent males exhibited a lower odds of MetS and multiple components (abdominal obesity, hypertriglyceridemia, low HDL, hyperglycemia) compared to non-Hispanic-white and Mexican-American adolescents. Compared to non-Hispanic-white adolescent males, Mexican-American adolescent males had less hypertension. There were no differences in MetS prevalence among adolescent females, though non-Hispanic-black girls exhibited less hypertriglyceridemia. CONCLUSION: Racial/ethnicity-specific differences in MetS and its components are present in both adolescence and adulthood, even after adjusting for environmental factors. These data help strengthen arguments for developing racial/ethnic-specific MetS criteria to better identify individuals at risk for future cardiovascular disease. PMID- 20708391 TI - Gender-specific inhibition of platelet aggregation following omega-3 fatty acid supplementation. AB - BACKGROUND AND AIMS: Increased platelet aggregation is a major risk factor for heart attacks, stroke and thrombosis. Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) reduce platelet aggregation; however studies in the published literature involving EPA and/or DHA supplementation have yielded equivocal results. Recent in vitro studies have demonstrated that inhibition of platelet aggregation by LCn-3PUFA is gender specific. We examined the acute effects of dietary supplementation with EPA or DHA rich oils on platelet aggregation in healthy male and females. METHODS AND RESULTS: A blinded placebo controlled trial involving 15 male and 15 female subjects. Platelet aggregation was measured at 0, 2, 5 and 24 h post supplementation with a single dose of either a placebo or EPA or DHA rich oil capsules. The relationship between LCn-3PUFA and platelet activity at each time point was examined according to gender vs. treatment. EPA was significantly the most effective in reducing platelet aggregation in males at 2, 5 and 24 h post supplementation (-11%, -10.6%, -20.5% respectively) whereas DHA was not effective relative to placebo. In contrast, in females, DHA significantly reduced platelet aggregation at 24 h (-13.7%) while EPA was not effective. An inverse relationship between testosterone levels and platelet aggregation following EPA supplementation was observed. CONCLUSION: Interactions between sex hormones and omega-3 fatty acids exist to differentially reduce platelet aggregation. For healthy individuals, males may benefit more from EPA supplementation while females are more responsive to DHA. PMID- 20708392 TI - Elevated advanced oxidation protein products (AOPPs) indicate metabolic risk in severely obese children. AB - BACKGROUND AND AIMS: The assessment of oxidative stress may aid in the identification of subsequent metabolic risk in obese children. The objective of this study was to determine whether the plasma level of advanced oxidation protein products, analyzed with a recently proposed modified assay that involves a delipidation step (mAOPPs), was related to metabolic risk factors (MRFs) in severely obese children. METHODS AND RESULTS: The plasma levels of mAOPPs were determined by spectrophotometry in 54 severely obese and 44 healthy children. We also measured lipid peroxidation biomarkers (thiobarbituric acid-reactive substances, malondialdehyde, and 8-isoprotane F(2alpha)) and sulfhydryl groups, a marker of antioxidant defense. Protein oxidation and lipid peroxidation markers were higher and sulfhydryl levels were lower in obese children compared with controls. Taking metabolic risk into account, obese children were subdivided according to the cutoff point (53.2 MUmol/L) obtained for their mAOPPs values from the ROC curve. Anthropometric measures and the existence of hypertension did not differ between groups. The presence of dyslipidemia and insulin resistance was significantly higher in the group with higher mAOPPs levels. The highest levels of mAOPPs were found in the children with >=3 MRFs. The level of mAOPPs was positively correlated with triglycerides and negatively correlated with high density lipoprotein cholesterol. There was no correlation of this marker of protein oxidation with biomarkers of lipid peroxidation. CONCLUSION: The determination of mAOPPs in delipidated plasma is an easy way to evaluate protein oxidation. It may be useful in severely obese children for better cardiovascular risk assessment. PMID- 20708393 TI - Effects of therapeutic lifestyle changes on peripheral artery tonometry in patients with abdominal obesity. AB - BACKGROUND AND AIMS: Abdominal obesity (AO) is associated with endothelial function (EF) alteration and increased global cardiovascular (CV) risk. Therapeutic lifestyle changes (TLSC) reduce CV risk, but the impact on EF assessed by peripheral artery tonometry (PAT) is unknown. In this study, we aimed to prospectively assess the effects of TLSC on EF measured by PAT in increased CV risk patients with AO. METHODS AND RESULTS: 150 patients with AO and moderate CV risk were randomized to groups receiving a one-year intervention of either conventional medical care (control group, CG) or an intensive TLSC program (intervention group, IG). Vascular studies (EF by PAT, intima-media thickness (IMT)) and lifestyle (LS) assessment were performed before and after intervention. The PAT ratio improved in the IG and worsened in the CG. The global CV risk was reduced (P = 0.017) in the IG due to a significant decrease in systolic blood pressure (P < 0.001), increase in HDL cholesterol and ApolipoproteinA1 (P = 0.013). More individuals in the IG than in the CG quit smoking (P = 0.001) and increased their physical activity (P = 0.014). The improvement in at least two LS components was associated with a PAT ratio increase (2.44 IC: 95% 0.99-6.00, P = 0.051). The PAT ratio increase determined less IMT progression (-1.1 IC: 95% 0.91-1.00, P = 0.053). CONCLUSIONS: Good adherence to a TLSC program reduces global CV risk and determines PAT ratio improvement. The PAT ratio increase is the main determinant of lower IMT progression. PMID- 20708394 TI - Major dietary patterns and risk of coronary heart disease in middle-aged persons from a Mediterranean country: the EPIC-Spain cohort study. AB - BACKGROUND AND AIM: No previous study has assessed the association between major dietary patterns and the risk of coronary heart disease (CHD) in a large cohort from a Mediterranean country. METHODS AND RESULTS: We studied prospectively 40,757 persons, aged 29-69 years, participating in the Spanish cohort of the EPIC study. Food consumption was collected between 1992 and 1996 with a validated history method. Individuals were followed-up until 2004 through record linkage with hospital discharge registers, population-based registers of myocardial infarction, and mortality registers to ascertain CHD events (fatal and non-fatal acute myocardial infarction or angina requiring revascularization). Two major dietary patterns were identified from factor analysis. The first pattern was labeled as Westernized, because of the frequent consumption of refined cereals and red meat; the second was called the evolved Mediterranean pattern, because of the frequent intake of plant-based foods and olive oil. During a median follow-up of 11 years, 606 CHD events were ascertained. No association was found between the Westernized pattern and CHD risk. In contrast, the score for the evolved Mediterranean pattern was inversely associated with CHD risk (p for trend = 0.0013); when compared with the lowest quintile of the evolved Mediterranean pattern score, the multivariable hazard ratios for CHD were 0.77 (95% confidence interval 0.61-0.98) for the second quintile, 0.64 (95% CI 0.50-0.83) for the third quintile, 0.56 (95% CI 0.43-0.73) for the fourth quintile, and 0.73 (95% CI 0.57-0.94) for the fifth quintile. CONCLUSION: A Mediterranean diet, as consumed in this study population, was associated with a lower risk of CHD. PMID- 20708395 TI - Presence of ochratoxin A in Tunisian blood nephropathy patients. Exposure level to OTA. AB - Ochratoxin A (OTA) produced by Aspergillus and Penicillium genera contaminates cereals and different food compounds. OTA presents a wide range of toxic effects, especially nephrotoxicity. It is also considered to be the main causal agent of Balkan Endemic Nephropathy (BEN) which is similar to the Chronic Interstitial Nephropathy with unknown aetiology seen in Tunisia. In this study, we attempted to confirm the relationship between OTA blood levels and the development of renal pathology. Hence, serum OTA levels were measured in several groups of patients having different renal diseases: a group presenting Chronic Interstitial Nephropathy (CIN) with unknown aetiology, a group presenting Chronic Interstitial Nephropathy (CIN) with known aetiology, a group presenting Chronic Glomerular Nephropathy (CGN), and a group presenting Chronic Vascular Nephropathy (CVN). Each group was compared to a healthy control group. In the healthy group, 49% of individuals showed OTA concentrations ranging from 1.7 to 8.5 ng/ml, with a mean value of 3.3+/-1.5 ng/ml. However, among nephropathic patients, the group with CIN of unknown aetiology showed the highest incidence (76%), ranging from 1.8 to 65 ng/ml with a mean value of 18+/-7 ng/ml. Even in the healthy group, the calculated Daily Intake (DI) ranged from 5.0 to 24.9 ng/kgb.w./day when compared to the recommended DI by the scientific committee on foods of 5 ng/kgb.w./day, indicating a high degree of exposure to OTA in the Tunisian population. Our study confirms the involvement of this nephrotoxic mycotoxin, present at high blood levels in the Tunisian population, in the outcome of this particular human nephropathy (CIN with unknown aetiology) which is similar to BEN. PMID- 20708396 TI - Phenotypic differences between asymptomatic airway hyperresponsiveness and remission of asthma. AB - BACKGROUND: The present study aimed to illustrate differences in characteristics and perception of dyspnea between young atopic adults who have no history of asthma (never-asthmatics) with or without asymptomatic airway hyperresponsiveness (AHR) and those who had childhood asthma and consider themselves to be grown out of the disease (past-asthmatics). METHODS: Blood parameters, lung function and methacholine PC(20) were measured in 88 never-asthmatics and 24 past-asthmatics. A perception score of dyspnea at 20% fall in FEV(1) (PS(20)) was obtained by interpolation of the two last points on the perception (modified Borg scale)/fall in FEV(1) curve during methacholine challenge. RESULTS: Thirty-one of 88 never asthmatics and eighteen of 24 past-asthmatics exhibited AHR (PC(20) was <8 mg/ml). Higher levels of specific IgE to house dust mite in past-asthmatics were observed than never-asthmatics with and without AHR. Mean values of FEV(1) and FEF(25-75) (%predicted) were significantly lower in past-asthmatics than never asthmatics without AHR, and the values in never-asthmatics with AHR were intermediate between never-asthmatics without AHR and past-asthmatics. PC(20) was not significantly different between past-asthmatics and never-asthmatics with AHR. Of particular interest was that PS(20) was significantly lower in never asthmatics with AHR compared with past-asthmatics. CONCLUSION: The present findings suggest the possibilities that presence or absence of past history of outgrow of childhood asthma might be associated with airway narrowing, sensitization to house dust mite and perception of dyspnea in young asymptomatic adults with atopy and AHR. PMID- 20708397 TI - Nuclear and spindle positioning during oocyte meiosis. AB - Female meiosis is unique in that an asymmetrically positioned meiotic spindle expels chromosomes into tiny, non-developing polar bodies. The extrusion of chromosomes into polar bodies is always mediated by meiotic spindles that are attached to the oocyte cortex by one pole. The asymmetric, cortical positioning of the oocyte meiotic spindle preserves the volume and contents of the oocyte. Recent work in C. elegans and mouse has provided mechanistic details of spindle positioning in oocytes. PMID- 20708398 TI - VE-cadherin: at the front, center, and sides of endothelial cell organization and function. AB - Endothelial cells form cell-cell adhesive structures, called adherens and tight junctions, which maintain tissue integrity, but must be dynamic for leukocyte transmigration during the inflammatory response and cellular remodeling during angiogenesis. This review will focus on Vascular Endothelial (VE)-cadherin, an endothelial-specific cell-cell adhesion protein of the adherens junction complex. VE-cadherin plays a key role in endothelial barrier function and angiogenesis, and consequently VE-cadherin availability and function are tightly regulated. VE cadherin also participates directly and indirectly in intracellular signaling pathways that control cell dynamics and cell cycle progression. Here we highlight recent work that has advanced our understanding of multiple regulatory and signaling mechanisms that converge on VE-cadherin and have consequences for endothelial barrier function and angiogenic remodeling. PMID- 20708399 TI - Characterization of the evanescent field profile and bound mass sensitivity of a label-free silicon photonic microring resonator biosensing platform. AB - Silicon photonic microring resonators have emerged as a sensitive and highly multiplexed platform for real-time biomolecule detection. Herein, we profile the evanescent decay of device sensitivity towards molecular binding as a function of distance from the microring surface. By growing multilayers of electrostatically bound polymers extending from the sensor surface, we are able to empirically determine that the evanescent field intensity is characterized by a 1/e response decay distance of 63 nm. We then applied this knowledge to study the growth of biomolecular assemblies consisting of alternating layers of biotinylated antibody and streptavidin, which follow a more complex growth pattern. Additionally, by monitoring the shift in microring resonance wavelength upon the deposition of a radioactively labeled protein, the mass sensitivity of the ring resonator platform was determined to be 14.7+/-6.7 [pg/mm(2)]/Deltapm. By extrapolating to the instrument noise baseline, the mass/area limit of detection is found to be 1.5+/-0.7 pg/mm(2). Taking the small surface area of the microring sensor into consideration, this value corresponds to an absolute mass detection limit of 125 ag (i.e. 0.8 zmol of IgG), demonstrating the remarkable sensitivity of this promising label-free biomolecular sensing platform. PMID- 20708400 TI - A signal-on electrochemical probe-label-free aptasensor using gold-platinum alloy and stearic acid as enhancers. AB - In the present study, a new electrochemical probe-label-free aptasensor for thrombin (TB) based on the amplification of gold-platinum alloy nanoparticles (Au PtNPs) and stearic acid was reported. Nafion@multiwalled carbon nanotubes (MWCNTs) coated electrode was firstly modified with electrochemical probe of methylene blue (MB). Then, Au-PtNPs were electrodeposited onto the electrode surface for the immobilization of aptamer and further hybridization of stearic acid labeled thrombin aptamer (TBA). In the presence of TB, the TBA bound with TB and released from the self-assembled duplex on the electrode into solution, decreasing the steric hindrance of the aptasensor and facilitating catalytic efficiency of Au-PtNPs in the presence of MB toward H2O2 with an enhanced electrochemical signal. With the enhanced effect of Au-PtNPs/MB modified electrode and stearic acid, a detection limit as low as 3pM for TB was achieved. The aptasensor also exhibited good selectivity and reproducibility. PMID- 20708401 TI - Strip-based amperometric detection of myeloperoxidase. AB - The development of a screen-printed strip-based amperometric biosensor for the determination of myeloperoxidase (MPO) levels is reported. The biosensor utilizes 3,3',5,5'-tetramethylbenzidine (TMB) as a redox mediator to enable high sensitivity quantification of physiological levels of MPO. A multivariate parameter optimization was performed. Under the optimal conditions, physiological levels of MPO between 3 and 18 U/L were detected in both acetate buffer (pH 4.5) and human serum using flexible screen-printed electrodes (SPE). The potential interference generated by common serum-based electroactive compounds and a similar peroxidase enzyme was also investigated. The proposed detection methodology offers a simpler, more rapid, and cost-effective alternative to conventional MPO immunoassays, thereby leading to further development in point-of care testing of acute cardiac events. PMID- 20708402 TI - Engineering in complex systems. AB - The implementation of the engineering design cycle of measure, model, manipulate would drastically enhance the success rate of biotechnological designs. Recent progress for the three elements suggests that the scope of the traditional engineering paradigm in biotechnology is expanding. Substantial advances were made in dynamic in vivo analysis of metabolism, which is essential for the accurate prediction of metabolic pathway behavior. Novel methods that require variable degrees of system knowledge facilitate metabolic system manipulation. The combinatorial testing of pre-characterized parts is particularly promising, because it can profit from automation and limits the search space. Finally, conceptual advances in orthogonalizing cells should enhance the reliability of engineering designs in the future. Coupled to improved in silico models of metabolism, these advances should allow a more rational design of metabolic systems. PMID- 20708403 TI - Protein engineering and design: from first principles to new technologies. PMID- 20708404 TI - Xylooligomers are strong inhibitors of cellulose hydrolysis by enzymes. AB - Typically, the enzymatic hydrolysis rate of lignocellulosic biomass is fast initially but then slows down more rapidly than can be explained by just consumption of substrate. Although several factors including enzyme inhibition, enzyme deactivation, a drop in substrate reactivity, or nonproductive binding of enzyme to lignin could be responsible for this loss of effectiveness, we recently reported evidence that xylose, xylan, and xylooligomers dramatically decrease conversion rates and yields, but clarification was still needed for the magnitude of their effect. Therefore, in this study, xylan and various xylooligomers were added to Avicel hydrolysis at low enzyme loadings and found to have a greater effect than adding equal amounts of xylose derived from these materials or when added separately. Furthermore, xylooligomers were more inhibitory than xylan or xylose in terms of a decreased initial hydrolysis rate and a lower final glucose yield even for a low concentration of 1.67 mg/ml. At a higher concentration of 12.5mg/ml, xylooligomers lowered initial hydrolysis rates of Avicel by 82% and the final hydrolysis yield by 38%. Mixed DP xylooligomers showed strong inhibition on cellulase enzymes but not on beta-glucosidase enzymes. By tracking the profile change of xylooligomers, a large portion of the xylooligomers was found to be hydrolyzed by Spezyme CP enzyme preparations, indicating competitive inhibition by mixed xylooligomers. A comparison among glucose sugars and xylose sugars also showed that xylooligomers were more powerful inhibitors than well established glucose and cellobiose. PMID- 20708405 TI - The European advocacy perspective on mammography screening. AB - Controversy and publicity about the value of mammography screening programs continue in Europe and across the globe. As Europe's breast cancer advocacy organisation, Europa Donna-The European Breast Cancer Coalition advocates for mammography screening as one of the essential services to which all women should have access, stipulating, however, that mammography screening programs must be set up and carried out in accordance with the European Guidelines for quality assurance in breast cancer screening and diagnosis. Europa Donna's involvement and history in following programs and progress in this area is extensive and dates back to 2001. The communication process for women eligible for screening is complicated and needs to be addressed appropriately in every country. However, the position of our organisation remains unchanged: Mammography screening carried out according to EU Guidelines is the best form of early detection available today and the scientific evidence shows that it improves mortality rates from the disease. PMID- 20708406 TI - The 3D structures of VDAC represent a native conformation. AB - The most abundant protein of the mitochondrial outer membrane is the voltage dependent anion channel (VDAC), which facilitates the exchange of ions and molecules between mitochondria and cytosol and is regulated by interactions with other proteins and small molecules. VDAC has been studied extensively for more than three decades, and last year three independent investigations revealed a structure of VDAC-1 exhibiting 19 transmembrane beta-strands, constituting a unique structural class of beta-barrel membrane proteins. Here, we provide a historical perspective on VDAC research and give an overview of the experimental design used to obtain these structures. Furthermore, we validate the protein refolding approach and summarize the biochemical and biophysical evidence that links the 19-stranded structure to the native form of VDAC. PMID- 20708407 TI - Peptidic HIV integrase inhibitors derived from HIV gene products: structure activity relationship studies. AB - Structure-activity relationship studies were conducted on HIV integrase (IN) inhibitory peptides which were found by the screening of an overlapping peptide library derived from HIV-1 gene products. Since these peptides located in the second helix of Vpr are considered to have an alpha-helical conformation, Glu-Lys pairs were introduced into the i and i+4 positions to increase the helicity of the lead compound possessing an octa-arginyl group. Ala-scan was also performed on the lead compound for the identification of the amino acid residues responsible for the inhibitory activity. The results indicated the importance of an alpha-helical structure for the expression of inhibitory activity, and presented a binding model of integrase and the lead compound. PMID- 20708409 TI - Amplification of background EMG activity affects the interpretation of H-reflex gain. AB - In many H-reflex studies, the modulation of the H-reflex is usually compared relative to the normal EMG activity within the muscle. Such comparisons enable the investigators to infer whether the change in the amplitude of the H-reflex was independent of normally occurring muscle activity. This interpretation of the H-reflex is regarded as H-reflex gain, a popular dependent variable in human H reflex studies. However, in many studies to date, the muscle activity level has been determined from the same EMG signal from which the H-reflex is recorded. This leads to an important methodological consideration: measuring the ongoing normal EMG activity from the same signal might result in an inaccurate measurement, since this EMG signal will need to be minimally amplified to capture the synchronous volley of the H-reflex amplitude. In this study we examined this possibility and found that comparing the EMG activity level from the seated position to standing position yields different results (on average 8.03% in the measurement of the increase of muscle activity). This difference was both dependent on the task and also on the EMG instrumentation used. To solve this problem we suggest the bifurcation of the EMG signal from the recording electrodes with differential amplification of the signal. With this method, both the naturally occurring muscle activity and the H-reflex signal are collected from the same area of the muscle and a more accurate measurement of the H-reflex gain will be yielded. PMID- 20708408 TI - 1,2,3-triazole analogs of combretastatin A-4 as potential microtubule-binding agents. AB - A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1 yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)-1H-1,2,3 triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore. PMID- 20708410 TI - Type II endoleak embolization after endovascular abdominal aortic aneurysm repair with use of real-time three-dimensional fluoroscopic needle guidance. AB - Current treatment for type II endoleak includes transarterial embolization and translumbar puncture, but each method has its drawbacks. With real-time three dimensional fluoroscopy guidance, a cone-beam computed tomography (CT) image is created in which the needle trajectory is determined. The trajectory is superimposed on the fluoroscopy image, allowing real-time needle placement for precise embolization. We have used this method to treat five patients with complex type II endoleaks. All interventions were successful and uncomplicated. At 6-month follow-up, CT scan showed no recurrences. Direct puncture and injection with real-time three-dimensional fluoroscopy guidance shows encouraging results as treatment for complex type II endoleaks after endovascular abdominal aortic aneurysm repair (EVAR). PMID- 20708411 TI - A potential role for endobronchial valves in patients with lung transplant. PMID- 20708412 TI - Immunohistochemical properties in the patients with Buerger's disease--possible role of plasminogen activator inhibitor-1 for preservation of vessel wall architecture. AB - BACKGROUND: The architecture of the arterial wall affected with Buerger's disease has been known to be preserved in all three layers, while the one affected by arteriosclerosis obliterans (ASO) is degenerated and destroyed. We analyzed affected arteries with immunohistochemical methods to clarify the differences between Buerger's disease and ASO. MATERIALS AND METHODS: Crural arteries obtained from 13 patients with Buerger's disease and 6 patients with ASO at our institute were studied. In addition, we examined seven specimens from six patients who were thought to be normal (without Buerger's disease or ASO) as negative control. Immunohistochemical studies were performed on paraffin-embedded tissues. The primary antibodies were urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-3 (MMP-3). Both are known to play an important role of extracellular proteolysis and to activate each other. Additionally, plasminogen activator inhibitor-1(PAI-1) was also examined. RESULTS: In Buerger's disease, PAI-1 was well expressed along the internal elastic lamina. Urokinase type plasminogen activator and MMP-3 were slightly positive in intima and media. In ASO, a slight amount of PAI-1 was recognized on vessel walls, and both uPA and MMP-3 were strongly positive in media. In addition, in the control group, PAI-1, uPA, and MMP-3 were well expressed in media. CONCLUSION: In Buerger's disease, PAI-1 was strongly expressed around the internal elastic lamina, while both uPA and MMP-3 were slightly recognized on vessel walls. These findings could be one of the reasons the general architecture of vessel walls in Buerger's disease is preserved. PMID- 20708414 TI - To engage in evidence-based practice, you must first find the evidence. PMID- 20708413 TI - Targeted intracellular catalase delivery protects neonatal rat myocytes from hypoxia-reoxygenation and ischemia-reperfusion injury. AB - Hypoxia followed by reoxygenation and ischemia reperfusion cause cell death in neonatal rat ventricular myocytes primarily through the generation of oxidative stress. Extracellular catalase has not been effective in reducing or eliminating ischemia reperfusion- or hypoxia-reoxygenation-induced cell death due both to extracellular degradation and to poor cellular uptake. AIMS: (1) To determine whether a cell-penetrating catalase derivative with enhanced peroxisome targeting efficiency (catalase-SKL) increases intracellular levels of the antioxidant enzyme in neonatal rat ventricular myocytes; and (2) to determine whether catalase-SKL protects against both hypoxia-reoxygenation and ischemia reperfusion injury. METHODS: Neonatal rat ventricular myocytes were subjected to 3 or 6 h of hypoxia-reoxygenation or to 1 h of ischemia reperfusion. Extracellular catalase concentration, activity, and subcellular distribution were determined using standard techniques. Reactive oxygen species and related oxidative stress were visualized using 2',7'-dichlorofluorescin diacetate. Cell death was measured using trypan blue exclusion or lactate dehydrogenase release assays. RESULTS: Extracellular catalase activity was higher in (catalase-SKL) transduced myocytes, was concentrated in a membranous cellular fraction, and potently inhibited oxidative stress. In contrast to nontransducible (unmodified) extracellular catalase, catalase-SKL-treated myocytes were protected against both hypoxia reoxygenation and ischemia reperfusion. CONCLUSIONS: (1) Catalase-SKL increased myocyte extracellular catalase content and activity and dramatically increased resistance to hydrogen peroxide-induced oxidation; (2) catalase-SKL protects against both hypoxia-reoxygenation and ischemia reperfusion; (3) catalase-SKL may represent a new therapeutic approach to protect hearts against myocardial hypoxia reoxygenation or ischemia reperfusion. PMID- 20708415 TI - Rapid oral fluid testing for HIV in veterans with mental health diagnoses and residing in community-assisted living facilities. AB - Veterans with a history of mental health and substance abuse diagnoses, residing in assisted living facilities, are more likely to have an undiagnosed HIV infection related to high-risk behaviors. We determined (a) the cross-sectional prevalence of HIV infection among 65 veterans of unknown HIV serostatus with mental health diagnoses who resided in 11 community-assisted living facilities, and (b) whether patients who had not consented to standard physician-initiated blood testing in the previous 5 years would consent to rapid oral fluid HIV testing by nurses familiar to the subjects. We found an HIV prevalence of 3.1% in the subjects who agreed to be tested (n = 64, 98%). High test acceptance, especially in a group with little HIV screening experience, and the identified high prevalence of disease, suggest that this diagnostic method is effective. Patients' familiarity with the nurses who conducted the testing most likely supported the success of the procedure. PMID- 20708416 TI - Impact of thiazolidinedione safety warnings on medication use patterns and glycemic control among veterans with diabetes mellitus. AB - AIMS: In 2007, safety warnings were publicized regarding the association between thiazolidinediones (TZDs) and cardiovascular risks. This study investigated the impact of the publicized safety warnings on glycemic outcomes in patients with diabetes mellitus (DM). MATERIALS AND METHODS: The Veterans Integrated Services Network 16 database included 13,293 DM patients using TZDs (n=13,037 rosiglitazone, n=246 pioglitazone, n=10 both) during a baseline period of 03/01/07 to 05/31/07. Three medication use patterns groups (09/01/07 to 11/30/07) were defined as follows: (1) continuation on TZD treatment, (2) switching to other non-TZD treatment, (3) discontinuation of TZD treatment without any antidiabetic treatment. Primary outcome (09/01/07 to 02/29/08) was change from baseline in A1c. The analysis of variance was used to test the association between use patterns and A1c change. A logistic regression model was used to identify the predictors for use patterns. RESULTS: Patients (45.1%, n=5999) discontinued their TZD use. Both Groups 2 and 3 had significant A1c increases (both P values <.0001). Significant predictors for TZD discontinuation included black race, baseline heart disease, and diabetic complication [odds ratio (OR), 1.43; OR, 1.54; OR, 1.30, respectively]. Of the patients remaining on TZD therapy, 11.8% experienced improved A1c levels, and a lower percentage of patients (9.53%) experienced a deterioration in A1c levels (P<.0001). Patients who switched or discontinued an antidiabetic medication experienced improvements in body mass index (P<.0001) and triglycerides (P<.0036). The three use pattern groups had similar changes with regard to blood pressure and low-density lipoprotein. CONCLUSION: Thiazolidinedione safety warnings may have negatively impacted the glycemic control in DM patients. PMID- 20708417 TI - The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes. AB - BACKGROUND: Cardiac autonomic neuropathy (CAN) is a common diabetes complication associated with poor prognosis. This cross-sectional study aimed to examine for associations between CAN and metabolic and other parameters in patients with either type 1 (T1DM) or type 2 (T2DM) diabetes. PATIENTS AND METHODS: A total of 600 patients (T1DM, n=200; T2DM, n=400) were recruited. Participants with overt nephropathy, macrovascular complications, and treated hypertension were excluded. CAN was diagnosed when two of the four classical autonomic function tests were abnormal. RESULTS: CAN was diagnosed in 42.0% and in 44.3% of the participants with T1DM and T2DM, respectively. Multivariate logistic regression analysis demonstrated that, in T1DM, the odds [OR (95% confidence intervals)] of CAN increased with higher waist circumference [1.36 (1.01-2.02)], systolic blood pressure [1.16 (1.03-1.31)], hypertension [1.19 (1.03-2.67)], smoking [1.10 (1.12 1.40], fasting glucose [1.01 (1.00-1.01)], HbA(1c) [1.69 (1.07-2.76)], pubertal diabetes onset [1.08 (1.03-1.24)], LDL cholesterol [1.01(1.00-1.02)], triglycerides [1.58 (1.24-1.48)], retinopathy [1.13 (1.04-1.41)], peripheral neuropathy [2.53 (1.07-2.99)], glomerular filtration rate [0.93 (0.87-0.99)], and microalbuminuria [1.24 (1.12-1.36)]. The same analysis in T2DM demonstrated that the odds of CAN increased with higher waist circumference [1.08 (1.00-1.39)], systolic blood pressure [1.06 (1.02-1.12)], hypertension [1.50 (1.24-2.03)], smoking [1.22 (1.14-1.49)], diabetes duration [1.20 (1.09-1.34)], fasting glucose [1.21 (1.12-1.31)], HbA(1c) [1.25 (1.08-1.45)], LDL cholesterol [1.35 (1.04 1.75)], triglycerides [1.30 (1.00-1.68)], retinopathy [1.24 (1.16-1.35)], peripheral neuropathy [1.79 (1.07-2.01)], glomerular filtration rate [0.96 (0.95 0.97)], and microalbuminuria [1.20 (1.14-1.36)]. CONCLUSIONS: CAN is common in diabetes and is associated with modifiable factors including central fat distribution, hypertension, dyslipidemia, worse diabetes control, and smoking, and with the other microvascular complications of diabetes. Our findings emphasize the need for a multifactorial intervention for the prevention of CAN. PMID- 20708418 TI - New onset type 1 diabetes presenting as ketoacidosis simultaneously presenting with autoimmune hyperthyroidism--a case report. AB - Autoimmune conditions are common with an estimated prevalence in the UK of 2.5%. The presence of one condition should always prompt the clinician to look for others if new symptoms arise. Autoimmune polyglandular syndromes are well described. However, it is unusual for two or more autoimmune conditions to present simultaneously. We describe a case of two autoimmune conditions--type 1 diabetes and Graves' disease--being diagnosed for the first time in the same individual at the same visit to the emergency department. We suggest that thyrotoxicosis be added to the list of potential precipitants for diabetic ketoacidosis. PMID- 20708419 TI - A prospective analysis of interscalene brachial plexus blocks performed under general anesthesia. AB - BACKGROUND: The purpose of this prospective study was to assess the safety and efficacy of interscalene brachial plexus block anesthesia when performed on patients who were anesthetized with a general anesthetic prior to the performance of the block. METHODS: Patients were assessed postoperatively through surveys, interviews, and physical examinations to document block success, duration of anesthesia, block side effects, and persistent neurological complications. Nine hundred fifty-one patients were available for the analysis. RESULTS: The overall block success rate was 97% and the mean duration of anesthesia provided by the blocks was 23.9 hours. Immediate postoperative block side effects occurred in 16% (142 of 910), persistent neurological complications occurred in 4.4% (40 of 910) of patients, and long-term neurologic complications occurred in 0.8% (8 of 910). CONCLUSION: Our study results suggest that the rates of success and complications associated with the performance of interscalene block regional anesthesia performed after induction of general anesthesia are similar to the results demonstrated in prior studies in which brachial plexus block was performed on nonanesthetized patients. Although significant complications were not common, this procedure is not without risk and can result in long-term neurologic complications. PMID- 20708420 TI - Simultaneous maxillomandibular distraction osteogenesis in severe progressive hemifacial atrophy with two distractors. AB - Progressive hemifacial atrophy is a rare disorder characterized by an acquired, idiopathic, self-limited, unilateral facial atrophy involving skin, subcutaneous tissue, fat, muscle, and bone. Symmetry and contour restoration are the main treatment challenges. Among many techniques, microvascular reconstruction has been introduced as the gold standard to correct the atrophic deformity. For some patients with severe manifestations, soft tissue reconstruction alone does not obtain the desired outcome. In this series, we used an effective method to restore the severe progressive hemifacial atrophy by simultaneous maxillomandibular distraction osteogenesis with 2 distractors. The results demonstrate an improvement in both the profile and the occlusion plane of the patients with corresponding satisfactory esthetic and functional outcomes. We conclude that the simultaneous maxillomandibular distraction osteogenesis with 2 distractors is an effective method for hemifacial atrophy and bone frame reconstruction, especially ones involved in the discrepancy of the occlusal plane. PMID- 20708422 TI - [Google: Searches, analyses and networking in the health care environment]. PMID- 20708421 TI - Bioequivalence studies for three formulations of a recombinant human growth hormone: challenges and lessons learned. AB - Two bioequivalence (BE) studies in healthy volunteers comparing new formulations of the recombinant human growth hormone (rhGH) Nutropin AQ (somatropin [rDNA origin] injection; Genentech, Inc., South San Francisco, CA) with the currently marketed formulation (5 mg/mL) were conducted to extend available dosing options. All formulations were administered by subcutaneous (SC) injection ranging in volume from 0.25 to 1.0 mL depending on the formulation concentration. Study A was a 2-period crossover design to assess the BE of 5 and 10 mg/mL. The estimate for relative bioavailability (AUC(0-24 h)) was within the prespecified BE interval (0.80-1.25). However, while the C(max) estimate (1.17) was contained within the range for BE, the 90% CI (0.986-1.38) extended beyond the prespecified BE interval. As a result, Study A failed to show BE between the 5 and 10mg/mL formulations. Review of the data showed unexpected increased variability in the observed C(max). Further review of individual data suggested that in 4 subjects, the GH concentration profile of 1 of the 2 injections closely resembled the absorption kinetics of an intramuscular injection rather than an SC injection. Because study conduct may have contributed to these results, we performed a second study, Study B. This study incorporated injection technique training, a defined injection site, and a larger sample size to accommodate variability. It also included a third formulation, creating a 3-period crossover design to assess the BE of 2.5, 5, and 10 mg/mL. Study B results demonstrated BE of the new 2.5- and 10-mg/mL formulations to the reference 5-mg/mL formulation, and BE to each other, with all 90% CIs within the BE range of 0.80 to 1.25. Thus the challenge of recognizing that design issues could affect outcomes gave us the tools to perform a second study, and the positive results taught us that demonstrating BE is an issue not only of pharmacology, but also of study methodology and execution. PMID- 20708423 TI - The metabolic syndrome defined by modified International Diabetes Federation criteria and mortality: a 9-year follow-up of the aged in Finland. AB - AIM: The aim of this study was to investigate the relationship between the metabolic syndrome (MetS) and mortality in the aged population. METHODS: In this prospective population-based study with a 9-year follow-up, the participants were all residents of the municipality of Lieto, Finland, aged 64 and over in 1998-99 (n=1529). Altogether, 1260 (82%) were included in the study. Cox proportional hazard models were used to estimate hazard ratios (HRs) for all-cause, cardiovascular (CVD), coronary heart disease (CHD) and cerebrovascular (CV) mortality as predicted by MetS (defined by modified International Diabetes Federation criteria). RESULTS: At baseline, 17% of the men and 21% of the women had MetS. During the 9-year follow-up, 422 deaths occurred. After multivariable adjustment, no significant differences were found between subjects with and without MetS for all-cause, CVD, CHD or CV mortality in all study participants or by gender. On evaluating MetS components separately, elevated blood pressure was found to predict lower all-cause mortality in all participants [HR: 0.65; 95% confidence interval (CI): 0.47-0.89], and lower CHD mortality in men (HR: 0.42; 95% CI: 0.18-0.97). In women, high triglyceride levels predicted lower all-cause mortality (HR: 0.67; 95% CI: 0.47-0.95), whereas low HDL cholesterol predicted higher all-cause (HR: 1.61; 95% CI: 1.15-2.24) and CV (HR: 2.44; 95% CI: 1.05 5.67) mortality. CONCLUSION: These findings suggest that MetS does not predict mortality later in life and, of the separate components of MetS, only low HDL cholesterol is predictive of mortality in women. Also, even markedly higher blood pressure values than those included in the criteria for MetS fail to predict mortality in this age group. PMID- 20708424 TI - Mediastinal radiotherapy after multidrug chemotherapy and prophylactic cranial irradiation in patients with SCLC--treatment results after long-term follow-up and literature overview. AB - INTRODUCTION: Curative therapy for patients with small-cell lung cancer (SCLC) is based on multidrug chemotherapy combinations and radiotherapy. After a long time follow-up, the aim of the study was to evaluate the efficacy and toxicity of sequential chemo-radiotherapy and the effect of prophylactic cranial irradiation (PCI). METHODS: From 1995-2005, 96 patients with SCLC (64 limited-disease [LD], 32 extensive-disease [ED]; median age 61 years [range 39-79]) were treated at our department with varying chemotherapy regimens and sequential mediastinal radiotherapy (50 Gy + 10 Gy boost in case of residual disease after chemotherapy). Afterwards, 15 patients with LD, good general condition and at least partial response after local treatment received PCI (30 Gy). RESULTS: After a median follow-up of 78.6 months, 20 patients remained alive (20.8%, median survival time 18.2 months). The 2-/5-year overall survival rates were 33.8% and 12.6%, the 2-/5-year loco-regional control rates were 30.3% and 24.5%, respectively. Distant metastases occurred in 43 patients (24 cerebral). Cerebral metastasis occurred in 6.7% and 27.2% of the patients with PCI and without PCI respectively. Only tumor stage showed a statistically significant impact on overall survival and loco-regional control in multivariate analysis. Radiotherapy was well tolerated. Grade 3/4 toxicity occurred in seven patients. Prognosis of patients with SCLC remains poor. Administration of PCI in selected patients bears a decrease in the incidence of cerebral metastases. Alternative chemotherapy schemes as well as irradiation schemes and techniques should be the substance of future randomized trials. PMID- 20708425 TI - Accessory muscle belly of peroneus tertius in the leg--a rare anatomical variation with clinical relevance--utility in reconstructions. AB - We report here a rare muscular anomaly of the lower leg in an adult male cadaver observed during routine cadaveric dissection. Peroneus tertius (PT) is peculiar to man, being a hallmark of bipedal locomotion and erect posture. During the course of gross anatomy dissection, a rare finding of accessory belly of PT muscle was discovered. A meticulous dissection was performed and the observations were noted. The PT displayed two distinct bellies of origin. Both the bellies were substantial in size and were eventually fused close to their insertion at the base of the fifth meta-tarsal bone. Innervation of both the bellies was derived from the deep peroneal nerve. Soft tissue defects of the leg may be effectively covered by local muscles in the vicinity of the wounds. PT has been reliably used in the past for local transposition flaps in the lower extremities. The relations of the superficial nerve and the PT during placement of the anterolateral portal in ankle arthroscopy are vital to avoid inadvertent neuromuscular injuries. The presence of two bellies of the PT muscle has been discussed in the comparative perspective. A precise and detailed knowledge of the anatomical details of the crural muscles is important for performing reconstructive surgeries. PMID- 20708426 TI - Built environment characteristics and perceived active park use among older adults: results from a multilevel study in Bogota. AB - OBJECTIVE: Examine the associations between selected built environment (BE) attributes and perceived active park use among older adults in Bogota. METHODS: A cross-sectional multilevel study was conducted. Participants included 1966 older adults in 50 neighborhoods. Socio-demographic covariates and BE attributes were measured. Multilevel logistic regression models were used for the analyses. RESULTS: Residents from areas with higher park density and high land-use mix were more likely to report active park use while those from areas with high connectivity were less likely. CONCLUSIONS: This study suggests that objective attributes of the residential BE are associated with perceived active park use. However, our study also points to the importance of surrounding environment, with the result of an inverse relationship between connectivity and physical activity, which highlights the potentially necessary interventions in the realm of traffic and pedestrian safety. PMID- 20708428 TI - Is latero-medial patellar mobility related to the range of motion of the knee joint after total knee arthroplasty? AB - Diminished range of motion (ROM) of the knee joint after total knee arthroplasty (TKA) is thought to be related to reduced patellar mobility. This has not been confirmed clinically due to a lack of quantitative methods adequate for measuring patellar mobility. We investigated the relationship between patellar mobility by a reported quantitative method and knee joint ROM after TKA. Forty-nine patients [osteoarthritis--OA: 29 knees; rheumatoid arthritis--RA: 20 knees] were examined after TKA. Respective medial and lateral patellar mobility was measured 1 and 6 months postoperatively using a patellofemoral arthrometer (PFA). Knee joint ROM was also measured in each of those 2 sessions. Although the flexion and extension of the knee joints improved significantly from 1 to 6 months after TKA, the medial and lateral patellar displacements (LPDs) failed to improve during that same period. Moreover, only the changes in knee flexion and medial patellar displacement (MPD) between the two sessions were positively correlated (r = 0.31, p < 0.05). However, our findings demonstrated that medial and lateral patellar mobility had no sufficient longitudinal relationship with knee ROM after TKA. PMID- 20708427 TI - Predicting maximal grip strength using hand circumference. AB - The objective of this study was to analyze the correlations between anthropometric data and maximal grip strength (MGS) in order to establish a simple model to predict "normal" MGS. Randomized bilateral measurement of MGS was performed on a homogeneous population of 100 subjects. MGS was measured according to a standardized protocol with three dynamometers (Jamar, Myogrip and Martin Vigorimeter) for both dominant and non-dominant sides. Several anthropometric data were also measured: height; weight; hand, wrist and forearm circumference; hand and palm length. Among these data, hand circumference had the strongest correlation with MGS for all three dynamometers and for both hands (0.789 and 0.782 for Jamar; 0.829 and 0.824 for Myogrip; 0.663 and 0.730 for Vigorimeter). In addition, the only anthropometric variable systematically selected by a stepwise multiple linear regression analysis was also hand circumference. Based on this parameter alone, a predictive regression model presented good results (r(2) = 0.624 for Jamar; r(2) = 0.683 for Myogrip and r(2) = 0.473 for Vigorimeter; all adjusted r(2)). Moreover a single equation was predictive of MGS for both men and women and for both non-dominant and dominant hands. "Normal" MGS can be predicted using hand circumference alone. PMID- 20708429 TI - A radiographic analysis of the influence of initial neck posture on cervical segmental movement at end-range extension in asymptomatic subjects. AB - In the management of neck pain disorders, McKenzie recommends performing neck extension exercises from a fully neck retracted position in order to achieve a maximum range of lower cervical extension. However, no study has investigated the impact of pre-positioning the neck prior to the extension exercise. This study compared end-range sagittal cervical segmental rotation and translation from three starting positions: the neck in neutral (Ex), retraction (Ret-Ex) and protraction (Pro-Ex). Twenty asymptomatic healthy volunteers were recruited. Lateral radiographs were taken in neutral and at each of the three end-range extension positions and differences in sagittal rotation angles and translation from the neck neutral posture were calculated at each segment. The results indicated that there was a significant difference in the pattern of the sagittal segmental rotation (P < 0.001) but no difference in summed rotations (total extension) between the three conditions (P > 0.05). Pro-Ex generated significantly (P < 0.05) greater extension range at C1-2 and Ret-Ex produced significantly (P < 0.05) greater extension range at C6-7 than alternate conditions. In contrast, there was no significant difference in segmental translation values between the three conditions (P > 0.05). These results indicate initial neck positions can influence cervical segmental extension range at C1-2 and C6-7. PMID- 20708430 TI - A one-dimensional polyoxometalate-based polymer [Cu(DMF)6][PMo(V)Mo(VI)11O40Cu(DMF)4].DMF: crystal structure and luminescent properties. AB - The polyoxometalate-based 1D coordination polymer [[Cu(DMF)6][PMo(V)Mo(VI)11O40Cu(DMF)4].DMF1 was synthesized and characterized by IR, UV spectroscopy and single-crystal X-ray diffraction analysis. Each Cu(II) center has a distorted octahedral coordination geometry. Cu(1) center interconnects with two [PMo(V)Mo(VI)11O40]4- anion subunits and each [PMo(V)Mo(VI)(11)O(40)]4- polyoxoanion acts as a didentate ligand to link two Cu centers through two terminal oxygen atoms to form a one-dimensional chain structure. The luminescent properties of 1 in the solution and in the solid state were investigated, respectively. PMID- 20708431 TI - Concentric needle jitter on stimulated Orbicularis Oculi in 50 healthy subjects. AB - OBJECTIVES: The aim of this study was to estimate the jitter parameters in healthy controls in stimulated Orbicularis Oculi (OOc) muscle using concentric needle electrode (CNE). METHODS: Fifty healthy subjects, 13 males and 37 females (21-56 years, mean age of 38+/-9.2 years) were studied. The zygomatic branch of facial nerve was stimulated with a bar electrode. Jitter was expressed as the mean consecutive difference (MCD). Filter settings 1000 Hz-10 kHz. RESULTS: The mean MCD from individual studies (n=50, Gaussian distribution) was 21.5+/-1.99 MUs (median=21 MUs), ranging from 17.8 to 26 MUs (upper limit, 97.5%, 25.5 MUs). The mean and median MCD from all potentials (n=1500, non-Gaussian distribution) were 21.6 and 21 MUs, ranging from 7.1 to 39 MUs (upper limit, 97.5%, 33.4 MUs). CONCLUSIONS: Suggested practical limits in the OOc for mean MCD was 26 MUs and for outliers 34 MUs. SIGNIFICANCE: Stimulation jitter recordings with CNE could be used in practice but borderline findings should be judged with great caution until larger database obtained with uniform setting available. PMID- 20708433 TI - Use of an antifungal drug, amphotericin B for isolation of thraustochytrids. AB - The inhibitory effect of amphotericin B (AMPH) on the growth of fungi during the isolation of thraustochytrids was examined. The growth of fungi was significantly inhibited by addition of AMPH, and therefore colonies of thraustochytrids were not overlaid with fungal mycelia, which resulted in increased efficiency of thraustochytrids isolation. PMID- 20708432 TI - Characterization of glucoamylase and alpha-amylase from Monascus anka: enhanced production of alpha-amylase in red koji. AB - To enhance glucoamylase and alpha-amylase production from Monascus anka, we investigated the influence of different culture conditions on enzyme production and purified and characterized these enzymes. The effect of different raw materials was investigated by using solid-state plates of raw materials such as barley and non-waxy or waxy rice. The barley plate was the most suitable for mycelial growth, but glucoamylase and alpha-amylase production per growth area did not differ according to the raw material. Investigation of the effect of temperature showed that incubation at 37 degrees C promoted maximal cell growth, while incubation at 25 degrees C and at 40 degrees C resulted in enhanced alpha amylase and glucoamylase production, respectively. Characterization of the purified enzymes revealed that alpha-amylase was unstable at acidic pH and less resistant to heat (stable at < 40 degrees C) than glucoamylase. When these culture conditions were applied to enzyme production in red koji, reducing the temperature from 35 degrees C to 25 degrees C for 48 h in the late stages of growth resulted in higher glucoamylase and alpha-amylase production (1.4 and 18 times, respectively) with a concomitant increase in protein stability. PMID- 20708434 TI - The construction and application of diploid sake yeast with a homozygous mutation in the FAS2 gene. AB - In Japanese sake brewing, cerulenin-resistant sake yeasts produce elevated levels of ethyl caproate, an important flavor component. The FAS2 mutation FAS2-1250S of Saccharomyces cerevisiae generates a cerulenin-resistant phenotype. This mutation is dominant, and, in general, cerulenin-resistant diploid sake yeast strains carry this mutation heterozygously. Here we constructed diploid sake yeast with a homozygous mutation of FAS2 using the high-efficiency loss of heterozygosity method. The homozygous mutants grew more slowly in YPD medium than did the wild type and heterozygous mutants, and they produced more ethyl caproate during sake brewing. In addition, although both the wild-type and heterozygous mutant were sensitive to 4 mg/l cerulenin, the homozygous mutant was resistant to more than 4 mg/l cerulenin. Next, we obtained a homozygous mutant of FAS2 without inducing genetic modification. After cultivating the heterozygous FAS2 mutant K-1801 in YPD, homozygous mutants were selected on medium containing high concentrations of cerulenin. Non-genetically modified yeast with a homozygous mutation of FAS2 produced 2.2-fold more ethyl caproate than did heterozygous yeast. Moreover, high quality Japanese sake with a very rich flavor could be brewed using yeast containing a homozygous mutation in the FAS2 gene. PMID- 20708435 TI - Barcoding Tetrahymena: discriminating species and identifying unknowns using the cytochrome c oxidase subunit I (cox-1) barcode. AB - DNA barcoding using the mitochondrial cytochromecoxidase subunit I (cox-1) gene has recently gained popularity as a tool for species identification of a variety of taxa. The primary objective of our research was to explore the efficacy of using cox-1 barcoding for species identification within the genusTetrahymena. We first increased intraspecific sampling forTetrahymena canadensis, Tetrahymena hegewischi, Tetrahymena pyriformis, Tetrahymena rostrata, Tetrahymena thermophila, and Tetrahymena tropicalis. Increased sampling efforts show that intraspecific sequence divergence is typically less than 1%, though it may be more in some species. The barcoding also showed that some strains might be misidentified or mislabeled. We also used cox-1 barcodes to provide species identifications for 51 unidentified environmental isolates, with a success rate of 98%. Thus, cox-1 barcoding is an invaluable tool for protistologists, especially when used in conjunction with morphological studies. PMID- 20708436 TI - Molecular analysis and mating behaviour of the Trichophyton mentagrophytes species complex. AB - Isolates of the Trichophyton mentagrophytes complex vary phenotypically. Whether the closely related zoophilic and anthropophilic anamorphs currently associated with Arthroderma vanbreuseghemii have to be considered as members of the same biological species remains an open question. In order to better delineate species in the T. mentagrophytes complex, we performed a mating analysis of freshly collected isolates from humans and animals with A. benhamiae and A. vanbreuseghemii reference strains, in comparison to internal transcribed spacer (ITS) and 28S rDNA sequencing. Mating experiments as well as ITS and 28S sequencing unambiguously allowed the distinction of A. benhamiae and A. vanbreuseghemii. We have also shown that all the isolates from tinea pedis and tinea unguium identified as T. interdigitale based on ITS sequences mated with A. vanbreuseghemii tester strains, but had lost their ability to give fertile cleistothecia. Therefore, T. interdigitale has to be considered as a humanized species derived from the sexual relative A. vanbreuseghemii. PMID- 20708437 TI - Systematic analysis of an amidase domain CHAP in 12 Staphylococcus aureus genomes and 44 staphylococcal phage genomes. AB - An alternative treatment for staphylococcal infections caused by antibiotic resistance strains is to lyse staphylococci with peptidoglycan hydrolases, for example, a cysteine, histidine-dependent amidohydrolase/peptidase (CHAP). Here, CHAPs were analyzed in 12 Staphylococcus aureus genomes and 44 staphylococcal phage genomes. There are 234 putative CHAP-containing proteins and only 64 non identical CHAP sequences. These CHAPs can be classified into phage CHAPs encoded in phages/prophages and bacterial CHAPs encoded on chromosomes and plasmids. The phage CHAPs contain a sequence signature 'F-[IV]-R', and the bacterial CHAPs mainly do not. The phage CHAPs are mostly positioned at the protein N-termini whereas the bacterial CHAPs are all positioned at the C-termini. The cell wall targeting domains LysM and SH3_5 are associated with the bacterial CHAPs and the phage CHAPs, respectively. The homology modeling reveals that five of six highly conserved residues are clustered at the putative active site and are exposed to the molecular surface. PMID- 20708438 TI - Challenge dose of methamphetamine affects kainic acid-induced seizures differently depending on prenatal methamphetamine exposure, sex, and estrous cycle. AB - Even though it is obvious that glutamate plays an important role in the effect of psychostimulants on seizures, the role of non-NMDA receptors remains uncertain. The aim of the present study was to determine whether acute methamphetamine (MA) administration changes sensitivity to seizures induced with kainic acid in prenatally MA-exposed adult rats. Adult male and female rats (prenatally MA exposed, prenatally saline exposed, and controls) were divided into groups that received a challenge dose (1mg/kg) of MA and groups that did not receive the MA challenge (saline injected). Systemic administration of 15 mg/kg kainic acid was used as a seizure model. Our results demonstrated that a single injection of MA (1mg/kg) affects kainic acid-induced seizures differently depending on prenatal exposure, sex, and female estrous cycle. Even though daily injections of MA (5mg/kg) in maternal rats did not have a long-term effect on susceptibility to seizures induced with kainic acid in adult progeny, sensitivity to the challenge dose of MA differed between the prenatal exposure groups. PMID- 20708439 TI - Neuropsychiatric evaluations of postictal behavioral changes. AB - Postictal behavioral changes (PBCs), including psychosis, aggression, and mood change, are commonly observed in patients with epilepsy. Recognition and description of the clinical manifestations of PBCs would help in understanding and treating patients. Additionally, various quantified objective scales that are widely available in clinical psychiatry could be used to assess the clinical symptoms of PBCs. There are few reports in which objective rating scales have been used to assess neuropsychiatric symptoms in patients with epilepsy. However, there have been a small number of studies on interictal psychosis and depression in which either the Brief Psychiatric Rating Scale or the Hamilton Depression Scale was used. These inventories are likely to be useful for the assessment of PBCs. Other rating scales used for schizophrenia, depression, mania, and aggressive behavior are reviewed here. The author suggests that cross-sectional and longitudinal neuropsychiatric measurement combined with other modalities, including functional neuroimaging, could provide clues to the pathophysiology of PBCs. PMID- 20708441 TI - WITHDRAWN: Response Letter to the Editor. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20708440 TI - Variations in health-related quality of life in Japanese men who underwent iodine 125 permanent brachytherapy for localized prostate cancer. AB - PURPOSE: The purpose of this study was to prospectively assess the variations in health-related quality of life (HR-QoL) in patients who underwent low-dose rate prostate brachytherapy using iodine-125 seed source during the first year after seed implantation. METHODS AND MATERIALS: Between July 2004 and December 2006, 109 patients underwent low-dose rate brachytherapy. The Medical Outcomes study 36 Item Short Form; the University of California, Los Angeles-Prostate Cancer Index; and the International Index of Erectile Function-5 were evaluated before and at 1, 3, 6, and 12 months after seed implantation. RESULTS: In Medical Outcomes study 36-Item Short Form analyses and the HR-QoL scores were well preserved during the first year after seed implantation. In the University of California, Los Angeles-Prostate Cancer Index analyses, the urinary function and bother scores showed significant decrease during 6 months after seed implantation. The bowel function and bother scores showed significant decrease at 3 months after seed implantation. The sexual function score showed significant decrease at 3, 6, and 12 months after seed implantation, whereas the sexual bother score showed no change during the first year. The International Index of Erectile Function-5 score dramatically decreased at 1, 3, 6, and 12 months after seed implantation. CONCLUSIONS: The general HR-QoL in the patients who underwent seed implantation was well preserved during the first year after seed implantation, whereas the urinary, bowel, and sexual function and bother scores showed transient deterioration during the first year after seed implantation. Especially, sexual function showed significant deterioration in Japanese men after seed implantation. PMID- 20708442 TI - Development and validation of a liquid chromatography-tandem mass spectrometry assay for the analysis of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and its metabolite 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH PhIP) in plasma, urine, bile, intestinal contents, faeces and eight selected tissues from mice. AB - The development and validation of a bioanalytical assay is described for the simultaneous analysis of 2-amino-1-methyl-6-phenylimidazo[4-5-b]pyridine (PhIP) and its main metabolite 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N OH-PhIP) in plasma, urine, faeces, bile, liver, kidney, testis, spleen, brain, as well as colon-, cecum- and small intestinal tissue and contents from mice. The effect of the matrix on the accuracy of the method was extensively investigated. The bioanalytical assay is based on reversed phase liquid chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple reaction monitoring for analyte quantification. The assay is validated from 1 to 250 ng/mL and the sample pretreatment consists of protein precipitation with acetonitrile using only 100 microL matrix (plasma, bile diluted in 4% (m/v) BSA, intestinal contents, faeces and tissue samples homogenized in 4% (m/v) BSA). The measured concentrations of PhIP and N-OH-PhIP in homogenates were expressed in ng/mL. Based on the weight of the isolated intestinal contents, faeces or tissue the amount of PhIP and N-OH-PhIP per mass unit intestinal content, faeces or tissue was calculated. The validated range for PhIP in urine is from 10 to 1000 ng/mL using 20 microL urine. For N-OH-PhIP quantification, mouse urine was diluted 100 x in blank human urine to compensate for matrix effects. The developed method is simple, robust and reproducible. The applicability of the method was demonstrated and the assay could be successfully used to support in vivo toxicokinetics studies of PhIP and N-OH-PhIP in mice. PMID- 20708443 TI - Recurrent interdigital pilonidal sinus treated with dorsal metacarpal artery perforator flap. AB - A 39-year-old otherwise healthy barber presented to our clinic complaining of frequent periods of swelling and purulent discharge in his second and third right web spaces. An excision was performed after administration of methylene blue to visualize the extent of both cysts located in his second and third web spaces. A distally based dorsal metacarpal artery perforator flap was chosen to close the defect on his second web space. Interdigital pilonidal sinus is a rare disease caused by repeated implantation of foreign hair to the interdigital web space. In secondary cases or in cases where an extensive resection has to be done in order to completely remove the cysts, closure with a skin flap can become compulsory. Dorsal metacarpal artery perforator flap is a good choice with minimal donor site morbidity and this flap might provide robust skin coverage which can possibly avoid further penetration of hair in to web space. PMID- 20708444 TI - Heart-focused anxiety as a mediating variable in the treatment of noncardiac chest pain by cognitive-behavioral therapy and paroxetine. AB - OBJECTIVE: We compared the efficacy of cognitive behavior therapy (CBT), paroxetine and placebo in the treatment of noncardiac chest pain (NCCP). We also investigated whether pre- to mid-treatment reduction of (heart-focused) anxiety mediated mid- to post-treatment pain reduction. METHODS: Sixty-nine adults with NCCP were randomly assigned to 16 weeks of outpatient treatment with CBT, paroxetine or placebo. The comparison between placebo and paroxetine was carried out in a double-blind fashion. The main outcome measure was a chest pain index (duration*intensity) as derived from daily pain diaries. Putative mediator measures were general anxiety (HADS:A) and heart-focused anxiety (Cardiac Anxiety Questionnaire). RESULTS: Eleven patients treated with paroxetine or placebo dropped out prematurely. Intent-to-treat analysis showed that CBT was significantly superior to placebo and to paroxetine in reducing NCCP at posttreatment. Only CBT significantly reduced heart-focused anxiety compared to placebo at mid- and post-treatment. Pre- to mid-treatment reduction of heart focused anxiety predicted mid- to post-treatment NCCP reduction. The indirect effect of CBT on pain reduction by reducing heart-focused anxiety was significant compared to placebo but not to paroxetine. CONCLUSION: CBT is an effective treatment option for patients with NCCP. Paroxetine is not more effective than placebo on the short term. Reduction of heart-focused anxiety by CBT seems to mediate subsequent reduction of NCCP compared to placebo. The results provide further support for cognitive-behavioral models of NCCP and point to the potential benefits of, in particular, cognitive-behavioral interventions to modify heart-focused anxiety. PMID- 20708445 TI - Heart-focused anxiety as a mediating variable in the treatment of non-cardiac chest pain by cognitive-behavioural and psychopharmacological treatment by paroxetine. PMID- 20708446 TI - Illusory touch and tactile perception in somatoform dissociators. AB - OBJECTIVE: The psychological mechanisms of somatoform dissociation (i.e., pseudoneurological symptoms) are poorly understood. This study evaluated recent theoretical predictions regarding the role of tactile perception in the development of somatoform dissociative symptoms. METHODS: Eighty nonclinical participants scoring either high or low on the Somatoform Dissociation Questionnaire (SDQ-20) completed the Somatic Signal Detection Task (SSDT), a novel perceptual paradigm designed to simulate the occurrence of somatoform symptoms in the laboratory. Prior to the SSDT, participants completed a memory task designed to produce either minimal or maximal activation of tactile representations in memory. RESULTS: The high SDQ-20 group exhibited a more liberal response criterion (c) on the SSDT than the low SDQ-20 group after controlling for negative affectivity, somatosensory amplification and depression. This effect was mainly attributable to an increased number of false alarms (i.e., illusory experiences of touch) in the high SDQ-20 group rather than an increased hit rate. General perceptual ability (i.e., tactile sensitivity) was comparable between the two groups. The memory manipulation had no effect on SSDT performance. CONCLUSIONS: Somatoform dissociators appear more likely to experience illusory perceptual events under conditions of sensory ambiguity than nondissociators, despite comparable perceptual abilities more generally. These findings support theories that identify distorted perceptual processing as a feature of somatoform dissociation. The SSDT has potential as a tool for further research in this area. PMID- 20708447 TI - Attention to the body in nonclinical somatoform dissociation depends on emotional state. AB - OBJECTIVE: Unexplained neurological symptoms ("somatoform dissociation") are common in health care settings and associated with disproportionately high levels of distress, disability, and resource utilization. Theory suggests that somatoform dissociation is associated with disturbed attentional processing, but there is a paucity of research in this area and the available evidence is contradictory. METHODS: We compared undergraduate participants (n=124) with high and low scores on the Somatoform Dissociation Questionnaire (SDQ-20) on a tactile cueing paradigm measuring the time course of attention to touch, following either a neutral film or a film designed to simulate the emotional effects of trauma exposure. RESULTS: Following the neutral film, high SDQ-20 participants exhibited delayed disengagement from tactile cue stimuli compared to the low SDQ-20 group. Following the "trauma" film, however, the high SDQ-20 group showed attentional effects suggesting avoidance of the tactile stimuli in this condition. Early attention to tactile cues following the trauma film predicted film-related intrusive thoughts after the experiment. CONCLUSION: These findings suggest that both body vigilance and body avoidance may be involved in the expression of somatoform dissociation. PMID- 20708448 TI - Characteristics of oligosymptomatic versus polysymptomatic presentations of somatoform disorders in patients with suspected allergies. AB - OBJECTIVE: Psychobehavioral characteristics of patients with somatoform disorders (SFDs), are increasingly discussed as possible positive criteria for this diagnostic group. However, little is known about psychobehavioral differences, or similarities, between the different SFD presentations, i.e., polysymptomatic [multisomatoform/somatization disorders (MSD)] versus mono- or oligosymptomatic courses [pain disorder (PD), undifferentiated somatoform disorder (USD)]. METHODS: This is a cross-sectional study including 268 consecutive allergology inpatients. After an Structured Clinical Interview for DSM-IV, patients completed several self-rating questionnaires. Results were compared within the different SFD presentations as well as between patients with versus without SFDs. RESULTS: We identified 72 patients with an SFD. There were fewer and smaller psychobehavioral differences within patients with the different SFD presentations (MSD, USDs, PDs) than between patients with undifferentiated versus no SFD. Patients with one of the three different SFD subdiagnoses scored similarly on many measures referring to psychosocial distress (e.g., psychological distress, mental health-related quality of life, dissatisfaction with care). The number of reported symptoms, somatic symptom severity, a self-concept of bodily weakness, the degree of disease conviction, and physical health-related quality of life discriminated the different SFD presentations not only from patients without SFDs but also from each other. CONCLUSIONS: Patients diagnosed with one of the different SFD subtypes share many psychobehavioral characteristics, mostly regarding the reporting of psychosocial distress. Perceived somatic symptom severity and physical impairment as indicators of bodily distress could either further define categorical subdivisions of SFD or dimensionally graduate one general SFD category defined by bothering bodily symptoms and disproportionate psychosocial distress. PMID- 20708449 TI - Diagnosing somatisation disorder (P75) in routine general practice using the International Classification of Primary Care. AB - OBJECTIVE: (i) To analyze general practitioners' diagnosis of somatisation disorder (P75) using the International Classification of Primary Care (ICPC)-2-E in routine general practice. (ii) To validate the distinctiveness of the ICD-10 to ICPC-2 conversion rule which maps ICD-10 dissociative/conversion disorder (F44) as well as half of the somatoform categories (F45.0-2) to P75 and codes the other half of these disorders (F45.3-9), including autonomic organ dysfunctions and pain syndromes, as symptom diagnoses plus a psychosocial code in a multiaxial manner. METHODS: Cross-sectional analysis of routine data from a German research database comprising the electronic patient records of 32 general practitioners from 22 practices. For each P75 patient, control subjects matched for age, gender, and practice were selected from the 2007 yearly contact group (YCG) without a P75 diagnosis using a propensity-score algorithm that resulted in eight controls per P75 patient. RESULTS: Of the 49,423 patients in the YCG, P75 was diagnosed in 0.6% (302) and F45.3-9 in 1.8% (883) of cases; overall, somatisation syndromes were diagnosed in 2.4% of patients. The P75 coding pattern coincided with typical characteristics of severe, persistent medically unexplained symptoms (MUS). F45.3-9 was found to indicate moderate MUS that otherwise showed little clinical difference from P75. Pain syndromes exhibited an unspecific coding pattern. Mild and moderate MUS were predominantly recorded as symptom diagnoses. Psychosocial codes were rarely documented. CONCLUSIONS: ICPC-2 P75 was mainly diagnosed in cases of severe MUS. Multiaxial coding appears to be too complicated for routine primary care. Instead of splitting P75 and F45.3-9 diagnoses, it is proposed that the whole MUS spectrum should be conceptualized as a continuum model comprising categorizations of uncomplicated (mild) and complicated (moderate and severe) courses. Psychosocial factors require more attention. PMID- 20708450 TI - Generalized hypervigilance in fibromyalgia patients: an experimental analysis with the emotional Stroop paradigm. AB - OBJECTIVE: In recent years, a good deal of serious research has been carried out on the hypothesized presence of generalized hypervigilance to sensory stimulation in fibromyalgia (FM). However, there are no studies which, following an operationalization of generalized hypervigilance as a propensity to attend to any task-irrelevant stimuli presented, make use of interference paradigms as the most appropriate experimental models for its analysis. The purpose of this study was to test the hypothesis of generalized hypervigilance in FM using the emotional modification of the Stroop task and to explore the possible mediating role of anxiety. METHODS: To this end, 25 women diagnosed with fibromyalgia and 25 matched controls were shown 32 stimulus words equally distributed in four categories: fibromyalgia symptoms, arousing-negative (A-), arousing-positive (A+), and neutral (N). These words had been selected on the basis of the results of an independent study. In addition to the emotional Stroop task, measures of trait and state anxiety were included. RESULTS: The results showed the possible presence of a generalized hypervigilance response in fibromyalgia patients based on significant slowness in the color-naming. This effect was mediated by the degree of perceived unpleasantness of the A-stimuli. However, the expected mediation effect of anxiety was not found. CONCLUSIONS: These results suggest the presence of a generalized hypervigilance response in FM patients that is not mediated by anxiety. Implications for the correct functioning of controlled self regulatory processes in fibromyalgia and similar pathologies are discussed. PMID- 20708451 TI - The association between tinnitus and mental health in a general population sample: results from the HUNT Study. AB - OBJECTIVES: Clinical studies indicate a strong association between tinnitus and mental health, but results from general population data are missing. The purpose of the study was to examine the association between tinnitus, mental health, and well-being in the general adult population and to identify factors that might mediate and moderate this association. METHODS: Data from 51,574 adults participating in the Nord-Trondelag Hearing Loss Study (1995-1997), part of the Nord-Trondelag Health Study (HUNT-2), were analyzed. The association between tinnitus symptom intensity and symptoms of depression, anxiety, self-esteem, and subjective well-being was examined by multivariate ANOVA, stratified by age group and sex. Explanatory variables were age, marital status, education, hearing, dizziness, vision, physical disability, and somatic illness. In a subsample of participants with tinnitus, the effects of "time since onset," "predictability of tinnitus episodes," and "noise sensitivity" were tested. RESULTS: Participants with tinnitus scored significantly higher on anxiety and depression and lower on self-esteem and well-being than people without tinnitus. The effect sizes were small and quite similar across levels of tinnitus symptom intensity. No significant effect of time since onset was found. A significant effect of predictability of tinnitus episodes and noise sensitivity was found in some groups. CONCLUSION: A weak association between tinnitus and mental health was found in this general population study. PMID- 20708452 TI - Qigong for the treatment of tinnitus: a prospective randomized controlled study. AB - OBJECTIVE: Tinnitus is a frequent disorder which is very difficult to treat. Qigong is a mindful exercise and an important constituent of traditional Chinese medical practice. Here we performed a randomized controlled trial to evaluate the effect of a Qigong intervention on patients with tinnitus. We hypothesized that especially tinnitus patients with somatosensoric components may benefit from the mind-body technique of Qigong. METHODS: Eighty patients with tinnitus of at least 3 months duration were randomly assigned to an intervention group (n=40) consisting of 10 Qigong training sessions in 5 weeks or a waiting-list control group (n=40). Tinnitus severity was assessed with a visual analogue scale (VAS) and with a tinnitus questionnaire (TBF-12) before treatment, immediately after treatment, and 1 and 3 months after treatment. RESULTS: Qigong did not cause any side effects and was completed by 80% of the assigned patients. Compared with the control group, Qigong participants experienced improvement in tinnitus severity, as reflected by a significant reduction in both the VAS and the TBF-12. In the subgroup of patients with somatosensoric tinnitus, Qigong effects were more pronounced, resulting in a highly significant improvement in both scales compared to the waiting-list group. CONCLUSION: These findings suggest that Qigong interventions could be a useful complement to the therapeutic management of patients with tinnitus and especially for those with somatosensoric components. Satisfaction with the intervention, a high degree of completion, and stability of the effects for at least 3 months after the intervention further underscore the potential of Qigong in the treatment of tinnitus. PMID- 20708453 TI - Methodological considerations in treatment evaluations of tinnitus distress: a call for guidelines. PMID- 20708454 TI - Physiological reactivity to phobic stimuli in people with fear of flying. AB - OBJECTIVE: The nature of the relationship between physiological and subjective responses in phobic subjects remains unclear. Phobics have been thought to be characterized by a heightened physiological response (physiological perspective) or by a heightened perception of a normal physiological response (psychological perspective). METHOD: In this study, we examined subjective measures of anxiety, heart rate (HR), and cardiac autonomic responses to flight-related stimuli in 127 people who applied for fear-of-flying therapy at a specialized treatment center and in 36 controls without aviophobia. RESULTS: In keeping with the psychological perspective, we found a large increase in subjective distress (eta(2)=.43) during exposure to flight-related stimuli in the phobics and no change in subjective distress in the controls, whereas the physiological responses of both groups were indiscriminate. However, in keeping with the physiological perspective, we found that, within the group of phobics, increases in subjective fear during exposure were moderately strong coupled to HR (r =.208, P=.022) and cardiac vagal (r =.199, P=.028) reactivity. In contrast to predictions by the psychological perspective, anxiety sensitivity did not modulate this coupling. CONCLUSION: We conclude that subjective fear responses and autonomic responses are only loosely coupled during mildly threatening exposure to flight-related stimuli. More ecologically valid exposure to phobic stimuli may be needed to test the predictions from the physiological and psychological perspectives. PMID- 20708456 TI - Multiple chemical sensitivity is a response to chemicals acting as toxicants via excessive NMDA activity. PMID- 20708455 TI - The development of the irritable bowel syndrome-behavioral responses questionnaire. AB - OBJECTIVE: Unhelpful behavior related to irritable bowel syndrome (IBS) is often targeted and expected to change in treatments such as cognitive behavioral therapies. However, no scale has previously been produced to assess these dimensions. The aim of this study was to develop and validate an IBS-specific behavioral responses questionnaire. METHODS: A total of 153 patients with IBS as diagnosed by a general practitioner completed the 28-item Irritable Bowel Syndrome-Behavioral Responses Questionnaire (IBS-BRQ). A total of 117 persons without IBS also completed the IBS-BRQ and were used as a control group. Tests of internal consistency and principal components analyses (PCAs) were performed on both sets of data. RESULTS: The scale was found to be both reliable and valid with a high degree of internal consistency for both IBS patients (Cronbach's alpha=.86) and controls (Cronbach's alpha=.89). The scale differentiated significantly between IBS patients and controls (F=221, P<.01). The PCA supported a two-factor solution in both sets of data. Two items were removed from the scale due to low discriminative ability. The criterion validity was high as evidenced by a strong correlation with the Cognitive Scale for Functional Bowel Disorders (CS-FBD) (r =.67, P<.001). CONCLUSION: The IBS-BRQ is a valid and reliable scale that can be used for clinical as well as empirical purposes. PMID- 20708458 TI - Leaving a legacy. PMID- 20708459 TI - Localization of nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. AB - The nephritis-associated plasmin receptor is a recently identified nephritogenic antigen associated with acute poststreptococcal glomerulonephritis and proposed to play a pathogenic role, but its precise glomerular localization in acute poststreptococcal glomerulonephritis has not been elucidated. We therefore analyzed renal biopsy sections from 10 acute poststreptococcal glomerulonephritis patients by using immunofluorescence staining with anti-nephritis-associated plasmin receptor antibody and various markers of glomerular components. Nephritis associated plasmin receptor was detected in the glomeruli of all patients, and double staining for nephritis-associated plasmin receptor and collagen IV showed nephritis-associated plasmin receptor to be predominantly on the inner side of the glomerular tufts. Nephritis-associated plasmin receptor-positive areas within glomerular tufts were further characterized with markers for neutrophils, mesangial cells, endothelial cells, and macrophages. In 6 of the patients, nephritis-associated plasmin receptor staining was seen mainly in neutrophils and to a lesser degree in mesangial and endothelial cells. In the other 4 patients, nephritis-associated plasmin receptor staining was seen mainly in mesangial cells and to a lesser degree in neutrophils and endothelial cells. In all patients, macrophages showed little staining. Elevated plasmin activity in glomerular neutrophils was identified by combining in situ zymography staining for plasmin activity and immunofluorescence staining for neutrophils. The glomerular localizations of nephritis-associated plasmin receptor and another nephritogenic antigen, streptococcal pyrogenic exotoxin B, were compared by double immunofluorescence staining and found to be similar. These findings indicate the nephritogenic potential of nephritis-associated plasmin receptor and offer valuable information with respect to the pathogenic mechanism of acute poststreptococcal glomerulonephritis. PMID- 20708460 TI - Paracoccidioides brasiliensis causing a rib lesion in an adult AIDS patient. AB - Paracoccidioidomycosis is a systemic mycosis with a geographic distribution that is limited to Central and South America; Brazil has the highest number of cases. Severe disseminated disease caused by paracoccidioidomycosis was observed in acquired immunodeficiency syndrome patients who live or have resided in endemic paracoccidioidomycosis areas. Here we describe a male patient admitted to a large public hospital with diffuse nodular infiltrates observed in chest radiographs and with erosion at the second rib near the sternum. Blood tests showed anti human immunodeficiency virus antibodies, a human immunodeficiency virus viral load of 59,700 (4.8 log), and CD4 144/mm(3), with negative serology result for fungal infections. Aspirate of the rib lesion showed cells with a typical morphology of Paracoccidioides brasiliensis, aside from benign inflammatory cells. The histology of the rib biopsy showed typical granulomas and immunostained fungal cells. Although there was no growth in the Sabouraud cultures, Paracoccidioides brasiliensis gp43 and rDNA genes were detected in the aspirate by polymerase chain reaction. Therapy with amphotericin resulted in complete recovery. This type of bone lesion is rare and has been described primarily in the juvenile form of paracoccidioidomycosis; it must be included in the differential diagnosis of bone lesions in adult acquired immunodeficiency syndrome patients of endemic areas. PMID- 20708461 TI - IMP3 expression in triple-negative breast carcinoma. PMID- 20708465 TI - Recruiting subjects for research studies in the era of Web 2.0. PMID- 20708466 TI - Differential usefulness of biomarkers thymus and activation-regulated chemokine and soluble CD30 during enteric coated mycophenolate sodium and cyclosporine therapy in atopic dermatitis. PMID- 20708467 TI - Rapid resolution of pyoderma gangrenosum after treatment with intravenous cyclosporine. PMID- 20708468 TI - Basal cell carcinoma and atypical fibroxanthoma: an unusual collision tumor. PMID- 20708469 TI - How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part I. Melanocytic skin tumors. AB - Dermoscopy is a noninvasive tool that can be helpful in the diagnosis of nonpigmented skin tumors. This is because dermoscopy permits the visualization of key vascular structures that are usually not visible to the naked eye. Much work has concentrated on the identification of specific morphologic types of vessels that allow a classification into melanocytic versus nonmelanocytic and benign versus malignant nonpigmented skin tumors. Among a broad spectrum of different types of vascular patterns, six main morphologies can be identified. These are comma-like, dotted, linear-irregular, hairpin, glomerular, and arborizing vessels. With some exceptions, comma, dotted, and linear irregular vessels are associated with melanocytic tumors, while the latter three vascular types are generally indicative of keratinocytic tumors. Aside from vascular morphology, the architectural arrangement of vessels within the tumor and the presence of additional dermoscopic clues are equally important for the diagnosis. This article provides a general overview of the dermoscopic evaluation of nonpigmented skin tumors and is divided into two parts. Part I discusses the dermoscopic vascular patterns of benign and malignant melanocytic skin tumors. Part II discusses the dermoscopic vascular patterns of benign and malignant nonmelanocytic nonpigmented skin tumors. In each part, additional special management guidelines for melanocytic and nonmelanocytic nonpigmented skin tumors, respectively, will be discussed. PMID- 20708470 TI - How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part II. Nonmelanocytic skin tumors. AB - Nonmelanoma skin cancer refers to a broad class of tumors, including actinic keratosis, basal cell carcinoma, and squamous cell carcinoma, and as a group these are the most frequent cancers occurring in light skinned humans. In contrast to the rarity of amelanotic melanoma, nonmelanoma skin cancer commonly lacks pigmentation. Although these tumors rarely cause death related to metastases, they commonly destroy underlying tissues and should be removed at the earliest possible stage. Dermoscopy improves the clinical diagnosis of nonpigmented skin tumors by allowing the visualization of specific vascular structures that are usually not visible to the naked eye. Dermoscopic vascular patterns of several nonmelanocytic nonpigmented skin tumors, such as sebaceous hyperplasia, seborrheic keratosis, clear cell acanthoma, Bowen disease, or nodular cystic basal cell carcinoma are highly specific, allowing a ready diagnosis in most cases. Others, such as actinic keratosis, pyogenic granuloma, or uncommon adnexal tumors, may be difficult to differentiate even with the aid of dermoscopy. For this reason, general guidelines have been established to assist in making the most appropriate management decision. In the second part of this review of dermoscopic vascular structures of nonpigmented skin tumors, the dermoscopic patterns associated with benign and malignant nonmelanocytic skin tumors and recommendations for the management of these tumors will be discussed. PMID- 20708471 TI - Bilateral forearm intravenous regional anesthesia with prilocaine for botulinum toxin treatment of palmar hyperhidrosis. AB - BACKGROUND: Treatment of palmar hyperhidrosis with botulinum toxin (BTX) requires effective anesthesia, but previous methods have not provided enough pain relief or have resulted in a prolonged impaired hand function. OBJECTIVE: This is a study of bilateral forearm intravenous regional anesthesia using prilocaine for BTX treatment of palmar hyperhidrosis. METHODS: In all, 166 patients (100 female and 66 male) were treated bilaterally with intracutaneous BTX type A injections using intravenous regional anesthesia with prilocaine (5 mg/mL). In a subgroup of patients, forearm nerves were studied with neurophysiologic methods and blood concentrations of prilocaine were measured. Pain evaluation with a visual analog scale was accompanied with a questionnaire about the treatment. RESULTS: In all, 95% of the patients answering the questionnaire (response rate 89%) were satisfied with the anesthetic effect. No serious adverse events occurred. There was a fast recovery of motor function (in median 6 minutes) and sensory function (in median 20 minutes). No subclinical signs of sensory nerve damage were found. LIMITATIONS: Recall and reporting bias are potential sources of limitations in this study. CONCLUSION: Bilateral forearm intravenous regional anesthesia provides an effective and well-tolerated anesthesia during BTX treatment of palmar hyperhidrosis. PMID- 20708472 TI - Deroofing: a tissue-saving surgical technique for the treatment of mild to moderate hidradenitis suppurativa lesions. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, often refractory to treatment. Patients with HS and dermatologists are in need of an effective, fast surgical intervention technique. Deroofing is a tissue-saving technique, whereby the "roof" of an abscess, cyst, or sinus tract is electrosurgically removed. The use of a probe is mandatory to explore the full extent of a lesion. OBJECTIVE: We sought to evaluate the efficacy and patient satisfaction of the deroofing technique for recurrent Hurley I (mild) or II (moderate) graded HS lesions at fixed locations. METHODS: An open study consisted of 88 deroofed lesions in 44 consecutive patients with HS, treated by a single clinician with a follow-up time of up to 5 years. RESULTS: Fifteen of 88 (17%) treated lesions showed a recurrence after a median of 4.6 months. In all, 73 treated lesions (83%) did not show a recurrence after a median follow-up of 34 months. The median patient satisfaction with the procedure rated 8 on a scale from 0 to 10. Of the treated patients, 90% would recommend the deroofing technique to other patients with HS. One side effect occurred in the form of postoperative bleeding. LIMITATIONS: Some patients were lost to follow-up. CONCLUSIONS: The deroofing technique is an effective, simple, minimally invasive, tissue-saving surgical intervention for the treatment of mild to moderate HS lesions at fixed locations and it is suitable as an office procedure. PMID- 20708473 TI - Commentary: unroofing for hidradenitis suppurativa, why and how. PMID- 20708474 TI - The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis. AB - BACKGROUND: Nephrogenic systemic fibrosis (NSF) occurs in patients with renal dysfunction and gadolinium exposure. Although little is known about the pathogenesis of this disease, increased expression of transforming growth factor beta has been recently demonstrated. Other fibrosing conditions have been shown to express an imbalance in matrix metalloproteinase (MMP) expression and their corresponding inhibitors. Myofibroblast differentiation, in which cells often express alpha-smooth muscle actin and achieve the ability to contract, is also a hallmark of fibrosis. OBJECTIVE: We theorized that NSF may overexpress tissue inhibitor of metalloproteinase-1 (TIMP-1), while simultaneously showing decreased expression of MMP-1. As a secondary aim, we sought to evaluate the presence of smooth muscle actin in our samples. METHODS: We applied immunohistochemistry to 16 skin biopsies from 10 patients with NSF using antibodies to TIMP-1, MMP-1, MMP 2, MMP-9, and alpha-smooth muscle actin. Samples from normal skin, scar, keloid and scleroderma were stained for comparison. RESULTS: TIMP-1 was strongly expressed in all NSF specimens compared to normal skin. MMP-1 expression was nearly absent in all tested samples. In all 16 NSF cases, the dermal spindle cells did not stain for alpha-smooth muscle actin. MMP-2 and MMP-9 expression was variable but was increased compared to normal skin. LIMITATIONS: The expression is semiquantitative and based on immunohistochemistry and unconfirmed by other techniques. CONCLUSIONS: In NSF, TIMP-1 is strongly expressed and MMP-1 is nearly absent, characteristic of the MMP imbalances seen in other fibrosing processes. Using smooth muscle actin immunohistochemistry, there was no evidence of myofibroblast differentiation. PMID- 20708475 TI - Dermatitis herpetiformis: pearls and pitfalls in diagnosis and management. PMID- 20708476 TI - Identification of a novel mutation in the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. PMID- 20708477 TI - Acute generalized exanthematous pustulosis associated with icodextrin. PMID- 20708478 TI - A nonsteroidal alternative to impetiginized eczema in the emergency room. PMID- 20708479 TI - Aleukemic leukemia cutis with extensive bone involvement. PMID- 20708480 TI - Onychopapilloma presenting as longitudinal leukonychia. PMID- 20708481 TI - JAAD Grand rounds quiz. Patch of "difficult to comb" hair. PMID- 20708482 TI - JAAD Grand rounds quiz. A woman with focal alopecia. PMID- 20708483 TI - JAAD Grand rounds quiz. Cicatricial alopecia. PMID- 20708485 TI - The beginning of a new journal. PMID- 20708486 TI - Sorafenib and radiation: a promising combination in colorectal cancer. AB - PURPOSE: To examine the combination of radiation and the multikinase inhibitor sorafenib in human colorectal cancer cell lines and xenografts. METHODS AND MATERIALS: HT29 and SW48 colorectal cancer cells were studied in vitro using MTT assays to establish the optimal timing of radiation and sorafenib. This optimal timing was then investigated in clonogenic survival assays. Xenografts were established, and the effect of a 3-week schedule of daily radiation and sorafenib was studied by growth delay. RESULTS: Sorafenib predominantly had minimal effects on cell growth or radiation response in MTT growth assays, though growth inhibition was significantly enhanced in HT29 cells when sorafenib was administered after radiation. The highest dose of sorafenib altered the alpha component of the cell survival curve in clonogenic assays. The combination of radiation and sorafenib was synergistic in SW48 xenografts, with a mean time to threshold tumor size of 11.4 +/- 1.0 days, 37.0 +/- 9.5 days, 15.5 +/- 3.2 days, and 98.0 +/- 11.7 days in the control, radiation, sorafenib, and combined treatment group, respectively. The effect on HT29 tumors was additive, with mean time to threshold volume of 12.6 +/- 1.1 days, 61.0 +/- 4.3 days, 42.6 +/- 11.7 days, and 100.2 +/- 12.4 days. CONCLUSIONS: Sorafenib had little effect on radiation response in vitro but was highly effective when combined with radiation in vivo, suggesting that inhibition of proliferation and interference with angiogenesis may be the basis for the interaction. PMID- 20708487 TI - Reporting of true spinal cord dose is encouraged for stereotactic body radiation therapy for spinal tumors. In regard to Sahgal et al. (Int J Radiat Oncol Biol Phys 2010;77:548-553). PMID- 20708488 TI - The rate of secondary malignancies after radical prostatectomy versus external beam radiation therapy for localized prostate cancer: a population-based study on 17,845 patients. In regard to Bhojani et al. (Int J Radiat Oncol Biol Phys 2010;76:342-348.). PMID- 20708490 TI - Response to "Dosimetric study of pelvic radiotherapy for high-risk prostate cancer." (Int J Radiat Oncol Biol Phys 2009;75:994-1002). PMID- 20708492 TI - Worry, emotion control, and anxiety control in older and young adults. AB - Young adults worry more than older adults; however, few studies have examined why age differences may exist in the frequency of worry. The present study aimed to identify age differences in worry frequency, and examine the relation of age and worry to control over one's emotions and control over anxiety. Older adults worried less often than young adults; however, young women worried more often than young men and older adults. Also, young women reported less control over their anxiety and less control over the external signs of their emotions compared to young men and older adults. Worriers had less perceived control over their anxiety, less control over the inner experience of emotions, and less control over the external signs of emotion. PMID- 20708493 TI - Emotional response patterns during social threat in individuals with generalized social anxiety disorder and non-anxious controls. AB - Patterns of synchrony in repeated measures of heart rate, skin conductance levels, negative affect, and positive affect were investigated in patients with social anxiety disorder and non-anxious controls during a speech task. Despite expected low levels of absolute concordance between measures of affect and arousal overall, results revealed clearly defined and specific patterns of emotional response coherence that distinguished between the two groups and depended on the types of measures used. Specifically, findings demonstrated that (a) for both patients and controls, increased heart rate was significantly synchronized with increased negative affect, with patients showing overall stronger levels of synchrony between these two measures than controls; (b) for controls only, increased heart rate was significantly synchronized with increased positive affect; and (c) for patients only, increased skin conductance was significantly synchronized with both increased negative affect and decreased positive affect. These findings are discussed in relation to current conceptualizations of the construct of emotion as well as directions for future research and potential implications for clinical practice. PMID- 20708494 TI - Prediction of neural tube defect using support vector machine. AB - OBJECTIVE: To predict neural tube birth defect (NTD) using support vector machine (SVM). METHOD: The dataset in the pilot area was divided into non overlaid training set and testing set. SVM was trained using the training set and the trained SVM was then used to predict the classification of NTD. RESULT: NTD rate was predicted at village level in the pilot area. The accuracy of the prediction was 71.50% for the training dataset and 68.57% for the test dataset respectively. CONCLUSION: Results from this study have shown that SVM is applicable to the prediction of NTD. PMID- 20708495 TI - Comparison of body mass index with body fat percentage in the evaluation of obesity in Chinese. AB - OBJECTIVE: To evaluate the present Chinese body mass index (BMI) criteria with body fat percentage (BF%) in determining obesity in Chinese population. METHODS: A total of 4 907 subjects (age: 20-90 yrs) were enrolled in the baseline survey of a longitudinal epidemiological study, and 2 638 of them were reevaluated in 5.5 years later. The Chinese BMI and WHO BF% were used to define obesity, respectively. RESULTS: The diagnostic agreement between the Chinese BMI and WHO BF% definitions for obesity was poor for both men (kappa: 0.210, 95% CI: 0.179 0.241) and women (kappa: 0.327, 95% CI: 0.296-0.358). However, BMI had a good correlation with BF% both in men (r: 0.785, P<0.01) and women (r: 0.864, P<0.01). The age and sex-adjusted relative risks (RR) for incidence of type 2 diabetes (T2DM) were significantly higher in subjects with intermediate BF% (BF%:20.1%-25% for men, 30.1%-35% for women) (RR: 2.35, 95% CI: 1.23-4.48) and high BF%(BF%>25% for men and > 35% for women)(RR: 2.89, 95% CI: 1.43-5.81), or in subjects with high BMI (BMI>or=28 kg/m(2)) (RR: 2.46, 95% CI: 1.31-4.63) when compared to those with low BF% (BF%ACC) (Ser-->Thr), 3 (2.6%) carried S315N (AGC-->AAC) and 27 (16.0%) had the mutation of inhA-15A-->T. 84 out of 122 SM-resistant isolates (68.9%) displayed mutations at the codons 43 or 88 with AAG-->AGG (Lys-->Arg) of the rpsL gene and 22 (18.0%) with the mutations at positions 513A-->C, 516C-->T or 905 A-->G in the rrs gene. Of 34 EMB-resistant isolates, 6 had mutation with M306V (ATG-->GTG), 3 with M306I (ATG-->ATT), 1 with M306I (ATG-->ATA), 1 with D328Y (GAT-->TAT), 1 with V348L (GTC-->CTC), and 1 with G406S (GGC-->AGC) in the embB gene. CONCLUSION: These novel findings extended our understanding of resistance-related mutations in the Beijing strains of M. tuberculosis and may provide a scientific basis for development of new strategies for diagnosis and control of tuberculosis in China and other countries where Beijing strains are prevalent. PMID- 20708498 TI - Precise microdeletion detection of Prader-Willi Syndrome with array comparative genome hybridization. AB - OBJECTIVE: Prader-Willi Sydrome (PWS) is a human disorder related to genomic imprinting defect on 15q11-13. It is characterized by a series of classic features such as hypotonia, hyperphagia, obesity, osteoporosis, typical facial and body dysmorphosis, hypogonadism, mental and behaviour disorders. Our study was designed to precisely detect the microdeletions, which accounts for 65%-70% of the PWS. METHODS: Physical and laboratory examinations were firstly performed to diagnose PWS clinically, and to discover novel clinical features. Then the patient was screened with bisulfite-specific sequencing and precisely delineated through high-density array CGH. RESULTS: With the bisulfite-specific sequencing, the detected CpG island in the PWS critical region was found homozygously hypermethylated. Then with array CGH, a 2.22 Mb type II microdeletion was detected, covering a region from MKRN3, MAGEL2, NDN, PWRN2, PWRN1, C12orf2, SNURF SNRPN, C/D snoRNAs, to distal of UBE3A. CONCLUSIONS: Array CGH, after the fast screening of Bisulfite-specific sequencing, is a feasible and precise method to detect microdeletions in PWS patients. A novel feature of metacarpophalangeal joint rigidity was also presented, which is the first time reported in PWS. PMID- 20708499 TI - Effects of exposure to GSM mobile phone base station signals on salivary cortisol, alpha-amylase, and immunoglobulin A. AB - OBJECTIVE: The present study aimed to test whether exposure to radiofrequency electromagnetic fields (RF-EMF) emitted by mobile phone base stations may have effects on salivary alpha-amylase, immunoglobulin A (IgA), and cortisol levels. METHODS: Fifty seven participants were randomly allocated to one of three different experimental scenarios (22 participants to scenario 1, 26 to scenario 2, and 9 to scenario 3). Each participant went through five 50-minute exposure sessions. The main RF-EMF source was a GSM-900-MHz antenna located at the outer wall of the building. In scenarios 1 and 2, the first, third, and fifth sessions were "low" (median power flux density 5.2 microW/m(2)) exposure. The second session was "high" (2126.8 microW/m(2)), and the fourth session was "medium" (153.6 microW/m(2)) in scenario 1, and vice versa in scenario 2. Scenario 3 had four "low" exposure conditions, followed by a "high" exposure condition. Biomedical parameters were collected by saliva samples three times a session. Exposure levels were created by shielding curtains. RESULTS: In scenario 3 from session 4 to session 5 (from "low" to "high" exposure), an increase of cortisol was detected, while in scenarios 1 and 2, a higher concentration of alpha-amylase related to the baseline was identified as compared to that in scenario 3. IgA concentration was not significantly related to the exposure. CONCLUSIONS: RF-EMF in considerably lower field densities than ICNIRP-guidelines may influence certain psychobiological stress markers. PMID- 20708500 TI - Recovery of aniline from wastewater by nitrobenzene extraction enhanced with salting-out effect. AB - OBJECTIVE: Nitrobenzene extraction enhanced by salting-out effect was employed to recover aniline from wastewater at 25 degrees C. METHOD: Batchwise experiments were conducted to elucidate the influence of various operating variables on the extracting performance, including acidity of wastewater, initial aniline concentration, ratios of solvent to wastewater, extraction stages, concentrations and different types of inorganic salts, such as NaCl, KCl, Na(2)SO(4), CaCl(2) and K(2)SO(4). RESULTS: Nitrobenzene with a concentration of 20% and a pH value of 9.1 at the temperature of 25 degrees C together with NaCl of a concentration of 14 wt.% realized nearly 100% aniline recovery at the fifth stage of wastewater treatment. CONCLUSIONS: High pH values and volume ratios of nitrobenzene/wastewater are more suitable for recovery of aniline. In addition, recovery of aniline is significantly elevated with increase of the concentration of salts, whose promoting effects are in the following order: NaCl>Na(2)SO(4)>K(2)SO(4)>CaCl(2)>KCl on the weight basis of wastewater. Furthermore, aniline in wastewater can be almost completely recovered by five stage sequential nitrobenzene extraction, which is promoted continuously by the salting-out effect. PMID- 20708501 TI - Characteristics and culture conditions of a bioflocculant produced by Penicillium sp. AB - OBJECTIVE: To study the characteristics of a bioflocculant named MBF7 produced by Penicillum strain HHE-P7 and the effects of cultivation conditions on bioflocculant production. METHODS: The chemical group in the bioflocculant molecules was shown by Fourier transform infrared (FTIR) spectra, and the average molecular weight of MBF7 was estimated by gel permeation chromatography. The effects of medium components on bioflocculant production and flocculating activity were studied. RESULTS: Phospho-, amino-, hydroxyl, and carboxyl groups were the major fractions of MBF7, and the molecule weight was about 3.0x10(5) Da. In addition, the carbon and nitrogen sources favorable for the bioflocculant production were glucose and yeast extract respectively. When the initial pH of the medium was adjusted to 5.0, high flocculant efficiency could be achieved. CONCLUSION: The bioflocculant MBF7 is a new macromolecule with high flocculating efficiency for Kaolin suspension, and could be produced under appropriate culture conditions. PMID- 20708502 TI - Sensitivity of different cytotoxic responses of Vero cells exposed to organic chemical pollutants and their reliability in the bio-toxicity test of trace chemical pollutants. AB - OBJECTIVE: To find a sensitive cytotoxic response to reflect the bio-toxicity of trace organic pollutants, the sensitivity and reliability of morphological change and proliferation inhibition of Vero cells exposed to 2, 4, 6-trichlorophenol (TCP) and the leachate from products related to drinking water (PRDW) were compared, and the mechanism of the morphological change in Vero cells exposed to chemical pollutants was studied. METHODS: Vero cells were treated by different concentration of TCP and the leachate from PRDW. Methylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide (MTT) assay was carried out for proliferation inhibition. Bioluminescence method was carried out as another method to test the toxicity of TCP. Flow Cytometry assay was used to test cell Apoptosis and damage of cell membrane. RESULTS: 0.25 mg/L TCP had an effect on cell morphology, and the proportion of morphologically changed cells increased with increasing TCP concentration. At low TCP concentrations, inhibition of cell proliferation did not seem to correlate to TCP concentration, and was negative when TCP concentration was <1.0 mg/L. After exposure to leachate from PRDW extracted at different temperatures, the percentage of morphologically changed cells increased with extracting temperature, but the inhibition of cell proliferation failed to reflect the correlation between extracting temperature and proliferation inhibition of Vero cells. Although the Sensitivity of bioluminescence method seems to be similar to morphological change in Vero cells, the bacterial in this method is not homologous enough with human body cells to reflect the toxicity to human body. These imply cell morphological change is a more sensitive and reliable method to reflect bio-toxicity of organic pollutants than proliferation inhibition. Flow cytometry analysis and cell rejuvenation experiments indicated cell membrane damage, which results in cell morphological change, was an early and sensitive cytotoxic response comparing with necrosis. CONCLUSION: These results indicated that the cell membrane toxicity represented by morphological changes is a more sensitive and reliable method to indicate the composite bio toxicity of trace chemicals than proliferation inhibition, inhibition on bioluminescence and necrosis. Nevertheless, the quantification of morphological change should be studied further. PMID- 20708503 TI - Exposure to environmental hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT) among rural children in north eastern China. AB - OBJECTIVE: To assess HCH and DDT exposure levels and associated risk factors among 262 children aged 6-10 years in a northeastern rural area of China between April and May of 2008. METHODS: Eight HCH and DDT metabolites in serum samples were monitored by gas chromatography. A questionnaire was administered to identify the sources of pesticides in children' serum samples. RESULTS: At least one pesticide metabolite was detected in 81.7% of the tested children. Higher amounts of pp'DDD were detected in 50% of them. Children's age and their father's occupation as farmers, together with not changing work clothes after work, were the main risk factors for HCH and DDT exposure among them. CONCLUSION: Children living in rural areas are experiencing multiple sources of organochlorine pesticide exposure. These pesticides may have been retained in the environment for a long period of time. PMID- 20708504 TI - Diurnal variations in solar ultraviolet radiation at typical anatomical sites. AB - OBJECTIVE: Solar ultraviolet (UV) radiation is an important environmental factor that affects human health. The understanding of diurnal variations of UV radiation at anatomical sites may be helpful in developing ways to protect humans from the harmful effects of UV radiation. METHODS: In order to characterize the diurnal variations, the UV exposure values were measured at 30 min intervals by using Solar-UV Sensors and a rotating manikin in Shenyang city of China (41 degrees 51'N, 123 degrees 27'E). Measurement data for four representative days (in each of the four seasons respectively) were analyzed. RESULTS: The diurnal variations in solar UV radiation at the shoulder, the forehead and the chest were similar to those associated with a horizontal control measurement. However, the diurnal variations at the eye and the cheek exhibited bimodal distributions with two peaks in spring, summer and autumn, and a unimodal distribution in winter. The UV exposure peaks at the eye and the cheek were measured at solar elevation angles (SEA) of about 30 degrees and 40 degrees , respectively. CONCLUSION: The protection of some anatomical sites such as the eye from high UV exposure should not be focused solely on the periods before and after noon, especially in the places and seasons with high SEA. PMID- 20708505 TI - LIPUS enhance elongation of neurites in rat cortical neurons through inhibition of GSK-3beta. AB - OBJECTIVE: Low-intensity pulsed ultrasound (LIPUS) has been reported to enhance proliferation and to alter protein production in various kinds of cells. In the present study, we measured the neurites length after LIPUS treatment to define the effectiveness of LIPUS stimulation on neurons, and then we examined the acticity of GSK-3beta to study the intracellular mechanism of neurite's outgrowth. METHODS: LIPUS was applied to cultured primary rat cortical neurons for 5 minutes every day with spatial- and temporal average intensities (SATA) of 10 mW/cm(2), a pulse width of 200 microseconds, a repetition rate of 1.5 KHz, and an operation frequency of 1 MHz. Neurons were photographed on the third day after LIPUS treatment and harvested at third, seventh, and tenth days for immunoblot and semi-quantitative RT-PCR analysis. RESULTS: Morphology change showed that neurite extension was enhanced by LIPUS. There was also a remarkable decrease of proteins, including p-Akt, p-GSK-3beta, and p-CRMP-2, observed on the seventh and tenth days, and of GSK-3beta mRNA expression, observed on the seventh day, in neurons treated with LIPUS. CONCLUSION: LIPUS can enhance elongation of neurites and it is possible through the decreased expression of GSK-3beta. PMID- 20708506 TI - Application of laparoscopic surgery in gynecological oncology. AB - The role of laparoscopic surgery in the management of gynecological cancers continues to expand. For early-stage cervical cancer, laparoscopically assisted radical vaginal hysterectomy is feasible, and radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy has emerged as a safe option for women who desire fertility preservation. In the treatment of early-stage endometrial cancer, the surgical staging of laparoscopic hysterectomy, peritoneal washings and pelvic lymph node dissection is effective and safe when compared with the same surgery performed via laparotomy. In ovarian malignancies, laparoscopic surgery has been incorporated to manage early-stage cancers. PMID- 20708507 TI - Acquired hyperplastic gastric polyps after treatment of ulcer. AB - BACKGROUND/PURPOSE: Healing of gastric ulcers requires repair by epithelial migration and proliferation. We have found a small proportion of patients with acquired hyperplastic polyps at the healed ulcer site. The aim of this study was to identify clinical characteristics that might be associated with the development of hyper-plastic polyps at the site of healed gastric ulcers. METHODS: This was a retrospective review of 86 patients with gastric ulcers from April 2006 to September 2008. After initial endoscopy, the patients were all treated with proton pomp inhibitors, after which a second endoscopy was performed. Demographic data, polyp characteristics (endoscopic and histological), Helicobacter pylori status, and duration of treatment were analyzed. RESULTS: A total of 24 hyperplastic gastric polyps were found in 18 patients; all at the site of the healed ulcer (20 in the antrum and 4 in the corpus). The mean size of the ulcers prior to treatment was 14.5 +/- 9.1 mm. Hyperplastic gastric polyps were more likely to occur at the site of ulcers larger than 10 mm (odds ratio = 9.57, 95% confidence interval =2.50-36.65). Age, sex, H. pylori status, ulcer location and duration of treatment did not differ significantly between patients with and without polyps. CONCLUSION: Hyperplastic polyps that develop after healing of gastric ulcers are likely to be extensive mucosal injury. A gastric ulcer larger than 10 mm is associated with a significantly increased risk of hyperplastic polyps. PMID- 20708508 TI - Hemothorax in a medical intensive care unit: incidence, comorbidity and prognostic factors. AB - BACKGROUND/PURPOSE: There is a lack of data regarding the occurrence of hemothorax in medical intensive care units (ICUs). The purpose of this study was to investigate the incidence, comorbidity and prognostic factors of hemothorax in medical ICU patients. METHODS: From January 1997 to December 2004, patients with hemothorax that developed during an ICU stay were studied. Hemothorax was considered procedure-related if it developed within 24 hours after an invasive procedure. Medical records were reviewed and analyzed with respect to patients' demographic data, underlying diseases, reasons for admission, Acute Physiology and Chronic Health Evaluation II score, procedures related to hemothorax, management, duration of ICU stay, and outcomes. RESULTS: Fifty-three patients (0.79%) suffered hemothorax during their ICU stay. Chronic kidney disease (77.4%) was the most common comorbidity. A total of 40 cases (75.5%) were procedure related. Thoracentesis and chest tube thoracostomy were the most common procedures. The 28-day mortality rate was 35.8%. Multivariate logistic regression analysis revealed that a prothrombin time/international normalized ratio > or = 1.6 (odds ratio = 10.99, 95% confidence interval = 1.08-112.05) and a hemoglobin decrease > or = 3 g/dL (odds ratio = 5.55, 95% confidence interval = 1.26-24.45) were significantly associated with 28-day mortality. CONCLUSION: Chronic kidney disease was the most common comorbidity associated with hemothorax. Patients with chronic kidney disease might require close observation for hemothorax after invasive procedures, such as thoracentesis and chest tube thoracostomy. Prolonged prothrombin time and decreased hemoglobin level might be of prognostic value for critically ill patients with hemothorax. PMID- 20708509 TI - Impact of therapeutic interventions on survival of patients with hepatic hydrothorax. AB - BACKGROUND/PURPOSE: Hepatic hydrothorax is an uncommon but important complication of liver cirrhosis. The optimal management of this condition remains unclear. This retrospective study evaluated the impact of therapeutic interventions on the outcome of patients with hepatic hydrothorax. METHODS: From August 1996 to March 2004, the medical charts of 52 patients with hepatic hydrothorax in the National Taiwan University Hospital were reviewed. Treatment methods, outcome of interventions, and survival time were described and analyzed. RESULTS: At the time of diagnosis, four patients were Child-Pugh class A, 20 were class B, and 28 were class C. Twenty-eight (53.8%) patients received supportive care with thoracentesis for symptom relief. Among the other 24 patients, 16 (30.8%) were treated by chemical pleurodesis, 14 (26.9%) underwent surgical interventions, and six (11.5%) received both interventions. Intervention success, defined as resolution of hydrothorax for at least 3 months after the procedure, was achieved in 37.5% and 42.9% of patients who underwent chemical pleurodesis and surgery, respectively, with an overall success rate of 50%. The median survival of all patients was 8.6 months (range, 0.2-77.6 months). The median survival of patients with intervention success (22.5 months) was significantly longer than those with intervention failure (5.4 months) and supportive care (6.3 months). Multivariate analysis showed that only intervention success (p = 0.010, hazard ratio = 0.25) was an independent predictor of survival. CONCLUSION: For patients with hepatic hydrothorax, aggressive medical or surgical intervention might improve survival over supportive management, especially when resolution of hydrothorax can be maintained for at least 3 months. PMID- 20708510 TI - Effect of epidural neuraxial blockade-dependent sedation on the Ramsay Sedation Scale and the composite auditory evoked potentials index in surgical intensive care patients. AB - BACKGROUND/PURPOSE: Peripheral deafferentation induced by neuraxial anesthesia reduces the degree of cortical arousal. This study investigated whether epidural analgesia blockade decreased sedation, as measured by the rapidly extracted auditory evoked potentials index, A-line autoregressive index (AAI) and Ramsay Sedation Scale (RSS) in sedated surgical intensive care patients, and looked at whether this was a concentration-dependent effect of lidocaine. METHODS: Forty patients underwent major lower abdominal surgery and received epidural analgesia in the surgical intensive care unit. Patients were continuously sedated with propofol to achieve an RSS value of 3, randomly divided into two groups, and received epidural analgesia with 10 mL of 0.5% or 1% lidocaine. Sedation was evaluated using the RSS and AAI, and analgesia was evaluated using a visual analog scale (VAS). RSS, AAI, electromyography (EMG) activity of AAI and VAS values were recorded at 5 minutes before and 30, 60 and 90 minutes after epidural lidocaine administration. RESULTS: Epidural 0.5% lidocaine produced a reduction of AAI, EMG and VAS at 30, 60 and 90 minutes after administration. For 1% epidural lidocaine administration, AAI, EMG and VAS were also reduced at 30, 60 and 90 minutes after epidural lidocaine administration. However, there was no difference in the AAI between the two concentrations; moreover, no significant change was observed in the RSS. CONCLUSION: Epidural lidocaine analgesia could potentiate sedation in patients evaluated by the AAI, but had no effect on the RSS. The present study suggests that the AAI could provide an objective and more precise index than the RSS in evaluation of sedation level in patients who are undergoing epidural pain management in the intensive care unit. PMID- 20708511 TI - Duration for apical barrier formation in necrotic immature permanent incisors treated with calcium hydroxide apexification using ultrasonic or hand filing. AB - BACKGROUND/PURPOSE: Traumatic injury usually results in pulp necrosis of immature permanent incisors in children aged 7-10 years. Calcium hydroxide apexification is the most common treatment for necrotic, immature permanent teeth. This study compared the duration for apical barrier formation in necrotic immature permanent incisors treated with calcium hydroxide apexification using ultrasonic or hand filing. METHODS: Thirty-two trauma-induced necrotic immature permanent incisors with or without a periapical lesion (PL) were selected from children aged 7-10 years. They were evenly divided into four groups. Teeth in groups 1 (with PL) and 2 (without PL) were treated with ultrasonic filing, and teeth in groups 3 (with PL) and 4 (without PL) were treated with hand filing. The canals were cleaned with 0.2% chlorhexidine solution during treatment and then compactly filled with calcium hydroxide. The patients were followed up once every 1-3 weeks to change the intracanal medication and to detect when the apical barrier formed. RESULTS: The mean duration for apical barrier formation was 11.1 +/- 1.1 weeks, 11.8 +/- 1.0 weeks, 13.3+/-0.9 weeks and 13.4 +/- 0.7 weeks for groups 1, 2, 3 and 4, respectively. Student's t test showed significant differences in the mean duration for apical barrier formation between groups 1+2 and 3 + 4 (p = 0.000), groups 1 and 3 (p = 0.000), and groups 2 and 4 (p = 0.002). These results indicated that teeth treated with ultrasonic filing required a shorter mean duration for apical barrier formation than teeth treated with hand filing regardless of the presence of PL or not. CONCLUSION: Ultrasonic filing with 0.2% chlorhexidine as an irrigant is effective for disinfection of the root canal and can shorten the duration for apical barrier formation in necrotic permanent incisors treated with calcium hydroxide apexification. PMID- 20708512 TI - Complications of fluoroscopically guided percutaneous gastrostomy with large-bore balloon-retained catheter in patients with head and neck tumors. AB - BACKGROUND/PURPOSE: To review the complications, mortality rate and nutritional status of patients with head and neck cancer after fluoroscopically guided percutaneous gastrostomy (FPG). METHODS: We retrospectively recruited 110 patients who had undergone FPG using 14-French balloon-retained catheters. The mortality rate, procedural and catheter-related complications, and Eastern Cooperative Oncology Group performance status were reviewed. Peritonitis, abscess, septicemia and bleeding were defined as major complications. Tube related problems, including dislodgment, obstruction, leakage, vomiting and infection, were classified as minor complications. RESULTS: Patients were stratified according to Eastern Cooperative Oncology Group performance status as follows: grade 0 (n=6); grade 1 (n=22); grade 2 (n=44); grade 3 (n=29); and grade 4 (n=7). The respective complication rates were 21%, 24%, 26%, and 29% for grades 1-4; however, there were no significant intergrade differences. The rates of major and minor complications were 1.9% and 20.0%, respectively. A total of 47 (43.5%) patients succumbed due to cancer deterioration; however, there was no gastrostomy-induced mortality. The catheter-occlusion rate of 3.7% in this cohort was significantly lower than that reported in other pigtail-retained gastrostomy studies. CONCLUSION: FPG is a safe method with low mortality and complication rate for constructing long-term enteral access in patients with head and neck cancer and esophageal abnormalities, who have no endoscopic access to the stomach. PMID- 20708513 TI - A modified approach of cystic puncture with contrast medium injection for diagnosis of obstructed hemivagina and urinary tract anomalies. AB - This study investigated the diagnostic value of a modification of the conventional technique of X-ray imaging after cystic puncture with injection of contrast medium for obstructed hemivagina and related urinary tract anomalies in girls. The modified procedure made the following diagnostic findings: ipsilateral obstructed hemivagina in one patient with renal agenesis; vaginal ectopic ureter and ipsilateral obstructed hemivagina in one patient with renal dysplasia; and vaginal ectopic ureter, Gartner's duct cyst and ipsilateral obstructed hemivagina in six patients with renal dysplasia or aplasia. This modified method might have improved diagnostic value over the traditional method, and accurately identify genitourinary tract anomalies. It could therefore serve as an alternative and complementary method of sonography. PMID- 20708514 TI - Pleomorphic hyalinizing angiectatic tumor of soft parts. AB - Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts is a rare, nonmetastasizing tumor of uncertain lineage which was first reported in 1996. Here, we report a case of PHAT and review the literature. A 49-year-old man presented with a soft and progressively enlarging mass over the right buttock for several years. On suspicion that the mass was a right gluteal lipoma, he underwent surgical excision. The excised lesion measured 14 x 6 x 3.5 cm. It had a variegated appearance with a white-tan to yellowish color on the cut surface. Some punctate hemorrhage and vessel thrombosis were seen. Microscopically, the tumor was a PHAT characterized by clusters of ectatic, fibrin-lined, thin-walled vessels, which were surrounded by a mitotically inert, spindled, pleomorphic, neoplastic stroma that contained a variable inflammatory component. Immunohistochemical study showed that the tumor cells were positive for CD34, and negative for S-100, HMB45 and actin. The patient experienced local recurrence 6 months later. The recurrent tumor was widely excised. No evidence of metastasis was found during the 18 months after the second operation. The recurrent lesion had a microscopic appearance that was similar to the initial lesion. PMID- 20708515 TI - Biochemical characterization of a lipase from olive fruit (Olea europaea L.). AB - Lipase (triacylglycerol acylhydrolase; EC 3.1.1.3) is the first enzyme of the degradation path of stored triacylglycerols (TAGs). In olive fruits, lipase may determine the increase of free fatty acids (FFAs) which level is an important index of virgin olive oil quality. However, despite the importance of virgin olive oil for nutrition and human health, few studies have been realized on lipase activity in Olea europaea fruits. In order to characterize olive lipase, fruits of the cv. Ogliarola, widely diffused in Salento area (Puglia, Italy), were harvested at four stages of ripening according to their skin colour (green, spotted I, spotted II, purple). Lipase activity was detected in the fatty layer obtained after centrifugation of the olive mesocarp homogenate. The enzyme exhibited a maximum activity at pH 5.0. The addition of calcium in the lipase assay medium leads to an increment of activity, whereas in the presence of copper the activity was reduced by 75%. Furthermore, mesocarp lipase activity increases during olive development but declined at maturity (purple stage). The data represent the first contribution to the biochemical characterization of an olive fruit lipase associated to oil bodies. PMID- 20708516 TI - Pathophysiology of increased fetal nuchal translucency thickness. AB - Increased fetal nuchal translucency thickness is associated with trisomy 13, trisomy 18, trisomy 21, Turner syndrome, other sex chromosome abnormalities, as well as many fetal anomalies and genetic syndromes. This article provides a comprehensive review of the cardinal proposed pathophysiology including altered composition of the extracellular matrix, abnormalities of the heart and great arteries, and disturbed or delayed lymphatic development. PMID- 20708518 TI - Abnormal ductus venosus flow and tricuspid regurgitation at 11-14 weeks' gestation have high positive predictive values for increased risk in first trimester combined screening test: results of a pilot study. AB - OBJECTIVE: To investigate the relationship between two novel first-trimester ultrasound markers (abnormal fetal ductus venosus [DV] flow and presence of tricuspid regurgitation [TR]) and the results of the first-trimester combined screening test in pregnancies with a normal karyotype. The screening test involves nuchal translucency measurement by ultrasound, and measurement of serum free beta-chorionic gonadotropin and pregnancyassociated plasma protein A. MATERIALS AND METHODS: The study included 58 pregnancies with amniocentesis proven normal karyotypes and ultrasound-proven normal fetal anatomy. DV flow and TR were initially evaluated by ultrasound at 11-14 weeks' gestation. Sensitivity, specificity, and positive and negative predictive values of abnormal DV flow and TR for determining increased test risk (> 1 in 300) were calculated. RESULTS: Abnormal DV flow and TR were detected in seven (12%) and six (10%) women, respectively. The sensitivities of abnormal DV flow, TR, and dual abnormalities (abnormal DV flow plus TR) for predicting increased risk in the combined screening test were low (33.3%, 27.7%, and 26.3%, respectively). However, their corresponding specificities (97.5%, 97.5%, and 100%) and positive predictive values (85.7%, 83.3%, and 100%) were reasonably high, with particularly low false positive rates (2.5%, 2.5%, and 0%). When abnormal DV flow and TR were both positive, the combined test risk was consistently above 1 in 300. CONCLUSION: Determination of DV flow and TR as initial markers in unselected pregnancies merits further investigation, as the combination of these parameters might reliably predict an increased risk in combined screening test result, with low false positivity. PMID- 20708517 TI - Expression of a Hoechst 33342 efflux phenomenon and common characteristics of pluripotent stem cells in a side population of amniotic fluid cells. AB - OBJECTIVE: The aim of this study was to verify the existence of a side population (SP) of cells in second-trimester amniotic fluid. MATERIALS AND METHODS: Amniotic fluid samples (n = 35) were obtained, and the number and size of viable amniotic fluid cells (AFCs) were analyzed. Small AFCs (SAFCs) and large AFCs (LAFCs) were isolated using a sterile 10-microm pore size strainer. Hoechst 33342 dye exclusion assay, flow cytometry analysis, reverse transcriptase polymerase chain reaction and immunocytochemistry were used to analyze the characteristics of SAFCs and LAFCs. RESULTS: The mean concentration of viable AFCs from 16 to 21 weeks of gestation was 0.3 x 10(5), 0.8 x 10(5), 1.1 x 10(5), 1.3 x 10(5), 1.0 x 10(5) and 1.0 x 10(5) cells/mL respectively. The mean percentage of SAFCs from 16 to 21 weeks of gestation was 27.3%, 40.5%, 49.7%, 60.2%, 41.0% and 58.2%, respectively. The Hoechst 33342 efflux phenomenon was obvious among SAFCs but was rare in the LAFC population. Flow cytometry analyses showed that cell surface antigen expression on LAFCs and SAFCs were positive for CD29, CD44, CD73, CD90, CD166 and HLA-I, but negative for CD31, CD34, CD45, CD117 and HLA-II. Importantly, Nanog, Oct-4, ABCG2 and SOX2 expression in cells was easily detectable among the SAFC population. Expression of Nanog and ABCG2 was not observed among LAFCs. CONCLUSION: Amniotic fluid contains a SP that was found mostly among the SAFCs. Enriched SP cells isolated by the efflux of Hoechst 33342 could be a novel and promising source of pluripotent-like amniotic derived stem cells for cellular therapy in the near future. PMID- 20708519 TI - Induction of labor: a comparative study of intravaginal misoprostol and dinoprostone. AB - OBJECTIVE: To compare the efficacy and safety of intravaginal misoprostol and dinoprostone for elective induction of labor in nulliparous women with an unfavorable cervix. MATERIALS AND METHODS: A quasi-experimental study was conducted in Bahawal Victoria Hospital, Bahawalpur, Pakistan, from July 1, 2005 to August 31, 2006. A total of 120 primigravid women with gestational ages of > 40 weeks to < 42 weeks were divided into two groups. Group A (n = 60) was given 50 microg of misoprostol and Group B (n = 60) was given 3 mg of dinoprostone every 6 hours, for a maximum of three doses. RESULTS: The induction to onset of significant uterine contractions and delivery intervals were lower in Group A than in Group B (6.1 vs. 7.2 hours; p = 0.16; and 8.2 vs. 11.0 hours; p = 0.007, respectively). Group A had a lower cesarean section rate than Group B (7% vs. 30%; p = 0.003), but a higher rate of uterine hyperstimulation (10% vs. 3%; p = 0.16), tachysystole (17% vs. 3%; p = 0.02), and neonatal admissions to the intensive care unit within 24 hours of delivery (4 vs. 3; p = 0.71) and after 24 hours (2 vs. 1; p = 0.56) than Group B. CONCLUSION: Vaginal misoprostol is more effective than dinoprostone for the elective induction of labor beyond 40 weeks of gestation, but is associated with more uterine hyperstimulation, tachysystole, and neonatal intensive care unit admissions. PMID- 20708520 TI - Acute fatty liver of pregnancy in a Taiwanese tertiary care center: a retrospective review. AB - OBJECTIVE: To evaluate the demographics, clinical presentations, laboratory findings, and maternal and fetal outcomes in patients with acute fatty liver of pregnancy. MATERIALS AND METHODS: A retrospective review was conducted of the records of pregnant patients with a diagnosis of acute fatty liver in a tertiary medical center over a 22-year period. RESULTS: Eighteen patients with acute fatty liver of pregnancy were recruited, all of whom developed the disease in the third trimester. Eleven women (61%) were primigravid and four (22%) had twin pregnancies; six (33%) were diagnosed antepartum, and the other 12 (67%) were diagnosed postpartum. There were two maternal deaths (11%) and four fetal deaths (18%). The most common complications apart from severe liver dysfunction were acute renal failure (83%), hypoglycemia (61%), and disseminated intravascular coagulation (61%). CONCLUSION: Women who become acutely ill during the third trimester of pregnancy should undergo tests for acute fatty liver of pregnancy, including laboratory tests for assessing liver function and coagulation profile. PMID- 20708521 TI - Insertion of the Mirena intrauterine system for treatment of adenomyosis associated menorrhagia: a novel method. AB - OBJECTIVE: Insertion of the levonorgestrel-releasing intrauterine system Mirena is difficult in women with adenomyosis, and the device is often subsequently expelled. We used a novel insertion technique (Yang's method) to overcome this problem. MATERIALS AND METHODS: This retrospective study enrolled 273 patients with adenomyosis who were receiving Mirena for treatment of menorrhagia and/or dysmenorrhea between 2001 and 2008. Clinical outcomes and expulsion rates were compared between patients treated using conventional insertion and those treated using Yang's insertion methods. RESULTS: Expulsion occurred in 25.3% of patients with the conventional method, compared with 10.2% of patients with Yang's method. Hemoglobin levels and dysmenorrhea improved greatly in both groups after Mirena insertion. CONCLUSION: Yang's insertion method for levonorgestrel-releasing intrauterine system is more reliable in some difficult cases, such as patients with severe adenomyosis. This method ensures correct positioning, thus reducing the risks of uterine perforation and/or expulsion. PMID- 20708522 TI - Analysis of cases of sexual assault presenting at a medical center in Taipei. AB - OBJECTIVE: Sexual assault is a form of interpersonal violence with significant consequential health problems. The purpose of this study was to describe the characteristics of the victims, assaults, and associated physical and psychologic trauma of sexual assault cases in Taipei. MATERIALS AND METHODS: Data were retrospectively collected from the medical records of sexual assault victims who visited the emergency department of a medical center in Taipei from 1991 to 2003. The characteristics of the victims, assaults, and factors associated with general body and genital trauma were analyzed. RESULTS: There were 114 sexual assault victims, including 107 females and seven males, aged from 3 to 49 years (mean, 17.9 years). Overall, 72.3% of victims had evidence of physical trauma. Genital/anal injuries (53.3%) occurred more often than general body trauma (41.0%). The presence of general body injuries was positively associated with physical examination within 72 hours, and negatively associated with a victim age younger than 18 years. Genital/anal lesions were significantly more common in victims without prior sexual intercourse. CONCLUSION: The results of physical examination in sexual assault victims were related to early examination, age, and sexual experience. PMID- 20708523 TI - Incidence of and risk factors for birth trauma in Iran. AB - OBJECTIVE: Birth trauma at delivery is a rare but significant prenatal complication. The aim of this study was to determine the incidence of birth trauma and risk factors related to fetal injury. MATERIALS AND METHODS: Birth trauma was evaluated in singleton fetuses with no major anomalies and with vertex presentations over a 3-year period from 2002 to 2005. One hundred and forty-eight neonates, who experienced birth trauma, were prospectively identified and compared with 280 normal neonates. Both groups were delivered vaginally. Maternal and infant characteristics were evaluated as possible risk factors for fetal injury. RESULTS: Among the 148 infants with birth trauma, nine had multiple injuries. The most common injury was cephalohematoma (n = 77). Other injuries included clavicle fractures (n = 56), brachial plexus paralysis (n = 13), asphyxia (n = 7), facial lacerations (n = 4), brain hemorrhage (n = 1), and skin hematoma (n = 2). Multiple regression analysis identified premature rupture of membranes, instrumental delivery, birth weight, gestational age, induction of labor, and academic degree of attendant physician at delivery as the most significant risk factors for birth trauma. CONCLUSION: The incidence of birth trauma was 41.16 per 1,000 vaginal deliveries. Induction of labor, premature rupture of membranes, academic degree of attendant physician at delivery, higher birth weight, and gestational age were associated with fetal injuries. PMID- 20708524 TI - Epicatechin gallate decreases the viability and subsequent embryonic development of mouse blastocysts. AB - OBJECTIVE: Catechins, a family of polyphenols found in tea, evoke various responses including cell death. We examined the cytotoxic effects of epicatechin gallate (ECG), a polyphenol extract from green tea, on the blastocyst stage of mouse embryos, subsequent embryonic attachment, and in vitro and in vivo outgrowth implantation after embryo transfer. MATERIALS AND METHODS: Mouse blastocysts were incubated in medium with or without ECG (12.5 microM, 25 microM or 50 microM) for 24 hours. Cell proliferation and growth were investigated using dual differential staining, apoptosis was analyzed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and implantation and post implantation development of embryos were measured by in vitro development analysis and in vivo embryo transfer, respectively. RESULTS: Blastocysts treated with 50 microM ECG exhibited a significant increase in apoptosis and a corresponding decrease in total cell number. Importantly, the implantation success rate of blastocysts pretreated with 50 microM ECG was lower than that of controls, and in vitro treatment with 50 microM ECG was associated with increased resorption of post-implantation embryos and decreased fetal weight. CONCLUSION: Our results collectively indicate that in vitro exposure to ECG induces apoptosis and retards early post-implantation development after transfer to host mice. The degree of teratogenic potential exerted by ECG in early human development is unknown at present and requires further investigation. PMID- 20708525 TI - Selenium supplementation and the incidence of preeclampsia in pregnant Iranian women: a randomized, double-blind, placebo-controlled pilot trial. AB - OBJECTIVE: Recent studies have reported that antioxidant status, including serum selenium concentrations, is altered in women who develop preeclampsia. We wished to examine the effects of selenium supplementation in the prevention of preeclampsia in high-risk pregnant women. DESIGN: We carried out a randomized, double-blind, placebo-controlled pilot trial. A total of 166 primigravid pregnant women, who were in the first trimester of pregnancy, were randomized to receive 100 microg of selenium (n = 83; dropouts, n = 22) or a placebo (n = 83; dropouts, n = 19) per day until delivery. The incidence of preeclampsia, serum selenium concentrations, lipid profile and high-sensitivity C-reactive protein status were evaluated at baseline and at the end of the study. RESULTS: Supplementation with selenium was not associated with any reported major side effects and was associated with a significant increase in mean serum selenium concentrations at term (p < 0.001). In contrast, mean serum selenium concentrations remained unchanged in the control group (p = 0.63). The incidence of preeclampsia was lower in the selenium group (n = 0) than in the control group (n = 3), although this was not statistically significant (p > 0.05). After treatment, systolic and diastolic blood pressure, serum total cholesterol, triglycerides, low-density and high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein were significantly increased in both groups compared with pretreatment levels (p < 0.05). CONCLUSION: Our findings indicate that selenium supplementation in pregnant women may be associated with a lower frequency of preeclampsia. PMID- 20708526 TI - Prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome derived from chromosome 18 and associated with a reciprocal translocation involving chromosomes 17 and 18. AB - OBJECTIVE: Prenatal diagnosis of small supernumerary marker chromosomes (sSMC) gives rise to difficulties in genetic counseling, and requires molecular cytogenetic technologies such as spectral karyotyping, fluorescence in situ hybridization, multicolor-fluorescence in situ hybridization, or array comparative genomic hybridization to identify the nature of the aberrant chromosome. We report such a case associated with a reciprocal translocation. MATERIALS, METHODS AND RESULTS: A 36-year-old woman, gravida 7, para 1, abortus 5, was referred for amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a reciprocal translocation between chromosomes 17q and 18q and an sSMC. The karyotype was 47,XY,t(17;18)(q11.1;q11.2), +mar. Chromosome preparations from blood lymphocytes revealed that she had the same reciprocal translocation and sSMC. Spectral karyotyping showed that the sSMC was derived from the centromeric region of chromosome 18, and there was a reciprocal translocation between chromosomes 17 and 18. The derivative chromosome 17 had positive 17p terminal (17pTEL) and chromosome 17 centromeric (cep17) signals but did not have a positive chromosome 18 centromeric signal (cep18). The derivative chromosome 18 had positive 18p terminal (18pTEL), chromosome 18 centromeric (cep18) and cep17 signals. The sSMC had only a positive cep18 signal. These findings suggested that a breakpoint occurred at 17q11.1 and another at 18q11.2 during translocation, and the sSMC originated from chromosome 18. The karyotype of the fetus was thus 47,XY,t(17;18)(q11.1;q11.2), +mar.ish der(17)t(17;18)(q11.1;q11.2)(17pTEL+,D17Z1+),der(18)t(17;18)(q11.1;q11.2)(18pTEL+ D18Z1+,D17Z1+), + der(18)(D18Z1+). Oligonucleotide-based array comparative genomic hybridization demonstrated no gain or loss of the gene dosage on chromosomes 17 and 18. CONCLUSION: Our case adds to the reported cases of sSMCs derived from the centromeric region of chromosome 18 without phenotypic consequences. PMID- 20708527 TI - Mastocytosis in pregnancy. AB - OBJECTIVE: Mastocytosis is a rare disorder characterized by abnormal accumulation of mast cells in various organs. Clinical complaints include pruritus, cutaneous flushing, dyspepsia, and episodes of anaphylaxis, and are usually the result of local and systemic mast cell mediator release. The triggers include a variety of factors including drugs, exercise, stress, anxiety, and temperature extremes. CASE REPORT: A 26-year-old primigravida at 40 weeks' gestation with urticaria pigmentosa presented to our hospital. She was diagnosed with cutaneous mastocytosis based on pathologic examination of her skin biopsy. There were no complications during pregnancy, except for cutaneous manifestations with pruritus and premature uterine contractions at 27 weeks' gestation. After admission, antihistamine agents were administered during labor to treat the above symptoms, and antibiotic agents were given for prophylaxis of chorioamnionitis. Labor pain was successfully managed with warm showers, frequent position changes and massage, and therefore, epidural analgesia was not carried out. After 6 hours of labor, the patient gave birth to a healthy female infant via normal spontaneous vaginal delivery with right mediolateral episiotomy. Neither local anesthetic agents nor antibiotic agents caused any reaction. The postpartum period was uneventful. CONCLUSION: Pregnant women with mastocytosis should be treated symptomatically and should avoid factors that may exacerbate symptoms of disease. Clinicians should be aware of preterm labor during pregnancy. As a preventive measure, resuscitation equipment should be available during the labor, delivery and postpartum period to treat unanticipated hypotension and shock. PMID- 20708528 TI - Placenta accreta following uterine artery embolization. AB - OBJECTIVE: Uterine artery embolization (UAE) is becoming a common treatment for symptomatic leiomyoma. Several pregnancies following UAE have been reported. However, reports are still limited and the risk of complications remains unknown. CASE REPORT: A primigravida conceived after UAE for leiomyoma. She delivered spontaneously at 34 weeks plus 2 days after premature rupture of the membranes. The placenta was located on the interstitial leiomyoma. The patient required manual placental extraction owing to retained placenta and subsequently underwent emergency supracervical hysterectomy for severe postpartum hemorrhage. Placenta accreta was confirmed histologically. CONCLUSION: Placenta accreta may occur during pregnancy following UAE. When the implantation site is on the leiomyoma with a hyperechoic rim, there is a high risk of abnormal placental adherence. PMID- 20708530 TI - Highly cellular leiomyoma mimics a malignant small round-cell tumor: a diagnostic dilemma on frozen sections. AB - OBJECTIVE: Cellular leiomyoma is characterized by significantly increased cellularity and may mimic malignant tumors. Our aim was to differentiate these from other malignant small round-cell tumors. CASE REPORT: We report a case of cellular leiomyoma that mimicked a malignant small round-cell tumor upon frozen section examination. CONCLUSION: Pathologists should be aware that highly cellular leiomyomas can mimic malignant tumors especially on frozen section analysis. PMID- 20708529 TI - Assisted reproductive treatment applications in men with normal phenotype but 45,X/46,XY mosaic karyotype: clinical and genetic perspectives. AB - OBJECTIVE: The 45,X/46,XY mosaic karyotype is expressed by a spectrum of genital phenotypes, ranging from normal males through to ambiguous genitalia and to normal females. CASE REPORTS: We present three cases of men with azoospermia or severe oligozoospermia, and a 45,X/46,XY mosaic karyotype and two with a Y chromosome microdeletion. Phenotypically, they appeared as normal males, with normal penis, scrotum and secondary sex characteristics. Testicular sperm extraction and aspiration were applied to patients, and couples were prepared for assisted reproductive therapy. All men with azoospermia or severe oligozoospermia were evaluated for karyotype and Y-chromosome microdeletion even if they had normal phenotypes. CONCLUSION: Possibilities for finding sperm and the biologic paternity in subjects with 45,X/46,XY karyotype should be considered. Furthermore, the increased risk for testicular neoplasia with mosaic karyotypes should be taken into consideration. PMID- 20708531 TI - Detection and comparison of cytomegalovirus DNA levels in amniotic fluid and fetal ascites in a second-trimester fetus with massive ascites, hyperechogenic bowel, ventriculomegaly and intrauterine growth restriction. AB - OBJECTIVE: To present a prenatal diagnosis of congenital cytomegalovirus (CMV) infection in a pregnancy with fetal ascites. CASE REPORT: A 33-year-old, gravida 6, para 2, woman was referred to a hospital at 20 weeks of gestation for management of fetal ascites. The woman had not experienced recent rubella or herpes simplex infections. The maternal blood group was O and Rh(D)-positive. The maternal serum thalassemia and syphilis screen results were negative. Fetal ascites was first noted at 17 weeks of gestation. At 18 weeks, she underwent amniocentesis revealing a 46,XX karyotype. At 20 weeks of gestation, maternal serum CMV IgG and CMV IgM were positive. At 21 gestational weeks, prenatal ultrasound showed fetal ascites, hyperechogenic bowel, ventriculomegaly, and intrauterine growth restriction. Repeated amniocentesis showed CMV DNA levels of 9.72 x 10(5) copies/mL and 6.03 x 10(5) copies/mL in amniocytes and amniotic fluid supernatant, respectively. Paracentesis showed CMV DNA levels of 1.64 x 10(3) copies/mL and 114 copies/mL in ascitic cells and ascitic supernatant, respectively. The pregnancy was terminated. Postnatally, CMV DNA was detected in the umbilical cord, amnion, placenta, cord blood, lungs, liver and brain by quantitative real-time polymerase chain reaction. CONCLUSION: A prenatal diagnosis of fetal ascites in association with ventriculomegaly, hyperechogenic bowel and intrauterine growth restriction should alert physicians to congenital CMV infection in addition to aneuploidy. The present case provides evidence that CMV DNA levels are higher in amniotic fluid (amniocytes and amniotic fluid supernatant) than in ascites (ascitic cells and ascitic supernatant) in cases of congenital CMV infection. PMID- 20708532 TI - Fertility preserving surgical management of methotrexate-resistant cesarean scar pregnancy. PMID- 20708533 TI - Spontaneously ruptured subcapsular liver hematoma associated with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. PMID- 20708534 TI - Parasitic leiomyosarcoma after myomectomy. PMID- 20708535 TI - A huge leiomyoma subjected to a myomectomy during a cesarean section. PMID- 20708536 TI - Bell palsy and preeclampsia superimposed on chronic hypertension. PMID- 20708537 TI - Gossypiboma mimicking an ovarian tumor in a young woman with a history of ovarian teratoma. PMID- 20708538 TI - Vertebral tumors mimicking exaggerated pregnancy symptoms--a need for careful evaluation. PMID- 20708539 TI - Apert syndrome associated with upper airway obstruction and gastroesophageal reflux inducing polyhydramnios in the third trimester. PMID- 20708540 TI - Mosaic tetrasomy 12p with discrepancy between fetal tissues and extraembryonic tissues: molecular analysis and possible mechanism of formation. PMID- 20708541 TI - Detection of balanced homologous acrocentric rearrangement rea(14q14q) and low grade X-chromosome mosaicism in a couple with repeated pregnancy losses. PMID- 20708542 TI - Fetal magnetic resonance imaging demonstration of central nervous system abnormalities and polydactyly associated with Joubert syndrome. PMID- 20708543 TI - State of the art brain tumor diagnostics, imaging, and therapeutics. Foreword. PMID- 20708544 TI - State of the art brain tumor diagnostics, imaging, and therapeutics. Preface. PMID- 20708545 TI - State-of-the-art pathology: new WHO classification, implications, and new developments. AB - To keep up with advances in central nervous system (CNS) tumor diagnosis and discovery of new entities, the classification of these tumors requires periodic review and revision. Since the initial 1979 publication from the World Health Organization (WHO) of Histological Typing of Tumours of the Central Nervous System, 3 further editions have been published, cataloging the advances in CNS tumor classification and diagnosis over the past 3 decades. In this article, we discuss select new additions to the current classification, including new diagnostic tools, differential diagnoses, and management implications. PMID- 20708546 TI - Molecular tools: biology, prognosis, and therapeutic triage. AB - Diffuse gliomas in adults continue to have a dismal prognosis with the current standard therapeutic methods, including maximal surgical resection, radiation, and chemotherapy. The pathogenesis of adult glioma is complex, involving the loss of function of tumor suppressor genes and activation of oncogenes, which are involved in a network of interconnected signaling pathways. Through activation of these pathways, characteristics of malignant gliomas, including uncontrolled proliferation and growth, invasion, and angiogenesis, are driven. Evolving therapeutic approaches are focused on specifically targeting these genetic lesions. This content gives an overview of the current knowledge about the pathogenesis of adult diffuse gliomas, emphasizing new targeted treatment approaches. PMID- 20708547 TI - Applications of nanotechnology to imaging and therapy of brain tumors. AB - In the past decade, numerous advances in the understanding of brain tumor physiology, tumor imaging, and tumor therapy have been attained. In some cases, these advances have resulted from refinements of pre-existing technologies (eg, improvements of contrast-enhanced magnetic resonance imaging). In other instances, advances have resulted from development of novel technologies. The development of nanomedicine (ie, applications of nanotechnology to the field of medicine) is an example of the latter. In this review, the authors explain the principles that underlay nanoparticle design and function as well as the means by which nanoparticles can be used for imaging and therapy of brain tumors. PMID- 20708549 TI - Advanced imaging in brain tumor surgery. AB - The advanced imaging techniques outlined in this article are only slowly establishing their place in surgical practice. Even a low risk of false information is unacceptable in neurosurgery, thus decision-making is necessarily conservative. As more validation studies and greater experience accrue, surgeons are becoming more comfortable weighing the quality of information from functional imaging studies. Advanced imaging information is highly complementary to established surgical "good practice" such as anatomic planning, awake craniotomy, and electrocortical stimulation; its greatest impact is perhaps on how neurosurgery is planned and discussed before the patient is ever brought to the operating room. Access to functional magnetic resonance (MR) imaging, diffusion tractography, and intraoperative MR imaging can influence neurosurgical decisions before, during, and after surgery. However, the widespread adoption of these techniques in neurosurgical practice remains limited by the lack of standardized methods, the need for validation across institutions, and the unclear cost effectiveness particularly for intraoperative MR imaging. Before advanced imaging results can be used therapeutically, it is incumbent on the neurosurgeon and neuroradiologist to develop a working understanding of each technique's strengths and weaknesses, positive and negative predictive values, and modes of failure. This content presents several imaging methods that are increasingly used in neurosurgical planning. As these techniques are progressively applied to surgery, radiologists, medical physicists, neuroscientists, and engineers will be necessary partners with the treating neurosurgeon to bridge the gap between the experimental and the therapeutic. PMID- 20708551 TI - Future potential of MRI-guided focused ultrasound brain surgery. AB - Magnetic resonance image-guided focused ultrasound surgery (MRgFUS) has surfaced as a viable noninvasive image-guided therapeutic method that integrates focused ultrasound (FUS), the therapeutic component, with magnetic resonance imaging (MRI), the image guidance module, into a real-time therapy delivery system with closed-loop control of energy delivery. The main applications for MRgFUS of the brain are thermal ablations for brain tumors and functional neurosurgery, and nonthermal, nonablative uses for disruption of the blood brain barrier (BBB) or blood clot and hematoma dissolution by liquification. The disruption of the BBB by FUS can be used for targeted delivery of chemotherapy and other therapeutic agents. MRI is used preoperatively for target definition and treatment planning, intraoperatively for procedure monitoring and control, and postoperatively for validating treatment success. Although challenges still remain, this integrated noninvasive therapy delivery system is anticipated to change current treatment paradigms in neurosurgery and the clinical neurosciences. PMID- 20708550 TI - Imaging of brain tumors: perfusion/permeability. AB - The use of biomarkers of microvascular structure and function from perfusion and permeability imaging is now well established in neuro-oncological research. There remain significant challenges to be overcome before these techniques and related biomarkers can find general clinical acceptance. Core to this is the standardization of acquisition and processing protocols for robust use across multiple clinical sites. The potential clinical benefits of these approaches are already becoming clear, particularly in the setting of novel antiangiogenic therapies. With an increasing body of evidence in the scientific literature, and with a steadily falling barrier to entry, the coming decade should see rapid developments in imaging biomarkers, and facilitate their transition into routine clinical practice. PMID- 20708548 TI - Imaging of brain tumors: MR spectroscopy and metabolic imaging. AB - The utility of magnetic resonance spectroscopy (MRS) in diagnosis and evaluation of treatment response to human brain tumors has been widely documented. The role of MRS in tumor classification, tumors versus nonneoplastic lesions, prediction of survival, treatment planning, monitoring of therapy, and post-therapy evaluation is discussed. This article delineates the need for standardization and further study in order for MRS to become widely used as a routine clinical tool. PMID- 20708552 TI - Liposomal contrast agents in brain tumor imaging. AB - Treatment of glioblastoma multiforme remains a major challenge despite advances in standard therapy, including surgery, radiation, and chemotherapy. The field of nanomedicine is expected to have a major impact on the treatment and management of brain tumors. Over the past decade, significant efforts have been made in using nanoparticles for diagnosis and treatment of brain tumors. One class of nanoparticles, liposomes, have received considerable attention for use as nanocarriers for delivery of therapeutics and contrast agents. The purpose of this article is to present the advances in the design and functional characteristics of liposomes for applications in brain tumor imaging. PMID- 20708553 TI - Imaging of brain tumors: functional magnetic resonance imaging and diffusion tensor imaging. AB - The eloquent brain can be identified using functional MR (fMR) imaging for the gray matter and diffusion tensor (DT) imaging for the white matter. fMR imaging and DT imaging are especially important for patients with tumors near the important motor and language centers of the brain, where the normal anatomic references may be distorted by the tumor and associated edema. This article explains fMR imaging and DT imaging techniques and illustrates their clinical applications and limitations. PMID- 20708554 TI - Radiation oncology in brain tumors: current approaches and clinical trials in progress. AB - Radiation therapy remains a critical therapeutic modality in the treatment of adult brain tumors. However, its use continues to evolve depending on the histologic findings of the brain tumor. In high-grade gliomas, current trials focus on the addition of systemic agents and optimization of target delineation to improve the therapeutic ratio of radiotherapy. In low-grade gliomas, the life expectancy is much greater, and the possibility of late effects of radiotherapy have shaped contemporary trials to attempt to identify groups that benefit from radiotherapy versus the ones that may defer radiotherapy until tumor progression. With primary central nervous system lymphoma, the advent of high-dose methotrexate-based chemotherapy and the risk of severe early neurocognitive toxicity have brought the role of radiotherapy into question. With meningioma, the use of normal tissue-sparing techniques such as radiosurgery has allowed for the successful treatment of patients who are eminently curable and with a life expectancy that is generally no different than that of the general population. Particular attention in this review is paid to current approaches, contemporary trials, and modern therapeutic dilemmas. PMID- 20708555 TI - Clinical trials in brain tumor surgery. AB - The prognosis for patients diagnosed with primary central nervous system tumors, such as gliomas, remains generally poor. Improved treatment (standard therapies and novel strategies) is needed. Glioma surgery is a key part of standard treatment and has established roles in providing tissue for diagnosis and in tumor debulking. Several techniques to increase safe surgical resection have been investigated. In addition, novel surgical modalities introducing therapeutic agents locally are increasingly common. This article reviews recent glioma surgery clinical trials, focusing on outcome studies, novel surgical techniques, and local therapeutic agent delivery. PMID- 20708556 TI - Novel medical therapeutics in glioblastomas, including targeted molecular therapies, current and future clinical trials. AB - The prognosis for glioblastoma is poor despite optimal therapy with surgery, radiation, and chemotherapy. New therapies that improve survival and quality of life are needed. Research has increased our understanding of the molecular pathways important for gliomagenesis and disease progression. Novel agents have been developed against these targets, including receptor tyrosine kinases, intracellular signaling molecules, epigenetic abnormalities, and tumor vasculature and microenvironment. This article reviews novel therapies for glioblastoma, with an emphasis on targeted agents. PMID- 20708557 TI - Voluntary school-based human papillomavirus vaccination: an efficient and acceptable model for achieving high vaccine coverage in adolescents. PMID- 20708558 TI - Fate, desire, and the centrality of the relationship to adolescent condom use. PMID- 20708559 TI - Encouraging physical activity and discouraging sedentary behavior in children and adolescents. PMID- 20708560 TI - Adolescent gambling: a review of an emerging field of research. AB - PURPOSE: The purpose of this review was to summarize the research on adolescent gambling with implications for research and prevention or intervention. METHOD: The methodology involved a comprehensive and systematic search of "adolescent or youth gambling" in three diverse electronic databases (MedlineAdvanced, PsycINFO, and Sociological Abstracts) and three peer-reviewed journals (International Journal of Gambling Studies, International Journal of Mental Health and Addiction, and Journal of Gambling Issues). RESULTS: The search resulted in 137 articles (1985-2010) focusing on gambling among youth aged between 9 and 21 years: 103 quantitative, 8 qualitative, and 26 non-empirical. The study of adolescent gambling can be summarized as follows: (a) it is conducted by a relatively small group of researchers in Britain, Canada, and the United States; (b) it is primarily prevalence-focused, quantitative, descriptive, school-based, and atheoretical; (c) it has most often been published in the Journal of Gambling Studies; (d) it is most often examined in relation to alcohol use; (e) it has relatively few valid and reliable screening instruments that are developmentally appropriate for adolescents, and (f) it lacks racially diverse samples. CONCLUSION: Four recommendations are presented for both research and prevention or intervention which are as follows: (1) to provide greater attention to the development and validation of survey instruments or diagnostic criteria to assess adolescent problem gambling; (2) to begin to develop and test more gambling prevention or intervention strategies; (3) to not only examine the co-morbidity of gambling and alcohol abuse, but also include other behaviors such as sexual activity; and (4) to pay greater attention to racial and ethnic differences in the study of adolescent gambling. PMID- 20708561 TI - Coverage and compliance of Human Papilloma Virus vaccines in Paris: demonstration of low compliance with non-school-based approaches. AB - OBJECTIVE: To evaluate the coverage and compliance of the Human Papilloma Virus (HPV) vaccine in Paris. METHODS: We selected a female population living in Paris, between the ages of 14 and 23 years (French recommendations) on December 31st, 2008, that was affiliated to social security (n = 77,744). We evaluated the dynamic of HPV vaccine dose reimbursement between July 2007 and April/May 2009 for this population. RESULTS: The coverage rate in the study population with at least one dose of the vaccine was 17%. A complete vaccination scheme (three doses) was observed in less than 43% of affiliates, whereas two doses have been reimbursed to 26% of the affiliates and only one dose to 31%. Higher rates of coverage and compliance were observed among girls between 15 and 17 years of age. CONCLUSION: Coverage and compliance rates corresponding to the French HPV vaccine program appear to be lower than those observed in countries with different recommendations and implementation strategies, and particularly school-based program. Our study suggests that health authorities should modify current recommendations. PMID- 20708562 TI - Examining future adolescent human papillomavirus vaccine uptake, with and without a school mandate. AB - PURPOSE: To develop a model of adolescent (HPV) human papillomavirus vaccine utilization that explored future HPV vaccination rates, with and without a school mandate, for the vaccine at middle school entry. METHODS: A dynamic, population based, compartmental model was developed that estimated over a 50-year time horizon HPV vaccine uptake among female adolescents living in the United States. The model incorporated data on parental attitudes about this vaccine and adolescent health care utilization levels. RESULTS: Without a mandate, our model predicted that 70% coverage, a lower threshold value used in many previous modeling studies of HPV vaccination, would not be achieved until a mean of 23 years after vaccine availability. Maximal coverage of 79% was achieved after 50 years. With a school mandate in place, utilization increased substantially, with 70% vaccination coverage achieved by year 8 and maximal vaccination coverage, 90%, achieved by year 43. CONCLUSIONS: Our results suggest that vaccine utilization is likely to be low for several years, though strong school mandates might improve HPV vaccine uptake. These results affect the interpretation of previous modeling studies that estimated the potential clinical effects of HPV vaccination under assumptions of very high vaccine utilization rates. PMID- 20708563 TI - Urban middle school parent perspectives: the vaccines they are willing to have their children receive using school-based immunization programs. AB - PURPOSE: With new vaccination recommendations for adolescents, school-based immunization programs become a valuable alternative site for immunization. This study seeks to determine factors associated with parental willingness to utilize school-based programs for immunizations. METHODS: A questionnaire was distributed to the parents of 11-14-year-olds attending 7 middle schools in a large, urban public school district. Participants were asked multiple questions including medical home enrollment, primary language spoken at home, site of last immunization, and comfort with their child receiving specific vaccines during school hours. Frequencies, chi-square analyses, and logistic regression analyses were performed using SPSS 17.0. RESULTS: A total of 615 parent questionnaires were included in the analyses; 81% of parents were Hispanic, 16% black, 39% spoke primarily English at home, and 77% indicated that they had a medical home for their child. Regarding specific vaccines, the largest percentage of parents were willing to have their child receive influenza vaccine (57%) and the smallest percentage were willing to have the human papillomavirus vaccine (27%) at school during school hours. Parents who had used a school-based clinic for their child's last immunization were more willing to receive each vaccine at school. CONCLUSIONS: This study indicates that there is significant interest and willingness among predominantly lower income, Hispanic middle school parents to have their children receive specific vaccines during school hours through school based immunization programs. More study is needed among a more diverse population of parents to help target the various needs of parents and adolescents and ultimately increase adolescent immunization rates. PMID- 20708564 TI - Condom negotiation strategies and actual condom use among Latino youth. AB - PURPOSE: To examine which condom negotiation strategies are effective in obtaining or avoiding condom use among Latino youth. METHOD: Interviews were conducted with 694 Latino youth, 61% female, aged 16-22. Participants reported on their condom negotiation strategies, perceptions of whether their sexual partner wanted to use condoms, and actual condom use. Three strategies to obtain condom use (risk information, direct verbal/nonverbal communication, insist) and four strategies to avoid condom use (emotional coercion, ignore condom use, dislike condoms, seduction) were examined. Data were analyzed using multiple linear regression, and included youth (n = 574) who reported wanting to use or avoid condoms. RESULTS: Almost 60% of participants reported wanting to use condoms, and nearly all of these used some strategy to obtain condom use. Young men who wanted to use condoms were more likely to do so, compared with young women. Risk information and direct verbal/nonverbal communication were effective strategies to obtain condom use, even among youth who perceived their sexual partners as not wanting to use condoms. Ignoring condom use was an effective condom avoidance strategy, even when youth thought their partners wanted to use condoms. Unexpectedly, young men who expressed dislike of condoms had higher rates of condom use than young men not using this condom avoidance strategy. CONCLUSIONS: This research identified condom negotiation strategies that are effective among Latino youth, even when they believe their partners do not want to use condoms. Health care providers could encourage Latino youth to use such condom negotiation strategies. PMID- 20708565 TI - Parent and family associations with weight-related behaviors and cognitions among overweight adolescents. AB - PURPOSE: To examine parent and family variables in relation to adolescent weight control and eating behaviors, body satisfaction, and importance of thinness among overweight adolescents. METHODS: This study examined parent-reported use of weight-control behaviors (i.e., healthy and unhealthy behaviors, behavioral changes, other diet strategies), parent psychosocial functioning (i.e., depression, self-esteem, body satisfaction, importance of thinness), and family functioning (i.e., cohesion and adaptability) in relation to adolescent weight control and eating behaviors, body satisfaction, and importance of thinness. Surveys were completed by 103 overweight (body mass index, >or=85th percentile) adolescents (aged 12-20 yr), and their parents. Height and weight were also measured. Linear regression equations were used for continuous outcomes and logistic regression equations for dichotomous outcomes. RESULTS: Adolescent report of lower body satisfaction and engagement in more "severe" or less healthy forms of weight-control behavior were associated with parent weight-control behaviors. Adolescent report of overeating was associated with lower scores of family cohesion and adaptability. Adolescent report of lower body satisfaction was positively associated with parent report of body satisfaction and self esteem. Adolescent report of greater importance placed on thinness was associated with parent report of lower self-esteem. CONCLUSIONS: Findings indicate that several parent and family variables are associated with weight-control behaviors, episodes of overeating, and body satisfaction and importance of thinness among overweight adolescents. Parent weight-control behaviors and adolescent cognitions about body image may be important variables to target within intervention research and treatment programs for overweight youth. PMID- 20708566 TI - Family weight talk and dieting: how much do they matter for body dissatisfaction and disordered eating behaviors in adolescent girls? AB - PURPOSE: To learn about parent weight talk, parent dieting, and family weight teasing in the homes of adolescent girls at risk for obesity and weight-related problems. To examine associations between these family variables and girls' weight status, body satisfaction, and disordered eating behaviors. METHODS: Data were collected at baseline from girls participating in a school-based intervention to prevent weight-related problems. Participants included 356 adolescent girls from 12 high schools. The girls' mean age was 15.8 years; 46% were overweight or obese; and more than 75% were racial/ethnic minorities. RESULTS: A high percentage of girls reported parent weight talk (i.e., comments about one's own weight and encouragement of daughter to diet), parent dieting, and family weight-teasing. For example, 45% of the girls reported that their mothers encouraged them to diet and 58% reported weight-teasing by family members. Weight-teasing was strongly associated with higher body mass index, body dissatisfaction, unhealthy and extreme weight control behaviors, and binge eating with loss of control in the girls. Parent weight talk, particularly by mothers, was associated with many disordered eating behaviors. Mother dieting was associated with girls' unhealthy and extreme weight control behaviors. In no instances were family weight talk and dieting variables associated with better outcomes in the girls. CONCLUSIONS: Parent weight-related comments and dieting behaviors, and family weight-teasing, may contribute to disordered eating behaviors in adolescent girls. Health care providers can help parents provide a supportive home environment by discouraging weight-based comments, which may be intended to be helpful, but can have unintentional harmful consequences. PMID- 20708567 TI - Clustering of oral and general health risk behaviors in Korean adolescents: a national representative sample. AB - PURPOSES: To investigate the distribution of modifiable oral and general health risk behaviors according to socioeconomic status and to examine the extent of clustering of risk behaviors among Korean adolescents. METHODS: Self-reported data from 71,404 adolescents were obtained using a stratified cluster sample of students in the 7th to 12th grades who participated in the Korea Youth Risk Behavior Web-based Survey. Multiple logistic regression analysis was used to determine the influence of family affluence on health behaviors and the strength of associations of general health behaviors in models for oral health behaviors. RESULTS: Adolescents of high family affluence level were more likely to frequently brush their teeth, receive preventive dental care, eat breakfast, exercise regularly and become drunk, and were less likely to frequently smoke compared with those from less affluent families. Those who brush their teeth frequently were 19% less likely to smoke, 1.26 times more likely to eat breakfast, and 1.15 times more likely to do exercise. Those who received preventive dental care during the past year were 1.1 times more likely to smoke frequently and 1.38 times more likely to experience drunkenness once or more during the past year. CONCLUSIONS: The co-occurrence of oral and general health risk behaviors among Korean adolescents and relatedness to the underlying socioeconomic environment suggest that clustering of health behaviors occurs before adulthood. Integrated efforts toward oral and general health promotion in the socioeconomic construct of the family environment may be needed to effect change in health risk behaviors among adolescents. PMID- 20708569 TI - The link between body dissatisfaction and self-esteem in adolescents: similarities across gender, age, weight status, race/ethnicity, and socioeconomic status. AB - PURPOSE: The present study examined whether the cross-sectional association between body dissatisfaction and low self-esteem varies across gender, age, body weight status, race/ethnicity, and socioeconomic status (SES). We also examined the association longitudinally. METHODS: A school-based survey of eating, weight, and related attitudes was conducted with a diverse sample of adolescents aged 11 18 years (N = 4,746). Height and weight were measured in the schools at Time 1. Participants were resurveyed through mails 5 years later (Time, 2; N = 2,516). RESULTS: The relationship between body dissatisfaction and self-esteem was strong and significant in both boys and girls (all p values < .0001), and did not differ significantly between genders (p = .16), or between the middle school and high school cohorts in either boys (p = .79) or girls (p = .80). Among girls, the relationship between body dissatisfaction and self-esteem was strong, but did vary across weight status, race/ethnicity, and SES (all p values = .0001-.03). The relationship was nonsignificant in underweight girls (p = .36), and weaker but still significant among black, Asian, and low SES group girls (all p values < .0001) in comparison to white and high SES group girls. Among boys, the association did not differ significantly across demographic groups (all p values = .18-.79). In longitudinal analyses, the strength of the association did not change significantly as adolescents grew older. CONCLUSIONS: Findings indicate that body dissatisfaction and self-esteem are strongly related among nearly all groups of adolescents. This suggests the importance of addressing body image concerns with adolescents of all backgrounds and ages. PMID- 20708568 TI - Progression through puberty in girls enrolled in a contemporary British cohort. AB - PURPOSE: Patterns of pubertal development reflect underlying endocrine function and exposures, and could affect future health outcomes. We used data from a longitudinal cohort to describe factors associated with breast and pubic hair stage and estimate average duration of puberty. METHODS: Data from the Avon Longitudinal Study of Parents and Children were used to describe timing and duration of pubertal development in girls. Self-reported Tanner stage of breast and pubic hair and menarche status were collected from ages 8-14 through mailed questionnaires. Factors associated with breast and pubic hair stage were identified using ordinal probit models. Age at entry into breast and pubic hair stages, and duration of puberty were estimated using interval-censored parametric survival analysis. RESULTS: Among the 3,938 participants, being overweight or obese, of non-white race, being the firstborn, and younger maternal age at menarche were associated with more advanced breast and pubic hair stages. Having an overweight or obese mother was associated with more advanced breast stages. Time spent in breast stages 2 and 3 was longer (1.5 years) than time spent in pubic hair stages 2 and 3 (1 year). The average age at menarche was 12.9 (95% CI, 12.8-12.9) years, and average duration of puberty (time from initiation of puberty to menarche) was 2.7 years. CONCLUSIONS: Girls in Avon Longitudinal Study of Parents and Children had a slightly longer duration of puberty compared to an earlier British cohort study. Various maternal and child characteristics were associated with breast and pubic hair stage, including both child and maternal body mass. PMID- 20708570 TI - School-based prevention of depression: a 2-year follow-up of a randomized controlled trial of the beyondblue schools research initiative. AB - PURPOSE: To investigate the effectiveness of a universal intervention designed to reduce depressive symptoms experienced by adolescents at high school. The results from annual assessments during the 3-year intervention and a 2-year follow-up are reported. METHODS: Twenty-five pairs of secondary schools matched on socio economic status were randomly assigned to either an intervention or a comparison group (n = 5,633 year 8 students, mean age = 13.1 years, SD = .5). The intervention used a comprehensive classroom curriculum program, enhancements to school climate, improvements in care pathways, and community forums. A range of measures completed by students and teachers was used to assess changes in depressive symptoms, risk and protective factors relevant to depression, and the quality of the school environment. RESULTS: Changes in the levels of depressive symptoms and in the levels of risk and protective factors experienced by students in the two groups did not differ significantly over the 5 years of the study. Statistically significant differences in the ratings of school climate across this time were found only for teacher-rated assessments. CONCLUSIONS: There was little evidence that a multicomponent universal intervention delivered over a 3 year period reduced levels of depressive symptoms among participating students. Implementing universal interventions to improve student mental health is difficult in school settings that commonly have a crowded agenda of educational and health-related programs. Successful implementation will require programs which are perceived by teachers and students as relevant to educational and learning goals, and which can be effectively delivered in conjunction with other school programs. PMID- 20708571 TI - How parents hear about human papillomavirus vaccine: implications for uptake. AB - PURPOSE: To examine correlates of human papillomavirus (HPV) vaccine awareness and information sources in a state requiring schools to inform parents about HPV vaccine. METHODS: Telephone survey of a North Carolina population-based sample of 696 parents of females aged 10-17 years about HPV vaccine awareness and information sources (daughters' schools, healthcare provider, drug company advertisements, news stories) was conducted. RESULTS: Overall, 91% of parents had heard of HPV vaccine. Parents were more likely to be aware if they had household incomes of $50,000 or higher, were women, had non-Hispanic white daughters, or had daughters vaccinated against meningitis. Information sources included drug company advertisements (64%), healthcare providers (50%), news stories (50%), and schools (9%). Only parents who heard from their children's healthcare providers were more likely to initiate HPV vaccine for their daughters. CONCLUSIONS: Parents had rarely heard of the vaccine through schools. The only source associated with vaccine initiation was hearing from a healthcare provider. PMID- 20708573 TI - Unintended pregnancy among U.S. adolescents: accounting for sexual activity. AB - Unintended pregnancy rates typically include all women in the denominator. This understates adolescent rates because many adolescents are not sexually active. When rates are recalculated including only sexually active people, adolescents aged 15-19 years have the highest rates, arguing for a continued focus on adolescents in efforts to reduce unintended pregnancy. PMID- 20708572 TI - Screen time, physical activity, and overweight in U.S. youth: national survey of children's health 2003. AB - The purpose was to examine screen-based leisure time sedentary behavior and physical activity and overweight in a national sample of children. Boys and girls who engage in low physical activity and high leisure time sedentary behavior are two times more likely to be overweight than more active, less sedentary children. PMID- 20708574 TI - Factors associated with communication-based sedentary behaviors among youth: are talking on the phone, texting, and instant messaging new sedentary behaviors to be concerned about? AB - PURPOSE: Sedentary behavior research typically only examines screen time activities and not communication time activities, such as talking on the phone, texting, or instant messaging. METHODS: Data from 2,449 grade 5 to 8 students were used to examine factors associated with the time youth spent in communication-based sedentary behaviors. RESULTS: Screen time, physical activity, grade, and gender were associated with moderate and high communication time. DISCUSSION: Future research on sedentary behavior should include measures of communication time. PMID- 20708575 TI - Functional integration of new neurons into hippocampal networks and poststroke comorbidities following neonatal stroke in mice. AB - Stroke in the developing brain is an important cause of chronic neurological morbidities including neurobehavioral dysfunction and epilepsy. Here, we describe a mouse model of neonatal stroke resulting from unilateral carotid ligation that results in acute seizures, long-term hyperactivity, spontaneous lateralized circling behavior, impaired cognitive function, and epilepsy. Exploration dependent induction of the immediate early gene Arc (activity-regulated cytoskeleton associated protein) in hippocampal neurons was examined in the general population of neurons versus neurons that were generated approximately 1 week after the ischemic insult and labeled with bromodeoxyuridine. Although Arc was inducible in a network-specific manner after severe neonatal stroke, it was impaired, not only in the ipsilateral injured but also in the contralateral uninjured hippocampi when examined 6 months after the neonatal stroke. Severity of both the stroke injury and the acquired poststroke epilepsy negatively correlated with Arc induction and new neuron integration into functional circuits in the injured hippocampi. PMID- 20708576 TI - Effect of eslicarbazepine acetate and oxcarbazepine on cognition and psychomotor function in healthy volunteers. AB - The results of two single-blind studies conducted to evaluate the cognitive and psychomotor effects of eslicarbazepine acetate and oxcarbazepine following single and repeated administration in healthy volunteers are reported. The cognitive and psychomotor evaluation consisted of several computerized and paper-and-pencil measures. Eslicarbazepine acetate and oxcarbazepine had similar overall cognitive profiles and did not cause clinically relevant cognitive impairment. The incidence of adverse events was lower with eslicarbazepine acetate than with oxcarbazepine. PMID- 20708577 TI - Remote memory deficits in epilepsy and the role of failed consolidation. PMID- 20708578 TI - Getting one's Fak straight. AB - Focal adhesion kinase (FAK) is a pivotal regulator of integrin signaling and responses to cell adhesive dynamics. In this issue of Developmental Cell, Ashton et al. demonstrate that Fak is critical for intestinal oncogenesis and regeneration after injury but not for day-to-day homeostasis, providing novel insights into intestinal biology and colorectal cancer therapy. PMID- 20708579 TI - Tuning mTORC1 activity for balanced self-renewal and differentiation. AB - Understanding the mechanisms that control stem cell self-renewal and differentiation are at the core of stem cell biology. In a recent issue of Cell, Hobbs et al. report that harnessing mTORC1 activity by the transcription factor PLZF is crucial to maintain the self-renewing activity of germline progenitors. PMID- 20708580 TI - Multiplexing MIM. AB - Signaling circuits often coordinate cellular membranes and actin filaments at distinct sites to direct cell behavior. In this issue of Developmental Cell, Bershteyn et al. outline how the molecular scaffold protein, MIM, which bends membranes and binds actin filaments, is at the middle of one such circuit to regulate ciliogenesis. PMID- 20708581 TI - On the fast track to organizer gene expression. AB - Many embryonic species are initially transcriptionally quiescent after fertilization. In this issue of Developmental Cell, Blythe et al. reveal that beta-catenin acts very early in Xenopus development to specifically modify the chromatin of organizer genes, poising them for rapid activation when transcription begins. PMID- 20708582 TI - Orienting cell-fate decisions: huntingtin joins the ranks. AB - How mitotic cell fate is regulated in the developing mammalian CNS is an important but largely unanswered question. Recently reporting in Neuron, Godin et al. showed that Huntingtin, the protein mutated in Huntington's disease, is required for both cerebral cortical neurogenesis and mitotic spindle function in neural progenitors. PMID- 20708584 TI - An early developmental role for miRNAs in the maintenance of extraembryonic stem cells in the mouse embryo. AB - The two first cell fate decisions taken in the mammalian embryo generate three distinct cell lineages: one embryonic, the epiblast, and two extraembryonic, the trophoblast and primitive endoderm. miRNAs are essential for early development, but it is not known if they are utilized in the same way in these three lineages. We find that in the pluripotent epiblast they inhibit apoptosis by blocking the expression of the proapoptotic protein Bcl2l11 (Bim) but play little role in the initiation of gastrulation. In contrast, in the trophectoderm, miRNAs maintain the trophoblast stem cell compartment by directly inhibiting expression of Cdkn1a (p21) and Cdkn1c (p57), and in the primitive endoderm, they prevent differentiation by maintaining ERK1/2 phosphorylation through blocking the expression of Mapk inhibitors. Therefore, we show that there are fundamental differences in how stem cells maintain their developmental potential in embryonic and extraembryonic tissues through miRNAs. PMID- 20708583 TI - Stretchy proteins on stretchy substrates: the important elements of integrin mediated rigidity sensing. AB - Matrix and tissue rigidity guides many cellular processes, including the differentiation of stem cells and the migration of cells in health and disease. Cells actively and transiently test rigidity using mechanisms limited by inherent physical parameters that include the strength of extracellular attachments, the pulling capacity on these attachments, and the sensitivity of the mechanotransduction system. Here, we focus on rigidity sensing mediated through the integrin family of extracellular matrix receptors and linked proteins and discuss the evidence supporting these proteins as mechanosensors. PMID- 20708585 TI - beta-Catenin primes organizer gene expression by recruiting a histone H3 arginine 8 methyltransferase, Prmt2. AB - An emerging concept in development is that transcriptional poising presets patterns of gene expression in a manner that reflects a cell's developmental potential. However, it is not known how certain loci are specified in the embryo to establish poised chromatin architecture as the developmental program unfolds. We find that, in the context of transcriptional quiescence prior to the midblastula transition in Xenopus, dorsal specification by the Wnt/beta-catenin pathway is temporally uncoupled from the onset of dorsal target gene expression, and that beta-catenin establishes poised chromatin architecture at target promoters. beta-catenin recruits the arginine methyltransferase Prmt2 to target promoters, thereby establishing asymmetrically dimethylated H3 arginine 8 (R8). Recruitment of Prmt2 to beta-catenin target genes is necessary and sufficient to establish the dorsal developmental program, indicating that Prmt2-mediated histone H3(R8) methylation plays a critical role downstream of beta-catenin in establishing poised chromatin architecture and marking key organizer genes for later expression. PMID- 20708586 TI - Condensins promote chromosome recoiling during early anaphase to complete sister chromatid separation. AB - Sister chromatid separation is initiated at anaphase onset by the activation of separase, which removes cohesins from chromosomes. However, it remains elusive how sister chromatid separation is completed along the entire chromosome length. Here we found that, during early anaphase in Saccharomyces cerevisiae, sister chromatids separate gradually from centromeres to telomeres, accompanied by regional chromosome stretching and subsequent recoiling. The stretching results from residual cohesion between sister chromatids, which prevents their immediate separation. This residual cohesion is at least partly dependent on cohesins that have escaped removal by separase at anaphase onset. Meanwhile, recoiling of a stretched chromosome region requires condensins and generates forces to remove residual cohesion. We provide evidence that condensins promote chromosome recoiling directly in vivo, which is distinct from their known function in resolving sister chromatids. Our work identifies residual sister chromatid cohesion during early anaphase and reveals condensins' roles in chromosome recoiling, which eliminates residual cohesion to complete sister chromatid separation. PMID- 20708587 TI - CLASP promotes microtubule rescue by recruiting tubulin dimers to the microtubule. AB - Spatial regulation of microtubule (MT) dynamics contributes to cell polarity and cell division. MT rescue, in which a MT stops shrinking and reinitiates growth, is the least understood aspect of MT dynamics. Cytoplasmic Linker Associated Proteins (CLASPs) are a conserved class of MT-associated proteins that contribute to MT stabilization and rescue in vivo. We show here that the Schizosaccharomyces pombe CLASP, Cls1p, is a homodimer that binds an alphabeta-tubulin heterodimer through conserved TOG-like domains. In vitro, CLASP increases MT rescue frequency, decreases MT catastrophe frequency, and moderately decreases MT disassembly rate. CLASP binds stably to the MT lattice, recruits tubulin, and locally promotes rescues. Mutations in the CLASP TOG domains demonstrate that tubulin binding is critical for its rescue activity. We propose a mechanism for rescue in which CLASP-tubulin dimer complexes bind along the MT lattice and reverse MT depolymerization with their bound tubulin dimer. PMID- 20708588 TI - Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. AB - The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer. PMID- 20708590 TI - The cytokinin-activated transcription factor ARR2 promotes plant immunity via TGA3/NPR1-dependent salicylic acid signaling in Arabidopsis. AB - Cytokinins affect plant immunity to various pathogens; however, the mechanisms coupling plant-derived cytokinins to pathogen responses have been elusive. Here, we found that plant-derived cytokinins promote resistance of Arabidopsis to Pseudomonas syringae pv. tomato DC3000 (Pst). Modulated cytokinin levels or signaling activity in CKX- or IPT-overexpressing plants or in ahk2 ahk3 mutants correlated with altered resistance. In fact, the cytokinin-activated transcription factor ARR2 contributes specifically to Pst resistance. The salicylic acid (SA) response factor TGA3 binds ARR2, and mutation of TGA-binding cis-elements in the Pr1 promoter abolished cytokinin- and ARR2-dependent Pr1 activation. Cytokinin treatment did not increase pathogen resistance in tga3 plants, as the cytokinin-dependent induction of Pr1 was eliminated. Moreover, SA signaling enhanced binding of ARR2/TGA3 to the Pr1 promoter. Taken together, these results show that cytokinins modulate the SA signaling to augment resistance against Pst, a process in which the interaction between TGA3 and ARR2 is important. PMID- 20708589 TI - MIM and cortactin antagonism regulates ciliogenesis and hedgehog signaling. AB - The primary cilium is critical for transducing Sonic hedgehog (Shh) signaling, but the mechanisms of its transient assembly are poorly understood. Previously we showed that the actin regulatory protein Missing-in-Metastasis (MIM) regulates Shh signaling, but the nature of MIM's role was unknown. Here we show that MIM is required at the basal body of mesenchymal cells for cilia maintenance, Shh responsiveness, and de novo hair follicle formation. MIM knockdown results in increased Src kinase activity and subsequent hyperphosphorylation of the actin regulator Cortactin. Importantly, inhibition of Src or depletion of Cortactin compensates for the cilia defect in MIM knockdown cells, whereas overexpression of Src or phospho-mimetic Cortactin is sufficient to inhibit ciliogenesis. Our results suggest that MIM promotes ciliogenesis by antagonizing Src-dependent phosphorylation of Cortactin and describe a mechanism linking regulation of the actin cytoskeleton with ciliogenesis and Shh signaling during tissue regeneration. PMID- 20708591 TI - Hemocyte-secreted type IV collagen enhances BMP signaling to guide renal tubule morphogenesis in Drosophila. AB - Details of the mechanisms that determine the shape and positioning of organs in the body cavity remain largely obscure. We show that stereotypic positioning of outgrowing Drosophila renal tubules depends on signaling in a subset of tubule cells and results from enhanced sensitivity to guidance signals by targeted matrix deposition. VEGF/PDGF ligands from the tubules attract hemocytes, which secrete components of the basement membrane to ensheath them. Collagen IV sensitizes tubule cells to localized BMP guidance cues. Signaling results in pathway activation in a subset of tubule cells that lead outgrowth through the body cavity. Failure of hemocyte migration, loss of collagen IV, or abrogation of BMP signaling results in tubule misrouting and defective organ shape and positioning. Such regulated interplay between cell-cell and cell-matrix interactions is likely to have wide relevance in organogenesis and congenital disease. PMID- 20708592 TI - BMP signals promote proepicardial protrusion necessary for recruitment of coronary vessel and epicardial progenitors to the heart. AB - The coronary vessels and epicardium arise from an extracardiac rudiment called the proepicardium. Failed fusion of the proepicardium to the heart results in severe coronary and heart defects. However, it is unknown how the proepicardium protrudes toward and attaches to the looping heart tube. Here, we show that ectopic expression of BMP ligands in the embryonic myocardium can cause proepicardial cells to target aberrant regions of the heart. Additionally, misexpression of a BMP antagonist, Noggin, suppresses proepicardium protrusion and contact with the heart. Finally, proepicardium explant preferentially expands toward a cocultured heart segment. This preference can be mimicked by BMP2/4 and suppressed by Noggin. These results support a model in which myocardium-derived BMP signals regulate the entry of coronary progenitors to the specific site of the heart by directing their morphogenetic movement. PMID- 20708593 TI - Downstream of identity genes: muscle-type-specific regulation of the fusion process. AB - In all metazoan organisms, the diversification of cell types involves determination of cell fates and subsequent execution of specific differentiation programs. During Drosophila myogenesis, identity genes specify the fates of founder myoblasts, from which derive all individual larval muscles. Here, to understand how cell fate information residing within founders is translated during differentiation, we focus on three identity genes, eve, lb, and slou, and how they control the size of individual muscles by regulating the number of fusion events. They achieve this by setting expression levels of Mp20, Pax, and mspo, three genes that regulate actin dynamics and cell adhesion and, as we show here, modulate the fusion process in a muscle-specific manner. Thus, these data show how the identity information implemented by transcription factors is translated via target genes into cell-type-specific programs of differentiation. PMID- 20708594 TI - Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. AB - During endochondral bone development, the first osteoblasts differentiate in the perichondrium surrounding avascular cartilaginous rudiments; the source of trabecular osteoblasts inside the later bone is, however, unknown. Here, we generated tamoxifen-inducible transgenic mice bred to Rosa26R-LacZ reporter mice to follow the fates of stage-selective subsets of osteoblast lineage cells. Pulse chase studies showed that osterix-expressing osteoblast precursors, labeled in the perichondrium prior to vascular invasion of the cartilage, give rise to trabecular osteoblasts, osteocytes, and stromal cells inside the developing bone. Throughout the translocation, some precursors were found to intimately associate with invading blood vessels, in pericyte-like fashion. A similar coinvasion occurs during endochondral healing of bone fractures. In contrast, perichondrial mature osteoblasts did not exhibit perivascular localization and remained in the outer cortex of developing bones. These findings reveal the specific involvement of immature osteoblast precursors in the coupled vascular and osteogenic transformation essential to endochondral bone development and repair. PMID- 20708596 TI - A protein phosphorylation-based assay for screening and monitoring of drugs modulating cyclic nucleotide pathways. AB - Cyclic nucleotide regulation is an important target for drug development, particularly for treatment and prophylaxis of cardiovascular diseases. Determination of cyclic nucleotide levels for screening and monitoring of cyclic nucleotide modulating drug action is necessary, yet the techniques available are cumbersome and not sufficiently accurate. Here we present an approach based on the detection of cyclic nucleotide-dependent protein phosphorylation. By use of a common substrate of cyclic nucleotide-dependent protein kinases, the protein vasodilator-stimulated phosphoprotein (VASP) featuring two phosphorylation sites specifically phosphorylated by these kinases, an assay was developed for the monitoring of intracellular cyclic nucleotide levels. The assay was tested with human platelets ex vivo treated with stimulants of nucleotide cyclases, kinases, and phosphodiesterase inhibitors. Phosphorylation of the protein VASP correlates with intracellular cyclic nucleotide concentration (R(2)>0.90 for cGMP and cAMP); however, VASP phosphorylation is more sensitive to elevated cyclic nucleotide levels and significantly more stable over time. Quantification of VASP phosphorylation offers a reliable and robust tool for fast and easy monitoring of cyclic nucleotide levels and is also applicable to unprocessed biological matrices. Owing to these properties, VASP is a promising biomarker for screening and monitoring of cyclic nucleotide modulating drugs. PMID- 20708595 TI - ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling. AB - The cranial neural crest (CNC) consists of multipotent embryonic cells that contribute to craniofacial structures and other cells and tissues of the vertebrate head. During embryogenesis, CNC is induced at the neural plate boundary through the interplay of several major signaling pathways. Here, we report that the metalloproteinase activity of ADAM13 is required for early induction of CNC in Xenopus. In both cultured cells and X. tropicalis embryos, membrane-bound Ephrins (Efns) B1 and B2 were identified as substrates for ADAM13. ADAM13 upregulates canonical Wnt signaling and early expression of the transcription factor snail2, whereas EfnB1 inhibits the canonical Wnt pathway and snail2 expression. We propose that by cleaving class B Efns, ADAM13 promotes canonical Wnt signaling and early CNC induction. PMID- 20708597 TI - ORF8a of SARS-CoV forms an ion channel: experiments and molecular dynamics simulations. AB - ORF8a protein is 39 residues long and contains a single transmembrane domain. The protein is synthesized using solid phase peptide synthesis and reconstituted into artificial lipid bilayers that forms cation-selective ion channels with a main conductance level of 8.9+/-0.8pS at elevated temperature (38.5 degrees C). Computational modeling studies including multi nanosecond molecular dynamics simulations in a hydrated POPC lipid bilayer are done with a 22 amino acid transmembrane helix to predict a putative homooligomeric helical bundle model. A structural model of a pentameric bundle is proposed with cysteines, serines and threonines facing the pore. PMID- 20708599 TI - Structural and functional views of salt-bridge interactions of lambda integrase in the higher order recombinogenic complexes visualized by genetic method. AB - The integrase protein encoded by bacteriophage lambda (Int) catalyzes site a specific DNA recombination by which the viral chromosome is inserted into and excised out of the host genome through the formation of higher order recombinogenic nucleoprotein complexes. Genetic and biochemical studies on the Int carried out by isolating "multimer-specific" mutants had revealed informative functional characteristics of specific electrostatic interactions occurring among the functional domains of Int. The lambda Int recombination system shows the usefulness of structural and functional investigation of multimeric protein complexes through genetic studies on the electrostatic interactions of proteins comprising multimeric complexes. This approach is especially powerful when combined with NMR and X-ray crystallography results providing biological evidences of specific molecular interactions among proteins. PMID- 20708598 TI - Characterization of superoxide overproduction by the D-Loop(Nox4)-Nox2 cytochrome b(558) in phagocytes-Differential sensitivity to calcium and phosphorylation events. AB - NADPH oxidase is a crucial element of phagocytes involved in microbicidal mechanisms. It becomes active when membrane-bound cytochrome b(558), the redox core, is assembled with cytosolic p47(phox), p67(phox), p40(phox), and rac proteins to produce superoxide, the precursor for generation of toxic reactive oxygen species. In a previous study, we demonstrated that the potential second intracellular loop of Nox2 was essential to maintaining NADPH oxidase activity by controlling electron transfer from FAD to O(2). Moreover, replacement of this loop by the Nox4-D-loop (D-loop(Nox4)-Nox2) in PLB-985 cells induced superoxide overproduction. In the present investigation, we demonstrated that both soluble and particulate stimuli were able to induce this superoxide overproduction. Superoxide overproduction was also observed after phosphatidic acid activation in a purified cell-free-system assay. The highest oxidase activity was obtained after ionomycin and fMLF stimulation. In addition, enhanced sensitivity to Ca(2+) influx was shown by thapsigargin, EDTA, or BTP2 treatment before fMLF activation. Mutated cytochrome b(558) was less dependent on phosphorylation triggered by ERK1/2 during fMLF or PMA stimulation and by PI3K during OpZ stimulation. The superoxide overproduction of the D-loop(Nox4)-Nox2 mutant may come from a change of responsiveness to intracellular Ca(2+) level and to phosphorylation events during oxidase activation. Finally the D-loop(Nox4)-Nox2-PLB-985 cells were more effective against an attenuated strain of Pseudomonas aeruginosa compared to WT Nox2 cells. The killing mechanism was biphasic, an early step of ROS production that was directly bactericidal, and a second oxidase-independent step related to the amount of ROS produced in the first step. PMID- 20708600 TI - Hormone-sensitive lipase is critical mediators of acute exercise-induced regulation of lipolysis in rat adipocytes. AB - The purpose of the present study was to investigate the effect of acute exercise on lipolysis via coordination of hormone-sensitive lipase (HSL) and scaffold proteins, i.e., perilipin A and comparative gene identification-58 (CGI-58), in rat primary adipocytes. Glycerol release was significantly elevated immediately (0h) and three hours (3h) after exercise. Both activity and localization to the pellet of HSL were significantly greater in the pellet fraction, which is included in lipid droplet associated-proteins, than in the supernatant fraction. In the pellet fraction, although neither perilipin A nor CGI-58 protein level changed, level of perilipin A/CGI-58 complex was significantly reduced, accompanied by up-regulated association of perilipin A/HSL at 0h and 3h after exercise. On the other hand, there were no changes in these molecules at 24h after exercise, despite a significant decrease in lipolysis that was observed in response to isoproterenol. These findings suggest that acute exercise enhances lipolysis up to at least 3h after exercise in a manner dependent on modification of HSL and its association with and alteration in scaffold protein. PMID- 20708601 TI - Protective effect of resolvin E1 on the development of asthmatic airway inflammation. AB - Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from the omega 3 fatty acid eicosapentaenoic acid (EPA), and strongly acts in the resolution of inflammation. We previously reported that RvE1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma. In the present study, to elucidate the effects of RvE1 on the development of asthmatic airway inflammation, we investigated whether RvE1 acts on different phases of an OVA sensitized and -challenged mouse model of asthma. RvE1 treatments at the time of either OVA sensitization or at the time of OVA challenge were investigated and compared with RvE1 treatments at the time of both OVA sensitization and challenge. After RvE1 was administered to mice intraperitoneally at the time of both OVA sensitization and challenge, there were decreases in airway eosinophil and lymphocyte recruitment, as well as a reduction in Th2 cytokine and airway hyperresponsiveness. RvE1 treatment at the time of either OVA sensitization or challenge also improved AHR and airway inflammation. Our results suggest that RvE1 acts on several phases of asthmatic inflammation and may have anti inflammatory effects on various cell types. PMID- 20708602 TI - AMP-activated protein kinase positively regulates FGF-2-stimulated VEGF synthesis in osteoblasts. AB - AMP-activated protein kinase (AMPK) is recognized as a regulator of energy homeostasis. We have previously reported that basic fibroblast growth factor (FGF 2) stimulates vascular endothelial growth factor (VEGF) release through the activation of p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of AMPK in FGF-2 stimulated VEGF release in these cells. FGF-2 time-dependently induced the phosphorylation of AMPK alpha-subunit (Thr-172). Compound C, an AMPK inhibitor, which suppressed the FGF-2-induced phosphorylation of AMPK, significantly inhibited the VEGF release stimulated by FGF-2. The AMPK inhibitor also reduced the mRNA expression of VEGF induced by FGF-2. The FGF-2-induced phosphorylation of both p44/p42 MAP kinase and SAPK/JNK was attenuated by compound C. These results strongly suggest that AMPK positively regulates the FGF-2-stimulated VEGF synthesis via p44/p42 MAP kinase and SAPK/JNK in osteoblasts. PMID- 20708603 TI - miR-27 promotes osteoblast differentiation by modulating Wnt signaling. AB - Canonical Wnt signaling is particularly important for differentiation of human mesenchymal stem cells into osteoblast. MicroRNAs (miRNAs) also play an essential role in regulating cell differentiation. However, the role of miRNAs in osteoblast differentiation remains poorly understood. Here we found that the expression of miR-27 was increased during hFOB1.19 cells differentiation. Moreover, ectopic expression of miR-27 promoted hFOB1.19 cells differentiation, whereas its repression was sufficient to inhibit cell differentiation. Western blot analysis showed that the expression level of miR-27 was positively correlated with that of beta-catenin, a key protein in Wnt signaling. Further, we verified that miR-27 directly targeted and inhibited adenomatous polyposis coli (APC) gene expression, and activated Wnt signaling through accumulation of beta catenin. This study suggests miR-27 is an important mediator of osteoblast differentiation, thus offering a new target for the development of preventive or therapeutic agents against osteogenic disorders. PMID- 20708604 TI - Efficiently differentiating vascular endothelial cells from adipose tissue derived mesenchymal stem cells in serum-free culture. AB - Adipose tissue-derived mesenchymal stem cells (ASCs) have been reported to be multipotent and to differentiate into various cell types, including osteocytes, adipocytes, chondrocytes, and neural cells. Recently, many authors have reported that ASCs are also able to differentiate into vascular endothelial cells (VECs) in vitro. However, these reports included the use of medium containing fetal bovine serum for endothelial differentiation. In the present study, we have developed a novel method for differentiating mouse ASCs into VECs under serum free conditions. After the differentiation culture, over 80% of the cells expressed vascular endothelial-specific marker proteins and could take up low density lipoprotein in vitro. This protocol should be helpful in clarifying the mechanisms of ASC differentiation into the VSC lineage. PMID- 20708605 TI - Activation of alpha7 nicotinic receptor affects APP processing by regulating secretase activity in SH-EP1-alpha7 nAChR-hAPP695 cells. AB - Multiple lines of evidence have implicated that nicotinic acetylcholine receptor (nAChR) may be an important therapeutic target for the treatment of Alzheimer's disease (AD). Although there are reports suggesting a link between alpha7 nAChR subtype and AD, there has been little report on the mechanism. The present study investigates whether and how alpha7 nAChR activation affects APP695 processing in SH-EP1 cell model. Cell line co-expressing alpha7 nAChR gene and human amyloid precursor protein 695 (hAPP695) gene were constructed by stable transfection. Expression of beta-amyloid, alpha-form of secreted APP (alphaAPPs) and APP1695 was measured by ELISA, western blotting and real-time PCR respectively. Additionally, alpha, beta, and gamma-secretase activities were also analyzed in constructed SH-EP1-alpha7 nAChR-hAPP695 cell line. The results showed that SH-EP1 alpha7 nAChR-hAPP695 cell line, expressing both hAPP695 gene and alpha7 nAChR subtype gene, was constructed successfully. The secreted Abeta was decreased and alphaAPPs was significantly increased by non-selective nAChR agonist nicotine (10 MUM) and specific alpha7 nAChR agonist GTS-21 (1 MUM), and APP expression was not affected. Furthermore, specific alpha7 nAChR antagonist methyllycaconitine (MLA) reversed the alterations induced by activation of alpha7 nAChR. CTF-alpha was increased and CTF-gamma was decreased when treated with nicotine (10 MUM). In addition, the results of enymatic activity analysis showed that nicotine (1MUM) and GTS-21 (0.1, 1 MUM) decreased gamma-secretase activity, but has no effects on alpha-secretase activity and beta-secretase activity. Our findings demonstrate that, through regulating gamma-secretase activity, alpha7 nAChR activation reduces APP processing in amyloidogenic pathway, and at the same time enhances APP processing in non-amyloidogenic pathway. The constructed SH-EP1-alpha7 nAChR hAPP695 cell line might be useful for screening specific nAChR agonists against AD. PMID- 20708606 TI - Neuroprotective effect of baicalin on compression spinal cord injury in rats. AB - The current study was performed to investigate the effect of baicalin (BC) on spinal cord injury (SCI) in rat. BC (10, 30 and 100mg/kg, i.p., respectively) was administered to rats immediately and every 24h following SCI. The BC therapy (100mg/kg) dramatically decreased (1) the water content of spinal cord tissue (by dry-wet weight method), (2) the permeability of blood-spinal cord barrier (measured by Evans blue), (3) oxidant stress (malondialdehyde values and glutathione levels evaluation), (4) proinflammatory cytokines expression (tumor necrosis factor-alpha and NF-kappaB) (5) and apoptosis (measured by Bax, Bcl-2 and Caspase-3 expression). And the treatment with BC also significantly improved the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly indicate that BC possesses potent anti-inflammatory and anti-apoptotic properties, attenuates the SCI and is a new promising therapeutic agent for human SCI in the future. PMID- 20708607 TI - Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells. AB - Oxaliplatin, a platinum derivative cancer drug, has been used for treating human colorectal cancers. Survivin has been proposed as a cancer target, which highly expressed in most cancer cells but not normal adult cells. In this study, we investigated the regulation of survivin expression by exposure to oxaliplatin in human colon cancer cells. Oxaliplatin (3-9MUM for 24h) markedly induced cytotoxicity, proliferation inhibition and apoptosis in the human RKO colon cancer cells. The survivin protein expression of RKO cells is dramatically reduced by oxaliplatin; however, the survivin gene expression is slightly altered. The survivin blockage of oxaliplatin elevated caspase-3 activation and apoptosis in RKO cells. Over-expression of survivin proteins by transfection with a survivin-expressed vector resisted the oxaliplatin-induced cancer cell death. Meantime, oxaliplatin elicited the phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB202190, a specific p38 MAP kinase inhibitor, restored the survivin protein level and attenuated oxaliplatin-induced cancer cell death. In addition, oxaliplatin increased the levels of phospho-p53 (Ser-15) and total p53 proteins. Inhibition of p53 expression by a specific p53 inhibitor pifithrin alpha reduced the phosphorylated p38 MAP kinase and active caspase-3 proteins in the oxaliplatin-exposed RKO cells. In contrast, SB202190 did not alter the oxaliplatin-induced p53 protein level. Furthermore, treatment with a specific proteasome inhibitor MG132 restored survivin protein level in the oxaliplatin treated colon cancer cells. Taken together, our results demonstrate for the first time that survivin is down-regulated by p38 MAP kinase and proteasome degradation pathway after treatment with oxaliplatin in the human colon cancer cells. PMID- 20708608 TI - Autoantibodies to cardiac troponin in acute coronary syndromes. AB - BACKGROUNDS: In a recent small study, patients with autoantibodies to cardiac troponin (cTnaAb) had higher cardiac troponin I (cTnI) release during an episode of acute coronary syndrome (ACS) than patients without cTnaAb and continued to have higher long-term levels of cTnI. However, the prognostic importance of the occurrence of cTnaAb is unknown. METHODS: In 957 nonST-elevation ACS patients cTnaAb and cTnI were analyzed at randomization and after 6 months. Outcomes were assessed through 5 years. RESULTS: Seven and 11% of the patients were cTnaAb positive at inclusion and 6months, respectively. The cardiac troponin I (cTnI) concentration at inclusion was independently associated with the development of cTnaAb (OR 1.53, 95% CI 1.25-1.88). The presence of cTnaAb was associated with an increased cTnI level at 6 months (OR 2.39, 95% CI 1.50-3.81). cTnaAb was not independently associated with death and AMI during follow-up (HR 0.97, 95% CI 0.61-1.54). CONCLUSION: Development of cTnaAb after an episode of nonST-elevation ACS is associated with the acute myocardial damage, but occurs only in a minority of patients. Furthermore, the presence of cTnaAb is associated with chronically elevated cTnI concentrations. However, the occurrence of cTnaAb is not associated with an adverse long-term prognosis. PMID- 20708609 TI - A sensitive assay to measure biomarker glycosylation demonstrates increased fucosylation of prostate specific antigen (PSA) in patients with prostate cancer compared with benign prostatic hyperplasia. AB - BACKGROUND: Prostate specific antigen (PSA) measurement is used for the diagnosis of prostate cancer (PCa) but the test lacks specificity due to the number of false positive readings. The glycosylation of PSA is altered in PCa but studies in this area have been limited to few clinical samples and/or require advanced laboratory facilities. An assay to assess PSA glycosylation was established using equipment available in most routine biomedical testing laboratories. METHODS: Serum samples from patients with PCa or benign prostatic hyperplasia (BPH) were used. PSA (range 4-10 ng/ml) was affinity purified, separated and probed with the lectin Ulex europaeus (UEA-1; specific for alpha1,2 linked fucose). An enzyme linked immunosorbent lectin assay (ELLA) with colorimetric detection was devised and PSA fucosylation assessed in a further independent set of 26 samples. RESULTS: Free PSA (fPSA) from PCa patients showed a significant increase in fucosylation compared with fPSA from patients with BPH. The ELLA was 92% specific and 69% sensitive for PCa over BPH. In comparison, fPSA measurement was 70% specific and 56% sensitive (threshold set to 25% tPSA) for PCa over BPH. CONCLUSIONS: Changes in glycosylation of PSA were identified using 50 MUl of serum with PSA in the range of 4-10 ng/ml, this represents a more specific and sensitive test for PCa based on fucosylation changes of fPSA. PMID- 20708610 TI - CD62L on neutrophil granulocytes, a useful, complementary marker for the prediction of ventriculitis in blood-containing CSF. AB - OBJECTIVES: Presence of residual blood is a common problem in cerebrospinal fluid (CSF) diagnostics of ventriculitis. We hypothesised that neutrophil granulocytes in infected, blood-containing CSF lose CD62L expression. Therefore CD62L expression on neutrophils may present a complementary marker to distinguish between patients with residual blood and infection. DESIGNS AND METHODS: Evaluation was performed in 64 ventricular CSF samples sent to the laboratory for diagnostic investigation. Cell count, microbiological culture, total protein and flow cytometric analysis of CSF were performed. RESULTS: Cell counts and CD62L expression were significantly different between the culture positive and negative group. ROC-analysis revealed a significant predictive value for cell count and CD62L expression. Optimal cut-offs were calculated and a decision tree was established to predict a positive culture. CONCLUSIONS: Cell count and CD62L expression were predictive for a positive culture and the combination helped to increase specificity and sensitivity for the detection of ventriculitis in blood containing CSF. PMID- 20708611 TI - The pathogenic role of transforming growth factor-beta2 in glaucomatous damage to the optic nerve head. AB - In patients with primary open angle glaucoma (POAG), the optic nerve head (ONH) shows characteristic cupping correlated with visual field defects. The progressive optic neuropathy is characterized by irreversible loss of retinal ganglion cells (RGC). The critical risk factor for axonal damage at the ONH is an elevated intraocular pressure (IOP). The increase in IOP correlates with axonal loss in the ONH, which might be due to an impaired axoplasmatic flow leading to the loss of RGCs. Damage to the optic nerve is thought to occur in the lamina cribrosa (LC) region of the ONH, which is composed of characteristic sieve-like connective tissue cribriform plates through which RGC axons exit the eye. The cupping of the optic disc, and the compression and excavation of LC are characteristic signs of glaucomatous ONH remodelling. In ONH of POAG patients a disorganized distribution and deposition of elastic fibers and a typical pronounced thickening of the connective tissue septae surrounding the optic nerve fibers is found. Transforming growth factor (TGF)-beta2 could be one of the pathogenic factors responsible for the structural alterations in POAG patients as the TGF-beta2 levels in the ONH of glaucomatous eyes are elevated as well as in the aqueous homour. TGF-beta2 leads to an increased synthesis of extracellular matrix (ECM) molecules mediated by connective tissue growth factor and to an impaired ECM degradation in cultured ONH astrocytes. Bone morphogenetic protein (BMP)-4 effectively antagonizes the effects of TGF-beta2 on matrix deposition. The BMP antagonist gremlin blocks this inhibition, allowing TGF-beta2 stimulation of ECM synthesis. Overall, the ECM in the ONH is kept in balance in the OHN by factors that augment or block the activity of TGF-beta2. PMID- 20708612 TI - DJ-1, an oncogene and causative gene for familial Parkinson's disease, is essential for SV40 transformation in mouse fibroblasts through up-regulation of c Myc. AB - Simian virus 40 (SV40) is a tumor virus and its early gene product large T antigen (LT) is responsible for the transforming activity of SV40. Parkinson's disease causative gene DJ-1 is also a ras-dependent oncogene, but the mechanism of its oncogene function is still not known. In this study, we found that there were no transformed foci when fibroblasts from DJ-1-knockout mice were transfected with LT. We also found that DJ-1 directly bound to LT and that the expression level of c-Myc in transformed cells was parallel to that of DJ-1. These findings indicate that DJ-1 is essential for SV40 transformation. PMID- 20708613 TI - Current inhibition of human EAG1 potassium channels by the Ca2+ binding protein S100B. AB - Voltage-dependent human ether a go-go (hEAG1) potassium channels are implicated in neuronal signaling as well as in cancer cell proliferation. Unique sensitivity of the channel to intracellular Ca(2+) is mediated by calmodulin (CaM) binding to the intracellular N- and C-termini of the channel. Here we show that application of the acidic calcium-binding protein S100B to inside-out patches of Xenopus oocytes causes Ca(2+)-dependent inhibition of expressed hEAG1 channels. Protein pull-down assays and fluorescence correlation spectroscopy (FCS) revealed that S100B binds to hEAG1 and shares the same binding sites with CaM. Thus, S100B is a potential alternative calcium sensor for hEAG1 potassium channels. PMID- 20708614 TI - Insights into the genomic features and evolutionary impact of the genes configuring duplicated pseudogenes in human. AB - Pseudogenes, regarded as 'genomic fossils', are DNA sequences resembling functional genes in perspective of sequence homology but completely non functional. In this study, we explored the unique characteristic features of human genes, configuring classical duplicated pseudogenes. We found that progenitors of duplicated pseudogenes are characterized by a high expressivity, and ability to encode hub-proteins in association with a high evolutionary rate. Such unusual features are endorsed by longer protein length, elevated CpG content, and a high recombination rate. The non-functionalization of their duplicated copies can be attributed to the overabundance of gene paralog number in concert with functional redundancy. PMID- 20708615 TI - The double mutation DeltaL6MW241F in PsbO, the photosystem II manganese stabilizing protein, yields insights into the evolution of its structure and function. AB - The W241F mutation in spinach manganese-stabilizing protein (PsbO) decreases binding to photosystem II (PSII); its thermostability is increased and reconstituted activity is lower [Wyman et al. (2008) Biochemistry 47, 6490-6498]. The results reported here show that W241F cannot adopt a normal solution structure and fails to reconstitute efficient Cl(-) retention by PSII. An N terminal truncation of W241F, producing the DeltaL6MW241F double mutant that resembles some features of cyanobacterial PsbO, significantly repairs the defects in W241F. Our data suggest that the C-terminal F->W mutation likely evolved in higher plants and green algae in order to preserve proper PsbO folding and PSII binding and assembly, which promotes efficient Cl(-) retention in the oxygen evolving complex. PMID- 20708616 TI - TFF2 mRNA transcript expression marks a gland progenitor cell of the gastric oxyntic mucosa. AB - BACKGROUND & AIMS: Gastric stem cells are located in the isthmus of the gastric glands and give rise to epithelial progenitors that undergo bipolar migration and differentiation into pit and oxyntic lineages. Although gastric mucus neck cells located below the isthmus express trefoil factor family 2 (TFF2) protein, TFF2 messenger RNA transcripts are concentrated in cells above the neck region in normal corpus mucosa, suggesting that TFF2 transcription is a marker of gastric progenitor cells. METHODS: Using a BAC strategy, we generated a transgenic mouse with a tamoxifen-inducible Cre under the control of the TFF2 promoter (TFF2-BAC Cre(ERT2)) and analyzed the lineage derivation from TFF2 mRNA transcript expressing (TTE) cells. RESULTS: TTE cells were localized to the isthmus, above and distinct from TFF2 protein-expressing mucus neck cells. Lineage tracing revealed that these cells migrated toward the bottom of the gland within 20 days, giving rise to parietal, mucous neck, and chief cells, but not to enterochromaffin-like-cell. Surface mucus cells were not derived from TTE cells and the progeny of the TTE lineage did not survive beyond 200 days. TTE cells were localized in the isthmus adjacent to doublecortin CaM kinase-like-1(+) putative progenitor cells. Induction of spasmolytic polypeptide-expressing metaplasia with DMP-777-induced acute parietal cell loss revealed that this metaplastic phenotype might arise in part through transdifferentiation of chief cells as opposed to expansion of mucus neck or progenitor cells. CONCLUSIONS: TFF2 transcript-expressing cells are progenitors for mucus neck, parietal and zymogenic, but not for pit or enterochromaffin-like cell lineages in the oxyntic gastric mucosa. PMID- 20708617 TI - Variants in IL28B in liver recipients and donors correlate with response to peg interferon and ribavirin therapy for recurrent hepatitis C. AB - BACKGROUND & AIMS: Patients with hepatitis C virus (HCV)-related liver disease frequently undergo orthotopic liver transplantation, but recurrent hepatitis C is still a major cause of morbidity. Patients are treated with peg-interferon and ribavirin (PEG-IFN/RBV), which has substantial side effects and is costly. We investigated genetic factors of host, liver donor, and virus that might predict sensitivity of patients with recurrent hepatitis C to PEG-IFN/RBV. METHODS: Liver samples were analyzed from 67 HCV-infected recipients and 41 liver donors. Liver recipient and donor DNA samples were screened for single nucleotide polymorphisms near the IL28B genes (rs12980275 and rs8099917) that affect sensitivity to PEG IFN/RBV. HCV RNA was isolated from patients and analyzed for mutations in the core, the IFN sensitivity-determining region, and IFN/RBV resistance-determining regions in nonstructural protein 5A. RESULTS: In liver recipients and donors, the IL28B single nucleotide polymorphism rs8099917 was significantly associated with a sustained viral response (SVR; P = 0.003 and P = .025, respectively). Intrahepatic expression of IL28 messenger RNA was significantly lower in recipients and donors that carried the minor alleles (T/G or T/T) in rs8099917 (P = .010 and .009, respectively). Genetic analyses of IL28B in patients and donors and of the core and nonstructural protein 5A regions encoded by HCV RNA predicted an SVR with 83% sensitivity and 82% specificity; this was more effective than analysis of any single genetic feature. CONCLUSIONS: In patients with recurrent HCV infection after orthotopic liver transplantation, combination analyses of single nucleotide polymorphisms of IL28B in recipient and donor tissues and mutations in HCV RNA allow prediction of SVR to PEG-IFN/RBV therapy. PMID- 20708618 TI - Microsatellite alterations at selected tetranucleotide repeats are associated with morphologies of colorectal neoplasias. AB - BACKGROUND & AIMS: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) occurs during microsatellite instability (MSI) that is not associated with major defects in DNA mismatch repair (MMR) but rather the reduced (heterogenous) expression of the MMR protein hMSH3; it occurs in sporadic colorectal tumors. We examined the timing of development of EMAST during progression of colorectal neoplasias and looked for correlations between EMAST and clinical and pathology features of tumors. METHODS: We evaluated tumor samples from a cohort of patients that had 24 adenomas and 84 colorectal cancers. EMAST were analyzed after DNA microdissection of matched normal and tumor samples using the polymorphic tetranucleotide microsatellite markers MYCL1, D9S242, D20S85, D8S321, and D20S82; data were compared with clinical and pathology findings. Traditional MSI analysis was performed and hMSH3 expression was measured. RESULTS: Moderately differentiated adenocarcinomas and poorly differentiated adenocarcinomas had higher frequencies of EMAST (56.9% and 40.0%, respectively) than well-differentiated adenocarcinomas (12.5%) or adenomas (33.3%) (P = .040). In endoscopic analysis, ulcerated tumors had a higher frequency of EMAST (52.3%) than flat (44.0%) or protruded tumors (20.0%) (P = .049). In quantification, all tumors with >3 tetranucleotide defects lost MSH3 (>75% of cells); nuclear heterogeneity of hMSH3 occurred more frequently in EMAST positive (40.0%) than in EMAST-negative tumors (13.2%) (P = .010). CONCLUSIONS: EMAST is acquired during progression of adenoma and well-differentiated carcinomas to moderately and poorly differentiated carcinomas; it correlates with nuclear heterogeneity for hMSH3. Loss of hMSH3 corresponds with multiple tetranucleotide frameshifts. The association between EMAST and ulcerated tumors might result from increased inflammation. PMID- 20708619 TI - Molecular characterisation of a novel family of cysteine-rich proteins of Toxoplasma gondii and ultrastructural evidence of oocyst wall localisation. AB - Among apicomplexan parasites, the coccidia and Cryptosporidium spp. are important pathogens of livestock and humans, and the environmentally resistant stage (oocyst) is essential for their transmission. Little is known of the chemical and molecular composition of the oocyst wall. Currently, the only parasite molecules shown to be involved in oocyst wall formation are the tyrosine-rich proteins gam56, gam82 and gam230 of Eimeria spp. and the cysteine-rich proteins COWP1 and COWP8 of Cryptosporidium parvum. In the present study, we searched the ToxoDB database for the presence of putative Toxoplasma gondii oocyst wall proteins (OWPs) and identified seven candidates, herein named TgOWP1 through TgOWP7, showing homology to the Cryptosporidium COWPs. We analysed a cDNA library from partially sporulated oocysts of T. gondii and cloned the full-length cDNAs encoding TgOWP1, TgOWP2 and TgOWP3, which consist of 499, 462 and 640 amino acids, respectively. The three proteins share 24% sequence identity with each other and a markedly similar overall structure, based on the presence of an N terminal leader peptide followed by tandem duplications of a six-cysteine amino acid motif closely related to the Type I repeat of COWPs. Using antisera to recombinant TgOWP1, TgOWP2 and TgOWP3, we showed by Western blot that these molecules are expressed in T. gondii oocysts but are not detectable in tachyzoites. The solubilisation of TgOWP1-3 strictly depended on the presence of reducing agents, consistent with a likely involvement of these proteins in multimeric complexes mediated by disulphide bridges. Immunofluorescence analysis allowed the localisation of TgOWP1, TgOWP2 and TgOWP3 to the oocyst wall. Additionally, using immunoelectron microscopy and the 1G12 monoclonal antibody, TgOWP3 was specifically detected in the outer layer of the oocyst wall, thus representing the first validated molecular marker of this structure in T. gondii. PMID- 20708620 TI - Identification of a mutation in the para-sodium channel gene of the cattle tick Rhipicephalus microplus associated with resistance to flumethrin but not to cypermethrin. AB - A mutation in the domain II S4-5 linker region of the para-sodium channel gene has been associated previously with synthetic pyrethroid (SP) resistance in the cattle tick (Rhipicephalus microplus) in Australia. This is a C->A mutation at nucleotide position 190, which results in a leucine to isoleucine amino acid substitution (L64I). In a survey of 15 cattle tick populations with known SP resistance status, sourced from Queensland and New South Wales in Australia, there was a strong relationship (r=0.98) between the proportion of ticks carrying the L64I homozygous resistant genotype and the survival percentage after exposure to a discriminating concentration of cypermethrin in the bioassay, as expected. However, among populations resistant only to flumethrin, the L64I homozygous genotype was not found. The sequence obtained for a 167 bp region including domain II S4-5 linker in flumethrin-resistant ticks identified a G->T non synonymous mutation at nucleotide position 214 that results in a glycine to valine substitution (G72V). The frequency of the G72V homozygous genotype in each population was found to be moderately related to the survival percentage at the discriminating concentration of flumethrin in the larval packet test (r=0.74). However, a much stronger relationship between genotype and resistance to flumethrin was observed when the heterozygotes of L64I and G72V were added to the G72V homozygotes (r=0.93). These results suggest that there is an interaction between the two mutations in the same gene, such that flumethrin resistance might be conferred by either two copies of the G72V mutation or by being a L64I and G72V heterozygote. PMID- 20708621 TI - Fulminant cryptosporidiosis associated with digestive adenocarcinoma in SCID mice infected with Cryptosporidium parvum TUM1 strain. AB - We recently demonstrated that Cryptosporidium parvum IOWA strain induces in situ ileo-caecal adenocarcinoma in an animal model. Herein, the ability of another C. parvum strain to induce digestive neoplasia in dexamethasone-treated SCID mice was explored. SCID mice infected with C. parvum TUM1 strain developed a fulminant cryptosporidiosis associated with intramucosal adenocarcinoma, which is considered an early histological sign of invasive cancer. Both evidence of a role of C. parvum in adenocarcinoma induction and the extended prevalence of cryptosporidiosis worldwide, suggest that the risk of C. parvum-induced gastro intestinal cancer in humans should be assessed. PMID- 20708622 TI - Differential susceptibility of human trophoblastic (BeWo) and uterine cervical (HeLa) cells to Neospora caninum infection. AB - Neospora caninum is an apicomplexan parasite, closely related to Toxoplasma gondii, and causes abortion and congenital neosporosis in cattle worldwide. Trophoblast cells act in mechanisms of innate immune defense at the fetal maternal interface and no data are available about the interaction of Neospora with human trophoblasts. Thus, this study aimed to verify the susceptibility of human trophoblastic (BeWo) compared with uterine cervical (HeLa) cell lines to N. caninum. BeWo and HeLa cells were infected with different parasite:cell ratios of N. caninum tachyzoites and analyzed at different times after infection for cell viability using thiazolyl blue tetrazole and lactate dehydrogenase assays. Both cell lines were also evaluated for cytokine production and parasite infection/replication assays when pre-treated or not with Neospora lysate antigen (NLA) or human recombinant IFN-gamma. Cell viability was increased up to 48 h of infection in both types of cells, suggesting that infection could inhibit early cell death and/or induce cell proliferation. Neospora infection induced up regulation of the macrophage migration inhibitory factor (MIF), mainly in HeLa cells, which was enhanced by cell pre-treatment by NLA or IFN-gamma. Conversely, parasite infection induced down-regulation of the transforming growth factor (TGF beta), mostly in BeWo cells, which was decreased with NLA or IFN-gamma pre treatment. HeLa cells were more susceptible to Neospora infection than BeWo cells and IFN-gamma pre-treatment resulted in reduced infection indices in both cell lines. Control of parasite growth was mediated by IFN-gamma through an indoleamine-2,3-dioxygenase-dependent mechanism in HeLa cells alone. Based on these results, we concluded that BeWo and HeLa cells are readily infected by N. caninum, although presenting differences in susceptibility to infection, cytokine production and cell viability. Thus, these host cells can be considered in comparative approaches to understand strategies used by N. caninum to survive at the maternal-fetal interface. PMID- 20708623 TI - Schistosoma co-infection protects against brain pathology but does not prevent severe disease and death in a murine model of cerebral malaria. AB - Co-infections of helminths and malaria parasites are common in human populations in most endemic areas. It has been suggested that concomitant helminth infections inhibit the control of malaria parasitemia but down-modulate severe malarial disease. We tested this hypothesis using a murine co-infection model of schistosomiasis and cerebral malaria. C57BL/6 mice were infected with Schistosoma mansoni and 8-9 weeks later, when Schistosoma infection was patent, mice were co infected with Plasmodium berghei ANKA strain. We found that a concomitant Schistosoma infection increased parasitemia at the beginning of the P. berghei infection. It did not protect against P. berghei-induced weight loss and hypothermia, and P. berghei-mono-infected as well as S. mansoni-P. berghei-co infected animals showed a high case fatality between days 6 and 8 of malarial infection. However, co-infection significantly reduced P. berghei-induced brain pathology. Over 40% of the S. mansoni-P. berghei-co-infected animals that died during this period were completely protected against haemorrhaging, plugging of blood vessels and infiltration, indicating that mortality in these animals was not related to cerebral disease. Schistosoma mansoni-P. berghei-co-infected mice had elevated plasma concentrations of IL-5 and IL-13 and on day 6 lower levels of IFN-gamma, IL-10, monocyte chemoattractant protein-1 (MCP-1) and monokine induced by IFN-gamma (MIG) than P. berghei-mono-infected mice. We conclude that in P. berghei infections, disease and early death are caused by distinct pathogenic mechanisms, which develop in parallel and are differentially influenced by the immune response to S. mansoni. This might explain why, in co-infected mice, death could be induced in the absence of brain pathology. PMID- 20708624 TI - Arteriogenesis requires toll-like receptor 2 and 4 expression in bone-marrow derived cells. AB - Adaptive collateral growth (arteriogenesis) is an important protective mechanism against ischemic injury in patients with cardiovascular disease. Arteriogenesis involves enlargement of pre-existent arterial anastomoses and shares many mechanistic similarities with inflammatory processes. Although infusion of the Toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) has shown to result in a significant stimulation of arteriogenesis and both Toll-like receptor 2 and 4 are involved in structural arterial adaptations, the requirement for TLRs in arteriogenesis has not yet been established. We therefore subjected TLR 2 null and TLR 4 defective mice to unilateral femoral artery occlusion. At 7 days, both TLR 2 null and TLR 4 defective mice showed a significant reduction (~35%) of collateral perfusion. Histological staining showed that TLR 2 and TLR 4 expression during arteriogenesis is mostly restricted to infiltrating leukocytes. To distinguish between the functional importance of vascular and leukocytic TLRs in arteriogenesis, cross-over bone marrow transplantation was performed 6 weeks before femoral artery occlusion. Perfusion measurements showed that transplantation of wild-type bone marrow into TLR 2 null and TLR 4 defective mice rescued the impaired arteriogenesis, while injection of TLR 2 null and TLR 4 defective bone marrow into wild-type mice significantly reduced collateral vessel growth to levels of TLR null/defective mice. RT-PCR analysis demonstrated a significant upregulation of two endogenous TLR ligands EDA and Hsp60 (91.7 fold and 1.9 fold respectively) in regions of collateral vessel formation. This study illustrates the involvement of TLR 2 and TLR 4 in adaptive collateral artery growth and shows the importance of TLR 2 and 4 expression by bone-marrow derived cells for this process. PMID- 20708625 TI - Crystal structure of the cyanobacterial signal transduction protein PII in complex with PipX. AB - P(II) proteins are highly conserved signal transducers in bacteria, archaea, and plants. They have a large flexible loop (T-loop) that adopts different conformations after covalent modification or binding to different effectors to regulate the functions of diverse protein partners. The P(II) partner PipX (P(II)interaction protein X), first identified from Synechococcus sp. PCC 7942, exists uniquely in cyanobacteria. PipX also interacts with the cyanobacterial global nitrogen regulator NtcA. The mutually exclusive binding of P(II) and NtcA by PipX in a 2-oxoglutarate (2-OG)-dependent manner enables P(II) to indirectly regulate the transcriptional activity of NtcA. However, the structural basis for these exclusive interactions remains unknown. We solved the crystal structure of the P(II)-PipX complex from the filamentous cyanobacterium Anabaena sp. PCC 7120 at 1.90 A resolution. A homotrimeric P(II) captures three subunits of PipX through the T-loops. Similar to P(II) from Synechococcus, the core structure consists of an antiparallel beta-sheet with four beta-strands and two alpha helices at the lateral surface. PipX adopts a novel structure composed of five twisted antiparallel beta-strands and two alpha-helices, which is reminiscent of the P(II) structure. The T-loop of each P(II) subunit extends from the core structure as an antenna that is stabilized at the cleft between two PipX monomers via hydrogen bonds. In addition, the interfaces between the beta-sheets of PipX and P(II) core structures partially contribute to complex formation. Comparative structural analysis indicated that PipX and 2-OG share a common binding site that overlaps with the 14 signature residues of cyanobacterial P(II) proteins. Our structure of PipX and the recently solved NtcA structure enabled us to propose a putative model for the NtcA-PipX complex. Taken together, these findings provide structural insights into how P(II) regulates the transcriptional activity of NtcA via PipX upon accumulation of the metabolite 2-OG. PMID- 20708626 TI - H-bonding and positive charge at the N5/O4 locus are critical for covalent flavin attachment in trametes pyranose 2-oxidase. AB - Flavoenzymes perform a wide range of redox reactions in nature, and a subclass of flavoenzymes carry covalently bound cofactor. The enzyme-flavin bond helps to increase the flavin's redox potential to facilitate substrate oxidation in several oxidases. The formation of the enzyme-flavin covalent bond--the flavinylation reaction--has been studied for the past 40 years. For the most advocated mechanism of autocatalytic flavinylation, the quinone methide mechanism, appropriate stabilization of developing negative charges at the flavin N(1) and N(5) loci is crucial. Whereas the structural basis for stabilization at N(1) is relatively well studied, the structural requisites for charge stabilization at N(5) remain less clear. Here, we show that flavinylation of histidine 167 of pyranose 2-oxidase from Trametes multicolor requires hydrogen bonding at the flavin N(5)/O(4) locus, which is offered by the side chain of Thr169 when the enzyme is in its closed, but not open, state. Moreover, our data show that additional stabilization at N(5) by histidine 548 is required to ensure high occupancy of the histidyl-flavin bond. The combination of structural and spectral data on pyranose 2-oxidase mutants supports the quinone methide mechanism. Our results demonstrate an elaborate structural fine-tuning of the active site to complete its own formation that couples efficient holoenzyme synthesis to conformational substates of the substrate-recognition loop and concerted movements of side chains near the flavinylation ligand. PMID- 20708628 TI - Allometry and catastrophic regime shifts in food chains. AB - Population dynamics can reflect the body mass distribution of species because there is an allometric relationship between the average body mass of species and its metabolic timescale. Since predators are generally larger than their prey, a hierarchical structure from fast timescales to slow timescales can be a general structure in food webs. In this paper, we show that changes of the metabolic timescale ratio can cause catastrophic shifts. Then, we investigate a two dimensional parameter space with the timescale ratio and the carrying capacity of basal species, and reveal that the timescale ratio characterizes the response of the system to environmental variation. Finally, in a bistable regime, we try to clarify the relationship between the trophic position of a species and the extent to which the species induces attractor switching. We saw that, in a 4-species food chain, top predators and second consumers induce attractor switching easily compared to first consumers and basal species. PMID- 20708627 TI - Dissecting the microscopic steps of the cyclophilin A enzymatic cycle on the biological HIV-1 capsid substrate by NMR. AB - Peptidyl-prolyl isomerases (PPIases) are emerging as key regulators of many diverse biological processes. Elucidating the role of PPIase activity in vivo has been challenging because mutagenesis of active-site residues not only reduces the catalytic activity of these enzymes but also dramatically affects substrate binding. Employing the cyclophilin A PPIase together with its biologically relevant and natively folded substrate, the N-terminal domain of the human immunodeficiency virus type 1 capsid (CA(N)) protein, we demonstrate here how to dissect residue-specific contributions to PPIase catalysis versus substrate binding utilizing NMR spectroscopy. Surprisingly, a number of cyclophilin A active-site mutants previously assumed to be strongly diminished in activity toward biological substrates based only on a peptide assay catalyze the human immunodeficiency virus capsid with wild-type activity but with a change in the rate-limiting step of the enzymatic cycle. The results illustrate that a quantitative analysis of catalysis using the biological substrates is critical when interpreting the effects of PPIase mutations in biological assays. PMID- 20708629 TI - Tree-grass co-existence in savanna: Interactions of rain and fire. AB - The mechanisms permitting the co-existence of tree and grass in savannas have been a source of contention for many years. The two main classes of explanations involve either competition for resources, or differential sensitivity to disturbances. Published models focus principally on one or the other of these mechanisms. Here we introduce a simple ecohydrologic model of savanna vegetation involving both competition for water, and differential sensitivity of trees and grasses to fire disturbances. We show how the co-existence of trees and grasses in savannas can be simultaneously controlled by rainfall and fire, and how the relative importance of the two factors distinguishes between dry and moist savannas. The stability map allows to predict the changes in vegetation structure along gradients of rainfall and fire disturbances realistically, and to clarify the distinction between climate- and disturbance-dependent ecosystems. PMID- 20708630 TI - Cooperation enhanced by the 'survival of the fittest' rule in prisoner's dilemma games on complex networks. AB - Prevalence of cooperation within groups of selfish individuals is puzzling in that it contradicts with the basic premise of natural selection, whereby we introduce a model of strategy evolution taking place on evolving networks based on Darwinian 'survival of the fittest' rule. In the present work, players whose payoffs are below a certain threshold will be deleted and the same number of new nodes will be added to the network to maintain the constant system size. Furthermore, the networking effect is also studied via implementing simulations on four typical network structures. Numerical results show that cooperators can obtain the biggest boost if the elimination threshold is fine-tuned. Notably, this coevolutionary rule drives the initial networks to evolve into statistically stationary states with a broad-scale degree distribution. Our results may provide many more insights for understanding the coevolution of strategy and network topology under the mechanism of nature selection whereby superior individuals will prosper and inferior ones be eliminated. PMID- 20708631 TI - New views of glutamate transporter structure and function: advances and challenges. AB - Neuronal and glial glutamate transporters limit the action of excitatory amino acids after their release during synaptic transmission. Recent structural and functional investigations have revealed much about the transport and conducting mechanisms of members of the sodium-coupled symporter family responsible for glutamate clearance in the nervous system. In this review we summarize emerging views on the general structure, binding sites for substrates and coupled ions, and transport mechanisms of mammalian glutamate transporters, integrating results from a large body of work on carrier structure-function relationships with several crystal structures obtained for the archaeal ortholog, Glt(Ph). PMID- 20708633 TI - Transmembrane signaling by GPCRs: insight from rhodopsin and opsin structures. AB - G-protein-coupled receptors (GPCRs), also known as seven-transmembrane (7TM) receptors, are the largest family of membrane proteins in the human genome. As versatile signaling molecules, they mediate cellular responses to extracellular signals. Diffusible ligands like hormones and neurotransmitters bind to GPCRs to modulate GPCR activity. An extraordinary and highly specialized GPCR is the photoreceptor rhodopsin which contains the chromophore retinal as its covalently bound ligand. For receptor activation the configuration of retinal is altered by photon absorption. To date, rhodopsin is the only GPCR for which crystal structures of inactive, active and ligand-free conformations are known. Although the photochemical activation is unique to rhodopsin, many mechanistic insights from this receptor can be generalized for GPCRs. PMID- 20708632 TI - Icariin attenuates beta-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive loss of neurons and production of beta-amyloid proteins (Abeta). Hyperphosphorylation of tau protein is proposed to be an early event for the evolution of AD, and may play an important role in Abeta-induced neurodegeneration. Icariin, a flavonoid compound from the herb Epimedium brevicornum Maxim, exerts a protective effect on learning and memory abilities in Abeta(25-35)-induced AD rats. However, the molecular mechanism of icariin-induced neuroprotective effect against tau protein hyperphosphorylation, which is one of the most representative hallmarks in AD, is still unknown. In the present study, we investigated the inhibitory effect of icariin on Abeta(25-35)-induced tau protein hyperphosphorylation on PC12 cells. The results showed that treatment with icariin significantly decreased Abeta(25-35)-induced cytotoxicity and apoptosis rate through inhibiting tau protein hyperphosphorylation at Ser396, Ser404 and Thr205 sites, respectively. Mechanism study showed that icariin could activate PI3K/Akt signaling pathway, resulting in an inhibitory effect on glycogen synthase kinase (GSK)-3beta, which is an important kinase response for tau protein hyperphosphorylation in the development of AD. These observations indicate that icariin is capable of attenuating Abeta(25-35)-induced tau protein hyperphosphorylation and promoting survival of neuronal cells, meanwhile also provide some insights into the potential signaling pathway that is involved. Thus, this study promises a great potential agent for Alzheimer's disease and other tau pathology-related neuronal degenerative diseases. PMID- 20708634 TI - GT-repeat polymorphism in the heme oxygenase-1 gene promoter is associated with cardiovascular mortality risk in an arsenic-exposed population in northeastern Taiwan. AB - Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO 1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (<27 repeats) or L allele (>= 27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16-0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure. PMID- 20708635 TI - Protective effect of N-acetyl-L-cysteine against disulfiram-induced oxidative stress and apoptosis in V79 cells. AB - This work investigated the effect of N-acetyl-L-cysteine (NAC) on disulfiram (DSF) induced oxidative stress in Chinese hamster fibroblast cells (V79). An increase in oxidative stress induced by DSF was observed up to a 200 MUM concentration. It was evidenced by a statistically significant increase of both GSH(t) and GSSG levels, as well as elevated protein carbonyl (PC) content. There was no increase in lipid peroxidation (measured as TBARS). DSF increased CAT activity, but did not change SOD1 and SOD2 activities. Analysis of GSH related enzymes showed that DSF significantly increased GR activity, did not change Se dependent GPx, but statistically significantly decreased non-Se-dependent GPx activity. DSF showed also pro-apoptotic activity. NAC alone did not produce any significant changes, besides an increase of GSH(t) level, in any of the variables measured. However, pre-treatment of cells with NAC ameliorated DSF-induced changes. NAC pre-treatment restored the viability of DSF-treated cells evaluated by Trypan blue exclusion assay and MTT test, GSSG level, and protein carbonyl content to the control values as well as it reduced pro-apoptotic activity of DSF. The increase of CAT and GR activity was not reversed. Activity of both GPx was significantly increased compared to their values after DSF treatment. In conclusion, oxidative properties are at least partially attributable to the cellular effects of disulfiram and mechanisms induced by NAC pre-treatment may lower or even abolish the observed effects. These observations illustrate the importance of the initial cellular redox state in terms of cell response to disulfiram exposure. PMID- 20708638 TI - HTLV-1 and HIV-1 "accessory" proteins: a misleading misnomer. PMID- 20708637 TI - Trends in low-risk lifestyle factors among adults in the United States: findings from the Behavioral Risk Factor Surveillance System 1996-2007. AB - OBJECTIVE: Our objective was to examine recent trends in low-risk lifestyle factors for chronic diseases (not currently smoking, any exercise during the past 30 days, consuming fruits and vegetables >=5 times per day, and body mass index <25kg/m(2)) among U.S. adults. METHODS: We used data from 1,580,220 adults aged >=18 years who participated in one of seven Behavioral Risk Factor Surveillance System surveys conducted from 1996 to 2007. RESULTS: The age-adjusted percentage of adults meeting all four low-risk lifestyle factors was 8.5% in 1996 and 7.7% in 2007 (p for linear trend <0.001). Significant decreasing trends were noted for men, women, whites, Hispanics, and most age groups. The percentages of participants who were not currently smoking, who had done any exercise during the past 30 days, who reported consuming fruits and vegetables >=5 times per day, and who had a body mass index <25kg/m(2) were 70.9%, 76.2%, 47.9% and 24.3%, respectively, in 1996 and 77.1%, 80.0%, 37.8%, and 24.5%, respectively, in 2007. Women and whites were more likely than their counterparts to meet all four criteria. CONCLUSIONS: From 1996 to 2007, the percentage of U.S. adults meeting all four low-risk lifestyle factors decreased slightly. PMID- 20708636 TI - Depletion of Werner helicase results in mitotic hyperrecombination and pleiotropic homologous and nonhomologous recombination phenotypes. AB - Werner syndrome (WS) is a rare, segmental progeroid syndrome caused by defects in the WRN gene, which encodes a RecQ helicase. WRN has roles in many aspects of DNA metabolism including DNA repair and recombination. In this study, we exploited two different recombination assays previously used to describe a role for the structure-specific endonuclease ERCC1-XPF in mitotic and targeted homologous recombination. We constructed Chinese hamster ovary (CHO) cell lines isogenic with the cell lines used in these previous studies by depleting WRN using shRNA vectors. When intrachromosomal, mitotic recombination was assayed in WRN-depleted CHO cells, a hyperrecombination phenotype was observed, and a small number of aberrant recombinants were generated. Targeted homologous recombination was also examined in WRN-depleted CHO cells using a plasmid-chromosome targeting assay. In these experiments, loss of WRN resulted in a significant decrease in nonhomologous integration events and ablation of recombinants that required random integration of the corrected targeting vector. Aberrant recombinants were also recovered, but only from WRN-depleted cells. The pleiotropic recombination phenotypes conferred by WRN depletion, reflected in distinct homologous and nonhomologous recombination pathways, suggest a role for WRN in processing specific types of homologous recombination intermediates as well as an important function in nonhomologous recombination. PMID- 20708639 TI - Investigation on the interaction between tamoxifen and human holo-transferrin: determination of the binding mechanism by fluorescence quenching, resonance light scattering and circular dichroism methods. AB - The interaction between tamoxifen (TMX) and human serum transferrin (HTF) was for the first time studied at varying pH values by fluorescence spectroscopy, circular dichroism (CD) and resonance light scattering (RLS). The fluorescence spectroscopy experiments were performed in order to study conformational changes, possibly due to a discrete reorganization of tryptophan residues during TMX-HTF binding at varying ligand concentrations, as well as quenching properties of the drug-serum transferrin complex and the differentiation between static and dynamic quenching. The binding affinity and number of binding sites were obtained for the TMX-HTF interaction at different pH. Second derivative fluorescence spectroscopy was employed for monitoring the complex and characterizing the transitions taking place in the environments of tyrosine and tryptophan (mainly tryptophans) in proteins. The variation of the K(SV) value suggested that hydrophobic and electrostatic interactions were the predominant intermolecular forces stabilizing the complex. The RLS technique was utilized to determine the protein type, and to investigate the effect of anticancer drugs on its determination. This is the first report of its kind. An explanation is also given of the enhancement in RLS intensity, which attributed to the new complex formation between TMX and the protein a self-aggregation process and the formation of a precipitate HTF occurred and a micelle came into being when the amount of TMX was augmented. The great increase of polarizability was one of the important factors for the enhancement of RLS and the formation of complexes. The results from synchronous fluorescence spectroscopy showed that the micro-environment around tryptophan and tyrosine demonstrated a faint red shift. The circular dichroism data revealed that the presence of TMX decreased the alpha-helix content of HTF and induced the remarkable unfolding of the polypeptides of the protein. This confirmed certain micro-environmental and conformational changes of the HTF molecule. The binding distance (r) between TMX and the tryptophan residue of HTF was obtained according to the Forster theory of non-radioactive energy transfer. This study on the interaction of drugs with HTF should prove helpful for realizing the distribution and transportation of drugs in vivo, elucidating the action mechanism and dynamics of a drug at the molecular level. It should moreover be of great use for understanding the pharmacokinetic and pharmacodynamic mechanisms of the drug. PMID- 20708641 TI - Impact of baseline prepulse inhibition on nicotine-induced locomotor sensitization in rats. AB - The rats having high locomotor reactivity to a novel environment (LRNE) are known to be more vulnerable to develop locomotor sensitization, which reflects the initial neuroplastic changes in brain systems related to addictive behaviours. The present study aimed to investigate whether sensorimotor gating level, measured by prepulse inhibition (PPI) of acoustic startle reflex, also reflects vulnerability for nicotine sensitization. A batch of rats was assigned into three groups according to their baseline PPI values. The highest 1/3 and the lowest 1/3 proportions were selected and defined as high-inhibitory (HI) and low-inhibitory (LI) groups. LRNE was measured in the rats, then they were treated with nicotine (1 mg/kg, tartrate salt, subcutaneously) or saline and locomotor activity (LMA) was immediately recorded for 15 min. This procedure was performed daily for 5 successive days. After a 3-day drug-free period, all rats were challenged with nicotine (1 mg/kg) on 9th day and with saline on 12th day. Same sensitization protocol was applied in another batch of rats, except assigning them into the high-responder (HR) and low-responder (LR) groups according to LRNE levels. There was no significant difference between HI and LI rats in LRNE. Although the acute effect of nicotine on LMA was higher in HI rats, a locomotor sensitization developed and expressed only in LI rats. In the following experiments, nicotine stimulated LMA both in HR and LR rats, but induced and expressed locomotor sensitization only in HR rats. The present study shows that acute locomotor stimulant effect and locomotor sensitization developing effects of nicotine are associated with the baseline PPI and LRNE levels. But these two factors are independent from each other. PMID- 20708640 TI - Global gene expression changes in type 1 diabetes: insights into autoimmune response in the target organ and in the periphery. AB - Type 1 diabetes (T1D) is an autoimmune disease caused by the selective destruction of the insulin-producing beta cells. Research into the pathogenesis of T1D has been hindered by the lack of detection of the autoimmune process during the asymptomatic period and by the inaccessibility to the target tissue. Therefore current understanding of the immunological phenomena that take place in the pancreas of the patients is very limited and much of the current knowledge on T1D has been obtained using animal models. Microarray technology and bioinformatics allow the comparison of the gene expression profile - transcriptome - in normal and pathological conditions, creating a global picture of altered processes. Microarray experiments have defined new transcriptional alterations associated with several autoimmune diseases, and are focused on the identification of specific biomarkers. In this review we summarize current data on gene expression profiles in T1D from an immunological point of view. Reported transcriptome studies have been performed in T1D patients and Non-Obese Diabetic mouse models analyzing peripheral blood, lymphoid organs and pancreas/islets. In the periphery, the distinctive profiles are inflammatory pathways inducible by IL 1beta and IFNs that can help in the identification of new biomarkers. In the target organ, a remarkable finding is the overexpression of inflammatory and innate immune response genes and the active autoimmune response at longstanding stages, contrary to the pre-existing concept of acute autoimmune process in T1D. PMID- 20708643 TI - Oxidative stress and alterations in actin cytoskeleton trigger glutathione efflux in Saccharomyces cerevisiae. AB - A marked deficiency in glutathione (GSH), the most abundant antioxidant in living systems, plays a major role in aging and the pathogenesis of diseases ranging from neurological disorders to early atherosclerosis and the impairment of various immunological functions. In an attempt to shed light on GSH homeostasis, we carried out the space experiment SCORE (Saccharomyces cerevisiae oxidative stress response evaluation) during the FOTON-M3 mission. Microgravity and hyperoxic conditions induced an enormous extracellular release of GSH from S. cerevisiae cells (~40% w/dw), changed the distribution of the buds, and activated the high osmolarity glycerol (HOG) and cell integrity/PKC pathways, as well as protein carbonylation. The results from the single spaceflight experiment were validated by a complete set of experiments under conditions of simulated microgravity and indicate that cytoskeletal alterations are mainly responsible for the observed effects. The results of ground experiments in which we induced cytoskeletal modifications by means of treatment with dihydrocytochalasin B (DHCB), a potent inhibitor of actin polymerisation, or (R)-(+)-trans-4-(1 aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride monohydrate (Y 27632), a selective ROCK (Rho-associated coiled-coil forming protein serine/threonine kinase) inhibitor, confirmed the role of actin in GSH efflux. We also found that the GSH release can be inhibited using the potent chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). PMID- 20708642 TI - Naloxone blocks ethanol-mediated appetitive conditioning and locomotor activation in adolescent rats. AB - Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS1], first-order conditioning phase). CS1 delivery occurred 30-45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS1 (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS2). Preference for CS2 was then tested. Adolescents given CS1-ethanol pairings exhibited greater preference for CS2 than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol-induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation. PMID- 20708644 TI - The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells. AB - SRPK1, the prototype of the serine/arginine family of kinases, has been implicated in the regulation of multiple cellular processes such as pre-mRNA splicing, chromatin structure, nuclear import and germ cell development. SRPK1a is a much less studied isoform of SRPK1 that contains an extended N-terminal domain and so far has only been detected in human testis. In the present study we show that SRPK1 is the predominant isoform in K562 cells, with the ratio of the two isoforms being critical in determining cell fate. Stable overexpression of SRPK1a induces erythroid differentiation of K562 cells. The induction of globin synthesis was accompanied by a marked decrease in proliferation and a significantly reduced clonogenic potential. Small interfering RNA-mediated down regulation of SRPK1 in K562 cells results similarly in a decrease in proliferative capacity and induction of globin synthesis. A decreased SRPK1/SRPK1a ratio is also observed upon hemin/DMSO-induced differentiation of K562 cells as well as in normal human erythroid progenitor cells. Mass spectrometric analysis of SRPK1a-associated proteins identified multiple classes of RNA-binding proteins including RNA helicases, heterogeneous nuclear ribonucleoproteins, ribosomal proteins, and mRNA-associated proteins. Several of the SRPK1a-copurifying proteins have been previously identified in ribosomal and pre-ribosomal complexes, thereby suggesting that SRPK1a may play an important role in linking ribosomal assembly and/or function to erythroid differentiation in human leukaemic cells. PMID- 20708645 TI - Insulin stimulation of PKCdelta triggers its rapid degradation via the ubiquitin proteasome pathway. AB - Insulin rapidly upregulates protein levels of PKCdelta in classical insulin target tissues skeletal muscle and liver. Insulin induces both a rapid increase in de novo synthesis of PKCdelta protein. In this study we examined the possibility that insulin may also inhibit degradation of PKCdelta. Experiments were performed on L6 skeletal muscle myoblasts or myotubes in culture. Phorbol ester (PMA)- and insulin-induced degradation of PKCdelta were abrogated by proteasome inhibition. Both PMA and insulin induced ubiquitination of PKCdelta, but not of that PKCalpha or PKCepsilon and increased proteasome activity within 5 min. We examined the role of tyrosine phosphorylation of PKCdelta in targeting PKCdelta for degradation by the ubiquitin-proteasome pathway. Transfection of cells with PKCdeltaY(311)F, which is not phosphorylated, resulted in abolition of insulin-induced ubiquitination of PKCdelta and increase in proteasome activity. We conclude that insulin induces degradation of PKCdelta via the ubiquitin proteasome system, and that this effect requires phosphorylation on specific tyrosine residues for targeting PKCdelta for degradation by the ubiquitin proteasome pathway. These studies provide additional evidence for unique effects of insulin on regulation of PKCdelta protein levels. PMID- 20708646 TI - Effects of mental challenge on neurovascular responses in healthy male subjects. AB - The purpose of this study was to examine the effects of mental challenge on total antioxidant capacity (TAC), forearm blood flow (FBF), vascular reactivity (VR), and the release of norepinephrine (NE). Furthermore, this study also examined the possible relationships of NE with FBF and VR following the mental challenge. Twenty healthy male subjects participated in twenty minutes of mental stress task (Stroop Color-Word Task [SCW] and mental arithmetic task [MA]). Our results showed that HR and NE increased significantly immediately following the mental challenge, whereas total antioxidant capacity did not change. Furthermore, the area-under-the-curves (AUCs) for both FBF at baseline and during reactive hyperemia, and VR elicited a significant change across time immediately post stress. The percent change in the HR was partially correlated with the percent change in the VR immediately post-stress (p=0.08). Additionally, the percent change in the NE was positively correlated with TAC immediately post-stress, whereas NE only demonstrated a partial relationship with FBF at baseline immediately following the mental challenge (p=0.10). These findings suggest that forearm vasodilation following the mental challenge may be mediated by the antioxidant defense and sympathetic activation. Further studies are warranted to elucidate the mechanisms that explain the responses and relationships presented in this investigation. PMID- 20708647 TI - mRNA transfection of cervical carcinoma and mesenchymal stem cells mediated by cationic carriers. AB - Messenger RNA encoding luciferase (mLUC) was complexed to the cationic lipids Lipofectamine or DOTAP/DOPE, and to the cationic polymer linear poly(ethyleneimine) (linPEI). The complexes were incubated with HeLa cells and luciferase expression was assessed. The type of non-viral carrier used determined the extent and duration of protein expression. Maximal duration of mRNA expression was about 9 days for Lipofectamine complexes, i.e. not very much shorter than with pDNA polyplexes. Interestingly, luciferase activity was already detected 30 min after adding the mRNA complexes to the cells, independent on the type of carrier. We also assessed the proportion of cells that become transfected by means of transfection with an mRNA encoding GFP. For both cationic lipids transfection with mRNA yielded a substantially larger fraction of transfected cells (more than 80%) than transfection with pDNA (40%). In addition we tested the carriers for their ability to mediate delivery of mRNA encoding CXCR4 into mesenchymal stem cells. The fraction of CXCR4-positive cells obtained with the mRNA-cationic lipid complexes was around 80%, as compared to 40% for the linPEI polyplexes. Our results demonstrate that the advantage of the use of mRNA over that of pDNA may under certain conditions outweigh the disadvantage of the somewhat shorter expression period. PMID- 20708648 TI - Androgen receptor as a therapeutic target. AB - Androgens function as sex hormone primarily via activation of a single androgen receptor (AR, or NR3C4). AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer. AR ligands of different chemical structures and/or pharmacological properties are widely used for these therapeutic applications, and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand-binding pocket (LBP) of the receptor. In the past ten years, our understanding of AR structure and molecular mechanism of action has progressed extensively, which has encouraged the rapid development of newer generation of AR ligands, particularly tissue-selective AR ligands. With improved tissue selectivity, future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs. This review will provide an overview of the common therapeutic applications of currently available AR ligands, and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development. PMID- 20708649 TI - Sex-dependent aromatase activity in rat offspring after pre- and postnatal exposure to triphenyltin chloride. AB - Triphenyltin (TPT) is an organotin compound (OTC) previously widely used as an antifouling agent in paints applied in the marine environment, a fungicide, and as an agricultural pesticide. In female aquatic invertebrates, certain OTCs induce the so-called imposex, an abnormal induction of male sex characteristics. OTC-induced environmental endocrine disruption also occurs in fish and mammals and a number of in vivo and in vitro studies have argued that OTCs may act through inhibition of the aromatase enzyme. In vivo studies supporting the aromatase inhibition hypothesis in mammals are lacking. Recently, the causal relationship between inhibition of aromatase and imposex was questioned, suggesting aromatase independent mechanisms of action for this phenomenon. We conducted a comprehensive investigation to identify the most sensitive window of exposure to TPTCl and to examine the effects of pre- and postnatal exposure on postnatal development in rats. The results on brain and gonadal aromatase activity obtained from offspring of dams exposed to 2 mg TPTCl/kg bw are reported here. Female and male offspring rats were exposed to 2 mg TPTCl/kg bw/d in utero from gestation day 6 through lactation until weaning on PND 21, or from gestation day 6 until termination at adulthood. Male offspring were sacrificed from PND 58 and female offspring at first estrus after PND 58. Pre- and postnatal TPT exposure clearly affected brain and gonadal aromatase activity in a sex-dependent fashion. While brain aromatase activity was significantly increased on PND 21 and at adulthood in female offspring, male offspring exhibited a significant decrease in brain aromatase activity only at adulthood. Ovarian aromatase activity was unaffected at both time points investigated. In contrast, testicular aromatase activity was significantly increased in males on PND 21 and significantly decreased at adulthood independent from the duration of treatment. The results of the present study confirm our previously reported observations regarding sex dependent differences in sexual development after TPT exposure with the male rat being more susceptible to disturbances through this endocrine active compound than the female. We conclude that TPT administered during the particularly vulnerable period of development can affect aromatase activity in rats. PMID- 20708650 TI - Disorder specificity despite comorbidity: resting EEG alpha asymmetry in major depressive disorder and post-traumatic stress disorder. AB - The approach-withdrawal and valence-arousal models highlight that specific brain laterality profiles may distinguish depression and anxiety. However, studies remain to be conducted in multiple clinical populations that directly test the diagnostic specificity of these hypotheses. The current study compared electroencephalographic data under resting state, eyes closed conditions in patients with major depressive disorder (MDD) (N=15) and post-traumatic stress disorder (PTSD) (N=14) relative to healthy controls (N=15) to examine the specificity of brain laterality in these disorders. Key findings included (1) reduced left-frontal activity in MDD, (2) a positive correlation between PTSD severity and right-frontal lateralisation, (3) greater activity in PTSD patients relative to MDD within the right-parietotemporal region, and (4) globally increased alpha power in MDD. Findings partially support the diagnostic applicability of the theoretical frameworks. Future studies may benefit from examining task-driven differences between groups. PMID- 20708651 TI - AT(1) receptor Galphaq protein-independent signalling transcriptionally activates only a few genes directly, but robustly potentiates gene regulation from the beta2-adrenergic receptor. AB - The angiotensin II type 1 receptor (AT(1)R) is known to signal through heterotrimeric G proteins, and Galphaq protein-independent signalling has only recently gained appreciation for profound impact on a diverse range of biological functions. beta-Arrestins, among other central mediators of Galphaq protein independent signalling from the AT(1)R interact with transcriptional regulators and promote phosphorylation of nuclear proteins. However, the relative contribution of Galphaq protein-independent signalling in AT(1)R mediated transcriptional regulation remains elusive. We here present a comprehensive comparative analysis of Galphaq protein-dependent and -independent regulation of AT(1)R mediated gene expression. We found angiotensin II to regulate 212 genes, whereas Galphaq-independent signalling obtained with the biased agonist, SII angiotensin II only regulated few genes. Interestingly, SII angiotensin II, like Ang II vastly potentiated beta2-adrenergic receptor-stimulated gene expression. These novel findings indicate that the Galphaq protein-independent signalling mainly modifies the transcriptional response governed by other signalling pathways, while direct induction of gene expression by the AT(1)R is dependent on classical Galphaq protein activation. PMID- 20708652 TI - Evolution of GPCR: change and continuity. AB - Once introduced into the very early eukaryotic blueprint, seven-transmembrane receptors soon became the central and versatile components of the evolutionary highly successful G protein-coupled transmembrane signaling mechanism. In contrast to all other components of this signal transduction pathway, G protein coupled receptors (GPCR) evolved in various structural families, eventually comprising hundreds of members in vertebrate genomes. Their functional diversity is in contrast to the conserved transmembrane core and the invariant set of intracellular signaling mechanisms, and it may be the interplay of these properties that is the key to the evolutionary success of GPCR. The GPCR repertoires retrieved from extant vertebrate genomes are the recent endpoints of this long evolutionary process. But the shaping of the fine structure and the repertoire of GPCR is still ongoing, and signatures of recent selection acting on GPCR genes can be made visible by modern population genetic methods. The very dynamic evolution of GPCR can be analyzed from different perspectives: at the levels of sequence comparisons between species from different families, orders and classes, and at the level of populations within a species. Here, we summarize the main conclusions from studies at these different levels with a specific focus on the more recent evolutionary dynamics of GPCR. PMID- 20708653 TI - Endocrine immune interactions in human parturition. AB - Human parturition is an inflammatory event, modulated and influenced by a host of other environmental and physiological processes, including the endocrine hormones. Complex bidirectional communication occurs between the two systems to bring about some of the changes that are seen in labour, an event that is not yet fully understood. Preterm birth is a major problem in obstetrics and neonatology, with dysfunctional labour or prolonged pregnancy also making increasingly significant contributions to maternal morbidity. With better understanding of normal and abnormal parturition we may be able to develop novel ways of treating these complications of pregnancy and reduce maternal and neonatal morbidity and mortality. This review discusses the crucial role that endocrine-immune interaction plays in the process of labour and in the processes of abnormal and preterm labour. We propose that amongst these complex interactions it is the immune system that is the driving force behind human parturition. PMID- 20708654 TI - Validating cancer drug targets through chemical genetics. AB - Targeted therapies for cancer promise to revolutionize treatment by specifically inactivating pathways needed for the growth of tumor cells. The most prominent example of such therapy is imatinib (Gleevec), which targets the BCR-ABL kinase and provides an effective low-toxicity treatment for chronic myelogenous leukemia. This success has spawned myriad efforts to develop similarly targeted drugs for other cancers. Unfortunately, the high expectations of these efforts have not yet been realized, likely due to the genetic diversity among and within tumors, as well as the complex and largely unpredictable interactions of drug like compounds with innumerable targets that affect cellular and organismal metabolism. While improvements in sequencing technologies are beginning to address the first problem, solving the second problem requires methods for linking specific features of the cancer genome to their optimally targeted therapies. One approach, referred to as chemical genetics, accomplishes this by genetic control of chemical susceptibility. Chemical genetics is a crucial tool for the rational development of cancer drugs. PMID- 20708655 TI - The Aurora-A/TPX2 complex: a novel oncogenic holoenzyme? AB - The Aurora-A kinase regulates cell division by phosphorylating multiple downstream targets in the mitotic apparatus. Aurora-A is frequently overexpressed in tumor cells and it is therefore regarded as a novel candidate target in anti cancer therapy. Its actual contribution to cell transformation, however, is not entirely clarified; furthermore, its transforming ability has been found to vary broadly depending on the systems and experimental conditions in which it was assayed. This variability suggests that Aurora-A overexpression requires the concomitant deregulation of partner factor(s) to fully elicit its oncogenic potential. Molecular and structural studies indicate that the full activation and correct mitotic localisation of Aurora-A require its interaction with the spindle regulator TPX2. In this review we propose a brief reappraisal of Aurora-A intrinsic oncogenic features. We then present literature screening data indicating that TPX2 is also overexpressed in many tumor types, and, furthermore, that Aurora-A and TPX2 are frequently co-overexpressed. We therefore propose that the association of Aurora-A and TPX2 gives rise to a novel functional unit with oncogenic properties. We also suggest that some of the roles that are conventionally attributed to Aurora-A in cell transformation and tumorigenesis could in fact be a consequence of the oncogenic activation of this unit. PMID- 20708656 TI - Opioid-salsolinol relationship in the control of prolactin release during lactation. AB - Endogenous opioid peptides (EOP) and dopamine (DA)-derived salsolinol are implicated in the suckling-induced prolactin surge. The aim of this study was to investigate the relationship between the opioidergic and salsolinergic activity in the mediobasal hypothalamus of nursing sheep. The sheep were infused intracerebroventricularly with opioid receptors antagonists: naloxone (all types of receptors, n=6); naloxonazine (MU receptor, n=6) or the vehicle (control, n=6) in a series of five 30-min infusions (60 MUg/60 MUl) from 10:00 to 15:00, at 30 min intervals. The period of the experiment included the non-suckling (10:00 12:30) and suckling (12:30-15:00) periods. Simultaneously, a push-pull perfusion of the infundibular nucleus/median eminence was performed in every sheep to study the dopaminergic system activity. Blood samples were also collected at 10-minute intervals to determine plasma prolactin concentration. Both the mean perfusate salsolinol and plasma prolactin concentrations were higher during the suckling vs. non-suckling (P<0.001) period in the control. The perfusate DA concentration was below the detection limit in this group. Treatment with either naloxone or naloxonazine significantly (P<0.01) diminished plasma prolactin concentration, as compared with the controls and blocked the prolactin surge during suckling. In drug-infused sheep, the perfusate salsolinol concentration was below the detection limit but the increased DA and its metabolite 3,4-dihydroxyphenylacetic acid concentrations were observed. In conclusion, the stimulatory action of EOP on prolactin secretion in nursing females is mediated, at least in part, by salsolinol, and the ligands for MU opioid receptor may be the primary factors of this relationship, especially with respect to the suckling-induced prolactin surge. PMID- 20708657 TI - The inhibitory effects of Gelam honey and its extracts on nitric oxide and prostaglandin E(2) in inflammatory tissues. AB - We investigated the effects of honey and its methanol and ethyl acetate extracts on inflammation in animal models. Rats' paws were induced with carrageenan in the non-immune inflammatory and nociceptive model, and lipopolysaccharide (LPS) in the immune inflammatory model. Honey and its extracts were able to inhibit edema and pain in inflammatory tissues as well as showing potent inhibitory activities against NO and PGE(2) in both models. The decrease in edema and pain correlates with the inhibition of NO and PGE(2). Phenolic compounds have been implicated in the inhibitory activities. Honey is potentially useful in the treatment of inflammatory conditions. PMID- 20708658 TI - Performance constraints in strength events in dogs (Canis lupus familiaris). AB - Ecological performance in animals is considered to be constrained by trade-offs between structural and physiological features. Some of the best anatomical and physiological data in support of this perspective are based on findings from canines, in which researchers have demonstrated skeletal shape trade-offs between running efficiency and strength. There has, however, actually been little examination of the link between these structural differences and relevant performance. In this paper I analyze the performance of six breeds of dogs in standardized weight pulling competitions. More brachycephalic shaped (broad headed) dogs are indeed significantly stronger than more dolichocephalic shaped (narrow headed) dogs even when controlling for body mass. Morphological trade offs between power and running ability may be an important constraint on the evolution of canines and other terrestrial vertebrates. PMID- 20708659 TI - Dogs choose a human informant: metacognition in canines. AB - The presence of metacognition in animals has been suggested by the observation that non-human primates will seek out information about the location of a hidden reward before responding. In experiment 1, dogs failed to make an information seeking response that involved re-positioning themselves in space so that they could view a cue that indicated the location of food. In experiments 2 and 3, dogs were allowed to choose between two people, an informant that pointed to the location of food and a non-informant that provided no information. Dogs showed a clear preference for the informant, even when choice of the informant led to no greater chance of reward than choice of the non-informant. In a procedure that involves human communication, dogs show information-seeking behavior. PMID- 20708660 TI - Characterizing spatial extinction in an abbreviated version of the Barnes maze. AB - Adult male Wistar rats were trained to find an escape box in the Barnes maze in order to characterize the extinction process of a learned spatial preference. To do so, once they had fully acquired the spatial task, they were repeatedly exposed to the maze without the escape box. Multiple behavioral measurements (grouped into motor skill and spatial preference indicators) were followed up throughout the complete training process. Animals gained efficiency in finding the escape box during acquisition, as indicated by the reduction in the time spent escaping from the maze, the number of errors, the length of the traveled path, and by the increase in exploration accuracy and execution speed. When their retention and preference were tested 24h later, all the subjects retained their enhanced performance efficiency and accuracy and displayed a clear-cut preference for the escape hole and its adjacent holes. Almost all motor skill indicators followed an inverse, though not monotonic, pattern during the extinction training, returning to basal levels after three trials without escape box, displaying a transient relapse during the fifth extinction trial. Preference indicators also followed a reverse pattern; however, it took seven trials for them to return to basal levels, relapsing during the eighth extinction trial. The abbreviated Barnes maze acquisition, evaluation, and extinction procedures described herein are useful tools for evaluating the effects of behavioral and/or pharmacological treatment on different stages of spatial memory, and could also be used for studying the neurophysiological and neurobiological underpinnings of this kind of memory. PMID- 20708661 TI - A random-walk interpretation of incentive effects in visual discrimination. AB - Previous studies have shown that changes in stimulus discriminability and changes in reward density affect pigeon reaction-time (RT) distributions in different ways. A random-walk model ("RWP") accounts for these differences and assigns a single parameter to each of the independent variables. This paper briefly reviews the model and illustrates its findings with hue discrimination data. A new analysis then presents fits to data showing that increased reward for stimulus "A" lengthens RT of pecks to an alternative stimulus "B", and that this effect on RT distributions is much the same as the effect caused by reduction of reward to B. RWP account for both effects by changes in its "bias" parameter. The remainder of the paper comments on the relations between reward, RT, incentive and bias. PMID- 20708662 TI - Proximity to an edge affects search strategy in adults and children. AB - When searching for a hidden goal, search patterns are often defined according to one of two main search strategies: an absolute strategy, which usually involves searching at a fixed learned distance and direction from a particular reference point, or a relational strategy, which involves searching at a point that maintains the relationship between two or more other points. Past research has shown that humans tend to prefer a relational strategy whereas most non-humans prefer an absolute strategy. However, recent research (Hartley et al., 2004) used a simulated 3D environment to demonstrate that proximity to a boundary affects strategy. In particular, when searching close to an edge, human participants were more likely to use an absolute strategy whereas when searching at a central location, participants were more likely to use a relational strategy. The current studies extend the findings of Hartley et al. Experiment 1 showed that adult humans use different strategies based on the goal's proximity to the edge of a search space, and that strategies differed between males and females. Experiment 2 suggested that children also use different strategies based on the goal's proximity to a boundary, and that some goal locations may be harder to learn than others. Taken together, our results show that search strategies are flexible and context-specific. PMID- 20708663 TI - Precedence of spatial pattern learning revealed by immediate reversal performance. AB - Human participants learned to choose eight correct locations in a 4 * 4 matrix on a computer display. The locations were arranged either in a structured spatial pattern or an unstructured but consistent spatial arrangement. When the assignment of correct and incorrect locations was reversed after initial learning, participants in the spatial pattern condition demonstrated reversal performance immediately (i.e., following the first choice after reversal of the contingencies). Follow-up experiments confirmed that immediate reversal performance depends on a structured spatial pattern among the locations and that a learned motor pattern cannot explain the immediate reversal performance. This pattern of results shows that learning the spatial relations among locations has precedence over learning about the individual locations, even when the individual locations are completely valid predictive cues. PMID- 20708664 TI - Cognitive representation in transitive inference: a comparison of four corvid species. AB - During operant transitive inference experiments, subjects are trained on adjacent stimulus pairs in an implicit linear hierarchy in which responses to higher ranked stimuli are rewarded. Two contrasting forms of cognitive representation are often used to explain resulting choice behavior. Associative representation is based on memory for the reward history of each stimulus. Relational representation depends on memory for the context in which stimuli have been presented. Natural history characteristics that require accurate configural memory, such as social complexity or reliance on cached food, should tend to promote greater use of relational representation. To test this hypothesis, four corvid species with contrasting natural histories were trained on the transitive inference task: pinyon jays, Gymnorhinus cyanocephalus; Clark's nutcrackers, Nucifraga columbiana; azure-winged magpies, Cyanopica cyanus; and western scrub jays, Aphelocoma californica. A simplified computer model of associative representation displayed a characteristic pattern of accuracy as a function of position in the hierarchy. Analysis of the deviation of each subject's performance from this predicted pattern yielded an index of reliance on relational representation. Regression of index scores against rankings of social complexity and caching reliance indicated that both traits were significantly and independently associated with greater use of relational representation. PMID- 20708665 TI - Toward a framework for the evaluation of feature binding in pigeons. AB - Pigeons were trained in a new procedure to test for visual binding errors between the dimensions of color and shape. In Experiment 1, pigeons learned to discriminate a target compound from 15 non-target compounds (constructed from four colors and shapes) by choosing one of two hoppers in a two-hopper choice task. The similarity of the target to non-target stimuli influenced choice responding. In Experiment 2, pigeons learned to detect a target compound when presented with a non-target compound within the same trial under conditions of simultaneity and sequentiality. Non-target trials were arranged to allow for the testing of binding errors (i.e., false identifications of the target on certain non-target trials). Transient evidence for binding errors in two of the birds occurred at the start of two-item training, but decreased with training. The experiments represent an important step toward developing a framework for the evaluation of visual feature binding in nonhumans. PMID- 20708666 TI - Associative symmetry and stimulus-class formation by pigeons: the role of non reinforced baseline relations. AB - Two experiments tested the assumption of Urcuioli's (2008) theory of pigeons' equivalence-class formation that consistent non-reinforcement of certain stimulus combinations in successive matching juxtaposed with consistent reinforcement of other combinations generates stimulus classes containing the elements of the reinforced combinations. In Experiment 1, pigeons were concurrently trained on symbolic (AB) and two identity (AA and BB) successive tasks in which half of all identity trials ended in non-reinforcement but all AB trials were reinforced, contingent upon either responding or not responding to the comparisons. Subsequent symmetry (BA) probe trials showed evidence of symmetry in one of four pigeons. In Experiment 2, pigeons learned three pair-comparison tasks in which left versus right spatial choices were reinforced after the various sample comparison combinations comprising AB, AA, and BB conditional discriminations. Non-differentially reinforced BA probe trials following acquisition showed some indication of symmetrical choice responding. The overall results contradict the theoretical predictions derived from Urcuioli (2008) and those from Experiment 2 challenge other stimulus-class analyses as well. PMID- 20708667 TI - Genome-wide survey for PilR recognition sites of the metal-reducing prokaryote Geobacter sulfurreducens. AB - Geobacter sulfurreducens is a species from the bacterial family Geobacteraceae, members of which participate in bioenergy production and in environmental bioremediation. G. sulfurreducens pili are electrically conductive and are required for Fe(III) oxide reduction and for optimal current production in microbial fuel cells. PilR is an enhancer binding protein, which is an activator acting together with the alternative sigma factor, RpoN, in transcriptional regulation. Both RpoN and PilR are involved in regulation of expression of the pilA gene, whose product is pilin, a structural component of a pilus. Using bioinformatic approaches, we predicted G. sulfurreducens sequence elements that are likely to be regulated by PilR. The functional importance of the genome region containing a PilR binding site predicted upstream of the pilA gene was experimentally validated. The predicted G. sulfurreducens PilR binding sites are similar to PilR binding sites of Pseudomonas and Moraxella. While the number of predicted PilR-regulated sites did not deviate from that expected by chance, multiple sites were predicted upstream of genes with roles in biosynthesis and function of pili and flagella, in secretory pathways, and in cell wall biogenesis, suggesting the possible involvement of G. sulfurreducens PilR in regulation of production and assembly of pili and flagella. PMID- 20708668 TI - Impact of DUSP1 on the apoptotic potential of deoxynivalenol in the epithelial cell line HepG2. AB - The trichothecene deoxynivalenol (DON) is the most common mycotoxin contaminant of cereal-based food products. Several studies revealed DON as a potent inducer of the three major mitogen-activated protein kinases (MAPKs). Until now, little is known about the role of negative regulators of MAPK pathway in the cellular response to DON. In this report we evaluated, for the first time, the impact of mitogen-activated protein kinase phosphatases (MKPs), particularly dual specific phosphatase 1 (DUSP1), on the toxic potential of DON in the epithelial cell line HepG2. Our results indicate that both low and high concentrations of DON trigger a strong and sustained DUSP1 mRNA and protein expression, mediated by the sustained activation of MEK/ERK pathway. Furthermore, the expression of DUSP1 protein correlates with the inactivation of JNK1/2, whereas a sustained activation of p38 and ERK1/2 was observed in the presence of DON. In contrast, treatment of DUSP1 knock-down cells with DON triggers a prolonged activation of JNK1/2, which leads to the induction of apoptosis. Taken together, we propose DUSP1 as a novel target gene of DON, which is essential for the prevention of DON induced apoptosis in the epithelial cell line HepG2. PMID- 20708669 TI - Genomics and proteomics in chemical warfare agent research: recent studies and future applications. AB - Medical research on the effects of chemical warfare agents (CWAs) has been ongoing for nearly 100 years, yet these agents continue to pose a serious threat to deployed military forces and civilian populations. CWAs are extremely toxic, relatively inexpensive, and easy to produce, making them a legitimate weapon of choice for terrorist organizations. While the mechanisms of action for many CWAs have been known for years, questions about their molecular effects following acute and chronic exposure remain largely unanswered. Global approaches that can pinpoint which cellular pathways are altered in response to CWAs and characterize long-term toxicity have not been widely used. Fortunately, innovations in genomics and proteomics technologies now allow for thousands of genes and proteins to be identified and subsequently quantified in a single experiment. Advanced bioinformatics software can also help decipher large-scale changes observed, leading to mapping of signaling pathways, functional characterization, and identification of potential therapeutic targets. Here we present an overview of how genomics and proteomics technologies have been applied to CWA research and also provide a series of questions focused on how these techniques could further our understanding of CWA toxicity. PMID- 20708670 TI - A method for MS(E) differential proteomic analysis of archival formalin-fixed celloidin-embedded human inner ear tissue. AB - Proteomic analysis of cadaveric formalin-fixed, celloidin-embedded (FFCE) temporal bone tissue has the potential to provide new insights into inner ear disorders. We have developed a liquid chromatography-mass spectrometry (LC-MS) method for tissue sections embedded with celloidin. Q-TOF (Quadrupole-time of flight mass spectrometry) MS(E) (mass spectrometry where E represents collision energy) and Identity(E)TM were used in conjunction with nano-UPLC (capillary ultrahigh pressure liquid chromatography) for robust identification and quantification of a large number of proteins. Formalin-fixed paraffin-embedded (FFPE) mouse liver sections were used to evaluate formalin de-cross-linking by five different methods. Unfixed fresh mouse liver tissue was used as a control. Five different methods for preparation of FFPE tissue for MS analysis were compared, as well as four methods for celloidin removal with FFCE mouse liver tissue. The methods judged best were applied to FFCE 20 MUm sections of mouse inner ear samples, and FFCE 20 MUm human inner ear and human otic capsule bone sections. Three of the five-tissue extraction methods worked equally in detecting peptides and proteins from FFPE mouse liver tissue. The modified Liquid Tissue kit protocol was chosen for further studies. Four different celloidin removal methods were compared and the acetone removal method was chosen for further analysis. These two methods were applied to the analysis of FFCE inner ear and otic capsule sections. Proteins from all major cellular components were detected in the FFCE archival human temporal bone sections. This newly developed technique enables the use of FFCE tissues for proteomic studies. PMID- 20708671 TI - Brainstem correlates of speech-in-noise perception in children. AB - Children often have difficulty understanding speech in challenging listening environments. In the absence of peripheral hearing loss, these speech perception difficulties may arise from dysfunction at more central levels in the auditory system, including subcortical structures. We examined brainstem encoding of pitch in a speech syllable in 38 school-age children. In children with poor speech-in noise perception, we find impaired encoding of the fundamental frequency and the second harmonic, two important cues for pitch perception. Pitch, an essential factor in speaker identification, aids the listener in tracking a specific voice from a background of voices. These results suggest that the robustness of subcortical neural encoding of pitch features in time-varying signals is a key factor in determining success with perceiving speech in noise. PMID- 20708672 TI - Threshold predictions of different pulse shapes using a human auditory nerve fibre model containing persistent sodium and slow potassium currents. AB - The ability of a human auditory nerve fibre computational model to predict threshold differences for biphasic, pseudomonophasic and alternating monophasic waveforms was investigated. The effect of increasing the interphase gap, interpulse interval and pulse rate on thresholds was also simulated. Simulations were performed for both anodic-first and cathodic-first stimuli. Results indicated that the model correctly predicted threshold reductions for pseudomonophasic compared to biphasic waveforms, although reduction for alternating monophasic waveforms was underestimated. Threshold reductions were more pronounced for cathodic-first stimuli compared to anodic-first stimuli. Reversal of the phases in pseudomonophasic stimuli suggested a threshold reduction for anodic-first stimuli, but a threshold increase in cathodic-first stimuli. Inclusion of the persistent sodium and slow potassium currents in the model resulted in a reasonably accurate prediction of the non-monotonic threshold behaviour for pulse rates higher than 1000 pps. However, the model did not correctly predict the threshold changes observed for low pulse rate biphasic and alternating monophasic waveforms. It was suggested that these results could in part be explained by the difference in the refractory periods between real and simulated auditory nerve fibres, but also by the lack of representation of stochasticity observed in real auditory nerve fibres in our auditory nerve model. PMID- 20708673 TI - Gathering of aging and estrogen withdrawal in vascular dysfunction of senescent accelerated mice. AB - The aim of this work was to characterize a mouse model of experimental menopause and cardiovascular aging that closely reflects menopause in women. Senescence accelerated mouse (SAM)-Resistant type 1 (SAMR1, n=30) and SAM-Prone type 8 (SAMP8, n=30) were separated at 5months of age into three groups: 1) sham operated (Sham); 2) ovariectomized (Ovx); and 3) ovariectomized chronically treated with estrogen (Ovx+E2). Contractile responses to KCl (60mM) and thromboxane A(2) were greater in aorta from SAMP8 mice compared with SAMR1 in all groups. Neither ovariectomy nor estrogen replacement modified the contractile responses from SAMR1 mice. Conversely, in Ovx SAMP8 the increased maximal contractions were reversed by estrogen treatment. Rings with endothelium from all SAMR1 groups showed a greater relaxation to acetylcholine than SAMP8 groups. In SAMR1, endothelium-dependent relaxation was not altered in Ovx or Ovx+E2 groups. Rings from Ovx SAMP8 showed a decreased maximal response to acetylcholine compared to Sham SAMP8. Estrogen replacement restored the response to acetylcholine altered by ovariectomy. Nitric oxide inhibition by L-NAME markedly reduced acetylcholine responses in all groups, but this effect was less pronounced in SAMP8 and Ovx groups (determined by area under the curve reduction). These results indicate that SAMP8 exhibit a significant decreased endothelium-dependent and NO-mediated relaxation and increased vasoconstrictor responses that are potentiated by the lack of estrogen. Because these responses are closely in agreement with vascular dysfunction observed in menopausal women, we propose SAMP8 Ovx as a new model to concomitantly study the effects of aging and menopause in female mice. PMID- 20708674 TI - Non-steroidal anti-inflammatory drugs may modulate the protease activity of Candida albicans. AB - The phenotypic pressure exerted by non-steroidal anti-inflammatory drugs (NSAIDs) on autochthonous and pathogenic microbiota remains sparsely known. In this study, we investigated if some NSAIDs increment or diminish the secretion of aspartyl proteases (Sap) by Candida albicans grown under different phenotypes and oxygen availability using a set of SAP knock-out mutants and other set for genes (EFG1 and CPH1) that codify transcription factors involved in filamentation and protease secretion. Pre-conditioned cells were grown under planktonic and biofilm phenotypes, in normoxia and anoxia, in the presence of plasma concentrations of acetylsalicylic acid, diclofenac, indomethacin, nimesulide, piroxicam, ibuprofen, and acetaminophen. For diclofenac, indomethacin, nimesulide, and piroxicam the secretion rates of Sap by SAP1-6, EFG1, and CPH1 mutants were similar or, even, inferior to parental wild-type strain. This suggests that neither Sap 1-6 isoenzymes nor Efg1/Cph1 pathways may be entirely responsible for protease release when exposed to these NSAIDs. Ibuprofen and acetaminophen enhanced Sap secretion rates in three environmental conditions (normoxic biofilm, normoxic planktonic and anoxic planktonic). In other hand, aspirin seems to reduce the Sap related pathogenic behavior of candidal biofilms. Modulation of Sap activity may occur according to candidal phenotypic state, oxygen availability, and type of NSAID to which the cells are exposed. PMID- 20708675 TI - The inhibitory effect of acrylamide on NCAM expression in human neuroblastoma cells: involvement of CK2/Ikaros signaling pathway. AB - Acrylamide has been known to have a neurotoxic effect which is associated with nerve damage in both the central and peripheral nervous systems. Since neural cell adhesion molecule (NCAM) plays an important role in the processes of neuronal development and synaptic plasticity, the down-regulation of NCAM may lead impaired spatial memory and reduced long-term potentiation. We examined the effect of acrylamide on NCAM expression and the mechanisms of its effect in human neuroblastoma cells. Treatment with acrylamide resulted in the decrease of NCAM expression, which was reversed by CK2 inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB). Moreover, Western blot analysis showed that acrylamide induced the expression of CK2. Acrylamide dose-dependently decreased the DNA binding affinity of the Ikaros transcription factor, which is a bifunctional differentiation factor. In addition, the cells treated with acrylamide and CK2 inhibitor showed increased Ikaros activity compared with the acrylamide treatment only. Small interfering RNA-mediated depletion of CK2-alpha also increased Ikaros activity in acrylamide-treated cells. Overall, these data suggest that acrylamide decreases the Ikaros DNA binding activity via the CK2 pathway, resulting in a decrease of NCAM expression and provide further insight into the mechanisms underlying acrylamide actions. PMID- 20708676 TI - Zinc oxide nanoparticle disruption of store-operated calcium entry in a muscarinic receptor signaling pathway. AB - The influences of ZnO nanoparticles on cellular responses to activation of muscarinic receptors were studied in Chinese hamster ovary cells expressing the human M3 muscarinic acetylcholine receptor. ZnO particles (20 nm) induced cytotoxicity in a time and concentration-dependent manner: following a 24h exposure, toxicity was minimal at concentrations below 20 MUg/ml but virtually complete at concentrations above 28 MUg/ml. ZnO particles did not affect antagonist binding to M3 receptors or allosteric ligand effects, but increased agonist binding affinity while eliminating guanine nucleotide sensitivity. At a noncytotoxic concentration (10 MUg/ml), ZnO increased resting [Ca(2+)](i) from 40 to 130 nM without compromising calcium homeostatic mechanisms. ZnO particles had minimal effects on IP3- or thapsigargin-mediated release of intracellular calcium from the endoplasmic reticulum, but strongly inhibited store-operated calcium entry (capacitive calcium entry). The latter effect was seen as (1) a decrease in the plateau phase of the response and (2) a decrease in Ca(2+) entry upon introduction of calcium to the extracellular medium following thapsigargin induced depletion of calcium from the endoplasmic reticulum (EC50's ~ 2 MUg/ml). Thus, ZnO nanoparticles interfere with two specific aspects of the M3 signaling pathway, agonist binding and store-operated calcium entry. PMID- 20708677 TI - Cultured cerebellar granule neurons as an in vitro aging model: topoisomerase IIbeta as an additional biomarker in DNA repair and aging. AB - Aging in the brain is a multicellular process manifesting as neurodegeneration and associated functional impairment. In the present study, we report that cerebellar granule neurons (CGNs) in culture show senescence-mediated molecular changes indicating establishment of aging processes in vitro. CGNs were viable for 5 weeks followed by cellular degeneration. Molecular changes correlated with cellular senescence and aging include the elevation of senescence-mediated beta galactosidase (SA-beta-gal) activity and intracellular Ca(2+) levels. Decreased base excision repair (BER) as well as non-homologous end joining (NHEJ) activities in CGNs were also observed upon aging in vitro. The decrease in NHEJ activity was shown correlated with corresponding decrease in the levels of topoisomerase IIbeta (topo IIbeta), Ku 70 and Ku 80 suggesting a crucial role for topo IIbeta in repair capacity of CGNs. These studies, besides establishing that CGNs would serve as a good in vitro model for analysis of aging phenomena, also brought out that topo IIbeta, by virtue of its significant role in controlling NHEJ activity, would serve as an additional biomarker for studying aging process. PMID- 20708678 TI - Peroxynitrite mediates right-ventricular dysfunction in nitric oxide-exposed juvenile rats. AB - Chronic pulmonary hypertension in infancy and childhood frequently culminates in right-ventricular (RV) failure and early death. Current management may include prolonged treatment with inhaled nitric oxide (iNO). Our objective was to examine the effects of iNO on established chronic hypoxic pulmonary hypertension in juvenile rats, a model of chronic neonatal pulmonary hypertension characterized by increased pulmonary vascular resistance, vascular remodeling (RV hypertrophy and arterial medial wall thickening), and significant RV dysfunction. Pups were exposed to air or hypoxia (13% O(2)) from postnatal day 1 to 21 while receiving iNO (20 ppm) from day 14 to 21. In hypoxia-exposed animals, treatment with iNO decreased pulmonary vascular resistance, but did not augment RV output or reverse vascular remodeling. In addition, RV output was significantly reduced in air exposed iNO-treated pups. Nitrotyrosine (a marker of peroxynitrite-mediated reactions), apoptosis, and expression of nitric oxide synthases 1 and 2 were increased in RV (but not left-ventricular) tissue from both air- and hypoxia exposed pups treated with iNO. Concurrent treatment with a peroxynitrite decomposition catalyst (FeTPPS, 30 mg/kg/day, ip) prevented apoptosis and completely normalized RV output in iNO-exposed animals. Our results provide the first evidence that iNO may adversely impact the right ventricle through increased local generation of peroxynitrite. PMID- 20708679 TI - Hydrogen peroxide mediates EGCG-induced antioxidant protection in human keratinocytes. AB - The beneficial health effects of (-)-epigallocatechin-3-gallate (EGCG), the main catechin of green tea, have been attributed to complex interactions with a focus on antioxidative properties. Susceptibility to autoxidation and production of cytotoxic reactive oxygen species (ROS), mostly H(2)O(2), have been suggested to occur in vitro but also in vivo. In this study, we address whether autoxidation derived H(2)O(2) may be involved in the cytoprotective effects of EGCG. To that end we investigated keratinocyte-derived HaCat and HL-60 promyelocytic leukemia cells with significantly different sensitivities to H(2)O(2) (IC(50) 117.3 versus 58.3 MUM, respectively) and EGCG (134.1 versus 84.1 MUM). HaCat cells significantly resisted cytotoxicity and DNA damage based on enhanced H(2)O(2) clearance, improved DNA repair, and reduced intracellular ROS generation. Cumulative versus bolus EGCG and H(2)O(2) treatment and H(2)O(2) pretreatment before subsequent high-dose EGCG and vice versa significantly reduced DNA damage and cytotoxicity in HaCat cells only. Addition of catalase abolished the protective activities of low-dose H(2)O(2) and EGCG. In summary, our data suggest that autoxidative generation of low-dose H(2)O(2) is a significant player in the cell-type-specific cytoprotection mediated by EGCG and support the hypothesis that regular green tea consumption can contribute as a pro-oxidant to increased resistance against high-dose oxidative stressors. PMID- 20708680 TI - Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old. AB - The role of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) redox signaling has not been characterized in human skeletal muscle despite an extensive delineation of oxidative stress in the etiology of aging and sarcopenia. We assessed whether the age-associated decline in antioxidant response is due, at least in part, to dysfunction in Nrf2-Keap1 redox signaling. We also evaluated whether an active lifestyle can conserve skeletal muscle cellular redox status via activation of Nrf2-Keap1 signaling. Here we show that a recreationally active lifestyle is associated with the activation of upstream modulators that induce the Nrf2-mediated antioxidant response cascade in skeletal muscle of the elderly. Conversely, a sedentary lifestyle is negatively associated with these adaptations mainly because of dysregulation of Nrf2-Keap1 redox signaling that renders the intracellular environment prone to reactive oxygen species-mediated toxicity. Our results indicate that an active lifestyle is an important determinant of cellular redox status. We propose that the metabolic induction of Nrf2-Keap1 redox signaling promises to be a viable therapy for attenuating oxidative stress-mediated damage in skeletal muscle associated with physical inactivity. PMID- 20708681 TI - Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain. AB - The studies presented here demonstrate the protective effect of acetyl-L carnitine (ALC) against alcohol-induced oxidative neuroinflammation, neuronal degeneration, and impaired neurotransmission. Our findings reveal the cellular and biochemical mechanisms of alcohol-induced oxidative damage in various types of brain cells. Chronic ethanol administration to mice caused an increase in inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine adduct formation in frontal cortical neurons but not in astrocytes from brains of these animals. Interestingly, alcohol administration caused a rather selective activation of NADPH oxidase (NOX), which, in turn, enhanced levels of reactive oxygen species (ROS) and 4-hydroxynonenal, but these were predominantly localized in astrocytes and microglia. Oxidative damage in glial cells was accompanied by their pronounced activation (astrogliosis) and coincident neuronal loss, suggesting that inflammation in glial cells caused neuronal degeneration. Immunohistochemistry studies indicated that alcohol consumption induced different oxidative mediators in different brain cell types. Thus, nitric oxide was mostly detected in iNOS-expressing neurons, whereas ROS were predominantly generated in NOX-expressing glial cells after alcohol ingestion. Assessment of neuronal activity in ex vivo frontal cortical brain tissue slices from ethanol-fed mice showed a reduction in long-term potentiation synaptic transmission compared with slices from controls. Coadministration of ALC with alcohol showed a significant reduction in oxidative damage and neuronal loss and a restoration of synaptic neurotransmission in this brain region, suggesting that ALC protects brain cells from ethanol-induced oxidative injury. These findings suggest the potential clinical utility of ALC as a neuroprotective agent that prevents alcohol-induced brain damage and development of neurological disorders. PMID- 20708682 TI - Cellular effects of photogenerated oxidants and long-lived, reactive, hydroperoxide photoproducts. AB - Reaction of radicals and singlet oxygen ((1)O(2)) with proteins results in both direct damage and the formation of long-lived reactive hydroperoxides. Elevated levels of protein hydroperoxide-derived products have been detected in multiple human pathologies, suggesting that these secondary oxidants contribute to tissue damage. Previous studies have provided evidence for protein hydroperoxide mediated inhibition of thiol-dependent enzymes and modulation of signaling processes in isolated systems. In this study (1)O(2) and hydroperoxides have been generated in J774A.1 macrophage-like cells using visible light and the photosensitizer rose bengal, with the consequences of oxidant formation examined both immediately and after subsequent (dark-phase) incubation. Significant losses of GSH (<=50%), total thiols (<=20%), and activity of thiol-dependent proteins (GAPDH, thioredoxin, protein tyrosine phosphatases, creatine kinase, and cathepsins B and L; 10-50% inhibition) were detected after 1 or 2 min photo oxidation. Non-thiol-dependent enzymes were not affected. In contrast, NADPH levels increased, together with the activity of glutathione reductase, glutathione peroxidase, and thioredoxin reductase; these increases may be components of a rapid global cytoprotective cellular response to stress. Neither oxidized thioredoxin nor radical-mediated protein oxidation products were detected at significant levels. Further decreases in thiol levels and enzyme activity occurred during dark-phase incubation, with this accompanied by decreased cell viability. These secondary events are ascribed to the reactions of long-lived hydroperoxides, generated by (1)O(2)-mediated reactions. Overall, this study provides novel insights into early cellular responses to photo-oxidative damage and indicates that long-lived hydroperoxides can play a significant role in cellular damage. PMID- 20708683 TI - Identification of genes downstream of the Shh signalling in the developing chick wing and syn-expressed with Hoxd13 using microarray and 3D computational analysis. AB - Sonic hedgehog (Shh) signalling by the polarizing region at the posterior margin of the chick wing bud is pivotal in patterning the digits but apart from a few key downstream genes, such as Hoxd13, which is expressed in the posterior region of the wing that gives rise to the digits, the genes that mediate the response to Shh signalling are not known. To find genes that are co-expressed with Hoxd13 in the posterior of chick wing buds and regulated in the same way, we used microarrays to compare gene expression between anterior and posterior thirds of wing buds from normal chick embryos and from polydactylous talpid3 mutant chick embryos, which have defective Shh signalling due to lack of primary cilia. We identified 1070 differentially expressed gene transcripts, which were then clustered. Two clusters contained genes predominantly expressed in posterior thirds of normal wing buds; in one cluster, genes including Hoxd13, were expressed at high levels in anterior and posterior thirds in talpid3 wing buds, in the other cluster, genes including Ptc1, were expressed at low levels in anterior and posterior thirds in talpid3 wing buds. Expression patterns of genes in these two clusters were validated in normal and talpid3 mutant wing buds by in situ hybridisation and demonstrated to be responsive to application of Shh. Expression of several genes in the Hoxd13 cluster was also shown to be responsive to manipulation of protein kinase A (PKA) activity, thus demonstrating regulation by Gli repression. Genes in the Hoxd13 cluster were then sub-clustered by computational comparison of 3D expression patterns in normal wing buds to produce syn-expression groups. Hoxd13 and Sall1 are syn-expressed in the posterior region of early chick wing buds together with 6 novel genes which are likely to be functionally related and represent secondary targets of Shh signalling. Other groups of syn-expressed genes were also identified, including a group of genes involved in vascularisation. PMID- 20708684 TI - Excitotoxicity through Ca2+-permeable AMPA receptors requires Ca2+-dependent JNK activation. AB - The GluA4-containing Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (Ca-AMPARs) were previously shown to mediate excitotoxicity through mechanisms involving the activator protein-1 (AP-1), a c Jun N-terminal kinase (JNK) substrate. To further investigate JNK involvement in excitotoxic pathways coupled to Ca-AMPARs we used HEK293 cells expressing GluA4 containing Ca-AMPARs (HEK-GluA4). Cell death induced by overstimulation of Ca AMPARs was mediated, at least in part, by JNK. Importantly, JNK activation downstream of these receptors was dependent on the extracellular Ca(2+) concentration. In our quest for a molecular link between Ca-AMPARs and the JNK pathway we found that the JNK interacting protein-1 (JIP-1) interacts with the GluA4 subunit of AMPARs through the N-terminal domain. In vivo, the excitotoxin kainate promoted the association between GluA4 and JIP-1 in the rat hippocampus. Taken together, our results show that the JNK pathway is activated by Ca-AMPARs upon excitotoxic stimulation and suggest that JIP-1 may contribute to the propagation of the excitotoxic signal. PMID- 20708685 TI - Characterization of gene expression induced by RTN-1C in human neuroblastoma cells and in mouse brain. AB - The endoplasmic reticulum (ER) stress-mediated pathway is involved in a wide range of human neurodegenerative disorders. Hence, molecules that regulate the ER stress response represent potential candidates as drug targets to tackle these diseases. In previous studies we demonstrated that upon acetylation the reticulon 1C (RTN-1C) variant of the reticulon family leads to inhibition of histone deacetylase (HDAC) enzymatic activity and endoplasmic reticulum stress-dependent apoptosis. Here, by microarray analysis of the whole human genome we found that RTN-1C is able to specifically regulate gene expression, modulating transcript clusters which have been implicated in the onset of neurodegenerative disorders. Interestingly, we show that some of the identified genes were also modulated in vivo in a brain-specific mouse model overexpressing RTN-1C. These data provide a basis for further investigation of RTN-1C as a potential molecular target for use in therapy and as a specific marker for neurological diseases. PMID- 20708686 TI - The receptor protein tyrosine phosphatase HmLAR1 is up-regulated in the CNS of the adult medicinal leech following injury and is required for neuronal sprouting and regeneration. AB - LAR-like receptor protein tyrosine phosphatases (RPTPs), which are abundantly expressed in the nervous systems of most if not all bilaterian animals thus far examined, have been implicated in regulating a variety of critical neuronal processes. These include neuronal pathfinding, adhesion and synaptogenesis during development and, in adult mammals, neuronal regeneration. Here we explored a possible role of a LAR-like RPTP (HmLAR1) in response to mechanical trauma in the adult nervous system of the medicinal leech. In situ hybridization and QPCR analyses of HmLAR1 expression in individual segmental ganglia revealed a significant up-regulation in receptor expression following CNS injury, both in situ and following a period in vitro. Furthermore, we observed up-regulation in the expression of the leech homologue of the Abelson tyrosine kinase, a putative signaling partner to LAR receptors, but not among other tyrosine kinases. The effects on neuronal regeneration were assayed by comparing growth across a nerve crush by projections of individual dorsal P neurons (P(D)) following single-cell injection of interfering RNAs against the receptor or control RNAs. Receptor RNAi led to a significant reduction in HmLAR1 expression by the injected cells and resulted in a significant decrease in sprouting and regenerative growth at the crush site relative to controls. These studies extend the role of the HmLARs from leech neuronal development to adult neuronal regeneration and provide a platform to investigate neuronal regeneration and gene regulation at the single cell level. PMID- 20708687 TI - Identification of eukaryotic elongation factor-2 as a novel cellular target of lithium and glycogen synthase kinase-3. AB - Inhibition of glycogen synthase kinase-3 (GSK-3) is thought to be a major consequence of the biological and clinical activity of the mood stabilizer lithium, however, lithium and GSK-3 may activate distinct cellular pathways. We employed a proteomic method to uncover new downstream targets of lithium, and then examined how these proteins are related to GSK-3. Proteomic analysis identified eukaryotic elongation factor-2 (eEF-2) as a cellular target of lithium. This was verified in SH-SY5Y cells and animal models. In cells, lithium decreased eEF-2 phosphorylation at its key inhibitory site, threonine 56, and blocked the enhancement of eEF-2 phosphorylation normally coupled with stress conditions such as nutrient and serum deprivation. Unexpectedly, inhibition of GSK-3 enhanced eEF-2 phosphorylation, and overexpression of GSK-3alpha or GSK 3beta resulted in a strong reduction in eEF-2 phosphorylation. Chronic administration of lithium reduced the hippocampal fraction of phospho-eEF-2 (phospho-eEF-2/total eEF-2) twofold in two different mouse strains. In summary, unexpectedly eEF-2 is activated by both lithium and GSK-3, whereas, lithium treatment and inhibition of GSK-3 have opposing effects on eEF-2. PMID- 20708688 TI - Mouse phenotyping. AB - Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum Munchen as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]). PMID- 20708690 TI - Ribonucleoprotein localization in mouse oocytes. AB - RNA molecules rarely function alone in cells. For most RNAs, their function requires formation of various ribonucleoprotein (RNP) complexes. For example, mRNP composition can determine mRNA localization, translational repression, level of translation or mRNA stability. RNPs are usually studied by biochemical methods. However, biochemical approaches are unsuitable for some model systems, such as mammalian oocytes and early embryos, due to the small amounts that can be obtained for experimental analysis. In such cases, microscopic techniques are often used to learn about RNPs. Here, we present a review of immunostaining, fluorescence in situ hybridization with subcellular resolution and a combination of both, with emphasis on the mouse oocyte and early embryos models. Application of these techniques to whole-mount fixed oocytes and early embryos can provide information about RNP composition and localization with three-dimensional resolution. PMID- 20708689 TI - Purification and characterization of HIV-human protein complexes. AB - To fully understand how pathogens infect their host and hijack key biological processes, systematic mapping of intra-pathogenic and pathogen-host protein protein interactions (PPIs) is crucial. Due to the relatively small size of viral genomes (usually around 10-100 proteins), generation of comprehensive host-virus PPI maps using different experimental platforms, including affinity tag purification-mass spectrometry (AP-MS) and yeast two-hybrid (Y2H) approaches, can be achieved. Global maps such as these provide unbiased insight into the molecular mechanisms of viral entry, replication and assembly. However, to date, only two-hybrid methodology has been used in a systematic fashion to characterize viral-host protein-protein interactions, although a deluge of data exists in databases that manually curate from the literature individual host-pathogen PPIs. We will summarize this work and also describe an AP-MS platform that can be used to characterize viral-human protein complexes and discuss its application for the HIV genome. PMID- 20708691 TI - Microarray analysis of gene expression in eastern oyster (Crassostrea virginica) reveals a novel combination of antimicrobial and oxidative stress host responses after dermo (Perkinsus marinus) challenge. AB - Dermo disease, caused by Perkinsus marinus, is one of the most severe diseases of eastern oysters, Crassostrea virginica. It causes serious mortalities in both wild and aquacultured oysters. Using existing expressed sequence tag (EST) resources, we developed a 12K in situ oligonucleotide microarray and used it for the analysis of gene expression profiles of oysters during the interactions between P. marinus and its oyster host. Significant gene expression regulation was found at day 30 post-challenge in the eastern oyster. Putative identities of the differentially expressed genes revealed a set of genes involved in several processes including putative antimicrobial defenses, pathogen recognition and uptake, anti-oxidation and apoptosis. Consistent with results obtained from previous, smaller-scale experiments, expression profiles revealed a large set of genes likely involved in an active mitigating response to oxidative stress and apoptosis induced by P. marinus. Additionally, a unique galectin from C. virginica, CvGal, which serves as a preferential receptor for P. marinus trophozoites, was found to be significantly down-regulated in gill tissue of oysters with both light and heavy infection, suggesting an attempt to control parasite uptake and proliferation in the later stages of infection. Potential histone-derived antimicrobial responses to P. marinus were also revealed in the gene expression profiles. PMID- 20708692 TI - Manual activity shapes structure and function in contralateral human motor hand area. AB - From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writer's cramp, we employed VBM to test whether suppression (i.e., immobilization) or enhancement (i.e., training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1(HAND)). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4 weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8 weeks. T1 weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4 weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1(HAND) along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1(HAND). The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1(HAND) is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability. PMID- 20708693 TI - Quantitative in vivo evidence for broad regional gradients in the timing of white matter maturation during adolescence. AB - A fundamental tenet in the field of developmental neuroscience is that brain maturation generally proceeds from posterior/inferior to anterior/superior. This pattern is thought to underlie the similar timing of cognitive development in related domains, with the dorsal frontal cortices-important for decision making and cognitive control-the last to fully mature. While this caudal to rostral wave of structural development was first qualitatively described for white matter in classical postmortem studies, and has been discussed frequently in the developmental neuroimaging literature and in the popular press, it has never been formally demonstrated continuously and quantitatively across the whole brain with magnetic resonance imaging (MRI). Here we use diffusion imaging to map developmental changes in the white matter in 32 typically-developing individuals age 5-28 years. We then employ a novel meta-statistic that is sensitive to the timing of this developmental trajectory, and use this integrated strategy to both confirm these long-postulated broad regional gradients in the timing of white matter maturation in vivo, and demonstrate a surprisingly smooth transition in the timing of white matter maturational peaks along a caudal-rostral arc in this cross-sectional sample. These results provide further support for the notion of continued plasticity in these regions well into adulthood, and may provide a new approach for the investigation of neurodevelopmental disorders that could alter the timing of this typical developmental sequence. PMID- 20708694 TI - In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study. AB - Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood. PMID- 20708695 TI - Oral delivery of BCG Moreau Rio de Janeiro gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination. AB - There is a need for an improved vaccine to better control human tuberculosis (TB), as the only currently available TB vaccine, bacillus Calmette-Guerin (BCG) delivered parenterally, offers variable levels of efficacy. Therefore, recombinant strains expressing additional antigens are being developed alongside alternative routes to parenteral delivery. There is strong evidence that BCG Moreau (RdJ) is a safe and effective vaccine in humans when given by the oral route. This study compared the efficacy of a single oral dose of wild type BCG Moreau Rio de Janeiro (RdJ), or a recombinant RdJ strain expressing Ag85B-ESAT6 fusion protein, formulated with and without lipid to enhance oral delivery, with subcutaneous BCG Danish 1331 and saline control groups in a guinea pig aerosol infection model of pulmonary tuberculosis. Protection was measured as survival at 30 weeks post-challenge and reduced bacterial load and histopathology in lungs and spleen. Results showed that a single oral dose of BCG Moreau (RdJ) or recombinant BCG Moreau (RdJ)-Ag85B-ESAT6, formulated with or without lipid, gave protection equivalent to subcutaneously delivered BCG Danish in the 30 weeks post challenge survival study. The orally delivered vaccines gave reduced pathology scores in the lungs (three of the four formulations) and spleens (all four formulations) compared to subcutaneously delivered BCG Danish. The oral wild type BCG Moreau (RdJ) in lipid and the unformulated oral wild type BCG Moreau (RdJ) vaccine also gave statistically lower bacterial loads in the lungs and spleens, respectively, compared to subcutaneously delivered BCG Danish. This study provides further evidence to show that lipid formulation does not impair vaccine efficacy and may enhance the delivery and stability of oral vaccines intended for use in countries with poor health infrastructure. Oral delivery also avoids needles (and associated cross-infection risks) and immunisation without the need for specially trained medical professional staff. PMID- 20708696 TI - Girls' preferences for HPV vaccination: a discrete choice experiment. AB - A discrete choice experiment was developed to investigate if girls aged 12-16 years make trade-offs between various aspects of human papillomavirus (HPV) vaccination, and to elicit the relative weight that girls' place on these characteristics. Degree of protection against cervical cancer, protection duration, risk of side-effects, and age of vaccination, all proved to influence girls' preferences for HPV vaccination. We found that girls were willing to trade off 38% protection against cervical cancer to obtain a lifetime protection instead of a protection duration of 6 years, or 17% to obtain an HPV vaccination with a 1 per 750,000 instead of 1 per 150,000 risk of serious side-effects. We conclude that girls indeed made a trade-off between degree of protection and other vaccine characteristics, and that uptake of HPV vaccination may change considerably if girls are supplied with new evidence-based information about the degree of protection against cervical cancer, the protection duration, and the risk of serious side-effects. PMID- 20708697 TI - Immunogenicity and protective efficacy of an elastase-dependent live attenuated swine influenza virus vaccine administered intranasally in pigs. AB - Influenza A virus is an important respiratory pathogen of swine that causes significant morbidity and economic impact on the swine industry. Vaccination is the first choice for prevention and control of influenza infections. Live attenuated influenza vaccines (LAIV) are approved for use in humans and horses and their application provides broad protective immunity, however no LAIV against swine influenza virus (SIV) exists in the market. Previously we reported that an elastase-dependent mutant SIV A/Sw/Sk-R345V (R345V) derived from A/Sw/Saskatchewan/18789/02 (H1N1) (SIV/Sk02) is highly attenuated in pigs. Two intratracheal administrations of R345V induced strong cell-mediated and humoral immune responses and provided a high degree of protection to antigenically different SIV infection in pigs. Here we evaluated the immunogenicity and the protective efficacy of R345V against SIV infection by intranasal administration, the more practical route for vaccination of pigs in the field. Our data showed that intranasally administered R345V live vaccine is capable of inducing strong antigen-specific IFN-gamma response from local tracheo-bronchial lymphocytes and antibody responses in serum and respiratory mucosa after two applications. Intranasal vaccination of R345V provided pigs with complete protection not only from parental wild type virus infection, but also from homologous antigenic variant A/Sw/Indiana/1726/88 (H1N1) infection. Moreover, intranasal administration of R345V conferred partial protection from heterologous subtypic H3N2 SIV infection in pigs. Thus, R345V elastase-dependent mutant SIV can serve as a live vaccine against antigenically different swine influenza viruses in pigs. PMID- 20708699 TI - Glutamate and aspartate measurements in individual planaria by rapid capillary electrophoresis. AB - INTRODUCTION: Planaria present a unique model organism for studying primitive central nervous systems. The major mammalian excitatory neurotransmitters, glutamate and aspartate, have previously been measured in planaria via high pressure liquid chromatography (HPLC). A faster extraction and analysis procedure using capillary electrophoresis (CE) was developed which confirms the presence of these amino acids in single planaria homogenates. METHOD: Following homogenization and centrifugation of individual planaria in hydrochloric acid/acetonitrile, glutamate and aspartate were derivatized with naphthalene-2, 3 dicarboxaldehyde (NDA). The labeled amino acids were measured using capillary electrophoresis with laser-induced fluorescence (CE-LIF). RESULTS: CE-LIF electropherograms were generated in less than 1 min. The mean +/- S.D. amounts of glutamate and aspartate were 1200 +/- 500 and 1900 +/- 700 pmol/mg-planarian (n=22), respectively. Spiked average recoveries of glutamate and aspartate were 96% and 91%, respectively. DISCUSSION: The high-throughput method provides the ability to quantitate changes in excitatory neurotransmitters under developmental or stimulatory conditions. The capability to monitor multiple neurotransmitter levels offers the opportunity to correlate behavioral responses with biochemical changes in planaria. PMID- 20708698 TI - Circulating pneumococcal specific plasma and memory B cells in the elderly two years after pneumococcal conjugate versus polysaccharide vaccination. AB - BACKGROUND: Polysaccharide conjugate vaccines prime for lasting memory responses in children and young adults. The potential value of these vaccines in the elderly is unclear. METHODS: We compared the frequency of circulating pneumococcal capsular polysaccharide (PPS) specific IgG, IgA and IgM plasma and memory cells by cultured ELISpot and supernatant screening two years after vaccination with the 7-valent pneumococcal conjugate vaccine (7vCRM) and/or the 23-valent pneumococcal polysaccharide vaccine (PPV) in 252 adults aged 50-80 years. Some individuals received a six-month boost with 7vCRM or PPV. PPS specific IgG memory detected two years post-primary vaccination was correlated with published matched serum IgG concentration pre- and up to one year post primary vaccination. RESULTS: There was no difference by vaccine schedule in the quantity of plasma or memory cells detected. The concentration of in vitro PPS IgG produced by memory B cells isolated two years post-vaccination correlated with pre-vaccination serum IgG concentration and not with D28 post-vaccination responses regardless of vaccination schedule. CONCLUSIONS: This study shows that circulating memory B cells numbers two years following immunisation with 7vCRM or PPV are best predicted by pre-vaccination serotype specific serum antibody concentration and not early post-vaccination serum antibody responses. PMID- 20708700 TI - Longitudinal investigation of Clostridium difficile shedding in piglets. AB - A longitudinal study of Clostridium difficile colonization in piglets was performed on a conventional swine farm in Ontario, Canada. Fecal samples were collected from 10 sows prior to their expected farrowing date, and then from all their piglets on days 2, 7, 30, 44 and 62 of life. C. difficile was isolated from 4/10 (40%) of sows prior to farrowing, 90/121 (74%) piglets on day 2, 66/117 (56%) on day 7, 45/113 (40%) on day 30, 23/101 (23%) on day 44 and 2/54 (3.7%) on day 62. There was a significant decrease in colonization over time (P < 0.0001). Overall, C. difficile was isolated from one or more samples from 116/121 (96%) piglets. There was an inverse association between sow colonization and piglet colonization on day 2 (P < 0.0001) and a positive association on day 7 (P = 0.001). Ribotype 078/toxinotype V predominated, accounting for 213/234 (91%) isolates. A toxinotype XIV strain that has been previously found in humans in the province was the 2nd most common, but was mainly found in sows, not piglets. Overall, 227/234 (97%) of isolates were from types that have been isolated from humans in the province. Intermittent colonization was detected in 11 (9.6%) piglets. The decline in C. difficile colonization over the first 2 months of life was remarkable. The variation in colonization over a relatively short period of time has important implications for the design and interpretation of studies evaluating C. difficile colonization in pigs, since relatively small differences in age may have a major confounding effect on the prevalence of colonization. The decline in prevalence over time may also have implications on public health concerns, since colonization rates of animals at the time of slaughter are presumably more relevant than those earlier in life. PMID- 20708701 TI - Exogenous Addition of Minor H Antigen HA-1+ Dendritic Cells to Skin Tissues Ex Vivo Causes Infiltration and Activation of HA-1-Specific Cytotoxic T Cells. AB - T cells specific for hematopoietic system restricted minor Histocompatibility (H) antigens target normal and malignant hematopoietic cells. Thus, cellular immune responses against the latter miHAS eradicate the recipient's hematopoiesis including residual leukemic cells after HLA-matched minor H antigen-mismatched stem-cell transplantation (SCT). However, there are controversial reports on the role of HA-1 in the development of graft-versus-host-disease (GVHD) as well. Here, we address the behavior of HA-1-specific cytotoxic T cells (CTLs) in an ex vivo in situ skin explant model wherein HA-1-expressing dendritic cells (DCs) were added as antigen-presenting cells (APCs). Infiltration and activation of HA 1 CTLs occurred only in those cases where both HLA-A2 and HA-1 were expressed, either by the skin or by the DCs, or by the combination of HLA-A2(+) skin and HA 1(+) DCs. These results point toward the role of recipient's HA-1(+) DCs in the chimeric patient suffering from GVHD after HA-1-mismatched SCT. Although in our model the infiltrated and activated CTLs did not cause skin tissue destruction, our results provide a first step in understanding the reported association of HA 1 mismatching with clinical GVHD. PMID- 20708702 TI - Human CD4(+)CD25(+) Cells in Combination with CD34(+) Cells and Thymoglobulin to Prevent Anti-hematopoietic Stem Cell T Cell Alloreactivity. AB - Cotransplantation of human CD34(+) hematopoietic stem cells (HSC) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) could prevent anti-HSC alloreactivity and reduce the risk of rejection in HLA mismatched transplants. To pursue this hypothesis we cocultured CD34(+) cells and CD4(+)CD25(+) cells immunomagnetically isolated (Milteny) from human peripheral blood (unmanipulated or granulocyte-colony stimulating factor [G-CSF] mobilized) or cord blood. Enriched Tregs obtained from the same source (autologous) of CD34(+) cells showed greater inhibitory effect on T cell alloreactivity than third-party (allogeneic) Tregs. The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic CD34(+) cells and Tregs did not modify the clonogenic activity of CD34(+) cells in vitro. Cotransplantation of Tregs with CD34(+) cells at 1:1 or 2:1 ratios in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice resulted in normal hematopoietic stem cell engraftment. Incubation with physiologic doses of rabbit antithymocyte globulin (rATG, thymoglobulin) did not affect the number of Tregs in 6-day culture. Upon exposure to thymoglobulin Tregs maintained their suppressive activity, increased expression of CCR7, and released multiple cytokines, primarily interleukin (IL)10. Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with CD34(+) cells after preparative regimens including thymoglobulin. PMID- 20708703 TI - Daidzein regulates secretion, production and gene expression of mucin from airway epithelial cells stimulated by proinflammatory factor and growth factor. AB - In this study, we investigated whether daidzein significantly affects secretion, production and gene expression of mucin from cultured airway epithelial cells. Confluent primary rat tracheal surface epithelial (RTSE) cells were pretreated with adenosine triphosphate (ATP) for 5 min and then chased for 30 min in the presence of daidzein to assess the effect on mucin secretion using ELISA. At the same time, confluent NCI-H292 cells were pretreated with daidzein for 30 min and then stimulated with EGF and PMA for 24 h, respectively. The MUC5AC mucin gene expression and mucin protein production were measured by RT-PCR and ELISA. The results were as follows: (1) daidzein significantly decreased ATP-induced mucin secretion from cultured RTSE cells; (2) daidzein inhibited the production of MUC5AC mucin protein induced by EGF or PMA from NCI-H292 cells; (3) daidzein also inhibited the expression of MUC5AC mucin gene induced by EGF or PMA from NCI-H292 cells. This result suggests that daidzein can regulate secretion, production and gene expression of mucin, by directly acting on airway epithelial cells. PMID- 20708704 TI - Serum biomarkers in idiopathic pulmonary fibrosis. AB - Within the group of Idiopathic Interstitial Pneumonias (IIPs), above all Idiopathic Pulmonary Fibrosis (IPF) poses a considerable diagnostic and therapeutic problem. Although genetic profiling indicates that IPF, Non Specific Interstitial Pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP) are distinctly different diseases, in every day practice these diseases can be difficult to tell apart. Furthermore, treatment of these diseases is notoriously difficult. Serum biomarkers reflect our understanding of the underlying pathogenesis and potentially fulfill a role in establishing a diagnosis, prognosis and therapy. While no single biomarker is currently able to accurately predict the presence or absence of an IIP, a composite of several markers holds promise for the future. Several biomarkers, such as KL-6, surfactant proteins and circulating fibrocytes, appear to contribute to our insight into disease progression and prognosis. It is however uncertain whether these markers give us additional information to common diagnostic tests and their value has as yet to be validated for every day practice. Fortunately, the potential of biomarkers is increasingly recognized and biomarker data are prospectively gathered in current placebo-controlled therapeutic trials. PMID- 20708705 TI - Plasma and brain angiotensin concentrations associated with water response behavior in the desert anuran, Scaphiopus couchii under natural conditions in the field. AB - Terrestrial amphibians obtain water by absorption across a specialized region of the ventral skin and exhibit a behavior, the water absorption response (WR) to place that region in contact with moist surfaces. Spadefoot toads (Scaphiopus couchii) spend dry months of the year in burrows, then emerge during brief periods of summer rainfall and seek water sources for rehydration and reproduction. We tested the hypothesis that these toads have changes in plasma and/or central angiotensin concentrations that are associated with seasonal emergence and WR behavior. Immunoreactive concentrations of combined angiotensin II and III (ir-ANG) were measured in plasma samples and microdissected regions of brain tissue taken from toads moving across the road or toads showing WR behavior in shallow puddles on the road. Plasma ir-ANG concentrations were not significantly different between these groups, but were significantly higher in the periventricular region of the hypothalamus in toads showing WR behavior. Concentrations in other brain regions, while highly variable among individuals, were not different between groups. Within the context of the natural history of a specialized desert toad, these results support the hypothesis that ir-ANG is associated with WR behavior in spadefoot toads in a manner analogous to oral drinking exhibited by other vertebrate clades. PMID- 20708706 TI - Isolation and characterization of two alginate lyase isozymes, AkAly28 and AkAly33, from the common sea hare Aplysia kurodai. AB - Two alginate lyase isozymes, AkAly28 and AkAly33, with approximate molecular masses of 28 and 33kDa, respectively, were isolated from the digestive fluid of the common sea hare, Aplysia kurodai. Both of AkAly28 and AkAly33 were regarded as the endolytic polymannuronate (poly(M)) lyase (EC 4.2.2.3) since they preferably degraded poly(M)-rich substrate producing unsaturated tri- and disaccharides and rapidly decreased the viscosity of sodium alginate solution in the initial phase of degradation. Optimal pH and temperature of the two enzymes were similarly observed at pH 6.7 and 40 degrees C, respectively. Temperature that caused a half inactivation of the two enzymes during 20-min incubation was also similar to each other, i.e., 38 degrees C. However, NaCl requirement and activity toward oligosaccharide substrates of the two enzymes were significantly different from each other. Namely, AkAly28 showed practically no activity in the absence of NaCl and the maximal activity at NaCl concentrations higher than 0.2 M, whereas AkAly33 showed ~20% of maximal activity despite the absence of NaCl and the maximal activity at around 0.1 M NaCl. AkAly28 hardly degraded oligosaccharides smaller than tetrasaccharide, while AkAly33 could degrade oligosaccharides larger than disaccharide producing disaccharide and 2-keto-3 deoxy-gluconaldehyde (an open chain form of unsaturated monosaccharide). Analysis of the N-terminal and internal amino-acid sequences of AkAly28 and AkAly33 indicated that both of the two enzymes belong to polysaccharide lyase family 14. PMID- 20708707 TI - Insulin-like growth factor binding protein-2 (IGFBP-2) in orange-spotted grouper, Epinephelus coioides: molecular characterization, expression profiles and regulation by 17beta-estradiol in ovary. AB - In the present study, a full-length cDNA encoding the insulin-like growth factor binding protein-2 (IGFBP-2) was cloned from the liver of orange-spotted grouper (Epinephelus coioides) by rapid amplification of cDNA ends technique. The IGFBP-2 cDNA sequence was 1413 bp long and had an open reading frame (ORF) of 813 bp encoding a predicted polypeptide of 270 amino acid residues. The deduced amino acid sequence contained a putative signal peptide of 22 amino acid residues resulting in a mature protein of 248 amino acids. Using semi-quantitative RT-PCR, tissue distribution pattern showed that IGFBP-2 mRNA was observed in all regions of brain with high levels, except lower levels in cerebellum and hypothalamus. In peripheral tissues, IGFBP-2 mRNA was most abundant in liver, although relatively high levels were observed in intestine, ovary and pituitary. Low or no IGFBP-2 mRNA expression was observed in other examined tissues. From the multicellular stage to the hatching stage, IGFBP-2 mRNA was expressed consecutively. Furthermore, 1 nM 17beta-estradiol could inhibit the ovarian IGFBP-2 mRNA expression significantly in vitro. The mRNA expression and regulation profiles suggest that the IGFBP-2 may play important physiological roles in fish growth and reproduction, as well as cell growth and organ differentiation during the embryonic developmental stages. PMID- 20708708 TI - Vitellin- and hemoglobin-digesting enzymes in Rhipicephalus (Boophilus) microplus larvae and females. AB - The aim of the present study was to address the involvement of Rhipicephalus microplus larval cysteine endopeptidase (RmLCE) in protein digestion in R. microplus larvae and adult females. In this work, an improved purification protocol for native RmLCE was developed. Partial amino acid sequence of the purified enzyme indicates that it is the same enzyme as Boophilus microplus cathepsin-L1 (BmCL1). When vitellin (Vt) degradation by egg and larval enzymes was analyzed, stage-specific differences for RmLCE activity in comparison to vitellin-degrading cysteine endopeptidase (VTDCE) were observed. RmLCE is also able to degrade host hemoglobin (Hb). In agreement, an acidic cysteine endopeptidase activity was detected in larval gut. It was shown that cysteine and aspartic endopeptidases are involved in Vt and Hb digestion in R. microplus larvae and females. Interestingly, we observed that the aspartic endopeptidase Boophilus yolk cathepsin (BYC) is associated with a cysteine endopeptidase activity, in larvae. Synergic hemoglobin digestion by BYC and RmLCE was observed and indicates the presence of an Hb-degrading enzymatic cascade involving these enzymes. Our results suggest that RmLCE/BmCL1 has a continued role in vitellin and hemoglobin digestion during tick development. PMID- 20708709 TI - Evaluation of oxidative DNA lesions in plasma and nuclear abnormalities in erythrocytes of wild fish (Liza aurata) as an integrated approach to genotoxicity assessment. AB - Genetic lesions (8-hydroxy-2'-deoxyguanosine (8-OHdG) and erythrocytic nuclear abnormalities (ENA) were seasonally quantified in the blood of Liza aurata caught at Ria de Aveiro (Portugal), a multi-contaminated aquatic system. Thus, five critical sites were assessed and compared with a reference site (Torreira). Oxidative DNA damage was found in Gafanha (harbour-water area), Laranjo (metal contaminated) and Vagos (contaminated with PAHs) in the spring; Rio Novo do Principe (near a former paper-mill effluent) in the autumn; Rio Novo do Principe and Vagos in the winter. ENA were higher than Torreira at VAG (spring and winter). Torreira did not display seasonal variation neither in terms of 8-OHdG or total ENA. A positive correlation between 8-OHdG and ENA was found, suggesting oxidative stress as a mechanism involved in the formation of ENA. This study clearly demonstrates the presence of DNA-damaging substances in Ria de Aveiro and recommends the use of 8-OHdG and ENA as biomarkers of environmental contamination. PMID- 20708710 TI - Genotoxic effects of occupational exposure measured in lymphocytes of waste incinerator workers. AB - Workers of solid-waste incinerators are exposed to a variety of pollutants such as dioxins, polycyclic aromatic hydrocarbons and heavy metals. It has been shown that the emissions and the fly ash produced by incineration have mutagenic properties. To our knowledge, no studies have been conducted in which genotoxic effects were investigated in exposed workers. Therefore, we monitored DNA damage by means of the single-cell gel electrophoresis (SCGE) and micronucleus (MN) assays in lymphocytes of individuals (n=23) who were temporarily (1-11 months) conducting maintenance works of an incinerator and in unexposed controls (n=19). Additionally, we measured the urinary concentrations of selected metals (Cr, Mn, Ni, As) with atomic absorption resonance. We found no differences in the levels of DNA migration and in the MN frequencies between different exposure groups and controls. Likewise, we also failed to find differences in the metal concentrations. Taken together, our results indicate that incinerator workers at the site investigated here have no increased health risks due to DNA damage. PMID- 20708711 TI - Catheter ablation of atrial fibrillation in patients with persistent left superior vena cava is associated with major intraprocedural complications. AB - BACKGROUND: A persistent left superior vena cava (PLSVC) is an uncommon cardiac anomaly. OBJECTIVE: The purpose of this study was to assess the complication rate and procedural outcome in patients with PLSVC who were referred for catheter ablation of atrial fibrillation (AF). METHODS: Between September 2006 and February 2009, seven patients referred for circumferential pulmonary vein (PV) isolation (PVI) demonstrated a PLSVC. PVI was confirmed by spiral catheter recording within the respective PVs. Ablation within the PLSVC was performed using an irrigated-tip catheter (energy settings 20 W, 43 degrees C, flow rate 17 mL/min) or, alternatively, a cryoballoon catheter (28 mm balloon, 300-second energy application). Patients were analyzed according to procedural outcome and rate of complications. RESULTS: Among seven patients (three female, mean age 57 +/- 8 years, two paroxysmal, five persistent AF, structural/congenital heart disease present in three patients, mean left atrial size 43 +/- 6 mm), 14 ablation procedures were performed. Two major complications (left phrenic nerve injury and cardiac tamponade) occurred in two of four patients undergoing PLSVC ablation. Of four of seven patients undergoing PLSVC ablation, two patients needed one and one patient needed two redo PLSVC ablation procedures. The first time procedural success rate was 29%, while the overall success rate reached 86% after a median follow-up period of 621 (339-1,289) days. CONCLUSION: In patients with ectopic activity from a PLSVC, the ablative strategy should include isolation of the PLSVC as a procedural endpoint, although multiple ablation procedures may be necessary to achieve stable sinus rhythm. Contrary to previous reports, complications are common if the PLSVC is targeted for ablation. PMID- 20708712 TI - Repetitive pacemaker spike during the vulnerable period in a cardiac resynchronization therapy defibrillator. PMID- 20708713 TI - Dual-chamber pacemaker implantation via both superior vena cavae in a patient with persistent left superior vena cava. PMID- 20708714 TI - Design and methods of the MAINTAIN study: a randomized controlled clinical trial of micronutrient and antioxidant supplementation in untreated HIV infection. AB - Micronutrient deficiencies are common in HIV positive persons and are associated with a poorer prognosis, but the role of micronutrient supplementation in the medical management of HIV infection remains controversial, as some but not all studies show immunological and clinical benefit. Micronutrients supplementation could be a relatively low cost strategy to defer the initiation of expensive, potentially toxic and lifelong antiretroviral therapy. The MAINTAIN study is a Canadian multi-center randomized control double blind clinical trial to evaluate if micronutrient supplementation of HIV positive persons slows progression of immune deficiency and delays the need to start antiretroviral therapy and is safe, compared to standard multivitamins. Untreated asymptomatic HIV positive adults will receive a micronutrient and antioxidant preparation (n = 109) or an identical appearing recommended daily allowance multivitamin and mineral preparation (n = 109) for two years. Participants will be followed quarterly and monitored for time from baseline to CD4 T lymphocyte count <350 mm(3), or emergence of CDC-defined AIDS-defining illness, or the start of antiretroviral therapy. We will also compare safety and health related quality of life between groups. Primary analysis will compare the incidence of the composite primary outcome between study groups and will be by intention-to-treat. The study was originally expected to last three years, with accrual over one year and a minimum of two years follow up of the last enrolled participant. We discuss here the study design and methods, often used for evaluation of complementary and adjunctive treatments for health maintenance in HIV infection, which are common interventions. PMID- 20708715 TI - The Extension Family Lifestyle Intervention Project (E-FLIP for Kids): design and methods. AB - The Extension Family Lifestyle Intervention Project (E-FLIP for Kids) is a three arm, randomized controlled trial assessing the effectiveness of two behavioral weight management interventions in an important and at-risk population, overweight and obese children and their parents in rural counties. Participants will include 240 parent-child dyads from nine rural counties in north central Florida. Dyads will be randomized to one of three conditions: (a) a Family-Based Behavioral Group Intervention, (b) a Parent-Only Behavioral Group Intervention, and (c) an Education Control Condition. Child and parent participants will be assessed at baseline (month 0), post-treatment (month 12) and follow-up (month 24). Assessment and intervention sessions will be held at Cooperative Extension Service offices within each participating county. The primary outcome measure is change in child BMI z-score. Additional key outcome measures include child body fat, waist circumference, dietary intake, physical activity, blood lipids, blood glucose, blood pressure, physical fitness, quality of life, and program and participants costs. Parent BMI, dietary intake, and physical activity also will be assessed. Randomized controlled trials testing the effectiveness of childhood obesity interventions in real-world community-based settings are extremely valuable, but much too rare. The E-FLIP for Kids trial will evaluate the impact of a community-based intervention delivered to families in rural settings utilizing the existing Cooperative Extension Service network on long-term child behavior, weight status and biological markers of diabetes and early cardiovascular disease. If successful, a Parent-Only intervention program may provide a cost-effective and practical intervention for families in underserved rural communities. PMID- 20708716 TI - Application of oligonucleotide array CGH in the detection of a large intragenic deletion in POLG associated with Alpers Syndrome. AB - Mutations in the polymerase gamma (POLG) gene are among the most common causes of mitochondrial disease and more than 160 POLG mutations have been reported. However, a large proportion of patients suspected of having POLG mutations only have one (heterozygous) definitive pathogenic mutation identified. Using oligonucleotide array CGH, we identified a compound heterozygous large intragenic deletion encompassing exons 15-21 of this gene in a child with Alpers syndrome due to mtDNA depletion. This is the first large POLG deletion reported and the findings show the clinical utility of using array CGH in cases where a single heterozygous mutation has been identified in POLG. PMID- 20708717 TI - The role of genetic variants in human longevity. AB - Human longevity is a complex phenotype with a strong genetic predisposition. Increasing evidence has revealed the genetic antecedents of human longevity. This article aims to review the data of various case/control association studies that examine the difference in genetic polymorphisms between long-lived people and younger subjects across different human populations. There are more than 100 candidate genes potentially involved in human longevity; this article particularly focuses on genes of the insulin/IGF-1 pathway, FOXO3A, FOXO1A, lipoprotein metabolism (e.g., APOE and PON1), and cell-cycle regulators (e.g., TP53 and P21). Since the confirmed genetic components for human longevity are few to date, further precise assessment of the genetic contributions is required. Gaining a better understanding of the contribution of genetics to human longevity may assist in the design of improved treatment methods for age-related diseases, delay the aging process, and, ultimately, prolong the human lifespan. PMID- 20708718 TI - MicroRNA and aging: a novel modulator in regulating the aging network. AB - miRNAs are a group of noncoding small RNA that are capable of modulating the expression of hundreds of genes via a near-perfect or partial complementary to target mRNA. The ability to regulate multiple targets simultaneously makes miRNA a crucial regulator in many physiological conditions, especially in the aging network and process. The tremendous capability of miRNA supports its ability in regulating ageing, which is a complex process involving multiple interconnected signaling pathways. Even though the relationship between miRNA and ageing is not fully understood, studies have provided evidence showing that miRNAs participate in regulating cell cycle progression, proliferation, stemness gene expression, and stress-induced responses. Molecular studies of ageing and miRNAs would provide a more comprehensive understanding of the mechanisms of ageing and, subsequently, help to ameliorate this universal process compromising our quality of life. In this review article, we focus our attention on miRNA targets in conserved pathways involved in organism aging and aging networks, as well as cellular senescence. PMID- 20708720 TI - Biopolymer scaffolds for use in delivering antimicrobial sophorolipids to the acne-causing bacterium Propionibacterium acnes. AB - Sophorolipids (SLs) are known to possess antimicrobial properties towards many species (particularly Gram-positive, or Gram(+)) of bacteria. However, these properties can only be exerted if the SLs can be introduced to the bacterial cells in an acceptable manner. Propionibacterium acnes is the common bacterial cause of acne. It is a Gram(+) facultative anaerobe that is susceptible to the antimicrobial effects of SLs. In this study we demonstrated that different biopolymer matrices could be used to produce SL composite films that exert various antimicrobial efficiencies against P. acnes. Increasing SL concentrations in poly-3-hydroxybutyrate (PHB) and PHB-co-10%-3-hydroxyhexanoate (PHB/HHx) resulted in noticeably improved (PHB/HHx was best) antimicrobial activity based on the size of the zones of inhibition using an overlay plating technique on synthetic growth medium. However, increasing concentrations of SLs in PHB and PHB/HHx films also increased film opacity, which diminishes the appeal for use especially in visible (facial) areas. Pectin and alginate improved the transparent character of SL composite films while also acting as successful carriers of SLs to P. acnes. The lactone form of the SLs proved to exhibit the best antimicrobial action and in concert with either pectin or alginate biopolymers provided a comparatively transparent, successful means of utilizing SLs as a renewable, environmentally benign anti-acne solution. PMID- 20708719 TI - Degree of endothelium injury promotes fibroelastogenesis in experimental acute lung injury. AB - We tested the hypothesis that at the early phase of acute lung injury (ALI) the degree of endothelium injury may predict lung parenchyma remodelling. For this purpose, two models of extrapulmonary ALI induced by Escherichia coli lipopolysaccharide (ALI-LPS) or cecal ligation and puncture (ALI-CLP) were developed in mice. At day 1, these models had similar degrees of lung mechanical compromise, epithelial damage, and intraperitoneal inflammation, but endothelial lesion was greater in ALI-CLP. A time course analysis revealed, at day 7: ALI-CLP had higher degrees of epithelial lesion, denudation of basement membrane, endothelial damage, elastic and collagen fibre content, neutrophils in bronchoalveolar lavage fluid (BALF), peritoneal fluid and blood, levels of interleukin-6, KC (murine analogue of IL-8), and transforming growth factor-beta in BALF. Conversely, the number of lung apoptotic cells was similar in both groups. In conclusion, the intensity of fibroelastogenesis was affected by endothelium injury in addition to the maintenance of epithelial damage and intraperitoneal inflammation. PMID- 20708721 TI - Support for international agricultural research: current status and future challenges. AB - The success of the first Green Revolution in the form of abundant food supplies and low prices over the past two decades has diverted the world's attention from agriculture to other pressing issues. This has resulted in lower support for the agricultural research work primarily undertaken by the 15 research centers of the Consultative Group on International Agricultural Research (CGIAR). The total support in real dollars for most of the last three decades has been more or less flat although the number of centers increased from 4 to 15. However, since 2000, the funding situation has improved for the CGIAR centers, with almost all the increase coming from grants earmarked for specific research projects. Even for some centers such as the International Rice Research Institute (IRRI), the downward trend continued as late as 2006 with the budget in real dollars reaching the 1978 level of support. The recent food crisis has renewed the call for a second Green Revolution by revitalizing yield growth to feed the world in the face of growing population and a shrinking land base for agricultural use. The slowdown in yield growth because of decades of neglect in agricultural research and infrastructure development has been identified as the underlying reason for the recent food crisis. For the second Green Revolution to be successful, the CGIAR centers will have to play a complex role by expanding productivity in a sustainable manner with fewer resources. Thus, it is crucial to examine the current structure of support for the CGIAR centers and identify the challenges ahead in terms of source and end use of funds for the success of the second Green Revolution. The objective of this paper is to provide a historical perspective on the support to the CGIAR centers and to examine the current status of funding, in particular, the role of project-specific grants in rebuilding capacity of these centers. The paper will also discuss the nature of the support (unrestricted vs. project-specific grants) that will be needed for a much-desired second Green Revolution. PMID- 20708722 TI - Achieving food security in times of crisis. AB - In spite of several World Food Summits during the past decade, the number of people going to bed hungry is increasing and now exceeds one billion. Food security strategies should therefore be revisited. Food security systems should begin with local communities who can develop and manage community gene, seed, grain and water banks. At the national level, access to balanced diet and clean drinking water should become a basic human right. Implementation of the right to food will involve concurrent attention to production, procurement, preservation and public distribution. Higher production in perpetuity should be achieved through an ever-green revolution based on the principles of conservation and climate-resilient farming. This will call for a blend of traditional ecological prudence with frontier technologies, particularly biotechnology and information communication technologies. PMID- 20708723 TI - Regulatory role of resveratrol on Th17 in autoimmune disease. AB - The immune system is balanced with cells that respond to microbes by developing into effector cells and cells that regulate the activity of effector cells. In many immune responses a subset of effector T cells termed Th17 are necessary for complete immunity because the cytokine IL-17 that they produce is critical to elimination of the pathogen. However, the activity of Th17 must be balance with development of regulatory T cells termed T(regs). Usually, when the activity of the effector cells is excessive and not balanced by regulatory cells of the immune system, there is the increased risk for development of autoimmune diseases. Therefore in many autoimmune diseases the activity of Th17 exceeds that of T(regs). Therapeutics for treatment of autoimmune diseases such as Multiple Sclerosis (MS) have focused upon immunosuppression, immunomodulation, or even immunoablation of effector cells such as Th17 followed by hematopoietic stem cell transplantation. Very few approaches have attempted to therapeutically increase immune regulatory cells such as T(regs) in the treatment of autoimmune disease. This review will focus upon the potential 'or the use of resveratrol, a natural plant compound that has already been shown to be a potent anti-inflammatory compound, as a complementary therapeutic for MS that increases the activity of T(regs) even though it also increases development of Th17. PMID- 20708724 TI - More neurons for respiratory adaptation: is neurogenesis at work? PMID- 20708725 TI - [Supraventricular tachycardia in infants]. AB - Supraventricular tachycardia in infants are variable. We try to summarize clinical, electrical and treatment particularities of supraventricular arrhythmia in infants. The majority of infants with supraventricular arrhythmia have a good clinical outcome and an excellent prognosis and may not require chronic antiarrhythmic therapy if they had precocious treatment. PMID- 20708726 TI - [Arterial hypertension in black subjects over 50 years of age in Lome: epidemiological aspects and evaluation of cardiovascular risk (prospective and longitudinal study of 1485 patients)]. AB - INTRODUCTION: High blood pressure is a public health problem for which the assumption of responsibility remains especially difficult in older subjects. Generally, it is associated with other cardiovascular risk factors. The objective of this study is to determine the prevalence of high blood pressure in older subjects in a particular environment and to evaluate the cardiovascular risk among these patients. METHODOLOGY: This is a longitudinal exploratory study undertaken on 1485 hypertensive subjects of 50 years of age or older, selected from 1999 patients received in three health professional training centers of the community of Lome, between June 1, 2004 and June 30, 2007. Information had been collected using a card of investigation. Classifications of high blood pressure were those of the JVCVII and the European Society of Cardiology. The data analysis had been made by computer tools. RESULTS: The prevalence high blood pressure was of 74.29%. We had noted a female prevalence (63.8%) with a sex ratio of 0,57 and one middle age of 62.08+/-9.3 years. Dyspnea (45.9%), chest pains (16.2%) and palpitations (13.2%) were the principal found symptoms. The various listed risk factors were: dyslipidemia (58.1%), obesity (36.12%), alcoholism (16.7%) and diabetes (10.6%). The complications were cardiac (87.81%), ocular (79.8%), renal (19.86%), neurological (4.92%) and arterial (0.99%). The cardiovascular risk was very high at 58.05% of the patients. The mortality rate was of 1.9%. CONCLUSION: High blood pressure is the most frequent cardiovascular risk factor in our country from 50 years of age. Assumption of responsibility for it is by information, education of the population and requires the mobilization of all the social components. PMID- 20708727 TI - [Screening of silent myocardial ischaemia by dobutamine stress echocardiography among type 2 diabetics at high cardiovascular risk in Senegal]. AB - INTRODUCTION: Diabetes is a major risk factor for coronary artery disease witch may develop insidiously. Several non-invasive methods are used to detect silent myocardial ischaemia, especially in diabetic patients at high cardiovascular risk. We project to screen, by dobutamine stress echocardiography, silent myocardial ischaemia in type 2 diabetics in Senegal. METHODOLOGY: We randomly recruited in hospital in Senegal type 2 diabetics aged at least 40 years and a dobutamine stress echocardiography was performed in those selected according to the French Society of Cardiology and the French Language Association for the Study of Diabetes and Metabolic Diseases. RESULTS: Dobutamine stress echocardiography was performed in 79 diabetics at high cardiovascular risk, including 56 women. The average age was 58.8+/-11.8 years. The exam was positive in 67.1% of cases (53/79), with a predominance of motion abnormalities in anterior territory (83%). Cardiovascular risk factors associated with positivity of test were microalbuminuria (p=0.0001), inactivity (p=0.0001), dyslipidemia (p=0.0002), arterial hypertension (p=0.001), smoking (0.003) and male sex (p=0.004). CONCLUSION: In Africa, dobutamine stress echocardiography has the advantage of its accessibility and its feasibility. Early detection of silent myocardial ischaemia in diabetics at high risk could optimize their care. PMID- 20708728 TI - Reducing understaffing and shift work with Temporal Profile Optimization (TPO). AB - The ergonomic quality of shift schedules can be improved by reducing time periods with understaffing (resulting in work-pressure, poor quality, etc.) and evening, night and/or weekend work. Improving the quality of forecasts regarding future workforce requirements as well as the optimization of work processes by moving as much work as possible to more suitable time zones are two approaches to this. We introduce and propose Temporal Profile Optimization (TPO) as a systematic approach to question the demand as well as its translation to workforce planning. Temporal profiles describe the number of employees needed over time (e.g. for different days of the week, times of day, for different calendar days) as well as the shift-times and staffing levels planned to meet this workforce demand. With Temporal Profile Forecasts we introduce a forecasting method that is based on time-stamped historical data and methodologically supplements traditional time series models like SARIMA in many ways. With Temporal Profile Reengineering we use systematic and often participatory methods from business process reengineering to identify moveable work and streamline the load lines by (re )distributing movable work such that shifts and schedules are improved. The approach is illustrated along two business cases. Using TP-Forecasts for air traffic controllers increased forecasting accuracy whereby a different shift design was possible resulting in 3-4% less shift work. In a warehouse of an Austrian freight carrier a TP-Forecast together with TP-Reengineering helped to rearrange work processes such that the resulting workforce requirements curve had a more even form. This allowed for shorter shifts than before (thereby decreasing overtime). Experiences made so far stress the potential of Temporal Profile Optimization. PMID- 20708729 TI - The role of urgency and its underlying psychological mechanisms in problematic behaviours. AB - The urgency facet of impulsivity, that is, the tendency to act rashly in response to intense emotional contexts [Cyders, M. A., & Smith, G. T. (2008). Emotion based dispositions to rash action: positive and negative urgency. Psychological Bulletin, 134, 807-828], has been related to a wide range of maladaptive behaviours. The present study further investigates the role of urgency in problematic behaviours by considering distinct psychological mechanisms that may underlie this component of impulsivity. With this aim, 95 volunteer participants were screened with self-reported questionnaires assessing urgency and three problematic behaviours (compulsive buying, excessive mobile phone use, excessive Internet use). They performed two laboratory tasks: a stop-signal task designed to assess the capacity to inhibit prepotent responses in response to both neutral and emotional stimuli; and the Iowa Gambling Task (IGT) measuring the ability to take into account the future consequences of an action. A poor ability to inhibit prepotent responses in the emotional condition of the stop-signal task was found to predict more disadvantageous choices in the IGT, which ultimately results in higher urgency and more problematic behaviours. These findings shed new light on the construct of urgency, its related psychological mechanisms, and its role in problematic behaviours. PMID- 20708730 TI - A new chitosan biopolymer derivative as metal-complexing agent: synthesis, characterization, and metal(II) ion adsorption studies. AB - In this study, a new chitosan biopolymer derivative (CTSL) has been synthesized by anchoring a new vanillin-based complexing agent or ligand, namely 4-hydroxy-3 methoxy-5-[(4-methylpiperazin-1-yl)methyl] benzaldehyde, (L) with chitosan (CTS) by means of condensation. The new material was characterized by elemental (CHN), spectral (FTIR and solid state (13)C NMR), thermal (TG-DTA and DSC), structural (powder XRD), and morphological (SEM) analyses. The CTSL was employed to study the equilibrium adsorption of various metal ions, namely, Mn(II), Fe(II), Co(II), Cu(II), Ni(II), Cd(II), and Pb(II), as functions of pH of the solutions. Its kinetics of adsorption was evaluated utilizing the pseudo first order and pseudo second order equation models and the equilibrium data were analyzed by Langmuir isotherm model. The CTSL shows good adsorption capacity for metal ions studied in the order Cu(II)>Ni(II)>Cd(II)> or =Co> or =Mn(II)>Fe(II)>Pb(II) in all studied pH ranges due to the presence of many coordinating moieties present in it. PMID- 20708731 TI - CrmA gene transfer rescued CsA-induced renal cell apoptosis in graft kidney. AB - Cyclosporine A(CsA) causes significant nephrotoxicity that contribute to kidney graft loss in the long-term, it can induce cell apoptosis in renal cortex and medulla, reduce kidney function. The mechanisms are complex and involved in six apoptosis pathways including classical pathway, mitochondrial pathway, endoplasmic reticulum pathway, angiotensin II pathway, NO- and hypertonicity related pathway. All these pathways may converge to a single way by activated Caspase-3, -6, -8, -9 and -12 that may become a potential new target for intervention. CrmA protein belonging to one of serine protease inhibitor family members, it widely inhibits the inflammatory Caspases and apoptotic Caspases and has a strong function on inhibiting apoptosis induced by many chemical inducers through effectively blocking Caspase-1, -3, -4, -5, -8, -9, and -10 enzymes. It is not reported if CrmA is resistant to apoptosis induced by immunosuppressant so far. Therefore we speculate CrmA can block down CsA-induced renal cell apoptosis through inhibiting the Caspase-3, -6, -8, -9 and -12 activated and further to eliminate CRD induced by CsA. PMID- 20708732 TI - Genetic variation in complement factor H and risk of coronary heart disease: eight new studies and a meta-analysis of around 48,000 individuals. AB - OBJECTIVES: To investigate the association of polymorphisms in complement factor H (CFH) and coronary heart disease (CHD) using meta-analysis. BACKGROUND: Age related macular degeneration (AMD) and CHD may share partially overlapping pathogenesis. A non-synonymous SNP (rs1061170/Y402H) in CFH encoding complement factor H (fH) is robustly associated with increased AMD risk but associations with CHD risk have been inconsistent. METHODS: We conducted de novo genotyping and genetic association analyses of incident and prevalent CHD in four studies, and in silico analysis of the same association in a further four cohorts. We pooled these data with information from all published studies using random effects meta-analysis, including a total of 48,646 participants of which 9097 were CHD cases. We also evaluated the association of Y402H with known risk factors for CHD by pooling results from new and in silico studies providing relevant data. RESULTS: CFH genotype was not associated with CHD. Compared to the reference TT homozygote group the pooled odds ratio (OR) for individuals homozygous for the C allele was 1.02, 95% CI (0.91, 1.13) and that for heterozygote TC individuals was 1.04 (0.98, 1.10). There was no association of CFH with systolic and diastolic blood pressure, total-, LDL- and HDL-cholesterol, or body mass index. Individuals who were CC compared to TT had higher triglyceride levels: pooled mean difference 0.06 (0.02, 0.10) mmol/L, p=0.005. CONCLUSIONS: The AMD-associated CFH genotype is not associated with CHD. With the possible exception of triglycerides, this CFH SNP was not associated with a wide range of other CHD risk factors. PMID- 20708733 TI - Tissue Factor-Factor VIIa complex induces cytokine expression in coronary artery smooth muscle cells. AB - OBJECTIVE: Within atherosclerotic lesions Tissue Factor (TF)-Factor VIIa (FVIIa) not only contributes to thrombotic events but also alters vascular remodeling through enhancement of migration. Moreover, the TF-FVIIa-FXa complex activates protease-activated receptors (PAR). TF/FVIIa/PAR-2 signaling has also been shown to promote proliferation and metastasis of tumor cells. Since coagulation factors promote inflammation which plays a major role during atherosclerosis as well as tumor metastasis this study sought to investigate the effects of FVIIa on the inflammatory response in vascular cells. METHODS/RESULTS: FVIIa induces interleukin-8 (IL-8) and IL-6 in primary smooth muscle cells (SMC), which was correlated to the expression of TF and PAR-2 as shown by immunoassay and qRT-PCR. The effect was dose-dependent and required TF, the proteolytic activity of FVIIa and PAR-2. Secondary effects of downstream coagulation factors were excluded. No proinflammatory FVIIa effect was observed in endothelial cells (EC) and mononuclear cells (MNC), expressing either TF or PAR-2. In atherosclerotic lesions mRNA expression of PAR-1, PAR-2 and IL-8 was elevated compared to healthy vessels indicating a role for PAR-1 and PAR-2 signaling in atherosclerosis. CONCLUSION: In addition to the procoagulant and promigratory role of the TF-FVIIa complex we identify a proinflammatory role of FVIIa in human SMC dependent on expression of TF and PAR-2 that provides yet another link between coagulation and inflammation. PMID- 20708734 TI - Computational analysis of bone remodeling during an anterior cervical fusion. AB - The anterior cervical fusion is an established surgical procedure for spine stabilization after the removal of an intervertebral disc. However, it is not yet clear which bone graft represents the best choice and whether surgical devices can be efficient and beneficial for fusion. The aim of this work is to study the influence of the spine instrumentation on bone remodeling after a cervical spine surgery and, consequently, on the fusion process. A finite element model of the cervical spine was developed, having computed tomography images as input. Bone was modeled as a porous material characterized by the relative density at each point and the bone remodeling law was derived assuming that bone self-adapts in order to achieve the stiffest structure for the supported loads, with the total bone mass regulated by the metabolic cost of maintaining bone tissue. Apart from the analysis of healthy cervical spine, different surgical scenarios were tested: bone graft with or without a cage and the use of a stabilization plate system. Results showed that the anterior and posterior regions of the disc space are more important to stress transmission and that spinal devices reduce bone growth within bone grafts, being plate systems the most interfering elements. The material of the interbody cages plays a major role in fusion and, therefore, it should be carefully chosen. PMID- 20708735 TI - Study of an infant brain subjected to periodic motion via a custom experimental apparatus design and finite element modelling. AB - This paper presents a rig that was specifically designed to simulate the shaking of mechanical models of biological systems, especially those related to shaken baby syndrome (SBS). The scope of this paper includes the testing of an anthropomorphic model that simulates an infant head and provides validation data for complex finite element (FE) modelling using three numerical methods (Lagrangian, Arbitrary-Lagrangian-Eulerian (ALE) and Eulerian method) for fluid structure coupling. The experiments for this study aim to provide an understanding of the influence of two factors on intracranial brain movement of the infant head during violent shaking: (1) the specific paediatric head structure: the anterior fontanelle and (2) the brain-skull interface. The results show that the Eulerian analysis method has significant advantages for the FSI modelling of brain-CSF-skull interactions over the more commonly used methods, e.g. the Lagrangian method. To the knowledge of the authors, this methodology has not been discussed in previous publication. The results indicate that the biomechanical investigation of SBS can provide more accurate results only if the skull with paediatric features and the brain-skull interface are correctly represented, which were overlooked in previous SBS studies. PMID- 20708736 TI - Molecularly imprinted polymer coated on stainless steel fiber for solid-phase microextraction of chloroacetanilide herbicides in soybean and corn. AB - A molecularly imprinted polymer (MIP) with metolachlor as template was firstly coated on stainless steel fiber through chemical bonding strategy to solve the fragility problem of silica fiber substrate for solid-phase microextraction. The surface pretreatment of stainless steel fiber and the polymerization conditions were investigated systematically to enhance the preparation feasibility and MIP coating performance, and then a porous and highly cross-linked MIP coating with 14.8-microm thickness was obtained with over 200 times re-usability which was supported by non-fragile stainless steel fiber adoption. The MIP coating possessed specific selectivities to metolachlor, its metabolites and other chloroacetanilide herbicides with the factors of 1.1-4.6. Good extraction capacities of metolachlor, propisochlor and butachlor were found with MIP coating under quick adsorption and desorption kinetics, and the detection limits of 3.0, 9.6 and 38 microg L(-1) were achieved, respectively. Moreover, the MIP-coated stainless steel fiber was evaluated for trace metolachlor, propisochlor and butachlor extraction in the spiked soybean and corn samples, and the enrichment factors of 54-60, 27-31 and 15-20 were obtained, respectively. PMID- 20708737 TI - The vector of calibration ratios: a simple transfer method for mass spectra. AB - A robust method for reduction of instrument differences, the vector of calibration ratios, was developed to eliminate differences in unit resolution mass spectra of fatty acid methyl esters (FAME) caused by experimental conditions. Mass spectra of FAMEs were analyzed by two different mass spectrometers and after application of different tune procedures. The proposed method could remove 51-95% of the systematic difference in spectra caused by instrumental conditions. Highly similar spectra, which were incorrectly identified because of the contribution from experimental conditions, could be correctly identified after application of the calibration vector. The proposed method is simple, easy to implement and shows robustness when applied on spectra that is outside the range spanned by the calibration sample. PMID- 20708738 TI - Effect of the concentration and composition on the size and shape of micelles of sodium oleate-cetyltrimethylammonium bromide mixtures. AB - The dependence of the aggregation number (N(agg)) on composition and concentration of sodium oleate-cetyltrimethylammonium bromide mixed micelles as revealed by cyclic voltammetry experiments shows a complex relationship with the total concentration and the composition of surfactant mixtures. This behavior is related to the evolution with composition of the HLB values and with the composition and the excess free energy of mixed micellization, and is explained by the inclusion of the double bonds of oleate chains in the micellar Stern layers. The increase in size probably leads to a reduction of the micelle surface available for the polar headgroups, causing a reduction in the proportion of double bonds in the hydrocarbon-water interface and a change in the mixed micelle composition. Therefore, the generally held supposition that the composition of mixed micelles does not change with concentration seems rather unrealistic. PMID- 20708739 TI - Adsorption of tetracycline on kaolinite with pH-dependent surface charges. AB - Kaolinite is a major type of clay minerals in soils of warm and humid climate. Although it has a much lower cation exchange capacity (CEC) and specific surface area compared to swelling clays, its ubiquitous existence as well as its pH dependent surface charge makes it an important component to study the interactions between contaminants and soils. Tetracycline (TC) is a group of broad spectrum antibiotics used extensively in human and veterinary medicine. It has a high aqueous solubility and a long environmental half-life. In this study, the interactions between TC and kaolinite in aqueous solution were investigated in batch tests and supplemented by FTIR analyses. The adsorption of TC on kaolinite was mainly on the external surfaces via cation exchange as confirmed by stoichiometric desorption of exchangeable cations and simultaneous adsorption of H(+) rather than due to complexation. Under acidic conditions, a reduction in surface charge, thus the CEC, resulted in more desorption of exchangeable cations compared to TC adsorption. Fitting of the experimental data to the adsorption of different species revealed that TC(+) accounted for 4/5 of the total TC adsorbed with the remaining by zwitterion TC(0), possible via hydrogen bonding. At higher temperature, the pKa2 and pKa3 values seem to shift a pH unit lower. Due to its pH-dependent charge of kaolinite, TC adsorption is more pH dependent. The TC adsorption capacity on kaolinite was much lower compared to that on swelling clays. However, the adsorption rate constant was faster than that on swelling clays owing to surface adsorption instead of intercalation. Despite its low TC adsorption capacity, the ubiquitous existence of kaolinite in soils of warm climate may play a vital role in the fate and transport of TC in these soils. PMID- 20708740 TI - Effect of ethanol on the gelation of aqueous solutions of Pluronic F127. AB - In dilute aqueous solution unimers of copolymer F127 (E(98)P(67)E(98)) associate to form micelles, and in more concentrated solution micelles pack to form high modulus gels. Cosolvents are known to affect these processes, and ethanol/water mixtures have been of particular interest. Dynamic light scattering from dilute solutions was used to confirm micellization, but major attention was directed towards the gels. Visual observation of mobility (tube inversion) was used to detect gel formation, oscillatory rheometry to confirm gel formation and provide values of the elastic moduli over a wide temperature range, and small-angle X-ray scattering to determine gel structure. The solvents were limited to 10, 20 and 30 wt.% ethanol/water. Critical concentrations for gel formation were similar for 10 and 20 wt.% ethanol/water but were significantly increased for 30 wt.% ethanol/water, e.g. at T=45 degrees C from c approximately 15 wt.% to c approximately 28 wt.%. The elastic moduli reached maximum values at T approximately 50 degrees C: e.g. G' approximately 25 kPa for 25 wt.% F127 in 10 and 20 wt.% ethanol/water and a similar value for 30 wt.% F127 in 30 wt.% ethanol/water. Hard gels of 30 and 35 wt.% F127 in ethanol/water at 25 and 40 degrees C had the body-centered cubic (bcc) structure. PMID- 20708742 TI - Experimental infection of turkeys and chickens with a clonal strain of Tetratrichomonas gallinarum induces a latent infection in the absence of clinical signs and lesions. AB - The pathogenicity of a mono-eukaryotic culture of Tetratrichomonas gallinarum in specific pathogen free (SPF) chickens and turkeys was studied. Two experiments of identical design were performed: the first with SPF chickens and the second with commercial turkeys. Each experiment included three groups. Groups 1 and 2 each contained 12 infected and three in-contact birds. The birds in these groups were infected on the first day of life, either cloacally (group 1) or orally (group 2). Group 3 consisted of four control birds. Re-isolation of the parasite from cloacal swabs was performed to verify the excretion of T. gallinarum. The infected birds excreted trichomonads from the second day post-infection. Spread of the flagellate from infected to in-contact birds was detected after 5 days post-infection (dpi), based on the re-isolation of the protozoa. No clinical signs or deaths were recorded in chickens or turkeys. Three birds were killed at 4, 8, 14 and 21dpi and various tissues were collected for pathological examination. No gross lesions were noted. Protozoal DNA was demonstrated in the oesophagus, duodenum, jejunum, caecum, liver, lung, bursa of Fabricius and brain by polymerase chain reaction and in-situ hybridization. No antibodies were detected in the serum of infected birds by enzyme linked immunosorbent assay. Microscopical changes were only present in the caecum, where there was sloughing of the epithelium associated with the presence of numerous flagellates on the epithelial surface, within the crypts of Lieberkuhn and in the lamina propria. These changes were found in caecal samples from infected and in-contact birds. These studies have demonstrated the rapid transmission of T. gallinarum between both turkeys and chickens and the establishment of a latent infection in both species. PMID- 20708741 TI - Subthalamic nucleus deep brain stimulation changes velopharyngeal control in Parkinson's disease. AB - PURPOSE: Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal control, and whether these changes were correlated with limb function and stimulation settings. METHODS: Seventeen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12h since their most recent dose of anti-PD medication. Testing occurred when STN DBS was on, and again 1h after STN DBS was turned off, and included aerodynamic measures during syllable production, and standard neurological ratings of limb function. RESULTS: We found that PD participants exhibited changes with STN DBS, primarily consistent with increased intraoral pressure (n=7) and increased velopharyngeal closure (n=5). These changes were modestly correlated with measures of limb function, and were correlated with stimulation frequency. CONCLUSION: Our findings suggest that STN DBS may change velopharyngeal control during syllable production in PD, with greater benefit associated with low frequency stimulation. However, DBS demonstrates a more subtle influence on speech-related velopharyngeal control than limb motor control. This distinction and its underlying mechanisms are important to consider when assessing the impact of STN DBS on PD. LEARNING OUTCOMES: As a result of this activity, the participant will be able to (1) describe the effects of deep brain stimulation on limb and speech function; (2) describe the effects of deep brain stimulation on velopharyngeal control; and (3) discuss the possible reasons for differences in limb outcomes compared with speech function with deep brain stimulation of the subthalamic nucleus. PMID- 20708743 TI - True hermaphroditism: first evidence of an ovotestis in a cetacean species. AB - An immature unilateral hermaphrodite common dolphin (Delphinus delphis) was found stranded on the southwest coast of the UK. The external phenotype was that of a female, but internally there was one ovotestis, containing both ovarian follicles and testicular tubular elements, and a contralateral ovary. Ovarian portions of the ovotestis appeared normal and demonstrated follicular development, whereas the testicular tissue exhibited hypoplasia and degeneration. This is the first reported case of an ovotestis in a cetacean species. PMID- 20708744 TI - Characterization of necrotizing lymphadenitis associated with porcine circovirus type 2 infection. AB - Necrotizing lymphadenitis is observed in approximately 2% of pigs affected by post-weaning multisystemic wasting syndrome (PMWS). The pathogenesis of the lesion has been linked to apoptosis induced by porcine circovirus type 2 (PCV2). The aim of the present study was to gain further insights into PCV2-associated lymphoid necrosis in pigs with PMWS. Three groups of animals were studied: (1) PMWS-affected pigs with necrotizing lymphadenitis (n=5), (2) PMWS-affected pigs without necrotizing lymphadenitis (n=5) and (3) healthy pigs with no PMWS-related lesions (n=5). Investigations performed included immunohistochemical evaluation of the expression of cleaved caspase-3 and von Willebrand factor, Mallory's staining for fibrin and in-situ hybridization for detection of the PCV2 genome. The results of the study suggested that lymphoid necrosis in PMWS-affected pigs may be related to hypertrophy and hyperplasia of high endothelial venules (HEVs). The mechanism underlying these changes in HEVs was not clearly defined, but necrotizing lymphadenitis in pigs with PMWS may develop following vascular damage with thrombosis and subsequent follicular necrosis. Apoptosis was not found to be involved in lymphocyte depletion in PMWS or in PMWS-associated necrotizing lymphadenitis. PMID- 20708745 TI - Similarity and difference in the processing of same- and other-race faces as revealed by eye tracking in 4- to 9-month-olds. AB - Fixation duration for same-race (i.e., Asian) and other-race (i.e., Caucasian) female faces by Asian infant participants between 4 and 9 months of age was investigated with an eye-tracking procedure. The age range tested corresponded with prior reports of processing differences between same- and other-race faces observed in behavioral looking time studies, with preference for same-race faces apparent at 3 months of age and recognition memory differences in favor of same race faces emerging between 3 and 9 months of age. The eye-tracking results revealed both similarity and difference in infants' processing of own- and other race faces. There was no overall fixation time difference between same race and other race for the whole face stimuli. In addition, although fixation time was greater for the upper half of the face than for the lower half of the face and trended higher on the right side of the face than on the left side of the face, face race did not impact these effects. However, over the age range tested, there was a gradual decrement in fixation time on the internal features of other-race faces and a maintenance of fixation time on the internal features of same-race faces. Moreover, the decrement in fixation time for the internal features of other-race faces was most prominent on the nose. The findings suggest that (a) same-race preferences may be more readily evidenced in paired comparison testing formats, (b) the behavioral decline in recognition memory for other-race faces corresponds in timing with a decline in fixation on the internal features of other-race faces, and (c) the center of the face (i.e., the nose) is a differential region for processing same- versus other-race faces by Asian infants. PMID- 20708746 TI - Energy expenditure and enjoyment of common children's games in a simulated free play environment. AB - OBJECTIVE: To measure the energy expenditure and enjoyment of children's games to be used in developing a school-based intervention for preventing excessive weight gain. STUDY DESIGN: Healthy weight (body mass index [BMI] < 85th percentile) and overweight or obese (BMI >= 85th percentile) third-grade children (15 boys; 13 girls) were recruited. In a large gymnasium, children performed 10 games randomly selected from 30 games used in previous interventions. Total energy expenditure was measured with a portable metabolic unit and perceived enjoyment was assessed using a 9-point Likert scale of facial expressions. Mean physical activity energy expenditure (PAEE = total energy expenditure minus resting metabolism) and enjoyment of the games were adjusted for sex and BMI classification. PAEE and enjoyment were compared using a repeated-measures ANOVA with sex, BMI classification, and games as main effects. RESULTS: The games elicited a moderate intensity effort (mean +/- standard deviation = 5.0 +/- 1.3 metabolic equivalents, 123 +/- 36 kcal/30 min). PAEE was higher for boys than for girls (0.12 +/- 0.04 versus 0.11 +/- 0.04 kcal/kg/min) and for healthy weight compared with overweight children (0.13 +/- 0.04 versus 0.11 +/- 0.03 kcal/kg/min). Twenty two of the 30 games elicited a sufficiently high PAEE (>= 100 kcal/30 min) and enjoyment (>= neutral expression) for inclusion in future school-based interventions. CONCLUSIONS: Not all children's games are perceived as enjoyable or resulted in an energy expenditure that was sufficiently high for inclusion in future physical activity interventions to prevent the excess weight gain associated with childhood obesity. PMID- 20708747 TI - Pediatric concussions in United States emergency departments in the years 2002 to 2006. AB - OBJECTIVES: To estimate the incidence and demographics of concussions in children coming to emergency departments (EDs) in the United States and describe the rates of neuroimaging and follow-up instructions in these patients. STUDY DESIGN: This is a cross-sectional study of children 0 to 19 years old diagnosed with concussion from the National Hospital Ambulatory Medical Care Survey. National Hospital Ambulatory Medical Care Survey collects data on approximately 25,000 visits annually to 600 randomly selected hospital emergency and outpatient departments. We examined visits to United States emergency departments between 2002 and 2006. Simple descriptive statistics were used. RESULTS: Of the 50,835 pediatric visits in the 5-year sample, 230 observations, representing 144,000 visits annually, were for concussions. Sixty-nine percent of concussion visits were by males. Thirty percent were sports-related. Sixty-nine percent of patients diagnosed with a concussion had head imaging. Twenty-eight percent of patients were discharged without specific instructions to follow-up with an outpatient provider for further treatment. CONCLUSIONS: Approximately 144,000 pediatric patients present to emergency departments each year with a concussion. Most of these patients undergo computed tomography of the head, and nearly one-third are discharged without specific instructions to follow-up with an outpatient provider for further treatment. PMID- 20708748 TI - Febrile urinary tract infections in 0- to 3-month-old infants: a prospective follow-up study. AB - OBJECTIVE: To track the clinical evolution of febrile urinary tract infection (UTI) diagnosed in 0- to 3-month-old infants and characterize uropathogen frequencies, antimicrobial resistance rates, renal abnormalities, and differences in the sexes in this age group. STUDY DESIGN: We observed prospectively 46 infants identified in a cohort of 209 children with first UTI diagnosed between July 2006 and July 2008 at the age of 0 to 3 months. Renal ultrasound scanning and voiding cystourethrography examinations were performed in all infants. RESULTS: Infants < 3 months old represented 21% of all children with first UTI. Of these children, 26% were female and 74% were male. Escherichia coli was isolated in 88% of cases and had a high rate of resistance to ampicillin (71%) and to trimethoprim/sulfamethoxazole (47%); 21% of children had vesicoureteral reflux, which was of low-grade in 67% of cases, with spontaneous resolution before 2 years in all cases. In infants with normal ultrasound scanning results, a low-grade vesicoureteral reflux was subsequently found in 10% of cases. CONCLUSION: Infants aged 0 to 3 months represent 21% of children treated for febrile UTI. Boys represent 74% of these cases. E coli is responsible for 88% of UTIs, with a high rate of resistance to antibiotics. When ultrasound scanning examination results are normal, the risk of missing a significant renal abnormality is expected to be extremely low. PMID- 20708749 TI - Development of preschool and academic skills in children born very preterm. AB - OBJECTIVE: To examine performance in preschool and academic skills in very preterm (gestational age <= 30 weeks) and term-born comparison children aged 4 to 12 years. STUDY DESIGN: Very preterm children (n = 200; mean age, 8.2 +/- 2.5 years) born between 1996 and 2004 were compared with 230 term-born children (mean age, 8.3 +/- 2.3). The Dutch National Pupil Monitoring System was used to measure preschool numerical reasoning and early linguistics, and primary school simple and complex word reading, reading comprehension, spelling, and mathematics/arithmetic. With univariate analyses of variance, we assessed the effects of preterm birth on performance across grades and on grade retention. RESULTS: In preschool, very preterm children performed comparably with term-born children in early linguistics, but perform more poorly (0.7 standard deviation [SD]) in numerical reasoning skills. In primary school, very preterm children scored 0.3 SD lower in complex word reading and 0.6 SD lower in mathematics/arithmetic, but performed comparably with peers in reading comprehension and spelling. They had a higher grade repeat rate (25.5%), although grade repeat did not improve their academic skills. CONCLUSIONS: Very preterm children do well in early linguistics, reading comprehension, and spelling, but have clinically significant deficits in numerical reasoning skills and mathematics/arithmetic, which persist with time. PMID- 20708750 TI - Nonoperative management of solid organ injury diminishes surgical resident operative experience: is it time for simulation training? AB - BACKGROUND: Nonoperative management (NOM) of solid abdominal organ injury (SAOI) is increasing. Consequently, training programs are challenged to ensure essential operative trauma experience. We hypothesize that the increasing use and success of NOM for SAOI negatively impacts resident operative experience with these injuries and that curriculum-based simulation might be necessary to augment clinical experience. MATERIALS AND METHODS: A retrospective cohort analysis of 1198 consecutive adults admitted to a Level I trauma center over 12 y diagnosed with spleen and/or liver injury was performed. Resident case logs were reviewed to determine operative experience (Cohort A: 1996-2001 versus Cohort B: 2002 2007). RESULTS: Overall, 24% of patients underwent operation for SAOI. Fewer blunt than penetrating injuries required operation (20% versus 50%, P < 0.001). Of those managed operatively, 70% underwent a spleen procedure and 43% had a liver procedure. More patients in Cohort A received an operation compared with Cohort B (34% versus 16%, P < 0.001). Patient outcomes did not vary between cohorts. Over the study period, 55 residency graduates logged on average 27 +/- 1 operative trauma cases, 3.4 +/- 0.3 spleen procedures, and 2.4 +/- 0.2 liver operations for trauma. Cohort A graduates recorded more operations for SAOI than Cohort B graduates (spleen 4.1 +/- 0.4 versus 3.0 +/- 0.2 cases, P = 0.020 and liver 3.2 +/- 0.3 versus 1.8 +/- 0.3 cases, P = 0.004). CONCLUSIONS: Successful NOM, especially for blunt mechanisms, diminishes traditional opportunities for residents to garner adequate operative experience with SAOI. Fewer operative occasions may necessitate an increased role for standardized, curriculum-based simulation training. PMID- 20708751 TI - A novel point mutation in the mitochondrial tRNA((Trp)) gene produces late-onset encephalomyopathy, plus additional features. AB - BACKGROUND: Mitochondrial diseases due to mitochondrial tRNA genes mutations are usually multisystem disorders with infantile or adult onset. OBJECTIVE: To identify the molecular defect underlying a mitochondrial encephalomyopathy. METHODS/PATIENTS: Case report of a 51year-old woman presenting with late-onset myoclonic epilepsy plus additional features. Proband's mother presented hypothyroidism and diabetes. RESULTS: Muscle biopsy showed mitochondrial changes. Respiratory chain activities were reduced. The novel G5538A mutation was identified in different tissues DNAs from the proband and from her mother. CONCLUSION: We were able to identify a novel mtDNA tRNA((Trp)) gene pathogenic mutation. PMID- 20708752 TI - Mitroflow pericardial aortic bioprosthesis in patients younger than 60 years. PMID- 20708753 TI - Intravenous omega-3, a technique to prevent an excessive innate immune response to cardiac surgery in a rodent gut ischemia model. AB - OBJECTIVES: Neutrophil infiltration of tissues as part of the inflammatory response to cardiac surgery is one of the major mediators of postoperative multiple-organ dysfunction. Omega-3 fatty acids markedly attenuate endothelial cell inflammatory responses, including upregulation of neutrophil adhesion molecules. The efficacy of a clinically safe form of omega-3 to produce this effect in vivo was examined. METHODS: Rat gut intravital microscopic analysis was used to visualize neutrophil transmigration from the microcirculation into the tissues of the gut. Inflammatory activation was in the form of 30 minutes of ischemia and 90 minutes of reperfusion. Sham, control (0.9% saline infusion over 4 hours), and omega-3 (Omegaven [Fresenius Kabi, Bad Homburg, Germany] infusion over 4 hours) pretreatments were compared. RESULTS: Ischemia-reperfusion resulted in a 4-fold increase in neutrophil adherence to the endothelium (baseline: 4.3 +/ 0.2 vs control group: 19.2 +/- 3.5 adherent neutrophils per 100 MUm, P < .01), which intravenous omega-3 suppressed (7.8 +/- 1.7 adherent neutrophils per 100 MUm, P < .01). Omega-3 pretreatment also reduced neutrophil transmigration into the tissues after reperfusion (sham group: 6.3 +/- 0.8 vs control group: 13.2 +/- 1.4 vs omega-3 group: 9.4 +/- 0.9 neutrophils per field, P = .037). Gut tissue levels of the neutrophil-released enzyme myeloperoxidase were similarly markedly reduced with omega-3 pretreatment (sham group: 10.5 +/- 1.6 vs control group: 19.0 +/- 3.3 vs omega-3 group: 10.1 +/- 1.2 U/g, P = .03). CONCLUSIONS: Four hours' pretreatment with a relatively safe form of intravenous omega-3 suppressed neutrophil adherence and tissue infiltration, resulting in lower levels of the tissue-damaging enzyme myeloperoxidase. This suggests a possible strategy for diminishing postoperative multiple-organ dysfunction. PMID- 20708754 TI - Infections occurring during extracorporeal membrane oxygenation use in adult patients. AB - OBJECTIVE: The application of extracorporeal membrane oxygenation in adults has been increasing, but infections occurring during extracorporeal membrane oxygenation use are rarely described. METHODS: We retrospectively analyzed the prospectively collected data on nosocomial infection surveillance of 334 patients aged 16 years or more undergoing their first extracorporeal membrane oxygenation for more than 48 hours at a university hospital from 1996 to 2007 for respiratory (20.4%) and cardiac (79.6%) support. RESULTS: During a total of 2559 extracorporeal membrane oxygenation days, 55 episodes of infections occurred in 45 patients (13.5%), including 38 bloodstream (14.85 per 1000 extracorporeal membrane oxygenation days), 6 surgical site, 4 respiratory tract, 3 urinary tract, and 4 other infections. Stenotrophomonas maltophilia (16.7%) and Candida species (14.6%) were the predominant blood isolates. In stepwise logistic regression analysis, longer duration of extracorporeal membrane oxygenation use (odds ratio 1.003; 95% confidence interval, 1.001-1.005; P = .004), mechanical complications (odds ratio, 4.849; 95% confidence interval, 1.569-14.991; P = .006), autoimmune disease (odds ratio, 6.997; 95% confidence interval, 1.541 31.766; P = .012), and venovenous mode (odds ratio, 4.473; 95% confidence interval, 1.001-19.977; P = .050) were independently associated with a higher risk for infections during extracorporeal membrane oxygenation use. Overall in hospital mortality was 68.3%, and its independent risk factors included older age (odds ratio, 1.037; 95% confidence interval, 1.021-1.054; P < .001), neurologic complications (odds ratio, 51.153; 95% confidence interval, 6.773-386.329; P < .001), and vascular complications (odds ratio, 1.922; 95% confidence interval, 1.112-3.320; P < .001), but not infections during extracorporeal membrane oxygenation use. CONCLUSIONS: Bloodstream infection was the most common infection during extracorporeal membrane oxygenation use. Duration of extracorporeal membrane oxygenation, mechanical complications, autoimmune disease, and venovenous mode seemed to be independently associated with infections. PMID- 20708755 TI - Tumor angiogenesis in predicting the survival of patients with stage I lung cancer. AB - OBJECTIVE: The effects of angiogenesis on survival were assessed by measuring the tumor microvessel density and vascular endothelial growth factor expression in patients with resected stage I non-small cell lung carcinoma. METHODS: The study population included 141 patients who underwent complete resection for stage pT1 and T2 N0 M0 tumors between 1999 and 2007. Lobectomy and pneumonectomy were performed in 131 and 10 patients, respectively. Tumor specimens were analyzed immunohistochemically for staining with anti-CD105 antibody to determine tumor microvessel density and anti-vascular endothelial growth factor antibody to determine the vascular endothelial growth factor expression level. Univariate and multivariate analyses were performed for factors influencing patients' survival. RESULTS: The overall 5-year survival was calculated as 68%, with rates of 76.9% for patients with T1 disease and 66.2% for patients with T2 disease (P = .4). The vascular endothelial growth factor expression rate was 94.3% for patients with stage I non-small cell lung carcinoma. Vascular endothelial growth factor expression did not influence survival (P = .9). The median microvessel density of the tumors measured based on the level of CD105 expression was 19.8. The effect of microvessel density on survival was significant (P = .02). The 5-year survivals of patients with tumors with 20 or more microvessels and less than 20 microvessels were 76.8% and 56.1%, respectively; this difference was highly significant (P = .004). The microvessel density was determined as an independent factor influencing survival on multivariate analysis (P = .03). CONCLUSIONS: The level of vascular endothelial growth factor expression in tumors was not a successful predictor of survival in patients with resected stage I non-small cell lung carcinoma. A high microvessel density based on CD105 is a strong predictor of prognosis in these patients. PMID- 20708756 TI - Pulsed ultrasounds accelerate healing of rib fractures in an experimental animal model: an effective new thoracic therapy? AB - OBJECTIVES: Rib fractures are a frequent traumatic injury associated with a relatively high morbidity. Currently, the treatment of rib fractures is symptomatic. Since it has been reported that pulsed ultrasounds accelerates repair of limb fractures, we hypothesized that the application of pulsed ultrasounds will modify the course of healing in an animal model of rib fracture. METHODS: We studied 136 male Sprague-Dawley rats. Animals were randomly assigned to different groups of doses (none, 50, 100, and 250 mW/cm(2) of intensity for 3 minutes per day) and durations (2, 10, 20, and 28 days) of treatment with pulsed ultrasounds. In every subgroup, we analyzed radiologic and histologic changes in the bone callus. In addition, we examined changes in gene expression of relevant genes involved in wound repair in both control and treated animals. RESULTS: Histologic and radiologic consolidation was significantly increased by pulsed ultrasound treatment when applied for more than 10 days. The application of 50 mW/cm(2) was the most effective dose. Only the 100 and 250 mW/cm(2) doses were able to significantly increase messenger RNA expression of insulin-like growth factor 1, suppressor of cytokine signaling-2 and -3, and vascular endothelial growth factor and decrease monocyte chemoattractant protein-1 and collagen type II-alpha 1. CONCLUSIONS: Our findings indicate that pulsed ultrasound accelerates the consolidation of rib fractures. This study is the first to show that pulsed ultrasound promotes the healing of rib fractures. From a translational point of view, this easy, cheap technique could serve as an effective new therapeutic modality in patients with rib fractures. PMID- 20708757 TI - Effects of pyrene and fluoranthene on the degradation characteristics of phenanthrene in the cometabolism process by Sphingomonas sp. strain PheB4 isolated from mangrove sediments. AB - Cometabolism has been suggested as an attractive approach to enhance the degradation rates of high-molecular-weight polycyclic aromatic hydrocarbons (PAHs). However, the effects of these recalcitrant PAHs on the degradation characteristics of low-molecular-weight PAHs are largely unknown. This study was conducted to investigate the effects of pyrene (PYR) and fluoranthene (FLA) on the degradation characteristics of phenanthrene (PHE) in the cometabolism process by Sphingomonas sp. strain PheB4 isolated from mangrove sediments. Based on the kinetics and characteristics of PHE metabolites, it was proposed that the transformation of hydroxylated PHE into 1-hydroxy-2-naphthoic acid was a rate limiting step in the degradation of PHE by strain PheB4. Compared to a single addition of PYR or FLA, the presence of a mixture of PYR and FLA decreased the degradation rate of PHE to a larger extent, which was likely because it could inhibit the production of 1-hydroxy-2-naphthoic acid more effectively. PMID- 20708758 TI - [Central nervous system medulloepithelioma. A report of three cases]. AB - Central nervous system medulloepithelioma is a rare, highly malignant childhood tumor. It might be confused with medulloblastoma or other primitive neuroectodermal tumors, but it is quite particular by its clinical, radiological, and pathological features. The mean survival varies depending on whether or not a gross-total resection is possible. Adjuvant radiochemotherapy is often indicated. Only two reported cases in the literature survived beyond 4 years after treatment by gross total resection and radiotherapy without chemotherapy. We report three cases of supratentorial medulloepithelioma occurring in three children aged 11-17 years. Two patients underwent a gross-total resection followed by radiotherapy and survived more than 4 years after treatment. The third case had, however, recurred twice within the 1st postoperative month despite a complete resection each time and metastasis to the lung developed. Chemotherapy was then carried out after the third procedure and the patient died 7 months later. PMID- 20708759 TI - Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadol in cats. AB - Tramadol is a synthetic codeine analogue used as an analgesic in human and veterinary medicine, but not approved for use in cats. Tramadol (2 mg/kg) was administered intravenously (IV) as preoperative analgesic in 12 cats (6 males) undergoing surgical gonadectomy. The pharmacokinetic profile of the drug and its O-desmethyl metabolite were determined in 8 animals (4 males), while intraoperative effects and postoperative analgesia, estimated by subjective pain score (0-24), were evaluated in all. Mean intraoperative isoflurane consumption was reduced, but hypoventilation was not observed. Sex-related differences were not observed, particularly in terms of postoperative analgesia: rescue analgesic was never administered. Concentrations of the active O-desmethyl metabolite were persistently high in all the animals. Considering the results obtained in this study, tramadol, at the dose of 2 mg/kg IV, did not produce any evident intraoperative cardiorespiratory side effects and with additional investigation may prove to be an appropriate intraoperative analgesic in cats undergoing gonadectomy. PMID- 20708761 TI - Time from diagnosis to definitive operative treatment of operable breast cancer in the era of multimodal imaging. AB - BACKGROUND: The primary objective of this study was to determine if the increasing use of multimodal breast imaging has influenced the time between the diagnosis of an operable breast cancer and definitive operative intervention over the past decade. Secondary objectives were to determine whether a higher number of imaging studies, or specifically magnetic resonance images (MRIs) were independent predictors of a longer treatment delay, or lead to a greater chance of having a mastectomy. METHODS: We retrospectively reviewed patients treated at a large, academic medical center with operable breast cancer between February 1, 1998, and August 31, 2008. RESULTS: Time to treatment significantly increased over the study time period (mean of 21.8 days in 1998, 31.3 days in 2003, 41.1 days in 2008). In 2008, the only study year in which MRI was routinely used, patients with an MRI had a longer median time to treatment of 43 days versus 32 days for those who did not (P = .054). Those who had a preoperative MRI had a higher relative risk of having a mastectomy at 1.8 (95% confidence interval, 0.85 3.76; P = .33), although this result did not reach significance. CONCLUSION: The time to treatment of operable breast cancer has increased over the past 10 years, and multimodal breast imaging is likely associated with this increase. The effect of this increase on the type of operative procedure chosen and the impact on subsequent outcomes is unknown. PMID- 20708762 TI - Catastrophic antiphospholipid syndrome (Asherson's syndrome) presenting with a splenic rupture. PMID- 20708763 TI - Endoscopic, endoluminal fundoplication for gastroesophageal reflux disease: initial experience and lessons learned. AB - BACKGROUND: Several devices have been developed to create an antireflux barrier endoscopically for the treatment of gastroesophageal reflux disease. All have failed to provide long-term symptom relief, were associated with clinically important complications, or were otherwise removed from the market. A new device, the Esophyx (Endogastric Solutions, Redmond, WA), provides the closest approximation experimentally to a standard Belsy fundoplication. This report describes an initial experience with this device. METHODS: Patients considered candidates for endoscopic fundoplication include those with symptomatic gastroesophageal reflux disease, a small (<2 cm) hiatal hernia, objective pathologic evidence of gastroesophageal reflux disease, and an absence of other esophageal motility disorders. The procedure was conducted under general anesthesia with a surgeon operating the device and an endoscopist operating the gastroscope. H-fasteners were placed from the esophagus to the gastric cardia with the goal of creating an approximately 270-300 degrees fundoplication approximately 3-4 cm in length. Symptom severity was measured with the GERD-HRQL instrument (best possible score 0, worst possible score 50). The patients were followed-up for complications and symptom improvement. RESULTS: In all, 26 patients underwent an attempted endoscopic fundoplication. Two patients could not be completed because of the inability to pass the device. Of the 24 patients who underwent endoscopic fundoplication, 20 had the typical symptoms of gastroesophageal reflux disease, 4 had symptoms of laryngopharyngeal reflux, and 4 had recurrent symptoms after a Nissen fundoplication. There was 1 major complication of a gastric mucosal tear that led to bleeding and the need for a blood transfusion. Nineteen (79%) patients reported satisfaction with their symptom relief. Of those dissatisfied, 2 had symptoms of laryngopharyngeal reflux, 1 had functional heartburn, 1 had associated gastroparesis, and 1 had clear failure with gastroesophageal reflux disease. The median GERD-HRQL score improved from 25 (interquartile range, 19.5-28.5) to 5 (interquartile range, 3-9; P = .0004). CONCLUSION: Endoscopic fundoplication with the Esophyx device is feasible with satisfactory initial results. Endoscopic fundoplication seems to be best suited for patients with small hiatal hernias and mild-to-moderate typical symptoms; however, subsequent trials are needed to assess the long-term effectiveness of the technique. PMID- 20708764 TI - A single institution's experience with single incision cholecystectomy compared to standard laparoscopic cholecystectomy. AB - BACKGROUND: The advent of single incision laparoscopic surgery has brought renewed attention to cholecystectomy due to the promise of improved cosmesis and less parietal trauma. Small series have demonstrated the feasibility of single incision laparoscopic cholecystectomy (LC). Our series adds to the literature by demonstrating a variety of ancillary techniques that may be employed to perform single incision LC safely, and compares our early experience with that of our standard LC. METHODS: We performed a retrospective chart review of patients who underwent single incision LC between February 2008 and April 2009. These patients were compared with an equal number of randomly selected patients undergoing LC during the same period. We identified 25 attempted single incision LC, which were included in our analysis. RESULTS: Single incision LC was successfully performed in 21 patients, with only 4 patients requiring conversion to LC. No patients in either group had acute cholecystitis. The critical view of safety was documented in 20 of 21 patients undergoing a successful single incision LC compared with all patients undergoing LC. Operative time was significantly longer in the single incision group. Complications were minor and comparable between the 2 groups. In 9 patients (43%), a suture passer helped to retract the gallbladder. In 8 patients (38%), 1 or 2 Prolene sutures placed by means of a Keith needle helped to retract the gallbladder over the liver and/or helped to retract the infundibulum. In 2 patients, >=1 supplemental 5-mm port was utilized. In 5 patients (24%), no supplementary retraction was necessary. CONCLUSION: Single incision LC is technically more challenging than LC, but can be performed safely by experienced laparoscopic surgeons with results comparable with LC. PMID- 20708765 TI - Pseudoangiomatous stromal hyperplasia of the breast: a contemporary approach to its clinical and radiologic features and ideal management. AB - BACKGROUND: Pseudoangiomatous stromal hyperplasia (PASH) is a benign, proliferative lesion of the breast whose clinical relevance, presentation, and optimal treatment remains described incompletely. The purpose of this study is to review the clinical, radiologic, and histopathologic features and appropriate management. METHODS: Patients diagnosed with PASH were identified from our pathology database between 2000 and 2009. Clinicopathologic data including presentation, diagnosis, imaging, and histology were reviewed. All specimens were confirmed by a single pathologist. RESULTS: We identified PASH in 80 patients. Median follow-up was 3.71 years (range, 0.45-9.42). Age ranged from 12 to 65 (median, 45) and 95% were female. Lesions were palpable in 56% and found on imaging in the remainder. Core biopsy was performed in 65 of 80 patients (81%), which confirmed a diagnosis of PASH in 65%. The other 23 of 65 patients (35%) required operative excision for diagnosis. There was a progression rate of 26% in the observation arm versus 13% in the excision arm. A diagnosis of cancer or carcinoma in situ was seen in 30% at or before the diagnosis of PASH. CONCLUSION: PASH may present as a mass, radiologic lesion, or incidentally in pathology specimens. It may be associated with cancerous or precancerous lesions. A diagnosis on core biopsy in the absence of suspicious radiologic features may be managed with follow-up and imaging at a 6-month interval. In this series, 35% of patients with PASH had a negative core biopsy. Growth, suspicious radiologic findings, or inconclusive biopsy warrants surgical excision. Close surveillance is necessary given its recurrence rate of 13-26%. PMID- 20708766 TI - Esophagogastroduodenoscopy-associated gastrointestinal perforations: a single center experience. AB - BACKGROUND: Esophagogastroduodenoscopy (EGD) is commonly used in the diagnosis and treatment of gastrointestinal (GI) disorders. Our aim was to define the risk of perforation associated with EGD and identify patients who required operative intervention. METHODS: We retrospectively reviewed 72 patients from our institution plus 5 transferred patients who sustained EGD-associated perforations from January 1996 through July 2008. Percutaneous endoscopic gastrostomy, endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography, transthoracic echocardiography, and concurrent colonoscopy procedures were excluded. RESULTS: Perforations in 72 of 217,507 EGD procedures were identified (incidence, 0.033%); 124,844 EGDs included an interventional procedure and 92,663 were examination only. The incidence of perforation was similar whether an interventional procedure was performed or not (0.040% vs 0.029%; P = .181). The esophagus was injured most commonly (51%), followed by the duodenum (32%), jejunum (6%), stomach (3%), and common bile duct (3%). Overall mortality after perforation was 17% with a morbidity rate of 40%. Thirty-eight patients (49%) were initially treated nonoperatively, 7 of whom (18%) failed nonoperative management. The only factors we could determine that were associated with failure were free fluid or contrast extravasation on computed tomography (75% vs 23% [P < .005] and 33% vs 0% [P = .047], respectively). The morbidity of failures was equivalent to those who underwent initial operative management (63% vs 61%; P = .917), with mortality seeming to be greater (43% vs 21%; P = .09). CONCLUSION: EGD is safe in the majority of patients; however, iatrogenic perforation is associated with considerable morbidity and mortality. Nonoperative management of GI perforation can be successful if there is no evidence of contrast extravasation or free fluid on radiographic studies. If nonoperative management fails, the outcomes may be worse than those treated initially with operative repair. PMID- 20708767 TI - An important role of the heat shock response in infected cells for replication of baculoviruses. AB - Baculoviruses serve as a stress factor that can activate both death-inducing and cytoprotective pathways in infected cells. In this report, induction of heat shock proteins (HSPs) of the 70-kDa family (HSP/HSC70) in Sf-9 cells after infection with AcMNPV was monitored by Western blot analysis. Two-dimensional electrophoresis in polyacrylamide gel revealed changes in the cellular pattern of HSP/HSC70s and synthesis of a new member of the HSP/HSC70 family in the infected cells. Although infection with AcMNPV moderately increased the HSP/HSC70 content in cells under standard conditions, the infection potentiated the response to heat shock boosting the HSP/HSC70s content in infected cells several-fold in comparison with uninfected cells. Addition of KNK437, a known inhibitor of inducible HSPs, decreased the rate of viral DNA synthesis in infected cells more than one order of magnitude and markedly suppressed the release of budded viruses indicating the importance of the heat shock response for baculovirus replication. PMID- 20708768 TI - Domain-III FG loop of the dengue virus type 2 envelope protein is important for infection of mammalian cells and Aedes aegypti mosquitoes. AB - The FG extended loop in domain III of the dengue virus type 2 (DENV2) envelope protein is postulated to be a molecular determinant for host cell infectivity. To determine the contribution of the FG loop to virus infectivity, an infectious cDNA clone of DENV2 was manipulated by deleting amino acids in the loop (VEPGDelta) to mimic tick-borne flaviviruses or by substituting these AAs with RGD or RGDK/S to mimic motifs present in other mosquito-borne flaviviruses. We found the FG loop to be dispensable for infection of C6/36 cells but critical for infection of Aedes aegypti mosquito midguts and mammalian cells. All the FG loop mutants were able to bind to and enter mammalian cells but replication of VEPGDelta in Vero cells at 37 degrees C was delayed until acquisition of secondary mutations. Reduced binding of DENV2 type-specific monoclonal antibody 3H5 to mutant viruses confirmed the FG loop motif as its target epitope. PMID- 20708769 TI - Mapping the subgenomic RNA promoter of the Citrus leaf blotch virus coat protein gene by Agrobacterium-mediated inoculation. AB - Citrus leaf blotch virus has a single-stranded positive-sense genomic RNA (gRNA) of 8747 nt organized in three open reading frames (ORFs). The ORF1, encoding a polyprotein involved in replication, is translated directly from the gRNA, whereas ORFs encoding the movement (MP) and coat (CP) proteins are expressed via 3' coterminal subgenomic RNAs (sgRNAs). We characterized the minimal promoter region critical for the CP-sgRNA expression in infected cells by deletion analyses using Agrobacterium-mediated infection of Nicotiana benthamiana plants. The minimal CP-sgRNA promoter was mapped between nucleotides -67 and +50 nt around the transcription start site. Surprisingly, larger deletions in the region between the CP-sgRNA transcription start site and the CP translation initiation codon resulted in increased CP-sgRNA accumulation, suggesting that this sequence could modulate the CP-sgRNA transcription. Site-specific mutational analysis of the transcription start site revealed that the +1 guanylate and the +2 adenylate are important for CP-sgRNA synthesis. PMID- 20708770 TI - Predicting microbial pollution concentrations in UK rivers in response to land use change. AB - The Water Framework Directive has caused a paradigm shift towards the integrated management of recreational water quality through the development of drainage basin-wide programmes of measures. This has increased the need for a cost effective diagnostic tool capable of accurately predicting riverine faecal indicator organism (FIO) concentrations. This paper outlines the application of models developed to fulfil this need, which represent the first transferrable generic FIO models to be developed for the UK to incorporate direct measures of key FIO sources (namely human and livestock population data) as predictor variables. We apply a recently developed transfer methodology, which enables the quantification of geometric mean presumptive faecal coliforms and presumptive intestinal enterococci concentrations for base- and high-flow during the summer bathing season in unmonitored UK watercourses, to predict FIO concentrations in the Humber river basin district. Because the FIO models incorporate explanatory variables which allow the effects of policy measures which influence livestock stocking rates to be assessed, we carry out empirical analysis of the differential effects of seven land use management and policy instruments (fiscal constraint, production constraint, cost intervention, area intervention, demand side constraint, input constraint, and micro-level land use management) all of which can be used to reduce riverine FIO concentrations. This research provides insights into FIO source apportionment, explores a selection of pollution remediation strategies and the spatial differentiation of land use policies which could be implemented to deliver river quality improvements. All of the policy tools we model reduce FIO concentrations in rivers but our research suggests that the installation of streamside fencing in intensive milk producing areas may be the single most effective land management strategy to reduce riverine microbial pollution. PMID- 20708771 TI - Comparative photochemical reactivity of spherical and tubular fullerene nanoparticles in water under ultraviolet (UV) irradiation. AB - Fullerene nanomaterials are finding an increasing number of applications in energy and environmental technologies. However, substantial production and use of fullerenes will likely lead to environmental exposure with unknown consequences. In this study, aqueous suspensions of three types of fullerenes nanoparticles, C(60) fullerene, single-wall (SW) and multi-wall (MW) carbon nanotubes (CNT) were prepared by sonication and tested for reactive oxygen species (ROS) production and oxidation of benchmark organic compounds under ultraviolet (UV)-A irradiation. All three fullerenes formed colloidal aggregates in water. SWCNTs showed the highest ROS production and 2-chlorophenol degradation followed by MWCNT, and fullerene. PMID- 20708772 TI - Longitudinal biomonitoring for polybrominated diphenyl ethers (PBDEs) in residents of the Great Lakes basin. AB - Cross-sectional surveys of human blood and breast milk show increasing concentrations of polybrominated diphenyl ethers (PBDEs) that parallel the expanded use in consumer products, but longitudinal studies are lacking. We compared levels of major BDE congeners in archived 1994-1995 blood samples collected from a cohort of frequent and infrequent Great Lakes fish consumers with levels in the blood collected from the same individuals in 2001-2003 and 2004-2005. In mixed linear regression models controlling for multiple measurements per individual and covariates, statistically significant increases were seen from 1994-1995 to 2001-2003 for ?PBDEs and BDE-47, 99, and 153 and from 1994-1995 to 2004-2005 for ?PBDEs and BDE-99, 100, and 153, but ?PBDEs and BDE congeners did not change significantly between 2001-2003 and 2004-2005. Changes in body burdens of ?PBDEs and BDE-47, 100, and 153 in men were modified by BMI, with greater increases in men with higher BMI. Increases in BDE-153 were greater for women than men, and a greater increase in BDE-100 was found in older participants. There was a shift in the congener distribution with a significant increase in the proportion of BDE-153 relative to BDE-47 from 2001-2003 to 2004 2005. PMID- 20708773 TI - Greenhouse gas emissions during composting of two-phase olive mill wastes with different agroindustrial by-products. AB - The evolution of CO(2), CH(4) and N(2)O were monitored in five composting mixtures prepared from two-phase olive mill waste (TPOMW) and different agroindustrial by-products in order to assess the effect of the initial composition and the N source on greenhouse gas emission. Surface gas fluxes were measured using a closed static chamber and compared to the changes in different organic matter fractions (organic and watersoluble C) and N forms (NH(4)(+) and NO(3)(-)). CH(4) emissions depended on the organic matter mineralisation dynamics and the incorporation of manure in the starting mixture. The highest CH(4) fluxes were registered during the intense degradation at early stages of the process (up to 100 g Cm(-2)d(-1)). The emission of N(2)O (0-0.9 g Nm(-2)d(-1)) occurred from 6th to 10th wk of composting (bioxidative phase), coinciding with an intense nitrification in the pile. The use of urea enhanced the N(2)O emission up to 3.7 g Nm(-2)d(-1), due to an increase in available mineral N in the pile. Even though well managed TPOMW composting piles only represent a minor source of CH(4) and N(2)O emissions, the addition of urea and easily available C fractions to the starting mixtures can significantly increase the environmental impact of TPOMW composting as far as greenhouse gas emissions are concerned. PMID- 20708774 TI - Exposure assessment through realistic laboratory simulation of a soccer stadium fire. AB - On Sunday April 13, 2008 a fire broke out on a grandstand in the Euroborg soccer stadium in Groningen The Netherlands. The polyamide chairs on the grandstand were set on fire and supporters were exposed to the emitted smoke which induced mild health effects. The Dutch government was concerned about potential health risks that such fires could have to exposed fans. Especially the exposure to toxic fumes was considered a risk because prior research has proven that large amounts of chemical compounds are emitted during the burning of chemical substances such as polyamide. Among these emitted compounds are HCN, CO, NO(x), NH(3) and volatile organic compounds. To study if supporters were exposed to hazardous chemical compounds we designed a laboratory controlled replica of a part of the grandstand of the Euroborg stadium to perform fire-experiments. This simulation of the fire under controlled circumstances proved that a wide variety of chemicals were emitted. Especially the emission of CO and NO(x) were high, but also the emission of formaldehyde might be toxicologically relevant. The emission of HCN and NH(3) were less than expected. Exposure assessment suggests that the exposure to NO(x) is the main health risk for the supporters that were present at the Euroborg fire. PMID- 20708775 TI - Evolution of middle-late Pleistocene human cranio-facial form: a 3-D approach. AB - The classification and phylogenetic relationships of the middle Pleistocene human fossil record remains one of the most intractable problems in paleoanthropology. Several authors have noted broad resemblances between European and African fossils from this period, suggesting a single taxon ancestral to both modern humans and Neanderthals. Others point out 'incipient' Neanderthal features in the morphology of the European sample and have argued for their inclusion in the Neanderthal lineage exclusively, following a model of accretionary evolution of Neanderthals. We approach these questions using geometric morphometric methods which allow the intuitive visualization and quantification of features previously described qualitatively. We apply these techniques to evaluate proposed cranio facial 'incipient' facial, vault, and basicranial traits in a middle-late Pleistocene European hominin sample when compared to a sample of the same time depth from Africa. Some of the features examined followed the predictions of the accretion model and relate the middle Pleistocene European material to the later Neanderthals. However, although our analysis showed a clear separation between Neanderthals and early/recent modern humans and morphological proximity between European specimens from OIS 7 to 3, it also shows that the European hominins from the first half of the middle Pleistocene still shared most of their cranio-facial architecture with their African contemporaries. PMID- 20708776 TI - Hydrology and water quality of the headwaters of the River Severn: Stream acidity recovery and interactions with plantation forestry under an improving pollution climate. AB - This paper presents new information on the hydrology and water quality of the eroding peatland headwaters of the River Severn in mid-Wales and links it to the impact of plantation conifer forestry further down the catchment. The Upper Hafren is dominated by low-growing peatland vegetation, with an average annual precipitation of around 2650 mm with around 250 mm evaporation. With low catchment permeability, stream response to rainfall is "flashy" with the rising limb to peak stormflow typically under an hour. The water quality is characteristically "dilute"; stormflow is acidic and enriched in aluminium and iron from the acid organic soil inputs. Baseflow is circum-neutral and calcium and bicarbonate bearing due to the inputs of groundwater enriched from weathering of the underlying rocks. Annual cycling is observed for the nutrients reflecting uptake and decomposition processes linked to the vegetation and for arsenic implying seasonal water-logging within the peat soils and underlying glacial drift. Over the decadal scale, sulphate and nitrate concentrations have declined while Gran alkalinity, dissolved organic carbon and iron have increased, indicating a reduction in stream acidification. Within the forested areas the water quality is slightly more concentrated and acidic, transgressing the boundary for acid neutralisation capacity as a threshold for biological damage. Annual sulphate and aluminium concentrations are double those observed in the Upper Hafren, reflecting the influence of forestry and the greater ability of trees to scavenge pollutant inputs from gaseous and mist/cloud-water sources compared to short vegetation. Acidification is decreasing more rapidly in the forest compared to the eroding peatland possibly due to the progressive harvesting of the mature forest reducing the scavenging of acidifying inputs. For the Lower Hafren, long-term average annual precipitation is slightly lower, with lower average altitude, at around 2520mm and evaporation is around double that of the Upper Hafren. PMID- 20708777 TI - Association of DNA polymorphisms within the CYP11B2/CYP11B1 locus and postoperative hypertension risk in the patients with aldosterone-producing adenomas. AB - OBJECTIVES: Hypertension often persists after adrenalectomy for primary aldosteronism. Traditional factors associated with postoperative hypertension were evaluated, but whether genetic determinants were involved remains poorly understood. The aim of this study was to investigate the association of DNA polymorphisms within steroid synthesis genes (CYP11B2, CYP11B1) and the postoperative resolution of hypertension in Chinese patients undergoing adrenalectomy for aldosterone-producing adenomas (APA). METHODS: Ninety-three patients with APA were assessed for postoperative resolution of hypertension. All patients were genotyped for rs1799998 (C-344 T), intron 2 conversion, rs4539 (A2718G) within CYP11B2 and rs6410 (G22 5A), rs6387 (A2803G) within CYP11B1. The associations between CYPB11B2/CYP11B1 polymorphisms and persistent postoperative hypertension were assessed by multivariate analysis. RESULTS: CYP11B2-CYP11B1 haplotype was associated with persistent postoperative hypertension in Chinese patients undergoing adrenalectomy with APA (P = .006). Specifically, the rs4539 (AA) polymorphism was associated with persistent postoperative hypertension (P = .002). Multivariate logistic regression revealed the common haplotypes H1 (AGACT), H2 (AGAWT), and H3 (AGAWC) were associated with the persistent postoperative hypertension (P = .01, 0.03, 0.005 after Bonferroni correction). Additional predictors of persistent postoperative hypertension included duration of hypertension (P <.0005), family history of hypertension (P = .001), and elevated systolic blood pressure (P = .015). CONCLUSIONS: The rs4539 (AA), H1, H2, and H3 are genetic predictors for postoperative persistence of hypertension for Chinese patients treated by adrenalectomy with APA. DNA polymorphisms at CYP11B2/B1 locus may confer susceptibility to postoperative hypertension of patients with APA. PMID- 20708778 TI - A 7% decrease in the differential renal uptake of MAG3 implies a loss in renal function. AB - OBJECTIVES: To address the fact that a decrease in the relative renal uptake of 99mTc-mercaptoacetyltriglycine (MAG3) on serial MAG3 scans may indicate a loss of function and require a change in management by providing guidance as to what constitutes a meaningful change in serial relative function measurements as well determining the normal variation of other common MAG3 renogram parameters. METHODS: A prospective study was conducted in 24 male urology patients with stable renal function. The mean age was 66.5 +/- 7.9 (SD) years; the mean serum creatinine was 1.38 +/- 0.57 (SD) mg/dL, and the MAG3 renal scans were performed a mean of 11 +/- 8 days apart. Each MAG3 scan included a measurement of relative function as well as the time to maximum counts and 20 minutes to maximum count ratios for both cortical and whole kidney regions of interest. RESULTS: The Pearson and intraclass correlations for the baseline and repeat measurements of relative renal function were both 0.98. Bland-Altman plots showed no bias between the baseline and repeat relative uptake measurements. The mean difference between 2 repeated measurements of the relative MAG3 uptake was 0.04 +/- 2.88% (SD) for the left kidney and 0.08 +/- 3.07% (SD) for the right kidney. Comparable results were obtained for the other renogram parameters. CONCLUSIONS: Measurements of relative renal uptake of MAG3 and common renogram parameters are highly reproducible; a decrease in relative uptake >=7% (ie, 50%-43%) implies a loss in renal function. PMID- 20708779 TI - Novel method for double-J stenting in retroperitoneal laparoscopic dismembered pyeloplasty. AB - OBJECTIVES: To describe a novel technique of double-J stenting in laparoscopic pyeloplasty. METHODS: Between January 2008 and July 2009, 22 patients with ureteropelvic junction obstruction underwent retroperitoneal laparoscopic dismembered pyeloplasty. A ureteral catheter was inserted into the midureter cystoscopically. During pyeloplasty, the ureteral catheter was pushed up and grasped outside the body through the laparoscopic port. Its proximal end was extracorporeally sutured to the distal end of the double-J stent with a silk. The length of the silk was about that of the urethra. The ureteral catheter was then pulled down until its proximal end exited the external orifice of the urethra, while the stent was pulled smoothly and antegrade into the ureter and bladder. After the proximal end of the stent was positioned in the renal pelvis, the silk was cut and the ureteral catheter was removed. RESULTS: The stent was correctly placed in all these patients without any stent-related complications. The mean time for cystoscopy to place the ureteral catheter was 5 minutes, 10 seconds, and the mean time for the stent placement was 2 minutes, 45 seconds. The mean time for a total of 2 parts was 9 minutes, 15 seconds. CONCLUSIONS: Our new method of laparoscopic double-J stenting is reliable and easily reproducible with the combined advantages of the antegrade and retrograde approaches to eliminate the risk of the stenting failure. PMID- 20708780 TI - Milk of calcium in abdomen. AB - A 45-year-old woman had an asymptomatic abnormality on a screening abdominal radiograph. The radiopaque mass in her right upper abdomen was surrounded by numerous "pearls" and resembled an abalone on the supine abdominal radiograph. We advised an additional upright abdominal radiograph, which showed a calcium fluid level. We also clarified the location of the cystic lesion at the right floating kidney, which changed its location between the supine and upright positions. Computed tomography of the abdomen revealed a right renal cyst with a calcium fluid interface owing to the milk of calcium. The patient was then followed up without additional investigation or the need for intervention. PMID- 20708781 TI - Does robotic technology mitigate the challenges of large prostate size? AB - OBJECTIVES: For radical prostatectomy, the advantages of robotic surgery may facilitate precise dissection and improve functional outcomes. However, patients with larger prostates may still pose increased challenges because of impaired visualization and mobility in the pelvis. For this reason, we undertook a study to better understand the relationships between large prostate size and robotic prostatectomy outcomes with respect to intraoperative and pathologic factors. METHODS: Patients undergoing robotic-assisted radical prostatectomy from 2003 to 2008 at our institution were included in this retrospective study. Prostate size was categorized into 3 groups (< 50, 50-100, > 100 g). We compared surgical and quality of life (Expanded Prostate Cancer Index Composite [EPIC] scores) outcomes among groups using generalized linear models and chi-square testing. RESULTS: Patients with the largest prostates had longer operative times (> 100 vs < 50 g, 250 vs 232 minutes, P < .01) and more blood loss (> 100 vs < 50 g, 250 vs 155 mL, P = .01). Conversely, these patients had fewer positive surgical margins and lower Gleason sums (both P < .01). Despite worse baseline irritative symptoms (> 100 vs < 50 g, 79.7 vs 90.0, P < .001) and sexual function (> 100 vs < 50 g, 38.2 vs 77.9, P < .001), these differences resolved at 3 months (P = .92, P = .88, respectively). Recovery of continence was relatively sluggish compared with that in patients with the smallest prostates (> 100 vs < 50 g; 44.0, 62.2, P = .03). CONCLUSIONS: Not surprisingly, larger prostate size was associated with increased operative times and blood loss, although of questionable clinical significance. While these patients appeared to benefit regarding irritative symptoms, recovery of continence was delayed. Longer follow-up is needed to further assess recovery. PMID- 20708782 TI - Does prior abdominal surgery influence outcomes or complications of robotic assisted laparoscopic radical prostatectomy? AB - OBJECTIVES: To determine whether robotic-assisted laparoscopic radical prostatectomy (RALP) in patients with prior abdominal surgery is associated with increased operating times, positive surgical margins, or complications. METHODS: An institutional review board-approved retrospective review of a prospective, prostatectomy database was performed. Patients undergoing surgery between January 1, 2004, and February 29, 2008 were included. Transition from open retropubic prostatectomy to RALP took place through 2004, at which point all surgical candidates were offered RALP, regardless of prior surgical history. Learning curves from all surgeons were included. Patients with prior abdominal surgery were compared with those patients without prior surgery with respect to total operating time, robotic-assist time, surgical margin positivity, and rate of complications. RESULTS: A total of 1083 patients underwent RALP between January 1, 2004, and February 29, 2008, at our institution; of these, 839 had sufficient data available for analysis. In all, 251 (29.9%) patients had prior abdominal surgery, whereas 588 (70.1%) had no prior abdominal surgery. Total operating times were 209 and 204 minutes (P = .20), robotic console times were 165 and 163 minutes (P = .59), and surgical margin positivity was 21.1% and 27.2% (P = .08) for patients with and without prior abdominal surgery, respectively. The incidence of complications was 14.3% and 17.3% for patients with and without prior abdominal surgery (P = .33). CONCLUSIONS: Prior abdominal surgery was not associated with a statistically significant increase in overall operating time, robotic assist time, margin positivity, or incidence of complications in patients undergoing RALP. Robotic prostatectomy can be safely and satisfactorily performed in patients who have had a wide variety of prior abdominal surgery types. PMID- 20708783 TI - Simplified laparoscopic partial nephrectomy using a single-layer closure and no bolsters for renal tumors. AB - OBJECTIVES: Surgical outcomes for a simplified LPN technique using a single-layer closure were reviewed for central and peripheral renal tumors. METHODS: A total of 159 consecutive patients who underwent LPN were identified using a single institution database. Renal tumors abutting the collecting system or renal sinus were considered central. After tumor excision, the tumor bed was repaired using a single layer closure by passing partially straightened CPX needles beneath the entire cut surface. Pathologic and postoperative outcomes were compared between the central tumor group (CTG) and the peripheral tumor group (PTG). RESULTS: There were 83 and 76 patients in the CTG and PTG, respectively. When compared with the PTG, the CTG had a larger mean tumor size (3.4 vs 2.3 cm, P <.0001) and greater depth of tumor invasion (2.3 vs 1.1 cm, P <.0001). In the CTG, 66 tumors were malignant, and 2 patients had a positive margin. In the PTG, 50 tumors were malignant, and 1 patient had a positive margin. There was no statistically significant difference between the groups in operative times, estimated blood loss, transfusion rates, complications, positive margins, and length of hospital stays. The CTG had a longer warm ischemia time (24 vs 18 minutes, P = .0002), but this did not result in a significant difference in postoperative creatinine clearance (86 vs 87, P = .842). CONCLUSIONS: During LPN, a single-layer closure without bolsters is safe and effective, and early surgical outcomes are similar for central and peripheral tumors. PMID- 20708784 TI - Bilateral Wilms' tumors: single-center experience with 22 cases and literature review. AB - OBJECTIVES: Bilateral Wilms' tumors represent a therapeutic challenge. The primary aim of management is eradication of the neoplasm and preservation of renal function. We present our experience in the management of such cases in a single-center experience. METHODS: This was a retrospective study of 22 patients with histologically proven bilateral nephroblastoma who were treated from 1993 to 2008 at our center. Of the 22 patients, 12 were girls and 10 were boys, with a median age of 3 years (range 1-9); 19 had a synchronous presentation and 3 a metachronous presentation. Of the 22 patients, 6 underwent initial surgical resection followed by chemotherapy and 16 underwent initial biopsy and preoperative chemotherapy. The final oncologic and renal outcomes were assessed. RESULTS: The median follow-up period was 3 years (range 1-11). Of the 22 patients, 8 died, for an overall survival rate of 63.5%. The survival for the initial chemotherapy and initial surgery groups was essentially similar. Of all the variables studied, unfavorable histologic findings had a significant negative effect on survival. Of the 5 patients with unfavorable histologic findings, 4 died during the follow-up period. The median volume of preserved renal parenchyma was 40%. All patients had good renal function during follow-up, except for 1 patient who had undergone bilateral nephrectomy. CONCLUSIONS: Bilateral Wilms' tumors impose 2 conflicting issues: elimination of the pathology and preservation of the renal function. Currently, treatment regimens involving initial chemotherapy followed by conservative surgery can achieve these goals in an important proportion of patients. PMID- 20708785 TI - SGO Washington Update: the price of a profession. PMID- 20708786 TI - Cervical dysplasia: assessing methylation status (Methylight) of CCNA1, DAPK1, HS3ST2, PAX1 and TFPI2 to improve diagnostic accuracy. AB - PURPOSE: Diagnosis of cervical neoplasia hinges upon microscopic inspection of cervical samples. This has inherent operator-dependent variability. Testing for high-risk human papilloma virus (HPV) may help to triage patients with pre invasive disease in determining clinical intervention and follow-up. However, HPV presence/absence does not reflect the cervical epithelial cell's molecular status. Epigenetic modifications, e.g. DNA methylation, have been observed in the early stages of neoplastic change, preceding gene mutations. Here, we assess the correlation between cytologic/histologic results and combined DNA methylation data of 5 genes in different grades of cervical dysplasia. EXPERIMENTAL DESIGN: Cervical specimens collected via the liquid-based cytology system were each microscopically examined. Residual cells were subjected to DNA methylation analysis (Methylight) of gene loci CCNA1, PAX1, HS3ST2, DAPK1 and TFPI2. Methylation data were compared with cytologic/histologic reports. Statistical methods were applied to assess the ability of DNA methylation status to subtype the cervical neoplastic lesions according to their corresponding cytologic/histologic reports. RESULTS: A total of 165 subjects provided cytologically proven 63 HSIL, 49 LSIL and 53 normal samples. All patients with HSIL and LSIL underwent colposcopic examination. Patients with LSIL were all found to be CIN1; patients with HSIL were subsequently subdivided into 10 squamous cell carcinoma (SCC), 31 CIN3, 10 CIN2 and 12 CIN1. For each gene, there was increasing frequency of methylation from normal and LSIL (CIN1), through HSIL (CIN2 and CIN3), to SCC. Methylation of >=1 of genes investigated was observed in 88% of combined HSIL (CIN2 and CIN3) and SCC cases. All genes showed significant increase in methylation level (PMR value) with increasing disease grade (p<0.005). CCNA1 was the only gene that was able to distinguish CIN2 from CIN3 specimens (p=0.016). Based on receiver operating characteristic (ROC) analysis, HS3ST2 was the most significant candidate in segregating HSIL/SCC from normal/LSIL cases (p<0.0001); at an optimal cutoff value, sensitivity and specificity between 70% and 80% were obtained. CONCLUSIONS: Development of DNA methylation status of a gene panel to improve diagnostic accuracy in cervical neoplasia is warranted. PMID- 20708788 TI - Effects of language comprehension on visual processing - MEG dissociates early perceptual and late N400 effects. AB - We investigated whether and when information conveyed by spoken language impacts on the processing of visually presented objects. In contrast to traditional views, grounded-cognition posits direct links between language comprehension and perceptual processing. We used a magnetoencephalographic cross-modal priming paradigm to disentangle these views. In a sentence-picture verification task, pictures (e.g. of a flying duck) were paired with three sentence conditions: A feature-matching sentence about a duck in the air, a feature-mismatching sentence about a duck in a lake, and an unrelated sentence. Brain responses to pictures showed enhanced activity in the N400 time-window for the unrelated compared to both related conditions in the left temporal lobe. The M1 time-window revealed more activation for the feature-matching than for the other two conditions in the occipital cortex. These dissociable effects on early visual processing and semantic integration support models in which language comprehension engages two complementary systems, a perceptual and an abstract one. PMID- 20708787 TI - Undernutrition during foetal to prepubertal life affects aquaporin 9 but not aquaporins 1 and 2 expression in the male genital tract of adult rats. AB - Expression of aquaporin water channels (AQPs) in the male excurrent ducts, is of major importance for local water movements. To study the influence of pre- and postnatal undernutrition on AQP-expression in the adult male genital tract, 4 pregnant female rats were fed ad libitum (control group) and 4 with 33.5% of gestational feed requirements (underfed group). Feeding restriction of underfed group pups continued up to weaning (25 days of age), then all pups were fed ad libitum until slaughtered at 100 days of age. Epididymides were sampled and processed for aquaporin immunohistochemistry. Expression of AQP1 was similar either in the control and underfed groups of rats, strongly evidenced at the apical and lateral plasma membrane of the efferent ducts non-ciliated cells, in the smooth muscle cells surrounding epididymal duct and in blood vessel endothelium throughout the epididymis. AQP2-immunoreactivity was present in the corpus and cauda regions, strongly expressed in the principal cells of both groups of rats. In contrast, AQP9 expression was modified by early life undernourishment, as it was weakly evidenced at the microvilli in the principal cells and strongly diminished or completely lacked in the clear cells of the cauda, in underfed group epididymides. Since it is known that clear cells are involved in luminal fluid acidification, this function might be altered in adult animals, which were underfed during early life. PMID- 20708789 TI - Jugular venous pressure: a cardinal sign. PMID- 20708790 TI - Non-destructive label-free monitoring of collagen gel remodeling using optical coherence tomography. AB - Matrix remodeling plays a fundamental role in physiological and pathological processes, as well as in tissue engineering applications. In this paper, optical coherence tomography (OCT), a non-destructive optical imaging technology, was used to image collagen gel remodeling by smooth muscle cells (SMCs). The optical scattering properties of collagen-SMC gels were characterized quantitatively by fitting OCT data to a theoretical model. Matrix remodeling over 5 days produced a 10-fold increase in the reflectivity of the collagen gels, corresponding to a decrease in scattering anisotropy from 0.91 to 0.46. The increase in reflectivity was corroborated in confocal mosaic images. Blocking matrix degradation in collagen-SMC gels with doxycycline, a non-specific matrix metalloproteinases (MMPs) inhibitor, impeded the decrease in scattering anisotropy and resulted in few macroscopic signs of remodeling. Causing matrix degradation in acellular gels with a 3 h treatment of MMP-8 (collagenase 2) partially mimicked the decrease in anisotropy measured in collagen-SMC gels after 5 days. These results suggest that the decrease in scattering anisotropy in the collagen-SMC gels was due to MMP activity that degrades collagen fibrils into smaller fragments. PMID- 20708791 TI - A cell sorter with modified bamboo charcoal for the efficient selection of specific antibody-producing hybridomas. AB - Monoclonal antibodies (mAbs) have been proven useful in research and clinical applications. However, the generation of mAbs by conventional hybridoma technology is time-, cost- and labor-consuming. Here we developed a simplified procedure for efficient generation and selection of antibody-producing hybridomas within 1 h, using a particular cell sorter design, a cytoflow reactor-based cell sorter (CBCS) which consists mainly of the "cytoflow reactor" that comprises two components, a reaction chamber and a glass tubing for air and medium exchange by gravity, and the "sorting material", human EGFR-conjugated bamboo charcoal, for specific B-cell enrichment. The high surface area and porous structure of bamboo charcoal greatly increased cell density and protein production. Moreover, from Raman, FT-IR spectroscopy and IFA analysis, the carboxylation and immobilization of bamboo charcoal can be introduced easily by nitric acid treatment and conjugated handily with human EGFR using EDC/NHS. Other evidences, such as IFA, showed that the specific hybridomas generated in this study could secrete specific anti-human EGFR antibodies. Our design allows the production of mAbs while avoiding time-consuming steps, such as large numbers of limiting dilutions and screening assays, and demonstrates that the CBCS could be a powerful tool for monoclonal antibody production. PMID- 20708792 TI - Tissue engineering the mechanosensory circuit of the stretch reflex arc: sensory neuron innervation of intrafusal muscle fibers. AB - The sensory circuit of the stretch reflex arc, composed of specialized intrafusal muscle fibers and type Ia proprioceptive sensory neurons, converts mechanical information regarding muscle length and stretch to electrical action potentials and relays them to the central nervous system. Utilizing a non-biological substrate, surface patterning photolithography and a serum-free medium formulation a co-culture system was developed that facilitated functional interactions between intrafusal muscle fibers and sensory neurons. The presence of annulospiral wrappings (ASWs) and flower-spray endings (FSEs), both physiologically relevant morphologies in sensory neuron-intrafusal fiber interactions, were demonstrated and quantified using immunocytochemistry. Furthermore, two proposed components of the mammalian mechanosensory transduction system, BNaC1 and PICK1, were both identified at the ASWs and FSEs. To verify functionality of the mechanoreceptor elements the system was integrated with a MEMS cantilever device, and Ca(2+) currents were imaged along the length of an axon innervating an intrafusal fiber when stretched by cantilever deflection. This system provides a platform for examining the role of this mechanosensory complex in the pathology of myotonic and muscular dystrophies, peripheral neuropathy, and spasticity inducing diseases like Parkinson's. These studies will also assist in engineering fine motor control for prosthetic devices by improving our understanding of mechanosensitive feedback. PMID- 20708793 TI - The effect of triethylene glycol dimethacrylate on p53-dependent G2 arrest in human gingival fibroblasts. AB - Dental resin composites have been reported to exert adverse effects on cells of the oral cavity. In this study, we demonstrate that a non-cytotoxic concentration of the resin co-monomer triethylene glycol dimethacrylate (TEGDMA) results in the reduction of the proliferation rate of human gingival fibroblasts (HGFs), by delaying them at the G2 phase of the cell cycle, and in the sustained production of reactive oxygen species. These phenomena are accompanied by an early transient de-phosphorylation of ERK1/2 and JNKs and a late activation of the p53-p21(WAF1) pRb molecular pathway. By using siRNA-mediated knocking down of the human p53 gene, we present evidence that the onco-suppressive protein p53 controls the TEGDMA-activated G2 checkpoint in HGFs and prevents their entry into mitosis, possibly in order to protect them from the detrimental genotoxic effects of the compound. PMID- 20708794 TI - A hydrophobic perfluoropolyether elastomer as a patternable biomaterial for cell culture and tissue engineering. AB - We present a systematic study of a perfluoropolyether (PFPE)-based elastomer as a new biomaterial. Besides its excellent long-term stability and inertness, PFPE can be decorated with topographical surface structures by replica molding. Micrometer-sized pillar structures led to considerably different cell morphology of fibroblasts. Although PFPE is a very hydrophobic material we could show that PFPE substrates allow cell adhesion and spreading of primary human fibroblasts (HDF) very similar to that observed on standard cell culture substrates. Less advanced cell spreading was observed for L929 (murine fibroblast cell line) cells during the first 5 h in culture which was accompanied by retarded recruitment of alpha(v)beta(3)-integrin into focal adhesions (FAs). After 24 h distinct FAs were evident also in L929 cells on PFPE. Furthermore, organization of soluble FN into a fibrillar ECM network was shown for hdF and L929 cells. Based on these results PFPE is believed to be a suitable substrate for several biological applications. On the one hand it is an ideal cell culture substrate for fundamental research of substrate-independent adhesion signaling due to its different characteristics (e.g. wettability, elasticity) compared to glass or TCPS. On the other hand it could be a promising implant material, especially due to its straightforward patternability, which is a tool to direct cell growth and differentiation. PMID- 20708795 TI - Angiogenesis induced by controlled release of neuropeptide substance P. AB - The in vivo recruitment of circulating host cells to the site to be regenerated is one of the promising strategies for therapeutic angiogenesis. Substance P (SP), a member of neuropeptides, mediates pain perception and regulates wound healing, inflammation, tumor cell proliferation, and angiogenesis. This SP enhanced the migration, adhesion, and angiogenic gene expression of granulocytes in vitro. A biodegradable hydrogel was prepared from an anionic derivative of gelatin to achieve the controlled release of SP in vivo. When the anionic gelatin hydrogels incorporating SP were subcutaneously implanted into the mouse back, significant angiogenesis was induced around the site implanted, in contrast to the injection of SP solution. In vivo accumulation of granulocytes around the implanted sites was observed. It is concluded that the controlled release of SP efficiently induced the recruitment and the subsequent activation of granulocytes, one of the circulating cells with angiogenic activities, from the blood circulation into the site implanted, resulting in enhanced angiogenesis. PMID- 20708796 TI - Hans Strahl's pioneering studies in comparative placentation. AB - Hans Strahl, a contemporary of Duval and Hubrecht, made many important contributions to comparative placentation. Despite this he is not well known and some of his original observations tend to be attributed to later authors. Strahl published a classification of placental types based on their shape and relationship to maternal tissues. This greatly influenced the work of Otto Grosser, who became better known in part because his work was more accessible to other scientists and clinicians. Strahl described the development of the fetal membranes across a broad range of mammalian orders extending his observations beyond parturition to the post partum involution of the uterus. He paid close attention to structures designed for histotrophic nutrition including the areolae of moles, haemophagous organs of carnivores and tenrecs and chorionic vesicles of lemurs and lorises. We here provide a summary of some of the most important findings made by Strahl including work on placentation in carnivores and higher primates that remains unsurpassed. PMID- 20708797 TI - Changes in the metabolic footprint of placental explant-conditioned medium cultured in different oxygen tensions from placentas of small for gestational age and normal pregnancies. AB - Being born small for gestational age (SGA) confers significantly increased risks of perinatal morbidity and mortality. Accumulating evidence suggests that an SGA fetus results from a poorly perfused and abnormally developed placenta. Some of the placental features seen in SGA, such as abnormal cell turnover and impaired nutrient transport, can be reproduced by culture of placental explants in hypoxic conditions. Metabolic footprinting offers a hypothesis-generating strategy to investigate factors absorbed by and released from this tissue in vitro. Previously, metabolic footprinting of the conditioned culture media has identified differences in placental explants cultured under normoxic and hypoxic conditions and between normal pregnancies and those complicated by pre-eclampsia. In this study we aimed to examine the differences in the metabolic footprint of placental villous explants cultured at different oxygen (O(2)) tensions between women who deliver an SGA baby (n = 9) and those from normal controls (n = 8). Placental villous explants from cases and controls were cultured for 96 h in 1% (hypoxic), 6% (normoxic) and 20% (hyperoxic) O(2). Metabolic footprints were analysed by Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap Mass Spectrometry (UPLC-MS). 574 metabolite features showed significant difference between SGA and normal at one or more of the oxygen tensions. SGA explant media cultured under hypoxic conditions was observed, on a univariate level, to exhibit the same metabolic signature as controls cultured under normoxic conditions in 49% of the metabolites of interest, suggesting that SGA tissue is acclimatised to hypoxic conditions in vivo. No such behaviour was observed under hyperoxic culture conditions. Glycerophospholipid and tryptophan metabolism were highlighted as areas of particular interest. PMID- 20708798 TI - Hyperviscosity syndrome in a patient with kappa light chain myeloma with cryoglobulin properties and alpha thalassemia. PMID- 20708799 TI - "Real-life" results of front-line treatment with Imatinib in older patients (>= 65 years) with newly diagnosed chronic myelogenous leukemia. AB - The age role was evaluated in 117 consecutive patients with newly diagnosed CML at our Institution treated with front-line Imatinib from 9/02 to 3/08. Forty patients (34.1%) aged >= 65 years and 77 (65.9%) <65 years. Thirty-four older patients (85%) had at least 1 comorbidity versus 39 younger patients (50.6%) (p<0.001). Complete cytogenetic response (CCyR) was achieved in 34/40 older patients (85%) as compared to 69/77 younger patients (89.6%), without statistically significant differences. Severe (grades 3-4 WHO) hematological and extra-hematological toxicities were more common in older patients (p=0.02 and p=0.017, respectively). Rates of permanent Imatinib discontinuation and dose reduction to 300 mg or less were significantly higher in older patients (p=0.009 and p=0.001, respectively). In conclusion, Imatinib in older patients with newly diagnosed CML seems to have the same efficacy as in younger patients, but tends to be more toxic, leading to higher rates of discontinuation and dose reduction. To overcome this problem, future trials concerning best dosage in this subset of patients could be useful. PMID- 20708800 TI - Zerumbone induces apoptosis in T-acute lymphoblastic leukemia cells. AB - Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this investigation, the anticancer properties of ZER were evaluated on cancer cells of T-acute lymphoblastic leukemia, CEM-ss. The results showed that ZER has cytotoxic effect against CEM-ss cells with an IC(50) of 8.4 +/- 1.9 MUg/ml (coefficient of variation < 30%). Comparatively, 5 fluorouracil (positive control), imposed an inhibitory effect on CEM-ss cells with an IC(50) of 1.94 +/- 0.06 MUg/ml. Scanning electron microscopy (SEM) results revealed abnormalities such as membrane blebbing, holes and cytoplasmic extrusions, all of which are characteristics of apoptosis. In addition, ZER has increased the number of TUNEL-positive stain and the cellular level of caspase-3, the hallmarks of apoptosis, on treated CEM-ss cells. It could be concluded that, ZER was able to produce apoptosis on T-acute lymphoblastic leukemia, CEM-ss. The current findings suggest that ZER might be helpful for improving the usefulness of anticancer agents in the therapy of leukemia. PMID- 20708801 TI - Activity levels of B-esterases in the tadpoles of 11 species of frogs in the middle Parana River floodplain: implication for ecological risk assessment of soybean crops. AB - Soybean fields provide habitats for many species of amphibians. However, the persistence and health of amphibian populations may be at risk from the increasing use of pesticides and other agricultural chemicals. We examined the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterases (CbEs) in 11 syntopic species of larval anurans. In vitro effects of malaoxon causing 50% BChE inhibition (IC(50)) were also studied. In addition, we calculated a relative risk index (RI) based on the geographic distributions of the anurans, the phenology of soybean cultivation, and basal enzymatic values related to potential pesticide detoxification. Among the 11 species, AChE activity varied from 17.5 +/- 1.6 to 68.2 +/- 4.7 nmol min(-1) mg( 1) protein (PT). BChE activity also varied significantly, ranging from 3.3 +/- 0.4 to 7.5 +/- 0.4 nmol min(-1) mg(-1)PT. Both measures of CbE activities varied widely (CbE alpha-NA: 2.1 +/- 0.5-12.4 +/- 1.1 nmol min(-1) mg(-1) PT; CbE-4NPV: 21.8 +/- 1.8-102.6 +/- 7.9 nmol min(-1) mg(-1) PT). We also corroborate that lower BChE activity levels for the tadpoles were associated at minor IC(50) values. The results of this study demonstrate significant variation in enzymatic levels among several tadpole species and intermediate to high RI values for 7 species. Based on these results, it appears that a conversion of native ecosystems to soybean crops may lead to increased ecological risk for anuran amphibians. PMID- 20708802 TI - Joseph Priestley: Docter Phlogiston or Reverend Oxygen? AB - In propaganda material, people are often presented in black-and-white terms as either a villain or a hero. Although Joseph Priestley is denigrated for believing in the discredited substance phlogiston, he is also celebrated for discovering oxygen. PMID- 20708803 TI - Cognitive correlates in toddlers born very low birth weight and full-term. AB - Understanding what contributes to children's cognitive development can improve our ability to identify those children at risk for later developmental disorders. We hypothesized that cognition would be more strongly associated with child and mother interaction variables such as communication, sensitivity and affect during play in contrast to medical variables in preterm children, and that these same variables would also be correlates of cognition in children born full-term. Cognition was measured by the Bayley Scales of Infant Development-II Mental Developmental Index and mother-toddler play interactions were coded with the Caregiver-Child Affect, Responsiveness and Engagement Scales (C-CARES) for child and mother affect, communication, and sensitivity in 40 very low birth weight (VLBW) and 54 full-term toddlers at 18-22 months of age, adjusted for gestational age. Two different multivariate models were identified that best predicted cognition in the two sets of toddlers. For the toddlers born VLBW, days on ventilation, maternal education and the three C-CARES Child Play scales (sensitivity, affect and communication) were the best predictors of cognition. In contrast, the multivariate model that best correlated with cognition for the children born full-term included the Maternal Communication scale of the C-CARES. The different multivariate models identified for toddlers born preterm compared to those born full-term emphasizes the importance of using identification and cognitive intervention techniques that are uniquely tailored for children born very low birth weight. Findings highlight the importance of investigating beyond more traditional measures of cognition by incorporating play-based socio emotional measures. PMID- 20708804 TI - Psychosocial treatment of posttraumatic stress disorder in adult refugees: a systematic review of prospective treatment outcome studies and a critique. AB - BACKGROUND: Refugees with posttraumatic stress disorder (PTSD) often present with complicated traumatic symptoms, prolonged and repeated exposure to traumatic events, acculturation, and social problems. A consensus about suitability of psychosocial treatments for refugees does not exist. Never the less there is a need to review the state of knowledge about effective treatments for traumatized refugees, to help guide the practitioners in their choice of treatment methods. METHODS: A systematic review of treatment outcome studies was carried out. RESULTS: Twenty-five studies were reviewed. The majority were treatment studies of different forms of cognitive-behavioral therapy (CBT). The rest were reports of outcomes of alternative treatments and a small group of studies of multidisciplinary treatments. LIMITATIONS: The amount of grey literature not covered by the review could not be estimated precisely. Included studies are methodologically diverse and consist of different refugee populations. This makes a broad interpretation of the treatment results only tentative. CONCLUSIONS: Very large effect sizes were obtained in some of the CBT studies, indicating a broad suitability of CBT in the treatment of core symptoms of PTSD in adult refugees. Empirical evidence also points to the possibility that the maladaptive traumatic reactions in refugees can take shape of more complex reactions than those strictly specified in the diagnostic category of PTSD. Effectiveness of CBT treatments has as yet not been tested on the whole range of symptoms in these complex cases. There are few studies of treatments alternative to CBT and they are less methodologically rigorous than the CBT studies. PMID- 20708805 TI - First direct comparison of platelet reactivity and thrombolytic status between Japanese and Western volunteers: possible relationship to the "Japanese paradox". AB - OBJECTIVE: To determine and compare thrombotic and endogenous thrombolytic status in Japanese and Western populations. BACKGROUND: Incidence of coronary heart disease (CHD) and AMI in Japan remains lower than in Western countries. Primary genetic effects are unlikely, given the increased CHD in Japanese migrants. For men, cholesterol and blood pressure have been similar in Japan and the U.S. Dietary factors are implicated, but how these effect CHD is unclear. We postulated that differences in thrombotic and/or thrombolytic status may contribute. METHODS: We measured thrombotic and thrombolytic status in 100 healthy Japanese (J) from Japan and 100 healthy Westerners (W) from the U.K. using the Global Thrombosis Test (GTT). The GTT employs non-anticoagulated blood to create platelet-rich thrombi under high shear (occlusion time OT; seconds), and then measures the restart of blood flow, due to spontaneous thrombolysis (lysis time LT; seconds). RESULTS: OT was longer in (J) compared to (W) (545 vs. 364, p<0.0001). LT was longer in (J) than in (W) (1753 vs. 1052, p<0.0001). Distribution of LT in (J) did not conform to a normal population, with markedly impaired thrombolytic status (LT>3,000 s) in 18%, compared to none of the Westerners (p<0.0001). CONCLUSIONS: There are marked differences in thrombotic and thrombolytic status, with (J) having less prothrombotic (longer OT) but less favourable endogenous thrombolytic profile (longer LT). This may be important in the aetiology of thrombotic events. Since platelets and thrombolysis were both inhibited in (J) and yet incidence of AMI is lower, OT would seem more important than LT as a determinant of overall thrombotic risk in this population. PMID- 20708806 TI - Five-year outcomes of sirolimus-eluting versus paclitaxel-eluting stents: a propensity matched study: clinical evidence of late catch-up? AB - BACKGROUND: Siroliums-eluting stents (SES) and paclitaxel-eluting stents (PES) have been widely used for the treatment of coronary artery disease. We investigated 5-year clinical outcomes of patients treated with SES versus PES in a multicenter registry. METHODS: We used a propensity score matching method with 2:1 matching, including 512 patients treated with SES and 256 patients treated with PES from March 2003 to December 2004. The primary endpoint was major adverse cardiac events, which included all-cause death, myocardial infarction (MI), and target vessel revascularization (TVR). RESULTS: After matching, baseline characteristics were similar between the two groups. At 5 years, cumulative survival free of major adverse cardiac events, MI, and stent thrombosis did not differ between the two groups. Survival free of TVR at 5 years was higher in the SES group (88.4%) than the PES group (84.3%, Log-rank p=0.016). In contrast to the trend toward more likely target lesion revascularization in the PES group during the first 2 years (hazard ratio 0.62, p=0.057), target lesion revascularization tended to occur more frequently in the SES group from 2 to 5 years (hazard ratio 2.26, p=0.099). CONCLUSIONS: Long-term risk of TVR was slightly lower with SES, compared with PES, despite no significant difference in major adverse cardiac events. However, the SES group had more frequent target lesion reintervention 2 to 5 years after stent implantation, whereas reintervention in the PES group occurred mainly within the first 2 years. This may reflect the temporal difference in neointimal growth of the two stent types. PMID- 20708807 TI - Age at which dairy cattle become Mycobacterium avium subsp. paratuberculosis faecal culture positive. AB - Age at which cattle become faecal culture positive for Mycobacterium avium subsp. paratuberculosis (Map) can be used as a proxy parameter for age at onset of faecal shedding, which is an important parameter in the control of Map in cattle herds. To investigate the age at becoming faecal culture positive, survival analysis methods were applied. The analyses were carried out on asynchronous interval censored data of faecal culture results of samples collected from 18,979 female Holstein-Frisian cattle in 353 Dutch herds between 1996 and 2002. The data were analysed with a Weibull proportional hazards model. The results indicate that the distribution of age at onset of faecal shedding in Holstein-Frisian dairy cattle in infected herds is associated with the within-herd prevalence. In higher classes of apparent prevalence, cattle started to shed Map at younger age on average. In herds with an apparent prevalence <0.05, 0.05-0.1, 0.1-0.2 and >=0.2, the proportion (95% CI) of cattle with onset of faecal shedding before 2 years of age was estimated at 1% (0.5%; 2%), 4% (3%; 5%), 8% (5%; 10%) and 20% (11%; 32%), respectively. This study indicates that a considerable proportion of young stock is shedding Map, especially in high prevalence herds. Therefore, infectious young stock should be a major concern in the control of paratuberculosis. PMID- 20708808 TI - Clinical evidence on PET-CT for radiation therapy planning in head and neck tumours. AB - The potential benefits of positron emission tomography (PET) imaging for the management of head and neck tumours are increasingly being recognized. Integrated PET-CT has found its way into the practice of radiation oncology providing both functional and anatomical tumour information for treatment planning and the implications for clinical practice are currently being investigated. First, it has been demonstrated that (18)F-fluorodeoxyglucose ((18)FDG)-PET can improve the accuracy of gross tumour volume delineation for radiation therapy planning. Next, PET using (18)FDG or more specific tracers may facilitate dose escalation to radioresistant tumour subvolumes. Finally, PET can provide tumour characterization prior to and during radiotherapy, facilitating adaptive radiotherapy and other tailored treatment strategies. Although these are promising prospects, unresolved issues remain and these applications are not yet ready for introduction into routine clinical practice. PMID- 20708809 TI - Detection and compensation of organ/lesion motion using 4D-PET/CT respiratory gated acquisition techniques. AB - PURPOSE: To describe the degradation effects produced by respiratory organ and lesion motion on PET/CT images and to define the role of respiratory gated (RG) 4D-PET/CT techniques to compensate for such effects. METHODS: Based on the literature and on our own experience, technical recommendations and clinical indications for the use of RG 4D PET/CT have been outlined. RESULTS: RG 4D-PET/CT techniques require a state of the art PET/CT scanner, a respiratory monitoring system and dedicated acquisition and processing protocols. Patient training is particularly important to obtain a regular breathing pattern. An adequate number of phases has to be selected to balance motion compensation and statistical noise. RG 4D PET/CT motion free images may be clinically useful for tumour tissue characterization, monitoring patient treatment and target definition in radiation therapy planning. CONCLUSIONS: RG 4D PET/CT is a valuable tool to improve image quality and quantitative accuracy and to assess and measure organ and lesion motion for radiotherapy planning. PMID- 20708810 TI - PET in radiotherapy planning: particularly exquisite test or pending and experimental tool? PMID- 20708811 TI - Clinical evidence on PET/CT for radiation therapy planning in prostate cancer. AB - The present chapter is focused on the role of positron emission tomography/computed tomography (PET/CT) and [11C]-labelled Choline ([11C]Choline) for the management of prostate cancer patients for radiation therapy planning. Although still a matter of debate, PET/CT with [11C]Choline is not routinely recommended for selecting patients for prostate cancer primary radiation treatment. However, due to its high accuracy in detecting and localizing recurrences when a biochemical failure occurs, [11C]Choline PET/CT may play a role in the re-staging phase to distinguish patients with local versus distant relapse, thus influencing patient management (curative versus palliative therapy). Limited data are currently available on the role of [11C]Choline PET/CT in target volume selection and delineation. According to available literature, [11C]Choline PET/CT is not clinically recommendable to plan target volume both for primary prostate treatment and for local recurrence. Nevertheless, promising data suggested a potential role of [11C]Choline PET/CT as an image guide tool for the irradiation of prostate cancer relapse. PMID- 20708812 TI - DPP-4 inhibitors: what may be the clinical differentiators? AB - Attenuation of the prandial incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), contributes to hyperglycemia in type 2 diabetes mellitus (T2DM). Since the launch of sitagliptin in 2006, a compelling body of evidence has accumulated showing that dipeptidyl peptidase-4 (DPP-4) inhibitors, which augment endogenous GLP-1 and GIP levels, represent an important advance in the management of T2DM. Currently, three DPP-4 inhibitors - sitagliptin, vildagliptin and saxagliptin - have been approved in various countries worldwide. Several other DPP-4 inhibitors, including linagliptin and alogliptin, are currently in clinical development. As understanding of, and experience with, the growing number of DPP-4 inhibitors broadens, increasing evidence suggests that the class may offer advantages over other antidiabetic drugs in particular patient populations. The expanding evidence base also suggests that certain differences between DPP-4 inhibitors may prove to be clinically significant. This therapeutic diversity should help clinicians tailor treatment to the individual patient, thereby increasing the proportion that safely attain target HbA(1c) levels, and reducing morbidity and mortality. This review offers an overview of DPP-4 inhibitors in T2DM and suggests some characteristics that may provide clinically relevant differentiators within this class. PMID- 20708813 TI - Cost-effectiveness of administering oral adsorbent AST-120 to patients with diabetes and advance-stage chronic kidney disease. AB - AIMS: AST-120, an oral adsorbent currently on-label only in Asian countries with phase III trials ongoing in the US, slows renal disease progression in patients with diabetes and advanced-stage chronic kidney disease (CKD). The objective of this study is to evaluate the cost-effectiveness of using AST-120 to treat patients with type 2 diabetes and advanced-stage CKD. METHODS: We used Markov model simulating the progression of diabetic nephropathy. Data were obtained from randomized trials estimating the progression of diabetic nephropathy with and without AST-120, and published literature. The base population was patients 60 years of age with type 2 diabetes and Stages 3 and 4 CKD. RESULTS: Treating patients with diabetes and advanced-stage CKD was found to be a dominant strategy, and quality of life improved further and more money was saved (0.22 quality-adjusted life years [QALYs] and $15,019 per patient) using AST-120 than the control strategy. Sensitivity analysis results were robust with regard to cost, adherence, and quality of life associated with AST-120 therapy, as well as age at diagnosis. The model was relatively sensitive to the effectiveness of AST 120. CONCLUSIONS: Treating patients with type 2 diabetes and advanced-stage CKD with AST-120 appears to extend life and reduce costs. PMID- 20708814 TI - Incretin action maintains insulin secretion, but not hepatic insulin action, in people with impaired fasting glucose. AB - AIMS: To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG). METHODS: People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6 (2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration. RESULTS: EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group. CONCLUSIONS: Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG. PMID- 20708815 TI - Association between ethnicity and prostate cancer outcomes across hospital and surgeon volume groups. AB - OBJECTIVE: We analyzed the association between ethnicity and outcomes among prostate cancer patients across hospital and surgeon volume groups. METHODS: In this retrospective cohort study using SEER-Medicare databases for the period between 1995 and 2003, prostate cancer cases were identified and retrospectively followed for one year pre- and up to eight years post-diagnosis. Based on volume, hospitals and surgeons were divided into three groups each. For each group, we fitted separate models to analyze the association between ethnicity and outcomes such as complications, eight-year mortality and cost, adjusting for covariates. Poisson (zero inflation), generalized linear model (log-link), and Cox regression models were used. RESULTS: African American ethnicity was associated with 30-day complications among medium volume hospital group. African American patients receiving care at medium volume hospitals and from medium volume surgeons had higher costs. Hispanic patients receiving care at low and medium volume hospitals had lower cost compared to white patients. Hispanic patients receiving care from a high-volume surgeon experienced increased hazard of long-term mortality. CONCLUSIONS: Association between ethnicity and outcomes varies across hospital and surgeon volume groups. Thus, volume based policy measures may need further exploration for understanding the interaction between structure, process, volume and outcomes. PMID- 20708816 TI - Potential primary health care savings for chronic disease care associated with Australian Aboriginal involvement in land management. AB - RATIONALE: To identify the possible savings in the cost of primary health care of chronic disease associated with the participation by Aboriginal people in land management. In so-doing we investigate the connection of health of Aboriginal people and the extent of their involvement in land management in remote-very remote Australia. METHODS: Possible savings in primary care costs for hypertension, renal disease and diabetes were estimated using multivariate regression to examine associations between Aboriginal involvement in land management and Northern Territory Government-defined chronic disease outcomes, controlling for socio-demographics and health behaviours. Participants were 298 Aboriginal adults aged 15-54 from a remote Aboriginal community, classified by their chronic disease status and a previously validated measure of self-reported participation in land management activities. RESULTS: Land management participants were significantly less likely to have diabetes, renal disease or hypertension. Using the sampled mean value of engagement in land management, we found the expected net annual savings for the community from involvement in land management of $268,000. This equates to a net present value of primary health care savings in chronic disease care for the sampled community over 25 years of $4.08 million. This estimate does not include further savings in other primary health conditions nor costs anticipated in referred and hospital-based health care for chronic disease. CONCLUSION: While the association between involvement in land management and better health requires further clarification, our findings indicate that significant and substantial primary health care cost savings may be associated with greater participation in land management activities. These estimated savings are in addition to the market and non-market economic benefits of a healthier population and environmental benefits. PMID- 20708817 TI - Iron-mediated trichloroethene reduction within nonaqueous phase liquid. AB - Aqueous slurries or suspensions containing reactive iron nanoparticles are increasingly suggested as a potential means for remediating chlorinated solvent nonaqueous phase liquid (NAPL) source zones. Aqueous-based treatment approaches, however, may be limited by contaminant dissolution from the NAPL and the subsequent contaminant transport to the reactive nanoparticles. Reactions occurring within (or at the interface) of the NAPL may alleviate these potential limitations, but this approach has received scant attention due to concerns associated with the reactivity of iron within nonaqueous phases. Results presented herein suggest that iron nanoparticles are reactive with TCE-NAPL and exhibit dechlorination rates proportional to the concentration of (soluble) water present within the NAPL. Reactivity was assessed over a 12-day period for five water contents ranging from 0.31 M to 4.3M, with n-butanol used to enhance water solubility in the NAPL. Rates of dechlorination were generally slower than those reported for aqueous-phase dechlorination, but were not observed to slow over the course of the 12-day period. The lack of observed deactivation may indicate the potential that highly efficient (with respect to utilization of available electrons) dechlorination reactions can be engineered to occur within nonaqueous liquids. These results suggest a need for subsequent investigations which focus on understanding the mechanisms of the reactions occurring within NAPL, as well as those assessing the utility of controlling both the iron and water content within a NAPL source zone. PMID- 20708818 TI - Annexin XIIIb guides raft-dependent and -independent apical traffic in MDCK cells. AB - Epithelial cells are characterized by a polarized organization of their plasma membrane that is divided into apical and basolateral domains. This architecture is maintained by a highly specific cargo sorting machinery that efficiently delivers components to their respective membrane domains. After TGN exit apical cargo is segregated by at least two distinct sorting mechanisms into lipid raft dependent or lipid raft-independent apical pathways. Annexin XIIIb had been shown to be a member of the lipid raft-dependent trafficking machinery. We now identify this annexin also in raft-independent apical trafficking by mass spectrometry, immunoblotting and confocal microscopy. Annexin XIIIb accumulates in endosomal organelles that are traversed by raft-dependent and raft-independent apical cargo after TGN release. Finally, a specific reduction of annexin XIIIb expression by RNA interference results in a significant decrease in the apical delivery of raft as well as non-raft apical markers. Taken together, our data suggest that annexin XIIIb plays a general role in post Golgi apical trafficking early after TGN release, before the two apical pathways are segregated. PMID- 20708819 TI - Interactions between iron and titanium metabolism in spinach: a chlorophyll fluorescence study in hydropony. AB - One of the elements showing strong beneficial effect on plants at low concentrations and toxic effects at higher concentrations is titanium (Ti). We investigated the interconnection between the Fe uptake and the Ti intoxication in model experiment on Fe-deficient spinach (Spinacia oleracea) plants to help to elucidate the mechanism of the biological activity of titanium in plants. The two different Ti (0 and 20 mg L-1) and two different Fe (0 and 1.35 mg L-1) concentrations in hydroponic medium were used in all four possible combinations. We compared chemical analysis of Ti and Fe in roots and shoots with the changes of the in vivo chlorophyll fluorescence. Although Fe and Ti concentration found in shoots of Ti-non-treated Fe-deficient plants was comparable with that in Ti treated Fe-deficient plants, the soluble form of Ti present in the growth media had a negative effect on photosynthetic activity monitored by chlorophyll fluorescence measurements. The presence of Fe in growth medium significantly decreased the Ti concentration in shoots and increased the photosynthetic activity. Here, we propose that Ti affect components of electron transport chain containing Fe in their structure (particularly photosystem I) and decrease the photosystem II efficiency. PMID- 20708820 TI - Photosynthetic down-regulation under elevated CO2 exposure can be prevented by nitrogen supply in nodulated alfalfa. AB - Increasing atmospheric CO2 concentrations are expected to enhance plant photosynthesis and yield. Nevertheless, after long-term exposure, plants acclimate and show a reduction in photosynthetic activity (called down regulation), which may cause a reduction in potential yield. Some authors suggest that down-regulation is related to nutrient availability, and more specifically, to an insufficient plant C sink strength caused by limited N supply. In this paper, we tested whether or not N availability prevents down-regulation of photosynthesis in nodulated alfalfa plants (Medicago sativa L.). To do so, we examined the effect of the addition of different levels of NH4NO3 (0, 10, and 15 mM) to 30-day-old nodulated alfalfa plants exposed to ambient (approximately 400 MUmol mol-1) or elevated CO2 (700 MUmol mol-1) during a period of 1 month in growth chambers. After 2 weeks of exposure to elevated CO2, no significant differences were observed in plant growth or photosynthesis rates. After 4 weeks of treatment, exclusively N2 fixing alfalfa plants (0 mM NH4NO3) showed significant decreases in photosynthesis and Vc(max). Photosynthetic down regulation of these plants was caused by the C/N imbalance as reflected by the carbohydrate and N data. On the other hand, plants supplied with 15 mM NH4NO3 grown under elevated CO2 maintained high photosynthetic rates owing to their superior C/N adjustment. The intermediate N treatment, 10 mM NH4NO3, also showed photosynthetic down-regulation, but to a lesser degree than with 0 mM treatment. The present study clearly shows that external N supply can reduce or even avoid acclimation of photosynthesis to elevated CO2 as a consequence of the increase in C sink strength associated with N availability. PMID- 20708821 TI - Comparative transcriptome analysis of contrasting foxtail millet cultivars in response to short-term salinity stress. AB - Soil salinity represents a major abiotic stress that adversely affects crop growth and productivity. In this study, 21-day-old seedlings of two foxtail millet (Setaria italica) cultivars differing in salt tolerance were found to also differ in lipid peroxidation, ion balance and activity of antioxidative enzymes (glutathione reductase and catalase) under short-term salinity stress (250 mM NaCl for 1-48 h). With the aim of better understanding the molecular mechanisms underlying plant responses to short-term salinity stress, two suppression subtractive hybridization cDNA libraries (forward and reverse) were constructed of these cultivars. A total of 249 non-redundant ESTs was identified by random EST sequencing and grouped into 11 functional categories. Macroarray analysis of these clones showed that 159 (63.9%) were differentially expressed (>= 2-fold) in response to salinity stress, with 115 (72.3%) up and 44 (27.7%) down-regulated. A data search of transcriptional profiling under salinity stress in other species revealed that 81 (51%) of the 159 differentially expressed transcripts found in foxtail millet have not been reported in previous studies. Hence, these new transcripts may represent untapped gene sources allowing specific responses to short-term salt-stress in an orphan crop known to possess a natural adaptation capacity to abiotic stress. Quantitative real-time PCR of 21 highly up-regulated (>= 2.5-fold) transcripts showed temporal variation in expression in both cultivars under salinity. Among them, several transcription factors and signalling genes were preferentially expressed in the tolerant cultivar. These results suggest that the tolerant cultivar possesses more effective signal perception mechanisms for metabolic adjustments in plants under harsh saline conditions. Our findings provide evidence that the unknown genes identified in this study, in addition to several known genes, may play important roles in stress tolerance mechanisms present in foxtail millet. PMID- 20708822 TI - Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer's disease. AB - Brain aging is associated with synaptic decline and synaptic function is highly dependent on mitochondria. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of several neurodegenerative diseases. Here we have investigated the repair of oxidative base damage, in synaptosomes of mouse brain during normal aging and in an AD model. During normal aging, a reduction in the base excision repair (BER) capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of presymptomatic and symptomatic AD mice harboring mutated amyolid precursor protein (APP), Tau, and presinilin-1 (PS1) (3xTgAD). Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed. PMID- 20708823 TI - TARDBP gene mutations among Chinese patients with sporadic amyotrophic lateral sclerosis. AB - Recently, several TARDBP mutations have been identified in sporadic amyotrophic lateral sclerosis (SALS) patients among different ethnicities. Our study aims to analyze the clinical features and mutations in the TARDBP gene among Chinese patients with SALS. One hundred sixty-five patients were studied. The mean age of onset was 50.8+/-12.0 years. The mean diagnostic delay was 18.8+/-17.1 months. A novel missense mutation (p.N378S) and a novel silent change (p.A321A) were detected in 2 male patients, respectively. A new variant of c.1098C>G in exon 6 and 2 reported variants, g.IVS1+85C>T in intron 1 and c.57A>G in exon 2, were found. The frequency of the "G" variant of c.57A>G in exon 2 and the "G" variant of c.1098C>G in exon 6 were significantly lower in the patient group than in the control (p=0.001 and p=0.024, respectively). Our findings provide first evidence that the frequency of TARDBP gene mutations is rare among Chinese SALS patients (0.61%). Several polymorphisms may influence susceptibility to amyotrophic lateral sclerosis. PMID- 20708824 TI - Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease. AB - Interleukin-33 (IL-33), a newly described member of the IL-1 family, is located on chromosome 9p24, a chromosomal region of interest in Alzheimer's disease (AD) defined by many genome-wide studies. Three intronic rs1157505, rs11792633, and rs7044343 single nucleotide polymorphisms (SNPs) within IL-33 have recently been reported to be associated with risk of AD in Caucasian populations. In order to assess the involvement of the IL-33 polymorphisms in the risk of developing late onset AD (LOAD), we analyzed the genotype and allele distributions of these 3 polymorphisms in 704 Han Chinese subjects. The minor alleles of the rs11792633 polymorphism within IL-33 was significantly associated with a reduced risk of LOAD (odds ratio [OR] = 0.73, p = 0.005). Furthermore, rs11792633 polymorphism was still strongly associated with LOAD (dominant model: OR = 0.67, p = 0.015; recessive model: OR 0.57, p = 0.021; additive model: OR = 0.71, p = 0.004) after adjusting for age, gender, and the apolipoprotein E (APOE) epsilon4 status. Our results support the evidence that genetic variants of IL-33 affect susceptibility to LOAD in Han Chinese. PMID- 20708825 TI - Synthesis and biological evaluation of N-antipyrine-4-substituted amino-3 chloromaleimide derivatives. AB - This paper describes the synthesis of new cyclic imides obtained by reaction with N-antipyrine-3,4-dichloromaleimides and different aromatic amines. The analgesic activity of the synthesized compounds was initially investigated against the writhing test in mice, followed by analysis of the most promising compounds in this model and in the formalin-induced model. The results indicate that the compounds containing the electron-withdrawing substituents in the para position of the substitute ring exerted more potent analgesic activity in mice, being much more potent than the prototype N-antipyrine-3,4-dichloromaleimide and some reference drugs. Some compounds exhibited activity against human opportunistic and pathogenic fungi, with MIC values of between 40 and 100 MUg/mL (91.74 and 236.96 MUM), and it was verified that only a few compounds presented potential for cytotoxic activity. PMID- 20708826 TI - Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities. AB - A series of novel sulfanilamide-derived 1,2,3-triazole compounds were synthesized in excellent yields via 1,3-dipolar cycloaddition and confirmed by MS, IR and NMR spectra as well as elemental analyses. All the compounds were screened in vitro for their antibacterial and antifungal activities. Preliminary results indicated that some target compounds exhibited promising antibacterial potency. Especially, 4-amino-N-((1-dodecyl-1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide, N-((1 (2,4-dichlorobenzyl)- 1H-1,2,3-triazol-4-yl)methyl)-4-aminobenzenesulfonamide and 4-amino-N-((1-(2,4-difluorobenzyl)- 1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide were found to be the most potent compounds against all the tested strains except for Candida albicans (ATCC76615) and Candida mycoderma. PMID- 20708827 TI - Bilateral cleft lip and nose repair. AB - Over the last three decades bilateral cleft lip and nose repair has been characterised by a trend towards more detailed reconstruction of the nasolabial muscles together with simultaneous correction of the deformity. An understanding of the true nature of the nasal deformity in bilateral cleft lip and palate (BCLP) has gradually emerged, and has inspired new approaches to their repair. This article discusses recent trends and controversies in primary cheilorhinoplasty for BCLP. PMID- 20708828 TI - Setting perinatal quality and safety goals: should we strive for best outcomes? PMID- 20708829 TI - Clinical governance and standards in UK maternity care to improve quality and safety. PMID- 20708830 TI - Safety in childbirth and the three 'C's: community, context and culture. PMID- 20708831 TI - Soil sterilization affects aging-related sequestration and bioavailability of p,p'-DDE and anthracene to earthworms. AB - Laboratory experiments investigated the effects of soil sterilization and compound aging on the bioaccumulation of spiked p,p'-DDE and anthracene by Eisenia fetida and Lumbricus terrestris. Declines in bioavailability occurred as pollutant residence time in both sterile and non-sterile soils increased from 3 to 203 d. Accumulation was generally higher in sterile soils during initial periods of aging (from 3-103 d). By 203 d, however, bioavailability of the compounds was unaffected by sterilization. Gamma irradiation and autoclaving may have altered bioavailability by inducing changes in the chemistry of soil organic matter (SOM). The results support a dual-mode partitioning sorption model in which the SOM components associated with short-term sorption (the 'soft' or 'rubbery' phases) are more affected than are the components associated with long term sorption (the 'glassy' or microcrystalline phases). Risk assessments based on data from experiments in which sterile soil was used could overestimate exposure and bioaccumulation of pollutants. PMID- 20708832 TI - Ozone, nitric acid, and ammonia air pollution is unhealthy for people and ecosystems in southern Sierra Nevada, California. AB - Two-week average concentrations of ozone (O3), nitric acid vapor (HNO3) and ammonia (NH3) were measured with passive samplers during the 2002 summer season across the central Sierra Nevada Mountains, California, along the San Joaquin River drainage. Elevated concentrations of the pollutants were determined with seasonal means for individual sites ranging between 62 and 88 ppb for O3, 1.0-3.8 microg m(-3) for HNO3, and 2.6-5.2 microg m(-3) for NH3. Calculated O3 exposure indices were very high, reaching SUM00-191 ppm h, SUM60-151 ppm h, and W126-124 ppm h. Calculated nitrogen (N) dry deposition ranged from 1.4 to 15 kg N ha(-1) for maximum values, and 0.4-8 kg N ha(-1) for minimum values; potentially exceeding Critical Loads (CL) for nutritional N. The U.S., California, and European 8 h O3 human health standards were exceeded during 104, 108, and 114 days respectively, indicating high risk to humans from ambient O3. PMID- 20708833 TI - "More natural but less normal": reconsidering medicalisation and agency through women's accounts of menstrual suppression. AB - This paper revisits the concept of medicalisation and considers its value as a framework for understanding the ongoing development of new reproductive technologies, and their impact on women's reproductive decision-making. This evaluation is drawn from a qualitative discourse analysis of the public debate about the first extended cycle oral contraception (ECOC) to suppress menstruation in the United States of America in 2003/2004, and subsequent interviews with women living in Australia who had already extended their cycles without it being medically approved for widespread practice. Firstly, the debates about menstrual suppression are couched within a discussion of the ongoing usefulness of medicalisation as an analytical tool. It is posited that medicalisation occurs in a particular social and cultural moment, and is a dynamic process where dominant social relations can be both reproduced and challenged. Secondly, qualitative interviews with women about practices of menstrual suppression are used to explore the productive nature of agency in this particular medicalisation contest. Specifically, the ways in which these women engage with the discourses of 'risk', 'choice' and 'nature', as canvassed by menstrual suppression advocates, reveal accommodation and modification as much as resistance and contradiction. This paper suggests that if the concept of medicalisation is to have ongoing traction as a frame of analysis, such a critique must incorporate a generative discussion of agency. PMID- 20708834 TI - [Early use of noninvasive mechanical ventilation in patients with acute hypercapnic respiratory failure in a respiratory ward: a prospective study]. AB - BACKGROUND: In recent years, the optimal location for noninvasive mechanical ventilation (NIMV) has been a matter of debate. Our aim was to detect the effectiveness of NIMV in acute hypercapnic respiratory failure (AHRF) in respiratory ward and factors associated with failure. METHODS: 69 patients treated with NIMV in respiratory ward were prospectively evaluated. The success of NIMV was defined as absence of need for intensive care unit (ICU) transfer with patient's discharge from hospital (group 1), failure of NIMV was defined as need for ICU transfer (group 2). RESULTS: The mean age was significantly higher in group 2. The cause of respiratory failure was COPD in 51 patients, obesity hypoventilation syndrome in 14 and kyphoscoliosis in 4 patients. NIMV was successful in 55 patients and unsuccessful in 14. There was no significant difference between the two groups for pretreatment pH, PaCO2 and PaO2/FiO2. After 1h and 3h of NIMV there was significant improvement in group 1. After 3h of NIMV, in group 1 respiratory rate was significantly decreased. The pretreatment APACHE II score, respiratory rate, frequency of pneumoniae, associated complication and comorbid disease was significantly higher in group 2. The success rate was higher in patients with good compliance to NIMV. CONCLUSION: NIMV can be successfully applied in patients with AHRF in respiratory ward. The associated factors with NIMV failure are absence of early improvement in blood gases and respiratory rate, bad compliance to NIMV, older age, presence of associated complication, comorbid disease, pneumonia and high baseline respiratory rate. PMID- 20708835 TI - [Idiopathic pulmonary haemosiderosis in a young adult. Autopsy findings]. PMID- 20708836 TI - Analysis of transthoracic impedance during real cardiac arrest defibrillation attempts in older children and adolescents: are stacked-shocks appropriate? AB - BACKGROUND: In 2005, the AHA changed the treatment recommendation for shockable rhythms from 3 transthoracic stacked-shocks to a single shock followed by immediate chest compressions. The stacked-shock recommendation was based on low first-shock efficacy of monophasic waveforms and the theoretical decrease in transthoracic impedance (TTI) following each shock. The objective of this study was to characterize TTI following biphasic defibrillation attempts in children >= 8 yrs during cardiac arrest to assess whether a stacked-shock approach may be appropriate to improve defibrillation success. METHODS: TTI (Ohms (Omega)) was collected via standard anterior-apical defibrillator electrode pads during consecutive in-hospital cardiac arrest biphasic defibrillation attempts in children >= 8 yrs. Analytic data points for TTI were: 0.1s pre-shock (baseline); post-shock at 0.1, 0.5, 1.0, 1.5, and 2.0 s. TTI variables analyzed with descriptive summaries/paired t-test. p values < 0.05 considered statistically significant after correction for multiple comparisons. RESULTS: Analysis yielded 13 evaluable shock events during 5 cardiac arrests (mean age 14.3 +/- 5 yrs, weight 47.4 +/- 7.3 kg) between September 2006 and May 2009. Compared to 0.1s pre shock baseline values (56.8 +/- 23.4 Omega), TTI was significantly lower immediately 0.1s post-shock (55.2 +/- 22.2 Omega, p = 0.003). Post-shock mean difference from baseline was 1.6 Omega at 0.1s (p = 0.015), 1.4 Omega at 0.5s (p = 0.019) 1.4 Omega at 1.0 s (p = 0.023), 1.1 Omega at 1.5 s (p = 0.028), and 0.95 Omega at 2.0 s (p = 0.096). Time to recharge our clinical defibrillators to standard biphasic shock dose was 2.80 +/- 0.05 s. CONCLUSIONS: During cardiac arrests in children >= 8 yrs, TTI decreased after biphasic shocks, but the limited magnitude and duration of TTI changes suggest that stacked-shocks would not improve defibrillation success. PMID- 20708837 TI - Role of NFKB2 on the early myeloid differentiation of CD34+ hematopoietic stem/progenitor cells. AB - To better understand the early events regulating lineage-specific hematopoietic differentiation, we analyzed the transcriptional profiles of CD34+ human hematopoietic stem and progenitor cells (HSPCs) subjected to differentiation stimulus. CD34+ cells were cultured for 12 and 40h in liquid cultures with supplemented media favoring myeloid or erythroid commitment. Serial analysis of gene expression (SAGE) was employed to generate four independent libraries. By analyzing the differentially expressed regulated transcripts between the un stimulated and the stimulated CD34+ cells, we observed a set of genes that was initially up-regulated at 12h but were then down-regulated at 40h, exclusively after myeloid stimulus. Among those we found transcripts for NFKB2, RELB, IL1B, LTB, LTBR, TNFRSF4, TGFB1, and IKBKA. Also, the inhibitor NFKBIA (IKBA) was more expressed at 12h. All those transcripts code for signaling proteins of the nuclear factor kappa B pathway. NFKB2 is a subunit of the NF-kappaB transcription factor that with RELB mediates the non-canonical NF-kappaB pathway. Interference RNA (RNAi) against NFKB1, NFKB2 and control RNAi were transfected into bone marrow CD34+HSPC. The percentage and the size of the myeloid colonies derived from the CD34+ cells decreased after inhibition of NFKB2. Altogether, our results indicate that NFKB2 gene has a role in the early commitment of CD34+HSPC towards the myeloid lineage. PMID- 20708838 TI - Removal of ammonium from aqueous solution by ion exchange on natural and modified chabazite. AB - The ammonium exchange capacity of a natural chabazite was studied in this work. The XRD analysis of the zeolite sample revealed that the main zeolitic phase was chabazite. The textural properties were determined by the N(2)-BET method and the surface morphology and charge were examined using a scanning electron microscope and a zetameter, respectively. The ion exchange equilibrium data were obtained in a batch adsorber and the Langmuir isotherm fitted plausibly well the equilibrium data. The effects of the temperature and pH on the ammonium exchange capacity of chabazite were investigated and the capacity increased augmenting the temperature from 15 to 35 degrees C and pH from 3 to 6. The natural chabazite was modified by a hydrothermal treatment using NaCl and KCl solutions and it was found that the modification influenced the ammonium exchange capacity of the chabazite. The ammonium capacity of natural chabazite was compared with that of a natural clinoptilolite and it was concluded that the chabazite capacity was 1.43 times higher than that of clinoptilolite. PMID- 20708839 TI - Nitric oxide/cyclic guanosine monophosphate signalling mediates an inhibitory action on sensory pathways of the micturition reflex in the rat. AB - BACKGROUND: Overactive bladder can be associated with a hyperexcitability of bladder afferent C-fibres. Several studies have suggested that nitric oxide (NO) or its downstream signalling could modulate the micturition reflex (MR) by reducing the excitability of bladder afferents. OBJECTIVES: To evaluate the role of the NO/cyclic guanosine monophosphate (cGMP) signalling pathway on the MR in a model of bladder hyperactivity (BHA) associated with C-fibre activation in the rat. DESIGN, SETTING, AND PARTICIPANTS: Adult female Sprague Dawley rats were used. MEASUREMENTS: Cystometry was performed in anaesthetised rats. The effects of 0.1 mg/kg of sodium nitroprusside (SNP), an NO donor; 10 mg/kg of 8Br-cGMP, a cGMP analogue; 3 mg/kg of sildenafil and 1 mg/kg of vardenafil, two phosphodiesterase type 5 inhibitors (PDE5-I); 10 mg/ml of L-N(G)-nitroarginine methyl ester (L-NAME), an NO synthase inhibitor; and 1 mg/kg of LY-83583, a guanylate cyclase inhibitor, were investigated on BHA during intravesical capsaicin (30 micromol/l) instillation. All drugs were delivered intravenously except for L-NAME, which was intravesically administered. RESULTS AND LIMITATIONS: SNP, 8Br-cGMP, and PDE5-I increased the intercontraction interval (ICI), while SNP and PDE5-I increased the micturition pressure threshold (MPT). L NAME and LY-83583 decreased MPT, and L-NAME decreased ICI. 8Br-cGMP decreased the maximum intravesical pressure (MP), contrary to L-NAME and LY-83583. SNP and PDE5 I had no effect on MP. SNP increased the voided volume (VV). PDE5-I and 8Br-cGMP also increased VV, although not significantly. In contrast, L-NAME tended to decrease VV. Although 8Br-cGMP decreased the baseline intravesical pressure, LY 83583 increased it. Neither SNP nor PDE5-I nor L-NAME had any effect on baseline pressure. CONCLUSIONS: Compounds activating the NO/cGMP pathway inhibited BHA, whereas compounds inhibiting the NO/cGMP pathway increased it. These results indicate that the NO/cGMP signalling pathway is involved in the regulation of the MR, with an action that seems more predominant on the sensory rather on the motor component of the MR in a rat model of BHA associated with C-fibre afferent activation. PMID- 20708840 TI - Challenges to neurosurgical professionalism. AB - At present, neurosurgical practice is confronted by an explosion of technology. Rapid advances in neurosurgical knowledge and technology are putting increased pressure on neurosurgeons to process huge quantities of information, with requirements for continuous learning and updating scientific knowledge and skills which are time consuming but essential. Changes to the venerated status quo of neurosurgical practice have created an environment that may have a negative impact upon neurosurgical professional behavior. As a result, neurosurgeons may find it increasingly difficult to meet their moral and ethical responsibilities to patients, trainees and colleagues, and society. In these circumstances, reaffirming the fundamental and universal principles and values of neurosurgical professionalism, which remain the ideals to be pursued by all neurosurgeons, becomes all the more important. PMID- 20708841 TI - The mini-open anterolateral approach for degenerative thoracolumbar disease. AB - INTRODUCTION: Anterolateral retroperitoneal, retrodiaphragmatic, and/or retropleural (RPDP) approaches have been used to treat a variety of spinal conditions. The traditional extensive thoracoabdominal approach can be modified to focus on the area of pathology. A less invasive "mini-open" anterolateral approach may be associated with fewer complications and shorter recovery than the thoracoabdominal procedure. There are few reports in the literature describing the technique and results of this less invasive approach to thoracolumbar degenerative pathology. METHODS: 417 spinal fusion cases from a single institution were reviewed from 1999 to 2006, and 23 anterolateral mini-open approaches to degenerative spinal pathology were identified. The mini-open approach entailed a 4-8cm oblique lateral incision with harvesting of a single rib for use in arthrodesis, followed by RPDP access to the lateral spine. A total of 36 levels were fused. These cases were retrospectively reviewed with a minimum of two-year follow-up to determine the feasibility of the approach as well as incidence of complications. In addition, preliminary clinical results were tabulated. RESULTS: One pseudarthrosis and four minor complications were identified. There were no major complications or deaths. Mean length of hospital stay was 4 days. Blood loss was less than 200cm(3) for all cases. Using modified Odom's criteria, 74% of patients had adequate resolution of their symptoms and rated their outcome as satisfactory, good, or excellent. CONCLUSIONS: Mini-open anterolateral approaches to the thoracolumbar spine are associated with acceptable outcomes with a low complication rate. Although no direct comparison with the more extensive thoracoabdominal approach has been performed, review of the literature suggests that the mini-open approach reduces complications and length of hospital stay. PMID- 20708842 TI - Prevalence of musculoskeletal pain in the general Swedish population from 1968 to 2002: age, period, and cohort patterns. AB - We examined age, period, and cohort patterns in musculoskeletal pain prevalence between 1968 and 2002 in the Swedish population. A repeated nationally representative survey allowed cross-sectional comparisons of ages 18-75 (5 waves n~5000), and ages 77+ at later waves (2 waves n~500). Cross-sectional 10-year age group differences in 5 waves, time-lag differences between waves (shifts across time) for age groups, and within-cohort differences between waves for 10-year birth cohorts followed over time were analyzed using graphs and ordered logistic regressions. The outcome scale was based on the three items measuring slight or severe pain in back, shoulder, and joints during the past 12 months. Age-period cohort models showed that pain prevalence increased with age - mild or severe at all locations. Adjusted for the age-related increase, the cohorts followed over time did not show significant period change, except for cohorts born during 1940s. Beginning with the 1940s' cohorts pain prevalence increased over the period, and after baseline later cohorts also entered adulthood and the study with a higher pain prevalence. The prevalence of pain in the adult population thus increased with the passage through age and time of the 1940s cohorts. While there were no pronounced cohort differences at baseline in 1968, results demonstrated strong age effects in pain. The results indicate that the prevalence of musculoskeletal pain among the oldest age groups may increase in the future, when more baby-boomers are entering their oldest ages. PMID- 20708843 TI - Image simulations of kinked vortices for transmission electron microscopy. AB - We present an improved model of kinked vortices in high-T(c) superconductors suitable for the interpretation of Fresnel or holographic observations carried out with a transmission electron microscope. A kinked vortex is composed of two displaced half-vortices, perpendicular to the film plane, connected by a horizontal flux-line in the plane, resembling a connecting Josephson vortex (JV) segment. Such structures may arise when a magnetic field is applied almost in the plane, and the line tension of the fluxon breaks down under its influence. The existence of kinked vortices was hinted in earlier observations of high-T(c) superconducting films, where the Fresnel contrast associated with some vortices showed a dumbbell like appearance. Here, we show that under suitable conditions the JV segment may reveal itself in Fresnel imaging or holographic phase mapping in a transmission electron microscope. PMID- 20708844 TI - Is self-immolation a distinct method for suicide? A comparison of Iranian patients attempting suicide by self-immolation and by poisoning. AB - OBJECTIVE: Patients who attempted suicide by self-immolation were compared to patients who attempted suicide by poisoning to identify features that might discriminate risk of self-immolation from other suicide methods. METHODS: Consecutive referrals for attempted suicide were recruited over a 4-month period (June-September 2008) from Kermanshah Imam Khomeini Hospital, Iran. Using questionnaire and interview techniques, demographic characteristics (age, gender, marital status, education level), psychosocial risk factors (prior suicide attempt, family history of suicide attempt, previous history of physical and mental disorders, family/marital conflict), and suicidal intent behavior were assessed from 200 patients who had attempted suicide (n = 63 by self-immolation; n = 137 by poisoning). RESULTS: Several significant differences between the groups emerged. Patients who had attempted suicide by self-immolation were more frequently female (p < 0.001), older (p < 0.007), less educated (p < 0.001), and married (p < 0.001). Suicidal intent was associated with increased risk of suicide by poisoning (p < 0.001). No other significant differences were found. CONCLUSION: In Iran, patients who attempt suicide by self-immolation have distinct and specific risk factors compared to patients who commit suicide by poisoning. Results have implications for intervention development targeting at risk populations. PMID- 20708845 TI - Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls. AB - The nonapeptide oxytocin and its receptor have been implicated in the regulation of mammalian social behavior and stress physiology. Evidence is accumulating that the quality of the parental environment is associated with oxytocin biology in children. The present study was designed to examine the interaction of the single nucleotide polymorphism (SNP) rs2254298 within the oxytocin receptor (OXTR) gene and quality of parental environment in predicting children's psychosocial functioning. More specifically, in a sample of 92 Caucasian adolescent girls (9 14 years old), we examined whether adverse parental environment, operationalized as mothers' history of recurrent major depressive disorder, interacts with the rs2254298 SNP on the OXTR gene to predict daughters' symptoms of depression and anxiety. Caucasian girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety. These findings highlight the potential importance of this OXTR gene polymorphism in the etiology of depression and anxiety disorders. PMID- 20708846 TI - Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. AB - Acute coagulopathy of trauma predicts a poor clinical outcome. Tissue trauma activates the sympathoadrenal system resulting in high circulating levels of catecholamines that influence hemostasis dose-dependently through immediate effects on the two major compartments of hemostasis, i.e., the circulating blood and the vascular endothelium. There appears to be a dose-dependency with regards to injury severity and the hemostatic response to trauma evaluated in whole blood by viscoelastic assays like thrombelastography (TEG), changing from normal to hypercoagulable, to hypocoagulable and finally hyperfibrinolytic in severely injured patients. Since high catecholamine levels may directly damage the endothelium and thereby promote systemic coagulation activation, we hypothesize that the progressive hypocoagulability and ultimate hyperfibrinolysis observed in whole blood with increasing injury severity, is an evolutionary developed response that counterbalances the injury and catecholamine induced endothelial activation and damage. Given this, the rise in circulating catecholamines in trauma patients may favor a switch from hyper- to hypocoagulability in the blood to keep the progressively more procoagulant microvasculature open. The hypothesis delineated in the present paper thus infers that the state of the fluid phase, including its cellular elements, is a consequence of the degree of the tissue injury and importantly, critically related to the degree of endothelial damage, with a progressively more procoagulant endothelium inducing a gradient of increasing anticoagulation towards the fluid phase. The implications of this hypothesis may include targeted treatment strategies according to the degree of sympathoadrenal response as evaluated by whole blood viscoelastical hemostatic assays in trauma patients. PMID- 20708847 TI - Merkel cell carcinoma: 27-year experience at the Peter MacCallum Cancer Centre. AB - PURPOSE: To retrospectively evaluate the treatment outcome of patients with Merkel cell carcinoma after local and/or regional treatment. METHODS AND MATERIALS: Patients presenting to our center between January 1980 and July 2006 with Merkel cell carcinoma and without distant metastases were reviewed. The primary endpoint was locoregional control. Secondary endpoints were distant recurrence, survival and treatment toxicity. RESULTS: A total of 176 patients were identified. The median age was 79 years. The median follow-up was 2.2 years for all patients and 3.9 years for those alive at the last follow-up visit. The most common primary site was the head and neck (56%), and 62 patients(35%) had regional disease at presentation. The initial surgery to the primary tumor involved (wide) local excision in 140 patients and biopsy only in 28 patients (8 patients had no identifiable primary tumor); 33 patients underwent nodal surgery. Of the 176 patients, 165 (94%) underwent radiotherapy (RT) and 29 of them also underwent concurrent chemotherapy. The median radiation dose was 50 Gy (range, 18 60). Locoregional recurrence developed in 33 patients(19%), with a median interval to recurrence of 8 months. Distant metastases developed in 43 patients(24%). Age, primary tumor size, and RT (no RT vs. < 45 Gy vs. >= 45 Gy) were predictive of locoregional control on univariate analysis. However, only RT remained significant on multivariate analysis. The estimated 5-year actuarial rate for locoregional control, progression-free survival, and overall survival was 76%, 60%, and 45%, respectively. CONCLUSION: The locoregional control rate for Merkel cell carcinoma in our study was comparable to those from other series using combined modality treatment with RT an integral part of treatment. PMID- 20708848 TI - External-beam accelerated partial breast irradiation using multiple proton beam configurations. AB - PURPOSE: To explore multiple proton beam configurations for optimizing dosimetry and minimizing uncertainties for accelerated partial breast irradiation (APBI) and to compare the dosimetry of proton with that of photon radiotherapy for treatment of the same clinical volumes. METHODS AND MATERIALS: Proton treatment plans were created for 11 sequential patients treated with three-dimensional radiotherapy (3DCRT) photon APBI using passive scattering proton beams (PSPB) and were compared with clinically treated 3DCRT photon plans. Monte Carlo calculations were used to verify the accuracy of the proton dose calculation from the treatment planning system. The impact of range, motion, and setup uncertainty was evaluated with tangential vs. en face beams. RESULTS: Compared with 3DCRT photons, the absolute reduction of the mean of V100 (the volume receiving 100% of prescription dose), V90, V75, V50, and V20 for normal breast using protons are 3.4%, 8.6%, 11.8%, 17.9%, and 23.6%, respectively. For breast skin, with the similar V90 as 3DCRT photons, the proton plan significantly reduced V75, V50, V30, and V10. The proton plan also significantly reduced the dose to the lung and heart. Dose distributions from Monte Carlo simulations demonstrated minimal deviation from the treatment planning system. The tangential beam configuration showed significantly less dose fluctuation in the chest wall region but was more vulnerable to respiratory motion than that for the en face beams. Worst-case analysis demonstrated the robustness of designed proton beams with range and patient setup uncertainties. CONCLUSIONS: APBI using multiple proton beams spares significantly more normal tissue, including nontarget breast and breast skin, than 3DCRT using photons. It is robust, considering the range and patient setup uncertainties. PMID- 20708849 TI - Prospective, risk-adapted strategy of stereotactic body radiotherapy for early stage non-small-cell lung cancer: results of a Phase II trial. AB - PURPOSE: Validation of a prospective, risk-adapted strategy for early-stage non small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Patients with a T1-3N0M0 (American Joint Committee on Cancer 6th edition) NSCLC were accrued. Using the Radiation Therapy Oncology Group definition, patients were treated to a total dose of 60,Gy in three fractions for peripherally located lesions and four fractions for centrally located lesions. The primary endpoint was toxicity, graded according to the Radiation Therapy Oncology Group acute and late morbidity scoring system, and the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Secondary endpoints were local control and survival. RESULTS: A total of 40 patients were included, 17 with a centrally located lesion. The lung toxicity-free survival estimate at 2 years was 74% and was related to the location (central vs. peripheral) and the size of the target volume. No dose volumetric parameters could predict the occurrence of lung toxicity. One patient died because of treatment-related toxicity. The 1-year and 2-year local progression-free survival estimates were 97% and 84%, respectively, and were related to stage (T1 vs. T2) related (p = 0.006). Local failure was not more frequent for patients treated in four fractions. The 1-year local progression free survival estimate dropped below 80% for lesions with a diameter of more than 4 cm. CONCLUSION: The proposed risk-adapted strategy for both centrally and peripherally located lesions showed an acceptable toxicity profile while maintaining excellent local control rates. The correlation between local control and tumor diameter calls for the inclusion of tumor stage as a variable in future study design. PMID- 20708850 TI - Potential of adaptive radiotherapy to escalate the radiation dose in combined radiochemotherapy for locally advanced non-small cell lung cancer. AB - PURPOSE: To evaluate the potential of adaptive radiotherapy (ART) for advanced stage non-small cell lung cancer (NSCLC) in terms of lung sparing and dose escalation. METHODS AND MATERIALS: In 13 patients with locally advanced NSCLC, weekly CT images were acquired during radio- (n=1) or radiochemotherapy (n=12) for simulation of ART. Three-dimensional (3D) conformal treatment plans were generated: conventionally fractionated doses of 66 Gy were prescribed to the planning target volume without elective lymph node irradiation (Plan_3D). Using a surface-based algorithm of deformable image registration, accumulated doses were calculated in the CT images acquired during the treatment course (Plan_4D). Field sizes were adapted to tumor shrinkage once in week 3 or 5 and twice in weeks 3 and 5. RESULTS: A continuous tumor regression of 1.2% per day resulted in a residual gross tumor volume (GTV) of 49%+/-15% after six weeks of treatment. No systematic differences between Plan_3D and Plan_4D were observed regarding doses to the GTV, lung, and spinal cord. Plan adaptation to tumor shrinkage resulted in significantly decreased lung doses without compromising GTV coverage: single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the mean lung dose by 5.0%+/-4.4%, 5.6%+/-2.9% and 7.9%+/-4.8%, respectively. This lung sparing with twice ART allowed an iso-mean lung dose escalation of the GTV dose from 66.8 Gy+/-0.8 Gy to 73.6 Gy+/-3.8 Gy. CONCLUSIONS: Adaptation of radiotherapy to continuous tumor shrinkage during the treatment course reduced doses to the lung, allowed significant dose escalation and has the potential of increased local control. PMID- 20708852 TI - Stereotactic fractionated radiotherapy and LINAC radiosurgery in the treatment of vestibular schwannoma-report about both stereotactic methods from a single institution. AB - PURPOSE: To evaluate tumor control and side effects associated with radiosurgery (RS) and stereotactic fractionated radiotherapy (SFR) for vestibular schwannomas (VSs) in a group of patients treated at the same institution. METHODS AND MATERIALS: Between May 1997 and June 2007, 115 consecutive cases of VS were treated in our department. The SFR group (47 patients), including larger tumors (maximum diameter >1.5 cm), received a total dose of 54 Gy at 1.8 Gy per fraction. The RS group (68 patients, maximum diameter <1.5 cm) received a total dose of 12 Gy at the 100% isodose. Evaluation included serial imaging tests (magnetic resonance imaging) and neurologic and functional hearing examinations. RESULTS: The tumor control rate was 97.9% in the SFR group for a mean follow-up time of 32.1 months and 98.5% in the RS group for a mean follow-up time of 30.1 months. Hearing function was preserved after RS in 85% of the patients and after SFR in 79%. Facial and trigeminal nerve function remained mostly unaffected after SFR. After RS, new trigeminal neuropathy occurred in 9 of 68 patients (13%). CONCLUSIONS: A high tumor control rate and low number of side effects are registered after SFR and RS of VS. These results confirm that considering tumor diameter, both RS and SFR are good treatment modalities for VS. PMID- 20708851 TI - Cognitive functioning after radiotherapy or chemoradiotherapy for head-and-neck cancer. AB - PURPOSE: To perform a comprehensive cognitive function (CF) assessment in patients who were relapse free after curative intent radiotherapy (RT) or chemoradiotherapy for squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients underwent neuropsychological tests to assess their objective CF; completed questionnaires to assess subjective CF, quality of life, and affect; and underwent blood tests to assess hematologic, biochemical, endocrine, and cytokine status. Retrospectively, the dosimetry of incidental radiation to the brain was determined for all patients, and the dose intensity of cisplatin was determined in those who had undergone chemoradiotherapy. RESULTS: A total of 10 patients were enrolled (5 treated with radiotherapy only and 5 with radiotherapy and cisplatin). The mean time from the end of treatment was 20 months (range, 9-41). All patients were able to complete the assessment protocol. Of the 10 patients, 9 had impaired objective CF, with memory the most severely affected. The severity of memory impairment correlated significantly with the radiation dose to the temporal lobes, and impaired dexterity correlated significantly with the radiation dose to the cerebellum, suggesting that these deficits might be treatment related. Patients receiving cisplatin appeared to have poorer objective CF than patients receiving only RT, although this difference did not achieve statistical significance, likely owing to the small sample size. Consistent with the published data, objective CF did not correlate with subjective CF or quality of life. No association was found between objective CF and patients' affect, hematologic, biochemical, endocrine, and cytokine status. CONCLUSION: Neuropsychological testing is feasible in squamous cell carcinoma of the head-and-neck survivors. The findings were suggestive of treatment-related cognitive dysfunction. These results warrant additional investigation. PMID- 20708853 TI - Health-related quality of life after single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for prostate cancer. AB - PURPOSE: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. METHODS AND MATERIALS: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. RESULTS: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose. CONCLUSION: EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life. PMID- 20708854 TI - Preclinical and pilot clinical studies of docetaxel chemoradiation for Stage III non-small-cell lung cancer. AB - PURPOSE: Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low dose radiosensitizing docetaxel CRT. METHODS AND MATERIALS: A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m(2) of docetaxel and 75 mg/m(2) of cisplatin on Day 1 and 150 mg/m(2) of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m(2) and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease. RESULTS: The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients. CONCLUSIONS: One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation. PMID- 20708855 TI - A Phase II trial of arc-based hypofractionated intensity-modulated radiotherapy in localized prostate cancer. AB - PURPOSE: To evaluate acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and biochemical control of hypofractionated, image-guided (fiducial markers or ultrasound guidance), simplified intensity-modulated arc therapy for localized prostate cancer. METHODS AND MATERIALS: This Phase II prospective clinical trial for T1a-2cNXM0 prostate cancer enrolled 66 patients who received 63.2 Gy in 20 fractions over 4 weeks. Fiducial markers were used for image guidance in 30 patients and daily ultrasound for the remainder. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: Median follow-up was 36 months. Acute Phase Grade 2 and 3 toxicity was 34% and 9% for GU vs. 25% and 10% for GI symptoms. One Grade 4 acute GI toxicity occurred in a patient with unrecognized Crohn's disease. Late Grade 2 and 3 toxicity for GU was 14% and 5%, and GI toxicity was 25% and 3%. One late GI Grade 4 toxicity was observed in a patient with significant comorbidities (anticoagulation, vascular disease). Acute GI toxicity >= Grade 2 was shown to be a predictor for late toxicity Grade >= 2 (p < 0.001). The biochemical disease-free survival at 3 years was 95%. CONCLUSIONS: Hypofractionated simplified intensity-modulated arc therapy radiotherapy given as 63.2 Gy in 20 fractions demonstrated promising biochemical control rates; however, higher rates of acute Grade 3 GU and GI toxicity and higher late Grade 2 GU and GI toxicity were noted. Ongoing randomized controlled trials should ultimately clarify issues regarding patient selection and the true rate of severe toxicity that can be directly attributed to hypofractionated radiotherapy. PMID- 20708856 TI - Pancreatic cancer tumor size on CT scan versus pathologic specimen: implications for radiation treatment planning. AB - PURPOSE: Pancreatic cancer primary tumor size measurements are often discordant between computed tomography (CT) and pathologic specimen after resection. Dimensions of the primary tumor are increasingly relevant in an era of highly conformal radiotherapy. METHODS AND MATERIALS: We retrospectively evaluated 97 consecutive patients with resected pancreatic cancer at two Boston hospitals. All patients had CT scans before surgical resection. Primary endpoints were maximum dimension (in millimeters) of the primary tumor in any direction as reported by the radiologist on CT and by the pathologist for the resected gross fresh specimen. Endoscopic ultrasound (EUS) findings were analyzed if available. RESULTS: Of the patients, 87 (90%) had preoperative CT scans available for review and 46 (47%) had EUS. Among proximal tumors (n = 69), 40 (58%) had pathologic duodenal invasion, which was seen on CT in only 3 cases. The pathologic tumor size was a median of 7 mm larger compared with CT size for the same patient (range, -15 to 43 mm; p < 0.0001), with 73 patients (84%) having a primary tumor larger on pathology than CT. Endoscopic ultrasound was somewhat more accurate, with pathologic tumor size being a median of only 5 mm larger compared with EUS size (range, -15 to 35 mm; p = 0.0003). CONCLUSIONS: Computed tomography scans significantly under-represent pancreatic cancer tumor size compared with pathologic specimens in resectable cases. We propose a clinical target volume expansion formula for the primary tumor based on our data. The high rate of pathologic duodenal invasion suggests a risk of duodenal under-coverage with highly conformal radiotherapy. PMID- 20708857 TI - [Maternal and obstetrical data in a retrospective cohort of 170 newborns from polydrug using mothers, in the Paris area, 1999-2008]. AB - OBJECTIVES: Polydrug use in pregnancy is harmful. This survey aimed to explore the issue of the associations of substances during pregnancy and to determine the consumer profiles. PATIENTS AND METHODS: One hundred and seventy newborns whose mothers were psychoactive substances users were identified over the period 1999 to 2008. The data relating to maternal consumption, their reproductive history, and their living environment were collated. RESULTS: At the end of their pregnancy, the mothers reported using on average 3.14 substances. Three profiles were determined: 65 women were heroin users or had consumed it in their lifetime and were currently on substitution treatment, and had a very unfavourable social living environment; 30 women were mainly consumers of alcohol, with or without benzodiazepines or other psychotropic drugs, and had a history of abortions; 75 women were mainly tobacco and cannabis smokers, with or without substitution treatment, had good social living conditions and had wanted the pregnancy. CONCLUSION: Polydrug use increases the risk for the women to avoid prenatal care and is often linked with a history of abortions. PMID- 20708858 TI - Effect of the threat of a disulfiram-ethanol reaction on cue reactivity in alcoholics. AB - RATIONALE: Little is known about the effect of disulfiram on subjective and autonomic nervous system cue reactivity in the laboratory. The dissuasive psychological effect manifested as a threat would seem to prevail over the pharmacological effect. OBJECTIVES: The primary objective was to determine whether there was a difference in cue reactivity responses during a threat condition compared to a neutral condition during alcohol cue exposure. METHODS: In a crossover randomized study, participants received threat and neutral messages during two cue exposure sessions. The threat condition consisted of leading the patients to believe they had ingested 500 mg of disulfiram and the neutral condition of informing them that they had ingested a placebo, while in both condition they received the same placebo. RESULTS: Physiological cue reactivity was demonstrated by a decrease in diastolic blood pressure during the threat compared to the neutral condition (p=0.04). Heart rate and subjective cue reactivity measures remained unchanged. There was a negative affect (assessed by the Positive and Negative Affect Scale) by condition by exposure interaction. CONCLUSIONS: The threat of a disulfiram-ethanol reaction appears to affect cue reactivity physiologically rather than subjectively. While the data does not show changes in subjective ratings, it is possible that there are alternative beneficial effects arising from other cognitive processes that are not captivated by self-reported craving scales, reflected by decreases in negative affect and blood pressure. From this perspective, disulfiram might be recast to be more acceptable to patients. PMID- 20708859 TI - Isolation of scFv fragments specific to OmpD of Salmonella Typhimurium. AB - Pork meat is one of the major sources for human infections with Salmonella enterica subspecies enterica serovars. Further, zoonoses caused by S. enterica subspecies enterica serovars are responsible for substantial economical losses in industrial countries. Quick and reliable detection of this infection is urgently needed to improve consumer security. Due to its capability to identify infections independent of the species, a competitive ELISA is the preferable method for the detection of anti-Salmonella antibodies in serum. Recombinant antibody fragments (scFvs) were isolated from the naive human antibody gene library HAL7 by phage display. Recombinant produced outer membrane protein D (OmpD) of Salmonella Typhimurium was used as antigen. The characterization of the isolated single chain Fv (scFv) antibodies was done by enzyme-linked immunosorbent assay (ELISA), immunoblot, sequencing, epitope mapping and size exclusion chromatography (SEC). The detection of anti-OmpD IgGs in swine sera by competitive ELISA was shown in a proof of principle concept. Furthermore, the developed competitive ELISA would be compatible to a recently published DIVA vaccine, allow to distinguish between infected and vaccinated pigs. PMID- 20708860 TI - Deletion of sua gene reduces the ability of Streptococcus uberis to adhere to and internalize into bovine mammary epithelial cells. AB - To elucidate the role of Streptococcus uberis adhesion molecule (SUAM) in the pathogenesis of S. uberis mastitis, sua deletion in S. uberis UT888 was achieved by homologous recombination using a thermosensitive plasmid. The deletion mutant was analyzed for sua deletion by PCR, southern blot and DNA sequencing, and was designated Deltasua S. uberis UT888. As compared to the isogenic parent strain, Deltasua S. uberis UT888 did not produce SUAM based on SDS-PAGE gel and western blot. Deletion of sua and lack of expression of SUAM by Deltasua S. uberis UT888 markedly reduced the ability of the sua gene deletion mutant of S. uberis to adhere to and internalize into mammary epithelial cells. These results confirm the central role of SUAM in adherence to and internalization of S. uberis into host cells. PMID- 20708861 TI - Analysis of unsupported gait in toddlers with autism. AB - AIMS: A number of studies have suggested the importance of motor development in autism. Motor development has been considered a possible bio-marker of autism since it does not depend on either social or linguistic development. In this study, using retrospective video analysis we investigated the first unsupported gait in toddlers with autism. METHODS: Fifty-five toddlers, belonging to three groups were recruited: toddlers with autistic disorder (AD, n=20, age 14.2mo, sd 1.4mo) and as comparison groups: typically developing toddlers (TD, n=20, age 12.9mo, sd 1.1mo) and toddlers with non-autistic developmental delays of mixed aetiology (DD, n=15, age 13.1mo, sd 0.8mo). The Walking Observation Scale (WOS) and the Positional Pattern for Symmetry during Walking (PPSW) were used to gather data on the first unsupported gait. The WOS includes 11 items that analyze gait through three axes: foot movements; arm movements; general movements while the PPSW analyses static and dynamical symmetry during gait. RESULTS: Our results have identified significant differences in gait patterns among the group of toddlers with AD as opposed to the control groups. Significant differences between AD and the two control groups were found for both WOS (p<.001) and PPSW (p<.001). CONCLUSION: The specificity of motor disturbances we have identified in autism (postural asymmetry) is consistent with previous findings that implicated cerebellar involvement in the motor symptoms of autism. PMID- 20708862 TI - Changes in cognitive functions of students in the transitional period from elementary school to junior high school. AB - BACKGROUND: When students proceed to junior high school from elementary school, rapid changes in the environment occur, which may cause various behavioral and emotional problems. However, the changes in cognitive functions during this transitional period have rarely been studied. METHODS: In 158 elementary school students from 4th- to 6th-grades and 159 junior high school students from 7th- to 9th-grades, we assessed various cognitive functions, including motor processing, spatial construction ability, semantic fluency, immediate memory, delayed memory, spatial and non-spatial working memory, and selective, alternative, and divided attention. RESULTS: Our findings showed that performance on spatial and non spatial working memory, alternative attention, divided attention, and semantic fluency tasks improved from elementary to junior high school. In particular, performance on alternative and divided attention tasks improved during the transitional period from elementary to junior high school. CONCLUSION: Our finding suggests that development of alternative and divided attention is of crucial importance in the transitional period from elementary to junior high school. PMID- 20708863 TI - Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome. AB - A 3-months-old boy presented with partial seizures that soon evolved into infantile spasms. Magnetic resonance imaging revealed bilateral perisylvian polymicrogyria with right-sided predominance. ACTH therapy successfully controlled epilepsy and electroencephalograms were normalized. Conventional G banded chromosomal analysis was performed due to his distinctive features and a derivative chromosome 1 derived from parental balanced translocation with a karyoptype of 46,XY,der(1)t(1;4)(p36.23;q35) was detected. Fluorescent in situ hybridization analysis confirmed the deleted region of 1p36 as large as 8.6Mb. This is the first delineation of concurrent complications of infantile spasms and polymicrogyria in patient with 1p36 deletion. 1p36 deletion syndrome should be broadly recognized as a differential diagnosis of regional polymicrogyria and/or infantile spasms. PMID- 20708864 TI - Clinical features of epilepsy with pervasive developmental disorder. AB - PURPOSE: To clarify the clinical features of patients with epilepsy and pervasive developmental disorder (PDD). METHODS: We examined 12 outpatients with epilepsy as well as PDD at Seiai Rehabilitation Hospital. RESULTS: The patients comprised 7 males and 5 females. The initial neurological symptoms appeared between 5 months and 4 years of age. The interval between the initial neurological symptoms/developmental delay and seizure onset ranged from several months to twenty years. The seizures started at 10-19 years of age in 8 out of the 12 cases. The types of seizures were astatic-drop in 2 cases, tonic-to-astatic in one, atypical absence (decreased consciousness) and generalized tonic clonic seizures (GTCS) in 3 cases, GTCS in 4 cases, or myoclonic and psychomotor in 2 cases. The mental development distributed from normal to extremely severe retardation. Paroxysmal abnormalities on eegs were focal at the frontal area in 7 cases (58%) and other findings in 5 cases. Presumptive risk factors were prenatal in 6 cases (family history for PDD in 1 case, for epilepsy in 1, twin pregnancy in 2 cases, and other in 2 cases), perinatal in 2 patients, postnatal in 1, and unknown in 3 cases. CONCLUSIONS: The seizures occurred most frequently after the onset of neurological symptoms or developmental delay. The frontal lobe dysfunction was associated with seizure onset in 58% of the cases based on the EEG findings. The risk factors were prenatal in 50% of the cases. PMID- 20708865 TI - [Current status of the knowledge on Moroccan anophelines (Diptera: Culicidae): systematic, geographical distribution and vectorial competence]. AB - This bibliographical study, based on published works, ministry of Health Reports, exploitation of the database relative to the entomological surveillance conducted in the framework of the National Malaria Control Program, as well as unpublished results obtained within the framework of the European project "Emerging disease in a changing European environment", summarizes and completes with new data current knowledge on the systematics, the distribution and the vectorial competence of moroccan anophelines. PMID- 20708866 TI - [Lyme borreliosis: census of adult patients hospitalized in Indre-et-Loire (France), from the Hospital Discharge Data (1999-2006)]. AB - BACKGROUND: To describe the clinical forms and epidemiology of Lyme borreliosis, in French adult patients hospitalized in Indre-et-Loire (Centre region). METHODS: Patients were recruited from standardized discharge summaries collected in the hospital database. All adult patients, hospitalized in public hospitals of the Indre-et-Loire administrative district, over a period of 8 years (1999-2006), who satisfied the European diagnostic criteria of Lyme borreliosis, were included. RESULTS: Encoding of Lyme borreliosis had a poor positive predictive value (65%). Forty-seven adult patients presented with the 50 following clinical forms: erythema migrans (n=5), neuroborreliosis (n=32), knee single-joint arthritis (n=4), acrodermatitis chronica atrophicans (n=3), carditis (n=2), ocular borreliosis (n=2), miscellaneous (n=2). Three patients had a combination of two different clinical forms. Meningoradiculitis was the most frequent neurologic manifestation. When a cranial nerve was involved, it was constantly the facial nerve, and mainly bilaterally. Few patients in our study had erythema migrans: these patients are usually treated in a general medicine setting. Although the incidence in the Centre region was lower than in some other regions of France and Europe, the clinical spectrum of the disseminated forms was similar. CONCLUSION: This cohort illustrates the diversity of clinical manifestations of Lyme borreliosis in hospitalized patients, particularly at disseminated and late stages as well as the complexity of its diagnosis and its epidemiological surveillance. PMID- 20708867 TI - Image quality and radiation dose in 256-slice cardiac computed tomography: comparison of prospective versus retrospective image acquisition protocols. AB - PURPOSE: To assess coronary artery image quality and patient radiation exposure in patients who underwent clinically indicated 256-slice CTA. METHODS: Consecutive patients (n=193) underwent 256-slice CTA, using (1) retrospective gating without radiation dose modulation, (2) retrospective gating with radiation dose modulation and (3) prospective gating. Image quality was determined by consensus of two experienced observers using a 5-grade scale. The effective dose was calculated. RESULTS: In all patients, CTA was performed without adverse events. Retrospective CTA was assessed in 39 patients with and 39 without dose modulation, while 115 patients underwent prospective CTA. Heart rate was related to image quality with all protocols (r=0.46, p<0.001). Up to a heart rate of 75 bpm no significant difference in overall image quality was observed for all three protocols, while no significant differences could be observed between retrospective CTA with and without dose modulation for any segments or heart rates. Prospective and retrospective CTA with dose modulation showed radiation savings of ~75 % and ~30 %, respectively compared to retrospective CTA without dose modulation (p<0.001). CONCLUSIONS: In patients with heart rates up to 75 bpm prospective CTA should be the first choice acquisition protocol. For heart rates >75 bpm, retrospective CTA with dose modulation should be considered. PMID- 20708868 TI - Measurements of diagnostic examination performance using quantitative apparent diffusion coefficient and proton MR spectroscopic imaging in the preoperative evaluation of tumor grade in cerebral gliomas. AB - PURPOSE: Tumor grading is very important both in treatment decision and evaluation of prognosis. While tissue samples are obtained as part of most therapeutic approaches, factors that may result in inaccurate grading due to sampling error (namely, heterogeneity in tissue sampling, as well as tumor-grade heterogeneity within the same tumor specimen), have led to a desire to use imaging better to ascertain tumor grade. The purpose in our study was to evaluate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and accuracy of diffusion weighted MR imaging (DWI), proton MR spectroscopic imaging (MRSI) or both in grading primary cerebral gliomas. MATERIALS AND METHODS: We performed conventional MR imaging (MR), DWI, and MRSI in 74 patients with newly diagnosed brain gliomas: 59 patients had histologically verified high-grade gliomas: 37 glioblastomas multiform (GBM) and 22 anaplastic astrocytomas (AA), and 15 patients had low-grade gliomas. Apparent diffusion coefficient (ADC) values of tumor and peritumoral edema, and ADC ratios (ADC in tumor or peritumoral edema to ADC of contralateral white matter, as well as ADC in tumor to ADC in peritumoral edema) were determined from three regions of interest. The average of the mean, maximum, and minimum for ADC variables was calculated for each patient. The metabolite ratios of Cho/Cr and Cho/NAA at intermediate TE were assessed from spectral maps in the solid portion of tumor, peritumoral edema and contralateral normal-appearing white matter. Tumor grade determined with the two methods was then compared with that from histopathologic grading. Logistic regression and receiver operating characteristic (ROC) curve analysis were performed to determine optimum thresholds for tumor grading. Measures of diagnostic examination performance, such as sensitivity, specificity, PPV, NPV, AUC, and accuracy for identifying high-grade gliomas were also calculated. RESULTS: Statistical analysis demonstrated a threshold minimum ADC tumor value of 1.07 to provide sensitivity, specificity, PPV, and NPV of 79.7%, 60.0%, 88.7%, and 42.9% respectively, in determining high-grade gliomas. Threshold values of 1.35 and 1.78 for peritumoral Cho/Cr and Cho/NAA metabolite ratios resulted in sensitivity, specificity, PPV, and NPV of 83.3%, 85.1%, 41.7%, 97.6%, and 100%, 57.4%, 23.1% and 100% respectively for determining high-grade gliomas. Significant differences were noted in the ADC tumor values and ratios, peritumoral Cho/Cr and Cho/NAA metabolite ratios, and tumoral Cho/NAA ratio between low- and high-grade gliomas. The combination of mean ADC tumor value, maximum ADC tumor ratio, peritumoral Cho/Cr and Cho/NAA metabolite ratios resulted in sensitivity, specificity, PPV, and NPV of 91.5%, 100%, 100% and 60% respectively. CONCLUSION: Combining DWI and MRSI increases the accuracy of preoperative imaging in the determination of glioma grade. MRSI had superior diagnostic performance in predicting glioma grade compared with DWI alone. The predictive values are helpful in the clinical decision-making process to evaluate the histologic grade of tumors, and provide a means of guiding treatment. PMID- 20708869 TI - Prostate cancer: 1.5 T endo-coil dynamic contrast-enhanced MRI and MR spectroscopy--correlation with prostate biopsy and prostatectomy histopathological data. AB - PURPOSE: To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data. MATERIALS AND METHODS: 43 patients, scheduled for radical prostatectomy, underwent prostate MR examination. Prostate cancer was identified by transrectal ultrasonographically (TRUS) guided sextant biopsy. MR examination was performed at 1.5 T with an endorectal MR coil. Cancer localisation was performed on sextant basis--for comparison between TRUS biopsy, MR techniques and histopathological findings on prostatectomy specimens. RESULTS: Prostate cancer was identified in all 43 patients by combination of the three MR techniques. The detection of prostate cancer on sextant-basis showed sensitivity and specificity: 50% and 91% for TRUS, 72% and 55% for T2WI, 49% and 69% for DCEMRI, and 46% and 78% for CSI. CONCLUSION: T2WI, DCEMRI and CSI in combination can identify prostate cancer. Further development of MR technologies for these MR methods is necessary to improve the detection of the prostate cancer. PMID- 20708870 TI - Reduced access to the National Clinicians' Post-Exposure Prophylaxis Hotline. A health care crisis. PMID- 20708871 TI - Pharmacologic unilateral mydriasis due to nebulized ipratropium bromide. PMID- 20708872 TI - Pediatric abscess characteristics associated with hospital admission from the ED. AB - OBJECTIVE: To determine the characteristics of pediatric soft tissue abscesses that result in hospital admission. METHODS: All visits for soft tissue abscesses to the study emergency department (ED) were examined during 2008. Detailed records were reviewed to determine ED disposition, abscess size, location, presence of fever, duration of symptoms, previous antibiotic therapy, prior ED visit(s), and wound and blood culture results. Data were analyzed to determine which of these characteristics were associated with hospital admission from the ED. RESULTS: Six hundred twenty-two patients met the inclusion criteria. One hundred thirteen (18%) patients were admitted to the hospital and 509 (82%) were discharged home. Compared to those sent home, abscesses resulting in admission were more likely to be located in the genital area (odds ratio [OR], 3.08; 95% confidence interval [CI], 1.37-6.90), breast (OR, 4.8; 95% CI, 1.08-21.4), or face (OR, 4.39; 95% CI, 1.86-10.3), and were more likely to be larger than 3 cm (OR, 3.66, 95% CI, 2.10-6.36). Patients who were admitted to the hospital were also more likely to have fever (OR, 5.93; 95% CI, 3.4-10.3) and have had a prior ED visit with the same complaint (OR, 3.81; 95% CI, 1.77-8.2). Seventy-seven percent of abscesses that were cultured were positive for methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Size and location (especially those in the genital region, breast, and face), appear to be associated with admission for pediatric abscesses. History of fever and previous ED visit also appear to be associated with hospital admission. Obtaining blood cultures for pediatric abscesses is likely of little clinical benefit. PMID- 20708873 TI - Utility of routine thyroid-stimulating hormone determination in new-onset atrial fibrillation in the ED. AB - INTRODUCTION: Hyperthyroidism is a relative uncommon but important cause of atrial fibrillation. The aim of this study was to investigate the utility of routine thyroid-stimulating hormone (TSH) determination in the emergency department (ED) in patients presenting to the ED with stable, new-onset atrial fibrillation. We derive a set of clinical criteria in which TSH is likely to be normal and therefore thyroid function evaluation deferrable to a different time from ED visit. METHODS: Cross-sectional observational study in a university hospital. Thyroid-stimulating hormone was measured in all patients admitted to the ED observational unit for new-onset atrial fibrillation in a 30 consecutive months' period. Patients' clinical characteristics and treatment received in the ED were recorded. Recursive partitioning analysis technique was used to determine which predictors were associated with a TSH level less than 0.35 MUIU/mL. RESULTS: Of 433 patients enrolled, 47 (10.8%) had a low TSH. Thyroid-stimulating hormone highly correlated with FT3 and FT4 levels (P < .001) confirming its good predictive value as screening tool. Recursive partitioning analysis showed that previous thyroid disease (P < .01), stroke/transient ischemic attack (P < .01), and hypertension (P = .10) were associated with low TSH. The final model had sensitivity of 93% and specificity of 31%, corresponding to a negative likelihood ratio of 0.02 (0.01-0.07). CONCLUSION: Hyperthyroidism is present in nearly 10% of new-onset atrial fibrillation. Although thyroid function screening is recommended in all patients, a simple model that included previous thyroid disease, stroke, and hypertension might help to identify those patients at high risk (low TSH) in the ED. PMID- 20708874 TI - Epidemiology of strain/sprain injuries among cheerleaders in the United States. AB - OBJECTIVE: The aim of this study is to describe the epidemiology of cheerleading related strain/sprain injuries by type of cheerleading team and type of event. METHODS: Athlete exposure (AE) and injury data were collected from 412 United States cheerleading teams via the Cheerleading Reporting Information Online surveillance tool, and injury rates were calculated. RESULTS: Strains/Sprains were the most common injury (53%; 0.5 injuries per 1000 AEs) sustained by cheerleaders during our 1-year study. The lower extremities (42%), particularly the ankles (28%), were injured most often. Most injuries occurred during practice (82%); however, the rate of injury was higher during competition (0.8 injuries per 1000 AEs; 95% confidence interval [CI], 0.6-1.0) than during practice (0.6 injuries per 1000 AEs; 95% CI, 0.5-0.6) for all team types. Injuries were sustained most frequently by high school cheerleaders (51%), although college cheerleaders had the highest injury rate (1.2 injuries per 1000 AEs). Strains/Sprains occurred most frequently while attempting a stunt (34%) or while tumbling (32%). Spotting/Basing other cheerleaders (19%) was the most common mechanism of injury and was more likely to result in a lower back strain/sprain than other mechanisms of injury (odds ratio, 3.38; 95% CI, 1.41-8.09; P < .01). CONCLUSIONS: Cheerleaders should increase their focus on conditioning and strength-building training, which may help to prevent strain/sprain injuries. Spotters and bases should additionally focus on proper lifting technique to help avoid back injury. Guidelines may need to be developed for return-to-play after cheerleading-related strain/sprain injuries. PMID- 20708875 TI - Adult asthma exacerbations and environmental triggers: a retrospective review of ED visits using an electronic medical record. AB - BACKGROUND: Despite familiarity with triggers for asthma, there is little recent study on the association of triggers with the emergency department (ED) presentation of adult asthma exacerbation. METHODS: Retrospective electronic chart review of adult patients treated in an urban teaching hospital ED with chief complaint and diagnostic coding related to asthma and upper respiratory tract infection (URI) was conducted. Monthly aeroallergen data and environmental conditions were obtained from a local allergen extract laboratory and local government sources. Data analysis was performed using Newey-West time series regression modeling with adjustment for autocorrelation or ordinary least squares linear regression modeling using outcome variables of asthma visits and admissions. RESULTS: There were 56, 747 visits, with 554 asthma visits and 1,514 URI visits. Asthma visits (R(2) = 0.631) were positively correlated with tree pollen counts (correlation coefficient = 0.458 [0.152-0.765]) and average humidity (correlation coefficient = 1.528 [0.296-2.760]). Asthma admissions (R(2) = 0.480) were negatively correlated with average temperature (correlation coefficient = -0.557 [-1.052 to -0.061]) when adjusting for confounding by fine particulate matter. CONCLUSIONS: The ED acute asthma exacerbation presentation is positively correlated with tree pollen and humidity, whereas need for admission is associated with dropping temperatures. These results reinforce the need for vigilance during periods of increased risk and perhaps focused preventative strategies. PMID- 20708876 TI - Impact of portable ultrasound in trauma care after the Haitian earthquake of 2010. PMID- 20708877 TI - Emergency endoscopic decompression of a delayed posttraumatic tension gastrothorax. PMID- 20708878 TI - Emergency medicine residents' use of psychostimulants and sedatives to aid in shift work. AB - OBJECTIVES: We evaluated the frequency that emergency medicine house staff report use of stimulants and sedatives to aid in shift work and circadian transitions. METHODS: We surveyed residents from 12 regional emergency medicine programs inviting them to complete a voluntary, anonymous electronic questionnaire regarding their use of stimulants and sedatives. RESULTS: Out of 485 eligible residents invited to participate in the survey, 226 responded (47% response frequency). The reported use of prescription stimulants for shift work is uncommon (3.1% of respondents.) In contrast, 201 residents (89%) report use of caffeine during night shifts, including 118 residents (52%) who use this substance every night shift. Eighty-six residents (38%) reported using sedative agents to sleep following shift work with the most common agents being anti histamines (31%), nonbenzodiazepine hypnotics such as zolpidem (14%), melatonin (10%), and benzodiazepines (9%). CONCLUSION: Emergency medicine residents report substantial use of several classes of hypnotics to aid in shift work. Despite anecdotal reports, use of prescription stimulants appears rare, and is notably less common than use of sedatives and non-prescription stimulants. PMID- 20708879 TI - Secretory phospholipase A2: a marker of infection in febrile children presenting to a pediatric ED. AB - BACKGROUND: Fever is a common presenting complaint to the emergency department (ED), and the evaluation of the febrile child remains a challenging task. OBJECTIVE: The aim of this study was to examine the relationship between secretory phospholipase A2 (sPLA2) and infection in febrile children. METHODS: A prospective convenience sample of children presenting with fever to an urban pediatric ED were studied. Blood and urine cultures, a complete blood count, and serum concentrations of sPLA2 were obtained, and patients were compared based on their final diagnosis of either a viral or bacterial infection. RESULTS: In the 76 patients enrolled, 60 were diagnosed with a viral infection, 14 with a bacterial infection, 1 with Kawasaki disease, and 1 with acute lymphoblastic leukemia. The difference in the serum concentration of sPLA2 in patients with viral infections (22 +/- 34 ng/mL) versus those with bacterial infections (190 +/ 179 ng/mL) was statistically significant (P < .0001). Receiver operator characteristic curve analysis revealed that sPLA2 was more accurate at predicting bacterial infection (area under the curve = 0.89) than the total white blood cell count (area under the curve = 0.71) and that a value of more than 20 ng/mL had a sensitivity of 93%, specificity of 67%, positive predictive value of 39%, and negative predictive value of 97%. CONCLUSION: Secretory phospholipase A2 differs significantly in children with viral versus bacterial infection and seems to be a reliable screening test for bacterial infection in febrile children. PMID- 20708880 TI - A novel hands-free carotid ultrasound detects low-flow cardiac output in a swine model of pulseless electrical activity arrest. AB - OBJECTIVE: To determine if a hands-free, noninvasive Doppler ultrasound device can reliably detect low-flow cardiac output by measuring carotid artery blood flow velocities. We compared the ability of observers to detect carotid artery flow velocity differences between pseudo-pulseless electrical activity (PEA) and true-PEA cardiac arrest. METHODS: Five swine were instrumented with aortic (Ao) and right atrial pressure-transducing catheters. The Doppler ultrasound device was adhered to the neck over the carotid artery. Continuous electrocardiogram, pressure readings, and Doppler signal were recorded. Each swine underwent multiple episodes of fibrillation and resuscitation. Episodes of true-PEA and pseudo-PEA were retrospectively identified from all resuscitation attempts by examination of electrocardiogram and Ao waveforms. The sensitivity and specificity of the device to detect pseudo-PEA was obtained using observers blinded to Ao waveform recordings. RESULTS: There was good interobserver reliability related to identification of pseudo- and true-PEA (kappa = 0.873). The observers blinded to Ao waveform recordings agreed on 8 of the 9 episodes of pseudo-PEA, whereas 4 false positives of 26 true-PEA events were reported (sensitivity, 0.89; specificity, 0.85). The Doppler device was able to detect carotid flow velocity over a wide range of Ao blood pressures. CONCLUSIONS: This hands-free, noninvasive Doppler ultrasound device can reliably differentiate pseudo-PEA from true-PEA during resuscitation from cardiac arrest, detecting pressure gradient changes of less than 5 mm Hg through to normotension. This device distinguishes conditions of no cardiac output from low cardiac output and may have applications for use during resuscitation from various etiologies of arrest and shock. PMID- 20708881 TI - Novel use of a urine pregnancy test using whole blood. AB - We present the case of a 35-year-old woman with hypotension and abdominal tenderness after acute vomiting and syncope. The patient had been breast-feeding since the birth of a child 8 months earlier, was not yet menstruating, and felt that she was having a reaction to sushi. She was unable to provide a urine sample during initial evaluation, and a drop of whole blood was therefore applied to a qualitative urine human chorionic gonadotropin point-of-care test. This test result was positive for pregnancy, ultrasound revealed free fluid in the abdominal cavity, and emergency laparotomy by our gynecologists confirmed ruptured ectopic pregnancy. Often, patients are too unstable or dehydrated to provide a urine sample; and serum human chorionic gonadotropin testing may be difficult to obtain in a timely fashion. This use of the point-of-care urine qualitative test has not been previously described and may be valuable in cases where rapid diagnosis is critical. PMID- 20708882 TI - Thrombolysis for massive pulmonary embolism in pregnancy: a case report. PMID- 20708883 TI - Hyperbaric oxygen therapy in a case of cholesterol crystal embolization. PMID- 20708884 TI - Pneumomediastinum caused by isolated oral-facial trauma. AB - Pneumomediastinum from isolated blunt or penetrating oral-facial trauma is a rare occurrence, which can be associated with facial fractures or may be iatrogenic. We present two cases caused by high-pressure-induced facial injuries that had very different management and outcomes. The first patient had asymptomatic pneumomediastinum and an uncomplicated recovery, whereas the second had a complicated clinical course requiring extensive surgical debridement. Neither patient developed mediastinitis as a complication of pneumomediastinum. This case series illustrates isolated facial trauma causing pneumomediastinum and reviews the literature over last 20 years for similar cases. The authors advocate emergency department management of pneumomediastinum from facial trauma. PMID- 20708885 TI - Large left upper quadrant mass. PMID- 20708886 TI - Oxcarbazepine-induced resistant ventricular fibrillation in an apparently healthy young man. PMID- 20708887 TI - Metformin-associated lactic acidosis treated with prolonged hemodialysis. PMID- 20708888 TI - Sonographic bedside detection of sialolithiasis with submandibular gland obstruction. PMID- 20708889 TI - Ultrasound-guided intercostal nerve block for traumatic pneumothorax requiring tube thoracostomy. PMID- 20708890 TI - Circadian, weekly, and seasonal mortality variations in out-of-hospital cardiac arrest in Japan: analysis from AMI-Kyoto Multicenter Risk Study database. AB - BACKGROUND: Several studies have reported circadian, weekly, and seasonal variations in the rates of out-of-hospital cardiac arrest (OHCA). However, variations in the mortality of OHCA are not well known. METHODS AND RESULTS: We investigated the 1396 consecutive cases of OHCA with cardiac etiology between October 2004 and September 2008. There were 2 peaks in the occurrence of OHCA in early morning and late evening. There was a weekly pattern with an increased incidence on Mondays. We found a significant seasonal variation in the frequency of events, with a maximum during winter. There was a trend of reduced mortality in warmest 3 months, especially among a subgroup of ventricular fibrillation/pulseless ventricular tachycardia with arrest witnessed. CONCLUSION: The present analyses demonstrated circadian, weekly and seasonal variations in the occurrence, and a seasonal variation in mortality in OHCA. Changes in temperature might influence the severity of OHCA and change the rate of success of cardiopulmonary resuscitation. PMID- 20708891 TI - The Pulmonary Embolism Rule-Out Criteria rule in a community hospital ED: a retrospective study of its potential utility. AB - BACKGROUND: The Pulmonary Embolism Rule-Out Criteria (PERC) rule identifies patients who can be safely discharged from the emergency department (ED) without undergoing laboratory or radiological investigation for possible pulmonary embolism (PE). It was shown to be 99% sensitive in a large validation series. Our objective was to assess the PERC rule's performance in a representative US community hospital. METHODS: A chart review of ED patients receiving computed tomographic scans (CTS) for possible PE during a 4-month study period was performed. The PERC rule was applied to this cohort, and its sensitivity and negative predictive value were determined. RESULTS: Two hundred thirteen patients underwent chest CTS to "rule out" PE. Forty-eight patients met PERC rule criteria, and all had negative CTS. Of the remaining 165 patients, 18 patients (11%) had scans positive for PE. The overall prevalence of PE was 8.45% (95% CI, 5.22-13.24%). The PERC rule's sensitivity was 100% (95% CI, 78.12-100%), with a negative predictive value of 100% (95% CI, 90.80-100%). Application of the PERC rule at the point-of-care would have reduced CTS by 23%. CONCLUSIONS: In our community hospital, the PERC rule successfully identified ED patients who did not require CTS evaluation for PE. Had the PERC rule been applied, nearly one-quarter of all CTS performed to "rule out PE" could have been avoided. PMID- 20708892 TI - The AutoPulse Assisted Prehospital International Resuscitation (ASPIRE) trial investigators respond to inhomogeneity and temporal effects assertions. PMID- 20708893 TI - The Airtraq laryngoscope for emergency tracheal intubation without interruption of chest compression. PMID- 20708894 TI - A case of rivastigmine toxicity caused by transdermal patch. PMID- 20708895 TI - Spontaneous urinoma: an unexpected cause of acute abdomen. PMID- 20708896 TI - Hypothermia is associated with poor outcome in pediatric trauma patients. AB - OBJECTIVE: The objective of the study was to determine if hypothermia in pediatric trauma patients is associated with increased mortality. METHODS: We reviewed the charts of level 1 trauma patients aged 3 months to 17 years who presented between September 2006 and March 2008. We analyzed data for patients with temperatures recorded within 30 minutes of arrival to the pediatric emergency department. Logistic regression models were used to test for associations of hypothermia with death while adjusting for mode of transport, season of year, and presence of intracranial pathology as documented by an abnormal head computed tomographic scan. RESULTS: Of the 226 level 1 trauma patients presenting during the study period, 190 met inclusion criteria. Twenty one patients (11%) died. The odds ratio (OR) of a hypothermic patient dying was 9.2 times that of a normothermic patient when adjusting for seasonal variation (95% confidence interval [CI], 3.2-26.2; P < 0.0001). The OR of a hypothermic patient dying was 8.7 times that of a normothermic patient when adjusting for mode of transport (ground vs air) (95% CI, 3.1-24.6; P < 0.0001). Although it did not reach statistical significance, there was a trend toward an association between hypothermia and the presence of traumatic brain injury as evidenced by an abnormal head computed tomographic scan (OR = 2.4; 95% CI, 0.9-6.0; P = .07). CONCLUSIONS: Hypothermia is a risk factor for increased mortality in pediatric trauma patients. This pilot study warrants a more detailed, multicenter analysis to assess the impact of hypothermia in the pediatric trauma patient. PMID- 20708897 TI - The impact of financial incentives on physician empathy: a study from the perspective of patients with private and statutory health insurance. AB - OBJECTIVE: We hypothesized that patients' ratings of physician empathy (PE) would be higher among those with private health insurance (PHI, referring to financial incentive) than among patients with statutory health insurance (SHI). METHODS: A postal survey was administered to 710 cancer patients. PE was assessed using the Consultation-and-Relational-Empathy measure. T-tests were conducted to analyse whether PHI and SHI-patients differ in their ratings of PE and variables relating to contact time with the physician. Structural-equation-modelling (SEM) verified mediating effects. RESULTS: PHI-patients rated physician empathy higher. SEM revealed that PHI-status has a strong significant effect on frequency of talking with the physician, which has a strong significant effect (1) on PE and (2) has a moderate effect on patients' perception of medical staff stress, thereby also affecting patients' ratings of PE. CONCLUSIONS: Our findings suggest that PHI status is one necessary precondition for physicians spending more time with the patient. Spending more time with the PHI-patient has two major effects: it results in a more positive perception of PE and positively impacts PHI-patients' perception of medical staff stress, which in turn, again influences PE. PRACTICAL IMPLICATIONS: Health policy should discuss these findings in terms of equality in receiving high-quality care. PMID- 20708898 TI - Medical students' self-assessment of performance: results from three meta analyses. AB - OBJECTIVE: Self-assessment is an important component of medical education. Meta analyses were conducted to better understand accuracy of self-assessment and direction of inaccuracy. METHODS: Three meta-analyses were conducted on results from 35 published articles on medical student self-assessment, one for each of the theoretically distinct ways of measuring accuracy of self-reported ability (correlational, paired comparison, and independent means comparison). Characteristics that potentially influence self-assessment accuracy, including gender, year in medical school, and type of self-assessment, were examined. RESULTS: Students are moderately able to self-assess performance and are more accurate later in medical school. Students as a whole do not significantly over- or underestimate, but are more likely to overestimate on communication-based, standardized patient encounters than objective, knowledge-based performance measures. Female students underestimate their performance more than male students, but gender analyses are often unreported. CONCLUSION: A deeper understanding of the causes and consequences of over- and underestimation is impossible without measurement and reporting of the direction of inaccuracy. PRACTICE IMPLICATIONS: To improve our understanding of self-assessment and increase its effectiveness as a teaching tool, research should report self assessment as both a correlation and a paired comparison, and conduct analyses of important moderators that can influence self-assessment accuracy. PMID- 20708899 TI - Delivery styles and formats for different stroke information topics: patient and carer preferences. AB - OBJECTIVE: To identify the preferences of patients with stroke and their carers for format and delivery style, of different categories of stroke information, and whether these preferences changed over time. METHODS: A semi-structured questionnaire, designed to explore preferences for four topic categories was administered to 34 acute stroke unit patients and 18 carers prior to discharge and again, 3 months after discharge to 27 of these patients and 16 of these carers. RESULTS: Overall format preferences were a combination of face-to-face, written and telephone for both patients and carers prior to discharge. This combination continued for carers following discharge, while patients preferred face-to-face, written and alternative formats of online and audiovisual at this time. Patients and carers most frequently preferred delivery styles appeared to be a mix of active and passive delivery styles, across all topics. Access to a telephone hotline was a popular delivery style. CONCLUSION: Patient and carer preferences varied, supporting the need to offer a variety of formats and delivery styles at each point of contact. PRACTICE IMPLICATIONS: By focusing on specific formats and delivery styles for different topics, health professionals may maximise the access to, and relevance of, stroke information for patients and their carers. PMID- 20708900 TI - Counselor motivational interviewing skills and young adult change talk articulation during brief motivational interventions. AB - The process of eliciting client language toward change (change talk [CT]) is implicated as a causal mechanism in motivational interviewing (MI) and brief motivational interventions (BMI). We investigated the articulation of counselor behaviors and CT during BMI with young men. We coded 149 sessions using the Motivational Interviewing Skill Code and summarized these codes into three counselor categories (MI-consistent [MICO], MI-inconsistent [MIIN], other) and three client categories (CT, counter CT [CCT], follow/neutral [F/N]). We then computed immediate transition frequencies and odds ratios using sequential analysis software. CT was significantly more likely following MICO behaviors, whereas MIIN behaviors only led to CCT and F/N. This strongly supports the use of MI skills to elicit CT during BMI with young men, whose speech also predicted counselor behaviors (particularly CT to MICO and CCT to MIIN). Additional analyses showed that among MICO behaviors, reflective listening may be a particularly powerful technique to elicit CT. PMID- 20708901 TI - Measurement of mental health in substance use disorder outpatients. AB - Few studies have examined mental health (MH) attributes of patients with substance use disorder (SUD). This study examines the internal consistency, concurrent validity, and comparative level of MH attributes (i.e., optimism, life attitudes, spirituality/religiousness, social support, positive mood, hope, and vitality) in patients with SUD compared with the instrument development group. The internal consistency of optimism, spirituality/religiousness, positive mood, hope, and vitality were similar in both groups. Some subscales of the social support and life attitude measures had lower internal consistency than was found for the original samples, although internal consistency of more global constructs were comparable. Patients with SUD had higher positive mood, spirituality/religiousness, and hope scores, whereas social support, life attitudes, and optimism scores were lower than in the original sample. Correlations between MH attributes and recent life problems of patients with SUD generally supported the concurrent validity of the MH measures. PMID- 20708902 TI - 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. AB - The role of various environmental factors in the pathogenesis of immune mediated diseases is well established. Of which, factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were associated with defined and non-defined immune mediated diseases both in animal models and in humans. In recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant. Furthermore, these four diseases share a similar complex of signs and symptoms which further support a common denominator.Thus, we review herein the current data regarding the role of adjuvants in the pathogenesis of immune mediated diseases as well as the amassed data regarding each of these four conditions. Relating to the current knowledge we would like to suggest to include these comparable conditions under a common syndrome entitled ASIA, "Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants". PMID- 20708903 TI - Effect of contrast-induced nephropathy on cardiac outcomes after use of nonionic isosmolar contrast media during coronary procedure. AB - Contrast-induced nephropathy (CIN) has been increasing and seems to be associated with clinical outcomes in ischemic heart disease. This study aimed to assess the incidence, predictors, and cardiac outcomes of CIN when nonionic isosmolar contrast media (iodixanol, Visipaque((r)), GE Healthcare, Cork, Ireland) was used. Between January 2005 and July 2008, 510 patients (69.2 +/- 9.0 years of age, 384 men) undergoing diagnostic coronary angiography (CAG) or percutaneous coronary intervention (PCI) were divided into two groups according to the development of CIN (CIN group: n=74; non-CIN group: n=436). CIN developed in 74 patients (14.5%). They were more likely to have diabetes (55.4% vs. 42.9%, p=0.045), decreased left ventricular ejection fraction (LVEF) (50.1 +/- 12.6% vs. 57.7 +/- 13.9%, p<0.001), and lower baseline hematocrit level (32.4 +/- 5.3% vs. 36.6 +/- 5.5%, p<0.001). Multiple logistic regression analysis revealed baseline hematocrit (odds ratio 0.900, 95% confidence interval 0.851-0.952, p<0.001), decreased LVEF (odds ratio 0.967, 95% confidence interval 0.949-0.986, p=0.001), and baseline creatinine level (odds ratio 2.317, 95% confidence interval 1.252 4.286, p=0.007) as independent predictors of CIN. At 1-year follow-up, patients with CIN were found to have more adverse outcomes than without CIN in Cox proportional hazards analysis (hazard ratio 13.068, 95% confidence interval 2.425 70.434, p=0.003). CIN was mostly associated with baseline creatinine level rather than CM amount using nonionic isosmolar CM. We found that patients with CIN had worse event-free survival than patients without CIN after multifactorial adjustment. PMID- 20708904 TI - Intramuscular and intravenous levetiracetam in humans: safety and pharmacokinetics. AB - A study in dogs demonstrated that the commercially available formulation of IV levetiracetam (LEV) could be given safely IM and was quickly and completely absorbed. In this crossover study, 5 women and 5 men were given IM and IV LEV. This study demonstrates that administration of 5ml (500mg) IM LEV is well tolerated and its bioavailability is equivalent to an IV injection. PMID- 20708905 TI - Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression. AB - Depression is a common condition in the community with a significant impact on affected individuals, their relatives and society. Many patients with depression do not seek treatment and are often concerned about the possible adverse effects of antidepressant drugs. Extract of Hypericum perforatum (St. John's wort) has long been recognized as a treatment for depression. Several published trials and meta-analyses have demonstrated the efficacy and tolerability of Hypericum extract for mild to moderate depression. Recent comparative trials of Hypericum extract and other antidepressants, including selective serotonin reuptake inhibitors (SSRIs), provide support for Hypericum extract efficacy. However, since the constituents of Hypericum extract differ between the individual manufacturers, the efficacy cannot be extrapolated from one extract to another. In this review, WS 5572, LI 160, WS 5570 and ZE 117 Hypericum extracts have been shown to be significantly more effective than placebo with at least similar efficacy and better tolerability compared to standard antidepressant drugs. PMID- 20708907 TI - Functional magnetic resonance imaging of BDNF val66met polymorphism in unmedicated subjects at high genetic risk of schizophrenia performing a verbal memory task. AB - Multiple strands of evidence suggest a role for Brain Derived Neurotrophic Factor (BDNF) in the pathophysiology of schizophrenia. It is not yet clear, however, how BDNF may contribute to altered brain function seen in the disorder, or in those at high genetic risk. The current study examines functional imaging correlates of the BDNF val66met polymorphism in a population at high genetic risk of schizophrenia. Subjects at high genetic risk for the disorder (n=58) provided both BDNF genotyping and fMRI data while performing a verbal memory task. During encoding, participants were presented with a word and asked to make a 'living'/'non-living' classification. During retrieval, individuals were requested to make an 'old'/'new' word classification. For encoding, we report decreased activation of the inferior occipital cortex and a trend in the cingulate cortex in Val homozygote individuals relative to Met carriers. For retrieval, we report decreases in activation in the prefrontal, cingulate cortex and bilateral posterior parietal regions in Val homozygote individuals versus Met carriers. These findings add to previous evidence suggesting that genetic variation in the BDNF gene modulates prefrontal and limbic functioning and suggests that it may contribute to differences in brain function seen in those at high risk of the disorder. PMID- 20708906 TI - fMRI activation in the amygdala and the orbitofrontal cortex in unmedicated subjects with major depressive disorder. AB - Although amygdala and frontal lobe functional abnormalities have been reported in patients with mood disorders, the literature regarding major depressive disorder (MDD) is inconsistent. Likely confounds include heterogeneity of patient samples, medication status, and analytic approach. This study evaluated the amygdala and frontal lobe activation in unmedicated MDD patients. Fifteen MDD patients and 15 matched healthy controls were scanned using fMRI during the performance of an emotional face task known to robustly activate the amygdala and prefrontal cortex (PFC). Whole-brain and region of interest analyses were performed, and correlations between clinical features and activation were examined. Significant amygdala and lateral PFC activation were seen within patient and control groups. In a between-group comparison, patients showed significantly reduced activation in the insula, temporal and occipital cortices. In MDD, the presence of anxiety symptoms was associated with decreased orbitofrontal activation. We found robust activation in both the MDD and control groups in fronto-limbic regions with no significant between-group differences using either analytic approach. The current study replicates previous research on unmedicated subjects showing no significant differences in amygdala function in depressed vs. control subjects with respect to simple tasks involving emotion observation. PMID- 20708908 TI - 2-Methoxy-2',4'-dichloro chalcone as an antimicrofoulant against marine bacterial biofilm. AB - Marine paint mixed with 2-methoxy-2',4'-dichloro chalcone is able to considerably reduce the formation of biofilm by Vibrio natriegens, a marine bacterium, on polycarbonate (PC), polymethylmethacrylate (PMMA) and glass fiber reinforced plastic (GFRP). These polymers have been selected for the study, since they have wide marine applications. Surfaces coated with dichloro chalcone containing marine paint had the lowest number of colony forming units (CFU) (1-5*10(6)), proteins (20-30 MUg/cm2) and carbohydrates (5-10 MUg/cm2) attached to them after 28 days of exposure to the organism when compared to surfaces coated with CuSO4 mixed paint (20-40*10(6) CFU/ml, proteins of 50-60 MUg/cm2 and carbohydrates of 40-50 MUg/cm2) or plain marine paint (30-40*10(6) CFU/ml, proteins of 120-150 MUg/cm2 and carbohydrates of 40-60 MUg/cm2). At the end of the study period, the biofilm on PMMA was 7, 10 and 12 MUm thick on chalcone, copper and plain paint coated surfaces, respectively. The first two paints increased the surface roughness but decreased the surface hydrophobicity when compared to the plain paint. Large number of dead cells was found on the chalcone mixed and predominantly live cells were found on plain paint coated surfaces. 15% of dichloro chalcone had leached out of PMMA surface after 28 days. The low amount of biofilm formed in the presence of dichlorochalcone can be associated to its antibacterial and slimicidal activity and also its ability to reduce the hydrophobicity of the surface. This dichlorochalcone appears to be a novel agent for decreasing the formation of marine biofilm. PMID- 20708909 TI - Phospholipids-embedded fully dilutable liquid nanostructures. Part 2: The role of sodium diclofenac. AB - Complex pseudo-ternary phase diagrams based on sucrose monolaurate (SE), propylene glycol (PG), and phosphatidylcholine (PC) as the "surfactant phase"; triacetin (TA) and decaglycerol ester (10G1CC) as the "oil phase"; and water as the aqueous phase were constructed, into which we solubilized the water-insoluble drug (sodium diclofenac, Na-DFC). In our previous study we demonstrated that the solubilization of Na-DFC in the oil+surfactant phases (prior to diluting it with water), was 90-fold greater than its dissolution in water, and that the system was pH-dependent. The greatest Na-DFC solubilization capacity was obtained at pH 7.2. In this study we examined the effect of the solubilization of Na-DFC in a phosphatidylcholine system using DLS, viscosity, electrical conductivity, SAXS, SD-NMR, and cryo-TEM measurements. It was found that: (1) the system remains micellar after aqueous dilution but with greater polydispersity and greater variety of shapes. We concluded that the structures in the absence of water (but in the presence of PG) were of direct spherical micelles (~4 nm) mixed with elongated cylindrical micelles (12-140 nm); (2) the aqueous dilution causes fragmentation of the cylinders into smaller spherical micelles; (3) solubilization of Na-DFC behaving like a kosmotropic agent or "structure maker" yields mostly spherical swollen micelles and more ordered systems than in its absence; and (4) Na-DFC is solubilized at the interface of the micelles without swelling the droplets. PMID- 20708910 TI - Fungal mediated biosynthesis of silver nanoparticles, characterization and antimicrobial activity. AB - Microbial assisted biosynthesis of nanoparticles is a rapidly progressing area of nanobiotechnology. In this paper Aspergillus niger assisted extracellular synthesis of silver nanoparticles is reported. The silver nanoparticles were characterized by UV-vis spectrophotometry, TEM, EDX and FTIR. TEM studies showed the size of the silver nanoparticles to be in the range of 3-30 nm. The probable mechanism for the extracellular synthesis of silver nanoparticles by Aspergillus niger was investigated. The nanoparticles showed antimicrobial activity against fungal and bacterial strains. PMID- 20708911 TI - HER2 testing, adjuvant trastuzumab use and results. Our experience in South Wales. PMID- 20708912 TI - The 2009 2nd Italian Consensus Conference on LDL-apheresis. AB - The '2009 2nd Italian Consensus Conference on LDL-apheresis' was held in Rome, Italy, 15 May 2009. The latest scientific evidence and the information processed in more than two decades of LDL-apheresis application require new guidelines. Experts were invited by the Consensus Panel to give a scientific specific contribution in their clinical area of specialty. The experts of interdisciplinary affiliation participated in the extension of 'The new guidelines and recommendations for the indications and the appropriate use of LDL apheresis'. The summary statement describing the frame and the lines of action of the scientific event and a supplementary document inherent to the Consensus available online at http://ees.elsevier.com/nmcd/ are reported. PMID- 20708913 TI - Relationship between serum uric acid and cerebral white matter lesions in the elderly. AB - BACKGROUND AND AIMS: Recent evidence suggests that hyperuricemia might increase the risk of cardiovascular disease. Cardiovascular risk factors are well recognized to be associated with cerebral white matter lesion (WML). We hypothesized that hyperuricemia is related to higher grade of WML in both men and women. METHODS AND RESULTS: A total of 108 men and 123 women were enrolled from those who signed up for the annual Health Examination for the Elderly Program in Taipei from 2006 to 2008. Information in interview data, clinical and laboratory examinations were collected. Hyperuricemia was defined by uric acid >=458.0 MUmol/L in men and >=392.6 MUmol/L in women. Two types of WML including periventricular hyper-intensity (PVH) and deep white matter hyper-intensity (DWMH), ascertained by cranial magnetic resonance imaging, were graded. Association between hyperuricemia and high grade WML was evaluated by using multiple logistic regression analysis. The prevalences of hyperuricemia were 13.9% and 17.9% for men and women, respectively. The prevalences of moderate-to severe PVH among men and women were 16.7% and 7.3%; while the prevalences of moderate-to-severe DWMH for men and women were 19.4% and 11.4%, respectively. Hyperuricemia was related to moderate-to-severe DWMH in men, after controlling for age, education years, smoking, alcohol consumption, metabolic Z score, silent infarct, and the use of anti-hypertensives, lipid-lowering and anti-diabetic agents, the association remained significant. The relationship was not evident among women. We did not find an association between hyperuricemia and PVH. CONCLUSIONS: Hyperuricemia was positively associated with high grade DWMH in older men, but not in women. PMID- 20708914 TI - Association of apolipoprotein A5 gene polymorphisms and serum lipid levels. AB - BACKGROUND AND AIMS: Apolipoprotein (APO) A5 gene polymorphisms have been associated with increased plasma triglyceride (TG), but the results are inconsistent. The present study was undertaken to detect the APOA5 gene polymorphisms and their associations with lipid profiles in the Guangxi Hei Yi Zhuang and Han populations. METHODS AND RESULTS: Genotyping of the APOA5 1131T>C, c.553G>T and c.457G>A was performed in 490 subjects of Hei Yi Zhuang and 540 participants of Han Chinese aged 15-89 years. The -1131C allele frequency was higher in high total cholesterol (TC) than in normal TC subgroups in both the ethnic groups (P<0.05). The c.553T allele frequency was higher in high TG than in normal TG subgroups (P<0.01), in high APOB than in normal APOB subgroups in Hei Yi Zhuang (P<0.05), or in females than in males in Han (P<0.01). The c.457A allele frequency in Han was higher in high TG than in normal TG subgroups, in low APOA1 than in normal APOA1 subgroups, in males than in females, or in normal APOB than in high APOB subgroups (P<0.05-0.01). The levels of TC, low-density lipoprotein cholesterol and APOB in Hei Yi Zhuang were correlated with -1131T>C genotype or allele, and the levels of TG were associated with c.553G>T genotype (P<0.05). The levels of TG, APOA1 and APOB in Han were correlated with c.457G>A genotype or allele, and the levels of TC were associated with -1131T>C allele (P<0.05). CONCLUSIONS: The differences in the lipid profiles between the two ethnic groups might partly result from different APOA5 gene-environmental interactions. PMID- 20708915 TI - Recycling of the product of thermal inertization of cement-asbestos for various industrial applications. AB - Recycling of secondary raw materials is a priority of waste handling in the countries of the European community. A potentially important secondary raw material is the product of the thermal transformation of cement-asbestos, produced by prolonged annealing at 1200-1300 degrees C. The product is chemically comparable to a Mg-rich clinker. Previous work has assured the reliability of the transformation process. The current challenge is to find potential applications as secondary raw material. Recycling of thermally treated asbestos-containing material (named KRY.AS) in traditional ceramics has already been studied with successful results. The results presented here are the outcome of a long termed project started in 2005 and devoted to the recycling of this secondary raw materials in various industrial applications. KRY.AS can be added in medium-high percentages (10-40 wt%) to commercial mixtures for the production of clay bricks, rock-wool glasses for insulation as well as Ca-based frits and glass-ceramics for the production of ceramic tiles. The secondary raw material was also used for the synthesis of two ceramic pigments; a green uvarovite-based pigment [Ca(3)Cr(2)(SiO(4))(3)] and a pink malayaite-based pigment [Ca(Sn,Cr)SiO(5)]. The latter is especially interesting as a substitute for cadmium-based pigments. This work also shows that KRY.AS can replace standard fillers in polypropylene plastics without altering the properties of the final product. For each application, a description and relevant results are presented and discussed. PMID- 20708916 TI - Ni2+-modulated homocysteine-capped CdTe quantum dots as a turn-on photoluminescent sensor for detecting histidine in biological fluids. AB - The high affinity of histidine to Ni2+ has long been recognized in metal ion affinity chromatography for the separation and purification of histidine-tagged proteins. Besides, such affinity pair has been explored in modern nanotechnology for constructing functional nanoparticle-histidine-tagged protein conjugates. However, the use of Ni2+-histidine affinity pair in conjunction with optically active nanomaterials for sensor design, to our knowledge, has not been reported yet. Here we report a turn-on photoluminescent sensor for histidine based on Ni2+ modulated homocysteine (Hcy)-capped CdTe quantum dots (QDs) by taking the advantages of this well-known Ni2+-histidine affinity pair and photoluminescent QDs. The photoluminescence of Hcy-capped CdTe QDs can be effectively quenched by Ni2+ due to the binding of Ni2+ to the Hcy on the surface of the QDs and the electron transfer from the photoexcited QDs to Ni2+. The high affinity of histidine to Ni2+ enables Ni2+ to be dissociated from the surface of Hcy-capped CdTe QDs to form stable complex with histidine in solution, thereby recovering the photoluminescence of Hcy-capped CdTe QDs. The Ni2+ induced photoluminescence quenching and subsequent histidine-induced photoluminescence recovery for Hcy capped CdTe QDs build a solid base for the present QD-based turn-on photoluminescent sensor for detecting histidine. The developed QD-based sensor gives excellent selectivity for histidine over other amino acids with the limit of detection (3 s) of 0.3 MUM. The relative standard deviation for 11 replicate detections of 15 MUM histidine was 2.7%. The developed sensor was applied to the determination of histidine in human urine samples with recoveries from 94.4% to 106%. PMID- 20708917 TI - Development of a novel method to detect intrinsic mRNA in a living cell by using a molecular beacon-immobilized nanoneedle. AB - We developed a novel nanobiosensor for monitoring mRNA expression in a single living cell by using an atomic force microscope (AFM) equipped with a nanoprobe. The nanoprobe was constructed by immobilizing a biotin-modified molecular beacon onto an ultrathin needle (nanoneedle) via neutravidin. In order to evaluate the effectiveness of the nanoprobe, we selected glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as the target. A single HeLa cell contained approximately 1000 copies of GAPDH mRNA. The nanoprobe was directly inserted into living HeLa cells, and it reacted with the intrinsic target mRNA within the cells. The nanoprobe could be renatured by pulling it out of the cells. Further, we successfully used the nanoprobe for continuous detection of GAPDH mRNA in multiple cells, i.e., the nanoprobe was highly specific and sensitive for the detection of intrinsic mRNA in single living cells. mRNAs are thought to be highly condensed because of the large number of organelles and complexes present in cells and the limited space available for distribution. Therefore, direct analysis of intrinsic mRNAs in living cells would be advantageous, and our novel nanoprobe is highly suitable for monitoring the RNAs in living cells. PMID- 20708918 TI - Dumbbell-like Au-Fe3O4 nanoparticles as label for the preparation of electrochemical immunosensors. AB - In this work, we developed a novel kind of label based on dumbbell-like Au-Fe3O4 nanoparticles (NPs) for the preparation of electrochemical immunosensor for the detection of cancer biomarker prostate specific antigen (PSA). The signal amplification strategy, using the synergetic effect present in Au-Fe3O4 to increase the reduction ability of the NPs toward H2O2, improves the sensitivity and detection limit of the immunosensor. With primary anti-PSA antibody (Ab1) immobilized onto graphene surface and secondary anti-PSA antibody (Ab2) adsorbed onto the Au of the Au-Fe3O4 NPs, the immunosensor prepared through a sandwich structure displays a wide linear range (0.01-10 ng/mL), low detection limit (5 pg/mL), good reproducibility and stability. These labels for immunosensors may provide many potential applications for the detection of different biomolecules. PMID- 20708919 TI - Challenges in synthetically designing mammalian circadian clocks. AB - Synthetic biology, in which complex, dynamic biological systems are designed or reconstructed from basic biological components, can help elucidate the design principles of such systems. However, this engineering approach has only been applied to a few simple biological systems. The circadian clock is appropriate for this approach, since it is a dynamic system with complex transcriptional and post-transcriptional circuits that have been comprehensively described. Rational synthesis of the properties of the suprachiasmatic nucleus, the central clock tissue of the circadian system that controls many dynamic behaviors, will be important for understanding the neural-circuit systems that control physiological behaviors. These approaches will provide a deeper understanding of the biological clock, and of clinical problems associated with it, such as sleep disorders. PMID- 20708920 TI - Cardiogenic shock following cesarean delivery due to undiagnosed tuberculous constrictive pericarditis. AB - We describe an uncommon cause of cardiogenic shock following cesarean delivery in a 24-year-old multiparous woman at 26 weeks of gestation. Hemodynamic instability was erroneously attributed to amniotic infection syndrome and sepsis, which resulted in delayed diagnosis and treatment of tuberculous constrictive pericarditis. Inotropic support, pericardectomy, and implantation of a left ventricular assist device were required for maternal survival. PMID- 20708921 TI - Obstetric anesthesia units in Israel: a national questionnaire-based survey. AB - BACKGROUND: This survey was performed to assess the organization and practice of obstetric anesthesia units in Israel. METHODS: A written questionnaire was mailed at the end of December 2005 to all Israeli anesthesia departments providing labor and delivery services in 2005 (n=25). RESULTS: A response rate of 100% accounted for 125,340 deliveries. All labor and delivery suites had on-site anesthesia department services. Data are presented as mean (range) or frequency. Eleven hospitals performed 2500-4999 deliveries/year, 6 hospitals 5000-7499 deliveries/year, and 4 hospitals 7500-9999 deliveries/year. The overall cesarean delivery rate was 20% (0-27). Anesthesia for cesarean delivery (elective and emergency combined) was provided by: general anesthesia 15% (0.5-50), epidural 14.5% (0-99.5), spinal 68% (0-98), or combined spinal-epidural technique 0% (0 30). There was an operating room within or immediately adjacent to the labor ward in 16/25 units, including 10/11 units with >5000 deliveries/year. Labor analgesia was provided by epidural techniques in 50% (4-93) and nitrous oxide in 0.5% (0 90) of deliveries. A total of 11 units had 24h dedicated anesthesiologist coverage, including all units >7500 deliveries but only 3/8 (38%) with 5000-7500 deliveries. Two of the 4 units with >7500 deliveries had no faculty member with formal training in obstetric anesthesia. Written protocols were available for labor analgesia (17/25), post-partum hemorrhage (12/25), aspiration prophylaxis (15/25) and maternal resuscitation (8/25). CONCLUSION: In this national appraisal of Israeli obstetric anesthesia services, a notable lack of written protocols, wide variations in staffing, and few specifically trained obstetric anesthesia personnel were observed. PMID- 20708922 TI - Computational glycoscience: characterizing the spatial and temporal properties of glycans and glycan-protein complexes. AB - Modern computational methods offer the tools to provide insight into the structural and dynamic properties of carbohydrate-protein complexes, beyond that provided by experimental structural biology. Dynamic properties such as the fluctuation of inter-molecular hydrogen bonds, the residency times of bound water molecules, side chain motions and ligand flexibility may be readily determined computationally. When taken with respect to the unliganded states, these calculations can also provide insight into the entropic and enthalpic changes in free energy associated with glycan binding. In addition, virtual ligand screening may be employed to predict the three dimensional (3D) structures of carbohydrate protein complexes, given 3D structures for the components. In principle, the 3D structure of the protein may itself be derived by modeling, leading to the exciting--albeit high risk--realm of virtual structure prediction. This latter approach is appealing, given the difficulties associated with generating experimental 3D structures for some classes of glycan binding proteins; however, it is also the least robust. An unexpected outcome of the development of algorithms for modeling carbohydrate-protein interactions has been the discovery of errors in reported experimental 3D structures and a heightened awareness of the need for carbohydrate-specific computational tools for assisting in the refinement and curation of carbohydrate-containing crystal structures. Here we present a summary of the basic strategies associated with employing classical force field based modeling approaches to problems in glycoscience, with a focus on identifying typical pitfalls and limitations. This is not an exhaustive review of the current literature, but hopefully will provide a guide for the glycoscientist interested in modeling carbohydrates and carbohydrate-protein complexes, as well as the computational chemist contemplating such tasks. PMID- 20708923 TI - Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy. AB - BACKGROUND: NGR-hTNF consists of human tumour necrosis factor (hTNF) fused with the tumour-homing peptide Asp-Gly-Arg (NGR), which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Preclinical antitumour activity was observed even at low doses. We evaluated the activity and safety of low-dose NGR-hTNF in colorectal cancer (CRC) patients failing standard therapies. PATIENTS AND METHODS: Thirty-three patients with progressive disease at study entry received NGR-hTNF 0.8 MUg/m(2) given intravenously every 3 weeks. The median number of prior treatment regimens was three (range, 2-5). One-quarter of patients had previously received four or more regimens and two-thirds targeted agents. Progression-free survival (PFS) was the primary study objective. RESULTS: NGR-hTNF was well tolerated. No treatment-related grade 3 to 4 toxicities were detected, most common grade 1 to 2 adverse events being short-lived, infusion time related chills (50.0%). One partial response and 12 stable diseases were observed, yielding a disease control rate of 39.4% (95% CI, 22.9-57.8%). Median PFS and overall survival were 2.5 months (95% CI, 2.1-2.8) and 13.1 months (95% CI, 8.9-17.3), respectively; whereas in patients who achieved disease control the median PFS and overall survival were 3.8 and 15.4 months, respectively. In an additional cohort of 13 patients treated at same dose with a weekly schedule, there was no increased toxicity and 2 patients experienced PFS longer than 10 months. CONCLUSION: Based on tolerability and preliminary evidence of disease control in heavily pretreated CRC patients, NGR-hTNF deserves further evaluation in combination with standard chemotherapy. PMID- 20708924 TI - A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. AB - PURPOSE: To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ?21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG. PATIENTS AND METHODS: Three strata were identified: stratum 1A--BSG; stratum IB--incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II--incompletely resected STMG receiving EIACD. Dose escalation using a modified 3+3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100mg/m(2)/d commencing with radiation therapy and the dose finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients. RESULTS: Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100mg/m(2)/d, 1 of 10 at 250 mg/m(2)/d and 3 of 12 at 375 mg/m(2)/d. Subsequently a second patient at 250 mg/m(2)/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples. CONCLUSION: This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m(2)/d was selected for the phase II trial. PMID- 20708925 TI - Undergraduate training in oncology: an ESO continuing challenge for medical students. AB - During the last six years the European School of Oncology (ESO) opened an undergraduate programme for European medical students, aiming to further improve their oncology knowledge and clinical skills. In this endeavour a 5-day course is organized every summer at the University of Ioannina, Greece, where distinguished European oncologists introduce preselected medical students to cancer medicine. The programme includes teaching of several oncological topic regarding diagnosis and treatment of the most common tumours; interactive case presentations and discussions were also incorporated. An overall of 229 medical students, mostly from European medical schools, have been taking part to this intensive summer course, from 2004 to 2009. This article presents the detailed educational programme, the evaluation results and the outcome of the last six ESO courses; an assessment of the oncological curricula available across European faculties is also presented. PMID- 20708926 TI - Molecular cloning and characterization of phenylalanine ammonia-lyase, cinnamate 4-hydroxylase and genes involved in flavone biosynthesis in Scutellaria baicalensis. AB - The involvement of genes in flavones biosynthesis was investigated in different organs and suspension cells obtained from Scutellaria baicalensis. Three full length cDNAs encoding phenylalanine ammonia-lyase isoforms (SbPAL1, SbPAL2, and SbAPL3) and one gene encoding cinnamate 4-hydroxylase (SbC4H) from S. baicalensis were isolated using rapid amplification of cDNA ends (RACE)-PCR. These cDNAs were used together with previously-isolated clones for 4-coumaroyl CoA ligase (4CL) and chalcone synthase (CHS) to show the expression level in different organs of S. baicalensis. These genes were upregulated in suspension cells of S. baicalensis with biotic/abiotic stress factors. The baicalin and baicalein contents in roots were 22 and 107 times higher than those in flowers, respectively. The treatment of suspension cells with methyl jasmonate (MeJa) enhanced the major flavones in S. baicalensis. Cumulatively, the results of this study should advance ability to biosynthesize important and useful medicinal compounds from a variety of plant species. PMID- 20708927 TI - Development of the cellulolytic fungus Trichoderma reesei strain with enhanced beta-glucosidase and filter paper activity using strong artificial cellobiohydrolase 1 promoter. AB - To improve the beta-glucosidase yield and total cellulase activity of Trichoderma reesei, extracellular beta-glucosidase (BGLI) was overexpressed under the control of the modified four-copy cbh1 promoter. Three transformants B2, B12 and B15 with successful integration of the bgl1 gene expression cassette were obtained, which exhibited 3.7-, 2.0- and 1.8-fold increase in beta-glucosidase activity than the parental strain RUT C30, respectively. The filter paper activities of the productive transformants B12 and B15 were improved by up to 130% and 55%, respectively. Saccharification of corncob residue with the crude enzyme dosages showed that the reducing sugar yields of B12 (5.59 mg/ml) and B15 (4.80 mg/ml) were 29% and 11% higher than that of RUT C30 (4.34 mg/ml), respectively. The present results proved that the modified four-copy cbh1 promoter was a useful tool for improving the cellulase activity of T. reesei, and the engineering strains developed in this study could be potentially used as promising cell factories for beta-glucosidase or cellulase production. PMID- 20708928 TI - Separation, hydrolysis and fermentation of pyrolytic sugars to produce ethanol and lipids. AB - This paper describes a new scheme to convert anhydrosugars found in pyrolysis oils into ethanol and lipids. Pyrolytic sugars were separated from phenols by solvent extraction and were hydrolyzed into glucose using sulfuric acid as a catalyst. Toxicological studies showed that phenols and acids were the main species inhibiting growth of the yeast Saccharomyces cerevisiae. The sulfuric acids, and carboxylic acids from the bio-oils, were neutralized with Ba(OH)(2). The phase rich in sugar was further detoxified with activated carbon. The resulting aqueous phase rich in glucose was fermented with three different yeasts: S. cerevisiae to produce ethanol, and Cryptococcus curvatus and Rhodotorula glutinis to produce lipids. Yields as high as 0.473 g ethanol/g glucose and 0.167 g lipids/g sugar (0.266 g ethanol equivalent/g sugar), were obtained. These results confirm that pyrolytic sugar fermentation to produce ethanol is more efficient than for lipid production. PMID- 20708929 TI - Novel pyrrolidine heterocycles as CCR1 antagonists. AB - A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1 expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development. PMID- 20708930 TI - The discovery of an orally efficacious positive allosteric modulator of the calcium sensing receptor containing a dibenzylamine core. AB - The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model. PMID- 20708931 TI - Styrylpyrones from the medicinal fungus Phellinus baumii and their antioxidant properties. AB - During the search for natural antioxidants from basidiomycetes, a new styrylpyrone, baumin (1), was isolated from the cultivated medicinal fungus Phellinus baumii, together with known compounds, davallialactone (2), hispidin (3), hypholomine B (4), interfungin A (5), inoscavin A (6), and phelligridin D (7), which were previously isolated from the medicinal fungi Phellinusignarius, Phellinuslinteus, and Inonotus xeranticus. Their structures were elucidated by extensive spectroscopic methods. These compounds exhibited antioxidant activity through Fenton reaction inhibition via iron chelation and free radical scavenging. PMID- 20708932 TI - Synthesis and biological activity of flavanone derivatives. AB - A series of new flavanone derivatives of farrerol was synthesized by a convenient method. The in vitro anti-tumor activity of these compounds was evaluated against human Bel-7402, HL-60, BGC-823 and KB cell lines, the protein tyrosine kinase (PTK) inhibitor activity was also tested. Their cytoprotective activity was tested using hydrogen peroxide (H2O2)-induced injury in human umbilical vein endothelial cells. Their in vitro anti-atherosclerosis activity was tested on vascular smooth muscle cells by the MTT method using tetrandrine as a positive contrast drug. The structures of all compounds synthesized were confirmed by 1H, 13C NMR and ESI-MS. Most of the compounds exhibited good pharmacological activity and the preliminary structure-activity relationships were described. PMID- 20708933 TI - Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands. AB - Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation. PMID- 20708934 TI - An Italian case of hereditary myopathy with early respiratory failure (HMERF) not associated with the titin kinase domain R279W mutation. AB - Hereditary myopathy with early respiratory failure (HMERF) is a rare disorder characterized by severe respiratory involvement at onset, muscle weakness starting in the early adulthood, and cytoplasmic bodies with peculiar immunohistochemical reactivity on muscle biopsy. Here we describe a patient who presented with hypercapnic coma at age 32. A detailed light and electron microscopy analysis on muscle biopsy was performed and, together with clinical data, led to the diagnosis. The R279W mutation in the TTN gene was excluded. This report expands the geographical region of incidence and encourages additional studies to clarify the genetic heterogeneity of the condition. PMID- 20708935 TI - Expanded endonasal endoscopic approach for resection of a juvenile nasopharyngeal angiofibroma with skull base involvement. AB - Juvenile nasopharyngeal angiofibromas (JNAs) are rare vascular tumors which arise in the nasopharynx of adolescent males. Patients with these tumors can be cured by surgery, which is the treatment of choice in the majority of patients. Traditional surgical techniques for patients with JNAs have been via open surgical approaches. Since 2000, however, the surgical management of JNAs has changed due to advances in endoscopic procedures and such approaches are standard for early stage lesions which are limited to the nasal cavity, nasopharynx and the paranasal sinuses. The role and limitations of endoscopic approaches for JNAs with skull base and intracranial involvement are being defined. In this report, we describe a patient with a JNA with skull base involvement who underwent an expanded endonasal endoscopic approach for a complete resection. Additionally, we review the literature of endoscopic approaches to JNAs with skull base involvement. PMID- 20708936 TI - Stimulation of the medial plantar nerve for complex regional pain syndrome. AB - We describe a 47-year old male with complex regional pain syndrome II in the distribution of the medial plantar nerve following metatarsal fracture, which was treated with peripheral nerve stimulation. Using a new technique of nerve stimulation with a percutaneous-type electrode, the patient experienced sustained relief at 12 months follow-up. To our knowledge, this is the first report of peripheral neurostimulation effectively managing pain for the medial plantar nerve. PMID- 20708937 TI - Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells. AB - The Wnt pathway is involved in cellular processes linked to either proliferation or differentiation. Therefore small molecules offer an attractive opportunity to modulate this pathway, whereas the key enzyme GSK-3beta is of special interest. In this study, non-symmetrically substituted indolylmaleimides have been synthesized and their ability to function as GSK-3beta inhibitors has been investigated in a human neural progenitor cell line. Among the newly synthesized compounds, the substance IM-12 showed a significant activity in several biological tests which was comparable or even outplayed the effects of the known GSK-3beta inhibitor SB-216763. Furthermore the treatment of human neural progenitor cells with IM-12 resulted in an increase of neuronal cells. Therefore we conclude that indolylmaleimides act via the canonical Wnt signalling pathway by inhibition of the key enzyme GSK-3beta. PMID- 20708939 TI - Synthesis and cytotoxic potency of novel tris(1-alkylindol-3-yl)methylium salts: role of N-alkyl substituents. AB - Novel derivatives of tris(indol-3-yl)methane and tris(indol-3-yl)methylium salts with the alkyl substituents at the N-atoms of the indole rings were synthesized. An easy substitution of indole rings in trisindolylmethanes for other indoles under the action of acids is demonstrated, and the mechanism of substitution is discussed. To obtain trisindolylmethylium salts, the environmentally safe method of oxidation of trisindolylmethanes with air oxygen in acidic conditions was developed. Tris(1-alkylindol-3-yl)methanes and tris(1-alkylindol-3-yl)methylium salts represent three-bladed molecular propellers whose physico-chemical and biological properties strongly depend on the N-alkyl substituent. The cytotoxicity of novel compounds increased with the number of C atoms in the alkyl chains, with optimal number n=3-5 whereas the derivatives with longer side chains were less cytotoxic. The most potent novel compounds killed human tumor cells at nanomolar-to-submicromolar concentrations, being one order of magnitude more potent than the prototype antibiotic turbomycin A [tris(indol-3-yl)methylium salt]. Apoptosis in HCT116 colon carcinoma cell line induced by tris(1-pentyl-1H indol-3-yl)methylium methanesulfonate was detectable at concentrations tolerable by normal blood lymphocytes. Thus, N-alkyl substituted tris(1-alkylindol-3 yl)methylium salts emerge as perspective anticancer drug candidates. PMID- 20708938 TI - Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives. AB - Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative. PMID- 20708941 TI - Modulators of the hedgehog signaling pathway. AB - Since its discovery by C. Nusslein-Volhard and E. F. Wieschaus, hedgehog (hh) signaling has come a long way. Today it is regarded as a key regulator in embryogenesis where it governs processes like cell proliferation, differentiation, and tissue patterning. Furthermore, in adults it is involved in the maintenance of stem cells, and in tissue repair and regeneration. But hh signaling has a second-much darker-face: it plays an important role in several types of human cancers where it promotes growth and enables proliferation of tumor stem cells. The etiology of medulloblastoma and basal cell carcinoma is tightly linked to aberrant hh activity, but also cancers of the prostate, the pancreas, the colon, the breasts, rhabdomyosarcoma, and leukemia, are dependent on irregular hh activity. Recent clinical studies have shown that hh signaling can be the basis of an important new class of therapeutic agents with far reaching implications in oncology. Thus, modulation of hh signaling by means of small molecules has emerged as a valuable tool in combating these hh-dependent cancers. Cyclopamine, a unique natural product with a fascinating history, was the first identified inhibitor of hh signaling and its story is closely linked to the progress in the whole field. In this review we will trace the story of cyclopamine, give an overview on the biological modes of hh signaling both in untransformed and malignant cells, and finally present potent modulators of the hh pathway-many of them already in clinical studies. For more than 30 years now the knowledge on hh signaling has grown steadily-an end to this development is far from being conceivable. PMID- 20708940 TI - Structure and functions of gamma-dodecalactone isolated from Antrodia camphorata for NK cell activation. AB - The preserved fungal species Antrodia camphorata has diverse health-promoting effects and has been popularly used in East Asia as a traditional herb. We isolated a volatile compound from the culture medium of A. camphorata and identified it as gamma-dodecalactone (gamma-DDL). Cytomic screening for immune modulating activity revealed that gamma-DDL can activate human NK cells to express the early activation marker CD69. Further experiments showed that gamma DDL not only can induce NK cells to express CD69 but also stimulate NK cells to secrete cytotoxic molecules (FasL and granzyme B) and Th1 cytokines (TNF-alpha and INF-gamma). Measuring the distribution of gamma-DDL in the subcellular compartments of NK cells revealed that gamma-DDL has been converted to 4 hydroxydodecanoic acid (an acyclic isomer of gamma-DDL) in a time-dependent manner in the cytoplasm. Synthetic (R,S)-4-hydroxydodecanoic acid activated NK cells to express CD69 mRNA within 10min, in contrast to gamma-DDL, which activated NK cells to express CD69 within 50min. This faster activation suggests that gamma-DDL has converted to 4-hydroxydodecanoic acid and to stimulate the NK cells to express CD69. Optically pure (R)-(+)-4-hydroxydodecanoic acid and (S)-( )-4-hydroxydodecanoic acid were obtained via: (1) synthesis of its diastereomeric esters of (R,S)-4-hydroxydodecanoic (R)-(-)-2-phenylpropionate; (2) separation of diastereomers via preparative HPLC, and (3) subsequent hydrolysis of the obtained optical pure ester of (R)-(+)-4-hydroxydodecanoic acid (R)-(-)-2-phenylpropionate and (R)-(-)-4-hydroxydodecanoic acid (R)-(-)-2-phenylpropionate, respectively. Further assays of NK cells activation using each enantiomer showed that only the (R)-(+)-4-hydroxydodecanoic acid can activate NK cells. PMID- 20708942 TI - Rose Bengal analogs and vesicular glutamate transporters (VGLUTs). AB - Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. Rose Bengal (RB) is the most potent known VGLUT inhibitor (Ki 25 nM); therefore we designed, synthesized and tested in brain preparations, a series of analogs based on this scaffold. We showed that among the two tautomers of RB, the carboxylic and not the lactonic form is active against VGLUTs and generated a pharmacophore model to determine the minimal structure requirements. We also tested RB specificity in other neurotransmitter uptake systems. RB proved to potently inhibit VMAT (Ki 64 nM) but weakly VACHT (Ki>9.7 microM) and may be a useful tool in glutamate/acetylcholine co-transmission studies. PMID- 20708943 TI - Biodistribution of technetium-99m pertechnetate after total colectomy in rats. AB - This study evaluated the effects of total colectomy on the biodistribution of technetium-99m pertechnetate ((99m)TcO(4)(-)) on the 28th postoperative day in rats. Samples of several organs were harvested for counting the percent of injected radioactivity/g of tissue (%ATI/g). The %ATI/g in colectomy rats was higher in the stomach and ileum than in sham and controls (p<0.05). Increase in mucosa and muscularis size of ileum was observed. Colectomy was associated with lower biodistribution in bladder and thyroid, T3, and T4, than in controls. PMID- 20708944 TI - Changes in the mandibular and dento-alveolar structures by the use of tooth borne mandibular symphyseal distraction devices. AB - PURPOSE: Different devices to perform a mandibular symphyseal distraction osteogenesis (MSDO) are available. This study evaluates how tooth borne distraction devices change to the teeth, the mandible and the condyles. MATERIALS AND METHODS: 19 patients (mean age 27.1) with anterior width deficiencies of the mandible were examined with routine pre- and postoperative CT-scans 1 month before and 4 months after a mean distraction width of 5.68 mm (SD 0.88). The anchorage teeth of the tooth borne device were examined concerning displacement of their axes as well as the movement of the condyles and the mandibular symphysis. The data were evaluated using Wilcoxon signed rank test and Spearman rho correlation. RESULTS: Significant tilting of the anchorage teeth was observed (p<0.01). The axes changed by 3.32 degrees (SD 1.57) in the first premolar and by 2.63 degrees (SD 1.75) in the first molar. A total of 2.67 mm (SD 1.17) of bone was formed on the symphysis. A significant correlation was found between distraction width and intercoronal distance changes of the anchorage teeth (p<0.01). No significant change of the intercondylar distance was found pre- and postoperatively in the Wilcoxon test. CONCLUSION: MSDO with tooth borne devices has strong effects on the anchorage teeth. No severe effects on the condyles were observed. The postoperative width gain is a result of newly generated bone in the symphysis and tooth tilting. Nevertheless stable postoperative bite corrections are achievable. PMID- 20708945 TI - Left intercostal aneurysm fistulised to azygos vein as a late complication of thoracic trauma. PMID- 20708946 TI - Preparation of visible light-responsive AgBiO(3) bactericide and its control effect on the Microcystis aeruginosa. AB - The bloom of Microcystis aeruginosa in water has adversely affected water quality, local economies, and human health. Therefore, restricting the overgrowth of M. aeruginosa is of particular interest. In this study, a novel, visible light responsive AgBiO(3) algaecide that could restrict the growth of M. aeruginosa and kill the bacteria when it is combined with simulated solar radiation energy was prepared and characterised. Compared with AgNO(3) and NaBiO(3), AgBiO(3) had a stronger deleterious effect on Microcystis cultured in BG11 with natural light, whereas NaBiO(3) was the weakest inhibitor. This data combined with the results of morphological analyses, the determination of chlorophyll a levels, and the rate of electrolyte leakage, demonstrates that AgBiO(3) can inhibit the proliferation of Microcystis due to its high photocatalytic activity, which irreversibly damages the cell walls and membranes. As such, AgBiO(3) could be a potential algaecide used to control Microcystis in natural light. PMID- 20708947 TI - A novel perspective for an orphan problem: old and new drugs for the medical management of malignant ascites. AB - Malignant ascites is defined as a condition in which fluid containing cancer cells accumulates in the abdomen. The cancers most commonly associated to ascites are ovarian (37%), pancreato-biliary (21%), gastric (18%), oesophageal (4%), colorectal (4%), and breast (3%). Treatment of malignant ascites remains a challenge. In the majority of patients systemic chemotherapy is ineffective and diuretics and paracentesis are still the only approaches, but new promising option are appearing, as cytoreductive debulking surgery and intraperitoneal (IP) or intravenous biological (target) therapies. More promising, after the recognition of potential epithelial targets as Epithelial Cell Adhesion Molecule (EpCAM), are the trifunctional antibodies able to bind these cell adhesion molecules and, at the same, time the immune system cells. These agents have been developed for malignant ascites with the aim also to prolong the need for subsequent paracentesis. So patients with malignant ascites may look at the future with hope and growing optimism. PMID- 20708948 TI - Vascular endothelial growth factor inhibition: conflicting roles in tumor growth. AB - Angiogenesis, the physiological process of sprouting of new blood vessels from pre-existing ones, is a key biological feature of almost all cancers. Among the multitude of factors driving tumor angiogenesis, vascular endothelial growth factor (VEGF) is the most potent, exerting myriad effects on vascular pruning and sprouting, permeability, network formation, proliferation, and cell death. Despite the initial unimpressive clinical performance of anti-VEGF antibody (bevacizumab) as cancer monotherapy, clear improvements in clinical outcomes following combination bevacizumab and chemotherapy regimens and multi-targeted VEGF receptor tyrosine kinase inhibitors (sorafenib and sunitinib) in select tumor types have established VEGF-targeted agents as an effective means of controlling cancer growth. Prolongation of overall survival and cure with these agents, however, remains elusive. Moreover, recent data has revealed key differences in the therapeutic and biological tumor response to antibody versus receptor kinase VEGF inhibitors and suggested, at least pre-clinically, that VEGF blockade in certain circumstances may actually promote more aggressive tumor growth. Given the diverse mechanisms and potentially opposing roles of VEGF neutralization in cancer biology, identification of novel biomarkers predictive of in vivo angiogenic responses may hold the key to optimizing therapeutic outcomes of anti-VEGF therapy in future cancer patients. PMID- 20708949 TI - Does chemical cross-linking with NHS esters reflect the chemical equilibrium of protein-protein noncovalent interactions in solution? AB - Chemical cross-linking in combination with mass spectrometry has emerged as a powerful tool to study noncovalent protein complexes. Nevertheless, there are still many questions to answer. Does the amount of detected cross-linked complex correlate with the amount of protein complex in solution? In which concentration and affinity range is specific cross-linking possible? To answer these questions, we performed systematic cross-linking studies with two complexes, using the N hydroxysuccinimidyl ester disuccinimidyl suberate (DSS): (1) NCoA-1 and mutants of the interacting peptide STAT6Y, covering a K(D) range of 30 nM to >25 MUM, and (2) alpha-thrombin and basic pancreatic trypsin inhibitor (BPTI), a system that shows a buffer-dependent K(D) value between 100 and 320 MUM. Samples were analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). For NCoA-1*STAT6Y, a good correlation between the amount of cross-linked species and the calculated fraction of complex present in solution was observed. Thus, chemical cross-linking in combination with MALDI-MS can be used to rank binding affinities. For the mid-affinity range up to about K(D) ~ 25 MUM, experiments with a nonbinding peptide and studies of the concentration dependence showed that only specific complexes undergo cross-linking with DSS. To study in which affinity range specific cross-linking can be applied, the weak alpha thrombin*BPTI complex was investigated. We found that the detected complex is a nonspecifically cross-linked species. Consequently, based on the experimental approach used in this study, chemical cross-linking is not suitable for studying low-affinity complexes with K(D) >> 25 MUM. PMID- 20708950 TI - Alternating stimulation of synergistic muscles during functional electrical stimulation cycling improves endurance in persons with spinal cord injury. AB - Therapeutic effects of functional electrical stimulation (FES) cycling for persons with spinal cord injury (SCI) are limited by high rates of muscular fatigue. FES-cycling performance limits and surface mechanomyography (MMG) of 12 persons with SCI were compared under two different stimulation protocols of the quadriceps muscles. One strategy used the standard "co-activation" protocol from the manufacturer of the FES cycle which involved intermittent simultaneous activation of the entire quadriceps muscle group for 400 ms. The other strategy was an "alternation" stimulation protocol which involved alternately stimulating the rectus femoris (RF) muscle for 100 ms and the vastus medialis (VM) and vastus lateralis (VL) muscles for 100 ms, with two sets with a 400 ms burst. Thus, during the alternation protocol, each of the muscle groups rested for two 100 ms "off" periods in each 400 ms burst. There was no difference in average cycling cadence (28 RPM) between the two protocols. The alternation stimulation protocol produced longer ride times and longer virtual distances traveled and used lower stimulation intensity levels with no differences in average MMG amplitudes compared to the co-activation protocol. These results demonstrate that FES cycling performance can be enhanced by a synergistic muscle alternation stimulation strategy. PMID- 20708951 TI - Psychiatric disorders in temporal lobe epilepsy: an overview from a tertiary service in Brazil. AB - PURPOSE: To evaluate the frequency and intensity of psychiatric disorders in a group of temporal lobe epilepsy (TLE) patients from a tertiary-care center. METHODS: Clinical and sociodemographic data of 73 patients were collected and a neuropsychiatric evaluation was performed with the following instruments: Mini Mental State Examination (MMSE), structured clinical interview (MINI-PLUS), Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D), Brief Psychiatric Rating Scale (BPRS). RESULTS: Patients with TLE showed a high frequency of lifetime psychiatric disorders (70%), the most frequent being mood disorders (49.3%). At assessment, 27.4% of the patients were depressed and 9.6% met criteria for bipolar disorder. Nevertheless, depression had not been properly diagnosed nor treated. Anxiety disorders were also frequent (42.5%), mainly generalized anxiety disorder (GAD) (21.9%). Obsessive compulsive disorder (OCD) was present in 11.0% and psychotic disorders in 5.5% of the sample. Patients with left mesial temporal sclerosis (LMTS) exhibited more psychopathologic features, mainly anxiety disorders (p=0.006), and scored higher on HAM-A and HAM-D (p<0.05 in both). CONCLUSION: TLE is related to a high frequency of psychiatric disorders, such as anxiety and depression, which are usually underdiagnosed and undertreated. Damage to the left mesial temporal lobe, seen in LMTS, seems to be an important pathogenic lesion linked to a broad range of psychopathological features in TLE, mainly anxiety disorders. The present study prompts discussion on the recognition of the common psychiatric disorders in TLE, especially on the Brazilian setting. PMID- 20708952 TI - [Evaluation of defining characteristics of the nutritional nursing diagnosis in children enrolled in a nursery]. AB - OBJECTIVE: To determine the occurrence of the defining characteristics (DC) of nutritional nursing diagnoses (NND), verifying the association between the DC and the variables: gender, age, weight and height. METHOD: A descriptive study was conducted on 69 children aged between 1 and 4 years old, enrolled in a public nursery. The evaluation tool consisted of a check-list that included DC of NND and the signs and symptoms associated with malnutrition and obesity identified in the literature. RESULTS: The study sample consisted of 57.9% females, with a mean age of 2.72 years (+/-0.765). The DC of "Readiness for enhanced nutrition" diagnosis was most frequently observed. A statistically significant association was seen between "follows an appropriate standard for intake" and female gender (P=0.022). Highest age mean was identified in children with clinical indicators p30.98), with test retest reliability ICCs of >0.98. Measurements in volunteers showed that SpineDMS((c)) was capable of detecting the shape and movement of the human back. This study showed that SpineDMS((c)) could be deployed as a reliable diagnostic tool for back posture, as well as movements in the sagittal plane. PMID- 20708958 TI - Genetics of Wilsons disease. AB - Wilson's disease is a rare autosomal recessive disorder of copper transport due to mutations in the ATP7B gene, responsible for transport of copper into bile from hepatocytes and its incorporation into apoceruloplasmin to form ceruloplasmin resulting in excessive accumulation of copper in the liver and extrahepatic tissues. Clinical features of WD result from toxic accumulation of copper in liver, brain and kidney. Early diagnosis is mandatory to initiate early treatment to prevent morbidity and mortality. More than 400 mutations have been reported, some of which are rather characteristic of geographical regions and ethnic population. Genetic testing is not useful as a routine procedure, but has its role in at risk individuals such as siblings and children of probands and in individuals with suggestive symptoms but where other tests are contradictory. PMID- 20708959 TI - Evaluation of four molecular assays for detection of pandemic influenza A (H1N1) 2009 virus in the routine diagnostic laboratory. AB - BACKGROUND: Detection and differentiation of influenza A viral RNA and influenza A (H1N1) 2009 viral RNA have gained significance because of their widespread community transmission. OBJECTIVE: To study the accuracy and the performance of four molecular assays for the detection and differentiation of influenza A viral RNA and influenza A (H1N1) 2009 viral RNA in the routine diagnostic laboratory. STUDY DESIGN: The accuracy of the molecular assays was determined with reference material. For evaluation of the performance, 104 clinical specimens were studied. Sample preparation was done on a fully automated extraction instrument. For amplification and detection of influenza RNA, all molecular assays evaluated were based on real-time PCR. RESULTS: When the accuracy was tested, the majority of assays yielded results as expected. When clinical samples were analyzed, 94 samples gave concordant results with all assays. One of the assays showed one false-negative result and another assay 10 false-negatives. CONCLUSION: The majority of assays evaluated in this study proved suitable for the detection and differentiation of influenza A viral RNA and influenza A (H1N1) 2009 viral RNA. All assays are easy to handle and provide results rapidly. PMID- 20708960 TI - Expanding character sampling for ciliate phylogenetic inference using mitochondrial SSU-rDNA as a molecular marker. AB - Molecular systematics of ciliates, particularly at deep nodes, has largely focused on increasing taxon sampling using the nuclear small subunit rDNA (nSSU rDNA) locus. These previous analyses have generally been congruent with morphologically-based classifications, although there is extensive non-monophyly at many levels. However, caution is needed in interpreting these results as nSSU rDNA is just a single molecular marker. Here the mitochondrial small subunit rDNA (mtSSU-rDNA) is evaluated for deep ciliate nodes using the Colpodea as an example. Overall, well-supported nodes in the mtSSU-rDNA and concatenated topologies are well supported in the nSSU-rDNA topology; e.g., the non-monophyly of the Cyrtolophosidida. The two moderately- to well-supported incongruences between the loci are the placement of the Sorogenida andColpoda aspera.Our analyses of mtSSU-rDNA support the conclusion, originally derived from nSSU-rDNA, that the morphological characters used in taxonomic circumscriptions of the Colpodea represent a mixture of ancestral and derived states. This demonstration of the efficacy of the mtSSU-rDNA will enable phylogenetic reconstructions of deep nodes in the ciliate tree of life to move from a single-locus to a multi locus approach. PMID- 20708961 TI - Facing unknowns: living cultures (Pirum gemmata gen. nov., sp. nov., and Abeoforma whisleri, gen. nov., sp. nov.) from invertebrate digestive tracts represent an undescribed clade within the unicellular Opisthokont lineage ichthyosporea (Mesomycetozoea). AB - During a culture-based survey of opisthokonts living in marine invertebrate digestive tracts, we isolated two new eukaryotes that differed from described taxa by more than 10% in their small subunit ribosomal DNA sequences. Phylogenetic analysis showed that the two isolates represented a divergent clade of ichthyosporeans known previously only from environmental clone sequences. We used light and electron microscopy to describe the isolates as new genera and species Pirum gemmata and Abeoforma whisleri. A. whislerihad a complex life cycle that remains incompletely known but involved walled spherical cells, plasmodia and amoebae. Asexual reproduction occurred via dispersal amoebae, endospores, binary fission and budding. In contrast P. gemmatahad a less complex life cycle with no amoeboid or plasmodial stages. Both species had membrane-bound tubular extensions of the cytoplasm embedded in the inner layers of their cell walls. By comparing P. gemmata and A. whislerito other ichthyosporea we speculate on the characters that may have been present in the ancestral ichthyosporean. P. gemmata and A. whisleri illustrate the unique and diverse forms that can be found by capturing taxa belonging to divergent and uncultured lineages. PMID- 20708962 TI - Does climate warming stimulate or inhibit soil protist communities? A test on testate amoebae in high-arctic tundra with free-air temperature increase. AB - Soil testate amoebae assemblages in a grassland area at Zackenberg (Northeast Greenland) were subjected to simulated climate-warming during the growing season using the Free-Air Temperature Increase technique. Samples were collected in upper (0 - 3cm) and deeper (3 - 6cm) soil horizons. Mean temperature elevations at 2.5 and 7.5 cm depth were 2.58 +/- SD 1.11 and 2.13+/-SD 0.77 degrees C, respectively, and did not differ significantly. Soil moisture in the top 11cm was not affected by the warming. During the manipulation, the densities of living amoebae and empty shells were higher in the experimental plots but only in the upper layer. Possibly, testate amoebae in the deeper layer were limited by other factors, suggesting that warming enhances the carrying capacity only in favourable conditions. Species richness, on the other hand, was only increased in the deeper horizon. Warming did not change the percentage of individuals belonging to small-sized species in any of the living assemblages, contrary to our expectation that those species would quickly increase their density. However, in the empty shell assemblages, the proportion of small-sized individuals in the experimental plots was higher in both layers, indicating a rapid, transient increase in small amoebae before the first sampling date. Changes in successional state of testate amoebae assemblages in response to future climate change might thus be ephemeral, whereas alterations in density and species richness might be more sustained. PMID- 20708963 TI - Identification and characterization of phage-displayed peptide mimetics of Neisseria meningitidis serogroup B capsular polysaccharide. AB - Neisseria meningitidis causes meningitis and septicemia. There is no single vaccine against all serogroup B meningococcal (MenB) strains up to now. Their capsular polysaccharide (MenB CPS) bears epitopes both cross-reacting and non cross-reactive with human polysialic acid. A bactericidal and protective antibody mAb (13D9) recognizing a unique epitope in MenB CPS was used to screen a phage displayed peptide library. Four peptides, able to bind mAb 13D9 in competition with MenB CPS, were identified. Immunization of mice with the phage-displayed peptides elicited anti-peptide IgG antibodies, mainly IgG(2a) for 3 of the peptides and bactericidal and protective antibody levels for one of them. Peptides specifically targeting the immune response toward epitopes found only in MenB CPS could be considered for a universal vaccine against serogroup B meningococcal strains. PMID- 20708964 TI - Listeria monocytogenes lineages: Genomics, evolution, ecology, and phenotypic characteristics. AB - Listeria monocytogenes consists of at least 4 evolutionary lineages (I, II, III, and IV) with different but overlapping ecological niches. Most L. monocytogenes isolates seem to belong to lineages I and II, which harbor the serotypes more commonly associated with human clinical cases, including serotype 1/2a (lineage II) and serotypes 1/2b and 4b (lineage I). Lineage II strains are common in foods, seem to be widespread in the natural and farm environments, and are also commonly isolated from animal listeriosis cases and sporadic human clinical cases. Most human listeriosis outbreaks are associated with lineage I isolates though. In addition, a number of studies indicate that, in many countries, lineage I strains are overrepresented among human isolates, as compared to lineage II strains. Lineage III and IV strains on the other hand are rare and predominantly isolated from animal sources. The apparent differences in the distribution of strains representing the L. monocytogenes lineages has lead to a number of studies aimed at identifying phenotypic differences among the different lineages. Interestingly, lineage II isolates seem to carry more plasmids than lineage I isolates and these plasmids often confer resistance to toxic metals and possibly other compounds that may be found in the environment. Moreover, lineage II isolates seem to be more resistant to bacteriocins than lineage I isolates, which probably confers an advantage in environments where bacteriocin-producing organisms are abundant. A large number of lineage II isolates and strains have been shown to be virulence-attenuated due to premature stop codon mutations in inlA and mutations in prfA. A subset of lineage I isolates carry a listeriolysin S hemolysin, which is not present in isolates belonging to lineages II, III, or IV. While lineage II isolates also show higher recombination rates than lineage I isolates, possibly facilitating adaptation of lineage II strains to diverse environments, lineage I isolates are clonal and show a low prevalence of plasmids and IS elements, suggesting that lineage I isolates may have mechanisms that limit the acquisition of foreign DNA by horizontal gene transfer. Diversifying selection has also been shown to have played an important role during evolution of the L. monocytogenes lineages and during divergence of L. monocytogenes from the non-pathogenic species L. innocua. Overall evidence thus suggests that the 4 L. monocytogenes lineages identified so far represent distinct ecologic, genetic, and phenotypic characteristics, which appear to affect their ability to be transmitted through foods and to cause human disease. Further insights into the ecology, evolution, and characteristics of these lineages will thus not only provide an improved understanding of the evolution of this foodborne pathogen, but may also facilitate improved control of foodborne listeriosis. PMID- 20708965 TI - Qualitative evidence of a primary intervention point for elite athlete doping. AB - Anti-doping activities in sport have shifted from secondary prevention (intervening after athletes have used) to educational strategies focused on primary prevention through promoting abstinence. There is no empirical evidence to guide targeting of anti-doping education initiatives. In this paper, a heuristic to guide education initiatives was derived by re-analysing a series of interviews (n=20) with athletes, coaches, sports managers, physiotherapists and sports nutritionists. The findings indicate primary prevention of doping may be enhanced by timing it around periods of career instability where athlete vulnerability to doping may increase as a function of winning or losing sponsorship. Sponsorship is broadly defined as financial (e.g. salary stipend) and non-financial support (e.g. training facilities). This provides a basis for targeting education interventions to promote abstinence. Two options are offered to mitigate the need to time prevention activity around career instability by lessening the effect of sponsorship on athlete doping. The first is liberalising access to legitimate performance enhancing technologies (e.g. training techniques or nutritional supplements). The second is to delay access to financial sponsorship (beyond living expenses) until retirement, with monetary gains (e.g. prize money) deposited into an account where penalties are debited if the athlete is caught doping. PMID- 20708966 TI - Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). AB - BACKGROUND: Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer. METHODS: Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m(2)) and then a bolus injection of fluorouracil (400 mg/m(2)) on day 1 and a continuous infusion of fluorouracil (2400 mg/m(2)) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258. FINDINGS: All randomised patients were included in the primary analysis. After a median follow up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1.077, 95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [4.7%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group. INTERPRETATION: Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer. FUNDING: Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd. PMID- 20708967 TI - Pre-exercise screening and prescription guidelines for cancer patients. PMID- 20708968 TI - Hemoglobin-based oxygen carriers: From mechanisms of toxicity and clearance to rational drug design. AB - Hemoglobin-based oxygen carriers (HBOCs) have been developed to support blood oxygen transport capacity during hemorrhagic shock, hemolysis and ischemic insult. Existing product candidates have demonstrated considerable efficacy in experimental animal models and in clinical trial subjects; however, severe adverse safety signals that appeared in recent phase II and phase III clinical trials involving certain HBOCs have in part hindered further development and licensing. Emerging insights into hemoglobin (Hb) toxicity as well as physiologic Hb scavengers such as haptoglobin and CD163 that are capable of detoxifying extracellular Hb in vivo suggest that alternative product candidates could be designed. Together with novel animal models and biomarkers tailored to monitor the effects of extracellular Hb, a new generation of HBOCs can be envisioned. PMID- 20708969 TI - Is SELDI-TOF a valid tool for diagnostic biomarkers? AB - The genome revolution is providing fresh insights into host and parasite genomes, and new tools are becoming available for examining host-parasite interactions at the proteome level. Technologies such as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) can be applied to discover biomarkers (alterations in both host and parasite proteomes) associated with parasitic diseases. Such biomarkers can represent host proteins, fragments of host proteins or parasite proteins that appear in body fluids or tissues following infection. Individual biomarkers or biomarker patterns not only have diagnostic utility (e.g. in active disease, prognosis, tests of cure) but can also provide unique insights into the mechanisms underlying host responses and pathogenesis. PMID- 20708970 TI - Functional MRI in chronic epilepsy: associations with cognitive impairment. AB - Chronic epilepsy is frequently accompanied by serious cognitive side-effects. Clinical factors are important, but cannot account entirely for this cognitive comorbidity. Therefore, research is focusing on the underlying cerebral mechanisms to understand the development of cognitive dysfunction. In the past two decades, functional MRI techniques have been applied extensively to the study of cognitive impairment in chronic epilepsy. However, because of wide variation in study designs, analysis methods, and data presentation, interpretation of these studies has become increasingly difficult for clinicians. In patients with localisation-related epilepsy, whether findings of functional MRI represent the underlying neuronal substrate for cognitive decline remains a subject of debate. PMID- 20708971 TI - Evaluation of terminology used to describe disorders of sex development. AB - OBJECTIVE: The terminology used to describe abnormalities of sex determination and sex differentiation was revised in 2006. It was anticipated that new terms, such as 'disorders of sex development' (DSD), would improve communication between health professionals, aid parental understanding and be acceptable to affected individuals. The purpose of this study was to evaluate the success of the new terminology. SUBJECTS AND METHODS: Using a questionnaire, we evaluated the acceptance of these new terms by parents of children with a DSD (n = 19), health professionals (n = 15) and parents of unaffected children (n = 25). RESULTS: Comparing the term 'DSD' to 'intersex', overall 86.4% of participants preferred the term 'DSD', and parents of a child with a DSD had an even higher preference (94.7%). Parents of an affected child considered the new term to improve their understanding of their child's condition (83.3%), and to aid explanation by parent to affected child (82.4%) and to wider family and friends (84.2%). Health professionals preferred the genotype-based terms, whereas parents considered these terms confusing. Overall, 59.3% of participants agreed DSD was an acceptable new term. CONCLUSIONS: There was broad support for the new terminology by parents and health professionals. The description 'disorder of sex development' may be helpful to parents at the time when it is not possible to assign gender, after which aetiologically based diagnoses should be used where possible. PMID- 20708972 TI - The prognostic impact of an abnormal initial renal ultrasound on early reflux resolution. AB - OBJECTIVE: In a group of children diagnosed with vesicoureteral reflux (VUR) we evaluated renal ultrasound findings, associated findings on renal scan, and prognostic impact on VUR resolution. METHODS: Medical records were reviewed for children with primary reflux and no history of antenatal hydronephrosis who underwent an initial renal ultrasound. Abnormal renal ultrasound was defined as hydronephrosis or relative difference in renal size >=1 cm. Reflux resolution was evaluated at 2 years post diagnosis. RESULTS: In 129 children with VUR (111 girls, 18 boys), 39 (30%) had an abnormal renal ultrasound. Two-year VUR resolution in the abnormal renal ultrasound group was 21% versus 46% in the group with normal renal ultrasound (P = 0.01). Combining grade II and III reflux, an abnormal ultrasound was associated with a statistically significantly lower resolution rate (grade II-III 23% vs 47%, P = 0.049). For children with moderate hydronephrosis, 8/9 (89%) had abnormal initial renal scans and all failed to achieve resolution of reflux at 2 years. CONCLUSIONS: In this cohort of children with VUR, 30% had abnormalities on renal ultrasound. The presence of moderate hydronephrosis on ultrasound may indicate a high likelihood of abnormality on renal scan and failure to achieve early resolution of VUR. PMID- 20708973 TI - Considerations for optimization and validation of an in vitro PBMC derived T cell assay for immunogenicity prediction of biotherapeutics. AB - An immune response to a biotherapeutic can be induced when the therapeutic is processed and presented by antigen presenting cell to T helper cells. This study evaluates the performance of an in vitro assay that can elicit antigen specific effector T cell responses. Two biotherapeutics with known clinical immunogenicity [FPX1 and FPX2] were assessed for their ability to induce antigen-specific IFN gamma secreting T cells in peripheral blood mononuclear cells (PBMC). The 24 amino acid peptide component of FPX1 elicited an antigen-specific response in 16/34 (47%) individual naive healthy donors. This in vitro effect was consistent with high rate of immunogenicity which was observed when this drug was administered in clinical trials. FPX2 did not induce antigen-specific T cells in vitro, which correlates with the low rate of development of anti-drug antibody responses to this molecule in the clinic. The assay has the potential to predict immunogenicity and help in the selection of biotherapeutics at the early development stage of a clinical candidate. PMID- 20708974 TI - 4-1BB-mediated expansion affords superior detection of in vivo primed effector memory CD8+ T cells from melanoma sentinel lymph nodes. AB - We have been studying the re-activation of tumor-associated antigen (TAA) specific CD8(+) T cells in sentinel lymph nodes (SLN) of melanoma patients upon intradermal administration of the CpG-B oligodeoxynucleotide PF-3512676. To facilitate functional testing of T cells from small SLN samples, high-efficiency polyclonal T cell expansion is required. In this study, SLN cells were expanded via classic methodologies with plate- or bead-bound anti-CD3/CD28 antibodies and with the K562/CD32/4-1BBL artificial APC system (K32/4-1BBL aAPC) and analyzed for responsiveness to common recall or TAA-derived peptides. K32/4-1BBL-expanded T cell populations contained significantly more effector/memory CD8(+) T cells. Moreover, recall and melanoma antigen-specific CD8(+) T cells were more frequently detected in K32/4-1BBL-expanded samples as compared with anti-CD3/CD28 expanded samples. We conclude that K32/4-1BBL aAPC are superior to anti-CD3/CD28 antibodies for the expansion of in vivo-primed specific CD8(+) T cells and that their use facilitates the sensitive monitoring of functional anti-tumor T cell immunity in SLN. PMID- 20708975 TI - Frequency of physician counseling and attitudes toward driving motor vehicles in people with epilepsy: comparing a mandatory-reporting with a voluntary-reporting state. AB - Driving for the person with epilepsy (PWE) remains an important issue. Requirements for reporting PWE to driving authorities vary across the United States. We studied the prior experiences of PWE regarding counseling for driving in a reporting state (37% in New Jersey) and a nonreporting state (52% in Arizona). A prospective voluntary anonymous survey was conducted among patients with new-onset epilepsy at two epilepsy referral centers. Subjects were queried about prior interactions with health care professionals regarding attitudes toward and knowledge of driving regulations. Practitioners caring for PWE are in the position to provide advice and counsel regarding driving regulations. Fifty percent or fewer subjects were appropriately counseled, regardless of residence requirements. PWE felt they were honest with their physician and 10% of subjects have driven against medical advice. A performance gap exists in the appropriate counseling regarding driving for PWE that has potentially significant safety and legal implications. PMID- 20708977 TI - Are lamotrigine kinetics altered in menopause? Observations from a drug monitoring database. AB - To assess possible alterations in the pharmacokinetics of lamotrigine (LTG) in menopause, we reviewed the database of the drug monitoring service at the Karolinska University Hospital. Dose/plasma concentration (D/C) ratios of LTG in different age groups of women under treatment with LTG were compared with ratios for men. For further comparison, D/C ratios were calculated for men and women treated with carbamazepine (CBZ). D/C ratios were available for 752 men and 1115 women on LTG, and for 3464 men and 3088 women on CBZ. The D/C ratios of CBZ were very similar among men and women in all age groups under study. In contrast, LTG D/C ratios seemed to decline in women 51-55 years of age, and were in this age group significantly lower among women than among men (P<0.05). Our data suggest that there may be a transient decline in clearance of LTG in conjunction with presumed menopause. PMID- 20708978 TI - Seizures during pregnancy modify the development of hippocampal interneurons of the offspring. AB - We investigated the effect of epileptic seizures during pregnancy on hippocampal expression of calcium-binding proteins in the offspring. Female Wistar rats were submitted to the pilocarpine model and mated during the chronic period. Seizure frequency was monitored over the entire pregnancy. Pups were perfused at postnatal days 6 and 13, and the brains processed for Nissl staining and immunohistochemistry for NeuN, calbindin, calretinin, and parvalbumin. Number of stained cells in the hippocampus was estimated through stereological methods. Our results showed a decrease in epileptic seizure frequency during pregnancy. No differences were observed in NeuN-positive, CR-positive cells, and Nissl-stained hippocampal neurons between the groups. However, there was a significant decrease in calbindin-positive cells (P=0.005) and a significant increase in parvalbumin positive cells (P=0.02) in the experimental group when compared with the control group. These results suggest that seizures during pregnancy affect the development of specific hippocampal interneurons of the offspring. PMID- 20708976 TI - Controversies in epilepsy: debates held during the Fourth International Workshop on Seizure Prediction. AB - Debates on six controversial topics were held during the Fourth International Workshop on Seizure Prediction (IWSP4) convened in Kansas City, KS, USA, July 4 7, 2009. The topics were (1) Ictogenesis: Focus versus Network? (2) Spikes and Seizures: Step-relatives or Siblings? (3) Ictogenesis: A Result of Hyposynchrony? (4) Can Focal Seizures Be Caused by Excessive Inhibition? (5) Do High-Frequency Oscillations Provide Relevant Independent Information? (6) Phase Synchronization: Is It Worthwhile as Measured? This article, written by the IWSP4 organizing committee and the debaters, summarizes the arguments presented during the debates. PMID- 20708979 TI - Non-Hodgkin's lymphoma presenting with multiple cranial nerve deficits. AB - BACKGROUND: Non-Hodgkin's lymphoma (NHL) is a neoplastic disease that originates in the lymphatic system but has the potential to disseminate to the central nervous system (CNS), known as secondary CNS lymphoma (SCNSL). SCNSL most commonly involves the leptomeninges and often presents with multiple cranial nerve signs. CASE REPORT: A 50-year-old black male presented to the clinic with complaints of vertigo and decreased vision in the left eye. The ophthalmic examination revealed reduced visual acuity, visual field loss, and limited abduction in the left eye. A review of the patient's medical record revealed a recent history of facial pain and numbness, as well as decreased taste. The totality of findings had a distinct neurological pattern consistent with multiple cranial nerve deficits. Subsequent neurological evaluation, neuroimaging, and laboratory testing confirmed a diagnosis of SCNSL. CONCLUSIONS: Systemic NHL is capable of manifesting within the CNS during periods of progression or relapse. When NHL breaches the CNS it can present with numerous neurological deficits, some of which may be detected during ophthalmic examination. This report summarizes the ocular manifestations of SCNSL and describes a case that presented with multiple cranial nerve deficits. PMID- 20708980 TI - Localized prostate cancer with intermediate- or high-risk features treated with combined external beam radiotherapy and iodine-125 seed brachytherapy. AB - OBJECTIVE: The aim of the study is to compare the results of the combined external beam radiotherapy (EBRT) with iodine-125 seed brachytherapy vs. brachytherapy alone for prostate cancer treatment in patients with intermediate and high risk of disease recurrence. METHODS AND MATERIALS: Ninety-six patients were treated from January 1998 to December 2006. Twenty-four patients received combined treatment and 72 patients received brachytherapy alone. Patients were classified into intermediate or high risk of recurrence according to the D'Amico's classification. The prescribed dose for brachytherapy was 145Gy as monotherapy and 110Gy for combined treatment. The dose of EBRT was 45Gy over 5 weeks, with 1.8Gy daily fractions. Results were analyzed based on Phoenix definition of biochemical recurrence, that is, nadir plus 2ng/mL. RESULTS: Biochemical control was achieved by 96% (23 of 24) of patients receiving combined treatment and by 72% (52 of 72) in the group treated by brachytherapy alone (p<0.015). The addition of EBRT resulted in a 94% biochemical disease-free survival at 5 years; and in brachytherapy alone group, the rate was 54% (p<0.011). Mean followup was 96 months (24-132 months; confidence interval 95%: 90-102). CONCLUSION: This study shows that in patients with localized prostate cancer, with intermediate and high risk of biochemical recurrence, the addition of EBRT can confer a significant biochemical control advantage when added to brachytherapy. PMID- 20708981 TI - Effect of the duration of daily aerobic physical training on cardiac autonomic adaptations. AB - The present study has investigated in conscious rats the influence of the duration of physical training sessions on cardiac autonomic adaptations by using different approaches; 1) double blockade with methylatropine and propranolol; 2) the baroreflex sensitivity evaluated by alternating bolus injections of phenylephrine and sodium nitroprusside; and 3) the autonomic modulation of HRV in the frequency domain by means of spectral analysis. The animals were divided into four groups: one sedentary group and three training groups submitted to physical exercise (swimming) for 15, 30, and 60min a day during 10 weeks. All training groups showed similar reduction in intrinsic heart rate (IHR) after double blockade with methylatropine and propranolol. However, only 30-min and 60-min physical training presented an increase in the vagal autonomic component for determination of basal heart rate (HR) in relation to group sedentary. Spectral analysis of HR showed that the 30-min and 60-min physical training presented the reduction in low-frequency oscillations (LF=0.20-0.75Hz) and the increase in high frequency oscillations (HF=0.75-2.5Hz) in normalized units. These both groups only showed an increased baroreflex sensitivity to tachycardiac responses in relation to group sedentary, however when compared, the physical training of 30 min exhibited a greater gain. In conclusion, cardiac autonomic adaptations, characterised by the increased predominance of the vagal autonomic component, were not proportional to the duration of daily physical training sessions. In fact, 30-minute training sessions provided similar cardiac autonomic adaptations, or even more enhanced ones, as in the case of baroreflex sensitivity compared to 60-minute training sessions. PMID- 20708982 TI - Homologous recombination protects mammalian cells from replication-associated DNA double-strand breaks arising in response to methyl methanesulfonate. AB - DNA-methylating agents of the S(N)2 type target DNA mostly at ring nitrogens, producing predominantly N-methylated purines. These adducts are repaired by base excision repair (BER). Since defects in BER cause accumulation of DNA single strand breaks (SSBs) and sensitize cells to the agents, it has been suggested that some of the lesions on their own or BER intermediates (e.g. apurinic sites) are cytotoxic, blocking DNA replication and inducing replication-mediated DNA double-strand breaks (DSBs). Here, we addressed the question of whether homologous recombination (HR) or non-homologous end-joining (NHEJ) or both are involved in the repair of DSBs formed following treatment of cells with methyl methanesulfonate (MMS). We show that HR defective cells (BRCA2, Rad51D and XRCC3 mutants) are dramatically more sensitive to MMS-induced DNA damage as measured by colony formation, apoptosis and chromosomal aberrations, while NHEJ defective cells (Ku80 and DNA-PK(CS) mutants) are only mildly sensitive to the killing, apoptosis-inducing and clastogenic effects of MMS. On the other hand, the HR mutants were almost completely refractory to the formation of sister chromatid exchanges (SCEs) following MMS treatment. Since DSBs are expected to be formed specifically in the S-phase, we assessed the formation and kinetics of repair of DSBs by gammaH2AX quantification in a cell cycle specific manner. In the cytotoxic dose range of MMS a significant amount of gammaH2AX foci was induced in S, but not G1- and G2-phase cells. A major fraction of gammaH2AX foci colocalized with 53BP1 and phosphorylated ATM, indicating they are representative of DSBs. DSB formation following MMS treatment was also demonstrated by the neutral comet assay. Repair kinetics revealed that HR mutants exhibit a significant delay in DSB repair, while NHEJ mutants completed S-phase specific DSB repair with a kinetic similar to the wildtype. Moreover, DNA-PKcs inhibition in HR mutants did not affect the repair kinetics after MMS treatment. Overall, the data indicate that agents producing N-alkylpurines in the DNA induce replication-dependent DSBs. Further, they show that HR is the major pathway of protection of cells against DSB formation, killing and genotoxicity following S(N)2-alkylating agents. PMID- 20708983 TI - A closer look at bibliometrics. PMID- 20708984 TI - Determination of esmolol and metabolite enantiomers within human plasma using chiral column chromatography. AB - A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of each of esmolol's enantiomers at the 25-1000 ng/ml concentrations observed in human plasma upon intravenous administration of this rapidly metabolized beta-adrenergic receptor blocking agent. Alternatively, a high performance liquid chromatography (HPLC) UV detection method has been developed for the simultaneous determination of each of the enantiomers for esmolol's metabolite which, in turn, achieve 2.5-50 microg/ml concentrations in human plasma. Utilizing chiral columns, these methods do not require a precolumn asymmetric derivatization step. Linearity in all cases was >0.99. Precision and accuracy at all but the lowest concentrations were within +/ 6% for the esmolol enantiomers and within +/-2.5% for the esmolol metabolite enantiomers. These values should be suitable for performing thorough pharmacokinetic studies for all of the stereoisomers of this prototypical soft drug and its corresponding metabolite. PMID- 20708985 TI - Duodenal submucosal tunnelization by fishbone. PMID- 20708986 TI - Toe syndactyly revisited. AB - INTRODUCTION: Toe syndactyly affects around 1/2000 people and is associated with significant psychological morbidity. There are multiple techniques of toe syndactyly repair described in the literature which is indicative that as yet, no one method has proved superior to others. Here we describe the technique we employ and present results of surgery including a review of patient satisfaction. METHODS: We use a modification of the technique originally described by Mondolfi using interdigitating triangular skin flaps to recreate the web space and a split thickness skin graft harvested from the instep to address the skin shortage. Patient satisfaction data were collected using a multiple response 10 point modified Likert scale questionnaire. RESULTS: 15 patients and 19 conjoined toes were operated on by a single surgeon with an average follow up time of 16.3 months (range 3-30 months). Overall satisfaction with the procedure was high with a significant increase in satisfaction from 1.3/10 preoperatively to 9.3/10 post operatively. Furthermore, patients were found to have a significant reduction in concern about their condition from a preoperative score of 8.67 to score of 0.67 following surgery (p < 0.05). Of the 19 toes divided, we had 1 skin graft failure, 1 case of mild web creep and all donor sites healed well. CONCLUSIONS: This is a simple technique that avoids unsightly dorsal scars and the glabrous skin graft provides excellent colour match with minimal morbidity. Complication rates seen with this technique are comparable or superior to those seen with other techniques already described in the literature. Toe syndactyly can be a relatively under treated condition and we have shown that offering these patients surgery can result in a highly satisfied patient group. PMID- 20708987 TI - Common peroneal nerve injury during a straight leg raising test, the result of an intraneural ganglion. AB - We report a case of iatrogenic common peroneal nerve (CPN) injury during a straight-leg raising test. Significant swelling in the CPN was observed on ultrasound, most likely due to the loss of the normal fascicular pattern. A postoperative pathological diagnosis indicated a sheath ganglion and high degree of mucinous degeneration of the CPN. A follow-up 3 months after the operation showed marked improvement in the patient's symptoms, corroborated by an electromyogram. PMID- 20708988 TI - Increased survival of free fat grafts with platelet-rich plasma in rabbits. AB - BACKGROUND: Numerous applications of autogenous platelet-rich plasma (PRP) have been studied so far; however, its property of enhancing the survival of free fat grafts has not been defined yet. In the literature, many reports are anecdotal and few include controls to definitely determine the role played by PRP in these grafts. OBJECTIVE: PRP was investigated to study its effect in free fat grafts' survival in a rabbit model. MATERIAL AND METHOD: A total of 30 New Zealand male rabbits aged 6 months received 0.8 g fat tissue (harvested by scissors dissection from the scapular area of the own animal) in the ears and were randomised into two groups. Group 1 (PRP group) was given the combination of 0.8 g of free fat graft and 1 ml of PRP. Group 2 (control group) received 0.8 g of free fat graft and 1 ml of saline solution. The rabbits were followed up for a period of 6 months after the procedure and then euthanised. The grafted tissue was stained with haematoxylin-eosin and submitted to microscopical evaluation. Graft histopathology was investigated for adipocyte viability, number of blood vessels and the presence of necrosis and fibrosis. All data were statistically analysed by the differences between the study groups. RESULTS: Three major effects of the addition of PRP in the free fat graft were observed. Group 1 showed a significantly higher fat survival weight as compared with the control group (P<0.05). Histopathological investigations revealed that the number of viable adipocytes and blood vessels was higher in group 1, and still, a larger number of necrotic areas and fibrosis were detected between group 2 (P<0.05). CONCLUSION: Application of autogenous PRP can enhance free fat graft survival in rabbits. PMID- 20708989 TI - Simultaneous laser depilation and perforator-based fasciocutaneous limberg flap for pilonidal sinus reconstruction. PMID- 20708990 TI - Perforator flaps: a new option in perineal reconstruction. AB - Over the past few decades, methodological progress and better anatomical knowledge have reduced the morbidity of reconstructive surgery. Muscle-sparing flaps and perforator flaps provide the surgeon with additional options for reconstruction. Based on a review of the local flaps used for perineal reconstruction, this article describes these new solutions and presents a decision tree (based on whether abdominal incision is required or not). If laparotomy is required, abdominal flaps should be preferred. If surgical excision is performed with the patient in the prone position, then gluteal and pudendal donor sites are recommended. PMID- 20708991 TI - A case report of a chemical burn due to the misuse of glacial acetic acid. AB - As young and elastic skin is what everyone dreams of, various measures have been implemented including chemical, laser resurfacing and dermabrasion to improve the condition of ageing skin. However, the high cost of these procedures prevents the poor from having access to treatment. Glacial acetic acid is widely used as a substitute for chemical peeling because it is readily easily available and affordable. However, its use can result in a number of serious complications. A 28-year-old female patient was admitted to our hospital with deep second-degree chemical burns on her face caused by the application of a mixture of glacial acetic acid and flour for chemical peeling. During a 6-month follow-up, hypertrophic scarring developed on the both nasolabial folds despite scar management. Glacial acetic acid is a concentrated form of the organic acid, which gives vinegar its sour taste and pungent smell, and it is also an important reagent during the production of organic compounds. Unfortunately, misleading information regarding the use of glacial acetic acid for chemical peeling is causing serious chemical burns. Furthermore, there is high possibility of a poor prognosis, which includes inflammation, hypertrophic scar formation and pigmentation associated with its misuse. Therefore, we report a case of facial chemical burning, due to the misuse of glacial acetic acid, and hope that this report leads to a better understanding regarding the use of this reagent. PMID- 20708992 TI - Prospective evaluation of the outcome of velopharyngeal insufficiency therapy after pharyngeal flap, a sphincter pharyngoplasty, a double Z-plasty and simultaneous Orticochea and Furlow operations. AB - Between 2001 and 2006 treated 84 patients with VPI. The patients were qualified for pharyngeal flap, Orticochea and Furlow's operations. Since 2007-2009 there were 22 consecutive patients who were qualified for Orticochea and Furlow operations performed at the same operation-stage. The best results were obtained by using Orticochea and Furlow operations. PMID- 20708993 TI - Use of the ipsilateral breast in anterolateral chest wall reconstruction. AB - Chest wall ablative surgery often requires autologous tissue transfer to reconstruct the resulting defect. The female breast is commonly of a suitable size to provide anteromedial chest wall coverage as a pedicled dermoglandular flap. In anterolateral defects the latissimus dorsi or serratus anterior flaps are often the preferred choice, in the absence of which free tissue transfer is an alternative technique. However these options may not always be available or suitable. A 90-year-old female presented with a large chest wall mass in keeping with recurrence of oesophageal squamous cell carcinoma in the thoracotomy scar following a previous oesophagectomy. The latissimus dorsi and serratus anterior muscles were transected during the previous thoracotomy. Following complete resection, the ipsilateral breast was used as a rotational dermoglandular flap to provide coverage over the exposed ribs. The use of breast as a local flap is an alternative option in anterolateral chest wall reconstruction. PMID- 20708994 TI - Elastofibroma dorsi. AB - Elastofibromas are rare benign soft tissue tumours that are usually located between the scapula and the rib cage deep in the serratus anterior muscle. Their anatomical location, distinctive clinical symptoms and radiological characteristics set them apart from malignant soft tissue tumours. Although they are rare, it is necessary to be aware of this benign tumour to avoid unnecessary biopsies; surgical resection may, however, be recommended to obtain a differential diagnosis from malignant sarcomas. We report three cases of elastofibroma dorsi in a 48-year-old man, a 33-year-old woman and a 42-year-old man. PMID- 20708995 TI - History of cancer and mortality in community-dwelling older adults. AB - BACKGROUND: The association between a history of cancer and mortality has not been studied in a propensity-matched population of community-dwelling older adults. METHODS: Of the 5795 participants in the Cardiovascular Health Study, 827 (14%) had self-reported physician-diagnosed cancer at baseline. Propensity scores for cancer were used to assemble a cohort of 789 and 3118 participants with and without cancer respectively who were balanced on 45 baseline characteristics. Cox regression models were used to determine the association between cancer and all cause mortality among matched patients, and to identify independent predictors of mortality among unmatched cancer patients. RESULTS: Matched participants had a mean (SD) age of 74 (6) years, 57% were women, 10% were African Americans, and 38% died from all causes during 12 years of follow-up. All-cause mortality occurred in 41% and 37% of matched participants with and without a history of cancer respectively (hazard ratio when cancer was compared with no cancer, 1.16; 95% confidence interval, 1.02-1.31; P=0.019). Among those with cancer, older age, male gender, smoking, lower than college education, fair-to-poor self-reported health, coronary artery disease, diabetes mellitus, chronic kidney disease, left ventricular hypertrophy, increased heart rate, low hemoglobin and low baseline albumin were associated with increased risk of mortality. CONCLUSIONS: Among community-dwelling older adults, a history of cancer was associated with increased mortality and among those with cancer, several socio-demographic variables and morbidities predicted mortality. These findings suggest that addressing traditional risk factors for cardiovascular mortality may help improve outcomes in older adults with a history of cancer. PMID- 20708997 TI - Necrotizing fasciitis of the thigh should raise suspicion of a rectal cancer. AB - Perforation of rectal cancer usually occurs intraperitoneally. Extraperitoneal perforation is rare and usually presents as perineal sepsis, leading to diagnosis and urgent surgical management plus antibiotic therapy. We report the case of a patient presenting with a perforated rectal carcinoma which presented as necrotizing fasciitis of the right thigh. PMID- 20708996 TI - Cardiorespiratory fitness and risk of prostate cancer: findings from the Aerobics Center Longitudinal Study. AB - OBJECTIVE: To examine the association between cardiorespiratory fitness (CRF) and risk of incident prostate cancer (PrCA). METHODS: Participants were 19,042 male subjects in the Aerobics Center Longitudinal Study (ACLS), ages 20-82years, who received a baseline medical examination including a maximal treadmill exercise test between 1976 and 2003. CRF levels were defined as low (lowest 20%), moderate (middle 40%), and high (upper 40%) according to age-specific distribution of treadmill duration from the overall ACLS population. PrCA was assessed from responses to mail-back health surveys during 1982-2004. Cox proportional hazards regression models, adjusted for potential confounders, were used to compute hazard ratios (HRs), 95% confidence intervals (95% CIs), and incidence rates (per 10,000 person-years of follow-up). RESULTS: A total of 634 men reported a diagnosis of incident PrCA during an average of 9.3 +/- 7.1 years of follow-up. Adjusted HRs (95% CIs) in men with moderate and high CRF relative to low CRF were, 1.68 (1.13-2.48) and 1.74 (1.15-2.62), respectively. The positive association between CRF and PrCA was observed only in the strata of men who were not obese, had >= 1 follow-up examination, or who were diagnosed <= 1995. CONCLUSIONS: Rather than revealing a causal relationship, the unexpected positive association observed between CRF and incident PrCA is most likely due to a screening/detection bias in more fit men who also are more health-conscious. Results have important implications for understanding the health-related factors that predispose men to receive PrCA screening that may lead to over-detection of indolent disease. PMID- 20708998 TI - Long-term immunity against pertussis induced by a single nasal administration of live attenuated B. pertussis BPZE1. AB - Duration of vaccine-induced immunity plays a key role in the epidemiology and in the pattern of transmission of a vaccine-preventable disease. In the case of whooping cough, its re-emergence has been attributed, at least partly, to the waning of immunity conferred by current pertussis vaccines. We have recently developed a highly attenuated live vaccine, named BPZE1, which has been shown to be safe and to induce strong protective immunity against Bordetella pertussis infection in mice. In this study, we evaluated the long-term immunogenicity and protective efficacy induced by a single intranasal dose of BPZE1. Up to 1 year after immunization, BPZE1 showed significantly higher efficacy to protect adult and infant mice against B. pertussis infection than two administrations of an acellular pertussis vaccine (aPV). B. pertussis-specific antibodies were induced by live BPZE1 and by aPV, with increasing amounts during the first 6 months post immunization before a progressive decline. Cell-mediated immunity was also measured 1 year after immunization and showed the presence of memory T cells in the spleen of BPZE1-immunized mice. Both cell-mediated and humoral immune responses were involved in the long-lasting protection induced by BPZE1, as demonstrated by adoptive transfer experiments to SCID mice. These data highlight the potential of the live attenuated BPZE1 candidate vaccine as part of a strategy to solve the problem of waning protective immunity against B. pertussis observed with the current aPV vaccines. PMID- 20708999 TI - IRX-2 increases the T cell-specific immune response to protein/peptide vaccines. AB - Therapeutic cancer vaccines are attractive due to the prospect of specificity and their lack of toxicity; however, their clinical development has been hampered by several biologic and clinical challenges. One of the most important biologic challenges is the relative lack of effective cellular immune adjuvants. Effective physiologic immune responses are characterized by the local generation of a complex cytokine environment that activates and regulates multiple immune cell types. IRX-2 is a primary cell-derived biologic with physiological levels of multiple active cytokine components, produced under pharmaceutical standards. The hypothesis that IRX-2 amplifies the T cell response to defined antigens was assessed in mice by measuring the T cell-specific peptide response to a dominant mouse peptide (NFT) derived from human prostate-specific membrane antigen (PSMA). IRX-2 enhances the T cell response to NFT when antigens were delivered either via irradiated cells expressing human PSMA, NFT peptide in Incomplete Freund's adjuvant (IFA) or NFT peptide conjugated to KLH. The T cell-specific activity was measured in spleen or lymph nodes cells by IFN-gamma ELISpot and/or IFN-gamma secretion over 6 days or in vivo by peptide-specific delayed-type hypersensitivity reaction (DTH). Further more, a single administration of IRX-2 with the antigen was not active as compared to 4 or 9 additional administrations which were sufficient to enhance the T cell response to antigens. The influence of IRX-2 on the B cell response to ovalbumin when it was used as a carrier protein was measured by ELISA. IRX-2 was compared to a commercially available combination adjuvant (MPL+TDM in squalene/Tween 80) which based on the literature is a potent adjuvant in murine systems. In the T cell assay IRX-2 was superior to the commercially available combination adjuvant and while IRX-2 also increased antibody titer, it was not as potent as the combination adjuvant. Mice immunized with IRX-2 and antigen also exhibited delayed tumor progression following challenge with PSMA-expressing tumor cells. These studies demonstrate that IRX-2 is an immunomodulator with adjuvant activity which preferentially enhances the T cell-specific responses to tumor associated antigens. Based on these studies, IRX 2 is a candidate for evaluation as a T cell adjuvant in a variety of preclinical vaccine delivery systems as well as in human clinical trials with cancer vaccine candidates. PMID- 20709000 TI - Immunogenicity and safety of intradermal influenza vaccination in renal transplant patients who were non-responders to conventional influenza vaccination. AB - Seasonal influenza epidemics are associated with high morbidity and mortality particularly in high-risk patients. Conventionally administered influenza vaccines show reduced efficacy in populations with weakened immune systems such as solid-organ transplant patients. This study assesses the safety and immunogenicity of an intradermally administered influenza vaccine in renal transplant patients previously identified as non-responders to a licensed trivalent inactivated influenza vaccine (TIV). Renal transplant patients with low or no hemagglutination inhibiting (HI) antibody response to an A influenza (H3N2) vaccine strain were enrolled in a descriptive phase II, open-label, randomized, multicentre trial: 31 received an investigational intradermal TIV, and 31 received a conventionally administered TIV. Both vaccines contained 15 MUg hemagglutinin (HA) per strain. The 62 study subjects were selected from 201 renal transplant patients aged 18-60 years who had been vaccinated in the previous year with a conventionally administered TIV. Vaccination was safe and well tolerated by each administration route. The immunogenicity results of this descriptive study showed ID TIV vaccination to induce HI antibody responses that trended higher in renal transplant patients than conventionally administered TIV. Our results suggest that ID influenza vaccination may offer enhanced immunogenicity and protection in persons who do not respond well to conventional TIV. Further studies should be conducted in immunocompromised populations to validate the trends for higher efficacy of ID vs. conventional route of immunization against influenza. PMID- 20709002 TI - Selection and identification of malaria vaccine target molecule using bioinformatics and DNA vaccination. AB - Following a genome-wide search for a blood stage malaria DNA-based vaccine using web-based bioinformatic tools, 29 genes from the annotated Plasmodium yoelii genome sequence (www.PlasmoDB.org and www.tigr.org) were identified as encoding GPI-anchored proteins. Target genes were those with orthologues in P. falciparum, containing an N-terminal signal sequence containing hydrophobic amino acid stretch and signal P criteria, a transmembrane-like domain and GPI anchor motif. Focusing on the blood stage, we extracted mRNA from pRBCs, PCR-amplified 22 out of the 29 selected genes, and eventually cloned nine of these into a DNA vaccine plasmid, pVAX 200-DEST. Biojector-mediated delivery of the nine DNA vaccines was conducted using ShimaJET to C57BL/6 mice at a dose of 4 MUg/mouse three times at an interval of 3 weeks. Two weeks after the second booster, immunized mice were challenged with P. y. yoelii 17XL-parasitized RBCs and the level of parasitaemia, protection and survival was assessed. Immunization with one gene (PY03470) resulted in 2-4 days of delayed onset and level of parasitaemia and was associated with increased survival compared to non-immunized mice. Antibody production was, however, low following DNA vaccination, as determined by immunofluorescence assay. Recombinant protein from this gene, GPI8p transamidase related protein (rPyTAM) in PBS or emulsified with GERBU adjuvant was also used to immunize another set of C57BL/6 mice with 10-20 MUg/mouse three times at 3 week interval. Higher antibody response was obtained as determined by ELISA with similar protective effects as observed after DNA vaccination. PMID- 20709001 TI - Protective immune responses elicited by immunization with a chimeric blood-stage malaria vaccine persist but are not boosted by Plasmodium yoelii challenge infection. AB - An efficacious malaria vaccine remains elusive despite concerted efforts. Using the Plasmodium yoelii murine model, we previously reported that immunization with the C-terminal 19 kDa domain of merozoite surface protein 1 (MSP1(19)) fused to full-length MSP8 protected against lethal P. yoelii 17XL, well beyond that achieved by single or combined immunizations with the component antigens. Here, we continue the evaluation of the chimeric PyMSP1/8 vaccine. We show that immunization with rPyMSP1/8 vaccine elicited an MSP8-restricted T cell response that was sufficient to provide help for both PyMSP1(19) and PyMSP8-specific B cells to produce high and sustained levels of protective antibodies. The enhanced efficacy of immunization with rPyMSP1/8, in comparison to a combined formulation of rPyMSP1(42) and rPyMSP8, was not due to improved conformation of protective B cell epitopes in the chimeric molecule. Unexpectedly, rPyMSP1/8 vaccine-induced antibody responses were not boosted by exposure to P. yoelii 17XL infected RBCs. However, rPyMSP1/8 immunized and infected mice mounted robust responses to a diverse set of blood-stage antigens. The data support the further development of an MSP1/8 chimeric vaccine but also suggest that vaccines that prime for responses to a diverse set of parasite proteins will be required to maximize vaccine efficacy. PMID- 20709003 TI - Polio vaccines and polio immunization in the pre-eradication era: WHO position paper--recommendations. AB - This article presents the WHO recommendations on the use of polio vaccines excerpted from the recently published Polio vaccines and polio immunization in the pre-eradication era: WHO position paper. This document replaces the WHO position paper entitled Introduction of inactivated poliovirus vaccine into oral poliovirus vaccine-using countries published in the Weekly Epidemiological Record in July 2003. Footnotes to this paper provide a limited number of core references; their abstracts as well as a more comprehensive list of references may be found at http://www.who.int/immunization/documents/positionpapers/en/index.html. Grading tables which assess the quality of scientific evidence for key conclusions are also available through this link and are referenced in the position paper. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This updated paper reflects the recent recommendations of WHO's Strategic Advisory Group of Experts on immunization, or SAGE. PMID- 20709004 TI - Vaccines delivered by integration-deficient lentiviral vectors targeting dendritic cells induces strong antigen-specific immunity. AB - We report a study of an integration-deficient lentiviral vector (IDLV) enveloped with a Sindbis virus glycoprotein mutant (SVGmu) capable of selectively binding to dendritic cells (DCs) for its potential as a vaccine carrier. The in vitro assays showed that the D64V point mutation in the catalytic domain of HIV-1 integrase efficiently inhibited the integration of the transgene upon vector transduction, while the targeting specificity of the vector to preferentially transduce and mediate durable expression in DCs was maintained. Substantial immune responses in C57BL/6 mice and complete protection against a challenge with the C57BL/6 thymoma EG.7 tumor expressing a delivered ovalbumin (OVA) antigen in mice have been achieved through the direct injection of the DC-directed IDLV encoding OVA. Thus, this DC-directed IDLV system represents a promising and efficient vector platform with remarkably improved safety for the future development of DC-based immunotherapy. PMID- 20709005 TI - Efficacy, heat stability and safety of intranasally administered Bacillus subtilis spore or vegetative cell vaccines expressing tetanus toxin fragment C. AB - Bacillus subtilis strains expressing tetanus toxin fragment C (TTFC) were tested as vaccine candidates against tetanus in adult mice. Mice received three intranasal (IN) exposures to 10(9) spores or 10(8) vegetative cells of B. subtilis expressing recombinant TTFC. Immunized mice generated protective systemic and mucosal antibodies and survived challenge with 2* LD(100) of tetanus toxin. Isotype analysis of serum antibody indicated a balanced Th1/Th2 response. Lyophilized vaccines stored at 45 degrees C for >= 12 months, remained effective. Immunized conventional and SCID mice remained well, and no histological changes in brain or respiratory tract were detected. Lyophilized/reconstituted B. subtilis tetanus vaccines administered IN to mice appear safe, heat-stable, and protective against lethal tetanus challenge. PMID- 20709006 TI - The hemagglutinin-neuraminidase gene of Newcastle Disease Virus: a powerful molecular adjuvant for DNA anti-tumor vaccination. AB - Plasmid-encoded DNA vaccine is a novel and potentially powerful tool for cancer therapy. Since the strength of immune responses induced by DNA vaccine is usually rather low, a major goal in DNA vaccine development is to enhance vaccine-induced immunity. In this study, we investigated an approach based on the use of a viral surface protein with pleiotropic function as a potential immune enhancer. To this end, we prepared bicistronic DNA plasmids encoding the hemagglutinin neuraminidase (HN) protein of Newcastle Disease Virus in addition to a tumor target antigen. We demonstrate a higher tumor antigen-specific T cell-mediated immune response and a lower humoral response upon vaccination with a bicistronic DNA plasmid with incorporated HN gene. In a prophylactic immunization tumor model with the surrogate tumor antigen beta-galactosidase (beta-gal) and in a therapeutic immunization tumor model with the xenogeneic tumor antigen human Epithelial Cell Adhesion Molecule (hEpCAM), HN gene incorporation into the DNA vaccine led to better survival and tumor regression in mice. There was also cross protection in the therapeutic tumor model against a second challenge by the parental mouse mammary carcinoma cells in mice vaccinated with the bicistronic plasmids. This is the first report describing the HN protein as an immunomodulator for enhanced antigen-specific T cell responses via DNA plasmids. The results show that co-expression of HN with a tumor target antigen through bicistronic vectors ensures precise temporal and spatial co-delivery to direct anti-tumor immune responses preferentially towards Th1. PMID- 20709007 TI - CD8+ T cell response in HLA-A*0201 transgenic mice is elicited by epitopes from SARS-CoV S protein. AB - Cytotoxic CD8(+) T lymphocytes (CTLs) play an important role in antiviral immunity. Several human HLA-A*0201 restricted CTL epitopes of severe acute respiratory syndrome (SARS) spike (S) protein have been identified in HLA-A*0201 transgenic (Tg) mice, but the mechanisms and properties of immune responses are still not well understood. In this study, HLA-A*0201 Tg mice were primed intramuscularly with SARS S DNA and boosted subcutaneously with HLA-A*0201 restricted peptides. The lymphocytes from draining lymph nodes, spleens and lungs were stimulated with the cognate peptides. Three different methods (ELISA, ELISPOT and FACS) were used to evaluate the immune responses during short and long periods of time after immunization. Results showed that peptide-specific CD8(+) T cells secreted IFN-gamma, TNF-alpha and IL-2 and expressed CD107a/b on cell surface. IFN-gamma(+)CD8(+) T cells and CD107a/b(+)CD8(+) T cells distributed throughout the lymphoid and non-lymphoid tissues, but the frequency of peptide-specific CD8(+) T cells was higher in lungs than in spleens and lymph nodes. The phenotype of the CD8(+) T cells was characterized based on the expression of IFN-gamma. Most of the HLA-A*0201 restricted peptide-specific CD8(+) T cells represented a memory subset with CD45RB(high) and CD62L(low). Taken together, these data demonstrate that immunization with SARS S DNA and HLA A*0201 restricted peptides can elicit antigen-specific CD8(+) T cell immune responses which may have a significant implication in the long-term protection. We provide novel information in cellular immune responses of SARS S antigen specific CD8(+) T cells, which are important in the development of vaccine against SARS-CoV infection. PMID- 20709008 TI - Functional immunogenicity of baculovirus expressing Pfs25, a human malaria transmission-blocking vaccine candidate antigen. AB - We have focused on development of a novel vaccine vector based on "Baculophage", a baculovirus display system for expression of proteins on the surface of the viral envelope, as a non-pathogenic and non-vertebrate insect virus. In the present study, recombinant baculovirus (AcNPV-Pfs25surf) were generated, which displayed Pfs25, a potent Plasmodium falciparum transmission-blocking vaccine candidate. Both intranasal and intramuscular immunizations of mice with AcNPV Pfs25surf induced high levels of Pfs25-specific antibodies, which strongly reacted with ookinetes of transgenic Plasmodium berghei expressing Pfs25 (TrPfs25Pb). Importantly, sera obtained from immunized rabbits exhibited a significant transmission-blocking effect (>90% reduction in infection intensity) in standard membrane feeding assay using P. falciparum gametocytes. Additionally, active immunization (both intranasal and intramuscular routes) of mice followed by challenge using TrPfs25Pb demonstrated an effective transmission-blocking response, with an 83% (intranasal) and ~95% (intramuscular) reduction in oocyst intensity, respectively. Thus, the baculovirus-based vaccines offer a promising new alternative to current human vaccine delivery platforms for the development of malaria multi-stage vaccines. PMID- 20709009 TI - Genetically modified Bifidobacterium displaying Salmonella-antigen protects mice from lethal challenge of Salmonella Typhimurium in a murine typhoid fever model. AB - We developed a novel vaccine platform utilizing Bifidobacterium as an antigen delivery vehicle for mucosal immunization. Genetically modified Bifidobacterium longum displaying Salmonella-flagellin on the cell surface was constructed for the oral typhoid vaccine. The efficiency of this vaccine was evaluated in a murine model of typhoid fever. We then orally administered 2.5 * 10(7) CFU of the recombinant Bifidobacterium longum (vaccine) or parental Bifidobacterium longum, or PBS to BALB/C mice every other day for 2 weeks. After the administration, a total of 42 mice (14 mice in each group) were challenged with Salmonella Typhimurium (1.0 * 10(7) CFU/mouse). While 12 mice in the PBS group, and 9 in the parental Bifidobacterium longum group died (median survival: 14 and 25 days), only two in the vaccine group died. These data support that our genetically modified Bifidobacterium antigen delivery system offers a promising vaccine platform for inducing efficient mucosal immunity. PMID- 20709010 TI - Immunogenic properties of chimeric protein from espA, eae and tir genes of Escherichia coli O157:H7. AB - Enterohemorrhagic Escherichia coli (EHEC) comprise an important group of enteric pathogens causing hemorrhagic colitis and hemolytic uremic syndrome. These bacteria need EspA (E) as a conduct for Tir (T) delivery to the host cell and surface arrayed intimin (I) which docks the bacterium to the translocated Tir. This phenomenon leads to attaching and effacing (A/E) lesions. A trivalent recombinant protein called rEIT composed of immunologically important portions of EspA, Intimin and Tir was constructed as a candidate vaccine. For high-level expression, the EIT gene was synthesized with codon bias of E. coli. The immunization was conducted in mice with purified rEIT. The results showed that this chimeric protein induced strong humoral response as well as protection against live challenges using EHEC. PMID- 20709012 TI - Trace detection of picloram using an electrochemical immunosensor based on three dimensional gold nanoclusters. AB - Picloram, a herbicide widely used for broadleaf weed control, is persistent and mobile in soil and water with adverse health and environmental effects. It is important to develop a sensitive method for accurate detection of trace picloram in the environment. In this article, a type of ordered three-dimensional (3D) gold (Au) nanoclusters obtained by two-step electrodeposition using the spatial obstruction/direction of the polycarbonate membrane is reported. Bovine serum albumin (BSA)-picloram was immobilized on the 3D Au nanoclusters by self assembly, and then competitive immunoreaction with picloram antibody and target picloram was executed. The horseradish peroxidase (HRP)-labeled secondary antibody was applied for enzyme-amplified amperometric measurement. The electrodeposited Au nanoclusters built direct electrical contact and immobilization interface with protein molecules without postmodification and positioning. Under the optimal conditions, the linear range for picloram determination was 0.001-10 MUg/ml with a correlation coefficient of 0.996. The detection and quantification limits were 5.0 * 10(-4) and 0.0021 MUg/ml, respectively. Picloram concentrations in peach and excess sludge supernatant extracts were tested by the proposed immunosensor, which exhibited good precision, sensitivity, selectivity, and storage stability. PMID- 20709011 TI - Diversity and prevalence of the C-terminal region of Plasmodium falciparum merozoite surface protein 1 in China. AB - Malaria continues to be a significant health concern for regions of southeastern Asia. Scientists have focused much effort on the development and regional testing of a vaccine against the most virulent of the pathogens that cause the disease, Plasmodium falciparum. The 19kDa COOH-terminal region of the merozoite surface protein 1 (PfMSP1-19) is considered to be a potentially important component of a malaria vaccine and yet, to date, there is little data from China with regard to Pfmsp1-19 diversity. We have collected samples from 300 individuals diagnosed with P. falciparum infections from Yunnan and Hainan provinces--two potential vaccine trial sites in China. We determined the sequence of DNA encoding PfMSP1 19 for each. We identified seven polymorphic positions; varying arrangements of which accounted for 10 distinct Pfmsp1-19 haplotypes. Four haplotypes, however, represented more than 93% of the total. Differences in the prevalence of haplotypes between Yunnan and Hainan provinces were observed, even though the distribution of haplotypes in Yunnan province seemed to be very similar to those reported for Vietnam and Thailand. These results provide necessary information for the design of a major human vaccine trial as well as a basis for subsequent interpretations of the results. On broader scale, the data should complement the existing database on the prevalence and distribution of Pfmsp1-19 haplotypes and therefore have potential use in the design of PfMSP1-19-based polyvalent vaccines for use in Southeastern Asian countries. PMID- 20709013 TI - Novel methoxy-carotenoids from the burgundy-colored plumage of the Pompadour Cotinga Xipholena punicea. AB - Recent advances in the fields of chromatography, mass spectrometry, and chemical analysis have greatly improved the efficiency with which carotenoids can be extracted and analyzed from avian plumage. Prior to these technological developments, Brush (1968) concluded that the burgundy-colored plumage of the male pompadour Cotinga Xipholena punicea is produced by a combination of blue structural color and red carotenoids, including astaxanthin, canthaxanthin, isozeaxanthin, and a fourth unidentified, polar carotenoid. However, X. punicea does not in fact exhibit any structural coloration. This work aims to elucidate the carotenoid pigments of the burgundy color of X. punicea plumage using advanced analytical methodology. Feathers were collected from two burgundy male specimens and from a third aberrant orange-colored specimen. Pigments were extracted using a previously published technique (McGraw et al. (2005)), separated by high-performance liquid chromatography (HPLC), and analyzed by UV/Vis absorption spectroscopy, chemical analysis, mass spectrometry, nuclear magnetic resonance (NMR), and comparison with direct synthetic products. Our investigation revealed the presence of eight ketocarotenoids, including astaxanthin and canthaxanthin as reported previously by Brush (1968). Six of the ketocarotenoids contained methoxyl groups, which is rare for naturally-occurring carotenoids and a novel finding in birds. Interestingly, the carotenoid composition was the same in both the burgundy and orange feathers, indicating that feather coloration in X. punicea is determined not only by the presence of carotenoids, but also by interactions between the bound carotenoid pigments and their protein environment in the barb rami and barbules. This paper presents the first evidence of metabolically-derived methoxy-carotenoids in birds. PMID- 20709014 TI - Regulation of cell proliferation and apoptosis through fibrocystin-prosaposin interaction. AB - Mutations in PKHD1 (polycystic kidney and hepatic disease gene 1) gene cause the autosomal recessive polycystic kidney disease (ARPKD). It is widely accepted that cystogenesis is owing to aberrant cell proliferation and apoptosis, increased fluid secretion, and extracellular matrix abnormality. Fibrocystin/polyductin (FPC), the encoded protein product by PKHD1, is a single transmembrane protein and believed to be a novel receptor-like molecule. FPC has been located mainly on the plasma membrane and cilium/basal body. However, its biological functions remain poorly understood. To investigate the roles of FPC in the pathogenesis of ARPKD, we searched for FPC-interacting proteins by yeast two-hybrid assay, and found a novel partner, prosaposin. Prosaposin is a glycoprotein with multiple functions. With GST pull-down assay and co-immunoprecipitation, we confirmed the interaction between FPC and prosaposin. In order to study the effects of FPC prosaposin interaction on cell proliferation and apoptosis, we have made stable cell lines in which FPC was overexpressed or knocked down alone or in combination with prosaposin overexpression. By MTT assay, we found that FPC knockdown and prosaposin overexpression increased cell proliferation, respectively, while overexpression of FPC C-tail did the opposite. With apoptosis assay, we found that overexpression of FPC C-tail promoted cell apoptosis. However, overexpression of prosaposin significantly enhanced cell survival in FPC knockdown cells. All these findings indicated that FPC and prosaposin may play significant roles in regulation of cell proliferation and apoptosis. Taken together, we have disclosed a novel signaling pathway of FPC, which may be important for the pathogenesis of ARPKD. PMID- 20709015 TI - Dynamics of glucosamine-6-phosphate synthase catalysis. AB - Glucosamine-6P synthase, which catalyzes glucosamine-6P synthesis from fructose 6P and glutamine, channels ammonia over 18A between its glutaminase and synthase active sites. The crystal structures of the full-length Escherichia coli enzyme have been determined alone, in complex with the first bound substrate, fructose 6P, in the presence of fructose-6P and a glutamine analog, and in the presence of the glucosamine-6P product. These structures represent snapshots of reaction intermediates, and their comparison sheds light on the dynamics of catalysis. Upon fructose-6P binding, the C-terminal loop and the glutaminase domains get ordered, leading to the closure of the synthase site, the opening of the sugar ring and the formation of a "closed" ammonia channel. Then, glutamine binding leads to the closure of the Q-loop to protect the glutaminase site, the activation of the catalytic residues involved in glutamine hydrolysis, the swing of the side chain of Trp74, which allows the communication between the two active sites through an "open" channel, and the rotation of the glutaminase domains relative to the synthase domains dimer. Therefore, binding of the substrates at the appropriate reaction time is responsible for the formation and opening of the ammonia channel and for the activation of the enzyme glutaminase function. PMID- 20709016 TI - Properties and tissue distribution of a novel aldo-keto reductase encoding in a rat gene (Akr1b10). AB - A recent rat genomic sequencing predicts a gene Akr1b10 that encodes a protein with 83% sequence similarity to human aldo-keto reductase (AKR) 1B10. In this study, we isolated the cDNA for the rat AKR1B10 (R1B10) from rat brain, and examined the enzymatic properties of the recombinant protein. R1B10 utilized NADPH as the preferable coenzyme, and reduced various aldehydes (including cytotoxic 4-hydroxy-2-hexenal and 4-hydroxy- and 4-oxo-2-nonenals) and alpha dicarbonyl compounds (such as methylglyoxal and 3-deoxyglucosone), showing low K(m) values of 0.8-6.1MUM and 3.7-67MUM, respectively. The enzyme also reduced glyceraldehyde and tetroses (K(m)=96-390MUM), although hexoses and pentoses were inactive and poor substrates, respectively. Among the substrates, 4-oxo-2-nonenal was most efficiently reduced into 4-oxo-2-nonenol, and its cytotoxicity against bovine endothelial cells was decreased by the overexpression of R1B10. R1B10 showed low sensitivity to aldose reductase inhibitors, and was activated to approximately two folds by valproic acid, and alicyclic and aromatic carboxylic acids. The mRNA for R1B10 was expressed highly in rat brain and heart, and at low levels in other rat tissues and skin fibroblasts. The results suggest that R1B10 functions as a defense system against oxidative stress and glycation in rat tissues. PMID- 20709017 TI - Disruption of quaternary structure in Escherichia coli dihydrodipicolinate synthase (DHDPS) generates a functional monomer that is no longer inhibited by lysine. AB - Escherichia coli dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52), a natively homotetrameric enzyme was converted to a monomeric species through the introduction of destabilising interactions at two different subunit interfaces allowing exploration of the roles of the quaternary structure in affecting catalytic competency. The double mutant DHDPS-L197D/Y107W displays gel filtration characteristics consistent with a single non-interacting monomeric species, which was confirmed by sedimentary velocity experiments. This monomer was shown to be catalytically active, but with reduced catalytic efficiency (k(cat)=9.8+/-0.5s( 1)), displaying 8% of the specific activity of the wild-type enzyme. The Michaelis constants for the substrates pyruvate and for (S)-aspartate semialdehyde increased by an order of magnitude, indicating that quaternary structure plays a significant role in substrate specificity. This monomeric species exhibited an enhanced propensity for aggregation and inactivation, indicating that whilst the oligomerization is not an intrinsic criterion for catalysis, higher oligomeric forms may benefit from both increased catalytic efficiency and diminished aggregation propensity. Furthermore, allosteric inhibition by (S)-lysine was abolished for DHDPS-L197D/Y107W, confirming the importance of the dimeric unit as the minimal functional assembly for efficient (S)-lysine binding. PMID- 20709018 TI - The simulation of interquinone charge transfer in a bacterial photoreaction center highlights the central role of a hydrogen-bonded non-heme iron complex. AB - We consider electron transfer between the quinones Q(A) and Q(B), one of the final steps in the photoinduced charge separation in the photoreaction center of Rhodobacter sphaeroides. The system is described by a model with atomic resolution using classical force fields and a carefully parameterized tight binding Hamiltonian. The rates estimated for direct interquinone charge transfer hopping involving a non-heme iron complex bridging the quinones and superexchange based on the geometry of the photochemically inactive dark state are orders of magnitude smaller than those obtained experimentally. Only if the iron complex is attached to both quinones via hydrogen bonds - as characteristic of the charge transfer active light state - the computed rate for superexchange involving the histidine ligands of the complex will become comparable to the experimental value of k(CT)=105s-1. PMID- 20709019 TI - Aldehyde dehydrogenase 1A3 is transcriptionally activated by all-trans-retinoic acid in human epidermal keratinocytes. AB - Retinoids are regulators of keratinocyte differentiation in the epidermis and important therapeutics in dermatology. The formation of the most active retinoid, all-trans-retinoic acid (RA) by oxidation of retinal is catalyzed by aldehyde dehydrogenases (ALDH), of which ALDH1A3 has been shown to be most efficient. Here we investigated the expression of ALDH1A3 in epidermal cultures. Three alternatively spliced mRNAs of ALDH1A3 were detected in skin cultures with the conventionally spliced mRNA being predominant. Among a panel of ALDH genes, only ALDH1A3 was upregulated by RA in primary keratinocytes. RA increased the expression of ALDH1A3 also in organotypic human skin cultures and in an epidermal explant in vitro whereas no upregulation was detected in dermal fibroblasts and HeLa cells. Our results indicate that the regulation of the retinoic acid metabolism in the epidermis involves transcriptional activation of ALDH1A3, possibly representing a positive feedback loop, which enhances the effect of exogenous RA. PMID- 20709020 TI - Scutellarin promotes in vitro angiogenesis in human umbilical vein endothelial cells. AB - Angiogenesis is critical to a wide range of physiological and pathological processes. Scutellarin, a major flavonoid of a Chinese herbal medicine Erigeron breviscapus (Vant.) Hand. Mazz. has been shown to offer beneficial effects on cardiovascular and cerebrovascular functions. However, scutellarin's effects on angiogenesis and underlying mechanisms are not fully elucidated. Here, we studied angiogenic effects of scutellarin on human umbilical vein endothelial cells (HUVECs) in vitro. Scutellarin was found by MTT assay to induce proliferation of HUVECs. In scutellarin-treated HUVECs, a dramatic increase in migration was measured by wound healing assay; Transwell chamber assay found significantly more invading cells in scutellarin-treated groups. Scutellarin also promoted capillary like tube formation in HUVECs on Matrigel, and significantly upregulated platelet endothelial cell adhesion molecule-1 at both mRNA and protein levels. Scutellarin's angiogenic mechanism was investigated in vitro by measuring expression of angiogenic factors associated with cell migration and invasion. Scutellarin strongly induced MMP-2 activation and mRNA expression in cultured HUVECs in a concentration-dependent manner. Taken together, these results suggest that scutellarin promotes angiogenesis and may form a basis for angiogenic therapy. PMID- 20709021 TI - Isolation and characterization of a novel peptide, osteoblast activating peptide (OBAP), associated with osteoblast differentiation and bone formation. AB - A long-standing goal in bone loss treatment has been to develop bone-rebuilding anabolic agents that can potentially be used to treat bone-related disorders. To purify and isolate a novel anabolic that acts to osteoblasts, we monitored changes in intracellular calcium concentrations ([Ca(2+)]i). We identified a novel, 24 amino-acid peptide from the rat stomach and termed this peptide osteoblast activating peptide (OBAP). Furthermore, we examined the effects of OBAP in osteoblasts. First, osteoblast differentiation markers (alkaline phosphatase [ALP], osteocalcin [OCN]) were analyzed using quantitative RT-PCR. We also examined the ALP activity in osteoblasts induced by OBAP. OBAP significantly increased the expression of osteoblast differentiation markers and the activity of ALP in vitro. Next, to address the in vivo effects of OBAP on bone metabolism, we examined the bone mineral density (BMD) of gastrectomized (Gx) rats and found that OBAP significantly increased BMD in vivo. Finally, to confirm the in vivo effects of OBAP on bone, we measured serum ALP and OCN in Gx rats and found that OBAP significantly increased serum ALP and OCN. Taken together, these results indicate that the novel peptide, OBAP, positively regulates bone formation by augmenting osteoblast differentiation. Furthermore, these results may provide a new therapeutic approach to anabolically treat bone-related disorders. PMID- 20709022 TI - Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15. AB - Several growth factors and transcription factors have been reported to play important roles in brown adipocyte differentiation and modulation of thermogenic gene expression, especially the expression of UCP1. In this study, we focused on KLF11 and KLF15, which were expressed highly in brown adipose tissue. Our data demonstrated that KLF11 and KLF15 interacted directly with the UCP1 promoter using GC-box and GT-boxes, respectively. Co-transfection of KLF11 and KLF15 in the mesenchymal stem cell line muBM3.1 during brown adipocyte differentiation enhanced the expression level of UCP1. KLF11, but not KLF15, was essential for UCP1 expression during brown adipocyte differentiation of muBM3.1. PMID- 20709023 TI - In vitro antiamyloidogenic properties of 1,4-naphthoquinones. AB - The aim of this study is to find out whether several 1,4-naphthoquinones (1,4-NQ) can interact with the amyloidogenic pathway of the amyloid precursor protein processing, particularly targeting at beta-secretase (BACE), as well as at beta amyloid peptide (Abeta) aggregation and disaggregating preformed Abeta fibrils. Compounds bearing hydroxyl groups at the quinoid (2) or benzenoid rings (5, 6) as well as some 2- and 3-aryl derivatives (11-15) showed BACE inhibitory activity, without effect on amyloid aggregation or disaggregation. The halogenated compounds 8 and 10 were selective for the inhibition of amyloid aggregation. On the other hand, 1,4-naphthoquinone (1), 6-hydroxy-1,4-naphthoquinone (4) and 2 (3,4-dichlorophenyl)-1,4-naphthoquinone (26) did not show any BACE inhibitory activity but were active on amyloid aggregation and disaggregation preformed Abeta fibrils. Juglone (5-hydroxy-1,4-naphthoquinone (3), and 3-(p-hydroxyphenyl) 5-methoxy-1,4-napththoquinone (19) were active on all the three targets. Therefore, we suggest that 1,4-NQ derivatives, specially 3 and 19, should be explored as possible drug candidates or lead compounds for the development of drugs to prevent amyloid aggregation and neurotoxicity in Alzheimer's disease. PMID- 20709024 TI - Dual oxidase in the intestinal epithelium of zebrafish larvae has anti-bacterial properties. AB - Reactive oxygen species (ROS) function in a range of physiological processes such as growth, metabolism and signaling, and also have a pathological role. Recent research highlighted the requirement for ROS generated by dual oxidase (DUOX) in host-defence responses in innate immunity and inflammatory disorders such as inflammatory bowel disease (IBD), but in vivo evidence to support this has, to date, been lacking. In order to investigate the involvement of Duox in gut immunity, we characterized the zebrafish ortholog of the human DUOX genes. Zebrafish duox is highly expressed in intestinal epithelial cells. Knockdown of Duox impaired larval capacity to control enteric Salmonella infection. PMID- 20709025 TI - An in vitro reconstitution system for the assessment of chromatin protein fluidity during Xenopus development. AB - Chromatin fluidity, which is one of the indicators of higher-order structures in chromatin, is associated with cell differentiation. However, little is known about the relationships between chromatin fluidity and cell differentiation status in embryonic development. We established an in vitro reconstitution system that uses isolated nuclei and cytoplasmic extracts of Xenopus embryos and a fluorescence recovery after photobleaching assay to measure the fluidities of heterochromatin protein 1 (HP1) and histone H1 during development. The HP1 and H1 fluidities of nuclei isolated from the tailbuds of early tadpole stage (stage 32) embryos in the cytoplasmic extracts of eggs and of late blastula stage (stage 9) embryos were higher than those in the cytoplasmic extracts of mid-neurula stage (stage 15) embryos. The HP1 fluidities of nuclei isolated from animal cap cells of early gastrula stage (stage 10) embryos and from the neural plates of neural stage (stage 20) embryos were higher than those isolated from the tailbuds of stage 32 embryos in egg extracts, whereas the HP1 fluidities of these nuclei were the same in the cytoplasmic extracts of stage 15 embryos. These results suggest that chromatin fluidity is dependent upon both cytoplasmic and nuclear factors and decreases during development. PMID- 20709026 TI - Drosophila Sld5 is essential for normal cell cycle progression and maintenance of genomic integrity. AB - Essential for the normal functioning of a cell is the maintenance of genomic integrity. Failure in this process is often catastrophic for the organism, leading to cell death or mis-proliferation. Central to genomic integrity is the faithful replication of DNA during S phase. The GINS complex has recently come to light as a critical player in DNA replication through stabilization of MCM2-7 and Cdc45 as a member of the CMG complex which is likely responsible for the processivity of helicase activity during S phase. The GINS complex is made up of 4 members in a 1:1:1:1 ratio: Psf1, Psf2, Psf3, And Sld5. Here we present the first analysis of the function of the Sld5 subunit in a multicellular organism. We show that Drosophila Sld5 interacts with Psf1, Psf2, and Mcm10 and that mutations in Sld5 lead to M and S phase delays with chromosomes exhibiting hallmarks of genomic instability. PMID- 20709027 TI - IFN-gamma activated JAK1 shifts CD40-induced cytokine profiles in human antigen presenting cells toward high IL-12p70 and low IL-10 production. AB - CD40Ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. CD40L induces activation of antigen-presenting cells (APCs) such as DCs, monocytes, B-cells and endothelial cells. However, CD40 activation alone, whilst inducing IL-10 production, is insufficient to induce interleukin (IL)-12p70 release in human APCs suggesting that additional cytokine signals (e.g. GM-CSF, IL-4 or IFN-gamma) are required for the induction of a pro inflammatory cytokine profile. We demonstrate that IFN-gamma-induced Janus kinase 1 (JAK1) enhances CD40-induced IL-12p70 release whilst simultaneously inhibiting IL-10 synthesis, resulting in a pro-inflammatory phenotype of CD40L-activated dendritic cells (DCs). JAK2 mediated enhancing effects on IL-12p70 but did not inhibit IL-10 release, whereas Tyk2 mediated inhibitory effects on IL-12p70 release in this system. The mechanism by which complementary IFN-gamma/JAK activities affect IL-12p70 production involves STAT1 activation and de novo induction of interferon-responsive factors (IRF)-1 and IRF-8. Simultaneously, JAK1 was unique in inhibiting IL-10 synthesis via STAT1 and IRF-8 with both transcription factors binding to the IL-10 promoter. We demonstrate that CD40- and JAK/STAT/IRF-signalling pathways are strictly complementary for the induction of a pro-inflammatory cytokine profile in human APCs. This suggests that a number of CD40 effects in chronic inflammatory diseases might be weakened by targeting JAK/STAT. PMID- 20709028 TI - Doxorubicin-induced cell death requires cathepsin B in HeLa cells. AB - The cysteine protease cathepsin B acts as a key player in apoptosis. Cathepsin B mediated cell death is induced by various stimuli such as ischemia, bile acids or TNFalpha. Whether cathepsin B can be influenced by anticancer drugs, however, has not been studied in detail. Here, we describe the modulation of doxorubicin induced cell death by silencing of cathepsin B expression. Previously, it was shown that doxorubicin, in contrast to other drugs, selectively regulates expression and activity of cathepsin B. Selective silencing of cathepsin B by siRNA or the cathepsin B specific inhibitor CA074Me modified doxorubicin-mediated cell death in Hela tumor cells. Both Caspase 3 activation and PARP cleavage were significantly reduced in cells lacking cathepsin B. Moreover, mitochondrial membrane permeabilization as well as the release of cytochrome C and AIF from mitochondria into cytosol induced by doxorubicin were significantly diminished in cathepsin B suppressed cells. In addition, doxorubicin associated down-regulation of XIAP was not observed in cathepsin B silenced cells. Lack of cathepsin B significantly modified cell cycle regulatory proteins such as cdk1, Wee1 and p21 without significant changes in G(1), S or G(2)M cell cycle phases maybe indicating further cell cycle independent actions of these proteins. Consequently, cell viability following doxorubicin was significantly elevated in cells with cathepsin B silencing. In summary, our data strongly suggest a role of cathepsin B in doxorubicin-induced cell death. Therefore, increased expression of cathepsin B in various types of cancer can modify susceptibility towards doxorubicin. PMID- 20709029 TI - Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: A comparative study of uptake, cell cycle and damage to cellular compartments. AB - The combretastatin A4 analogous chalcone (2E)-3-(3-hydroxy-4-methoxyphenyl)-1 (3,4,5-trimethoxyphenyl)prop-2-en-1-one 1 and its dichloridoplatinum(II) (6 aminomethylnicotinate) complex 2 were previously found to be highly active against a variety of cancer cell lines while differing in their apoptosis induction and long-term regrowth retardation (Schobert et al. [1]). Further differences were identified now. The cellular uptake of complex 2, like that of oxaliplatin, occurred mainly via organic cation transporters (OCT-1/2; ~32%) and copper transporter related proteins (Ctr1; ~24%), whereas that of chalcone 1 was dependent on endocytosis (~80%). Complex 2 was more tumour-specific than 1 concerning neural cells. This was apparent from the ratios of IC(50)(48h) values against primary astrocytes versus human glioma cells U87 (>7000 for complex 2; 55 for compound 1). In tubulin-rich neurons and 518A2 melanoma cells complex 2 disrupted microtubules and actin filaments. Cancer cells treated with 2 could repair the cytoskeletal damage but ceased to proliferate and perished. Complex 2 was particularly cytotoxic against P-gp-rich cells. It acted as a substrate for ABC-transporters of types BCRP, MRP3, and MRP1 and so was less active against the corresponding cancer cell lines. Complex 2 arrested the cell cycle of the melanoma cells in G(1) and G(2)/M phases. A fragmentation of their Golgi apparatus was observed by TEM for incubation with complex 2 but not with 1. In conclusion, unlike chalcone 1, its platinum complex 2 is highly cell line specific, is taken up via cell-controlled transporters and induces apoptosis by triggering multiple targets. PMID- 20709030 TI - miR-106b aberrantly expressed in a double transgenic mouse model for Alzheimer's disease targets TGF-beta type II receptor. AB - MicroRNAs (miRNAs) are abundantly expressed in the brain and play an important role in disorders of the brain, including Alzheimer's diseases (AD). Growing body of evidence suggests that the TGF-beta signaling pathway plays a key role in the pathogenesis of AD. However, it is unclear whether miRNAs involved in AD pathogenesis by regulating TGF-beta signaling. Here we found that miR-106b and TGF-beta type II receptor (TbetaR II) were aberrantly expressed in APPswe/PS?E9 mice (a double transgenic mouse model for AD). Sequence analysis revealed two putative binding sites for miR-106b in the 3' UTR of the TbetaR II mRNA. Our results showed that the expression of miR-106b was inversely correlated with TbetaR II protein levels and miR-106b can directly inhibit the TbetaR II translation in vitro. After induced neurodifferentiation with all-trans retinoic acid, we observed significant neurodegeneration in SH-SY5Y cells stably transfected with miR-106b. Western blot analysis revealed unchanged total Smad2/3 protein levels, but reduced phospho-Smad2/3 (p-Smad2/3) and increased Smad6/7 protein levels in the miR-106b stably transfected cell line. Exposure of SH-SY5Y cells to Abeta42 oligomers led to the expression of miR-106b was first increased and then decreased and TbetaR II levels reduced. Our in vitro results suggested that Abeta42 oligomer-induced miR-106b leads to impairment in TGF-beta signaling through TbetaR II, concomitant with retinoic acid-induced neurodegeneration in SH SY5Y cells. These results show that TbetaR II is a functional target of miR-106b and that miR-106b may influence TGF-beta signaling, thereby contributing to the pathogenesis of AD. PMID- 20709031 TI - Age-dependent modifications in the mRNA levels of the rat excitatory amino acid transporters (EAATs) at 48hour reperfusion following global ischemia. AB - This study reports the mRNA levels of some excitatory amino acid transporters (EAATs) in response to ischemia-reperfusion (I/R) in rat hippocampus and cerebral cortex. The study was performed in 3-month-old and 18-month-old animals to analyze the possible role of age in the I/R response of these transporters. The I/R resulted in a reduced transcription of both the neuronal EAAC1 (excitatory amino acid carrier-1) and the neuronal and glial GLT-1 (glial glutamate transporter 1), while the glial GLAST1a (l-glutamate/l-aspartate transporter 1a) transcription increased following I/R. The changes observed were more striking in 3-month-old animals than in 18-month-old animals. We hypothesize that increases in the GLAST1a mRNA levels following I/R insult can be explained by increases in glial cells, while the GLT-1 response to I/R mirrors neuronal changes. GLAST1a transcription increases in 3-month-old animals support the hypothesis that this transporter would be the main mechanism for extracellular glutamate clearance after I/R. Decreases in EAAC1 and GLT-1 mRNA levels would represent either neuronal changes due to the delayed neuronal death or a putative protective down regulation of these transporters to decrease the amount of glutamate inside the neurons, which would decrease their glutamate release. This study also reports how the treatment with the anti-inflammatory agent meloxicam attenuates the transcriptional response to I/R in 3-month-old rats and decreases the survival of the I/R-injured animals. PMID- 20709032 TI - Biphasic effects of the anterior cingulate cortex stimulation on glabrous skin blood flow in rats. AB - A growing body of evidence indicates that the anterior cingulate cortex (ACC) is associated with sensory, cognition and emotion processing. We have shown that electrical stimulation of rat ACC depressed the spinal cord dorsal horn neuron activity in response to noxious stimuli, possibly through a release of GABA. GABA may elicit dorsal root reflexes (DRRs) to induce peripheral vasodilatation. On the other hand, the ACC may also regulate autonomic flow via the lateral hypothalamus (LH). The goal of this work was to investigate the role of ACC in regulating autonomic activity. A laser Doppler imager was used to continuously monitor rat glabrous skin blood perfusion in both hind paws, while a simultaneous heart rate (HR) and DRRs were recorded to assess contributions of sympathetic flow and sensory afferent to the ACC-induced vascular change. Twenty-three rats were divided into three groups: a unilateral electrolytic LH lesion group (n = 6), a sham lesion group (n = 9), and a control group (neither lesion nor stimulation, n = 8). ACC stimulation induced a biphasic systemic vascular response, with an initial transient cutaneous vasoconstriction followed by a prolonged vasodilatation. Unilateral LH lesion did not alter this biphasic response. A short-term tachycardia occurred in response to the ACC stimulation, but did not correlate with the prolonged vasodilatation. No significant change in DRRs was found (in 35 fibers). ACC stimulation induced a biphasic vascular response in the skin. Data are consistent with sympathetic contribution. However, other mechanisms should also be involved. PMID- 20709033 TI - Plasminogen and plasmin in Alzheimer's disease. AB - In Alzheimer's disease, abnormal accumulation of Abeta leads to neuronal death and impaired Abeta degradation may play an important role in this accumulation. Plasmin is the key active protease in the plasminogen system and is capable of cleaving Abeta. Here we investigate plasminogen mRNA levels, plasminogen and plasmin protein levels and plasmin activity levels in post-mortem AD and control brain tissue. Plasminogen and plasmin distribution in the human brain was demonstrated by immunoperoxidase staining. Plasminogen mRNA levels were measured in 20 AD, 20 control and 15 Vascular dementia (VaD) brains by real-time PCR (RT PCR). In an expanded cohort of 38 AD and 38 control brains plasminogen and plasmin protein levels were measured by dot blot and Western blot, respectively, while plasmin activity levels were measured by fluorogenic assay. Plasminogen and plasmin were present mainly in the neurons. Plasminogen mRNA levels were unaltered in the AD or VaD groups compared to the controls. Plasminogen and plasmin protein levels were not significantly altered in AD compared to controls. Plasmin activity was reduced in AD but this did not reach statistical significance. In contrast to some studies these data do not support the involvement of plasmin in the abnormal accumulation of Abeta in AD. PMID- 20709034 TI - Physiological evidence for two classes of mitral cells in the rat olfactory bulb. AB - The spontaneous activity of mitral cells was recorded in vivo from the main olfactory bulb of freely breathing anesthetized rats. Single units recorded extracellularly from the mitral cell body layer were further identified as mitral cells by antidromic activation of the lateral olfactory tract and the posterior piriform cortex. Hierarchical cluster analysis of their spontaneous activity showed that at least two classes of mitral cells could be distinguished. A post hoc multivariate analysis of variance indicated significant differences between the two groups based on mean rate, latency, and the coefficient of variation in interspike interval. Univariate tests showed that the groups differed in mean rate, but not in latency, or in the coefficient of variation in interspike interval. Autocorrelation analysis showed that the high frequency group tended to fire in bursts. Functional implications of these putative subclasses of mitral cells are discussed. PMID- 20709035 TI - Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. AB - Male animals exhibit greater neuronal damage following focal cerebral ischemic injury in many experimental injury models, however the mechanism of this is unknown. This study used cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in male mice exposed to physiological vs. pharmacological doses of testosterone and tested the hypothesis that testosterone increases damage following global cerebral ischemia. Analysis of histological damage 72h after resuscitation revealed a complex dose-response curve for testosterone, such that low and high doses of testosterone exacerbated ischemic neuronal damage, while intermediate doses had no effect on neuronal survival. In agreement with these histological observations of neuronal damage, both low and high doses of testosterone increased sensorimotor deficit following CA/CPR compared to vehicle treated animals. Finally, the androgen receptor antagonist flutamide inhibited the increase in neuronal damage and sensorimotor impairment observed in testosterone treated mice. Our data showed that low and supra-physiological levels of testosterone increase neuronal damage following global cerebral ischemia and that blockade of androgen receptors limits this injury. Therefore, this study indicated that testosterone may have a role in determining sex-linked differences in cerebrovascular disease as well as having important health implications in clinical conditions of elevated testosterone. PMID- 20709036 TI - Relationship between methamphetamine-induced behavioral activation and hyperthermia. AB - Methamphetamine (METH) changes core temperature and induces behavioral activation. Behavioral activation is also known to change core temperature. The purpose of this report was to 1.) evaluate the extent to which the behavioral activation induced by METH showed a temporal relationship to METH-induced hyperthermia; and 2.) describe the temporal pattern of METH-induced hyperthermia over an extended dose range. Rats were treated with saline or METH (0.5 10.0mg/kg) in computer-controlled chambers with ambient temperature maintained at 24 degrees C. Continuous telemetric core temperature measurements were made during a 7h test period. Behavioral observations were made once every 15 min using an 11-point scale ranging from 0 (quiet awake) to 10 (focused licking or biting). The onset of METH-induced behavioral activation occurred at 15-30 min after treatment for all doses and preceded core temperature increases; the onset of METH-induced hyperthermia ranged from 45 min post-treatment to 120 min post treatment. This behavior-temperature delay was 15-30 min at the lowest (0.5 and 1.0mg/kg) and the highest (7.0, 8.0, and 10.0mg/kg) doses tested; the delay was increased between 1.0 and 4.0mg/kg METH (105 min delay at 4.0mg/kg) and then decreased again from 4.0 to 10.0mg/kg. The strongest relationship between core temperature and behavioral activation occurred at 180 min post-treatment. These data suggest that factors other than behavior are primarily responsible for the observed core temperature effects during the initial post-treatment period (60 min peak); possible effects from movement are masked. For the latter post treatment period (180 min peak) the stronger relationship between temperature and behavior suggests a role for movement in METH-induced hyperthermia. PMID- 20709037 TI - Isoflurane preconditioning and postconditioning in rat hippocampal neurons. AB - The volatile anesthetic isoflurane is capable of inducing preconditioning and postconditioning effects in the brain. However, the mechanisms for these neuroprotective effects are not fully understood. Here, we showed that rat hippocampal neuronal cultures exposed to 2% isoflurane for 30min at 24h before a 1h oxygen-glucose deprivation (OGD) and a 24h simulated reperfusion had a reduced lactate dehydrogenase release. Similarly, this OGD and simulated reperfusion induced lactate dehydrogenase release was attenuated by exposing the neuronal cultures to 2% isoflurane for 1h at various times after the onset of the simulated reperfusion (isoflurane postconditioning). The combination of isoflurane preconditioning and postconditioning induced a better neuroprotection than either alone. Inhibition of the calcium/calmodulin-dependent protein kinase II (CaMKII), inhibition of N-methyl d-aspartate (NMDA) receptors, or activation of adenosine A2A receptors resulted in reduction of the OGD and simulated reperfusion-induced cell injury. The combination of CaMKII inhibition and isoflurane preconditioning or postconditioning did not provide better protection than CaMKII inhibition, isoflurane preconditioning, or isoflurane postconditioning alone. The combination of NMDA receptor inhibition and isoflurane postconditioning was not better than NMDA receptor inhibition or isoflurane postconditioning alone for neuroprotection. However, the combination of adenosine A2A receptor activation with either isoflurane preconditioning or isoflurane postconditioning induced a better neuroprotective effect than adenosine A2A receptor activation, isoflurane preconditioning, or isoflurane postconditioning alone. The combination of NMDA receptor inhibition and isoflurane preconditioning caused a better neuroprotective effect than NMDA receptor inhibition or isoflurane preconditioning alone. These results suggest that isoflurane preconditioning- and postconditioning-induced neuroprotection can be additive. Isoflurane preconditioning and isoflurane postconditioning may involve CaMKII inhibition, but may not involve adenosine A2A receptor activation. Inhibition of NMDA receptors may mediate the effects of isoflurane postconditioning, but not isoflurane preconditioning. PMID- 20709038 TI - Olfactory deficit detected by fMRI in early Alzheimer's disease. AB - Alzheimer's disease (AD) is accompanied by smell dysfunction, as measured by psychophysical tests. Currently, it is unknown whether AD-related alterations in central olfactory system neural activity, as measured by functional magnetic resonance imaging (fMRI), are detectable beyond those observed in healthy elderly. Moreover, it is not known whether such changes are correlated with indices of odor perception and dementia. To investigate these issues, 12 early stage AD patients and 13 nondemented controls underwent fMRI while being exposed to each of three concentrations of lavender oil odorant. All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale-2 (DRS 2), and the Clinical Dementia Rating Scale (CDR). The blood oxygen level dependent (BOLD) signal at primary olfactory cortex (POC) was weaker in AD than in HC subjects. At the lowest odorant concentration, the BOLD signals within POC, hippocampus, and insula were significantly correlated with UPSIT, MMSE, DRS-2, and CDR scores. The BOLD signal intensity and activation volume within the POC increased significantly as a function of odorant concentration in the AD group, but not in the control group. These findings demonstrate that olfactory fMRI is sensitive to the AD-related olfactory and cognitive functional decline. PMID- 20709039 TI - Effects of estrogen and aging on the synaptic distribution of phosphorylated Akt immunoreactivity in the CA1 region of the female rat hippocampus. AB - The estrogen 17beta-estradiol (E) increases the axospinous synaptic density and plasticity in the hippocampal CA1 region of young female rats but fails to do so in aged female rats. This E stimulus on synaptic plasticity is associated with the phosphorylation-dependent activation of Akt kinase. Our previous findings demonstrated that increased estrogen levels subsequently increase phosphorylated Akt (pAkt)-immunoreactivity (-IR) within the dendritic shafts and spines of pyramidal neurons in young female rats. Therefore, because Akt can promote cell survival and growth, we tested the hypothesis that the less plastic synapses of aged female rats would contain less E-stimulated pAkt-IR. Here, young (3-4 months) and aged (22-23 months) female rats were ovariectomized 7 days prior to a 48-h administration of either vehicle or E. The pAkt-IR synaptic distribution was then analyzed using post-embedding electron microscopy. In both young and aged rats, pAkt-IR was found in dendritic spines and terminals, and pAkt-IR was particularly abundant at the post-synaptic density. Quantitative analyses revealed that the percentage of pAkt-labeled synapses was significantly greater in young rats compared to aged rats. Nonetheless, E treatment significantly increased pAkt-IR in pre- and post-synaptic profiles of both young and aged rats, although the stimulus in young rats was notably more widespread. These data support the evidence that hormone-activated signaling associated with cell growth and survival is diminished in the aged brain. However, the observation that E can still increase pAkt-IR in aged synapses presents this signaling component as a candidate target for hormone replacement therapies. PMID- 20709040 TI - Developmental expression of multidrug resistance phosphoglycoprotein (P-gp) in the mouse fetal brain and glucocorticoid regulation. AB - The multidrug resistance gene (Abcb1) protein product, phosphoglycoprotein (P-gp) is expressed on the luminal surface of capillary endothelial cells of the adult blood-brain barrier (bbb). P-gp is critical for neuroprotection as it actively pumps substrates back into the capillary lumen. The fetal brain represents a primary target for many P-gp substrates; however, the developmental expression, function and regulation of Abcb1 in the fetal brain are not well understood. Approximately 10% of pregnant women undergo synthetic glucocorticoid therapy for the management of preterm labor (PTL), though the effects of synthetic glucocorticoid on P-gp in the fetal brain are not known. We hypothesize that in the fetal brain: 1) expression and function of Abcb1 will increase with advancing gestation; 2) synthetic glucocorticoids will up-regulate the expression of Abcb1 and 3) this increased expression will correspond to a decrease in brain accumulation of P-gp substrates. Pregnant FVB dams were euthanized on embryonic day (E) 15.5 or E18.5 and fetal brains were collected and analyzed for [(3)H]digoxin accumulation or P-gp expression. In another group, pregnant FVB dams were injected daily with either dexamethasone (DEX; 0.1mg/kg or 1mg/kg) or vehicle from E9.5-E15.5 (mid-gestation) or E12.5-E18.5 (late-gestation) and analyzed on E15.5 or E18.5. Abcb1a mRNA (P<0.01) and P-gp protein increased near term, corresponding to decreased [(3)H]digoxin accumulation in the fetal brain (P<0.001). DEX treatment during mid-gestation modified Abcb1 mRNA expression and P-gp function in a dose-, gestational age-, and sex-specific manner. In conclusion, P-gp mediated protection of the fetal brain increases with advancing gestation in an isoform-specific manner. Synthetic glucocorticoid exposure can modify expression and function of multidrug-resistance in the fetal brain, and this will likely have clinical implication given the extensive use of synthetic glucocorticoid in the management of PTL. PMID- 20709041 TI - Antioxidant activity of costunolide and eremanthin isolated from Costus speciosus (Koen ex. Retz) Sm. AB - Antioxidant properties of many medicinal plants have been widely recognized and some of them have been commercially exploited. Plant derived antioxidants play a very important role in alleviating problems related to oxidative stress. The present study was aimed at assessing the antioxidant property of costunolide and eremanthin isolated from a medicinal plant Costus speciosus (Koen ex. Retz) Sm. rhizome. Experimental diabetes was induced by a single dose of STZ (60mg/kg, i.p.) injection. The oxidative stress was measured by tissue thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) content and enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in brain, liver, heart, kidney and pancreas. An increase in TBARS level, a significant reduction in GSH content along with decreased enzymatic activities of SOD, CAT, and GPx were seen in untreated diabetic rats. Administration of either costunolide (20mg/kg day) or eremanthin (20mg/kg day) for 60 days caused a significant reduction in TBARS level and a significant increase in GSH content along with increased enzymatic activities of SOD, CAT and GPx in the treated rats when compared to untreated diabetic rats. Acute toxicity test revealed the non-toxic nature of the compounds. The results indicated for the first time the protective effect of costunolide and eremanthin from oxidative stress, thus opening the way for their use in medication. PMID- 20709042 TI - INNO-LiPA HBV genotyping is highly consistent with direct sequencing and sensitive in detecting B/C mixed genotype infection in Chinese chronic hepatitis B patients and asymptomatic HBV carriers. AB - BACKGROUND: Different HBV genotypes have effect on the progression and outcome of chronic hepatitis B (CHB) and on the response to antiviral therapy. Accurate and sensitive genotyping methods are needed in clinical practice. METHODS: In this multicenter retrospective study, 504 HBV DNA positive serum or plasma samples of CHB patients or asymptomatic carriers were genotyped by INNO-LiPA HBV genotyping and direct sequencing. A part of the consistent and discrepant results were confirmed by clonal sequencing. RESULTS: Except two samples with indeterminate results by INNO-LiPA, 463 had the same genotype results by INNO-LiPA and direct sequencing with a concordance of 92.23% (463/502). However 24 had completely inconsistent results by the two methods, seven of which were confirmed by clonal sequencing as the same genotype as by direct sequencing. Fifteen samples were determined as B/C mixed genotypes by INNO-LiPA but singe B or C genotype by direct sequencing, five of which were confirmed by clonal sequencing as B/C mixed infection. Further studies showed INNO-LiPA could detect 6% of genotype B and genotype C among mixed genotype samples at HBV DNA >=3*10(3) IU/ml. CONCLUSIONS: INNO-LiPA is accurate and sensitive in detecting B, C, D and B/C mixed genotype infection in Chinese CHB patients and asymptomatic carriers. PMID- 20709043 TI - Effects of humidity on the dried-droplet sample preparation for MALDI-TOF MS peptide profiling. PMID- 20709044 TI - Enzyme-linked immunosorbent serum assays (ELISAs) for rat and human N-terminal pro-peptide of collagen type I (PINP)--assessment of corresponding epitopes. AB - OBJECTIVES: The present study describes two newly developed N-terminal pro peptides of collagen type I (PINP) competitive enzyme-linked immunosorbent assays (ELISAs) for the assessment of corresponding PINP epitopes in the rat- and human species. METHODS: Monoclonal antibodies were raised against corresponding rat and human PINP sequences and competitive assays were developed for each species. They were evaluated in relevant pre-clinical or clinical studies. RESULTS: The antibody characterizations indicated that PINP indeed was recognized. Technical robust assays were obtained. Rat PINP and tALP showed similar patterns in the gold standard osteoporosis rat ovariectomized (OVX) model. No liver contribution was observed in the liver fibrosis rat bile duct ligation model (BDL). In an osteoporosis study, the human serum PINP levels were significantly decreased after ibandronate treatment compared to placebo. CONCLUSIONS: The two corresponding PINP assays were specific and these bone turnover markers may improve translational science for the evaluation for bone-related diseases. PMID- 20709045 TI - Diagnostic performance of BNP and NT-ProBNP measurements in children with heart failure based on congenital heart defects and cardiomyopathies. AB - OBJECTIVES: To test the diagnostic performance of BNP and NT-ProBNP in children with different hemodynamic dysfunctions. DESIGN AND METHODS: Seventy children who underwent echocardiography and were classified into left and right ventricle volume and pressure overload (LVvO, LVpO, RVvO, and RVpO, respectively) and biventricular volume overload (BVvO) were enrolled. RESULTS: BNP and NT-ProBNP levels in all groups were higher than those in the control group (p<0.001, p<0.001). The increase in peptide levels was strongly correlated with the severity of heart failure (p<0.001, p<0.001). There was no significant difference in peptide levels in-between LVvO, LVpO, RVvO, RVpO and BVvO groups. Both measurements were significantly correlated (r=0.76, p<0.001) with each other. NT ProBNP showed a high sensitivity, whereas BNP showed a high specificity and accuracy. AUCs in ROC-curve were 0.97 for BNP and 0.96 for NT-ProBNP. CONCLUSIONS: NT-ProBNP may be used in screening of risk groups for cardiac failure because of its' higher sensitivity, but BNP may be specifically used in monitoring patients with heart failure. PMID- 20709046 TI - GC/MS determination of guanidinoacetate and creatine in urine: A routine method for creatine deficiency syndrome diagnosis. AB - OBJECTIVES: To further facilitate the diagnosis of creatine deficiency syndromes (CDS) a modified method was developed for the quantification of urinary creatine and guanidinoacetoacetate using gas chromatography/mass spectrometry (GC/MS) and having the additional advantage of using the same derivatizing agents, column and equipment usually used for the diagnosis of the organic acidurias in the clinical biochemistry laboratories. MATERIAL AND METHODS: Guanidinoacetic acid, creatine standard solutions and pooled urines and pathological samples were used to validate a new and simple GC/MS technique modified from reported methods; its accuracy was assessed by comparing with liquid chromatography-electrospray tandem mass spectrometry (HPLC-MS/MS) method. RESULTS: The method is precise: intra assay and inter assay variability for low and high concentrations were 3%, 6.4%/1.4%, 6.9% for creatine and 1.4%, 6.4%/0.9%, 6.9% for guanidinoacetoacetate. Agreement with HPLC/MS-MS method is good. CONCLUSION: The GC/MS modified method is fast, reliable and practical for the diagnosis of CDS using the same means as those for organic acidurias diagnosis. PMID- 20709047 TI - Heart-type fatty acid binding protein is an early marker of myocardial damage after radiofrequency catheter ablation. AB - OBJECTIVES: Radiofrequency (RF) ablation of arrhythmias induces myocardial damage and release of biomarkers. This study aimed to assess the kinetics of heart-type fatty acid-binding protein (h-FABP), a cytosolic protein released after myocardial injury incurred by both atrial and ventricular RF ablation, compared to other markers of myocardial injury. DESIGN AND METHODS: h-FABP, cTnI, CK MB(mass) and myoglobin were evaluated in 30 patients with atrial or ventricular tachyarrhythmias before, immediately after and at 3, 6 and 24h after the procedure. RESULTS: h-FABP increased immediately after the procedure in all subjects (6.6 +/- 1.2 MUg/L vs 2.7 +/- 0.3, p<0.001) but increased significantly only in ventricular ablations. The peak of h-FABP significantly correlates with the values of time for mean power of RF application in both the entire patient cohort and in ventricular ablations. CONCLUSIONS: h-FABP may be an early parameter for monitoring RF-induced lesions and the site of ablation was relevant for biomarker increase. PMID- 20709048 TI - LC-MS/MS progress in newborn screening. AB - Newborn screening programs detect treatable disorders in infants before they become symptomatic. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has greatly increased the screening possibilities by monitoring levels of amino acids and acylcarnitines. After the initial screening step, LC-MS/MS can also be used in screening positive samples as a second tier test to differentiate between true and false positive samples. As the list of disorders screened for by LC-tandem MS increases, questions arise about screening for untreatable disorders, such as some lysosomal storage diseases (LSDs). For LSDs screening methods are being developed and tested more quickly than treatments are becoming available. This goes against one of the main tenets of newborn screening which requires that a treatment be available. LC-MS/MS can detect several disorders with a single injection, which is important in high throughput laboratories. Measuring different amino acids and acylcarnitines can be used to detect up to 45 different inherited disorders depending on how diseases are counted. The LSD assays are designed in a similar way to detect multiple disorders with common sample preparation and a single injection. The clinical implications of applying this technology to NBS on a large scale in many jurisdictions across the world are discussed. PMID- 20709049 TI - HDL 2 particles are associated with hyperglycaemia, lower PON1 activity and oxidative stress in type 2 diabetes mellitus patients. AB - OBJECTIVES: In this study we examined the relationship of oxidative stress and hyperglycaemia to antioxidative capacity of high-density cholesterol (HDL-C) particles in type 2 diabetes mellitus (DM). DESIGN AND METHODS: Oxidative stress status parameters (superoxide anion (O2(-)), superoxide dismutase (SOD) activity and paraoxonase (PON1) status were assessed in 114 patients with type 2 DM and 91 healthy subjects. HDL particle diameters were determined by non-denaturing polyacrylamide gradient (3-31%) gel electrophoresis. RESULTS: Patients had significantly higher concentrations of oxidative stress parameter O2(-)(p<0.001) and antioxidative defence, SOD activity (p<0.001). Paraoxonase activity was significantly lower in diabetics (p<0.001). The PON1(192) phenotype distribution among study groups was not significantly different. HDL 3 phenotype was significantly prevalent among patients (p<0.001). Paraoxonase activity was significantly lower in patients with predominantly HDL 2 particles than in controls. CONCLUSIONS: The results of our current study indicate that the diabetic HDL 2 phenotype is associated with hyperglycaemia, lower PON1 activity and elevated oxidative stress. PMID- 20709050 TI - Recent advances of liquid chromatography-(tandem) mass spectrometry in clinical and forensic toxicology. AB - Liquid chromatography (LC) coupled to mass spectrometry (MS) or tandem mass spectrometry (MS/MS) has become increasingly important in clinical and forensic toxicology as well as doping control and is now a robust and reliable technique for routine analysis in these fields. In recent years, methods for LC-MS(/MS) based systematic toxicological analysis using triple quadrupole or ion trap instruments have been considerably improved and a new screening approach based on high-resolution MS analysis using benchtop time-of-flight MS instruments has been developed. Moreover, many applications for so-called multi-target screening and/or quantification of drugs, poisons, and or their metabolites in various biomatrices have been published. The present paper will provide an overview and discuss these recent developments focusing on the literature published after 2006. PMID- 20709051 TI - The effect of UGT1A1 promoter polymorphism on bilirubin response to hydroxyurea therapy in hemoglobinopathies. AB - OBJECTIVES: Hydroxyurea is known to reduce ineffective erythropoiesis and thereby hemolysis leading to a reduction in bilirubin levels in patients with hemoglobinopathies. However, the effect of hydroxyurea on hyperbilirubinemia in relation to the UGT1A1 gene promoter polymorphism is not known in Indian patients with different hemoglobinopathies. DESIGN AND METHODS: We studied 112 patients (77 sickle cell anemia, 22 beta-thalassemia intermedia and 13 HbE-beta thalassemia) who were on hydroxyurea therapy for 2 years for their response towards hyperbilirubinemia associated with UGT1A1 promoter polymorphism. RESULTS: The patients with (TA)(7)/(TA)(7) repeats had significantly higher serum bilirubin levels than those with (TA)(6)/(TA)(6) repeats in all the groups and the reduction in serum bilirubin after hydroxyurea therapy was still higher among patients with (TA)(7)/(TA)(7) repeats when compared with (TA)(6)/(TA)(6) repeats. CONCLUSIONS: Higher bilirubin levels were associated with the (TA)(7)/(TA)(7) sequence however they did not come down to normal levels after hydroxyurea therapy. PMID- 20709052 TI - Serum 1,5-anhydroglucitol levels in patients with fulminant type 1 diabetes are lower than those in patients with type 2 diabetes. AB - OBJECTIVES: We investigated clinical relevance of serum 1,5-anhydroglucitol (1,5 AG) levels in fulminant type 1 diabetes mellitus (FT1DM) patients, because 1,5-AG is known to reflect short term glycemic control. DESIGN AND METHODS: Subjects comprised 7 patients with FT1DM and 32 patients with type 2 diabetes mellitus (T2DM) with HbA1c <8.5%. All of them have never been treated for diabetes. RESULTS: HbA(1C) showed no significant difference between both groups. On the other hand, serum 1,5-AG levels were significantly lower in the FT1DM patients than in the T2DM patients. Serum 1,5-AG levels were < 5.0 MUg/ml in 6 of 7 (86%) FT1DM patients, compared with only 1 of 32 (3%) T2DM patients. CONCLUSIONS: Serum 1,5-AG levels were lower in the FT1DM patients than in the T2DM patients. Serum 1,5-AG, but not HbA(1C), reflects short-term exacerbation of glycemia in patients with FT1DM. PMID- 20709053 TI - Characterization of the medaka (Oryzias latipes) primary ciliary dyskinesia mutant, jaodori: Redundant and distinct roles of dynein axonemal intermediate chain 2 (dnai2) in motile cilia. AB - Cilia and flagella are highly conserved organelles that have diverse motility and sensory functions. Motility defects in cilia and flagella result in primary ciliary dyskinesia (PCD). We isolated a novel medaka PCD mutant, jaodori (joi). Positional cloning showed that axonemal dynein intermediate chain 2 (dnai2) is responsible for joi. The joi mutation was caused by genomic insertion of the medaka transposon, Tol1. In the joi mutant, cilia in Kupffer's vesicle (KV), an organ functionally equivalent to the mouse node in terms of left-right (LR) specification, are generated but their motility is disrupted, resulting in a LR defect. Ultrastructural analysis revealed severe reduction in the outer dynein arms in KV cilia of joi mutants. We also found the other dnai2 gene in the medaka genome. These two dnai2 genes function either redundantly or distinctly in tissues possessing motile cilia. PMID- 20709054 TI - TGFbeta signaling positions the ciliary band and patterns neurons in the sea urchin embryo. AB - The ciliary band is a distinct region of embryonic ectoderm that is specified between oral and aboral ectoderm. Flask-shaped ciliary cells and neurons differentiate in this region and they are patterned to form an integrated tissue that functions as the principal swimming and feeding organ of the larva. TGFbeta signaling, which is known to mediate oral and aboral patterning of the ectoderm, has been implicated in ciliary band formation. We have used morpholino knockdown and ectopic expression of RNA to alter TGFbeta signaling at the level of ligands, receptors, and signal transduction components and assessed the differentiation and patterning of the ciliary band cells and associated neurons. We propose that the primary effects of these signals are to position the ciliary cells, which in turn support neural differentiation. We show that Nodal signaling, which is known to be localized by Lefty, positions the oral margin of the ciliary band. Signaling from BMP through Alk3/6, affects the position of the oral and aboral margins of the ciliary band. Since both Nodal and BMP signaling produce ectoderm that does not support neurogenesis, we propose that formation of a ciliary band requires protection from these signals. Expression of BMP2/4 and Nodal suppress neural differentiation. However, the response to receptor knockdown or dominant negative forms of signal transduction components indicate signaling is not acting directly on unspecified ectoderm cells to prevent their differentiation as neurons. Instead, it produces a restricted field of ciliary band cells that supports neurogenesis. We propose a model that incorporates spatially regulated control of Nodal and BMP signaling to determine the position and differentiation of the ciliary band, and subsequent neural patterning. PMID- 20709055 TI - Ginkgolide B protects hippocampal neurons from apoptosis induced by beta-amyloid 25-35 partly via up-regulation of brain-derived neurotrophic factor. AB - Alzheimer's disease is a complex genetic disease in the global prevalence of up to 15 million people. The accumulation of beta-amyloid peptides leads to the subsequent disruption of neuronal process, abnormal phosphorylation of tau and ultimately the dysfunction and death of neurons. Ginkgolide B is a well-defined plant extract which is safe in nature, effective, economic and has minor side effects. This study aims at investigating the neuroprotective effects of Ginkgolide B against Abeta25-35-induced apoptosis in cultured hippocampal neurons, and further exploring the possible mechanisms concerned. We first conducted the study of the Abeta25-35-induced apoptosis characterized by the changes in cell viability, morphology, extracellular K(+) concentration, lactate dehydrogenase level, and the caspase-3 activity in hippocampal neurons. Moreover, the expression of brain-derived neurotrophic factor mRNA and the protein synthesis in neurons were detected via RT-PCR and Western-blot assay. It was found out that Abeta25-35-induced apoptosis was attenuated by Ginkgolide B. Ginkgolide B caused brain-derived neurotrophic factor up-regulation when cells were subjected to Abeta25-35 insults. The above results indicate that Ginkgolide B may significantly dampen Abeta25-35-induced apoptosis, and the neuroprotective effects may be intimately associated with brain-derived neurotrophic factor up regulation caused by Ginkgolide B. These findings may demonstrate the neuroprotective effects of Ginkgolide B and offer new evidences to the possible mechanisms. PMID- 20709056 TI - alphaA-Crystallin associates with alpha6 integrin receptor complexes and regulates cellular signaling. AB - alpha-Crystallins are small heat-shock proteins important to lens transparency that provide the lens with its refractive properties. In their role as molecular chaperones, these crystallins also prevent protein aggregation, affect cytoskeletal remodeling, enhance resistance to cell stress, and provide lens cells with protection against apoptosis. While many of the functions assigned to alphaA-crystallin are attributable to its presence in the cytoplasm of lens cells, alphaA-crystallin also has been detected at the lens plasma membrane. However, how alphaA-crystallin becomes linked to the plasma membrane or what its functions are at this site has remained unknown. In this study, we examined the mechanisms by which alphaA-crystallin becomes associated with the lens membrane, focusing specifically on its interaction with membrane receptors, and the differentiation-specificity of these interactions. We also determined how the long-term absence of alphaA-crystallin alters receptor-linked signaling pathways. alphaA-crystallin association with membrane receptors was determined by co immunoprecipitation analysis; its membrane localization was examined by confocal imaging; and the effect of alphaA-crystallin loss-of-function on the activation state of signaling molecules in pathways linked to membrane receptors was determined by immunoblot analysis. The results show that, in lens epithelial cells, plasma membrane alphaA-crystallin was primarily localized to apicolateral borders, reflecting the association of alphaA-crystallin with E-cadherin complexes. These studies also provide the first evidence that alphaA-crystallin maintained its association with the plasma membrane in lens cortical fiber cells, where it was localized to lateral interfaces, and further show that this association was mediated, in part, by alphaA-crystallin interaction with alpha6 integrin receptor complexes. We report that the absence of alphaA-crystallin led to constitutive activation of the stress kinases p38 and JNK, classical inducers of apoptotic cell death, and the loss of the phospho-Bad pro-survival signal, effects that were greatest in differentiating lens fiber cells. Concurrent with this, activation of FAK and ERK kinases was increased, demonstrating that these receptor-linked pathways also were dysregulated in the absence of alphaA crystallin. These data link alphaA-crystallin plasma membrane association to its differentiation-state-specific interaction with E-cadherin and alpha6 integrin receptor complexes. The changes in cell signaling in alphaA-crystallin-null lenses suggest that dysregulation of receptor-linked cell-signaling pathways that accompany the failure of alphaA-crystallin to associate with membrane receptors may be responsible for the induction of apoptosis. The observed changes in lens cell signaling likely reflect long-term functional adaptations to the absence of the alphaA-crystallin chaperone/small heat-shock protein. PMID- 20709057 TI - Mesothelial proteins are expressed in the human cornea. AB - The goal of our study was to determine whether proteins typical of the human mesothelial cell phenotype, such as mesothelin, HBME-1 (Hector Battifora mesothelial cell-1) protein and calbindin 2, are expressed in the human cornea, especially in endothelial cells. Cryosections and endothelial and epithelial imprints of sixteen human cadaverous corneoscleral discs were used. The presence of proteins was examined using immunohistochemistry and Western blotting, while mRNA levels were determined by qRT-PCR. A strong signal for mesothelin was present in the corneal epithelium, while less intense staining was visible in the endothelium. Similarly, higher and lower mRNA levels were detected using qRT-PCR in the corneal epithelium and endothelium, respectively. HBME-1 antibody strongly stained the corneal endothelium and stromal keratocytes. Marked positivity was present in the corneal stromal extracellular matrix, while no staining was present in the sclera. Calbindin 2 was detected using immunohistochemistry and Western blotting in the corneal epithelium, endothelium and stroma. qRT-PCR confirmed its expression in epithelial and endothelial cells. Three proteins expressed constitutively in mesothelial cells were detected in the human cornea. The possible function of mesothelin in cell-cell contact on the ocular surface is discussed. The presence of HBME-1 protein in the endothelial layer may indicate a still unknown function that could be shared with mesothelial cells of the pleura and peritoneum. The much more pronounced occurrence of calbindin 2 in the corneal epithelium compared to fewer positive endothelial cells explains the higher turnover of epithelial cells compared to the proliferatively inactive endothelium. PMID- 20709059 TI - Sodium channel mutations and epilepsy: association and causation. PMID- 20709060 TI - The JNK inhibitor SP600125 enhances dihydroartemisinin-induced apoptosis by accelerating Bax translocation into mitochondria in human lung adenocarcinoma cells. AB - The C-Jun N-terminal Kinase (JNK) inhibitor SP600125 is widely used to inhibit the JNK-mediated Bax activation and cell apoptosis. However, this report demonstrates that SP600125 synergistically enhances the dihydroartemisinin (DHA) induced human lung adenocarcinoma cell apoptosis by accelerating Bax translocation and subsequent intrinsic apoptotic pathway involving mitochondrial membrane depolarization, cytochrome c release, caspase-9 and caspase-3 activation. The dynamical analysis of GFP-Bax mobility inside single living cells using fluorescence recovery after photobleaching revealed that SP600125 aggravated the DHA-induced decrease of Bax mobility and Bax translocation. These results for the first time present a novel pro-apoptotic action of SP600125 in DHA-induced apoptosis. PMID- 20709058 TI - The immune response in glaucoma: a perspective on the roles of oxidative stress. AB - Neurodegenerative insults and glial activation during glaucomatous neurodegeneration initiate an immune response to restore tissue homeostasis and facilitate tissue cleaning and healing. However, increasing risk factors over a chronic and cumulative period may lead to a failure in the regulation of innate and adaptive immune response pathways and represent a route for conversion of the beneficial immunity into a neuroinflammatory degenerative process contributing to disease progression. Oxidative stress developing through the pathogenic cellular processes of glaucoma, along with the aging-related component of oxidative stress, likely plays a critical role in shifting the physiological equilibrium. This review aims to provide a perspective on the complex interplay of cellular events during glaucomatous neurodegeneration by proposing a unifying scheme that integrates oxidative stress-related risk factors with the altered regulation of immune response in glaucoma. PMID- 20709062 TI - Seasonal changes of brain GnRH-I, -II, and -III during the final reproductive period in adult male and female sea lamprey. AB - Sea lampreys are anadromous and semelparous, i.e., they spawn only once in their lifetime, after which they die. Sexual maturation is thus a synchronized process coordinated with the life stages of the lamprey. Recently, a novel gonadotropin releasing hormone, lamprey GnRH-II (lGnRH-II), was identified in lampreys and suggested to have a hypothalamic role in reproduction (Kavanaugh et al., 2008). To further understand the role of lGnRH-II, changes in ovarian morphology, brain gonadotropin-releasing hormone (lGnRH-I, -II, and -III), and plasma estradiol were examined during the final two months of the reproductive season of adult male and female sea lamprey. The results showed significant correlations between water temperature, fluctuation of brain GnRHs, plasma estradiol and reproductive stages during this time. In males, lGnRH-I concentration increased early in the season, peaked, then declined with a subsequent increase with the final maturational stages. In comparison, lGnRH-II and -III concentrations were also elevated early in the season in males, dropped and then peaked in mid-season with a subsequent decline of lGnRH-II or increase of lGnRH-III at spermiation. In females, lGnRH-III concentration peaked in mid-season with a drop at ovulation while lGnRH-I remained unchanged during the season. In contrast, lGnRH-II concentrations in females were elevated at the beginning of the season and then dropped and remained low during the rest of the season. In summary, these data provide evidence that there are seasonal and differential changes of the three GnRHs during this final reproductive period suggesting specific roles for each of the GnRHs in male and female reproduction. PMID- 20709061 TI - Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2. AB - The BET family proteins recognize acetylated chromatin through their two bromodomains, acting as transcriptional activators or tethering viral genomes to the mitotic chromosomes of their host. The structural mechanism for how the N terminal bromodomain of human BRD2 (BRD2-BD1) deciphers the mono-acetylated status of histone H4 tail was recently reported. Here we show the crystal structure of the second bromodomain of BRD2 (BRD2-BD2) in complex with the di acetylated histone H4 tail (H4K5ac/K12ac). To our surprise, a single K5ac/K12ac peptide interacts with two BRD2-BD2 molecules simultaneously: the K5ac residue binds to one BRD2-BD2 molecule while the K12ac residue binds to another. These results provide a structural basis for the recognition of two different patterns of the histone acetylation status by a single bromodomain. PMID- 20709063 TI - Eliminating the artificial effect of sample mass on avian fecal hormone metabolite concentration. AB - Avian endocrinology is a productive field that could benefit from increased application of non-invasive techniques. Although assay protocols vary, most studies that measure hormone metabolites in avian feces struggle with an artificial effect of sample mass on steroid metabolite concentration. Hormone metabolite concentrations measured in small samples are consistently higher than concentrations in larger samples, and this appears to be due to multiple methodological problems. We systematically tested several causal hypotheses for the mass effect. Based on results from these tests, we modified and validated our assay protocol to effectively eliminate the mass effect. Future studies should implement the following procedures when measuring hormone metabolites from small fecal samples (particularly of birds and reptiles): (1) remove urates from the fecal sample as completely as possible; (2) lyophilize the sample prior to extraction; (3) maximize accuracy of small mass measurements; (4) increase the volume of ethanol in the extraction to 15 ml per 0.05-0.1g of dried feces; and (5) eliminate ethanol from all samples prior to radioimmunoassay by drying down extract solutions and rehydrating in buffer. By applying these precautions we successfully eliminated the mass effect from fecal samples ranging in mass from 0.001 to 0.1 g using a radioimmunoassay commonly employed for studies of fecal glucocorticoid metabolites. These corrections also resulted in a more than 3-fold increase in effect size in glucocorticoid concentrations from a controlled test of the effects of 1h motorcycle exposure on northern spotted owls. These methods have important implications not only for avian studies, but for any study measuring hormone metabolites from small fecal samples. PMID- 20709064 TI - Physiological evidence for beta3-adrenoceptor in frog (Rana esculenta) heart. AB - beta3-Adrenergic receptors (ARs) have been recently identified in mammalian hearts where, unlike beta1- and beta2-ARs, induce cardio-suppressive effects. The aim of this study was to describe beta3-AR role in the frog (Rana esculenta) heart and to examine its signal transduction pathway. The presence of beta3-AR, by using Western blotting analysis, has been also identified. BRL(37344), a selective beta3-AR agonist, induced a dose-dependent negative inotropic effect at concentrations from 10(-12) to 10(-6)M. This effect was not modified by nadolol (beta1/beta2-AR antagonist) and by phentolamine (alpha-AR antagonist), but it was suppressed by the beta3-AR-specific antagonist SR(59230) and by exposure to the Gi/o proteins inhibitor Pertussis Toxin. In addition, the involvement of EE-NOS cGMP-PKG/PDE2 pathway in the negative inotropism of BRL(37344) has been assessed. BRL(37344) treatment induced eNOS and Akt phosphorylation as well as an increase of cGMP levels. beta3-ARs activation induce a non-competitive antagonism against ISO stimulation which disappeared in presence of PKG and PDE2 inhibition. Taken together our findings provide, for the first time in the frog, a role for beta3 ARs in the cardiac performance modulation which involves Gi/o protein and occurs via an EE-NO-cGMP-PKG/PDE2 cascade. PMID- 20709065 TI - Molecular cloning and characterization of a type 3 iodothyronine deiodinase in the pine snake Pituophis deppei. AB - The three distinct but related isotypes of the iodothyronine deiodinase family: D1, D2, and D3, have been amply studied in vertebrate homeotherms and to a lesser extent in ectotherms, particularly in reptiles. Here, we report the molecular and kinetic characteristics of both the native and the recombinant hepatic D3 from the pine snake Pituophis deppei (PdD3). The complete PdD3 cDNA (1680 bp) encodes a protein of 287 amino acids (aa), which is the longest type 3 deiodinase so far cloned. PdD3 shares 78% identity with chicken and 71% with its other orthologs. Interestingly, the hinge domain in D3s, including PdD3, is rich in proline. This structural feature is shared with D1s, the other inner-ring deiodinases, and deserves further study. The kinetic characteristics of both native and recombinant PdD3 were similar to those reported for D3 in other vertebrates. True K(m) values for T(3) IRD were 9 and 11 nM for native and recombinant PdD3, respectively. Both exhibited a requirement for a high concentration of cofactor (40 mM DTT), insensitivity to inhibition by PTU (>2 mM), and bisubstrate, sequential-type reaction kinetics. In summary, the present data demonstrate that the liver of the adult pine snake P. deppei expresses D3. Furthermore, this is the first report of the cloning and expression of a reptilian D3 cDNA. The finding of hepatic D3 expression in the adult pine snake P. deppei is consistent with results in adult piscine species in which the dietary T(3) content seems to regulate liver deiodinase expression. Thus, our present results support the proposal that hepatic D3 in adult vertebrates plays a sentinel role in avoiding an inappropriate overload of exogenous T(3) secondary to feeding in those species that devour the whole prey. PMID- 20709066 TI - Physiological actions of corticosterone and its modulation by an immune challenge in reptiles. AB - Hormones are an important interface between genome and environment, because of their ability to modulate the animal's phenotype. In particular, corticosterone, the stress hormone in lizards, is known to reallocate energy from non-essential functions to affect morphological, physiological and behavioral traits that help the organism to deal with acute or chronic stressors. However, the effects of corticosterone on life history stages are still unclear primarily because of the dependence of life history stages on both internal and external factors. Using a cross-design, we tested the effect of elevated levels of exogenous corticosterone on the physiology of pregnant females in different immune contexts in a wild population of common lizards (Lacerta vivipara). Immune challenge was induced by the injection of sheep red blood cells (SRBC) and corticosterone levels were increased using a transdermal administration of corticosterone. Thereafter, reproductive traits, metabolism and cellular immune responses were measured. The elevation of corticosterone in pregnant females significantly altered reproductive and physiological performance. The corticosterone treatment decreased clutch success, juvenile size and body condition, but enhanced measures of physiological performance, such as metabolism and catalase activity. These first results reinforce the understanding of the physiological actions of corticosterone in reptiles. The data also demonstrated different direct impacts of immune challenge by SRBC on inflammatory response and antioxidant activity. The injection of SRBC stimulated the SOD activity in larger females. Finally, we demonstrated experimentally the modulation of the corticosterone action by the immune challenge on stamina and hatching date. PMID- 20709067 TI - Colombian Trypanosoma cruzi major genotypes circulating in patients: minicircle homologies by cross-hybridization analysis. AB - Here we present compelling evidence of Trypanosoma cruzi genotypes infecting 77 human cases of Chagas disease in Santander Department of Colombia. The patients were clinically studied and classified according to the presence of cardiac symptoms. We describe the distribution of the major T. cruzi genotypes circulating in this area by means of direct PCR analysis of blood samples. PCR was directed to minicircles and amplified DNAs were hybridized using genotype specific DNA probes. These samples were previously genotyped with miniexon, 24 alpha rRNA and cytochrome oxidase subunit II (COII) markers. Minicircle DNA analyses were more sensitive than miniexon, 24 alpha rRNA and CO II genes in detecting infective T. cruzi II (Tc II). Two Tc II genotypes were identified by hybridization using two complementary DNA probes in 27.3% of the patients, with 15.3% using all three markers. These corresponded to 10 cases genotyped only by hybridization. The lineage Tc I, determined by hybridization, was the most prevalent singly or combined with different genotypes (72.7%), and at least three different T. cruzi genotypes were identified. Attempts to find two T. cruzi genotypes Tc I and Tc II in other endemic areas of Colombia revealed that one similar to the most prevalent Tc I genotype was detected in distant geographical areas. A similar Tc II genotype was found in Bolivia and Chile, revealing the great distribution of some ancestral T. cruzi genotypes. We did not detect any association between infective Tc I and Tc II lineages and the severity of the patients' cardiac symptoms. PMID- 20709068 TI - Isotopic fractionation in a large herbivorous insect, the Auckland tree weta. AB - Determining diet and trophic position of species with stable isotopes requires appropriate trophic enrichment estimates between an animal and its potential foods. These estimates are particularly important for cryptic foragers where there is little comparative dietary information. Nonetheless, many trophic enrichment estimates are based on related taxa, without confirmation of accuracy using laboratory trials. We used stable isotope analysis to investigate diet and to resolve trophic relationships in a large endemic insect, the Auckland tree weta (Hemideina thoracica White). Comparisons of isotopes in plant foods fed to captive wetas with isotope ratios in their frass provided variable results, so frass isotope values had limited usefulness as a proxy indicator of trophic level. Isotopic values varied between different tissues, with trophic depletion of (15)N highest in body fat and testes. Tissue fractionation was consistent in captive and wild caught wetas, and isotopic values were not significantly different between the two groups, suggesting that this weta species is primarily herbivorous. Whole-body values in captive wetas demonstrated trophic depletion (Deltadelta) for delta(15)N of about -0.77 0/00 and trophic enrichment of 4.28 0/00 for delta(13)C. These values differ from commonly estimated trophic enrichments for both insects and herbivores and indicate the importance of laboratory trials to determine trophic enrichment. Isotopic values for femur muscles from a number of local wild weta populations did not vary consistently with body weight or size, suggesting that juveniles eat the same foods as adults. Considerable variation among individuals within and between populations suggests that isotopic values are strongly influenced by food availability and individual foraging traits. PMID- 20709069 TI - Epigenetic transmission of phase in the desert locust, Schistocerca gregaria: determining the stage sensitive to crowding for the maternal determination of progeny characteristics. AB - Desert locust female adults respond to crowded conditions by changing progeny characteristics such as egg size, clutch size (no. of eggs per pod), hatchling body size and coloration. This study was conducted to determine the stage sensitive to crowding in this locust. Reproductively active females reared in isolation increased egg size and decreased clutch size and the proportion of green hatchlings after exposure to crowded conditions (in which each female was kept with four male adults). These changes depended not only on the timing of exposure to crowded conditions during the reproductive cycle but also on the length of the exposure. By varying the time and length of the exposure, it was found that crowding had no influence on progeny characteristics during the last two days of egg development at 31 degrees C and that there was a four-day sensitive stage before this period. The sensitive stage coincided with the time when the affected oocytes were 1.5-4mm long, while the sensitivity to crowding appeared to be constant over the sensitive stage. The larger the magnitude of the increase in egg size after exposure to crowding, the smaller the proportion of green hatchlings (and the larger the proportion of gregarized dark hatchlings); there was a sigmoidal relationship between the two variables. Based on these results, we propose a model for determining the stage sensitive to crowding in both the female parent and the oocytes. PMID- 20709070 TI - Pupal diapause of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) mediated by larval host plants: pupal weight is important. AB - Facultative diapause, a strategy that allows insects to initiate additional generations when conditions are favorable or to enter diapause when they are not, has a profound effect on the ecology and evolution of species. Most previous studies have concentrated on the role of photoperiod and temperature in inducing facultative diapause in insects. In contrast, here we studied pupal diapause mediated by larval host plants in the cotton bollworm Helicoverpa armigera, and confirmed that pupal weight is a critical factor. Two groups of third instar H. armigera larvae, kept at 25 degrees C with L:D=8:16 and 20 degrees C with photoperiod of L:D=8:16, respectively, were fed on six host plants and on artificial diet (as a control) to determine how larval host plants affect diapause incidence and related traits (such as pupal weight and developmental duration). The data showed larval host plants affected diapause incidence significantly and the effects could be masked by low temperature. Further analysis showed that pupal size, not the length of the sensitive stage, affected the decision to enter diapause. In a further experiment, third-instar to final stage larvae deprived of artificial diet for 2 days demonstrated a direct relationship between pupal weight and diapause incidence. These results suggest that larval host plants, by affecting pupal size, may influence diapause occurrence in H. armigera. This has important adaptive significance for both over wintering survival and the possibility for completing an additional generation. PMID- 20709071 TI - Antioxidant responses of citrus red mite, Panonychus citri (McGregor) (Acari: Tetranychidae), exposed to thermal stress. AB - Relatively low or high temperatures are responsible for a variety of physiological stress responses in insects and mites. Induced thermal stress was recently associated with increased reactive oxygen species (ROS) generation, which caused oxidative damage. In this study, we examined the time-related effect of the relatively low (0, 5, 10, and 15 degrees C) or high (32, 35, 38, and 41 degrees C) temperatures on the activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), peroxidases (POX), and glutathione-S transferase (GST), and the total antioxidant capacity (TEAC) of the citrus red mite, Panonychus citri (McGregor). The malondialdehyde (MDA) concentration, as a marker of lipid peroxidation in organisms, was also measured in the citrus red mite under thermal stress conditions. Results showed that SOD and GST activities were significantly increased and play an important role in the process of antioxidant response to thermal stress. Lipid peroxidation levels increased significantly (P<0.001) and changed in a time-dependent manner. CAT and POX activity, as well as TEAC, did not vary significantly and play a minor role to remove the ROS generation. These results suggest that thermal stress leads to oxidative stress and antioxidant enzymes play an important role in reducing oxidative damage in the citrus red mite. PMID- 20709072 TI - Gross and microscopic morphology of lesions in Cnidaria from Palmyra Atoll, Central Pacific. AB - We conducted gross and microscopic characterizations of lesions in Cnidaria from Palmyra Atoll, Central Pacific. We found growth anomalies (GA) to be the most commonly encountered lesion. Cases of discoloration and tissue loss were rare. GAs had a focal or multi-focal distribution and were predominantly nodular, exophytic, and umbonate. In scleractinians, the majority of GAs manifested as hyperplasia of the basal body wall (52% of cases), with an associated absence or reduction of polyp structure (mesenteries and filaments, actinopharynx and tentacles), and depletion of zooxanthellae in the gastrodermis of the upper body wall. In the soft corals Sinularia sp. and Lobophytum sp., GAs exclusively manifested as prominent hyperplasia of the coenenchyme with an increased density of solenia. In contrast to scleractinians, soft coral GAs displayed an inflammatory and necrotizing component with marked edema of the mesoglea, accompanied by infiltrates of variably-sized granular amoebocytes. Fungi, algae, sponges, and Crustacea were present in some scleractinian GAs, but absent in soft coral GAs. Fragmentation of tissues was a common finding in Acropora acuminata and Montipora cf. dilatata colonies with tissue loss, although no obvious causative agents were seen. Discoloration in the zoanthid, Palythoa tuberculosa, was found to be the result of necrosis, while in Lobophytum sp. discoloration was the result of zooxanthellar depletion (bleaching). Soft corals with discoloration or tissue loss showed a marked inflammatory response, however no obvious causative organisms were seen. Lesions that appeared similar at the gross level were revealed to be distinct by microscopy, emphasizing the importance of histopathology. PMID- 20709073 TI - ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice. AB - Pathological cardiac hypertrophy caused by diverse etiologies eventually leads to cardiac dilation and functional decompensation. We have recently reported that genetic deletion of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) inhibited several pathological events including cardiomyocyte apoptosis in compensated hypertrophic hearts. The present study investigated whether ROCK1 deficiency can prevent the transition from hypertrophy to heart failure. Transgenic mice with cardiac-restricted overexpression of Galphaq develop compensated cardiac hypertrophy at young ages, but progress into lethal cardiomyopathy accompanied by increased apoptosis after pregnancy or at old ages. The studies were first carried out using age- and pregnancy-matched wild-type, Galphaq, ROCK1(-/-), and Galphaq/ROCK1(-/-) mice. The potent beneficial effect of ROCK1 deletion is demonstrated by abolishment of peripartum mortality, and significant attenuation of left ventricular (LV) dilation, wall thinning, and contractile dysfunction in the peripartum Galphaq transgenic mice. Increase in cardiomyocyte apoptosis was suppressed by ROCK1 deletion, associated with increased extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activation and inhibition of mitochondrial translocation of Bax. In addition, ROCK1 deficiency also improved survival, inhibited cardiomyocyte apoptosis, and preserved LV dimension and function in old Galphaq mice at 12 months. Furthermore, transgenic overexpression of ROCK1 increased cardiomyocyte apoptosis and accelerated hypertrophic decompensation in Galphaq hearts in the absence of pregnancy stress. The present study provides for the first time in vivo evidence for the long-term beneficial effects of ROCK1 deficiency in hypertrophic decompensation and suggests that ROCK1 may be an attractive therapeutic target to limit heart failure progression. PMID- 20709074 TI - Adult stem cells for cardiac tissue engineering. AB - Cell therapy and tissue engineering attract increasing attention as a potential approach for cardiac repair. Adult stem cells from autologous origin are a practically safe and appealing source for cell-based regenerative therapies that may hold realistic clinical potential. A plethora of interesting concepts have been introduced aiming at regenerating ischemic myocardium through adult stem cell-based bioartificial cardiac tissue supplements. Yet, current pre-clinical concepts have not reached translational applicability, and successes are only episodic. This review will provide a brief overview of the latest concepts and breakthroughs in the emerging field of cardiac adult stem cell-based tissue engineering, and discuses the challenges that this field needs to overcome to achieve realistic therapeutic translation into the clinical arena. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". PMID- 20709075 TI - Global network analysis of lipid-raft-related proteins reveals their centrality in the network and their roles in multiple biological processes. AB - Lipid rafts are specialized cholesterol-enriched microdomains in the cell membrane. They have been known as a platform for protein-protein interactions and to take part in multiple biological processes. Nevertheless, how lipid rafts influence protein properties at the proteomic level is still an open question for researchers using traditional biochemical approaches. Here, by annotating the lipid raft localization of proteins in human protein-protein interaction networks, we performed a systematic analysis of the function of proteins related to lipid rafts. Our results demonstrated that lipid raft proteins and their interactions were critical for the structure and stability of the whole network, and that the interactions between them were significantly enriched. Furthermore, for each protein in the network, we calculated its "lipid raft dependency (LRD)," which indicates how close it is topologically associated with lipid rafts, and we then uncovered the connection between LRD and protein functions. Proteins with high LRD tended to be essential for mammalian development, and malfunction of these proteins was inclined to cause human diseases. Coordinated with their neighbors, high-LRD proteins participated in multiple biological processes and targeted many pathways in diseases pathogenesis. High-LRD proteins were also found to have tissue specificity of expression. In summary, our network-based analysis denotes that lipid raft proteins have higher centrality in the network, and that lipid-raft-related proteins have multiple functions and are probably concerned with many biological processes in disease development. PMID- 20709076 TI - Unstructured hydrophilic sequences in prokaryotic proteomes correlate with dehydration tolerance and host association. AB - Water loss or desiccation is among the most life-threatening stresses. It leads to DNA double-strand breakage, protein aggregation, cell shrinkage, and low water activity precluding all biological functions. Yet, in all kingdoms of life, rare organisms are resistant to desiccation through prevention or reversibility of such damage. Here, we explore possible hallmarks of prokaryotic desiccation tolerance in their proteomes. The content of unstructured, low complexity (LC) regions was analyzed in a total of 460 bacterial and archaeal proteomes. It appears that species endowed with proteomes abundant in unstructured hydrophilic LC regions are desiccation-tolerant or sporulating bacteria, halophilic archaea and bacteria, or host-associated species. In the desiccation- and radiation resistant bacterium Deinococcus radiodurans, most proteins that contain large hydrophilic LC regions have unassigned function, but those with known function are mostly involved in diverse cellular recovery processes. Such LC regions are typically absent in orthologous proteins in desiccation-sensitive species. D. radiodurans encodes also special LC proteins, akin to those associated with desiccation resistance of plant seeds and some plants and animals. Therefore, we postulate that large unstructured hydrophilic LC regions and proteins provide for cellular resistance to dehydration and we discuss mechanisms of their protective activity. PMID- 20709078 TI - Proteome-level interplay between folding and aggregation propensities of proteins. AB - With the advent of proteomics, there is an increasing need of tools for predicting the properties of large numbers of proteins by using the information provided by their amino acid sequences, even in the absence of the knowledge of their structures. One of the most important types of predictions concerns whether proteins will fold or aggregate. Here, we study the competition between these two processes by analyzing the relationship between the folding and aggregation propensity profiles for the human and Escherichia coli proteomes. These profiles are calculated, respectively, using the CamFold method, which we introduce in this work, and the Zyggregator method. Our results indicate that the kinetic behavior of proteins is, to a large extent, determined by the interplay between regions of low folding and high aggregation propensities. PMID- 20709077 TI - Modeling studies of chromatin fiber structure as a function of DNA linker length. AB - Chromatin fibers encountered in various species and tissues are characterized by different nucleosome repeat lengths (NRLs) of the linker DNA connecting the nucleosomes. While single cellular organisms and rapidly growing cells with high protein production have short NRL ranging from 160 to 189 bp, mature cells usually have longer NRLs ranging between 190 and 220 bp. Recently, various experimental studies have examined the effect of NRL on the internal organization of chromatin fiber. Here, we investigate by mesoscale modeling of oligonucleosomes the folding patterns for different NRL, with and without linker histone (LH), under typical monovalent salt conditions using both one-start solenoid and two-start zigzag starting configurations. We find that short to medium NRL chromatin fibers (173 to 209 bp) with LH condense into zigzag structures and that solenoid-like features are viable only for longer NRLs (226 bp). We suggest that medium NRLs are more advantageous for packing and various levels of chromatin compaction throughout the cell cycle than their shortest and longest brethren; the former (short NRLs) fold into narrow fibers, while the latter (long NRLs) arrays do not easily lead to high packing ratios due to possible linker DNA bending. Moreover, we show that the LH has a small effect on the condensation of short-NRL arrays but has an important condensation effect on medium-NRL arrays, which have linker lengths similar to the LH lengths. Finally, we suggest that the medium-NRL species, with densely packed fiber arrangements, may be advantageous for epigenetic control because their histone tail modifications can have a greater effect compared to other fibers due to their more extensive nucleosome interaction network. PMID- 20709079 TI - Quantitative proteomic analysis of ribosome assembly and turnover in vivo. AB - Although high-resolution structures of the ribosome have been solved in a series of functional states, relatively little is known about how the ribosome assembles, particularly in vivo. Here, a general method is presented for studying the dynamics of ribosome assembly and ribosomal assembly intermediates. Since significant quantities of assembly intermediates are not present under normal growth conditions, the antibiotic neomycin is used to perturb wild-type Escherichia coli. Treatment of E. coli with the antibiotic neomycin results in the accumulation of a continuum of assembly intermediates for both the 30S and 50S subunits. The protein composition and the protein stoichiometry of these intermediates were determined by quantitative mass spectrometry using purified unlabeled and (15)N-labeled wild-type ribosomes as external standards. The intermediates throughout the continuum are heterogeneous and are largely depleted of late-binding proteins. Pulse-labeling with (15)N-labeled medium time-stamps the ribosomal proteins based on their time of synthesis. The assembly intermediates contain both newly synthesized proteins and proteins that originated in previously synthesized intact subunits. This observation requires either a significant amount of ribosome degradation or the exchange or reuse of ribosomal proteins. These specific methods can be applied to any system where ribosomal assembly intermediates accumulate, including strains with deletions or mutations of assembly factors. This general approach can be applied to study the dynamics of assembly and turnover of other macromolecular complexes that can be isolated from cells. PMID- 20709080 TI - SAXS and X-ray crystallography suggest an unfolding model for the GDP/GTP conformational switch of the small GTPase Arf6. AB - The small GTPases Arf1 and Arf6 have nonoverlapping functions in cellular traffic despite their very high sequence and structural resemblance. Notably, the exquisite isoform specificity of their guanine nucleotide exchange factors and their distinctive sensitivity to the drug brefeldin A cannot be explained by any straightforward structural model. Here we integrated structural and spectroscopic methods to address this issue using Delta13Arf6-GDP, a truncated mutant that mimics membrane-bound Arf6-GDP. The crystal structure of Delta13Arf6-GDP reveals an unprecedented unfolding of the GTPase core beta-strands, which is fully accounted for by small-angle X-ray scattering data in solution and by ab initio three-dimensional envelope calculation. NMR chemical shifts identify this structural disorder in Delta13Arf6-GDP, but not in the closely related Delta17Arf1-GDP, which is consistent with their comparative thermodynamic and hydrodynamic analyses. Taken together, these experiments suggest an unfolding model for the nucleotide switch of Arf6 and shed new light on its biochemical differences with Arf1. PMID- 20709081 TI - Micelle-like architecture of the monomer ensemble of Alzheimer's amyloid-beta peptide in aqueous solution and its implications for Abeta aggregation. AB - Aggregation of amyloid-beta (Abeta) peptide, a 39- to 43-residue fragment of the amyloid precursor protein, is associated with Alzheimer's disease, the most common form of dementia in the elderly population. Several experimental studies have tried to characterize the atomic details of amyloid fibrils, which are the final product of Abeta aggregation. Much less is known about species forming during the early stages of aggregation, in particular about the monomeric state of the Abeta peptide that may be viewed as the product of the very first step in the hypothesized amyloid cascade. Here, the equilibrium ensembles of monomeric Abeta alloforms Abeta(1-40) and Abeta(1-42) are investigated by Monte Carlo simulations using an atomistic force field and implicit solvent model that have been shown previously to correctly reproduce the ensemble properties of other intrinsically disordered polypeptides. Our simulation results indicate that at physiological temperatures, both alloforms of Abeta assume a largely collapsed globular structure. Conformations feature a fluid hydrophobic core formed, on average, by contacts both within and between the two segments comprising residues 12-21 and 24-40/42, respectively. Furthermore, the 11 N-terminal residues are completely unstructured, and all charged side chains, in particular those of Glu22 and Asp23, remain exposed to solvent. Taken together, these observations indicate a micelle-like? architecture at the monomer level whose implications for oligomerization, as well as fibril formation and elongation, are discussed. We establish quantitatively the intrinsic disorder of Abeta and find the propensity to form regular secondary structure to be low but sequence specific. In the presence of a global and unspecific bias for backbone conformations to populate the beta-basin, the beta-sheet propensity along the sequence is consistent with the arrangement of the monomer within the fibril, as derived from solid-state NMR data. These observations indicate that the primary sequence partially encodes fibril structure, but that fibril elongation must be thought of as a templated assembly step. PMID- 20709083 TI - Influence of the cytoplasmic domains of aquaporin-4 on water conduction and array formation. AB - Phosphorylation of Ser180 in cytoplasmic loop D has been shown to reduce the water permeability of aquaporin (AQP) 4, the predominant water channel in the brain. However, when the structure of the S180D mutant (AQP4M23S180D), which was generated to mimic phosphorylated Ser180, was determined to 2.8 A resolution using electron diffraction patterns, it showed no significant differences from the structure of the wild-type channel. High-resolution density maps usually do not resolve protein regions that are only partially ordered, but these can sometimes be seen in lower-resolution density maps calculated from electron micrographs. We therefore used images of two-dimensional crystals and determined the structure of AQP4M23S180D at 10 A resolution. The features of the 10-A density map are consistent with those of the previously determined atomic model; in particular, there were no indications of any obstruction near the cytoplasmic pore entrance. In addition, water conductance measurements, both in vitro and in vivo, show the same water permeability for wild-type and mutant AQP4M23, suggesting that the S180D mutation neither reduces water conduction through a conformational change nor reduces water conduction by interacting with a protein that would obstruct the cytoplasmic channel entrance. Finally, the 10-A map shows a cytoplasmic density in between four adjacent tetramers that most likely represents the association of four N termini. This finding supports the critical role of the N terminus of AQP4 in the stabilization of orthogonal arrays, as well as their interference through lipid modification of cysteine residues in the longer N-terminal isoform. PMID- 20709082 TI - Visualizing the structural changes of bacteriophage Epsilon15 and its Salmonella host during infection. AB - The efficient mechanism by which double-stranded DNA bacteriophages deliver their chromosome across the outer membrane, cell wall, and inner membrane of Gram negative bacteria remains obscure. Advances in single-particle electron cryomicroscopy have recently revealed details of the organization of the DNA injection apparatus within the mature virion for various bacteriophages, including epsilon15 (E15) and P-SSP7. We have used electron cryotomography and three-dimensional subvolume averaging to capture snapshots of E15 infecting its host Salmonella anatum. These structures suggest the following stages of infection. In the first stage, the tailspikes of E15 attach to the surface of the host cell. Next, E15's tail hub attaches to a putative cell receptor and establishes a tunnel through which the injection core proteins behind the portal exit the virion. A tube spanning the periplasmic space is formed for viral DNA passage, presumably from the rearrangement of core proteins or from cellular components. This tube would direct the DNA into the cytoplasm and protect it from periplasmic nucleases. Once the DNA has been injected into the cell, the tube and portal seals, and the empty bacteriophage remains at the cell surface. PMID- 20709084 TI - NMR Structure of the SARS-CoV Nonstructural Protein 7 in Solution at pH 6.5. AB - The NMR structure of the severe acute respiratory syndrome coronavirus nonstructural protein (nsp) 7 in aqueous solution at pH 6.5 was determined and compared with the results of previous structure determinations of nsp7 in solution at pH 7.5 and in the crystals of a hexadecameric nsp7/nsp8 complex obtained from a solution at pH 7.5. All three structures contain four helices as the only regular secondary structures, but there are differences in the lengths and sequence locations of the four helices, as well as between the tertiary folds. The present study includes data on conformational equilibria and intramolecular rate processes in nsp7 in solution at pH 6.5, which provide further insights into the polymorphisms implicated by a comparison of the three presently available nsp7 structures. PMID- 20709085 TI - Non-local models for the formation of hepatocyte-stellate cell aggregates. AB - Liver cell aggregates may be grown in vitro by co-culturing hepatocytes with stellate cells. This method results in more rapid aggregation than hepatocyte only culture, and appears to enhance cell viability and the expression of markers of liver-specific functions. We consider the early stages of aggregate formation, and develop a new mathematical model to investigate two alternative hypotheses (based on evidence in the experimental literature) for the role of stellate cells in promoting aggregate formation. Under Hypothesis 1, each population produces a chemical signal which affects the other, and enhanced aggregation is due to chemotaxis. Hypothesis 2 asserts that the interaction between the two cell types is by direct physical contact: the stellates extend long cellular processes which pull the hepatocytes into the aggregates. Under both hypotheses, hepatocytes are attracted to a chemical they themselves produce, and the cells can experience repulsive forces due to overcrowding. We formulate non-local (integro-partial differential) equations to describe the densities of cells, which are coupled to reaction-diffusion equations for the chemical concentrations. The behaviour of the model under each hypothesis is studied using a combination of linear stability analysis and numerical simulations. Our results show how the initial rate of aggregation depends upon the cell seeding ratio, and how the distribution of cells within aggregates depends on the relative strengths of attraction and repulsion between the cell types. Guided by our results, we suggest experiments which could be performed to distinguish between the two hypotheses. PMID- 20709087 TI - Impact of paper filtered coffee on oxidative DNA-damage: results of a clinical trial. AB - Coffee is among the most frequently consumed beverages worldwide and epidemiological studies indicate that its consumption is inversely related to the incidence of diseases in which reactive oxygen species (ROS) are involved (liver cirrhosis, certain forms of cancer and neurodegenerative disorders). It has been postulated that antioxidant properties of coffee may account for this phenomenon. To find out if consumption of paper filtered coffee which is the most widely consumed form in Central Europe and the US protects humans against oxidative DNA damage, a controlled intervention trial with a cross-over design was conducted in which the participants (n=38) consumed 800ml coffee or water daily over 5 days. DNA-damage was measured in peripheral lymphocytes in single cell gel electrophoresis assays. The extent of DNA-migration attributable to formation of oxidised purines (formamidopyrimidine glycosylase sensitive sites) was decreased after coffee intake by 12.3% (p=0.006). Biochemical parameters of the redox status (malondialdehyde, 3-nitrotyrosine and the total antioxidant levels in plasma, glutathione concentrations in blood, intracellular ROS levels and the activities of superoxide dismutase and glutathione peroxidase in lymphocytes) were not markedly altered at the end of the trial, also the urinary 8 isoprostaglandine F2alpha concentrations were not affected. Overall, the results indicate that coffee consumption prevents endogenous formation of oxidative DNA damage in human, this observation may be causally related to beneficial health effects of coffee seen in earlier studies. PMID- 20709088 TI - Resolution of controversies in drug/receptor interactions by protein structure. Limitations and pharmacological solutions. AB - Structural biology offers breakthroughs for key issues in receptors, ion channels and transporters. Unfortunately, while knowledge is growing exponentially about receptors and drug targets, there is also an exponential knowledge of all the variables involved. A key issue for structure-based drug design is if there are distinct outcomes from a single structurally defined site. The ways in which drugs can interact with G-protein-coupled receptors (GPCRs) at the orthosteric site can be multiple, and ligands can also interact with allosteric sites. Receptors may exist as homo- or heterodimers, with the potential for distinct pharmacology, and NC-IUPHAR has proposed stringent criteria for recognition of heterodimers (Pin et al., 2007). Furthermore, some drugs have the capacity for activating different signalling cascades from a single receptor (Urban et al., 2007) indicating unique pharmacology. Thus although specific drugs were the main tool by which receptors were (and still can be, if appropriate precautions are taken) classified, drugs may also have distinct pharmacology at certain receptors depending on their chemical structure, showing drug-specific pharmacology rather than the specific-drug pharmacology which had been used in the past to define (and limit) drug classes. Primary structure is an essential but occasionally treacherous tool for defining receptors because distinct primary structures may evolve to perform similar function. This has immense implications in drug screening, and development - which also entails much testing, and selection, in pathophysiological situations. PMID- 20709086 TI - Calpain- and talin-dependent control of microvascular pericyte contractility and cellular stiffness. AB - Pericytes surround capillary endothelial cells and exert contractile forces modulating microvascular tone and endothelial growth. We previously described pericyte contractile phenotype to be Rho GTPase- and alpha-smooth muscle actin (alphaSMA)-dependent. However, mechanisms mediating adhesion-dependent shape changes and contractile force transduction remain largely equivocal. We now report that the neutral cysteine protease, calpain, modulates pericyte contractility and cellular stiffness via talin, an integrin-binding and F-actin associating protein. Digital imaging and quantitative analyses of living cells reveal significant perturbations in contractile force transduction detected via deformation of silicone substrata, as well as perturbations of mechanical stiffness in cellular contractile subdomains quantified via atomic force microscope (AFM)-enabled nanoindentation. Pericytes overexpressing GFP-tagged talin show significantly enhanced contractility (~two-fold), which is mitigated when either the calpain-cleavage resistant mutant talin L432G or vinculin are expressed. Moreover, the cell-penetrating, calpain-specific inhibitor termed CALPASTAT reverses talin-enhanced, but not Rho GTP-dependent, contractility. Interestingly, our analysis revealed that CALPASTAT, but not its inactive mutant, alters contractile cell-driven substrata deformations while increasing mechanical stiffness of subcellular contractile regions of these pericytes. Altogether, our results reveal that calpain-dependent cleavage of talin modulates cell contractile dynamics, which in pericytes may prove instrumental in controlling normal capillary function or microvascular pathophysiology. PMID- 20709089 TI - Individual differences in executive functioning modulate age effects on the ERP correlates of retrieval success. AB - The present study aimed to investigate whether the level of executive functioning modulated the effects of aging on episodic memory performance and on the electrophysiological correlates of retrieval success ('old/new effect'). We used a differential approach in which young and older adults were divided into four groups of 14 participants according to their scores on a composite executive index: young-high, young-low, old-high and old-low. ERPs were recorded while participants performed a word-stem cued-recall task. Behavioral results demonstrated that age-related deficits in memory performance were reduced but not eliminated in individuals with a higher executive functioning level. Young participants exhibited ERP old/new effects on frontal and parietal areas. At posterior sites, the effect was entirely left-sided for young-low adults while for young-high participants it was bilateral, maximal at left sites and of greater amplitude. For the old-low group, both frontally-based and parietally based processes appeared to be affected by the aging process. They also demonstrated a late frontal negative component, which might indicate an unsuccessful additional attempt to cope with retrieval difficulties. In the old high group, ERP effects on frontal areas were relatively intact while the parietal effect was impaired compared to young adults. However, old-high subjects exhibited earlier, larger and more symmetrical effects than did old-low adults, which was in line with their better memory performance. These findings provide some support for the executive decline hypothesis of cognitive aging by showing that neural correlates of retrieval success in episodic memory are differentially affected by aging according to executive functioning level. They are consistent with the view that a high executive functioning level may help older adults recruit a cerebral pattern which enables them to perform a memory task more efficiently. PMID- 20709090 TI - Orchiectomy modifies the antidepressant-like response of nicotine in the forced swimming test. AB - Several studies have demonstrated that nicotine (NIC) exhibits antidepressant like effects. In addition, it has been suggested that sexual hormones participate in the antidepressant actions of antidepressives. The present study was designed to analyze the effect of orchiectomy and the supplementation of testosterone propionate (TP) or 17beta-estradiol (E(2)) on the antidepressant properties of NIC using the forced swimming test (FST), as well as to determine possible changes in the FST during different time periods after orchiectomy. In order to evaluate the influences of orchiectomy on the effects of NIC, the study first evaluated the effects of different time periods on orchiectomized rats (15, 21, 30, 45 and 60 days) that were subjected to the FST. Then, different doses of NIC (0.2, 0.4, 0.8, 1.6 mg/kg, sc) were administered for 14 days to both intact and orchiectomized rats (after 21 day) which were then also subjected to the FST. Finally, the influence of the TP or E(2) supplementation on the antidepressant like effect of NIC on orchiectomized rats (after 21 days) was also analyzed. Results reveal that orchiectomy significantly increased immobility behavior and decreased swimming and climbing up to 60 days after castration. In contrast, NIC decreased immobility behavior and increased swimming in intact rats; whereas orchiectomy suppressed this antidepressant effect of NIC. Only with E(2) supplementation was it possible to restore the sensitivity of the castrated rats to NIC. These results suggest that E(2) was able to facilitate the antidepressant response of NIC in orchiectomized rats. PMID- 20709091 TI - Hepatically-metabolized and -excreted artificial oxygen carrier, hemoglobin vesicles, can be safely used under conditions of hepatic impairment. AB - The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbV were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings. PMID- 20709092 TI - Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition. AB - Troglitazone, a thiazolidinedione class antidiabetic drug, was withdrawn from the market because of its severe idiosyncratic hepatotoxicity. It causes a mitochondrial permeability transition (MPT), which may in part contribute to its hepatotoxicity. In the present study, the mechanism of troglitazone mitochondrial toxicity was investigated in isolated rat liver mitochondria. Mitochondrial swelling induced by 10 MUM troglitazone was attenuated by bromoenol lactone (BEL), an inhibitor of Ca2+-independent phospholipase A2 (iPLA2). In contrast, that induced by 50 MUM troglitazone was exacerbated by BEL. This exacerbation was diminished by addition of 2mM glutathione, an antioxidant. Oxygen consumption by state 3 respiration in isolated mitochondria was also decreased by troglitazone, but it was not affected by BEL. Mitochondrial swelling induced by 10 MUM troglitazone was completely attenuated in the absence of Ca2+ while that induced by 50 MUM troglitazone was not affected. Addition of 1 MUM cyclosporin A (CsA), an inhibitor of MPT pores, completely attenuated swelling induced by 10 MUM troglitazone while it only partly diminished that induced by 50 MUM troglitazone. Thus, the MPT induced by 10 and 50 MUM troglitazone are regulated by different mechanism; the MPT induced by 10 MUM troglitazone is regulated by the activation of iPLA2 and caused by the opening of CsA-regulating MPT pores followed by accumulation of Ca2+ in mitochondria, while that induced by 50 MUM troglitazone is partly regulated by reactive oxygen species and mainly caused by the opening of CsA-insensitive MPT pores. PMID- 20709094 TI - Localization of speed differences of context stimuli during fixation and smooth pursuit eye movements. AB - The visual system can detect speed changes of moving objects only by means of alterations of retinal image motion, which is also subject to changes induced by head or eye movements. Here we investigated whether smooth pursuit eye movements affect the ability to localize short speed perturbations of large context stimuli. Psychophysical thresholds for localization, discrimination and detection of speed perturbations in one of two context stimuli were measured under two main conditions: in fixation trials subjects fixated a central stationary spot, in pursuit trials they followed a horizontally moving target with their eyes. Context stimuli were vertically oriented sine wave gratings moving simultaneously above and below the fixation or pursuit target for one second in the same direction at the same or a different speed as the pursuit target. During the movement one of the gratings suddenly changed its speed for 500 ms and returned to its original speed. Observers were asked to discern the location of the speed change (two-alternative spatial forced choice task). While detection (two interval forced choice) and discrimination thresholds for the kind of speed perturbation were in the normal range of Weber fractions of 10-15%, thresholds for the location of the speed perturbation were dramatically increased to 30-50%. Localization thresholds were particularly high when the retinal motion was mainly due to the context movements as during fixation or slow pursuit and significantly reduced when the retinal motion was mainly due to pursuit. This result indicates that the origin of retinal motion, whether it is caused by object motion or by voluntary pursuit is important. We conclude that the localization of speed perturbations affecting one of two peripheral moving objects is exceedingly complicated for the visual system probably due to the dominance of relative motion. During smooth pursuit the ability to localize speed perturbations of non foveated objects seems to be improved by additional information gained from pursuit such as corollary discharge. PMID- 20709093 TI - Fitts's Law and speed/accuracy trade-offs during sequences of saccades: Implications for strategies of saccadic planning. AB - Strategies of saccadic planning must take into account both the required level of accuracy of the saccades, and the time and resources needed to plan and execute the movements. To determine relationships between accuracy and time, we studied sequences of saccades made to scan a set of stationary targets located at the corners of an imaginary square. Target separation and size varied. The time taken to complete saccadic sequences increased with the required level of precision, in agreement with the classical Fitts's Law (1954) relationship. This was mainly due to the use of error-correcting secondary saccades, whose frequency increased with target separation and decreased with target size. Increases in the time spent fixating near each target did not increase the accuracy of the next primary saccade in the sequence. Instead, secondary saccades were the principal means of correcting landing errors of primary saccades. The results are consistent with a scanning strategy that discourages careful planning of individual saccades in favor of increasing the rate of saccadic production (i.e., exploration), using secondary saccades as needed to correct saccadic landing errors. PMID- 20709095 TI - Visual responses in the lateral geniculate evoked by Cx36-independent rod pathways. AB - Emerging evidence indicates rods can communicate with retinal ganglion cells (RGCs) via pathways that do not involve gap-junctions. Here we investigated the significance of such pathways for central visual responses, using mice lacking a key gap junction protein (Cx36(-/-)) and carrying a mutation that disrupts cone phototransduction (Gnat2(cpfl3)). Electrophysiological recordings spanning the lateral geniculate revealed rod-mediated ON and OFF visual responses in virtually every cell from all major anatomical sub-compartments of this nucleus. Hence, we demonstrate that one or more classes of RGC receive input from Cx36-independent rod pathways and drive extensive ON and OFF responses across the visual thalamus. PMID- 20709097 TI - Structure and dynamics of water in native and tanned collagen fibers: Effect of crosslinking. AB - The influence of crosslinking on the hydration structure of collagen has been investigated. Nuclear magnetic resonance, dielectric relaxation and thermoporometry were used to investigate water structure in native and crosslinked collagen fibers on both wet and dried specimen. Measurements reveal the influence of different chemical treatments on the transverse relaxation time and polarization of the collagen fibers. The frequency dependence of dielectric constant of collagen fibers displays an induction behavior on low frequencies. Bound water constrained in collagen fibers seems to provide signatures for changes induced by crosslinking agents on the pore diameter and distribution in collagen fibers. A correlation of transverse relaxation time of water in dry and wet states presented in this study presents an experimental tool for examining the differences in efficacy of crosslinking agents. Changes in the dielectric relaxation, dynamics of water structure and hydroporometric structure of collagen are dependent on the nature of crosslinking material. PMID- 20709098 TI - Effect of preservatives for food grade C-Phycoerythrin, isolated from marine cyanobacteria Pseudanabaena sp. AB - C-Phycoerythrin is water soluble red color chromo-protein, which is used as a natural food colorant. The effect of selected edible preservatives like citric acid, sodium chloride, sucrose and calcium chloride on the stability of C Phycoerythrin at 0+/-5 degrees C and 35+/-5 degrees C was studied in aqueous solution. Experiment was carried out to select a stabilizing agent having Hofmeister series behavior acting on hydrophobic interactions. The denaturation of phycoerythrin with urea as denaturant and effect of different pH on C Phycoerythrin was studied. Citric acid (4 mg/ml) was observed to be one of the best preservative for C-Phycoerythrin at 35+/-5 degrees C and 0+/-5 degrees C in aqueous solution for 45 days. Citric acid was able to maintain the stability of C Phycoerythrin in the solution. The amount of C-Phycoerythrin left in the solution containing citric acid after 30 and 45 days was 46 and 37.8% respectively at higher temperature. PMID- 20709096 TI - The effect of restraint stress on prepulse inhibition and on corticotropin releasing factor (CRF) and CRF receptor gene expression in Wistar-Kyoto and Brown Norway rats. AB - Stress plays a role in many psychiatric disorders that are characterized by deficits in prepulse inhibition (PPI), a form of sensorimotor gating. Corticotropin-releasing factor (CRF) is one of the most important neurotransmitters involved in behavioral components of the stress response, and central infusion of CRF decreases PPI in rodents. We recently demonstrated that restraint stress decreases PPI and attenuates the increase in PPI caused by repeated testing. To broaden our investigation into how restraint affects PPI, we subjected Wistar-Kyoto (WKY) and Brown Norway (BN) rats to 10 consecutive days of 2-hour restraint, or to brief handling, prior to assessing PPI. We next examined the effects of 1 or 10days of 2-hour restraint on plasma corticosterone levels in order to determine whether the endocrine response to stress parallels the behavioral effect of stress. Finally, we examined the effects of 1 or 10days of 2 hour restraint on CRF and CRF receptor gene expression in the amygdala, hippocampus, frontal cortex, and hypothalamus in order to determine whether a temporal pattern of gene expression parallels the change in the behavioral response to stress. The major findings of the present study are that 1) restraint stress attenuates the increase in PPI caused by repeated testing in both WKY and BN rats, and BN rats are more sensitive to the effects of restraint on PPI than WKY rats, 2) restraint-induced increases in corticosterone levels mirror the effect of restraint on PPI in WKY rats but not in BN rats, 3) laterality effects on gene expression were observed for the amygdala, whereby restraint increases CRF gene expression in the left, but not right, amygdala, and 4) some restraint induced changes in CRF and CRF receptor gene expression precede changes in PPI while other changes coincide with altered PPI in a rat strain- and brain region dependent manner. PMID- 20709099 TI - Characterization of the cryptic plasmid pTXW from Lactobacillus paracasei TXW. AB - A cryptic plasmid from Lactobacillus paracasei TXW isolated from koumiss, designated as pTXW, was sequenced and characterized. It is 3178 bp in length with a G+C content of 42.9%. The plasmid pTXW was predicted to encode 4 putative ORFs. RepB shared high homology with initiator proteins of plasmids from the rolling circle replication (RCR) pMV158 family. copG was predicted to encode a transcriptional repressor, which was involved in plasmid copy number control together with a putative antisense RNA. Mob putatively acts as a relaxase and belongs to the MOB(V) relaxase family. Sequence analysis revealed a double strand origin (dso) located upstream the repB gene, which contained the conserved nick sequence of the pMV158 family. A putative single strand origin (sso-like) consisting of successive inverted repeats was also detected. Mung bean nuclease analysis and Southern hybridization confirmed the presence of single-stranded DNA (ssDNA) intermediates, suggesting that pTXW replicates via the RCR mechanism. Furthermore, the relative copy number of pTXW was estimated to be 73.5+/-1.2 copies in each cell by real-time PCR. The new RCR plasmid would be valuable to construct vectors for application in food industry. PMID- 20709100 TI - Genetic manipulation of Vibrio cholerae by combining natural transformation with FLP recombination. AB - Even though Vibrio cholerae is a well-known human pathogen, it is also a normal member of aquatic habitats. Within this environment it often forms biofilms on the chitin-containing exoskeleton of crustaceans and their molts. Chitin not only serves as nutrient source but also induces a developmental program called natural competence. Naturally competent bacteria take up free DNA and integrate it into their genome by homologous recombination, thereby becoming naturally transformed. In this study, we made use of the knowledge on the environmental lifestyle of V. cholerae to genetically manipulate its genome. We achieved this by combining the methods of chitin-induced natural transformation and Flp recombination. Using this approach, we disrupted several genes by insertion of FRT-site-flanked antibiotic-resistance cassettes. The cassettes were subsequently excised by induction of the Flp recombinase, which acts on the FRT sites. This method represents a simplified and faster alternative to standard gene deletion techniques, which often depend on bacterial conjugation and the availability of suicide vectors. PMID- 20709101 TI - Neural influence on cold induced vasodilatation using a new set-up for bilateral measurement in the rat hind limb. AB - Cold induced vasoconstriction (CIVC) is a way for mammals to reduce heat loss in an effort to maintain body core temperature. As blood flow to a cooled extremity is reduced, the amount of body heat lost at the cooled location is minimised. However, when the extremity temperature gets below a certain threshold, Cold induced vasodilatation (CIVD) occurs, a phenomenon that is believed to reduce the risk of local cold injuries. Many theories explaining the mechanism of the CIVD reaction have been postulated, but no consensus has been found. One of these theories is that the CIVD reaction is controlled neurally. To study the effect of neural influence on the vascularisation and rewarming patterns a new experimental set-up was designed. This set-up is able to measure responses in both hind paws simultaneously, creating the opportunity to study the effect of nerve injury on one limb and use the contralateral limb as a control. Ten rats received a sciatic nerve transection and repair of either the left (n=5) or the right (n=5) hind limb. Measurements were performed, 1 day pre-operatively, directly post operatively, and at days 1, 7, 14, 21, 35 and 49 post-operatively. Although results are not significant, there is a tendency for the CIVD reaction to be reduced in the nerve injured paw until the nerve is regenerated around day 35. Further investigation of neural influence on the CIVD reaction will be necessary; this set-up may prove to be useful in future experiments to elucidate the mechanism of the CIVD reaction. PMID- 20709102 TI - Production of a monoclonal antibody, against human alpha-synuclein, in a subpopulation of C57BL/6J mice, presenting a deletion of the alpha-synuclein locus. AB - Analyses using antibodies directed against alpha-synuclein play a key role in the understanding of the pathologies associated with neurodegenerative disorders such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). However, the generation of antibodies against immunogens with significant sequence similarity to host proteins such as alpha-synuclein is often hindered by host immunotolerance. In contrast to wild-type C57BL/6J and BALB/c mice immunized with recombinant human alpha-synuclein, C57BL/6S Deltasnca mice presenting a natural deletion of the alpha-synuclein locus, bypassed the immunotolerance process which resulted in a much higher polyclonal antibody response. The native or fibrillized conformation of alpha-synuclein used as the immunogen did not have an impact on the amounts of specific antibodies in sera of the host. The immunization protocols resulted in the generation of the IgG AS11, raised against fibrillized recombinant human alpha-synuclein in C57BL/6S Deltasnca mice. This monoclonal antibody, recognizing an N-terminal alpha synuclein epitope, was selected for its specificity and significant reactivity in Western-blot, immunofluorescence and immunohistochemistry assays. The ability of AS11 to detect both soluble and aggregated forms of alpha-synuclein present in pathological cytoplasmic inclusions was further assessed using analysis of human brains with PD or MSA, transgenic mouse lines expressing A53T human alpha synuclein, and cellular models expressing human alpha-synuclein. Taken together, our study indicates that novel antibodies helpful to characterize alterations of alpha-synuclein leading to neurodegeneration in PD and related disorders could be efficiently developed using this original immunization strategy. PMID- 20709103 TI - Expression of IFNgammaR2 mutated in a dileucine internalization motif reinstates IFNgamma signaling and apoptosis in human T lymphocytes. AB - In T lymphocytes, the internalization of the R2 chain of the IFN-gamma receptor (IFN-gammaR2) prevents the switching-on of pro-apoptotic and anti-proliferative genes induced by the IFN-gamma/STAT1 pathway. In fibroblasts, a critical role of controlling the IFN-gammaR2 internalization is played by the LI(255-256) intracellular motif. Here we show that, in human malignant T cells, the expression of a mutated IFN-gammaR2 chain in which the LI(255-256) internalization motif is replaced by two alanines (LI(255-256)AA) induces cell surface accumulation of the receptor and reinstates the cell sensitivity to IFN gamma. In comparison with T cells that expressed wild-type IFN-gammaR2, cells that expressed the mutated receptor displayed, in response to IFN-gamma a sustained activation of STAT1. The activation of this signaling pathway leads to higher induction of MHC class I and FasL expression and triggered apoptosis. Malignant ST4 cells transduced with either wild-type or mutated receptor were able to grow in SCID mice, but only the proliferation of T cells expressing the mutated receptor was inhibited by IFN-gamma. Finally, lentiviral-mediated transduction of the mutated receptor in T lymphoblasts from healthy donors reinstated their IFN-gamma-dependent apoptosis. As a whole, these data indicate that perturbation of IFN-gammaR2 internalization by mutating the LI(255-256) motif induces a timely coordinated activation of IFN-gamma/STAT1 signaling pathways that leads to the apoptosis of T cells. PMID- 20709104 TI - Interleukin 1 receptor antagonist polymorphisms are associated with the risk of developing acute coronary syndrome in Mexicans. AB - Inflammation plays an essential role in the development and progression of atherosclerotic lesions. Cytokines of the interleukin-1 family are central regulators in immunoinflammatory mechanisms. In the present work, the role of interleukin 1 (IL-1) and IL-1 receptor antagonist (IL-1RN) gene polymorphisms as susceptibility markers for acute coronary syndrome (ACS) was evaluated. Six polymorphisms in the IL-1 gene cluster members were genotyped by 5' exonuclease TaqMan genotyping assays in 289 ACS patients and 248 healthy controls. Haplotypes were constructed after linkage disequilibrium analysis. Statistically significant associations were found between three polymorphisms of the IL-1RA gene (rs419598, rs315951, and rs2234663) and the development ACS. The polymorphism RN.4T>C (rs419598) was associated with hypertension, previous myocardial infarction, and major adverse cardiac events. To establish the functional effect of the IL-1RN6/2 (rs315951) polymorphism (principal IL-1RN polymorphism associated with ACS in our study), monocytes were obtained from a group of 27 healthy individuals and the production of IL-1 receptor antagonist (IL-1Ra) was determined. Monocytes from individuals with rs315951 CC genotype showed similar production of IL-1Ra as individuals with GG and CG genotypes. The analysis of linkage disequilibrium of the IL-1RA polymorphisms showed four out of eight different possible allele combinations with differences between the studied groups. Patients with ACS showed increased frequency of "T1C" haplotype when compared to healthy controls. The results suggest that IL-1RN gene polymorphisms could be involved in the risk of developing ACS in Mexican individuals. PMID- 20709105 TI - Adjuvant effect of Bacillus firmus on the expression of cytokines and toll-like receptors in mouse nasopharynx-associated lymphoid tissue (NALT) after intranasal immunization with inactivated influenza virus type A. AB - Due to the persisting threat of development of new highly pathogenic influenza A subtypes, a mucosal vaccination which would induce a potent and cross-protective reaction is desirable. We succeeded in mucosal immunization of mice with an inactivated influenza A virus by using delipidated Bacillus firmus (DBF) as adjuvant. The mechanism of adjuvant effect was followed in NALT by comparing the response after intranasal immunization by inactivated influenza virus type A (H1N1) alone, adjuvant alone (DBF), or by a mixture of virus+DBF. Expression of selected gene groups was tested via qPCR at 7 different time-points: cytokines (IL-2, IFN-gamma, IL-4, IL-6, and IL-10), type I interferons (IFN-alpha4, IFN alpha11, IFN-alpha12, and IFN-beta), toll-like receptors (TLR2, TLR3, TLR7, and TLR9), iNOS and CCR7. Intranasally administered DBF and the mixture of virus+DBF induced an elevated expression of IFN-gamma, IL-6 and IL-10 cytokines, type I interferons, iNOS, and pDC markers in NALT. Multimarker qPCR data was analyzed by relative quantification and by principal component analysis. DBF has been shown to be a very efficient adjuvant for the stimulation of innate immunity after IN immunization. DBF accelerated, increased, and prolonged the antiviral response. PMID- 20709106 TI - Application of an In-Cell Western assay for measurement of influenza A virus replication. AB - Influenza A pandemics present enormous challenges to modern medicine. To control such pandemics, quantitative assays characterised by rapidity, high sensitivity, and high-throughput are critical in determining the susceptibility of the influenza A virus to antiviral drugs and for screening chemicals that can inhibit viral replication effectively. In the present study, a rapid and quantitative method to determine influenza A virus replication was developed by an In-Cell Western (ICW) assay. This assay was found to be useful for monitoring the kinetics of influenza A virus replication, as viral nucleoprotein production could be correlated to both increasing doses of viral infection and to the lapse of time during viral infection. Compared to other conventional assays, such as TCID(50), quantitative real-time RT-PCR, and the indirect immunofluorescence assay, the ICW assay exhibits high accuracy, reproducibility, and ease of use. The antiviral effect of amantadine and ribavirin can be determined readily by the ICW assay in 96-well formats, providing a means of rapid antiviral drug screening. Thus, the ICW assay can be used for detecting viral replication, quantifying virus production, and assessing drug-susceptibility in high throughput applications. PMID- 20709107 TI - Development of a new primer-probe energy transfer method for the differentiation of neuropathogenic and non-neuropathogenic strains of equine herpesvirus-1. AB - Equine herpesvirus-1 (EHV-1) is a major pathogen of horses with worldwide distribution that can cause various clinical signs ranged from mild respiratory disease to neurological symptoms. Comparison of neuropathogenic and non neuropathogenic EHV-1 strains revealed that a single non-synonymous nucleotide substitution (A/G2254) in the ORF30 region is associated with the altered functions of the viral DNA polymerase and therefore the neuropathogenicity of EHV 1 virus strains. The aim of the present study was the development of a new differentiation method of this particular single nucleotide polymorphism on the basis of the primer-probe energy transfer (PriProET) technique that has been successfully applied for the detection and classification of various DNA and RNA viruses. The results of melting temperature analysis showed an exact correlation with the sequence variations of the targeted region of ORF30, and the two genotypes (A/G2254) could be easily identified by the different peaks of melting temperatures. The new method is simple, fast, specific and robust as well as more flexible than the previous tests. PMID- 20709108 TI - Generation of VSV pseudotypes using recombinant DeltaG-VSV for studies on virus entry, identification of entry inhibitors, and immune responses to vaccines. AB - Vesicular stomatitis virus (VSV) is a prototypic enveloped animal virus that has been used extensively to study virus entry, replication and assembly due to its broad host range and robust replication properties in a wide variety of mammalian and insect cells. Studies on VSV assembly led to the creation of a recombinant VSV in which the glycoprotein (G) gene was deleted. This recombinant (rVSV DeltaG) has been used to produce VSV pseudotypes containing the envelope glycoproteins of heterologous viruses, including viruses that require high-level biocontainment; however, because the infectivity of rVSV-DeltaG pseudotypes is restricted to a single round of replication the analysis can be performed using biosafety level 2 (BSL-2) containment. As such, rVSV-DeltaG pseudotypes have facilitated the analysis of virus entry for numerous viral pathogens without the need for specialized containment facilities. The pseudotypes also provide a robust platform to screen libraries for entry inhibitors and to evaluate the neutralizing antibody responses following vaccination. This manuscript describes methods to produce and titer rVSV-DeltaG pseudotypes. Procedures to generate rVSV DeltaG stocks and to quantify virus infectivity are also described. These protocols should allow any laboratory knowledgeable in general virological and cell culture techniques to produce successfully replication-restricted rVSV DeltaG pseudotypes for subsequent analysis. PMID- 20709109 TI - Semi-solid gels function as physical barriers to human immunodeficiency virus transport in vitro. AB - Vaginal gels may act as physical barriers to HIV during sexual transmission. However, the extent and significance of this effect are not well understood. During male-to-female sexual transmission of HIV, semen containing infectious HIV is present within the lower female reproductive tract. In cases where a topical gel has previously been applied to the vaginal epithelium, virions must move through gel layers before reaching vulnerable tissue. This additional barrier could affect the functioning of anti-HIV microbicide gels and placebos. To better understand HIV transport in gels, we: (1) quantified diffusion coefficients of HIV virions within semi-solid delivery vehicles; and (2) tested the barrier functioning of thin gel layers in a Transwell system. Two gels used as placebos in microbicides clinical trials, hydroxyethyl cellulose (HEC) and methylcellulose (MC), were found to hinder HIV transport in vitro. The diffusion coefficients for HIV virions in undiluted HEC and MC were 4+/-2 x 10-12 and 7+/-1 x 10-12 cm2/s, respectively. These are almost 10,000 times lower than the diffusion coefficient for HIV in water. Substantial gel dilution (80%:diluent/gel, v/v) was required before diffusion coefficients rose to even two orders of magnitude lower than those in water. In the Transwell system, gel layers of approximately 150-MUm thickness reduced HIV transport. There was a log reduction in the amount of HIV that had breached the Transwell membrane after 0-, 4-, and 8-h incubations. The ability of a gel to function as a physical barrier to HIV transport from semen to tissue will also depend on its distribution over the epithelium and effects of dilution by vaginal fluids or semen. Results here can serve as a baseline for future design of products that act as barriers to HIV transmission. The potential barrier function of placebo gels should be considered in the design and interpretation of microbicides clinical trials. PMID- 20709110 TI - Bifunctional fusion proteins of the human engineered antibody domain m36 with human soluble CD4 are potent inhibitors of diverse HIV-1 isolates. AB - Currently used antiretroviral therapy is highly successful but there is still a need for new effective and safe prophylactics and therapeutics. We have previously identified and characterized a human engineered antibody domain (eAd), m36, which exhibits potent broadly neutralizing activity against HIV-1 by targeting a highly conserved CD4 binding-induced (CD4i) structure on the viral envelope glycoprotein (Env) gp120. m36 has very small size (~15kDa) but is highly specific and is likely to be safe in long-term use thus representing a novel class of potentially promising HIV-1 inhibitors. Major problems with the development of m36 as a candidate therapeutic are possible short serum half life and lack of effector functions that could be important for effective protection in vivo. Fusion of m36 to human IgG1 Fc resulted in dramatically diminished neutralization potency most likely due to the sterically restricted nature of the m36 epitope that limits access of large molecules. To confer effector functions and simultaneously increase the potency, we first matured m36 by panning and screening a mutant library for mutants with increased binding to gp120. We next fused m36 and its mutants with the first two domains (soluble CD4, sCD4) of the human CD4 using a polypeptide linker. Our results showed that the selected m36 mutants and the sCD4 fusion proteins exhibited more potent antiviral activities than m36. The m36-sCD4 fusion proteins with human IgG1 Fc showed even higher potency likely due to their bivalency and increased avidity although with a greater increase in molecular size. Our data suggest that m36 derivatives are promising HIV-1 candidate therapeutics and tools to study highly conserved gp120 structures with implications for understanding mechanisms of entry and design of vaccine immunogens and small-molecule inhibitors. PMID- 20709111 TI - Radiolabeled antiviral drugs and antibodies as virus-specific imaging probes. AB - A number of small-molecule drugs inhibit viral replication by binding directly to virion structural proteins or to the active site of a viral enzyme, or are chemically modified by a viral enzyme before inhibiting a downstream process. Similarly, antibodies used to prevent or treat viral infections attach to epitopes on virions or on viral proteins expressed on the surface of infected cells. Such drugs and antibodies can therefore be thought of as probes for the detection of viral infections, suggesting that they might be used as radiolabeled tracers to visualize sites of viral replication by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. A current example of this approach is the PET imaging of herpes simplex virus infections, in which the viral thymidine kinase phosphorylates radiolabeled thymidine analogues, trapping them within infected cells. One of many possible future applications might be the use of a radiolabeled hepatitis C protease inhibitor to image infection in animals or humans and provide a quantitative measure of viral burden. This article reviews the basic features of radionuclide imaging and the characteristics of ideal tracer molecules, and discusses how antiviral drugs and antibodies could be evaluated for their suitability as virus specific imaging probes. The use of labeled drugs as low-dose tracers would provide an alternative application for compounds that have failed to advance to clinical use because of insufficient in vivo potency, an unsuitable pharmacokinetic profile or hepato- or nephrotoxicity. PMID- 20709112 TI - Inertial stimuli generated by arena rotation are important for acquisition of the active place avoidance task. AB - The active place avoidance task is used for testing cognitive abilities in rats. A rat, placed on a rotating circular arena, should avoid an unmarked sector defined with respect to stable extra-arena cues. We hypothesized that the inertial stimuli generated by the arena rotation may contribute to the performance in the task. These stimuli provide permanent information to the rat concerning changes in its position with respect to the extra-arena cues, it means to the reference frame in which the to-be-avoided sector is defined. To test the hypothesis, we trained one group of rats on a stable arena while extra-arena cues rotated around the arena. This eliminated the inertial stimuli generated by the arena rotation while preserving other aspects of the task. Six out of seven rats from this group did not learn this modified task. The remaining rat learned it equally well as rats from a control group learned the standard active place avoidance task. After six days of training, we changed the tasks between the groups. The control rats solved the modified task as well as the standard task. We conclude that the inertial stimuli generated by the arena rotation are important for acquisition of the active place avoidance task but not for performance once the task has been mastered. We suggest that rats must perceive the distal extra-arena cues as stable in order to associate the position of the to-be-avoided sector with these cues. PMID- 20709113 TI - Treadmill running improves spatial memory in an animal model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by a decline in cognitive function and severe neuronal loss in the cerebral cortex and certain subcortical regions of the brain including nucleus basalis magnocellularis (NBM) that play an important role in learning and memory. There are few therapeutic regimens that influence the underlying pathogenic phenotypes of AD, however, of the currently available therapies, exercise training is considered to be one of the best strategies for attenuating the pathological phenotypes of AD for people with AD. Here, we sought to investigate the effect of treadmill running on spatial memory in Alzheimer-induced rats. Male Wistar rats were split into two groups namely shams (n=7) and lesions with the lesion group subdivided further into the lesion-rest (n=7) and lesion-exercise (n=7). The lesion-exercise and shams were subjected to treadmill running at 17 meters per minute (m/min) for 60 min per day (min/day), 7 days per week (days/wk), for 60 days. Spatial memory was investigated using the Morris Water Maze test in the rats after 60 days of Alzheimer induction and the exercise. Our data demonstrated that spatial memory was indeed impaired in the lesion group compared with the shams. However, exercise notably improved spatial memory in the lesion-exercised rats compared to lesion-rested group. The present results suggest that spatial memory is affected under Alzheimer conditions and that treadmill running improves these effects. Our data suggested that treadmill running contributes to the alleviation of the cognitive decline in AD. PMID- 20709114 TI - Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status. AB - Converging lines of evidence associate gluco-regulatory abnormalities and peroxisome-proliferator-activated receptor (PPAR) gamma function with increased risk for Alzheimer's disease (AD). In this study, we used the Tg2576 AD mouse model to test the hypothesis that cognitive improvement following 1 month of PPAR gamma agonism with rosiglitazone (RTZ) correlates with peripheral gluco regulatory status. We assessed cognition and peripheral gluco-regulatory status of Tg2576 mice following 1 month treatment with RTZ initiated prior to, coincident with, or after, the onset of peripheral gluco-regulatory abnormalities (4, 8, and 12 months of age, respectively). Whereas 5 months old (MO) and 13 MO Tg2576 did not gain cognitive improvement after 1 month treatment with RTZ, 9 MO Tg2576 mice exhibited reversal of associative learning and memory deficits. Peripheral gluco-regulatory abnormalities were improved in 9 and 13 MO Tg2576 with RTZ treatment; RTZ treatment had no effect on the normal glucose status of 5 MO Tg2576 mice. These findings suggest that RTZ-mediated cognitive improvement does not correlate with peripheral gluco-regulatory abnormalities per se, but reflects the age-dependent mechanistic differences that underlie cognitive decline in this mouse model. PMID- 20709115 TI - Robust reporter system based on chalcone synthase rppA gene from Saccharopolyspora erythraea. AB - Industrial overproducing strains present unique hosts for expression of heterologous gene clusters encoding secondary metabolite biosynthesis. For this purpose, efficient gene expression tools and methods are needed. A robust and versatile reporter system based on the rppA gene from Saccharopolyspora erythraea is presented as the method of choice when studying gene expression in actinomycete hosts. The method is easily scalable to accommodate high-throughput procedure, and collected samples can be easily stored and re-tested when needed. The product of RppA is an inert 1,3,6,8-tetrahydroxynaphthalene which spontaneously oxidises to a dark-red quinone flaviolin providing a qualitative visual assessment of gene expression on an agar plate as well as a quantitative spectrophotometric measurement in liquid broth without the need for invasive procedures or external substrate addition. The applicability of the reporter system has been demonstrated by expressing the rppA gene under the control of the heterologous promoters actII-ORF4/PactI, ermE and its upregulated variant ermE*. The model streptomycete Streptomyces coelicolor, and three industrially important species, Streptomyces tsukubaensis (FK506), Streptomyces cinnamonensis (monensin) and Streptomyces rimosus (oxytetracycline) were used as hosts. The reporter system has shown its utility independently of cultivation conditions or composition of growth medium, from simple laboratory to complex industrial media. The simplicity and robustness of the system, demonstrated even in industrial settings, shows great potential for wider use in different microbial hosts and applications, and may thus represent a new generic and versatile tool useful to a wider scientific community. PMID- 20709116 TI - The first complete genome sequence of a non-chicken aviadenovirus, proposed to be turkey adenovirus 1. AB - The complete genome sequence of an adenovirus, isolated from turkey and proposed to be turkey adenovirus type 1 (TAdV-1), was determined to extend our knowledge about the genome organisation and phylogeny of aviadenoviruses. The longest adenovirus genome, consisting of 45,412 bp, with the highest G+C content (of 67.55%) known to date, was found. The central part of the TAdV-1 genome has the conserved gene set and arrangement that are characteristic for every other adenovirus analysed to date. This genome core is flanked by the terminal early regions 1 and 4 (E1 and E4). Aviadenovirus-specific genus-common genes were found in these regions, each containing nine such open reading frames (ORFs). Additionally a type-specific novel ORF, designated as ORF50, was found in E4. Phylogenetic analysis as well as the presence of the genus-specific genes, splice sites and protease cleavage sites confirmed the classification of TAdV-1 in the genus Aviadenovirus. Intrageneric analyses of two genus-specific genes demonstrated the distinctness of TAdV-1 from other aviadenoviruses, thus supporting the proposal for the establishment of a new species, Turkey adenovirus B for TAdV-1. PMID- 20709117 TI - Distinct propagation efficiencies of H5N1 influenza virus Thai isolates in newly established murine respiratory region-derived cell clones. AB - Inbred mice have been widely used for the study of influenza viruses as a mammalian model, while suitable cell lines derived from murine tissue have been limited. Here, we established several immortalized cell clones from respiratory regions of inbred mice (C57BL/6 and BALB/c) by transformation using simian virus 40 large T antigen expression vector. Twenty-five cell clones from C57/BL and BALB/c, designated as MRDC/C and MRDC/B series, respectively, showed different susceptibility to Thai isolates of influenza A virus H5N1. Two murine cell clones, C6 and B7 which were extensively studied expressed both SAalpha2,3 and SAalpha2,6 sialic acid receptors. Interestingly, the 6 Thai patient-derived H5N1 isolates examined showed varied virus propagation efficiency in murine cell clones, although there were only slight differences in their propagation in MDCK and A549 cell lines. The results indicate that the murine cell clones are useful for examining the propagation efficiency of H5N1 viruses in vitro. PMID- 20709118 TI - Genetic control of host resistance to porcine reproductive and respiratory syndrome virus (PRRSV) infection. AB - This manuscript focuses on the advances made using genomic approaches to identify biomarkers that define genes and pathways that are correlated with swine resistance to infection with porcine reproductive and respiratory syndrome virus (PRRSV), the most economically important swine viral pathogen worldwide. International efforts are underway to assess resistance and susceptibility to infectious pathogens using tools such as gene arrays, single nucleotide polymorphisms (SNPs) chips, genome-wide association studies (GWAS), proteomics, and advanced bioinformatics. These studies should identify new candidate genes and biological pathways associated with host PRRS resistance and alternate viral disease processes and mechanisms; they may unveil biomarkers that account for genetic control of PRRS or, alternately, that reveal new targets for therapeutics or vaccines. Previous genomic approaches have expanded our understanding of quantitative trait loci (QTL) controlling traits of economic importance in pig production, e.g., feed efficiency, meat production, leanness; only recently have these included health traits and disease resistance. Genomic studies should have substantial impact for the pig industry since it is now possible to include the use of biomarkers for basic health traits alongside broader set of markers utilized for selection of pigs for improved performance and reproductive traits, as well as pork quality. Additionally these studies may reveal alternate PRRS control mechanisms that can be exploited for novel drugs, biotherapeutics and vaccine designs. PMID- 20709119 TI - Experimental ostreid herpesvirus 1 infection of the Pacific oyster Crassostrea gigas: kinetics of virus DNA detection by q-PCR in seawater and in oyster samples. AB - Herpes- and herpes-like viruses are known to infect a wide range of bivalve mollusc species throughout the world. Abnormal summer mortalities associated to the detection of ostreid herpesvirus 1 (OsHV-1) have been currently reported in France among larvae and spat of the Pacific cupped oyster Crassostrea gigas. In the present work, we have developed an experimental protocol of horizontal transmission based on the cohabitation between healthy and experimentally infected oysters. Through a cohabitation trial, the kinetics of OsHV-1 detection in different oyster organs and seawater samples were investigated and characterized for the first time using real time quantitative PCR. PMID- 20709120 TI - Systemic delivery of insulin via the nasal route using a new microemulsion system: In vitro and in vivo studies. AB - The main purpose of this study was to investigate the nasal absorption of insulin from a new microemulsion spray preparation in rabbits. The bioavailability of insulin lispro via the nasal route using a W/O microemulsion was found to reach 21.5% relative to subcutaneous administration, whereas the use of an inverse microemulsion as well as a plain solution yielded less than 1% bioavailability. The profile of plasma glucose levels obtained after nasal spray application of the microemulsion (1IU/kg lispro) was similar to the subcutaneous profile of 0.5IU/kg at the first 90min after application and resulted in a 30-40% drop in glucose levels. The microemulsion system was characterized by DLS, TEM, viscosity measurements, and by construction of pseudo-ternary phase diagram. The average droplet size of an insulin-unloaded and insulin-loaded microemulsions containing 20% aqueous phase (surfactants-to-oil ratio=87:13) was 2nm and 2.26nm in diameter, respectively. In addition, the effect of the microemulsion on FITC labeled insulin permeation was examined across the porcine nasal mucosa in vitro. The permeability coefficient of FITC-insulin via the microemulsion was 0.210+/ 0.048cm/h with a lag time of 10.9+/-6.5min, whereas the permeability coefficient from a plain solution was 0.082+/-0.043cm/h with a lag time of 36.3+/-10.1min. In view of the absorption differences of insulin between 20%, 50% water-containing microemulsions and an aqueous solution obtained in vitro and in vivo, it has been concluded that the acceleration in the intramucosal transport process is the result of encapsulating insulin within the nano-droplet clusters of a W/O microemulsion, while the microemulsion ingredients seems to have no direct role. PMID- 20709121 TI - Self-assembling peptide nanofiber scaffolds for controlled release governed by gelator design and guest size. AB - The aim of this study was to develop controlled drug delivery by network scaffolds based on self-assembling peptide RADAFI and RADAFII. These two peptides self-assembled into interconnected nanofibrilar network structures with distinct physical morphologies. The hydrogels were also utilized for entrapment and release of some model guests, promising their future application as a drug delivery vehicle. Fickian diffusion controlled the release kinetics. Furthermore, the obtained release function was dependent on both rational design of the peptides used for hydrogel formation and choice of the entrapped molecules. On the basis of the striking different releases of these two peptide scaffolds, we suggested that guest size and lipophilicity influenced the release competitively. The release of RADAFI system was dominated by guest size, and the guest lipophilicity controlled the release behavior in RADAFII system. In a word, this work would potentially provide a spatially and temporally controlled delivery system for some functional drugs in the future. PMID- 20709122 TI - Nano PGE1 promoted the recovery from spinal cord injury-induced motor dysfunction through its accumulation and sustained release. AB - The effect of Nano PGE(1) (nanoparticles containing prostaglandin E(1)) on spinal cord injury (SCI) was investigated in rat model. Nano PGE(1) significantly and dose-dependently promoted the recovery from SCI-induced motor dysfunction, and the potency of Nano PGE(1) was comparable with successive treatment of Lipo PGE(1), and was superior to single treatment of Lipo PGE(1). Distribution study revealed that Nano PGE(1) sustained longer in the blood. In the injured spinal cord, gradual accumulation and longer retention were observed. Lipo PGE(1) was also accumulated with time, but over 10 fold less. It should be noted that over 80 fold more of PGE(1) were detected in Nano PGE(1)-treated injured spinal cord as compared with that in normal ones. Nano PGE(1)-treated injured spinal cord had less lesion cavity with increased MBP expression. Also, HGF production significantly increased as compared with that of SCI control. These findings could lead to the conclusion that Nano PGE(1) had the therapeutic potential for SCI, which might be partly ascribed by the efficient distribution of Nano PGE(1) to the injured spinal cord. The sustained release of PGE(1) would have increased HGF production, and both would have promoted cell survival and endogenous repair. PMID- 20709123 TI - Ultrasound triggered, image guided, local drug delivery. AB - Ultrasound allows the deposition of thermal and mechanical energies deep inside the human body in a non-invasive way. Ultrasound can be focused within a region with a diameter of about 1mm. The bio-effects of ultrasound can lead to local tissue heating, cavitation, and radiation force, which can be used for 1) local drug release from nanocarriers circulating in the blood, 2) increased extravasation of drugs and/or carriers, and 3) enhanced diffusivity of drugs. When using nanocarriers sensitive to mechanical forces (the oscillating ultrasound pressure waves) and/or sensitive to temperature, the content of the nanocarriers can be released locally. Thermo-sensitive liposomes have been suggested for local drug release in combination with local hyperthermia more than 25 years ago. Microbubbles may be designed specifically to enhance cavitation effects. Real-time imaging methods, such as magnetic resonance, optical and ultrasound imaging have led to novel insights and methods for ultrasound triggered drug delivery. Image guidance of ultrasound can be used for: 1) target identification and characterization; 2) spatio-temporal guidance of actions to release or activate the drugs and/or permeabilize membranes; 3) evaluation of bio distribution, pharmacokinetics and pharmacodynamics; and 4) physiological read outs to evaluate the therapeutic efficacy. PMID- 20709125 TI - Mood and the macro-nutrient composition of breakfast and the mid-day meal. AB - Six hundred and eighty-six individuals were approached at mid-day after they had chosen a meal in a cafeteria. They were asked to rate their mood during the morning and list what they had eaten that morning. Both males and females who had eaten breakfast rather than fasting reported that they had been happier and more relaxed during the morning. The macro-nutrient compositions of breakfast and lunch were calculated and related to mood during the morning. In males, but not females, the consumption of more carbohydrate in the morning was associated with feeling happy rather than sad and relaxed rather than stressed. Further examination demonstrated that in males the amount of fat, protein and total energy consumed was not associated with mood; that is there was a selective relationship between carbohydrate intake and mood. It was not possible to establish whether the nature of breakfast influenced mood or the pre-existing mood influenced the choice of breakfast although both explanations are plausible. In females, however, there was no relationship between carbohydrate intake and mood, possibly a reflection of the smaller amounts consumed. The suggestion that mood during the morning might influence food choice at mid-day was considered but no association was found. PMID- 20709127 TI - Dining in the dark. The importance of visual cues for food consumption and satiety. AB - How important are visual cues for determining satiation? To find out, 64 participants were served lunch in a "dark" restaurant where they ate in complete darkness. Half the participants unknowingly received considerably larger "super size" portions which subsequently led them to eat 36% more food. Despite this difference, participants' appetite for dessert and their subjective satiety were largely unaffected by how much they had consumed. Consistent with expectations, participants were also less accurate in estimating their actual consumption quantity than a control group who ate the same meal in the light. PMID- 20709126 TI - Are female athletes at increased risk for disordered eating and its complications? AB - The purpose of the study was to make a systematic review and describe and confront recent studies that compare the presence of disordered eating and its complications in young female athletes and controls subjects - PubMed, Scielo, Medline, ScienceDirect, WILEY InterScience, Lilacs and Cochrane were the databases used for this review. Out of 169 studies 22 were selected and 11,000 women from 68 sports were studied. The short version of the EAT was the most common instrument used to track disordered eating. Results showed that 55% found no significant difference in the percentage of disordered eating between athletes and controls. Also a higher percentage of studies reported higher frequency of menstrual dysfunction in athletes than controls and finally 50% of the studies found incidence of low bone mass in controls. Not all the studies that investigated all the conditions in the triad, but the authors concluded that it seemed that athletes were in more severe stage of this disorder. Due to the heterogeneity of the studies, a definitive conclusion about the groups and at highest risk for disordered eating and its complications remains to be elucidated. PMID- 20709124 TI - Imaging and drug delivery using theranostic nanoparticles. AB - Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown in combining both paradigms into clinically effective formulations. This concept, recently coined as theranostics, is highly relevant to agents that target molecular biomarkers of disease and is expected to contribute to personalized medicine. Here we review state-of-the-art nanoparticles from a therapeutic and a diagnostic perspective and discuss challenges in bringing these fields together. Major classes of nanoparticles include, drug conjugates and complexes, dendrimers, vesicles, micelles, core shell particles, microbubbles, and carbon nanotubes. Most of these formulations have been described as carriers of either drugs or contrast agents. To observe these formulations and their interactions with disease, a variety of contrast agents have been used, including optically active small molecules, metals and metal oxides, ultrasonic contrast agents, and radionuclides. The opportunity to rapidly assess and adjust treatment to the needs of the individual offers potential advantages that will spur the development of theranostic agents. PMID- 20709128 TI - Acute oral toxicity: variability, reliability, relevance and interspecies comparison of rodent LD50 data from literature surveyed for the ACuteTox project. AB - The ACuteTox project has aimed to optimise and prevalidate an in vitro testing strategy for predicting human acute toxicity. Ninety-seven reference substances were selected and an in vivo acute toxicity database was compiled. Comprehensive statistical analyses of the in vivo LD50 data to evaluate variability and reliability, interspecies correlation, predictive capacities with regard to EU and GHS toxicity categories, and deduction of performance criteria for in vitro methods is presented. For the majority of substances variability among rodent data followed a log normal distribution where good reproducibility was found. Rat and mouse interspecies comparison of LD50 studies by ordinary regression showed high correlation, with coefficients of determination, ranging between 0.8 and 0.9. Substance specific differences were only significant for warfarin and cycloheximide. No correlation of compound LD50 range with presumed study quality rank (by assigning Klimisch reliability scores) was found. Modelling based on LD50 variability showed that with at least 90% probability ~54% of the substances would fall into only one GHS category and ~44% would fall within two adjacent categories. These results could form the basis for deriving a predictive capacity that should be expected from alternative approaches to the conventional in vivo acute oral toxicity test. PMID- 20709129 TI - An enhanced tiered toxicity testing framework with triggers for assessing hazards and risks of commodity chemicals. AB - This paper presents an enhanced integrated testing framework based on tiered testing and endpoint-specific decision triggers envisioned for application to commodity chemical safety assessments. The framework has two tiers in which exposure information can be integrated with hazard data at each Tier. Tier 1 tests are used to screen chemicals for major toxic effects (i.e., acute toxicity potential, target organs of repeat dose toxicity, genotoxicity potential, neurotoxicity potential, reproductive toxicity potential, immunotoxicity potential, and developmental toxicity potential), and to direct planning for more complex and targeted testing in Tier 2. The proposed decision triggers coupled with information on use and potential for exposure allow for scientifically-based decisions to be made about further testing in Tier 2, indicating which specific endpoints and tests warrant further evaluation, and which do not. The testing framework addresses risks to humans during all stages of development and provides data relevant to assessing hazards to sensitive subpopulations, such as infants and children. The REACH program in Europe and TSCA in the United States have led to an increased focus on development of hazard and risk information for chemicals used in industrial processes and consumer products. This framework and its toxicity decision triggers will allow for scientifically justified evaluation of chemicals that is comprehensive in terms of hazard screening, focuses resources on the specific complex tests that are most important for hazard characterization, and minimizes the use of animals. PMID- 20709130 TI - Natural variability in abundance of prevalent soybean proteins. AB - Soybean is an inexpensive source of protein for humans and animals. Genetic modifications (GMO) to soybean have become inevitable on two fronts, both quality and yield will need to improve to meet increasing global demand. To ensure the safety of the crop for consumers it is important to determine the natural variation in seed protein constituents as well as any unintended changes that may occur in the GMO as a result of genetic modification. Understanding the natural variation of seed proteins in wild and cultivated soybeans that have been used in conventional soybean breeding programs is critical for determining unintended protein expression in GMO soybeans. In recent years, proteomic technologies have been used as an effective analytical tool for examining modifications of protein profiles. We have standardized and applied these technologies to determine and quantify the spectrum of proteins present in soybean seed. We used two dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS), and liquid chromatography mass spectrometry (LC-MS) for the separation, quantification, and identification of different classes of soybean seed proteins. We have observed significant variations in different classes of proteins, including storage, allergen and anti-nutritional protein profiles, between non-GMO cultivated and wild soybean varieties. This information is useful for scientists and regulatory agencies to determine whether the unintended expression of proteins found in transgenic soybean is within the range of natural variation. PMID- 20709131 TI - Extensive changes to occupational exposure limits in Korea. AB - Occupational exposure limits (OELs) are used as an important tool to protect workers from adverse chemical exposures and its detrimental effects on their health. The Ministry of Labor (MOL) can establish and publish OELs based on the Industrial Safety and Health Act in Korea. The first set of OELs was announced by the MOL in 1986. At that time, it was identical to the Threshold Limit Values of the American Conference of Governmental Industrial Hygienists. Until 2006, none the first OELs except for those of three chemicals (asbestos, benzene, and 2 bromopropane) were updated during the last twenty years. The Hazardous Agents Review Committee established under the MOL selected 126 chemicals from 698 chemicals covered by OELs using several criteria. From 2005 to 2006, the MOL provided research funds for academic institutions and toxicological laboratories to gather the evidence documenting the need to revise the outdated OELs. Finally, the MOL notified the revised OELs for 126 chemicals from 2007 to 2008. The revised OELs of 58 substances from among these chemicals were lowered to equal or less than half the value of the original OELs. This is the most substantial change in the history of OEL revisions in Korea. PMID- 20709132 TI - The antipsychotics haloperidol and chlorpromazine increase bone metabolism and induce osteopenia in female rats. AB - The main objective of this study was to evaluate the effects of the antipsychotic drugs haloperidol (HAL) and chlorpromazine (CPZ) on bone mineral density (BMD) in female rats and to examine the relationship between the effects on bone and reproductive organs or hormone concentrations. Female rats were orally administered HAL (2 or 10 mg/kg) or CPZ (25 or 50 mg/kg) once daily (7 days/week) for 6 months resulting in a significant increase in prolactin. Hyperprolactinemia resulted in enlarged corpora lutea in the ovary, because prolactin has a luteotropic activity. Thus, atrophy in the uterus, epithelial mucification in the vagina and continuous diestrus stages were observed. These events in the reproductive organs induced a decrease in estradiol, elevation of biochemical markers of bone metabolism, significant reductions of BMD in trabecular bone of the femur and decreased trabecular bone in the femur. The bone loss is associated with an increase in bone resorption due to decreased estradiol derived from the luteotropic activity of prolactin. The mechanism of dopamine blockers to induce bone loss in female rats is considered to be rodent specific because the luteotropic effects of prolactin are confined primarily to rodents. Also, it appears that chronic hyperprolactinemia and maintained corpora lutea leading to bone loss are commonly inducible in female rats receiving long-term treatment with antipsychotic drugs possessing dopamine D2 receptor antagonist activity. PMID- 20709133 TI - Human variation in CYP-specific chlorpyrifos metabolism. AB - Chlorpyrifos, an organophophorothioate insecticide, is bioactivated to the neurotoxic metabolite, chlorpyrifos-oxon (CPO) by cytochromes P450 (CYPs). To determine the variability in chlorpyrifos bioactivation, CPO production by human liver microsomes from 17 individual donors was compared relative to phenotype and genotype. CPO production varied over 14-fold between individuals in incubations utilizing 20 MUM chlorpyrifos as substrate, while CPO production varied 57-fold in incubations with 100 MUM chlorpyrifos. For all but two samples, the formation of the less toxic metabolite, 3,5,6-trichloro-2-pyridinol (TCP), was greater than CPO production. TCP production varied 9-fold in incubations utilizing 20 MUM chlorpyrifos as substrate and 19-fold using 100 MUM chlorpyrifos. Chlorpyrifos metabolism by individual human liver microsomes was significantly correlated with CYP2B6, CYP2C19 and CYP3A4 related activity. CPO formation was best correlated with CYP2B6 related activity at low (20 MUM) chlorpyrifos concentrations while CYP3A4 related activity was best correlated with CPO formation at high concentrations (100 MUM) of chlorpyrifos. TCP production was best correlated with CYP3A4 activity at all substrate concentrations of chlorpyrifos. The production of both CPO and TCP was significantly lower at a concentration of 20 MUM chlorpyrifos as compared to 100 MUM chlorpyrifos. Calculations of percent total normalized rates (% TNR) and the chemical inhibitors ketoconazole and ticlopidine were used to confirm the importance of CYP2B6, CYP2C19, and CYP3A4 for the metabolism of chlorpyrifos. The combination of ketoconazole and ticlopidine inhibited the majority of TCP and CPO formation. CPO formation did not differ by CYP2B6 genotype. Individual variations in CPO production may need to be considered in determining the risk of chlorpyrifos poisoning. PMID- 20709134 TI - Transduced PEP-1-ribosomal protein S3 (rpS3) ameliorates 12-O tetradecanoylphorbol-13-acetate-induced inflammation in mice. AB - This study investigated the preventive effect of ribosomal protein S3 (rpS3) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in mice. A cell permeable expression vector PEP-1-rpS3 was constructed. Topical application of the vector markedly inhibited TPA-induced expression levels of cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines. Application of PEP-1-rpS3 also resulted in a significant reduction in the activation of nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) in TPA-treated ears. These results indicate that PEP-1-rpS3 inhibits inflammatory response cytokines and enzymes by blocking NF-kB and MAPK, prompting the suggestion that PEP-1-rpS3 can be used as a therapeutic agent against skin inflammation. PMID- 20709135 TI - Activation of PERK signaling through fluoride-mediated endoplasmic reticulum stress in OS732 cells. AB - Our proteomical analysis of osteoblasts exposed to fluoride revealed a distinctive upregulation of proteins in osteoblast. These upregulated proteins play key roles in the protein folding. The PRK-like ER kinase (PERK) signaling, one branch of unfolded protein response (UPR) to combat ER stress, is a transcription factor needed for osteoblast proliferation and differentiation. The mechanism of skeletal fluorosis by which fluoride regulates osteoblast is not fully defined. Here we studied the effect of fluoride on PERK signaling genes and x-box binding protein 1 (xbp-1) in OS7232 cells (human osteoblast-like cell line). Meantime, genes associated with bone turnover were examined in this study. We found that early and continuous fluoride exposure increased the binding immunoglobulin protein (BiP) expression and activated the PERK signaling pathway, resulting in activation of transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The altered expression of cbfa1, osteoprotegerin (OPG)/nuclear factor kappa B ligand (RANKL) were viewed in this study. These results showed fluoride impelled a distinctive ER stress response in OS732 cells, primarily by activating PERK and PERK-dependent signaling. Little effects were viewed for activating xbp-1, a common target of the other two canonical sensors of ER stress, ATF6 and IRE1. In this study the altered expression of bone turnover genes were consistent with activation of ER stress and PERK signaling. This study proved that PERK signaling play major roles in action of fluoride on osteoblast, and suggested that bone response in skeletal fluorosis may be due in part to PERK signaling pathway. PMID- 20709137 TI - A double-blind randomized clinical trial of two carbamide peroxide tooth bleaching agents: 2-year follow-up. AB - OBJECTIVES: This double-blind randomized clinical trial aimed to evaluate the whitening effect of two at-home tooth bleaching agents and the effect of dietary habits after 2 years. The patients' view about bleaching longevity was also investigated. METHODS: Ninety-two subjects with mean shade of C1 or darker for the six maxillary anterior teeth were randomized into two groups (n=46) according to the carbamide peroxide (CP) concentration: 10% (CP10) or 16% (CP16). The treatment was performed using the whitening agent in a tray for 2h/day during 3 weeks. Shade evaluations were done with a shade guide and a spectrophotometer at baseline, 1-month, 6-month, 1-year and 2-year post-bleaching. RESULTS: Eighty-one (88%) of the original 92 subjects enrolled in the study were recalled at 2-year follow-up and, the tooth shade remained significantly lighter than at baseline, in both treatment groups, considering the tooth shade median values (p<0.001) or the color parameters: L*a* (p<0.001) for CP10 and, L*b* for CP16 group (p<0.001). Subjects from CP10 and CP16 reported a consumption of beverage and food stains as high as at 6-month and 1-year recalls and, more than 66% of the participants from each group reported a tooth shade relapse from mild to moderate (p=0.6). SIGNIFICANCE: At 2-year post-bleaching, tooth shade remained lighter than at baseline for both CP concentrations tested. Tooth shade relapse associated to increasing of a* and b* color parameters were observed for both groups when compared to the end of the treatment (CEP # 37/05). PMID- 20709138 TI - Characterization of specific cDNA background synthesis introduced by reverse transcription in RT-PCR assays. AB - To block expression of NMDA receptor NR1 subunit, we injected into rat hippocampus a Herpes Simplex Virus type 1 derived vector bearing a sequence for NR1 antisense. RT-PCR assays with RNA from hippocampus of animals injected either with NR1 antisense vector, control vector or vehicle, showed an amplification signal compatible with NR1 antisense which could be attributed either to an endogenous NR1 antisense or to an artifact. RT-PCR was performed either with different primers or without primers in the RT, using RNA from different tissues. RNAse protection assay was carried out to characterize the amplified signal nature. Our results show that the template for the unexpected amplified fragment was NR1 mRNA currently expressed in nervous tissue. We considered this basal amplification of a mRNA in a RT-PCR assay as "background amplification". After background subtraction, a significant signal only remained when samples from NR1 antisense vector injected animals were used, demonstrating that this was the only source for NR1 antisense. Background amplification at RT in the absence of primers, can constitute a troubling factor in quantitative nucleic acid determination, leading to major interference, particularly when both sense and antisense sequences are present in the sample. Since RT introduced a significant background signal for every gene analyzed, we propose that RT must be always performed also without primers. Then, this signal should be identified, quantified and subtracted from the specific reaction amplification signal. PMID- 20709136 TI - Grape seed proanthocyanidins increase collagen biodegradation resistance in the dentin/adhesive interface when included in an adhesive. AB - OBJECTIVES: Contemporary methods of dentin bonding could create hybrid layers (HLs) containing voids and exposed, demineralised collagen fibres. Proanthocyanidins (PA) have been shown to cross-link and strengthen demineralised dentin collagen, but their effects on collagen degradation within the HL have not been widely studied. The purpose of this study was to compare the morphological differences of HLs created by BisGMA/HEMA model adhesives with and without the addition of grape seed extract PA under conditions of enzymatic collagen degradation. METHODS: Model adhesives formulated with and without 5% PA were bonded to the acid etched dentin. 5-MUm-thick sections cut from the bonded specimens were stained with Goldner's trichrome. The specimens were then exposed to 0.1% collagenase solution for 0, 1, or 6 days. Following collagenase treatment, the specimens were analysed with SEM/TEM. RESULTS: Staining did not reveal a difference in the HLs created with the two adhesives. SEM showed the presence of intact collagen fibrils in all collagenase treatment conditions for specimens bonded with adhesive containing PA. These integral collagen fibrils were not observed in the specimens bonded with adhesive without PA after the same collagenase treatment. TEM confirmed that the specimens containing PA still showed normal collagen fibril organisation and dimensions after treatment with collagenase solution. In contrast, disorganised collagen fibrils in the interfacial zone lacked the typical cross-banding of normal collagen after collagenase treatment for specimens without PA. CONCLUSIONS: The presence of grape seed extract PA in dental adhesives may inhibit the biodegradation of unprotected collagen fibrils within the HL. PMID- 20709139 TI - trans-Resveratrol downregulates Txnip overexpression occurring during liver ischemia-reperfusion. AB - Txnip (thioredoxin-interacting protein) is a protein with multifunctional roles in cellular responses and stress-related diseases. Txnip is involved in intracellular redox regulation and has been recently described as a possible link between redox state and metabolism. trans-Resveratrol (T-res) is a natural phytoalexin with antiproliferative, antiapoptotic and antioxidative effects. However, to date there have been no reports of the implication of Txnip in a model of liver acute stress such as ischemia-reperfusion (I/R) and no work has looked for a T-res effect on Txnip. Here we studied the effects of a post ischemic treatment of T-res on the liver thioredoxin (Trx)/Txnip system and investigated whether the T-res effects were dependent on *NO production. In this work, liver I/R induced hepatic Txnip expression and T-res inhibited I/R Txnip expression. This decrease in Txnip expression by T-res was associated with an increase in liver Trx redox activity and a decrease in hepatic I/R-induced Trx-1 expression with no effect on Trx-2, on plasma Trx redox activity or on liver and plasma Trx reductase activity, independently of *NO production. In conclusion, these results show that in our model, not only did T-res protect Trx redox activity by diminishing the Txnip protein expression; it also reduced secretion of Trx1. This is the first report of a major implication of the Trx1/Txnip system in hepatic I/R injuries. It also affirms the importance of the antioxidant effect of T-res on the Trx1/Txnip system. PMID- 20709140 TI - Regulation of lysophosphatidate signaling by autotaxin and lipid phosphate phosphatases with respect to tumor progression, angiogenesis, metastasis and chemo-resistance. AB - Evidence from clinical, animal and cell culture studies demonstrates that increased autotaxin (ATX) expression is responsible for enhancing tumor progression, cell migration, metastases, angiogenesis and chemo-resistance. These effects depend mainly on the rapid formation of lysophosphatidate (LPA) by ATX. Circulating LPA has a half-life of about 3 min in mice and it is degraded by the ecto-activities of lipid phosphate phosphatases (LPPs). These enzymes also hydrolyze extracellular sphingosine 1-phosphate (S1P), a potent signal for cell division, survival and angiogenesis. Many aggressive tumor cells express high ATX levels and low LPP activities. This favors the formation of locally high LPA and S1P concentrations. Furthermore, LPPs attenuate signaling downstream of the activation of G-protein coupled receptors and receptor tyrosine kinases. Therefore, we propose that the low expression of LPPs in many tumor cells makes them hypersensitive to growth promoting and survival signals that are provided by LPA, S1P, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). One of the key signaling pathways in this respect appears to be activation of phospholipase D (PLD) and phosphatidate (PA) production. This is required for the transactivations of the EGFR and PDGFR and also for LPA-induced cell migration. PA also increases the activities of ERK, mTOR, myc and sphingosine kinase-1 (SK-1), which provide individual signals for cells division, survival, chemo-resistance and angiogenesis. This review focuses on the balance of signaling by bioactive lipids including LPA, phosphatidylinositol 3,4,5 trisphosphate, PA and S1P versus the action of ceramides. We will discuss how these lipid mediators interact to produce an aggressive neoplastic phenotype. PMID- 20709141 TI - Nucleosome stability and accessibility of its DNA to proteins. AB - In this paper we present a theoretical description of the accessibility of nucleosomal DNA to proteins. We reassess the classical analysis of Polach and Widom (1995) who demonstrated that proteins (in their case restriction enzymes) gain access to buried binding sites inside a nucleosome through spontaneous unwrapping of DNA from the protein spool. We introduce a straightforward nucleosome model the predictions of which show good agreement with experimental data. By fitting the model to the data we obtain the values of two quantities: the adsorption energy to the histone octamer per length of DNA and the extra length that the DNA needs to unwrap beyond the binding site of an enzyme before the enzyme can act as effectively as on bare DNA. Our results indicate that the effective binding energy is surprisingly low which suggests that the nucleosomal parameters are tuned such that two large energies, the DNA bending energy and the pure adsorption energy, nearly cancel. This paper is based on a lecture presented at the summer school "DNA and Chromosomes 2009: Physical and Biological Applications". We follow the lecture as closely as possible which is why we spend more time than usual on issues that are already well-known in the field, and why we discuss some well-known results from a different perspective. PMID- 20709142 TI - Unraveling algal lipid metabolism: Recent advances in gene identification. AB - Microalgae are now the focus of intensive research due to their potential as a renewable feedstock for biodiesel. This research requires a thorough understanding of the biochemistry and genetics of these organisms' lipid biosynthesis pathways. Genes encoding lipid-biosynthesis enzymes can now be identified in the genomes of various eukaryotic microalgae. However, an examination of the predicted proteins at the biochemical and molecular levels is mandatory to verify their function. The essential molecular and genetic tools are now available for a comprehensive characterization of genes coding for enzymes of the lipid-biosynthesis pathways in some algal species. This review mainly summarizes the novel information emerging from recently obtained algal gene identification. PMID- 20709143 TI - Prenatal and lactational exposure to low-doses of bisphenol A alters brain monoamine concentration in adult mice. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in industry and dentistry. We have previously reported that BPA affects murine neocortical development by accelerating neuronal differentiation/migration resulting in abnormal neocortical architecture as well as apparent thalamocortical connections in adult mice brains. The aim of this study was to investigate whether or not prenatal and lactational BPA-exposure affects the level of neurotransmitters in mice brains. Pregnant mice were injected subcutaneously with 20MUg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. The brains were removed and dissected into six regions for biochemical assays (n=7-8) at postnatal 3 weeks (P3W) and P10-15W. The concentration of the neurotransmitters was determined by high-performance liquid chromatography. The levels of dopamine and its metabolite significantly increased in the caudate/putamen and dorsal raphe nucleus, whereas serotonin and its metabolite increased in the caudate/putamen, dorsal raphe nucleus, thalamus and Substantia nigra in the BPA-exposure group at both P3W and/or P14-15W. These results suggested that prenatal and lactational BPA-exposure might perturb the neurotransmitter system in adult mice. PMID- 20709144 TI - 5-HT(1A)-like receptor activation inhibits abstinence-induced methamphetamine withdrawal in planarians. AB - No pharmacological therapy is approved to treat methamphetamine physical dependence, but it has been hypothesized that serotonin (5-HT)-enhancing drugs might limit the severity of withdrawal symptoms. To test this hypothesis, we used a planarian model of physical dependence that quantifies withdrawal as a reduction in planarian movement. Planarians exposed to methamphetamine (10 MUM) for 60 min, and then placed (tested) into drug-free water for 5 min, displayed less movement (i.e., withdrawal) than either methamphetamine-naive planarians tested in water or methamphetamine-exposed planarians tested in methamphetamine. A concentration-related inhibition of withdrawal was observed when methamphetamine-exposed planarians were placed into a solution containing either methamphetamine and 5-HT (0.1-100 MUM) or methamphetamine and the 5-HT(1A) receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) (10, 20 MUM). Planarians with prior methamphetamine exposure displayed enhanced withdrawal when tested in a solution of the 5-HT(1A) receptor antagonist N-[2-[4-(2 methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635) (1 MUM). Methamphetamine-induced withdrawal was not affected by the 5 HT(2B/2C) receptor agonist meta-chlorophenylpiperazine (m-CPZ) (0.1-20 MUM). These results provide pharmacological evidence that serotonin-enhancing drugs inhibit expression of methamphetamine physical dependence in an invertebrate model of withdrawal, possibly through a 5-HT(1A)-like receptor-dependent mechanism. PMID- 20709145 TI - Functional connectivity from area 5 to primary motor cortex via paired-pulse transcranial magnetic stimulation. AB - In non-human primates area 5 is dominated by the representation of the hand and forelimb, and has direct connectivity with primary motor cortex (M1) implicating its role in the control of hand movements. To date, few studies have investigated the function of area 5 in humans or its connectivity with M1. Using paired-pulse TMS, the present study investigates the functional connectivity between putative area 5 within the medial superior parietal lobule and ispilateral M1 in humans. Specifically, the motor evoked potential (MEP) from the first dorsal interosseous muscle of the right hand was quantified with and without conditioning TMS stimuli applied to left-hemisphere area 5. The timecourse of functional connectivity was examined during cutaneous stimulation applied to the thumb and index finger and also during rest whereby no somatosensory processing demands were imposed. Results indicate that area 5 facilitates and inhibits the MEP at 6 and 40ms, respectively, during somatosensory processing. No net influence of area 5 on M1 output was observed during rest. We conclude that area 5 has a task-dependent and temporally specific influence on M1 output, and suggest that the interaction between these areas presents a novel path with which to alter the motor output, and possibly movement of hand muscles. PMID- 20709146 TI - Slowly adapting pulmonary stretch receptor spike patterns carry lung distension information. AB - Slowly adapting pulmonary stretch receptors (SARs) provide the respiratory and cardiovascular control systems with information regarding the rate and depth of breathing. Previous information theoretical analysis demonstrated that SAR spike count provides a reliable representation of lung distension. This study examines whether SAR spike patterns may also provide information about lung distension. To investigate this, artificial spike trains were generated with the same number of spikes (but randomized intervals) as those recorded from SARs in response to three different lung inflation volumes in urethane-anesthetized rabbits. Three different spike train classification methods were applied to estimate which stimulus evoked them, and the accuracy with which artificial spike trains were classified was compared to that of real SAR spike trains using the same methods. Because real SAR spike trains were classified with higher accuracies than artificial ones containing the same number of spikes, we conclude that SAR spike patterns, in addition to spike counts, contain information concerning the amplitude of lung distension. PMID- 20709147 TI - Tactile spatial acuity is reduced by skin stretch at the human wrist. AB - The skin is an elastic organ that is continuously distorted as our limbs move. The hypothesis that the precision of human tactile localisation is reduced when the skin is stretched, with concurrent expansion of receptive fields (RFs) was tested. Locognosic acuity over the dorsal wrist area was quantified during application of background stretch by (a) Wrist-Bend (skin stretch combined with non-cutaneous proprioceptor activation) and (b) Skin-Pull (skin stretch alone). Participants identified the perceived direction (distal or proximal) of brief test stimuli, applied along a 7-point linear array, relative to a central reference locus. Performance was significantly reduced during the large amplitude compared to the small amplitude of tonic skin stretch, but there was no effect of stretch mode (Wrist-Bend, Skin-Pull), nor was the effect of stretch amplitude modulated by the mode of stretch. Locognosic acuity was poorer than baseline accuracy for the large amplitude skin stretches, for both application modes, but did not differ significantly from baseline for either of the small amplitude stretches. We interpret these observations as corroborating the long-held assumption that tactile localisation is primarily dependent upon the RF dimensions, and associated innervation densities, of regional touch units. The finding that performance was reduced to a similar extent under Skin-Pull and Wrist-Bend conditions suggests that non-cutaneous proprioceptors had rather little tonic modulatory effect. PMID- 20709148 TI - Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat. AB - We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states. PMID- 20709150 TI - Task-related differences in temporo-parietal cortical activation during human phonatory behaviors. AB - Functional magnetic resonance imaging (fMRI) was used to investigate cortical activity related to differential control of the human phonatory system during a sentence production task. Our focus in this report was on activation of the temporo-parietal (TP) junctional region, suggested by recent models in speech production/perception to play a critical role between self-generated acoustic and associated somatosensory inputs related to the consequences of speech. Thirteen healthy participants produced multiple trials of phonetically balanced sentences during each of three performance conditions: "covert", "whisper" and "voice". An event-related, sparse sampling fMRI method was used to examine TP activity associated with sentence production during each condition. Results demonstrated differential responsiveness in the TP region bilaterally as a function of task conditions, with covert production generating the highest level of TP activation. These results suggest that the TP region is differentially responsive to phonation-specific production variables. Our finding that covert production instead of overt voicing resulted in the greatest activity in TP is consistent with recent reports demonstrating TP activation related to temporal ordering judgments and task-dependent memory use. PMID- 20709149 TI - Mice lacking Melanin Concentrating Hormone 1 receptor are resistant to seizures. AB - The Melanin Concentrating Hormone (MCH) system is widely expressed throughout the central nervous system and regulates a variety of physiological functions. It has been reported that acute central administration of MCH inhibits pentylenetetrazol (PTZ)-induced seizures in rats. In the present study MCH(1) receptor knockout mice (MCH(1)R-KO) were used to investigate the role of MCH signaling in modulating seizure susceptibility. Seizure behaviors were compared between MCH(1)R-KO and wild type (MCH(1)R-WT) mice following administration of the convulsant compounds PTZ or pilocarpine. PTZ injection induced clonic seizures in MCH(1)R-WT mice but failed to induce them in MCH(1)R-KO mice. More than twice as many injections of intermittently administered low dose PTZ were required to induce clonic seizures in MCH(1)R-KO mice than in MCH(1)R-WT mice. Following pilocarpine injection, MCH(1)R-WT mice experienced clonic seizures and most had tonic seizures and entered status epilepticus, while all MCH(1)R-KO mice were completely resistant to these effects. MCH(1)R-KO mice were also observed to be strongly protected from the development of PTZ kindling. Genetic deletion of MCH(1)R conferred resistance to all seizure models tested in this study. The data indicate that the MCH system is involved in the regulation of PTZ and pilocarpine seizure threshold. PMID- 20709151 TI - Elevated cerebral blood flow and vascular density in the amygdala after status epilepticus in rats. AB - Cerebrovascular changes following status epilepticus (SE) are not well understood, yet they may contribute to epileptogenesis. We studied hemodynamic changes in the cerebral cortex and amygdala by arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) MRI at 2 days and 14 days after pilocarpine induced SE in rats. There were no cortical hemodynamic changes, yet in the amygdala we found prolonged elevation in cerebral blood flow (CBF, 129% of control mean, day 14, p<0.01). There was a trend towards increased cerebral blood volume (CBV) during the same imaging sessions. Through immunohistochemistry, we observed increased vessel density in the amygdala (127% of control mean, day 14, p<0.05). In conclusion, epileptogenesis may involve hemodynamic changes that are associated with vascular reorganization during post-SE remodeling in the amygdaloid complex. PMID- 20709152 TI - Post-treatment of a BiP inducer prevents cell death after middle cerebral artery occlusion in mice. AB - We previously reported the effect of a selective inducer of BiP (a BiP inducer X; BIX) after permanent middle cerebral artery occlusion (MCAO) in mice. However, in acute stroke, almost all drugs have been used clinically after the onset of events. We evaluated the effect of post-treatment of BIX after permanent MCAO in mice, and examined its neuroprotective properties in in vivo mechanism. BIX (intracerebroventricular injection at 20MUg) administered either at 5min or 3h after occlusion reduced both infarct volume and brain swelling, but at 6h after occlusion there was no reduction. BIX protected against the decrease in a dose dependent manner. Furthermore, BIX reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells induced by the ischemia in ischemic penumbra. These findings indicate that post-treatment with BIX after ischemia has neuroprotective effects against acute ischemic neuronal damage in mice even when given up to 3h after MCAO. BIX may therefore be a potential drug for stroke. PMID- 20709153 TI - The influences of sphingolipid metabolites on gentamicin-induced hair cell loss of the rat cochlea. AB - Sphingolipid metabolites inducing ceramide, sphingosine, and sphingosine-1 phosphate (S1P) play important roles in the regulation of cell proliferation, survival, and death. Aminoglycoside antibiotics including gentamicin induce inner ear hair cell loss and sensorineural hearing loss. Apoptotic cell death is considered to play a key role in this injury. The present study was designed to investigate the possible involvement of ceramide and S1P in hair cell death due to gentamicin. In addition, the effects of other metabolites of ceramide, gangliosides GM1 (GM1) and GM3 (GM3), on gentamicin ototoxicity were also investigated. Basal turn organ of Corti explants from p3 to p5 rats were maintained in tissue culture and exposed to 20 or 35MUM gentamicin for 48h. The effects of ceramide, S1P, GM1, and GM3 on gentamicin-induced hair cell loss were examined. Gentamicin-induced hair cell loss was increased by ceramide but was decreased by S1P. GM1 and GM3 exhibited protective effects against gentamicin induced hair cell death at the limited concentrations. These results indicate that ceramide enhances gentamicin ototoxicity by promoting apoptotic hair cell death, and that S1P, GM1, and GM3 act as cochlear protectants. In conclusion, sphingolipid metabolites influence the apoptotic reaction of hair cells to gentamicin ototoxicity. PMID- 20709154 TI - Acupuncture is effective to attenuate stress and stimulate lymphocyte proliferation in the elderly. AB - Acupuncture has increasingly been used to treat many conditions, including psychiatric disorders and immunological-related disorders. However, the effects of acupuncture as stress management and immune functions in the elderly are largely unclear. Here we investigated the effects of acupuncture on stress related psychological symptoms and cellular immunity in young adults and elderly subjects. The acupuncture treatment consisted of six sessions and the procedures included the insertion of needles at bilateral acupoints LI4, SP6 and ST36. Psychological variables (depression, anxiety and stress) were investigated by means of self-assessment inventories. Peripheral blood mononuclear cells were isolated and cultured in vitro to measure mitogen-induced T-cell proliferation as well as cellular sensitivity to dexamethasone. All data were assessed before and after the intervention. Acupuncture was able to significantly reduce depression (p<0.001), anxiety (p<0.001) and stress (p<0.001) scores. The intervention also increased T-cell proliferation, with greater intensity in the elderly group (p=0.004). No changes in cellular sensitivity to dexamethasone were observed following acupuncture. We conclude that acupuncture was efficient to attenuate the psychological distress as well as to increase an important feature of cellular immunosenescence. PMID- 20709155 TI - Spontaneous itch in the absence of hyperalgesia in a mouse hindpaw dry skin model. AB - We presently investigated if chronic dry skin treatment of the mouse hindpaw results in itch-related behavior, with or without accompanying hyperalgesia and allodynia. Following a 10-day period of treatment of one hindpaw with a mixture of acetone-diethylether-water (AEW), mice exhibited a significant increase in spontaneous biting behavior directed to the treated hindpaw compared to control animals in which one hindpaw was similarly treated with water only (W). Biting in the AEW group was significantly attenuated by the MU-opioid antagonist naltrexone but was unaffected by the MU-agonist morphine. There were no significant differences in hindpaw heat withdrawal latency, mechanical withdrawal threshold, or cold-plate latency between W and AEW treatment groups. These results indicate that chronic AEW treatment induces spontaneous itch but does not alter pain sensitivity, supporting the utility of this model for studies of chronic dry skin itch. PMID- 20709156 TI - Meta-analysis of FKBP5 gene polymorphisms association with treatment response in patients with mood disorders. AB - The aim of our study was to assess the association between FKBP5 gene polymorphisms and treatment response in patients with mood disorders using a meta analysis. Eight separate studies that included data from 2199 subjects were identified. Meta-analysis was performed for three FKBP5 gene polymorphisms (rs1360780, rs3800373, and rs4713916). A significant association of FKBP5 gene rs4713916 polymorphism and response rate was found in patients with mood disorders (Overall: A versus G: OR=1.28, 95%CI=1.06-1.53, P=0.01; GA+AA versus GG: OR=1.32, 95%CI=1.05-1.67, P=0.02. Caucasian: A versus G: OR=1.28, 95%CI=1.06 1.55, P=0.01; GA+AA versus GG: OR=1.33, 95%CI=1.04-1.70, P=0.02). However, we did not detect the association between FKBP5 gene rs1360780 and rs3800373 polymorphisms and treatment response in patients with mood disorders (P>0.05). This meta-analysis demonstrates that treatment response in patients with mood disorders is associated with FKBP5 gene rs4713916 polymorphism, but not rs1360780 and rs3800373. PMID- 20709157 TI - Gene regulation by SMAR1: Role in cellular homeostasis and cancer. AB - Changes in the composition of nuclear matrix associated proteins contribute to alterations in nuclear structure, one of the major phenotypes of malignant cancer cells. The malignancy-induced changes in this structure lead to alterations in chromatin folding, the fidelity of genome replication and gene expression programs. The nuclear matrix forms a scaffold upon which the chromatin is organized into periodic loop domains called matrix attachment regions (MAR) by binding to various MAR binding proteins (MARBPs). Aberrant expression of MARBPs modulates the chromatin organization and disrupt transcriptional network that leads to oncogenesis. Dysregulation of nuclear matrix associated MARBPs has been reported in different types of cancers. Some of these proteins have tumor specific expression and are therefore considered as promising diagnostic or prognostic markers in few cancers. SMAR1 (scaffold/matrix attachment region binding protein 1), is one such nuclear matrix associated protein whose expression is drastically reduced in higher grades of breast cancer. SMAR1 gene is located on human chromosome 16q24.3 locus, the loss of heterozygosity (LOH) of which has been reported in several types of cancers. This review elaborates on the multiple roles of nuclear matrix associated protein SMAR1 in regulating various cellular target genes involved in cell growth, apoptosis and tumorigenesis. PMID- 20709158 TI - Noradrenaline release in the locus coeruleus modulates memory formation and consolidation; roles for alpha- and beta-adrenergic receptors. AB - Noradrenaline, essential for the modulation of memory, is released in various parts of the brain from nerve terminals controlled by the locus coeruleus (LoC). Noradrenaline release consequent upon input from higher brain areas also occurs within the LoC itself. We examined the effect of noradrenaline on adrenergic receptors in the LoC on memory processing, using colored bead discrimination learning in the young domestic chick. We have shown previously that the release of noradrenaline in the hippocampus and cortex (mesopallium) is essential for acquisition and consolidation of short-term to intermediate and to long-term memory. Noradrenaline release within the LoC is triggered by the glutamatergic input from the forebrain. Inhibition by LoC injection of NMDA or AMPA receptor antagonists is rescued by injection of beta2-and beta3-adrenoceptor (AR) agonists in the hippocampus. We show that inhibition of alpha2A-ARs by BRL44408 in the LoC up to 30 min post-training consolidates weakly-reinforced learning. Conversely activation of alpha2A-ARs in the LoC at the times of consolidation between short term and intermediate and long-term memory caused memory loss, which is likely to be due to a decreased release of noradrenaline within these two time windows. The alpha2A-AR antagonist will block presynaptic inhibitory receptors leading to an increase in extracellular noradrenaline. This interpretation is supported by the actions of noradrenaline uptake blockers that produce the same memory outcome. BRL44408 in the mesopallium also caused memory enhancement. beta2-ARs are important in the first time window, whereas alpha1-, alpha2C-and beta3-ARs are important in the second time window. The results reveal that for successful memory formation noradrenaline release is necessary within the LoC as well as in other brain regions, at the time of consolidation of memory from short-term to intermediate and from intermediate to long-term memory. PMID- 20709159 TI - TNF-alpha transiently induces endoplasmic reticulum stress and an incomplete unfolded protein response in the hypothalamus. AB - In diet-induced obesity, hypothalamic inflammation is triggered as an outcome of prolonged exposure to dietary fats. Toll-like receptor 4 (TLR4) activation plays a central role in this process, inducing endoplasmic reticulum stress and activating inflammatory cytokine gene transcription. Although saturated fatty acids can induce endoplasmic reticulum stress in the hypothalamus, it is unknown whether inflammatory cytokines alone can activate this mechanism. Here, rats were treated with TNF-alpha or lyposaccharide (LPS) and endoplasmic reticulum stress and unfolded protein response were evaluated by immunoblot and polymerase chain reaction (PCR). Activation of TLR4 by LPS was capable of inducing a complete endoplasmic reticulum stress and unfolded protein response through the PERK/eIF2alpha and IRE1alpha/XBP1 pathways. Conversely, TNF-alpha, injected either locally or systemically, was unable to induce a complete program of unfolded protein response, although the activation of endoplasmic reticulum stress was achieved to a certain degree. Thus, in the hypothalamus, the isolated action of TNF-alpha is insufficient to produce the activation of a complete program of unfolded protein response. PMID- 20709160 TI - Expression of the nuclear transport protein importin beta-1 and its association with the neurokinin 3 receptor in the rat hypothalamus following acute hyperosmotic challenge. AB - The tachykinin NK3 receptor (NK3R) is a G-protein coupled receptor that is activated, internalized, and trafficked to the nuclei of magnocellular neurons in the paraventricular nucleus of the hypothalamus (PVN) in response to acute hyperosmolarity. The lack of information on the nuclear import pathway raises concerns about the physiological role of nuclear NK3R. NK3R contains a nuclear localizing sequence (NLS) and this raises the possibility that importins are involved in transport of NK3R through the nuclear pore complex. The following experiments utilized: (1) co-immunoprecipitation to determine if NK3R is associated with importin beta-1 following activation in response to acute hyperosmolarity in vivo, and (2) immuno-neutralization of importin beta-1 in vitro to determine if nuclear transport of NK3R was blocked. Rats were given an i.v. injection of hypertonic saline (2 M) and 10 min after the infusion, the PVN was removed and homogenized. Importin beta-1 co-immunoprecipitated with the NK3R following treatment with 2 M NaCl, but not following isotonic saline treatment. Immuno-neutralization of importin beta-1 decreased the transport of NK3R into the nuclei in a time dependent fashion. The results indicate that in response to acute hyperosmotic challenge, NK3R associates with importin beta-1 which enables the nuclear transport of NK3R. This is the first in vivo study linking importin beta-1 and the nuclear transport of a G protein coupled receptor, the NK3R, in brain. PMID- 20709161 TI - Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons. AB - Along with its ability to directly regulate gene expression, estradiol influences cell signaling and brain functions via rapid, membrane-initiated events. In the female rat striatum, estradiol activates membrane-localized estrogen receptors to influence synaptic neurotransmission, calcium channel activity, and behaviors related to motor control. Yet, the mechanism by which estradiol acts to rapidly affect striatal physiology has remained elusive. Here we find that membrane estrogen receptors (ERs) couple to the metabotropic glutamate receptors mGluR5 and mGluR3, providing the framework to understand how membrane estrogen receptors affect striatal function. Using CREB phosphorylation as a downstream measure of ER/mGluR activation, membrane-localized estrogen receptor alpha (ERalpha) activates mGluR5 signaling to mediate mitogen-activated protein kinase (MAPK) dependent CREB phosphorylation. Further, ERalpha and estrogen receptor beta (ERbeta) activate mGluR3 to attenuate L-type calcium channel-dependent CREB signaling. Interestingly, while this fundamental mechanism of ER/mGluR signaling was initially characterized in hippocampal neurons, estrogen receptors in striatal neurons are paired with a different set of mGluRs, resulting in the potential to functionally isolate membrane-initiated estrogen signaling across brain regions via use of specific mGluR modulators. These results provide both a mechanism for the rapid actions of estrogens within the female striatum, as well as demonstrate that estrogen receptors can interact with a more diverse set of surface membrane receptors than previously recognized. PMID- 20709162 TI - Epidermal growth factor receptor antagonists and CNS axon regeneration: mechanisms and controversies. AB - The reasons for the failure of central nervous system (CNS) axons to regenerate include the presence of myelin- and non-myelin derived inhibitory molecules, neuronal apoptosis and the absence of a potent neurotrophic stimulus. Transactivation of the epidermal growth factor receptor (EGFR) has been implicated in signalling inhibition of axon growth in the CNS. Small molecule EGFR inhibitors such as AG1478 and PD168393 promote CNS axon growth after optic nerve transection despite the presence of inhibitory molecules in the environment of the regenerating axon. However, our results demonstrate that phosphorylated EGFR (pEGFR) is not present on regenerating axons and that the majority of pEGFR is present in glia, suggesting that EGFR cannot play a direct intra-axonal role in signalling inhibition and thus disinhibited CNS axon growth must be indirectly mediated by glia. We argue that EGFR may not have a role in signalling axon growth inhibition since AG1478 and PD168393 promotes neuronal neurite outgrowth in CNS myelin-inhibited cultures after EGFR knockdown. This review discusses the current evidences for and against the involvement of EGFR in signalling myelin inhibition. PMID- 20709163 TI - Non-neuronal cell transplantation as a possible therapeutic approach for epilepsy treatment. AB - This is a letter to the editor about a recently published article. This letter provides evidence that suggest non-neuronal cell transplantation merits investigation as a possible novel therapeutic approach for epilepsy treatment. PMID- 20709164 TI - Two conserved Z9-octadecanoic acid desaturases in the red flour beetle, Tribolium castaneum. AB - Z9 Desaturases catalyse the formation of a cis-unsaturated bond in the Delta9 position of the saturated fatty acids stearate and palmitate. They are considered essential enzymes in eukaryotic organisms as their Z9 unsaturated fatty acid products are required for homeostatic roles such as maintenance of membrane fluidity. Two putative Z9 acyl Coenzyme-A desaturase genes were identified in the red flour beetle, Tribolium castaneum, genome (TcasZ9desA and B) based on their similarity to acyl CoA-desaturases of other insects. TcasZ9desA and B share 75% nucleic acid sequence identity and appear to be functionally conserved; the genes were cloned and expressed in the yeast strain Saccharomyces cerevisiae (ole1); both genes complemented the yeast requirement for Z9 fatty acids and produced substantial quantities of Z9 desaturated products with a stearate>palmitate chain length preference. Quantitative PCR analysis of transcripts in RNA obtained from adult, larval and pupal stages of the beetles show TcasZ9desA and B are expressed at similar levels in all stages, with the pupal stage having the lowest expression. PMID- 20709165 TI - Induction of selective plasticity in the frequency tuning of auditory cortex and auditory thalamus neurons by locus coeruleus stimulation. AB - Neurons in primary sensory cortices display selective receptive field plasticity in behavioral situations ranging from classical conditioning to attentional tasks, and it is generally assumed that neuromodulators promote this plasticity. Studies have shown that pairing a pure-tone and a stimulation of the nucleus basalis magnocellularis mimics the selective receptive field facilitations described after classical conditioning. Here, we evaluated the consequences of repeated pairings between a particular sound frequency and a phasic stimulation of locus coeruleus (LC) on the frequency tuning of auditory thalamus and auditory cortex neurons. Selective alterations for the paired frequency were observed for more than 30% of the cells recorded both in cortex and in thalamus. There were as much selective increases as selective decreases at the cortical level, whereas selective increases were prevailing at the thalamic level. Selective changes usually persisted 15 min after pairing in cortex; they dissipated in thalamus, and so did the general increases in both structures. In animals with stimulation sites outside the LC, pairing induced either general changes or no effect. These results indicate that the selective plasticity induced in the frequency tuning of auditory cortex neurons by LC stimulation is bidirectional, thereby suggesting that noradrenergic activation can contribute to the different forms of plasticity observed after distinct behavioral paradigms. PMID- 20709166 TI - Harmonic pitch: dependence on resolved partials, spectral edges, and combination tones. AB - Perceptual weights were estimated in a pitch-comparison experiment to assess the relative influences of individual partial tones on listeners' pitch judgments. The stimuli were harmonic sounds (F0=200 Hz) with partials up to the 12th. Low numbered partials were removed step-by-step, so that the remaining higher numbered partials would have a better chance of showing any effect. The individual frequencies of the partials were perturbed randomly on each stimulus presentation, and weights were estimated as the correlation coefficients between the frequency perturbations and the listeners' responses. When the harmonic sounds contained all twelve partials, the listeners depended mostly on the low numbered, resolved partials within the well-established dominance region. As the low-numbered partials were taken out of the dominance region, the listeners mostly listened to the lowest and highest partials at the spectral edges. For one listener, such an edge-listening strategy took the form of relying on nonlinear combination tones. Overall, there was no indication of any influence on pitch from unresolved partials, thus no evidence of contribution to pitch from temporal cues carried by this group of partials. The estimated patterns of weights were well described by the predictions of Goldstein's optimal-processor model. The predicted weights were inversely proportional to the amount of error for estimating the individual frequencies of the partials. The agreement between the predicted and measured weights suggests that, for harmonic sounds, partials whose frequencies are perceived with the best precision will likely have the greatest influence on perceived pitch. PMID- 20709167 TI - An ethnopharmacological study on Verbascum species: from conventional wound healing use to scientific verification. AB - AIM OF THE STUDY: The leaves, flowers, and whole aerial parts of Verbascum L. (Scrophulariaceae) species are used to treat eczema and other types of inflammatory skin conditions and as a desiccant for wounds in Turkish traditional medicine. In the present study, the methanolic extracts of 13 Verbascum species growing in Turkey, including Verbascum chionophyllum Hub.-Mor., Verbascum cilicicum Boiss., Verbascum dudleyanum (Hub.-Mor.) Hub.-Mor., Verbascum lasianthum Boiss., Verbascum latisepalum Hub.-Mor., Verbascum mucronatum Lam., Verbascum olympicum Boiss., Verbascum pterocalycinum var. mutense Hub.-Mor., Verbascum pycnostachyum Boiss. & Heldr., Verbascum salviifolium Boiss., Verbascum splendidum Boiss., Verbascum stachydifolium Boiss. & Heldr and Verbascum uschackense (Murb.) Hub.-Mor. were assessed for their in vivo wound healing activity. MATERIAL AND METHODS: In vivo wound healing activity of the plants were evaluated by linear incision and circular excision experimental models subsequently histopathological analysis. The healing potential was comparatively assessed with a reference ointment Madecassol((r)), which contains 1% extract of Centella asiatica. RESULTS: The methanolic extracts of Verbascum olympicum, Verbascum stachydifolium and Verbascum uschackense demonstrated the highest activities on the both wound models. Moreover, the methanolic extracts of Verbascum latisepalum, Verbascum mucronatum, and Verbascum pterocalycinum var. mutense were found generally highly effective. On the other hand, the rest of the species did not show any remarkable wound healing effect. Results of the present study support the continued and expanded utilization of these plant species employed in Turkish folk medicine. CONCLUSION: The experimental study revealed that Verbascum species display remarkable wound healing activity. PMID- 20709168 TI - BWtrs: A tool for searching for tandem repeats in DNA sequences based on the Burrows-Wheeler transform. AB - Genomes of organisms contain a variety of repeated structures of various length and type, interspersed or tandem. Tandem repeats play important role in molecular biology as they are related to genetic backgrounds of inherited diseases, and also they can serve as markers for DNA mapping and DNA fingerprinting. Improving the efficiency of algorithms for searching for tandem repeats in DNA sequences can lead to many useful applications in the area of genomics. We introduce a very efficient, web-based tool for large scale searching for exact tandem repeats in genomes, based on the use of the Burrows-Wheeler Transform. The service is a remarkably efficient and powerful application that allows analyzing complete genomes without any restrictions. The Burrows-Wheeler Tandem Repeat Searcher (BWtrs) is an on-line application that searches for the exact occurrences of tandem repetitions in DNA sequences. The BWtrs service is freely available at: http://bioinfo.polsl.pl/BWtrs. We present examples of the use of our web application and we compare results of our computations with the results obtained by using other existing tools for searches for exact tandem repeats. PMID- 20709169 TI - Transcriptional interactions between the pannier isoforms and the cofactor U shaped during neural development in Drosophila. AB - The pannier (pnr) gene of Drosophila melanogaster encodes two isoforms that belong to the family of GATA transcription factors. The isoforms share an expression domain in the wing discs where they exhibit distinct functions during regulation of the proneural achaete/scute (ac/sc) genes. We previously identified two regions in the pnr locus that drive reporter expression in transgenic lines in patterns that recapitulate the essential features of expression of the two isoforms. Here, we identify promoter regions driving isoform expression, showing that pnr-alpha regulatory sequences are close to the transcription start site while pnr-beta expression requires functional interactions between proximal and distal regulatory elements. We find that the promoter domains necessary for reporter expression also mediate autoregulation of Pnr-beta and repression of pnr alpha by Pnr-beta. The cofactor U-shaped (Ush), which is known to down-regulate the function of Pnr during thorax patterning postranscriptionally, in addition represses pnr-beta required for ac/sc activation. Moreover, Ush negatively regulates its own expression, while the pnr isoforms positively regulate ush. Our study uncovers complex transcriptional interactions between the pnr isoforms and the cofactor Ush that may be important for regulation of proneural expression and thorax patterning. PMID- 20709170 TI - Synthesis, characterization, and in vivo evaluation of poly(ethylene oxide-co glycidol)-platinate conjugate. AB - Poly(ethylene oxide-co-glycidol) (poly(EO-co-Gly)), a member of polyether polyol (PEP), resembles polyethylene glycol (PEG) in the polymer backbone but distinguishes itself by having multiple pendent groups along the main chain. We showed that this new bioconjugation material is biocompatible by its lack of toxicity on fibroblast cell growth, inactivity in hemolysis, and the absence of side effects after injection in mice. The usefulness of poly(EO-co-Gly) as a polymeric drug carrier was demonstrated via the preparation and characterization of a new anticancer polymer-drug conjugate, poly(EO-co-Gly)-platinate. The drug loading was 9.1-12.6% (cisplatin/conjugate w/w), at least four times higher than a PEG conjugate of similar molecular weight. The aqueous solubility of cisplatin was increased by around 10 folds after conjugation. Platinum complexes were released from the conjugate in a sustained manner over 2 days. The release of active drugs was confirmed by the antitumor activity of poly(EO-co-Gly)-platinate in vitro against HONE-1 (human nasopharyngeal carcinoma) and MCF-7 (human breast cancer), albeit at a potency lower than free cisplatin. Poly(EO-co-Gly)-platinate improved the therapeutic index of cisplatin in vivo. The conjugate had a similar antitumor activity as free cisplatin in nude mice bearing HONE-1 xenografts, and achieved 52% inhibition of tumor growth at the conclusion of the study. While free cisplatin injection caused a severe loss in body weight (>20%), poly(EO-co Gly)-platinate resulted in mild side effects. These findings support that poly(EO co-Gly) is a suitable drug carrier. PMID- 20709171 TI - Molecular and biochemical characterisation of a dual proteolytic system in vine weevil larvae (Otiorhynchus sulcatus Coleoptera: Curculionidae). AB - The ability of phytophagous insects to utilise the relatively low nitrogen content of plant tissues is typically the limiting factor in their nutritional uptake. In the larval stage, the vine weevil feeds predominantly on root tissues of plants. The root tissue as a whole has low levels of free amino acids, and thus effective hydrolysis of dietary proteins is essential for survival. In contrast to previous reports the present study demonstrates through both molecular and biochemical studies the presence of proteolytic enzymes from two mechanistic classes, cysteine and serine proteases, in the gut of larval vine weevil; with the latter being the predominant form. cDNA clones encoding cathepsin B-like and serine-like sequences were isolated from a gut specific cDNA library; the cathepsin B-like clone has the Cys-His-Asn catalytic triad. However, the sequence showed the replacement of the conserved His-His sequence in the "occluding loop" region of the enzyme with Asp-His. This may result in a change to the substrate specificity. Two trypsin precursors contained evidence of a signal peptide, activation peptide, and conserved N-termini (IVGG). Other structural features included typical His, Asp, and Ser residues of the catalytic amino acid triad indicative of serine proteases, characteristic residues in the substrate-binding pocket, and four pairs of cysteine residues for disulfide bridges. The apparent abundance of the trypsin-like cDNA clones compared to the cathepsin B clones suggests that serine proteases are the predominant form, thus supporting data from the biochemical studies. PMID- 20709172 TI - Expression of cellobiose dehydrogenase from Neurospora crassa in Pichia pastoris and its purification and characterization. AB - A gene encoding cellobiose dehydrogenase (CDH) from Neurospora crassa strain FGSC 2489 has been cloned and expressed in the heterologous host Pichia pastoris, under the control of the AOX1 methanol inducible promoter. Recombinant CDH without the native signal sequence and fused with a His(6)-tag (rNC-CDH1) was successfully expressed and secreted. rNC-CDH1 was produced at the level of 652 IU/L after 2 days of cultivation in the induction medium. The His(6)-tagged rNC CDH1 was purified through a one-step Ni-NTA affinity column under non-denaturing conditions. The purified rNC-CDH1 has a CDH activity of 745 1IU/L (0.89 mg protein/mL), with a specific CDH activity of 8.37 IU/mg. The purity of the enzyme was examined by SDS-PAGE, and a single band corresponding to a molecular weight of about 120 kDa was observed. Activity staining confirmed the CDH activity of the protein band. The purified rNC-CDH1 has maximum CDH activity at pH 4.5, and a rather broad temperature optimum of 25-70 degrees C. Kinetic analysis showed cellobiose and cellooligosaccharides are the best substrates for rNC-CDH1. The K(m) value of the rNC-CDH1 for cellooligosaccharide increases with the elongation of glucosyl units. k(cat) remains relatively constant when the chain length changes. PMID- 20709173 TI - Activation by phosphorylation and purification of human c-Jun N-terminal kinase (JNK) isoforms in milligram amounts. AB - c-Jun N-terminal kinases (JNKs) are part of the mitogen-activated protein kinase (MAPK) signaling cascade. They are activated through dual phosphorylation of two residues in the activation loop, a threonine and a tyrosine, by MAP2 kinases (MKK4 and 7) in response to various extracellular stresses such as UV or osmotic shock, as well as by cytokines and growth factors. Only small amounts of phosphorylated, active JNKs have previously been produced because of difficulties in expressing these phosphorylated kinases in Escherichia coli, which lack the appropriate upstream kinases. We have now established a novel activation and purification method that allows for reproducible production of milligram amounts of active, phosphorylated JNKs suitable for a variety of enzymatic, biophysical and structural characterizations. We utilize N-terminally His-tagged MKK4 that is coexpressed in E. coli with a constitutively active form of MEKK1. This phosphorylated, active His-MKK4 is purified by Ni-NTA chromatography and used to phosphorylate milligram amounts of three different isoforms of human JNKs (JNK1alpha1, JNK1alpha2 and JNK2alpha2) that had separately been expressed and purified from E. coli in their inactive forms. These in vitro activated JNKs are phosphorylated on both residues (T183, Y185) in their activation loops and are active towards their substrate, ATF2. PMID- 20709174 TI - High-yield production and characterization of biologically active GST-tagged human topoisomerase IIalpha protein in insect cells for the development of a high throughput assay. AB - DNA topoisomerase type II enzymes are well-validated targets of anti-bacterial and anti-cancer compounds. In order to facilitate discovery of these types of inhibitors human topoisomerase II in vitro assays can play an important role to support drug discovery processes. Typically, human topoisomerase IIalpha proteins have been purified from human cell lines or as untagged proteins from yeast cells. This study reports a method for the rapid over-expression and purification of active GST-tagged human topoisomerase IIalpha using the baculovirus mediated insect cell expression system. Expression of the GST fused protein was observed in the nuclear fraction of insect cells. High yields (40 mg/L i.e. 8 mg/10(9) cells) at >80% purity of this target was achieved by purification using a GST HiTrap column followed by size exclusion chromatography. Functional activity of GST-tagged human topoisomerase IIalpha was demonstrated by ATP-dependent relaxation of supercoiled DNA in an agarose gel based assay. An 8-fold DNA dependent increase in ATPase activity of this target compared to its intrinsic activity was also demonstrated in a high-throughput ATPase fluorescence based assay. Human topoisomerase IIalpha inhibitors etoposide, quercetin and suramin were tested in the fluorescence assay. IC(50) values obtained were in good agreement with published data. These inhibitors also demonstrated >= 30-fold potency over the anti-bacterial topoisomerase II inhibitor ciprofloxacin in the assay. Collectively these data validated the enzyme and the high-throughput fluorescence assay as tools for inhibitor identification and selectivity studies. PMID- 20709175 TI - Pattern motion representation in primary visual cortex is mediated by transcortical feedback. AB - A highly important question in visual neuroscience is to identify where in the visual system information from different processing channels is integrated to form the complex scenery we perceive. A common view to this question is that information is processed hierarchically because small and selective receptive fields in lower visual areas melt into larger receptive fields in specialized higher visual areas. However, a higher order area in which all incoming signals ultimately converge has not yet been identified. Rather, modulation of subthreshold influences from outside the classical receptive field related to contextual integration occurs already in early visual areas. So far it is unclear how these influences are mediated (Gilbert, 1998; Angelucci and Bullier, 2003; Gilbert and Sigman, 2007). In the present study, we show that feedback connections from a higher motion processing area critically influence the integration of subthreshold global motion cues in early visual areas. Global motion cues are theoretically not discernible for a local motion detector in V1, however, imprints of pattern motion have been observed in this area (Guo et al., 2004; Schmidt et al., 2006). By combining reversible thermal deactivation and optical imaging of intrinsic signals we demonstrate that feedback signals from the posteromedial suprasylvian sulcus are critical for the discrimination between global and local motions already in early visual areas. These results suggest that global features of the visual scenery are fed back to lower visual processing units in order to facilitate the integration of local cues into a global construct. PMID- 20709176 TI - Detecting stable distributed patterns of brain activation using Gini contrast. AB - The relationship between spatially distributed fMRI patterns and experimental stimuli or tasks offers insights into cognitive processes beyond those traceable from individual local activations. The multivariate properties of the fMRI signals allow us to infer interactions among individual regions and to detect distributed activations of multiple areas. Detection of task-specific multivariate activity in fMRI data is an important open problem that has drawn much interest recently. In this paper, we study and demonstrate the benefits of random forest classifiers and the associated Gini importance measure for selecting voxel subsets that form a multivariate neural response. The Gini importance measure quantifies the predictive power of a particular feature when considered as part of the entire pattern. The measure is based on a random sampling of fMRI time points and voxels. As a consequence the resulting voxel score, or Gini contrast, is highly reproducible and reliably includes all informative features. The method does not rely on a priori assumptions about the signal distribution, a specific statistical or functional model or regularization. Instead, it uses the predictive power of features to characterize their relevance for encoding task information. The Gini contrast offers an additional advantage of directly quantifying the task-relevant information in a multiclass setting, rather than reducing the problem to several binary classification subproblems. In a multicategory visual fMRI study, the proposed method identified informative regions not detected by the univariate criteria, such as the t-test or the F-test. Including these additional regions in the feature set improves the accuracy of multicategory classification. Moreover, we demonstrate higher classification accuracy and stability of the detected spatial patterns across runs than the traditional methods such as the recursive feature elimination used in conjunction with support vector machines. PMID- 20709177 TI - Remedial action and feedback processing in a time-estimation task: evidence for a role of the rostral cingulate zone in behavioral adjustments without learning. AB - The present study examined the role of the rostral cingulate zone (RCZ) in feedback processing, and especially focused on effects of modality of the feedback stimulus and remedial action. Participants performed a time-estimation task in which they had to estimate a 1-second interval. After the estimation participants received verbal (correct/false) or facial (fearful face/happy face) feedback. Percentage of positive and negative feedback was kept at 50% by dynamically adjusting the interval in which estimations were labeled correct. Contrary to predictions of the reinforcement learning theory, which predicts more RCZ activation when the outcome of behavior is worse than expected, we found that the RCZ was more active after positive feedback than after negative feedback, independent of the modality of the feedback stimulus. More in line with the suggested role of the RCZ in reinforcement learning was the finding that the RCZ was more active after negative feedback that was followed by a correct adjustment as compared to negative feedback followed by an incorrect adjustment. Both findings can be explained in terms of the RCZ being involved in facilitating remedial action as opposed to the suggested signaling function (outcome is worse than expected) proposed by the reinforcement learning theory. PMID- 20709178 TI - On meta-analyses of imaging data and the mixture of records. AB - Neumann et al. (2010) aim to find directed graphical representations of the independence and dependence relations among activities in brain regions by applying a search procedure to merged fMRI activity records from a large number of contrasts obtained under a variety of conditions. To that end, Neumann et al., obtain three graphical models, justifying their search procedure with simulations that find that merging the data sampled from probability distributions characterized by two distinct Bayes net graphs results in a graphical object that combines the edges in the individual graphs. We argue that the graphical objects they obtain cannot be interpreted as representations of conditional independence and dependence relations among localized neural activities; specifically, directed edges and directed pathways in their graphical results may be artifacts of the manner in which separate studies are combined in the meta-analytic procedure. With a larger simulation study, we argue that their simulation results with combined data sets are an artifact of their choice of examples. We provide sufficient conditions and necessary conditions for the merger of two or more probability distributions, each characterized by the Markov equivalence class of a directed acyclic graph, to be describable by a Markov equivalence class whose edges are a union of those for the individual distributions. Contrary to Neumann et al., we argue that the scientific value of searches for network representations from imaging data lies in attempting to characterize large scaled neural mechanisms, and we suggest several alternative strategies for combining data from multiple experiments. PMID- 20709179 TI - Chemokine profile of synovial fluid from normal, osteoarthritis and rheumatoid arthritis patients: CCL25, CXCL10 and XCL1 recruit human subchondral mesenchymal progenitor cells. AB - OBJECTIVE: The microfracture technique activates mesenchymal progenitors that enter the cartilage defect and form cartilage repair tissue. Synovial fluid (SF) has been shown to stimulate the migration of subchondral progenitors. The aim of our study was to determine the chemokine profile of SF from normal, rheumatoid arthritis (RA) and osteoarthritis (OA) donors and evaluate the chemotactic effect of selected chemokines on human subchondral progenitor cells. METHOD: Chemokine levels of SF were analyzed using human chemokine antibody membrane arrays. The chemotactic potential of selected chemokines on human mesenchymal progenitors derived from subchondral cortico-spongious bone was tested using 96-well chemotaxis assays. Chemokine receptor expression of subchondral progenitors was assessed by real-time gene expression analysis and immuno-histochemistry. RESULTS: Chemokine antibody array analysis showed that SF contains a broad range of chemokines. Ten chemokines that showed significantly reduced levels in RA or OA compared to normal SF or robustly high levels in all SF tested were used for further chemotactic analysis. Chemotaxis assays showed that the chemokines MDC/CCL22, CTACK/CCL27, ENA78/CXCL5 and SDF1alpha/CXCL12 significantly inhibited migration of progenitors, while TECK/CCL25, IP10/CXCL10 and Lymphotactin/XCL1 effectively stimulated cell migration. MCP1/CCL2, Eotaxin2/CCL24 and NAP2/CXCL7 showed no chemotactic effect on subchondral progenitors. Gene expression and immuno-histochemical analysis of corresponding chemokine receptors document presence of low levels of chemokine receptors in subchondral progenitors, with the CXCL10 receptor CXCR3 showing the highest expression level. CONCLUSION: These results suggest that SF contains chemokines that may contribute to the recruitment of human mesenchymal progenitors from the subchondral bone in microfracture. PMID- 20709180 TI - Purine receptors modulate chondrocyte extracellular inorganic pyrophosphate production. AB - OBJECTIVE: Extracellular inorganic pyrophosphate (ePPi) plays a key role in the regulation of normal and pathologic mineralization. The purpose of this work was to evaluate the role of P1 and P2 purine receptors in modulating ePPi production by articular chondrocytes. METHODS: Porcine cartilage explants and chondrocyte monolayers were cultured in the presence of P1 agonists, or a P2 agonist or antagonist and inhibitors of P2 signaling. Ambient media ePPi concentrations were measured after 48-96h. RESULTS: The P1 agonists NECA and CGS 21680 significantly decreased ePPi concentrations surrounding chondrocytes and cartilage explants. The P2 agonist, ADP, increased ePPi levels, and the P2 antagonist, suramin, decreased ePPi concentrations. Thapsigargin and 1,2 bis-(2-aminophenoxy)ethane N,N,N'N'-tetra acetic acid (BAPTA), which dampen Ca(2+)-related P2 signaling, suppressed the response to ADP. CONCLUSIONS: Purine receptors are important regulators of ePPi production by chondrocytes. P1 receptor stimulation diminishes and P2 receptor stimulation enhances ePPi production. Alterations in receptor signaling or aberrations of extracellular purine nucleotide metabolism resulting in abnormal quantities or proportions of P1 and P2 receptor ligands could foster changes in ePPi production that in turn affect mineralization. We propose a homeostatic role for extracellular purine nucleotides and purine receptors in stabilizing ePPi concentrations. PMID- 20709181 TI - Evaluation of the prevalence of enterotoxigenic Bacteroides fragilis and the distribution bft gene subtypes in patients with diarrhea. AB - The aim of this study was to determine the prevalence of enterotoxigenic Bacteroides fragilis (ETBF) in the patients with diarrhea in our region and to assess the association between diarrhea and bft gene subtypes. The presence of ETBF and bft gene subtypes were investigated in 200 stool samples from patients with diarrhea, diagnosed as gastroenteritis, which were sent to Clinical Microbiology Laboratory at Zonguldak Karaelmas University, Training and Research Hospital and in 200 stool samples from age-matched healthy subjects between April 14, 2009 and October 28, 2009. Nested - polymerase chain reaction was used to detect the presence of bft gene directly from stool samples. The bft gene subtypes were determined by PCR in case of ETBF detection. The presence of bft gene was detected in 29 (15%) of patients and 27 (14%) of control group. bft-1 and bft-2 were found in 24 and five stool samples from 29 diarrheic patients with ETBF, respectively. Among 27 control patients with ETBF, bft-1 and bft-2 were found in 24 and three samples, respectively. No bft-3 subtypes were identified in our study. ETBF was found as a single pathogen in 9% of the patients with diarrhea, while there was an accompanying pathogen in 6% of the patients. The proportion of coinfection with another pathogen among ETBF positive patients was 38%. Cooccurance with ETBF was present in nine of 18 patients with Rotavirus and two of five patients with Entamoeba histolytica. In conclusion; there was no statistically significant difference between the prevalence of ETBF in diarrheal patients and that of the control group. When the patients and controls were compared for each age group, no statistically significant difference in ETBF rates was found. There was no significant difference between groups with respect to bft subtypes; bft-1 was identified as the most common subtype. The rate of coinfection of ETBF and Rotavirus was high. PMID- 20709182 TI - Arylhydrocarbon receptor (AhR) activation in airway epithelial cells induces MUC5AC via reactive oxygen species (ROS) production. AB - The dioxins and dioxin-like compounds in cigarette smoke regulate various immunological responses via the arylhydrocarbon receptor (AhR). These environmental toxicants are known to cause bronchitis, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Recent studies have demonstrated that AhR activation upregulates the expression of mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) in the airway epithelial cell line. However, the mechanism for the production of mucin has not been clarified. In this study, we investigated the role and pathway of AhR in airway epithelial cells by using selective agonists and antagonists. After stimulation with or without benzopyrene (B[a]P), an AhR agonist, MUC5AC expression was measured by real-time RT-PCR. The mechanism of AhR-induced MUC5AC expression in airway epithelial cells was studied in terms of the production of cytokine and reactive oxygen species (ROS). Treatment with B[a]P increased ROS generation in NCI-H292 cells. Furthermore, B[a]P-induced MUC5AC upregulation and mucin production were inhibited by AhR siRNA or the use of an antioxidative agent. These results suggest that the AhR-induced increase of mucin production is partially mediated by ROS generation. An antioxidant therapy approach may help to cure AhR-induced mucus hypersecretory diseases. PMID- 20709183 TI - Computational quantum chemistry and adaptive ligand modeling in mechanistic QSAR. AB - Drugs are adaptive molecules. They realize this peculiarity by generating different ensembles of prototropic forms and conformers that depend on the environment. Among the impressive amount of available computational drug discovery technologies, quantitative structure-activity relationship approaches that rely on computational quantum chemistry descriptors are the most appropriate to model adaptive drugs. Indeed, computational quantum chemistry descriptors are able to account for the variation of the intramolecular interactions of the training compounds, which reflect their adaptive intermolecular interaction propensities. This enables the development of causative, interpretive and reasonably predictive quantitative structure-activity relationship models, and, hence, sound chemical information finalized to drug design and discovery. PMID- 20709184 TI - Prenatal PAH exposure is associated with chromosome-specific aberrations in cord blood. AB - Chromosomal aberrations are associated with increased cancer risk in adults. Previously, we demonstrated that stable aberrations involving chromosomes 1-6 in cord blood are associated with prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) measured in air and are disproportionate to genomic content. We now examine whether the association with air PAHs is chromosome-specific and extends to smaller chromosomes. Using whole chromosome paints for chromosomes 1 6, 11, 12, 14 and 19, and a 6q sub-telomere specific probe, we scored 48 cord bloods (1500 metaphases per sample) from newborns monitored prenatally for airborne PAH exposure in the Columbia Center for Children's Environmental Health cohort. Frequencies of stable aberrations were calculated as incident aberrations per 100 cell equivalents scored, and examined for association with airborne PAHs. Aberrations in chromosome 6 occurred more frequently than predicted by genomic content (p<0.008). Levels of both prenatal airborne PAHs and stable aberration frequency in chromosomes 1-6 decreased to half the levels reported previously in the same cohort (mean PAH decreased from 3.6 to 1.8ng/m(3); mean stable aberration frequency from 0.56 to 0.24, SD=0.19). The mean stable aberration frequency was 0.45 (SD=0.15) in chromosomes 11-19. After adjusting for gender, ethnicity, and household smokers, the mean stable aberration frequency increased with increasing PAH exposure: with a doubling of prenatal PAH exposure, the mean stable aberration frequency for the chromosome1-6 group increased by a factor of 1.49 (95% CI: 0.84, 2.66; p=0.17); for chromosomes 11-19 mean stable aberration frequency increased by 2.00 (95% CI: 1.11, 3.62; p=0.02); for chromosome 6 alone, it increased by 3.16 (95% CI: 0.93, 10.77; p=0.06); there was no increase for chromosomes 1-5 (p>0.8). Aberrations in chromosomes 11, 12, 14, 19 and 6 were associated with prenatal exposure to PAHs in air, even at lower levels of PAH in air. The observed chromosome-specific effects of prenatal airborne PAHs raise concern about potential cancer risk. PMID- 20709185 TI - Uracil in DNA--its biological significance. AB - Uracil may arise in DNA as a result of spontaneous cytosine deamination and/or misincorporation of dUMP during DNA replication. In this paper we will review: (i) sources of the origin of uracil in DNA; (ii) some properties of the enzymes responsible for the excision of uracil and their role in the Ig diversification process, which comprises somatic hypermutation and class switch recombination; and (iii) consequences of cytosine deamination in other than the Ig loci, in cell types different than B lymphocytes. Furthermore, the issue concerning the basal level of uracil in DNA and consequences of the presence of U:A pairs for DNA stability and cell functions will be discussed. Finally, we will discuss the clinical significance of aberrant uracil incorporation into DNA and possible involvement of aberrantly expressed AID and the enzyme-induced presence of uracil, in carcinogenesis. Based on the literature data we conclude/hypothesize that the non-canonical base uracil may be present and well tolerated in DNA mostly as U:A pairs, likely in quantities of 10(4) per genome. Although a role of uracil in DNA is not fully defined, it is possible that an ancestral system which once used uracil in primordial genetic material (uracil-DNA), may have evolved to use this molecule in regulatory processes such as: (i) meiotic cell division to facilitate chromatid exchange during crossing-over (in spermatocytes); (ii) it is possible that uracil present in DNA may be a signaling molecule during metamorphosis of Drosophila melanogaster; and (iii) during transcription since some regulatory proteins (Escherichia coli lac repressor) and GCN4 can recognize uracil versus thymine in specific DNA regulatory sequences. Moreover, recent data suggest that in transcriptionally active chromatin the dUTP/dTTP pool may be significantly increased, which in turn may lead to massive uracil incorporation into DNA. PMID- 20709186 TI - Helminthic invasion of the central nervous system: many roads lead to Rome. AB - Invasion of the central nervous system (CNS) by parasitic worms often represents most severe complication of human helminthiasis. The pathways from the portal of entry to the CNS are manifold and differ from species to species. In this mini review, we analysed the contemporary knowledge and current concepts of the routes pathogenic helminths take to gain access to brain, spinal cord and subarachnoid space. PMID- 20709187 TI - The Equity in Prescription Medicines Use Study: using community pharmacy databases to study medicines utilisation. AB - PURPOSE: Pharmacy dispensing databases provide a comprehensive source of data on medicines use free from many of the biases inherent in administrative databases. There are challenges associated with using pharmacy databases however. This paper describes the methods we used, and their performance, so that other researchers considering using pharmacy databases may benefit from our experiences. METHODS: Data were collected from all nine pharmacy dispensing databases in an isolated New Zealand town for the period October 2005-September 2006. Probabilistic record matching was used to link individuals across pharmacies. Patient addresses from the pharmacy data were geo-located to small areas so an area measure of socioeconomic deprivation could be assigned. Medicines were coded according to the ATC-DDD drug classification system. RESULTS: Data on 619,264 dispensings were collected. Record matching reduced an initial pool of individuals from 54,484 to 38,027. Socioeconomic deprivation ranks were assigned for 30,972 (93%) of the 33,375 unique addresses identified, or 36,048 (95%) of individuals. ATC codes were assigned to 613,490 (99%) of the dispensings, with DDDs assigned to 561,223 (91%). Overall, 93% of dispensing records had complete demographic and drug information. CONCLUSIONS: The methods described in this paper generated a rich dataset for medicines use research. These methods, while initially resource intensive, can to a great extent be automated and applied to other locations, and will hopefully prove useful to other researchers facing similar challenges with using pharmacy databases. However, it is difficult to envisage these methods being viable on a long-term or national scale. PMID- 20709188 TI - Detecting hedge cues and their scope in biomedical text with conditional random fields. AB - OBJECTIVE: Hedging is frequently used in both the biological literature and clinical notes to denote uncertainty or speculation. It is important for text mining applications to detect hedge cues and their scope; otherwise, uncertain events are incorrectly identified as factual events. However, due to the complexity of language, identifying hedge cues and their scope in a sentence is not a trivial task. Our objective was to develop an algorithm that would automatically detect hedge cues and their scope in biomedical literature. METHODOLOGY: We used conditional random fields (CRFs), a supervised machine learning algorithm, to train models to detect hedge cue phrases and their scope in biomedical literature. The models were trained on the publicly available BioScope corpus. We evaluated the performance of the CRF models in identifying hedge cue phrases and their scope by calculating recall, precision and F1-score. We compared our models with three competitive baseline systems. RESULTS: Our best CRF-based model performed statistically better than the baseline systems, achieving an F1-score of 88% and 86% in detecting hedge cue phrases and their scope in biological literature and an F1-score of 93% and 90% in detecting hedge cue phrases and their scope in clinical notes. CONCLUSIONS: Our approach is robust, as it can identify hedge cues and their scope in both biological and clinical text. To benefit text-mining applications, our system is publicly available as a Java API and as an online application at http://hedgescope.askhermes.org. To our knowledge, this is the first publicly available system to detect hedge cues and their scope in biomedical literature. PMID- 20709189 TI - Lacidipine has antiatherosclerotic effects independent of its actions on lipid metabolism and blood pressure. AB - The antiatherosclerotic effect of lacidipine has been attributed to its actions on cholesterol levels, lipid metabolism or oxidant stress in advanced disease. The purpose of the present experiments was to examine whether lacidipine is protective of intimal thickening and vascular dysfunction in early atherosclerosis in the absence of the hypertension and hypercholesterolemia. A second goal was to determine whether and to what extent MMP-9 and oxidant stress are involved in possible beneficial effects of lacidipine. Lacidipine treatment (5 mg/kg/day, p.o. for 3 weeks) significantly prevented the collar-induced intimal thickening. MMP-9 expressions were increased by collar but not effected by lacidipine treatment. Nitrotyrosine staining, a marker for oxidant stress was not changed neither by collar nor lacidipine treatment in early atherosclerosis. The enhanced sensitivity to serotonine and diminished sensitivity to acetylcholine in collared arteries were restored to normal levels with treatment. These results demonstrate that the lacidipine treatment prevents the collar induced intimal thickening and accompanying vascular dysfunction in early atherosclerosis without cholesterol loading. These beneficial effects of lacidipine were not associated with changes in either MMP-9 expression or oxidant stress. However, enhanced endothelium-dependent relaxations by lacidipine, suggest that vascular protective effects of nitric oxide may be at least partly, responsible from antiatherosclerotic effects of lacidipine. PMID- 20709191 TI - Catheter ablation for ventricular tachycardia after failed endocardial ablation: epicardial substrate or inappropriate endocardial ablation? AB - BACKGROUND: The substrate of myocardial ventricular tachycardia (VT) may involve the subepicardial myocardium. OBJECTIVE: The purpose of this study was to assess the incidence of epicardial substrates in patients with a previously failed endocardial ablation attempt for VT as well as the safety and effectiveness of epicardial ablation. METHODS: Using an electroanatomic mapping system, endocardial and epicardial maps were acquired. Irrigated radiofrequency current ablations of all inducible VTs were performed. RESULTS: Between 2005 and 2009, 59 patients with or without structural heart disease underwent epicardial VT ablation. Pericardial access failed in 3 (5%) of these patients. Of the remaining 56 patients, an epicardial substrate was found in 41 (73%). Overall, acute success was achieved in 46 (78%) of 59 patients, with complete VT abolition in 27 (46%) and partial abolition in 19 (32%). Successful outcomes were the result of endocardial ablation only in 14 (24%) patients, epicardial ablation in 21 (36%), and endocardial/epicardial in 11 (19%). Ablation failed to prevent reinduction in 8 (13%) patients, and VTs were noninducible prior to ablation in 5 (8%). Two periprocedural deaths occurred, one after right ventricular perforation and one due to electromechanical dissociation. Hepatic bleeding occurred in two patients. Recurrence of any VT occurred in 27 (47%) of 57 surviving patients during median follow-up of 362 days (q1-q3; 180-468 days). Repeat epicardial mapping was not feasible due to adhesions in 3 (25%) of 12 patients. CONCLUSION: In patients with a previously failed endocardial VT ablation, epicardial mapping reveals a VT substrate in nearly three fourths of all patients, and epicardial ablation is required for successful VT abolition in more than half of patients. However, life threatening complications may occur. Repeat epicardial access was not possible in 25% due to local pericardial adhesions. PMID- 20709190 TI - Doxorubicin selectively suppresses mRNA expression and production of endothelin-1 in endothelial cells. AB - Doxorubicin (DXR) is a widely used cytostatic agent, but its administration is limited by its cardiovascular side effects. The endothelium is one of the largest organs in the human body and due to its direct contact with blood; it is exposed to the toxic effects of DXR. The aim of this study was to investigate in endothelial cells the effects of DXR on the expression of genes involved in cardiovascular diseases. We used in vitro cultured human umbilical vein endothelial cells (HUVEC) as a model; gene expression was assessed by SuperArray and qPCR. Out of the 96 representative genes of cardiovascular importance, the expression of only the ET-1 gene changed significantly. ET-1 mRNA expression was 10.9% of the untreated control (p=0.0049). This result was confirmed by qPCR (2.41% of control, p=0.0022). DXR also suppressed ET-1 production at protein level (p=0.0116). Both the early decrease in endothelial ET-1 production in the presence of DXR and the high plasma level of DXR during chemotherapy may influence the toxic effects of the drug. PMID- 20709192 TI - Hypoxia, innate immunity and infection in the lung. AB - The mucosal surface of the lung is the key interface between the external atmosphere and the bloodstream. Normally, this well oxygenated tissue is maintained in state of sterility by a number of innate immune processes. These include a physical and dynamic mucus barrier, the production of microbiocidal peptides and the expression of specific pattern recognition receptors on alveolar epithelial cells and resident macrophages and dendritic cells which recognise microbial structures and initiate innate immune responses which promote the clearance of potentially infectious agents. In a range of diseases, the mucosal surface of the lung experiences decreased oxygen tension leading to localised areas of prominent hypoxia which can impact upon innate immune and subsequent infectious and inflammatory processes. Under these conditions, the lung is generally more susceptible to infection and subsequent inflammation. In the current review, we will discuss recent data pertaining to the role of hypoxia in regulating both host and pathogen in the lung during pulmonary disease and how this contributes to innate immunity, infection and inflammation. PMID- 20709193 TI - Inhibitory activities of the heterotrimers formed from two alpha-type phospholipase A2 inhibitory proteins with different enzyme affinities and importance of the intersubunit electrostatic interaction in trimer formation. AB - alpha-type phospholipase A2 inhibitory protein (PLIalpha) isolated from the serum of the venomous snake Glyoidius brevicaudus, GbPLIalpha, is a homotrimer of subunits having a C-type lectin-like domain. The serum protein from nonvenomous snake Elaphe quadrivirgata, EqPLIalpha-LP, is homologous to GbPLIalpha, but it does not show any inhibitory activity against PLA2s. When a mixture of denaturant treated monomeric forms of GbPLIalpha and EqPLIalpha-LP was used to reconstitute their trimers, no significant amounts of heterotrimers composed of GbPLIalpha and EqPLIalpha-LP subunits could be formed. On the other hand, when a mixture of denaturant-treated monomeric forms of GbPLIalpha and the recombinant chimeric EqPLIalpha-LP, Eq13Gb37Eq, in which the residues 13-36 were replaced by those of GbPLIalpha, was used to reconstitute their trimers, significant amounts of their heterotrimers were observed. Furthermore, when a mixture of denaturant-treated monomeric forms of EqPLIalpha-LP and the recombinant chimeric GbPLIalpha, Gb13Eq37Gb, in which the residues 13-36 were replaced by those of EqPLIalpha-LP, was used, significant amounts of their heterotrimers were observed. By comparison of the respective inhibitory activities of the heterotrimeric subspecies, it was suggested that the inhibitory activity of the trimer was governed by one subunit with the highest activity, and not affected by the number of these subunits. The intermolecular electrostatic interactions between Glu23 and Lys28 of GbPLIalpha were also suggested to be important in stabilizing the trimeric structure. The importance of the electrostatic interaction was supported by the less stability of the homotrimeric structure of a mutant GbPLIalpha with a single amino acid substitution, GbPLIalpha(K28E). PMID- 20709194 TI - Proteomics of skeletal muscle glycolysis. AB - Glycolysis represents one of the best-understood and most ancient metabolic pathways. In skeletal muscle fibres, energy for contraction is supplied by adenosine triphosphate via anaerobic glycolysis, the phosphocreatine shuttle and oxidative phosphorylation. In this respect, the anaerobic glycolytic pathway supports short duration performances of contractile tissues of high intensity. The catalytic elements associated with glycolysis are altered during development, muscle differentiation, physiological adaptations and many pathological mechanisms, such as muscular dystrophy, diabetes mellitus and age-related muscle weakness. Although gel electrophoresis-based proteomics is afflicted with various biological and technical problems, it is an ideal analytical tool for studying the abundant and mostly soluble enzymes that constitute the glycolytic system. This review critically examines the proteomic findings of recent large-scale studies of glycolytic enzymes and associated components in normal, transforming and degenerating muscle tissues. In the long term, proteins belonging to the glycolytic pathway may be useful as biomarkers of muscle adaptations and pathophysiological mechanisms and can be employed to improve diagnostics and in the identification of novel therapeutic targets in neuromuscular disorders. PMID- 20709195 TI - Commentary: Deciphering the link between architecture and biological response of a bone graft substitute. AB - Hundreds of studies have been devoted to the search for the ideal architecture for bone scaffold. Despite these efforts, results are often contradictory, and rules derived from these studies are accordingly vague. In fact, there is enough evidence to postulate that ideal scaffold architecture does not exist. The aim of this document is to explain this statement and review new approaches to decipher the existing but complex link between scaffold architecture and in vivo response. PMID- 20709196 TI - Uptake and intracellular distribution of silver nanoparticles in human mesenchymal stem cells. AB - Silver nanoparticles (Ag-NP) are widely used due to their well-known antibacterial effects. In medicine Ag-NP have found applications as wound dressings, surgical instruments and bone substitute biomaterials, e.g. silver containing calcium phosphate cements. Depending on the coating technique, during resorption of a biomaterial Ag-NP may come into close contact with body tissues, including human mesenchymal stem cells (hMSC). Despite the widespread uses of Ag NP, there is a serious lack of information concerning their biological effects on human cells. In this study the uptake of Ag-NP into hMSC has been analyzed and the intracellular distribution of Ag-NP after exposure determined. Non agglomerated (dispersed) Ag-NP from the cell culture medium were detected as agglomerates of nanoparticles within the hMSC by combined focused ion beam/scanning electron microscopy. The silver agglomerates were typically located in the perinuclear region, as determined by light microscopy. Specific staining of cellular structures (endo-lysosomes, nuclei, Golgi complex and endoplasmatic reticulum) using fluorescent probes showed that the silver nanoparticles occurred mainly within endo-lysosomal structures, not in the cell nucleus, endoplasmic reticulum or Golgi complex. Quantitative determination of the uptake of Ag-NP by flow cytometry (scattergram analysis) revealed a concentration-dependent uptake of the particles which was significantly inhibited by chlorpromazine and wortmannin but not by nystatin, indicating clathrin-dependent endocytosis and macropinocytosis as the primary uptake mechanisms. PMID- 20709197 TI - Responses of bone-forming cells on pre-immersed Zr-based bulk metallic glasses: Effects of composition and roughness. AB - Bulk metallic glasses (BMGs) demonstrate attractive properties for potential biomedical applications, owing to their amorphous structure. The present work has investigated the biocompatibility of Zr-based BMGs by studying the cellular behavior of bone-forming mouse MC3T3-E1 pre-osteoblast cells. A Ti-6Al-4V alloy was used as a reference material. Pre-immersion treatment was performed on BMG samples in phosphate-buffered saline prior to cell experiments. The effects of 1at.% yttrium alloying and surface roughness on cellular behavior were examined. The general biosafety of Zr-based BMGs for MC3T3-E1 cells was revealed as normal cell responses. Pre-immersion treatment was found to effectively reduce the surface concentrations of alloying elements. Micro-alloying with 1 at.% yttrium did not significantly affect cell adhesion and proliferation, but slightly decreased alkaline phosphatase (ALP) activity on rough surfaces. Lower cell adhesion and proliferation were found on smooth surfaces of Zr-based BMGs compared to their rougher counterparts. Higher ALP activity was detected on rougher surfaces. To obtain a mechanistic understanding surface free energy was correlated with cell adhesion. PMID- 20709198 TI - Mechano-topographic modulation of stem cell nuclear shape on nanofibrous scaffolds. AB - Stem cells transit along a variety of lineage-specific routes towards differentiated phenotypes. These fate decisions are dependent not just on the soluble chemical cues that are encountered or enforced in vivo and in vitro, but also on physical cues from the cellular microenvironment. These physical cues can consist of both nano- and micro-scale topographical features, as well as mechanical inputs provided passively (from the base properties of the materials to which they adhere) or actively (from extrinsic applied mechanical deformations). A suitable tool to investigate the coordination of these cues lies in nanofibrous scaffolds, which can both dictate cellular and cytoskeletal orientation and facilitate mechanical perturbation of seeded cells. Here, we demonstrate a coordinated influence of scaffold architecture (aligned vs. randomly organized fibers) and tensile deformation on nuclear shape and orientation. Sensitivity of nuclear morphology to scaffold architecture was more pronounced in stem cell populations than in terminally differentiated fibrochondrocytes. Tension applied to the scaffold elicited further alterations in nuclear morphology, greatest in stem cells, that were mediated by the filamentous actin cytoskeleton, but not the microtubule or intermediate filament network. Nuclear perturbations were time and direction dependent, suggesting that the modality and direction of loading influenced nuclear architecture. The present work may provide additional insight into the mechanisms by which the physical microenvironment influences cell fate decisions, and has specific application to the design of new materials for regenerative medicine applications with adult stem cells. PMID- 20709199 TI - Characterization of glycidyl methacrylate - crosslinked hyaluronan hydrogel scaffolds incorporating elastogenic hyaluronan oligomers. AB - Prior studies on two-dimensional cell cultures suggest that hyaluronic acid (HA) stimulates cell-mediated regeneration of extracellular matrix structures, specifically those containing elastin, though such biologic effects are dependent on HA fragment size. Towards being able to regenerate three-dimensional (3-D) elastic tissue constructs, the present paper studies photo-crosslinked hydrogels containing glycidyl methacrylate (GM)-derivatized bio-inert high molecular weight (HMW) HA (1 * 10(6)Da) and a bioactive HA oligomer mixture (HA-o: MW ~0.75 kDa). The mechanical (rheology, degradation) and physical (apparent crosslinking density, swelling ratio) properties of the gels varied as a function of incorporated HA oligomer content; however, overall, the mechanics of these hydrogels were too weak for vascular applications as stand-alone materials. Upon in vivo subcutaneous implantation, only a few inflammatory cells were evident around GM-HA gels, however their number increased as HA-o content within the gels increased, and the collagen I distribution was uniform. Smooth muscle cells (SMC) were encapsulated into GM hydrogels, and calcein acetoxymethyl detection revealed that the cells were able to endure twofold the level of UV exposure used to crosslink the gels. After 21 days of culture, SMC elastin production, measured by immunofluorescence quantification, showed HA-o to increase cellular deposition of elastic matrix twofold relative to HA-o-free GM-HA gels. These results demonstrate that cell response to HA/HA-o is not altered by their methacrylation and photo-crosslinking into a hydrogel, and that HA-o incorporation into cell encapsulating hydrogel scaffolds can be useful for enhancing their production of elastic matrix structures in a 3-D space, important for regenerating elastic tissues. PMID- 20709200 TI - Macrophage-mediated degradation of crosslinked collagen scaffolds. AB - Biological scaffolds used in tissue engineering are incorporated in vivo by a process of cellular in-growth, followed by host-mediated degradation and replacement of these scaffolds, in which phagocytic cells from the monocyte/macrophage cell lineage play a key role. The chemical degradation of scaffolds with collagenases is well established, but to date this has not been correlated with an in vitro model of cell mediated scaffold degradation. RAW264.7, a murine monocyte/macrophage cell line, was cultured on collagen scaffolds crosslinked either by dehydrothermal treatment (DHT) or by carbodiimide (EDC). These cells attached to collagen scaffolds, proliferated and exhibited macrophage aggregation to form giant cells. Crosslinking the scaffolds by either DHT or EDC increased the resistance of the scaffold to degradation by macrophages. Increasing the amount of crosslinking in the scaffold made them more resistant to degradation by collagenase. However, while EDC increased the scaffolds' thermal and mechanical properties and decreased the swelling ratio, DHT increased the mechanical properties, but decreased the denaturation temperature and swelling ratio. Altering the scaffold properties by crosslinking affects the rate of degradation by macrophages, and this is correlated with chemical degradation (r=0.658, p<0.01). This will help in the design of scaffolds with task-specific profiles for use in tissue engineering. PMID- 20709201 TI - Signaling of extracellular inorganic phosphate up-regulates cyclin D1 expression in proliferating chondrocytes via the Na+/Pi cotransporter Pit-1 and Raf/MEK/ERK pathway. AB - As chondrocytes mature, the concentration of inorganic phosphate (Pi) increases in the extracellular milieu. It was demonstrated that the progressive accumulation of Pi started from the proliferative zone and peaked in the hypertrophic zone of growth plate. Although extracellular Pi is reported to be involved in the apoptosis and mineralization of mature chondrocytes, its role in proliferating chondrocytes remains unclear. Here we investigated this role utilizing ATDC5, an established cell model of chondrocytic differentiation. In proliferating ATDC5 cells, we found that the expression of cyclin D1 was up regulated, and that of alkaline phosphatase (ALP) was down-regulated in response to an increase in extracellular Pi within 24h. Moreover, an increase in extracellular Pi-induced activation of the Raf/MEK/ERK pathway, and treatment with a MEK inhibitor PD98059 abolished the effects on the expression of cyclin D1 and ALP, indicating that extracellular Pi regulates the expression of these genes through the Raf/MEK/ERK pathway. Consistent with its up-regulation of cyclin D1 expression, the extracellular Pi facilitated the proliferation of ATDC5 cells. Treatment with phosphonoformic acid (PFA), an inhibitor of sodium/phosphate (Na(+)/Pi) cotransporters, abrogated the activation of the Raf/MEK/ERK pathway and gene expression induced by the increase in extracellular Pi. Knocking down of the type III Na(+)/Pi cotransporter Pit-1 diminished the responsiveness of ATDC5 cells to the increase in extracellular Pi. Interestingly, the increased extracellular Pi induced the phosphorylation of fibroblast growth factor receptor substrate 2alpha (FRS2alpha), which was also cancelled by knocking down of the expression of Pit-1. In primary chondrocytes isolated from mouse rib cages as well, increased extracellular Pi induced the phosphorylation of ERK1/2 and alterations in the expression of cyclin D1 and ALP, both of which were abolished by treatment with PFA. These results suggest that signaling by extracellular Pi is mediated by Pit-1 and FRS2alpha, and leads to activation of the Raf/MEK/ERK pathway and increased expression of cyclin D1, which facilitates the proliferation of immature chondrocytes. PMID- 20709202 TI - Gastric mucosa-associated lymphoid tissue lymphoma. PMID- 20709203 TI - The role of anti-tumor necrosis factor receptor agents in cancer survivors revisited. PMID- 20709204 TI - Cancer prevention I: introduction. PMID- 20709205 TI - Principles of cancer screening: lessons from history and study design issues. AB - Early detection of cancer has held great promise and intuitive appeal in the medical community for well over a century. Its history developed in tandem with that of the periodic health examination, in which any deviations--subtle or glaring--from a clearly demarcated "normal" were to be rooted out, given the underlying hypothesis that diseases develop along progressive linear paths of increasing abnormalities. This model of disease development drove the logical deduction that early detection, by "breaking the chain" of cancer development, must be of benefit to affected individuals. In the latter half of the 20th century, researchers and guidelines organizations began to explicitly challenge the core assumptions underpinning many clinical practices. A move away from intuitive thinking began with the development of evidence-based medicine. One key method developed to explicitly quantify the overall risk-benefit profile of a given procedure was the analytic framework. The shift away from pure deductive reasoning and reliance on personal observation was driven, in part, by a rising awareness of critical biases in cancer screening that can mislead clinicians, including healthy volunteer bias, length-biased sampling, lead-time bias, and overdiagnosis. A new focus on the net balance of both benefits and harms when determining the overall worth of an intervention also arose: it was recognized that the potential downsides of early detection were frequently overlooked or discounted because screening is performed on basically healthy persons and initially involves relatively noninvasive methods. Although still inconsistently applied to early detection programs, policies, and belief systems in the United States, an evidence-based approach is essential to counteract the misleading- even potentially harmful--allure of intuition and individual observation. PMID- 20709207 TI - Molecular markers for early detection. AB - A common belief is that the earlier that cancer is detected, the better the chance exists for reduced mortality and morbidity. The advent of new and emerging molecular, genetic, and imaging technologies has broadened the possible strategies for early detection and prevention, but a beneficial impact on mortality needs to be supported by clinical evidence. Molecular markers are being identified that are enhancing our ability to predict and detect cancer before it develops and at the earliest signs of impending carcinogenic transformation. Of the innumerable molecular markers in development, a standalone early detection marker with acceptable sensitivity and specificity is available for bladder cancer, although for most cancer sites there are promising avenues of research that will likely produce results in the next decade. The perfect molecular marker would be one that is inherently related to the disease, specifically to the processes of malignant tumorigenesis or to the defense mechanisms of the individual. For example, mutations associated with increased cancer risk often produce gene products that interfere with tumor-suppressor pathways (eg, DNA repair or cell-cycle control) or support oncogenic pathways (eg, through genetic instability or silencing the apoptotic pathway). Finding molecular markers associated with these processes, and where in the process they produce their actions, can lead to interventions based on maintaining support for the normal process and interrupting the action of the products of the mutation. The search for molecular markers for cancer prevention and early detection presents a formidable challenge that requires a systematic and scientifically sound validation process. The search encompasses a broad range of scientific disciplines, including biochemistry, genetics, histology, immunology, informatic technologies, and epidemiology; strategies to identify and understand molecular markers are approached with multidisciplinary teams focused on understanding the mechanistic basis of cancer and the processes and pathways that underlie carcinogenesis. PMID- 20709206 TI - Cancer screening trials: nuts and bolts. AB - The most rigorous and valid approach to evaluating cancer screening modalities is the randomized controlled trial (RCT). RCTs are major undertakings and the intricacies of trial design, operations, and management are generally underappreciated by the typical researcher. The purpose of this article is to inform the reader of the "nuts and bolts" of designing and conducting cancer screening RCTs. Following a brief introduction as to why RCTs are critical in evaluating screening modalities, we discuss design considerations, including the choice of design type and duration of follow-up. We next present an approach to sample-size calculations. We then discuss aspects of trial implementation, including recruitment, randomization, and data management. A discussion of commonly employed data analyses comes next, and includes methods for the primary analysis (comparison of cause-specific mortality rates between the screened and control arms for the cancer of interest), as well as for secondary endpoints such as sensitivity. We follow with a discussion of sequential monitoring and interim analysis techniques, which are used to examine the primary outcome while the trial is ongoing. We close with thoughts on lessons learned from past cancer screening RCTs and provide recommendations for future trials. Throughout the presentation we illustrate topics with examples from completed or ongoing RCTs, including the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST). PMID- 20709208 TI - Cellular proliferation, apoptosis and angiogenesis: molecular targets for nutritional preemption of cancer. AB - Malignant cells are characterized by abnormal signaling pathways involving proliferation, apoptosis, and angiogenesis. These cancer centric pathways are known to be modified by several bioactive dietary components, although admittedly there are inconsistencies in the response. The response is dependent on the amount and duration of exposure to the dietary component and the cell type. While caution should be exercised when extrapolating in vitro data to in vivo conditions, such studies do provide valuable insights into plausible mechanisms. Significant gene-nutrient and nutrient-nutrient interactions may contribute to the uncertainty of the response to foods and/or their components. One of the challenges is the identification of which process(es), either singly or in combination, is/are most important in leading to a dietary-mediated phenotypic change. The dearth of controlled intervention studies that have investigated molecular targets for nutritional preemption in humans make firm dietary recommendations difficult. Until more definite information surfaces, a balanced but varied diet is most prudent. PMID- 20709209 TI - Cancer prevention with natural compounds. AB - Botanical and nutritional compounds have been used for the treatment of cancer throughout history. These compounds also may be useful in the prevention of cancer. Population studies suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great interest. There are numerous reports of cancer chemopreventive activity of dietary botanicals, including cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and onion, green tea, Citrus fruits, soybeans, tomatoes, berries, and ginger, as well as medicinal plants. Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action. PMID- 20709211 TI - The role of physical activity in breast cancer etiology. AB - Considerable research interest has been given in the past 25 years to examining the role of physical activity in breast cancer prevention given the scarcity of modifiable risk factors for this major cause of cancer incidence and mortality in women. A review of the observational epidemiologic evidence and recent randomized exercise intervention trials on the association between physical activity and breast cancer risk is presented. As of March 2010, 73 separate studies out of 91 publications worldwide were identified as having sufficient data for this review. Across these 73 studies, the average reduction in breast cancer risk, when comparing the most to the least physically active women, was 25%. There also was evidence for a dose-response effect found in the majority of studies that examined this trend. The strongest associations were found for recreational and household activities and for activity that was of at least moderate intensity and sustained over a lifetime. Within population subgroups, a stronger effect was seen in women who are normal weight, in women without a family history of breast cancer, and in women who are parous. Women of all races benefitted from physical activity; however, a particularly strong effect on breast cancer risk was observed in non-Caucasian women. Future research should focus on elucidating the exact type, dose, and timing of physical activity required to reduce breast cancer risk. Prospective observational epidemiologic studies of lifetime physical activity patterns and breast cancer risk would help in this regard, as well as randomized controlled exercise intervention trials employing hypothesized biomarkers of breast cancer risk as outcome measures. Additional consideration to the role of sedentary behavior and light-intensity activity also is needed, as well as improved physical activity assessment methods. These additional data will be useful in improving public health recommendations regarding physical activity for breast cancer risk reduction. PMID- 20709213 TI - New guidelines for genetic tests are welcome but insufficient. PMID- 20709212 TI - On trial: clinical research in the USA. PMID- 20709214 TI - China takes action against tuberculosis and HIV co-infection. PMID- 20709210 TI - Epidemiological and clinical studies of nutrition. AB - In this review, we briefly summarize some of the key developments in nutritional epidemiology and cancer over the past two decades with a focus on the strengths and limitations of study designs and dietary assessment methods. We present the evidence on dietary fat, meat, fiber, antioxidant nutrients, and calcium in relation to carcinogenesis from large cohort studies and randomized clinical trials (RCTs) and refer to the conclusions of the 2007 World Cancer Research Fund/American Institute for Cancer Research summary report. One prominent theme that emerged is the lack of concordance of results from RCTs and observational studies. There are multiple potential reasons for these discrepancies, including differences in study population, dose and timing of the exposure, adherence to an intervention, length of follow-up, and the primary endpoint. Therefore, null findings of RCTs do not necessarily indicate a lack of effect for the tested dietary factors on cancer risk, as some of these nutrients may have chemopreventive effects if given at the right time and in the right dose. It is likely that potential benefits from diet are due to a combination of food constituents rather than single components acting in isolation. Future efforts need to recognize the integrative nature of dietary exposures and attempt to study nutrients in the larger context of the foods and diets in which they are consumed. PMID- 20709215 TI - Rimonabant: obituary for a wonder drug. PMID- 20709216 TI - After CAPRISA 004: time to re-evaluate the HIV lexicon. PMID- 20709217 TI - Africa is desperate for praziquantel. PMID- 20709218 TI - Health workers lost to international bodies in poor countries. PMID- 20709220 TI - Roberto Ferrari: outgoing ESC President and dynamic cardiologist. PMID- 20709221 TI - Para-aortic lymphadenectomy in endometrial cancer. PMID- 20709222 TI - Para-aortic lymphadenectomy in endometrial cancer. PMID- 20709223 TI - Para-aortic lymphadenectomy in endometrial cancer. PMID- 20709225 TI - Prioritisation of health research. PMID- 20709226 TI - Prioritisation of health research. PMID- 20709227 TI - Patients' information sheets and multicentre studies. PMID- 20709228 TI - Use of unregulated stem-cell based medicinal products. PMID- 20709229 TI - Maternal mortality and abortion. PMID- 20709230 TI - Family physicians' satisfaction in Iran: a long path ahead. PMID- 20709231 TI - Primary-care reform in the USA. PMID- 20709232 TI - A UN summit on global mental health. PMID- 20709234 TI - A cheesy diagnosis. PMID- 20709235 TI - Alterations of consciousness in the emergency department. Foreword. PMID- 20709236 TI - Alterations of consciousness in the emergency department. Preface. PMID- 20709237 TI - The mental status examination in emergency practice. AB - A systematic approach to assessing mental status in the emergency department is key to identifying alterations in mental status and to directing diagnostic testing and management. After initial stabilization of the patient, it is critical to assess a patient's alertness, attention, and cognition, and perform a brief psychiatric assessment to fully evaluate a patient with mental status changes. This article offers an approach to allow better management of a patient with altered mental status. PMID- 20709238 TI - Dizzy and confused: a step-by-step evaluation of the clinician's favorite chief complaint. AB - This article covers the general approach to patients who present to the emergency department with a complaint of dizziness or vertigo, and altered mentation. Patients' histories and physical examination findings are discussed first, then a pertinent differential diagnosis, ranging from neurological causes and poor perfusion states to toxicologic causes, is described along with the distinguishing features and potential diagnostic pitfalls of each problem. Case scenarios are presented and the treatment and disposition of patients from the emergency department are discussed. PMID- 20709239 TI - Diagnosis and evaluation of syncope in the emergency department. AB - With a careful history, physical examination, and directed investigation, physicians can determine the likely cause of syncope in more than 50% and perhaps up to 80% of patients. Understanding the cause of syncope allows clinicians to determine the disposition of high- and low-risk patients. Patients with a potential malignant cause, such as a cardiac or neurologic condition, should be treated and admitted. Those with benign causes can be safely discharged. This article reviews the diagnosis and ED work-up of syncope, the different classifications of syncope, and prognosis. The use of specific decision rules in risk stratification and syncope in the pediatric population are discussed in another article. PMID- 20709240 TI - The emergency department approach to syncope: evidence-based guidelines and prediction rules. AB - Syncope is a sudden, transient loss of consciousness associated with inability to maintain postural tone followed by spontaneous recovery and return to baseline neurologic status. Global cerebral hypoperfusion is the final pathway common to all presentations of syncope, but this symptom presentation has a broad differential diagnosis. It is important to identify patients whose syncope is a symptom of a potentially life-threatening condition. This article reviews the current status of syncope from the emergency department perspective, focusing on the current evidence behind the various clinical decision rules derived during the past decade. PMID- 20709242 TI - Seizures as a cause of altered mental status. AB - The differential diagnosis and empiric management of altered mental status and seizures often overlap. Altered mental status may accompany seizures or simply be the manifestation of a postictal state. This article provides an overview of the numerous causes of altered mental status and seizures: metabolic, toxic, malignant, infectious, and endocrine causes. The article focuses on those agents that should prompt the emergency physician to initiate unique therapy to abate the seizure and correct the underlying cause. PMID- 20709241 TI - Pediatric syncope: cases from the emergency department. AB - Pediatric syncope is a common presentation in the emergency department. Most causes are benign, but an evaluation must exclude rare life-threatening disorders. The lack of objective findings can pose a challenge. This case-based review emphasizes the importance of a detailed history and physical examination with electrocardiogram in determining high-risk patients. PMID- 20709243 TI - Central nervous system infections as a cause of an altered mental status? What is the pathogen growing in your central nervous system? AB - There are several central nervous system (CNS) infections (meningitis, encephalitis, and brain abscess), any of which may present with an altered level of consciousness. Because CNS infections can have a devastating outcome, it is important to recognize the presence of a CNS infection and begin treatment as soon as possible because early appropriate therapy may, in some cases, limit morbidity and mortality. PMID- 20709245 TI - Psychiatric considerations in patients with decreased levels of consciousness. AB - When patients present to the emergency department with changes in behavior and levels of consciousness, psychiatric causes often move to the top of the list of diagnostic considerations. It is important to thoroughly assess such patients for medical causes. Although it is not common for primary psychiatric conditions to present with altered levels of consciousness, severe cases may present in this fashion. Altered mental states may also be caused by adverse reactions to psychiatric medications. In this article, the authors review some of the psychiatric causes of decreased levels of consciousness, as well as certain adverse drug reactions to psychotropic medications. PMID- 20709244 TI - Traumatic alterations in consciousness: traumatic brain injury. AB - Mild traumatic brain injury (mTBI) refers to the clinical condition of transient alteration of consciousness as a result of traumatic injury to the brain. The priority of emergency care is to identify and facilitate the treatment of rare but potentially life-threatening intracranial injuries associated with mTBI through the judicious application of appropriate imaging studies and neurosurgical consultation. Although post-mTBI symptoms quickly and completely resolve in the vast majority of cases, a significant number of patients will complain of lasting problems that may cause significant disability. Simple and early interventions such as patient education and appropriate referral can reduce the likelihood of chronic symptoms. Although definitive evidence is lacking, mTBI is likely to be related to significant long-term sequelae such as Alzheimer disease and other neurodegenerative processes. PMID- 20709247 TI - Is salt, vitamin, or endocrinopathy causing this encephalopathy? A review of endocrine and metabolic causes of altered level of consciousness. AB - Altered level of consciousness describes the reason for 3% of critical emergency department (ED) visits. Approximately 85% will be found to have a metabolic or systemic cause. Early laboratory studies such as a bedside glucose test, serum electrolytes, or a urine dipstick test often direct the ED provider toward endocrine or metabolic causes. This article examines common endocrine and metabolic causes of altered mentation in the ED via sections dedicated to endocrine-, electrolyte-, metabolic acidosis-, and metabolism-related causes. PMID- 20709246 TI - Delirium in the older emergency department patient: a quiet epidemic. AB - Delirium is defined as an acute change in cognition that cannot be better accounted for by a preexisting or evolving dementia. This form of organ dysfunction commonly occurs in older patients in the emergency department (ED) and is associated with a multitude of adverse patient outcomes. Consequently, delirium should be routinely screened for in older ED patients. Once delirium is diagnosed, the ED evaluation should focus on searching for the underlying cause. Infection is one of the most common precipitants of delirium, but multiple causes may exist concurrently. PMID- 20709249 TI - Twenty per hour: altered mental state due to ethanol abuse and withdrawal. AB - This article discusses the physiology and clinical syndromes involved in ethanol absorption, intoxication, and withdrawal, with special emphasis on the evidentiary backing for common treatments, as well as some discussion of the medicolegal sequelae of treatment of ethanol abusers in the emergency department. PMID- 20709248 TI - Drugs of abuse: the highs and lows of altered mental states in the emergency department. AB - The diagnosis and management of poisoned patients presenting with alterations in mental status can be challenging, as patients are often unable (or unwilling) to provide an adequate history. Several toxidromes exist. Recognition hinges upon vital signs and the physical examination. Understanding these "toxic syndromes" may guide early therapy and management, providing insight into the patient's underlying medical problem. Despite toxidrome recognition guiding antidotal therapy, the fundamental aspect of managing these patients involves meticulous supportive care. The authors begin with a discussion of various toxidromes and then delve into the drugs responsible for each syndrome. They conclude with a discussion on drug-facilitated sexual assault ("date rape"), which is both an underrecognized problem in the emergency department (ED) and representative of the drug-related problems faced in a modern ED. PMID- 20709250 TI - Disparities in the food environments of New York City public schools. AB - BACKGROUND: Studies of the food environment near schools have focused on fast food. Research is needed that describes patterns of exposure to a broader range of food outlet types and that examines the influence of neighborhood built environments. PURPOSE: Using data for New York City, this paper describes the prevalence of five different food outlet types near schools, examines disparities by economic status and race/ethnicity in access to these food outlets, and evaluates the extent to which these disparities are explained by the built environment surrounding the school. METHODS: National chain and local fast-food restaurants, pizzerias, small grocery stores ("bodegas"), and convenience stores within 400 m of public schools in New York City were identified by matching 2005 Dun & Bradstreet data to 2006-2007 school locations. Associations of student poverty and race/ethnicity with food outlet density, adjusted for school level, population density, commercial zoning, and public transit access, were evaluated in 2009 using negative binomial regression. RESULTS: New York City's public school students have high levels of access to unhealthy food near their schools: 92.9% of students had a bodega within 400 m, and pizzerias (70.6%); convenience stores (48.9%); national chain restaurants (43.2%); and local fast-food restaurants (33.9%) were also prevalent within 400 m. Racial/ethnic minority and low-income students were more likely to attend schools with unhealthy food outlets nearby. Bodegas were the most common source of unhealthy food, with an average of nearly ten bodegas within 400 m, and were more prevalent near schools attended by low-income and racial/ethnic minority students; this was the only association that remained significant after adjustment for school and built environment characteristics. CONCLUSIONS: Nearly all New York City public school students have access to inexpensive, energy-dense foods within a 5-minute walk of school. Low-income and Hispanic students had the highest level of exposure to the food outlets studied here. PMID- 20709251 TI - Recommended levels of physical activity to avoid an excess of body fat in European adolescents: the HELENA Study. AB - BACKGROUND: It is unclear how much physical activity is necessary to prevent obesity during adolescence. PURPOSE: The purpose of this study was to examine whether the current physical activity guidelines for youth are associated with a lower risk of excess of body fat in European adolescents. METHODS: A sample of 2094 adolescents from the HELENA cross-sectional study was selected. Levels of moderate, vigorous, and moderate to vigorous physical activity (MVPA) were assessed using accelerometers. BMI and percentage of body fat (skinfolds) were calculated and used to categorize the adolescents as normal-weight/normal-fat, overweight/overfat, and obese. Data were collected during 2006-2007. Receiver operating characteristic (ROC) analysis, performed in 2009, was used to determine thresholds that best discriminate between weight and body fat categories. RESULTS: ROC analysis showed that >/=18 minutes/day in vigorous physical activity and >/=55 minutes/day in MVPA significantly discriminated between normal-weight and overweight+obesity categories. Moreover, >/=9 minutes/day of vigorous physical activity and >/=49 minutes/day of MVPA discriminated between normal-fat and overfat/obese adolescents. Adolescents who did not meet the current physical activity guidelines for youth of 60 minutes/day in MVPA increased the risk of having overweight+obesity (OR=1.24, 95% CI=1.01, 1.534) and overfat+obesity (OR=1.79, 95% CI=1.33, 2.42). ORs increased when adolescents did not meet the guidelines of at least 15 minutes/day in vigorous physical activity. CONCLUSIONS: Current physical activity guidelines seem to be appropriate to prevent excess of body fat in European adolescents. However, participation in vigorous physical activity might have additional importance in preventing obesity. PMID- 20709252 TI - Environmental determinants of outdoor play in children: a large-scale cross sectional study. AB - BACKGROUND: Outdoor play is a cheap and natural way for children to be physically active. PURPOSE: This study aims to identify physical as well as social correlates of outdoor play in the home and neighborhood environment among children of different age groups. METHODS: Cross-sectional data were derived from 6470 parents of children from 42 primary schools in four Dutch cities by means of questionnaires (2007-2008). Multivariate sequential Poisson GEE analyses were conducted (2010) to quantify the correlation between physical and social home and neighborhood characteristics and outdoor play among boys and girls aged 4-6 years, 7-9 years, and 10-12 years. RESULTS: This study showed that next to proximal (home) environmental characteristics such as parental education (RR=0.93 0.97); the importance parents pay to outdoor play (RR=1.32-1.75); and the presence of electronic devices in the child's own room (RR=1.04-1.15), several neighborhood characteristics were significantly associated with children's outdoor play. Neighborhood social cohesion was related to outdoor play in five of six subgroups (RR=1.01-1.02), whereas physical neighborhood characteristics (e.g., green neighborhood type, presence of water, diversity of routes) were associated with outdoor play in specific subgroups only. CONCLUSIONS: Neighborhood social cohesion was related to outdoor play among children of different age and gender, which makes it a promising point of action for policy development. Policies aimed at improving physical neighborhood characteristics in relation to outdoor play should take into account age and gender of the target population. PMID- 20709253 TI - Obesity-related quality-adjusted life years lost in the U.S. from 1993 to 2008. AB - BACKGROUND: Although trends in the prevalence of obesity and obesity-attributable deaths have been examined, little is known about the resultant burden of disease associated with obesity. PURPOSE: This study examined trends in the burden of obesity by estimating the obesity-related quality-adjusted life years (QALYs) lost-defined as the sum of QALYs lost due to morbidity and future QALYs lost in expected life years due to premature deaths-among U.S. adults along with differences by gender, race/ethnicity, and state. METHODS: Health-related quality of-life data were taken from the 1993-2008 Behavioral Risk Factor Surveillance System to calculate QALYs lost due to morbidity. Age-specific mortality data were used to calculate QALYs lost due to mortality. RESULTS: QALYs lost due to obesity in U.S. adults have more than doubled from 1993 to 2008. Black women had the most QALYs lost due to obesity, at 0.0676 per person in 2008. This number was 31% higher than the QALYs lost in black men and about 50% higher than the QALYs lost in white women and white men. A strong and positive relationship between obesity related QALYs lost and the percentage of the population reporting no leisure-time physical activity at the state level (r=0.71) also was found. CONCLUSIONS: This analysis enables the overall impact of obesity on both morbidity and mortality to be examined using a single value. The overall health burden of obesity has increased since 1993 and such increases were observed in all gender-by-race subgroups and in all 50 states and the District of Columbia. PMID- 20709254 TI - Coronary mortality declines in the U.S. between 1980 and 2000 quantifying the contributions from primary and secondary prevention. AB - BACKGROUND: Coronary heart disease (CHD) mortality rates in the U.S. have halved since 1980. However, CHD remains a leading cause of death. The relative importance of secondary and primary prevention in explaining falls in coronary heart disease mortality is debated. PURPOSE: The aim of this study was to quantify the primary and secondary preventive contributions to the U.S. CHD mortality fall between 1980 and 2000. METHODS: The IMPACT model was used to estimate contributions to the U.S. CHD mortality fall from risk factor declines in asymptomatic individuals (primary prevention) and in CHD patients (secondary prevention). Analyses were carried out in 2008. RESULTS: Approximately 316,100 fewer deaths were attributable to risk factor declines: 64,930 in CHD patients (21%) and 251,170 in asymptomatic individuals (79%). Smoking declines accounted for approximately 8390 fewer deaths in CHD patients and for 46,315 fewer deaths in asymptomatic people. Cholesterol falls gave approximately 22,210 fewer deaths in CHD patients and 107,300 fewer deaths in asymptomatic people. Statins accounted for approximately 16,580 fewer deaths, that is, one sixth of this mortality fall. Systolic blood pressure declines accounted for approximately 34,330 fewer deaths among CHD patients and 97,555 fewer deaths in asymptomatic individuals. Antihypertensive medications accounted for approximately 23,845 fewer deaths. CONCLUSIONS: Half of the U.S. mortality fall in coronary heart disease between 1980 and 2000 was attributable to risk factor declines, with primary prevention producing substantially larger mortality reductions than secondary. PMID- 20709255 TI - The diabetes primary prevention initiative interventions focus area: a case study and recommendations. AB - BACKGROUND: In 2005, CDC began the Diabetes Primary Prevention Initiative Interventions Focus Area (DPPI-IFA), which funded five state Diabetes Prevention and Control Programs (DPCPs) to translate diabetes primary prevention trials into real-world settings by developing and implementing a framework for state-level diabetes primary prevention. PURPOSE: The purpose of this case study, conducted in 2007, was to describe DPPI-IFA implementation, including facilitators and challenges to the initiative. METHODS: Case studies of the five DPCPs in the DPPI IFA involving site visits with key informant interviews of state staff and partners and archival record collection. RESULTS: Partners recruited for DPPI-IFA activities included local or state public health agencies (three of five DPCPs); regional or state nonprofit organizations (five DPCPs); businesses or employers (three DPCPs); and healthcare organizations (four DPCPs). The DPCPs implemented a variety of interventions in three main domains: diabetes primary prevention and prediabetes awareness, screening activities and lifestyle interventions, and prediabetes-related health policy efforts. Preliminary outcomes are described at the individual and organization/partnership levels. Results suggest the importance of utilizing preexisting partnerships to extend work into diabetes prevention, providing even small amounts of funding to partners, and prior program planning for diabetes prevention. Challenges for the DPPI-IFA included recruiting participants, establishing links with providers to obtain diagnostic testing for people screened for prediabetes, and offering a lifestyle intervention. CONCLUSIONS: The DPPI-IFA represents a unique effort by state public health programs in the translation of diabetes primary prevention trials into real-world settings. The experiences of the DPPI-IFA programs offer valuable lessons for future community-based diabetes prevention initiatives, especially regarding the need to strengthen clinical-community partnerships for referral of people with prediabetes to evidence-based lifestyle programs. PMID- 20709256 TI - Uptake of regular chlamydia testing by U.S. women: a longitudinal study. AB - BACKGROUND: Routine chlamydia screening is a recommended preventive intervention for sexually active women aged or=30 mm) were invited for an interview. In total, 10 men were interviewed. The semi-structured interview was conducted by using an interview guide. Data was analyzed by using an interpretative phenomenological method. Three themes were identified: (i) feeling secure being under superintendence; (ii) living as usual, but repressing thoughts; and (iii) feeling disillusionment due to negative outcome. Being given the message that an enlarged aorta was discovered at the screening was manageable; hence, continuing growth of the aorta led to some unpleasant feelings. The men were living as usual; however, they all had some reflections about having an AAA and that something could happen when they least expected it. They reported thoughts about the consequences of the enlarged aorta itself and the surgery. In a one-year retrospective interview, men who have had an aneurysm detected in a screening program for AAA reported feeling secure being under superintendence. The one finding in our study concerning worries and effects on life situation could be interpreted as disillusionment due to negative outcomes. Decisions to introduce screening for AAA in Sweden and other countries with ongoing programs should be considered to include guidelines for how to handle disillusionment. PMID- 20709267 TI - Integrating complementary and alternative medicine: use of myrrh in wound management. PMID- 20709268 TI - Review of an article: Self-management for oral anticoagulation (2009). Garcia Alamino JM, Martin JLR, Subirana M & Gich I. Cochrane, Database of Systematic Reviews 4(CD003839). DOI 10.1002/14651858.CD003839. PMID- 20709269 TI - Who speaks up for science. PMID- 20709270 TI - Reliability of a two-dimensional footprint measurement approach. AB - Although footprint evidence can be taken from the scene of a crime, the science underpinning such measurement in forensic science has not been fully explored. A literature search revealed various measuring approaches, all of which demonstrated either little or no measurement rigour in terms of reliability. The aim of this study was to apply a robust measurement approach for testing the reliability of two-dimensional footprint impressions. Three dynamic and three static footprints were taken from the right foot of thirty female and thirty one male volunteers using the 'Inkless Shoeprint Kit'. The images were digitised. Lengths, widths and angles were measured using a selection of currently employed methods. An investigation of the reliability of the chosen measuring method suggested high intra-rater agreement: for example, the length measurement suggested an intraclass correlation coefficient (ICC) 0.99, 95% Confidence Interval (CI) -0.28 to 0.01, standard error of measurement (SEM) 0.07, Limits of Agreement (LOA) -0.91 to 0.65. Inter-rater reliability between three operators was also high: SEM ranged from 0.05 mm to 0.07 mm, ICC 0.99. Our study has established a reliable two-dimensional measuring technique that could be used for footprint comparison in further research. PMID- 20709271 TI - National survey of the incidence of missing anterior teeth: potential use in bite mark analysis in the Brazilian context. AB - Bite mark analysis in forensic dentistry presupposes that the human dentition is unique and that its characteristics can be transferred precisely to several materials. The aim of the present study was to register the frequency of missing anterior teeth in the Brazilian adult population, discussing its potential importance in bite mark analysis. Data from the Brazilian Oral Health Survey were used; 13,431 male and female individuals aged 35 to 44 were examined according to the criteria of the World Health Organization. The analysis of Poisson regression was performed in order to calculate the rating ratios and the respective confidence interval at 95%. A total of 13,431 adults participated in the study. Among male individuals, 2063 (47.00%) were dentate and 2036 (46.40%) had at least one missing tooth. Only 254 (5.83%) were totally edentulous. A significant number of males and females presented 6 missing teeth in the same dental arch, revealing the poor state of oral health of adult Brazilians. Missing teeth were more frequent in the upper dental arch than in the lower arch. In the upper dental arch, the incisor group (central and lateral) was missing the most. In the lower dental arch, however, a certain lack of homogeneity was observed among the different dental groups as regards missing teeth. White individuals presented a smaller proportion of missing teeth compared to the other ethnic groups. Females were 1.61 (CI 1.50-1.73) times more likely than males to present missing teeth. The absence of upper teeth and the presence of lower teeth were observed in 16.10% of the individuals. Further research should also include an analysis of different age groups. This would increase the potential of applying this kind of information to bite mark analysis. PMID- 20709272 TI - A content analysis of fingerprint literature for educational curricula. AB - Forensic science is being required to justify and elucidate its scientific foundations. One way of doing this is through academic curricula. For many native forensic sciences, these curricula do not exist. A content analysis of nine major books in fingerprints was conducted to develop a structure for curricula in that field. The results of this study can be used to organize course content and serve as a model for other disciplines with published materials but no coherent or standard curricula. PMID- 20709273 TI - A population study of polyurethane foam fragments recovered from the surface of 100 outer-garments. AB - One hundred outer-garments were examined for microscopic fragments of polyurethane foam. Low power stereomicroscopy was used to classify fragments into 18 groups according to macroscopic colour. Amber, pale yellow and black were the most frequently encountered, whilst navy, pale blue, bright pink, beige, brown, pale green, peach and white were the least frequently encountered. High power comparison/fluorescence microscopy was used to discriminate 166 populations within 16 colour groupings. The majority (95.2%) of populations consisted of three fragments or less. This study demonstrates that the background population of foam fragments on an outer-garment consists of low numbers representing various colours. Therefore, finding a large population of microscopically indistinguishable fragments within a casework situation has the potential to be considered highly significant evidentially. PMID- 20709274 TI - The evidential value of singed hairs in arson cases. AB - The prevalence of singed hairs on hands was examined in a representative sample comprised primarily of Hamburg LKA staff members to determine the evidential value of such traces in criminal cases. Hair samples were taken from the hands of 160 subjects and examined under a microscope. Evidence of singing was found in 53 of the samples. These traces were largely restricted to a limited number of areas. Distribution of singed hairs over a wide area was observed in just 3 subjects all of whom reported contact with an open flame. The presence of singed hair on the back of the hand can be of great evidential value, though the corresponding distribution pattern must be carefully interpreted. PMID- 20709275 TI - Geophysics and the search of freshwater bodies: a review. AB - Geophysics may assist scent dogs and divers in the search of water bodies for human and animal remains, contraband, weapons and explosives by surveying large areas rapidly and identifying targets or environmental hazards. The most commonly applied methods are described and evaluated for forensic searches. Seismic reflection or refraction and CHIRPS are useful for deep, open water bodies and identifying large targets, yet limited in streams and ponds. The use of ground penetrating radar (GPR) on water (WPR) is of limited use in deep waters (over 20 m) but is advantageous in the search for non-metallic targets in small ditches and ponds. Large metal or metal-bearing targets can be successfully imaged in deep waters by using towfish magnetometers: in shallow waters such a towfish cannot be used, so a non-metalliferous boat can carry a terrestrial magnetometer. Each device has its uses, depending on the target and location: unknown target make-up (e.g. a homicide victim with or without a metal object) may be best located using a range of methods (the multi-proxy approach), depending on water depth. Geophysics may not definitively find the target, but can provide areas for elimination and detailed search by dogs and divers, saving time and effort. PMID- 20709276 TI - Nano-scale composition of commercial white powders for development of latent fingerprints on adhesives. AB - Titanium dioxide based powders are regularly used in the development of latent fingerprints on dark surfaces. For analysis of prints on adhesive tapes, the titanium dioxide can be suspended in a surfactant and used in the form of a powder suspension. Commercially available products, whilst having nominally similar composition, show varying levels of effectiveness of print development, with some powders adhering to the background as well as the print. X-ray fluorescence (XRF), analytical transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and laser particle sizing of the fingerprint powders show TiO(2) particles with a surrounding coating, tens of nanometres thick, consisting of Al and Si rich material, with traces of sodium and sulphur. Such aluminosilicates are commonly used as anti-caking agents and to aid adhesion or functionality of some fingerprint powders; however, the morphology, thickness, coverage and composition of the aluminosilicates are the primary differences between the white powder formulations and could be related to variation in the efficacy of print development. PMID- 20709278 TI - Regionalisation of trauma services in England & Wales: implications for Scotland. PMID- 20709279 TI - Clinical presentation and waiting time targets do not affect prognosis in patients with pancreatic cancer. AB - INTRODUCTION: The prognosis of patients with pancreatic cancer remains poor despite recent advances in treatment. It is not known whether delays in referring, diagnosing and treating these patients and the way they present can affect their survival. AIMS: In our study we investigated the impact of clinical presentation (jaundice, abdominal pain, weight loss) and delays in management of these patients on their treatment and survival. METHODS: Data on all patients with pancreatic cancer referred to the Pancreatic Unit (1997-2002) were collected prospectively and analysed using SPSS 16((R).) The delay in diagnosis and treatment for each patient was measured by estimating the time from the beginning of symptoms to the date of the referral letter (T1), the time from the referral date to the date of first review at the Unit (T2) and the time from date of review to the date of diagnosis/treatment (T3). Treatments were defined as 1) pancreatic resections, 2) gastric and biliary bypass and 3) biliary stents. The term 'operability' was used to describe patients thought to have a potentially removable tumour and had an operation and 'resectability' applied to the patients whose tumour was actually removed at the operation. Follow-up time and survival were recorded by reviewing the patient's notes, hospital electronic databases and by contacting patients General Practitioners. RESULTS: There were a total of 355 patients with pancreatic cancer. Median age at diagnosis was 64 (i.q.r. 56-71) years and median follow-up was 8 (i.q.r. 4-14) months. The overall 1, 3 and 5 years patient's survival was 26%, 5% and 4% respectively. 1, 3 and 5 years survival of inoperable patients was 24%, 2% and 0% and for operable patients was 35%, 13% and 9% respectively. The median survival time for those patients that underwent operation was significantly higher than those that did not (12 vs 6 months, p < 0.001). The overall median time from initial symptoms to diagnosis/treatment (T1 + T2 + T3) was 102 (i.q.r. 56-182) days, T1 was 65 (i.q.r. 31-143), T2 17 (i.q.r. 8-28) and T3 11 (i.q.r. 6-21) days. The time delay from symptoms to referral (T1) had minimal clinical relevance to survival, with a hazard ratio of only 1.001 (95% CI 0.001-0.002, p = 0.043) per day. Of all 355 patients, 305 (86%) were reviewed and treated within 62 days from the GP referral (T2 + T3). There was no significant difference in operability, resectability and survival of patients that were diagnosed/treated before or after 62 days from referral (T2 + T3) (median months 6.5 and 7.9 respectively, p = 0.134). Patients presenting with jaundice were referred (T1, median 56 vs 103) and diagnosed/treated (T2 + T3, median 96 vs 130) days (p < 0.001) sooner, had a higher operability rate (33% vs 21%, p = 0.035) but not a significantly higher resectability rate of (37% vs 29%) (p = 0.608). Isolated or combined mode of clinical presentation had no significant effect on survival (p = 0.965). On multivariate regression analysis, prognostic factors of survival were a resectable tumour and the time from the beginning of symptoms to referral. CONCLUSION: This study showed that pre-hospital delays in referring patients to a specialist unit, but not hospital related 62 days target, had an no impact on operability, resectability and survival. Clinical presentation also had no impact on the survival. We confirmed that pancreatic resection is the most important factor in determining the length of survival in patients with pancreatic cancer. Our study implies that the successful implementation of the 62 days National Cancer Waits Target across the UK is unlikely to have an impact on prognosis in patients with pancreatic cancer. Focusing on early referral to specialist Pancreatic Units might be more effective. PMID- 20709280 TI - 2-Week wait referrals in suspected skin cancer: does an instructional module for general practitioners improve diagnostic accuracy? AB - The two-week wait (2WW) scheme in the United Kingdom for suspected skin cancer has been criticised for having low pick up rates, with a high proportion of clinically benign lesions being referred as suspicious. We studied the referral patterns of skin cancer to our hospital under the 2WW initiative, and aimed to quantify the effect of a targeted continuing medical education (CME) module on improving diagnostic accuracy. All referrals to our hospital (dermatology and plastic surgery) under the 2WW rule were audited between July and September 2006. A targeted CME module was sent to GPs describing and illustrating common lesions. After 11 months, all 2WW referrals were prospectively studied between August and October 2007. The main outcome measure was the percentage of correctly referred squamous cell carcinomas (SCCs) and melanomas. 237 referrals were made between July and August 2006, and 223 referrals between August and October 2007. The proportion of appropriately referred skin cancers (SCCs and melanomas) was 23.2% before CME, and 20.6% after CME. There were no differences in pick up rates before and after the CME amongst suspected SCCs (21.1% vs. 29.7%) or melanomas (24.6% vs. 15.1% respectively). Referrals to Plastic Surgery were more likely to be confirmed histologically as melanomas or SCCs (23.6% and 33.7% respectively) than those made to Dermatology (17.5% and 15.3% respectively). The proportion of correctly suspected skin malignancies under the 2WW initiative remains low despite education. A targeted CME module sent to GPs fails to improve pick up rates. There is a need for continuing dermatology training amongst referring physicians. PMID- 20709281 TI - Nipple discharge and the efficacy of duct cytology in evaluating breast cancer risk. AB - BACKGROUND: Nipple discharge accounts for up to 5% of referrals to breast surgical services. With the vast majority of breast carcinomas originating in the ductal system, symptomatic dysfunction of this system often raises disproportionate clinical concern. The aim of this study is firstly, to evaluate the clinical importance of nipple discharge as an indicator of underlying malignancy and secondly, to assess the diagnostic application of duct cytology in patients presenting with nipple discharge. STUDY DESIGN: We performed a retrospective analysis of all patients presenting with nipple discharge as their primary symptom to the symptomatic breast unit at a tertiary referral center over a 30-month period (n = 313). The Hospital Inpatient Enquiry (HIPE) System and BreastHealth database were used to identify our study cohort. Parameters evaluated included patient demographics, clinical presentation, clinical evaluation, radiological assessment and histological/cytological analysis. RESULTS: Three-hundred and thirteen patients presented with nipple discharge as their primary complaint. Invasive breast carcinoma was diagnosed by Triple Assessment in 5% of patients. 24% of patients presenting with nipple discharge underwent nipple aspiration and cytological analysis. Duct cytology was diagnostic of the underlying breast carcinoma in 50% of triple assessment diagnosed carcinoma. Four risk factors were identified as having a significant association with breast carcinoma, these included (a) age >50 years (p < 0.0001), (b) bloody nipple discharge (p < 0.008), (c) presence of a breast lump (p < 0.0001) and (d) single duct discharge (p < 0.006). CONCLUSIONS: Nipple discharge is a poor indicator of an underlying malignancy. Use of nipple aspiration and duct cytology for the assessment of nipple discharge is of limited diagnostic benefit. However, by utilizing the systematic, gold standard approach of Triple Assessment (clinical, radiological and cytological evaluation), the risk of underlying carcinoma can be accurately defined. PMID- 20709282 TI - Irish (Republic) versus British (North West) orthopaedic trainees: what are the differences? AB - British Trainees have gradually had their working week curtained over the last 8 years. The Republic of Ireland Trainees have not been subjected to the European Working Time Directive prior to 2009 and have therefore worked on average, more hours than their British counterparts. We wanted to see if the differing schemes had an impact on recruiting and training orthopaedic surgeons. We surveyed Republic of Ireland orthopaedic specialist registrars (SpRs) and North West (NW) British SpRs/specialist trainees (ST3 and above) to see if there were any discernable differences in working patterns and subsequent training exposure. A standard proforma was given to Irish Trainees and to NW SpRs/STs at their National or regional teaching (January/February 2009). 62% of Irish and 47% of British NW Trainees responded. Irish trainees were more likely to have obtained a post-graduate degree (p = 0.03). The Irish worked more hours per week (p < 0.001) doing more trauma operative lists (p = 0.003) and more total cases per 6 months than the NW British (p = 0.003). This study suggests that more hours worked, equals more operative exposure, without detriment to the academic side of training. Obviously it is not possible to say whether fewer operations make for a poorer surgeon, but the evidence suggests that it may be true. PMID- 20709283 TI - Up-regulation of signal transducer and activator of transcription-3 is associated with aggravation of ulcerative colitis. AB - OBJECTIVE: The signal transducers and activators of transcription (STAT) family of proteins are intracellular signal transduction molecules involved in the expression of numerous proinflammatory genes in inflammatory cells. This study was executed to determine the association between the expression pattern of STAT 3 in the colonic mucosa of patients with ulcerative colitis (UC) and the progression of this disease. METHODS: We carried out the real-time reverse transcription-polymerase chain reaction (RT-PCR), Western-blot analysis and immunohistochemical staining to examine the expression of STAT-3 at both mRNA and protein levels in 25 patients with UC and 10 normal controls. The association between STAT-3 expression pattern and the severity of the disease was also analyzed. RESULTS: The expression of STAT-3 mRNA and protein in the ulcerated and inflamed colonic mucosa was significantly higher than that in the non-inflamed colonic mucosa (for mRNA: P = 0.001, 0.02 and for protein: P = 0.003, 0.03, respectively), but there was no statistically significant difference in the non inflamed colonic mucosa of UC patients and normal controls (for mRNA: P = 0.062 and for protein: P = 0.063). Furthermore, immunohistochemical analysis showed that among the inactive, mild approximately moderate, and severe colonic mucosae of UC patients, the positive rates of STAT-3 expression were 60.0%, 66.7%, and 88.9%, respectively. CONCLUSION: Our study provides convincing evidence for the first time that the up-regulation of STAT-3 in colonic mucosa may be associated with the progression of human UC and STAT-3 may be a potential therapeutic target for this disease. PMID- 20709284 TI - Brain-machine interface: the challenge of neuroethics. AB - The burning question surrounding the use of Brain-Machine Interface (BMI) devices is not merely whether they should be used, but how widely they should be used, especially in view of some ethical implications that arise concerning the social and legal aspects of human life. As technology advances, it can be exploited to affect the quality of life. Since the effects of BMIs can be both positive and negative, it is imperative to address the issue of the ethics surrounding them. This paper presents the ways in which BMIs can be used and focuses on the ethical concerns to which neuroscience is thus exposed. The argument put forward supports the use of BMIs solely for purposes of medical treatment, and invites the legal framing of this. PMID- 20709285 TI - Short bowel syndrome. AB - The short bowel syndrome (SBS) is a state of malabsorption following intestinal resection where there is less than 200 cm of intestinal length. The management of short bowel syndrome can be challenging and is best managed by a specialised multidisciplinary team. A good understanding of the pathophysiological consequences of resection of different portions of the small intestine is necessary to anticipate and prevent, where possible, consequences of SBS. Nutrient absorption and fluid and electrolyte management in the initial stages are critical to stabilisation of the patient and to facilitate the process of adaptation. Pharmacological adjuncts to promote adaptation are in the early stages of development. Primary restoration of bowel continuity, if possible, is the principle mode of surgical treatment. Surgical procedures to increase the surface area of the small intestine or improve its function may be of benefit in experienced hands, particularly in the paediatric population. Intestinal transplant is indicated at present for patients who have failed to tolerate long term parenteral nutrition but with increasing experience, there may be a potentially expanded role for its use in the future. PMID- 20709286 TI - Recent advances in video-assisted thoracoscopic approach to posterior mediastinal tumours. AB - Minimal invasive video-assisted thoracic surgery can be a safe alternative technique in the assessment, diagnosis and surgical resection of posterior mediastinal tumours. Video-assisted thoracic surgery may be particularly suited for the management of posterior mediastinal tumours as most are benign. Surgical technique continues to evolve from the classic 3-port access in order to tackle more complex tumours positioned at the apical and inferior recesses of the posterior mediastinum. The preoperative identification of dumbbell tumours is important to facilitate arrangements for a single-stage combined resection for both the intra-thoracic and intraspinal tumour. Results from Video-assisted thoracic surgery posterior mediastinal tumour resection are comparable with conventional surgical techniques in terms of symptomatic improvement, recurrence and survival. Video-assisted thoracic surgery approach has been shown to result in less post-operative pain, improved cosmesis, shorter hospital stay, and more rapid recovery and return to normal activities. In over a decade, video-assisted thoracic surgery has gradually matured and is now a promising therapeutic alternative to open approach. In certain selected patients, video-assisted thoracic surgery may be considered the standard of care for conditions of the posterior mediastinum. Recent developments in robotic surgery for the management of mediastinal tumours are promising, however, long-term results are pending. PMID- 20709287 TI - Hyperhidrosis: evolving concepts and a comprehensive review. AB - Hyperhidrosis (primary or secondary) describes a disorder of excessive sweating. It has a significant negative impact on quality of life and affects nearly 1% of the population living in the United Kingdom (UK). Axillary involvement is the most common affecting 80% of cases. A common link to these disorders is an extreme non-thermoregulatory sympathetic stimulus of exocrine sweat glands, mostly due to emotional stimuli. Non-surgical treatment involves topical medication, iontophoresis and systemic anti-cholinergics. More recently the use of intradermal botulinum toxin has gained popularity. Surgical treatment reserved for severe cases, not responding to conservative management involves local excision, curettage and thoracoscopic sympathectomy. Evolving concepts for treatment, risks and benefits are discussed in the paper herein. PMID- 20709288 TI - Skin-sparing mastectomy: a novel method to maximise training opportunities. PMID- 20709289 TI - Autophagy employs a new DAGger against bacteria. AB - Autophagy can orchestrate innate immune responses to bacterial infection by targeting invading pathogens for lysosomal degradation. In this issue of Cell Host & Microbe, Shahnazari et al. (2010) unveil the role played by the diacylglycerol-PKC pathway in the routing of intracellular Salmonella to autophagy. PMID- 20709290 TI - Mammalian PGRPs also mind the fort. AB - Peptidoglycan recognition proteins (PGRPs or Pglyrps) regulate antibacterial responses in Drosophila, yet their functions in humans remain unclear. In this issue of Cell Host & Microbe, Saha and colleagues report that mammalian PGRPs can prevent aberrant interferon-gamma--induced inflammatory damage in vivo by modulating the composition of the intestinal bacterial flora. PMID- 20709291 TI - STAT activation during viral infection in vivo: where's the interferon? AB - In this issue of Cell Host & Microbe, O'Gorman et al. (2010) identify a key role for early TLR2-mediated IL-6 production and STAT3 activation in generating protective immunity against poxviruses. These findings highlight the importance of early inflammatory cytokine production in antiviral defense and have implications for enhancing vaccination efficacy. PMID- 20709292 TI - Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma. AB - There are multiple mechanisms that protect the intestine from an excessive inflammatory response to intestinal microorganisms. We report here that all four mammalian peptidoglycan recognition proteins (PGRPs or Pglyrps) protect the host from colitis induced by dextran sulfate sodium (DSS). Pglyrp1(-/-), Pglyrp2(-/-), Pglyrp3(-/-), and Pglyrp4(-/-) mice are all more sensitive than wild-type mice to DSS-induced colitis due to a more inflammatory gut microflora, higher production of interferon-gamma, higher expression of interferon-inducible genes, and an increased number of NK cells in the colon upon initial exposure to DSS, which leads to severe hyperplasia of the lamina propria, loss of epithelial cells, and ulceration in the colon. Thus, during experimental colitis, PGRPs protect the colon of wild-type mice from an early inflammatory response and the loss of the barrier function of intestinal epithelium by promoting normal bacterial flora and by preventing damaging production of interferon-gamma by NK cells in response to injury. PMID- 20709293 TI - Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle. AB - The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts. PMID- 20709294 TI - Alternate mechanisms of initial pattern recognition drive differential immune responses to related poxviruses. AB - Vaccinia immunization was pivotal to successful smallpox eradication. However, the early immune responses that distinguish poxvirus immunization from pathogenic infection remain unknown. To address this, we developed a strategy to map the activation of key signaling networks in vivo and applied this approach to define and compare the earliest signaling events elicited by immunizing (vaccinia) and lethal (ectromelia) poxvirus infections in mice. Vaccinia induced rapid TLR2 dependent responses, leading to IL-6 production, which then initiated STAT3 signaling in dendritic and T cells. In contrast, ectromelia did not induce TLR2 activation, and profound mouse strain-dependent responses were observed. In resistant C57BL/6 mice, the STAT1 and STAT3 pathways were rapidly activated, whereas in susceptible BALB/c mice, IL-6-dependent STAT3 activation did not occur. These data link early immune signaling events to infection outcome and suggest that activation of different pattern-recognition receptors early after infection may be important in determining vaccine efficacy. PMID- 20709295 TI - Direct complement restriction of flavivirus infection requires glycan recognition by mannose-binding lectin. AB - An intact complement system is crucial for limiting West Nile virus (WNV) dissemination. Herein, we define how complement directly restricts flavivirus infection in an antibody-independent fashion. Mannose-binding lectin (MBL) recognized N-linked glycans on the structural proteins of WNV and Dengue virus (DENV), resulting in neutralization through a C3- and C4-dependent mechanism that utilized both the canonical and bypass lectin activation pathways. For WNV, neutralization occurred with virus produced in insect cells, whereas for DENV, neutralization of insect and mammalian cell-derived virus was observed. Mechanism of action studies suggested that the MBL-dependent neutralization occurred, in part, by blocking viral fusion. Experiments in mice showed an MBL-dependent accelerated intravascular clearance of DENV or a WNV mutant with two N-linked glycans on its E protein, but not with wild-type WNV. Our studies show that MBL recognizes terminal mannose-containing carbohydrates on flaviviruses, resulting in neutralization and efficient clearance in vivo. PMID- 20709296 TI - Sindbis virus usurps the cellular HuR protein to stabilize its transcripts and promote productive infections in mammalian and mosquito cells. AB - How viral transcripts are protected from the cellular RNA decay machinery and the importance of this protection for the virus are largely unknown. We demonstrate that Sindbis virus, a prototypical single-stranded arthropod-borne alphavirus, uses U-rich 3' UTR sequences in its RNAs to recruit a known regulator of cellular mRNA stability, the HuR protein, during infections of both human and vector mosquito cells. HuR binds viral RNAs with high specificity and affinity. Sindbis virus infection induces the selective movement of HuR out of the mammalian cell nucleus, thereby increasing the available cytoplasmic HuR pool. Finally, knockdown of HuR results in a significant increase in the rate of decay of Sindbis virus RNAs and diminishes viral yields in both human and mosquito cells. These data indicate that Sindbis virus and likely other alphaviruses usurp the HuR protein to avoid the cellular mRNA decay machinery and maintain a highly productive infection. PMID- 20709298 TI - Spinal cord injury in postearthquake Haiti: lessons learned and future needs. PMID- 20709299 TI - Rehabilitation outcomes of stroke patients treated with tissue plasminogen activator. AB - OBJECTIVE: To investigate the influence of thrombolysis on functional outcomes after rehabilitation. BACKGROUND: Systemic thrombolysis with tissue plasminogen activator (tPA) is considered the mainstay of acute stroke therapy and was found to improve short-term outcome. DESIGN: Matched case-controlled design. SETTING: Inpatient neurology and rehabilitation departments. PARTICIPANTS: Thirty-seven patients given tPA and 37 control patients not treated with lytics because of protocol limits. METHODS: We retrospectively analyzed data from a cohort of stroke patients who were treated with systemic tPA. The rehabilitation outcome of thrombolysis-treated patients was compared with that observed for tPA-ineligible and age- and stroke severity-matched patients treated at the same neurology and rehabilitation departments. MAIN OUTCOME MEASURE: Neurological evaluation was assessed with the National Institutes of Health stroke scale (NIHSS). Activity of daily living was measured using the Functional Independence Measure (FIM) instrument. Functional outcome was measured using the modified Rankin scale (mRS). RESULTS: The treatment group included 37 patients given tPA; 37 tPA ineligible patients served as controls. On admission to rehabilitation, there were no significant differences in functional, neurological, and rehabilitation parameters between the groups. At the end of the rehabilitation period, NIHSS scores were significantly lower in the thrombolysis group (P = .036). More patients in the thrombolysis group reached functional independence defined as mRS < or =2 (20/37 versus 10/37; P = .03). At the end of rehabilitation, total FIM score (mean 102.8 versus 93.9; P = .039), total FIM gain (mean 27.8 versus 21.4; P = .09), and total FIM efficiency scores (0.8 versus 0.43; P = .013) were higher in the thrombolysis group and more patients in this group were discharged home. CONCLUSIONS: Although the bulk of neurological improvement occurred before the inpatient rehabilitation, thrombolysis-treated patients continue to improve faster and to a larger extent during the rehabilitation period suggesting that the beneficial effects of thrombolysis continue beyond the acute phase. PMID- 20709297 TI - Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses. AB - Apicomplexan parasites release factors via specialized secretory organelles (rhoptries, micronemes) that are thought to control host cell responses. In order to explore parasite-mediated modulation of host cell signaling pathways, we exploited a phylogenomic approach to characterize the Toxoplasma gondii kinome, defining a 44 member family of coccidian-specific secreted kinases, some of which have been previously implicated in virulence. Comparative genomic analysis suggests that "ROPK" genes are under positive selection, and expression profiling demonstrates that most are differentially expressed between strains and/or during differentiation. Integrating diverse genomic-scale analyses points to ROP38 as likely to be particularly important in parasite biology. Upregulating expression of this previously uncharacterized gene in transgenic parasites dramatically suppresses transcriptional responses in the infected cell. Specifically, parasite ROP38 downregulates host genes associated with MAPK signaling and the control of apoptosis and proliferation. These results highlight the value of integrative genomic approaches in prioritizing candidates for functional validation. PMID- 20709301 TI - Effectiveness of aquatic exercise for obese patients with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To design an aquatic exercise (AQE) and land-based exercise (LBE) program to enhance knee function and reduce body fat in patients with obesity and knee osteoarthritis and to investigate the effectiveness of AQE and LBE on body fat, functional fitness, and functional status. SETTING: Outpatient clinic at a Seoul National University Bundang Hospital. PARTICIPANTS: Obese patients with knee osteoarthritis were recruited from patients who visited the rehabilitation, orthopedic surgery, and geriatric outpatient clinics at the hospital. Study participants were limited to those who met the following criteria: body mass index more than 25 kg/m(2), abdominal circumference more than 90 cm (men) or 85 cm (women), clinically diagnosed osteoarthritis with Kellgren-Lawrence scale 2 or higher on radiographic studies, and independent ambulation state. METHODS: Participants were randomly allocated into 3 groups: AQE (n = 26), LBE (n = 25), and the control group (n = 24). Exercise interventions were conducted 3 times a week for 8 weeks. OUTCOME MEASURES: Body fat analysis, brief pain inventory, Western Ontario and McMaster Universities' osteoarthritis index, Short Form-36 questionnaire, and knee isokinetic tests were evaluated to assess changes in body fat composition, pain, physical function, and quality of life before and after the exercise program. RESULTS: Although no significant difference was found in general characteristics among the 3 groups before exercise, body fat proportion in the AQE group decreased significantly (mean +/- SD, from 34.4 +/- 4.7 to 33.3 +/- 4.7; P = .031) after intervention. The body mass index was slightly reduced after intervention, but it was not statistically significant. The AQE group showed significant improvements in pain, disability, and quality of life. Notably, the change in pain interference in the AQE group (mean +/- SD, from 25.8 +/- 15.1 to 18.8 +/- 13.1; P = .009) was greater than that of the LBE group. Both exercise groups showed significant improvements in Western Ontario and McMaster Universities' osteoarthritis index disability compared with the control group. CONCLUSIONS: AQE had an advantage in controlling the interference with activity because of pain. AQE may be an effective tool for patients with obesity who have difficulties with active exercise due to knee osteoarthritis. PMID- 20709300 TI - Morbid obesity is associated with fear of movement and lower quality of life in patients with knee pain-related diagnoses. AB - OBJECTIVE: To compare fear of movement in patients with different body mass index (BMI) values referred for rehabilitative care of the knee and to examine whether this fear contributed to self-reported knee-related function. We hypothesized that fear of movement would be elevated with increasing BMI and that fear would correspond with lower self-report knee-related function and lower quality of life (QOL). DESIGN: Retrospective cross-sectional study. SETTING: Outpatient therapy clinic affiliated with a tertiary care hospital. PATIENTS: Patients with knee pain diagnoses (n = 278) were stratified into 4 BMI groups (in < or =25 kg/m(2) nonobese; 25-29.9 kg/m(2) overweight; 30-39.9 kg/m(2) obese; > or =40 kg/m(2) morbidly obese). MAIN OUTCOME MEASUREMENTS: The Tampa Scale of Kinesiophobia (TSK; fear of movement), International Knee Documentation (IKDC; knee function), and Short-Form 8 (SF-8; QOL) scores were main outcomes. Pain and straight leg raise test scores also were collected. METHODS: After review of the medical records, descriptive statistics and nonparametric tests were performed, and TSK, QOL, and SF-8 scores were compared. Hierarchical regression modeling determined the contribution of TSK scores to the variance of IKDC scores. RESULTS: Pain scores were greatest in the nonobese group and lowest in the morbidly obese group (7.5 +/- 2.6 points vs 4.8 +/- 3.1 points; P < .05). TSK scores in morbidly obese patients were greater than in nonobese patients (27.1 +/- 7.7 points vs 22.0 +/- 6.6 points; P = .002). The SF-8 mental-physical subscores were 27% to 32% lower in the morbidly obese than nonobese patients (both P < .0001). IKDC scores were lower in the morbidly obese than nonobese patients (32.1 +/- 19.2 points vs 50.9 +/- 23.8 points; P = .0001). Pain severity and TSK scores contributed 28.6% and 7.1% to the variance of the IKDC scores (overall R(2) = 68.6). CONCLUSIONS: Morbid obesity is associated with elevated fear of movement. Pain was the strongest predictor of IKDC scores, and fear of movement enhanced this predictive value of the regression model. Despite lower absolute pain severity in the morbidly obese group, this fear may influence IKDC scores in this population. Morbidly obese patients might benefit from rehabilitation activities that reduce fear of movement to optimize participation in rehabilitation activity. PMID- 20709303 TI - Assessing syndromes of catheter malfunction with SynchroMed infusion systems: the value of spiral computed tomography with contrast injection. PMID- 20709302 TI - Nutritional factors that influence change in bone density and stress fracture risk among young female cross-country runners. AB - OBJECTIVE: To identify nutrients, foods, and dietary patterns associated with stress fracture risk and changes in bone density among young female distance runners. DESIGN AND SETTING: Two-year, prospective cohort study. Observational data were collected in the course of a multicenter randomized trial of the effect of oral contraceptives on bone health. PARTICIPANTS: One hundred and twenty-five female competitive distance runners ages 18-26 years. ASSESSMENT OF RISK FACTORS: Dietary variables were assessed with a food frequency questionnaire. MAIN OUTCOME MEASUREMENTS: Bone mineral density and content (BMD/BMC) of the spine, hip, and total body were measured annually by dual x-ray absorptiometry (DEXA). Stress fractures were recorded on monthly calendars, and had to be confirmed by radiograph, bone scan, or magnetic resonance imaging. RESULTS: Seventeen participants had at least one stress fracture during follow-up. Higher intakes of calcium, skim milk, and dairy products were associated with lower rates of stress fracture. Each additional cup of skim milk consumed per day was associated with a 62% reduction in stress fracture incidence (P < .05); and a dietary pattern of high dairy and low fat intake was associated with a 68% reduction (P < .05). Higher intakes of skim milk, dairy foods, calcium, animal protein, and potassium were associated with significant (P < .05) gains in whole-body BMD and BMC. Higher intakes of calcium, vitamin D, skim milk, dairy foods, potassium, and a dietary pattern of high dairy and low fat were associated with significant gains in hip BMD. CONCLUSIONS: In young female runners, low-fat dairy products and the major nutrients in milk (calcium, vitamin D, and protein) were associated with greater bone gains and a lower stress fracture rate. Potassium intake was also associated with greater gains in hip and whole-body BMD. PMID- 20709304 TI - Health care reform's impact on physician practices. PMID- 20709305 TI - Patellofemoral pain: is there a role for orthoses? PMID- 20709306 TI - Botulinum toxin type A for the treatment of postamputation residual limb myokymia: a case report. PMID- 20709307 TI - A variation of musculocutaneous neuropathy: implications for electromyographers. PMID- 20709308 TI - Optimizing patient positioning and fluoroscopic imaging for the performance of cervical interlaminar epidural steroid injections. PMID- 20709309 TI - [Utility of bone replacement material in cochlear implant, skull base and sinus surgery: our experience]. AB - INTRODUCTION: To solve certain problems that arise in cochlear implant, sinus and skull base surgery, the use of bone cement (PolyBone(r)) has been introduced in our department. With the goal of making use of surgical bone cements, combining bone growth factors and polyphosphates has allowed the study of these biological materials. MATERIALS AND RESULTS: We present a total of 28 patients aged between 2 and 69 years (mean age of 29.2 years) in whom PolyBone(r) has been used as an additional therapeutic tool in the ENT surgical area. Complications occurred in 2 patients (7.4%). One was minor, solved with conservative treatment; one was a major complication that required surgery to extract the material and remove the implant. In the other 26 patients (92.6%), excellent results were achieved. CONCLUSIONS: Different autogenous and alloplastic materials are of great utility for fistula management, cavity filling or sinus obliteration, among other uses. The surgeon must understand their biological properties, fundamental characteristics, production technique and potential surgical applications to be able to prevent future complications. Among these materials, bone cement (PolyBone(r)) is an effective alternative that should be considered in surgical management of ENT pathology. PMID- 20709310 TI - Contact lens-induced subconjunctival hemorrhage. AB - PURPOSE: To present the first detailed assessment of the clinical features of CL induced subconjunctival hemorrhage and associated risk factors. DESIGN: Cross sectional and case-control study of age-matched randomized groups. METHODS: A total of 45 CL wearers with subconjunctival hemorrhage aged 18 to 45 years (CL Hemorrhage group), 200 age-matched healthy control subjects (non-CL group), and 200 age-matched CL wearers (CL group) were enrolled. The conjunctiva was divided into the following 8 equal areas: superior, superior/nasal, nasal, inferior/nasal, inferior, inferior/temporal, temporal, and superior/temporal. The site of hemorrhage, the grade, and other parameters of conjunctivochalasis at 3 locations (nasal, middle, and temporal), and the grade of pinguecula on the nasal or temporal conjunctiva were determined in all subjects. RESULTS: Typically, subconjunctival hemorrhage affected 1 or 2 regions of the temporal conjunctiva. The grade of conjunctivochalasis and pinguecula was higher in both the affected and unaffected eyes of the CL-Hemorrhage group than the non-CL and CL groups (all P < .00001). The effect of downward gaze or digital pressure on the extent of conjunctivochalasis was more marked in the CL-Hemorrhage group and superficial punctate keratitis was more common (all P < .00001). Multivariate logistic regression analysis of variables revealed that the presence of conjunctivochalasis and pinguecula were associated with an increased risk of CL induced subconjunctival hemorrhage (all P < .05). CONCLUSIONS: These results suggest that the major risk factors for CL-induced subconjunctival hemorrhage are conjunctivochalasis and pinguecula. PMID- 20709311 TI - Photodynamic therapy for symptomatic circumscribed macular choroidal hemangioma in Chinese patients. AB - PURPOSE: To evaluate the efficacy and safety of photodynamic therapy (PDT) for macular circumscribed choroidal hemangioma in Chinese patients. DESIGN: Retrospective, consecutive, noncomparative case series. METHODS: Twenty-five eyes (25 patients) with macular circumscribed choroidal hemangioma, 18 subfoveal and 7 perifoveal, with vision impairment attributable to subfoveal fluid and retinal detachment underwent visual acuity testing, fundus fluorescein angiography, ultrasonography, and optical coherence tomography (OCT) examinations to evaluate the efficacy and safety of PDT treatment. PDT was performed with a standard concentration of verteporfin and intravenous injection time. Laser was used at 50 J/cm2 for 83 seconds on subfoveal and 75 J/cm2 for 125 seconds on perifoveal lesions. More than 1 spot was used for large lesions and spots overlapped only outside the fovea. RESULTS: The mean follow-up time was 35.5 +/- 15 months. All patients were treated with 1 session except in 2 subfoveal cases. The mean best corrected visual acuity (BCVA) increased from 0.09 +/- 0.11 to 0.31 +/- 0.37 (P < .01) and 11 patients (44%) had their vision improve over 4 lines. The remaining 14 patients (56%) had stabilized vision with the retina reattached. The mean thickness of the hemangioma before the treatment was 3.2 +/- 0.9 mm and decreased to 1.3 +/- 1.0 mm post treatment (P < .01), with complete regression of tumor in 7 cases (28%). CONCLUSIONS: PDT with individualized laser parameters for macular circumscribed choroidal hemangioma is effective and safe, leading to improved or stabilized BCVA as a result of tumor shrinkage and the resolution of the subretinal fluid. PMID- 20709312 TI - [Cardiac involvement in polymyositis]. AB - Cardiovascular involvement in polymyositis constitutes a major cause of death. However, the cardiac location is rarely symptomatic and does not usually represent the principle clinical feature at the time of the initial presentation. We present here an unusual case of polymyositis with severe and polymorph cardiac disturbances that predominant the muscular signs. PMID- 20709313 TI - [Aortopulmonary infectious endocarditis with fatal evolution: a case report]. AB - We report the case of an aortic and pulmonary infective endocarditis in a 25-year old patient originating from Guinea Conakry. The patient did not have any particular cardiovascular antecedent. He is allowed in a table of total heart failure and fever. The transthoracic echocardiography found vegetations on the level of sigmoid aortic and pulmonary ones. A probabilistic bi-antibiotherapy was instituted while waiting for the results of hemocultures. The patient was apyretic after one week, with regression of inflammatory biological syndrome. However, he was deceased after 20 days in a table of heart failure. The necropsy found vegetations on the level of sigmoid aortic and pulmonary ones, which were perforated, a right lung oedema and a cardiac liver. PMID- 20709314 TI - ["Smoker's paradox" and reperfusion's strategy in acute myocardial infarction]. AB - Previous studies have shown that smokers with acute myocardial infarction (AMI) treated by thrombolysis have lower mortality rates than nonsmokers, a phenomenon often termed "smoker's paradox". This "smoker's paradox" has been rarely studied in case of primary angioplasty. AIM OF THE STUDY: To evaluate the impact of smoking status on the early mortality of patients admitted with AMI with regard to the strategy of reperfusion (intravenous thrombolysis versus primary angioplasty). PATIENTS AND METHODS: Study undertaken from the Monsatir registry of ST elevation MI including 688 patients having had either a hospital or a prehospital thrombolysis (n=397) or a primary angioplasty (n=291). Among those patients, 482 (70.1%) were active smokers. RESULTS: In the thrombolysis group, the prevalence of hypertension, diabetes and anterior location of MI was significantly less among smokers. In the group primary angioplasty, only diabetes and hypertension were less frequent. The immediate mortality was significantly less among smokers in case of thrombolysis comparatively to non-smokers (5.3 vs 13%; p=0.008). By multivariate analysis, cardiogenic shock (p<0.0001), anterior MI (p=0.03) and active smoking (p=0.03) were independent predictive factors of mortality in case of thrombolysis. A trend toward a lower mortality among smokers was observed in the primary angioplasty group (10 vs 17.6%; p=0.07). CONCLUSION: "The smoker's paradox" seems to be observed mainly among patients having had thrombolysis. PMID- 20709315 TI - Conformational preferences of alpha,alpha-trehalose in gas phase and aqueous solution. AB - This work presents an investigation on the conformational preferences of alpha,alpha-trehalose in gas phase and aqueous solution. Eighty-one systematically selected structures were studied at the B3LYP/6 311++G(d,p)//B3LYP/6-31G(d) level, giving rise to 40 unique conformers. The 19 lower energy structures and some selected other were further re-optimized at the B3LYP/6-311++G(d,p) level. The main factors accounting for the conformer's stability were pointed out and discussed. NBO and QTAIM analyses were performed in some selected conformers in order to address the anomeric and exo-anomeric effects as well as intramolecular hydrogen bonding. The effect of solvent water on the relative stability of the conformers was accounted for by applying the conductor-like polarizable continuum model, CPCM. PMID- 20709316 TI - Structure and gene cluster of the O-antigen of Salmonella enterica O44. AB - The O-polysaccharide (O-antigen) of Salmonella enterica O44 was studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy. The following structure of the pentasaccharide repeating unit containing only common monosaccharides was established: [Formula: see text]. The O-antigen gene cluster of S. enterica O44 was sequenced. The gene functions were tentatively assigned by comparison with sequences in the available databases and found to be in full agreement with the S. enterica O44-polysaccharide structure. PMID- 20709318 TI - The value of an admissions proforma for elderly patients with trauma. AB - The authors worked in a busy regional fracture unit, where it was noted that important data was being omitted from the medical notes. In an attempt to improve on this, an admission proforma was formulated. This was designed to be easily and quickly completed. Notes were audited on 2 separate weeks, the first before, and the second after introduction of the proforma.The overall results demonstrate statistically significant improvements in documentation with a proforma, and concur with the limited previous literature in this area. PMID- 20709317 TI - Akt pathway is required for oestrogen-mediated attenuation of lung injury in a rodent model of cerulein-induced acute pancreatitis. AB - BACKGROUND: The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is known to be an endogenous negative feedback or compensatory mechanism that serves to limit pro-inflammatory and chemotactic events in response to injury. The aim of this study is to elucidate whether Akt plays any role in 17beta-estradiol (E2) mediated attenuation of lung injury after acute pancreatitis (AP). MATERIALS AND METHODS: Male Sprague-Dawley rats underwent cerulein-induced AP. Rats were treated with vehicle (cyclodextrin), E2 (1 mg/kg body weight [BW]), or E2 plus PI3K/Akt inhibitor Wortmannin (100 MUg/kg BW) 1h after the onset of AP. At 8 h after sham operation or AP, various parameters were measured. RESULTS: AP led to a significant decrease in lung Akt phosphorylation, which was associated with increased lung tissue myeloperoxidase (MPO) activity, wet-to-dry weight ratios, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-3 levels. Administration of E2 after AP restored the AP-induced decrease in Akt phosphorylation and attenuated the increase in lung injury markers (MPO activity and wet-to dry weight ratios) and pro-inflammatory mediator production. The effects of E2 on the lung were abolished by co-administration of Wortmannin. CONCLUSIONS: These results collectively suggest evidences that the Akt pathway seems to be required for E2 mediated protection of lung injury after AP. PMID- 20709319 TI - Is a single or double arm technique more advantageous in triple jumping? AB - Triple jumpers employ either an asymmetrical 'single-arm' action or symmetrical 'double-arm' action in the takeoff of each phase of the jump. This study investigated which technique is more beneficial in each phase using computer simulation. Kinematic data were obtained from an entire triple jump using a Vicon automatic motion capture system. A planar 13-segment torque-driven subject specific computer simulation model was evaluated by varying torque generator activation timings using a genetic algorithm in order to match performance data. The matching produced a close agreement between simulation and performance, with differences of 3.8%, 2.7%, and 3.1% for the hop, step, and jump phases, respectively. Each phase was optimised for jump distance and an increase in jump distance beyond the matched simulations of 3.3%, 11.1%, and 8.2% was obtained for the hop, step, and jump, respectively. The optimised technique used symmetrical shoulder flexion whereas the triple jumper had used an asymmetrical arm technique. This arm action put the leg extensors into slower concentric conditions allowing greater extensor torques to be produced. The main increases in work came at the joints of the stance leg but the largest increases in angular impulse came at the shoulder joints, indicating the importance of both measures when assessing the impact of individual joint actions on changes in technique. Possible benefits of the double-arm technique include: cushioning the stance leg during impact; raising the centre of mass of the body at takeoff; facilitating an increase in kinetic energy at takeoff; allowing a re-orientation of the body during flight. PMID- 20709320 TI - A three-dimensional mathematical model of the thoracolumbar fascia and an estimate of its biomechanical effect. AB - The thoracolumbar fascia (TLF) provides a means of attachment to the lumbar spine for several muscles including the transverse abdominis, and parts of the latissimus dorsi and internal oblique muscles. Previous biomechanical models of the lumbar spine either tend to omit the TLF on the assumption that its contribution would be negligible or incorporate only part of the TLF. Here, a three-dimensional model of the posterior and middle layers of the TLF is presented to enable its action to be included in future three-dimensional models of the spine. It is used illustratively to estimate the biomechanical influence of this structure on the lumbar spine. The formulation of the model allows the lines of action of the fibres comprising the fascia to be calculated for any posture whilst ensuring that anatomical constraints are satisfied. Application of the model suggests that the TLF produces moments primarily in flexion and extension. The simulated results demonstrate that the abdominal muscles, acting via the TLF, are capable of contributing extension moments comparable to those produced by other smaller muscles associated with the lumbar spine. PMID- 20709321 TI - Chromatographic biopanning for the selection of peptides with high specificity to Pb2+ from phage displayed peptide library. AB - Toxic heavy metal pollution is a global problem occurring in air, soil as well as water. There is a need for a more cost effective, renewable remediation technique, but most importantly, for a recovery method that is selective for one specific metal of concern. Phage display technology has been used as a powerful tool in the discovery of peptides capable of exhibiting specific affinity to various metals or metal ions. However, traditional phage display is mainly conducted in batch mode, resulting in only one equilibrium state hence low efficiency selection. It is also unable to monitor the selection process in real time mode. In this study, phage display technique was incorporated with chromatography procedure with the use of a monolithic column, facilitating multiple phage-binding equilibrium states and online monitoring of the selection process in search of affinity peptides to Pb2+. In total, 17 candidate peptides were found and their specificity toward Pb2+ was further investigated with bead based enzyme immunoassay (EIA). A highly specific Pb2+ binding peptide ThrAsnThrLeuSerAsnAsn (TNTLSNN) was obtained. Based on our knowledge, this is the first report on a new chromatographic biopanning method coupled with monolithic column for the selection of metal ion specific binding peptides. It is expected that this monolith-based chromatographic biopanning will provide a promising approach for a high throughput screening of affinity peptides cognitive of a wide range of target species. PMID- 20709322 TI - Tetrahydrofuran-water extraction, in-line clean-up and selective liquid chromatography/tandem mass spectrometry for the quantitation of perfluorinated compounds in food at the low picogram per gram level. AB - A new solvent extraction system was developed for extraction of PFCs from food. The extraction is carried out with 75:25 (v/v) tetrahydrofuran:water, a solvent mixture that provides an appropriate balance of hydrogen bonding, dispersion and dipole-dipole interactions to efficiently extract PFCs with chains containing 4 14 carbon atoms from foods. This mixture provided recoveries above 85% from foods including vegetables, fruits, fish, meat and bread; and above 75% from cheese. Clean-up with a weak anion exchange resin and Envi-carb SPE, which were coupled in line for simplicity, was found to minimize matrix effects (viz. enhancement or suppression of electrospray ionization). The target analytes (PFCs) were resolved on a perfluorooctyl phase column that proved effective in separating mass interferences for perfluorooctane sulfonate (PFOS) in fish and meat samples. The mass spectrometer was operated in the negative electrospray ionization mode and used to record two transitions per analyte and one per mass-labeled method internal standard. The target PFCs were quantified from solvent based calibration curves. The limits of detection (LODs) were as low as 1-5 pg analyte g(-1) food; by exception, those for C(4) and C(5) PFCs were somewhat higher (25-30 pg g(-1)) owing to their less favourable mass response. To the best of our knowledge these are among the best LODs for PFCs in foods reported to date. The analysis of a variety of foods revealed contamination with PFCs at levels from 4.5 to 75 pg g( 1) in 25% of samples (fish and packaged spinach). C(10)-C(14) PFCs were found in fish, which testifies to the need to control long-chain PFCs in this type of food. The proposed method is a useful tool for the development of a large-scale database for the presence of PFCs in foods. PMID- 20709323 TI - Fluorescent magnetic nanoprobes: design and application for cell imaging. AB - Multifunctional nanoprobes combining magnetic nanoparticles with organic dyes have attracted tremendous interest due to their promising applications in biomedical field. Here we demonstrate a facile and general strategy for the fabrication of robust fluorescent magnetic nanoprobes with high payloads of dye molecules and their use as multimodal nanoprobes for cell imaging. These nanoprobes not only effectively keep photochemical stability of dyes, but also provide a platform for grafting other functional or targeted moieties into silica surface via primary amines. Moreover, the nanoprobes are uniformly spherical morphology and can be dispersed well in aqueous solution, which are very desirable for biomedical applications. Importantly, this method can be extended to synthesize other bifunctional nanoprobes by using the dyes with isothiocyanate group. PMID- 20709324 TI - Phase and rheological behavior of the hexadecyl(trimethyl)azanium; 2 hydroxybenzoate/water system. AB - The phase and rheological behavior of hexadecyl(trimethyl)azanium; 2 hydroxybenzoate (CTAS), and water as a function of surfactant concentration and temperature are investigated here. The critical micellization concentration (cmc(1)) and the concentration at which the structure of aggregates changes (cmc(2)) as well as the Krafft temperature (T(K)) are reported. A large micellar solution region exhibiting high viscosity, as well as hexagonal- and lamellar phase regions were identified. In the dilute region, below the overlapping entanglement concentration (C*), the micellar solutions exhibit shear thickening. Above C*, wormlike micelles form and the solutions show strong viscoelasticity with Maxwell behavior in the linear regime and shear banding flow in the non linear regime. The linear viscoelastic regime was analyzed with the Granek-Cates model, showing that the relaxation is controlled by the kinetics of reformation and-scission of the micelles. The steady response in the non-linear regime is compared with the predictions of the Bautista-Manero-Puig (BMP) and the Giesekus models. PMID- 20709325 TI - Dissolution kinetics and mechanism of Mg-Al layered double hydroxides: a simple approach to describe drug release in acid media. AB - Layered double hydroxides (LDHs) weathering in acidic media is one of the main features that affects their applications in drug delivery systems. In this work, the dissolution kinetics of biocompatible Mg-Al LDHs was studied at different initial pH values and solid concentrations using a simple and fast experimental method that coupled flow injection analysis and amperometric detection. A carbonate intercalated sample was used to determine the controlling step of the process and the dissolution mechanism. Finally, the study was extended to an ibuprofen intercalated LDH. The obtained results showed that the weathering process was mainly controlled by the exposed area and surface reactivity of LDHs particles. The dissolution mechanism at the particle surface was described in two steps: fast formation of surface reactive sites by hydroxyl group protonation and slow detachment of metal ions from surface. At strongly acidic conditions, the reaction rate was pH dependent due to the equilibrium between protonated (active) and deprotonated (inactive) hydroxyl groups. On the other hand, at mildly acidic conditions, the dissolution behavior was also ruled by the equilibrium attained between the particle surface reactive sites and the dissolved species. LDHs solubility and dissolution rate presented strong dependence with the interlayer anion. The ibuprofen intercalated sample was more soluble and more rapidly dissolved than the carbonate intercalated one in acetic/acetate buffer. On the other hand, the dissolution mechanism was invariant with the interlayer anion. PMID- 20709326 TI - Low surface energy surfaces from self-assembly of perfluoropolymer with sticky functional groups. AB - Fluorinated methacrylic copolymer containing catechol and perfluoroalkyl pendant side groups is synthesized by the free radical polymerization of a catechol containing methacrylate monomer N-(3,4-dihydroxyphenyl)ethyl methacrylamide and 1H,1H-perfluorooctyl methacrylate using alpha,alpha'-azobisisobutyronitrile (AIBN) as initiator. The fluorinated copolymer can assemble onto surfaces of a wide variety of materials including Ti, Al, Cu, steel, silicon, glass, mica, polyimide, polystyrene, and polymethylmethacrylate using catechol groups as multivalent H-bonding anchors. X-ray photoelectron spectroscopy and contact-angle data provide solid evidence of the formation of the assembly films that exhibit the surface free energy as low as 8.0 mJ m(-2). PMID- 20709327 TI - Superhydrophobic antibacterial cotton textiles. AB - We present a facile and effective method to prepare superhydrophobic cotton textiles. Silver particles were produced on cotton fibers by treatment with aqueous KOH and AgNO(3), followed by reduction treatment with ascorbic acid in the presence of a polymeric steric stabilizer to generate a dual-size surface roughness. Further modification of the particle-containing cotton textiles with octyltriethoxysilane led to hydrophobic surfaces. Surfaces prepared showed a sticky property, which exhibits a static water contact angle of 151 degrees for a 10 microL droplet that water drop did not slid off even when the sample was held upside down. The modified cotton has potent antibacterial activity toward both Gram-positive and Gram-negative bacteria. The Ag particles were uniformly and stably distributed on the substrate surface and killed bacteria. These modified cotton textiles are potentially useful; as superhydrophobic antibacterial fabrics in a wide variety of biomedical and general use applications. PMID- 20709328 TI - Surface-initiated ring-opening metathesis polymerization of 5 (perfluorohexyl)norbornene on carbon paper electrodes. AB - Hydrophobic coatings on carbon paper electrodes are known to provide effective water management, superior gas transfer, and improved mechanical stability of the paper in fuel cell applications. Here, we describe the surface-initiated ring opening metathesis polymerization (ROMP) of 5-(perfluorohexyl)norbornene (NBF6) to prepare fluorocarbon-rich films on carbon paper substrates that were pre treated with O(2) plasma. For our reaction scheme, the growth of the pNBF6 films is dependent on the concentration of hydroxyl groups on the carbon paper substrate. X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) were used to determine the required time for O(2) plasma exposure to saturate the surface with hydroxyl-termini. Complete, conformal pNBF6 films were grown on carbon paper electrodes exposed to O(2) plasma for at least 45 s. These films exhibit hydrophobic and oleophobic surface properties and serve as insulative barriers to the diffusion of aqueous ions to the conductive carbon fibers. PMID- 20709329 TI - Photocatalytic degradation in aqueous solution using quantum-sized ZnO particles supported on sepiolite. AB - Quantum-sized ZnO particles supported on sepiolite (ZnO/sepiolite) was prepared by sol-gel method using the sepiolite of acid activation as carrier, zinc acetate dihydrate (Zn(CH(3)COO)(2).2H(2)O) and lithium hydroxide monohydrate (LiOH.H(2)O) as raw material. The size of ZnO which supported on fibrous sepiolite is about 5 nm when calcined at 200 degrees C. The behavior of ZnO/sepiolite composites in the degradation of C.I. Reactive Blue 4 was investigated. Under the optimal preparation conditions, when the content of ZnO was about 70 wt.% in the nanocomposites, the photocatalytic property of the ZnO/sepiolite was excellent. The degradation rate of 20 mg/L C.I. Reactive Blue 4 could get to 98% in 120 min at room temperature when the concentration of catalyst was 0.2 g/L. The photocatalytic decomposition of organic pollutants accords with a pseudo first order kinetic. The pH and H(2)O(2) influence the degradation rate of the ZnO/sepiolite. The experiment indicated that after the catalyst had been used 5 times repeatedly, the degradation rate had been still above 80%. PMID- 20709330 TI - Effects of gustatory stimulation on brain activity during hunger and satiety in females with restricting-type anorexia nervosa: an fMRI study. AB - BACKGROUND: Previous research has demonstrated altered neuronal responses to visual stimulation with food in anorexia nervosa, varying with the motivational state of hunger or satiety. The aim of the present fMRI study was to assess hunger- and satiety-dependent alterations in the gustatory processing of stimulation with food in anorexia nervosa. METHODS: After food abstention (hunger condition) and after eating bread rolls with cheese (satiety condition), 12 females with restricting-type anorexia nervosa and 12 healthy females drank chocolate milk and water via a tube in a blocked design during image acquisition. Additionally, heart rate was registered during the measurements, and subjective ratings of hunger/satiety and of the valence of chocolate milk were assessed using a Likert scale. RESULTS: In participants with anorexia nervosa, drinking chocolate milk in the hunger condition induced significant activations in the right amygdala and in the left medial temporal gyrus relative to healthy controls. When contrasting neuronal responses to drinking chocolate milk during satiety with those evoked during hunger, a significant activation was found in the left insula in healthy controls, whereas in participants with anorexia nervosa, neuronal activity in the inferior temporal gyrus, covering the extrastriate body area, was observed. CONCLUSIONS: Neuronal responses evoked by gustatory stimulation differ depending on hunger and satiety. Activations located in the amygdala and in the extrastriate body area might reflect fear of weight gain, representing one of the core symptoms of anorexia nervosa. PMID- 20709331 TI - Hypoglycemia as a trigger for the syndrome of acute bilateral basal ganglia lesions in uremia. AB - The syndrome of acute bilateral basal ganglia lesions is a rarely described complication of uremia occurring typically in the setting of concurrent long standing diabetes mellitus. Reversible symmetrical lesions located in basal ganglia found on brain magnetic resonance imaging are hallmarks of this syndrome. Clinical presentation includes parkinsonism and/or involuntary movements. The cause of this syndrome is largely unknown. Among the factors that are believed to contribute to its pathogenesis are uremic toxins, metabolic acidosis and diabetic microangiopathy. Here we report a patient with uremia and newly diagnosed diabetes, who developed the syndrome of acute bilateral basal ganglia lesions after an incidence of severe hypoglycemia induced by oral hypoglycemic agents. We consider hypoglycemia as a candidate trigger factor for the syndrome of acute bilateral basal ganglia lesions and highlight the importance of strict glucose control in uremic patients. PMID- 20709332 TI - Telomere length and ApoE polymorphism in mild cognitive impairment, degenerative and vascular dementia. AB - BACKGROUND: Clarifying the aetiology of dementia is of crucial importance in the management of patients as well as for research purposes but it is not always possible clinically. Therefore the identification of biological markers should complement clinical approaches. Telomere shortening is emerging as an important mechanism in vascular aging and the pathogenesis of hypertension and atherosclerosis. Thus, telomere length could be a potential candidate to accurately separate vascular from degenerative cognitive impairment. OBJECTIVES: To evaluate the usefulness of telomere length alone or combined with ApoE polymorphism in diagnosing mild cognitive impairment (MCI) and in differentiating Alzheimer's disease (AD) from vascular (VaD) and mixed dementia (MD). METHODS: Telomere length in peripheral blood lymphocytes was performed by flow cytometry in 439 patients (mean age, 85.1 years): 204 cognitively normal, 187 demented patients: 80 AD, 86 MD, and 21 with VaD; and 48 patients with MCI. Simple and multiple ordered logistic regressions were used to predict the risk of dementia from telomere length, ApoE polymorphism and age. RESULTS: ApoEepsilon4 was statistically associated with patients with dementia (p<0.001) compared to cognitively normal or MCI patients; but not with the aetiologies of dementia (AD, VaD and MD) (p=0.385). No significant differences in telomere length were found among patients with different aetiologies or severities of dementia. In the global model, the combination of telomere length and ApoE polymorphism did not confer a significantly higher dementia risk (OR=0.95, 95% CI=0.69-1.32; p=0.784) than APOEepsilon4 alone (OR=2.12, 95% CI=1.15-3.9; p=0.016). CONCLUSION: This longitudinal study in very old patients provided no evidence suggesting that telomere length alone could be used to distinguish between the different types of dementia or MCI, nor combined with the ApoE polymorphism. PMID- 20709333 TI - Role of biofilm in Staphylococcus aureus and Staphylococcus epidermidis ventricular assist device driveline infections. AB - OBJECTIVE: Infections, especially those involving drivelines, are among the most serious complications that follow ventricular assist device implantation. Staphylococci are the most common causes of these infections. Once driveline infections are established, they can remain localized or progress as an ascending infection to cause metastatic seeding of other tissue sites. Although elaboration of biofilm appears to be critical in prosthetic device infections, its role as a facilitator of staphylococcal infection and migration along the driveline and other prosthetic devices is unclear. METHODS: A murine model of driveline infection was used to investigate staphylococcal migration along the driveline. A biofilm-producing strain of Staphylococcus epidermidis and a Staphylococcus aureus strain and its intercellular adhesion gene cluster (ica)-negative (biofilm deficient) isogenic mutant were used in these studies. Bacterial density on the driveline and the underlying tissue was measured over time. Scanning electron microscopy was used to examine the morphology of S epidermidis biofilm formation as the infection progressed. RESULTS: The biofilm-deficient S aureus mutant was less effective at infecting and migrating along the driveline than the wild-type strain over time. However, the ica mutation had no effect on the ability of the strain to infect underlying tissue. S aureus exhibited more rapid migration than S epidermidis. Scanning electron microscopy revealed the deposition of host matrix on the Dacron material after implantation. This was followed by elaboration of a bacterial biofilm that correlated with more rapid migration along the driveline. CONCLUSIONS: Biofilm formation is a critical virulence determinant that facilitates the progression of drivelines infections. PMID- 20709334 TI - Heparinized cardiopulmonary bypass circuits and low systemic anticoagulation: an analysis of nearly 6000 patients undergoing coronary artery bypass grafting. AB - OBJECTIVE: Heparin coating of cardiopulmonary bypass circuits reduces the inflammatory response and increases the thromboresistance during extracorporeal circulation. These properties enables a lower systemic heparin dose, which has been shown to reduce the need for blood transfusions. Experience with this technique accumulated over 11 years has been analyzed. METHODS: All patients underwent on-pump coronary artery bypass grafting with heparin-coated circuits. Apart from some patients receiving a high intraoperative dose of aprotinin, the systemic heparin dose was reduced, with a lower level of an activated clotting time of 250 seconds during extracorporeal circulation. The overall strategy aimed at a fast-track regimen, with early extubation, minimal use of blood transfusions, and rapid postoperative recovery. RESULTS: Altogether, 5954 patients were included; 1131 (19.0%) were female (median age, 70 years), and 4823 were male (median age, 65 years). The median additive EuroSCORE was 3 (range, 0 14; mean 3.5 +/- 2.5). No significant signs of clotting were seen in any part of the extracorporeal circuit. Bank blood products were given to 427 (7.2%) patients. Median extubation time was 1.7 hours. The stroke rate was 1.0%, transient neurologic deficits occurred in 0.7%, and perioperative myocardial infarction occurred in 1.2%. On the fifth day, 88.1% of the patients were physically rehabilitated and ready for discharge. Thirty-day mortality was 0.9% (54 patients). CONCLUSIONS: The experience with this patient cohort including mostly low- to medium-risk patients with a relatively short cardiopulmonary bypass time indicates that coronary artery bypass grafting performed with heparin coated circuits and reduced level of systemic heparinization is safe and results in a very satisfactory clinical course. No signs of clotting or other technical incidents were recorded. PMID- 20709335 TI - Echocardiographically based treatment of chronic ischemic mitral regurgitation. AB - OBJECTIVES: We evaluated results of an echocardiographically based strategy combining mitral annuloplasty with other procedures to treat chronic ischemic mitral regurgitation. METHODS: From March 2006 to February 2009, 147 patients underwent mitral valve surgery for chronic ischemic mitral regurgitation. Mean effective regurgitant orifice was 36 +/- 11 mm(2), and ejection fraction was 35% +/- 9%. On the basis of echocardiographic findings, in 10 cases a prosthesis was inserted and mitral annuloplasty was performed in 137 cases, isolated in 83, associated with chordal cutting in 12 cases (in 5 anterior leaflet was augmented with pericardial patch), and with exclusion of anteroseptal (n = 35) or inferior (n = 7) scars in 42. RESULTS: Thirty-day mortality was 4.8%; 3-year survival was 86% +/- 3%. None of the 126 survivors were in New York Heart Association functional class III or IV. Among 117 survivors of mitral valve repair, after 18 +/- 6 months mean effective regurgitant orifice reduced from 34.1 +/- 10.2 mm(2) to 2.3 +/- 0.4 mm(2) (P < .001). Nine patients showed residual effective regurgitant orifice 10 to 19 mm(2). Reverse remodeling was present in 69 patients (59.0%), no remodeling in 40 (34.1%), and continuous remodeling in 8 (6.9%). Ejection fraction changed from 37% +/- 10% to 43% +/- 10% (P < .001), improving in 47, remaining unchanged in 63, and worsening in 7. CONCLUSIONS: Echocardiographically based strategy contributed to reduced postoperative mitral regurgitation persistence (effective regurgitant orifice >= 10 mm(2) in 7.7% of cases, with no patients showing effective regurgitant orifice >= 20 mm(2)). All patients remained in New York Heart Association functional class I or II, but more than mitral annuloplasty was performed in close to 40%. PMID- 20709336 TI - Outcomes of 11/2- or 2-ventricle conversion for patients initially treated with single-ventricle palliation. AB - OBJECTIVE: As outcomes for the Fontan procedure have improved, it has become more difficult to select between a single-ventricle repair or biventricular repair for patients with complex anatomy and 2 ventricles. However, late complications after the Fontan procedure remain a concern. Our strategy, which has favored an aggressive preferential approach for biventricular repair in these patients, has also been applied to patients initially treated on a single-ventricle track elsewhere. METHODS: Nine patients (4 male patients) who had previously undergone the Fontan procedure (n=3) or bidirectional cavopulmonary shunting (n=6) with intent for a later Fontan procedure were referred to our center for complex 11/2- or 2-ventricle repair over the last 10 years. Indications for conversion in these patients were protein-losing enteropathy (n=2), pulmonary arteriovenous malformation (n=1), and preference for biventricular anatomy (n=6). The conversion mainly consisted of takedown of the Fontan procedure or bidirectional cavopulmonary shunt connection, reconstruction of 1 or both of venae cavae, creation of an intraventricular pathway for left ventricular output, and placement of a right ventricle-pulmonary artery conduit (Rastelli-type operation). RESULTS: Five patients underwent 11/2-ventricle repair, and 4 had complete biventricular repair. Median cardiopulmonary bypass and aortic crossclamp times were 202 minutes (range, 169-352 minutes) and 129 minutes (range, 100-168 minutes), respectively. There were 2 early deaths and 1 late death. At a median follow-up of 27 months (range, 3.3-99.8 months), all survivors are in New York Heart Association class I. CONCLUSIONS: Patients initially treated with intent to perform single-ventricle palliation can be converted to 11/2- or 2-ventricle physiology with acceptable outcomes. PMID- 20709338 TI - Spatial and temporal distribution of zooplankton related to the environmental conditions in the coral reef lagoon of New Caledonia, Southwest Pacific. AB - The distribution of zooplanktonic prey of fish larvae was examined in three bays and two lagoonal stations in the Southwest lagoon of New Caledonia. Water column conditions were characterized by increasing chlorophyll a and particulate organic matter (POM) concentrations from the lagoon to the estuarine bay. The mean zooplankton settled volume and total density were significantly higher in the estuarine bay, reaching 35.1 mL m(-3) and 3.5 x 10(5) individuals m(-3), respectively. The total zooplankton density also progressively increased along the sampling period. The composition of assemblages differed between the lagoon and the bays, and was similar in the three bays. Wind speed, surface temperature, chlorophyll a and POM explained these variations, as revealed by a co-inertia analysis (COIA). The prey preferred by fish larvae, i.e. small crustaceans and small copepods, were more abundant in bays. Sheltered bays, most influenced by terrigenous inputs, are likely to provide the best feeding conditions. PMID- 20709337 TI - Covered stents for the treatment of life-threatening cervical esophageal anastomotic leaks. PMID- 20709339 TI - The size, mass, and composition of plastic debris in the western North Atlantic Ocean. AB - This study reports the first inventory of physical properties of individual plastic debris in the North Atlantic. We analyzed 748 samples for size, mass, and material composition collected from surface net tows on 11 expeditions from Cape Cod, Massachusetts to the Caribbean Sea between 1991 and 2007. Particles were mostly fragments less than 10mm in size with nearly all lighter than 0.05 g. Material densities ranged from 0.808 to 1.24 g ml(-1), with about half between 0.97 and 1.04 g ml(-1), a range not typically found in virgin plastics. Elemental analysis suggests that samples in this density range are consistent with polypropylene and polyethylene whose densities have increased, likely due to biofouling. Pelagic densities varied considerably from that of beach plastic debris, suggesting that plastic particles are modified during their residence at sea. These analyses provide clues in understanding particle fate and potential debris sources, and address ecological implications of pelagic plastic debris. PMID- 20709340 TI - Anthropogenic organic matter inputs indicated by sedimentary fecal steroids in a large South American tropical estuary (Paranagua estuarine system, Brazil). AB - Urban sewage is considered one of the most important sources of marine pollution in South America, because most coastal cities do not have proper facilities to treat and dispose of sewage. The Paranagua estuarine system is an important estuarine environment of the South American coast where fishing, urban and tourist activities, industries and the main Brazilian grain shipping port are potential sources of pollution in this area. The anthropogenic input of sedimentary organic matter, represented by sewage contribution, was evaluated by fecal steroid concentrations. The coprostanol levels were comparatively low (<0.10 MUg g(-1)), except at the sites close to Paranagua city, where the coprostanol concentration reached 2.22 MUg g(-1) showing strong sewage contamination. Fecal steroid levels were comparable to the lower to midrange concentrations reported for coastal sediments worldwide. The results of this work demonstrated that sewage pollution can be considered a problem for a small part of the Paranagua estuary. PMID- 20709341 TI - Plasma concentrations of buprenorphine after epidural administration in conscious cats. AB - Buprenorphine plasma concentrations were measured after administering buprenorphine (20 MUg/kg) into the lumbosacral epidural space of conscious cats chronically instrumented with an epidural catheter. Blood was collected from a jugular vein before injection and 15, 30, 45 and 60 min and 2, 3, 4, 5, 6, 8, 12 and 24 h after administration. Plasma buprenorphine concentrations were measured using ELISA. Background concentration (before injection) was 1.27 +/- 0.27 ng/mL (mean +/- SD). Including background concentration, the mean peak plasma concentration was obtained 15 min after injection (5.82 +/- 3.75 ng/mL), and ranged from 3.79 to 2.20 ng/mL (30 min-3 h), remaining between 1.93 and 1.77 ng/mL (4-12 h), and declined to 1.40 +/- 0.62 ng/mL at 24h. Elimination half-life was 58.8 +/- 40.2 min and clearance 56.7 +/- 21.5 mL/min. Results indicate early rapid systemic uptake of buprenorphine from epidural administration with plasma concentrations similar to using buccal or IM routes by 15 min postinjection. PMID- 20709342 TI - Trends in age for hepatoportoenterostomy in the United States. AB - BACKGROUND: Biliary atresia is a rare but devastating disease for which hepatoportoenterostomy remains the primary intervention. Increased age at the time of hepatoportoenterostomy is associated with unfavorable outcomes. In this study, we examined trends in age at the time of hepatoportoenterostomy and explored hospital and patient factors associated with more timely diagnosis and treatment. METHODS: Median ages of patients undergoing hepatoportoenterostomy for biliary atresia were compared using the Kids' Inpatients Database from 1997, 2000, 2003, and 2006. The patient and hospital factors associated with later treatment were compared. RESULTS: Of 192 patients, 13.5% had surgery in 1997, 13.5% in 2000, 36.5% in 2003, and 36.5% in 2006. The overall median age was 65.5 days; the median age was 64 days in 1997, 57.5 days in 2000, 69 days in 2003, and 64 days in 2006 (P = .80). Overall, 71% of patients were treated at nonchildren's hospitals, and although the proportion has increased over time, the trend did not reach significance (P = .12). Hispanic and African American patients were more likely to undergo hepatoportoenterostomy after 60 days of life compared with white patients (Hispanic patients: odds ratio, 3.6; 95% confidence interval, 1.1 12.5; P = .04; African American patients: odds ratio, 2.2; 95% confidence interval, 0.8-6.3; P = .14). Compared with specialized children's centers, treatment at nonchildren's hospitals was associated with delayed hepatoportoenterostomy (odds ratio, 3.5; 95% confidence interval, 1.2-9.8; P = .02). CONCLUSION: Although early hepatoportoenterostomy is associated with improved outcomes for children with biliary atresia, our study shows the median age at surgery has not significantly changed over 2 decades. Both hospital and socioeconomic factors play a role in the early treatment of biliary atresia. PMID- 20709343 TI - Malpractice litigation after thyroid surgery: the role of recurrent laryngeal nerve injuries, 1989-2009. AB - BACKGROUND: Recurrent laryngeal nerve injuries remain a complication that is a source of concern to both surgeons and patients. RLN monitoring has gained popularity in recent years despite a lack of evidence showing decreased rates of recurrent laryngeal nerve injury when nerve monitoring is used. We sought to explore malpractice litigation in thyroid surgery with respect to recurrent laryngeal nerve monitoring. With increased public awareness and surgeon use of recurrent laryngeal nerve monitoring, we hypothesize an increase in its use in malpractice litigation in the area of thyroid surgery. METHODS: Using the LexisNexis Academic legal database, a retrospective review of all relevant federal and state cases from 1989 to 2009 was performed using the search terms "thyroid," "surgery," and "medical malpractice." From this search, data were compiled including year and state of the court's decision, the outcome of the trial, the type of complication, any mention of recurrent laryngeal nerve monitoring, and the specialty of the surgeon who performed the procedure. The cases that were settled out of court were not included in this analysis. RESULTS: A total of 143 medical malpractice cases involving thyroid surgery were retrieved from our search from 1989 to 2009. After reviewing all cases, 33 cases in which the alleged negligence occurred after thyroid surgery were used for analysis. Of these cases, 15 involved recurrent laryngeal nerve injury; interestingly, no mention of recurrent laryngeal nerve monitoring was noted in any of the cases. CONCLUSION: Although recurrent laryngeal nerve monitoring has become more widely available and used, there is no evidence that its use or nonuse has played a role in malpractice litigation in the last 20 years. recurrent laryngeal nerve injury remains a cause of malpractice litigation. PMID- 20709344 TI - Not again! AB - A 58-year-old white man presented with a second episode of vision loss in the same eye. Diagnostic evaluations conducted at each episode were unrevealing for an underlying etiology, and a presumptive diagnosis of recurrent non-arteritic anterior ischemic optic neuropathy (NAION) was made. The evaluation of recurrent NAION is discussed. PMID- 20709345 TI - Cpr1 cyclophilin and Ess1 parvulin prolyl isomerases interact with the tombusvirus replication protein and inhibit viral replication in yeast model host. AB - To identify host proteins interacting with the membrane-bound replication proteins of tombusviruses, we performed membrane yeast two-hybrid (MYTH) screens based on yeast cDNA libraries. The screens led to the identification of 57 yeast proteins interacting with replication proteins of two tombusviruses. Results from a split ubiquitin assay with 12 full-length yeast proteins and the viral replication proteins suggested that the replication proteins of two tombusviruses interact with a similar set of host proteins. Follow-up experiments with the yeast Cpr1p cyclophilin, which has prolyl isomerase activity that catalyzes cis trans isomerization of peptidyl-prolyl bonds, confirmed that Cpr1p interacted with the viral p33 replication protein in yeast and in vitro. Replication of Tomato bushy stunt virus replicon RNA increased in cpr1Delta yeast, while over expression of Cpr1p decreased viral replication. We also show that the Ess1p parvulin prolyl isomerase partly complements Cpr1p function as an inhibitor of tombusvirus replication. PMID- 20709346 TI - Transmission and reassortment of avian influenza viruses at the Asian-North American interface. AB - Twenty avian influenza viruses were isolated from seven wild migratory bird species sampled at St. Lawrence Island, Alaska. We tested predictions based on previous phylogenetic analyses of avian influenza viruses that support spatially dependent trans-hemispheric gene flow and frequent interspecies transmission at a location situated at the Asian-North American interface. Through the application of phylogenetic and genotypic approaches, our data support functional dilution by distance of trans-hemispheric reassortants and interspecific virus transmission. Our study confirms infection of divergent avian taxa with nearly identical avian influenza strains in the wild. Findings also suggest that H16N3 viruses may contain gene segments with unique phylogenetic positions and that further investigation of how host specificity may impact transmission of H13 and H16 viruses is warranted. PMID- 20709347 TI - Comparison of fouling characteristics in different pore-sized submerged ceramic membrane bioreactors. AB - Membrane fouling, the key disadvantage that inevitably occurs continuously in the membrane bioreactor (MBR), baffles the wide-scale application of MBR. Ceramic membrane, which possesses high chemical and thermal resistance, has seldom been used in MBR to treat municipal wastewater. Four ceramic membranes with the same materials but different pore sizes, ranging from 80 to 300 nm, were studied in parallel using four lab-scale submerged MBRs (i.e., one type of ceramic membrane in one MBR). Total COD and ammonia nitrogen removal efficiencies were observed to be consistently above 94.5 and 98%, respectively, in all submerged ceramic membrane bioreactors. The experimental results showed that fouling was mainly affected by membrane's microstructure, surface roughness and pore sizes. Ceramic membrane with the roughest surface and biggest pore size (300 nm) had the highest fouling potential with respect to the TMP profile. The 80 nm membrane with a smoother surface and relatively uniform smaller pore openings experienced least membrane fouling with respect to TMP increase. The effects of the molecular weight distribution, particle size distribution and other biomass characteristics such as extracellular polymeric substances, zeta potential and capillary suction time, were also investigated in this study. Results showed that no significant differences of these attributes were observed. These observations indicate that the membrane surface properties are the dominant factors leading to different fouling potential in this study. PMID- 20709348 TI - Effect of imposed anaerobic conditions on metals release from acid-mine drainage contaminated streambed sediments. AB - Remediation of streams influenced by mine-drainage may require removal and burial of metal-containing bed sediments. Burial of aerobic sediments into an anaerobic environment may release metals, such as through reductive dissolution of metal oxyhydroxides. Mining-impacted aerobic streambed sediments collected from North Fork Clear Creek, Colorado were held under anaerobic conditions for four months. Eh, pH, and concentrations of Cd, Cu, Fe, Mn, and Zn (filtered at 1.5 MUm, 0.45 MUm, and 0.2 MUm), sulfate, and dissolved organic carbon (DOC) were monitored in stream water/sediment slurries. Two sediment size fractions were examined (2 mm 63 MUm and <63 MUm). Sequential extractions evaluated the mineral phase with which metals were associated in the aerobic sediment. Released Cu was re sequestered within 5 weeks, while Fe and Mn still were present at 16 weeks. Mn concentration was lower than in the initial stream water at and beyond 14 weeks for the smaller sized sediment. Cd was not released from either sediment size fraction. Zn was released at early times, but concentrations never exceeded those present in the initial stream water and all was re-sequestered over time. The greatest concentrations of Cu, Fe, Mn, and Zn were associated with the Fe/Mn reducible fraction. Sulfate and Fe were strongly correlated (r = 0.90), seeming to indicate anaerobic dissolution of iron oxy-hydroxy-sulfate minerals. DOC and sulfate were strongly correlated (r = 0.81), with iron having a moderately strong correlation with DOC (r = 0.71). Overall concentrations of DOC, sulfate, Cu, Fe, and Zn and pH were significantly higher (p < 0.05) in the water overlying the small sized sediment samples, while the concentrations of Mn released from the larger sized sediment samples were greater. PMID- 20709349 TI - Development of microbial and chemical MST tools to identify the origin of the faecal pollution in bathing and shellfish harvesting waters in France. AB - The microbiological quality of coastal or river waters can be affected by faecal pollution from human or animal sources. An efficient MST (Microbial Source Tracking) toolbox consisting of several host-specific markers would therefore be valuable for identifying the origin of the faecal pollution in the environment and thus for effective resource management and remediation. In this multidisciplinary study, after having tested some MST markers on faecal samples, we compared a selection of 17 parameters corresponding to chemical (steroid ratios, caffeine, and synthetic compounds), bacterial (host-specific Bacteroidales, Lactobacillus amylovorus and Bifidobacterium adolescentis) and viral (genotypes I-IV of F-specific bacteriophages, FRNAPH) markers on environmental water samples (n = 33; wastewater, runoff and river waters) with variable Escherichia coli concentrations. Eleven microbial and chemical parameters were finally chosen for our MST toolbox, based on their specificity for particular pollution sources represented by our samples and their detection in river waters impacted by human or animal pollution; these were: the human specific chemical compounds caffeine, TCEP (tri(2-chloroethyl)phosphate) and benzophenone; the ratios of sitostanol/coprostanol and coprostanol/(coprostanol+24-ethylcopstanol); real-time PCR (Polymerase Chain Reaction) human-specific (HF183 and B. adolescentis), pig-specific (Pig-2-Bac and L. amylovorus) and ruminant-specific (Rum-2-Bac) markers; and human FRNAPH genogroup II. PMID- 20709350 TI - Free nitrous acid inhibition on the aerobic metabolism of poly-phosphate accumulating organisms. AB - In full-scale wastewater treatment systems, phosphorus removal typically occurs together with nitrogen removal. Nitrite, an intermediate of both the nitrification and denitrification processes, can accumulate in the reactor. The inhibitory effect of nitrite/free nitrous acid (FNA) on the aerobic metabolism of poly-phosphate accumulating organisms (PAOs) is investigated. A culture highly enriched (90 +/- 5%) in Candidatus "Accummulibacter phosphatis", a well-known PAO, was used to perform a series of batch experiments at various nitrite and pH levels. FNA was found to inhibit all key aerobic metabolic processes performed by PAOs, namely PHA oxidation, phosphate uptake, glycogen replenishment and growth. The inhibitory effect on the anabolic processes (growth, phosphate uptake and glycogen production) was much stronger than that on the catabolic processes (PHA oxidation). 50% inhibition on all anabolic processes occurred at FNA concentrations of approximately 0.5 * 10(-3) mg HNO(2)-N/L (equivalent to 2.0 mg NO(2)(-)-N/L at pH 7.0), while full inhibition occurred at FNA concentrations of approximately 6.0 * 10(-3) mg HNO(2)-N. These concentrations could be found in full-scale wastewater treatment systems that achieve nitrogen removal via the nitrite pathway. In comparison, PHA oxidation remained at 40-50% of the highest rate at FNA concentrations in the range 2.0 * 10(-3)-10.0 * 10(-3) mg HNO(2)-N/L. Interestingly, PAOs were able to reduce nitrite under aerobic conditions (DO ~ 3 mg/L), with the rate increasing substantially with the FNA concentration. The inhibition on phosphate uptake was found to be reversible. PMID- 20709351 TI - Simultaneous nitrification and denitrification process in a new Tubificidae reactor for minimizing nutrient release during sludge reduction. AB - Nutrient release is reported as one of the main disadvantage of sludge reduction induced by aquatic worm. In this study, a Static Sequencing Batch Worm Reactor (SSBWR) was proposed with novel structure of perforated panels, combined aeration system and cycle operation. Effective simultaneous nitrification and denitrification were obtained owing to the stratified sludge layer containing aerobic and anoxic microzone formed on each carrier during most of the operation time in the SSBWR, which created suitable conditions for remarkable sludge reduction and nutrient removal. The results showed that the total nitrogen (TN) concentration, NO(3)(-)-N + NO(2)(-)-N concentration and NH(4)(+)-N release could be reduced by 67.5%, 98.5% and 63.0%, respectively. And the soluble chemical oxygen demand (sCOD) released by sludge predation was also proved to provide a carbon source for denitrification leading to carbon release control and substantial cost savings. A schematic diagram of the stratified sludge layer and the mass balance of the nitrification-denitrification cycle were given, providing further insight into the nutrient (sCOD and nitrogen compounds) transformation during the worm predation in the SSBWR. For the mixed sludge liquid of 3000 mg TSS/L, 30 mg/L sCOD and 40 mg/L NO(3)(-)-N, the NO(3)(-)-N and NO(2)(-)-N came close to zero, and the sludge concentration, NH(4)(+)-N release and sCOD release was reduced by 33.6%, 63.0% and 72.5%, respectively, during 48 h' predation. PMID- 20709352 TI - Kinetic and structural characterization of DmpI from Helicobacter pylori and Archaeoglobus fulgidus, two 4-oxalocrotonate tautomerase family members. AB - The tautomerase superfamily consists of structurally homologous proteins that are characterized by a beta-alpha-beta fold and a catalytic amino-terminal proline. 4 Oxalocrotonate tautomerase (4-OT) family members have been identified and categorized into five subfamilies on the basis of multiple sequence alignments and the conservation of key catalytic and structural residues. Representative members from two subfamilies have been cloned, expressed, purified, and subjected to kinetic and structural characterization. The crystal structure of DmpI from Helicobacter pylori (HpDmpI), a 4-OT homolog in subfamily 3, has been determined to high resolution (1.8A and 2.1A) in two different space groups. HpDmpI is a homohexamer with an active site cavity that includes Pro-1, but lacks the equivalent of Arg-11 and Arg-39 found in 4-OT. Instead, the side chain of Lys-36 replaces that of Arg-11 in a manner similar to that observed in the trimeric macrophage migration inhibitory factor (MIF), which is the title protein of another family in the superfamily. The electrostatic surface of the active site is also quite different and suggests that HpDmpI might prefer small, monoacid substrates. A kinetic analysis of the enzyme is consistent with the structural analysis, but a biological role for the enzyme remains elusive. The crystal structure of DmpI from Archaeoglobus fulgidus (AfDmpI), a 4-OT homolog in subfamily-4, has been determined to 2.4A resolution. AfDmpI is also a homohexamer, with a proposed active site cavity that includes Pro-1, but lacks any other residues that are readily identified as catalytic ones related to 4-OT activity. Indeed, the electrostatic potential of the active site differs significantly in that it is mostly neutral, in contrast to the usual electropositive features found in other 4-OT family members, suggesting that AfDmpI might accommodate hydrophobic substrates. A kinetic analysis has been carried out, but does not provide any clues about the type of reaction the enzyme might catalyze. PMID- 20709353 TI - Determination of the soil-water partition coefficients (logK(OC)) of some mono- and poly-substituted phenols by reversed-phase thin-layer chromatography. AB - In order to determine the soil-water partition coefficient for eleven mono- and poly-substituted phenolic compounds, for which there is still no literature data available, the possibility of using thin-layer chromatography (TLC) as a means for rapid and reliable logK(OC) estimation was examined. A series of chromatographically derived descriptors: R(M)(0), b, C(0) and PC1 (first principal component), calculated from retention data obtained under reversed phase conditions, were used for the assessment of models as well as for a direct calibration procedure. The final calibration models are discussed with regard to the achieved accuracy and statistical quality, the type of descriptors used and the corresponding chromatographic conditions. The estimated logK(OC) values of the studied phenols were compared with those obtained by other means: (a) the present OECD guideline based on an HPLC technique; (b) the KOCWIN software package, available free of charge from the US Environmental Protection Agency web site and (c) general LSER models established by Nguyen and coworkers, and Poole and coworkers. The proposed method showed the best agreement with the results obtained by the OECD procedure, followed by the LSER models of Poole and Nguyen. Lower quality correlations were achieved with the KOCWIN calculated values, especially those predicted by molecular connectivity indices. PMID- 20709354 TI - Analysis of pesticides and PCBs in waste wood and house dust. AB - The use of the pesticides - DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane) and lindane (gamma-hexachlorocyclohexane) - and of PCBs (polychlorinated biphenyls) has been limited or forbidden for several decades. Nevertheless, due to their persistence and bioaccumulative potentials they are still ubiquitous in the environment. Therefore, the main objective of this study was to determine analytical methods to analyse the pesticides lindane and DDT, its metabolites DDD (1,1-dichloro-2,2-bis(4-chlorophenyl)ethane) and DDE (1,1-dichloro-2,2-bis(4 chlorophenyl)ethene), and PCBs in waste wood and house dust. An ultrasonic extraction was performed followed by a sample clean up by filtration or silica gel column. The prepared samples were measured by GC/MS. Quantification through internal standard calibration delivered low limits of detection. Specific amounts of the target compounds were detected in all analysed dust samples. The comparison of the contamination between dust samples of eastern Germany (former German Democratic Republic - GDR) and western Germany partly revealed significant differences of the contamination levels. Furthermore, it was examined whether older wooden material might cause a constant volatilisation of pesticides in apartments. Waste wood samples of different contamination categories were analysed. Apparently, these samples are potentially responsible for a constant DDX (Sigma(DDT, DDD, DDE)) and lindane volatilisation, but not for PCBs. PMID- 20709355 TI - Brominated flame retardants and perfluorinated compounds in indoor dust from homes and offices in Flanders, Belgium. AB - The increasing time spent indoors combined with the abundant usage of diverse indoor chemicals led to concerns involving the impact of these compounds on human health. The current study focused on two groups of important indoor contaminants i.e. Brominated flame retardants (BFRs) and Perfluorinated compounds (PFCs). Concentrations of both compound classes have been measured in Flemish indoor dust samples from homes and offices. SigmaPolybrominated diphenyl ethers (PBDEs) (BDE 47, 99, 100, 154, 153, 197, 196 and 203) and BDE 209 in homes ranged between 4 1214 ng g(-1)dw (median 35) and <5-5295 ng g(-1)dw (median 313), respectively. Hexabromocyclododecane (SigmaHBCD) levels ranged from 5 to 4,2692 ng g(-1)dw (median 130), with alpha-HBCD being the major isomer (mean 59%). In addition, tetrabromobisphenol A (TBBPA) ranged between <3 and 419 ng g(-1)dw (median 12). For all BFRs, median levels in office dust were up to an order of magnitude higher than in home dust. SigmaPFCs (sum of perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA)) concentrations in homes ranged from 0.2 to 336 ng g(-1) (median 3.0 ng g(-1)). Levels in office dust were higher (p<0.01) than in house dust with SigmaPFCs ranging between 2.2 and 647 ng g(-1) (median 10 ng g(-1)) and median (PFOA) and perfluorooctane sulfonate values of 2.9 and 2.2 ng g(-1), respectively. The congener pattern was dominated by PFOA, followed by PFOS. Calculated human exposure was below the reference dose values set by the US-EPA for BDE 209, HBCD and below the provisional tolerable daily intakes proposed by European Food Safety Authority for PFOS and PFOA. PMID- 20709356 TI - Assessment of fatty acid as a differentiator of usages of urban soils. AB - The determination of fatty acids (FA) has been extensively used as a sensitive and reproducible parameter for characterizing the soil microorganism communities and to detect various environmental stresses. The aim of this study was to assess the variability of FA in urban soils, in an attempt to use it as a differentiator of urban soil usage. FA were extracted from soils of five different usages (ornamental gardens, ornamental gardens/roadsides, roadsides, parks and urban agricultural areas) in three Portuguese cities and FA concentration was determined by gas chromatography coupled to mass spectrometry (GC-MS). A total of fifteen FA have been detected and the concentration of each FA, in general, decreased in the following order: Lisbon>Estarreja>Viseu, for all the usages of urban soil. According to soil microbial indicators, the concentration of Gram negative bacteria was lower than the concentration of Gram-positive bacteria, which together were, in turn, higher than the concentration of fungi for all the usages of urban soil and city. This study assessed the FA profiles of urban soils, which differ as a function of soil usage. The FA profile also is at the source of the inference that stress in soil microorganism communities results from the different urban environment in each city. PMID- 20709357 TI - Electrochemical degradation of crystal violet with BDD electrodes: effect of electrochemical parameters and identification of organic by-products. AB - This paper explores the applicability of electrochemical oxidation on a triphenylmethane dye compound model, hexamethylpararosaniline chloride (or crystal violet, CV), using BDD anodes. The effect of the important electrochemical parameters: current density (2.5-15 m A cm(-2)), dye concentration (33-600 mg L(-1)), sodium sulphate concentration (7.1-50.0 g L(-1)) and initial pH (3-11) on the efficiency of the electrochemical process was evaluated. The results indicated that while the current density was lower than the limiting current density, no side products (hydrogen peroxide, peroxodisulphate, ozone and chlorinated oxidizing compounds) were generated and the degradation, through OH radical attack, occurred with high efficiency. Analysis of intermediates using GC-MS investigation identified several products: N-methylaniline, N,N-dimethylaniline, 4-methyl-N,N-dimethylaniline, 4-methyl-N methylaniline, 4-dimethylaminophenol, 4-dimethylaminobenzoic acid, 4-(N,N dimethylamino)-4'-(N',N'-dimethylamino) diphenylmethane, 4-(4 dimethylaminophenyl)-N,N-dimethylaniline, 4-(N,N-dimethylamino)-4'-(N',N' dimethylamino) benzophenone. The presence of these aromatic structures showed that the main CV degradation pathway is related to the reaction of CV with the OH radical. Under optimal conditions, practically 100% of the initial substrate and COD were eliminated in approximately 35 min of electrolysis; indicating that the early CV by-products were completely degraded by the electrochemical system. PMID- 20709358 TI - Clinical and biological significance of GSK-3beta inactivation in breast cancer an immunohistochemical study. AB - Glycogen synthase kinase 3beta, recently found to be functionally abnormal in various types of human disease, is negatively regulated by the PI3K/Akt signaling pathway. As Akt is constitutively activated in a subset of breast cancer, we hypothesized that glycogen synthase kinase 3beta is inappropriately inactivated in these cases. In this study, we aimed to assess (1) the overall frequency of glycogen synthase kinase 3beta inactivation in breast cancer; (2) whether there is an association between Akt activation and glycogen synthase kinase 3beta inactivation; and (3) whether there is a correlation between glycogen synthase kinase 3beta inactivation and various pathologic and clinical parameters. The phosphorylated form of glycogen synthase kinase 3beta (pGSK-3beta) and Akt (pAkt) were used as surrogate markers for glycogen synthase kinase 3beta inactivation and Akt activation, respectively. Immunohistochemistry applied to paraffin embedded tissues was used to assess 72 consecutive invasive mammary carcinomas, of which 50 were estrogen receptor positive. Overall, pGSK-3beta and pAkt were positive in 34 (47.2%) and 35 (48.6%) cases, respectively. These 2 markers were significantly correlated with each other in the overall group and in the estrogen receptor-positive subgroup (P = .01 and .003, Spearman, respectively). Importantly, pGSK-3beta, but not pAkt, significantly correlated a worse clinical outcome in this cohort (P = .004, log rank). In summary, evidence of glycogen synthase kinase 3beta inactivation was found in approximately half of the invasive mammary carcinomas. Our data suggest that this abnormality is likely attributed to Akt activation and that glycogen synthase kinase 3beta inactivation confers a worse clinical outcome. PMID- 20709359 TI - Primary angiosarcomas of the anterior mediastinum: a clinicopathologic and immunohistochemical study of 9 cases. AB - We report 9 cases of primary angiosarcomas of the anterior mediastinum. Patient ages ranged from 25 to 62 years (mean, 40.7 years); 5 patients were male and 4 were female. Main presenting symptoms included chest pain, dyspnea, and cough. The tumor size ranged from 3 to 12.5 cm. Macroscopically, the lesions were ill defined hemorrhagic masses. Histologically, the growth patterns ranged from large vascular spaces to capillary-like proliferations. These were either lined by bland or more pleomorphic endothelial cells. The mitotic activity was variable and corresponded to the degree of differentiation. A rim of thymic tissue was observed in 2 cases suggesting a thymic origin of the tumors. No teratomatous components were identified. Immunohistochemical studies showed that all 9 cases were reactive for vascular markers including factor VIII-related antigen, CD31, and CD34, and negative for cytokeratin CAM5.2. All cases were treated by complete resection and 3 patients received adjuvant chemotherapy. Follow-up information available for 6 patients revealed that 4 were alive and free of disease at intervals ranging from 6 to 36 months after diagnosis and 1 was alive with recurrence at 48 months. One patient had died of the disease 10 months after diagnosis. Primary angiosarcomas of the anterior mediastinum are rare tumors that need to be added to the differential diagnosis of primary anterior mediastinal neoplasms. Despite their histologic similarity to angiosarcomas at other sites, primary angiosarcomas of the anterior mediastinum appear to follow a more protracted clinical course than their counterparts in other organ systems. PMID- 20709360 TI - Expression of Sox2 in human cervical carcinogenesis. AB - Sox2 is a key transcription factor for embryonic development and plays a critical role in determining the fate of stem cells. Recently, Sox2 has been detected in several human tumors, indicating a potential function in tumorigenesis. We initially reported remarkably increased nuclear Sox2 staining in cervical carcinomas compared with normal cervix (P < .05). Furthermore, Sox2 staining was detected in most tumorsphere cells isolated from fresh cervical cancer tissues but not among the differentiated tumorsphere cells. When Sox2 was stably expressed in cervical cancer cells (SiHa and HeLa), Sox2-overexpressing cells had increased proliferation, clonogenicity, and tumorigenicity in vitro and in vivo than control cells. These results suggest that Sox2 may participate in carcinogenesis of cervical carcinomas and may be a potential therapeutic target molecule for cervical cancers. PMID- 20709361 TI - Occurrence of endocrine disrupting compounds in tissues and body fluids of Belgian dairy cows and its implications for the use of the cow as a model to study endocrine disruption. AB - The reproductive performance of high producing dairy cows has dropped severely throughout the last decades. It has already been suggested that the presence of endocrine disrupting compounds (EDCs) in the environment could be one of the reasons for this declining fertility. Reliable data concerning tissue and body fluid concentrations of these chemicals are thus crucial, but currently only scarcely available. Therefore, we selected dairy cows (>=6years) from diverse locations in Belgium and analysed tissues (liver, adipose tissue, muscle, kidney, and ovaria) and body fluids (serum, follicular fluid, and milk) for their content of potential EDCs, such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs). Furthermore, we collected milk and serum samples from high producing dairy cows 2-3weeks post partum to verify if the massive lipolysis required to sustain milk production is accompanied with an increase in EDC concentrations in milk and serum. Overall, contamination was very low (median sum PCBs liver: 11.7ngg(-1) lw), with follicular fluid samples showing no detectable contamination. CB 153 was present in each tissue sample. Strong correlations could be found between EDCs in the same tissue. The increased PCB concentrations observed in milk samples from high producing dairy cows could indicate that massive lipolysis can play a role in liberating and thereby increasing EDC concentrations in milk. Because concentrations of the most prevalent EDCs in dairy cow tissues and body fluids are very low, exposure to EDCs can hardly be considered as a major cause of declining fertility in high producing dairy cows in Belgium. As a result of this low contamination and the similarities between the female bovine and human reproductive physiology, in vitro studies based on Belgian dairy cow ovarian follicles can be considered as a valuable model to study the effects of EDCs on human reproduction. PMID- 20709362 TI - Partial replacement of fossil fuel in a cement plant: risk assessment for the population living in the neighborhood. AB - In cement plants, the substitution of traditional fossil fuels not only allows a reduction of CO(2), but it also means to check-out residual materials, such as sewage sludge or municipal solid wastes (MSW), which should otherwise be disposed somehow/somewhere. In recent months, a cement plant placed in Alcanar (Catalonia, Spain) has been conducting tests to replace fossil fuel by refuse-derived fuel (RDF) from MSW. In July 2009, an operational test was progressively initiated by reaching a maximum of partial substitution of 20% of the required energy. In order to study the influence of the new process, environmental monitoring surveys were performed before and after the RDF implementation. Metals and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were analyzed in soil, herbage, and air samples collected around the facility. In soils, significant decreases of PCDD/F levels, as well as in some metal concentrations were found, while no significant increases in the concentrations of these pollutants were observed. In turn, PM(10) levels remained constant, with a value of 16MUgm(-3). In both surveys, the carcinogenic and non-carcinogenic risks derived from exposure to metals and PCDD/Fs for the population living in the vicinity of the facility were within the ranges considered as acceptable according to national and international standards. This means that RDF may be a successful choice in front of classical fossil fuels, being in accordance with the new EU environmental policies, which entail the reduction of CO(2) emissions and the energetic valorization of MSW. However, further long-term environmental studies are necessary to corroborate the harmlessness of RDF, in terms of human health risks. PMID- 20709363 TI - Oak forest exploitation and black-locust invasion caused severe shifts in epiphytic lichen communities in Northern Italy. AB - In the last two centuries, native European oak forests have undergone a dramatic decline related to increasing human pressure for agriculture and urbanization. Oak forests were either completely eradicated and transformed into agricultural landscapes or replaced by second-growth formations. Intensive forest management and the replacement of native forests with production forests or arable lands are recognized amongst the main threats to many lichens in Europe. In this study, we used historical information on the epiphytic lichen biota which was hosted in a native oak-dominated forest of Northern Italy to identify shifts of lichen communities due to the changes in land use which occurred during the last two centuries. We also compared the epiphytic lichen communities inhabiting remnant oak forests with those found in the habitats that have replaced native forests: black-locust forests and agrarian landscapes. Almost all the species sampled during the 19th century are now extinct. The loss of native habitat and the subsequent invasion by black locust were probably the most influential factors which affected the composition of lichen communities, causing the local extinction of most of the species historically recorded. Despite the fact that oak remnants host only a few species which were historically recorded, and that they currently are the lichen poorest habitat in the study region, they host lichen assemblages differing from those of black-locust forests and agrarian stands. In these habitats lichen assemblages are mainly composed of species adapted to well-lit, dry conditions and tolerating air pollution and eutrophication. This pattern is likely to be common also in other lowland and hilly regions throughout Northern Italy where oak forests are targeted among the habitats of conservation concern at the European level. For this reason, a national strategy for biodiversity conservation and monitoring of lowlands forests should provide the framework for local restoration projects. PMID- 20709364 TI - Venous thromboembolism in medical patients treated in the setting of primary care: a nationwide case-control study in Italy. AB - OBJECTIVES: The risk of venous thrombotic events (VTE) among medical outpatients is still not clear and it remains to be clarified whether medical diseases involve the same risk if managed at home or in hospital. The aim of this study was to evaluate in the setting of outpatient family medicine the relationship between VTE and medical conditions known to be at risk during a hospital stay. DESIGN AND SETTING: The study involved a nationwide retrospective observation according to a nested case-control method; 400 general practitioners throughout Italy constituted the network for data collection. Between 2001 and 2004, all cases recorded as having VTE were entered; ten control patients without VTE, matched by sex, physician, and age, were selected from the database for each case. RESULTS: The eligible population comprised 372,000 patients and 1,624 incident VTE were recorded. Univariate analysis indicated hospitalization (OR 5.02; 95% CI 4.01-6.29), cancer (OR 3.06; 95% CI 2.47-3.79), acute infectious disease (OR 2.93; 95% CI 1.94-4.43), neurological disease (OR 2.60; 95% CI 1.56 4.33), congestive heart failure (CHF) (OR 2.48; 95% CI 1.68-3.69), paralysis (OR 1.87; 95% CI 1.51-2.32), COPD (OR 1.58; 95% CI 1.29-1.95), stroke (OR 1.62; 95% CI 1.24-2.12), superficial venous thrombosis (OR 1.51; 95% CI 1.11-2.04, and rheumatic diseases (OR 1.49; 95% CI 1.28-1.74) as significantly associated with an increased risk for VTE. After adjustment, only transient or definitive paralysis, cancer, acute infectious disease, congestive heart failure, neurological diseases, and previous hospitalization remained associated. CONCLUSIONS: This large study indicates that VTE outpatients seen by general practitioners in Italy have a high prevalence of the same medical diseases associated with VTE among patients treated in hospital. PMID- 20709365 TI - The effect of escitalopram on platelet activity. PMID- 20709366 TI - Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. AB - INTRODUCTION: CT Pulmonary Angiography has been shown to be equivalent to Ventilation/ Perfusion scanning in 3-month outcome studies, but it detects more pulmonary emboli. Isolated subsegmental pulmonary emboli are thought to account for some of the increase in diagnosis, but it is not known whether these emboli represent a harbinger for future thromboembolic events. The objective of this study was to determine the 3-month clinical outcomes of a cohort of patients diagnosed with isolated subsegmental pulmonary emboli. MATERIALS AND METHODS: Review of 10,453 consecutive CTPA radiology reports over 74-month period since the implementation of Multidetector CT Pulmonary Angiography identified a cohort of 93 patients found to have acute pulmonary embolism isolated to subsegmental pulmonary arteries without other evidence of deep venous thrombosis at one institution. The study measured 3-month clinical outcomes (anticoagulation use, recurrence, death, hemorrhage) determined by review of records and telephone interviews with physicians. RESULTS: Seventy-one patients (76%) were treated with anticoagulation and/or IVC filter, while 22 (24%) were observed without therapy. One patient (1/93, 1.05%; 95% CI: 0-6.6%) who was treated with anticoagulants and a vena caval filter had a recurrent subsegmental pulmonary embolus. No patients died of pulmonary embolism. There were 8 hemorrhages, including 5 (5.3%) major hemorrhages without any hemorrhage-related mortality. CONCLUSIONS: Patients diagnosed with isolated subsegmental pulmonary emboli have favorable 3-month outcomes. Short-term prognosis for recurrent thromboembolism may be lower than the risk of adverse events with anticoagulation in patients at high risk of hemorrhage. PMID- 20709367 TI - Plasma factor and inhibitor composition contributes to thrombin generation dynamics in patients with acute or previous cerebrovascular events. AB - INTRODUCTION: More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events. MATERIALS AND METHODS: We studied (1) 100 patients with acute ischemic stroke (n=50) or transient ischemic attack (TIA) (n=50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n=50) or TIA (n=50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI). RESULTS: The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p<=0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p<0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced. CONCLUSION: Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors. PMID- 20709368 TI - The fibrinogen gamma 10034C>T polymorphism is not associated with Peripheral Arterial Disease. AB - Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD. PMID- 20709369 TI - Baseline renal function status limits patient eligibility to receive perioperative chemotherapy for invasive bladder cancer and is minimally affected by radical cystectomy. AB - OBJECTIVES: To evaluate the proportion of patients with muscle-invasive urothelial carcinoma (UC) who would be eligible to receive cisplatin-based chemotherapy before and after radical cystectomy based on renal function. METHODS: We identified 194 consecutive patients who underwent cystectomy for cT2 T4 UC. Serum creatinine (SCr) immediately before and nadir SCr 1-3 months after surgery were used to calculate creatinine clearance (CrCl) and glomerular filtration rate (GFR). A cut-off CrCl >= 60 mL/min or GFR >= 60 mL/min/1.73 m(2) was used to determine eligibility for chemotherapy. RESULTS: Median patient age was 70.5 years (IQR 63.77) and median preoperative SCr was 1.05 mg/dL (0.9, 1.3). In total, 80/194 (41%) and 64/194 (33%) patients had inadequate renal function to receive chemotherapy before cystectomy based on CrCl and GFR, respectively. The frequency of inadequate baseline renal function increased significantly with patient age, from 12% of patients < 65 to 54% of patients >65 years of age (P < 0.0001). Surgery did not adversely affect the proportion of patients eligible to receive chemotherapy based on renal function, regardless of age. In fact, after controlling for gender, race, preoperative renal function, hydronephrosis, and choice of diversion, patients <65 years of age were found to have a 14% increase in CrCl (P = .01) and an 11% increase in GFR (P = .04) after cystectomy. CONCLUSIONS: Approximately 40% of patients who would be candidates for neoadjuvant chemotherapy could not receive cisplatin because of poor renal function. Surgery did not affect patients' eligibility to receive chemotherapy based on renal function status. Development of effective non-cisplatin-based regimens is therefore necessary to optimize survival. PMID- 20709370 TI - Nondismembered ureteroplasty for congenital midureteral stenosis: a new application of an old technique. AB - OBJECTIVES: To share our experience with nondismembered ureteroplasty (NDU), a novel application of an old technique in congenital midureteral stenosis (CMS). METHODS: A 35-year-old man was diagnosed as a case of CMS, a rare benign condition on the basis of extensive evaluation, including ultrasonography, intravenous urography, ethylenedicystine renal scan, antegrade and retrograde contrast study of the left kidney and ureter, and a 64-slice computed tomographic angiography of the abdomen with 3-dimensional reconstruction. He was managed by open NDU, where a longitudinal incision over the narrowed segment was closed transversely using the Heineke-Mikulicz principle, thereby preserving the midureteral blood supply, which is considered tenuous. RESULTS: The patient had a successful outcome and is asymptomatic at 1-year follow-up, with significant resolution of hydroureteronephrosis on ultrasonography, and a nonobstructed left kidney with 37% differential renal function on renal scan. CONCLUSIONS: Nondismembered ureteroplasty is a meticulous surgical technique emphasizing blood supply preservation; it can be a useful option in relatively long-segment CMS and adds another method in the surgeon's armamentarium for repairing this rare condition. This technique can be especially useful during laparoscopic or robotic repair of such stenosis. PMID- 20709371 TI - Adjuvant radiotherapy use and patterns of care analysis for margin-positive prostate adenocarcinoma with extracapsular extension: postprostatectomy adjuvant radiotherapy: a SEER analysis. AB - OBJECTIVES: To perform a patterns of care analysis for patients with prostate cancer and high-risk pathologic factors following radical prostatectomy with regards to adjuvant radiation. METHODS: A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Program. We identified men from 2004 to 2005 with prostate adenocarcinoma (PA) who had undergone radical prostatectomy (RP) and were found to have extracapsular extension (ECE) with positive margins. RESULTS: We identified 1427 PA patients with ECE and positive margins after an RP. Most were clinically staged as T1 or T2 before surgery (95.8%). Using the D'Amico Risk Stratification, 52.0% were high risk, 39.7% were intermediate-risk, and 8.3% were low-risk. Of these, 18.2% (260) received ART, whereas 81.8% (1167) did not. Those who received ART had worse prognostic factors, such as Gleason scores > 7 (38.5% vs 24.8%; P < .0001), prostate-specific antigen level > 10 (44.6% vs 35.2%; P = .0045), pathologically positive lymph nodes (11.5% vs 6.4%; P = .006), and D'Amico high-risk disease (66.8% vs 48.7%; P < .0001). The use of ART based on geographic region ranged from 8.3%-34.2%. CONCLUSIONS: Less than 20% of patients with pT3 disease and positive margins received ART in the study period just before the publication of randomized data demonstrating an improvement in biochemical failure with ART in this SEER retrospective analysis. This is the largest patterns of care analysis to date of ART in patients with margin-positive pT3 prostate adenocarcinoma. PMID- 20709372 TI - Does previous robot-assisted radical prostatectomy experience affect outcomes at robot-assisted radical cystectomy? Results from the International Robotic Cystectomy Consortium. AB - OBJECTIVES: To evaluate the effect of previous robot-assisted radical prostatectomy (RARP) case volume on the outcomes of robot-assisted radical cystectomy. Little is known regarding the effect of previous robotic surgical experience on the implementation and execution of robot-assisted radical cystectomy. METHODS: Using the International Robotic Cystectomy Consortium database, 496 patients were identified who had undergone robot-assisted radical cystectomy by 21 surgeons at 14 institutions from 2003 to 2009. The surgeons were divided into 4 groups according to their previous RARP experience (<= 50, 51-100, 101-150, and > 150 cases). The overall operative time, blood loss, lymph node yield, pathologic stage, and surgical margin status were compared among the 4 groups using chi-square analysis. RESULTS: The mean operative time was 386 minutes (range 178-827). The mean estimated blood loss was 408 mL (range 25 3500). The operative time and blood loss were both significantly associated with previous RARP experience (P < .001). The mean lymph node count was 17.8 nodes (range 0-68). Lymph node yield and increased pathologic stage were significantly associated with previous RARP experience (P < .001). Finally, 34 (7.0%) of the 482 patients had a positive surgical margin. Margin status was not significantly associated with previous RARP experience (P = .089). CONCLUSIONS: Previous RARP case volume might affect the operative time, blood loss, and lymph node yield at robot-assisted radical cystectomy. In addition, surgeons with increased RARP experience operated on patients with more advanced tumors. Previous RARP experience, however, did not appear to affect the surgical margin status. PMID- 20709373 TI - Efficacy of epididymectomy in treatment of chronic epididymal pain: a comparison of patients with and without a history of vasectomy. AB - OBJECTIVES: To evaluate the surgical outcome in, and satisfaction with treatment of, patients undergoing epididymectomy for postvasectomy pain syndrome. METHODS: A total of 49 patients were included. All participants had undergone epididymectomy for chronic epididymal pain from January 2000 to June 2009. Of the 49 patients, 4 had undergone bilateral epididymectomy, and the total number of procedures was 53: 18 in patients with postvasectomy pain syndrome (group 1, n = 16), 21 in patients with chronic epididymitis and no history of vasectomy (group 2, n = 19), and 14 in patients with an epididymal cyst and no history of vasectomy (group 3, n = 14). The preoperative and postoperative pain scale scores and surgical outcome were analyzed. RESULTS: For the total patient sample, the mean age was 52.91 +/- 13.51 years, and the mean body mass index was 24.10 +/- 3.22 kg/m(2). The mean duration of pain was 1.3 years (range 0.25-20), and the mean duration of postoperative follow-up was 4.2 years (range 0.05-10.25). The mean preoperative pain score was 6.91 +/- 0.97. The mean postoperative pain scale score was 1.92 +/- 1.54 (P < .01). Statistically significant differences in the preoperative and postoperative pain scores were found for each group: group 1, 5.38 +/- 1.47 (range 3-8); group 2, 4.10 +/- 1.41 (range 2-6), and group 3, 5.21 +/- 1.88 (range 2-8; P = .004). In group 1, excellent surgical outcomes and high patient satisfaction were reported for 94.5% (17 of 18) of the procedures performed. CONCLUSIONS: The results of our study have shown that epididymectomy is more effective in patients with a history of vasectomy than in those without. PMID- 20709374 TI - Treatment of recurrent urinary incontinence after artificial urinary sphincter placement using the AdVance male sling. AB - OBJECTIVES: We report on the use of the AdVance male sling to treat men who had an artificial urinary sphincter placed and subsequently developed recurrent urinary incontinence. METHODS: Nineteen men who had undergone placement of an artificial urinary sphincter for post prostatectomy urinary incontinence, and who had developed recurrent incontinence, were treated by placing an AdVance sling. Self-reported pad use preoperatively was 2-5 pads per day. RESULTS: All 19 patients (100%) reported improvement in their incontinence as documented by decreased pad use. Of these men, 15 (79%) became dry, using no further pads, and four (21%) decreased pad use to 1 pad per day. Of the 15 dry patients, 8 remained dry without reactivation of the artificial sphincter (53%); the other 7 maintained complete continence with a combination of the sling and an activated artificial sphincter. CONCLUSIONS: Men who suffer from recurrent urinary incontinence secondary to cuff compression atrophy can be made continent by the placement of a male sling. The technique of sling placement requires no special modification in these patients. By not revising the artificial urinary sphincter the capsule surrounding the device is not violated, which may decrease the risk of postoperative infection. In addition, the patient may not need to rely upon the use of his artificial sphincter to maintain continence. PMID- 20709375 TI - Microscopic invasion of perivesical fat by urothelial carcinoma: implications for prognosis and pathology practice. AB - OBJECTIVE: To determine whether microscopic invasion of perivesical fat by urothelial carcinoma (stage pT3a) confers a different prognosis relative to deep muscle invasion (pT2b) and/or gross extravesical extension (pT3b) among patients with a given nodal status treated by cystectomy. METHODS: Cancer records for patients diagnosed with stage pT2b-pT3b bladder cancer from 1998-2006 were obtained from the SEER database (n = 2388). Pathologic substage (pT3a vs pT2b vs pT3b) was the primary covariate of interest. Other covariates included age, sex, race, grade, number of nodes examined, number of positive nodes, nodal stages, and radiotherapy. Cox regression model was used to estimate the covariate adjusted effect of tumor substages on all-cause mortality. RESULTS: The risk of nodal metastases increased with increasing substage (pT2b = 20%, pT3a = 36%, pT3b = 48%, trend P <.001). Among patients with node-negative tumors, the adjusted hazard ratios for all-cause mortality were 1.68 (P <.001) for pT3a vs pT2b and 1.03 (P = .78) for pT3b vs pT3a tumors, whereas for node-positive disease, they were 1.42 (P = .009) for pT3a vs pT2b and 1.44 (P = .001) for pT3b vs pT3a tumors. CONCLUSIONS: Microscopic invasion of perivesical fat was associated with significantly inferior survival relative to pT2b disease of the same nodal status. For node-positive pT3 tumors, more advanced pathologic substage (pT3b vs pT3a) was also associated with decreased survival. Our findings support the current practice of pathologic distinction between pT2b and pT3a disease and substaging of extravesical tumors based on microscopic versus gross extravesical extension. PMID- 20709376 TI - Which patients with undetectable PSA levels 5 years after radical prostatectomy are still at risk of recurrence?--implications for a risk-adapted follow-up strategy. AB - OBJECTIVES: To determine the predictors of late prostate-specific antigen (PSA) failure among men with an undetectable PSA level 5 years after radical prostatectomy (RP). METHODS: A total of 505 men who had undergone RP for prostate cancer from 1985 to 2000 at Brigham and Women's Hospital and who had >= 5 years of recurrence-free survival (ie, all PSA levels < 0.2 ng/mL) constituted the study cohort. Cox multivariate regression analysis was used to determine the factors associated with PSA failure after 5 years. Kaplan-Meier analysis was used to estimate the PSA failure-free survival rate. RESULTS: The median follow-up was 10.7 years after RP (interquartile range 7.8-13.3). No patient had PSA failure at year 5, but the PSA failure-free survival rate for this cohort at year 10 was 88% (95% confidence interval 84.4%-91.0%) and, at year 13, was 82% (95% confidence interval 77.0%-86.0%). On multivariable regression analysis, the factors associated with failure after year 5 were Gleason score 7 (adjusted hazard ratio [AHR] 1.88, P = .036), Gleason score 8-10 (AHR 4.81, P <= .002), extracapsular extension (AHR 2.37, P = .003), and seminal vesicle invasion (AHR 1.52, P = .062). CONCLUSIONS: Among men with an undetectable PSA level 5 years after RP, Gleason score 7, Gleason score 8-10, extracapsular extension, and seminal vesicle invasion were significant predictors of subsequent late PSA failure. Patients with these factors (particularly Gleason score 8-10 or seminal vesicle invasion) should have continued close monitoring of their PSA level and consideration of early salvage, as appropriate. However, patients with Gleason score 6 disease were very unlikely to develop late recurrence and might be candidates for less intense follow-up once they have passed the 5-year mark. PMID- 20709377 TI - Lymphovascular invasion and the presence of more than three tumors are associated with poor outcomes of muscle-invasive bladder cancer after bladder-conserving therapies. AB - OBJECTIVES: To identify the predictive factors for survival and recurrence of patients with muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) after bladder-conserving therapies and to determine the efficacy of partial cystectomy plus chemotherapy and radiotherapy in the treatment of MIBC. METHODS: From 2002 through 2007, 100 patients with MIBC (pT2 74%, pT3-4 26%) underwent partial cystectomy (PC). Subjects who had stage pT3-4 disease received adjuvant chemotherapy and radiotherapy. Univariate and multivariate analyses were performed to determine the predictive factors. RESULTS: At median follow-up of 31.5 months (range 6-66 months), 46% patients experienced superficial local recurrence and 14% developed muscle-invasive local recurrence. At the end of follow-up, 24 patients died of bladder cancer, and 71 patients (71%) survived with intact bladders. The 5-year bladder-intact survival rate was 63%. The 5-year cancer-specific survival (CSS) rate was 68%. By multivariate analysis, the presence of more than 3 tumors (P = .002, RR 2.718, 95% CI 1.455-5.079) and nonpapillary growth patterns (P = .005, RR 4.537, 95% CI 1.573-13.081) were predictive factors for local cancer recurrence; the presence of more than 3 tumors (P = .002, RR 4.109, 95% CI 1.676-10.072), lymphovascular invasion (P = .001, RR 6.098, 95% CI 2.038-18.246), and partial cystectomy plus ureteral reimplantation (PC plus UR) (P = .011, RR 0.129, 95% CI .027-0.627) were significantly associated with 5-year CSS, and PC plus UR promoted survival. CONCLUSIONS: PC plus chemotherapy and radiotherapy is a rational alternative to radical cystectomy for the treatment of MIBC. Lymphovascular invasion and the presence of more than 3 tumors predict poor outcomes in MIBC after bladder sparing therapy. PMID- 20709378 TI - Proteome of human calcium kidney stones. AB - OBJECTIVES: Idiopathic calcium oxalate (CaOx) stones are believed to develop attached to papillary subepithelial deposits called Randall's plaques. Calcium phosphate (CaP) stones, conversely, are thought to arise within the inner medullary collecting ducts, enlarging and damaging surround tubular structures as they expand. If this is true, we theorize that differences will be seen within the organic portion (matrix) of CaOx stones compared with CaP stones using a mass spectroscopy (MS) approach. METHODS: From a cohort of 47 powdered stones, 25 calculi (13 CaOx, 12 CaP) were confirmed to contain a dominant mineral content of >80% by powder x-ray diffraction. Matrix proteins were then extracted, purified, and digested. Peptide tandem MS data were acquired, and spectra were searched against a large human protein database to identify protein matches. RESULTS: No significant differences were seen between pattern profiles of CaOx and CaP stones. However, variations in protein expression patterns were seen within individual CaOx (monohydrate and dihydrate) and CaP (apatite and brushite) mineral subtypes, suggesting a relationship between crystal-surface binding properties and matrix composition. Both groups contain a large number of inflammatory proteins and a catalog of common proteins is included. CONCLUSIONS: Calcium kidney stone matrix contains hundreds of proteins and is predominated by proteins associated with inflammatory response. Many of the same proteins were identified in both CaOx and CaP stones, suggesting inflammation as a unifying origin or a common secondary role in calcium stone pathogenesis. PMID- 20709379 TI - Huge adrenal ganglioneuroma. AB - We describe a 53-year-old man who presented with epigastralgia for 1 month. He had 3-year history of increased stool frequency and hypertension. An incidental adrenal mass 19 cm in largest diameter was discovered by computed tomography. Open tumor excision was performed. His symptoms of epigastralgia, hypertension, and chronic diarrhea had subsided after operation. He was tumor-free at 2-year follow-up. PMID- 20709380 TI - A novel technique for the repair of urostomal hernias using human acellular dermal matrix. AB - OBJECTIVE: To report a new technique to reconstruct the abdominal wall at the site of the hernia with 2 separate layers of human acellular dermal matrix (hADM). Parastomal hernia is the most commonly encountered complication of ileal conduit urinary diversion, occurring at a rate of 5%-25%. Multiple methods of parastomal hernia repair, including primary fascial repair, mesh repair, and stoma resiting have been reported, with a wide variety of approaches and materials being used. METHODS: Between 2008 and 2009, 4 patients underwent surgical repair of urostomal hernias using hADM (LifeCell, Branchburg, NJ). All were operated on by a single surgeon using a standard technique of open repair whereby the posterior and anterior rectus fascia at the stoma site were reconstructed with hADM. Demographic data, preoperative and intraoperative risk factors, immediate postoperative complications, and hernia recurrence were collected and analyzed. RESULTS: Four patients underwent urostomal hernia repair with Alloderm without intraoperative complications. Mean operative time was 261.25 +/- 80.8 minutes. Mean hospital stay was 9 +/- 3 days. With an average of 270 +/- 104-days' follow-up, there were no recurrent hernias detected. CONCLUSIONS: In patients with urostomal hernia, reconstruction of the stoma site and abdominal wall with hADM appears to be a safe and effective management solution and avoids the difficulty with relocating the urostomy or placing prosthetic material in the site. PMID- 20709381 TI - MRI-guided transurethral ultrasound therapy of the prostate gland using real-time thermal mapping: initial studies. AB - OBJECTIVE: To confirm the correlation between planning and thermal injury of the prostate as determined by magnetic resonance imaging (MRI) and histology in canine and humans treated with transurethral ultrasound. MATERIAL AND METHODS: Canine studies: 2 sets of in vivo studies were performed under general anesthesia in 1.5 T clinical MRI. Nine dogs were treated using single transducer; 8 dogs were treated using urethral applicator with multiple transducers. Rectal cooling was maintained. After initial imaging, a target boundary was selected and high intensity ultrasound energy delivered. The spatial temperature distribution was measured continuously every 5 seconds with MR thermometry using the proton resonant frequency shift method. The goal was to achieve 55 degrees C at the target boundary. After treatment, the prostate was harvested and fixed with adjoining tissue, including rectum. Temperature maps, anatomical images, and histologic sections were registered to each other and compared. Human studies: To date, 5 patients with localized prostate cancer have been treated immediately before radical prostatectomy. Approximately 30% of the gland volume was targeted. RESULTS: A continuous pattern of thermal coagulation was successfully achieved within the target region, with an average spatial precision of 1-2 mm. Radical prostatectomy was routine, with an uncomplicated postoperative course in all patients. The correlation between anatomical, thermal, and histologic images was <=3 mm. Treatment time was <30 minutes. No thermal damage to rectal tissue was observed. CONCLUSIONS: Thermal ablation within the prescribed target of the prostate has been successfully demonstrated in canine studies. The treatment is also feasible in humans. PMID- 20709382 TI - Neoadjuvant chemotherapy followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for Stage IB2-IIB cervical cancer--irinotecan and platinum chemotherapy. AB - OBJECTIVE: To evaluate the effectiveness of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for stage IB2-IIB cervical cancer. METHODS: Forty-six consecutive patients with stage IB2-IIB cervical cancer were treated with NAC followed by radical hysterectomy plus postoperative chemotherapy. Median (range) body mass index (BMI) of the patients was 20.2 (16.2-26.4). Regimens for NAC and postoperative chemotherapy were irinotecan and cisplatin (CPT-11/CDDP) or CPT-11 and nedaplatin (CPT-11/NDP). A total of six cycles of NAC and postoperative chemotherapy were prescribed. No use of radiotherapy was scheduled, except in the case of a recurrence. RESULTS: With a median follow-up period for survivors of 38.8 months (range 24-54 months), the 2- and 3-year progression-free survival rates were 91.2% and 86.1%, respectively. Overall response rate of NAC was 80.4%. Recurrence was observed in seven patients. In the absence of radiotherapy, pelvic recurrence was observed in only three patients; another two had para-aortic lymph nodes and the remaining two distant metastases. Toxicities due to chemotherapy were generally tolerable. Postoperative complications included urinary fistula (four patients, 8.7%) and bowel obstruction (two patients, 4.3%), all of which required surgical intervention. CONCLUSION: The results indicate that NAC followed by surgery plus postoperative chemotherapy but no radiotherapy offers a viable option in the treatment of stage IB2-IIB cervical cancer. Although a relatively large incidence of postsurgical complications was observed among low BMI patients, this treatment offers the advantage of minimizing radiation-induced morbidity, allowing radiotherapy to be reserved for the possible event of pelvic recurrence. PMID- 20709383 TI - The role of the T cell in asthma. AB - Since the initial detection of T(H)2 cytokines in asthmatic airways, our understanding of the complexity of T-cell subtypes and flexibility and of the potential role of airway structural cells in the immunopathology of asthma has increased. Cytokines derived from airway epithelium, including IL-25, IL-33, and thymic stromal lymphopoietin, might be important drivers of T(H)2-type inflammation in asthma. The balance between effector T(H)2 cells and suppressive regulatory T cells is skewed toward a proinflammatory T(H)2 response in atopy and asthma, and there is much interest in how to redress this equilibrium. Novel T cell subsets, including T(H)17, T(H)9, and T(H)22, have been described, although their role in asthma remains unclear. Other T cells, including natural killer T cells, gammadelta T cells, and CD8 T cells, have also been implicated in asthma, although their importance remains to be confirmed. Therapeutic strategies aimed at T(H)2 cytokines are beginning to bear fruit in patients with asthma, although like many biologic agents, these might need specific targeting at subgroups of patients. Strategies directed specifically at the T cells are currently being evaluated, including novel forms of allergen immunotherapy. T cells remain an exciting potential target for new treatments in patients with asthma. PMID- 20709384 TI - Acinar effect of inhaled steroids evidenced by exhaled nitric oxide. AB - BACKGROUND: The effects of inhaled corticosteroids (ICSs) on distal lung inflammation, as assessed by alveolar nitric oxide concentration (C(A)NO), are a matter of debate. Recently, a theoretic study suggested that acinar airway obstruction that is relieved by ICS treatment and associated with a decrease in fraction of exhaled nitric oxide (FeNO) concentration might, paradoxically, increase C(A)NO. This increase could be a hallmark effect of ICSs at the acinar level. OBJECTIVE: In the light of this new hypothesis, we studied changes in C(A)NO and FeNO after administration of ICSs. METHODS: C(A)NO and FeNO were measured before and after ICS treatment of 38 steroid-naive patients with uncontrolled asthma who showed clinical improvement after ICS therapy. RESULTS: The average FeNO decreased from 78.3 to 28.9 ppb (P < .001); C(A)NO decreased from 7.7 to 4.3 ppb (P = .009). In 14 subjects (low-slope group), slope (= DeltaC(A)NO/DeltaFeNO) values (Delta = post-ICS - pre-ICS value) were less than the 95% normal CI (average DeltaFeNO = -32.7 ppb and average DeltaC(A)NO= +2.9 ppb). In this group, baseline C(A)NO was abnormally low when FeNO was taken into account. In 11 subjects (the high-slope group), the slope was above the normal interval (average DeltaFeNO = -42.5 ppb and average DeltaC(A)NO = -14.7 ppb). CONCLUSION: Opposite patterns (one that was predicted) can indicate peripheral actions of ICSs; this difference might account for conflicting data reported from studies using C(A)NO to determine the peripheral action of ICSs. We show that a low C(A)NO does not preclude distal inflammation. PMID- 20709385 TI - The role of domain-general frontal systems in language comprehension: evidence from dual-task interference and semantic ambiguity. AB - Neuroimaging studies have shown that the left inferior frontal gyrus (LIFG) plays a critical role in semantic and syntactic aspects of speech comprehension. It appears to be recruited when listeners are required to select the appropriate meaning or syntactic role for words within a sentence. However, this region is also recruited during tasks not involving sentence materials, suggesting that the systems involved in processing ambiguous words within sentences are also recruited for more domain-general tasks that involve the selection of task relevant information. We use a novel dual-task methodology to assess whether the cognitive system(s) that are engaged in selecting word meanings are also involved in non-sentential tasks. In Experiment 1, listeners were slower to decide whether a visually presented letter is in upper or lower case when the sentence that they are simultaneously listening to contains words with multiple meanings (homophones), compared to closely matched sentences without homophones. Experiment 2 indicates that this interference effect is not tied to the occurrence of the homophone itself, but rather occurs when listeners must reinterpret a sentence that was initially misparsed. These results suggest some overlap between the cognitive system involved in semantic disambiguation and the domain-general process of response selection required for the case-judgement task. This cognitive overlap may reflect neural overlap in the networks supporting these processes, and is consistent with the proposal that domain general selection processes in inferior frontal regions are critical for language comprehension. PMID- 20709386 TI - Expansion of cancer care and control in countries of low and middle income: a call to action. AB - Substantial inequalities exist in cancer survival rates across countries. In addition to prevention of new cancers by reduction of risk factors, strategies are needed to close the gap between developed and developing countries in cancer survival and the effects of the disease on human suffering. We challenge the public health community's assumption that cancers will remain untreated in poor countries, and note the analogy to similarly unfounded arguments from more than a decade ago against provision of HIV treatment. In resource-constrained countries without specialised services, experience has shown that much can be done to prevent and treat cancer by deployment of primary and secondary caregivers, use of off-patent drugs, and application of regional and global mechanisms for financing and procurement. Furthermore, several middle-income countries have included cancer treatment in national health insurance coverage with a focus on people living in poverty. These strategies can reduce costs, increase access to health services, and strengthen health systems to meet the challenge of cancer and other diseases. In 2009, we formed the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, which is composed of leaders from the global health and cancer care communities, and is dedicated to proposal, implementation, and evaluation of strategies to advance this agenda. PMID- 20709387 TI - Efficient delivery of siRNA to cortical neurons using layered double hydroxide nanoparticles. AB - Small interfering RNAs (siRNAs) are capable of targeting and destroying specific mRNAs, making them particularly suited to the treatment of neurodegenerative conditions such as Huntington's Disease where the production of abnormal proteins results in a gain-of-function phenotype. Although a variety of nanoparticle formulations are currently under development as siRNA delivery systems, application of these technologies has been limited by their high cytotoxicity, low drug loading capacity and release, and inability to penetrate cell membranes. Layered double hydroxide (LDH) nanoparticles are now emerging as a potential new drug delivery system as they exhibit low cytotoxicity and are highly biocompatible. Here we present the first study investigating LDH delivery of siRNAs to primary cultured neurons. We show that internalization by neurons is rapid, dose-dependent and saturable, and markedly more efficient than in other cell types. We demonstrate that siRNA-LDH complexes are internalized by clathrin dependent endocytosis at the cell body and in neurites, with subsequent retrograde transport to the cell body followed by efficient release into the cytoplasm. Finally we show that LDH mediated siRNA delivery effectively silences neuronal gene expression. This study therefore confirms the potential of LDH nanoparticles as a drug delivery system for patients suffering from neurodegenerative disease. PMID- 20709388 TI - Paclitaxel and suramin-loaded core/shell microspheres in the treatment of brain tumors. AB - This work presents a modified method, namely coaxial electrohydrodynamic atomization, for the preparation of microspheres with distinct core/shell structures. This allows the encapsulation of two drugs with different characteristics in hydrophilic properties in one single step. Variation of ratios between outer flow and inner flow produces polymer microspheres with different core/shell ratios, and consequently results in variable release rates of drugs. Significant changes in release patterns were demonstrated when the distributions of the two drugs in microspheres were swapped. Moreover, cell culture experiments and animal experiments have been carried out to testify the performances of different microspheres in cytotoxicity, cellular apoptosis in vitro and tumor inhibition against subcutaneous U87 glioma xenograft in BALB/c nude mice. These findings present the advantages and possible application of this kind of multi drug release system in treating brain tumors. Moreover, the release rates and characteristic sequences of multi-drugs can be tailored and tuned according to treatment necessity and applied in treating other kinds of tumors. PMID- 20709389 TI - Bioengineered 3D platform to explore cell-ECM interactions and drug resistance of epithelial ovarian cancer cells. AB - The behaviour of cells cultured within three-dimensional (3D) structures rather than onto two-dimensional (2D) culture plastic more closely reflects their in vivo responses. Consequently, 3D culture systems are becoming crucial scientific tools in cancer cell research. We used a novel 3D culture concept to assess cell matrix interactions implicated in carcinogenesis: a synthetic hydrogel matrix equipped with key biomimetic features, namely incorporated cell integrin-binding motifs (e.g. RGD peptides) and the ability of being degraded by cell-secreted proteases (e.g. matrix metalloproteases). As a cell model, we chose epithelial ovarian cancer, an aggressive disease typically diagnosed at an advanced stage when chemoresistance occurs. Both cell lines used (OV-MZ-6, SKOV-3) proliferated similarly in 2D, but not in 3D. Spheroid formation was observed exclusively in 3D when cells were embedded within hydrogels. By exploiting the design flexibility of the hydrogel characteristics, we showed that proliferation in 3D was dependent on cell-integrin engagement and the ability of cells to proteolytically remodel their extracellular microenvironment. Higher survival rates after exposure to the anti-cancer drug paclitaxel were observed in cell spheroids grown in hydrogels (40-60%) compared to cell monolayers in 2D (20%). Thus, 2D evaluation of chemosensitivity may not reflect pathophysiological events seen in patients. Because of the design flexibility of their characteristics and their stability in long-term cultures (28 days), these biomimetic hydrogels represent alternative culture systems for the increasing demand in cancer research for more versatile, physiologically relevant and reproducible 3D matrices. PMID- 20709390 TI - The role of stiffness of gelatin-hydroxyphenylpropionic acid hydrogels formed by enzyme-mediated crosslinking on the differentiation of human mesenchymal stem cell. AB - We report the stimulation of neurogenesis and myogenesis of human mesenchymal stem cells (hMSCs) on the surfaces of biodegradable hydrogels with different stiffness. The hydrogels were composed of gelatin-hydroxyphenylpropionic acid (Gtn-HPA) conjugate were formed using the oxidative coupling of phenol moieties catalyzed by hydrogen peroxide (H(2)O(2)) and horseradish peroxidase (HRP). The storage modulus of the hydrogels was readily tuned from 600 to 12800 Pa. It was found that the stiffness of the hydrogel strongly affected the cell attachment, focal adhesion, migration and proliferation rate of hMSCs. The hMSCs on stiffer surfaces have a larger spreading area, more organized cytoskeletons, more stable focal adhesion, faster migration and a higher proliferation rate. The gene expression related to the extracellular matrix and adhesion molecules also differed when the cells were cultured on hydrogels with different stiffness. The differentiation of hMSCs on the surface of the hydrogel was closely linked to the hydrogel stiffness. The cells on a softer hydrogel (600 Pa) expressed more neurogenic protein markers, while cells on a stiffer hydrogel (12000 Pa) showed a higher up-regulation of myogenic protein markers. PMID- 20709391 TI - The liver X receptor (LXR) and its target gene ABCA1 are regulated upon low oxygen in human trophoblast cells: a reason for alterations in preeclampsia? AB - OBJECTIVES: The Liver X receptors (LXR) alpha and beta and their target genes such as the ATP-binding cassette (ABC) transporters have been shown to be crucially involved in the regulation of cellular cholesterol homeostasis. The aim of this study was to characterize the role of LXR alpha/beta in the human placenta under normal physiological circumstances and in preeclampsia. STUDY DESIGN: We investigated the expression pattern of the LXRs and their target genes in the human placenta during normal pregnancy and in preeclampsia. Placental explants and cell lines were studied under different oxygen levels and pharmacological LXR agonists. MAIN OUTCOME MEASURES: Gene expressions (Taqman PCR) and protein levels (Western Blot) were combined with immunohistochemistry to analyze the expression of LXR and its target genes. RESULTS: In the human placenta, LXRA and LXRB expression increased during normal pregnancy. This was paralleled by the expression of their prototypical target genes, e.g., the cholesterol transporter ABCA1. Interestingly, early-onset preeclamptic placentae revealed a significant upregulation of ABCA1. Culture of JAr trophoblast cells and human first trimester placental explants under low oxygen lead to increased expression of LXRA and ABCA1 which was further enhanced by the LXR agonist T0901317. CONCLUSIONS: LXRA together with ABCA1 are specifically expressed in the human placenta and can be regulated by hypoxia. Deregulation of this system in early preeclampsia might be the result of placental hypoxia and hence might have consequences for maternal-fetal cholesterol transport. PMID- 20709392 TI - Alpha-lipoic acid inhibits thrombin-induced fetal membrane weakening in vitro. AB - Cytokine-mediated inflammation and abruption-induced thrombin generation are separately implicated in matrix metalloproteinase (MMP)-mediated weakening of fetal membranes (FM) leading to preterm premature rupture of the fetal membranes (PPROM). At term, FM of both labored vaginal and unlabored Cesarean deliveries exhibit a weak zone overlying the cervix exhibiting ECM remodeling characterized by increased MMP9 protein and activity. We have reproduced these biochemical changes as well as FM weakening in vitro using tumor necrosis factor-alpha (TNF) and interleukin (IL)-1beta, inflammatory cytokines implicated in PPROM. Additionally, we have reported that the antioxidant and NFkappaB inhibitor alpha lipoic Acid (LA) blocks these TNF-induced effects. We now present the first direct evidence that thrombin also can induce FM weakening in vitro, and LA treatment inhibits this thrombin-induced-weakening. Full thickness FM fragments from unlabored Cesarean deliveries were incubated with increasing doses of thrombin (0-100 u/ml) for 48 h. Fragments were then strength tested (breaking force and work to rupture) using our published methodology. MMP3 and 9 levels in tissue extracts were determined by Western blot and densitometry. To determine the effect of LA, FM fragments were incubated with control medium or 10 u/ml thrombin, with or without 0.25 mM LA. Strength testing and MMP induction were determined. Thrombin induced a dose-dependent decrease in FM strength (42% baseline rupture force and 45% work to rupture) coupled with a dose-dependent increase in MMP3 and 9 expression (all p < 0.001). Treatment of FM with 0.25 mM LA completely inhibited thrombin-induced FM weakening and MMP expression (all p < 0.001). Thrombin treatment of cultured FM induces mechanical weakening and increased MMP3 and 9. Treatment of FM with LA inhibits these thrombin-induced effects. We speculate LA may prove clinically useful in prevention of PPROM associated with abruption. PMID- 20709393 TI - The role of anorexigenic and orexigenic neuropeptides and peripheral signals on quartiles of weight loss in obese adolescents. AB - Obesity is characterized as an inflammatory state associated with a modification in the pattern of adipokine secretion. The present study aimed to assess the role of anorexigenic and orexigenic neuropeptides and peripheral signals in obese adolescents submitted to 1 year of weight loss interdisciplinary therapy and grouped according to quartiles of weight loss. A total of 111 post-puberty adolescents, with a BMI >95th percentile, were included. Glycemia and lipid profiles were analyzed. Insulin resistance was estimated by HOMA-IR. Cytokine concentrations were measured by ELISA. The results are presented according to quartiles of weight loss: 1st (<2.5 kg)=low; 2nd (2.5-8 kg)=low to moderate; 3rd (8-14 kg)=moderate; and 4th (>14 kg)=massive. The most important finding was that the NPY concentration increased significantly only in the first phase of weight loss. Moreover, alpha-MSH variation was an independent factor in explaining the NPY changes during the intervention, confirming the role of the alpha-MSH concentration in the peripheral control of energy balance in obese adolescents. Indeed, BMI reduction was correlated with increased alpha-MSH (p<0.05). Massive weight loss promoted a significant increase in alpha-MSH concentration, and hyperleptinemia was reduced after intervention. All together, our findings, which contribute to our understanding of how orexigenic and anorexigenic systems are regulated by weight loss, will provide insight into the pathogenesis and treatment of obesity and other metabolic diseases, especially in obese adolescents. PMID- 20709394 TI - Effects of subchronic fungicide exposure on the energy processing of Gammarus fossarum (Crustacea; Amphipoda). AB - Current aquatic environmental risk assessment of plant protection products or biocides does not consider effects on organisms involved in leaf litter breakdown, a fundamental ecosystem process in streams. Therefore, direct ecotoxicological implications of tebuconazole, a frequently used triazole fungicide, on the leaf-shredding amphipod Gammarus fossarum, were assessed. While acute toxicity was low (96h-LC(50)=1347 MUg/L), feeding rate, a sublethal endpoint, was significantly reduced after seven days of exposure to 600 MUg/L. At the same concentration, but during a three week exposure under semi-static conditions, gammarids showed significant reductions in feeding, but also in assimilation and growth. At 200 MUg/L, however, only assimilation was significantly affected. As these endpoints can be used to evaluate the ecotoxicity of a broad range of chemicals and to deduce possible implications in the functioning of ecosystems, the inclusion of similar experimental set-ups might further improve aquatic environmental risk assessment. PMID- 20709395 TI - Chemical risks and consumer products: the toxicity of shoe soles. AB - The European chemicals legislation, REACH, aims to ensure a high level of protection of human health and the environment. However, chemicals included in consumer products are covered only to a very limited extent even though they constitute the main source of chemical emissions. Shoes are large volume products and the overall aim of the present study was to study the ecotoxicological effects of three types of shoe soles and relate these effects to chemical emissions to the aquatic environment. The shoe soles were abraded and leached in water for 29 days and the alga Ceramium tenuicorne and the crustacean Nitocra spinipes were exposed to different concentrations of the leachate. Chemical analyses were performed to determine the chemical contents of the leachate. The main conclusions are that the shoe soles contain substances that are toxic to both test organisms, and that the toxicity is mainly explained by the presence of zinc. The estimated concentration of zinc from shoe soles in storm water runoff is low, but it still contributes to the overall load of chemicals and metals in the environment. The outlined test procedures may, in our view, provide a useful screening tool for assessing the risk that chemicals in consumer articles pose to the environment. PMID- 20709396 TI - Time- and dose-dependency of the effects of nitrogen pollution on lichens. AB - The present work aims at testing if exposure time and dose play a role in the response of lichen species to nitrogen (N) pollution. To this purpose, samples of the N-sensitive Evernia prunastri and the N-tolerant Xanthoria parietina were treated for 5 weeks either with solutions of NH(4)NO(3) 0.05 and 1 M, or (NH(4))(2)SO(4) 0.025 and 0.5 M. Photosynthetic efficiency was measured as an indicator of sample vitality. The results showed that the lowest concentrations were ineffective at the beginning, but after several supplies both compounds inhibited photosynthetic activity of E. prunastri. The highest concentrations had a deleterious effect, but with a temporal trend. For X. parietina no effect was found for the lowest concentrations, while the same trend shown by E. prunastri was instead observed following treatments with the highest concentrations. It was concluded that the response of lichens to N supply is not only species-specific, but also time- and dose-dependent. The results give a clue on field studies on the relationships between lichens and N pollution. PMID- 20709397 TI - Acute exposure to diphenyl ditelluride causes oxidative damage in rat lungs. AB - The present study evaluated the effect of acute exposure to diphenyl ditelluride [(PhTe)(2)] on oxidative status in lungs of rats. Rats were exposed to a single subcutaneous application of (PhTe)(2) at the doses of 0.3, 0.6, 0.9 MUmol/kg or vehicle. After 72 h of exposure to (PhTe)(2), biochemical parameters of oxidative stress were carried out in lungs of rats. The lungs of rats exposed to (PhTe)(2) showed an increase in the levels of lipid peroxidation, reactive species and non protein thiol. Alterations in superoxide dismutase activity were observed at all tested doses. (PhTe)(2) caused an increase in catalase activity and a reduction in ascorbic acid levels at the dose of 0.9 MUmol/kg. The oxidative damage was more pronounced in animals treated with the highest dose of (PhTe)(2). Thus, this study demonstrated that acute exposure to (PhTe)(2) induced oxidative damage and an adaptive response of antioxidants in pulmonary tissue of rats. PMID- 20709398 TI - Cesium-137 monitoring using lichens from W. Macedonia, N. Greece. AB - (137)Cs content in lichens and substrate (soil, bark) collected from W. Macedonia, Greece was measured 20 years after the Chernobyl reactor accident. Archive material from previous collections was also used for comparison and a diachronic estimation of the radio-contamination status. A gradual decrease was detected which depended on various factors such as the collected species, location, growth rate and substrate. Maximum accumulation capacity of (137)Cs was observed in epilithic lichens in comparison to epigeic or epiphytic ones. Furthermore, foliose or crustose lichens such as Parmelia sulcata, Xanthoria parietina, Xanthoria calcicola, Xanthoparmelia somloensis were more contaminated than filamentose at the same biotope. Among filamentose or fruticose species those with large surface area to biomass ratio e.g. Usnea sp. showed also greater accumulation capacity. Autoradiography revealed an amount of (137)Cs distributed more or less uniformly in lichen thalli. The high (137)Cs activities found in lichens 20 years after Chernobyl suggest that these primitive plants are effective, suitable and inexpensive biological detectors of the distribution and burden of fallout radionuclide fallout pattern. PMID- 20709399 TI - Is there a link between the human TRIM21 and Trypanosoma cruzi Clone 36 genes in Chagas' disease? AB - The homology between TRIM21 and Trypanosoma cruzi Antigen Clone 36 nucleotide sequence was discovered in 1998 (Winkler et al., Parasite 5, 94-95) prior to the functions of Ro52, the TRIM21 protein product, being understood. Ro52 has since been shown to be an Ubiquitin ligase targeting transcription factors, Interferon Regulatory Factor 1 (IRF1) and Interferon Regulatory Factor 3 (IRF3), in immune cells. This communication explores the possibility that there is a connection between the Clone 36 homologous sequence and perturbation of the host immune system in Chagas' disease. RNA interference by the Clone 36 transcripts is hypothesized as a mechanism for host immune suppression during acute Chagas' disease and/or for autoimmunity in chronic Chagas' disease through down regulation of Ro52. In the chronic forms of the disease such as Chagas Cardiomyopathy, Clone 36 RNA containing its repetitive motif may down-regulate levels of Ro52 in monocytes, fibroblasts, or T cells, allowing IRF 1 and IRF3 to continuously stimulate transcription of interferons alpha and beta, a pro inflammatory state favoring autoimmunity. In acute Chagas' disease, messenger RNA from Clone 36 could interfere with host macrophage Ro52 RNA, down-regulating the level of Ro52 so that it would stimulate less cytokine production, including IL 12/p40. This theory is thought to help the parasite avoid attack by the innate immune system early in the acute phase of the disease. Experiments with transgenic mice and genetically modified T. cruzi are discussed which may provide insight to addressing these questions. PMID- 20709400 TI - Development of an activity-based costing model to evaluate physician office practice profitability. AB - OBJECTIVE: Newer treatment regimens for age-related macular degeneration have significantly affected traditional and non-traditional retinal services across all types of practice settings around the country as they seek to find a balance among delivering best patient care, keeping operating costs under control, and maintaining profitability. DESIGN: A systematic retrospective review of a multi city, multi-physician retinal practice's accounting system to obtain data on revenues, expenses, and profit. Data reviewed were from practice management systems to obtain claims level data on clinical procedures across 7 primary activity centers: non-laser surgery, laser surgery, office visits, optical coherence tomography (OCT), non-OCT diagnostics, drugs and drug injections, and research. PARTICIPANTS: All treated patients from a retina practice from January 1, 2005, to December 31, 2007. METHODS: Retrospective claims data review from a multi-physician retina practice detailing Current Procedural Terminology and Healthcare Common Procedure Coding System procedures performed and billed, submitted charges, allowed charges, and net collections. Analyses were performed by an outside firm and verified by a risk advisory firm. MAIN OUTCOME MEASURES: Identifying practice efficiencies/inefficiencies as they relate to patient care. RESULTS: An elaborate analysis using activity-based costing (ABC) showed that increased office visits and OCT and non-OCT diagnostics had a significant negative impact on the practice's profit margins, whereas surgical procedures contributed to the majority of the practice's profit margins because of the lower operating costs associated with surgery. CONCLUSIONS: The practice was able to accommodate the demand in patient volume, medical retina services, and medical imaging with the advent of anti-vascular endothelial growth factor therapy and realized a seismic shift in operating costs. The practice attempted to deliver state-of-the-art patient care in a cost-effective manner, yet underwent a significant decline in its financial health. PMID- 20709401 TI - Atlas of fluorescein angiographic findings in eyes undergoing laser for retinopathy of prematurity. AB - PURPOSE: We sought to examine the clinical features of severe retinopathy of prematurity (ROP) using fluorescein angiography (FA). DESIGN: Retrospective case series of eyes with severe acute-phase ROP that underwent FA at the time of laser photocoagulation. PARTICIPANTS: We included 22 eyes of 11 infants that developed ROP stage 3 in zone 1 with plus disease, 8 eyes of 4 infants classified as ROP stage 3 in zone 1 without plus disease, and 21 eyes of 11 infants that developed ROP stage 3 in zone 2 with plus disease. All eyes underwent laser photocoagulation. A total of 51 sets of digital images including FA were obtained immediately before treatment. METHODS: RetCam (Clarity, Pleasanton, CA) fundus images and video digital FAs were performed under general anesthesia right before laser treatment. A 10% solution of fluorescein was intravenously administered as a bolus at a dose of 0.1 ml/kg, followed by an isotonic saline flush. MAIN OUTCOMES MEASURES: Fluorescein angiograms were examined retrospectively to catalog different retinal and choroidal findings RESULTS: In eyes with severe ROP, FA clearly shows extreme variability in both retinal circulation and choroidal filling pattern. Different patterns of vessels branching at the junction between vascular and avascular retina (V-Av junction) are noted. Posterior to the V-Av junction, hypoperfused retinal areas with or without hyperfluorescent "cotton-wool-like" or "popcorn-like" lesions due to dye leakage are documented by FA. Focal dilatation of capillaries, capillary tufts formations, and rosary-bead-like hyperfluorescent lesions inside the vessels were seen; sometimes all 3 are noted. Various macular abnormalities are noted including absence of foveal avascular area and significant exudative component. CONCLUSIONS: Fluorescein angiography was useful to distinguish the deceptively featureless zone 1 junction between the vascularized and nonvascularized retina. Further studies are needed to understand the role of vascular abnormalities observed in zone 1 vascularized retina. PMID- 20709402 TI - Visual impairment and delay in presentation for surgery in chinese pediatric patients with cataract. AB - PURPOSE: To report visual impairment and blindness and delay in presentation for surgery in Chinese pediatric patients with cataract. DESIGN: Retrospective case series. PARTICIPANTS: A total of 196 children (309 eyes) with congenital or developmental cataract. METHODS: Surgery was performed in all patients. Visual impairment and blindness were defined as best-corrected visual acuity < 20/60. The characteristics, visual acuity, and time delay to surgery of these children were evaluated. MAIN OUTCOME MEASURES: Incidence of visual impairment and blindness, ages at disease recognition and at surgery, and duration of delay in presentation for surgery. RESULTS: Visual acuity was 20/25 or better in 22 eyes (7.1%), between 20/25 and 20/40 in 72 eyes (23.3%), and between 20/40 and 20/60 in 87 eyes (28.2%). Visual impairment and blindness occurred in 41.4% of eyes, 52.0% of patients, 35.4% of patients with bilateral cataract, and 74.7% of patients with unilateral cataract. The frequency of visual impairment and blindness in eyes with combined nystagmus, combined strabismus, total cataract, nuclear cataract, and posterior polar cataract was 84.4%, 75%, 63.8%, 48%, and 48.3%, respectively. Severe postoperative complications resulted in 14.8% of visual impairment and blindness. The mean ages at disease recognition and at surgery were 22.6 +/- 30.4 months and 68.3 +/- 40.0 months, respectively. The mean delay of presentation for surgery was 49.6 +/- 39.8 months in all patients and 35.7 +/- 32.2 months in the patients with congenital cataract. The disease was recognized within 6 months of age in 46 children (40.7%) with bilateral cataract and 10 children (12.0%) with unilateral cataract. Among these children, only 18 (15.9%) with bilateral cataract and 1 (1.2%) with unilateral cataract underwent surgery between 3 and 6 months of age. No patients received surgical intervention within 3 months. CONCLUSIONS: Severe visual impairment is common in pediatric patients with cataract in China. Delayed presentation to the hospital and late surgical treatment are the major reasons and deserve greater attention. PMID- 20709403 TI - Geriatric traumatic open globe injuries. AB - PURPOSE: To characterize the pattern of ocular trauma in the geriatric population. DESIGN: Retrospective, comparative case series. PARTICIPANTS: Eight hundred forty-six consecutive patients comprising 848 open globe injuries, of which 166 injuries occurred in geriatric patients (defined as 65 years old or older at the time of injury), with the remaining patients serving as control subjects. METHODS: Charts of open globe injuries (848 in total) treated surgically at the Massachusetts Eye and Ear Infirmary between January 2000 and April 2009 were retrospectively reviewed. MAIN OUTCOME MEASURES: Ocular Trauma Score, age, gender, mechanism of injury, zone of injury, site of injury, time of day, visual acuity at presentation, and best post-repair visual acuity were analyzed. RESULTS: Of 848 open globe injuries, 166 occurred in the geriatric population. The mean patient age in the geriatric group was 79.8 years. Females comprised most (58%) of this subpopulation. The most common mechanisms of injury were fall (65%), blunt trauma (16%), and motor vehicle accident (6%). The geriatric traumas tended to happen in late morning or late at night. There were no cases of endophthalmitis and fewer instances of enucleation in this group. The median raw Ocular Trauma Score was 47 in the geriatric population, compared with 70 in the younger subset (P < 0.0001). The injuries more often were in zones II and III in the geriatric population compared with the nongeriatric population (P < 0.0001). The geriatric patients were much more likely to have undergone previous intraocular surgery (P < 0.0001), which consisted of primarily cataract procedures. Visual acuity at presentation was significantly worse in the geriatric population than the nongeriatric population (P<0.0001). Similarly, the best postoperative visual acuity was worse in the elderly group than the younger group (P < 0.0001). CONCLUSIONS: The elderly represent a unique, yet neglected ocular trauma population. The pattern of ophthalmic injury and outcome differs greatly between the geriatric and nongeriatric populations. A better understanding of these injuries is necessary to improve prevention and treatment strategies for potentially devastating open globe injuries in this susceptible population. PMID- 20709404 TI - Short-term repeatability of diurnal intraocular pressure patterns in glaucomatous individuals. AB - PURPOSE: To evaluate the short-term repeatability of diurnal intraocular pressure (IOP) patterns in eyes with primary open-angle glaucoma (POAG). DESIGN: Observational cohort study. PARTICIPANTS: Forty-seven subjects with treated POAG. METHODS: Subjects underwent assessment of IOP using Goldmann tonometry every 2 hours from 0800 to 2000 on 2 visits 1 week apart. Intervisit agreement of IOP by time point and of IOP change between time points was assessed using intraclass correlation coefficients (ICCs). MAIN OUTCOME MEASURES: Diurnal IOP patterns. RESULTS: Between-visit agreement of IOP values at each time point was generally fair to good, with ICCs ranging from 0.45 to 0.71 in right eyes and from 0.51 to 0.71 in left eyes. Between-visit agreement of IOP change over time periods between time points was uniformly poor, with ICCs ranging from -0.08 to 0.38 in right eyes and from -0.11 to 0.36 in left eyes. CONCLUSIONS: Treated POAG patients do not manifest a repeatable diurnal IOP pattern from day to day when measured by Goldmann tonometry. Measurement of single-day IOP variation poorly characterized short-term IOP variation. PMID- 20709405 TI - Combined 25-gauge vitrectomy and posterior tube shunt placement for advanced glaucoma. AB - PURPOSE: To report the initial clinical outcomes of a combined procedure utilizing 25-gauge vitrectomy and posterior tube shunt placement in eyes with refractory glaucoma not amenable to standard treatment. DESIGN: Retrospective chart review. PARTICIPANTS: We included 10 eyes (10 consecutive adult patients, mean age 61 years) with advanced glaucoma and anterior segment abnormalities precluding tube placement in the anterior chamber who were treated with combined 25-gauge vitrectomy and posterior tube shunt placement. METHODS: Records of consecutive patients were reviewed for demographics, etiology of glaucoma, preoperative clinical data (visual acuity, intraocular pressure, number of ocular antihypertensive medications), and postoperative outcome measures at predetermined time points. MAIN OUTCOME MEASURES: (1) Intraocular pressure (IOP) at 1, 2, 6, and 12 months postoperatively; (2) number of ocular antihypertensive medications needed at 12 months postoperatively; (3) visual acuity (VA) at 12 months postoperatively; and (4) incidence of hypotony, retinal detachment, endophthalmitis, and corneal decompensation. RESULTS: Preoperatively, mean IOP was 31 mmHg, and patients required a mean of 2.5 ocular antihypertensive medications. Mean IOP at 1, 2, 6, and 12 months postoperatively were 17.0, 16.1, 17.8, and 16.1 mmHg, respectively, and significantly lower than preoperative IOP (P < 0.005 at all time points). At 1 year postoperatively, 90% of patients had an IOP < 20 mmHg, and 50% of patients required <= 2 ocular antihypertensive medications. At 1 year postoperatively, VA was the same or improved in 70% of patients, and no worse than 1 Snellen line in any patient. Corneal edema developed in 2 patients. No patient developed hypotony or endophthalmitis. CONCLUSIONS: Combined 25-gauge vitrectomy and posterior tube shunt placement can be successful in lowering IOP in eyes with advanced glaucoma not amenable to other therapies. PMID- 20709406 TI - Meta-analysis: clinical outcomes of laser-assisted subepithelial keratectomy and photorefractive keratectomy in myopia. AB - PURPOSE: To examine possible differences in clinical outcomes between laser assisted subepithelial keratectomy (LASEK) and photorefractive keratectomy (PRK) for myopia. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: Patients from previously reported randomized controlled trials (RCTs) and comparative studies of LASEK and PRK with clinical outcomes. METHODS: A comprehensive literature search was performed using the Cochrane Collaboration methodology to identify RCTs and comparative studies comparing LASEK and PRK for myopia. MAIN OUTCOME MEASURES: Primary outcome parameters included uncorrected visual acuity (UCVA) of 20/20 or better, manifest refractive spherical equivalent (SE) within +/- 0.50 diopters (D), final refractive SE, and final UCVA of 20/40 or worse. Secondary outcome parameters included healing time of corneal epithelium, postoperative pain, and corneal haze. RESULTS: Twelve studies were identified and used for comparing PRK (499 eyes) with LASEK (512 eyes) for myopia. There were no significant differences in odds ratio (OR), weighted mean difference (WMD), and standardized mean difference (SMD) in the primary and secondary outcome measures. The final mean refractive SE (WMD, 0.00; 95% confidence interval [CI], -0.08 to 0.07; P = 0.95), manifest refractive SE within +/- 0.50 D of the target (OR, 0.90; 95% CI, 0.63-1.29; P = 0.56), patients achieving UCVA of 20/20 or better (OR, 0.86; 95% CI, 0.61-1.20; P = 0.37), final UCVA of 20/40 or worse (OR, 1.26; 95% CI, 0.63-2.51; P = 0.52), re-epithelialization time (WMD, 0.08; 95% CI, -0.44 to 0.59; P = 0.77), and postoperative pain (SMD, 0.26; 95% CI, -0.20 to 0.72; P = 0.27) were analyzed. However, LASEK-treated eyes showed less corneal haze at 1 month after surgery (WMD, 0.25; 95% CI, 0.10-0.39; P = 0.0007) and 3 months after surgery (WMD, 0.14; 95% CI, 0.01-0.26; P = 0.03) compared with PRK. No statistically significant difference was observed between the 2 groups at 6 months after surgery (WMD, 0.14; 95% CI, -0.02 to 0.30; P = 0.08). CONCLUSIONS: In this meta-analysis, LASEK-treated eyes had no significant benefits over PRK treated ones with regard to clinical outcomes. Less corneal haze was observed in LASEK-treated eyes at 1 to 3 months after surgery. PMID- 20709407 TI - Intralesional rituximab: a new therapeutic approach for patients with conjunctival lymphomas. AB - OBJECTIVE: The tolerability and activity of the intralesional administration of rituximab, a chimeric monoclonal antibody that targets the CD20 antigen, was assessed in patients with conjunctival B-cell lymphoma. The systemic administration of rituximab has varying response rates with different types of lymphoma, generally with a mild toxicity level. Intralesional administration of this drug has increased local disease control in cases of cutaneous mucosa associated lymphoid tissue (MALT) lymphoma. DESIGN: This was an interventional pilot study of 3 patients with relapsed CD20+ conjunctival lymphomas treated with intralesional injections of rituximab. PARTICIPANTS: Two patients with conjunctival MALT lymphoma refractory to previous systemic treatment with rituximab and 1 patient with relapsed follicular lymphoma of the eyelid were included in the study. METHODS: Patients received 4 weekly intralesional injections followed by 6 monthly injections of undiluted rituximab together with xylocaine 2%. MAIN OUTCOME MEASURES: Side effects and tumor response were assessed before each intralesional injection and at 3-month intervals after treatment conclusion. RESULTS: The 2 conjunctival MALT lymphoma patients achieved complete remission after intraconjunctival rituximab treatment, which shows that this method of administration can overcome the primary resistance to this monoclonal antibody. The patient with the eyelid follicular lymphoma did not achieve tumor regression after the first intralesional injections of rituximab. In this patient, the addition of autologous serum resulted in lymphoma remission at the end of treatment, suggesting that drug inefficacy can be related to the low bioavailability of effectors in the tumor tissue. CONCLUSIONS: Although follow-up is still short, these preliminary findings suggest that intralesional rituximab is a well-tolerated strategy in marginal-zone and follicular lymphomas of the conjunctiva. An increased bioavailability of effectors in the tumor tissue, by means of the addition of autologous serum, may improve rituximab activity. This strategy could be used in other extranodal CD20+ indolent lymphomas to improve local control, even in patients who are initially refractory to systemic rituximab treatment. PMID- 20709408 TI - Modification of the heme active site to increase the peroxidase activity of thermophilic cytochrome P450: a rational approach. AB - The site specific mutants of the thermophilic P450 (P450 175A1 or CYP175A1) were designed to introduce residues that could act as acid-base catalysts near the active site to enhance the peroxidases activity. The Leu80 in the distal heme pocket of CYP175A1 was located at a position almost equivalent to the Glu183 that is involved in stabilization of the ferryl heme intermediate in chloroperoxidase (CPO). The Leu80 residue of CYP175A1 was mutated with histidine (L80H) and glutamine (L80Q) that could potentially form hydrogen bond with hydrogen peroxide and facilitate formation and stabilization of the putative redox intermediate of the peroxidase cycle. The mutants L80H and L80Q of CYP175A1 showed higher peroxidase activity compared to that of the wild type (WT) CYP175A1 enzyme at 25 degrees C. The activity constants (k(cat)) for the L80H and L80Q mutants of CYP175A1 were higher than those of myoglobin and wild type cytochrome b562 at 25 degrees C. The optimum temperature for the peroxidase activity of the WT and mutants of CYP175A1 was ~ 70 degrees C. The rate of catalysis at temperatures above ~ 70 degrees C was higher for L80Q mutant of CYP175A1 compared to that of the well known natural peroxidase, horseradish peroxidase (HRP) that denatures at such high temperature. The peroxidase activities of the mutants of CYP175A1 were maximum at pH 9, unlike that of HRP which is at pH ~5. The results have been discussed in the light of understanding the structure-function relationship of the peroxidase properties of these thermostable heme proteins. PMID- 20709409 TI - Synthesis, characterization and cytotoxicity studies of palladium(II)-proflavine complexes. AB - An investigation of the reaction of Pd(II) complexes with proflavine (3,6 diaminoacridine) resulted in the isolation of the compounds [Pd(terpy)(proflavine)](NO(3))(HSO(4))*3H(2)O, 1, (terpy = 2,2':6',2" terpyridine), [Pd(en)(proflavineH))](NO(3))(SO(4)), 2, (en = ethylenediamine), and [Pd(proflavineH)Cl(2)](SO(4))(0.5)*H(2)O, 3. They have been isolated and characterized by NMR, IR, and electro-spray ionization mass spectrometry techniques and by elemental analyses. The proflavine was bonded to the Pd(II) through the endocyclic nitrogen in 1, but through the proflavine NH(2) in 2. Compound 3 appeared to be polymeric in the solid state with a 1:1 mole ratio of Pd(II):proflavine. Upon solution of 3 in DMSO, two unique species were formed. In one species the Pd(II) was bonded to two proflavines through the endocyclic nitrogen (1:2 mole ratio) and in the other species, a Pd(II) was bonded to each NH(2) group of a single proflavine (2:1 mole ratio). Molecular modeling of the equilibrium geometry by Spartan 8 produced structures which were consistent with the experimental data on the solutions of the three compounds. In vitro cytotoxicity testing against two breast cancer cell lines and one ovarian cancer cell line showed that compounds 1 and 3 had significant activity. PMID- 20709411 TI - Modified toxin-binding inhibition (ToBI) test for epsilon antitoxin determination in serum of immunized rabbits. AB - The aim of the present study was to evaluate and standardize the ToBI test in vitro as a substitute for the serum neutralization test in mice for quality control of clostridial vaccines. The ToBI test in vitro was used to evaluate 40 serum samples of known antibody content, obtained from rabbits immunized against clostridiosis with experimental vaccine. The correlation between epsilon antitoxin titers in rabbit sera, determined by the ToBI test and serum neutralization in mice, ranged from 0.222% to 0.452% in polyvalent vaccines and from 0.154% to 0.387% in monovalent vaccines. Interplate coefficients of variation were not significant, reaching 0.350% in polyvalent vaccines and 0.400% in monovalent vaccines, indicating high homogeneity. In conclusion, the ToBI test in vitro is suitable for assessing the potency of clostridial vaccines and may be used as an alternative method able to replace current in vivo tests. PMID- 20709412 TI - Classical swine fever in 6- and 11-week-old pigs: haematological and immunological parameters are modulated in pigs with mild clinical disease. AB - The severity of classical swine fever virus (CSFV) infection is believed to be determined by different factors, including the virulence of the strain as well as factors related to the host. In the present study, we infected 6- and 11-week-old pigs of unique sanitary status with CSFV strain Eystrup to elucidate the influence of age on virulence. In both age-groups, a mild clinical course correlated well with the gross-pathological findings at necropsy. The minor variations of clinical, pathological, haematological and immunological parameters between the various age-groups demonstrated that a time-span of approximately 1 month of age did not play a significant role for the severity of CSF disease in young, weaned pigs. The detailed analysis of various haematological and cellular immunological parameters proved to provide a valuable set of objective reference values for healthy control pigs and for pigs with mild clinical CSF disease. Despite that only mild disease occurred in the infected pigs, modulations of haematological and immunological parameters were observed. Depletion of B cell and a number of T cell populations in peripheral blood was observed in both age groups, however, the changes being most pronounced in the 6-week-old pigs. In the infected pigs, but not in any of the controls, a population of large granulocytes (LG) developed in peripheral blood. The LG, which were demonstrated to be identical to low-density granulocytes, appeared before the development of viraemia. Therefore, we suggest detection of LDG to be used as an additional tool in early CSF diagnosis. The observation that pigs with a unique, high sanitary status only developed mild disease after infection with CSFV strain Eystrup emphasizes the important role of the host in the CSFV virulence puzzle. PMID- 20709410 TI - Epidemiological aspects of intermittent explosive disorder in Japan; prevalence and psychosocial comorbidity: findings from the World Mental Health Japan Survey 2002-2006. AB - The purpose of the present study is to evaluate the prevalence of intermittent explosive disorder (IED) as well as its comorbidity with other mental disorders in a Japanese community sample. Subjects were 4,134 residents in selected sites in Japan. Diagnoses of mental disorders are based on the World Mental Health Survey Initiative Version of the World Health Organization Composite International Diagnostic Interview. Lifetime and 12-month prevalence of IED were 2.1% and 0.7%, respectively, whereas those of narrow IED were 1.2% and 0.6%, respectively. Male gender and young age were positively associated with an increased prevalence of IED. Mood and anxiety disorders as well as suicidal ideation were shown to be associated with IED in both genders. The overall association between anxiety disorders and IED was stronger in women than in men. Positive association of substance use problems with IED was also observed. Similar findings were observed between those psychosocial factors and narrow IED. These results suggest that people having those mixed complications might have a high suicidal risk. Further research using psychological measures for anger suppression will lead to more thorough understanding of the effects of IED on psychosocial comorbidity and suicidal risk. PMID- 20709413 TI - Proliferative and protective effects of SurR9-C84A on differentiated neural cells. AB - Targeting survivin has the ability to inhibit apoptosis and regulate mitosis for the protection of neuronal cells, and it offers several advantages for neuronal repair and protection. We found that the BIR motif mutant of survivin (SurR9 C84A) can bind to microtubules and regulate their stability, induce cell division, increase proliferation and activate the expression of cell cycle and neuronal markers in differentiated SK-N-SH and HCN-2 neurons. We further showed the protective effects of SurR9-C84A against post differentiation retinoic acid induced neurotoxicity. These abilities of SurR9-C84A offer a great potential for future neuronal repair therapy. PMID- 20709414 TI - Enhanced Th17 phenotype in individuals with generalized anxiety disorder. AB - The generalized anxiety disorder (GAD) is often a debilitating chronic condition, characterized by long-lasting anxiety that is not focused on any object or situation. Besides being clearly linked to increased susceptibility to infectious diseases, anxiety is also known to contribute to the pathogenesis of many inflammatory/autoimmune disorders. The present work aimed to explore the T cell profile following in vitro activation in cultures obtained from a group of individuals with GAD, comparing them with healthy control individuals. Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation as compared with the control group. The analysis of the cytokine profile revealed Th1 and Th2 cytokine deficiencies in the anxious group, as compared with the control subjects. On the other hand, this cellular and humoral immune damage was followed by enhanced production of Th17-derived cytokines. In particular, the levels of TNF-alpha and IL-17 were significantly higher in cell cultures containing activated T cells from GAD individuals. Therefore, besides a deficiency on Th1 phenotype, an elevated proinflammatory status of these individuals might be related to both glucocorticoid immune resistance and lower IL-10 levels produced by activated T cells. In conclusion, our results demonstrated a T cell functional dysregulation in individuals with GAD, and can help to explain the mechanisms of immune impairment in these subjects and their relationship with increased susceptibility to infections and autoimmune diseases. PMID- 20709415 TI - Free-roaming dog control among OIE-member countries. AB - A questionnaire was distributed to the state veterinary services of all 172 OIE countries to collect data on the different national approaches to dog population control. We used all 81 completed questionnaires with >=80% of the question answered to identify the different national approaches to the issue. The intensity of the free-roaming dog (FRD) problem was negatively correlated with the value of the UN's human development index recognized for each country. Dog bites/attacks and rabies were the main problems associated with FRDs, and these problems were reported disproportionately by less-developed countries. Dog control programs (DCP) were more widely used among the more-developed countries. In less-developed countries, DCPs (when they existed at all) tended to employ killing methods (including poisoned baits), that are not recommended on animal welfare grounds. PMID- 20709416 TI - PET/CT (and CT) instrumentation, image reconstruction and data transfer for radiotherapy planning. AB - The positron emission tomography in combination with CT in hybrid, cross-modality imaging systems (PET/CT) gains more and more importance as a part of the treatment-planning procedure in radiotherapy. Positron emission tomography (PET), as a integral part of nuclear medicine imaging and non-invasive imaging technique, offers the visualization and quantification of pre-selected tracer metabolism. In combination with the structural information from CT, this molecular imaging technique has great potential to support and improve the outcome of the treatment-planning procedure prior to radiotherapy. By the choice of the PET-Tracer, a variety of different metabolic processes can be visualized. First and foremost, this is the glucose metabolism of a tissue as well as for instance hypoxia or cell proliferation. This paper comprises the system characteristics of hybrid PET/CT systems. Acquisition and processing protocols are described in general and modifications to cope with the special needs in radiooncology. This starts with the different position of the patient on a special table top, continues with the use of the same fixation material as used for positioning of the patient in radiooncology while simulation and irradiation and leads to special processing protocols that include the delineation of the volumes that are subject to treatment planning and irradiation (PTV, GTV, CTV, etc.). General CT acquisition and processing parameters as well as the use of contrast enhancement of the CT are described. The possible risks and pitfalls the investigator could face during the hybrid-imaging procedure are explained and listed. The interdisciplinary use of different imaging modalities implies a increase of the volume of data created. These data need to be stored and communicated fast, safe and correct. Therefore, the DICOM-Standard provides objects and classes for this purpose (DICOM RT). Furthermore, the standard DICOM objects and classes for nuclear medicine (NM, PT) and computed tomography (CT) are used to communicate the actual image data created by the modalities. Care must be taken for data security, especially when transferring data across the (network-) borders of different hospitals. Overall, the most important precondition for successful integration of functional imaging in RT treatment planning is the goal orientated as well as close and thorough communication between nuclear medicine and radiotherapy departments on all levels of interaction (personnel, imaging protocols, GTV delineation, and selection of the data transfer method). PMID- 20709417 TI - Clinical evidence on PET-CT for radiation therapy planning in cervix and endometrial cancers. AB - PET-CT plays an increasing role in the diagnosis and treatment of gynaecological cancers. In cervix cancer, whilst MRI remains the best imaging technique for initial primary tumor staging, PET-CT has been showed to be a highly sensitive method to determine lymph node status, except in patients with early-stage cervical cancer where PET-CT cannot replace surgical exploration of pelvic lymph nodes. In patients with advanced cervical cancer, PET-CT has the potential of showing lymph node metastasis not only within the pelvis, but also outside the pelvis, more particularly in the para-aortic area. PET-CT has also been described as a useful tool in 3-D-based adaptative brachytherapy. In endometrial cancer, the issues are different, as the recent decade has seen a therapeutic decrease in early-stage disease, especially in postoperative radiation therapy, whilst more advanced disease have been approached with more aggressive treatments, integrating chemotherapy and external beam radiotherapy. Lymph node status is also an important issue and PET-Scan may replace lymph node surgical procedure particularly in obese patients. PMID- 20709418 TI - Antioxidant activity of lees cell surface during sparkling wine sur lie aging. AB - Given the importance of the interactions between wine and lees cell surface during sparkling wine aging, and in view of recent results proving the antioxidant potential of yeast cell wall biomolecules, the antioxidant capacity of lees cell surface was investigated to establish its possible role in the antioxidative effect of lees. The surface antioxidant activity of lees from wines with different aging periods was determined on the whole cell by two widely used methods (DPPH and FRAP assays), obtaining maximum values of 24.5micromol Trolox/g cells (fresh weight) by the DPPH assay, and 21.3micromol Trolox/g cells (fresh weight) by the FRAP assay. Lees surface antioxidant activity was influenced by base wine characteristics and inversely related to sur lie aging period. Conversely, the percentage depletion of lees surface antioxidant activity during aging was mainly determined by the length of aging, regardless of wine characteristics. To examine the influence of cell wall thiol groups and adsorbed polyphenols on lees' protective effect, their presence on cell surfaces was assessed. They accounted for 25+/-11% and 54+/-7% of the antioxidant activity measured by DPPH, respectively, and 0.3+/-0.1% and 39+/-8% measured by FRAP, respectively. Only a part of the remnant antioxidant activity of lees surface measured by FRAP could be theoretically explained by the presence of cell wall mannans. PMID- 20709419 TI - Ochratoxigenic fungi and ochratoxin A in cocoa during farm processing. AB - This study investigated the occurrence of fungi with the potential to produce ochratoxin A (OTA), and the occurrence of OTA, in Brazilian cocoa beans. Two hundred and twenty two samples of cocoa were evaluated, taken at various stages of fermentation, drying and storage. Samples were collected from Bahia, the main cocoa producing region in Brazil. Fungi with the potential to produce OTA were isolated by direct plating of cocoa beans on Dichloran 18% Glycerol agar after surface disinfection, and identified by standard techniques. The ability of the fungi to produce OTA was estimated using the agar plug technique and TLC. The presence of OTA in cocoa samples was determined by HPLC after immunoaffinity column clean up. The most common ochratoxigenic species found were Aspergillus carbonarius and A. niger aggregate, with lower numbers of A. melleus, A. westerdijkiae and Av. ochraceus. A considerable increase in the numbers of these species was observed during drying and storage. OTA was found at all stages of cocoa processing, with the major incidence during drying and storage. The OTA levels found were in general low and there was a strong positive correlation between the presence of A. carbonarius and OTA contamination in the beans. PMID- 20709420 TI - Informal payments and the quality of health care: Mechanisms revealed by Tanzanian health workers. AB - Informal payments for health services are common in many transitional and developing countries. The aim of this paper is to investigate the nature of informal payments in the health sector of Tanzania and to identify mechanisms through which informal payments may affect the quality of health care. Our focus is on the effect of informal payments on health worker behaviours, in particular the interpersonal dynamics among health workers at their workplaces. We organised eight focus groups with 58 health workers representing different cadres and levels of care in one rural and one urban district in Tanzania. We found that health workers at all levels receive informal payments in a number of different contexts. Health workers sometimes share the payments received, but only partially, and more rarely within the cadre than across cadres. Our findings indicate that health workers are involved in 'rent-seeking' activities, such as creating artificial shortages and deliberately lowering the quality of service, in order to extract extra payments from patients or to bargain for a higher share of the payments received by their colleagues. The discussions revealed that many health workers think that the distribution of informal payments is grossly unfair. The findings suggest that informal payments can impact negatively on the quality of health care through rent-seeking behaviours and through frustrations created by the unfair allocation of payments. Interestingly, the presence of corruption may also induce non-corrupt workers to reduce the quality of care. Positive impacts can occur because informal payments may induce health workers to increase their efforts, and maybe more so if there is competition among health workers about receiving the payments. Moreover, informal payments add to health workers' incomes and might thus contribute to retention of health workers within the health sector. PMID- 20709421 TI - The stem cell gene "inhibitor of differentiation 1" (ID1) is frequently expressed in non-small cell lung cancer. AB - AIMS: Inhibitor of differentiation 1 (ID1) plays a role in cellular differentiation, proliferation, angiogenesis and tumor invasion. As shown recently, ID1 is positively regulated by the tyrosine kinase SRC in lung carcinoma cell lines and with that appears as a potential new therapeutic target in non-small cell carcinoma (NSCLC). To substantiate this hypothesis we examined ID1, SRC and matrix metalloproteinase-9 (MMP-9) immunohistochemically in human NSCLC specimens. METHODS: From 61 consecutive patient tissue samples of a tumor tissue bank a one core tissue microarray (TMA) was produced and whole slide tissue samples of preinvasive lesions used. The staining of commercial antibodies was assessed by the H-score. Statistical analyses based on Spearman's rank correlation coefficient. RESULTS: ID1 was expressed in the nucleus in 70% of squamous cell carcinomas and 50% of non-squamous cell carcinomas and in vascular endothelium of non-tumor tissue. Cytoplasmic staining was found in all samples for SRC and in 93% for MMP-9. ID1-positive tissue samples co-expressed SRC and MMP-9 in 94%. In non-squamous cell carcinomas, H-scores of ID1 and SRC correlated with each other (p=0.04). H-score of MMP-9 correlated with tumor grade (p=0.04). The carcinoma findings were reflected in preinvasive lesions. CONCLUSIONS: We describe for the first time the immunohistochemical expression of ID1 in the majority of NSCLC samples. The almost general co-expression of ID1, SRC and MMP-9 supports their cooperation in vivo and warrants further investigation of ID1 as a therapeutic target. PMID- 20709422 TI - Mutants of the Saccharomyces cerevisiae VPS genes CCZ1 and YPT7 are blocked in different stages of sporulation. AB - The CCZ1 gene is a member of the class B VPS (vacuolar protein sorting) genes and it is engaged in the last stage of delivery of multiple kinds of cargo to the yeast vacuole. In the process of fusion of the multivesicular body (MVB) with the vacuole, Ccz1p forms a complex with Ypt7p. Both genes are non-essential for vegetative growth, but their deletions cause a complete block in spore formation. The results of this study indicate that ccz1Delta cells initiate the meiotic program, properly proceed through premeiotic DNA replication and through the pairing of homologous chromosomes, but fail to progress through the first meiotic divisions and arrest in prophase I with a single nucleus. The mutant cells are defective in spindle formation as well as in duplication and/or separation of the SPBs. ypt7Delta cells, on the other hand, cannot execute DNA synthesis. We also show that expression of a mutated variant of the YPT7 gene suppresses the sporulation and autophagy defects of ccz1Delta cells to a quantitatively similar level, suggesting that restoration of autophagy in the ccz1Delta strain is sufficient to enable its sporulation. PMID- 20709423 TI - abLIM3 is a novel component of adherens junctions with actin-binding activity. AB - The interactions of adhesion molecules with dense actin filaments via cytoplasmic plaque proteins are crucial for the adhesive function of adherens junctions (AJs) in epithelial and endothelial cells. Using localization-based expression cloning, we identified abLIM3, a member of the actin-binding LIM (abLIM) protein family, as a component of the junctional complex. Immunolocalization studies revealed that abLIM3 was localized at AJs in limited cell types, including hepatocytes, bronchial epithelial cells, mesothelial cells and endothelial cells lining muscular tissues. Deletion mutant analyses in cultured cells showed that the C terminal dematin-like domain of abLIM3, which bound to actin filaments in vitro, was colocalized with phalloidin-stained filamentous actin, whereas the N-terminal LIM domains of abLIM3 were sufficient for recruitment to cell-cell contacts. These results suggest that abLIM3 is involved in anchoring LIM domain-binding components of AJs to circumferential actin bundles in specific cell types. PMID- 20709424 TI - Native type IV collagen induces cell migration through a CD9 and DDR1-dependent pathway in MDA-MB-231 breast cancer cells. AB - CD9 is a member of the tetraspanin family and is widely expressed in the plasma membrane of several cell types as well as malignant cells. CD9 associates with a number of transmembrane proteins, which facilitates biological processes, including cell signaling, adhesion, migration and proliferation. DDR1 is activated by native type IV collagen and overexpressed in human breast cancer. Type IV collagen is the main component of basement membranes, and may interact with cell surface biomolecules, promoting adhesion and motility. However, the role of DDR1 and type IV collagen in the regulation of CD9-cell surface levels and migration in breast cancer cells has not been studied in detail. We demonstrate here that native type IV collagen induces a transient increase of CD9 cell surface levels through a DDR1-dependent pathway in MDA-MB-231 breast cancer cells, as revealed by flow cytometry and Western blotting using specific antibodies that recognize CD9. In contrast, type IV collagen does not induce any increase of CD9-cell surface levels in the mammary non-tumorigenic epithelial cells MCF10A and MCF12A. Transient increase of CD9-cell surface levels is coupled with clathrin-mediated endocytosis and it is dependent of DDR1 expression. In addition, type IV collagen induces cell migration through a DDR1 and CD9 dependent pathway. In summary, our data demonstrate, for the first time, that native type IV collagen induces a transient increase of CD9-cell surface levels and cell migration through a DDR1 and CD9-dependent pathway in MDA-MB-231 breast cancer cells. PMID- 20709425 TI - Component interactions, regulation and mechanisms of chloroplast signal recognition particle-dependent protein transport. AB - The chloroplast proteome comprises nuclear- and plastome-encoded proteins. In order to function correctly these proteins must be transported, either cotranslationally or posttranslationally, to their final destination in the chloroplast. Here the chloroplast signal recognition particle (cpSRP) which is present in two different stromal pools plays an essential role. On the one hand, the conserved 54kDa subunit (cpSRP54) is associated with 70S ribosomes to function in the cotranslational transport of the plastid-encoded thylakoid membrane protein D1. On the other hand, the cpSRP consists of cpSRP54 and a unique 43kDa subunit (cpSRP43) and facilitates the transport of nuclear-encoded light-harvesting chlorophyll-binding proteins (LHCPs), the most abundant membrane proteins of the thylakoids. In addition to cpSRP, the cpSRP receptor cpFtsY and the thylakoid membrane protein Alb3 are required for posttranslational LHCP integration in a GTP-dependent manner. In contrast to the universally conserved cytosolic SRP, the chloroplast SRP of higher plants lacks an SRP-RNA component. Interestingly, cpSRP-RNA genes have been identified in the plastome of lower plants, indicating that their cpSRP structure resembles the cytosolic SRP. PMID- 20709426 TI - Nitric oxide synthase activity is required for development of functional nodules in soybean. AB - The effects of a nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine) on soybean growth parameters and nodule functioning were investigated, along with soybean nodule cell viability and cysteine endopeptidase activity. N(omega)-nitro L-arginine reduced soybean growth parameters, inhibited nodule nitrogenase activity, and caused a decrease in nodule cell viability. The negative effects of N(omega)-nitro-L-arginine were reversed by the nitric oxide donor 2,2' (hydroxynitrosohydrazono)bis-ethanimine. Cysteine endopeptidase activity was higher in plants treated with N(omega)-nitro-L-arginine than untreated plants (controls), but decreased to levels similar to the controls when plants were exposed to a combination of N(omega)-nitro-L-arginine and 2,2' (hydroxynitrosohydrazono)bis-ethanimine. These results suggest that nitric oxide, resulting from nitric oxide synthase activity, is required for development of functional soybean nodules. PMID- 20709427 TI - Convergent evidence for a role of WIR1 proteins during the interaction of barley with the powdery mildew fungus Blumeria graminis. AB - Pathogen attack triggers a multifaceted defence response in plants that includes the accumulation of pathogenesis-related proteins and their corresponding transcripts. One of these transcripts encodes for WIR1, a small glycine- and proline-rich protein of unknown function that appears to be specific to grass species. Here we describe members of the HvWIR1 multigene family of barley with respect to phylogenetic relationship, transcript regulation, co-localization with quantitative trait loci for resistance to the barley powdery mildew fungus Blumeria graminis (DC.) E.O. Speer f.sp. hordei, the association of single nucleotide polymorphisms or gene haplotypes with resistance, as well as phenotypic effects of gene silencing by RNAi. HvWIR1 is encoded by a multigene family of moderate complexity that splits up into two major clades, one of those being also represented by previously described cDNA sequences from wheat. All analysed WIR1 transcripts accumulated in response to powdery mildew attack in leaves and all mapped WIR1 genes were associated with quantitative trait loci for resistance to B. graminis. Moreover, single nucleotide polymorphisms or haplotypes of WIR1 members were associated with quantitative resistance of barley to B. graminis, and transient WIR1 gene silencing affected the interaction of epidermal cells with the pathogen. The presented data provide convergent evidence for a role of the HvWIR1a gene and possibly other family members, during the interaction of barley with B. graminis. PMID- 20709428 TI - Longitudinal erythronychia: suggestions for evaluation and management. AB - Longitudinal erythronychia is a frequent nail presentation with a limited differential diagnosis. This clinical entity may be divided into cases that involve one (localized) or multiple (polydactylous) nails. The different presentations have distinct differential diagnoses and workups yet often share a common pathogenesis. Localized longitudinal erythronychia most commonly represents onychopapilloma, yet malignancies may present identically. Therefore biopsy may be required. Polydactylous longitudinal erythronychia usually coincides with a regional or systemic cause. Occasionally, it may herald an important underlying disease. A thorough understanding of the pathogenesis, clinical presentations, and possible diagnoses is necessary for successful evaluation and management. PMID- 20709429 TI - Progressive overgrowth of the cerebriform connective tissue nevus in patients with Proteus syndrome. AB - BACKGROUND: Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. OBJECTIVE: Our purpose was to evaluate progression of skin lesions in patients with Proteus syndrome. METHODS: Skin findings were documented in 36 patients with Proteus syndrome. Progression of skin lesions in 16 of these patients was assessed by comparing photographs obtained on repeated visits for an average total duration of 53 months. RESULTS: The skin lesion most characteristic of Proteus syndrome, the cerebriform connective tissue nevus, showed progression in 13 children but not in 3 adults. The cerebriform connective tissue nevus progressed by expansion into previously uninvolved skin, increased thickness, and development of new lesions. Lipomas increased in size, number, or both in 8 of 10 children with lipomas. In contrast, epidermal nevi and vascular malformations generally did not spread or increase in number. LIMITATIONS: Only 3 adults with Proteus syndrome were evaluated longitudinally. CONCLUSION: The cerebriform connective tissue nevus in Proteus syndrome grows throughout childhood but tends to remain stable in adulthood. PMID- 20709431 TI - Nurse teaching and research: Symbiotic partners or estranged relatives? PMID- 20709432 TI - Vaccination competence of graduating public health nurse students. AB - BACKGROUND: Vaccination is a globally significant health prevention method implemented by health care professionals around the world. To date, however, there has been little research measuring vaccinators' vaccination competence. AIM: This paper evaluates the vaccination competence of graduating Finnish public health nurse students in order to develop teaching in vaccinators' basic and continuing education. METHODS: Data were collected using a structured instrument developed for this study. The participants were graduating public health nurse students (n=129). The measurement focused on the students' self-assessment of their vaccination competence using a Visual Analog Scale (VAS), whereas their vaccination knowledge was tested with a knowledge test. RESULTS: Students assessed their level of vaccination competence as high. According to the self assessment, their best competence area was achieved in the outcome of the implementation of vaccination. The students' poorest competence area was displayed in their qualities as vaccinators. In the knowledge test, the students distinguished vaccination recommendations and common contraindications well, but managing an anaphylactic reaction as well as knowing the names of vaccines showed room for improvement. CONCLUSIONS: Vaccination competence can be measured by means of the structured instrument we developed. In Finland, more vaccination education in basic and continuing education is needed to maintain and develop vaccination competence. PMID- 20709430 TI - Late-life hemoglobin and the incidence of Parkinson's disease. AB - Brain iron promotes neurodegeneration in Parkinson's disease (PD). While hemoglobin (Hb) is the most abundant source of peripheral iron in humans, its relationship with PD is uncertain. This report examines the association between Hb in late life and PD incidence. From 1991 to 1993, Hb was measured in 3507 men in the Honolulu-Asia Aging Study. Men were aged 71-93 years and without PD. Participants were followed until 2001 for incident PD. Hb levels declined markedly with age. For men aged 71-75 years, 14.8% had levels < 14 g/dL versus 53.6% in those aged 86 and older (p < 0.001). During follow-up, 47 men developed PD (19.8/10,000 person-years). After age adjustment, PD incidence rose significantly from 10.3 to 34.9/10,000 person-years as Hb increased from < 14 to >= 16 g/dL (p = 0.024; relative hazard 3.2; 95% confidence interval, 1.2-8.9). Associations persisted after accounting for early mortality and adjustments for concomitant risk factors. While Hb declines with advancing age, evidence suggests that Hb that remains high in elderly men is associated with an increased risk of PD. PMID- 20709433 TI - Exploring the sustainability of obstetric near-miss case reviews: a qualitative study in the South of Benin. AB - INTRODUCTION: near-miss case reviews are one of a number of audit approaches currently being used and evaluated by those with an interest in reducing high rates of maternal mortality in developing countries. Researchers are beginning to take an interest in issues relating to the sustainability of audits. OBJECTIVE: to develop an understanding of the barriers and facilitators to the sustainability of obstetric near-miss case reviews in five hospitals in southern Benin. DESIGN AND METHODS: semi-structured interviews were designed to explore health workers' and policy makers' views and experiences of the sustainability of near-miss case reviews aimed to improve quality of care and reduce maternal mortality. SETTING: five hospitals in three regions in the south of Benin. PARTICIPANTS: two Ministry of Health officials and eight health-care workers involved in a feasibility study conducted in 1998-2001 that introduced near-miss case reviews. ANALYSIS: framework analysis to identify themes. FINDINGS: while all participants believed in the importance and value of audit, all hospitals had stopped performing near-miss case reviews within two years of completing the feasibility study. Ten qualitative interviews identified six themes relating to the sustainability of case reviews: clear advantages in ensuring quality of care, fear of blame and punishment, availability of resources, training, supportive hospital work environment, and broader policy issues. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: implementing and sustaining audit is a complex intervention that requires careful planning and consideration. It is important to consider both the content and the context in which audit takes place when developing strategies for sustainability. PMID- 20709434 TI - A novel approach for characterization of polycyclic aromatic hydrocarbon (PAH) pollution patterns in sediments from Guanabara Bay, Rio de Janeiro, Brazil. AB - A novel multivariate method based on principal component analysis of pre processed sections of chromatograms is used to characterize the complex PAH pollution patterns in sediments from Guanabara Bay, Brazil. Five distinct sources of 3- to 6-ring PAHs could be revealed. The harbour is the most contaminated site in the bay, its plume stretches in a South West to North East direction and the chemical profile indicates mainly pyrogenic sources mixed with a fraction of high molecular-weight petrogenic PAHs. Rio Sao Joao de Meriti is the second largest source of PAHs, and introduces mainly a fraction of low-molecular-weight petrogenic PAHs from the western region of Rio de Janeiro. The sites close to the ruptured pipeline at the Duque de Caxias Refinery show a distinctive pollution pattern indicating a heavy petroleum fraction. The method also led to the identification of new potential indicator ratios also involving coeluting peaks (e.g., triphenylene and chrysene). PMID- 20709435 TI - A GIS model-based assessment of the environmental distribution of gamma hexachlorocyclohexane in European soils and waters. AB - The MAPPE GIS based multimedia model is used to produce a quantitative description of the behaviour of gamma-hexachlorocyclohexane (gamma-HCH) in Europe, with emphasis on continental surface waters. The model is found to reasonably reproduce gamma-HCH distributions and variations along the years in atmosphere and soil; for continental surface waters, concentrations were reasonably well predicted for year 1995, when lindane was still used in agriculture, while for 2005, assuming severe restrictions in use, yields to substantial underestimation. Much better results were yielded when same mode of release as in 1995 was considered, supporting the conjecture that for gamma-HCH, emission data rather that model structure and parameterization can be responsible for wrong estimation of concentrations. Future research should be directed to improve the quality of emission data. Joint interpretation of monitoring and modelling results, highlights that lindane emissions in Europe, despite the marked decreasing trend, persist beyond the provisions of existing legislation. PMID- 20709436 TI - Protection of plants from ambient ozone by applications of ethylenediurea (EDU): a meta-analytic review. AB - A meta-analysis was conducted to quantitatively assess the effects of ethylenediurea (EDU) on ozone (O3) injury, growth, physiology and productivity of plants grown in ambient air conditions. Results indicated that EDU significantly reduced O3-caused visible injury by 76%, and increased photosynthetic rate by 8%, above-ground biomass by 7% and crop yield by 15% in comparison with non-EDU treated plants, suggesting that ozone reduces growth and yield under current ambient conditions. EDU significantly ameliorated the biomass and yield of crops and grasses, but had no significant effect on tree growth with an exception of stem diameter. EDU applied as a soil drench at a concentration of 200-400 mg/L has the highest positive effect on crops grown in the field. Long-term research on full-grown tree species is needed. In conclusion, EDU is a powerful tool for assessing effects of ambient [O3] on vegetation. PMID- 20709437 TI - A computerized provider order entry intervention for medication safety during acute kidney injury: a quality improvement report. AB - BACKGROUND: Frequently, prescribers fail to account for changing kidney function when prescribing medications. We evaluated the use of a computerized provider order entry intervention to improve medication management during acute kidney injury. STUDY DESIGN: Quality improvement report with time series analyses. SETTING & PARTICIPANTS: 1,598 adult inpatients with a minimum 0.5-mg/dL increase in serum creatinine level over 48 hours after an order for at least one of 122 nephrotoxic or renally cleared medications. QUALITY IMPROVEMENT PLAN: Passive noninteractive warnings about increasing serum creatinine level appeared within the computerized provider order entry interface and on printed rounding reports. For contraindicated or high-toxicity medications that should be avoided or adjusted, an interruptive alert within the system asked providers to modify or discontinue the targeted orders, mark the current dosing as correct and to remain unchanged, or defer the alert to reappear in the next session. OUTCOMES & MEASUREMENTS: Intervention effect on drug modification or discontinuation, time to modification or discontinuation, and provider interactions with alerts. RESULTS: The modification or discontinuation rate per 100 events for medications included in the interruptive alert within 24 hours of increasing creatinine level improved from 35.2 preintervention to 52.6 postintervention (P < 0.001); orders were modified or discontinued more quickly (P < 0.001). During the postintervention period, providers initially deferred 78.1% of interruptive alerts, although 54% of these eventually were modified or discontinued before patient death, discharge, or transfer. The response to passive alerts about medications requiring review did not significantly change compared with baseline. LIMITATIONS: Single tertiary-care academic medical center; provider actions were not independently adjudicated for appropriateness. CONCLUSIONS: A computerized provider order entry-based alerting system to support medication management after acute kidney injury significantly increased the rate and timeliness of modification or discontinuation of targeted medications. PMID- 20709438 TI - Cystatin C, albuminuria, and 5-year all-cause mortality in HIV-infected persons. AB - BACKGROUND: Compared with controls, human immunodeficiency virus (HIV)-infected persons have a greater prevalence of kidney disease, assessed according to high cystatin C level and albuminuria, but not according to creatinine level. However, the clinical importance of increased cystatin C level and albuminuria in the HIV infected population has not been studied. STUDY DESIGN: We conducted an observational cohort study to determine the association of kidney disease (measured according to albuminuria, cystatin C, and serum creatinine) with mortality. SETTING & PARTICIPANTS: 922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) Study. PREDICTOR: Serum cystatin C and serum creatinine levels were used to estimate glomerular filtration rates (eGFR(SCysC) and eGFR(SCr), respectively). Albuminuria was defined as a positive urine dipstick result (>= 1+) or urine albumin-creatinine ratio >30 mg/g. OUTCOME: 5-Year mortality. RESULTS: At baseline, decreased kidney function (eGFR(SCysC) <60 mL/min/1.73 m(2)) or albuminuria was present in 28% of participants. After 5 years of follow-up, mortality was 48% in those with both eGFR(SCysC) < 60 mL/min/1.73 m(2) and albuminuria, 23% in those with eGFR(SCysC) < 60 mL/min/1.73 m(2) alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory marker levels, eGFR(SCysC) < 60 mL/min/1.73 m(2) and albuminuria were associated with a nearly 2 fold increase in mortality, whereas eGFR(SCr) < 60 mL/min/1.73 m(2) did not appear to have a substantial association with mortality. Together, eGFR(SCysC) <60 mL/min/1.73 m(2) and albuminuria accounted for 17% of the population-level attributable risk of mortality. LIMITATIONS: Vital status was unknown in 261 participants from the original cohort. CONCLUSIONS: Kidney disease marked by albuminuria or increased cystatin C level appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice. PMID- 20709440 TI - Treating profound hyponatremia: a strategy for controlled correction. AB - An alcoholic patient presented with profound hyponatremia (serum sodium concentration, 96 mEq/L) caused by the combined effects of a thiazide diuretic, serotonin reuptake inhibitor, beer potomania, and hypovolemia. A computed tomographic scan of the brain was indistinguishable from one obtained 3 weeks earlier when he was normonatremic. Concurrent administration of 3% saline solution and desmopressin controlled the rate of correction to an average of 6 mEq/L daily and resulted in full neurologic recovery without evidence of osmotic demyelination. This case illustrates the value of controlled correction of profound hyponatremia. PMID- 20709439 TI - Warfarin dosing in patients with impaired kidney function. AB - BACKGROUND: In patients with kidney impairment, warfarin, a drug metabolized primarily by the cytochrome P-450 system, is initiated at similar doses and managed similarly as in the general medical population. Unfortunately, few data exist to guide dose adjustment in patients with decreased kidney function. Here, we determine the degree of warfarin dose reduction associated with kidney impairment and make recommendations for warfarin dosing. STUDY DESIGN: Cross sectional analysis. SETTING & PARTICIPANTS: Long-term warfarin users followed up at anticoagulation clinics (n = 980); 708 participants from the University of Alabama (UAB) and 272 participants from the University of Chicago (UIC). PREDICTOR: No/mild (estimated glomerular filtration rate [eGFR] >= 60 mL/min/1.73 m(2)), moderate (eGFR, 30-59 mL/min/1.73 m(2)), and severe (eGFR < 30 mL/min/1.73 m(2)) kidney impairment; CYP2C9 and VKORC1 genotype; age; race; sex; body mass; sociodemographic factors; smoking status; alcohol; vitamin K intake; comorbid conditions (eg, congestive heart failure); and drug interactions (eg, amiodarone and statins). OUTCOME & MEASUREMENT: Warfarin dose (milligrams per day) was evaluated using linear regression after adjustment for clinical, demographic, and genetic factors. RESULTS: Prevalences of moderate (31.8% and 27.6%) and severe kidney impairment (8.9% and 6.6%) were similar in the UAB and UIC cohorts. Warfarin dose requirements were significantly lower in patients with moderate and severe kidney impairment compared with those with no/mild kidney impairment in the UAB (P < 0.001) and UIC (P < 0.001) cohorts. Compared with patients with no/mild kidney impairment, patients with moderate kidney impairment required 9.5% lower doses (P < 0.001) and patients with severe kidney impairment required 19% lower doses (P < 0.001). LIMITATIONS: No measurement of warfarin, serum albumin, vitamin K, and coagulation factors; no evaluation of other markers (eg, cystatin). CONCLUSION: Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements. PMID- 20709441 TI - Against the organization of misery? The Marmot Review of health inequalities. PMID- 20709442 TI - Cortical integration of audio-visual speech and non-speech stimuli. AB - Using fMRI we investigated the neural basis of audio-visual processing of speech and non-speech stimuli using physically similar auditory stimuli (speech and sinusoidal tones) and visual stimuli (animated circles and ellipses). Relative to uni-modal stimuli, the different multi-modal stimuli showed increased activation in largely non-overlapping areas. Ellipse-Speech, which most resembles naturalistic audio-visual speech, showed higher activation in the right inferior frontal gyrus, fusiform gyri, left posterior superior temporal sulcus, and lateral occipital cortex. Circle-Tone, an arbitrary audio-visual pairing with no speech association, activated middle temporal gyri and lateral occipital cortex. Circle-Speech showed activation in lateral occipital cortex, and Ellipse-Tone did not show increased activation relative to uni-modal stimuli. Further analysis revealed that middle temporal regions, although identified as multi-modal only in the Circle-Tone condition, were more strongly active to Ellipse-Speech or Circle Speech, but regions that were identified as multi-modal for Ellipse-Speech were always strongest for Ellipse-Speech. Our results suggest that combinations of auditory and visual stimuli may together be processed by different cortical networks, depending on the extent to which multi-modal speech or non-speech percepts are evoked. PMID- 20709443 TI - Affordability of residential water tariffs: alternative measurement and explanatory factors in southern Spain. AB - Using information on a basic or "lifeline" level of domestic water use obtained from a water demand function based on a Stone-Geary utility function, a minimum water threshold of 128 m(3) per household per year was estimated in a sample of municipalities in Southern Spain. As a second objective, water affordability indexes were then calculated that relate the cost of such lifeline to average municipal income levels. The analysis of the factors behind the differences in that ratio across Andalusian municipalities shows that the relative cost of purchasing the lifeline appears inversely related to average income levels, revealing an element of regressivity in the component of water tariffs affecting the least superfluous part of the household's consumption. The main policy recommendation would involve redesigning water tariffs in order to improve access for lower income households to an amount of water sufficient to cover their basic needs. The proposed methodology could be applied to other geographical areas, both from developed and from developing countries, in order to analyze the degree of progressivity of the water tariffs currently in effect and in order to guide the design of more equitable regulatory policies. PMID- 20709444 TI - Tension-free vaginal tape versus transobturator suburethral tape: five-year follow-up results of a prospective, randomised trial. AB - BACKGROUND: Many studies have assessed the equivalent effectiveness of tension free vaginal tape (TVT) and transobturator suburethral tape (TVT-O) at short- to medium-term follow-up, but no long-term randomised trials appear in the literature. OBJECTIVE: We compared the use of TVT to TVT-O, providing a longer follow-up than currently appears in the literature. DESIGN, SETTING, AND PARTICIPANTS: Seventy-two consecutive patients affected by stress urinary incontinence (SUI) were included in this randomised, controlled trial. Patients were randomly allocated to the TVT or TVT-O procedure using a predetermined, computer-generated randomisation code. INTERVENTION: After preoperative assessment, patients were randomly allocated to the TVT or TVT-O procedure. MEASUREMENTS: This 5-yr study represents the extension of our original randomised trial, which was designed to assess the incidence of long-term complications (primary end point) and successes (secondary end point) for both techniques. RESULTS AND LIMITATIONS: At 60-mo follow-up, 52 patients (72%) were objectively cured of SUI (72.9% after TVT-O and 71.4% after TVT), but only 44 patients (61%) were satisfied. The late complication rate was 16.6% (10 women): five women (16.1%) in the TVT-O group and five women (17.2%) in the TVT group (p=1). In this follow-up, 62% of the patients from the TVT-O group and 60% from the TVT group (p=1) expressed that they were satisfied or very satisfied with the results. The mean cause of dissatisfaction was the development of sexual dysfunction resulting from dyspareunia or incontinence during intercourse, which was found in 6 of 16 dissatisfied patients (37.5%). The limitations of our study included the adequate but small sample size and the lack of questionnaires. CONCLUSIONS: Both surgical techniques are safe, with similar results (72.9% and 71% of patients objectively cured after TVT-O and TVT, respectively) and low complication rates (16.6%: 16.1% and 17.2%, respectively, for TVT-0 and TVT), even after 5-yr follow-up. PMID- 20709445 TI - Vasoactive intestinal peptide (VIP) induces malignant transformation of the human prostate epithelial cell line RWPE-1. AB - The carcinogenic potential of vasoactive intestinal peptide (VIP) was analyzed in non-tumor human prostate epithelial cells (RWPE-1) and in vivo xenografts. VIP induced morphological changes and a migratory phenotype consistent with stimulation of expression/activity of metalloproteinases MMP-2 and MMP-9, decreased E-cadherin-mediated cell-cell adhesion, and increased cell motility. VIP increased cyclin D1 expression and cell proliferation that was blocked after VPAC(1)-receptor siRNA transfection. Similar effects were seen in RWPE-1 tumors developed by subcutaneous injection of VIP-treated cells in athymic nude mice. VIP acts as a cytokine in RWPE-1 cell transformation conceivably through epithelial-mesenchymal transition (EMT), reinforcing VIP role in prostate tumorigenesis. PMID- 20709446 TI - Variation in performance of surfactant loading and resulting nitrate removal among four selected natural zeolites. AB - Surfactant modified zeolites (SMZs) have the capacity to target various types of water contaminants at relatively low cost and thus are being increasingly considered for use in improving water quality. It is important to know the surfactant loading performance of a zeolite before it is put into application. In this work we compare the loading capacity of a surfactant, hexadecyltrimethylammonium bromide (HDTMA-Br), onto four natural zeolites obtained from specific locations in the USA, Croatia, China, and Australia. The surfactant loading is examined using thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, and Raman spectroscopy. We then compare the resulting SMZs performance in removing nitrate from water. Results show that TGA is useful to determine the HDTMA loading capacity on natural zeolites. It is also useful to distinguish between a HDTMA bi-layer and a HDTMA mono-layer on the SMZ surface, which has not been previously reported in the literature. TGA results infer that HDTMA (bi-layer) loading decreases in the order of US zeolite>Croatian zeolite>Chinese zeolite>Australian zeolite. This order of loading explains variation in performance of nitrate removal between the four SMZs. The SMZs remove 8-18 times more nitrate than the raw zeolites. SMZs prepared from the selected US and Croatian zeolites were more efficient in nitrate removal than the two zeolites commercially obtained from Australia and China. PMID- 20709447 TI - Domino effect in chemical accidents: main features and accident sequences. AB - The main features of domino accidents in process/storage plants and in the transportation of hazardous materials were studied through an analysis of 225 accidents involving this effect. Data on these accidents, which occurred after 1961, were taken from several sources. Aspects analyzed included the accident scenario, the type of accident, the materials involved, the causes and consequences and the most common accident sequences. The analysis showed that the most frequent causes are external events (31%) and mechanical failure (29%). Storage areas (35%) and process plants (28%) are by far the most common settings for domino accidents. Eighty-nine per cent of the accidents involved flammable materials, the most frequent of which was LPG. The domino effect sequences were analyzed using relative probability event trees. The most frequent sequences were explosion->fire (27.6%), fire->explosion (27.5%) and fire->fire (17.8%). PMID- 20709448 TI - Air pollution effect of O3 on crop yield in rural India. AB - Measurement of surface ozone (O(3)) mixing ratio was made from January 2006 to December 2007 in Ahmednagar (19.1 degrees N, 74.8 degrees E, 657 m above sea level), India. The monthly average of daytime maximum of O(3) mixing ratio ranged from 14 to 57 parts per billion by volume (ppbv) with an annual average of about 20 ppbv. The estimated winter wheat and summer crop yield reduction by 10% and 15%, respectively from present O(3) pollution level associated with AOT40 (accumulation exposure of O(3) concentration over a threshold of 40 ppbv) index values 7370-9150 ppbv h in rural areas. PMID- 20709449 TI - Removal of lead from aqueous solution by activated carbon prepared from Enteromorpha prolifera by zinc chloride activation. AB - Activated carbon was prepared from Enteromorpha prolifera (EP) by zinc chloride activation. The physico-chemical properties of EP-activated carbon (EPAC) were characterized by thermal stability, zeta potential and Boehm titration methods. The examination showed that EPAC has a porous structure with a high surface area of 1688 m(2)/g. Batch adsorption experiments were carried out to study the effect of various parameters such as initial pH, adsorbent dosage, contact time and temperature on Pb(II) ions adsorption properties by EPAC. The kinetic studies showed that the adsorption data followed a pseudo second-order kinetic model. The isotherm analysis indicated that the adsorption data can be represented by Freundlich isotherm model. Thermodynamic studies indicated that the adsorption reaction was a spontaneous and endothermic process. PMID- 20709450 TI - The removal of heavy metal ions from aqueous solutions by novel pH-sensitive hydrogels. AB - Novel non-ionic hydrogels were synthesized by radical homopolymerization of N vinyl-2-pyrrolidone (VP) or by radical copolymerization of VP with methylacrylate (MA). A macroinimer (MIM) was used as a crosslinker and initiator, as well. The percentage of mass swelling ratios (S(M)), the molecular weight between crosslinks (M(c)) and Young's modulus of the hydrogels were investigated. The hydrogels were used as binding materials for different heavy metal ions such as Cu(2+), Cd(2+), Ni(2+) and Zn(2+) under varying conditions. The binding capability of the hydrogels toward the metal ions decreases in the following order: Cu(2+)>Ni(2+)>Zn(2+)>Cd(2+). PMID- 20709452 TI - Decomposition of 1,2-dichloroethane over CeO2 modified USY zeolite catalysts: effect of acidity and redox property on the catalytic behavior. AB - CeO(2) modified ultrastable Y zeolite (CeO(2)-USY) catalysts were prepared and were used as the catalysts for the decomposition of 1,2-dichloroethane (DCE). The catalytic behavior of these catalysts was evaluated by micro-reaction and temperature-programmed surface reaction (TPSR) technique. The results reveal that CeO(2)-USY catalysts exhibit good catalytic activity for DCE decomposition and high selectivity to the formation of CO(2) and HCl. Both acidity and redox property play important roles in the DCE decomposition, and the synergy between CeO(2) species and USY zeolite shows an enhancement in the catalytic activity for DCE decomposition. CeO(2)-USY (1:8) with high dispersion of CeO(2) species and a much more suitable combination of acidity and redox property exhibits the best catalytic activity. PMID- 20709451 TI - Effect of fireworks events on urban background trace metal aerosol concentrations: is the cocktail worth the show? AB - We report on the effect of a major firework event on urban background atmospheric PM(2.5) chemistry, using 24-h data collected over 8 weeks at two sites in Girona, Spain. The firework pollution episode (Sant Joan fiesta on 23rd June 2008) measured in city centre parkland increased local background PM(2.5) concentrations as follows: Sr (x86), K (x26), Ba (x11), Co (x9), Pb (x7), Cu (x5), Zn (x4), Bi (x4), Mg (x4), Rb (x4), Sb (x3), P (x3), Ga (x2), Mn (x2), As (x2), Ti (x2) and SO(4)(2-) (x2). Marked increases in these elements were also measured outside the park as the pollution cloud drifted over the city centre, and levels of some metals remained elevated above background for days after the event as a reservoir of metalliferous dust persisted within the urban area. Transient high-PM pollution episodes are a proven health hazard, made worse in the case of firework combustion because many of the elements released are both toxic and finely respirable, and because displays commonly take place in an already polluted urban atmosphere. PMID- 20709453 TI - Tributyltin toxicity in abalone (Haliotis diversicolor supertexta) assessed by antioxidant enzyme activity, metabolic response, and histopathology. AB - A toxicity test was performed to investigate the possible harmful effects of tributyltin (TBT) on abalone (Haliotis diversicolor supertexta). Animals were exposed to TBT in a range of environmentally relevant concentrations (2, 10 and 50 ng/L) for 30 days under laboratory conditions. TBT-free conditions were used as control treatments. The activity of antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD), and malondialdehyde (MDA), along with levels of haemolymph metabolites, and hepatopancreas histopathology were analyzed. The results showed that TBT decreased SOD activity, and increased POD level and MDA production in a dose-dependent way, indicating that oxidative injury was induced by TBT. Haemolymph metabolite measurements showed that TBT increased alanine and glutamate levels, and decreased glucose content, which suggested perturbation of energy metabolism. Elevated levels of acetate and pyruvate in the haemolymph indicated partial alteration of lipid metabolism. A decrease in lactate and an increase in succinate, an intermediate of the tricarboxylic acid (TCA) cycle, indicated disturbance of amino acid metabolism. Hepatopancreas tissues also exhibited inflammatory responses characterized by histopathological changes such as cell swelling, granular degeneration, and inflammation. Taken together, these results demonstrated that TBT was a potential toxin with a variety of deleterious effects on abalone. PMID- 20709454 TI - Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice. AB - Interleukin-6 (IL-6) is an inflammatory cytokine known to modulate muscle pain. However, the mechanisms underlying this effect still remain unclear. Here we show that the injection of IL-6 into mice gastrocnemius muscle evoked a time- and dose dependent mechanical hyperalgesia. This effect is in part dependent on the presence of gp130 expression in inflammatory cells in the gastrocnemius muscle as well as in DRG neurons. We also demonstrated an increased inflammatory cell recruitment and cytokines levels, namely TNF-alpha, IL-1beta and KC. TNFR1(-/-) mice or mice pre-treated with the selective CXCR2 antagonist, SB225002, with the anti-macrophage, anti-TNF-alpha or anti-KC antibodies or with IL-1 receptor antagonist (IL-1RA) showed decreased IL-6-mediated mechanical hyperalgesia. Furthermore, systemic pre-treatment with the classically used drugs indomethacin, celecoxib, guanetidine, morphine, thalidomide or dexamethasone, also prevented IL 6-induced muscle pain. Likewise, local pre-treatment with inhibitors of phospholipase A2 (PACOCF3), phospholipase C (U73122), protein kinase C (GF109203X), protein kinase A (KT-5720) or with phosphatidylinositol 3-kinase (AS605204) also consistently diminished IL-6-induced muscle hyperalgesia. The intramuscular injection of the selective inhibitors of p38 MAPK (SB203580), ERK (PD98059) or JNK (SP60015) also prevented IL-6-mediated muscular pain. Simultaneous flow cytometry measurements revealed that ERK, p38 MAPK and JNK were phosphorylated as early as 5 min after IL-6 injection. These findings provided new evidence indicating that IL-6 exerts a relevant role in the development and maintenance of muscular hyperalgesia. The IL-6-mediated muscular pain response involves resident cell activation, polymorphonuclear cell infiltration, cytokine production, prostanoids and sympathomimetic amines release and the activation of intracellular pathways, especially MAPKs. PMID- 20709456 TI - Topotecan for relapsed small cell lung cancer: a systematic review and economic evaluation. AB - BACKGROUND: Topotecan is a relatively new drug for use as a second-line treatment in patients with relapsed small cell lung cancer (SCLC). We performed a systematic review and economic evaluation of topotecan, and consider it here in relation to the NICE end of life criteria. METHODS: Seventeen bibliographic databases (including Cochrane library, Medline and Embase) were searched from 1990 to February 2009, and experts and manufacturers were consulted, to identify relevant randomised controlled trials (RCTs) which were selected according to prospectively defined criteria. An economic evaluation was undertaken to assess cost effectiveness compared with best supportive care (BSC) in the UK. RESULTS: Five RCTs were included. The clinical evidence indicates a statistically significant benefit of oral topotecan plus BSC compared to BSC alone for overall survival. Intravenous topotecan was similar in efficacy to both oral topotecan and CAV (cyclophosphamide, doxorubicin and vincristine). In the survival model, oral topotecan plus BSC was associated with an average gain in life expectancy of approximately 4 months, resulting in a gain of 0.183 quality-adjusted life years (QALYs). At an incremental cost of approximately L6200 the incremental cost effectiveness ratio (ICER) is L33,851 per QALY gained. CONCLUSIONS: Compared with BSC alone, oral topotecan for patients with relapsed SCLC was associated with improved health outcomes but at increased cost. The ICER is at the upper extreme of the range conventionally regarded as cost effective from an NHS decision making perspective. However, this treatment may fall under supplementary guidance for life extending, end of life treatments. PMID- 20709455 TI - Enhanced scratching evoked by PAR-2 agonist and 5-HT but not histamine in a mouse model of chronic dry skin itch. AB - Chronic itch is a symptom of many skin conditions and systemic disease, and it has been hypothesized that the chronic itch may result from sensitization of itch signaling pathways. We induced experimental chronic dry skin on the rostral back of mice, and observed a significant increase in spontaneous hindlimb scratches directed to the dry skin. Spontaneous scratching was significantly attenuated by a PAR-2 antibody and 5-HT2A receptor antagonist, indicating activation of these receptors by endogenous mediators released under dry skin conditions. We also observed a significant increase in the number of scratch bouts evoked by acute intradermal injections of a protease-activated receptor (PAR)-2 agonist and serotonin (5-HT), but not histamine. We additionally investigated if pruritogen evoked activity of dorsal root ganglion (DRG) neurons is enhanced in this model. DRG cells from dry skin mice exhibited significantly larger responses to the PAR 2 agonist and 5-HT, but not histamine. Spontaneous scratching may reflect ongoing itch, and enhanced pruritogen-evoked scratching may represent hyperknesis (enhanced itch), both potentially due to sensitization of itch-signaling neurons. The correspondence between enhanced behavioral scratching and DRG cell responses suggest that peripheral pruriceptors that respond to proteases and 5-HT, but not histamine, may be sensitized in dry skin itch. PMID- 20709458 TI - Psychoanalysis on the couch: can neuroscience provide the answers? AB - Over a century after Freud's attempt to establish psychoanalysis as a natural science, there is renewed interest in the integration of psychoanalytic and neuroscientific findings within a single theoretical and experimental framework. However, it is important that any intellectual exchange is not motivated only by declining confidence in psychoanalytic theory and practice or awareness of the rising fortunes of the brain sciences. The present paper considers three possible ways in which psychoanalysis and neuroscience might be integrated. These include the investigation of the neurological organisation of psychoanalytically defined phenomena; the evaluation of psychoanalytic theories based on their neurobiological evidence; and the use of neuroimaging techniques to assess the progress and outcome of psychoanalytic treatment. The author argues that these exercises are unlikely to provide psychoanalysis with the "unlimited opportunities for overcoming its uncertainties and doubts" that some have anticipated. For instance, the argument that mapping psychoanalytically defined phenomena in the brain may provide biological validity to these phenomena should be considered an expression of logical confusion; the evaluation of psychoanalytic theories based on their biological evidence is critically dependent on speculative interpretation of what the theories predict at neuronal level; and the supposedly objective evaluation of the progress and outcome of psychoanalytic treatment on the basis of neurobiological data relies on the subjective reports of the patient and analyst. In light of this conclusion, there are a number of outstanding questions which remain to be addressed, including whether psychoanalysis should adhere to scientific canons and whether this would necessarily require an experimental methodology. PMID- 20709457 TI - Volatile anesthetics might be more beneficial than propofol for postoperative liver function in cirrhotic patients receiving hepatectomy. AB - Hepatic inflow occlusion during the liver surgery may result in a transient ischemia period followed by reperfusion, and may initiate liver injury and lead to postoperative liver dysfunction. Especially in cirrhotic patients, the tolerance time of ischemia is much shorter and the outcome would be worse. Recently, clinical trials had proved that volatile anesthetics rather than propofol can protect myocardial cells from ischemia reperfusion (IR) injury in cardiac surgery. Meanwhile, animal studies had revealed that volatile anesthetics could induce some endogenous protective molecules in the liver such as hypoxia induced factor-1 (HIF-1), heme oxygenase (HO) enzyme system and inducible nitric oxide synthase (iNOS), which make the volatile anesthetics posing the extraordinary anti-oxidative, anti-inflammatory, anti-apoptotic, and vasodilatory characteristics. However, there is still lack of trials to compare the postoperative outcomes such as liver function in cirrhotic patients undergoing liver surgery with inflow occlusion between volatile anesthetics and propofol anesthesia. Hence we hypothesize that with its anti-IR injury characteristics, volatile anesthetics might be the more appropriate choice in cirrhotic patients undergoing liver surgery with occlusion. PMID- 20709459 TI - A possible role for Progressive Muscle Relaxation in the treatment of persecutory ideation. AB - Persecutory ideation is one of the most commonly reported psychiatric symptoms in individuals with schizophrenia and is associated with significant patient distress and impairment. Therefore, much attention has recently been devoted to theoretical explanations of persecutory ideation that can help inform and guide patient care. A cognitive model of persecutory ideation suggests that individuals with psychosis who experience anxiety along with other stressors are at increased risk for developing intense "threat" or persecutory beliefs. Correlational studies have found evidence for this proposed link between anxiety levels and the persistence, distress levels, and degree of conviction associated with persecutory ideation. Importantly, recent research has found support for a possible prospective/causal role for anxiety in the generation and maintenance of paranoid beliefs. Existing interventions for persecutory ideation consist of pharmacological treatments that have variable efficacy and often entail serious side-effects, and cognitive behavioral treatments (CBT) that target persecutory thoughts, but are often unavailable, require high level of clinician expertise, and may be difficult to conduct with patients who are cognitively impaired or apprehensive about openly exploring their paranoid beliefs. Given the empirical support for a prospective relationship between anxiety and persecutory ideation, it is reasonable to predict that clinicians could impact persecutory ideations indirectly by making good use of existing evidence-based interventions for anxiety. Progressive Muscle Relaxation (PMR) is an effective method for reducing physiological arousal and treating various anxiety disorders, and has been shown to be feasible with patients with psychosis. We offer that exportability and ease of use makes PMR a promising intervention for mental health practitioners to target anxiety precipitating persecutory ideation. We hypothesize that PMR could be used to help ameliorate anxiety in patients who are at risk or already experiencing persecutory ideation, subsequently reducing the frequency, level of conviction, and distress associated with persecutory thoughts. Our hypothesis could be tested through feasibility and randomized control trials of PMR for treatment of persecutory ideation in individuals with schizophrenia. We expect the relationship between PMR and persecutory ideation will be mediated by reduction in anxiety. Potential advantages of examining our hypothesis include identifying a viable, efficacious, cost-effective novel intervention for paranoia in patients with psychosis. In addition, PMR could be easily facilitated by practitioners with varying levels of training and integrated with other existing interventions for persecutory ideation. PMID- 20709460 TI - Effect of ageing and MU-calpain markers on meat quality from Brangus steers finished on pasture. AB - Brangus steers (n=247) finished on pasture were used to evaluate the effects of post-mortem ageing and polymorphism CAPN1 316 and CAPN1 4751 markers on meat tenderness and objective colour measurements (CIEL*a*b*) of m. Longissimus dorsi. Ageing meat for 7 days decreased shear force (SF) by 13.7% and improved a* (8.4%) and b* (10%) compared to ageing for 1 day. No difference between 7 and 14 days of ageing was found for SF, a* and b*. However, L* increased markedly with ageing. Fitting both markers simultaneously, CAPN1 316 showed association with SF and L* and CAPN1 4751 with a* and b*. Fitting the markers individually, CAPN1 4751 affected all traits and CAPN1 316 showed association with SF and L*. Post-mortem ageing and the use of markers represent two independent and alternative tools that could be used for improving quality of meat from Brangus cattle. PMID- 20709461 TI - Assessment of GH1, CAPN1 and CAST polymorphisms as markers of carcass and meat traits in Bos indicus and Bos taurus-Bos indicus cross beef cattle. AB - The objective of this study was to investigate the effects of bovine GH1, CAPN1 and CAST gene polymorphisms on carcass and meat traits in Nellore and Nellore x Bos taurus beef cattle. Three hundred animals were genotyped for GH1/MspI (TC/G in intron 3), CAPN316 (AF_252504.2:g.5709C>G) and CAST/RsaI (AY_008267.1:g282C>G) and phenotyped for rib eye area, backfat thickness, intramuscular fat, shear force (SF), and myofibrillar fragmentation index (MFI). No significant associations were observed between the GH1/MspI and CAST/RsaI polymorphisms and phenotypes, although the relation between the CAST/RsaI genotypes and meat tenderness evaluated by MFI approached significant. The fact that the CAPN316 polymorphism did not show adequate segregation in Nellore cattle confirms the difficulty of using this marker in breeding programs of different Bos indicus breeds. However, the positive results of the association analysis obtained for Nellore x B. taurus crosses contributed to the validation of previous findings. PMID- 20709462 TI - The influence of forage diets and aging on beef palatability. AB - To investigate the influence of diet and aging on beef palatability, lipid oxidative stability, and fatty acid composition, crossbred steers were assigned to Feedlot S (alfalfa and grain), Forage TR (triticale and annual ryegrass), Forage TK (triticale and kale), or Forage+Feedlot (grazing ryegrass, fescue and orchardgrass, finished on alfalfa and grain) dietary treatments. Heifers were finished on Feedlot H (alfalfa and grain). Longissimus and tricep muscles were sampled from these animals for steaks and ground beef, respectively. Steaks were either dry- or wet-aged for 14 d. Ground beef was dry-aged, wet-aged for 14 d, or not aged. Trained sensory panelists evaluated palatability attributes of steaks and ground beef. Diet did not influence sensory attributes of steaks or ground beef. Aging impacted (P<0.05) sensory attributes of ground beef. Diet and aging had no impact on lipid oxidative stability but affected fatty acid composition of raw ground beef. PMID- 20709463 TI - Biological impact of vascular endothelial growth factor on vessel density and survival in multiple myeloma and plasmacytoma. AB - We compared the differences in a number of angiogenesis-related immunohistochemical parameters, including microvascular density (MVD) and tumor cell activity, between multiple myeloma (MM) and solitary plasmacytoma (SP). Tissue sections from tumors of MM and SP were immunohistochemically stained and analyzed using ImageJ image analysis software for the expression of vascular endothelial growth factor (VEGF), VEGF receptors (Flt-1 and Flk-1), inducible nitric oxide (iNOS), and anti-apoptotic (Bcl-2) protein. Tumor tissues were cytologically graded as high-, intermediate-, or low-grade. Two pathologists determined the MVD of each section independently by recording the average number of CD34+ blood vessels in 500 unit fields. The arithmetic means for MVD were statistically analyzed using the Student's t-test and the significance level was calculated at P-value <0.001. The results indicate a direct correlation between upregulation of iNOS/VEGF in high-grade tumors. For MM, an increase in MVD is also correlated with a high-grade. Tumor survival signaling by Bcl-2 in both SP and MM emphasizes the fact that VEGF has a bimodal role that is mainly angiogenic in MM and tumorigenic, promoting tumor cell survival in SP. PMID- 20709464 TI - Histologic, immunohistochemical, microbiological, molecular biological and ultrastructural characterization of pulmonary tularemia. AB - Tularemia is a rare zoonotic disease caused by Francisella tularensis, a Gram negative bacteria. The clinical manifestations of pulmonary tularemia resemble those of other airways infections. Recently, a case of pulmonary tularemia was diagnosed at Tufts Medical Center. The purpose of the current report is to document the utility of applying several diagnostic tools, including immunohistochemistry, electron microscopy, microbiology and molecular biology in confirming the diagnosis of pulmonary tularemia, particularly in convalescing cases (up to 3 weeks postpresentation) and after antibiotic therapy. Our study demonstrates the usefulness of microbiological studies followed by morphological evaluation and the limitation of the molecular biology analysis of posttherapy samples. PMID- 20709465 TI - Mechanical feasibility of immediate mobilization of the brachioradialis muscle after tendon transfer. AB - PURPOSE: Tendon transfer is often used to restore key pinch after cervical spinal cord injury. Current postoperative recommendations include elbow immobilization in a flexed position to protect the brachioradialis-flexor pollicis longus (BR FPL) repair. The purpose of this study was to measure the BR-FPL tendon tension across a range of wrist and elbow joint angles to determine whether joint motion could cause repair rupture. METHODS: We performed BR-to-FPL tendon transfers on fresh-frozen cadaveric arms (n = 8) and instrumented the BR-FPL tendon with a buckle transducer. Arms were ranged at 4 wrist angles from 45 degrees of flexion to 45 degrees of extension and 8 elbow angles from 90 degrees of flexion to full extension, measuring tension across the BR-FPL repair at each angle. Subsequently, the BR-FPL tendon constructs were removed and elongated to failure. RESULTS: Over a wide wrist and elbow range of motion, BR-FPL tendon tension was under 20 N. Two-way analysis of variance with repeated measures revealed a significant effect of wrist joint angle (p<.001) and elbow joint angle (p<.001) with significant interaction between elbow and joint angles (p<.001). Because the failure load of the repair site was 203 +/- 19 N, over 10 times the loads that would be expected to occur at the repair site, our results demonstrate that the repair has a safety factor of at least 10. CONCLUSIONS: Our tendon force measurements support the assertion that the elbow joint need not be immobilized when the BR is used as a donor muscle in tendon transfer to the FPL. This is based on the fact that maximum passive tendon tension was only about 20 N in our cadaveric model and the failure strength of this specific repair was over 200 N. We suggest that it is possible to consider performing multiple tendon transfers in a single stage, avoiding immobilization, which may adversely affect functional recovery. These results must be qualified by the fact that issues unique to living tissues such as postoperative edema and tendon gliding cannot be accounted for by this cadaveric model. PMID- 20709466 TI - Distraction arthrolysis using an external fixator and flexor tenolysis for proximal interphalangeal joint extension contracture after severe crush injury. AB - PURPOSE: To introduce a technique for distraction arthrolysis with an external fixator followed by flexor tendon tenolysis for extension contracture of the proximal interphalangeal (PIP) joint after severe crush injury. We also assessed the results of this method in all patients treated. METHODS: Five fingers of 4 men with extension contracture of the PIP joint after severe injury underwent distraction arthrolysis using an external fixator, followed by flexor tenolysis. On the day of attaching the external fixator, moderate distraction was applied to the joint and the gap was widened to approximately 2 mm. From the following day onward, the PIP joint was gradually widened for 10 days until a gap of about 5 mm was attained. After sustaining this amount of distraction for 3 or 4 days, the fixator was removed. Passive range of motion was performed for about one week until swelling of the affected digit subsided. Then, flexor tenolysis was performed. Patients were follow-up for an average of 31 months after surgery. RESULTS: After tenolysis, the average improvement of active range of motion was 20 degrees, average gain of active flexion was 41 degrees, and average loss of active extension was 21 degrees. The average range of active motion was from 6 degrees to 38 degrees preoperatively, and from 27 degrees to 79 degrees postoperatively. The average median of active motion was 22 degrees preoperatively, and 52 degrees postoperatively. In all fingers, there was no significant difference in the total arc of active motion preoperatively and postoperatively, but there was a significant difference between preoperative and postoperative maximum active flexion. In all patients, painless motion was maintained and arthritic changes of the PIP joint did not worsen during the follow-up period. CONCLUSIONS: Distraction arthrolysis with an external fixator followed by flexor tenolysis was a useful treatment for our patients with extension contracture of the PIP joint and tendon adhesions after severe crush injury. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20709467 TI - Staged description of the Finkelstein test. AB - We have revisited the original description of the Finkelstein test and review the reasons for its subsequent erroneous description. We have also outlined a staged description of this test, which we have found to be reliable and minimally painful for the diagnosis of de Quervain's tendonitis within our clinical practice. PMID- 20709468 TI - Intra-articular fracture of the distal radius: arthroscopic-assisted reduction. PMID- 20709469 TI - Current issues in the physician-patient relationship. AB - This review is one of a series of articles reflecting the sections of the Code of Ethics of the American Society for Surgery of the Hand. The physician-patient relationship has been subjected to numerous stressors over the past several decades. This report reviews historical elements of the relationship and discusses current issues related to it: asymmetry, challenges to the physician, and interpersonal, systemic, and societal challenges. PMID- 20709470 TI - The influence of heroin abuse on glutathione-dependent enzymes in human brain. AB - Heroin is an illicit narcotic abused by millions of people worldwide. In our earlier studies we have shown that heroin intoxication changes the antioxidant status in human brain. In the present work we continued our studies by estimating the effect of heroin abuse on reduced glutathione (GSH) and enzymes related to this cofactor, such as glutathione S-transferase detoxifying electrophilics (GST) and organic peroxides (as Se-independent glutathione peroxidase-GSHPx), and Se dependent glutathione peroxidase (Se-GSHPx) specific mainly for hydrogen peroxide. Studies were conducted on human brains obtained from autopsy of 9 heroin abusers and 8 controls. The level of GSH and the activity of glutathione related enzymes were determined spectrophotometrically. The expression of GST pi on mRNA and protein level was studied by RT-PCR and Western blotting, respectively. The results indicated significant increase of GST and GSHPx activities, unchanged Se-GSHPx activity, and decreased level of GSH in frontal, temporal, parietal and occipital cortex, brain stem, hippocampus, and white matter of heroin abusers. GST pi expression was increased on both mRNA and protein levels, however the increase was lower in brain stem than in other regions. Heroin affects all regions of human brain, and especially brain stem. Its intoxication leads to an increase of organic rather then inorganic peroxides in various brain regions. Glutathione S-transferase plays an important role during heroin intoxication, however its protective effect is lower in brain stem than in brain cortex or hippocampus. PMID- 20709471 TI - Detection of duck circovirus in China: A proposal on genotype classification. AB - Since the first description of duck circovirus (DuCV)-associated disease, there are several reports about the distribution of the disease. However, the information regarding the genetic variation of DuCV in recent years is unclear. In the present study, the complete genomic sequences of 9 DuCV strains, which were obtained by PCR screening from 90 dead or diseased ducks collected from different regions in China between 2008 and 2010, were determined and compared with previously available DuCV sequences in public databases. Phylogenetic analysis on the basis of genomic and ORF C1 sequences demonstrated that the DuCV strains could be divided into two genotypes, designated genotypes 1 and 2. In pairwise comparisons of complete genomic sequences and ORF C1 nucleotide and amino acid sequences, DuCVs of the same genotype were clearly distinguished from those of heterologous genotypes. Analysis of the amino acid sequences of the capsid protein exhibited the existence of 18 genotype-specific substitutions. Our analysis also showed that genotypes 1 and 2 were co-circulating in China in recent years. The present work contributes to the understanding of DuCV molecular epidemiology. PMID- 20709472 TI - Epidemiology of Pestivirus infection in wild ungulates of the French South Alps. AB - Inter-species transmission is often incriminated in the epidemiology of Pestivirus diseases. The purpose of this study was to investigate the prevalence of Pestivirus in some mountain wild ungulates and to determine their role in Pestivirus transmission, as mountain pastures are a place where cohabitations between wild and domestic ungulates are particularly high. Between 2003 and 2007, a longitudinal epidemiological study was carried out on hunted ungulates in the French Hautes-Alpes department. Pestivirus-specific antibodies against p80 protein (also named NS3) common to all Bovine Viral Diarrhea Virus (BVDV) and Border Disease Virus (BDV) were found in 45.9% (95% confidence interval [CI95%]: 40.5-51.3%) of the 343 tested chamois (Rupicapra rupicapra). In addition, mouflons (Ovis gmelinii musimon) were shown for the first time to be strongly infected (61.1%; CI95%: 38.6-83.6) by a Pestivirus. These serological ELISA results were confirmed by comparative virus neutralization tests, performed on seven Pestivirus strains by using 15 seropositive samples. The highest antibody titers were directed against 2 BDV strains (Av and 33s strains), rather than BDV 4, a strain responsible for Pyrenean-chamois epizooties. Virus neutralization tests confirm a BDV circulation in wild ungulates in the French South Alps. However, no Pestivirus RNA was detected by reverse-transcriptase polymerase chain reaction in serum and spleen samples from seronegative animals and no virus was isolated from those samples either. Efforts should be made to improve the protocol in order to be able to isolate and characterize the local strain. Finally, the oldness (age) and femaleness (gender) increase the risk of seroconversion in chamois. PMID- 20709473 TI - Computerized fetal heart rate monitoring after vibroacoustic stimulation in the anencephalic fetus. AB - BACKGROUND: To quantify changes in fetal heart rate (FHR) parameters after vibroacoustic stimulation (VAS) and to evaluate the usefulness of VAS testing (VAST) in anencephalic fetuses. Our findings may also help to clarify the route(s) of vibration and sound transmission during VAST. STUDY DESIGN AND SUBJECTS: We obtained the antepartum FHR tracings of 16 anencephalic fetuses, including both the nonstress test (NST) and VAST. Using a computerized monitoring system, HYFM, we determined all FHR parameters from data collected for 10 min before and 10 min after VAS, at successive gestational stages. RESULTS: We observed three false reactive responses at term. The false reactive rate for VAST (3/16) was higher than that for NST (1/16). No FHR parameters increased significantly after VAS except for the number of fetal movements (FM), which increased significantly in all gestational groups (25th-32nd and 33rd-40th weeks). CONCLUSIONS: These findings call attention to an increased probability of a false reactive response in VAST analysis, when the fetus is affected by a CNS disorder. Increased numbers of FM after VAS suggest that the vibratory pathway is more likely to elicit fetal response than the auditory pathway in this setting, and that the vibratory stimulation travels by subcortical rather than by cortical pathways. PMID- 20709474 TI - Motor trajectories from 4 to 18 months corrected age in infants born at less than 30 weeks of gestation. AB - BACKGROUND: Preterm infants are recognised as developing at a significantly slower rate than their full-term peers and with different movement quality. AIM: This study aimed to describe the longitudinal gross motor trajectories of these infants in the first 18 months of (corrected) age and investigate factors associated with gross motor development. STUDY DESIGN: A longitudinal study was conducted with convenience samples of 58 preterm infants born < or = 29 weeks of gestation and 52 control full-term infants in Australia. OUTCOME MEASURES: The infants were assessed at 4, 8, 12 and 18 months of (corrected) age using the Alberta Infant Motor Scale (AIMS). RESULTS: Forty-six preterm and 48 control infants completed all four assessments. The preterm group scored significantly lower on various sub-scores at all age levels. Almost half of the preterm infants demonstrated less progression in the sit sub-scale from 4 to 8 months (corrected) age, possibly due to an imbalance between flexor and extensor strength in the trunk. At 12 and 18 months of (corrected) age, lack of rotation and fluency in their movements were evident in some preterm infants. Presence of intra ventricular haemorrhage and chronic lung disease were associated with poor motor performance at 4 months and use of postnatal steroids was associated with poor motor performance at 4, 8 and 18 months of corrected age. CONCLUSION: The imbalance between flexor and extensor muscle strength in preterm infants had a stronger impact on motor development than usually expected. The AIMS appears to be a sensitive assessment tool to demonstrate the unique movement characteristics in this preterm cohort. PMID- 20709475 TI - Maternal sensitivity moderates the impact of prenatal anxiety disorder on infant mental development. AB - BACKGROUND: Animal studies have shown that postnatal rearing style can modify the association between prenatal stress exposure and offspring neurodevelopmental outcomes. However, little is known about how parenting quality impacts the association between maternal prenatal anxiety and development in human infants. AIM: This prospective study examined the impact of maternal prenatal anxiety disorder and maternal caregiving sensitivity on cognitive and psychomotor development in healthy, full-term, 7-month-old infants. MEASURES: Women completed a clinical interview during the third trimester of pregnancy to assess anxiety symptoms meeting DSM-IV diagnostic criteria. At infant age 7 months, maternal sensitivity to infant distress and non-distress were observed and coded during the still-face procedure. Maternal postnatal (concurrent) anxiety and depression were also assessed at this time. Infant mental and psychomotor development was assessed at infant age 7 months using the Bayley Scales of Infant Development II. RESULTS: Analyses were based on 77 mother-infant dyads. Maternal sensitivity to infant distress moderated the association between maternal prenatal anxiety disorder and infant mental development, F (1, 77)=5.70, p=.02. Whereas there was a significant positive association between sensitivity and mental development among infants whose mothers were anxious during pregnancy, sensitivity had little impact on mental development among infants of control (non-anxious) women. Results were independent of prenatal depression and postnatal anxiety and depression. A caregiving moderation effect was not found for infant psychomotor development, p>.10. CONCLUSIONS: These findings are consistent with a cumulative risk model suggesting that maternal prenatal anxiety and quality of maternal care act in concert to shape infant outcomes. PMID- 20709476 TI - Effects of antioxidants on boar spermatozoa during sorting and storage. AB - Sorting procedures submit sperm cells to a set of stressful steps that can trigger an increase of ROS production and consequently reduce sorted semen quality. This study evaluated the effect of supplementation with different antioxidants (EGCG, Na pyruvate+catalase, SOD) on acrosome and plasma membrane integrity, activation of caspases (as assayed by FITC-VAD/PI staining) and immunolocalization of Hsp70 of boar spermatozoa after sperm preparation (Hoechst 33342 staining) and sorting procedure. The effect of antioxidants, with or without seminal plasma, on sorted spermatozoa stored for 24h at 15 degrees C was also evaluated. Antioxidants did not exert any preventive action on sperm modification induced by staining and sorting. After 24h of storage at 15 degrees C, sorted samples supplemented with either EGCG or SOD plus seminal plasma showed a significant (p<0.05) increase of the percentage of viable spermatozoa, while no positive effect on the other tested parameters was observed; EGCG seems to exert an inhibition on caspase activation in that a decrease of the number of dead cells FITC-VAD+/PI+ was recorded. In conclusion, our results indicate that EGCG and SOD in association with seminal plasma are effective in exerting some compensatory protection against the detrimental effects of storage of sorted semen while their action is not evident during steps of the sorting procedure. PMID- 20709478 TI - Improving low-dose abdominal CT images by Weighted Intensity Averaging over Large scale Neighborhoods. AB - PURPOSE: Though highly desirable in radiologic procedures, low-dose CT (LDCT) images tend to be severely degraded by quantum noise and non-stationary artifacts. The purpose of this paper is to improve the abdominal LDCT images by the approach of Weighted Intensity Averaging over Large-scale Neighborhoods (WIA LN). MATERIALS AND METHODS: In the implementation of the proposed WIA-LN method, the processed pixel intensities are adaptively calculated as the weighted intensity averaging of the pixels with similar surrounding structures throughout a large-scale neighborhood. Both phantom and clinical abdominal CT images from a 16 detector rows Siemens CT were acquired at standard and 80% reduced tube current time products (150 mAs and 30 mAs corresponding to standard-dose and low dose protocols, respectively). Visual comparison, statistical qualitative analysis (image quality scores and hepatic cyst diagnosis), and quantitative calculation (noise and contrast-to-noise ratio) are made. RESULTS: Better vision and quantitative performance are realized using the proposed WIA-LN method. Compared to original LDCT and standard-dose CT (SDCT) images, statistically significant improvement of noise/artifacts suppression, contrast preservation and hepatic cyst detection in LDCT images are achieved by using the proposed method (P<0.05). CONCLUSION: With the tube current reduced to approximate one-fifth of the standard tube current setting, clinically acceptable images can still be obtained by using the proposed method. PMID- 20709477 TI - Pharmacogenetics in palliative care. AB - Response to analgesics, anticancer pharmacotherapy and pharmacotherapy of other cancer related symptoms vary broadly between individuals. Age, disease, comorbidities, concomitant medication, organ function and patients' compliance may partly explain the differences. However, the focus of ongoing research has shifted towards genomic variants of phase I and II drug metabolizing enzymes with one important goal being an individual dose adjustment according to a patient's genotype. Polymorphisms of the cytochrome P 450 2D6 influence the metabolism of many drugs including the analgesics codeine, tramadol, hydrocodone and oxycodone, as well as the metabolism of tricyclic antidepressants and the anticancer drug tamoxifen. Other candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy in pain management are discussed. Although pharmacogenetics as a diagnostic tool has the potential to improve patient therapy, study results are often equivocal and limited by small sample sizes and often by their retrospective design. Well designed studies are needed to demonstrate superiority of pharmoacogenetics to conventional dosing regimes. PMID- 20709479 TI - Background enhancement in breast MR: correlation with breast density in mammography and background echotexture in ultrasound. AB - OBJECTIVE: This study aimed to determine whether background enhancement on MR was related to mammographic breast density or ultrasonographic background echotexture in premenopausal and postmenopausal women. MATERIALS AND METHODS: We studied 142 patients (79 premenopausal, 63 postmenopausal) who underwent mammography, ultrasonography, and breast MR. We reviewed the mammography for overall breast density of the contralateral normal breast according to the four-point scale of the BI-RADS classification. Ultrasound findings were classified as homogeneous or heterogeneous background echotexture according to the BI-RADS lexicon. We rated background enhancement on a contralateral breast MR into four categories based on subtraction images: absent, mild, moderate, and marked. All imaging findings were interpreted independently by two readers without knowledge of menstrual status, imaging findings of other modalities. RESULTS: There were significant differences between the premenopausal and postmenopausal group in distribution of mammographic breast density, ultrasonographic background echotexture, and degree of background enhancement. Regarding the relationship between mammographic density and background enhancement, there was no significant correlation. There was significant relationship between ultrasonographic background echotexture and background enhancement in both premenopausal and postmenopausal groups. CONCLUSION: There is a significant correlation between ultrasonographic background echotexture and background enhancement in MR regardless of menopausal status. Interpreting breast MR, or scheduling for breast MR of women showing heterogeneous background echotexture needs more caution. PMID- 20709481 TI - Outcomes in open repair of the thoracic and thoracoabdominal aorta. PMID- 20709480 TI - Outcomes of planned celiac artery coverage during TEVAR. AB - OBJECTIVE: Successful thoracic endovascular aneurysm repair (TEVAR) requires adequate proximal and distal fixation and seal. We report our experience of planned celiac artery coverage during endovascular repair of complex thoracic aortic aneurysms (TAA). METHODS: Since 2004, 228 patients underwent TEVAR under elective (n=162, 71%) and emergent circumstances (66, 29%). Patients with inadequate distal stent grafts landing zones during TEVAR underwent detailed evaluation of the gastroduodenal arcade with communicating collaterals between the celiac and superior mesenteric artery (SMA) by computed tomography angiography and intraoperative arteriogram. If needed, in presence of a patent SMA and demonstration of collaterals to the celiac artery, the stent grafts were extended to the SMA with celiac artery coverage. Furthermore, instances when further lengthening of distal thoracic stent graft landing zone was needed to obtain an adequate seal, the SMA was partially covered with the endograft, and a balloon expandable stent was routinely deployed in proximal SMA to maintain patency. Outcome data were prospectively collected and analyzed retrospectively. RESULTS: Thirty-one of 228 (14%) patients with TEVAR required celiac artery interruption; 24 (77%) had demonstrable collaterals to the SMA. Twelve (39%) of 31 patients underwent additional partial SMA coverage by stent graft, and proximal SMA stent. The majority of patients were females (n=20, 65%), the mean age was 74 years (range 55-87 years), and the mean TAA size was 6.5 cm. Postoperative complications included visceral ischemia in 2 (6%) patients, paraplegia in 2 (6%) patients, and death in 2 (6%) patients. All type 1b endoleaks (n=2, 6%) and type 2 endoleaks vial retrograde flow from the celiac artery (n=3, 10%) were successfully treated by transfemoral coil embolization. Over a mean follow-up of 15 months, there have been no other complications of mesenteric ischemia, spinal cord ischemia, SMA in-stent stenosis, or conversion to open surgical repair. CONCLUSIONS: Our findings suggest that celiac artery coverage to facilitate adequate distal sealing during TEVAR with complex TAA is relatively safe in the presence of SMA-celiac collaterals. Pre-existing SMA stenosis can be successfully treated by balloon expandable stents during TEVAR, and endoleaks arising from distal stent grafts attachment site or via retrograde flow from the celiac artery can be successfully managed by transfemoral coil embolization. Although early results are encouraging, long-term efficacy of these procedures remains to be determined and vigilant follow-up is needed. PMID- 20709483 TI - Staged total exclusion of the aorta for chronic type B aortic dissection. AB - Hybrid techniques using extra-anatomic bypass of critical aortic branches to enable endovascular treatment of complex aortic pathology have been previously described. A staged endograft repair of a complex, chronic Stanford type B aortic dissection with aneurysmal degeneration is reported in a 50-year-old man. The aneurysmal portion of the dissection extended from the distal arch to both common iliac arteries and was covered with an endograft from the ascending aorta to both external iliac arteries. Aortic arch branches, visceral, and renal arteries were bypassed using open technique. The patient had no neurologic complications. This case report illustrates the feasibility of the hybrid technique in selected high risk patients when confronted with complex aortic pathology. PMID- 20709482 TI - Finnvasc score and modified Prevent III score predict long-term outcome after infrainguinal surgical and endovascular revascularization for critical limb ischemia. AB - BACKGROUND: Estimation of the risk of adverse long-term outcome is of paramount importance in the treatment of critical limb ischemia (CLI). METHODS: We evaluated the accuracy of two specific risk score systems, the Finnvasc score and the modified Prevent III (mPIII) score, in 1425 CLI patients who underwent unilateral, infrainguinal surgical (47.6%) or endovascular (52.4%) revascularization. The receiver operating characteristic (ROC) curve analysis was used to estimate the predictive value of these risk scoring methods. RESULTS: The area under the ROC curve of Finnvasc score for prediction of 30-day amputation was 0.609 (95% confidence interval [CI] 0.549-0.677) and of mPIII score 0.533 (95% CI 0.457-0.609). The area under ROC curve of Finnvasc score for prediction of 30-day amputation-free survival was 0.622 (95% CI 0.573-0.671) and of mPIII score 0.588 (95% CI 0.533-0.642). The area under the ROC curve of Finnvasc score for prediction of 1-year amputation-free survival was 0.630 (95% CI 0.597-0.663, P<.0001) and of mPIII score 0.634 (95% CI 0.600-0.667, P<.0001). Finnvasc score predicted leg salvage (relative risk [RR] 1.431, 95% CI 1.319-1.551), survival (RR 1.233, 95% CI 1.116-1.363), and amputation-free survival (RR 1.422, 95% CI 1.319-1.534). mPIII score also predicted leg salvage (RR 1.190, 95% CI 1.108 1.277), survival (RR 1.245, 95% CI 1.193-1.300), and amputation-free survival (RR 1.223, 95% CI 1.176-1.272). CONCLUSIONS: Finnvasc and modified PIII risk scoring methods predict long-term outcome of patients undergoing infrainguinal revascularization for CLI. Finnvasc score seems to perform well also in predicting immediate postoperative outcome. PMID- 20709484 TI - Conduits and endoconduits, percutaneous access. PMID- 20709485 TI - Preoperative cytological and histological diagnosis of breast lesions: A critical review. AB - BACKGROUND: Non-operative pathology diagnoses constitute an essential part of the work-up of breast lesions. With fine needle aspiration (FNA) and core needle biopsy (CNB) both having unique advantages, there is an increasing acceptance of CNB. This paper aims to outline the scientific basis of this trend. Additionally, we provide an update on novel techniques that derive cytological specimens from CNB (i.e., touch imprint (TI) and core wash (CW) cytology) in an attempt to get the best of both worlds. METHODS: In addition to using the authors' experience, we performed a search of the Medline database combining the search terms "breast cancer diagnosis", "core needle biopsy", "fine needle aspiration", "touch imprint cytology", "core wash cytology" and "complications". We defined a conclusive non operative diagnosis as "malignant" in lesions that were malignant on follow-up and "benign" in lesions that were benign on follow-up. RESULTS: CNB was more often conclusive than FNA in benign and malignant lesions in 4 prospective studies. Although the more rapid diagnoses by FNA result in less patient anxiety during diagnostic work-up, CNB allows for fairly reliable estimation of invasion, histological type, grade, and receptor expression. CW and TI cytology seem promising techniques with conclusiveness rates that are roughly comparable to that of FNA. CONCLUSIONS: All new suspicious breast lesions require careful non operative investigation by CNB. However, additional cytological assessment by FNA can still be useful as a same-day diagnosis decreases patient anxiety and facilitates surgical treatment planning. TI and CW cytology techniques are promising same-day diagnosis modalities. PMID- 20709486 TI - [Haemodynamic effects of intralipid after local anaesthetics intoxication may be due to a direct effect of fatty acids on myocardial voltage-dependent calcium channels]. PMID- 20709487 TI - [Massive thromboembolism complications associated with transient lupic anticoagulant acquired after traumatic brain injury]. PMID- 20709488 TI - [Pulmonary embolism due to rupture of an hepatic hydatid cyst]. PMID- 20709489 TI - [Ultrasound-guided supraclavicular subclavian vein catheterization: a novel approach in children]. AB - The subclavian vein (SCV) is often the preferred site for long-term central venous catheterization in children. It has many advantages over the internal jugular vein. But with the classical landmark technique for SCV catheterization the ultrasound-guidance technique is usually not suitable, because of the clavicle (a bright hyperechoic structure with an acoustic shadow beneath it). Because the SCV can easily be visualized via a supraclavicular approach, we developed a useful ultrasound-guided approach for SCV catheterization in infants and children. PMID- 20709490 TI - Anaesthetic management for caesarean section in a parturient with uncorrected coarctation of the aorta. AB - We present the case of a woman who refused RMI examination to diagnose a coarctation of her aorta before her third pregnancy. At term of 34 weeks of gestation the caesarean delivery was scheduled under spinal-epidural anaesthesia. Despite the use of a titrated regional anaesthesia, an important arterial hypotension occurred, restored with low doses of vasopressive agents. PMID- 20709491 TI - Traumatic rupture of the abdominal aorta after spinal fracture from low fall. PMID- 20709492 TI - The efficacy and psychophysiological correlates of dual-attention tasks in eye movement desensitization and reprocessing (EMDR). AB - This study aimed to investigate the psychophysiological correlates and the effectiveness of different dual-attention tasks used during eye movement desensitization and reprocessing (EMDR). Sixty-two non-clinical participants with negative autobiographical memories received a single session of EMDR without eye movements, or EMDR that included eye movements of either varied or fixed rate of speed. Subjective units of distress and vividness of the memory were recorded at pre-treatment, post-treatment, and 1 week follow-up. EMDR-with eye movements led to greater reduction in distress than EMDR-without eye movements. Heart rate decreased significantly when eye movements began; skin conductance decreased during eye movement sets; heart rate variability and respiration rate increased significantly as eye movements continued; and orienting responses were more frequent in the eye movement than no-eye movement condition at the start of exposure. Findings indicate that the eye movement component in EMDR is beneficial, and is coupled with distinct psychophysiological changes that may aid in processing negative memories. PMID- 20709493 TI - Examining the relation between posttraumatic stress disorder and suicidal ideation in an OEF/OIF veteran sample. AB - This study examined the relation between posttraumatic stress disorder (PTSD) and suicidal ideation among U.S. military veterans deployed during Operation Enduring Freedom and/or Operation Iraqi Freedom. Specific aims included investigation of (1) whether PTSD was associated with suicidal ideation after controlling for combat exposure and history of suicide attempt(s), (2) whether PTSD was associated with suicidal ideation absent a co-occurring depressive disorder (MDD) or alcohol use disorder (AUD), (3) whether co-occurring MDD or AUD increased risk of suicidal ideation among those with PTSD and (4) whether PTSD/MDD symptom clusters were differentially associated with suicidal ideation. Results pointed to unique effects associated with prior suicide attempt(s), PTSD and MDD. PTSD diagnosed participants with co-occurring MDD or AUD were not significantly more likely to endorse suicidal ideation than PTSD-diagnosed participants without such comorbidity. The 'emotional numbing' cluster of PTSD symptoms and the 'cognitive affective' cluster of MDD symptoms were uniquely associated with suicidal ideation. PMID- 20709495 TI - An adaptive wavelet neural network for spatio-temporal system identification. AB - Starting from the basic concept of coupled map lattices, a new family of adaptive wavelet neural networks (AWNN) is introduced for spatio-temporal system identification, by combining an efficient wavelet representation with a coupled map lattice model. A new orthogonal projection pursuit (OPP) method, coupled with a particle swarm optimization (PSO) algorithm, is proposed for augmenting the proposed network. A novel two-stage hybrid training scheme is developed for constructing a parsimonious network model. In the first stage, by applying the orthogonal projection pursuit algorithm, significant wavelet neurons are adaptively and successively recruited into the network, where adjustable parameters of the associated wavelet neurons are optimized using a particle swarm optimizer. The resultant network model, obtained in the first stage, may however be redundant. In the second stage, an orthogonal least squares algorithm is then applied to refine and improve the initially trained network by removing redundant wavelet neurons from the network. The proposed two-stage hybrid training procedure can generally produce a parsimonious network model, where a ranked list of wavelet neurons, according to the capability of each neuron to represent the total variance in the system output signal is produced. Two spatio-temporal system identification examples are presented to demonstrate the performance of the proposed new modelling framework. PMID- 20709494 TI - Domestic violence against people with disabilities: prevalence and trend analyses. AB - The present study analyzed national data from "Domestic Violence Report System" derived primarily from the Council of Domestic Violence and Sexual Assaults Prevention, Ministry of the Interior, Taiwan, to describe the reported prevalence of domestic violence in people with disabilities and to examine the time-effect on the prevalence from years 2006 to 2009. The annual reported prevalence of domestic violence victims in people with disabilities was slightly lower than the general population. However, the reported rate changed significantly in people with disabilities over the period of 2006-2009, the victim number and rate (per ten-thousand) of reported cases in different years were 1260 (12.84), 1725 (16.90), 2163 (20.79) and 3157 (29.48). People with voice or speech disability, chronic psychosis and intellectual disability were the most domestic violence reported prevalence among the disabilities in the study. Those disabilities, such as chronic psychosis, intellectual disability, vision disability, hearing disability and multi-disabilities show increased significantly in annual reported rate in curve estimation for linear model over the period of 2006-2009. Finally, we found the average increase rate of annual reported prevalence in people of disabilities was 3.7 times of the general population (9.79% vs. 36.08%). Intellectual disability (41.52%), vision or speech disability (38.59%) and chronic psychosis (37.96%) were the most increasing disability type in average of annual reported prevalence of domestic violence among disabilities during the period of 2006-2009. The present study suggests health and welfare authorities should play vital roles in identifying and providing appropriate services for people with disabilities who encounter domestic violence. PMID- 20709496 TI - Haemophilic pseudotumour of the mandible in a 5-year-old patient. AB - A haemophilic pseudotumour was identified in the mandible of a 5-year-old male with severe haemophilia A. The patient initially experienced painless swelling of the mandible. Computed tomography revealed a marked enlargement of the lower right mandibular border, which was associated with a low-density area, and irregular absorption of the lingual cortex bone. A malignant tumour was suspected, and a biopsy was performed after the administration of coagulation factor (Factor VII). A histopathologic diagnosis of haemophilic pseudotumour was made and the patient subsequently underwent surgical treatment. A cavity was created in the multilocular bone cyst and surgical curettage and irrigation were performed with the same haemorrhagic control as in the biopsy procedure. The multilocular cyst was contained within a haematoma and was surrounded by thin granular tissue. Three years after surgery, no abnormal signs have been detected by radiography during follow-up examinations. This case involved a rare haemophilic pseudotumour located in the mandible; the pathogenetic mechanism was attributed to pressure necrosis due to intraosseous bleeding. PMID- 20709497 TI - Friend leukaemia insertion (Fli)-1 is a prediction marker candidate for radiotherapy resistant oral squamous cell carcinoma. AB - Radiotherapy is commonly used to treat oral squamous cell carcinoma (OSCC), but its therapeutic effects are unpredictable. To determine which genes correlate with radiation resistance in oral cancer, the authors evaluated radiation sensitivity using a standard colony formation assay with a gene microarray system for seven OSCC cell lines. They found significant associations between dozens of gene-expression levels and radiation resistance of OSCC cell lines. Following analysis of the different radiosensitive cancer cell lines, the friend leukaemia insertion (Fli)-1 gene was selected as a prediction marker gene for OSCC radiotherapy resistance. Fli-1 expression was associated with radiation resistance in OSCC patients. These data help to predict the effects radiation therapy has on OSCC, in turn contributing to the development of alternative radiation therapies. PMID- 20709498 TI - Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure. AB - BACKGROUND: Nicorandil injection, a potent vasodilator with K(ATP) channel opening action and nitrate-like action, has been used for treatment of unstable angina. In the present investigation, we examined the effect of intravenous nicorandil on hemodynamics in patients with acute decompensated heart failure (ADHF). METHODS: ADHF patients admitted to hospital with pulmonary artery wedge pressure (PAWP)>=18 mm Hg were enrolled. Patients received nicorandil by an intravenous bolus injection of 0.2mg/kg/5 min followed by continuous infusion at a rate of 0.05, 0.10, or 0.20mg/kg/h for 6h. RESULTS: Nicorandil administration caused a significant decrease in PAWP and increase in the cardiac index (CI) that began immediately after the injection and were maintained during the continuous infusion. After 6h, nicorandil administration at 0.2mg/kg/5 min followed by 0.20mg/kg/h resulted in a decrease in PAWP (26.5%, p<0.01), an increase in CI (15.8%, p<0.05), and a decrease in total peripheral resistance (13.8%, p<0.01) in a dose-dependent manner. Nicorandil decreased blood pressure significantly, without an excessive decrease or negative impact even in patients with lower systolic blood pressure. CONCLUSION: Intravenous administration of nicorandil, by bolus injection followed by continuous infusion, improves PAWP and CI in ADHF patients immediately and continuously as a potent vasodilator with combined preload and afterload reduction. These results demonstrate that nicorandil is a safe and effective new medication for the treatment of ADHF. PMID- 20709499 TI - Impact of myocardial perfusion abnormality on prognosis in patients with non ischemic dilated cardiomyopathy. AB - BACKGROUND: Myocardial perfusion imaging shows various patterns in patients with non-ischemic dilated cardiomyopathy (DCM). However, influences of regional abnormalities of myocardial perfusion or ventricular wall motion on prognosis in DCM patients remains to be clarified. Accordingly, we investigated a relation between myocardial perfusion patterns and long-term prognosis in DCM patients. METHODS AND RESULTS: Sixty-two patients were divided into 2 groups according to patterns of (99m)Tc-Tetrofosmin scintigraphy, i.e. large focal defects (focal) and minimally impaired perfusion or multiple small defects (non-focal). There were no differences between the 2 groups in left ventricular (LV) end-diastolic dimensions (63.4 +/- 9.1 and 63.8.4 +/- 7.5mm, respectively) and LV ejection fraction (30.3 +/- 9.2 and 27.9 +/- 7.8%, respectively), indicating LV systolic dysfunction was comparable between the groups. The focal group had a higher prevalence of brain natriuretic peptide ? 200 ng/dl and plasma norepinephrine ? 500 pg/ml than the non-focal group (p<0.05), and had longer QRS durations (p<0.05). The focal group had non-sustained ventricular tachycardia (VT) (p<0.05) on 24-h electrocardiogram recording and a history of VT/ventricular fibrillation more frequently (p<0.05), and had higher New York Heart Association functional class than the non-focal group (p<0.05). The mortality was significantly higher in the focal group (56.0%) than in the non-focal group (28.6%) and the survival curves revealed worse prognosis in the focal group during a follow-up period of 5.3 +/- 2.8 years. CONCLUSIONS: Non-ischemic DCM patients with focal defects are accompanied by more advanced heart failure and poor prognosis compared to those with minimally impaired perfusion or multiple small defects, despite comparable LV systolic dysfunction. PMID- 20709500 TI - The uncommon causes of status epilepticus: a systematic review. AB - This paper reports the first systematic review of uncommon causes of status epilepticus reported in the literature between 1990 and 2008. Uncommon causes are defined as those not listed in the main epidemiological studies of status epilepticus. 181 causes were identified. These were easily categorised into 5 specific aetiological categories: immunological disorders, mitochondrial disorders, infectious diseases, genetic disorders and drugs/toxins. A sixth category of 'other causes' has also been included. Knowledge of these causes is important for clinical management and treatment, and also for a better understanding of the pathophysiology of status epilepticus. PMID- 20709501 TI - Effects of AEDs on biomarkers in people with epilepsy: CRP, HbA1c and eGFR. AB - The standardised mortality ratio in people with epilepsy is raised to between 2 and 3 compared with the general population. Some biomarker levels, including higher C-reactive protein (CRP), higher glycosylated haemoglobin (HbA1c) and lower estimated glomerular filtration rate (eGFR), are associated with an increase risk of premature mortality. These biomarkers were measured in 125 people with refractory epilepsy to estimate the potential effect of antiepileptic drug (AED) use on these markers. Multiple regression analysis showed that valproate (N=50) use was associated with 55% lower mean CRP concentrations and higher mean eGFR values; and phenytoin (N=32) use with 4% lower mean HbA1c values. These potentially represent health markers improved by AEDs. On the other hand, lamotrigine use (N=48) was associated with 13% lower mean eGFR and this may represent a negative effect on a health marker. These preliminary observations clearly require further controlled studies ideally in people on AED monotherapy. PMID- 20709502 TI - Surface modification with PEG and hirudin for protein resistance and thrombin neutralization in blood contact. AB - In this work, we hypothesize that a surface modified with both polyethylene glycol (PEG) and hirudin may provide a non-fouling, thrombin-neutralizing surface suitable for blood contacting applications. With gold as a model substrate we used two different approaches to the preparation of such a surface: (1) a "direct" method in which PEG was conjugated to hirudin and the conjugate was then immobilized on the gold; (2) a "sequential" method in which PEG was immobilized on the gold and hirudin then attached to the immobilized PEG. The surfaces were characterized by water contact angle, ellipsometry and XPS. The biological properties were investigated by measuring protein adsorption (fibrinogen and thrombin) from buffer and plasma; thrombin inhibition was measured using a chromogenic substrate assay. Hirudin immobilization was found to be more efficient on surfaces prepared by the "direct" method. "Sequential" surfaces, however, despite having a lower density of hirudin, showed greater biological activity (thrombin binding and inhibition). PMID- 20709503 TI - Viscoelastic and fractal characteristics of a supramolecular hydrogel hybridized with clay nanoparticles. AB - The supramolecular hydrogels derived from low-molecular-mass gelators represent a unique class of soft matters and have important potential applications in biomedical fields, separation technology and cosmetic science. However, they suffer usually from weak mechanical and viscoelastic properties. In this work, we carry out the in situ hybridization of clay nanoparticles (Laponite RD) into the supramolecular hydrogel formed from a low-molecular-mass hydrogelator, 2,6-di[N (carboxyethyl carbonyl)amino]pyridine (DAP), and investigate the viscoelastic and structural characteristics of resultant hybrid hydrogel. It was found that a small concentration of Laponite RD could lead to a significant increase in the storage modulus, loss modulus or complex viscosity. Compared with neat DAP hydrogel, the hybrid hydrogel has a greater hydrogel strength and a lower relaxation exponent. In particular, the enhancement of the clay nanoparticles to the viscoelastic properties of the DAP hydrogel is more effective in the case of higher DAP concentration. By relating its macroscopic elastic properties to a scaling fractal model, such a hybrid hydrogel was confirmed to be in the strong link regime and to have a more complex network structure with a higher fractal dimension when compared with neat DAP hydrogel. PMID- 20709504 TI - [Persistent left vena cava in a 2-year-old girl]. PMID- 20709506 TI - [Multifocal inflammatory syndrome after invasive infection due to an M1 strain of Streptococcus pyogenes]. AB - We report on a case of Streptococcus pyogenes invasive disease with toxic shock syndrome due to an M1 strain producing SpeA and SmeZ superantigenic toxins. Post streptococcal sequelae included several episodes of reactive arthritis and orchitis whose outcome was favorable with corticosteroid therapy. Invasive streptococcal infections are increasingly reported and may associate septic, toxinic, and immunological diseases. High-grade systemic inflammation may induce nonsuppurative complications and autoimmune diseases by molecular mimicry. Among them, reactive arthritis has been recognized as a separate entity from acute rheumatic fever and post-streptococcal orchitis has not been described before. Treatment should be quickly started and should be effective on the etiologic agent but also on its toxins due to the severity of the invasive infections associated with the spread of highly virulent bacterial clones and the potential development of multifocal nonsuppurative sequelae. PMID- 20709507 TI - [Granulomatous pulmonary involvement preceding diagnosis of Crohn disease: a pediatric case report]. AB - Crohn disease (CD) is a chronic bowel disorder that may affect many other organs such as the eyes, hepatobiliary system, skin, and joints. Pulmonary involvement in association with CD is a classic but uncommon manifestation. It can be primitive with granulomas or secondary to treatments. We report on the case of a teenager in whom the onset of CD was dominated by respiratory symptoms. Because of this presentation, we also suspected opportunistic infections such as tuberculosis and other granulomatous pulmonary diseases such as sarcoidosis or hypersensitivity pneumonitis. PMID- 20709508 TI - [Characteristics of tuberous sclerosis in children]. AB - Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartic development of many organs, most notably the brain, heart, kidneys, lungs, and skin. This autosomic dominant disorder results from mutations in one of two genes, TSC1 and TSC2, coding for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The clinical presentation is highly variable and most features of tuberous sclerosis become evident only in childhood after the child is several years of age, limiting their usefulness for early diagnosis. The aim of this article is to define the pediatric clinical manifestations of tuberous sclerosis in correlation with patient age. Sometimes, a prenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. However, newborns are most often asymptomatic. In the 1st year, seizures are the most common symptoms, with a high incidence of infantile spasms. In children between 2 and 10 years of age, neurological symptoms are the most frequent with epilepsy, mental retardation, and autism, but extraneurological manifestations can be diagnosed. In adolescents, most features of tuberous sclerosis become evident and renal and pulmonary manifestations must be sought. The knowledge of age-dependent clinical features of tuberous sclerosis can provide an earlier diagnosis and improve the management of these patients with a special role for multidisciplinary consultation. PMID- 20709509 TI - [Seizures and epilepsy: popular thinking and beliefs from antiquity to the 19th century]. PMID- 20709510 TI - [Toe walker]. AB - Toe walking is a frequent situation for a clinic in pediatric orthopedic. It is, in most cases, an idiopathic trouble. Neurologic examination is very important to recognize spastic diplegia or neuromuscular disease. A contracture of the triceps can occur and will require a specific treatment from physiotherapy to surgery. A psychological approach is sometimes necessary. PMID- 20709511 TI - [Methylprednisolone pulse in treatment of childhood chronic inflammatory demyelinating polyneuropathy]. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) in children is rare and treatment is based primarily on intravenous immunoglobulins or oral corticosteroids. Boluses of methylprednisolone (MP) are a possible alternative. We report 3 cases of CIDP in children with good outcome after MP pulse therapy. One male (7 years of age) and 2 females (4 and 5 years of age) presented with recurring episodes of functional impotence of both lower limbs and walking impairment, partially reversible without treatment. Clinical and electrophysiological data and the analysis of the cerebrospinal fluid were compatible with CIDP. MP pulses were administered: the total number of pulses varied from 5 to 8, very satisfactory progression on the clinical and electrophysiological pattern was noted, without recurrence in the 3 cases. Childhood CIDP presents clinical, electrophysiological outcome, and prognostic particularities, recurring readily, and the outcome is good. Boluses of MP are an alternative for treatment of these neuropathies in childhood. PMID- 20709512 TI - [Rationale for the use of extracorporeal photochemotherapy in children]. AB - The management of immune diseases in children remains challenging, although significant advances have been made. In addition to pharmacological approaches, extracorporeal photochemotherapy (ECP) is distinctive in its ability to provide immunomodulation without immune suppression or toxicity. However, in practice, this therapy is not widely used because of logistical issues and the lack of robust clinical pediatric studies. Here, we discuss the potential clinical applications of ECP in children and emphasize the need for a rigorous and specifically pediatric clinical evaluation of ECP. PMID- 20709513 TI - The temporal effect of a wild blueberry (Vaccinium angustifolium)-enriched diet on vasomotor tone in the Sprague-Dawley rat. AB - BACKGROUND AND AIMS: We have previously reported that wild blueberry (Vaccinium angustifolium)-enriched diets (WB) attenuate aortic adrenergic response through endothelial-mediated pathways. The duration of dietary intervention necessary to induce the positive changes on vasomotor tone has not been studied to date. Thus, our objective was to investigate the temporal effect of WB consumption on vascular function and reactivity in Sprague-Dawley (SD) rat aorta after 4 and 7 weeks of dietary treatment. METHODS AND RESULTS: Forty male SD rats were randomly assigned to a control (AIN-93) (C) or a WB diet for 4 or 7 weeks. Vascular ring studies were conducted in 3-mm isolated rat aortic rings to investigate vasoconstriction induced by six doses of the alpha(1)-adrenergic agonist, L phenylephrine (Phe, 10(-8)-3*10(-6) M) alone or in the presence of the NOS inhibitor, L-N(G)-monomethyl-arginine (L-NMMA, 10(-4)M). The maximum force of contraction (F(max)) and vessel sensitivity (pD(2)) were determined. Analysis of variance revealed no significant differences on F(max) after 4 weeks of the WB diet but only a significant increase in pD(2) in the absence of L-NMMA. Seven week WB consumption significantly attenuated contraction in response to L-Phe and resulted in lower pD(2). Inhibition of NOS induced a significant increase in the constrictor response in both diet groups at both time periods, with the WB group fed for 7 weeks having the greater response. CONCLUSION: Thus wild blueberries incorporated into the diet at 8% w/w positively affect vascular smooth muscle contractility and sensitivity but these effects are evident only after 7 weeks of WB consumption. PMID- 20709514 TI - Effects of chronic elevation of atrial natriuretic peptide and free fatty acid levels in the induction of type 2 diabetes mellitus and insulin resistance in patients with mitral valve disease. AB - BACKGROUND AND AIMS: The relationship between atrial natriuretic peptide (ANP), increased free fatty acid (FFA) and insulin resistance in patients with mitral valve disease (MVD), a group characterised by elevated atrial pressure and increased ANP levels, is not defined. The present study was performed to evaluate, in MVD patients, the relationship between increased ANP and FFA levels and insulin resistance and the role of mitral valve replacement/repair in ameliorating these metabolic alterations. Conversely, coronary heart disease (CHD) patients were evaluated before and after coronary artery bypass grafting (CABG), since they are known to be insulin resistant in the presence of chronic FFA increase. METHODS AND RESULTS: Fifty MVD patients and 55 CHD patients were studied before and 2 months after surgery and compared with 166 normal subjects. Before surgery, 56% of MVD patients had impaired glucose tolerance or newly diagnosed type 2 diabetes after a standard oral glucose load and this percentage decreased to 46% after surgery. In CHD, impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetic patients were 67% of patients before and after CABG. In MVD, left atrial (LA) volume, ANP, FFA incremental area and insulin levels were higher and Insulin Sensitivity (IS) index significantly reduced while after surgery, LA volume, ANP and FFA significantly decreased and IS index significantly improved. In CHD, insulin resistance and hyperinsulinaemia were present both before and after surgery with increased tumour necrosis factor (TNF) alpha and interleukin (IL)-6 levels. CONCLUSION: In MVD, a higher degree of abnormal glucose tolerance and insulin resistance are associated to increased levels of ANP and FFA, while these metabolic alterations are improved by mitral valve replacement/repair surgery. Clinical Trial.gov registration number NCT 00520962. PMID- 20709515 TI - Exposure to isoflavone-containing soy products and endothelial function: a Bayesian meta-analysis of randomized controlled trials. AB - BACKGROUND AND AIMS: To determine whether and to what degree exposure to isoflavone-containing soy products affects EF. Endothelial dysfunction has been identified as an independent coronary heart disease risk factor and a strong predictor of long-term cardiovascular morbidity and mortality. Data on the effects of exposure to isoflavone-containing soy products on EF are conflicting. METHODS AND RESULTS: A comprehensive literature search was conducted using the PUBMED database (National Library of Medicine, Bethesda, MD) inclusively through August 21, 2009 on RCTs using the keywords: soy, isoflavone, phytoestrogen, EF, flow mediated vasodilation, and FMD. A Bayesian meta-analysis was conducted to provide a comprehensive account of the effect of isoflavone-containing soy products on EF, as measured by FMD. A total of 17 RCTs were selected as having sufficient data for study inclusion. The overall mean absolute change in FMD (95% Bayesian CI) for isoflavone-containing soy product interventions was 1.15% ( 0.52, 2.75). When the effects of separate interventions were considered, the treatment effect for isolated isoflavones was 1.98% (0.07, 3.97) compared to 0.72% (-1.39, 2.90) for isoflavone-containing soy protein. The models were not improved when considering study-specific effects such as cuff measurement location, prescribed dietary modification, and impaired baseline FMD. CONCLUSIONS: Cumulative evidence from the RCTs included in this meta-analysis indicates that exposure to soy isoflavones can modestly, but significantly, improve EF as measured by FMD. Therefore, exposure to isoflavone supplements may beneficially influence vascular health. PMID- 20709516 TI - Increases in airway eosinophilia and a th1 cytokine during the chronic asymptomatic phase of asthma. AB - BACKGROUND: Studies using allergen challenge models have suggested Th2 cytokines promote airway inflammation in asthma. We assessed mediators of airway inflammation during the chronic asymptomatic phase of asthma. METHODS: Nine non atopic asthma (NAA) patients, 19 atopic asthma (AA) patients, 20 atopic controls (AC), and 38 normal controls (NC) underwent sputum induction while asymptomatic. Sputum total cell counts and differentials were determined; levels of cytokines IL-4, IL-5, IL-13, GM-CSF, and IFN-gamma, and chemokines eotaxin (CCL11) and RANTES (CCL5) were measured by ELISA; and levels of eosinophil-derived neurotoxin (EDN) were measured by radioimmunoassay. RESULTS: NAA patients showed higher % eosinophils and total eosinophils compared to AA. NAA and AA patients showed higher IFN-gamma and EDN levels compared to AC and NC, with no differences in IL 4, IL-5, or IL-13 levels among the four groups. GM-CSF levels were higher in AA patients compared to AC or NC. In NAA, AA, and AC patients, % eosinophils and EDN levels correlated positively with IFN-gamma, GM-CSF, eotaxin, and RANTES, but not with IL-5 levels. CONCLUSIONS: Baseline airway inflammation of intrinsic and extrinsic asthma is characterized by eosinophilic inflammation and the Th1 cytokine, IFN-gamma. GM-CSF, instead of IL-5, and chemokines may coordinate airway eosinophilia during the chronic asymptomatic phase of asthma. PMID- 20709517 TI - Montelukast added to fluticasone propionate does not alter inflammation or outcomes. AB - BACKGROUND: Airway inflammation is a key pathological feature of asthma which underlies its clinical presentation. OBJECTIVES: To examine whether adding a leukotriene modifier to an inhaled corticosteroid produces further clinical and/or anti-inflammatory benefits in patients symptomatic on short-acting beta(2) agonists. METHODS: Patients uncontrolled on short-acting beta(2)-agonists were treated for 12 weeks with either fluticasone propionate (100mcg BD) or fluticasone propionate (100mcg BD) and montelukast (10mg QD) in a randomized, double-blind, parallel group study. Bronchoscopy with endobronchial biopsy and bronchoalveolar lavage (BAL) was performed before and after treatment to compare effects on airway inflammation. RESULTS: Of 103 subjects enrolled, 89 subjects completed treatment and 82 subjects had matched pair biopsy samples. Submucosal eosinophil counts, the primary endpoint, and asthma control improved to similar extents after both treatments (p= 2-year duration), with an AOR (95% CI) of 2.11 (1.51-2.94). Interestingly, a significant higher risk was observed among cases with new-onset DM (<2-year duration), with an AOR of 4.43 (3.44-5.72) compared to controls without DM. In addition, we found a synergistic interaction between cigarette smoking and DM on modifying the risk of pancreatic cancer development (AOR=6.17, 95% CI 3.82-9.94). Similarly, a synergistic interaction between new-onset DM and family history of pancreatic cancer was found for pancreatic cancer risk, with an AOR (95% CI) of 11.04 (2.51-48.53). This study suggested that DM could be both an early manifestation of pancreatic cancer and an aetiologic factor. Possible effect modification on DM by family history of pancreatic cancer and smoking status should be further explored in future aetiologic studies. PMID- 20709529 TI - Elevated LDH predicts poor outcome of recurrent germ cell tumours treated with dose dense chemotherapy. AB - AIMS OF THE STUDY: Prognostic factors for recurrent germ cell tumours (GCTs) treated with dose dense salvage chemotherapy have not been identified. This study determines whether lactate dehydrogenase (LDH) or established prognostic models can predict the outcome of recurrent GCTs treated with dose dense cisplatin-based chemotherapy. PATIENTS AND METHODS: Retrospective analysis of 117 consecutive male patients with a first recurrence of a GCT treated with dose dense chemotherapy at a single cancer centre. Characteristics associated with progression-free survival (PFS) and overall survival (OS) were identified by univariate and multivariate analyses. Prognostic criteria published by the Medical Research Council (MRC) and the Memorial Sloan Kettering Cancer Centre (MSK) were also applied in an attempt to validate them and to compare their performance to that of LDH. RESULTS: Raised LDH was significantly associated with poor PFS (hazard ratio (HR)=3.7; p<0.001) and OS (HR=3.4; p=0.001). Further factors associated with poor PFS and OS, respectively, were failure to achieve a complete response or marker negative partial response for at least 6 months (HR=2.1; p=0.033) and seminoma histology (HR=3.4; p=0.003). The MRC prognostic model, but not the MSK model, identified groups of patients with statistically significant differences in PFS and OS but raised LDH predicted OS and PFS with a higher HR. CONCLUSIONS: Raised LDH is associated with a poor prognosis in recurrent GCTs and outperforms established prognostic models in this setting. LDH as a prognostic factor should be validated prospectively and should also be assessed in patients receiving conventional dose chemotherapy regimens. PMID- 20709530 TI - Pyrolysis kinetics and decomposition characteristics of pine trees. AB - Pine trees comprise over 35% of the forests in Korea, since 1989, pine wilt disease introduced via the Japanese pine sawyer has been infecting many of these trees. As a renewable resource, pine can be converted to bio-oil, gas, and char through pyrolysis. In this study, the pyrolysis characteristics of pine trees were investigated using thermogravimetric analyzer, with most of the materials decomposing between 330 and 370 degrees C at heating rates of 5-20 degrees C/min. The apparent activation energy increased from 145 to 302 kJ mol(-1) with increasing pyrolysis conversion. The kinetics of pine tree pyrolysis were experimentally and mathematically evaluated. The kinetic parameters were determined using nonlinear least-squares regression of the experimental data assuming first-order kinetics. It was found from the kinetic rate constants that the predominant reaction pathway was A (pine) to gas (C(1)-C(4)) rather than A to bio-oil at temperatures of 330-370 degrees C. PMID- 20709531 TI - Enzymatic saccharification of woody biomass micro/nanofibrillated by continuous extrusion process II: effect of hot-compressed water treatment. AB - An extrusion process involving a twin-screw extruder was used for the micro/nanofibrillation of Douglas fir and Eucalyptus treated with hot-compressed water (HCW). Partial removal of hemicellulose and lignin by HCW treatment effectively improved the fibrillation by extrusion. Only HCW treatment produced glucose less than 5 weight percent (wt.%) in Douglas fir in a temperature range of 140-180 degrees C by enzymatic hydrolysis. Glucose production yields of 18 and 26 wt.% were obtained by HCW treatment at 170 and 180 degrees C, respectively, in Eucalyptus. Use of extrusion after HCW treatment drastically improved monosaccharide production yield in both woods. In the case of Douglas fir, the obtained values were 5 times higher than those obtained by HCW treatment alone. Total monosaccharide production yields were higher in Eucalyptus than in Douglas fir. The extruded production had a fine fibrous morphology on a sub micro/nanoscopic scale. This result shows the great potential of the extrusion process after HCW treatment as a cost-effective pretreatment for enzymatic saccharification of woody biomass. PMID- 20709532 TI - Engineered heat treated methanogenic granules: a promising biotechnological approach for extreme thermophilic biohydrogen production. AB - In the present study, two granular systems were compared in terms of hydrogen production rate, stability and bacterial diversity under extreme thermophilic conditions (70 degrees C). Two EGSB reactors were individually inoculated with heat treated methanogenic granules (HTG) and HTG amended with enrichment culture with high capacity of hydrogen production (engineered heat treated methanogenic granules - EHTG), respectively. The reactor inoculated with EHTG (R(EHTG)) attained a maximum production rate of 2.7l H(2)l(-1)day(-1) in steady state. In comparison, the R(HTG) containing the HTG granules was very unstable, with low hydrogen productions and only two peaks of hydrogen (0.8 and 1.5l H(2)l(-1)day( 1)). The presence of active hydrogen producers in the R(EHTG) system during the reactor start-up resulted in the development of an efficient H(2)-producing bacterial community. The results showed that "engineered inocula" where known hydrogen producers are co-inoculated with HTG is an efficient way to start up biohydrogen-producing reactors. PMID- 20709533 TI - A new route for preparation of hydrochars from rice husk. AB - In the present work, a green and sustainable route for preparation of hydrochars from sulfuric acid hydrolysis solution of rice husk under low temperature and atmospheric pressure was described. This route was achieved with the catalysis of sulfuric acid. The sphere-like carbon materials with regular size of about 500 nm were obtained at 95 degrees C for 6h when the acid concentration was 42% and 52%. The morphology of the hydrochars changed with sulfuric acid concentration increased. The surface of the materials contained a large number of functional groups. Furthermore, the localized graphitic nature of the materials was proved by X-ray diffraction pattern. High surface area porous carbons could be prepared from the hydrochars after activation, and they exhibited good electrochemical performance. PMID- 20709534 TI - Putting microbes to work in sequence: recent advances in temperature-phased anaerobic digestion processes. AB - Methane biogas production through anaerobic digestion (or biomethanation) is one of the few technologies that both produce bioenergy and protect the environment. When the focus of anaerobic digestion (AD) is shifted from primarily wastewater treatment to bioenergy production, efficiency and process stability become critical to the economic viability of AD technologies. Temperature-phased anaerobic digestion (TPAD) is a promising process that can significantly enhance both digestion efficiency and process robustness. A TPAD system separates the conventional AD process into two phases, so both phases can be optimized according to their individual functional needs. In the first, thermophilic phase, the often rate-limiting hydrolysis step of polymeric feedstock is accelerated by elevated temperatures, while in the second, mesophilic phase, the fastidious syntrophic acetogens and methanogens are provided with permissive conditions where inhibitions to key guilds (e.g., syntrophic acetogens and methanogens) are attenuated. Although large-scale TPAD systems have not been applied widely, researchers have demonstrated the potential superiority of TPAD systems over single-stage digesters and other AD processes with enhanced VS (volatile solids) and pathogen removal; increased methane yield, process stability, OLR (organic loading rate); shorter HRT (hydraulic retention time); decreased foaming and short-chain fatty acids in effluent. PMID- 20709535 TI - Anaerobic co-digestion of livestock wastes with vegetable processing wastes: a statistical analysis. AB - Anaerobic digestion of livestock wastes with carbon rich residues was studied. Swine manure and poultry litter were selected as livestock waste, and vegetable processing waste was selected as the rich carbon source. A Central Composite Design (CCD) and Response Surface Methodology (RSM) were employed in designing experiments and determine individual and interactive effects over methane production and removal of volatile solids. In the case of swine manure co digestion, an increase in vegetable processing waste resulted in higher volatile solids removal. However, without a proper substrate/biomass ratio, buffer capacity of swine manure was not able to avoid inhibitory effects associated with TVFA accumulation. Regarding co-digestion with poultry litter, substrate concentration determined VS removal achieved, above 80 g VSL(-1), NH(3) inhibition was detected. Statistical analysis allowed us to set initial conditions and parameters to achieve best outputs for real-scale plant operation and/or co-digestion mixtures design. PMID- 20709536 TI - The humic acid analogue antraquinone-2,6-disulfonate (AQDS) serves as an electron shuttle in the electricity-driven microbial dechlorination of trichloroethene to cis-dichloroethene. AB - Quinone moieties in humic substances have previously been shown to serve as extracellular electron acceptors in different metabolic pathways. Here we show that the humic acid analogue antraquinone-2,6-disulfonate (AQDS) can also serve as an electron donor in the microbial reductive dechlorination of TCE to cis-DCE. In a bioelectrochemical system (BES), equipped with a glassy carbon electrode (cathode) polarized at -250mV vs. SHE, electrically reduced AQDS served as the shuttle of electrons between the electrode surface and the dechlorinating bacteria. Interestingly, AQDS selectively stimulated only the first step of the TCE dechlorination sequence, leading to the formation of cis-DCE. Bioelectrochemical experiments carried out using a dechlorinating culture, highly enriched in the cis-DCE dechlorinating microorganism Dehalococcoides spp., confirmed the inability of reduced AQDS to serve as an electron donor for cis-DCE dechlorination. The results of this study have implications for the development of bioelectrochemical systems for groundwater remediation, as well as for the biogeochemical fate of chlorinated solvents in humic substances-rich subsurface environments. PMID- 20709537 TI - Preliminary trials of in situ ammonia stripping from source segregated domestic food waste digestate using biogas: effect of temperature and flow rate. AB - Batch experiments to remove ammonia from food waste digestate were set up, and preliminary runs undertaken. These experiments were based on gas stripping in a heated column reactor; the effects of different temperatures (35, 55 and 70 degrees C) and gas flow rates (0.125, 0.250 and 0.375 L(biogas)L(digestate)( 1)min(-1)) were considered using biogas as the stripping gas. At 35 degrees C, an increase in the ammonia removal rate by approximately 4.5 times was observed when the flow rate increased from 0.125 to 0.375 L(biogas)L(digestate)(-1)min(-1). At 55 degrees C, and flow rates of 0.250 and 0.375 L(biogas)L(digestate)(-1)min(-1), ammonia removal of 3.46 and 9.38%day(-1), respectively, were achieved. The highest values of removal of ammonia were reached at 70 degrees C: 18.4 and 10.4%day(-1), for 0.250 and 0.375 L(biogas)L(digestate)(-1)min(-1) flow rates, respectively. PMID- 20709538 TI - High-rate nitrogen removal by the Anammox process with a sufficient inorganic carbon source. AB - This study focused on high-rate nitrogen removal by the anaerobic ammonium oxidation (Anammox) process with a sufficient inorganic carbon (IC) source. Experiments were carried out in an up-flow column Anammox reactor fed with synthetic inorganic wastewater for 110 days. The IC source was added into the influent tank in the form of bicarbonate. The results confirmed the positive impact of inorganic matter on stimulating Anammox activity. After the addition of sufficient IC, the nitrogen removal rate sharply increased from 5.2 to 11.8 kg Nm(-3)day(-1) within only 32 days. NO(2)-N inhibition was not observed even at NO(2)-N concentrations greater than 460 mgN/L, indicating the enriched Anammox consortium adapted to high NO(2)-N concentrations. The ratio of NO(2)-N removal, NO(3)-N production and NH(4)-N removal for the reactor was correspondingly changed from 1.21:0.21:1 to 1.24:0.18:1. Simultaneously, the sludge volume index of the Anammox granules decreased markedly from 36.8 to 21.5 mL/g, which was attributed to the implementation of proper operational strategy. In addition, DNA analysis revealed that a shift from the KSU-1 strain to the KU2 strain occurred in the Anammox community. PMID- 20709539 TI - Micro-sized microbial fuel cell: a mini-review. AB - This review presents the development of micro-sized microbial fuel cells (including mL-scale and MUL-scale setups), with summarization of their advantageous characteristics, fabrication methods, performances, potential applications and possible future directions. The performance of microbial fuel cells (MFCs) is affected by issues such as mass transport, reaction kinetics and ohmic resistance. These factors are manipulated in micro-sized MFCs using specially allocated electrodes constructed with specified materials having physically or chemically modified surfaces. Both two-chamber and air-breathing cathodes are promising configurations for mL-scale MFCs. However, most of the existing MUL-scale MFCs generate significantly lower volumetric power density compared with their mL-counterparts because of the high internal resistance. Although MUL-scale MFCs have not yet to provide sufficient power for operating conventional equipment, they show great potential in rapid screening of electrochemically microbes and electrode performance. Additional possible applications and future directions are also provided for the development of micro sized MFCs. PMID- 20709540 TI - Dosing of anaerobic granular sludge bioreactors with cobalt: impact of cobalt retention on methanogenic activity. AB - The effect of dosing a metal limited anaerobic sludge blanket (UASB) reactor with a metal pulse on the methanogenic activity of granular sludge has thus far not been successfully modeled. The prediction of this effect is crucial in order to optimize the strategy for metal dosage and to prevent unnecessary losses of resources. This paper describes the relation between the initial immobilization of cobalt in anaerobic granular sludge cobalt dosage into the reactor and the evolution of methanogenic activity during the subsequent weeks. An operationally defined parameter (A0.B0) was found to combine the amount of cobalt immobilized instantaneously upon the pulse (B0) and the amount of cobalt immobilized within the subsequent 24h (A0). In contrast with the individual parameters A0 and B0, the parameter A0.B0 correlated significantly with the methanogenic activity of the sludge during the subsequent 16 or 35 days. This correlation between metal retention and activity evolution is a useful tool to implement trace metal dosing strategies for biofilm-based biotechnological processes. PMID- 20709541 TI - The effect of raw material contamination with mycotoxins on the composition of alcoholic fermentation volatile by-products in raw spirits. AB - The effects of the mycotoxins, aflatoxin B(1), B(2), G(1), G(2) (AF), ochratoxin A, (OTA), zearalenone (ZEA), deoxynivalenol (DON), and fumonisin B(1) (FB(1)) added to corn grain mashes on the composition of fermentation volatile by products in raw spirits were determined. Except for FB(1), the mycotoxins increased acetaldehyde concentration in the obtained spirits from about 30% to 100% in relation to the control set (30.9+/-1.0mg of acetaldehyde/L EtOH). The largest effect was observed for OTA and AF contaminations (65.9+/-5.9 and 62.4+/ 5.0mg/L EtOH, respectively). At the concentrations used (ppb): FB(1), 1875; FB(2), 609; FB(3), 195; DON, 2274; ZEA, 352; AFB(1), 11.65; AFB(2), 12.6; AFG(1), 12.34; AFG(2), 12.04; OTA, 177.5, the mycotoxins did not have a significant effect on the total level of higher alcohols in distillates. As compared to the control, contamination with OTA and FB(1) decreased the 3-methyl-1-butanol concentration by 11.2% and 12.6% respectively, whereas AF decreased the 2-methyl 1-butanol concentration by 14.9%. The mycotoxins AF, ZEA, FB(1), had no significant effect on the concentration of total esters. Whereas OTA caused twofold higher esters concentration in the distillates, DON lowered esters concentration by 32% as compared to control. Presented results show that quantitative changes in composition of volatile fermentation by-products in raw spirits can be related to the presence of increased level of mycotoxins in raw material, especially in the absence of other identifiable factors disturbing the normal course of process. PMID- 20709542 TI - Immobilization of horseradish peroxidase on nanoporous copper and its potential applications. AB - Nanoporous copper (NPC) with a pore size of 100-200 nm was prepared by simply dealloying Al(60)Cu(40) alloy in a 5 wt.% HCl solution. The NPC was characterized by scanning electron microscopy and nitrogen adsorption techniques. Horseradish peroxidase (HRP) was immobilized on NPC by adsorption. Compared with free enzyme, the thermal stability of the immobilized enzyme was greatly improved due to the multiple attachments between the enzyme molecule and the NPC surface. After 2h incubation at 50 degrees C, the immobilized HRP retained ca. 90% of the initial activity while only ca. 10% initial activity remained for the free enzyme. The interaction between HRP and the porous surface also made the K(m) and K(cat) values of the immobilized enzyme increase (from 0.43 to 0.80 mM) and decrease (from 8.1 x 10(3) to 2.2 x 10(3)min(-1)), respectively. Based on the good electric conductivity and electrocatalytic activity of the NPC electrode, an electrochemical biosensor for O-phenylenediamine (OPD) was made. The calibration curve of the biosensor was linear from 0.5 microM to 14.5 microM OPD with a sensitivity of 0.37 microA microM(-1). The stability and reproducibility of the biosensor were also demonstrated to be good. When positioned at -0.45 V for 200 s, its current response toward 10 microM OPD remained ca. 80% of its initial value. For five HRP-loaded NPC electrodes, the relative standard deviation (RSD) of the current response toward 10 microM OPD was ca. 4.5%. All these results indicated that NPC was a good support for the HRP immobilization and its low price would facilitate its large-scale application. PMID- 20709543 TI - Coupling aerobic biodegradation of methanol vapors with heterologous protein expression of endochitinase Ech42 from Trichoderma atroviride in Pichia pastoris. AB - Methanol is included among the most hazardous air pollutants, and an effort of vapors biofiltration by using microbial consortiums has been reported. The aim of this work was to couple the methanol vapors biodegradation with the production of recombinant endochitinase (ech42) from Trichoderma atroviride in Pichia pastoris transformed with the pPIC-ech42 plasmid. After carrying out batch experiments at 0.5% (w/v) of methanol concentration, the recombinant P. pastoris Mut(+) strain was selected because it showed methanol biodegradation rates similar to those of wild type GS115 strain (39 g/m(3)h), but 15% higher than the transformed Mut(S) strain. In addition, the recombinant Ech42 protein production was higher in Mut(+) than Mut(S). After various methanol vapor concentrations were evaluated, the maximum recombinant protein recovery was 317 mg/l and the volumetric methanol consumption rate was 88.7 g/m(3)h at 0.5% (w/v) of methanol concentration. This research underlines the promising application of linking methanol vapors biodegradation with the production of recombinant protein with high biotechnological interests. PMID- 20709544 TI - Synthesis of polyhydroxylated aromatics having amidation of piperazine nitrogen as HIV-1 integrase inhibitor. AB - (E)-N-[3-(4-cinnamoylpiperazin-1-yl)propyl]-3,4-dihydroxybenzamide and (E)-N-[3 (4-cinnamoylpiperazin-1-yl)propyl]-3,4,5-trihydroxybenzamide were designed and synthesized as potential HIV-1 integrase inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, however, corresponding 3,4-dihydroxylated aromatic derivatives appear little inhibition of HIV-1 integrase. PMID- 20709545 TI - Substituted biaryl pyrazoles as sodium channel blockers. AB - Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain. PMID- 20709547 TI - The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors. AB - The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized. PMID- 20709546 TI - Synthesis and evaluation of antimigratory and antiproliferative activities of lipid-linked [13]-macro-dilactones. AB - The biological activities of a family of novel, lipid-linked 13-membered-ring macro-dilactones are reported. These [13]-macro-dilactones were synthesized by diacylation of functionalized diols, followed by ring-closing metathesis under conditions we had previously reported. Antimigratory, cytostatic and cytotoxic activities of the compounds against cancer cells were evaluated. Compound 13 was the most potent in the series, while compound 10 had the broadest concentration range of subtoxic antiproliferative activity. These compounds share common structural components, namely the [13]-macro-dilactone templated by an octyl alpha-glucoside 4,6-diol. PMID- 20709549 TI - 72/74As-labeling of HPMA based polymers for long-term in vivo PET imaging. AB - In the context of molecular imaging, various polymers based on the clinically approved N-(2-hydroxypropyl)-methacrylamide (HPMA) have been radio-labeled using longer-living positron emitters 72As t1/2=26 h or 74As t1/2=17.8 d. This approach may lead to non-invasive determination of the long-term in vivo fate of polymers by PET (positron emission tomography). Presumably, the radio label itself will not strongly influence the polymer structure due to the fact that the used nuclide binds to already existing thiol moieties within the polymer structure. Thus, the use of additional charges or bulky groups can be avoided. PMID- 20709548 TI - Application of a novel in silico high-throughput screen to identify selective inhibitors for protein-protein interactions. AB - Increasing numbers of target protein structures available for computational studies makes the structure-based screening paradigm more attractive for initial hit indentification. We have developed a novel in silico screening methodology incorporating Molecular Mechanics (MM)/implicit solvent methods to evaluate binding free energies and applied this technology to the identification of inhibitors of the TLR4/MD-2 interaction. PMID- 20709550 TI - The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists. AB - A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro cognitive in the novel object recognition rat model of temporal induced memory deficit. PMID- 20709551 TI - Synthesis and structure-activity relationships of sinenxan A derivatives as multidrug resistance reversal agents. AB - Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure-activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity. PMID- 20709553 TI - The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the second clinical candidate having a shorter and favorable human half-life. AB - In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX 2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t(1/2)=360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2)=34 h. PMID- 20709552 TI - Substituted biaryl oxazoles, imidazoles, and thiazoles as sodium channel blockers. AB - Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency. PMID- 20709554 TI - Sedation practice in three Norwegian ICUs: a survey of intensive care nurses' perceptions of personal and unit practice. AB - OBJECTIVES: To describe intensive care nurses' perceptions of unit and personal sedation practice in the context of nursing and medical treatment of adult intensive care patients sedated and ventilated for more than 24 hours. METHODS: Self-administered questionnaire. SETTING: Three general ICUs in three university hospitals in Norway. RESULTS: Eighty-six questionnaires were returned (response rate 47%). Continuous infusions of fentanyl and midazolam were perceived as most common and nurses often gave both analgesics and sedatives prior to care. Daily interruption of sedation or analgesia-based sedation was not perceived as practice in the units. MAAS was most commonly used, whilst protocols or objective scoring systems were not. Documentation of sedation levels was fairly routine, whereas documentation of patient needs was not perceived as important. Collaboration with physicians was viewed as most important, whilst no significance was assigned to collaboration with relatives. CONCLUSION: The study shows that a focus on analgesia-based sedation and continual control of the sedation level should be considered in order to decrease the risk of oversedation. Inclusion of relatives' opinions, increased collaboration between nurses and physicians, and implementation of sedation tools, may contribute to even better patient outcome and should be focus in further studies. PMID- 20709555 TI - Spinal epidural lipomatosis due to a bronchial ACTH-secreting carcinoid tumour. AB - Spinal epidural lipomatosis (SEL) is a rare condition characterized by abnormal deposits of fat in the epidural space. In a severe form this may cause compression of neural elements. This is the second report of SEL secondary to a carcinoid tumour. Our patient was a 34-year-old Caucasian male farm worker presenting with acute spinal cord compression. He had gained 11kg, and had developed Type II diabetes mellitus in the preceding 12months. On examination he displayed characteristic features of Cushing's syndrome. MRI demonstrated posterior epidural lipomatosis, with cord compression from T3 to T8. Urgent spinal cord decompression was performed. Further investigation confirmed a biochemical Cushing's syndrome secondary to an ACTH-producing pulmonary carcinoid tumour. PMID- 20709557 TI - Dialkylaminoalkyl derivatives of bicyclic compounds with antiplasmodial activity. AB - Dialkylaminoalkyl derivatives of 2-azabicyclo[3.2.2]nonanes and of bicyclo[2.2.2]octanes were prepared and their activities determined in vitro against the multiresistant K1 strain of Plasmodium falciparum. Several of the new compounds exhibited very promising antiplasmodial activity and selectivity. The results were compared to those of formerly synthesized analogues and of drugs in use. Structure-activity relationships were detected. Some of the more potent compounds were tested in vivo against Plasmodium berghei showing weak to moderate activity. A single compound was able to increase the mean survival days of infected mice. PMID- 20709556 TI - 2,3-diarylxanthones as strong scavengers of reactive oxygen and nitrogen species: a structure-activity relationship study. AB - Xanthones are a class of oxygen-containing heterocyclic compounds widely distributed in nature. The natural derivatives can present different substitutions in the xanthone core that include hydroxyl, methoxyl, prenyl and glycosyl groups. The inclusion of aryl groups has only been reported for a few synthetic derivatives, the 2,3-diaryl moiety being recently introduced by our group. Xanthones are endowed with a broad spectrum of biological activities, many of them related to their antioxidant ability, including the scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as well as metal chelating effects. Considering the interesting and promising antioxidant activities present in compounds derived from the xanthone core, the main goal of this work was to evaluate the scavenging activity of the new 2,3-diarylxanthones for ROS, including superoxide radical (O2-), hydrogen peroxide (H2O2), singlet oxygen (1O2), peroxyl radical (ROO.) and hypochlorous acid (HOCl), and RNS, including nitric oxide (.NO) and peroxynitrite anion (ONOO-). The obtained results revealed that the tested 2,3-diarylxanthones are endowed with outstanding ROS and RNS scavenging properties, considering the nanomolar to micromolar range of the IC50 values found. The xanthones with two catechol rings were the most potent scavengers of all tested ROS and RNS. In conclusion, the new 2,3 diarylxanthones are promising molecules to be used for their potential antioxidant properties. PMID- 20709558 TI - Cytotoxicity of new pyrazino[1,2-b]isoquinoline and 6,15-iminoisoquino[3,2-b]3 benzazocine compounds. AB - Looking for optimised analogues of compound 2 that might be useful in colon cancer therapy, we here explore the in vitro cytotoxicity against MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma and HT-29 human colon carcinoma cell lines of several analogues and derivatives. The effect of the R2 substituent and/or the introduction of an arylmethyl side-chain at C-3, as well as the presence of a double bond in the skeleton or a methoxy group at C-1 have been investigated. New 6,15-iminoisoquino[3,2-b]3-benzazocine compounds, related to the saframycin family, in which the C(7)-N(8)-C(9)-substructure contains a lactam function, a fused oxazolidine or an aminonitrile function were also studied, and many of them showed low micromolar GI50 values. PMID- 20709559 TI - Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists. AB - The octahydrobenzo[h]isoquinoline scaffold is of interest as a conformationally restricted phenethylamine that may be useful for constructing biologically active products. Surprisingly, however, no tractable synthesis of this ring system has been reported. We now describe a facile method for obtaining this framework, and illustrate that our approach is easily amenable to substitutions at the 5 position. Importantly, we demonstrate that the 7,8-dihydroxy-5-phenyl-substituted ligand is an extremely potent, high-affinity, full D1 dopamine receptor-selective agonist. PMID- 20709560 TI - Launois-Bensaude syndrome involving the orbits. AB - BACKGROUND: We report the first description of a Launois-Bensaude syndrome involving the orbit. CASE REPORT: Launois-Bensaude syndrome was diagnosed in a 70 year-old-man who presented with severe bilateral proptosis (Hertel value 26mm). We performed a bilateral transpalpebral orbital decompression by resection of intraorbital fat without bone removal. The surgery was uneventful. The volume of resected orbital fat was 16cc in both sides. Proptosis reduction was 7mm. Postoperative Hertel values were 19mm in both eyes. CONCLUSION: The proptosis was managed successfully. Orbital lipectomy lead to minimal sequelae and, may be repeated if necessary in this case. PMID- 20709561 TI - Pilot study of modification of the bilateral sagittal split osteotomy (BSSO) in pig mandibles. AB - OBJECTIVE: This study investigated a new technique for the bilateral sagittal split osteotomy (BSSO) by adding a new osteotomy line at the inferior border of the mandible in the Obwegeser-Dal Pont operation. MATERIAL AND METHODS: For this purpose a test system was designed and 100 pig mandibles were split to assess the test's reliability, to compare the torque necessary to split the mandible in both techniques and to record the fracture lines. The splitting technique was standardized, avoiding any contact with the inferior alveolar nerve. All outcomes were statistically examined by paired t-tests. RESULTS: By using the new technique, we demonstrated a decrease in the torque force required to split the mandible of 29.7% (t(69)=-12.68; p<0.05, paired t-test) compared to the Obwegeser Dal Pont technique. The fracture lines were close to ideal. CONCLUSION: The additional osteotomy facilitates the BSSO technique and it reduces the likelihood of bad splits and damage to the inferior alveolar nerve in pig mandibles. PMID- 20709562 TI - Closure of persisting air leaks in patients with severe pleural empyema--use of endoscopic one-way endobronchial valve. AB - Parapneumonic pleural empyema is a critical illness with mortality up to 20%. Patients often have severe comorbidity and are not always suitable for major thoracic surgery. Peripheral bronchopleural fistula adds further difficulty. This may result in a situation where recovery is impossible. Therefore, we developed a combination of minimally invasive surgical debridement and closure of the air leak with a bronchoscopic one-way endobronchial valve. Thus far, two patients received the combined treatment. Both patients suffered from a pleural empyema and because of severe comorbidity were not fit for major thoracic surgery. First, minimally invasive surgical debridement of the pleural cavity was performed. In both patients, a persisting peripheral bronchopleural fistula occurred. Via bronchoscopy the leak could be localized in both cases in the lower lobe segment 8. In each case, we implanted an endobronchial one-way valve designed for the treatment of lung emphysema. After the bronchoscopic valve implantation, the leakage ceased in both cases and healing of the pleural empyema was achieved. The valves were subsequently removed via bronchoscopy. Successful closure of peripheral air leaks in patients with pleural empyema using an endoscopic one-way valve is feasible. It is a treatment option in patients who are not fit for major thoracic surgery. PMID- 20709563 TI - Chemical and photochemical degradation of human hair: a free-volume microprobe study. AB - The microstructural changes in human hair due to chemical and photochemical oxidative processes have been monitored in terms of free volume employing Positron Annihilation Lifetime Spectroscopy (PALS). The results show that upon UV exposure the photosensitive amino acid residues present in the amorphous domains of virgin/bleached hair cross-link under ambient conditions. Further, the bleached hair readily undergoes photodamage in comparison with the virgin hair implying the diminished photoprotective action of the melanin granules within it. Swelling of hair fiber was evident in the early stages of UV exposure (<300h), bleaching, and humidification subsequent to irradiation. Swelling and cross linking were the two main processes observed following UV exposure, which oppositely affect the free volume holes size. Supplementary techniques such as DSC and XRD were used to support/extend the interpretation of the PALS results. The UV irradiation resulted in reduction of the average crystallite size in hair, which is attributed to the possible fragmentation of protein domains. The present work is the first positron lifetime measurement on human hair that demonstrates the ability of PALS to provide information on hair damage at molecular level, a vital input for cosmetic industry and applicable to biopolymers research as well. PMID- 20709564 TI - The chemokine network, a newly discovered target in high grade gliomas. AB - Chemokines are small cytokines, characterised by their ability to induce directional migration of cells by binding to chemokine receptors. They are known to play a role in tumour development, angiogenesis and metastasis. Interestingly, the chemokine network also contributes to the progression of gliomas, mainly by intensifying their characteristic invasive character. The main hurdle in treatment of these tumours is their infiltration of surrounding tissues, hampering complete surgical tumour removal. Standard postsurgical treatment with radio- and chemotherapy is of limited effect. Therefore drugs that target the chemokine system in high grade gliomas might fill the gap existing in the current approach. This review presents the current knowledge of the role of chemokine network in the development of the central nervous system, in brain physiology and the involvement in brain tumour progression. Finally, current studies exploring new compounds targeting the chemokine network in cancer patient are discussed. PMID- 20709565 TI - Predictive value of geriatric assessment for patients older than 70 years, treated with chemotherapy. AB - INTRODUCTION: Comprehensive geriatric assessment (CGA) gives useful information on the functional status of older cancer patients. However, its meaning for a proper selection of elderly patients before chemotherapy and, even more important, the influence of chemotherapy on the outcome of geriatric assessment is unknown. METHODS: 202 cancer patients, for whom an indication for chemotherapy was made by the medical oncologist, underwent a GA before start of chemotherapy by Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Index (GFI) and Mini Mental State Examination (MMSE). After completion of a minimum of four cycles of chemotherapy or at 6 months after the start of chemotherapy the GFI and MMSE assessment was repeated. RESULTS: Frailty was shown in 10% of patients by means of MMSE, 32% by MNA, 37% by GFI and in 15% by IQCODE. Compared to patients who received 4 or more cycles of chemotherapy, the MNA and MMSE scores were significantly lower for patients treated with less than 4 cycles (p = 0.001 and p = 0.04 respectively). The mortality rate after start of chemotherapy was increased for patients with low MNA and high GFI scores with hazard ratios of 2.19 (95% confidence interval [CI]: 1.42-3.39; p < 0.001) and 1.80 (95% CI: 1.17 2.78; p = 0.007), respectively. After adjusting for sex, age, purpose of chemotherapy and type of malignancy these hazard ratios remained significant (p < 0.001 and p = 0.004), respectively. Finally, for the 51 patients who underwent repeated post-chemotherapy evaluation by GFI and MMSE, a statistically significant deterioration for the MMSE (p = 0.041) was found but not for the GFI. CONCLUSIONS: Both inferior MNA and MMSE scores increased the probability not to complete chemotherapy. Also, an inferior score for MNA and GFI showed an increased mortality risk after the start of chemotherapy. The mean MMSE score worsened significantly during chemotherapy. PMID- 20709566 TI - Paget's disease of bone is not associated with common polymorphisms in interleukin-6, interleukin-8 and tumor necrosis factor alpha genes. AB - BACKGROUND: Cytokines, specially interleukin (IL)-6, play an important role in the differentiation and activation of osteoclasts and might be involved in osteoblast stimulation in Paget's disease of bone (PDB). OBJECTIVES: The aim of this study was to investigate the association of polymorphisms in IL-6, IL-8 and tumor necrosis factors-alpha (TNFA) genes among Spanish patients with PDB. METHODS: We studied four single nucleotide polymorphisms (-174 G>C IL-6, -251 T>A IL-8, -238 G>A TNFA and -308 G>A TNFA) in 172 PDB patients and 150 healthy controls. Distribution of alleles and pro-inflammatory genotypes were studied for association with the presence of the disease and with clinical and laboratory data, as well as the response to bisphosphonate treatment in PDB patients. RESULTS: We found no statistically significant association between genotype and allele distribution of any of the cytokines polymorphism studied and PDB. No association between the clinical and therapeutic characteristics of PDB and the investigated polymorphism were found. CONCLUSIONS: This study does not support the hypothesis that the analyzed IL6, IL8 and TNFA polymorphism are associated with PDB. PMID- 20709568 TI - Evaluation of fourth international standard for whole cell pertussis vaccine. AB - Whole cell pertussis vaccine is still widely used in many countries. An International Standard is needed for its potency control. The Third International Standard for Pertussis Vaccine was prepared about 40 years ago and its replacement was recommended by the Expert Committee for Biological Standardisation (ECBS) of the WHO. Material in ampoules coded 94/532 was prepared as a candidate replacement and has been evaluated in international collaborative studies which consisted of two parts. The first part, to assess the suitability of the candidate standard by comparing it with the Second International Standard for Pertussis Vaccine (IS2) involved 14 laboratories in 11 countries. The second part to compare the candidate standard with the Third International Standard for Pertussis Vaccine (IS3) involved 16 laboratories in 14 countries. Since 1995 various other studies have included the international standards and the results of these are also considered in assessing likely continuity of the IU for potency of whole cell pertussis vaccine. The preparation in ampoules coded 94/532 was adopted by the WHO ECBS in October 2006 as the 4th International Standard for whole cell pertussis vaccine and assigned an activity of 40 IU per ampoule on the basis of the studies reported here. PMID- 20709570 TI - Intravascular volume therapy with colloids in cardiac surgery. PMID- 20709569 TI - A randomized, controlled trial on dexmedetomidine for providing adequate sedation and hemodynamic control for awake, diagnostic transesophageal echocardiography. AB - OBJECTIVE: Transesophageal echocardiography (TEE) has become established as a sensitive and accurate diagnostic method for the rapid assessment of myocardial function. It was theorized that dexmedetomidine (Precedex; Hospira, Inc, Lake Forest, IL) might prove to be useful for sedating patients while undergoing TEE. DESIGN: A prospective, randomized trial was designed comparing dexmedetomidine versus standard therapy (eg, midazolam and opioids) for sedation. SETTING: This trial was performed in a tertiary care, single-institution university hospital. PARTICIPANTS: Males and females, American Society of Anesthesiologists I to IV, ages 18 to 65 years, requiring diagnostic TEE. Patients were excluded if pregnant, if they had taken benzodiazepines or opioids within 24 hours, or if they were deemed to be too unstable to receive any kind of sedation. INTERVENTIONS: Patients were randomized to standard therapy or dexmedetomidine infusion groups. Sedation was assessed at 6 time points. Pulse oximetry, electrocardiogram, heart rate, noninvasive blood pressure, and respiratory rate were monitored. Additional variables measured were the amount of each drug given, the time of the TEE procedure, and the time to recovery. MEASUREMENTS AND MAIN RESULTS: A survey about the quality of sedation, the level of comfort, and whether or not they would accept this type of sedation again was administered after recovery from sedation. Demographic data and patient questionnaire responses were reported as means and standard errors or percents and were analyzed with the t test and chi-square test. Twenty-two patients were enrolled. Hemodynamics were statistically different between the two groups at several time points. Both systolic and diastolic blood pressures (BP) were elevated in the standard therapy group, whereas the dexmedetomidine group had a lower BP. Heart rate was elevated significantly in the standard therapy group compared with the dexmedetomidine group. There was no statistical or clinical difference between the groups in terms of oxygenation or respiratory rate. CONCLUSIONS: The authors concluded that dexmedetomidine appears equivalent in achieving adequate levels of sedation without increasing the rate of respiratory depression or decreasing oxygen saturation compared with standard therapy, and it may be better in achieving desired hemodynamic results. PMID- 20709571 TI - A new technique of peripheral venous access under surgical drapes in thoracic anesthesia. PMID- 20709572 TI - Temporal changes in the use of blood products for coronary artery bypass graft surgery in North America: an analysis of the Society of Thoracic Surgeons Adult Cardiac Database. PMID- 20709573 TI - Percutaneous coronary sinus catheterization for minimally invasive cardiac surgery--more questions than answers? PMID- 20709574 TI - Post-traumatic stress disorder and neuropsychologic impairment among cardiac surgery patients. PMID- 20709575 TI - Integrating evidence-based medicine into the perioperative care of cardiac surgery patients. PMID- 20709576 TI - Accessing the meaning of invisible words. AB - Previous research has shown implicit semantic processing of faces or pictures, but whether symbolic carriers such as words can be processed this way remains controversial. Here we examine this issue by adopting the continuous flash suppression paradigm to ensure that the processing undergone is indeed unconscious without the involvement of partial awareness. Negative or neutral words projected into one eye were made invisible due to strong suppression induced by dynamic-noise patterns shown in the other eye through binocular rivalry. Inverted and scrambled words were used as controls to provide baselines at orthographic and feature levels, respectively. Compared to neutral words, emotion-described and emotion-induced negative words required longer time to release from suppression, but only for upright words. These results suggest that words can be processed unconsciously up to semantic level since under interocular suppression completely invisible words can lead to different processing speed due to the emotion information they carry. PMID- 20709577 TI - Reading and interpreting the scientific evidence. PMID- 20709578 TI - Comments regarding 'Carotid endarterectomy for symptomatic, but "haemodynamically insignificant" carotid stenosis'. PMID- 20709579 TI - Carotid artery disease: novel pathophysiological mechanisms identified by gene expression profiling of peripheral blood. AB - OBJECT: The pathogenesis of carotid artery stenosis (CAS) as well as the mechanisms underlying the different localisation of the atherosclerotic lesions remains poorly understood. We used microarray technology to identify novel systemic mediators that could contribute to CAS pathogenesis. Moreover, we compared gene-expression profile of CAS with that of patients affected by abdominal aortic aneurysm (AAA), previously published by our group. METHODS AND RESULTS: By global gene-expression profiling in a pool of 10 CAS patients and 10 matched controls, we found 82 genes differentially expressed. Validation study in pools used for profiling and replication study in larger numbers of CAS patients (n = 40) and controls (n = 40) of 14 genes by real-time polymerase chain reaction (RT-PCR) confirmed microarray results. Fourteen out of 82 genes were similarly expressed in AAA patients. Gene ontology analysis identified a statistically significant enrichment in CAS of differentially expressed transcripts involved in immune response and oxygen transport. Whereas alteration of oxygen transport is a common tract of the two localisations, alteration of immune response in CAS and of lipid metabolic process in AAA represents distinctive tracts of the two atherosclerotic diseases. CONCLUSIONS: We describe the systemic gene-expression profile of CAS, which provides an extensive list of potential molecular markers. PMID- 20709580 TI - Gestational diabetes and gestational impaired glucose tolerance in 1653 teenage pregnancies: prevalence, risk factors and pregnancy outcomes. AB - STUDY OBJECTIVE: The aim of this study was to determine the prevalence of gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (GIGT) in adolescent pregnancies, associated risk factors, and pregnancy complications. DESIGN: Retrospective study. SETTINGS: Community-based teaching hospital. PARTICIPANTS: Results of 1653 pregnant women age <= 19 years in 2005 2007 were reviewed. INTERVENTION: All pregnant women screened with 50-g glucose challenge test (GCT) and patients with a GCT result >= 140 mg/dl underwent a 3 hour 100-g oral glucose tolerance test (OGTT). MAIN OUTCOME MEASURES: GDM was diagnosed with at least two abnormal results and GIGT was diagnosed with one abnormal result. GDM and GIGT cases were evaluated for the presence of any associated risk factors and effects of presence of risk factors on pregnancy outcomes. RESULTS: The prevalence of GDM was 0.85% (95% CI, 0.41-1.29), GIGT was 0.5% (95% CI, 0.15-0.81) and GDM+GIGT was 1.35% (95% CI, 0.78-1.88) by Carpenter and Coustan criteria. 68% of patients had at least one of the risk factors including body mass index >= 25, family history of diabetes and polycystic ovary syndrome (PCOS). Only 9.1% (n = 2) of them required insulin for glucose regulation during pregnancy with 9.1% (n = 2) macrosomia rate. All patients were primiparous and cesarean delivery rate was 27.3% (n = 6). We could not find any effect of presence of risk factors on pregnancy outcomes in GDM and GIGT cases. CONCLUSION: We demonstrated that GDM and GIGT are strongly associated with high BMI before pregnancy, PCOS, and family history of diabetes. Since GDM is a state of prediabetes, it is important to diagnose in adolescent pregnancies considering their life expectancy to take preventive measures to avoid diabetes mellitus. PMID- 20709581 TI - The acceptability of human papillomavirus vaccine among parents and guardians of newborn to 10-year-old children. AB - STUDY OBJECTIVE: The purpose of our study was to evaluate HPV vaccine acceptance among parents and guardians of children aged 0-10 years. DESIGN: Prospective questionnaire study. SETTING: Cleveland Clinic Children's Hospital. PARTICIPANTS: Parents and guardians of children aged 0-10 years. INTERVENTIONS: Brief HPV vaccine educational intervention. OUTCOME MEASURE: Desire for child to get HPV vaccine. RESULTS: We enrolled 81 participants in the study; 70 (86%) were female, and 39 (49%) were Caucasian. Prior to receiving an educational fact sheet about HPV and the HPV vaccine, only 49% of participants reported that they wanted their young child to receive the HPV vaccine when it becomes available. After receiving the fact sheet, this number increased to 70%, suggesting that a simple educational intervention could significantly affect vaccine acceptance in this population (P = .001). Other significant results of this study included that HPV vaccination would receive greater acceptance if the participants believed that it can prevent HPV infection in their child (P = .0024), it was perceived to be safe (P = .0005), and if the vaccine were recommended by a physician (P < .0001). Participants' attitudes about HPV vaccination were not affected by concerns over whether receiving the vaccine might mean the child is more likely to have sex or to have multiple sexual partners. CONCLUSIONS: Our results suggest that if it were approved for children aged 0-10 years, the HPV vaccine would be accepted by the parents and guardians provided they received adequate educational information about it. PMID- 20709582 TI - Relationship between weight and bone mineral density in adolescents on hormonal contraception. AB - STUDY OBJECTIVE: Since bone loss has been observed among adolescents on depot medroxyprogesterone acetate (DMPA), a clinical population that commonly experiences weight gain, we were interested in examining the direct relationship between body weight and bone mineral density (BMD) in adolescents on DMPA as compared to those on oral contraceptive pills (OC) or on no hormonal contraception (control). DESIGN: Prospective, Longitudinal study. SETTING: Four urban adolescent health clinics in a large metropolitan area. PARTICIPANTS: Postmenarcheal girls, age 12-18 years, selecting DMPA, OC or no hormonal contraception. INTERVENTIONS: At baseline, 6, 12, 18, and 24 months, all study participants underwent measurement of weight and BMD of the hip and spine. MAIN OUTCOME MEASURES: The correlation between weight and BMD, and the correlation between change in weight and change in BMD were assessed at each time point. RESULTS: Body weight was significantly (P < 0.05) positively correlated with femoral neck BMD and spine BMD at each time point regardless of contraceptive method. Change in body weight at 12 and 24 months was highly correlated with change in femoral neck BMD (P < 0.0001) for all treatment groups. No statistically significant correlation between change in weight and change in spine BMD was seen in the DMPA, OC, or control subjects at 12 or 24 months. CONCLUSION: Weight gain on DMPA may mitigate loss of BMD among adolescent users. PMID- 20709583 TI - Ovarian tumors in children and adolescents--a clinical study of 52 patients in a university hospital. AB - STUDY OBJECTIVE: To review the clinical presentation of ovarian tumors in children and adolescents treated at the University of Dammam and King Fahad University Hospital. DESIGN: Data of the patients was noted retrospectively from the hospital medical records regarding age, presentation, diagnosis, treatment, and outcome. SETTING: The study was carried out in the Ob/Gyn department at King Fahad Hospital of Dammam University, Saudi Arabia between January 1985 and December 2009. PARTICIPANTS: There were 52 patients between 6 and 20 years of age who presented with an ovarian tumor during the study period. INTERVENTION: Preoperative diagnostic approach included history, physical examination, ultrasonography, radiological examination, tumor markers, operative treatment, and histopathological examination of the tumor. Chemotherapy was given to patients where indicated. RESULTS: The main presenting symptom was abdominal pain in 30 (58%) patients. Of the neoplastic tumors, 87% were germ cell tumors, of which 73% were benign while 13% were malignant. Operative procedures included 48 (92%) exploratory laparotomies and 4 (8%) laparoscopic resections. Ovarian cystectomy was done in 23 (44%) patients and salpingoophorectomy in 28 (54%) patients. Of the 7 (13%) patients with malignant tumors, five received postoperative chemotherapy. Three patients with malignancy died in the series. CONCLUSION: Early diagnosis of ovarian masses in young girls is important. Since most of these masses are benign, operation should be designed to optimize future fertility, while the treatment of malignant tumors would involve complete staging, resection of the tumor, postoperative chemotherapy when indicated, to give the patient a chance for future childbearing. PMID- 20709584 TI - Longitudinal changes in vaginal microbiota composition assessed by gram stain among never sexually active pre- and postmenarcheal adolescents in Rakai, Uganda. AB - STUDY OBJECTIVE: To describe changes in vaginal microbiota and pH over time among never sexually active adolescents at different menarcheal stages. DESIGN: A cohort of 49 sexually inexperienced Ugandan adolescents provided weekly self collected vaginal swabs and behavioral/health information for up to two years. Menarcheal stage was classified as: not experiencing menarche during follow-up (premenarcheal, n = 9), achieving menarche during follow-up (perimenarcheal, n = 20), and being postmenarcheal (n = 20) at enrollment. Vaginal microbiota were characterized as morphotypes of large gram-positive rods, small gram-negative or variable rods, and curved gram-negative rods based on Nugent Gram-stain criteria. Baseline measures were compared using nonparametric tests. Mean changes (beta) in morphotypes and pH over time were estimated using longitudinal mixed-effects models. RESULTS: The baseline median (IQR: interquartile range) Nugent score was 8 (7-8) in premenarcheal, 4.5 (1-8) in perimenarcheal, and 1 (0-3) in postmenarcheal girls (P = 0.001). For each respective menarcheal stage, the median (IQR) counts of gram-positive rods were 0 (0-0), 10 (0-30), and 30 (18-30) (P = 0.002) and gram-negative or variable rods were 30 (30-30), 16 (0.5-30), and 0.5 (0-2.5) (P = 0.002) at enrollment. Counts of gram-positive rods increased (beta = 0.259, 95% CI: 0.156, 0.362) and gram-negative or variable rods decreased (beta = -0.201, 95% CI:-0.298,-0.103) significantly over time in premenarcheal girls, but not in other groups. Vaginal pH declined significantly in peri- and postmenarcheal girls only. CONCLUSION: Vaginal microbiota composition varied by menarcheal stage at enrollment. Over time, significant changes in vaginal morphotypes occurred in premenarcheal girls, suggesting this may be an important period of transition. PMID- 20709585 TI - Are adolescents' decisions about prenatal screening for Down syndrome informed? A controlled, prospective study. AB - STUDY OBJECTIVE: Maternal serum screening is routinely offered to pregnant women in public hospitals in Victoria, Australia, regardless of their age. The aim of this study was to determine whether pregnant adolescents are less likely to make informed choices about undertaking this test than adult pregnant women. DESIGN: Controlled, prospective design. SETTING: Public hospital antenatal clinics in Victoria, Australia. PARTICIPANTS: Adolescents up to 20 years of age were recruited at young mothers' clinics before they were offered second trimester maternal screening. They completed self-report questionnaires prior to maternal serum screening and again after the screening result was known. MAIN OUTCOME MEASURES: A validated measure of informed choice was used to determine whether adolescents made informed choices about undertaking second trimester maternal serum screening. RESULTS: Complete data were available for 147 adolescents. These data were combined with data from 85 adults which had been collected in an identical way. Ten percent of the adolescents made informed decisions about having the maternal serum screening, compared with 37% of the adult participant group (P < 0.05). Adolescent women were significantly less likely to make an informed choice than adult women, when relevant demographic and reproductive history variables were controlled for (adjusted OR = 0.25; P = 0.004; 95% CI for OR: 0.10, 0.63). CONCLUSION: Few pregnant adolescents made informed decisions about maternal serum screening. Clinicians face a challenge to improve adolescents' knowledge about maternal serum screening. PMID- 20709586 TI - Composition of uroliths in small domestic animals in the United Kingdom. AB - The mineral composition of 7819 small animal uroliths in the UK was determined by semi-quantitative X-ray diffraction over a period of 90 months from 2002 to 2010. Canine and feline uroliths constituted 97% of the study population and the mineral phase detected most frequently was struvite (43%), followed by calcium oxalate (41%). Uroliths from crossbreeds, Dalmatians, Yorkshire terriers and Shih Tzus accounted for almost 30% of all canine uroliths, with the highest frequency in Dalmatians, which had a predominance of urate uroliths. The average ages of dogs and cats with uroliths were 7.0 years and 7.4 years, respectively. The ratio of the number of dogs presenting with struvite compared to oxalate phases reached a maximum at 3years of age. PMID- 20709587 TI - [How to prevent postoperative intrauterine adhesions?]. AB - Operative hysteroscopic surgery can lead to intra-uterine adhesions reducing procreation chances. Prevention of this kind of adhesions is necessary. Several pre-, per-, and post-operative means have been proposed against these adhesions. However data concerning their functional interest are lacking. PMID- 20709588 TI - Effect of energy-gathered ultrasound on Alcalase. AB - This research was to explore the mechanism of ultrasonic impact on protease activity. The effects of energy-gathered ultrasound on the activity, kinetics, thermodynamics and molecular structure of Alcalase were investigated with the aid of the chemical reaction kinetics model, Arrhenius equation, Eyring transition state theory, fluorescence spectroscopy and circular dichroism (CD) spectroscopy. Results showed that ultrasound had effect on the activity of Alcalase. The highest Alcalase activity was achieved when the sample was treated with energy gathered ultrasound at 80 W for 4 min, under which the enzyme activity was increased by 5.8% over the control. After the treatment, thermodynamics parameters Ea, DeltaH, DeltaS and DeltaG were reduced by 70.0%, 75.8%, 34.0% and 1.3%, respectively. Besides, fluorescence and CD spectra revealed that the ultrasonic treatment had increased the number of tryptophan on Alcalase surface slightly, increased number of alpha-helix by 5.2%, and reduced the number of random coil by 13.6%. PMID- 20709589 TI - A musculoskeletal shoulder model based on pseudo-inverse and null-space optimization. AB - The goal of the present work was assess the feasibility of using a pseudo-inverse and null-space optimization approach in the modeling of the shoulder biomechanics. The method was applied to a simplified musculoskeletal shoulder model. The mechanical system consisted in the arm, and the external forces were the arm weight, 6 scapulo-humeral muscles and the reaction at the glenohumeral joint, which was considered as a spherical joint. The muscle wrapping was considered around the humeral head assumed spherical. The dynamical equations were solved in a Lagrangian approach. The mathematical redundancy of the mechanical system was solved in two steps: a pseudo-inverse optimization to minimize the square of the muscle stress and a null-space optimization to restrict the muscle force to physiological limits. Several movements were simulated. The mathematical and numerical aspects of the constrained redundancy problem were efficiently solved by the proposed method. The prediction of muscle moment arms was consistent with cadaveric measurements and the joint reaction force was consistent with in vivo measurements. This preliminary work demonstrated that the developed algorithm has a great potential for more complex musculoskeletal modeling of the shoulder joint. In particular it could be further applied to a non-spherical joint model, allowing for the natural translation of the humeral head in the glenoid fossa. PMID- 20709590 TI - Mosquito politics: local vector control policies and the spread of West Nile Virus in the Chicago region. AB - Differences in mosquito control practices at the local level involve the interplay of place, scale and politics. During the Chicago West Nile Virus (WNV) outbreak of 2002, mosquito abatement districts represent distinct suburban clusters of human WNV cases, independent of characteristics of the local population, housing and physical environment. We examine how the contrasting actions of four districts reveal a distinct local politics of mosquito control that may have contributed to local-scale geographic differences in WNV incidence. This politics is rooted in political, economic and philosophical differences within and between administrative boundaries. PMID- 20709591 TI - The effect of a simulated manipulation position on internal carotid and vertebral artery blood flow in healthy individuals. AB - The simulated manipulation position is one of several premanipulative screening tests recommended to assist in identifying patients at risk of complications from high velocity thrust manipulation of the cervical spine. The effects of this position on blood flow in the vertebral artery has been measured, but not in the internal carotid artery. Fourteen healthy subjects participated in a pre-test post-test single group study to determine the effect of a simulated manipulation position on blood flow in both the internal carotid and vertebral arteries. Duplex ultrasound with colour Doppler imaging was used to image the internal carotid and vertebral arteries and to measure blood flow velocity with the neck in neutral and simulated manipulation positions. A measure of distal vascular resistance, the resistance index, was calculated. There was a significant (p<0.05) reduction in the resistance index in the vertebral arteries ipsilateral to the rotation component of the simulated manipulation position. Placing the cervical spine in a simulated manipulation position, did not adversely affect blood flow through the internal carotid and vertebral arteries. Further research is needed to determine how the simulated manipulation position affects internal carotid and vertebral artery blood flow in individuals who have signs or symptoms of neurovascular insufficiency. PMID- 20709592 TI - Semi-automatic construction of reference standards for evaluation of image registration. AB - Quantitative evaluation of image registration algorithms is a difficult and under addressed issue due to the lack of a reference standard in most registration problems. In this work a method is presented whereby detailed reference standard data may be constructed in an efficient semi-automatic fashion. A well distributed set of n landmarks is detected fully automatically in one scan of a pair to be registered. Using a custom-designed interface, observers define corresponding anatomic locations in the second scan for a specified subset of s of these landmarks. The remaining n-s landmarks are matched fully automatically by a thin-plate-spline based system using the s manual landmark correspondences to model the relationship between the scans. The method is applied to 47 pairs of temporal thoracic CT scans, three pairs of brain MR scans and five thoracic CT datasets with synthetic deformations. Interobserver differences are used to demonstrate the accuracy of the matched points. The utility of the reference standard data as a tool in evaluating registration is shown by the comparison of six sets of registration results on the 47 pairs of thoracic CT data. PMID- 20709593 TI - Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient. AB - INTRODUCTION: The efficacy of antiviral therapy with pegylated interferon (PEGIFN) plus ribavirin (RBV) in patients with HIV and hepatitis C virus (HCV) coinfection is limited. Intravenous silibinin (ivSIL), a milk thistle extract with proven antiviral effects represents a novel therapeutic strategy for virological nonresponders. METHODS: We report a case of an HIV-HCV coinfected patient, who has not responded to a prior course of PEGIFN-alpha2a (180 MUg/week/s.c.) and RBV (1000 mg/day/p.o.). Testing for IL-28beta small nucleotid polymorphism revealed the nonfavourable genotype T/T. Antiretroviral therapy was not prescribed because the patients presented with well-preserved CD4+ cell counts and low HIV-RNA levels. She received retreatment with ivSIL for two weeks followed by PEGIFN/RBV combination therapy starting at week 1. RESULTS: After 2 weeks of ivSIL therapy both HCV-RNA and HIV-RNA become undetectable. On ivSIL monotherapy we noticed a trend towards an increase of CD4+ cell counts and a decrease of HIV-RNA. After 16 weeks PEGIFN+RBV was discontinued due to patients wish because of adverse events. HCV-RNA was still negative 24 weeks after cessation of therapy, while HIV-RNA returned to baseline levels. CONCLUSION: ivSIL may represent a potential treatment option for retreatment of HIV-HCV coinfected patients nonresponding to PEGIFN+RBV combination therapy. Further investigations on the possible beneficial effects of ivSIL on CD4+ cell counts and HIV-RNA levels are necessary. PMID- 20709594 TI - Contextual processing deficits in Parkinson's disease: the role of the frontostriatal system. AB - OBJECTIVE: We investigated the role of the frontostriatal system in contextual processing, by examining neural correlates of local contextual processing in Parkinson's disease (PD). Local context was defined as the occurrence of a short predictive series of visual stimuli occurring before delivery of a target event. METHODS: EEG was recorded in eight PD patients and eight controls. Recording blocks consisted of targets preceded by randomized sequences of standards and by sequences including a predictive sequence signaling the occurrence of a subsequent target event. Subjects pressed a button in response to targets. Peak P3b amplitude and latency were evaluated for targets after predictive and non predictive sequences. RESULTS: Behavioral and electrophysiological measures showed that controls processed predicted and random targets differentially, while PD patients processed these similarly. Reaction times were shorter for predictable than for random targets in controls but not in patients. PD patients failed to generate the expected P3b latency shift between predicted and random targets, which is observed in controls. CONCLUSIONS: These findings show that predictive local context effects on target detection are altered in PD patients. SIGNIFICANCE: The findings suggest a key role for the frontostriatal system in contextual processing. PMID- 20709595 TI - Robust sensory gating in the cortical visual evoked potential using two spatially separated stimuli. AB - OBJECTIVE: Sensory gating has been reported to be either absent or weak in the cortical visual evoked potential (VEP) response to diffuse or spatially overlapping stimuli. In this study, the authors evaluated sensory gating to two spatially separated visual stimuli. METHODS: Spatially separated stimuli were presented either singly or in combination at the same or different onset times and the VEP recorded at either Oz, or O1 and O2, referenced to Cz. RESULTS: When one visual stimulus is flashed on, the VEP response to another non-overlapping stimulus is almost completely suppressed. CONCLUSIONS: The VEP does not reflect the bulk activation of retinotopically organized visual cortex, but rather it primarily reflects a distributed mode of visual cortical activity that only indicates that at least one visual stimulus was presented, and not how many or in what order. SIGNIFICANCE: Other studies performing intracortical recordings of the local field potential (LFP) in visual cortex have identified a slow distributed component that exhibits the same nonlinearity found here in the VEP, suggesting that these two phenomena are related. PMID- 20709596 TI - The ocular vestibular-evoked myogenic potential to air-conducted sound; probable superior vestibular nerve origin. AB - OBJECTIVE: Intense air-conducted sound (ACS) elicits an ocular vestibular-evoked myogenic potential (oVEMP), and it has been suggested that it does so by stimulating saccular receptors and afferents in the inferior vestibular nerve and so activating a crossed sacculo-ocular pathway. Bone conducted vibration (BCV) also elicits an oVEMP probably by activating utricular receptors and a crossed utriculo-ocular pathway. Are there two separate pathways mediating oVEMPs for ACS and BCV? If saccular receptors and afferents are primarily responsible for the oVEMP to ACS, then the oVEMP to ACS should be normal in patients with reduced or absent utricular function--unilateral superior vestibular neuritis (SVN). If utricular receptors and afferents are primarily responsible for oVEMP n10, then oVEMP to ACS should be reduced or absent in SVN patients, and in these patients there should be a close relationship between the size of the oVEMP n10 to BCV and to ACS. METHODS: The n10 component of the oVEMP to 500 Hz BCV and to 500 Hz ACS was recorded in 10 patients with unilateral SVN but who had saccular and inferior vestibular nerve function preserved, as shown by their normal cVEMP responses to ACS. RESULTS: In SVN patients with normal saccular and inferior vestibular nerve function, the oVEMP n10 in response to ACS was reduced or absent. Across SVN patients there was a very close correspondence between the size of oVEMP n10 for ACS and for BCV. CONCLUSIONS: The n10 component of the oVEMP to ACS is probably mediated predominantly by the superior vestibular nerve and so most likely by utricular receptors and afferents. SIGNIFICANCE: The n10 component of the oVEMP to either ACS or BCV probably indicates mainly superior vestibular nerve function. PMID- 20709598 TI - Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. AB - Tuberculous meningitis (TBM) causes a devastating morbidity and mortality in adults and children. Even in patients presenting at an early stage of disease, deterioration may occur despite apparently adequate therapy. The literature relating to cerebrospinal fluid penetration of antituberculosis agents is reviewed. Amongst the essential antituberculosis agents isoniazid has the best CSF pharmacokinetics reaching peak concentrations (C(max)) only slightly less than in blood. Pyrazinamide also has good CSF penetration and in children receiving dosages of 40 mg/kg the CSF C(max) exceeds the proposed minimal inhibitory concentration of 20 MUg/ml. Streptomycin other aminoglycosides and ethambutol have poor CSF penetration and cannot be agents of first choice for TBM treatment. Rifampicin at dosages used in adults seldom reaches CSF concentrations exceeding MIC, but does so more frequently in children when dosages of up to 20 mg/kg are used. The non-essential agents ethionamide, the fluoroquinolones, with the exception of ciprofloxacin, and cycloserine (terizadone) have relatively good CSF penetration and are recommended for TBM treatment. The dosages of the essential agents recommended for the treatment of TBM in children are INH 10 mg/kg (range 6-15 mg/kg bodyweight), rifampicin 15 mg/kg (range 10-20 mg/kg), pyrazinamide 35 mg/kg (range 30-40 mg/kg), ethambutol 20 mg/kg (range 15-25 mg/kg) and streptomycin 15 mg/kg (range 12-18 mg/kg). Amongst second-line agents ofloxacin, levofloxacin and moxifloxacin should be used in dosages of 15-20 mg/kg, ethionamide 20 mg/kg in a single dose, if tolerated, and for cycloserine (terizadone) 15 mg/kg. Antituberculous chemotherapy should be started as soon as the diagnosis of TBM is considered. PMID- 20709600 TI - Reduced FOXP3 expression causes IPEX syndrome onset: An implication from an IPEX patient and his disease-free twin brother. PMID- 20709601 TI - Selecting patients for epilepsy surgery: synthesis of data. AB - The consideration of epilepsy surgery for those with medically refractory seizure disorders requires a well-functioning multidisciplinary team and a systematic approach to investigations, with the aim of advising patients of their chances of being seizure free following surgery, and the risks of any procedure. Investigatory pathways may be outlined that cover most clinical situations, and the indications for invasive EEG studies. It is crucial that patients and their families are given realistic expectations of what may, and may not, be achieved with surgical treatment, and that long-term follow-up is maintained post operatively. PMID- 20709602 TI - Functional neuroimaging in the postictal state. AB - The postictal state is defined as manifestation of seizure-induced reversible alterations in neuronal function, but not structure. Following a seizure, it is common to experience feelings of exhaustion, both mental and physical, that can last a day or two. There are three major hypotheses regarding what cellular and molecular mechanisms could cause the observed postictal symptoms: neurotransmitter depletion or changes in receptor concentration, active inhibition, and cerebral blood flow changes. Here, we describe the contributions of functional neuroimaging studies to the understanding of postictal symptoms. PMID- 20709603 TI - Effects of sleep on the postictal state. AB - The postictal state can be particularly confusing when occurring in association with sleep. Some seizures tend to occur predominantly or exclusively during sleep; as the patient may be unaware of the seizure itself, the postictal state may be the only observed manifestation. Seizures and postictal phenomena occurring during sleep can also lead to diagnostic confusion particularly with parasomnias. Confusion or apparent sleepwalking, for example, could be a postictal phenomenon or could be an independent parasomnia. Awareness of the various manifestations of sleep disorders, seizures, and postictal phenomena during sleep is critical to optimal diagnosis and treatment of patients with epilepsy. PMID- 20709604 TI - Heart and lung in the postictal state. AB - Ictal events include those of the autonomic nervous system. This sympathetic stimulation may persist into the postictal period, affecting cardiopulmonary function. Such postictal effects include potentially fatal alterations in cardiac rhythm and ventilatory function, management challenges such as pulmonary edema, and diagnostically confusing laboratory abnormalities such as fever and cerebrospinal fluid pleocytosis. These and other effects on the heart and lung in the postictal period are accordingly reviewed. PMID- 20709605 TI - Poly(3,4-ethylene-dioxythiophene) electrode for the selective determination of dopamine in presence of sodium dodecyl sulfate. AB - A novel biosensor using poly(3,4-ethylene dioxythiophene) (PEDOT) modified Pt electrode was developed for selective determination of dopamine (DA) in presence of high concentrations of ascorbic acid (AA) and uric acid (UA) with a maximum molar ratio of 1/1000, and 1/100 in the presence of sodium dodecyl sulfate (SDS). SDS forms a monolayer on PEDOT surface with a high density of negatively charged end directed outside the electrode. The electrochemical response of dopamine was improved by SDS due to the enhanced accumulation of protonated dopamine via electrostatic interactions. The common overlapped oxidation peaks of AA, UA and DA can be resolved by using SDS as the DA current signal increases while the corresponding signals for AA and UA are quenched. The use of SDS in the electrochemical determination of dopamine using linear sweep voltammetry at modified electrode PEDOT/Pt resulted in detecting dopamine at relatively lower concentrations. The DA concentration could be measured in the linear range of 0.5 to 25MUmol L(-1) and 30MUmol L(-1) to 0.1mmol L(-1) with correlation coefficients of 0.998 and 0.993 and detection limits 61nmol L(-1) and 86nmol L(-1), respectively. The validity of using this method in the determination of dopamine in human urine was also demonstrated. PMID- 20709606 TI - Development, validation, and implementation of a questionnaire assessing disease knowledge and understanding in adult cystic fibrosis patients. AB - BACKGROUND: The number of adults living with cystic fibrosis (CF) is increasing, necessitating an assessment of knowledge in this growing population. METHODS: A questionnaire assessing CF knowledge was completed by 100 CF patients (median age: 26.0 years, range 17-49 years; median FEV1: 57.0% predicted, range 20-127% predicted). Level of knowledge was correlated with clinical and sociodemographic characteristics. RESULTS: Questionnaire validation showed acceptable internal consistency (alpha=0.75) and test-retest reliability (0.94). Patients had fair overall understanding of CF (mean=72.4%, SD=13.1), with greater knowledge of lung and gastrointestinal topics (mean=81.6%, SD=11.6) than reproduction and genetics topics (mean=57.9%, SD=24.1). Females and those with post-secondary education scored significantly higher (p<0.05). CONCLUSIONS: This study validated a questionnaire that can be utilized to assess CF knowledge. Although CF patients understand most aspects of their disease, knowledge deficits are common - particularly regarding genetics and reproduction - and should be considered when developing CF education programs. PMID- 20709609 TI - Topological, statistical, and dynamical origins of genetic code. Comment on "A colorful origin for the genetic code: information theory, statistical mechanics and the emergence of molecular codes" by T. Tlusty. PMID- 20709610 TI - A scientific open season. Comment on 'A colorful origin for the genetic code: information theory, statistical mechanics and the emergence of molecular codes' by T. Tlusty. PMID- 20709611 TI - Cloning, characterization, and expression analysis of Toll-like receptor-7 cDNA from common carp, Cyprinus carpio L. AB - The Toll-like receptor 7 (TLR7) is activated by single strand RNA and RNA-like compounds (imidazoquinoline), and it induces interferon production. We identified and described carp TLR7 cDNA and its mRNA expression. The full-length cDNA of carp TLR7 gene is 3427 bp, encoding 1049 amino acids (AB553573). The similarities of carp TLR7 with zebrafish, rainbow trout, fugu, and human TLR7 were 89.6, 83.4, 80.6 and 74.6%, respectively, at the amino acid sequence level. Furthermore, the expression of TLR7 mRNA was investigated in normal tissues of carp by semi quantitative RT-PCR analysis. Carp TLR7 expression was exhibited in healthy tissues (kidney, brain, spleen, skin, intestine, muscle, liver, gills and heart) and though the expression level in each tissue varied among healthy fish. Carp TLR7 expression was significantly increased in head kidney stimulated with TLR7 agonist, imiquimod, at 8, 24 and 48 h in vitro when compared to expression in the control group. Moreover, carp head kidney leukocytes produced elevated levels of pro-inflammatory and type 1 interferon cytokine mRNA in response to imiquimod stimulation. PMID- 20709612 TI - Reconstruction of partial-thickness vermilion defects with a mucosal V-Y advancement flap based on the orbicularis oris muscle. AB - Repair of a large, trauma-induced partial-thickness vermilion defect is considered a challenging task. Ideally, such defects should be corrected by methods that use tissues similar in colour and texture to the normal vermilion. When the length of a defect is greater than half that of the vermilion and the width of the defect is greater than 1.5 cm, however, effective repair is not always achieved using the traditional mucosal V-Y advancement flap. In this article, a modified mucosal V-Y advancement flap containing the orbicularis oris muscle is described. This flap possesses the mobility sufficient to serve as the pedicle for the transfer and repair of large vermilion defects. Between August 2006 and January 2009 vermilion reconstruction using this modified flap was performed on eight patients, with satisfactory cosmetic and functional outcomes obtained in all cases. This simple and useful approach to vermilion reconstruction provides excellent outcomes with minimal injury to the donor site. PMID- 20709613 TI - Treatment algorithm for abdomino-torso body contouring in massive weight-loss patients in the presence of scars--a comprehensive review. AB - BACKGROUND: Patients requiring surgical skin excision after massive weight loss are challenging and require a structured approach. The characteristic abdominal deformity includes a draping apron of panniculus, often extending to the glutaeal, back and thigh areas. Occasionally, these deformities are associated with previous surgical scars in the upper abdomen resulting from open gastric bypass surgery or from other procedures, such as open cholecystectomy. These scars can compromise the blood supply of the abdominal skin. For adequate and safe body contouring, both the excess skin and fat as well as the remaining perfusion of the remaining tissues must be addressed to achieve satisfactory results. METHOD: We propose an algorithmic treatment approach for body contouring of the abdomino-torso area in the presence of scars in the upper abdomen. RESULTS: The key to satisfactory results is a thorough analysis of the horizontal and vertical skin and fat excess of the abdomino-torso, buttock and flank areas and choosing an adequate and safe procedure addressing the respective areas of skin and fat excess while preserving the blood supply of the abdomino-torso area in a scarred abdomen. Our algorithmic approach can help in achieving these goals. CONCLUSION: Our algorithmic approach enables the surgeon to perform safe abdomino torso body contouring through a structured analysis of the fat and skin excess in the respective body areas even in the presence of surgical scars in the upper abdomen. PMID- 20709614 TI - Dermal substitutes do well on dura: comparison of split skin grafting+/ artificial dermis for reconstruction of full-thickness calvarial defects. AB - Large, full-thickness calvarial defects present a series of significant reconstructive challenges involving a range of techniques, including local and free flaps. Occasionally these conventional methods may not be possible due to technical, or patient, factors. Artificial dermis is already widely used in burns surgery and is increasing in oncological reconstruction. We believe that artificial dermis coupled with split-thickness skin grafting provides an excellent option for closure of these defects when other techniques are not appropriate. PMID- 20709615 TI - Training in bilateral breast reduction and breast augmentation: the results of a supra-regional audit. AB - INTRODUCTION: Bilateral breast reduction (BBR) and bilateral breast augmentation (BBA) represent ideal training procedures. This study prospectively audited BBR and BBA training opportunities at six plastic surgery units. METHODS: Operative numbers and training opportunities were audited at 6 plastic surgical units in the south west region. RESULTS: The results demonstrated considerable variations in training opportunities between different hospitals. In some cases, trainees did not operate on a single BBR or BBA, despite relatively high overall operative numbers. These differences did not relate to trainee seniority or patient demographics. CONCLUSION: The variations and deficiencies in training opportunities identified in this study may be due to a number of factors, such as local attitudes to training, external pressure on operative lists and the EWTD restrictions. These findings are unlikely to be confined to one region and should encourage wider audit of training provision. PMID- 20709616 TI - Persistent infection by HCV and EBV in peripheral blood mononuclear cells and risk of non-Hodgkin's lymphoma. AB - Hepatitis C virus (HCV) and Epstein-Barr virus (EBV) have been repeatedly associated with risk of non-Hodgkin's lymphoma (NHL) in studies focusing on serological evidence of infection. We investigated NHL risk in association with detection of HCV-RNA or EBV-DNA in the peripheral blood mononuclear cells (PBMC). The study involved 91 NHL cases and 182 controls nested in the Italian branch of the EPIC (European Prospective Investigation of Cancer and nutrition) cohort, which obtained blood samples from 47,749 healthy volunteers between 1993 and 1998 in 5 Italian cities. NHL cases were identified until June 2005 through linkage with records of the Cancer, Mortality, and Hospital Discharge Registries. For all study subjects, we performed viral genome analyses on DNA and RNA extracted from buffy-coats and analysed EBV and HCV antibodies. The odds ratios (ORs) of NHL were 1.2 (95% confidence intervals: 0.4-3.8; 5 exposed cases) for PBMC HCV infection and 1.2 (0.7-2.3; 24 exposed cases) for PBMC EBV infection. Similar OR estimates were found for detection of EBV and HCV antibodies. These null results, although based on a relatively small sample size, suggest that persistent EBV and HCV infection in the PBMC is not a stronger predictor of NHL risk than serological evidence of infection. PMID- 20709617 TI - Liver resection for intrahepatic stones in congenital bile duct dilatation. AB - OBJECTIVE: This study reports our clinical experience with liver resection for congenital dilatation of the intrahepatic bile duct and intrahepatic gallstones to evaluate results and define indications for treatment. PATIENTS AND METHODS: We studied the clinical data of patients who underwent hepatic resection for intrahepatic lithiasis from January 1992 to December 2008 and assessed the immediate and long-term results of these interventions. RESULTS: Of 49 treated patients, 47 underwent liver resection. In the majority of cases, the disease was limited to the left lobe and left hepatectomy was the most commonly performed surgical procedure. The operative mortality was zero with morbidity in 24.5% of patients. Cholangiocarcinoma was diagnosed in six cases (12.2%). In 91.6% of cases the long-term results were good or satisfactory. CONCLUSION: Treatment goals in all cases should be the elimination of intrahepatic stones, the prevention of recurrent lithiasis, and prevention or cure of cholangiocarcinoma. Surgical excision is the best possible treatment for symptomatic patients with localized disease and atrophy of the affected liver. PMID- 20709618 TI - Endodontically treated teeth: characteristics and considerations to restore them. AB - The restoration of endodontically treated teeth is a topic that is extensively studied and yet remains controversial. This article emphasizes the characteristics of endodontically treated teeth and some principles to be observed when restorations of these teeth are planned. It was concluded that the amount of remaining coronal tooth structure and functional requirements determine the best way to restore these teeth, indicating the material to be used, direct or indirect restorations, associated or not to posts. PMID- 20709620 TI - A role in the regulation of transcription by light for RCO-1 and RCM-1, the Neurospora homologs of the yeast Tup1-Ssn6 repressor. AB - The activation of gene transcription by light is transient since light-dependent mRNA accumulation ceases after long exposures to light. This phenomenon, photoadaptation, has been observed in plants and fungi, and allows the perception of changes in light intensities. In the fungus Neurosporacrassa photoadaptation involves the transient binding of the photoresponsive White Collar Complex (WCC) to the promoters of light-regulated genes. We show that RCO-1 and RCM-1, the Neurospora homologs of the components of the yeast Tup1-Ssn6 repressor complex, participate in photoadaptation. Mutation in either rco-1 or rcm-1 result in high and sustained accumulation of mRNAs for con-10 and other light-regulated genes after long exposures to light. The mutation of rco-1 increased the sensitivity to light for con-10 activation and delayed synthesis and/or degradation of con-10 and con-6 mRNAs without altering the amount or the light-dependent phosphorylation of the photoreceptor WC-1. RCO-1 and RCM-1 are located in the Neurospora nuclei were they regulate gene transcription. We show that RCO-1 and RCM-1 participate in the light-transduction pathway of Neurospora and has a role in photoadaptation by repressing gene transcription after long exposures to light. PMID- 20709619 TI - Cytokinesis through biochemical-mechanical feedback loops. AB - Cytokinesis is emerging as a control system defined by interacting biochemical and mechanical modules, which form a system of feedback loops. This integrated system accounts for the regulation and kinetics of cytokinesis furrowing and demonstrates that cytokinesis is a whole-cell process in which the global and equatorial cortices and cytoplasm are active players in the system. Though originally defined in Dictyostelium, features of the control system are recognizable in other organisms, suggesting a universal mechanism for cytokinesis regulation and contractility. PMID- 20709621 TI - Inhibitive effect of celecoxib on the adhesion and invasion of human tongue squamous carcinoma cells to extracellular matrix via down regulation of MMP-2 expression. AB - The effect of cyclooxygenase 2 (COX-2) and its inhibitor on metastasis and invasion of tumor and its relationship with matrix metalloproteinase are getting more and more attention. Down regulation of matrix metalloproteinase (MMP) expression could inhibit the invasion and adhesion ability of cancer cells. Our study observed the inhibitive effect of selective COX-2 inhibitor, celecoxib, on adhesion and invasion ability of human tongue squamous carcinoma cell line Tca8113 and its relationship with MMP-2 secretion. COX-2 expression of Tca8113 cell was detected by Western blot analysis. Ratio of COX-2 positive Tca8113 cell was determined by flow cytometry analysis. MMP-2 and PGE2 secretion was measured by ELISA. Invasion of a Matrigel-coated membrane by Tca8113 cells was quantitatively assessed by counting migrated cells. Results showed that COX-2 expression was positive in Tca8113 cell and could be significantly inhibited by celecoxib. Celecoxib could inhibit PGE2 production of Tca8113 cell in a dose dependent manner, down-regulate MMP-2 secretion of Tca8113 cell, and at the same time significantly inhibit invasion and adhesion ability of these cells. Adding extrinsic PGE2 could antagonize the inhibitive effect of celecoxib not only on MMP-2 secretion of Tca8113 cell, but also on invasion and adhesion ability of the cells. The results suggested that celecoxib had chemoprevention effect on invasion and metastasis of oral carcinoma. PMID- 20709622 TI - When bacteria become mutagenic and carcinogenic: lessons from H. pylori. AB - More and more convincing data link bacteria to the development of cancers. How bacteria act as mutagens by altering host genomes, what are the different strategies they develop and what consequences do they have on infection associated pathogenesis are the main questions addressed in this review, which focuses in particular on Helicobacter pylori infection. H. pylori is a major risk factor for gastric cancer development. Its oncogenic role is mediated by the chronic active inflammation it elicits in the gastric mucosa, associated with its capacity to persistently colonize the human stomach. However, direct genotoxicity of H. pylori through the action of bacterial cytotoxin or resulting from a DNA damaging effect of its metabolic derivatives as nitroso compounds cannot be excluded. Numerous studies have investigated inflammation-associated DNA damaging activity and mutagenic response due to H. pylori infection in both human and animal models. Recent findings on its mutagenic effects at the nuclear and mitochondrial genome and related DNA damage are reviewed. This genotoxic activity associated with oxidative species produced during inflammation is linked to the decreased efficiency of DNA repair systems. DNA methylation, which plays an important role in the regulation of the host response to H. pylori infection, is also documented. Furthermore, H. pylori affects genome integrity by increasing activation-induced cytidine deaminase (AID), a DNA/RNA editing cytidine deaminase linking mutagenesis and tumorigenesis. These different strategies occurring during bacteria-host cell interaction, lead to nucleotide modifications and genome instabilities recognized as early events in the carcinogenesis process and contribute to the oncogenic properties of H. pylori infection. PMID- 20709623 TI - Effects of azinphos methyl and carbaryl on Rhinella arenarum larvae esterases and antioxidant enzymes. AB - Organophosphate (OP) and carbamate pesticides are anticholinesterasic agents also able to alter antioxidant defenses in different organisms. Amphibian larvae are naturally exposed to these pesticides in their aquatic environments located within agricultural areas. We studied the effect of the carbamate carbaryl (CB) and the OP azinphos methyl (AM), compounds extensively used in Northern Patagonian agricultural areas, on reduced glutathione (GSH) levels and the activities of esterases and antioxidant enzymes of the toad Rhinella arenarum larvae. Larvae were exposed 48 h to AM 3 and 6 mg/L or CB 10 and 20 mg/L. Cholinesterase and carboxylesterases were strongly inhibited by CB and AM. In insecticide-exposed larvae, carboxylesterases may serve as alternative targets protecting cholinesterase from inhibition. GSH-S-transferase (GST) activity was significantly increased by CB and AM. Superoxide dismutase activity increased in tadpoles exposed to 6 mg/L AM. Conversely, catalase (CAT) was significantly inhibited by both pesticides. GSH levels, GSH reductase and GSH peroxidase activities were not significantly affected by pesticide exposure. GST increase constitutes an important adaptive response to CB and AM exposure, as this enzyme has been related to pesticide tolerance in amphibian larvae. Besides, the ability to sustain GSH levels in spite of CAT inhibition indicates quite a good antioxidant response. In R. arenarum larvae, CAT and GST activities together with esterases could be used as biomarkers of CB and AM exposure. PMID- 20709624 TI - Comparative structural and functional studies of nanoparticle formulations for DNA and siRNA delivery. AB - The transfection efficiencies of 25-kDa branched polyethylenimine (B-PEI) and 22 kDa linear PEI (L-PEI) with both DNA and small interfering RNA (siRNA) were compared and correlated with their biophysical properties relating to complex formation, stability, and disassembly. L-PEI-DNA complexes transfected (5.18 * 10(8) relative luminescence units [RLU]/mg) around fivefold better than B-PEI-DNA complexes (0.95 * 10(8) RLU/mg), whereas B-PEI-siRNA complexes gave approximately 60% gene knockdown and L-PEI-siRNA complexes were inactive. Both B-PEI and L-PEI packaged DNA and siRNA to form positively charged nanoparticles; however, L-PEI nanoparticles were less stable than B-PEI nanoparticles, particularly with siRNA. The poor stability of L-PEI-siRNA complexes seemed to be the major factor contributing to an observed lack of cellular uptake and hence poor transfection. The more stable B-PEI-siRNA complexes, however, were bound, internalized, and detectable in the cytoplasm. These results highlight the importance of particle stability for efficient siRNA and plasmid delivery, while retaining the ability to readily dissociate within the cell. FROM THE CLINICAL EDITOR: Comparison of branched versus linear cationic polymers, i.e, polyethylenimine (PEI), were compared for their formation of condensed DNA and SiRNA complexes. Branched complexes were superior for transfection due to improved structural stability, making this PEI approach more likely to succeed as a nanotherapy. PMID- 20709625 TI - Multistep and multitask Bax activation. AB - Bax is a pro-apoptotic protein allowing apoptosis to occur through the intrinsic, damage-induced pathway, and amplifying that one occurring via the extrinsic, receptor mediated pathway. Bax is present in viable cells and activated by pro apoptotic stimuli. Activation implies structural changes, consisting of exposure of the N terminus and hydrophobic domains; changes in localization, consisting in migration from cytosol to mitochondria and endoplasmic reticulum membranes; changes in the aggregation status, from monomer to dimer and multimer. Bax has multiple critical domains, namely the N terminus exposed after activation; two hydrophobic stretches exposed for membrane anchorage; two reactive cysteines allowing multimerization; the BH3 domain for interactions with the Bcl-2 family members; alpha helix 1 for t-Bid interaction. Bax has also multiple functions: it releases different mitochondrial factors such as cytochrome c, SMAC/diablo; it regulates mitochondrial fission, the mitochondrial permeability transition pore; it promotes Ca(2+) leakage through ER membrane. Altogether, Bax activation is a complex multi-step phenomenon. Here, we analyze these events as logically separable or alternative steps, attempting to assess their role, timing and reciprocal relation. PMID- 20709626 TI - Metabolic flexibility and cell hierarchy in metastatic cancer. AB - Cancer is characterized by disturbed homeostasis of self-renewing cell populations, and their ability to seed and grow in multiple microenvironments. This overarching cellular property of metastatic cancer emerges from the contentious cancer stem cell hypothesis that underpins the more generic hallmarks of cancer (Hanahan and Weinberg, 2000) and its subsequent add-ons. An additional characteristic, metabolic flexibility, is related to concepts developed by Warburg and to subsequent work by mid 20th century biochemists who elucidated the bioenergetic workings of mitochondria. Metabolic flexibility may circumvent limitations inherent in the increasingly popular but erroneous view that aerobic glycolysis is a universal property of cancer cells. Cancer research in the second half of the 20th century was largely the domain of geneticists and molecular biologists using reductionist approaches. Integrated approaches that address cancer cell hierarchy and complexity, and how cancer cells adapt their metabolism according to their changing environment are now beginning to emerge, and these approaches promise to address the poor mortality statistics of metastatic cancer. PMID- 20709628 TI - Azoospermia in a man with a constitutional ring 22 chromosome. AB - A mosaic ring chromosome 22 (mos 46,XY,r(22)[93]/45,XY,-22[7]) was found in an euploid azoospermic otherwise phenotypically normal individual. Testicular cytological analysis showed hypospermatogenesis with a complete spermatogonial arrest. The majority of subjects with constitutional r(22) are dysmorphic and mentally retarded due to deletion of a sizable segment of the chromosome 22q. Only a few cases of r(22) chromosome are known in which deletion of the very distal telomeric regions is associated with unremarkable phenotype and fertility, both in males and females. The present patient is the first example of male infertility associated with this cytogenetic anomaly. It is likely that infertility arose from a mechanical block of meiosis, resulting from pairing failure of chromosomes 22, similarly to azoospermia occurring in few known males with r(21) chromosomes. PMID- 20709629 TI - First experience of enzyme replacement therapy with idursulfase in Spanish patients with Hunter syndrome under 5 years of age: case observations from the Hunter Outcome Survey (HOS). AB - Hunter syndrome (mucopolysaccharidosis type II [MPS II], OMIM309900) is a rare X linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2 sulphatase, resulting in accumulation of glycosaminoglycans (GAGs), multisystem organ failure and early death. Enzyme replacement therapy (ERT) with idursulfase is commercially available since 2007. Early access programs were established since 2005. However, limited information on the effects of ERT in young children is available to date. The aim of this analysis was therefore to determine the effects of ERT on patients younger than 5 years of age. We report data from six Spanish patients with confirmed Hunter syndrome who were younger than 5 years at the start of ERT, and had been treated with weekly intravenous infusions of idursulfase between 6 and 14 months. Baseline and treatment data were obtained from the Hunter Outcome Survey (HOS). HOS is an international database of MPS II patients on ERT or candidates to be treated, that collects data in a registry manner. HOS is supported by Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA). At baseline, all patients showed neurological abnormalities, including ventriculomegaly, hydrocephaly, cerebral atrophy, perivascular changes and white matter lesions. Other signs and symptoms included thoracic deformity, otitis media, joint stiffness and hepatosplenomegaly, demonstrating that children under 5 years old can also be severely affected. ERT reduced urinary GAG levels, and reduced spleen (n = 2) and liver size (n = 1) after only 8 months. Height growth was maintained within the normal range during ERT. Joint mobility either stabilized or improved during ERT. In conclusion, this case series confirms the early onset of signs and symptoms of Hunter syndrome and provides the first evidence of ERT beneficial effects in patients less than 5 years of age. Similar efficacy and safety profiles to those seen in older children can be suggested, although further studies including a direct comparison with older patients would still be required. PMID- 20709627 TI - Contemporary human genetic strategies in aging research. AB - Human aging is a complex, multifactorial process influenced by a number of genetic and non-genetic factors. This article first reviews genetic strategies for human aging research and considers the advantages and disadvantages of each. We then discuss the issue of phenotypic definition for genetic studies of aging, including longevity/life span, as well as disease-free survival and other endophenotypes. Finally, we argue that extensions of this area of research, including incorporation of gene*environment interactions, multivariate phenotypes, integration of functional genomic annotations, and exploitation of orthology - many of which are already initiated and ongoing - are critical to advancing this field. PMID- 20709630 TI - Bleach-boosting effect of crude xylanase from Bacillus stearothermophilus SDX on wheat straw pulp. AB - Pretreatment of wheat straw pulp using cellulase-free xylanase produced from Bacillus stearothermophilus SDX at 60 degrees C for 120min resulted in 4.75% and 22.31% increase in brightness and whiteness, respectively. Enzyme dose of 10U/g of oven dried pulp at pH 9 decreased the kappa number and permanganate number by 7.14% and 5.31%, respectively. Further chlorine dioxide and alkaline bleaching sequences (CDED(1)D(2)) resulted in 1.76% and 3.63% increase in brightness and whiteness, respectively. Enzymatic prebleaching of pulp decreased 20% of chlorine consumption without any decrease in brightness. Improvement in various pulp properties like viscosity, burst factor, burstness, breaking length, double fold, gurley porosity, tear factor, and tearness were also observed after bleaching of xylanase treated wheat straw pulp. PMID- 20709631 TI - One-pot enzymatic synthesis of docosahexaenoic acid-rich triacylglycerols at the sn-1(3) position using by-product from selective hydrolysis of tuna oil. AB - Docosahexaenoic acid (DHA)-rich oil has been industrially produced by selective hydrolysis of tuna oil with a lipase that acts weakly on DHA. The free fatty acids (FFAs) generated in this process as by-products contain a high DHA concentration (46wt%) but are treated as industrial waste. This study attempted to reuse these by-product FFAs using a one-pot process, and succeeded in producing triacylglycerols (TAGs) through the esterification of the by-product FFAs with glycerol using immobilized Rhizomucor miehei lipase. Regiospecific analysis of the resulting TAGs showed that the content of DHA at the sn-1(3) position (51.7mol%) was higher than the content of DHA at the sn-2 position (17.3mol%). The DHA distribution in TAGs synthesized in this study was similar to the DHA distribution in TAGs from seal oil. PMID- 20709632 TI - Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5 dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors. AB - Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E 6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib. These drugs inhibited mitogen-mediated T cell proliferation as well as Interleukin (IL)-2, tumor necrosis factor (TNF)-alpha and Interferon (IFN)-gamma synthesis by activated T cells, independently of their ability to inhibit COX-2 enzymatic activity. Immunosuppressive effects of these drugs seem to be due to their interference on transcription factor activation as induced transcription from Nuclear Factor (NF)-kappaB and Nuclear Factor of Activated T cells (NFAT) dependent enhancers was inhibited in a dose-dependent manner, being the latter effect the most sensitive to the action of those compounds. Both NFAT dephosphorylation, required for its nuclear translocation, as well as transcriptional activity of a GAL4-NFAT chimera were diminished in the presence of these compounds. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory actions of NSAIDs, which may have important implications in anti-inflammatory therapy, through inhibition of NFAT. PMID- 20709633 TI - Compression behaviour of biphasic calcium phosphate and biphasic calcium phosphate-agarose scaffolds for bone regeneration. AB - There is an acknowledged need for shaping 3-D scaffolds with adequate porosity and mechanical properties for biomedical applications. The mechanical properties under static and cyclic compressive testing of dense and designed porous architecture bioceramic scaffolds based on the biphasic calcium phosphate (BCP) systems and BCP-agarose systems have been evaluated. The dense and designed porous architecture scaffolds in BCP systems exhibited a brittle behaviour. Agarose, a biocompatible and biodegradable hydrogel, has been used to shape designed architecture ceramic-agarose scaffolds following a low-temperature shaping method. Agarose conferred toughness, ductility and a rubbery consistency for strains of up to 60% of in ceramic BCP-agarose systems. This combination of ceramic and organic matrix helps to avoid the inherent brittleness of the bioceramic and enhances the compression resistance of hydrogel. The presence of mechanical hysteresis, permanent deformation after the first cycle and recovery of the master monotonous curve indicate a Mullins-like effect such as that observed in carbon-filled rubber systems. We report this type of mechanical behaviour, the Mullins effect, for the first time in bioceramics and bioceramic agarose systems. PMID- 20709634 TI - Development of a microwave-accelerated metal-enhanced fluorescence 40 second, <100 cfu/ml point of care assay for the detection of Chlamydia trachomatis. AB - An inexpensive technology to both lyse Chlamydia trachomatis (CT) and detect DNA released from CT within 40 s is demonstrated. In a microwave cavity, energy is highly focused using 100-nm gold films with "bow-tie" structures to lyse CT within 10 s. The ultrafast detection of the released DNA from less than 100 cfu/mL CT is accomplished in an additional 30 s by employing the microwave accelerated metal-enhanced fluorescence technique. This new "release and detect" platform technology is a highly attractive alternative method for the lysing of bacteria, DNA extraction, and the fast quantification of bacteria and potentially other pathogenic species and cells as well. Our approach is a significant step forward for the development of a point of care test for CT. PMID- 20709635 TI - Analysis of wormlike robotic locomotion on compliant surfaces. AB - An inherent characteristic of biological vessels and tissues is that they exhibit significant compliance or flexibility, both in the normal and tangential directions. The latter in particular is atypical of standard engineering materials and presents additional challenges for designing robotic mechanisms for navigation inside biological vessels by crawling on the tissue. Several studies aimed at designing and building wormlike robots have been carried out, but little was done on analyzing the interactions between the robots and their flexible environment. In this study, we will analyze the interaction between earthworm robots and biological tissues where contact mechanics is the dominant factor. Specifically, the efficiency of locomotion of earthworm robots is derived as a function of the tangential flexibility, friction coefficients, number of cells in the robot, and external forces. PMID- 20709636 TI - Assessment of human body impedance for safety requirements against contact currents for frequencies up to 110 MHz. AB - This paper deals with contact currents that may occur when the human body is in contact with two electrodes at different electrical potentials, e.g., an electrical/electronic device and the floor. Actually, any device must comply not only with electromagnetic compatibility and safety requirements, but also with specific electromagnetic field exposure recommendations in order to prevent health hazards for the occupational and general public population. Since the contact currents depend on the applied voltage and on the human body impedance, this last parameter has been measured for several configurations in a broadband frequency range, from 40 Hz to 110 MHz. From the measurement results, a new equivalent circuit of the human body impedance is derived by using a vector fitting procedure. This equivalent circuit is very easy and can be adopted for compliance tests against contact currents. PMID- 20709637 TI - From vascular corrosion cast to electrical analog model for the study of human liver hemodynamics and perfusion. AB - Hypothermic machine perfusion (HMP) is experiencing a revival in organ preservation due to the limitations of static cold storage and the need for better preservation of expanded criteria donor organs. For livers, perfusion protocols are still poorly defined, and damage of sinusoidal endothelial cells and heterogeneous perfusion are concerns. In this study, an electrical model of the human liver blood circulation is developed to enlighten internal pressure and flow distributions during HMP. Detailed vascular data on two human livers, obtained by combining vascular corrosion casting, micro-CT-imaging and image processing, were used to set up the electrical model. Anatomical data could be measured up to 5--6 vessel generations in each tree and showed exponential trend lines, used to predict data for higher generations. Simulated flow and pressure were in accordance with literature data. The model was able to simulate effects of pressure-driven HMP on liver hemodynamics and reproduced observations such as flow competition between the hepatic artery and portal vein. Our simulations further indicate that, from a pure biomechanical (shear stress) standpoint, HMP with low pressures should not result in organ damage, and that fluid viscosity has no effect on the shear stress experienced by the liver microcirculation in pressure-driven HMP. PMID- 20709638 TI - Novel hysteretic noisy chaotic neural network for broadcast scheduling problems in packet radio networks. AB - Noisy chaotic neural network (NCNN), which can exhibit stochastic chaotic simulated annealing (SCSA), has been proven to be a powerful tool in solving combinatorial optimization problems. In order to retain the excellent optimization property of SCSA and improve the optimization performance of the NCNN using hysteretic dynamics without increasing network parameters, we first construct an equivalent model of the NCNN and then control noises in the equivalent model to propose a novel hysteretic noisy chaotic neural network (HNCNN). Compared with the NCNN, the proposed HNCNN can exhibit both SCSA and hysteretic dynamics without introducing extra system parameters, and can increase the effective convergence toward optimal or near-optimal solutions at higher noise levels. Broadcast scheduling problem (BSP) in packet radio networks (PRNs) is to design an optimal time-division multiple-access (TDMA) frame structure with minimal frame length, maximal channel utilization, and minimal average time delay. In this paper, the proposed HNCNN is applied to solve BSP in PRNs to demonstrate its performance. Simulation results show that the proposed HNCNN with higher noise amplitudes is more likely to find an optimal or near-optimal TDMA frame structure with a minimal average time delay than previous algorithms. PMID- 20709639 TI - Identification of finite state automata with a class of recurrent neural networks. AB - A class of recurrent neural networks is proposed and proven to be capable of identifying any discrete-time dynamical system. The application of the proposed network is addressed in the encoding, identification, and extraction of finite state automata (FSAs). Simulation results show that the identification of FSAs using the proposed network, trained by the hybrid greedy simulated annealing with a modified cost function in the training stage, generally exhibits better performance than the conventional identification procedures. PMID- 20709640 TI - Analysis and design of a k -winners-take-all model with a single state variable and the heaviside step activation function. AB - This paper presents a k-winners-take-all (kWTA) neural network with a single state variable and a hard-limiting activation function. First, following several kWTA problem formulations, related existing kWTA networks are reviewed. Then, the kWTA model model with a single state variable and a Heaviside step activation function is described and its global stability and finite-time convergence are proven with derived upper and lower bounds. In addition, the initial state estimation and a discrete-time version of the kWTA model are discussed. Furthermore, two selected applications to parallel sorting and rank-order filtering based on the kWTA model are discussed. Finally, simulation results show the effectiveness and performance of the kWTA model. PMID- 20709641 TI - Scalable large-margin Mahalanobis distance metric learning. AB - For many machine learning algorithms such as k-nearest neighbor ( k-NN) classifiers and k-means clustering, often their success heavily depends on the metric used to calculate distances between different data points. An effective solution for defining such a metric is to learn it from a set of labeled training samples. In this work, we propose a fast and scalable algorithm to learn a Mahalanobis distance metric. The Mahalanobis metric can be viewed as the Euclidean distance metric on the input data that have been linearly transformed. By employing the principle of margin maximization to achieve better generalization performances, this algorithm formulates the metric learning as a convex optimization problem and a positive semidefinite (p.s.d.) matrix is the unknown variable. Based on an important theorem that a p.s.d. trace-one matrix can always be represented as a convex combination of multiple rank-one matrices, our algorithm accommodates any differentiable loss function and solves the resulting optimization problem using a specialized gradient descent procedure. During the course of optimization, the proposed algorithm maintains the positive semidefiniteness of the matrix variable that is essential for a Mahalanobis metric. Compared with conventional methods like standard interior-point algorithms or the special solver used in large margin nearest neighbor , our algorithm is much more efficient and has a better performance in scalability. Experiments on benchmark data sets suggest that, compared with state-of-the-art metric learning algorithms, our algorithm can achieve a comparable classification accuracy with reduced computational complexity. PMID- 20709642 TI - A Q-modification neuroadaptive control architecture for discrete-time systems. AB - This brief extends the new neuroadaptive control framework for continuous-time nonlinear uncertain dynamical systems based on a Q -modification architecture to discrete-time systems. As in the continuous-time case, the discrete-time update laws involve auxiliary terms, or Q-modification terms, predicated on an estimate of the unknown neural network weights which in turn involve a set of auxiliary equations characterizing a set of affine hyperplanes. In addition, we show that the Q -modification terms in the discrete-time update law are designed to minimize an error criterion involving a sum of squares of the distances between the update weights and the family of affine hyperplanes. PMID- 20709643 TI - Flocking of multiple mobile robots based on backstepping. AB - This paper considers the flocking of multiple nonholonomic wheeled mobile robots. Distributed controllers are proposed with the aid of backstepping techniques, results from graph theory, and singular perturbation theory. The proposed controllers can make the states of a group of robots converge to a desired geometric pattern whose centroid moves along a desired trajectory under the condition that the desired trajectory is available to a portion of the group of robots. Since communication delay is inevitable in distributed control, its effect on the performance of the closed-loop systems is analyzed. It is shown that the proposed controllers work well if communication delays are constant. To show effectiveness of the proposed controllers, simulation results are included. PMID- 20709644 TI - Differential response to trichloroethylene-induced hepatosteatosis in wild-type and PPARalpha-humanized mice. AB - BACKGROUND: Trichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor alpha (PPAR) alpha, which is involved in lipid homeostasis and anti-inflammation. OBJECTIVE: We examined the role of mouse and human PPARalpha in TRI-induced hepatic steatosis and toxicity. METHODS: Male wild-type (mPPARalpha), Pparalpha-null, and humanized PPARalpha (hPPARalpha) mice on an Sv/129 background were exposed via inhalation to 0, 1,000, and 2,000 ppm TRI for 8 hr/day for 7 days. We assessed TRI-induced steatosis or hepatic damage through biochemical and histopathological measurements. RESULTS: Plasma alanine aminotransferase and aspartate aminotransferase activities increased in all mouse lines after exposure to 1,000 and 2,000 ppm TRI. Exposure induced hepatocyte necrosis and inflammatory cells in all mouse lines, but hepatic lipid accumulation was observed only in Pparalpha null and hPPARalpha mice. No differences were observed in TRI-mediated induction of hepatic PPARalpha target genes except for a few genes that differed between mPPARalpha and hPPARalpha mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacyl-glicerol acyltransferases, and PPARgamma in Pparalpha-null and hPPARalpha mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NFkappaB) p52 mRNA and protein in all mice regardless of PPARalpha genotype. CONCLUSIONS: NFkappaB-p52 is a candidate molecular marker for inflammation caused by TRI, and PPARalpha may be involved in TRI-induced hepatosteatosis. However, human PPARalpha may afford only weak protection against TRI-mediated effects compared with mouse PPARalpha. PMID- 20709645 TI - Topical photodynamic therapy for nevus sebaceous on the face. AB - Recently, topical photodynamic therapy (PDT) has been tried to treat sebaceous gland disorders. However, only one case of nevus sebaceous treated with PDT has been reported. Our aim was to investigate the outcomes of PDT on nevus sebaceus on the face. A total of 12 patients were treated with topical 20% ALA or methyl aminolevulinate (MAL) after CO(2) laser ablasion. The lesions were irradiated with light emitting diodes (LED) device. The regimen was delivered repeatedly at 1 to 4 week intervals to each patient. Clinical improvement was visually assessed at 1 month after treatment by the lesional responses; No response was defined as less than 25%, mild improvement as 25-50%, moderate improvement as 51-75% and marked improvement as more than 75% decrease of lesional volume. All 12 patients showed mild (3 patients, 25%), moderate (7 patients, 58%), and marked (2 patients, 17%) improvement of the lesions. However, 2 patients showed partial recurrences after completion of treatment. There was no significant side effect.These results suggest that topical PDT may be considered as an effective alternative treatment modality of nevus sebaceous on the face. PMID- 20709646 TI - Idiopathic eruptive macular pigmentation in a 50-year-old man. PMID- 20709647 TI - Multidisciplinary management of soft tissue sarcomas: it's time to make a team! PMID- 20709650 TI - Aflibercept (VEGF Trap): one more double-edged sword of anti-VEGF therapy for cancer? AB - The use of vascular endothelial growth factor (VEGF)-targeted agents for treating cancer has increased dramatically over recent decades. These drugs provide considerable benefits in terms of progression-free (PFS) or overall (OS) survival for cancer patients. Of particular importance to clinicians treating cancer patients by using VEGF-targeted agents is VEGF-inhibition-induced hypertension, proteinuria, thrombosis and hemorrhage. Aflibercept is a new, successful example of targeting VEGF for therapy of solid tumors. Though results from phase I and II clinical trials demonstrated aflibercept is well tolerated, it inevitably has severe adverse effects unique to this class of agents. In this review, we discuss the adverse effects associated with aflibercept (VEGF Trap), focusing on vascularassociated hypertension, proteinuria, hemorrhage, and thrombosis, and further discuss the mechanisms, significance, and potential management of these adverse effects. PMID- 20709649 TI - Circulating endothelial and endothelial progenitor cells in non-small-cell lung cancer. AB - New treatments have recently been introduced for treating non-small-cell lung cancer. Chemotherapeutic agents, such as pemetrexed, and targeted therapies, such as bevacizumab, erlotinib or gefitinib, have extended treatment options for selected histological subgroups. Antiangiogenic treatments, either associated with conventional chemotherapeutic drugs or given alone as maintenance therapy, constitute an active clinical research field. However, not all lung cancer patients benefit from antiangiogenic compounds. Moreover, tumour response assessment is often difficult when using these drugs, since targeted therapies generally do not cause rapid and measurable tumour shrinkage but, rather, long stabilisations and slight density changes on imaging tests. The finding of clinical or biological factors that might identify patients who will better benefit from these treatments, as well as identifying surrogate markers of tumour response and prognosis, is an issue of great interest. In that sense, different research lines have investigated the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. Circulating endothelial (CECs) and endothelial progenitor cells (CEPCs) are of prognostic value in different types of cancers, and relevant data are published about their potential usefulness as predictors of response to chemotherapy and antiangiogenic treatments. In this review, we discuss the data available on the role of CECs and CEPCs as prognostic factors and as surrogate markers of treatment response in non small-cell lung cancer. PMID- 20709651 TI - Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome. AB - The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5 fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optimising patient outcomes and avoiding unnecessary toxicities. PMID- 20709652 TI - Multidisciplinary management of soft tissue sarcomas. AB - Musculoskeletal sarcomas are a heterogeneous group of malignant neoplasms derived from connective tissue. Sarcomas represent about 1% of cancer in adults. The annual incidence in adults in Europe is around 14,000 new cases of soft tissue sarcomas (STS) and 4,800 new cases of bone sarcomas. Musculoskeletal tumours arise anywhere in the body, although lower extremities are the most common site of appearance, followed by upper extremities, trunk, retroperitoneum and head and neck area. Adequate management of STS is a stimulating challenge for oncologists. The aim of treatment should be focused on four main aspects: improving survival, avoiding local recurrence, maximising organ function and, finally, minimising morbidity. Surgery, radiotherapy and, sometimes though increasingly, chemotherapy are the pillars on which rests the modern treatment of sarcomas. The optimal management of musculoskeletal tumour requires a multidisciplinary integration of these different approaches in treatment planning right from the initial diagnoses. Referring patients to qualified centres should be desirable to achieve the maximum probability of control and even cure for STS. PMID- 20709654 TI - Serum C-telopeptide levels predict the incidence of skeletal-related events in cancer patients with secondary bone metastases. AB - INTRODUCTION: We evaluated serum C-telopeptides (CTX) to see whether they may be useful as predictive markers for disease progression in cancer patients with bone metastases who are being treated with zoledronic acid (ZA). PATIENTS AND METHODS: This was a prospective, nonrandomised study in which 26 patients with solid tumours and confirmed bone metastases were treated with ZA (4 mg every 3-4 weeks) for 24 months or until a skeletal-related event (SRE) was observed. Serum CTX levels were determined at baseline and 6, 12, 18 and 24 months after study initiation. SRE were evaluated using bone scintigraphy. RESULTS: Study participants had prostate (50%), breast (31%), lung (11%) or bladder (8%) tumours. Mean age was 69 (range 52-84) years, and 65% men. At baseline, overall mean CTX levels were 562.47 +/- 305.17 pg/dl. Patients who showed disease progression during the study period showed significantly higher CTX levels at baseline and after 18 months of ZA treatment than patients who did not progress (p = 0.040 and p = 0.006, respectively). Patients with >= 5 bone metastases at diagnosis had significantly higher CTX levels after 18 months of ZA treatment than patients with < 5 bone metastasis (p = 0.001). Similarly, at 12 and 18 months, patients without SRE had significantly lower CTX levels than patients in whom a SRE was observed (p = 0.005 and p = 0.001, respectively). CONCLUSIONS: Changes in serum CTX levels seem to predict the potential for tumour control and the likelihood of developing an SRE in a sample of patients with solid tumours and bone metastases treated with ZA. PMID- 20709655 TI - Diagnosis of unknown primary cancer based on molecular techniques may influence therapeutic approach and improve survival. AB - Unknown primary cancer (UPC) is a common clinical syndrome classically associated with a poor prognosis. Pathological examination including immunohistochemistry continues to be essential in tumour origin characterization, although in many cases primary tumour site remains unknown. Gene expression based analysis may offer important diagnostic information that could lead to therapeutic decisions. PMID- 20709653 TI - Gastrointestinal toxicity associated to radiation therapy. AB - Radiation therapy in combination with other treatments, such as surgery and chemotherapy, increases locoregional control and survival in patients with thoracic, abdominal and pelvic malignancies. Nevertheless, significant clinical toxicity with combined treatments may be seen in these patients. With the advent of tridimensional conformal radiotherapy (3D-CRT), dose-volume histograms (DVH) can be generated to assess the dose received by the organs at risk. The possible relationship between these parameters and clinical, anatomical and, more recently, genetic factors has to be considered. Treatment options include initial conservative medical therapies, endoscopic procedures, hyperbaric oxygen and surgery. Some pharmacological agents to prevent gastrointestinal toxicity are under investigation. PMID- 20709656 TI - Tracheal chondrosarcoma. AB - Tracheal chondrosarcoma are rare diseases, with only 15 cases previously described in the literature between 1959 and 2008. Here we present a rare case of tracheal chondrosarcoma and a review of the literature. Our patient, a 72-year old man, had progressive throat pain for 2 years before diagnosis. Clinical and imaging investigation revealed a giant tracheal mass that was partially debulked by laser for symptomatic relief. Histologically, the mass was characterized as a low-grade tracheal chondrosarcoma. The patient underwent external-beam radiotherapy (EBRT) and received 60 Gy. At the time this report was written, 7 years after the end of the treatment, the patient was alive and asymptomatic without evidence of locoregional disease. This case and some described in the literature demonstrate the value of EBRT as a single treatment modality in achieving local control. More experience is required to establish the definitive role of radiotherapy in low-grade tracheal chondrosarcoma. PMID- 20709660 TI - Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future. AB - Recent studies show that multiple myeloma (MM) is consistently preceded by an asymptomatic precursor state. Smoldering MM (SMM) is a MM precursor defined by an M-protein concentration >or= 3 g/dL and/or >or= 10% bone marrow plasma cells, in the absence of end-organ damage. Compared with individuals diagnosed with monoclonal gammopathy of undetermined significance (MGUS), patients with SMM have a much higher annual risk of developing MM. However, based on clinical observations, the natural history of SMM varies greatly, from stable MGUS-like disease to highly progressive disease. Using conventional clinical markers, SMM patients can be stratified into 3 risk groups. Importantly, because of considerable molecular heterogeneity, we currently lack reliable markers to predict prognosis for individual SMM patients. Furthermore, until recently, potent drugs with reasonable toxicity profiles have not been available for the development of early MM treatment strategies. Consequently, current clinical guidelines emphasize the application of close clinical monitoring followed by treatment when the patient develops symptomatic MM. This review focuses on novel biomarkers, molecular profiles, and microenvironmental interactions of interest in myelomagenesis. We also discuss how the integration of novel biologic markers and clinical monitoring of SMM could facilitate the development of early treatment strategies for high-risk SMM patients in the future. PMID- 20709659 TI - The sarcoid-lymphoma syndrome. AB - Whether a relationship exists between sarcoidosis and lymphoma is controversial. We present 4 patients diagnosed with sarcoidosis either during or after the treatment of lymphoma, review the data surrounding the entity known as "sarcoid lymphoma syndrome" and discuss the diagnostic pitfalls it can present. As both entities are fluorine-18 fluorodeoxyglucose avid, histologic verification and clinical acumen are needed to avoid misdiagnosis before initiating therapy. PMID- 20709657 TI - Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias. AB - INTRODUCTION: For nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre's experience with the use of CKs and TKIs in the treatment of patients with advanced RCC. MATERIALS AND METHODS: This study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival. RESULTS: Ninety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3-4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1-2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82-162] and with TKIs 201 days (65-337) in the first and 346 days (256-436) in second line treatment groups. The median overall survival (OS) was 229 days (142-316) and 2,074 days (1,152-2,996) for patients treated with CKs and TKIs. CONCLUSIONS: Our results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level. PMID- 20709661 TI - Yttrium-90 ibritumomab tiuxetan as a single agent in patients with pretreated B cell lymphoma: evaluation of the long-term outcome. AB - BACKGROUND: Based on historical data on the role of radioimmunotherapy (RIT) in pretreated non-Hodgkin lymphoma, we reviewed our hospital's clinical database. PATIENTS AND METHODS: Between 2005 and 2008, 57 patients previously treated with at least 1 rituximab-containing chemotherapy were treated with Yttrium-90-labeled ibritumomab tiuxetan ((90)Y-IT). The median number of pretreatments was 3 (range, 1-9 pretreatments). A total of 46 patients had stage III/IV disease (31 with bone marrow involvement); 6 had bulky disease. According to histology, 53 were follicular lymphoma (FL), 2 were marginal zone lymphoma, and 2 were small lymphocytic lymphoma. RESULTS: Overall response rate was 93% (53 of 57); complete response (CR) rate was 70% (40 of 57). Twenty-six of 40 patients (65%) who obtained a CR are in continuous CR (CCR) with a median follow-up of 20 months (range, 10-42 months); 4 of them still maintain their CCR after 36 months. All patients achieving a CCR had FL, and 21 of them with stage III/IV disease; 12 of 26 had been heavily pretreated (>or= 3 previous treatments), and 2 had had autologous stem cell transplantation. Toxicity was primarily hematologic and mostly transient; no grade 4 extrahematologic toxicity was observed. CONCLUSION: This study confirms the safety and high efficacy of (90)Y-IT RIT in heavily pretreated FL patients, with the possibility of having a subset of long-term responders. PMID- 20709662 TI - Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) is an effective and safe salvage regimen in relapsed/refractory B-cell non-Hodgkin lymphoma. AB - BACKGROUND: Salvage therapy for patients with refractory/relapsed B-cell non Hodgkin lymphoma (NHL) is based on polychemotherapy, followed by high-dose therapy and autologous stem cell transplantation in eligible patients (HDT/ASCT). R-DHAP combines rituximab with cisplatin, cytarabine, and dexamethasone. PATIENTS AND METHODS: We substituted cisplatin with oxaliplatin to avoid nephrotoxicity and retrospectively analyzed a large series of 91 patients with refractory/relapsed B-cell NHL to evaluate toxicities, response rates (RRs), and survival. Median age at R-DHAX (rituximab/dexamethasone/cytarabine/oxaliplatin) treatment was 60 years (range, 28-82 years). Renal insufficiency was present in 18 patients. The most frequent histologic subtypes were diffuse large B-cell lymphoma (n = 42) and follicular lymphoma (n = 30). Seventeen patients (19%) were naive to rituximab at time of R-DHAX. RESULTS: Grade III/IV toxicities were mainly hematologic, including anemia (n = 9), neutropenia (n = 44), and thrombocytopenia (n = 47). Grade I/II neurologic toxicities, sensitive or motor, were observed, and these were mainly transient except for 3 cases of motor neuropathy associated with previous exposure to vincristine. Neither renal toxicities nor degradation of previous renal insufficiency were observed. The overall RR was 75%, with a complete RR of 57%, with no statistical difference between patients previously treated with rituximab versus without rituximab. At a median follow-up of 23 months, 2-year probability rates of overall survival and progression-free survival were 75% and 43%, respectively, with a significant difference between patients treated with HDT/ASCT and patients not eligible for HDT/ASCT. CONCLUSION: R-DHAX is an efficient regimen in patients with relapsed/refractory B-cell NHL even in elderly patients if hematologic toxicities are closely managed. PMID- 20709663 TI - Surveillance computed tomography scans for patients with lymphoma: is the risk worth the benefits? AB - BACKGROUND: Concerns regarding the risks of cancer and cancer-related death as a result of radiation from computed tomography (CT) scans and the lack of data demonstrating a survival advantage for surveillance CT scans following lymphoma therapy have raised questions regarding their benefit. We compared the radiation related lifetime cancer incidence (LCI) and mortality risks (LCMRs) associated with CT scans for staging and surveillance of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) with the cumulative probability of lymphoma death (CPLD) during surveillance. PATIENTS AND METHODS: The LCI and LCMR were calculated using published estimates of the cumulative organ-specific radiation doses from full body CT scans and sex-, age-, and organ-dependent cancer risks per 0.1 Gy provided by the Biologic Effects of Ionizing Radiations VII report. Surveillance, Epidemiology, and End Results (SEER) data were used to identify cases between 2000 and 2006 from 17 SEER registries and calculate CPLD for specified cohorts. RESULTS: For a 70-year-old patient, a single full-body CT examination is associated with a LCI of 0.044% and 0.057%, and a LCMR of 0.032% and 0.044% for males and females, respectively. For 20-year-old patients the LCMRs were 0.071% for men and 0.108% for women. The LCI and LCMR were lower for males and were markedly less than the CPLD at 5 years for most lymphoma subtypes, but relevant for younger women with HL. CONCLUSION: Although the LCMR from CT scans is small compared with lymphoma-related deaths for most subgroups, these data should be discussed with patients in formulating plans for surveillance following lymphoma therapy. PMID- 20709664 TI - Comparison of serum immunofixation electrophoresis and free light chain assays in the detection of monoclonal gammopathies. AB - BACKGROUND: Diagnosis of monoclonal gammopathies (MGs) is determined by demonstration of a monoclonal immunoglobulin molecule or chain in serum and/or urine. Previous results on immunofixation electrophoresis (IFE) and quantitative free light chain (FLC) measurements have been conflicting. PATIENTS AND METHODS: The purpose of this study was to compare IFE with serum FLC assays in the detection of MG. Between November 2006 and November 2007, results on routinely ordered serum IFE specimens were compared with independently conducted FLC assays. RESULTS: Monoclonal gammopathies were identified in 144 specimens by IFE; 73 patients (50.7%) had a normal kappa/lambda ratio in the FLC assay. Also, 44.6% of samples with IgG and IgA M-proteins had a normal kappa/lambda ratio. Of 357 sera that showed no M-protein by IFE, 95.8% exhibited a normal kappa/lambda ratio. Out of 11 patients with light chain disease, 9 had abnormal kappa/lambda ratios. It is unclear why half of the patients with MG by IFE had normal kappa/lambda ratios. Lower M-components in these patients suggested that some had monoclonal gammopathy of undetermined significance. CONCLUSION: For screening purposes, serum IFE should be carried out in patients with suspected MG. PMID- 20709665 TI - Phase II study of sunitinib in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. AB - BACKGROUND: Changes in the bone marrow microenvironment in myelofibrosis are triggered by a cytokine burst and consist of fibrosis, osteosclerosis, and angiogenesis. Sunitinib is a multitargeted small-molecule inhibitor of the receptor tyrosine kinases involved in cell proliferation and angiogenesis, including vascular endothelial growth factor receptors. PATIENTS AND METHODS: Fourteen patients with myelofibrosis were treated with sunitinib at a daily continuous dose of 37.5 mg orally. The median duration of sunitinib treatment was 5.2 months (range, 1-18 months). RESULTS: One patient (7%) showed a clinical improvement of anemia (increase in hemoglobin of 4 g/dL), with improvement in anemia-associated symptoms. The time to response was 6 months, and the benefit was sustained for 12 months. However, 8 patients (57%) experienced a total of 13 incidents of significant (grade 3-4) adverse events possibly related to sunitinib (fatigue, gastrointestinal disturbances, anemia, leukopenia, and thrombocytopenia were the most common). In 7 patients (50%), sunitinib was held, and subsequently the dose was reduced to 25 mg daily. Overall, 29% of patients withdrew from the study because of toxicity. CONCLUSION: Sunitinib therapy, as applied here, was not well-tolerated by patients with myelofibrosis, and the benefits were minimal. Our experience with sunitinib combined with previous experience with other antiangiogenic medications suggest that this class of drugs may have limited usefulness in myelofibrosis when used as a single-agent therapy. PMID- 20709667 TI - Improved survival for multiple myeloma in denmark based on autologous stem cell transplantation and novel drug therapy in collaborative trials: analysis of accrual, prognostic variables, selection bias, and clinical behavior on survival in more than 1200 patients in trials of the nordic myeloma study group. AB - BACKGROUND: An unexplained survival difference was observed in the Nordic Myeloma Study Group (NMSG) high-dose therapy trial 5/94 in Denmark compared with Sweden and Norway; however, this difference was eliminated in the subsequent NMSG trial 7/98. It was hypothesized that a detailed analysis of potential explanations would reveal important information for future designs of clinical trials for multiple myeloma (MM) patients in Denmark. PATIENTS AND METHODS: The analysis is based on 3 consecutive clinical trials coordinated by NMSG from 1990 to 2000: NMSG 4/90 including 583 patients, NMSG 5/94 including 274 patients and NMSG 7/98 including 414 patients with newly diagnosed MM. Event-free and total survival rates were calculated according to the Kaplan-Meier method, and survival comparisons were made by the log-rank test. The Cox proportional hazards regression model was used to estimate the prognostic importance of selected variables. RESULTS: The analysis revealed no differences in disease stages, prognostic variables, or inclusion bias at diagnosis between the 3 consecutive NMSG trials. However, the number of initial treatment failures was low, and post relapse survival was superior in Swedish patients as compared to Danish patients. These differences were explained by a defensive clinical practice in Denmark during 1994-1997 for patients with poor risk refractory or relapsed disease. CONCLUSION: These initially observed differences were subsequently eliminated most likely as a consequence of international collaboration improving diagnosis, research infrastructure, clinical training, and education as planned within the European Myeloma Network (EMN). PMID- 20709666 TI - Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. AB - BACKGROUND: Myelofibrosis (MF) is a disease characterized by the overexpression of the antiapoptotic BCL-2 family of proteins (eg, BCL-XL and MCL-1). PATIENTS AND METHODS: We conducted a multicenter, open-label, noncomparative phase II study of obatoclax mesylate, a small-molecule pan-BCL-2 antagonist, in patients with MF. Obatoclax was administered as a 24-hour infusion (on an outpatient basis) every 2 weeks at a fixed dose of 60 mg. RESULTS: A total of 22 patients were enrolled, with a median age of 63 years (range, 43-89 years). Twelve were men, and all 22 patients were previously treated (median of 2 previous therapies). Ten patients (45%) had a Lille score of 1, and 9 patients (41%) had a Lille score of 2. Thirteen (59%) were red blood cell transfusion dependent. A median of 7 cycles of obatoclax were administered. No patient achieved complete or partial response according to International Working Group criteria. One patient (4%) demonstrated a clinical improvement (in terms of hemoglobin and platelet count) after 7 cycles of therapy. The improvement was sustained for 4 cycles of therapy, after which he underwent allogeneic stem cell transplantation. The most common adverse events included low-grade ataxia and fatigue in 50% of the patients. Dose reduction because of toxicity was required in 1 patient, whereas 2 patients were taken off the study because of grade 3 ataxia and grade 3 heart failure. Grade 3/4 anemia and thrombocytopenia were evident in 6 (27%) and 4 (18%) patients, respectively. CONCLUSION: Obatoclax exhibits no significant clinical activity in patients with MF at the dose and schedule evaluated. PMID- 20709668 TI - Chronic lymphocytic leukemia and focusing on epidemiology and management in everyday hematologic practice: recent data from the Czech Leukemia Study Group for Life (CELL). AB - PURPOSE: Currently, pathogenesis, new prognostic factors, or new therapy in chronic lymphocytic leukemia (CLL) are frequently discussed; however, up-to-date data concerning the incidence and the management of CLL in everyday hematologic practice are still missing. The aim of our study was to find out the accurate epidemiologic situation of CLL and the diagnostic and therapeutic preferences of hematologists in the preselect area: the South Moravian Region (1,127,718 inhabitants, white race). PATIENTS AND METHODS: The total number of 540 patients (median age at the time of diagnosis, 65 years; sex, 306 men and 234 women) who had been followed in 2008 were included in the analysis. RESULTS: In the years 2006 and 2007, the incidence of CLL was 5.8 and 6.2, respectively, per 100,000; the prevalence was 48 per 100,000. Chronic lymphocytic leukemia treatment was indicated in 194 patients (36%); 93 (17%) of them also underwent the second line of treatment. Of these 194 patients, 64 patients (33%) were given fludarabine based regimens, and 74 patients (38%) received chlorambucil as a first line of treatment. Thirty patients were treated within clinical trials. Although the treatment was indicated in only one third of patients (36%), new prognostic factors were examined in > 50% of patients. CONCLUSION: The ascertained incidence of CLL in our region is higher than declared incidence in the past. Evidently, CLL became an often misdiagnosed and underreported disease. PMID- 20709672 TI - [Effect of DNA methylation and histone modification during the development of cloned animals.]. AB - Somatic cell nuclear transfer (SCNT) has great potential for agricultural applications, generation of medical model animals, transgenic farm animals or generating human embryonic stem cells for treatment of human diseases. Cloned animals derived from somatic cells have been generated in several mammal species, but there are still some unsolved problems with current cloning technology, for example, the low efficiency of animal cloning and the abnormal development of cloned animals. One critical factor of these developmental failures of cloned embryos is the aberrant epigenetic reprogramming. This review focuses on DNA methylation and histone modifications and the relationship between these two epigenetic modifications and the development of cloned embryos. Understanding the mechanisms of epigenetic regulation will be useful to solve the technical problems of SCNT and enable better applications of this technology. PMID- 20709669 TI - Peripheral blasts on day 21 of induction chemotherapy in a patient with core binding factor acute myeloid leukemia: more than meets the eye. AB - The combination of fludarabine, high-dose cytarabine, gemtuzumab ozogamicin, and granulocyte colony-stimulating factor (G-CSF), the FLAG-GO protocol, has resulted in excellent response rates and superior relapse-free survival as first-line therapy for patients with core binding factor acute myeloid leukemia (AML). A side effect of administration of G-CSF is an increase in peripheral white blood cell count and blast cell percentage during the recovery phase of the bone marrow after induction chemotherapy. A 60-year-old man with inversion 16 AML was admitted for induction chemotherapy with the FLAG-GO protocol at our institution. On day 21 of his induction regimen, he was noted to have blasts in both the peripheral smear and in the bone marrow that resolved on their own without any intervention by day 28. Our case report underscores the importance of recognizing this phenomenon associated with the administration of G-CSF, and waiting for 5-7 days before administering re-induction therapy or classifying the disease as primary refractory AML. PMID- 20709673 TI - [Review on the genomic imprinting at the mammalian DLK1-DIO3 cluster.]. AB - The mammalian imprinting domain DLK1-DIO3 is located on distal human chromosome 14, mouse chromosome 12 and sheep chromosome 18. This cluster contains three imprinted protein-coding genes (Dlk1, Rtl1, and Dio3), which were expressed from the paternally inherited chromosome and several imprinted noncoding RNA genes expressed from the maternally inherited allele, such as miRNAs, snoRNAs, and large noncoding RNA Gtl2. The altered gene dosage of DLK1-DIO3 cluster resulted in several severe abnormal phenotypes in human and mouse, even death, suggesting the importance of these genes for normal development. This review focuses on the function of imprinted genes on this domain and the mechanism of their imprinting regulation. PMID- 20709674 TI - [Function study advances of Parkinson disease related genes]. AB - Parkinson cents disease (PD) is a common extrapyramidal disease, of which the cardinal symptoms are hypokinesia, muscular rigidity, and tremor. The main pathological characteristics of this disease are loss of dopamine neurons in substantia nigra pars compacta, and residual neurons often contain Lewy bodies. The PD pathogenesis is still not well known, while it is generally recognized that age and environmental factors participate in it. In recent years, genetic research on PD has made considerable progresses that genetic factors play important roles on the pathogenesis of PD, and multiple PD related genes, such as SNCA, LRRK2, PINK1, parkin, UCHL1, and DJ1, have been identified. This article summarizes recent progresses on these genes to provide reference for PD study. PMID- 20709675 TI - [Regulation of the JNK signaling pathway by dual leucine zipper kinase DLK.]. AB - The C-Jun NH2-terminal kinase (JNK) belongs to the evolutionarily conserved sub group of mitogen-activated protein (MAP) kinases family. Many studies have shown that JNK pathway plays physiological roles in cell proliferation, differentiation, migration and apoptosis, and its deregulation has been associated with developmental defects and various human diseases. Dual leucine zipper kinase (DLK) is a member of the mixed-lineage kinases that performs important cellu-lar functions as a MAP triple kinase (MAPKKK) in regulating the JNK signaling pathway. In this paper, we described the DLK protein structures, physiological roles, and their functional interactions with JNK signaling, as well as the molecular mechanisms underlying their involvement in various human diseases. PMID- 20709676 TI - [The motive force of evolution based on the principle of organismal adjustment evolution.]. AB - From the analysis of the existing problems of the prevalent theories of evolution, this paper discussed the motive force of evolution based on the knowledge of the principle of organismal adjustment evolution to get a new understanding of the evolution mechanism. In the guide of Schrodinger's theory - "life feeds on negative entropy", the author proposed that "negative entropy flow" actually includes material flow, energy flow and information flow, and the "negative entropy flow" is the motive force for living and development. By modifying my own theory of principle of organismal adjustment evolution (not adaptation evolution), a new theory of "regulation system of organismal adjustment evolution involved in DNA, RNA and protein interacting with environment" is proposed. According to the view that phylogenetic development is the "integral" of individual development, the difference of negative entropy flow between organisms and environment is considered to be a motive force for evolution, which is a new understanding of the mechanism of evolution. Based on such understanding, evolution is regarded as "a changing process that one subsystem passes all or part of its genetic information to the next generation in a larger system, and during the adaptation process produces some new elements, stops some old ones, and thereby lasts in the larger system". Some other controversial questions related to evolution are also discussed. PMID- 20709677 TI - [Research progress on genomic integrity regulated by epigenetics using yeast as a model.]. AB - Genomic integrity is crucial for normal cell replication, proliferation and differentiation. DNA lesions resulted from exogenous and endogenous factors will lead to genomic instability, and consequently the cause for various diseases. Epigenetic regulation (including DNA methylation, histone modifications and non coding RNA) plays important roles in DNA lesion repair and cell cycle regulation as well as maintaining the genetic integrity. The yeast, a type of single cell eukaryotic organism, is an ideal model for the researches of epigenetics, especially in the area of DNA lesion repair and the formation of heterochromatin. Previous researches on epigenetics were mainly focus on histone modifications. Recent re-searches have observed that non-coding RNAs are able to direct the cytosine methylation and histone modifications that are related to gene expression regulation. This paper discuss the mechanism, research progress and future development of epi-genetics in maintaining the genomic integrity, using the yeast as a model. PMID- 20709678 TI - [Association and meta-analysis of ENPP1 K121Q with type 2 diabetes in Han Chinese.]. AB - Multiple meta-analyses in Europeans showed that ENPP1 K121Q polymorphism was associated with type 2 diabetes. However, no association in Japanese, Korean, and Chinese in Taiwan, and inconsistent results in mainland Chinese were reported. In this study, the single nucleotide polymorphism K121Q of the ENPP1gene was genotyped in 539 type 2 diabetes patients and 404 healthy controls. No difference was observed in the genotypic and alle-lic frequencies of ENPP1 K121Q between the cases and the controls. Logistic regression analysis with adjustment of sex, age, and BMI suggested that the XQ genotype was significantly associated with the risk of type 2 diabetes (OR=1.5, 95%CI: 1.39-1.62, P<0.001). Sub-group analysis by gender revealed that the association between ENPP1 K121Q and type 2 diabetes was observed only in women (Q: 12.4% vs. 6.1%, P=0.001; XQ: 23.7% vs. 11.7%, P=0.001). Our results suggest that the association of ENPP1 K121Q with type 2 diabetes in Hubei Han Chinese population is more evident in women. The first meta analysis of 10 Chinese studies indicated that the Q allele increased the risk of type 2 diabetes (OR=1.42, P=0.042). PMID- 20709679 TI - [Mutation analysis of LITAF, RAB7, LMNA and MTMR2 genes in Chinese Charcot-Marie Tooth disease.]. AB - The purpose of this study was to understand the mutation features of lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF), ras associated protein RAB7 (RAB7), lamin A/C (LMNA) and myotubularin-related protein 2 (MTMR2) genes in Chinese Charcot-Marie-Tooth disease (CMT) patients. Mutation analysis of LITAF gene was carried out using PCR combined with DNA sequencing, and mutation analysis of RAB7 gene by PCR-single strand conformation polymorphism (PCR-SSCP) combined with DNA sequencing in 33 CMT patients including 6 probands of autosomal domi-nated CMT families and 27 sporadic patients; mutation analysis of LMNA and MTMR2 genes was observed using PCR-SSCP combined with DNA sequencing in 41 CMT patients, including 14 probands of autosomal recessive CMT fami-lies and 27 sporadic patients. Two sequence variations c.269G-->A and c.274A-->G were detected in LITAF gene and two sequence variations c.1243G-->A and c.1910C-->T were detected in LMNA gene. No sequence variation was found in RAB7 and MTMR2 gene. Variations of c.269G-->A in LITAF gene and c.1243G-->A, c.1910C-->T in LMNA gene are newly found SNPs in this study. Variation of c.274A-->G in LITAF gene is known SNP reported in SNP database. Mutations in LITAF, RAB7, LMNA, and MTMR2 genes are rare in Chinese CMT patients. PMID- 20709680 TI - [Construction and identification of the chromosome specific DNA library.]. AB - The objective of the present study was to construct a human chromosome 21 specific DNA library for further use in research of genetic disease. Human chromosome 21 microdissected from the peripheral blood cells were subjected to repeatedly incubation in gradient temperature bath to release DNA. The library of chromosome 21 was constructed using the DNA fragment of 100-500 bp and 500-2 000 bp recovered from the products of DOP-PCR. Florescence in situ hy-bridization (FISH) and dot blotting analyses were carried out to assess the chromosome 21 specificity of the DNA library. The results indicated that DNA of chromosome 21 was released easily after repeatedly incubation in gradient temperature bath. Recovery of DNA fragments from DOP-PCR in different size ranges improved the efficiency of cloning of large fragments. Both FISH and dot blotting analyses revealed that the DNA library constructed in this study was chromosome 21 specific. This DNA library facilitates identification and investigation of the chromosome 21 related abnormality. PMID- 20709681 TI - [Transcriptome atlas of serine family amino acid metabolism-related genes in eight rat regenerating liver cell types.]. AB - To explore the transcription profiles of serine family amino acid metabolism related genes in eight liver cell types during rat liver regeneration (LR), eight types of rat regenerating liver cells were isolated using the combination of percoll density gradient centrifugation and immunomagnetic bead methods. Then, the expression profiles of the genes associated with metabolism of serine family amino acid in rat liver regeneration were detected by Rat Genome 230 2.0 Array. The expression patterns of these genes were analyzed through the software of Cluster and Treeview. The activities of serine family amino acid metabolism were analyzed by the methods of bioinformatics and systems biology. The results showed that 27 genes were significantly expressed. Among them, the numbers of genes showing significant expression changes in hepatocytes, biliary epithelial cells, oval cells, hepatic stellate cells, sinusoidal endothelial cells, Kupffer cells, pit cells and dendritic cells were 13, 16, 11, 14, 13, 11, 12, and 14, respectively. The numbers of up-, down-, and up-/down-regulated genes in corresponding cells were 7, 6, and 0; 2, 10, and 4; 2, 8, and 1; 8, 3, and 3; 6, 5, and 2; 4, 6, and 1; 2, 10, and 0; and 6, 6, and 2. Overall, the genes in the eight types of cells were mostly down-regulated during liver regeneration, but most LR-related genes in hepatic stellate cells and sinusoidal endothelial cells were up-regulated in priming phase. It is suggested that biosynthesis of serine family amino acid was enhanced in hepatocytes, hepatic stellate cells, sinusoidal endothelial cells and Kupffer cells in the priming phase. The catabolism of them was enhanced in hepatocytes, biliary epithelial cells, pit cells and dendritic cells in progressive phase. PMID- 20709682 TI - [Isolation of OsFAD2, OsFAD6 and FAD family members response to abiotic stresses in Oryza sativa L.]. AB - Unsaturated fatty acids are synthesized by fatty acid desaturase in plant, which play an important role in plant development and defense to abiotic stresses. The key enzymes for the conversion of oleic into linoleic acid were isolated from rice (Oryza sativa L.) and were designated OsFAD2 and OsFAD6, respectively. The open reading frame (ORF) of OsFAD2 was 1 167 bp in length, which encoded a 388 amino acids sequence with the isoelectric point of 8.17 and molecular mass of 52.24 kDa, the OsFAD2 protein contained a C-terminal ER retrieval motif. The ORF of OsFAD6 was 1 365 bp in length and the predicted OsFAD6 protein has 454 amino acids with an estimated molecular mass of 44.35 kDa and an isoelectric point of 9.24, the predicted OsFAD6 protein possessed a putative N-terminal plastidial signal peptide. Both of them had three his-boxes, which were peculiar to membrane integrated fatty acid desaturase by Clustal X analysis. RT-PCR analysis showed that both genes were expressed in all tissues rice seedlings, with the maximum transcript accumulation in leaves. Among FAD family members of Oryza sativa L., the mRNA abundance of OsFAD2 and OsFAD6 in leaves did not change under cold stress; however, the mRNA abundance of OsFAD7 and OsFAD8 increased in the same condition. It was also found that the expression of FAD family members had diurnal rhythm phenomena. Based on the results of this study, it suggested that diurnal rhythm expression of OsFAD6 and OsFAD7 was related to the change of NADPH abundance. PMID- 20709683 TI - [Expression profiles of AtWRKY25, AtWRKY26 and AtWRKY33 under abiotic stresses.]. AB - The transcription factor WRKY family is one type of key regulatory components of plant development and defense against stress factors. The expression profiles of three AtWRKY genes under abiotic stresses were analyzed by Northern blotting analysis. The expression of AtWRKY25, AtWRKY26, and AtWRKY33 changed during stress treatments including thermal factors, NaCl, abscisic acid (ABA) and osmotic stress, and significantly under NaCl and cold treatments, suggesting a specific role of the three AtWRKYs in adaptation to environmental stresses in plants. We also found that the three AtWRKY genes showed distinct expression patterns under thermal stresses. AtWRKY25 and AtWRKY26 were gradually induced during heat and cold treatments, whereas AtWRKY33 was suppressed by heat treatment and induced rapidly during cold stress, indicating that the three AtWRKYs may play different roles in response to temperature factors. In addition, we analyzed the sequence of the promoters with bioinformatics approach, and some cis-elements involved in abiotic stresses and hormonal responses were revealed. The results provided important information for studying biological functions of three AtWRKY genes. PMID- 20709684 TI - [Construction of genetic linkage map for rubber tree (Hevea brasiliensis) based on SSR markers.]. AB - Out of 260 polymorphic loci screened from a total of 441 pairs of EST-SSR and genomic-SSR primers, 176 were used for constructing the genetic map of rubber tree (Hevea brasiliensis) by an F1 segregating population including 94 progenies from the cross Reyan 88-13xIAN873. Chi-square test carried out on the polymorphic loci used in constructing the map showed that 147 loci followed a segregation ratio of 1:1 and 12 loci followed a ratio of 1:2:1 and 17 loci followed a ratio of 1:1:1:1. Only 13 (7.38%) loci were distorted from the Mendelian ratio. The genetic linkage map consisted of 91 marker loci in 18 linkage groups and covered 1 937.06 cM with an average genetic distance of 21.29 cM between adjacent markers. The largest linkage group consisted of 16 marker loci, while the smallest one contained only 2 marker loci. PMID- 20709685 TI - [The exploration and implication of the concept map in genetics teaching.]. AB - The concept map is a kind of chart used to represent and reveal the relationship among the knowledge structures. In genetics teaching, selectively using the concept map can help teachers to organize and review the course contents and also to detect students' academic achievement. It can also promote students' cognitive level, assist students to establish a system integrated knowledge hierarchy, etc. The exploration and implication of concept map in genetics teaching are reviewed in this paper. PMID- 20709686 TI - Conservation of Arabidopsis thaliana photoperiodic flowering time genes in onion (Allium cepa L.). AB - The genetics underlying onion development are poorly understood. Here the characterization of onion homologs of Arabidopsis photoperiodic flowering pathway genes is reported with the end goal of accelerating onion breeding programs by understanding the genetic basis of adaptation to different latitudes. The expression of onion GI, FKF1 and ZTL homologs under short day (SD) and long day (LD) conditions was examined using quantitative reverse transcription-PCR (qRT PCR). The expression of AcGI and AcFKF1 was examined in onion varieties which exhibit different daylength responses. Phylogenetic trees were constructed to confirm the identity of the homologs. AcGI and AcFKF1 showed diurnal expression patterns similar to their Arabidopsis counterparts, while AcZTL was found to be constitutively expressed. AcGI showed similar expression patterns in varieties which exhibit different daylength responses, whereas AcFKF1 showed differences. It is proposed that these differences could contribute to the different daylength responses in these varieties. Phylogenetic analyses showed that all the genes isolated are very closely related to their proposed homologs. The results presented here show that key genes controlling photoperiodic flowering in Arabidopsis are conserved in onion, and a role for these genes in the photoperiodic control of bulb initiation is predicted. This theory is supported by expression and phylogenetic data. PMID- 20709687 TI - Lower lung cancer mortality in obesity. AB - BACKGROUND: Malignancy is the leading cause of death in Hong Kong, and lung cancer tops the list of all cancer deaths. METHODS: A cohort of clients aged >=65 years, enrolled at 18 elderly health centres in Hong Kong from 2000 to 2003, was followed up prospectively through linkage with the territory-wide death registry for causes of death until 31 December 2008, using the identity card number as unique identifier. All subjects with suspected cancer, significant weight loss of >5% within past 6 months or obstructive lung disease at the baseline were excluded. RESULTS: After a total of 423 061 person-years of follow-up, 932, 690 and 1433 deaths were caused by lung cancer, other tobacco-related malignancies and non-tobacco-related malignancies, respectively. Body mass index (BMI) was independently (and negatively) associated with death from lung cancer after adjustment for other baseline variables, whereas there was only a minor or no effect for other smoking-related malignancies and non-tobacco-related malignancies. Obesity with BMI >=30 [adjusted hazard ratio (HR), 0.55, 95% confidence interval (CI) 0.38-0.80] was associated with reduced lung cancer mortality, which was more prominent than the opposing effect of underweight (adjusted HR, 1.38, 95% CI 1.05-1.79). Consistent effects of BMI were observed after stratification into never-smokers and ever-smokers and in sensitivity analysis after excluding deaths within the first 3 years. CONCLUSION: Obesity was associated with lower lung cancer mortality in this prospective cohort analysis. As the effect was rather specific for lung cancer, further studies are indicated to explore the underlying mechanism. PMID- 20709688 TI - Defect of synthesis of very long-chain fatty acids confers resistance to growth inhibition by inositol phosphorylceramide synthase repression in yeast Saccharomyces cerevisiae. AB - Aureobasidin A (AbA) inhibits Aur1p, an enzyme catalysing the formation of inositol phosphorylceramide in the yeast Saccharomyces cerevisiae. AbA treatment results not only in reductions in complex sphingolipid levels but also in accumulation of ceramides, both of which are believed to lead to the growth defect caused by this inhibitor. We screened for mutants showing resistance to this drug, and found that a lack of ELO3, the gene involved in synthesis of very long-chain fatty acids, confers resistance to the inhibitor. The resistance as to growth inhibition by reduction in Aur1p activity was also confirmed by repression of AUR1 expression under the control of a tetracycline-regulatable promoter. Under the AUR1-repressive conditions, the ELO3 mutant showed reduction in the complex sphingolipid levels and the accumulation of ceramide, like wild-type cells. However, with repression of LCB1 encoding serine palmitoyltransferase or LIP1 encoding the ceramide synthase subunit, the ELO3 mutation did not confer resistance to growth inhibition induced by the impaired sphingolipid biosynthesis. Therefore, it is suggested that the ELO3 mutant shows resistance as to accumulation of ceramides, implying that the chain lengths of fatty acids in ceramide are a critical factor for the ceramide-induced growth defect under AUR1 repressive conditions. PMID- 20709689 TI - QuantProReloaded: quantitative analysis of microspot immunoassays. AB - Protein microarrays are well-established as sensitive tools for proteomics. Particularly, the microspot immunoassay (MIA) platform enables a quantitative analysis of (phospho-) proteins in complex solutions (e.g. cell lysates or blood plasma) and with low consumption of samples and reagents. Despite numerous biological and clinical applications of MIAs there is currently no user-friendly open source data analysis software available with versatile options for data analysis and data visualization. Here, we introduce the open source software QuantProReloaded that is specifically designed for the analysis of data from MIA experiments. AVAILABILITY AND IMPLEMENTATION: QuantProReloaded is written in R and Java and is open for download under the BSB license at http://code.google.com/p/quantproreloaded/. PMID- 20709690 TI - Text mining meets workflow: linking U-Compare with Taverna. AB - Text mining from the biomedical literature is of increasing importance, yet it is not easy for the bioinformatics community to create and run text mining workflows due to the lack of accessibility and interoperability of the text mining resources. The U-Compare system provides a wide range of bio text mining resources in a highly interoperable workflow environment where workflows can very easily be created, executed, evaluated and visualized without coding. We have linked U-Compare to Taverna, a generic workflow system, to expose text mining functionality to the bioinformatics community. AVAILABILITY: http://u compare.org/taverna.html, http://u-compare.org. PMID- 20709691 TI - Search and clustering orders of magnitude faster than BLAST. AB - MOTIVATION: Biological sequence data is accumulating rapidly, motivating the development of improved high-throughput methods for sequence classification. RESULTS: UBLAST and USEARCH are new algorithms enabling sensitive local and global search of large sequence databases at exceptionally high speeds. They are often orders of magnitude faster than BLAST in practical applications, though sensitivity to distant protein relationships is lower. UCLUST is a new clustering method that exploits USEARCH to assign sequences to clusters. UCLUST offers several advantages over the widely used program CD-HIT, including higher speed, lower memory use, improved sensitivity, clustering at lower identities and classification of much larger datasets. AVAILABILITY: Binaries are available at no charge for non-commercial use at http://www.drive5.com/usearch. PMID- 20709692 TI - A cell-based simulation software for multi-cellular systems. AB - CellSys is a modular software tool for efficient off-lattice simulation of growth and organization processes in multi-cellular systems in 2D and 3D. It implements an agent-based model that approximates cells as isotropic, elastic and adhesive objects. Cell migration is modeled by an equation of motion for each cell. The software includes many modules specifically tailored to support the simulation and analysis of virtual tissues including real-time 3D visualization and VRML 2.0 support. All cell and environment parameters can be independently varied which facilitates species specific simulations and allows for detailed analyses of growth dynamics and links between cellular and multi-cellular phenotypes. AVAILABILITY: CellSys is freely available for non-commercial use at http://msysbio.com/software/cellsys. The current version of CellSys permits the simulation of growing monolayer cultures and avascular tumor spheroids in liquid environment. Further functionality will be made available ongoing with published papers. CONTACT: hoehme@izbi.uni-leipzig.de; dirk.drasdo@inria.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20709693 TI - ChEA: transcription factor regulation inferred from integrating genome-wide ChIP X experiments. AB - MOTIVATION: Experiments such as ChIP-chip, ChIP-seq, ChIP-PET and DamID (the four methods referred herein as ChIP-X) are used to profile the binding of transcription factors to DNA at a genome-wide scale. Such experiments provide hundreds to thousands of potential binding sites for a given transcription factor in proximity to gene coding regions. RESULTS: In order to integrate data from such studies and utilize it for further biological discovery, we collected interactions from such experiments to construct a mammalian ChIP-X database. The database contains 189,933 interactions, manually extracted from 87 publications, describing the binding of 92 transcription factors to 31,932 target genes. We used the database to analyze mRNA expression data where we perform gene-list enrichment analysis using the ChIP-X database as the prior biological knowledge gene-list library. The system is delivered as a web-based interactive application called ChIP Enrichment Analysis (ChEA). With ChEA, users can input lists of mammalian gene symbols for which the program computes over-representation of transcription factor targets from the ChIP-X database. The ChEA database allowed us to reconstruct an initial network of transcription factors connected based on shared overlapping targets and binding site proximity. To demonstrate the utility of ChEA we present three case studies. We show how by combining the Connectivity Map (CMAP) with ChEA, we can rank pairs of compounds to be used to target specific transcription factor activity in cancer cells. AVAILABILITY: The ChEA software and ChIP-X database is freely available online at: http://amp.pharm.mssm.edu/lib/chea.jsp. PMID- 20709694 TI - Prognostic factors in patients with primary mediastinal germ cell tumors, a surgical multicenter retrospective study. AB - Mediastinal germ cell tumors are a rare heterogeneous entity. This study tries to determine the prognostic factors of these tumors. We designed a retrospective study of 31 patients with primary mediastinal germ cell tumors treated in three centers, in France, from 1986 to 2009. The data were statistically reviewed; univariate and multivariate analyses were performed. Twenty-nine patients were males and two were females (sex ratio 14.5) with a median age of 28 years (range 16-60 years), including: non-seminomatous germ cell tumors 61.3% (n=19), seminoma 32.3% (n=10) and immature teratoma 6.4% (n=2). They had extramediastinal disease at diagnosis in 53% (n=16). The five-year overall survival (OS) was 56.3%. Univariate analysis showed that age, gender, extent of disease at diagnosis, tumor markers at diagnosis and normalization of markers after first-line chemotherapy were not statistically significant, meanwhile tumor histology (P=0.009), surgical resection of the tumor (P=0.023), and pathological evidence of persistent viable tumor in resected remnants (P=0.008) were statistically significant. Multivariate analysis identified surgical resection of the tumor as an independent favorable factor of OS (OR=5.10; 95% CI 1.49-17.45; P=0.009). Determining relevant prognostic factors has been difficult until now, largely because of the low incidence of these tumors. Raising the patient numbers by expanding the centers studied may allow the prognostic factors to be identified more precisely. PMID- 20709695 TI - Alterations in the medial layer of the main pulmonary artery in a patient with longstanding Fontan circulation. AB - In the past, pulmonary arterial (PA) structure has been extensively investigated with the aim of providing an insight into operative indication for patients with congenital heart disease (CHD). Although PA histological analysis is applied less frequently in the current era, demographic changes of CHD patients require a refocussing of attention. With an exponential increase in the number of adult CHD patients, it is important to realise how structural changes evolve long after previous procedures as a certain proportion of such cases necessitate surgical or interventional manipulation on their PAs. Herein we present our findings on main PA tissues obtained from a 35-year-old woman who had been palliated with a classic Fontan operation 23 years earlier. Immunohistological analysis showed severe alterations, especially in the medial layer; not only attenuation of muscular component but also disarray and fragmentation of elastic fibres were remarkable, which should represent the adaptive response to longstanding diminished lung perfusion. To our knowledge, these observations have not been well described in the literature, presumably because previous studies were conducted primarily with respect to 'increased' pulmonary flow, and hence little is known regarding structural alterations in response to 'decreased' perfusion. Our findings are provided with a review of the literature. PMID- 20709696 TI - Place of extracorporeal membrane oxygenation in acute aortic dissection. AB - Coronary artery dissection (CAD) is a rare but serious complication of type A aortic dissection (AD) which may be discovered preoperatively in the presence of clinical or ECG signs of ischemia, or intraoperatively after dissection of the coronary ostium. Treatment of CAD consists of surgical repair with glue and, if necessary, coronary artery bypass graft. No case of AD with CAD complicated by major arrhythmias treated by assisted circulation has been reported in the literature. We report the first case of AD with implementation of extracorporeal membranous oxygenation following cardiotomy with a favorable outcome. PMID- 20709697 TI - Minimum cause--maximum effect: the travelogue of a bullet. AB - This case report involves a 57-year-old male, accidentally shot in the chest with a small bore firearm. The bullet entered the left hemithorax, disrupting the left internal mammarian artery. It then penetrated the anterior wall of the right ventricle causing a pericardial tamponade. After leaving the base of the right heart it perforated the diaphragm, the liver, the spleen and the pancreas. Finally, it penetrated the abdominal aorta 3 cm proximally to the coeliac trunk and reached its final position paravertebrally. This case report illustrates that the management of even minimum gunshot wounds requires a maximum variety of surgical skills. PMID- 20709698 TI - Should asymptomatic bronchogenic cysts in adults be treated conservatively or with surgery? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether asymptomatic bronchogenic cysts in adults require surgery or whether they can be adequately managed with conservative treatment or observation only. Altogether more than 310 papers were found using the reported search of which 23 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The papers identified included 683 adult patients with bronchogenic cysts. There was a substantial variation between the papers in the proportion of patients presenting with symptoms (6-79%), and all patients with symptoms were managed surgically. The majority of asymptomatic patients underwent empirical surgery to prevent the development of symptoms, to confirm the diagnosis and to rule out malignant transformation. A total of 74 asymptomatic patients were treated conservatively or had definitive diagnosis or treatment delayed. The longest period of observation was 22 years. In total, 33 (45%) of asymptomatic patients eventually developed symptoms requiring surgery. There was no evidence to suggest that surgery following a cyst-related complication increased the postoperative morbidity or mortality, although it was noted to increase the technical difficulty of the procedure. There were no descriptions of misdiagnosis of malignancy as bronchogenic cyst, but 5 (0.7%) of the 683 cysts studied were found to be associated with malignant cells in the cyst wall. The figures cited, however, represent only symptomatic or incidental presentations. As the prevalence of these otherwise benign entities is not known, the rates of progression to symptoms and associated malignancy may be lower than those described. We would advocate informing asymptomatic patients diagnosed with bronchogenic cyst of the 20% morbidity of surgery whether immediate or delayed, the 45% risk of developing symptoms, some of which may be serious, and the 0.7% risk of malignancy. Should patients opt for conservative management, this can be offered only if close long-term follow-up can be guaranteed. PMID- 20709699 TI - Role of gender and age on early mortality after coronary artery bypass graft in different hospitals: data from a national administrative database. AB - The aim of this study is to evaluate the effect of gender and age on outcome following coronary surgery in several hospitals enrolled in a national quality assessment program. Patients undergoing isolated coronary artery bypass graft (CABG) during 2003-2005 in Italy were included in the study (n=74,577). The outcome measure was 30-day in-hospital mortality. Comorbidities recorded during previous and current hospitalizations were used to define patients' health status and to build the adjustment model. The interaction term (gender*hospital) was introduced into the model to test the effect modification of gender; if present, gender specific models were analyzed to test the effect modification of age. A significant effect modification by gender was found in 39 hospitals; the adjusted odds ratios (AdjORs) showed significant increased risk for females (AdjORs ranging from 3.7 to 21.6). In three of these hospitals a significant increased risk was found for older age (AdjORs for elderly patients ranging from 8.1 to 14.6). Two hospitals showed a significant excess risk for patients >=75 years (AdjORs=6.6 and 13.8). The technical aspects of surgery could account for the excess risk found in female patients; differences in the entire care process (intraoperative and postoperative management) could explain the variations in outcome among elderly patients. PMID- 20709700 TI - Rescue mitral valve repair one hour after birth. AB - Congenital mitral regurgitation is rare and usually part of complex cardiac anomalies. When needed, early surgery represents a great challenge. In small babies avoiding valve replacement is desirable, but valve repair may be extremely complex. We describe an isolated congenital mitral regurgitation, successfully treated with conservative surgery about 1 h after birth. In a 30-year-old pregnant woman, fetal echocardiography revealed mitral annular dilatation with massive regurgitation, functional aortic atresia and a very small patent foramen ovale. Realizing that the baby had a poor chance of survival after birth, a cesarean section was scheduled at 37 weeks of pregnancy. The procedure was performed in the operating room next to the cardiac surgery theatre, where the newborn was urgently transferred. After an unsuccessful attempt of percutaneous atrial septostomy, a rescue surgical mitral repair was performed. To avoid mitral replacement, moderate residual regurgitation was accepted. Postoperative hospital stay was 57 days and the baby was discharged in good clinical condition. Residual mitral regurgitation was moderate at discharge and decreased thereafter. During a five-year follow-up the child remained asymptomatic with normal growth. Preserved ventricular function and progressive volume reduction of left heart chambers were observed. PMID- 20709701 TI - Large solitary fibrous tumor with overexpression of insulin-like growth factor-2. AB - We present the case of a 66-year-old woman in whom a large solitary fibrous tumor (SFT) in the right thoracic cavity caused intermittent symptoms of hypoglycemia. A diagnosis was made of non-islet cell tumor hypoglycemia on the basis of the presence of hypoglycemia requiring continuous glucose infusion, elevated serum insulin-like growth factor-2 (IGF-2), and a large well-defined tumor in the right thoracic cavity. The patient underwent complete resection of the tumor. Histological examination revealed spindle tumor cells with a hemangiopericytoma like vascular pattern. Mitotic figures and necrotic areas were rare, and cellular atypia and nuclear pleomorphism were mild. Under immunohistochemical examination, the tumor cells were positive for CD34. Overexpression of IGF-2 mRNA in the tumor was detected by reverse-transcription polymerase-chain reaction. The diagnosis of SFT with IGF-2 production was confirmed. Immediately after surgery, her serum glucose level was normalized (without the need for glucose infusion) and serum IGF-2 level was decreased. Two years after surgery, the patient remains alive and well, with no signs of recurrence or hypoglycemia. PMID- 20709703 TI - Disclosure of patient safety incidents: a comprehensive review. AB - PURPOSE: Adverse events are increasingly recognized as a source of harm to patients. When such harm occurs, problems arise in communicating the situation to patients and their families. We reviewed the literature on disclosure across individual and international boundaries, including patients', healthcare professionals' and other stakeholders' perspectives in order to ascertain how the needs of all groups could be better reconciled. DATA SOURCES: A systematic review of the literature was carried out using the search terms 'patient safety', 'medical error', 'communication', 'clinicians', 'healthcare professionals' and 'disclosure'. All articles relating to either patients' or healthcare professionals' experiences or attitudes toward disclosure were included. RESULTS: Both patients and healthcare professionals support the disclosure of adverse events to patients and their families. Patients have specific requirements including frank and timely disclosure, an apology where appropriate and assurances about their future care. However, research suggests that there is a gap between ideal disclosure practice and reality. Although healthcare is delivered by multidisciplinary teams, much of the research that has been conducted has focused on physicians' experiences. Research indicates that other healthcare professionals also have a role to play in the disclosure process and this should be reflected in disclosure policies. CONCLUSIONS: This comprehensive review, which takes account of the perspectives of the patient and members of the care team across multiple jurisdictions, suggests that disclosure practice can be improved by strengthening policy and supporting healthcare professionals in disclosing adverse events. Increased openness and honesty following adverse events can improve provider-patient relationships. PMID- 20709702 TI - Is close radiographic and clinical control after repair of acute type A aortic dissection really necessary for improved long-term survival? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether radiographic and clinical control after surgery for acute type A aortic dissection (AAD) is needed for improved long-term survival. Altogether, 118 relevant papers were identified using the reported search, of which seven represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that most patients after surgery for AAD remain at risk for dissection-related aortic complications. Late aortic growth is often slow and linear, but the occurrence of major aortic events is unpredictable and can initially present more than a decade postoperatively. Risk factors for rapid late aortic enlargement and reoperations include patent or partially thrombosed false lumen, large aortic size, Marfan syndrome and younger age. Whether performing a more extensive first procedure (e.g. aortic arch replacement+/-elephant trunk) can be translated into improved outcome and a lower incidence of aorta-related reoperations remains to be elucidated. Aortic reoperation rates range between 10% and >20% within the first 10 years. Optimal systolic blood pressure control (<120 mmHg), including beta-blocker therapy, seems to decrease late aortic dilatation and the incidence of aortic reoperations. Close and careful lifelong surveillance of patients after AAD repair including radiographic and clinical controls to evaluate the status of the remaining aorta, and thus to facilitate adaptations of medical therapy and planning of timely reprocedures seems mandatory for improved long-term survival. A suggested timeframe for computed tomographic (CT) imaging after surgery for AAD is before discharge, at six and 12 months postdissection and, if stable, annually thereafter. Patients with large aneurysms (aortic diameter>=50 mm) should be maintained at radiographic intervals of six months or less. If the thoracic aneurysm is moderate in size and remains stable over time, magnetic resonance imaging instead of CT-scanning is reasonable to minimize the patient's radiation exposure. PMID- 20709705 TI - Sustainable healthcare accreditation: messages from Europe in 2009. AB - BACKGROUND: Healthcare accreditation has grown rapidly since the 1980s but critics question the value of accreditation rather than certification or inspection. Research has focused more on evidence of impact on provider institutions than on health systems; little has been published on the determinants of growth or decline of accreditation organizations and programmes. OBJECTIVE: To describe the development of national accreditation organizations in Europe in relation to incentives, funding and market position in 2009; to identify trends over time using data from previous surveys. METHODS: Contacts in 24 countries, identified by previous surveys, were invited to complete a web based questionnaire comprising 183 items seeking numerical data or posing multiple choice options. Preliminary results were verified with respondents and agreed for publication. MAIN OUTCOME MEASURES: National healthcare environment, incentives, government policy, legislation, regulation; programme governance, development, funding. RESULTS: The survey identified 18 active national accreditation organizations in Europe. Older ones tend to be independent, profession-dominated and self-financing; they have shown little growth in activity and coverage of the potential market. Newer ones have broad stakeholder governance, support from government policy and growth sustained by legal or financial incentives-giving wide coverage across the healthcare system. The traditional collegial model of accreditation is moving towards a semi-regulatory model of external assessment which could integrate minimal standards of licensing, public safety and accountability with aspirational standards for organizational development and improvement. CONCLUSIONS: The principal challenges to sustainable accreditation appear to be market size, consistency of policy support, programme funding and financial incentives for participation. PMID- 20709704 TI - Clinical handover incident reporting in one UK general hospital. AB - OBJECTIVE: To determine the prevalence and characteristics of clinical handover incidents that occurred across a medium-size UK hospital. DESIGN: A retrospective review of 36 consecutive months of data from the hospital electronic database of critical incidents was conducted. MAIN OUTCOME MEASURES: Number of incidents reported, characterization of handover incidents according to clinical setting, severity and type of incidents. RESULTS: We identified 334 handover incidents. The number of reported incidents increased over the 3 years. The transfer of patient care within the same specialty accounted for 51% (170) of incidents of which 75% (143) occurred during a change of shift. The specialties reporting the highest number of adverse events were: Obstetrics and Gynaecology, 42% (140); Medicine for the Elderly, 12.2% (41) and General Medicine, 12% (40). The most common types of handover incident scenario were poor or incomplete handover, 45% (151) and no handover of a patient at all, 29% (98). Reported severity was generally low (99%). CONCLUSIONS: Current reporting rate is low if compared with prospective studies highlighting an issue of under-reporting. Many incidents appear to be of modest harm for patients because of response time; however, further research is required to assess potential severity and level of harm linked to low-quality handovers. PMID- 20709706 TI - Dying safely. PMID- 20709707 TI - DASH and sollerman test scores after hand injury from powered wood splitters. AB - The purpose of the study was to describe the outcome after hand injury from powered wood splitters, and to investigate the relation between injury severity and outcome. Injury severity was rated according to the Hand Injury Severity Scoring System (HISS system) and the Injury Severity Score method. The patients were evaluated with the Disabilities of the Arm Shoulder and Hand outcome questionnaire (DASH), and 26 of the most severely injured patients were evaluated with the Sollerman test. The mean DASH score was moderately elevated at 15, indicating that many of these patients have sequelae. A statistically significant correlation between HISS and DASH scores was found, implying that initial injury severity is of importance for outcome. The mean Sollerman score in the injured hand was 66, which amounts to a significantly impaired hand function. PMID- 20709708 TI - Percutaneous A1 pulley release vs steroid injection for trigger digit: the results of a prospective, randomized trial. AB - This study compared the results of percutaneous A1 pulley release and steroid injection in 105 trigger digits in 95 patients. The patients were randomly assigned to either surgery (43 patients, 46 digits) or steroid injection (52 patients, 59 digits). The results were assessed at 1 and 6 months and the measurements included rate of recurrence (primary outcome measure), pain on movement, active range of movement of the affected digit and grip strength. No recurrences were seen at 1 month. At the 1 month assessment, patients after steroid injection achieved greater active range of movement of the fingers (270 degrees vs 264 degrees ) and stronger grip (99% vs 85%) than those treated by percutaneous release. At the 6 month assessment six recurrences (11%) occurred in the steroid injection group and none in the percutaneous release group (P = 0.005). Patients after percutaneous release had less pain on movement of the involved digit (VAS 0.4 vs 1.3), but still had lower AROM of the fingers (265 degrees vs 270 degrees after steroid injection). We conclude that percutaneous A1 pulley release is more effective medium-term therapy for trigger digit than steroid injection, because of lower risk of recurrence. PMID- 20709709 TI - WNT pathways and upper limb anomalies. AB - The various Wnt pathways that are related to upper limb anomalies are reviewed. Abnormalities in the Wnt7a pathway (located in the dorsal ectoderm) produce several clinically relevant conditions such as the palmar duplication syndrome, nail patella syndrome, ulnar ray deficiency, limb hypoplasia, polysyndactyly and the palmar nail syndrome. Abnormalities of the Wnt3/3a pathway (located in the apical ectodermal ridge) include tetra-amelia and loss of the distal phalanges/nails. Abnormalities of the Wnt5/5a pathway (located in the apical ectodermal ridge as well as in the mesoderm) will affect chondrogenesis of the developing limb and experimental Wnt5a(-/-) limbs have terminal adactyly. Chondrogenesis and limb muscle differentiation are both affected by several Wnt pathways and these will be reviewed in details. Abnormalities in LRP 5/6 (a co receptor for Wnts) lead to congenital bone disease and Wnt4 is specifically involved in joint development. Finally, the relationship between the Wnt pathway and SALL4 (mutations of which cause Okihiro/Duane-radial ray deficiency in humans) are discussed. PMID- 20709710 TI - The epidemiology of fractures of the hand and the influence of social deprivation. AB - This study investigates the relationship between the epidemiology of hand fractures and social deprivation. Data were collected prospectively in a single trauma unit serving a well-defined population. The 1382 patients treated for 1569 fractures of the metacarpals or phalanges represented an incidence of hand fracture of 3.7 per 1000 per year for men and 1.3 per 1000 per year for women. Deprivation was not directly associated with the incidence of hand fracture. Common mechanisms of injury are gender specific. Fractures of the little finger metacarpal were common (27% of the total) and were associated with social deprivation in men (P = 0.017). For women, fractures where the mechanism of injury was unclear or the patient was intoxicated and could not recall the mechanism showed a clear association with deprivation. Affluent patients were more likely to receive operative treatment. Social deprivation influences both the pattern and management of hand fractures. PMID- 20709711 TI - What's in a Name? Word descriptors of cancer-related fatigue. AB - Many different words are used to describe fatigue. It is unclear whether these word descriptors represent the same cancer symptom or dimension. The objective of this study was to identify clinical associations of three fatigue word descriptors (FWDs): 'easy fatigue', 'weakness', and 'lack of energy' (LOE). One thousand consecutive palliative medicine patients completed a 38-item symptom checklist. The prevalence of the three FWDs alone and in combination was calculated. Spearman correlations assessed associations between FWDs. Logistic regression analysis identified univariable and multivariable predictors for each FWD. Survival was estimated using the Kaplan-Meier method, individually and for 0 1 versus 2-3 FWDs, and compared using log-rank tests. The prevalence of easy fatigue was 69%, weakness 66%, and LOE 61%. Correlations between the FWDs were high (0.65-0.79). In multivariable models, clinical associations (particularly neuro-psychiatric symptoms and performance status) of the FWDs were variable. Weakness was associated with performance status, but not anxiety or depression. LOE was associated with anxiety and depression, but not performance status. Fatigue was associated with depression, but not anxiety or performance status. All FWDs were associated with dry mouth, early satiety, sleep problems, and weight loss. The worst survival was associated with two or three reported FWDs compared with none or one (P < 0.001). Weakness and LOE had distinct clinical associations that differed from fatigue. Evaluation of fatigue should use multiple descriptors (particularly weakness), as they are not synonymous. Further research is necessary to identify biological associations for discrete FWDs. PMID- 20709712 TI - Is it possible to determine use of hospice palliative care services by matching hospice and cancer registry data? AB - Population-based studies investigating access to palliative care often use death in a hospice as a proxy for service use. We linked data from a large South London hospice to Thames Cancer Registry (TCR) data to determine whether patients who received hospice services differed from those who did not. We matched hospice data for 2474 cancer patients dying between 2000 and 2006, while resident within a restricted catchment area, to TCR data for residents in this area. During matching 14.2% (n = 352) of hospice patients were excluded due to differing key dates or addresses. In addition, 5.6% (n= 175) of residents initially defined as not receiving hospice services were recorded as dying in a hospice in the TCR dataset. The problems of overlapping catchment areas and of defining patients receiving services meant we could not adequately determine use of hospice services. This method might be applied more successfully to non-urban hospices, primary care trusts or larger regions. PMID- 20709714 TI - Taking healthcare interventions from trial to practice. PMID- 20709715 TI - Process mapping the patient journey: an introduction. PMID- 20709719 TI - Patient perspective of systemic lupus erythematosus in relation to health-related quality of life concepts: a qualitative study. AB - We sought to understand the patients' 'lived experiences of systemic lupus erythematosus (SLE)' by exploring, describing and clarifying the patients' perspective of how they felt about having SLE and how the disease impacted on their lives, both positively and/or negatively. An interpretative phenomenological approach was employed. Semi-structured interviews were undertaken with 30 females with SLE across a wide range of age (21 to 75 years), disease characteristics, disease duration (1 to 28 years) and ethnicity (Whites, South Asians). Eleven themes emerged as important to the patients: prognosis and course of disease; body image; effects of treatment; emotional difficulties; inability to plan due to disease unpredictability; fatigue; pain; career prospects and loss of income; memory loss/concentration; reliance on others to assist with everyday tasks; and pregnancy issues. Most patients reported a negative impact of SLE on their lives although a few patients found positive aspects to having SLE. The findings of this study identified themes important to patients with SLE and these themes will inform clinicians on the patients' perspective of having SLE. PMID- 20709720 TI - Cardiovascular manifestations in men and women carrying a FBN1 mutation. AB - AIMS: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. METHODS AND RESULTS: A total of 1,013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11-34), male gender 53%] had data suitable for analysis. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94-97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67-81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [<= 30 years: 57% (95% CI: 52-63) vs. 50% (95% CI: 45-55), P = 0.0076] and aortic events [<= 30 years: 21% (95% CI: 17 26) vs. 11% (95% CI: 8-16), P < 0.0001; adjusted HR: 1.4 (1.1-1.8), P = 0.005]. The prevalence of mitral valve (MV) prolapse [<= 60 years: 77% (95% CI: 72-82)] and MV regurgitation [<= 60 years: 61% (95% CI: 53-69)] also increased steadily with age, but surgery limited to the MV remained rare [<= 60 years: 13% (95% CI: 8-21)]. No difference between genders was observed (for all P> 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend = 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend = 0.01). CONCLUSION: The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation. PMID- 20709722 TI - Optimal timing of coronary angiography and potential intervention in non-ST elevation acute coronary syndromes. AB - AIMS: An invasive approach is superior to medical management for the treatment of patients with acute coronary syndromes without ST-segment elevation (NSTE-ACS), but the optimal timing of coronary angiography and subsequent intervention, if indicated, has not been settled. METHODS AND RESULTS: We conducted a meta analysis of randomized trials addressing the optimal timing (early vs. delayed) of coronary angiography in NSTE-ACS. Four trials with 4013 patients were eligible (ABOARD, ELISA, ISAR-COOL, TIMACS), and data for longer follow-up periods than those published became available for this meta-analysis by the ELISA and ISAR COOL investigators. The median time from admission or randomization to coronary angiography ranged from 1.16 to 14 h in the early and 20.8-86 h in the delayed strategy group. No statistically significant difference of risk of death [random effects risk ratio (RR) 0.85, 95% confidence interval (CI) 0.64-1.11] or myocardial infarction (MI) (RR 0.94, 95% CI 0.61-1.45) was detected between the two strategies. Early intervention significantly reduced the risk for recurrent ischaemia (RR 0.59, 95% CI 0.38-0.92, P = 0.02) and the duration of hospital stay (by 28%, 95% CI 22-35%, P < 0.001). Furthermore, decreased major bleeding events (RR 0.78, 95% CI 0.57-1.07, P = 0.13), and less major events (death, MI, or stroke) (RR 0.91, 95% CI 0.82-1.01, P = 0.09) were observed with the early strategy but these differences were not nominally significant. CONCLUSION: Early coronary angiography and potential intervention reduces the risk of recurrent ischaemia, and shortens hospital stay in patients with NSTE-ACS. PMID- 20709721 TI - Echocardiography, dyssynchrony, and the response to cardiac resynchronization therapy. AB - Biventricular pacing or cardiac resynchronization therapy (CRT) has been a considerable advance in the therapy of chronic heart failure. However, it is clear that not all patients benefit either in terms of symptoms or cardiac function, and some may be worsened by CRT. In this review, we consider the arguments, both clinical and economical, in favour of improved selection of patients for CRT other than those in current guidelines. It also seems clear that the fundamental mechanism of CRT is correction of dyssynchrony, and we review the various methodologies available to detect dyssynchrony. Other factors are probably also important in determining outcomes such as lead position, the extent and form of myocardial damage, optimizing pacemaker performance, and clinical expertise. The potential costs of inappropriate CRT implantation are high to our patients and to the health economy, and it behooves the cardiology community to develop better selection criteria. The current guidelines can and should be improved. PMID- 20709723 TI - Comparison of craniofacial characteristics of typical Chinese and Caucasian young adults. AB - The purpose of this study was to determine the cephalometric norms of typical Chinese young adult subjects with normal occlusions and well-balanced faces and to compare these norms with those derived from a matched Caucasian sample. Lateral cephalograms of 65 untreated Chinese adults (25 males, mean age 19.3 +/- 3.0 years and 40 females, mean age 20.3 +/- 3.4 years) were compared with a sample of 90 untreated Caucasian adults (30 males, mean age 24.1 +/- 5.7 years and 60 females, mean age 22.9 +/- 5.2 years). Each lateral cephalogram was traced and digitized, and conventional cephalometric analyses were applied. Independent sample t-tests were used to compare the values between the two ethic samples. Smaller midfaces and shorter mandibles were observed in Chinese young adults compared with those of Caucasians. The average value of lower anterior face height (ANS-Me) was longer in the Chinese females than that in the Caucasian females (P < 0.001). A greater vertical dimension also was seen in Chinese males compared with Caucasian males when evaluated by analysis of the facial axis angle (P < 0.05). The upper and lower lips were more protrusive in the Chinese, and a more convex facial profile was seen compared with the Caucasian sample. Significant differences in hard and soft tissue characteristics were found between Chinese and Caucasian young adults with normal occlusions and well balanced faces. Gender and racial/ethnic differences must be taken into consideration during orthodontic diagnosis and treatment planning for the individual patient. PMID- 20709724 TI - Analysis of the performance of different orthodontic devices for mandibular symphyseal distraction osteogenesis. AB - The aim of this study was to investigate the performance of different orthodontic devices for mandibular symphyseal distraction osteogenesis (MSDO). Two performance parameters were analysed, the first of which concerned the stability guaranteed by a distractor in the fracture gap under mastication loads and the second the level of reliability with which a distractor transfers a given expansion to the mandibular bone, inasmuch as the more reliable the device the smaller the difference between the degree of expansion provided to the device and the displacement achieved on the mandibular arch. Hence, a non-linear finite element (FE) model of a human mandible with different devices (tooth-borne, bone borne, and hybrid) was constructed and then utilized to assess the structural behaviour of the mandibular bone under distraction and mastication loads. An ad hoc algorithm was developed to simulate progressive expansion of the devices; a distraction protocol comprising a 10 day latency period and a 6 day distraction period was hypothesized. The first hypothetical expansion given to the device was 2 mm, and the five subsequent expansions were 1 mm. The results showed that the hybrid device was the most stable appliance under mastication loads, followed by the tooth- and bone-borne devices. However, parasitic rotations of the mandibular arms caused by mastication might counteract the benefits of distraction. The tooth-borne device was found to have the highest reliability in transferring expansion to the mandibular bone. For this device, mandibular expansion was less than the nominal aperture of the distractor by no more than 15 per cent. Lower values of reliability were achieved with the bone-borne device. As the values of the aperture of the appliances increased, the stability guaranteed in the fracture gap increased while the reliability in transferring expansion to the mandibular arch decreased. PMID- 20709725 TI - Increasing productivity by matching farming system management and genotype in water-limited environments. AB - Improvements in water productivity and yield arise from interactions between varieties (G) and their management (M). Most G*M interactions considered by breeders and physiologists focus on in-crop management (e.g. sowing time, plant density, N management). However, opportunities exist to capture more water and use it more effectively that involve judicious management of prior crops and fallows (e.g. crop sequence, weed control, residue management). The dry-land wheat production system of southern Australia, augmented by simulation studies, is used to demonstrate the relative impacts and interactions of a range of pre crop and in-crop management decisions on water productivity. A specific case study reveals how a novel genetic trait, long coleoptiles that enable deeper sowing, can interact with different management options to increase the water limited yield of wheat from 1.6 t ha(-1) to 4.5 t ha(-1), reflecting the experience of leading growers. Understanding such interactions will be necessary to capture benefits from new varieties within the farming systems of the future. PMID- 20709726 TI - NMR metabolomics of esca disease-affected Vitis vinifera cv. Alvarinho leaves. AB - Esca is a destructive disease that affects vineyards leading to important losses in wine production. Information about the response of Vitis vinifera plants to this disease is scarce, particularly concerning changes in plant metabolism. In order to study the metabolic changes in Vitis plants affected by esca, leaves from both infected and non-affected cordons of V. vinifera cv. Alvarinho (collected in the Vinho Verde region, Portugal) were analysed. The metabolite composition of leaves from infected cordons with visible symptoms [diseased leaves (dl)] and from asymptomatic cordons [healthy leaves (hl)] was evaluated by 1D and 2D (1)H-nuclear magnetic resonance (NMR) spectroscopy. Principal component analysis (PCA) of the NMR spectra showed a clear separation between dl and hl leaves, indicating differential compound production due to the esca disease. NMR/PCA analysis allowed the identification of specific compounds characterizing each group, and the corresponding metabolic pathways are discussed. Altogether, the study revealed a significant increase of phenolic compounds in dl, compared with hl, accompanied by a decrease in carbohydrates, suggesting that dl are rerouting carbon and energy from primary to secondary metabolism. Other metabolic alterations detected comprised increased levels of methanol, alanine, and gamma aminobutyric acid in dl, which might be the result of the activation of other defence mechanisms. PMID- 20709727 TI - Effects of anhedonia on days to relapse among smokers with a history of depression: a brief report. AB - INTRODUCTION: Despite the strong co-occurrence between lifetime prevalence of depression and smoking, a history of major depressive disorder (MDD history) does not reliably predict smoking cessation outcomes. However, depression is a heterogeneous syndrome comprising several dimensions (e.g., anhedonia, vegetative symptoms, negative affect), and each symptom expression may differentially influence cessation failure. Measuring proximal depressive dimensions may provide a more reliable way of identifying MDD history smokers most at risk for smoking relapse. Anhedonia, in particular, is a core feature of depression that may increase risk for smoking relapse among MDD history smokers. The primary goal of the present study was to investigate the relation between anhedonia and relapse latency among MDD history smokers following a brief smoking cessation workshop. METHODS: Participants (N = 45, 48.9% female), who were euthymic regular smokers with a history of MDD, were randomized to 1 of 3 treatment groups that all involved participation in a daylong group workshop. Workshops were followed by 48 hr of bioverified abstinence and weekly follow-up visits for 1 month. RESULTS: Cox proportional hazard modeling was used to evaluate the effect of anhedonia on relapse latency 30 days following quitting smoking. Results showed that higher levels of anhedonia predicted reduced relapse latencies, both with and without prequit depressive symptom severity included in the model. DISCUSSION: Results suggest that anhedonia may constitute a proximal risk factor identifying depressive history smokers more likely to relapse to smoking. PMID- 20709728 TI - High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness. AB - Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, a perturbation observed in inflammatory states, tumor angiogenesis, atherosclerosis, and both sepsis and acute lung injury. Therefore, agents that enhance EC barrier integrity have important therapeutic implications. We observed that binding of high-molecular-weight hyaluronan (HMW-HA) to its cognate receptor CD44 within caveolin-enriched microdomains (CEM) enhances human pulmonary EC barrier function. Immunocytochemical analysis indicated that HMW-HA promotes redistribution of a significant population of CEM to areas of cell-cell contact. Quantitative proteomic analysis of CEM isolated from human EC demonstrated HMW-HA mediated recruitment of cytoskeletal regulatory proteins (annexin A2, protein S100-A10, and filamin A/B). Inhibition of CEM formation [caveolin-1 small interfering RNA (siRNA) and cholesterol depletion] or silencing (siRNA) of CD44, annexin A2, protein S100-A10, or filamin A/B expression abolished HMW-HA-induced actin cytoskeletal reorganization and EC barrier enhancement. To confirm our in vitro results in an in vivo model of inflammatory lung injury with vascular hyperpermeability, we observed that the protective effects of HMW-HA on LPS induced pulmonary vascular leakiness were blocked in caveolin-1 knockout mice. Furthermore, targeted inhibition of CD44 expression in the mouse pulmonary vasculature significantly reduced HMW-HA-mediated protection from LPS-induced hyperpermeability. These data suggest that HMW-HA, via CD44-mediated CEM signaling events, represents a potentially useful therapeutic agent for syndromes of increased vascular permeability. PMID- 20709729 TI - Linoleic acid supplement in cystic fibrosis: friend or foe? PMID- 20709730 TI - Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin. AB - To determine the separate and interactive effects of fetal inflammation and neonatal hyperoxia on the developing lung, we hypothesized that: 1) antenatal endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate hyperoxia (O2, 80% O2 at Denver's altitude, ~65% O2 at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused right ventricular hypertrophy (RVH) and decreased lung vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein contents at birth. In ETX exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate hyperoxia increased lung VEGF and VEGFR-2 protein contents in ETX-O2 rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe hyperoxia (>=95% O2 at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal pulmonary hypertension and causes persistent abnormalities of lung structure with sustained pulmonary hypertension in infant rats. Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy. PMID- 20709731 TI - Rho kinase modulates postnatal adaptation of the pulmonary circulation through separate effects on pulmonary artery endothelial and smooth muscle cells. AB - At birth, pulmonary vasodilation occurs concomitant with the onset of air breathing life. Whether and how Rho kinase (ROCK) modulates the perinatal pulmonary vascular tone remains incompletely understood. To more fully characterize the separate and interactive effects of ROCK signaling, we hypothesized that ROCK has discrete effects on both pulmonary artery (PA): 1) endothelial cell (PAEC) nitric oxide (NO) production and contractile state; and 2) smooth muscle cell tone independent of endothelial NO synthase (eNOS) activity. To test these hypotheses, NO production and endothelial barrier function were determined in fetal PAEC under baseline hypoxia and following exposure to normoxia with and without treatment with Y-27632, a specific pharmacological inhibitor of ROCK. In acutely instrumented, late-gestation ovine fetuses, eNOS was inhibited by nitro-l-arginine infusion into the left PA (LPA). Subsequently, fetal lambs were mechanically ventilated (MV) with 100% oxygen in the absence (control period) and presence of Y-27632. In PAEC, treatment with Y 27632 had no effect on cytosolic calcium but did increase normoxia-induced NO production. Moreover, acute normoxia increased PAEC barrier function, an effect that was potentiated by Y-27632. In fetal lambs, MV during the control period had no effect on LPA flow. In contrast, MV after Y-27632 increased LPA flow and fetal arterial P(O)2 (Pa(O2)) and decreased PA pressure. In conclusion, ROCK activity modulates vascular tone in the perinatal pulmonary circulation via combined effects on PAEC NO production, barrier function, and smooth muscle tone. ROCK inhibition may represent a novel treatment strategy for neonatal pulmonary vascular disease. PMID- 20709732 TI - Dense-body aggregates as plastic structures supporting tension in smooth muscle cells. AB - The wall of hollow organs of vertebrates is a unique structure able to generate active tension and maintain a nearly constant passive stiffness over a large volume range. These properties are predominantly attributable to the smooth muscle cells that line the organ wall. Although smooth muscle is known to possess plasticity (i.e., the ability to adapt to large changes in cell length through structural remodeling of contractile apparatus and cytoskeleton), the detailed structural basis for the plasticity is largely unknown. Dense bodies, one of the most prominent structures in smooth muscle cells, have been regarded as the anchoring sites for actin filaments, similar to the Z-disks in striated muscle. Here, we show that the dense bodies and intermediate filaments formed cable-like structures inside airway smooth muscle cells and were able to adjust the cable length according to cell length and tension. Stretching the muscle cell bundle in the relaxed state caused the cables to straighten, indicating that these intracellular structures were connected to the extracellular matrix and could support passive tension. These plastic structures may be responsible for the ability of smooth muscle to maintain a nearly constant tensile stiffness over a large length range. The finding suggests that the structural plasticity of hollow organs may originate from the dense-body cables within the smooth muscle cells. PMID- 20709733 TI - Comparative analysis of metabolic networks provides insight into the evolution of plant pathogenic and nonpathogenic lifestyles in Pseudomonas. AB - Plant pathogenic pseudomonads such as Pseudomonas syringae colonize plant surfaces and tissues and have been reported to be nutritionally specialized relative to nonpathogenic pseudomonads. We performed comparative analyses of metabolic networks reconstructed from genome sequence data in order to investigate the hypothesis that P. syringae has evolved to be metabolically specialized for a plant pathogenic lifestyle. We used the metabolic network comparison tool Rahnuma and complementary bioinformatic analyses to compare the distribution of 1,299 metabolic reactions across nine genome-sequenced strains of Pseudomonas, including three strains of P. syringae. The two pathogenic Pseudomonas species analyzed, P. syringae and the opportunistic human pathogen P. aeruginosa, each displayed a high level of intraspecies metabolic similarity compared with nonpathogenic Pseudomonas. The three P. syringae strains lacked a significant number of reactions predicted to be present in all other Pseudomonas strains analyzed, which is consistent with the hypothesis that P. syringae is adapted for growth in a nutritionally constrained environment. Pathway predictions demonstrated that some of the differences detected in metabolic network comparisons could account for differences in amino acid assimilation ability reported in experimental analyses. Parsimony analysis and reaction neighborhood approaches were used to model the evolution of metabolic networks and amino acid assimilation pathways in pseudomonads. Both methods supported a model of Pseudomonas evolution in which the common ancestor of P. syringae had experienced a significant number of deletion events relative to other nonpathogenic pseudomonads. We discuss how the characteristic metabolic features of P. syringae could reflect adaptation to a pathogenic lifestyle. PMID- 20709734 TI - A new test for detecting recent positive selection that is free from the confounding impacts of demography. AB - It has been a long-standing interest in evolutionary biology to search for the traces of recent positive Darwinian selection in organisms. However, such efforts have been severely hindered by the confounding signatures of demography. As a consequence, neutrality tests often lead to false inference of positive selection because they detect the deviation from the standard neutral model. Here, using the maximum frequency of derived mutations (MFDM) to examine the unbalanceness of the tree of a locus, I propose a statistical test that is analytically free from the confounding effects of varying population size and has a high statistical power (up to 90.5%) to detect recent positive selection. When compared with five well-known neutrality tests for detecting selection (i.e., Tajima's D test, Fu and Li's D test, Fay and Wu's H test, the E test, and the joint DH test), the MFDM test is indeed the only one free from the confounding impacts of bottlenecks and size expansions. Simulations based on wide-range parameters demonstrated that the MFDM test is robust to background selection, population subdivision, and admixture (including hidden population structure). Moreover, when two high frequency mutations are introduced, the MFDM test is robust to the misinference of derived and ancestral variants of segregating sites due to multiple hits. Finally, the sensitivity of the MFDM test in detecting balancing selection is also discussed. In summary, it is demonstrated that summary statistics based on tree topology can be used to detect selection, and this work provides a reliable method that can distinguish selection from demography even when DNA polymorphism data from only one locus is available. PMID- 20709735 TI - Fluoroquinolones induce the expression of patA and patB, which encode ABC efflux pumps in Streptococcus pneumoniae. AB - BACKGROUND: Active efflux is a common mechanism of resistance to fluoroquinolones in Streptococcus pneumoniae. Two efflux systems have been described so far in this species: PmrA, a member of the major facilitator superfamily; and the two ABC transporters PatA and PatB. We studied the inducibility of expression of pmrA, patA and patB by using subinhibitory concentrations of fluoroquinolones. METHODS: A wild-type susceptible strain, two clinical isolates resistant to fluoroquinolones and two efflux mutants selected in vitro after exposure to ciprofloxacin were studied. MICs were determined for these strains and their mutants in which pmrA, patA or patB had been disrupted. Gene expression was determined after exposure to half the MIC of norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin or gemifloxacin and quantified by real-time PCR. RESULTS: Increased MICs of norfloxacin, ciprofloxacin and levofloxacin (to a lesser extent) and increased expression of patA and patB were seen for all resistant strains; these were reduced in patA or patB disruptants or in the presence of reserpine. Exposure to any of the five fluoroquinolones caused a reversible increase in expression of patA and patB, but not of pmrA. Mitomycin C, an inducer of the competence system in S. pneumoniae, also induced patA and patB expression in the two strains tested. CONCLUSION: The ABC efflux system PatA/PatB is induced upon exposure to subinhibitory concentrations of fluoroquinolones, whether substrates of the transporter or not. This effect, possibly resulting from the activation of the competence pathway, may contribute to resistance. PMID- 20709736 TI - Urinary biomarkers--silver bullets to faster drug development and nephron protection. PMID- 20709737 TI - Nephrolithiasis is associated with an increased prevalence of cardiovascular disease. AB - BACKGROUND: Nephrolithiasis has been associated with hypertension, obesity and diabetes mellitus. The prevalence of adverse cardiovascular outcomes among kidney stone formers (KSF) is unknown. METHODS: We examined the IV Portuguese National Health Survey for documenting possible associations between nephrolithiasis, cardiovascular diseases, diabetes and obesity in the Portuguese adult population. RESULTS: We obtained 23 349 questionnaires from individuals >= 15 years old. The prevalence of kidney stone disease (KSD) was 7.3%. The prevalence of hypertension was higher among KSF when compared with the general population (50.4 vs 30.2%; P < 0.001). Age and obesity significantly increase the risk for nephrolithiasis. After adjusting for age and body mass index, KSF have higher prevalence of hypertension [odds ratio (OR), 1.841; 95% CI, 1.651-2.053], diabetes mellitus (OR, 1.475; 95% CI, 1.283-1.696; P < 0.001), myocardial infarction (OR, 1.338; 95% CI, 1.003-1.786; P < 0.05) and stroke (OR, 1.330; 95% CI, 1.015-1.743; P < 0.05) compared with non-stone formers. CONCLUSIONS: KSD is associated with a higher prevalence of chronic diseases and adverse cardiovascular outcomes when compared with the general population. PMID- 20709738 TI - The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far. METHODS: In NZBW/F1 female mice, we examined the glomerular expression of Akt and mTOR by immunofluorescence and western blot. We also searched for specific phosphorylations of these kinases known to ensue during activation of the PI3K/Akt/mTOR pathway. In parallel, we examined the therapeutic role of rapamycin either before or after the development of overt lupus nephritis. RESULTS: We found that in untreated mice, as opposed to healthy controls, Akt and mTOR were over-expressed and phosphorylated at key activating residues. Rapamycin prolonged survival, maintained normal renal function, normalized proteinuria, restored nephrin and podocin levels, reduced anti-dsDNA titres, ameliorated histological lesions, and reduced Akt and mTOR glomerular expression activation. CONCLUSIONS: These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment. PMID- 20709739 TI - Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. METHODS: We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. RESULTS: Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). CONCLUSIONS: EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EPS. PMID- 20709740 TI - The link between bone and coronary calcifications in CKD-5 patients on haemodialysis. AB - BACKGROUND: Vascular calcifications are frequent in Stage 5 chronic kidney disease (CKD-5) patients receiving haemodialysis. The current study was designed to evaluate the associations between bone turnover/volume and coronary artery calcifications (CAC). METHODS: In 207 CKD-5 patients, bone biopsies, multislice computed tomography of the coronary arteries and blood drawings for relevant biochemical parameters were done. The large number of CKD-5 patients enrolled allowed separate evaluation of patients with CAC versus patients without CAC and adjustment for traditional and non-traditional risk factors for CAC. RESULTS: When all patients were analysed, associations were found between CAC and bone turnover, bone volume, age, gender and dialysis vintage. When only patients with CAC were included, there was a U-shaped relationship between CAC and bone turnover, whilst the association with bone volume was lost. In these patients, the relationship of CAC with age, gender and dialysis vintage remained. CONCLUSIONS: Beyond the non-modifiable risk factors of age, gender and dialysis vintage, these data show that bone abnormalities of renal osteodystrophy amenable to treatment should be considered in the management of patients with CAC. PMID- 20709742 TI - Use of handgrip strength in the assessment of the muscle function of chronic kidney disease patients on dialysis: a systematic review. AB - BACKGROUND: Even though handgrip strength (HGS) is considered a simple and reliable method to evaluate muscle function and, indirectly, the nutritional status in clinical settings, there is still no consensus concerning its use in patients with chronic kidney disease (CKD) undergoing dialysis. This study presents a systematic review of the literature on the use of HGS as a parameter for nutritional assessment and a prognostic marker in patients on dialysis. METHODS: The MEDLINE database (1966 to October 2009) was consulted for this systematic review by using the search terms hand strength or muscle strength dynamometer and dialysis. Eighteen articles were identified and included in the analysis. RESULTS: Similar to the general population, HGS values were associated with age and gender. The analysed studies showed correlation between muscle function estimated by HGS and variables used in the assessment of muscle mass and nutritional status, as well as the prediction of clinical complications. CONCLUSIONS: The analysis indicates that HGS is a useful tool for continuous and systematic assessment of muscle mass related to nutritional status in patients on dialysis. However, it is still necessary to standardize the techniques used for HGS, especially with respect to the position of measurement, the evaluation period, the choice of arm side and the diagnostic criterion. PMID- 20709741 TI - Serum ratio of soluble triggering receptor expressed on myeloid cells-1 to creatinine is a useful marker of infectious complications in myeloperoxidase antineutrophil cytoplasmic antibody-associated renal vasculitis. AB - BACKGROUND: The contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated. METHODS: Soluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD). RESULTS: There was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection. CONCLUSIONS: The serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis. PMID- 20709743 TI - Osseous metaplasia in a kidney allograft. AB - Osseous metaplasia is defined by the presence of heterotopic normal bone tissue in a soft tissue. The bone matrix is associated with osteoblasts, osteoclasts, adipocytes and haematopoietic stem cells. Osseous metaplasia pathophysiology is not well known, but many factors have been incriminated including chronic inflammation and chronic ischaemia. We describe the second case of osseous metaplasia in a kidney allograft. Numerous factors might favour its development including factors linked to transplantation failure environment. PMID- 20709744 TI - Glomerular haematuria, renal interstitial haemorrhage and acute kidney injury. AB - Macroscopic haematuria of glomerular origin has been associated with acute kidney injury. We report a patient with IgA nephropathy, macroscopic haematuria and acute kidney injury. Systemic anticoagulation may have aggravated haematuria. There was extensive interstitial and intratubular red blood cell extravasation, and interstitial haemosiderin deposits. The abundant presence of macrophages expressing the haemoglobin scavenger receptor CD163 and of cells stained for oxidative stress markers (NADPH-p22 phox and heme-oxigenase-1) in areas of interstitial haemorrhage and red blood cell cast-containing tubules provided evidence for a role for free haemoglobin in tubulointerstitial renal injury in human glomerular disease. PMID- 20709745 TI - The epsin family of endocytic adaptors promotes fibrosarcoma migration and invasion. AB - Abnormalities in the process of endocytosis are classically linked to malignant transformation through the deficient down-regulation of signaling receptors. The present study describes a non-classical mechanism that does not require internalization by which endocytic proteins affect cell migration and basement membrane invasion. Specifically, we found that the endocytic adaptor epsin binds and regulates the biological properties of the signaling molecule RalBP1 (Ral binding protein 1). Epsin interacted with the N terminus of RalBP1 via its characteristic epsin N-terminal homology (ENTH) domain. A combination of siRNA mediated knock-down and transfection of siRNA-resistant constructs in fibrosarcoma cells demonstrated that impairment of the epsin-RalBP1 interaction led to cell migration and basement membrane invasion defects. We found the ENTH domain was necessary and sufficient to sustain normal cell migration and invasion. Because all the epsin endocytic motifs reside in the C-terminal part of the molecule, these results suggest that this novel regulatory circuit does not require endocytosis. In addition, cells depleted of epsin-RalBP1 complex displayed deficient activation of Rac1 and Arf6 suggesting a signaling function for this novel interaction. Further, overexpression of either epsin or RalBP1 enhanced migration and invasion of fibrosarcoma cells. Collectively, our results indicate that epsin regulates RalBP1 function in Rac1- and Arf6-dependent pathways to ultimately affect cell migration and invasion. We propose that the observed up-regulation of both epsin and RalBP1 in certain cancers contributes to their invasive characteristics. PMID- 20709746 TI - Sss1p is required to complete protein translocon activation. AB - Protein translocation across the endoplasmic reticulum membrane occurs at the Sec61 translocon. This has two essential subunits, the channel-forming multispanning membrane protein Sec61p/Sec61alpha and the tail-anchored Sss1p/Sec61gamma, which has been proposed to "clamp" the channel. We have analyzed the function of Sss1p using a series of domain mutants and found that both the cytosolic and transmembrane clamp domains of Sss1p are essential for protein translocation. Our data reveal that the cytosolic domain is required for Sec61p interaction but that the transmembrane clamp domain is required to complete activation of the translocon after precursor targeting to Sec61p. PMID- 20709747 TI - Co-assembly of Kv4 {alpha} subunits with K+ channel-interacting protein 2 stabilizes protein expression and promotes surface retention of channel complexes. AB - Members of the K(+) channel-interacting protein (KChIP) family bind the distal N termini of members of the Shal subfamily of voltage-gated K(+) channel (Kv4) pore forming (alpha) subunits to generate rapidly activating, rapidly inactivating neuronal A-type (I(A)) and cardiac transient outward (I(to)) currents. In heterologous cells, KChIP co-expression increases cell surface expression of Kv4 alpha subunits and Kv4 current densities, findings interpreted to suggest that Kv4.KChIP complex formation enhances forward trafficking of channels (from the endoplasmic reticulum or the Golgi complex) to the surface membrane. The results of experiments here, however, demonstrate that KChIP2 increases cell surface Kv4.2 protein expression (~40-fold) by an order of magnitude more than the increase in total protein (~2-fold) or in current densities (~3-fold), suggesting that mechanisms at the cell surface regulate the functional expression of Kv4.2 channels. Additional experiments demonstrated that KChIP2 decreases the turnover rate of cell surface Kv4.2 protein by inhibiting endocytosis and/or promoting recycling. Unexpectedly, the experiments here also revealed that Kv4.2.KChIP2 complex formation stabilizes not only (total and cell surface) Kv4.2 but also KChIP2 protein expression. This reciprocal protein stabilization and Kv4.KChIP2 complex formation are lost with deletion of the distal (10 amino acids) Kv4.2 N terminus. Taken together, these observations demonstrate that KChIP2 differentially regulates total and cell surface Kv4.2 protein expression and Kv4 current densities. PMID- 20709748 TI - Splice variants of SmgGDS control small GTPase prenylation and membrane localization. AB - Ras and Rho small GTPases possessing a C-terminal polybasic region (PBR) are vital signaling proteins whose misregulation can lead to cancer. Signaling by these proteins depends on their ability to bind guanine nucleotides and their prenylation with a geranylgeranyl or farnesyl isoprenoid moiety and subsequent trafficking to cellular membranes. There is little previous evidence that cellular signals can restrain nonprenylated GTPases from entering the prenylation pathway, leading to the general belief that PBR-possessing GTPases are prenylated as soon as they are synthesized. Here, we present evidence that challenges this belief. We demonstrate that insertion of the dominant negative mutation to inhibit GDP/GTP exchange diminishes prenylation of Rap1A and RhoA, enhances prenylation of Rac1, and does not detectably alter prenylation of K-Ras. Our results indicate that the entrance and passage of these small GTPases through the prenylation pathway is regulated by two splice variants of SmgGDS, a protein that has been reported to promote GDP/GTP exchange by PBR-possessing GTPases and to be up-regulated in several forms of cancer. We show that the previously characterized 558-residue SmgGDS splice variant (SmgGDS-558) selectively associates with prenylated small GTPases and facilitates trafficking of Rap1A to the plasma membrane, whereas the less well characterized 607-residue SmgGDS splice variant (SmgGDS-607) associates with nonprenylated GTPases and regulates the entry of Rap1A, RhoA, and Rac1 into the prenylation pathway. These results indicate that guanine nucleotide exchange and interactions with SmgGDS splice variants can regulate the entrance and passage of PBR-possessing small GTPases through the prenylation pathway. PMID- 20709749 TI - Involvement of the serum response factor coactivator megakaryoblastic leukemia (MKL) in the activin-regulated dendritic complexity of rat cortical neurons. AB - Dynamic changes in neuronal morphology and transcriptional regulation play crucial roles in the neuronal network and function. Accumulating evidence suggests that the megakaryoblastic leukemia (MKL) family members, which function not only as actin-binding proteins but also as serum response factor (SRF) transcriptional coactivators, regulate neuronal morphology. However, the extracellular ligands and signaling pathways, which activate MKL-mediated morphological changes in neurons, remain unresolved. Here, we demonstrate that in addition to MKL1, MKL2, highly enriched in the forebrain, strongly contributes to the dendritic complexity, and this process is triggered by stimulation with activin, a member of the transforming growth factor beta (TGF-beta) superfamily. Activin promoted dendritic complexity in a SRF- and MKL-dependent manner without drastically affecting MKL localization and protein levels. In contrast, activin promoted the nuclear export of suppressor of cancer cell invasion (SCAI), which is a corepressor for SRF and MKL. Furthermore, overexpression of SCAI blocked activin-induced SRF transcriptional responses and dendritic complexity. Collectively, these results strongly suggest that activin-SCAI-MKL signaling is a novel pathway that regulates the dendritic morphology of rat cortical neurons by excluding SCAI from the nucleus and activating MKL/SRF-mediated gene expression. PMID- 20709750 TI - Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion. AB - The functional impact of adiponectin on pancreatic beta cells is so far poorly understood. Although adiponectin receptors (AdipoR1/2) were identified, their involvement in adiponectin-induced signaling and other molecules involved is not clearly defined. Therefore, we investigated the role of adiponectin in beta cells and the signaling mediators involved. MIN6 beta cells and mouse islets were stimulated with globular (2.5 MUg/ml) or full-length (5 MUg/ml) adiponectin under serum starvation, and cell viability, proliferation, apoptosis, insulin gene expression, and secretion were measured. Lysates were subjected to Western blot analysis to determine phosphorylation of AMP-activated protein kinase (AMPK), Akt, or ERK. Functional significance of signaling was confirmed using dominant negative mutants or pharmacological inhibitors. Participation of AdipoRs was assessed by overexpression or siRNA. Adiponectin failed to activate AMPK after 10 min or 1- and 24-h stimulation. ERK was significantly phosphorylated after 24-h treatment with adiponectin, whereas Akt was activated at all time points examined. 24-h stimulation with adiponectin significantly increased cell viability by decreasing cellular apoptosis, and this was prevented by dominant negative Akt, wortmannin (PI3K inhibitor), and U0126 (MEK inhibitor). Moreover, adiponectin regulated insulin gene expression and glucose-stimulated insulin secretion, which was also prevented by wortmannin and U0126 treatment. Interestingly, the data also suggest adiponectin-induced changes in Akt and ERK phosphorylation and caspase-3 may occur independent of the level of AdipoR expression. This study demonstrates a lack of AMPK involvement and implicates Akt and ERK in adiponectin signaling, leading to protection against apoptosis and stimulation of insulin gene expression and secretion in pancreatic beta cells. PMID- 20709751 TI - Regulation of the unfolded protein response by eif2Bdelta isoforms. AB - Cells respond to a variety of stresses, including unfolded proteins in the endoplasmic reticulum (ER), by phosphorylating a subunit of translation initiation factor eIF2, eIF2alpha. eIF2alpha phosphorylation inactivates the eIF2B complex. The inactivation of eIF2B not only suppresses the initiation of protein translation but paradoxically up-regulates the translation and expression of transcription factor ATF-4. Both of these processes are important for the cellular response to ER stress, also termed the unfolded protein response. Here we demonstrate that cellular response resulting from eIF2alpha phosphorylation is attenuated in several cancer cell lines. The deficiency of the unfolded protein response in these cells correlates with the expression of a specific isoform of a regulatory eIF2B subunit, eIF2Bdelta variant 1 (V1). Replacement of total eIF2Bdelta with V1 renders cells insensitive to eIF2alpha phosphorylation; specifically, they neither up-regulate ATF-4 and ATF-4 targets nor suppress protein translation. Expression of variant 2 eIF2Bdelta in ER stress response deficient cells restores the stress response. Our data suggest that V1 does not interact with the eIF2 complex, a requisite for eIF2B inhibition by eIF2alpha phosphorylation. Together, these data delineate a novel physiological mechanism to regulate the ER stress response with a large potential impact on a variety of diseases that result in ER stress. PMID- 20709752 TI - Active site metal ion in UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) switches between Fe(II) and Zn(II) depending on cellular conditions. AB - UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) catalyzes the deacetylation of UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate in Gram-negative bacteria. This second, and committed, step in lipid A biosynthesis is a target for antibiotic development. LpxC was previously identified as a mononuclear Zn(II) metalloenzyme; however, LpxC is 6-8-fold more active with the oxygen-sensitive Fe(II) cofactor (Hernick, M., Gattis, S. G., Penner-Hahn, J. E., and Fierke, C. A. (2010) Biochemistry 49, 2246-2255). To analyze the native metal cofactor bound to LpxC, we developed a pulldown method to rapidly purify tagged LpxC under anaerobic conditions. The metal bound to LpxC purified from Escherichia coli grown in minimal medium is mainly Fe(II). However, the ratio of iron/zinc bound to LpxC varies with the metal content of the medium. Furthermore, the iron/zinc ratio bound to native LpxC, determined by activity assays, has a similar dependence on the growth conditions. LpxC has significantly higher affinity for Zn(II) compared with Fe(II) with K(D) values of 60 +/- 20 pM and 110 +/- 40 nM, respectively. However, in vivo concentrations of readily exchangeable iron are significantly higher than zinc, suggesting that Fe(II) is the thermodynamically favored metal cofactor for LpxC under cellular conditions. These data indicate that LpxC expressed in E. coli grown in standard medium predominantly exists as the Fe(II)-enzyme. However, the metal cofactor in LpxC can switch between iron and zinc in response to perturbations in available metal ions. This alteration may be important for regulating the LpxC activity upon changes in environmental conditions and may be a general mechanism of regulating the activity of metalloenzymes. PMID- 20709753 TI - Selenium compounds activate ATM-dependent DNA damage response via the mismatch repair protein hMLH1 in colorectal cancer cells. AB - Epidemiological and animal studies indicate that selenium supplementation suppresses risk of colorectal and other cancers. The majority of colorectal cancers are characterized by a defective DNA mismatch repair (MMR). Here, we have employed the MMR-deficient HCT 116 colorectal cancer cells and the MMR-proficient HCT 116 cells with hMLH1 complementation to investigate the role of hMLH1 in selenium-induced DNA damage response, a tumorigenesis barrier. The ATM (ataxia telangiectasia mutated) protein responds to clastogens and initiates DNA damage response. We show that hMLH1 complementation sensitizes HCT 116 cells to methylseleninic acid, methylselenocysteine, and sodium selenite via reactive oxygen species and facilitates the selenium-induced oxidative 8-oxoguanine damage, DNA breaks, G(2)/M checkpoint response, and ATM pathway activation. Pretreatment of the hMLH1-complemented HCT 116 cells with the antioxidant N acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl or the ATM kinase inhibitor KU55933 suppresses hMLH1-dependent DNA damage response to selenium exposure. Selenium treatment stimulates the association between hMLH1 and hPMS2 proteins, a heterodimer critical for functional MMR, in a manner dependent on ATM and reactive oxygen species. Taken together, the results suggest a new role of selenium in mitigating tumorigenesis by targeting the MMR pathway, whereby the lack of hMLH1 renders the HCT 116 colorectal cancer cells resistant to selenium induced DNA damage response. PMID- 20709754 TI - Overlapping binding sites of structurally different antiarrhythmics flecainide and propafenone in the subunit interface of potassium channel Kv2.1. AB - Kv2.1 channels, which are expressed in brain, heart, pancreas, and other organs and tissues, are important targets for drug design. Flecainide and propafenone are known to block Kv2.1 channels more potently than other Kv channels. Here, we sought to explore structural determinants of this selectivity. We demonstrated that flecainide reduced the K(+) currents through Kv2.1 channels expressed in Xenopus laevis oocytes in a voltage- and time-dependent manner. By systematically exchanging various segments of Kv2.1 with those from Kv1.2, we determined flecainide-sensing residues in the P-helix and inner helix S6. These residues are not exposed to the inner pore, a conventional binding region of open channel blockers. The flecainide-sensing residues also contribute to propafenone binding, suggesting overlapping receptors for the drugs. Indeed, propafenone and flecainide compete for binding in Kv2.1. We further used Monte Carlo-energy minimizations to map the receptors of the drugs. Flecainide docking in the Kv1.2 based homology model of Kv2.1 predicts the ligand ammonium group in the central cavity and the benzamide moiety in a niche between S6 and the P-helix. Propafenone also binds in the niche. Its carbonyl group accepts an H-bond from the P-helix, the amino group donates an H-bond to the P-loop turn, whereas the propyl group protrudes in the pore and blocks the access to the selectivity filter. Thus, besides the binding region in the central cavity, certain K(+) channel ligands can expand in the subunit interface whose residues are less conserved between K(+) channels and hence may be targets for design of highly desirable subtype-specific K(+) channel drugs. PMID- 20709755 TI - RNA-binding protein Muscleblind-like 3 (MBNL3) disrupts myocyte enhancer factor 2 (Mef2) {beta}-exon splicing. AB - Mammalian MBNL (muscleblind-like) proteins are regulators of alternative splicing and have been implicated in myotonic dystrophy, the most common form of adult onset muscular dystrophy. MBNL3 functions as an inhibitor of muscle differentiation and is expressed in proliferating muscle precursor cells but not in differentiated skeletal muscle. Here we demonstrate that MBNL3 regulates the splicing pattern of the muscle transcription factor myocyte enhancer factor 2 (Mef2) by promoting exclusion of the alternatively spliced beta-exon. Expression of the transcriptionally more active (+)beta isoform of Mef2D was sufficient to overcome the inhibitory effects of MBNL3 on muscle differentiation. These data suggest that MBNL3 antagonizes muscle differentiation by disrupting Mef2 beta exon splicing. MBNL3 regulates Mef2D splicing by directly binding to intron 7 downstream of the alternatively spliced exon in the pre-mRNA. The RNA binding activity of MBNL3 requires the CX(7)CX(4-6)CX(3)H zinc finger domains. Using a cell culture model of myotonic dystrophy and myotonic dystrophy patient tissue, we have evidence that expression of CUG expanded RNAs can lead to an increase in MBNL3 expression and a decrease in Mef2D beta-exon splicing. These studies suggest that elevating MBNL3 activity in myogenic cells could lead to muscle degeneration disorders such as myotonic dystrophy. PMID- 20709756 TI - Cysteine is not the sulfur source for iron-sulfur cluster and methionine biosynthesis in the methanogenic archaeon Methanococcus maripaludis. AB - Three multiprotein systems are known for iron-sulfur (Fe-S) cluster biogenesis in prokaryotes and eukaryotes as follows: the NIF (nitrogen fixation), the ISC (iron sulfur cluster), and the SUF (mobilization of sulfur) systems. In all three, cysteine is the physiological sulfur source, and the sulfur is transferred from cysteine desulfurase through a persulfidic intermediate to a scaffold protein. However, the biochemical nature of the sulfur source for Fe-S cluster assembly in archaea is unknown, and many archaea lack homologs of cysteine desulfurases. Methanococcus maripaludis is a methanogenic archaeon that contains a high amount of protein-bound Fe-S clusters (45 nmol/mg protein). Cysteine in this archaeon is synthesized primarily via the tRNA-dependent SepRS/SepCysS pathway. When a DeltasepS mutant (a cysteine auxotroph) was grown with (34)S-labeled sulfide and unlabeled cysteine, <8% of the cysteine, >92% of the methionine, and >87% of the sulfur in the Fe-S clusters in proteins were labeled, suggesting that the sulfur in methionine and Fe-S clusters was derived predominantly from exogenous sulfide instead of cysteine. Therefore, this investigation challenges the concept that cysteine is always the sulfur source for Fe-S cluster biosynthesis in vivo and suggests that Fe-S clusters are derived from sulfide in those organisms, which live in sulfide-rich habitats. PMID- 20709757 TI - Vacuolar cation/H+ antiporters of Saccharomyces cerevisiae. AB - We previously demonstrated that Saccharomyces cerevisiae vnx1Delta mutant strains displayed an almost total loss of Na(+) and K(+)/H(+) antiporter activity in a vacuole-enriched fraction. However, using different in vitro transport conditions, we were able to reveal additional K(+)/H(+) antiporter activity. By disrupting genes encoding transporters potentially involved in the vnx1 mutant strain, we determined that Vcx1p is responsible for this activity. This result was further confirmed by complementation of the vnx1Deltavcx1Delta nhx1Delta triple mutant with Vcx1p and its inactivated mutant Vcx1p-H303A. Like the Ca(2+)/H(+) antiporter activity catalyzed by Vcx1p, the K(+)/H(+) antiporter activity was strongly inhibited by Cd(2+) and to a lesser extend by Zn(2+). Unlike as previously observed for NHX1 or VNX1, VCX1 overexpression only marginally improved the growth of yeast strain AXT3 in the presence of high concentrations of K(+) and had no effect on hygromycin sensitivity. Subcellular localization showed that Vcx1p and Vnx1p are targeted to the vacuolar membrane, whereas Nhx1p is targeted to prevacuoles. The relative importance of Nhx1p, Vnx1p, and Vcx1p in the vacuolar accumulation of monovalent cations will be discussed. PMID- 20709758 TI - The cystic fibrosis transmembrane conductance regulator impedes proteolytic stimulation of the epithelial Na+ channel. AB - Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) that prevent its proper folding and trafficking to the apical membrane of epithelial cells. Absence of cAMP-mediated Cl(-) secretion in CF airways causes poorly hydrated airway surfaces in CF patients, and this condition is exacerbated by excessive Na(+) absorption. The mechanistic link between missing CFTR and increased Na(+) absorption in airway epithelia has remained elusive, although substantial evidence implicates hyperactivity of the epithelial Na(+) channel (ENaC). ENaC is known to be activated by selective endoproteolysis of the extracellular domains of its alpha- and gamma-subunits, and it was recently reported that ENaC and CFTR physically associate in mammalian cells. We confirmed this interaction in oocytes by co-immunoprecipitation and found that ENaC associated with wild-type CFTR was protected from proteolytic cleavage and stimulation of open probability. In contrast, DeltaF508 CFTR, the most common mutant protein in CF patients, failed to protect ENaC from proteolytic cleavage and stimulation. In normal airway epithelial cells, ENaC was contained in the anti-CFTR immunoprecipitate. In CF airway epithelial cultures, the proportion of full-length to total alpha-ENaC protein signal was consistently reduced compared with normal cultures. Our results identify limiting proteolytic cleavage of ENaC as a mechanism by which CFTR down-regulates Na(+) absorption. PMID- 20709759 TI - GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. AB - Dysregulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad panel of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and gastric cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. Therefore, we used an FGFR2-IIIb-specific antibody, GP369, to investigate the importance of FGFR2 signaling in vitro and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. PMID- 20709761 TI - RyR1 expression and the cell boundary theorem. PMID- 20709760 TI - CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. AB - Caveolin-1 (CAV1) is the main structural component of caveolae, which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events. Although evidence describing the function of CAV1 in several cancer types has recently accumulated, its role in melanoma tumor formation and progression remains poorly explored. Here, by using B16F10 melanoma cells as an experimental system, we directly explore the function of CAV1 in melanoma tumor growth and metastasis. We first show that CAV1 expression promotes proliferation, whereas it suppresses migration and invasion of B16F10 cells in vitro. When orthotopically implanted in the skin of mice, B16F10 cells expressing CAV1 form tumors that are similar in size to their control counterparts. An experimental metastasis assay shows that CAV1 expression suppresses the ability of B16F10 cells to form lung metastases in C57Bl/6 syngeneic mice. Additionally, CAV1 protein and mRNA levels are found to be significantly reduced in human metastatic melanoma cell lines and human tissue from metastatic lesions. Finally, we show that following integrin activation, B16F10 cells expressing CAV1 display reduced expression levels and activity of FAK and Src proteins. Furthermore, CAV1 expression markedly reduces the expression of integrin beta(3) in B16F10 melanoma cells. In summary, our findings provide experimental evidence that CAV1 may function as an antimetastatic gene in malignant melanoma. PMID- 20709763 TI - A population based analysis of subclinical psychosis and help-seeking behavior. AB - Clinically defined psychosis is recognizable and distinguishable from nonclinical or subclinical psychosis by virtue of its clinical relevance (ie, its associated distress and its need for care and/or treatment). According to the continuum hypothesis, subclinical psychosis is merely quantitatively different from more extreme phenotypic expressions and as such should also be indicative of distress and help-seeking behavior but to a lesser extent. Using data from the Adult Psychiatric Morbidity Survey, the current study focused on self-reported psychosis and help-seeking experiences in a general population sample free from clinically defined psychosis (N = 7266). After statistically controlling for the effects of a series of potential help-seeking correlates the findings showed that subclinical psychosis symptom experience was significantly associated with various forms of help-seeking behavior. Individuals who reported subclinical experiences of thought control, paranoia, and strange experiences were on average 2 times more likely to attend their general practitioner for emotional problems compared with those individuals who reported no psychosis. Individuals who reported subclinical experiences of paranoia were 3 times more likely to be in receipt of counseling/therapy compared with those with no experience of paranoia. Multiple subclinical psychotic experiences also predicted elevated help-seeking behavior. These findings may have a positive impact on the detection of individuals who are at increased risk of psychological distress and aid in the design and implementation of more effective treatments at both clinical and subclinical levels. PMID- 20709765 TI - Republished paper: Nice guidance on the investigation of chest pain. PMID- 20709764 TI - Patient safety incidents associated with tracheostomies occurring in hospital wards: a review of reports to the UK National Patient Safety Agency. AB - BACKGROUND: Tracheostomies are increasingly common in hospital wards due to the rising use of percutaneous and surgical tracheostomies in critical care and bed pressures in these units. Hospital wards may lack appropriate infrastructure to care for this vulnerable group and significant patient harm may result. OBJECTIVES: To identify and analyse tracheostomy related incident reports from hospital wards between 1 October 2005 and 30 September 2007, and to make recommendations to improve patient safety based on the recurrent themes identified. The study was performed between August 2008 and August 2009. METHODS: 968 tracheostomy related critical incidents reported to the National Patient Safety Agency over the 2 year period, identified by key letter searches, were analysed. Incidents were categorised to identify common themes, and root cause analysis attempted where possible. RESULTS: In the 453 incidents where patients were directly affected, 338 (75%) were associated with some identifiable patient harm, of which 83 (18%) were associated with more than temporary harm. In 29 incidents (6%) some intervention was required to maintain life, and in 15 cases the incident may have contributed to the patient's death. Equipment was involved in 176 incidents and 276 incidents involved tracheostomies becoming blocked or displaced. CONCLUSIONS: By identifying and analysing themes in incident reports associated with tracheostomies, recommendations can be made to improve safety for this group of patients. These recommendations include improvements in infrastructure, competency and training, equipment provision, and in communication. PMID- 20709766 TI - Inadequate pain management: myth, stigma and professional fear. AB - The ability to effectively relieve pain has been available to health professionals for generations. It should be a primary concern in treating patients but is still often given a low priority or ignored completely. Apathy toward the suffering experienced may be mixed with a fear of the use of the common analgesics. Our own prejudices and ignorance can also contribute. Failures in the primary education of health professionals may be the single most important cause and the identity of the remedy. Raising the profile of pain as an essential educational topic and, more broadly, realising that this is a major public health matter are the way forward. PMID- 20709767 TI - Speed, accuracy, and confidence in Google, Ovid, PubMed, and UpToDate: results of a randomised trial. AB - BACKGROUND: The explosion of biomedical information has led to an 'information paradox'-the volume of biomedical information available has made it increasingly difficult to find relevant information when needed. It is thus increasingly critical for physicians to acquire a working knowledge of biomedical informatics. AIM: To evaluate four search tools commonly used to answer clinical questions, in terms of accuracy, speed, and user confidence. METHODS: From December 2008 to June 2009, medical students, resident physicians, and attending physicians at the authors' institution were asked to answer a set of four anaesthesia and/or critical care based clinical questions, within 5 min, using Google, Ovid, PubMed, or UpToDate (only one search tool per question). At the end of each search, participants rated their results on a four point confidence scale. One to 3 weeks after answering the initial four questions, users were randomised to one of the four search tools, and asked to answer eight questions, four of which were repeated. The primary outcome was defined as a correct answer with the highest level of confidence. RESULTS: Google was the most popular search tool. Users of Google and UpToDate were more likely than users of PubMed to answer questions correctly. Subjects had the most confidence in UpToDate. Searches with Google and UpToDate were faster than searches with PubMed or Ovid. CONCLUSION: Non-Medline based search tools are not inferior to Medline based search tools for purposes of answering evidence based anaesthesia and critical care questions. PMID- 20709768 TI - Vitiligo: concise evidence based guidelines on diagnosis and management. AB - Vitiligo is a common disease that causes a great degree of psychological distress. In its classical forms it is easily recognised and diagnosed. This review provides an evidence based outline of the management of vitiligo, particularly with the non-specialist in mind. Treatments for vitiligo are generally unsatisfactory. The initial approach to a patient who is thought to have vitiligo is to make a definite diagnosis, offer psychological support, and suggest supportive treatments such as the use of camouflage cosmetics and sunscreens, or in some cases after discussion the option of no treatment. Active therapies open to the non-specialist, after an explanation of potential side effects, include the topical use of potent or highly potent steroids or calcineurin inhibitors for a defined period of time (usually 2 months), following which an assessment is made to establish whether or not there has been a response. Patients whose condition is difficult to diagnose, unresponsive to straightforward treatments, or is causing psychological distress, are usually referred to a dermatologist. Specialist dermatology units have at their disposal phototherapy, either narrow band ultraviolet B or in some cases photochemotherapy, which is the most effective treatment presently available and can be considered for symmetrical types of vitiligo. Depigmenting treatments and possibly surgical approaches may be appropriate for vitiligo in selected cases. There is no evidence that presently available systemic treatments are helpful and safe in vitiligo. There is a need for further research into the causes of vitiligo, and into discovering better treatments. PMID- 20709769 TI - Freezing of gait in older people: associated conditions, clinical aspects, assessment and treatment. AB - Freezing of gait (FOG) is a disabling condition in older people. It is common in Parkinson's disease (PD) and other parkinsonian syndromes. The assessment of this condition poses challenges due to its episodic and transient nature and its frequent association with cognitive impairment. The pathophysiology of FOG is complex and poorly understood. Morphological brain imaging is of limited value in the evaluation of FOG, and functional imaging techniques are currently being developed to study the phenomenon. The treatment of 'off' time FOG in PD is relatively straight forward, but 'on' freezing in PD and FOG associated with other conditions may be difficult to treat. FOG is a strong risk factor for falls and adversely affects the quality of life of patients and carers. A multidisciplinary team approach is essential for optimum management. PMID- 20709770 TI - Role of imaging in the diagnosis of acute bacterial meningitis and its complications. AB - Acute bacterial meningitis is a common neurological emergency and a leading cause of death and neurological disability worldwide. Diagnosis is based on clinical and microbiological findings with neuroimaging in the form of CT reserved for those with specific adverse clinical features or when an underlying cause such as mastoiditis is suspected. MRI is extremely useful for detecting and monitoring the complications of meningitis. These can be remembered by the mnemonic HACTIVE (hydrocephalus, abscess, cerebritis/cranial nerve lesion, thrombosis, infarct, ventriculitis/vasculopathy and extra-axial collection). Diffusion weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) are useful to distinguish abscess from other ring enhancing lesions. PMID- 20709771 TI - Chronic viral hepatitis and chronic kidney disease. AB - Chronic kidney disease (CKD) has become a major public health problem worldwide over the past few decades because of the increasing prevalence of hypertension, diabetes mellitus, and elderly individuals in most countries. Chronic viral hepatitis (due to hepatitis B virus (HBV) and hepatitis C virus (HCV)) also poses significant morbidity and mortality globally. Both these viruses can cause CKD and these infections can occur as a consequence of CKD management. CKD patients acquiring HBV or HCV infection have higher morbidity and mortality rates, and the management of these infections among CKD patients with antiviral agents is associated with high rates of adverse effects. The optimal management of CKD associated with HBV and HCV is not well defined because of insufficient data from clinical trials. This review discusses the pathogenesis, clinical characteristics and management issues related to chronic viral hepatitis and CKD. PMID- 20709772 TI - Non-cystic fibrosis bronchiectasis: diagnosis and management in 21st century. AB - Bronchiectasis is permanently dilated airways caused by chronic bronchial inflammation secondary to inappropriate clearance of various micro-organisms and recurrent infections in the airways. At diagnosis, one should search for the underlying disease process, most of the time excluding cystic fibrosis (CF). However, in a substantial number of patients no cause is found. Next, patients need individualised therapy and follow-up by monitoring of their symptoms. Useful tools are the Leicester Cough Questionnaire and the Sputum Colour Chart. Screening patients for bacterial colonisation on a regular basis seems to be equally important, as many patients become colonised by pathogenic micro organisms. Treatment for non-cystic fibrosis bronchiectasis differs in certain aspects from cystic fibrosis bronchiectasis and often lacks evidence. Overall, bronchiectasis is an underestimated disease, not only in prevalence and incidence, but also in its ability to cause morbidity and mortality. Further research into the underlying pathophysiological mechanisms and trials evaluating new treatments are an absolute necessity. PMID- 20709773 TI - Republished paper: Emergency department triage revisited. AB - Triage is a process that is critical to the effective management of modern emergency departments. Triage systems aim, not only to ensure clinical justice for the patient, but also to provide an effective tool for departmental organisation, monitoring and evaluation. Over the last 20 years, triage systems have been standardised in a number of countries and efforts made to ensure consistency of application. However, the ongoing crowding of emergency departments resulting from access block and increased demand has led to calls for a review of systems of triage. In addition, international variance in triage systems limits the capacity for benchmarking. The aim of this paper is to provide a critical review of the literature pertaining to emergency department triage in order to inform the direction for future research. While education, guidelines and algorithms have been shown to reduce triage variation, there remains significant inconsistency in triage assessment arising from the diversity of factors determining the urgency of any individual patient. It is timely to accept this diversity, what is agreed, and what may be agreeable. It is time to develop and test an International Triage Scale (ITS) which is supported by an international collaborative approach towards a triage research agenda. This agenda would seek to further develop application and moderating tools and to utilise the scales for international benchmarking and research programmes. PMID- 20709774 TI - The firework display of fungal endogenous endophthalmitis. PMID- 20709775 TI - Calcinosis in juvenile dermatomyositis. PMID- 20709776 TI - Taking risks seriously. PMID- 20709777 TI - Tobacco smoking in seven Latin American cities: the CARMELA study. AB - OBJECTIVE: This study aimed to explore tobacco smoking in seven major cities of Latin America. METHODS: The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study is a cross-sectional epidemiological study of 11 550 adults between 25 and 64 years old in Barquisimeto, Venezuela; Bogota, Colombia; Buenos Aires, Argentina; Lima, Peru; Mexico City, Mexico; Quito, Ecuador; and Santiago, Chile. Tobacco smoking, including cigarettes, cigars and pipes, was surveyed among other cardiovascular risk factors. RESULTS: Santiago and Buenos Aires had the highest smoking prevalence (45.4% and 38.6%, respectively); male and female rates were similar. In other cities, men smoked more than women, most markedly in Quito (49.4% of men vs 10.5% of women). Peak male smoking prevalence occurred among the youngest two age groups (25-34 and 35 44 years old). Men and women of Buenos Aires smoked the highest number of cigarettes per day on average (15.7 and 12.4, respectively). Men initiated regular smoking earlier than women in each city (ranges 13.7-20.0 years vs 14.2 21.1 years, respectively). Exposure to secondhand tobacco smoke at workplace for more than 5 h per day was higher in Barquisimeto (28.7%), Buenos Aires (26.8%) and Santiago (21.5%). The highest prevalence of former smokers was found among men in Buenos Aires, Santiago and Lima (30.0%, 26.8% and 26.0% respectively). CONCLUSIONS: Smoking prevalence was high in the seven CARMELA cities, although patterns of smoking varied among cities. A major health and economic burden is inevitable in urban Latin America unless effective comprehensive tobacco control measures recommended by the World Health Organisation Framework Convention on Tobacco Control are implemented. PMID- 20709778 TI - A case of double exclusion. PMID- 20709779 TI - Alcohol and the elderly: the time to act is now! PMID- 20709780 TI - Knowledge of a patient-dependant phase of acute myocardial infarction in Polish adults: the role of physician's advice. AB - BACKGROUND: Effective management of acute myocardial infarction (AMI) is limited by patient delay in calling an ambulance. We aimed to assess knowledge related to a patient-dependant phase of AMI and its determinants in adults. METHODS: Questionnaire survey was conducted among a random sample of 942 men (48%) and women (52%) aged 63.50 +/- 6.50 selected from population registers in Cracow (Poland). Questions from the Behavioral Risk Factor Surveillance System were used to assess knowledge of AMI symptoms. The respondents were further asked about the first thing they would do in response to AMI symptoms, the emergency phone number and whether a doctor advised them about AMI. RESULTS: All suggested AMI symptoms were recognized by 51 (5.4%) respondents. More persons would call an ambulance in response to AMI symptoms in another person than if they appear in themselves (87.4% vs. 74.4%, P = 0.02). Only 644 (68%) participants knew the emergency phone number and 104 (11%) were advised about AMI by their doctors. Such advice was associated with higher rates of knowledge of AMI symptoms and the emergency phone number but not with a declaration of the appropriate reaction to AMI symptoms. Participants after AMI did not represent better knowledge of a patient-dependant phase of AMI but paradoxically less frequently than other persons declared calling an ambulance in response to AMI symptoms. CONCLUSION: Improvement in knowledge and attitudes related to a patient-dependant phase of AMI is needed in adults even if they experienced AMI before. A routine advice from a doctor may contribute significantly to this improvement. PMID- 20709781 TI - Alcohol consumption and harm among elderly Europeans: falling between the cracks. PMID- 20709782 TI - Hospitalization admission rates for low-income subjects with full health insurance coverage in France. AB - BACKGROUND: Complementary Universal Health insurance (CMUC) providing free access to health care has been available in France, since 2000 for people with an annual income <50% of the poverty threshold. METHODS: Data were derived from the French national health insurance reimbursements and short-stay admissions database for 2007 (80% of subjects under the age of 60 years in France, including 4.8 million CMUC beneficiaries). Rate ratios were calculated by dividing the rate of CMUC beneficiaries by that of other beneficiaries standardized for the sex and age distribution of CMUC beneficiaries. RESULTS: The hospitalization rate of CMUC beneficiaries was 17.2% and the standardized rate for non-CMUC beneficiaries was 13.2% (ratio: 1.3). It was equally raised regardless of gender and age of CMUC beneficiaries. The hospital mortality rate was 0.61% for CMUC beneficiaries and the adjusted rate for non-CMUC beneficiaries was 0.35% (1.8). The hospitalization ratio for CMUC beneficiaries was >1 for all of the 22 major diagnostic categories, including psychiatry, toxicology and alcohol (3.7), HIV (3.3), infectious diseases other than HIV (1.9), burns (2.6), trauma (1.7) and female genital tract tumours (1.6) but not breast tumours (0.8). Hospitalizations for investigations such as endoscopies were also more frequent, as well as stays of <48 h for radiotherapy (1.6), chemotherapy (1.5) and dialysis (2.2). CONCLUSIONS: In this low-income population with free access to health care, hospitalization and hospital mortality rates were higher for many diseases that are known targets for prevention and screening actions. PMID- 20709783 TI - Job attitudes and well-being among public vs. private physicians: organizational justice and job control as mediators. AB - BACKGROUND: The present study examined whether there are differences in job related attitudes and well-being among physicians working in private sector and public sector. In addition, we examined whether psychosocial factors (organizational justice and job control) could mediate these possible differences in different sectors. METHODS: Cross-sectional survey data from the Finnish Health Professional Study was used. A random sample of Finnish physicians included 1522 women and 1047 men aged 25-65 years. Outcome variables were job satisfaction, organizational commitment, psychological distress, work ability and sleeping problems. Job control and organizational justice were measured using established questionnaires. Series of regression analyses were performed and the mediational effects were tested following the procedures outlined by Baron and Kenny. RESULTS: Physicians working in private sector had higher levels of job satisfaction and organizational commitment and lower levels of psychological distress and sleeping problems when compared with physicians working in public sector. Private physicians also had higher levels of organizational justice, which acted as a mediator behind more positive attitudes and better well-being in private sector. Private physicians had higher levels of job control but it did not act as a mediator. CONCLUSIONS: Private physicians feel better than public physicians and this is partly due to higher organizational justice in private sector. Public health care organizations should invest effort to increase the fairness in their organizations and management and pay more attention in improving the well-being of their employees, which could possibly increase the attractiveness of public sector as a career option. PMID- 20709784 TI - Genome dynamics are influenced by food source in Allogromia laticollaris strain CSH (Foraminifera). AB - Across the eukaryotic tree of life, genomes vary within populations and within individuals during their life cycle. Understanding intraspecific genome variation in diverse eukaryotes is key to elucidating the factors that underlie this variation. Here, we characterize genome dynamics during the life cycle of Allogromia laticollaris strain CSH, a member of the Foraminifera, using fluorescence microscopy and reveal extensive variation in nuclear size and DNA content. Both nuclear size and DNA content are tightly correlated across a 700 fold range in cell volume. In contrast to models in yeast where nuclear size is determined solely by cell size, the relationship in A. laticollaris CSH differs according to both life cycle stage and food source. Feeding A. laticollaris CSH a diet that includes algae results in a 2-fold increase in DNA content in reproductive cells compared with a diet of bacteria alone. This difference in DNA content likely corresponds to increased fecundity, as reproduction occurs through segregation of the polyploid nucleus into numerous daughter nuclei. Environmentally mediated variation in DNA content may be a widespread phenomenon, as it has been previously reported in the plant flax and the flagellate Euglena. We hypothesize that DNA content is influenced by food in other single-celled eukaryotes with ploidy cycles and that this genome flexibility may enable these eukaryotes to maximize fitness across changing environmental conditions. PMID- 20709785 TI - Heterologous expression of Candida albicans cell wall-associated adhesins in Saccharomyces cerevisiae Reveals differential specificities in adherence and biofilm formation and in binding oral Streptococcus gordonii. AB - Colonization and infection of the human host by opportunistic pathogen Candida albicans derive from an ability of this fungus to colonize mucosal tissues and prosthetic devices within the polymicrobial communities present. To determine the functions of C. albicans cell wall proteins in interactions with host or bacterial molecules, Saccharomyces cerevisiae was utilized as a surrogate host to express C. albicans cell wall proteins Als3p, Eap1p, Hwp1p, and Rbt1p. Salivary pellicle and fibrinogen were identified as novel substrata for Als3p and Hwp1p, while only Als3p mediated adherence of S. cerevisiae to basement membrane collagen type IV. Parental S. cerevisiae cells failed to form biofilms on salivary pellicle, polystyrene, or silicone, but cells expressing Als3p or Hwp1p exhibited significant attachment to each surface. Virulence factor Rbt1p also conferred lower-level binding to salivary pellicle and polystyrene. S. cerevisiae cells expressing Eap1p formed robust biofilms upon polystyrene surfaces but not salivary pellicle. Proteins Als3p and Eap1p, and to a lesser degree Hwp1p, conferred upon S. cerevisiae the ability to bind cells of the oral primary colonizing bacterium Streptococcus gordonii. These interactions, which occurred independently of amyloid aggregate formation, provide the first examples of specific C. albicans surface proteins serving as receptors for bacterial adhesins. Streptococcus gordonii did not bind parental S. cerevisiae or cells expressing Rbt1p. Taken collectively, these data suggest that a network of cell wall proteins comprising Als3p, Hwp1p, and Eap1p, with complementary adhesive functions, promotes interactions of C. albicans with host and bacterial molecules, thus leading to effective colonization within polymicrobial communities. PMID- 20709786 TI - The Saccharomyces cerevisiae anaphase-promoting complex interacts with multiple histone-modifying enzymes to regulate cell cycle progression. AB - The anaphase-promoting complex (APC), a large evolutionarily conserved ubiquitin ligase complex, regulates cell cycle progression through mitosis and G(1). Here, we present data suggesting that APC-dependent cell cycle progression relies on a specific set of posttranslational histone-modifying enzymes. Multiple APC subunit mutants were impaired in total and modified histone H3 protein content. Acetylated H3K56 (H3K56(Ac)) levels were as reduced as those of total H3, indicating that loading histones with H3K56(Ac) is unaffected in APC mutants. However, under restrictive conditions, H3K9(Ac) and dimethylated H3K79 (H3K79(me2)) levels were more greatly reduced than those of total H3. In a screen for histone acetyltransferase (HAT) and histone deacetylase (HDAC) mutants that genetically interact with the apc5(CA) (chromatin assembly) mutant, we found that deletion of GCN5 or ELP3 severely hampered apc5(CA) temperature-sensitive (ts) growth. Further analyses showed that (i) the elp3Delta gcn5Delta double mutant ts defect was epistatic to that observed in apc5(CA) cells; (ii) gcn5Delta and elp3Delta mutants accumulate in mitosis; and (iii) turnover of the APC substrate Clb2 is not impaired in elp3Delta gcn5Delta cells. Increased expression of ELP3 and GCN5, as well as genes encoding the HAT Rtt109 and the chromatin assembly factors Msi1 and Asf1, suppressed apc5(CA) defects, while increased APC5 expression partially suppressed elp3Delta gcn5Delta growth defects. Finally, we demonstrate that Gcn5 is unstable during G(1) and following G(1) arrest and is stabilized in APC mutants. We present our working model in which Elp3/Gcn5 and the APC work together to facilitate passage through mitosis and G(1). To progress into S, we propose that at least Gcn5 must then be targeted for degradation in an APC-dependent fashion. PMID- 20709787 TI - The transcriptional regulator Nrg1p controls Candida albicans biofilm formation and dispersion. AB - The ability of Candida albicans to reversibly switch morphologies is important for biofilm formation and dispersion. In this pathogen, Nrg1p functions as a key negative regulator of the yeast-to-hypha morphogenetic transition. We have previously described a genetically engineered C. albicans tet-NRG1 strain in which NRG1 expression levels can be manipulated by the presence or absence of doxycycline (DOX). Here, we have used this strain to ascertain the role of Nrg1p in regulating the different stages of the C. albicans biofilm developmental cycle. In an in vitro model of biofilm formation, the C. albicans tet-NRG1 strain was able to form mature biofilms only when DOX was present in the medium, but not in the absence of DOX, when high levels of NRG1 expression blocked the yeast-to hypha transition. However, in a biofilm cell retention assay in which biofilms were developed with mixtures of C. albicans tet-NRG1 and SC5314 strains, tet-NRG1 yeast cells were still incorporated into the mixed biofilms, in which an intricate network of hyphae of the wild-type strain provided for biofilm structural integrity and adhesive interactions. Also, utilizing an in vitro biofilm model under conditions of flow, we demonstrated that C. albicans Nrg1p exerts an exquisite control of the dispersal process, as overexpression of NRG1 leads to increases in dispersion of yeast cells from the biofilms. Our results demonstrate that manipulation of NRG1 gene expression has a profound influence on biofilm formation and biofilm dispersal, thus identifying Nrg1p as a key regulator of the C. albicans biofilm life cycle. PMID- 20709788 TI - Ccq1p and the condensin proteins Cut3p and Cut14p prevent telomere entanglements in the fission yeast Schizosaccharomyces pombe. AB - The Schizosaccharomyces pombe telomere-associated protein Ccq1p has previously been shown to participate in telomerase recruitment, heterochromatin formation, and suppression of checkpoint activation. Here we characterize a critical role for Ccq1p in mitotic transit. We show that mitotic cells lacking Ccq1p lose minichromosomes at high frequencies but that conditional knockdown of Ccq1p expression results in telomere bridging within one cell cycle. Elevating Ccq1p expression resolves the telomere entanglements caused by decreased Taz1p activity. Ccq1p affects telomere resolution in the absence of changes in telomere size, indicating a role for Ccq1p that is independent of telomere length regulation. Using affinity purification, we identify the condensin proteins Cut3p and Cut14p as candidate Ccq1p interactors in this activity. Condensin loss-of function disrupts Ccq1p telomeric localization and normal intertelomere clustering, while condensin overexpression relieves the chromosome segregation defects associated with conditional Ccq1p knockdown. These data suggest that Ccq1p and condensins collaborate to mediate resolution of telomeres in mitosis and regulate intertelomeric clustering during interphase. PMID- 20709789 TI - Phosphatidylinositol 3-phosphate, an essential lipid in Plasmodium, localizes to the food vacuole membrane and the apicoplast. AB - Phosphoinositides are important regulators of diverse cellular functions, and phosphatidylinositol 3-monophosphate (PI3P) is a key element in vesicular trafficking processes. During its intraerythrocytic development, the malaria parasite Plasmodium falciparum establishes a sophisticated but poorly characterized protein and lipid trafficking system. Here we established the detailed phosphoinositide profile of P. falciparum-infected erythrocytes and found abundant amounts of PI3P, while phosphatidylinositol 3,5-bisphosphate was not detected. PI3P production was parasite dependent, sensitive to a phosphatidylinositol-3-kinase (PI3-kinase) inhibitor, and predominant in late parasite stages. The Plasmodium genome encodes a class III PI3-kinase of unusual size, containing large insertions and several repetitive sequence motifs. The gene could not be deleted in Plasmodium berghei, and in vitro growth of P. falciparum was sensitive to a PI3-kinase inhibitor, indicating that PI3-kinase is essential in Plasmodium blood stages. For intraparasitic PI3P localization, transgenic P. falciparum that expressed a PI3P-specific fluorescent probe was generated. Fluorescence was associated mainly with the membrane of the food vacuole and with the apicoplast, a four-membrane bounded plastid-like organelle derived from an ancestral secondary endosymbiosis event. Electron microscopy analysis confirmed these findings and revealed, in addition, the presence of PI3P positive single-membrane vesicles. We hypothesize that these vesicles might be involved in transport processes, likely of proteins and lipids, toward the essential and peculiar parasite compartment, which is the apicoplast. The fact that PI3P metabolism and function in Plasmodium appear to be substantially different from those in its human host could offer new possibilities for antimalarial chemotherapy. PMID- 20709790 TI - The ROCO kinase QkgA is necessary for proliferation inhibition by autocrine signals in Dictyostelium discoideum. AB - AprA and CfaD are secreted proteins that function as autocrine signals to inhibit cell proliferation in Dictyostelium discoideum. Cells lacking AprA or CfaD proliferate rapidly, and adding AprA or CfaD to cells slows proliferation. Cells lacking the ROCO kinase QkgA proliferate rapidly, with a doubling time 83% of that of the wild type, and overexpression of a QkgA-green fluorescent protein (GFP) fusion protein slows cell proliferation. We found that qkgA(-) cells accumulate normal levels of extracellular AprA and CfaD. Exogenous AprA or CfaD does not slow the proliferation of cells lacking qkgA, and expression of QkgA-GFP in qkgA(-) cells rescues this insensitivity. Like cells lacking AprA or CfaD, cells lacking QkgA tend to be multinucleate, accumulate nuclei rapidly, and show a mass and protein accumulation per nucleus like those of the wild type, suggesting that QkgA negatively regulates proliferation but not growth. Despite their rapid proliferation, cells lacking AprA, CfaD, or QkgA expand as a colony on bacteria less rapidly than the wild type. Unlike AprA and CfaD, QkgA does not affect spore viability following multicellular development. Together, these results indicate that QkgA is necessary for proliferation inhibition by AprA and CfaD, that QkgA mediates some but not all of the effects of AprA and CfaD, and that QkgA may function downstream of these proteins in a signal transduction pathway regulating proliferation. PMID- 20709791 TI - Moving Canadian governmental policies beyond a focus on individual lifestyle: some insights from complexity and critical theories. AB - This paper explores why Canadian government policies, particularly those related to obesity, are 'stuck' at promoting individual lifestyle change. Key concepts within complexity and critical theories are considered a basis for understanding the continued emphasis on lifestyle factors in spite of strong evidence indicating that a change in the environment and conditions of poverty isare needed to tackle obesity. Opportunities to get 'unstuck' from individual-level lifestyle interventions are also suggested by critical concepts found within these two theories, although getting 'unstuck' will also require cross-sectoral collective action. Our discussion focuses on the Canadian context but will undoubtedly be relevant to other countries, where health promoters and others engage in similar struggles for fundamental government policy change. PMID- 20709794 TI - Tired with all those supplements? PMID- 20709793 TI - Gene dysregulations driven by somatic copy number aberrations-biological and clinical implications in colon tumors: a paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology. AB - The majority of colorectal cancer (CRC) cases have chromosomal instability, in which the tumor genome is characterized by gross chromosomal aberrations such as gains in 20q, 13q, 8q, and 7, and losses in 4, 8p, 18q, and 17p. These somatic copy number changes (gains, losses, and somatic uniparental disomies) are crucial to CRC progression as they drive genes toward cancer-promoting (oncogenic or tumor suppressive) states. Numerous studies have shown that the loss of 18q or 8p is associated with poorer clinical outcome in CRCs. Either chromosomal arm may contain a tumor suppressor gene (or genes), whose deactivation by copy loss (loss of wild-type allele, decreased expression) can be crucial to the later stages of cancer progression. Our own integrated genomic analysis (single nucleotide polymorphism array, expression array) of more than 200 CRC tumor and normal samples indicates that the overall down-regulation of genes within the 8p or 18q arm is associated with lower survival rate. Among the often down-regulated, poor prognosis-associated 8p genes is MTUS1, whose gene product (a mitotic spindle associated protein) was recently demonstrated to have a tumor suppressive property. Within 18q is ATP5A1, which codes for the catalytic a component of mitochondrial H(+)-ATP synthase. Like SMAD4 (also in 18q), the decreased expression of ATP5A1 appears to be a marker of unfavorable clinical outcome in CRCs. PMID- 20709792 TI - Reliable gene expression measurements from fine needle aspirates of pancreatic tumors: effect of amplicon length and quality assessment. AB - BACKGROUND AND AIMS: Biomarker use for pancreatic cancer diagnosis has been impaired by a lack of samples suitable for reliable quantitative RT-PCR (qRT PCR). Fine needle aspirates (FNAs) from pancreatic masses were studied to define potential causes of RNA degradation and develop methods for accurately measuring gene expression. METHODS: Samples from 32 patients were studied. RNA degradation was assessed by using a multiplex PCR assay for varying lengths of glyceraldehyde 3-phosphate dehydrogenase, and effects on qRT-PCR were determined by using a 150 bp and a 80-bp amplicon for RPS6. Potential causes of and methods to circumvent RNA degradation were studied by using FNAs from a pancreatic cancer xenograft. RESULTS: RNA extracted from pancreatic mass FNAs was extensively degraded. Fragmentation was related to needle bore diameter and could not be overcome by alterations in aspiration technique. Multiplex PCR for glyceraldehyde-3-phosphate dehydrogenase could distinguish samples that were suitable for qRT-PCR. The use of short PCR amplicons (<100 bp) provided reliable gene expression analysis from FNAs. When appropriate samples were used, the assay was highly reproducible for gene copy number with minimal (0.0003 or about 0.7% of total) variance. CONCLUSIONS: The degraded properties of endoscopic FNAs markedly affect the accuracy of gene expression measurements. Our novel approach to designate specimens "informative" for qRT-PCR allowed accurate molecular assessment for the diagnosis of pancreatic diseases. PMID- 20709795 TI - Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation. AB - Light damage to the retina accelerates retinal degeneration in human diseases and rodent models. Recently, the polyphenolic phytoalexin resveratrol has been shown to exert various bioactivities in addition to its classical antioxidant property. In the present study, we investigated the effect of resveratrol on light-induced retinal degeneration together with its underlying molecular mechanisms. BALB/c mice with light exposure (5000-lux white light for 3 hours) were orally pretreated with resveratrol at a dose of 50 mg/kg for 5 days. Retinal damage was evaluated by TdT-mediated dUTP nick-end labeling, outer nuclear layer morphometry, and electroretinography. Administration of resveratrol to mice with light exposure led to a significant suppression of light-induced pathological parameters, including TdT-mediated dUTP nick-end labeling-positive retinal cells, outer nuclear layer thinning, and electroretinography changes. To clarify the underlying molecular mechanisms, the nuclear translocation of activator protein-1 subunit c-fos was evaluated by enzyme-linked immunosorbent assay, and the retinal activity of sirtuin 1 was measured by deacetylase fluorometric assay. Retinal activator protein-1 activation, up-regulated following light exposure, was significantly reduced by application of resveratrol. In parallel, retinal sirtuin 1 activity, reduced in animals with light damage, was significantly augmented by resveratrol treatment. Our data suggest the potential use of resveratrol as a therapeutic agent to prevent retinal degeneration related to light damage. PMID- 20709796 TI - Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. AB - Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip(+/-) mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIP associated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas. PMID- 20709797 TI - Epigenetic silencing of a proapoptotic cell adhesion molecule, the immunoglobulin superfamily member IGSF4, by promoter CpG methylation protects Hodgkin lymphoma cells from apoptosis. AB - The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) are believed to derive from germinal center (GC) B cells, but lack expression of a functional B cell receptor. As apoptosis is the normal fate of B-cell receptor negative GC B cells, mechanisms that abrogate apoptosis are thus critical in HL development, such as epigenetic disruption of certain pro-apoptotic cancer genes including tumor suppressor genes. Identifying methylated genes elucidates oncogenic mechanisms and provides valuable biomarkers; therefore, we performed a chemical epigenetic screening for methylated genes in HL through pharmacological demethylation and expression profiling. IGSF4/CADM1/TSLC1, a pro-apoptotic cell adhesion molecule of the immunoglobulin superfamily, was identified together with other methylated targets. In contrast to its expression in normal GC B cells, IGSF4 was down-regulated and methylated in HL cell lines, most primary HL, and microdissected HRS cells of 3/5 cases, but not in normal peripheral blood mononuclear cells and seldom in normal lymph nodes. We also detected IGSF4 methylation in sera of 14/18 (78%) HL patients but seldom in normal sera. Ectopic IGSF4 expression decreased HL cells survival and increased their sensitivity to apoptosis. IGSF4 induction that normally follows heat shock stress treatment was also abrogated in methylated lymphoma cells. Thus, our data demonstrate that IGSF4 silencing by CpG methylation provides an anti-apoptotic signal to HRS cells important in HL pathogenesis. PMID- 20709799 TI - Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis. AB - Transforming growth factor-beta1 (TGF-beta1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-beta1 enhances beta(1) integrin levels in NMuMG cells, the detailed molecular mechanisms underlying TGF-beta1 induced beta(1) integrin gene expression and the role of beta(1) integrin during EMT in the renal system are still unclear. In this study, we examined the role of beta(1) integrin in TGF-beta1-induced EMT both in vitro and in vivo. TGF-beta1 induced augmentation of beta(1) integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-beta1-induced augmentation of beta(1) integrin. TGF-beta1 triggered beta(1) integrin gene promoter activity as assessed by luciferase activity assay. Both knockdown of Smad3 and mutation of the Smad-binding element to block binding to the beta(1) integrin promoter markedly reduced TGF-beta1-induced beta(1) integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-beta1 enhanced Smad3 binding to the beta(1) integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of beta(1) integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of beta(1) integrin and alpha-smooth muscle actin in tubule epithelia. Blockade of beta(1) integrin signaling dampened the progression of fibrosis. Taken together, beta(1) integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of beta(1) integrin is a possible therapeutic target for prevention of renal fibrosis. PMID- 20709800 TI - Loss of inducible nitric oxide synthase expression in the mouse renal cell carcinoma cell line RENCA is mediated by microRNA miR-146a. AB - Tumor-associated macrophages can potentially kill tumor cells via the high concentrations of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS); however, tumor-associated macrophages actually support tumor growth, as they are skewed toward M2 activation, which is characterized by low amounts of NO production and is proangiogenic. We show that the mouse renal cell carcinoma cell line, RENCA, which, on stimulation, expresses high levels of iNOS mRNA, loses its ability to express the iNOS protein. This effect is mediated by the microRNA miR 146a, as inhibition of RENCA cells with anti-miR- 146a restores iNOS expression and NO production (4.8 +/- 0.4 versus 0.3 +/- 0.1 MUmol/L in uninhibited cells, P < 0.001). In vivo, RENCA tumor cells do not stain for iNOS, while infiltrating tumor-associated macrophages showed intense staining, and both cell types expressed iNOS mRNA. Restoring iNOS protein expression in RENCA cells using anti miR-146a increases macrophage-induced death of RENCA cells by 73% (P < 0.01) in vitro and prevents tumor growth in vivo. These results suggest that, in addition to NO production by macrophages, tumor cells must produce NO to induce their own deaths, and some tumor cells may use miR-146a to reduce or abolish endogenous NO production to escape macrophage-mediated cell death. Thus, inhibiting miR-146a may render these tumor cells susceptible to therapeutic strategies, such as adoptive transfer of M1-activated macrophages. PMID- 20709801 TI - Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy. AB - Acute kidney injury (AKI) is a serious problem in critically ill patients of intensive care units. It has been reported previously that AKI can induce acute lung injury (ALI), as well as cause injuries to other remote organs, including the lungs. Patients with AKI complicated by ALI show remarkably high mortality. ALI is characterized by neutrophil infiltration into the lung. Neutrophil elastase (NE) is a key enzyme for tissue injury caused by activated neutrophils, such as occurs in ALI. Therefore, this study investigated the role of NE in AKI induced ALI using a specific NE inhibitor, sivelestat sodium hydrate (ONO-5046), in a mouse bilateral nephrectomy model. Bilateral nephrectomy showed not only a remarkable increase in blood urea nitrogen levels, but also demonstrated neutrophil infiltration into the lung, increased pulmonary inflammatory cytokine expression [interleukin-6, neutrophil chemokine keratinocyte-derived chemokine, and tumor necrosis factor-alpha], and protein leakage with early increases in both systemic and pulmonary NE activity. ONO-5046 treatment reduced NE activity and improved these pulmonary inflammatory responses. Additionally, ONO-5046 treated animals had longer survival times. These data demonstrate that increasing NE activity induces pulmonary inflammatory damage in a bilateral nephrectomy model. Blockade of NE activity will be a useful therapeutic strategy for ALI complications in AKI patients. PMID- 20709802 TI - Adiponectin-mediated heme oxygenase-1 induction protects against iron-induced liver injury via a PPARalpha dependent mechanism. AB - Protective effects of adiponectin (APN; an adipocytokine) were shown against various oxidative challenges; however, its therapeutic implications and the mechanisms underlying hepatic iron overload remain unclear. Herein, we show that the deleterious effects of iron dextran on liver function and iron deposition were significantly reversed by adiponectin gene therapy, which was accompanied by AMP-activated protein kinase (AMPK) phosphorylation and heme oxygenase (HO)-1 induction. Furthermore, AMPK-mediated peroxisome proliferator-activated receptor alpha (PPARalpha) activation by APN was ascribable to HO-1 induction. Additionally, we revealed direct transcriptional regulation of HO-1 by the binding of PPARalpha to a PPAR-responsive element (PPRE) by various experimental assessments. Interestingly, overexpression of HO-1 in hepatocytes mimicked the protective effect of APN in attenuating iron-mediated injury, whereas it was abolished by SnPP and small interfering HO-1. Furthermore, bilirubin, the end product of the HO-1 reaction, but not CO, protected hepatocytes from iron dextran mediated caspase activation. Herein, we demonstrate a novel functional PPRE in the promoter regions of HO-1, and APN-mediated HO-1 induction elicited an antiapoptotic effect and a decrease in iron deposition in hepatocytes subjected to iron challenge. PMID- 20709803 TI - Pigment epithelium-derived factor is an intrinsic antifibrosis factor targeting hepatic stellate cells. AB - The liver is the major site of pigment epithelium-derived factor (PEDF) synthesis. Recent evidence suggests a protective role of PEDF in liver cirrhosis. In the present study, immunohistochemical analyses revealed lower PEDF levels in liver tissues of patients with cirrhosis and in animals with chemically induced liver fibrosis. Delivery of the PEDF gene into liver cells produced local PEDF synthesis and ameliorated liver fibrosis in animals treated with either carbon tetrachloride or thioacetamide. In addition, suppression of peroxisome proliferator-activated receptor gamma expression, as well as nuclear translocation of nuclear factor-kappa B was found in hepatic stellate cells (HSCs) from fibrotic livers, and both changes were reversed by PEDF gene delivery. In culture-activated HSCs, PEDF, through the induction of peroxisome proliferator-activated receptor gamma, reduced the activity of nuclear factor kappa B and prevented the nuclear localization of JunD. In conclusion, our observations that PEDF levels are reduced during liver cirrhosis and that PEDF gene delivery ameliorates cirrhosis suggest that PEDF is an intrinsic protector against liver cirrhosis. Direct inactivation of HSCs and the induction of apoptosis of activated HSCs may be two of the mechanisms by which PEDF suppresses liver cirrhosis. PMID- 20709804 TI - The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma. AB - The lack of reliable molecular markers for normal differentiated epithelial cells limits understanding of human gastric carcinogenesis. Recognized precursor lesions for gastric adenocarcinoma are intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM), defined here by ectopic CDX2 and TFF2 expression, respectively. In mice, expression of the bHLH transcription factor MIST1, normally restricted to mature chief cells, is down-regulated as chief cells undergo experimentally induced metaplasia. Here, we show MIST1 expression is also a specific marker of human chief cells. SPEM, with and without MIST1, is present in human lesions and, akin to murine data, likely represents transitional (TFF2(+)/MIST1(+) = "hybrid"-SPEM) and established (TFF2(+)/MIST1(-) = SPEM) stages. Co-visualization of MIST1 and CDX2 shows similar progressive loss of MIST1 with a transitional, CDX2(+)/MIST1(-) hybrid-intestinal metaplasia stage. Interinstitutional analysis and comparison of findings in tissue microarrays, resection specimens, and biopsies (n > 400 samples), comprising the entire spectrum of recognized stages of gastric carcinogenesis, confirm MIST1 expression is restricted to the chief cell compartment in normal oxyntic mucosa, rare in established metaplastic lesions, and lost in intraepithelial neoplasia/dysplasia and carcinoma of various types with the exception of rare chief cell carcinoma ( approximately 1%). Our findings implicate MIST1 as a reliable marker of mature, healthy chief cells, and we provide the first evidence that metaplasia in humans arises at least in part from the chief cell lineage. PMID- 20709805 TI - Peroxisome proliferator-activated receptor {delta} regulates inflammation via NF {kappa}B signaling in polymicrobial sepsis. AB - The nuclear peroxisome proliferator-activated receptor delta (PPARdelta) is an important regulator of lipid metabolism. In contrast to its known effects on energy homeostasis, its biological role on inflammation is not well understood. We investigated the role of PPARdelta in the modulation of the nuclear factor kappaB (NF-kappaB)-driven inflammatory response to polymicrobial sepsis in vivo and in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPARdelta ligand, provided beneficial effects to rats subjected to cecal ligation and puncture, as shown by reduced systemic release of pro-inflammatory cytokines and neutrophil infiltration in lung, liver, and cecum, when compared with vehicle treatment. Molecular analysis revealed that treatment with GW0742 reduced NF-kappaB binding to DNA in lung and liver. In parallel experiments, heterozygous PPARdelta-deficient mice suffered exaggerated lethality when subjected to cecal ligation and puncture and exhibited severe lung injury and higher levels of circulating tumor necrosis factor-alpha (TNFalpha) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, GW0742 reduced TNFalpha production by inhibiting NF-kappaB activation. RNA silencing of PPARdelta abrogated the inhibitory effects of GW0742 on TNFalpha production. Chromatin immunoprecipitation assays revealed that PPARdelta displaced the NF-kappaB p65 subunit from the kappaB elements of the TNFalpha promoter, while recruiting the co-repressor BCL6. These data suggest that PPARdelta is a crucial anti inflammatory regulator, providing a basis for novel sepsis therapies. PMID- 20709807 TI - A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis. AB - More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported. PMID- 20709806 TI - Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of the vessel wall. Recent evidence suggests that chronic vascular inflammation ensues as an imbalance between pro- and anti-inflammatory mediators. Recently identified lipid mediators (eg, lipoxins and resolvins) play active roles in promoting the resolution of inflammation. Alterations in vascular smooth muscle cell (VSMC) phenotype, which manifest as a loss of contractile protein expression and increased proliferation and migration, are prominent mechanistic features of both atherosclerosis and restenosis following various interventions (eg, angioplasty and bypass grafting). We sought to determine whether human atherosclerosis is associated with a "resolution deficit" and whether lipoxins and resolvins influence VSMC phenotype. Here we report that plasma levels of aspirin-triggered lipoxin are significantly lower in patients with symptomatic peripheral artery disease than in healthy volunteers. Both aspirin-triggered lipoxin and resolvin E1 block platelet-derived growth factor-stimulated migration of human saphenous vein SMCs and decrease phosphorylation of the platelet-derived growth factor receptor-beta. Importantly, receptors for aspirin-triggered lipoxin and resolvin E1 (ALX and ChemR23, respectively) were identified in human VSMCs. Overall, these results demonstrate that stimulatory lipid mediators confer a protective phenotypic switch in VSMCs and elucidate new functions for these mediators in the regulation of SMC biology. These results also suggest that peripheral artery disease is associated with an inflammation-resolution deficit and highlight a potential therapeutic opportunity for the regulation of vascular injury responses. PMID- 20709808 TI - Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells. AB - Age-related macular degeneration (AMD) is characterized by the loss or dysfunction of retinal pigment epithelium (RPE) and is the most common cause of vision loss among the elderly. Stem-cell-based strategies, using human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs), may provide an abundant donor source for generating RPE cells in cell replacement therapies. Despite a significant amount of research on deriving functional RPE cells from various stem cell sources, it is still unclear whether stem-cell-derived RPE cells fully mimic primary RPE cells. In this report, we demonstrate that functional RPE cells can be derived from multiple lines of hESCs and hiPSCs with varying efficiencies. Stem-cell-derived RPE cells exhibit cobblestone-like morphology, transcripts, proteins and phagocytic function similar to human fetal RPE (fRPE) cells. In addition, we performed global gene expression profiling of stem-cell-derived RPE cells, native and cultured fRPE cells, undifferentiated hESCs and fibroblasts to determine the differentiation state of stem-cell-derived RPE cells. Our data indicate that hESC-derived RPE cells closely resemble human fRPE cells, whereas hiPSC-derived RPE cells are in a unique differentiation state. Furthermore, we identified a set of 87 signature genes that are unique to human fRPE and a majority of these signature genes are shared by stem-cell derived RPE cells. These results establish a panel of molecular markers for evaluating the fidelity of human pluripotent stem cell to RPE conversion. This study contributes to our understanding of the utility of hESC/hiPSC-derived RPE in AMD therapy. PMID- 20709809 TI - Melioidosis in an urban-dwelling Taiwanese man with splenic abscesses. AB - We report a case of melioidosis with splenic abscesses caused by Burkholderia pseudomallei in an urban-dwelling, 54-year-old Taiwanese man. The patient presented with prolonged fever and abdominal pain. A splenectomy was performed, followed by successful treatment with ceftazidime and amoxicillin-clavulanate. The patient recovered fully. PMID- 20709810 TI - High prevalence of multidrug-resistant strains of Vibrio cholerae, in a cholera outbreak in Tehran-Iran, during June-September 2008. AB - Following the occurrence of suspected cases of Vibrio cholerae in Karaj in 2008, this study was conducted in order to determine whether or not the cases were infected with cholera and, if so, to describe the prevalence of serotypes, route of transmission and the antimicrobial resistance profile. In this cross-sectional study, 6505 rectal swabs were collected from patients with acute gastroenteritis. Serotypes and biotypes of the isolates were determined by standard procedures. The antimicrobial susceptibility of 45 Inaba and 30 non-agglutinating (NAG) strains was determined. From 6505 specimens, 110 (1.69%) were defined as V. cholerae, including 70 (63.3%) V. cholerae O1 serotype Inaba biotype El Tor and 40 (36.4%) NAG Vibrios. The case fatality rate was 0.9%. Inaba strains were 100% resistant to nalidixic acid and amoxicillin, 95.7% resistant to trimethoprim sulfamethoxazole, 91.3% resistant to furazolidone while the highest frequency of resistance in NAG Vibrios was 77.4% to erythromycin. The lowest resistance rate belonged to ciprofloxacin to which just one NAG strain was resistant. Results suggests an increase in resistance of V. cholerae to several antibiotics. Ciprofloxacin can still be used as first-line treatment of cholera in this region. PMID- 20709811 TI - Pharmacological targeting of constitutively active truncated androgen receptor by nigericin and suppression of hormone-refractory prostate cancer cell growth. AB - In prostate cancer, blockade of androgen receptor (AR) signaling confers a therapeutic benefit. Nevertheless, this standard therapy allows relapse of hormone-refractory prostate cancer (HRPC) with a poor prognosis. HRPC cells often express variant ARs, such as point-mutated alleles and splicing isoforms, resulting in androgen-independent cell growth and resistance to antiandrogen (e.g., flutamide). However, a pharmacological strategy to block such aberrant ARs remains to be established. Here, we established a reporter system that monitors AR-mediated activation of a prostate-specific antigen (PSA) promoter. Our chemical library screening revealed that the antibiotic nigericin inhibits AR mediated activation of the PSA promoter and PSA production in prostate cancer cells. Nigericin suppressed the androgen-dependent LNCaP cell growth even though the cells expressed a flutamide-resistant mutant AR. These effects were caused by AR suppression at the mRNA and post-translational levels. In HRPC 22Rv1 cells, which express the full-length AR and the constitutively active, truncated ARs lacking the carboxyl-terminal ligand-binding domain, small interfering RNA mediated knockdown of both AR isoforms efficiently suppressed the androgen independent cell growth, whereas knockdown of the full-length AR alone had no significant effect. It is noteworthy that nigericin was able to mimic the knockdown of both AR isoforms: it reduced the expression of the full-length and the truncated ARs, and it induced G(1) cell-cycle arrest and apoptosis of 22Rv1 cells. These observations suggest that nigericin-like compounds that suppress AR expression at the mRNA level could be applied as new-type therapeutic agents that inhibit a broad spectrum of AR variants in HRPC. PMID- 20709812 TI - Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion. AB - BACKGROUND: Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. PURPOSE: The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. MATERIAL AND METHODS: An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. RESULTS: The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. CONCLUSION: This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy. PMID- 20709813 TI - Neoadjuvant capecitabine and docetaxel (plus trastuzumab): an effective non anthracycline-based chemotherapy regimen for patients with locally advanced breast cancer. AB - BACKGROUND: To evaluate capecitabine-docetaxel (XT), with trastuzumab (H) in human epidermal growth factor receptor 2 (HER2)-positive disease, in inoperable locally advanced breast cancer (LABC). PATIENTS AND METHODS: Patients received up to six neoadjuvant 21-day cycles of capecitabine 900 mg/m(2) twice daily, days 1 14, plus docetaxel 36 mg/m(2), days 1 and 8. Patients with HER2-positive disease also received trastuzumab 6 mg/kg every 3 weeks. The primary end point was pathologic complete response (pCR) rate, evaluated separately in HER2-negative and HER2-positive cohorts. Secondary end points included clinical response rates and tolerability. RESULTS: The pCR rate was 15% [95% confidence interval (CI) 7 28] in 53 patients receiving XT and 40% (95% CI 26-55) in 50 patients receiving HXT. After neoadjuvant therapy, 50 patients receiving XT and 45 receiving HXT underwent surgery. No unexpected toxicity was observed: the most common grade >=3 adverse events were diarrhea/mucositis (30% and 20%, respectively) and grade 3 hand-foot syndrome (11% and 6%, respectively). Disease-free survival and overall survival were similar with XT and HXT after median follow-up of 22 months in the XT cohort and 21 months in the HXT cohort. CONCLUSION: Neoadjuvant XT (HXT in HER2-positive disease) is highly effective in inoperable LABC, demonstrating pCR rates of 15% and 40%, respectively. This non-anthracycline-containing regimen offers obvious benefits in early disease, where avoidance of long-term cardiotoxicity is particularly important. PMID- 20709814 TI - The type II Arabidopsis formin14 interacts with microtubules and microfilaments to regulate cell division. AB - Formins have long been known to regulate microfilaments but have also recently been shown to associate with microtubules. In this study, Arabidopsis thaliana FORMIN14 (AFH14), a type II formin, was found to regulate both microtubule and microfilament arrays. AFH14 expressed in BY-2 cells was shown to decorate preprophase bands, spindles, and phragmoplasts and to induce coalignment of microtubules with microfilaments. These effects perturbed the process of cell division. Localization of AFH14 to microtubule-based structures was confirmed in Arabidopsis suspension cells. Knockdown of AFH14 in mitotic cells altered interactions between microtubules and microfilaments, resulting in the formation of an abnormal mitotic apparatus. In Arabidopsis afh14 T-DNA insertion mutants, microtubule arrays displayed abnormalities during the meiosis-associated process of microspore formation, which corresponded to altered phenotypes during tetrad formation. In vitro biochemical experiments showed that AFH14 bound directly to either microtubules or microfilaments and that the FH2 domain was essential for cytoskeleton binding and bundling. However, in the presence of both microtubules and microfilaments, AFH14 promoted interactions between microtubules and microfilaments. These results demonstrate that AFH14 is a unique plant formin that functions as a linking protein between microtubules and microfilaments and thus plays important roles in the process of plant cell division. PMID- 20709816 TI - Airway endothelial dysfunction in asthma and chronic obstructive pulmonary disease: a challenge for future research. AB - Endothelial dysfunction in the extrapulmonary circulation has been linked to cardiovascular disease. Recent investigations have revealed that in the airway circulation, cigarette smoking, chronic obstructive pulmonary disease (COPD), and asthma are also accompanied by endothelial dysfunction. Inhaled glucocorticosteroids can partially or fully restore normal endothelium-dependent vasodilation in these conditions, thereby identifying the airway endothelium as a novel therapeutic target in the treatment of airway disease. The role of the defective endothelium-dependent vasodilation in the pathophysiology in asthma and COPD is still subject to speculation. However, there appears to be an association between COPD and extrapulmonary vascular dysfunction, and the possibility exists that the use of inhaled glucocorticosteroids has a beneficial effect on cardiovascular disease in COPD as suggested by database studies showing that inhaled glucocorticosteroids reduce the incidence of nonfatal and fatal cardiovascular events in COPD. PMID- 20709815 TI - Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. AB - RATIONALE: Adipose-derived stem cells express multiple growth factors that inhibit endothelial cell apoptosis, and demonstrate substantial pulmonary trapping after intravascular delivery. OBJECTIVES: We hypothesized that adipose stem cells would ameliorate chronic lung injury associated with endothelial cell apoptosis, such as that occurring in emphysema. METHODS: Therapeutic effects of systemically delivered human or mouse adult adipose stem cells were evaluated in murine models of emphysema induced by chronic exposure to cigarette smoke or by inhibition of vascular endothelial growth factor receptors. MEASUREMENTS AND MAIN RESULTS: Adipose stem cells were detectable in the parenchyma and large airways of lungs up to 21 days after injection. Adipose stem cell treatment was associated with reduced inflammatory infiltration in response to cigarette smoke exposure, and markedly decreased lung cell death and airspace enlargement in both models of emphysema. Remarkably, therapeutic results of adipose stem cells extended beyond lung protection by rescuing the suppressive effects of cigarette smoke on bone marrow hematopoietic progenitor cell function, and by restoring weight loss sustained by mice during cigarette smoke exposure. Pulmonary vascular protective effects of adipose stem cells were recapitulated by application of cell-free conditioned medium, which improved lung endothelial cell repair and recovery in a wound injury repair model and antagonized effects of cigarette smoke in vitro. CONCLUSIONS: These results suggest a useful therapeutic effect of adipose stem cells on both lung and systemic injury induced by cigarette smoke, and implicate a lung vascular protective function of adipose stem cell derived paracrine factors. PMID- 20709818 TI - Acute stress-induced increases in exhaled nitric oxide in asthma and their association with endogenous cortisol. AB - RATIONALE: psychosocial stress is known to influence the pathophysiology of asthma. Although stress has been linked to serum markers of inflammatory activity and exaggerated response to allergen challenge in asthma, few studies have examined inflammatory activity in the airways linked to psychosocial stress alone. Furthermore, although studies have demonstrated lower levels or reactivity of endogenous cortisol in asthma, the association with airway inflammatory activity in stress remains unexplored. OBJECTIVES: we therefore studied airway inflammation and cortisol response to a standardized laboratory task inducing acute psychosocial stress. METHODS: airway inflammation by the fraction of exhaled nitric oxide (FeNO) and saliva cortisol were sampled before and up to 45 minutes after experimental challenge with the Trier Social Stress Test in 20 adult patients with asthma and 19 healthy control subjects. Respiratory inductive plethysmography was used to control for changes in ventilatory activity that impact FeNO levels. MEASUREMENTS AND MAIN RESULTS: FeNO levels were generally higher in patients with asthma than healthy control subjects and salivary cortisol levels were lower. Increases in cortisol levels were observed after the stress protocol in both groups (P < 0.001). FeNO levels at the time of peak cortisol increase after stress were significantly higher than before stress in both groups (P < 0.05). FeNO increases were independent of changes in ventilation. In patients with asthma, higher cortisol levels and stronger increases in cortisol after stress were significantly associated with smaller increases in FeNO (P < 0.05). CONCLUSIONS: acute psychosocial stress alone increases airway inflammatory markers and this increase is attenuated by stronger stress-related activity of the hypothalamic-pituitary-adrenal axis in asthma. PMID- 20709819 TI - Shape of the right ventricular Doppler envelope predicts hemodynamics and right heart function in pulmonary hypertension. AB - RATIONALE: Systolic deceleration or "notching" of the right ventricular outflow tract Doppler flow velocity envelope (FVE(RVOT)) relates to pathologic wave reflection in the setting of elevated pulmonary artery impedance. OBJECTIVES: We investigated whether simple visual assessment of FVE(RVOT) morphology aids in hemodynamic differentiation and detection of pulmonary vascular disease among a referral pulmonary hypertension (PH) cohort. METHODS: We reviewed hemodynamics, echocardiography, and clinical data for 88 patients referred for PH and 32 subjects with systolic heart failure and PH. The FVE(RVOT) was categorized as normal (no notch [NN]); late systolic notch (LSN); or midsystolic notch (MSN). MEASUREMENTS AND MAIN RESULTS: The pulmonary vascular resistance (PVR) was highest in the MSN group (9.2 +/- 3.5 Wood's units [WU]; P < 0.001) versus the LSN (5.7 +/- 3.1 WU) and NN (3.3 +/- 2.4 WU) groups. The ratio of stroke volume to pulse pressure (compliance) also differed by FVE(RVOT) morphology (MSN = 1.2 +/- 0.5; LSN = 1.7 +/- 0.8; NN = 2.6 +/- 1.7; P = 0.001 and 0.04, respectively, vs. NN). MSN was 96% specific and 71% sensitive for a PVR >5 WU (positive predictive value, 98%). The MSN group had severe right ventricular dysfunction (tricuspid annular plane systolic excursion 1.6 +/- 0.5 cm) relative to the LSN and NN groups (tricuspid annular plane systolic excursion 1.9 +/- 0.6 vs. 2.2 +/- 0.6 cm; both P < 0.05). In the PH cohort, any FVE(RVOT) notching (MSN or LSN) was highly associated with PVR >3 WU (odds ratio, 22.3; 95% confidence interval, 5.2 96.4), whereas the NN pattern predicted a PVR less than or equal to 3WU and pulmonary artery wedge pressure greater than 15 mm Hg (odds ratio, 30.2; 95% confidence interval, 6.3-144.9). CONCLUSIONS: Visual inspection of the shape of the FVE(RVOT) provides insight into the hemodynamic basis of PH in a referral PH cohort. MSN is associated with the most severe pulmonary vascular disease and right heart dysfunction. PMID- 20709817 TI - Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. AB - RATIONALE: There is epidemiological evidence that the use of acetaminophen may increase the risk of developing asthma. OBJECTIVES: To investigate the risk of asthma and other allergic disorders associated with the current use of acetaminophen in 13- to 14-year-old children in different populations worldwide. METHODS: As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, 13- to 14-year-old children completed written and video questionnaires obtaining data on current symptoms of asthma, rhinoconjunctivitis, and eczema, and a written environmental questionnaire obtaining data on putative risk factors, including acetaminophen use in the past 12 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was the odds ratio (OR) of current asthma symptoms associated with acetaminophen use calculated by logistic regression. A total of 322,959 adolescent children from 113 centers in 50 countries participated. In the multivariate analyses the recent use of acetaminophen was associated with an exposure-dependent increased risk of current asthma symptoms (OR, 1.43 [95% confidence interval, 1.33-1.53] and 2.51 [95% confidence interval, 2.33-2.70] for medium and high versus no use, respectively). Acetaminophen use was also associated with an exposure-dependent increased risk of current symptoms of rhinoconjunctivitis and eczema. CONCLUSIONS: Acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis, and eczema in adolescent children. PMID- 20709821 TI - Statin reverses smoke-induced pulmonary hypertension and prevents emphysema but not airway remodeling. AB - RATIONALE: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. OBJECTIVES: to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. METHODS: we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. MEASUREMENTS AND MAIN RESULTS: cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. CONCLUSIONS: simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD. PMID- 20709820 TI - Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema. AB - RATIONALE: chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors. OBJECTIVES: to identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD. METHODS: we performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than -950 Hounsfield units) in all three cohorts. MEASUREMENTS AND MAIN RESULTS: we identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 * 10(-7) with at least mild emphysema vs. control subjects; P = 4.8 * 10(-8) with moderate and more severe emphysema vs. control subjects). CONCLUSIONS: our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT00292552). PMID- 20709822 TI - An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor beta receptor. AB - RATIONALE: Fibrotic response to lung injury depends on development of a fibrogenic population of myofibroblasts. The importance of resident interstitial fibroblasts and role of transforming growth factor beta (TGFbeta) in this process is unclear. OBJECTIVES: To define the importance of TGFbeta signaling in resident lung fibroblasts in the development of experimental pulmonary fibrosis. METHODS: A compound genetic strategy in which mice homozygous for a floxed high-affinity type II TGFbeta receptor (TbetaRII) allele were crossed with a transgenic strain harboring a fibroblast-specific transgene encoding ligand-dependent Cre recombinase was used. TbetaRII was deleted by postnatal administration of tamoxifen over 5 days to compound mutant mice with appropriate littermate controls. Illumina microarray gene profiling and quantitative reverse transcriptase-polymerase chain reaction were used to confirm anergy to TGFbeta in explanted lung fibroblasts. Bleomycin lung injury was used to induce lung fibrosis, which was analyzed by histology and biochemical methods. Immunofluorescence was used to define cell populations after lung injury. MEASUREMENTS AND MAIN RESULTS: There was significant attenuation of fibrosis in mice after deletion of TbetaRII in resident fibroblasts. At 7 days after injury the number of fibrocytes and myofibroblasts was substantially reduced. Potential regulators of fibrosis were suggested by gene expression profiles that identified key candidate profibrotic genes, including connective tissue growth factor and endothelin-1 expressed by wild-type but not mutant lung fibroblasts. CONCLUSIONS: Intact TGFbeta signaling in resident pulmonary fibroblasts is essential for pulmonary fibrosis to develop. Our data support a key regulatory role of these cells in determining fibrocyte recruitment and myofibroblast differentiation. PMID- 20709823 TI - Mucoid and nonmucoid Burkholderia cepacia complex bacteria in cystic fibrosis infections. AB - RATIONALE: infection with Burkholderia cepacia complex (BCC) bacteria in cystic fibrosis (CF) is associated with an unpredictable rate of pulmonary decline. Some BCC, but not others, elaborate copious mucoid exopolysaccharide, endowing them with a gross mucoid phenotype, the clinical significance of which has not been described. OBJECTIVES: to determine whether there was a correlation between bacterial mucoid phenotype, as assessed in a semiquantitative manner from plate culture, and severity of disease as assessed by the rate of decline in lung function. METHODS: we performed a retrospective clinical review of 100 patients with CF attending the Vancouver clinics between 1981 and 2007 and analyzed the rate of lung function decline (% predicted FEV(1)). MEASUREMENTS AND MAIN RESULTS: patients infected exclusively with nonmucoid BCC had a more rapid decline in lung function (annual FEV(1) change, -8.51 +/- 2.41%) than those infected with mucoid bacteria (-3.01 +/- 1.09%; P < 0.05). Linear mixed-effects data modeling revealed a statistically significant inverse association between semiquantitative mucoid exopolysaccharide production and rate of decline of lung function. In vitro incubation of BCC with ceftazidime and ciprofloxacin but not meropenem caused conversion of BCC from mucoid to nonmucoid. CONCLUSIONS: our data suggest an inverse correlation between the quantity of mucoid exopolysaccharide production by BCC bacteria and rate of decline in CF lung function. Certain antibiotics may induce a change in bacterial morphology that enhances their virulence. A simple in vitro test of bacterial mucoidy may be useful in predicting the rate of decline of respiratory function in CF. PMID- 20709824 TI - The T-helper cell type 1 immune response to gram-negative bacterial infections is impaired in COPD. AB - RATIONALE: The increased susceptibility to bacterial infections in chronic obstructive pulmonary disease (COPD) is critical for exacerbations. Toll-like receptor-4 (TLR4) detects bacteria via LPS and induces IFN-gamma-based immune responses. The direct responsiveness of Th1 lymphocytes to LPS is disputed because they lack surface expression of the TLR4 coreceptor CD14. OBJECTIVES: We hypothesized that the Th1-mediated adaptive immune response to bacterial infections is impaired in COPD. METHODS: LPS-induced TLR4 expression and IFN gamma release in and from ex vivo-generated Th1 cells was compared among nonsmokers (n = 14), smokers without COPD (n = 13), and smokers with COPD (n = 25) via quantitative reverse transcription polymerase chain reaction, Western blot, and ELISA. TLR4 transfection experiments were performed to functionally link receptor to IFN-gamma dysregulation in COPD. MEASUREMENTS AND MAIN RESULTS: Short-chain LPS from Salmonella species and nontypeable Haemophilus influenzae and nontypeable Haemophilus influenzae whole-cell extract all induced TLR4 expression via TLR4/MyD88/IRAK/mitogen-activated protein-kinase signaling and IFN gamma release via TLR4/TRIF/IKKepsilon/TBK1 signaling in Th1 cells of nonsmokers. These effects were all impaired in smokers with and without COPD. The LPS responses were partially dependent on soluble CD14 and correlated positively to lung-function parameters but negatively to cigarette smoking (pack-years). Endogenous MyD88/IRAK signaling antagonists were up-regulated in Th1 cells of smokers and COPD, and TLR4 overexpression in Th1 cells of COPD restored LPS dependent IFN-gamma release. CONCLUSIONS: Th1 cells directly respond to short chain LPS. Cigarette smoking suppresses Th1-mediated immune responses to gram negative bacterial infections by interfering with MyD88/IRAK signaling thereby reducing LPS-induced TLR4 expression. This can explain the increased susceptibility to bacterial infections in COPD. Targeting TLR signaling might be useful to reduce exacerbation rates. PMID- 20709825 TI - Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells. AB - RATIONALE: bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available. OBJECTIVES: to test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs). METHODS: the protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM treated DCs were assessed by administering before ovalbumin exposure. MEASUREMENTS AND MAIN RESULTS: treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM(+)) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM(+) DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs. CONCLUSIONS: the results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients. PMID- 20709826 TI - A novel phycobiliprotein alleviates allergic airway inflammation by modulating immune responses. AB - RATIONALE: it has been claimed that phycocyanin exhibits pharmaceutical functions in inhibiting histamine release and leukotriene biosynthesis. In allergic asthma, these inflammatory mediators are crucial for disease progression. OBJECTIVES: the aim of this study was to evaluate the therapeutic potential of R-phycocyanin (R PC) against allergic airway inflammation. METHODS: mouse bone marrow-derived dendritic cells (BMDCs) were used to evaluate the immunomodulatory functions of R PC. In addition, an airway inflammatory model was used to evaluate the therapeutic potential of R-PC. MEASUREMENTS AND MAIN RESULTS: R-PC treatment resulted in a decrease of endocytosis, increase of costimulatory molecule expression, and enhancement of interleukin-12 production in mouse BMDCs. Moreover, R-PC-treated cultured dendritic cells were able to promote CD4(+) T cell stimulatory capacity and increase interferon-gamma expression in CD4(+) T cells. Intraperitoneal administration of R-PC suppressed ovalbumin (OVA)-induced airway hyperresponsiveness, serum levels of OVA-specific IgE and IgG1, eosinophil infiltration, Th2 cytokine levels, and eotaxin in bronchoalveolar lavage fluid of mice. Antibody against Toll-like receptor-4 was able to inhibit R-PC-induced IL 12 p70 production. Moreover, inhibition of nuclear factor-kappaB (NF-kappaB) by helenalin and inhibition of the JNK pathway by JNK inhibitor II inhibited R-PC induced IL-12 p70 production. Western blotting and electrophoretic mobility shift assays showed that R-PC augmented phosphorylation of the inhibitors of NF-kappaB and inhibitors of NF-kappaB kinase and facilitated NF-kappaB activity. CONCLUSIONS: our data demonstrated that R-PC promoted activation and maturation of cultured dendritic cells and skewed the immunological function toward Th1 activity. Therefore, R-PC may have potential in regulating immune responses and application in reducing allergic asthma. PMID- 20709827 TI - Three-dimensional reconstruction of living mouse liver tissues using cryotechniques with confocal laser scanning microscopy. AB - Soluble proteins and glycogen particles are well preserved in paraffin-embedded sections prepared by in vivo cryotechnique (IVCT) and cryobiopsy followed by freeze substitution fixation. We performed confocal laser scanning microscopic analyses on the distributions of glycogen with periodic acid-Schiff (PAS) staining and serum proteins with immunostaining for mouse liver tissues. Livers of fully fed mice showed a strong fluorescence signal of PAS staining in all hepatocytes and immunofluorescence of immunoglobulin kappa light chain (Igkappa) in blood vessels and bile canaliculi. However, some hepatocytes in mechanically damaged livers were PAS-negative and Igkappa-immunopositive, showing extraction of glycogen particles and infiltration of serum proteins in hepatocytes. By three dimensional (3D) reconstruction of serial optical sections, interconnecting hepatic sinusoids and bile canaliculi were detected with Igkappa immunostaining between trabecular hepatocytes that were PAS stained. In PAS-stained samples under fasting conditions, interstitial structures along sinusoids were clarified in vivo by 3D reconstruction because of the lower PAS staining intensity of hepatocytes. In addition, 100-MUm-thick eosin-stained slices provided 3D structural images more than 30 MUm in thickness away from tissue surfaces, showing blood vessels with flowing erythrocytes and networks of bile ducts and canaliculi. IVCT and cryobiopsy with histochemical analyses enabled us to visualize native hepatocytic glycogen and 3D structures, such as vascular networks, reflecting their living states by confocal laser scanning microscopy. PMID- 20709828 TI - Toward in vivo chemical imaging of epicuticular waxes. AB - Epicuticular waxes, which are found on the outer surface of plant cuticles, are difficult to study in vivo. To monitor the growth, development, and structural alterations of epicuticular wax layers, coherent anti-Stokes Raman scattering (CARS) might be used. CARS, as a Raman-based technique, not only provides structural insight but also chemical information by imaging the spatial distribution of Raman-active vibrations. Here, we present a comparative study using CARS and scanning electron microscopy to characterize the structure of epicuticular waxes. The ability of CARS to provide detailed structural information on the biologically important wax layer was detailed on the examples of cherry laurel (Prunus laurocerasus), hoya (Hoya carnosa), and ceriman/Swiss cheese plant (Monstera sp. aff. deliciosa). We anticipate that the work presented will open a doorway for online monitoring of formation and alterations of epicuticular wax layers. PMID- 20709829 TI - Rapid assessment of gene function in the circadian clock using artificial microRNA in Arabidopsis mesophyll protoplasts. AB - Rapid assessment of the effect of reduced levels of gene products is often a bottleneck in determining how to proceed with an interesting gene candidate. Additionally, gene families with closely related members can confound determination of the role of even a single one of the group. We describe here an in vivo method to rapidly determine gene function using transient expression of artificial microRNAs (amiRNAs) in Arabidopsis (Arabidopsis thaliana) mesophyll protoplasts. We use a luciferase-based reporter of circadian clock activity to optimize and validate this system. Protoplasts transiently cotransfected with promoter-luciferase and gene-specific amiRNA plasmids sustain free-running rhythms of bioluminescence for more than 6 d. Using both amiRNA plasmids available through the Arabidopsis Biological Resource Center, as well as custom design of constructs using the Weigel amiRNA design algorithm, we show that transient knockdown of known clock genes recapitulates the same circadian phenotypes reported in the literature for loss-of-function mutant plants. We additionally show that amiRNA designed to knock down expression of the casein kinase II beta-subunit gene family lengthens period, consistent with previous reports of a short period in casein kinase II beta-subunit overexpressors. Our results demonstrate that this system can facilitate a much more rapid analysis of gene function by obviating the need to initially establish stably transformed transgenics to assess the phenotype of gene knockdowns. This approach will be useful in a wide range of plant disciplines when an endogenous cell-based phenotype is observable or can be devised, as done here using a luciferase reporter. PMID- 20709830 TI - Abscisic acid deficiency causes changes in cuticle permeability and pectin composition that influence tomato resistance to Botrytis cinerea. AB - A mutant of tomato (Solanum lycopersicum) with reduced abscisic acid (ABA) production (sitiens) exhibits increased resistance to the necrotrophic fungus Botrytis cinerea. This resistance is correlated with a rapid and strong hydrogen peroxide-driven cell wall fortification response in epidermis cells that is absent in tomato with normal ABA production. Moreover, basal expression of defense genes is higher in the mutant compared with the wild-type tomato. Given the importance of this fast response in sitiens resistance, we investigated cell wall and cuticle properties of the mutant at the chemical, histological, and ultrastructural levels. We demonstrate that ABA deficiency in the mutant leads to increased cuticle permeability, which is positively correlated with disease resistance. Furthermore, perturbation of ABA levels affects pectin composition. sitiens plants have a relatively higher degree of pectin methylesterification and release different oligosaccharides upon inoculation with B. cinerea. These results show that endogenous plant ABA levels affect the composition of the tomato cuticle and cell wall and demonstrate the importance of cuticle and cell wall chemistry in shaping the outcome of this plant-fungus interaction. PMID- 20709831 TI - Increased activity of the vacuolar monosaccharide transporter TMT1 alters cellular sugar partitioning, sugar signaling, and seed yield in Arabidopsis. AB - The extent to which vacuolar sugar transport activity affects molecular, cellular, and developmental processes in Arabidopsis (Arabidopsis thaliana) is unknown. Electrophysiological analysis revealed that overexpression of the tonoplast monosaccharide transporter TMT1 in a tmt1-2::tDNA mutant led to increased proton-coupled monosaccharide import into isolated mesophyll vacuoles in comparison with wild-type vacuoles. TMT1 overexpressor mutants grew faster than wild-type plants on soil and in high-glucose (Glc)-containing liquid medium. These effects were correlated with increased vacuolar monosaccharide compartmentation, as revealed by nonaqueous fractionation and by chlorophyll(ab) binding protein1 and nitrate reductase1 gene expression studies. Soil-grown TMT1 overexpressor plants respired less Glc than wild-type plants and only about half the amount of Glc respired by tmt1-2::tDNA mutants. In sum, these data show that TMT activity in wild-type plants limits vacuolar monosaccharide loading. Remarkably, TMT1 overexpressor mutants produced larger seeds and greater total seed yield, which was associated with increased lipid and protein content. These changes in seed properties were correlated with slightly decreased nocturnal CO(2) release and increased sugar export rates from detached source leaves. The SUC2 gene, which codes for a sucrose transporter that may be critical for phloem loading in leaves, has been identified as Glc repressed. Thus, the observation that SUC2 mRNA increased slightly in TMT1 overexpressor leaves, characterized by lowered cytosolic Glc levels than wild-type leaves, provided further evidence of a stimulated source capacity. In summary, increased TMT activity in Arabidopsis induced modified subcellular sugar compartmentation, altered cellular sugar sensing, affected assimilate allocation, increased the biomass of Arabidopsis seeds, and accelerated early plant development. PMID- 20709832 TI - Hydrogen cycling by the unicellular marine diazotroph Crocosphaera watsonii strain WH8501. AB - The hydrogen (H2) cycle associated with the dinitrogen (N2) fixation process was studied in laboratory cultures of the marine cyanobacterium Crocosphaera watsonii. The rates of H2 production and acetylene (C2H2) reduction were continuously measured over the diel cycle with simultaneous measurements of fast repetition rate fluorometry and dissolved oxygen. The maximum rate of H2 production was coincident with the maximum rates of C2H2 reduction. Theoretical stoichiometry for N2 fixation predicts an equimolar ratio of H2 produced to N2 fixed. However, the maximum rate of net H2 production observed was 0.09 nmol H2 MUg chlorophyll a (chl a)-1 h-1) compared to the N2 fixation rate of 5.5 nmol N2 MUg chl a-1 h-1, with an H2 production/N2 fixation ratio of 0.02. The 50-fold discrepancy between expected and observed rates of H2 production was hypothesized to be a result of H2 reassimilation by uptake hydrogenase. This was confirmed by the addition of carbon monoxide (CO), a potent inhibitor of hydrogenase, which increased net H2 production rates ~40-fold to a maximum rate of 3.5 nmol H2 MUg chl a-1 h-1. We conclude that the reassimilation of H2 by C. watsonii is highly efficient (> 98%) and hypothesize that the tight coupling between H2 production and consumption is a consequence of fixing N2 at nighttime using a finite pool of respiratory carbon and electrons acquired from daytime solar energy capture. The H2 cycle provides unique insight into N2 fixation and associated metabolic processes in C. watsonii. PMID- 20709833 TI - High stability and fast recovery of expression of the TOL plasmid-carried toluene catabolism genes of Pseudomonas putida mt-2 under conditions of oxygen limitation and oscillation. AB - Pseudomonas putida mt-2 harbors the TOL plasmid (pWWO), which contains the genes encoding the enzymes necessary to degrade toluene aerobically. The xyl genes are clustered in the upper operon and encode the enzymes of the upper pathway that degrade toluene to benzoate, while the genes encoding the enzymes of the lower pathway (meta-cleavage pathway) that are necessary for the conversion of benzoate to tricarboxylic acid cycle intermediates, are encoded in a separate operon. In this study, the effects of oxygen availability and oscillation on the expression of catabolic genes for enzymes involved in toluene degradation were studied by using P. putida mt-2 as model bacterium. Quantitative reverse transcription-PCR was used to detect and quantify the expression of the catabolic genes xylM (a key gene of the upper pathway) and xylE (a key gene of the lower pathway) in cultures of P. putida mt-2 that were grown with toluene as a carbon source. Toluene degradation was shown to have a direct dependency on oxygen concentration, where gene expression of xylM and xylE decreased due to oxygen depletion during degradation. Under oscillating oxygen concentrations, P. putida mt-2 induced or downregulated xylM and xylE genes according to the O2 availability in the media. During anoxic periods, P. putida mt-2 decreased the expression of xylM and xylE genes, while the expression of both xylM and xylE genes was immediately increased after oxygen became available again in the medium. These results suggest that oxygen is not only necessary as a cosubstrate for enzyme activity during the degradation of toluene but also that oxygen modulates the expression of the catabolic genes encoded by the TOL plasmid. PMID- 20709835 TI - Phylogenetic groups and pathogenicity island markers in fecal Escherichia coli isolates from asymptomatic humans in China. AB - The study of phylogenetic groups and pathogenicity island (PAI) markers in commensal Escherichia coli strains from asymptomatic Chinese people showed that group A strains are the most common and that nearly half of all fecal strains which were randomly selected harbor PAIs. PMID- 20709834 TI - Mycobacterium avium infections of Acanthamoeba strains: host strain variability, grazing-acquired infections, and altered dynamics of inactivation with monochloramine. AB - Stable Mycobacterium avium infections of several Acanthamoeba strains were characterized by increased infection resistance of recent environmental isolates and reduced infectivity in the presence of other bacteria. Exposure of M. avium in coculture with Acanthamoeba castellanii to monochloramine yielded inactivation kinetics markedly similar to those observed for A. castellanii alone. PMID- 20709836 TI - Site-directed mutagenesis of the Anabaena sp. strain PCC 7120 nitrogenase active site to increase photobiological hydrogen production. AB - Cyanobacteria use sunlight and water to produce hydrogen gas (H2), which is potentially useful as a clean and renewable biofuel. Photobiological H2 arises primarily as an inevitable by-product of N2 fixation by nitrogenase, an oxygen labile enzyme typically containing an iron-molybdenum cofactor (FeMo-co) active site. In Anabaena sp. strain 7120, the enzyme is localized to the microaerobic environment of heterocysts, a highly differentiated subset of the filamentous cells. In an effort to increase H2 production by this strain, six nitrogenase amino acid residues predicted to reside within 5 A of the FeMo-co were mutated in an attempt to direct electron flow selectively toward proton reduction in the presence of N2. Most of the 49 variants examined were deficient in N2-fixing growth and exhibited decreases in their in vivo rates of acetylene reduction. Of greater interest, several variants examined under an N2 atmosphere significantly increased their in vivo rates of H2 production, approximating rates equivalent to those under an Ar atmosphere, and accumulated high levels of H2 compared to the reference strains. These results demonstrate the feasibility of engineering cyanobacterial strains for enhanced photobiological production of H2 in an aerobic, nitrogen-containing environment. PMID- 20709837 TI - Bovine norovirus: carbohydrate ligand, environmental contamination, and potential cross-species transmission via oysters. AB - Noroviruses (NoV) are major agents of acute gastroenteritis in humans and the primary pathogens of shellfish-related outbreaks. Previous studies showed that some human strains bind to oyster tissues through carbohydrate ligands that are similar to their human receptors. Thus, based on presentation of shared norovirus carbohydrate ligands, oysters could selectively concentrate animal strains with increased ability to overcome species barriers. In comparison with human GI and GII strains, bovine GIII NoV strains, although frequently detected in bovine feces and waters of two estuaries of Brittany, were seldom detected in oysters grown in these estuaries. Characterization of the carbohydrate ligand from a new GIII strain indicated recognition of the alpha-galactosidase (alpha-Gal) epitope not expressed by humans, similar to the GIII.2 Newbury2 strain. This ligand was not detectable on oyster tissues, suggesting that oysters may not be able to accumulate substantial amounts of GIII strains due to the lack of shared carbohydrate ligand and that they should be unable to contribute to select GIII strains with an increased ability to recognize humans. PMID- 20709838 TI - Variation in pH optima of hydrolytic enzyme activities in tropical rain forest soils. AB - Extracellular enzymes synthesized by soil microbes play a central role in the biogeochemical cycling of nutrients in the environment. The pH optima of eight hydrolytic enzymes involved in the cycles of carbon, nitrogen, phosphorus, and sulfur, were assessed in a series of tropical forest soils of contrasting pH values from the Republic of Panama. Assays were conducted using 4 methylumbelliferone-linked fluorogenic substrates in modified universal buffer. Optimum pH values differed markedly among enzymes and soils. Enzymes were grouped into three classes based on their pH optima: (i) enzymes with acidic pH optima that were consistent among soils (cellobiohydrolase, beta-xylanase, and arylsulfatase), (ii) enzymes with acidic pH optima that varied systematically with soil pH, with the most acidic pH optima in the most acidic soils (alpha glucosidase, beta-glucosidase, and N-acetyl-beta-glucosaminidase), and (iii) enzymes with an optimum pH in either the acid range or the alkaline range depending on soil pH (phosphomonoesterase and phosphodiesterase). The optimum pH values of phosphomonoesterase were consistent among soils, being 4 to 5 for acid phosphomonoesterase and 10 to 11 for alkaline phosphomonoesterase. In contrast, the optimum pH for phosphodiesterase activity varied systematically with soil pH, with the most acidic pH optima (3.0) in the most acidic soils and the most alkaline pH optima (pH 10) in near-neutral soils. Arylsulfatase activity had a very acidic optimum pH in all soils (pH <=3.0) irrespective of soil pH. The differences in pH optima may be linked to the origins of the enzymes and/or the degree of stabilization on solid surfaces. The results have important implications for the interpretation of hydrolytic enzyme assays using fluorogenic substrates. PMID- 20709839 TI - A targeted multilocus genotyping assay for lineage, serogroup, and epidemic clone typing of Listeria monocytogenes. AB - A 30-probe assay was developed for simultaneous classification of Listeria monocytogenes isolates by lineage (I to IV), major serogroup (4b, 1/2b, 1/2a, and 1/2c), and epidemic clone (EC) type (ECI, ECIa, ECII, and ECIII). The assay was designed to facilitate rapid strain characterization and the integration of subtype data into risk-based inspection programs. PMID- 20709840 TI - Comparison of single- and multilocus genetic diversity in the protozoan parasites Cryptosporidium parvum and C. hominis. AB - The genotyping of numerous isolates of Cryptosporidium parasites has led to the definition of new species and a better understanding of the epidemiology of cryptosporidiosis. A single-locus genotyping method based on the partial sequence of a polymorphic sporozoite surface glycoprotein gene (GP60) has been favored by many for surveying Cryptosporidium parvum and C. hominis populations. Since genetically distinct Cryptosporidium parasites recombine in nature, it is unclear whether single-locus classifications can adequately represent intraspecies diversity. To address this question, we investigated whether multilocus genotypes of C. parvum and C. hominis cluster according to the GP60 genotype. C. hominis multilocus genotypes did not segregate according to this marker, indicating that for this species the GP60 sequence is not a valid surrogate for multilocus typing methods. In contrast, in C. parvum the previously described "anthroponotic" genotype was confirmed as a genetically distinct subspecies cluster characterized by a diagnostic GP60 allele. However, as in C. hominis, several C. parvum GP60 alleles did not correlate with distinct subpopulations. Given the rarity of some C. parvum GP60 alleles in our sample, the existence of additional C. parvum subgroups with unique GP60 alleles cannot be ruled out. We conclude that with the exception of genotypically distinct C. parvum subgroups, multilocus genotyping methods are needed to characterize C. parvum and C. hominis populations. Unless parasite virulence is controlled at the GP60 locus, attempts to find associations within species or subspecies between GP60 and phenotype are unlikely to be successful. PMID- 20709842 TI - Denitrification response patterns during the transition to anoxic respiration and posttranscriptional effects of suboptimal pH on nitrous [corrected] oxide reductase in Paracoccus denitrificans. AB - Denitrification in soil is a major source of atmospheric N(2)O. Soil pH appears to exert a strong control on the N(2)O/N(2) product ratio (high ratios at low pH), but the reasons for this are not well understood. To explore the possible mechanisms involved, we conducted an in-depth investigation of the regulation of denitrification in the model organism Paracoccus denitrificans during transition to anoxia both at pH 7 and when challenged with pHs ranging from 6 to 7.5. The kinetics of gas transformations (O(2), NO, N(2)O, and N(2)) were monitored using a robotic incubation system. Combined with quantification of gene transcription, this yields high-resolution data for direct response patterns to single factors. P. denitrificans demonstrated robustly balanced transitions from O(2) to nitric oxide-based respiration, with NO concentrations in the low nanomolar range and marginal N(2)O production at an optimal pH of 7. Transcription of nosZ (encoding N(2)O reductase) preceded that of nirS and norB (encoding nitrite and NO reductase, respectively) by 5 to 7 h, which was confirmed by observed reduction of externally supplied N(2)O. Reduction of N(2)O was severely inhibited by suboptimal pH. The relative transcription rates of nosZ versus nirS and norB were unaffected by pH, and low pH had a moderate effect on the N(2)O reductase activity in cells with a denitrification proteome assembled at pH 7. We thus concluded that the inhibition occurred during protein synthesis/assembly rather than transcription. The study shed new light on the regulation of the environmentally essential N(2)O reductase and the important role of pH in N(2)O emission. PMID- 20709841 TI - Deletion of genes encoding cytochrome oxidases and quinol monooxygenase blocks the aerobic-anaerobic shift in Escherichia coli K-12 MG1655. AB - The constitutive activation of the anoxic redox control transcriptional regulator (ArcA) in Escherichia coli during aerobic growth, with the consequent production of a strain that exhibits anaerobic physiology even in the presence of air, is reported in this work. Removal of three terminal cytochrome oxidase genes (cydAB, cyoABCD, and cbdAB) and a quinol monooxygenase gene (ygiN) from the E. coli K-12 MG1655 genome resulted in the activation of ArcA aerobically. These mutations resulted in reduction of the oxygen uptake rate by nearly 98% and production of d lactate as a sole by-product under oxic and anoxic conditions. The knockout strain exhibited nearly identical physiological behaviors under both conditions, suggesting that the mutations resulted in significant metabolic and regulatory perturbations. In order to fully understand the physiology of this mutant and to identify underlying metabolic and regulatory reasons that prevent the transition from an aerobic to an anaerobic phenotype, we utilized whole-genome transcriptome analysis, (13)C tracing experiments, and physiological characterization. Our analysis showed that the deletions resulted in the activation of anaerobic respiration under oxic conditions and a consequential shift in the content of the quinone pool from ubiquinones to menaquinones. An increase in menaquinone concentration resulted in the activation of ArcA. The activation of the ArcB/ArcA regulatory system led to a major shift in the metabolic flux distribution through the central metabolism of the mutant strain. Flux analysis indicated that the mutant strain had undetectable fluxes around the tricarboxylic acid (TCA) cycle and elevated flux through glycolysis and anaplerotic input to oxaloacetate. Flux and transcriptomics data were highly correlated and showed similar patterns. PMID- 20709843 TI - Bar-coded pyrosequencing of 16S rRNA gene amplicons reveals changes in ileal porcine bacterial communities due to high dietary zinc intake. AB - Feeding high levels of zinc oxide to piglets significantly increased the relative abundance of ileal Weissella spp., Leuconostoc spp., and Streptococcus spp., reduced the occurrence of Sarcina spp. and Neisseria spp., and led to numerical increases of all Gram-negative facultative anaerobic genera. High dietary zinc oxide intake has a major impact on the porcine ileal bacterial composition. PMID- 20709845 TI - Improving biocatalyst performance by integrating statistical methods into protein engineering. AB - Directed evolution and rational design were used to generate active variants of toluene-4-monooxygenase (T4MO) on 2-phenylethanol (PEA), with the aim of producing hydroxytyrosol, a potent antioxidant. Due to the complexity of the enzymatic system-four proteins encoded by six genes-mutagenesis is labor intensive and time-consuming. Therefore, the statistical model of Nov and Wein (J. Comput. Biol. 12:247-282) was used to reduce the number of variants produced and evaluated in a lab. From an initial data set of 24 variants, with mutations at nine positions, seven double or triple mutants were identified through statistical analysis. The average activity of these mutants was 4.6-fold higher than the average activity of the initial data set. In an attempt to further improve the enzyme activity to obtain PEA hydroxylation, a second round of statistical analysis was performed. Nine variants were considered, with 3, 4, and 5 point mutations. The average activity of the variants obtained in the second statistical round was 1.6-fold higher than in the first round and 7.3-fold higher than that of the initial data set. The best variant discovered, TmoA I100A E214G D285Q, exhibited an initial oxidation rate of 4.4 +/- 0.3 nmol/min/mg protein, which is 190-fold higher than the rate obtained by the wild type. This rate was also 2.6-fold higher than the activity of the wild type on the natural substrate toluene. By considering only 16 preselected mutants (out of ~13,000 possible combinations), a highly active variant was discovered with minimum time and effort. PMID- 20709844 TI - Novel glycoside hydrolases identified by screening a Chinese Holstein dairy cow rumen-derived metagenome library. AB - One clone encoding glycoside hydrolases was identified through functional screening of a rumen bacterial artificial chromosome (BAC) library. Of the 68 open reading frames (ORFs) predicted, one ORF encodes a novel endo-beta-1,4 xylanase with two catalytic domains of family GH43 and two cellulose-binding modules (CBMs) of family IV. Partial characterization showed that this endo xylanase has a greater specific activity than a number of other xylanases over a wide temperature range at neutral pH and could be useful in some industrial applications. PMID- 20709846 TI - Genotype and antibiotic resistance analyses of Campylobacter isolates from ceca and carcasses of slaughtered broiler flocks. AB - To obtain genetic information about Campylobacter jejuni and Campylobacter coli from broilers and carcasses at slaughterhouses, we analyzed and compared 340 isolates that were collected in 2008 from the cecum right after slaughter or from the neck skin after processing. We performed rpoB sequence-based identification, multilocus sequence typing (MLST), and flaB sequence-based typing; we additionally analyzed mutations within the 23S rRNA and gyrA genes that confer resistance to macrolide and quinolone antibiotics, respectively. The rpoB-based identification resulted in a distribution of 72.0% C. jejuni and 28.0% C. coli. The MLST analysis revealed that there were 59 known sequence types (STs) and 6 newly defined STs. Most of the STs were grouped into 4 clonal complexes (CC) that are typical for poultry (CC21, CC45, CC257, and CC828), and these represented 61.8% of all of the investigated isolates. The analysis of 95 isolates from the cecum and from the corresponding carcass neck skin covered 44 different STs, and 54.7% of the pairs had matching genotypes. The data indicate that cross contamination from various sources during slaughter may occur, although the majority of Campylobacter contamination on carcasses appeared to originate from the slaughtered flock itself. Mutations in the 23S rRNA gene were found in 3.1% of C. coli isolates, although no mutations were found in C. jejuni isolates. Mutations in the gyrA gene were observed in 18.9% of C. jejuni and 26.8% of C. coli isolates, which included two C. coli strains that carried mutations conferring resistance to both classes of antibiotics. A relationship between specific genotypes and antibiotic resistance/susceptibility was observed. PMID- 20709847 TI - Transcriptomic analysis of Escherichia coli O157:H7 and K-12 cultures exposed to inorganic and organic acids in stationary phase reveals acidulant- and strain specific acid tolerance responses. AB - The food-borne pathogen Escherichia coli O157:H7 is commonly exposed to organic acid in processed and preserved foods, allowing adaptation and the development of tolerance to pH levels otherwise lethal. Since little is known about the molecular basis of adaptation of E. coli to organic acids, we studied K-12 MG1655 and O157:H7 Sakai during exposure to acetic, lactic, and hydrochloric acid at pH 5.5. This is the first analysis of the pH-dependent transcriptomic response of stationary-phase E. coli. Thirty-four genes and three intergenic regions were upregulated by both strains during exposure to all acids. This universal acid response included genes involved in oxidative, envelope, and cold stress resistance and iron and manganese uptake, as well as 10 genes of unknown function. Acidulant- and strain-specific responses were also revealed. The acidulant-specific response reflects differences in the modes of microbial inactivation, even between weak organic acids. The two strains exhibited similar responses to lactic and hydrochloric acid, while the response to acetic acid was distinct. Acidulant-dependent differences between the strains involved induction of genes involved in the heat shock response, osmoregulation, inorganic ion and nucleotide transport and metabolism, translation, and energy production. E. coli O157:H7-specific acid-inducible genes were identified, suggesting that the enterohemorrhagic E. coli strain possesses additional molecular mechanisms contributing to acid resistance that are absent in K-12. While E. coli K-12 was most resistant to lactic and hydrochloric acid, O157:H7 may have a greater ability to survive in more complex acidic environments, such as those encountered in the host and during food processing. PMID- 20709848 TI - Differential involvement of the five RNA helicases in adaptation of Bacillus cereus ATCC 14579 to low growth temperatures. AB - Bacillus cereus ATCC 14579 possesses five RNA helicase-encoding genes overexpressed under cold growth conditions. Out of the five corresponding mutants, only the DeltacshA, DeltacshB, and DeltacshC strains were cold sensitive. Growth of the DeltacshA strain was also reduced at 30 degrees C but not at 37 degrees C. The cold phenotype was restored with the cshA gene for the DeltacshA strain and partially for the DeltacshB strain but not for the DeltacshC strain, suggesting different functions at low temperature. PMID- 20709849 TI - Correlation of particular bacterial PCR-denaturing gradient gel electrophoresis patterns with bovine ruminal fermentation parameters and feed efficiency traits. AB - The influence of rumen microbial structure and functions on host physiology remains poorly understood. This study aimed to investigate the interaction between the ruminal microflora and the host by correlating bacterial diversity with fermentation measurements and feed efficiency traits, including dry matter intake, feed conversion ratio, average daily gain, and residual feed intake, using culture-independent methods. Universal bacterial partial 16S rRNA gene products were amplified from ruminal fluid collected from 58 steers raised under a low-energy diet and were subjected to PCR-denaturing gradient gel electrophoresis (DGGE) analysis. Multivariate statistical analysis was used to relate specific PCR-DGGE bands to various feed efficiency traits and metabolites. Analysis of volatile fatty acid profiles showed that butyrate was positively correlated with daily dry matter intake (P < 0.05) and tended to have higher concentration in inefficient animals (P = 0.10), while isovalerate was associated with residual feed intake (P < 0.05). Our results suggest that particular bacteria and their metabolism in the rumen may contribute to differences in host feed efficiency under a low-energy diet. This is the first study correlating PCR DGGE bands representing specific bacteria to metabolites in the bovine rumen and to host feed efficiency traits. PMID- 20709850 TI - Optimization of protease secretion in Bacillus subtilis and Bacillus licheniformis by screening of homologous and heterologous signal peptides. AB - Bacillus subtilis and Bacillus licheniformis are widely used for the large-scale industrial production of proteins. These strains can efficiently secrete proteins into the culture medium using the general secretion (Sec) pathway. A characteristic feature of all secreted proteins is their N-terminal signal peptides, which are recognized by the secretion machinery. Here, we have studied the production of an industrially important secreted protease, namely, subtilisin BPN' from Bacillus amyloliquefaciens. One hundred seventy-three signal peptides originating from B. subtilis and 220 signal peptides from the B. licheniformis type strain were fused to this secretion target and expressed in B. subtilis, and the resulting library was analyzed by high-throughput screening for extracellular proteolytic activity. We have identified a number of signal peptides originating from both organisms which produced significantly increased yield of the secreted protease. Interestingly, we observed that levels of extracellular protease were improved not only in B. subtilis, which was used as the screening host, but also in two different B. licheniformis strains. To date, it is impossible to predict which signal peptide will result in better secretion and thus an improved yield of a given extracellular target protein. Our data show that screening a library consisting of homologous and heterologous signal peptides fused to a target protein can identify more-effective signal peptides, resulting in improved protein export not only in the original screening host but also in different production strains. PMID- 20709851 TI - Polyphasic characterization of a thermotolerant siderophilic filamentous cyanobacterium that produces intracellular iron deposits. AB - Despite the high potential for oxidative stress stimulated by reduced iron, contemporary iron-depositing hot springs with circum-neutral pH are intensively populated with cyanobacteria. Therefore, studies of the physiology, diversity, and phylogeny of cyanobacteria inhabiting iron-depositing hot springs may provide insights into the contribution of cyanobacteria to iron redox cycling in these environments and new mechanisms of oxidative stress mitigation. In this study the morphology, ultrastructure, physiology, and phylogeny of a novel cyanobacterial taxon, JSC-1, isolated from an iron-depositing hot spring, were determined. The JSC-1 strain has been deposited in ATCC under the name Marsacia ferruginose, accession number BAA-2121. Strain JSC-1 represents a new operational taxonomical unit (OTU) within Leptolyngbya sensu lato. Strain JSC-1 exhibited an unusually high ratio between photosystem (PS) I and PS II, was capable of complementary chromatic adaptation, and is apparently capable of nitrogen fixation. Furthermore, it synthesized a unique set of carotenoids, but only chlorophyll a. Strain JSC-1 not only required high levels of Fe for growth (>=40 MUM), but it also accumulated large amounts of extracellular iron in the form of ferrihydrite and intracellular iron in the form of ferric phosphates. Collectively, these observations provide insights into the physiological strategies that might have allowed cyanobacteria to develop and proliferate in Fe-rich, circum-neutral environments. PMID- 20709852 TI - Characterization of a cellobiohydrolase (MoCel6A) produced by Magnaporthe oryzae. AB - Three GH-6 family cellobiohydrolases are expected in the genome of Magnaporthe grisea based on the complete genome sequence. Here, we demonstrate the properties, kinetics, and substrate specificities of a Magnaporthe oryzae GH-6 family cellobiohydrolase (MoCel6A). In addition, the effect of cellobiose on MoCel6A activity was also investigated. MoCel6A contiguously fused to a histidine tag was overexpressed in M. oryzae and purified by affinity chromatography. MoCel6A showed higher hydrolytic activities on phosphoric acid-swollen cellulose (PSC), beta-glucan, and cellooligosaccharide derivatives than on cellulose, of which the best substrates were cellooligosaccharides. A tandemly aligned cellulose binding domain (CBD) at the N terminus caused increased activity on cellulose and PSC, whereas deletion of the CBD (catalytic domain only) showed decreased activity on cellulose. MoCel6A hydrolysis of cellooligosaccharides and sulforhodamine-conjugated cellooligosaccharides was not inhibited by exogenously adding cellobiose up to 438 mM, which, rather, enhanced activity, whereas a GH-7 family cellobiohydrolase from M. oryzae (MoCel7A) was severely inhibited by more than 29 mM cellobiose. Furthermore, we assessed the effects of cellobiose on hydrolytic activities using MoCel6A and Trichoderma reesei cellobiohydrolase (TrCel6A), which were prepared in Aspergillus oryzae. MoCel6A showed increased hydrolysis of cellopentaose used as a substrate in the presence of 292 mM cellobiose at pH 4.5 and pH 6.0, and enhanced activity disappeared at pH 9.0. In contrast, TrCel6A exhibited slightly increased hydrolysis at pH 4.5, and hydrolysis was severely inhibited at pH 9.0. These results suggest that enhancement or inhibition of hydrolytic activities by cellobiose is dependent on the reaction mixture pH. PMID- 20709853 TI - Functional characterization of pGKT2, a 182-kilobase plasmid containing the xplAB genes, which are involved in the degradation of hexahydro-1,3,5-trinitro-1,3,5 triazine by Gordonia sp. strain KTR9. AB - Several microorganisms have been isolated that can transform hexahydro-1,3,5 trinitro-1,3,5-triazine (RDX), a cyclic nitramine explosive. To better characterize the microbial genes that facilitate this transformation, we sequenced and annotated a 182-kb plasmid, pGKT2, from the RDX-degrading strain Gordonia sp. KTR9. This plasmid carries xplA, encoding a protein sharing up to 99% amino acid sequence identity with characterized RDX-degrading cytochromes P450. Other genes that cluster with xplA are predicted to encode a glutamine synthase-XplB fusion protein, a second cytochrome P450, Cyp151C, and XplR, a GntR type regulator. Rhodococcus jostii RHA1 expressing xplA from KTR9 degraded RDX but did not utilize RDX as a nitrogen source. Moreover, an Escherichia coli strain producing XplA degraded RDX but a strain producing Cyp151C did not. KTR9 strains cured of pGKT2 did not transform RDX. Physiological studies examining the effects of exogenous nitrogen sources on RDX degradation in strain KTR9 revealed that ammonium, nitrite, and nitrate each inhibited RDX degradation by up to 79%. Quantitative real-time PCR analysis of glnA-xplB, xplA, and xplR showed that transcript levels were 3.7-fold higher during growth on RDX than during growth on ammonium and that this upregulation was repressed in the presence of various inorganic nitrogen sources. Overall, the results indicate that RDX degradation by KTR9 is integrated with central nitrogen metabolism and that the uptake of RDX by bacterial cells does not require a dedicated transporter. PMID- 20709854 TI - Development and application of a new method for specific and sensitive enumeration of spores of nonproteolytic Clostridium botulinum types B, E, and F in foods and food materials. AB - The highly potent botulinum neurotoxins are responsible for botulism, a severe neuroparalytic disease. Strains of nonproteolytic Clostridium botulinum form neurotoxins of types B, E, and F and are the main hazard associated with minimally heated refrigerated foods. Recent developments in quantitative microbiological risk assessment (QMRA) and food safety objectives (FSO) have made food safety more quantitative and include, as inputs, probability distributions for the contamination of food materials and foods. A new method that combines a selective enrichment culture with multiplex PCR has been developed and validated to enumerate specifically the spores of nonproteolytic C. botulinum. Key features of this new method include the following: (i) it is specific for nonproteolytic C. botulinum (and does not detect proteolytic C. botulinum), (ii) the detection limit has been determined for each food tested (using carefully structured control samples), and (iii) a low detection limit has been achieved by the use of selective enrichment and large test samples. The method has been used to enumerate spores of nonproteolytic C. botulinum in 637 samples of 19 food materials included in pasta-based minimally heated refrigerated foods and in 7 complete foods. A total of 32 samples (5 egg pastas and 27 scallops) contained spores of nonproteolytic C. botulinum type B or F. The majority of samples contained <100 spores/kg, but one sample of scallops contained 444 spores/kg. Nonproteolytic C. botulinum type E was not detected. Importantly, for QMRA and FSO, the construction of probability distributions will enable the frequency of packs containing particular levels of contamination to be determined. PMID- 20709856 TI - SMART lunch box intervention to improve the food and nutrient content of children's packed lunches: UK wide cluster randomised controlled trial. AB - BACKGROUND: Government standards are now in place for children's school meals but not for lunches prepared at home. The aim of this trial is to improve the content of children's packed lunches. METHODS: A cluster randomised controlled trial in 89 primary schools across the UK involving 1291 children, age 8-9 years at baseline. Follow-up was 12 months after baseline. A "SMART" lunch box intervention programme consisted of food boxes, bag and supporting materials. The main outcome measures were weights of foods and proportion of children provided with sandwiches, fruit, vegetables, dairy food, savoury snacks and confectionery in each packed lunch. Levels of nutrients provided including energy, total fat, saturated fat, protein, non-milk extrinsic sugar, sodium, calcium, iron, folate, zinc, vitamin A and vitamin C. RESULTS: Moderately higher weights of fruit, vegetables, dairy and starchy food and lower weights of savoury snacks were provided to children in the intervention group. Children in the intervention group were provided with slightly higher levels of vitamin A and folate. 11% more children were provided with vegetables/salad in their packed lunch, and 13% fewer children were provided with savoury snacks (crisps). Children in the intervention group were more likely to be provided with packed lunches meeting the government school meal standards. CONCLUSIONS: The SMART lunch box intervention, targeting parents and children, led to small improvements in the food and nutrient content of children's packed lunches. Further interventions are required to bring packed lunches in line with the new government standards for school meals. Current controlled trials ISRCTN77710993. PMID- 20709855 TI - Decontamination options for Bacillus anthracis-contaminated drinking water determined from spore surrogate studies. AB - Five parameters were evaluated with surrogates of Bacillus anthracis spores to determine effective decontamination alternatives for use in a contaminated drinking water supply. The parameters were as follows: (i) type of Bacillus spore surrogate (B. thuringiensis or B. atrophaeus), (ii) spore concentration in suspension (10(2) and 10(6) spores/ml), (iii) chemical characteristics of the decontaminant (sodium dichloro-S-triazinetrione dihydrate [Dichlor], hydrogen peroxide, potassium peroxymonosulfate [Oxone], sodium hypochlorite, and VirkonS), (iv) decontaminant concentration (0.01% to 5%), and (v) exposure time to decontaminant (10 min to 1 h). Results from 138 suspension tests with appropriate controls are reported. Hydrogen peroxide at a concentration of 5% and Dichlor or sodium hypochlorite at a concentration of 2% were highly effective at spore inactivation regardless of spore type tested, spore exposure time, or spore concentration evaluated. This is the first reported study of Dichlor as an effective decontaminant for B. anthracis spore surrogates. Dichlor's desirable characteristics of high oxidation potential, high level of free chlorine, and a more neutral pH than that of other oxidizers evaluated appear to make it an excellent alternative. All three oxidizers were effective against B. atrophaeus spores in meeting the EPA biocide standard of greater than a 6-log kill after a 10-min exposure time and at lower concentrations than typically reported for biocide use. Solutions of 5% VirkonS and Oxone were less effective as decontaminants than other options evaluated in this study and did not meet the EPA's efficacy standard for a biocide, although they were found to be as effective for concentrations of 10(2) spores/ml. Differences in methods and procedures reported by other investigators make quantitative comparisons among studies difficult. PMID- 20709857 TI - Estimating the impact of mandatory fortification of bread with iodine on pregnant and post-partum women. AB - BACKGROUND: Iodine deficiency has re-emerged in Australia. Pregnant and breastfeeding women need higher iodine intakes (estimated average requirements: 160 MUg/day and 190 MUg/day) than non-pregnant women (100 MUg/day) because iodine is critical for early infant development. The impact of iodine fortification of bread on women's iodine intake is evaluated by reproductive status using 2003 Australian Longitudinal Study on Women's Health (ALSWH) food frequency data and projected onto 1995 National Nutrition Survey (NNS) daily food consumption data for women of child-bearing age. METHODS: Recent iodine analyses of Australian foods were combined with reported intakes of key foods to estimate iodine intake before and after fortification for 665 pregnant, 432 zero to 6 months postpartum, 467 seven to 12 months postpartum and 7324 non-pregnant women. Differences in mean iodine intake between these groups were projected onto NNS estimates of total iodine intake for women of child-bearing age. RESULTS: Pregnant and postpartum women reported eating more bread than did non-pregnant women. Mean iodine intakes (MUg/day before; and after fortification) from key foods were higher in pregnant (78; 124), 0-6 months postpartum (75; 123) and 7-12 months postpartum (71; 117) than in non-pregnant women (65; 103). Projecting ALSWH results onto the NNS yields total mean iodine intakes of 167, 167, 160 and 146 for the same groups. CONCLUSION: Current iodine intakes are well below dietary recommendations. The impact of iodine fortification of bread would be greater for pregnant and postpartum women than has been previously estimated using general population intakes, but additional strategies to increase intakes by these groups are still needed. PMID- 20709858 TI - Increasing maternal age at first pregnancy planning: health outcomes and associated costs. AB - OBJECTIVES: To describe the consequences in terms of health outcomes, care and associated healthcare costs for three hypothetical cohorts of women planning their first pregnancy at a fixed, different age. DESIGN: Decision model based on data from perinatal registries and the literature. SETTING: The Netherlands. POPULATION: 3 hypothetical cohorts of 100, 000 women aged 23, 29 and 36 years, planning a first pregnancy. MAIN OUTCOME MEASURES: Live birth, pregnancy complications for mother and child and associated healthcare costs. Results For the three cohorts of 23-, 29- and 36-year-old women, 1.6%, 4.6% and 14% of women would not succeed in an ongoing pregnancy (spontaneous or after assisted reproductive technology). The cohort aged 36 gave 9% more miscarriages, 8% more fertility treatment and 1.4% more multiple births than the cohort aged 29. The proportion of caesarean sections among low risk women was 4.9% and 11% higher respectively for the cohorts aged 29 and 36, compared with the cohort aged 23 at start. Eventually, 98%, 95% and 85% of the women in each of the three cohorts gave live birth. The costs for the two older cohorts were ?415 and ?1662 higher per ongoing pregnancy than the cohort aged 23 years. CONCLUSIONS: Spontaneous conception and mode of delivery are most susceptible to increasing maternal age leading to involuntary childlessness and non-spontaneous labour. The increase in assisted reproduction technology, twin pregnancies and delivery complications results in higher costs along with fewer ongoing pregnancies at higher age. PMID- 20709859 TI - Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts. AB - Pre- and postconditioning depend on the activation of adenosine receptors (ARs) at the end of the index ischemia. The aim of this study was to determine which receptor subtypes must be activated. In situ mouse hearts underwent 30 min of regional ischemia, followed by 2 h of reperfusion. As expected, either ischemic postconditioning (6 cycles of 10 s of reperfusion and 10 s of coronary occlusion) or infusion of the selective A(2b) adenosine receptor (A(2b)AR) agonist BAY60 6583 (BAY60) for 60 min, starting 5 min before reperfusion reduced infarct size in wild-type C57Bl/6N mice. Protection from either was abolished by the selective A(2b)AR antagonist MRS-1754, confirming a role for A(2b)AR. Additionally, the coadministration of ischemic postconditioning and a selective A(2a)AR antagonist led to the loss of protection as well. 5'-Ectonucleotidase (CD73) is thought to be necessary for the production of adenosine during ischemia. As predicted, ischemic postconditioning did not protect CD73 knockout mice. Selective agonists of either A(2b)AR (BAY60) or A(2a)AR (CGS-21680), as well as the coadministration of ischemic postconditioning and BAY60, also failed to protect hearts of the CD73 knockout mice. But the nonselective A(1)/A(2)AR agonist 5'-(N ethylcarboxamido)adenosine (NECA) was protective, suggesting that the activation of multiple AR subtypes might be required. The coadministration of CGS-21680 and BAY60 also elicited profound protection, indicating that two AR subtypes, A(2a) and A(2b), must be simultaneously activated for protection to occur. PMID- 20709860 TI - Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue. AB - Lidocaine is a class I antiarrhytmic drug that blocks Na(+) channels and exists in both neutral and charged forms at a physiological pH. In this work, a mathematical model of pH and the frequency-modulated effects of lidocaine has been developed and incorporated into the Luo-Rudy model of the ventricular action potential. We studied the effects of lidocaine on Na(+) current, maximum upstroke velocity, and conduction velocity and demonstrated that a decrease of these parameters was dependent on pH, frequency, and concentration. We also tested the action of lidocaine under pathological conditions. Specifically, we investigated its effects on conduction block under acute regional ischemia. Our results in one dimensional fiber simulations showed a reduction of the window of block in the presence of lidocaine, thereby highlighting the role of reduced conduction velocity and safe conduction. This reduction may be related to the antifibrillatory effects of the drug by hampering wavefront fragmentation. In bidimensional acute ischemic tissue, lidocaine increased the vulnerable window for reentry and exerted proarrhythmic effects. In conclusion, the present simulation study used a newly formulated model of lidocaine, which considers pH and frequency modulation, and revealed the mechanisms by which lidocaine facilitates the onset of reentries. The results of this study also help to increase our understanding of the potential antifibrillatory effects of the drug. PMID- 20709861 TI - Age-dependent cardiopulmonary interaction during airway obstruction: a simulation model. AB - Inspiratory fall in arterial blood pressure (Pa) during airway obstruction was ascribed to ventricular interdependence, afterload, and transmission of intrathoracic pressure swings. We have shown this effect significantly reduced in the elderly, but the underlying reasons remain unclear. Here we compare the results of inspiratory loading in young and older subjects with a mathematical model that simulated beat-by-beat fluctuations in cardiopulmonary variables. By increasing arterial and left ventricular elastance parameters in the older group, simulations strongly correlated with the experimental Pa and identified a linear increase of left ventricular transmural pressures with negative intrathoracic pressure that was nearly 38% larger than that in the younger group. The apparent perfusion preservation by less Pa decline with obstruction in the elderly could be misleading, since it reflects an increased afterload and diastolic dysfunction. PMID- 20709862 TI - Essential role of ER-alpha-dependent NO production in resveratrol-mediated inhibition of restenosis. AB - Resveratrol (Resv), a red wine polyphenol, is known to exhibit vascular protective effects and reduce vascular smooth muscle cell mitogenesis. Vascular smooth muscle cell proliferation is a critical factor in the pathogenesis of restenosis, the renarrowing of vessels that often occurs after angioplasty and/or stent implantation. Although Resv has been shown to be an estrogen receptor (ER) modulator, the role of the ER in Resv-mediated protection against restenosis has not yet been elucidated in vivo. Therefore, with the use of a mouse carotid artery injury model, our objective was to determine the role of ER in modulating Resv-mediated effects on neointimal hyperplasia. Female wild-type and ER-alpha(-/ ) mice were administered a high-fat diet +/- Resv for 2 wk. A carotid artery endothelial denudation procedure was conducted, and the mice were administered a high-fat diet +/- Resv for an additional 2 wk. Resv-treated wild-type mice exhibited a dramatic decrease in restenosis, with an increased arterial nitric oxide (NO) synthase (NOS) activity and NO production. However, in the ER-alpha(-/ ) mice, Resv failed to afford protection and failed to increase NO production, apparently because of a decreased availability of the NOS cofactor tetrahydrobiopterin. To verify the role of NO in Resv-mediated effects, mice were coadministered Resv plus a nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME). Cotreatment with l-NAME significantly attenuated the antirestenotic properties of Resv. These data thus suggest that Resv inhibits vascular proliferative responses after injury, predominately through an ER-alpha dependent increase in NO production. PMID- 20709864 TI - Two-photon microscopy-guided femtosecond-laser photoablation of avian cardiogenesis: noninvasive creation of localized heart defects. AB - Embryonic heart formation is driven by complex feedback between genetic and hemodynamic stimuli. Clinical congenital heart defects (CHD), however, often manifest as localized microtissue malformations with no underlying genetic mutation, suggesting that altered hemodynamics during embryonic development may play a role. An investigation of this relationship has been impaired by a lack of experimental tools that can create locally targeted cardiac perturbations. Here we have developed noninvasive optical techniques that can modulate avian cardiogenesis to dissect relationships between alterations in mechanical signaling and CHD. We used two-photon excited fluorescence microscopy to monitor cushion and ventricular dynamics and femtosecond pulsed laser photoablation to target micrometer-sized volumes inside the beating chick hearts. We selectively photoablated a small (~100 MUm radius) region of the superior atrioventricular (AV) cushion in Hamburger-Hamilton 24 chick embryos. We quantified via ultrasound that the disruption causes AV regurgitation, which resulted in a venous pooling of blood and severe arterial constriction. At 48 h postablation, quantitative X ray microcomputed tomography imaging demonstrated stunted ventricular growth and pronounced left atrial dilation. A histological analysis demonstrated that the laser ablation produced defects localized to the superior AV cushion: a small quasispherical region of cushion tissue was completely obliterated, and the area adjacent to the myocardial wall was less cellularized. Both cushions and myocardium were significantly smaller than sham-operated controls. Our results highlight that two-photon excited fluorescence coupled with femtosecond pulsed laser photoablation should be considered a powerful tool for studying hemodynamic signaling in cardiac morphogenesis through the creation of localized microscale defects that may mimic clinical CHD. PMID- 20709863 TI - Disruption of adenylyl cyclase type V does not rescue the phenotype of cardiac specific overexpression of Galphaq protein-induced cardiomyopathy. AB - Adenylyl cyclase (AC) is the principal effector molecule in the beta-adrenergic receptor pathway. AC(V) and AC(VI) are the two predominant isoforms in mammalian cardiac myocytes. The disparate roles among AC isoforms in cardiac hypertrophy and progression to heart failure have been under intense investigation. Specifically, the salutary effects resulting from the disruption of AC(V) have been established in multiple models of cardiomyopathy. It has been proposed that a continual activation of AC(V) through elevated levels of protein kinase C could play an integral role in mediating a hypertrophic response leading to progressive heart failure. Elevated protein kinase C is a common finding in heart failure and was demonstrated in murine cardiomyopathy from cardiac-specific overexpression of G(alphaq) protein. Here we assessed whether the disruption of AC(V) expression can improve cardiac function, limit electrophysiological remodeling, or improve survival in the G(alphaq) mouse model of heart failure. We directly tested the effects of gene-targeted disruption of AC(V) in transgenic mice with cardiac specific overexpression of G(alphaq) protein using multiple techniques to assess the survival, cardiac function, as well as structural and electrical remodeling. Surprisingly, in contrast to other models of cardiomyopathy, AC(V) disruption did not improve survival or cardiac function, limit cardiac chamber dilation, halt hypertrophy, or prevent electrical remodeling in G(alphaq) transgenic mice. In conclusion, unlike other established models of cardiomyopathy, disrupting AC(V) expression in the G(alphaq) mouse model is insufficient to overcome several parallel pathophysiological processes leading to progressive heart failure. PMID- 20709865 TI - Roles for soluble guanylate cyclase and a thiol oxidation-elicited subunit dimerization of protein kinase G in pulmonary artery relaxation to hydrogen peroxide. AB - We have previously provided evidence that hydrogen peroxide (H(2)O(2)) stimulates soluble guanylate cyclase (sGC) under conditions where it relaxes isolated endothelium-removed bovine pulmonary arteries (BPAs). Since it was recently reported that H(2)O(2) induces coronary vasorelaxation associated with a nitric oxide/cGMP-independent thiol oxidation/subunit dimerization-elicited activation of protein kinase G (PKG), we investigated whether this mechanism participates in the relaxation of BPAs to H(2)O(2). BPAs precontracted with serotonin (incubated under hypoxia to lower endogenous H(2)O(2)) were exposed to increasing concentrations of H(2)O(2). It was observed that 0.1-1 mM H(2)O(2) caused increased PKG dimerization and relaxation. These responses were associated with increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at the serine-239 site known to be mediated by PKG. Treatment of BPAs with 1 mM DTT attenuated PKG dimerization, VASP phosphorylation, and relaxation to H(2)O(2). An organoid culture of BPAs for 48 h with 10 MUM 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one (ODQ), a heme oxidant inhibitor of sGC activation, depleted sGC expression by 85%, associated with a 67% attenuation of VASP phosphorylation and 48% inhibition of relaxation elicited by 100 MUM H(2)O(2). Thus both a sGC activation/cGMP-dependent and a thiol oxidation subunit dimerization/cGMP independent activation of PKG appear to contribute to the relaxation of BPAs elicited by H(2)O(2). PMID- 20709866 TI - Suppression of circulating free fatty acids with acipimox in chronic heart failure patients changes whole body metabolism but does not affect cardiac function. AB - Circulating free fatty acids (FFAs) may worsen heart failure (HF) due to myocardial lipotoxicity and impaired energy generation. We studied cardiac and whole body effects of 28 days of suppression of circulating FFAs with acipimox in patients with chronic HF. In a randomized double-blind crossover design, 24 HF patients with ischemic heart disease [left ventricular ejection fraction: 26 +/- 2%; New York Heart Association classes II (n = 13) and III (n = 5)] received 28 days of acipimox treatment (250 mg, 4 times/day) and placebo. Left ventricular ejection fraction, diastolic function, tissue-Doppler regional myocardial function, exercise capacity, noninvasive cardiac index, NH(2)-terminal pro-brain natriuretic peptide (NT-pro-BNP), and whole body metabolic parameters were measured. Eighteen patients were included for analysis. FFAs were reduced by 27% in the acipimox-treated group [acipimox vs. placebo (day 28-day 0): -0.10 +/- 0.03 vs. +0.01 +/- 0.03 mmol/l, P < 0.01]. Glucose and insulin levels did not change. Acipimox tended to increase glucose and decrease lipid utilization rates at the whole body level and significantly changed the effect of insulin on substrate utilization. The hyperinsulinemic euglycemic clamp M value did not differ. Global and regional myocardial function did not differ. Exercise capacity, cardiac index, systemic vascular resistance, and NT-pro-BNP were not affected by treatment. In conclusion, acipimox caused minor changes in whole body metabolism and decreased the FFA supply, but a long-term reduction in circulating FFAs with acipimox did not change systolic or diastolic cardiac function or exercise capacity in patients with HF. PMID- 20709867 TI - Ionic mechanisms of electrophysiological heterogeneity and conduction block in the infarct border zone. AB - The increased incidence of arrhythmia in the healing phase after infarction has been linked to remodeling in the epicardial border zone (EBZ). Ionic models of normal zone (NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insights into how ion channel remodeling affects action potential (AP) duration (APD) and refractoriness, vulnerability to conduction block, and conduction safety postinfarction. We found that EBZ tissue exhibited abnormal APD restitution. The remodeled Na(+) current (I(Na)) and L type Ca(2+) current (I(Ca,L)) promoted increased effective refractory period and prolonged APD at a short diastolic interval. While postrepolarization refractoriness due to remodeled EBZ I(Na) was the primary determinant of the vulnerable window for conduction block at the NZ-to-EBZ transition in response to premature S2 stimuli, altered EBZ restitution also promoted APD dispersion and increased the vulnerable window at fast S1 pacing rates. Abnormal EBZ APD restitution and refractoriness also led to abnormal periodic conduction block patterns for a range of fast S1 pacing rates. In addition, we found that I(Na) remodeling decreased conduction safety in the EBZ but that inward rectifier K(+) current remodeling partially offset this decrease. EBZ conduction was characterized by a weakened AP upstroke and short intercellular delays, which prevented I(Ca,L) and transient outward K(+) current remodeling from playing a role in EBZ conduction in uncoupled tissue. Simulations of a skeletal muscle Na(+) channel SkM1-I(Na) injection into the EBZ suggested that this recently proposed antiarrhythmic therapy has several desirable effects, including normalization of EBZ effective refractory period and APD restitution, elimination of vulnerability to conduction block, and normalization of conduction in tissue with reduced intercellular coupling. PMID- 20709868 TI - Tumor necrosis factor inhibitors as novel therapeutic tools for vascular remodeling diseases. AB - Vascular remodeling diseases (VRDs) are characterized by enhanced inflammation and proliferative and apoptosis-resistant vascular smooth muscle cells (VSMCs). The sustainability of this phenotype has been attributed in part to the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). There is evidence that circulating cytokines can act as HIF-1 activators in a variety of tissues, including VSMCs. Increased circulating tumor necrosis factor (TNF) levels have been associated with vascular diseases, but the mechanisms involved remain unknown. We hypothesized that increased circulating levels of TNF promotes VRDs by the activation of HIF-1, resulting in VSMC proliferation and resistance to apoptosis. Circulating TNF levels were significantly increased in patients with vascular diseases (n = 19) compared with healthy donors (n = 15). Using human carotid artery smooth muscle cells (CASMCs), we demonstrated that TNF (100 ng/ml) activates HIF-1 (HIF-1alpha expression), leading to increased CASMC proliferation (Ki-67 and PCNA staining) and resistance to mitochondrial-dependent apoptosis [tetramethylrhodamine methyl ester perchlorate (TMRM), terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL), annexin-V staining]. In vivo, TNF inhibition using polyethylene glycol coupled with TNF membrane receptor 1 (PEGsTNFR1), a soluble TNF receptor inhibiting circulating TNF, prevented carotid artery postinjury media remodeling and neointima development in rats. This effect was associated with lowered HIF-1 activation and decreased CASMC proliferation. In conclusion, we demonstrate for the first time that the inhibition of the TNF/Akt/HIF-1 axis prevents vascular remodeling. TNF inhibitors may therefore represent new and interesting therapeutic tools against VRDs. PMID- 20709869 TI - Comparison of in vitro digestibility estimates using the DaisyII incubator with in vivo digestibility estimates in horses. AB - The objective of this study was to determine if in vitro methodologies developed for the Ankom Daisy(II) incubator could produce accurate estimates of in vivo equine DM digestibility (DMD) and NDF digestibility (NDFD) when equine feces were used as the inoculum source. Four mature geldings were utilized in a 4 * 4 Latin square design experiment with a 2 * 2 factorial arrangement of dietary treatments (timothy hay, alfalfa hay, timothy hay plus oats, and alfalfa hay plus oats), in which the geldings were individually housed and fed. During each 5-d total fecal collection period, feces were collected and composited daily and used to calculate in vivo digestibility. Digestion of the 4 treatment diets was evaluated in vitro using the Daisy(II) incubator. Each incubation vessel of the Daisy(II) was assigned to 1 of the horses and contained 18 filter bags (6 containing the assigned treatment hay, 6 containing hay-oat mix, and 6 containing oats). Three incubation periods were evaluated: 30, 48, and 72 h. Although the 30- and 48-h in vitro estimates were consistently less than the in vivo estimates, they ranked diets in the same order as the in vivo method. For the alfalfa oat diet, timothy diet, and the timothy oat diet, the mean 72-h in vitro DMD and in vivo DMD were not different (P = 0.1444). However, for the alfalfa diet, the DMD estimate from 72-h in vitro incubation was less than the in vivo estimate (P < 0.010). For NDFD, the timothy diet was the only diet, in which the mean 72-h in vitro NDFD estimate was not different than the in vivo estimate. However, the in vitro method correctly ranked the alfalfa-based diets as having greater NDFD estimates than the timothy-based diets. Of the 3 incubation periods, the 72-h period provided digestibility estimates most similar to the in vivo data. Using the methodologies described in this research, the Daisy(II) incubator and equine feces can be used to estimate in vivo DMD of horse feeds. PMID- 20709870 TI - Bioavailability of dietary cyanocobalamin (vitamin B12) in growing pigs. AB - The present project aimed to estimate bioavailability of dietary vitamin B(12), for which little information is available in growing pigs. Two approaches, each using 2 quantities of dietary cyanocobalamin, were compared; the first was based on whole body retention for 8 d and the second was based on nycthemeral portal net flux of vitamin B(12). In the first trial, 15 blocks of 3 pigs (31.7 +/- 0.5 kg of BW) were formed according to their vitamin B(12) status. Within each block, 1 pig (CONT) was killed and tissues were sampled for vitamin B(12) determination. The remaining 2 piglets were fed 25 (B(12)-25) or 250 (B(12)-250) MUg daily of cyanocobalamin for 8 d. Urine was sampled twice daily, and the pigs were killed and sampled as CONT pigs. The total content of vitamin B(12) in the carcass, urine, and intestinal tract was affected by the dietary treatments (P < 0.01) but not in the liver (P > 0.019). The whole body retention of vitamin B(12) was greater (P = 0.02) in B(12)-250 than B(12)-25 pigs, but the corresponding bioavailability was estimated to be 5.3 and 38.2%, respectively. In trial 2, 11 pigs (35.1 +/- 4.0 kg of BW and 75.4 +/- 5.9 d of age) fed a diet unsupplemented with vitamin B(12) from weaning at 28 d of age were surgically equipped with catheters in the portal vein and carotid artery and an ultrasonic flow probe around the portal vein. Each pig received 3 boluses of 0 (B(12)-0), 25, and 250 MUg of dietary vitamin B(12) according to a crossover design. Postprandial nycthemeral arterial plasma concentrations of vitamin B(12) reached minimum values (P < 0.01) between 15 and 18 h postmeal that were 29.6, 15.6, and 10.0% less than the premeal values for B(12)-0, B(12)-25, and B(12)-250 pigs, respectively (linear, P < 0.01). The cumulative net flux of vitamin B(12) for 24 h corresponded to 2.4 and 5.1 ug for B(12)-25 and B(12)-250 treatments, respectively, and the corresponding bioavailability was estimated to be 9.7 and 2.0%, respectively. Although bioavailability estimates varied according to approaches, both showed the inverse relationship between dietary vitamin B(12) and bioavailability of the vitamin. The dietary supplement of 25 ug was sufficient to maximize hepatic vitamin B(12) retention and to attenuate the nycthemeral decrease of arterial plasma concentration of the vitamin. PMID- 20709871 TI - In situ disappearance of dry matter and fiber from fall-grown cereal-grain forages from the north-central United States. AB - Recent research has demonstrated that fall-grown wheat (Triticum aestivum L.), triticale (X Triticosecale Wittmack), and oat (Avena sativa L.) forages contain limited lignin and exhibit relatively stable estimates of in vitro true DM disappearance, as well as TDN, across a wide fall-harvest window. These traits suggest that ruminal availability of forage fiber is extensive. Our objectives were to evaluate this premise by assessing in situ DM and NDF disappearance for Kaskaskia wheat, Trical 2700 triticale, Ogle oat (grain-type, mid-maturity rating), and ForagePlus oat (forage-type, late maturity rating) grown and harvested during fall in Wisconsin. During 2006, ruminal disappearance rate (K(d)) of DM declined linearly (P <= 0.002) across fall harvest dates for all cultivars; K(d) ranged narrowly (0.091 to 0.100/h) on the initial September 15 harvest date, but by October 30, K(d) generally was slower for oat (0.042 to 0.053/h) than for triticale (0.069/h) or wheat (0.072/h). Estimates of effective ruminal disappearance of DM (RDDM) were large for all cultivars (72.0 to 82.8% of DM), and generally exhibited polynomial trends over harvest dates that displayed both linear (P <= 0.003) and quadratic (P <= 0.004) character. For 2007, RDDM was extensive across all forages (70.5 to 83.1%), except for Ogle oat harvested on October 10 (61.5% of DM) or November 7 (57.0% of DM), at which time tillers had reached the boot- and fully headed stages of growth, respectively. For ruminal disappearance of NDF, K(d) declined linearly (P <= 0.002) across harvest dates for all cultivars during 2006 and 2007; a quadratic (P <= 0.033) effect also was detected for ForagePlus oat, but not for other cultivars (P >= 0.072). During both years, effective ruminal disappearance of NDF (RDNDF) declined linearly (P <= 0.008) over harvest dates for all cultivars, but detection of additional quadratic responses was dependent on cultivar and year. Concentrations of RDNDF for all cultivars ranged from 60.5 to 68.8% of NDF on mid-September harvest dates. Generally, these estimates declined to 51.4 to 60.0% of NDF by the final harvest date for all cultivars except Ogle oat, which reached numerical minimums of 46.8 and 37.2% of NDF on the final harvest dates of 2006 and 2007, respectively. Cereal-grain cultivars that elongate during fall will exhibit relatively stable RDDM and RDNDF through stem elongation; however, these estimates may decline substantially after tillers exhibit visible seedheads. PMID- 20709872 TI - Winter grazing system and supplementation of beef cows during late gestation influence heifer progeny. AB - A 2 * 2 factorial arrangement of treatments was used to evaluate effects of dam winter grazing system and supplementation in the last third of gestation on subsequent BW gain, feed efficiency, and reproduction in heifer progeny. Crossbred cows (yr 1, n = 109; yr 2, n = 114; yr 3, n = 116) grazed range (WR) or corn residue (CR) during winter and within grazing treatment received 0.40 kg/d of 31% CP (DM basis) cubes (PS) or no supplement (NS). Heifer calves (yr 1, n = 56; yr 2, n = 56; yr 3, n = 54) grazed dormant pasture for 114 d postweaning and were individually fed for 87 d before a 45-d natural service breeding. Dam PS reduced (P = 0.04) heifer birth date and CR tended to increase (P = 0.07) heifer birth BW. Both PS and CR increased (P <= 0.05) heifer weaning BW; however, adjusted 205-d weaning BW was only lighter (P = 0.03) if the dam grazed WR with NS. Heifers from PS dams tended to be younger (P = 0.09) at puberty than NS, and there was a trend (P = 0.11) for more heifers to be pubertal by breeding if the dam grazed WR with PS compared with other treatment groups. Heifers from WR-NS dams tended to weigh less (P <= 0.09) at breeding and at pregnancy diagnosis than WR PS. There was a trend (P = 0.13) for pregnancy rate to be greater for heifers born to PS dams. Individually fed heifer DMI was not affected (P = 0.25) by treatment; however, heifers from dams that grazed CR with PS gained the least BW (P = 0.04) during individual feeding and had the smallest (P = 0.03) G:F. In contrast, there were no differences (P > 0.15) in feed efficiency when expressed as residual feed intake. The first calf birth and weaning BW of the heifer was unaffected (P > 0.15) by dam treatment. Heifers from dams that grazed WR with NS tended to have lighter (P = 0.09) BW before the second breeding season but similar (P = 0.97) pregnancy rates. Cows grazing CR with NS produced the most valuable heifer calf at weaning; however, heifers from cows that grazed WR with NS cost the least to develop per pregnant heifer. Winter grazing system and late gestation supplementation affected heifer progeny BW, feed efficiency, and fertility. PMID- 20709873 TI - Effects of dietary supplementation with alkyl polyglycoside, a nonionic surfactant, on nutrient digestion and ruminal fermentation in goats. AB - The effects of dietary alkyl polyglycoside [APG, a nonionic surfactant (NIS), derived from a reaction of corn starch glucose and a natural fatty alcohol] inclusion on digestion of nutrients and ruminal fermentation in goats were examined in a 4 * 4 Latin square design using 4 ruminally and duodenally cannulated wethers (mean BW: 19.5 +/- 0.8 kg). The animals were assigned to 4 dietary treatments of APG supplementation at 0, 3, 6, and 12 g/kg of DM diets and were designated as control, APG3, APG6, and APG12, respectively. The results showed that dietary APG inclusion tended to increase the intestinal digestibility of OM (linear, P = 0.09) and NDF (linear, P = 0.1), and quadratically increased (P <= 0.02) total tract digestibility of OM and NDF, the duodenal microbial N flow, and efficiency of microbial protein synthesis. The true ruminal digestibility and apparent total tract digestibility of N quadratically increased (P < 0.01) with increasing dietary APG. The ruminal pH values were not affected by dietary APG inclusion (P > 0.05), but the concentration of NH(3)-N (P < 0.01) and total VFA (linear and quadratic, P < 0.01) increased in the rumen fluid. Dietary APG inclusion also increased the activities of ruminal carboxymethyl cellulase (quadratic, P < 0.01) and xylanase (linear and quadratic, P < 0.01). It is concluded that APG is a potential feed additive that can be used in ruminant production; 6 g/kg in the total mixed rations for goats is recommended. It is necessary to validate the effectiveness of dietary APG inclusion in ruminant diets with more animals in further studies. PMID- 20709874 TI - Effect of shade on body temperature and performance of feedlot steers. AB - A 120-d feedlot study using 164 Angus steers (BW = 396.7 +/- 7.0 kg) was undertaken in Queensland Australia (24 degrees 84' S, 149 degrees 78' N) to determine the effect of shade on body temperature (T(B)) and performance. Cattle were allocated to 20 pens: 16 with an area of 144 m(2) (8 steers/pen) and 4 with an area of 168 m(2) (9 steers/pen). Treatments (10 pens/treatment) were unshaded (NS) vs. shaded (SH). Shade (3.3 m(2)/steer) was provided by 80% solar block shade cloth. Before the study (d -31), 63 steers were implanted (between the internal abdominal muscle and the peritoneum at the right side flank) with a T(B) transmitter. Within each pen, 3 steers had a T(B) transmitter. Individual T(B) was obtained every 30 min. The cattle were fed a feedlot diet and had ad libitum access to water. Water usage and DMI were recorded daily on a pen basis. Average daily gain and G:F were calculated on a pen basis. Climatic variables were obtained from an on-site weather station every 30 min. Individual panting scores (PS) were obtained daily at 0600, 1200, and 1600 h. From these, mean PS (MPS) were calculated for each pen. At slaughter (d 121), individual HCW, loin muscle area (LMA), rump fat depth (P8), 12th-rib fat depth, and marbling score were obtained. Mean T(B) was not affected (P > 0.05) by treatment (SH = 39.58 degrees C; NS = 39.60 degrees C). However, during a 21-d heat wave when cattle were exposed to a mean ambient temperature (T(AM)) > 30 degrees C for 8 h each d (T(AM) between 0800 and 1800 h = 29.7 degrees C, and 23.4 degrees C between 1830 and 0730 h), the T(B) of SH steers (40.41 +/- 0.10 degrees C) was less (P < 0.01) than the T(B) of NS steers (41.14 +/- 0.10 degrees C). During this period, pen MPS were greater (P < 0.05) for the NS cattle at all observation times. Over the first 6 d of the heat wave, MPS of NS steers at 1200 h was 2.47 (P < 0.01) vs. 1.39 for SH steers. Hip height, DMI, ADG, and G:F were greater (P < 0.05) for SH cattle. Exit BW (final BW) of SH steers (596.1 kg) was greater (P < 0.05) when compared with NS steers (578.6 kg). During the heat wave, DMI was 51% less for NS steers and 39% less for SH steers when compared with the pre-heat wave period (P < 0.01). The HCW of SH steers (315.4 +/- 0.8 kg) was greater (P < 0.05) than for NS steers (321.4 +/- 0.8 kg). No treatment differences (P > 0.05) were found for LMA, P8, or marbling score. Access to shade improved (P < 0.05) ADG and G:F, increased HCW, and decreased MPS; however, shade did not completely eliminate the impact of high heat load. PMID- 20709876 TI - In the company we keep: social physique anxiety levels differ around parents and peers. AB - This study examined the psychometric properties of two scales which assessed social physique anxiety (SPA) in the context of peers (peer SPA) and parents (parent SPA), and differences in reported levels of peer SPA and parent SPA. Young adults (N = 381, 161 males, M(age) = 18.69 years) completed self-report measures. Results supported the internal consistency, convergent validity and factor structure of the peer SPA and parent SPA scales. Also, participants reported significantly higher levels of peer SPA compared to parent SPA. Findings offer preliminary support for the investigation of contextualized SPA using the scales tested in this study, and suggest more research is needed to better understand the processes that may increase or decrease SPA when surrounded by peers and parents. PMID- 20709875 TI - Unwanted horses: The role of nonprofit equine rescue and sanctuary organizations. AB - Closure of US equine slaughter facilities in 2007 along with the concomitant economic recession have contributed to a sharp increase in the number of unwanted horses throughout the United States, with estimates totaling 100,000 horses per year. The objective of the study was to obtain comprehensive data regarding nonprofit organizations caring for unwanted horses, along with the characteristics and outcome of horses relinquished to these organizations. Nonprofit organizations that accept relinquished equines were contacted to participate in a 90-question survey. Responding organizations (144 of 326 eligible) in 37 states provided information on 280 cases representative of the 7,990 horses relinquished between 2007 and 2009. Data collected characterized these organizations as being in existence for 6 yr, financially supported through donations and personal funds, dedicated to the care of only 10 to 20 horses on a property of just over 30 acres, and reliant on volunteers for help. Funding was the greatest challenge to continued operation of nonprofit equine organizations, with maintenance costs for the care of a relinquished horse averaging $3,648 per year. Financial hardship, physical inability, or lack of time to care for the horses by owners were the most common reasons for relinquishment, followed by seizure through law enforcement agencies for alleged neglect or abuse. Relinquished horses consisted of mostly light horse breeds (79.3%), with Thoroughbreds and Quarter Horses as the most represented breeds. The age of relinquished horses ranged from 3 d to 42 yr old (12.4 +/- 0.5 yr). About one half of the horses entered in the survey were considered unhealthy due to illness, injury, lameness, or poor body condition. For every 4 horses relinquished to a nonprofit organization, only 3 horses were adopted or sold between 2006 and 2009, and many organizations had refused to accept additional horses for lack of resources. The estimated maximum capacity for the 326 eligible registered nonprofit equine rescue facilities of 13,400 is well below the widely published estimate of 100,000 horses that become unwanted in the United States every year. Nonprofit equine rescue and sanctuary facilities have historically played an important role in safeguarding the welfare of horses in society, but funding and capacity are limiting factors to their potential expansion in continuing to care for the current population of unwanted and neglected horses in the United States. PMID- 20709877 TI - A qualitative exploration of young women's attitudes towards the thin ideal. AB - The thin ideal has been identified as playing a central role in female body dissatisfaction. However, research into idealization of thinness in young women tends to focus on quantitative measures that can mask the complexity of attitudes and experiences. This article describes a series of focus groups with 41 females aged 16-26 and explores the multifaceted relationship young women have with the thin ideal. Thematic qualitative analysis revealed differences between individuals in the construct of the thin ideal and explored the conflict and ambivalence experienced by young women who are confronted by these ideals on a daily basis. PMID- 20709879 TI - Making sense of the cleft. Young adults' accounts of growing up with a cleft and deviant speech. AB - Individuals born with a cleft lip and palate risk developing a deviant appearance and speech during childhood and sometimes also as adults. In this study, 13 young adults born with a cleft (lip and) palate, who had had deviant speech in adolescence, participated in semi-structured interviews. The core category Making sense of the cleft, comprising the two categories Shaping one's attitude to the cleft and Dealing with being different with seven subcategories, describes the processes of developing self-image in relation to the cleft. The findings are believed to be relevant for individuals born with a cleft, their parents and caregivers. PMID- 20709878 TI - The Southampton Initiative for Health: a complex intervention to improve the diets and increase the physical activity levels of women from disadvantaged communities. AB - The Southampton Initiative for Health is a training intervention with Sure Start Children's Centre staff designed to improve the diets and physical activity levels of women of childbearing age. Training aims to help staff to support women in making changes to their lifestyles by improving three skills: reflection on current practice; asking 'open discovery' questions; and goal-setting. The impact of the training on staff practice is being assessed. A before and after non randomized controlled trial is being used to evaluate the effectiveness and cost effectiveness of the intervention in improving women's diets and increasing their physical activity levels. PMID- 20709881 TI - The role of interpersonal influence in families in understanding children's eating behavior: a social relations model analysis. AB - This study investigates children's eating behavior in a context of bidirectional parent-child influences. Parents and children were asked about their sense of influence and of being influenced concerning food rules. For parents, these feelings seemed to be partly correlated with children's eating behavior. Additionally, Social Relations Model analysis revealed that parents' and children's feelings of influence and being influenced were not only dependent on characteristics of the rater or actor, but also characteristics of the partner and of the unique relationship were found to be important. Furthermore, evidence was found for bidirectional influences, but only for the mother-older sibling dyad. PMID- 20709880 TI - Psychological adjustment among women living with genital herpes. AB - This study investigated the psychosocial factors that influence psychological adjustment among women with genital herpes, while taking into account the physical factors. Women with herpes (N = 105, age 18-30) completed an on-line survey about factors related to their diagnosis and herpes-related quality of life. Perceived stigma, acceptance coping, denial coping, support from the Internet, and support from religious/spiritual figures accounted for 65.9 percent of the variance in quality of life scores. The findings reveal the importance of specific coping strategies and sources of support on psychological adjustment to herpes. Furthermore, a significant interaction between stigma and acceptance coping suggests a complex relationship between these two psychosocial factors that warrants future research. PMID- 20709882 TI - Leisure and depression in midlife: a Taiwanese national survey of middle-aged adults. AB - We aimed to explore middle-aged people's leisure experiences and their associations with depression in a national representative sample of Taiwanese people (N = 1143, aged 45-65). We found that: (1) being female and low family income were demographic risk factors of depressive symptoms; (2) poor physical health and disability were positively related to depressive symptoms; (3) social support was negatively related to depressive symptoms; and (4) having controlled for effects of demographics, physical health and social support, positive leisure experiences were negatively related to depressive symptoms. The benefits of leisure pursuits for successful midlife transition and prospective ageing were discussed. PMID- 20709883 TI - Self-regulatory problems mediate the association of contextual stressors and unprotected intercourse among rural, African American, young adult men. AB - In this brief report, the hypothesis that self-regulatory problems would mediate the association between contextual stressors and unprotected intercourse among rural African American young adult men was investigated. Family support and religiosity were hypothesized to ameliorate the influence of contextual stressors on self-regulatory problems. Hypotheses were tested on 79 sexually active men from a sample recruited with Respondent Driven Sampling; episodes of unprotected intercourse constituted the criterion variable. Analyses supported the mediating role of self-regulatory problems in linking young adult men's contextual stressors with a heightened likelihood of unprotected intercourse. Religious involvement and family support interacted with contextual stressors to predict diminished associations with self-regulatory problems. PMID- 20709886 TI - The construct validity of social inhibition and the type-D taxonomy. AB - In contrast to the prognostic validity of the type-D personality, there is still little knowledge on the construct validity. In a sample of 102 healthy young adults the construct validity was analysed against the Big-Five dimensions, four of the 16 PF factors, and repressive emotion regulation. Social inhibition was associated with Apprehensiveness, and low scores in social competencies and self deception. The three non-type-D clusters clearly differed; the restrained cluster emerged as opposite to the type-D cluster in nearly every personality dimension and type of emotion regulation. The article concludes that emotion regulation in socially inhibited persons deserves further investigation. PMID- 20709884 TI - Reporting guidelines for music-based interventions. AB - Music-based interventions are used to address a variety of problems experienced by individuals across the developmental lifespan (infants to elderly adults). In order to improve the transparency and specificity of reporting music-based interventions, a set of specific reporting guidelines is recommended. Recommendations pertain to seven different components of music-based interventions, including theory, content, delivery schedule, interventionist, treatment fidelity, setting, and unit of delivery. Recommendations are intended to support Consolidated Standards for Reporting Trials (CONSORT) and Transparent Reporting of Evaluations with Non-randomized Designs (TREND) statements for transparent reporting of interventions while taking into account the variety, complexity, and uniqueness of music-based interventions. PMID- 20709885 TI - Effects of Alzheimer caregiving on allostatic load. AB - This study aimed to determine if Alzheimer caregivers have increased allostatic load compared to non-caregivers. Potential psychological moderators (mastery, depression, and role overload) of the relationship between caregiving status and allostatic load were also explored. Eighty-seven caregivers and 43 non-caregivers underwent biological assessment of allostatic load and psychological assessments. Caregivers had significantly higher allostatic load compared to non-caregivers ( p < .05). Mastery, but not depression or overload, moderated the relationship between caregiving status and allostatic load. In conclusion, allostatic load may represent a link explaining how stress translates to downstream pathology, but more work is necessary to understand the role of psychological factors. PMID- 20709887 TI - Forgiveness, health, and problematic drinking among college students in southern Appalachia. AB - Evidence is growing regarding the salutary relationships between spirituality and health, including alcohol problems, yet little is known about spirituality and health in the context thereof. Cross-sectional associations between forgiveness and health were examined among college student problematic drinkers (n = 126; ? = 60%; M (age) = 22) in Southern Appalachia. Controlling for demographic variables (including religiosity), dimensions of forgiveness accounted for 7-33 percent of the variance in the health-related variables in a salutary fashion. Forgiveness of Self appears to be the most important dimension of forgiveness measured, yet the most difficult to develop. PMID- 20709888 TI - Staphylococcus coagulase-positive skin inflammation associated with epidermal growth factor receptor-targeted therapy: an early and a late phase of papulopustular eruptions. AB - OBJECTIVE: Cutaneous eruptions, mainly papulopustular, are the most common associated side effects of epidermal growth factor receptor inhibitors (EGFRIs). This study investigated the possible role of bacterial infection in EGFRI-induced eruptions and its relation to clinical morphology. PATIENTS AND METHODS: The study group consisted of all 29 patients referred for dermatologic evaluation of side effects of cetuximab or erlotinib from March 2008 to November 2009. Specimens were taken for bacterial culture from pustules in patients with grade >1 papulopustular rash and from periungual secretions in patients with paronychia. RESULTS: Twenty-four of 29 patients had a papulopustular reaction; five of 29 had paronychia/xerosis. Of the papulopustular eruption patients, time to rash appearance yielded two distinct groups: early-phase, median 8 days after drug initiation, located mainly on the face (n = 17) and late-phase, median ~200 days after drug initiation, located mainly on the trunk (n = 7). Bacterial culture grew Staphylococcus aureus (SA) in seven of 13 early-phase patients tested and in all late-phase patients. Treatment consisted of topical steroids with or without topical/systemic antibiotics. All patients had a clear improvement in their cutaneous symptoms within a few days. Dose reduction or temporary discontinuation of the EGFRI was necessary in only four of 29 patients. CONCLUSIONS: As described in the literature, EGFRI-induced papulopustular eruption may appear early and probably is an inflammatory process with or without SA secondary infection. The papulopustular eruption may also appear as a late phase, described here for the first time, which is an infectious process with all patients being SA(+). The >50% overall incidence of SA infection in our study highlights the need for routine bacterial cultures from EGFRI-induced eruption. PMID- 20709889 TI - Lenalidomide-induced acute interstitial nephritis. PMID- 20709890 TI - Education and disability pension: a stronger association than previously found. AB - INTRODUCTION: Although the Norwegian Welfare Law includes rigorous medical criteria for granting disability pensions, several non-medical factors have been shown to be associated with and possible causal factors of pensioning. OBJECTIVES: We analysed the relationship between disability pension and detailed information on educational attainment in different diagnostic groups. METHODS: All ethnic Norwegians aged 18-66 years and alive on 31 December 2003 (n = 2,522,430) were included. Age, sex, the receipt of a disability pension on 31 December 2003, and the diagnosis on the medical certificate were taken from a national social security file. The file also included six levels of education: primary school, low-level secondary school, secondary school, low-level university, university, and research level. RESULTS: We found a dramatic increase in the prevalence of persons granted disability pension with decreasing years of education across all levels of education. The disparities were much stronger than those seen for other health-related parameters and were especially strong for those with musculoskeletal diagnoses. The disability pension is more a consequence of health problems than a proxy for health status. The demonstrated relationship between education and disability pension may be partly explained by exclusion from the work force because of health-related work problems. CONCLUSIONS: To facilitate a more inclusive working life, attention should be focused on the work place's capacity to include people with different levels of competence and functioning rather than on the health problems of the employees. PMID- 20709891 TI - Are low back pain and low physical capacity risk indicators for dropout among recently qualified eldercare workers? A follow-up study. AB - BACKGROUND: A high job turnover and dropout among eldercare workers has led to a significant shortage of qualified manpower in the Danish eldercare sector. OBJECTIVES: The predictive effect of some non-work-related causes for leaving the eldercare sector 2 years after qualification, physical capacity, duration, and severity of previous low back pain, was investigated. DESIGN AND SETTING: A 2 year prospective cohort study of all the Danish eldercare workers, who finished their education during 2004 (n = 6347). Questionnaire data from 2004 were followed up by register data on attachment to labour market, educational status, and association to trade from Statistics Denmark in 2006. METHODS: Data on physical capacity, duration, and severity of low back pain the last 12 months among the female participants were analysed by multinomial logistic regression to estimate odds-ratios for being either in the eldercare sector, in other health- and welfare sectors, in all other sectors, under education, or outside labour market, 2 years after qualification. RESULTS: Disability due to and duration of low back pain were significant predictors for dropout from the eldercare sector 2 years after qualification. Low physical capacity was not. Data on duration of low back pain suggest a trend towards a dose-response relationship: The longer the duration of low back pain, the higher odds for dropout. CONCLUSIONS: Low back pain and disability due to low back pain during the last year of education were independent predictors for dropout from the eldercare sector 2 years after qualification. However, low self-rated physical capacity did not predict job dropout or turnover. PMID- 20709892 TI - Elucidation of beta-oxidation pathways in Ralstonia eutropha H16 by examination of global gene expression. AB - Ralstonia eutropha H16 is capable of growth and polyhydroxyalkanoate production on plant oils and fatty acids. However, little is known about the triacylglycerol and fatty acid degradation pathways of this bacterium. We compare whole-cell gene expression levels of R. eutropha H16 during growth and polyhydroxyalkanoate production on trioleate and fructose. Trioleate is a triacylglycerol that serves as a model for plant oils. Among the genes of note, two potential fatty acid beta oxidation operons and two putative lipase genes were shown to be upregulated in trioleate cultures. The genes of the glyoxylate bypass also exhibit increased expression during growth on trioleate. We observed that single beta-oxidation operon deletion mutants of R. eutropha could grow using palm oil or crude palm kernel oil as the sole carbon source, regardless of which operon was present in the genome, but a double mutant was unable to grow under these conditions. A lipase deletion mutant did not exhibit a growth defect in emulsified oil cultures but did exhibit a phenotype in cultures containing nonemulsified oil. Mutants of the glyoxylate shunt gene for isocitrate lyase were able to grow in the presence of oils, while a malate synthase (aceB) deletion mutant grew more slowly than wild type. Gene expression under polyhydroxyalkanoate storage conditions was also examined. Many findings of this analysis confirm results from previous studies by our group and others. This work represents the first examination of global gene expression involving triacylglycerol and fatty acid catabolism genes in R. eutropha. PMID- 20709893 TI - Domain analysis of a modular alpha-L-Arabinofuranosidase with a unique carbohydrate binding strategy from the fiber-degrading bacterium Fibrobacter succinogenes S85. AB - Family 43 glycoside hydrolases (GH43s) are known to exhibit various activities involved in hemicellulose hydrolysis. Thus, these enzymes contribute to efficient plant cell wall degradation, a topic of much interest for biofuel production. In this study, we characterized a unique GH43 protein from Fibrobacter succinogenes S85. The recombinant protein showed alpha-l-arabinofuranosidase activity, specifically with arabinoxylan. The enzyme is, therefore, an arabinoxylan arabinofuranohydrolase (AXH). The F. succinogenes AXH (FSUAXH1) is a modular protein that is composed of a signal peptide, a GH43 catalytic module, a unique beta-sandwich module (XX domain), a family 6 carbohydrate-binding module (CBM6), and F. succinogenes-specific paralogous module 1 (FPm-1). Truncational analysis and site-directed mutagenesis of the protein revealed that the GH43 domain/XX domain constitute a new form of carbohydrate-binding module and that residue Y484 in the XX domain is essential for binding to arabinoxylan, although protein structural analyses may be required to confirm some of the observations. Kinetic studies demonstrated that the Y484A mutation leads to a higher k(cat) for a truncated derivative of FSUAXH1 composed of only the GH43 catalytic module and the XX domain. However, an increase in the K(m) for arabinoxylan led to a 3-fold decrease in catalytic efficiency. Based on the knowledge that most XX domains are found only in GH43 proteins, the evolutionary relationships within the GH43 family were investigated. These analyses showed that in GH43 members with a XX domain, the two modules have coevolved and that the length of a loop within the XX domain may serve as an important determinant of substrate specificity. PMID- 20709894 TI - In vitro analysis of the Staphylococcus aureus lipoteichoic acid synthase enzyme using fluorescently labeled lipids. AB - Lipoteichoic acid (LTA) is an important cell wall component of Gram-positive bacteria. The key enzyme responsible for polyglycerolphosphate lipoteichoic acid synthesis in the Gram-positive pathogen Staphylococcus aureus is the membrane embedded lipoteichoic acid synthase enzyme, LtaS. It is presumed that LtaS hydrolyzes the glycerolphosphate head group of the membrane lipid phosphatidylglycerol (PG) and catalyzes the formation of the polyglycerolphosphate LTA backbone chain. Here we describe an in vitro assay for this new class of enzyme using PG with a fluorescently labeled fatty acid chain (NBD-PG) as the substrate and the recombinant soluble C-terminal enzymatic domain of LtaS (eLtaS). Thin-layer chromatography and mass spectrometry analysis of the lipid reaction products revealed that eLtaS is sufficient to cleave the glycerolphosphate head group from NBD-PG, resulting in the formation of NBD diacylglycerol. An excess of soluble glycerolphosphate could not compete with the hydrolysis of the fluorescently labeled PG lipid substrate, in contrast to the addition of unlabeled PG. This indicates that the enzyme recognizes and binds other parts of the lipid substrate, besides the glycerolphosphate head group. Furthermore, eLtaS activity was Mn(2+) ion dependent; Mg(2+) and Ca(2+) supported only weak enzyme activity. Addition of Zn(2+) or EDTA inhibited enzyme activity even in the presence of Mn(2+). The pH optimum of the enzyme was 6.5, characteristic for an enzyme that functions extracellularly. Lastly, we show that the in vitro assay can be used to study the enzyme activities of other members of the lipoteichoic acid synthase enzyme family. PMID- 20709895 TI - Comparative genome biology of a serogroup B carriage and disease strain supports a polygenic nature of meningococcal virulence. AB - Neisseria meningitidis serogroup B strains are responsible for most meningococcal cases in the industrialized countries, and strains belonging to the clonal complex ST-41/44 are among the most prevalent serogroup B strains in carriage and disease. Here, we report the first genome and transcriptome comparison of a serogroup B carriage strain from the clonal complex ST-41/44 to the serogroup B disease strain MC58 from the clonal complex ST-32. Both genomes are highly colinear, with only three major genome rearrangements that are associated with the integration of mobile genetic elements. They further differ in about 10% of their gene content, with the highest variability in gene presence as well as gene sequence found for proteins involved in host cell interactions, including Opc, NadA, TonB-dependent receptors, RTX toxin, and two-partner secretion system proteins. Whereas housekeeping genes coding for metabolic functions were highly conserved, there were considerable differences in their expression pattern upon adhesion to human nasopharyngeal cells between both strains, including differences in energy metabolism and stress response. In line with these genomic and transcriptomic differences, both strains also showed marked differences in their in vitro infectivity and in serum resistance. Taken together, these data support the concept of a polygenic nature of meningococcal virulence comprising differences in the repertoire of adhesins as well as in the regulation of metabolic genes and suggest a prominent role for immune selection and genetic drift in shaping the meningococcal genome. PMID- 20709896 TI - CztR, a LysR-type transcriptional regulator involved in zinc homeostasis and oxidative stress defense in Caulobacter crescentus. AB - Caulobacter crescentus is a free-living alphaproteobacterium that has 11 predicted LysR-type transcriptional regulators (LTTRs). Previously, a C. crescentus mutant strain with a mini-Tn5lacZ transposon inserted into a gene encoding an LTTR was isolated; this mutant was sensitive to cadmium. In this work, a mutant strain with a deletion was obtained, and the role of this LTTR (called CztR here) was evaluated. The transcriptional start site of this gene was determined by primer extension analysis, and its promoter was cloned in front of a lacZ reporter gene. beta-galactosidase activity assays, performed with the wild type and mutant strains, indicated that this gene is 2-fold induced when cells enter stationary phase and that it is negatively autoregulated. Moreover, this regulator is essential for the expression of the divergent cztA gene at stationary phase, in minimal medium, and in response to zinc depletion. This gene encodes a hypothetical protein containing 10 predicted transmembrane segments, and its expression pattern suggests that it encodes a putative zinc transporter. The cztR strain was also shown to be sensitive to superoxide (generated by paraquat) and to hydrogen peroxide but not to tert-butyl hydroperoxide. The expression of katG and ahpC, but not that of the superoxide dismutase genes, was increased in the cztR mutant. A model is proposed to explain how CztR binding to the divergent regulatory regions could activate cztA expression and repress its own transcription. PMID- 20709897 TI - Integration of metabolism and virulence by Clostridium difficile CodY. AB - CodY, a global regulatory protein that monitors the nutrient sufficiency of the environment by responding to the intracellular levels of GTP and the branched chain amino acids, was previously shown to be a potent repressor of toxin gene expression in Clostridium difficile during growth in rich medium. In the intestinal tract, such derepression of toxin synthesis would lead to destruction of epithelial cells and the liberation of potential nutrients for the bacterium. CodY is likely to play an important role in regulating overall cellular physiology as well. In this study, DNA microarray analysis and affinity purification of CodY-DNA complexes were used to identify and distinguish the direct and indirect effects of CodY on global gene transcription. A codY null mutation resulted in >4-fold overexpression of 146 genes (organized in 82 apparent transcription units) and underexpression of 19 genes. In addition to the toxin genes, genes for amino acid biosynthesis, nutrient transport, fermentation pathways, membrane components, and surface proteins were overexpressed in the codY mutant. Genome-wide analysis identified more than 350 CodY binding regions, many of which are likely to correspond to sites of direct CodY-mediated regulation. About 60% of the CodY-repressed transcription units were associated with binding regions. Several of these genes were confirmed to be direct targets of CodY by gel mobility shift and DNase I footprinting assays. PMID- 20709898 TI - Metabolic network analysis of Pseudomonas aeruginosa during chronic cystic fibrosis lung infection. AB - System-level modeling is beginning to be used to decipher high throughput data in the context of disease. In this study, we present an integration of expression microarray data with a genome-scale metabolic reconstruction of Pseudomonas aeruginosa in the context of a chronic cystic fibrosis (CF) lung infection. A genome-scale reconstruction of P. aeruginosa metabolism was tailored to represent the metabolic states of two clonally related lineages of P. aeruginosa isolated from the lungs of a CF patient at different points over a 44-month time course, giving a mechanistic glimpse into how the bacterial metabolism adapts over time in the CF lung. Metabolic capacities were analyzed to determine how tradeoffs between growth and other important cellular processes shift during disease progression. Genes whose knockouts were either significantly growth reducing or lethal in silico were also identified for each time point and serve as hypotheses for future drug targeting efforts specific to the stages of disease progression. PMID- 20709899 TI - Identification, source, and metabolism of N-ethylglutamate in Escherichia coli. AB - N-Ethylglutamate (NEG) was detected in Escherichia coli BL21 cells grown on LB broth, and it was found to occur at a concentration of ~4 mM in these cells under these conditions. The same cells grown on M9 glucose medium contained no detectable amount of NEG. Analysis of the LB broth showed the presence of NEG, a compound never before reported as a natural product. Isotope dilution analysis showed that it occurred at a concentration of 160 MUM in LB broth. Analyses of yeast extract and tryptone, the organic components of LB broth, both showed the presence NEG. It was demonstrated that NEG can be generated during the autolysis of the yeast used in the preparation of the yeast extract. Growth of these E. coli cells in LB broth prepared in deuterated water showed no incorporation of deuterium into NEG, demonstrating that E. coli cells did not generate the NEG. Cell growth rates were not affected by the addition of 5 mM NEG to either LB or M9 glucose medium. l-[ethyl-(2)H(4)]NEG was found to be readily incorporated into the cells and metabolized by the cells. From these results, it was concluded that all of the NEG present in the cells was taken up from the medium. NEG could serve as the sole nitrogen source for E. coli when grown on M9 glucose medium in the presence of glucose but could not serve as the sole carbon source on M9 medium in the absence of glucose. PMID- 20709900 TI - Small genes under sporulation control in the Bacillus subtilis genome. AB - Using an oligonucleotide microarray, we searched for previously unrecognized transcription units in intergenic regions in the genome of Bacillus subtilis, with an emphasis on identifying small genes activated during spore formation. Nineteen transcription units were identified, 11 of which were shown to depend on one or more sporulation-regulatory proteins for their expression. A high proportion of the transcription units contained small, functional open reading frames (ORFs). One such newly identified ORF is a member of a family of six structurally similar genes that are transcribed under the control of sporulation transcription factor sigma(E) or sigma(K). A multiple mutant lacking all six genes was found to sporulate with slightly higher efficiency than the wild type, suggesting that under standard laboratory conditions the expression of these genes imposes a small cost on the production of heat-resistant spores. Finally, three of the transcription units specified small, noncoding RNAs; one of these was under the control of the sporulation transcription factor sigma(E), and another was under the control of the motility sigma factor sigma(D). PMID- 20709901 TI - Brochothrix thermosphacta bacteriophages feature heterogeneous and highly mosaic genomes and utilize unique prophage insertion sites. AB - Brochothrix belongs to the low-GC branch of Gram-positive bacteria (Firmicutes), closely related to Listeria, Staphylococcus, Clostridium, and Bacillus. Brochothrix thermosphacta is a nonproteolytic food spoilage organism, adapted to growth in vacuum-packaged meats. We report the first genome sequences and characterization of Brochothrix bacteriophages. Phage A9 is a myovirus with an 89 nm capsid diameter and a 171-nm contractile tail; it belongs to the Spounavirinae subfamily and shares significant homologies with Listeria phage A511, Staphylococcus phage Twort, and others. The A9 unit genome is 127 kb long with 11 kb terminal redundancy; it encodes 198 proteins and 6 tRNAs. Phages BL3 and NF5 are temperate siphoviruses with a head diameter of 56 to 59 nm. The BL3 tail is 270 nm long, whereas NF5 features a short tail of only 94 nm. The NF5 genome (36.95 kb) encodes 57 gene products, BL3 (41.52 kb) encodes 65 products, and both are arranged in life cycle-specific modules. Surprisingly, BL3 and NF5 show little relatedness to Listeria phages but rather demonstrate relatedness to lactococcal phages. Peptide mass fingerprinting of viral proteins indicate programmed -1 translational frameshifts in the NF5 capsid and the BL3 major tail protein. Both NF5 and BL3 feature circularly permuted, terminally redundant genomes, packaged by a headful mechanism, and integrases of the serine (BL3) and tyrosine (NF5) types. They utilize unique target sequences not previously described: BL3 inserts into the 3' end of a RNA methyltransferase, whereas NF5 integrates into the 5'-terminal part of a putative histidinol-phosphatase. Interestingly, both genes are reconstituted by phage sequence. PMID- 20709903 TI - Efficient osteoclast differentiation requires local complement activation. AB - Previous studies using blocking antibodies suggested that bone marrow (BM) derived C3 is required for efficient osteoclast (OC) differentiation, and that C3 receptors are involved in this process. However, the detailed underlying mechanism and the possible involvement of other complement receptors remain unclear. In this report, we found that C3(-/-) BM cells exhibited lower RANKL/OPG expression ratios, produced smaller amounts of macrophage colony-stimulating factor and interleukin-6 (IL-6), and generated significantly fewer OCs than wild type (WT) BM cells. During differentiation, in addition to C3, WT BM cells locally produced all other complement components required to activate C3 and to generate C3a/C5a through the alter-native pathway, which is required for efficient OC differentiation. Abrogating C3aR/C5aR activity either genetically or pharmaceutically suppressed OC generation, while stimulating WT or C3(-/-) BM cells with exogenous C3a and/or C5a augmented OC differentiation. Furthermore, supplementation with IL-6 rescued OC generation from C3(-/-) BM cells, and neutralizing antibodies to IL-6 abolished the stimulatory effects of C3a/C5a on OC differentiation. These data indicate that during OC differentiation, BM cells locally produce components, which are activated through the alternative pathway to regulate OC differentiation. In addition to C3 receptors, C3aR/C5aR also regulate OC differentiation, at least in part, by modulating local IL-6 production. PMID- 20709902 TI - AmrZ beta-sheet residues are essential for DNA binding and transcriptional control of Pseudomonas aeruginosa virulence genes. AB - AmrZ is a putative ribbon-helix-helix (RHH) transcriptional regulator. RHH proteins utilize residues within the beta-sheet for DNA binding, while the alpha helices promote oligomerization. AmrZ is of interest due to its dual roles as a transcriptional activator and as a repressor, regulating genes encoding virulence factors associated with both chronic and acute Pseudomonas aeruginosa infection. In this study, cross-linking revealed that AmrZ forms oligomers in solution but that the amino terminus, containing an unordered region and a beta-sheet, were not required for oligomerization. The first 12 unordered residues (extended amino terminus) contributed minimally to DNA binding. Mutagenesis of the AmrZ beta sheet demonstrated that residues 18, 20, and 22 were essential for DNA binding at both activation and repressor sites, suggesting that AmrZ utilizes a similar mechanism for binding to these sites. Mice infected with amrZ mutants exhibited reduced bacterial burden, morbidity, and mortality. Direct in vivo competition assays showed a 5-fold competitive advantage for the wild type over an isogenic amrZ mutant. Finally, the reduced infection phenotype of the amrZ-null strain was similar to that of a strain expressing a DNA-binding-deficient AmrZ variant, indicating that DNA binding and transcriptional regulation by AmrZ is responsible for the in vivo virulence defect. These recent infection data, along with previously identified AmrZ-regulated virulence factors, suggest the necessity of AmrZ transcriptional regulation for optimal virulence during acute infection. PMID- 20709904 TI - Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. AB - Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet alpha-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B(12) as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421. PMID- 20709905 TI - Polyphosphate exerts differential effects on blood clotting, depending on polymer size. AB - Polyphosphate, a linear polymer of inorganic phosphate, is secreted by activated platelets and accumulates in many infectious microorganisms. We recently showed that polyphosphate modulates the blood coagulation cascade at 3 steps: it triggers the contact pathway, it accelerates factor V activation, and it enhances fibrin polymerization. We now report that polyphosphate exerts differential effects on blood clotting, depending on polymer length. Very long polymers (>= 500mers, such as those present in microorganisms) were required for optimal activation of the contact pathway, while shorter polymers (~ 100mers, similar to the polymer lengths released by platelets) were sufficient to accelerate factor V activation and abrogate the anticoagulant function of the tissue factor pathway inhibitor. Optimal enhancement of fibrin clot turbidity by polyphosphate required >= 250mers. Pyrophosphate, which is also secreted by activated platelets, potently blocked polyphosphate-mediated enhancement of fibrin clot structure, suggesting that pyrophosphate is a novel regulator of fibrin function. In conclusion, polyphosphate of the size secreted by platelets is very efficient at accelerating blood clotting reactions but is less efficient at initiating them or at modulating clot structure. Microbial polyphosphate, which is highly procoagulant, may function in host responses to pathogens. PMID- 20709906 TI - Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. AB - Adoptive transfer of viral antigen-specific memory T cells can reconstitute antiviral immunity, but in a recent report a majority of virus-specific cytotoxic T-lymphocyte (CTL) lines showed in vitro cross-reactivity against allo-human leukocyte antigen (HLA) molecules as measured by interferon-gamma secretion. We therefore reviewed our clinical experience with adoptive transfer of allogeneic hematopoietic stem cell transplantation donor-derived virus-specific CTLs in 153 recipients, including 73 instances where there was an HLA mismatch. There was no de novo acute graft-versus-host disease after infusion, and incidence of graft versus-host disease reactivation was low and not significantly different in recipients of matched or mismatched CTL. However, we found that virus-specific T cell lines recognized up to 10% of a panel of 44 HLA disparate targets, indicating that virus-specific T cells can have cross-reactivity with HLA mismatched targets in vitro. These data indicate that the adoptive transfer of partially HLA-mismatched virus-specific CTL is safe despite in vitro recognition of recipient HLA molecules. PMID- 20709909 TI - The transcription factor Srf regulates hematopoietic stem cell adhesion. AB - Adhesion properties of hematopoietic stem cells (HSCs) in the bone marrow (BM) niches control their migration and affect their cell-cycle dynamics. The serum response factor (Srf) regulates growth factor-inducible genes and genes controlling cytoskeleton structures involved in cell spreading, adhesion, and migration. We identified a role for Srf in HSC adhesion and steady-state hematopoiesis. Conditional deletion of Srf in BM cells resulted in a 3-fold expansion of the long- and short-term HSCs and multipotent progenitors (MPPs), which occurs without long-term modification of cell-cycle dynamics. Early differentiation steps to myeloid and lymphoid lineages were normal, but Srf loss results in alterations in mature-cell production and severe thrombocytopenia. Srf null BM cells also displayed compromised engraftment properties in transplantation assays. Gene expression analysis identified Srf target genes expressed in HSCs, including a network of genes associated with cell migration and adhesion. Srf-null stem cells and MPPs displayed impair expression of the integrin network and decreased adherence in vitro. In addition, Srf-null mice showed increase numbers of circulating stem and progenitor cells, which likely reflect their reduced retention in the BM. Altogether, our results demonstrate that Srf is an essential regulator of stem cells and MPP adhesion, and suggest that Srf acts mainly through cell-matrix interactions and integrin signaling. PMID- 20709908 TI - APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status. AB - A proliferation-inducing ligand (APRIL) promotes survival and drug resistance in multiple myeloma (MM) cell lines. We studied the effect of APRIL on cell-cycle behavior in primary MM cells and correlated our findings with D-type cyclin expression by immunohistochemistry and/or Western blotting. In MM cases, expressing cyclin D2 APRIL significantly increased the percentage of CD138(+) cells in S + G(2)/M phase (from 8.4% +/- 1.9% to 14.3% +/- 2.6%, n = 15, P < .01), whereas a lesser effect was seen in cases expressing cyclin D1 (n = 18). Cell-cycle response to APRIL was most marked for cyclin D2-expressing cases with IgH translocations (P < .01) and was accompanied by increased expression of cyclin D2, CDK4, CDK6, and phospho-retinoblastoma protein. Cell-cycle proteins in cyclin D1(+) cells were not modulated by APRIL. Surface expression of B-cell maturation antigen and transmembrane activator and calcium-modulating cyclophilin ligand interactor was not significantly different between cyclin D1(+) and D2(+) MM cells. We observed activation of nuclear factor-kappaB and PI3-kinase pathways in response to APRIL in both cyclin D1(+) and D2(+) MM cells. In conclusion, APRIL stimulates G(1)/S progression in cyclin D2(+) MM cells bearing IgH translocations but has minimal effect on cyclin D1(+) cells, suggesting MM cells from different cyclin D/translocation classes rely on different mechanisms for cell-cycle re-entry. PMID- 20709907 TI - microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. AB - Although individuals with homozygous sickle cell disease (HbSS) share the same genetic mutation, the severity and manifestations of this disease are extremely heterogeneous. We have previously shown that the microRNA expression in normal and HbSS erythrocytes exhibit dramatic differences. In this study, we identify a subset of HbSS patients with higher erythrocytic miR-144 expression and more severe anemia. HbSS erythrocytes are known to have reduced tolerance for oxidative stress, yet the basis for this phenotype remains unknown. This study reveals that miR-144 directly regulates nuclear factor-erythroid 2-related factor 2, a central regulator of cellular response to oxidative stress, and modulates the oxidative stress response in K562 cell line and primary erythroid progenitor cells. We further demonstrate that increased miR-144 is associated with reduced NRF2 levels in HbSS reticulocytes and with decreased glutathione regeneration and attenuated antioxidant capacity in HbSS erythrocytes, thereby providing a possible mechanism for the reduced oxidative stress tolerance and increased anemia severity seen in HbSS patients. Taken together, our findings suggest that erythroid microRNAs can serve as genetic modifiers of HbS-related anemia and can provide novel insights into the clinical heterogeneity and pathobiology of sickle cell disease. PMID- 20709910 TI - Yeast profilin complements profilin deficiency in transgenic tomato fruits and allows development of hypoallergenic tomato fruits. AB - Gene silencing of Lyc e 1 leads to reduced allergenicity of tomato fruits but impaired growth of transgenic tomato plants. The aim of the study was to restore growth of Lyc e 1-deficient tomato plants while retaining reduced allergenicity by simultaneous complementation of profilin deficiency by expression of nonallergenic yeast profilin. Transgenic plants were generated and tested by RT PCR and immunoblotting; allergenicity of yeast profilin and transgenic fruits was investigated by IgE binding, basophil activation, and skin-prick tests. Lyc e 1 content of transgenic tomato fruits was <5% of that of wild-type plants, causing significantly reduced IgE antibody binding. Simultaneous coexpression of yeast profilin restored growth and biomass production almost to wild-type levels. Yeast profilin, sharing 32.6% amino acid sequence identity with Lyc e 1, displayed low IgE-binding capacity and allergenic potency. Among 16 tomato-allergic patients preselected for sensitization to Lyc e 1, none showed significant reactivity to yeast profilin. Yeast profilin did not induce mediator release, and coexpression of yeast profilin did not enhance the allergenicity of Lyc e 1-reduced fruits. Simultanous coexpression of yeast profilin allows silencing of tomato profilin and generation of viable plants with Lyc e 1-deficient tomato fruits. Therefore, a novel approach to allergen avoidance, genetically modified foods with reduced allergen accumulation, can be generated even if the allergen fulfills an essential cellular function in the plant. In summary, our findings of efficiently complementing profilin-deficient tomato plants by coexpression of low allergenic yeast profilin demonstrate the feasibility of creating low-allergenic food even if the allergen fulfills essential cellular functions. PMID- 20709913 TI - Sulfuritalea hydrogenivorans gen. nov., sp. nov., a facultative autotroph isolated from a freshwater lake. AB - A novel facultatively autotrophic bacterium, designated strain sk43H(T), was isolated from water of a freshwater lake in Japan. Cells of the isolate were curved rods, motile and gram-reaction-negative. Strain sk43H(T) was facultatively anaerobic and autotrophic growth was observed only under anaerobic conditions. The isolate oxidized thiosulfate, elemental sulfur and hydrogen as sole energy sources for autotrophic growth and could utilize nitrate as an electron acceptor. Growth was observed at 8-32 degrees C (optimum 25 degrees C) and 6.4-7.6 (optimum pH 6.7-6.9). Optimum growth of the isolate occurred at NaCl concentrations of less than 50 mM. The G+C content of genomic DNA was around 67 mol%. The fatty acid profile of strain sk43H(T) when grown on acetate under aerobic conditions was characterized by the presence of C(16 : 0) and summed feature 3 (C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH) as the major components. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain was a member of the class Betaproteobacteria showing highest sequence similarity with Georgfuchsia toluolica G5G6(T) (94.7 %) and Denitratisoma oestradiolicum AcBE2-1(T) (94.3 %). Phylogenetic analyses were also performed using genes involved in sulfur oxidation. On the basis of its phylogenetic and phenotypic properties, strain sk43H(T) ( = DSM 22779(T) = NBRC 105852(T)) represents a novel species of a new genus, for which the name Sulfuritalea hydrogenivorans gen. nov., sp. nov. is proposed. PMID- 20709911 TI - Unliganded thyroid hormone receptor alpha1 impairs adult hippocampal neurogenesis. AB - Thyroid hormone regulates adult hippocampal neurogenesis, a process involved in key functions, such as learning, memory, and mood regulation. We addressed the role of thyroid hormone receptor TRalpha1 in adult hippocampal neurogenesis, using mice harboring a TRalpha1 null allele (TRalpha1(-/-)), overexpressing TRalpha1 6-fold (TRalpha2(-/-)), and a mutant TRalpha1 (TRalpha1(+/m)) with a 10 fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TRalpha1(-/-) mice exhibited a significant increase in doublecortin positive immature neurons and increased survival of bromodeoxyuridine-positive (BrdU(+)) progenitors as compared to wild-type controls. In contrast, the TRalpha1(+/m) and the TRalpha2(-/-) mice, where the overexpressed TRalpha1 acts as an aporeceptor, showed a significant decline in surviving BrdU(+) progenitors. TRalpha1(-/-) and TRalpha2(-/-) mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TRalpha2(-/-) and TRalpha1(+/m) mice could be rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TRalpha1(+/m) mice. These mice also exhibited a decrease in NeuroD(+) cell numbers in the dentate gyrus, suggesting an effect on early postmitotic progenitors. Our results provide the first evidence of a role for unliganded TRalpha1 in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis. PMID- 20709912 TI - The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair. AB - Kidney damage due to injury rarely resolves completely, and there are currently no therapies capable of promoting repair. In addition to understanding mechanisms by which tissues are damaged, illuminating mechanisms of repair and regeneration is also of great importance. Here we show that the melanoma-associated, transmembrane glycoprotein, Gpnmb, is up-regulated 15-fold following ischemic damage in kidney tissue and by more than 10-fold in macrophages and 3-fold in surviving epithelial cells. Gpnmb-expressing macrophages and epithelial cells were found to contain apoptotic bodies at 3 times the rate of nonexpressing cells. Either mutation of Gpnmb or ablation of inflammatory macrophages prevents normal repair of the kidney. Significantly, the kidneys from postischemic Gpnmb mutant mice exhibited a 5-fold increase in apoptotic cellular debris compared to wild-type mice. These mice also experienced an 85% increase in mortality following bilateral ischemic kidney. Finally, we demonstrate that Gpnmb is a phagocytic protein that is necessary for recruitment of the autophagy protein LC3 to the phagosome where these proteins are colocalized and for lysosomal fusion with the phagosome and hence bulk degradation of their content. Therefore, Gpnmb is a novel prorepair gene that is necessary for crosstalk between the macroautophagic degradation pathway and phagocytosis. PMID- 20709914 TI - Phaeospirillum oryzae sp. nov., a spheroplast-forming, phototrophic alphaproteobacterium from a paddy soil. AB - Two strains (JA317(T) and JA559) of spiral shaped, spheroplast-forming, anaerobic, gram-negative, motile purple non-sulfur bacteria were isolated from rhizosphere soils of paddy and were characterized by a polyphasic taxonomic approach. Bacteriochlorophyll a and carotenoids, rhodopin, lycopene and rhodopin glucoside, were present as photosynthetic pigments. Intracellular photosynthetic membranes were of stacked type. The major fatty acids were C(18 : 1)omega7c, C(16 : 0) and C(16 : 1)omega6c/C(16 : 1)omega7c in both strains. The genomic DNA G+C content was 63.3+/-0.8 mol%. The two strains were closely related (mean DNA-DNA hybridization >85 %). Phylogenetic analysis showed that the strains clustered with the species of the genus Phaeospirillum, which belongs to the family Rhodospirillaceae within the class Alphaproteobacteria. Based on 16S rRNA gene sequence analysis, strains JA317(T) and JA559 showed highest sequence similarity with the type strains of Phaeospirillum chandramohanii (98.2 %), Phaeospirillum molischianum (97.4 %) and Phaeospirillum fulvum (97.1 %) of the family Rhodospirillaceae. Strain JA317(T) can be clearly distinguished from P. chandramohanii with respect to spheroplast formation and several other morphological and physiological properties. DNA-DNA relatedness of strain JA317(T) with its closest relatives of the genus Phaeospirillum was less than 55 %. It is evident from the phenotypic, chemotaxonomic and molecular genetic evidence that strain JA317(T) represents a novel species of the genus Phaeospirillum, for which the name Phaeospirillum oryzae sp. nov., is proposed. The type strain of the species is JA317(T) ( = NBRC 104938(T) = KCTC 5704(T)). PMID- 20709915 TI - Burkholderia bannensis sp. nov., an acid-neutralizing bacterium isolated from torpedo grass (Panicum repens) growing in highly acidic swamps. AB - Two strains of acid-neutralizing bacteria, E25(T) and E21, were isolated from torpedo grass (Panicum repens) growing in highly acidic swamps (pH 2-4) in actual acid sulfate soil areas of Thailand. Cells of the strains were gram-negative, aerobic, non-spore-forming rods, 0.6-0.8 um wide and 1.6-2.1 um long. The strains showed good growth at pH 4.0-8.0 and 17-37 degrees C. The organisms contained ubiquinone Q-8 as the predominant isoprenoid quinone and C(16 : 0), C(17 : 0) cyclo and C(18 : 1)omega7c as the major fatty acids. Their fatty acid profiles were similar to those reported for other Burkholderia species. The DNA G+C content of the strains was 65 mol%. On the basis of 16S rRNA gene sequence similarity, the strains were shown to belong to the genus Burkholderia. Although the calculated 16S rRNA gene sequence similarity of E25(T) to strain E21 and the type strains of Burkholderia unamae, B. tropica, B. sacchari, B. nodosa and B. mimosarum was 100, 98.7, 98.6, 97.6, 97.4 and 97.3 %, respectively, strains E25(T) and E21 formed a group that was distinct in the phylogenetic tree; the DNA DNA relatedness of E25(T) to E21 and B. unamae CIP 107921(T), B. tropica LMG 22274(T), B. sacchari LMG 19450(T), B. nodosa LMG 23741(T) and B. mimosarum LMG 23256(T) was 90, 42, 42, 42, 45 and 35 %, respectively. The results of physiological and biochemical tests including whole-cell protein pattern analysis allowed phenotypic differentiation of these strains from previously described Burkholderia species. Therefore, strains E25(T) and E21 represent a novel species, for which the name Burkholderia bannensis sp. nov. is proposed. The type strain is E25(T) ( = NBRC 103871(T) = BCC 36998(T)). PMID- 20709917 TI - A new look for the JEB website. PMID- 20709916 TI - Phylogenetic analysis of the genera Proteus, Morganella and Providencia by comparison of rpoB gene sequences of type and clinical strains suggests the reclassification of Proteus myxofaciens in a new genus, Cosenzaea gen. nov., as Cosenzaea myxofaciens comb. nov. AB - Phylogenetic analysis of partial rpoB gene sequences of type and clinical strains belonging to different 16S rRNA gene-fingerprinting ribogroups within 11 species of enterobacteria of the genera Proteus, Morganella and Providencia was performed and allowed the definition of rpoB clades, supported by high bootstrap values and confirmed by >=2.5 % nucleotide divergence. None of the resulting clades included strains belonging to different species and the majority of the species were confirmed as discrete and homogeneous. However, more than one distinct rpoB clade could be defined among strains belonging to the species Proteus vulgaris (two clades), Providencia alcalifaciens (two clades) and Providencia rettgeri (three clades), suggesting that some strains represent novel species according to the genotypes outlined by rpoB gene sequence analysis. Percentage differences between the rpoB gene sequence of the type strain of Proteus myxofaciens and other members of the same genus (17.3-18.9 %) were similar to those calculated amongst strains of the genus Providencia (16.4-18.7 %), suggesting a genetic distance at the genus-level between Proteus myxofaciens and the rest of the Proteus Providencia group. Proteus myxofaciens therefore represents a member of a new genus, for which the name Cosenzaea gen. nov., is proposed. PMID- 20709918 TI - Oxidative stress in cold-induced hyperthyroid state. AB - Exposure of homeothermic animals to low environmental temperature is associated with oxidative stress in several body tissues. Because cold exposure induces a condition of functional hyperthyroidism, the observation that tissue oxidative stress also happens in experimental hyperthyroidism, induced by 3,5,3' triiodothyronine (T(3)) treatment, suggests that this hormone is responsible for the oxidative damage found in tissues from cold-exposed animals. Examination of T(3)-responsive tissues, such as brown adipose tissue (BAT) and liver, shows that changes in factors favoring oxidative modifications are similar in experimental and functional hyperthyroidism. However, differences are also apparent, likely due to the action of physiological regulators, such as noradrenaline and thyroxine, whose levels are different in cold-exposed and T(3)-treated animals. To date, there is evidence that biochemical changes underlying the thermogenic response to cold as well as those leading to oxidative stress require a synergism between T(3)- and noradrenaline-generated signals. Conversely, available results suggest that thyroxine (T(4)) supplies a direct contribution to cold-induced BAT oxidative damage, but contributes to the liver response only as a T(3) precursor. PMID- 20709919 TI - Goal seeking in honeybees: matching of optic flow snapshots? AB - Visual landmarks guide humans and animals including insects to a goal location. Insects, with their miniature brains, have evolved a simple strategy to find their nests or profitable food sources; they approach a goal by finding a close match between the current view and a memorised retinotopic representation of the landmark constellation around the goal. Recent implementations of such a matching scheme use raw panoramic images ('image matching') and show that it is well suited to work on robots and even in natural environments. However, this matching scheme works only if relevant landmarks can be detected by their contrast and texture. Therefore, we tested how honeybees perform in localising a goal if the landmarks can hardly be distinguished from the background by such cues. We recorded the honeybees' flight behaviour with high-speed cameras and compared the search behaviour with computer simulations. We show that honeybees are able to use landmarks that have the same contrast and texture as the background and suggest that the bees use relative motion cues between the landmark and the background. These cues are generated on the eyes when the bee moves in a characteristic way in the vicinity of the landmarks. This extraordinary navigation performance can be explained by a matching scheme that includes snapshots based on optic flow amplitudes ('optic flow matching'). This new matching scheme provides a robust strategy for navigation, as it depends primarily on the depth structure of the environment. PMID- 20709920 TI - Elasticity and stress relaxation of rhesus monkey (Macaca mulatta) vocal folds. AB - Fundamental frequency is an important perceptual parameter for acoustic communication in mammals. It is determined by vocal fold oscillation, which depends on the morphology and viscoelastic properties of the oscillating tissue. In this study, I tested if stress-strain and stress-relaxation behavior of rhesus monkey (Macaca mulatta) vocal folds allows the prediction of a species' natural fundamental frequency range across its entire vocal repertoire as well as of frequency contours within a single call type. In tensile tests, the load-strain and stress-relaxation behavior of rhesus monkey vocal folds and ventricular folds has been examined. Using the string model, predictions about the species' fundamental frequency range, individual variability, as well as the frequency contour of 'coo' calls were made. The low- and mid-frequency range (up to 2 kHz) of rhesus monkeys can be predicted relatively well with the string model. The discrepancy between predicted maximum fundamental frequency and what has been recorded in rhesus monkeys is currently ascribed to the difficulty in predicting the behavior of the lamina propria at very high strain. Histological sections of the vocal fold and different staining techniques identified collagen, elastin, hyaluronan and, surprisingly, fat cells as components of the lamina propria. The distribution of all four components is not uniform, suggesting that different aspects of the lamina propria are drawn into oscillation depending on vocal fold tension. A differentiated recruitment of tissue into oscillation could extend the frequency range specifically at the upper end of the frequency scale. PMID- 20709921 TI - Switching attraction to inhibition: mating-induced reversed role of sex pheromone in an insect. AB - In the moth, Agrotis ipsilon, newly mated males cease to be attracted to the female-produced sex pheromone, preventing them from re-mating until the next night, by which time they would have refilled their reproductive glands for a potential new ejaculate. The behavioural plasticity is accompanied by a decrease in neuron sensitivity within the primary olfactory centre, the antennal lobe (AL). However, it was not clear whether the lack of the sexually guided behaviour results from the absence of sex pheromone detection in the ALs, or if they ignore it in spite of detection, or if the sex pheromone itself inhibits attraction behaviour after mating. To test these hypotheses, we performed behavioural tests and intracellular recordings of AL neurons to non-pheromonal odours (flower volatiles), different doses of sex pheromone and their mixtures in virgin and newly mated males. Our results show that, although the behavioural and AL neuron responses to flower volatiles alone were similar between virgin and mated males, the behavioural response of mated males to flower odours was inhibited by adding pheromone doses above the detection threshold of central neurons. Moreover, we show that the sex pheromone becomes inhibitory by differential central processing: below a specific threshold, it is not detected within the AL; above this threshold, it becomes inhibitory, preventing newly mated males from responding even to plant odours. Mated male moths have thus evolved a strategy based on transient odour-selective central processing, which allows them to avoid the risk-taking, energy-consuming search for females and delay re-mating until the next night for a potential new ejaculate. PMID- 20709922 TI - Phenotypic plasticity of gas exchange pattern and water loss in Scarabaeus spretus (Coleoptera: Scarabaeidae): deconstructing the basis for metabolic rate variation. AB - Investigation of gas exchange patterns and modulation of metabolism provide insight into metabolic control systems and evolution in diverse terrestrial environments. Variation in metabolic rate in response to environmental conditions has been explained largely in the context of two contrasting hypotheses, namely metabolic depression in response to stressful or resource-(e.g. water) limited conditions, or elevation of metabolism at low temperatures to sustain life in extreme conditions. To deconstruct the basis for metabolic rate changes in response to temperature variation, here we undertake a full factorial study investigating the longer- and short-term effects of temperature exposure on gas exchange patterns. We examined responses of traits of gas exchange [standard metabolic rate (SMR); discontinuous gas exchange (DGE) cycle frequency; cuticular, respiratory and total water loss rate (WLR)] to elucidate the magnitude and form of plastic responses in the dung beetle, Scarabaeus spretus. Results showed that short- and longer-term temperature variation generally have significant effects on SMR and WLR. Overall, acclimation to increased temperature led to a decline in SMR (from 0.071+/-0.004 ml CO(2) h(-1) in 15 degrees C acclimated beetles to 0.039+/-0.004 ml CO(2) h(-1) in 25 degrees C-acclimated beetles measured at 20 degrees C) modulated by reduced DGE frequency (15 degrees C acclimation: 0.554+/-0.027 mHz, 20 degrees C acclimation: 0.257+/-0.030 mHz, 25 degrees C acclimation: 0.208+/-0.027 mHz recorded at 20 degrees C), reduced cuticular WLRs (from 1.058+/-0.537 mg h(-1) in 15 degrees C-acclimated beetles to 0.900+/-0.400 mg h(-1) in 25 degrees C-acclimated beetles measured at 20 degrees C) and reduced total WLR (from 4.2+/-0.5 mg h(-1) in 15 degrees C-acclimated beetles to 3.1+/-0.5 mg h(-1) in 25 degrees C-acclimated beetles measured at 25 degrees C). Respiratory WLR was reduced from 2.25+/-0.40 mg h(-1) in 15 degrees C acclimated beetles to 1.60+/-0.40 mg h(-1) in 25 degrees C-acclimated beetles measured at 25 degrees C, suggesting conservation of water during DGE bursts. Overall, this suggests water conservation is a priority for S. spretus exposed to longer-term temperature variation, rather than elevation of SMR in response to low temperature acclimation, as might be expected from a beetle living in a relatively warm, low rainfall summer region. These results are significant for understanding the evolution of gas exchange patterns and trade-offs between metabolic rate and water balance in insects and other terrestrial arthropods. PMID- 20709923 TI - The last piece in the cellulase puzzle: the characterisation of beta-glucosidase from the herbivorous gecarcinid land crab Gecarcoidea natalis. AB - A 160 kDa enzyme with beta-glucosidase activity was purified from the midgut gland of the land crab Gecarcoidea natalis. The enzyme was capable of releasing glucose progressively from cellobiose, cellotriose or cellotetraose. Although beta-glucosidases (EC 3.2.1.21) have some activity towards substrates longer than cellobiose, the enzyme was classified as a glucohydrolase (EC 3.2.1.74) as it had a preference for larger substrates (cellobiose=89%) and two minor metabolites (totaling <=11%). Similarly to GLP-1, liraglutide was cleaved in vitro by DPP-IV in the Ala8-Glu9 position of the N terminus and degraded by NEP into several metabolites. The chromatographic retention time of DPP-IV-truncated liraglutide correlated well with the primary human plasma metabolite [GLP-1(9-37)], and some of the NEP degradation products eluted very close to both plasma metabolites. Three minor metabolites totaling 6 and 5% of the administered radioactivity were excreted in urine and feces, respectively, but no liraglutide was detected. In conclusion, liraglutide is metabolized in vitro by DPP-IV and NEP in a manner similar to that of native GLP-1, although at a much slower rate. The metabolite profiles suggest that both DPP-IV and NEP are also involved in the in vivo degradation of liraglutide. The lack of intact liraglutide excreted in urine and feces and the low levels of metabolites in plasma indicate that liraglutide is completely degraded within the body. PMID- 20709940 TI - Myeloid cells are tunable by a polyanionic polysaccharide derivative and co determine host rescue from lethal virus infection. AB - Insight into molecular and cellular mechanisms of innate immunity is critical to understand viral pathogenesis and immunopathology and might be exploited for therapy. Whereas the molecular mechanisms of the IFN defense are well established, cellular mechanisms of antiviral immunity are only emerging, and their pharmacological triggering remains unknown. COAM is a polysaccharide derivative with antiviral activity but without comprehension about its mechanism of action. The COAM mixture was fractionated, and prophylactic treatment of mice with COAM polymers of high MW resulted in a conversion from 100% lethal mengovirus infection to an overall survival rate of 93% without obvious clinical sequelae. Differential and quantitative analysis of peritoneal leukocytes demonstrated that COAM induced a profound influx of neutrophils. Selective cell depletion experiments pointed toward neutrophils and macrophages as key effector cells in the rescue of mice from lethal mengovirus. COAM was able to induce mRNA and protein expression of the mouse neutrophil chemokine GCP-2. Binding of GCP-2 to COAM was demonstrated in solution and confirmed by SPR technology. Although COAM was not chemotactic for neutrophils, COAM-anchored muGCP-2 retained chemotactic activity for human and mouse neutrophils. In conclusion, this study established that COAM rescued mice from acute and lethal mengovirus infection by recruiting antiviral leukocytes to the site of infection, as proposed through the induction, binding, and concentration of endogenous chemokines. These findings reinforce the role of neutrophils and macrophages as critical cells that can be manipulated toward antiviral defense. PMID- 20709941 TI - B cell receptor triggering sensitizes human B cells to TRAIL-induced apoptosis. AB - TRAIL is known to cause death in tumor cells, but physiological regulation of its activity remains poorly characterized. We demonstrate that BCR triggering sensitizes transformed centroblast-like BL cells and peripheral blood memory B cells to TRAIL-mediated apoptosis. The sensitization correlated with surface down regulation and intracellular retention of TRAIL-R4, along with changes in the expression of several Bcl-2 protein family members. Although enhancing FAS mediated cell death, CD40 activation protected B cells from TRAIL-induced apoptosis. Combination of Ig cross-linking with CD40 ligation did not prevent TRAIL-R4 down-regulation but induced changes in the mitochondria-regulated pathway of apoptosis that are known to be associated with resistance to TRAIL. Human CD5(+) B cells, presumably stimulated by reactivity to self without immunological help, exhibited very high ex vivo sensitivity to TRAIL. Our results define the first B-lymphocyte-specific physiological signal that increases cellular sensitivity to TRAIL. This may be important for our understanding of TRAIL involvement in the control of B cell responses and aid in designing TRAIL based therapies for B cell lymphomas. PMID- 20709942 TI - Prevalence comparison of accompanying lesions between primary and recurrent anterior dislocation in the shoulder. AB - BACKGROUND: Many authors have reported the presence of intra-articular lesions after primary dislocation of the shoulder joint. However, few studies have focused on their prevalence or the differences in accompanying lesions between primary and recurrent dislocations of the shoulder joint. PURPOSE: This study was undertaken to investigate and analyze accompanying lesions, including types of anteroinferior labrum injuries, using diagnostic arthroscopy and magnetic resonance arthrography (MRA) in 144 patients with traumatic anterior dislocation of the shoulder joint. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: There were 33 patients with 33 dislocations in the primary dislocation group and 111 patients with 111 dislocations in the recurrent dislocation group. Preoperative magnetic resonance arthrography and diagnostic arthroscopy were performed on all patients. RESULTS: In the primary dislocation group, 8 Bankart lesions, 9 free anterior labrum periosteal sleeve avulsion (ALPSA) lesions, 4 bony Bankart lesions, and 1 adhesive ALPSA lesion were observed. In the recurrent dislocation group, 68 Bankart lesions, 11 free ALPSA lesions, 13 bony Bankart lesions, 16 adhesive ALPSA lesions, and 1 glenoid articular rim disruption lesion were found. There were 22 (66.6%) and 109 (98.1%) patients with lesions in the anteroinferior labrum in the primary and recurrent groups, respectively. There was a statistically significant difference between the 2 groups (P = .002). Also, there was a significant difference between the 2 groups in the prevalence of the Hill-Sachs lesion and inverted pear-shaped glenoid lesion (P = .008/P = .047). Inverted pear-shaped glenoids were observed in 15 patients in the recurrent group. In 139 of 144 patients, surgical findings of accompanying lesions coincided with magnetic resonance arthrography findings (96.5%). CONCLUSION: Various forms of anteroinferior labral lesions were seen in patients with traumatic anterior dislocation of shoulder. The recurrent dislocation group showed a significantly higher prevalence of anteroinferior labral lesions and bony lesions in comparison with the primary group. In our study, magnetic resonance arthrography was an accurate method to assess accompanying lesions in first-time and recurrent anterior dislocation of the shoulder, suggesting that this may be a useful tool for determining a treatment method. PMID- 20709943 TI - Revision anterior cruciate ligament reconstruction. AB - Revision reconstruction of the anterior cruciate ligament (ACL) introduces several diagnostic and technical challenges in comparison with primary ACL reconstruction. With the increasing numbers of original reconstructions combined with the continued expectation of high-level athletic participation, revision ACL reconstruction is likely to become more frequent. The purpose of this article was to summarize the causes of failure and the evaluation of the patient with recurrent instability. A review of the literature regarding results after revision ACL reconstruction was performed to assist in the decision-making process and patient counseling. Good results can be obtained in terms of functional stability after revision reconstruction, but chondral and meniscal injury as well as unrecognized associated pathologic instability may play a role in diminished outcomes. In addition, a wide variety of surgical techniques are reviewed to address problems associated with tunnel malposition, widening, and pre-existing hardware. PMID- 20709944 TI - Predictors of activity level 2 years after anterior cruciate ligament reconstruction (ACLR): a Multicenter Orthopaedic Outcomes Network (MOON) ACLR cohort study. AB - OBJECTIVE: The study was conducted to quantify activity level 2 years after anterior cruciate ligament reconstruction and identify explanatory variables measured at baseline (demographics, concomitant meniscal/articular cartilage injuries and their treatment) associated with activity level at short-term follow up (2 years). STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: In 2002, the Multicenter Orthopaedic Outcomes Network (MOON) consortium began enrolling patients undergoing anterior cruciate ligament reconstruction at 6 recruitment sites. The current study reports 2-year follow-up of patients enrolled in 2002. Participants completed a series of validated, patient-oriented questionnaires that included activity level assessment. Measurement of intra-articular pathology, techniques of anterior cruciate ligament reconstruction, and secondary procedures were recorded at baseline by participating surgeons. Multivariable proportional odds ordinal logistic regression was used to assess predictors of activity level after adjusting for baseline patient characteristics. Interquartile range (IQR) odds ratios (ORs) are given for continuous variables. The fitted model that used ORs to specify predicted probabilities of exceeding any activity level was translated into predicted mean activity level. RESULTS: Of the 446 patients who underwent unilateral anterior cruciate ligament reconstruction, follow-up was obtained on 393 (88%). Male patients comprise 56% of the cohort, with a median age of 23 years. The median and IQR International Knee Documentation Committee subjective score was 53 (range, 40-65) preoperatively and increased to 84 (range, 74-92) 2 years postoperatively. Median and IQR activity level was 12 (range, 8-16) at baseline, and declined to 9 (range, 3-13) at follow-up. The proportion of participants returning to the same or higher level of activity 2 years after anterior cruciate ligament reconstruction was 45%. After controlling for other baseline factors such as age, marital and student status, contralateral knee status, sport and competition level, and articular cartilage/meniscal injuries, factors associated with higher activity levels at 2 years were higher baseline activity (IQROR = 3.84; 95% confidence interval [CI], 1.98-7.43; P < .0001) and lower baseline body mass index (IQROR = 1.37; 95% CI, 1.04-1.82; P = .027). The following baseline factors were associated with lower activity: female sex (OR = 0.60; 95% CI, 0.39-0.91; P = .015), smoking within 6 months prior to surgery (OR = 0.55; 95% CI, 0.33-0.92; P = 0.023), and revision anterior cruciate ligament reconstruction (OR = 0.41; 95% CI, 0.20-0.83; P = .014). Factors presumably related to functional status of the knee such as the condition of the articular cartilage and menisci, as well as normalcy of the contralateral knee, were not predictive of activity level at 2 years. CONCLUSION: (1) Evaluation of posttreatment activity levels should control for patients' preoperative activity because this is a strong predictor of future activity. (2) Assuming physical activity is an important component of a healthy person, investigation of potential interventions to improve future activity could target modifiable exposures such as weight. (3) Further evaluation is needed to explore the association of sex and revision surgery on activity level following anterior cruciate ligament reconstruction. PMID- 20709945 TI - Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis. AB - The histone variant H2A.Z has been implicated in the regulation of gene expression, and in plants antagonizes DNA methylation. Here, we ask whether a similar relationship exists in mammals, using a mouse B-cell lymphoma model, where chromatin states can be monitored during tumorigenesis. Using native chromatin immunoprecipitation with microarray hybridization (ChIP-chip), we found a progressive depletion of H2A.Z around transcriptional start sites (TSSs) during MYC-induced transformation of pre-B cells and, subsequently, during lymphomagenesis. In addition, we found that H2A.Z and DNA methylation are generally anticorrelated around TSSs in both wild-type and MYC-transformed cells, as expected for the opposite effects of these chromatin features on promoter competence. Depletion of H2A.Z over TSSs both in cells that are induced to proliferate and in cells that are developing into a tumor suggests that progressive loss of H2A.Z during tumorigenesis results from the advancing disease state. These changes were accompanied by increases in chromatin salt solubility. Surprisingly, ~30% of all genes showed a redistribution of H2A.Z from around TSSs to bodies of active genes during the transition from MYC-transformed to tumor cells, with DNA methylation lost from gene bodies where H2A.Z levels increased. No such redistributions were observed during MYC-induced transformation of wild type pre-B cells. The documented role of H2A.Z in regulating transcription suggests that 30% of genes have the potential to be aberrantly expressed during tumorigenesis. Our results imply that antagonism between H2A.Z deposition and DNA methylation is a conserved feature of eukaryotic genes, and that transcription coupled H2A.Z changes may play a role in cancer initiation and progression. PMID- 20709946 TI - Interventions with family caregivers of cancer patients: meta-analysis of randomized trials. AB - Family caregivers of cancer patients receive little preparation, information, or support to perform their caregiving role. However, their psychosocial needs must be addressed so they can maintain their own health and provide the best possible care to the patient. The purpose of this article is to analyze the types of interventions offered to family caregivers of cancer patients, and to determine the effect of these interventions on various caregiver outcomes. Meta-analysis was used to analyze data obtained from 29 randomized clinical trials published from 1983 through March 2009. Three types of interventions were offered to caregivers: psychoeducational, skills training, and therapeutic counseling. Most interventions were delivered jointly to patients and caregivers, but they varied considerably with regard to dose and duration. The majority of caregivers were female (64%) and Caucasian (84%), and ranged in age from 18 to 92 years (mean age, 55 years). Meta-analysis indicated that although these interventions had small to medium effects, they significantly reduced caregiver burden, improved caregivers' ability to cope, increased their self-efficacy, and improved aspects of their quality of life. Various intervention characteristics were also examined as potential moderators. Clinicians need to deliver research-tested interventions to help caregivers and patients cope effectively and maintain their quality of life. PMID- 20709948 TI - The novel activated microglia/macrophage WAP domain protein, AMWAP, acts as a counter-regulator of proinflammatory response. AB - Microgliosis is a common phenomenon in neurodegenerative disorders, including retinal dystrophies. To identify candidate genes involved in microglial activation, we used DNA-microarray analysis of retinal microglia from wild-type and retinoschisin-deficient (Rs1h(-/Y)) mice, a prototypic model for inherited retinal degeneration. Thereby, we cloned a novel 76 aa protein encoding a microglia/macrophage-restricted whey acidic protein (WAP) termed activated microglia/macrophage WAP domain protein (AMWAP). The gene consists of three exons and is located on mouse chromosome 11 in proximity to a chemokine gene cluster. mRNA expression of AMWAP was detected in microglia from Rs1h(-/Y) retinas, brain microglia, and other tissue macrophages. AMWAP transcription was rapidly induced in BV-2 microglia upon stimulation with multiple TLR ligands and IFN-gamma. The TLR-dependent expression of AMWAP was dependent on NF-kappaB, whereas its microglia/macrophage-specific transcription was regulated by PU.1. Functional characterization showed that AMWAP overexpression reduced the proinflammatory cytokines IL-6 and IL-1beta and concomitantly increased expression of the alternative activation markers arginase 1 and Cd206. Conversely, small interfering RNA knockdown of AMWAP lead to higher IL-6, IL-1beta, and Ccl2 transcript levels, whereas diminishing arginase 1 and Cd206 expression. Moreover, AMWAP expressing cells had less migratory capacity and showed increased adhesion in a trypsin-protection assay indicating antiserine protease activity. In agreement with findings from other WAP proteins, micromolar concentrations of recombinant AMWAP exhibited significant growth inhibitory activity against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis. Taken together, we propose that AMWAP is a counter-regulator of proinflammatory microglia/macrophage activation and a potential modulator of innate immunity in neurodegeneration. PMID- 20709947 TI - APCs expressing high levels of programmed death ligand 2 sustain the development of CD4 T cell memory. AB - The role APCs play in the transition of T cells from effector to memory remains largely undefined. This is likely due to the low frequency at which long-lived T cells arise, which hinders analysis of the events involved in memory development. In this study, we used TCR transgenic T cells to increase the frequency of long lived T cells and developed a transfer model suitable for defining the contribution of APCs to the development of CD4 T cell memory. Accordingly, naive TCR transgenic T cells were stimulated in vitro with Ag presented by different types of APCs and transferred into MHC class II-deficient mice for parking, and the hosts were later analyzed for long-lived T cell frequency or challenged with suboptimal dose of Ag, and the long-lived cells-driven memory responses were measured. The findings indicate that B cells and CD8alpha(+) dendritic cells sustained elevated frequencies of long-lived T cells that yielded rapid and robust memory responses upon rechallenge with suboptimal dose of Ag. Furthermore, both types of APCs had significant programmed death (PD) ligand 2 expression prior to Ag stimulation, which was maintained at a high level during presentation of Ag to T cells. Blockade of PD ligand 2 interaction with its receptor PD-1 nullified the development of memory responses. These previously unrecognized findings suggest that targeting specific APCs for Ag presentation during vaccination could prove effective against microbial infections. PMID- 20709949 TI - Neisseria lactamica selectively induces mitogenic proliferation of the naive B cell pool via cell surface Ig. AB - Neisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen Neisseria meningitidis, there is an absence of adaptive cell-mediated immunity to N. lactamica during the peak age of carriage. Instead, outer membrane vesicles derived from N. lactamica mediate a B cell dependent proliferative response in mucosal mononuclear cells that is associated with the production of polyclonal IgM. We demonstrate in this study that this is a mitogenic human B cell response that occurs independently of T cell help and any other accessory cell population. The ability to drive B cell proliferation is a highly conserved property and is present in N. lactamica strains derived from diverse clonal complexes. CFSE staining of purified human tonsillar B cells demonstrated that naive IgD(+) and CD27(-) B cells are selectively induced to proliferate by outer membrane vesicles, including the innate CD5(+) subset. Neither purified lipooligosaccharide nor PorB from N. lactamica is likely to be responsible for this activity. Prior treatment of B cells with pronase to remove cell-surface Ig or treatment with BCR-specific Abs abrogated the proliferative response to N. lactamica outer membrane vesicles, suggesting that this mitogenic response is dependent upon the BCR. PMID- 20709950 TI - A complementary role for the tetraspanins CD37 and Tssc6 in cellular immunity. AB - The cooperative nature of tetraspanin-tetraspanin interactions in membrane organization suggests functional overlap is likely to be important in tetraspanin biology. Previous functional studies of the tetraspanins CD37 and Tssc6 in the immune system found that both CD37 and Tssc6 regulate T cell proliferative responses in vitro. CD37(-/-) mice also displayed a hyper-stimulatory dendritic cell phenotype and dysregulated humoral responses. In this study, we characterize "double knockout" mice (CD37(-/-)Tssc6(-/-)) generated to investigate functional overlap between these tetraspanins. Strong evidence for a cooperative role for these two proteins was identified in cellular immunity, where both in vitro T cell proliferative responses and dendritic cell stimulation capacity are significantly exaggerated in CD37(-/-)Tssc6(-/-) mice when compared with single knockout counterparts. Despite these exaggerated cellular responses in vitro, CD37(-/-)Tssc6(-/-) mice are not more susceptible to autoimmune induction. However, in vivo responses to pathogens appear poor in CD37(-/-)Tssc6(-/-) mice, which showed a reduced ability to produce influenza-specific T cells and displayed a rapid onset hyper-parasitemia when infected with Plasmodium yoelii. Therefore, in the absence of both CD37 and Tssc6, immune function is further altered when compared with CD37(-/-) or Tssc6(-/-) mice, demonstrating a complementary role for these two molecules in cellular immunity. PMID- 20709951 TI - Alport alloantibodies but not Goodpasture autoantibodies induce murine glomerulonephritis: protection by quinary crosslinks locking cryptic alpha3(IV) collagen autoepitopes in vivo. AB - The noncollagenous (NC1) domains of alpha3alpha4alpha5(IV) collagen in the glomerular basement membrane (GBM) are targets of Goodpasture autoantibodies or Alport posttransplant nephritis alloantibodies mediating rapidly progressive glomerulonephritis. Because the autoepitopes but not the alloepitopes become cryptic upon assembly of alpha3alpha4alpha5NC1 hexamers, we investigated how the accessibility of B cell epitopes in vivo influences the development of glomerulonephritis in mice passively immunized with human anti-GBM Abs. Alport alloantibodies, which bound to native murine alpha3alpha4alpha5NC1 hexamers in vitro, deposited linearly along the mouse GBM in vivo, eliciting crescentic glomerulonephritis in Fcgr2b(-/-) mice susceptible to Ab-mediated inflammation. Goodpasture autoantibodies, which bound to murine alpha3NC1 monomer and dimer subunits but not to native alpha3alpha4alpha5NC1 hexamers in vitro, neither bound to the mouse GBM in vivo nor induced experimental glomerulonephritis. This was due to quinary NC1 crosslinks, recently identified as sulfilimine bonds, which comprehensively locked the cryptic Goodpasture autoepitopes in the mouse GBM. In contrast, non-crosslinked alpha3NC1 subunits were identified as a native target of Goodpasture autoantibodies in the GBM of squirrel monkeys, a species susceptible to Goodpasture autoantibody-mediated nephritis. Thus, crypticity of B cell autoepitopes in tissues uncouples potentially pathogenic autoantibodies from autoimmune disease. Crosslinking of alpha3alpha4alpha5NC1 hexamers represents a novel mechanism averting autoantibody binding and subsequent tissue injury by posttranslational modifications of an autoantigen. PMID- 20709952 TI - The MAPK/ERK and PI3K pathways additively coordinate the transcription of recombination-activating genes in B lineage cells. AB - Rag-1 and Rag-2 are essential for the construction of the BCR repertoire. Regulation of Rag gene expression is tightly linked with BCR expression and signaling during B cell development. Earlier studies have shown a major role of the PI(3)K/Akt pathway in regulating the transcription of Rag genes. In this study, by using the 38c13 murine B cell lymphoma we show that transcription of Rag genes is also regulated by the MEK/ERK pathways, and that both pathways additively coordinate in this regulation. The additive effect is observed for both ligand-dependent (upon BCR ligation) and ligand independent (tonic) signals. However, whereas the PI(3)K/Akt regulation of Rag transcription is mediated by Foxo1, we show in this study that the MEK/ERK pathway coordinates with the regulation of Rag by controlling the phosphorylation and turnover of E47 and its consequential binding to the Rag enhancer regions. Our results suggest that the PI(3)K and MEK/ERK pathways additively coordinate in the regulation of Rag transcription in an independent manner. PMID- 20709954 TI - Kit ligand and Il7 differentially regulate Peyer's patch and lymph node development. AB - Hematopoietic lymphoid tissue inducer (LTi) cells initiate lymph node (LN) and Peyer's patch (PP) development during fetal life by inducing the differentiation of mesenchymal organizer cells. The growth factor signals underlying LTi cell development and LN and PP organogenesis remain poorly understood. LTi cells express the Il7r and the receptor tyrosine kinase Kit, whereas organizer cells express their cognate ligands. To determine the relative significance of Il7 and Kit signaling in LTi cell homeostasis and PP and LN development, we have analyzed mice deficient for Kit (Kit(W/Wv)), Il7 (Il7(-/-)), or both (Il7(-/-) Kit(W/Wv)). Unlike Kit(W/Wv) and Il7(-/-) single mutants, Il7(-/-) Kit(W/Wv) mice were almost devoid of LTi cells in their mesenteric LN anlage. This LTi deficiency was associated with a block in mesenchymal LN organizer cell generation and the absence of almost all LNs. In contrast, intestinal LTi cell numbers, PP organizer cell generation, and PP development were strongly affected by impaired Kit signaling, but were independent of Il7. Hence, Kit and Il7 act synergistically in LN organogenesis, whereas Kit signaling, but not Il7, critically regulates PP organogenesis and LTi cell numbers in the intestine. Consistent with these differential growth factor requirements for PP and LN development, PP organizer cells expressed higher Kitl and lower Il7 levels than did LN organizer cells. Collectively, these results demonstrate that Kit and Il7 differentially control PP and LN organogenesis through the local growth factor-driven regulation of LTi cell numbers. PMID- 20709953 TI - Position-dependent silencing of germline Vbeta segments on TCRbeta alleles containing preassembled VbetaDJbetaCbeta1 genes. AB - The genomic organization of TCRbeta loci enables Vbeta-to-DJbeta2 rearrangements on alleles with assembled VbetaDJbetaCbeta1 genes, which could have deleterious physiologic consequences. To determine whether such Vbeta rearrangements occur and, if so, how they might be regulated, we analyzed mice with TCRbeta alleles containing preassembled functional VbetaDJbetaCbeta1 genes. Vbeta10 segments were transcribed, rearranged, and expressed in thymocytes when located immediately upstream of a Vbeta1DJbetaCbeta1 gene, but not on alleles with a Vbeta14DJbetaCbeta1 gene. Germline Vbeta10 transcription was silenced in mature alphabeta T cells. This allele-dependent and developmental stage-specific silencing of Vbeta10 correlated with increased CpG methylation and decreased histone acetylation over the Vbeta10 promoter and coding region. Transcription, rearrangement, and expression of the Vbeta4 and Vbeta16 segments located upstream of Vbeta10 were silenced on alleles containing either VbetaDJbetaCbeta1 gene; sequences within Vbeta4, Vbeta16, and the Vbeta4/Vbeta16-Vbeta10 intergenic region exhibited constitutive high CpG methylation and low histone acetylation. Collectively, our data indicate that the position of Vbeta segments relative to assembled VbetaDJbetaCbeta1 genes influences their rearrangement and suggest that DNA sequences between Vbeta segments may form boundaries between active and inactive Vbeta chromatin domains upstream of VbetaDJbetaCbeta genes. PMID- 20709955 TI - Eye mucosa: an efficient vaccine delivery route for inducing protective immunity. AB - The external part of the eye shares mucosa-associated common characteristics and is an obvious entry site for foreign Ags. We assessed the potential of eyedrop vaccination for effective delivery of vaccines against viral or bacterial infection in mice. Both OVA-specific IgG Ab in serum and IgA Ab in mucosal compartments were induced by eyedrops of OVA with cholera toxin (CT). Eyedrop vaccination of influenza A/PR/8 virus (H1N1) induced both influenza virus specific systemic and mucosal Ab responses and protected mice completely against respiratory infection with influenza A/PR/8 virus. In addition, eyedrop vaccination of attenuated Salmonella vaccine strains induced LPS-specific Ab and complete protection against oral challenge of virulent Salmonella. Unlike with the intranasal route, eyedrop vaccinations did not redirect administered Ag into the CNS in the presence of CT. When mice were vaccinated by eyedrop, even after the occlusion of tear drainage from eye to nose, Ag-specific systemic IgG and mucosal IgA Abs could be induced effectively. Of note, eyedrops with OVA plus CT induced organogenesis of conjunctiva-associated lymphoid tissue and increased microfold cell-like cells on the conjunctiva-associated lymphoid tissue in the nictitating membrane on conjunctiva, the mucosal side of the external eye. On the basis of these findings, we propose that the eyedrop route is an alternative to mucosal routes for administering vaccines. PMID- 20709956 TI - Activation of macrophages by P2X7-induced microvesicles from myeloid cells is mediated by phospholipids and is partially dependent on TLR4. AB - ATP-mediated activation of the purinergic receptor P2X(7) elicits morphological changes and proinflammatory responses in macrophages. These changes include rapid shedding of microvesicles (MV) and the nonconventional secretion of cytokines, such as IL-1beta and IL-18 following priming. In this study, we demonstrate the activation potential of P2X(7)-induced MV isolated from nonprimed murine macrophages. Cotreatment of nonprimed macrophages with ATP and calcium ionophore induced a rapid release of MV that were predominantly 0.5-1 microm in size. Exposure of primary murine bone marrow-derived macrophages to these MV resulted in costimulatory receptor upregulation and TNF-alpha secretion. Cell homogenates or supernatants cleared of MV did not activate macrophages. MV-mediated activation was p38 MAPK and NF-kappaB dependent, and partially dependent on TLR4 activity, but was high-mobility group box 1 independent. Biochemical fractionation of the MV demonstrated that the phospholipid fraction, not the protein fraction, mediated macrophage activation through a TLR4-dependent process. P2X(7) activation is known to induce calcium-independent phospholipase A(2), calcium-dependent phospholipase A(2), and phospholipase D activities, but inhibition of these enzymes did not inhibit MV generation or shedding. However, blocking phospholipase D activity resulted in release of MV incapable of activating recipient macrophages. These data demonstrate a novel mechanism of macrophage activation resulting from exposure to MV from nonprimed macrophages, and identifies phospholipids in these MV as the biologically active component. We suggest that phospholipids delivered by MV may be mediators of sterile inflammation in a number of diseases. PMID- 20709957 TI - Trans- but not cis-resveratrol impairs angiotensin-II-mediated vascular inflammation through inhibition of NF-kappaB activation and peroxisome proliferator-activated receptor-gamma upregulation. AB - Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1alpha. In an in vitro flow chamber system, t-RESV (1-10 microM) undermined the adhesion of human leukocytes under physiological flow to Ang-II-activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-kappaB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-gamma in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-gamma also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease. PMID- 20709958 TI - Patterning by heritage in mouse molar row development. AB - It is known from paleontology studies that two premolars have been lost during mouse evolution. During mouse mandible development, two bud-like structures transiently form that may represent rudimentary precursors of the lost premolars. However, the interpretation of these structures and their significance for mouse molar development are highly controversial because of a lack of molecular data. Here, we searched for typical tooth signaling centers in these two bud-like structures, and followed their fate using molecular markers, 3D reconstructions, and lineage tracing in vitro. Transient signaling centers were indeed found to be located at the tips of both the anterior and posterior rudimentary buds. These centers expressed a similar set of molecular markers as the "primary enamel knot" (pEK), the signaling center of the first molar (M1). These two transient signaling centers were sequentially patterned before and anterior to the M1 pEK. We also determined the dynamics of the M1 pEK, which, slightly later during development, spread up to the field formerly occupied by the posterior transient signaling center. It can be concluded that two rudimentary tooth buds initiate the sequential development of the mouse molars and these have previously been mistaken for early stages of M1 development. Although neither rudiment progresses to form an adult tooth, the posterior one merges with the adjacent M1, which may explain the anterior enlargement of the M1 during mouse family evolution. This study highlights how rudiments of lost structures can stay integrated and participate in morphogenesis of functional organs and help in understanding their evolution, as Darwin suspected long ago. PMID- 20709959 TI - Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire. AB - The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability. PMID- 20709960 TI - RNA silencing amplification in plants: size matters. PMID- 20709961 TI - Preferences and perceived involvement in treatment decision making among Chinese patients with chronic hepatitis. AB - OBJECTIVES: The objectives of this study were to measure the preferences for and perceived involvement in treatment decision making among Chinese patients with chronic hepatitis and to explore the factors that may influence patients' preferences. The study also aimed to analyze patients' satisfaction with decision and information provision and their relationships with the decisional role. METHODS: Semistructured interviews were performed with 178 chronic hepatitis patients. The Control Preferences Scale was translated into Chinese from English and adopted to measure patients' preferred and perceived decisional role. Patients' satisfaction with decision and information provision was also investigated by a 5-point Likert-type scale. RESULTS: Patients with chronic hepatitis in the study generally preferred a collaborative role (45%) or passive role (44%); only 11% of patients preferred an active role in treatment decision making. The agreement between patients' perceived and preferred role was not perfect (Bowker's S = 33.8, P < 0.001). Age and education level were significantly associated with patients' preferences: Younger, better educated patients tended to prefer more active roles. A total of 54% of patients felt satisfied with treatment decisions, whereas 39% of patients felt satisfied with information provision. Patients' levels of satisfaction with their treatment decisions were correlated not only with the perceived role itself but also with its agreement with the preferred role. Patients' satisfaction with information provision was significantly correlated with patients' preferred role. Moreover, there was a significant correlation between patients' satisfaction with the treatment decision and information provision. CONCLUSIONS: Patients' preferences for participation in treatment decision making should be considered seriously by doctors during the encounter. Health providers should make a greater effort to improve doctor-patient communication and decrease the mismatch between patients' perceived and preferred decisional role. PMID- 20709962 TI - Berberine: a multipotent remedy with unknown cellular target? PMID- 20709963 TI - Forty years of monensin for the control of coccidiosis in poultry. AB - In July 1971, the polyether ionophorous antibiotic monensin was introduced in the United States for the control of coccidiosis in poultry. At that time, prospects for new anticoccidial agents were not good. Amprolium had enjoyed several years of use, but many other compounds had been abandoned as resistance to them developed. After the introduction of monensin, most commercial broilers were medicated with the drug and it is still widely used for this purpose today. Apart from in poultry, monensin is also used to control coccidiosis in game birds, sheep, and cattle. Indeed, more animals have been medicated with ionophores, such as monensin, for control of disease than any other medicinal agents in the history of veterinary medicine. In this review, we discuss the discovery, mode of action, and efficacy of monensin, together with matters of importance to the poultry industry such as commercial use, drug resistance, toxicity, pharmacology and residues, host immunity to coccidiosis, and effects in other avian species. PMID- 20709964 TI - Ammonia emissions from broiler production in the San Joaquin Valley. AB - Ammonia is the primary basic gas in the atmosphere and has the most important role in the neutralization of atmospheric acids generated by fossil fuel combustion. The reaction product forms a NH(4)(+) aerosol, which is a major component of atmospheric particulates. These NH(4)(+) particulates are part of atmospheric haze and may be transported long distances from the production site before returning to the surface by dry deposition or scavenged by precipitation. Animal production produces a significant component of anthropogenic NH(3) emissions and the National Academy of Sciences concluded that NH(3) emissions estimates from animal feeding operations have not been characterized sufficiently, leading the US Environmental Protection Agency to institute studies in the United States to obtain NH(3) emissions from animal feeding operations under the US Environmental Protection Agency Air Consent Agreement. The objective of this study is to obtain additional broiler NH(3) emissions estimates using a backward Lagrangian stochastic technique. This technique uses NH(3) concentrations measured upwind and downwind of the farm, wind observations, and atmospheric dispersion model calculations to obtain whole-farm emissions. Ammonia emissions were low at bird placement and increased steadily after about the third week of growth. At the end of the flock (47 d, ~297,000 birds), cumulative emissions for the flock cycle period were 0.016 kg of NH(3).bird(-1).flock(-1). Between-flock emissions, including bird harvest, cleanout, temporary storage of litter outside of the buildings, and downtime (buildings closed), added another 0.003 kg of NH(3).bird(-1).flock(-1). Emissions from this broiler farm were less than from some eastern US broiler farms but were comparable to broiler farms in Europe. Based on the results of this study and a similar winter study at this same farm, total flock wintertime and summertime (flock cycle plus between-flock) NH(3) emissions from this farm represented 7.8 and 8.3% of feed N as NH(3)-N, respectively, or an annual average of 8.1%. PMID- 20709965 TI - Pulmonary vascular pressure profiles in broilers selected for susceptibility to pulmonary hypertension syndrome: age and sex comparisons. AB - Broilers that are susceptible to pulmonary hypertension syndrome (PHS, ascites) have an elevated pulmonary arterial pressure (PAP) when compared with PHS resistant broilers. Two distinctly different syndromes, pulmonary arterial hypertension and pulmonary venous hypertension (PVH), both are associated with increases in PAP. Pulmonary arterial hypertension occurs when the right ventricle must elevate the PAP to overcome increased resistance to flow through restrictive pulmonary arterioles upstream from the pulmonary capillaries. In contrast, PVH is commonly caused by increased downstream (postcapillary) resistance. The sites of resistance to pulmonary blood flow are deduced by making contemporaneous measurements of the PAP and the wedge pressure (WP) and calculating the transpulmonary pressure gradient (TPG) (TPG = PAP - WP). We obtained PAP and WP values from 8-, 12-, 16-, 20-, and 24-wk-old anesthetized male and female broilers from a PHS-susceptible line. Pressures were recorded as a catheter was advanced through a wing vein to the pulmonary artery and onward until the WP was obtained. In addition to sex and age comparisons of vascular pressure gradients, the data also were pooled to obtain 3 cohorts for broilers having the lowest PAP values (n = 52; range: 12 to 22.9 mmHg), intermediate PAP values (n = 63; range: 23 to 32.9 mmHg), and highest PAP values (n = 62; range: 33 to 62 mmHg) independent of age or sex. Within each of the age, sex, and PAP cohort comparisons, broilers with elevated PAP consistently exhibited the hemodynamic characteristics of pulmonary arterial hypertension (elevated PAP and TPG combined with a normal WP) and not PVH (elevated PAP and WP combined with a normal or reduced TPG). Susceptibility to PHS can be attributed primarily to pulmonary arterial hypertension associated with increased precapillary (arteriole) resistance. PMID- 20709966 TI - Identification of the heart-type fatty acid-binding protein as a major gene for chicken fatty acid metabolism by Bayesian network analysis. AB - Twenty genes involved in fatty acid metabolism were studied to reveal their effects on chicken fatness traits. To explore the interactions among these genes and evaluate their effects on fat accumulation in chickens, a Bayesian network of candidate genes in fatty acid metabolism and growth was constructed in terms of these genes' mRNA expression data derived from DNA microarray and the effects of these genes on fatness traits were analyzed. A full-sib family Beijing-You chicken population was raised and sampled for investigating the hepatic mRNA expression and measuring the fatness traits at 5 time points from 42 to 98 d. By using a Bayesian network toolbox, we obtained a Bayesian-directed acyclic network, which has 19 nodes and 28 edges. The results showed that the heart-type fatty acid-binding protein (H-FABP) was the hub of the network with connection to 7 other genes. The hepatic mRNA expression of H-FABP was significantly related to i.m. fat content (r = -0.44, P < 0.05) at 70 d of age. The results indicated that the H-FABP gene plays the most important role among these genes associated with fatty acid metabolism and affects i.m. fat content of chickens. PMID- 20709967 TI - Response to selection and genetic parameters of body and carcass weights in Japanese quail selected for 4-week body weight. AB - The current study was conducted to investigate the effect of short-term selection in Japanese quail for 4-wk BW and estimate genetic parameters of BW, carcass traits, and egg weight. A selected line and control line were randomly selected from a base population. In each generation, 39 sires and 78 dams were used as parents for the next generation. Data were collected over 2 consecutive hatches for 4 generations, and 1,554 records from 151 sires and 285 dams were used to estimate the genetic parameters. The genetic improvement of 4-wk BW was 9.6, 8.8, and 8.2 g in generations 2, 3, and 4, respectively. There was a significant effect of sex, generation, and line (P < 0.001). There was a significant difference for BW and carcass weights but not for carcass percentage components between sexes (P < 0.01). Females showed higher figures than males. The realized heritability for 4-wk BW was 0.55, reflecting the accuracy of selection. However the estimated heritability by using pedigree information was 0.26 +/- 0.05. The genetic correlation among BW and carcass traits was relatively high (ranging from 0.85 to 0.91). Inbreeding caused a decline in the mean for all of the traits, but its effect was only significant for 4-wk BW and carcass weight (P < 0.05). Selection for 4-wk BW improved feed conversion ratio 0.16 units over the selection period. Results showed there was a strong genetic correlation between 4 wk BW and carcass traits that suggests that early 4-wk BW can be used as a selection criterion to improve carcass traits. Also, intense selection resulting in high rates of inbreeding might result in decreased response to selection due to inbreeding depression. PMID- 20709968 TI - Estimation of heritability and breeding values for early egg production in laying hens from pooled data. AB - Under commercial conditions, data on egg production in laying hens are usually collected per cage rather than individually. In current breeding programs, genetic evaluations are, however, based on individually recorded egg production. Because commercial flocks are not maintained in single cages, this environmental difference between the breeding and commercial setting may result in a genotype x environment interaction. This study was aimed at estimating genetic parameters and predicting estimated breeding values for early egg production of laying hens by using pooled data (i.e., data from multiple bird cages) from pedigree birds housed in 4-bird cages. Using cage records, we compared 2 different methods of handling pooled data: cage sums and the assignment of cage means to individual birds, referred to as the approximate method. The 2 methods were compared by using cross-validation. Data from 3 purebred White Leghorn layer lines were used. Estimated heritability for early egg production was 0.36 when cage sums were used and 0.30 with the approximate method. The correlation of estimated breeding values between the cage sums method and the approximate method was 0.88. Cross validation showed that the use of cage sums led to better predictions of missing phenotypes compared with the approximate method. The results of the research demonstrate that pooled data can be used in the genetic evaluation of laying hens and show that using directly pooled records (e.g., cage sums) gives better results than assigning group means to the birds of the group, thus simulating individual records. PMID- 20709969 TI - A quantitative trait locus for a primary antibody response to keyhole limpet hemocyanin on chicken chromosome 14--confirmation and candidate gene approach. AB - A QTL involved in the primary antibody response toward keyhole limpet hemocyanin (KLH) was detected on chicken chromosome 14 in the experimental population, which was created by crossing commercial White Leghorn and a Polish native chicken breed (green-legged partridgelike). The current QTL location is a validation of previous experiments pointing to the same genomic location for the QTL linked to a primary antibody response to KLH. An experimental population was typed with microsatellite markers distributed over the chicken chromosome 14. Titers of antibodies binding KLH were measured for all individuals by ELISA. Statistical models applied in the Grid QTL Web-based software were used to analyze the data: a half-sib model, a line-cross model, and combined analysis in a linkage disequilibrium and linkage analysis model. Candidate genes that have been proposed were genotyped with SNP located in genes exons. Statistical analyses of single SNP associations were performed pointing out 2 SNP of an axis inhibitor protein (AXIN1) gene as significantly associated with the trait of an interest. PMID- 20709970 TI - Reduced variance of gene expression at numerous loci in a population of chickens selected for high feather pecking. AB - Changes in gene expression in response to selection were studied by comparing microarray expression profiles among a population of domestic chickens selected for high feather pecking (FP) with a control population and a population selected for low FP. No transcripts showed significant differences among populations with respect to mean expression scores, but numerous transcripts showed reduced variance in expression scores in the high FP population in comparison to control and low FP populations. The reduction in variance in the high FP population generally involved transcripts whose expression scores had a negatively skewed distribution in the control population but not in the high FP population. A certain number of these transcripts corresponded to genes whose expression was significantly associated with either severe FP (SFP) or gentle FP. The patterns of gene expression associated with SFP and gentle FP were distinct, suggesting that very distinct underlying neural mechanisms underlie these 2 behaviors, with SFP showing more signs of an association with synaptic plasticity and with an immunosuppressive stress response. PMID- 20709971 TI - Immune response of broiler chickens fed different levels of arginine and vitamin E to a coccidiosis vaccine and Eimeria challenge. AB - One-day-old broiler chicks (n = 300) were orally vaccinated (Coccivac-B) and divided into 6 groups to evaluate Arg at 3 levels of supplementation, 0, 0.3, or 0.6% [normal level (NARG), medium level (MARG), or high level (HARG), respectively], and 2 levels of vitamin E (VE), 40 or 80 IU/kg of feed (VE40 or VE80, respectively), in a factorial experiment. Birds were reared in floor pens with fresh pine shavings and provided a corn-soybean-based diet and water ad libitum. At d 14, all chickens were orally challenged with a mixture of Eimeria field isolates (Eimeria acervulina, Eimeria maxima, and Eimeria tenella). In vitro heterophil and monocyte oxidative burst (HOB and MOB, respectively) was measured at d 21 from cells isolated from peripheral blood. Antibody levels (IgG, IgM, and IgA isotypes, ELISA) and NO were measured at d 14 and 28. The HOB was lower in birds fed the VE40 diets but was increased with the MARG and HARG treatments, whereas birds fed the VE80 diet had a higher HOB irrespective of Arg level. Birds fed the VE80 diet had high levels of MOB, which was not further improved by Arg, whereas birds fed the VE40-MARG diet had the highest MOB response. Plasma NO was not affected by diet at d 14, but at d 28, plasma NO was higher in birds fed the VE80-MARG or the VE40-NARG diet and lower in birds fed the VE80-NARG or the VE40-MARG diet. Birds fed the VE40-HARG or VE80-MARG diet had the highest IgG levels at d 14, but at d 28, birds fed the VE80-MARG diet had the highest IgG levels. The IgM concentration was lower in birds fed NARG levels irrespective of VE levels at d 14, but at d 28, IgM levels were higher in birds fed the VE40-HARG or the VE80-MARG feed. The IgA concentration was not consistently affected at d 14 or 28. These results suggest that Arg and VE fed at levels higher than those recommended by the NRC may play complementary roles on the innate and humoral immune response against an Eimeria challenge, potentially improving vaccine efficacy and response to field infections. PMID- 20709972 TI - Effects of silymarin on gossypol toxicosis in divergent lines of chickens. AB - Gossypol, a pigment of cotton, is a hepatic toxin for chickens. Thus, despite its high protein content, inclusion of cottonseed meal in poultry diets is problematic. Silymarin, an extract from milk thistle, has hepatoprotective qualities and could potentially serve as a feed additive to offset the toxicity of gossypol. The objective of this study was to determine if silymarin could counteract gossypol toxicosis. Cockerels (n = 144) from lines divergently selected for humoral immunity were used. Three individuals from each line were randomly assigned to a cage and fed a corn-soybean meal (control) diet for 14 d. Six cages per line were then randomly assigned 1 of 4 dietary treatments (1,000 mg/kg of gossypol, 1,000 mg/kg of silymarin, 1,000 mg/kg of both gossypol and silymarin, or a control diet). Body weight and feed intake data were collected for 21 d, with chickens bled weekly to collect plasma and determine hematocrits. Chickens were then killed, and livers were collected for subsequent histology and enzymatic activity analyses. Endpoints measured weekly were analyzed with repeated measures and regression methodologies. Plasma and liver enzyme activities, and histological measures, were analyzed using ANOVA. No significant interactions between diets and lines were observed. Chickens assigned to the gossypol and gossypol-silymarin diets stopped gaining weight at d 14 (P < 0.001) and lost weight by d 21 (P < 0.001). Gamma glutamyltransferase was also elevated in these chickens at d 14; activities increased further by d 21 (P < 0.001). Histological examination of liver slices indicated substantial lipidosis (P < 0.001). Furthermore, quinone reductase activity was higher in gossypol- and gossypol-silymarin-treated chickens than in control and silymarin-treated chickens (P < 0.001). Silymarin did not alleviate any clinical effects of gossypol toxicosis. PMID- 20709973 TI - Evaluation of XPC and prototypes on aflatoxin-challenged broilers. AB - Various products and prototypes were added to poultry diets during an aflatoxin challenge on growth and histological parameters. Male broiler chicks were randomly assigned to 8 treatment groups with 8 replicates/treatment and 3 birds/replicate. Treatments were as follows: 1) negative control containing no aflatoxin (NC); 2) positive control containing aflatoxin (PC); 3) 0.1% glucomannan mycotoxin standard industry ameliorator (STD); 4) 0.1% prototype A, a proprietary mixture of a Saccharomyces cerevisiae product and diatomaceous clay; 5) 0.2% prototype A; 6) 0.15% prototype B, a proprietary mixture of a S. cerevisiae product and diatomaceous clay (PB); 7) 0.0625% XPC (S. cerevisiae fermentation product); and 8) 0.125% XPC (XPC2). All treatments except NC contained 2,280 +/- 102 ng/g of aflatoxin and were fed for 28 d. Body weight and feed intake were measured weekly. Livers were collected on d 28, weighed, and used for histopathological evaluation. Beginning weights were similar across treatments, but BW were lower (P /= 0.05) different among the treatment groups. Liver weights relative to BW were higher (P /= 0.05) compared with NC. Overall, BW gain in treatment groups PB and XPC2 was not different from NC and that corresponded to protective effects against liver lesions. Benefits observed during an aflatoxin challenge when broilers were supplemented with XPC, a fermentation product that does not contain any adsorbents, may be attributed to something other than adsorption as a primary mechanism. PMID- 20709974 TI - Analysis of gut immune-modulating activity of beta-1,4-mannobiose using microarray and real-time reverse transcription polymerase chain reaction. AB - beta-1,4-Mannobiose (MNB) supplementation has been shown to prevent Salmonella Enteritidis infection in broilers by improving Salmonella Enteritidis clearance and increasing IgA production. This study examined in detail the gut immunomodulatory activity of MNB using microarray and real-time quantitative PCR analysis. One-day-old chicks were orally administered 0.1% (wt/wt) MNB 3 times a week for 28 d. Control birds received vehicle alone. Body weights and fecal IgA levels were monitored weekly. On d 28, spleen and bursa of Fabricius were removed and weights were recorded; samples of ileum, jejunum, cecum, spleen, thymus, and bursa of Fabricius were collected for histological examination; and ileum samples were collected for RNA extraction. No significant difference in BW or organ weights was observed between MNB-treated and untreated control birds, and no histological abnormalities were observed in any of the tissues examined. The MNB treated chickens had significantly higher levels of fecal IgA over all 4 wk when compared with control birds. Microarray and reverse transcription PCR analysis revealed the upregulation of several genes involved in immune responses, including those involved in antigen recognition, processing and presentation (MHC class I and II), interferon-related genes, and genes involved in host defense. These results provide insight into the mechanism of action of dietary MNB in the intestine and confirm that MNB acts as a potent immune-modulating agent, exerting combined effects on the intestinal immune system. PMID- 20709975 TI - Heat stress impairs performance parameters, induces intestinal injury, and decreases macrophage activity in broiler chickens. AB - Studies on environmental consequences of stress on animal production have grown substantially in the last few years for economic and animal welfare reasons. Physiological, hormonal, and immunological deficits as well as increases in animals' susceptibility to diseases have been reported after different stressors in broiler chickens. The aim of the current experiment is to describe the effects of 2 different heat stressors (31 +/- 1 and 36 +/- 1 degrees C/10 h per d) applied to broiler chickens from d 35 to 42 of life on the corticosterone serum levels, performance parameters, intestinal histology, and peritoneal macrophage activity, correlating and discussing the obtained data under a neuroimmune perspective. In our study, we demonstrated that heat stress (31 +/- 1 and 36 +/- 1 degrees C) increased the corticosterone serum levels and decreased BW gain and food intake. Only chickens submitted to 36 +/- 1 degrees C, however, presented a decrease in feed conversion and increased mortality. We also showed a decrease of bursa of Fabricius (31 +/- 1 and 36 +/- 1 degrees C), thymus (36 +/- 1 degrees C), and spleen (36 +/- 1 degrees C) relative weights and of macrophage basal (31 +/- 1 and 36 +/- 1 degrees C) and Staphylococcus aureus-induced oxidative burst (31 +/- 1 degrees C). Finally, mild multifocal acute enteritis characterized by an increased presence of lymphocytes and plasmocytes within the jejunum's lamina propria was also observed. The stress-induced hypothalamic-pituitary-adrenal axis activation was taken as responsible for the negative effects observed on the chickens' performance and immune function and also the changes of the intestinal mucosa. The present obtained data corroborate with others in the field of neuroimmunomodulation and open new avenues for the improvement of broiler chicken welfare and production performance. PMID- 20709976 TI - Development and application of an indirect immunohistochemical method for the detection of duck plague virus vaccine antigens in paraffin sections and localization in the vaccinated duckling tissues. AB - The objective of the present study was to develop and apply a streptavidin alkaline phosphatase labeling system of indirect immunohistochemistry (SP-IHC) to detect antigenic distribution and localization regularity of duck plague virus (DPV) vaccine antigens in paraformaldehyde-fixed paraffin-embedded tissues of experimentally vaccinated ducklings. Male New Zealand rabbits were immunized with purified DPV antigens, which were engaged by a combination of differential centrifugation and sucrose-density gradient ultracentrifugation. The rabbit anti DPV polyclonal antibodies were purified and used as the primary antibodies. Forty eight 28-d-old DPV-free Pekin ducklings were subcutaneously inoculated with attenuated DPV vaccine in the immunization group and sterile PBS in the control group. The tissues were collected at sequential time points between 4 h and 18 wk postvaccination (PV) and were prepared for SP-IHC observation. The presence of DPV-specific antigens was first observed in the liver and spleen at 12 h PV; in the bursa of Fabricius, thymus, Harderian gland, esophagus, and intestinal tract at 1 d PV; and in the heart, lung, kidney, pancreas, and brain at 3 d PV. The positive staining reaction could be detected in the vaccinated duckling tissues until 18 wk PV, and no positive staining cells could be observed in the controls. The highest levels of positive staining reaction were found in the liver, spleen, bursa of Fabricius, thymus, and intestinal tract, whereas a few DPV vaccine antigens were distributed in the heart, pancreas, and esophagus. The target cells had a ubiquitous distribution, especially in the mucosal epithelial cells, lamina propria cells, macrophages, hepatocytes, and lymphocytes, which served as the principal sites for antigen localization. These findings demonstrated that SP-IHC was a reliable method for detecting antigenic distribution and localization regularity of DPV vaccine antigens in routine paraffin sections. The present study may be useful for describing proliferation and distribution regularity of DPV vaccine in the vaccinated duckling tissues and enhance further studies and clinical application of attenuated DPV vaccine. PMID- 20709977 TI - Performance and immune responses to dietary beta-glucan in broiler chicks. AB - During the first week posthatch, the avian immune system is immature and inefficient at protecting chicks from invading pathogens. Among immunomodulators, beta-glucans are known as biological response modifiers due to their ability to activate the immune system. Current research suggests that beta-glucans may enhance avian immunity; however, very little is known about their influence on regulation of immune function. A study was performed to evaluate the effects of dietary beta-glucan on growth performance, immune organ weights, peripheral blood cell profiles, and immune-related gene expression in the intestine. One-day-old chicks were fed a diet containing 0, 0.02, or 0.1% yeast beta-glucan (n = 30/treatment). On d 7 and 14 posthatch, body and relative immune organ weights were measured and small intestinal sections were collected to evaluate gene expression by quantitative real-time PCR. Peripheral blood samples were also collected to determine heterophil:lymphocyte ratios. Supplementation of beta glucan did not significantly affect BW gains, and no significant differences were observed among groups for relative immune organ weights or heterophil:lymphocyte ratios. Compared with controls, expression of interleukin (IL)-8 was downregulated in the beta-glucan-treated groups on d 7 and 14. On d 14, beta glucan inclusion resulted in increased inducible nitric oxide synthase expression. Expression of IL-18 was upregulated on d 7 but reduced on d 14 due to beta-glucan supplementation. On d 7, interferon-gamma and IL-4 expression decreased in the beta-glucan-treated groups. However, on d 14, IL-4 expression was upregulated in the supplemented groups. Intestinal expression of IL-13 was also downregulated in the beta-glucan-treated birds on d 7. These results suggest that dietary inclusion of beta-glucans altered the cytokine-chemokine balance; however, it did not elicit a robust immune response in the absence of a challenge, resulting in no deleterious effects on performance. PMID- 20709979 TI - Multi-carbohydrase and phytase supplementation improves growth performance and liver insulin receptor sensitivity in broiler chickens fed diets containing full fat rapeseed. AB - The effect of a combination of carbohydrase and phytase enzymes on growth performance, insulin-like growth factor 1 gene expression, insulin status, and insulin receptor sensitivity in broiler chickens fed wheat-soybean meal diets containing 6% (starter) and 12% (grower-finisher) of full-fat rapeseed (canola type; low glucosinolate, low erucic acid) from 1 to 42 d of age was studied. A total of 510 one-day-old male broiler chickens were randomly assigned to 3 dietary treatments, with 17 pens per treatment and 10 birds per pen. The dietary treatments consisted of a control diet and P- and Ca-deficient diets supplemented with either phytase (500 U/kg) or a combination of phytase and a multi carbohydrase enzyme (Superzyme OM). The diets were pelleted at 78 degrees C and were fed ad libitum throughout the starter (9 d), grower (18 d), and finisher (15 d) phases of the experiment. Over the entire trial, growth performance of birds fed the phytase-supplemented diet did not differ from birds fed the control diet. The use of phytase in combination with a multicarbohydrase enzyme improved (P = 0.007) the feed conversion ratio from 1.90 to 1.84. Insulin liver receptor sensitivity increased by 9.3 and 12.3% (P = 0.004) for the phytase- and the carbohydrase-phytase-supplemented diets, respectively. There was no effect of phytase alone or carbohydrase and phytase supplementation on total plasma cholesterol, high-density lipoprotein cholesterol, and blood glucose levels. However, low-density lipoprotein cholesterol decreased (P = 0.007) for the phytase-carbohydrase treatment. Gene expression of insulin-like growth factor 1 tended to decrease by 32% (P = 0.083) after phytase-carbohydrase supplementation. The combination of carbohydrase and phytase enzymes may serve as an attractive means of facilitating nutrient availability for digestion and thus enhance the feeding value of wheat-soybean meal-based diets containing full-fat rapeseed. However, the extent to which the effects of enzyme addition on insulin receptors are associated with growth performance of broiler chicken requires further research. PMID- 20709978 TI - Alleviation of cyclic heat stress in broilers by dietary supplementation of mannan-oligosaccharide and Lactobacillus-based probiotic: dynamics of cortisol, thyroid hormones, cholesterol, C-reactive protein, and humoral immunity. AB - Heat stress (HS), one of the major problems of tropical and subtropical countries, adversely affects the production performance of poultry. Keeping this in view, the present study was designed to investigate some of the biological markers of HS in broilers as modulated by dietary supplementation of mannan oligosaccharide (MOS) and a Lactobacillus-based probiotic (LBP), either alone or in combination. Two hundred fifty 1-d-old-chicks were randomly divided into 5 groups. From d 22, the birds were either kept at the thermoneutral zone (TN) or exposed to HS to the conclusion of study, d 42. Birds were fed either a corn based basal diet (TN and HS groups) or the same diet supplemented with 0.5% MOS (HS-MOS group), 0.1% LBP (HS-LBP group), or their combination. Birds were immunized against Newcastle disease virus on d 4 (intraocular; live attenuated) and d 20 (drinking water; live attenuated) and infectious bursal disease virus on d 8 (intraocular; live intermediate strain) and d 24 (drinking water; live attenuated). Birds were killed on d 42 to collect serum for determination of cortisol, thyroid hormones, cholesterol, C-reactive protein, and postvaccinal antibody titers. Results revealed that dietary supplementations decreased (P < 0.05) the serum cortisol and cholesterol concentrations and increased (P < 0.05) thyroxine concentration compared with the HS group without affecting triiodothyronine concentration. The percentage of the C-reactive protein-positive birds was higher (P < 0.05) in the HS group compared with the TN group. Dietary supplementations improved humoral immunity against Newcastle disease virus and infectious bursal disease virus during HS. In conclusion, dietary supplementation of either MOS or LBP alone or in combination can reduce some of the detrimental effects of HS in broilers. PMID- 20709980 TI - Contribution of exogenous dietary carbohydrases to the metabolizable energy value of corn distillers grains for broiler chickens. AB - The objectives of this study were to determine the ileal digestible energy (IDE), ME, and ME(n) contents of corn distillers grains (CDG) for broiler chickens and to quantify these energy utilization responses to carbohydrase supplementation by the regression method. The CDG sample used in the current experiment contained (by analysis) 936 g/kg of DM, 4,894 kcal/kg of gross energy, 315.1 g/kg of CP, 94.6 g/kg of crude fat, 94.8 g/kg of crude fiber, 495.6 g/kg of neutral detergent fiber, 179.1 g/kg of acid detergent fiber, 0.19 g/kg of Ca, and 4.8 g/kg of P. The studies were conducted at 2 locations (Purdue or Louisiana State University) and CDG were incorporated into a practical corn-soybean meal diet at 3 levels (0, 300, or 600 g/kg) without or with added carbohydrase in a 2 x 3 x 2 factorial arrangement. The carbohydrase premix was added to supply 2,000 U of xylanase + 1,800 U of amylase/kg of feed. The diets were fed to 288 broiler chickens from d 15 to 22 posthatch with 6 birds per cage and 8 replicate cages per diet in a randomized complete block design at each of 2 locations. The broiler chicks were fed a standard broiler starter diet from d 1 to 15 posthatch. The IDE of diets decreased both linearly (P < 0.01) and quadratically (P < 0.05) as CDG increased from 0 to 600 g/kg regardless of carbohydrase supplementation. There was a linear (P < 0.01) decrease in ME of diet from 3,239 to 2,510 kcal/kg as CDG increased from 0 to 600 g/kg in the diets without added carbohydrase, whereas for birds fed the carbohydrase-supplemented diets, there were both linear (P < 0.01) and quadratic (P < 0.01) decreases from 3,398 to 2,613 kcal/kg as CDG increased from 0 to 600 g/kg. Dietary ME(n) linearly decreased (P < 0.01) regardless of carbohydrase supplementation as CDG increased from 0 to 600 g/kg. Supplementation with carbohydrase improved (P < 0.01) IDE, ME, and ME(n). Regressions of CDG associated IDE, ME, or ME(n) intake in kilocalories against kilograms of CDG intake without added carbohydrase generated the following: IDE = 44 + 2,340X, r(2) = 0.953; ME = 10 + 2,315X, r(2) = 0.993; and ME(n) = 10 + 2,132X, r(2) = 0.991. Corresponding regressions when carbohydrase was added were as follows: IDE = -17 + 2,622X, r(2) = 0.985; ME = -25 + 2,448X, r(2) = 0.979; and ME(n) = -22 + 2,264X, r(2) = 0.978. These data indicate that the respective IDE, ME, and ME(n) values (kcal/kg of DM) of the CDG sample evaluated were 2,340, 2,315, and 2,132 when carbohydrase was not added and 2,622, 2,448, and 2,264 when carbohydrase was added. Comparison using ANOVA procedures indicated that the slope when carbohydrase was added was greater (P < 0.05) than when carbohydrase was not added. This response implies that carbohydrase supplementation improved (P < 0.05) the IDE, ME, and ME(n) of CDG in practical corn-soybean meal-based diets used in this current study by 12, 5.7, and 6.2%, respectively. PMID- 20709981 TI - Digestive tract measurements and histological adaptation in broiler lines divergently selected for digestive efficiency. AB - Two lines of broilers divergently selected for a high (D+) or a low (D-) AME(n) on a wheat-based diet were studied for morphological and histological characteristics of the digestive tract. A total of 630 birds of both lines were slaughtered after a 23-d feeding period. Digestive tract morphology and intestinal histology were investigated on a total of 24 birds to describe the consequences of divergent selection. Birds of the D+ line had 34% heavier gizzards (P < 0.001) and 22% heavier proventriculi than their D- counterparts. In contrast, intestines were 15 to 40% heavier in D- birds, mainly in the jejunum (P < 0.001) and ileum (P < 0.001). Intestinal segments were also longer (between 3 and 6%) in the D- birds. Intestinal villi were larger and longer in D- birds (P < 0.001), mainly in the jejunum (14 to 16%), and crypts were 10 to 15% deeper for the 3 intestinal segments in D- birds (P < 0.001). Muscle layers of the intestine were 17 to 24% thicker (P < 0.001) and goblet cells were 27 to 34% more numerous in the jejunum and ileum of D- birds (P = 0.027). This new characterization of the 2 lines shows that divergent selection based on AME(n) modified the morphology of the proventriculus and gizzard, suggesting greater activity of this compartment in D+ than in D- birds. Intestinal adaptation revealed by visceral organ weight and length and histological modifications in D- birds can be viewed as an attempt to compensate for the low functionality of the gastric area. PMID- 20709982 TI - Metabolizable energy and amino acid digestibility of decorticated extruded safflower meal. AB - An experiment was conducted to determine TME and amino acid digestibility of several dehulled extruded safflower meals. Finely ground partially dehulled extruded (ESM), partially dehulled solvent-extracted (SESM), extensively cleaned dehulled and extruded safflower meal (CSM), or soybean meal 44 (SBM 44) was intubated to 9 fasted mature roosters with 40 g per rooster and total excreta was collected.The concentrations of all essential amino acids in CSM were higher than those in ESM and SESM. Also, compared with SBM 44, CSM was deficient in lysine, slightly higher in TSAA and tryptophan, but much higher in arginine. The AME(n) and TME(n) of CSM were 2,413 and 2,832 kcal/kg, respectively, and were higher than those of SBM 44 (P < 0.01). The true lysine digestibilities of CSM and SBM 44 were similar but were higher than those of ESM and SESM (P < 0.05). However, ESM, SESM, and CSM had similar true tryptophan and threonine digestibilities that were lower than that of SBM 44 (P < 0.05). With respect to TSAA, all feed ingredients under investigation had similar apparent and true digestibilities. In conclusion, extensive hull removal of safflower seeds followed by cold extrusion produced a low-fiber CSM rich in both energy and protein that makes it a promising feed ingredient for poultry. PMID- 20709984 TI - Risk of Salmonella transmission via cryopreserved semen in turkey flocks. AB - To investigate the possibility to carry pathogen bacteria in turkey flocks via cryopreserved semen, research was carried out 1) to investigate the microbial contamination of fresh and frozen thawed turkey semen and 2) to evaluate the effect of the freezing-thawing process on the survival of 3 serovars of Salmonella spp. experimentally inoculated in turkey semen. Five pools of semen diluted 4-fold were cooled, added with 8% of dimethylacetamide as a cryoprotectant, and aliquots of 80 muL were directly plunged into liquid nitrogen to form frozen pellets. Mesophilic viable counts, total and fecal coliforms, Enterobacteriaceae, enterococci, Campylobacter spp., and Salmonella spp. were investigated on fresh and thawed samples. Further, 5 pools of diluted semen were each divided into 3 subsamples, inoculated with 7.8 +/- 0.2 log cfu.mL(-1) of Salmonella Liverpool, Salmonella Montevideo, and Salmonella Braenderup, respectively, and cryopreserved before to assess the postthaw viability of Salmonella spp. strains. Fresh semen was highly contaminated by all of the saprophytic bacteria investigated and the cryopreservation process reduced the amount of mesophilic viable count and total coliforms (P < 0.05) and fecal coliforms, Enterobacteriaceae, and enterococci (P < 0.01) by about 1 log cfu.mL( 1). Conversely, neither Campylobacter spp. nor Salmonella spp. were found as endogenous bacteria in semen. In the inoculated semen, both Salmonella Liverpool, Salmonella Montevideo, and Salmonella Braenderup colonies were recovered postthaw, showing a significant reduction of 2.03 +/- 0.28, 3.08 +/- 0.22, and 2.72 +/- 0.23 log cfu.mL(-1), respectively, compared with the fresh semen (P < 0.001). In conclusion, the cryopreservation process allowed us to obtain a low reduction of microbial count both in endogenous saprophytic bacteria and artificially inoculated Salmonella spp. strains; therefore, the possibility of Samonella spp. transmission to flocks through the use of infected cryopreserved semen does exist. PMID- 20709983 TI - The effect of glucagon-like peptide 2 injection on performance, small intestinal morphology, and nutrient transporter expression of stressed broiler chickens. AB - An experiment was conducted to determine the effect of injecting glucagon-like peptide 2 (GLP-2) on the small intestinal weight, morphology, and nutrient transporter expression in pharmacologically stressed broiler chickens. A total of 144 seven-day-old birds were fed either a basal diet (CTRL) or a basal diet plus 30 mg of corticosterone (CORT)/kg of diet for a total of 14 d. Half of the birds from each group were injected daily with GLP-2 (6.7 nmol/kg of BW) or saline for 14 d. The average final BW, ADG, ADFI, and the ratio of feed intake to weight gain (F:G) was recorded over 21 d for the 4 groups of 36 birds, namely CTRL + saline, CTRL + GLP-2, CORT + saline, and CORT + GLP-2. In addition, the absolute and relative small intestinal weight, villus height (VH), and crypt depth (CD) of the duodenum and jejunum, as well as the abundance of sodium and glucose co transporter 1 (SGLT-1), vitamin D-dependent calcium-binding protein-28,000 molecular weight (CaBP-D28k), and peptide transporter 1 (PepT-1) mRNA in the duodenum and of liver fatty acid-binding protein (L-FABP) mRNA in the jejunum. The total DNA, RNA, and protein content in small intestinal mucosa were also determined. The results showed that CORT administration significantly lowered average final BW, ADG, ADFI, absolute small intestinal weight, VH, and CD of duodenum and jejunum (P < 0.05) while increasing the relative small intestinal weight, F:G, relative abundance of SGLT-1, CaBP-D28k, PepT-1, and L-FABP mRNA (P < 0.05). Glucagon-like peptide 2 injection increased the average final BW, ADG, VH, and CD in duodenum and jejunum and relative abundance of SGLT-1, CaBP-28k, PepT1, and PepT1 mRNA of broiler chickens, respectively (P < 0.05), and decreased F:G (P < 0.05). In chickens fed basal diet plus CORT, injecting GLP-2 decreased F:G (P < 0.05); increased VH and CD of duodenum and CD of jejunum; and increased relative abundance of SGLT-1, CaBP-D28k, PepT-1, and L-FABP mRNA, RNA, and total protein content in small intestine compared with the injection of saline (P < 0.05). In birds fed the basal diet, GLP-2 injection decreased F:G (P < 0.05) and increased final BW, ADG, small bowel weight, CD of jejunum, and relative abundance of CaBP-D28k and PepT-1 mRNA compared with injecting saline (P < 0.05). In conclusion, GLP-2 injection reversed the negative effect of stress on the weight and morphology and the absorptive function of small bowel of broiler chickens. Glucagon-like peptide 2 injection also had a positive effect on the growth performance of healthy broiler chickens. PMID- 20709985 TI - Effects of the thyroid hormone responsive spot 14alpha gene on chicken growth and fat traits. AB - The thyroid hormone responsive spot 14alpha (THRSPalpha) gene plays important roles in chicken growth and fat deposition. The aim of this study was to identify new variations in the gene to determine their effects on growth and fat traits in chicken and to observe the effects of the THRSPalpha gene on chicken lipid profile and lipoprotein and glucose and triiodothyronine effects on the THRSPalpha expression in liver and fat cells. Two new variations, namely A197835978G and G197836086A, and a reported 9-bp insertion-deletion (indel) of the THRSPalpha gene were genotyped by single-stranded conformational polymorphism in a Xinghua x White Recessive Rock F(2) full-sib resource population. The results showed that the A197835978G was significantly associated with hatch weight and BW at 28 d of age and breast muscle weight at 90 d of age in chickens (P < 0.05). The G197836086A was significantly associated with cingular fat width (P = 0.0349) and breast muscle crude fat content (P = 0.0349). The indel was significantly associated with abdominal fat weight (P = 0.0445). The above new THRSPalpha polymorphisms were also significantly associated with the total cholesterol and low-density lipoprotein, in which the THRSPalpha GA/AG genotype was associated with lipid and lipoprotein and the THRSPalpha BB indel genotype was significantly associated with liver weight in chicken breeds. The mRNA expression analysis in vivo and in vitro culture studies suggested that the THRSPalpha gene is more responsive to glucose than triiodothyronine. In conclusion, the 3 variations of the chicken THRSPalpha gene were associated with both growth and fat traits in this study. Such effects of the THRSPalpha gene were further supported from the data of observations in association analysis of the gene with phenotypic records and plasma lipid profiles, in the THRSPalpha gene expression in chicken development, and in vivo and in vitro cell culture observation of liver and abdominal fat tissues. PMID- 20709986 TI - Influence of air composition during egg storage on egg characteristics, embryonic development, hatchability, and chick quality. AB - Egg storage beyond 7 d is associated with an increase in incubation duration and a decrease in hatchability and chick quality. Negative effects of prolonged egg storage may be caused by changes in the embryo, by changes in egg characteristics, or by both. An adjustment in storage air composition may reduce negative effects of prolonged egg storage because it may prevent changes in the embryo and in egg characteristics. An experiment was conducted to investigate the effects of high CO(2) concentrations or a low O(2) concentration in the storage air on egg characteristics, embryonic development, hatchability, and chick quality. Eggs were stored for 14 d in 4 different storage air compositions: normal air (control; 20.9% O(2), 0.05% CO(2), 78.1% N(2)), 0.74% CO(2) treatment (20.8% O(2), 0.74% CO(2), 77.5% N(2)), 1.5% CO(2) treatment (20.6% O(2), 1.5% CO(2), 77.0% N(2))(,) or 3.0% O(2) treatment (3.0% O(2), 0.04% CO(2), 96.0% N(2)). The storage temperature was 16 degrees C and the RH was 75%. Results showed that the change in albumen pH and albumen height between oviposition and the end of storage was less in the 0.74 and 1.5% CO(2) treatments than in the control and 3.0% O(2) treatments (P < 0.001 and P < 0.001, respectively). None of the treatments affected the stage of embryonic development on d 4 of incubation, hatchability, or chick quality on the day of hatch in terms of BW, chick length, and yolk-free body mass. Although high CO(2) concentrations in the storage air had a positive effect on albumen height and albumen pH, it is concluded that the storage air compositions, studied in the current study, do not affect embryonic development, hatchability, or chick quality when eggs are stored for 14 d at a storage temperature of 16 degrees C. PMID- 20709987 TI - Reproductive hormones, hepatic deiodinase messenger ribonucleic acid, and vasoactive intestinal polypeptide-immunoreactive cells in hypothalamus in the heat stress-induced or chemically induced hypothyroid laying hen. AB - Heat stress (HS) effects on reproductive and thyroid hormones have been well documented; however, mechanisms of action are not well understood. Two studies were conducted to determine whether HS-induced and hypothyroid-induced effects are similar in the laying hen, with regard to reproductive hormones and vasoactive intestinal polypeptide (VIP)-immunoreactive cells in the hypothalamus. In study 1, thirty 32-wk-old Hy-Line W-36 laying hens, housed at 22 degrees C, were cannulated. On d 0 and then on d 1 to 5 of HS (35 degrees C, 50% RH), a daily blood sample was obtained and assayed for triiodothyronine (T(3)), thyroxine (T(4)), 17beta-estradiol (E(2)), progesterone (P(4)), prolactin (PRL), and VIP, and T(3):T(4)was calculated. On d 0, 1, 3, and 5, livers were obtained for hepatic type I deiodinase mRNA (cDI-1) determination. In study 2, eighty 32 wk-old hens were randomly assigned to 4 treatments of 20 birds each: 1) HS (36.5 degrees C, 50% RH), 2) thiouracil-induced hypothyroidism (HY), 3) HY + T(4) administration, and 4) control (22 degrees C). Beginning on d 1 of the 5-d study, daily blood samples (3.0 mL) were removed and assayed as in study 1. On d 5, brains were removed from 3 hens/treatment and immunoreactivity of VIP cells was determined. In study 1, HS reduced E(2), P(4), T(3) (P = 0.0001), T(3):T(4) ratio (P = 0.0078), and hepatic type I deiodinase mRNA (P = 0.0204) and increased T(4) (P = 0.0013); there was no effect on VIP or PRL. In study 2, HS and HY reduced T(3), T(3):T(4) ratio, and E(2) (P = 0.0001) and increased PRL (P = 0.0045); HS alone decreased P(4) (P = 0.0001). In HY + T(4), plasma E(2) and PRL were similar to control. Vasoactive intestinal polypeptide increased in plasma of HY birds, but there was no effect of HS or HY + T(4). Immunoreactive VIP cells increased (P = 0.0036) in nucleus inferior hypothalami of HS and HY brains. In HY + T(4), VIP immunoreactive cell numbers were similar to control. It appears that HY induced chemically or by HS exerts similar effects on reproductive hormones in the hen; the results suggest involvement of the VIP-PRL pathway even though peripheral blood concentrations were not consistent between studies. PMID- 20709988 TI - Effect of eggshell temperature and oxygen concentration on survival rate and nutrient utilization in chicken embryos. AB - Environmental conditions during incubation such as temperature and O(2) concentration affect embryo development that may be associated with modifications in nutrient partitioning. Additionally, prenatal conditions can affect postnatal nutrient utilization. Using broiler chicken embryos, we studied the effects of eggshell temperature (EST; 37.8 or 38.9 degrees C) and O(2) (17, 21, or 25%) applied from d 7 until 19 of incubation in a 2 x 3 factorial design. Effects of these factors on embryonic survival, development, and nutrient utilization were assessed in the pre- and posthatch period. High EST reduced yolk-free body mass compared with normal EST (36.1 vs. 37.7 g), possibly through reduced incubation duration (479 vs. 487 h) and lower efficiency of protein utilization for growth (83.6 vs. 86.8%). Increasing O(2) increased yolk-free body mass (from 35.7 to 38.3 g) at 12 h after emergence from the eggshell, but differences were larger between the low and normal O(2) than between the normal and high O(2). This might be due to the lower efficiency of nutrient utilization for growth at low O(2). However, the effects of O(2) that were found at 12 h were less pronounced at 48 h posthatch. When O(2) was shifted to 21% for all treatments at d 19 of incubation, embryos incubated at low O(2) used nutrients more efficiently than those incubated at normal or high O(2). An additional negative effect on survival and chick development occurred when embryos were exposed to a combination of high EST and low O(2). Possible explanations include reduced nutrient availability for hatching, decreased body development to fulfill the energy-demanding hatching process, and higher incidence of malpositions. In conclusion, EST and O(2) during incubation affect nutrient utilization for growth, which may explain differences in survival and development. Embryos raised under suboptimal environmental conditions in the prenatal period may develop adaptive mechanisms that still continue in the posthatch period. PMID- 20709989 TI - Monocytes-macrophages phagocytosis as a potential marker for disease resistance in generation 1 of dwarf chickens. AB - Monocytes-macrophages play an indispensable role in the immune system. The current study investigated the effect of selection for monocytes-macrophages phagocytosis on disease resistance in generation 1 (G1) of dwarf chickens. Five hundred dwarf chickens of generation 0 (G0) were divided into high and low phagocytic index (PI) groups (HPIG and LPIG, respectively) based on their PI of monocytes-macrophages at 290 d of age. Then, 2 x 2 mating combinations were conducted. Sixty G0 chickens from another dwarf chicken group were used to measure the levels of monocytes-macrophages phagocytosis at different developmental stages. Among a total of 2,500 randomly selected G1 chickens, 2,100 individuals were used for a surviving and growing test under adverse feeding circumstances, and the other 400 individuals were tested for Salmonella Pullorum challenge. The results showed that progenies of HPIG hens (female symbol) were more resistant to Salmonella Pullorum. After challenge, the death rate of progeny from HPIG female symbol (28.9%) was only 58% that of progeny from LPIG female symbol (49.4%, P < 0.001). In addition, the natural infection rate of Salmonella Pullorum before 207 d for offspring from HPIG female symbol (35.0%) was significantly lower than that for offspring from LPIG female symbol (48.3%, P < 0.001). The natural mortality before 56 d in progeny of HPIG female symbol (22.6%) was significantly lower than that in progeny of LPIG female symbol (29.1%) with a P-value of 0.001. The G1 chickens of HPIG G0 female symbol weighed more than those born to LPIG G0 female symbol at 28 and 42 d of age, whereas the difference was not statistically significant at 56 d of age. The heritability of monocytes-macrophages phagocytosis was 0.40, which was moderate. The PI values were at a low level before 126 d and increased dramatically until they declined significantly after 294 d. It could be concluded that phagocytosis of monocytes macrophages is a marker for breeding excellent progeny with strong disease resistance. PMID- 20709990 TI - Molecular analysis of Salmonella serotypes at different stages of commercial turkey processing. AB - Salmonella isolates were collected from 2 commercial turkey processing plants (A and B) located in different US geographical locations. Isolates recovered at different stages of processing were subjected to 2 genotype techniques [PAGE and denatured gradient gel electrophoresis (DGGE)] to determine their usefulness for Salmonella serotyping. Primers used for PCR amplification were to a highly conserved spacer region located between the 16S and 23S rDNA genes. Sampling sites at plant A were 1) postscald, 2) pre-inside-outside bird wash, 3) post IOBW, and 4) postchill with 30, 44, 36, and 12 Salmonella isolates recovered, respectively. Plant B had an additional site and these locations were 1) prescald, 2) postscald, 3) pre-inside-outside bird wash, 4) post-IOBW, and 5) postchill with 16, 54, 24, 35, and 24 Salmonella isolates recovered, respectively. In plant A, 4 different Salmonella serotypes were identified: Derby, Hadar, Montevideo, and Senftenberg. In plant B, 10 serotypes were identified: Agona, Anatum, Brandenburg, Derby, Hadar, Meleagridis, Montevideo, Reading, Senftenberg, and Typhimurium. Salmonella Derby was predominant in plant A (83%), whereas Salmonella Typhimurium was the most common serotype recovered in plant B (39%). Genotype analyses of the Salmonella serotypes were expressed in dendrograms with comparisons interpreted as percentage similarity coefficients. Both PAGE and DGGE were able to distinguish serotype band patterns. However, DGGE was more discriminating than PAGE. Isolates of the same serotypes were grouped together on the dendrogram of band patterns generated by DGGE. In contrast, PAGE failed to group all like serotypes together on the corresponding dendrogram. The results of the study suggest that genotyping techniques can be very useful in discriminating Salmonella serotypes collected from the processing plant environment of commercial poultry production. These molecular techniques may offer more cost-effective means to identify Salmonella serotypes from large numbers of isolates and with more immediate results than those currently achieved with conventional typing techniques. PMID- 20709991 TI - Comparison of the statistics of Salmonella testing of chilled broiler chicken carcasses by whole-carcass rinse and neck skin excision. AB - Whether a required Salmonella test series is passed or failed depends not only on the presence of the bacteria but also on the methods for taking samples, the methods for culturing samples, and the statistics associated with the sampling plan. The pass-fail probabilities of the 2-class attribute sampling plans used for testing chilled chicken carcasses in the United States and Europe were compared by calculation and simulation. Testing in the United States uses whole carcass rinses (WCR), with a maximum number of 12 positives out of 51 carcasses in a test set. Those numbers were chosen so that a plant operating with a Salmonella prevalence of 20%, the national baseline result for broiler chicken carcasses, has an approximately 80% probability of passing a test set. The European Union requires taking neck skin samples of approximately 8.3 g each from 150 carcasses, with the neck skins cultured in pools of 3 and with 7 positives as the maximum passing score for a test set of 50 composite samples. For each of these sampling plans, binomial probabilities were calculated and 100,000 complete sampling sets were simulated using a random number generator in a spreadsheet. Calculations indicated that a 20% positive rate in WCR samples was approximately equivalent to an 11.42% positive rate in composite neck skin samples or a 3.96% positive rate in individual neck skin samples within a pool of 3. With 20% as the prevalence rate, 79.3% of the simulated WCR sets passed with 12 or fewer positive carcasses per set, very near the expected 80% rate. Under simulated European conditions, a Salmonella prevalence of 3.96% in individual neck skin samples yielded a passing rate of 79.1%. The 2 sampling plans thus have roughly equivalent outcomes if WCR samples have a Salmonella-positive rate of 20% and individual neck skin samples have a positive rate of 3.96%. Sampling and culturing methods must also be considered in comparing the different standards for Salmonella. PMID- 20709995 TI - In vitro comparisons of two antimicrobial intravenous connectors. AB - Fifty percent of catheter-related bloodstream infections (CR-BSI) caused by organism migration through the fluid pathway (intraluminal) via a connector can be colonized within 24 hr. With a mean hospital stay of 4.8 days, intraluminal contamination is a primary source of CR-BSI. Purpose of this research was to determine which antimicrobial needleless connector produced the least bacterial colony-forming units (CFUs) in vitro and to compare these CFUs to the leading nonantimicrobial connector shown in previous research to have the lowest CFUs. Independent laboratory tested 2 antimicrobial (Baxter V-LinkTM, RyMed-7001 Nano((r))) and 1 nonantimicrobial (RyMed-5001) connector, 20 connectors each, 3 controls, each of 4 days, 4 organisms, under the same laboratory conditions. Baxter V-LinkTM produced 2.0 to 8.8 times more bacteria than the RYM-5001( (r)) and RYM-7001((r)) connectors, regardless of bacteria type. The antimicrobial connector with the most and consistent bacteria (13, 675 CFUs) over 4 days was the V-LinkTM and the connector with no consistent bacteria was the RyMed 7001((r)). Nurses and researchers must include technological design, connector types, and methods of coating/ impregnating connectors as factors in evaluation. PMID- 20709992 TI - Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. AB - BACKGROUND: In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer. METHODS: The WHI study is a randomized, double-blind, placebo controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided. RESULTS: After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79). CONCLUSION: Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer. PMID- 20709996 TI - Comparison of bacterial CFUs in five intravenous connectors. AB - This study determines if there are differences in colony forming units (CFU) of bacteria between five different needleless intravenous connectors. CFUs create environments for bloodstream infections with 1 CFU to begin an infection and 15 to develop infection. Intraluminal pathway protection is a most significant way to eliminate 50% bloodstream infections. Five different connectors were evaluated by independent laboratory in vitro regarding >=15 CFUs, 4 organisms over 4 days. Q-SyteTM had significantly higher mean number days CFUs >=15 than all other devices, Rymed-5001((r)) having the least (p < .0001). Q-SyteTM and TKO+Clave((r)) had significantly more CFUs >=15 on one or more days. Nonantimicrobial connectors differ on CFU counts in vitro. CFUs are ranked highest to lowest CFUs as follows: Q-SyteTM, TKOTMClave((r)), MicroCLAVE((r)), MaxPlus((r)) Clear, and Rymed-5001((r)). Best nonantimicrobial connector products for intraluminal protection are Rymed-5001((r)) followed by MaxPlus((r)) Clear. Using the best connector can significantly prevent infections as part of nursing care. PMID- 20709997 TI - The family care coordinator: paving the way to seamless care. AB - The care of a child/adolescent with cancer or a blood disorder is complex and often long term, involving many interdisciplinary team members across services and geographical boundaries. This experience can be overwhelming for patients and their families, highlighting the need for a family care coordinator (FCC) to help them navigate their care path. The purpose of this article is to illustrate the concept of family care coordination as experienced by the IWK Health Center in Nova Scotia, Canada, with the intent of sharing a valuable model of care with other pediatric hematology/oncology services. Key components of the role are ongoing assessment, education, partnerships, communication, support, and advocacy. Essential resources and pathways are required to implement the role and optimize patient/family outcomes, facilitating consistent and accessible care, enhancing quality and safety, building trust, and gleaning efficiencies. Inherent FCC challenges are identified as time constraints, replacement issues, maintaining professional boundaries, and emotional burnout. A FCC can enable seamless, individualized care for children/adolescents and their families with pediatric oncological and hematological disorders, optimizing the outcomes for all involved. PMID- 20709998 TI - What's the Pence Line? PMID- 20709999 TI - My friend, advocate Ellen Pence. AB - This is a tribute to Ellen Pence's exemplary advocacy on behalf of battered women. It traces Ellen's vital contributions to the field of antidomestic violence advocacy through two organizations, DAIP and Praxis. The history of Ellen's relentless efforts to transform legal and social institutions that led her to create the coordinated community response (CCR) and the institutional audit tool to assess safety and accountability are also elaborated. The author characterizes Ellen Pence's work as meta-advocacy. PMID- 20710000 TI - The contributions of Ellen Pence to batterer programming. AB - Ellen Pence helped build the foundation of batterer programming with the Duluth program. The program forged new ground and bridged the concerns of advocates and criminal justice officials by developing its "Power and Control Wheel" from women's experiences with abuse. Its dialogical format, responding to vignettes and control logs, helps to engage men in a reflective process, to monitor their behavior, and to identify alternative outlooks and responses. At the same time, Ellen's work remains rooted in a gender analysis and a coordinated community response. Critics of Duluth programming miss the mark with a distorted caricature of Duluth, neglect of substantiating research, and the bias from their own personal agendas. Ellen's personal touch of insightful humor and personal interest has helped to move forward the lessons of Duluth and the field itself. Her groundbreaking program helps to sort through the disarray of approaches among batterer programs today. PMID- 20710001 TI - Discussing the Duluth Curriculum: creating a process of change for men who batter. AB - This is an edited version of a heretofore unpublished conversation between Ellen Pence and Luis Aravena. It provides a clear explanation of the philosophy and method of the Duluth Model men's program, emphasizing the need to put the experience of women who have been abused at the center of our work with abusive men, especially by helping abusive men become more self-reflective with regard to their behavior. PMID- 20710002 TI - With "equal regard": an overview of how Ellen Pence focused the supervised visitation field on battered women and children. AB - Ellen Pence has changed the framework for doing supervised visitation and safe exchanges in cases of domestic violence. Ellen challenged the basic tenets of "neutrality" and a primary focus on "safety for children" in the supervised visitation field. By incorporating equal regard for the safety of adult victims of domestic violence and children, Ellen challenged supervised visitation centers to reexamine their mission, role, intake/orientation, documentation, and rules for their programming. She designed services for supervised visitation that would account for battering of women and children while not being excessively policing and providing a respectful and fair atmosphere for men who batter. PMID- 20710003 TI - The Praxis Safety and Accountability Audit: practicing a "sociology for people". AB - Ellen Pence has crafted the Praxis Safety and Accountability Audit (Safety Audit) on the social change foundation of the battered women's movement, the idea of a coordinated community response to domestic violence, and institutional ethnography's emphasis on asking questions from the standpoint of people in their everyday lives. Conducted by an interagency team of advocates and practitioners, the Safety Audit uses interviews, observations, and text analysis to examine the ways in which institutions standardize and coordinate workers' actions to produce interventions and outcomes that enhance or diminish safety for battered women and their children. With the Safety Audit, Pence has provided a new and distinctive tool for community change. PMID- 20710004 TI - Ellen Pence appreciation: letters from Britain and Europe. AB - Letters from Britain and Europe were compiled and edited by Rebecca Emerson Dobash and Russell Dobash and includes contributions from the following: Scotland Monica Wilson, formerly codirector of CHANGE and now Advisor to the Caledonian System, currently being developed by the Scottish government; Dave Morran, former codirector of CHANGE, now Lecturer in Social Work, University of Stirling, Scotland; Dorothy Anderson, previous Administrator of CHANGE. England -Neill Blacklock, Development Director, Respect, London. Respect is the national association for professionals working with people to end their abusive behavior. Europe-Rosa Logar (Austria) and Ute Roesemann (Germany), WAVE network -Women Against Violence Europe. PMID- 20710005 TI - Ellen's Hand. AB - This essay offers reflections, both personal and professional, on the contributions of Ellen Pence to changes in law enforcement responses to domestic violence victims and offenders. PMID- 20710006 TI - Health trajectories among older movers. AB - OBJECTIVE: To examine health trajectories among older migrants by reason for move. METHOD: Data from the 1992 to 2006 Health and Retirement Study (HRS) are used to model trajectories of self-rated health and activity of daily living (ADL) limitations that occurred prior seven types of moves. RESULTS: There are substantial differences across the reason-for-move groups in initial levels of self-rated health. Declines in self-rated health among nursing home movers are more than two times steeper than the other reason-for-move groups. Employment, comfort, economic security, life crisis, and affiliation movers have low initial levels of ADL limitations and slow increases in ADL limitations. Health and nursing home movers have higher initial ADL limitations and increases in ADL limitations that are three and seven times higher respectively than the other groups. DISCUSSION: The results are consistent with the predictions of Litwak and Longino's (1987) typology of later-life migration and the extant literature on later-life migration. Implications for communities are considered. PMID- 20710007 TI - One step closer to personalized genomic medicine. PMID- 20710008 TI - Minor head injury: do you get what you expect? PMID- 20710009 TI - Neuralgic amyotrophy associated with Bartonella henselae infection. PMID- 20710010 TI - Atopic myelitis in a European woman residing in Japan. AB - Nearly 100 cases of atopic myelitis have been reported in Japan. However, it has only been described in two non-Japanese patients, both from Western Europe. We report a European individual who developed cervical myelitis while resident in Japan. This showed a partial response to corticosteroids. There was no clinical or radiological dissemination for over 5 years, at which time she had a brainstem relapse caused by a new lesion in the medulla oblongata. The patient had high serum total IgE with evidence of allergy to several antigens, including house dust mite and soya. It is possible that the incidence of atopic myelitis may be underestimated where it is not standard practice to measure serum IgE levels in patients with myelopathy. Such cases will instead be subsumed into the diagnostic category of clinically isolated syndrome. However, it remains uncertain whether atopic myelitis is a distinct disease or falls within the spectrum of demyelinating diseases. Further studies are required to fully elucidate the relationship between atopy and the incidence and severity of CNS inflammatory disorders. PMID- 20710011 TI - Systemic energy homeostasis in Huntington's disease patients. AB - BACKGROUND: Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the HTT gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in fat and glucose homeostasis and a higher prevalence of diabetes mellitus, the causes of which are unknown. Therefore, a detailed analysis of systemic energy homeostasis in HD patients in relation to disease characteristics was performed. METHODS: Indirect calorimetry combined with a hyperinsulinaemic-euglycaemic clamp with stable isotopes ([6,6-2H2]-glucose and [2H5]- glycerol) was performed to assess energy expenditure and glucose and fat metabolism in nine early stage, medication free HD patients and nine age, sex and body mass index matched controls. RESULTS: Compared with controls, fasting energy expenditure was higher in HD patients (1616 +/- 72 vs 1883 +/- 93 kcal/24 h, p=0.037) and increased even further after insulin stimulation (1667 +/- 87 vs 2068 +/- 122 kcal/24 h, p=0.016). During both basal and hyperinsulinaemic conditions, glucose and glycerol disposal rates, endogenous glucose production and hepatic insulin sensitivity were similar between HD patients and controls. In HD patients, energy expenditure increased with disease duration but not with a greater degree of motor or functional impairment. Moreover, a higher mutant CAG repeat size was associated with lower insulin sensitivity (r=-0.84, p=0.018). CONCLUSION: These findings suggest sympathetic hyperactivity as an underlying mechanism of increased energy expenditure in HD, as well as peripheral polyglutamine length dependent interference of mutant huntingtin with insulin signalling that may become clinically relevant in carriers of mutations with large CAG repeat sizes. PMID- 20710012 TI - Cervical cord and brain grey matter atrophy independently associate with long term MS disability. PMID- 20710013 TI - Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy. AB - Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the polyomavirus JC (JCV) in immunosuppressed people. There is no cure for PML but 1-year survival has increased from 10% to 50% in HIV infected individuals treated with highly active antiretroviral therapy. We describe herein the clinical outcome of 24 PML patients whose survival exceeded 5 years, with a mean follow-up of 94.2 months (range, 60-188 months). Of all patients, only two were females including one who had non-Hodgkin's lymphoma and was HIV negative. All 23 HIV-positive patients received highly active antiretroviral therapy, and additional experimental therapies were not associated with a better clinical outcome. Marked neurological improvement occurred in 4/24 (17%) of patients, while 11/24 (46%) had partial improvement and 9/24 (37%) remained stable. By the end of the period of observation, 8/24 (33%) of patients had no significant disability despite persistent symptoms (modified Rankin disability scale (MRDS) =1), 6/24 (25%) had slight disability and were living independently (MRDS=2), 5/24 (21%) were moderately disabled, requiring some help during activities of daily living (MRDS=3) and 5/24 (21%) had moderately severe disability, requiring constant help or institutionalisation (MRDS=4). Patients with cerebellar lesions tended to have a worse clinical outcome. MRI showed leukomalacia with ventricular enlargement secondary to destruction of the white matter at the site of previous PML lesions, and focal areas of subcortical atrophy with preservation of the cortical ribbon. Of 20 patients tested, 19(95%) had detectable CD8+ cytotoxic T-lymphocytes against JCV in their blood. In absence of a specific treatment, immunotherapies aiming at boosting the cellular immune response against JCV may improve the prognosis of PML. PMID- 20710015 TI - Happy birthday European Heart Journal: in 30 years, from Cinderella to centre stage. PMID- 20710017 TI - The utility of the post-concussive symptom questionnaire. AB - The Post-concussive Symptom Questionnaire (PCSQ) and its short forms were evaluated to determine their utility in measuring symptom validity as brief self report measures in 112 individuals referred for a neuropsychological evaluation. First, the relationships between the PCSQ forms and measures of cognitive performance (Wechsler Adult Intelligence Scale-Fourth Edition Full-Scale IQ, California Verbal Learning Test-Second Edition Trials 1-5 Total T-score, Trails B, FAS), general distress (Minnesota Multiphasic Personality Inventory [MMPI]-2 M8), and self-report symptom validity (MMPI-2 FBS Symptom Validity Scale [FBS] and Response Bias Scale [RBS]) were investigated to determine construct validity. Measures of self-report symptom validity explained the greatest amount of variance. Second, receiver operating characteristics curve analyses were conducted to determine the predictive value of the PCSQ forms in detecting over reporting on the FBS and the RBS in addition to establishing optimal cutoff scores. On the basis of the proposed cutoff scores, sensitivity, specificity, positive predictive power, negative predictive power, and hit rates were calculated. PMID- 20710016 TI - Oxidized low-density lipoprotein activates adipophilin through ERK1/2 signal pathway in RAW264.7 cells. AB - It has been reported that oxidized low-density lipoprotein (Ox-LDL) can increase the expression of adipophilin. However, the detailed mechanisms are not fully understood. The aim of this study was to investigate the mechanism of Ox-LDL on adipophilin expression and the intracellular lipid droplet accumulation. A mouse macrophage-like cell line, RAW264.7, was used throughout, and it was found that Ox-LDL induced adipophilin expression in a dose-dependent manner. Moreover, Ox LDL induced peroxisome proliferator-activated receptor-gamma (PPARgamma) expression and PPARgamma-specific inhibitor T0070907 abrogated Ox-LDL-induced adipophilin expression, but specific agonist GW1929 not. Furthermore, Ox-LDL induced phosphorylation of ERK1/2, and ERK1/2-specific inhibition by PD98059 suppressed the Ox-LDL-induced PPARgamma and adipophilin expression. The results showed that ERK1/2 or PPARgamma-specific inhibition decreased the amounts of intracellular lipid droplets. Meanwhile, the PPARgamma-specific agonist increased intracellular lipid droplets. These results suggested that Ox-LDL-induced increase in adipophilin level via ERK1/2 activation is one of the mechanisms of inducing greater amounts of intracellular lipid droplets in RAW264.7 cells, which indicated that adipophilin is involved in atherosclerotic progression. PMID- 20710018 TI - Stress echocardiography in the age of multi-detector computed tomography. PMID- 20710019 TI - Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia. AB - BACKGROUND: The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of the microcirculatory dysfunction seen in sepsis. The mixed endothelin receptor antagonist tezosentan and the selective endothelin A-receptor antagonist TBC3711 were used to investigate the importance of the different endothelin receptors in modulating splanchnic regional blood flow and microvascular blood flow in endotoxaemia. METHODS: Eighteen anaesthetized pigs were i.v. infused with endotoxin (Escherichia coli lipopolysaccharide, serotype 0111:b4) for 300 min. After 120 min, six animals received tezosentan and six animals received TBC3711. Six animals served as endotoxin-treated controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and ileum. Superior mesenteric artery flow (SMA(FI)) and portal vein flow (PV(FI)) were measured with ultrasonic flow probes, and air tonometry was used to measure Pco2 in the ileal mucosa. RESULTS: TBC3711 did not improve splanchnic regional blood flow or splanchnic microvascular blood flow compared with endotoxin-treated controls. Tezosentan increased PV(FI) (P<0.05), but SMA(FI) was not improved compared with the other groups. In the tezosentan group, microvascular blood flow in the ileal mucosa (MCQ(muc)) improved and mucosal arterial Pco2 gap decreased (P<0.05 for both) compared with endotoxin-treated controls and the TBC3711 group. CONCLUSIONS: Tezosentan improved MCQ(muc) without any concomitant increase in SMA(FI), implying a direct positive effect on the microcirculation. TBC3711 was not effective in improving regional splanchnic blood flow or splanchnic microvascular blood flow. Dual endothelin receptor antagonism was necessary to improve MCQ(muc), indicating a role for the endothelin B-receptor in mediating the microcirculatory failure in the ileal mucosa. PMID- 20710020 TI - Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model. AB - BACKGROUND: The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. METHODS: Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40 120 min, 10-8-6-5 mg kg(-1) h(-1) infusion. Arterial blood samples were withdrawn at 1, 3, 5 min after induction, every 10-20 min during propofol infusion, and every 10-30 min for 2 h after stopping the propofol infusion. Arterial samples were processed by high-performance liquid chromatography. Time-concentration data profiles from this study were pooled with data from two other propofol PK studies available at http://www.opentci.org. Population PK modelling was performed using non-linear mixed effects model. RESULTS: The study involved 19 obese adults who contributed 163 observations. The pooled analysis involved 51 patients (weight 93 sd 24 kg, range 44-160 kg; age 46 sd 16 yr, range 25-81 yr; BMI 33 sd 9 kg m(-2), range 16-52 kg m(-2)). A three-compartment model was used to investigate propofol PK. An allometric size model using total body weight (TBW) was superior to all other models investigated (linear TBW, free fat mass, lean body weight, normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a function showing a decrease in both parameters with age. CONCLUSIONS: We have derived a population PK model using obese and non-obese data to characterize propofol PK over a wide range of body weights. An allometric model using TBW as the size descriptor of volumes and clearances was superior to other size descriptors to characterize propofol PK in obese patients. PMID- 20710021 TI - PR-segment deviation during cryoballoon ablation. PMID- 20710022 TI - Clarification to the article 'Magnetic resonance imaging of pacemakers and implantable cardioverter-defibrillators without specific absorption rate restrictions'. PMID- 20710023 TI - Sport injuries: a review of outcomes. AB - Injuries can counter the beneficial aspects related to sports activities if an athlete is unable to continue to participate because of residual effects of injury. We provide an updated synthesis of existing clinical evidence of long term follow-up outcome of sports injuries. A systematic computerized literature search was conducted on following databases were accessed: PubMed, Medline, Cochrane, CINAHL and Embase databases. At a young age, injury to the physis can result in limb deformities and leg-length discrepancy. Weight-bearing joints including the hip, knee and ankle are at risk of developing osteoarthritis (OA) in former athletes, after injury or in the presence of malalignment, especially in association with high impact sport. Knee injury is a risk factor for OA. Ankle ligament injuries in athletes result in incomplete recovery (up to 40% at 6 months), and OA in the long term (latency period more than 25 years). Spine pathologies are associated more commonly with certain sports (e.g. wrestling, heavy-weight lifting, gymnastics, tennis, soccer). Evolution in arthroscopy allows more accurate assessment of hip, ankle, shoulder, elbow and wrist intra articular post-traumatic pathologies, and possibly more successful management. Few well-conducted studies are available to establish the long-term follow-up of former athletes. To assess whether benefits from sports participation outweigh the risks, future research should involve questionnaires regarding the health related quality of life in former athletes, to be compared with the general population. PMID- 20710024 TI - Hallux valgus: effectiveness and safety of minimally invasive surgery. A systematic review. AB - Minimally invasive techniques for hallux valgus correction include arthroscopy, percutaneous and minimum incision surgery. In the last few decades, several techniques have been increasingly used. We performed a comprehensive search of CINAHL, Embase, Medline, HealthSTAR and the Cochrane Central Registry of Controlled Trials, from inception of the database to 4 January 2010, using various combinations of the keywords terms 'Bosch', 'PDO', 'percutaneous distal osteotomy', 'SERI', 'percutaneous', 'minimal incision', 'minimum incision', 'minimally invasive', 'less invasive', 'mini-invasive', 'hallux valgus', 'bunion', 'surgery', 'arthroscopy', 'metatarsal' 'forefoot'. Only articles published in peer reviewed journals were included in this systematic review. Several new techniques are available for minimally invasive correction of the hallux valgus. Minimally invasive correction of the hallux valgus may provide better outcome for patients who would not recover well from traditional open approaches, because of decreasing recovery and rehabilitation times, as surgical exposure and deep tissue dissection are smaller and gentler to the soft tissues. Data are lacking to allow definitive conclusions on the use of these techniques for routine management of patients with hallux valgus. Given the limitations of the current case series, especially the extensive clinical heterogeneity, it is not possible to determine clear recommendations regarding the systematic use of minimally invasive surgery for hallux valgus correction, even though preliminary results are encouraging. Studies of higher levels of evidence, concentrating on large adequately powered randomized trials, should be conducted to help answer these questions. PMID- 20710025 TI - Managing ankle sprains in primary care: what is best practice? A systematic review of the last 10 years of evidence. AB - To summarize the best available evidence in the last decade for managing ankle sprains in the community, data were collected using MEDLINE database from January 2000 to December 2009. Terms utilized: 'ankle injury primary care' (102 articles were found), 'ankle sprain primary care' (34 articles), 'ankle guidelines primary care' (25 articles), 'ankle pathways primary care' (2 articles), 'ankle sprain community' (18 articles), 'ankle sprain general practice' (22 articles), 'Cochrane review ankle' (58 articles). Of these, only 33 satisfied the inclusion criteria. The search terms identified many of the same studies. Two independent reviewers reviewed the articles. The study results and generated conclusions were extracted, discussed and finally agreed on. Ankle sprains occur commonly but their management is not always readily agreed. The Ottawa Ankle Rules are ubiquitous in the clinical pathway and can be reliably applied by emergency care physicians, primary care physicians and triage nurses. For mild-to-moderate ankle sprains, functional treatment options (which can consist of elastic bandaging, soft casting, taping or orthoses with associated coordination training) were found to be statistically better than immobilization for multiple outcome measures. For severe ankle sprains, a short period of immobilization in a below knee cast or pneumatic brace results in a quicker recovery than tubular compression bandage alone. Lace-up supports are a more effective functional treatment than elastic bandaging and result in less persistent swelling in the short term when compared with semi-rigid ankle supports, elastic bandaging and tape. Semi-rigid orthoses and pneumatic braces provide beneficial ankle support and may prevent subsequent sprains during high-risk sporting activity. Supervised rehabilitation training in combination with conventional treatment for acute lateral ankle sprains can be beneficial, although some of the studies reviewed gave conflicting outcomes. Therapeutic hyaluronic acid injections in the ankle are a relatively novel non-surgical treatment but may have a role in expediting return to sport after ankle sprain. There is a role for surgical intervention in severe acute and chronic ankle injuries, but the evidence is limited. PMID- 20710026 TI - Insights into an unusual nonribosomal peptide synthetase biosynthesis: identification and characterization of the GE81112 biosynthetic gene cluster. AB - The GE81112 tetrapeptides (1-3) represent a structurally unique class of antibiotics, acting as specific inhibitors of prokaryotic protein synthesis. Here we report the cloning and sequencing of the GE81112 biosynthetic gene cluster from Streptomyces sp. L-49973 and the development of a genetic manipulation system for Streptomyces sp. L-49973. The biosynthetic gene cluster for the tetrapeptide antibiotic GE81112 (getA-N) was identified within a 61.7-kb region comprising 29 open reading frames (open reading frames), 14 of which were assigned to the biosynthetic gene cluster. Sequence analysis revealed the GE81112 cluster to consist of six nonribosomal peptide synthetase (NRPS) genes encoding incomplete di-domain NRPS modules and a single free standing NRPS domain as well as genes encoding other biosynthetic and modifying proteins. The involvement of the cloned gene cluster in GE81112 biosynthesis was confirmed by inactivating the NRPS gene getE resulting in a GE81112 production abolished mutant. In addition, we characterized the NRPS A-domains from the pathway by expression in Escherichia coli and in vitro enzymatic assays. The previously unknown stereochemistry of most chiral centers in GE81112 was established from a combined chemical and biosynthetic approach. Taken together, these findings have allowed us to propose a rational model for GE81112 biosynthesis. The results further open the door to developing new derivatives of these promising antibiotic compounds by genetic engineering. PMID- 20710029 TI - Congenital cerebral and cerebellar lesions of unknown aetiology in calves. PMID- 20710028 TI - Oxidized cholesteryl esters and phospholipids in zebrafish larvae fed a high cholesterol diet: macrophage binding and activation. AB - A novel hypercholesterolemic zebrafish model has been developed to study early events of atherogenesis. This model utilizes optically transparent zebrafish larvae, fed a high cholesterol diet (HCD), to monitor processes of vascular inflammation in live animals. Because lipoprotein oxidation is an important factor in the development of atherosclerosis, in this study, we characterized the oxidized lipid milieu in HCD-fed zebrafish larvae. Using liquid chromatography mass spectrometry, we show that feeding an HCD for only 2 weeks resulted in up to 70-fold increases in specific oxidized cholesteryl esters, identical to those present in human minimally oxidized LDL and in murine atherosclerotic lesions. The levels of oxidized phospholipids, such as 1-palmitoyl-2-oxovaleroyl-sn glycero-3-phosphocholine, and of various lysophosphatidylcholines were also significantly elevated. Moreover, lipoproteins isolated from homogenates of HCD fed larvae induced cell spreading as well as ERK1/2, Akt, and JNK phosphorylation in murine macrophages. Removal of apoB-containing lipoproteins from the zebrafish homogenates with an anti-human LDL antibody, as well as reducing lipid hydroperoxides with ebselen, resulted in inhibition of macrophage activation. The TLR4 deficiency in murine macrophages prevented their activation with zebrafish lipoproteins. Using biotinylated homogenates of HCD-fed larvae, we demonstrated that their components bound to murine macrophages, and this binding was effectively competed by minimally oxidized LDL but not by native LDL. These data provide evidence that molecular lipid determinants of proatherogenic macrophage phenotypes are present in large quantities in hypercholesterolemic zebrafish larvae and support the use of the HCD-fed zebrafish as a valuable model to study early events of atherogenesis. PMID- 20710030 TI - Risk factors for culling in Holstein-Friesian dairy cows. AB - Risk factors associated with voluntary and involuntary culling within a Holstein Friesian dairy cow research herd were identified. Data were studied from 3498 completed lactations from the Langhill Holstein-Friesian dairy herd between January 1990 and June 2008. During this period the cows were based on two different farms in Scotland. The culling rate of the milking herd was approximately 25 per cent per annum. Approximately 68 per cent of cows culled were classified as involuntary. The association between different risk factors and the incidence of culling was investigated using a general linear mixed model. Of the 838 cows culled, 59 per cent were culled before the fourth lactation. Culling was associated with cows that had an assisted calving (P<0.01), aborted (P<0.01) and/or suffered from mastitis (P<0.05). Cows that were culled were also more likely to be older cows (P<0.01), have a low number of milking days (P<0.001) and/or a greater number of days from calving to conception (P<0.01). Culling was also associated with conception failure (r=0.752, P<0.001). Further work might help reduce the number of animals culled involuntarily, by identifying key factors associated with the incidence of an assisted calving, abortion and mastitis, and improving milking and fertility performance using detailed data from the Langhill herd. PMID- 20710031 TI - Use of transcutaneous external pacing during transvenous pacemaker implantation in dogs. AB - The aim of this retrospective study was to evaluate the utility of transcutaneous external pacing (TEP) during transvenous pacemaker implantation in dogs. Eighty two pacemakers were implanted in 77 dogs because of third-degree atrioventricular block (AVB) (58 cases; 70.7 per cent), sinus node dysfunction (SND) (nine cases; 11.0 per cent), high-grade second-degree AVB (six cases; 7.3 per cent), persistent atrial standstill (PAS) (four cases; 4.9 per cent), post radiofrequency catheter ablation of the bundle of His (four cases; 4.9 per cent) and vasovagal syncope with atrial fibrillation (one case; 1.2 per cent). TEP was initiated during general anaesthesia after the onset of asystole or profound bradycardia, and stopped when permanent pacing was started. The use of TEP was necessary in 27 cases: 19 cases of third-degree AVB, five of SND, two of PAS and one of vasovagal syncope. External pacing was successful in all but two dogs. PMID- 20710027 TI - Novel changes in NF-{kappa}B activity during progression and regression phases of hyperplasia: role of MEK, ERK, and p38. AB - Utilizing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we measured hyperplasia and NF-kappaB activation during progression (days 6 and 12 post-infection) and regression (days 20-34 post infection) phases of TMCH. NF-kappaB activity increased at progression in conjunction with bacterial attachment and translocation to the colonic crypts and decreased 40% by day 20. NF-kappaB activity at days 27 and 34, however, remained 2-3-fold higher than uninfected control. Expression of the downstream target gene CXCL-1/KC in the crypts correlated with NF-kappaB activation kinetics. Phosphorylation of cellular IkappaBalpha kinase (IKK)alpha/beta (Ser(176/180)) was elevated during progression and regression of TMCH. Phosphorylation (Ser(32/36)) and degradation of IkappaBalpha, however, contributed to NF-kappaB activation only from days 6 to 20 but not at later time points. Phosphorylation of MEK1/2 (Ser(217/221)), ERK1/2 (Thr(202)/Tyr(204)), and p38 (Thr(180)/Tyr(182)) paralleled IKKalpha/beta kinetics at days 6 and 12 without declining with regressing hyperplasia. siRNAs to MEK, ERK, and p38 significantly blocked NF kappaB activity in vitro, whereas MEK1/2-inhibitor (PD98059) also blocked increases in MEK1/2, ERK1/2, and IKKalpha/beta thereby inhibiting NF-kappaB activity in vivo. Cellular and nuclear levels of Ser(536)-phosphorylated (p65(536)) and Lys(310)-acetylated p65 subunit accompanied functional NF-kappaB activation during TMCH. RSK-1 phosphorylation at Thr(359)/Ser(363) in cellular/nuclear extracts and co-immunoprecipitation with cellular p65-NF-kappaB overlapped with p65(536) kinetics. Dietary pectin (6%) blocked NF-kappaB activity by blocking increases in p65 abundance and nuclear translocation thereby down regulating CXCL-1/KC expression in the crypts. Thus, NF-kappaB activation persisted despite the lack of bacterial attachment to colonic mucosa beyond peak hyperplasia. The MEK/ERK/p38 pathway therefore seems to modulate sustained activation of NF-kappaB in colonic crypts in response to C. rodentium infection. PMID- 20710032 TI - Comparison of anaesthetic and cardiorespiratory effects of xylazine or medetomidine in combination with tiletamine/zolazepam in pigs. AB - Two different combinations of anaesthetics were evaluated and compared in a prospective randomised crossover experimental study in pigs. One of the two combinations was administered intramuscularly to each of six Landrace x Yorkshire mixed-breed pigs. The combinations were: 2.2 mg/kg xylazine and 4.4 mg/kg tiletamine/zolazepam (2.2 mg/kg tiletamine plus 2.2 mg/kg zolazepam) (XTZ); and 0.04 mg/kg medetomidine and 4.4 mg/kg tiletamine/zolazepam (MTZ). The anaesthesia and recovery times, score for anaesthetic effect and cardiopulmonary parameters were recorded for each pig. Anaesthesia was successfully induced in all of the pigs. Both drug combinations provided smooth induction and good immobilisation, and their anaesthetic effects were similar. In both treatment groups, the mean heart rate decreased significantly five minutes after the drugs were administered and remained consistent for 70 minutes, with no significant difference between the XTZ and MTZ groups. However, there were differences in cardiopulmonary effects between the groups. The arterial pressure was significantly higher in the MTZ group than in the XTZ group. The initial hypertension associated with medetomidine was more marked than the initial hypertension associated with xylazine. Arterial oxygen partial pressure and arterial oxygen saturation decreased significantly from baseline in both groups. The respiratory rates and levels of blood gases were similar in both groups. Hypoventilation and hypoxaemia were observed in both groups. The scores for anaesthetic effect, induction time, anaesthesia time and recovery times were similar in the two groups. PMID- 20710034 TI - Scandinavian bovine practitioners' attitudes to the use of analgesics in cattle. PMID- 20710033 TI - Repeated cross-sectional skin testing for bovine tuberculosis in cattle kept in a traditional husbandry system in Ethiopia. AB - Representative repeated cross-sectional skin testing for bovine tuberculosis (TB) was conducted over a period of three years in a total of 5377 cattle in three randomly selected woredas (districts) in Ethiopia (Meskan, Woldia and Bako-Gazer) that had never previously been tested for TB. Almost all (99 per cent) of the animals included local zebus kept in traditional husbandry systems. The comparative intradermal tuberculin test with two diagnostic thresholds were used to define positive test results, one according to the World Organisation for Animal Health (OIE) recommended cut-off of more than 4 mm, and the other with a cut-off of >2 mm. Data analysis was performed using a logistic regression model with a random effect at the village level. Applying the OIE definition, the overall representative apparent prevalence of bovine TB in skin test-positive local zebus was 0.9 per cent (95 per cent confidence interval [CI] 0.6 to 1.3 per cent). Using a cut-off of more than 2 mm the overall representative prevalence increased to 4 per cent (95 per cent CI 2.4 to 4.8 per cent). Due to the low apparent prevalence, the true prevalence could be calculated only in Meskan (4.5 per cent) and Bako-Gazer (2.4 per cent) for the more than 2 mm cut-off. With the exception of Meskan, prevalence by woreda did not change significantly over the years. Mycobacterium avium reactor animals were found at all study sites, but there were significant geographical variations. Overall, bulls and oxen were more at risk of being positive reactors (odds ratio [OR] 1.6, 95 per cent CI 1.1 to 2.3; OR 2, 95 per cent CI 1.4 to 2.6, respectively), as were animals in good body condition (OR 2, 95 per cent CI 1.5 to 2.9). Similar results were found at woreda level with the exception of Woldia, where none of the analysed variables was significantly associated with a positive test result. PMID- 20710035 TI - Tetrameres species parasites in tawny owls (Strix aluco). PMID- 20710036 TI - Reporting vaccine failures as suspected adverse reactions. PMID- 20710037 TI - Dicrocoelium dendriticum in Devon. PMID- 20710039 TI - A brighter side of ROS revealed by selective activation of beta-adrenergic receptor subtypes. PMID- 20710040 TI - Oxidative stress fine-tunes the dance of hERG K+ channels. PMID- 20710042 TI - Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells. AB - The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein composed of two extracellular alpha subunits and two beta subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here, we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to alpha- and beta-subunit domains. Cell-surface IGF-1R translocates to the nucleus following clathrin-mediated endocytosis, regulated by IGF levels. The IGF-1R is unusual among transmembrane receptors that undergo nuclear import, in that both alpha and beta subunits traffic to the nucleus. Nuclear IGF-1R is phosphorylated in response to ligand and undergoes IGF-induced interaction with chromatin, suggesting direct engagement in transcriptional regulation. The IGF dependence of these phenomena indicates a requirement for the receptor kinase, and indeed, IGF-1R nuclear import and chromatin binding can be blocked by a novel IGF-1R kinase inhibitor. Nuclear IGF-1R is detectable in primary renal cancer cells, formalin-fixed tumors, preinvasive lesions in the breast, and nonmalignant tissues characterized by a high proliferation rate. In clear cell renal cancer, nuclear IGF-1R is associated with adverse prognosis. Our findings suggest that IGF-1R nuclear import has biological significance, may contribute directly to IGF-1R function, and may influence the efficacy of IGF-1R inhibitory drugs. PMID- 20710043 TI - Metastasis-associated protein 1 short form stimulates Wnt1 pathway in mammary epithelial and cancer cells. AB - Although Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antigen 1 short form (MTA1s) are elevated in human breast cancer, it remains unknown whether a regulatory cross-talk exists between these two pathways. Here, we provide evidence of a remarkable correlation between the levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabilization of beta-catenin and stimulation of Wnt1 target genes in the murine mammary epithelial and human breast cancer cells. We found that MTA1s influences Wnt1 pathway through extracellular signal-regulated kinase (ERK) signaling as selective silencing of the endogenous MTA1s or ERK, or its target glycogen synthase kinase 3beta resulted in a substantial decrease in beta-catenin expression, leading to the inhibition of Wnt1 target genes. Furthermore, downregulation of beta-catenin in cells with elevated MTA1s level was accompanied by a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role for the ERK/glycogen synthase kinase 3beta/beta-catenin pathway in the stimulation of the Wnt1 target genes by MTA1s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice mimicked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivation of the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of beta-catenin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal carcinoma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells. PMID- 20710044 TI - Presence of a putative tumor-initiating progenitor cell population predicts poor prognosis in smokers with non-small cell lung cancer. AB - Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC. PMID- 20710046 TI - Retraction: Spontaneous human adult stem cell transformation. PMID- 20710045 TI - Intratumoral localization of aromatase and interaction between stromal and parenchymal cells in the non-small cell lung carcinoma microenvironment. AB - Estrogens produced as a result of intratumoral aromatization has been recently shown to play important roles in proliferation of human non-small cell lung carcinomas (NSCLC), but the details have remained largely unknown. Therefore, in this study, we evaluated the possible roles of intratumoral aromatase in NSCLCs as follows: (a) evaluation of intratumoral localization of aromatase mRNA/protein in six lung adenocarcinoma cases using laser capture microdissection combined with quantitative reverse transcriptase-PCR and immunohistochemistry; (b) examination of the possible effects of isolated stromal cells from lung carcinoma tissues on aromatase mRNA transcript expression in lung carcinoma cell lines (A549 and LK87) through a coculture system; and (c) screening of cytokines derived from stromal LK001S and LK002S cells using cytokine antibody arrays and subsequent evaluation of effects of these cytokines on aromatase expression in A549 and LK87. Both aromatase mRNA and protein were mainly detected in intratumoral carcinoma cells but not in stromal cells. Aromatase expression of A549 and LK87 was upregulated in the presence of LK001S or LK002S cells. Several cytokines such as interleukin-6 (IL-6), oncostatin M, and tumor necrosis factor alpha, all known as inducible factors of aromatase gene, were detected in conditioned media of LK001S and LK002S cells. Treatment of both oncostatin M and IL-6 induced aromatase gene expression in A549 an LK87, respectively. These results all indicated that intratumoral microenvironments, especially carcinoma stromal cell interactions, play a pivotal role in the regulation of intratumoral estrogen synthesis through aromatase expression in human lung adenocarcinomas. PMID- 20710047 TI - FSH dystrophy and a subtelomeric 4q haplotype: a new assay and associations with disease. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with contraction of arrays of tandem 3.3-kb units (D4Z4) on subtelomeric 4q. Disease-linked arrays usually have fewer than 11 repeat units. Equally short D4Z4 arrays at subtelomeric 10q are not linked to FSHD. The newly described 4qA161 haplotype, which is more prevalent in pathogenic 4q alleles, involves sequences in and near D4Z4. METHODS: We developed two new assays for 4qA161, which are based upon direct sequencing of PCR products or detecting restriction fragment length polymorphisms. They were used to analyse single nucleotide polymorphisms (SNPs) indicative of 4q161 alleles. RESULTS: All (35/35) FSHD patients had one or two 4qA161 alleles (60% or 40%, respectively). In contrast, 46% (21/46) of control individuals had no 4qA161 allele (p<10(-4)), and 26% had homozygous 4qB163 alleles. CONCLUSIONS: Our results from a heterogeneous population are consistent with the previously described association of the 4qA161 haplotype with FSHD, but a causal association with pathogenesis is uncertain. In addition, we found that haplotype analysis is complicated by the presence of minor 10q alleles. Nonetheless, our sequencing assay for the 4qA161allele can enhance molecular diagnosis of FSHD, including prenatal diagnosis, and is simpler to perform than the previously described assay. PMID- 20710048 TI - Delayed interval of involvement of the second eye in a male patient with bilateral Chandler's syndrome. PMID- 20710049 TI - National survey of the use of intraoperative antibiotics for prophylaxis against postoperative endophthalmitis following cataract surgery in the UK. PMID- 20710050 TI - Ribavirin monitoring in chronic hepatitis C therapy: anaemia versus efficacy. AB - The standard treatment of HCV infection with pegylated interferon-alpha2a or alpha2b and ribavirin is effective in <50% of HCV genotype-1-infected patients. To improve this figure, it might be desirable to obtain optimal plasma concentrations of the drug by increasing the dose. Unfortunately, there is great interpatient variability in ribavirin pharmacokinetics. In the present review, we describe the mechanism of ribavirin-induced anaemia in detail, evaluate host predictive factors for this harmful side effect and assess the literature data on attempts to improve the sustained virological response rate by increasing the dose of ribavirin. We suggest an optimal steady-state concentration range for ribavirin in monoinfected and coinfected patients. Lastly, we propose that it would be of particular value to monitor ribavirin concentrations in HCV genotype 1-infected patients and (regardless of the genotype) coinfected patients, haemodialyzed patients and obese patients. PMID- 20710051 TI - Medicinal herbal extracts of Sophorae radix, Acanthopanacis cortex, Sanguisorbae radix and Torilis fructus inhibit coronavirus replication in vitro. AB - BACKGROUND: Cimicifuga rhizome, Meliae cortex, Coptidis rhizome and Phellodendron cortex have been previously shown to exhibit anti-coronavirus activity. Here, an additional 19 traditional medicinal herbal extracts were evaluated for antiviral activities in vitro. METHODS: A plaque assay was used to evaluate the effects of 19 extracts, and the concentration of extract required to inhibit 50% of the replication (EC(50)) of mouse hepatitis virus (MHV) A59 strain (MHV-A59) was determined. The 50% cytotoxic concentration (CC(50)) of each extract was also determined. Northern and western blot analyses were conducted to evaluate antiviral activity on viral entry, viral RNA and protein expression, and release in MHV-infected DBT cells. RESULTS: Sophorae radix, Acanthopanacis cortex and Torilis fructus reduced intracellular viral RNA levels with comparable reductions in viral proteins and MHV-A59 production. The extracts also reduced the replication of the John Howard Mueller strain of MHV, porcine epidemic diarrhoea virus and vesicular stomatitis virus in vitro. Sanguisorbae radix reduced coronavirus production, partly as a result of decreased protein synthesis, but without a significant reduction in intracellular viral RNA levels. The EC(50) values of the four extracts ranged from 0.8 to 3.7 microg/ml, whereas the CC(50) values ranged from 156.5 to 556.8 microg/ml. Acanthopanacis cortex and Torilis fructus might exert their antiviral activities in MHV-A59-infected cells by inducing cyclooxygenase-2 expression via the activation of extracellular signal related kinase (ERK) and p38 or ERK alone, respectively. CONCLUSIONS: Sophorae radix, Acanthopanacis cortex, Sanguisorbae radix and Torilis fructus might be considered as promising novel anti-coronavirus drug candidates. PMID- 20710053 TI - Novel influenza A(H1N1) 2009 in vitro reassortant viruses with oseltamivir resistance. AB - BACKGROUND: With the recent emergence of the novel A(H1N1) virus in 2009, the efficacy of available drugs, such as neuraminidase (NA) inhibitors, is of great concern for good patient care. Influenza viruses are known to be able to acquire resistance. In 2007, A(H1N1) viruses related to A/Brisbane/59/2007 (H1N1) (A[H1N1] Brisbane-like virus), which are naturally resistant to oseltamivir, emerged. Resistance to oseltamivir can be acquired either by spontaneous mutation in the NA (H275Y in N1), or by reassortment with a mutated NA. It is therefore crucial to determine the risk of pandemic A(H1N1) 2009 virus acquiring resistance against oseltamivir by reassortment. METHODS: We estimated the capacity of reassortment between the A(H1N1) 2009 virus and an oseltamivir-resistant A(H1N1) Brisbane-like virus by in vitro coinfections of influenza-permissive cells. The screening and the analysis of reassortant viruses was performed by specific reverse transcriptase PCRs and by sequencing. RESULTS: Out of 50 analysed reassortant viruses, two harboured the haemagglutinin (HA) segment from the pandemic A(H1N1) 2009 virus and the mutated NA originated from the A(H1N1) Brisbane-like virus. The replicating capacities of these viruses were measured, showing no difference as compared to the two parental strains, suggesting that acquisition of the mutated NA segment did not impair viral fitness in vitro. CONCLUSIONS: Our results suggest that the novel A(H1N1) 2009 virus can acquire by in vitro genetic reassortment the H275Y mutated NA segment conferring resistance to oseltamivir. PMID- 20710052 TI - Pharmacokinetics of once-daily etravirine without and with once-daily darunavir/ritonavir in antiretroviral-naive HIV type-1-infected adults. AB - BACKGROUND: A pharmacokinetic trial was conducted to evaluate the potential for once-daily etravirine in antiretroviral regimens without and with darunavir/ritonavir. METHODS: During this multicentre, open-label, Phase IIa trial, treatment-naive patients aged > or =18 years with HIV type-1 (HIV-1) received etravirine 400 mg once daily with tenofovir disoproxil fumarate/emtricitabine 300/200 mg once daily from days 1-14; on days 15-28, darunavir/ritonavir 800/100 mg once daily was added. On day 29, etravirine was discontinued and patients continued with the other medications to day 42. Serial blood sampling for etravirine pharmacokinetics was performed over 24 h on day 14 and 28; patients fasted for > or =10 h prior to these visits. RESULTS: Of 23 enrolled patients (male 87%, Caucasian 39%), pharmacokinetic profiles for etravirine were available for 21 and 20 patients on day 14 and 28, respectively. The plasma concentration-time profile and pharmacokinetics for etravirine were unchanged with or without darunavir/ritonavir. The mean maximum plasma concentration (C(max)) was reached 4 h after administration and was 790 and 801 ng/ml on day 14 and 28, respectively; mean area under the plasma concentration time curve (AUC) from before administration to 24 h after administration was 10,410 ng*h/ml on day 14 and 10,720 ng*h/ml on day 28. In a post-hoc analysis, etravirine C(max) was higher, minimum plasma concentration was lower and AUC was similar when compared with etravirine 200 mg twice daily. CONCLUSIONS: Addition of darunavir/ritonavir to etravirine, all dosed once daily, did not have a clinically significant effect on the pharmacokinetics of etravirine. Findings support further investigation of etravirine 400 mg once daily in HIV-1-infected patients. (Trial registration number NCT00534352.). PMID- 20710054 TI - Control of African swine fever virus replication by small interfering RNA targeting the A151R and VP72 genes. AB - BACKGROUND: African swine fever virus (ASFV) is the unique member of the Asfarviridae family and Asfivirus genus. It is an enveloped double-stranded DNA arbovirus that replicates in the cell cytoplasm, similar to poxviruses. There is no vaccine and no treatment available to control this virus. METHODS: We describe the use of small interfering RNA (siRNA) targeting the A151R and VP72 (B646L) genes to control the ASFV replication in vitro. RESULTS: Results suggest that siRNA targeting the A151R and VP72 genes can reduce both the virus replication and its levels of messenger RNA transcripts. The reduction was up to 4 log(10) copies on the virus titre and up to 3 log(10) copies on virus RNA transcripts levels. The combination of multiple siRNA did not improve the antiviral effect significantly, compared with use of individual siRNAs. CONCLUSIONS: The function of the A151R gene product in the virus replication cycle is yet unclear, but is essential. We also demonstrate that it is possible to inhibit, using small interfering RNA, a virus that replicates exclusively in the cell cytoplasm in specific viral factories. PMID- 20710055 TI - Interferon-lambda in immunocompetent individuals with a history of recurrent herpes labialis. AB - BACKGROUND: Herpes labialis (HL) is the most common manifestation of recurrent oral herpes simplex virus type-1 (HSV-1) infection. Between 20% and 40% of the population is affected by recurrent HL. The biological basis for the difference between HSV-1-infected individuals who do and who do not suffer recurrences, has long been investigated. Interferon (IFN)-alpha and IFN-lambda are essential for antiviral immunity, but the precise role of IFN-lambda in vivo is not yet well understood. METHODS: Healthy immunocompetent patients with or without a history of recurrent HL were recruited from the Policlinico of the University of Rome Tor Vergata (Rome, Italy), and HSV-1-seronegative individuals were recruited from the Department of Experimental Medicine of the University of Rome Tor Vergata, between July 2007 and December 2008. Participants were interviewed by medically trained investigators and underwent a blood test. Peripheral blood mononuclear cells (PBMCs) were obtained from heparinized blood of patients and stimulated in vitro with intact HSV-1 strain F1 (1 plaque-forming unit/cell). PBMC supernatants were assayed for IFN-alpha, IFN-gamma and IFN-lambda production by ELISA at 24 and 48 h after viral challenge. RESULTS: PBMC from patients with a history of recurrent HL produced markedly lower levels of IFN-lambda and marginally lower levels of IFN-alpha and IFN-gamma than those from the history-negative HSV-1 seropositive controls. Among individuals with HL recurrences, those with more frequent and severe manifestations showed a significant trend towards lower levels of IFN-lambda production. CONCLUSIONS: A reduced IFN-lambda response might correlate with the development of recurrent HSV-1 infection in immunocompetent individuals. Testing for IFN-lambda response might be useful to predict individual patterns of antiviral response, contributing to more successful therapeutic or prophylactic interventions. PMID- 20710056 TI - GB virus C coinfection in advanced HIV type-1 disease is associated with low CCR5 and CXCR4 surface expression on CD4(+) T-cells. AB - BACKGROUND: Coinfection with the flavivirus GB virus C (GBV-C) is frequent in patients suffering from HIV type-1 (HIV-1) infection because of shared routes of transmission. GBV-C coinfection has been proposed to exert a beneficial influence on HIV-1 infection. In vitro studies demonstrated down-regulation of C-C chemokine receptor type 5 (CCR5) as a potential mechanism by which GBV-C modulates HIV-1 disease progression. We therefore studied surface expression of the two major HIV-1 coreceptors, CCR5 and CXC chemokine receptor type 4 (CXCR4), on CD4(+) and CD8(+) T-cells in 128 HIV-1-positive patients stratified with respect to their GBV-C status, immune function and highly active antiretroviral therapy (HAART) status in vivo. METHODS: GBV-C infection was studied in 128 HIV-1 infected patients by nested reverse transcriptase PCR. Fluorescence-activated cell sorting analysis was used to measure CCR5 and CXCR4 surface expression on CD4(+) and CD8(+) T-cells. RESULTS: GBV-C RNA replication was detected in 30% (38/128) of patients. In HIV-1-positive patients with advanced immunodeficiency, we found up-regulation of CCR5 surface expression on CD4(+) T-cells; however, in patients with GBV-C coinfection, no up-regulation of CCR5 CD4(+) T-cells was detected. Furthermore, CXCR4 surface expression was reduced in GBV-C-coinfected patients. These findings were independent of HAART status and HIV-1 viral load. HIV-1 coreceptor expression on CD8(+) T-cells was not altered in patients with GBV-C coinfection. CONCLUSIONS: GBV-C coinfection in HIV-1 disease leads to reduced expression of the two major HIV-1 coreceptors, CCR5 and CXCR4, on CD4(+) T-cells in patients at an advanced stage of immunodeficiency, providing a possible molecular explanation for the clinical benefit of GBV-C coinfection in late-stage HIV-1 disease. PMID- 20710057 TI - Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine. AB - BACKGROUND: Unexpected cases of severe liver disease in HIV-infected patients have been reported and an association with didanosine (ddI) has been suggested. Transient elastography (TE) might detect patients harbouring such a condition. Our objective was to search for the presence of abnormal liver stiffness (LS) in a cohort of HIV-infected patients without HBV or HCV coinfection and to assess the related factors. METHODS: A cross-sectional prospective study was conducted. LS was assessed by TE in 258 HIV-infected patients without HBV or HCV coinfection and with no evidence of acute hepatotoxicity or other origins of liver disease. LS values > or =7.2 kPa were considered abnormal. Multivariate analyses were performed to identify factors associated with abnormal LS. RESULTS: Abnormal LS was observed in 29 (11.2%) patients. A total of 18 (16.4%) patients previously treated with ddI and 11 (7.4%) of those who never received ddI had LS values > or =7.2 kPa (P=0.02). The prevalence of abnormal LS was higher in patients previously treated with abacavir than in those who had never received abacavir (15 [21.7%] versus 14 [7.4%]; P=0.001). After multivariate analyses, age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.002-1.1; P=0.004) alcohol intake >50 g/day (AOR 7.2, 95% CI 2.6-19.7; P<0.0001), CD4(+) T-cell count <200 cells/ml (AOR 3.4, 95% CI 1.06-11.007; P=0.03), time on ddI treatment (AOR 1.31, 95% CI 1.12-1.52; P=0.001) and previous abacavir exposure (AOR 3.01, 95% CI 1.18-7.67; P=0.02) were independently associated with abnormal LS. CONCLUSIONS: The prevalence of abnormal LS in HIV-infected patients without HBV or HCV coinfection is substantial. Long-term exposure to ddI is a major cause of liver damage in these patients. PMID- 20710058 TI - Safety and antiviral activity of JTK-652: a novel HCV infection inhibitor. AB - BACKGROUND: Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK-652, a novel pyrrolopyridazin-derived HCV infection inhibitor. METHODS: JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1x10(5) IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks. RESULTS: JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment. CONCLUSIONS: Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level. PMID- 20710059 TI - Antiretroviral therapy in pregnancy: balancing the risk of preterm delivery with prevention of mother-to-child HIV transmission. AB - BACKGROUND: Highly active antiretroviral therapy (HAART) for pregnant HIV positive women reduces the risk of mother-to-child transmission, but is associated with an increased risk of preterm delivery (<37 weeks gestation). We aimed to quantify the incremental risk-benefit ratio for HAART compared with zidovudine monotherapy with respect to these outcomes. METHODS: Two-stage Monte Carlo simulation methods were used to estimate the risk-benefit ratio for HAART in pregnancy. Estimates of mother-to-child transmission and preterm delivery rates were obtained from UK and Ireland surveillance data collected through the National Study of HIV in Pregnancy and Childhood. RESULTS: At a population level, HAART was associated with a more than sevenfold reduction in mother-to-child transmission compared with zidovudine monotherapy (adjusted odds ratio [AOR] 0.13, 95% confidence interval [CI] 0.06-0.27), but with a 1.4-fold increased odds of preterm delivery (AOR 1.43, 95% CI 1.10-1.86) and twofold increased odds of severe preterm delivery (<32 weeks; AOR 2.06, 95% CI 1.09-3.88). The incremental risk-benefit ratio for HAART in pregnancy compared with monotherapy was 0.63 (95% simulation interval 0.06-1.96) additional preterm births and 0.23 (95% simulation interval -0.02-0.88) severe preterm births for each infection prevented. CONCLUSIONS: It is estimated that for every 100 HIV transmissions prevented through the use of HAART (rather than monotherapy), 63 additional preterm deliveries would occur, including 23 at <32 weeks gestation. Interpretation of these ratios is context-dependent and requires additional information about morbidity, mortality and costs associated with the outcomes. PMID- 20710060 TI - Cidofovir does not prevent caprine herpesvirus type-1 neural latency in goats. AB - BACKGROUND: Cidofovir (CDV) is an acyclic nucleoside phosphonate that exhibits a potent antiviral activity against several DNA viruses. In previous studies, CDV has been shown to significantly reduce the clinical severity and the viral shedding in primary caprine herpesvirus type-1 (CpHV-1) infection in goats. CpHV 1 is an alpha-herpesvirus showing many biological similarities with human herpesvirus type-2 (HHV-2); therefore, studies conducted on the CpHV-1 goat model could provide useful information on the pathogenesis, therapy and prevention of HHV-2 infection in humans. METHODS: CDV was administered to goats infected by vaginal route with CpHV-1. Real-time PCR was carried out on sacral ganglia from CpHV-1-infected goats to detect and quantify latent CpHV-1 DNA. RESULTS: Viral DNA was variably found in all five pairs of sacral ganglia, with a more frequent involvement of the third and fourth pair. In CDV-treated goats, the amount of CpHV-1 DNA did not appear to be related either to the severity of the clinical signs or the titre of the virus shed during primary CpHV-1 infection. CONCLUSIONS: CDV failed to prevent CpHV-1 latency. Thus, vaginal CDV administration during primary herpesvirus infection, although providing immediate clinical benefits to the host might not influence the establishment of latency and, consequently, the rate of recurrent infections. PMID- 20710061 TI - Ongoing drug use and outcomes from highly active antiretroviral therapy among injection drug users in a Canadian setting. AB - BACKGROUND: The effect of ongoing illicit drug use on HIV treatment remains controversial, especially in countries where access to HIV treatment for active injection drug users (IDUs) is limited because of presumed non-adherence. We sought to investigate the influence of drug use patterns on adherence to antiretroviral therapy and virological suppression among IDUs. METHODS: Using generalized estimating equation logistic regression, we explored the effect of abstinence versus ongoing drug use on adherence and virological suppression using data from a community-recruited cohort of IDUs in Vancouver (BC, Canada). RESULTS: A total of 381 HIV-positive IDUs were included in this analysis, among whom the median follow-up time was 30 months. In a multivariate model, no relationship was found between abstinence (reference) and active injection (adjusted odds ratio [AOR] 0.88, 95% confidence interval [CI] 0.65-1.17) and non injection (AOR 0.97, 95% CI 0.67-1.41) drug use with adherence. In subanalyses, ongoing injection drug use was associated with a lower odds of virological suppression in comparison to abstinence (AOR 0.74, 95% CI 0.57-0.97; P=0.026) and both active IDUs and active non-IDUs had lower odds of virological suppression compared with abstinent participants when longer periods of virological suppression were considered. CONCLUSIONS: Given the absence of a strong relationship between abstinence and ongoing drug use and adherence among HIV positive IDUs, programmes that restrict antiretrovirals to abstinent individuals should be re-examined. The lower rates of virological suppression associated with ongoing drug use nevertheless highlight the importance of comprehensive systems of care and addiction treatment for active drug users. PMID- 20710062 TI - Response to anti-HCV therapy in HIV-HCV-coinfected patients: does the lipid profile really have an effect? AB - BACKGROUND: Because high serum low-density lipoprotein (LDL) and total cholesterol concentrations before treatment have been found to be significant positive prognostic factors for a sustained virological response to HCV therapy in monoinfected patients, the aim of this study was to assess this relationship in HIV-HCV-coinfected patients. METHODS: Pretreatment fasting lipid parameters (in particular total cholesterol, LDL, high-density lipoprotein [HDL], apolipoprotein B [apoB] and triglycerides [TG]) were assessed in 315 patients from the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) HC02-Ribavic therapeutic trial. RESULTS: There was a significant correlation between pretreatment lipid parameters and steatosis (total cholesterol r=-0.23, P<0.0001; LDL r=-0.23, P<0.0001; HDL r=-0.28, P<0.0001; and TG r=0.18, P=0.002), but not with fibrosis. None of these lipid parameters were significant predictors of a sustained virological response to HCV therapy, even after adjustment for the type of interferon treatment and for the main known prognostic factors for a response to HCV therapy. CONCLUSIONS: The possible effect of lipid metabolism on virological response is outweighed by other prognostic factors that affect response to HCV therapy in the ANRS HC02-Ribavic study. PMID- 20710063 TI - Looking for an active conformation of the future HIV type-1 non-nucleoside reverse transcriptase inhibitors. AB - HIV type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV infection. NNRTI-based HAART regimes effectively suppress viral reproduction, are not cytotoxic and show favourable pharmacokinetic properties. First-generation NNRTIs suffer the rapid selection of viral variants, hampering the binding of inhibitors into the reverse transcriptase (RT) non nucleoside binding site (NNBS). Efforts to improve these first inhibitors led to the discovery of second-generation NNRTIs that proved to be effective against the drug-resistant mutant HIV-1 strains. The success of such agents launched a new season of NNRTI design and synthesis. This paper reviews the characteristics of second-generation NNRTIs, including etravirine, rilpivirine, RDEA-806, UK-453061, BIRL 355 BS, IDX 899, MK-4965 and HBY 097. In particular, the binding modes of these inhibitors into the NNBS of the HIV-1 RT and the most clinically relevant mutant RTs are analysed and discussed. PMID- 20710064 TI - Procyanidin B1 purified from Cinnamomi cortex suppresses hepatitis C virus replication. AB - BACKGROUND: A combination of pegylated interferon and ribavirin is the current standard therapy for hepatitis C virus (HCV) infection, but this combination provides relatively low efficacy, especially in some patients with HCV genotype 1 infection; therefore, the development of novel therapeutic agents is required for further improvement in the treatment of chronic HCV infection. METHODS: HCV pseudotype and subgenomic replicon assays were used in this study. The interaction of compounds with HCV receptors was examined using flow cytometry. Intracellular RNA levels were determined by semi-quantitative reverse transcriptase PCR. RESULTS: Procyanidin B1 (PB1), a dimer of (-)-epicatechin and (+)-catechin, purified from Cinnamomi cortex, inhibits infection by vesicular stomatitis virus and HCV pseudotype virus in Huh-7 cells, with 50% effective concentrations of 29 and 15 microM, respectively. No inhibitory effects were observed in each component of PB1. We found that PB1 does not interfere with viral entry or receptor expression, but inhibits HCV RNA synthesis in a dose dependent manner. CONCLUSIONS: These results indicate that PB1 suppresses HCV RNA synthesis, possibly as a HCV RNA polymerase inhibitor. Our results might contribute towards the development of more effective inhibitors for HCV infection from natural plants. PMID- 20710065 TI - Phenylboronic-acid-based carbohydrate binders as antiviral therapeutics: monophenylboronic acids. AB - BACKGROUND: The development of carbohydrate-binding agents as novel therapeutics for the inhibition of highly glycosylated enveloped viruses has generated much attention in recent literature. Possessing a potential dual mode of action by inhibiting virus entry and exposing the virion to neutralization by the host immune system upon the deletion of envelope glycans under drug pressure, these substances might provide a new direction in antiviral treatment. Phenylboronic acids are widely known to bind the cis-diol functionality of carbohydrate structures, thereby identifying themselves as potential lead structures. To date, few details have been disclosed of the structure-activity relationship of these substances in correlation to their antiviral activity. METHODS: In this study, a compound library of a diverse range of ortho-, meta- and para- ring-substituted monophenylboronic acids and glutamine phenylboronic acid analogues was prepared, characterized and evaluated to probe antiviral activity versus a broad range of (enveloped) viruses. RESULTS: The compounds described herein lack antiviral activity. They also did not show measurable binding to HIV type-1 (HIV-1) gp120, using surface plasmon resonance technology. However, of note is the general lack of toxicity, which suggests that further investigation of the compounds as potential therapeutics is needed. CONCLUSIONS: The monophenylboronic acids tested exhibited no antiviral activity as potential carbohydrate binders versus a broad range of enveloped and non-enveloped viruses. The compounds tested did not bind HIV-1 gp120, possibly because of their small size and lack of multivalency. PMID- 20710066 TI - Synthesis and biological evaluation of heat-shock protein 90 inhibitors: geldanamycin derivatives with broad antiviral activities. AB - BACKGROUND: Previous studies have suggested that geldanamycin (GA) inhibits the replication of several viruses in vitro. Here, we aimed to synthesize and evaluate the antiviral activity of 17-amino-17-demethoxygeldanamycin derivatives. METHODS: A series of 17-substituted and 17-,19-disubstituted GA derivatives were screened for antiviral activities against eight different viral strains, including herpesvirus, hepatitis virus, retrovirus and picornavirus. RESULTS: Most of the tested compounds showed inhibitory activity against the viruses and showed reduced cytotoxicity in vitro as compared with the parent compound GA. In vivo efficacy evaluation results showed that compound 6 noticeably inhibited duckling hepatitis B virus DNA replication in duckling serum after oral administration. Viral rebound did not occur after termination of the treatment. The modified GA derivatives also showed median lethal dose values that were higher than that of the parent GA in mice intraperitoneally treated with the study compounds. CONCLUSIONS: Targeting heat-shock protein 90 could be a new antiviral approach that is not prone to the development of drug resistance. The 17-amino-17-demethoxygeldanamycin derivatives could be novel agents with potential antiviral activity. PMID- 20710067 TI - Propulsive efficiency of a biomorphic pulsed-jet underwater vehicle. AB - The effect of the velocity program and duty cycle (St(L)) on the propulsive efficiency of pulsed-jet propulsion was studied experimentally on a self propelled, pulsed-jet underwater vehicle, dubbed Robosquid due to the similarity of essential elements of its propulsion system with squid jet propulsion. Robosquid was tested for jet slug length-to-diameter ratios (L/D) in the range 2 6 and St(L) in the range 0.2-0.6 with jet velocity programs commanded to be triangular or trapezoidal. Digital particle image velocimetry was used for measuring the impulse and energy of jet pulses to calculate the pulsed-jet propulsive efficiency and compare it with an equivalent steady jet system. Robosquid's Reynolds number (Re) based on average vehicle velocity and vehicle diameter ranged between 1300 and 2700 for the conditions tested. The results indicated better propulsive efficiency of the trapezoidal velocity program (up to 20% higher) compared to the triangular velocity program. Also, an increase in the ratio of the pulsed-jet propulsive efficiency to the equivalent steady jet propulsive efficiency (eta(P)/eta(P, ss)) was observed as St(L) increased and L/D decreased. For cases of short L/D and high St(L), eta(P)/eta(P, ss) was found to be as high as 1.2, indicating better performance of pulsed jets. This result demonstrates a case where propulsion using essential elements of a biological locomotion system can outperform the traditional mechanical system equivalent in terms of efficiency. It was also found that changes in St(L) had a proportionately larger effect on propulsive efficiency compared to changes in L/D. A simple model is presented to explain the results in terms of the contribution of over-pressure at the nozzle exit plane associated with the formation of vortex rings with each jet pulse. PMID- 20710068 TI - Optical surface profiling of orb-web spider capture silks. AB - Much spider silk research to date has focused on its mechanical properties. However, the webs of many orb-web spiders have evolved for over 136 million years to evade visual detection by insect prey. It is therefore a photonic device in addition to being a mechanical device. Herein we use optical surface profiling of capture silks from the webs of adult female St Andrews cross spiders (Argiope keyserlingi) to successfully measure the geometry of adhesive silk droplets and to show a bowing in the aqueous layer on the spider capture silk between adhesive droplets. Optical surface profiling shows geometric features of the capture silk that have not been previously measured and contributes to understanding the links between the physical form and biological function. The research also demonstrates non-standard use of an optical surface profiler to measure the maximum width of a transparent micro-sized droplet (microlens). PMID- 20710070 TI - Abstracts of the XXVI Barany Society Meeting, Reykjavik, Iceland, August 18-21, 2010. PMID- 20710069 TI - Differential pressure measurement using a free-flying insect-like ornithopter with an MEMS sensor. AB - This paper presents direct measurements of the aerodynamic forces on the wing of a free-flying, insect-like ornithopter that was modeled on a hawk moth (Manduca sexta). A micro differential pressure sensor was fabricated with micro electro mechanical systems (MEMS) technology and attached to the wing of the ornithopter. The sensor chip was less than 0.1% of the wing area. The mass of the sensor chip was 2.0 mg, which was less than 1% of the wing mass. Thus, the sensor was both small and light in comparison with the wing, resulting in a measurement system that had a minimal impact on the aerodynamics of the wing. With this sensor, the 'pressure coefficient' of the ornithopter wing was measured during both steady airflow and actual free flight. The maximum pressure coefficient observed for steady airflow conditions was 1.4 at an angle of attack of 30 degrees . In flapping flight, the coefficient was around 2.0 for angles of attack that ranged from 25 degrees to 40 degrees . Therefore, a larger aerodynamic force was generated during the downstroke in free flight compared to steady airflow conditions. PMID- 20710082 TI - The effect of fatigue on lower-limb biomechanics during single-limb landings: a systematic review. AB - STUDY DESIGN: Systematic literature review. OBJECTIVE: To evaluate the quality and outcomes of published research papers on the topic of fatigue-induced biomechanical changes in single-limb landings. BACKGROUND: Lower extremity fatigue causes a number of biomechanical alterations that may increase the risk of knee injury. It has therefore been suggested that fatigue elements be incorporated into injury prevention programs. For this to be successful, protocols that reliably induce fatigue need to be identified and the effect fatigue has on the lower-limb joints needs to be documented. METHODS: A systematic review was conducted to identify published studies that assessed the effect of fatigue on lower-limb biomechanics during single-limb landing tasks. Studies were identified by searching 6 databases, reference lists, and citation tracking. The methodological quality of each paper was assessed, and effect sizes were calculated to allow comparison of results across studies. RESULTS: Eight studies met the inclusion criteria. Numerous methodological differences between the studies made synthesis of data challenging. There was some evidence to show that vertical ground reaction forces and hip and knee joint moments were reduced after fatigue. Kinematic changes were less consistent and require further study. CONCLUSION: The current body of studies showed mixed findings, particularly in relation to landing kinematics after fatigue. Future studies should focus on developing standardized fatigue protocols that include both local and central fatigue effects and monitor progression of fatigue over time. This area of research should be extended to include individuals recovering from musculoskeletal injury or surgery. PMID- 20710083 TI - Standardization of adverse event terminology and reporting in orthopaedic physical therapy: application to the cervical spine. AB - SYNOPSIS: Orthopaedic physical therapy is considered safe, based on a lack of reported harms. Most of the research until now has focused on benefits. Consideration of benefits and harm involves informed consent, clinical decision making, and cost-benefit analyses. Benefits and harms are treatment and dosage specific. There is currently an insufficient number of dosage trials in orthopaedic physical therapy to identify optimal dosage for common interventions, including exercise and manual therapy. Published cases of severe adverse events following chiropractic manipulation illustrate the need for physical therapy to have high-quality data documenting the safety of orthopaedic physical therapy, including cervical manipulation. A recent systematic review identified poor reporting standards of harms within clinical research in this area. Lack of standardization of terminology has contributed to this problem. Pharmacovigilence provides a framework for terms that orthopaedic physical therapy can adapt and thereafter adopt into clinical practice and research. Adverse events are unexpected events that occur following an intervention without evidence of causality. Where temporality of an event is highly suggestive of causality, the term "adverse reaction" may be more appropriate. Future studies in orthopaedic physical therapy should adopt the CONSORT statement extension on the reporting of harms, published in 2004, to ensure better reporting. Consistent reporting of harms in both research and clinical practice requires professional consensus on terminology pertaining to harms, as well as defining what constitutes an adverse event or an adverse reaction. Widespread consultation and consensus should support optimal definitions and processes and facilitate their implementation into practice. This paper is focused on theoretical considerations and evidence in terms of harm reporting within physical therapy using cervical manual therapy as an example. PMID- 20710084 TI - Augmented low dye taping changes muscle activation patterns and plantar pressure during treadmill running. AB - STUDY DESIGN: Randomized, crossover study. OBJECTIVE: To examine changes in muscle activity and plantar pressure during running with the application of augmented low Dye (ALD) taping. BACKGROUND: ALD taping is used clinically as part of management for lower limb injury. As of yet, no studies have examined the effect of this taping method on muscle activity and plantar pressure during running, simultaneously. METHODS: Thirteen healthy recreational runners(mean +/- SD age, 31.7 +/- 4.9 years; height, 181.7 +/- 4.6 cm; body mass, 81.6 +/- 5.9 kg) completed a 6-minute run on a treadmill at a speed of 10 km.h-1, with 3 different taping conditions (ALD, control tape, no tape), applied in randomized order. Peak and average EMG signal amplitude, onset time, and burst duration were calculated for the vastus medialis, vastus lateralis, and the gluteus medius. In-shoe plantar pressures were also recorded. All data were calculated based on an average of 20 steps collected after 5 minutes of treadmill running. RESULTS: ALD taping significantly altered muscle activity and plantar pressure during treadmill running by (1) delaying the onset of the EMG signal of the gluteus medius, vastus medialis, and vastus lateralis, and (2) increasing lateral midfoot plantar pressure. CONCLUSION: ALD taping significantly alters plantar pressure and muscle activation patterns during treadmill running. These findings give insight into the neuromuscular effect of a taping procedure that is used commonly in a clinical setting. PMID- 20710085 TI - Juvenile osteochondritis dissecans of the knee. PMID- 20710086 TI - Lower thoracic spine pain in a 33-year-old female. PMID- 20710087 TI - Patient education based on principles of cognitive behavioral therapy for a patient with persistent low back pain: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: Cognitive behavioral therapy (CBT) is an effective intervention for patients with persistent pain. Recent research indicates that physical therapists self-perceive a lack of knowledge, skills, and time to provide this intervention. The purpose of this case report is to describe how specific CBT strategies can be integrated with multimodal physical therapist management of a patient with persistent low back pain. CASE DESCRIPTION: The patient was a 70-year-old female with activity limitations of walking, standing, and forward bending. Oswestry Disability Questionnaire score was 19/50 and Fear Avoidance Belief Questionnaire physical activity subscale was 23/24. The Low Back Activity Confidence Scale revealed 19%, 100%, and 84% for function, symptom self regulation, and exercise, respectively. CBT-based patient education was provided in combination with manual therapy and exercise. CBT techniques included cognitive restructuring, goal setting, activity pacing, problem-solving strategies, graded exposure, encouraging exposure to pleasant experiences, and maintenance strategies. OUTCOMES: The patient was discharged after 7 visits distributed over 21 weeks. Her Oswestry Disability Questionnaire score was reduced 10% and Fear-Avoidance Belief Questionnaire physical activity subscale score reduced 48%. On the Low Back Activity Confidence Scale the patient's scores were 19%, 87%, and 94% for function, symptom self-regulation, and exercise, respectively. DISCUSSION: This case report describes the use of CBT techniques during patient education by a physical therapist. The patient demonstrated clinically measurable and significant improvements in disability. Improvements in both self-efficacy beliefs related to exercise and activity avoidance beliefs were associated with improvement in disability. Additional research is needed to determine best practices for CBT-based patient education by physical therapists. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 20710088 TI - Comprehensive impairment-based exercise and manual therapy intervention for patients with subacromial impingement syndrome: a case series. AB - STUDY DESIGN: Case series. BACKGROUND: Few studies have defined the dosage and specific techniques of manual therapy and exercise for rehabilitation for patients with subacromial impingement syndrome. This case series describes a standardized treatment program for subacromial impingement syndrome and the time course and outcomes over a 12-week period. CASE DESCRIPTION: Ten patients (age range, 19-70 years) with subacromial impingement syndrome defined by inclusion and exclusion criteria were treated with a standardized protocol for 10 visits over 6 to 8 weeks. The protocol included a 3-phase progressive strengthening program, manual stretching, thrust and nonthrust manipulation to the shoulder and spine, patient education, activity modification, and a daily home exercise program of stretching and strengthening. Patients completed a history and measures of impairments and functional disability at 2, 4, 6, and 12 weeks. OUTCOMES: Treatment success was defined as both a 50% improvement on the Disabilities of the Arm, Shoulder, and Hand (DASH) score and a global rating of change of at least "moderately better." At 6 weeks, 6 of 10 patients had a successful (mean +/- SD) DASH outcome score (initial, 33.9 +/- 16.2; 6 weeks, 8.1 +/- 9.2). At 12 weeks, 8 of 10 patients had a successful DASH outcome score (initial, 33.1 +/- 14; 12 weeks, 8.3 +/- 6.4). As a group, the largest improvement was in the first 2 weeks. The most common impairments for all 10 patients were rotator cuff and trapezius muscle weakness (10 of 10 patients), limited shoulder internal rotation motion (8 of 10 patients), and reduced kyphosis of the midthoracic area (7 of 10 patients). DISCUSSION: A program aimed at strengthening rotator cuff and scapular muscles, with stretching and manual therapy aimed at thoracic spine and the posterior and inferior soft-tissue structures of the glenohumeral joint appeared to be successful in the majority of patients. This case series describes a comprehensive impairment-based treatment which resulted in symptomatic and functional improvement in 8 of 10 patients in 6 to 12 weeks. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 20710089 TI - Dynamic nature of the placebo response. PMID- 20710090 TI - Manual magic: the method is not the trick. PMID- 20710091 TI - Pain response classification does not predict long-term outcome in patients with low back pain who are sick-listed. AB - STUDY DESIGN: Prospective cohort study nested in a randomized clinical trial. OBJECTIVE: To investigate the prognostic value of pain response classification at initial physiotherapy examination in patients with low back pain (LBP) who are sick-listed. BACKGROUND: Recurrent and chronic LBP accounts for a substantial proportion of all absence from work. In predicting outcome in patients with LBP, psychosocial factors are thought to play an important role, while findings from clinical examination seem to be of more limited value. Mechanical evaluation, using repeated end range spinal movements that result in specific pain responses, has been shown to be of some value. METHODS: The study included 351 patients sick listed because of LBP with or without sciatica. Prior to clinical examination, the patients completed a comprehensive questionnaire including questions on pain, function, and psychosocial factors. The physiotherapy examination included a standardized mechanical evaluation. Patients were classified into 3 groups according to their pain response: centralization, peripheralization, or no response. Outcomes were obtained by national register data, medical records, and a postal questionnaire at 1 year. RESULTS: At 1-year follow-up, 65% of the patients had returned to work. All pain response groups showed significant and clinically important improvements in both pain and disability. No significant differences were found between pain response groups in any outcome measure. Results remained unchanged after adjustment for potential confounders. CONCLUSION: The prognostic value of pain response classification seems limited in patients sick-listed from work because of LBP. PMID- 20710092 TI - Effect of posture on acromiohumeral distance with arm elevation in subjects with and without rotator cuff disease using ultrasonography. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVES: To examine the effects of altering posture on the subacromial space (SAS) in subjects with rotator cuff disease and subjects without shoulder pain. BACKGROUND: Poor upper quadrant posture has been linked to altered scapular mechanics, which has been theorized to excessively reduce SAS. However, no study has examined the direct effects of altering upper quadrant posture on SAS. We hypothesized that upright posture would increase and slouched posture would decrease the SAS, as compared to a normal posture, when measured both with the shoulder at rest along the side of the trunk and when maintained in 45 degrees of active shoulder abduction. METHODS: Participants included 2 groups: the subjects with shoulder pain and rotator cuff disease, as diagnosed via magnetic resonance imaging (n = 31), and control subjects without shoulder pain (n = 29). The SAS was imaged with ultrasound using a 7.5-MHz linear transducer placed in the coronal plane over the posterior to midportion of the acromion. The SAS was measured on ultrasound images using the acromiohumeral distance (AHD), defined as the shortest distance between the acromion and the humerus. The AHD was measured in 2 trials at 2 arm angles (at rest along the trunk and at 45 degrees of active abduction) and across 3 postures (normal, slouched, and upright), and averaged for data analysis. RESULTS: Two mixed-model analyses of variance, 1 for each arm angle, were used to compare AHD across postures and between groups. There was no interaction between group and posture, and no significant main effect of group for either arm position. There was no significant main effect of posture for the arm at rest (P = .26); however, there was a significant main effect of posture on AHD at the 45 degrees abduction arm angle (P = .0002), with a significantly greater AHD in upright posture (mean AHD, 9.8 mm), as compared to normal posture (mean AHD, 8.6 mm). CONCLUSION: The effect of posture on SAS, as measured by the 2-dimensional AHD using ultrasound of the posterior to middle aspect of the SAS, is small. The AHD increased with upright posture by 1.2 mm compared to normal posture, when the arm was in 45 degrees active abduction. PMID- 20710093 TI - Outcomes before and after total knee arthroplasty compared to healthy adults. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: To measure changes in muscle strength, range of motion, and function from 2 weeks before to 6 months after total knee arthroplasty (TKA) and compare outcomes with data from a control group consisting of healthy adults. BACKGROUND: Total knee arthroplasty successfully alleviates pain from knee osteoarthritis, but deficits in function can persist long term. How impairments and functional limitations change over the first 6 months after TKA, compared to data from healthy adults, has not been well reported in the literature. METHODS: Twenty-four patients who underwent a primary unilateral TKA were compared to healthy adults (n = 17). All patients participated in a standardized rehabilitation program following surgery. Isometric quadriceps torque was assessed using an electromechanical dynamometer. Range of motion was measured actively and passively. Functional performance was assessed using the stair-climbing test, timed up-and-go test, 6-minute walk test, and single-limb stance time. Patients underwent testing at 2 weeks preoperatively and at 1, 3, and 6 months postoperatively. RESULTS: Compared to healthy older adults, patients performed significantly worse at all times for all measures (P<.05), except for single-limb stance time at 6 months (P>.05). One month postoperatively, patients experienced significant losses from preoperative levels in all outcomes. Patients recovered to preoperative levels by 6 months postoperatively on all measures, except knee flexion range of motion, but still exhibited the same extent of limitation they did prior to surgery. CONCLUSION: The persistent impairments and functional limitations 6 months after TKA with standard rehabilitation suggest that more intensive therapeutic approaches may be necessary to restore function of patients following TKA to the levels of healthy adults. PMID- 20710095 TI - The effects of thoracic manipulation on posteroanterior spinal stiffness. AB - STUDY DESIGN: Controlled laboratory study, with measurements taken before and after a standardized clinical intervention. OBJECTIVES: To determine if thoracic manipulation alters the posteroanterior (PA) spinal stiffness of the thoracic spine, and the factors associated with any potential changes in stiffness. BACKGROUND: Spinal manipulation is commonly used to treat thoracic pain and dysfunction. Therapists use manual assessment of PA spinal stiffness to determine the appropriateness and effectiveness of treatment, with potential changes in spinal stiffness possibly contributing to symptomatic improvement following manipulation. METHODS: Thoracic PA spinal stiffness was measured at 5 vertebral levels (manipulated level and 2 levels above and below), in 24 asymptomatic subjects, before and after manipulation. Five cycles of standardized mechanical PA force were applied to the spinous process while recording resistance to movement and concurrent displacement, with stiffness defined as the slope of the linear portion of the force-displacement curve. A 2-way repeated-measures analysis of variance determined differences between premanipulation and postmanipulation among multiple spinal levels. Linear regression determined the relationship between stiffness magnitude and its change following manipulation. Generalized linear mixed models were used to determine if subject age, gender, spinal level, premanipulation stiffness, or manipulative thrust parameters were associated with postmanipulation stiffness. RESULTS: Thoracic spine PA stiffness differed between spinal levels (F4,92=21.1, P<.001) but was not significantly different following manipulation. The mean change in spinal stiffness correlated with stiffness magnitude at the manipulated spinal level only but not other levels (Pearson r, -0.65; P<.001). Greater postmanipulation stiffness was associated with being male (regression coefficient, 1.16; 95% CI: 0.52, 1.79; P<.001) and with higher premanipulation stiffness (regression coefficient, 0.63; 95% CI: 0.49, 0.77; P<.001). Manipulation force parameters were not associated with postmanipulation stiffness. CONCLUSION: In asymptomatic individuals, thoracic PA spinal stiffness is not significantly different when measured before and after thrust manipulation, but any potential mechanical effects appear associated with the manipulated spinal level rather than other levels. PMID- 20710094 TI - Neuromuscular training improves performance on the star excursion balance test in young female athletes. AB - STUDY DESIGN: Controlled cohort repeated-measures experimental design. OBJECTIVES: To determine if a neuromuscular training program (NMTP) focused on core stability and lower extremity strength would affect performance on the star excursion balance test (SEBT). We hypothesized that NMTP would improve SEBT performance in the experimental group and there would be no side-to-side differences in either group. BACKGROUND: The SEBT is a functional screening tool that is used to assess dynamic stability, monitor rehabilitation progress, assess deficits following an injury, and identify athletes at high risk for lower extremity injury. The SEBT requires lower extremity coordination, balance, flexibility, and strength. METHODS: Twenty uninjured female soccer players (13 experimental, 7 control) participated. Players trained together as a team, so group allocation was not randomized. The SEBT was administered prior to and following 8 weeks of NMTP in the experimental group and 8 weeks of no NMTP in the control group. A 3-way mixed-model ANOVA was used to determine the effect of group (experimental versus control), training (pretraining versus posttraining), and limb (right versus left). RESULTS: After participation in a NMTP, subjects demonstrated a significant improvement in the SEBT composite score (mean +/- SD) on the right limb (pretraining, 96.4% +/- 11.7%; posttraining, 104.6% +/- 6.1%; P = .03) and the left limb (pretraining, 96.9% +/- 10.1%; posttraining, 103.4% +/- 8.0%; P = .04). The control group had no change on the SEBT composite score for the right (pretraining, 95.7% +/- 5.2%; posttraining, 94.4% +/- 5.2%; P = .15) or the left (97.4% +/- 7.2%; 93.6% +/- 5.0%; P = .09) limb. Further analysis identified significant improvement for the SEBT in the posterolateral direction on both the right (P = .008) and left (P = .040) limb and the posteromedial direction of the left limb (P = .028) in the experimental group. CONCLUSION: Female soccer players demonstrated an improved performance on the SEBT after NMTP that focused on core stability and lower extremity strength. PMID- 20710096 TI - Plasticity of muscle architecture after supraspinatus tears. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVES: To measure the architectural properties of rat supraspinatus muscle after a complete detachment of its distal tendon. METHODS: Supraspinatus muscles were released from the left humerus of 29 Sprague-Dawley rats (mass, 400-450 g), and the animals were returned to cage activity for 2 weeks (n=12), 4 weeks (n=9), or 9 weeks (n=8), before euthanasia. Measurements of muscle mass, pennation angle, fiber bundle length (sarcomere number), and sarcomere length permitted calculation of normalized fiber length, serial sarcomere number, and physiological cross sectional area. RESULTS: Coronal oblique sections of the supraspinatus confirmed surgical transection of the supraspinatus muscle at 2 weeks, with reattachment by 4 weeks. Muscle mass and length were significantly lower in released muscles at 2 weeks, 4 weeks, and 9 weeks. Sarcomere lengths in released muscles were significantly shorter at 2 weeks but not different by 4 weeks. Sarcomere number was significantly reduced at 2 and 4 weeks, but returned to control values by 9 weeks. The opposing effects of smaller mass and shorter fibers produced significantly smaller physiological cross-sectional area at 2 weeks, but physiological cross-sectional area returned to control levels by 4 weeks. CONCLUSIONS: Release of the supraspinatus muscle produced early radial and longitudinal atrophy of the muscle. The functional implications of these adaptations would be most profound at early time points (particularly relevant for rehabilitation), when the muscle remains smaller in cross-sectional area and, due to reduced sarcomere number, would be forced to operate over a wider range of the length-tension curve and at higher velocities, all adaptations resulting in compromised force-generating capacity. These data are relevant to physical therapy because they provide tissue-level insights into impaired muscle and shoulder function following rotator cuff injury. PMID- 20710098 TI - An overview of the diagnosis and management of prostate cancer in Nigeria: experience from a north-central state of Nigeria. PMID- 20710097 TI - A progressive 5-week exercise therapy program leads to significant improvement in knee function early after anterior cruciate ligament injury. AB - STUDY DESIGN: Prospective cohort study without a control group. OBJECTIVES: Firstly, to present our 5-week progressive exercise therapy program in the early stage after anterior cruciate ligament (ACL) injury. Secondly, to evaluate changes in knee function after completion of the program for patients with ACL injury in general and also when classified as potential copers or noncopers, and, finally, to examine potential adverse events. BACKGROUND: Few studies concerning early-stage ACL rehabilitation protocols exist. Consequently, little is known about the tolerance for, and outcomes from, short-term exercise therapy programs in the early stage after injury. METHODS: One-hundred patients were included in a 5-week progressive exercise therapy program, within 3 months after injury. Knee function before and after completion of the program was evaluated from isokinetic quadriceps and hamstrings muscle strength tests, 4 single-leg hop tests, 2 different self-assessment questionnaires, and a global rating of knee function. A 2-way mixed-model analysis of variance was conducted to evaluate changes from pretest to posttest for the limb symmetry index for muscle strength and single leg hop tests, and the change in scores for the patient-reported questionnaires. In addition, absolute values and the standardized response mean for muscle strength and single-leg hop tests were calculated at pretest and posttest for the injured and uninjured limb. Adverse events during the 5-week period were recorded. RESULTS: The progressive 5-week exercise therapy program led to significant improvements (P<.05) in knee function from pretest to posttest both for patients classified as potential copers and noncopers. Standardized response mean values for changes in muscle strength and single-leg hop performance from pretest to posttest for the injured limb were moderate to strong (0.49-0.84), indicating the observed improvements to be clinically relevant. Adverse events occurred in 3.9% of the patients. CONCLUSION: Short-term progressive exercise therapy programs are well tolerated and should be incorporated in early-stage ACL rehabilitation, either to improve knee function before ACL reconstruction or as a first step in further nonoperative management. LEVEL OF EVIDENCE: Therapy, level 2b. PMID- 20710099 TI - An overview of cancer of the prostate diagnosis and management in Nigeria: the experience in a Nigerian tertiary hospital. AB - OBJECTIVE: To review our experience with cancer of prostate management, highlighting the mode of presentation, method of diagnosis, and the treatment outcome. METHODS: Medical records of patients managed for cancer of prostate were retrospectively reviewed over a 10-year period. Relevant information which included the year of diagnosis, age at presentation, mode of presentation, digital rectal examination (DRE) findings, ultrasound (USS) assessment of the prostate, the prostate-specific antigen (PSA) value, the histology report, treatment offered and the outcome were extracted. Data were analyzed with SPSS version 11 software. RESULTS: A total of 192 patients were managed for cancer of prostate within the study period but only 90 case notes were available for analysis. There was a 7.7 fold increase in the incidence of cancer of prostate. The mean age (+/-SD) at presentation was 68.4 (+/-10.1) years with an age range of 47-91 years and the peak incidence occurred in the seventh and eighth decades of life. The mean duration of symptoms prior to presentation was 10.3 (+/-17.1) months. A total of 66.7% of cases presented within 6 months of the onset of symptoms as against 14.4% of cases presented after a year. Majority of cases (88.9%) presented as locally advanced or metastatic disease and only 4.4% of cases were found incidentally. Only 38.9% had histologic confirmation of the diagnosis before management was instituted. DRE gave a false negative finding in 28.6% in this study. The sensitivity and false negative value of USS was 50% each and 3.3% had PSA within normal value. Bilateral orchidectomy was offered to 64 of 90 (71.1%) and the cancer related death (CRD) was 15.6%. The maximum follow-up period was 36 months in this study and 36.9% are still attending follow-up clinic. CONCLUSION: There was an apparent increase in the incidence of cancer of prostate from the present study with majority still presenting with advanced disease. The sensitivity of DRE was high; this probably accounted for the treatment without establishing the histologic diagnosis in majority of the cases. Such a practice of clinical diagnosis alone should be discouraged. PMID- 20710100 TI - Premenstrual dysphoric disorder among medical students of a Nigerian university. AB - BACKGROUND/OBJECTIVE: This study aimed at estimating the prevalence and associated factors of premenstrual dysphoric disorder (PMDD) among medical students in a University in the North-Central State of Nigeria. PMDD is the severest form of premenstrual symptoms and is associated with impairment of social and role functioning. METHODS: A cross-sectional study of female medical students of the University of Ilorin College of Health Sciences (n=208), which involves completing a questionnaire to elicit socio-demographic and gynecological information as well as the GHQ-12 questionnaires. They were later interviewed with DSM-IV PMDD instrument. RESULTS: Seventy-five (36.1%) of the respondents met the criteria for the diagnosis of PMDD. Sixty-five (%) of the PMDD cases reported having pain during menses among whom 14 (21.5%) reported mild, 32 (49.2%) moderate and 19 (29.2%) severe form of menstrual pain. Forty-two persons (20.2%) were categorized as having probable psychiatric morbidity using a cut-off of >or= 3 on GHQ 12. There was neither a causal relationship between psychiatric morbidity (>or= 3 score), and PMDD, nor any association between gynecological factors and PMDD. However, menstrual pain was significantly associated with PMDD (P=0.019). CONCLUSION: The rate of PMDD in this study is high. Dysmenorrhoea of moderate/severe intensity correlated significantly with the possibility of having PMDD. Efforts should therefore be made to alleviate the pain associated with menses. In addition, the College's health-care providers should take into account the issues of dysmenorrhoea and its management more seriously by intensifying health education on dysmenorrhoea and PMDD in order to improve the quality of life of the students. PMID- 20710101 TI - Prevalence of intestinal parasitic infestation in HIV seropositive and seronegative patients in Ilorin, Nigeria. AB - OBJECTIVE: To determine the prevalence, severity and pattern of intestinal parasitic infestation in HIV-seropositive patients. METHODS: A Cross-sectional study from January 2007 to December 2008.Patients were recruited from the HIV clinics of the hospital. Paired blood and single stool specimens were collected from each patient. The stool sample was investigated for intestinal parasites while the blood sample was tested for antibodies to HIV-1 and 2. HIV-seropositive subjects also had CD4 + cells count done. RESULT: Ninety each of stool and blood samples were collected from HIV-seropositive and HIV-seronegative patients. Four species each of helminthes and protozoan parasites and three species of coccidian parasites were isolated from the stool of both HIV-seropositive and seronegative subjects. The prevalence of these parasites was two and a halve times higher among the HIV seropositive patients than the seronegative ones. The range of CD4 cells count was 20-680 cells/microl with a median of 259 cells/microl. Patients with CD4+ count <200/microl had more coccidian parasites in their stool and also had higher prevalence of intestinal polyparasitism ranging from 2 to 4 different species per stool sample. CONCLUSION: The frequency of both AIDS defining and non AIDS defining intestinal parasitic infestation was higher among the HIV infected patients. Patients' CD4+ cells count was an important determinant of the rate and number of parasitic infestation. PMID- 20710102 TI - The reported preparedness and disposition by students in a Nigerian university towards the use of information technology for medical education. AB - BACKGROUND: The computer and information technology (IT) revolution have transformed modern health care systems in the areas of communication, storage, retrieval of medical information and teaching, but little is known about IT skill and use in most developing nations. OBJECTIVES: The aim of this study has been to evaluate the reported preparedness and disposition by medical students in a Nigerian university toward the use of IT for medical education. METHODS: A self administered structured questionnaire containing 24 items was used to obtain information from medical students in the University of Ilorin, Nigeria on their level of computer usage, knowledge of computer software and hardware, availability and access to computer, possession of personal computer and e-mail address, preferred method of medical education and the use of computer as a supplement to medical education. RESULTS: Out of 479 medical students, 179 (37.4%) had basic computer skills, 209 (43.6%) had intermediate skills and 58(12.1%) had advanced computer skills. Three hundred and thirty (68.9%) have access to computer and 451(94.2%) have e-mail addresses. For medical teaching, majority (83.09%), preferred live lecture, 56.78% lecture videos, 35.1% lecture handout on web site and 410 (85.6%) wants computer as a supplement to live lectures. Less than half (39.5%) wants laptop acquisition to be mandatory. Students with advanced computer skills were well prepared and disposed to IT than those with basic computer skill. CONCLUSION: The findings revealed that the medical students with advanced computer skills were well prepared and disposed to IT based medical education. Therefore, high level of computer skill is required for them to be prepared and favorably disposed to IT based medical education. PMID- 20710103 TI - Jaundice in typhoid patients: differentiation from other common causes of fever and jaundice in the tropics. AB - BACKGROUND: While typhoid fever is common in our environment, presentation with jaundice is unusual. The aim of this study has been to determine the clinical and laboratory features that allow early diagnosis of typhoid fever in patients that present with jaundice and differentiate it from other common causes of fever and jaundice in the tropics. MATERIALS AND METHODS: This prospective study was conducted between May 1997 and October 1998 at Center Hopitalier Regional de Hombo Anjuoan, Comoros Islands. Patients with clinical and laboratory evidence of typhoid fever were included. Viral or toxic hepatitis, chronic liver disease, sickle cell disease and other causes of jaundice were excluded by clinical examination and appropriate investigations. Serial evaluation of liver function test and abdominal ultrasound were done. Patients were resuscitated with fluids and electrolytes and treated with appropriate antibiotics. Liver involvement was determined using clinical and laboratory parameters. RESULTS: Of the 254 patients with confirmed diagnosis of typhoid fever, 31 (12.2%) presented with jaundice. Their mean age was 24.6+/-9.2SD years. Fever preceded the appearance of jaundice by 8-27 days. In 27 (87.1%) patients, there was hepatosplenomegaly. Serum bilirubin ranged 38-165 micromol/l with mean of 117+/-14SD. Conjugated bilirubin ranged 31-150 micromol/l with mean of 95+/-8SD. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were raised with mean values of 180, 105 and 136 IU, respectively. Six (19.4%) patients died compared to 12.1% of non-icteric patients. CONCLUSION: Typhoid patients may present with varying degrees of jaundice and fever that may be confused with viral, malarial or amebic hepatitis, diseases that are common in the tropics. Physical examination and simple biochemical tests would identify the typhoid patients who should be treated with appropriate antibiotics even before the results of blood culture are available. PMID- 20710104 TI - Correlation of oxidative stress and inflammatory markers with the severity of sickle cell nephropathy. AB - BACKGROUND: Reactive oxygen species have been shown to mediate inflammatory process and may be involved in lipid peroxidation. METHODS: This study evaluates superoxide dismutase, glutathione peroxidase, catalase, malondialdehyde, C- reactive protein and fibrinogen in the serum of patients with sickle cell disease and their correlation with renal insufficiency. Superoxide dismutase, glutathione peroxides and C - reactive protein were assayed using sandwich ELISA technique while malondialdehyde and fibrinogen were determined using thiobarbituric reactive substance and turbidometric technique, respectively. RESULTS: The study group consisted of 40 patients with sickle cell disease along with macroalbuminuria, 16 with chronic kidney disease and 144 sickle cell disease controls. Superoxide dismutase, glutathione peroxidase and catalase were decreased while malondialdehyde, C-reactive protein and fibrinogen were increased in patients with sickle cell disease along with renal insufficiency. These parameters correlated with the severity of renal disease. CONCLUSION: Oxidative stress and inflammatory parameters correlate with sickle cell disease nephropathy. PMID- 20710105 TI - An audit of spirometry at the University of Ilorin Teaching Hospital, Ilorin, Nigeria (2002-2009). AB - BACKGROUND: Spirometry is a noninvasive and cost-effective physiologic test that greatly complements other investigative procedures in evaluation of respiratory conditions. This study was aimed at auditing the spirometry performed at the University of Ilorin Teaching Hospital (UITH) Ilorin, Nigeria, and highlighting some of the challenges associated with the procedure. METHODS: We reviewed and analyzed the record of spirometry performed at the cardiopulmonary unit of the hospital from June 2002 to December 2009. RESULTS: A total of 119 patients had spirometry tests from 2002 to 2009 and their age ranged from 15 to 85 years with a mean of 47.6 +/- 14.8 years. There were 69 (58%) males and the male:female ratio was 1.4:1. More than half (65%) of the tests were in patients <50 years old. The rate of spirometry performed annually increased from 12 (10.1%) in 2002 to 31 (26.1%) in year 2009. Evaluation of bronchial asthma was the most common indication for spirometry (43 patients; 36.1%). Majority of the requests (84 patients; 70.6%) were from adult respiratory physicians. The identified challenges were lack of awareness of the range of diseases that could be investigated by spirometry, lack of skills in interpreting the results, lack of time and delays in replacing exhausted consumables and faulty components of spirometer. CONCLUSION: Gradually, the trend of spirometry request is increasing in UITH; however, a wider acceptability could be achieved for this test by raising the level of awareness and improving the skills of all doctors on the usefulness and interpretation of spirometry. PMID- 20710106 TI - Pattern of prescription drug use in Nigerian army hospitals. AB - BACKGROUND: Most health expenditure of developing countries is on drugs and medical sundries but inappropriate use of such resources is common. To our knowledge, only few studies have been done in Africa on this issue , with inadequate consideration of the sociological context of the knowledge, attitude and practice of the prescribers especially doctors. This study presents the pooled data of the pattern of prescription drug use from three Nigerian Army hospitals using some WHO criteria, and the knowledge and attitude underlying doctors' prescribing practices in these hospitals. METHODS: Retrospective cross sectional survey of one year (March 2006-February 2007). Systematic random sample of general out patient case notes from three hospitals were collected using WHO criteria. The knowledge, attitude and practice survey of doctors at each study site towards the concept of rational drug use (RDU) were assessed using a self administered questionnaire. RESULTS: Data collected from 660 case notes showed that average number of drugs per encounter was 2.8 while 49.3% of drugs were prescribed in the generic form. An average of 28.1% of patients encountered antibiotics. From the knowledge, attitude and practice survey, it is evident that 90.5% of 74 prescribers were aware of the existence of national essential drugs list but 58.1% of them did not use it as basis of prescriptions. In describing types of medicines preferred, 56.7% of prescribers claimed they prescribed a mixture of generic and branded drugs. Only 12.1% of prescribers could accurately detail the 5 steps of rational prescribing. CONCLUSION: The pattern of prescription drug use in Nigerian Army hospitals is unsatisfactory. It is characterised by high number of drugs per prescription, high rate of antibiotic usage and unscientific prescription by doctors. There is a need for further education and research on rational drug use among prescribers in Nigerian military health facilities. PMID- 20710107 TI - Contact tracing/pre-employment screening for pulmonary tuberculosis: should positive Mantoux test necessitates routine chest X-ray? AB - BACKGROUND: Pulmonary tuberculosis (PTB) remains a scourge in most developing countries. Mantoux skin test and more commonly chest radiography are some of the methods of diagnosing the disease, especially with regard to contact tracing and pre-employment screening. Regular use of radiography has both safety and cost implications. This study aimed at establishing if any justification exists in requesting for chest radiographs in asymptomatic subjects with a positive Mantoux skin test reaction. METHODS: 174 adults comprising PTB contacts and newly employed/admitted university staff/students were recruited into the study. They were 89 males (51.1%) and 85 females (48.9%). All subjects had Mantoux test (using purified protein derivative, PPD). Patients who had positive Mantoux reaction subsequently were subjected to posteroanterior chest radiographic examination. Mantoux test and chest radiographic findings were then correlated with each other. RESULTS: 102 subjects (59.2%) had positive Mantoux reactions, while 27 subjects (31.1%) had abnormal chest radiographs. There was no significant correlation between Mantoux readings and chest radiographic findings (P=0.106). CONCLUSION: It is concluded that other ancillary tests like sputum examination and/or, where available, Interferon and ESAT tests should be carried out before chest radiograph is requested in subjects with positive Mantoux reaction. PMID- 20710108 TI - Rectal cancer: pattern and outcome of management in University of Ilorin Teaching Hospital, Ilorin, Nigeria. AB - BACKGROUND: Cancer of the colon and rectum was considered to be rare in Africa three to four decades ago. This is no longer true though it is not as common as in Western Europe and North America. The aim of this study is to determine the incidence of rectal cancer, its pattern of presentation, diagnosis, treatment and outcome of treatment at the University of Ilorin Teaching Hospital (UITH), Ilorin, Nigeria. METHODS: This is a prospective study of all the patients with rectal cancer seen at the UITH from January 1998 to December 2002. Clinical and radiologic findings as well as findings at surgery were recorded and evaluated. They were all histologically confirmed. The data were analyzed using SPSS 10.0. RESULTS: Thirty-six patients with rectal cancer were seen during the period. The male to female ratio was 1:1. Fourteen (38.9%) of the patients were younger than 40 years. Only three (8.3%) patients presented as emergency. Eighteen patients had resectable lesions at presentation. Ten had abdomino-perineal (A-P) resection and eight had anterior resection. Operative mortality was 5.9%. Ten (60%) of the patients who had A-P resection were alive at 5 years and 62.5% of those who had anterior resection were alive at 5 years. None of the patients who had unresectable tumors was alive at 5 years. CONCLUSION: Rectal cancer is not rare in Africans. Surgical therapy still remains as the main treatment. When patients present early, outcome is satisfactory. Since most cases in this environment are accessible to digital rectal examination (DRE), the need for this procedure in patients with lower gastrointestinal symptoms cannot be overemphasized. PMID- 20710109 TI - Social consequences of epilepsy: a study of 231 Nigerian patients. AB - BACKGROUND: Epilepsy is the commonest neurological disorder and majority of the sufferers are found in the developing countries. It is associated with psychological and social problems. The aim of this study was to determine the social difficulties experienced by epileptic patients and the factors that are associated with these difficulties. METHODS: Two hundred and thirty-one consecutive epileptic patients who were of age 10 years and above, and who had no co-morbid major psychiatric disorder, seen over a 6-month period at the outpatient clinic of Federal Neuro-psychiatric Hospital, Kaduna, were interviewed. We used an instrument designed for the purpose of this study, which focused on people's attitudes to epilepsy, relationship/marital, employment and academic problems. RESULTS: The mean age of the subjects was 28 +/- 13.2 years; 59.3% were males; 44.6% said people make negative remarks about their illness; 14.1% have been denied leadership role; 36.4% were irregular at work; 37.3% performed poorly at work; 22.5% have had their marriage proposals rejected; 19.5% have been abandoned by spouse. At least 39.4% had poor academic performance while 19.5% were withdrawn from school because of epilepsy. Short seizure-free period, long duration of seizure disorder and family history of epilepsy were significantly associated with social problems. CONCLUSION: Social difficulties are common among epileptics. Effort should be made to educate the society about epilepsy, and physicians treating patients with epilepsy should aim at achieving a good seizure control. PMID- 20710110 TI - Awareness and perception toward referral in health care: a study of adult residents in Ilorin, Nigeria. AB - BACKGROUND AND OBJECTIVE: The Nigeria Health System operates three levels of health care, which correspond to the tiers of government and interacts through a referral system. The national health policy recommends the Primary Health Care (PHC) as the entry point to health care system. However, these facilities are poorly managed leading to underutilization. Therefore, people usually attend any facility that will meet their needs, not considering the appropriateness of the level of care. This study is to determine the awareness and perception of adult residents in Ilorin toward referral in health care. METHODS: A cross-sectional descriptive survey was conducted among 366 adult residents in Ilorin, selected by multi-stage sampling technique. Data were obtained using a semi-structured questionnaire, appropriately scored and analyzed with Epi-Info 2005 computer software. RESULTS: Only 22 (6.0%) respondents knew that PHC is supposed to be the fi rst point of call when ill and 25 (6.8%) were aware that referral hospitals have the right to reject patients without referral. More than two third, 256 (69.9%) of the respondents felt it will be unreasonable for any hospital to reject patients on the basis of not being referred. The level of education was significantly associated with the knowledge and perception of referral in the health care. CONCLUSION: There is low awareness and poor perception of referral protocol in the health care system among the people of Ilorin. The higher the level of education, the more knowledge the respondents have about referral in the health system and the more likely they have correct perception of referral in health care. The Nigeria health care system policy on referral and appropriate hospital utilization could be more effective if public awareness is created about it via the media while making effort to improve the credibility of the PHC. PMID- 20710111 TI - Pediatric ophthalmic indications for examination under anesthesia in Ilorin, Nigeria. AB - OBJECTIVE: To determine the ophthalmic indications and challenges for pediatric ocular examination under anesthesia (EUA). METHODS: The surgical register and patients' records of children who underwent EUA between 1990 and 2007 were examined to document patients' bio data, diagnoses and details of procedures and anesthesia. RESULTS: Thirty-nine children underwent EUA during the 18-year period. The indications included congenital glaucoma (20 cases, 21.3%) and congenital cataract (5 cases, 12.8%). There were two cases each (5.1%) of microphthalmia, megalocornea, and squint. A case each of other indications constituted the remaining 10.3%. CONCLUSION: The commonest ophthalmic indication for EUA among children is congenital glaucoma. Most of the children (36, 92.3%) had inhalational anesthesia administered by anesthetists at great cost to their parents. We recommend the use of ketamine anesthesia administered by nonanesthetist with some training in anesthetic resuscitation procedure, for short pediatric procedure such as EUA in resource-challenged settings. PMID- 20710112 TI - Pilot study on multidrug resistant tuberculosis in Nigeria. AB - BACKGROUND: Drug resistant tuberculosis (TB) has lately emerged and it represents a serious public health problem. We set out to determine drug resistance among TB patients. METHODS: Using automated BACTEC cultures, multidrug resistant tuberculosis (MDR-TB) was investigated in 117 diagnosed cases in Abuja, Nigeria. RESULTS: Ten (31%) of 32 culture-positive patients were resistant to at least one and four (13%) to all of the four drugs tested. No association between drug resistance and human immunodeficiency virus (HIV) infection was found. CONCLUSIONS: MDR-TB is present in Nigeria and larger studies are urgently required. TB clinical management and control efforts should be improved. PMID- 20710113 TI - Malaria among antenatal clients attending primary health care facilities in Kano state, Nigeria. AB - BACKGROUND: Malaria in pregnancy remains a major public health problem especially in sub-Saharan Africa. However, the prevalence of clinical and asymptomatic infection among antenatal client (ANC) attendees is largely unknown, especially at primary health care (PHC) level in northern Nigeria. This study assessed the prevalence of fever, malarial parasitemia and anemia among pregnant women attending PHC facilities in Kano, northern Nigeria. METHODS: A cross-sectional descriptive study was conducted among 360 ANCs attending PHC facilities in two Local Government Areas (LGAs) in Kano state. Data were collected using a pre tested semi-structured interviewer administered questionnaire. Blood samples were also obtained for thin blood smear for malaria parasite using Giemsa staining technique. Hemoglobin was estimated from the Packed Cell Volume (PCV) determined using hematocrit. RESULTS: Age of the subjects ranged from 15 to 42 years with a mean +/- SD of 24.0 +/- 6.0. Up to 39.2% (n = 141) (95% Confidence Interval = 34.1-44.4%) of the subjects were found to have malarial parasitemia. Exactly 36.2% (n = 51) of those with parasitemia had fever (temperature >or= 37.5 degrees C) while 63.8% (n = 90) of them were asymptomatic. Anemia, (hemoglobin of or= 35 (77% versus 44% respectively, P < 0.004). Provider survey results suggest that providers do not document obesity because it is not considered to be an acute issue (67%), and they elect not to address obesity because they lack the time (63%), skill (37%), and they believe that their efforts will be unsuccessful (33%). CONCLUSION: Documentation of obesity by hospitalist providers is poor. Because an inpatient admission has been characterized as a teachable moment when patients are willing to reflect on behavior change, this may be an ideal time to counsel and educate obese patients. PMID- 20710131 TI - Chronic calcific pancreatitis: combination ERCP and extracorporeal shock wave lithotripsy for pancreatic duct stones. AB - BACKGROUND: Chronic pancreatitis is commonly associated with debilitating abdominal pain, in part due to pancreatic duct obstruction. Pancreatic stones are often impossible to extract from the duct with endoscopic retrograde cholangiopancreatography alone. Extracorporeal shock wave lithotripsy (ESWL) is commonly used for fragmentation of obstructing nephrolithiasis and has demonstrated effectiveness in management of pancreatic stones. Our aim was to examine the outcomes of the first 30 patients with symptomatic pancreatic stones treated with a combination of ESWL and endoscopic therapies. METHODS: Patients with symptomatic chronic calcific pancreatitis referred for ESWL (2005-2009) were included. Technical success of ESWL was defined as a) stone fragmentation sufficient to allow extraction of main duct stones at ERCP or b) absence of the targeted main pancreatic duct stones on follow-up radiography. Clinical success of ESWL was defined by Patient Global Impression of Improvement (PGII) score of at least slightly improved. RESULTS: Thirty patients underwent ESWL. One patient was excluded due to adenocarcinoma. Technical success was achieved in 17/29 (58.6%) patients. 25 (86.2%) patients were available for follow-up (median 35 months, range 3-52 months). Fifteen of twenty-five (60%) patients experienced clinical improvement (10 patients very much improved), but there was no significant reduction in the proportion taking narcotics (50% before vs. 44.4% after ESWL). Pancreatic surgery has been avoided to date in 16 (64%) of the 25 patients. CONCLUSIONS: A multidisciplinary approach, combining ERCP and ESWL, to painful obstructing pancreatic duct stones provided symptomatic improvement and allowed pancreatic surgery to be avoided in the majority of patients. PMID- 20710132 TI - Access to medical care, dental care, and prescription drugs: the roles of race/ethnicity, health insurance, and income. AB - BACKGROUND: After accounting for socioeconomic factors and other demographic characteristics, racial/ethnic disparities in access to care were examined. METHODS: Using nationally representative data on 34,403 individuals from the 2004 Medical Expenditure Panel Survey (MEPS), multiple logistic regression analyses for five outcome measures were conducted: self-reports of being unable to get medical care, dental care, or prescriptions in the past year; and having no doctor or dentist visits in the past year. The main independent variables were race/ethnicity, income, and insurance status. RESULTS: Blacks and Hispanics were less likely to report difficulties in accessing medical care, dental care, and prescriptions as compared to whites. These disparities occurred primarily among the uninsured and Medicaid insured. More objective measures of utilization (ie, no doctor visit or dental visit during the past year) showed that minorities experienced less access than whites. CONCLUSIONS: Racial/ethnic disparities in access to care persist, and cannot be entirely explained by socioeconomic differences. In addition, the nature of these disparities depends on the socioeconomic position of racial/ethnic groups as well as the access measure used. PMID- 20710133 TI - Association of reduction in waist circumference with normalization of mood in obese women initiating exercise supported by the Coach Approach protocol. AB - BACKGROUND: Interrelations of exercise, mood, and weight reduction are unclear in the behavioral treatment of obesity. METHODS: Obese women volunteers with high tension (anxiety) (T), depression (D), or total mood disturbance (TMD) scores, who were previously randomized into conditions of (1) exercise supported by The Coach Approach: a protocol based on social cognitive and self-efficacy theory (CA; n = 53, 66, and 60, respectively), (2) personal demonstration and follow up of exercise methods (EX; n = 27, 27, and 21, respectively), and (3) exercise suggested through written information only (INFO; n = 24, 28, and 20, respectively), were subjects. Identical nutrition information was provided to all subjects in a small group format. RESULTS: Minutes of exercise over the 6-month study were greatest in the CA condition, with minutes in the EX condition greater than the INFO condition. T, D, and TMD scores were reduced to normal levels mostly in the CA condition, with the EX condition having significantly more normalized D scores than the INFO. Across conditions, normalized mood scores generally predicted a greater reduction in waist circumference, with CA associated with additional benefits when D scores were considered. CONCLUSION: Properly accounting for exercise-induced mood change may be important in the behavioral treatment of obesity. PMID- 20710134 TI - Usefulness of CRP and ESR in predicting septic joints. AB - OBJECTIVE: To determine whether erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or a combination of both was better in diagnosing a septic joint. METHODS: A retrospective chart review was done in all patients who had serum assays for ESR or CRP as well as joint fluid analysis over a two-year period. Based on lab and operative findings, patients (cohorts) were categorized as having normal, inflammatory, or septic joints. Sensitivities (SEN), specificities (SP), positive and negative predictive values (PPV, NPV) were obtained using our lab's positive cutoffs of 15 for ESR and 0.8 for CRP. Contingency tables were used for comparisons between predictor variables and the presence of septic joints. Receiver operator curves (ROC) were obtained for CRPs and ESRs. RESULTS: Of 163 patients, 72 had inflammatory joints, 44 had septic joints, and 47 were normal. Fifteen admitted to drug use and 43 to alcohol consumption. There were 120 males and 42 females. The mean CRP for septic joints was 13, 8.5 for inflammatory joints, and 6 for normal. The mean ESR for septic joints was 57, 48 for inflammatory joints, and 43 for normal joints. By univariate analysis, drug use and elevated CRPs were significantly associated with septic joints while alcohol use, ESRs, and gender were not. A regression model with 4 variables indicated that drug use and CRP were predictive of septic joint; alcohol and ESR were not. CONCLUSION: CRP is helpful in determining the presence of a septic joint; ESR is not. PMID- 20710135 TI - Faith and religious beliefs in an outpatient military population. AB - BACKGROUND: This study of outpatients at a military medical center seeks to evaluate the extent that this population relies on religion and spirituality to cope with health-related stress. This study also assesses outpatients' desire for spiritual intervention in the context of their medical appointments. METHODS: A cross-sectional survey was conducted using a convenience sample of 670 outpatients presenting at a military medical center. RESULTS: The majority of respondents endorsed a Christian religious affiliation (87%), a belief in God (91%), and attendance at religious services at least a few times a month (53%). Respondents who were male, younger than age 43, and on active duty were significantly less likely to attend religious services, believe in God (or a 'higher power'), or rely on religion or spirituality to cope with illness. Outpatients presenting for procedures or treatments were more likely to desire prayer or other religious intervention, as compared to patients who had regular clinic appointments. CONCLUSIONS: Compared to the general US population, a higher percentage of this patient population believes in God (91% vs. 78%), attends religious services once a week or more (42% vs. 30%), and endorses a Christian religious affiliation (87% vs. 73%). Because one-third of the surveyed outpatients desired prayer or other religious support, we concluded that all outpatients should be explicitly notified of the pastoral care and counseling services that are available for them. PMID- 20710136 TI - Challenges of abdominal organ transplant in obesity. AB - Obesity is a worldwide epidemic and public health crisis associated with severe comorbidity leading to end organ dysfunction and poorer transplant outcome. Large population studies show decreased patient and graft survival in obese kidney transplant patients. Despite the poorer outcomes, kidney transplant is considered because of the survival benefit as compared to the wait-listed dialysis patients. In liver transplantation, the benefit of transplant as compared to remaining on the list is obvious because there is no viable liver dialysis at this time.Obesity in potential organ donors impacts both medical and surgical issues. Obesity-related kidney disease affects both the remaining and transplanted kidney. Pancreas donor organs are associated with decreased early graft survival. Liver donor organs with significant steatosis lead to an increased risk for delayed function or nonfunction of the organ.Immunosuppressive drugs with variable lipophilicity and altered volume of distribution can greatly affect the therapeutic usefulness of these drugs.Transplant candidates benefit from a multidisciplinary team approach to their care. As the epidemic progresses and less invasive treatments for metabolic surgery evolve, we are likely to see more patients lose weight before transplant as we continue to strive for improved outcomes. PMID- 20710137 TI - Acute radiation syndrome: assessment and management. AB - Primary care physicians may be unprepared to diagnose and treat rare, yet potentially fatal, illnesses such as acute radiation syndrome (ARS). ARS, also known as radiation sickness, is caused by exposure to a high dose of penetrating, ionizing radiation over a short period of time. The time to onset of ARS is dependent on the dose received, but even at the lowest doses capable of causing illness, this will occur within a matter of hours to days. This article describes the clinical manifestations of ARS, provides guidelines for assessing its severity, and makes recommendations for managing ARS victims. PMID- 20710138 TI - Nonalcoholic steatohepatitis: a review of the literature and updates in management. AB - Nonalcoholic steatohepatitis is a common cause of liver inflammation and is associated with obesity, insulin resistance, and hyperlipidemia. There are concerns that it may turn out to be the most common cause of liver failure as prevalence of obesity increases. It leads to increased morbidity and mortality. Other causes of liver inflammation, especially alcoholic liver disease, must be ruled out. The diagnosis is suggested by abnormalities in the blood work and metabolic panel in an obese patient. Despite advances made in our understanding regarding the pathogenesis and trials with multiple drugs targeting mechanisms in pathogenesis, there are no consistent guidelines regarding treatment. However, multiple sources advocate weight reduction, optimum blood glucose control, and elimination of medications that cause fatty infiltration. The purpose of our article is to detail advances made in identifying disease mechanisms and treatment modalities, including surgery to promote weight loss. PMID- 20710139 TI - Pathologic cervical burst fracture presenting with airway compromise. AB - Mechanical airway compromise following cervical spine injury or fracture is a rare but known entity. It most commonly is the result of the development of a retropharyngeal hematoma or prevertebral soft tissue edema that obstructs the airway, leading to respiratory distress and emergent need for airway management and possible surgical intervention. We present a novel case of airway compromise following a C3 burst fracture without associated retropharyngeal hematoma or prevertebral soft tissue edema. Surgical management is discussed, and a review of relevant literature is provided. Pathological cervical spine fracture must be included in the differential diagnosis of a patient presenting with acute airway obstruction of unknown etiology. PMID- 20710140 TI - Anti-immunoglobulin e in the treatment of refractory atopic dermatitis. AB - Atopic dermatitis (AD) is a common diagnosis seen in both children and adults, and it is often the first manifestation of atopic disease. Research has shown a strong correlation between serum IgE levels, the severity of atopic dermatitis, and co-existing asthma and/or allergic rhinitis. Omalizumab (Xolair, East Hanover, NJ; Genentech, South San Francisco, CA) is a monoclonal antibody to human IgE and is currently Food and Drug Administration (FDA) approved for the treatment of asthma. We present 3 patients with severe, treatment resistant atopic dermatitis whose cutaneous symptoms significantly improved by treatment with omalizumab. PMID- 20710142 TI - Diagnostic puzzle of inflammatory pseudotumor of the urinary bladder: a case report with brief literature review. AB - Inflammatory pseudotumor of the urinary bladder is a rare reactive proliferation with a clinical presentation similar to malignant neoplasms. We present the case of a 35-year-old woman who presented with left lower quadrant pain and gross hematuria. A diagnosis of cystitis glandularis was initially considered; however, the symptoms did not resolve following transurethral resection. Subsequently, a partial cystectomy was performed after malignancy was excluded based on intraoperative frozen sections. Further histopathological evaluation confirmed the diagnosis of inflammatory pseudotumor. PMID- 20710141 TI - Streptococcus sanguinis brain abscess as complication of subclinical endocarditis: emphasizing the importance of prompt diagnosis. AB - A 19-year-old male patient was diagnosed with S. sanguinis brain abscess of unknown etiopathology as a complication of subclinical endocarditis. While viridans streptococci are implicated in dental seeding to the heart, S. sanguinis brain abscesses are rare. Six previous cases of S. sanguinis brain abscess in the literature reported dental procedures and maxillofacial trauma. In our patient, there was no obvious source of infective endocarditis preceding the development of brain abscess. This demonstrates the importance of prompt diagnosis and initiation of antimicrobial therapy given the potential for long-term sequelae such as focal deficits and seizures. PMID- 20710143 TI - Spigelian hernia as a cause of small bowel obstruction. AB - Spigelian hernia is a rare abdominal wall defect usually appearing between the abdominal muscle lateral to the rectus abdominis and through a debilitated spigelian aponeurosis. Spigelian hernias account for 0.12% to 2.4% of all abdominal wall hernias with a 17-24% risk of strangulation. We report the case of a 77-year-old male that presented with small bowel obstruction with incarcerated spigelian hernia which was successfully treated with a Ventralex hernia patch (Bard Access Systems, Inc., Murray Hill, NJ). A small open incision over the incarcerated hernia was a safe and effective method of repairing an incarcerated spigelian hernia in an urgent fashion. PMID- 20710145 TI - Chronic cough as the presenting symptom of hydrocephalus. AB - Chronic cough is defined as a daily cough lasting for more than eight weeks. We report an unusual case of chronic cough as the primary manifestation of obstructive hydrocephalus. Chronic cough in our case was determined to be of neurogenic origin only after exhaustive investigations failed to reveal a systemic cause, and, in particular, after a positive response to treatment of the hydrocephalus was observed. To the best of our knowledge, this is the first report of hydrocephalus presenting as chronic cough. We believe this case will remind physicians of the importance of considering neurological disease as a cause of chronic cough after common causes are excluded. PMID- 20710144 TI - Refractory diffuse bony pain 20 years after jejunoileal bypass. AB - Osteomalacia can be a late but unrecognized complication following jejunoileal bypass. We describe a 53-year-old man who underwent jejunoileal bypass for morbid obesity twenty years earlier who suffered from progressive diffuse bony pain refractory to nonsteroidal anti-inflammatory drugs. He was initially diagnosed with a malignancy with bone metastasis. However, pertinent laboratory data were notable for hypocalcemia (7.5 mg/dL, albumin 4.1 mg/dL) with low urinary calcium excretion (14 mg/day), hypophosphatemia (2.0 mg/dL) with low urinary phosphate excretion (53 mg/day), hypomagnesemia (1.5 mg/dL) with low urine magnesium excretion (23 mg/day), low 1, 25 (OH)2 vitamin D3, and elevated serum alkaline phosphatase and intact parathyroid hormone (iPTH). These laboratory findings pointed to a defect in calcium, phosphate, and magnesium handling in the gastrointestinal tract. Bone biopsy of the iliac crest clearly demonstrated typical changes of osteomalacia with excessive osteoid accumulation and reduced mineralization. His clinical symptoms were refractory to oral 1, 25 (OH)2 vitamin D3 and calcium supplementation but significantly improved with the addition of intermittent intravenous active 1, 25 (OH)2 vitamin D3, calcium, phosphate, and magnesium supplementation. Osteomalacia is an easily misdiagnosed late complication of jejunoileal bypass. Early recognition can avoid circuitous diagnosis and inappropriate management. PMID- 20710146 TI - Scimitar syndrome: a rare cause of dyspnea in adults. AB - Scimitar syndrome is a rare congenital malformation resulting in anomalous pulmonary venous return and lung malformations. Symptoms commonly develop in the first year of life, leading to diagnosis and surgical correction. In this case, the atypical presentation of scimitar syndrome in an adult woman with complaints of dyspnea on exertion is reported. Although uncommon, congenital conditions should be considered in patients who present with dyspnea and an abnormal chest radiograph. PMID- 20710147 TI - Incomplete facial nerve palsy: new lessons from activated orbicularis oculi muscles. AB - Motor nerve conduction studies (MNCS) and blink reflexes (BR) were done on a 42 year-old female patient who presented with peripheral facial nerve palsy (PFNP); these investigations were done while she had her facial muscles relaxed ("A"), and contracted ("B"). While in the "A" state, MNCS of the facial nerves had prolonged latency and low amplitude and R3 of the blink reflex was absent in the affected side; an early contralateral R1 response was recorded on the unaffected side. In state "B," the third silent period was "prolonged" on the affected side and absent on the unaffected one. This is an illustrative case of a variant of facial nerve palsy in humans. PMID- 20710148 TI - Interferon alpha-induced hashimoto thyroiditis followed by transient graves disease in a patient with chronic HCV infection. AB - The case of a 37-year-old man with chronic hepatitis C virus (HCV) infection is presented. The patient had received a 6-month course of antiviral therapy with peg interferon alpha-2a and ribavirin, with concomitant clearance of hepatitis C virus ribonucleic acid (HCV-RNA) from serum at the end of treatment. Three months after the treatment course he developed clinical and laboratory features of hypothyroidism along with high titers of thyroid peroxidase antibodies. Later on, while on treatment with levothyroxine, he developed all the clinical features of Graves disease along with increased levels of thyroid stimulating hormone (TSH) receptor antibodies.This patient exhibited a rare sequence of immune-mediated thyroid disorders as a result of interferon alpha treatment. At the end of treatment, the patient developed Hashimoto thyroiditis, a typically Th1-response mediated disease, followed sequentially after 6 months by Graves disease, a typically Th2-response-mediated disorder. Although both clinical entities have been described in patients receiving interferon-based regimens, to our knowledge, the changing pattern of immune-mediated thyroid disease in the same individual has not been reported in the literature. PMID- 20710149 TI - Implications of occult cranial injuries for perpetrator identification in cases of alleged abusive head trauma. PMID- 20710150 TI - Thirteen years' survival after glioblastoma. PMID- 20710151 TI - Ankle-brachial index measurement in the primary care setting. PMID- 20710152 TI - Splatter-free compression cryotherapy for skin lesions. PMID- 20710153 TI - Lymphocytic colitis in Satoyoshi syndrome. PMID- 20710154 TI - Swallowed dental bridge perforating the terminal ileum. PMID- 20710155 TI - Standing at the crossroads-will the increments in resident clinic sessions help? PMID- 20710156 TI - Secondary aortoenteric fistula presenting with recurrent episodes of sepsis. PMID- 20710157 TI - Can a normal colonic mucosa harbor an aggressive underlying lymphoma? PMID- 20710158 TI - Acute profound thrombocytopenia following eptifibatide administration. PMID- 20711029 TI - Glaucoma in India: estimated burden of disease. AB - Over the last decade the prevalence of glaucoma has been reported by the Vellore Eye Survey, Andhra Pradesh Eye Disease Study, Aravind Comprehensive Eye Survey, Chennai Glaucoma Study, and West Bengal Glaucoma Study. There have been some differences largely because of methodologic variations. We use the reported age and gender stratified prevalence estimates from these studies and the Indian population census estimates to calculate the number of persons with glaucoma or at risk of the disease in the country. On the basis of the available data, we estimate that there are approximately 11.2 million persons aged 40 years and older with glaucoma in India. Primary open angle glaucoma is estimated to affect 6.48 million persons. The estimated number with primary angle-closure glaucoma is 2.54 million. Those with any form of primary angle-closure disease could comprise 27.6 million persons. Most of those with disease are undetected and there exist major challenges in detecting and treating those with disease. In the light of the existing manpower and resource constraints, we evaluate options for improving case detection rates in the country. PMID- 20711031 TI - 25-on-25: twenty-five perspectives on twenty-five years of cardiopulmonary imaging. Part III. PMID- 20711032 TI - ACR Appropriateness Criteria hemoptysis. AB - Hemoptysis is defined as the expectoration of blood originating from the tracheobronchial tree or pulmonary parenchyma, ranging from 100 mL to 1 L in volume over a 24-hour period. This article reviews the literature on the indications and usefulness of radiologic studies for the evaluation of hemoptysis. The following recommendations are the result of evidence-based consensus by the American College of Radiology Appropriateness Criteria Expert Panel on Thoracic Radiology: (1) Initial evaluation of patients with hemoptysis should include a chest radiograph; (2) Patients at high risk for malignancy (>40 y old, >40 pack-year smoking history) with negative chest radiograph, computed tomography (CT) scan, and bronchoscopy can be followed with observation for the following 3 years. Radiography and CT are recommended imaging modalities for follow-up. Bronchoscopy may complement imaging during the period of observation; (3) In patients who are at high risk for malignancy and have suspicious chest radiograph findings, CT is suggested for initial evaluation; CT should also be considered in patients who are active or exsmokers, despite a negative chest radiograph; and (4) Massive hemoptysis can be effectively treated with either surgery or percutaneous embolization. Contrast-enhanced multidetector CT before embolization or surgery can define the source of hemoptysis as bronchial systemic, nonbronchial systemic, and/or pulmonary arterial. Percutaneous embolization may be used initially to halt the hemorrhage before definitive surgery. PMID- 20711034 TI - What are the greatest opportunities and challenges for radiology during the coming twenty-five years? PMID- 20711035 TI - Cardiac computed tomography and magnetic resonance imaging: the clinical use from a cardiologist's perspective. AB - The introduction and continued evolution of cardiac computed tomography and magnetic resonance imaging have added considerable noninvasive diagnostic insight into a wide range of frequently encountered clinical cardiology scenarios. With an increasing range of imaging modalities, and multiple methods of image acquisition in each, a detailed understanding of the clinical question at hand is often necessary to select the proper study and make optimal use of imaging data. We review common cardiac issues from a clinician's perspective, along with the unique role to be played by computed tomography and magnetic resonance imaging in each condition. This review will hopefully facilitate a strong dialogue between imagers and managing clinicians, creating a shared knowledge of both the capabilities of imaging and the management challenges that treating clinicians face. PMID- 20711036 TI - Radiation dose at cardiac computed tomography: facts and fiction. AB - Cardiac computed tomography (CT) dosimetry makes use of two radiation parameters: a volume CT dose index (CTDI) and a dose length product (DLP). The volume CTDI quantifies the intensity of the radiation used to perform CT examinations, whereas DLP quantifies the amount of radiation used. CTDI metrics can be converted into patient dose metrics by using dose/CTDI conversion factors. In cardiac CT imaging, these need to take into account the x-ray tube voltage, scan length, and scan region, as well as patient size. Organ doses to patients in cardiac CT can be converted into cancer risks when patient demographic factors are taken into account. A risk analysis of patients undergoing cardiac CT angiography at our institution showed that a majority (62%) were males, with a median age of approximately 60 years and a median weight of approximately 90 kg. The median DLP was approximately 1100 mGy cm, corresponding to an effective dose of approximately 29 mSv in normal-sized patients. The average patient lifetime risk for a radiation-induced cancer was estimated to be 0.12%, with 85% of it attributed to lung cancer. Patients with an age and weight at the 10th percentile, who also received a DLP at the 90th percentile, would have cancer risk estimates approximately double the average value. Radiation risks are required to determine whether examinations are indicated, defined as examinations in which individual patient benefit exceeds corresponding patient risk. Understanding radiation risks in cardiac CT encourages operators to use the least amount of radiation to achieve satisfactory diagnostic performance. PMID- 20711037 TI - Practical strategies for low radiation dose cardiac computed tomography. AB - Concerns have been raised regarding the increasing radiation exposure associated with cardiac computed tomography (CT). Traditional cardiac CT imaging techniques comprise simultaneous recording of the electrocardiogram signal combined with continuous slow-pitch spiral/helical scan acquisition with a relatively high incident radiation dose. Because of the increasing number of cardiac CT studies and further anticipated growth, the contribution of cardiac CT to radiation exposure of the population is not negligible. With growing radiation dose awareness, a variety of strategies have been developed aimed at improving the dose efficiency of electrocardiogram-synchronized cardiac CT acquisition techniques. Recent innovations have demonstrated that the radiation dose at cardiac CT can be substantially reduced without detrimental effects on diagnostic image quality. This study reviews currently available strategies for successfully reducing radiation dose in cardiac CT. PMID- 20711038 TI - Coming of age: coronary computed tomography angiography. AB - Technical development has substantially improved diagnostic performance of coronary computed tomography angiography (CCTA). A large number of studies have addressed proof of concept, feasibility, and clinical robustness of this noninvasive diagnostic technique, and most have consistently described the ability of CCTA to reliably rule out significant coronary artery stenosis. Clinical evidence supports the significant role of CCTA in an increasing number of scenarios, including the detection of coronary disease in symptomatic patients who are at intermediate risk and evaluation of coronary revascularization procedures. After initial feasibility testing, the scientific evaluation of CCTA now points toward analyzing prognosis, outcome, and cost-effectiveness of this noninvasive diagnostic tool. In this article, appropriate clinical indications, diagnostic performance, current clinical applications, prognostic value, and cost effectiveness of CCTA are reviewed. PMID- 20711039 TI - Integrative computed tomography imaging of ischemic heart disease. AB - The introduction of coronary computed tomography (CT) angiography has reinvigorated the debate regarding whether management of patients with suspected coronary artery disease should be based primarily on physiologic versus anatomic testing. Recent advances in multidetector row CT (MDCT) technology have created new opportunities in integrative medical imaging and provided new insight into a variety of disease states. Anatomic testing (ie, invasive catheterization) enables direct visualization and grading of coronary artery stenoses, but it has problems in gauging the hemodynamic significance of lesions for myocardial perfusion. Conversely, stress/rest myocardial perfusion imaging has been extensively validated for assessing the clinical significance of coronary artery disease. This imaging shows fixed or reversible perfusion defects but has only limited anatomic information. Although the evaluation of coronary artery stenosis will remain the primary clinical indication for cardiac CT, simultaneous assessment of ventricular function, plaque formation, myocardial perfusion, and viability becomes feasible with a single modality. Newer generations of MDCT scanners with a dual-energy mode may effectively combine anatomic and functional information and create a new frontier for integrative imaging. The purpose of this study is to describe the practical application of MDCT technology for the comprehensive diagnosis of ischemic heart disease. PMID- 20711040 TI - Imaging the heart-lung relationships during a chest computed tomography examination: is electrocardiographic gating the only option? AB - Before the advent of fast-scanning multidetector-row computed tomography (CT) technology, thoracic CT studies were exclusively used for the morphologic assessment of thoracic organs, as the concurrent examination of the heart was hampered by image degradation from cardiac motion artifacts. The introduction of fast rotation speed and dedicated cardiac reconstruction algorithms has opened new possibilities for chest imaging, starting with the possibility to integrate cardiac morphologic and functional information into a diagnostic CT scan of the chest. Initiated with 16-slice multidetector-row CT, this concept of integrating morphology and function has been further simplified with 64-slice CT scanners, thus allowing radiologists to provide vital information in the management of patients with a wide variety of acute or chronic respiratory disorders. Because this CT technology offers the possibility of generating high-resolution and motion-free images of the coronary arteries, evaluation of the coronary arteries during CT examinations of the chest should further widen the clinical applications of CT for respiratory patients, keeping in mind that cigarette smoking is a shared risk factor for both impaired lung function and cardiovascular events. The recent advent of high temporal resolution and high pitch modes with dual-source CT simplifies the concept of integrated cardiothoracic imaging, introducing non-electrocardiographic-gated coronary artery imaging. The purpose of this article is to review the successive approaches of these redefined borders of thoracic imaging. PMID- 20711041 TI - Imaging of congenital cardiovascular disease: the case for computed tomography. AB - Computed tomographic angiography is a rapidly evolving modality that is well suited for congenital cardiac imaging. Although echocardiography and magnetic resonance imaging carry an established role for evaluating patients with congenital cardiovascular disease, computed tomographic angiography provides important advantages over each of these modalities in certain clinical scenarios. Its practicality, high spatial resolution, inherent 3-dimensional nature, and decreased need for sedation make it a very useful tool in this patient population. This study reviews the utility of computed tomographic angiography and addresses the risks and benefits of this modality in comparison with other imaging modalities. Despite the exposure to ionizing radiation, newer technologies and techniques are being introduced that are decreasing the risks associated with computed tomographic imaging to exceedingly small levels. When viewed in the context of other risks these patients encounter, computed tomographic angiography is a useful adjunct to echocardiography in patients with congenital heart disease and is often preferable to magnetic resonance imaging in certain patients. PMID- 20711042 TI - Computed tomography of pediatric cardiovascular disease. AB - Advances in multidetector computed tomography (CT) technology have revolutionized cardiovascular imaging in children. Faster acquisition times and high-quality reconstructions have enabled CT to become a valuable modality for the evaluation of cardiac and vascular pathology. Identification of congenital cardiovascular anomalies and their complications is important for patient management and treatment planning. CT offers an excellent technology in this patient population. The confident diagnosis of congenital cardiovascular lesions requires awareness of the appearances of these defects on CT, before and after surgery. In addition, understanding the techniques for performing CT in the pediatric population, including the risks, is essential for the radiologist. PMID- 20711043 TI - Failed arthroscopic shoulder surgery. PMID- 20711044 TI - Revision arthroscopic Bankart repair. AB - When stabilization surgery fails, both patient and treating physician face disappointment as well as additional stress in attempting to solve this difficult clinical challenge. The treating physician must: (1) review the basics of what constitutes stability, (2) confirm the correct diagnosis by performing a thorough examination supplemented by appropriate imaging, (3) determine the reason for failure, (4) determine the expectations and needs of the patient, and (5) decide which operative or nonoperative approach provides the best potential result for the patient. This review article will provide a basic review of the key principles in the evaluation and management of patients with recurrent instability after a failed arthroscopic anterior stabilization. PMID- 20711045 TI - Management of glenoid and humeral bone loss. AB - Glenoid and humeral head bone deficiency is a common reason for recurrent anterior shoulder instability and failure of capsulolabral reconstruction. There is a strong association between the severity of the bone defects and the number and ease of recurrent instability. Clinical evaluation, advanced imaging, examination under anesthesia, and diagnostic arthroscopy are important in decision making. Glenoid bone loss greater than 20%, an engaging Hill-Sachs lesion, or Instability Severity Index Score greater than 6 are indications for an open bony procedure to restore the glenoid articular arc. Hill-Sachs lesions greater than 30% should be directly addressed with either an arthroscopic remplissage technique or open bone grafting procedure. PMID- 20711046 TI - Management of the failed posterior/multidirectional instability patient. AB - Although the results of operative treatment of posterior and multidirectional instability (P-MDI) of the shoulder have improved, they are not as reliable as those treated for anterior instability of the shoulder. This may be attributed to the complexities in the classification, etiology, and physical examination of a patient with suspected posterior and multidirectional instability. Failure to address the primary and concurrent lesion adequately and the development of pain and/or stiffness are contributing factors to the failure of P-MDI procedures. Other pitfalls include errors in history and physical examination, failure to recognize concomitant pathology, and problems with the surgical technique or implant failure. Patulous capsular tissues and glenoid version also play in role management of failed P-MDI patients. With an improved understanding of pertinent clinical complaints and physical examination findings and the advent of arthroscopic techniques and improved implants, successful strategies for the nonoperative and operative management of the patient after a failed posterior or multidirectional instability surgery may be elucidated. This article highlights the common presentation, physical findings, and radiographic workup in a patient that presents after a failed P-MDI repair and offers strategies for revision surgical repair. PMID- 20711047 TI - Surgical management of the failed SLAP repair. AB - Repair of superior labral tears anterior to posterior (SLAP) lesions has become an increasingly common procedure, despite the low incidence rates reported in the literature. As the incidence of these procedures increases, the surgeons will be increasingly confronted with patients with painful shoulders after SLAP repair. Persistent pain after SLAP repair is multifactorial; careful preoperative workup is necessary to elucidate the cause of pain. Simple failure of the prior SLAP repair will rarely be the cause of persistent pain. Use of tacks is especially worrisome, and suture anchor repair is preferable. Articular cartilage injuries because of either bioabsorbable or metal hardware will often create significant residual disability. Recent literature suggests that older patients may be better served by primary biceps tenodesis rather than SLAP repair. PMID- 20711048 TI - Management of the failed AC joint reconstruction: causation and treatment. AB - With recent studies showing improved biomechanical behavior of anatomic acromioclavicular joint reconstructions, these techniques are more frequently being performed. With both the more historic methods of fixation such as coracoacromial ligament transfer along with the newer anatomic reconstruction, potential for failure exists. However, there is a paucity of literature addressing these failures and possible treatment options. The purpose of this review is to report cases of failed reconstructions, describe failure mechanisms, and propose treatment options. PMID- 20711049 TI - Management of failed biceps tenodesis or tenotomy: causation and treatment. AB - The purpose of this paper is to review the management of long head biceps tendon pathology, with a particular emphasis on a prior failed biceps tenotomy or tenodesis. Failed biceps tenotomy generally results from a lack of thorough preoperative discussion of potential outcomes rather than from technical problems. Patients with unsatisfactory results can be treated with conversion to a biceps tenodesis. Failed biceps tenodesis is usually recognized with persistent pain in the area of the bicipital groove, often caused by either the mechanical failure of the tenodesis or associated shoulder pathology that is not addressed at the time of the primary surgery. Operative treatment options include revision tenodesis or biceps tenotomy. The subpectoral approach provides excellent versatility and ability to meet technical objectives when performing revision tenodesis, by removing the tendon completely from the groove and preserving biceps function. PMID- 20711050 TI - Postarthroscopic glenohumeral chondrolysis of the shoulder. AB - Postarthroscopic glenohumeral chondrolysis is a devastating, poorly understood, and relatively rare complication. True chondrolysis involves the dissolution of articular cartilage, including the matrix and cellular elements, leading to premature and irreversible articular cartilage loss. Several factors have been implicated in this phenomenon; however, to date, no study has conclusively ascertained the causation. Potential causative agents include subclinical infection, high volume intra-articular infusion of certain anesthetics, arthroscopic implants, suture material, and thermal energy. One must also consider the possibility that chondrolysis represents an ongoing immunogenic process interrupted or possibly potentiated by surgical intervention. The complex homeostasis of articular cartilage is undoubtedly sensitive to agents introduced into the joint including mechanical, chemical, and temperature-dependent interventions. To date, several papers have described the phenomenon and the potential associations; however, there is no definitive answer although the use of high-dose bupivacaine as an intra-articular anesthetic seems to be contraindicated. The purpose of this article is to review the basic science regarding chondrolysis and to assess the current literature which focuses on postarthroscopic glenohumeral chondrolysis, as well as innovative treatment alternatives. It is unlikely that postoperative chondrolysis will be clearly understood until controlled studies are available, of which there are currently none. PMID- 20711051 TI - Management of the failed rotator cuff surgery: causation and management. AB - Rotator cuff repair is a common orthopedic procedure. Techniques have evolved from open procedures to an arthroscopic (assisted) procedure in many patients. Tendon healing is anticipated, but complications may occur. There is approximately 90% patient satisfaction with index surgery, but imaging studies reveal defect recurrence in approximately one-third of the larger tears. For patients who are limited by pain, revision surgery is considered. Newer techniques of stabilizing the damaged structures, combined with delay in rehabilitation, improved the number of successful surgeries. Revision surgery for pain relief is promising when causes of persistent pain have been identified. Strength deficits may persist, particularly if permanent atrophy and fatty infiltration within the cuff muscles are demonstrated preoperatively. PMID- 20711052 TI - Postarthroscopic arthrofibrosis of the shoulder. AB - Arthrofibrosis after shoulder surgery may be challenging to treat. Certain factors, including diabetes and history of keloid formation, predispose patients to the development of postoperative arthrofibrosis. Etiologies include rotator cuff repair, labral repair, capsulorrhaphy, shoulder arthroplasty, and proximal humerus fracture fixation. Systematic evaluation with thorough history and physical examination is essential to determine the proper treatment and to counsel patients on expectations for recovery. Nonoperative treatment focused on physical therapy is the first step in management. Manipulation under anesthesia may be an effective treatment for failure of physical therapy regimens in idiopathic adhesive capsulitis, however it is less successful in cases of postsurgical adhesions. In cases of postoperative stiffness, treatment options include arthroscopic and open capsular releases. Adequate postoperative pain control and adherence to a rigorous physical therapy regimen are integral to the success of surgical release. Surgical treatment is effective in the majority of patients with postsurgical arthrofibrosis. PMID- 20711053 TI - Management of the failed arthroscopic subacromial decompression: causation and treatment. AB - Arthroscopic subacromial decompression is an effective treatment for impingement syndrome, with published success rates between 77% and 90%. Failure of subacromial decompression is defined as persistent pain and disability after surgery despite adequate postoperative rehabilitation. Potential causes of failure after subacromial decompression are varied and may include technical error, incorrect diagnosis, inadequate rehabilitation, or unrealistic postoperative expectations. A methodical approach to the patient with persistent symptoms after subacromial decompression will allow for accurate diagnosis and treatment of the underlying problem in the majority of cases. PMID- 20711054 TI - The evaluation and management of failed distal clavicle excision. AB - Excision of the distal clavicle (DCE) is a commonly carried out surgical procedure used in the management of acromioclavicular joint pathology. Although successful outcomes after both open and arthroscopic distal clavicle excision occur in a high percentage of patients, treatment failures have been reported, creating a difficult clinical scenario for the treating orthopedic surgeon. The most common mode of failure after DCE is persistent pain and potential etiologies include under-resection, over-resection leading to joint instability, postoperative stiffness, heterotopic ossification, untreated concomitant shoulder pathology, and postoperative infection. Less common causes of failure include distal clavicle fracture, reossification or fusion across the acromioclavicular joint, suprascapular neuropathy, and psychiatric illness. Persistent symptoms and disability after distal clavicle excision require a careful assessment of these potential causes of treatment failure and the formulation of a treatment plan, which may include conservative care, revision surgery, or coracoclavicular ligament reconstruction. Although careful patient selection, preoperative planning, proper surgical technique, and appropriate rehabilitation during the index procedure can minimize the likelihood of poor outcome, this paper reviews the work-up and management of cases of failed distal clavicle excision. PMID- 20711055 TI - Biomedical informatics: changing what physicians need to know and how they learn. AB - The explosive growth of biomedical complexity calls for a shift in the paradigm of medical decision making-from a focus on the power of an individual brain to the collective power of systems of brains. This shift alters professional roles and requires biomedical informatics and information technology (IT) infrastructure. The authors illustrate this future role of medical informatics with a vignette and summarize the evolving understanding of both beneficial and deleterious effects of informatics-rich environments on learning, clinical care, and research. The authors also provide a framework of core informatics competencies for health professionals of the future and conclude with broad steps for faculty development. They recommend that medical schools advance on four fronts to prepare their faculty to teach in a biomedical informatics-rich world: (1) create academic units in biomedical informatics; (2) adapt the IT infrastructure of academic health centers (AHCs) into testing laboratories; (3) introduce medical educators to biomedical informatics sufficiently for them to model its use; and (4) retrain AHC faculty to lead the transformation to health care based on a new systems approach enabled by biomedical informatics. The authors propose that embracing this collective and informatics-enhanced future of medicine will provide opportunities to advance education, patient care, and biomedical science. PMID- 20711056 TI - Local wound care for malignant and palliative wounds. AB - PURPOSE: To enhance the clinician's competence in providing local wound care for malignant and palliative wounds. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: PMID- 20711057 TI - Seeking a diagnosis for memory problems: the experiences of caregivers and families in 5 limited English proficiency communities. AB - Limited data exist on how members of different cultures understand dementia. The Northwestern Cognitive Neurology and Alzheimer's Disease Center in collaboration with Coalition of Limited English Speaking Elderly and Alzheimer's Association Greater Illinois Chapter collaborated to raise awareness in 5 limited English proficiency (LEP) communities (Assyrian, Arabic, Bosnian, Hindi, and Urdu) during 2005 to 2008 through a grant from the Administration on Aging Alzheimer's Disease Demonstration Grants to States. After the second year of the program, 267 individuals with cognitive impairment were identified with cognitive impairment and enrolled; however, only 13% of those sought a medical evaluation to obtain a diagnosis or further help for their memory problems. This project sought to: (1) understand how these LEP community groups conceptualize dementia and (2) understand reasons LEP communities sought or did not seek a diagnosis. Using a community-based participatory research approach, ethnic community leaders conducted 48 interviews in a convenience sample of persons enrolled in the previous Administration on Aging demonstration grant. These interviews were conducted with family members of identified persons with dementia in their native language. Interview notes were translated and subjected to thematic analysis. The majority view memory loss as explainable and normative--due to aging, reaction to medication or trauma experienced by war, family problems, or the immigration experience. This conceptualization and the perception that a doctor cannot help influenced whether they sought an evaluation. Those who saw a doctor were looking for medical treatment and help with difficult behaviors. Experience in the doctor's office was variable. Discussion of analysis with ethnic communities revealed the significance of stigma in the data gathering. Continued community based participatory research approaches with LEP communities could further highlight needs for culturally relevant education and intervention. PMID- 20711058 TI - Temporal stability of receptiveness to clinical research on Alzheimer disease. AB - Research advance directives are a proposed mechanism for ensuring that decisions with regard to research participation adhere to preferences voiced by persons with Alzheimer disease (AD) before losing decisional capacity. Although this approach rests on the assumption that preferences with regard to research participation are consistent over time, little is known about the stability of such preferences. The purpose of this study was to evaluate the temporal stability of older adults' receptiveness to participation in clinical trials, neuroimaging studies, and psychosocial investigations on AD. One hundred and four participants in the University of Pittsburgh Alzheimer Disease Research Center were annually surveyed with regard to their willingness to be contacted with regard to clinical drug trials, neuroimaging studies, and psychosocial research for which they might be eligible. Receptiveness to contact with regard to AD research was compared at 2 time points, 1 year apart. At baseline, most respondents were willing to be contacted with regard to their eligibility for drug trials, imaging studies, and psychosocial research. Thirty-seven percent of respondents voiced a different set of preferences at year 2 as compared with year 1. Differences included both increased and decreased willingness to be contacted. Neither stability of preferences nor direction of change (more vs. less willing) varied by diagnostic group. Bivariate analyses revealed that participation in at least 1 ancillary research study was associated with an overall increase in willingness to be contacted. We conclude that a significant proportion of research-friendly individuals voice different sets of preferences with regard to the possibility of research participation when queried at different points in time. Amenability to participating in clinical research on AD is a relatively dynamic personal attribute that may be influenced by personal experience with research participation. This finding has relevance for the policy debate around research advance directives, an approach which assumes that preferences with regard to research participation are consistent over time. PMID- 20711059 TI - Barriers and facilitators of African American participation in Alzheimer disease biomarker research. AB - African Americans experience a greater risk of Alzheimer disease (AD), but are underrepresented in AD research. Our study examined barriers and facilitators of AD research participation among African Americans. Investigators conducted 11 focus groups with African American participants (n=70) who discussed barriers and facilitators to AD research participation including lumbar puncture studies. The moderator and comoderator independently reviewed the transcripts, identified themes, and coded transcripts for analysis. Participants were predominately female (73%) with a mean age of 52 years (range 21 to 86 y). Concerns and attitudes were consistent across education, socioeconomic status, and sex. Mistrust was a fundamental reason for nonparticipation. Additional barriers included insufficient information dissemination in the African American community, inconvenience, and reputation of the researcher and research institution. Barriers to participation in AD biomarker studies were fear of the unknown and adverse effects. Altruism and relevance of research projects to the individual, family members, or the African American community facilitate participation. Increased participation results from relationships with the community that extend beyond immediate research interests, dissemination of research findings, and emphasis on relevance of proposed studies. Pervasive barriers impede African American participation in AD research but can be overcome through a sustained presence in the community. PMID- 20711060 TI - Challenges and opportunities: recruitment and retention of African Americans for Alzheimer disease research: lessons learned. AB - For more than 3 decades, the recruitment and retention of African Americans for research in Alzheimer disease have been regarded as difficult undertakings with poor results. The typical explanation for failure to respond to research participation options is a widespread mistrust of research and the biomedical community. Mistrust is a reasonable response; given the historic reality of malfeasance, victimization, and mistreatment over the course of the research participation history of African Americans. The challenges are real but there are opportunities for successful recruitment and retention of African Americans for research including research on Alzheimer disease. Participation, however, comes with specific terms and considerations. Two of the most prominent criteria for research recruitment and retention are the transparency and accountability of the investigator, which may determine how he or she proceeds from the start of the process throughout the steps of recruitment, retention, and subsequent follow-up with the community. PMID- 20711062 TI - Cutaneous type adnexal tumors outside the skin. AB - Cutaneous adnexal neoplasms are complex lesions, including benign and malignant neoplasms in addition to malformations and hamartomas. They show one or several features of differentiation along follicular, sebaceous, apocrine, and eccrine lines. Rarely, cutaneous adnexal neoplasms or their mimics may arise outside the skin. In some organs, such as the parotid gland, a number of tumors comprise well established entities, whereas in the majority of cases an extracutaneous occurrence of cutaneous-type adnexal lesions is a rare and often diagnostically challenging finding. This review discusses various authentic cutaneous-type adnexal neoplasms or related lesions presented according to the organ involved. PMID- 20711061 TI - Prion protein codon 129 polymorphism modifies age at onset of frontotemporal dementia with the C.709-1G>A progranulin mutation. AB - Frontotemporal lobar degeneration because of mutations in the progranulin (PGRN) gene presents a high variability both in the clinical phenotype and age of onset of disease. Factors that influence this variability remain largely unknown. The aim of our study was to determine whether selected genetic variables modify age at onset of disease in our series of 21 patients with a single splicing mutation (c.709-1G>A) in the PGRN gene, all of whom were of Basque descent. In our analysis, we included the following genetic variables: PGRN rs5848 and rs9897526 polymorphisms, APOE and microtubule-associated protein tau genotypes, and PRNP codon 129 polymorphism. We found no association between PGRN polymorphisms, APOE and microtubule-associated protein tau genotypes, and age at onset of the disease; whereas we report evidence for an association between PRNP codon 129 polymorphism and age at onset of disease in frontotemporal dementia-PGRN(+) patients. MM homozygous carriers presented onset of disease on average 8.5 years earlier than patients who carried at least 1 valine on their PRNP codon 129 (MV or VV). The biological justification for this association remains speculative. PMID- 20711063 TI - Lichen scrofulosorum mimicking lichen planus. AB - Lichen scrofulosorum is the most uncommon clinicopathologic variant of the tuberculids. Usually, the eruption appears in children and adolescents with strong immune sensitivity to Mycobacterium tuberculosis and consists of tiny follicular papules, closely resembling lichen nitidus. We report a case of lichen scrofulosorum in an adult male with active cervical scrofuloderma who developed lesions of lichen scrofulosorum mimicking clinically lichen planus. Histopathologic study demonstrated granulomas around the hair follicles, although acid-fast bacilli stains, immunohistochemical stain for mycobacteria, polymerase chain reaction investigations and cultures failed to demonstrate Mycobacterium tuberculosis in the cutaneous lesions. The most striking features of the reported case were the onset of the eruption in an adult patient and the clinical appearance of the lesions, resembling lichen planus. PMID- 20711064 TI - An alternative point of view: getting by with less: what's wrong with perfection? AB - OBJECTIVE: Predictions about the future impact of technologic and process innovations inspire optimistic visions. Optimism and speculation require a counterweight. Because results often do not turn out as expected, anticipating failure is useful, and anticipating unintended consequences is visionary. MEASUREMENTS: A history of unfulfilled prognostications was explored with the intent of finding something essential to the complexities of medicine. Do missed predictions signal another side to innovation that also helps us uncover new information about our world? MAIN RESULTS: Serendipity is an important theme in medical innovation. There is no reason to think this will change. Things do not necessarily go as planned, but often the results are as important as the original prediction was supposed to be. It will not be clear where we end up until we get there. CONCLUSIONS: Ideal goals are useful but speculative and subjective. There in fact might be several ideals and contingency is important. The detours and incidental stops on the way to an ideal are more fruitful than the goal itself. PMID- 20711065 TI - Feasibility of physical and occupational therapy beginning from initiation of mechanical ventilation. AB - OBJECTIVE: Physical and occupational therapy are possible immediately after intubation in mechanically ventilated medical intensive care unit patients. The objective of this study was to describe a protocol of daily sedative interruption and early physical and occupational therapy and to specify details of intensive care unit-based therapy, including neurocognitive state, potential barriers, and adverse events related to this intervention. DESIGN AND PATIENTS: Detailed descriptive study of the intervention arm of a trial of mechanically ventilated patients receiving early physical and occupational therapy. SETTING: Two tertiary care academic medical centers participating in a randomized controlled trial. INTERVENTION: Patients underwent daily sedative interruption followed by physical and occupational therapy every hospital day until achieving independent functional status. Therapy began with active range of motion and progressed to activities of daily living, sitting, standing, and walking as tolerated. MEASUREMENTS AND MAIN RESULTS: Forty-nine mechanically ventilated patients received early physical and occupational therapy occurring a median of 1.5 days (range, 1.0-2.1 days) after intubation. Therapy was provided on 90% of MICU days during mechanical ventilation. While endotracheally intubated, subjects sat at the edge of the bed in 69% of all physical and occupational therapy sessions, transferred from bed to chair in 33%, stood in 33%, and ambulated during 15% (n = 26 of 168) of all physical and occupational therapy sessions (median distance of 15 feet; range, 15-20 feet). At least one potential barrier to mobilization during mechanical ventilation (acute lung injury, vasoactive medication administration, delirium, renal replacement therapy, or body mass index >= 30 kg/m) was present in 89% of patient encounters. Therapy was interrupted prematurely in 4% of all sessions, most commonly for patient-ventilator asynchrony and agitation. CONCLUSION: Early physical and occupational therapy is feasible from the onset of mechanical ventilation despite high illness acuity and presence of life support devices. Adverse events are uncommon, even in this high risk group. PMID- 20711066 TI - Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions. AB - OBJECTIVES: To investigate the effects of cardiac arrest and the reperfusion syndrome on blood-brain barrier permeability and evaluate whether methylene blue counteracts blood-brain barrier disruption in a pig model of controlled cardiopulmonary resuscitation. DESIGN: Randomized, prospective, laboratory animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Forty-five piglets. INTERVENTIONS: Forty-five anesthetized piglets were subjected to cardiac arrest alone or 12-min cardiac arrest followed by 8 mins cardiopulmonary resuscitation. The first group (n = 16) was used to evaluate blood-brain barrier disruptions after untreated cerebral ischemia after 0, 15, or 30 mins after untreated cardiac arrest. The other two groups received either an infusion of saline (n = 10) or infusion of saline with methylene blue (n = 12) 1 min after the start of cardiopulmonary resuscitation and continued 50 mins after return of spontaneous circulation. In these groups, brains were removed for immunohistological analyses at 30, 60, and 180 mins after return of spontaneous circulation. MEASUREMENTS AND MAIN RESULTS: An increase of injured neurons and albumin immunoreactivity was demonstrated with increasing duration of ischemia/reperfusion. Less blood-brain barrier disruption was observed in subjects receiving methylene blue as demonstrated by decreased albumin leakage (p < .01), water content (p < .05), and neuronal injury (p < .01). Methylene blue treatment reduced cerebral tissue nitrite/nitrate content (p < .05) and the number of inducible and neuronal nitric oxide synthase-activated cortical cells during administration (p < .01). Meanwhile, the number of cortical endothelial nitric oxide synthase-activated cells increased over time (p < .001). CONCLUSION: Cerebral tissue water content, blood-brain barrier permeability and neurologic injury were increased early in reperfusion after cardiac arrest. Methylene blue exerted neuroprotective effects against the brain damage associated with the ischemia/reperfusion injury and ameliorated the blood-brain barrier disruption by decreasing nitric oxide metabolites. PMID- 20711067 TI - MORE for multiple organ dysfunction syndrome: Multiple Organ REanimation, REgeneration, and REprogramming. AB - Those who care for the critically ill and injured rightfully celebrate the advances made by our field over its first 50 yrs. Advances in systems, tissue, and molecular engineering, together defined as "health engineering," will provide unprecedented opportunities to treat multiple organ dysfunction syndrome in the 21st century. In the future, Multiple Organ REanimation, REgeneration, and REprogramming will be responsible for new treatment approaches for those with multiple organ dysfunction syndrome; several examples are presented here. Thus, as we spent the first 50 yrs of care for the critical ill and injured learning how best to hook humans up to machines, we will spend the next 50 yrs understanding better how to liberate patients from mechanical support. It is difficult to know when these advances will be realized given that the rate of change continues to increase and the seemingly impossible goal of reprogramming fully differentiated cells was accomplished recently by manipulating a few transcription factors. It is not unrealistic to expect that in the next couple of decades that it will be possible to dedifferentiate dysfunctional somatic cells in vivo to a more robust, resistant cell phenotype. Our future should be aimed in part at refining our skill sets and refocusing (even rebranding) critical care as health engineering aimed at Multiple Organ REanimation, REgeneration, and REprogramming. PMID- 20711068 TI - Rescue therapy in adult and pediatric patients with pH1N1 influenza infection: a tertiary center intensive care unit experience from April to October 2009. AB - OBJECTIVE: Severe respiratory failure is a well-recognized complication of pH1N1 influenza infection. Limited data regarding the efficacy of rescue therapies, including high-frequency oscillatory ventilation and extracorporeal membrane oxygenation, have been previously reported in the setting of pH1N1 influenza infection in the United States. DESIGN: Retrospective, single-center cohort study. SETTING: Pediatric, cardiac, surgical, and medical intensive care units in a single tertiary care center in the United States. PATIENTS: One hundred twenty seven consecutive patients with confirmed influenza A infection requiring hospitalization between April 1, 2009, and October 31, 2009. INTERVENTIONS: Electronic medical records were reviewed for demographic and clinical data. MEASUREMENTS AND MAIN RESULTS: The number of intensive care unit admissions appears inversely related to age with 39% of these admissions <20 yrs of age. Median duration of intensive care unit care was 10.0 days (4.0-24.0), and median duration of mechanical ventilation was 8.0 days (0.0-23.5). Rescue therapy (high frequency oscillatory ventilation or extracorporeal membrane oxygenation) was used in 36% (12 of 33) of intensive care unit patients. The severity of respiratory impairment was determined by Pao2/Fio2 ratio and oxygenation index. High-frequency oscillatory ventilation at 24 hrs resulted in improvements in median Pao2/Fio2 ratio (71 [58-93] vs. 145 [126-185]; p < .001), oxygenation index (27 [20-30] vs. 18 [12-25]; p = .016), and Fio2 (100 [70-100] vs. 45 [40 55]; p < .001). Extracorporeal membrane oxygenation resulted in anticipated improvement in parameters of oxygenation at both 2 hrs and 24 hrs after initiation of therapy. Despite the severity of oxygenation impairment, overall survival for both rescue therapies was 75% (nine of 12), 80% (four of five) for high-frequency oscillatory ventilation alone, and 71% (five of seven) for high frequency oscillatory ventilation + extracorporeal membrane oxygenation. CONCLUSION: In critically ill adult and pediatric patients with pH1N1 infection and severe lung injury, the use of high-frequency oscillatory ventilation and extracorporeal membrane oxygenation can result in significant improvements in Pao2/Fio2 ratio, oxygenation index, and Fio2. However, the impact on mortality is less certain. PMID- 20711069 TI - Symptoms experienced by intensive care unit patients at high risk of dying. AB - OBJECTIVE: To provide a focused, detailed assessment of the symptom experiences of intensive care unit patients at high risk of dying and to evaluate the relationship between delirium and patients' symptom reports. DESIGN: Prospective, observational study of patients' symptoms. SETTING: Two intensive care units in a tertiary medical center in the western United States. PATIENTS: One hundred seventy-one intensive care unit patients at high risk of dying. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were interviewed every other day for up to 14 days. Patients rated the presence, intensity (1 = mild; 2 = moderate; 3 = severe), and distress (1 = not very distressing; 2 = moderately distressing; 3 = very distressing) of ten symptoms (that is, pain, tired, short of breath, restless, anxious, sad, hungry, scared, thirsty, confused). The Confusion Assessment Method-Intensive Care Unit was used to ascertain the presence of delirium. A total of 405 symptom assessments were completed by 171 patients. Patients' average age was 58 +/- 15 yrs; 64% were males. Patients were mechanically ventilated during 34% of the 405 assessments, and 22% died in the hospital. Symptom prevalence ranged from 75% (tired) to 27% (confused). Thirst was moderately intense, and shortness of breath, scared, confusion, and pain were moderately distressful. Delirium was found in 34.2% of the 152 patients who could be evaluated. Delirious patients were more acutely ill and received significantly higher doses of opioids. Delirious patients were significantly more likely to report feeling confused (43% vs. 22%, p = .004) and sad (46% vs. 31%, p = .04) and less likely to report being tired (57% vs. 77%, p = .006) than nondelirious patients. CONCLUSIONS: Study findings suggest that unrelieved and distressing symptoms are present for the majority of intensive care unit patients, including those with delirium. Symptom assessment in high-risk intensive care unit patients may lead to more focused interventions to avoid or minimize unnecessary suffering. PMID- 20711071 TI - Panton-Valentine leukocidin expressing Staphylococcus aureus pneumonia managed with extracorporeal membrane oxygenation: experience and outcome. AB - OBJECTIVE: Panton-Valentine leukocidin expressing Staphylococcus aureus pneumonia, an infection that affects predominantly young people, has a mortality rate of > 70% despite aggressive conventional management. Little information is available on the management of patients with Panton-Valentine leukocidin expressing S. aureus pneumonia with extracorporeal membrane oxygenation support. As a large extracorporeal membrane oxygenation center, we reviewed our experience and outcomes with Panton-Valentine Leukocidin expressing S. aureus pneumonia. DATA SOURCES: Locally held register of all extracorporeal membrane oxygenation patients at Glenfield Hospital. STUDY SELECTION: Retrospective study including all patients with sputum-positive Panton-Valentine leukocidin expressing S. aureus pneumonia managed with extracorporeal membrane oxygenation support at a single extracorporeal membrane oxygenation center. DATA SYNTHESIS: On review of our database held from September 1989 until date, there were four patients with sputum-confirmed Panton-Valentine leukocidin expressing S. aureus pneumonia managed with extracorporeal membrane oxygenation. Refractory hypoxemia and/or uncompensated hypercapnia despite optimal conventional management were the indications for extracorporeal membrane oxygenation. After varying periods on extracorporeal membrane oxygenation with appropriate antibiotic and ancillary care, all four patients were discharged home. CONCLUSIONS: Panton-Valentine leukocidin expressing S. aureus pneumonia can cause severe, necrotizing pneumonia associated with acute respiratory distress syndrome, which can be particularly challenging to manage. Extracorporeal membrane oxygenation support permits low pressure lung ventilation, avoiding barotrauma to lungs made friable by Panton Valentine leukocidin expressing S. aureus infection. Although this is a small number of patients, the results are encouraging. PMID- 20711072 TI - Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. AB - OBJECTIVE: Spinal cord injury results in loss of neurons, degeneration of axons, formation of glial scar, and severe functional impairment. Human umbilical cord mesenchymal stem cells can be induced to form neural cells in vitro. Thus, these cells have a potential therapeutic role for treating spinal cord injury. DESIGN AND SETTING: Rats were randomly divided into three groups: sham operation group, control group, and human umbilical cord mesenchymal stem cell group. All groups were subjected to spinal cord injury by weight drop device except for sham group. SUBJECTS: Thirty-six female Sprague-Dawley rats. INTERVENTIONS: The control group received Dulbecco's modified essential media/nutrient mixture F-12 injections, whereas the human umbilical cord mesenchymal stem cell group undertook cells transplantation at the dorsal spinal cord 2 mm rostrally and 2 mm caudally to the injury site at 24 hrs after spinal cord injury. MEASUREMENTS: Rats from each group were examined for neurologic function and contents of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and neurotrophin-3. Survival, migration, and differentiation of human umbilical cord mesenchymal stem cells, regeneration of axons, and formation of glial scar were also explored by using immunohistochemistry and immunofluorescence. MAIN RESULTS: Recovery of hindlimb locomotor function was significantly enhanced in the human umbilical cord mesenchymal stem cells grafted animals at 5 wks after transplantation. This recovery was accompanied by increased length of neurofilament-positive fibers and increased numbers of growth cone-like structures around the lesion site. Transplanted human umbilical cord-mesenchymal stem cells survived, migrated over short distances, and produced large amounts of glial cell line-derived neurotrophic factor and neurotrophin-3 in the host spinal cord. There were fewer reactive astrocytes in both the rostral and caudal stumps of the spinal cord in the human umbilical cord-mesenchymal stem cell group than in the control group. CONCLUSIONS: Treatment with human umbilical cord mesenchymal stem cells can facilitate functional recovery after traumatic spinal cord injury and may prove to be a useful therapeutic strategy to repair the injured spinal cord. PMID- 20711070 TI - Anti-infective external coating of central venous catheters: a randomized, noninferiority trial comparing 5-fluorouracil with chlorhexidine/silver sulfadiazine in preventing catheter colonization. AB - OBJECTIVE: The antimetabolite drug, 5-fluorouracil, inhibits microbial growth. Coating of central venous catheters with 5-fluorouracil may reduce the risk of catheter infection. Our objective was to compare the safety and efficacy of central venous catheters externally coated with 5-fluorouracil with those coated with chlorhexidine and silver sulfadiazine. DESIGN: Prospective, single-blind, randomized, active-controlled, multicentered, noninferiority trial. SETTING: Twenty-five US medical center intensive care units. PATIENTS: A total of 960 adult patients requiring central venous catheterization for up to 28 days. INTERVENTIONS: Patients were randomized to receive a central venous catheter externally coated with either 5-fluorouracil (n = 480) or chlorhexidine and silver sulfadiazine (n = 480). MEASUREMENTS AND MAIN RESULTS: The primary antimicrobial outcome was a dichotomous measure (<15 colony-forming units or >= 15 colony-forming units) for catheter colonization determined by the roll plate method. Secondary antimicrobial outcomes included local site infection and catheter-related bloodstream infection. Central venous catheters coated with 5 fluorouracil were noninferior to chlorhexidine and silver sulfadiazine coated central venous catheters with respect to the incidence of catheter colonization (2.9% vs. 5.3%, respectively). Local site infection occurred in 1.4% of the 5 fluorouracil group and 0.9% of the chlorhexidine and silver sulfadiazine group. No episode of catheter-related bloodstream infection occurred in the 5 fluorouracil group, whereas two episodes were noted in the chlorhexidine and silver sulfadiazine group. Only Gram-positive organisms were cultured from 5 fluorouracil catheters, whereas Gram-positive bacteria, Gram-negative bacteria, and Candida were cultured from the chlorhexidine and silver sulfadiazine central venous catheters. Adverse events were comparable between the two central venous catheter coatings. CONCLUSIONS: Our results suggest that central venous catheters externally coated with 5-fluorouracil are a safe and effective alternative to catheters externally coated with chlorhexidine and silver sulfadiazine when used in critically ill patients. PMID- 20711073 TI - Cognitive decline following major surgery is associated with gliosis, beta amyloid accumulation, and tau phosphorylation in old mice. AB - OBJECTIVE: Elderly patients undergoing major surgery often develop cognitive dysfunction and the mechanism of this postoperative complication remains elusive. We sought to determine whether postoperative cognitive dysfunction in old mice is associated with the pathogenesis of Alzheimer's disease. DESIGN: Prospective, randomized study. SETTING: University teaching hospital-based research laboratory. SUBJECTS: One-hundred and twenty C57BL/6 14-mo-old male mice (weighing 30-40 g). INTERVENTIONS: Mice received intraperitoneal injections of either vehicle or Celastrol (a potent anti-inflammatory compound) for 3 days before undergoing sham surgery or partial hepatectomy, on the surgery day, and for a further 4 days after surgery. Cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease were assessed 1 day after surgery day 1, 3, or 7. MEASUREMENTS AND MAIN RESULTS: Cognitive impairment following surgery was associated with the appearance of certain pathologic hallmarks of Alzheimer's disease: microgliosis, astrogliosis, enhanced transcriptional and translational activity of beta-amyloid precursor protein, beta-amyloid production, and tau protein hyperphosphorylation in the hippocampus. Surgery-induced changes in cognitive dysfunction were prevented by the administration of Celastrol as were changes in beta-amyloid and tau processing. CONCLUSIONS: These data suggest that surgery can provoke astrogliosis, beta amyloid accumulation, and tau phosphorylation in old subjects, which is likely to be associated with the cognitive decline seen in postoperative cognitive dysfunction. PMID- 20711075 TI - Epidemiology of invasive candidiasis. AB - PURPOSE OF REVIEW: This review covers candidaemia in numbers, susceptibility issues, host groups, risk factors and outcome. RECENT FINDINGS: The incidence of candidaemia has increased over the last decades. Candida glabrata is particularly common in the northern hemisphere and with increasing age whilst the opposite is true for C. parapsilosis, C. glabrata, C. krusei and a number of emerging species are not fully susceptible to azoles. C. parapsilosis and C. guilliermondii are not fully susceptible to echinocandins. Increasing rates of C. parapsilosis have been observed at centres with a high use of echinocandins, and outcome for this species is not superior comparing echinocandins with fluconazole. Acquired azole resistance has recently been described in as many as a third of 19% resistant isolates and echinocandin resistance has emerged and been detected as early as day 12 of echinocandin therapy. ICU stay and abdominal surgery are among the most important risk factors. Outcome is dependent on species involved, timing, dosing and choice of therapy and management of the primary focus of infection. However, host factors are dominating predictors of mortality in recent studies of ICU candidiasis. SUMMARY: The changing epidemiology highlights the need for close monitoring of local incidence, species distribution and susceptibility in order to optimize therapy and outcome. PMID- 20711074 TI - Stress ulcer prophylaxis in the new millennium: a systematic review and meta analysis. AB - BACKGROUND: Recent observational studies suggest that bleeding from stress ulceration is extremely uncommon in intensive care unit patients. Furthermore, the risk of bleeding may not be altered by the use of acid suppressive therapy. Early enteral tube feeding (initiated within 48 hrs of intensive care unit admission) may account for this observation. Stress ulcer prophylaxis may, however, increase the risk of hospital-acquired pneumonia and Clostridia difficile infection. OBJECTIVE: A systematic review of the literature to determine the benefit and risks of stress ulcer prophylaxis and the moderating effect of enteral nutrition. DATA SOURCES: MEDLINE, Embase, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles. STUDY SELECTION: Randomized, controlled studies that evaluated the association between stress ulcer prophylaxis and gastrointestinal bleeding. We included only those studies that compared a histamine-2 receptor blocker with a placebo. DATA EXTRACTION: Data were abstracted on study design, study size, study setting, patient population, the histamine-2 receptor blocker and dosage used, the incidence of clinically significant gastrointestinal bleeding, hospital-acquired pneumonia, mortality, and the use of enteral nutrition. DATA SYNTHESIS: Seventeen studies (which enrolled 1836 patients) met the inclusion criteria. Patients received adequate enteral nutrition in three of the studies. Overall, stress ulcer prophylaxis with a histamine-2 receptor blocker reduced the risk of gastrointestinal bleeding (odds ratio 0.47; 95% confidence interval, 0.29-0.76; p < .002; I = 44%); however, the treatment effect was noted only in the subgroup of patients who did not receive enteral nutrition. In those patients who were fed enterally, stress ulcer prophylaxis did not alter the risk of gastrointestinal bleeding (odds ratio 1.26; 95% confidence interval, 0.43-3.7). Overall histamine 2 receptor blockers did not increase the risk of hospital-acquired pneumonia (odds ratio 1.53; 95% confidence interval, 0.89-2.61; p = .12; I = 41%); however, this complication was increased in the subgroup of patients who were fed enterally (odds ratio 2.81; 95% confidence interval, 1.20-6.56; p = .02; I = 0%). Overall, stress ulcer prophylaxis had no effect on hospital mortality (odds ratio 1.03; 95% confidence interval, 0.78-1.37; p = .82). The hospital mortality was, however, higher in those studies (n = 2) in which patients were fed enterally and received a histamine-2 receptor blocker (odds ratio 1.89; 95% confidence interval, 1.04-3.44; p = .04, I = 0%). Sensitivity analysis and meta-regression demonstrated no relationship between the treatment effect (risk of gastrointestinal bleeding) and the classification used to define gastrointestinal bleeding, the Jadad quality score nor the year the study was reported. CONCLUSIONS: The results of this meta-analysis suggest that, in those patients receiving enteral nutrition, stress ulcer prophylaxis may not be required and, indeed, such therapy may increase the risk of pneumonia and death. However, because no clinical study has prospectively tested the influence of enteral nutrition on the risk of stress ulcer prophylaxis, our findings should be considered exploratory and interpreted with some caution. PMID- 20711076 TI - Continuum of hospital care: the role of intensive care. AB - PURPOSE OF REVIEW: This review outlines the way the specialty of intensive care has expanded over the last decade in response to the changing population of hospital patients, being older with more comorbidities and having more complex interventions. The previous disjointed professional and geographical silos, providing patient care, are being challenged and a more patient focussed continuum of care is replacing it. RECENT FINDINGS: There have been many reports over the last few years, describing patient centred systems, constructed around the needs of the seriously ill, at-risk patient, including trauma systems and Medical Emergency Team-type systems. There is now general agreement that in most settings these systems are responsible for a significant reduction in mortality and serious adverse events such as cardiac arrest rates. SUMMARY: The implications for the move towards systems to improve patient outcome and decrease mortality in hospitals are having a significant impact on the way we practise medicine, resulting in an emphasis, among other things, of constructing our care around the needs of patients, rather than rigidly practice medicine from within our own tribal boundaries, for example professional boundaries, medical specialty boundaries and geographical boundaries. PMID- 20711077 TI - Inotropes in cardiac patients: update 2011. AB - PURPOSE OF REVIEW: ICU patients frequently develop low output syndromes due to cardiac dysfunction, myocardial injury, and inflammatory activation. Conventional inotropic agents seem to be useful in restoring hemodynamic parameters and improving peripheral organ perfusion, but can increase short-term and long-term mortality in these patients. Novel inotropes may be promising in the management of ICU patients, having no serious adverse effects. This review summarizes all the current knowledge about the use of conventional and new inotropic agents in various clinical entities of critically ill patients. RECENT FINDINGS: In recent European Society of Cardiology guidelines, inotropic agents are administered in patients with low output syndrome due to impaired cardiac contractility, and signs and symptoms of congestion. The most recommended inotropes in this condition are levosimendan and dobutamine (both class of recommendation: IIa, level of evidence: B). Recent data indicate that levosimendan may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively. Furthermore, calcium sensitizing by levosimendan can be effectively used for weaning of mechanical ventilation in postcardiac surgery patients and has also cardioprotective effect as expressed by the absence of troponin release in this patient population. Finally, new agents, such as istaroxime and cardiac myosin activators may be safe and improve central hemodynamics in experimental models of heart failure and heart failure patients in phase II clinical trials; however, large-scale randomized clinical trials are required. SUMMARY: In an acute cardiac care setting, short-term use of inotropic agents is crucial for the restoration of arterial blood pressure and peripheral tissue perfusion, as well as weaning of cardiosurgery. New promising agents should be tested in randomized clinical trials. PMID- 20711078 TI - Prophylaxis, empirical and preemptive treatment of invasive candidiasis. AB - PURPOSE OF REVIEW: Invasive candidiasis remains an important infection for ICU patients, associated with poor clinical outcomes. It has been increasingly recognized that the traditional paradigm of culture-directed antifungal treatment is unsatisfactory, and that earlier antifungal intervention strategies, such as prophylaxis, preemptive therapy, and empiric therapy, are required to improve patient outcomes. The purpose of this review is to summarize the recent supportive evidence for such strategies and to highlight the current challenges in their implementation. RECENT FINDINGS: Despite new antifungal agents and classes, the mortality from invasive candidiasis remains high. Antifungal prophylaxis remains the best-studied early antifungal intervention strategy; however, unless targeted to patients at highest risk, is inefficient. Recent data suggests that although risk predictive models, using a combination of clinical risk factors and Candida colonization parameters, may be a relatively simple and practical approach to guide prophylaxis or preemptive therapy, further validation of these models is required. A single trial has demonstrated that empiric antifungal therapy is not of benefit when instituted to patients with antibiotic refractory fever alone. SUMMARY: On the basis of current knowledge, it is difficult to universally recommend antifungal prophylaxis, apart from patient groups with a known very high risk, such as those with necrotising pancreatitis or recurrent gastrointestinal perforations. Antifungal prophylaxis may also be reasonable where local incidence rates and epidemiology are compelling. Among stable patients with multifocal Candida colonization and/or a multitude of clinical-risk factors, preemptive therapy is currently not indicated, although the development of better risk predictive models may assist with such patients. Among patients with refractory fever despite broad-spectrum antibacterial therapy, empiric antifungal therapy may be reasonable where local incidence rates are high (e.g. >10%); however, a thorough search for alternate causes must be instituted. PMID- 20711079 TI - Pathogenesis of invasive candidiasis. AB - PURPOSE OF REVIEW: Disseminated candidiasis remains a life-threatening disease in the ICU. The development of invasive disease with Candida albicans is dependent on multiple factors, such as colonization and efficient host defense at the mucosa. In the present review, we describe the host defense mechanisms against Candida that are responsible for counteracting mucosal invasion, and eliminating the pathogen once invasion has taken place. RECENT FINDINGS: The newly described T-helper subset Th17 is critical for mucosal anti-Candida host defense and plays a major role in controlling C. albicans colonization, whereas the Th1 response and monocyte-dependent cytokines such as IL-1 and TNF are predominantly responsible for activation of neutrophils and macrophages during disseminated candidiasis. SUMMARY: This knowledge provides the basis of exploring new treatment options in the fight against invasive candidiasis. Reports of beneficial effects of recombinant cytokine therapy in fungal infections, renders them prime candidates for adjuvant immunotherapy in Candida sepsis. PMID- 20711080 TI - Is altered bone health part of the metabolic syndrome? PMID- 20711081 TI - Simplifying screening for osteoporosis in Australian primary care: the Prospective Screening for Osteoporosis; Australian Primary Care Evaluation of Clinical Tests (PROSPECT) study. AB - OBJECTIVE: Although bone density by dual-energy x-ray absorptiometry (DXA) is the standard measure for the diagnosis of osteoporosis, as a screening tool, it has significant cost and availability of DXA is not universal. Prospective Screening for Osteoporosis; Australian Primary Care Evaluation of Clinical Tests (PROSPECT) was a national study undertaken to establish an effective prescreening protocol to be used in primary care facilitating targeted radiological investigation for osteoporosis in older women. METHODS: Two hundred sixty-seven primary care physicians recruited 2,466 women 70 years and older who had no previous diagnosis of osteoporosis in a community-based cross-sectional study. The main outcome measures used were lumbar spine and femoral neck T-scores on DXA and presence of a vertebral fracture on thoracolumbar x-ray. Participant characteristics, gap-on wall occiput test, and rib-to-pelvis distance measurements were provided by each primary care physician. RESULTS: Of the study population, 21.8% (95% CI, 19.9% 23.8%) had osteoporosis of the femoral neck and/or lumbar spine based on DXA, and 24.7% (95% CI, 22.5%-26.9%) had at least one vertebral fracture. Only 7.3% (95% CI, 6.2%-8.3%) had both osteoporosis and radiological vertebral fracture. Univariate and multivariate regression modeling of the demographic and clinical data collected resulted in a three-factor predictive tool for the diagnosis of osteoporosis and/or vertebral fracture that included the following variables: rib pelvis distance greater than 2 fingerbreadths (yes/no), ever use of estrogen for more than 6 months (yes/no), and body mass index (<25, 25-30, >30 kg/m2). Only screening women classified as moderate to high risk by the tool DXA plus plain x ray would then result in 14% of women 70 years or older who were not being screened, with 93% of cases being detected. CONCLUSIONS: The Prospective Screening for Osteoporosis; Australian Primary Care Evaluation of Clinical Tests tool will contribute to the diagnosis and management of osteoporosis by facilitating targeted screening and hence reducing the need for unnecessary radiology tests at the primary care level. PMID- 20711082 TI - Ethanol extract of Fructus Ligustri Lucidi increases circulating 1,25 dihydroxyvitamin D3 by inducing renal 25-hydroxyvitamin D-1alpha hydroxylase activity. AB - OBJECTIVE: The present study was designed to determine whether Fructus Ligustri Lucidi (FLL) ethanol extract can directly regulate vitamin D metabolism both in vivo and in vitro. METHODS: Eleven-month-old, aged Sprague-Dawley sham-operated and ovariectomized (OVX) female rats were fed a normal-calcium (Ca) diet (0.6% Ca, 0.65% phosphorus) and received either FLL (700 mg/kg) or vehicle daily for 12 weeks. The in vitro effects of FLL on vitamin D metabolism were studied using primary cultures of the rat renal proximal tubules. mRNA and protein expressions of 25-hydroxyvitamin D-1alpha hydroxylase (1-OHase) and vitamin D receptor (VDR) in the kidney and proximal tubule were measured using real-time polymerase chain reaction and Western blotting, respectively. The concentrations of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) synthesized by renal 1-OHase were measured by a competitive enzyme immunoassay. RESULTS: FLL treatment significantly increased serum 1,25(OH)2D3 levels in both sham (P < 0.01) and OVX (P < 0.05) rats. FLL increased renal 1-OHase and VDR protein and mRNA expressions in sham rats. Protein expression of renal 1-OHase, but not VDR, was also up-regulated in OVX rats during FLL treatment. 1-OHase mRNA and 1-OHase activity were increased by FLL treatment in primary cultures of renal proximal tubule cells. CONCLUSIONS: FLL could increase the circulating levels of 1,25(OH)2D3 in vivo in aged female rats by directly stimulating 1-OHase activity. Thus, it might be an ideal oral agent that can help to improve the ability to induce 1,25(OH)2D3 synthesis and Ca balance in postmenopausal women who are of high risk of developing osteoporosis. PMID- 20711084 TI - Role of real-time reverse transcription polymerase chain reaction for detection of respiratory viruses in critically ill children with respiratory disease: Is it time for a change in algorithm? AB - OBJECTIVES: To identify the respiratory viral pathogens associated with acute lower respiratory tract infection in critically ill pediatric patients by using real-time reverse transcription-polymerase chain reaction, and compare results with those of direct fluorescence antibody assay testing. DESIGN: Observational cohort study. SETTING: Pediatric intensive care unit at a tertiary care academic hospital. PATIENTS: Pediatric patients admitted to the pediatric intensive care unit with severe respiratory symptoms consistent with viral lower respiratory tract infection. INTERVENTIONS: None. MEASUREMENTS: Respiratory samples of pediatric patients admitted to the pediatric intensive care unit with severe respiratory symptoms between January 2008 and July 2009 were tested with direct fluorescence antibody assay and real-time reverse transcription-polymerase chain reaction. MAIN RESULTS: At least one viral agent was detected in 70.5% of specimens by real-time reverse transcription-polymerase chain reaction and in 16.5% by direct fluorescence antibody assay (p < .001). Real-time reverse transcription-polymerase chain reaction increased the total viral yield five-fold compared to direct fluorescence antibody assay. Rhinovirus was the most commonly identified virus (41.6%). For viruses included in the direct fluorescence antibody assay panel, direct fluorescence antibody assay had a sensitivity of 0.42 (95% confidence interval 0.25-0.61) and a specificity of 1 (95% confidence interval 0.86-1.00) compared with real-time reverse transcription-polymerase chain reaction. Coinfections were not uncommon, in particular with rhinovirus, and these patients tended to have higher mortality. CONCLUSIONS: Direct fluorescence antibody assay testing is a suboptimal method for the detection of respiratory viruses in critically ill children with lower respiratory tract infection. Given the importance of a prompt and accurate viral diagnosis for this group of patients, we suggest that real-time reverse transcription-polymerase chain reaction becomes part of the routine diagnostic algorithm in critically ill children when a viral etiology is suspected, even if conventional tests yield a negative result. PMID- 20711083 TI - Brain-systemic temperature gradient is temperature-dependent in children with severe traumatic brain injury. AB - OBJECTIVES: To understand the gradient between rectal and brain temperature in children after severe traumatic brain injury. We hypothesized that the rectal temperature and brain temperature gradient will be influenced by the child's body surface area and that this relationship will persist over physiologic temperature ranges. DESIGN: Retrospective review of a prospectively collected pediatric neurotrauma registry. SETTING: Academic, university-based pediatric neurotrauma program. PATIENTS: Consecutive children (n = 40) with severe traumatic brain injury (Glasgow coma scale of <8) who underwent brain temperature monitoring (July 2003 to December 2008) were studied after informed consent was obtained. A subset of children (n = 24) were concurrently enrolled in a randomized, controlled clinical trial of early-moderate hypothermia for neuroprotection. INTERVENTIONS: Data extraction of multiple clinical variables, including demographic data, body surface area, and rectal and brain temperature at recorded at hourly intervals. MEASUREMENTS AND MAIN RESULTS: Paired brain and rectal temperature measurements (in degrees Celsius, n = 4369) were collected hourly and compared by using Pearson correlations. Patients were stratified according to body surface area (<1.0 m, 1.0-1.99 m, 2.0-2.99 m, and >3.0 m) and based on brain temperature (<=34.0, 34.1-36.0; 36.1-38, >=38.1). Body surface area and brain temperature were compared between groups by using Pearson correlations with correction for repeated measures. Mean brain temperature-rectal temperature difference was calculated for stratified brain temperature ranges. Overall, brain and rectal temperatures were highly correlated (r = .86, p < .001). During brain hyperthermia, brain temperature-rectal temperature was similar to that reported in previous studies with brain temperature higher than rectal temperature (1.75 +/- 0.4; r = .54). Surprisingly, this relationship was reversed during brain hypothermia (brain temperature-rectal temperature = -1.87 +/- 0.8; r = .37), indicating a reversal of the brain-systemic temperature gradient. When stratified for body surface area, the correlation between rectal temperature and brain temperature remained strong (r = .78, 0.91, 0.79 and 0.95, respectively, p < .001). However, the correlation between brain temperature and rectal temperature was substantially decreased when stratified for brain temperature (r = .37, 0.58, 0.48, 0.54, p < .001). In particular, during moderate brain hypothermia (brain temperature <=34), the correlation between brain temperature and rectal temperature was weakest, indicating the greatest variability during this condition which is often targeted for therapeutic trials. CONCLUSIONS: Brain temperature and rectal temperature are generally well-correlated in children with traumatic brain injury. This relationship is different at the extremes of the physiologic temperature range, with the temperature gradient reversed during brain hypothermia and hyperthermia. Given that studies showing neuroprotection from hypothermia in animal models of brain injury generally target brain temperature, our data suggest the possibility that, if brain temperature were the therapeutic target in clinical trials, this would result in somewhat higher systemic temperature and potentially fewer side effects. This relationship may be exploited in future clinical trials to maintain brain hypothermia (for neurologic protection) at slightly higher systemic temperatures (and potentially fewer systemic side effects). PMID- 20711085 TI - Clinical spectrum of acute otitis media complicating upper respiratory tract viral infection. AB - BACKGROUND: acute otitis media (AOM) often occurs as a complication of upper respiratory tract infection (URI). OBJECTIVE: to describe otoscopic findings during URI, the full clinical spectrum of AOM, and outcome of cases managed with watchful waiting. METHODS: : In a prospective study of 294 healthy children (6 months-3 years), characteristics of AOM complicating URI were studied. Otoscopic findings were categorized by tympanic membrane (TM) position, color, translucency, and mobility. Otoscopic score was assigned based on McCormick otoscopy scale (OS)-8 scale. RESULTS: during days 1 to 7 of URI, otoscopic findings at 1114 visits were consistent with AOM in 22%; myringitis (inflamed TM, no fluid) was diagnosed in 7%. In AOM episodes diagnosed within 28 days of URI onset, TM position was described as: nonbulging (19%), mild bulging (45%), bulging (29%), and TM perforation occurred in (6%). OS-8 scale showed mild TM inflammation (OS, 2-3) in 6%, moderate (OS, 4-5) in 59%, and severe (OS, 6-8) in 35%. In 54% of 126 bilateral AOM episodes, inflammation of both TMs was at different stages. Of 28 cases of nonsevere AOM managed with watchful waiting, 4 progressed and 3 later required an antibiotic. CONCLUSIONS: AOM is a spectrum of infection that may present at various stages, even in the same child with bilateral disease. During URI, otoscopic changes are observed from the first day of onset. Understanding the wide clinical spectrum of AOM is needed to help with future clinical trial design and development of a scoring system to establish treatment criteria that will minimize antibiotic use. PMID- 20711086 TI - Angiogenic and inflammatory markers in the intraocular fluid of eyes with diabetic macular edema and influence of therapy with bevacizumab. AB - PURPOSE: The purpose of this study was to determine the concentrations of angiogenic and inflammatory markers in human eyes with diffuse diabetic macular edema before and during therapy with intravitreal bevacizumab and their association with disease activity. METHODS: In a prospective clinical trial, 10 eyes of 10 consecutive patients with vision loss because of diabetic macular edema were compared with 10 eyes of 10 age-matched controls. Bevacizumab was administered at baseline; retreatments were given monthly according to disease activity. During a follow-up of 6 months, aqueous humor samples were taken each time intravitreal therapy was administered. A multiplex assay was used for measurement of 12 different growth factors and cytokines. RESULTS: Aqueous humor of eyes with diabetic macular edema demonstrated a significantly increased expression of monocyte chemoattractant protein-1 and interleukin-8 and higher, but not significant, levels of interleukin-6 and vascular endothelial growth factor. Intravitreal therapy with bevacizumab resulted in a significant decrease of vascular endothelial growth factor below physiologic levels. This change was not associated with clinical disease activity as measured by visual acuity and central retinal thickness. CONCLUSION: Eyes with diabetic macular edema showed a different profile of monocyte chemoattractant protein-1 and interleukin-8 as compared with controls. The intraocular vascular endothelial growth factor expression decreased significantly after the first intravitreal injection of bevacizumab; this reduction was prolonged by consecutive monthly retreatment. PMID- 20711087 TI - The safety and efficacy of passive removal of silicone oil with 23-gauge transconjunctival sutureless system. AB - PURPOSE: To evaluate the safety and efficacy of passive removal of silicone oil with 23-gauge (G) transconjunctival sutureless system. METHODS: This is a single center, prospective, interventional, randomized control study. Forty eyes of 40 patients were enrolled in this study and randomized into 2 groups. Group 1 (n = 20) patients underwent passive removal of silicone oil with 23-G transconjunctival sutureless system. Group 2 (n = 20) underwent 20-G active silicone oil removal using all three 20-G ports. In both groups, air-fluid exchange was performed and the globe was left air filled at the end of surgery. All eyes in both groups received 360 degrees endolaser. We recorded surgical time, time for silicone oil removal, number of sutured 23-G sclerotomy sites, presence of preoperative scarring at sclerotomy site, postoperative hypotony, endophthalmitis, and inflammation at sclerotomy site. RESULTS: Opening and closing times were significantly shorter in Group 1 than in Group 2. Only 3 cases (15%) in Group 1 required 1 additional suture each in the superior sclerotomy site. Both groups were similar in safety in terms of chance of endophthalmitis, redetachment rate, and postoperative hypotony. Only 1 patient of Group 1 (5%) and 5 patients of Group 2 (25%) showed significant conjunctival inflammation at the end of 2 weeks. CONCLUSION: Passive removal of silicone oil with 23-G transconjunctival sutureless system may hasten postoperative recovery by decreasing overall surgical time and postoperative inflammation. It is a safe and effective procedure when compared with 20-G active silicone oil removal for 1000 centistoke oil. PMID- 20711089 TI - [Muscle involvement in Systemic Sclerosis - diagnosis evaluation]. AB - In Systemic Sclerosis skeletal muscle may be involved. Several published series describe different involvement percentages, depending on the diagnostic criteria used. To date, there are no uniform criteria for the diagnosis of this entity and, the use of new methods, namely imunohistoquimic techniques, will be necessary to highlight the different types of muscle involvement occurring in this disease. The present article intends to make a review about the diagnosis of the myopathy occurring in Systemic Sclerosis. PMID- 20711088 TI - Oral contraceptives and systemic lupus erythematosus: what should we advise to our patients? AB - Oral contraceptives (OC) are the contraceptive method of choice for the majority of Western world women. Decision on giving OC to patients with Systemic Lupus Erythematosus (SLE) puts special issues and concerns. In fact, OC have been evocated as etiologic risk factors for SLE and also associated with an increased risk of flares. During periods of active disease an effective contraception is mandatory, but OC puts safety problems in this setting. On the other hand, many SLE patients will be on a low activity or remission state with much less aggressive medication for most of the time. Cumulative damage due to SLE and comorbidities such as cardiovascular disease, antiphospholipid syndrome/ antibodies also has to be considered for pregnancy and contraception decisions. Advice on the benefits and risks of OC is an important and difficult aspect of the care of women with SLE. This advice should be done based on the best evidence and always considering our particular subject and its changing risk profile. This review will focus on OC in SLE women and particularly on current evidence on safety. PMID- 20711090 TI - [Autoinflammatory syndromes]. AB - Autoinflammatory syndromes (AIS) are a heterogeneous group of congenital diseases characterized by the presence of recurrent episodes of fever and local or generalized inflammation, in the absence of infectious agents, detectable auto antibodies or antigen-specific autoreactive T-cells. These diseases have been much better understood during the past 15 years, mainly due to the marked advances of the Human Genoma Project and its implications in the identification and characterization of genetic mutations. In this paper we make a revision of the classification of AIS and focus our attention specially on the cryopyrin associated periodic syndromes (CAPS), in particular the CINCA syndrome that shares many clinical characteristics with juvenile idiopathic arthritis. PMID- 20711091 TI - [Autoantibodies as predictors of biological therapy for early rheumatoid arthritis]. AB - INTRODUCTION: The association between serological markers with the need of biological therapy for early rheumatoid arthritis (ERA) is not known, with few available data addressing this question. OBJECTIVES: To prospectively evaluate a cohort of patients with ERA (less than 12 months of symptoms) in order to determine the possible association between serological markers (rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP), and citrullinated anti-vimentin (anti-Sa) with parameters of therapeutic outcome (this later defined by the need of introducing biological therapy). PATIENTS AND METHODS: Forty patients with early RA were evaluated at the time of diagnosis and have been followed for 3 years, in use of standardized therapeutic treatment. Demographic and clinical data were recorded, as well as serology tests (ELISA) for RF (IgM, IgG and IgA), anti-CCP (CCP2, CCP3 and CCP3.1) and anti-Sa in the initial evaluation and at 3, 6, 12, 18, 24 and 36 months of follow-up. As outcomes of the RA development, the need or not for biological therapy during the follow-up period were considered. Comparisons were made through the Student t test, mixed-effects regression analysis and analysis of variance (significance level of 5%). RESULTS: The mean age was 45 (+/- 12) years; a female predominance was observed (90%). At the time of diagnosis, RF was observed in 50% of cases (RF IgA - 42%, RF IgG - 30% and RF IgM - 50%), anti-CCP in 50% (no difference between CCP2, CCP3 and CCP3. 1) and anti-Sa in 10%. After 3 years, no change in the RF prevalence neither in the anti-CCP was observed, but the anti-Sa increased to 17.5% (p = 0.001). Biological therapy was necessary in 22.5% of patients. The mean RF IgA and anti-CCP 2 levels during the 3 years were higher among patients who needed biological therapy (p <0.05 for both). CONCLUSION: Higher titles of RF and anti-CCP over time were associated with the need for biological therapy. PMID- 20711092 TI - Radiological scoring methods in ankylosing spondylitis: a comparison of the reliability of available methods. AB - OBJECTIVE: To assess intra and inter-rater reliability of available radiological scoring methods in ankylosing spondylitis (AS). PATIENTS AND METHODS: Two trained raters evaluated 44 complete sets of AS radiographs. The cervical and lumbar spine was graded from zero to 4 according to the Bath Ankylosing Spondylitis Radiology Index (BASRI). Hip joints were graded according to the BASRI-hip method. Sacroiliac (SI) joints were scored according to the New York method (0 4). The anterior and posterior sites of the lumbar spine were scored according to the Stoke Ankylosing Spondylitis Spinal Score (SASSS) method (0-72). Modified SASSS was assessed by using the anterior sites of both the cervical and lumbar spine (0-72). RESULTS: Both intra and inter-rater reliability were almost perfect for all the methods and intra-class correlation coefficient (ICC) for all the methods was relatively similar to each other. The BASRI-spine and BASRI-total showed intra and inter-rater ICC between 0.78 and 0.98. Both SASSS and modified- SASSS reached perfect intra and inter-rater reliability with ICC between 0.86 and 0.99. The ICC of the BASRI-hip was substantial to perfect, ranging from 0.77 to 0.88. Time spent to score a set of radiographs using the BASRI-spine was <45 seconds, whereas >60 seconds for both SASSS and mSASSS methods. CONCLUSION: After training, all of these methods have demonstrated almost perfect intra and inter rater reliability. The BASRI was easier to perform and less time consuming than SASSS methods. PMID- 20711093 TI - [Skin manifestation in systemic sclerosis]. AB - OBJECTIVE: To assess cutaneous manifestations in a population of patients with systemic sclerosis (SSc). METHOD: The study population was constituted by 50 patients with a diagnosis of SSc, according to the classification criteria for SSc established by the American College of Rheumatology. According to the criteria proposed by LeRoy and cols., the disease was classified as diffuse SSc, or limited SSc, depending on the extent of skin involvement. Through history and physical exam the following variables were assessed: skin sclerosis, Raynaud's phenomenon, digital pitting scars, ischemic ulcers, telangiectasia, leucomelanoderma, microstomy, calcinosis and pruritus. RESULTS: In the study population, 88% were women, with a mean age of 52.3+/-12.4 years. Limited SSc was the most frequent subset, being present in 70% of the evaluated patients. We found Raynaud's phenomenon in 100% of the patients, telangiectasia in 94%, leucomelanoderma in 38%, pruritus in 50%, calcinosis in 40%, microstomy in 62%, digital scars in 66% and ischemic ulcers in 58%. The modified Rodnan skin score values ranged from 3 to 32, with a median of 14, and percentile 25 of 9 and percentile 75 of 17.75. CONCLUSION: Cutaneous manifestations are very common in ES, being responsible for important limitations on daily activities and stigmatization of patients. PMID- 20711094 TI - From a neutrophilic synovial tissue infiltrate to a challenging case of rheumatoid arthritis. AB - The herein report illustrates how a synovial tissue heavily infiltrated by neutrophils in the first weeks of arthritis, can evolve in few months to a synovial infiltration by lymphocytes with a characteristic pattern of rheumatoid arthritis (RA). This observation suggests a critical initial role of neutrophils in RA onset, which is eventually surpassed by the activation of the adaptive immune system. In addition, this patient, despite the absence of rheumatoid factors and anti-cyclic citrullinated peptide antibodies, progressed to a highly destructive and disabling disease, that was only controlled adequately with rituximab, due to the lack of response to methotrexate and serious adverse effects with TNF blockers therapy. PMID- 20711095 TI - Central diabetes insipidus induced by tuberculosis in a rheumatoid arthritis patient. AB - Tuberculosis, a polymorphic disease, is a diagnostic challenge, particularly when arises concomitantly to an autoimmune disease such as rheumatoid arthritis (RA). Herein, the authors describe a 33-year-old woman with nodular RA who was being treated with methotrexate, sulfasalazine and corticosteroids and presented with subcutaneous nodules simultaneously with aseptic meningitis. Mycobacterium tuberculosis was identified in cultures from a biopsy of an axillary nodule. The patient also developed polyuria and polydipsia with normal glycemia; antidiuretic hormone (ADH) treatment before and after a 3% saline infusion test was performed and diabetes insipidus was diagnosed. An encephalic MRI showed sellar and suprasellar masses, suggesting central diabetes insipidus (CDI). The patient received standard tuberculosis (TB) treatment for 6 months and also DDAVP (desmopressin acetate) during this period. Control of CDI was observed. A pre surgical magnetic resonance imaging (MRI) showed no pituitary mass. It is known that intrasellar tuberculoma occurs in only 1% of TB patients. TB should be considered in the differential diagnosis of CDI, especially in immunosupressed patients and in countries where this infection is a serious public health problem. PMID- 20711097 TI - [Extensive cutaneous necrosis as an initial manifestation of secondary antiphospholipid syndrome (APS)]. AB - Diffuse necrotic-hemorrhagic lesions limited to the skin in secondary antiphospholipid antibody syndrome (APS) to systemic lupus erythematosus (SLE) are not frequent. We report the case of a white woman, 37 years of age, hospitalized in September 2007 with a history of psychosis of several years' duration, presenting with polyarthritis and erythematous, maculopapular, bullous skin lesions on the upper and lower limbs, rapidly followed by extensive necrosis and skin ulceration on all four limbs who was diagnosed with SLE and positive lupus anticoagulant. The investigators highlight the occurrence of skin necrosis of catastrophic characteristics, as a possible initial manifestation of secondary APS without systemic vascular involvement that evolved satisfactorily with a combination treatment of anticoagulation and immunomodulation. PMID- 20711096 TI - [Acute pancreatitis and spontaneous rupture of pancreatic pseudocyst in systemic lupus erythematosus]. AB - Systemic Lupus Erythematosus (SLE) is an autoimmune disease, with multisystemic involvement. Gastrointestinal symptoms are common, like nausea, vomiting and dyspepsia. Acute pancreatitis is an unusual manifestation of SLE, being an important differential diagnosis in evaluation of abdominal pain. The patients usually presents with pain of variable intensity, some occasions simulating acute abdomen. Several factors have been implicated in the pathogenesis of this condition, such as vasculitis, drugs and antiphospholipid antibodies. The role of corticosteroids as etiologic factor remains controversial. Due to the rarity of SLE associated to pancreatitis, we report two cases of patients with severe inflammatory process. In one case, it was used corticosteroids in high doses during treatment, with good outcome. In another, the patient died because of pancreatic pseudocyst rupture and its postoperative hemodynamic complications. In the reported cases, predisposing factors for acute pancreatitis were not verified, so it was considered a primary manifestation of SLE activity. PMID- 20711098 TI - [Livedoid vasculitis in a patient with antiphospholipid syndrome]. AB - The authors present a clinical case of a 30 year old male patient admitted to the hospital for recurrent cyanosis and feet pain lasting for one year. In addition he presented bilateral purpuric lesions in the lateral maleolar region, one of which with ulceration. The finding of anticardiolipin antibodies associated with intraluminal thrombosis in the dermal vessels, allowed to conclude for Antiphospholipid syndrome. The cutaneous changes identified are named livedoid vasculitis. PMID- 20711099 TI - [Inflammatory myopathy with an unusual evolution]. AB - Inflammatory myopathies are a heterogeneous group of conditions characterized by proximal muscle weakness, nonsuppurative inflammation of skeletal muscle, with elevated muscle enzyme levels and characteristic electromyography and muscle biopsy findings. The authors describe a clinical case of a young woman, admitted with a four day history of bilateral thigh myalgia. She was afebrile and without skin, mucosal or joint involvement. Thigh muscle palpation was painful. Complete blood count revealed leukopenia and thrombocytopenia. High levels of creatine kinase, serum aminotransferases and myoglobin were detected. Metabolic, toxic and drug-related causes were excluded as well as infectious diseases, malignant tumours and endocrine myopathies. Auto-antibodies for connective diseases were negative. Magnetic resonance imaging and electromyography of lower limbs were suggestive of inflammatory myopathy. Generalized muscle weakness and dysphagia were reported subsequently. Clinical and laboratorial improvement was seen after corticotherapy. Muscle biopsy revealed myopathy signs without inflammatory changes or vasculitis. After prednisolone reduction, presently without treatment, she remains asymptomatic with normal laboratorial findings. The authors emphasize in this case of inflammatory myopathy the unusual clinical and laboratory evolution and the importance of a cautious differential diagnosis. PMID- 20711100 TI - Adult-Onset Still's Disease and cytomegalovirus infection. AB - We present a case of a previously asymptomatic 34-year-old man that presented to the emergency department with two weeks of fever, arthralgia of the wrists and knees and sore throat. He was diagnosed with cytomegalovirus (CMV) mononucleosis. The patient remained symptomatic in the 5 following months. After an extensive workup to exclude other clinical conditions, a liver biopsy was performed and CMV hepatitis was diagnosed. He started valganciclovir therapy. Approximately one year after the initial complaints, the patient remained ill and presented clinical criteria compatible with Adult Onset Still's Disease. The patient had a marked improvement after institution of prednisolone, an effect that has been sustained during the following months. PMID- 20711102 TI - [Gout tophi with an atypical location in a patient with multiple septic gout tophi]. PMID- 20711101 TI - [Calcinosis in scleroderma patient: to treat or not to treat?]. PMID- 20711103 TI - [Juvenile amyopathic dermatomyositis: report of an unusual entity]. PMID- 20711104 TI - Occular complications following dental local anesthesia. AB - OBJECTIVE: To determine the frequency of appearance and the factors most commonly associated with ocular complications following dental local anesthesia, also establishing the location and type of anesthesia used. STUDY DESIGN: An indexed search in the Pubmed and Compludoc databases was carried out with the keywords "oral anesthesia", "ocular", "ophthalmologic", "damage", "complications", "injection". We established a limitation that the literature had to have been published after the year 1970. A total of 19 articles were obtained, forming a total sample of 37 patients. The patient's sex, age, nerve anesthetized, type of anesthetic used, ophthalmological complication present, recovery time, treatment and side effects were analyzed. RESULTS: There is a higher involvement of females (77%). The average age was 34.2 years. There was no preference for an anesthetic technique. Diplopia was the most common complication (65%), which coincides with the data from other authors. Almost all of the complications were of a temporary nature, with an average recovery time of 68 minutes. CONCLUSIONS: This is one of the few studies of its kind in dental literature, it thus being difficult to make precise conclusions. Ophthalmological complications are seldom a problem, diplopia being the most common among them. The authors appear to indicate an intravascular injection of the anesthetic as the cause of the problem, and therefore, it should be avoided in order to prevent accidents at the ocular level. PMID- 20711105 TI - Social demand for oral surgery in third age patients and its association with systemic pathologies. AB - OBJECTIVES: To determine the frequency of systemic pathologies in patients aged 65 years or more, who require oral care and possibly oral surgery. STUDY DESIGN: We carried out a cross-sectional descriptive study reviewing 3,388 medical histories for patients from the Department of Medicine and Oral Surgery of the School of Dentistry at the Complutense University of Madrid, who had requested surgical treatment. Those selected were at least 65 years of age or more, and were grouped according to their medical histories into categories of pathologies, which include: systemic, cardiovascular, digestive, respiratory, endocrine metabolic, genitourinary, osteoarticular, nervous system and the sensory organs. RESULTS: Patients over the age of 65 most commonly present cardiovascular and digestive pathologies, which represent values of 30.8% and 13.75%, respectively. The rest of the systemic pathologies analyzed were categorized according to frequency, as follows: endocrino-metabolic pathologies 6.66%, respiratory pathologies 6.25%, genitourinary pathologies 3.75%, osteoarticular pathologies 2.91%, and pathologies of the nervous system and sensory organs 2.08%. CONCLUSIONS: The demand for surgical treatments by third age patients was relatively low, representing 2.18%. However, the presence of systemic pathologies was constant, and therefore, the anamnesis and patient medical history are fundamental for any surgical treatment. PMID- 20711106 TI - Meta-analytic study on the frequency and treatment of oral antral communications. AB - OBJECTIVE: To determine the optimum surgical treatment for oral antral communications (OAC) and to understand the main post-operative complications. STUDY DESIGN: Meta-analytical, observational and retrospective study of 1.072 cases of OAC obtained from a literature review of 15 articles. RESULTS: OAC occur slightly more often in men and during the fourth decade of life. Its primary etiological factor is dental extraction, most often affecting the third molar. The most common treatment has been the use of Bichat's fat pad grafts, whereas the technique with the highest percentage of complications has been the use of the palatal rotation flap. The most frequent complication has been the fistulization of the OAC. CONCLUSIONS: Early diagnosis of OAC and its treatment within 48 hours of evolution are fundamental in order to properly resolve this pathology. The use of Bichat's fat pad grafts is a simple technique that offers excellent vascularization and results. PMID- 20711107 TI - Peri-implant bone mechanobiology. Review of the literature. AB - The mechanical load applied during bone regeneration in implant treatments influences the early formation of peri-implant bone tissue through the activation of different pathways. The aim of this review was to determine the currently available scientific evidence in this field. MATERIAL AND METHOD: Electronic search in medical databases (Medline, Pubmed and Cochrane Library) of experimental studies in animal models published from 2003 to 2009. RESULTS: There is scientific evidence that the immediate application of an axial load in implantology stimulates bone formation, as measured by various histomorphometric parameters. Different physiological mechanisms (e.g., production of nitric oxide, prostaglandin E2) participate in this effect, although their action has not been fully elucidated. CONCLUSION: The precise role of mechanical loading in the osseointegration process remains unknown. Further studies are required to demonstrate the biological mechanisms involved and the load range producing the most effective response and to develop devices for obtaining predictable clinical outcomes. PMID- 20711108 TI - Mesiodistal sizes and intermaxillary tooth-size ratios of two populations; Spanish and Peruvian. A comparative study. AB - INTRODUCTION: Adequate tooth-size ratios are required to ensure the satisfactory outcome of orthodontic treatment. Consequently, various methods of measuring tooth-size ratios have been developed being the Bolton ratio the most commonly accepted, known and used one. This ratio depending directly on mesiodistal tooth size has been associated with different ethnic backgrounds. Some authors suggest the need for specific standards for every population. OBJECTIVES: The objectives of our study were; to measure and to compare mesiodistal tooth sizes and the Anterior and Overall Bolton ratios in two different populations, one Peruvian and the other Spanish with the same digital method. MATERIAL AND METHODS: The sample included 149 individuals composed of two groups; 99 Spanish (mean age 14.19), 65 being females and 34 males and 50 Peruvian (mean age 14.46), 18 being males and 32 females. The mesiodistal sizes of each of the patients were measured using a digital method and the Anterior and Overall Bolton ratios were calculated. RESULTS: Tooth size does indeed involve a strong ethnic component, and the Anterior Bolton ratio is specific for each ethnic group. CONCLUSIONS: The conclusions are; tooth sizes of the Peruvian population were greater than those of the Spanish population. The Anterior Bolton ratio of Peruvian individuals was greater than that of the Spanish, whereas no differences were found for Overall Bolton ratio. These differences suggest the need for specific standards for the Spanish and Peruvian population. PMID- 20711109 TI - Study of the effect of oral health on physical condition of professional soccer players of the Football Club Barcelona. AB - OBJECTIVES: The objective of this study was to evaluate the oral health status of professional soccer players of F.C. Barcelona and its relation to the incidence of sport lesions. METHODS: Thirty professional soccer players were consecutively evaluated in the seasons 2003/4, 2004/5 and 2005/6. A research protocol to assess their oral health was developed. DMFT, Quigley & Hein plaque index (PI), Loe & Silness gingival index (GI), World Health Organization malocclusion index, Ramfjord teeth probing pocket depth (PPD), TMJ examination and history of dental trauma were recorded. All physical injuries sustained by players during the season were documented from F.C. Barcelona medical services. RESULTS: Mean DMFT score was 5.7 (SD 4.1), Quigley & Hein plaque index score was 2.3 (SD 1.1), Loe & Silness gingival index was 1.1 (SD 0.8), and periodontal pocket depth was 1.9 mm (SD 0.3). Pearson's analysis showed a significant correlation between PI and GI (p<0.01). Nine players (30%) presented bruxism--the same proportion of those with severe malocclusion. Seven (23.3%) players had suffered uncomplicated crown fractures. The mean incidence of physical injuries was 8 (SD 3.4) per player. PI and PPD showed a statistically significant correlation to muscle injuries (p<0.05). CONCLUSIONS: Soccer players, despite intensive medical follow-up, have significant oral health problems such as untreated caries, gingivitis or malocclusion, and suffer dental trauma as a result of sports activities. Their physical condition could also be associated to oral health. PMID- 20711110 TI - Pilomatrixoma. Review of 205 cases. AB - AIMS: To determine the incidence and clinical features of patients diagnosed with pilomatrixoma. PATIENTS AND METHOD: A retrospective analysis was made of 205 cases of pilomatrixoma diagnosed according to clinical and histological criteria, with an evaluation of the incidence, patient age at presentation, gender, lesion location and size, single or multiple presentation, differential diagnosis, histopathological and clinical findings and relapses. RESULTS: Pilomatrixoma was seen to account for 1.04% of all benign skin lesions. It tended to present in pediatric patients--almost 50% corresponding to individuals under 20 years of age -with a slight male predilection (107/98). Approximately 75% of all cases presented as single lesions measuring less than 15 mm in diameter. Multiple presentations were seen in 2.43% of cases. The most frequent locations were the head and orofacial zones (particularly the parotid region), with over 50% of all cases, followed by the upper (23.9%) and lower limbs (12.7%). Only one relapse was documented following simple lesion excision. CONCLUSIONS: The frequency of pilomatrixomas was 1.04% of all benign skin lesions--the lesions being predominantly located in the maxillofacial area. Due to the benign features of this disorder, simple removal of the lesion is considered to be the treatment of choice, and is associated with a very low relapse rate. PMID- 20711111 TI - Trends in frequency and prevalence of oral cancer and oral squamous cell carcinoma in Mexicans. A 20 years retrospective study. AB - OBJECTIVE: To establish the time trends of the frequency and prevalence of oral cavity cancer in regard to age and gender in a 20-years (time period 1989 - 2008) cohort of Mexicans. DESIGN AND SETTING: 13,235 head and neck biopsies from the archive of the Oral Pathology Laboratory, Dental School, National Autonomous University of Mexico were revised. The cases with diagnoses of oral cancer were selected. Gender and age at diagnosis was obtained from medical records. The frequency and prevalence of oral cavity cancer and oral squamous cell carcinoma were assessed biannually in regard to the total number of population served by the oral pathology laboratory. The statistical significance of trends was established using the linear logistic regression (curve estimation) test (s 0.05). RESULTS: 298 cases (138 males; 160 females) of oral cancer were included; 167 (92 females; 75 males; female:male ratio: 1.1:1) corresponded to oral squamous cell carcinoma. From 1989 to 2008 the prevalence of oral cancer and oral squamous cell carcinoma increased 200% (s 0.05) and 100% (s 0.000) respectively. The increase of frequency and prevalence was observed in both genders however only in females was significant (s 0.000). We do not identify changes in the age at diagnosis. CONCLUSIONS: Oral cancer, specifically oral squamous cell carcinoma, has increase in Mexicans females in the last 20 years. PMID- 20711112 TI - Assessment of periapical status: a comparative study using film-based periapical radiographs and digital panoramic images. AB - AIM: To compare the use of film-based periapical radiographs and digital panoramic images displayed on monitor and glossy paper in the assessment of the periapical status of the teeth. METHODOLOGY: A total of 86 subjects were examined. All participants underwent a full-mouth radiographic survey (14 periapical radiographs) and a digital panoramic radiography. The periapical status of all appraised teeth was assessed. RESULTS: Periapical radiographs allowed the assessment of the periapical status of a significantly higher percentage of teeth (87.4%) Digital radiography had a significantly reduced potential to allow assessment of the periapical status (p<0.01). Only 58.0% and 34.3% of teeth could be appraised using digital panoramic images displayed on monitor and glossy paper respectively (p<0.01). The total percentage of teeth with periapical pathosis was four-fold higher when assessed with digital panoramic images displayed on glossy paper compared with periapical radiographs (p<0.01). CONCLUSIONS: Periapical radiographs allowed the assessment of a significantly higher percentage of teeth when comparing to digital radiography, which had a significantly lower potency in the assessment of periapical status of the teeth. Digital panoramic images displayed on a monitor resulted in a significantly higher percentage of appraised teeth compared to digital images displayed on glossy paper. Apical periodontitis was scored more often on paper than on screen, and more often on screen than in periapical radiographs. PMID- 20711113 TI - Oral mucosal melanoma: conservative treatment including laser surgery. AB - OBJECTIVE: To discuss the convenience of laser surgery as optimal treatment for melanoma of the oral mucosa. PATIENTS AND METHODS: A retrospective evaluation of four patients with primary oral melanomas treated at a single Cancer Institution in Mexico City. RESULTS: Two patients were treated with resection of the melanoma with CO2 laser together with extraction of the involved dental organs and curettage of the alveolar walls. These two cases had melanoma in situ with multiple isolated foci. The third patient had a lesion with vertical growth, who was submitted to partial maxillectomy along with selective dissection of bilateral neck levels I-V with a negative report and the fourth patient had a history of oral nodular melanoma and presented with lymph node metastasis. According to follow-up status, there was no distant metastasis in any of the patients reported here. CONCLUSION: In our experience, conservative management with CO2 laser is adequate for melanomas of the oral mucosa with extraction of the dental organs and curettage of the alveoli to achieve complete surgical resection microscopically without sacrifice of the quality of life. Management of the neck is controversial. We recommend selective therapeutic resection of the neck only if it is found to be clinically positive. Elective dissection has not shown to have an impact in overall survival. PMID- 20711114 TI - A novel trephine design for sinus lift lateral approach. Case report. AB - Various techniques are described in the literature, either by crestal or lateral approach. Sinus augmentation has a high percentage of success, but presents a number of intraoperative and postoperative complications. The most frequent complication is the Schneiderian membrane perforation with a percentage of perforations between 11% and 56% according to authors. The aim of this study is to describe another membrane approach technique for the sinus lateral wall osteotomy that minimizes the risk of Schneiderian membrane perforation. We present a case of a 50 year old patient attended the University Dental Clinic (UDC) of International University of Catalonia for implant and crown treatment due to the loss of a right maxillary first molar. To insert an implant in position 1.6 a computerized tomography (CT) was requested to determine with greater accuracy the quantity of residual crestal bone. It showed a height of 5 mm and width of 8 mm. The lateral osteotomy was performed with a (SLA KIT(r) Neobiotech) trephine mounted in the same implant handpiece with which the field for the implant and the implant itself were prepared. It can be concluded that in the case described, the use of trephine drills of the SLA system mounted in a handpiece allows better access to lateral approach due to its perpendicular position relative to the sinus wall minimizing the membrane perforation risk. PMID- 20711115 TI - Correlation between clinical and pathologic diagnosis in oral leukoplakia in 54 patients. AB - The main aim of this study was to establish a correlation between the clinical and pathologic diagnosis of oral leukoplakia with a particular focus on epithelial dysplasia. We reviewed the medical records of 54 patients with a clinical and histologic diagnosis of oral leukoplakia who were seen at our center between 2002 and 2008. We found that the disease was more common in men (59.3%) than in women and we also detected a significantly greater prevalence of alcohol and tobacco consumption in men. The mean age of the patients was 62.57 years. Three patients had been histologically diagnosed with invasive cancer and 4 with carcinoma in situ. The most common lesion site for leukoplakias with severe dysplasia and invasive carcinoma was the lateral aspect of the tongue, the floor of the mouth, and the gums. It is therefore essential to include these sites in the clinical examination to aid early diagnosis. A higher degree of dysplasia should be suspected in non-homogeneous leukoplakias. While dysplasia is associated with a greater risk of malignant transformation, it is also important to monitor leukoplakias without dysplastic features as they can occasionally be the site of carcinoma. PMID- 20711116 TI - Severe odontogenic infections: epidemiological, microbiological and therapeutic factors. AB - OBJECTIVES: A retrospective study is made of the odontogenic infections treated in La Paz University Hospital (Madrid, Spain) during 2007 and 2008, with an epidemiological and microbiological analysis of a large group of patients. STUDY DESIGN: A retrospective descriptive study was made, involving the consecutive inclusion of all patients with odontogenic infection requiring admission to our hospital in the period between January 2007 and December 2008. RESULTS: A total of 151 patients were included, with a mean age of 40.3 years and a balanced gender distribution. The most frequently affected teeth were those located in the posterior mandibular segments, caries being the main underlying cause. Most isolates comprised mixed flora, particularly viridans streptococci, different species of Prevotella, Micromonas micros, and different species of Actinomyces. Susceptibility analysis of the microbial isolates showed a high percentage resistance to clindamycin (42.8% of all isolates), particularly among Viridans Streptococci. CONCLUSIONS: The use of antibiotics in head and neck infections requires updated protocols based not only on the existing scientific evidence but also on the epidemiological reality of each center. On the other hand, identification is required of the surgical factors determining infection and how they influence morbidity associated with this type of pathology. PMID- 20711117 TI - Effect of two prophylaxis methods on adherence of Streptococcus mutans to microfilled composite resin and giomer surfaces. AB - OBJECTIVES: Surface attributes of a restoration play an important role in adherence of plaque bacteria. Prophylaxis methods may be involved in modification of or damaging the restoration surface. The aim of the present study was to evaluate the effect of two prophylaxis methods on adherence of Streptococcus mutans to the surface of two restorative materials. STUDY DESIGN: A total of 60 specimens were prepared from each material; a microfilled composite resin (HelioProgress) and a giomer (Beautifil II). For each material, the specimens were randomly divided into three groups (n=20). Group 1: no prophylaxis treatment (control); Group 2: prophylaxis with pumice and rubber cup; Group 3: prophylaxis with air-powder polishing device (APD). The surfaces of selected specimens from each group were evaluated under a scanning electron microscope (SEM), and the surface topography formed by the two prophylaxis methods was determined by atomic force microscopy (AFM). Adherence of Streptococcus mutans to the surface of specimens was determined by the plate counting method following immersion in a bacterial innoculum for 4 hours, rinsing and sonication. Data were analyzed by two-way ANOVA and post hoc Tukey test for multiple comparisons. Statistical significance was set at P<0.05. RESULTS: Bacterial adherence was significantly affected by both factors: restorative material type and prophylaxis method (P<0.0005). Mean bacterial adhesion was significantly higher in composite groups compared to corresponding giomer groups. Within each material, bacterial adherence was significantly lower in the control group compared to prophylaxis groups. Prophylaxis with pumice and rubber cup resulted in a significantly lower bacterial adherence compared to prophylaxis with APD. CONCLUSIONS: Based on the results of the present study, giomer specimens demonstrated lower bacterial adherence compared to composite resin specimens. In both materials, the highest bacterial adherence was observed with prophylaxis with APD, pumice and rubber cup and the control group, respectively. PMID- 20711118 TI - An immunohistochemical study of androgen receptor in carcinoma arising in pleomorphic salivary adenoma. AB - Carcinoma originating within a pre-existing in pleomorphic adenoma is well-known phenomena and is occasionally debated in the field of surgical pathology. The use of the hormone treatment in salivary gland cancers is controversial. The management of patients who show positive reactivity to androgen receptor in prostate carcinomas has guided the researchers to assess the expression of this receptor in a variety of other tumors, including those arising in the salivary glands and particularly in carcinoma ex pleomorphic adenoma. OBJECTIVE: Our study aimed to characterize alteration in the immunohistochemical expression of androgen receptor in the tumor cells of carcinoma arising in pleomorphic adenoma. STUDY DESIGN: 20 cases of carcinoma arising in pleomorphic adenoma (undifferentiated and adenocarcinoma types) were examined. RESULTS: The results showed that 10 (50%) of 20 cases had negative nuclear staining, whereas 10 (50%) of 20 cases had positive nuclear staining for androgen receptor. CONCLUSION: Our data suggest that carcinoma arising in pleomorphic adenoma may be dependent on endocrine function. PMID- 20711119 TI - vacA genotypes in oral cavity and Helicobacter pylori seropositivity among adults without dyspepsia. AB - OBJECTIVE: The aims of this research were to determine the prevalence of Helicobacter pylori and its vacA genotypes in oral cavity in persons without dyspepsia and to establish the association between the presence of H. pylori in oral cavity and oral hygiene. The seroprevalence of anti-H. pylori antibodies and its associated factors were analyzed too. STUDY DESIGN: For the study, 200 adults without dyspepsia symptoms were selected. Dental plaque and saliva samples from each subject were obtained. H. pylori detection in oral samples was carried out by polymerase chain reaction (PCR) and for vacA genotyping a semi-nested and nested PCR was used. The enzyme-linked immunosorbent assay (ELISA) was used to detect anti-H. pylori IgG and IgM. The data were analyzed with Chi square and Fisher exact test and the statistical significance was set to 0.05. RESULTS: Of 200 subjects tested, 124 (62%) were seropositive. H. pylori was detected in the oral cavity of 34 subjects (17%) and vacA allelotypes were typified in 12 of those samples. The s1 allele was detected in 8 (66.7%) samples and in one of them m1 y m2 alleles were found. In four subjects vacA m1 subtypes were found and in two of those both m1 and m2 alleles were detected. The prevalence of H. pylori in oral cavity was higher (18.5%) among seropositive subjects compared with seronegative persons. No association was found between the presence of H. pylori and oral hygiene habits. CONCLUSIONS: The presence of H. pylori in oral cavity is more frequent in seropositive subjects without dyspepsia symptoms and could represent the source of gastric infection and bacterial transmission. The data suggest that more than one H. pylori strain may exist in the mouth of asymptomatic persons. PMID- 20711120 TI - Traumatic dental injuries among schoolchildren in Valencia, Spain. AB - AIM: The aim of the present study was to identify some factors related to the occurrence of dental trauma in mixed and permanent dentition. DESIGN OF THE STUDY: Over a period of two months 1325, 6 to 18 year olds from three primary schools in Valencia were examined. Data was collected through clinical examinations and interviews and their Dental trauma was classified according to IADT's criteria. RESULTS: The prevalence of dental injuries was 6%; boys aged between 12-18 years old experienced more injuries than girls. There was a statistical difference between the types of fractures. Non complicated coronal fractures were the most frequent (9.18%). Games were the main cause of trauma (40%) in both sexes. In 14.3% of patients a dental colour change was observed. Angle's class I was the most frequent in traumatized injured children (41.2%). CONCLUSIONS: The present study revealed a relatively low prevalence of dental trauma, but this figure still represents a large number of children. Therefore, educational programs are to be initiated for the community regarding causes , prevention and treatments of traumatic dental injuries. PMID- 20711121 TI - Histopathological findings in oral lichen planus and their correlation with the clinical manifestations. AB - OBJECTIVES: To highlight the most characteristic histopathological findings of oral lichen planus and their correlation with the clinical manifestations and forms. STUDY DESIGN: We performed a retrospective study of 50 biopsied and diagnosed cases of oral lichen planus obtained over a period of 11 years, spanning from May 1998 to April 2009. We analyzed the age and sex of the patient, type of lichen planus, location and different histopathological findings, comparing them with the clinical lesions. RESULTS: Seventy eight percent of the patients are female and 22% are male, with an average age of 56.06 years for both sexes. The most frequent clinical form is reticular, present in 78% of the cases, and the most common location is the buccal mucosa, present in 70% of the patients. Hydropic degeneration of the basal layer and lymphocytic infiltration in the subepithelial layer are observed in the entire sample. Signs of atypia were identified in 4% of the cases, but without dysplasic features. Other common histological findings were the presence of necrotic keratinocytes (92%), hyperplasia (54%), hyperkeratosis (66%), acanthosis (48%), and less frequently, serrated ridges (30%) and the presence plasma cells (26%). CONCLUSIONS: Oral lichen planus is a disease that is more common in women, usually appearing in the fifth and sixth decades of life. The most common clinical form is reticular, manifesting mainly in the buccal mucosa. Histological findings characteristic of oral lichen planus include hydropic degeneration of the basal layer, lymphocytic infiltration in the subepithelial layer and the absence of epithelial dysplasia; however, it is also frequent to observe hyperplasia phenomena at the epithelial level, hyperkeratosis, acanthosis and the presence of necrotic keratinocytes. PMID- 20711122 TI - Predictability of the resonance frequency analysis in the survival of dental implants placed in the anterior non-atrophied edentulous mandible. AB - BACKGROUND: Dental primary implant stability is considered essential in the success of the osseointegration process. The recent advent of the resonance frequency analysis (RFA) seems to effectively measure primary implant stability, although its relationship with implant survival has to be further established. PATIENTS AND METHODS: Seventy patients with complete mandibular edentulism underwent dental implant rehabilitation by means of the placement of 68 dental implants within the interforaminal region and subsequent placement of an overdenture. Primary implant stability was measured by means of RFA and it was expressed in terms of implant stability quotient (ISQ) on the day of the implant insertion and at the time of the healing abutment placement in a conventional implant two-stage surgical procedure. RESULTS: Overall implant survival rate was 97.1% at the end of the follow-up period. The mean ISQ value for 3.75 and 4.25 mm diameter implants was 78.4 +/- 5.46 and 80.83 +/- 5.35 respectively, at the time of the implant placement; and 76.68 +/- 4.34 and 78.22 +/- 6.87 respectively, at the second surgical stage. No statistical differences were observed in relation to changes in mean ISQ value along the healing process. CONCLUSIONS: No statistical differences in terms of primary and secondary implant stability measured by RFA exists between 3.75 mm and 4.25 mm diameter implants in the conventional implant two-stage surgical procedure in patients with non-atrophied edentulous mandible being restored with an overdenture. Furthermore, no statistical association between RFA and the implant insertion torque was observed for endosseous dental implant placement at the first surgical stage. PMID- 20711123 TI - An in vitro evaluation of two dentine adhesive systems to seal the pulp chamber using a glucose penetration model. AB - OBJECTIVES: To evaluate the sealing capability of CavitTM G with or without ClearfilTM S3 Bond and Prime & Bond NT placed in the pulp chamber. STUDY DESIGN: Forty single rooted premolars, extracted for orthodontic and periodontal reasons, with intact coronal surface and mature apices, were standardized to a length of 15 mm. The teeth were instrumented, filled with a gutta-percha master cone and divided into three groups to obturate the pulp chambers: CavitTM G; ClearfilTM S3 Bond plus CavitTM G and Prime & Bond(r) NT plus CavitTM G. A glucose leakage model was used for evaluating the coronal microleakage. The Mann-Whitney test was used to evaluate the differences in the means of the glucose leakage. RESULTS: An increase in glucose penetration was observed during the first week in groups CavitTM G and CavitTM G+PBNT. The glucose penetration values of all groups were similar at 30 and 45 days, and there were no significant differences among them in both time periods (p=0.736 and p=0.581, respectively). CONCLUSIONS: The adhesive systems did not improve the capability of CavitTM G to seal the pulp chamber over time. PMID- 20711124 TI - Recurrent intraoral HSV-1 infection: A retrospective study of 58 immunocompetent patients from Eastern Europe. AB - OBJECTIVES: To revise the clinical features of the recurrent intraoral herpetic infection (RIOH) with respect to precipitating factors, demographic, clinical features and outcome. STUDY DESIGN: Fifty-eight, unrelated Caucasian, immunocompetent patients with positive laboratory test for intraoral Herpes simplex virus infection were studied. RESULTS: The mean age in the women's group (n=42) was 41.23 years (+/- 21.73) and in the men's group was 32.25 years (+/ 15.68). Possible trigger factors were identified in 9 cases (15.5%). General symptoms were noted in 20 cases (34.48%). Most of patients in this study presented multiple lesions. 14 patients had vermillion lesions associated with intraoral lesions. In most of the cases both fixed and mobile mucosa was concomitantly involved. Treatment was prescribed in order to control the symptoms and to shorten the evolution with minimal side effects. CONCLUSIONS: Intraoral secondary herpetic infection could be polymorphous and sometimes associated with general symptoms. The recognition of its atypical features may prevent unnecessary and costly investigations and treatments for unrelated though clinically similar-appearing disorders. PMID- 20711125 TI - Ergonomics and musculoskeletal pain among postgraduate students and faculty members of the School of Dentistry of the University of Barcelona (Spain). A cross-sectional study. AB - OBJECTIVES: To evaluate the intensity and location of musculoskeletal pain suffered by students and professors from different postgraduate programs of the School of Dentistry of the University of Barcelona (Spain), to identify the variables related to the occurrence of musculoskeletal symptoms and signs, and to establish possible preventive measures for such disorders. MATERIALS AND METHODS: A cross-sectional study was made among students and faculty members from different postgraduate courses of the School of Dentistry at the University of Barcelona between May and June 2007. A total of 74 dentists (54 postgraduate students and 20 faculty members) completed an anonymous questionnaire containing 19 questions. The variables were divided into three main groups: sociodemographic information, ergonomic features and musculoskeletal pain arising from professional practice. RESULTS: Most of the dentists (79.8%) had experienced some kind of musculoskeletal pain in the last 6 months. On comparing the different locations of pain (lumbar, cervical, dorsal, wrist, shoulder and others), the neck was found to be the most commonly affected location (58% of all subjects), and only 34% of the respondents took some preventive measures against musculoskeletal disorders. Women showed a higher frequency of intense pain involving the cervical, lumbar, dorsal and wrist areas (p<0.05). A higher incidence of wrist pain was recorded in professionals exclusively dedicated to oral surgery (p<0.05). No statistically significant correlation was found between the workload (hours) and pain in the different anatomical locations (p>0.05). CONCLUSIONS: An important incidence of pain symptoms secondary to musculoskeletal disorders was observed, particularly in the cervical region. Females and younger dentists showed a higher frequency of such symptoms. The implementation of preventive measures is necessary, in view of the high incidence of these disorders. PMID- 20711126 TI - Do third molars weaken the mandibular angle? AB - OBJECTIVE: The purpose of this study is to estimate how is the magnitude of the impact of a mandibular third molar on the mandibular angle stiffness. STUDY DESIGN: It was performed a literature search on whole MEDLINE and LILACS data base to find articles that match the following inclusion criteria: cohort studies presenting data on patients with mandibular fractures and third molars; that had a similar angle fracture definition; and that present data available to be cross classified in a statistic analysis. RESULTS: The sample was composed by 4 studies, involving 2533 patients from USA, Nigeria, Germany and Jordan, evaluated between 1976 and 2001. The analysis of the sample shows a relative risk for a mandibula to fracture, comparing patients with and without third molars, ranging from 1,18 to 2,25. The data of the sample was grouped because of the homogeneity of the articles methods. The estimated relative risk across the 4 studies was 1,94 (95% CI 1,6 - 2,35). CONCLUSIONS: The presence of a third molar may double the risk of an angle fracture of the mandible to occur. Even with this data, the present study cannot support conditions related to the third molar that may affect this impact. Further studies are necessary to discuss the true indication of removal of these teeth as a prophylactic measure in population groups more predisposed to fracture. PMID- 20711127 TI - Effect of psychological stress on orthodontic tooth movement in rats. AB - INTRODUCTION: The purpose of this study was to investigate the effect of psychological stress on orthodontic tooth movement in Wistar rats. MATERIALS AND METHODS: Forty-eight female ten-week old Wistar rats with an average weight of 188 +/-12 gr were selected and randomly divided into two experimental and control groups. The experimental group received crowded environment-induced and cat odour stresses 4 weeks before spring insertion. On the 29th day in both groups, maxillary incisors were moved by the insertion of springs and exactly after 7 days, 9 rats from each group and after 14 days the remaining rats were sacrificed. Then the mesioincisal distance between maxillary incisors was measured. Afterwards, histological sections were prepared to count osteoclasts under a light microscope. The data on the extent of orthodontic tooth movement and the number of osteoclasts were analyzed by independent sample t-test. RESULTS: The results indicated that on the 7th day after spring placement the orthodontic tooth movement was significantly higher in the control group compared to the experimental group (p<0.05). The number of osteoclasts at a significance level of alpha=0.1 in the control group was higher compared to the experimental group. On the 14th day after spring placement, the orthodontic tooth movement in the control group was significantly higher compared to the experimental group (p<0.05). However, there were no significant differences in the number of osteoclasts between the two groups. The rats experienced weight loss in the experimental group (p<0.05). CONCLUSIONS: Psychological stress led to a decrease in orthodontic tooth movement and in the number of osteoclasts around the root in the movement direction in rats, but a decrease in osteoclast counts was not parallel with time and demonstrated a nonlinear pattern. In addition, psychological stress led to weight loss in rats. PMID- 20711128 TI - Biocompatibility of a chlorhexidine local delivery system in a subcutaneous mouse model. AB - OBJECTIVE: This study aimed evaluating histologically and histomorphometrically the response of the conjunctive tissue face to the implant of chlorhexidine chips in the subcutaneous tissues of rats. STUDY DESIGN: In this research 35 male rats Wistar were used to analyze the biocompatibility and the degradation process of chlorhexidine chip. In each animal, it was made 2 incisions for subcutaneous implantation of chlorhexidine chip (test group) and a polytetrafluorethylene membrane (control group). The morphological changes in subcutaneous implantations were assessed after 1, 3, 5, 7, 10, 14, 21 days. The data were submitted to Friedman nonparametric test to analyze the comparisons among observation periods and to allow the comparison among groups. RESULTS: Differences were found in the analysis of the inflammatory response when comparing the tested materials (p values <= 0.05). In test group was observed hemorrhage, edema and intense inflammatory infiltrate predominantly neutrophilic around material. From 3-day and subsequent periods was verified granulation tissue externally at this infiltrate. From 10-day on was observed crescent area of degradation of chlorhexidine chip, associated with neutrophilic and macrophagic infiltrate, that maintained until 21-day. In the control group, moderate inflammatory infiltrate was observed initially, predominantly polymorphonuclear, edema and granulation tissue 3-day period. The inflammatory infiltrate was gradually replaced for granulation tissue, culminating in a fibrous capsule. Giant multinucleate cells situated at contact interface with the coating was examined since 3-day and persisted until 21-day. CONCLUSION: The chlorhexidine chip induces an intense acute inflammatory response at subcutaneous tissue of rats. Therefore, at conditions of this study was not biocompatible. PMID- 20711129 TI - Dentifrices--an update. AB - OBJECTIVES: The objective of this paper was to review the published evidence concerning the efficacy and potential for adverse reactions of modern dentifrices toothpastes. DATA SOURCES: Publications cited on MEDLINE since 1990. Some further pre-1990 publications are also referenced. DATA SELECTION: Studies concerning the efficacy of dentifrices and their components and any related putative adverse incidents. DATA EXTRACTION: Papers were scrutinised for scientific and trial data. DATA SYNTHESIS: Data concerning the efficacy of dentifrice components were summarised. CONCLUSIONS: The efficacy of fluoride salts in dentifrices in reducing dental caries is well established. Toothpastes, containing triclosan, are effective in improving plaque control, gingivitis and periodontal health. Other toothpaste formulations are effective in reducing the formation of calculus, extrinsic tooth stain, dentine sensitivity and oral malodour. The consumer now has available a range of toothpastes which deliver oral health benefits. Adverse reactions to toothpastes are rare but should be considered in unexplained skin or respiratory allergies and gingival or lip lesions. PMID- 20711130 TI - Prevalence of odontogenic sinus tracts in 728 endodontically treated teeth. AB - OBJECTIVES: The primary aim of this study was to assess the prevalence of sinus tracts in endodontically treated teeth in an Iranian population. The second aim was to seek and analyze the relationship between the clinically detected sinus tracts and factors such as sex, age, tooth type and location. STUDY DESIGN: A total of 728 patients' records and radiographs were reviewed of 427 females and 301 males for demographic data, preoperative pulpoperiapical status of treated teeth and the presence of sinus tract. Data were analyzed using chi-square test. RESULTS: No significant differences were found for the prevalence of sinus tracts between two genders. Data showed that the highest prevalence of sinus tracts was in 10-19 year age group. Of 725 treated teeth, 107 teeth had sinus tracts (14.7%). Most odontogenic sinus tracts were associated with mandibular anterior teeth. Of 348 teeth with preoperative status of periapical inflammation and radiolucency, 107 teeth (30.75%) had an odontogenic sinus tract. CONCLUSION: Data showed that almost one in seven teeth referred for root canal treatment had a sinus tract. PMID- 20711131 TI - Periodontal health and esthetic results in impacted teeth exposed by apically positioned flap technique. AB - OBJECTIVES: This study evaluates the periodontal health status and the esthetic results of teeth subjected to orthodontic traction, after their exposure by an apically positioned flap. STUDY DESIGN: Fifteen patients were included in the study, ages between 11 and 28 years old. The fenestrated teeth and their homologous contralateral normally erupted teeth, used as control, were evaluated. RESULTS: Statistically significant differences were found in the position of the gingival margin (p = 0.005), with an average distance between cemento-enamel junction (CEJ) and gingival margin of 2.47 mm (SD 1.19) in control teeth and of 1 mm (SD 1.31) in the operated teeth, and in the depth of palatal probing (p = 0.031), with 2.1 mm (SD 0.9) for the experimental teeth and 1.7 mm (SD 0.8) for the control teeth. The gingival index, the bleeding during probing and the probing depth did not show statistically significant differences. The patient's subjective esthetic evaluation was more favorable for the control teeth in most of the cases. CONCLUSIONS: The surgical approach for the impacted teeth by means of the apically positioned flap resulted to be a predictable technique allowing the maintenance of the periodontal health on a long-term basis. PMID- 20711132 TI - Analysis of the morphology and composition of tooth apices apicectomized using three different ablation techniques. AB - OBJECTIVES: To investigate apicectomies performed using burs, a CO2 laser or an Er:YAG laser and to evaluate the following aspects: morphology of apicectomized surfaces, presence of failures at the dentin/obturation material interface (marginal fit) of the apical portions of the root canals, and the proportions of chemical elements in the apicectomized surfaces. STUDY DESIGN: Twenty-four teeth were divided into three groups of eight and each group underwent apicectomy by one of three different ablation techniques: bur, CO2 laser or Er:YAG laser. The morphology of the apicectomized surfaces was then analyzed using scanning electron microscopy and their chemical composition was analyzed by energy dispersive spectroscopy. RESULTS: Surfaces produced with ablation by bur exhibited less surface irregularities and better marginal fit, while ablation with the CO2 laser caused intense surface carbonization and failures in obturation material fit. CONCLUSIONS: Our results suggest that, taking into consideration their clinical application, ablation of tooth apices using burs proved to be the best option among those tested here. PMID- 20711133 TI - Mandibular solitary plasmocytoma of the jaw: a case report. AB - Plasma cell tumors are lymphoid neoplasms with an uncontrolled proliferation of B cells. These are divided into localized forms (solitary bone plasmocytoma -SBP- and extramedullary plasmocytoma -EP-) and disseminated forms (multiple myeloma-MM ). The SBP is a rare and controversial disease. The aim of this article is the analysis of this entity based on the presentation of a 64-year-old man without previous medical history, with a mass in the left mandibular angle extending to the parotid region on the same side. The panoramic radiography, computed tomography and magnetic resonance imaging showed an osteolytic lesion 6.5 x 5 x 6.7 cm in the mandibular angle with infiltration of the masticator space and left parotid region. The normality of the extension study, and histopathological examination confirmed the diagnosis of SBP. The patient received treatment with radiotherapy with good outcome. PMID- 20711134 TI - Shaping ability of NiTi rotary versus stainless steel hand instruments in simulated curved canals. AB - OBJECTIVES: The purpose of this in-vitro study was to compare shaping ability of NiTi rotary Mtwo and FlexMaster with stainless steel hand K-Flexofile in simulated curved root canals. STUDY DESIGN: Forty-five simulated canals in resin blocks were prepared with Mtwo, FlexMaster and stainless steel hand K-Flexofile (15 blocks in each group). Using pre- and post- instrumentation images, straightening of the canal curvature was determined with a computer image analysis program. Material removal was measured at 5 measuring points, beginning 1 mm from the apex. Changes of working length (WL) were also recorded. The data were analyzed statistically using paired T-test and one way ANOVA. RESULTS: The mean material removal from the inner canal wall was different from the outer canal wall at all measuring points for each system (p<0.0001) except for FlexMaster at WL-9 (p=0.123) and K-Flexofile at WL-5 (p=0.093). The mean ratio of material removal (inner/outer) at all measuring points was different for all systems except for FlexMaster and Mtwo at 3, 5 mm (p=0.984, p=0.242), and K Flexofile and rotary systems at 1, 3 mm from the apex (p=0.565, p=0.218) (p=0.794, p=0.693). A mean loss of working length of 0.02 mm for Mtwo and 0.01 mm for FlexMaster and K-Flexofile was measured although the difference was not significant. CONCLUSIONS: In the apical points of the curvature (1, 3 mm), there was no significant difference between three systems. At point 5mm from the apex, K-Flexofile remained better centered, while in the coronal points (7, 9 mm) NiTi rotary systems achieved better canal geometry. PMID- 20711135 TI - Combination of alpha lipoic acid and gabapentin, its efficacy in the treatment of Burning Mouth Syndrome: a randomized, double-blind, placebo controlled trial. AB - Burning Mouth Syndrome (BMS) is a disease that manifests as burning in the tongue or in any area of the oral mucosa, in the absence of clinically verifiable injuries. OBJECTIVES: To verify the efficacy of alpha lipoic acid (ALA) and gabapentin (GABA), used individually and jointly, to reduce the burning in patients with burning mouth and establish a drug therapy for the BMS. STUDY DESIGN: During April and May 2008, we conducted a randomized, double-blind, placebo-controlled trial in the Department of Clinical Stomatology, Faculty of Dentistry, Rosario, Argentina. The gathering of patients was between those ones with BMS who were treated in our service between March 2003 and March 2008 without complying with the applied treatments. The 120 patients were randomly divided into 4 groups and were provided, by lot and in a blinded fashion, with four different treatment cycles consisting of the following drugs: Group A (n = 20) 600 mg / day of alpha lipoic acid for two months, Group B (n = 20) 300 mg / day of gabapentin for two months, Group C (n = 20) a combination of both drugs for two months and Group D (n = 60) 100 mg / day of cellulose starch for two months (control group). RESULTS AND CONCLUSIONS: all 120 patients completed the treatment. The best response was obtained with the combination of ALA + GABA, with a 70% of the cases with reduced burning in this group and a 13.2 times greater chance of presenting positive changes for these patients than those taking placebo. The combined use of drugs that act at different levels of the nociceptive system can be useful for the treatment of this syndrome. PMID- 20711136 TI - Dental implications in oral cancer patients. AB - OBJECTIVES: A study is made of the dental implications of oral cancer, with a view to avoiding the complications that appear once oncological treatment is started. PATIENTS AND METHODS: The study comprised a total of 22 patients diagnosed with oral cancer according to clinical and histological criteria in the Service of Maxillofacial Surgery (Dental Clinic of the University of Barcelona, Spain) during the period 1996-2005, and posteriorly treated in different hospital centers in Barcelona. RESULTS: Of the 22 patients diagnosed with oral cancer in our Service, the present study finally analyzed the 12 subjects who reported for the dental controls. As regards the remaining 10 patients, 5 had died and 5 could not be located; these subjects were thus excluded from the analysis. All of the smokers had abandoned the habit. The most common tumor location was the lateral margin of the tongue. None of the patients visited the dentist regularly before the diagnosis of oral cancer. T1N0M0 was the most common tumor stage. Surgery was carried out in 50% of the cases, while 8.4% of the patients received radiotherapy and 41.6% underwent surgery with postoperative radiotherapy. In turn, 66.6% of the patients reported treatment sequelae such as dysgeusia, xerostomia or speech difficulties, and one patient suffered osteoradionecrosis. Forty-one percent of the patients did not undergo regular dental controls after cancer treatment. As regards oral and dental health, 16.6% presented caries, and 50% had active periodontal disease. CONCLUSIONS: Protocols are available for preventing the complications of oral cancer treatment, and thus for improving patient quality of life. However, important shortcomings in the application of such protocols on the part of the public health authorities make it difficult to reach these objectives. PMID- 20711137 TI - Cone-beam dental computerized tomography for evaluating changes of aging in the dimensions central superior incisor root canals. AB - OBJECTIVES: Cone-beam dental computerize tomography (CBCT), a noninvasive imaging method, was used to image the pulp-dentin complex. Pulp changes histologically with aging. While many studies have investigated the histological changes in pulp, few studies have focused on the changes in the shape of the root canals. This study evaluated the changes in the root canals with aging of central superior teeth using CBCT. STUDY DESIGN: The study examined 100 non-carious maxillary central teeth. These teeth were divided into five groups according to the age of the patients: Group A:15-24, Group B: 25-34, Group C: 35-44, Group D: 45-54 and Group E: 55 years and older. CBCT was used to determine root length, and pulp width at the cervical, apical 1/2, and apical 1/3. RESULTS: On comparing the groups using one-way analysis of variance (ANOVA), the root length did not differ (P>0.05), while the pulp width at the cervical, apical 1/2, and apical 1/3 differed between the groups (P<0.001). CONCLUSIONS: The pulp length did not change with aging, while the pulp width did change. CBCT can be used to determine the precise root length and width, to prevent iatrogenic exposure of the apex, complementing existing methods. This will improve the prediction of the prognosis of root canal treatment. PMID- 20711138 TI - Cross-cultural adaptation of the orthognathic quality of life questionnaire (OQLQ) in a Brazilian sample of patients with dentofacial deformities. AB - OBJECTIVES: The aim of this study is to translate into Portuguese-Brazilian language and adapt cross-culturally to the Brazilian population the Orthognathic Quality of Life Questionnaire (OQLQ). STUDY DESIGN: The cross-cultural adaptation process followed six stages which are; (I) initial translation, (II) synthesis of the translation, (III) back translation, (IV) expert committee and (V) test of the prefinal version. For validation process, the OQLQ results were compared with Oral Health Impact Profile Questionnaire (OHIP-49), with the generic SF-36 Quality of Life Questionnaire and a visual analogue scale. A convenience sample of 25 patients was selected in two Southern Brazilian states of Santa Catarina and Rio Grande do Sul. RESULTS: Internal consistency analysis of the OQLQ Brazilian showed good correlation for items or domains and the test-retest reliability also presented excellent intra-class correlation coefficients. OQLQ Brazilian exhibited a weak and negative correlation with SF-36, and good correlation with OHIP-49. CONCLUSION: The OQLQ-Brazilian preserved and reached equivalence with its original source and the findings also corroborate that there is good evidence for the construct validity. The demonstration of its reproducibility, reliability and validity makes this instrument an additional useful parameter for evaluation of the impact of dentofacial deformity over the quality of life for Brazilians. PMID- 20711139 TI - Effect of low-calcium diet and grind diet on bone turnover of ovariectomized female rats. AB - OBJECTIVE: The variety of methodologies used to investigate ovariectomized female rats shows different results, which makes a clinical application of these results difficult. The purpose of this work was to evaluate the effect of masticatory effort reduction and of low-calcium diet on maxillary bone turnover of ovariectomized female rats. STUDY DESIGN: Eighty-four female rats were divided into four groups of 21 animals each as follows: SHAM--sham-operated; OVZ- ovariectomized and fed a standard commercial diet; LCD--fed a low calcium diet, and GCD--fed a grind commercial diet. The inferior first molars were extracted bilaterally 15 days after the ovariectomy, and the animals were euthanized 3, 5 and 8 weeks after ovaries removal. The maxillae were embedded in methylmetacrilate. The results were submitted to analysis of variance. RESULTS: The daily mineral apposition rate lowered with time and was not different between SHAM and OVZ groups. The trabecular bone volume of SHAM and OVZ animals was similar and decreased with time. The GCD animals presented the lowest means and the LCD the highest in comparison to the OVZ group. CONCLUSION: It was concluded that ovariectomy and a low calcium diet did not cause significant maxillary bone loss in the first molar region, and even in the absence of the antagonist tooth, they did not cause maxillary bone turnover. The grind commercial diet is a good alternative for the study of maxillary bone loss in ovariectomized female rats. PMID- 20711140 TI - Validation of the CPQ8-10ESP in Mexican school children in urban areas. AB - The current indicators used to gather information on oral health in children are basically clinical indexes that register mainly dental caries, periodontal disease, and malocclusion. These indexes should be complemented with emotional and social aspects related to the individual experience and perception of oral health status. In order to obtain this information, valid instruments capable of evaluating the impact of oral health as it relates to the quality of life (OHRQoL) are required. The objective of the Child Perceptions Questionnaire (CPQ8 10) is to assess OHRQoL in children aged eight to ten years. CPQ8-10 consists of 25 questions divided into four domains: oral symptoms, functional limitation, emotional well-being, and social well-being. OBJECTIVE: The aim of this study was to validate the translated Spanish version of the Child Perceptions Questionnaire (CPQ8-10ESP) in use with Mexican urban children. MATERIAL AND METHODS: Three hundred fifteen students in Mexico City aged eight- to ten-years-old participated in this study. The CPQ8-10ESP questionnaire was self-administered in the classroom. Clinical data about caries and malocclusion were obtained. To assess test-retest reliability, the questionnaire was reapplied to a subgroup of children. RESULTS: Cronbach's alpha reliability coefficient was 0.89 for the total CPQ8-10ESP scale. The intraclass correlation coefficient was 0.67; a statistically significant difference was found in the CPQ8-10ESP mean score between children with caries and malocclusion; a significant correlation between general well-being ratings with all domains was found (p<0.001). General perception of oral health was associated with both oral symptoms (p=0.049) and emotional well-being (p=0.022) domains, as well as with the total scale (p=0.015). CONCLUSIONS: The CPQ8-10ESP version showed good validity and reliability for use with Mexican schoolchildren from urban areas. PMID- 20711141 TI - Mesenchymal chondrosarcoma of maxilla: a rare case report. AB - Mesenchymal chondrosarcoma (MC) is a rare variant of chondrosarcoma (CS) that accounts for upto 3-9% of all CS and has high predilection for the head and neck region. It is usually seen in younger age group compared to conventional CS and maxillary anterior alveolus is the most common site. The tumor is most unusual as it has been described as a particularly aggressive neoplasm with a high tendency for late recurrence and delayed metastasis. It is a biphasic tumor with areas comprising of spindle cell mesenchyme interspread with areas of chondroid differentiation. A 75 year old male presented to us as a painless mass in maxilla. Contrast enhanced computed tomography (CECT) revealed a lytic expansile lesion in the left maxillary bone with foci of calcification within soft tissue lesion. Fine needle aspiration cytology (FNAC) and incisional biopsy was performed which confirmed the diagnosis of maxillary MC. The patient underwent right and left subtotal maxillectomy with 2 cm margins. The review of literature shows that very few cases of maxillary MC have been reported so far. Thus an attempt is made to add this rare case of MC of maxillary alveolus in the English literature. PMID- 20711142 TI - Hemodynamic and ventilatory changes during implant surgery with intravenous conscious sedation. AB - PURPOSE: This study was conducted to determine the hemodynamic and ventilatory changes during implant surgery with intravenous conscious sedation, and whether preoperative anxiety, gender or age influence these parameters. PATIENTS AND METHODS: A prospective study carried out between May 2004 and February 2007, on 102 patients treated with dental implants under local anesthesia and conscious intravenous sedation. Patients completed a questionnaire prior to surgery to evaluate preoperative dental anxiety using Corah's scale. The hemodynamic and ventilatory changes were evaluated by monitoring systolic pressure (SP), diastolic pressure (DP), heart rate (HR) and oxygen saturation (SaO2). These values were collected at 5 points during surgery; before commencing the operation (baseline value), during local anesthetic injection, at the moment of incision and raising of a mucoperiosteal flap, during implant placement, and finally at suturing. Intravenous conscious sedation was administered between baseline value and injection of the local anesthetic. RESULTS: The highest SP and DP were recorded at baseline and at suturing. The highest HR was recorded at the moment of incision and raising of the mucoperiosteal flap; the lowest SaO2 was recorded at local anesthetic injection. There was no relationship between hemodynamic and ventilatory values and preoperative anxiety or gender. A greater age was associated with higher SP and lower SaO2, these differences being statistically significant. CONCLUSIONS: Most of the cardiovascular and ventilatory changes induced by the implant surgery with intravenous conscious sedation were within normal ranges. The results indicate that midazolam with fentanyl do not produce important hemodynamic and ventilatory changes, being a good association for intravenous conscious sedation in dental implant surgery. PMID- 20711143 TI - The influence of local anesthetic solutions storage on tissue inflammatory reaction. AB - OBJECTIVE: This study aimed to analyze the influence of storage conditions of local anesthetic solutions in the inflammatory reaction after injection in rats. STUDY DESIGN: Twenty-four rats received in their oral mucosa the injection of 2% lidocaine with epinephrine 1:100.000 solutions (LA) submitted to the following storage conditions during a twelve-month period: G1--inside the original packaging, in refrigerator (5+/-1 degrees C); G2--inside the original box, under light shelter, at room temperature; G3--outside the original box at room temperature (exposed to artificial light for 12 hours/day) and G4--brand new solution. For the controls tests, 0.9% sodium chloride solution was injected in the opposite side. After 6 and 24 hours, three animals of each group were sacrificed and their maxilla along with the soft tissue were removed and submitted to histological analysis (HE). RESULTS: The pH of LA was measured before and after the storage period and no statistically differences were observed between G1 and G4, but both were different from G2 and G3. All the scores of the testing solutions were higher than their respective negative controls, except for G1 at 6 hours. The order of the scores of inflammation after 6 hours was G3>G4>G2=G1. After 24 hours the order was G3>G2>G1>G4. CONCLUSION: The study showed that the method of storage can influence the pH and the level of inflammatory reaction after the injection of 2% lidocaine with epinephrine 1:100.000. PMID- 20711144 TI - Complications of guided surgery and immediate loading in oral implantology: a report of 12 cases. AB - OBJECTIVES: The growing interest in minimally invasive surgery, together with the possibility of fitting prostheses with immediate function, have led to the development of software capable of planning and manufacturing a surgical guide and prosthesis that can be placed upon conclusion of the implant surgery step. The present study evaluates the surgical and prosthetic complications of implant treatment with the guided surgery technique, together with patient comfort during and after treatment. PATIENTS AND METHODS: A retrospective observational study was made of 19 patients with partially or totally edentulous upper and/or lower maxillae, involving the placement of a total of 122 implants. All cases were planned and operated upon with the guided surgery technique. RESULTS: A total of 122 implants were placed in 14 males and 5 females. The intraoperative surgical complications comprised a lack of primary stability, while the postoperative complications consisted of infections and a lack of implant osteointegration. Ten implants failed. The prosthetic complications in turn comprised loosening of the provisional prosthesis screws, prosthesis tooth fracture, and a lack of passive fit of the immediate prosthesis. The degree of patient satisfaction was evaluated using a verbal scale. CONCLUSIONS: Implant restoration with the guided surgery technique and immediate functional loading is a predictable procedure, provided patient selection and the surgical technique are adequate, affording lesser postoperative morbidity and increased patient satisfaction thanks to the immediate restoration of esthetics and function. PMID- 20711145 TI - Use of Bichat's buccal fat pad for the sealing of orosinusal communications. A presentation of 8 cases. AB - OBJECTIVES: To determine the efficacy of the pediculate flap with the buccal fat pad in the sealing of orosinusal communications, describe the surgical technique used, and report the main complications. PATIENTS AND METHOD: A retrospective study was made of 8 patients seen in the Service of Oral Surgery of the University of Barcelona Dental Clinic (Spain) for the treatment of orosinusal communications between the years 2007 and 2009. In all cases a pediculate flap with the buccal fat pad was used to solve the problem. RESULTS: All of the orosinusal communications were successfully resolved with this technique. The immediate postoperative complications were pain (37.5%), inflammation (37.5%), edema (32.5%), trismus (37.5%), halitosis (14.3%), suppuration (12.5%) and rhinorrhea (12.5%). CONCLUSIONS: The use of Bichat's buccal fat pad is not regarded as the technique of choice for sealing small to medium sized orosinusal communications. However, in the case of large communications, it is a good option, and the results obtained are optimum. PMID- 20711146 TI - Dental treatment of Marfan syndrome. With regard to a case. AB - Marfan syndrome (MS) is the most common dominant autosomic genetic disorder of the connective tissue. It has a reported incidence of 1 per each 5000 individuals without any distinction of gender or ethnicity. This pathology's diagnosis is mainly based on physical characteristics, presenting three main different symptomatic charts: neonatal Marfan, infant Marfan and classical Marfan. The mayor characteristic of these patients consists of an exaggerated length of the upper and lower limbs, hyperlaxity, scoliosis, alterations in the cardiovascular and pulmonary systems and atypical bone overgrowth. The individual implied in the present investigation concerned to a 14 year old male patient presenting multiple mouth lesions and dental alterations, attended in the Department of Pediatric Dentistry degree at the Dentistry School in the Santa Maria University. The patient has been treated following the necessary considerations required according to his systemic compromise under oral premedication for decrease the anxiety and make easier the behavior management. The patient with MS has multiple oral decrease that may be diagnosed as treated on time to increase the life quality of the patient. PMID- 20711147 TI - Altered passive eruption (APE): a little-known clinical situation. AB - Gummy smile constitutes a relatively frequent aesthetic alteration characterized by excessive exhibition of the gums during smiling movements of the upper lip. It is the result of an inadequate relation between the lower edge of the upper lip, the positioning of the anterosuperior teeth, the location of the upper jaw, and the gingival margin position with respect to the dental crown. Altered Passive Eruption (APE) is a clinical situation produced by excessive gum overlapping over the enamel limits, resulting in a short clinical crown appearance, that gives the sensation of hidden teeth. The term itself suggests the causal mechanism, i.e., failure in the passive phase of dental eruption, though there is no scientific evidence to support this. While there are some authors who consider APE to be a risk situation for periodontal health, its clearest clinical implication refers to oral esthetics. APE is a factor that frequently contributes to the presence of a gummy or gingival smile, and it can easily be corrected by periodontal surgery. Nevertheless, it is essential to establish a correct differential diagnosis and good treatment plan. A literature review is presented of the dental eruption process, etiological hypotheses of APE, its morphologic classification, and its clinical relevance. PMID- 20711148 TI - Salivary levels of Tumour Necrosis Factor-alpha in patients with recurrent aphthous stomatitis. AB - OBJECTIVES: Recurrent aphthous stomatitis (RAS) is a common pathology of the oral mucosa with a complex and multifactorial etiology. Tumour Necrosis Factor-alpha (TNFalpha) is a cytokine with an important but not well-known role in the development of new lesions in RAS patients. Modifications of salivary levels of TNFalpha in RAS patients during the active periods of the disease have been measured in this work. The possible implication of TNFalpha in RAS etiology is also discussed. STUDY DESIGN: The study group was composed of 20 patients previously diagnosed with RAS and randomly selected. As a control group 10 healthy patients were also randomly selected. In both groups a TNFalpha assessment was carried out in non stimulated saliva. All the patients in the study group presented active lesions at the moment of the salivary sample collection. Values oscillating between 0 and 8.1 pg/ml were considered as normal. RESULTS: Salivary TNFalpha levels are 2 to 5 times higher in RAS patients than those of healthy patients. CONCLUSIONS: TNFalpha has a possible implication in the RAS etiology and it may also have an important role in the search of new treatments for this disease. PMID- 20711149 TI - Oral contraceptive use and salivary C-erbB-2, CEA and CA15-3 in healthy women: a case-control study. AB - OBJECTIVES: Oral contraceptives (OCP) are highly effective, safe and widely used. Higher exposure to endogenous and exogenous estrogens is generally thought to increase the risk of breast cancer. Therefore, this study was conducted to determine if oral contraceptive use affected the expression of CA 15-3, CEA and C erb B-2 in the saliva of healthy women. STUDY DESIGN: The participants consisted of 87 healthy women (43 controls and 44 using oral contraceptives) ranging in age from 20 to 54 years. The volunteers participated by giving one - time stimulated whole saliva samples. Then the samples were analysed for CA 15-3, CEA and C-erb B 2 concentrations. RESULTS: The student t-test was used to compare group means for variables with comparable variability. The mean of C-erb B-2, CEA, and CA 15-3 concentrations (in the case and control groups) was (1.93, 1.70), (34.46, 31.62) and (12.58, 16.19) respectively. These differences were not statistically significant. CONCLUSIONS: Our findings suggest that the levels of the cancer biomarkers C-erb B-2, CEA and CA 15-3 were not affected by increased levels of estrogens in the body. PMID- 20711150 TI - Long-term sealing ability of GuttaFlow versus Ah Plus using different obturation techniques. AB - OBJECTIVE: To compare the long-term sealing ability of GuttaFlow(r) using different obturation techniques. STUDY DESIGN: Three hundred teeth, prepared with a crown-down technique, were divided into thirty experimental groups (n=10) to evaluate the apical and coronal leakage, at 3, 30 and 120 days, of lateral compaction gutta-percha+AH Plus TM, lateral compaction gutta-percha+GuttaFlow(r), single cone+AH Plus TM, single cone+GuttaFlow(r), and GuttaFlow(r) only. RESULTS: Both coronal and apical leakage, at the three times of measurement, no significant differences were found among GuttaFlow(r)+lateral compaction gutta percha and GuttaFlow(r)+single cone groups, whereas the only GuttaFlow(r) reached the highest leakage values at 30 and 120 days. AH Plus TM, using both techniques, showed high levels of leakage after 120 days to the coronal leakage and after 30 days to the apical leakage when compared silicon based sealer. CONCLUSION: GuttaFlow(r), using with lateral compaction and single cone techniques, shows a greater apical and coronal sealing ability than AH Plus TM over time. GuttaFlow(r) when used as only creates a poorer sealing when used with lateral compaction gutta-percha or single cone techniques. PMID- 20711151 TI - Vertical distraction osteogenesis of a free vascularized fibula flap in a reconstructed hemimandible for mandibular reconstruction and optimization of the implant prosthetic rehabilitation. Report of a case. AB - Free vascularized fibular flap is considered the treatment of choice in mandibular reconstruction for extensive bone defects (over 6 centimeters) resulting from trauma, infections or tumor resections. But, when the reconstruction involves a dentate mandible, the fibula has the limit as it does not offer sufficient bone height to restore the alveolar arch up to the occlusal plane. Therefore, the deficiency in bone height makes implant placement impractical. We report a case of vertical distraction osteogenesis of a free vascularized fibula flap used to reconstruct a hemimandible after resection of an odontogenic myxoma, for optimization of the implant prosthetic rehabilitation. The distraction device was applied intraorally. After 10 days of latency period, distraction protocol was performed at a distraction rate of 0.5 mm per day. A consolidation period of 3 months followed. Afterwards the distraction device was removed and 3 osseointegrated dental implants were placed in the distracted area. As a result, the vertical discrepancy between the fibula and the native hemimandible was corrected. The amount of vertical height achieved after distraction was 17 milimeters. The increase of vertical bone height was stable and enabled placement of dental implants without any complications. In conclusion, we consider that vertical distraction osteogenesis of free vascularized flaps is a reliable technique that optimizes implant positioning for ideal prosthetic rehabilitation, after mandibular reconstruction following tumor surgery. PMID- 20711152 TI - Satisfaction of patients fitted with implant-retained overdentures. AB - OBJECTIVE: to evaluate patient satisfaction with implant-retained overdentures, and its relationship with age, sex, period of follow-up, the rehabilitated jaw (maxilla, mandible or both), number of implants, splinting, type of attachment and the antagonist. MATERIAL AND METHODS: the study comprised patients with overdentures fitted between January 1996 and June 2007, and with a minimum follow up of one year. Data regarding patients and prostheses were collected. The patients indicated their overall satisfaction on a visual analogue scale (VAS) from 0 to 10, as well as satisfaction for individual items such as aesthetics, speech, mastication, prosthetic stability and self-esteem. These data were collected one month after fitting the prostheses, at 12 months and at a final examination. Statistical analyses were made using the SPSS version 15, statistical significance was considered for p<0.05. RESULTS: the study included 95 patients, 43 men and 52 women, with a mean age of 55.9 years; 76 edentulous mandibles and 31 edentulous maxillae were rehabilitated with 107 overdentures. One hundred and thirty-seven implants were placed in the maxilla, and 224 in the mandible. The mean level of overall satisfaction was 9 at one month of fitting the prosthesis, 8.8 at 12 months and 8.7 at the final control (mean 71 months). CONCLUSIONS: the patients fitted with implant-retained overdentures expressed a high level of overall satisfaction, independently of age, sex, length of follow up, rehabilitated jaw, number of implants per overdenture, whether splinted or non-splinted, and type of attachment. Men were more satisfied with mastication and stability. PMID- 20711153 TI - Evaluation of bleeding risk and measurement methods in dental patients. AB - OBJECTIVE: The present study explores bleeding manifestations in routine dental surgical procedures, evaluates the influence of antithrombotic drugs upon bleeding risk, and validates the efficiency of a clinical method for the measurement of bleeding. MATERIAL AND METHOD: A prospective observational study was made involving a cohort of 99 patients in the setting of normal clinical practice, with the added conduction of prior hematological tests including baseline hemostasis and platelet function, based on a new method (Multiplate System(r)). For evaluation of the bleeding manifestations, a clinical method was selected that evaluates bleeding on the basis of its duration and the hemostatic measures needed to resolve the problem. RESULTS: Almost one-third of the patients (27.3%) were receiving treatment with oral antiplatelet drugs, while 19.2% received oral anticoagulants and 9% received combined therapy with acetylsalicylic acid plus clopidogrel. In turn, an 8% incidence of moderate bleeding episodes was detected correlated to the ASPI platelet function test and to advanced patient age. CONCLUSION: The incorporation of platelet function tests increases the safety of oral surgery in elderly patients subjected to antiplatelet treatment, particularly with acetylsalicylic acid and clopidogrel. PMID- 20711154 TI - Orofacial dermoid cysts in pediatric patients: a review of 8 cases. AB - OBJECTIVE: The aim was to analyze the clinical characteristics, treatment and outcome of 8 orofacial dermoid cysts (DC) in pediatric patients. MATERIAL AND METHODS: A retrospective observational study was made, reviewing the medical records with clinical diagnosis of dermoid cyst between 1987 and 2006 in the Children's Maxillofacial Surgery Department of the Hospital Universitario La Fe, Valencia, Spain. The following data were collected: sex, age, location, size and duration of the lesion, treatment, length of follow-up, and recurrence. RESULTS: Eight patients (3 girls and 5 boys) with a mean age of 2.7 years (range 0-12 years). Four DC were located in the oral area (3 sublingual and 1 lingual), one in the periorbital and three in the nasal areas. The size ranged from 0.8 cm to 4 cm. The mean duration of the lesion was 13.7 months (range 4 days to 2 years). All DC were diagnosed pathologically following surgical removal of the lesion. There were no recurrences. CONCLUSION: The appearance of DC in the maxillofacial region of pediatric patients is uncommon. The floor of the mouth is the most frequently affected area in the oral cavity. Treatment is surgical removal of the lesion. Recurrence is unusual. PMID- 20711155 TI - Histological evaluation of bone repair using beta-tricalcium phosphate. AB - OBJECTIVES: The aim of the present study was to evaluate bone repair in defects induced in the cranium of Wistar rats using beta-tricalcium phosphate. STUDY DESIGN: In this research, we used 30 rats, randomly distributed in three groups of 10 animals (G1, G2 and G3), corresponding respectively to time of histological evaluation (7, 15 and 30 days). This was a paired study, a defect being induced in the parietal bone on either side of the median sagittal suture of the animals, being the left-hand side the experimental subgroup (filled by biomaterial) and the right control. The histological evaluation was performed by means of light microscopy. The collected data were submitted to the Fisher Exact test for comparison between the groups and to the McNemar test for comparison between the subgroups (P > 5%). RESULTS: The results showed no statistically significant differences between the groups and bone regeneration was similar at the different times of evaluation. CONCLUSIONS: Therefore, we concluded that beta-tricalcium phosphate has not contributed significantly to repair process of defects induced in the cranium of Wistar rats. PMID- 20711156 TI - Candida-associated denture stomatitis. AB - Candida albicans is a dimorphic yeast strongly gram positive able to live as normal commensal organism in the oral cavity of healthy people. It is the yeast more frequently isolated in the oral cavity. Under local and systemic factors related to the host conditions, it becomes virulent and responsible of oral diseases known as oral candidiasis. It has been shown that the presence of denture is a predisposing factor to the onset of pathologies related to C. albicans. Clinical studies have shown that C. albicans is not only able to adhere to the mucous surfaces, but also to stick to the acrylic resins of the dental prostheses. Both the plaque accumulated on the denture and the poor oral hygiene contribute to the virulence of Candida, offering the clinical picture of Candida associated denture stomatitis. The therapeutic strategies currently adopted in the clinical practice to overcome these fungal infections provide for the use of topical and/or systemic antifungal and topical antiseptics and disinfectants, the irradiation with microwaves and the accurate mechanical removal of the bacterial plaque from the denture surfaces and from the underlying mucosa. A correct oral hygiene is important for the control of the bacterial biofilm present on the denture and on the oral mucosa and it is the fundamental base for the prophylaxis and the therapy of the Candida-associated denture stomatitis. PMID- 20711157 TI - Intraorifice sealing ability of different materials in endodontically treated teeth. AB - OBJECTIVES: To evaluate Cavit TM G, ProRoot TM MTA and Tetric(r) EvoFlow as intraorifice barriers to prevent coronal microleakage in root canal treatment. STUDY DESIGN: Forty-two human single rooted teeth were divided randomly in three experimental groups of 10 specimens each and two control groups. The experimental groups were prepared with hand instrumentation and cold lateral condensed technique of the gutta-percha. Four millimetres of coronal gutta-percha were removed and replaced by one of the following filling materials: Cavit TM G, Tetric(r) EvoFlow or ProRoot TM MTA. In the experimental groups, leakage was measured by the concentration of leaked glucose in the apical reservoir at 1, 7, 30, and 45 days, using the enzymatic glucose oxidase method. Data were analyzed by means of Mann-Whitney U and Kruskal-Wallis tests at alpha=0.05. RESULTS: The glucose penetration results of three experimental groups increased gradually over time. No significant differences were found among groups at 24 hours and 1 week. At thirty and forty-five days, Cavit TM and Tetric(r) EvoFlow values were significantly different (p=0.007 and p=0.023, respectively). CONCLUSIONS: The sealing ability of the Cavit TM G, ProRoot TM MTA and Tetric(r) EvoFlow used as intraorifice materials tends to be similar over time. PMID- 20711158 TI - Tuberous sclerosis complex with oral manifestations: a case report and literature review. AB - INTRODUCTION: Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome produced by a number of genetic mutations. The disease is characterized by the development of benign tumors affecting different body systems. The most common oral manifestations of TSC are fibromas, gingival hyperplasia and enamel hypoplasia. CLINICAL CASE: A 35-year-old woman diagnosed with TSC presented with a reactive fibroma of considerable size and rapid growth in the region of the right lower third molar. DISCUSSION: In the present case the association of TSC with dental malpositioning gave rise to a rapidly evolving reactive fibroma of considerable diameter. Few similar cases can be found in the literature. Patients with TSC present mutations of the TSC1 and TSC2 genes, which intervene in cell cycle regulation and are important for avoiding neoplastic processes. No studies have been found associating TSC with an increased risk of oral cancer, though it has been shown that the over-expression of TSC2 could exert an antitumor effect. Careful oral and dental hygiene, together with regular visits to the dentist, are needed for the prevention and early detection of any type of oral lesion. The renal, pulmonary and cardiac alterations often seen in TSC must be taken into account for the correct management of these patients. PMID- 20711159 TI - Clinical and histopathological analysis of oral squamous cell carcinoma of young patients in Mashhad, Iran: a retrospective study and review of literature. AB - OBJECTIVES: Oral Squamous cell carcinoma (OSCC) is primarily a disease that mainly occurs in males in their sixth and seventh decades of life and is rare in young adults. STUDY DESIGN: In this retrospective study, records of patients under the age of 40, with the diagnosis of OSCC in the Oral Medicine Department of Mashhad Dental Faculty during the past 13 years were analyzed. Their socioeconomic data, demographic, clinical and histopathological characteristics, risk factors, familial history were assessed and applicable studies and case reports in the literatures were reviewed. PCR (Polymerase chain reaction) analysis was also done for detection of human papilloma virus (HPV). RESULTS: From 158 cases of OSCC diagnosed in our centre, 21 patients were younger than 40 years. Most of them were young men (12 cases). There was no significant risk factor in this group. The most common site of involvement was the tongue. The most common clinical presentation was exophytic lesion with ulcer. No HPV DNA was detected in these patients. CONCLUSION: Characteristics of OSCC in young patients are different from older age group. Major risk factors (smoking and alcohol consumption and HPV) were not etiologic factors for OSCC in young patients in our province. PMID- 20711160 TI - Antifungal and post-antifungal effects of chlorhexidine, fluconazole, chitosan and its combinations on Candida albicans. AB - OBJECTIVE: The aim of this work was to assess the antifungal and post-antifungal effects of chlorhexidine, fluconazole, chitosan and its combinations on virulence factors of Candida albicans. STUDY DESIGN: Ten isolated strains of Candida albicans obtained from 10 patients with oral candidiasis and a collection strain of C. albicans were treated with antifungal agents in different concentrations or combinations of them. Virulence factors analyzed were the cell surface hydrophobicity, the germinative tube development, the phospholipase activity and the post-antifungal effect of that exposure. RESULTS: Virulence factors of the isolated strains obtained from patients together with the collection strain showed significant decreases with the different antifungal treatments, except for hydrophobicity and phospholipase activity. The development of germinative tube was the most sensitive factor to all the antifungal agents used. Untreated strains as well as the ones treated with antifungal agents showed a positive correlation among the virulence factors analyzed. No synergic effects arose from the combinations of the used drugs. CONCLUSIONS: C. albicans isolated strains from patients showed high phospholipase activity and germinative tube production, which corroborates their capacity to infect the oral mucosa and the high prevalence of species. As a whole, our results imply that short exposures to sub inhibitory concentrations of the antifungal agents under analysis, isolated or combined, can modulate the way virulence factors get manifested, thus decreasing their pathogenicity. PMID- 20711161 TI - Validation of a computer-assisted system on classifying lower third molars. AB - OBJECTIVES: The present study evaluates the reliability of the Radio Memory(r) software (Radio Memory; Belo Horizonte, Brasil.) on classifying lower third molars, analyzing intra- and interexaminer agreement of the results. STUDY DESIGN: An observational, descriptive study of 280 lower third molars was made. The corresponding orthopantomographs were analyzed by two examiners using the Radio Memory(r) software. The exam was repeated 30 days after the first observation by each examiner. Both intra- and interexaminer agreement were determined using the SPSS v 12.0 software package for Windows (SPSS; Chicago, USA). RESULTS: Intra- and interexaminer agreement was shown for both the Pell & Gregory and the Winter classifications, p<0.01, with 99% significant correlation between variables in all the cases. CONCLUSIONS: The use of Radio Memory(r) software for the classification of lower third molars is shown to be a valid alternative to the conventional method (direct evaluation on the orthopantomograph), for both clinical and investigational applications. PMID- 20711162 TI - Effect of three prophylaxis methods on surface roughness of giomer. AB - OBJECTIVES: Plaque and stains are removed by prophylaxis methods from tooth surfaces. Since prophylaxis methods can have a detrimental effect on the surface finish of restorations, the aim of this in vitro study was to investigate the effect of three prophylaxis methods, including pumice with rubber cup, pumice with brush, and air-powder polishing device (APD) on the surface roughness of giomer. STUDY DESIGN: Sixty four cylindrical giomer (Beautifil II, Shofu) samples with a diameter of 6 mm and a height of 2 mm were used. Subsequent to a 3-month period of storage in distilled water at 37 degrees C, the samples were randomly divided into four groups of 16. In group 1 (control), no prophylaxis procedure was carried out. In groups 2 to 4 the samples were exposed to pumice with rubber cup, pumice with brush, and APD prophylaxis methods, respectively. The surface roughness of the samples was measured using a profilometer and the effect of different prophylaxis methods on surface topography was characterized by atomic force microscopy (AFM). All data were analyzed by one-way ANOVA and Duncan's post hoc test at a significance level of P < 0.05. RESULTS: There were statistically significant differences in surface roughness among the groups (P < 0.0005). Furthermore, in pairwise comparisons there were statistically significant differences between all the groups (P < 0.05). The roughest surfaces, in descending order, were observed with the use of APD, pumice with brush, and pumice with rubber cup. CONCLUSIONS: The use of different prophylaxis methods resulted in an increased surface roughness of giomer compared with the control group. APD prophylaxis exerted the most detrimental effects on the surface of giomer. PMID- 20711163 TI - Relation between bone density and primary implant stability. AB - AIMS: This study aims to relate bone density in Hounsfield units (Hu) with the primary implant stability measured by insertion torque (Ncm) and resonance frequency analysis (ISQ). MATERIALS AND METHODS: Ten patients were included in this study. A total of 54 implant sites were provided from 10 computerized tomography scans. The computerized tomography scan was used for the preoperative evaluation of bone density for each patient. The bone mean density around planned implants was determined with Physioplanet TM software. Bone quality according resistance to drilling, insertion torque and resonance frequency measurements were recorded. RESULTS: A statistically significant relationship was observed between bone quality density and location with ISQ values. CONCLUSIONS: This research demonstrates a strong relationship between the bone density values from computerized tomography and the location in the maxillaries. A correlation exists between bone quality, according to the Lekholm & Zarb classification, and Hu computerized tomography values. The primary implant stability measured with resonance frequency analysis depends on bone density values, bone quality and implant location. PMID- 20711164 TI - Lateral pterygoid muscle dystonia. A new technique for treatment with botulinum toxin guided by electromyography and arthroscopy. AB - Lateral pterygoid muscle dystonia is characterized by mandibular displacement towards the opposite side of the affected muscle. It may be associated with functional disorders affecting speech, swallowing, chewing and facial symmetry. Injection with botulinum toxin is recognized as the most effective treatment. Locating the lower head of the lateral pterygoid muscle for the injection is not difficult using electromyographic guidance; however, location of the upper head is more complicated, even with electromyography. We report a case of lateral pterygoid muscle dystonia in which precise injection of the upper head was achieved with the aid of arthroscopy. PMID- 20711165 TI - Clinical characteristics, treatment and outcome of 28 oral haemangiomas in pediatric patients. AB - OBJECTIVE: To present a large series of oral haemangiomas in children, analyzing the clinical characteristics, treatment and outcome of oral haemangiomas in 28 children. MATERIAL AND METHODS: We conducted an observational retrospective study, reviewing medical records with clinical diagnosis of haemangioma between 1990 and 2006 at the Children's Maxillofacial Surgery Service of the Hospital Universitario la Fe, Valencia. All patients with a clinical, radiographic, pathologically confirmed diagnosis of oral haemangioma were included. RESULTS: The study included 28 patients (19 females and 9 males) with a mean age of 4.27 years (range 0-14 years). Nine were congenital haemangioma. The most frequent location of oral haemangioma was in the lip with 23 cases, followed by three cases in the tongue and 2 in the buccal mucosa. The mean diameter of the lesion was 1.67 cm (range 1-3 cm). The mean duration of the lesion was 6.3 months (range 1 month to 5 years). Of the 28 haemangiomas, 13 were surgically removed, 2 were treated with embolization and 13 disappeared spontaneously. The mean follow up was 2.7 months (1-8 months). There were no cases of recurrence. CONCLUSIONS: Haemangiomas usually present in children, and can be seen from birth. They have a predilection for females. They are uncommon in the oral cavity. In the oral region, the most common location is the lip. Most congenital haemangioma regress spontaneously without treatment. The treatment of choice is surgical excision of the lesion. PMID- 20711166 TI - Incidence of impacted and supernumerary teeth-a radiographic study in a North Greek population. AB - OBJECTIVES: The aim of the present study was to investigate the prevalence of impacted and supernumerary teeth, apart from third molars. STUDY DESIGN: This was a retrospective study of 1.239 panoramic radiographs taken of patients who presented to the Department of Dentoalveolar Surgery, Implantology and Radiology at the School of Dentistry of the Aristotle University of Thessaloniki, Greece between 1991 and 1999. The panoramic radiographs and dental records were reviewed in order to determine whether there were impacted or supernumerary teeth. Observations were also made on the space in dentition, corresponding to the position of each impacted tooth, the lack of space for tooth eruption, transmigration, retained primary teeth or prosthetic restoration. RESULTS: A total of 170 (13.7%) patients presented with at least one impacted tooth. None of them had an impacted incisor. Impacted canines were the most prevalent dental anomaly (8.8%), followed by impacted premolars (2.2%). Supernumerary teeth (1.8%) and impacted molars (1%) were the least common anomalies. Among the 225 impacted teeth, the most frequently affected teeth were the canines (59.6%), followed by premolars (19.1%), and supernumerary teeth (15.1%), while the incidence of impacted molars was substantially lower (6.2%). CONCLUSIONS: The most frequently impacted teeth were the maxillary canine, the second mandibular premolar and the second mandibular molar. The majority of the supernumerary teeth consisted of mesiodens. There was space in the dentition of each impacted tooth in 29.3% of the cases examined; there was a retained primary tooth in 25.1%, and a prosthetic restoration had been constructed in 24%. Insufficient space for the eruption of the impacted tooth and transmigration was observed in 17.3% and 4.2% of the cases, respectively. PMID- 20711167 TI - An ESRP-regulated splicing programme is abrogated during the epithelial mesenchymal transition. AB - Alternative splicing achieves coordinated changes in post-transcriptional gene expression programmes through the activities of diverse RNA-binding proteins. Epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) are cell-type specific regulators of transcripts that switch splicing during the epithelial mesenchymal transition (EMT). To define a comprehensive programme of alternative splicing that is regulated during the EMT, we identified an extensive ESRP regulated splicing network of hundreds of alternative splicing events within numerous genes with functions in cell-cell adhesion, polarity, and migration. Loss of this global ESRP-regulated epithelial splicing programme induces the phenotypic changes in cell morphology that are observed during the EMT. Components of this splicing signature provide novel molecular markers that can be used to characterize the EMT. Bioinformatics and experimental approaches revealed a high-affinity ESRP-binding motif and a predictive RNA map that governs their activity. This work establishes the ESRPs as coordinators of a complex alternative splicing network that adds an important post-transcriptional layer to the changes in gene expression that underlie epithelial-mesenchymal transitions during development and disease. PMID- 20711168 TI - A Dyn2-CIN85 complex mediates degradative traffic of the EGFR by regulation of late endosomal budding. AB - The epidermal growth factor receptor (EGFR) is over-expressed in a variety of human cancers. Downstream signalling of this receptor is tightly regulated both spatially and temporally by controlling its internalization and subsequent degradation. Internalization of the EGFR requires dynamin 2 (Dyn2), a large GTPase that deforms lipid bilayers, leading to vesicle scission. The adaptor protein CIN85 (cbl-interacting protein of 85 kDa), which has been proposed to indirectly link the EGFR to the endocytic machinery at the plasma membrane, is also thought to be involved in receptor internalization. Here, we report a novel and direct interaction between Dyn2 and CIN85 that is induced by EGFR stimulation and, most surprisingly, occurs late in the endocytic process. Importantly, disruption of the CIN85-Dyn2 interaction results in accumulation of internalized EGFR in late endosomes that become aberrantly elongated into distended tubules. Consistent with the accumulation of this receptor is a sustention of downstream signalling cascades. These findings provide novel insights into a previously unknown protein complex that can regulate EGFR traffic at very late stages of the endocytic pathway. PMID- 20711169 TI - Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication. AB - BLM, the helicase defective in Bloom syndrome, is part of a multiprotein complex that protects genome stability. Here, we show that Rif1 is a novel component of the BLM complex and works with BLM to promote recovery of stalled replication forks. First, Rif1 physically interacts with the BLM complex through a conserved C-terminal domain, and the stability of Rif1 depends on the presence of the BLM complex. Second, Rif1 and BLM are recruited with similar kinetics to stalled replication forks, and the Rif1 recruitment is delayed in BLM-deficient cells. Third, genetic analyses in vertebrate DT40 cells suggest that BLM and Rif1 work in a common pathway to resist replication stress and promote recovery of stalled forks. Importantly, vertebrate Rif1 contains a DNA-binding domain that resembles the alphaCTD domain of bacterial RNA polymerase alpha; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for Rif1 to resist replication stress in vivo. Our data suggest that Rif1 provides a new DNA-binding interface for the BLM complex to restart stalled replication forks. PMID- 20711170 TI - Growth habit determination by the balance of histone methylation activities in Arabidopsis. AB - In Arabidopsis, the rapid-flowering summer-annual versus the vernalization requiring winter-annual growth habit is determined by natural variation in FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). However, the biochemical basis of how FRI confers a winter-annual habit remains elusive. Here, we show that FRI elevates FLC expression by enhancement of histone methyltransferase (HMT) activity. EARLY FLOWERING IN SHORT DAYS (EFS), which is essential for FRI function, is demonstrated to be a novel dual substrate (histone H3 lysine 4 (H3K4) and H3K36)-specific HMT. FRI is recruited into FLC chromatin through EFS and in turn enhances EFS activity and engages additional HMTs. At FLC, the HMT activity of EFS is balanced by the H3K4/H3K36- and H3K4-specific histone demethylase (HDM) activities of autonomous-pathway components, RELATIVE OF EARLY FLOWERING 6 and FLOWERING LOCUS D, respectively. Loss of HDM activity in summer annuals results in dominant HMT activity, leading to conversion to a winter annual habit in the absence of FRI. Thus, our study provides a model of how growth habit is determined through the balance of the H3K4/H3K36-specific HMT and HDM activities. PMID- 20711171 TI - Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. AB - Malignant astrocytoma includes anaplastic astrocytoma (grade III) and glioblastoma (grade IV). Among them, glioblastoma is the most common primary brain tumor with dismal responses to all therapeutic modalities. We performed a large-scale, genome-wide microRNA (miRNA) (n=756) expression profiling of 26 glioblastoma, 13 anaplastic astrocytoma and 7 normal brain samples with an aim to find deregulated miRNA in malignant astrocytoma. We identified several differentially regulated miRNAs between these groups, which could differentiate glioma grades and normal brain as recognized by PCA. More importantly, we identified a most discriminatory 23-miRNA expression signature, by using PAM, which precisely distinguished glioblastoma from anaplastic astrocytoma with an accuracy of 95%. The differential expression pattern of nine miRNAs was further validated by real-time RT-PCR on an independent set of malignant astrocytomas (n=72) and normal samples (n=7). Inhibition of two glioblastoma-upregulated miRNAs (miR-21 and miR-23a) and exogenous overexpression of two glioblastoma downregulated miRNAs (miR-218 and miR-219-5p) resulted in reduced soft agar colony formation but showed varying effects on cell proliferation and chemosensitivity. Thus we have identified the miRNA expression signature for malignant astrocytoma, in particular glioblastoma, and showed the miRNA involvement and their importance in astrocytoma development. PMID- 20711172 TI - Fibroblast-activation protein: a single marker that confidently differentiates morpheaform/infiltrative basal cell carcinoma from desmoplastic trichoepithelioma. AB - Microscopically, differentiating desmoplastic trichoepithelioma from morpheaform/infiltrative basal cell carcinoma can be difficult as both show 'islands and strands of basaloid cells embedded in a sclerotic stroma'. A superficial shave biopsy further compounds the diagnostic conundrum. Although a plethora of immunohistochemical markers have been touted as being of use as adjunct histologic tools, none thus far appears to be consistent and reliable in terms of specificity and/or sensitivity. Fibroblast-activation protein, a type II membrane-bound glycoprotein belonging to the serine protease family, is expressed in the granulation tissue of healing wounds. More recently, it has been identified as a marker of reactive tumor stromal fibroblasts, as it is reportedly selectively expressed in peritumoral stromal fibroblasts of multiple epithelial cancers including cutaneous malignancies such as basal cell carcinoma. Given this, we sought to ascertain the use of fibroblast-activation protein in distinguishing morpheaform/infiltrative basal cell carcinoma from desmoplastic trichoepithelioma. Immunohistochemical staining for fibroblast-activation protein was performed on desmoplastic trichoepithelioma (n=25) and morpheaform/infiltrative basal cell carcinoma (n=25), with the control group comprising scars from reexcision specimens (n=10). As expected, fibroblast activation protein expression was observed in stromal fibroblasts of all control cases (10 of 10, 100%). Of interest, fibroblast-activation protein expression was observed in peritumoral fibroblasts of all cases of morpheaform/infiltrative basal cell carcinoma (25 of 25, 100%) but not in any cases of desmoplastic trichoepithelioma (0 of 25, 0%). A gradient of fibroblast-activation protein expression was observed in morpheaform/infiltrative basal cell carcinoma with more intense expression noted in fibroblasts abutting the tumor cells, a less intense expression in the distal peritumoral stromal portion, and minimal to loss of expression in adjacent normal tissue. In summary, findings from this study underscore the use of fibroblast-activation protein as a histologic adjunct in confidently differentiating morpheaform/infiltrative basal cell carcinoma from desmoplastic trichoepithelioma. PMID- 20711173 TI - Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. AB - Label-free biosensor technology based on dynamic mass redistribution (DMR) of cellular constituents promises to translate GPCR signaling into complex optical 'fingerprints' in real time in living cells. Here we present a strategy to map cellular mechanisms that define label-free responses, and we compare DMR technology with traditional second-messenger assays that are currently the state of the art in GPCR drug discovery. The holistic nature of DMR measurements enabled us to (i) probe GPCR functionality along all four G-protein signaling pathways, something presently beyond reach of most other assay platforms; (ii) dissect complex GPCR signaling patterns even in primary human cells with unprecedented accuracy; (iii) define heterotrimeric G proteins as triggers for the complex optical fingerprints; and (iv) disclose previously undetected features of GPCR behavior. Our results suggest that DMR technology will have a substantial impact on systems biology and systems pharmacology as well as for the discovery of drugs with novel mechanisms. PMID- 20711174 TI - Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. AB - Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. PMID- 20711175 TI - Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. AB - We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome. PMID- 20711176 TI - A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population. AB - Keloid is a dermal fibroproliferative growth that results from dysfunction of the wound healing processes. Through a multistage genome-wide association study using 824 individuals with keloid (cases) and 3,205 unaffected controls in the Japanese population, we identified significant associations of keloid with four SNP loci in three chromosomal regions: 1q41, 3q22.3-23 and 15q21.3. The most significant association with keloid was observed at rs873549 (combined P = 5.89 x 10(-23), odds ratio (OR) = 1.77) on chromosome 1. Associations on chromosome 3 were observed at two separate linkage disequilibrium (LD) blocks: rs1511412 in the LD block including FOXL2 with P = 2.31 x 10(-13) (OR = 1.87) and rs940187 in another LD block with P = 1.80 x 10(-13) (OR = 1.98). Association of rs8032158 located in NEDD4 on chromosome 15 yielded P = 5.96 x 10(-13) (OR = 1.51). Our findings provide new insights into the pathophysiology of keloid formation. PMID- 20711177 TI - Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. AB - Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development. PMID- 20711178 TI - An index for characterization of nanomaterials in biological systems. AB - In a physiological environment, nanoparticles selectively absorb proteins to form 'nanoparticle-protein coronas', a process governed by molecular interactions between chemical groups on the nanoparticle surfaces and the amino-acid residues of the proteins. Here, we propose a biological surface adsorption index to characterize these interactions by quantifying the competitive adsorption of a set of small molecule probes onto the nanoparticles. The adsorption properties of nanomaterials are assumed to be governed by Coulomb forces, London dispersion, hydrogen-bond acidity and basicity, polarizability and lone-pair electrons. Adsorption coefficients of the probe compounds were measured and used to create a set of nanodescriptors representing the contributions and relative strengths of each molecular interaction. The method successfully predicted the adsorption of various small molecules onto carbon nanotubes, and the nanodescriptors were also measured for 12 other nanomaterials. The biological surface adsorption index nanodescriptors can be used to develop pharmacokinetic and safety assessment models for nanomaterials. PMID- 20711179 TI - Ultrahigh-power micrometre-sized supercapacitors based on onion-like carbon. AB - Electrochemical capacitors, also called supercapacitors, store energy in two closely spaced layers with opposing charges, and are used to power hybrid electric vehicles, portable electronic equipment and other devices. By offering fast charging and discharging rates, and the ability to sustain millions of cycles, electrochemical capacitors bridge the gap between batteries, which offer high energy densities but are slow, and conventional electrolytic capacitors, which are fast but have low energy densities. Here, we demonstrate microsupercapacitors with powers per volume that are comparable to electrolytic capacitors, capacitances that are four orders of magnitude higher, and energies per volume that are an order of magnitude higher. We also measured discharge rates of up to 200 V s(-1), which is three orders of magnitude higher than conventional supercapacitors. The microsupercapacitors are produced by the electrophoretic deposition of a several-micrometre-thick layer of nanostructured carbon onions with diameters of 6-7 nm. Integration of these nanoparticles in a microdevice with a high surface-to-volume ratio, without the use of organic binders and polymer separators, improves performance because of the ease with which ions can access the active material. Increasing the energy density and discharge rates of supercapacitors will enable them to compete with batteries and conventional electrolytic capacitors in a number of applications. PMID- 20711180 TI - The initialization and manipulation of quantum information stored in silicon by bismuth dopants. AB - A prerequisite for exploiting spins for quantum data storage and processing is long spin coherence times. Phosphorus dopants in silicon (Si:P) have been favoured as hosts for such spins because of measured electron spin coherence times (T2) longer than any other electron spin in the solid state: 14 ms at 7 K with isotopically purified silicon. Heavier impurities such as bismuth in silicon (Si:Bi) could be used in conjunction with Si:P for quantum information proposals that require two separately addressable spin species. However, the question of whether the incorporation of the much less soluble Bi into Si leads to defect species that destroy coherence has not been addressed. Here we show that schemes involving Si:Bi are indeed feasible as the electron spin coherence time T2 is at least as long as for Si:P with non-isotopically purified silicon. We polarized the Si:Bi electrons and hyperpolarized the I=9/2 nuclear spin of (209)Bi, manipulating both with pulsed magnetic resonance. The larger nuclear spin means that a Si:Bi dopant provides a 20-dimensional Hilbert space rather than the four dimensional Hilbert space of an I=1/2 Si:P dopant. PMID- 20711181 TI - Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells. AB - When vertebrate cells exit mitosis various cellular structures are re-organized to build functional interphase cells. This depends on Cdk1 (cyclin dependent kinase 1) inactivation and subsequent dephosphorylation of its substrates. Members of the protein phosphatase 1 and 2A (PP1 and PP2A) families can dephosphorylate Cdk1 substrates in biochemical extracts during mitotic exit, but how this relates to postmitotic reassembly of interphase structures in intact cells is not known. Here, we use a live-cell imaging assay and RNAi knockdown to screen a genome-wide library of protein phosphatases for mitotic exit functions in human cells. We identify a trimeric PP2A-B55alpha complex as a key factor in mitotic spindle breakdown and postmitotic reassembly of the nuclear envelope, Golgi apparatus and decondensed chromatin. Using a chemically induced mitotic exit assay, we find that PP2A-B55alpha functions downstream of Cdk1 inactivation. PP2A-B55alpha isolated from mitotic cells had reduced phosphatase activity towards the Cdk1 substrate, histone H1, and was hyper-phosphorylated on all subunits. Mitotic PP2A complexes co-purified with the nuclear transport factor importin-beta1, and RNAi depletion of importin-beta1 delayed mitotic exit synergistically with PP2A-B55alpha. This demonstrates that PP2A-B55alpha and importin-beta1 cooperate in the regulation of postmitotic assembly mechanisms in human cells. PMID- 20711183 TI - Parallel processing of visual space by neighboring neurons in mouse visual cortex. AB - Visual cortex shows smooth retinotopic organization on the macroscopic scale, but it is unknown how receptive fields are organized at the level of neighboring neurons. This information is crucial for discriminating among models of visual cortex. We used in vivo two-photon calcium imaging to independently map ON and OFF receptive field subregions of local populations of layer 2/3 neurons in mouse visual cortex. Receptive field subregions were often precisely shared among neighboring neurons. Furthermore, large subregions seem to be assembled from multiple smaller, non-overlapping subregions of other neurons in the same local population. These experiments provide, to our knowledge, the first characterization of the diversity of receptive fields in a dense local network of visual cortex and reveal elementary units of receptive field organization. Our results suggest that a limited pool of afferent receptive fields is available to a local population of neurons and reveal new organizational principles for the neural circuitry of the mouse visual cortex. PMID- 20711182 TI - Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. AB - Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTR(F508del) induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS-TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro, in vivo in Scnn1b-transgenic and Cftr(F508del) homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTR(F508del) to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation. PMID- 20711184 TI - Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities. AB - In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities. PMID- 20711185 TI - MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. AB - The X-linked transcriptional repressor methyl CpG binding protein 2 (MeCP2), known for its role in the neurodevelopmental disorder Rett syndrome, is emerging as an important regulator of neuroplasticity in postmitotic neurons. Cocaine addiction is commonly viewed as a disorder of neuroplasticity, but the potential involvement of MeCP2 has not been explored. Here we identify a key role for MeCP2 in the dorsal striatum in the escalating cocaine intake seen in rats with extended access to the drug, a process that mimics the increasingly uncontrolled cocaine use seen in addicted humans. MeCP2 regulates cocaine intake through homeostatic interactions with microRNA-212 (miR-212) to control the effects of cocaine on striatal brain-derived neurotrophic factor (BDNF) levels. These data suggest that homeostatic interactions between MeCP2 and miR-212 in dorsal striatum may be important in regulating vulnerability to cocaine addiction. PMID- 20711186 TI - MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. AB - MeCP2 is a methyl DNA-binding transcriptional regulator that contributes to the development and function of CNS synapses; however, the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the nucleus accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Mecp2 hypomorphic mutant mice have more NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore, these mice show deficient plasticity of striatal immediate early gene inducibility after repeated AMPH administration. Notably, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal new roles for MeCP2 both in mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors. PMID- 20711187 TI - Molecular basis of FIR-mediated c-myc transcriptional control. AB - The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration. PMID- 20711189 TI - A split active site couples cap recognition by Dcp2 to activation. AB - Decapping by Dcp2 is an essential step in 5'-to-3' mRNA decay. In yeast, decapping requires an open-to-closed transition in Dcp2, though the link between closure and catalysis remains elusive. Here we show using NMR that cap binds conserved residues on both the catalytic and regulatory domains of Dcp2. Lesions in the cap-binding site on the regulatory domain reduce the catalytic step by two orders of magnitude and block the formation of the closed state, whereas Dcp1 enhances the catalytic step by a factor of 10 and promotes closure. We conclude that closure occurs during the rate-limiting catalytic step of decapping, juxtaposing the cap-binding region of each domain to form a composite active site. This work suggests a model for regulation of decapping where coactivators trigger decapping by stabilizing a labile composite active site. PMID- 20711188 TI - Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. AB - To gain global insights into the role of the well-known repressive splicing regulator PTB, we analyzed the consequences of PTB knockdown in HeLa cells using high-density oligonucleotide splice-sensitive microarrays. The major class of identified PTB-regulated splicing event was PTB-repressed cassette exons, but there was also a substantial number of PTB-activated splicing events. PTB repressed and PTB-activated exons showed a distinct arrangement of motifs with pyrimidine-rich motif enrichment within and upstream of repressed exons but downstream of activated exons. The N-terminal half of PTB was sufficient to activate splicing when recruited downstream of a PTB-activated exon. Moreover, insertion of an upstream pyrimidine tract was sufficient to convert a PTB activated exon to a PTB-repressed exon. Our results show that PTB, an archetypal splicing repressor, has variable splicing activity that predictably depends upon its binding location with respect to target exons. PMID- 20711190 TI - Nuclear pore formation but not nuclear growth is governed by cyclin-dependent kinases (Cdks) during interphase. AB - Nuclear volume and the number of nuclear pore complexes (NPCs) on the nucleus almost double during interphase in dividing cells. How these events are coordinated with the cell cycle is poorly understood, particularly in mammalian cells. We report here, based on newly developed techniques for visualizing NPC formation, that cyclin-dependent kinases (Cdks), especially Cdk1 and Cdk2, promote interphase NPC formation in human dividing cells. Cdks seem to drive an early step of NPC formation because Cdk inhibition suppressed generation of 'nascent pores', which we argue are immature NPCs under the formation process. Consistent with this, Cdk inhibition disturbed proper expression and localization of some nucleoporins, including Elys/Mel-28, which triggers postmitotic NPC assembly. Strikingly, Cdk suppression did not notably affect nuclear growth, suggesting that interphase NPC formation and nuclear growth have distinct regulation mechanisms. PMID- 20711191 TI - Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus. AB - Myotonic dystrophy, caused by DM1 CTG/CAG repeat expansions, shows varying instability levels between tissues and across ages within patients. We determined DNA replication profiles at the DM1 locus in patient fibroblasts and tissues from DM1 transgenic mice of various ages showing different instability. In patient cells, the repeat is flanked by two replication origins demarcated by CTCF sites, with replication diminished at the expansion. In mice, the expansion replicated from only the downstream origin (CAG as lagging template). In testes from mice of three different ages, replication toward the repeat paused at the earliest age and was relieved at later ages-coinciding with increased instability. Brain, pancreas and thymus replication varied with CpG methylation at DM1 CTCF sites. CTCF sites between progressing forks and repeats reduced replication depending on chromatin. Thus, varying replication progression may affect tissue- and age specific repeat instability. PMID- 20711192 TI - Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. AB - Allergies to nickel (Ni(2+)) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4 deficient mice allowed efficient sensitization to Ni(2+) and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses. PMID- 20711193 TI - MicroRNAs modulate the noncanonical transcription factor NF-kappaB pathway by regulating expression of the kinase IKKalpha during macrophage differentiation. AB - MicroRNAs are key regulators of many biological processes, including cell differentiation. Here we show that during human monocyte-macrophage differentiation, expression of the microRNAs miR-223, miR-15a and miR-16 decreased considerably, which led to higher expression of the serine-threonine kinase IKKalpha in macrophages. In macrophages, higher IKKalpha expression in conjunction with stabilization of the kinase NIK induced larger amounts of p52. Because of low expression of the transcription factor RelB in untreated macrophages, high p52 expression repressed basal transcription of both canonical and noncanonical NF-kappaB target genes. However, proinflammatory stimuli in macrophages resulted in greater induction of noncanonical NF-kappaB target genes. Thus, a decrease in certain microRNAs probably prevents macrophage hyperactivation yet primes the macrophage for certain responses to proinflammatory stimuli. PMID- 20711194 TI - High-resolution mapping of protein sequence-function relationships. AB - We present a large-scale approach to investigate the functional consequences of sequence variation in a protein. The approach entails the display of hundreds of thousands of protein variants, moderate selection for activity and high throughput DNA sequencing to quantify the performance of each variant. Using this strategy, we tracked the performance of >600,000 variants of a human WW domain after three and six rounds of selection by phage display for binding to its peptide ligand. Binding properties of these variants defined a high-resolution map of mutational preference across the WW domain; each position had unique features that could not be captured by a few representative mutations. Our approach could be applied to many in vitro or in vivo protein assays, providing a general means for understanding how protein function relates to sequence. PMID- 20711195 TI - Comprehensive comparative analysis of strand-specific RNA sequencing methods. AB - Strand-specific, massively parallel cDNA sequencing (RNA-seq) is a powerful tool for transcript discovery, genome annotation and expression profiling. There are multiple published methods for strand-specific RNA-seq, but no consensus exists as to how to choose between them. Here we developed a comprehensive computational pipeline to compare library quality metrics from any RNA-seq method. Using the well-annotated Saccharomyces cerevisiae transcriptome as a benchmark, we compared seven library-construction protocols, including both published and our own methods. We found marked differences in strand specificity, library complexity, evenness and continuity of coverage, agreement with known annotations and accuracy for expression profiling. Weighing each method's performance and ease, we identified the dUTP second-strand marking and the Illumina RNA ligation methods as the leading protocols, with the former benefitting from the current availability of paired-end sequencing. Our analysis provides a comprehensive benchmark, and our computational pipeline is applicable for assessment of future protocols in other organisms. PMID- 20711196 TI - A small-molecule inhibitor shows that pirin regulates migration of melanoma cells. AB - The discovery of small molecules that bind to a specific target and disrupt the function of proteins is an important step in chemical biology, especially for poorly characterized proteins. Human pirin is a nuclear protein of unknown function that is widely expressed in punctate subnuclear structures in human tissues. Here, we report the discovery of a small molecule that binds to pirin. We determined how the small molecule bound to pirin by solving the cocrystal structure. Either knockdown of pirin or treatment with the small molecule inhibited melanoma cell migration. Thus, inhibition of pirin by the small molecule has led to a greater understanding of the function of pirin and represents a new method of studying pirin-mediated signaling pathways. PMID- 20711197 TI - Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. AB - Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors. Here we report the discovery of the first potent non-bisphosphonate FPPS inhibitors. These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment based approaches using NMR and X-ray crystallography. This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue. PMID- 20711199 TI - Comorbidity: preventable premature morbidity and mortality due to skin disease. PMID- 20711198 TI - Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. AB - A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery. PMID- 20711203 TI - Is your patient with neurofibromatosis likely to develop a malignancy? PMID- 20711204 TI - Scientific highlights from the Society for Investigative Dermatology 2010 Annual Meeting. PMID- 20711205 TI - Cutaneous features predict paraspinal neurofibromas in neurofibromatosis type 1. AB - In neurofibromatosis type 1 (NF-1), malignant transformation of internal plexiform neurofibromas carries a poor prognosis, in part because they are not evident clinically. In this issue, Sbidian et al. describe a novel "NF-1Score" equation that employs four easily observable traits to predict the presence of paraspinal neurofibromas. This tool can identify at-risk patients during regular screening to help reduce mortality. PMID- 20711206 TI - X-linked inhibitor of apoptosis protein as a therapeutic target in metastatic melanoma. AB - Melanoma is the most dangerous type of skin cancer, with notorious resistance to current chemotherapy and immunotherapy. In this issue, Hiscutt et al. report on the prognostic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma. The finding that XIAP inhibition significantly increases endoplasmic reticulum stress-mediated apoptosis in melanoma cells suggests that XIAP is a potential therapeutic target for melanoma therapy. PMID- 20711207 TI - Comment on "Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT". PMID- 20711209 TI - mGluR2-Positive allosteric modulators: Therapeutic potential for treating cocaine abuse? PMID- 20711212 TI - Abstracts of the 40th Annual Meeting of the European Society for Dermatological Research. September 9-11, 2010. Helsinki, Finland. PMID- 20711215 TI - The biochemical efficacy of primary cryoablation combined with prolonged total androgen suppression compared with radiotherapy on high-risk prostate cancer: a 3 year pilot study. AB - To gain beneficial effects in the management of high-risk prostate cancer, an integrated approach that combines local therapy and androgen deprivation therapy (ADT) was used. We compared biochemical responses between primary cryosurgical ablation of the prostate (CSAP) combined with prolonged ADT and radiation combined with ADT, which is the established modality in high-risk disease. A total of 33 high-risk patients received CSAP combined with ADT for 3 months before and up to 24 months after treatment. This patient group was matched with another 33 patients who had undergone three-dimensional conformal radiation therapy (3D-CRT) with the same protocol for ADT. Biochemical recurrence (BCR) was assessed by the American Society for Therapeutic Radiation Oncology (ASTRO) definition, the Phoenix definition and a prostate-specific antigen (PSA) cutoff of 0.5 ng mL(-1). Median follow-up was 61.0 +/- 11.9 months for the CSAP + ADT group and 86.0 +/- 15.8 months for the 3D-CRT + ADT group. In the CSAP group, major complications including rectourethral fistula and incontinence were not noted. In the CSAP + ADT group, 57.0% had BCR using the ASTRO definition, 21.2% using the Phoenix definition and 54.5% using a PSA cutoff of 0.5 ng mL(-1). In the 3D-CRT + ADT group, 54.5%, 21.2% and 54.5% had BCR using the ASTRO, Phoenix and PSA definition, respectively. In the CSAP + ADT group, the BCR-free survival (BRFS) was 54 +/- 10 months using the ASTRO definition, 65 +/- 5 months using the Phoenix definition and 51 +/- 4 months using a PSA cutoff of 0.5 ng mL(-1). In the 3D-CRT + ADT group, the BRFS was 68 +/- 12, 93 +/- 19 and 70 +/- 18 months using the ASTRO, Phoenix and PSA definition, respectively. By the log-rank test, the BRFS values for each group were not statistically different. This intermediate-term result indicated that primary CSAP combined with prolonged ADT offers a parallel biochemical response compared with radiotherapy in high-risk prostate cancer. PMID- 20711216 TI - Novel approaches for the molecular classification of prostate cancer. PMID- 20711218 TI - The role of ezrin-associated protein network in human sperm capacitation. AB - Membrane modifications in sperm cells represent a key step in sperm capacitation; however, the molecular basis of these modifications is not fully understood. Ezrin is the best-studied member of the ezrin/radixin/merlin family. As a cross linker between the cortical cytoskeleton and plasma membrane proteins, ezrin contributes to remodeling of the membrane surface structure. Furthermore, activated ezrin and the Rho dissociation inhibitor, RhoGDI, promote the formation of cortical cytoskeleton-polymerized actin through Rho activation. Thus, ezrin, actin, RhoGDI, Rho and plasma membrane proteins form a complicated network in vivo, which contributes to the assembly of the structure of the membrane surface. Previously, we showed that ezrin and RhoGDI1 are expressed in human testes. Thus, we sought to determine whether the ezrin-RhoGDI1-actin-membrane protein network has a role in human sperm capacitation. Our results by Western blot indicate that ezrin is activated by phosphorylation of the threonine567 residue during capacitation. Co-immunoprecipitation studies revealed that, during sperm capacitation, the interaction between ezrin and RhoGDI1 increases, and phosphostaining of two dimensional electrophoresis gels showed that RhoGDI1 is phosphorylated, suggesting that RhoGDI1 dissociates from RhoA and leads to actin polymerization on the sperm head. We speculate that activated ezrin interacts with polymerized actin and the glycosylated membrane protein cd44 after capacitation. Blocking sperm capacitation using ezrin- or actin-specific monoclonal antibodies decreases their acrosome reaction (AR) rate, but has no effect on the AR alone. Taken together, our results show that a network consisting of ezrin, RhoGDI1, RhoA, F-actin and membrane proteins functions to influence the modifications that occur on the membrane of the sperm head during human sperm capacitation. PMID- 20711217 TI - Androgen receptor signaling and mutations in prostate cancer. AB - Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues. PMID- 20711220 TI - Double target concept for smoking cessation. AB - Tobacco use is estimated to be the largest single cause of premature death in the world. Nicotine is the major addictive substance in tobacco products. After cigarette smoking, nicotine quickly acts on its target, nicotinic acetylcholine receptors (nAChRs), which are widely distributed throughout the mammalian central nervous system and are expressed as diverse subtypes on cell bodies, dendrites and/or nerve terminals. Through the nAChRs in brain reward circuits, nicotine alters dopaminergic (DA) neuronal function in the ventral tegmental area (VTA) and increases dopamine release from VTA to nuclear accumbens (NA), which leads to nicotine reward, tolerance and dependence. After quitting smoking, smokers experience withdrawal symptoms, including depression, irritability, difficulty concentrating or sleeping, headache, and tiredness. Recently, evidence has been accumulated to reveal the molecular and cellular mechanisms of nicotine reward, tolerance and dependence. The outcomes of these investigations provide pharmacological basis for smoking cessation. Here, I briefly summarize recent advancements of our understanding of nicotine reward, tolerance and dependence. Based on these understandings, I propose a double target hypothesis, in which nAChRs and dopamine release process are two important targets for smoking cessation. Dysfunction of nAChRs (antagonism or desensitization) is crucial to abolish nicotine dependence and the maintenance of an appropriate level of extracellular dopamine eliminates nicotine withdrawal syndromes. Therefore, the medications simultaneously act on these two targets should have the desired effect for smoking cessation. I discuss how to use this double target concept to interpret recent therapies and to develop new candidate compounds for smoking cessation. PMID- 20711219 TI - Clinical application and evaluation of anti-TNF-alpha agents for the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease that dramatically impairs quality of life. A number of compounds are available to treat RA, but they vary in effectiveness. Thus, no optimal treatment strategy has been defined. Currently, disease-modifying anti-rheumatic drugs (DMARDs) and anti tumor necrosis factor-alpha (anti-TNF-alpha) agents are considered the treatments of choice. For patients with inadequate responses to DMARD therapy, one recommended therapeutic alternative is anti-TNF-alpha therapy. Anti-TNF-alpha agents are effective and have rapid onset of action compared with DMARDs. Elucidating the differences in effectiveness of anti-TNF-alpha compounds has important clinical implications. By comparing the efficacy, safety and use principle of different treatment options, this review focuses on providing important information about three anti-TNF-alpha compounds (etanercept, infliximab, and adalimumab) to help define optimal treatments for RA patients. PMID- 20711221 TI - AMPK in cardiovascular health and disease. AB - AbstractAdenosine Monophosphate-activated Protein Kinase (AMPK), a serine/threonine kinase and a member of the Snf1/AMPK protein kinase family, consists of three protein subunits that together make a functional enzyme. AMPK, which is expressed in a number of tissues, including the liver, brain, and skeletal muscle, is allosterically activated by a rise in the AMP: ATP ratio (ie in a low ATP or energy depleted state). The net effect of AMPK activation is to halt energy consuming (anabolic) pathways but to promote energy conserving (catabolic) cellular pathways. AMPK has therefore often been dubbed the "metabolic master switch". AMPK also plays a critical physiological role in the cardiovascular system. Increasing evidence suggest that AMPK might also function as a sensor by responding to oxidative stress. Mostly importantly, AMPK modulates endogenous antioxidant gene expression and/or suppress the production of oxidants. AMPK promotes cardiovascular homeostasis by ensuring an optimum redox balance on the heart and vascular tissues. Dysfunctional AMPK is thought to underlie several cardiovascular pathologies. Here we review this kinase from its structure and discovery to current knowledge of its adaptive and maladaptive role in the cardiovascular system. PMID- 20711222 TI - Kruppel-like factor 4 interacts with p300 to activate mitofusin 2 gene expression induced by all-trans retinoic acid in VSMCs. AB - AIM: To elucidate how kruppel-like factor 4 (KLF4) activates mitofusin 2 (mfn-2) expression in all-trans retinoic acid (ATRA)-induced vascular smooth muscle cell (VSMC) differentiation. METHODS: The mfn-2 promoter-reporter constructs and the KLF4 acetylation-deficient or phosphorylation-deficient mutants were constructed. Adenoviral vector of KLF4-mediated overexpression and Western blot analysis were used to determine the effect of KLF4 on mfn-2 expression. The luciferase assay and chromatin immunoprecipitation were used to detect the transactivation of KLF4 on mfn-2 gene expression. Co-immunoprecipitation and GST pull-down assays were used to determine the modification of KLF4 and interaction of KLF4 with p300 in VSMCs. RESULTS: KLF4 mediated ATRA-induced mfn-2 expression in VSMCs. KLF4 bound directly to the mfn-2 promoter and activated its transcription. ATRA increased the interaction of KLF4 with p300 by inducing KLF4 phosphorylation via activation of JNK and p38 MAPK signaling. KLF4 acetylation by p300 increased its activity to transactivate the mfn-2 promoter. CONCLUSION: ATRA induces KLF4 acetylation by p300 and increases the ability of KLF4 to transactivate the mfn-2 promoter in VSMCs. PMID- 20711223 TI - New perspectives on vascular wall signaling: role of perivascular adipocytes and fibroblasts. AB - This communication represents personal perspectives of recent development in the newly evolved areas in vascular signaling mechanisms at the anatomical level of vascular walls from outside in, that is, from perivascular adventitial side to effectuate the control of vascular reactivity. Since half a century ago, the focus of interest in vascular biology has been confined primarily to the study of the excitation-contraction coupling of vascular smooth muscle (VSM) as well as neuroeffector mechanisms. During the past 3 decades, considerable advancement in the understanding of vascular signaling has been made via the discovery of endothelium-derived relaxation factors (EDRF), endothelium-derived hyperpolarizing factors (EDHF) and endothelium-derived contracting factors (EDCF). The discovery of nitric oxide (NO) as a major cellular messenger has also helped open up another huge area of research in oxidative stress and vascular diseases. In the past decade, concepts on vascular wall signaling have been extended from vascular endothelial cells and then translated to the other seemingly inert cellular components, such as perivascular adipocytes and adventitial fibroblasts. Growing body of evidences show that these cellularities contribute to both functional as well as structural integrity in vasculature with significant pathophysiological implications. PMID- 20711224 TI - Purinergic signaling: a novel mechanism in immune surveillance. AB - Purinergic receptors and the associated signaling cascades are known to play critical roles in cardiovascular, nervous, respiratory, gastrointestinal and urinogenital systems. Recent studies have also shed light on the importance of nucleotides and purinergic receptors in the regulation of the immune response. With a better understanding of the distribution and the receptor subtypes, the purinoceptors have the potential to become important therapeutic targets in inflammation, chemotaxis and immune-related diseases. PMID- 20711225 TI - Kv1.3: a potential pharmacological target for diabetes. AB - K(+) channels, which are ubiquitous membrane proteins, play a central role in regulating the resting membrane potential and the shape and duration of the action potential in pancreatic beta-cells. There are at least three types of K(+) channels (K(ATP), K(Ca), and Kv2.1 channels) that are involved in glucose stimulated insulin secretion in pancreatic beta-cells, and one type (Kv1.3) that is associated with the regulation of insulin sensitivity in peripheral target tissues. This article reviews the function of Kv1.3 channels that contribute to mediating insulin action in insulin-sensitive tissues. Pharmacological strategies for targeting Kv1.3 are then discussed with a focus on a rationale for the potential therapeutic use of Kv1.3 blocker in diabetic treatment. PMID- 20711226 TI - Hypoxia inducible factor 1 (HIF-1) and cardioprotection. AB - Since its discovery in early 1990s, hypoxia inducible factor 1 (HIF-1) has been increasingly recognized for its key role in transcriptional control of more than a hundred genes that regulate a wide-spectrum of cellular functional events, including angiogenesis, vasomotor control, glucose and energy metabolism, erythropoiesis, iron homeostasis, pH regulation, cell proliferation and viability. Evidence accumulated during the past 7 years suggests a critical role for HIF-1alpha in mediating cardioprotection. The purpose of our present article is to provide an updated overview on this important regulator of gene expression in the cellular stress-responsive and adaptive process. We have particularly emphasized the involvement of HIF-1 in the induction of cardioprotective molecules, such as inducible nitric oxide synthase (iNOS), hemeoxygenase 1 (HO 1), and erythropoietin (EPO), which in turn alleviate myocardial damages caused by harmful events such as ischemia-reperfusion injury. Despite these advances, further in-depth studies are needed to elucidate the possible coordination or interaction between HIF-1alpha and other key transcription factors in regulating protein expression that leads to cardioprotection. PMID- 20711227 TI - Therapeutic implications of chemokine-mediated pathways in atherosclerosis: realistic perspectives and utopias. AB - Current perspectives on the pathogenesis of atherosclerosis strongly support the involvement of inflammatory mediators in the establishment and progression of atherosclerostic lesions. Chemokine-mediated mechanisms are potent regulators of such processes by orchestrating the interactions of inflammatory cellular components of the peripheral blood with cellular components of the arterial wall. The increasing evidence supporting the role of chemokine pathways in atherosclerosis renders chemokine ligands and their receptors potential therapeutic targets. In the following review, we aim to highlight the special structural and functional features of chemokines and their receptors in respect to their roles in atherosclerosis, and examine to what extent available data can be applied in disease management practices. PMID- 20711228 TI - COX-mediated endothelium-dependent contractions: from the past to recent discoveries. AB - Endothelial cells release various substances to control the tone of the underlying vascular smooth muscle. Nitric oxide (NO) is the best defined endothelium-derived relaxing factor (EDRF). Endothelial cells can also increase vascular tone by releasing endothelium-derived contracting factors (EDCF). The over-production of EDCF contributes to the endothelial dysfunctions which accompanies various vascular diseases. The present review summarizes and discusses the mechanisms leading to the release of EDCFs derived from the metabolism of arachidonic acid. This release can be triggered by agonists such as acetylcholine, adenosine nucleotides or by stretch. All these stimuli are able to induce calcium influx into the endothelial cells, an effect which can be mimicked by calcium ionophores. The augmentation in intracellular calcium ion concentration initiates the release of EDCF. Downstream processes include activation of phospholipase A(2) (PLA(2)), cyclooxygenases (COX) and the production of reactive oxygen species (ROS) and vasoconstrictor prostanoids (endoperoxides, prostacyclin, thromboxane A(2) and other prostaglandins) which subsequently diffuse to, and activate thromboxane-prostanoid (TP) receptors on the vascular smooth muscle cells leading to contraction. PMID- 20711229 TI - Natural killer cell-triggered vascular transformation: maternal care before birth? AB - Natural killer (NK) cells are found in lymphoid and non-lymphoid organs. In addition to important roles in immune surveillance, some NK cells contribute to angiogenesis and circulatory regulation. The uterus of early pregnancy is a non lymphoid organ enriched in NK cells that are specifically recruited to placental attachment sites. In species with invasive hemochorial placentation, these uterine natural killer (uNK) cells, via secretion of cytokines, chemokines, mucins, enzymes and angiogenic growth factors, contribute to the physiological change of mesometrial endometrium into the unique stromal environment called decidua basalis. In humans, uNK cells have the phenotype CD56(bright)CD16(dim) and they appear in great abundance in the late secretory phase of the menstrual cycle and early pregnancy. Gene expression studies indicate that CD56(bright)CD16(dim) uterine and circulating cells are functionally distinct. In humans but not mice or other species with post-implantation decidualization, uNK cells may contribute to blastocyst implantation and are of interest as therapeutic targets in female infertility. Histological and genetic studies in mice first identified triggering of the process of gestation spiral arterial modification as a major uNK cell function, achieved via interferon (IFN)-gamma secretion. During spiral arterial modification, branches from the uterine artery that traverse the endometrium/decidua transiently lose their muscular coat and ability to vasoconstrict. The expression of vascular markers changes from arterial to venous as these vessels dilate and become low-resistance, high-volume channels. Full understanding of the vascular interactions of human uNK cells is difficult to obtain because endometrial time-course studies are not possible in pregnant women. Here we briefly review key information concerning uNK cell functions from studies in rodents, summarize highlights concerning human uNK cells and describe our preliminary studies on development of a humanized, pregnant mouse model for in vivo investigations of human uNK cell functions. PMID- 20711230 TI - Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN beta induction by disrupting the VISA-associated complex. AB - Viral RNAs produced during viral infection are recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5). A central adapter protein downstream of RIG-I and MDA5 is the mitochondrial membrane protein virus-induced signaling adaptor (VISA), which mediates the induction of type I interferons (IFNs) through the activation of transcription factors such as nuclear factor-kappaB (NF-kappaB) and IFN regulatory factor-3 (IRF3). Here we found that hepatitis B virus (HBV)-encoded X protein (HBx) acts as an inhibitor of virus-triggered IRF3 activation and IFN beta induction. Reporter and plaque assays indicate that HBx inhibits signaling by components upstream but not downstream of VISA. Immunoprecipitation experiments indicate that HBx interacts with VISA and disrupts the association of VISA with its upstream and downstream components. These findings suggest that HBx acts as a suppressor of virus-triggered induction of type I IFNs, which explains the observation that HBV causes transient and chronic infection in hepatocytes but fails to activate the pattern recognition receptor-mediated IFN induction pathways. PMID- 20711231 TI - A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. AB - The activation of receptor tyrosine kinases, particularly ErbB2, has an important role in the genesis of breast cancer. ErbB2 kinase activity promotes Ras-mediated stimulation of downstream protein kinase cascades, including the Ras/Raf 1/MAPK/ERK kinase (Mek)/extracellular signal-regulated kinase (Erk) pathway, leading to tumor cell growth and migration. Signaling through the Ras-Erk pathway can be influenced by p21-activated kinase-1 (Pak1), an effector of the Rho family GTPases Rac and Cdc42. In this study, we asked if ErbB2 expression correlates with Pak1 and Erk activity in human breast cancer specimens, and if Pak1 signaling is required for ErbB2 transformation in a three-dimensional (3D) in vitro setting and in xenografts. We found a correlation between ErbB2 expression and activation of Pak in estrogen receptor-positive human breast tumor samples and observed that in 3D cultures, activation of Rac-Pak1 pathway by ErbB2 homodimers induced growth factor-independent proliferation and promoted disruption of 3D mammary acinar-like structures through activation of the Erk and Akt pathways. Further, we found that inhibition of Pak1 by small molecules compromised activation of Erk and Akt, resulting in reversion of the malignant phenotype and restoration of normal acinar architecture. Finally, ErbB2-amplified breast cancer cells expressing a specific Pak inhibitor showed delayed tumor formation and downregulation of Erk and Akt signaling in vivo. These data imply that the Rac-Pak pathway is vital to ErbB2-mediated transformation and that Pak inhibitors represent plausible drug targets in breast cancers in which ErbB2 signaling is activated. PMID- 20711232 TI - Regulation of DNA-dependent protein kinase by protein kinase CK2 in human glioblastoma cells. AB - The DNA-dependent protein kinase (DNA-PK) is a nuclear serine/threonine protein kinase composed of a large catalytic subunit (DNA-PKcs) and a heterodimeric DNA targeting subunit Ku. DNA-PK is a major component of the nonhomologous end joining pathway of DNA double-strand breaks repair. Although DNA-PK has been biochemically characterized in vitro, relatively little is known about its functions in the context of DNA repair and how its kinase activity is precisely regulated in vivo. Here, we report that cellular depletion of the individual catalytic subunits of protein kinase CK2 by RNA interference leads to significant cell death in M059K human glioblastoma cells expressing DNA-PKcs, but not in their isogenic counterpart, that is M059J cells, devoid of DNA-PKcs. The lack of CK2 results in enhanced DNA-PKcs activity and strongly inhibits DNA damage induced autophosphorylation of DNA-PKcs at S2056 as well as repair of DNA double strand breaks. By the application of the in situ proximity ligation assay, we show that CK2 interacts with DNA-PKcs in normal growing cells and that the association increases upon DNA damage. These results indicate that CK2 has an important role in the modulation of DNA-PKcs activity and its phosphorylation status providing important insights into the mechanisms by which DNA-PKcs is regulated in vivo. PMID- 20711233 TI - Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. AB - Mitogen-activated protein kinase (MAPK) and AKT pathways are frequently co activated in melanoma through overexpression of receptor tyrosine kinases, mutations in their signaling surrogates, such as RAS and BRAF, or loss of negative regulators such as PTEN. As RAS can be a positive upstream regulator of PI3-K, it has been proposed that the loss of PTEN and the activation of RAS are redundant events in melanoma pathogenesis. Here, in genetically engineered mouse models of cutaneous melanomas, we sought to better understand the genetic interactions between HRAS activation and PTEN inactivation in melanoma genesis and progression in vivo. We showed that HRAS activation cooperates with Pten+/- and Ink4a/Arf-/- to increase melanoma penetrance and promote metastasis. Correspondingly, gain- and loss-of-function studies established that Pten loss increases invasion and migration of melanoma cells and non-transformed melanocytes, and such biological activity correlates with a shift to phosphorylation of AKT2 isoform and E-cadherin down-regulation. Thus, Pten inactivation can drive the genesis and promote the metastatic progression of RAS activated Ink4a/Arf deficient melanomas. PMID- 20711234 TI - The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma. AB - Genomic translocations have been implicated in cancer. In this study, we performed a screen for genetic translocations in gliomas based on exon-level expression profiles. We identified a translocation in the contactin-associated protein-like 2 (CASPR2) gene, encoding a cell adhesion molecule. CASPR2 mRNA was fused to an expressed sequence tag that likely is part of the nuclear receptor coactivator 1 gene. Despite high mRNA expression levels, no CASPR2 fusion protein was detected. In a set of 25 glioblastomas and 22 oligodendrogliomas, mutation analysis identified two additional samples with genetic alterations in the CASPR2 gene and all three identified genetic alterations are likely to reduce CASPR2 protein expression levels. Methylation of the CASPR2 gene was also observed in gliomas and glioma cell lines. CASPR2-overexpressing cells showed decreased proliferation rates, likely because of an increase in apoptosis. Moreover, high CASPR2 mRNA expression level is positively correlated with survival and is an independent prognostic factor. These results indicate that CASPR2 acts as a tumor suppressor gene in glioma. PMID- 20711235 TI - Oncogenic function of the MUC1 receptor subunit in gene regulation. AB - The mucin 1 (MUC1) oncoprotein is overexpressed by diverse human cancers; however, it has remained largely unclear how MUC1 contributes to tumorigenesis. In this issue of Oncogene and in concert with published work, Behrens et al. report that the MUC1 receptor subunit activates genes involved in invasion, angiogenesis and metastasis. PMID- 20711236 TI - Biological reprogramming in acquired resistance to endocrine therapy of breast cancer. AB - Endocrine therapies targeting the proliferative effect of 17beta-estradiol through estrogen receptor alpha (ERalpha) are the most effective systemic treatment of ERalpha-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERalpha. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERalpha transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERalpha were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERalpha-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy. PMID- 20711237 TI - LAPTM4B: a novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling. AB - LAPTM4B (lysosomal protein transmembrane 4 beta) is a newly identified cancer associated gene. Both of its mRNA and the encoded LAPTM4B-35 protein are significantly upregulated with more than 70% frequency in a wide variety of cancers. The LAPTM4B-35 level in cancer is evidenced to be an independent prognostic factor and its upregulation promotes cell proliferation, migration and invasion, as well as tumorigenesis in nude mice. In contrary, knockdown of LAPTM4B-35 expression by RNA interference (RNAi) reverses all of the above malignant phenotypes. We herein reveal a new role of LAPTM4B-35 in promoting multidrug resistance of cancer cells. Upregulation of LAPTM4B-35 motivates multidrug resistance by enhancement of efflux from cancer cells of a variety of chemodrugs with variant structures and properties, including doxorubicin, paclitaxel and cisplatin through colocalization and interaction of LAPTM4B-35 with multidrug resistance (MDR) 1 (P-glycoprotein, P-gp), and also by activation of PI3K/AKT signaling pathway through interaction of PPRP motif contained in the N-terminus of LAPTM4B-35 with the p85alpha regulatory subunit of PI3K. The specific inhibitors of PI3K and knockdown of LAPTM4B-35 expression by RNAi eliminate the multidrug resistance effect motivated by upregulation of LAPTM4B 35. In conclusion, LAPTM4B-35 motivates multidrug resistance of cancer cells by promoting drug efflux through colocalization and interaction with P-gp, and anti apoptosis by activating PI3K/AKT signaling. These findings provide a promising novel strategy for sensitizing chemical therapy of cancers and increasing the chemotherapeutic efficacy through knockdown LAPTM4B-35 expression by RNAi. PMID- 20711238 TI - Trisomy 21 leukemias: finding the hits that matter. AB - Down syndrome is associated with a markedly increased risk of childhood leukemias, and identification of chromosome 21 sequences that have a role in leukemogenesis may provide insights into critical pathways and suggest targets for therapy and prevention. A study in this issue of Oncogene, defines human chromosome 21 sequences that alter hematopoiesis and induce expression of leukemia-associated markers. PMID- 20711239 TI - C-terminal binding protein and poly(ADP)ribose polymerase 1 contribute to repression of the p21(waf1/cip1) promoter. AB - Transcriptional repression by the C-terminal binding protein (CtBP) is proposed to require nicotinamide adenine dinucleotide dehydrogenase (NAD(H). Previous studies have implicated CtBP in transcriptional repression of the p21(waf1/cip1) gene. Similarly, the NAD-dependent poly(adenosine diphosphate)ribose polymerase 1 (PARP1) may affect p21 expression via its NAD-dependent enzymatic activity; we therefore asked if PARP1 and CtBP were functionally linked in regulating p21 transcription. We found that restraint of basal p21 transcription requires both CtBP and PARP1. PARP inhibition attenuated activation of p21 transcription by both p53-independent and p53-dependent processes, in a CtBP-dependent manner. CtBP1+2 or PARP1+2 knockdown partially activated p21 gene expression, suggesting relief of a corepressor function dependent on both proteins. We localized CtBP responsive repression elements to the proximal promoter region, and found ZBRK1 overexpression could also overcome DNA damage-dependent, but not p53-dependent activation through this region. By chromatin immunoprecipitation we find dismissal of CtBP from the proximal promoter following DNA-damage, and that PARP1 associates with a CtBP corepressor complex in nuclear extracts. We propose a model in which both CtBP and PARP functionally interact in a corepressor complex as components of a molecular switch necessary for p21 repression, and following DNA damage signals activation of p21 transcription by corepressor dismissal and co-activator recruitment. PMID- 20711240 TI - p66(Shc) and Ras: controlling anoikis from the inside-out. AB - Protection from detachment-induced cell death, termed anoikis, facilitates metastasis. Though anoikis is largely attributed to the loss of integrin-related 'outside-in' survival signals, Terada and colleagues demonstrate a novel 'inside out' attachment sensing role for the adapter protein p66(Shc) in promoting anoikis and suppressing metastasis via Ras-dependent control of proliferation and survival. PMID- 20711241 TI - Graft source determines human hematopoietic progenitor distribution pattern within the CD34(+) compartment. AB - The CD34(+) compartment of grafts for clinical allogeneic hematopoietic cell transplantation (HCT) is very heterogeneous. It contains hematopoietic stem cells and several different progenitor cell populations. This study assesses (1) the content of these populations in clinical grafts from G-CSF-mobilized PBMCs, BM and cord blood, (2) the functional correlation of the graft composition with time to engraftment of neutrophils, platelets and reticulocytes and (3) donor age related changes. Quantitative flow cytometry showed that the distribution of the progenitor subsets differed significantly between the graft sources and that donor age-related changes occur. In patients after myeloablative allogeneic HCT, accelerated platelet and reticulocyte engraftment correlated with the content of common myeloid and/or megakaryocyte erythroid progenitors in the graft. These findings show that a better understanding of the progenitor compartment in human hematopoietic grafts could lead to improved strategies for the development of cellular therapies, for example in situations where platelet engraftment is delayed. PMID- 20711242 TI - Targeted i.v. BU and fludarabine (t-i.v. BU/Flu) provides effective control of AML in adults with reduced toxicity. AB - Myeloablative doses of BU and fludarabine followed by allogeneic hematopoietic cell transplantation offer effective therapy for AML. We anticipated that pharmacokinetic targeting of i.v. BU to 5300 MUM/L min/day * 4 (targeted i.v. BU and fludarabine (t-i.v. BU/Flu)) would limit nonrelapse mortality (NRM) in adults up to 70 years of age. We assessed the safety and efficacy of t-i.v. BU/Flu in a series of 100 adults (median age 48, range 22-69 years) with AML in the first CR (CR1) with high risk of treatment failure (n=49), second CR (CR2, n=25), relapsed disease (REL, n=9), primary induction failure (PIF, n=16) and untreated (n=1). NRM was 3% at 100 days and 15% at 1 year. The cumulative incidence of relapse was 30.6% for CR1, 41.7% for CR2, 55.6% for REL and 58.6% for PIF. OS for primary AML in CR1 was 66% (95% confidence interval (CI): 46-80%) at 1 year, and 62% (95% CI: 42-77%) at 2 years. On multivariable modeling, remission status, moderate/severe chronic GVHD and day-90 BM chimerism >=90% predicted improved OS. Importantly, there was no effect of age. t-i.v. BU/Flu provides effective disease control with encouraging NRM in patients up to age of 70 years. PMID- 20711244 TI - The challenge of metastatic colorectal cancer. AB - Colorectal cancer (CRC) is a very common disease with a high rate of mortality around the world, representing the second most frequent cause of cancer-related death. As the majority of patients are diagnosed with advanced cancer with a subsequent low five-year survival rate (10%), it is imperative to develop new strategies to treat this challenging patient population. Traditionally, patients received successive lines of chemotherapy and discontinued the treatment or switched to a different one in the event of disease progression. But despite the therapeutic advances achieved with combination chemotherapy regimens, particularly FOLFOX and FOLFIRI, considerable research has been necessary to further optimize chemotherapy for patients with metastatic colorectal cancer (mCRC). However, progress has been achieved over recent years. The most relevant relates to the approval of several new effective therapeutic drugs, such as monoclonal antibodies, which have greatly improved the outcomes for metastatic disease. The last agent approved has been panitumumab, which has been designed to target the epidermal growth factor receptor molecular pathway involved in the appearance and spread of cancer. PMID- 20711243 TI - Low-dose MTX combined with low-dose methylprednisolone as a first-line therapy for the treatment of acute GVHD: safety and feasibility. AB - To study the efficacy and safety of a low dose of MTX combined with a low dose of methylprednisolone (MP) as a first-line therapy in the treatment of acute GVHD (aGVHD) after allogeneic hematopoietic SCT, 32 patients received i.v. MTX at a dose of 10 mg or oral MTX at a dose of 15 mg every 3-7 days (repeated at day 3 after the first dose and then at a weekly interval) combined with a low dose of MP (0.5 mg/kg/day) until a complete or partial response was achieved, or until treatment failure or intolerable side effects occurred. The overall treatment response rate was 81% (26/32 patients) and the response rate at day 28 was 75% (24/32 patients). The response rate for GVHD involving various organs was 88% (23/26) in the skin, 75% (3/4) in the liver and 81% (9/11) in the gut. Grade 3 toxicities occurred in only three patients presenting cytopenias. The estimated survival at 2 years was 77%. From this analysis, MTX in combination with a low dose of MP appears to be a well-tolerated, effective and inexpensive regime when used as a first-line treatment for aGVHD. PMID- 20711245 TI - Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors. AB - THE AGENTS CURRENTLY APPROVED FOR USE IN METASTATIC RENAL CELL CARCINOMA (MRCC) CAN BE DIVIDED BROADLY INTO TWO CATEGORIES: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naive patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein. PMID- 20711246 TI - How much can we learn about missing data?: an exploration of a clinical trial in psychiatry. AB - When a randomized controlled trial has missing outcome data, any analysis is based on untestable assumptions, e.g. that the data are missing at random, or less commonly on other assumptions about the missing data mechanism. Given such assumptions, there is an extensive literature on suitable methods of analysis. However, little is known about what assumptions are appropriate. We use two sources of ancillary data to explore the missing data mechanism in a trial of adherence therapy in patients with schizophrenia: carer-reported (proxy) outcomes and the number of contact attempts. This requires additional assumptions to be made whose plausibility we discuss. Proxy outcomes are found to be unhelpful in this trial because they are insufficiently associated with patient outcome and because the ancillary assumptions are implausible. The number of attempts required to achieve a follow-up interview is helpful and suggests that these data are unlikely to depart far from being missing at random. We also perform sensitivity analyses to departures from missingness at random, based on the investigators' prior beliefs elicited at the start of the trial. Wider use of techniques such as these will help to inform the choice of suitable assumptions for the analysis of randomized controlled trials. PMID- 20711249 TI - Convergent evolution in aquatic tetrapods: insights from an exceptional fossil mosasaur. AB - Mosasaurs (family Mosasauridae) are a diverse group of secondarily aquatic lizards that radiated into marine environments during the Late Cretaceous (98-65 million years ago). For the most part, they have been considered to be simple anguilliform swimmers--i.e., their propulsive force was generated by means of lateral undulations incorporating the greater part of the body--with unremarkable, dorsoventrally narrow tails and long, lizard-like bodies. Convergence with the specialized fusiform body shape and inferred carangiform locomotory style (in which only a portion of the posterior body participates in the thrust-producing flexure) of ichthyosaurs and metriorhynchid crocodyliform reptiles, along with cetaceans, has so far only been recognized in Plotosaurus, the most highly derived member of the Mosasauridae. Here we report on an exceptionally complete specimen (LACM 128319) of the moderately derived genus Platecarpus that preserves soft tissues and anatomical details (e.g., large portions of integument, a partial body outline, putative skin color markings, a downturned tail, branching bronchial tubes, and probable visceral traces) to an extent that has never been seen previously in any mosasaur. Our study demonstrates that a streamlined body plan and crescent-shaped caudal fin were already well established in Platecarpus, a taxon that preceded Plotosaurus by 20 million years. These new data expand our understanding of convergent evolution among marine reptiles, and provide insights into their evolution's tempo and mode. PMID- 20711250 TI - Ambient temperature influences Australian native stingless bee (Trigona carbonaria) preference for warm nectar. AB - The interaction between flowers and insect pollinators is an important aspect of the reproductive mechanisms of many plant species. Several laboratory and field studies indicate that raising flower temperature above ambient can be an advantage in attracting pollinators. Here we demonstrate that this preference for warmer flowers is, in fact, context-dependent. Using an Australian native bee as a model, we demonstrate for the first time a significant shift in behaviour when the ambient temperature reaches 34 degrees C, at which point bees prefer ambient temperature nectar over warmer nectar. We then use thermal imaging techniques to show warmer nectar maintains the flight temperature of bees during the period of rest on flowers at lower ambient temperatures but the behavioural switch is associated with the body temperature rising above that maintained during flight. These findings suggest that flower-pollinator interactions are dependent upon ambient temperature and may therefore alter in different thermal environments. PMID- 20711251 TI - Using DNA methylation patterns to infer tumor ancestry. AB - BACKGROUND: Exactly how human tumors grow is uncertain because serial observations are impractical. One approach to reconstruct the histories of individual human cancers is to analyze the current genomic variation between its cells. The greater the variations, on average, the greater the time since the last clonal evolution cycle ("a molecular clock hypothesis"). Here we analyze passenger DNA methylation patterns from opposite sides of 12 primary human colorectal cancers (CRCs) to evaluate whether the variation (pairwise distances between epialleles) is consistent with a single clonal expansion after transformation. METHODOLOGY/PRINCIPAL FINDINGS: Data from 12 primary CRCs are compared to epigenomic data simulated under a single clonal expansion for a variety of possible growth scenarios. We find that for many different growth rates, a single clonal expansion can explain the population variation in 11 out of 12 CRCs. In eight CRCs, the cells from different glands are all equally distantly related, and cells sampled from the same tumor half appear no more closely related than cells sampled from opposite tumor halves. In these tumors, growth appears consistent with a single "symmetric" clonal expansion. In three CRCs, the variation in epigenetic distances was different between sides, but this asymmetry could be explained by a single clonal expansion with one region of a tumor having undergone more cell division than the other. The variation in one CRC was complex and inconsistent with a simple single clonal expansion. CONCLUSIONS: Rather than a series of clonal expansion after transformation, these results suggest that the epigenetic variation of present-day cancer cells in primary CRCs can almost always be explained by a single clonal expansion. PMID- 20711252 TI - Assessment of a syndromic surveillance system based on morbidity data: results from the Oscour network during a heat wave. AB - BACKGROUND: Syndromic surveillance systems have been developed in recent years and are now increasingly used by stakeholders to quickly answer questions and make important decisions. It is therefore essential to evaluate the quality and utility of such systems. This study was designed to assess a syndromic surveillance system based on emergency departments' (ED) morbidity rates related to the health effects of heat waves. This study uses data collected during the 2006 heat wave in France. METHODS: Data recorded from 15 EDs in the Ile-de-France (Paris and surrounding area) from June to August, 2006, were transmitted daily via the Internet to the French Institute for Public Health Surveillance. Items collected included diagnosis (ICD10), outcome, and age. Several aspects of the system have been evaluated (data quality, cost, flexibility, stability, and performance). Periods of heat wave are considered the most suitable time to evaluate the system. RESULTS: Data quality did not vary significantly during the period. Age, gender and outcome were completed in a comprehensive manner. Diagnoses were missing or uninformative for 37.5% of patients. Stability was recorded as being 99.49% for the period overall. The average cost per day over the study period was estimated to be euro287. Diagnoses of hyperthermia, malaise, dehydration, hyponatremia were correlated with increased temperatures. Malaise was most sensitive in younger and elderly adults but also the less specific. However, overall syndrome groups were more sensitive with comparable specificity than individual diagnoses. CONCLUSION: This system satisfactorily detected the health impact of hot days (observed values were higher than expected on more than 90% of days on which a heat alert was issued). Our findings should reassure stakeholders about the reliability of health impact assessments during or following such an event. These evaluations are essential to establish the validity of the results of syndromic surveillance systems. PMID- 20711253 TI - A detailed phylogenetic analysis of FIV in the United States. AB - BACKGROUND: Feline immunodeficiency virus (FIV) is a lentivirus associated with AIDS-like illnesses in cats and has been used as a model for the study of human immunodeficiency virus (HIV). A feature of HIV and FIV infection is the continually increasing divergence among viral isolates between different individuals, as well as within the same individuals. METHODOLOGY/PRINCIPAL FINDINGS: The goal of this study was to determine the phylogenetic patterns of viral isolates obtained within the United States (U.S.) by focusing on the variable, V3-V4, region of the FIV envelope gene. CONCLUSIONS/SIGNIFICANCE: Data indicate that FIV, from within the U.S., localize to four viral clades, A, B, C, and F. Also shown is the geographic isolation of strains where clade A and clade B are found predominately on the west coast; however, clade B is also found throughout the U.S. and represents the predominant clade. This study presents a complete and conclusive analysis of FIV isolates from within the U.S. and may be used as the essential basis for the development of an effective multi-clade vaccine. PMID- 20711254 TI - Indiscriminate males: mating behaviour of a marine snail compromised by a sexual conflict? AB - BACKGROUND: In promiscuous species, male fitness is expected to increase with repeated matings in an open-ended fashion (thereby increasing number of partners or probability of paternity) whereas female fitness should level out at some optimal number of copulations when direct and indirect benefits still outweigh the costs of courtship and copulation. After this fitness peak, additional copulations would incur female fitness costs and be under opposing selection. Hence, a sexual conflict over mating frequency may evolve in species where females are forced to engage in costly matings. Under such circumstance, if females could avoid male detection, significant fitness benefits from such avoidance strategies would be predicted. METHODOLOGY/PRINCIPAL FINDINGS: Among four Littorina species, one lives at very much higher densities and has a longer mating season than the other three species. Using video records of snail behaviour in a laboratory arena we show that males of the low-density species discriminate among male and female mucous trails, trailing females for copulations. In the high-density species, however, males fail to discriminate between male and female trails, not because males are unable to identify female trails (which we show using heterospecific females), but because females do not, as the other species, add a gender-specific cue to their trail. CONCLUSIONS/SIGNIFICANCE: We conclude that there is likely a sexual conflict over mating frequency in the high-density species (L. saxatilis) owing to females most likely being less sperm-limited in this species. This has favoured the evolution of females that permanently or optionally do not release a cue in the mucus to decrease excessive and costly matings resulting in unusually high frequencies of male-male copulating attempts in the wild. This is one of few examples of masking gender identity to obtain fewer matings. PMID- 20711255 TI - High fidelity--no evidence for extra-pair paternity in Siberian jays (Perisoreus infaustus). AB - Extra-pair paternity (EPP) in birds is related to a number of ecological and social factors. For example, it has been found to be positively related with breeding density, negatively with the amount of paternal care and especially high rates have been observed in group-living species. Siberian jays (Perisoreous infaustus) breed at low densities and have extended parental care, which leads to the expectation of low rates of EPP. On the other hand, Siberian jays live in groups which can include also unrelated individuals, and provide opportunities for extra-pair matings. To assess the potential occurrence of EPP in Siberian jays, we analysed a large data pool (n=1029 offspring) covering ca. 30 years of samples from a Finnish Siberian jay population. Paternities were assigned based on up to 21 polymorphic microsatellite markers with the additional information from field observations. We were unable to find any evidence for occurrence of EPP in this species. Our findings are in line with earlier studies and confirm the generally low rates of EPP in related Corvid species. These results suggest that ecological factors may be more important than social factors (group living) in determining costs and benefits of extra-pair paternity. PMID- 20711256 TI - Formation of complex and unstable chromosomal translocations in yeast. AB - Genome instability, associated with chromosome breakage syndromes and most human cancers, is still poorly understood. In the yeast Saccharomyces cerevisiae, numerous genes with roles in the preservation of genome integrity have been identified. DNA-damage-checkpoint-deficient yeast cells that lack Sgs1, a RecQ like DNA helicase related to the human Bloom's-syndrome-associated helicase BLM, show an increased rate of genome instability, and we have previously shown that they accumulate recurring chromosomal translocations between three similar genes, CAN1, LYP1 and ALP1. Here, the chromosomal location, copy number and sequence similarity of the translocation targets ALP1 and LYP1 were altered to gain insight into the formation of complex translocations. Among 844 clones with chromosomal rearrangements, 93 with various types of simple and complex translocations involving CAN1, LYP1 and ALP1 were identified. Breakpoint sequencing and mapping showed that the formation of complex translocation types is strictly dependent on the location of the initiating DNA break and revealed that complex translocations arise via a combination of interchromosomal translocation and template-switching, as well as from unstable dicentric intermediates. Template-switching occurred between sequences on the same chromosome, but was inhibited if the genes were transferred to different chromosomes. Unstable dicentric translocations continuously gave rise to clones with multiple translocations in various combinations, reminiscent of intratumor heterogeneity in human cancers. Base substitutions and evidence of DNA slippage near rearrangement breakpoints revealed that translocation formation can be accompanied by point mutations, and their presence in different translocation types within the same clone provides evidence that some of the different translocation types are derived from each other rather than being formed de novo. These findings provide insight into eukaryotic genome instability, especially the formation of translocations and the sources of intraclonal heterogeneity, both of which are often associated with human cancers. PMID- 20711257 TI - Sensitivity of the quantiferon-gold in-tube assay in sputum smear positive TB cases in Indonesia. AB - BACKGROUND: As part of a formal evaluation of the Quantiferon-Gold in-tube assay (QFT-IT) for latent TB infection we compared its sensitivity to the tuberculin skin test (TST) in confirmed adult TB cases in Indonesia. Smear-positive TB disease was used as a proxy gold standard for latent TB infection. METHODS AND FINDINGS: We compared the sensitivity of QFT-IT and TST in 98 sputum smear and chest x-ray positive TB cases and investigated risk factors for negative and discordant results in both tests. Both tests showed high sensitivity; (QFT-IT; 88.7%: TST; 94.9%), not significantly different from each other (p value 0.11). Very high sensitivity was seen when tests were combined (98.9%). There were no variables significantly associated with discordant results or with a negative TST. For QFT-IT which particular staff member collected blood was significantly associated with test positivity (p value 0.01). Study limitations include small sample size and lack of culture confirmation or HIV test results. CONCLUSIONS: The QFT-IT has similar sensitivity in Indonesian TB cases as in other locations. However, QFT-IT, like the TST cannot distinguish active TB disease from LTBI. In countries such as Indonesia, with high background rates of LTBI, test specificity for TB disease will likely be low. While our study was not designed to evaluate the QFT-IT in the diagnosis of active TB disease in TB suspects, the data suggest that a combination of TST and QFT-IT may prove useful for ruling out TB disease. Further research is required to explore the clinical role of QFT-IT in combination with other TB diagnostic tests. PMID- 20711258 TI - Variability in avian eggshell colour: a comparative study of museum eggshells. AB - BACKGROUND: The exceptional diversity of coloration found in avian eggshells has long fascinated biologists and inspired a broad range of adaptive hypotheses to explain its evolution. Three main impediments to understanding the variability of eggshell appearance are: (1) the reliable quantification of the variation in eggshell colours; (2) its perception by birds themselves, and (3) its relation to avian phylogeny. Here we use an extensive museum collection to address these problems directly, and to test how diversity in eggshell coloration is distributed among different phylogenetic levels of the class Aves. METHODOLOGY AND RESULTS: Spectrophotometric data on eggshell coloration were collected from a taxonomically representative sample of 251 bird species to determine the change in reflectance across different wavelengths and the taxonomic level where the variation resides. As many hypotheses for the evolution of eggshell coloration assume that egg colours provide a communication signal for an avian receiver, we also modelled reflectance spectra of shell coloration for the avian visual system. We found that a majority of species have eggs with similar background colour (long wavelengths) but that striking differences are just as likely to occur between congeners as between members of different families. The region of greatest variability in eggshell colour among closely related species coincided with the medium-wavelength sensitive region around 500 nm. CONCLUSIONS: The majority of bird species share similar background eggshell colours, while the greatest variability among species aligns with differences along a red-brown to blue axis that most likely corresponds with variation in the presence and concentration of two tetrapyrrole pigments responsible for eggshell coloration. Additionally, our results confirm previous findings of temporal changes in museum collections, and this will be of particular concern for studies testing intraspecific hypotheses relating temporal patterns to adaptation of eggshell colour. We suggest that future studies investigating the phylogenetic association between the composition and concentration of eggshell pigments, and between the evolutionary drivers and functional impacts of eggshell colour variability will be most rewarding. PMID- 20711259 TI - Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis. AB - In this review, I first provide relevant background information about normal epidermal barrier structure and function. I then update recent information about how inherited defects in either filaggrin and/or in the serine protease inhibitor, lymphoepithelial Kazal-type inhibitor 1, converge to stimulate the development of atopic dermatitis (AD). Next I explain the multiple mechanisms whereby a primary barrier abnormality in AD can lead to inflammation. Furthermore, I explore how certain acquired stressors, such as a reduced external humidity, high pH soaps/surfactants, psychological stress, as well as secondary Staphylococcus aureus infections initiate or further aggravate AD. Finally, and most importantly, I compare various therapeutic paradigms for AD, highlighting the risks and benefits of glucocorticoids and immunomodulators vs. corrective, lipid replacement therapy. PMID- 20711260 TI - Enhancement of keratinocyte differentiation by rose absolute oil. AB - BACKGROUND: Through differentiation processes, keratinocytes provide a physical barrier to our bodies and control skin features such as moisturization, wrinkles and pigmentation. Keratinocyte differentiation is disturbed in several skin diseases such as psoriasis and atopic dermatitis. OBJECTIVE: The aim of this study is to evaluate the keratinocyte differentiation-enhancing effect of rose absolute oil (RAO). METHODS: Primary cultured human normal keratinocytes were treated with RAO, and differentiation then checked by the expression of marker genes. RESULTS: RAO did not induce cytotoxicity on cultured keratinocytes at a dose of 10microM. The level of involucrin, an early marker for keratinocyte differentiation, was significantly increased by RAO. Concomitantly, RAO increased involucrin promoter activity, indicating that RAO increased involucrin gene expression at the mRNA level. Furthermore, RAO increased the level of filaggrin in cultured keratinocytes, and in the granular layer of mouse skin. In line with these results, RAO decreased the proliferation of keratinocytes cultured in vitro. When RAO was applied topically on the tape-stripped mouse skins, it accelerated the recovery of disturbed barrier function. CONCLUSION: These results suggest that RAO may be applicable for the control of skin texture and keratinocyte differentiation-related skin diseases. PMID- 20711261 TI - Comparison of Marketed Cosmetic Products Constituents with the Antigens Included in Cosmetic-related Patch Test. AB - BACKGROUND: Currently, cosmetic series (Chemotechnique Diagnostics, Sweden) is the most widely used cosmetic-related patch test in Korea. However, no studies have been conducted on how accurately it reflects the constituents of the cosmetics in Korea. OBJECTIVE: We surveyed the constituents of various cosmetics and compare with the cosmetic series, to investigate whether it is accurate in determining allergic contact dermatitis caused by cosmetics sold in Korea. METHODS: Cosmetics were classified into 11 categories and the survey was conducted on the constituents of 55 cosmetics, with 5 cosmetics in each category. The surveyed constituents were classified by chemical function and compared with the antigens of cosmetic series. RESULTS: 155 constituents were found in 55 cosmetics, and 74 (47.7%) of constituents were included as antigen. Among them, only 20 constituents (27.0%) were included in cosmetic series. A significant number of constituents, such as fragrance, vehicle and surfactant were not included. Only 41.7% of antigens in cosmetic series were found to be in the cosmetics sampled. CONCLUSION: The constituents not included in the patch test but possess antigenicity are widely used in cosmetics. Therefore, the patch test should be modified to reflect ingredients in the marketed products that may stimulate allergies. PMID- 20711262 TI - The Roles of Reactive Oxygen Species Produced by Contact Allergens and Irritants in Monocyte-derived Dendritic Cells. AB - BACKGROUND: Although reactive oxygen species (ROS) have been produced in both mouse bone marrow-derived dendritic cells (DCs) and XS-106 DCs by contact sensitizers and irritants in previous studies, the generation of ROS in human monocyte-derived DCs (MoDCs) and their role in contact hypersensitivity (CHS) has yet to be elucidated. OBJECTIVE: The purpose of this study was to determine whether contact allergens and irritants induce ROS in MoDCs and, if so, to evaluate the role of contact allergen and irritant induced-ROS in MoDCs in CHS. METHODS: Production of ROS was measured by 5-(and-6)-chloromethyl-2',7' dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA) assay. Surface CD86 and HLA DR molecules were detected by flow cytometry. Protein carbonylation was detected by Western blotting. RESULTS: ROS were produced by contact allergens such as dinitrochlorobenzene (DNCB) and thimerosal and the irritant benzalkonium chloride (BKC). DNCB-induced, but not BKC-induced, ROS increased surface CD86 and HLA-DR molecules on MoDCs and induced protein carbonylation. These changes were reduced in the presence of antioxidant N-acetyl cysteine. CONCLUSION: Our results suggest that DNCB-induced ROS may be different from those induced by irritant BKC. The DNCB-induced ROS may be associated with the CHS response, because they activate surface molecules on DCs that are important for generating immune reactions. PMID- 20711263 TI - Erythrocyte malondialdehyde and glutathione levels in vitiligo patients. AB - BACKGROUND: Vitiligo is an acquired and progressive hypomelanotic disease that manifests as circumscribed depigmented patches on the skin. Although the precise mechanism remains to be elucidated, an imbalance of the oxidant/antioxidant system has been proposed as an important etiologic mechanism. OBJECTIVE: The objective of this study was to evaluate the oxidant/antioxidant status of vitiligo patients at the erythrocyte level. METHODS: Fifty-three vitiligo patients and 65 phototype-, age-, and sex-matched healthy controls were included in this study. Blood samples were collected from all subjects, and all patients were instructed to answer a questionnaire. RESULTS: Erythrocyte levels of malondialdehyde (MDA) and glutathione (GSH) were measured. All patients were told to answer a questionnaire regarding their habitual behavior, including frequency of smoking and type of diet. We observed significantly lower levels of GSH in vitiligo patients, but the levels of MDA did not differ between patients and controls. Vitiligo patients who smoked showed significantly lower GSH levels compared to non-smoking patients, but the levels of MDA were unchanged between the 2 groups. CONCLUSION: From our results, we conclude that reduced erythrocytic or systemic GSH levels constitute a distinctive feature in vitiligo patients regardless of disease activity. PMID- 20711264 TI - The Immunohistochemical Patterns of the beta-Catenin Expression in Pilomatricoma. AB - BACKGROUND: Pilomatricoma is a benign follicular tumor that is composed of basaloid cells, transitional cells and shadow cells. beta-Catenin is a 92-kDa protein, and it plays important roles in cell-cell adhesion at the cell membrane and signal transduction in the nucleus. beta-Catenin has recently been shown to play an important role in the formation of hair follicle-related tumors, including pilomatricoma. However, the pattern and the intracellular localization of the beta-Catenin expression are still controversial. OBJECTIVE: We wanted to evaluate the pattern and the intracellular localization of the beta-Catenin expression in pilomatricoma by performing immunohistochemical staining. METHODS: Twenty-seven paraffin-embedded tissue samples that were diagnosed as pilomatricoma were immunohistochemically stained with beta-Catenin antibody. RESULTS: Basaloid cells were found 15 samples of the total 27 pilomatricomas. All (15/15) of the basaloid cells strongly expressed beta-Catenin, but the transitional cells and the shadow cells did not. In the basaloid cells, the nuclei and membranes showed prominent beta-Catenin immunoreactivities, but the cytoplasm showed weak beta-Catenin immunoreactivity. CONCLUSION: This study confirmed that the nucleus and membrane of all the basaloid cells in the pilomatricomas showed a strong beta-Catenin expression, but the transitional cells and shadow cells showed negative beta-Catenin immunoreactivity. PMID- 20711265 TI - Epidermal Hyperplasia and Elevated HB-EGF are More Prominent in Retinoid Dermatitis Compared with Irritant Contact Dermatitis Induced by Benzalkonium Chloride. AB - BACKGROUND: 'Retinoid dermatitis' is a retinoid-induced irritant contact dermatitis (ICD). The mechanism of retinoid dermatitis may be different from that of other ICDs. However, it remains uncertain how topical retinoid induce ICD. OBJECTIVE: We compared several aspects of contact dermatitis induced by topical retinol and benzalkonium chloride (BKC) on hairless mice skin. METHODS: 2% retinol or 2.5% BKC was applied to hairless mice and transepidermal water loss (TEWL), ear thickness, histologic and immunohistochemical findings were compared. We also compared mRNA expression of inflammatory cytokines, epidermal differential markers, cyclooxygenases (COXs) and heparin binding epidermal growth factor like growth factor (HB-EGF). RESULTS: Topical application of 2% retinol and 2.5% BKC increased TEWL and ear thickness in similar intensity. Epidermal hyperplasia was more prominent in retinol treated skin. Proliferating cell nuclear antigen, involucrin and loricrin expression were higher in retinol treated skin than in BKC-treated skin. Filaggrin, however, was more expressed in BKC-treated skin. The mRNA expression of IL-8, TNF-alpha, COX-2, involucrin, loricrin and filaggrin were increased in both retinol- and BKC-treated skin in similar intensity. HB-EGF was more significantly increased in retinol-treated skin. CONCLUSION: Elevated HB-EGF and epidermal hyperplasia are more prominent features of retinoid dermatitis than in BKC-induced ICD. PMID- 20711266 TI - Association between Psoriasis and Cardiovascular Risk Factors in Korean Patients. AB - BACKGROUND: Previous studies have shown a possible association between psoriasis and cardiovascular risk factors. OBJECTIVE: We wanted to study the association between psoriasis and cardiovascular risk factors, including metabolic syndrome. METHODS: We determined the relationship of psoriasis with the cardiovascular risk factors, metabolic syndrome and cardiovascular disease. For the proper level of low-density lipoprotein (LDL) cholesterol, we calculated the proportion of psoriasis patients who needed lifestyle changes or drug therapy. RESULTS: This study included 197 patients with psoriasis and 401 controls. We found a higher prevalence of metabolic syndrome (17.8%, p=0.021), cardiovascular disease (4.6%, p=0.044), hypertension (32.5%, p=0.000) and hyperlipidemia (22.3%, p=0.025) in patients with psoriasis, as compared with that of the controls. To maintain proper LDL levels, 25.3% of the psoriasis patients needed lifestyle changes and 11.7% needed drug therapy. CONCLUSION: Our results demonstrate a possible association between psoriasis and cardiovascular diseases and their risk factors (metabolic syndrome, hypertension and hyperlipidemia) in Korean patients. We also demonstrated that a substantial portion of patients with psoriasis need lifestyle changes and drug therapy to prevent cardiovascular events. Further studies will be necessary to establish the association and causality between psoriasis and the cardiovascular risk factors. PMID- 20711267 TI - Four cases of facial discoid lupus erythematosus successfully treated with topical pimecrolimus or tacrolimus. AB - Discoid lupus erythematosus (DLE), which is a cutaneous form of lupus erythematosus (LE), is generally refractory to a wide range of topical or systemic therapies. Although the main treatment option for DLE is topical steroids, it is often ineffective or likely to produce long-term side effects. New drugs, including tacrolimus and pimecrolimus, have been developed to overcome the adverse effects of steroids and treat the lesions of DLE for a prolonged period. We herein report 4 cases of facial DLE successfully treated with therapeutic adjuvants, topical tacrolimus or pimecrolimus. PMID- 20711268 TI - A case of hydroa vacciniforme. AB - Hydroa vacciniforme (HV) is a rare and chronic pediatric disorder that is characterized by photosensitivity and recurrent vesicles that heal with vacciniforme scarring. The pathogenesis of HV is unknown; no chromosome abnormality has been identified. HV patients have no abnormal laboratory results, so the diagnosis of HV is based on identifying the associated histological findings in a biopsy specimen and using repetitive ultraviolet phototesting to reproduce the characteristic vesicles on a patient's skin. Herein, we present a case of HV in a 7-year-old female who was diagnosed with HV according to histopathology and ultraviolet phototesting. PMID- 20711269 TI - A case of morpheaform sarcoidosis. AB - Sarcoidosis is an idiopathic multisystem disease with various cutaneous presentations, and it is characterized by the presence of non-caseating granulomas in the affected organs. The specific manifestations are papules, plaques, nodules, ulcers and scar. We report here on a variant of sarcoidosis on a 71-year-old woman who showed an indurated plaque on the forearm. Her lesion's appearance was clinically similar to that of a morphea and the appearance of the lesion was unlike the commonly observed manifestations of sarcoidosis. PMID- 20711270 TI - A Case of Tubular Apocrine Adenoma with Syringocystadenoma Papilliferum that Developed in a Nevus Sebaceus. AB - Tubular apocrine adenoma (TAA) is a very rare sweat gland tumor. TAA and syringocystadenoma papilliferum (SCAP) rarely develop together in a nevus sebaceus (NS). Herein, we report on a 40-year-old Korean woman with TAA associated with SCAP that developed in a NS located on the scalp. PMID- 20711271 TI - A case of linear lichen planus pigmentosus. AB - Lichen planus pigmentosus (LPP) is chronic pigmentary disorder that shows diffuse or reticulated hyperpigmented, dark brown macules on the sun-exposed areas such as the face, neck and other flexural folds. Clinically, it is different from classical lichen planus because LPP has a longer clinical course and it manifests with dark brown macules. In case of LPP, involvement of the scalp, nail or mucosal area is rare. The histopathological findings of the lesions show an atrophic epidermis, the presence of melanophages and a vacuolar alteration of the basal cell layer with a sparse lymphohistiocytic lichenoid infiltration. Although there have been a few reports of LPP, there have only 3 cases of linear LPP along the lines of Blaschko in the Korean dermatologic literature. Our patient had lesions on the neck and chin with a linear pattern. In this report, we describe a very rare case of LPP with a linear distribution related to Blaschko's lines on the neck and chin areas. PMID- 20711272 TI - Treatment of oral lichen sclerosus with 1% pimecrolimus cream. AB - Lichen sclerosus is a chronic inflammatory mucocutaneous disorder predominately affecting prepubertal girls and postmenopausal women. Isolated lichen sclerosus affecting the oral mucosa is exceedingly rare, and only 13 patients with biopsy proved isolated oral disease have been reported in the literature. We report on a 7-year-old Korean girl with a well-demarcated 1.2x1.2 cm atrophic white plaque with an erythematous border and focal telangiectasia on the left vermillion lip, extending to the labial mucosa. No other cutaneous surfaces, including genitalia, were involved. An incisional biopsy of the plaque on the lip revealed a patchy lichenoid infiltrate of lymphocytes associated with sclerosis of the papillary dermis and a thinned epidermis consistent with a diagnosis of linear orofacial lichen sclerosus. Treatment with a short course of 1% pimecrolimus cream effectively prevented the progression of this lesion. PMID- 20711273 TI - A case of clear cell eccrine porocarcinoma. AB - Eccrine porocarcinoma (EP) is a rare malignant tumor arising from the intraepidermal eccrine duct. The tumor cells frequently contain glycogen, but prominent clear cell changes in EP are rarely reported. A 78-year-old woman presented with a slightly pruritic, erythematous, verrucous plaque on her left thigh. Histopathological examination revealed intraepidermal tumor cell nests composed of small basaloid cells and duct-like structures lined by periodic acid Schiff (PAS)-positive cuticles. Besides the typical findings of EP, clear cell changes were predominantly observed in the tumor cell aggregations. Herein we report a case of the clear cell variant of EP rarely reported in previous literature. PMID- 20711274 TI - A case of dermatofibroma of the upper lip. AB - Dermatofibroma (DF) is a common benign mesenchymal tumor composed of fibroblastic and histiocytic cells. It occurs anywhere on the body surface but has a propensity for the extremities. To our knowledge, DF arising in the oral cavity, especially on the lip, is quite rare. DFs of the head and neck region have been known to be most often of the cellular type and frequently recur, so a wider initial excision is recommended. Herein we report a case of DF in a 41-year-old female who presented with a deep-seated nodule on her upper lip. PMID- 20711275 TI - A case of polypoid clear cell acanthoma on the nipple. AB - Clear cell acanthoma (CCA) is a rare benign epidermal tumor. It usually presents as a flat nodule or dome-shaped plaque and is often localized on the legs of the elderly. We observed an unusual case of polypoid CCA on the nipple of a 14-year old girl. At present, a few cases of CCA on the nipple area have been reported in the literature. However, CCA presented as a polypoid tumor on the nipple area has been reported very rarely. We herein report the very rare case of polypoid CCA on the nipple and suggest that CCA should be included in the clinical differential diagnosis of polypoid lesions on the nipple. PMID- 20711276 TI - Three cases of primary inoculation tuberculosis as a result of illegal acupuncture. AB - Primary inoculation tuberculosis results from the direct inoculation of Mycobacterium tuberculosis into the skin of a person who has no natural or artificially acquired immunity to the organism. The pathogenesis requires a break in the skin from an abrasion or injury that allows entry of the tubercle bacilli. We report 3 cases of primary inoculation tuberculosis resulting from illegal acupuncture. Three patients over 70 years old presented with erythematous, ulcerative, indurated plaques on the back. Skin lesions had developed at the acupuncture sites 1 or 2 weeks after a session of acupuncture, which was intended to relieve back pain. An unlicensed, non-medically trained person conducted each session. The patients' past medical and family histories were unremarkable. Granulomatous inflammatory infiltration and acid-fast bacilli were observed histologically. M. tuberculosis was identified by mycobacterial culture and polymerase chain reaction. Nine months after the initiation of antituberculosis medication, skin lesions improved, and no evidence of recurrence or other organ involvement was observed at the 1-year follow-up visit. PMID- 20711277 TI - Two cases of idiopathic localized involutional lipoatrophy. AB - Localized involutional lipoatrophy (LIL) is a rare distinctive idiopathic form of localized lipoatrophy. The characteristic features in histopathology of LIL are diminutive fat lobules composed of small adipocyte resembling fetal fat tissue. LIL is not a well-known disorder, there have been only a few reports on LIL in the English literature. We herein report 2 cases of LIL and review the previously published cases. PMID- 20711278 TI - Recalcitrant atopic dermatitis treated with omalizumab. AB - Atopic dermatitis (AD) is a chronic cutaneous inflammatory disease. Various categories of therapeutic medications are used for treating AD. Omalizumab is a monoclonal anti-IgE antibody that binds to IgE molecules at the high-affinity receptor (FcepsilonRI) binding site. Therefore, omalizumab can be used as a potential new systemic treatment agent for recalcitrant AD patients with elevated IgE levels. A 34-year-old man had been treated for AD with several topical and oral agents. However, he was refractory to these therapies and his serum IgE levels were very high. We treated him with omalizumab. After 8 months of the treatment, his symptoms were notably improved and the SCORAD index was decreased. Thus, we report on the first case of recalcitrant AD that was successfully treated with omalizumab in Korea. PMID- 20711280 TI - Angiolymphoid hyperplasia with eosinophilia on the palm. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon dermal angioproliferating tumor, characterized by red to brown papules or nodules on the head and neck, though also occurring in the mouth, trunk, extremities and inguinal area. The palm is a very unusual site for ALHE, and there have been very few cases reported globally thus far. ALHE can be pruritic and painful and histopathologic findings show vascular proliferation with infiltration of eosinophils and lymphocytes in the dermis. Plump endothelial cells protrude into the lumen. We report a case of ALHE occurring at an unusual site, the right palm, in a 62-year-old man, who had suffered from a solitary pinkish-colored, central depressed round hyperkeratotic plaque on his palm for 4 years. On the basis of clinical and histopathologic data, a diagnosis of ALHE was made. To our knowledge, this is the first report of ALHE on the palm in Korean dermatologic literature. PMID- 20711279 TI - A Case of Xanthoma Disseminatum Accentuating over the Eyelids. AB - Xanthoma disseminatum (XD) is a rare, benign non-familial mucocutaneous disorder, which is a subset of non-Langerhans cell histiocytosis. It is characterized by mucocutaneous xanthomas in a disseminated form typically involving the eyelids, trunk, face, and proximal extremities and occurs in flexures and folds such as axillae and the groin. Mucosal involvement of the respiratory or gastrointestinal tracts may lead to hoarseness or intestinal obstruction from a mechanical mass effect. This paper outlines the case of a 47-year-old female with progressive yellow-to-brown confluent nodules and plaques of various sizes on her scalp, face, oral mucosa, neck, shoulder, axillary folds, and perianal area. Xanthomas accentuating over the eyelids and eyelashes led to partial obstruction of her visual field and interfered with blinking. Further, she suffered from xerophthalmia. The presentation of histopathological features including foamy histiocytes, inflammatory cells, and Touton giant cells in conjunction with her clinical findings indicated a diagnosis of XD. Evaluations for extracutaneous involvement including the central nervous system, respiratory tract, gastrointestinal tract, and bone resulted in nonspecific findings. Although she has been treated with surgical excisions, CO(2) laser therapy, and oral prednisolone, new lesions are still emerging. PMID- 20711281 TI - Chromoblastomycosis Caused by Phialophora richardsiae. AB - Chromoblastomycosis is a chronic fungal disease of the skin and subcutaneous tissues caused by a group of dematiaceous (black) fungi. The most common etiologic agents are Fonsecaea pedrosoi and Cladophialophora carrionii, both of which can be isolated from plant debris. The infection usually follows traumatic inoculation by a penetrating thorn or splinter wound. Several months after the injury, painless papules or nodules appear on the affected area; these papules then progress to scaly and verrucose plaques. We report a case of chromoblastomycosis caused by Phialophora richardsiae, which has been rarely associated with chromoblastomycosis. The case involved a 43-year-old male, who for the past 2 months had noted an erythematous, pustulous plaque that was somewhat dark brown in color on his right shin; the plaque also had intermittent purulent discharge and crust formation. On histopathological examination, chronic granulomatous inflammation and sclerotic cells were seen. The tissue fungus culture grew out the typical black fungi of P. richardsiae, which was confirmed by polymerase chain reaction. The patient has been treated with a combination of terbinafine and itraconazole for 3 months with a good clinical response. PMID- 20711282 TI - Syringomas Treated by Intralesional Insulated Needles without Epidermal Damage. AB - Syringoma is a benign adnexal tumor derived from intradermal eccrine ducts; it predominantly occurs in women at puberty or later in life. Although syringoma is a common benign neoplasm, there have been no effective therapies for its removal. Conventional therapies for syringomas, including surgical excision, electrodessication, chemical peeling, topical atropine or tretinoin, cryosurgery, and laser therapy, can lead to cosmetic defects such as hyperpigmentation or scarring due to epidermal damage. In contrast, treatment using intralesional insulated needles, which are insulated at the point of epidermal contact, has been shown to result in good cosmetic outcomes due to selective destruction of dermal lesions. This could be an effective and highly satisfying treatment for syringomas. We herein present 2 patients with syringomas treated with intralesional insulated needles. PMID- 20711283 TI - Cutaneous malignant melanoma associated with papillary thyroid cancer. AB - As the survival from cutaneous malignant melanoma and its clinical concerns have been steadily increasing, the possibility has been raised of an increased risk of second primary cancers in the patients with malignant melanoma. Especially, recent studies have identified an association between cutaneous malignant melanoma and thyroid carcinoma. We here report on a case of cutaneous malignant melanoma that developed in a 61-year-old female patient who had hypothyroidism caused by papillary thyroid carcinoma. We suggest that the individuals who have cutaneous malignant melanoma may be predisposed to other primary cancers and especially thyroid carcinoma. Continuous monitoring of the thyroid function in melanoma patients is required because hypothyroidism can worsen due to malignant melanoma and this is probably associated with thyroid carcinoma. PMID- 20711284 TI - Regional cooperation for mental health in South Asia: Opportunities and challenges. PMID- 20711285 TI - Psychological autopsy of suicide-a cross-sectional study. AB - BACKGROUND: Psychological autopsy is the reconstruction of events leading to death. There are few studies on psychological autopsy. AIM: To understand the profile of suicide completers and find out ways of dealing with it. METHODS: Fifty suicide cases were analysed. Using a semi-structured, self-designed questionnaire, the family, friends and relatives of the deceased were interviewed. RESULTS: The presence of some type of psychiatric disorder and stressful life events are two important reasons for committing suicide. CONCLUSION: Psychological autopsy is a very important tool for assessing the causes and precipitants of suicide. More and more studies in this field are required with a larger sample size for the evaluation of suicides. PMID- 20711286 TI - Suicidal behaviour among terminally ill cancer patients in India. AB - BACKGROUND: Passive suicidal thoughts are relatively common in patients with terminal cancer. There is a need for more information about the factors that influence these patients to desire death. AIM: To examine the prevalence of suicidal ideation among terminally ill cancer patients. METHODS: Fifty-four terminally ill inpatients (27 men and 27 women) from the palliative care unit of the Oncology department of Kasturba Hospital, Manipal were evaluated on various rating scales for depression, hopelessness and suicidal ideation, and the correlation of suicidal ideation with medical symptoms such as pain, as well as awareness of the diagnosis and understanding of the illness. RESULTS: Most patients (79.7%) denied having suicidal thoughts or wishing for an early death; only 9.2% had severe suicidal ideation. Two patients (3.8%) with severe suicidal ideation had a past history of major depression. Factors such as the presence of pain, awareness of the diagnosis and understanding of the illness contributed to depressive mood states. CONCLUSION: Suicidal ideation and a desire for death appear to be linked exclusively to the presence of a mental disorder. In addition, poor pain control, and awareness of the diagnosis may also contribute to suicidal ideation. PMID- 20711287 TI - Comparison of the efficacy and safety of moclobemide and imipramine in the treatment of depression in Indian patients. AB - BACKGROUND: Moclobemide, a benzamide, is one of the new-generation monoamine oxidase-A inhibitors (MAO-AIs) which belongs to the class of reversible inhibitors of monoamine oxidase (RIMA). Numerous studies have shown that moclobemide is well-tolerated and as effective as other antidepressants. So far, there is no evidence available regarding its efficacy and tolerability in India. AIM: To compare the efficacy and safety of moclobemide with that of imipramine, a tricyclic antidepressant, in the treatment of major depressive disorder. METHODS: In this prospective study, patients (n=60) were randomly assigned to treatment with moclobemide or imipramine for 6 weeks. Efficacy of the drugs was assessed by observing the mean change in scores on the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Depression Scale (MADRS). RESULTS: Both the groups showed significant decrease in scores at the end of 6 weeks. Patients who received moclobemide had a better side-effect profile. CONCLUSION: Moclobemide is an effective antidepressant and is better tolerated than imipramine. PMID- 20711288 TI - Efficacy and safety of citalopram versus amitriptyline in the treatment of major depression. AB - BACKGROUND: Double-blind clinical trials comparing citalopram with amitriptyline or other tricyclic antidepressants are lacking in India. AIM: To evaluate the efficacy and safety of the newer antidepressant citalopram in the treatment of major depression. METHODS: The clinical acceptability and safety profile of citalopram was assessed and compared with that of amitriptyline in 40 patients in an outpatient set-up. Patients aged 18 to 65 years who fulfilled the diagnostic criteria for a single or recurrent major depressive disorder (as defined by DSM IV) for a minimum of 2 weeks were enrolled. Patient assessment was done at screening, baseline, end of week 1, week 2, week 3, week 4, week 5 and week 6 for efficacy and safety parameters such as Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI) Scale, adverse event follow up, blood pressure and pulse. Three-level statistical analysis including ANOVA was performed on all efficacy measures. RESULTS: On the HDRS the percentage reduction in the mean score for the citalopram group (Group 1) was 72.12%, while that for the amitriptyline group (Group 2) was 67.93%. On the CGI-Improvement Scale, the percentage reduction at the end of the study for the citalopram group was 56.79% while in the amitriptyline group it was 44.70%. Twenty per cent of patients in Group 1 reported adverse events compared to 75% in Group 2. CONCLUSIONS: Citalopram is effective in the treatment of major depression at the dosages range of 20-60 mg/day and its efficacy is equivalent to that of standard tricyclic antidepressants such as amitriptyline, with a substantially better tolerability profile. PMID- 20711290 TI - Cognitive decline in elderly medical and surgical inpatients. AB - BACKGROUND: Impairment in cognitive function increases with age. AIM: To study the prevalence of cognitive decline in inpatients >/=60 years of age. METHODS: One hundred and thirty patients (85 men and 45 women), admitted to a community general hospital for medical or surgical treatment, were selected. The Mini Mental State Examination (MMSE) was used to identify subjects with cognitive dysfunction. Patients were categorized as having cognitive decline or normal cognition. The Global Rating of Memory Decline (GRMD) and Global Rating of Intellectual Decline (GRID) scales were used to assess the decline in memory, thinking and reasoning ability. RESULTS: Cognitive decline was diagnosed in 54 subjects (41.5%). Significantly more patients >/=70 years of age had cognitive decline compared to patients /=70 years of age with an acute medical problem are the most likely to have cognitive problems. PMID- 20711289 TI - Life skills profile of patients with schizophrenia and its correlation to a feeling of rejection among key family carers. AB - BACKGROUND: The behaviour of patients with schizophrenia is of great concern to key family carers. Life skills profile (LSP) is the measure that has considerable importance in assessing the functioning of people with schizophrenia in the community. AIM: To assess the sociodemographic correlates of LSP, and to find the correlation between LSP and the rejection response of key family carers. METHODS: The LSP of 48 patients with chronic schizophrenia (29 men and 19 women) was assessed. The rejection responses of key family carers (28 men and 20 women) were evaluated using the Patient Rejection Scale. RESULTS: The LSP did not significantly differ on the variables of gender, income level or attendance of day-care centre. However, there were differences between patients from urban and rural areas. A new dimension of family harmony, added as a subscale to LSP, also did not show any significant difference on the above variables. The rejection responses of key family carers were found to be significantly related to the LSP of the patients and, among the subscales, family harmony and communication were positively related to rejection. CONCLUSION: Though family interventions have been found to have positive implications on relapse and social functioning of patients with schizophrenia, a model of a family intervention programme for families of patients with schizophrenia needs to be developed. PMID- 20711291 TI - Effectiveness of clozapine in treatment-resistant schizophrenia. AB - BACKGROUND: Clozapine has been shown to be superior to chlorpromazine in improving the positive and negative symptoms of schizophrenia. However, technical experience with clozapine in Indian patients has not been documented. AIM: To assess the improvement in psychopathology of treatment-resistant schizophrenia with clozapine therapy and to study the relationship between sociodemographic and various psychopathology variables among patients with treatment-resistant schizophrenia. METHODS: Twenty-two patients with treatment-resistant schizophrenia were evaluated using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, Calgary Depression Scale, Global Assessment of Functioning (GAF) Scale and Abnormal Involuntary Movement Scale (AIMS). These scales were used to determine the level of psychopathology, depression, overall functioning and severity of abnormal involuntary movements in the patients. The patients were admitted to the hospital for a short time to initiate clozapine therapy. At discharge, patients were stabilized on 300-400 mg/day of clozapine. The patients were re-evaluated after 20 months. RESULTS: The study group showed better global functioning after clozapine therapy. The therapy was well-tolerated though moderate side-effects were seen. Suicidal thoughts declined with clozapine therapy. There was a significant reduction in the negative symptom and general psychopathology scores of PANSS. CONCLUSION: Clozapine has therapeutic efficacy in some but not all treatment-resistant patients with schizophrenia. PMID- 20711292 TI - An epidemic of mass hysteria in a village in West Bengal. AB - This is a report of an outbreak of mass hysteria, attributed to an unknown infectious disease, in a small village near Baruipur, South 24 Parganas district of West Bengal. The epidemic was triggered following the death of 2 persons of the same family on the same day. Thereafter, several other family members and villagers became ill and complained of similar symptoms. They were hospitalized for observation and all were discharged after a couple of days. We report the detailed sequence of events and the management of this mini epidemic. PMID- 20711293 TI - Comparison of three instruments used in the assessment of dementia in Sri Lanka. AB - BACKGROUND: Dementia is poorly recognized even by physicians. This study compares three instruments used to assess dementia in a community setting in Sri Lanka. METHOD: Translated and culturally adapted versions of the Mini Mental State Examination (MMSE), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and Clinical Dementia Rating (CDR) were administered to 363 individuals selected by stratified random sampling in a periurban community in Sri Lanka. The results on the three instruments were compared with the independent psychiatric evaluation done on a concentrated sample of 37 individuals from the study population. RESULTS: Culturally adapted MMSE, IQCODE and CDR can be used to screen dementia in Sri Lanka. IQCODE is the best among the three instruments with a sensitivity of 71.4% and a specificity of 82.6% when 3.5 is the cut-off. In addition, IQCODE is culturally acceptable, easy to administer and can be used in those with a low level of literacy as well as in those with hearing or visual impairment. CONCLUSION: IQCODE was found to be more effective and culturally acceptable as a screening tool for dementia in Sri Lanka, compared with MMSE and CDR. PMID- 20711294 TI - Sleep disorders in children with attention-deficit hyperactivity disorder. AB - BACKGROUND: Sleep disturbances are frequently associated with attention-deficit hyperactivity disorder (ADHD) though they are not included in the current classification systems such as the DSM-IV and ICD-10. These problems may complicate the course of the illness as they may be associated with the treatment given AIM: To evaluate children with ADHD for sleep-related problems. METHODS: The study group comprised 32 children with ADHD and their 20 healthy siblings made up the control group. Sleep-related problems were assessed on a checklist prepared on the basis of the Children Sleep Questionnaire-parent version. RESULTS: A majority of the children with ADHD had at least one sleep-related problem. Comparison with healthy siblings revealed non-significant differences on the parameters of sleep-related movement disorders and parasomnias. CONCLUSION: There is a need for more detailed studies involving sensitive parameters. PMID- 20711295 TI - Rett syndrome. AB - Rett syndrome is a rare, progressive, neurodevelopmental disorder that has been reported only in the girl child. We describe the case of a 6.9-year-old girl with Rett syndrome. She had normal development till the age of 2 years. However, over the next 4-5 months, she lost her acquired, purposeful hand skills; expressive and receptive language; and reciprocal social interaction; and gradually developed a broad-based gait and typical midline stereotyped hand movements (mouthing, rubbing). PMID- 20711296 TI - Syndrome of inappropriate ADH secretion (SIADH) associated with citalopram use. AB - Selective serotonin reuptake inhibitors (SSRIs) can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH is associated with hyponatraemia without oedema. We report the case of a patient who developed acute onset hyponatraemia that progressed rapidly to serious neurological dysfunction shortly after the introduction of citalopram. All SSRIs including citalopram should be used with care in the elderly. The water and electrolyte balance should be monitored carefully during SSRI therapy. PMID- 20711297 TI - Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TEN) overlap associated with carbamazepine use. AB - A benign pruritic rash occurs in 10%-15% of persons treated with carbamazepine. A small fraction of them may experience life-threatening dermatological syndromes such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The case of an 18-year-old female suffering from bipolar affective disorder (mania) who was being treated with carbamazepine, lithium, chlorpromazine and benzhexol is presented. After 10 days of treatment, she developed high-grade fever and mucocutaneous manifestations of SJS-TEN overlap. She was treated in hospital with systemic corticosteroids, antibiotics, intravenous fluids and other supportive measures, and recovered after 3 weeks. PMID- 20711298 TI - Treatment-refractory, juvenile-onset bipolar affective disorder. AB - A case of juvenile-onset bipolar affective disorder with a childhood history of attention-deficit hyperactivity disorder (ADHD) is presented. As the patient was refractory to treatment with mood stabilizers, clozapine was given, which succeeded in achieving remission. The disorder's natural history needs further study. Data also need to be collected for optimal pharmacotherapeutic guidance. PMID- 20711299 TI - Historicizing Indian psychiatry. AB - Our historical endeavour to map Indian psychiatry has largely remained linear, positivistic and evolutionary. Whether it starts from the ancient times or modern, it shows our past as a tale of victory for the western science, without questioning the borrowed paradigm. The use of historical methods for serious enquiry of psychiatry has been ignored. Emergence of a new genre of historicism that is critical of both colonialism and psychiatry as a universal science, has raised hopes to critically review the emergence of psychiatric knowledge. PMID- 20711300 TI - Reboxetine-induced urinary hesitancy. PMID- 20711302 TI - Antipsychiatry: Meeting the challenge. PMID- 20711301 TI - Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice. AB - Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5 methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3 yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co cultures prepared from WT (wild-type) mice. This protection was lost if the co cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN. PMID- 20711303 TI - Parental deprivation due to death in male soldiers with psychiatric disorders. AB - BACKGROUND: The importance of early relationship with parents has been stressed by most personality theorists. Deprivation of the nurturing influence can lead to an adverse impact. AIM: To study the effect of early parental loss in the development of adult psychiatric disorder. METHODS: A total of 289 soldiers suffering from assorted ICD-10 identified psychiatric disorders were studied to ascertain parental losses during their developmental period. The findings were compared with those of 127 patients drawn from general medical wards. RESULTS: A higher percentage of psychiatric patients had lost their parents before the age of 18 years compared with medical patients (21.5% vs. 8.7%). The difference, which was highly significant, was due to bipolar disorder to some extent and alcohol dependence syndrome to a larger extent. Loss of the father appears to be more significant than loss of the mother. Parental loss is found to be not a significant factor in depression and neurotic disorders. There is no excess of maternal loss in cases of depression. CONCLUSION: This study indicates that parental loss is a significant factor in the future development of psychiatric disorders. It does not appear to be an important factor in the development of neurotic disorders. The aspect requires comprehensive evaluation. PMID- 20711304 TI - Tobacco and alcohol use in rural elderly Indian population. AB - BACKGROUND: Tobacco and alcohol use are serious health problems. Studies focusing on problems associated with tobacco and alcohol use in the elderly are limited. AIM: To find out the prevalence of tobacco and alcohol use among rural elderly population. METHODS: This cross-sectional study was conducted in the intensive field practice area of the Comprehensive Rural Health Services Project in Ballabgarh in Faridabad, Haryana, a rural field practice area of the Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi. The sample was selected using stratified random cluster sampling. The participants were >/=60 years of age at the time of interview. Data on tobacco and alcohol use pattern of 1117 elderly were collected during the interview. RESULTS: The prevalence of smoking was 71.8% in men (n=490) and 41.4% in women (n=497). Among men smokers, 41.5% were light smokers (20 beedis/day). Among women smokers, 71.8% were light smokers, 23.8% were moderate smokers and 4.4% were heavy smokers. Regular alcohol intake was seen in 16.3% of the men compared with 0.8% of the women. CONCLUSION: The finding of a high prevalence of smoking and alcohol consumption among men in this rural population of India is of serious concern and therefore needs remedial measures. PMID- 20711305 TI - A comparative study of coping skills and body image: Mastectomized vs. lumpectomized patients with breast carcinoma. AB - BACKGROUND: The diagnosis of breast cancer encompasses not only physical, but also social and psychological implications because of the importance of the breast in a woman's body image, sexuality and motherhood. Women may experience a range of concerns and fears including physical appearance and disfigurement, the uncertainty about recurrence and the fear of death. There are no Indian studies on this subject. AIM: This study explores the various concerns of mastectomized and lumpectomized (breast conserved) patients, determines the coping mechanisms employed and the resolution of concerns. The levels of anxiety and depression in both groups were also studied. METHODS: Seventy-five patients with breast carcinoma (50 mastectomized and 25 lumpectomized) were evaluated. The concern and coping checklist of Devlen was used. The severity of anxiety and depression was measured using the Hospital Anxiety and Depression Scale (HADS). RESULTS: Body image or disfigurement was a concern only in the mastectomized group. Concerns were equally resolved between the two groups except for sexual role and performance, wherein the concern was resolved to a lesser extent in the mastectomized group. Coping strategies employed were effective in the resolution of concerns except for sexual role and performance, and recurrence or relapse. No statistically significant difference was found in the depression and anxiety levels of the two groups. CONCLUSION: Concern regarding sexual role and performance was resolved to a lesser extent in the mastectomized group. Specific psychological intervention is necessary to enhance coping strategies with regard to concerns of body image, and sexual role and performance. PMID- 20711307 TI - Perspective from a general hospital psychiatric unit. PMID- 20711306 TI - Overview and emerging trends. PMID- 20711308 TI - Perspective from an NGO. PMID- 20711309 TI - A community-based perspective. PMID- 20711310 TI - Family education in schizophrenia: A comparison of two approaches. AB - BACKGROUND: Family education programme (FEP) for families of persons with schizophrenia is practised in several centres as a part of patient-and family related services. AIM: This paper describes two models of FEP conducted at the Schizophrenia Research Foundation (SCARF), Chennai. METHODS: The first programme was a part of a research study and was structured utilizing standard evaluation instruments. The second was flexible and tailored to the needs of the family members. RESULTS: After the first programme, the psychopathology of patients and the burden of caregiving on primary caregivers did not show any significant difference but there was a significant gain in caregivers' knowledge with information and experience sharing. Most families seemed to prefer the second programme, which recorded better attendance and participation. CONCLUSION: Informal educational sessions with periodic 'across-the-table' re-inforcers may be more effective and practical in the Indian setting. PMID- 20711311 TI - Psychiatric co-morbidity among alcohol dependants. AB - BACKGROUND: Psychiatric disorders are common in alcoholics and such patients have a poorer prognosis. AIM: To determine the prevalence of psychiatric co-morbidity among alcohol-dependent subjects and to compare the prevalence of specific psychiatric disorders between them and a control group. METHODS: The study assessed the prevalence of psychiatric co-morbidity in 100 alcohol-dependent subjects and 100 controls. A semi-structured proforma was used to record the sociodemographic variables and the history of alcohol abuse. Statistical analysis was done using the chi-square test. RESULTS: The prevalence rate of psychiatric co-morbidity in alcohol-dependent subjects and controls was found to be 92% and 12%, respectively. The most common disorders were depression, antisocial personality disorder (ASPD) and phobia. There was a significant difference in the prevalence of psychiatric co-morbidity between alcohol-dependent subjects and controls. CONCLUSION: The findings indicate the need for an active consultation service for better insight into the prevention, treatment and outcome of alcohol dependence. PMID- 20711312 TI - Suicidal ideation and attempts in patients with major depression: Sociodemographic and clinical variables. AB - BACKGROUND: There is a high risk of suicidal attempt in patients with depression. This risk varies according to the sociodemographic status and clinical presentation. AIM: To assess the prevalence of suicidal ideation and attempt in patients with major depressive disorder, and to find the correlation between the two. METHODS: Sixty patients with major depressive disorder having suicidal ideation were recruited in the study. Of these, 10 had a history of suicidal attempt made in the past or current episode. Sociodemographic details were evaluated and the Hamilton Rating Scale for Depression (HAM-D) was administered. RESULTS: Analysis of the data showed that the incidence of suicidal attempt was 16.6% in patients with suicidal ideation. Statistically, a higher risk of suicidal attempt was found in individuals <30 years of age. Single men, married women and students were more likely to attempt suicide; higher education was also a vulnerability factor. Attempters scored significantly higher in severity of suicidal ideation, agitation and paranoid symptoms whereas among non-attempters, hypochondriasis and general somatic symptoms were more often present. CONCLUSION: All patients expressing suicidal ideation do not attempt suicide. Young patients with depression, especially unmarried men, married women and students, having severe suicidal ideation with agitation or paranoid symptoms are more likely to attempt suicide. PMID- 20711314 TI - Dermatitis artefacta. AB - Dermatitis artefacta, also known as factitious dermatitis, is a condition in which cutaneous lesions are self-inflicted and are the result or manifestation of some psychological conflicts. This report presents the case of a 20-year-old man, whose initial presentation resembled a dermatological disorder. Psychological and personality factors as well as issues in the management are discussed. PMID- 20711313 TI - Psychological symptoms in women in a primary care setting in Tamil Nadu. AB - BACKGROUND: Common mental disorders, especially depression, are likely to increase as a result of globalization and industrialization and it is likely that the resultant burden of care will increase proportionately. Women have a higher prevalence of depression and also carry the burden of caring for the affected individuals. AIM: To study the psychological symptoms with possible common mental disorders in a primary care setting. METHODS: One hundred two women of Tamil ethnicity were approached to take part in answering the Self-Report Questionnaire (SRQ). The mean age of cases and non-cases were 39 years and 33 years, respectively. RESULTS: Nearly three-fifths scored above the cut-off point. Age, physical illness and chronic pain were found to be important factors in the genesis of depression in particular. CONCLUSION: These findings have major implications for any preventative or intervention strategies. PMID- 20711315 TI - Management of trichotillomania. AB - Hallopeau, a French dermatologist, coined the term trichotillomania (TM) to describe alopecia (baldness) caused by self-traction of the hair, but the term now encompasses the entire syndrome of pathological hair-pulling. It is a disorder of impulse control. The authors present three (adult and child) cases of TM managed successfully using a combination of pharmacotherapy and a package of behaviour therapy. Some psychopathological aspects of the disorder are also discussed. PMID- 20711316 TI - Isolated sleep paralysis. AB - Sleep paralysis (SP) is a cardinal symptom of narcolepsy. However, little is available in the literature about isolated sleep paralysis. This report discusses the case of a patient with isolated sleep paralysis who progressed from mild to severe SP over 8 years. He also restarted drinking alcohol to be able to fall asleep and allay his anxiety symptoms. The patient was taught relaxation techniques and he showed complete remission of the symptoms of SP on follow up after 8 months. PMID- 20711317 TI - Effectiveness of fluoxetine in the treatment of skin-picking. AB - The case of an 18-year-old girl with skin-picking is reported. The patient used to pick at healthy skin and small skin lesions, leading to ulceration, hyperpigmentation and disfigurement. She recovered almost fully with fluoxetine. The implications of diagnosis and the need for early treatment are discussed. PMID- 20711318 TI - Psychotropic drug utilization pattern among patients with schizophrenia. PMID- 20711319 TI - Combination of ECT and clozapine in drug-resistant schizophrenia. PMID- 20711320 TI - Experience of depression: Need for support. PMID- 20711321 TI - An eight-week, open-label, prospective case series of acamprosate calcium as monotherapy for patients with comorbid anxiety symptoms and alcohol misuse: an evaluation for alcohol sobriety and anxiolysis. PMID- 20711322 TI - "Dearth of an axis...". PMID- 20711323 TI - Electroconvulsive therapy in a schizophrenic patient with neuroleptic malignant syndrome and pulmonary embolism: a case report. PMID- 20711325 TI - Psychiatric Evaluations of Asylum Seekers: Is it Ethical Practice or Advocacy? PMID- 20711324 TI - Strattera: ups, downs, and emerging uses. AB - Although overall prescribing of atomoxetine hydrochloride (HCI) (Strattera) continues to decline, recent anecdotal reports suggest emerging uses of the product in combination therapy. In this article we examine trends in atomoxetine (HCI) prescribing as well as use in combination with other psychotropic classes. An expert commentary is provided on the data. PMID- 20711326 TI - Increased suicidality in mania complicated by alcoholism. AB - Objective. This retrospective study was done to assess the impact of concurrent alcohol use on the illness presentation of patients hospitalized for mania.Design. Retrospective demographic and clinical data were systematically collected from the hospital records of 122 patients hospitalized for an index episode of mania between 1988 and 1995. Comorbid alcoholism was defined as alcohol abuse/dependence, based on DSM-IV criteria. Blind to alcohol use and treatment intervention, a retrospective clinical assessment of illness severity was made by the Clinical Global Impression (CGI) at the end point of hospital discharge. Demographic and clinical differences between the alcoholic and nonalcoholic manic subjects were analyzed by chi-square and independent t-tests. Survival analyses with hospital length of stay as the dependent variable were conducted on the two groups.Setting. Tertiary care university hospital.Participants. Patients with bipolar disorder hospitalized for mania.Measurements. Clinical Global Impression (CGI), clinical variables (suicidality, polysubstance abuse, hospital length of stay).Results. Alcoholic manic and nonalcoholic manic patients differed significantly in two categorical measures: suicidality on admission (36.7 vs. 18.5%) and current polysubstance abuse/dependence (46.6 vs. 7.6%). There was no significant difference in length of hospitalization between the two groups.Conclusions. The results of this study are consistent with previous studies that have found an association between alcoholism and increased suicidality and polysubstance abuse in bipolar disorder. PMID- 20711327 TI - Borderline personality and the pain paradox. AB - Clinical observations and empirical studies indicate that patients with borderline personality are both sensitive and insensitive to pain. This dichotomy may be explained by the context of the pain. For acute self-induced pain, borderline patients seem to experience attenuated pain responses. For chronic endogenous pain, borderline patients appear pain intolerant. In this paper, we explain this unusual paradox. We then discuss the psychiatric assessment of chronic pain, emphasizing the importance of initially determining the patient's status with regard to borderline personality disorder. For those chronic pain patients who have comorbid borderline personality disorder, we recommend a specific pain-management strategy that addresses the self-regulation difficulties of these patients and minimizes the risks of treatment. PMID- 20711328 TI - Recognizing and managing erotic and eroticized transferences. AB - Transference has been proposed as a critical concept in psychotherapy. The transference may be positive, negative, or sexualized. When the transference becomes sexualized, there are potentially damaging outcomes depending on the management of the transference. This paper addresses the significance of early experiences in residency training with sexualized transference and focuses on the therapeutic relationship in which the transference has become eroticized. The author will explore the potential benefits and challenges of properly managing such transference. PMID- 20711329 TI - Neuroscience and psychoanalysis: approaches to consciousness and thinking. AB - There exists an enormous amount of biological and scientific data in the field of neuroscience, which are daunting and laborious to those who are not directly engaged in these specialized areas. The intricacies and complexities of the role of the central nervous system (CNS) in psychiatric disorders and human behavior are, of course, acknowledged. In this article, observations and speculations of some prominent workers in the field of neuroscience are described with focus on their conclusions, rather than specific findings as they pertain to the mind-body relationship. The mind-brain/body issue has not been resolved insofar as clarifying the connections between CNS activity and thinking is concerned. Currently, it is useful to accept the concept of parallelism between CNS activity and thought. An argument will be made for the inclusion of the psychoanalytic method as an essential component of the scientific effort to elucidate consciousness and thinking. PMID- 20711330 TI - Will improving cognition change functional outcomes in schizophrenia? PMID- 20711331 TI - Psychiatric Evaluations of Asylum Seekers: It's Both Ethical Practice and Advocacy, and That's OK! PMID- 20711332 TI - Emsam: the first year. AB - We investigated the use of EMSAM in the first year post-launch in the US-April of 2006 through March of 2007. According to our data, EMSAM represents <0.1 percent of total prescriptions for antidepressants in the US and is prescribed most often by psychiatrists (83%of prescriptions). The impact of the product on the MAO inhibitor class, however, has been significant. We found that EMSAM now represents 30 percent of all MAO inhibitor use and has been a catalyst for growth in the overall MAO inhibitor class. An expert commentary is provided on the data. PMID- 20711333 TI - Enhancing medication adherence: in older adults with bipolar disorder. AB - OBJECTIVE: The number of older adults with bipolar disorder is increasing, yet little is known about the optimal clinical management of these patients. Medication adherence is a vital to effective long-term treatment of these patients; thus enhancement of adherence is often an important clinical goal. DESIGN: We reviewed available evidence about the characteristics of later-life bipolar disorder along with behavioral and organizational strategies to enhance adherence in this population. RESULTS: Based on available data, cognitive impairment, medical comorbidity, and functional limitations are frequent and are likely to impact treatment adherence in this population. In terms of treatment, there have been no placebo-controlled randomized clinical trials of medications or psychosocial interventions for this population. Based on extrapolation from intervention research on younger adults with bipolar disorder and older adults with other chronic illness, psychosocial interventions that reduce effortful cognitive processing in managing medications and reduce organizational barriers to adherence may be beneficial in enhancing adherence in this population. CONCLUSIONS: Much more research needs to be done to understand the impact of aging on bipolar disorder, along with optimization of treatment. Interventions to enhance adherence in this population need to be adapted to fit with the unique needs of older adults with bipolar disorder. PMID- 20711335 TI - Delayed reaction to trauma in an aging woman. AB - Events of later life may awaken long-suppressed memories and feelings and yield emotional or behavioral problems that are evidence of an early traumatic experience. It is believed that posttraumatic stress disorder (PTSD)-like symptoms are more prevalent in the younger general population, but the lack of data supporting PTSD in the elderly may be due to the complicated presentation. The elderly often present to psychotherapy with comorbid diagnoses and may underreport their symptoms, or the symptoms may be masked by other diagnoses. PTSD is associated with increased rates of major depressive disorder, substance related disorders, panic disorder, agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder, social phobia, specific phobia, and bipolar disorder. Most of the literature on PTSD in the elderly stems from research on Holocaust or World War II survivors. In this paper, we will explore this particular dimension of late-life onset mental disorder with attention to the relevance of old trauma in performing psychodynamic psychotherapy. PMID- 20711334 TI - Efficacy and tolerability of duloxetine treatment in elderly patients with major depressive disorder and concurrent anxiety symptoms. AB - OBJECTIVE: To compare the efficacy and tolerability of duloxetine 60mg/day versus placebo in treating elderly patients with major depressive disorder (MDD) and concurrent anxiety symptoms. METHODS: Patients (>/=65) were randomized to eight weeks of treatment with duloxetine 60mg/day (n=207) or placebo (n=104). Anxiety measures were analyzed for all patients, by age (<75 and >/=75), and in patients having concurrent high anxiety (HAMD(17), item 10; Psychic Anxiety baseline score of 2, 3, or 4). Psychic Anxiety, Somatic Anxiety item 11, and the Anxiety/Somatization subscale were analyzed for all patients and subgroups by mean change from baseline to endpoint and repeated measures. Tolerability was assessed via treatment-emergent adverse events (TEAEs), and adverse events were reported as the reason for discontinuation. The analyses presented are primarily post hoc in nature. RESULTS: Duloxetine produced significantly greater reductions than placebo in Psychic Anxiety (least-squares mean change: -0.62 vs. -0.18, p<0.001) and the Anxiety/Somatization subscale (-1.88 vs. -0.99, p=0.002). Repeated measures analyses showed separation between the treatment groups beginning at Week 1 for Psychic Anxiety and Week 4 for the Anxiety/Somatization subscale. Significant improvement occurred in the <75 and >/=75 age groups for Psychic Anxiety, but only the <75 group for the Anxiety/Somatization subscale. Duloxetine-treated patients with high anxiety showed significant improvement compared with placebo-treated patients on Psychic Anxiety, Anxiety/Somatization subscale, the 17-item Hamilton Depression Rating Scale (HAMD(17)) total score, and several other measures. Duloxetine and placebo had similar TEAE rates and discontinuation rates due to adverse events. CONCLUSION: Duloxetine (60mg/day) was efficacious and tolerable in elderly patients with MDD and concurrent anxiety symptoms. PMID- 20711336 TI - Pulmonary embolism as a complication of major depressive disorder with catatonic features: a case report. AB - Catatonia in the setting of a mood disorder, an organic process, or a psychotic disorder presents significant risk to the patient's well-being, as well as an additional barrier to treating the underlying disorder. The signs and symptoms of catatonia interfere severely with essential activities of daily living; they also at times compromise the ability of caregivers to evaluate and treat the patient's primary disorder driving the catatonia. This interference often leads to medical emergencies, such as marked dehydration and pressure ulcers. Another life threatening complication of the immobility commonly seen in catatonic patients is the development of deep vein thromboses (DVT) and pulmonary emboli. As with all patients, it is critical to provide preventative measures where possible to minimize risk of complications. Routine anticoagulation perhaps deserves more consideration in the case of catatonia, such as the one presented in this case report. PMID- 20711337 TI - Blood Brain Barrier: The Role of GAD Antibodies in Psychiatry. AB - OBJECTIVE: Goal of our case control study was to establish the presence of antibodies to glutamic acid decarboxylase (GAD) in patients with chronic psychotic disorders. METHODS: Serum levels of GAD antibodies in 12 patients with chronic psychotic disorders (schizophrenia and schizoaffective disorders) and 10 age-matched healthy control subjects were evaluated utilizing enzyme linked immunosorbitent assay (ELISA). RESULTS: Antibodies to GAD in patients with chronic psychotic disorders have a higher mean than nonpatient control individuals. CONCLUSION: Our findings provide the first in-vivo evidence of positive GAD antibodies in chronic psychotic disorders and potentially may be used as a screening for these disorders. PMID- 20711338 TI - Characterizing the community structure of complex networks. AB - BACKGROUND: Community structure is one of the key properties of complex networks and plays a crucial role in their topology and function. While an impressive amount of work has been done on the issue of community detection, very little attention has been so far devoted to the investigation of communities in real networks. METHODOLOGY/PRINCIPAL FINDINGS: We present a systematic empirical analysis of the statistical properties of communities in large information, communication, technological, biological, and social networks. We find that the mesoscopic organization of networks of the same category is remarkably similar. This is reflected in several characteristics of community structure, which can be used as "fingerprints" of specific network categories. While community size distributions are always broad, certain categories of networks consist mainly of tree-like communities, while others have denser modules. Average path lengths within communities initially grow logarithmically with community size, but the growth saturates or slows down for communities larger than a characteristic size. This behaviour is related to the presence of hubs within communities, whose roles differ across categories. Also the community embeddedness of nodes, measured in terms of the fraction of links within their communities, has a characteristic distribution for each category. CONCLUSIONS/SIGNIFICANCE: Our findings, verified by the use of two fundamentally different community detection methods, allow for a classification of real networks and pave the way to a realistic modelling of networks' evolution. PMID- 20711339 TI - Determining frequent patterns of copy number alterations in cancer. AB - Cancer progression is often driven by an accumulation of genetic changes but also accompanied by increasing genomic instability. These processes lead to a complicated landscape of copy number alterations (CNAs) within individual tumors and great diversity across tumor samples. High resolution array-based comparative genomic hybridization (aCGH) is being used to profile CNAs of ever larger tumor collections, and better computational methods for processing these data sets and identifying potential driver CNAs are needed. Typical studies of aCGH data sets take a pipeline approach, starting with segmentation of profiles, calls of gains and losses, and finally determination of frequent CNAs across samples. A drawback of pipelines is that choices at each step may produce different results, and biases are propagated forward. We present a mathematically robust new method that exploits probe-level correlations in aCGH data to discover subsets of samples that display common CNAs. Our algorithm is related to recent work on maximum margin clustering. It does not require pre-segmentation of the data and also provides grouping of recurrent CNAs into clusters. We tested our approach on a large cohort of glioblastoma aCGH samples from The Cancer Genome Atlas and recovered almost all CNAs reported in the initial study. We also found additional significant CNAs missed by the original analysis but supported by earlier studies, and we identified significant correlations between CNAs. PMID- 20711340 TI - Positive feedback regulation between phospholipase D and Wnt signaling promotes Wnt-driven anchorage-independent growth of colorectal cancer cells. AB - BACKGROUND: Aberrant activation of the canonical Wnt/beta-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Phopholipase D (PLD) has been implicated in progression of colorectal carcinoma However, an understanding of the targets and regulation of this important pathway remains incomplete and besides, relationship between Wnt signaling and PLD is not known. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that PLD isozymes, PLD1 and PLD2 are direct targets and positive feedback regulators of the Wnt/beta-catenin signaling. Wnt3a and Wnt mimetics significantly enhanced the expression of PLDs at a transcriptional level in HCT116 colorectal cancer cells, whereas silencing of beta-catenin gene expression or utilization of a dominant negative form of T cell factor-4 (TCF-4) inhibited expression of PLDs. Moreover, both PLD1 and PLD2 were highly induced in colon, liver and stomach tissues of mice after injection of LiCl, a Wnt mimetic. Wnt3a stimulated formation of the beta-catenin/TCF complexes to two functional TCF-4 binding elements within the PLD2 promoter as assessed by chromatin immunoprecipitation assay. Suppressing PLD using gene silencing or selective inhibitor blocked the ability of beta-catenin to transcriptionally activate PLD and other Wnt target genes by preventing formation of the beta-catenin/TCF-4 complex, whereas tactics to elevate intracellular levels of phosphatidic acid, the product of PLD activity, enhanced these effects. Here we show that PLD is necessary for Wnt3a-driven invasion and anchorage-independent growth of colon cancer cells. CONCLUSION/SIGNIFICANCE: PLD isozyme acts as a novel transcriptional target and positive feedback regulator of Wnt signaling, and then promotes Wnt-driven anchorage-independent growth of colorectal cancer cells. We propose that therapeutic interventions targeting PLD may confer a clinical benefit in Wnt/beta-catenin-driven malignancies. PMID- 20711341 TI - Motor-coordination-dependent learning, more than others, is impaired in transgenic mice expressing pseudorabies virus immediate-early protein IE180. AB - The cerebellum in transgenic mice expressing pseudorabies virus immediate-early protein IE180 (TgIE96) was substantially diminished in size, and its histoarchitecture was severely disorganized, resulting in severe ataxia. TgIE96 mice can therefore be used as an experimental model to study the involvement of cerebellar circuits in different learning tasks. The performance of three-month old TgIE96 mice was studied in various behavioral tests, including associative learning (classical eyeblink conditioning), object recognition, spatial orientation (water maze), startle response and prepulse inhibition, and passive avoidance, and compared with that of wild-type mice. Wild-type and TgIE96 mice presented similar reflexively evoked eyeblinks, and acquired classical conditioned eyelid responses with similar learning curves for both trace and delay conditioning paradigms. The two groups of mice also had similar performances during the object recognition test. However, they showed significant differences for the other three tests included in this study. Although both groups of animals were capable of swimming, TgIE96 mice failed to learn the water maze task during the allowed time. The startle response to a severe tone was similar in both control and TgIE96 mice, but the latter were unable to produce a significant prepulse inhibition. TgIE96 mice also presented evident deficits for the proper accomplishment of a passive avoidance test. These results suggest that the cerebellum is not indispensable for the performance of classical eyeblink conditioning and for object recognition tasks, but seems to be necessary for the proper performance of water maze, prepulse inhibition, and passive avoidance tests. PMID- 20711343 TI - Rhizome severing increases root lifespan of Leymus chinensis in a typical steppe of Inner Mongolia. AB - BACKGROUND: Root lifespan is an important trait that determines plants' ability to acquire and conserve soil resources. There have been several studies investigating characteristics of root lifespan of both woody and herbaceous species. However, most of the studies have focused on non-clonal plants, and there have been little data on root lifespan for clonal plants that occur widely in temperate grasslands. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of rhizome severing on overall root lifespan of Leymus chinensis, a clonal, dominant grass species in the temperate steppe in northern China, in a 2 year field study using modified rhizotron technique. More specifically, we investigated the effects of rhizome severing on root lifespan of roots born in different seasons and distributed at different soil depths. Rhizome severing led to an increase in the overall root lifespan from 81 to 103 days. The increase in root lifespan exhibited spatial and temporal characteristics such that it increased lifespan for roots distributed in the top two soil layers and for roots born in summer and spring, but it had no effect on lifespan of roots in the deep soil layer and born in autumn. We also examined the effect of rhizome severing on carbohydrate and N contents in roots, and found that root carbohydrate and N contents were not affected by rhizome severing. Further, we found that root lifespan of Stipa krylovii and Artemisia frigida, two dominant, non-clonal species in the temperate steppe, was significantly longer (118 d) than that of L. chinensis (81 d), and this value became comparable to that of L. chinensis under rhizome severing (103 d). CONCLUSIONS/SIGNIFICANCE: We found that root lifespan in dominant, clonal L. chinensis was shorter than for the dominant, non-clonal species of S. krylovii and A. frigida. There was a substantial increase in the root lifespan of L. chinensis in response to severing their rhizomes, and this increase in root lifespan exhibited temporal and spatial characteristics. These findings suggest that the presence of rhizomes is likely to account for the observed short lifespan of clonal plant species in the temperate steppe. PMID- 20711342 TI - Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells. AB - BACKGROUND: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs. CONCLUSIONS/SIGNIFICANCE: Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in the management for brain tumours. PMID- 20711344 TI - Integrated population modeling of black bears in Minnesota: implications for monitoring and management. AB - BACKGROUND: Wildlife populations are difficult to monitor directly because of costs and logistical challenges associated with collecting informative abundance data from live animals. By contrast, data on harvested individuals (e.g., age and sex) are often readily available. Increasingly, integrated population models are used for natural resource management because they synthesize various relevant data into a single analysis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the performance of integrated population models applied to black bears (Ursus americanus) in Minnesota, USA. Models were constructed using sex-specific age-at harvest matrices (1980-2008), data on hunting effort and natural food supplies (which affects hunting success), and statewide mark-recapture estimates of abundance (1991, 1997, 2002). We compared this approach to Downing reconstruction, a commonly used population monitoring method that utilizes only age-at-harvest data. We first conducted a large-scale simulation study, in which our integrated models provided more accurate estimates of population trends than did Downing reconstruction. Estimates of trends were robust to various forms of model misspecification, including incorrectly specified cub and yearling survival parameters, age-related reporting biases in harvest data, and unmodeled temporal variability in survival and harvest rates. When applied to actual data on Minnesota black bears, the model predicted that harvest rates were negatively correlated with food availability and positively correlated with hunting effort, consistent with independent telemetry data. With no direct data on fertility, the model also correctly predicted 2-point cycles in cub production. Model-derived estimates of abundance for the most recent years provided a reasonable match to an empirical population estimate obtained after modeling efforts were completed. CONCLUSIONS/SIGNIFICANCE: Integrated population modeling provided a reasonable framework for synthesizing age-at-harvest data, periodic large-scale abundance estimates, and measured covariates thought to affect harvest rates of black bears in Minnesota. Collection and analysis of these data appear to form the basis of a robust and viable population monitoring program. PMID- 20711345 TI - Identifying modules of coexpressed transcript units and their organization of Saccharopolyspora erythraea from time series gene expression profiles. AB - BACKGROUND: The Saccharopolyspora erythraea genome sequence was released in 2007. In order to look at the gene regulations at whole transcriptome level, an expression microarray was specifically designed on the S. erythraea strain NRRL 2338 genome sequence. Based on these data, we set out to investigate the potential transcriptional regulatory networks and their organization. METHODOLOGY/PRINCIPAL FINDINGS: In view of the hierarchical structure of bacterial transcriptional regulation, we constructed a hierarchical coexpression network at whole transcriptome level. A total of 27 modules were identified from 1255 differentially expressed transcript units (TUs) across time course, which were further classified in to four groups. Functional enrichment analysis indicated the biological significance of our hierarchical network. It was indicated that primary metabolism is activated in the first rapid growth phase (phase A), and secondary metabolism is induced when the growth is slowed down (phase B). Among the 27 modules, two are highly correlated to erythromycin production. One contains all genes in the erythromycin-biosynthetic (ery) gene cluster and the other seems to be associated with erythromycin production by sharing common intermediate metabolites. Non-concomitant correlation between production and expression regulation was observed. Especially, by calculating the partial correlation coefficients and building the network based on Gaussian graphical model, intrinsic associations between modules were found, and the association between those two erythromycin production-correlated modules was included as expected. CONCLUSIONS: This work created a hierarchical model clustering transcriptome data into coordinated modules, and modules into groups across the time course, giving insight into the concerted transcriptional regulations especially the regulation corresponding to erythromycin production of S. erythraea. This strategy may be extendable to studies on other prokaryotic microorganisms. PMID- 20711347 TI - The SWR1 histone replacement complex causes genetic instability and genome-wide transcription misregulation in the absence of H2A.Z. AB - The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 in yeast) at specific chromatin regions. This dynamic alteration in nucleosome structure provides a molecular mechanism to regulate transcription, gene silencing, chromosome segregation and DNA repair. Here we show that genetic instability, sensitivity to drugs impairing different cellular processes and genome-wide transcriptional misregulation in htz1Delta can be partially or totally suppressed if SWR1 is not formed (swr1Delta), if it forms but cannot bind to chromatin (swc2Delta) or if it binds to chromatin but lacks histone replacement activity (swc5Delta and the ATPase-dead swr1-K727G). These results suggest that in htz1Delta the nucleosome remodelling activity of SWR1 affects chromatin integrity because of an attempt to replace H2A with Htz1 in the absence of the latter. This would impair transcription and, either directly or indirectly, other cellular processes. Specifically, we show that in htz1Delta, the SWR1 complex causes an accumulation of recombinogenic DNA damage by a mechanism dependent on phosphorylation of H2A at Ser129, a modification that occurs in response to DNA damage, suggesting that the SWR1 complex impairs the repair of spontaneous DNA damage in htz1Delta. In addition, SWR1 causes DSBs sensitivity in htz1Delta; consistently, in the absence of Htz1 the SWR1 complex bound near an endonuclease HO-induced DSB at the mating-type (MAT) locus impairs DSB-induced checkpoint activation. Our results support a stepwise mechanism for the replacement of H2A with Htz1 and demonstrate that a tight control of this mechanism is essential to regulate chromatin dynamics but also to prevent the deleterious consequences of an incomplete nucleosome remodelling. PMID- 20711346 TI - A genome-wide gene function prediction resource for Drosophila melanogaster. AB - Predicting gene functions by integrating large-scale biological data remains a challenge for systems biology. Here we present a resource for Drosophila melanogaster gene function predictions. We trained function-specific classifiers to optimize the influence of different biological datasets for each functional category. Our model predicted GO terms and KEGG pathway memberships for Drosophila melanogaster genes with high accuracy, as affirmed by cross validation, supporting literature evidence, and large-scale RNAi screens. The resulting resource of prioritized associations between Drosophila genes and their potential functions offers a guide for experimental investigations. PMID- 20711348 TI - Quantitative organization of GABAergic synapses in the molecular layer of the mouse cerebellar cortex. AB - In the cerebellar cortex, interneurons of the molecular layer (stellate and basket cells) provide GABAergic input to Purkinje cells, as well as to each other and possibly to other interneurons. GABAergic inhibition in the molecular layer has mainly been investigated at the interneuron to Purkinje cell synapse. In this study, we used complementary subtractive strategies to quantitatively assess the ratio of GABAergic synapses on Purkinje cell dendrites versus those on interneurons. We generated a mouse model in which the GABAA receptor alpha1 subunit (GABAARalpha1) was selectively removed from Purkinje cells using the Cre/loxP system. Deletion of the alpha1 subunit resulted in a complete loss of GABAAR aggregates from Purkinje cells, allowing us to determine the density of GABAAR clusters in interneurons. In a complementary approach, we determined the density of GABA synapses impinging on Purkinje cells using alpha-dystroglycan as a specific marker of inhibitory postsynaptic sites. Combining these inverse approaches, we found that synapses received by interneurons represent approximately 40% of all GABAergic synapses in the molecular layer. Notably, this proportion was stable during postnatal development, indicating synchronized synaptogenesis. Based on the pure quantity of GABAergic synapses onto interneurons, we propose that mutual inhibition must play an important, yet largely neglected, computational role in the cerebellar cortex. PMID- 20711349 TI - A model for a correlated random walk based on the ordered extension of pseudopodia. AB - Cell migration in the absence of external cues is well described by a correlated random walk. Most single cells move by extending protrusions called pseudopodia. To deduce how cells walk, we have analyzed the formation of pseudopodia by Dictyostelium cells. We have observed that the formation of pseudopodia is highly ordered with two types of pseudopodia: First, de novo formation of pseudopodia at random positions on the cell body, and therefore in random directions. Second, pseudopod splitting near the tip of the current pseudopod in alternating right/left directions, leading to a persistent zig-zag trajectory. Here we analyzed the probability frequency distributions of the angles between pseudopodia and used this information to design a stochastic model for cell movement. Monte Carlo simulations show that the critical elements are the ratio of persistent splitting pseudopodia relative to random de novo pseudopodia, the Left/Right alternation, the angle between pseudopodia and the variance of this angle. Experiments confirm predictions of the model, showing reduced persistence in mutants that are defective in pseudopod splitting and in mutants with an irregular cell surface. PMID- 20711350 TI - Computational models of HIV-1 resistance to gene therapy elucidate therapy design principles. AB - Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents. PMID- 20711352 TI - A Wnt-Frz/Ror-Dsh pathway regulates neurite outgrowth in Caenorhabditis elegans. AB - One of the challenges to understand the organization of the nervous system has been to determine how axon guidance molecules govern axon outgrowth. Through an unbiased genetic screen, we identified a conserved Wnt pathway which is crucial for anterior-posterior (A/P) outgrowth of neurites from RME head motor neurons in Caenorhabditis elegans. The pathway is composed of the Wnt ligand CWN-2, the Frizzled receptors CFZ-2 and MIG-1, the co-receptor CAM-1/Ror, and the downstream component Dishevelled/DSH-1. Among these, CWN-2 acts as a local attractive cue for neurite outgrowth, and its activity can be partially substituted with other Wnts, suggesting that spatial distribution plays a role in the functional specificity of Wnts. As a co-receptor, CAM-1 functions cell-autonomously in neurons and, together with CFZ-2 and MIG-1, transmits the Wnt signal to downstream effectors. Yeast two-hybrid screening identified DSH-1 as a binding partner for CAM-1, indicating that CAM-1 could facilitate CWN-2/Wnt signaling by its physical association with DSH-1. Our study reveals an important role of a Wnt Frz/Ror-Dsh pathway in regulating neurite A/P outgrowth. PMID- 20711351 TI - Induced effects of sodium ions on dopaminergic G-protein coupled receptors. AB - G-protein coupled receptors, the largest family of proteins in the human genome, are involved in many complex signal transduction pathways, typically activated by orthosteric ligand binding and subject to allosteric modulation. Dopaminergic receptors, belonging to the class A family of G-protein coupled receptors, are known to be modulated by sodium ions from an allosteric binding site, although the details of sodium effects on the receptor have not yet been described. In an effort to understand these effects, we performed microsecond scale all-atom molecular dynamics simulations on the dopaminergic D(2) receptor, finding that sodium ions enter the receptor from the extracellular side and bind at a deep allosteric site (Asp2.50). Remarkably, the presence of a sodium ion at this allosteric site induces a conformational change of the rotamer toggle switch Trp6.48 which locks in a conformation identical to the one found in the partially inactive state of the crystallized human beta(2) adrenergic receptor. This study provides detailed quantitative information about binding of sodium ions in the D(2) receptor and reports a possibly important sodium-induced conformational change for modulation of D(2) receptor function. PMID- 20711353 TI - Stochastic ion channel gating in dendritic neurons: morphology dependence and probabilistic synaptic activation of dendritic spikes. AB - Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites. PMID- 20711354 TI - Host immune response to mosquito-transmitted chikungunya virus differs from that elicited by needle inoculated virus. AB - BACKGROUND: Mosquito-borne diseases are a worldwide public health threat. Mosquitoes transmit viruses or parasites during feeding, along with salivary proteins that modulate host responses to facilitate both blood feeding and pathogen transmission. Understanding these earliest events in mosquito transmission of arboviruses by mosquitoes is essential for development and assessment of rational vaccine and treatment strategies. In this report, we compared host immune responses to chikungunya virus (CHIKV) transmission by (1) mosquito bite, or (2) by needle inoculation. METHODS AND FINDINGS: Differential cytokine expression was measured using quantitative real-time RT-PCR, at sites of uninfected mosquito bites, CHIKV-infected mosquito bites, and needle-inoculated CHIKV. Both uninfected and CHIKV infected mosquitoes polarized host cytokine response to a TH2 profile. Compared to uninfected mosquito bites, expression of IL-4 induced by CHIKV-infected mosquitoes were 150 fold and 527.1 fold higher at 3 hours post feeding (hpf) and 6 hpf, respectively. A significant suppression of TH1 cytokines and TLR-3 was also observed. These significant differences may result from variation in the composition of uninfected and CHIKV-infected mosquito saliva. Needle injected CHIKV induced a robust interferon-gamma, no detectable IL-4, and a significant up-regulation of TLR-3. CONCLUSIONS: This report describes the first analysis of cutaneous cytokines in mice bitten by CHIKV-infected mosquitoes. Our data demonstrate contrasting immune activation in the response to CHIKV infection by mosquito bite or needle inoculation. The significant role of mosquito saliva in these earliest events of CHIKV transmission and infection are highlighted. PMID- 20711355 TI - Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. AB - Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extra-chromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment. PMID- 20711356 TI - Mouse TRIP13/PCH2 is required for recombination and normal higher-order chromosome structure during meiosis. AB - Accurate chromosome segregation during meiosis requires that homologous chromosomes pair and become physically connected so that they can orient properly on the meiosis I spindle. These connections are formed by homologous recombination closely integrated with the development of meiosis-specific, higher order chromosome structures. The yeast Pch2 protein has emerged as an important factor with roles in both recombination and chromosome structure formation, but recent analysis suggested that TRIP13, the mouse Pch2 ortholog, is not required for the same processes. Using distinct Trip13 alleles with moderate and severe impairment of TRIP13 function, we report here that TRIP13 is required for proper synaptonemal complex formation, such that autosomal bivalents in Trip13-deficient meiocytes frequently displayed pericentric synaptic forks and other defects. In males, TRIP13 is required for efficient synapsis of the sex chromosomes and for sex body formation. Furthermore, the numbers of crossovers and chiasmata are reduced in the absence of TRIP13, and their distribution along the chromosomes is altered, suggesting a role for TRIP13 in aspects of crossover formation and/or control. Recombination defects are evident very early in meiotic prophase, soon after DSB formation. These findings provide evidence for evolutionarily conserved functions for TRIP13/Pch2 in both recombination and formation of higher order chromosome structures, and they support the hypothesis that TRIP13/Pch2 participates in coordinating these key aspects of meiotic chromosome behavior. PMID- 20711357 TI - The battle for iron between bacterial pathogens and their vertebrate hosts. PMID- 20711358 TI - Transmission of mitochondrial DNA diseases and ways to prevent them. AB - Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy-the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders. PMID- 20711359 TI - Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold. AB - Emergence of a new influenza strain leads to a rapid global spread of the virus due to minimal antibody immunity. Pre-existing CD8(+) T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP(336-374) peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross reactive T cell responses. The engineered virus induced a diminished CD8(+) T cell response and selected a narrowed T cell receptor (TCR) repertoire within two V beta regions (V beta 8.3 and V beta 9). This can be partially explained by the H-2D(b)NPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2D(b), including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the naive and immune NPN3A specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type (wt) virus, both are markedly lower than wt->wt challenge. Such decreased CD8(+) responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Thus, the protective efficacy of cross-reactive CD8(+) T cells recognising mutant viral epitopes depend on peptide-MHC-I structural interactions and functional avidity. Our study does not support vaccine strategies that include immunization against commonly selected cross-reactive variants with mutations at partially-solvent exposed residues that have characteristics comparable to NPN3A. PMID- 20711361 TI - Correlation of influenza virus excess mortality with antigenic variation: application to rapid estimation of influenza mortality burden. AB - The variants of human influenza virus have caused, and continue to cause, substantial morbidity and mortality. Timely and accurate assessment of their impact on human death is invaluable for influenza planning but presents a substantial challenge, as current approaches rely mostly on intensive and unbiased influenza surveillance. In this study, by proposing a novel host-virus interaction model, we have established a positive correlation between the excess mortalities caused by viral strains of distinct antigenicity and their antigenic distances to their previous strains for each (sub)type of seasonal influenza viruses. Based on this relationship, we further develop a method to rapidly assess the mortality burden of influenza A(H1N1) virus by accurately predicting the antigenic distance between A(H1N1) strains. Rapid estimation of influenza mortality burden for new seasonal strains should help formulate a cost-effective response for influenza control and prevention. PMID- 20711360 TI - Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation. AB - The Polo-Like Kinase 1 (PLK1) acts as a central regulator of mitosis and is over expressed in a wide range of human tumours where high levels of expression correlate with a poor prognosis. PLK1 comprises two structural elements, a kinase domain and a polo-box domain (PBD). The PBD binds phosphorylated substrates to control substrate phosphorylation by the kinase domain. Although the PBD preferentially binds to phosphopeptides, it has a relatively broad sequence specificity in comparison with other phosphopeptide binding domains. We analysed the molecular determinants of recognition by performing molecular dynamics simulations of the PBD with one of its natural substrates, CDC25c. Predicted binding free energies were calculated using a molecular mechanics, Poisson Boltzmann surface area approach. We calculated the per-residue contributions to the binding free energy change, showing that the phosphothreonine residue and the mainchain account for the vast majority of the interaction energy. This explains the very broad sequence specificity with respect to other sidechain residues. Finally, we considered the key role of bridging water molecules at the binding interface. We employed inhomogeneous fluid solvation theory to consider the free energy of water molecules on the protein surface with respect to bulk water molecules. Such an analysis highlights binding hotspots created by elimination of water molecules from hydrophobic surfaces. It also predicts that a number of water molecules are stabilized by the presence of the charged phosphate group, and that this will have a significant effect on the binding affinity. Our findings suggest a molecular rationale for the promiscuous binding of the PBD and highlight a role for bridging water molecules at the interface. We expect that this method of analysis will be very useful for probing other protein surfaces to identify binding hotspots for natural binding partners and small molecule inhibitors. PMID- 20711362 TI - The Mycobacterium tuberculosis proteasome active site threonine is essential for persistence yet dispensable for replication and resistance to nitric oxide. AB - Previous work revealed that conditional depletion of the core proteasome subunits PrcB and PrcA impaired growth of Mycobacterium tuberculosis in vitro and in mouse lungs, caused hypersusceptibility to nitric oxide (NO) and impaired persistence of the bacilli during chronic mouse infections. Here, we show that genetic deletion of prcBA led to similar phenotypes. Surprisingly, however, an active site mutant proteasome complemented the in vitro and in vivo growth defects of the prcBA knockout (Delta prcBA) as well as its NO hypersensitivity. In contrast, long-term survival of M. tuberculosis in stationary phase and during starvation in vitro and in the chronic phase of mouse infection required a proteolytically active proteasome. Inhibition of inducible nitric oxide synthase did not rescue survival of Delta prcBA, revealing a function beyond NO defense, by which the proteasome contributes to M. tuberculosis fitness during chronic mouse infections. These findings suggest that proteasomal proteolysis facilitates mycobacterial persistence, that M. tuberculosis faces starvation during chronic mouse infections and that the proteasome serves a proteolysis-independent function. PMID- 20711363 TI - Chromosome axis defects induce a checkpoint-mediated delay and interchromosomal effect on crossing over during Drosophila meiosis. AB - Crossovers mediate the accurate segregation of homologous chromosomes during meiosis. The widely conserved pch2 gene of Drosophila melanogaster is required for a pachytene checkpoint that delays prophase progression when genes necessary for DSB repair and crossover formation are defective. However, the underlying process that the pachytene checkpoint is monitoring remains unclear. Here we have investigated the relationship between chromosome structure and the pachytene checkpoint and show that disruptions in chromosome axis formation, caused by mutations in axis components or chromosome rearrangements, trigger a pch2 dependent delay. Accordingly, the global increase in crossovers caused by chromosome rearrangements, known as the "interchromosomal effect of crossing over," is also dependent on pch2. Checkpoint-mediated effects require the histone deacetylase Sir2, revealing a conserved functional connection between PCH2 and Sir2 in monitoring meiotic events from Saccharomyces cerevisiae to a metazoan. These findings suggest a model in which the pachytene checkpoint monitors the structure of chromosome axes and may function to promote an optimal number of crossovers. PMID- 20711364 TI - Rheological and chemical analysis of reverse gelation in a covalently crosslinked Diels-Alder polymer network. AB - A network polymer, incorporating dynamic and reversible crosslinks, was synthesized using the Diels-Alder reaction. Fourier transform infrared (FTIR) spectroscopy was used to characterize the reaction rate and thermodynamic equilibrium over a broad temperature range. Equilibrium conversion of the furan and maleimide varied from 74% at 85 degrees C to 24% at 155 degrees C, demonstrating significant depolymerization via the retro-Diels-Alder reaction. The gel point temperature, as determined by rheometry using the Winter-Chambon criterion, was 92 degrees C, corresponding to a gel-point conversion of 71%, consistent with the Flory-Stockmayer equation. The scaling exponents for the complex moduli, viscosity, and plateau modulus, in the vicinity of the gel-point, were determined and compared with experimental and theoretical literature values. Further, the material exhibited a low frequency relaxation owing to dynamic rearrangement of crosslinks by the Diels-Alder and retro-Diels-Alder reactions. PMID- 20711366 TI - Rational use of medicines: Achievements and challenges. PMID- 20711365 TI - Optimal Illumination Patterns for Fluorescence Tomography. AB - Fluorescence tomography has become increasingly popular for detecting molecular targets for imaging gene expression and other cellular processes in vivo in small animal studies. In this imaging modality, multiple sets of data are acquired by illuminating the animal surface with different excitation patterns, each of which produces a distinct spatial pattern of fluorescence. This work addresses one of the most intriguing, yet unsolved, problems of fluorescence tomography, which is to determine how to optimally illuminate the animal surface so as to maximize the information content in the acquired data. The key idea of this work is to parameterize the illumination pattern and to maximize the information content in the data by improving the conditioning of the Fisher information matrix. We formulate our problem as a constrained optimization problem. We compare the performance of different geometric illumination schemes with those generated by this optimization approach using the Digimouse atlas. PMID- 20711367 TI - Immunomodulatory activity of a Chinese herbal drug Yi Shen Juan Bi in adjuvant arthritis. AB - OBJECTIVE: To investigate the immunomodulating mechanisms of a Chinese herbal medicine Yi Shen Juan Bi (YJB) in treatment of adjuvant arthritis (AA) in rats. MATERIALS AND METHODS: Levels of serum tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured by the Enzyme-Linked Immunosorbent Assay (ELISA). Expression of TNF-alpha mRNA and IL-1beta mRNA in synovial cells was measured with the semi-quantitative technique of reverse transcription polymerase chain reaction (RT-PCR), while caspase-3 was examined by western blot analysis. RESULTS: The administration of YJB significantly decreased the production of serum TNF-alpha and IL-1beta. It also decreased significantly the TNF-alpha mRNA, IL-1beta mRNA, and caspase-3 expression in synoviocytes. CONCLUSIONS: YJB produces the immunomodulatory effects by downregulating the over activated cytokines, while it activates caspase-3, which is the key executioner of apoptosis in the immune system. This may be the one of the underlying mechanisms that explains how YJB treats the rheumatoid arthritis. PMID- 20711368 TI - A study of the antidiabetic activity of Barleria prionitisLinn. AB - OBJECTIVES: To study the antidiabetic activity of Barleria prionitis Linn in normal and alloxan-induced diabetic rats. MATERIALS AND METHODS: Alcoholic extract of leaf and root of B. prionitis was tested for their antidiabetic activity. Albino rats were divided into six groups of six animals each. In three groups, diabetes was induced using alloxan monohydrate (150 mg/kg b.w., i.p.) and all the rats were given different treatments consisting of vehicle, alcoholic extract of leaves, and alcoholic extract roots of B. prionitis Linn (200 mg/kg) for 14 days. The same treatment was given to the other three groups, comprising non-diabetic (normal) animals. Blood glucose level, glycosylated hemoglobin, liver glycogen, serum insulin, and body weight were estimated in normal and alloxan-induced diabetic rats, before and 2 weeks after administration of drugs. RESULTS: Animals treated with the alcoholic extract of leaves of B. prionitis Linn showed a significant decrease in blood glucose level (P<0.01) and glycosylated hemoglobin (P<0.01). A significant increase was observed in serum insulin level (P<0.01) and liver glycogen level (P<0.05), whereas the decrease in the body weight was arrested by administration of leaf extract to the animals. The alcoholic extract of roots showed a moderate but non-significant antidiabetic activity in experimental animals. CONCLUSION: The study reveals that the alcoholic leaf extract of B. prionitis could be added in the list of herbal preparations beneficial in diabetes mellitus. PMID- 20711369 TI - Effect of clonidine as adjuvant in bupivacaine-induced supraclavicular brachial plexus block: A randomized controlled trial. AB - OBJECTIVE: Clonidine has been used as adjuvant to local anesthetics in order to extend the duration of analgesia in various regional and central neuraxial blocks. It is previously reported that clonidine added to bupivacaine increases analgesia duration in brachial plexus block. We evaluated the effect of this combination in supraclavicular brachial plexus block for upper limb orthopedic procedures. MATERIALS AND METHODS: A randomized double-blind placebo controlled trial was done with 70 patients of American Society of Anesthesiologists Grade I or II status undergoing upper limb orthopedic procedures. Group A (n = 35) patients received 25 ml of 0.5% bupivacaine and 0.2 ml (30 mcg) clonidine, whereas group B (n = 35) received 25 ml of 0.5% bupivacaine and 0.2 ml normal saline through a supraclavicular approach for brachial plexus block. Vital parameters were recorded 10 min prior to block placement and every 3 min thereafter till the end of the procedure. Onset and duration of both sensory and motor blocks and sedation score were recorded. All patients were observed in postanesthesia care unit and received tramadol injection as soon as they complained of pain as rescue analgesic. Duration of analgesia was taken as the time from placement of block till injection of rescue analgesic. RESULTS: Analgesia duration was 415.4 +/- 38.18 min (mean +/- standard deviation) in Group A (clonidine) compared to 194.2 +/- 28.74 min in Group B (control). No clinically significant difference was observed in heart rate, blood pressure, and oxygen saturation. Sedation score was higher in the clonidine group. CONCLUSION: Addition of a small dose of clonidine to 0.5% bupivacaine significantly prolonged the duration of analgesia without producing any clinically important adverse reactions other than sedation. PMID- 20711370 TI - Effect of ascorbic acid supplementation on nitric oxide metabolites and systolic blood pressure in rats exposed to lead. AB - BACKGROUND: Extended exposure to low levels of lead causes high blood pressure in human and laboratory animals. The mechanism is not completely recognized, but it is relatively implicated with generation of free radicals, oxidant agents such as ROS, and decrease of available nitric oxide (NO). In this study, we have demonstrated the effect of ascorbic acid as an antioxidant on nitric oxide metabolites and systolic blood pressure in rats exposed to low levels of lead. MATERIALS AND METHODS: The adult male Wistar rats weighing 200-250 g were divided into four groups: control, lead acetate (receiving 100 ppm lead acetate in drinking water), lead acetate plus ascorbic acid (receiving 100 ppm lead acetate and 1 g/l ascorbic acid in drinking water), and ascorbic acid (receiving 1 g/l ascorbic acid in drinking water) groups. The animals were anesthetized with ketamin/xylazine (50 and 7 mg/kg, respectively, ip) and systolic blood pressure was then measured from the tail of the animals by a sphygmomanometer. Nitric oxide levels in serum were measured indirectly by evaluation of its stable metabolites (total nitrite and nitrate (NOchi)). RESULTS: After 8 and 12 weeks, systolic blood pressure in the lead acetate group was significantly elevated compared to the control group. Ascorbic acid supplementation could prevent the systolic blood pressure rise in the lead acetate plus ascorbic acid group and there was no significant difference relative to the control group. The serum NOchi levels in lead acetate group significantly decreased in relation to the control group, but this reduction was not significantly different between the lead acetate plus ascorbic acid group and the control group. CONCLUSION: Results of this study suggest that ascorbic acid as an antioxidant prevents the lead induced hypertension. This effect may be mediated by inhibition of NOchi oxidation and thereby increasing availability of NO. PMID- 20711371 TI - The antiepileptic effect of Centella asiatica on the activities of Na/K, Mg and Ca-ATPases in rat brain during pentylenetetrazol-induced epilepsy. AB - BACKGROUND: To study the anticonvulsant effect of different extracts of Centella asiatica (CA) in male albino rats with reference to Na(+)/K(+), Mg(2+) and Ca(2+) ATPase activities. MATERIALS AND METHODS: Male Wistar rats (150+/-25 g b.w.) were divided into seven groups of six each i.e. (a) control rats treated with saline, (b) pentylenetetrazol (PTZ)-induced epileptic group (60 mg/kg, i.p.), (c) epileptic group pretreated with n-hexane extract (n-HE), (d) epileptic group pretreated with chloroform extract (CE), (e) epileptic group pretreated with ethyl acetate extract (EAE), (f) epileptic group pretreated with n-butanol extract (n-BE), and (g) epileptic group pretreated with aqueous extract (AE). RESULTS: The activities of three ATPases were decreased in different regions of brain during PTZ-induced epilepsy and were increased in epileptic rats pretreated with different extracts of CA except AE. CONCLUSION: The extracts of C. asiatica, except AE, possess anticonvulsant and neuroprotective activity and thus can be used for effective management in treatment of epileptic seizures. PMID- 20711372 TI - Student evaluation of teaching and assessment methods in pharmacology. AB - BACKGROUND: The students are in the best position to comment on the effectiveness of any teaching system and they may be regarded as the best judges to assess the teaching and evaluation methods. OBJECTIVE: This study was designed to obtain student feedback on teaching and assessment methods in the subject of pharmacology and use it for improvement. MATERIALS AND METHODS: Based on student feedback from batch 2006, innovative strategies were implemented. To know the effect of these strategies feedback was obtained from subsequent batch 2007 using a written validated questionnaire covering various aspects of teaching and assessment methods. RESULTS: Students were satisfied with all teaching methods except lecture, seminars and pharmacy exercises. Majority of the students showed preference for tutorials, short answer questions and revision classes. All students felt that there should be more time for clinical pharmacology and bedside teaching. The performance score of the students (batch 2007) indicated improvement in their scores (12%) when earlier feedback suggestions were implemented. The pass percentage of the subsequent batch in university examinations improved from 90 to 100%. CONCLUSION: The implementation of suggestions obtained from students resulted in improvement in their performance. Hence, it is very essential to synchronize teaching and evaluation methods with special requirements of medical students. PMID- 20711373 TI - Reproductive toxicity of sodium valproate in male rats. AB - OBJECTIVES: To assess the effects of sodium valproate on rat sperm morphology, sperm count, motility, and histopathological changes in testis. MATERIALS AND METHODS: Male Wistar rats (12 week old) were treated with sodium valpraote and sacrificed at the end of 2(nd), 4(th), 5(th), 7(th), 10(th) and 15(th) week after the last exposure to sodium valproate. Epididymal sperm count, sperm motility, sperm morphology, and histopathology of testes were analyzed. RESULTS: Sperm count and sperm motility were decreased significantly by sodium valproate. The percentage of abnormal sperms increased in a dose-dependent manner. A histopathological study revealed that sodium valproate had caused sloughing of epithelial cells in testes. CONCLUSION: Sodium valproate causes reversible change in sperm motility, sperm count, morphology, and cytoarchitecture of testes. PMID- 20711374 TI - Use of potentially inappropriate medicines in elderly: A prospective study in medicine out-patient department of a tertiary care teaching hospital. AB - OBJECTIVE: The present study was undertaken with the aim to detect extent of drug use in elderly at medicine outpatient department at tertiary care hospital and to evaluate inappropriate prescribing with the help of Beers' criteria 2002. MATERIALS AND METHODS: The study was carried out at medicine out patient department of our hospital. 407 geriatric patients were included during the study period of three and half months. The data was collected in a proforma which included the patients' details and the prescriptions. RESULTS: The results reveal that 7.42% of total drugs were prescribed in an inappropriate manner and 23.59% of total patients received at least one inappropriate drug prescription. Administration of a drug which is avoided in elderly forms a common category of inappropriate drug use. Antihistamines, anticholinergic, sedatives and hypnotics and cardiac glycosides are the most common drug groups prescribed in inappropriate manner. CONCLUSION: To conclude, this study shows high prevalence of inappropriate use of drugs in geriatric practice suggesting urgent need for sincere efforts to improve the situation. PMID- 20711375 TI - In vitro and in vivo hepatoprotective effects of the total alkaloid fraction of Hygrophila auriculata leaves. AB - OBJECTIVE: To investigate the total alkaloid fraction of the methanol extract of leaves of Hygrophila auriculata for its hepatoprotective activity against CCl4 induced toxicity in freshly isolated rat hepatocytes, HepG2 cells, and animal models. MATERIALS AND METHODS: Mature leaves of H. auriculata were collected, authenticated, and subjected to methanolic extraction followed by isolation of total alkaloid fraction. Freshly isolated rat hepatocytes were exposed to CCl4 (1%) along with/without various concentrations of the total alkaloid fraction (80 40 microg/ml). Protection of human liver-derived HepG2 cells against CCl4-induced damage was determined by the MTT assay. Twenty-four healthy Wistar albino rats (150-200 g) of either sex were used for the in vivo investigations. Liver damage was induced by administration of 30% CCl4 suspended in olive oil (1 ml/kg body weight, i.p). RESULTS: The antihepatotoxic effect of the total alkaloid fraction was observed in freshly isolated rat hepatocytes at very low concentrations (80 40 microg/ml). A dose-dependent increase in the percentage viability was observed when CCl4-exposed HepG2 cells were treated with different concentrations of the total alkaloid fraction. Its in vivo hepatoprotective effect at 80 mg/kg body weight was comparable with that of the standard Silymarin at 250 mg/kg body weight. CONCLUSION: The total alkaloid fraction was able to normalize the biochemical levels which were altered due to CCl4 intoxication. PMID- 20711376 TI - In vitro antibacterial evaluation of Anabaena sp. against several clinically significant microflora and HPTLC analysis of its active crude extracts. AB - The present study was conducted to evaluate the possible antibacterial activity of Anabaena extracts. Anabaena was isolated from a natural source and cultured in vitro. after suitable growth, cyanobacterial culture was harvested using different solvents. Extracts, thus prepared, were evaluated for their antibacterial potential by agar-well diffusion assay against bacterial species of clinical significance. MIC values were determined further to check the concentration ranges for significant inhibition. HPTLC analysis was done to separate the components of active crude extract in an attempt to identify the bio active chemical entity. Methanol extract exhibited more potent activity than that of hexane and ethyl acetate extracts. No inhibitory effect was found against Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumoniae. Staphylococcus aureus required about 256 microg/ml of the crude methanol extract for effective inhibition. HPTLC evaluation at lambda 254 nm was performed for the separation of a complex mixture of the methanol extract. The results provide evidence that Anabaena sp. extracts might indeed be potential sources of new antibacterial agents. PMID- 20711377 TI - Pyrazinamide induced thrombocytopenia. AB - Thrombocytopenia is an uncommon but potentially life-threatening complication of certain antitubercular drugs and is characterized by rapid destruction of platelets whenever offending drug is taken by a susceptible person. We report a case of pyrazinamide-induced thrombocytopenia in a patient receiving anti tubercular drugs. PMID- 20711378 TI - Possible cross-sensitivity between sertraline and paroxetine in a panic disorder patient. AB - Cross-sensitivity due to paroxetine and sertraline, the SSRIs, is rarely reported in the literature. We report an adverse drug reaction to paroxetine and sertraline in a patient of panic disorder, who initially developed a maculopapular, erythematous, pruritic rash in the third week with sertraline 50 mg/day. The rash resolved within 2 days of its discontinuation and oral supplementation of diphenhydramine and betamethasone. 10 days following discontinuation of sertraline, the patient was shifted on sustain release paroxetine 12.5 mg/day when another skin reaction with the same appearance and distribution appeared on day 4 of it, suggesting a possibility of cross sensitivity, a drug class effect. This case report intends to improve the awareness among clinicians to use caution when choosing an alternative SSRIs. PMID- 20711380 TI - The journal club. PMID- 20711379 TI - Amisulpride induced mania. AB - Amisulpride is an atypical antipsychotic used for the management of schizophrenia and other conditions like dysthymia. It has also been used for the management of bipolar disorders as an add on therapy. Here, we report a patient of schizophrenia who developed a manic episode while on amisulpride. PMID- 20711381 TI - A prospective analysis of adverse effects of antiretroviral agents: Additional points to consider. PMID- 20711382 TI - Authors' reply. PMID- 20711383 TI - Pharmacovigilance in vaccines. PMID- 20711384 TI - A prospective analysis of drug-induced acute cutaneous reactions reported in patients at a tertiary care hospital. PMID- 20711385 TI - Golden jubilee, 2008. PMID- 20711386 TI - Demographic aging: Implications for mental health. PMID- 20711387 TI - Suicide and its prevention: The urgent need in India. PMID- 20711388 TI - Cellular and molecular mechanisms of drug dependence: An overview and update. AB - Drug dependence is a major cause of morbidity and loss of productivity. Various theories ranging from economic to psychological have been invoked in an attempt to explain this condition. With the advent of research at the cellular and subcellular levels, perspectives on the etiology of drug dependence have also changed. Perhaps the greatest advance has been in the identification of specific receptors for each of the drugs, their target neurotransmitter systems and the intracellular changes produced by them. These receptors also provide potential targets for treatment strategies of drug dependence. This overview attempts to present the mechanisms in the development of dependence and the newer treatment strategies for the major drugs of abuse like alcohol, opioids, cannabis, nicotine and cocaine. PMID- 20711389 TI - Seasonal pattern of psychiatry service utilization in a tertiary care hospital. AB - BACKGROUND: Seasonal and monthly variations in utilization of psychiatric services have been inadequately studied in India. AIMS: This study sought to determine the pattern of psychiatric services utilization by patients with four broad categories of diagnosis (mood disorders (F30-39): neurotic stress-related and somatoform disorders (F40-48), schizophrenia, schizotypal and delusional disorders (F20-29) and mental and behavioral disorders due to psychoactive substance use (F10-19) in different seasons and months of the last six years. MATERIALS AND METHODS: We conducted a teaching hospital data-based study of new patients diagnosed with psychiatric illness in the department of psychiatry, Government Medical College and Hospital, Chandigarh. Four diagnostic groups consisting of 12058 psychiatric patients who had been diagnosed and treated in the department of psychiatry of this institute from 1999-2004 were included in this evaluation. Bed occupancy rate (BOR), average length of stay (ALOS) of inpatients and seasonal index were determined. Information about weather variables (mean daily temperature, mean rainfall) was collected from the meterological department of Chandigarh. RESULTS: Psychiatric services were utilized by 31.1% of patients with mood disorders in the summer and by 34.23% of patients with neurotic, stress-related and somatoform disorders in the autumn. Statistical analysis revealed significant difference in new cases of these two groups of disorders in different seasons. CONCLUSION: Our study showed a significant relationship between utilization of psychiatric patients especially with mood disorders and neurotic, stress related and somatoform disorders with season (summer and autumn respectively). PMID- 20711390 TI - Stressful life events among adolescents: The development of a new measure. AB - BACKGROUND: Adolescence can be a stressful time for children, parents and adults who work with teens. We believe that a scale measuring the events perceived as stressful by an average Indian adolescent is necessary due to the presence of irrelevant items and absence of items related to our culture on foreign scales. AIM: This study was done to adapt and test the validity of a scale measuring stress caused due to life events in an Indian adolescent; to assess clinical value of the instrument in exploring causal relationships between stressful events and behavioral problems; and to compare the degree of overlap in stress causing events between adolescents and their parents during the same timeframe. MATERIALS AND METHODS: An adolescent life event stress scale (ALESS) containing 41 items was administered to 156 adolescents for formulation and 102 adolescents for validation. A third set of 112 adolescents was used to compare ALESS scores with child behavior checklist (CBCL) scores and parental stress scores due to life events. RESULTS: The comparison showed a strong positive correlation with CBCL scores with a model fit (r(2) = 0.32) and a weak positive correlation with parental stress (Pearson's coefficient = 0.011) due to life events. CONCLUSION: Thus, a life event scale for adolescents was especially adapted to the Indian conditions. PMID- 20711391 TI - Prevalence and risk factors of psychiatric disorders in an industrial population in India. AB - BACKGROUND: Recent information on psychiatric morbidity in industrial employees is not available in India. Such information may help in building mental health care for this population. AIM: The aim was to study the prevalence of psychiatric morbidity and the risk factors associated with it in an industrial population. MATERIALS AND METHODS: Two hundred thirty-eight individuals were selected by a stratified randomisation technique and screened using the General Health Questionnaire-12 (GHQ-12), Johns Hopkins University Hospital Test for alcoholism and a semistructured questionnaire for other substance use, sleep problems and past psychiatric history. Following a detailed clinical interview, diagnoses were based on International Classification of Diseases (ICD)-10, Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research (DCR). RESULTS: The prevalence rate for psychiatric disorder of one month's duration in the study population was 51.7%. Substance use, depression, anxiety and sleep disorders were common. Comorbidities were found in 65% of the subjects. Both univariate analysis and stepwise multiple regression revealed that educational level, perceived stress, job satisfaction and stressful life events were the independent determinants of psychiatric morbidity. CONCLUSION: A significant proportion of industrial employees had psychiatric morbidity and many psychosocial factors were associated with caseness. PMID- 20711392 TI - Prevalence of sexual dysfunction in male subjects with alcohol dependence. AB - BACKGROUND: Chronic and persistent alcohol use is known to induce sexual dysfunction, which leads to marked distress and interpersonal difficulty. AIM: We attempted to assess the prevalence of sexual dysfunction in a clinical sample of subjects with alcohol dependence. MATERIALS AND METHODS: One hundred male subjects admitted to a deaddiction centre with a diagnosis of alcohol dependence syndrome with simple withdrawal symptoms (F10.30, ICD-10 criteria) were assessed for sexual dysfunction using a sexual dysfunction checklist, constructed using items from the Diagnostic Criteria for Research [ICD-10] for sexual dysfunction. RESULTS: Seventy-two per cent had one or more sexual dysfunction, the most common being premature ejaculation, low sexual desire and erectile dysfunction. The amount of alcohol consumed appeared to be the most significant predictor of developing sexual dysfunction. CONCLUSION: Sexual dysfunction is common in patients with alcohol dependence. Heavy drinking proportionately increases the risk. Clinicians need to routinely assess sexual functioning in alcoholic patients so that other factors contributing to sexual dysfunction can be ruled out. PMID- 20711393 TI - The trail making test in India. AB - The trail making test (TMT) is a short and convenient estimate of cognitive functions, principally attention and working memory. Like most neuropsychological tests, it is derived from and primarily applicable to English-speaking individuals. Norms for other ethnic minorities may differ significantly. The application of majority or mixed norms to specific ethnic subcultures may introduce systematic bias. To examine the impact of an English test on primarily nonEnglish-speaking individuals, outpatients attending the dermatology department of a large Indian hospital (n = 120) were asked to complete the English version of the TMT. The time taken to complete the TRAILS was unexpectedly long, although all the subjects scored within normal limits on the modified mini mental status examination and a test for general knowledge. Possible reasons for the delayed completion times are discussed below. PMID- 20711394 TI - Pesticide poisoning in nonfatal, deliberate self-harm: A public health issue. AB - BACKGROUND: Nonfatal, deliberate self-harm (DSH), particularly with pesticides, is a major public health problem in many developing countries of the world. Agriculture is the primary occupation of most people living in the Sundarban region in West Bengal, India. Pesticides are extensively used in agriculture and these agents are most frequently used in DSH. AIM: This study sought to identify the nature of methods and agents used in nonfatal DSH attempts in the Sundarban area under South 24 Parganas district of West Bengal. MATERIALS AND METHODS: Detailed demographic and clinical data on DSH cases of 13 Block Primary Health Centres (BPHCs') admission registers were analysed. Focus Group Discussions (FGDs) were conducted with the Panchayat Samithy of each block to elicit their perception about the problem of pesticide-related DSH or suicide in the region. RESULTS: Five thousand, one hundred and seventy-eight (1,887 male and 3,291 female) subjects were admitted in the BPHCs during the study period from 1999 to 2001. Organophosphorous pesticide poisoning was found to be the most common method (85.1%) in DSH. This emphasizes the importance of developing an urgent poisoning prevention program with a special focus on improving clinical services as well as initiating farmers' education programs focusing on safe pesticide practices at the primary care level. PMID- 20711395 TI - Escitalopram induced mania. AB - This is a report of a case of recurrent depression with hypertension, ischemic heart disease and diabetes mellitus which switched to mania while on escitalopram. Escitalopram, one of the newer selective serotonin reuptake inhibitors (SSRIs), is considered to have fewer adverse effects and a lower propensity for drug interactions. However, escitalopram may induce mania at a maximum dose of 20 mg especially when given with Alprazolam which is known to boost efficacy of SSRIs. PMID- 20711396 TI - Somnambulism: Diagnosis and treatment. AB - Somnambulism is an arousal disorder that is usually benign, self-limited and only infrequently requires treatment. Chronic sleepwalking in children has been shown to be associated with behavioral problems and poor emotional regulation. Most cases can be diagnosed with careful noting of case history and epilepsy is an important differential diagnosis. Management with pharmacological and behavioural measures is usually safe and effective. We present two cases of somnambulism that highlight the importance of the diagnosis and treatment of this condition. PMID- 20711397 TI - Why is alcohol excluded and opium included in NDPS act, 1985? PMID- 20711398 TI - Confounding. AB - BACKGROUND: Confounding is a statistical concept that is important to all researchers. MATERIALS AND METHODS: The concept of confounding is explained with the help of an amusing but true example. Simple explanations about and examples of confounding are provided. Methods to deal with confounding are detailed and their applications and disadvantages are examined. CONCLUSIONS: Attention to confounding is necessary at the time of study design as well as during the statistical analysis of data. The failure to identify and control for confounding can result in the faulty interpretation of study outcomes. PMID- 20711399 TI - The limbic system. PMID- 20711400 TI - Anger and the mahaabhaarata. PMID- 20711401 TI - Unusual side effects with acamprosate. PMID- 20711402 TI - Do popular media such as movies aggravate the stigma of mental disorders? PMID- 20711403 TI - Patients and electroconvulsive therapy: Knowledge or attitudes? PMID- 20711404 TI - Psycrossword 1. PMID- 20711406 TI - Limits to diffusive O2 transport: flow, form, and function in nudibranch egg masses from temperate and polar regions. AB - BACKGROUND: Many aquatic animals enclose embryos in gelatinous masses, and these embryos rely on diffusion to supply oxygen. Mass structure plays an important role in limiting or facilitating O2 supply, but external factors such as temperature and photosynthesis can play important roles as well. Other external factors are less well understood. METHODOLOGY/PRINCIPAL FINDINGS: We first explored the effects of water flow on O2 levels inside nudibranch embryo masses and compared the effects of flow on masses from temperate and polar regions. Water flow (still vs. vigorously bubbled) had a strong effect on central O2 levels in all masses; in still water, masses were considerably more hypoxic than in bubbled water. This effect was stronger in temperate than in polar masses, likely due to the increased metabolic demand and O2 consumption of temperate masses. Second, we made what are to our knowledge the first measurements of O2 in invertebrate masses in the field. Consistent with laboratory experiments, O2 in Antarctic masses was high in masses in situ, suggesting that boundary-layer effects do not substantially limit O2 supply to polar embryos in the field. CONCLUSIONS/SIGNIFICANCE: All else being equal, boundary layers are more likely to depress O2 in masses in temperate or tropical regions; thus, selection on parents to choose high-flow sites for mass deposition is likely greater in warm water. Because of the large number of variables affecting diffusive O2 supply to embryos in their natural environment, field observations are necessary to test hypotheses generated from laboratory experiments and mathematical modeling. PMID- 20711405 TI - Human embryonic and rat adult stem cells with primitive endoderm-like phenotype can be fated to definitive endoderm, and finally hepatocyte-like cells. AB - Stem cell-derived hepatocytes may be an alternative cell source to treat liver diseases or to be used for pharmacological purposes. We developed a protocol that mimics mammalian liver development, to differentiate cells with pluripotent characteristics to hepatocyte-like cells. The protocol supports the stepwise differentiation of human embryonic stem cells (ESC) to cells with characteristics of primitive streak (PS)/mesendoderm (ME)/definitive endoderm (DE), hepatoblasts, and finally cells with phenotypic and functional characteristics of hepatocytes. Remarkably, the same protocol can also differentiate rat multipotent adult progenitor cells (rMAPCs) to hepatocyte-like cells, even though rMAPC are isolated clonally from cultured rat bone marrow (BM) and have characteristics of primitive endoderm cells. A fraction of rMAPCs can be fated to cells expressing genes consistent with a PS/ME/DE phenotype, preceding the acquisition of phenotypic and functional characteristics of hepatocytes. Although the hepatocyte like progeny derived from both cell types is mixed, between 10-20% of cells are developmentally consistent with late fetal hepatocytes that have attained synthetic, storage and detoxifying functions near those of adult hepatocytes. This differentiation protocol will be useful for generating hepatocyte-like cells from rodent and human stem cells, and to gain insight into the early stages of liver development. PMID- 20711408 TI - Herbivore and fungal pathogen exclusion affects the seed production of four common grassland species. AB - Insect herbivores and fungal pathogens can independently affect plant fitness, and may have interactive effects. However, few studies have experimentally quantified the joint effects of insects and fungal pathogens on seed production in non-agricultural populations. We examined the factorial effects of insect herbivore exclusion (via insecticide) and fungal pathogen exclusion (via fungicide) on the population-level seed production of four common graminoid species (Andropogon gerardii, Schizachyrium scoparium, Poa pratensis, and Carex siccata) over two growing seasons in Minnesota, USA. We detected no interactive effects of herbivores and pathogens on seed production. However, the seed production of all four species was affected by either insecticide or fungicide in at least one year of the study. Insecticide consistently doubled the seed production of the historically most common species in the North American tallgrass prairie, A. gerardii (big bluestem). This is the first report of insect removal increasing seed production in this species. Insecticide increased A. gerardii number of seeds per seed head in one year, and mass per seed in both years, suggesting that consumption of flowers and seed embryos contributed to the effect on seed production. One of the primary insect species consuming A. gerardii flowers and seed embryos was likely the Cecidomyiid midge, Contarinia wattsi. Effects on all other plant species varied among years. Herbivores and pathogens likely reduce the dispersal and colonization ability of plants when they reduce seed output. Therefore, impacts on seed production of competitive dominant species may help to explain their relatively poor colonization abilities. Reduced seed output by dominant graminoids may thereby promote coexistence with subdominant species through competition-colonization tradeoffs. PMID- 20711407 TI - Dietary protein and blood pressure: a systematic review. AB - BACKGROUND: Elevated blood pressure (BP), which is a major risk factor for cardiovascular disease, is highly prevalent worldwide. Recently, interest has grown in the role of dietary protein in human BP. We performed a systematic review of all published scientific literature on dietary protein, including protein from various sources, in relation to human BP. METHODOLOGY/PRINCIPAL FINDINGS: We performed a MEDLINE search and a manual search to identify English language studies on the association between protein and blood pressure, published before June 2010. A total of 46 papers met the inclusion criteria. Most observational studies showed no association or an inverse association between total dietary protein and BP or incident hypertension. Results of biomarker studies and randomized controlled trials indicated a beneficial effect of protein on BP. This beneficial effect may be mainly driven by plant protein, according to results in observational studies. Data on protein from specific sources (e.g. from fish, dairy, grain, soy, and nut) were scarce. There was some evidence that BP in people with elevated BP and/or older age could be more sensitive to dietary protein. CONCLUSIONS/SIGNIFICANCE: In conclusion, evidence suggests a small beneficial effect of protein on BP, especially for plant protein. A blood pressure lowering effect of protein may have important public health implications. However, this warrants further investigation in randomized controlled trials. Furthermore, more data are needed on protein from specific sources in relation to BP, and on the protein-BP relation in population subgroups. PMID- 20711411 TI - Photoconductive and polarization properties of individual CdTe nanowires. PMID- 20711409 TI - Synergy in efficacy of fungal entomopathogens and permethrin against West African insecticide-resistant Anopheles gambiae mosquitoes. AB - BACKGROUND: Increasing incidences of insecticide resistance in malaria vectors are threatening the sustainable use of contemporary chemical vector control measures. Fungal entomopathogens provide a possible additional tool for the control of insecticide-resistant malaria mosquitoes. This study investigated the compatibility of the pyrethroid insecticide permethrin and two mosquito pathogenic fungi, Beauveria bassiana and Metarhizium anisopliae, against a laboratory colony and field population of West African insecticide-resistant Anopheles gambiae s.s. mosquitoes. METHODOLOGY/FINDINGS: A range of fungus insecticide combinations was used to test effects of timing and sequence of exposure. Both the laboratory-reared and field-collected mosquitoes were highly resistant to permethrin but susceptible to B. bassiana and M. anisopliae infection, inducing 100% mortality within nine days. Combinations of insecticide and fungus showed synergistic effects on mosquito survival. Fungal infection increased permethrin-induced mortality rates in wild An. gambiae s.s. mosquitoes and reciprocally, exposure to permethrin increased subsequent fungal-induced mortality rates in both colonies. Simultaneous co-exposure induced the highest mortality; up to 70.3+/-2% for a combined Beauveria and permethrin exposure within a time range of one gonotrophic cycle (4 days). CONCLUSIONS/SIGNIFICANCE: Combining fungi and permethrin induced a higher impact on mosquito survival than the use of these control agents alone. The observed synergism in efficacy shows the potential for integrated fungus-insecticide control measures to dramatically reduce malaria transmission and enable control at more moderate levels of coverage even in areas where insecticide resistance has rendered pyrethroids essentially ineffective. PMID- 20711410 TI - Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens. CONCLUSION/SIGNIFICANCE: Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8. PMID- 20711412 TI - Advances in Auditory and Vestibular Medicine. AB - Auditory and Vestibular medicine is becoming more accepted as a specialty of its own, Medical NeurOtology. Recent advances in the field have been instrumental in the understanding of the scientific foundations, pathophysiology, clinical approach and management of patients with hearing and vestibular disorders. This paper will review these advances. PMID- 20711413 TI - Geometric and electronic structure and reactivity of a mononuclear "side-on" nickel(III)-peroxo complex. AB - Metal-dioxygen adducts, such as metal-superoxo and -peroxo species, are key intermediates often detected in the catalytic cycles of dioxygen activation by metalloenzymes and biomimetic compounds. The synthesis and spectroscopic characterization of an end-on nickel(II)-superoxo complex with a 14-membered macrocyclic ligand was reported previously. Here we report the isolation, spectroscopic characterization, and high-resolution crystal structure of a mononuclear side-on nickel(III)-peroxo complex with a 12-membered macrocyclic ligand, [Ni(12-TMC)(O(2))](+) (1) (12-TMC = 1,4,7,10-tetramethyl-1,4,7,10 tetraazacyclododecane). Different from the end-on Ni(II)-superoxo complex, the Ni(III)-peroxo complex is not reactive in electrophilic reactions, but is capable of conducting nucleophilic reactions. The Ni(III)-peroxo complex transfers the bound dioxygen to manganese(II) complexes, thus affording the corresponding nickel(II) and manganese(III)-peroxo complexes. The present results demonstrate the significance of supporting ligands in tuning the geometric and electronic structures and reactivities of metal-O(2) intermediates that have been shown to have biological as well as synthetic usefulness in biomimetic reactions. PMID- 20711414 TI - Amide-Directed Arylation of sp C-H Bonds using Pd(II) and Pd(0) Catalysts. AB - Protocols to effect beta-arylation of sp(3) C-H bonds via Pd(II)/(IV) and Pd(0)/(II) catalytic cycles have been achieved using a newly developed monodentate CONHC(6)F(5) directing group. These reactions provide an unprecedented means to functionalize sp(3) C-H bonds in aliphatic carboxylic acid derived substrates. PMID- 20711416 TI - RecA-independent single-stranded DNA oligonucleotide-mediated mutagenesis. AB - The expression of Beta, the single-stranded annealing protein (SSAP) of bacteriophage lambda in Escherichia coli promotes high levels of oligonucleotide (oligo)-mediated mutagenesis and offers a quick way to create single or multiple base pair insertions, deletions, or substitutions in the bacterial chromosome. High rates of mutagenesis can be obtained by the use of mismatch repair (MMR) resistant mismatches or MMR-deficient hosts, which allow for the isolation of unselected mutations. It has recently become clear that many bacteria can be mutagenized with oligos in the absence of any SSAP expression, albeit at a much lower frequency. Studies have shown that inactivation or inhibition of single stranded DNA (ssDNA) exonucleases in vivo increases the rate of SSAP-independent oligo-mediated mutagenesis. These results suggest that lambda Beta, in addition to its role in annealing the oligo to ssDNA regions of the replication fork, promotes high rates of oligo-mediated mutagenesis by protecting the oligo from destruction by host ssDNA exonucleases. PMID- 20711415 TI - Long Term Effects of Energy-Restricted Diets Differing in Glycemic Load on Metabolic Adaptation and Body Composition. AB - A randomized controlled trial of high glycemic load (HG) and low glycemic load (LG) diets with food provided for 6 months and self-administered for 6 additional months at 30% caloric restriction (CR) was performed in 29 overweight adults (mean+/-SD, age 35+/-5y; BMI 27.5+/-1.5 kg/m(2)). Total energy expenditure (TEE), resting metabolic rate (RMR), fat and fat free mass (FFM), were measured at 3, 6 and 12 months. Changes in TEE, but not changes in RMR, were greater than accounted for by the loss of FFM and fat mass (P=0.001-0.013) suggesting an adaptive response to long-term CR. There was no significant effect of diet group on change in RMR or TEE. However, in subjects who lost >5% body weight (n=26), the LG diet group had a higher percentage of weight loss as fat than the HG group (p<0.05), a finding that may have implications for dietary recommendations during weight reduction. PMID- 20711417 TI - Economically Disadvantaged Children's Transitions Into Elementary School: Linking Family Processes, School Contexts, and Educational Policy. AB - Working from a core perspective on the developmental implications of economic disadvantage, this study attempted to identify family-based mechanisms of economic effects on early learning and their potential school-based remedies. Multilevel analysis of the Early Childhood Longitudinal Study-Kindergarten Cohort revealed that the accumulation of markers of economic disadvantage reduced math and reading testing gains across the primary grades. Such disparities were partially mediated by corresponding differences in children's socioemotional problems, parenting stress, and parents' human capital investments. These patterns appeared to be robust to observed and unobserved confounds. Various teacher qualifications and classroom practices were assessed as moderators of these family mediators, revealing teacher experience in grade level as a fairly consistent buffer against family-based risks for reading. PMID- 20711418 TI - Electronic Control of Product Distribution in the [5+5]-Coupling of ortho Alkynylbenzaldehyde Derivatives and gamma,delta-Unsaturated Carbene Complexes. AB - The coupling of highly oxygenated ortho-alkynylbenzaldehyde derivatives with gamma,delta-carbene complexes was evaluated systematically. In all of the electron-rich systems investigated the exclusive product of the reaction is the dihydrophenanthrene derivative. Only the extremely electron withdrawing methanesulfonate group can prevent this process from occurring. The use of the base additive collidine resulted in a surprising yield enhancement but no other discernable effect on the course of the reaction. Dihydrophenanthrene formation was attributed to rapid dehydration after the opening of a benzo-oxanorbornene intermediate. PMID- 20711419 TI - A high throughput method for identifying personalized tumor-associated antigens. AB - Circulating autoantibodies against tumor-associated antigens (TAAs) and their pattern of glycosylation can be used as diagnostic indicators of cancer. Using random peptide library screening, we identified patient-specific sets of peptides recognized by colon cancer patients' serum IgG and IgM antibodies. We demonstrate a strategy for analyzing BLAST search results for identifying tumor-associated antigens represented by peptides that mimic sequential epitopes. Statistical analysis of the frequency with which the proteins are retrieved by BLAST homology searching and an estimation of the probability of a match by chance can identify the proteins that are the real targets of the immune response against tumors. In addition, we observed an over-expression of the mRNA for the match-producing protein only in the corresponding tumor sample, out of fourteen tumor and normal samples analyzed. This observation confirms that personalized tumor-associated antigens can be identified by BLAST homology search following random peptide library screening on cancer patient's serum antibodies. PMID- 20711420 TI - Reading Medicine: Mind, Body, and Meditation in One Interpretive Community. PMID- 20711421 TI - Genome-Wide Significance Levels and Weighted Hypothesis Testing. AB - Genetic investigations often involve the testing of vast numbers of related hypotheses simultaneously. To control the overall error rate, a substantial penalty is required, making it difficult to detect signals of moderate strength. To improve the power in this setting, a number of authors have considered using weighted p-values, with the motivation often based upon the scientific plausibility of the hypotheses. We review this literature, derive optimal weights and show that the power is remarkably robust to misspecification of these weights. We consider two methods for choosing weights in practice. The first, external weighting, is based on prior information. The second, estimated weighting, uses the data to choose weights. PMID- 20711422 TI - Understanding Dichromic Fluorescence Manifested in Certain ICG Analogs. AB - Fluorescence has advanced our understanding in various aspects of biological processes. Fluorescence in the near infrared (NIR) region avoids background autofluorescence from biological samples leading to improved image quality. In searching for indocyanine green (ICG) analogs that can be attached to biomolecules, we observed that dichromic fluorescence manifested in some mono reactive-group functionalized ICG analogs. The two emission bands are distinctively separate from each other, making it a unique feature of fluorescent probes found in biological studies. We further demonstrated that the dichromism comes from the structure and is transferable from dye to its bioconjugates. In this paper, we used Resonance Theory and Molecular Orbital Theory to explain the fluorophore photochemistry in an effort to understand the general fluorescence feature of ICG analogs and provide understanding of the secondary emission band. PMID- 20711423 TI - Diffeomorphic Matching of Diffusion Tensor Images. AB - This paper proposes a method to match diffusion tensor magnetic resonance images (DT-MRI) through the large deformation diffeomorphic metric mapping of tensor fields on the image volume, resulting in optimizing for geodesics on the space of diffeomorphisms connecting two diffusion tensor images. A coarse to fine multi resolution and multi-kernel-width scheme is detailed, to reduce both ambiguities and computation load. This is illustrated by numerical experiments on DT-MRI brain and images. PMID- 20711424 TI - Mimicking PAMAM Dendrimers with Ampholytic, Hybrid Triazine Dendrimers: A Comparison of Dispersity and Stability. AB - Two strategies are applied to mimic the ampholytic nature of the surfaces of half generation PAMAM dendrimers and yet retain the very narrow dispersity inherent of triazine dendrimers. Both strategies start with a monodisperse, single-chemical entity, generation two triazine dendrimer presenting twelve surface amines that is available at the kilogram scale. The first method relies on reaction with methyl bromoacetate. Complete conversion of the surface primary amines to tertiary amines occurs to provide 24 surface esters. Extended reaction times lead to quarternization of the amines while other unidentified species are also present. The resulting polyester can be quantitatively hydrolyzed using 4M aqueous HCl to yield a dendrimer with 12 tertiary amines and 24 carboxylic acids about a hydrophobic triazine core. The second method utilizes Michael additions of methyl acrylate to yield 24 surface esters. This reaction proceeds more rapidly and more cleanly than the former strategy. Hydrolysis of this material proceeds quantitatively using 4M aqueous HCl to yield desired dendrimer. In both cases, MALDI-TOF mass spectrometry provides compelling evidence of reaction progress. Electrophoretic analysis confirms the ampholytic nature of these materials with the former targets having a pI value in the 1.8 < pI < 3.4 range, and the latter having a pI value in the 4.7 < pI < 5.9. These ranges bookend the pH range within which PAMAM dendrimers become zwitterionic, 3.4 < pI < 4.7. The strategy of using monodisperse amine-terminated dendrimer constructs as core offers significant advantage over PAMAM homopolymers including dispersity, ease of characterization and batch-to-batch reproducibility. These triazine dendrimers could ultimately be adopted into materials with applications wherein the demands of purity have hitherto remained unsatisfied. PMID- 20711425 TI - RGD dendron bodies; synthetic avidity agents with defined and potentially interchangeable effector sites that can substitute for antibodies. AB - Poly(amidoamine) (PAMAM) dendrons were synthesized with c(RGDyK) peptide on the surface to create a scaffold for cellular targeting and multivalent binding. Binary dendron-RGD conjugates were synthesized with a single Alexa Fluor 488, biotin, methotrexate drug molecule, or additional functionalized dendron at the focal point. The targeted dendron platform was shown to specifically target alphavbeta3 integrin expressing human umbilical vein endothelial cells (HUVEC) and human glioblastoma cells (U87MG) in Vitro via flow cytometry. Specific targeting of the dendron-RGD platform was further confirmed by confocal microscopy. Biological activity of the targeted drug conjugate was confirmed via XTT assay. The orthogonal reaction chemistry used at the dendron focal point gives a precise 1:1 ratio of the attachment of multiple functionalities to a small-molecular-weight, chemically stable, high avidity molecule. These studies serve as a framework to selectively combine biologically relevant functions with enhanced specific binding activity to substitute for antibodies in many diagnostic and therapeutic applications. PMID- 20711426 TI - Polarized secretion of interleukin (IL)-6 and IL-8 by human airway epithelia 16HBE14o- cells in response to cationic polypeptide challenge. AB - BACKGROUND: The airway epithelium participates in asthmatic inflammation in many ways. Target cells of the epithelium can respond to a variety of inflammatory mediators and cytokines. Damage to the surface epithelium occurs following the secretion of eosinophil-derived, highly toxic cationic proteins. Moreover, the surface epithelium itself is responsible for the synthesis and release of cytokines that cause the selective recruitment, retention, and accumulation of various inflammatory cells. To mimic the damage seen during asthmatic inflammation, the bronchial epithelium can be challenged with highly charged cationic polypeptides such as poly-L-arginine. METHODOLOGY/PRINCIPAL FINDINGS: In this study, human bronchial epithelial cells, 16HBE14o- cells, were "chemically injured" by exposing them to poly-l-arginine as a surrogate of the eosinophil cationic protein. Cytokine antibody array data showed that seven inflammatory mediators were elevated out of the 40 tested, including marked elevation in interleukin (IL)-6 and IL-8 secretion. IL-6 and IL-8 mRNA expression levels were elevated as measured with real-time PCR. Cell culture supernatants from apical and basolateral compartments were collected, and the IL-6 and IL-8 production was quantified with ELISA. IL-6 and IL-8 secretion by 16HBE14o- epithelia into the apical compartment was significantly higher than that from the basolateral compartment. Using specific inhibitors, the production of IL-6 and IL-8 was found to be dependent on p38 MAPK, ERK1/2 MAPK, and NF-kappaB pathways. CONCLUSIONS/SIGNIFICANCE: The results clearly demonstrate that damage to the bronchial epithelia by poly-L-arginine stimulates polarized IL-6 and IL-8 secretion. This apically directed secretion of cytokines may play an important role in orchestrating epithelial cell responses to inflammation. PMID- 20711427 TI - Deep sequencing of the vaginal microbiota of women with HIV. AB - BACKGROUND: Women living with HIV and co-infected with bacterial vaginosis (BV) are at higher risk for transmitting HIV to a partner or newborn. It is poorly understood which bacterial communities constitute BV or the normal vaginal microbiota among this population and how the microbiota associated with BV responds to antibiotic treatment. METHODS AND FINDINGS: The vaginal microbiota of 132 HIV positive Tanzanian women, including 39 who received metronidazole treatment for BV, were profiled using Illumina to sequence the V6 region of the 16S rRNA gene. Of note, Gardnerella vaginalis and Lactobacillus iners were detected in each sample constituting core members of the vaginal microbiota. Eight major clusters were detected with relatively uniform microbiota compositions. Two clusters dominated by L. iners or L. crispatus were strongly associated with a normal microbiota. The L. crispatus dominated microbiota were associated with low pH, but when L. crispatus was not present, a large fraction of L. iners was required to predict a low pH. Four clusters were strongly associated with BV, and were dominated by Prevotella bivia, Lachnospiraceae, or a mixture of different species. Metronidazole treatment reduced the microbial diversity and perturbed the BV-associated microbiota, but rarely resulted in the establishment of a lactobacilli-dominated microbiota. CONCLUSIONS: Illumina based microbial profiling enabled high though-put analyses of microbial samples at a high phylogenetic resolution. The vaginal microbiota among women living with HIV in Sub-Saharan Africa constitutes several profiles associated with a normal microbiota or BV. Recurrence of BV frequently constitutes a different BV associated profile than before antibiotic treatment. PMID- 20711428 TI - Delayed treatment with systemic (S)-roscovitine provides neuroprotection and inhibits in vivo CDK5 activity increase in animal stroke models. AB - BACKGROUND: Although quite challenging, neuroprotective therapies in ischemic stroke remain an interesting strategy to counter mechanisms of ischemic injury and reduce brain tissue damage. Among potential neuroprotective drug, cyclin dependent kinases (CDK) inhibitors represent interesting therapeutic candidates. Increasing evidence indisputably links cell cycle CDKs and CDK5 to the pathogenesis of stroke. Although recent studies have demonstrated promising neuroprotective efficacies of pharmacological CDK inhibitors in related animal models, none of them were however clinically relevant to human treatment. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we report that systemic delivery of (S)-roscovitine, a well known inhibitor of mitotic CDKs and CDK5, was neuroprotective in a dose-dependent manner in two models of focal ischemia, as recommended by STAIR guidelines. We show that (S)-roscovitine was able to cross the blood brain barrier. (S)-roscovitine significant in vivo positive effect remained when the compound was systemically administered 2 hrs after the insult. Moreover, we validate one of (S)-roscovitine in vivo target after ischemia. Cerebral increase of CDK5/p25 activity was observed 3 hrs after the insult and prevented by systemic (S)-roscovitine administration. Our results show therefore that roscovitine protects in vivo neurons possibly through CDK5 dependent mechanisms. CONCLUSIONS/SIGNIFICANCE: Altogether, our data bring new evidences for the further development of pharmacological CDK inhibitors in stroke therapy. PMID- 20711429 TI - Effects of the AMPA antagonist ZK 200775 on visual function: a randomized controlled trial. AB - BACKGROUND: ZK 200775 is an antagonist at the alpha-Amino-3-hydroxy-5-methyl-4 isoxazolepropionate (AMPA) receptor and had earned attention as a possible neuroprotective agent in cerebral ischemia. Probands receiving the agent within phase I trials reported on an alteration of visual perception. In this trial, the effects of ZK 200775 on the visual system were analyzed in detail. METHODOLOGY: In a randomised controlled trial we examined eyes and vision before and after the intravenous administration of two different doses of ZK 200775 and placebo. There were 3 groups of 6 probands each: Group 1 recieved 0.03 mg/kg/h, group 2 0.75 mg/kg/h of ZK 200775, the control group received 0.9% sodium chloride solution. Probands were healthy males aged between 57 and 69 years. The following methods were applied: clinical examination, visual acuity, ophthalmoscopy, colour vision, rod absolute threshold, central visual field, pattern-reversal visual evoked potentials (pVEP), ON-OFF and full-field electroretinogram (ERG). PRINCIPAL FINDINGS: No effect of ZK 200775 was seen on eye position or motility, stereopsis, pupillary function or central visual field testing. Visual acuity and dark vision deteriorated significantly in both treated groups. Color vision was most remarkably impaired. The dark-adapted ERG revealed a reduction of oscillatory potentials (OP) and partly of the a- and b-wave, furthermore an alteration of b-wave morphology and an insignificantly elevated b/a-ratio. Cone ERG modalities showed decreased amplitudes and delayed implicit times. In the ON OFF ERG the ON-answer amplitudes increased whereas the peak times of the OFF answer were reduced. The pattern VEP exhibited lower amplitudes and prolonged peak times. CONCLUSIONS: The AMPA receptor blockade led to a strong impairment of typical OFF-pathway functions like color vision and the cone ERG. On the other hand the ON-pathway as measured by dark vision and the scotopic ERG was affected as well. This further elucidates the interdependence of both pathways. TRIAL REGISTRATION: ClinicalTrials.gov NCT00999284. PMID- 20711430 TI - Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice. AB - Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were identified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21+/- animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21+/- animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues. PMID- 20711431 TI - The hemorrhagic coli pilus (HCP) of Escherichia coli O157:H7 is an inducer of proinflammatory cytokine secretion in intestinal epithelial cells. AB - BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) O157:H7, the causative agent of hemorrhagic colitis and the hemolytic uremic syndrome (HUS), produces long bundles of type IV pili (TFP) called hemorrhagic coli pili (HCP). HCP are capable of mediating several phenomena associated with pathogenicity: i) adherence to human and bovine epithelial cells; ii) invasion of epithelial cells; iii) hemagglutination of rabbit erythrocytes; iv) biofilm formation; v) twitching motility; and vi) specific binding to laminin and fibronectin. HCP are composed of a 19 kDa pilin subunit (HcpA) encoded by the hcpA chromosomal gene (called prepilin peptidase-dependent gene [ppdD] in E. coli K-12). METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigated the potential role of HCP of E. coli O157:H7 strain EDL933 in activating the release of pro- and anti-inflammatory cytokines from a variety of host epithelial cells. We found that purified HCP and a recombinant HcpA protein induced significant release of IL-8 and TNF-alpha, from cultured polarized intestinal cells (T84 and HT-29 cells) and non-intestinal HeLa cells. Levels of proinflammatory IL-8 and TNF-alpha, but not IL-2, IL6, or IL-10 cytokines, were increased in the presence of HCP and recombinant HcpA after 6 h of incubation with >or=50 ng/ml of protein, suggesting that stimulation of IL 8 and TNF-alpha are dose and time-dependent. In addition, we also demonstrated that flagella are potent inducers of cytokine production. Furthermore, MAPK activation kinetics studies showed that EHEC induces p38 phosphorylation under HCP-producing conditions, and ERK1/2 and JNK activation was detectable after 3 h of EHEC infection. HT-29 cells were stimulated with epidermal growth factor stimulation of HT-29 cells for 30 min leading to activation of three MAPKs. CONCLUSIONS/SIGNIFICANCE: The HcpA pilin monomer of the HCP produced by EHEC O157:H7 is a potent inducer of IL-8 and TNF-alpha release, an event which could play a significant role in the pathogenesis of hemorrhagic colitis caused by this pathogen. PMID- 20711432 TI - Prospectively isolated cancer-associated CD10(+) fibroblasts have stronger interactions with CD133(+) colon cancer cells than with CD133(-) cancer cells. AB - Although CD133 has been reported to be a promising colon cancer stem cell marker, the biological functions of CD133+ colon cancer cells remain controversial. In the present study, we investigated the biological differences between CD133+ and CD133- colon cancer cells, with a particular focus on their interactions with cancer-associated fibroblasts, especially CD10+ fibroblasts. We used 19 primary colon cancer tissues, 30 primary cultures of fibroblasts derived from colon cancer tissues and 6 colon cancer cell lines. We isolated CD133+ and CD133- subpopulations from the colon cancer tissues and cultured cells. In vitro analyses revealed that the two populations showed similar biological behaviors in their proliferation and chemosensitivity. In vivo analyses revealed that CD133+ cells showed significantly greater tumor growth than CD133- cells (P=0.007). Moreover, in cocultures with primary fibroblasts derived from colon cancer tissues, CD133+ cells exhibited significantly more invasive behaviors than CD133- cells (P<0.001), especially in cocultures with CD10+ fibroblasts (P<0.0001). Further in vivo analyses revealed that CD10+ fibroblasts enhanced the tumor growth of CD133+ cells significantly more than CD10- fibroblasts (P<0.05). These data demonstrate that the in vitro invasive properties and in vivo tumor growth of CD133+ colon cancer cells are enhanced in the presence of specific cancer associated fibroblasts, CD10+ fibroblasts, suggesting that the interactions between these specific cell populations have important roles in cancer progression. Therefore, these specific interactions may be promising targets for new colon cancer therapies. PMID- 20711433 TI - Cross-reactivity of herpesvirus-specific CD8 T cell lines toward allogeneic class I MHC molecules. AB - Although association between persistent viral infection and allograft rejection is well characterized, few examples of T-cell cross-reactivity between self MHC/viral and allogeneic HLA molecules have been documented so far. We appraised in this study the alloreactivity of CD8 T cell lines specific for immunodominant epitopes from human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). CD8 T cell lines were generated after sorting with immunomagnetic beads coated with either pp65(495-503)/A*0201, BMLF1(259-267)/A*0201, or BZLF1(54-64)/B*3501 multimeric complexes. Alloreactivity of the CD8 T cell lines against allogeneic class I MHC alleles was assessed by screening of (i) TNF-alpha production against COS-7 cells transfected with as many as 39 individual HLA class I-encoding cDNA, and (ii) cytotoxicity activity toward a large panel of HLA-typed EBV-transformed B lymphoblastoid cell lines. We identified several cross-reactive pp65/A*0201 specific T cell lines toward allogeneic HLA-A*3001, A*3101, or A*3201. Moreover, we described here cross-recognition of HLA-Cw*0602 by BZLF1/B*3501-specific T cells. It is noteworthy that these alloreactive CD8 T cell lines showed efficient recognition of endothelial cells expressing the relevant HLA class I allele, with high level TNF-alpha production and cytotoxicity activity. Taken together, our data support the notion that herpes virus-specific T cells recognizing allo-HLA alleles may promote solid organ rejection. PMID- 20711434 TI - Puma and Trail/Dr5 pathways control radiation-induced apoptosis in distinct populations of testicular progenitors. AB - Spermatogonia- stem cells and progenitors of adult spermatogenesis- are killed through a p53-regulated apoptotic process after gamma-irradiation but the death effectors are still poorly characterized. Our data demonstrate that both intrinsic and extrinsic apoptotic pathways are involved, and especially that spermatogonia can be split into two main populations, according to apoptotic effectors. Following irradiation both Dr5 and Puma genes are upregulated in the alpha6-integrin-positive Side Population (SP) fraction, which is highly enriched in spermatogonia. Flow cytometric analysis confirms an increased number of Dr5 expressing SP cells, and Puma-beta isoform accumulates in alpha6-integrin positive cellular extracts, enriched in spermatogonia. Trail-/- or Puma-/- spermatogonia display a reduced sensitivity to radiation-induced apoptosis. The TUNEL kinetics strongly suggest that the extrinsic and intrinsic pathways, via Trail/Dr5 and Puma respectively, could be engaged in distinct subpopulations of spermatogonia. Indeed flow cytometric studies show that Dr5 receptor is constitutively present on more than half of the undifferentiated progenitors (Kit alpha6+ SP) and half of the differentiated ones (Kit+ alpha6+ SP). In addition after irradiation, Puma is not detected in the Dr5-positive cellular fraction isolated by immunomagnetic purification, while Puma is present in the Dr5 negative cell extracts. In conclusion, adult testicular progenitors are divided into distinct sub-populations by apoptotic effectors, independently of progenitor types (immature Kit-negative versus mature Kit-positive), underscoring differential radiosensitivities characterizing the stem cell/progenitors compartment. PMID- 20711435 TI - Update on the management of constipation in the elderly: new treatment options. AB - Constipation disproportionately affects older adults, with a prevalences of 50% in community-dwelling elderly and 74% in nursing-home residents. Loss of mobility, medications, underlying diseases, impaired anorectal sensation, and ignoring calls to defecate are as important as dyssynergic defecation or irritable bowel syndrome in causing constipation. Detailed medical history on medications and co-morbid problems, and meticulous digital rectal examination may help identify causes of constipation. Likewise, blood tests and colonoscopy may identify organic causes such as colon cancer. Physiological tests such as colonic transit study with radio-opaque markers or wireless motility capsule, anorectal manometry, and balloon expulsion tests can identify disorders of colonic and anorectal function. However, in the elderly, there is usually more than one mechanism, requiring an individualized but multifactorial treatment approach. The management of constipation continues to evolve. Although osmotic laxatives such as polyethylene glycol remain mainstay, several new agents that target different mechanisms appear promising such as chloride-channel activator (lubiprostone), guanylate cyclase agonist (linaclotide), 5HT(4) agonist (prucalopride), and peripherally acting mu-opioid receptor antagonists (alvimopan and methylnaltrexone) for opioid-induced constipation. Biofeedback therapy is efficacious for treating dyssynergic defecation and fecal impaction with soiling. However, data on efficacy and safety of drugs in elderly are limited and urgently needed. PMID- 20711436 TI - Simple equations to predict concentric lower-body muscle power in older adults using the 30-second chair-rise test: a pilot study. AB - Although muscle power is an important factor affecting independence in older adults, there is no inexpensive or convenient test to quantify power in this population. Therefore, this pilot study examined whether regression equations for evaluating muscle power in older adults could be derived from a simple chair-rise test. We collected data from a 30-second chair-rise test performed by fourteen older adults (76 +/- 7.19 years). Average (AP) and peak (PP) power values were computed using data from force-platform and high-speed motion analyses. Using each participant's body mass and the number of chair rises performed during the first 20 seconds of the 30-second trial, we developed multivariate linear regression equations to predict AP and PP. The values computed using these equations showed a significant linear correlation with the values derived from our force-platform and high-speed motion analyses (AP: R = 0.89; PP: R = 0.90; P < 0.01). Our results indicate that lower-body muscle power in fit older adults can be accurately evaluated using the data from the initial 20 seconds of a simple 30-second chair-rise test, which requires no special equipment, preparation, or setting. PMID- 20711437 TI - Functional mobility and balance in community-dwelling elderly submitted to multisensory versus strength exercises. AB - It is well documented that aging impairs balance and functional mobility. The objective of this study was to compare the efficacy of multisensory versus strength exercises on these parameters. We performed a simple blinded randomized controlled trial with 46 community-dwelling elderly allocated to strength ([GST], N = 23, 70.2-years-old +/- 4.8 years) or multisensory ([GMS], N = 23, 68.8-years old +/- 5.9 years) exercises twice a week for 12 weeks. Subjects were evaluated by blinded raters using the timed 'up and go' test (TUG), the Guralnik test battery, and a force platform. By the end of the treatment, the GMS group showed a significant improvement in TUG (9.1 +/- 1.9 seconds (s) to 8.0 +/- 1.0 s, P = 0.002); Guralnik test battery (10.6 +/- 1.2 to 11.3 +/- 0.8 P = 0.009); lateromedial (6.1 +/- 11.7 cm to 3.1 +/- 1.6 cm, P = 0.02) and anteroposterior displacement (4.7 +/- 4.2 cm to 3.4 +/- 1.0 cm, P = 0.03), which were not observed in the GST group. These results reproduce previous findings in the literature and mean that the stimulus to sensibility results in better achievements for the control of balance and dynamic activities. Multisensory exercises were shown to be more efficacious than strength exercises to improve functional mobility. PMID- 20711438 TI - Is there an optimal management for localized prostate cancer? AB - Widespread screening with prostate-specific antigen (PSA) has led to a significant increase in the detection of early stage, clinically localized prostate cancer (CaP). Various treatment options for localized CaP are discussed in this review article including active surveillance, radical prostatectomy, radiation therapy, and cryotherapy. The paucity of high-level evidence adds a considerable amount of controversy when choosing the "optimal" intervention, for both the treating physician and the patient. The long time course of CaP intervention outcomes, combined with continuing modifications in treatments, further complicate the matter. Lacking randomized trials that compare treatment options, this review article attempts to summarize the different treatment options and associated side-effects, including effects on health-related quality of life, from current published literature. PMID- 20711439 TI - Preferences for heat, cold, or contrast in patients with knee osteoarthritis affect treatment response. AB - OBJECTIVE: This investigation assessed preferences for, and effects of, 5 days of twice daily superficial heat, cold, or contrast therapy applied with a commercially available system permitting the circulation of water through a wrap around garment, use of an electric heating pad, or rest for patients with level II-IV osteoarthritis (OA) of the knee. METHODS: We employed a within subject, randomized order design to study 34 patients receiving each treatment in 1-week blocks. A knee injury and osteoarthritis outcome score (KOOS) questionnaire and visual analog pain scale was completed at baseline, and twice each week. Treatment preferences were assessed in the last week of the study. RESULTS: Treatment with the device set to warm was preferred by 48% of subjects. Near equal preferences were observed for cold (24%) and contrast (24%). Pain reduction and improvements in KOOS subscale measures were demonstrated for each treatment but responses were (P < 0.05) greater with preferred treatments. Most patients preferred treatment with the water circulating garment system over a heating pad. CONCLUSIONS: We recommend that when superficial heat or cold is considered in the management of knee OA that patients experiment to identify the intervention that offers them the greatest relief and that contrast is a treatment option. PMID- 20711441 TI - An Association Test for Multiple Traits Based on the Generalized Kendall's Tau. AB - In many genetics studies, especially in the investigation of mental illness and behavioral disorders, it is common for researchers to collect multiple phenotypes to characterize the complex disease of interest. It may be advantageous to analyze those phenotypic measurements simultaneously if they share a similar genetic mechanism. In this study, we present a nonparametric approach to studying multiple traits together rather than examining each trait separately. Through simulation we compared the nominal type I error and power of our proposed test to an existing test, i.e., a generalized family-based association test. The empirical results suggest that our proposed approach is superior to the existing test in the analysis of ordinal traits. The advantage is demonstrated on a data set concerning alcohol dependence. In this application, the use of our methods enhanced the signal of the association test. PMID- 20711440 TI - Assessment and management of nutrition in older people and its importance to health. AB - Nutrition is an important element of health in the older population and affects the aging process. The prevalence of malnutrition is increasing in this population and is associated with a decline in: functional status, impaired muscle function, decreased bone mass, immune dysfunction, anemia, reduced cognitive function, poor wound healing, delayed recovery from surgery, higher hospital readmission rates, and mortality. Older people often have reduced appetite and energy expenditure, which, coupled with a decline in biological and physiological functions such as reduced lean body mass, changes in cytokine and hormonal level, and changes in fluid electrolyte regulation, delay gastric emptying and diminish senses of smell and taste. In addition pathologic changes of aging such as chronic diseases and psychological illness all play a role in the complex etiology of malnutrition in older people. Nutritional assessment is important to identify and treat patients at risk, the Malnutrition Universal Screening Tool being commonly used in clinical practice. Management requires a holistic approach, and underlying causes such as chronic illness, depression, medication and social isolation must be treated. Patients with physical or cognitive impairment require special care and attention. Oral supplements or enteral feeding should be considered in patients at high risk or in patients unable to meet daily requirements. PMID- 20711442 TI - Livelihood diversification in tropical coastal communities: a network-based approach to analyzing 'livelihood landscapes'. AB - BACKGROUND: Diverse livelihood portfolios are frequently viewed as a critical component of household economies in developing countries. Within the context of natural resources governance in particular, the capacity of individual households to engage in multiple occupations has been shown to influence important issues such as whether fishers would exit a declining fishery, how people react to policy, the types of resource management systems that may be applicable, and other decisions about natural resource use. METHODOLOGY/PRINCIPAL FINDINGS: This paper uses network analysis to provide a novel methodological framework for detailed systemic analysis of household livelihood portfolios. Paying particular attention to the role of natural resource-based occupations such as fisheries, we use network analyses to map occupations and their interrelationships- what we refer to as 'livelihood landscapes'. This network approach allows for the visualization of complex information about dependence on natural resources that can be aggregated at different scales. We then examine how the role of natural resource-based occupations changes along spectra of socioeconomic development and population density in 27 communities in 5 western Indian Ocean countries. Network statistics, including in- and out-degree centrality, the density of the network, and the level of network centralization are compared along a multivariate index of community-level socioeconomic development and a gradient of human population density. The combination of network analyses suggests an increase in household level specialization with development for most occupational sectors, including fishing and farming, but that at the community-level, economies remained diversified. CONCLUSIONS/SIGNIFICANCE: The novel modeling approach introduced here provides for various types of livelihood portfolio analyses at different scales of social aggregation. Our livelihood landscapes approach provides insights into communities' dependencies and usages of natural resources, and shows how patterns of occupational interrelationships relate to socioeconomic development and population density. A key question for future analysis is how the reduction of household occupational diversity, but maintenance of community diversity we see with increasing socioeconomic development influences key aspects of societies' vulnerability to environmental change or disasters. PMID- 20711443 TI - From grazing resistance to pathogenesis: the coincidental evolution of virulence factors. AB - To many pathogenic bacteria, human hosts are an evolutionary dead end. This begs the question what evolutionary forces have shaped their virulence traits. Why are these bacteria so virulent? The coincidental evolution hypothesis suggests that such virulence factors result from adaptation to other ecological niches. In particular, virulence traits in bacteria might result from selective pressure exerted by protozoan predator. Thus, grazing resistance may be an evolutionarily exaptation for bacterial pathogenicity. This hypothesis was tested by subjecting a well characterized collection of 31 Escherichia coli strains (human commensal or extra-intestinal pathogenic) to grazing by the social haploid amoeba Dictyostelium discoideum. We then assessed how resistance to grazing correlates with some bacterial traits, such as the presence of virulence genes. Whatever the relative population size (bacteria/amoeba) for a non-pathogenic bacteria strain, D. discoideum was able to phagocytise, digest and grow. In contrast, a pathogenic bacterium strain killed D. discoideum above a certain bacteria/amoeba population size. A plating assay was then carried out using the E. coli collection faced to the grazing of D. discoideum. E. coli strains carrying virulence genes such as iroN, irp2, fyuA involved in iron uptake, belonging to the B2 phylogenetic group and being virulent in a mouse model of septicaemia were resistant to the grazing from D. discoideum. Experimental proof of the key role of the irp gene in the grazing resistance was evidenced with a mutant strain lacking this gene. Such determinant of virulence may well be originally selected and (or) further maintained for their role in natural habitat: resistance to digestion by free living protozoa, rather than for virulence per se. PMID- 20711444 TI - SUMOylation by Pias1 regulates the activity of the Hedgehog dependent Gli transcription factors. AB - BACKGROUND: Hedgehog (Hh) signaling, a vital signaling pathway for the development and homeostasis of vertebrate tissues, is mediated by members of the Gli family of zinc finger transcription factors. Hh signaling increases the transcriptional activity of Gli proteins, at least in part, by inhibiting their proteolytic processing. Conversely, phosphorylation by cAMP-dependent protein kinase (PKA) inhibits Gli transcriptional activity by promoting their ubiquitination and proteolysis. Whether other post-translational modifications contribute to the regulation of Gli protein activity has been unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here we provide evidence that all three Gli proteins are targets of small ubiquitin-related modifier (SUMO)-1 conjugation. Expression of SUMO-1 or the SUMO E3 ligase, Pias1, increased Gli transcriptional activity in cultured cells. Moreover, PKA activity reduced Gli protein SUMOylation. Strikingly, in the embryonic neural tube, the forced expression of Pias1 increased Gli activity and induced the ectopic expression of the Gli dependent gene Nkx2.2. Conversely, a point mutant of Pias1, that lacks ligase activity, blocked the endogenous expression of Nkx2.2. CONCLUSIONS/SIGNIFICANCE: Together, these findings provide evidence that Pias1-dependent SUMOylation influences Gli protein activity and thereby identifies SUMOylation as a post translational mechanism that regulates the hedgehog signaling pathway. PMID- 20711445 TI - A minimal model of signaling network elucidates cell-to-cell stochastic variability in apoptosis. AB - BACKGROUND: Signaling networks are designed to sense an environmental stimulus and adapt to it. We propose and study a minimal model of signaling network that can sense and respond to external stimuli of varying strength in an adaptive manner. The structure of this minimal network is derived based on some simple assumptions on its differential response to external stimuli. METHODOLOGY: We employ stochastic differential equations and probability distributions obtained from stochastic simulations to characterize differential signaling response in our minimal network model. Gillespie's stochastic simulation algorithm (SSA) is used in this study. CONCLUSIONS/SIGNIFICANCE: We show that the proposed minimal signaling network displays two distinct types of response as the strength of the stimulus is decreased. The signaling network has a deterministic part that undergoes rapid activation by a strong stimulus in which case cell-to-cell fluctuations can be ignored. As the strength of the stimulus decreases, the stochastic part of the network begins dominating the signaling response where slow activation is observed with characteristic large cell-to-cell stochastic variability. Interestingly, this proposed stochastic signaling network can capture some of the essential signaling behaviors of a complex apoptotic cell death signaling network that has been studied through experiments and large-scale computer simulations. Thus we claim that the proposed signaling network is an appropriate minimal model of apoptosis signaling. Elucidating the fundamental design principles of complex cellular signaling pathways such as apoptosis signaling remains a challenging task. We demonstrate how our proposed minimal model can help elucidate the effect of a specific apoptotic inhibitor Bcl-2 on apoptotic signaling in a cell-type independent manner. We also discuss the implications of our study in elucidating the adaptive strategy of cell death signaling pathways. PMID- 20711446 TI - Expanding the diagnostic use of PCR in leptospirosis: improved method for DNA extraction from blood cultures. AB - BACKGROUND: Leptospirosis is a neglected zoonosis of ubiquitous distribution. Symptoms are often non-specific and may range from flu-like symptoms to multi organ failure. Diagnosis can only be made by specific diagnostic tests like serology and PCR. In non-endemic countries, leptospirosis is often not suspected before antibiotic treatment has been initiated and consequently, relevant samples for diagnostic PCR are difficult to obtain. Blood cultures are obtained from most hospitalized patients before antibiotic therapy and incubated for at least five days, thus providing an important source of blood for PCR diagnosis. However, blood cultures contain inhibitors of PCR that are not readily removed by most DNA extraction methods, primarily sodium polyanetholesulfonate (SPS). METHODOLOGY/PRINCIPAL FINDINGS: In this study, two improved DNA extraction methods for use with blood cultures are presented and found to be superior in recovering DNA of Leptospira interrogans when compared with three previously described methods. The improved methods were easy and robust in use with all tested brands of blood culture media. Applied to 96 blood cultures obtained from 36 patients suspected of leptospirosis, all seven patients with positive convalescence serology were found positive by PCR if at least one anaerobic and one aerobic blood culture, sampled before antibiotic therapy were tested. CONCLUSIONS/SIGNIFICANCE: This study suggests that a specific and early diagnosis can be obtained in most cases of severe leptospirosis for up to five days after initiation of antimicrobial therapy, if PCR is applied to blood cultures already sampled as a routine procedure in most septic patients. PMID- 20711447 TI - Coulomb interactions between cytoplasmic electric fields and phosphorylated messenger proteins optimize information flow in cells. AB - BACKGROUND: Normal cell function requires timely and accurate transmission of information from receptors on the cell membrane (CM) to the nucleus. Movement of messenger proteins in the cytoplasm is thought to be dependent on random walk. However, Brownian motion will disperse messenger proteins throughout the cytosol resulting in slow and highly variable transit times. We propose that a critical component of information transfer is an intracellular electric field generated by distribution of charge on the nuclear membrane (NM). While the latter has been demonstrated experimentally for decades, the role of the consequent electric field has been assumed to be minimal due to a Debye length of about 1 nanometer that results from screening by intracellular Cl- and K+. We propose inclusion of these inorganic ions in the Debye-Huckel equation is incorrect because nuclear pores allow transit through the membrane at a rate far faster than the time to thermodynamic equilibrium. In our model, only the charged, mobile messenger proteins contribute to the Debye length. FINDINGS: Using this revised model and published data, we estimate the NM possesses a Debye-Huckel length of a few microns and find this is consistent with recent measurement using intracellular nano-voltmeters. We demonstrate the field will accelerate isolated messenger proteins toward the nucleus through Coulomb interactions with negative charges added by phosphorylation. We calculate transit times as short as 0.01 sec. When large numbers of phosphorylated messenger proteins are generated by increasing concentrations of extracellular ligands, we demonstrate they generate a self screening environment that regionally attenuates the cytoplasmic field, slowing movement but permitting greater cross talk among pathways. Preliminary experimental results with phosphorylated RAF are consistent with model predictions. CONCLUSION: This work demonstrates that previously unrecognized Coulomb interactions between phosphorylated messenger proteins and intracellular electric fields will optimize information transfer from the CM to the NM in cells. PMID- 20711448 TI - A common left occipito-temporal dysfunction in developmental dyslexia and acquired letter-by-letter reading? AB - BACKGROUND: We used fMRI to examine functional brain abnormalities of German speaking dyslexics who suffer from slow effortful reading but not from a reading accuracy problem. Similar to acquired cases of letter-by-letter reading, the developmental cases exhibited an abnormal strong effect of length (i.e., number of letters) on response time for words and pseudowords. RESULTS: Corresponding to lesions of left occipito-temporal (OT) regions in acquired cases, we found a dysfunction of this region in our developmental cases who failed to exhibit responsiveness of left OT regions to the length of words and pseudowords. This abnormality in the left OT cortex was accompanied by absent responsiveness to increased sublexical reading demands in phonological inferior frontal gyrus (IFG) regions. Interestingly, there was no abnormality in the left superior temporal cortex which--corresponding to the onological deficit explanation--is considered to be the prime locus of the reading difficulties of developmental dyslexia cases. CONCLUSIONS: The present functional imaging results suggest that developmental dyslexia similar to acquired letter-by-letter reading is due to a primary dysfunction of left OT regions. PMID- 20711449 TI - TIP-1 translocation onto the cell plasma membrane is a molecular biomarker of tumor response to ionizing radiation. AB - BACKGROUND: Tumor response to treatment has been generally assessed with anatomic and functional imaging. Recent development of in vivo molecular and cellular imaging showed promise in time-efficient assessment of the therapeutic efficacy of a prescribed regimen. Currently, the in vivo molecular imaging is limited with shortage of biomarkers and probes with sound biological relevance. We have previously shown in tumor-bearing mice that a hexapeptide (HVGGSSV) demonstrated potentials as a molecular imaging probe to distinguish the tumors responding to ionizing radiation (IR) and/or tyrosine kinase inhibitor treatment from those of non-responding tumors. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have studied biological basis of the HVGGSSV peptide binding within the irradiated tumors by use of tumor-bearing mice and cultured cancer cells. The results indicated that Tax interacting protein 1 (TIP-1, also known as Tax1BP3) is a molecular target that enables the selective binding of the HVGGSSV peptide within irradiated xenograft tumors. Optical imaging and immunohistochemical staining indicated that a TIP-1 specific antibody demonstrated similar biodistribution as the peptide in tumor-bearing mice. The TIP-1 antibody blocked the peptide from binding within irradiated tumors. Studies on both of human and mouse lung cancer cells showed that the intracellular TIP-1 relocated to the plasma membrane surface within the first few hours after exposure to IR and before the onset of treatment associated apoptosis and cell death. TIP-1 relocation onto the cell surface is associated with the reduced proliferation and the enhanced susceptibility to the subsequent IR treatment. CONCLUSIONS/SIGNIFICANCE: This study by use of tumor-bearing mice and cultured cancer cells suggested that imaging of the radiation-inducible TIP-1 translocation onto the cancer cell surface may predict the tumor responsiveness to radiation in a time-efficient manner and thus tailor radiotherapy of cancer. PMID- 20711450 TI - The native copper- and zinc-binding protein metallothionein blocks copper mediated Abeta aggregation and toxicity in rat cortical neurons. AB - BACKGROUND: A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (Abeta) plaques. There are compelling data suggesting that Abeta aggregation is catalysed by reaction with the metals zinc and copper. METHODOLOGY/PRINCIPAL FINDINGS: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper mediated aggregation of Abeta1-40 and Abeta1-42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Abeta, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Abeta aggregation. Furthermore, Zn7MT 2A blocked Cu(II)-Abeta induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. CONCLUSIONS/SIGNIFICANCE: These results indicate that MTs of the type represented by MT-2A are capable of protecting against Abeta aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Abeta leaving a metal free Abeta that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Abeta leaves the Abeta in a Zn-bound, relatively inert form. PMID- 20711451 TI - Declining orangutan encounter rates from Wallace to the present suggest the species was once more abundant. AB - BACKGROUND: Bornean orangutans (Pongo pygmaeus) currently occur at low densities and seeing a wild one is a rare event. Compared to present low encounter rates of orangutans, it is striking how many orangutan each day historic collectors like Alfred Russel Wallace were able to shoot continuously over weeks or even months. Does that indicate that some 150 years ago encounter rates with orangutans, or their densities, were higher than now? METHODOLOGY/PRINCIPAL FINDINGS: We test this hypothesis by quantifying encounter rates obtained from hunting accounts, museum collections, and recent field studies, and analysing whether there is a declining trend over time. Logistic regression analyses of our data support such a decline on Borneo between the mid-19th century and the present. Even when controlled for variation in the size of survey and hunting teams and the durations of expeditions, mean daily encounter rates appear to have declined about 6-fold in areas with little or no forest disturbance. CONCLUSIONS/SIGNIFICANCE: This finding has potential consequences for our understanding of orangutans, because it suggests that Bornean orangutans once occurred at higher densities. We explore potential explanations-habitat loss and degradation, hunting, and disease-and conclude that hunting fits the observed patterns best. This suggests that hunting has been underestimated as a key causal factor of orangutan density and distribution, and that species population declines have been more severe than previously estimated based on habitat loss only. Our findings may require us to rethink the biology of orangutans, with much of our ecological understanding possibly being based on field studies of animals living at lower densities than they did historically. Our approach of quantifying species encounter rates from historic data demonstrates that this method can yield valuable information about the ecology and population density of species in the past, providing new insight into species' conservation needs. PMID- 20711452 TI - Comparative immunogenicity of HIV-1 clade C envelope proteins for prime/boost studies. AB - BACKGROUND: Previous clinical efficacy trials failed to support the continued development of recombinant gp120 (rgp120) as a candidate HIV vaccine. However, the recent RV144 HIV vaccine trial in Thailand showed that a prime/boost immunization strategy involving priming with canarypox vCP1521 followed by boosting with rgp120 could provide significant, although modest, protection from HIV infection. Based on these results, there is renewed interest in the development of rgp120 based antigens for follow up vaccine trials, where this immunization approach can be applied to other cohorts at high risk for HIV infection. Of particular interest are cohorts in Africa, India, and China that are infected with clade C viruses. METHODOLOGY/PRINCIPAL FINDINGS: A panel of 10 clade C rgp120 envelope proteins was expressed in 293 cells, purified by immunoaffinity chromatography, and used to immunize guinea pigs. The resulting sera were collected and analyzed in checkerboard experiments for rgp120 binding, V3 peptide binding, and CD4 blocking activity. Virus neutralization studies were carried out with two different assays and two different panels of clade C viruses. A high degree of cross reactivity against clade C and clade B viruses and viral proteins was observed. Most, but not all of the immunogens tested elicited antibodies that neutralized tier 1 clade B viruses, and some sera neutralized multiple clade C viruses. Immunization with rgp120 from the CN97001 strain of HIV appeared to elicit higher cross neutralizing antibody titers than the other antigens tested. CONCLUSIONS/SIGNIFICANCE: While all of the clade C antigens tested were immunogenic, some were more effective than others in eliciting virus neutralizing antibodies. Neutralization titers did not correlate with rgp120 binding, V3 peptide binding, or CD4 blocking activity. CN97001 rgp120 elicited the highest level of neutralizing antibodies, and should be considered for further HIV vaccine development studies. PMID- 20711453 TI - The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. AB - BACKGROUND: Obstructive Sleep Apnea (OSA) is tightly linked to some components of Metabolic Syndrome (MetS). However, most of the evidence evaluated individual components of the MetS or patients with a diagnosis of OSA that were referred for sleep studies due to sleep complaints. Therefore, it is not clear whether OSA exacerbates the metabolic abnormalities in a representative sample of patients with MetS. METHODOLOGY/PRINCIPAL FINDINGS: We studied 152 consecutive patients (age 48+/-9 years, body mass index 32.3+/-3.4 Kg/m2) newly diagnosed with MetS (Adult Treatment Panel III). All participants underwent standard polysomnography irrespective of sleep complaints, and laboratory measurements (glucose, lipid profile, uric acid and C-reactive protein). The prevalence of OSA (apnea-hypopnea index>or=15 events per hour of sleep) was 60.5%. Patients with OSA exhibited significantly higher levels of blood pressure, glucose, triglycerides, cholesterol, LDL, cholesterol/HDL ratio, triglycerides/HDL ratio, uric acid and C reactive protein than patients without OSA. OSA was independently associated with 2 MetS criteria: triglycerides: OR: 3.26 (1.47-7.21) and glucose: OR: 2.31 (1.12 4.80). OSA was also independently associated with increased cholesterol/HDL ratio: OR: 2.38 (1.08-5.24), uric acid: OR: 4.19 (1.70-10.35) and C-reactive protein: OR: 6.10 (2.64-14.11). Indices of sleep apnea severity, apnea-hypopnea index and minimum oxygen saturation, were independently associated with increased levels of triglycerides, glucose as well as cholesterol/HDL ratio, uric acid and C-reactive protein. Excessive daytime sleepiness had no effect on the metabolic and inflammatory parameters. CONCLUSIONS/SIGNIFICANCE: Unrecognized OSA is common in consecutive patients with MetS. OSA may contribute to metabolic dysregulation and systemic inflammation in patients with MetS, regardless of symptoms of daytime sleepiness. PMID- 20711455 TI - Acaricidal activity of eugenol based compounds against scabies mites. AB - BACKGROUND: Human scabies is a debilitating skin disease caused by the "itch mite" Sarcoptes scabiei. Ordinary scabies is commonly treated with topical creams such as permethrin, while crusted scabies is treated with topical creams in combination with oral ivermectin. Recent reports of acaricide tolerance in scabies endemic communities in Northern Australia have prompted efforts to better understand resistance mechanisms and to identify potential new acaricides. In this study, we screened three essential oils and four pure compounds based on eugenol for acaricidal properties. METHODOLOGY/PRINCIPAL FINDINGS: Contact bioassays were performed using live permethrin-sensitive S. scabiei var suis mites harvested from pigs and permethrin-resistant S. scabiei var canis mites harvested from rabbits. Results of bioassays showed that clove oil was highly toxic against scabies mites. Nutmeg oil had moderate toxicity and ylang ylang oil was the least toxic. Eugenol, a major component of clove oil and its analogues- acetyleugenol and isoeugenol, demonstrated levels of toxicity comparable to benzyl benzoate, the positive control acaricide, killing mites within an hour of contact. CONCLUSIONS: The acaricidal properties demonstrated by eugenol and its analogues show promise as leads for future development of alternative topical acaricides to treat scabies. PMID- 20711454 TI - CHL1 is a selective organizer of the presynaptic machinery chaperoning the SNARE complex. AB - Proteins constituting the presynaptic machinery of vesicle release undergo substantial conformational changes during the process of exocytosis. While changes in the conformation make proteins vulnerable to aggregation and degradation, little is known about synaptic chaperones which counteract these processes. We show that the cell adhesion molecule CHL1 directly interacts with and regulates the activity of the synaptic chaperones Hsc70, CSP and alphaSGT. CHL1, Hsc70, CSP and alphaSGT form predominantly CHL1/Hsc70/alphaSGT and CHL1/CSP complexes in synapses. Among the various complexes formed by CHL1, Hsc70, CSP and alphaSGT, SNAP25 and VAMP2 induce chaperone activity only in CHL1/Hsc70/alphaSGT and CHL1/CSP complexes, respectively, indicating a remarkable selectivity of a presynaptic chaperone activity for proteins of the exocytotic machinery. In mice with genetic ablation of CHL1, chaperone activity in synapses is reduced and the machinery for synaptic vesicle exocytosis and, in particular, the SNARE complex is unable to sustain prolonged synaptic activity. Thus, we reveal a novel role for a cell adhesion molecule in selective activation of the presynaptic chaperone machinery. PMID- 20711456 TI - miRNAs in newt lens regeneration: specific control of proliferation and evidence for miRNA networking. AB - BACKGROUND: Lens regeneration in adult newts occurs via transdifferentiation of the pigment epithelial cells (PECs) of the dorsal iris. The same source of cells from the ventral iris is not able to undergo this process. In an attempt to understand this restriction we have studied in the past expression patterns of miRNAs. Among several miRNAs we have found that mir-148 shows an up-regulation in the ventral iris, while members of the let-7 family showed down-regulation in dorsal iris during dedifferentiation. METHODOLOGY/PRINCIPAL FINDINGS: We have performed gain- and loss-of-function experiments of mir-148 and let-7b in an attempt to delineate their function. We find that up-regulation of mir-148 caused significant decrease in the proliferation rates of ventral PECs only, while up regulation of let-7b affected proliferation of both dorsal and ventral PECs. Neither miRNA was able to affect lens morphogenesis or induction. To further understand how this effect of miRNA up-regulation is mediated we examined global expression of miRNAs after up-regulation of mir148 and let-7b. Interestingly, we identified a novel level of mirRNA regulation, which might indicate that miRNAs are regulated as a network. CONCLUSION/SIGNIFICANCE: The major conclusion is that different miRNAs can control proliferation in the dorsal or ventral iris possibly by a different mechanism. Of interest is that down-regulation of the let-7 family members has also been documented in other systems undergoing reprogramming, such as in stem cells or oocytes. This might indicate that reprogramming during newt regeneration shares common molecular signatures with reprogramming in stem or germ cells. On the other hand that miRNAs can regulate the levels of other miRNAs is a novel level of regulation, which might provide new insights on their function. PMID- 20711457 TI - Reduction in structural disorder and functional complexity in the thermal adaptation of prokaryotes. AB - Genomic correlates of evolutionary adaptation to very low or very high optimal growth temperature (OGT) values have been the subject of many studies. Whereas these provided a protein-structural rationale of the activity and stability of globular proteins/enzymes, the point has been neglected that adaptation to extreme temperatures could also have resulted from an increased use of intrinsically disordered proteins (IDPs), which are resistant to these conditions in vitro. Contrary to these expectations, we found a conspicuously low level of structural disorder in bacteria of very high (and very low) OGT values. This paucity of disorder does not reflect phylogenetic relatedness, i.e. it is a result of genuine adaptation to extreme conditions. Because intrinsic disorder correlates with important regulatory functions, we asked how these bacteria could exist without IDPs by studying transcription factors, known to harbor a lot of function-related intrinsic disorder. Hyperthermophiles have much less transcription factors, which have reduced disorder compared to their mesophilic counterparts. On the other hand, we found by systematic categorization of proteins with long disordered regions that there are certain functions, such as translation and ribosome biogenesis that depend on structural disorder even in hyperthermophiles. In all, our observations suggest that adaptation to extreme conditions is achieved by a significant functional simplification, apparent at both the level of the genome and individual genes/proteins. PMID- 20711458 TI - Characterization of ftsZ mutations that render Bacillus subtilis resistant to MinC. AB - BACKGROUND: Cell division in Bacillus subtilis occurs precisely at midcell. Positional control of cell division is exerted by two mechanisms: nucleoid occlusion, through Noc, which prevents division through nucleoids, and the Min system, where the combined action of the MinC, D and J proteins prevents formation of the FtsZ ring at cell poles or recently completed division sites. METHODOLOGY/PRINCIPAL FINDINGS: We used a genetic screen to identify mutations in ftsZ that confer resistance to the lethal overexpression of the MinC/MinD division inhibitor. The FtsZ mutants were purified and found to polymerize to a similar or lesser extent as wild type FtsZ, and all mutants displayed reduced GTP hydrolysis activity indicative of a reduced polymerization turnover. We found that even though the mutations conferred in vivo resistance to MinC/D, the purified FtsZ mutants did not display strong resistance to MinC in vitro. CONCLUSIONS/SIGNIFICANCE: Our results show that in B. subtilis, overproduction of MinC can be countered by mutations that alter FtsZ polymerization dynamics. Even though it would be very likely that the FtsZ mutants found depend on other Z-ring stabilizing proteins such as ZapA, FtsA or SepF, we found this not to be the case. This indicates that the cell division process in B. subtilis is extremely robust. PMID- 20711460 TI - A geospatial modelling approach integrating archaeobotany and genetics to trace the origin and dispersal of domesticated plants. AB - BACKGROUND: The study of the prehistoric origins and dispersal routes of domesticated plants is often based on the analysis of either archaeobotanical or genetic data. As more data become available, spatially explicit models of crop dispersal can be used to combine different types of evidence. METHODOLOGY/PRINCIPAL FINDINGS: We present a model in which a crop disperses through a landscape that is represented by a conductance matrix. From this matrix, we derive least-cost distances from the geographical origin of the crop and use these to predict the age of archaeological crop remains and the heterozygosity of crop populations. We use measures of the overlap and divergence of dispersal trajectories to predict genetic similarity between crop populations. The conductance matrix is constructed from environmental variables using a number of parameters. Model parameters are determined with multiple-criteria optimization, simultaneously fitting the archaeobotanical and genetic data. The consilience reached by the model is the extent to which it converges around solutions optimal for both archaeobotanical and genetic data. We apply the modelling approach to the dispersal of maize in the Americas. CONCLUSIONS/SIGNIFICANCE: The approach makes possible the integrative inference of crop dispersal processes, while controlling model complexity and computational requirements. PMID- 20711459 TI - Clinical prediction rule for stratifying risk of pulmonary multidrug-resistant tuberculosis. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB), resistance to at least isoniazid and rifampin, is a worldwide problem. OBJECTIVE: To develop a clinical prediction rule to stratify risk for MDR-TB among patients with pulmonary tuberculosis. METHODS: Derivation and internal validation of the rule among adult patients prospectively recruited from 37 health centers (Peru), either a) presenting with a positive acid-fast bacillus smear, or b) had failed therapy or had a relapse within the first 12 months. RESULTS: Among 964 patients, 82 had MDR TB (prevalence, 8.5%). Variables included were MDR-TB contact within the family, previous tuberculosis, cavitary radiologic pattern, and abnormal lung exam. The area under the receiver-operating curve (AUROC) was 0.76. Selecting a cut-off score of one or greater resulted in a sensitivity of 72.6%, specificity of 62.8%, likelihood ratio (LR) positive of 1.95, and LR negative of 0.44. Similarly, selecting a cut-off score of two or greater resulted in a sensitivity of 60.8%, specificity of 87.5%, LR positive of 4.85, and LR negative of 0.45. Finally, selecting a cut-off score of three or greater resulted in a sensitivity of 45.1%, specificity of 95.3%, LR positive of 9.56, and LR negative of 0.58. CONCLUSION: A simple clinical prediction rule at presentation can stratify risk for MDR-TB. If further validated, the rule could be used for management decisions in resource limited areas. PMID- 20711461 TI - Adaptation to delayed force perturbations in reaching movements. AB - Adaptation to deterministic force perturbations during reaching movements was extensively studied in the last few decades. Here, we use this methodology to explore the ability of the brain to adapt to a delayed velocity-dependent force field. Two groups of subjects preformed a standard reaching experiment under a velocity dependent force field. The force was either immediately proportional to the current velocity (Control) or lagged it by 50 ms (Test). The results demonstrate clear adaptation to the delayed force perturbations. Deviations from a straight line during catch trials were shifted in time compared to post adaptation to a non-delayed velocity dependent field (Control), indicating expectation to the delayed force field. Adaptation to force fields is considered to be a process in which the motor system predicts the forces to be expected based on the state that a limb will assume in response to motor commands. This study demonstrates for the first time that the temporal window of this prediction needs not to be fixed. This is relevant to the ability of the adaptive mechanisms to compensate for variability in the transmission of information across the sensory-motor system. PMID- 20711462 TI - Mediator of DNA damage checkpoint 1 (MDC1) contributes to high NaCl-induced activation of the osmoprotective transcription factor TonEBP/OREBP. AB - BACKGROUND: Hypertonicity, such as induced by high NaCl, increases the activity of the transcription factor TonEBP/OREBP whose target genes increase osmoprotective organic osmolytes and heat shock proteins. METHODOLOGY: We used mass spectrometry to analyze proteins that coimmunoprecipitate with TonEBP/OREBP in order to identify ones that might contribute to its high NaCl-induced activation. PRINCIPAL FINDINGS: We identified 20 unique peptides from Mediator of DNA Damage Checkpoint 1 (MDC1) with high probability. The identification was confirmed by Western analysis. We used small interfering RNA knockdown of MDC1 to characterize its osmotic function. Knocking down MDC1 reduces high NaCl-induced increases in TonEBP/OREBP transcriptional and transactivating activity, but has no significant effect on its nuclear localization. We confirm six previously known phosphorylation sites in MDC1, but do not find evidence that high NaCl increases phosphorylation of MDC1. It is suggestive that MDC1 acts as a DNA damage response protein since hypertonicity reversibly increases DNA breaks, and other DNA damage response proteins, like ATM, also associate with TonEBP/OREBP and contribute to its activation by hypertonicity. CONCLUSIONS/SIGNIFICANCE: MDC1 associates with TonEBP/OREBP and contributes to high NaCl-induced increase of that factor's transcriptional activity. PMID- 20711463 TI - MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under expressed in MS whole blood. AB - It is well established that Multiple Sclerosis (MS) is an immune mediated disease. Little is known about what drives the differential control of the immune system in MS patients compared to unaffected individuals. MicroRNAs (miRNAs) are small non-coding nucleic acids that are involved in the control of gene expression. Their potential role in T cell activation and neurodegenerative disease has recently been recognised and they are therefore excellent candidates for further studies in MS. We investigated the transcriptome of currently known miRNAs using miRNA microarray analysis in peripheral blood samples of 59 treatment naive MS patients and 37 controls. Of these 59, 18 had a primary progressive, 17 a secondary progressive and 24 a relapsing remitting disease course. In all MS subtypes miR-17 and miR-20a were significantly under-expressed in MS, confirmed by RT-PCR. We demonstrate that these miRNAs modulate T cell activation genes in a knock-in and knock-down T cell model. The same T cell activation genes are also up-regulated in MS whole blood mRNA, suggesting these miRNAs or their analogues may provide useful targets for new therapeutic approaches. PMID- 20711464 TI - Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra. AB - The protein alpha-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal alpha-synuclein burden. Here, feasibility and safety of alpha-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against alpha-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of alpha-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40-50% suppression of alpha-synuclein expression. These findings could not be attributable to non specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in alpha-synuclein. Infusion with alpha-synuclein siRNA, while lowering alpha-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-alpha-synuclein intervention in the primate substantia nigra and support further development of RNA interference based therapeutics. PMID- 20711465 TI - Mammalian sperm head formation involves different polarization of two novel LINC complexes. AB - BACKGROUND: LINC complexes are nuclear envelope bridging protein structures formed by interaction of SUN and KASH proteins. They physically connect the nucleus with the peripheral cytoskeleton and are critically involved in a variety of dynamic processes, such as nuclear anchorage, movement and positioning and meiotic chromosome dynamics. Moreover, they are shown to be essential for maintaining nuclear shape. FINDINGS: Based on detailed expression analysis and biochemical approaches, we show here that during mouse sperm development, a terminal cell differentiation process characterized by profound morphogenic restructuring, two novel distinctive LINC complexes are established. They consist either of spermiogenesis-specific Sun3 and Nesprin1 or Sun1eta, a novel non nuclear Sun1 isoform, and Nesprin3. We could find that these two LINC complexes specifically polarize to opposite spermatid poles likely linking to sperm specific cytoskeletal structures. Although, as shown in co transfection/immunoprecipitation experiments, SUN proteins appear to arbitrarily interact with various KASH partners, our study demonstrates that they actually are able to confine their binding to form distinct LINC complexes. CONCLUSIONS: Formation of the mammalian sperm head involves assembly and different polarization of two novel spermiogenesis-specific LINC complexes. Together, our findings suggest that theses LINC complexes connect the differentiating spermatid nucleus to surrounding cytoskeletal structures to enable its well-directed shaping and elongation, which in turn is a critical parameter for male fertility. PMID- 20711466 TI - Chitosan modification of adenovirus to modify transfection efficiency in bovine corneal epithelial cells. AB - BACKGROUND: The purpose of this study is to modulate the transfection efficiency of adenovirus (Ad) on the cornea by the covalent attachment of chitosan on adenoviral capsids via a thioether linkage between chitosan modified with 2 iminothiolane and Ad cross-linked with N-[gamma-maleimidobutyryloxy]succinimide ester (GMBS). METHODOLOGY/PRINCIPAL FINDINGS: Modified Ad was obtained by reaction with the heterobifunctional crosslinking reagent, GMBS, producing maleimide-modified Ad (Ad-GMBS). Then, the chitosan-SH was conjugated to Ad-GMBS via a thioether bond at different ratios of Ad to GMBS to chitosan-SH. The sizes and zeta potentials of unmodified Ad and chitosan-modified Ads were measured, and the morphologies of the virus particles were observed under transmission electron microscope. Primary cultures of bovine corneal epithelial cells were transfected with Ads and chitosan-modified Ads in the absence or presence of anti-adenovirus antibodies. Chitosan modification did not significantly change the particle size of Ad, but the surface charge of Ad increased significantly from -24.3 mV to nearly neutral. Furthermore, primary cultures of bovine corneal epithelial cells were transfected with Ad or chitosan-modified Ad in the absence or presence of anti-Ad antibodies. The transfection efficiency was attenuated gradually with increasing amounts of GMBS. However, incorporation of chitosan partly restored transfection activity and rendered the modified antibody resistant to antibody neutralization. CONCLUSIONS/SIGNIFICANCE: Chitosan can provide a platform for chemical modification of Ad, which offers potential for further in vivo applications. PMID- 20711467 TI - Synaesthetic colour in the brain: beyond colour areas. A functional magnetic resonance imaging study of synaesthetes and matched controls. AB - BACKGROUND: In synaesthesia, sensations in a particular modality cause additional experiences in a second, unstimulated modality (e.g., letters elicit colour). Understanding how synaesthesia is mediated in the brain can help to understand normal processes of perceptual awareness and multisensory integration. In several neuroimaging studies, enhanced brain activity for grapheme-colour synaesthesia has been found in ventral-occipital areas that are also involved in real colour processing. Our question was whether the neural correlates of synaesthetically induced colour and real colour experience are truly shared. METHODOLOGY/PRINCIPAL FINDINGS: First, in a free viewing functional magnetic resonance imaging (fMRI) experiment, we located main effects of synaesthesia in left superior parietal lobule and in colour related areas. In the left superior parietal lobe, individual differences between synaesthetes (projector-associator distinction) also influenced brain activity, confirming the importance of the left superior parietal lobe for synaesthesia. Next, we applied a repetition suppression paradigm in fMRI, in which a decrease in the BOLD (blood-oxygenated-level dependent) response is generally observed for repeated stimuli. We hypothesized that synaesthetically induced colours would lead to a reduction in BOLD response for subsequently presented real colours, if the neural correlates were overlapping. We did find BOLD suppression effects induced by synaesthesia, but not within the colour areas. CONCLUSIONS/SIGNIFICANCE: Because synaesthetically induced colours were not able to suppress BOLD effects for real colour, we conclude that the neural correlates of synaesthetic colour experience and real colour experience are not fully shared. We propose that synaesthetic colour experiences are mediated by higher-order visual pathways that lie beyond the scope of classical, ventral-occipital visual areas. Feedback from these areas, in which the left parietal cortex is likely to play an important role, may induce V4 activation and the percept of synaesthetic colour. PMID- 20711468 TI - Optic nerve compression and retinal degeneration in Tcirg1 mutant mice lacking the vacuolar-type H-ATPase a3 subunit. AB - BACKGROUND: Vacuolar-type proton transporting ATPase (V-ATPase) is involved in the proper development of visual function. Mutations in the Tcirg1 (also known as Atp6V0a3) locus, which encodes the a3 subunit of V-ATPase, cause severe autosomal recessive osteopetrosis (ARO) in humans. ARO is often associated with impaired vision most likely because of nerve compression at the optic canal. We examined the ocular phenotype of mice deficient in Tcirg1 function. METHODOLOGY/PRINCIPAL FINDINGS: X-ray microtomography showed narrowed foramina in the skull, suggesting that optic nerve compression occurred in the a3-deficient (Tcirg1-/-) mice. The retina of the mutant mice had normal architecture, but the number of apoptotic cells was increased at 2-3 wks after birth. In the ocular system, the a3 subunit accumulated in the choriocapillary meshwork in uveal tissues. Two other subunit isoforms a1 and a2 accumulated in the retinal photoreceptor layer. We found that the a4 subunit, whose expression has previously been shown to be restricted to several transporting epithelia, was enriched in pigmented epithelial cells of the retina and ciliary bodies. The expression of a4 in the uveal tissue was below the level of detection in wild-type mice, but it was increased in the mutant choriocapillary meshwork, suggesting that compensation may have occurred among the a subunit isoforms in the mutant tissues. CONCLUSIONS: Our findings suggest that a similar etiology of visual impairment is involved in both humans and mice; thus, a3-deficient mice may provide a suitable model for clinical and diagnostic purposes in cases of ARO. PMID- 20711469 TI - Targeting of embryonic stem cells by peptide-conjugated quantum dots. AB - BACKGROUND: Targeting stem cells holds great potential for studying the embryonic stem cell and development of stem cell-based regenerative medicine. Previous studies demonstrated that nanoparticles can serve as a robust platform for gene delivery, non-invasive cell imaging, and manipulation of stem cell differentiation. However specific targeting of embryonic stem cells by peptide linked nanoparticles has not been reported. METHODOLOGY/PRINCIPAL FINDINGS: Here, we developed a method for screening peptides that specifically recognize rhesus macaque embryonic stem cells by phage display and used the peptides to facilitate quantum dot targeting of embryonic stem cells. Through a phage display screen, we found phages that displayed an APWHLSSQYSRT peptide showed high affinity and specificity to undifferentiated primate embryonic stem cells in an enzyme-linked immunoabsorbent assay. These results were subsequently confirmed by immunofluorescence microscopy. Additionally, this binding could be completed by the chemically synthesized APWHLSSQYSRT peptide, indicating that the binding capability was specific and conferred by the peptide sequence. Through the ligation of the peptide to CdSe-ZnS core-shell nanocrystals, we were able to, for the first time, target embryonic stem cells through peptide-conjugated quantum dots. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that our established method of screening for embryonic stem cell specific binding peptides by phage display is feasible. Moreover, the peptide-conjugated quantum dots may be applicable for embryonic stem cell study and utilization. PMID- 20711470 TI - TLR4 Asp299Gly and Thr399Ile polymorphisms: no impact on human immune responsiveness to LPS or respiratory syncytial virus. AB - BACKGROUND: A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV)--driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction. METHODOLOGY: To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7-9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV. PRINCIPAL FINDINGS: In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with "at risk" clinical phenotypes. CONCLUSIONS/SIGNIFICANCE: Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at risk groups characterized by prior infantile broncholitis or current asthma. PMID- 20711471 TI - Rat adipose tissue-derived stem cells transplantation attenuates cardiac dysfunction post infarction and biopolymers enhance cell retention. AB - BACKGROUND: Cardiac cell transplantation is compromised by low cell retention and poor graft viability. Here, the effects of co-injecting adipose tissue-derived stem cells (ASCs) with biopolymers on cell cardiac retention, ventricular morphometry and performance were evaluated in a rat model of myocardial infarction (MI). METHODOLOGY/PRINCIPAL FINDINGS: 99mTc-labeled ASCs (1x10(6) cells) isolated from isogenic Lewis rats were injected 24 hours post-MI using fibrin a, collagen (ASC/C), or culture medium (ASC/M) as vehicle, and cell body distribution was assessed 24 hours later by gamma-emission counting of harvested organs. ASC/F and ASC/C groups retained significantly more cells in the myocardium than ASC/M (13.8+/-2.0 and 26.8+/-2.4% vs. 4.8+/-0.7%, respectively). Then, morphometric and direct cardiac functional parameters were evaluated 4 weeks post-MI cell injection. Left ventricle (LV) perimeter and percentage of interstitial collagen in the spare myocardium were significantly attenuated in all ASC-treated groups compared to the non-treated (NT) and control groups (culture medium, fibrin, or collagen alone). Direct hemodynamic assessment under pharmacological stress showed that stroke volume (SV) and left ventricle end diastolic pressure were preserved in ASC-treated groups regardless of the vehicle used to deliver ASCs. Stroke work (SW), a global index of cardiac function, improved in ASC/M while it normalized when biopolymers were co-injected with ASCs. A positive correlation was observed between cardiac ASCs retention and preservation of SV and improvement in SW post-MI under hemodynamic stress. CONCLUSIONS: We provided direct evidence that intramyocardial injection of ASCs mitigates the negative cardiac remodeling and preserves ventricular function post MI in rats and these beneficial effects can be further enhanced by administering co-injection of ASCs with biopolymers. PMID- 20711472 TI - Integrating ion mobility mass spectrometry with molecular modelling to determine the architecture of multiprotein complexes. AB - Current challenges in the field of structural genomics point to the need for new tools and technologies for obtaining structures of macromolecular protein complexes. Here, we present an integrative computational method that uses molecular modelling, ion mobility-mass spectrometry (IM-MS) and incomplete atomic structures, usually from X-ray crystallography, to generate models of the subunit architecture of protein complexes. We begin by analyzing protein complexes using IM-MS, and by taking measurements of both intact complexes and sub-complexes that are generated in solution. We then examine available high resolution structural data and use a suite of computational methods to account for missing residues at the subunit and/or domain level. High-order complexes and sub-complexes are then constructed that conform to distance and connectivity constraints imposed by IM MS data. We illustrate our method by applying it to multimeric protein complexes within the Escherichia coli replisome: the sliding clamp, (beta2), the gamma complex (gamma3deltadelta'), the DnaB helicase (DnaB6) and the Single-Stranded Binding Protein (SSB4). PMID- 20711473 TI - Auditory cortex tracks both auditory and visual stimulus dynamics using low frequency neuronal phase modulation. AB - Integrating information across sensory domains to construct a unified representation of multi-sensory signals is a fundamental characteristic of perception in ecological contexts. One provocative hypothesis deriving from neurophysiology suggests that there exists early and direct cross-modal phase modulation. We provide evidence, based on magnetoencephalography (MEG) recordings from participants viewing audiovisual movies, that low-frequency neuronal information lies at the basis of the synergistic coordination of information across auditory and visual streams. In particular, the phase of the 2-7 Hz delta and theta band responses carries robust (in single trials) and usable information (for parsing the temporal structure) about stimulus dynamics in both sensory modalities concurrently. These experiments are the first to show in humans that a particular cortical mechanism, delta-theta phase modulation across early sensory areas, plays an important "active" role in continuously tracking naturalistic audio-visual streams, carrying dynamic multi-sensory information, and reflecting cross-sensory interaction in real time. PMID- 20711474 TI - ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. AB - BACKGROUND: Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment. METHODOLOGY/PRINCIPAL FINDINGS: We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro. CONCLUSIONS/SIGNIFICANCE: GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer. PMID- 20711475 TI - Foxp1 and lhx1 coordinate motor neuron migration with axon trajectory choice by gating Reelin signalling. AB - Topographic neuronal maps arise as a consequence of axon trajectory choice correlated with the localisation of neuronal soma, but the identity of the pathways coordinating these processes is unknown. We addressed this question in the context of the myotopic map formed by limb muscles innervated by spinal lateral motor column (LMC) motor axons where the Eph receptor signals specifying growth cone trajectory are restricted by Foxp1 and Lhx1 transcription factors. We show that the localisation of LMC neuron cell bodies can be dissociated from axon trajectory choice by either the loss or gain of function of the Reelin signalling pathway. The response of LMC motor neurons to Reelin is gated by Foxp1- and Lhx1 mediated regulation of expression of the critical Reelin signalling intermediate Dab1. Together, these observations point to identical transcription factors that control motor axon guidance and soma migration and reveal the molecular hierarchy of myotopic organisation. PMID- 20711476 TI - Using touchscreen electronic medical record systems to support and monitor national scale-up of antiretroviral therapy in Malawi. PMID- 20711478 TI - Incorporating genomics and bioinformatics across the life sciences curriculum. PMID- 20711479 TI - Protein aggregation increases with age. PMID- 20711477 TI - Widespread protein aggregation as an inherent part of aging in C. elegans. AB - Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in beta-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease. PMID- 20711480 TI - A dog's eye view of morphological diversity. PMID- 20711483 TI - Ready or not? Expectations of faculty and medical students for clinical skills preparation for clerkships. AB - BACKGROUND: Preclerkship clinical-skills training has received increasing attention as a foundational preparation for clerkships. Expectations among medical students and faculty regarding the clinical skills and level of skill mastery needed for starting clerkships are unknown. Medical students, faculty teaching in the preclinical setting, and clinical clerkship faculty may have differing expectations of students entering clerkships. If students' expectations differ from faculty expectations, students may experience anxiety. Alternately, congruent expectations among students and faculty may facilitate integrated and seamless student transitions to clerkships. AIMS: To assess the congruence of expectations among preclerkship faculty, clerkship faculty, and medical students for the clinical skills and appropriate level of clinical-skills preparation needed to begin clerkships. METHODS: Investigators surveyed preclinical faculty, clerkship faculty, and medical students early in their basic clerkships at a North American medical school that focuses on preclerkship clinical-skills development. Survey questions assessed expectations for the appropriate level of preparation in basic and advanced clinical skills for students entering clerkships. RESULTS: Preclinical faculty and students had higher expectations than clerkship faculty for degree of preparation in most basic skills. Students had higher expectations than both faculty groups for advanced skills preparation. CONCLUSIONS: Preclinical faculty, clerkship faculty, and medical students appear to have different expectations of clinical-skills training needed for clerkships. As American medical schools increasingly introduce clinical-skills training prior to clerkships, more attention to alignment, communication, and integration between preclinical and clerkship faculty will be important to establish common curricular agendas and increase integration of student learning. Clarification of skills expectations may also alleviate student anxiety about clerkships and enhance their learning. PMID- 20711484 TI - Syntheses of Isomerically Pure Reference Octalins and Hydrindanes. AB - We describe herein the development of efficient and stereoselective synthetic routes to a range of cis- and trans- octalin and hydrindane target compounds. PMID- 20711481 TI - The effect of raltegravir intensification on low-level residual viremia in HIV infected patients on antiretroviral therapy: a randomized controlled trial. AB - BACKGROUND: Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. METHODS AND FINDINGS: Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. CONCLUSION: In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00515827 PMID- 20711485 TI - "Applied" Aspects of the Drug Resistance Strategies Project. AB - This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of "applied" from the traditional notion of utilizing theory, which we call "applied.1", in order to consider theory-grounded, theory testing and theory developing applied research. We label this new definition "applied.2" research. We then explain that our descriptive work describing the social processes of adolescent substance use, identity and use, and drug norms, as well as the subsequent development and dissemination of our keepin' it REAL middle school substance use curriculum are examples of "applied.1" work. In the "applied.2" realm, we include our theory testing (e.g., tests of multiculturalism, narrative and performance theories, the Focus Theory of Norms) and theory-developing (e.g., parent-child communication, cultural grounding) research as well our new directions in theory development (e.g., adaptation processes). We conclude with a call for space in the discipline for "applied.2" work that builds and tests theory through application to significant social issues that contribute to our communities. We note obstacles in departmental and scholarly norms but express optimism about the prospects for "applied.2" research in the future of communication research. PMID- 20711482 TI - Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies. AB - BACKGROUND: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. METHODS AND FINDINGS: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (<1% parasite prevalence in all age-groups) provided usage levels are high and sustained. In two of the moderate-transmission settings (EIR approximately 43 and 81 ibppy), additional rounds of IRS with DDT coupled with MSAT could drive parasite prevalence below a 1% threshold. However, in the third (EIR = 46) with An. arabiensis prevailing, these interventions are insufficient to reach this threshold. In both high-transmission settings (EIR approximately 586 and 675 ibppy), either unrealistically high coverage levels (>90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. CONCLUSIONS: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required. PMID- 20711486 TI - Improving spatial resolution of a fiber bundle optical biopsy system. AB - To reduce the number of invasive tissue biopsies and needle aspirations performed during cancer screenings, endo-microscopes can be used to image tissue in vivo. However, when optical fiber bundles are used to transmit the image, the resolution of such systems is limited by undersampling due to the spacing of the bundle's individual fibers for a given field of view. We propose a method to increase the sampling of an optical biopsy system and thereby improve the system's resolution. The method involves taking several images, shifting the object and fiber bundle slightly relative to each other from one image to the next. Multiple shifting patterns were evaluated to determine which provided the greatest increase in resolution. The shifted images are later realigned and recombined by a custom algorithm. By combining four shifted images of a USAF resolution target, we were able to measure an improvement in the resolution of the system from approximately 3.9 MUm to 2.2 MUm. When tested on cultured cells, a visible increase in detail was detectable. This technique can provide the basis for improving the diagnostic abilities of optical biopsy systems. PMID- 20711487 TI - Identity Development and Forgivingness: Tests of Basic Relations and Mediational Pathways. AB - Adaptive identity development leads to increases in personality traits that allow for social well-being. The current study tested this claim with respect to forgivingness, a dispositional tendency to forgive others. In a sample of university undergraduates (N = 214), we examined the relations between forgivingness and two indicators of identity development: commitment and exploration. Forgivingness uniquely positively related with both identity variables, controlling for the other. Next, we tested mediational models to examine the mechanisms underlying these relationships. Our results suggest that, in part, the association between identity development and forgivingness is mediated by levels of agreeableness and neuroticism, as measured by the Big Five Inventory. PMID- 20711488 TI - Background Current Elimination in Thin Layer Ion-Selective Membrane Coulometry. AB - A promising method for the elimination of undesired capacitive currents in view of realizing a potentially calibration free coulometric ion detection system is presented. The coulometric cell is composed of a porous polypropylene tube doped with a liquid calcium-selective membrane and a silver/silver chloride wire as an inner electrode, forming a thin layer sample between wire and tubing. The total charge passed through the system during potential controlled electrolysis of the thin layer sample is indeed found to be proportional to the amount of calcium present, but non-Faradaic processes do contribute to the obtained signal. We introduce here a multi-pulse procedure that allows one to perform a second excitation pulse at the same excitation potential after exhaustive ion transfer voltammetry of calcium has taken place. The intercept of the calibration curve after background subtraction is found as 20.6 +/- 0.6 muC, significantly lower than the value of 54.1 +/- 0.8 muC for the uncorrected curve. Changes in sample temperature (from 23 degrees C to 38 degrees C) did equally not affect the background corrected coulometric readings, supporting that the procedure renders the readout principle more robust. PMID- 20711489 TI - Facile Pyrolytic Synthesis of Silicon Nanowires. AB - One-dimensional nanostructures such as silicon nanowires (SiNW) are attractive candidates for low power density electronic and optoelectronic devices including sensors. A new simple method for SiNW bulk synthesis[1, 2] is demonstrated in this work, which is inexpensive and uses low toxicity materials, thereby offering a safe, energy efficient and green approach. The method uses low flammability liquid phenylsilanes, offering a safer avenue for SiNW growth compared with using silane gas. A novel, duo-chamber glass vessel is used to create a low-pressure environment where SiNWs are grown through vapor-liquid-solid mechanism using gold nanoparticles as a catalyst. The catalyst decomposes silicon precursor vapors of diphenylsilane and triphenylsilane and precipitates single crystal SiNWs, which appear to grow parallel to the substrate surface. This opens up possibilities for synthesizing nano-junctions amongst wires which is important for the grid architecture of nanoelectronics proposed by Likharev[3]. Even bulk synthesis of SiNW is feasible using sacrificial substrates such as CaCO(3) that can be dissolved post-synthesis. Furthermore, by dissolving appropriate dopants in liquid diphenylsilane, a controlled doping of the nanowires is realized without the use of toxic gases and expensive mass flow controllers. Upon boron doping, we observe a characteristic red shift in photoluminescence spectra. In summary, an inexpensive and versatile method for SiNW is presented that makes these exotic materials available to any lab at low cost. PMID- 20711491 TI - Gender Differences in Drug Offers of Rural Hawaiian Youths: A Mixed-Methods Analysis. AB - This study examined the gender differences in drug-offer situations of Native Hawaiian youths in rural communities. Youths from seven middle or intermediate schools (N 194) on the Big Island of Hawai'i completed a survey that focused on the drug offers they had received. Multivariate and bivariate analyses indicated that the girls received significantly more drug offers than did the boys in the sample and found it more difficult to refuse drugs in such situations. Qualitative data gathered from communities in the survey's sampling frame elucidated the quantitative findings. Limitations of the study and implications for prevention practice are discussed. PMID- 20711490 TI - A simple genetic architecture underlies morphological variation in dogs. AB - Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (< or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species. PMID- 20711492 TI - Mechanisms of growth cone repulsion. AB - Research conducted in the last century suggested that chemoattractants guide cells or their processes to appropriate locations during development. Today, we know that many of the molecules involved in cellular guidance can act as chemorepellents that prevent migration into inappropriate territories. Here, we review some of the early seminal experiments and our current understanding of the underlying molecular mechanisms. PMID- 20711493 TI - Lessons from the Total Synthesis of (+/-) Phalarine: Insights Into the Mechanism of the Pictet-Spengler Reaction. AB - The furanobisindole alkaloid, phalarine, possesses a unique structural framework within the alkaloid family of natural products. Our laboratory recently disclosed the racemic total synthesis of phalarine, featuring an efficient azaspiroindolenine rearrangement; this achievement is revisited in detail. Upon completion of the first-generation total synthesis, we explored some interesting mechanism-level issues with regard to the key azaspiroindolenine rearrangement. These investigations provided valuable insights into the mechanism of racemization during the azaspiroindolenine rearrangement en route to synthetic phalarine. In addition, in the course of these studies, we demonstrated the Pictet-Spengler capture reaction for C(2)-aryl indoles, and successfully isolated the elusive azaspiroindolenine intermediate of the Pictet-Spengler reaction. Key insights into the remarkably subtle stereoelectronics that govern this rearrangement for C(2)-arylated indoles are discussed. PMID- 20711494 TI - A New and Efficient Poisson-Boltzmann Solver for Interaction of Multiple Proteins. AB - We derive a new numerical approach to solving the linearized Poisson Boltzmann equation (PBE) by representing the protein surface as a collection of spheres in which the surface charges can then be iteratively solved by new analytical multipole methods previously introduced by us [Lotan & Head-Gordon, 2006]. We show that our Poisson Boltzmann semi-analytical method, PB-SAM, realizes better accuracy, more flexible memory management, and at reduced cost relative to either finite difference or boundary element method PBE solvers. We provide two new benchmarks of PBE solution accuracy to test the numerical PBE solutions based on (1) arrays of up to hundreds of spherical low dielectric geometries with asymmetric charges in which mutual polarization is treated exactly, and (2) two overlapping spheres with increasing charge asymmetry by solving the PB-SAM method to very high pole order. We illustrate the strength of the PB-SAM approach by computing the potential profile of an array of 60 T1-particle forming monomers of the bromine mosaic virus. PMID- 20711495 TI - Interactions between spider silk and cells--NIH/3T3 fibroblasts seeded on miniature weaving frames. AB - BACKGROUND: Several materials have been used for tissue engineering purposes, since the ideal matrix depends on the desired tissue. Silk biomaterials have come to focus due to their great mechanical properties. As untreated silkworm silk has been found to be quite immunogenic, an alternative could be spider silk. Not only does it own unique mechanical properties, its biocompatibility has been shown already in vivo. In our study, we used native spider dragline silk which is known as the strongest fibre in nature. METHODOLOGY/PRINCIPAL FINDINGS: Steel frames were originally designed and manufactured and woven with spider silk, harvesting dragline silk directly out of the animal. After sterilization, scaffolds were seeded with fibroblasts to analyse cell proliferation and adhesion. Analysis of cell morphology and actin filament alignment clearly revealed adherence. Proliferation was measured by cell count as well as determination of relative fluorescence each after 1, 2, 3, and 5 days. Cell counts for native spider silk were also compared with those for trypsin-digested spider silk. Spider silk specimens displayed less proliferation than collagen- and fibronectin-coated cover slips, enzymatic treatment reduced adhesion and proliferation rates tendentially though not significantly. Nevertheless, proliferation could be proven with high significance (p<0.01). CONCLUSION/SIGNIFICANCE: Native spider silk does not require any modification to its application as a biomaterial that can rival any artificial material in terms of cell growth promoting properties. We could show adhesion mechanics on intracellular level. Additionally, proliferation kinetics were higher than in enzymatically digested controls, indicating that spider silk does not require modification. Recent findings concerning reduction of cell proliferation after exposure could not be met. As biotechnological production of the hierarchical composition of native spider silk fibres is still a challenge, our study has a pioneer role in researching cellular mechanics on native spider silk fibres. PMID- 20711496 TI - Spatio-temporal progression of grey and white matter damage following contusion injury in rat spinal cord. AB - Cellular mechanisms of secondary damage progression following spinal cord injury remain unclear. We have studied the extent of tissue damage from 15 min to 10 weeks after injury using morphological and biochemical estimates of lesion volume and surviving grey and white matter. This has been achieved by semi-quantitative immunocytochemical methods for a range of cellular markers, quantitative counts of white matter axonal profiles in semi-thin sections and semi-quantitative Western blot analysis, together with behavioural tests (BBB scores, ledged beam, random rung horizontal ladder and DigiGait analysis). We have developed a new computer-controlled electronic impactor based on a linear motor that allows specification of the precise nature, extent and timing of the impact. Initial (15 min) lesion volumes showed very low variance (1.92+/-0.23 mm3, mean+/-SD, n=5). Although substantial tissue clearance continued for weeks after injury, loss of grey matter was rapid and complete by 24 hours, whereas loss of white matter extended up to one week. No change was found between one and 10 weeks after injury for almost all morphological and biochemical estimates of lesion size or behavioural methods. These results suggest that previously reported apparent ongoing injury progression is likely to be due, to a large extent, to clearance of tissue damaged by the primary impact rather than continuing cell death. The low variance of the impactor and the comprehensive assessment methods described in this paper provide an improved basis on which the effects of potential treatment regimes for spinal cord injury can be assessed. PMID- 20711497 TI - Sox6 is necessary for efficient erythropoiesis in adult mice under physiological and anemia-induced stress conditions. AB - BACKGROUND: Definitive erythropoiesis is a vital process throughout life. Both its basal activity under physiological conditions and its increased activity under anemia-induced stress conditions are highly stimulated by the hormone erythropoietin. The transcription factor Sox6 was previously shown to enhance fetal erythropoiesis together and beyond erythropoietin signaling, but its importance in adulthood and mechanisms of action remain unknown. We used here Sox6 conditional null mice and molecular assays to address these questions. METHODOLOGY/PRINCIPAL FINDINGS: Sox6fl/flErGFPCre adult mice, which lacked Sox6 in erythroid cells, exhibited compensated anemia, erythroid cell developmental defects, and anisocytotic, short-lived red cells under physiological conditions, proving that Sox6 promotes basal erythropoiesis. Tamoxifen treatment of Sox6fl/flCaggCreER mice induced widespread inactivation of Sox6 in a timely controlled manner and resulted in erythroblast defects before reticulocytosis, demonstrating that impaired erythropoiesis is a primary cause rather than consequence of anemia in the absence of Sox6. Twenty five percent of Sox6fl/flErGFPCre mice died 4 or 5 days after induction of acute anemia with phenylhydrazine. The others recovered slowly. They promptly increased their erythropoietin level and amplified their erythroid progenitor pool, but then exhibited severe erythroblast and reticulocyte defects. Sox6 is thus essential in the maturation phase of stress erythropoiesis that follows the erythropoietin dependent amplification phase. Sox6 inactivation resulted in upregulation of embryonic globin genes, but embryonic globin chains remained scarce and apparently inconsequential. Sox6 inactivation also resulted in downregulation of erythroid terminal markers, including the Bcl2l1 gene for the anti-apoptotic factor Bcl-xL, and in vitro assays indicated that Sox6 directly upregulates Bcl2l1 downstream of and beyond erythropoietin signaling. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that Sox6 is necessary for efficient erythropoiesis in adult mice under both basal and stress conditions. It is primarily involved in enhancing the survival rate and maturation process of erythroid cells and acts at least in part by upregulating Bcl2l1. PMID- 20711498 TI - Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. AB - BACKGROUND: We aimed to determine the effect of resistance exercise intensity (%1 repetition maximum-1RM) and volume on muscle protein synthesis, anabolic signaling, and myogenic gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Fifteen men (21+/-1 years; BMI=24.1+/-0.8 kg/m2) performed 4 sets of unilateral leg extension exercise at different exercise loads and/or volumes: 90% of repetition maximum (1RM) until volitional failure (90FAIL), 30% 1RM work-matched to 90%FAIL (30WM), or 30% 1RM performed until volitional failure (30FAIL). Infusion of [ring 13C6] phenylalanine with biopsies was used to measure rates of mixed (MIX), myofibrillar (MYO), and sarcoplasmic (SARC) protein synthesis at rest, and 4 h and 24 h after exercise. Exercise at 30WM induced a significant increase above rest in MIX (121%) and MYO (87%) protein synthesis at 4 h post-exercise and but at 24 h in the MIX only. The increase in the rate of protein synthesis in MIX and MYO at 4 h post-exercise with 90FAIL and 30FAIL was greater than 30WM, with no difference between these conditions; however, MYO remained elevated (199%) above rest at 24 h only in 30FAIL. There was a significant increase in AktSer473 at 24h in all conditions (P=0.023) and mTORSer2448 phosphorylation at 4 h post-exercise (P=0.025). Phosporylation of Erk1/2Tyr202/204, p70S6KThr389, and 4E-BP1Thr37/46 increased significantly (P<0.05) only in the 30FAIL condition at 4 h post exercise, whereas, 4E-BP1Thr37/46 phosphorylation was greater 24 h after exercise than at rest in both 90FAIL (237%) and 30FAIL (312%) conditions. Pax7 mRNA expression increased at 24 h post-exercise (P=0.02) regardless of condition. The mRNA expression of MyoD and myogenin were consistently elevated in the 30FAIL condition. CONCLUSIONS/SIGNIFICANCE: These results suggest that low-load high volume resistance exercise is more effective in inducing acute muscle anabolism than high-load low volume or work matched resistance exercise modes. PMID- 20711500 TI - The human-bacterial pathogen protein interaction networks of Bacillus anthracis, Francisella tularensis, and Yersinia pestis. AB - BACKGROUND: Bacillus anthracis, Francisella tularensis, and Yersinia pestis are bacterial pathogens that can cause anthrax, lethal acute pneumonic disease, and bubonic plague, respectively, and are listed as NIAID Category A priority pathogens for possible use as biological weapons. However, the interactions between human proteins and proteins in these bacteria remain poorly characterized leading to an incomplete understanding of their pathogenesis and mechanisms of immune evasion. METHODOLOGY: In this study, we used a high-throughput yeast two hybrid assay to identify physical interactions between human proteins and proteins from each of these three pathogens. From more than 250,000 screens performed, we identified 3,073 human-B. anthracis, 1,383 human-F. tularensis, and 4,059 human-Y. pestis protein-protein interactions including interactions involving 304 B. anthracis, 52 F. tularensis, and 330 Y. pestis proteins that are uncharacterized. Computational analysis revealed that pathogen proteins preferentially interact with human proteins that are hubs and bottlenecks in the human PPI network. In addition, we computed modules of human-pathogen PPIs that are conserved amongst the three networks. Functionally, such conserved modules reveal commonalities between how the different pathogens interact with crucial host pathways involved in inflammation and immunity. SIGNIFICANCE: These data constitute the first extensive protein interaction networks constructed for bacterial pathogens and their human hosts. This study provides novel insights into host-pathogen interactions. PMID- 20711499 TI - PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER. AB - BACKGROUND: Abolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we postulated that PDE8 is an important regulator of Teff cell functions. METHODOLOGY/PRINCIPAL FINDINGS: We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells. Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem-/- mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5. In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cell-selective laser-capture microdissection. CONCLUSION/SIGNIFICANCE: Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells. PMID- 20711501 TI - High-throughput analysis of total plasma fatty acid composition with direct in situ transesterification. AB - BACKGROUND: Plasma fatty acid (FA) composition reflects dietary intake and endogenous turnover and is associated with health outcomes on a short and long term basis. The total plasma FA pool represents the composition of all FA containing lipid fractions. We developed a simplified and affordable high throughput method for the analysis of total plasma FA composition, suitable for large studies. METHODOLOGY/PRINCIPAL FINDINGS: The total lipid FA from 100 microl plasma is transferred in situ into methyl esters, avoiding initial extraction and drying steps. The fatty acid methyl esters are extracted once and analyzed by gas chromatography. For the new direct in situ transesterification method optimal, reaction parameters were determined. Intra-assay analysis (n=8) revealed coefficients of variation below 4% for FA contributing more than 1% to total FA. CONCLUSIONS/SIGNIFICANCE: The results show good agreement with FA concentrations obtained by a reference method. The new direct in situ transesterification method is robust and simple. Sample preparation time and analysis costs are reduced to a minimum. This method is an economically and ecologically superior alternative to conventional methods for assessing plasma FA status in large studies. PMID- 20711502 TI - Tuberculosis management by private practitioners in Mumbai, India: has anything changed in two decades? AB - SETTING: Mumbai, India. A study conducted in Mumbai two decades ago revealed the extent of inappropriate tuberculosis (TB) management practices of private practitioners. Over the years, India's national TB programme has made significant progress in TB control. Efforts to engage private practitioners have also been made with several successful documented public-private mix initiatives in place. OBJECTIVE: To study prescribing practices of private practitioners in the treatment of tuberculosis, two decades after a similar study conducted in the same geographical area revealed dismal results. METHODS: Survey questionnaire administered to practicing general practitioners attending a continuing medical education programme. RESULTS: The participating practitioners had never been approached or oriented by the local TB programme. Only 6 of the 106 respondents wrote a prescription with a correct drug regimen. 106 doctors prescribed 63 different drug regimens. There was tendency to over treat with more drugs for longer durations. Only 3 of the 106 respondents could write an appropriate prescription for treatment of multidrug-resistant TB. CONCLUSIONS: With a vast majority of private practitioners unable to provide a correct prescription for treating TB and not approached by the national TB programme, little seems to have changed over the years. Strategies to control TB through public sector health services will have little impact if inappropriate management of TB patients in private clinics continues unabated. Large scale implementation of public-private mix approaches should be a top priority for the programme. Ignoring the private sector could worsen the epidemic of multidrug-resistant and extensively drug resistant forms of TB. PMID- 20711503 TI - Statistical modeling of Agatston score in multi-ethnic study of atherosclerosis (MESA). AB - The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing study of the prevalence, risk factors, and progression of subclinical cardiovascular disease in a multi-ethnic cohort. It provides a valuable opportunity to examine the development and progression of CAC (coronary artery calcium), which is an important risk factor for the development of coronary heart disease. In MESA, about half of the CAC scores are zero and the rest are continuously distributed. Such data has been referred to as "zero-inflated data" and may be described using two-part models. Existing two-part model studies have limitations in that they usually consider parametric models only, make the assumption of known forms of the covariate effects, and focus only on the estimation property of the models. In this article, we investigate statistical modeling of CAC in MESA. Building on existing studies, we focus on two-part models. We investigate both parametric and semiparametric, and both proportional and nonproportional models. For various models, we study their estimation as well as prediction properties. We show that, to fully describe the relationship between covariates and CAC development, the semiparametric model with nonproportional covariate effects is needed. In contrast, for the purpose of prediction, the parametric model with proportional covariate effects is sufficient. This study provides a statistical basis for describing the behaviors of CAC and insights into its biological mechanisms. PMID- 20711504 TI - An ancient origin for the enigmatic flat-headed frogs (Bombinatoridae: Barbourula) from the islands of Southeast Asia. AB - BACKGROUND: The complex history of Southeast Asian islands has long been of interest to biogeographers. Dispersal and vicariance events in the Pleistocene have received the most attention, though recent studies suggest a potentially more ancient history to components of the terrestrial fauna. Among this fauna is the enigmatic archaeobatrachian frog genus Barbourula, which only occurs on the islands of Borneo and Palawan. We utilize this lineage to gain unique insight into the temporal history of lineage diversification in Southeast Asian islands. METHODOLOGY/PRINCIPAL FINDINGS: Using mitochondrial and nuclear genetic data, multiple fossil calibration points, and likelihood and Bayesian methods, we estimate phylogenetic relationships and divergence times for Barbourula. We determine the sensitivity of focal divergence times to specific calibration points by jackknife approach in which each calibration point is excluded from analysis. We find that relevant divergence time estimates are robust to the exclusion of specific calibration points. Barbourula is recovered as a monophyletic lineage nested within a monophyletic Costata. Barbourula diverged from its sister taxon Bombina in the Paleogene and the two species of Barbourula diverged in the Late Miocene. CONCLUSIONS/SIGNIFICANCE: The divergences within Barbourula and between it and Bombina are surprisingly old and represent the oldest estimates for a cladogenetic event resulting in living taxa endemic to Southeast Asian islands. Moreover, these divergence time estimates are consistent with a new biogeographic scenario: the Palawan Ark Hypothesis. We suggest that components of Palawan's terrestrial fauna might have "rafted" on emergent portions of the North Palawan Block during its migration from the Asian mainland to its present-day position near Borneo. Further, dispersal from Palawan to Borneo (rather than Borneo to Palawan) may explain the current day disjunct distribution of this ancient lineage. PMID- 20711505 TI - An efficient strategy to induce and maintain in vitro human T cells specific for autologous non-small cell lung carcinoma. AB - BACKGROUND: The efficient expansion in vitro of cytolytic CD8+ T cells (CTLs) specific for autologous tumors is crucial both for basic and translational aspects of tumor immunology. We investigated strategies to generate CTLs specific for autologous Non-Small Cell Lung Carcinoma (NSCLC), the most frequent tumor in mankind, using circulating lymphocytes. PRINCIPAL FINDINGS: Classic Mixed Lymphocyte Tumor Cultures with NSCLC cells consistently failed to induce tumor specific CTLs. Cross-presentation in vitro of irradiated NSCLC cells by autologous dendritic cells, by contrast, induced specific CTL lines from which we obtained a high number of tumor-specific T cell clones (TCCs). The TCCs displayed a limited TCR diversity, suggesting an origin from few tumor-specific T cell precursors, while their TCR molecular fingerprints were detected in the patient's tumor infiltrating lymphocytes, implying a role in the spontaneous anti-tumor response. Grafting NSCLC-specific TCR into primary allogeneic T cells by lentiviral vectors expressing human V-mouse C chimeric TCRalpha/beta chains overcame the growth limits of these TCCs. The resulting, rapidly expanding CD4+ and CD8+ T cell lines stably expressed the grafted chimeric TCR and specifically recognized the original NSCLC. CONCLUSIONS: This study defines a strategy to efficiently induce and propagate in vitro T cells specific for NSCLC starting from autologous peripheral blood lymphocytes. PMID- 20711506 TI - The probabilistic niche model reveals the niche structure and role of body size in a complex food web. AB - The niche model has been widely used to model the structure of complex food webs, and yet the ecological meaning of the single niche dimension has not been explored. In the niche model, each species has three traits, niche position, diet position and feeding range. Here, a new probabilistic niche model, which allows the maximum likelihood set of trait values to be estimated for each species, is applied to the food web of the Benguela fishery. We also developed the allometric niche model, in which body size is used as the niche dimension. About 80% of the links in the empirical data are predicted by the probabilistic niche model, a significant improvement over recent models. As in the niche model, species are uniformly distributed on the niche axis. Feeding ranges are exponentially distributed, but diet positions are not uniformly distributed below the predator. Species traits are strongly correlated with body size, but the allometric niche model performs significantly worse than the probabilistic niche model. The best fit parameter set provides a significantly better model of the structure of the Benguela food web than was previously available. The methodology allows the identification of a number of taxa that stand out as outliers either in the model's poor performance at predicting their predators or prey or in their parameter values. While important, body size alone does not explain the structure of the one-dimensional niche. PMID- 20711507 TI - The impact of augmented information on visuo-motor adaptation in younger and older adults. AB - BACKGROUND: Adjustment to a visuo-motor rotation is known to be affected by ageing. According to previous studies, the age-related differences primarily pertain to the use of strategic corrections and the generation of explicit knowledge on which strategic corrections are based, whereas the acquisition of an (implicit) internal model of the novel visuo-motor transformation is unaffected. The present study aimed to assess the impact of augmented information on the age related variation of visuo-motor adjustments. METHODOLOGY/PRINCIPAL FINDINGS: Participants performed aiming movements controlling a cursor on a computer screen. Visual feedback of direction of cursor motion was rotated 75 degrees relative to the direction of hand motion. Participants had to adjust to this rotation in the presence and absence of an additional hand-movement target that explicitly depicted the input-output relations of the visuo-motor transformation. An extensive set of tests was employed in order to disentangle the contributions of different processes to visuo-motor adjustment. Results show that the augmented information failed to affect the age-related variations of explicit knowledge, adaptive shifts, and aftereffects in a substantial way, whereas it clearly affected initial direction errors during practice and proprioceptive realignment. CONCLUSIONS: Contrary to expectations, older participants apparently made no use of the augmented information, whereas younger participants used the additional movement target to reduce initial direction errors early during practice. However, after a first block of trials errors increased, indicating a neglect of the augmented information, and only slowly declined thereafter. A hypothetical dual-task account of these findings is discussed. The use of the augmented information also led to a selective impairment of proprioceptive realignment in the younger group. The mere finding of proprioceptive realignment in adaptation to a visuo-motor rotation in a computer-controlled setup is noteworthy since visual and proprioceptive information pertain to different objects. PMID- 20711508 TI - Conditions for Global Stability of Monotone Tridiagonal Systems with Negative Feedback. AB - This paper studies monotone tridiagonal systems with negative feedback. These systems possess the Poincare-Bendixson property, which implies that, if orbits are bounded, if there is a unique steady state and this unique steady state is asymptotically stable, and if one can rule out periodic orbits, then the steady state is globally asymptotically stable. Two different approaches are discussed to rule out period orbits, one based on direct linearization and another one based on the theory of second additive compound matrices. Among the examples that illustrate the theoretical results is the classical Goldbeter model of the circadian rhythm. PMID- 20711509 TI - Electrosorption/Electrodesorption of Arsenic on a Granular Activated Carbon in the Presence of Other Heavy Metals. AB - The adsorption, electrosorption, and electrodesorption of aqueous, inorganic arsenic on the granular activated carbon (GAC), DARCO((R)) 12x20 GAC was investigated in solutions containing arsenic as the only contaminant, as well as with chromium, nickel and iron. Darco 1220 was selected for these investigations primarily because it is relatively ineffective as a normal (unassisted) arsenic adsorbent in the chosen electrolytes at the low loadings used. It is shown that the application of anodic potentials in the 1.0 - 1.5V range, however, result in enhanced uptake, most probably due to charging of the electrochemical double layer at the electrode surface. 100% regeneration of electrosorbed arsenic was achieved via electrodesorption at a cathodic potential of 1.50V. The presence of ad-metal ions was observed to have a significant and complex effect on arsenic adsorption, electrosorption, and electrodesorption. In particular, the Cr:As ratio was shown to have complex effects, decreasing adsorption uptake when present as 3:2, but enhancing adsorption when present as 5:1. Nickel was found to have less of an effect than chromium except at the highest anodic potential used of 1.50V, where it exhibited better performance than chromium. The presence of iron significantly enhanced uptake. With a 1.50V anodic potential, the bulk arsenic concentration was reduced to less than detectable limits, well below the USEPA MCL for drinking water. Regeneration efficiency by electrodesorption for the As-Fe system was greater than about 90%. PMID- 20711511 TI - Relative risk estimated from the ratio of two median unbiased estimates. AB - Clinical trials often include binary endpoints. In some cases, no successes are observed and the usual large-sample estimates of relative risk are undefined. This paper proposes an estimator for relative risk based on the median unbiased estimator. The proposed relative risk estimator is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and a SAS MACRO is available to perform the necessary calculations. An ongoing randomized clinical trial motivated the development of the estimator and is used to illustrate the approach. PMID- 20711510 TI - Tat-Mediated Peptide Intervention in Analgesia and Anesthesia. AB - Membrane-permeable peptide carriers are attractive drug delivery tools. Among such carriers, the protein transduction domain (PTD) of the human immunodeficiency virus-type 1 Tat protein is most frequently used and has been successfully shown to deliver a large variety of cargoes. The Tat PTD can facilitate the uptake of large, biologically active molecules into mammalian cells, and recent studies have shown that it can mediate the delivery of different cargoes into tissues throughout a living organism. Given that the Tat PTD-mediated delivery is size-independent, this technology could make previously non-applicable large molecules usable to modulate biological function in vivo and treat human diseases. It is likely that the peptide carrier-mediated intracellular delivery process encompasses multiple mechanisms, but endocytic pathways are the predominant internalization routes. Tat PTD has been successfully used in preclinical models for the study of cancer, ischemia, inflammation, analgesia, and anesthesia. Our recent studies have shown that intraperitoneally injected fusion Tat peptide Tat-PSD-95 PDZ2 can be delivered into the spinal cord to dose-dependently disrupt protein-protein interactions between PSD-95 and NMDA receptors. This peptide significantly inhibits chronic inflammatory pain and reduces the threshold for halothane anesthesia. The ability of the Tat PTD to target any cell is advantageous in some respects. However, the drug delivery system will be more attractive if we can modify the Tat PTD to deliver cargo only into desired organs to avoid possible side effects. PMID- 20711512 TI - Sounds like a Narcissist: Behavioral Manifestations of Narcissism in Everyday Life. AB - Little is known about narcissists' everyday behavior. The goal of this study was to describe how narcissism is manifested in everyday life. Using the Electronically Activated Recorder (EAR), we obtained naturalistic behavior from participants' everyday lives. The results suggest that the defining characteristics of narcissism that have been established from questionnaire and laboratory-based studies are borne out in narcissists' day-to-day behaviors. Narcissists do indeed behave in more extraverted and less agreeable ways than non narcissists, skip class more (among narcissists high in exploitativeness/entitlement only), and use more sexual language. Furthermore, we found that the link between narcissism and disagreeable behavior is strengthened when controlling for self-esteem, thus extending prior questionnaire-based findings (Paulhus, Robins, Trzesniewski, & Tracy, 2004) to observed, real-world behavior. PMID- 20711514 TI - Improved Dynamic Cardiac Phantom Based on 4D NURBS and Tagged MRI. AB - We previously developed a realistic phantom for the cardiac motion for use in medical imaging research. The phantom was based upon a gated magnetic resonance imaging (MRI) cardiac study and using 4D non-uniform rational b-splines (NURBS). Using the gated MRI study as the basis for the cardiac model had its limitations. From the MRI images, the change in the size and geometry of the heart structures could be obtained, but without markers to track the movement of points on or within the myocardium, no explicit time correspondence could be established for the structures. Also, only the inner and outer surfaces of the myocardium could be modeled. We enhance this phantom of the beating heart using 4D tagged MRI data. We utilize NURBS surfaces to analyze the full 3D motion of the heart from the tagged data. From this analysis, time-dependent 3D NURBS surfaces were created for the right (RV) and left ventricles (LV). Models for the atria were developed separately since the tagged data only covered the ventricles. A 4D NURBS surface was fit to the 3D surfaces of the heart creating time-continuous 4D NURBS models. Multiple 4D surfaces were created for the left ventricle (LV) spanning its entire volume. The multiple surfaces for the LV were spline interpolated about an additional dimension, thickness, creating a 4D NURBS solid model for the LV with the ability to represent the motion of any point within the volume of the LV myocardium at any time during the cardiac cycle. Our analysis of the tagged data was found to produce accurate models for the RV and LV at each time frame. In a comparison with segmented structures from the tagged dataset, LV and RV surface predictions were found to vary by a maximum of 1.5 mm's and 3.4 mm's respectively. The errors can be attributed to the tag spacing in the data (7.97 mm's). The new cardiac model was incorporated into the 4D NURBS-based Cardiac-Torso (NCAT) phantom widely used in imaging research. With its enhanced abilities, the model will provide a useful tool in the study of cardiac imaging and the effects of cardiac motion in medical images. PMID- 20711513 TI - An implicit solvent model for SCC-DFTB with Charge-Dependent Radii. AB - Motivated by the need of rapidly exploring the potential energy surface of chemical reactions that involve highly charged species, we have developed an implicit solvent model for the approximate density functional theory, SCC-DFTB. The solvation free energy is calculated using the popular model that employs Poisson-Boltzmann for electrostatics and a surface-area term for non-polar contributions. To balance the treatment of species with different charge distributions, we make the atomic radii that define the dielectric boundary and solute cavity depend on the solute charge distribution. Specifically, the atomic radii are assumed to be linearly dependent on the Mulliken charges and solved self-consistently together with the solute electronic structure. Benchmark calculations indicate that the model leads to solvation free energies of comparable accuracy to the SM6 model (especially for ions), which requires much more expensive DFT calculations. With analytical first derivatives and favorable computational speed, the SCC-DFTB based solvation model can be effectively used, in conjunction with high-level QM calculations, to explore the mechanism of solution reactions. This is illustrated with a brief analysis of the hydrolysis of mono-methyl mono-phosphate ester (MMP) and tri-methyl mono-phosphate ester (TMP). Possible future improvements are also briefly discussed. PMID- 20711515 TI - Optimization of the Production of the Lantibiotic Mutacin 1140 in Minimal Media. AB - Mutacin 1140 is produced by Streptococcus mutans and belongs to the type A lantibiotic family. Experiments were done to optimize production of mutacin 1140 in minimal media enabling a more cost efficient downstream purification method. The development of a small volume fermentation method enabled a rapid screen of several variables in a standard shaking incubator. This method provided a fast approach for determining components that promote mutacin 1140 production in minimal media broth. Lactose was determined to be the optimal carbon source for mutacin 1140 production. High concentrations of CaCl(2) (0.3% w/v) and MgSO(4) (0.77% w/v) promoted an increase in mutacin 1140 production, while ZnCl(2) and FeCl(3) appeared to impair production. Optimization of mutacin 1140 production in minimal media resulted in more than a 100-fold increase in production compared to the base medium used to begin our optimizations. The yield has been estimated by RP-HPLC to be ~10 mg/L. PMID- 20711516 TI - Total Synthesis of (+)-Papulacandin D. AB - A total synthesis of (+)-papulacandin D has been achieved in 31 steps, in a 9.2% overall yield from commercially available materials. The synthetic strategy divided the molecule into two nearly equal sized subunits, the spirocyclic C arylglycopyranoside and the polyunsaturated fatty acid side chain. The C arylglycopyranoside was prepared in 11 steps in a 30% overall yield from triacetoxyglucal. The fatty acid side chain was also prepared in 11 steps in a 30% overall yield from geraniol. The key strategic transformations in the synthesis are: (1) a palladium-catalyzed, organosilanolate-based cross-coupling reaction of a dimethylglucal-silanol with an electron rich and sterically hindered aromatic iodide and (2) a Lewis base-catalyzed, enantioselective allylation reaction of a dienal and allyltrichlorosilane. A critical element in the successful execution of the synthesis was the development of a suitable protecting group strategy that satisfied a number of stringent criteria. PMID- 20711517 TI - Towards mRNA with superior translational activity: synthesis and properties of ARCA tetraphosphates with single phosphorothioate modifications. AB - We describe the chemical synthesis and preliminary biophysical and biochemical characterization of a series of mRNA 5' end (cap) analogs designed as reagents for obtaining mRNA molecules with augmented translation efficiency and stability in vivo and as useful tools to study mRNA metabolism. The analogs share three structural features: (i) 5',5'- bridge elongated to tetraphosphate to increase their affinity to translation initiation factor eIF4E (ii) a single phosphorothioate modification at either the alpha, beta, gamma or delta-position of the tetraphosphate to decrease their susceptibility to enzymatic degradation and/or to modulate their interaction with specific proteins and (iii) a 2'-O methyl group in the ribose of 7-methylguanosine, characteristic to Anti-Reverse Cap Analogs (ARCAs), which are incorporated into mRNA during in vitro transcription exclusively in the correct orientation. The dinucleotides bearing modified tetraphosphate bridge were synthesized by ZnCl(2) mediated coupling between two mononucleotide subunits with isolated yields of 30-65%. The preliminary biochemical results show that mRNAs capped with new analogs are 2.5 4.5 more efficiently translated in a cell free system than m(7)GpppG-capped mRNAs, which makes them promising candidates for RNA-based therapeutic applications such as gene therapy and anti-cancer vaccines. PMID- 20711518 TI - Targeting the Pentose Phosphate Pathway in Syndrome X-related Cardiovascular Complications. AB - Syndrome X is a combination or co-occurrence of several known cardiovascular risk factors (including central obesity, dyslipidemias, fatty liver disease, hyperinsulinemia, insulin resistance, and hypertension) that affects at least one in five people in developed countries. Syndrome X shortens life and increases morbidity by contributing to the development of both diabetes and cardiovascular disease. Type 1 or 2 diabetes affects approximately 170 million people globally and these numbers are rapidly rising. In patients with diabetes, vascular diseases develop early and progress at an accelerated rate. It has recently become evident that glucose-6-phosphate dehydrogenase (G6PD), the rate limiting enzyme in the pentose-phosphate pathway and its reaction products play key roles in regulating vascular function. Epidemiological studies have also shown that G6PD deficiency markedly reduces retinopathy and mortality due to cardiovascular diseases in males from certain Mediterranean regions. Conversely, G6PD expression and activity are upregulated in rat and mouse models of obesity, hyperglycemia and hyperinsulinemia, and a role for G6PD in the development of insulin resistance in type 2 diabetes has been proposed. Unfortunately, there are no selective drugs available to validate the hypothesis that G6PD and its products are involved in the development of Syndrome X in humans. This review discusses the potential mechanisms by which G6PD could be implicated in vascular diseases in Syndrome X and the need to develop new approaches, including new drugs and molecular tools, to ameliorate diabetes-induced vascular dysfunction and vasculopathies. PMID- 20711519 TI - A comparative analysis of extra-embryonic endoderm cell lines. AB - Prior to gastrulation in the mouse, all endodermal cells arise from the primitive endoderm of the blastocyst stage embryo. Primitive endoderm and its derivatives are generally referred to as extra-embryonic endoderm (ExEn) because the majority of these cells contribute to extra-embryonic lineages encompassing the visceral endoderm (VE) and the parietal endoderm (PE). During gastrulation, the definitive endoderm (DE) forms by ingression of cells from the epiblast. The DE comprises most of the cells of the gut and its accessory organs. Despite their different origins and fates, there is a surprising amount of overlap in marker expression between the ExEn and DE, making it difficult to distinguish between these cell types by marker analysis. This is significant for two main reasons. First, because endodermal organs, such as the liver and pancreas, play important physiological roles in adult animals, much experimental effort has been directed in recent years toward the establishment of protocols for the efficient derivation of endodermal cell types in vitro. Conversely, factors secreted by the VE play pivotal roles that cannot be attributed to the DE in early axis formation, heart formation and the patterning of the anterior nervous system. Thus, efforts in both of these areas have been hampered by a lack of markers that clearly distinguish between ExEn and DE. To further understand the ExEn we have undertaken a comparative analysis of three ExEn-like cell lines (END2, PYS2 and XEN). PYS2 cells are derived from embryonal carcinomas (EC) of 129 strain mice and have been characterized as parietal endoderm-like [1], END2 cells are derived from P19 ECs and described as visceral endoderm-like, while XEN cells are derived from blastocyst stage embryos and are described as primitive endoderm-like. Our analysis suggests that none of these cell lines represent a bona fide single in vivo lineage. Both PYS2 and XEN cells represent mixed populations expressing markers for several ExEn lineages. Conversely END2 cells, which were previously characterized as VE-like, fail to express many markers that are widely expressed in the VE, but instead express markers for only a subset of the VE, the anterior visceral endoderm. In addition END2 cells also express markers for the PE. We extended these observations with microarray analysis which was used to probe and refine previously published data sets of genes proposed to distinguish between DE and VE. Finally, genome-wide pathway analysis revealed that SMAD-independent TGFbeta signaling through a TAK1/p38/JNK or TAK1/NLK pathway may represent one mode of intracellular signaling shared by all three of these lines, and suggests that factors downstream of these pathways may mediate some functions of the ExEn. These studies represent the first step in the development of XEN cells as a powerful molecular genetic tool to study the endodermal signals that mediate the important developmental functions of the extra-embryonic endoderm. Our data refine our current knowledge of markers that distinguish various subtypes of endoderm. In addition, pathway analysis suggests that the ExEn may mediate some of its functions through a non-classical MAP Kinase signaling pathway downstream of TAK1. PMID- 20711520 TI - A symbolic/subsymbolic interface protocol for cognitive modeling. AB - Researchers studying complex cognition have grown increasingly interested in mapping symbolic cognitive architectures onto subsymbolic brain models. Such a mapping seems essential for understanding cognition under all but the most extreme viewpoints (namely, that cognition consists exclusively of digitally implemented rules; or instead, involves no rules whatsoever). Making this mapping reduces to specifying an interface between symbolic and subsymbolic descriptions of brain activity. To that end, we propose parameterization techniques for building cognitive models as programmable, structured, recurrent neural networks. Feedback strength in these models determines whether their components implement classically subsymbolic neural network functions (e.g., pattern recognition), or instead, logical rules and digital memory. These techniques support the implementation of limited production systems. Though inherently sequential and symbolic, these neural production systems can exploit principles of parallel, analog processing from decision-making models in psychology and neuroscience to explain the effects of brain damage on problem solving behavior. PMID- 20711521 TI - Neighborhood Disadvantage, Stressful Life Events, and Adjustment Among Mexican American Early Adolescents. AB - This study examined a stress-process model in which stressful life events and association with delinquent peers mediated the relationship of neighborhood disadvantage to Mexican American early adolescents' mental health. We also proposed that child gender, child generation, and neighborhood informal social control would moderate the relationship of neighborhood disadvantage to children's experiences of stressful life events. With data from 738 Mexican American early adolescents, results generally provided support for the theoretical model although the relationships of neighborhood disadvantage to stressful life events and adjustment were weaker than expected. Additional research is needed to corroborate these results and determine why neighborhood disadvantage may have different relationships to adjustment for Mexican American early adolescents than for others. PMID- 20711522 TI - Serious Video Games for Health How Behavioral Science Guided the Development of a Serious Video Game. AB - Serious video games for health are designed to entertain players while attempting to modify some aspect of their health behavior. Behavior is a complex process influenced by multiple factors, often making it difficult to change. Behavioral science provides insight into factors that influence specific actions that can be used to guide key game design decisions. This article reports how behavioral science guided the design of a serious video game to prevent Type 2 diabetes and obesity among youth, two health problems increasing in prevalence. It demonstrates how video game designers and behavioral scientists can combine their unique talents to create a highly focused serious video game that entertains while promoting behavior change. PMID- 20711523 TI - Photoreceptor spectral sensitivity in the bumblebee, Bombus impatiens (Hymenoptera: Apidae). AB - The bumblebee Bombus impatiens is increasingly used as a model in comparative studies of colour vision, or in behavioural studies relying on perceptual discrimination of colour. However, full spectral sensitivity data on the photoreceptor inputs underlying colour vision are not available for B. impatiens. Since most known bee species are trichromatic, with photoreceptor spectral sensitivity peaks in the UV, blue and green regions of the spectrum, data from a related species, where spectral sensitivity measurements have been made, are often applied to B impatiens. Nevertheless, species differences in spectral tuning of equivalent photoreceptor classes may result in peaks that differ by several nm, which may have small but significant effects on colour discrimination ability. We therefore used intracellular recording to measure photoreceptor spectral sensitivity in B. impatiens. Spectral peaks were estimated at 347, 424 and 539 nm for UV, blue and green receptors, respectively, suggesting that this species is a UV-blue-green trichromat. Photoreceptor spectral sensitivity peaks are similar to previous measurements from Bombus terrestris, although there is a significant difference in the peak sensitivity of the blue receptor, which is shifted in the short wave direction by 12-13 nm in B. impatiens compared to B. terrestris. PMID- 20711526 TI - Colorectal cancer screening using flexible sigmoidoscopy: United Kingdom study demonstrates significant incidence and mortality benefit. PMID- 20711524 TI - Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological dysfunctions. AB - Trypanosoma vivax is the main species involved in trypanosomosis, but very little is known about the immunobiology of the infective process caused by this parasite. Recently we undertook to further characterize the main parasitological, haematological and pathological characteristics of mouse models of T. vivax infection and noted severe anemia and thrombocytopenia coincident with rising parasitemia. To gain more insight into the organism's immunobiology, we studied lymphocyte populations in central (bone marrow) and peripherical (spleen and blood) tissues following mouse infection with T. vivax and showed that the immune system apparatus is affected both quantitatively and qualitatively. More precisely, after an initial increase that primarily involves CD4(+) T cells and macrophages, the number of splenic B cells decreases in a step-wise manner. Our results show that while infection triggers the activation and proliferation of Hematopoietic Stem Cells, Granulocyte-Monocyte, Common Myeloid and Megacaryocyte Erythrocyte progenitors decrease in number in the course of the infection. An in depth analysis of B-cell progenitors also indicated that maturation of pro-B into pre-B precursors seems to be compromised. This interferes with the mature B cell dynamics and renewal in the periphery. Altogether, our results show that T. vivax induces profound immunological alterations in myeloid and lymphoid progenitors which may prevent adequate control of T. vivax trypanosomosis. PMID- 20711527 TI - The rate of prescribing gastrointestinal prophylaxis with either a proton pump inhibitor or an H2-receptor antagonist in Nova Scotia seniors starting nonsteroidal anti-inflammatory drug therapy. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used agents that can cause serious gastrointestinal (GI) side effects. For patients at increased risk of NSAID-related GI complications, prophylaxis with either a nonselective NSAID plus gastroprotective agent (GPA) or, alternatively, therapy with a cyclooxygenase-2 selective inhibitor with or without a GPA such as a proton pump inhibitor (PPI), is recommended. AIM: To describe the rate, timing and duration of GI prophylaxis in Nova Scotia seniors receiving nonselective NSAIDs. METHODS: The Nova Scotia Seniors' Pharmacare Program beneficiaries for the years 1998 to 2002 were studied. A cohort of incident NSAID and GPA users was selected from all nonselective NSAID users (no prescribed NSAID dispensed 12 months before the index month and no GPA dispensed two months before the index prescription). Monthly coprescribing rates were calculated by dividing the number of patients in the cohort using GPAs by the number of NSAID users. GI prophylactic coprescribing was defined as the coprescribing rate present at the first month (index month) of prescribing an NSAID. RESULTS: The cohort consisted of 12,906 patients. Seventy-five per cent of the nonselective NSAID prescriptions dispensed were for up to two months duration, with only 2.3% longer than one year. GI prophylaxis was given to only 3.8% of patients starting NSAIDs who were not on a GPA in the two months before starting NSAIDs. Of this 3.8%, 92.7% of the patients received H2-receptor antagonists (H2RAs), and 7% received PPIs. The rate of H2RA coprescribing increased with the number of consecutive months on an NSAID from 3.5% in the first month to 24.1% at 48 months. For PPIs, the coprescribing rate increased from 0.3% to 1.9% of all NSAID users in the cohort. The rate of gastroprophylaxis coprescribing for patients receiving NSAIDs did not rise with increasing age. CONCLUSION: In Nova Scotian seniors using nonselective NSAIDs, the rate of GI prophylaxis was low. Most patients received H2RAs as GPAs despite evidence that they offer insufficient protection. PMID- 20711528 TI - A one-year economic evaluation of six alternative strategies in the management of uninvestigated upper gastrointestinal symptoms in Canadian primary care. AB - BACKGROUND: The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinalsymptoms remains controversial. OBJECTIVE: To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting. METHODS: The present study analyzed data from four randomized trials assessing homogeneous and complementary populations of Canadian patients with uninvestigated upper gastrointestinal symptoms with comparable outcomes. Symptom free months, qualityadjusted life-years (QALYs) and direct costs in Canadian dollars of two management approaches based on the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool, and four additional strategies (two empirical antisecretory agents, and two prompt endoscopy) were examined and compared. Prevalence data, probabilities, utilities and costs were included in a Markov model, while sensitivity analysis used Monte Carlo simulations. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were determined. RESULTS: Empirical omeprazole cost $226 per QALY ($49 per symptom-free month) per patient. CanDys omeprazole and endoscopy approaches were more effective than empirical omeprazole, but more costly. Alternatives using H2 receptor antagonists were less effective than those using a proton pump inhibitor. No significant differences were found for most incremental cost effectiveness ratios. As willingness to pay (WTP) thresholds rose from $226 to $24,000 per QALY, empirical antisecretory approaches were less likely to be the most costeffective choice, with CanDys omeprazole progressively becoming a more likely option. For WTP values ranging from $24,000 to $70,000 per QALY, the most clinically relevant range, CanDys omeprazole was the most cost-effective strategy (32% to 46% of the time), with prompt endoscopy-proton pump inhibitor favoured at higher WTP values. CONCLUSIONS: Although no strategy was the indisputable cost effective option, CanDys omeprazole may be the strategy of choiceover a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.

PMID- 20711529 TI - Long-term management of patients with celiac disease: current practices of gastroenterologists in Canada. AB - BACKGROUND: Long-term follow-up of patients with celiac disease is important for monitoring their clinical status, dietary compliance and complications. AIM: To examine the current practices of Canadian gastroenterologists providing long-term care to patients with celiac disease. METHODS: All gastroenterologists in Canada (n=585) were surveyed regarding their practice demographics, familiarity with celiac disease practice guidelines, and follow-up clinical examination and investigations. RESULTS: Of the 585 surveys mailed to gastroenterologists, 567 were expected to be returned. A total of 242 completed surveys (43%) were received. Of these, 237 (184 adult, 51 pediatric and two mixed) had an active practice that included patients with celiac disease. Long-term follow-up care was provided routinely by 76% of respondents. Follow-up consisted of annual clinic visits (67%), dietary review (77%), reinforcement of the need for adherence to a gluten-free diet (90%) and recommending membership in an advocacy group (65%). Physical examination was performed by 78%; most ordered laboratory tests including serology (65%).Adult gastroenterologists performed routine follow-up intestinal biopsy more often than their pediatric counterparts (46% versus 10%), but performed serology less frequently (48% versus 86%). Pediatric patients were more likely to be followed by a multidisciplinary team. All pediatric gastroenterologists were familiar with at least one celiac disease practice guideline, whereas 15% of adult gastroenterologists were not familiar with any practice guideline. The majority of gastroenterologists who did not routinely provide follow-up expected care to be provided by the patient's primary physician (86%). CONCLUSIONS: Most gastroenterologists in Canada who responded to the survey provided long-term follow-up care to patients with celiac disease. The diverse practices reported underscore the need to develop consensus-based guidelines for long-term care of these patients. PMID- 20711534 TI - A genetically encoded photocaged Nepsilon-methyl-L-lysine. AB - A photocaged N(epsilon)-methyl-L-lysine has been genetically incorporated into proteins at amber codon positions in Escherichia coli using an evolved pyrrolysyl tRNA synthetase-pylT pair. Its genetic incorporation and following photolysis to recover N(epsilon)-methyl-L-lysine at physiological pH provide a convenient method for the biosynthesis of proteins with monomethylated lysines at specific sites. PMID- 20711533 TI - The emerging process of Top Down mass spectrometry for protein analysis: biomarkers, protein-therapeutics, and achieving high throughput. AB - Top Down mass spectrometry (MS) has emerged as an alternative to common Bottom Up strategies for protein analysis. In the Top Down approach, intact proteins are fragmented directly in the mass spectrometer to achieve both protein identification and characterization, even capturing information on combinatorial post-translational modifications. Just in the past two years, Top Down MS has seen incremental advances in instrumentation and dedicated software, and has also experienced a major boost from refined separations of whole proteins in complex mixtures that have both high recovery and reproducibility. Combined with steadily advancing commercial MS instrumentation and data processing, a high-throughput workflow covering intact proteins and polypeptides up to 70 kDa is directly visible in the near future. PMID- 20711535 TI - Detection of enzyme activities based on the synthesis of gold nanoparticles in HEPES buffer. AB - The reduction of tetrachloroaurate ions (AuCl(4)(-)) with 2-[4-(2-hydroxyethyl)-1 piperazinyl]ethanesulfonic acid (HEPES) was used to detect alkaline phosphatase (ALP) activity. PMID- 20711536 TI - Modular blue fluorescent RNA sensors for label-free detection of target molecules. AB - A blue fluorescent RNA was applied to modular blue fluorescent RNA sensors, wherein a "recognition" event of the target molecule by the aptamer domain is transmitted through a "communication" module, to a "signaling" fluorescent RNA domain, which "lights up". PMID- 20711537 TI - Multidimensional glycan arrays for enhanced antibody profiling. AB - Carbohydrate-binding antibodies play a critical role in basic and clinical research. Monoclonal antibodies that bind glycans are used to measure carbohydrate expression, and serum antibodies to glycans can be important elements of the immune response to pathogens and vaccines. Carbohydrate antigen arrays, or glycan arrays, have emerged as powerful tools for the high-throughput analysis of carbohydrate-protein interactions. Our group has focused on the development and application of neoglycoprotein arrays, a unique array format wherein carbohydrates are covalently attached to a carrier protein prior to immobilization on the surface. The neoglycoprotein format permits variations of glycan structure, glycan density, and neoglycoprotein density on a single array. The focus of this study was on the effects of neoglycoprotein density on antibody binding. First, we evaluated binding of five monoclonal antibodies (81FR2.2, HE 195, HE-193, B480, and Z2A) to the blood group A antigen and found that neoglycoprotein density had a substantial effect on recognition. Next, we profiled serum antibodies in 15 healthy individuals and showed that inclusion of multiple neoglycoprotein densities helps distinguish different subpopulations of antibodies. Finally, we evaluated immune responses induced by a prostate cancer vaccine and showed that variations in neoglycoprotein density enable one to detect antibody responses that could not be detected otherwise. Neoglycoprotein density is a useful element of diversity for evaluating antibody recognition and, when combined with variations in glycan structure and glycan density, provides multidimensional glycan arrays with enhanced performance for monoclonal antibody development, biomarker discovery, and vaccine optimization. PMID- 20711540 TI - Determinants of overweight in children under 4 years of age. AB - OBJECTIVES: To describe the prevalence of and factors associated with overweight in children under 4 years of age in Feira de Santana, state of Bahia, Brazil. METHODS: Cross-sectional study nested within a birth cohort of 793 children born in Feira de Santana, Brazil. Independent variables were related to infant characteristics, social and demographic factors, maternal reproductive aspects, and diet of the child at age 4 months. The dependent variable was nutritional status, as assessed by weight-for-height ratio compared to Multicentre Growth Reference Study standards and obtained with the use of the software ANTHRO. Z scores of -2 and +2 above or below the median for the reference population were established as normality cutoff points. Child height and weight were measured with an anthropometer and digital scales, respectively; all measurements were taken in triplicate. The study was approved by the Research Ethics Committee of the Universidade Estadual de Feira de Santana (CEP/UEFS), under registration number 096/2006. RESULTS: The prevalence of overweight was 12.5%. Adequate birth weight (RR 2.75; 95%CI 1.50-5.05), primiparity (RR 1.61; 95%CI 1.09-2.35), and maternal employment outside the home at age 4 months (RR 1.73; 95%CI 1.16-2.59) were associated with overweight. CONCLUSIONS: In this study, adequate birth weight, primiparity and maternal employment outside the home were associated with overweight in children. The rate of overweight found, which surpassed that reported by other studies conducted across the country (including Bahia), point to a risk of child obesity in Feira de Santana. PMID- 20711542 TI - Spinal muscular atrophy: diagnosis, treatment and future prospects. AB - OBJECTIVE: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. SOURCES: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SUMMARY OF THE FINDINGS: SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. CONCLUSIONS: SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy. PMID- 20711541 TI - Vitamin E in human serum and colostrum under fasting and postprandial conditions. AB - OBJECTIVE: To evaluate alpha-tocopherol concentrations in maternal serum and colostrum under fasting and postprandial conditions. METHODS: Thirty healthy childbearing women were recruited in a public maternity hospital, and samples of blood, fasting colostrum, and postprandial colostrum were collected from them up to 12 hours after delivery. RESULTS: The serum alpha-tocopherol concentration was 1,939.8+/-766.0 microg/dL. Alpha-tocopherol levels in fasting colostrum (1,603.4+/-911.0 microg/dL) and in postprandial colostrum (1,515.0+/-890.9 microg/dL) did not demonstrate a statistically significant difference (p > 0.05). There was correlation between alpha-tocopherol levels in fasting and postprandial colostrum (p < 0.05), but not between serum and colostrum. CONCLUSION: The lack of correlation between alpha-tocopherol levels in plasma and in colostrum, and the correlation between alpha-tocopherol concentrations in fasting and postprandial colostrum support the existence of a mechanism that controls the transfer of this nutrient, regardless of dietary intake. PMID- 20711543 TI - Excess sodium and insufficient iron content in complementary foods. AB - OBJECTIVES: To determine, by chemical analysis, the macronutrient, energy, sodium, and iron contents of homemade foods prepared for infants in two socioeconomic classes in Belem, state of Para, Brazil. METHODS: Cross-sectional study of 78 infants (aged 6 to 18 months) distributed into two groups according to socioeconomic status (high or low). Chemical analyses were performed on samples of homemade complementary foods prepared for each infant's lunch. Daily food intake was estimated on the basis of two 24-hour dietary intake recall. RESULTS: Chemical analyses showed that the energy content of some food samples was lower than recommended, both in the low socioeconomic status (SES) group (29.8% of samples) and in the high-SES group (43.0%; p = 0.199). The iron content of all samples, regardless of group, was lower than minimum recommended levels (6.0 mg/100 g). On the other hand, excessive sodium levels (200 mg/100 g) were found in 89.2 and 31.7% of samples in the low- and high-SES groups, respectively (p = 0.027). Dietary recalls showed that energy intake exceeded 120% of the Estimated Energy Requirement in 86.5% of infants in the low-SES group and 92.7% of those in the high-SES group (p = 0.483). Lunch and dinner provided 35.2+/-14.6 and 36.4+/-12.0% of daily energy intake in the low- and high-SES groups, respectively (p = 0.692). CONCLUSION: Homemade complementary foods for infants were found to be low in iron. A significant portion of samples had excessive sodium content, most frequently those prepared for infants in low-SES status families. PMID- 20711544 TI - Assessment of the profile of births and deaths in a referral hospital. AB - OBJECTIVE: To compare perinatal health indicators in a referral hospital in Belo Horizonte, Brazil. METHODS: Perinatal results and indicators of single live births in Hospital das Clinicas of Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil, were compared for two periods, 1995-1998 and 2003-2006. The chi-square test and Student's t test were applied with 5% significance level and 95% confidence interval. Data were obtained from the Perinatal Information System (Sistema Informatico Perinatal, SIP), Latin American Center for Perinatology (Centro Latinoamericano de Perinatologia, CLAP), Pan American Health Organization (PAHO), Hospital das Clinicas, and from medical records. RESULTS: Mothers were approximately 26 years old on average. The number of prenatal appointments had an average increase of one appointment, regardless of birth weight, and there was a significant decrease in the number of caesarean deliveries in the second period. The average gestational age was 38 weeks in both periods, with a high rate of premature births (17.0 and 16.7%, respectively). The rate of newborns < 2,500 g was high in both periods (17.6 and 16.6%, respectively) with a decrease in the rate of newborns considered small for their gestational age. When congenital malformations were excluded, early neonatal mortality risk decreased from 12.4 per 1,000 live births in the first period to 8.0 per 1,000 live births in the second period, with considerable decrease for newborns with gestational age < 34 weeks. CONCLUSIONS: Important differences were verified concerning health care assistance procedures and perinatal results, and they are compatible with the global improvement in neonatal health observed in the 2003-2006 period. However, the persistence of unfortunate neonatal incidents that can be reduced with the use of available perinatal technologies reveals the need for constant monitoring of perinatal hospital care for all groups of newborns. PMID- 20711545 TI - Disposal of human milk donated to a human milk bank before and after measures to reduce the amount of milk unsuitable for consumption. AB - OBJECTIVE: To evaluate the causes of disposal of donated human milk and the impact of the measures taken to reduce the amount of milk unsuitable for consumption. METHODS: A quasi-experimental, observational, comparative study was conducted with different populations of external donors in 2006 and 2008. In 2006, a simple form was used to record the criteria for disposal of the donated milk. We also interviewed the donors to find the reason of changes in the milk. In 2008, a checklist containing comprehensive guidance for milk collection and pre-storage was handed out to the donors. Next, we continued to survey the disposal criteria after the intervention using the same form administered in 2006. A case was defined as all bottles of milk of the same donor discarded per day. Data were analyzed by calculations based on comparison of proportions for 2006 and 2008. RESULTS: Twenty-four percent of the milk collected was discarded in 2006, while in 2008 only 10.5% of the milk was discarded. There was significant reduction in the disposal of milk for the items: cigarette odor; forgetting the milk outside the refrigerator, inside it or on its door; problems with the freezer; frequent opening of the refrigerator and freezer; expiration date; and unidentified cases. However, there was a significant increase in milk disposal for first milk collection without guidance; use of inappropriate bottle; milk transportation from work to home; and indirect guidance. CONCLUSIONS: The use of the step-by-step checklist had a positive impact on the reduction of the volume of donated milk discarded and changed the frequency of the causes of disposal, eliminating some of these causes. PMID- 20711546 TI - Breastfeeding practice in the Brazilian capital cities and the Federal District: current status and advances. AB - OBJECTIVES: To present the breastfeeding (BF) indicators obtained in the Second Survey on Prevalence of Breastfeeding in the Brazilian Capitals and the Federal District and to analyze their evolution from 1999 to 2008. METHODS: A cross sectional study was conducted in children younger than 1 year old who participated in the second phase of the multivaccination campaign in 2008. We used two-stage cluster sampling. The questionnaire consisted of closed questions, including data on consumption of breast milk, other types of milk, and other foods on the day prior to the survey. We analyzed the prevalence of BF in the first hour of life; exclusive BF in children younger than 6 months; BF in children aged 9 to 12 months; and medians of exclusive BF and BF. The time variation of BF was established by comparing the medians of exclusive BF and BF in 1999 and 2008. RESULTS: We obtained data from 34,366 children. We found that 67.7% (95%CI 66.7-68.8) of the children were breastfed in the first hour of life; the prevalence of exclusive BF in children aged 0 to 6 months was 41% (95%CI 39.7 42.4), while the prevalence of BF in children aged 9 to 12 months was 58.7% (95%CI 56.8-60.7). There was an increase of 30.7 days in the median duration of exclusive BF and 45.7 days in the median of BF. CONCLUSION: There was a significant improvement in the breastfeeding prevalence in the last decade. However, further efforts are required so that Brazil can reach BF rates compatible with the recommendations of the World Health Organization. PMID- 20711547 TI - Metabolic syndrome: comparison of diagnosis criteria. AB - OBJECTIVE: To propose a new criterion for the diagnosis of metabolic syndrome (MS) in adolescents and to check its consistency with those proposed by Jolliffe and Janssen and by the International Diabetes Federation (IDF). METHOD: This is a cross-sectional study of 80 obese adolescents aged 14 to 19 years. Anthropometric (weight, height, and waist circumference) and laboratory (fasting triglycerides, HDLc, glucose, and insulin) parameters, as well as blood pressure were evaluated. The HOMA-IR index was used to characterize insulin resistance, and the presence of steatosis was assessed by hepatic ultrasound. Agreement analyses across the three criteria were made using the kappa coefficient. RESULTS: The prevalence of MS was 13.5, 15, and 25% for IDF and Jolliffe and Janssen's criteria and the proposed method, respectively. A nearly perfect agreement between Jolliffe and Janssen's and IDF (kappa = 0.94) criteria and a moderate agreement between the new criteria and the previous two (kappa = 0.46 and 0.41, respectively) were observed. CONCLUSIONS: The highest prevalence of MS was observed with the criterion proposed in this study, which included steatosis and insulin resistance as parameters, thus being able to diagnose a larger number of adolescents at metabolic risk. PMID- 20711548 TI - Wheezing in children and adolescents living next to a petrochemical plant in Rio Grande do Norte, Brazil. AB - OBJECTIVE: To examine the association between wheezing in children and adolescents and living downwind of the dispersion plume of atmospheric pollutants emitted by the Guamare Petrochemical Complex, in the state of Rio Grande do Norte, Brazil. METHODS: Cross-sectional study of wheezing in children and adolescents (aged 0 to 14 years) living in the vicinity of the Guamare petrochemical complex in 2006. The standardized International Study of Asthma and Allergies in Childhood questionnaire was used, with additional questions concerning tobacco use, income, living conditions, and educational achievement. Daily concentrations of PM10, PM2.5, black carbon, SO2, NO2, O3, benzene, toluene, and xylenes were measured at a fixed monitoring station. According to their position relative to wind direction, communities present in the area affected by plant emissions were categorized into one of two groups, exposed communities and reference communities. RESULTS: Two hundred and nine children and adolescents took part in the study. Mean daily concentrations of the monitored pollutants were consistently below established acceptable upper limits. The prevalence of wheezing in the 12 months prior to study was 27.3%. After adjustment, statistically significant associations were found between wheezing and living in exposed communities (adjusted odds ratio [ORadj] 2.01; 95% confidence interval [95%CI] 1.01-4.01), male gender (ORadj 2.50; 95%CI 1.21 5.18), and age 0 to 6 years (ORadj 5.00; 95%CI 2.41-10.39). CONCLUSION: Even with low levels of atmospheric pollutants, respiratory symptoms in children and adolescents were associated with living downwind of a petrochemical plant. Male preschoolers were the most vulnerable group. PMID- 20711549 TI - Physical activity in children with type 1 diabetes. AB - OBJECTIVE: To discuss the practical aspects of safe physical activity and sports participation in children and adolescents with type 1 diabetes mellitus. SOURCES: A literature search was conducted using national (SciELO) and international (PubMed/MEDLINE) databases and the reference lists of the articles found, adopting the following limits: articles on physical activity published in the last 10 years, preferably conducted in children and adolescents with type 1 diabetes. Most studies had an experimental design or were meta-analyses. SUMMARY OF THE FINDINGS: Skeletal muscle glucose uptake is greater during aerobic metabolism in order to generate energy for muscle contraction, which suppresses hepatic gluconeogenesis and thus promotes a decrease in blood glucose levels and increased risk of hypoglycemia. Adequate carbohydrate replacement before, during, and after exercise and reduction of preprandial rapid-acting insulin doses are the main allies in avoiding severe hypoglycemic events among diabetic children and adolescents. CONCLUSIONS: Type, duration, and intensity of physical activity must be considered when planning carbohydrate replacement and insulin dose reduction, as must the timing of exercise. Nonetheless, physical activity and participation in many individual and team sports is possible and highly recommended in the treatment of type 1 diabetes in children and adolescents. PMID- 20711551 TI - Toward high quality medical care for sickle cell disease: are we there yet? PMID- 20711550 TI - Celiac disease in first-degree relatives of patients. AB - OBJECTIVE: To determine the prevalence of celiac disease and to describe the histological alterations, clinical manifestations, and conditions associated with a group of first-degree relatives of celiac disease patients in the municipality of Recife, Northeast Brazil. METHOD: The study was conducted in outpatient clinics of pediatric gastroenterology located in Recife. We included in the study 174 first-degree relatives who were screened for the anti-transglutaminase IgA antibody. Those relatives who had positive serological tests were invited to undergo a small intestine biopsy (classified according to Marsh). They were also evaluated regarding weight, height, clinical symptoms and conditions associated with celiac disease. The chi-square test and Fisher's exact test were used to assess the differences with a significance level of p < 0.05. RESULTS: The anti transglutaminase IgA antibody was positive for 20.1% (34/174) of the relatives (95%CI 14.6-26.5). There was no difference in terms of positive serological tests regarding either degree of kinship or sex. Twenty-two patients underwent biopsy. Thirteen had histological alterations classified as Marsh stage 3; seven had stage 1; and two had stage zero, with a probable prevalence of 11.5%. All patients, except for one, had symptoms; the only patient with no symptoms was short. CONCLUSION: Celiac disease prevalence in this group of relatives was high. All new cases identified were symptomatic or had associated conditions. In this group, there was a high frequency of individuals with positive serological tests, symptoms suggestive of celiac disease, and no evidence of villous atrophy in the intestinal mucosa. PMID- 20711552 TI - Diagnosis of cow milk allergy in the gut, never an easy task. PMID- 20711554 TI - [Solid, asymptomatic nodules on several toes in a child]. AB - The term infantile digital fibromatosis describes a benign tumor of the group of fibromatoses. The prevalence rate is approximately 2.5% of all fibromatoses. The etiopathogenesis of infantile digital fibromatosis is unknown. These tumors can appear already at birth, but usually manifest during the first 3 years of life as solid, pink or skin-colored asymptomatic nodules on one or several fingers or toes. Because of the postoperative recurrence rate of 50-75% and the possibility of spontaneous regression, excision is not recommended according to currently available evidence. PMID- 20711555 TI - [Therapeutic alternatives for antihistamine-refractory urticaria]. AB - Patients with chronic spontaneous urticaria, the most frequent non-acute form of urticaria, generally exhibit a clinical picture of persistent disease, a high degree of disease activity, considerable impairment of quality of life, and poor response to treatment. More than half of the patients continue to develop symptoms despite standard therapy with non-sedating antihistamines. In these cases, the antihistamine dose should be increased (up to four times the daily dose). If this approach also does not result in symptom control, the high-dose antihistamine should be combined with a leukotriene antagonist and if necessary an H2 blocker. If the patient does not respond to this combination therapy, cyclosporin A, dapsone, or omalizumab should be administered. PMID- 20711556 TI - The mitochondrion as a Swiss army knife: implications for cardiovascular disease. PMID- 20711557 TI - Reconstructing the anatomy of the 42-million-year-old fossil Mengea tertiaria (Insecta, Strepsiptera). AB - Fossilization in amber is unique in preserving specimens with microscopic fidelity; however, arthropod inclusions are rarely examined beyond the exoskeleton as this requires destructive sampling when traditional techniques are used. We report the first complete, digital 3D, non-destructive reconstruction of the anatomy of an insect fossil, a specimen of Mengea tertiaria embedded in a 42 Ma Baltic amber. This was made possible using Synchrotron micro-CT. The species belongs to the stem group of the phylogenetically enigmatic and extremely specialized Strepsiptera. Most internal structures of the fossil are preserved, but small parts of the lumen had decayed due to incomplete infiltration of the resin. Data on internal organs provided additional information for resolving phylogenetic relationships. A sister group relationship between Mengea and all extant lineages of the group was confirmed with characters previously not accessible. The newly gained information also yielded some insights in the biology of Mengea and the early evolutionary history of Strepsiptera. The technique has a tremendous potential for a more accurate interpretation of diverse fossil arthropods preserved in ambers from 130 Ma to the present. PMID- 20711558 TI - Survival of Theriosuchus (Mesoeucrocodylia: Atoposauridae) in a Late Cretaceous archipelago: a new species from the Maastrichtian of Romania. AB - Small terrestrial non-eusuchian mesoeucrocodylians are common components of Cretaceous assemblages of Gondwanan provinces with notosuchians and araripesuchids as flagship taxa in South America, Africa and Madagascar, well into the Late Cretaceous. On the other hand, these are exceedingly rare in Laurasian landmasses during the Late Cretaceous. Small terrestrial mesoeucrocodylians from Europe were often referred to the genus Theriosuchus, a taxon with stratigraphic range extending from the Late Jurassic to the late Early Cretaceous. Theriosuchus is abundantly reported from various European localities, although Asiatic and possibly North American members are also known. It has often been closely associated with the first modern crocodilians, members of the Eusuchia, because of the presence of procoelous vertebrae, a widespread key character diagnosing the Eusuchia. Nevertheless, the relationships of Theriosuchus have not been explored in detail although one species, Theriosuchus pusillus, has been extensively described and referred in numerous works. Here, we describe a new basal mesoeucrocodylian, Theriosuchus sympiestodon sp. nov. from the Maastrichtian of the Hateg Basin, Romania, suggesting a large temporal gap (about 58 myr) in the fossil record of the genus. Inclusion of the new taxon, along with Theriosuchus guimarotae, in a phylogenetic analysis confirms its referral to the genus Theriosuchus, within a monophyletic atoposaurid clade. Although phylogenetic resolution within this clade is still poor, the new taxon appears, on morphological grounds, to be most closely related to T. pusillus. The relationships of Atoposauridae within Mesoeucrocodylia and especially to Neosuchia are discussed in light of the results of the present contribution as well as from recent work. Our results raise the possibility that Atoposauridae might not be regarded as a derived neosuchian clade anymore, although further investigation of the neosuchian interrelationships is needed. Reports of isolated teeth referable to a closely related taxon from the Upper Cretaceous of Romania and France, together with the presence of Doratodon and Ischyrochampsa, indicate a previously unsuspected diverse assemblage of non-eusuchian mesoeucrocodylians in the Late Cretaceous European archipelago. PMID- 20711561 TI - Trends in solid-state NMR spectroscopy and their relevance for bioanalytics. AB - Based on continuous methodical advances and developments, solid-state NMR spectroscopy has become a powerful tool for the investigation of various materials, including polymers, glasses, zeolites, fullerenes, and many others. During the past decade, solid-state NMR spectroscopy also found increasing interest for the study of biomolecules. For example, membrane proteins reconstituted into lipid environments such as bilayers or vesicles, protein aggregates such as amyloid fibrils, as well as carbohydrates can now be studied by solid-state NMR spectroscopy. This review briefly introduces the principles of solid-state NMR spectroscopy and highlights novel methodical trends. Selected applications demonstrate the possibilities of solid-state NMR spectroscopy as a valuable bioanalytical tool. PMID- 20711562 TI - Short-term habituation of auditory evoked potential and neuromagnetic field components in dependence of the interstimulus interval. AB - Repeated auditory stimulation results usually in a response decrement of event related potential components. In the current study, we investigated the impact of the interstimulus interval (ISI) on the response decrement. Healthy subjects were stimulated with trains of five tones, with an ISI of 600, 1,200, or 1,800 ms within the trains. Auditory evoked potentials (AEP) were recorded from the vertex, as well as neuromagnetic auditory evoked fields (AEF) from the left temporal region. Stimulus repetition led to a response decrement for the studied AEP components (N100 and P200) and AEF components (N100m and P200m). However, for all used ISIs, there was no further response decrement after the 2nd stimulus. The ISI affected only the magnitude but not the kind of the response decrement. No evidence for a gradual response decrement was revealed at any used ISI. This finding indicates that the response decrement is probably due to the refractoriness of cell assemblies involved in the generation of AEP and AEF components, rather than the result of a genuine habituation process. The finding questions habituation as the mechanism behind short-term decrements of AEP/AEF components. PMID- 20711564 TI - Studying space representation within a neuropsychological perspective. PMID- 20711563 TI - Event-related potentials before saccades and antisaccades and their relation to reaction time. AB - In the present study, reaction time (RT) was measured in 12 healthy subjects in a saccade and antisaccade task while recording electroencephalographic activity (EEG) from 62 electrodes on the scalp. Event-related potentials averaged both on target appearance and on saccade onset were larger in amplitude (increased negativity) for the antisaccade task compared to the saccade task. The relation of RT variability to EEG amplitude was studied by averaging stimulus-aligned and movement-aligned individual trials for each subject into four RT quartile groups. The analysis showed a relation of EEG amplitude to RT for both saccades and antisaccades. More specifically, the ERP negativity at 100-120 ms after stimulus onset in the saccade task and at 160-200 ms after stimulus onset in the antisaccade task for stimulus-aligned ERPs decreased monotonically with increasing RT as would be expected if this signal would be related to the eye movement preparation processes. This was much more pronounced and wide spread for the antisaccades than for visually triggered saccades. The peak negativity before movement onset for movement-aligned ERPs also covaried with RT suggesting no relation of this activity to movement preparation processes. This study then confirmed that only a particular ERP signal variation was related to the saccadic eye movement preparatory processes while other components of the ERP have no specific relation to the movement preparation. This particular signal was more prominent for antisaccades compared to visually triggered saccades supporting previous evidence for the cortical involvement in the preparation of these voluntary eye movements. In conclusion, this study validates the use of ERPs in the study of the planning and execution of saccadic eye movements. PMID- 20711565 TI - Competitive effects on steady-state visual evoked potentials with frequencies in- and outside the alpha band. AB - Multiple concurrently presented stimuli are thought to compete for neuronal processing resources. Such competitive stimulus interactions can be investigated by "frequency tagging" each stimulus with an individual temporal frequency. In this case, all stimuli will drive distinct steady-state visual evoked potentials (SSVEPs), hence allowing for an assessment of the distribution of processing resources. Here, we investigated whether competitive effects on SSVEP amplitudes are dependent upon the choice of tagging frequency of either the driving stimulus or a close-by competing stimulus. In particular, we were interested whether changes in amplitude are specific to a 10-Hz SSVEP, as it has been suggested that tagging frequencies within the alpha band drive uniquely characterized neural networks. If this was the case, an additional competition might be introduced when two stimuli are tagged with frequencies within the alpha band and thus compete for processing resources in similar networks. Additionally, we tested whether effects on SSVEP amplitude differ when the competing stimulus is tagged with a frequency of 12 Hz that produces a perceptible flicker when compared to an imperceptible 60-Hz flicker. We found a significant decrease in amplitude of 10- and 15-Hz SSVEPs upon presentation of the competing stimulus regardless of its tagging frequency. Our results clearly indicate that an SSVEP with a frequency within the alpha band and a 15-Hz SSVEP show similar sensitivity to effects of competition. Furthermore, the observed effects of competition on SSVEP amplitude occur independently of flicker perceptibility. PMID- 20711566 TI - Cortical and behavioral adaptations in response to short-term inphase versus antiphase bimanual movement training. AB - Bimanual movement training (BMT) may be an effective rehabilitative protocol for movement-related deficits following a stroke; however, it is unclear how varying types of BMT induce cortical adaptations in the healthy population. Moreover, we lack a methodology to measure cortical adaptations in response to modes of movement training. Therefore, the present study measured the cued movement related potential (MRP) to investigate cortical adaptations during cued inphase versus antiphase BMT that transferred to a unimanual task and how cortical modulations related to behavior. Three specific hypotheses were investigated: (1) cued inphase BMT would induce cortical adaptations within regions subserving motor preparation and movement execution, (2) repetitive cued unimanual training would induce cortical activity modulations associated with motor execution, and (3) increased cortical activity would be associated with enhanced performance. On three separate days, EEG was recorded from 22 electrodes during three types of cued movement training: inphase BMT, antiphase BMT and repetitive unimanual movement, in addition to pre- and post-training unimanual movement trials involving cued right wrist flexion. The MRP was measured for each repetition during each trial. Results showed a significant training-related increase in preparatory activation correlated with a behavioral enhancement following cued inphase BMT. This effect was not attributable to a change in arousal. No significant training-related modulation occurred in response to cued antiphase BMT or repetitive unimanual movement training. These results suggest that cortical adaptations in relation to the preparation of a cued movement enhance in response to cued inphase BMT, and the MRP is an effective measurement tool to assess training-related adaptations in response to inphase BMT specifically. PMID- 20711567 TI - Stimulating effect of external Myo-inositol on the expression of mutant forms of aquaporin 2. AB - Myo-inositol (MI; hexahydroxycyclohexane, C(6)H(6)O(12)) is a small neutral molecule used as a compatible osmolyte in the kidney medulla. At high concentrations, MI appears to act as a chemical chaperone and was shown to promote plasma membrane expression of the impaired cystic fibrosis chloride channel (Delta508-CFTR). In the present study, we measured whether MI could increase expression of two human aquaporin 2 (AQP2) mutants which were recently identified as causing nephrogenic diabetes insipidus (NDI). Both proteins (D150E and G196D) were expressed in Xenopus laevis oocytes, but only D150E displayed an increase in oocyte water permeability (P (f)). Adding 5 mM MI to the bathing solution for 24 h produced a 50% increase in the D150E-associated P (f), while it had no effect on noninjected oocytes or on oocytes expressing wt-AQP2 or G196D. Western blots performed on purified plasma membrane preparations confirmed that MI increased the amount of D150E present at the plasma membrane, while G196D was always undetectable. X. laevis oocytes are remarkably impermeable to MI, and the effect of MI on D150E expression does not require the presence of intracellular MI. The effect of external MI was dose-dependent (K (0.5) was 130 microM) and specific with respect to other forms of inositols. Further studies on a second group of AQP2 mutants causing NDI showed that K228E activity was similarly stimulated by MI, while V71M, A70D and S256L were not. It is concluded that physiological concentrations of extracellular MI can stimulate the expression of a specific subgroup of AQP2 mutants. PMID- 20711568 TI - Left atrial appendage thrombus in a preterm neonate in sinus rhythm with septic shock. PMID- 20711569 TI - Three-dimensional echocardiographic imaging of a giant eustachian valve in an infant with reversed cyanosis. PMID- 20711570 TI - Duplicated bladder. PMID- 20711571 TI - Utility of diffusion-weighted imaging in the presurgical diagnosis of an infected urachal cyst. AB - Urachal cysts are one of a spectrum of urachal abnormalities that occur following failure of regression of the allantois and presumptive bladder between 4 weeks and 6 weeks of gestation. Infection is the most common complication of this rare congenital anomaly. The nonspecific presentation may mimic other pathological processes, underlining their clinical and radiological significance. Imaging investigations typically include US and CT, both of which are limited in their ability to characterize lesions. We report the case of a 5-year-old presenting with macroscopic haematuria in whom diffusion-weighted MRI (DWI) suggested the diagnosis of an infected urachal cyst, which was confirmed surgically. We discuss the radiological findings in multiple imaging modalities and present the application of DWI in this context as a means of improving the radiological diagnostic yield. PMID- 20711572 TI - Development of sucrose-utilizing Escherichia coli K-12 strain by cloning beta fructofuranosidases and its application for L-threonine production. AB - Sucrose is one of the most promising carbon sources for industrial fermentation. To achieve sucrose catabolism, the sucrose utilization operons have been introduced into microorganisms that are not able to utilize sucrose. However, the rates of growth and sucrose uptake of these engineered strains were relatively low to be successfully employed for industrial applications. Here, we report a practical example of developing sucrose-utilizing microorganisms using Escherichia coli K-12 as a model system. The sucrose utilizing ability was acquired by introducing only beta-fructofuranosidase from three different sucrose utilizing organisms (Mannheimia succiniciproducens, E. coli W, and Bacillus subtilis). Among them, the M. succiniciproducens beta-fructofuranosidase was found to be the most effective for sucrose utilization. Analyses of the underlying mechanism revealed that sucrose was hydrolyzed into glucose and fructose in the extracellular space and both liberated hexoses could be transported by their respective uptake systems in E. coli K-12. To prove that this system can also be applied for the production of useful metabolites, the M. succiniciproducens beta-fructofuranosidase was introduced into the engineered L threonine production strain of E. coli K-12. This recombinant strain was able to produce 51.1 g/L L-threonine by fed-batch culture, resulting in an overall yield of 0.284 g L-threonine per g sucrose. This simple approach to make E. coli K-12 to acquire sucrose-utilizing ability and its successful biotechnological application can be employed to develop sustainable bioprocesses using renewable biomass. PMID- 20711573 TI - Xanthophyllomyces dendrorhous for the industrial production of astaxanthin. AB - Astaxanthin is a red xanthophyll (oxygenated carotenoid) with large importance in the aquaculture, pharmaceutical, and food industries. The green alga Haematococcus pluvialis and the heterobasidiomycetous yeast Xanthophyllomyces dendrorhous are currently known as the main microorganisms useful for astaxanthin production at the industrial scale. The improvement of astaxanthin titer by microbial fermentation is a requirement to be competitive with the synthetic manufacture by chemical procedures, which at present is the major source in the market. In this review, we show how the isolation of new strains of X. dendrorhous from the environment, the selection of mutants by the classical methods of random mutation and screening, and the rational metabolic engineering, have provided improved strains with higher astaxanthin productivity. To reduce production costs and enhance competitiveness from an industrial point of view, low-cost raw materials from industrial and agricultural origin have been adopted to get the maximal astaxanthin productivity. Finally, fermentation parameters have been studied in depth, both at flask and fermenter scales, to get maximal astaxanthin titers of 4.7 mg/g dry cell matter (420 mg/l) when X. dendrorhous was fermented under continuous white light. The industrial scale-up of this biotechnological process will provide a cost-effective method, alternative to synthetic astaxanthin, for the commercial exploitation of the expensive astaxanthin (about $2,500 per kilogram of pure astaxanthin). PMID- 20711574 TI - Construction of an in vitro trans-sialylation system: surface display of Corynebacterium diphtheriae sialidase on Saccharomyces cerevisiae. AB - Sialidases can be used to transfer sialic acids from sialoglycans to asialoglycoconjugates via the trans-glycosylation reaction mechanism. Some pathogenic bacteria decorate their surfaces with sialic acids which were often scavenged from host sialoglycoconjugates using their surface-localized enzymes. In this study, we constructed an in vitro trans-sialylation system by reconstructing the exogenous sialoglycoconjugate synthesis system of pathogens on the surfaces of yeast cells. The nanH gene encoding an extracellular sialidase of Corynebacterium diphtheriae was cloned into the yeast surface display vector pYD1 based on the Aga1p-Aga2p platform to immobilize the enzyme on the surface of the yeast Saccharomyces cerevisiae. The surface-displayed recombinant NanH protein was expressed as a fully active sialidase and also transferred sialic acids from pNP-alpha-sialoside, a sialic acid donor substrate, to human-type asialo-N glycans. Moreover, this system was capable of attaching sialic acids to the glycans of asialofetuin via alpha(2,3)- or alpha(2,6)-linkage. The cell surface expressed C. diphtheriae sialidase showed its potential as a useful whole cell biocatalyst for the transfer of sialic acid as well as the hydrolysis of N glycans containing alpha(2,3)- and alpha(2,6)-linked sialic acids for glycoprotein remodeling. PMID- 20711575 TI - Clavulanic acid biosynthesis and genetic manipulation for its overproduction. AB - Clavulanic acid, a beta-lactamase inhibitor, is used together with beta-lactam antibiotics to create drug mixtures possessing potent antimicrobial activity. In view of the clinical and industrial importance of clavulanic acid, identification of the clavulanic acid biosynthetic pathway and the associated gene cluster(s) in the main producer species, Streptomyces clavuligerus, has been an intriguing research question. Clavulanic acid biosynthesis was revealed to involve an interesting mechanism common to all of the clavam metabolites produced by the organism, but different from that of other beta-lactam compounds. Gene clusters involved in clavulanic acid biosynthesis in S. clavuligerus occupy large regions of nucleotide sequence in three loci of its genome. In this review, clavulanic acid biosynthesis and the associated gene clusters are discussed, and clavulanic acid improvement through genetic manipulation is explained. PMID- 20711576 TI - Quantitative analysis of the difference between an intact complete discoid lateral meniscus and a torn complete discoid meniscus on MR imaging: a feasibility study for a new classification. AB - OBJECTIVE: To determine the quantitative difference between an intact complete discoid lateral meniscus (CDLM) and a torn CDLM on MR imaging. MATERIALS AND METHODS: Between May 2005 to November 2009, 137 patients with a CDLM (107 intact CDLM and 30 torn CDLM) and 92 patients with a normal meniscus were included in this study. The evaluated parameters were the height of the posterior horn of the lateral and medial menisci on the sagittal images and their ratio as assessed by two observers twice at an interval of 1 month. Each parameter was analyzed based on the Kruskal Wallis test, and the analysis using the mixed model. Intraclass correlation coefficient (ICC) was used to determine the interobserver reliabilities at session 2. RESULTS: The mean heights of the posterior horn of the lateral and medial menisci on the sagittal images for an intact CDLM, a torn CLDM, and a normal meniscus were 6.5, 7.3, 5.7 and 6.6, 6.4, 6.7 mm at session 1, respectively. The mean heights of the posterior horn of the lateral and medial menisci on the sagittal images for an intact CDLM, a torn CDLM, and a normal meniscus for both observers were 6.5, 7.2, 5.7 and 6.6, 6.3, 6.8 mm at session 2, respectively. The ratio of the height of the lateral to the height of the medial meniscus for an intact CDLM at both sessions for both observers was 1.0. The ratios were 1.2 and 0.8 for a torn CDLM and for a normal meniscus, respectively, at both sessions for observer 1. The ratios were 1.2 and 0.9 for a torn CDLM and for a normal meniscus, respectively, at session 2 for observer 2. The heights of the posterior horn of the lateral meniscus on the sagittal images and the ratios of the heights of the lateral to the medial menisci in all three groups were statistically significantly different for both sessions (p < 0.0001). The interobserver ICCs for each parameter of both an intact CDLM and a torn CDLM at session 2 showed high correlations (p < 0.0001). CONCLUSION: The height of the lateral meniscus and the ratio of the height of the lateral to the height of the medial meniscus for a torn CDLM were significantly higher than those for an intact CDLM. PMID- 20711578 TI - EANM YIM 2010--report. PMID- 20711577 TI - 18F-FDG PET and biomarkers for tumour angiogenesis in early breast cancer. AB - PURPOSE: Tumour angiogenesis is an independent and strong prognostic factor in early breast carcinoma. We performed this study to investigate the ability of (18)F-FDG to detect angiogenesis in early breast carcinoma using PET/CT. METHODS: Twenty consecutive patients with early (T1-T2) breast carcinoma were recruited prospectively for 18F-FDG PET/CT. The PET/CT data were used to calculate whole tumour maximum standardized uptake value (SUV(max)) and mean standardized uptake value (SUV(mean)). All patients underwent subsequent surgery without prior chemotherapy or radiotherapy. The excised tumour underwent immunohistochemistry for vascular endothelial growth factor (VEGF), CD105 and glucose transporter protein 1 (GLUT1). RESULTS: The SUV(max) showed the following correlation with tumour histology: CD105: r = 0.60, p = 0.005; GLUT1: r = 0.21, p = 0.373; VEGF: r = -0.16, p = 0.496. The SUV(mean) showed the following correlation with tumour histology: CD105: r = 0.65, p = 0.002; GLUT1: r = 0.34, p = 0.144; VEGF: r = 0.18, p = 0.443 CONCLUSION: (18)F-FDG uptake is highly significantly associated with angiogenesis as measured by the immunohistochemistry with CD105 for new vessel formation. Given that tumour angiogenesis is an important prognostic indicator and a predictor of treatment response, (18)F-FDG PET may have a role in the management of primary breast cancer patients even in early-stage disease. PMID- 20711582 TI - [Clonal relationship of Hodgkin lymphoma and its recurrence]. AB - In this study, we investigated whether recurrences of classical Hodgkin's lymphoma (HL) are true relapses arising from the primary tumour or clonally unrelated secondary neoplasias. Formalin-fixed, paraffin-embedded tissue specimens of eleven patients with recurrent HL were analyzed. Hodgkin and Reed Sternberg cells were microdissected after immunohistochemical staining for CD30 using laser-capture technique. Immunoglobulin heavy chain (IgH) gene fragment lengths were analyzed applying consensus FR3 and J primers. Two early relapses after the first HL diagnosis were clonally related to the initial tumour, while three of four early recurrences after a first or second relapse were not. Three patients presenting with late relapses had clonally unrelated neoplasms. Therefore, we conclude that recurrent HL may represent a novel neoplasm, a finding which might play a role in clinical decision-making. PMID- 20711581 TI - In vitro management of hospital Pseudomonas aeruginosa biofilm using indigenous T7-like lytic phage. AB - Pseudomonas aeruginosa, a human pathogen capable of forming biofilm and contaminating medical settings, is responsible for 65% mortality in the hospitals all over the world. This study was undertaken to isolate lytic phages against biofilm forming Ps. aeruginosa hospital isolates and to use them for in vitro management of biofilms in the microtiter plate. Multidrug resistant strains of Ps. aeruginosa were isolated from the hospital environment in and around Pimpri Chinchwad, Maharashtra by standard microbiological methods. Lytic phages against these strains were isolated from the Pavana river water by double agar layer plaque assay method. A wide host range phage bacterial virus Ps. aeruginosa phage (BVPaP-3) was selected. Electron microscopy revealed that BVPaP-3 phage is a T7 like phage and is a relative of phage species gh-1. A phage at MOI-0.001 could prevent biofilm formation by Ps. aeruginosa hospital strain-6(HS6) on the pegs within 24 h. It could also disperse pre-formed biofilms of all hospital isolates (HS1-HS6) on the pegs within 24 h. Dispersion of biofilm was studied by monitoring log percent reduction in cfu and log percent increase in pfu of respective bacterium and phage on the peg as well as in the well. Scanning electron microscopy confirmed that phage BVPaP-3 indeed causes biofilm reduction and bacterial cell killing. Laboratory studies prove that BVPaP-3 is a highly efficient phage in preventing and dispersing biofilms of Ps. aeruginosa. Phage BVPaP-3 can be used as biological disinfectant to control biofilm problem in medical devices. PMID- 20711580 TI - Safety of liver resections in obese and overweight patients. AB - BACKGROUND: The new global epidemic, overweight and obesity, has a significant role in the etiology of liver tumors. However, the impact of body weight on the outcome after liver resection is unknown. METHODS: We carried out a prospective study of 684 patients who underwent liver resections. Patients were stratified according their body mass index (BMI) as follows: normal (<25 kg/m(2)) (52%), overweight (25-29 kg/m(2)) (34%), and obese (>=30 kg/m(2)) (14%), and according to the extent of resection, as either minor or major hepatectomy. Preoperative and intraoperative characteristics and outcomes were prospectively studied. The Dindo-Clavien classification of morbidity was used. RESULTS: Overall postoperative morbidity and morbidity rates were not influenced by BMI. Pulmonary complications were significantly more frequent in obese patients irrespective of the extent of resection. During major resection obese had longer pedicular clamping and more frequently required blood transfusion. After major resection, major morbidity (Dindo-Clavien grade III or more) was more frequent in obese (57%) and overweight (54%) patients than in patients of normal body weight (35%; P < 0.05), including a higher rate of respiratory complications and ascites and longer intensive care unit (ICU) and hospital stays. Obesity and overweight were independent predictors of major morbidity (OR 2.6, 95% CI 1.2-5.8 and OR 1.9, 95% CI 1.2-3.2, respectively), and obesity was a predictor of the need for blood transfusion (OR 3.3, 95% CI 1.4-7.9) after major resections. CONCLUSIONS: Obese and overweight patients are at increased risk of potentially life-threatening morbidity after major hepatic resections. Because the risk of mortality is not increased significantly, there is no justification for a compromise in the indication or extent of surgery. PMID- 20711583 TI - [Molecular pathology of sarcomas. Update on the research group "Molecular Diagnosis of Sarcomas"]. AB - To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG). PMID- 20711584 TI - [Molecular mechanisms of progression in human hepatocarcinogenesis]. AB - Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors worldwide with poor prognosis. Based on high-throughput screening technology, we and others have identified factors and pathways that are pivotal for tumor progression including transcription factors and microtubule-interacting proteins. In addition, aberrant activation of the IGF signalling pathway is frequently observed in HCCs which is predominantly based on high level expression of its ligand IGF-II. Because protumorigenic effects of IGF-II such as proliferation, anti-apoptosis, and migration are transmitted through its receptor IGF-1R, selective inhibition of this tyrosine kinase by small molecule compounds might reduce IGF-II-driven tumor growth. Indeed, administration of IGF-1R-selective inhibitors reduces IGF-II-induced effects and was associated with a significant reduction of tumor growth in a xenograft transplantation model. In conclusion, the IGF-II/IGF-1R signalling pathway is critically involved in the regulation of tumor growth and tumor cell dissemination, representing a promising therapeutic target structure in the treatment of HCC. PMID- 20711585 TI - [Non-coding RNA in malignant tumors. A new world of tumor biomarkers and target structures in cancer cells]. AB - Only about 2% of the human genome constitute protein-coding genes - nevertheless, medical research has focused mainly on this portion in recent decades. Since up to 70% of the human genome is transcribed into RNA, the genome contains much more non-coding information than coding, which is present in the cell as non-coding RNA (ncRNA). Many of these ncRNAs are highly expressed, specifically regulated and evolutionarily conserved, arguing in favor of their functional significance. MicroRNAs are the most well-known ncRNAs, but many other long ncRNAs exist. Differential ncRNA or microRNA expression patterns correlate with diagnosis or prognosis in many tumor entities and can thus serve as an extensive source of new biomarkers. The expression of the long ncRNA MALAT1 correlates with tumor development, progression or survival in lung, liver and breast cancer. Functionally active ncRNAs can provide novel insights into the mechanisms underlying tumor development. The large number of different, often as yet unidentified ncRNAs promises new stimuli for the diagnosis, prognosis and therapy of many diseases. PMID- 20711586 TI - [R248C FGFR3 mutation. Effect on cell growth, apoptosis and attachment in HaCaT keratinocytes]. AB - Activating FGFR3 mutations have been identified in a variety of benign skin lesions (seborrheic keratosis, epidermal nevus, solar lentigo). However, the functional consequences of these mutations in the human epidermis are unknown. We therefore analyzed functional effects of the common R248C mutation in HaCaT keratinocytes. The cells were stably transduced with the R248C FGFR3 mutation or FGFR3-IIIb wildtype sequence using a retroviral system. The R248C mutant keratinocytes revealed significantly enhanced cell growth compared with wildtype cells after reaching confluence. Likewise, apoptosis and attachment to fibronectin were significantly reduced in mutant cells. In contrast, there was no difference regarding migration and oncogene-induced senescence. Gene expression analysis revealed only a few differentially expressed genes between mutant and wildtype HaCaT keratinocytes. ERK1/2 appear to be involved in the FGFR3-dependent signalling of R248C mutant keratinocytes. Our results indicate that an increased cell number at confluence along with reduced apoptosis may contribute to the growth of benign acanthotic tumors in the human epidermis. PMID- 20711587 TI - [Mesenchymal stem cells for bone tissue engineering]. AB - Human mesenchymal stem cells (MSC) represent an attractive option for cell replacement strategies (tissue engineering, TE). TE applications require stability of a stem cell/biomaterial-hybrid via cell migration, matrix remodelling and differentiation. We focus on these mechanisms in organotypic culture systems for bone TE using MSC from the umbilical cord (UC-MSC) and from bone marrow (BM-MSC). For the organotypic differentiation of MSC into functional osteoblasts, MSC were embedded in a collagenous matrix and subjected to osteogenic differentiation. Under these culture conditions, UC-MSC exceeded BM MSC in the expression and synthesis of extracellular matrix (ECM) proteins, while BM-MSC show enhanced osteogenic gene upregulation. In both cell types the biosynthetic activity was accompanied by the ultrastructural appearance of hydroxyapatite/calcium crystals. Following secretion of matrix metalloproteinases, both MSC types migrated into and colonised the collagenous matrix causing matrix strengthening and contraction. In conclusion, MSC promise a broad therapeutical application for a variety of connective tissues requiring ECM synthesis and remodelling. PMID- 20711588 TI - [Update on protein analysis of fixed tissues]. AB - Tissue samples have been routinely used for decades to distinguish healthy from diseased tissue in histopathological characterization. While nucleic acid-based methodologies have been successfully in use for many years, protein-based techniques, in contrast, are at a very early stage (with the exception of immunohistochemistry). One reason for this delay may be that the scientific community has long thought that formalin-fixed and paraffin embedded (FFPE) tissues are unfit for protein analysis. However, recent reports demonstrate that many protein methods that are routinely used for frozen tissues can also be applied for FFPE tissues, including Western blot, protein microarray, matrix assisted laser desorption/ionization (MALDI) imaging and 2D gel electrophoresis. The present article provides an overview of recent developments in this field, focussing particular attention on quantitative analysis and high throughput technologies that have the potential to be integrated into the routine workflow of clinical pathology laboratories. PMID- 20711589 TI - [TNM classification of breast cancer: changes and comments on the 7th edition]. AB - The 7th edition of the TNM classification includes only minor changes in the main TNM categories for breast cancer. Only ductal and lobular carcinoma in situ (DCIS, LCIS), and isolated Paget's disease of the nipple are classified as pTis, but not precursor lesions such as atypical ductal or lobular hyperplasia (ADH, ALH). AJCC emphasizes that microscopic measurement is the most accurate and preferred method to determine pT in small invasive cancers and stresses the importance of strict adherence to criteria for T4 cancers. For better distinction from micrometastases in regional lymph nodes, small clusters of cells not greater than 0.2 mm, or nonconfluent or nearly confluent clusters of cells not exceeding 200 cells in a single histologic lymph node cross section are classified as isolated tumour cells (pN0(i+)). The pN classification has otherwise remained unchanged. In the setting of patients having received neoadjuvant therapy, ypT1 ypT3 is based on the total extent of viable tumour cells, irrespective of tumour regression. Stage I breast tumours have been subdivided into Stage IA and Stage IB; Stage IB includes small tumours (TI) with lymph node micrometastases (N1mi). These changes and clarifications will contribute to maintaining the clinical and prognostic relevance of TNM in breast cancer. PMID- 20711590 TI - [TNM classification of malignant tumors 2010: General aspects and amendments in the general section]. AB - In the 7th edition of the TNM classification most tumor entities have been left unchanged compared to the 6th edition, while some tumor entities and anatomical localizations have been newly introduced, thus following the basic principle of keeping classifications stable over time. In the 7th edition the categories "MX" and "pMX" have been eliminated because of misunderstandings and misuse. Only the categories "M0", "M1" and "pM1" are still valid and "pM0" is not to be used except after performing an autopsy. The classification of perineural invasion (Pn classification) has been newly established and its use is optional. The presence or absence of invasion of perineural spaces does not affect the T category but is considered an additional prognostic factor in some tumor entities. PMID- 20711591 TI - Description of the registry of patients with ankylosing spondylitis in Turkey: TRASD-IP. AB - A web-based application patient follow-up program was developed to create a registry of patients with ankylosing spondylitis (AS) by the Turkiye Romatizma Arastirma Savas Dernegi (TRASD) AS Study Group. This study describes the methodological background and patient characteristics. The patient follow-up program is a web-based questionnaire, which contains sections on socio demographic data, anamnesis, personal and family history, systemic and musculoskeletal examination, laboratory and imaging data and treatment. Between October 1, 2007 and February 28, 2009, 1,381 patients from 41 centers were included in the registry (1,038 males [75.2%]; mean age 39.5 +/- 10.7 years). Mean disease duration was 12.1 +/- 8.5 years, and mean time from initial symptom to diagnosis was 5 +/- 6.8 years (median 2 years). HLA-B27 positivity was detected in 73.7% of 262 patients tested. Manifestations of extraarticular involvement were anterior uveitis (13.2%), psoriasis and other skin and mucous membrane lesions (6%) and inflammatory bowel disease (3.8%). The prevalence of peripheral arthritis was 11.2%. In 51.7% of patients, the Bath AS Disease Activity Index was >=4. But since our patients consisted of the ones with more severe disease who referred to the tertiary centers and needed a regular follow up, they may not represent the general AS population. Disease-modifying anti rheumatic drugs were being used by 41.9% of patients, with 16.4% using anti-TNF agents. TRASD-IP (Izlem Programi: Follow-up program) is the first AS registry in Turkey. Such databases are very useful and provide a basis for data collection from large numbers of subjects. TRASD-IP gives information on the clinical and demographic profiles of patients, and the efficacy and safety of anti-TNF drugs, examines the impact on quality of life, and provides real-life data that may be used in cost-effectiveness analyses. PMID- 20711592 TI - Early endoscopy in systemic sclerosis without gastrointestinal symptoms. AB - Investigation into the upper GI-tract of patients suffering from systemic sclerosis [SSc] and mixed connective tissue disease [MCTD] without symptoms of GI tract involvement early in the course of the disease to diagnose inflammatory and motility disorders. We retrospectively analysed patients with SSc and MCTD who underwent oesophago-gastro-duodenoscopy [OGD] within a year of the first diagnosis. Patients with a Rodnan skin score above 5, proton pump inhibitors and treatment regimes potentially harmful to the mucosa of the upper GI-tract were excluded. Mucosal damage of the oesophagus was classified according to the Los Angeles Classification. Oesophageal dysmotility was assessed during OGD and confirmed by video cineradiography. A total of thirteen patients with SSc and six with MCTD fulfilled the inclusion criteria. OGD revealed reflux-oesophagitis in 77%, dysmotility of the distal oesophagus in 85%, gastritis in 92% [31% erosive gastritis] and Helicobacter pylori positivity in 38% of our patients suffering from SSc. Patients with MCTD showed features of reflux-oesophagitis, dysmotility of the distal oesophagus, gastritis and dysmotility of the stomach in 0.6%. In all thirteen patients with SSc, significant pathology of the upper GI-tract was found. The results of this study might indicate that OGD should be performed early in patients diagnosed with SSc, even if they do not report typical symptoms. An early diagnose of GI involvement might be followed by an effective therapy and therefore subsequently may improve the prognosis. PMID- 20711593 TI - Interpeduncular arachnoid cysts in infants and children: insight into the entity based on a case series with long-term follow-up. AB - OBJECTIVE: Arachnoid cysts occupying the suprasellar region comprise 10-15% of intracranial distribution. Unlike large suprasellar cysts, pure interpeduncular cysts (IPCs) are rare, and their natural history is unknown. We describe a small series of children diagnosed with IPC and their long-term natural history. METHODS: A retrospective review was conducted of interpeduncular arachnoid cysts diagnosed over the years 2000-2010 at our center. Patients with clearly suprasellar cysts were excluded. Serial magnetic resonance imaging and long-term follow-up examinations were analyzed. Additionally, we conducted an extensive literature review focusing on the differences between suprasellar cysts and IPCs. RESULTS: We identified three pediatric patients with "pure" IPC; all of these had a follow-up of more than 5 years, and none was operated. Only six additional cases were identified in the literature. In both our experience and in the literature review, IPCs proved stable over the course of time, both radiologically as well as clinically. CONCLUSIONS: The clinical and radiological features of IPCs are not well defined. Variations in the relationship of arachnoid cysts in this area to Liliequist's membrane may explain the different subgroups that have been identified as well as the confusing nomenclature. IPCs are usually diagnosed as incidental findings or present with mild endocrine disorders. Associated findings of hydrocephalus, mass effect, and compression of neighboring structures, such as the chiasm, are not as frequent as with suprasellar cysts. Given the high likelihood of continuing stability, a conservative strategy of follow-up is recommended for pure IPCs that demonstrate preservation of the third ventricle. PMID- 20711594 TI - Galectin-3 expression: a useful tool in the differential diagnosis of posterior fossa tumors in children. AB - OBJECTIVE: Galectin-3 (Gal-3) is a glycan-binding protein highly expressed in several tumors, including brain neoplasms. This protein has been demonstrated to be correlated with adverse prognosis in some tumor types. However, the role of Gal-3 in pediatric posterior fossa tumors (PPFTs) has not yet been fully addressed. The goals of this study were to evaluate Gal-3 expression in a series of PPFTs and verify whether this expression is related to patient outcome. MATERIAL AND METHODS: Gal-3 expression was analyzed by immunohistochemistry in 42 cases of surgically resected primary PPFTs. Surgeries were performed in our institution from January 2003 to December 2006. Tumor samples consisted of 21 pilocytic astrocytomas (PAs), 13 medulloblastomas, 4 ependymomas, 2 diffuse cerebellar astrocytomas, and 2 atypical teratoid/rhabdoid tumors (AT/RTs). RESULTS: All PAs and ependymomas strongly showed Gal-3 expression, whereas no immunostaining was observed in medulloblastomas and diffuse astrocytomas. In AT/RTs, Gal-3 expression was conspicuous but heterogeneous, being mainly observed in rhabdoid cells. Concerning the Gal-3 expressing tumors, no relationship was observed between the degree of expression and patient survival. Gal-3 was strongly expressed in reactive astrocytes, normal endothelial cells, and macrophages in the adjacent non-neoplastic brain parenchyma. Interestingly, the endothelial cells in the tumor bulk of PAs lacked Gal-3 expression. CONCLUSIONS: Gal-3 is differentially expressed in PPFTs, but its expression shows no correlation with patient outcome. However, the evaluation of Gal-3 is helpful in establishing a differential diagnosis among PPFTs, especially between PAs and diffuse astrocytomas, and in some circumstances between medulloblastomas and AT/RTs. PMID- 20711595 TI - Medullary cistern choroid plexus papilloma. PMID- 20711596 TI - Systematic review and meta-analysis of enterocolitis after one-stage transanal pull-through procedure for Hirschsprung's disease. AB - PURPOSE: The transanal one-stage pull-through procedure (TERPT) has gained worldwide popularity over open and laparoscopic-assisted one-stage techniques in children with Hirschsprung's disease (HD). It offers the advantages of avoiding laparotomy, laparoscopy, scars, abdominal contamination, and adhesions. However, enterocolitis associated with Hirschsprung's disease (HAEC) still remains to be a potentially life-threatening complication after pull-through operation. The reported incidence of HAEC ranges from 4.6 to 54%. This meta-analysis was designed to evaluate postoperative incidence of HAEC following TERPT procedure. METHODS: A meta-analysis of cases of TERPT reported between 1998 and 2009 was performed. Detailed information was recorded regarding intraoperative details and postoperative complications with particular emphasis on incidence of HAEC. Diagnosis of HAEC in a HD patient was based on the clinical presentation of diarrhoea, abdominal distension, and fever. RESULTS: Of the 54 published articles worldwide, 27 articles, including 899 patients were identified as reporting entirely TERPT procedure. Postoperative HAEC occurred in 92 patients (10.2%). Recurrent episodes of HAEC were reported in 18 patients (2%). Conservative treatment of HAEC was successful in 75 patients (81.5%), whereas in 17 patients (18.5%) surgical treatment was needed. CONCLUSIONS: This systematic review reveals that TERPT is a safe and less-invasive procedure with a low incidence of postoperative HAEC. PMID- 20711597 TI - Kyphoscoliosis complicating pregnancy: maternal and neonatal outcome. AB - OBJECTIVE: To assess the outcome of pregnancies complicated by kyphoscoliosis in modern obstetric and orthopedic care. METHODS: A total of 22 kyphoscoliotic patients with 34 pregnancies were identified from 46,828 pregnancies between 1998 and 2009. Their obstetric records and associated orthopedic problem were studied. RESULTS: The incidence of kyphoscoliosis complicating pregnancy was 0.072%. The mean age of the patients in their index pregnancy was 28.4 years (range 23-35), mean height 130 cm (range 125-138). The cause of kyphoscoliosis included idiopathic (majority), poliomyelitis and traumatic injury. Only 1 of the patient had previous spinal surgery. The cesarean rate was very high and none had any significant cardiorespiratory problem during anesthesia. There was no maternal or perinatal mortality. CONCLUSIONS: The high maternal and perinatal risks associated with kyphoscoliosis reported earlier no longer exist. PMID- 20711598 TI - Acute urinary retention caused by endometrial carcinoma with large cystic cervix. AB - INTRODUCTION: Several pelvic masses have been known to cause urinary retention due to a mass effect with the bladder being obstructed secondary to compression of the urethra or bladder neck. MATERIALS AND METHODS: We report the extremely rare case of endometrial carcinoma with an enlarged cystic cervix which resulted in acute urinary retention. A 92-year-old woman was referred for acute urinary retention. Vaginal ultrasound revealed a 70 * 70 * 65 cm-sized cystic lesion in the cervix. Voiding became normal immediately after the incision and drainage of the mass. Ultrasound performed after the incision revealed a hyperechogenic mass with a honeycomb appearance in the uterine cavity. Endometrial biopsy revealed well-differentiated adenocarcinoma of the endometrium. Total hysterectomy and bilateral salpingo-oophorectomy was performed. CONCLUSION: The possible existence of endometrial carcinoma should be considered when the enlargement of cervix is clinically suspected in an elderly woman even if there is no vaginal discharge or bleeding. PMID- 20711600 TI - Concentration ratios of stable elements for selected biota in Japanese estuarine areas. AB - For the estimation of radiation doses to organisms, concentration ratios (C ( R )s) of radionuclides are required. In the present study, C(R)s of various elements were obtained as analogues of radionuclides for algae, molluscs, and crustaceans, in eight estuarine areas around Japan. The elements measured were Na, Mg, K, Ca, V, Mn, Fe, Co, Ni, Cu, Rb, Sr, Y, Mo, Cd, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Pb, and U. The geometric mean (GM) values of C(R)s (GM-C(R)s) for alkali and alkaline earth elements, Mo, and U for all biota, as well as V for crustaceans, were less than 100 L/kg, while GM-C(R)s for the other elements were higher. When the obtained GM-C(R)s were compared with the C(R)s recommended in IAEA Technical Report Series 422 for marine organisms, no big differences between them were found; however, several elements (i.e. Cd and U for algae, Mn for molluscs, and Pb for crustaceans) were lower than the recommended C(R)s. In the present study, conversion factors (the ratio of C(R) for the whole body to that for muscle) for molluscs and crustaceans were also calculated, since data on edible parts of these organisms are generally available in the literature. For crustaceans, GM conversion factors of all the elements were more than one. For molluscs, GM conversion factors of rare earth elements and U were slightly higher than those for crustaceans, while GM conversion factors of the other elements were almost the same and less than 10. These results indicate that some elements tend to be concentrated in the internal organs of biota collected in the estuarine areas. For environmental radiological assessment, conversion factors from tissue to whole-body C(R) values are useful parameters. PMID- 20711599 TI - Psychological distress and C-reactive protein: do health behaviours and pathophysiological factors modify the association? AB - The objective of this study is to examine the association of psychological distress to high-sensitivity C-reactive protein (hsCRP) levels and to examine the potential mediating role of health behaviours and pathophysiological factors. A total of 883 (393 men and 490 women) subjects, aged 36-56 years, participated in a population-based, cross-sectional study from 1997 to 1998 in Pieksamaki, Finland. Various clinical, biochemical and behavioural factors were measured, including hsCRP concentration. Psychological distress was measured using the 12 item General Health Questionnaire (GHQ-12). Subjects with low psychological distress (0 points in GHQ-12) were younger and more physically active, and their mean hsCRP level was lower when compared to subjects with medium (1-3 points) or high (4-12 points) psychological distress (1.26 +/- 1.36, 1.53 +/- 1.75 and 1.70 +/- 1.68 mg/l, respectively, P for linearity = 0.003). Psychological distress was also associated with high relative cardiovascular risk (hsCRP >3.00 mg/l). After adjusting for gender, age, BMI, smoking, use of alcohol and leisure time physical activity, odds ratios for hsCRP >3.00 mg/l in the groups that had medium and high psychological distress were 1.32 (95% CI: 0.81-2.16) and 1.79 (95% CI: 1.05 3.04), respectively, compared with the low distress group (P for linearity 0.032). Psychological distress was associated with elevated hsCRP levels representing high relative cardiovascular risk. This association remained after adjusting for health behaviours and pathophysiological factors, supporting a direct, physiological link between psychological distress and inflammation. CRP could be an important pathophysiological mechanism through which psychological factors are associated with cardiovascular disease. PMID- 20711601 TI - Development of image analysis tool for the classification of muscle fibre type using immunohistochemical staining. AB - An accurate characterisation of muscle fibres is essential for studying muscle plasticity. During some transient events such as ageing, myogenesis, physical activity or conversion of muscle to meat, the morphological parameters and/or the fibre type distribution may change. Nowadays, this information is generally obtained using immunohistology techniques, but these analyses are acknowledged to be laborious and time-consuming. In fact, each myofibre, from thousands, must be measured individually and its expression profile in response to different anti myosin antibodies must be established step by step. In this paper, we describe a new histological approach using double-labelling (laminin, myosin) serial sections, fluorescence microscopy visualisation and, finally, semi-automatic image analysis. The goal of the study was to propose a tool allowing faster fibre type characterisation, including the identification of hybrid fibres from pure ones. The steps in the image processing prone to subjectivity have been fully automated. On the other hand, the expert retained control of all image analysis procedures requiring visual diagnosis. The tool that we developed with the Visilog software allowed a rapid and objective fibre typing and morphometric characterisation of two different bovine muscles. The results were in agreement with our previous histological and densitometric assays. The method and the tool proved to be potentially more efficient than other techniques used in our institute or described in the literature. A more global evaluation will be considered in other laboratories as well as on other animal species. PMID- 20711602 TI - Temporal association of elevations in serum cardiac troponin T and myocardial oxidative stress after prolonged exercise in rats. AB - The objective of this study was to determine if prolonged exercise resulted in the appearance of cardiac troponin T (cTnT) in serum and whether this was associated with elevated levels of myocardial oxidative stress. Forty-five male Sprague-Dawley rats were randomized into four groups and killed before (PRE-EX), immediately (0HR), 2 (2HR) and 24 h (24HR) after a 3-h bout of swimming with 5% body weight attached to their tail. In all animals serum cTnT was assayed using 3rd generation electrochemiluminescence. In homogenized heart tissue myocardial malondialdehyde (MDA), a marker of lipid peroxidation, glutathione (GSH), and a non-enzymatic estimate of total antioxidant capacity (T-AOC) were assessed spectrophotometrically. At PRE-EX cTnT was undetectable in all animals. At 0HR (median, range: 0.055, 0.020-0.100) and 2HR post-exercise (0.036, 0.016-2.110) cTnT was detectable in all animals (P < 0.05). At 24HR post-exercise cTnT was undetectable in all animals. An elevation in MDA was observed 0HR (mean +/- SD: 1.7 +/- 0.2 nmol mgpro(-1)) and 2HR (1.6 +/- 0.3 nmol mgpro(-1)) post-exercise compared with PRE-EX (1.3 +/- 0.2 nmol mgpro(-1); P < 0.05). The antioxidant response to this challenge was a significant (P < 0.05) decrease in GSH 2HR and 24HR post-exercise. Despite this T-AOC did not alter across the trial (P > 0.05). The results indicated that prolonged and strenuous exercise in rats resulted in an elevation in cTnT, a biomarker of cardiomyocyte damage, in all animals 0HR and 2HR after exercise completion. The time course of cTnT elevation was temporally associated with evidence of increased lipid peroxidation in the rat heart. PMID- 20711603 TI - Effects of anti-saccade training with neck flexion on eye movement performance, presaccadic potentials and prefrontal hemodynamics in the elderly. AB - Anti-saccade performance, with strong contributions from frontal brain regions, reportedly deteriorates with age and maintenance of neck flexion and is known to cause brain activation. We investigated the effects of anti-saccade training on eye movement performance and frontal activity, and synergistic effects of training with neck flexion in the elderly. Thirty elderly individuals were divided into three equal groups: training group at neck resting position (NRT); training group at 20 degrees neck flexion position (NFT); and untrained group. NRT and NFT performed approximately 200 anti-saccades (a block of 10-12 anti saccades for 30 s * 20 blocks) per day over 3 weeks. Before and after training, horizontal eye movement, presaccadic potentials, and oxygenated hemoglobin concentration (oxy-Hb) in the prefrontal cortex during anti-saccades were tested in neck resting and 20 degrees neck flexion conditions. In NRT and NFT, reaction time (-50 ms), percentage of erroneous saccades (-24%), and period between peak of presaccadic negativity and onset of spike potential (-16 ms) were significantly decreased through training. Only in NFT, after training, slight shortening of reaction time associated with neck flexion was recognized (-10 ms), and peak amplitude of presaccadic negativity was increased in both test neck conditions. Oxy-Hb was not significantly affected by trainings and test neck conditions. We demonstrated that in the elderly, anti-saccade training with both neck postures improved performance and facilitated related neural pathways. Moreover, training with neck flexion showed small but synergistic effects on performance and frontal activity. However, these trainings would be insufficient for elderly individuals to automatically control anti-saccade. PMID- 20711604 TI - Identifying differentially expressed genes in leaves of Glycine tomentella in the presence of the fungal pathogen Phakopsora pachyrhizi. AB - To compare transcription profiles in genotypes of Glycine tomentella that are differentially sensitive to soybean rust, caused by the fungal pathogen Phakopsora pachyrhizi, four cDNA libraries were constructed using the suppression subtractive hybridization method. Libraries were constructed from rust-infected and non-infected leaves of resistant (PI509501) and susceptible (PI441101) genotypes of G. tomentella, and subjected to subtractive hybridization. A total of 1,536 sequences were obtained from these cDNA libraries from which 195 contigs and 865 singletons were identified. Of these sequenced cDNA clones, functions of 646 clones (61%) were determined. In addition, 160 clones (15%) had significant homology to hypothetical proteins; while the remaining 254 clones (24%) did not reveal any hits. Of those 646 clones with known functions, different genes encoding protein products involved in metabolism, cell defense, energy, protein synthesis, transcription, and cellular transport were identified. These findings were subsequently confirmed by real time RT-PCR and dot blot hybridization. PMID- 20711605 TI - Xyloglucan endotransglycosylase/hydrolase genes in cotton and their role in fiber elongation. AB - Plant cell wall extensibility is mediated, in part, by xyloglucan endotransglycosylases/hydrolases (XTH) that are able to cleave and reattach xyloglucan polymers that make up the hemicelluloses matrix of type I cell walls. In Arabidopsis and other plants, XTHs are encoded by relatively large gene families that are regulated in specific spatial and temporal patterns. In silico screening of a cotton expressed sequence tag (EST) database identified 23 sequences with close sequence similarity to Arabidopsis XTH coding sequences. Analysis of full-length cotton cDNAs derived from these ESTs allow for the identification of three distinct GhXTH cDNAs (denoted GhXTH1, GhXTH2 and GhXTH3) based primarily on their 3' untranslated sequences. The three GhXTH genes were expressed differently with GhXTH1 predominantly expressed in elongating cotton fibers. The function of GhXTH1 in mediating cotton fiber elongation was analyzed in transgenic cotton plants that express a transgene consisting of the GhXTH1 coding sequence under transcriptional control of the CaMV 35S promoter. Plants that over-expressed GhXTH1 had increased XTH activity and produced mature cotton fibers that were between 15 and 20% longer than wild-type cotton plants under both greenhouse and field growth conditions. Segregation analysis showed that the 35S::GhXTH1 transgene acts as a dominant fiber length allele in transgenic cotton. These results confirm that GhXTH1 is the predominant XTH in elongating fibers and its expression limits cotton fiber elongation. PMID- 20711607 TI - The tensor-based model for growth and cell divisions of the root apex. II. Lateral root formation. AB - In this work, the formation of the virtual lateral root (VLR) is shown. The VLR is formed using the 2D simulation model of growth and cell divisions based on the concept of growth tensor, specified for radish. Growth is generated by the field of growth rates of an unsteady type (GT field). Principal directions of growth (PDGs) are assumed to define the orientation of cell divisions. Temporal sequences of the VLR formation are a result of an application of the GT field to the polygon meshwork representing cell pattern of already initiated primordium. The computer-generated lateral root (LR) develops realistically, and its cell pattern is vivid and similar to that observed in anatomical sections. The real and virtual LRs show similar cellular organization, both originate from a small group of cells situated in two-cell layers of the pericycle and both layers are engaged in the LR development. The LR formation seems to be controlled at the tensor level and individual cells presumably detect PDGs and obey them in the course of the cell divisions. PDGs are postulated to affect the cellular organization of the LR. Using the method of computer simulations, cellular aspects of the LR morphogenesis are discussed. PMID- 20711606 TI - The transcriptome of cis-jasmone-induced resistance in Arabidopsis thaliana and its role in indirect defence. AB - cis-jasmone (CJ) is a plant-derived chemical that enhances direct and indirect plant defence against herbivorous insects. To study the signalling pathway behind this defence response, we performed microarray-based transcriptome analysis of CJ treated Arabidopsis plants. CJ influenced a different set of genes from the structurally related oxylipin methyl jasmonate (MeJA), suggesting that CJ triggers a distinct signalling pathway. CJ is postulated to be biosynthetically derived from jasmonic acid, which can boost its own production through transcriptional up-regulation of the octadecanoid biosynthesis genes LOX2, AOS and OPR3. However, no effect on these genes was detected by treatment with CJ. Furthermore, CJ-responsive genes were not affected by mutations in COI1 or JAR1, which are critical signalling components in MeJA response pathway. Conversely, a significant proportion of CJ-inducible genes required the three transcription factors TGA2, TGA5 and TGA6, as well as the GRAS regulatory protein SCARECROW like 14 (SCL14), indicating regulation by a different pathway from the classical MeJA response. Moreover, the biological importance was demonstrated in that mutations in TGA2, 5, 6, SCL14 and the CJ-inducible gene CYP81D11 blocked CJ induced attraction of the aphid parasitoid Aphidius ervi, demonstrating that these components play a key role in CJ-induced indirect defence. Collectively, our results identify CJ as a member of the jasmonates that controls indirect plant defence through a distinct signalling pathway. PMID- 20711608 TI - Muscle development in the marbled crayfish--insights from an emerging model organism (Crustacea, Malacostraca, Decapoda). AB - The development of the crustacean muscular system is still poorly understood. We present a structural analysis of muscle development in an emerging model organism, the marbled crayfish--a representative of the Cambaridae. The development and differentiation of muscle tissue and its relation to the mesoderm forming cells are described using fluorescent and non-fluorescent imaging tools. We combined immunohistochemical staining for early isoforms of myosin heavy chain with phallotoxin staining of F-actin, which distinguishes early and more differentiated myocytes. We were thus able to identify single muscle precursor cells that serve as starting points for developing muscular units. Our investigations show a significant developmental advance in head appendage muscles and in the posterior end of the longitudinal trunk muscle strands compared to other forming muscle tissues. These findings are considered evolutionary relics of larval developmental features. Furthermore, we document the development of the muscular heart tissue from myogenic precursors and the formation and differentiation of visceral musculature. PMID- 20711610 TI - Spatial heterogeneity in the relative impacts of foliar quality and predation pressure on red oak, Quercus rubra, arthropod communities. AB - Predation pressure and resource availability often interact in structuring herbivore communities, with their relative influence varying in space and time. The operation of multiple ecological pressures and guild-specific herbivore responses may combine to override simple predictions of how the roles of plant quality and predation pressure vary in space. For 2 years at the Coweeta LTER in the Southern Appalachian Mountains, we conducted a bird exclosure experiment on red oak (Quercus rubra) saplings to investigate the effects of bird predation on red oak arthropod communities. We established bird exclosures at six sites along an elevational gradient and estimated variation in foliar nitrogen and bird predation pressure along this gradient. Foliar nitrogen concentrations increased with elevation while our index of bird predation pressure was variable across sites. Greater arthropod densities were detected inside exclosures; however, this result was mainly driven by the response of phloem feeders which were much more prevalent inside exclosures than on control trees. There was little evidence for an effect of bird predation on the other arthropod guilds. Consequently, there was no evidence of a trophic cascade either in terms of leaf damage or tree growth. Finally, we found more variation in arthropod density among trees within sites than variation in arthropod density among sites, indicating the importance of micro-site variation in structuring arthropod communities. PMID- 20711609 TI - DNA methylation changes in ex-adenoma carcinoma of the large intestine. AB - Ex-adenoma carcinoma (EAC) is a carcinoma with contiguous adenoma element in its vicinity which provides a morphological evidence for adenoma-carcinoma sequence. During multistep colorectal carcinogenesis, promoter CpG island hypermethylation has been known to increase in a stepwise manner whereas diffuse genomic hypomethylation has been known to be an early event and not progress. However, some controversies exist. EAC is a good model to study the timing of hypermethylation and hypomethylation changes during multistep carcinogenesis, which this study aimed to elucidate. We analyzed 39 cases of EAC for their methylation status in eight DNA methylation markers of CpG island methylator phenotype (CIMP) panel, ten CIMP-nonrelated, cancer-specific markers, and three repetitive DNA elements (ALU, LINE-1, and SAT2) using MethyLight assay or combined bisulfite restriction analysis. Twenty-two cases of cancers had contiguous tubulovillous adenomas and 17 cases had contiguous tubular adenomas. Regardless of CIMP markers or nonrelated markers, a significant increase in the number of methylated genes was found from normal mucosa to adenoma, whereas no increase was found from adenoma to carcinoma. Both ALU and LINE-1 showed a significant decrease of methylation levels from normal mucosa to adenoma (p < 0.05), but there is no difference between adenoma and cancer. However, SAT2 methylation level exhibited a stepwise decrease from normal mucosa to adenoma to cancer. Our findings suggest that morphological progression from traditional adenoma to carcinoma does not appear to be accompanied by increases in promoter CpG island hypermethylation or repetitive DNA hypomethylation, except for SAT2 hypomethylation which showed continuous progression during multistep carcinogenesis. PMID- 20711611 TI - Modified calibration protocol evaluated in a model-based testing of SBR flexibility. AB - The purpose of this paper is to refine the BIOMATH calibration protocol for SBR systems, in particular to develop a pragmatic calibration protocol that takes advantage of SBR information-rich data, defines a simulation strategy to obtain proper initial conditions for model calibration and provides statistical evaluation of the calibration outcome. The updated calibration protocol is then evaluated on a case study to obtain a thoroughly validated model for testing the flexibility of an N-removing SBR to adapt the operating conditions to the changing influent wastewater load. The performance of reference operation using fixed phase length and dissolved oxygen set points and two real-time control strategies is compared to find optimal operation under dynamic conditions. The results show that a validated model of high quality is obtained using the updated protocol and that the optimization of the system's performance can be achieved in different manners by implementing the proposed control strategies. PMID- 20711612 TI - Long-term experience with liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: The effect of the model for end-stage liver disease (MELD) system on the post-transplant survival of patients with hepatocellular carcinoma (HCC) has not been fully elucidated. Our objective is to review the results of liver transplantation (LT) for HCC at the Massachusetts General Hospital over a period of 12 years, with special emphasis on the effect of the MELD system. METHODS: A retrospective review of 73 patients who underwent liver transplantation for HCC between 1995 and 2007. Outcome measures included demographics, tumor stage at explant, patient survival, and tumor recurrence. RESULTS: On pathologic review of the explanted liver, 12.3% of patients were classified as stage I; 42.5% as stage II, 21.9% as stage III, and 23.3% as stage IV. The overall actual survival rate was 85% at 1 year, 82% at 3 years, 73% at 5 years, and 66% at 10 years. Overall tumor recurrence was 11%. Survival rates were higher after the MELD system (5 year survival 60% before MELD vs. 85% after MELD). Recurrence decreased from 21% to 7.5%. CONCLUSION: We showed improved survival for HCC after LT over the last 12 years, and especially improved survival and decreased recurrence in the time since the implementation of the MELD system. PMID- 20711613 TI - Evaluation of new subclassification of type V(I) pit pattern for determining the depth and type of invasion of colorectal neoplasm. AB - BACKGROUND: Colorectal neoplasms with a type V(I) pit pattern include various lesions, such as adenomas, intramucosal cancers, and submucosal carcinomas. METHODS: We analyzed 96 colorectal neoplasms with a type V(I) pit pattern and identified six different variants: (1) unclear outline of the pit; (2) irregular margins of the pit; (3) narrowing of the pit; (4) ragged array of the pit; (5) high residual density of the pit; (6) abnormal branching of the pit. We examined the relationship between the appearance of each V(I) pit pattern and histology, including the depth of invasion. RESULTS: In univariate logistic regression analysis the unclear outline, irregular margins, and narrowing of the pit were significantly associated with a submucosal (SM) invasion >=1000 MUm (P < 0.01). In multivariate logistic regression analysis, unclear outline of the pit was shown to be the only significant predictor of highly invasive submucosal cancer (odds ratio = 24.20, P < 0.0001). Regarding tumor morphology, the following were significantly associated with an SM invasion >=1000 MUm: in protruded type, ragged array (P = 0.022), irregular margins of the pit (P = 0.011), and unclear outline of the pit (P < 0.01); in flat type, irregular margins of the pit (P < 0.01) and unclear outline of the pit (P < 0.01); and in the depressed type, narrowing of the pit (P = 0.015) and unclear outline of the pit (P < 0.01). CONCLUSIONS: Subclassification of the type V(I) pit pattern is useful for determining the depth of invasion of colorectal neoplasms. PMID- 20711615 TI - Anesthesia for a 16-month-old patient with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a rare disorder of chromosome abnormalities in which the paternal genes in chromosome 15 are lacking. The clinical course is characterized by hypotonia, hyperphagia, and morbid obesity. Both general and regional anesthesia in these patients is difficult due to morbid obesity and hypotonia. We report our anesthetic management in a patient with PWS with a body mass index (BMI) of 29.43 kg/m2 who underwent orchiopexy and hypospadias repair. The clinical course of the patient was uneventful during the procedure and postoperative period. However, arrangements with a pediatric intensive care setting for the postoperative period are recommended for patients with PWS undergoing surgery. PMID- 20711614 TI - Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus. AB - BACKGROUND: Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV). METHODS: A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received. RESULTS: The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age >=57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6-20 ng/mL (HR 1.942, P = 0.030) and >=20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6-20, and >=20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively. CONCLUSIONS: Not only high (>20 ng/mL), but also even slightly elevated (6-20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage. PMID- 20711616 TI - An unusual cause of carbon dioxide rebreathing in a circle absorber system. PMID- 20711617 TI - Effective control of paroxysmal tachycardia with landiolol hydrochloride during cesarean section in a patient with hypertrophic obstructive cardiomyopathy. AB - Hypertrophic obstructive cardiomyopathy (HOCM) involves marked hypertrophy of cardiac muscle, resulting in myocardial ischemia and arrhythmia because of left ventricular diastolic dysfunction. In perioperative management of HOCM, hemodynamic stabilization is required, by prevention of arrhythmia and tachycardia and maintenance of preload and afterload. Here, we describe anesthesia management during cesarean section in a patient complicated by HOCM. The patient was a 27-year-old woman who underwent elective cesarean section scheduled at 36 weeks of pregnancy given her history of HOCM. She was managed with spinal anesthesia with monitoring of invasive blood pressure and arterial pressure cardiac output. Administration of landiolol hydrochloride was initiated, because of paroxysmal tachycardia after delivery. Approximately 5 min after initiation of administration, her heart rate decreased gradually and blood pressure rose. Circulatory dynamics stabilized and landiolol was discontinued 3 h after she was admitted to the intensive care unit. Her circulatory dynamics remained stable after discontinuation of landiolol, and she was moved to a general ward on the following day. She was discharged on postoperative day 14, with her child. PMID- 20711618 TI - The influence of age, anthropometrics and range of motion on the morphometry of the synovial folds of the lateral atlanto-axial joints: a pilot study. AB - The purpose of this study was to investigate the effect of age, anthropometrics and cervical range of motion upon synovial fold volume. Ten healthy female subjects aged 20-40 years were included in the study. Age, height, body mass, dimensions of the head and neck and cervical range of motion of each subject were measured. Magnetic resonance (MR) images of the cervical spine were acquired; the volume of the ventral and dorsal synovial folds of the right and the left lateral atlanto-axial joints was measured using seed growing and thresholding methods. Using Spearman's correlation coefficient, it was determined that there was no correlation between synovial fold volume and age. Synovial fold volume was positively correlated with subject height and neck length but negatively correlated with body mass, body mass index and the circumference of the head and neck. The relationship between synovial fold volume and range of cervical motion varied with the plane of movement. The ability to image the synovial folds of the lateral atlanto-axial joints using MR imaging to determine their normal morphology provides the basis for investigating synovial fold pathology in patients with neck pain and headache. PMID- 20711619 TI - Proteomic analysis of childhood de novo acute myeloid leukemia and myelodysplastic syndrome/AML: correlation to molecular and cytogenetic analyses. AB - The aim of this study was to investigate the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML) and to provide additional data regarding the proteomic analysis of AML. The protein profiles obtained were correlated to cytogenetic and molecular analyses. Bone marrow (BM) and peripheral blood (PB) samples were obtained during MDS diagnosis, at MDS transformation to AML, at de novo AML diagnosis and 3 months following treatment. As controls, non leukemic pediatric patients were studied. Cytogenetic and molecular analyses were carried out by G banding and polymerase chain reaction followed by sequencing, respectively. Differential proteomic analysis was performed by two-dimensional gel electrophoresis and protein identification by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. No significant correlations were noted between protein patterns and cytogenetic or molecular analyses. Certain suppressor genes, metabolic enzymes, immunoglobulins and actin-binding proteins were differentially expressed by BM or PB plasma and cell lysates compared to controls. The obtained data showed that vitamin D and gelsolin played contradicting roles in contributing and restraining leukemogenesis, while MOES, EZRI and AIFM1 could be considered as biomarkers for AML. PMID- 20711620 TI - Tracking of appendicular bone mineral density for 6 years including the pubertal growth spurt: Japanese Population-based Osteoporosis kids cohort study. AB - Bone development up to early adulthood plays an important role in determining the risk of osteoporosis later in life. However, bone development in children has not been fully documented by longitudinal studies in Japanese children. The purpose of this study is to determine the degree of tracking of areal bone mineral density (aBMD) from pre-puberty to 6-year follow-up, and to determine the target period to achieve maximal peak aBMD. This study was conducted as the pediatric part of a larger cohort study, the Japanese Population-based Osteoporosis (JPOS) study. Of 448 children aged 9-12 years who completed the baseline survey, 225 participated in the follow-up study 6 years later (follow-up rate: 50.2%). aBMD at the forearm was measured using dual-energy X-ray absorptiometry. aBMD values in pre-pubertal children at baseline showed a significant tracking correlation with aBMD obtained at 6-year follow-up in both genders (boys r = 0.655, girls r = 0.759). Although boys and girls in the lowest quartile of aBMD pre-pubertally had greater annual increases in aBMD from pre-puberty to 6-year follow-up than those in other aBMD quartiles, they still showed the lowest mean aBMD at 6-year follow up. Children with lower pre-pubertal aBMD showed greater increases in BMD up until 6-year follow-up, but the increase was not great enough to catch up with other children. About 50% of the variance in aBMD at 6-year follow-up was determined by the aBMD achieved during the pre-pubertal period. Activities that increase aBMD are important not only for children during puberty, but also for younger pre-pubertal children. PMID- 20711621 TI - Evidence that His349 acts as a pH-inducible switch to accelerate receptor mediated iron release from the C-lobe of human transferrin. AB - His349 in human transferrin (hTF) is a residue critical to transferrin receptor (TFR)-stimulated iron release from the C-lobe. To evaluate the importance of His349 on the TFR interaction, it was replaced by alanine, aspartate, lysine, leucine, tryptophan, and tyrosine in a monoferric C-lobe hTF construct (Fe(C)hTF). Using a stopped-flow spectrofluorimeter, we determined rate processes assigned to iron release and conformational events (in the presence and in the absence of the TFR). Significantly, all mutant/TFR complexes feature dampened iron release rates. The critical contribution of His349 is most convincingly revealed by analysis of the kinetics as a function of pH (5.6-6.2). The Fe(C)hTF/TFR complex titrates with a pK(a) of approximately 5.9. By contrast, the H349A mutant/TFR complex releases iron at higher pH with a profile that is almost the inverse of that of the control complex. At the putative endosomal pH of 5.6 (in the presence of salt and chelator), iron is released from the H349W mutant/TFR and H349Y mutant/TFR complexes with a single rate constant similar to the iron release rate constant for the control; this suggests that these substitutions bypass the required pH-induced conformational change allowing the C lobe to directly interact with the TFR to release iron. The H349K mutant proves that although the positive charge is crucial to complete iron release, the geometry at this position is also critical. The H349D mutant shows that a negative charge precludes complete iron release at pH 5.6 both in the presence and in the absence of the TFR. Thus, histidine uniquely drives the pH-induced conformational change in the C-lobe required for TFR interaction, which in turn promotes iron release. PMID- 20711622 TI - Crisis in the operating room: fires, explosions and electrical accidents. AB - Fires, explosions and electrical accidents in the operating theater are rare events, but are devastating in terms of structural damage to the equipment in theaters and to human lives. While various circumstances lead to these troubles, we can avoid and manage them by learning from the instructive cases accumulated so far. We describe operating room crises such as fires, explosions and electrical breakdowns, and discuss causes and countermeasures. PMID- 20711624 TI - Leaf anatomical structures of Paphiopedilum and Cypripedium and their adaptive significance. AB - Paphiopedilum and Cypripedium are closely related in phylogeny, but have contrasting leaf traits and habitats. To understand the divergence in leaf traits of Paphiopedilum and Cypripedium and their adaptive significance, we analyzed the leaf anatomical structures, leaf dry mass per area (LMA), leaf lifespan (LL), leaf nitrogen concentration (N (mass)), leaf phosphorus concentration (P (mass)), mass-based light-saturated photosynthetic rate (A (mass)), water use efficiency (WUE), photosynthetic nitrogen use efficiency (PNUE) and leaf construction cost (CC) for six species. Compared with Cypripedium, Paphiopedilum was characterized by drought tolerance derived from its leaf anatomical structures, including fleshy leaves, thick surface cuticles, huge adaxial epidermis cells, lower total stoma area, and sunken stomata. The special leaf structures of Paphiopedilum were accompanied by longer LL; higher LMA, WUE, and CC; and lower N (mass), P (mass), A (mass), and PNUE compared with Cypripedium. Leaf traits in Paphiopedilum helped it adapt to arid and nutrient-poor karst habitats. However, the leaf traits of Cypripedium reflect adaptations to an environment characterized by rich soil, abundant soil water, and significant seasonal fluctuations in temperature and precipitation. The present results contribute to our understanding of the divergent adaptation of leaf traits in slipper orchids, which is beneficial for the conservation of endangered orchids. PMID- 20711623 TI - The importance of a judicious and early empiric choice of antimicrobial for methicillin-resistant Staphylococcus aureus bacteraemia. AB - The purpose of this investigation was to examine the impact of antimicrobial regimens administered for hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia on the all-cause, 14-day mortality. We retrospectively examined the characteristics of the most effective empiric antimicrobial therapy in 87 consecutive patients, hospitalised at a single institution between April 2003 and March 2008, who presented with clinically and microbiologically confirmed MRSA bacteraemia. The all-cause mortality was measured 14 days after the diagnosis was made. The administration of an effective antimicrobial against MRSA <48 h after the collection of blood cultures was the single, significant predictor of survival (odds ratio 3.85; 95% confidence interval 1.37-10.80; p = 0.01). The survival of patients treated with vancomycin versus other antimicrobial agents was similar. Among subgroups treated with vancomycin, the lowest mortality (6%) was observed among patients treated (a) within 48 h after the collection of blood cultures and (b) with doses sufficient to keep the blood concentrations in the area under the 0-24 h curve >400 MUg h/ml (>=2.0 g/day). The empiric administration of antimicrobials effective against MRSA bacteraemia within 48 h after the collection of blood cultures increased the 14-day survival. If vancomycin is chosen, >=2.0 g/day should be administered, starting within 48 h. PMID- 20711625 TI - Homogeneous genetic structure and variation in tree architecture of Larix kaempferi along altitudinal gradients on Mt. Fuji. AB - Variations in tree architecture and in the genetic structure of Larix kaempferi on Mt. Fuji were surveyed along altitudinal gradients using 11 nSSR loci. In total, 249 individuals from six populations along three trails at altitudes ranging from approximately 1,300 to 2,700 m were investigated. Gradual changes in tree architecture with increasing elevation, from erect trees to flag trees and krummholz mats, were observed in the high-altitude populations (> 2,000 m) on all trails. These findings suggest that tree architecture is correlated with the severe environmental conditions associated with increasing elevation, such as strong winds. In contrast to obvious variations in tree architecture, the genetic diversity of populations along the trails was almost uniform (H (E) = 0.717 0.762) across the altitudinal range. The results of the AMOVA and STRUCTURE analyses, and the analysis for isolation by distance pattern, suggest homogeneous genetic structuring across all populations on Mt. Fuji, while the pairwise F (ST) showed barriers to gene flow between altitudinal populations that were demarcated as high- or low-altitude populations by Abies-Tsuga forest. Although the evergreen coniferous forests on the mountainside may hinder gene flow, this may be explained by the long-distance seed dispersal of the Japanese larch and/or a short population history resulting from eruptions or slush avalanches, although evergreen coniferous forests on the mountainside may hinder gene flow. PMID- 20711626 TI - Health literacy in a population of primary health-care patients in Belgrade, Serbia. AB - OBJECTIVE: Our objective was to evaluate the health literacy and its association with sociodemographic variables, the self-perception of health and the presence of chronic conditions in primary health-care patients. METHODS: A cluster survey was conducted. A total of 1,500 patients were enrolled. Functional health literacy was measured by the Serbian version of the Short Test of Functional Health Literacy in Adults. Chi-square testing and multilevel logistic regression analyses were applied. RESULTS: We found that health literacy was inadequate and marginal in 436 (32%) and 195 participants (14.4%), respectively, and adequate in 730 participants (53.6%). A better health literacy score was present among the following participants: younger, employed, and those with a high level of education, a good self-perception of health, a good socioeconomic status and no chronic conditions. If, on multilevel analysis, the primary health center and individual variables were included, the probability for adequate health literacy was higher among younger, employed, higher educated and those with no chronic conditions. CONCLUSIONS: Primary health-care patients do not have the literacy skills necessary to function adequately in the health-care environment. PMID- 20711627 TI - Isolation and characterization of a novel epsilon-poly-L-lysine producing strain: Streptomyces griseofuscus. AB - epsilon-poly-L-lysine (epsilon-PL) is a homo-poly-amino acid of L-lysine which is used as a safe food preservative. The productivity of epsilon-PL in currently reported wild type strains is low. This study was aimed at finding novel epsilon PL producing strains with higher productivity and new fermentative characters. An improved detection method was employed using methylene blue as an epsilon-PL secretion indicator. 137 strains forming transparent circles were isolated. The best one was identified as Streptomyces griseofuscus according to the morphological characteristics and the comparison of internal transcribed spacer (ITS) ribosomal DNA (rDNA) gene sequences. The fermentative behavior of S. griseofuscus was investigated, and the epsilon-PL production was enhanced to 2.3 g/L in 5-L bioreactor by a pH control strategy. The yield of epsilon-PL reached 7.5 g/L in the fed-batch process. Compared with the reported wild type strains, S. griseofuscus produced relatively higher amounts of epsilon-PL, and might be a promising Streptomyces for epsilon-PL production. PMID- 20711629 TI - Lignocellulosic polysaccharides and lignin degradation by wood decay fungi: the relevance of nonenzymatic Fenton-based reactions. AB - The brown rot fungus Wolfiporia cocos and the selective white rot fungus Perenniporia medulla-panis produce peptides and phenolate-derivative compounds as low molecular weight Fe3+-reductants. Phenolates were the major compounds with Fe3+-reducing activity in both fungi and displayed Fe3+-reducing activity at pH 2.0 and 4.5 in the absence and presence of oxalic acid. The chemical structures of these compounds were identified. Together with Fe3+ and H2O2 (mediated Fenton reaction) they produced oxygen radicals that oxidized lignocellulosic polysaccharides and lignin extensively in vitro under conditions similar to those found in vivo. These results indicate that, in addition to the extensively studied Gloeophyllum trabeum--a model brown rot fungus--other brown rot fungi as well as selective white rot fungi, possess the means to promote Fenton chemistry to degrade cellulose and hemicellulose, and to modify lignin. Moreover, new information is provided, particularly regarding how lignin is attacked, and either repolymerized or solubilized depending on the type of fungal attack, and suggests a new pathway for selective white rot degradation of wood. The importance of Fenton reactions mediated by phenolates operating separately or synergistically with carbohydrate-degrading enzymes in brown rot fungi, and lignin-modifying enzymes in white rot fungi is discussed. This research improves our understanding of natural processes in carbon cycling in the environment, which may enable the exploration of novel methods for bioconversion of lignocellulose in the production of biofuels or polymers, in addition to the development of new and better ways to protect wood from degradation by microorganisms. PMID- 20711630 TI - A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma. AB - Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promising activity in some tumors. In this trial, 10 patients with metastatic renal cell carcinoma refractory to previous therapy with sunitinib or sorafenib (median age 61 years, 80% performance status 0, 60% intermediate MSKCC risk classification) received tandutinib 500 mg bid daily with RECIST-defined response as the primary endpoint and progression-free survival (PFS) and overall survival (OS) as secondary endpoints. No patient had more than 2 cycles of therapy and 50% of patients only received 1 cycle with 70% of patients discontinuing for progressive disease and 30% for toxicity. Tandutinib was not well tolerated with dose reduction in 60% of patients due to adverse events. The most common grade 3 toxicity was fatigue (30%). Tandutinib had no clinical activity and due to the excessive toxicity should not be developed further in patients with sunitinib or sorafenib-refractory metastatic renal cell carcinoma. PMID- 20711631 TI - Antitumor and antiangiogenic effects of GA-13315, a gibberellin derivative. AB - This study showed that 13-chlorine-3,15-dioxy-gibberellic acid methyl ester (GA 13315), a gibberellin derivative, possessed high antitumor and antiangiogenic activity in vitro and in vivo. Cytotoxicity assays showed that GA-13315 was a potential and efficient antitumor compound, with inhibitory concentration 50 (IC(50)) values ranging from 0.13 to 30.28 MUg/ml in 12 human tumor cell lines, and it showed moderate toxicity to peripheral blood mononuclear cells with an IC(50) value of 14.2 MUg/ml. Administration of 0.5 or 2.5 mg/kg GA-13315 for 23 days significantly inhibited tumor growth of human non-small cell lung tumor (A549) xenografts, with relative growth rates ranging from 29.91% to 35.05%. Acute toxicity was determined in ICR mice, and the lethal dose 50 (LD(50)) was 4.19 g/kg after intragastric administration. The high antitumor potency of GA 13315 occurred in parallel with its antiangiogenic activity. In vitro, GA-13315 inhibited recombinant human epithelial growth factor-induced chemotactic motility and capillary-like tube formation of primary cultured human endothelial cells. Furthermore, GA-13315 decreased the factor VIII(+) microvessel density and vascular endothelial growth factor expression in A549 tumors, indicating its antiangiogenic efficacy in vivo. These results indicate that the antiangiogenic activity of GA-13315 contributes to its anticancer properties. Further studies are needed to investigate the use of GA-13315 as an anticancer drug. PMID- 20711632 TI - Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma. AB - Sunitinib is associated with a robust objective response rate in patients with metastatic clear cell renal cell carcinoma (RCC). The primary objective of this phase II clinical trial was to assess the overall response rate for sunitinib in patients with papillary metastatic RCC as well as other non-clear cell histologies. A Simon 2-stage design was used to determine the number of papillary metastatic RCC patients for enrollment, and allowed for descriptive response data for other non-clear cell histologies. Twenty-three patients were enrolled, including 8 with papillary renal cell carcinoma (RCC) and the remainder with other non-clear cell histologies (unclassified in 5 patients). All patients received 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2). The trial was stopped early because of slow accrual; no responses were observed in the 8 patients with papillary RCC. In the 22 evaluable patients, best response to sunitinib included a partial response in 1 patient with unclassified RCC, stable disease in 15, and progression in 6. The median progression-free survival was 5.5 months (95% CI, 2.5-7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4-7.1). The robust objective responses sunitinib had produced in clear cell RCC could not be demonstrated in this study comprised of patients with non-clear cell histologies. PMID- 20711633 TI - Conditional preferences and refusal of treatment. AB - In this essay, I will use a minimalist standard of decision-making capacity (DMC) to ascertain two cases in the medical ethics literature: the 1978 case of Mary C. Northern and a more recent case involving a paranoid war veteran (call him Jack). In both cases the patients refuse medical treatment out of denial that they are genuinely ill. I believe these cases illustrate two matters: (1) the need of holding oneself to a minimal DMC standard so as to make as salient as possible the patient's own reasons for sometimes unusual treatment denials; (2) the need for clinicians and other relevant parties to exercise great sensitivity toward engaging, on the patient's own terms, idiosyncratic treatment refusals through regard for what I will call the patient's "conditional preferences." These are particularly relevant matters when a patient's DMC is questionable yet he/she registers what may well be his/her settled preferences. PMID- 20711635 TI - The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer. AB - Multiple cellular signaling pathways have been involved in the processes of cancer cell invasion and metastasis. Among many signaling pathways, Wnt and Hedgehog (Hh) signaling pathways are critically involved in embryonic development, in the biology of cancer stem cells (CSCs) and in the acquisition of epithelial to mesenchymal transition (EMT), and thus this article will remain focused on Wnt and Hh signaling. Since CSCs and EMT are also known to be responsible for cancer cell invasion and metastasis, the Wnt and Hedgehog signaling pathways are also intimately associated with cancer invasion and metastasis. Emerging evidence suggests the beneficial role of chemopreventive agents commonly known as nutraceutical in cancer. Among many such agents, soy isoflavones, curcumin, green tea polyphenols, 3,3'-diindolylmethane, resveratrol, lycopene, vitamin D, etc. have been found to prevent, reverse, or delay the carcinogenic process. Interestingly, these agents have also shown to prevent or delay the progression of cancer, which could in part be due to their ability to attack CSCs or EMT-type cells by attenuating the Wnt and Hedgehog signaling pathways. In this review, we summarize the current state of our knowledge on the role of Wnt and Hedgehog signaling pathways, and their targeted inactivation by chemopreventive agents (nutraceuticals) for the prevention of tumor progression and/or treatment of human malignancies. PMID- 20711636 TI - Ultra-porous titanium oxide scaffold with high compressive strength. AB - Highly porous and well interconnected titanium dioxide (TiO(2)) scaffolds with compressive strength above 2.5 MPa were fabricated without compromising the desired pore architectural characteristics, such as high porosity, appropriate pore size, surface-to-volume ratio, and interconnectivity. Processing parameters and pore architectural characteristics were investigated in order to identify the key processing steps and morphological properties that contributed to the enhanced strength of the scaffolds. Cleaning of the TiO(2) raw powder removed phosphates but introduced sodium into the powder, which was suggested to decrease the slurry stability. Strong correlation was found between compressive strength and both replication times and solid content in the ceramic slurry. Increase in the solid content resulted in more favourable sponge loading, which was achieved due to the more suitable rheological properties of the ceramic slurry. Repeated replication process induced only negligible changes in the pore architectural parameters indicating a reduced flaw size in the scaffold struts. The fabricated TiO(2) scaffolds show great promise as load-bearing bone scaffolds for applications where moderate mechanical support is required. PMID- 20711634 TI - A clinical cardiology perspective of thrombophilias. AB - Thrombophilias, an inherited and/or acquired predisposition to vascular thrombosis beyond hemostatic needs are common in cardiovascular medicine and include systemic disorders such as coronary atherosclerosis, atrial fibrillation, exogenous obesity, metabolic syndrome, collagen vascular disease, human immunodeficiency virus, blood replacement therapy and several commonly used medications. A contemporary approach to patients with suspected thrombophilias, in addition to a very selective investigation for gain-of-function and loss-of function gene mutations affecting thromboresistance, must consider prevalent diseases and management decisions encountered regularly by cardiologists in clinical practice. An appropriate recognition of common disease states as thrombophilias will also stimulate platforms for much needed scientific investigation. PMID- 20711638 TI - The effect of ionic dissolution products of Ca-Sr-Na-Zn-Si bioactive glass on in vitro cytocompatibility. AB - Many commercial bone grafts cannot regenerate healthy bone in place of diseased bone. Bioactive glasses have received much attention in this regard due to the ability of their ionic dissolution products to promote cell proliferation, cell differentiation and activate gene expression. Through the incorporation of certain ions, bioactive glasses can become therapeutic for specific pathological situations. Calcium-strontium-sodium-zinc-silicate glass bone grafts have been shown to release therapeutic levels of zinc and strontium, however the in vitro compatibility of these materials is yet to be reported. In this study, the in vitro cytocompatibility of three different calcium-strontium-sodium-zinc-silicate glasses was examined as a function of their ion release profiles, using Novabone(r) bioglass as a commercial comparison. Experimental compositions were shown to release Si(4+) ranging from 1 to 81 ppm over 30 days; comparable or enhanced release in comparison to Novabone. The maximum Ca(2+) release detected for experimental compositions was 9.1 ppm, below that reported to stimulate osteoblasts. Sr(2+) release was within known therapeutic ranges, and Zn(2+) release ranged from 0.5 to 1.4 ppm, below reported cytotoxic levels. All examined glass compositions show equivalent or enhanced in vitro compatibility in comparison to Novabone. Cells exposed to BT112 ionic products showed enhanced cell viabilities indicating cell proliferation was induced. The ion release profiles suggest this effect was due to a synergistic interaction between certain combinations and concentrations of ions. Overall, results indicate that the calcium-strontium-sodium-zinc-silicate glass compositions show equivalent or even enhanced in vitro compatibility compared to Novabone(r). PMID- 20711639 TI - Genomics of metastatic progression. PMID- 20711637 TI - Fabrication and evaluation of chitosan-gelatin based buckling implant for retinal detachment surgery. AB - The traditional nonabsorbable silicone buckling implant (buckle) may cause some long-term complications when it is used in the retinal detachment surgery. In this study we fabricated a chitosan-gelatin based buckling implant to replace the traditional one. We evaluated its biocompatibility with human scleral fibroblasts (HSF) in vitro and its cytotoxicity with L929 cell. To evaluate elasticity and hardness of the blends buckle, the mechanical properties of the chitosan-gelatin buckle were compared with the traditional silicone buckle. The light and electron microscopy coupled with immunocytochemistry demonstrated that chitosan-gelatin blends supported the survival and growth of primarily cultured HSF without significant cytotoxic effects. MTT analysis and cell cycle analysis indicated that chitosan-gelatin blends promoted the proliferation of HSF. A preliminary in vivo implantation test indicated that chitosan-gelatin buckling implant were compatible with the surrounding tissue. The results collectively demonstrated that chitosan-gelatin blends could be a candidate biodegradable material for scleral buckling surgery. PMID- 20711643 TI - 2020 foresight: practicing ethically while doing things that don't yet exist. AB - The APA Ethical Code struggles to offer guidance in the rapidly changing field of clinical health psychology. Professional challenges anticipated in the next decade are described, and their implications for ethical practice examined. This paper is based in part on a presentation at the 2009 Conference at the Association of Psychologists in Academic Health Centers held in St. Louis, Missouri. PMID- 20711642 TI - Nonmuscle myosin IIA with a GFP fused to the N-terminus of the regulatory light chain is regulated normally. AB - Nonmuscle myosin II plays a crucial role in a variety of cellular processes (e.g., polarity formation, cell motility, and cytokinesis). It is composed of two heavy chains, two regulatory light chains and two essential light chains. The ATPase activity of the myosin II motor domain is regulated through phosphorylation of the regulatory light chain (RLC) by myosin light chain kinase. To study myosin function and localization in cellular processes, GFP-fused RLCs are widely used; however, the exact kinetic properties of myosins with bound GFP RLC are poorly described. More importantly, it has not been shown that a regulatory light chain fused at its N-terminus with GFP can maintain the normal phosphorylation-dependent regulation of nonmuscle myosin or serve as a substrate for myosin light chain kinase. We coexpressed N-terminal GFP-RLC with a heavy meromyosin (HMM)-like fragment of nonmuscle myosin IIA and essential light chain to characterize the phosphorylation dynamics and in vitro kinetic properties of the resulting HMM. Myosin light chain kinase phosphorylates the GFP-RLC bound to HMM IIA with the same V(max) as it does the wild type RLC bound to HMM IIA, but the K(m) is about two fold higher for the GFP fusion protein, meaning that it is a somewhat poorer substrate. The steady-state actin-activated MgATPase activity of the GFP-RLC HMM is very low in the absence of phosphorylation demonstrating that the GFP moiety does not prevent formation of the off state. The actin activated MgATPase activity of phosphorylated GFP-RLC-HMM and is about half that of wild type phosphorylated HMM. The ability of phosphorylated GFP-RLC-HMM to move actin filaments in the actin gliding assay is also slightly compromised. These data indicate that despite some kinetic differences the N-terminal GFP fusion to the regulatory light chain is a reasonable model system for studying myosin function in vivo. PMID- 20711644 TI - Detection of abnormalities for diagnosing of children with autism disorders using of quantitative electroencephalography analysis. AB - Quantitative electroencephalography (qEEG) has been used as a tool for neurophysiologic diagnostic. We used spectrogram and coherence values for evaluating qEEG in 17 children (13 boys and 4 girls aged between 6 and 11) with autism disorders (ASD) and 11 control children (7 boys and 4 girls with the same age range). Evaluation of qEEG with statistical analysis demonstrated that alpha frequency band (8-13 Hz) had the best distinction level of 96.4% in relaxed eye opened condition using spectrogram criteria. The ASD group had significant lower spectrogram criteria values in left brain hemisphere, (p < 0.01) at F3 and T3 electrodes and (p < 0.05) at FP1, F7, C3, Cz and T5 electrodes. Coherence values at 171 pairs of EEG electrodes indicated that there are more abnormalities with higher values in the connectivity of temporal lobes with other lobes in gamma frequency band (36-44 Hz). PMID- 20711646 TI - Evaluating the direction of effects in the relationship between religious versus non-religious activities, academic success, and substance use. AB - This longitudinal study tested the influence of involvement and selection hypotheses for the association between religious versus non-religious activity involvement and two salient indicators of adolescent psychosocial adjustment (substance use and academic achievement). Participants included 3,993 Canadian adolescents (49.4% girls) who were surveyed each year from grades 9-12. More frequent religious attendance (but not non-religious club involvement) in one grade predicted lower levels of substance use in the next grade. Higher levels of non-religious club involvement (but not religious service attendance) in one grade predicted higher academic achievement in the next grade, and higher academic achievement in one grade predicted more frequent non-religious club involvement in the next grade. The effects were robust, as they were invariant across grade and significant after controlling for individual, peer, and family characteristics. Most importantly, these results suggest that religious activities are not just another club, but, rather, that different developmental assets may be fostered in religious as compared to non-religious activities. PMID- 20711645 TI - Esperanza y Vida: training lay health advisors and cancer survivors to promote breast and cervical cancer screening in Latinas. AB - The use of lay health advisors (LHAs) to promote community-based health education programs is well documented and is considered an effective way to reach underserved communities. Esperanza y Vida (Hope & Life) is an educational outreach program to increase breast and cervical cancer screening for diverse Latinas. It incorporates Latino LHAs (men and women) and cancer survivor role models, sobrevivientes, in the program delivery. An interactive training program, conducted by bilingual staff across three sites (Little Rock, Arkansas; Buffalo, New York and New York City) included 74 sobrevivientes and LHAs who were recruited and trained. All training attendees completed an initial application assessing socio-demographics, experience and availability as well as, true/false surveys at the beginning (pre-) and end of the training (post-) measuring knowledge levels of breast and cervical cancer health. Data analysis indicated a significant increase of both breast and cervical cancer knowledge for attendees trained as LHAs (pre = 60%; post = 80%; p = 0.000), whereas sobrevivientes had a higher baseline knowledge of breast health (74%), and therefore did not show a significant increase following training (79%). However, sobrevivientes did display a significant increase in cervical cancer knowledge (p = 0.003). These findings demonstrate the impact of training and how LHAs may be recruited at different levels of knowledge and experience and be successfully trained in key program elements. Moreover, results indicate that sobrevivientes may be impacted differently, or require variations in training approaches. This information can be useful in developing and customizing curriculum for future lay health training programs. PMID- 20711647 TI - Posttranslational modification of mammalian AP endonuclease (APE1). AB - A key issue in studying mammalian DNA base excision repair is how its component proteins respond to a plethora of cell-signaling mediators invoked by DNA damage and stress-inducing agents such as reactive oxygen species, and how the actions of individual BER proteins are attributed to cell survival or apoptotic/necrotic death. This article reviews the past and recent progress on posttranslational modification (PTM) of mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1). PMID- 20711648 TI - Alpha-synuclein deficiency leads to increased glyoxalase I expression and glycation stress. AB - The presynaptic protein alpha-synuclein has received much attention because its gain-of-function is associated with Parkinson's disease. However, its physiological function is still poorly understood. We studied brain regions of knock-out mice at different ages with regard to consistent upregulations of the transcriptome and focused on glyoxalase I (GLO1). The microarray data were confirmed in qPCR, immunoblot, enzyme activity, and behavior analyses. GLO1 induction is a known protective cellular response to glucose stress, representing efforts to decrease toxic levels of methylglyoxal (MG), glyoxal and advanced glycation endproducts (AGEs). Mass spectrometry quantification demonstrated a ubiquitous increase in MG and fructosyl-lysine as consequences of glucose toxicity, and consistent enhancement of certain AGEs. Thus, GLO1 induction in KO brain seems insufficient to prevent AGE formation. In conclusion, the data demonstrate GLO1 expression and glycation damage to be induced by alpha-synuclein ablation. We propose that wild-type alpha-synuclein modulates brain glucose metabolism. PMID- 20711650 TI - A comparison of HIV infection and related risks among male sex workers in different venues in Shenzhen, China. AB - Different risks of HIV infection have been reported among different types of male sex workers (MSW). In order to compare the prevalence of HIV infection and related risk behaviors of MSW in different venues in Shenzhen, China, a time location sampling survey was conducted in 2008. 5.1% of the 394 MSWs were tested positive for HIV, with 6.9% in those working in parks (PMSW), 11.3% in small family clubs (FMSW) and 1.7% in entertainment venues. PMSWs and FMSWs reported a higher proportion of self-identified homosexual/gay. Moreover, FMSWs reported a lower coverage of HIV-related education and services and were more likely to self report coming from provinces with higher HIV prevalence. The results indicated that MSWs in small venues and parks were comparatively at higher risk of being infected and suggested that current HIV preventive intervention needs to be expanded to the small venues in Shenzhen. PMID- 20711649 TI - Early developmental regression in autism spectrum disorder: evidence from an international multiplex sample. AB - The characteristics of early developmental regression (EDR) were investigated in individuals with ASD from affected relative pairs recruited to the International Molecular Genetic Study of Autism Consortium (IMGSAC). Four hundred and fifty eight individuals with ASD were recruited from 226 IMGSAC families. Regression before age 36 months occurred in 23.9% of individuals. The observed concordance rate for EDR within sibling pairs (18.9%) was not significantly above the rate expected under independence (13.5%, p = 0.10). The rate of regression in individuals with ASD from multiplex families was similar to that reported in singleton and epidemiological samples. Regression concordance data were not supportive of a separate familial influence on EDR, other than as a part of autism itself. PMID- 20711651 TI - Persons newly diagnosed with HIV infection are at high risk for depression and poor linkage to care: results from the Steps Study. AB - Little is known about the prevalence and impact of depression in persons newly diagnosed with HIV infection. The Steps Study is a prospective, observational cohort study of persons newly diagnosed with HIV infection. Participants were administered a battery of instruments, including the CES-D. Linkage to care was defined as attending at least one clinic appointment in each of the first two 90 day intervals following diagnosis. Of 180 participants, 67% screened positive for depression. In multivariate analysis, depression was associated with female sex, income <$25,000, recent substance abuse, baseline poor access to medical care, and low self-efficacy. Fifty-six and sixty-eight percent of depressed and not depressed participants linked to care, respectively. In multivariate analysis, depression was a borderline significant predictor of poor linkage. Depression is very prevalent in persons newly diagnosed with HIV infection. Interventions targeting linkage to care should address depression, substance abuse, and barriers to care. PMID- 20711653 TI - Commentary on: "Effect of obesity on survival in women with breast cancer: systematic review and meta-analysis" (Melinda Protani, Michael Coory, Jennifer H. Martin). PMID- 20711652 TI - Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study. AB - The objective of this study is to define the survival outcomes associated with distinct molecular phenotypes defined by immunohistochemical staining of paraffin embedded tissues among invasive breast cancer cases identified from the Nurses' Health Study (NHS). Tissue microarrays were constructed from archived tissue blocks of women diagnosed with breast cancer in the NHS (1976-1997). Invasive non metastatic breast cancer tumors (n = 1,945) were classified into 1 of 5 molecular phenotypes based on immunohistochemistry assays for estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and grade. Survival outcomes were estimated using the Kaplan Meier product limit method. Cox-proportional hazards models were fitted to determine the association of molecular phenotype with survival outcomes after adjusting for covariates. 1,279 (65.8%) tumors were classified as luminal A, 279 (14.3%) as luminal B, 95 (4.9%) as HER2 type, 203 (10.4%) as basal-like and 89 (4.6%) tumors were unclassified. The 5-year breast cancer-specific survival estimates for women with luminal A, luminal B, HER2-type, basal-like and unclassified tumors were 96, 88, 81, 89 and 85%, respectively. In the multivariable model, compared to cases with luminal A tumors, cases with luminal B (HR 1.90, 95% CI 1.33-2.71), HER2-type (HR 1.36, 95% CI 0.87-2.12), basal-like (HR 1.58, 95% CI 1.05-2.39) and unclassified (HR 1.38, 95% CI 0.87-2.20) tumors had higher hazard of breast cancer death. Similar trends were observed for both overall and recurrence-free survival. In conclusion, compared to women who have luminal A tumors those with luminal B, HER2-type, basal-like and unclassified tumors had a worse prognosis, when tumor subtype was defined by immunohistochemistry. This method may provide a cost-effective means of determining prognosis in the clinical setting. PMID- 20711654 TI - Epidemiology of breast cancer in young women. AB - Breast cancer is mainly a postmenopausal disease, but in younger women breast tumors often exhibit more aggressive features and worse prognosis. Furthermore, high-risk and low-risk tumors present different age distributions suggesting that breast cancer comprises a mixture of two different disease processes. In agreement with this hypothesis, breast cancer presents different epidemiologic traits in pre- and postmenopausal women. Regarding racial distribution, incidence is higher in black women at younger ages in US, while the reverse is true among women older than 50 years. Genetic predisposition is a stronger risk factor in young women. On the contrary, nulliparity and obesity decrease the risk of early onset breast cancers while are associated with higher incidence in older women. Epidemiologic data related with the hormonal exposure in utero suggest that the effect is stronger in early breast cancers. In most developed countries, breast cancer has shown an upward trend until recent years in postmenopausal women, while incidence rates in younger women have been stable. However, Spain is an exception to this rule: Spanish women younger than 45 years of age have registered a steady increase of breast cancer that may be related with the remarkable lifestyle changes experienced by women born in the second half of the twentieth century. PMID- 20711655 TI - Therapeutic approaches in young women with advanced or metastatic breast cancer. PMID- 20711656 TI - Impact of breast cancer treatment on fertility. PMID- 20711657 TI - Quality of life during treatment in young women with breast cancer. PMID- 20711658 TI - Histologic diagnosis in young women with breast cancer. PMID- 20711663 TI - Hereditary breast cancer and genetic counseling in young women. PMID- 20711665 TI - Imaging diagnosis of young women with breast cancer. PMID- 20711666 TI - Adjuvant endocrine therapy in premenopausal women with breast cancer. PMID- 20711667 TI - Radiation therapy in young women with breast cancer. PMID- 20711668 TI - Neoadjuvant treatment in young women with breast cancer. PMID- 20711669 TI - Adjuvant chemotherapy in young women with breast cancer. PMID- 20711670 TI - Surgical treatment of breast cancer in young women. PMID- 20711671 TI - Contralateral risk-reducing mastectomy in young women. PMID- 20711672 TI - Purification and characterization of three trypsin isoforms from viscera of sardinelle (Sardinella aurita). AB - Three trypsin isoforms A, B and C were purified to homogeneity from the viscera of sardinelle (Sardinella aurita). Purification was achieved by ammonium sulfate precipitation (20-70% (w/v)), Sephadex G-100 gel filtration and Mono Q-Sepharose anion-exchange chromatography. The molecular weights of these purified enzymes were estimated to be 28.8 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Based on the native PAGE and casein-zymography, each purified trypsin appeared as a single band. Trypsins A and C exhibited the maximal activity at 55 degrees C, while trypsin B at 50 degrees C. All isoforms showed the same optimal pH (pH 9.0) using Nalpha-benzoyl-DL: -arginine-p nitroanilide (BAPNA) as a substrate. The three trypsins were stable at temperatures below 40 degrees C and over a broad pH range (7.0-11.0). The activities of the three isoforms were strongly inhibited by soybean trypsin inhibitor and phenylmethylsulfonyl fluoride, a serine protease inhibitor, and partially inhibited by ethylenediaminetetraacetic acid, a metalloenzyme inhibitor. Kinetic constants of trypsins A, B and C for BAPNA were evaluated at 25 degrees C and pH 9.0. The values of K (m) and k (cat) were 0.125, 0.083 and 0.10 mM, and 2.24, 1.21 and 5.76 s(-1), respectively. The N-terminal sequences of the first 10 amino acids were "I V G G Y E C Q K Y" for trypsin A and "I V G G Y E A Q S Y" for trypsins B and C. These sequences showed highly homology to other fish trypsins. PMID- 20711673 TI - Metal sensitivity of the embryonic development of the ramshorn snail Marisa cornuarietis (Prosobranchia). AB - We investigated the effects of metal ions on the embryonic development of the ramshorn snail, Marisa cornuarietis, by exposing embryos to varying concentrations of copper (0, 50, 100, and 250 MUg Cu(2+)/L), lead (0, 5, 10, and 15 mg Pb(2+)/L), lithium (0, 1, 2.5, and 3 mg Li(+)/L), or palladium (0, 50, 100, and 500 MUg Pd(2+)/L). Effects of these metals were examined by recording mortality, the rate of tentacles and eyes formation, heart rate, hatching success, and weight after hatching. Compared to the control, we found a significant delay in the formation of tentacles and eyes after treatment with 100 MUg Cu(2+)/L, 15 mg Pb(2+)/L, 2.5 mg Li(+)/L or 500 MUg Pd(2+)/L. The heart rate decreased significantly at 500 MUg Pd(2+)/L. At 10 mg Pb(2+)/L, 2.5 mg Li(+)/L, or 500 MUg Pd(2+)/L, hatching was delayed significantly; 50 MUg Cu(2+)/L induced a significantly earlier hatching, and reduced body weight. The LC(50) values were calculated to be about 50 MUg Cu(2+)/L, 500 MUg Pd(2+)/L, 2500 MUg Li(+)/L, and 10000 MUg Pb(2+)/L. These results show that the embryonic development of M. cornuarietis is about as sensitive to copper and lithium, compared to the most sensitive fishes used in embryo toxicity testing. Even though the MariETT is a laboratory-based assay focusing on toxicological endpoints of a selected model species, future application is envisaged to include testing of "natural" samples such as stream water or sediment interstitial water. PMID- 20711675 TI - Molecular signatures for the Crenarchaeota and the Thaumarchaeota. AB - Crenarchaeotes found in mesophilic marine environments were recently placed into a new phylum of Archaea called the Thaumarchaeota. However, very few molecular characteristics of this new phylum are currently known which can be used to distinguish them from the Crenarchaeota. In addition, their relationships to deep branching archaeal lineages are unclear. We report here detailed analyses of protein sequences from Crenarchaeota and Thaumarchaeota that have identified many conserved signature indels (CSIs) and signature proteins (SPs) (i.e., proteins for which all significant blast hits are from these groups) that are specific for these archaeal groups. Of the identified signatures 6 CSIs and 13 SPs are specific for the Crenarchaeota phylum; 6 CSIs and >250 SPs are uniquely found in various Thaumarchaeota (viz. Cenarchaeum symbiosum, Nitrosopumilus maritimus and a number of uncultured marine crenarchaeotes) and 3 CSIs and ~10 SPs are found in both Thaumarchaeota and Crenarchaeota species. Some of the molecular signatures are also present in Korarchaeum cryptofilum, which forms the independent phylum Korarchaeota. Although some of these molecular signatures suggest a distant shared ancestry between Thaumarchaeota and Crenarchaeota, our identification of large numbers of Thaumarchaeota-specific proteins and their deep branching between the Crenarchaeota and Euryarchaeota phyla in phylogenetic trees shows that they are distinct from both Crenarchaeota and Euryarchaeota in both genetic and phylogenetic terms. These observations support the placement of marine mesophilic archaea into the separate phylum Thaumarchaeota. Additionally, many CSIs and SPs have been found that are specific for different orders within Crenarchaeota (viz. Sulfolobales-3 CSIs and 169 SPs, Thermoproteales-5 CSIs and 25 SPs, Desulfurococcales-4 SPs, and Sulfolobales and Desulfurococcales-2 CSIs and 18 SPs). The signatures described here provide novel means for distinguishing the Crenarchaeota and the Thaumarchaeota and for the classification of related and novel species in different environments. Functional studies on these signature proteins could lead to discovery of novel biochemical properties that are unique to these groups of archaea. PMID- 20711674 TI - Diversity of culturable thermo-resistant aquatic bacteria along an environmental gradient in Cuatro Cienegas, Coahuila, Mexico. AB - At the desert oasis of Cuatro Cienegas in Coahuila, Mexico, more than 300 oligotrophic pools can be found and a large number of endemic species of plants and animals. The most divergent taxa of diatoms, snail and fishes are located in the Churince hydrological system, where we analyzed the local diversification of cultivable Firmicutes and Actinobacteria. The Churince hydrological system is surrounded by gypsum dunes and has a strong gradient for salinity, temperature, pH and dissolved oxygen. In August 2003, surface water samples were taken in 10 sites along the Churince system together with the respective environmental measurements. 417 thermo-resistant bacteria were isolated and DNA was extracted to obtain their BOX-PCR fingerprints, revealing 55 different patterns. In order to identify similarities and differences in the diversity of the various sampling sites, an Ordination Analysis was applied using Principal Component Analysis. This analysis showed that conductivity is the environmental factor that explains the distribution of most of the microbial diversity. Phylogenetic reconstruction from their 16S rRNA sequences was performed for a sample of 150 isolates. Only 17 sequences had a 100% match in the Gene Bank (NCBI), representing 10 well known cosmopolitan taxa. The rest of the sequences cluster in 22 clades for Firmicutes and another 22 clades for Actinobacteria, supporting the idea of high diversity and differentiation for this site. PMID- 20711676 TI - Relationship between positive self-recognition of maternal role and psychosocial factors in Japanese mothers with severe mental illness. AB - Mothers with mental illness have positive self-recognition of maternal role (PM), and it is important for parenting. The purpose of this study was to determine the psychosocial factors related to the PM. We recruited a total of 74 women diagnosed as having schizophrenia or mood disorders according to the DSM-IV-TR and who had minor children. Participant completed devaluation-discrimination measure, The social support questionnaire, self-efficacy for community life scale (SECL), parenting stress-short form scale (PS-SF), and Acceptance of maternal role scale. To identify factors predicting the PM, we utilized hierarchical regression analysis. The variables in all blocks explained 53% of the variance in the PM. In the final model, 'hard' living conditions (beta = -0.31, P < 0.05), SECL (beta = 0.34, P < 0.01) and PS-SF (beta = -0.45, P < 0.01) were significant predictors of the PM. Our result indicates that psychosocial approach could enhance the PM. PMID- 20711677 TI - Mechanical left ventricular dyssynchrony detection by endocardium displacement analysis with 3D speckle tracking technology. AB - Myocardium deformation and displacement analysis by echocardiography has proven useful to evaluate the synchrony of myocardial mechanics. The aim of our study was to evaluate the mean standard deviation of time to longitudinal peak displacement in 16 cardiac segments by 3D echo wall motion Speckle Tracking analysis. We studied 15 patients with ventricular dyssynchrony-defined by a QRS > 120 ms in the ECG. We obtained the differences between time peaks of endocardial longitudinal displacement for 16 segments of the heart by 3D echo Speckle Tracking. We compared the temporal dispersion of these peaks with results obtained in a control group of 13 healthy individuals without dyssynchrony. The results showed a significant difference (p < 0.001) between the dispersion of standard deviation in the 13 patients in the control group (34 ms +/- 19) and the 15 patients in the dyssynchrony group (117 ms +/- 57). We describe a new parameter obtained by 3D echo wall motion Speckle Tracking analysis for the detection of dyssynchrony. It can be useful to identify dyssynchrony of left ventricular myocardial mechanics, to indicate the resynchronization therapy, to optimize the parameters of the device and to achieve a less operator-dependent evaluation. PMID- 20711678 TI - The irony of supporting physician-assisted suicide: a personal account. AB - Under other circumstances, I would have written an academic paper rehearsing the arguments for and against legalization of physician-assisted suicide: autonomy and the avoidance of pain and suffering on the pro side, the wrongness of killing, the integrity of the medical profession, and the risk of abuse, the "slippery slope," on the con side. I've always supported the pro side. What this paper is, however, is a highly personal account of the challenges to my thinking about right-to-die issues. In November 2008, my husband suffered a C2/C3 spinal cord injury in a bicycle collision, leaving him ventilator-dependent, almost completely paralyzed, and in the hospital--but fully alert and profoundly self reflective. What if he wanted to die? This paper draws from two multimedia presentations- file:///Users/margaretbattin/Documents/BROOKE'S%20ACCIDENT/The%20Salt%20Lake%20Tr bune%20%7C%20Multimedia:%20Metamorphosis.webarchive and file:///Users/margaretbattin/Documents/BROOKE'S%20ACCIDENT/The%20Salt%20Lake%20Tr bune%20%7C%20Multimedia:%20Learning%20to%20live%20again.webarchive--and personal material concerning quality of life (he'd rank at the bottom on the SF-36 and similar scales) and concerning autonomy (his own accounts, verbatim). This is a detailed portrait of a man whose life involves extraordinary suffering but also luminous experience some of the time. It only makes the question harder: What if he wanted to die? PMID- 20711679 TI - Is metabolic syndrome a mild form of Cushing's syndrome? AB - The Metabolic Syndrome is a diagnosis of increasing prevalence that is noted to share multiple clinical features with Cushing's syndrome. Several studies suggest abnormalities in the Hypothalamic-Pituitary-Adrenal axis to be associated with this disease and tissue-specific hypercortisolemia is being investigated as a possible contributing factor. More research is needed to explore the relation between cortisol and the metabolic syndrome which, if confirmed, will have major therapeutic and public health implications. PMID- 20711681 TI - Extra-peritoneal rectal perforation caused by water jet: a case report and literature review. AB - INTRODUCTION: The use of motorised watercrafts has been increasing steadily over the past few years, and consequently, also injuries secondary to the use of these watercrafts [1]. METHOD: This is a case presentation and review of literature. We present a case of isolated extraperitoneal rectal perforation secondary to hydrostatic pressure sustained. Both PubMed and Web of Science were searched using the following keywords: rectal perforations; intra-peritoneal; extra peritoneal; motorised watercraft; and Jet Ski. RESULTS: We found two similar rectal injuries caused by motorised watercrafts, but both were intraperitoneal rectal perforations. To our knowledge, this is the first reported case of extra peritoneal rectal perforation after falling off a motorised watercraft. On the other hand, vaginal perforation after such a trauma is well documented in many series. CONCLUSION AND RECOMMENDATION: Though there injuries are not very common, they can be life-threatening. Simple measures like wearing protective garments might be enough to prevent them. Complete defunctioning colostomy is better in these cases than partially defunctioning colostomy. PMID- 20711680 TI - Mechanisms of nocturnal gastroesophageal reflux events in obstructive sleep apnea. AB - PURPOSE: Obstructive sleep apnea (OSA) is associated with increased nocturnal gastroesophageal reflux (nocturnal GER) events and symptoms. Treatment of OSA with continuous positive airway pressure (CPAP) reduces nocturnal GER in patients with OSA. This study sought to determine the: (1) relationship of nocturnal GER events with apnea/hypopnea and arousal, (2) effect of upper airway obstruction on the barrier function of the lower esophageal sphincter (LES), (3) mechanism of LES failure for each nocturnal GER event and (4) effect of CPAP on LES function during sleep. METHODS: Eight patients with OSA and nocturnal GER underwent polysomnography with esophageal manometry and pH monitoring. The first half of the night was spent without CPAP and the second half with 10 cmH(2)O CPAP. RESULTS: Baseline LES barrier pressure (P (b)) was low in these patients. When patients were off CPAP, there were 2.7 +/- 1.8 nocturnal GER events per hour and 70 +/- 39 obstructive respiratory events per hour. There was no direct relationship between the occurrence of GER and obstructive events. While upper airway obstruction did not alter P (b), CPAP tended to increase the nadir P (b) during LES relaxation (LESR) and decreased the duration of LESR. CONCLUSIONS: Upper airway obstructive and nocturnal GER events are not directly related. The relatively low P (b) in these OSA patients raises the possibility of weakening of the gastroesophageal junction from repetitive strain associated with obstructed breathing events. The favourable effect of CPAP on nocturnal GER is possibly due to an increase in nadir P (b) and decrease in the duration for which the LES relaxes during swallow-induced and transient LESR. PMID- 20711682 TI - Efficacy of allicin in decreasing lead (Pb) accumulation in selected tissues of lead-exposed common carp (Cyprinus carpio). AB - The objective of this study was to evaluate the effects of allicin, the main biologically active component of garlic clove extracts, on lead levels in different common carp tissues including liver, kidney, brain, bone, and blood following experimental lead poisoning. Fish were divided randomly into five groups depending on the combination of lead acetate and allicin treatments. Lead acetate exposure (7.0 mgL(-1), 10 days) caused a significant increase in mean Pb concentrations in all examined tissues in comparison to control unexposed fish (p < 0. 001). The results showed that allicin supplementation is effective in decreasing lead accumulation in all examined tissues of common carp. The promising ameliorative effects of allicin on tissue lead levels of common carp make it a good candidate for therapeutic intervention of lead poisoning. However, more studies are required to elucidate the pharmacokinetic effects of allicin and also molecular basis of the ameliorative properties of allicin in lead poisoning. PMID- 20711684 TI - Gene expression of neuropilin-1 and its receptors, VEGF/Semaphorin 3a, in normal and cancer cells. AB - Extracellular domains of the transmembrane glycoprotein, neuropilin-1 (Np1), specifically bind an array of factors and co-receptors including class-3 semaphorins (Sema3a), vascular endothelial growth factor (VEGF), hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor-beta 1 (TGF-beta1), and fibroblast growth factor2 (FGF2). Np1 may have a role in immune response, tumor cell growth, and angiogenesis, but its relative expression in comparison to its co-primary receptors, VEGF and Sema3a, is not known. In this study we determined the mRNA expression of Np1 and its co-receptors, VEGF and Sema3a, and the ratio of VEGF/Sema3a in different human and rodent cell lines. Expression of Np1, VEGF and Sema3a is very low in cells derived from normal tissues, but these proteins are highly expressed in tumor-derived cells. Furthermore, the ratio of VEGF/Sema3a is highly variable in different tumor cells. The elevated mRNA expression of Np1 and its putative receptors in tumor cells suggests a role for these proteins in tumor cell migration and angiogenesis. As different tumor cells exhibit varying VEGF/Sema3a ratios, it appears that cancer cells show differential response to angiogenic factors. These results bring to light the individual variation among the cancer-related genes, Np1, VEGF, and Sema3a, and provide an important impetus for the possible personalized therapeutic approaches for cancer patients. PMID- 20711683 TI - Effect of diets supplemented with different levels of manganese, zinc, and copper from their organic or inorganic sources on egg production and quality characteristics in laying hens. AB - This experiment was conducted to evaluate the effect of zinc, manganese, and copper sources (inorganic vs. organic) in the diet on laying performance and eggshell quality characteristics. One hundred and eighty Hy-Line W-36 layers at 38 weeks of age were allocated to 36-layer cages of five hens each. Each six cages were randomly assigned to one of the six experimental diets fed from 38 to 53 week of age. In three experimental treatments, the basal diet was supplemented with 65-75-7 or 65-75-7 or 40-40-7 mg/kg of Zn, Mn, and Cu, respectively, from their oxide or sulfate sources. Three other groups were fed diets supplemented with 20-20-3.5 or 40-40-7.5 or 60-60-10.5 mg/kg of organic forms of Zn, Mn, and Cu, respectively. Dietary treatments significantly did affect feed intake (P < 0.001), feed conversion ratio (P < 0.001) and percentage of broken eggs (P < 0.05). Substitution of Zn and Mn oxides (65 and 75 mg kg(-1), respectively) with equal amounts of their sulfate forms significantly improved feed intake, feed conversion ratio, percentage of broken eggs, and Haugh Unit (P < 0.05). In addition, laying hens maintained their performance when substitution of Zn and Mn oxides and Cu sulfate (65, 75, and 7 mg kg(-1), respectively) reduced up to 20, 20, and 3.5 mg kg(-1) by amino acid complexes of the microelements. The results showed that a corn-soybean diet supplemented with the organic forms of Zn, Mn, and Cu at a dosage 50% to 75% lower than NRC recommendation is sufficient to maintain laying performance and can improve eggshell and albumen qualities of the egg in laying hens. PMID- 20711685 TI - Clinical grading scales in intracerebral hemorrhage. PMID- 20711686 TI - Severe craniofacial trauma and foreign bodies (teeth) in tracheobronchial tree. PMID- 20711687 TI - Decompressive craniectomy for acute disseminated encephalomyelitis. AB - BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a rare, acute demyelinating condition. Although it usually presents in an acute or subacute manner over days, its clinical course may be rapid with symptoms and signs of severe intracerebral mass effect secondary to cerebral oedema. METHODS: Case report and literature review. RESULTS: We report a case of a patient presenting with a hyperacute course manifested by rapid loss of consciousness and focal neurological signs. Management with emergency hemicraniectomy and steroids resulted in rapid neurological improvement and minimal long-term deficit. CONCLUSIONS: We believe that only surgical decompression is likely to be life saving in similar cases of hyperacute cerebral oedema due to ADEM. The wide decompression performed was concordant with that indicated for traumatic brain swelling. Such aggressive management is vindicated by the rapid recovery shown by our patient within days of surgery and the finding of minimal neurological sequelae at 3 months. PMID- 20711688 TI - A 67-year-old woman with BRCA 1 mutation associated with pancreatic adenocarcinoma. AB - INTRODUCTION: There are approximately 40,000 new cases of pancreatic adenocarcinoma diagnosed in the USA each year. It is estimated that 5-10% of all patients with pancreatic cancer have a first-degree relative with the disease, while up to 20% of cases have a hereditary component. Individuals who carry a germline mutation in the BRCA 1 or 2 genes have an increased lifetime risk of developing pancreatic adenocarcinoma when compared with the general population. CASE REPORT: Here, we present a case of metastatic pancreatic adenocarcinoma arising in a 67-year-old carrier of a BRCA 1 germline mutation. DISCUSSION: In patients with known BRCA 1 or 2 mutation-associated pancreatic adenocarcinoma, the addition of a DNA cross-linking agent such as cisplatin, oxaliplatin, or mitomycin to a standard gemcitabine chemotherapy backbone should be considered. Poly ADP-ribose inhibitors are a novel class of drug, which have demonstrated promising efficacy in trials of BRCA 1 and 2 mutant breast and ovarian cancer, and are currently undergoing prospective evaluation in advanced pancreatic cancer. PMID- 20711689 TI - Human embryonic stem cell-extracts inhibit the differentiation and function of monocyte-derived dendritic cells. AB - Embryonic stem cells (ESC) possess inherent properties of immune privilege with the capacity to evade allogeneic immune responses. Moreover, ESCs have been shown to prevent immune activation in response to third party antigen presenting cells in vitro and have the capacity to promote allograft survival in vivo. However, clinical use of human ESCs to treat immunological disorders may risk teratoma or ectopic tissue formation. Here, we show that cellular extracts from both human and mouse ESCs retain the immune modulatory properties of intact cells. ESC extracts that contained 12-24 MUg of total protein effectively prevented T cell proliferation in allogeneic mixed lymphocyte reactions (MLR), whereas control fibroblast extracts did not affect proliferation. Cellular mechanisms underlying hESC extract-mediated immune modulation involve the maturation of monocyte derived dendritic cells (mDC). hESC extract-treated mDCs had reduced surface expression of co-stimulatory and maturation markers CD80, HLA-DR and CD83 and secreted lower levels of IL12p40. Accordingly, hESC extract-treated DCs were found to be poor stimulators of purified allogeneic T cells compared to those DCs treated with vehicle or fibroblast extracts. Our results demonstrate that ESC extracts retain the immune modulatory properties of ESCs and for the first time demonstrates that ESC derived factors can inhibit human mDC maturation and function. PMID- 20711690 TI - ROCK inhibitor Y-27632 increases thaw-survival rates and preserves stemness and differentiation potential of human Wharton's jelly stem cells after cryopreservation. AB - The ROCK inhibitor Y-27632 inhibits apoptosis and increases proliferation of frozen-thawed cells. We examined the role of Y-27632 on human umbilical cord Wharton's jelly stem cells (hWJSCs) for (1) thaw-survival (2) proliferation and (3) preservation of stemness and differentiation potential after cryopreservation. hWJSCs were allotted to 4 groups [Gp I: Untreated hWJSC controls; Gp II: Pretreatment with Y-27632 (10 MUM) for 24 h before freezing; Gp III: Y-27632 (10 MUM) in freezing medium and Gp IV: Pretreatment with Y-27632 (10 MUM) for 24 h and inclusion in freezing medium]. All groups were frozen using a rapid freezing method and stored at -196 degrees C in liquid nitrogen for 90 days before evaluation for apoptosis, cell proliferation, stemness and differentiation. After thawing, Groups II, III and IV showed improved cell attachment, increased thaw-survival (live/dead cell counts) and increased cell proliferation (Trypan blue and MTT assay) compared to controls. CD marker stemness profiles, morphology and normal karyotypes were maintained in the treatment groups after thawing and there was no obvious evidence of apoptosis (Annexin V-FITC and TUNEL assays). After thawing, qRT-PCR demonstrated up regulation of the anti-apoptotic BCL2 gene and down-regulation of the pro apoptotic BAX gene and cell cycle regulators (P53 and P21) in the treatment groups. Treated frozen-thawed hWJSCs from all groups differentiated into a neuronal phenotype (neuronal morphology and expression of GFAP, beta-3 tubulin and SOX2). Increased thaw-survival and retention of stemness and differentiation potential in hWJSCs following cryopreservation is useful for their storage in cord blood banks for future regenerative medicine purposes. PMID- 20711691 TI - A review of conduction aphasia. AB - In this paper, a historical overview of the interpretation of conduction aphasia is initially presented. It is emphasized that the name conduction aphasia was proposed by Wernicke and was interpreted as a disconnection between the temporal and frontal brain language areas; this interpretation was re-taken by Geschwind, attributing the arcuate fasciculus the main role in speech repetition disturbances and resulting in the so-called Wernicke-Geschwind model of language. With the introduction of contemporary neuroimaging techniques, this interpretation of conduction aphasia as a disconnection syndrome due to an impairment of the arcuate fasciculus has been challenged. It has been disclosed that the arcuate fasciculus does not really connect Wernicke's and Broca's areas, but Wernicke's and motor/premotor frontal areas. Furthermore, conduction aphasia can be found in cases of cortical damage without subcortical extension. It is concluded that conduction aphasia remains a controversial topic not only from the theoretic point of view, but also from the understanding of its neurologic foundations. PMID- 20711692 TI - Does rasagiline have a disease-modifying effect on Parkinson's disease? PMID- 20711693 TI - Saturated fatty acids and risk of coronary heart disease: modulation by replacement nutrients. AB - Despite the well-established observation that substitution of saturated fats for carbohydrates or unsaturated fats increases low-density lipoprotein (LDL) cholesterol in humans and animal models, the relationship of saturated fat intake to risk for atherosclerotic cardiovascular disease in humans remains controversial. A critical question is what macronutrient should be used to replace saturated fat. Substituting polyunsaturated fat for saturated fat reduces LDL cholesterol and the total cholesterol to high-density lipoprotein cholesterol ratio. However, replacement of saturated fat by carbohydrates, particularly refined carbohydrates and added sugars, increases levels of triglyceride and small LDL particles and reduces high-density lipoprotein cholesterol, effects that are of particular concern in the context of the increased prevalence of obesity and insulin resistance. Epidemiologic studies and randomized clinical trials have provided consistent evidence that replacing saturated fat with polyunsaturated fat, but not carbohydrates, is beneficial for coronary heart disease. Therefore, dietary recommendations should emphasize substitution of polyunsaturated fat and minimally processed grains for saturated fat. PMID- 20711694 TI - Mast cells. AB - Mast cells have been considered for many years to participate specifically in allergic reactions through the release of cytokines, chemokines, proteases, leukotrienes, and bioactive polyamines. Emerging roles for mast cells have been identified recently, which highlight their relevance in both innate and adaptive immunity. Mast cells play a role in many different processes, including clearance of enteric pathogens, food allergies, visceral hypersensitivity, and intestinal cancer. The activation of mast cells can initiate inflammatory reactions that are life-saving in some circumstances (eg, nematode infection) but life-threatening in others (eg, allergy). In recent years, mast cells, their products, and the mechanisms by which mast cell activity can be regulated by the microenvironment are a major area of investigation. The purpose of this review article is to summarize and highlight the latest findings in mast cell biology associated with intestinal homeostasis and pathologies. PMID- 20711695 TI - Physical properties of gum karaya-starch-essential oil patches. AB - Essential oils are used in foods, cosmetics, and pharmaceuticals. Despite the recent marketing of novel essential-oil-containing patches, there is no information on their production, constituents, or physical properties. The objectives of this study were to produce essential-oil patches and characterize their physical properties. The essential oil of Lavandula angustifolia (lavender) was included at concentrations of 2.5% to 10% in patches manufactured from the exudate gum karaya, propylene glycol, glycerol, emulsifier, and optionally, potato starch as filler. Inclusion of essential oil reduced patch strength, stiffness, and elasticity relative to patches without essential oil. Inclusion of starch in the essential-oil patches strengthened them, but reduced their elasticity. Patches' adhesion to substrate was examined by both peeling and probe tack tests: the higher the inclusion of essential oils within the patch, the larger the decrease in its adhesion to substrate. Addition of starch to essential oil-containing patches increased their adhesion relative to their essential-oil only counterparts. Scanning electron micrographs of the patches provided evidence of entrapped starch granules. Although inclusion of essential oil reduced both the mechanical properties and adhesion of the patches, a high proportion of essential oil can still be included without losing patch integrity or eliminating its adhesiveness to the skin. PMID- 20711697 TI - Implant design influences tibial post wear damage in posterior-stabilized knees. AB - BACKGROUND: The tibial post in posterior-stabilized total knees is a potential source of polyethylene wear debris, but the relationship between the shape and location of the tibial post in relation to the tibiofemoral bearing surfaces and the subsequent wear damage patterns remains unknown. QUESTIONS/PURPOSES: We used observations made on retrieved implant components from three contemporary posterior-stabilized knee designs to examine how differences in tibial post design affected wear damage on the post. METHODS: We examined 113 retrieved Zimmer NexGen((r)), 103 Exactech Optetrak((r)), and 58 Smith and Nephew Genesis((r)) II posterior-stabilized inserts using a subjective scale to grade post damage. RESULTS: All 274 inserts demonstrated wear damage. Total wear scores and scores for wear damage on the anterior post differed among designs: Optetrak((r)) 20 +/- 4 and 5 +/- 1, NexGen((r)) 13 +/- 4 and 3 +/- 1, and Genesis((r)) II 8 +/- 3 and 1 +/- 1, respectively. The Optetrak((r)) had predominantly anterior wear damage, the NexGen((r)) had more global wear damage, and the Genesis((r)) II had predominantly posterior wear damage. Tibial post wear damage and anterior post wear damage were primarily determined by implant design and to a lesser extent by length of implantation and revision diagnosis. CONCLUSIONS: Although tibial post wear damage is multifactorial, the primary determinant of wear damage, and specifically anterior wear damage, is implant design. CLINICAL RELEVANCE: The constraint provided by the posterior-stabilized post-cam contact in modern knee arthroplasties is reflected in the wear damage patterns that occur during in vivo use. Unintended constraint such as anterior impingement should be addressed through design modifications for future posterior stabilized knee arthroplasties. PMID- 20711698 TI - Excess thyroid hormone inhibits embryonic neural stem/progenitor cells proliferation and maintenance through STAT3 signalling pathway. AB - Hyperthyroidism is prevalent during pregnancy, but little is known about the effects of excess thyroid hormone on the development of embryonic neural stem/progenitor cells (NSCs), and the mechanisms underlying these effects. Previous studies indicate that STAT3 plays a crucial role in determining NSC fate during neurodevelopment. In this study, we investigated the effects of a supraphysiological dose of 3,5,3'-L-triiodothyronine (T3) on the proliferation and maintenance of NSCs derived from embryonic day 13.5 mouse neocortex, and the involvement of STAT3 in this process. Our results suggest that excess T3 treatment inhibits NSC proliferation and maintenance. T3 decreased tyrosine phosphorylation of JAK1, JAK2 and STAT3, and subsequently inhibited STAT3-DNA binding activity. Furthermore, proliferation and maintenance of NSCs were decreased by inhibitors of JAKs and STAT3, indicating that the STAT3 signalling pathway is involved in the process of NSC proliferation and maintenance. Taken together, these results suggest that the STAT3 signalling pathway is involved in the process of T3-induced inhibition of embryonic NSC proliferation and maintenance. These findings provide data for understanding the effects of hyperthyroidism during pregnancy on fetal brain development, and the mechanisms underlying these effects. PMID- 20711699 TI - Minocycline prevents morphine-induced apoptosis in rat cerebral cortex and lumbar spinal cord: a possible mechanism for attenuating morphine tolerance. AB - Tolerance to the chronic administration of opioids such as morphine reduces the utility of these drugs in pain management. Despite significant investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. It has been indicated that tolerance to the analgesic effect of morphine is associated with apoptosis in the central nervous system. The aim of this study was to examine the effects of the intracerebroventricular (icv) administration of minocycline (a second-generation tetracycline) on morphine-induced apoptosis in the cerebral cortex and lumbar spinal cord of rats after morphine-induced tolerance. Different groups of rats received either morphine (ip) and distilled water (icv) or morphine and different doses of minocycline (icv) or minocycline alone once per day. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method was used to analyze apoptosis. The anti-apoptotic factors, Bcl-2 and HSP 70 and the pro-apoptotic element caspase-3 were evaluated by immunoblotting. The results indicated that minocycline attenuated the number of apoptotic cells in both the cerebral cortex and lumbar spinal cord. Immunoblotting findings showed that the amounts of anti-apoptotic agents (Bcl-2 and HSP 70) were greater in the treatment groups than in the controls in both regions. Although minocycline did not change the level of caspase-3 at the doses used with morphine but the minocycline treated rats showed a significantly lower increase in caspase-3 activity than did in the control. In conclusion, minocycline decreased the number of TUNEL-positive cells and increased the amount of anti-apoptotic factors (Bcl-2 and HSP 70), but did not change the caspase-3 content. PMID- 20711701 TI - A bird's view on cell biology. PMID- 20711700 TI - Overexpression of chromokinesin KIF4 inhibits proliferation of human gastric carcinoma cells both in vitro and in vivo. AB - Gastric carcinoma is a common type of malignant tumors and is associated with high death rates. The pathogenesis of gastric carcinoma is still unclear, and increasing evidence shows that many factors contribute to this process. Chromokinesin KIF4 is involved in multiple critical cellular processes. Recently, it has become apparent that KIF4 plays a crucial suppressive role in tumorigenesis. However, the role of KIF4 in human gastric cancer is still unclear. In this study, we examined expression profiles of KIF4 in gastric carcinoma specimens and generated gastric cancer cells that stably express GFP KIF4 fusion protein (designated as BGC-GFP-KIF4 cells) followed by cell proliferation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and soft agar colony-formation assays. Simultaneously, we further examined the capability of tumor formation of BGC-GFP-KIF4 cells in nude mice. The results showed that among 23 gastric carcinoma specimens, 13 cases (56.6%) had lower expression of KIF4 compared with corresponding adjacent tissues. In addition, there was a significant correlation between low expression of KIF4 and poor differentiation of tumor (P = 0.024). Overexpression of KIF4 in BGC cells inhibited cell proliferation in vitro, as well as their ability to form tumors in vivo. Our findings suggest that human chromokinesin KIF4 functions as an inhibitor of gastric cancer cell proliferation and might serve as a novel biological target to cure human gastric carcinoma. PMID- 20711702 TI - Relationship of BRCA1 and BRCA2 mutations with cancer burden in the family and tumor incidence. AB - The aim of the present study is to analyze the relationship of the incidence of mutations in the two major genes BRCA1 and BRCA2 conferring risk of breast cancer (BC) and ovarian cancer (OC) with the cancer burden in families and with the presence and age of onset of BC/OC. We included 704 index patients (IP) and 668 family members of the IP who tested positive for BRCA1/BRCA2 who were studied in the Program of Genetic Counselling in Cancer of the Valencia Community (Spain). We found 129 IPs with deleterious mutations (18.3%), 59 in BRCA1 and 70 in BRCA2, detecting 396 mutations in this kindred. The incidence of mutations and their distribution between BRCA1 and BRCA2 showed a significantly uneven incidence among the family groups (P < 0.001). We found 179 tumors in the 396 mutation carriers (45%) and detected only 11 cancers among the 272 non-mutation carriers (P < 0.001). No differences in the tumor prevalence or the age of onset of cancer between the genes among the mutation carriers were found. The mutation carriers showed a 50% probability of having BC/OC at a median age of 49 years (95% CI 46 52 years) and 78% at the age of 70 years (95% CI: 71-85%). In conclusion the family burden of BC and OC is strongly associated with the incidence of BRCAs mutations and could foretell which of the two BRCAs genes is more likely to have mutations. Mutation carriers have a 50% risk of having BC/OC by the age of 50 years. PMID- 20711703 TI - The case for complement and inflammation in AMD: open questions. AB - The complement cascade has been identified as a key factor in the pathogenesis of age-related macular degeneration (AMD). As a result, pharmacological modulation of the complement cascade is being investigated as a therapeutic strategy for AMD. The genetic data point to a triggering of the complement cascade, which subsequently cannot be damped down. Despite promising genetic, preclinical and immunolabeling data, important questions remain to be answered regarding the role of complement in the pathogenesis of AMD. The involvement of the complement cascade in the vision threatening stages of AMD, e.g. geographic atrophy and choroidal neovascularization, remain unknown. Additionally, the optimal component(s) of the complement cascade to be targeted for modulation still need to be identified. Answering these and other questions will provide investigators with a clear framework with which to evaluate progress in the field and help guide the development of future clinical therapeutics. PMID- 20711704 TI - The role of complement in AMD. AB - Age related macular degeneration (AMD) is a common form of blindness in the western world and genetic variations of several complement genes, including the complement regulator Factor H, the central complement component C3, Factor B, C2, and also Factor I confer a risk for the disease. However deletion of a chromosomal segment in the Factor H gene cluster on human chromosome 1, which results in the deficiency of the terminal pathway regulator CFHR1, and of the putative complement regulator CFHR3 has a protective effect for development of AMD. The Factor H gene encodes two proteins Factor H and FHL1 which are derived from alternatively processed transcripts. In particular a sequence variation at position 402 of both Factor H and FHL1 is associated with a risk for AMD. A tyrosine residue at position 402 represents the protective and a histidine residue the risk variant. AMD is considered a chronic inflammatory disease, which can be caused by defective and inappropriate regulation of the continuously activated alternative complement pathway. This activation generates complement effector products and inflammatory mediators that stimulate further inflammatory reactions. Defective regulation can lead to formation of immune deposits, drusen and ultimately translate into damage of retinal pigment epithelial cells, rupture of the interface between these epithelial cells and the Bruch's membrane and vision loss. Here we describe the role of complement in the retina and summarize the current concept how defective or inappropriate local complement control contributes to inflammation and the pathophysiology of AMD. PMID- 20711705 TI - Multiple interactions of complement Factor H with its ligands in solution: a progress report. AB - Factor H (FH) is the major regulator of the central complement protein C3b in the alternative pathway of complement activation, and is comprised of 20 SCR domains. A FH Tyr402His polymorphism in SCR-7 is associated with age-related macular degeneration (AMD) and leads to deposition of complement in drusen. The unravelling of how FH interacts with five major physiological and patho physiological ligands is complicated by the weak nature of these interactions, coupled with the multivalency of FH. Using multiple biophysical methods, we summarise our recent results for these five FH ligands: (1) FH by itself shows a folded-back SCR domain structure in solution, and self-associates in a manner dependent on electrostatic forces. (2) FH activity is inhibited by zinc, which causes FH to aggregate. The onset of FH-zinc aggregation for zinc concentrations above 20 muM appears to be enhanced with the His402 allotype, and may be relevant to AMD. (3) The FH and C-reactive protein (CRP) interaction has been controversial; however our new work resolves earlier discrepancies. The FH-CRP interaction is only observed when native CRP is at high acute-phase concentration levels, and CRP binds weakly to the His402 FH allotype to suggest a molecular mechanism that leads to AMD. (4) Heparin is an analogue of the polyanionic host cell surface, and FH forms higher oligomers with larger heparin fragments, suggesting a mechanism for more effective FH regulation. (5) The interaction of C3b with FH also depends on buffer, and FH forms multimers with the C3d fragment of C3b. This FH-C3d interaction at high FH concentration may also facilitate complement regulation. Overall, our results to date suggest that the FH interactions involving zinc and native CRP have the closest relevance for explaining the onset of AMD. PMID- 20711706 TI - Genetic control of complement activation in humans and age related macular degeneration. AB - The major focus of our research is to understand how age-related macular degeneration (AMD) develops. It is known that genetic variation can explain much of the risk of developing AMD. However, we do not know what controls the transition between a normal fundus and the extensive accumulation of subretinal inflammatory material that we recognize as drusen in AMD. We do know that the accumulation of this inflammatory material that characterizes the maculopathy underlying AMD is by far the most important predictor of late AMD. Late or advanced forms of AMD include geographic atrophy in which there is patchy death of the retina and exudation in which abnormal neovascularization invades the subretinal or subretinal pigment epithelial space. Thus, preventing the accumulation of the inflammatory debris underneath the retina could be expected to alleviate much of the vision loss from this devastating disease. PMID- 20711707 TI - Bisretinoids of RPE lipofuscin: trigger for complement activation in age-related macular degeneration. AB - Genetic association studies and investigations of the constituents of subretinal deposits (drusen) have implicated complement dysregulation as one factor predisposing individuals to increased risk of age-related macular degeneration (AMD). Here we review evidence that molecular fragments released by photooxidation of the bisretinoids of retinal pigment epithelial lipofuscin, can activate complement. Complement activation by this mechanism is dependent on the alternative pathway. The diretinal conjugates comprising RPE lipofuscin accumulate in the cells throughout the lifetime of an individual. As such, these photooxidative processes, in a setting of complement dysregulation could contribute to chronic inflammation underlying AMD pathogenesis. PMID- 20711708 TI - The role of the classical complement cascade in synapse loss during development and glaucoma. AB - Glaucoma is one of the leading causes of vision loss worldwide, yet the signals that initiate the progressive degeneration of optic nerve axons and the selective loss of retinal ganglion neurons (RGCs) remain elusive. Reactive gliosis, release of inflammatory cytokines, and complement upregulation all occur in the early stages of glaucoma in several disease models. Recent work has implicated the classical complement cascade in the elimination of excess synaptic connections in the developing visual system and in early synapse loss associated with glaucoma, suggesting that mechanisms of developmental synapse elimination may be aberrantly re-activated in glaucoma. This review describes current evidence in support of this "synaptic" hypothesis and places complement in the context of other well described mechanisms of neurodegeneration occurring in the glaucomatous eye. PMID- 20711709 TI - A role for complement in glaucoma? AB - Chronic open angle glaucoma is a degenerative optic neuropathy that can lead to blindness. We have shown that one of the major genes with altered expression in the glaucomatous retina is complement component C1q in both animal models of the disease as well as in humans. These observations together with evidence of upregulation of other complement components within the retina suggest a role for complement in the pathogenesis of this disease. We review the current evidence that supports such a role and discuss possible mechanisms through which complement may act. A thorough understanding of these mechanisms is important in allowing us to rationally design new therapeutic approaches. PMID- 20711711 TI - Suppression of drusen formation by compstatin, a peptide inhibitor of complement C3 activation, on cynomolgus monkey with early-onset macular degeneration. AB - For the past 10 years, number of evidence has shown that activation of complement cascade has been associated with age-related macular degeneration (AMD). The genome wide association study in American population with dominantly dry-type AMD has revealed strong association with single nucleotide polymorphism (SNP) of complement genes. Protein composition of drusen, a deposit observed in sub retinal space between Bruch's membrane and retinal pigment epithelial (RPE), contains active complement molecules in human and monkey. These evidences have leaded us to consider the possibility of suppressing complement cascade in the retina to delay or reverse the onset of AMD. To test is hypothesis we used the C3 inhibitor Compstatin on primate model with early-onset macular degeneration which develop drusen in less than 2 years after birth. Our preliminary result showed drusen disappearance after 6 months of intravitreal injection. PMID- 20711710 TI - The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. AB - ATP-binding cassette transporters (ABC transporters) utilize the energy of ATP hydrolysis to translocate an unusually diverse set of substrates across cellular membranes. ABCA4, also known as ABCR, is a approximately 250 kDa single-chain ABC transporter localized to the disk margins of vertebrate photoreceptor outer segments. It is composed of two symmetrically organized halves, each comprising six membrane-spanning helices, a large glycosylated exocytoplasmic domain located inside the disk, and a cytoplasmic domain with an ATP-binding cassette. Hundreds of mutations in ABCA4 are known to cause impaired vision and blindness such as in Stargardt disease as well as related disorders. Biochemical and animal model studies in combination with patient analyses suggest that the natural substrate of ABCA4 is retinylidene-phosphatidylethanolamine (N-retinylidene-PE), a precursor of potentially toxic diretinal compounds. ABCA4 prevents accumulation of N-retinylidene-PE inside the disks by transporting it to the cytoplasmic side of the disk membrane where it can dissociate, allowing the released all-trans retinal to enter the visual cycle. The pathogenesis of diseases caused by mutations in ABCA4 is complex, comprising a loss-of-function component as well as photoreceptor stress caused by protein mislocalization and misfolding. PMID- 20711713 TI - Complement depletion with humanized cobra venom factor in a mouse model of age related macular degeneration. AB - The effect of complement depletion with humanized cobra venom factor (CVF) on retinal lesion development/neovascularization was determined in a mouse model of wet age-related macular degeneration (AMD). Mice were treated with the humanized CVF protein HC3-1496 prior to, and once daily for 28 days after laser coagulation surgery of the retina. CVF transgenic mice exhibiting permanently low levels of serum complement activity and PBS-treated mice served as positive and negative controls, respectively. Fluorescein isothiocyanate (FITC)-dextran funduscopy after laser surgery indicated the presence of lesions in all mice that underwent laser surgery. In HC3-1496-treated mice as well as CVF transgenic mice smaller lesions were seen after 8 days. Measurement of lesion sizes by histopathological examination of eyes after 28 days revealed a significant reduction of lesion area and volume in both HC3-1496-treated animals and CVF transgenic animals compared to PBS-treated control animals. Systemic complement depletion with a complement depletor, such as the humanized CVF protein HC3-1496, represents a promising therapeutic concept for patients with wet AMD. PMID- 20711712 TI - A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration. AB - Genetic variations in complement factor H (fH), an inhibitor of the complement alternative pathway (CAP), and oxidative stress are associated with age-related macular degeneration (AMD). Recently, novel complement therapeutics have been created with the capacity to be "targeted" to sites of complement activation. One example is our recombinant form of fH, CR2-fH, which consists of the N-terminus of mouse fH that contains the CAP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. CR2-fH was investigated in vivo in the mouse model of choroidal neovascularization (CNV) and in vitro in oxidatively stressed RPE cell monolayers. RPE deterioration and CNV development were found to require CAP activation, and specific CAP inhibition by CR2-fH reduced the loss of RPE integrity and angiogenesis in CNV. In both the in vivo and in vitro paradigm of RPE damage, a model requiring molecular events known to be involved in AMD, complement-dependent VEGF production, was confirmed. These data may open new avenues for AMD treatment strategies. PMID- 20711714 TI - Multidrug therapy in a patient with Rabson-Mendenhall syndrome. PMID- 20711715 TI - Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment. AB - AIMS/HYPOTHESIS: The value of managing children with type 1 diabetes using a combination of insulin pump and continuous glucose monitoring starting from diagnosis for improving subsequent glycaemic control and preserving residual beta cell function was determined. METHODS: A total of 160 children (aged 1-16 years, mean +/- SD: 8.7 +/- 4.4 years; 47.5% girls) were randomised to receive insulin pump treatment with continuous glucose monitoring or conventional self-monitoring blood glucose measurements. The primary outcome was the level of HbA(1c) after 12 months. Other analyses included fasting C-peptide, glycaemic variability, sensor usage, adverse events, children's health-related quality of life and parent's wellbeing. RESULTS: HbA(1c) was not significantly different between the two groups, but patients with regular sensor use had lower values (mean 7.1%, 95% CI 6.8-7.4%) compared with the combined group with no or low sensor usage (mean 7.6%, 95% CI 7.3-7.9%; p=0.032). At 12 months, glycaemic variability was lower in the sensor group (mean amplitude of glycaemic excursions 80.2 +/- 26.2 vs 92.0 +/ 33.7; p=0.037). Higher C-peptide concentrations were seen in sensor-treated 12- to 16-year-old patients (0.25 +/- 0.12 nmol/l) compared with those treated with insulin pump alone (0.19 +/- 0.07 nmol/l; p=0.033). Severe hypoglycaemia was reported only in the group without sensors (four episodes). CONCLUSION/INTERPRETATION: Sensor-augmented pump therapy starting from the diagnosis of type 1 diabetes can be associated with less decline in fasting C peptide particularly in older children, although regular sensor use is a prerequisite for improved glycaemic control. TRIAL REGISTRATION: ISRCTN.org ISRCTN05450731 FUNDING: Medtronic International Trading Sarl, Tolochenaz, Switzerland. PMID- 20711716 TI - Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. AB - AIMS/HYPOTHESIS: An earlier meta-analysis showed that diabetes is a risk factor for the development and/or recurrence of depression. Yet whether this risk is different for studies using questionnaires than for those relying on diagnostic criteria for depression has not been examined. This study examined the association of diabetes and the onset of depression by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. METHODS: EMBASE, MEDLINE and PsycInfo were searched for articles published up to September 2009. All studies that examined the relationship between type 2 diabetes and the onset of depression were included. Pooled relative risks were calculated using fixed and random effects models. RESULTS: Eleven studies met our inclusion criteria for this meta-analysis. Based on the pooled data, including 48,808 cases of type 2 diabetes without depression at baseline, the pooled relative risk was 1.24 (95% CI 1.09-1.40) for the random effects model. This risk was significantly higher for studies relying on diagnostic criteria of depression than for studies using questionnaires. However, this difference was no longer significant when controlled for year of publication. CONCLUSIONS/INTERPRETATION: Compared with non diabetic controls, people with type 2 diabetes have a 24% increased risk of developing depression. The mechanisms underlying this relationship are still unclear and warrant further research. PMID- 20711717 TI - Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: an analysis of 15,780 patients from the INTERHEART study. AB - AIMS/HYPOTHESIS: Although diabetes is an established risk factor for myocardial infarction (MI), disease control may vary. HbA(1c) is a reliable index of ambient glucose levels and may provide more information on MI risk than diabetes status. METHODS: The relationship between HbA(1c) levels in MI patients and controls who participated in the 52 country INTERHEART study was analysed. RESULTS: In 15,780 participants with a HbA(1c) value (1,993 of whom had diabetes), the mean (SD) levels for HbA(1c) were 6.15% (1.10) in the 6,761 MI patients and 5.85% (0.80) in the control participants. After adjustment for age, sex and nine major MI risk factors (including diabetes), higher HbA(1c) fifths above the lowest fifth (HbA(1c) <5.4%) were associated with progressively higher OR of MI, with OR for the highest HbA(1c) fifth (>= 6.12%) being 1.55 (95% CI 1.37-1.75). When analysed as a continuous variable after adjustment for the same factors, every 1% higher HbA(1c) value was associated with 19% (95% CI 14-23) higher odds of MI, while every 0.5% higher HbA(1c) was associated with 9% higher odds of MI (95% CI 7-11). Concordant relationships were noted across subgroups, with a higher OR noted in younger people, patients without diabetes or hypertension, and those from some regions and ethnicities. CONCLUSIONS/INTERPRETATION: The HbA(1c) value provides more information on MI odds than self-reported diabetes status or many other established risk factors. Every 1% increment independently predicts a 19% higher odds of MI after accounting for other MI risk factors including diabetes. PMID- 20711718 TI - A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus. AB - AIMS/HYPOTHESIS: Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end stage renal disease (ESRD). METHODS: In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria >= 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. RESULTS: The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). CONCLUSIONS/INTERPRETATION: CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements. PMID- 20711719 TI - Effects of water cadmium concentrations on bioaccumulation and various oxidative stress parameters in Rhamdia quelen. AB - The effects of sublethal cadmium concentrations on oxidative stress parameters were evaluated in Rhamdia quelen. The fish were exposed to 0.44, 236, and 414 MUg l-1 cadmium for 7 and 14 days, followed by the same time periods for recovery. Enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione S transferase (GST), and indicators of oxidative stress, such as thiobarbituric acid-reactive species (TBARS) and protein carbonyl, were verified in fish tissues. In addition, the accumulation of cadmium was evaluated in these tissues. Our results indicate that CAT and GST levels decreased in gills after exposure periods associated with increased TBARS levels. In hepatic tissue, CAT, GST, TBARS, and protein carbonyl levels increased after 7 days of exposure, whereas SOD activity decreased after exposure for 14 days. In the kidney, TBARS levels decreased after exposure for 7 days and increased after exposure for 14 days. During the recovery periods, some variations persisted in gills, liver, and kidney. Cadmium accumulation was most significant in liver, followed by kidney and gills. These results indicate that cadmium concentrations studied invoke a stress response in silver catfish. PMID- 20711720 TI - In vivo and in vitro effects of metals in reactive oxygen species production, protein carbonylation, and DNA damage in land snails Eobania vermiculata. AB - Heavy metals are known to induce oxidative damage by way of enhancement of intracellular reactive oxygen species (ROS) production, which often preludes the onset of alterations, such as protein carbonylation and DNA damage. In this study, our aim was to examine the early responses of land snails Eobania vermiculata to environmental contaminants by investigating the use of a modified enzyme-linked immunosorbent assay (ELISA) assay for the measurement of protein carbonylation as a new biomarker of terrestrial pollution as well as by measuring ROS production and DNA damage. Land snails were treated with heavy metals cadmium, lead, or copper-in vivo (15 or 40 ppm) for 25 days or in vitro (0.5, 5, 50 or 500 MUM) for 30 min in the laboratory, and the previously mentioned biomarkers were determined in digestive gland and haemolymph of the treated animals. A statistically significant increase in ROS production, protein carbonylation, and DNA damage was shown in the snails treated with pollutants compared with the untreated snails. The results indicate the effectiveness of measuring ROS production and DNA damage, as well as using the present ELISA method, as sensitive tools of terrestrial pollution biomonitoring studies. Statistically significant correlations among the previously mentioned techniques further enhance their role as promising biomarkers in terrestrial pollution studies. PMID- 20711721 TI - The effect of cadmium on steroid hormones and their receptors in women with uterine myomas. AB - Cadmium (Cd) is one of the environmental metalloestrogens, and its role in uterine tissues has not yet been fully elucidated. The aim of the study was to investigate estrogenic properties of Cd in uterine tissues by analyzing the expression of estrogen receptor (ER) and progesterone receptor (PR) as well as estrogen and progesterone levels in serum and Cd concentrations in blood and tissues. The samples of tissues (leiomyoma and surrounding myometrium) collected intrasurgically and blood samples drawn from 53 women (age 39 to 52 years) with uterine myomas were thoroughly analyzed. In the study group, blood Cd concentration ranged from 0.33 to 3.5 MUg/L. Cd concentration in leiomyoma tissues was twice as low [corrected] as that in surrounding myometrium (0.047 and 0.075 MUg Cd/g [corrected] wet tissue, respectively), albeit the difference was not statistically significant. Cd concentrations in blood significantly correlated with Cd concentrations in tissues (leiomyoma and surrounding myometrium). The measurement of ER expression showed no difference between leiomyoma tissues and surrounding myometrium. The statistical analysis showed a significant correlation between ER expression and Cd concentration in both tissues under study. An additional statistical analysis (path analysis) demonstrated the correlation of uterine tissue levels of Cd and ER expression. However, there was no association between ER expression in both tissues and E(2) level in serum. Our results suggest a metalloestrogenic effect of Cd by way of ER stimulation in the uterus. PMID- 20711724 TI - Associations between coinfection prevalence of Borrelia lusitaniae, Anaplasma sp., and Rickettsia sp. in hard ticks feeding on reptile hosts. AB - An increasing number of studies reveal that ticks and their hosts are infected with multiple pathogens, suggesting that coinfection might be frequent for both vectors and wild reservoir hosts. Whereas the examination of associations between coinfecting pathogen agents in natural host-vector-pathogen systems is a prerequisite for a better understanding of disease maintenance and transmission, the associations between pathogens within vectors or hosts are seldom explicitly examined. We examined the prevalence of pathogen agents and the patterns of associations between them under natural conditions, using a previously unexamined host-vector-pathogen system--green lizards Lacerta viridis, hard ticks Ixodes ricinus, and Borrelia, Anaplasma, and Rickettsia pathogens. We found that immature ticks infesting a temperate lizard species in Central Europe were infected with multiple pathogens. Considering I. ricinus nymphs and larvae, the prevalence of Anaplasma, Borrelia, and Rickettsia was 13.1% and 8.7%, 12.8% and 1.3%, and 4.5% and 2.7%, respectively. The patterns of pathogen prevalence and observed coinfection rates suggest that the risk of tick infection with one pathogen is not independent of other pathogens. Our results indicate that Anaplasma can play a role in suppressing the transmission of Borrelia to tick vectors. Overall, however, positive effects of Borrelia on Anaplasma seem to prevail as judged by higher-than-expected Borrelia-Anaplasma coinfection rates. PMID- 20711725 TI - Ipsilateral fractures of the femoral neck, shaft and distal end: long-term outcome of five cases. AB - Out of 52 cases of ipsilateral femoral fractures treated at a level I trauma centre between June 1994 and March 2008, the diaphyseal fracture was accompanied by a intracapsular neck fracture in only 20 cases. In the rest of the cases, the diaphyseal fracture was combined with either an extracapsular or pertrochanteric fracture. Five of these patients also had fractures of the distal femur. In three of those patients we began treatment with osteosynthesis of the femoral neck and shaft, using a reconstruction nail, then stabilized the distal fracture with a 95 degrees blade plate or with lag screws. In the other two cases, initial treatment dealt with the distal femoral fracture, stabilizing it with a 95 degrees blade plate, which was also used for stabilization of the diaphyseal fracture. In these patients, the proximal fracture was treated using dynamic hip screws (DHS). All fractures healed, two after initial treatment, while the other three needed one reoperation. The follow-up period was 2-13 years after the injury. The order in which fractures are treated is best left to the discretion of the physician and the circumstances. In our experience, two implants are sufficient for osteosynthesis, one for stabilizing one end of the femur together with the shaft, and the other is used for treating the other end of the femur. PMID- 20711726 TI - Computed tomographic angiography of the superior sagittal sinus and bridging veins. AB - PURPOSE: The primary aim of our paper was to describe typical anatomical patterns of the superior sagittal sinus (SSS) and bridging veins (BV) using cerebral venous computed tomographic angiography (CTA) with a focus on the direction of the BV entering the SSS. METHODS: We retrospectively analyzed venous CTA of 30 patients to estimate the total number and direction of the BV entering the SSS. Maximum intensive projections were analyzed for length, diameter and cross sectional area of the SSS. RESULTS: Thee hundred and fifty-four BV were assessed. The mean total length of the SSS was 25.6 +/- 1.6 cm (mean +/- 1 SD). The mean horizontal diameter at the level of the coronary suture was 6.7 +/- 2.0 mm, and the mean vertical diameter at the coronary suture measured 5.3 +/- 1.8 mm. Most BV emptied into the SSS, at the level of or distal to the coronary suture (74%). The BV draining into the SSS at the level of the coronary suture typically joined into a lacunar formation (43%). Veins draining into the sinus more than 3 cm distal from the coronary suture presented a predominantly retrograde inflow direction (77%). CONCLUSIONS: Despite large variations in the location and course of BV, typical anatomical patterns were noted especially in relation to the direction of BV entering the SSS. The present anatomical analysis of the cerebral convexity veins by cerebral venous CTA provides an overview of the configuration of these veins which is useful information in neurosurgical preoperative planning. PMID- 20711727 TI - Large 3' UTR of sugar beet rps3 is truncated in cytoplasmic male-sterile mitochondria. AB - Genomic alteration near or within mitochondrial gene is often associated with cytoplasmic male sterility (CMS). Its influence on the expression of the mitochondrial gene was proposed as one of the possible causes of CMS. In sugar beet mitochondrial rps3, whose downstream 1,056-bp region contains Norf246, an apparently non-functional open reading frame (ORF), was deleted in CMS mitochondria. In our previous study, normal rps3 (3.8 kb), CMS rps3 (2.7 kb), and Norf246 (3.8 and 0.9 kb) were shown to be transcribed. The present study was conducted to determine whether the deletion affected gene expression. Reverse transcription (RT)-PCR analysis revealed the co-transcription of rps3 and Norf246. By circularized RNA (CR) RT-PCR analysis, the 5' and 3' termini of the 3.8- and the 0.9-kb transcripts were determined. The results suggested that the 3.8-kb transcripts were the rps3 mRNA bearing ~464-base 5' untranslated region (UTR) and ~1,508-base 3' UTR, whereas no functional ORF was observed in the 0.9 kb transcripts. CR-RT-PCR revealed that the 3' UTR of the 2.7-kb transcripts was reduced to ~460 bases. However, no difference in the accumulation of RPS3 polypeptide and RNA editing was detected by protein gel blot analysis and cDNA sequencing. Although the deleted region encoded the truncated-atp9 that was edited, no influence on the pattern and frequency of RNA editing of genuine atp9 was evident. The results eliminated rps3 as a candidate for the CMS gene, making preSatp6, a unique ORF fused with CMS atp6, the sole CMS-associated region in sugar beet. PMID- 20711728 TI - An embryogenic suspension cell culture system for Agrobacterium-mediated transformation of citrus. AB - A method for the genetic transformation of several citrus cultivars is described, including cultivars observed to be recalcitrant to conventional epicotyl-mediated transformation. Embryogenic cell suspension cultures, established from unfertilized ovules were used as target tissues for Agrobacterium-mediated transformation. Several modifications were made to the culture environment to investigate factors required for efficient transfer of the T-DNA and the subsequent regeneration of transgenic citrus plants. It was determined that co cultivation of citrus cells and Agrobacterium in EME medium supplemented with maltose (EME-M) and 100 MUM acetosyringone for 5 days at 25 degrees C was optimum for transformation of each of the citrus cultivars. Efficient selection was obtained and escapes were prevented when the antibiotic hygromycin B was used as a selection antibiotic following transformation with an Agrobacterium strain containing hptII in the T-DNA region. Transgenic embryo regeneration and development was enhanced in medium that contained a liquid overlay consisting of a 1:2 mixture of 0.6 M BH3 and 0.15 M EME-M media. PCR and Southern blot analyses confirmed the presence of the T-DNA and the stable integration into the genome of regenerated plants, while RT-PCR demonstrated variable amounts of RNA being transcribed in different transgenic lines. This protocol can create an avenue for insertion of useful traits into any polyembryonic citrus cultivar that can be established as embryogenic cell suspension cultures, including popular specialty mandarins and seedless cultivars. PMID- 20711729 TI - CT colonography and transient bacteraemia: implications for antibiotic prophylaxis. AB - OBJECTIVES: To determine the prevalence of transient bacteraemia after CT colonography (CTC). METHODS: Blood cultures were obtained at 5, 10 and 15 min after CTC from 100 consecutive consenting patients. Blood samples were cultured in both aerobic and anaerobic media and positive blood culture samples were analysed by a microbiologist. RESULTS: Blood culture samples were positive for growth in sixteen patients. All positive blood culture samples were confirmed skin contaminants. There were no cases of significant bacteraemia. The estimated significant bacteraemia rate as a result of CTC is 0-3.7%, based on 95% confidence intervals around extreme results using Wilson's score method. CONCLUSIONS: American Heart Association and National Institute for Clinical Excellence guidelines advise that antibiotic prophylaxis before lower gastrointestinal endoscopy is not indicated in patients with at risk cardiac lesions (ARCL) as the risk of a transient bacteraemia leading to infective endocarditis is low. These data show that the prevalence of transient bacteraemia after CTC is also low. It follows that patients with ARCL do not require antibiotic prophylaxis before CTC. PMID- 20711730 TI - Optimized intravenous Flat Detector CT for non-invasive visualization of intracranial stents: first results. AB - OBJECTIVE: As stents for treating intracranial atherosclerotic stenosis may develop in-stent re-stenosis (ISR) in up to 30%, follow-up imaging is mandatory. Residual stenosis (RS) is not rare. We evaluated an optimised Flat Detector CT protocol with intravenous contrast material application (i.v. FD-CTA) for non invasive follow-up. METHODS: In 12 patients with intracranial stents, follow-up imaging was performed using i.v. FD-CTA. MPR, subtracted MIP and VRT reconstructions were used to correlate to intra-arterial angiography (DSA). Two neuroradiologists evaluated the images in anonymous consensus reading and calculated the ISR or RS. Correlation coefficients and a Wilcoxon test were used for statistical analysis. RESULTS: In 4 patients, no stenosis was detected. In 6 patients RS and in two cases ISR by intima hyperplasia perfectly visible on MPR reconstructions of i.v. FD-CTA were detected. Wilcoxon's test showed no significant differences between the methods (p > 0.05). We found a high correlation with coefficients of the pairs DSA/ FD-CT MIP r = 0.91, DSA/ FD-CT MPR r = 0.82 and FD-CT MIP/ FD-CT MPR r = 0.8. CONCLUSION: Intravenous FD-CTA could clearly visualise the stent and the lumen, allowing ISR or RS to be recognised. FD-CTA provides a non-invasive depiction of intracranial stents and might replace DSA for non-invasive follow-up imaging. PMID- 20711731 TI - Clinical value of a combined multi-phase contrast enhanced DOPA-PET/CT in neuroendocrine tumours with emphasis on the diagnostic CT component. AB - OBJECTIVE: To assess the clinical value of multi-phase, contrast-enhanced DOPA PET/CT with emphasis on the diagnostic CT component in patients with neuroendocrine tumours (NET). METHODS: Sixty-five patients with NET underwent DOPA-cePET/CT. The DOPA-PET, multi-phase CT and combined DOPA cePET/CT data were evaluated and diagnostic accuracies compared. The value of ceCT in DOPA cePET/CT concerning lesion detection and therapeutic impact was evaluated. Sensitivities, specificities and accuracies were calculated. Histopathology and clinical follow up served as the standard of reference. Differences were tested for statistical significance by McNemar's test. RESULTS: In 40 patients metastatic and/or primary tumour lesions were detected. Lesion-based analysis for the DOPA-PET showed sensitivity, specificity and accuracy of 66%, 100% and 67%, for the ceCT data 85%, 71% and 85%, and for the combined DOPA cePET/CT data 97%, 71% and 96%. DOPA cePET/CT was significantly more accurate compared with dual-phase CT (p < 0.05) and PET alone (p < 0.05). Additional lesion detection was based on ceCT in 12 patients; three patients underwent significant therapeutic changes based on the ceCT findings. CONCLUSION: DOPA cePET/CT was significantly more accurate than DOPA-PET alone and ceCT alone. The CT component itself had a diagnostic impact in a small percentage but contributed to the therapeutic strategies in selected patients. PMID- 20711732 TI - Ascending colon rotation following patient positional change during CT colonography: a potential pitfall in interpretation. AB - OBJECTIVE: To investigate the degree and pattern of ascending colonic rotation as patients moved from supine to prone positions during CTC. METHODS: A search of our CTC and colonoscopy database found 37 patients (43 eligible lesions) who fulfilled the following criteria: colonoscopy-proven sessile polyps >= 6 mm in the straight mid-ascending colon, lesion visualisation in both supine and prone CTC, and optimal colonic distension. A coordinate system was developed to designate the polyp radial location ( degrees ) along the luminal circumference, unaffected by rotation of the torso. The degree/direction of polyp radial location change (i.e. ascending colonic rotation) between supine and prone positions correlated with anthropometric measurements. RESULTS: Movement from supine to prone positions resulted in a change in the radial polyp location of between -23 degrees and 79 degrees (median, 21 degrees ), demonstrating external rotation of the ascending colon in almost all cases (2 degrees to 79 degrees in 36/37 patients and 42/43 lesions). The degree/direction of rotation mildly correlated with the degree of abdominal compression in the anterior posterior direction in prone position (r = 0.427 [P = 0.004] and r = 0.404 [P = 0.007]). CONCLUSION: The ascending colon was usually found to rotate externally as patients moved from supine to prone positions, partly dependent on the degree of abdominal compression. PMID- 20711733 TI - Dual-energy CT with tin filter technology for the discrimination of renal lesion proxies containing blood, protein, and contrast-agent. An experimental phantom study. AB - PURPOSE: To differentiate proxy renal cystic lesions containing protein, blood, iodine contrast or saline solutions using dual-energy CT (DECT) equipped with a new tin filter technology (TFT). MATERIALS AND METHODS: 70 proxies (saline, protein, blood and contrast agent) were placed in unenhanced and contrast enhanced kidney phantoms. DECT was performed at 80/140 kV with and without tin filtering. Two readers measured the CT attenuation values in all proxies twice. An 80/140 kV ratio was calculated. RESULTS: All intra- and interobserver agreements were excellent (r = 0.93-0.97; p < 0.001). All CT attenuation values were significantly higher in the enhanced than in the unenhanced setting (p < 0.05; average increase, 12.5 +/- 3.6 HU), while the ratios remained similar (each, p > 0.05). The CT attenuation of protein, blood and contrast agent solution differed significantly with tin filtering (p < 0.01-0.05). Significant differences were found between the ratios of protein and blood compared to contrast medium solution (each, p < 0.05) and between the ratios of protein and blood in both phantoms with tin filtering (each, p < 0.05). CONCLUSION: DECT allows discrimination between a proxy renal lesion containing contrast agent and lesions containing protein and blood through their different attenuation at 80 kV and 140 kV. Further discrimination between protein and blood containing proxies is possible when using a tin filter. PMID- 20711734 TI - Optimising diffusion-weighted imaging in the abdomen and pelvis: comparison of image quality between monopolar and bipolar single-shot spin-echo echo-planar sequences. AB - OBJECTIVE: To compare geometric distortion, signal-to-noise ratio (SNR), apparent diffusion coefficient (ADC), efficacy of fat suppression and presence of artefact between monopolar (Stejskal and Tanner) and bipolar (twice-refocused, eddy current-compensating) diffusion-weighted imaging (DWI) sequences in the abdomen and pelvis. MATERIALS AND METHODS: A semiquantitative distortion index (DI) was derived from the subtraction images with b = 0 and 1,000 s/mm(2) in a phantom and compared between the two sequences. Seven subjects were imaged with both sequences using four b values (0, 600, 900 and 1,050 s/mm(2)) and SNR, ADC for different organs and fat-to-muscle signal ratio (FMR) were compared. Image quality was evaluated by two radiologists on a 5-point scale. RESULTS: DI was improved in the bipolar sequence, indicating less geometric distortion. SNR was significantly lower for all tissues and b values in the bipolar images compared with the monopolar (p < 0.05), whereas FMR was not statistically different. ADC in liver, kidney and sacrum was higher in the bipolar scheme compared to the monopolar (p < 0.03), whereas in muscle it was lower (p = 0.018). Image quality scores were higher for the bipolar sequence (p <= 0.025). CONCLUSION: Artefact reduction makes the bipolar DWI sequence preferable in abdominopelvic applications, although the trade-off in SNR may compromise ADC measurements in muscle. PMID- 20711737 TI - Surgical treatment concepts for patients with pancreatic cancer in Germany- results from a national survey conducted among members of the "Chirurgische Arbeitsgemeinschaft Onkologie" (CAO) and the "Arbeitsgemeinschaft Internistische Onkologie" (AIO) of the Germany Cancer Society (DKG). AB - BACKGROUND: To date, only limited data are available regarding the routine surgical management of patients with exocrine pancreatic cancer (PC) in German community and university hospitals. METHODS: With the use of a standardized questionnaire, a national survey on surgical and oncological treatment concepts for PC in Germany was conducted on behalf of the Chirurgische Arbeitsgemeinschaft Onkologie and Arbeitsgemeinschaft Internistische Onkologie. The surgical part of that questionnaire contained 25 questions on criteria regarding resectability, surgical techniques, perioperative patient management, and palliative surgical procedures in advanced PC. Data were collected centrally and analyzed using the SPSS((r)) software. Additionally, predefined subgroup analyses, classifying the results by the professional site of the responding physician and the local annual number of treated patients, were carried out. RESULTS: One-hundred and two questionnaires on the surgical survey section were returned. For the majority of the survey respondents, arterial infiltration is the most important criterion for non-resectability of PC (common hepatic artery, 69.9%; superior mesenteric artery, 85.3%; celiac trunk, 86.3%), whereas only 17.6% would define non resectability based on portal vein infiltration; 69.9% consider extrapancreatic tumor manifestations as a criterion of surgical non-resectability. Of the survey participants, 53.9% perform a biliary drainage in case of preoperative cholestasis, whereas 43.1% reject this preoperative endoscopic-interventional approach. For cancers of the pancreatic head, 24.5% of surgical units recommend a classical Kausch-Whipple procedure, 52.9% prefer the pylorus-preserving partial pancreatoduodenectomy, and 20.6% use both procedures; 74.5% routinely perform a standard lymphadenectomy, whereas 16.7% prefer an extended procedure. A radical pancreatic resection would be performed by 63.7% of survey respondents also if a single liver metastasis would be found intraoperatively. CONCLUSION: Surgical treatment of PC in Germany is heterogeneous; future efforts to implement an evidence-based and standardized surgical management will be necessary. PMID- 20711735 TI - BNP controls early load-dependent regulation of SERCA through calcineurin. AB - Heart failure is characterised by reduced expression of sarcoplasmic reticulum calcium-ATPase (SERCA) and increased expression of B-type natriuretic peptide (BNP). The present study was performed to investigate causality of this inverse relationship under in vivo conditions in the transversal aortic constriction mouse model (TAC). Left ventricular SERCA-mRNA expression was significantly upregulated in TAC by 32% after 6 h, but not different from sham after 24 h. Serum proANP and BNP levels were increased in TAC after 24 h (BNP +274%, p < 0.01; proANP +60%, p < 0.05), but only proANP levels were increased after 6 h (+182%, p < 0.01). cGMP levels were only increased 24 h after TAC (+307%, p < 0.01), but not 6 h after TAC. BNP infusion inhibited the increase in SERCA expression 6 h after TAC. In BNP-receptor-knockout animals (GC-A), the expression of SERCA was still significantly increased 24 h after TAC at the mRNA level by 35% (p < 0.05), as well as at the protein level by 25% (p < 0.05). MCIP expression as an indicator of calcineurin activity was regulated in parallel to SERCA after 6 and 24 h. MCIP-mRNA was increased by 333% 6 h after TAC, but not significantly different from sham after 24 h. In the GC-A-KO mice, MCIP-mRNA was significantly increased in TAC compared to WT after 24 h. In mice with BNP infusion, MCIP was significantly lower 6 h after TAC compared to control animals. In conclusion, mechanical load leads to an upregulation of SERCA expression. This is followed by upregulation of natriuretic peptides with subsequent suppression of SERCA upregulation. Elevated natriuretic peptides may suppress SERCA expression by inhibition of calcineurin activity via activation of GC-A. PMID- 20711738 TI - No association between the SNPs (rs3749446 and rs1402000) in the PARL gene and LHON in Chinese patients with m.11778G>A. AB - According to a recent genome-wide linkage scan and association study of families with m.11778G>A in Thailand, two single nucleotide polymorphisms (SNPs) (rs3749446 and rs1402000) in the presenilins-associated rhomboid-like (PARL) gene were found to be associated with Leber hereditary optic neuropathy (LHON). In order to verify this association in Chinese LHON patients, we genotyped three PARL gene variants (rs3749446, rs953419, and rs1402000) in 179 patients with m.11778G>A and 170 patients with suspected LHON, and compared them to a control population containing the HapMap Chinese and 58 normal individuals analyzed in this study. We identified no association between these PARL gene SNPs and LHON in Chinese patients with m.11778G>A (P>0.05). Haplotype analysis also showed no statistical difference among the three Chinese populations. PMID- 20711739 TI - Acute glomerulonephritis and acute kidney injury associated with 2009 influenza A:H1N1 in an infant. PMID- 20711741 TI - Complete nucleotide sequence of the envelope gene of pseudocowpox virus isolates from Indian dromedaries (Camelus dromedarius). PMID- 20711740 TI - Pediatric urinary tract infections: an analysis of hospitalizations, charges, and costs in the USA. AB - This study evaluates the impact of pediatric urinary tract infection (UTI)s on the economy and inpatient healthcare utilization in the USA. A retrospective analysis of patient demographics and hospital economics was performed on children less than 18 years of age admitted with a UTI between 2000 and 2006 using the Healthcare Cost and Utilization Project Kids' Inpatient Database. Our results were stratified as follows. Hospital admissions-nearly 50,000 children/year were admitted with a UTI. Pediatric UTIs represented 1.8% of all pediatric hospitalizations. Seventy-three percent of patients were female and 40% were under 1 year of age. Payer information-from 2000 to 2006, pediatric insurance coverage shifted from the private sector to the public sector. Hospital cost-in 2000, estimated hospital costs for UTIs were $2,858 per hospitalization and rose to $3,838 by 2006. Mean hospital charges increased from $6,279 to $10,489 per stay. By 2006, aggregate hospital charges exceeded $520 million. Our results indicate that UTIs are among the most common pediatric admission diagnoses. Hospitalization is more common in females and younger children. Since 2000, hospital charges for UTIs increased disproportionately to hospital costs. Over time, more children hospitalized with a UTI depend on public agencies to cover healthcare expense. More efforts are needed to evaluate cost-effective strategies for evaluation and treatment of UTIs. PMID- 20711743 TI - Stromal optical properties: differentiating normal and cancerous stroma. AB - This work reports on the measurement of optical properties from nine normal and cancerous human esophageal stroma pairs using reflectance-based confocal microscopy. It was found that the scattering coefficient of cancerous stroma is significantly lower than that of normal stroma. The results suggest that the decreased scattering in cancerous stroma may provide a possible indicator for differentiating normal and cancerous stroma. PMID- 20711745 TI - Lattice-gas cellular automaton models for biology: from fluids to cells. AB - Lattice-gas cellular automaton (LGCA) and lattice Boltzmann (LB) models are promising models for studying emergent behaviour of transport and interaction processes in biological systems. In this chapter, we will emphasise the use of LGCA/LB models and the derivation and analysis of LGCA models ranging from the classical example dynamics of fluid flow to clotting phenomena in cerebral aneurysms and the invasion of tumour cells. PMID- 20711744 TI - Host age, sex, and reproductive seasonality affect nematode parasitism in wild Japanese macaques. AB - Parasites are characteristically aggregated within hosts, but identifying the mechanisms underlying such aggregation can be difficult in wildlife populations. We examined the influence of host age and sex over an annual cycle on the eggs per gram of feces (EPG) of nematode parasites infecting wild Japanese macaques (Macaca fuscata yakui) on Yakushima Island. Five species of nematode were recorded from 434 fecal samples collected from an age-structured group of 50 individually recognizable macaques. All parasites exhibited aggregated EPG distributions. The age-infection profiles of all three directly transmitted species (Oesophagostomum aculeatum, Strongyloides fuelleborni, and Trichuris trichiura) exhibited convex curves, but concavity better characterized the age infection curves of the two trophically transmitted species (Streptopharagus pigmentatus and Gongylonema pulchrum). There was a male bias in EPG and prevalence of infection with directly transmitted species, except in the prevalence of O. aculeatum, and no sex bias in the other parasites. Infection with O. aculeatum showed a female bias in prevalence among young adults, and additional interactions with sex and seasonality show higher EPG values in males during the mating season (fall) but in females during the birth season (spring). These patterns suggest that an immunosuppressive role by reproductive hormones may be regulating direct, but not indirect, life-cycle parasites. Exposure at an early age may trigger an immune response that affects all nematodes, but trophically transmitted species appear to accumulate thereafter. Although it is difficult to discern clear mechanistic explanations for parasite distributions in wildlife populations, it is critical to begin examining these patterns in host species that are increasingly endangered by anthropogenic threats. PMID- 20711746 TI - Fungal delignification of lignocellulosic biomass improves the saccharification of cellulosics. AB - The biological delignification of lignocellulosic feedstocks, Prosopis juliflora and Lantana camara was carried out with Pycnoporus cinnabarinus, a white rot fungus, at different scales under solid-state fermentation (SSF) and the fungal treated substrates were evaluated for their acid and enzymatic saccharification. The fungal fermentation at 10.0 g substrate level optimally delignified the P. juliflora by 11.89% and L. camara by 8.36%, and enriched their holocellulose content by 3.32 and 4.87%, respectively, after 15 days. The fungal delignification when scaled up from 10.0 g to 75.0, 200.0 and 500.0 g substrate level, the fungus degraded about 7.69-10.08% lignin in P. juliflora and 6.89 7.31% in L. camara, and eventually enhanced the holocellulose content by 2.90 3.97 and 4.25-4.61%, respectively. Furthermore, when the fungal fermented L. camara and P. juliflora was hydrolysed with dilute sulphuric acid, the sugar release was increased by 21.4-42.4% and the phenolics content in hydrolysate was decreased by 18.46 and 19.88%, as compared to the unfermented substrate acid hydrolysis, respectively. The reduction of phenolics in acid hydrolysates of fungal treated substrates decreased the amount of detoxifying material (activated charcoal) by 25.0-33.0% as compared to the amount required to reduce almost the same level of phenolics from unfermented substrate hydrolysates. Moreover, an increment of 21.1-25.1% sugar release was obtained when fungal treated substrates were enzymatically hydrolysed as compared to the hydrolysis of unfermented substrates. This study clearly shows that fungal delignification holds potential in utilizing plant residues for the production of sugars and biofuels. PMID- 20711747 TI - Degradation of fluoranthene by a newly isolated strain of Herbaspirillum chlorophenolicum from activated sludge. AB - A fluoranthene-degrading bacterial strain FA1 was isolated from activated sludge and identified as Herbaspirillum chlorophenolicum, a newfound bacterial species that can grow well on fluoranthene as sole carbon and energy source. The kinetic characteristic of strain FA1 was tested in the aqueous model system (AMS) and the effects of nonionic surfactants on fluoranthene biodegradation in the AMS were then investigated. Tween 80 exhibited the best solubilization capacity for fluoranthene among three surfactants and its bioavailability decreased with an increase in its concentration and its degradation kinetics fit well with the first-order of power index model. The biotransformation of fluoranthene was greatly improved by Tween 80, and 58.5% fluoranthene degradation was obtained as Tween 80 was 100 mg/l. However, the bioavailability of fluoranthene decreased gradually with the increase of Tween 80 concentration. Bioremediation tests for fluoranthene in soil-water system were designed further to examine the degrading ability of strain FA1 with the presence of indigenous flora or not. The measurements showed that in the presence of indigenous flora, the optimum 30-day fluoranthene degradation in soil-water system reached 77.4%. Evidently, strain FA1 seems both efficient and high-effective and deserves further exploration on the enhanced bioremediation technologies for the treatment of fluoranthene polluted soil. PMID- 20711748 TI - Reliability of inhibition models to correctly identify type of inhibition. AB - PURPOSE: Type of inhibition (e.g. competitive, noncompetitive) is frequently evaluated to understand transporter structure/function relationships, but reliability of nonlinear regression to correctly identify inhibition type has not been assessed. The purpose was to assess the ability of nonlinear regression to correctly identify inhibition type. METHODS: This aim was pursued through three objectives that compared the competitive, noncompetitive, and uncompetitive inhibition models to best fit simulated competitive and noncompetitive data. The first objective involved conventional inhibition data and entailed simulated data for the common situation where substrate concentration was fixed at a single level but inhibitor concentration varied. The second objective involved Dixon type data where both substrate and inhibitor concentrations varied. A third objective involved nonconventional inhibition data, where substrate concentration was varied and inhibitor was fixed at a single concentration. Experimental data were also examined. RESULTS: Nonlinear regression performed poorly in identifying the correct inhibition model for conventional inhibition data, but performed moderately well for Dixon-type data. Interestingly, nonlinear regression performed well for nonconventional inhibition data, particularly at higher inhibitor concentrations. Experimental data support simulation findings. CONCLUSIONS: Conventional inhibition data is a poor basis to determine inhibition type, while Dixon-type data affords modest success. Nonconventional inhibition data merits further consideration. PMID- 20711749 TI - Effect of donor-acceptor chromophores on photophysical properties of newly synthesized pyrazolo-pyrrolo-pyrimidines (PPP). AB - Novel pyrazolo-pyrrolo-pyrimidine (PPP) derivatives having remarkable photophysical properties are designed with the help of theoretical semiempirical calculations. These compounds then synthesized successfully and studied effect of substituents on its photophysical properties. PMID- 20711750 TI - New onset postural orthostatic tachycardia syndrome following ablation of AV node reentrant tachycardia. AB - BACKGROUND: Autonomic dysfunction presenting as inappropriate sinus tachycardia has been reported to occur following slow pathway ablation for atrioventricular node tachycardia. We report on a series of patients who developed new onset postural orthostatic tachycardia syndrome (POTS) following successful radiofrequency ablation of atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: The study was a retrospective analysis that was approved by our Institutional Review Board. Patients were identified from those seen at our Syncope and Autonomic Disorders Clinic. A total of six patients were identified who were previously healthy except for supraventricular tachycardia. Each was found to have AVNRT during electrophysiology study and each underwent successful radiofrequency modification of the slow atrioventricular nodal pathway. Following ablation each patient developed the new onset of symptoms of orthostatic intolerance consistent with POTS. RESULTS: After an initial symptom-free period (3-6 weeks) post ablation each patient began to experience symptoms of orthostatic intolerance. All six patients began to experience progressive severe fatigue. Orthostatic tachycardia was reported by five patients, syncope by three patients, and presyncope by all six patients. Each patient reported the occurrence of symptom while upright that were relieved by becoming supine. Each patient had experienced symptoms for greater than 6 months prior to being seen at our center. Three patients reported such severe symptoms of orthostatic tachycardia that they underwent repeat electrophysiology study; however, none had evidence of AVNRT. Each patient demonstrated a POTS response within the first 10 min of upright tilt with reproduction of their clinical symptoms that had occurred post ablation. CONCLUSION: POTS may be a complication of radiofrequency ablation of AVNRT. PMID- 20711751 TI - Tamoxifen decreases ovarian follicular loss from experimental toxicant DMBA and chemotherapy agents cyclophosphamide and doxorubicin in the rat. AB - INTRODUCTION: we serendipitously observed a protective effect of tamoxifen against depletion of ovarian follicles by 7,12-dimethylbenzanthracene (DMBA), a chemical carcinogen, during a cancer prevention study. Such ovarian protection is being sought as an alternative approach to fertility preservation in human cancer patients. METHODS: rats received tamoxifen (0, 1 mg or 2.5 mg/kg/d) and DMBA (0, 1, 2 mg/kg/wk) or cyclophosphamide (0, 35, 50 mg/kg/wk). Ovarian follicles were quantified and effects on fertility and litter size were tested. Cultured oocytes were exposed to chemotherapy drug doxorubicin, with or without 4-hydroxytamoxifen (4HT). RESULTS: DMBA and cyclophosphamide decreased the number of primordial and total follicles, and this reduction was prevented by tamoxifen. Cyclophosphamide tended to reduce fertility and lessened neonatal survival. Tamoxifen reversed these defects. Doxorubicin caused oocyte fragmentation which was prevented by 4HT. CONCLUSIONS: tamoxifen decreases follicle loss and improves reproductive function following exposure to ovarian toxicants including chemotherapy drugs in the female rat. PMID- 20711752 TI - Association between neuropeptide oxytocin and male infertility. AB - PURPOSE: To investigate the relationship between oxytocin (OT) and male infertility, serum OT baseline concentration and oxytocin receptor (OTR) gene expression in fertile and infertile men were investigated. METHODS AND PATIENTS: Twenty obstructive azoospermia patients, twenty five idiopathic asthenozoospermia patients, twenty idiopathic oligozoospermia patients and twenty healthy subjects were taken into consideration. Serum OT baseline concentration was determined by radioimmunoassay. Moreover, serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) were determined by chemoluminescence to evaluate the correlation with OT. OTR gene promotor and OTR mRNA expressions were determined by polymerase chain reaction and reverse transcriptase-polymerase chain reaction, respectively. OTR protein expression was also performed by Western Blot. RESULTS: Serum OT baseline concentrations in infertile groups were significantly higher than in fertile group (F0.05/2(2,82) = 8.29, p < 0.001). Serum baseline concentration of OT was not correlated with that of LH, FSH and T. There was no significant difference in gene sequences of OTR gene promotor and OTR mRNA when comparing infertile patients with fertile. Human OTR was in the form of oligomers and monomers, and the oligomers were in the majority containing tetramers and hexamers. Monomer expression was significantly higher in idiopathic asthenozoospermia and idiopathic oligozoospermia than that in obstructive azoospermia and control group (F0.05/2(2,82) = 115.50, p < 0.001). There was no significant difference in oligomer expression between different groups, but 20% of idiopathic asthenozoospermia cases showed a decrease. CONCLUSIONS: Significantly different OT baseline concentrations and OTR expressions between fertile and infertile men strongly suggest that OT/OTR system is likely to be linked with male infertility, providing new insights into the pathogenesis and treatment of male infertility. PMID- 20711753 TI - Nutritional value of sugarcane silage enriched with corn grain, urea, and minerals as feed supplement on growth performance of beef steers grazing stargrass. AB - The objectives were to evaluate the silage quality of sugarcane silage enriched (as fed) with corn grain ground (10%), urea (1.5%), and mineral premix (0.5%) and its effects as a feed supplement on growth performance of beef steers grazing stargrass. Firstly, in micro-silages, whole sugarcane enriched with corn grain, urea, and minerals (WSCE) were ensilaged by 0, 20, 40, and 60 days. Crude protein (CP) and lactic acid (LA) increased linearly (P < 0.05) and true protein decreased linearly (P < 0.05) as fermentation time increased. The pH values in silages were affected quadratically by fermentation time. Thus, after a 20-day fermentation, the pH values were below 4.5. Secondly, in micro-silos WSCE and stem sugarcane enriched with corn grain, urea, and minerals (SSCE) with and without calcium propionate were ensilaged by 30 days, but it did not affect any chemical composition trait in the silage. The SCCE silages had higher CP and LA and lower pH than WSCE silages. Finally, for 120 days, 20 beef steers (378 +/- 33 kg initial BW) grazing stargrass were supplemented (daily by 1-h free access) with WSCE silage. Supplemental silage increased total dry matter intake, total gain, and the average daily gain, without any affectation on feed conversion and total tract digestion of dry matter. It is concluded that whole sugarcane silage is an alternative feed supplement to improve growth performance in beef steers grazing stargrass. PMID- 20711755 TI - Mental health care and the politics of inclusion: a social systems account of psychiatric deinstitutionalization. AB - This paper provides an interpretation, based on the social systems theory of German sociologist Niklas Luhmann, of the recent paradigmatic shift of mental health care from an asylum-based model to a community-oriented network of services. The observed shift is described as the development of psychiatry as a function system of modern society and whose operative goal has moved from the medical and social management of a lower and marginalized group to the specialized medical and psychological care of the whole population. From this theoretical viewpoint, the wider deployment of the modern social order as a functionally differentiated system may be considered to be a consistent driving force for this process; it has made asylum psychiatry overly incompatible with prevailing social values (particularly with the normative and regulative principle of inclusion of all individuals in the different functional spheres of society and with the common patterns of participation in modern function systems) and has, in turn, required the availability of psychiatric care for a growing number of individuals. After presenting this account, some major challenges for the future of mental health care provision, such as the overburdening of services or the overt exclusion of a significant group of potential users, are identified and briefly discussed. PMID- 20711754 TI - Refinement of elastic, poroelastic, and osmotic tissue properties of intervertebral disks to analyze behavior in compression. AB - Intervertebral disks support compressive forces because of their elastic stiffness as well as the fluid pressures resulting from poroelasticity and the osmotic (swelling) effects. Analytical methods can quantify the relative contributions, but only if correct material properties are used. To identify appropriate tissue properties, an experimental study and finite element analytical simulation of poroelastic and osmotic behavior of intervertebral disks were combined to refine published values of disk and endplate properties to optimize model fit to experimental data. Experimentally, nine human intervertebral disks with adjacent hemi-vertebrae were immersed sequentially in saline baths having concentrations of 0.015, 0.15, and 1.5 M and the loss of compressive force at constant height (force relaxation) was recorded over several hours after equilibration to a 300-N compressive force. Amplitude and time constant terms in exponential force-time curve-fits for experimental and finite element analytical simulations were compared. These experiments and finite element analyses provided data dependent on poroelastic and osmotic properties of the disk tissues. The sensitivities of the model to alterations in tissue material properties were used to obtain refined values of five key material parameters. The relaxation of the force in the three bath concentrations was exponential in form, expressed as mean compressive force loss of 48.7, 55.0, and 140 N, respectively, with time constants of 1.73, 2.78, and 3.40 h. This behavior was analytically well represented by a model having poroelastic and osmotic tissue properties with published tissue properties adjusted by multiplying factors between 0.55 and 2.6. Force relaxation and time constants from the analytical simulations were most sensitive to values of fixed charge density and endplate porosity. PMID- 20711756 TI - Chemical constituents of the stems and twigs of Lindera umbellata. AB - The chemical constituents of the stems and twigs of Lindera umbellata were investigated, and a new lignan derivative and four known compounds were isolated. The structure of the new compound was established as (2S,3S)-2,3-bis[(4-hydroxy 3,5-dimethoxyphenyl)methyl]-1,4-butanediol 1,4-diferulate on the basis of spectroscopic analysis and the result of alkaline methanolysis. The isolated compounds were evaluated for their scavenging effects on 1,1-diphenyl-2 picrylhydrazyl and O(2) (-) radicals. PMID- 20711757 TI - Ectopic overexpression of orexin alters sleep/wakefulness states and muscle tone regulation during REM sleep in mice. AB - Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased orexinergic transmission tone, which might be important for understanding the effects of orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-orexin transgene driven by a beta actin/cytomegalovirus hybrid promoter (CAG/orexin transgenic mice). CAG/orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states. PMID- 20711758 TI - Hypertension in the elderly: what is the goal blood pressure target and how can this be attained? AB - For the aging populations of Europe, many emerging health problems in addition to myocardial infarction and stroke are associated with hypertension. Recently, the role of hypertension in the risk of vascular cognitive impairment and dementia has been highlighted, and there are studies to show that control of hypertension may slow this process. Furthermore, as many elderly individuals will also develop type 2 diabetes or impaired renal function, the risk of hypertension in these patients is more pronounced. New guidelines have tried to provide evidence-based treatment algorithms in which control of hypertension is just one aspect of general risk factor control, with the aim of decreasing the total risk. PMID- 20711759 TI - Backbone chemical shifts assignments of D-allose binding protein in the free form and in complex with D-allose. AB - D-allose binding protein (ALBP) belongs to the family of perisplamic receptors of the bacterial ABC transporter system. ALBP experiences a significant conformational rearrangement upon binding to the sugar. Here, we report the sequential backbone assignment for the ALBP from Escherichia coli in the free form (BMRB no. 16982) and in complex with D-allose (BMRB no. 16984). PMID- 20711760 TI - NMR assignments of 1H, 13C and 15N resonances of the C-terminal subunit from Azotobacter vinelandii mannuronan C5-epimerase 6 (AlgE6R3). AB - The 19.9 kDa C-terminal module (R3) from Azotobacter vinelandii mannronan C5 epimerase AlgE6 has been (13)C, (15)N isotopically labelled and recombinantly expressed. We report here the (1)H, (13)C, (15)N resonance assignment of AlgE6R3. PMID- 20711761 TI - 1H, 13C, and 15N chemical shift assignments of ZCCHC9. AB - ZCCHC9 is a human nuclear protein with sequence homology to yeast Air1p/Air2p proteins which are RNA-binding subunits of the Trf4/Air2/Mtr4 polyadenylation (TRAMP) complex involved in nuclear RNA quality control and degradation in yeast. The ZCCHC9 protein contains four retroviral-type zinc knuckle motifs. Here, we report the NMR spectral assignment of the zinc knuckle region of ZCCHC9. These data will allow performing NMR structural and RNA-binding studies of ZCCHC9 with the aim to investigate its role in the RNA quality control in human. PMID- 20711762 TI - Resonance assignment and secondary structure prediction of the N-terminal domain of hERG (Kv11.1). AB - The hERG (human ether-a-go-go related gene) channel is a member of the eag voltage-gated K(+) channel family. In common with other members of this family, it has a subunit topology of six trans-membrane helices that tetramerise to form a functional ion-channel. In addition, hERG has an N-terminal PAS (Per, Arnt and Sim) domain and a C-terminal cyclic nucleotide binding domain (cNBD). Both these cytosolic domains are involved in regulation of the gating of the ion channel as demonstrated by inheritable mutations in these domains that result in either a loss, or a gain, in function. Here we report near complete backbone and side chain (15)N, (13)C and (1)H assignments for the N-terminal domain (residues 1 135) including the functionally critical first 26 residues. Comparison with the secondary structure of the crystal structure (residues 26-135) suggests that the solution and crystal structures are very similar except that the solution structure contains an additional helix between residues 12-23; a region of the protein important for channel gating. PMID- 20711763 TI - Nonclinical dose formulation analysis method validation and sample analysis. AB - Nonclinical dose formulation analysis methods are used to confirm test article concentration and homogeneity in formulations and determine formulation stability in support of regulated nonclinical studies. There is currently no regulatory guidance for nonclinical dose formulation analysis method validation or sample analysis. Regulatory guidance for the validation of analytical procedures has been developed for drug product/formulation testing; however, verification of the formulation concentrations falls under the framework of GLP regulations (not GMP). The only current related regulatory guidance is the bioanalytical guidance for method validation. The fundamental parameters for bioanalysis and formulation analysis validations that overlap include: recovery, accuracy, precision, specificity, selectivity, carryover, sensitivity, and stability. Divergence in bioanalytical and drug product validations typically center around the acceptance criteria used. As the dose formulation samples are not true "unknowns", the concept of quality control samples that cover the entire range of the standard curve serving as the indication for the confidence in the data generated from the "unknown" study samples may not always be necessary. Also, the standard bioanalytical acceptance criteria may not be directly applicable, especially when the determined concentration does not match the target concentration. This paper attempts to reconcile the different practices being performed in the community and to provide recommendations of best practices and proposed acceptance criteria for nonclinical dose formulation method validation and sample analysis. PMID- 20711764 TI - Co-morbid PTSD and suicidality in individuals with schizophrenia and substance and alcohol abuse. AB - BACKGROUND: Suicide risk is high in schizophrenic patients and is further elevated in dual diagnosis patients. Suicide behaviour is a continuum from ideation, plans to attempts. Exposure to traumatic stress and co-morbid PTSD is elevated in schizophrenic patients. Suicide behaviour is also common in non psychotic PTSD patients. This study aimed to investigate the effect of trauma and co-morbid PTSD on suicide behaviour in dual diagnosis patients and whether co morbid PTSD would further elevate suicide risk. METHOD: This was a cross sectional study in which suicide behaviour was compared in those with and without co-morbid PTSD in 110 patients suffering schizophrenia and alcohol and/or substance abuse. RESULTS: 100 (91%) reported at least one traumatic event with an average of 4.3 events. 31 (28%) patients met criteria for full PTSD. Current suicidal ideation was reported by 39 (35%) and 23 (21%) reported plans and ideation, 69 (63%) reported at least one previous suicide attempt. Suicide behaviour was significantly associated with an increasing number of traumatic events. Suicidality was significantly associated and elevated with co-morbid PTSD. Analysis indicated that the effect of trauma on suicide behaviour appeared to be mediated by hopelessness. CONCLUSIONS: Suicide behaviour was not associated with exposure to trauma per se but was associated with incremental exposure to traumatic experiences. Consistent with the study hypotheses, co-morbid PTSD further adds to the risk of suicide behaviour in an already vulnerable group. PMID- 20711765 TI - Role of (-)-epigallocatechin-3-gallate in cell viability, lipogenesis, and retinol-binding protein 4 expression in adipocytes. AB - (-)-Epigallocatechin-3-gallate (EGCG), a bioactive compound of green tea, is known to combat obesity by reducing the viability and lipid accumulation of adipocytes. In this study, we evaluated the mechanism and clinical relevance on those actions of EGCG. We measured the viability of 3T3-L1 preadipocytes and adipocytes by the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide assay. Lipid accumulation was measured by Oil Red O staining. Intracellular accumulation of reactive oxygen species (ROS) was determined using a flow cytometer. Cellular glucose uptake was determined with 2-deoxy-[(3)H]-glucose. The protein levels of peroxisome proliferator-activated receptor (PPAR)-gamma and adiponectin in 3T3-L1 adipocytes, as well as the protein level and secretion of plasma retinol-binding protein (RBP4) in human adipocytes, were measured by western blot. EGCG at concentrations higher than 10 MUM induced ROS generation and decreased the viability and lipid accumulation of adipocytes. It also decreased the expression of PPAR-gamma and adiponectin. At concentrations readily achievable in human plasma via green tea intake (<=10 MUM), EGCG inhibited cellular glucose uptake and enhanced the expression and secretion of RBP4 in adipocytes. Pharmacological doses of EGCG showed cytotoxic effects in preadipocytes and adipocytes. EGCG-mediated glucose uptake inhibition in adipocytes may be clinically relevant and is probably linked to the increase in the expression and secretion of RBP4. Because secreted RBP4 from adipocytes inhibits muscular glucose uptake and enhance hepatic glucose output, the systemic effect of EGCG associated with its effect on RBP4 secretion should be further determined, as it may negatively regulate whole-body insulin sensitivity, contrary to general belief. PMID- 20711766 TI - Coelenterazine-v ligated to Ca2+-triggered coelenterazine-binding protein is a stable and efficient substrate of the red-shifted mutant of Renilla muelleri luciferase. AB - It has been shown that the coelenterazine analog, coelenterazine-v, is an efficient substrate for a reaction catalyzed by Renilla luciferase. The resulting bioluminescence emission maximum is shifted to a longer wavelength up to 40 nm, which allows the use of some "yellow" Renilla luciferase mutants for in vivo imaging. However, the utility of coelenterazine-v in small-animal imaging has been hampered by its instability in solution and in biological tissues. To overcome this drawback, we ligated coelenterazine-v to Ca(2+)-triggered coelenterazine-binding protein from Renilla muelleri, which apparently functions in the organism for stabilizing and protecting coelenterazine from oxidation. The coelenterazine-v bound within coelenterazine-binding protein has revealed a greater long-term stability at both 4 and 37 degrees C. In addition, the coelenterazine-binding protein ligated by coelenterazine-v yields twice the total light over free coelenterazine-v as a substrate for the red-shifted R. muelleri luciferase. These findings suggest the possibility for effective application of coelenterazine-v in various in vitro assays. PMID- 20711768 TI - ICP-MS for multiplex absolute determinations of proteins. AB - In the last few years MS-based proteomics has been turning quantitative because only the quantity of existing proteins or changes of their abundance in a studied sample reflect the actual status and the extent of possible changes in a given biological system. So far, however, only relative quantifications are common place. Recently, the ideal analytical features of ICP-MS that allow robust, accurate and precise absolute determinations of heteroelements (present in proteins and their peptides) have opened the door to its use, as a complementary ion source of MALDI- and/or ESI-(MS), in achieving the "absolute" quantification of a protein. Unfortunately, so far such "heteroatom-tagged proteomics" applications deal with only single-heteroatom measurements. Thus, the outstanding capability of ICP-MS for multi-element (-isotope) simultaneous determinations is somewhat wasted. On the other hand, multiplexed determinations of proteins (e.g. in common or new multiplexed formats) today constitute a pressing need in medical science (e.g. to determine accurately many biomarkers at a time). This is a clear trend in analytical science where ICP-MS could eventually play an important role. Therefore, reported approaches to multiplex protein determinations using ICP-MS, with liquid sample nebulisation and with laser direct sampling from a solid, are discussed here. Apart from such multiplex bioassays for absolute protein determinations, efforts to simultaneously quantitate enzyme activities are also discussed. It appears that the time is ripe to combine the multi-isotopic character of ICP-MS with well-known multi-analyte separation techniques (e.g. HPLC or multiplex immunoassays) to tackle the challenge of analysing abundances and activities of several proteins and enzymes, respectively, in a single assay. Many attractive opportunities for creative work and interdisciplinary developments for analytical atomic spectroscopists seem to lie ahead related to multiplexed quantitative targeted proteomics via ICP-MS. PMID- 20711769 TI - LC-MS analysis of low molecular weight organic acids derived from root exudation. AB - A sensitive method for quantification of citric, fumaric, malic, malonic, oxalic, trans aconitic, and succinic acid in soil- and root-related samples is presented. The method is based on a novel, fast, and simple esterification procedure and subsequent analysis via liquid chromatography-mass spectrometry. Derivatization comprises in situ generation of HCl, which catalyzes the Fischer esterification with benzyl alcohol. As a key advance, the esterification with the aromate allows reversed-phase separation and improves electrospray ionization efficiency. The method provided procedural detection limits of 1 nM for citric, 47 nM for fumaric, 10 nM for malic, 10 nM for malonic, 16 nM for oxalic, 15 nM for succinic, and 2 nM for aconitic acid utilizing 500 MUL of liquid sample. The working range was 3 nM to 10 MUM for citric acid, 158 nM to 10 MUM for fumaric acid, 34 nM to 10 MUM for malic acid, 33 nM to 10 MUM for malonic acid, 53 nM to 10 MUM for oxalic acid, 48 nM to 10 MUM for succinic acid, and 6 nM to 10 MUM for aconitic acid. Quantification of the analytes in soil-related samples was performed via external calibration of the entire procedure utilizing (13)C labeled oxalic and citric acid as internal standards. The robustness of the method was tested with soil extracts and samples from hydroponic experiments. The latter concerned the regulation of phosphorus solubilization via plant root exudation of citric, malic, and oxalic acid. PMID- 20711770 TI - Focus on sensor interfaces. PMID- 20711771 TI - Testosterone metabolism revisited: discovery of new metabolites. AB - The metabolism of testosterone is revisited. Four previously unreported metabolites were detected in urine after hydrolysis with KOH using a liquid chromatography-tandem mass spectrometry method and precursor ion scan mode. The metabolites were characterized by a product ion scan obtained with accurate mass measurements. Androsta-4,6-dien-3,17-dione, androsta-1,4-dien-3,17-dione, 17 hydroxy-androsta-4,6-dien-3-one and 15-androsten-3,17-dione were proposed as feasible structures for these metabolites on the basis of the mass spectrometry data. The proposed structures were confirmed by analysis of synthetic reference compounds. Only 15-androsten-3,17-dione could not be confirmed, owing to the lack of a commercially available standard. That all four compounds are testosterone metabolites was confirmed by the qualitative analysis of several urine samples collected before and after administration of testosterone undecanoate. The metabolite androsta-1,4-dien-3,17-dione has a structure analogous to that of the exogenous anabolic steroid boldenone. Specific transitions for boldenone and its metabolite 17beta-hydroxy-5beta-androst-1-en-3-one were also monitored. Both compounds were also detected after KOH treatment, suggesting that this metabolic pathway is involved in the endogenous detection of boldenone previously reported by several authors. PMID- 20711772 TI - Single-walled carbon nanotubes for improved enantioseparations on a chiral ionic liquid stationary phase in GC. AB - In order to investigate whether the use of single-walled carbon nanotubes can improve enantioseparations on an ionic liquid stationary phase, a chiral ionic liquid, (R)-N,N,N-trimethyl-2-aminobutanol-bis(trifluoromethanesulfon)imidate, was synthesized. Two capillary columns, one containing the chiral ionic liquid and the other containing the single-walled carbon nanotubes and the chiral ionic liquid, were then prepared for GC. The results of the separations achieved with these columns show that coating the chiral ionic liquid stationary phase onto the capillary column containing single-walled carbon nanotubes improves the enantioselectivety of the chiral ionic liquid. This work indicates that using single-walled carbon nanotubes in this manner enables the application range of such GC chiral separations to be extended. PMID- 20711773 TI - Characterizing a spheroidal nanocage drug delivery vesicle using multi-detector hydrodynamic chromatography. AB - The biological application of nanoparticles has resulted in an increased need for the development of robust, accurate, and precise methods for quality control analysis and characterization. Parameters such as particle size, particle shape, and their distributions affect end-use properties such as chemical reactivity, diffusivity, permeability, and transport. Introduced here is a hydrodynamic chromatography (HDC) method utilizing multi-angle static light scattering, quasi elastic light scattering, differential viscometry, and differential refractometry detection for characterizing nanoscale vesicles. Quadruple-detector HDC was used to determine multiple sizing parameters and their statistical moments and distributions. Molar mass and molar mass averages were determined in a calibrant independent fashion. Both the sizing parameters and the molar mass were measured across the HDC elution profile. The shape and structure of the nanoparticle were monitored as a function of HDC elution volume through the dimensionless ratio rho=R(G,z)/R(H,z). The HDC results were comparable to those obtained by transmission electron microscopy, but more extensive characterization was possible by HDC, which provided distributions of both particle size and particle shape. PMID- 20711774 TI - Determination of marker pteridines in urine by HPLC with fluorimetric detection and second-order multivariate calibration using MCR-ALS. AB - A liquid chromatographic method has been developed, in combination with the multivariate curve resolution-alternating least squares algorithm (MCR-ALS), for the simultaneous determination of marker pteridines in urine samples. A central composite design has been applied to optimize the factors influencing the separation (buffer concentration, buffer pH, flow rate, oven temperature, mobile phase composition). A set of 15 calibration samples were randomly prepared, in a concentration range of 0.5-10.5 ng mL(-1) for neopterin, biopterin, and pterin; 4.0-8.0 ng mL(-1) for xanthopterin; and 0.5-4.5 ng mL(-1) for isoxanthopterin. The validation was carried out with fortified urine samples from healthy adults. The optimized conditions were a mobile-phase composition of 10 mM citric buffer at pH 5.44 and acetonitrile (94.5/5.5, v/v), a flow rate of 1.0 mL min(-1), and an oven temperature of 25 degrees C. The detection system consisted of a fast scanning spectrofluorimeter, which allows obtaining of second-order data matrices containing the fluorescence intensity as a function of retention time and emission wavelength. In this work, MCR-ALS was used to cope with coeluting interferences, on account of the second-order advantage inherent to this algorithm which, in addition, is able to handle data sets deviating from trilinearity, like the high-performance liquid chromatography data analyzed in the present report. The developed approach enabled us to determine five pteridines, some of them with overlapped profiles, reducing the experimental time and reagent consumption. Ratio values for pteridines/creatinine in urine, for infected children with different pathologies, are reported in this work. PMID- 20711776 TI - Was Wright right? The canonical genetic code is an empirical example of an adaptive peak in nature; deviant genetic codes evolved using adaptive bridges. AB - The canonical genetic code is on a sub-optimal adaptive peak with respect to its ability to minimize errors, and is close to, but not quite, optimal. This is demonstrated by the near-total adjacency of synonymous codons, the similarity of adjacent codons, and comparisons of frequency of amino acid usage with number of codons in the code for each amino acid. As a rare empirical example of an adaptive peak in nature, it shows adaptive peaks are real, not merely theoretical. The evolution of deviant genetic codes illustrates how populations move from a lower to a higher adaptive peak. This is done by the use of "adaptive bridges," neutral pathways that cross over maladaptive valleys by virtue of masking of the phenotypic expression of some maladaptive aspects in the genotype. This appears to be the general mechanism by which populations travel from one adaptive peak to another. There are multiple routes a population can follow to cross from one adaptive peak to another. These routes vary in the probability that they will be used, and this probability is determined by the number and nature of the mutations that happen along each of the routes. A modification of the depiction of adaptive landscapes showing genetic distances and probabilities of travel along their multiple possible routes would throw light on this important concept. PMID- 20711775 TI - Low pH-induced pore formation by the T domain of botulinum toxin type A is dependent upon NaCl concentration. AB - Botulinum neurotoxins (BoNTs) undergo low pH-triggered membrane insertion, resulting in the translocation of their light (catalytic) chains into the cytoplasm. The T (translocation) domain of the BoNT heavy chain is believed to carry out translocation. Here, the behavior of isolated T domain from BoNT type A has been characterized, both in solution and when associated with model membranes. When BoNT T domain prepared in the detergent dodecylmaltoside was diluted into aqueous solution, it exhibited a low pH-dependent conformational change below pH 6. At low pH the T domain associated with, and formed pores within, model membrane vesicles composed of 30 mol% dioleoylphosphatidylglycerol/70 mol% dioleoylphosphatidylcholine. Although T domain interacted with vesicles at low (50 mM) and high (400 mM) NaCl concentrations, the interaction required much less lipid at low salt. However, even at high lipid concentrations pore formation was much more pronounced at low NaCl concentrations than at high NaCl concentration. Increasing salt concentration after insertion in the presence of 50 mM NaCl did not decrease pore formation. A similar effect of NaCl concentration upon pore formation was observed in vesicles composed solely of dioleoylphosphatidylcholine, showing that the effect of NaCl did not solely involve modulation of electrostatic interactions between protein and anionic lipids. These results indicate that some feature of membrane-bound T domain tertiary structure critical for pore formation is highly dependent upon salt concentration. PMID- 20711777 TI - Variability in the dynamics of mortality and immobility responses of freshwater arthropods exposed to chlorpyrifos. AB - The species sensitivity distribution (SSD) concept is an important probabilistic tool for environmental risk assessment (ERA) and accounts for differences in species sensitivity to different chemicals. The SSD model assumes that the sensitivity of the species included is randomly distributed. If this assumption is violated, indicator values, such as the 50% hazardous concentration, can potentially change dramatically. Fundamental research, however, has discovered and described specific mechanisms and factors influencing toxicity and sensitivity for several model species and chemical combinations. Further knowledge on how these mechanisms and factors relate to toxicologic standard end points would be beneficial for ERA. For instance, little is known about how the processes of toxicity relate to the dynamics of standard toxicity end points and how these may vary across species. In this article, we discuss the relevance of immobilization and mortality as end points for effects of the organophosphate insecticide chlorpyrifos on 14 freshwater arthropods in the context of ERA. For this, we compared the differences in response dynamics during 96 h of exposure with the two end points across species using dose response models and SSDs. The investigated freshwater arthropods vary less in their immobility than in their mortality response. However, differences in observed immobility and mortality were surprisingly large for some species even after 96 h of exposure. As expected immobility was consistently the more sensitive end point and less variable across the tested species and may therefore be considered as the relevant end point for population of SSDs and ERA, although an immobile animal may still potentially recover. This is even more relevant because an immobile animal is unlikely to survive for long periods under field conditions. This and other such considerations relevant to the decision-making process for a particular end point are discussed. PMID- 20711778 TI - Surfinoma: a case report on a pseudotumor developing after a surfing sports injury. AB - We describe an unusual pseudotumor of the upper thorax, axillary, and shoulder girdle region with presentation 4 years after a surfing sports injury. We offer the coined term "Surfinoma" to describe a pseudotumor arising from a penetrating piece of fiberglass surf board, which induced a foreign body reaction. PMID- 20711779 TI - Imaging characteristics of tenosynovial and bursal chondromatosis. AB - OBJECTIVES: Our purpose was to identify imaging characteristics of tenosynovial and bursal chondromatosis. MATERIALS AND METHODS: We retrospectively reviewed 25 pathologically confirmed cases of tenosynovial (n = 21) or bursal chondromatosis (n = 4). Patient demographics and clinical presentation were reviewed. Imaging was evaluated by two musculoskeletal radiologists with agreement by consensus, including radiography (n = 21), bone scintigraphy (n = 1), angiography (n = 1), ultrasonography (n = 1), CT (n = 8), and MR (n = 8). Imaging was evaluated for lesion location/shape, presence/number of calcifications, evidence of bone involvement, and intrinsic characteristics on ultrasonography/CT/MR. RESULTS: Average patient age was 44 years (range 7 to 75 years) with a mild male predilection (56%). A slowly increasing soft tissue mass was the most common clinical presentation (53%). Lesion locations included the foot (n = 8), hand (n = 6), shoulder (n = 3), knee (n = 2), ankle (n = 2) and one each in the upper arm, forearm, wrist, and cervical spine. All lesions were located in a known tenosynovial (21 cases, 84%) or bursal (four cases, 16%) location. All cases of bursal chondromatosis were round/oval in shape. Tenosynovial lesions were fusiform (65%) or round/oval (35%). Radiographs commonly showed a soft tissue mass (86%) and calcification (90%). Calcifications were predominantly chondroid (79%) or osteoid (11%) in character with >10 calcified bodies in 48%. CT detected calcifications in all cases. The intrinsic characteristics of the nonmineralized component showed low attenuation on CT (75%), high signal intensity on T2 weighted MR (76%) and a peripheral/septal contrast enhancement pattern (100%). CONCLUSIONS: Imaging of tenosynovial and bursal chondromatosis is often characteristic with identification of multiple osteochondral calcifications (90% by radiographs; 100% by CT). CT and MR also revealed typical intrinsic characteristics of chondroid tissue and lesion location in a known tendon sheath or bursa. PMID- 20711780 TI - Minimizing collision risk between migrating raptors and marine wind farms: development of a spatial planning tool. AB - An increased focus on renewable energy has led to the planning and construction of marine wind farms in Europe. Since several terrestrial studies indicate that raptors are especially susceptible to wind turbine related mortality, a Spatial Planning Tool is needed so that wind farms can be sited, in an optimal way, to minimize risk of collisions. Here we use measurements of body mass, wingspan and wing area of eight European raptor species, to calculate their Best Glide Ratio (BGR). The BGR was used to construct a linear equation, which, by the use of initial take-off altitude, could be used to calculate a Theoretical Maximum Distance (TMD) from the coast, attained by these soaring-gliding raptor species. If the nearest turbine, of future marine wind farms, is placed farther away from the coast than the estimated TMD, the collision risk between the turbine blades and these gliding raptors will be minimized. The tool was demonstrated in a case study at the Rodsand II wind farm in Denmark. Data on raptor migration altitude were gathered by radar. From the TMD attained by registered soaring-gliding raptors in the area, we concluded that the Rodsand II wind farm is not sited ideally, from an ornithological point of view, as potentially all three registered species are at risk of gliding through the area swept by the turbine rotor blades, and thereby at risk of colliding with the wind turbines. PMID- 20711781 TI - Oral administration of Clostridium butyricum for modulating gastrointestinal microflora in mice. AB - This study aimed to evaluate the safety of Clostridium butyricum and to investigate the effect of C. butyricum on mice ecosystem in the intestinal tract by way of examining the population of different microorganisms isolated from caecal contents. We firstly evaluated the safety of C. butyricum using acute toxicity test and Ames test. Then forty male BALB/c mice were divided into the following four treatment groups, each consisting of ten mice: normal group, low dose group, medium-dose group and high-dose group. Caecal contents were removed aseptically, immediately placed into an anaerobic chamber, and dissolved in sterile pre-reduced PBS. The determination of Enterococcus spp., Enterobacter spp., Lactobacillus spp., Bifidobacterium spp. and Clostridium perfringens was analyzed by the spread plate method, cell morphologies and biochemical profiles. The results showed the oral maximum tolerated dose of C. butyricum was more than 10 g/kg body weight in mice and no mutagenicity judged by negative experimental results of Ames test. And in medium- and high-dose groups, the populations of Bifidobacterium spp. and Lactobacillus spp. increased in caecum, as well as the ratios of Bifidobacterium spp. and Lactobacillus spp. to Clostridium perfringens (P < 0.01) as compared with the normal group. This research showed the intake of C. butyricum significantly improved the ecosystem of the intestinal tract in BALB/c mice by increasing the amount of probiotics and reducing the populations of unwanted bacteria. PMID- 20711782 TI - Risk factors for avascular bone necrosis in patients with systemic lupus erythematosus. AB - The objective was to investigate the predictive factors for avascular necrosis (AVN) of bone in patients with systemic lupus erythematosus (SLE). The records of 868 patients with SLE from four centers were reviewed retrospectively. Forty-nine patients with AVN were identified. A total of 154 patients with SLE who did not have clinically apparent AVN during the follow-up were evaluated as a control group. The demographic, clinical, laboratory and management characteristics of these two groups of patients were recorded according to predefined protocol and compared. The prevalence of AVN was detected 6% in our SLE population. The highest dose corticosteroid administered within 4 months and total cumulative prednisolone dose were significantly higher in the SLE patients with AVN. The use of cytotoxic agent significantly higher proportion of patients with AVN. AVN tends to develop more frequently in male gender and younger patients. Oral ulcer, pleuritis, Raynaud's phenomenon, cutaneous vasculitis, lymphadenopathy, autoimmune thyroiditis, peripheral neuropathy and Sjogren's syndrome were higher incidence in SLE patients with AVN. The bilateral femoral heads were the commonest site of involvement of AVN in our patients with SLE. PMID- 20711783 TI - Reversible auditory brainstem responses screening failures in high risk neonates. AB - This work is aimed at assessing the frequency of occurrence of reversible auditory brainstem responses (ABR) abnormalities within a targeted hearing screening program for high risk (HR) newborns. The effect of age on screening is also evaluated and some important clinical issues are highlighted. The audiological records of 1,294 HR neonates were retrospectively reviewed. All children were tested for hearing loss using ABR within a 17-year period. Initial failures were re-examined 4-6 months later. The mean age of infants who scored "pass" and "refer" at initial test, as well as the referral rates were calculated and compared. One hundred and seventy-eight infants (13.8%) demonstrated abnormal recordings at initial screening. From those who were present on re-examination, 64.2% showed complete and 15% partial recovery. Reversible abnormalities have been detected not only for conductive threshold elevation but also for sensorineural losses. Remarkably, 50% of the cases with absent waveforms or ABR threshold >= 80 dBnHL demonstrated complete recovery to normal. Statistically, higher rates of abnormal results were inversely associated with the newborn's age at initial testing. In conclusion, reversible ABR abnormalities are common among HR infants due to temporary auditory dysfunction, secondary to external and middle ear pathology or retarded central nervous system maturation. The observed high rates of transient ABR abnormalities give rise to some practical questions regarding the implementation time of hearing screening for HR infants. Moreover, given that central nervous system maturation changes may still be in progress, the definite decision for an early cochlear implantation in this pediatric subset should be made after obtaining reliable behavioral hearing tests. PMID- 20711784 TI - Negative schizophrenic symptoms and the frontal lobe syndrome: one and the same? AB - The negative symptoms of schizophrenia have been considered to be a psychiatric form of the frontal lobe syndrome. However, no studies have compared these two disorders at the clinical level. In this study, 12 negative symptom schizophrenic patients and 11 patients with behavioural variant frontotemporal dementia (bv FTD) were rated for negative symptoms and for occurrence of frontal lobe behaviours in everyday life. They were also rated for speech disorder and were given a series of executive tests. Both patient groups showed positive ratings on negative symptoms and frontal lobe behaviours in daily life; however, the schizophrenic patients had higher negative symptom scores and the bv-FTD patients had higher carer ratings on frontal behaviours in daily life. Both groups were impaired on the executive tests, but the bv-FTD patients showed significantly greater impairment on verbal fluency and a test requiring inhibition of prepotent responses. A minority of the bv-FTD patients unexpectedly showed speech abnormalities typically associated with schizophrenia. The findings indicate that the negative syndrome in schizophrenia and the frontal lobe syndrome resemble each other clinically in important respects. Some of the differences may be attributable to the additional presence of disinhibition in the frontal lobe syndrome. PMID- 20711786 TI - Neoadjuvant chemoradiotherapy for rectal carcinoma: effects on anastomotic leak rate and postoperative bladder dysfunction after non-emergency sphincter preserving anterior rectal resection. Results of the Quality Assurance in Rectal Cancer Surgery multicenter observational trial. AB - INTRODUCTION: Randomized trials have demonstrated a reduction in local recurrence rate in rectal cancer patients treated with preoperative chemoradiotherapy and total mesorectal excision (TME) compared to patients undergoing TME alone. Accordingly, preoperative chemoradiotherapy in all UICC stages II and III rectal cancers has been recommended in the German treatment guidelines as of 2004. However, this policy has been questioned in recent years, partly due to concern regarding an increase in postoperative complications through preoperative therapy. Studies on this issue are sparse; most have been conducted in specialized centers, included relatively few patients, and yielded partly contradicting results. It was the aim of our analysis to investigate the influence of preoperative chemoradiotherapy on anastomotic leak rate and postoperative bladder dysfunction in rectal cancer patients using a representative data set from the Quality Assurance in Rectal Cancer Surgery multicenter observational trial. METHOD: This is a retrospective analysis of data from the Quality Assurance in Rectal Cancer Surgery prospective multicenter observational trial. Data of all patients undergoing curatively intended sphincter-preserving resection for UICC stage I through III rectal carcinoma between 01 Jan 2005 and 31 Dec 2007 with or without preoperative chemoradiotherapy (groups A and B, respectively) were included. Multivariate statistical analysis using propensity score analysis was carried out regarding outcome parameters total anastomotic leak rate, rate of anastomotic leaks requiring reoperation, and postoperative bladder dysfunction. RESULTS: A total of 2,085 patients were included (group A, n = 676, group B, n = 1,409). Significant differences were present between groups regarding age, sex, distance of the tumor from the anal verge, pT-stage, UICC stage, hepatic risk factors, and use of protective enterostomy by univariate analysis. Multivariate logistic regression including these parameters was used to calculate the propensity score (likelihood to be assigned to group A or B as a consequence of the individual profile of these factors) for each patient. When outcome parameters were compared between groups A and B after stratification for propensity score, no significant differences regarding postoperative bladder dysfunction (p = 0.12), total anastomotic leak rate (p = 0.56), and anastomotic leaks requiring reoperation (p = 0.56) could be demonstrated. CONCLUSION: Neoadjuvant chemoradiotherapy for rectal carcinoma does not increase the risk for anastomotic leakage or postoperative bladder dysfunction after curatively intended sphincter-preserving rectal resection. PMID- 20711787 TI - Surgical endocrinology--update 2010. PMID- 20711785 TI - Functional architecture of behavioural thermoregulation. AB - The human thermoregulatory system relies primarily on behavioural adaptation and secondarily on autonomic and endocrine responses for thermal homeostasis. This is because autonomic and endocrine responses have a limited capacity in preventing hyper/hypothermia in extreme environments. Until recently, the neuroanatomy of behavioural thermoregulation as well as the neuroanatomic substrate of the various thermoregulatory behaviours remained largely unknown. However, this situation has changed in recent years as behavioural thermoregulation has become a topic of considerable attention. The present review evaluates the current knowledge on behavioural thermoregulation in order to summarize the present state of-the-art and to point towards future research directions. Findings on the fundamental distinction between thermal (dis)comfort and sensation are reviewed showing that the former drives behaviour while the latter initiates autonomic thermoregulation. Moreover, the thermosensitive neurons and thermoeffector functions of behavioural thermoregulation are presented and analysed in a detailed discussion. PMID- 20711788 TI - Mortality risk in children after renal allograft failure: a NAPRTCS study. AB - Studies have shown that adult dialysis patients with a failed renal allograft face a greater risk of mortality on dialysis compared with transplant-naive patients. The outcome of children returning to dialysis after allograft failure has not been previously studied. Using the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, we studied patients aged 2-21 years who initiated dialysis from 1 January 1992 to 31 December 2007. Of a total of 5,006 patients, 1,031 patients had a prior history of allograft failure and 3,975 did not (transplant-naive). Demographic characteristics, including age at dialysis initiation, race, dialysis modality, primary renal disease, era of dialysis initiation, height Z score, and weight Z score were significantly different between the groups (p < 0.0001). Survival probability between the transplant-naive and allograft failure groups was not significantly different (94.3% and 93.7% at 3 years respectively, log-rank p = 0.08). After covariate adjustment, allograft failure was not a significant factor contributing to increased mortality risk on dialysis (HR 0.98, CI 0.64-1.50, p = 0.94) based on Cox regression analysis. Children with failed allografts who return to dialysis are not at greater risk of mortality than their transplant-naive dialysis counterparts. PMID- 20711789 TI - Thoracic transdural spinal cord herniation at a level caudal to prior discectomy. AB - To outline a scenario of acquired transdural spinal cord herniation not previously described. The authors report their experience with a patient found to harbor a thoracic transdural spinal cord herniation at the disk space immediately caudal to a prior discectomy. Documentation of the radiographic progression of this patient's spinal cord herniation is presented, spanning the course of 13 years. The patient underwent intradural repair of his dural defect via a lateral extracavitary approach. The herniated spinal cord was successfully reduced. The patient had modest improvement in his symptoms at 2-year follow-up. To the best of the authors' knowledge, this case represents the first reported case documenting this anomaly at a level adjacent to that of a previous surgery within the thoracic spine. PMID- 20711790 TI - MR imaging characteristics of oligodendroglial tumors with assessment of 1p/19q deletion status. AB - PURPOSE: Patients with oligodendrogliomas with allelic loss of chromosomal arm 1p and 19q have been shown, especially with anaplastic oligodendrogliomas, to have both a better initial and long-term response to chemotherapy as well as an improved overall survival. Effective treatment of patients with brain tumors requires accurate diagnostic techniques. MR imaging can be used to help differentiate between low- and high-grade tumors. We hypothesize that certain MR imaging characteristics can be used to differentiate between patients with and without 1p and 19q deletion. METHODS: Using the clinical database at the University of Virginia Neuro-Oncology Center, we identified adult patients with grade II and III oligodendroglial tumors who underwent treatment from 2002 to 2007. Age at diagnosis, gender, tumor grade, chromosomal deletion status, duration of follow-up, and MR imaging characteristics were analyzed; the latter was read by a blinded neuroradiologist. RESULTS: One hundred and four patients met the inclusion criteria. Of these patients, 44 manifested 1p/19q co-deletion and 60 patients lacked this deletion. The greatest cross-sectional area (mean) of the tumor measured 23.4 cm(2) for patients with the co-deletion and 31.7 cm(2) for patients with intact alleles (p = 0.008). In addition, inner table thinning was noted directly adjacent to seven tumors with intact 1p and 19q alleles and in no tumors with the 1p/19q co-deletion (p = 0.020). Amongst patients with pure oligodendrogliomas, those with 1p/19q co-deletion had tumors more often confined to a single lobe as compared with those patients without the co-deletion (p = 0.023). Finally, tumors with intact alleles were more often found in the temporal lobe (45.0%) as compared with co-deleted tumors (22.7%) (p = 0.011). CONCLUSION: MR imaging is a valuable imaging modality for differentiating between oligodendrogliomas with or without the 1p/19q deletion. While imaging will never replace definitive tissue diagnosis, imaging characteristics such as tumor size, location, and overlying skull thinning can assist clinicians in assessing patients with oligodendroglial tumors prior to surgical or medical intervention. PMID- 20711791 TI - Social play impairment following status epilepticus during early development. AB - Neonatal status epilepticus (SE) disrupts prefrontal cortex and thalamus, brain regions related to social play. Juvenile play was evaluated using the "intruder resident" paradigm following SE in 9-day-old Wistar pups of both genders. Quite interestingly, we demonstrated for the first time that neonatal SE produces social impairment in male rats, reduces locomotor activity in both genders and enhances self-grooming in female. Additional studies are necessary to clarify if these effects can impair social behavior across the life span. PMID- 20711792 TI - Microbial diversity in acid mine drainage of Xiang Mountain sulfide mine, Anhui Province, China. AB - To understand the composition and structure of microbial communities in acid (pH 3.0) mine drainage (AMD) associated with pyrite mine tailings in Anhui Province, China, molecular diversities of 16S rRNA and 18S rRNA genes were examined using a PCR-based cloning approach. Bacterial, archaeal and microeukaryotic clone libraries were constructed. In contrast to typical dominance of autotrophic acidophiles, genus Acidiphilium, which consists of mixotrophic acidophiles capable of chemoorganotrophic and photosynthetic metabolisms, was the largest group in the bacterial clone library. These mixotrophic organisms may be advantageous in the oligotrophic AMD environment of the study site (certain amounts of dissolved organic carbon and light) by switching between two modes of metabolisms. Unexpectedly, a large fraction of bacterial clones (12.7%) were related to the neutrophilic genus Legionella, which can cause Legionnaires' disease, a potentially lethal pneumonia. The eukaryotic 18S rRNA gene sequences were mostly related to Oxytricha, Nuclearia, and Penicillium. In the archaeal clone library, all the sequences were affiliated to the phylum Crenarchaeota, while the Euryarchaeota was not present. PMID- 20711793 TI - Mechanistic investigation of the base-promoted cycloselenoetherification of pent 4-en-1-ol. AB - The mechanism of phenylselenoetherification of pent-4-en-1-ol using some bases (pyridine, triethylamine, quinoline, 2,2'-bipyridine) as catalyst was examined through studies of kinetics of the cyclization, by UV-VIS spectrophotometry. It was demonstrated that the intramolecular cyclization is facilitated in the presence of bases caused by the hydrogen bond between base and alkenol's OH group. The obtained values for rate constants have shown that the reaction with triethylamine is the fastest one. Quantum chemical calculations (MP2(fc)/6 311+G**//B3LYP/6-311+G**) show, that the transition state of the cyclisation is S(N)2 like. PMID- 20711794 TI - Experimental and computational studies indicate the mutation of Glu12 to increase the thermostability of oligomeric protease from Pyrococcus horikoshii. AB - The intracellular protease from Pyrococcus horikoshii (PhpI) is a member of the DJ-1/ThiJ/PfpI superfamily, which is suggested to be involved in cellular protection against environmental stresses. In this study, flexible docking approach was employed to dock the ligand into the active site of PhpI. By analyzing the results, active site architecture and certain key residues responsible for substrate specificity were identified on the enzyme. Our docking result indicates that Glu12 plays an important role in substrate binding. The kinetic experiment conducted by Zhan shows that the E12T mutant is more stable than that of the wild-type. We also predict that Glu15, Lys43, and Tyr46 may be important in the catalytic efficiency and thermostability of enzyme. The new structural and mechanistic insights obtained from computational study should be valuable for detailed structures and mechanisms of the member of the DJ-1 superfamily. PMID- 20711795 TI - Clinical characteristics and outcomes of patients with vancomycin-susceptible Enterococcus faecalis and Enterococcus faecium bacteraemia in cancer patients. AB - The purpose of this investigation was to compare the risk factors, clinical features and outcomes in cancer patients with bacteraemia caused by vancomycin susceptible Enterococcus faecalis and E. faecium. A retrospective, observational 7-year study was carried out in a 450-bed, acute-care university-affiliated hospital. We performed univariate comparisons between the two groups and then multivariate analysis to identify patient risk factors for E. faecium isolation. Seventy-three patients were included in the analysis: 54 (74.0%) with bacteraemia caused by E. faecalis and 19 (26.0%) by E. faecium. The Simplified Acute Physiological Score (SAPS) value was significantly greater in E. faecium isolates (40.7 vs. 35.2; p = 0.009). Diabetes mellitus was more frequently diagnosed in patients with E. faecium bacteraemia (52.6% vs. 24.1%; p = 0.021). Prior penicillin exposure was more frequent in patients with E. faecium bacteraemia (68.4% vs. 29.6%; p = 0.003). There was a trend toward higher mortality in E. faecium bacteraemia patients (47.4% vs. 25.9%; p = 0.084). Independent patient risk factors for E. faecium isolation were prior penicillin exposure (odds ratio [OR], 6.479; p = 0.003) and SAPS > 34 (OR, 6.896; p = 0.009). When compared to E. faecalis bacteraemia, E. faecium bacteraemia in cancer patients is independently associated with more severe illness and prior use of penicillins; therefore, empiric treatment which would cover E. faecium should be considered in cancer patients suspected of having bacteraemia. PMID- 20711796 TI - Lipid production by Rhodosporidium toruloides Y4 using different substrate feeding strategies. AB - Microbial lipid is a potential alternative feedstock for the biodiesel industry. New culture strategies remain to be developed to improve the economics of microbial lipid technology. This work describes lipid production by the oleaginous yeast Rhodosporidium toruloides Y4 using a 15-l bioreactor with different substrate feeding strategies. Among these strategies, the intermittent feeding mode gave a lipid productivity of 0.36 g l(-1) h(-1), whereas the constant glucose concentration II (CC-II) mode gave the highest lipid productivity of 0.57 g l(-1) h(-1). The repeated fed-batch mode according to the CC-II mode was performed with a duration time of 358 h, and the overall lipid productivity was 0.55 g l(-1) h(-1). Our results suggested that substrate feeding modes had a great impact on lipid productivity and that the repeated fed-batch process was the most appealing method by which to enhance microbial lipid production. PMID- 20711797 TI - High-throughput screening and selection of yeast cell lines expressing monoclonal antibodies. AB - The methylotrophic yeast Pichia pastoris has recently been engineered to express therapeutic glycoproteins with uniform human N-glycans at high titers. In contrast to the current art where producing therapeutic proteins in mammalian cell lines yields a final product with heterogeneous N-glycans, proteins expressed in glycoengineered P. pastoris can be designed to carry a specific, preselected glycoform. However, significant variability exists in fermentation performance between genotypically similar clones with respect to cell fitness, secreted protein titer, and glycan homogeneity. Here, we describe a novel, multidimensional screening process that combines high and medium throughput tools to identify cell lines producing monoclonal antibodies (mAbs). These cell lines must satisfy multiple selection criteria (high titer, uniform N-glycans and cell robustness) and be compatible with our large-scale production platform process. Using this selection process, we were able to isolate a mAb-expressing strain yielding a titer (after protein A purification) in excess of 1 g/l in 0.5-l bioreactors. PMID- 20711798 TI - Asymmetrical growth of the photopic hill during the light adaptation effect. AB - In response to progressively stronger flashes delivered against a rod saturating background light, the amplitude of the photopic ERG b-wave first increases, reaches a maximal value (V (max)) and then decreases gradually to a plateau where the amplitude of the b-wave equals that of the a-wave, a phenomenon known as the photopic hill (PH). The purpose of this study was to investigate how the PH grew during the course of the light adaptation (LA) process that follows a period of dark adaptation (DA): the so-called light adaptation effect (LAE). Photopic ERG (time-integrated) luminance-response (LR) functions were obtained prior to (control-fully light adapted) and at 0, 5 and 10 min of LA following a 30-min period of DA. A mathematical model combining a Gaussian and a logistic growth function, suggested to reflect the OFF and ON retinal contribution to the PH respectively, was fitted to the LR functions thus obtained. Our results indicate that the magnitude of the cone ERG LAE is modulated by the stimulus luminance, with b-wave enhancements being maximal for luminance levels that result in the descent of the PH. The Gaussian function grew significantly with LA while the logistic growth function remained basically unchanged. Our findings would therefore suggest that the LAE reflects primarily an increase in the retinal OFF response during LA. PMID- 20711799 TI - Female ixodid ticks grow endocuticle during the rapid phase of engorgement. AB - Lees (Proc Zool Soc Lond 121:759-772, 1952) concluded that the ixodid tick Ixodes ricinus grows endocuticle during the slow but not during the rapid, phase of engorgement, a conclusion supported by Andersen and Roepstorff (Insect Biochem Mol Biol 35:1181-1188, 2005) for the same species. In this study analysis of dimensional data and cuticle weight measurements from female ixodid ticks (Amblyomma hebraeum) were used to test this hypothesis. Both approaches showed that endocuticle growth continues during the rapid phase, tapering to zero at a fed/unfed weight ratio of ~60. Of the total mass of cuticle in the engorged tick 32-43% was formed during the rapid phase. We demonstrate that if cuticle growth stopped at the end of the slow phase, there would not be sufficient cuticle to account for the thickness of cuticle observed at the end of engorgement. This finding is consistent with prior studies of Rhipicephalus (Boophilus) microplus, and with a dimensional analysis of the cuticle thickness data of Lees for I. ricinus, in contradiction to his conclusion from an analysis of tick cuticle weight measurements. An examination of cuticle weight measurements for I. ricinus by Andersen and Roepstorff similarly supports the finding of cuticle growth during the rapid phase. All ixodid ticks undergo major body expansion, typically tenfold or more, during a rapid phase of engorgement and require sufficient cuticle at the end of that process to contain their body. The fact that cuticle grows during the rapid phase of engorgement in three species suggests that this is a general characteristic of the family Ixodidae. PMID- 20711800 TI - Multiple transcripts encode glucose 6-phosphate dehydrogenase in the southern cattle tick, Rhipicephalus (Boophilus) microplus. AB - Glucose 6-phosphate dehydrogenase (G6PDH) is an enzyme that plays a critical role in the production of NADPH. Here we describe the identification of four transcripts (G6PDH-A, -B, -C, and -D) that putatively encode the enzyme in the southern cattle tick, Rhipicephalus (Boophilus) microplus. The genomic DNA that is spliced to produce G6PDH-A and -B is 8,600-9,000 bases in length and comprises 12 exons. Comparison of the R. microplus G6PDH gene structure with those available from insects and mammals revealed that the tick gene is most like that of humans. Detection of the four transcripts was evaluated by quantitative RT-PCR using template from larvae, unfed adult females and males, salivary gland tissues from 2- to 3-day-fed adult females and males, and salivary gland tissue of 4- to 5-day-fed adult females. The G6PDH-A and -C transcripts were present in all templates, and both displayed induced expression in salivary gland tissue of fed, adult females but not matched males. The G6PDH-D transcript was detected only in unfed adults and in larvae, a stage in which it was most abundant relative to the other three transcripts. The G6PDH-B transcript, while detectable in all templates, was of low copy number suggesting it is a rare transcript. Induced expression of G6PDH-A and G6PDH-C in fed females may play a role in the tolerance of oxidative stress that is induced upon feeding, and the transcript abundance in fed females may be a function of bloodmeal volume and the time adult females spend on the host relative to adult males. PMID- 20711801 TI - Rhipicephalus (Boophilus) microplus: a most successful invasive tick species in West-Africa. AB - The cattle tick Rhipicephalus (Boophilus) microplus is known to be a highly reproductive and efficient vector of Babesia bovis, two characters which make this tick a threat to livestock keeping in many continents. The authors identified this tick in Ivory Coast, West Africa, in 2007, and hypothesized the spread to be minimal, as this tick was not observed in previous years. To determine the extent of its distribution and to a lesser extent the possible impact of the tick on the livelihoods of Ivorian smallholders, a cross-sectional survey was carried out in the Abidjan and Agboville Departments of Ivory Coast, in April 2008. The results of the study reveal that the newly introduced tick has almost completely displaced all indigenous Rhipicephalus (Boophilus) species in the study area and gave rise to unsuccessful tick control, inappropriate pesticide use, loss of milk production and even increased mortality in dairy cattle. PMID- 20711802 TI - Secretory process of salivary glands of female Amblyomma cajennense (Acari: Ixodidae) ticks fed on resistant rabbits. AB - Ticks have great economic and health importance since infested animals have reduced milk and meat production, and, besides that, they are expensive ectoparasites to control. While feeding, ticks can transmit to their hosts a large amount of pathogens, including Rickettsia rickettsii responsible for the "spotted fever" or "fever of the mountains." It is known that animals infested with ticks or artificially immunized with their salivary gland extracts develop resistance, which is related to a decrease in engorged female weight, in egg laying by adults, in egg viability and, in some cases, in the capacity of pathogens transmission. The present study aimed to examine morpho-histochemically the female salivary glands of semi and engorged Amblyomma cajennense fed on resistant rabbits. The results revealed that acinus I had no changes when compared to that of females fed on naive rabbits. The c cells of acinus II showed signs of early degeneration, which may result in feeding efficiency decrease. In acinus III d cells, activity time was longer. Such occurrence was associated with the time of female fixation, which increased in females fed on resistant hosts. PMID- 20711803 TI - Ticks infesting the endangered Italian hare (Lepus corsicanus) and their habitat in an ecological park in southern Italy. AB - The Italian hare (Lepus corsicanus) is an endangered species whose natural populations have decreased in recent years. This study's objective was to identify ticks infesting hares and their habitats in a wildlife reserve in southern Italy. In June 2009, ticks were collected by dragging in three transects set in a meadow habitat within an enclosure inhabited by hares and in three similar transects outside this enclosure. Fifty-five ticks were collected by dragging, being 54 inside and 1 outside the enclosure. Ticks were identified as Hyalomma marginatum (34 males, 17 females), Dermacentor marginatus (2 males, 1 female), and Rhipicephalus bursa (1 female). In September 2009, ticks were collected from 17 Italian hares and identified as Ixodes ricinus (2 larvae, 45 nymphs, 35 males, 37 females), Rhipicephalus turanicus (2 males, 1 nymph), and Hyalomma sp. (165 nymphs). PCR amplification and sequencing of a partial region of the 12S rDNA gene of Hyalomma nymphs allowed their identification as H. marginatum. This study suggests that host presence is a factor determining the level of environmental tick infestation as well as the free-living tick species in the study area and that Italian hares are hosts for I. ricinus and H. marginatum. Studies to assess whether these ticks could limit the survival and fitness of Italian hares and affect their conservation status are needed. Moreover, it is necessary to investigate whether these ticks are infected with pathogens of medical and veterinary concern. PMID- 20711804 TI - Modifiable predictors associated with having a gestational weight gain goal. AB - The goal of this paper was to determine predictors of having a weight gain goal in early pregnancy. In 2008, we administered a 48-item survey to 249 pregnant women attending obstetric visits. We examined predictors of women having a goal concordant or discordant with 1990 Institute of Medicine (IOM) guidelines, vs. no goal, using binary and multinomial logistic regression. Of the 292 respondents, 116 (40%) had no gestational weight gain goal, 112 (39%) had a concordant goal and 61 (21%) had a goal discordant with IOM guidelines. Predictors of a guideline concordant goal, vs. no goal, included sugar sweetened beverage consumption < vs. >= 1 serving per week (OR = 2.4, 95%CI: 1.1, 5.7), physical activity >= vs. <2.5 h per week (OR = 3.6, 95%CI: 1.7, 7.5), agreeing that 'I tried to keep weight down not to look pregnant' (OR = 14.3, 95%CI: 1.4, 140.5). Other predictors only of having a discordant goal (vs. no goal) included agreeing that 'as long as I am eating well, I don't care how much I gain' (OR = 0.3, 95%CI: 0.2, 0.8) and agreeing that 'if I gain too much weight one month, I try to keep from gaining the next' (OR = 4.1, 95%CI: 1.6, 10.4). Women whose doctors recommended weight gains consistent with IOM guidelines were more likely to have a concordant goal (vs. no goal) (OR = 5.3, 95%CI: 1.5, 18.6). Engaging in healthy behaviors and having health providers offer IOM weight gain recommendations may increase the likelihood of having a concordant gestational weight gain goal, which, in turn, is predictive of actual weight gains that fall within IOM guidelines. PMID- 20711806 TI - Glycemic index, glycemic load, and the risk of pancreatic cancer among postmenopausal women in the women's health initiative observational study and clinical trial. AB - BACKGROUND: Several reports have suggested that conditions associated with hyperinsulinemia and insulin resistance, such as diets high in carbohydrates, may influence the risk of pancreatic cancer, although results from prior studies have been mixed. METHODS: We utilized data from the population-based women's health initiative (WHI) cohort to determine whether dietary factors that are associated with increased postprandial blood glucose levels are also associated with an increased risk of pancreatic cancer. The WHI included 161,809 postmenopausal women of ages 50-79, in which 332 cases of pancreatic cancer were identified over a median of 8 years of follow-up; 287 of these cases met the criteria for analysis. A validated 122-item food frequency questionnaire was used to estimate dietary glycemic load (GL), glycemic index (GI), total and available carbohydrates, fructose and sucrose. Baseline questionnaires and physical exams provided information on demographic, medical, lifestyle, and anthropometric characteristics. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the exposures of interest and pancreatic cancer risk, with adjustment for potential confounders. RESULTS: Dietary GL, GI, carbohydrates, fructose, and sucrose were not associated with increased risk of pancreatic cancer. The multivariable adjusted HR for the highest vs. the lowest quartile of GL was 0.80 (95% CI = 0.55 1.15, trend p = 0.31) and 1.13 (95% CI = 0.78-1.63, trend p = 0.94) for GI. The results remained negative when individuals with a history of diabetes were excluded. CONCLUSIONS: Our results do not support the hypothesis that dietary intake of carbohydrates is associated with increased risk of pancreatic cancer. PMID- 20711807 TI - The effect of modifiable potentials on hypermethylation status of retinoic acid receptor-beta2 and estrogen receptor-alpha genes in primary breast cancer. AB - Epigenetic silencing of retinoic acid receptor-beta2 (RARbeta2) and estrogen receptor-alpha (ERalpha) expressions have been revealed to be important in the development of approaches for diagnosis and therapy of breast cancer. We aimed to explore the correlation of some potential factors with the hypermethylation status of RARbeta2 and ERalpha genes among Iranian breast cancer patients. The hypermethylation status was investigated in 137 dissected tissues from primary breast cancer patients through methylation-specific PCR. Overall, the methylation frequencies of RARbeta2 and ERalpha genes were observed in 36.5 and 51.1% of participants, respectively. The hypermethylated RARbeta2 was associated with younger age at diagnosis and negative family history of breast cancer. The hypermethylation of ERalpha was correlated positively with smoking, duration of estradiol exposure, ER-negativity in tumors and body mass index (at 5 years ago). The plasma levels of folate and vitamin B(12) were inversely related to the hypermethylation status of ERalpha, after controlling for covariates. The risk of ERalpha hypermethylation was increased with high plasma level of total homocysteine. In conclusion, our data provide new insights into the possible effect of some lifestyle-related factors on the aberrant methylation drift of ERalpha and RARbeta2 genes in breast cancer. PMID- 20711805 TI - Functional analysis of Spodoptera litura nucleopolyhedrovirus p49 gene during Autographa californica nucleopolyhedrovirus infection of SpLi-221 cells. AB - The Spodoptera litura nucleopolyhedrovirus (SpltNPV) antiapoptotic gene Splt-p49 is able to rescue replication of a p35-null Autographa californica nucleopolyhedrovirus (AcMNPV) in AcMNPV-permissive Sf9 cells. In this study, an AcMNPV p35 knockout bacmid was generated through ET homologous recombination in Escherichia coli and designated as vAc(P35-KO). The Splt-p49 gene was transposed into the polyhedrin locus of vAc(P35-KO) to investigate if Splt-p49 has any antiapoptotic activity in the context of AcMNPV infection of AcMNPV-nonpermissive SpLi-221 cells. Our results demonstrated that Splt-p49 could not inhibit the apoptosis induced by AcMNPV infection of SpLi-221 cells when it was under the control of its native promoter. Western blot analysis showed that Splt-P49 was poorly expressed. When the expression of Splt-P49 was under the control of Drosophila hsp70 promoter, the expression of Splt-P49 was advanced, and a higher level of Splt-P49 was detected. As a result, the apoptosis of SpLi-221 cells was inhibited; however, budded-virus production did not improve in comparison with that in AcMNPV-infected SpLi-221 cells. These data indicated that there are other barrier(s) to AcMNPV replication in the nonpermissive SpLi-221 cells besides apoptosis. PMID- 20711809 TI - Adult weight gain in relation to breast cancer risk by estrogen and progesterone receptor status: a meta-analysis. AB - Adult weight gain is positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk. To date, no meta analysis has been conducted to assess this association by estrogen receptor (ER) and progesterone receptor (PR) status. We searched PubMed for relevant studies published through March 2010. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random effects or fixed effects models. We retrieved nine articles on weight gain from adulthood to reference age and ER- and/or PR-defined breast cancer risk, reporting on three prospective cohort studies and eight case-control studies. Comparing the highest versus the lowest categories of adult weight gain, risk was increased for ER(+)PR(+) and ER(+) tumors combined (11 studies; RE = 2.03; 95% CI 1.62, 2.45). Statistically significant heterogeneity (p (heterogeneity) = 0.002) was shown between REs for a mixed population of pre- and postmenopausal women combined (4 studies; RE = 1.54; 95% CI 0.86, 2.22) and for postmenopausal women only (7 studies; RE = 2.33; 95% CI 2.05, 2.60). Risk for ER(-)PR(-) tumors among postmenopausal women was also slightly increased (7 studies; RE = 1.34; 95% CI 1.06, 1.63), but statistically significantly different from risk for ER(+)PR(+) tumors (p (heterogeneity) < 0.0001). No associations were observed for ER(+)PR(-) tumors whereas risk for ER( )PR(+) tumors could not be assessed. In conclusion, the association between adult weight gain and postmenopausal breast cancer risk is heterogeneous according to ER/PR status and stronger for ER(+)PR(+) than for ER(-)PR(-) tumors. PMID- 20711808 TI - Polymorphisms in oxidative stress and inflammation pathway genes, low-dose ionizing radiation, and the risk of breast cancer among US radiologic technologists. AB - OBJECTIVE: Ionizing radiation, an established breast cancer risk factor, has been shown to induce oxidative damage and chronic inflammation. Polymorphic variation in oxidative stress and inflammatory-mediated pathway genes may modify radiation related breast cancer risk. METHODS: We estimated breast cancer risk for 28 common variants in 16 candidate genes involved in these pathways among 859 breast cancer cases and 1,083 controls nested within the US Radiologic Technologists cohort. We estimated associations between occupational and personal diagnostic radiation exposures with breast cancer by modeling the odds ratio (OR) as a linear function in logistic regression models and assessed heterogeneity of the dose-response across genotypes. RESULTS: There was suggestive evidence of an interaction between the rs5277 variant in PTGS2 and radiation-related breast cancer risk. The excess OR (EOR)/Gy from occupational radiation exposure = 5.5 (95%CI 1.2-12.5) for the GG genotype versus EOR/Gy < 0 (95%CI < 0-3.8) and EOR/Gy < 0 (95%CI < 0-14.8) for the GC and CC genotypes, respectively, (p (interaction) = 0.04). The association between radiation and breast cancer was not modified by other SNPs examined. CONCLUSIONS: This study suggests that variation in PTGS2 may modify the breast cancer risk from occupational radiation exposure, but replication in other populations is needed to confirm this result. PMID- 20711810 TI - Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. AB - Intraoperative radiotherapy with electrons (ELIOT) after conservative surgery for breast carcinoma was introduced at the IEO in 1999 as a research programme. The results on 1,822 patients treated from January 2000 to December 2008 are reported. Women with unicentric primary breast carcinoma of less than 2.5 cm in the largest diameter were assessed by imaging. All patients were treated with breast-conserving surgery (quadrantectomy). ELIOT was delivered by two mobile linear accelerators immediately after breast resection with a single dose of 21 Gy. Local side effects of ELIOT were mainly liponecrosis (4.2%) and fibrosis (1.8%). After a mean follow-up of 36.1 months, 42 women (2.3%) developed a local recurrence, 24 (1.3%) a new primary ipsilateral carcinomas and 26 (1.4%) distant metastases as first event. Forty-six women died (2.5%), 28 for breast carcinoma and 18 for other causes. Five- and ten-year survivals were, respectively, 97.4 and 89.7%. ELIOT appears a promising feature in early breast cancer treated with breast conserving surgery, reducing the exposure of normal tissues to radiations and shortening the radiation course from 6 weeks to one single session. PMID- 20711811 TI - Assessing the combination effects of environmental estrogens in fish. AB - The method on combined effects of environmental estrogens and mixture environmental risk assessment was discussed. Batch tests were conducted to assess the in vivo potency of mixtures of estrogens using plasma vitellogenin concentrations in male crucian carp (Carassius carassius) as the endpoint. A nonlinear regression was determined on the concentration response relationship for the single chemical of 17beta-estradiol (E(2)), 17alpha-ethynylestradiol (EE(2)), 4-tert-octylphenol (OP), bisphenol A (BPA), and that of the mixed compounds at equipotent concentrations (E(2)-EE(2), E(2)-EE(2)-OP-BPA), the mixture was tested using a fixed-ratio design. On the basis of statistical selection criteria, the best-fit model is chosen individually for each set of data. Furthermore, the bootstrap methodology is applied for constructing confidence intervals for the estimated effect concentrations. The combined effects of the mixture can be predicted using biomathematical models based on the concentration and potency of the individual mixture components. The finding of non-monotonic dose-response relationship and the combined effects can be accurately predicted in whole range of exposure concentration by the reference models, whereas the outcome of simple effect summation with a great deal of indetermination. Results suggested that there can be a risk of mixture effects. The potential impact of components on mixture would depend predominantly on its concentration, the mixture ratio, and its relative potency. Existing environmental risk assessment procedures are limited in their ability to evaluate the combined effects of chemical mixtures, therefore further improvement is needed. PMID- 20711812 TI - Estimates of (co)variance components and genetic parameters for growth traits in Sirohi goat. AB - Data were collected over a period of 21 years (1988-2008) to estimate (co)variance components for birth weight (BWT), weaning weight (WWT), 6-month weight (6WT), 9-month weight (9WT), 12-month weight (12WT), average daily gain from birth to weaning (ADG1), weaning to 6WT (ADG2), and from 6WT to 12WT (ADG3) in Sirohi goats maintained at the Central Sheep and Wool Research Institute, Avikanagar, Rajasthan, India. Analyses were carried out by restricted maximum likelihood, fitting six animal models with various combinations of direct and maternal effects. The best model was chosen after testing the improvement of the log-likelihood values. Heritability estimates for BWT, WWT, 6WT, 9WT, 12WT, ADG1, ADG2, and ADG3 were 0.39 +/- 0.05, 0.09 +/- 0.03, 0.06 +/- 0.02, 0.09 +/- 0.03, 0.11 +/- 0.03, 0.10 +/- 0.3, 0.04 +/- 0.02, and 0.01 +/- 0.01, respectively. For BWT and ADG1, only direct effects were significant. Estimate of maternal permanent environmental effect were important for body weights from weaning to 12WT and also for ADG2 and ADG3. However, direct maternal effects were not significant throughout. Estimate of c (2) were 0.06 +/- 0.02, 0.03 +/- 0.02, 0.06 +/- 0.02, 0.05 +/- 0.02, 0.02 +/- 0.02, and 0.02 +/- 0.02 for 3WT, 6WT, 9WT, 12WT, ADG2, and ADG3, respectively. The estimated repeatabilities across years of ewe effects on kid body weights were 0.10, 0.08, 0.05, 0.08, and 0.08 at birth, weaning, 6, 9, and 12 months of age, respectively. Results suggest possibility of modest rate of genetic progress for body weight traits and ADG1 through selection, whereas only slow progress will be possible for post-weaning gain. Genetic and phenotypic correlations between body weight traits were high and positive. High genetic correlation between 6WT and 9WT suggests that selection of animals at 6 months can be carried out instead of present practice of selection at 9 months. PMID- 20711813 TI - Life extension and the position of the hormetic zone depends on sex and genetic background in Drosophila melanogaster. AB - Hormesis, the beneficial effect of a mild stress, has been proposed as a means to prolong the period of healthy ageing as it can increase the average lifespan of a cohort. However, if we want to use hormesis therapeutically it is important that the treatment is beneficial on the individual level and not just on average at the population level. Long lived lines have been shown not to benefit from a, in other lines, hormesis inducing heat treatment in Drosophila melanogaster, D. buzzatii and mice. Also in many experiments hormesis has been reported to occur in one sex only, usually males but not in females. Here we investigated the interaction between the hormetic response and genetic background, sex and duration of a mild heat stress in D. melanogaster, using three replicate lines that have been selected for increased longevity and their respective control lines. We found that genetic background influences the position of the hormetic zone. The implication of this result could be that in a genetically diverse populations a treatment that is life prolonging in one individual could be life shortening in other individuals. However, we did find a hormetic response in all combinations of line and sex in at least one of the experiments which suggests that if it is possible to identify the optimal hormetic dose individually hormesis might become a therapeutic treatment. PMID- 20711814 TI - Pharmacotherapy update in the management of paediatric cancer. AB - Great advances in the treatment of childhood cancer have been made over the last 30 years because of developments in supportive care, the increasing use of advanced technology to detect and diagnose disease, developments in the understanding and relevance of cell biology and by the successful recruitment of children into nationally co-coordinated clinical trials. For some childhood malignancies where the survival rate is high, trials are ongoing to see if treatment can be stratified and directed according to patient risk, with those that fall into a favourable risk category potentially being cured with less treatment and therefore less short term and long term toxicity. PMID- 20711815 TI - Impaired aortic distensibility measured by computed tomography is associated with the severity of coronary artery disease. AB - Impaired aortic distensibility index (ADI) is associated with cardiovascular risk factors. This study evaluates the relation of ADI measured by computed tomographic angiography (CTA) with the severity of coronary atherosclerosis in subjects with suspected coronary artery disease (CAD). Two hundred and twenty nine subjects,age 63 +/- 9 years, 42% female, underwent coronary artery calcium (CAC) scanning and CTA, and their ADI and Framingham risk score (FRS) were measured. End-systolic and end-diastolic (ED) cross-sectional-area(CSA) of ascending-aorta (AAo) was measured 15-mm above the left-main coronary ostium. ADI was defined as: [(Deltalumen-CSA)/(lumen-CSA in ED * systemic-pulse-pressure) * 10(3)]. ADI measured by 2D-trans-thoracic echocardiography (TTE) was compared with CTA-measured ADI in 26 subjects without CAC. CAC was defined as 0, 1-100, 101-400 and 400+. CAD was defined as luminal stenosis 0, 1-49% and 50%+. There was an excellent correlation between CTA- and TTE-measured ADI (r(2)=0.94, P=0.0001). ADI decreased from CAC 0 to CAC 400+; similarly from FRS 1-9% to FRS 20% + (P<0.05). After adjustment for risk factors, the relative risk for each standard deviation decrease in ADI was 1.66 for CAC 1-100, 2.26 for CAC 101-400 and 2.32 for CAC 400+ as compared to CAC 0; similarly, 2.36 for non-obstructive CAD and 2.67 for obstructive CAD as compared to normal coronaries. The area under the ROC-curve to predict significant CAD was 0.68 for FRS, 0.75 for ADI, 0.81 for CAC and 0.86 for the combination (P<0.05). Impaired aortic distensibility strongly correlates with the severity of coronary atherosclerosis. Addition of ADI to CAC and traditional risk factors provides incremental value to predict at risk individuals. PMID- 20711816 TI - The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate release. AB - The endocannabinoid system and endocannabinoid receptor-driven modulation of glutamate release were studied in rat brain cortex astroglial gliosomes. These preparations contained the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, as well their major biosynthetic (N-acyl phosphatidylethanolamines-hydrolyzing-phospholipase D and diacylglycerol-lipase) and catabolic (fatty acid amide-hydrolase and monoacylglycerol-lipase) enzymes. Gliosomes expressed type-1 (CB1R), type-2 (CB2R) cannabinoid, and type-1 vanilloid (TRPV1) receptors, as ascertained by Western blotting and confocal microscopy. Methanandamide, a stable analogue of anandamide acting as CB1R, CB2R, and TRPV1 agonist, stimulated or inhibited the depolarization-evoked gliosomal [(3)H]D: -aspartate release, at lower and higher concentrations, respectively. Experiments with ACEA (arachidonyl-2'-chloroethylamide), JWH133 ((6aR,10aR)-3 (1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]-pyran) and capsaicin, selective agonists at CB1R, CB2R and TRPV1, respectively, demonstrated that potentiation of [(3)H]D: -aspartate release was due to CB1R while inhibition to CB2R and TRPV1 engagement. These findings were confirmed by using selective receptor antagonists. Furthermore, CB1R activation caused increase of intracellular IP3 and Ca(2+) concentration, suggesting an involvement of phospholipase C. PMID- 20711817 TI - Similarities in solar ultraviolet irradiance and other environmental factors may explain much of the family link between uveal melanoma and other cancers. PMID- 20711818 TI - The molecular cloning of glial fibrillary acidic protein in Gekko japonicus and its expression changes after spinal cord transection. AB - The glial fibrillary acidic protein (GFAP) is an astrocyte-specific member of the class III intermediate filament proteins. It is generally used as a specific marker of astrocytes in the central nervous system (CNS). We isolated a GFAP cDNA from the brain and spinal cord cDNA library of Gekko japonicus, and prepared polyclonal antibodies against gecko GFAP to provide useful tools for further immunochemistry studies. Both the real-time quantitative PCR and western blot results revealed that the expression of GFAP in the spinal cord after transection increased, reaching its maximum level after 3 days, and then gradually decreased over the rest of the 2 weeks of the experiment. Immunohistochemical analyses demonstrated that the increase in GFAP-positive labeling was restricted to the white matter rather than the gray matter. In particular, a slight increase in the number of GFAP positive star-shaped astrocytes was detected in the ventral and lateral regions of the white matter. Our results indicate that reactive astrogliosis in the gecko spinal cord took place primarily in the white matter during a short time interval, suggesting that the specific astrogliosis evaluated by GFAP expression might be advantageous in spinal cord regeneration. PMID- 20711819 TI - Enhanced laccase production in white-rot fungus Rigidoporus lignosus by the addition of selected phenolic and aromatic compounds. AB - The white rot fungus Rigidoporus lignosus produces substantial amounts of extracellular laccase, a multicopper blue oxidase which is capable of oxidizing a wide range of organic substrates. Laccase production can be greatly enhanced in liquid cultures supplemented with various aromatic and phenolic compounds. The maximum enzyme activity was reached at the 21st or 24th day of fungal cultivation after the addition of inducers. The zymograms of extracellular fluid of culture preparation in the presence of inducers, at maximum activity day, revealed two bands with enzymatic activity, called Lac1 and Lac2, having different intensities. Lac2 band shows the higher intensity which changed with the different inducers. Laccase induction can be also obtained by adding to the culture medium olive mill wastewaters, which shows a high content of phenolic compounds. PMID- 20711820 TI - Neuro-ophthalmologic complications of syringobulbia. AB - Syringobulbia is an uncommon condition, usually a late complication of syringomyelia. It has predilection for the dorsolateral region of the medulla leading to damage to vestibular nuclei and their connections, as well as to the descending sympathetic fibers. Oscillopsia, nystagmus, and Horner syndrome are frequent manifestations of syringobulbia. Oscillopsia may be a disturbing symptom for the patient, whereas Horner syndrome is usually an asymptomatic finding. MRI detection of syringomyelia has led to earlier treatment of syringomyelia and prevention of upward extension of the cavity. This probably explains why syringobulbia is less frequently encountered at present. We propose to describe the neuro-ophthalmologic symptoms and signs that may be observed in patients with syringobulbia and the mechanisms involved in their appearance. PMID- 20711821 TI - Maintenance chemotherapy: an evolving and increasingly acceptable strategy in cancer management. AB - Individual randomized phase 3 trials and meta-analyses of previously published studies have provided support for the general concept of the clinical utility of extending the duration of antineoplastic drug therapy in an effort to prolong ("maintain") a favorable clinical state. This commentary briefly reviews data from several of these reports. PMID- 20711823 TI - [Growth promoting operation in juvenile scoliosis]. PMID- 20711822 TI - Identification of HLA-A*0201-restricted cytotoxic T lymphocyte epitope from proliferating cell nuclear antigen. AB - Peptide-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and prolong survival in patients with various cancers. Protein antigens and their specific epitopes are formulation targets for anti-tumor vaccines. Bioinformatical approaches to predict major histocompatibility complex binding peptides can facilitate the resource-consuming effort of T cell epitope identification. Proliferating cell nuclear antigen including Ki-67 and PCNA, associated with the proliferation process of the cell, seems to be an attractive new target for tumor-specific immunotherapy. In this study, we predicted seven HLA-A*0201-restricted CTL candidate epitope of Ki-67 and eight epitope of PCNA by computer algorithm SYFPEITHI, BIMAS, and IEDB_ANN. Subsequently, biological functions of these peptides were tested by experiments in vitro. We found Ki-67((280-288)) (LQGETQLLV) had the strongest binding-affinity with HLA-A*0201. Further study revealed that Ki-67((280-288)) increased the frequency of IFN-gamma-producing T cells compared to a negative peptide. Because Ki-67 was broadly expressed in most advanced malignant tumors, indicating a potential anti-tumor application in the future. PMID- 20711824 TI - [Operative treatment of scolioses with the VEPTR instrumentation]. AB - OBJECTIVE: In 1993, A. Campel published the VEPTR (vertical expandable prosthetic titanium rib) instrumentation for the treatment of thoracic insufficiency syndrome (TIS). The goal of surgery is to lengthen and expand the constricted concave hemithorax to the height of the convex sides to increase thoracic volume, to obtain thoracic symmetry, to improve thoracic function, to maintain these improvement during growth of the child, and to avoid growth inhibition procedures, if possible. INDICATIONS: TIS. Congenital scoliosis. Early-onset scoliosis (EOS). Neurogenic scoliosis. CONTRAINDICATIONS: Hyperkyphosis > 70 degrees according to Cobb. Osteoporotic bone. Children > 10 years. SURGICAL TECHNIQUE: Through a standard thoracotomy incision, an openingwedge thoracocostotomy is performed by cutting a transverse osteotomy from transverse process to sternum through the fused ribs at the apex of the thoracic deformity. The interval is distracted by lamina spreaders. A vertical expandable prosthetic titanium rib (VEPTR) is inserted to hold the acute operative correction. Curves going into the lumbar spine are treated with a hybrid device. In follow-up surgeries at intervals of 4-6 months the devices are expanded through a limited incision at their base to maintain correction with growth. POSTOPERATIVE MANAGEMENT: Postoperative Management Patients can be mobilized after the 3rd day of surgery without a brace. RESULTS: From 2005 to 2009, 39 patients (24 female, 15 male, mean age at surgery 7.5 years [3-13 years]) were treated with VEPTR. The diagnosis was congenital scoliosis in 16, neurogenic scoliosis in eleven, and EOS in twelve cases. Seven of the 39 patients had undergone previous surgery. The curve was measured according to Cobb. The mean Cobb angle was 65 degrees (45-130 degrees ) preoperatively and 32 degrees (25-75 degrees ) postoperatively. During the first surgery, no complications occurred. Mean operating time was 95 min (65 185 min). Mean blood loss amounted to 125 ml (65-180 ml). 29 of the 39 patients had one to nine lengthening procedures. The mean correction achieved was 15.7 degrees (19.8%). In three cases, the VEPTR instrumentation was removed and a final fusion performed. All parents and patients were satisfied with the operation and would undergo it again. PMID- 20711825 TI - [Surgical treatment of early-onset scoliosis with the StarLock implant system]. AB - OBJECTIVE: The problem of early-onset scoliosis is the progression of spine curvature. With the StarLock instrumentation a corrected spinal growth can be achieved. Distraction is necessary once or twice a year. INDICATIONS: Idiopathic, congenital and neuromuscular scoliosis. CONTRAINDICATIONS: Ostoeoporosis. Arthrogryposis. Kyphosis. SURGICAL TECHNIQUE: The use of a C-arm (anterior posterior and lateral view) has to be possible. Pedicle screws are placed at the proximal and distal end of the curvature. Through distraction of the rods which are screwed to each other via parallel connectors, correction of the scoliosis can be achieved. POSTOPERATIVE MANAGEMENT: Mobilization should be started 1 day postoperatively using an individual corset for 6 months. Distraction has to be done once or twice a year. RESULTS: From March 2003 to October 2005, 14 children with early- onset scoliosis were treated with the StarLock instrumentation. After the first operation, the Cobb angle improved from 65 degrees (42-80 degrees ) to 26.5 degrees (18-45 degrees ) in the thoracic spine and from 22 degrees (18-55 degrees ) to 15 degrees (10-32 degrees ) in the lumbar spine. Lenghtenings were done every 6.8 months (5-9 months). The follow-up time was 4.5 years (3-6 years). COMPLICATIONS: three rods and two screws broke. Infections and neurologic deficits were not observed. PMID- 20711826 TI - [Growth modulation in operative treatment of juvenile scoliosis by USS paediatric]. AB - OBJECTIVE: Growth modulation in operative treatment of juvenile scoliosis can be done by USS paediatric instrumentation to control spinal growth in patients of small stature with juvenile scoliosis. The double-rod system has to be distracted every 4-6 months. The system is used in young patients too tall for VEPTR (vertical expandable prosthetic titanium rib) instrumentation. The system with a very low profile allows reduced soft-tissue pressure saving soft tissue from atrophy or the development of pseudocysts above the screws. With this procedure controlled growth with growth modulation of the spine is possible and final spondylodesis can be done later. INDICATIONS: Congenital, idiopathic and neuromuscular scolioses. Children, who are too tall and big for a VEPTR instrumentation. Cobb angle > 40 degrees or progression > 10 degrees during brace therapy. CONTRAINDICATIONS: Adults. Dysplastic pedicles with vertebral anomalies. Arthrogryposis. SURGICAL TECHNIQUE: The patient should be positioned prone, lying flat on the table. Median skin incision with subperiosteal preparation of the paraspinal muscles is done to expose the vertebrae. Next, the pedicle is prepared with a tap, and the USS paediatric pedicle screw system with its very low profile is inserted under fluoroscopic control in anterior-posterior and lateral view. In the upper thoracic spine the authors use screws 4.2 mm in diameter, in the lower thoracic spine 5-mm screws, and in the lumbar spine 6-mm screws. Measurement of the rod length and insertion of the rod are performed. When spinal growth for > 4 years is expected, distraction of the double-rod system by the use of two dominos is done on the concave and convex side of the curve to modulate spinal growth. When spinal growth for 2-4 years is expected, distraction is done just at the concave side of the curve. For correction of the curve, either segmental correction or classic derotation by the Cotrel-Dubousset technique can be performed. POSTOPERATIVE MANAGEMENT: Postoperative on block rotation. Mobilization of the patient on day 2 after surgery with a rigid brace. Individual rigid custom-made plaster brace for 3-8 months. During postoperative recovery, muscular efforts should be reduced for 6 months after first implantation. Distraction of the system is necessary every 4-6 months to modulate spinal growth. RESULTS: From 2004 to 2008, 26 patients (15 girls, eleven boys) with a mean age of 9 years (6-13 years) were treated using this technique. Follow-up examinations were performed 3, 6, 12, and 24 months after surgery. The mean follow-up was 26 months (6-40 months). At first implantation of the scoliosis instrumentation, just little scoliosis correction was done depending on the quality of bone. At every distraction, an average correction of the Cobb angle of 5 degrees was reached. The Cobb angle could be reduced from 71 degrees to 34 degrees on average. Fusion rate in the cranial and caudal part was evaluated by X ray. 5-mm rods have a reduced stiffness of 50% compared to USS 6-mm rods. Average spinal growth was about 5.6 cm (4.0-8.1 cm) over a period of 3.2 +/- 1.2 years. During 2-year follow-up, rod or pedicle screw breakage, dislocation, or loosening of the Cobb angle did not occur. PMID- 20711827 TI - [Modified primary stable ventral derotation spondylodesis with Halm-Zielke instrumentation for the treatment of idiopathic scoliosis]. AB - OBJECTIVE: Surgical technique with an anterior double-rod system for thoracic, thoracolumbar, or lumbar scoliosis. The aim of the system is to correct the coronal plane deformity and normalize the sagittal balance. INDICATIONS: Scoliosis which should have a coronal Cobb measurement of at least 40 degrees and should usually not exceed 90 degrees in between T4 and L4. In the Lenke classification, the curve types 1 (main thoracic) and curve type 5 (thoracolumbar/lumbar) are amenable to anterior instrumentation and fusion. CONTRAINDICATIONS: Osteoporosis. Infection. Allergic reaction to implants. Minor curves that do not correct to < 25 degrees on flexibility maneuvers. Structured kyphosis in the major curve. Severe sagittal plane malalignment with pathologic kyphosis cranial or caudal of the instrumented segments. SURGICAL TECHNIQUE: The spine is exposed via an open thoracotomy or a thoracoabdominal approach. After completion of diskectomies at each level, the anterior double-rod system is fixed with two bicortical screws per vertebral body. The longitudinal components consist of a solid rod and a threaded rod. The rods are contoured to maintain normal sagittal and coronal contour. The proximal screws are engaged first and then a cantilever force is used to correct the deformity. Occasionally, a partial rod rotation maneuver or intersegmental compression is performed. Morselized autograft (typically rib) is placed in the disk spaces. Intraoperative radiographs are taken to evaluate the correction. POSTOPERATIVE MANAGEMENT: Brace free mobilization. Physiotherapy. Respiratory therapy. RESULTS: Very high rate of successful spondylodesis. Excellent frontal correction of about 60-70%. Very good spontaneous correction of adjacent minor curves of around 40%. Restoration of a physiological profile. Correction angle and length of fusion comparable to modern transpedicular double-rod systems. PMID- 20711828 TI - [Muscular torticollis]. AB - OBJECTIVE: Correction of malalignment of the cervical spine with the head tilted to the side of the shortened muscle and rotation to the opposite side due to a contract sternocleidomastoid muscle. Attainment of an increased range of motion of the cervical spine and a better cosmetic appearance. Regression of a facial asymmetry. INDICATIONS: Contract sternocleidomastoid muscle with deformity intolerable by the patients and their parents. CONTRAINDICATIONS: Bony anomalies with consecutive torticollis. Torticollis caused by other muscular contractures (trapezoid muscle). Torticollis due to acute rheumatoid arthritis or other inflammation around the neck. Other forms of torticollis (psychogenic, ocular, vestibular or spasmodic torticollis). SURGICAL TECHNIQUE: In younger children, subcutaneous tenotomy of the distal part of the sternocleidomastoid muscle. At preschool age, additional incision of the deep cervical fascial layer with an open tenotomy. In delayed operations, open distal and proximal tenotomy together with incision of the deep fascial layer or complete excision of the sternocleidomastoid muscle. POSTOPERATIVE MANAGEMENT: Until the age of 6 years, application of a Minerva cast after surgery for 6 weeks. Subsequently, physical therapy for 6 months. In children of school age and older people, application of a soft cervical bandage for 6 weeks with functional physiotherapy. RESULTS: In 83 reexamined patients with muscular torticollis, 76 biterminal and seven distal tenotomies had been performed. Regarding the age at the time of operation and the interval to follow-up, an improvement of facial symmetry could be achieved. At the control, 25 patients showed complete recovery of facial asymmetry, 43 had a slight and 15 a severe asymmetry. The complication rate was low with one injury to the external jugular vein and one transient facial nerve paresis. In two patients, passive overcorrection in the cast resulted in transient paresis. Two patients developed a recurrence of muscular torticollis. PMID- 20711829 TI - [Posterior approach to the shoulder]. AB - OBJECTIVE: Safe approach to the posterior shoulder and scapula. INDICATIONS: Posterior shoulder stabilization. Posterior bony reconstruction of the glenoid. Corrective osteotomies of the glenoid. Treatment of scapular neck fractures. Treatment of posterior glenoid rim fractures. Treatment of fractures of the acromion. Arthrodesis of the shoulder. Biopsy. Tumor resection. Relative: shoulder joint replacement with simultaneous posterior glenoid reconstruction. Relative: treatment of posterior dislocated proximal humerus fractures. CONTRAINDICATIONS: General contraindications. SURGICAL TECHNIQUE: Landmarks: scapular spine and acromion. Incision depending on goal of surgery: from horizontal to oblique or vertical: - horizontal incision along the scapular spine to the posterior corner of acromion, - oblique incision along the lateral border of scapula. Authors' preference: angle bisector between scapular spine and lateral border of scapula. Detachment of the deltoid with a bony chip from scapular spine beginning laterally (subacromial space). Under the deltoid the infraspinatus is exposed. Approach to glenoid: the internervous plane is between the infraspinatus (suprascapular nerve) and teres minor (axillary nerve). Approach to scapular neck (attention: identify axillary nerve!): more dangerous internervous plane between teres minor (axillary nerve) and teres major (subscapular nerve). If needed, detachment of infraspinatus from tendinous insertion for better visualization of posterior capsule and glenoid. POSTOPERATIVE MANAGEMENT: According to the operated pathology. RESULTS: Results are according to the operated pathology. As an example, results from the authors' clinic are presented. Between 1982 to 1995, 24 patients (26 shoulders) with posterior instability underwent open posteroinferior capsular shift. Mean follow up was 7.6 years. The average relative Constant-Murley Score amounted to 91%. Subjective result was good to excellent for 24 and fair for two shoulders. Recurrence occurred in 23% (all cases with surgery before index procedure or new trauma). No approach-related complications (weakness or insufficiency) were noted. PMID- 20711830 TI - [Management of severe soft-tissue trauma in the upper extremity - shoulder, upper and lower arm]. AB - OBJECTIVE: Salvage of the respective extremity. Standardized approach to adequate soft-tissue coverage (isolated severe soft-tissue trauma) and preconditioning for fracture healing (in complex trauma) as a basis for functional restoration. Limitation of secondary soft-tissue loss. Prevention of infection. INDICATIONS: Isolated extended severe soft-tissue trauma (crush trauma, degloving injury) in the region of the shoulder and the upper extremity. Complex trauma with soft tissue involvement Gustilo IIIB/C or Tscherne GIII/IV. Segmental soft-tissue/bone loss. Subtotal or partial amputations. CONTRAINDICATIONS: Unstable polytraumatized patient with vital hazards and the priority for lifesaving measures. Irretrievable devascularization or unreconstructable neural destruction, extended severe loss of multiple muscular units. SURGICAL TECHNIQUE: Systematic, eventually serial debridement, temporary joint transfixation, reconstruction of macrocirculation, dermatofasciotomy in compartment syndrome, preferably primary shortening in segmental soft-tissue/bone loss, temporary soft tissue coverage, systematic conditioning of soft tissues, postprimary or secondary soft-tissue reconstruction, secondary change to preferably internal fixation techniques. POSTOPERATIVE MANAGEMENT: Individualized earliest possible passive or assisted mobilization of nontransfixed joints, early removal of transfixation and change to internal fixation modes, eventually secondary reconstructive measures (e.g., augmentation of bone defects, flap correction, secondary nerve reconstruction, functional muscle transposition procedures, arthrolyses). RESULTS: Patency rate after vascular reconstruction > 90%, flap survival > 95%, need for amputation is a rare entity; main determinants of prognosis: severity of soft-tissue trauma, neural damage, and potential for reconstruction. PMID- 20711831 TI - [A minimally invasive dorsal approach to the medial femoral condyle as a donor site for osteochondral transfer procedures]. AB - OBJECTIVE: Long-lasting reconstruction of joint surface by using an osteochondral transfer procedure (OCT). Reduction of donor site morbidity by using a minimally invasive approach to the dorsal medial femoral condyle. INDICATIONS: Grade 3 and 4 cartilage lesions (according to ICRS [International Cartilage Repair Society]), osteochondral lesions, and osteochondrosis dissecans. CONTRAINDICATIONS: Grade 2 or higher-graded cartilage lesions at the dorsal medial femoral condyle, infection, axis deviation of more than 5 degrees in the frontal plane, advanced osteoarthritis. SURGICAL TECHNIQUE: Cylinders at recipient site are removed first, thereby determining number and diameter of donor cylinders. Supine position, skin incision over the dorsal medial femoral condyle. After dissection of soft tissue and superficial fascia, semitendinosus tendon and medial gastrocnemius muscle are retracted to the lateral side, followed by arthrotomy, introduction of two Hohmann retractors medial and lateral of the condyle, and harvesting of the donor cylinders with a tubular chisel. Advantages of the described approach: reduction of soft-tissue trauma, easy surgical technique, additional donor site area besides femoral trochlea and intercondylar notch. POSTOPERATIVE MANAGEMENT: Partial weight bearing of 10-20 kg for 4-6 weeks. Limitation of knee flexion to 90 degrees for 6 weeks. RESULTS: Between 01/2006 and 04/2007, the dorsal medial femoral condyle was used as a donor site in 16 patients. All patients were evaluated preoperatively and after 1 year using the American Knee Society Score (KSS), the Western Ontario and McMaster Universities (WOMAC) Score, the Tegner Score, and the visual analog scale (VAS) pain. The mean follow- up was 13.9 (+/-4.3) months. The mean defect area was 4.6 (+/-2.2) cm(2). The mean KSS, Tegner Score, and WOMAC Score improved from 123.1 (+/-41.5), 2.8 (+/-0.9), and 73.3 (+/-50.2) points preoperatively to 171.3 (+/-16.9), 3.4 (+/ 0.6), and 26.1 (+/-17.6) points after 13.9 months (p < 0.05). The VAS pain improved from 5.3 (+/-2.7) to 2.4 (+/-1.8) points (p < 0.05). One patient with an osteochondral defect of 8 cm(2) at the medial femoral condyle (Ahlback's disease) still complains of pain during deep squatting. The dorsal medial femoral condyle can be recommended as donor site for OCT. The minimally invasive approach has proven to be safe and simple with a low complication rate. PMID- 20711832 TI - [The minimally invasive anterolateral approach to L2-L5]. AB - OBJECTIVE: Minimally invasive anterolateral retroperitoneal approach to the lumbar spinal levels L2-L5. INDICATIONS: Anterior interbody fusion for the treatment of degenerative disk disease (DDD), degenerative instability, isthmic and degenerative spondylolisthesis, tumors, degenerative scoliosis, fractures, spondylodiscitis, failed back syndrome (pseudarthrosis, post-diskectomy). CONTRAINDICATIONS: No absolute contraindications. Relative contraindications are previous surgeries via a sinistral retroperitoneal approach or a far lateral anatomy of the left iliac common vein covering the lateral annulus of the disk space L4/5. SURGICAL TECHNIQUE: A small skin incision over the left abdominal wall is followed by a blunt muscle-splitting approach to the retroperitoneal space and the anterolateral circumference of the lumbar spine. A diskectomy, corporectomy and/or grafting (iliac crest or cage) may be performed for a solid ventral fusion. POSTOPERATIVE MANAGEMENT: Early mobilization from the 1st postoperative day in all cases of combined ALIF (anterior lumbar interbody fusion)/ posterior instrumentation procedures. Thromboembolic prophylaxis with fractionated heparin. Light meals up until recovery of the first bowel movements. A brace is recommended depending on the type of the intervention for a duration of up to 12 weeks. No limitations for standing, walking or sitting in the immediate postoperative period. RESULTS: Minimally invasive anterior interbody fusion procedures with iliac crest bone graft were performed in 120 patients (average age 56.3 years, range 26-84 years) in combination with a dorsal instrumentation. 16 patients were treated with a double-level procedure. Duration of surgery ranged between 50 and 192 min (mean 102.2 min). The intraoperative blood loss was 67.3 cm(3). At the 6-month follow-up, the fusion rate was 95.6%. No vessel, bowel, kidney or spleen injuries were observed. PMID- 20711834 TI - Assessment of bone microarchitecture in chronic kidney disease: a comparison of 2D bone texture analysis and high-resolution peripheral quantitative computed tomography at the radius and tibia. AB - Bone microarchitecture can be studied noninvasively using high-resolution peripheral quantitative computed tomography (HR-pQCT). However, this technique is not widely available, so more simple techniques may be useful. BMA is a new 2D high-resolution digital X-ray device, allowing for bone texture analysis with a fractal parameter (H(mean)). The aims of this study were (1) to evaluate the reproducibility of BMA at two novel sites (radius and tibia) in addition to the conventional site (calcaneus), (2) to compare the results obtained with BMA at all of those sites, and (3) to study the relationship between H(mean) and trabecular microarchitecture measured with an in vivo 3D device (HR-pQCT) at the distal tibia and radius. BMA measurements were performed at three sites (calcaneus, distal tibia, and radius) in 14 healthy volunteers to measure the short-term reproducibility and in a group of 77 patients with chronic kidney disease to compare BMA results to HR-pQCT results. The coefficient of variation of H(mean) was 1.2, 2.1, and 4.7% at the calcaneus, radius, and tibia, respectively. We found significant associations between trabecular volumetric bone mineral density and microarchitectural variables measured by HR-pQCT and H(mean) at the three sites (e.g., Pearson correlation between radial trabecular number and radial H(mean) r = 0.472, P < 0.001). This study demonstrated a significant but moderate relationship between 2D bone texture and 3D trabecular microarchitecture. BMA is a new reproducible technique with few technical constraints. Thus, it may represent an interesting tool for evaluating bone structure, in association with biological parameters and DXA. PMID- 20711835 TI - Plasma clusterin levels in predicting the occurrence of coronary artery lesions in patients with Kawasaki disease. AB - Kawasaki disease (KD) is the leading cause of acquired heart disease during childhood in the developed countries. Coronary artery lesions (CAL) are the major complications of KD. A unique proteomic profiling with increased or decreased fibrinogen, alpha-1-antitrypsin, clusterin, and immunoglobulin free light chains were noted in KD in our previous study. The purpose of this study was to evaluate relations between these biomarkers and CAL in KD and to establish within the markers the appropriate cut-off value with which to predict the occurrence of CAL. A total of 47 KD patients were enrolled, including 14 with CAL and 33 without CAL. Plasma samples from patients with KD before intravenous immunoglobulin administration were indicated for measurement of these biomarkers. A potential relation among CAL, clinical characteristics, and these biomarkers was investigated, and a receiver operating characteristic curve was used to identify a cut-off value of the significant marker that best predicated the occurrence of CAL. Among these biomarkers, only plasma clusterin level was associated with the occurrence of CAL. Using a cut-off value of clusterin <12.0 mg/l, the relative risk for CAL was 4.53-fold (95% confidence interval [CI] 1.060 19.347%, P = 0.014). Results from this study suggest that plasma clusterin level <12.0 mg/l in KD is significantly associated with the occurrence of CAL. Results from this study provide a potential biomarker of KD that may help predict the occurrence of CAL. PMID- 20711836 TI - Ruptured aneurysm of intercostal arteriovenous malformation associated with neurofibromatosis type 1: a case report. AB - Intercostal arteriovenous malformations (AVM) are rare, with most being secondary to trauma or iatrogenic therapeutic procedures. Only one case of presumably congenital AVM has been reported. Here we report the first case of a ruptured aneurysm of intercostal AVM associated with neurofibromatosis type 1 in a 32-year old woman who experienced hypovolemic shock caused by massive hemothorax. PMID- 20711837 TI - Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. AB - PURPOSE: Irreversible electroporation (IRE) is a newly developed nonthermal tissue-ablation technique in which high-voltage electrical pulses of microsecond duration are applied to induce irreversible permeabilisation of the cell membrane, presumably through nanoscale defects in the lipid bilayer, leading to apoptosis. The purpose of this study was to assess the feasibility and safety of ablating renal cell carcinoma (RCC) tissue by IRE. METHODS: Six patients scheduled for curative resection of RCC were included. IRE was performed during anaesthesia immediately before the resection with electrographic synchronisation. Central haemodynamics were recorded before and 5 min after electroporation. Five channel electrocardiography (ECG) was used for detailed analysis of ST waveforms. Blood sampling and 12-lead ECG were performed before, during, and at scheduled intervals after the intervention. RESULTS: Analysis of ST waveforms and axis deviations showed no relevant changes during the entire study period. No changes in central haemodynamics were seen 5 min after IRE. Similarly, haematological, serum biochemical, and ECG variables showed no relevant differences during the investigation period. No changes in cardiac function after IRE therapy were found. One case of supraventricular extrasystole was encountered. Initial histopathologic examination showed no immediate adverse effects of IRE (observation of delayed effects will require a different study design). CONCLUSION: IRE seems to offer a feasible and safe technique by which to treat patients with kidney tumours and could offer some potential advantages over current thermal ablative techniques. PMID- 20711838 TI - Novel demonstration of amyloid-beta oligomers in sporadic inclusion-body myositis muscle fibers. AB - Accumulation of amyloid-beta (Abeta) within muscle fibers has been considered an upstream step in the development of the s-IBM pathologic phenotype. Abeta42, which is considered more cytotoxic than Abeta40 and has a higher propensity to oligomerize, is preferentially increased in s-IBM muscle fibers. In Alzheimer disease (AD), low-molecular weight Abeta oligomers and toxic oligomers, also referred to as "Abeta-Derived Diffusible Ligands" (ADDLs), are considered strongly cytotoxic and proposed to play an important pathogenic role. ADDLs have been shown to be increased in AD brain. We now report for the first time that in s-IBM muscle biopsies Abeta-dimer, -trimer, and -tetramer are identifiable by immunoblots. While all the s-IBM samples we studied had Abeta-oligomers, their molecular weights and intensity varied between the patient samples. None of the control muscle biopsies had Abeta oligomers. Dot-immunoblots using highly specific anti-ADDL monoclonal antibodies also showed highly increased ADDLs in all s-IBM biopsies studied, while controls were negative. By immunofluorescence, in some of the abnormal s-IBM muscle fibers ADDLs were accumulated in the form of plaque-like inclusions, and were often increased diffusely in very small fibers. Normal and disease-controls were negative. By gold-immuno-electron microscopy, ADDL-immunoreactivities were in close proximity to 6-10 nm amyloid-like fibrils, and also were immunodecorating amorphous and floccular material. In cultured human muscle fibers, we found that inhibition of autophagy led to the accumulation of Abeta oligomers. This novel demonstration of Abeta42 oligomers in s-IBM muscle biopsy provides additional evidence that intra-muscle fiber accumulation of Abeta42 oligomers in s-IBM may contribute importantly to s-IBM pathogenic cascade. PMID- 20711839 TI - Estimating transfer parameters in the absence of data. AB - The calculation of transfer of radionuclides from the abiotic to the biotic environment is a well-established practice in radiological assessments. Concentration ratios provide simple means to estimate radionuclide activity in biota, from measured (or estimated) radionuclide concentrations in either a food source or an abiotic component such as soil or water. They are typically reported by element, and data compilations may include information such as soil type (e.g., sand, loam, clay) and species. The data may be for multiple species at a single location, single species at multiple locations, or represent compilations from multiple sources. Recently published guidance suggests that estimates are best made using data from the same ecosystem. This paper examines this recent guidance, in the context of using measured data from within a single ecosystem and comparing results to more generic values. Results suggest that generic values may be an adequate substitute for site-specific information. It illustrates how ionic potential may be used as an alternative to group chemical properties in estimating transfer factors. Lastly, limited evidence is found to support the concept of allometric scaling functions for elemental concentrations in plants. PMID- 20711840 TI - The transfer of radionuclides to wildlife. PMID- 20711841 TI - Radionuclide concentration ratios in Australian terrestrial wildlife and livestock: data compilation and analysis. AB - Radionuclide concentrations in Australian terrestrial fauna, including indigenous kangaroos and lizards, as well as introduced sheep and water buffalo, are of interest when considering doses to human receptors and doses to the biota itself. Here, concentration ratio (CR) values for a variety of endemic and introduced Australian animals with a focus on wildlife and livestock inhabiting open rangeland are derived and reported. The CR values are based on U- and Th-series concentration data obtained from previous studies at mining sites and (241)Am and (239/240)Pu data from a former weapons testing site. Soil-to-muscle CR values of key natural-series radionuclides for grazing Australian kangaroo and sheep are one to two orders of magnitude higher than those of grazing cattle in North and South America, and for (210)Po, (230)Th, and (238)U are one to two orders of magnitude higher than the ERICA tool reference values. When comparing paired kangaroo and sheep CR values, results are linearly correlated (r = 0.81) for all tissue types. However, kidney and liver CR values for kangaroo are typically higher than those of sheep, particularly for (210)Pb, and (210)Po, with values in kangaroo liver more than an order of magnitude higher than those in sheep liver. Concentration ratios for organs are typically higher than those for muscle including those for (241)Am and (239/240)Pu in cooked kangaroo and rabbit samples. This study provides CR values for Australian terrestrial wildlife and livestock and suggests higher accumulation rates for select radionuclides in semi arid Australian conditions compared with those associated with temperate conditions. PMID- 20711843 TI - Benchmarking in the SWISSspine registry: results of 52 Dynardi lumbar total disc replacements compared with the data pool of 431 other lumbar disc prostheses. AB - The SWISSspine registry is the first mandatory registry of its kind in the history of Swiss orthopaedics and it follows the principle of "coverage with evidence development". Its goal is the generation of evidence for a decision by the Swiss federal office of health about reimbursement of the concerned technologies and treatments by the basic health insurance of Switzerland. Recently, developed and clinically implemented, the Dynardi total disc arthroplasty (TDA) accounted for 10% of the implanted lumbar TDAs in the registry. We compared the outcomes of patients treated with Dynardi to those of the recipients of the other TDAs in the registry. Between March 2005 and October 2009, 483 patients with single-level TDA were documented in the registry. The 52 patients with a single Dynardi lumbar disc prosthesis implanted by two surgeons (CE and OS) were compared to the 431 patients who received one of the other prostheses. Data were collected in a prospective, observational multicenter mode. Surgery, implant, 3-month, 1-year, and 2-year follow-up forms as well as comorbidity, NASS and EQ-5D questionnaires were collected. For statistical analyses, the Wilcoxon signed-rank test and chi-square test were used. Multivariate regression analyses were also performed. Significant and clinically relevant reduction of low back pain and leg pain as well as improvement in quality of life was seen in both groups (P < 0.001 postop vs. preop). There were no inter-group differences regarding postoperative pain levels, intraoperative and follow-up complications or revision procedures with a new hospitalization. However, significantly more Dynardi patients achieved a minimum clinically relevant low back pain alleviation of 18 VAS points and a quality of life improvement of 0.25 EQ-5D points. The patients with Dynardi prosthesis showed a similar outcome to patients receiving the other TDAs in terms of postoperative low back and leg pain, complications, and revision procedures. A higher likelihood for achieving a minimum clinically relevant improvement of low back pain and quality of life in Dynardi patients was observed. This difference might be due to the large number of surgeons using other TDAs compared to only two surgeons using the Dynardi TDA, with corresponding variations in patient selection, patient-physician interaction and other factors, which cannot be assessed in a registry study. PMID- 20711842 TI - Small increases in serum creatinine are associated with prolonged ICU stay and increased hospital mortality in critically ill patients with cancer. AB - PURPOSE: Declining kidney function has been associated with adverse hospital outcome in cancer patients. ICU literature suggests that small changes in serum creatinine are associated with poor outcome. We hypothesized that reductions in renal function previously considered trivial would predict a poor outcome in critically ill patients with malignant disease. We evaluated the effects on hospital mortality and ICU length of stay of small changes in creatinine following admission to the intensive care unit. METHODS: We conducted a retrospective cohort study utilizing clinical, laboratory and pharmacy data collected from 3,795 patients admitted to the University of Texas M.D. Anderson Cancer Center's Intensive Care Unit. We conducted univariate and multivariate regression analysis to determine those factors associated with adverse ICU and hospital outcome. RESULTS: Increases in creatinine as small as 10% (0.2 mg/dl) were associated with prolonged ICU stay (5 days vs 6.6 days, p < 0.001) and increased mortality (14.6% vs 25.5%, p < 0.0001). Patients with a 25% rise in creatinine during the first 72 h of ICU admission were twice as likely to die in the hospital (14.3% vs 30.1%, p < 0.001). RIFLE criteria were accurate predictors of outcome, though they missed much of the risk of even smaller increases in creatinine. CONCLUSIONS: Even small rises in serum creatinine following admission to the ICU are associated with increased morbidity and mortality in oncologic patients. The poor outcome in those with rising creatinine could not be explained by severity of illness or other risk factors. These small changes in creatinine may not be trivial, and should be regarded as evidence of a decline in an individual patient's condition. PMID- 20711844 TI - Yoga and disc degenerative disease in cervical and lumbar spine: an MR imaging based case control study. AB - The objective of the current study was to find out whether yoga practice was beneficial to the spine by comparing degenerative disc disease in the spines of long-time yoga practitioners and non-yoga practicing controls, using an objective measurement tool, magnetic resonance imaging. This matched case-control study comprised 18 yoga instructors with teaching experience of more than 10 years and 18 non-yoga practicing asymptomatic individuals randomly selected from a health checkup database. A validated grading scale was used to grade the condition of cervical and lumbar discs seen in magnetic resonance imaging of the spine, and the resulting data analyzed statistically. The mean number of years of yoga practice for the yoga group was 12.9 +/- 7.5. The overall (cervical + lumbar) disc scores of the yoga group were significantly lower (indicating less degenerative disc disease) than those of the control group (P < 0.001). The scores for the cervical vertebral discs of the yoga group were also significantly lower than those of the control group (P < 0.001), while the lower scores for the yoga group in the lumbar group approached, but did not reach, statistical significance (P = 0.055). The scores for individual discs of yoga practitioners showed significantly less degenerative disease at three disc levels, C3/C4, L2/L3 and L3/L4 (P < 0.05). Magnetic resonance imaging showed that the group of long term practitioners of yoga studied had significantly less degenerative disc disease than a matched control group. PMID- 20711845 TI - Mechanisms of insulin secretion in malnutrition: modulation by amino acids in rodent models. AB - Protein restriction at early stages of life reduces beta-cell volume, number of insulin-containing granules, insulin content and release by pancreatic islets in response to glucose and other secretagogues, abnormalities similar to those seen in type 2 diabetes. Amino acids are capable to directly modulate insulin secretion and/or contribute to the maintenance of beta-cell function, resulting in an improvement of insulin release. Animal models of protein malnutrition have provided important insights into the adaptive mechanisms involved in insulin secretion in malnutrition. In this review, we discuss studies focusing on the modulation of insulin secretion by amino acids, specially leucine and taurine, in rodent models of protein malnutrition. Leucine supplementation increases insulin secretion by pancreatic islets in malnourished mice. This effect is at least in part due to increase in the expression of proteins involved in the secretion process, and the activation of the PI3K/PKB/mTOR pathway seems also to contribute. Mice supplemented with taurine have increased insulin content and secretion as well as increased expression of genes essential for beta-cell functionality. The knowledge of the mechanisms through which amino acids act on pancreatic beta-cells to stimulate insulin secretion is of interest for clinical medicine. It can reveal new targets for the development of drugs toward the treatment of endocrine diseases, in special type 2 diabetes. PMID- 20711846 TI - The macrophage pattern recognition scavenger receptors SR-A and CD36 protect against microbial induced pregnancy loss. AB - OBJECTIVES AND DESIGN: Microbial products can act via stress-induced signaling cascades to link dysregulated endogenous microbiota to immune activation (e.g., macrophages) and pregnancy loss. Our previous studies demonstrated that mice deficient in the macrophage pattern recognition scavenger receptors, SR-A and CD36, are more susceptible to inflammatory complications including gut leakiness and experimental colitis. We hypothesized that bacterial penetration of the maternal mucosal surfaces and replication in embryonic fluids compromise the fetal status and can result in miscarriage. MATERIALS AND METHODS: Eighty pregnant ICR and SR-A/CD36-deficient mice were injected via tail vein or intraperitoneally with commensal bacteria (Streptococcus cricetus and/or Actinobacillus sp.) or sham controls. Dams were monitored daily for physical distress, pain and abortion. RESULTS: Dams injected with single dose bacterial inoculum did not develop clinical symptoms. Day old pups injected with bacteria developed internal focal abscesses, lost weight but recovered after 1 week. Dams receiving a second bacterial inoculum delivered dead fetuses. However, SR-A/CD36 deficnet dams demonstrated 100% fetal death via aborted fetuses, and significant up-regulation of the proinflammatory markers (IL-6, serum Amyloid A) 24-74 h after single inoculum. CONCLUSIONS: These data indicate that macrophage scavenger receptors are required for the fetal protection against microbial attack and support that maternal transfer of innate immunity contributes to this protection. PMID- 20711847 TI - Corrosion behaviour of beta-Ti20Mo alloy in artificial saliva. AB - To evaluate the potential of beta-Ti20Mo alloy as a dental material, we tested its corrosion behaviour in artificial saliva in comparison to that of cp-Ti. Open circuit potential (E(OC)), potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) were used as electrochemical methods to characterize the corrosion behaviour of Ti20Mo alloy and cp-Ti, respectively. Corrosion current and passive current densities obtained from the polarization curves showed low values indicating a typical passive behaviour for Ti20Mo alloy. The EIS technique enabled us to study the nature of the passive film formed on the binary Ti20Mo alloy at various imposed potentials. The Bode phase spectra obtained for Ti20Mo alloy in artificial saliva exhibited two-time constants at higher potential (0.5 V, 1.0 V), indicating a two-layer structure. According to our experimental measurements, Ti20Mo alloy appears to possess superior corrosion resistance to that of cp-Ti in artificial saliva. PMID- 20711848 TI - The etiology of stability and change in religious values and religious attendance. AB - Studies have demonstrated little to no heritability for adolescent religiosity but moderate genetic, shared environmental, and nonshared environmental influences on adult religiosity. Only one longitudinal study of religiosity in female twins has been conducted (Koenig et al., Dev Psychol 44:532-543, 2008), and reported that persistence from mid to late adolescence is due to shared environmental factors, but persistence from late adolescence to early adulthood was due to genetic and shared environmental factors. We examined the etiology of stability and change in religious values and religious attendance in males and females during adolescence and early adulthood. The heritability of both religious values and religious attendance increased from adolescence to early adulthood, although the increase was greater for religious attendance. Both genetic and shared environmental influences contributed to the stability of religious values and religious attendance across adolescence and young adulthood. Change in religious values was due to both genetic and nonshared environmental influences specific to early adulthood, whereas change in religious attendance was due in similar proportions to genetic, shared environmental, and non-shared environmental influences. PMID- 20711850 TI - The estimation of the cardiac time-varying parameters during the ejection phase of the cardiac cycle using the Ito calculus. AB - Evaluation of the time-varying parameters (Compliance, Resistance, and Inertance) that describe the right and left ventricles has been of interest for some years. Analyses usually involve a particular assertion regarding energy contributions or of the nature of the parameters themselves. It is of interest to engage the issue with a more general approach by restricting prior assumptions only to that raw data measurement may be noisy and that the parameters are non negative. Here a polynomial in time model is utilized to develop each parameter. Coefficients of the polynomials are estimated from the observed data with use of the maximum likelihood method and stochastic calculus. The pump equation was finally evaluated in full from un-processed pressure and flow data and the method is provided herein. PMID- 20711849 TI - Identification of histones as endogenous antibiotics in fish and quantification in rainbow trout (Oncorhynchus mykiss) skin and gill. AB - Antimicrobial polypeptides (AMPPs) are increasingly recognized as a critical component of innate host defense. Among the AMPPs, polypeptides related to histones have been identified from many animals. Using peptide mapping, we further confirm the identity of two histone-like proteins from fish as members of the H2B (sunshine bass) and H1 (rainbow trout) histone groups. We optimized the conditions for measuring rainbow trout HLP-1/H2B via sandwich ELISA. We used two antibodies, one to the amino terminus and one to the carboxyl terminus, of trout histone H2B, as the capture antibodies, and we used peroxidase-labeled antibody raised to calf histone H2B as the secondary antibody. Specificity of the detecting antibody was confirmed by specific reactivity with histone H2B in tissue extracts via western blotting. The test was reproducible and capable of detecting as little as 5 ng of histone H2B (0.05 MUg/ml). Histone H2B levels expressed in gill tissue of juvenile, healthy rainbow trout were well within concentrations that are lethal to important fish pathogens. However, there was a significant, age (size)-dependent decline in histone H2B concentrations as fish matured, until levels became virtually undetectable in market-size fish. In contrast, levels in skin appeared to remain high and unchanged in small versus large fish. Antibacterial activity in skin and gill tissues was closely correlated with histone H2B concentration measured via ELISA, which supports our previous finding that histones are the major AMPPs in rainbow trout skin and gill. PMID- 20711851 TI - The elusive Minnie G.: revisiting Cushing's case XLV, and his early attempts at improving quality of life. AB - Although researchers have discovered that Minnie G. had nearly 50 years of progression-free survival, the absence of her original surgical records have precluded anything more than speculation as to the etiology of her symptoms or the details of her admission. Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the microfilm surgical records from the Johns Hopkins Hospital, 1896-1912 were reviewed. Using the surgical number provided in Cushing's publications, the record for Minnie G. was recovered for further review. Cushing's diagnosis relied largely on history and physical findings. Minnie G. presented with stigmata associated with classic Cushings Syndrome: abdominal stria, supraclavicular fat pads, and a rounded face. However, she also presented with unusual physical findings: exophthalmos, and irregular pigmentation of the extremities, face, and eyelids. A note in the chart indicates Minnie G. spoke very little English, implying the history-taking was fraught with opportunities for error. Although there remains no definitive etiology for Minnie G.'s symptoms, this report contributes additional information about her diagnosis and treatment. PMID- 20711853 TI - Clinical manifestations of cerebellar infarction according to specific lobular involvement. AB - Lesions in the cerebellum produce various symptoms related to balance and motor coordination. However, the relationship between the exact topographical localization of a lesion and the resulting symptoms is not well understood in humans. In this study, we analyzed 66 consecutive patients with isolated cerebellar infarctions demonstrated on diffusion-weighted magnetic resonance imaging. We identified the involved lobules in these patients using a cross referencing tool of the picture archiving and communication system, and we investigated the relationships between the sites of the lesions and specific symptoms using chi (2) tests and logistic regression analysis. The most common symptoms in patients with isolated cerebellar infarctions were vertigo (87%) and lateropulsion (82%). Isolated vertigo or lateropulsion without any other symptoms was present in 38% of patients. On the other hand, limb ataxia was a presenting symptom in only 40% of the patients. Lateropulsion, vertigo, and nystagmus were more common in patients with a lesion in the caudal vermis. Logistic regression analysis showed that lesions in the posterior paravermis or nodulus were independently associated with lateropulsion. Lesions in the nodulus were associated with contralateral pulsion, and involvement of the culmen was associated with ipsilateral pulsion and isolated lateropulsion without vertigo. Nystagmus was associated with lesions in the pyramis lobule, while lesions of the anterior paravermis were associated with dysarthria and limb ataxia. Our results showed that the cerebellar lobules are responsible for producing specific symptoms in cerebellar stroke patients. PMID- 20711854 TI - Do musculoskeletal degenerative diseases affect mortality and cause of death after 10 years in Japan? AB - There are several reports from Europe and the United States on mortality from musculoskeletal degenerative diseases; however, no reports have been published from Japan. This study is the first that has examined whether musculoskeletal degenerative diseases affect life prognosis in Japan. As many as 944 persons who were 60 years of age and older and who underwent one or more musculoskeletal checkups (knee, lower back, and bone mineral density examination) were enrolled. Survival and death after 10 years were examined. For each knee, lower back, and bone mineral density examination, subjects were divided into normal and abnormal groups. For each of the examinations (knee, lower back, or bone mineral density), 10-year mortality was compared between the two groups. Also, causes of death were examined after 10 years. As many as 805 subjects survived and 125 died. For those with and without osteoarthritis of the knee, mortality after 10 years was 17 and 10%, respectively. For those with and without lower back abnormalities, mortality after 10 years was 12 and 14%, respectively. For those with or without low bone mineral density, mortality after 10 years was 17 and 10%, respectively. Multivariate analysis adjusted for age, gender, body mass index, and lifestyle revealed that odds ratio of death after 10 years was 2.32 and 2.33 in the presence of osteoarthritis of the knee and a low bone mineral density, respectively, and thus the risk of death after 10 years was significantly high. With regard to the cause of death, cerebrovascular and cardiovascular diseases were most frequently evident in patients with osteoarthritis of the knee. Musculoskeletal degenerative diseases influence mortality after 10 years. PMID- 20711855 TI - A radio-sensitive primary osteosarcoma in the lung. AB - We report an unusual case of a primary osteosarcoma of the lung in an asymptomatic 77-year-old male, who underwent lobectomy with complete resection of the lung lesion. His pattern of relapse was to multiple lymph nodes. The first relapse was 11 weeks after lobectomy in subcarinal lymph nodes, confirmed on needle aspiration to be consistent with sarcoma. Given his excellent performance status, this was treated with radical radiotherapy to 70 Gy in 35 fractions with good control. He relapsed to other lymph node regions. A biopsy of the external iliac lymph node was done and revealed osteoid production, consistent with osteosarcoma. He received palliative radiotherapy to several nodal areas with good clinical response. We review the literature of this rare tumor with an unusual pattern of relapse. PMID- 20711856 TI - Substrate specificity and nucleotides binding properties of NM23H2/nucleoside diphosphate kinase homolog from Plasmodium falciparum. AB - Nucleoside diphosphate kinases (NDKs) play a key role in maintaining the intracellular energy resources as well as the balance of nucleotide pools. Recently, attention has been directed to NDKs owing to its role in activating various chemotherapeutic agents. The binding affinity of different nucleotides with P. falciparum NDK was varied according to the following order ADP ~ GDP > dGDP > dADP > dTDP > CDP > dCDP > UDP. The binding of purines nucleotides was stronger than pyrimidines. Furthermore, PfNDK showed more preferences to ribonucleotides over deoxyribonucleotides. Pyrimidines showed lower negative free energy compared with that of purines. The interaction of all nucleotides showed favorable enthalpic and entropic terms. However, the enthalpic terms were the main deriving forces for purine nucleotides, while the entropic contributions were the predominant forces for pyrimidines. Interestingly, TDP showed marked affinity and more favorable enthalpic and less entropic contributions. In conclusion, the size of nucleotide was the critical factor in PfNDK ligand affinity. PMID- 20711857 TI - Evaluating the use of predatory insects as bioindicators of metals contamination due to sugarcane cultivation in neotropical streams. AB - Streams located in areas of sugarcane cultivation receive high concentrations of metal ions from soils of the adjacent areas causing accumulation of metals in the aquatic sediment. This impact results in environmental problems and leads to bioaccumulation of metal ions in aquatic organisms. In the present study, metal concentrations in different predatory insects were studied in streams near sugarcane cultivation and compared to reference sites. Possible utilisation of predatory insects as bioindicators of metal contamination due to sugarcane cultivation from 13 neotropical streams was evaluated. Ion concentrations of Al, Cd, Cr, Cu, Zn, Fe, and Mn in adult Belostomatidae (Hemiptera) and in larvae of Libellulidae (Odonata) were analysed. Nine streams are located in areas with sugarcane cultivation, without riparian vegetation (classified as impacted area) and four streams were located in forested areas (reference sites). Metal concentrations in insects were higher near sugarcane cultivations than in control sites. Cluster analysis, complemented by an ANOSIM test, clearly showed that these insect groups are good potential bioindicators of metal contamination in streams located in areas with sugarcane cultivation and can be used in monitoring programmes. We also conclude that Libellulidae appeared to accumulate higher concentrations of metals than Belostomatidae. PMID- 20711858 TI - Distribution patterns of nitroaromatic compounds in the water, suspended particle and sediment of the river in a long-term industrial zone (China). AB - Nitroaromatic compounds are known to be hazardous to ecological and human health. To assess the status of nitroaromatic compounds contamination in the main rivers in the important industrial bases of the northeastern China, we collected water, suspended particulate matter (SPM) and sediment samples from 28 sites in the Daliao River watershed and analysed them for eight nitroaromatic compounds by gas chromatography. The total concentrations of eight nitrobenzenes in the water column including aqueous and SPM phases ranged from 740 to 15,828 ng L( - 1), with a mean concentration of 3,460 ng L( - 1). The total concentrations of eight nitrobenzenes in the sediment were 7.47 to 8,185.76 ng g( - 1), with a mean concentration of 921.98 ng g( - 1), and several times higher than those found from the Yellow River in China. 4-Nitrotoluene was the predominant contaminant in the water and sediment of the three rivers of the Daliao River watershed. 2,6 Dichloro-4-nitroaniline was generally dominant in the SPM. The levels of nitroaromatic compounds were different among different sites in the Daliao River watershed, mainly caused by the distribution of pollution sources. No obvious correlation was found between the total concentrations of eight nitrobenzenes concentrations and TOC or the slit-clay content of the sediments. PMID- 20711860 TI - Status and future of the forest health indicators program of the USA. AB - For two decades, the US Department of Agriculture, Forest Service, has been charged with implementing a nationwide field-based forest health monitoring effort. Given its extensive nature, the monitoring program has been gradually implemented across forest health indicators and inventoried states. Currently, the Forest Service's Forest Inventory and Analysis program has initiated forest health inventories in all states, and most forest health indicators are being documented in terms of sampling protocols, data management structures, and estimation procedures. Field data from most sample years and indicators are available on-line with numerous analytical examples published both internally and externally. This investment in national forest health monitoring has begun to yield dividends by allowing evaluation of state/regional forest health issues (e.g., pollution and invasive pests) and contributing substantially to national/international reporting efforts (e.g., National Report on Sustainability and US EPA Annual Greenhouse Gas Estimates). With the emerging threat of climate change, full national implementation and remeasurement of a forest health inventory should allow for more robust assessment of forest communities that are undergoing unprecedented changes, aiding future land management and policy decisions. PMID- 20711859 TI - Heavy metal concentrations in some macrobenthic fauna of the Sundarbans mangrove forest, south west coast of Bangladesh. AB - Heavy metal concentrations in some macrobenthic fauna have been reported for the first time from the Sundarbans mangrove forest, south west coast of Bangladesh, in the northern part of Bay of Bengal. The concentration of Fe, Cu, Zn, Cd and Pb in macrobenthos ranged from 235 +/- 10.11 to 1,051 +/- 38.42, 3.66 +/- 0.89 to 7.55 +/- 1.29, 76.8 +/- 8.55 to 98.5 +/- 6.49, 0.46 +/- 0.11 to 0.859 +/- 0.2 and 4.66 +/- 1.17 to 6.77 +/- 2.1 MUg/g, respectively. Significant variations (p <= 0.05) in heavy metal concentrations have been observed among the mud crab, mudskipper and gastropod. However, heavy metal burdens did not vary significantly among the hermit and horseshoe crabs. In mud crab, horseshoe crab and gastropod, heavy metal concentrations were recorded in the sequence: Fe > Zn > Pb > Cu > Cd. Hermit crab and mudskipper contained heavy metals in the order of Fe > Zn > Cu > Pb > Cd. Fe and Zn concentrations were found significantly (p <= 0.05) higher in macrobenthos. The lead (Pb) concentration found in the edible portion of macrobenthos exceeded the international permissible limits certified by the WHO. Bioconcentration factors >1.00 obtained for Fe (17.05 in mudskipper) and Cd (1.87 in gastropod) indicated that these metals were highly bioaccumulated and biomagnified in benthic fauna of Sundarbans. The findings of this study refer to the potential impact of heavy metals in the mangrove ecosystem of Bangladesh. PMID- 20711861 TI - Monitoring and identification of spatiotemporal landscape changes in multiple remote sensing images by using a stratified conditional Latin hypercube sampling approach and geostatistical simulation. AB - This study develops a stratified conditional Latin hypercube sampling (scLHS) approach for multiple, remotely sensed, normalized difference vegetation index (NDVI) images. The objective is to sample, monitor, and delineate spatiotemporal landscape changes, including spatial heterogeneity and variability, in a given area. The scLHS approach, which is based on the variance quadtree technique (VQT) and the conditional Latin hypercube sampling (cLHS) method, selects samples in order to delineate landscape changes from multiple NDVI images. The images are then mapped for calibration and validation by using sequential Gaussian simulation (SGS) with the scLHS selected samples. Spatial statistical results indicate that in terms of their statistical distribution, spatial distribution, and spatial variation, the statistics and variograms of the scLHS samples resemble those of multiple NDVI images more closely than those of cLHS and VQT samples. Moreover, the accuracy of simulated NDVI images based on SGS with scLHS samples is significantly better than that of simulated NDVI images based on SGS with cLHS samples and VQT samples, respectively. However, the proposed approach efficiently monitors the spatial characteristics of landscape changes, including the statistics, spatial variability, and heterogeneity of NDVI images. In addition, SGS with the scLHS samples effectively reproduces spatial patterns and landscape changes in multiple NDVI images. PMID- 20711862 TI - Assessment of seawater impact using major hydrochemical ions: a case study from Sadras, Tamilnadu, India. AB - The impact of seawater intrusion was investigated using major hydrogeochemical ions to evaluate the origin of salinity in Sadras watershed located between Buckingham Canal and Bay of Bengal in the southeastern coast of India. From empirical data collected twice during pre- and post-monsoon seasons, it was found that groundwater was slightly acidic to mildly alkaline, and more than 44% of groundwater samples had EC > 3,000 MUS/cm in both the seasons. Results of principle component analysis (PCA) showed that Na( + ), Cl( - ), Mg(2 + ), and SO[Formula: see text] concentrations had the highest loading factor and the samples affected by saline/seawater were separated from the cluster. Hydrochemical processes that accompany the saline/seawater were identified using ionic changes. It was observed during sampling periods that the mixing due to saline/seawater intrusion varied from 4.82-7.86%. Negative values of ionic change (e (change)) for Na( + ) and K( + ) decreased with the increasing fraction of seawater. Furthermore, salinity, sodium adsorption ratio, percentage of sodium Na (%), and exchangeable sodium percentage in well samples showed that groundwater was unsuitable for irrigation purposes. PMID- 20711863 TI - A methodology for rapid assessment of the environmental status of the shallow aquifer of "Tavoliere di Puglia" (Southern Italy). AB - Anticipating the European Water Framework Directive (2000/60/EC), the Italian Government issued Legislative Decree n.152/99 which sets out rules for classifying the environmental status of national water bodies in order to achieve specific qualitative objectives by 2016. The most recent European Groundwater Directive (2006/118/EC), which was only recognized by Italy in early 2009 (Legislative Decree 30/09), requires such resources to be characterized from a qualitative standpoint and the risk of their being polluted by individual pollutants or groups of pollutants to be evaluated. This paper reports a simple methodology, based on easy-to-apply rules, for the rapid classification of groundwater, and the results of its application to the shallow aquifer of the plain of Tavoliere delle Puglie located in south Italy. Data collected during well-water monitoring campaigns carried out from 2002 to 2003 made it possible to assess the environmental status of the Tavoliere which, unfortunately, was found to be characterized by "significant anthropic pressures on quality and/or quantity of groundwater and necessitating specific improvement actions". PMID- 20711864 TI - Utilization rate of bariatric surgery in an employee-based healthcare system following surgery coverage. AB - Incidence rates for obesity co-morbidities are high for individuals with class III morbid obesity. Bariatric surgery resolves/improves these co-morbidities, along with reduction in healthcare costs. Despite surgery benefits, payors are reluctant to provide coverage for fear of increased demand and costs. This study examines surgery utilization rates following coverage by an employee-based healthcare system. Bariatric surgery utilization rates were measured 1 year before and after healthcare coverage. The data show before coverage that 18 persons had bariatric surgery for a utilization rate of 1.71%. In the year after surgery, 16 persons elected to have bariatric surgery for a utilization rate of 1.42%. These findings should help to dispel the notion by employee-based insurers that coverage of bariatric surgery will lead to high utilization and associated costs in the early-coverage period. PMID- 20711865 TI - Clinical trial report-the final frontier: small intestine. PMID- 20711866 TI - The basal calcium level in fibers of the rat soleus muscle under gravitational unloading: the mechanisms of its increase and the role in calpain activation. PMID- 20711868 TI - Arabinogalactan, a plant polysaccharide, as a new tool for pharmacon clathration. PMID- 20711867 TI - Tris-(2-hydroxyethyl)ammonium 2-methyl- and 2-methyl-4-chlorophenoxyacetate serve as effective inhibitors of thrombocyte aggregation and antioxidants. PMID- 20711869 TI - Changes in the structure of animal communities accompanying eutrophication and pollution of aquatic ecosystems. PMID- 20711870 TI - Genetic variation of Oplopanax elatus (Araliaceae) populations estimated using DNA molecular markers. PMID- 20711871 TI - Organization of the tentacular apparatus of the vestimentiferan tubeworm Riftia pachyptila, Jones 1981 (Annelida, Vestimentifera). PMID- 20711872 TI - Genetic analysis of the intraspecific structure of kilka Clupeonella cultiventris (Nordmann, 1840) (Actinopterigii: Clupeidae). PMID- 20711873 TI - First report of diagonal musculature in phoronids (Lophophorata: Phoronida). PMID- 20711874 TI - Frequency of meiotic recombination in G and R chromosome bands of the common shrew (Sorex araneus). PMID- 20711875 TI - Morphological features of the inertial mass in statocysts of the terrestrial gastropods Helix lucorum and Pomatias rivulare exposed to microgravity. PMID- 20711877 TI - Interspecific relationships of symbiotic amphipods on the red king crab in the Barents Sea. PMID- 20711876 TI - Glutathione and glutathione-S-transferase activities of the vacuoles of the beet (Beta vulgaris L.) roots. PMID- 20711878 TI - A new genus of triconodont mammals from the Early Cretaceous of Western Siberia. PMID- 20711879 TI - The structure of the rat left ventricular myocardium in models of microgravity and artificial gravitation. PMID- 20711880 TI - Effect of the C-terminal domain peptide fragment (65-76) of monocytic chemotactic protein-1 (MCP-1) on the interaction between MCP-1 and heparin. PMID- 20711882 TI - Erratum to: Effects of Anesthetic and Related Agents on Calcium-induced Calcium Release from Sarcoplasmic Reticulum Isolated from Rabbit Skeletal Muscle. PMID- 20711881 TI - Changes in the store-dependent calcium influx in a cellular model of Huntington's disease. PMID- 20711885 TI - Mitochondrial dysfunction and oxidative stress in seizure-induced neuronal cell death. AB - Epilepsy is considered one of the most common neurological disorders worldwide. The burst firing associated with prolonged epileptic discharges could lead to a large number of changes and cascades of events at the cellular level. From its role as the cellular powerhouse, the mitochondrion is emerging as a key participant in cell death because of its association with an ever-growing list of apoptosis-related proteins. Prolonged seizures may result in the mitochondrial dysfunction and increased production of reactive oxygen species and nitric oxide (NO) precede neuronal cell death and cause subsequent epileptogenesis. Emerging evidences also showed that intrinsic mitochondrial apoptotic pathway may contribute to the neuropathology of human epilepsy, particularly in the hippocampus. Subsequent laboratory studies in the animal model of status epilepticus provide credence to the notion that activation of nuclear factor kappaB upregulates NO synthase (NOS) II gene expression with temporal correlation of NOS II derived NO-, superoxide anion- and peroxynitrite-dependent reduction in mitochondrial Complex I activity, leading to apoptotic neuronal cell death in the hippocampus. These results will broaden our understanding on the intimate link between mitochondrial function, oxidative stress and mitochondria-dependent apoptotic signaling triggered by epileptic seizures. It will open a new vista in the development of more effective neuroprotective strategies against seizure induced brain damage by modification of bioenergetic failure in the mitochondria and in the design of novel treatment perspectives for therapy-resistant forms of epilepsy. PMID- 20711886 TI - How late is too late? Timeliness to scheduled visits as an antiretroviral therapy adherence measure in Nairobi, Kenya and Lusaka, Zambia. AB - Collecting self-reported data on adherence to highly active antiretroviral therapy (HAART) can be complicated by patients' reluctance to report poor adherence. The timeliness with which patients attend visits might be a useful alternative to estimate medication adherence. Among Kenyan and Zambian women receiving twice daily HAART, we examined the relationship between self-reported pill taking and timeliness attending scheduled visits. We analyzed data from 566 Kenyan and Zambian women enrolled in a prospective 48-week HAART-response study. At each scheduled clinic visit, women reported doses missed over the preceding week. Self-reported adherence was calculated by summing the total number of doses reported taken and dividing by the total number of doses asked about at the visit attended. A participant's adherence to scheduled study visits was defined as "on time" if she arrived early or within three days, "moderately late" if she was four-seven days late, and "extremely late/missed" if she was more than eight days late or missed the visit altogether. Self-reported adherence was <95% for 29 (10%) of 288 women who were late for at least one study visit vs. 3 (1%) of 278 who were never late for a study visit (odds ratios [OR] 10.3; 95% confidence intervals [95% CI] 2.9, 42.8). Fifty-one (18%) of 285 women who were ever late for a study visit experienced virologic failure vs. 32 (12%) of 278 women who were never late for a study visit (OR 1.7; 95% CI 1.01, 2.8). A multivariate logistic regression model controlling for self-reported adherence found that being extremely late for a visit was associated with virologic failure (OR 2.0; 95% CI 1.2, 3.4). Timeliness to scheduled visits was associated with self reported adherence to HAART and with risk for virologic failure. Timeliness to scheduled clinic visits can be used as an objective proxy for self-reported adherence and ultimately for risk of virologic failure. PMID- 20711887 TI - Accelerated HIV testing for PMTCT in maternity and labour wards is vital to capture mothers at a critical point in the programme at district level in Malawi. AB - Round the clock (24 hours*7 days) HIV testing is vital to maintain a high prevention of mother to child transmission (PMTCT) coverage for women delivering in district health facilities. PMTCT coverage increases when most of the pregnant women will have their HIV status tested. Therefore routine offering of HIV testing should be integrated and seen as a part of comprehensive antenatal care. For women who miss antenatal care and deliver in a health facility without having had their HIV status tested, the labour and maternity ward could still serve as other entry points. PMID- 20711888 TI - Literacy, education and adherence to antiretroviral therapy in The Gambia. AB - We examined the relationship of patients' literacy and education to antiretroviral therapy (ART) adherence in an urban treatment centre in The Gambia. Information on education and literacy systematically collected before ART initiation was compared against selected adherence outcomes. Formally educated patients were significantly more likely to achieve virological suppression at both six and 12 months (87% vs. 67%, OR=3.13, P=0.03; 88% vs. 63%, OR=4.49, P=0.007, respectively). Literate patients had similar benefit at 12 months (OR=3.39 P=0.03), with improved virological outcomes associated with degree of literacy (P=0.003). A trend towards similar results was seen at 6 months for Koranically educated patients; however, this was no longer apparent at 12 months. No significant correlation was seen between socio-demographic characteristics and missed appointments. Our study suggests that literacy, formal education and possibly Koranic education may impact favourably on adherence to ART. PMID- 20711889 TI - Changing sexual behaviour to reduce HIV transmission - a multi-faceted approach to HIV prevention and treatment in a rural South African setting. AB - This community household survey undertaken in Melmoth, a rural area in KwaZulu Natal, South Africa, investigated the influence of cumulative exposure of complementary interventions by a non-governmental organisation, LoveLife which aimed to bring changes in beliefs about HIV and AIDS prevention and treatment, and to reduce sexual risk behaviour. Amongst the 1294 respondents (15-40 years of age) increasing the number of exposures to different LoveLife interventions included use of television and radio messages, billboards, a free monthly magazine for youth, special school sports and community events, involvement of youth peer educators, and support for schools through classroom programmes and by linking clinic staff and peer educators. Cumulative exposure to LoveLife interventions resulted in more respondents believing that HIV could be prevented (p<0.005) and treated (p=0.007) and that people should test for HIV (p=0.03). Half of the respondents reported using a condom at last sex and cumulative exposure to LoveLife was associated with increased condom use (p<0.005). However, despite exposure to LoveLife, only 41.9% respondents had ever tested for HIV and cumulative exposure to LoveLife did not significantly influence respondents going to hospital for anti-retroviral treatment. The dose-response effect of cumulative LoveLife exposure appeared to have a positive influence on some beliefs and practices, but did not discriminate the extent of LoveLife exposure nor exposure to other HIV/AIDS interventions. PMID- 20711890 TI - The living arrangement may differentially influence IDU parents' motivation to reduce HIV risk as a function of gender. AB - Studies that examine data from drug-abusing parents typically investigate the impact of parental behavior on their children's well-being and focus almost exclusively on the impact of mothers. Other approaches have examined the level of parental involvement among parents in drug treatment and find that a higher level of parental involvement is related to lower levels of addiction severity. Recent research examines the specific role of fathers and suggests that the promotion of responsible parenting may serve as a positive motivational influence among fathers participating in drug treatment. The present study investigated the influence of the living arrangement on improvements in HIV-risk reduction variables among 151 IDU parents who participated in the Community-friendly Health Recovery Program intervention. A gender*living arrangement interaction demonstrated greater enhancements in social and personal motivation to reduce HIV risk among fathers currently living with their children vs. fathers not living with their children while the opposite pattern of outcomes was demonstrated for mothers. Findings indicate that a parenting role that includes living with children may differentially influence parents' HIV-risk reduction motivation as a function of gender. PMID- 20711891 TI - Patient referral from nurses to doctors in a nurse-led HIV primary care clinic in South Africa: implications for training and support. AB - Health services in sub-Saharan Africa are under great pressure to provide adequate clinical care due to the continued HIV epidemic, and nurse-driven models of care are one means to address physician shortages. This case-control study examines the reasons for and correlates of patient referral from nurses to physicians at HIV primary care clinics in South Africa prior to initiating antiretroviral treatment. Ninety-seven HIV-infected cases who required physician consolation and 160 controls who did not require physician consultation (matched on gender, age, and date of clinic visit) were consecutively enrolled at both an urban and rural HIV primary care clinic during a 12-month period beginning in March 2006. Univariate and multivariate logistic regression models were used to assess correlates of patient referral to a physician. Cases were more likely to have lower CD4 cell counts and have WHO Stages III and IV disease compared to controls (p<0.05). Predictors of patient referral were a CD4 cell count between 50 and 200 cells/ul (adj OR: 5.27, 95% CI: 2.16-12.88, p<0.0001), a CD4 cell count below 50 cells/ul (adj OR: 3.47, 95% CI: 1.12-10.78, p=0.032), and Stage IV disease (adj OR: 4.58, 95% CI: 1.35-15.60, p=0.015). Additionally, the following ICD-10 clinical diagnoses were associated with patient referral: tuberculosis, aplastic and other anemias, and lower respiratory tract infection (p<0.05). Nurses can provide adequate clinical and diagnostic management for certain clinical conditions to HIV-infected patients. Further studies are needed to examine specifically how HIV healthcare delivery can be scaled-up in resource limited settings with a high burden of HIV, but with a minimal healthcare infrastructure. PMID- 20711894 TI - Structural changes induced by a lytic bacteriophage make ciprofloxacin effective against older biofilm of Klebsiella pneumoniae. AB - Bacteria have evolved multiple mechanisms, such as biofilm formation, to thwart antibiotic action. Yet antibiotics remain the drug of choice against clinical infections. It has been documented that young biofilm of Klebsiella pneumoniae could be eradicated significantly by ciprofloxacin treatment alone. Since age of biofilm is a decisive factor in determining the outcome of antibiotic treatment, in the present study biofilm of K. pneumoniae, grown for extended periods was treated with ciprofloxacin and/or depolymerase producing lytic bacteriophage (KPO1K2). The reduction in bacterial numbers of older biofilm was greater after application of the two agents in combination as ciprofloxacin alone could not reduce bacterial biomass significantly in older biofilms (P > 0.05). Confocal microscopy suggested the induction of structural changes in the biofilm matrix and a decrease in micro-colony size after KPO1K2 treatment. The role of phage associated depolymerase was emphasized by the insignificant eradication of biofilm by a non-depolymerase producing bacteriophage that, however, eradicated the biofilm when applied concomitantly with purified depolymerase. These findings demonstrate that a lytic bacteriophage alone can eradicate older biofilms significantly and its action is primarily depolymerase mediated. However, application of phage and antibiotic in combination resulted in slightly increased biofilm eradication confirming the speculation that antibiotic efficacy can be augmented by bacteriophage. PMID- 20711893 TI - A longitudinal examination of factors predicting anxiety during the transition to middle school. AB - The transition from elementary to middle or junior high school is commonly regarded as a period of stress and turmoil for young adolescents, and has been associated with changes in anxiety and other psychological problems. However, less is known about risk and resilience factors that may predict these changes. This study examined changes in anxiety, as well as predictors of these changes among 77, predominantly Caucasian (88%), male and female (52%) adolescents from Grades 6 to 8. Repeated measures analysis of variance was conducted to examine the predicted grade and gender differences. Multiple regression analyses were conducted to examine the prediction of eighth grade anxiety symptoms by sixth grade self-worth, perceived social acceptance, and social support, as well as the potential moderating role of gender in these relations. Results suggested a significant decrease in anxiety, particularly social anxiety, over this period for boys but not girls. Examination of predictors of changes in anxiety suggested that, in general, global self-worth, social acceptance, and gender were each associated with overall and social anxiety. Findings are integrated with extant literature on developmental changes associated with anxiety and school transitions and clinical implications of these findings are discussed. PMID- 20711895 TI - Hindering biofilm formation with zosteric acid. AB - The antifoulant, zosteric acid, was synthesized using a non-patented process. Zosteric acid at 500 mg l(-1) caused a reduction of bacterial (Escherichia coli, Bacillus cereus) and fungal (Aspergillus niger, Penicillium citrinum) coverage by 90% and 57%, respectively. Calculated models allowed its antifouling activity to be predicted at different concentrations. Zosteric acid counteracted the effects of some colonization-promoting factors. Bacterial and fungal wettability was not affected, but the agent increased bacterial motility by 40%. A capillary accumulation test showed that zosteric acid did not act as a chemoeffector for E. coli, but stimulated a chemotactic response. Along with enhanced swimming migration of E. coli in the presence of zosteric acid, staining showed an increased production of flagella. Reverse transcriptase-PCR revealed an increased transcriptional level of the fliC gene and isolation and quantification of flagellar proteins demonstrated a higher flagellin amount. Biofilm experiments confirmed that zosteric acid caused a significant decrease in biomass (-92%) and thickness (-54%). PMID- 20711897 TI - British Poultry Science, 1960-2009: an analysis of the first 50 volumes. PMID- 20711896 TI - Important scientific subject in the Journal over the last 50 years. Editorial. PMID- 20711898 TI - Behaviour and welfare. AB - 1. We have chosen papers which we feel are representative of important subjects which have been covered by the Journal over a period of 50 years. We would not claim that these are objectively the best papers, for that is a matter of personal judgement, but we consider that they have made significant contributions to knowledge and understanding in poultry behaviour and welfare. 2. John Savory has selected 8 papers from Volumes 1-25 of British Poultry Science (1960-1984), which deal with 5 different aspects of behaviour and welfare: embryonic responses, feather pecking and cannibalism, cage floor preferences, lameness in broilers and myopathy in turkeys. 3. Barry Hughes has selected 11 papers from Volumes 26-50 (1985-2009) of British Poultry Science. Four topics been chosen: broken bones in layers, furnished cages, interaction of birds with machines, and stocking density and bird space. PMID- 20711899 TI - Poultry housing and husbandry. AB - 1. In order to conduct this anniversary review, 10 excellent papers were carefully selected from the 148 available papers published on housing and husbandry in British Poultry Science (BPS) over the past 50 years. 2. The 10 selected papers on this subject covered mainly the housing and husbandry of laying hens, but two of them dealt with various aspects of broiler production. 3. Aspects of housing considered included a wide range of intensive and extensive systems of broiler and egg production. Specific topics included the effects of husbandry system on bird welfare, including skeletal damage in laying hens and contact dermatitis in broiler chickens, as well as the design and management of nest boxes, perches, feeders and drinkers, conventional laying cages (CCs), furnished laying cages (FCs) and non-cage systems (NCs). 4. A variety of the findings in these and related papers have enlightened our understanding of many aspects of poultry housing and husbandry; most of them have found application in the poultry industry and thus improved its efficiency. PMID- 20711900 TI - Lighting, ventilation and temperature. PMID- 20711901 TI - Developments in poultry genetic research 1960-2009. AB - Major advances in the study of inheritance were made in the early 20th century that became the basis for the systematic improvement of chickens for specialised egg or meat production in the last 50 years. The developing sciences of applied poultry breeding are reflected in publications in British Poultry Science during this period and are illustrated by a selection of papers in five areas: (i) papers on the measurement of new phenotypes (disease resistance and egg shell strength); (ii) undesirable correlated responses to selection (reproductive efficiency and bone strength); (iii) genetic interactions (gene-gene and gene environment); (iv) selection for production efficiency (feed conversion efficiency and residual feed intake); and (v) papers illustrating the potential role of technology based on knowledge of variation at the level of the DNA (Quantitative Trait Loci for ascites resistance and polymorphisms in the growth hormone receptor gene). PMID- 20711902 TI - The eggshell: strength, structure and function. AB - In making a journey through the literature of the last 50 years one can easily highlight a sequence of seminal works-but the route has not been direct and to avoid the many profitable diversions and detours that have enriched and deepened our collective understanding of the subject of eggshell structure and function is to do the subject a serious disservice. This is a route march of science enabled by advances in technology. PMID- 20711903 TI - Research into poultry meat quality. AB - 1. Research in the field of poultry meat quality has become more varied during the last 50 years. Besides meat content and microbial condition, animal welfare issues during the slaughter process, muscle morphology, physiology of meat ripening, impact of slaughter process on meat quality, sensory attributes of meat and meat processing have come into focus. 2. The present review summarizes findings and developments in the fields of muscle physiology, meat ripening and meat quality aberrations (like PSE), nutrient composition and sensory qualities, effect of the slaughter process on carcass and meat quality, hygienic conditions and product safety during slaughtering, all based on selected papers published in British Poultry Science during the last 50 years. 3. Some special findings and conclusions are lifted out of the whole results presented in the papers to indicate their importance and to show their contribution to the development of knowledge in the respective field. PMID- 20711904 TI - Nutrition. PMID- 20711905 TI - Novel silver-based nanoclay as an antimicrobial in polylactic acid food packaging coatings. AB - This paper presents a comprehensive performance study of polylactic acid (PLA) biocomposites, obtained by solvent casting, containing a novel silver-based antimicrobial layered silicate additive for use in active food packaging applications. The silver-based nanoclay showed strong antimicrobial activity against Gram-negative Salmonella spp. Despite the fact that no exfoliation of the silver-based nanoclay in PLA was observed, as suggested by transmission electron microscopy (TEM) and wide angle X-ray scattering (WAXS) experiments, the additive dispersed nicely throughout the PLA matrix to a nanoscale, yielding nanobiocomposites. The films were highly transparent with enhanced water barrier and strong biocidal properties. Silver migration from the films to a slightly acidified water medium, considered an aggressive food simulant, was measured by stripping voltammetry. Silver migration accelerated after 6 days of exposure. Nevertheless, the study suggests that migration levels of silver, within the specific migration levels referenced by the European Food Safety Agency (EFSA), exhibit antimicrobial activity, supporting the potential application of this biocidal additive in active food-packaging applications to improve food quality and safety. PMID- 20711907 TI - Archstone Foundation preface. PMID- 20711906 TI - Predicting conversion from mild cognitive impairment to Alzheimer's disease using neuropsychological tests and multivariate methods. AB - Behavioral markers measured through neuropsychological testing in mild cognitive impairment (MCI) were analyzed and combined in multivariate ways to predict conversion to Alzheimer's disease (AD) in a longitudinal study of 43 MCI patients. The test measures taken at a baseline evaluation were first reduced to underlying components (principal component analysis, PCA), and then the component scores were used in discriminant analysis to classify MCI individuals as likely to convert or not. When empirically weighted and combined, episodic memory, speeded executive functioning, recognition memory (false and true positives), visuospatial memory processing speed, and visuospatial episodic memory were together strong predictors of conversion to AD. These multivariate combinations of the test measures achieved through the PCA were good, statistically significant predictors of MCI conversion to AD (84% accuracy, 86% sensitivity, and 83% specificity). Importantly, the posterior probabilities of group membership that accompanied the binary prediction for each participant indicated the confidence of the prediction. Most of the participants (81%) were in the highly confident probability bins (.70-1.00), where the obtained prediction accuracy was more than 90%. The strength and reliability of this multivariate prediction method were tested by cross-validation and randomized resampling. PMID- 20711908 TI - Journal of Elder Abuse & Neglect. Introduction. PMID- 20711910 TI - Advancing the field: the design of the Archstone Foundation Elder Abuse and Neglect Initiative. AB - The Archstone Foundation is a private grantmaking organization whose mission is to contribute toward the preparation of society in meeting the needs of an aging population. In 2006, the Archstone Foundation launched a 5-year $8 million Elder Abuse and Neglect Initiative (Initiative) with the goal of improving the quality and coordination of elder abuse and neglect services in the state of California. Lessons learned through the Initiative may serve to inform the field of elder abuse and the larger philanthropic community. PMID- 20711911 TI - The Archstone Foundation Elder Abuse and Neglect Initiative: outcomes and lessons learned in three years from 2006 to 2008. AB - An independent evaluation of the Archstone Foundation Elder Abuse and Neglect Initiative was conducted to identify major outcomes and lessons learned collectively by 20 funded projects, as well as to document innovative program models for dissemination. Data from the first three years of this initiative show these projects have been productive and have had a measurable impact on services for elder abuse and neglect. Major lessons learned address issues in recruiting, engaging, and maintaining active involvement of diverse stakeholders, as well as innovative and effective models of education, training, and direct services for elder abuse and neglect. PMID- 20711912 TI - The center of excellence on elder abuse and neglect at the University of California, Irvine. AB - The Center of Excellence on Elder Abuse and Neglect at the University of California, Irvine, integrates the work of five discrete but interacting domains related to elder mistreatment. These domains are local projects, research, training and education, technical assistance, and policy and advocacy. The Center is structured in such a way as to maximize information sharing and cross pollination between the domains, build on lessons learned, and explore new ideas. This article describes the history of the Center, offers examples that highlight how the Center works, and considers the future of this model for the field of elder mistreatment. PMID- 20711913 TI - Elder abuse forensic centers. AB - Elder abuse forensic centers present a new model of multidisciplinary collaboration on elder abuse cases. The "clients" of a forensic center are Adult Protective Services (APS), law enforcement, and the Long-term Care Ombudsman. Centers take the basic multidisciplinary team model and add a geriatrician and a psychologist. Additionally, forensic center team members make home visits with APS and others for the purposes of conducting psychological or medical evaluations, lessening the burden of multiple interviews for the alleged abuse victims, and gathering evidence for possible prosecution. The challenges and successes of the four California forensic center teams are discussed. PMID- 20711914 TI - The Bet Tzedek legal services model: how a legal services model addresses elder abuse and neglect. AB - Bet Tzedek, Hebrew for the "House of Justice," provides free legal assistance to older adults in Los Angeles County. Their civil attorneys work alongside prosecutors and service providers for the elderly as members of multidisciplinary teams to assist older adults with complicated elder abuse and neglect cases. Case examples demonstrate how civil attorneys collaborate with the Los Angeles County Elder Abuse Forensic Center to address financial abuse, real estate fraud, and self-neglect issues. Cooperation among the courts, Bet Tzedek, and other county agencies has resulted in more user-friendly processes to expedite filing of conservatorships and elder abuse restraining orders. PMID- 20711915 TI - Geriatricians and psychologists: essential ingredients in the evaluation of elder abuse and neglect. AB - This article describes the clinical work that three sets of geriatricians and psychologists provided in three elder abuse forensic centers in California. After a brief history of how the clinical services in each program developed, the contributions of geriatricians and psychologists within these elder abuse teams are detailed through the use of several case anecdotes. Beyond providing physical and psychological evaluations, geriatricians and psychologists provide consultations and education to other professionals and to elder abuse victims and their caregivers. These clinical teams emphasize the importance of conducting home visits and functional assessments, working with interdisciplinary team members, and providing expert testimony. PMID- 20711916 TI - The successes and challenges of seven multidisciplinary teams. AB - The teams highlighted in this article represent a diversity of Multidisciplinary Teams (MDTs) but share similar challenges and successes. These shared experiences provide an opportunity to explore the key issues germane to MDTs. A hallmark of the elder abuse prevention community from its earliest days, the MDT has proven itself as a helpful and effective tool, one that will continue to add value to the field into the foreseeable future. These teams show that MDTs play a valuable role in helping communities increase collaboration, promoting efficiency in handling complex cases of elder abuse, educating the public, and ultimately safeguarding vulnerable adults from abuse. PMID- 20711917 TI - Changing systems to address elder abuse: examples from aging services, the courts, the long-term care ombudsman, and the faith community. AB - The authors describe their use of systems change as a means of ameliorating elder abuse. After assessing the needs of their target audiences, projects developed a variety of strategies. These include disseminating promising practices in courts, creating Elder Law Clinics to assist with conservatorships, educating older adults about predatory mortgage lending, building a new response system for complaints of abuse and neglect in unlicensed care facilities, and convening clergy and lay leader groups to learn how faith communities can make a difference in elder abuse and neglect. The authors share tips on replicating their work, describing barriers to implementation and possible solutions. PMID- 20711918 TI - Strategies to address financial abuse. AB - Financial abuse is a growing problem for older adults. This article outlines four major strategies for addressing elder financial abuse: (a) education and outreach, (b) general detection and universal screening, (c) legal interventions, and (d) multidisciplinary teams. Future efforts should be devoted to understanding the efficiency and effectiveness of these various strategies in order to keep older adults from becoming victims of financial abuse and to intervene as soon as possible once financial abuse has been identified. PMID- 20711919 TI - Promoting practice-based policy. AB - When service providers participating in the Archstone Foundation's Elder Abuse and Neglect Initiative met to discuss common concerns, they highlighted the need for a sustained and proactive approach to improving California's response to elder abuse. The Advocacy Work Group formed to identify unmet needs and barriers, including the shortage of mental health services for vulnerable older adults, the need for alternatives to guardianship, and insufficient coordination with other constituencies. The Work Group is currently developing a blueprint for promoting dynamic partnerships among stakeholders, facilitating the exchange of information, and advancing informed public policy and service development. PMID- 20711920 TI - Education and training of mandated reporters: innovative models, overcoming challenges, and lessons learned. AB - Several Archstone Foundation funded projects developed and implemented training curricula on elder abuse for mandated reporters such as dentists, adult protective services workers, paramedics, and coroner investigators. Common education and training issues emerged, including the need to provide basic content on normal aging and the need for creating standardized trainings. Strategies include integrating elder abuse and neglect content into existing courses, building relationships with stakeholders, and customizing content and delivery to student needs and preferences. Projects developed relevant, practice based content, decided on curriculum delivery methods, engaged learners, and provided feedback to them. A main outcome is the permanent institution of elder abuse content in training curricula. PMID- 20711921 TI - Creating large systems that work. AB - To meet the challenge of underfunding, creative partnerships are being developed to enhance government and nonprofit programs. This article will describe how to build large systems that work to ameliorate elder abuse and neglect. Projects funded through the Archstone Foundation Elder Abuse and Neglect Initiative in California identify key components of system change, the process by which systems have been built to overcome barriers, and lessons learned for replication. PMID- 20711922 TI - Vision for 2020. AB - This article reflects the collective thoughts of the 20 projects supported by the Archstone Foundation Elder Abuse and Neglect Initiative on offering a vision for improving the response system for elder abuse and, in turn, the lives of older adults between now and the year 2020. Five key areas were identified as critically important for advancing the field in the next ten years: (a) increased public awareness and shifting public attitudes, (b) improved identification and triage of cases, (c) increased integrated service models, (d) improved justice system response, and (e) leveraging and utilizing emerging and untapped resources. The lessons learned from the experiences of these 20 projects in California can serve as demonstration models for other communities to adopt, adapt, and improve response systems for elder abuse and neglect. PMID- 20711923 TI - Maintaining functionality in later years: a review of nutrition and physical activity interventions in postmenopausal women. AB - Independence and quality of life of postmenopausal women are influenced by functional status. Nutrition and physical activity impact functional changes through changes in body composition. The article presents a narrative review of the literature to identify interventions that improve the functionality of community-dwelling postmenopausal women. The authors used the Evidence Analysis Approach developed by the American Dietetic Association to appraise current research. Strong evidence does exist that interventions that incorporate both physical activity and nutrition can improve physical function of older women. However, research focusing on functional status and quality of life, in addition to nutrition and exercise, is extremely limited. PMID- 20711924 TI - Impact of participation in Home-Delivered Meals on nutrient intake, dietary patterns, and food insecurity of older persons in New York state. AB - The aim of this study was to determine if (1) participation in Home-Delivered Meals (HDM) results in improved dietary patterns and nutrient intake, lower food insecurity, and reduced loss of weight; (2) subgroups of older persons are more likely to benefit; and (3) nutritional indicators of impact other than nutrient intake may be useful. The design used was quasi-experimental, with longitudinal assessment of individuals on HDM at baseline (before receipt of services), 6, and 12 months, and comparison to non-randomized group receiving other services. Outcomes included measured weight and height, 24-hour dietary recall, and food insecurity. Paired t test, multiple linear regression, and selection models using multiple logistic regression were performed. All older persons in three New York State counties referred for aging services over a 5-month period were asked to participate (n = 456), and 212 agreed (171 on HDM). At 6 months, the sample size was 101 (34 discharged, 42 hospital/died/moved, 26 chose not to continue), and at 12 months it was 68 (similar reasons). After receiving meals for 6 and 12 months, participants showed greater improvement in most dietary intake variables than either a non-HDM comparison group or HDM participants who ate no HDM meal on the day of assessment. Compared to initial values, participants improved significantly in some variables for dietary patterns, nutrient intake, and nutrient density, and were less likely to be food insecure. Furthermore, HDM was more likely to impact those living alone and those with poorer initial status. This study provides strong evidence that HDM has a positive impact on the nutritional well-being of older persons. Food insecurity and dietary patterns are useful nutritional indicators of impact. PMID- 20711925 TI - Repeatability and validation of a short, semi-quantitative food frequency questionnaire designed for older adults living in Mediterranean areas: the MEDIS FFQ. AB - The aim of the present work was to evaluate the repeatability and the validity of a short food frequency questionnaire (FFQ) that could be used for older people living in Mediterranean areas. The semi-quantitative FFQ included questions regarding the frequency of consumption of the main food groups and beverages typically consumed in the Mediterranean areas as well as some questions regarding eating habits of older persons. During 2006-2007, for the repeatability assessment (within 10-30 days), 150 individuals (51 +/- 17 yrs, 40% males) were studied, while another 190 individuals (74 +/- 9 yrs, 52% males) were enrolled for the validation purposes. Agreement of the FFQ with the 3-day food records was evaluated using the Bland-Altman method and the Kendall's tau-b coefficient. Repeatability was tested using the Cohen's kappa coefficient. Between 3-day food records and the FFQ, good agreement for alcohol (tau-b = 0.64, p < 0.001) was found, while moderate agreement for food and beverage groups of greens (tau-b = 0.32, p < 0.001), fruits (tau-b = 0.35, p < 0.001), cereals (tau-b = 0.61, p < 0.001), sweets (tau-b = 0.51, p < 0.001), and coffee (tau-b = 0.58, p < 0.001) was observed. Low, but still significant, agreement for fish (tau-b = 0.21, p = 0.001), legumes (tau-b = 0.23, p < 0.001), vegetables (tau-b = 0.23, p < 0.001), pasta (tau-b = 0.25, p < 0.001), potatoes (tau-b = 0.17, p = 0.006) and meat consumption (tau-b = 0.14, p < 0.001) were also found. The FFQ was also valid regarding the estimation of macronutrients and energy intake. Sensitivity analyses by sex, age category ( 75 yrs), and education status showed similar validity of the FFQ in each subgroup, except for elders older than 75 years. The repeatability of the FFQ was fair in all foods tested (Cohen's kappa coefficients varied between 0.15-0.39, p-values < 0.05). The suggested FFQ seems to be a reasonably valid and repeatable measure of dietary intake and can be used in older persons living in the Mediterranean areas. PMID- 20711926 TI - Nutrition knowledge of rural older populations: can congregate meal site participants manage their own diets? AB - Congregate meal sites were funded to assist socioeconomically disadvantaged, rural older individuals in improving their health-related practices. Although the participants in the program are largely female, the meals are designed to meet one third of the daily caloric intake of a 70-year-old male, and to satisfy his recommended dietary allowances for total fat, fiber, calcium, and sodium. The actual percentage of the required nutrient intake contributed by meals served at congregate sites is indefinite. Moreover, the ability of congregate meal participants to manage their diets and their receptiveness to helpful nutrition information in that regard is unknown. Our objective was to promote nutritional knowledge in economically disadvantaged, rural older participants by studying its impact on their ability to benefit from congregate meal programs. We used a test, intervention, retest methodology to examine the effect of short-term nutrition interventions on congregate meal site participants' nutrition knowledge. The objective was to determine the participants' potential for managing their own diets (e.g., their ability to determine what diet behaviors are appropriate for specific chronic conditions). We found that while congregate meal site participants have knowledge of nutrition recommendations, their ability to apply this information in helping themselves to prevent or control their chronic conditions remains in question. PMID- 20711927 TI - Toxicity of copper in drinking water. PMID- 20711928 TI - A chronic reference value for 1,3-butadiene based on an updated noncancer toxicity assessment. AB - A chronic noncancer toxicity assessment for 1,3-butadiene (BD) has been conducted by the Texas Commission on Environmental Quality (TCEQ) using information not available to the U.S. Environmental Protection Agency (U.S. EPA) in 2002. The TCEQ developed a chronic reference value (ReV) of 33 microg/m3 (15 ppb). The chronic ReV is based on the same animal study and critical endpoint used by U.S. EPA for ovarian atrophy in B6C3F1 mice, but uses mode of action (MOA) information that indicates the diepoxide metabolite is responsible for ovarian atrophy. In addition, diepoxide-specific hemoglobin adduct data in mice, rats, and humans and other experimental data that became available after 2002 were used to support a conservative data-derived toxicokinetic animal-to-human uncertainty factor (UFA) of 0.3. The default toxicodynamic UFA of 3 was used, together with the data derived toxicokinetic UFA of 0.3, resulting in a total UFA of 1. The necessary experimental data were not available to calculate a chemical-specific adjustment factor, although supporting data suggest the toxicokinetic UFA may range from 0.01 to 0.2. The chronic ReV value, along with a unit risk factor developed by the TCEQ, will be used to evaluate ambient air monitoring data so that the general public is protected against adverse health effects from chronic exposure to BD. PMID- 20711929 TI - Jatropha toxicity--a review. AB - Jatropha is a nonedible oil seed plant belonging to Euphorbiaceae family. Global awareness of sustainable and alternative energy resources has propelled research on Jatropha oil as a feedstock for biodiesel production. During the past two decades, several cultivation projects were undertaken to produce Jatropha oil. In future, the increased cultivation of toxic Jatropha plants and utilization of its agro-industrial by-products may raise the frequency of contact with humans, animals, and other organisms. An attempt was thus made to present known information on toxicity of Jatropha plants. The toxicity of Jatropha plant extracts from fruit, seed, oil, roots, latex, bark, and leaf to a number of species, from microorganisms to higher animals, is well established. Broadly, these extracts possess moluscicidal, piscicidal, insecticidal, rodenticidal, antimicrobial, and cytotoxic properties, and exert adverse effects on animals including rats, poultry, and ruminants. The toxicity attributed to these seeds due to their accidental consumption by children is also well documented. An attempt was also made to identify areas that need further study. The information provided in this review may aid in enhancing awareness in agroindustries involved in the cultivation, harvesting, and utilization of Jatropha plants and its products with respect to the potential toxicity of Jatropha, and consequently in application and enforcement of occupational safety measures. Data on the wide range of bioactivities of Jatropha and its products were collated and it is hoped will create new avenues for exploiting these chemicals by the phamaceutical industry to develop chemotherapeutic agents. PMID- 20711930 TI - Genetic variation at a metallothionein 2A promoter single-nucleotide polymorphism in white and black females in Midwestern United States. AB - Genetic variation leading to differences in expression and regulation of metallothionein proteins may contribute to observed differences among individuals in terms of cadmium (Cd) uptake and metabolism. The aim of this study was to determine the frequency of the A and G alleles at rs28366003, which lies in the 5' promoter region of MT2A, in White and Black females in the Midwestern United States. One-milliliter saliva samples were collected from 298 White or Black adult female volunteers, and DNA was isolated from each sample using Oragene*DNA kits. Allele-specific PCR with gel visualization of amplification products was used to genotype SNP rs28366003. Of the 291 participants (Black = 142; White = 149), the average yield of DNA extracted from the saliva samples was 23.4 microg. The samples, quantitated on a spectrophotometer, achieved an average 260/280 optical density reading of 1.61. The frequency of the G allele was 1.1% for Blacks and 6.4% for Whites. Data demonstrated that the G allele is not common in both the Midwestern U.S. Black and White female population and is less frequent than that reported for an Asian population. PMID- 20711931 TI - Effects of cigarette smoke on the activation of oxidative stress-related transcription factors in female A/J mouse lung. AB - Cigarette smoke contains a high concentration of free radicals and induces oxidative stress in the lung and other tissues. Several transcription factors are known to be activated by oxidative stress, including nuclear factor-kappaB (NF kappaB), activator protein-1 (AP-1), and hypoxia-inducible factor (HIF). Studies were therefore undertaken to examine whether cigarette smoke could activate these transcription factors, as well as other transcription factors that may be important in lung carcinogenesis. Female A/J mice were exposed to cigarette smoke for 2, 5, 10, 15, 20, 42, or 56 d (6 hr/d, 5 d/wk). Cigarette smoke did not increase NF-kappaB activation at any of these times, but NF-kappaB DNA binding activity was lower after 15 d and 56 d of smoke exposure. The DNA binding activity of AP-1 was lower after 10 d and 56 d but was not changed after 42 d of smoke exposure. The DNA binding activity of HIF was quantitatively increased after 42 d of smoke exposure but decreased after 56 d. Whether the activation of other transcription factors in the lung could be altered after exposure to cigarette smoke was subsequently examined. The DNA binding activities of FoxF2, myc-CF1, RORE, and p53 were examined after 10 d of smoke exposure. The DNA binding activities of FoxF2 and p53 were quantitatively increased, but those of myc-CF1 and RORE were unaffected. These studies show that cigarette smoke exposure leads to quantitative increases in DNA binding activities of FoxF2 and p53, while the activations of NF-kappaB, AP-1, and HIF are largely unaffected or reduced. PMID- 20711932 TI - Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing hepatitis B vaccine: influence of gestational age and birth weight. AB - This study examined whether acquisition of neonatal reflexes in newborn rhesus macaques was influenced by receipt of a single neonatal dose of hepatitis B vaccine containing the preservative thimerosal (Th). Hepatitis B vaccine containing a weight-adjusted Th dose was administered to male macaques within 24 h of birth (n = 13). Unexposed animals received saline placebo (n = 4) or no injection (n = 3). Infants were tested daily for acquisition of nine survival, motor, and sensorimotor reflexes. In exposed animals there was a significant delay in the acquisition of root, snout, and suck reflexes, compared with unexposed animals. No neonatal responses were significantly delayed in unexposed animals. Gestational age (GA) and birth weight (BW) were not significantly correlated. Cox regression models were used to evaluate main effects and interactions of exposure with BW and GA as independent predictors and time invariant covariates. Significant main effects remained for exposure on root and suck when controlling for GA and BW, such that exposed animals were relatively delayed in time-to-criterion. Interaction models indicated there were various interactions between exposure, GA, and BW and that inclusion of the relevant interaction terms significantly improved model fit. This, in turn, indicated that lower BW and/or lower GA exacerbated the adverse effects following vaccine exposure. This primate model provides a possible means of assessing adverse neurodevelopmental outcomes from neonatal Th-containing hepatitis B vaccine exposure, particularly in infants of lower GA or BW. The mechanisms underlying these effects and the requirements for Th requires further study. PMID- 20711933 TI - Mutagenicity of diesel exhaust particles from an engine with differing exhaust after treatments. AB - This study was conducted to investigate the effects of engine operating conditions and exhaust aftertreatments on the mutagenicity of diesel particulate matter (DPM) collected directly in an underground mine environment. A number of after-treatment devices are currently used on diesel engines in mines, but it is critical to determine whether reductions in DPM concentrations result in a corresponding decrease in adverse health effects. An eddy-current dynamometer was used to operate naturally aspirated mechanically controlled engine at several steady-state conditions. The samples were collected when the engine was equipped with a standard muffler, a diesel oxidation catalytic converter, two types of uncatalyzed diesel particulate filter systems, and three types of disposable diesel particulate filter elements. Bacterial gene mutation activity of DPM was tested on acetone extracts using the Ames Salmonella assay. The results indicated strong correlation between engine operating conditions and mutagenic activity of DPM. When the engine was fitted with muffler, the mutagenic activity was observed for the samples collected from light-load, but not heavy-load operating conditions. When the engine was equipped with a diesel oxidation catalyst, the samples did not exhibit mutagenic activity for any of four engine operating conditions. Mutagenic activity was observed for the samples collected when the engine was retrofitted with three types of disposable filters and sintered metal diesel particulate filter and operated at light load conditions. However, those filtration systems substantially reduced the concentration-normalized mutagenic activity from the levels observed for the muffler. PMID- 20711934 TI - Public perceptions of natural resource damages and the resources that require restoration. AB - The public and health professionals are interested in restoring degraded ecosystem to provide goods and services. This study examined public perceptions in coastal New York and New Jersey about who is responsible for restoration of resources, which resources should be restored, by whom, and do they know the meaning of natural resource damage assessment (NRDA). More than 98% felt that resources should be restored; more (40%) thought the government should restore them, rather than the responsible party (23%). The highest rated resources were endangered wildlife, fish, mammals, and clams/crabs. Only 2% of respondents knew what NRDA meant. These data indicate that people felt strongly that resources should be restored and varied in who should restore them, suggesting that governmental agencies must clarify the relationship between chemical discharges, resource injury, NRDA, and restoration of those resources to produce clean air and water, fish and wildlife, and recreational opportunities. PMID- 20711935 TI - Nitrates in drinking water and the risk of death from rectal cancer: does hardness in drinking water matter? AB - The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and increased risk of death from rectal cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the effects of nitrate on development of rectal cancer. A matched case-control study was used to investigate the relationship between the risk of death from rectal cancer and exposure to nitrate in drinking water in Taiwan. All rectal cancer deaths of Taiwan residents from 2003 through 2007 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to the cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO(3)-N), Ca, and Mg in drinking water was collected from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO(3)-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO(3)-N exposure level was <0.38 ppm, the adjusted odds ratio (OR) (95% CI) for rectal cancer occurrence was 1.15 (1.01-1.32) for individuals who resided in municipalities served by drinking water with a NO(3)-N exposure > or =0.38 ppm. There was no apparent evidence of an interaction between drinking water NO(3)-N levels with low Mg intake via drinking water. However, evidence of a significant interaction was noted between drinking-water NO(3)-N concentrations and Ca intake via drinking water. Our findings showed that the correlation between NO(3)-N exposure and risk of rectal cancer development was influenced by Ca in drinking water. This is the first study to report effect modification by Ca intake from drinking water on the association between NO(3)-N exposure and risk of rectal cancer occurrence. Increased knowledge of the mechanistic interaction between Ca and NO(3)-N in reducing rectal cancer risk will aid in public policymaking and setting threshold standards. PMID- 20711936 TI - Infantile experience and play motivation. AB - Fully-fledged affective systems in mature animals are in part the result of the impact of infantile experience on brain development. The present experimental series examines whether tactile stimulation in infancy (early handling) influences rough-and-tumble play (R&T) throughout the juvenile period, using a testing regime of 17 days divided into five parts where handled (H) and nonhandled (NH) Wistar rats are assessed daily. In Parts 1 and 2 (age range at the start: 30-33 days) the objective is to study the amount of R&T that the rats are capable of exhibiting under varying lengths of social deprivation. In Part 3 (37-40 days) the objective is to determine whether familiarity with the experimental situation has independent or interactive effects with early handling. In Part 4 (40-43 days) the objective is to obtain evidence of the suppressing effects of an unexpected contextual change. In Part 5 (56-59 days) the objective is to study whether the effects of early handling can still be present at an age when R&T has practically vanished in NH rats. Results show that early handling invigorates R&T affecting pins (i.e., the most rewarding component) at the expense of dorsal contacts by enhancing play motivation in a specific manner, and that it is able to dilate the inverted-U developmental curve of this behavior, thereby providing strong evidence for a direct effect on the neuropsychological systems for play motivation. PMID- 20711937 TI - Generating value(s): psychological value hierarchies reflect context-dependent sensitivity of the reward system. AB - Values are motivational constructs that determine what is important to us and which goals we choose to pursue. Cross-cultural research suggests that the structure of the human value system is universal, but people and cultures differ in terms of relative value priorities. Differences in psychological value hierarchies can be parsimoniously described using the orthogonal dimensions self interest and openness to change. Using fMRI, we investigated whether individual differences in these universal dimensions are reflected in basic neural reward mechanisms during a donation task and a GO/NOGO-task. Individuals with high self interest value sacrificed less money for charitable donations and showed higher activation of the ventral striatum when receiving monetary rewards. Furthermore, individuals with high openness to change value showed a greater sensitivity of the dorsal striatum when trying to inhibit habitual prepotent responses. Our findings suggest that context-dependent neural reward sensitivity biases reflect (and may even determine) differences in individual value hierarchies and underlie the effects of values on decisions and behaviors. PMID- 20711939 TI - Squeeze me, but don't tease me: human and mechanical touch enhance visual attention and emotion discrimination. AB - Being touched by another person influences our readiness to empathize with and support that person. We asked whether this influence arises from somatosensory experience, the proximity to the person and/or an attribution of the somatosensory experience to the person. Moreover, we were interested in whether and how touch affects the processing of ensuing events. To this end, we presented neutral and negative pictures with or without gentle pressure to the participants' forearm. In Experiment 1, pressure was applied by a friend, applied by a tactile device and attributed to the friend, or applied by a tactile device and attributed to a computer. Across these conditions, touch enhanced event related potential (ERP) correlates of picture processing. Pictures elicited a larger posterior N100 and a late positivity discriminated more strongly between pictures of neutral and negative content when participants were touched. Experiment 2 replicated these findings while controlling for the predictive quality of touch. Experiment 3 replaced tactile contact with a tone, which failed to enhance N100 amplitude and emotion discrimination reflected by the late positivity. This indicates that touch sensitizes ongoing cognitive and emotional processes and that this sensitization is mediated by bottom-up somatosensory processing. Moreover, touch seems to be a special sensory signal that influences recipients in the absence of conscious reflection and that promotes prosocial behavior. PMID- 20711938 TI - Amygdala involvement in self-blame regret. AB - Regret-related brain activity is dependent on free choice, but it is unclear whether this activity is a function of more subtle differences in the degree of responsibility a decision-maker exerts over a regrettable outcome. In this experiment, we show that trial-by-trial subjective ratings of regret depend on a higher subjective sense of responsibility, as well as being dependent on objective responsibility. Using fMRI we show an enhanced amygdala response to regret-related outcomes when these outcomes are associated with high, as compared to low, responsibility. This enhanced response was maximal in participants who showed a greater level of enhancement in their subjective ratings of regret engendered by an objective increase in responsibility. Orbitofrontal and cingulate cortex showed opposite effects, with an enhanced response for regret related outcomes when participants were not objectively responsible. The findings indicate that the way the brain processes regret-related outcomes depends on both objective and subjective aspects of responsibility, highlighting the critical importance of the amygdala. PMID- 20711941 TI - Who cares for the caregivers? Why medical social workers belong on end-of-life care teams. AB - Changes within the health care industry have resulted in a shift that, to a large extent, places patients in the position of managing their own health care. While self-determination is desirable, it can also lead to new challenges, as when patients who are critically ill and/or dying must rely on family members to function as primary caregivers and managers of their treatment plans. Typically, patients and their families lack the guidance and oversight of a medical professional to coordinate a multifaceted health care regimen instituted by the variety of specialists involved in patients' diagnoses and treatments. As the patients' health declines and treatment plans become more complex, so too does the level of involvement of family caregivers, who often must manage treatment plans in addition to providing bedside care. This article cites the example of a woman who was exhausted by her role as sole caregiver for her dying husband and describes her feelings of powerlessness within the hospital setting as she struggled to coordinate assistance from her husband's medical specialists during end-of-life decision making. This case illustrates the importance of the following: (a) in cases involving hospitalized patients who require complex care from multiple specialists, it should become standard practice to enlist medical social workers to provide an overall assessment of the patients' status, prognoses, and home care plans, (b) in cases involving prolonged home care culminating in end-of-life decisions, the needs of nonprofessional caregivers must be recognized, evaluated, and addressed. PMID- 20711940 TI - Medial prefrontal cortex subserves diverse forms of self-reflection. AB - The ability to think about oneself--to self--reflect--is one of the defining features of the human mind. Recent research has suggested that this ability may be subserved by a particular brain region: the medial prefrontal cortex (MPFC). However, although humans can contemplate a variety of different aspects of themselves, including their stable personality traits, current feelings, and physical attributes, no research has directly examined the extent to which these different forms of self-reflection are subserved by common mechanisms. To address this question, participants were scanned using functional magnetic resonance imaging (fMRI) while making judgments about their own personality traits, current mental states, and physical attributes as well as those of another person. Whereas some brain regions responded preferentially during only one form of self reflection, a robust region of MPFC was engaged preferentially during self reflection across all three types of judgment. These results suggest that- although dissociable--diverse forms of self-referential thought draw on a shared cognitive process subserved by MPFC. PMID- 20711942 TI - Hardships of raising children with special health care needs (a commentary). AB - Providing health care services for youngsters with special health care needs (SHCN) requires understanding of the medical circumstances that impact on the particular youngster, as well as an increased awareness and sensitivity to their particular family setting, and the issues that impact on the child, his/her parents, and siblings. To this end a review was carried out regarding the variable affects on these youngsters, such as poverty, parental, and family issues, as well as considerations of who is at risk for SHCN and demographics of individuals with SHCN who have unmet health needs. The particular need for dental services, the health service most commonly reported as needed, but not received, is highlighted. PMID- 20711943 TI - "Knowledge is power": educating children about their parent's mental illness. AB - Given the prevalence and associated vulnerabilities of children of parents with a mental illness (COPMI) it is essential to develop appropriate interventions. While education is an important component in many interventions, little is known about what topics are covered, delivery mode, and the efficacy in meeting the needs of this target group. Eighteen facilitators responsible for delivering COPMI programs across Australia were interviewed, fifteen of whom include education about mental illness in their treatment programs. According to program facilitators, education about mental health was important because they believed that knowledge equates to power, and can be cathartic. Education chiefly consisted of signs, symptoms, and treatments of various mental illnesses. The dominant mode of delivery was small and large group discussion. When delivering education, there was some consideration for children's ages. However, there was less differentiation in programs according to the diagnosis of parents' mental illness. Clinical and research implications conclude the article. PMID- 20711944 TI - Analysis of the Uniform Accident And Sickness Policy Provision Law: lessons for social work practice, policy, and research. AB - The Uniform Accident and Sickness Policy Provision Law (UPPL) is a state statute that allows insurance companies in 26 states to deny claims for accidents and injuries incurred by persons under the influence of drugs or alcohol. Serious repercussions can result for patients and health care professionals as states enforce this law. To examine differences within the laws that might facilitate amendments or reduce insurance companies' ability to deny claims, a content analysis was carried out of each state's UPPL law. Results showed no meaningful differences between each state's laws. These results indicate patients and health professionals share similar risk related to the UPPL regardless of state. PMID- 20711945 TI - HIV/AIDS scholarship: an analysis of groundbreaking programs and individuals. AB - The authors report on a bibliometric study of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) scholarship among scholars in schools of social work in the United States. A sample of these HIV/AIDS scholars were accumulated from the faculty interest pages at social work programs accredited by the Council on Social Work Education. From this sample, the publication records, including citations, were examined and those individuals meeting the operational definition of "scholar" were ranked in the final analysis. Social work institutions are also ranked in terms of productivity and impact. Last, the journal outlets that publish the work of social work HIV/AIDS scholars are ranked by publication productivity. The article concludes with a discussion of the strengths and limitations of the method used and future research directions. PMID- 20711946 TI - Screening for intimate partner violence in reproductive health centers: an evaluation study. AB - This study compared rates of intimate partner violence reports on a new, empirically-developed screening tool completed by 385 women in 2007 to those from an older tool completed by 420 women in 2006. Data were obtained from randomly selected medical charts across three health center locations, which were part of the same reproductive health care organization. Chi-square analyses were conducted to test associations between demographic characteristics and partner violence reports. Multiple regression analyses were used to compare odds ratios of disclosure by type of screening tool, adjusting for associated demographic factors associated with partner violence reports. Women completing the old and new tools were similar across all demographic characteristics. After adjusting for age and center location, women completing the new screening form were more than 2.5 times as likely to report any partner violence. When analyzed by mutually exclusive violence history categories, women completing the new screening form were over 2.5 times as likely to report past or current violence and over 4 times as likely to report experiencing both past and current violence. Findings suggest that implementing empirically developed brief screening tools for partner violence in reproductive health settings may elicit more disclosures from patients than more traditional tools. PMID- 20711947 TI - Beliefs about breast cancer and help-seeking intentions for the disease among women in India. AB - Breast cancer is the most frequently occurring malignancy among women in India, however, the recorded stage distribution at presentation in India is less favorable than in Europe. Health beliefs are important in help-seeking for potential symptoms of disease, which may be particularly important among women who do not have access to breast screening programs. The purpose of this study was to examine Indian women's beliefs about breast cancer and help-seeking for the disease and how these beliefs related to their intentions to seek help for a symptom of breast cancer. Furthermore, the study aimed to examine differences in the beliefs of urban- and rural-based women. Of 800 women, 685 were recruited in Allahabad in Northern India (response rate 86%). The women completed a questionnaire examining beliefs about breast cancer and help-seeking. One in four women reported that they would delay seeking help for at least one month following the discovery of a symptom of breast cancer. Rural respondents held more negative beliefs about breast cancer and were also more likely to report less positive attitudes toward help-seeking and a belief that they would be discouraged from seeking help. The findings of the study provide suggestions for the targeting of an intervention aimed at improving early detection and help seeking for breast cancer symptoms. This may be of particular importance in India where a breast cancer screening program does not currently exist and is being debated. PMID- 20711948 TI - The effects of a woman-focused, woman-held resource on preventive health behaviors during pregnancy: the pregnancy pocketbook. AB - We evaluated the effectiveness of a woman-held pregnancy record ('The Pregnancy Pocketbook') on improving health behaviors important for maternal and infant health. The Pregnancy Pocketbook was developed as a woman-focused preventive approach to pregnancy health based on antenatal management guidelines, behavior change evidence, and formative research with the target population and health service providers. The Pregnancy Pocketbook was evaluated using a quasi experimental, two-group design; one clinic cohort received the Pregnancy Pocketbook (n = 163); the other received Usual Care (n = 141). Smoking, fruit and vegetable intake, and physical activity were assessed at baseline (service-entry) and 12-weeks. Approximately two-thirds of women in the Pregnancy Pocketbook clinic recalled receiving the resource. A small, but significantly greater proportion of women at the Pregnancy Pocketbook site (7.6%) than the UC site (2.1%) quit smoking. No significant effect was observed of the Pregnancy Pocketbook on fruit and vegetable intake or physical activity. Few women completed sections that required health professional assistance. The Pregnancy Pocketbook produced small, but significant effects on smoking cessation, despite findings that indicate minimal interaction about the resource between health staff and the women in their care. A refocus of antenatal care toward primary prevention is required to provide essential health information and behavior change tools more consistently for improved maternal and infant health outcomes. PMID- 20711949 TI - Uncertainty and liver transplantation: women with primary biliary cirrhosis before and after transplant. AB - Uncertainty is a frequent feature of chronic illness and can have a particularly important impact in the case of organ transplantation. This study of 100 women with primary biliary cirrhosis who were either waiting for or had already had a liver transplant focused on both changes in uncertainty with transplant and the correlates of uncertainty both pre- and post-transplant. While those who were post-transplant had significantly lower uncertainty scores (measured by the Mishel Uncertainty in Illness Scale-Adult Version-MUIS-A) than those on the waiting list, uncertainty was still persistent and associated with a reduced quality of life. The most significant factors in relation to uncertainty were fatigue, depression, anxiety, and dissatisfaction with medical information received. It is important for both patients and transplant team members to recognize the impact of uncertainty on a patient's well-being, both before and after a transplant, and to address the underlying factors that continue to compromise quality of life even after a life-saving procedure. PMID- 20711950 TI - Promoting folic acid to Spanish-speaking Hispanic women: evaluating existing campaigns to guide new development. AB - Hispanic women are 1.5-3 times as likely as non-Hispanic white women to have a child affected by neural tube defects. This disparity exists in spite of varied interventions designed to address the problem. The purpose of this research was to investigate Hispanic women's knowledge of folic acid, perceptions of existing education campaigns, and provide guidance for future promotion efforts. Three focus groups with Hispanic mothers (N = 18) were conducted to garner insights on these issues. Results suggested that these women understood the benefits of folic acid, did not see major cultural barriers to consuming folic acid-rich foods, and did not perceive insurmountable challenges to consuming a multivitamin with folic acid. For many women, an initial pregnancy served as their initial cue to action, suggesting a need for the continued development of education strategies that communicate the benefits of folic acid supplementation prior to pregnancy. Such strategies may necessitate targeting younger audiences, including teenagers. PMID- 20711951 TI - Effects of maternal high-fat diet on serum lipid concentration and expression of peroxisomal proliferator-activated receptors in the early life of rat offspring. AB - Peroxisomal proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. The aim of this study was to investigate the effects of a maternal high-fat (HF) diet on serum lipid concentration and PPAR gene expression in liver and adipose tissue in the early life of the rat offspring. Female Sprague-Dawley rats were fed either an HF or control (CON) diet 6 weeks before mating and throughout gestation and lactation. Blood and tissue samplings of male offspring were carried out at birth or weaning. Birth weights were similar and serum triglyceride (TG) and nonesterified fatty acid (NEFA) levels showed no significant difference between HF and CON newborns, despite greatly increased hepatic PPARalpha mRNA expression in the HF newborns (p<0.05). Both HF newborns and weanlings revealed significantly decreased hepatic PPARgamma expression compared with controls (p<0.0001). Hepatic PPARalpha expression in the HF weanlings was reduced markedly compared with CON weanlings (p<0.0001) and showed a negative correlation with serum TG levels (r=-0.743, p<0.05). However, epididymal expression of PPARgamma in the HF weanlings was upregulated significantly compared with controls (p<0.05) and demonstrated a positive correlation with epididymal fat mass (r=0.733, p<0.05). These were accompanied by obesity as well as a rise in serum TG by 79% (p<0.05) and NEFA concentration by 36% (p<0.05) in these HF weanlings. Our findings suggest that maternal HF diet leads to alterations in PPAR gene expression in the weanling offspring, which is associated with the disturbed lipid homeostasis. PMID- 20711952 TI - Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. AB - Vitamin D Receptor (VDR) is expressed in both animal and human ovarian tissue, however, the role of vitamin D in human ovarian steroidogenesis is unknown. Cultured human ovarian cells were incubated in tissue culture medium supplemented with appropriate substrates, with or without 50 pM-150 pM or 50 nM-150 nM of 1,25 (OH)2D3, and in the presence or absence of insulin. Progesterone, testosterone, estrone, estradiol, and IGFBP-1 concentrations in conditioned tissue culture medium were measured. Vitamin D receptor was present in human ovarian cells. 1,25 (OH)2D3 stimulated progesterone production by 13% (p<0.001), estradiol production by 9% (p<0.02), and estrone production by 21% (p<0.002). Insulin and 1,25-(OH)2D3 acted synergistically to increase estradiol production by 60% (p<0.005). 1,25 (OH)2D3 alone stimulated IGFBP-1 production by 24% (p<0.001), however, in the presence of insulin, 1,25-(OH)2D3 enhanced insulin-induced inhibition of IGFBP-1 production by 13% (p<0.009). Vitamin D stimulates ovarian steroidogenesis and IGFBP-1 production in human ovarian cells likely acting via vitamin D receptor. Insulin and vitamin D synergistically stimulate estradiol production. Vitamin D also enhances inhibitory effect of insulin on IGFBP-1 production. PMID- 20711953 TI - Diabetes and bone. AB - Traditionally, patients with type 1 diabetes were regarded to be at an increased risk of fractures whereas type 2 diabetics were assumed to be protected from fractures since many of them have high bone mineral density. Nevertheless, several clinical studies consistently demonstrated that type 2 diabetes is a paradigm of a disease with an increased risk of fractures in the presence of high bone mass. The pathophysiology of decreased bone strength in diabetes mellitus is multifactorial: insulin deficiency, insulin resistance, osteoblast insufficiency, vitamin D deficiency, formation of advanced glycation end-products in bone, and microvascular complications appear to contribute. Drugs used for the treatment of type 2 diabetes also may influence bone fragility: thiazolidinedione use has been associated with an increased risk of fractures. PMID- 20711955 TI - [Impact on outcome of whole-body computed tomography during resuscitation of major trauma patients]. PMID- 20711954 TI - [Treatment of complex aortic aneurysms with fenestrated endografts--first results]. AB - BACKGROUND: The continuous development of endografts allows the treatment of complex aneurysms including the renovisceral and thoracoabdominal aortic segment with fenestrated and branched systems. Long-term follow-up studies of the endovascular method do not exist so far. The intention of this retrospective study is to analyse the long-term benefit of this technique. METHOD/PATIENTS: We included 61 patients in this study, who were treated with fenestrated or branched endografts from August 2001 until December 2007 because of abdominal or thoracoabdominal aneurysms. The 56 males and 5 females--73+/-8 years old--were mostly classified as high-risk patients (72% ASA III, 13% ASA VI). All patients underwent clinical follow-up examination and a CT scan. In 60 cases (98%) the endograft was implanted by a percutaneous technique. 85% of the operations could be done under local or regional anaesthesia. In total we integrated 139 renal and visceral vessels in the grafts. RESULTS: The 30-day mortality rate was 0%. During the postoperative days until discharge we documented general--especially cardiac and pulmonary--complications in 16% of the cases. After a mean follow-up time of 27 months (8-84 months) the late mortality rate was 21.3% (n=13). The aneurysm related mortality rate was 4.9% (n=3). The endoleak rate was 6.6% (n=4). During the follow-up time 7 patients permanently became dialysis dependent (11%). The main reasons were acute progressions of chronic renal insufficiency after contrast administration (n=2) and device fractures of bare metal stents. CONCLUSION: The results of this study show the feasibility of endovascular treatment of complex aortic aneurysms even in multimorbid patients with minor postoperative mortality and morbidity. One essential factor for success is a strict patient selection on the basis of anatomic criteria and the use of durable stent material (covered stent grafts as a bridging device). PMID- 20711956 TI - [Indication and extent of cervical lymph node dissection in differentiated thyroid carcinoma]. AB - INTRODUCTION: Indication and extent of lymph node dissection in differentiated thyroid carcinoma are still subject to controversy. The overall favourable prognosis, low study numbers and the different biological features of papillary and follicular carcinoma lead to few evidence-based recommendations and a low level of evidence. The different therapeutic and operative strategies are illustrated on the principles of evidence-based medicine. MATERIAL AND METHODS: A literature search was carried out in Medline and EMBase using the keywords differentiated/papillary/follicular thyroid carcinoma, lymphadenectomy, lymph node dissection. RESULTS: PTC: Eleven retrospective studies outline the effect of prophylactic vs. no lymph node dissection on tumour relapse rate and long-term survival. Six of these studies combine PTC and FTC. A minor evidence-based recommendation for prophylactic cervico-central lymph node dissection in PTC can be given (evidence level 3). Lymph node dissections involving the cervico-lateral compartment can be recommended in the case of clinically pathological findings at the lymph nodes (evidence level 3). A prophylactic mediastinal lymph node dissection is not indicated (evidence level 4), a therapeutic mediastinal LAD cannot be recommended because of higher morbidity and mortality (evidence level 3). FTC: 3 retrospective studies outline the effect of prophylactic lymph node dissection on tumour relapse rate and long-term survival. Based on these, a recommendation for prophylactic cervico-central systematic lymph node dissection can be given for invasive follicular carcinoma (evidence level 3). There is no indication for prophylactic cervico-lateral or mediastinal lymph node dissection (evidence level 3). CONCLUSION: The following recommendations can be given in differentiated thyroid carcinoma: In the case of clinically pathological findings in cervical lymph nodes, a systematic lymph node dissection of the lateral and central compartment is indicated (evidence level 3). Prophylactic cervico-central lymph node dissection is recommended for PTC larger than 10 mm in diameter and invasive FTC, a cervico-lateral or mediastinal prophylactic lymph node dissection is not indicated (evidence level 3). In papillary microcarcinoma and minimally invasive follicular carcinoma, a prophylactic lymph node dissection is not indicated (evidence level 3). PMID- 20711957 TI - [Technical aspects, indications and results of small bowel videocapsule endoscopy]. AB - BACKGROUND: Videocapsule endoscopy is a new non-invasive endoscopic tool useful for small bowel examination. AIM: The aims of this review are to precise the technical aspects of videocapsule endoscopy, indications and results of this technique in clinical practice. METHODS: Literature review. RESULTS: The main indication of videocapsule endoscopy is obscure gastrointestinal bleeding. Videocapsule endoscopy can precise the aetiology of the bleeding and guide the therapeutic approach. The second indication is Crohn's disease, in establishment of the diagnosis, evaluation of small bowel extension or in differential diagnosis of indeterminate colitis. Videocapsule endoscopy is also useful in patients with small bowel neoplasia, polyposis and some patients with celiac sprue. CONCLUSION: Videocapsule endoscopy is an important endoscopic technique which is must be quickly part of endoscopic diagnosis tools. PMID- 20711958 TI - [Tobacco use among paramedical students in Tunis]. AB - AIM: To assess smoking habits among Tunisian paramedical students, and their attitudes and knowledge about smoking. METHODS: During the first quarter of the school year 2002-2003 we investigate 1288 paramedical students of the College of Sciences and Techniques of the Health in Tunis. The smoker was the student who declare to smoke daily or by occasionally at the time of the survey. RESULTS: About three quarters of the students (77,2 %) were female and half of them was less than 20 years old. Smokers were those who smoked daily or occasionally. The prevalence of smoking was weak but it was 10 fold higher in male than in female (35,5% vs 3,5%) The rate of the ex-smokers was 4,1 %. Progress in studies does not affect smoking behaviour. The knowledge of tobacco induced diseases was generally good. However, there was substantial underestimation of tobacco contribution to causing bladder cancer, coronary artery disease and peripheral vascular disease. The study evidences insufficient awareness of medical students about their responsibilities for heath education and prevention. CONCLUSION: It is recommended to improve tobacco control educational programs at the paramedical students with elaboration of practical smoking cessation trainings. PMID- 20711959 TI - [The prophylaxis of the thromboembolic disease in the head trauma]. AB - BACKGROUND: The prophylaxis of the thromboembolic disease in the severe head trauma remains a controversy. AIM: In this study, we are interested to the determination of under groups of patients for whom the advantages of the prophylaxis of the thromboembolic disease (TED) are higher than its disadvantages. METHODS: We proceeded to a retrospective study based on patient medical records ranging from March 2003 until March 2004, enrolling 56 consecutive patients. The data collected related to the age, the gender, past medical history, the type of trauma, results of the initial CT scan, the treatment, appearance or not of the thromboembolic disease and its prophylaxis therapy. RESULTS: The average age was of 36 +/- 19 years. 76.8% did not have significant past medical history. All the patients profited from an elastic compression stocking. The LMWH were used among 15 patients victim of severe head trauma associated with other injuries and 72 hours after stabilization of hemorrhagic attacks. A thromboembolic disease diagnosis was based clinical or biological assumptions. Among 56 patients, 4 of them showed a TED with an incidence of 7.1 including 3 DVT and one case of pulmonary embolism. The 4 patients sustain severe multiple trauma; 3 of them received an early anti coagulation therapy. In the group of patients with TED, the OMEGA scores and IGS are high; all of them are multiple traumatized patients with shock requiring a blood transfusion in 75 of the cases. Only the blood transfusion is correlated at the risk of TED, statistically established. CONCLUSION: The risk to develop a thromboembolic complication in the traumatic patients with head injury is high particularly in case of associated muscleskeletal injuries. Elastic compression technique is not always effective but considered as an interesting alternative to the pharmacological prevention of thrombosis. The use of the anticoagulants therapy must be careful. It is contra-indicated in case of cerebral haemorrhage in progress and must be considered upon individual case of each patient. PMID- 20711960 TI - [The contribution of the new scale for assessing disability]. AB - PROBLEM: The assessment of disability and its management is complex and problematic. With a view to ensuring equality of opportunity between disabled people and others, a new law adopted in August 2005 proposed a new method for assessing disability is applicable on a wider scale by GPs. AIM: Assessing the contribution of the new scale for assessing disability in patients suffering from debilitating diseases, to verify compliance in Tunisia. METHODS: Cross-sectional study on 60 hemiplegic, paraplegic and post traumatic head injuries. The patients underwent clinical evaluation and a functional assessment. The assessment tools used were: the classification of the American Spinal Injury Association, the Barthel Index, Glasgow Outcome Scale, Functional Independence Measure, the Health Assessement Questionnaire and the Social Function-36. Patients were also evaluated with the new scale of disability. RESULTS: concerning paraplegic patients, limitation of activity concerned mobility, maintenance staff, domestic life, social relationships, community life and major areas of life. On the hemiplegic, areas related to communication, mobility, maintenance staff, domestic life, social relationships, community life and major areas of life have been affected. We have noted a correlation between the new scale and the Barthel Index. Regarding traumatic brain injury, the areas most affected were those related to mobility, maintenance staff, domestic life and the major areas of life. A correlation was found between the new scale and the Functional Independence Measure in three populations, as well as the quality of life that has been correlated with disability. Disability was observed in 90% of paraplegics, 80% and 50% of hemiplegic patients with severe brain injury. The handicap was the heaviest seen in traumatic brain injury patients with a frequency of 20%. CONCLUSION: The new scale for assessing disability has reproduced disability and special needs of paraplegic patients, stroke patients and traumatic brain injury. PMID- 20711961 TI - [Posterior uretral valves. About a series of 44 cases]. AB - OBJECTIVE: To explore the physical symptoms and radiological findings for the diagnosis of posterior urethral valves (PUV), to point of the therapeutic snags depending on gravity and delay of lesions. METHODS: We reviewed the records of 44 patients with PUV. Mean age: 2 years 1/2 (range 1 day-13 years). More than 75% of patients were less than 2 years old. RESULTS: In utero diagnosis was made in 8 patients (14%). After birth, the diagnosis was based on urological signs (as frequent as diagnosis is made belatedly) and extra urological signs. Cystourethrography (CUG) showed posterior urethral dilatation in all cases. Ultrasonography (US) showed abnormalities in 30 cases and intravenous urography (IVU), made in 21 cases, was normal in appearance in 7 of them. At diagnosis, it was a renal failure in 36 patients and 8 of them had a terminal renal deficiency. Urethroscopy made in 40 patients, showed PUV in all cases. There were 29 type I valves, 3 type II valves, 5 type III and 3 unclassifiables cases. Treatment was endoscopic in 41 cases and by lamination in the 3 others. Mean follow up is 9 years (range 16 months-19 years) and 19 patients have terminal renal failure from which 3 are deceased. CONCLUSION: PUV are dangerous obstructive uropathies in boy whom end at terminal renal failure in more than 33% of cases. Precocious diagnosis and early ablation of PUV are able to limit the complications inherent to this pathology. PMID- 20711962 TI - [Epidemiological and chronological profile of the parturientes in the extreme ages in the monastir region between 1994 and 2003]. AB - BACKGROUND: Pregnancy outside 19 - 34 years interval is risk factors of the maternal and fetal morbidity and mortality. Tunisia, witch known an epidemiological transition, implanted the national program of perinatality since 1990 and one of its objectives is the surveillance of the high risk pregnancies. AIM: The aim of this study is to draw up the epidemiological profile of the parturient in extreme ages in the region of Monastir and to study the chronological tendencies of the associated factors during a decade (1994 - 2003). METHOD: In all, the study interest 13225 extreme ages parturient, representing 22.5% of all women admitted for delivery in the public maternities of the district. RESULTS: The means age was 18.6 +/- 0.6 years for the parturient less than 20 years and 37 +/- 2 years for the older than 35 years and more, among them 40% were older primipara. The prenatal care was inadequate for 35.4% of younger women and 47.6% of aged women. During the decade, we notice a significant decrease of the frequency of pregnancy for teenager parturient (from 3 in 1994 to 1.99% in 2003), and increase for the aged parturient (from 14.7 in 1994 to 17.7% in 2003) (p < 0.001). Adequate prenatal care increased and the frequency of parturient without any follow-up decreased (from 17.2 to 2%) (p < 0.001). CONCLUSION: Given to this demographic and social transition, our healthcare system is called for greater vigilance and a more rigorous application of the recommendations of the national program of perinatality. PMID- 20711963 TI - Relationship between subcutaneous adipose tissue expression of leptin and obesity in Tunisian patients. AB - BACKGROUND: The incidence of obesity has dramatically increased in overall the world. It is a consequence of imbalance between energy intake and energy expenditure. Leptin is a fat derived adipokine that has emerged over the past decade as a key hormone in the regulation of food intake and energy expenditure. Elevated leptin levels are found in obese humans, suggesting a role of leptin in regulating body weight and adiposity. AIM: The aim of this study was to investigate the change of leptin mRNA expression level and its correlation with obesity and several metabolic variables in Tunisian patients. METHODS: Real time quantitative polymerase chain reaction (QPCR) analysis was carried out among two groups who underwent an abdominal surgery: controls (n = 9) and obese patients (n = 7). RESULTS: Leptin mRNA expression in subcutaneous adipose tissue was markedly increased in obese patients (p < 0.01). It was positively correlated with measures of obesity waist circumference (WC) (r = 0, 71, p < 0.01) and body mass index (BMI) (r = 0, 68, p < 0.01). Interestingly, leptin gene expression was also correlated to insulin resistance index (r = 0, 72, p < 0.01). CONCLUSION: The present study is the first investigation of leptin regulation in subcutaneous adipose tissue of Tunisian population. Our data showed that leptin levels are higher in obese subjects than in control subjects. This indicates that the subcutaneous adipose plays an important role in impaired adipokine regulation, and consequently in developing metabolic disorder. PMID- 20711964 TI - Correlation between liver biopsy and fibrotest in the evaluation of hepatic fibrosis in patients with chronic hepatitis C. AB - AIM: To assess the diagnostic value of Fibrotest in comparison with liver biopsy, for the evaluation of hepatic fibrosis in patients with chronic hepatitis C. METHODS: This prospective study included in 2 years (2006-2007), consecutive patients with chronic hepatitis C naive to treatment. Fibrotest and liver biopsy were performed. Receiver operating characteristics (ROC) curves , the sensitivity, specificity, positive and negative predictive values were used to assess the diagnostic value of Fibrotest in comparison with the METAVIR classification. RESULTS: We recruited a total of 65 patients: 28 males and 37 females (mean age: 50 years); 92% of the patients had genotype 1. The histological fibrosis results were: 3.1% F0; 24.6% F1; 32.3% F2; 29.2% F3 and 10.8 % F4. The diagnostic value of Fibrotest in the detection of significant fibrosis (F2-F4) was 0. 87. A score > 0.5 has a sensitivity of 85. 1%, a specificity of 72. 2%, a positive predictive value of 88. 9%,and a negative predictive value of 65%. The diagnostic value of Fibrotest in the detection of cirrhosis (F4) was 0. 85. There were 13/65 cases of discordance (20%) for fibrosis, 4 cases were attributable to biopsy and 6 cases to Fibrotest. The discordance was unexplained in 3 cases. the size of biopsy< 15 mm [OR=2. 82, 95% CI, 1. 3-6. 07; p = 0. 008] and the stage of fibrosis F0, F1, F2 [OR =3. 35 , 95% CI, 1. 1-10. 2; p=0. 03] were considered as risk factors of discordance in multivariate analysis. CONCLUSION: This prospective study confirmed the good diagnostic value of Fibrotest as compared with the histological analysis of liver biopsy. PMID- 20711965 TI - Medical research productivity of Lebanon: a bibliometric study of papers indexed in Medline, 1985-2004. AB - BACKGROUND: Analysis of biomedical publications of a country is used to monitor research trends which leads to a better formulation of health policy planning and management. AIM: We sought to describe the Lebanese medical publications productivity over a 20 years period from 1985 to 2004. METHODS: Medline's database was consulted and the query contained the name of the country, the medical universities, the main teaching hospitals, and cities, both in French and in English. The articles with a Lebanese health affiliation were included and the articles of dentistry, veterinary, nursing and pharmacy were excluded. RESULTS: We counted 1964 medical articles over a two-decade period. The productivity was 2,9 articles/100000 capita/year and 9,2 articles/billion US dollars GDP/year. The growth rate of publication drew a decline passing from 202% (1990-1994) to 55,3% (2000- 2004). The four most productive specialties (Anesthesiology, Internal medicine, Gynecology, Pediatrics) published 611 articles (31,1%). The governorate of Beirut, the American University of Beirut and its teaching hospital published the most with respectively 1926 (98%), 568 (28,9%), and 601 articles (30,6%). CONCLUSION: The Lebanese medical productivity was weak and unstable mainly due to the lack of financial resources and the instability of the region. Increasing research funding, improving the physicians' research methodology and writing capacities are likely needed to improve the Lebanese medical output. PMID- 20711966 TI - [Management of blunt duodenal and pancreatic injuries in children (about a series of 8 cases)]. AB - AIM: The aim of this retrospective study is to report eight cases of blunt duodeno-pancreatic trauma in infants, emphasizing on the role of imaging in acute assessment of the lesions and in further management. METHODS: We reported eight cases of duodeno-pancreatic injuries between 2006 and 2008, 5 boys and 3 girls with an age ranging from 3 to 12 years (median age: 7 years). Trauma circumstances were: car accident (n=2), domestic injury (n=5) and bicycle's fall injury (n=1). All patients underwent abdominal ultrasonography and CT scan in the initial evaluation and during the follow-up. RESULTS: Imaging showed the following pancreatic lesions: 3 corporeal fractures, 2 caudal fractures and one between the corporeal and the caudal portions. Four pancreatic haematomas were found. The associated lesions were duodenal, splenic, hepatic and renal. Two isolated duodenal haematomas were found. Two patients improved spontaneously, the six others developed complications: 4 acute pancreatitis, two infections, 3 pseudocysts and one retroperitoneal collection. Management was chirurgical in one case, medical in two cases, endoscopic in 2 cases and three percutaneaous drainages were performed. CONCLUSION: Blunt duodeno-pancreatic injuries in children have to be evaluated by an early imaging modality, in order to perform acute assessment of the lesions. Primary conservative treatment is advocated while clinic, biologic and imaging follow-up is required to detect complications, which management can be endoscopic, percutaneous or surgical. PMID- 20711967 TI - [The mobile: a new addiction upon adolescents]. AB - AIM: This survey was conducted to investigate mobile phone use and dependence in Tunisian high school students. METHODS: Questionnaires were anonymously distributed to 120 adolescents looking for the modalities of use of mobiles. SMS dependency was assessed with the French version of the Igarashi scale. RESULTS: The two most used means for communication were SMS and missing calls. 83.2% of the sample sent more than 6 missing calls per day. According to the Igarashi scale, adolescents reported perception of excessive use in 31. Seven percent of cases, emotional reaction in 33.4% of cases and exclusive relationship maintenance thanks to mobile in 18% of cases. CONCLUSION: This study demonstrated a anew addictgion to mobile phone among tunisian high school students. PMID- 20711968 TI - Rosacea: 244 Tunisian cases. AB - BACKGROUND: Rosacea is a common, chronic facial dermatosis of uncertain etiology, several well-defined types and variable progression. There is a paucity of epidemiologic studies from North African countries especially in Tunisia. AIM: to determine epidemiological, clinical, histological features, treatment and outcome of rosacea in a Tunisian study. METHODS: A retrospective study of all rosacea cases diagnosed in the outpatient Dermatology Department of Charles Nicolle hospital of Tunis was conducted between 1990, January and 2003, May. RESULTS: Our study included 244 patients. The diagnosis of rosacea was made on symptoms and clinical features in 185 cases and on histological findings in 59 patients. The hospital prevalence of rosacea was 0.2%. The sex ratio M/F was 0,4. Patient's Mean age was of 49 years. Triggered factors mentioned included most often: sun exposure (64%) and thermal stimuli (25%). Mean duration between the onset of symptoms and the first consultation was about 20 months. The rosacea subtypes were: erythematotelangiectatic type (12%), papulopustular rosacea (69%), and rhinophyma (3.7%). Granulomatous rosacea was diagnosed in 8 patients and steroid rosacea in 28 cases. Ocular rosacea was observed in 41 cases. Treatment modalities included: topical treatment (1.6%), systemic treatment (85%), systemic and topical treatment (5%) and surgical procedures (1.2%). CONCLUSIONS: Rosacea seems to be a frequent dermatosis in Tunisia where most of the population is phenotype IV-V. It affects mostly middle-aged women. Most of our patients present with papulopustular rosacea (69%). More epidemiological and clinical studies in North African countries should be conducted to emphasize these results. PMID- 20711969 TI - Mediastina Tuberculosis mass in a three-month-old boy. AB - BACKGROUND: Mediastinal mass of tuberculous origin is exceedingly rare in infant. AIM: to report an exceedingly rare case of mediastinal mass of tuberculous origin. CASE REPORT: We report a three-month-old boy who presented a one month history of wheezing and persistent pneumopathy. Radiological investigations showed a large posterior mediastinal mass which infiltrates lungs. Thoracoscopic biopsy showed caseous necrosis with granuloma suggestive of tuberculosis. The outcome was favourable with antituberculous chemotherapy. CONCLUSION: Mediatinal mass of tuberculous origin should considered in differential diagnosis of mediastinal masses in children; be suggested in mediastinal mass in children. PMID- 20711970 TI - [Unexpected diagnosis of a cystic pelvic mass: benign mesothelioma of the uterus: case report]. AB - BACKGROUND: Benign mesothelioma is a rare tumour mostly found in the genital tract. CASE: We report the case of 30-years old woman presenting pelvic pain. The ultrasound scan revealed a cystic pelvic mass. Laparoscopic exploration showed a uterine posterior formation. The resection of the dome was performed. Histologic exam and immnunochemistry concluded to a benign cystic mesothelioma. CONCLUSION: The benign mesothelioma of the uterus is usually discovered in histology, differential diagnosis for solid forms can be made with leiomyoma or adenomyoma, whereas the cystic forms can be discussed essentially with the ovarian cysts. The presence of mesothelial immunophenotype in immunochemistry improves diagnosis. Clinical outcome is always favourable without recurrence or malignant transformation. PMID- 20711971 TI - [Pseudotumoral villonodular synovitis : a case report]. AB - BACKGROUND: Pseudotumoral pigmented villonodular synovitis is rare and diagnosis is difficult. AIM: Report of new case. CASE: We report an original observation of a pseudotumoral pigmented villonodular synovitis occurred in a 28 years old patient with no recurrence after surgical treatment. A review of the literature was made in order to precise the epidemiological, diagnostic and therapeutic characteristics. PMID- 20711972 TI - Pallister-Killian syndrome with additional manifestations of cleft palate and sacral appendage. AB - AIM: Reppor of a rare congenital abnormalities. OBSERVATION: We report a rare case of Pallister-Killian syndrome in a 33 weeks gestation infant. In addition to the characteristic phenotype, this patient had a cleft palate, diaphragmatic hernia and sacral appendage. These additional manifestations are not among the Pallister-Killian syndrome's features. The diagnosis was made in antenatal period by cytogenetic studies and showed mosaic 47, XY+i (12p). Presence of diaphragmatic hernia makes this syndrome, prenatally letal, similar to the Fryns syndrome and then requires skin biopsy and fibroblast chromosome examination for cytogenetic diagnosis. PMID- 20711973 TI - [A particular form of fracture separation of extra-pedicle-laminar body: value of tomodensitometry]. PMID- 20711974 TI - [Disseminated miliary lupus of the face]. PMID- 20711975 TI - Developmental hematopoiesis - preface. PMID- 20711976 TI - Developmental hematopoiesis: historical background and perspectives. An interview with Nicole le Douarin. Interview by Charles Durand and Thierry Jaffredo. AB - Nicole le Douarin has shown a long lasting interest for developmental hematopoiesis. Starting from her early research experience, we travel along the main discoveries and concepts that have shaped the modern view of developmental hematopoiesis. All through, we survey the seminal contribution of the "Ecole de Nogent" about lymphocyte homing and the discovery of endothelial-specific tyrosine kinases. This interview is a promenade through the past and present of developmental hematopoiesis narrated by an exceptional personality and an outstanding scientist. PMID- 20711977 TI - Dissecting hematopoietic differentiation using the embryonic stem cell differentiation model. AB - Embryonic stem cells (ESCs) have been successfully used to study the generation of the hematopoietic lineage. The ESC differentiation model provides access to distinct developmental stages during hematopoietic differentiation enabling us to study developmental transitions in a manner that is difficult to do with embryos. The identification of the bipotential hemangioblast/blast-colony forming cell (BL CFC) which represents the earliest stage of hematopoietic commitment in ESC cultures has enabled the study of signalling pathways, transcription factors and enzymes at the level of this developmental stage. Reporter ESC lines, flow cytometry and serum-free culture reagents are helping the field to transition from serum-containing protocols to step-wise serum-free differentiation strategies that attempt to mimic the developmental processes in the embryo. This serves as a framework with which to approach directed differentiation of human ESCs for the purposes of regenerative medicine. This review is focused on the contributions that the ESC differentiation system has made to understanding hematopoiesis and will highlight the strengths of this model of development and the challenges it still faces. PMID- 20711979 TI - Primitive erythropoiesis in the mammalian embryo. AB - Erythropoiesis in adult mammals is characterized by the progressive maturation of hematopoietic stem cells to lineage-specific progenitors, to morphologically identifiable precursors which enucleate to form mature erythrocytes. In contrast, primitive erythropoiesis is characterized by the appearance within the yolk sac of a transient, lineage-restricted progenitor population which generates a wave of erythroid precursors. These precursors undergo progressive maturation in the bloodstream, characterized by nuclear condensation and embryonic hemoglobin accumulation. This process is dependent on erythropoietin signaling through its cognate receptor, as well as the function of several erythroid-specific transcription factors, including GATA1 and EKLF. Targeted disruption of genes in the mouse that result in failure of the emergence or maturation of the primitive erythroid lineage leads to early fetal death, indicating that the primitive erythroid lineage is necessary for survival of the mammalian embryo. While it was thought for over a century that primitive erythroid cells were uniquely nucleated mammalian red cells, it is now recognized that they, like their definitive erythroid counterparts, enucleate to form reticulocytes and pyrenocytes. This surprising finding indicates that the primitive erythroid lineage is indeed mammalian, rather than non-mammalian, in character. PMID- 20711980 TI - The origin and fate of yolk sac hematopoiesis: application of chimera analyses to developmental studies. AB - During mammalian development, as exemplified by mice, hematopoietic cells first appear in the yolk sac blood islands, then in the dorsal aorta of the aorta-gonad mesonephros (AGM) region and the placenta, eventually seeding into liver, spleen and then bone marrow. The formation of hematopoietic stem cells from mesodermal precursors has finished by mid-fetal life. Once established, the hematopoietic system must supply blood cells to host circulation and tissues for the entire life of the animal. Easy access to hematopoietic cells has enabled a vast number of studies over the last several decades, and much is now understood about the different hematopoietic lineages, how they differentiate, and their derivation from immature progenitors. Yet to be elucidated are the following two intriguing questions: do yolk sac and AGM hematopoietic cells arise from a common precursor or from distinct precursor cells?; and what is the lineage relationship between blood and endothelial cells. In this review, we will survey the state of our current knowledge in these areas, and discuss the potential use of multicolor chimera analyses to elucidate unresolved questions. PMID- 20711978 TI - Novel methods for determining hematopoietic stem and progenitor cell emergence in the murine yolk sac. AB - The mammalian yolk sac is known to play a prominent role in emergence of the hematopoietic system. The extent of this contribution has been a subject of debate in recent years largely due to effects of the early circulation that obscures the site of origin of hematopoietic stem and progenitor cells. This review discusses the limitations of some of the standard assays currently employed to study hematopoietic stem and progenitor cell emergence and highlights several recently reported novel methods that address this problem from new perspectives. Two methods directly alter the circulation by either preventing it from occurring in the first place or by removing vascular connections between the embryo and the yolk sac. Other approaches have altered the ability of hematopoietic cells to interact with their environment, resulting in the lack of migration or an inability to bind to potential hematopoietic niches. A third set of experiments utilize lineage tracing techniques to follow the migration of early progenitors once they enter the circulation. Taken together, these novel methods provide new evidence for the contribution of yolk sac hematopoietic stem and progenitor cells to the adult hematopoietic system. PMID- 20711981 TI - Aortic remodelling during hemogenesis: is the chicken paradigm unique? AB - Since the era of the ancient Egyptians and Greeks, the avian embryo has been a subject of intense interest to visualize the first steps of development. It has served as a pioneer model to scrutinize the question of hematopoietic development from the beginning of the 20th century. It's large size and easy accessibility have permitted the development of techniques dedicated to following the origins and fates of different cell populations. Here, we shall review how the avian model has brought major contributions to our understanding of the development of the hematopoietic system in the past four decades and how these discoveries have influenced our knowledge of mammalian hematopoietic development. The discovery of an intra-embryonic source of hematopoietic cells and the developmental link between endothelial cells and hematopoietic cells will be presented. We shall then point to the pivotal role of the somite in the construction of the aorta and hematopoietic production and demonstrate how two somitic compartments cooperate to construct the definitive aorta. We shall finish by showing how fate-mapping experiments have allowed the identification of the tissue which gives rise to the sub-aortic mesenchyme. Taken together, this review aims to give an overview of how and to what extent the avian embryo has contributed to our knowledge of developmental hematopoiesis. PMID- 20711982 TI - Hematopoietic stem cell activity in the aorta-gonad-mesonephros region enhances after mid-day 11 of mouse development. AB - The E11.5 aorta-gonad-mesonephros (AGM) region is a site of hematopoietic stem cell (HSC) development prior to colonisation of the embryonic liver. The generation of HSCs in the embryo starting from E11 is very rapid. Here, we have assessed hematopoietic development in the AGM region during E11 at precise somitic ages. Although the numbers of committed hematopoietic precursors fluctuate throughout the day, the repopulation activity in the AGM region noticeably increases from mid (44 s.p.) to end (48 s.p.) day 11 of gestation. While prior to mid day 11 two thirds of AGM regions contain no definitive HSCs, shortly prior to liver colonisation, all older day 11 embryos contain definitive HSC. Nevertheless, all E11 AGM regions even at early somitic stages have the capacity to expand numbers of definitive HSCs ex vivo. Quantitative anatomical analysis confirmed preferential localization of intra-aortic clusters (IACs) to the ventral domain of the dorsal aorta during entire day 11 of development. No clear correlation was established between IAC numbers and the presence of definitive HSCs. PMID- 20711983 TI - Embryonic origin of human hematopoiesis. AB - Hematopoietic stem cells (HSC) are at the origin of the adult hematopoietic system. They give rise to all blood cells through a complex series of proliferation and differentiation events that occur throughout the lifespan of the individual. Because of their potential clinical importance in transplantation, recent research has focused on the developmental origins of embryonic HSC. During development in vertebrate embryos, two independent anatomical sites generate hematopoietic cells. The yolk sac is responsible for a first ephemeral hematopoiesis, characterized by the early appearance of hematopoietic progenitors with limited development ability that rapidly differentiate toward erythro-myeloid lineages. Self-renewing, multipotent adult type HSC that also exhibit B and T lymphoid potentials emerge autonomously in the aorta/gonad/mesonephros (AGM) region inside the embryo. In this review, we provide a brief summary of recent developments regarding the origins of hematopoietic stem cells in the early human embryo. The recent discovery that angiotensin-converting enzyme (ACE) is a novel cell surface marker of human HSC is discussed in detail. PMID- 20711985 TI - The quest for hematopoietic stem cells in the embryo. An interview with Francoise Dieterlen-Lievre. Interview by Thierry Jaffredo and Charles Durand. AB - Francoise Dieterlen-Lievre is probably the scientist who has most contributed to our basic knowledge of developmental hematopoiesis. She has dedicated her career to answering cutting edge questions on the origin of hematopoietic stem cells in the embryo. Her seminal contributions, widely recognized by the scientific community, have paved the way for generations of developmental hematologists questioning the origins of hematopoietic stem cells. After having demonstrated the intra-embryonic origin of hematopoietic stem cells, established the dual origin of the endothelial network in the embryo and revealed the hematopoietic function of the allantois in birds, she has switched to mammals and contributed to demonstrating that the aorta and allantois/placenta are new sites of hematopoietic production in the mouse embryo. The manifold insights generated by the pivotal work of Francoise Dieterlen-Lievre have created multiple paradigm shifts which continue to challenge the field of developmental hematopoiesis. PMID- 20711984 TI - Mpl receptor defect leads to earlier appearance of hematopoietic cells/hematopoietic stem cells in the Aorta-Gonad-Mesonephros region, with increased apoptosis. AB - In a previous study, we underlined the functional role of the TPO receptor, Mpl, in the establishment of definitive mouse hematopoiesis, by demonstrating that the lack of Mpl led to a delayed production of definitive hematopoietic cells in the aorta-gonad-mesonephros (AGM) region, and resulted in the production of hematopoietic stem cells (HSCs) with an impaired activity at E11.5. In order to more accurately estimate the role of Mpl during generation of HSCs in the aorta, we performed an analysis of these AGMs at the time of the first HSC emergence (E10.5). Our results indicated that while Mpl-/- AGMs were found to contain more hematopoietic cells (HC) than C57Bl6 AGMs at E10.5, a defect in the expansion process of the HC/HSCs was detected in explant cultures of these AGMs, likely due to an increased apoptosis of these cells. To determine the molecular mechanisms by which invalidation of Mpl receptor affects the temporal distribution and expansion of HC/HSCs in the AGM, a study of the transcription level of of Mpl target genes was conducted. Expression of Runx1, a master transcription factor for the formation of hematopoietic progenitor (HP) cells and HSCs from the vasculature, as well as expression of Meis1 and HoxB4, known to play a role in self-renewal and expansion of HSCs, were found to be down regulated in E10.5 Mpl /- AGMs. Our data indicate that Mpl is an active player during the first steps of definitive hematopoiesis establishment through direct regulation of the expression of transcription factors or genes important for the self-renewal, proliferation and apoptosis of HSCs. PMID- 20711987 TI - The placenta as a haematopoietic organ. AB - The recent description of the placenta as a tissue rich in haematopoietic stem and progenitor cells has not only opened up a whole new line of investigation into how haematopoiesis is regulated in this unique mammalian tissue, but has also resulted in the revisiting of long-standing and yet unanswered questions about the significance of having multiple haematopoietic organs during development. Due to its remarkable capacity for haematopoietic stem/progenitor cell expansion, the study of placental haematopoiesis is also of obvious clinical interest. In the following pages, we summarise what is currently known about the haematopoietic regulatory processes in the murine placenta and describe our most recent data demonstrating that the human placenta, like its murine counterpart, is also a source of haematopoietic stem and progenitor cells throughout development. PMID- 20711986 TI - Hematopoietic stem cell development in the placenta. AB - The placenta is a highly vascularized organ that mediates fetal-maternal exchange during pregnancy and is thereby vital for the survival and growth of the developing embryo. In addition to having this well-established role in supporting pregnancy, the placenta was recently shown to function as a hematopoietic organ. The placenta is unique among other fetal hematopoietic organs, as it is capable of both generating multipotential hematopoietic cells de novo and establishing a major hematopoietic stem cell (HSC) pool in the conceptus, while protecting HSCs from premature differentiation. The mouse placenta contains two distinct vascular regions that support hematopoiesis: the large vessels in the chorionic plate where HSCs/progenitors are thought to emerge and the labyrinth vasculature where nascent HSCs/progenitors may colonize for expansion and possible functional maturation. Defining how this cytokine- and growth factor rich organ supports HSC generation, maturation and expansion may ultimately help to establish culture protocols for HSC expansion or de novo generation from pluripotent cells. PMID- 20711988 TI - Transcription factor interplay during Drosophila haematopoiesis. AB - Transcription factors play a key role in regulating blood cell fate choice and differentiation. In this review, we examine current knowledge of the function and mode of action of the transcription factors implicated in haematopoiesis in Drosophila. We particularly emphasize regulation by transcription factors and cofactors, such as GATA, FOG and RUNX, whose homologues in mammals also control blood cell formation and we discuss the cross talks between these transcriptional regulators at the different stages of haematopoietic cell fate decision. PMID- 20711990 TI - Hematopoietic development in the zebrafish. AB - The model organism Danio rerio, also known as the zebrafish, is an excellent system for studying the developmental process of hematopoiesis. It is an ideal model for in vivo imaging, and it is useful for large-scale genetic screens. These have led to the discovery of previously unknown players in hematopoiesis, as well as helped our understanding of hematopoietic development. In this review, we will summarize hematopoiesis in the zebrafish and discuss how genetic approaches using the zebrafish system have helped to build our current knowledge in the field of hematopoiesis. PMID- 20711989 TI - Ontogeny of the Drosophila larval hematopoietic organ, hemocyte homeostasis and the dedicated cellular immune response to parasitism. AB - Over the years, the fruit fly Drosophila melanogaster has become a major invertebrate model to study developmental and evolutionary aspects of both humoral and cellular aspects of innate immunity. Drosophila hematopoiesis which supplies three types of circulating hemocytes, occurs in two spatially and temporally distinct phases during development. The first embryonic phase is described in detail in accompanying reviews in this Int. J. Dev. Biol. Special Issue. The second phase takes place at the end of larval development in a specialised hematopoietic organ, termed the lymph gland. We review here recent studies on the ontogeny of the lymph gland, focusing on the formation and role of the Posterior Signalling Center which acts as a niche for hematopoietic progenitors. We then report recent progress in understanding the dedicated cellular immune response of Drosophila larvae against parasitization by Hymenopterae, a common threat for many Dipterae. This response involves the differentiation of lamellocytes, a cryptic cell fate, revealing the high degree of plasticity of Drosophila hematopoiesis. We end up by integrating studies in Drosophila within a more general picture of insect hematopoiesis and hemocyte homeostasis. PMID- 20711991 TI - Genetic control of hematopoietic development in Xenopus and zebrafish. AB - Blood development has been highly conserved during evolution. Hematopoietic cells in amphibian and fish embryos, as in mammalian embryos, emerge and progressively differentiate in several locations. Hematopoiesis, including of the immune system, is similar in the amphibian, Xenopus, to mammals and the embryos are ideal for tissue transplantation and lineage labelling experiments, which have enabled the elucidation of the distinct origins of embryonic and adult hematopoietic cells, as well as their migration pathways and organ colonisation behaviours. The zebrafish hematopoietic system is less well understood, but these embryos have recently emerged as a powerful system for both genetic analysis and imaging. In this review, we summarise our current knowledge of the cellular and genetic basis of ontogeny of the hematopoietic system in Xenopus and zebrafish embryos. PMID- 20711993 TI - Definitive human and mouse hematopoiesis originates from the embryonic endothelium: a new class of HSCs based on VE-cadherin expression. AB - Hematopoietic stem cells (HSCs) arise first in the third week of human ontogeny inside yolk sac developing blood vessels, and independently, from the wall of the embryonic aorta and vitelline arteries one week later. HSCs produced in the yolk sac and in the embryonic truncal arteries migrate to and transiently colonize the embryonic liver (EL), and thereafter the bone marrow (BM), their permanent site of residence. At the moment, the origin of human HSCs is still controversial; one of the main hypotheses being that they are generated by hemogenic endothelial cells (ECs). To prove definitively the endothelial origin of HSCs that arise within the human embryo, we previously purified ECs from either the yolk sac or the truncal arteries and reported that they were able to produce blood cells in vitro. We then found that some of the HSCs present in the human EL were co expressing vascular endothelial (VE)-cadherin, an endothelial marker, CD45, a pan hematopoietic marker, and CD34, a common endothelial and hematopoietic marker, and demonstrated that these HSCs bearing a dual hemato-endothelial phenotype were endowed with remarkably high self renewal and proliferative potentials. Furthermore, a transgenic mouse model based on the VE-cadherin cis-regulating elements that we engineered to trace the fate of the first VE-cadherin expressing cells allowed us to clearly demonstrate that a majority of adult BM HSCs derived from a VE-cadherin ancestor. Altogether our studies strongly suggest that at least a part of both the human and the murine hematopoietic systems arise from an endothelium-like ancestor. PMID- 20711994 TI - The Notch pathway in the developing hematopoietic system. AB - The main function of the Notch signaling pathway is to generate cell diversity during both embryonic development and adult tissue homeostasis. The extended use of this pathway, together with its conservation during evolution, is indicative of its importance. During embryonic development, the vascular and hematopoietic systems are intimately associated and Notch signals are responsible for the correct specification of both systems. More explicitly, Notch is required for the induction of the arterial program; however, it is simultaneously or consecutively also involved in the generation of hematopoietic stem cells. Although both genetic programs are different, they are both implemented in endothelial cells of the dorsal aorta in the midgestation embryo. This close association during the development of arteries and blood has hindered our understanding of Notch function in the generation of hematopoietic stem cells. Here, we will review the work from recent years showing how Notch participates in the embryonic development of hematopoiesis in the mouse, but also in other organisms such as chick, zebrafish and flies. PMID- 20711995 TI - The roles of BMP and IL-3 signaling pathways in the control of hematopoietic stem cells in the mouse embryo. AB - During mouse ontogeny, the first adult-type hematopoietic stem cells (HSC) are autonomously generated at mid-gestation in the AGM (Aorta-Gonad-Mesonephros) region. Successively present in different anatomical sites where they will expand, HSCs will finally colonize the bone marrow (BM) where they will reside during the entire adult life. In the bone marrow, both HSC self-renewal and differentiation are controlled at cellular and molecular levels by interactions with the stromal microenvironment. So far, very little is known about the extracellular factors involved in the regulation of embryonic HSC emergence, survival and expansion. In the present review, we outline the BMP and IL-3 signaling pathways that are critical for the growth and potential of embryonic HSCs. We will also discuss how these pathways might be integrated with the ones of Notch and Mpl/thrombopoietin, also identified as important key regulators of AGM HSC activity. PMID- 20711996 TI - Gene regulatory networks governing haematopoietic stem cell development and identity. AB - Development can be viewed as a dynamic progression through regulatory states which characterise the various cell types within a given differentiation cascade. To understand the progression of regulatory states that define the origin and subsequent development of haematopoietic stem cells, the first imperative is to understand the ontogeny of haematopoiesis. We are fortunate that the ontogeny of blood development is one of the best characterized mammalian developmental systems. However, the field is still in its infancy with regard to the reconstruction of gene regulatory networks and their interactions with cell signalling cascades that drive a mesodermal progenitor to adopt the identity of a haematopoietic stem cell and beyond. Nevertheless, a framework to dissect these networks and comprehend the logic of its circuitry does exist and although they may not as yet be available, a sense for the tools that will be required to achieve this aim is also emerging. In this review we cover the fundamentals of network architecture, methods used to reconstruct networks, current knowledge of haematopoietic and related transcriptional networks, current challenges and future outlook. PMID- 20711992 TI - Hematopoietic stem cell emergence in the conceptus and the role of Runx1. AB - Hematopoietic stem cells (HSCs) are functionally defined as cells that upon transplantation into irradiated or otherwise immunocompromised adult organisms provide long-term reconstitution of the entire hematopoietic system. They emerge in the vertebrate conceptus around midgestation. Genetic studies have identified a number of transcription factors and signaling molecules that act at the onset of hematopoiesis, and have begun to delineate the molecular mechanisms underlying the formation of HSCs. One molecule that has been a particularly useful marker of this developmental event in multiple species is Runx1 (also known as AML1, Pebp2alpha). Runx1 is a sequence-specific DNA-binding protein, that along with its homologues Runx2 and Runx3 and their shared non-DNA binding subunit CBFbeta, constitute a small family of transcription factors called core-binding factors (CBFs). Runx1 is famous for its role in HSC emergence, and notorious for its involvement in leukemia, as chromosomal rearrangements and inactivating mutations in the human RUNX1 gene are some of the most common events in de novo and therapy related acute myelogenous leukemia, myelodysplastic syndrome and acute lymphocytic leukemia. Here we will review the role of Runx1 in HSC emergence in the mouse conceptus and describe some of the genetic pathways that operate upstream and downstream of this gene. Where relevant, we will include data obtained from other species and embryonic stem (ES) cell differentiation cultures. PMID- 20711999 TI - Development of the posterior lateral line system in Thunnus thynnus, the Atlantic blue-fin tuna, and in its close relative Sarda sarda. AB - The lateral line system of amphibians and fish comprises a large number of individual mechanosensory organs, the neuromasts, and their sensory neurons. The pattern of neuromasts varies markedly between species, yet the embryonic pattern is highly conserved from the relatively basal zebrafish, Danio rerio, to more derived species. Here we examine in more detail the development of the posterior lateral line (PLL) in embryos and early larvae of one of the most derived fish species, the blue-fin tuna Thunnus thynnus, and of its close relative, the Atlantic bonito Sarda sarda. We show that the basic features of embryonic PLL development, including the migratory properties of the PLL primordium, the patterning of neuromasts and their innervation, are largely conserved between zebrafish and tuna. However, Thunnus and Sarda embryos differ from Danio in three respects: the larger size of the neuromast cupula, the capability of mature neuromasts to migrate dorsally, and the presence of a single, precisely located terminal neuromast. PMID- 20711997 TI - Induction of neural crest cells from mouse embryonic stem cells in a serum-free monolayer culture. AB - The neural crest (NC) is a group of cells located in the neural folds at the boundary between the neural and epidermal ectoderm. NC cells differentiate into a vast range of cells,including neural cells, smooth muscle cells, bone and cartilage cells of the maxillofacial region, and odontoblasts. The molecular mechanisms underlying NC induction during early development remain poorly understood. We previously established a defined serum-free culture condition for mouse embryonic stem (mES) cells without feeders. Here, using this defined condition, we have developed a protocol to promote mES cell differentiation into NC cells in an adherent monolayer culture. We found that adding bone morphogenetic protein (BMP)-4 together with fibroblast growth factor (FGF)-2 shifts mES cell differentiation into the NC lineage. Furthermore, we have established a cell line designated as P0-6 that is derived from the blastocysts of P0-Cre/Floxed-EGFP mice expressing EGFP in an NC-lineage-specific manner. P0-6 cells cultured using this protocol expressed EGFP. This protocol could be used to help clarify the mechanisms by which cells differentiate into the NC lineage and to assist the development of applications for clinical therapy. PMID- 20711998 TI - Synergy between two transcription factors directs gene expression in Dictyostelium tip-organiser cells. AB - cotC requires the transcription factor CudA for its expression in the posterior, prespore cells of the slug, while the expL7 gene requires CudA for its expression in the anterior, tip-organiser region. In order to identify additional transcription factors that might mediate tip-organiser specific expression, we performed affinity chromatography on slug nuclear extracts. The affinity matrix bore cap-site distal sequences from region A of the expL7 promoter; an essential region located upstream of the CudA binding domain. One of the proteins purified was G-box binding factor (GBF), a zinc finger transcription factor which binds to G-rich elements, known as G boxes, that are present in the promoters of many developmental genes, including cotC. Previous work identified an essential sequence motif within region A and we show that this element is a G box, that binds recombinant GBF. Moreover, a G box from within the cotC promoter can substitute for region A of expL7 in directing tip-organiser specific expression of expL7. Thus the same two transcription factors, CudA and GBF, seem to co operate to direct both tip-organiser and prespore gene expression. How then is specificity achieved? Replacing a CudA binding region in the cotC promoter with the CudA binding domain from expL7 strongly represses cotC promoter activity. Hence we suggest that differences in the topology of the multiple CudA half- sites contained within the two different CudA binding regions, coupled with differences in the signalling environment between tip-organiser cells and prespore cells, ensure correct expL7 expression. PMID- 20712000 TI - Vestigial like gene family expression in Xenopus: common and divergent features with other vertebrates. AB - The Drosophila Vestigial and Scalloped proteins form heterodimers that control wing development and are involved in muscle differentiation. Four vestigial like genes have been described in mammals. Similar to the Drosophila vestigial gene, they encode a short conserved domain (TONDU) required for interaction with the mammalian paralogues of Drosophila Scalloped (i.e., TEAD proteins). We previously identified two TEAD genes in Xenopus laevis and we report here the expression of four distinct vestigial like genes in Xenopus (vgll1-4) that represent amphibian orthologs of the mammalian vestigial like genes. Vgll1 has a unique expression pattern which is restricted to epidermal cells, both in the embryo and in the adult. Vgll2 is expressed in the skeletal muscle lineage downstream of myogenic factors and in the embryonic brain similar to the avian and mammalian orthologues. Vgll3 expression is transient, identifies embryonic hindbrain rhombomere 2, and is negatively regulated by en2, but not by egr2. Vgll4 is mainly expressed in anterior neural structures. In summary, the four Xenopus vgll genes have unique/complex expression profiles and they are differently expressed during embryogenesis. Moreover, these amphibian vestigial like genes display distinct responses to the major signaling pathways (i.e., activin, FGF or BMP) that orchestrate pattern-formation during early development. PMID- 20712001 TI - The lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) receptor gene families: cloning and comparative expression analysis in Xenopus laevis. AB - Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are endogenous bioactive lipids which mediate a variety of biological cell responses such as cell proliferation, migration, differentiation and apoptosis. Their actions are mediated by binding to the G-protein-coupled endothelial differentiation gene (Edg) receptor subfamily, referred to as S1P1-5 and LPA1-5, and regulate a variety of signalling pathways involved in numerous physiological processes and pathological conditions. Their importance during embryogenesis has been demonstrated by the generation of knock-out mice and specific roles have been assigned to these receptors. However, potential functional redundancy and the lethality of some mutants have complicated functional analysis in these models. Here we report the cloning of the S1P and LPA receptors in Xenopus laevis and tropicalis. Phylogenetic analyses demonstrate the high level of conservation of these receptors between amphibian and other vertebrate species. We have conducted a comparative expression analysis of these receptors during development and in the adult frog, by both RT-PCR and whole mount in situ hybridisation. In particular, we show that S1P1, 2 and 5 display distinct embryonic specific expression patterns, suggesting potentially different developmental roles for these receptors, and therefore for their ligands, during amphibian embryogenesis. PMID- 20712002 TI - Zebrafish epiboly: mechanics and mechanisms. AB - Gastrulation involves of a series of coordinated cell movements to organize the germ layers and establish the major body axes of the embryo. One gastrulation movement is epiboly, which involves the thinning and spreading of a multilayered cell sheet. Epiboly plays a prominent role in zebrafish gastrulation and studies of zebrafish epiboly have provided insights into basic cellular properties and mechanisms of morphogenesis that are widely used in animal development. Although considerable progress has been made in identifying molecules that are required for epiboly, we still understand very little about how these factors cooperate to drive the process. Here, we review work on the molecular and cellular basis of zebrafish epiboly in order to identify unifying themes and to highlight some of the current open questions. PMID- 20712003 TI - Complement component C3 functions as an embryotrophic factor in early postimplantation rat embryos. AB - A presumed embryotrophic factor for early postimplantation rat embryos, partially purified from rat serum, was identified as complement component C3 (C3), the central component of the complement system, by sequence analysis of its N terminal. Purified rat C3 showed embryotrophic activity for rat embryos cultured from day 9.5 of gestation for 48 h in the culture medium composed of rabbit serum. The maximum embryotrophic activity of C3 was observed around 0.5 mg/ml, a level which is lower than rat serum C3 levels. In the culture medium composed of rat serum, cultured rat embryos selectively consumed C3, and C3-depletion by cobra venom factor affected embryonic growth. Inactivation of the internal thiolester bond of C3, the critical functional site for its activity in the complement system, by methylamine had no effects on its embryotrophic activity. Purified rabbit C3 had only weak embryotrophic activity for cultured rat embryos, suggesting species specificity of the embryotrophic activity of C3. Immunochemical analyses showed the specific presence of C3 on the visceral yolk sac, but not on the embryo proper of day 9.5 or 10.5 rat embryos both in utero and in vitro. In analysis using fluorescein-labeled rat C3, unfragmented C3s bound to the visceral yolk sac stronger than C3b, the primary active fragment of C3 in the complement system. These results indicate that C3, which has always been considered to be detrimental to embryos, functions as an embryotrophic factor by novel mechanisms probably through the visceral yolk sac. The present study thus provides new insights into functions of C3 and postimplantation embryonic growth. PMID- 20712004 TI - Characterization of the 38 kDa protein lacking in gastrula-arrested mutant Xenopus embryos. AB - We have reported elsewhere that offspring from the No. 65 female of Xenopus laevis cleaved normally, but their development was arrested at the onset of gastrulation, like the Ambystoma ova-deficient (o) mutant, irrespective of mating with different wild-type males, and that an acidic, 38 kDa protein present in wild-type eggs was lacking in eggs of the female. In the current study, we first determined the partial amino acid sequence (VANLE) of one of the well-separated tryptic peptides from the protein, which was found in elongation factor 1 delta (Ef1delta) in Xenopus, and finally identified the protein as one of the Ef1delta isoforms, Ef1delta2, by peptide mass spectrometry. RT-PCR analyses for Ef1delta2 and its close homolog Ef1delta1 in wild-type oocytes and embryos demonstrated that both transcripts are maternal and Ef1delta1 is present more abundantly than Ef1delta2 throughout the stages examined. Importantly, the amount of the Ef1delta2 transcript per embryo decreased gradually after gastrulation, in accordance with the gradual decrease of the 38 kDa protein per embryo reported in our earlier study. Because pharmacological inhibition of translation induces gastrulation arrest in wild-type embryos, it is reasonable to conclude that the mutant embryos arrest in development due to the lack of Ef1delta2 that is indispensable for translation. Thus, the present study provides the first molecular information on the cause of the gastrulation-defective mutation in Amphibia. PMID- 20712005 TI - Role of TGFbeta and myofibroblasts in supporting the propagation of human embryonic stem cells in vitro. AB - The feeder layer constitutes a prerequisite for the undifferentiated proliferation of human embryonic stem (hES) cells in vitro. However, a few feeders have been reported to be non-supportive in nature, suggesting that these feeders exhibit a different transcriptome and proteome, in comparison to their supportive counterparts. In an attempt to identify factors required for undifferentiated growth and many downstream applications of hES cells, transcriptomes of supportive (mouse fibroblasts derived from 13.5dpc embryos and human fetal fibroblasts) and non-supportive (mouse fibroblasts derived from 18.5dpc embryos) feeders were analyzed. Furthermore, the parallel correlation of data generated in the microarray study with the published proteome data of supportive feeder fibroblasts, helped us to focus on the proteins which seem to be likely candidates in supporting the undifferentiated expansion of ES cells in vitro. Our results indicated that TGFbeta and its associated signaling molecules facilitate the undifferentiated proliferation of hES cells in vitro. The transient differentiation of feeder fibroblasts into myofibroblasts may be the decisive factor for a feeder layer to be supportive or non-supportive in nature. We propose that the microenvironment of feeder myofibroblasts dictates TGFbeta to support proliferation and apparently plays the contradictory role of facilitating differentiation when feeder support is withdrawn, possibly by acting through different signaling mechanisms. PMID- 20712006 TI - HSP90 expression in two migratory cell types during ascidian development: test cells deposit HSP90 on the larval tunic. AB - Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperone that controls the folding, assembly and activity of proteins, many of which are involved in signal transduction. Recent work has shown that HSP90 is present extracellularly, indicating a heretofore under-appreciated requirement for extracellular chaperoning, particularly among migratory cells. We applied immunological and surgical techniques to document the differential expression of HSP90 during ascidian development. Relative to other cell types during development, test cells and trunk lateral cells (TLCs), two migratory cell types in the ascidian Boltenia villosa, express elevated levels of HSP90. Late in embryogenesis, test cells deposit HSP90 onto the tunic, the second report of extracellular HSP90 during animal development. The pyurid ascidian Halocynthia igaboja and the styelids Cnemidocarpa finmarkiensis and Botrylloides violaceus all express HSP90 at elevated levels in larval mesenchyme, suggesting that this pattern of expression is widespread in the Ascidiaceae. We show that HSP90 expression in TLCs and test cells is coincident with the presence of HNK-1. Whereas in B. violaceous, cell populations expressing elevated levels of HSP90 are distinct from those expressing HNK-1, in B. villosa both these antigens are present in the TLCs. We evaluate existing hypotheses about test cell function and, in reference to the similarities between test cells and some of the descendants of TLCs, hypothesize that test cells are TLC descendants. Implications for the proposed evolutionary relationship between TLCs and neural crest are briefly discussed. PMID- 20712007 TI - The cellular expression of GABA(A) receptor alpha1 subunit during spermatogenesis in the mouse testis. AB - GABA(A) receptors are pentamers in structure and are mainly composed of alpha, beta and gamma subunits. These receptors are known to function as chloride channels. We observed alpha5, beta1 and gamma3 subunit immunoreactivity in the mouse testes, specifically in the cytoplasm surrounding the nucleus in the spermatocytes and spermatids. In the current study, alpha1 subunit immunoreactivity was located in the nucleus of spermatogonia, spermatocytes and round spermatids. Immunoelectron microscopy revealed that the alpha1 subunit was localized within the nucleus of pachytene and diplotene spermatocytes in the area of condensed chromatin rather than extended chromatin. Protein sequence analysis revealed that the alpha1 subunit included DM DNA binding domains that were related to transcription factors involved in testicular differentiation in adult mice. These findings suggest that the alpha1 subunit may undertake a gene transcription function during the maturation of germ cells. a1 immunoreactivity was also detected within the mitochondria of spermatocytes and in the acrosome of round and elongated spermatids. Although the precise physiological role of the GABA(A) receptor alpha1 subunit in mitochondria remains unknown, we hypothesize that its function in the acrosome may be related to the acrosome reaction during fertilization or during spermatogenesis. PMID- 20712008 TI - Angiogenesis index CD105 (endoglin)/CD31 (PECAM-1) as a predictive factor for invasion and proliferation in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. AB - BACKGROUND: Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is an increasingly diagnosed entity since its definition by the World Health Organization in 1996. It has a broad clinical spectrum ranging from benign to malignant tumors. Optimum treatment is controversial and a better understanding of the development of IPMN of the pancreas and identification of potential prognostic factors will help to address this. Angiogenesis plays an elementary role in the development of malignant tumors and may well also be important in the development of IPMN of the pancreas. Therefore we investigated endothelial cell marker CD31 (PECAM-1) and angiogenesis associated marker CD105 (endoglin) by immunohistochemistry. METHODS: Thirty-two cases of surgically resected IPMN were chosen retrospectively and clinical data were obtained. Specimens were stained for proliferation marker (Ki-67), CD31 and CD105 by immunohistochemistry. A CD105/CD31 Angiogenesis ratio (AR) was established to determine the proliferating fraction of endothelial cells. RESULTS: The AR is significantly elevated in invasive IPMN of the pancreas (Mann-Whitney-U Test, p<0.05) and is associated with the Ki-67-labelling-index, demonstrating synergy between tumor-growth and neovascularisation. Invasive IPMN of the pancreas is associated with significantly lower recurrence-free and overall survival. CONCLUSIONS: Neovascularisation plays an important role in the tumorigenesis of invasive IPMN of the pancreas, and therefore angiogenesis-associated molecules like CD105 and CD31 might be useful tools as prognostic markers. Furthermore, the results indicate a potential role for adjuvant anti-angiogenic therapies in selected patients with recurring and/or invasive IPMN of the pancreas. PMID- 20712009 TI - Intermediate conductance Ca2+ activated K+ channels are expressed and functional in breast adenocarcinomas: correlation with tumour grade and metastasis status. AB - K+ channels are key molecules in the progression of several cancer types and are considered to be potential targets for cancer therapy. In this study, we investigated the intermediate- conductance Ca2+-activated K+ channels (hKCa3.1) expression in both breast carcinoma (BC) specimens and human breast cancer epithelial primary cell cultures (hBCE) using immuno-histochemistry (60 samples), quantitative Real-Time RT-PCR (30 samples) and Western blot assay (30 samples). We also looked at whether or not the expression of these channels is correlated with breast carcinomas grade tumours and metastasis status. Furthermore, we characterized the hKCa3.1 channel activity in hBCE cells by using the Whole Cell Patch Clamp Technique. We found that hKCa3.1 transcripts and proteins were expressed in both BC samples and hBCE cells. Clinicopathologic evaluation indicated a significant correlation between hKCa3.1-expression and tumour grade. hKCa3.1 mRNA and protein were more highly expressed in grade III tumours than in both grades I and II. However, the hKCa3.1 expression-increase according to grade was only observed in tumours with negative metastasis status. Moreover, the hKCa3.1 channels expressed in hBCE cells are functional. This was attested by patch-clamp recordings showing typical hKCa3.1-mediated currents in these cells. In conclusion, these data suggest that hKCa3.1 might contribute to breast tumour progression and can serve as a useful prognostic marker for breast cancer. PMID- 20712010 TI - Comparison of the dysadherin and E-cadherin expression in primary lung cancer and metastatic sites. AB - Dysadherin, a cancer associated cell membrane glycoprotein, has been reported to downregulate E-cadherin. Aberrant expression of E-cadherin has been associated with the development of metastases in patients with cancer. Even though the expression of dysadherin and E-cadherin has been studied in primary non-small cell lung carcinoma, little is known about its expression at the distant metastases sites. We investigate by immunohistochemistry the relationship between E-cadherin and dysadherin in 111 cases of primary lung carcinomas (53 squamous cell carcinomas, 21 adenocarcinomas, 13 large cell carcinomas, and 24 small cell carcinomas), and their distant metastases. The intensity, the expression pattern and the percentage of neoplastic cell staining were recorded and the results were correlated with clinicopathological findings of the subjects. Dysadherin immunostain was expressed in 61 (54.95%) of the cases, and increased dysadherin expression was significantly correlated with tumour size (p=0.003), distant metastases (p=0.0034), and metastasis size (p=0.0008). Reduced E-cadherin expression was noted in 46 (41.45%) of the cases, and was correlated with high grade tumour (p=0.02), infiltrative growth pattern (p=0.042), and advanced stage (p=0.032). Although the correlation between the expression of dysadherin and E cadherin was not significant, a group of patients showed reduced E-cadherin expression with dysadherin overexpression. In lung carcinomas dysadherin expression seems to reflect tumour aggressiveness and may be considered a positive marker of poor prognosis when considered alone or/and in combination with down-regulation of E-cadherin. PMID- 20712011 TI - Nuclear accumulation of glioma-associated oncogene 2 protein and enhanced expression of forkhead-box transcription factor M1 protein in human hepatocellular carcinoma. AB - The hedgehog (Hh) signaling pathway has been reported to be crucial in human carcinogenesis and tumor progression. Glioma-associated oncogenes (Gli), are zinc finger transcription factors which mediate the transcriptional response to Hh signaling. To explore the role of Gli in the development and progression of hepatocellular carcinoma (HCC), we investigated the expression of Gli2 and FoxM1 (forkhead-box transcription factor M1) which is one of the Gli downstream target genes modulating cell cycle progression in 91 specimens of human HCCs with immunohistochemistry. These immunostaining results were compared with various clinicopathologic parameters. Immunoreactivity of Gli2 and FoxM1 was observed respectively in 84.6% (77/91) and 80.2% (73/91) cases of HCC tumor tissues, and this was considerably higher than expression in the peritumoral tissues. Distribution of Gli2 and FoxM1 proteins in tumor cells was nuclear with or without cytoplasmic staining, or cytoplasmic alone. Statistically, increased nuclear immunopositivity of Gli2 protein correlated significantly with poorer tumor differentiation (P<0.05), as well as with portal vein tumor thrombosis (P<0.05). In addition, overexpression of FoxM1 protein was significantly associated with increased tumor grade (P<0.01) and advanced tumor stage (P<0.05). Moreover, there was a significant association between the expressions of Gli2 and FoxM1 proteins in HCC (r=0.464, P=0.000). This is consistent with the concept that in human HCC, the Hh signaling pathway is involved in the differentiation and proliferation of tumor cells, in part through inducing nuclear accumulation of Gli2 protein and subsequent upregulation of FoxM1 protein. PMID- 20712012 TI - Ultrastructural morphology of equine adipose-derived mesenchymal stem cells. AB - Mesenchymal stem cells are a virtually ubiquitous population of adult stem cells, able to differentiate into various tissue lineages. As they are multipotent and easy to grow in culture, they are at present considered very attractive candidates for tissue repair and gene therapy. With the exception of a few reports, mesenchymal stem cell morphology has been widely disregarded in the past years. In this paper we discuss the establishment of mesenchymal stem cell cultures from equine adipose tissue and describe their fine structure by transmission electron microscopy. The cultured cells revealed a fibroblastoid appearance and were characterized by an eccentric nucleus with multiple nucleoli, dense cytoplasm rich in ribosomes, a rough endoplasmic reticulum with dilated cisternae, elongated mitochondria and heterogeneous vacuolar inclusions. In addition, they were often interconnected by adhesion structures located on the cell body and on cytoplasmic processes contacting other cells. The features observed are evocative of an undifferentiated cellular phenotype and of an intense synthetic and metabolic activity. PMID- 20712013 TI - Lung carcinoma with rhabdoid component. A series of seven cases associated with uncommon types of non-small cell lung carcinomas and alveolar entrapment. AB - Rhabdoid tumor, included in the WHO classification among large cell carcinomas of the lung, is an uncommon type of lung carcinoma with poor prognosis. We report a series of 7 cases of lung carcinomas with rhabdoid component in 10% and 80% of the tumor. The associated tumor was adenocarcinoma in 3 cases--one of them with focal micropapillary pattern--large cell carcinoma in 2 cases, squamous cell carcinoma in 1 case and pleomorphic carcinoma in 1 case. Two adenocarcinomas showed a focal spindle cell component. Micropapillary and pleomorphic types had not been reported before as a component associated with rhabdoid carcinomas. All cases were positive for vimentin, and AE1/AE3 cytokeratin and 5 cases for cytokeratin 7. All cases were negative for muscle and endothelial markers and for chromogranin A. Synaptophysin was focally positive only in one case. Alveolar trapping inside the tumor was present in 3 cases--a phenomenon not well studied in lung carcinomas and also not reported in tumors with rhabdoid component. Five patients died because of the tumor within 2 to 31 months after diagnosis, one of myocardial infarction and only one is alive and disease free 123 months after the diagnosis. In summary, we describe 7 new cases of this uncommon lung tumor with aggressive clinical course, associated with infrequent histological types in nonrhabdoid component and with alveolar trapping, a nondescribed finding. PMID- 20712014 TI - Peroxiredoxins in colorectal neoplasms. AB - Peroxiredoxins (Prxs) are novel group proteins with efficient antioxidant capacity, and some of them also have effects on cell proliferation, differentiation, apoptosis, and chemotherapy and radiotherapy resistance. Altogether six distinct Prxs expressions were investigated in histological samples of colorectal neoplasm and the distant normal tissues and investigated associatedly with parameters such as clinical stage and lymphnodes metastasis. Normal colorectal tissues were almost negative for Prxs, except Prx4 (15/32). In colorectal cancer tissues, the most prominent reactivity was observed with Prx2 in 23/32 cases, while the corresponding figures for others was 21/32 (Prx1), 18/32 (Prx3, Prx5, Prx6) and 8/32 (Prx4). Prx1 (P=0.023), Prx2 (P=0.012), and Prx5 (P=0.028) were the isoforms that showed significantly increased expression in colorectal cancer patients with stage III or lymphnodes metastasis-positive cases. There was a significant relationship between the expression of Prx1 and Prx2 (rs=0.425, P=0.015) and between Prx3 and Prx4 (rs=0.364, P=0.041). Additionally, 8 cases were studied by western analysis. Prx1, 2, 3, 5 and 6 were particularly elevated in tumors compared to nonmalignant tissue as assessed by immunohistochemistry. It appeared that some Prxs were upexpression in colorectal cancer tissues and may have some prognostic significance; the induction of Prxs could be explained by increased production of reactive oxygen species in carcinomatous tissue. PMID- 20712015 TI - Comparison of ultrastructure and lectin histochemistry on the anterior medial gland of nasal septum in rat and gerbil. AB - The anterior medial gland (AMG), located in the submucosa of rodent nasal septum, is suggested to provide fluid for humidification of inspired air. Tremendous variation of the environmental air humidity, on which rats and gerbils depend to live, leads us to expect a multiplicity on ultrastructure and various subcellular glycoconjugate distribution within the AMG acinar cells between these two species. Electron microscopy revealed that: (1) The nucleus of AMG acinar cells in rat was irregular-shaped, but that in gerbil was round or elliptical; (2) Secretory granules in rat AMG acinar cells contained homogenous content with various electron density. However, two types of secretory granules in gerbil AMG acinar cells were found: one with lamellated-structure and high electron density, while the others had particulate materials; (3) Myoepithelial cells were present in the acinus of medial and posterior regions in rat AMG, but absent in gerbil; and (4) Nerve terminals were present only in the medial and posterior rat AMG, but in all three regions of the gerbil AMG. Lectin histochemistry demonstrated that: (1) Rat and gerbil AMG acinar cells expressed strong affinity toward Con A and WGA, but neither showed any reactivity toward UEA and PNA; and (2) Varying degrees of reactivity toward different lectins, including DBA, PNA, SBA and EBL, were recognized in rat and gerbil AMG acinar cells. We confirm the species variation on the ultrastructure and lectin histochemistry of AMG in rats and gerbils, and speculate that these variations may be due to the different living environment. PMID- 20712016 TI - The role of neurotrophins related to stress in saliva and salivary glands. AB - Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well studied neurotrophins involved in neurogenesis, differentiation, growth, and maintenance of selected peripheral and central populations of neuronal cells during development and adulthood. Neurotrophins, in concert with the hypothalamic pituitary-adrenal (HPA) axis, play key roles in modulating brain plasticity and behavioral coping, especially during ontogenetic critical periods, when the developing brain is particularly sensitive to external stimuli. Early life events, such as psychophysical stress, affect NGF and BDNF levels and induce dysregulation of the HPA axis, thereby affecting brain development and contributing to inter-individual differences in vulnerability to stress or psychiatric disorders. Immobilization stress modifies BDNF mRNA expression in some organs. We studied the effect of immobilization stress on BDNF and its receptor tyrosine receptor kinase B (TrkB) in rat submandibular glands, and found increased BDNF expression in duct cells under immobilization stress. Upon further investigation on the influence of salivary glands on plasma BDNF using an acute immobilization stress model, we found that acute immobilization stress lasting 60 min significantly increases the plasma BDNF level. However, plasma BDNF elevation is markedly suppressed in bilaterally sialoadenectomized rats. This suggests that salivary glands may be the primary source of plasma BDNF under acute immobilization stress. This report reviews the structure of salivary glands, the role of neurotrophins in salivary glands, and the significance of BDNF in saliva and salivary glands, followed by a summary of the evidence that indicates the relationship between immobilization stress and BDNF expression within salivary glands. PMID- 20712017 TI - HuR, a key post-transcriptional regulator, and its implication in progression of breast cancer. AB - HuR, an ubiquitously expressed member of the Hu family, selectively binds and stabilizes ARE-containing mRNAs encoding proto-oncogenes, cell cycle regulators, cytokines and growth factors. The mechanism of HuR stabilization on target mRNAs is believed to be mediated through competition with destabilizing ARE-BPs. HuR is mainly localized within the cell nucleus and the nucleo-cytoplasmic shuttling of HuR is generally assumed as the initial and critical step of its stabilizing effects. A number of signaling pathways are believed to be involved in HuR shuttling. Due to the pivotal role played by HuR in stabilizing the mRNA of key factors or cytokines involved in carcinogenesis and subsequent progression, its implication and therapeutic potential in cancer have been investigated intensively since its discovery in 1996. This review discusses the role of HuR in the stabilization of key mRNAs and it's the nucleo-cytoplasmic shuttling. The review also covers the current knowledge of HuR's role in carcinogenesis, particularly its involvement in breast cancer, and the feasibility of using HuR as a therapeutic target for the treatment of breast cancer. PMID- 20712018 TI - Piecemeal degranulation in human eosinophils: a distinct secretion mechanism underlying inflammatory responses. AB - Secretion is a fundamental cell process underlying different physiological and pathological events. In cells from the human immune system such as eosinophils, secretion of mediators generally occurs by means of piecemeal degranulation, an unconventional secretory pathway characterized by vesicular transport of small packets of materials from the cytoplasmic secretory granules to the cell surface. During piecemeal degranulation in eosinophils, a distinct transport vesicle system, which includes large, pleiomorphic vesiculo-tubular carriers is mobilized and enables regulated release of granule-stored proteins such as cytokines and major basic protein. Piecemeal degranulation underlies distinct functions of eosinophils as effector and immunoregulatory cells. This review focuses on the structural and functional advances that have been made over the last years concerning the intracellular trafficking and secretion of eosinophil proteins by piecemeal degranulation during inflammatory responses. PMID- 20712020 TI - Trends in the consumption of antidepressants in Castilla y Leon (Spain). Association between suicide rates and antidepressant drug consumption. AB - OBJECTIVE: To learn the evolution of antidepressant and lithium use in Castilla y Leon (Central Spain) and its relationship with suicide rates. METHODS: A search in the ECOM (Especialidades Consumo de Medicamentos) database of the Spanish Ministry of Health for antidepressants and lithium was carried out for the period 1992-2005. Defined daily doses (DDD) per 1000 inhabitants per day were obtained as consumption data. Population and suicide rates data come from the Spanish National Statistics Institute. RESULTS: Antidepressant consumption increased 7 fold, from 6.9 DDD per 1000 inhabitants per day in 1992 to 47.3 in 2005; the corresponding increase in cost was more than 10-fold. Selective serotonin reuptake inhibitors (SSRIs) comprised 77% of the total consumption. Venlafaxine consumption multiplied by 2.2. The consumption of monoamine oxidase inhibitors (MAOIs) decreased after venlafaxine and mirtazapine were marketed. Lithium consumption increased by 76% during the period studied, but it plateaued in 2000. CONCLUSIONS: The consumption of antidepressants in Castilla y Leon has increased remarkably and the pattern has changed; there is an increase in the consumption of the new and more expensive antidepressants such as venlafaxine and escitalopram. No association was observed between suicide rates and antidepressant consumption. PMID- 20712019 TI - A pediatric phase I trial and pharmacokinetic study of ispinesib: a Children's Oncology Group phase I consortium study. AB - PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors. SUBJECTS AND METHODS: Ispinesib was administered as 1-hr intravenous infusion weekly * 3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12 mg/m(2) /dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose. RESULTS: Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12 mg/m(2) dose level dose limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9 mg/m(2) dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44) hr and the plasma drug clearance was 5 (1-14) L/hr/m(2) . CONCLUSIONS: The maximum tolerated and recommended phase II dose for ispinesib administered weekly * 3 every 28 days for children with solid tumors is 9 mg/m(2) /dose. Plans for a phase II trial in select pediatric solid tumors are in development. PMID- 20712021 TI - Effects of delay in infusion of N-acetylcysteine on appearance of adverse drug reactions after acetaminophen overdose: a retrospective study. AB - PURPOSE: To investigate the relationship between different types of adverse drug reaction (ADR) and late time to N-acetylcysteine (NAC) infusion in patients presenting to the hospital with acetaminophen overdose. METHODS: This is a retrospective study of patients admitted to the hospital for acute acetaminophen overdose over a period of 5 years (1 January 2004 to 31 December 2008). The primary outcome of interest was the relationship between ADR, if any, and late time to NAC infusion. Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis. RESULTS: Of 305 patients with acetaminophen overdose, 146 (47.9%) were treated with intravenous NAC and 139 (45.6%) were included in this study. Different types of ADR were observed in 94 (67.6%) patients. Late time to NAC infusion was significantly associated with cutaneous anaphylactoid reactions when compared to patients without this type of ADR (p < 0.001). However, there were no significant differences in time to NAC infusion between patients with and without the following ADR: gastrointestinal reactions (p = 0.11), respiratory reactions (p = 0.77), central nervous reactions (p = 0.64), and cardiovascular reactions (p = 0.63). CONCLUSION: Late time to NAC infusion is a risk factor for developing cutaneous anaphylactoid reactions, suggesting, rather than proving, that early NAC infusion (<= 8 hours) may be protective against this type of ADR. PMID- 20712023 TI - The use of prescription medicines and self-medication among children--a population-based study in Finland. AB - PURPOSE: The aim of this study was to investigate the prevalence and concomitant use of prescription medicines and self-medication, including over-the-counter (OTC) medicines, vitamins, and complementary and alternative medicines (CAMs) among Finnish children aged under 12 years. METHODS: We carried out a nationwide postal survey of the use of medicines by a representative sample (n = 6000) of Finnish children aged under 12 years in spring 2007. A response rate of 67% (n = 4032) was achieved. The current use of prescription medicines and the use of OTC medicines, vitamins, and CAMs in the preceding 2 days were the main outcome measures. RESULTS: In total, 17% of children had used prescription medicines and 50% some self-medication. The corresponding figures for OTC medicines, vitamins, and CAMs use were 17, 37, and 11%, respectively. Drugs for obstructive airway diseases were the most common prescription medicines, whereas analgesics and antipyretics, including non-steroidal-anti-inflammatory-medicines (NSAID), were the most common OTC medicines reported. Vitamin D was the most common vitamin, while fish oils and fatty acids were the most common CAMs used. Ten percent of the children had used prescription medicines and self-medication concomitantly. CONCLUSIONS: Most of the children's medication consists of self-medication, and especially of vitamin use. However, also a considerable proportion had used prescription medicines, and a minority prescription medicines and self-medication concomitantly. In three of the cases, a combination of prescription and OTC medicine with a potential risk for interactions were found. Physicians should be aware of this wide use of self-medication when prescribing medicines. PMID- 20712022 TI - Patterns of asthma medication use: early asthma therapy initiation and asthma outcomes at age 8. AB - Wheeze has many underlying pathophysiologies in childhood, but is the main reason for anti-asthma drugs prescription. This study was conducted to describe asthma medication use patterns among children in their first eight years of life. Longitudinal medication use data from 777 children participating in the PIAMA study were used. Medication patterns were described for four groups that started therapy before the third birthday, when the peak in prescriptions occurred in our cohort; short-acting beta-agonists (SABA), inhaled corticosteroids (ICS), SABA + ICS or none of these. One third (n = 255) of the children received a first SABA or ICS prescription before age 8. Only three children (1.2%) used medication continuously during follow-up. Of the children who started SABA, 53.8% discontinued within 1-2 years. Of the children who started ICS before age 3, 42.1% discontinued within 1-2 years and 31.6% received additional SABA. 41.5% of the children who started SABA + ICS used this short-term (<=1 -2 years) and 21.5% long-term (>= 3 years). Fifteen percent of children who did not start asthma therapy in their first 3 years of life did receive prescriptions between age 3 and 8. Children prescribed SABA + ICS before age 3 had the highest prevalence of hyper responsiveness at age 8, and similar prevalence of atopy as the other groups. Asthma medication is prescribed frequently in the first 8 years of life, particularly before age 3, and only few children use it continuously. ICS and SABA prescription occurs especially in those who were more likely to develop signs of asthma at age 8. PMID- 20712024 TI - A method for selecting and monitoring medication sales for surveillance of gastroenteritis. AB - PURPOSE: Monitoring appropriate categories of medication sales can provide early warning of certain disease outbreaks. This paper presents a methodology for choosing and monitoring medication sales relevant for the surveillance of gastroenteritis and assesses the operational characteristics of the selected medications for early warning. METHODS: Acute diarrhoea incidences in mainland France were obtained from the Sentinelles network surveillance system for the period 2000-2009. Medication sales grouped by therapeutic classes were obtained on the same period. Hierarchical clustering was used to select therapeutic classes correlating with disease incidence over the period. Alert thresholds were defined for the selected therapeutic classes. Single and multiple voter algorithms were investigated for outbreak detection based on sales crossing the thresholds. Sensitivity and specificity were calculated respective to known outbreaks periods. RESULTS: Four therapeutic classes were found to cluster with acute diarrhoea incidence. The therapeutic class other antiemetic and antinauseants had the best sensitivity (100%) and timeliness (1.625 weeks before official alerts), for a false alarm rate of 5%. Multiple voter algorithm was the most efficient with the rule: 'Emit an outbreak alert when at least three therapeutic classes are over their threshold' (sensitivity 100%, specificity 95%, timeliness 1.750 weeks before official alerts). CONCLUSIONS: The presented method allowed selection of relevant therapeutic classes for surveillance of a specific condition. Multiple voter algorithm based on several therapeutic classes performed slightly better than the best therapeutic class alone, while improving robustness against abrupt changes occurring in a single therapeutic class. PMID- 20712025 TI - There is a trend in the utilization of psychotropics among elderly towards recommended drugs. AB - PURPOSE: To analyse trends in sales of potentially inappropriate psychotropic substances (PIPS) in relation to drugs recommended by Drug and Therapeutics Committees (DTC drugs) among 75-year olds and among individuals born 1925 in Sweden. METHODS: Trends in sales of PIPS and DTC drugs among 75-year olds and among individuals born 1925 in Sweden during 2000-2008 were analysed with linear regression models. Sales were measured as defined daily doses per 1000 inhabitants and day. PIPS were defined according to a proposal from the Swedish National Board of Health and Welfare. The selection of DTC drugs was based on a review of recommendations from local DTCs. RESULTS: Among 75-year olds, PIPS sales decreased 38% and DTC drugs sales increased 31% from 2000 to 2008. The hypnotic PIPS decreased 45%, while the DTC hypnotics increased 36%. The total sales of PIPS to individuals born in 1925 decreased 12% from 2000 to 2008. The DTC drugs increased 115%. Sales of hypnotic PIPS decreased 12%, and the hypnotic DTC drugs increased 120%. CONCLUSIONS: The findings indicate a trend towards the utilization of DTC drugs rather than PIPS. PMID- 20712026 TI - How are antibacterials used in nursing homes? Results from a point-prevalence prescription study in 44 Norwegian nursing homes. AB - PURPOSE: To describe the use of antibacterials among nursing home residents in Norway according to diagnosis, therapy choice, doses and expected duration of treatment. METHODS: A one-day point-prevalence study was carried out in 44 Norwegian nursing homes, spring 2006. Use of systemic antibacterials was recorded by indication, antibiotic name, dose and expected length of treatment. RESULTS: Of the 1473 nursing home residents, 224 (15%) were prescribed antibiotics. 149 (10%) were given antibiotics as prophylaxis, while 85 residents (6%) were treated with an antibiotic for an infection. 10 residents received both prophylaxis and treatment simultaneously. Antibiotics for treatment were in 66% of the cases for urinary tract infections (UTI) and in 20% for respiratory tract infections (RTI) with pivmecillinam and phenoxymethylpenicillin most frequently used, respectively. CONCLUSIONS: Antibiotics are often used in nursing homes, both as treatment and prophylaxis. The most common infections treated with antibiotics were UTIs, followed by RTIs. Choice of antibacterial, dosage and duration of treatment were in accordance with recommendations in guidelines. PMID- 20712027 TI - Retraction: Facile palladium-catalyzed arylation of heterocycles and nonactivated arenes with aryl chlorides. PMID- 20712030 TI - Nanowire-based sensors. AB - Nanowires are important potential candidates for the realization of the next generation of sensors. They offer many advantages such as high surface-to-volume ratios, Debye lengths comparable to the target molecule, minimum power consumption, and they can be relatively easily incorporated into microelectronic devices. Accordingly, there has been an intensified search for novel nanowire materials and corresponding platforms for realizing single-molecule detection with superior sensing performance. In this work, progress made towards the use of nanowires for achieving better sensing performance is critically reviewed. In particular, various nanowires types (metallic, semiconducting, and insulating) and their employment either as a sensor material or as a template material are discussed. Major obstacles and future steps towards the ultimate nanosensors based on nanowires are addressed. PMID- 20712033 TI - Artificial light-gated catalyst systems. AB - Having control over an entity or even an entire process is arguably the ultimate demonstration of its understanding and it will enable its potential to be fully exploited. With this in mind, chemists have not only been creating and optimizing a myriad of different catalysts for most (relevant) chemical reactions over the past decades, but have recently started to implement controlling elements into the catalyst design. These incorporated gates operate upon exposure to suitable control stimuli, and light represents perhaps the scientifically and technologically most attractive stimulus. In principle, irradiation can thereby induce activity and selectivity in a given catalyst system with high spatial and temporal control, leading to an overall localization and amplification of an optical signal and translation into chemical action. While nature has developed and utilized this concept, in particular in the processes of vision and photomovement, such artificial photocontrolled catalyst systems offer unique opportunities and have high potential for future applications. In this Review, we outline the general concept of light-gated catalysis based on photocaged and also photoswitchable systems, and discuss relevant examples of the past and recent literature. PMID- 20712034 TI - Unprecedented rate enhancements of hydrogen-atom transfer to a manganese(V)-oxo corrolazine complex. PMID- 20712035 TI - Combined magnetic susceptibility measurements and 57Fe Mossbauer spectroscopy on a ferromagnetic {Fe(III)4Dy4} ring. PMID- 20712036 TI - Inwards buildup of concentric polymer layers: a method for biomolecule encapsulation and microcapsule encoding. PMID- 20712039 TI - Editorial: expanding the former limits of biocatalytic applications. PMID- 20712044 TI - Digestive proteolytic and amylolytic activities of Helicoverpa armigera in response to feeding on different soybean cultivars. AB - BACKGROUND: Digestive proteolytic and amylolytic activities of the larvae of Helicoverpa armigera (Hubner) fed either on artificial diet or on different soybean cultivars (356, M4, M7, M9, Clark, Sahar, JK, BP, Williams, L17, Zane, Gorgan3 and DPX) and response of the larvae to feeding on some soybean-based protease inhibitors were studied. RESULTS: The highest general and specific proteolytic activities were in artificial-diet-fed larvae. Although the highest general proteolytic activity was in the larvae fed on L17, M4 and Sahar cultivars, the lowest tryptic activity was on L17 and Sahar, which may be due to the presence of some serine protease inhibitors in these two cultivars, resulting in hyperproduction of chymotrypsin- and elastase-like enzymes in response to the inhibition of these enzymes. The highest amylolytic activity was on M4, and the lowest was on Williams and DPX. General proteolytic activity of SKTI-fed larvae was the highest compared with SBBI- and STI-fed larvae. CONCLUSION: The findings demonstrated that the cultivars L17 and Sahar were partially resistant to this pest, probably because of some secondary chemicals or proteinaceous protease inhibitors of these cultivars. PMID- 20712045 TI - Natural orifice transluminal endoscopic surgery in pancreatic diseases. AB - Natural orifice transluminal endoscopic surgery (NOTES) is a surgical technique that has received considerable interest in recent years. Although minimal access surgery has increasingly replaced traditional open abdominal surgical approaches for a wide spectrum of indications, in pancreatic diseases its widespread use is limited to few indications because of the challenging and demanding nature of major pancreatic operations. Nonetheless, there have been attempts in animal models as well as in the clinical setting to perform diagnostic and resectional NOTES for pancreatic diseases. Here, we review and comment upon the available data regarding currently analyzed and performed pancreatic NOTES procedures. Potential indications for NOTES include peritoneoscopy, cyst drainage, and necrosectomy, palliative procedures such as gastroenterostomy, as well as resections such as distal pancreatectomy or enucleation. These procedures have already been shown to be technically feasible in several studies in animal models and a few clinical trials. In conclusion, NOTES is a rapidly developing concept/technique that could potentially become an integral part of the armamentarium dealing with surgical approaches to pancreatic diseases. PMID- 20712046 TI - First-line eradication of Helicobacter pylori: are the standard triple therapies obsolete? A different perspective. AB - Studies concerning the eradication of Helicobacter pylori have resulted in a proliferation of meta-analyses. To date, there are 303 meta-analyses cited in PubMed, 113 dealing with the therapy of the infection. A chronological analysis of the results of meta-analyses performed between 1998 and 2010 shows that first line standard triple therapies achieved eradication rates on an intention-to treat basis of around 80%; prolonging treatment to 14, but not 10 d should improve the results. The proton pump inhibitors have a similar efficiency, and giving a double dose is more efficient than the standard doses of these drugs. Triple and quadruple therapies proved to be equivalent. Based on meta-analytical data, the decrease in efficiency over time cannot be substantiated: eradication rates < 80% followed from the introduction of triple therapies. As alternatives, ranitidine bismuth citrate-, levofloxacin- or furazolidone-based therapies were shown to obtain the same eradication rates as standard triple regimens. Sequential therapies and quadruple non-bismuth-based therapies were superior to standard triple therapies but their use is limited to certain countries. In the author's opinion, and from a meta-analytical viewpoint, standard triple therapies cannot yet be considered obsolete. Furthermore, non-inferiority trials are proposed for the future, including assessment of local contemporary antimicrobial resistance profiles and the CagA and CYP2C19 status of the enrolled patients. PMID- 20712047 TI - Therapeutic implications of colon cancer stem cells. AB - Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy. PMID- 20712048 TI - Hepatitis B virus infection and renal transplantation. AB - Although the prevalence of chronic hepatitis B virus (HBV) infection has declined in renal transplant recipients (RTRs), it remains a relevant clinical problem with high morbidity and mortality in long-term follow up. A thorough evaluation, including liver biopsy as well as assessment of HBV replication in serum (i.e. hepatitis B e antigen and/or HBV DNA) is required before transplantation. Interferon should not be used in this setting because of low efficacy and precipitation on acute allograft rejection. The advent of effective antiviral therapies offers the opportunity to prevent the progression of liver disease after renal transplantation. However, as far as we are aware, no studies have compared prophylactic and preemptive strategies. To date, the majority of RTRs with HBV-related liver disease have had a high virological and biochemical response to lamivudine use. However, lamivudine resistance is frequent with a prolonged course of therapy. Considering long-term treatment, antiviral agents with a high genetic barrier to resistance and lack of nephrotoxicity are suggested. The optimal strategy in RTRs with HBV infection remains to be established in the near future. PMID- 20712049 TI - Glucocorticoid receptor gene haplotype structure and steroid therapy outcome in IBD patients. AB - AIM: To study whether the glucocorticoid receptor (GR/NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically significant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome. PMID- 20712050 TI - Expression of protein S100A4 is a predictor of recurrence in colorectal cancer. AB - AIM: To investigate the prognostic significance of S100A4 expression in colorectal cancer and its correlation with expression of E-cadherin and p53. METHODS: A cohort of archival formalin-fixed paraffin-embedded specimens was selected from 127 patients with colorectal cancer who underwent surgical resection between April 2000 and March 2004 at the Department of Surgery, Korea University Guro Hospital. The expression of protein S100A4 was evaluated according to the proportion of positively stained cancer cells. In each case, three core biopsies with a diameter of 2 mm were punched out and positioned in a recipient paraffin array block. Four-microm sections of these tissue array blocks were used for immunohistochemical analysis of protein S100A4, E-cadherin, and p53. Clinicopathological data were based on the original histopathologic reports and clinical records of patients. RESULTS: In normal colorectal mucosa, protein S100A4 immunoreactivity was clearly absent in both cytoplasm and nucleus. However, positive immunoreactivity of protein S100A4 was detected in 45 (35.4%) of the tumor cases. There was no significant association between positive immunoreactivity of protein S100A4 and clinicopathological parameters such as tumor differentiation or TNM stage, and also no correlation between the reactivity and E-cadherin or p53 expression. However, positive immunoreactivity of protein S100A4 was found to be associated with tumor recurrence (P = 0.004), and was also associated with significantly worse overall survival in the Kaplan Meyer survival analysis (P = 0.044). After adjustment for tumor differentiation, tumor depth and nodal status, however, it failed to achieve statistical significance (P = 0.067). CONCLUSION: The expression of protein S100A4 is associated with tumor recurrence and poor overall survival in patients with colorectal cancer. PMID- 20712051 TI - Prospective randomized controlled trial evaluating cap-assisted colonoscopy vs standard colonoscopy. AB - AIM: To study the significance of cap-fitted colonoscopy in improving cecal intubation time and polyp detection rate. METHODS: This study was a prospective randomized controlled trial conducted from March 2008 to February 2009 in a tertiary referral hospital at Sydney. The primary end point was cecal intubation time and the secondary endpoint was polyp detection rate. Consecutive cases of total colonoscopy over a 1-year period were recruited. Randomization into either standard colonoscopy (SC) or cap-assisted colonoscopy (CAC) was performed after consent was obtained. For cases randomized to CAC, one of the three sizes of cap was used: D-201-15004 (with a diameter of 15.3 mm), D-201-14304 (14.6 mm) and D 201-12704 (13.0 mm). All of these caps were produced by Olympus Medical Systems, Japan. Independent predictors for faster cecal time and better polyp detection rate were also determined from this study. RESULTS: There were 200 cases in each group. There was no significant difference in terms of demographic characteristics between the two groups. CAC, when compared to the SC group, had no significant difference in terms of cecal intubation rate (96.0% vs 97.0%, P = 0.40) and time (9.94 +/- 7.05 min vs 10.34 +/- 6.82 min, P = 0.21), or polyp detection rate (32.8% vs 31.3%, P = 0.75). On the subgroup analysis, there was no significant difference in terms of cecal intubation time by trainees (88.1% vs 84.8%, P = 0.40), ileal intubation rate (82.5% vs 79.0%, P = 0.38) or total colonoscopy time (23.24 +/- 13.95 min vs 22.56 +/- 9.94 min, P = 0.88). On multivariate analysis, the independent determinants of faster cecal time were consultant-performed procedures (P < 0.001), male patients (P < 0.001), non-usage of hyoscine (P < 0.001) and better bowel preparation (P = 0.01). The determinants of better polyp detection rate were older age (P < 0.001), no history of previous abdominal surgery (P = 0.04), patients not having esophagogastroduodenoscopy in the same setting (P = 0.003), trainee-performed procedures (P = 0.01), usage of hyoscine (P = 0.01) and procedures performed for polyp follow-up (P = 0.01). The limitations of the study were that it was a single-center experience, no blinding was possible, and there were a large number of endoscopists. CONCLUSION: CAC did not significantly different from SC in term of cecal intubation time and polyp detection rate. PMID- 20712052 TI - Anti-proliferative and pro-apoptotic effects of tectorigenin on hepatic stellate cells. AB - AIM: To investigate the effect of tectorigenin on proliferation and apoptosis of hepatic stellate cells (HSC)-T6 cells. METHODS: HSC-T6 cells were incubated with tectorigenin at different concentrations, and their proliferation was assessed by bromodeoxyuridine incorporation assay. Apoptosis was detected by flow cytometry assay with Hoechst 33342 staining. Also, generation of reactive oxygen species (ROS), intracellular [Ca(2+)](i), potential of mitochondrial membrane, activities of cytochrome c and caspase-9 and -3 were investigated to explore a conceivable apoptotic pathway. RESULTS: Tectorigenin suppressed the proliferation of HSC-T6 cells and induced apoptosis of HSC-T6 cells in a time- and dose-dependent manner. Tectorigenin at the concentration of 100 microg/mL greatly inhibited the viability of HSC-T6 cells and induced the condensation of chromatin and fragmentation of nuclei. When treated for 48 h, the percentage of cell growth and apoptosis reached 46.3% +/- 2.37% (P = 0.004) and 50.67% +/- 3.24% (P = 0.003), respectively. Furthermore, tectorigenin-induced apoptosis of HSC-T6 cells was associated with the generation of ROS, increased intracellular [Ca(2+)](i), loss of mitochondrial membrane potential, translocation of cytochrome c, and activation of caspase-9 and -3. CONCLUSION: Tectorigenin inhibits proliferation of HSC-T6 cells and induces apoptosis of HSC-T6 cells. PMID- 20712053 TI - Mapping of liver-enriched transcription factors in the human intestine. AB - AIM: To investigate the gene expression pattern of hepatocyte nuclear factor 6 (HNF6) and other liver-enriched transcription factors in various segments of the human intestine to better understand the differentiation of the gut epithelium. METHODS: Samples of healthy duodenum and jejunum were obtained from patients with pancreatic cancer whereas ileum and colon was obtained from patients undergoing right or left hemicolectomy or (recto)sigmoid or rectal resection. All surgical specimens were subjected to histopathology. Excised tissue was shock-frozen and analyzed for gene expression of liver-enriched transcription factors by semiquantitative reverse transcription polymerase chain and compared to the human colon carcinoma cell line Caco-2. Protein expression of major liver-enriched transcription factors was determined by Western blotting while the DNA binding of HNF6 was investigated by electromobility shift assays. RESULTS: The gene expression patterning of liver-enriched transcription factors differed in the various segments of the human intestine with HNF6 gene expression being most abundant in the duodenum (P < 0.05) whereas expression of the zinc finger protein GATA4 and of the HNF6 target gene ALDH3A1 was most abundant in the jejunum (P < 0.05). Likewise, expression of FOXA2 and the splice variants 2 and 4 of HNF4alpha were most abundantly expressed in the jejunum (P < 0.05). Essentially, expression of transcription factors declined from the duodenum towards the colon with the most abundant expression in the jejunum and less in the ileum. The expression of HNF6 and of genes targeted by this factor, i.e. neurogenin 3 (NGN3) was most abundant in the jejunum followed by the ileum and the colon while DNA binding activity of HNF4alpha and of NGN3 was confirmed by electromobility shift assays to an optimized probe. Furthermore, Western blotting provided evidence of the expression of several liver-enriched transcription factors in cultures of colon epithelial cells, albeit at different levels. CONCLUSION: We describe significant local and segmental differences in the expression of liver-enriched transcription factors in the human intestine which impact epithelial cell biology of the gut. PMID- 20712054 TI - Liver sinusoidal endothelial and biliary cell repopulation following irradiation and partial hepatectomy. AB - AIM: To investigate whether irradiation (IR) and partial hepatectomy (PH) may prepare the host liver for non-parenchymal cell (NPC) transplantation. METHODS: Livers of dipeptidyl peptidase IV (DPPIV)-deficient rats were pre-conditioned with external beam IR (25 Gy) delivered to two-thirds of the right liver lobules followed by a one-third PH of the untreated lobule. DPPIV-positive liver cells (NPC preparations enriched for liver sinusoidal endothelial cells (LSECs) and hepatocytes) were transplanted via the spleen into the recipient livers. The extent and quality of donor cell engraftment and growth was studied over a long term interval of 16 wk after transplantation. RESULTS: Host liver staining demonstrated 3 different repopulation types. Well defined clusters of donor derived hepatocytes with canalicular expression of DPPIV were detectable either adjacent to or in between large areas of donor cells (covering up to 90% of the section plane) co-expressing the endothelial marker platelet endothelial cell adhesion molecule. The third type consisted of formations of DPPIV-positive duct like structures which co-localized with biliary epithelial CD49f. CONCLUSION: Liver IR and PH as a preconditioning stimulus enables multiple cell liver repopulation by donor hepatocytes, LSECs, and bile duct cells. PMID- 20712055 TI - Helicobacter pylori CagA protein polymorphisms and their lack of association with pathogenesis. AB - AIM: To investigate Helicobacter pylori (H. pylori) CagA diversity and to evaluate the association between protein polymorphisms and the occurrence of gastric pathologies. METHODS: One hundred and twenty-two clinical isolates of H. pylori cultured from gastric biopsies obtained from Colombian patients with dyspepsia were included as study material. DNA extracted from isolates was used to determine cagA status, amplifying the C-terminal cagA gene region by polymerase chain reaction. One hundred and six strains with a single amplicon were sequenced and results were used to characterize the 3' variable region of the cagA gene. To establish the number and type of tyrosine phosphorylation motifs Glutamine acid-Proline-Isoleucine-Tyrosine-Alanine (EPIYA) bioinformatic analysis using Amino Acid Sequence Analyzer-Amino Acid Sequence Analyzer software was conducted. Analysis of the association between the number of EPIYA motifs and the gastric pathology was performed using chi(2) test and analysis of the presence of EPIYA-C motifs in relation to the pathology was made by logistic regression odds ratios. Comparisons among EPIYA types found and those reported in GenBank were performed using a proportion test in Statistix Analytical Software version 8.0. RESULTS: After amplification of the 3' of the cagA gene, 106 from 122 isolates presented a single amplicon and 16 showed multiple amplicons. As expected, diversity in the size of the cagA unique fragments among isolates was observed. The 106 strains that presented a single amplicon after 3' cagA amplification came from patients with gastritis (19 patients), atrophic gastritis (21), intestinal metaplasia (26), duodenal ulcer (22) and gastric cancer. DNA sequence analysis showed that the differences in size of 3' cagA unique fragments was attributable to the number of EPIYA motifs: 1.9% had two EPIYA motifs, 62.3% had three, 33.0% had four and 2.8% had five motifs. The majority of tested clinical strains (62.3%) were found to harbor the ABC combination of EPIYA motifs and a significant statistical difference was observed between the frequencies of ABCC tyrosine phosphorylation motifs and Western strains sequences deposited in GenBank. CONCLUSION: The present report describes a lack of association between H. pylori CagA-protein polymorphisms and pathogenesis. ABCC high frequency variations compared with Western-strains sequences deposited in GenBank require more investigation. PMID- 20712057 TI - Mechanism underlying carbon tetrachloride-inhibited protein synthesis in liver. AB - AIM: To study the mechanism underlying carbon tetrachloride (CCl(4)) -induced alterations of protein synthesis in liver. METHODS: Male Sprague-Dawley rats were given CCl(4) (1 mL/100 g body weight) and (3)H-leucine incorporation. Malondialdehyde (MDA) level in the liver, in vitro response of hepatocyte nuclei nucleotide triphosphatase (NTPase) to free radicals, and nuclear export of total mRNA with 3'-poly A(+) were measured respectively. Survival response of HepG2 cells to CCl(4) treatment was assessed by methyl thiazolyl tetrazolium. Km and Vmax values of nuclear envelope NTPase activity in liver of rats treated with CCl(4) were assayed by a double-reciprocal plot. RESULTS: The protein synthesis was inhibited while the MDA level was significantly increased in liver of rats treated with CCl(4). In addition, CCl(4) decreased the NTPase binding capacity of nuclear envelope (Km value) in cultured HepG2 cells. Moreover, in vitro ferrous radicals from Fenton's system suppressed the NTPase activity of liver nuclear envelope in a dose-dependent manner. Down-regulation of the nuclear envelope NTPase activity indicated a lower energy provision for nucleocytoplasmic transport of mRNA molecules, an evidence in CCl(4)-treated HepG2 cells correspondingly supported by the nuclear sequestration of poly (A)(+) mRNA molecules in morphological hybridization research. CONCLUSION: Inhibition of mRNA transport, suggestive of decreased NTPase activity of the nuclear envelope, may be involved in carbon tetrachloride-inhibited protein synthesis in liver. PMID- 20712056 TI - Steatosis and steatohepatitis in postmortem material from Northwestern Greece. AB - AIM: To determine the prevalence of steatosis and steatohepatitis in a series of autopsies in Northwestern Greece. METHODS: Liver biopsy material from a total of 600 autopsies performed over a period of 2 years (2006-2008) to define the cause of death was subjected to histological examination. Patient demographic data were also collected. Tissue sections were stained with different dyes for the evaluation of liver architecture, degree of fibrosis and other pathological conditions when necessary. RESULTS: Satisfactory tissue samples for histological evaluation were available in 498 cases (341 male, 157 female) with a mean age of 64.51 +/- 17.78 years. In total, 144 (28.9%) had normal liver histology, 156 (31.3%) had evidence of steatosis, and 198 (39.8%) had typical histological findings of steatohepatitis. The most common causes of death were ischemic heart disease with or without myocardial infarction (43.4%), and traffic accidents (13.4%). CONCLUSION: A high prevalence of steatosis and steatohepatitis was detected in postmortem biopsies from Northwestern Greece. Since both diseases can have serious clinical consequences, they should be considered as an important threat to the health of the general population in Greece. PMID- 20712058 TI - Usefulness of CT angiography in diagnosing acute gastrointestinal bleeding: a meta-analysis. AB - AIM: To analyze the accuracy of computed tomography (CT) angiography in the diagnosis of acute gastrointestinal (GI) bleeding. METHODS: The MEDLINE, EMBASE, Cancerlit, Cochrane Library database, Sciencedirect, Springerlink and Scopus, from January 1995 to December 2009, were searched for studies evaluating the accuracy of CT angiography in diagnosing acute GI bleeding. Studies were included if they compared CT angiography to a reference standard of upper GI endoscopy, colonoscopy, angiography or surgery in the diagnosis of acute GI bleeding. Meta analysis methods were used to pool sensitivity and specificity and to construct summary receiver-operating characteristic. RESULTS: A total of 9 studies with 198 patients were included in this meta-analysis. Data were used to form 2 x 2 tables. CT angiography showed pooled sensitivity of 89% (95% CI: 82%-94%) and specificity of 85% (95% CI: 74%-92%), without showing significant heterogeneity (chi(2) = 12.5, P = 0.13) and (chi(2) = 22.95, P = 0.003), respectively. Summary receiver operating characteristic analysis showed an area under the curve of 0.9297. CONCLUSION: CT angiography is an accurate, cost-effective tool in the diagnosis of acute GI bleeding and can show the precise location of bleeding, thereby directing further management. PMID- 20712059 TI - Multiple primary malignant tumors of upper gastrointestinal tract: a novel role of 18F-FDG PET/CT. AB - AIM: To evaluate the capacity of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) for detecting multiple primary cancer of upper gastrointestinal (UGI) tract. METHODS: Fifteen patients (12 without cancer histories and 3 with histories of upper GI tract cancer) were investigated due to the suspicion of primary cancer of UGI tract on X-ray barium meal and CT scan. Subsequent whole body (18)F-FDG PET/CT scan was carried out for initial staging or restaging. All the patients were finally confirmed by endoscopic biopsy or surgery. The detection rate of multiple primary malignant cancers was calculated based on (18)F-FDG PET/CT and endoscopic examinations. RESULTS: (18)F-FDG PET/CT scan was positive in 32 suspicious lesions, 30/32 were true positive primary lesions, and 2/32 were false positive. In 15 suspicious lesions with negative (18)F-FDG PET/CT scan, 12/15 were true negative and 3/15 were false negative. Among the 15 patients, 12 patients had 29 primary synchronous tumors confirmed by pathology, including 8 cases of esophageal cancers accompanied with gastric cancer and 4 of hypopharynx cancers with esophageal cancer. The other 3 patients had 4 new primary metachronous tumors, which were multiple primary esophageal cancers. PET/CT imaging detected local lymph node metastases in 11 patients. Both local lymph node metastases and distant metastases were detected in 4 patients. On a per-primary lesion basis, the sensitivity, specificity, accuracy, negative predictive value and positive predictive value of (18)F-FDG PET/CT for detecting multiple primary cancer of UGI tract were 90.9%, 85.7%, 89.4%, 80% and 93.7%, respectively. CONCLUSION: The whole body (18)F-FDG PET/CT may play an important role in evaluating the multiple primary malignant tumors of UGI tract cancer. PMID- 20712060 TI - Use of pre-, pro- and synbiotics in patients with acute pancreatitis: a meta analysis. AB - AIM: To assess the clinical outcomes of pre-, pro- and synbiotics therapy in patients with acute pancreatitis. METHODS: The databases including Medline, Embase, the Cochrane Library, Web of Science and Chinese Biomedicine Database were searched for all relevant randomized controlled trials that studied the effects of pre-, pro- or synbiotics in patients with acute pancreatitis. Main outcome measures were postoperative infections, pancreatic infections, multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS), length of hospital stay, antibiotic therapy and mortality. RESULTS: Seven randomized studies with 559 acute pancreatic patients were included. Pre-, pro- or synbiotics treatment showed no influence on the incidence of postoperative infections [odds ratios (OR) 0.30, 95% confidence interval (CI): 0.09-1.02, P = 0.05], pancreatic infection (OR 0.50, 95% CI: 0.12-2.17, P = 0.36), MOF (OR 0.88, 95% CI: 0.35-2.21, P = 0.79) and SIRS (OR 0.78, 95% CI: 0.20-2.98, P = 0.71). There were also no significant differences in the length of antibiotic therapy (OR 0.75, 95% CI: 0.50 - 1.14, P = 0.18) and the mortality (OR 0.75, 95% CI: 0.25 2.24, P = 0.61). However, Pre-, pro- or synbiotics treatment was associated with a reduced length of hospital stay (OR -3.87, 95% CI: -6.20 to -1.54, P = 0.001). When stratifying for the severity of acute pancreatitis, the main results were similar. CONCLUSION: Pre-, pro- or synbiotics treatment shows no significant influence on patients with acute pancreatitis. There is a lack of evidence to support the use of probiotics/synbiotics in this area. PMID- 20712061 TI - Living donor liver transplantation using dual grafts: ultrasonographic evaluation. AB - AIM: To evaluate the dual-graft living donor liver transplantation (LDLT) with ultrasonography, with special emphasis on the postoperative complications. METHODS: From January 2002 to August 2007, 110 adult-to-adult LDLTs were performed in West China Hospital of Sichuan University. Among them, dual-graft implantations were performed in six patients. Sonographic findings of the patients were retrospectively reviewed. RESULTS: All the six recipients survived the dual-graft adult-to-adult LDLT surgery. All had pleural effusion. Four patients had episodes of postoperative abdominal complications, including fluid collection between the grafts in three patients, intrahepatic biliary dilatation in two, hepatofugal portal flow of the left lobe in two, and atrophy of the left lobe in one. CONCLUSION: Although dual-graft LDLT takes more efforts and is technically complicated, it is safely feasible. Postoperative sonographic monitoring of the recipient is important. PMID- 20712062 TI - Multiple bowel intussusceptions from metastatic localized malignant pleural mesothelioma: a case report. AB - Localized malignant pleural mesothelioma (LMPM) is a rare occurrence, and gastrointestinal intra-luminal metastases have not previously been reported. Herein, we report a patient with LMPM who presented with a local recurrence 10 mo after initial en bloc surgical resection. Abdominal computed tomography was performed for intractable, vague abdominal pain with episodic vomiting, which showed a "target sign" over the left lower quadrant. Laparotomy revealed several intra-luminal metastatic tumors in the small intestine and colon and a segmental resection of metastatic lesions was performed. Unfortunately, the patient died of sepsis despite successful surgical intervention. Though local recurrence is more frequent in LMPM, the possibility of distant metastasis should not be ignored in patients with non-specific abdominal pain. PMID- 20712063 TI - Poultry veterinarians' perspectives on antimicrobial resistance. PMID- 20712064 TI - Abortifacient vaccines and bovine herpesvirus-1. PMID- 20712065 TI - Additional views on the costs of feral cat control. PMID- 20712066 TI - Erratum: Ranibizumab and Nonocular Hemorrhage. PMID- 20712067 TI - Systematic ranking of inborn errors of metabolism as targets for gene therapy. PMID- 20712068 TI - Retraction. Fatty acid synthase is a novel therapeutic target in multiple myeloma. PMID- 20712069 TI - Liver: Proof of principle for the generation of a transplantable recellularized liver graft. PMID- 20712070 TI - Crohn's disease and preterm birth. PMID- 20712071 TI - Cirrhosis: Role of endocannabinoid system confirmed in patients with cirrhosis. PMID- 20712072 TI - Imaging: Confocal endomicroscopy enables deeper in vivo imaging of human liver. PMID- 20712073 TI - Endoscopy: Snoring while under conscious sedation during colonoscopy is linked to obstructive sleep apnea. PMID- 20712074 TI - Celiac disease: Celiac disease in children is associated with cesarean delivery. PMID- 20712075 TI - Economic evidence in intellectual disabilities: a review. AB - PURPOSE OF REVIEW: There has been a drive to meet the needs of people with intellectual disabilities in an environment of resource scarcity. It is also recognized that intervention has the potential to improve social and economic welfare. Economic analyses can be used to inform decision makers about what additional investment is needed (if any) and the impacts on a range of stakeholders of intervention. RECENT FINDINGS: There is a paucity of economic studies in intellectual disability. The lack of economic studies is a barrier to making policy and practice decisions for people with intellectual disabilities. In the period of review, 10 economic studies were found. SUMMARY: Information on resource and cost implications of various treatments and support for people with intellectual disabilities is needed. Economic evaluation techniques can be used to inform decision making. We conducted a systematic review of the literature from January 2006 to February 2010. There was a paucity of economic studies in the field. Analyses assessing a wide range of outcomes alongside costs were the most widely used evaluation method in the review. There is a need for more economic studies in this area. PMID- 20712077 TI - To have some friends: A tribute to Robert Goldwyn, M.D., 1930 to 2010 - Plastic and Reconstructive Surgery editor emeritus dies at age 79. PMID- 20712076 TI - A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model. AB - BACKGROUND: Regulatory T cells (Tregs) actively regulate alloimmune responses and promote transplantation tolerance. Thymoglobulin, a rabbit polyclonal antithymocyte globulin (ATG), is a widely used induction therapy in clinical organ transplantation that depletes peripheral T cells. However, resistance to tolerance induction is seen with certain T-cell depleting strategies and is attributed to alterations in the balance of naive, memory and Tregs. The exact mechanism of action of ATG and its effects on the homeostasis and balance between Tregs and T-effector-memory cells (Tem) are unknown. METHODS: A novel antibody reagent, rabbit polyclonal anti-murine thymocyte globulin (mATG), generated by the same process used to manufacture thymoglobulin, was used alone or in combination with CTLA4Ig or sirolimus (SRL) in a stringent fully major histocompatibility complex-mismatched murine skin allograft model to study graft survival and mechanisms involved. RESULTS: mATG depletes T cells but preferentially spares CD25+ natural Tregs which limit skewing of T-cell repertoire toward Tem phenotype among the recovering T cells. T-cell depletion with mATG combined with CTLA4Ig and SRL synergize to prolong graft survival by tipping the Treg/Tem balance further in favor of Tregs by preserving Tregs, facilitating generation of new Tregs by a conversion mechanism and limiting Tem expansion in response to alloantigen and homeostatic proliferation. CONCLUSIONS: Simultaneous T-cell depletion with ATG and costimulatory blockade, combined with SRL, synergizes to promote regulation and prolong allograft survival in a stringent transplant model. These results provide the rationale for translating such novel combination therapy to promote regulation in primate and human organ transplantation. PMID- 20712079 TI - Abstracts of the 4th ESF Conference on Functional Genomics and Disease, 14-17 April 2010, Dresden, Germany. PMID- 20712078 TI - MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. AB - MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Dysregulated expression of miRNAs is associated with several diseases, including cancer. In this study, we report that the expression of microRNA-101 (miR-101) is down-regulated in gastric cancer tissues and cells, and ectopic expression of miR-101 significantly inhibits cellular proliferation, migration and invasion of gastric cancer cells by targeting EZH2, Cox-2, Mcl-1 and Fos. Our animal study also indicates that miR 101 could potentially suppress tumour growth in vivo. Collectively, these results suggest that miR-101 may function as a tumour suppressor in gastric cancer, as it has an inhibitory role not only in cellular proliferation, migration and invasion in vitro, but also in tumour growth in vivo. PMID- 20712080 TI - British West Indies peregrinations. PMID- 20712081 TI - Clinical Roundtable Monograph: current treatment options for NHL patients refractory to standard therapy: recent data in single-agent and combination therapy. AB - Rituximab plays an important role in the treatment of non-Hodgkin lymphoma (NHL). In spite of high response rates achieved with this monoclonal antibody, however, many patients with NHL tend to relapse and become refractory to rituximab over time. At the 2009 meeting of the American Society of Hematology (ASH), researchers presented results from several new approaches that may provide a boost to the NHL treatment armamentarium.Important long-term safety data were presented for bendamustine, a bifunctional alkylating agent that was approved by the US Food and Drug Administration in 2008 for chronic lymphocytic leukemia and indolent B-cell NHL that is resistant to rituximab. In addition, emerging evidence concerning the combination of bendamustine, rituximab, and bortezomib was presented. Other trials discussed the use of novel monoclonal antibodies such as of atumumab, GA101, PRO131921, and inotuzumab ozogamicin, which are directed at new biological targets for the treatment of NHL. Researchers also discussed recent trials of lenalidomide, an oral immunomodulator, alone and in combination with rituximab. Other novel agents discussed at the ASH meeting included clofarabine and CAL-101. PMID- 20712082 TI - The triad of Columella deformities. PMID- 20712083 TI - The island flap in cleft palate surgery. PMID- 20712084 TI - Reconstruction of a functioning vagina following radiation therapy for cancer cervix. PMID- 20712085 TI - Medicaid program and Children's Health Insurance program (CHIP); revisions to the Medicaid Eligibility Quality Control and Payment Error Rate Measurement programs. Final rule. AB - This final rule implements provisions from the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA) (Pub. L. 111-3) with regard to the Medicaid Eligibility Quality Control (MEQC) and Payment Error Rate Measurement (PERM) programs. This final rule also codifies several procedural aspects of the process for estimating improper payments in Medicaid and the Children's Health Insurance Program (CHIP). PMID- 20712086 TI - Medicare program; end-stage renal disease prospective payment system. Final rule. AB - This final rule implements a case-mix adjusted bundled prospective payment system (PPS) for Medicare outpatient end-stage renal disease (ESRD) dialysis facilities beginning January 1, 2011 (ESRD PPS), in compliance with the statutory requirement of the Medicare Improvements for Patients and Providers Act (MIPPA), enacted July 15, 2008. This ESRD PPS also replaces the current basic case-mix adjusted composite payment system and the methodologies for the reimbursement of separately billable outpatient ESRD services. PMID- 20712087 TI - Medicare Program; hospital inpatient prospective payment systems for acute care hospitals and the long-term care hospital prospective payment system changes and FY2011 rates; provider agreements and supplier approvals; and hospital conditions of participation for rehabilitation and respiratory care services; Medicaid program: accreditation for providers of inpatient psychiatric services. Final rules and interim final rule with comment period. AB - : We are revising the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital-related costs of acute care hospitals to implement changes arising from our continuing experience with these systems and to implement certain provisions of the Affordable Care Act and other legislation. In addition, we describe the changes to the amounts and factors used to determine the rates for Medicare acute care hospital inpatient services for operating costs and capital-related costs. We also are setting forth the update to the rate-of increase limits for certain hospitals excluded from the IPPS that are paid on a reasonable cost basis subject to these limits. We are updating the payment policy and the annual payment rates for the Medicare prospective payment system (PPS) for inpatient hospital services provided by long-term care hospitals (LTCHs) and setting forth the changes to the payment rates, factors, and other payment rate policies under the LTCH PPS. In addition, we are finalizing the provisions of the August 27, 2009 interim final rule that implemented statutory provisions relating to payments to LTCHs and LTCH satellite facilities and increases in beds in existing LTCHs and LTCH satellite facilities under the LTCH PPS. We are making changes affecting the: Medicare conditions of participation for hospitals relating to the types of practitioners who may provide rehabilitation services and respiratory care services; and determination of the effective date of provider agreements and supplier approvals under Medicare. We are also setting forth provisions that offer psychiatric hospitals and hospitals with inpatient psychiatric programs increased flexibility in obtaining accreditation to participate in the Medicaid program. Psychiatric hospitals and hospitals with inpatient psychiatric programs will have the choice of undergoing a State survey or of obtaining accreditation from a national accrediting organization whose hospital accreditation program has been approved by CMS. We are also issuing an interim final rule with comment period to implement a provision of the Preservation of Access to Care for Medicare Beneficiaries and Pension Relief Act of 2010 relating to Medicare payments for outpatient services provided prior to a Medicare beneficiary's inpatient admission. PMID- 20712088 TI - Nearly 2.5 million nonelderly California women uninsured at some time during 2007. AB - Health insurance coverage is a key component of access to the health care system. For women, such coverage facilitates access to the array of services they require across their lifetimes. This brief provides an overview of uninsured women ages 18--64 in California, examining subgroups of women at higher risk of being without coverage and looking at family incomes of uninsured women and at uninsured rates across counties. The information in the brief is based on data from the 2007 California Health Interview Survey (CHIS 2007). PMID- 20712090 TI - The process of translation as seen in 1969. PMID- 20712089 TI - [The first external quality control assessment of cytomegalovirus DNA detection by polymerase chain reaction in the Czech Republic]. PMID- 20712091 TI - The unregulated employment of aboriginal children in Queensland, 1842-1902. PMID- 20712092 TI - Obstacles in diagnosing and confirmation of occupational diseases in private farming in Poland. PMID- 20712093 TI - [Crime in the German empire, 1883-1902: a social environmental analysis]. PMID- 20712094 TI - Pestis redux: the initial years of the third bubonic plague pandemic, 1894-1901. PMID- 20712095 TI - Fatma Aliye's Stories: Ottoman marriages beyond the harem. AB - The harem image has dominated the conceptualizations of the family and the private sphere in the Ottoman empire at the turn of the century. This essay aims to review these conceptualizations and locate family life in both public and private spheres. The main source of inquiry will be the literary writings of Fatma Aliye (1862-1936) who wrote about women, marriage, education, poverty, and slavery. In these works, she outlined common dreams for Eastern and Western women, such as the love and companionship of an honest, monogamous man. These dreams envisioned Muslim women performing a variety of roles and thus transcended the given expectations from the family and from Muslim women as a monolithic category. In this light, this essay seeks to contextualize Aliye's works within the history of the family by evaluating Aliye's views particularly on marriage. PMID- 20712096 TI - December 2009: rural Medicare Advantage enrollment grows 15% in 2009. PMID- 20712097 TI - Severe snoring can signal apnea. PMID- 20712099 TI - Multivitamins: most we tested were fine, so select by price. PMID- 20712098 TI - Dangerous supplements: what you don't know about these 12 ingredients could hurt you. PMID- 20712100 TI - A comment on 'surgical management of large segmental femoral and radial bone defects'. PMID- 20712101 TI - A comment on studies using force-plate analysis. PMID- 20712102 TI - Global oral health in a flattening world. PMID- 20712103 TI - The winds of change in dentistry--1950 and 2000. AB - SERIES SYNOPSIS: This series examines how scientific, political, and social forces have impacted modern dental practice and is divided into four parts. Parts 1 and 3 examine the scientific, political, and social changes that occurred in the United States in two periods: one from 1850 to 1900 and the other from 1950 to 2000. Parts 2 and 4 study how these transformations impacted dental practice and dentistry as a profession. (Parts 1 and 2 may be read at www.compendiumlive.com.) The series compares the events of two 50-year periods and their effect on the subsequent decades. From this analysis, it might be possible to make some predications for dentistry in the 21st century. PMID- 20712104 TI - Smile designing for the malcontent patient. AB - Patients and dentists may have conflicting opinions regarding the definition of an esthetically pleasing smile. Every dentist is likely to encounter malcontent patients who may have difficulty communicating their esthetic desires for smiles and may even refuse to pay for successful treatment outcomes that they misperceive as failures. Learning how to work with such patients is essential. Part of achieving patient satisfaction is encouraging their participation in designing their smile. With the use of a crown-bridge-veneer pattern, tried-on prepared teeth, or implants, an exacting acrylic wax smile is designed. This pattern is used to analytically and objectively design porcelain contours for the finished smile design. This technique works well for veneers, full crowns, or bridges. PMID- 20712105 TI - Dental economics and the aging population. AB - In 2011, the oldest segment of the baby boom generation will be 65 years of age, marking the beginning of an important demographic shift for dentistry. As seniors, boomers will continue to need dental care, more than previous cohorts of seniors. However, many may lack the means to fully finance their dental care. With the associations between oral and systemic health becoming clearer, dental practitioners will become increasingly involved in promoting their patients' overall health. This article reviews recent trends and projections in dental spending and how an aging population may impact clinical practice and dental business operations. PMID- 20712106 TI - Complete denture prosthodontics in children with ectodermal dysplasia: review of principles and techniques. AB - Ectodermal dysplasia (ED) is a hereditary condition in which a minimum of two ectodermal structures fail to develop. Anodontia, or hypodontia, is one of the most common manifestations of this condition. As a result, it is critical that prosthodontic habilitation or rehabilitation is started early. Complete dentures are a simple, inexpensive, and reversible option. Several case reports have demonstrated the successful use of complete dentures in children with ED. However, few articles have exclusively addressed the principles of complete denture prosthodontics in these individuals. This report critically analyzes the literature with respect to complete denture principles and techniques in children. Evidence to date is insufficient for advocating any one technique; therefore, the authors recommend a simplified yet scientific approach in fabricating complete dentures for children. This can aid the practicing dentist in using this simple therapeutic option to provide esthetic, functional, and psychological benefits for children with ED and other congenital anomalies related to missing teeth. PMID- 20712107 TI - Periodontitis and cancer...a link? A review of the recent literature. PMID- 20712108 TI - Fears and concerns of individuals contemplating esthetic restorative dentistry. AB - Questionnaires that focus on the fear of dental treatment typically include a narrow list of previous treatment-related factors. By omitting items concerned with psychologic, emotional, and interpersonal traits that impact treatment, practitioners often fail to gain additional valuable information on related anxiety issues. This study was undertaken to identify previously unrecognized or poorly discussed sources of fear and anxiety in patients seeking esthetic dental treatment. The Esthetic Clinic at Tufts University School of Dental Medicine recruited 62 participants who were asked to score their level of anxieties and concerns based on 24 different items on a 0 to 5 Likert scale. In addition, age, gender, and type of procedure in consideration were the only other variables recorded. The item that elicited the highest level of anxiety was "not feeling happy with my new smile." Thirty-eight respondents (61.3%) said they feel "markedly anxious"or "severely anxious" or answered "avoid completely." Concerns "that the outcome might look false and unnatural" or "that the dentist might not redo it if I am not satisfied with the outcome" both received 37 out of 62 (59.7%) similar responses. These results suggest obstacles to treatment exist not only in areas typically investigated but also in factors rarely discussed during the patient-practitioner encounter. The practitioner needs to consider a broader range of issues when addressing the patient's concerns. PMID- 20712109 TI - Interdisciplinary treatment of an end-to-end occlusion due to congenitally missing maxillary lateral incisors. AB - Odontogenic aplasia, or the congenital absence of permanent teeth, is relatively common. When the missing teeth include the maxillary lateral incisors, treatment considerations must reconcile both esthetic and functional objectives. In developing dentition, erupting adjacent teeth can drift from their intended positions into the edentulous space created by the congenitally missing tooth. When this movement happens (e.g., cuspids shifting more mesially than normal), esthetic and functional problems occur. A restorative solution for missing maxillary lateral incisors subsequent to the loss of the maxillary incisor spaces is presented while highlighting the use of a leucite-reinforced material. This approach allowed for a minimal preparation design and conservation of tooth structure, providing an optimal bond. PMID- 20712111 TI - [Recent advances in chromatography]. PMID- 20712110 TI - Soft-tissue management. The key to the perfect impression. PMID- 20712112 TI - [Analysis of volatile oils of Ligusticum chuanxiong Hort. from different geographical origins by comprehensive two-dimensional gas chromatography/time-of flight mass spectrometry]. AB - The volatile oils of 23 Ligusticum chuanxiong Hort. samples from 4 different regions were analyzed by comprehensive two-dimensional gas chromatography/time-of flight mass spectrometry (GC x GC/TOF MS). The group-type separation of 4 terpenoids and phthalides was well accomplished based on a DB-Petro x DB-17 column system. With the MS library search, 215 compounds were tentatively identified based on the NIST database and the 43 compounds of them were confirmed by using the retention index or comparing with the standard compounds in a typical sample from Xindu City. Twenty three samples were apparently classified into 4 groups by partial least square-discriminant analysis. A brief list of 20 differential compounds is presented, including cnidilide, 3-n-butylphthalide and butylidene phthalide. DPPH (1,1-diphenyl-2-picrylhydrazyl), stable free radical scavenging assay was adopted to differentiate the antioxidative potency of these samples, which was expressed as EC50. Based on the orthogonal partial least square model the biochemical discrimination of samples was achieved with ligustilide, senkyunolide A and neocnidilide as important differential compounds according to geographical origins. All the results indicated that phthalides exert a great influence on the chemical and biochemical classifications of Rhizoma Chuanxiong, and the samples from Pengzhou City have the highest contents of phthalides. PMID- 20712113 TI - [Determination of nitrogen compounds in catalytic gasolines by gas chromatography nitrogen chemiluminescence detection]. AB - A method for the separation and determination of nitrogen compounds in catalytic gasolines by gas chromatography-nitrogen chemiluminescence detection (GC-NCD) was established. The effects of the flow rate of carrier gas and the oven temperature on the resolution were studied. More than 20 nitrogen compounds, including amines, pyridine, aniline, 2-methyl aniline, 3-methyl aniline, 4-methyl aniline, quinoline, and indole, in catalytic gasoline were identified based on the retention time of some pure nitrogen compounds and by gas chromatography-mass spectrometry. The relative standard deviations of the peak areas of main nitrogen compounds in a catalytic gasoline sample were less than 2.5% and the detection limits for nitrogen were 1.0 mg/L under the chosen conditions. The linear ranges were 1.0-100 mg/L nitrogen for each nitrogen compound. The correlation coefficients were more than 0.998. The method can be successfully applied for the determination of each nitrogen compound in different catalytic gasolines. PMID- 20712114 TI - [Determination of benzoylurea and bishydrazide pesticide residues in vegetables by ultra performance liquid chromatography-tandem mass spectrometry with matrix solid phase dispersion]. AB - A method for the determination of nine pesticides including benzoylureas (diflubenzuron, chlorobenzuron, triflumuron, teflubenzuron, flufenoxuron, chlorfluazuron, hexaflumuron) and bishydrazides (methoxyfenozide, tebufenozide) in vegetables was developed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with matrix solid phase dispersion. The sample was graphitized with neutral alumina as dispersant and carbon black as purifying, and eluted with ethyl acetate. The separation was achieved by UPLC, and then the identification and quantification were performed using MS/MS with multiple reaction monitoring and electrospray ionization in positive or negative mode. The following results were obtained: The calibration curves showed good linearity in the ranges of 1-100 microg/L with R2 > or = 0.99. The recoveries were 78.5% 112.8% at four spiked levels of 1, 5, 10, 100 microg/kg, and the relative standard deviations were 2.3%-10.2%. The limits of determination were 0.5-1.0 microg/kg. The method has the advantages of easy to operate, fast to perform, lower limits of quantification, consuming less sample and organic solvents. It can meet the demands of practical use for the rapid and simultaneous determination of benzoylureas and bishydrazides in vegetables. PMID- 20712115 TI - [Determination of 20 carbamate pesticide residues in food by high performance liquid chromatography-tandem mass spectrometry]. AB - A new method of determination and conformation for 20 carbamate pesticide residues in food by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed. The residual carbamate pesticides in food were extracted with acetonitrile, cleaned up with C18 solid phase extraction column or Carb/NH2 solid phase extraction column, and the targets were detected and confirmed by HPLC-MS/MS using external standard method. The recoveries of the 20 carbamate pesticides in spiked levels (from 0.005 to 0.025 mg/kg) ranged from 51.2% to 125.0% with the relative standard deviations (RSDs) from 1.4% to 19.8%; the concentration range of linearity was 0.005-0.1 mg/kg; the correlation coefficients were 0.991 7-0. 999 6. The method is fast, easy, sensitive and reliable. It also demonstrates that this method can meet the requirements for the simultaneous determination of 20 carbamate pesticide residues in food. PMID- 20712116 TI - [Determination of 27 industrial dyes in juice and wine using ultra performance liquid chromatography with electrospray ionization tandem quadrupole mass spectrometry]. AB - A method for the determination of 27 industrial dyes in juice and wine has been developed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/ MS). Acetonitrile was used as extraction solvent, and sodium chloride was added to salt out the analytes from the samples. Chromatographic separation was performed on a C18 column with the gradient elution and the mass spectrometric acquisition was carried out under the mode of multiple reaction monitoring (MRM). Twenty-four of the 27 dyes were detected under positive ionization mode using the mobile phase of acetonitrile and water containing 0.1% formic acid. The other 3 dyes were analyzed under negative ionization mode with the mobile phase of acetonitrile and water. As a result, the average recoveries of 27 dyes spiked in juice ranged from 57.0% to 117.7% with the relative standard deviations (RSDs) of 2.4%-17.7%, and the average recoveries of 27 dyes spiked in wine ranged from 40.8% to 109.4% with the RSDs of 1.6%-17.9%. The limits of quantification (LOQs) of 27 dyes spiked in juice were in the range of 0.1-50 microg/kg, and 0.2-50 microg/kg for those spiked in wine. This method can be applied to rapid detection of illegally added dyes in soft drinks due to its simplicity and high sensitivity. PMID- 20712117 TI - [Determination of azaspiracid-1 in shellfishes by liquid chromatography with tandem mass spectrometry]. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of azaspiracid-1 (AZA1) in shellfishes was described. After being extracted using methanol and water (80:20, v/v), the extract was cleaned-up by solid phase extraction (SPE) of MAX column, then determined by using a reversed phase high performance liquid chromatography (HPLC) isocratic program coupled with tandem mass spectrometry in selected reaction monitoring mode (SRM). And the extract was eluted with acetonitrile-water (80:20, v/v) on an Atlantis dC18 column (150 mm x 4.6 mm, 5.0 microm) with mobile phase containing 50 mmol/L formic acid and 2 mmol/L ammonium formate. The detection limit was 11.00 pg/g. The calibration curve was linear (R2 = 0.998 1) in the range of 48.85-2 442 ng/L. The average recoveries of the shellfish tissue extract at three spiked levels (36.64, 73.27, 146.54 pg/g) were from 75.8% to 82.5% (n = 6). The relative standard derivations (RSDs) were less than 10%. The 112 shellfish samples from the local markets of Dalian, Qingdao, Guangzhou were detected by the method, and AZA1 was detected in some samples from Dalian and Guangzhou. The results showed that the method is simple, rapid, sensitive and suitable for the detection of AZA1 in shellfishes. PMID- 20712118 TI - [Optimization of conditions for the separation of peptide mixtures using strong cation exchange chromatography]. AB - The separation conditions for strong cation exchange chromatography were investigated and compared using tryptic digest of protein extract from yeast. The conditions included the loading amount of the sample, the type of the salt in mobile phase, the type of the acid used to adjust the pH of the mobile phase and the proportion of organic solvent added in the elution solution. The experimental results indicated that high separation efficiency can be obtained by using ammonium chloride solution as optimal mobile phase, phosphoric acid to adjust the pH of mobile phases and 30% (v/v) organic solvent in mobile phases. The results suggested that a beneficial reference was presented for the selection of separation conditions of strong cation exchange chromatography when applying in two-dimensional chromatography-mass spectrometry strategy in proteomic research. PMID- 20712119 TI - [Two-step chromatographic method for the separation and purification of recombinant porcine beta2-adrenoceptors]. AB - Beta2-Adrenoceptors are the members of cell surface receptors which perform their signal transduction to the interior of the cells by coupling to heterotrimeric G proteins. On the foundation of successful clone and expression of beta2 adrenoceptors, a two-step chromatographic method using Ni-chelated Sepharose High Performance affinity media and Quaternary Sepharose Fast Flow anion exchangers was established to prepare recombinant beta2-adrenoceptors expressed in E. coli BL21 (DE3) as histidine-tagged protein. In the affinity chromatographic column, the buffer A was consisted of 20 mmol/L phosphate buffered saline (PBS) containing 500 mmol/L NaCl (pH 7.4), and the buffer B was consisted of buffer A with the addition of 0.5 mol/L imidazole (pH 7.4); in anion chromatographic column, the buffer A was 20 mmol/L PBS (pH 7.4), and the buffer B was consisted of buffer A with 800 mmol/L NaCl (pH 7.4). The analysis results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and high performance size exclusion chromatography (Shim-pack Diol-300) showed that the purity of obtained beta2-adrenoceptors was about 95%. Furthermore, the bioactivity of beta2 adrenoceptors was studied by receptor ligand combination test, and the results assured the object protein possessed good bioactivity. Finally the conclusion can be reached that the method can effectively separate active recombined beta2 adrenoceptors. PMID- 20712120 TI - [Determination of trigonelline in Trigonella foenum-graecum L. by hydrophilic interaction chromatography]. AB - A method of hydrophilic interaction chromatography (HILIC) was established for the quantitative determination of trigonelline in Trigonella foenum-graecum L. HILIC analysis was performed on a Waters Atlantis HILIC Silica column (150 mm x 2.1 mm, 3 microm). The mobile phase consisted of acetonitrile-ammonium acetate (pH 4.4) (70:30, v/v), and the flow rate was 0. 4 mL/min. The detection wavelength was set at 265 nm. The method has good linearity in the range of 2.50 100 mg/L for trigonelline (r = 0.999 6). The recoveries were on an average of 102% by adding 29.2 mg/L and 43.8 mg/L with relative standard deviations (RSDs) of 4.17% and 2.28% (n = 3), respectively. The results indicate that the method is simple and rapid for the determination of strong polar trigonelline in Trigonella foenum-graecum L. Furthermore, it significantly reduces the equilibration time compared with ion-pair liquid chromatography (IPLC) recorded in the Pharmacopoeia of China. This new method can be used as a valid method for the quality control of Trigonella foenum-graecum L. PMID- 20712121 TI - [Isolation and purification of flavones from Murraya exotica L. by high-speed counter-current chromatography]. AB - High-speed counter-current chromatography (HSCCC) was used to isolate and purify flavones from Murraya exotica L. The optimum separation conditions were as follows: A two-phase solvent system was petroleum ether-ethyl acetate-methanol water (5:5:4.8:5, v/v/ v/v). The lower phase as the mobile phase was operated at a flow rate of 2.0 mL/min, while the apparatus rotated at 800 r/min. Each time 200 mg of the sample was loaded. Under these conditions, 54.31 mg of recrystallized 5,7,3',4',5'-pentamethoxyflavone, 107.68 mg of 5-hydroxy-6,7,3',4' tetramethoxyflavone, 215.54 mg of 5-hydroxy-6,7, 8,3', 4'-pentamethoxyflavone, and 84.36 mg of 5-hydroxy-6,7,8,3',4',5 '-hexamethoxyflavone with their purities over 95% were successfully obtained from 4.0 g of the crude extract of Murraya exotica L. The four compounds were analyzed by high performance liquid chromatography (HPLC), and identified by mass spectrometry (MS), ' H-nuclear magnetic resonance (NMR) and 13C-NMR. The compound 5-hydroxy-6,7,3',4' tetramethoxyflavone was for the first time isolated and purified from Murraya exotica L. PMID- 20712122 TI - [Determination of five hormone drug residues in fish tissue by high performance liquid chromatography with gel permeation chromatographic clean-up]. AB - A method was developed for the determination of five hormone residues in fish tissue by high performance liquid chromatography (HPLC) with gel permeation chromatographic (GPC) clean-up. The sample was extracted with ethyl acetate methanol (8:2, v/v). The extract was cleaned-up on a Pharmadex LH-20 gel permeation column (450 mm x 15 mm) and eluted with methanol-ethyl acetate-acetic acid (800:200:2, v/v/v). The analysis was performed on an Agilent TC-C18 column (250 mm x 4. 6 mm, 5 microm) using acetonitrile-water (45:55, v/v) as the mobile phase at a flow rate of 1.2 mL/min and the detection wavelengths were set at 222 nm and 245 nm. All of the 5 hormone residues had good linear relationships (r > 0.999) in the range of 0.05-2.5 mg/L. The limits of detection (LOD) were from 10 to 24 microg/kg. The average recoveries for all the five hormone residues were from 60.1% to 89.0%, with relative standard deviations (RSDs) from 2.0% to 7.4%. The method is simple, rapid, and can be applied for the analysis of the five hormone residues in fish tissue. PMID- 20712123 TI - [Determination of Monacolin K in red fermented rice by micellar electrokinetic capillary chromatography]. AB - A method for Monacolin K determination in red fermented rice based on micellar electrokinetic capillary chromatography has been developed. The assay conditions including pH and the concentration of running buffer, organic additive, the concentration of sodium dodecyl sulfate (SDS), and the separation voltage were optimized. Under the optimized conditions (20 mmol/L borate buffer (pH 10.6, containing 10% (v/v) methanol, 40 mmol/L SDS), the Monacolin K can be separated within 23 min, with the linear working range of 5.00-100.00 mg/L (r = 0.997 6) and a limit of detection (S/N = 3) of 0.13 mg/L. It had good recoveries (98.5% 99. 5%) and the relative standard deviations lower than 3%. The method is simple, rapid, sensitive, highly reproducible and can be successfully applied in the determination of Monacolin K in red fermented rice. PMID- 20712124 TI - [Two dimensional capillary zone electrophoresis/micellar electrokinetic capillary chromatography for the analysis of drugs and their enantiomers in urine samples]. AB - A new two dimensional method, which interfaced capillary zone electrophoresis (CZE) and micellar electrokinetic capillary chromatography (MEKC) by a polytetrafluoroethylene (PTFE) tube with a hole of 30-40 microm diameter on the top, was developed for the analysis of drugs and their enantiomers. The CZE was used as the first dimensional separation, from which the eluting components were transferred and further analyzed by MEKC. Online dual concentration method, pH junction-sweeping, was used to avoid sample zone diffusion at the interface. The separation efficiencies and detection limits were (2.8-4.3) x 10(4)/m and 0.015 0.052 mg/L, respectively. The proposed method has successfully demonstrated that in the separation of four drugs and their enantiomers in urine samples, the relative standard deviations (RSDs) of peak area and migration time were in the ranges of 1.7%-3.8% and 1.3%-4.6%, respectively. The method was proved to have good reproducibility, high sensitivity and resolution, large peak capacity. It is reliable and suitable to separate and determine multi-drugs and their enantiomers in urine samples simultaneously. PMID- 20712125 TI - [Simultaneous determination of the five alkaloids in Rhizoma Coptidis by nonaqueous capillary electrophoresis]. AB - A method for the simultaneous determination of berberine, palmatine, jatrorrhizine, magnoflorine and coptisine from Rhizoma Coptidis samples based on the nonaqueous capillary electrophoresis (NACE) mode has been developed. The effects of several important factors, such as nonaqueous solvents, running buffer system and its concentration and pH, separation voltage, temperature and detection wavelength, were investigated to acquire the optimum conditions. The optimum conditions for the separation were as follows: the selected running buffer was a methanol solution (pH 5.8) containing 40 mmol/L sodium acetate and 40 mmol/L ammonium acetate; the separation voltage was 25 kV; detection wavelength was set at 254 nm; the sample was injected at 5 kPa x 6 s and the column temperature was maintained at 20 degrees C. The analytes can be obtained good baseline resolutions in a 64.5 cm x 75 microm capillary (56 cm of effective length) within 20 min. The average recoveries of the established method were between 98.37% and 101.03%. The method is simple, accurate and reproducible, and can be used for the quality control analysis of Rhizoma Coptidis. PMID- 20712126 TI - [Determination of isoxanthopterin in human urine by solid phase extraction-high performance anion-exchange chromatography coupled with integrated pulsed amperometric detection]. AB - A sensitive, selective and environmental friendly method for the determination of isoxanthopterin in human urine by solid phase extraction (SPE)-high performance anion exchange chromatography (HPAEC) with integrated pulsed amperometric detector has been developed. The tandem solid phase extraction was employed to purify isoxanthopterin from human urine. The separation of isoxanthopterin was carried out on an IonPac AS21 anion-exchange column with eluent of 0.025 mol/L NaOH at the flow rate of 0.40 mL/min. Under the optimized conditions, the detection limit for isoxanthopterin was 0.003 mg/L, and the linear range was 0.005-0.200 mg/L. The spiked recoveries ranging from 95.4% to 96.8% were obtained in the urine samples from healthy persons and cancer patients, and the relative standard deviation (RSD) was less than 5%. The present method was successfully applied to the determination of isoxanthopterin in urine from healthy individuals and cancer patients. PMID- 20712127 TI - [Recognition mechanism of supramolecular systems of beta-cyclodextrin derivatives and applications in chiral separation]. AB - Beta-cyclodextrin (beta-CD) has the cavity in which the exterior is relatively hydrophilic and the interior is relatively lipophilic and multi-hydroxyl groups on it. So beta-CD can be modified by different substituent groups and form supramolecular systems with guests, and are applied to many fields. Recognition mechanism of beta-CD derivatives supramolecular systems is reviewed herein. Effects of structures of host and guest, solvent, buffer pH and linkage styles of stationary phase and study methods of ultraviolet-visible, fluorescence spectroscopy, circular dichroism spectrum, nuclear magnetic resonance, thermodynamics, X-ray and molecular dynamics simulation on mechanism are expounded. The applications in chiral separation are also introduced. This might lay a foundation for studying the general law of recognition mechanism. PMID- 20712128 TI - [Simultaneous determination of iodide and thiocyanate powdered milk using ion chromatography with mixed-mode column]. AB - The contents of iodide and thiocyanate are important detection items in powdered milk quality testing. Due to the complexity of the powdered milk matrix, chromatographic analysis is easily subjected to interference. Acclaim Mixed-Mode WAX-1 column incorporated both hydrophobic and weak anion-exchange properties was used to separate iodide and thiocyanate from interfering substances in powdered milk matrix, and detected by Ultraviolet (UV) detection. After powdered milk was dissolved in water, the protein was precipitated by acetonitrile. Then OnGuard RP pre-treatment column was used to remove the organic matters which might pollute the column. The eluent was acetonitrile-100 mmol/L phosphate buffer (pH 6)-water (45:5:50,v/v/v). The UV detection wavelength was 226 nm. The limits of detection of iodide and thiocyanate were 4.6 microg/L and 13.8 microg/L respectively, and the relative standard deviations of peak areas were 1.2% (n = 6) and 1.7% (n = 6) for 0.2 mg/L iodide and thiocyanate standard solutions. The method is accurate and reliable, and has wide linear range, low limit of detection. This method provides a viable approach for powdered milk quality dairy products. PMID- 20712129 TI - [Comparison of chiral separations of felodipine by high performance liquid chromatography using two cellulose tris (4-methyl benzoate) stationary phases]. AB - Chiral resolutions of felodipine (FEL) were compared using two cellulose tris (4 methyl benzoate) stationary phases, Chiralcel OJ-R and Chiralcel OJ-H. The effects of the mobile phase and the column temperature on the retention and separation were compared. Using n-hexane/2-propanol (90:10, v/v) as mobile phase, the FEL can be enantioseparated. There are transition temperatures in the van't Hoff plots of the two columns. In the higher temperature region the enantioseparation was enthalpy controlled, and in the lower temperature region it was entropy controlled. The higher temperature was good for the resolution of FEL enantiomers even though the selectivity was change with maximum value at 19 degrees C for OJ-R and 14 degrees C for OJ-H. The two columns showed similar mechanism in the FEL chiral separation. PMID- 20712130 TI - Use of isoxsuprine hydrochloride as a tocolytic agent in the treatment of preterm labour: a systematic review of previous literature. AB - The aim of this systematic review was to evaluate the efficacy of isoxsuprine (1 (4-hydroxyphenyl)-2-(1-methyl-2-phe-noxyethylamino)-1-propanol, CAS 395-28-8), a tocolytic agent used in both preterm labour and risk of abortion. Two analyses were conducted on data reporting the use of isoxsuprine in the prevention of preterm delivery. The first analysis examined two double-blind studies to determine the effect of isoxsuprine compared to placebo. The second analysis reviewed data from 25 publications containing individual and general patient data. Main outcome measures included delay of pregnancy and patient outcome. Analysis of double-blind studies demonstrated a positive outcome with isoxsuprine in 92% of cases compared to placebo control (44.4%, p < 0.001). This beneficial effect was maintained when either risk of abortion (92.5% in isoxsuprine treated compared to 46.4% in placebo, p < 0.001) or risk of premature delivery (89.5% in isoxsuprine treated compared to 29.4% in placebo, p < 0.001) was examined. Secondary analysis of individual patient data also revealed a beneficial effect of isoxsuprine in prolonging pregnancy in 54.5% of women at risk of abortion and in 82.3% of women at risk of premature delivery. Combination of individual and general data revealed a beneficial effect of isoxsuprine in 77.3% of cases at risk of abortion and 89% for risk of premature delivery. These findings provide preliminary evidence in favour of the effectiveness of isoxsuprine in prolonging pregnancy in women at risk of abortion or premature delivery. PMID- 20712131 TI - Effects of charcoal on the absorption and elimination of the antiepileptic drugs lamotrigine and oxcarbazepine. AB - OBJECTIVE: The effects of single and repeated doses of oral activated charcoal (OAC) on the absorption and elimination of the antiepileptic drugs, lamotrigine (CAS 84057-84-1, LTG, Lamictal) and oxcarbazepine (CAS 28721-07-5, OXC, Trileptal) were studied in healthy volunteers to assess the therapeutic potential of OAC in the treatment of LTG and OXC overdose. METHODS: In three open, randomized, cross-over sessions with > or = 14 days washout, LTG 100 mg and OXC 600 mg were given orally, each to 6 subjects. In one session the drugs were given alone, and in two others with single (50 g) or repeated (20 g) doses of OAC as water suspension. The single OAC dose was given 30 min after the drugs, and repeated doses 6-72 h after LTG and 12-48 h after OXC. Serum concentrations of the parent drugs as well as those of the pharmacolocigally active metabolite of OXC, 10,11-dihydro-10-hydroxy-carbamazepine (MHD), were measured with reverse phase high-performance liquid chromatography. Pharmacokinetic variables were calculated by non-compartmental analysis. RESULTS: Single OAC dose decreased AUC0 infinity of LTG, OXC and MHD to 58%, 2.8% and 4.2% of the respective variables without OAC. Also Tmax of OXC and MHD decreased to 4.4% and 8.1%, respectively. Repeated OAC doses after LTG decreased its AUC from 6 h to infinity (AUC6 infinity) to 39% and t1/21beta to 44%. Repeated OAC doses after a single dose of OXC decreased the AUC12-infinity and t/12beta of MHD to 46% and 45% of the respective variables without OAC. CONCLUSION: OAC greatly reduces gastrointestinal absorption of LTG and especially that of OXC, and it accelerates the elimination of LTG and MHD. The use of OAC is hence strongly favoured in the treatment of overdose with these drugs. PMID- 20712132 TI - Glycerol lidocaine eardrops for the treatment of acute abacterial otitis externa. AB - Inflammations of the external auditory canal number among the most frequently occurring ear-nose-throat diseases. For local treatment, substances from various groups of active ingredients are used as combinations and as single-agent drugs, e.g. antibiotics, glucocorticoids or analgesics [1]. In the case of acute otitis externa, treatment measures focus on the reduction of pain and swelling. The study described here investigates the efficacy and safety of glycerol lidocaine eardrops for the treatment of acute abacterial otitis externa (CAS No. for glycerol: 56-81-5, lidocaine-HCl: 73-78-9). In this double-blind, three-arm study, 105 patients diagnosed with acute abacterial otitis externa were included and randomized to receive either glycerol eardrops, glycerol eardrops with 0.5% lidocaine, or glycerol eardrops with 2% lidocaine for seven days. The primary outcome parameter was the change of the five typical clinical symptoms, earache, itching, otorrhea, hearing impairment, and "clogged ear" at Visit 2 (Day 7) based on the initial examination on Day 0. Both therapy groups treated with a combination of glycerol and lidocaine exhibited definite improvement in overall symptoms after seven days. This improvement differed from the mild reduction of symptoms under treatment with glycerol eardrops alone. Overall improvement of symptoms, expressed by the area under the curve of the baseline-adjusted symptom sum score, yielded a mean value of 10.95 (standard deviation 27.4) for the morning survey of the groups receiving eardrops containing only glycerol; in comparison, for eardrops containing glycerol and 2% lidocaine it was 15.71 (+/- 23.6) and for glycerol with 0.5% lidocaine, 23.16 (+/- 19.4). No severe adverse events occurred. Five adverse events were documented during the clinical investigation, none of which was considered by the investigators to be related to the study medication. Local therapy with glycerol lidocaine eardrops is a safe, and cost-effective treatment for the widely spread clinical picture of acute abacterial otitis externa. The advantage regarding efficacy of this combination compared with glycerol eardrops must be demonstrated in an adequately powered clinical trial. PMID- 20712133 TI - Comparison of liquid chromatography-ultraviolet and chromatography-tandem mass spectrometry for the determination of indapamide in human whole blood and their applications in bioequivalence studies. AB - The aim of this study was to compare two methods which were based on liquid chromatography with ultraviolet detection (LC-UV) and liquid chromatography tandem mass spectrometry (LC-MS/MS), respectively, to determine indapamide (CAS 26807-65-8) and to apply them to bioequivalence studies. The universal parameters, including selectivity, linearity, precision, and quantification limit, served as gold standard for the comparison of the two methods. As a result, the two methods were both very consistent and reliable. Furthermore, the LC-MS/MS method required only one-fifth the blood volume needed by the other method and was approximately 25 times more sensitive than the other method. The total run time of the LC-MS/MS method was 3.5 min per sample as opposed to 11 min for the other method. Forty healthy male Chinese volunteers were selected as subjects. One half were orally administrered 2.5 mg indapamide immediate release tablets while the other half were orally administered 1.5 mg indapamide sus tained release coated tablets. The collected blood samples were determined with the two methods described above. The pharmacokinetic parameters were determined using a noncompartmental method. For the bioequivalence studies, the pharmacokinetic parameters acquired here were in line with the literature and parameters met the criteria set by the State Food and Drug Administration of China (SFDA) for bioequivalence study, indicating that generic drugs are bioequivalent to branded drugs. The present study suggests that the two methods based on LC-UV and LC-MS/MS were suitable for bioavailability studies of indapamide with different pharmaceutical formulations. Consequently, it can be believed that the criterion that each individual expected concentration range would need a given bioassay with the requested sensitivity is not absolutely right. In practice, most of the time, the highest sensitivity allows to bioassay concentrations in a higher range. PMID- 20712134 TI - Comparative bioavailability of betahistine tablet formulations administered in healthy subjects. AB - OBJECTIVE: To assess the comparative bioavailability of two formulations (16 mg tablet) of betahistine (CAS 5579-84-0) in healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval. Plasma samples were obtained for up to 36 h post dose. Plasma 2-pyridylacetic acid concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the 2 pyridylacetic acid plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained for AUCIast and Cmax. RESULTS: The limit of quantification was 4 ng/mL for plasma 2-pyridylacetic acid analysis. The geometric mean and 90% confidence interval (CI) of test/reference percent ratios were: 98.94% (92.21%-106.16%) for Cmax, 95.42% (91.74%-99.25%) for AUClast. CONCLUSION: Since the 90% CI for Cmax and AUCs ratios were all within the 80-125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the test formulation is bioequivalent to the reference for both the rate and the extent of absorption. PMID- 20712135 TI - Effect of atorvastatin on aldosterone production induced by glucose, LDL or angiotensin II in human renal mesangial cells. AB - Nephropathy is a major complication of diabetes mellitus, thus development of rational therapeutic means is critical for improving public health. It was previously reported that human mesangial cells locally produced aldosterone, a steroid hormone that plays an important role in the development of diabetic nephropathy. The present experiments clarified the effect of glucose, LDL and angiotensin II, the molecules frequently elevated in patients with diabetic nephropathy, on aldosterone production in human primary mesangial cells. These cells expressed the CYP11B2 mRNA, a rate-limiting enzyme in the aldosterone biosynthesis. LDL and angiotensin II stimulated CYP11B2 mRNA expression in these cells, while a high concentration of glucose, angiotensin II and/or LDL increased aldosterone production. Importantly, atorvastatin (CAS 134523-03-8), an HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor, strongly suppressed their effects on aldosterone production. Atorvastatin also suppressed positive effects of these compounds on the mRNA expression of the angiotensin II receptor type 1, thus atorvastatin exerted its negative effect in part through changing expression of this receptor. Since elevated levels of glucose and LDL, and increased action of the renin-angiotensin-aldosterone system is known to participate in the progression of diabetic nephropathy, it is speculated that the mesangial endocrine system that produces aldosterone locally is a promising therapeutic target for diabetic nephropathy where HMG-CoA reductase inhibitors provide a beneficial effect. PMID- 20712136 TI - Synthesis and antimicrobial, acetylcholinesterase and butyrylcholinesterase inhibitory activities of novel ester and hydrazide derivatives of 3(2H) pyridazinone. AB - In the current study, some novel ethyl 6- [(substituted-phenylpiperazine]-3(2H) pyridazinone-2-yl propionate III and 6-[(substituted-phenylpiperazine]-3(2H) pyridazinone-2-yl propionohydrazide IV derivatives were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H NMR spectra and elementary analysis. 6-Substituted-3(2H)-pyridazinone-2-yl propionate IIIa-e derivatives showed significant inhibitory activity against AChE and BChE. 6-[4-(3-Trifluoromethylphenyl)piperazine]-3(2H)-pyridazinone-2-yl propionate IIIe has been found to be the most active compound in terms of inhibition of either AChE or BChE. Compound IIIe exhibited inhibitory activity close to that of galantamine (CAS 357-70-0) and did not show any selectivity between the two enzymes. Also the antimicrobial activities of III and IV derivatives have been evaluated. All III and IV derivatives exhibited poor antibacterial activities but moderate antifungal activities. PMID- 20712137 TI - In vitro study on the effects of iron sucrose, ferric gluconate and iron dextran on redox-active iron and oxidative stress. AB - Concerns exist that administration of intravenous (i.v.) iron preparations is associated with oxidative stress. Therefore iron sucrose (CAS 8047-67-4), ferric gluconate (CAS 34098-81-1) and iron dextran (CAS 9004-66-4) were assessed for redox-active iron by a dichlorofluorescein assay and for intracellular reactive oxygen species (ROS) generation and cytotoxicity in HepG2 cells. Examining each i.v. iron preparation at its maximum concentration achieved following clinically frequently used doses in a 70 kg individual in in vitro experiments, redox-active iron was highest with ferric gluconate, followed by iron dextran and iron sucrose. Interestingly, when the i.v. iron preparations were diluted in human serum instead of buffer, redox-active iron was highest with iron dextran, followed by iron sucrose, and practically disappeared with ferric gluconate. ROS production in HepG2 cells was increased by all i.v. iron preparations. However, in the neutral red cytotoxicity assay all i.v. iron preparations were non-toxic. In conclusion, ferric gluconate showed the highest increase in intracellular ROS production in HepG2 cells and the highest amount of redox-active iron in buffer in the in vitro assays. In contrast to the other i.v. iron preparations, redox active iron from ferric gluconate was rendered completely redox-inactive by serum, indicating that redox-active iron in the various preparations has different chemical properties. PMID- 20712138 TI - Beyond depression: yearning for the loss of a loved one. AB - Studies assessing the impact of relationship quality and social support on marital bereavement have typically focussed on depressive symptoms as the major (and often only) bereavement outcome. Although sadness and depression are important symptoms of grieving, they are neither the only nor necessarily the most important ones. We argue that in addition to measures of depression, grief measures need to be used in assessing bereavement outcome. However, grief measures do not only assess reactions that are specific to bereavement such as yearning, but also general responses that grief shares with other critical life events (e.g., anxiety, shock, anger, intrusive thoughts, and despair). We would expect marital quality to only affect yearning for the loved one who died, but not other more general grief reactions. In contrast, experiencing support from family and friends, though unlikely to reduce yearning, might ameliorate these general grief symptoms as well as depression. Using data on widows from the Changing Lives of Older Couples (CLOC) study, a large-scale prospective study of older couples, we assessed the relationship between marital quality and social support with depression and grief on the death of a spouse. Consistent with hypotheses, social support but not relationship quality was associated with depression and general grief reactions. In contrast, relationship quality but not social support was associated with yearning. The theoretical and practical implications of these findings are discussed. PMID- 20712139 TI - An examination of stage theory of grief among individuals bereaved by natural and violent causes: a meaning-oriented contribution. AB - Despite its popularity, few attempts have been made to empirically test the stage theory of grief. The most prominent of these attempts was conducted by Maciejewski, Zhang, Block, and Prigerson (2007), who found that different states of grieving may peak in a sequence that is consistent with stage theory. The present study aimed to provide a conceptual replication and extension of these findings by examining the association between time since loss and five grief Indicators (focusing on disbelief, anger, yearning, depression, and acceptance), among an ethnically diverse sample of young adults who had been bereaved by natural (n=441) and violent (n=173) causes. We also examined the potential salience of meaning-making and assessed the extent to which participants had made sense of their losses. In general, limited support was found for stage theory, alongside some evidence of an "anniversary reaction" marked by heightened distress and reduced acceptance for participants approaching the second anniversary of the death. Overall, sense-making emerged as a much stronger predictor of grief Indicators than time since loss, highlighting the relevance of a meaning-oriented perspective. PMID- 20712140 TI - African-American teen girls grieve the loss of friends to homicide: meaning making and resilience. AB - Few studies have examined the bereavement experiences of African-American teen girls who have mourned the loss of friends due to homicide. This qualitative study examined such bereavement experiences with a sample of 20 African-American teen girls, ages 16-19, living in a large northeastern U.S. city. Meaning making, adolescent developmental theory, ideas regarding traumatic loss, and resilience provided a framework to understand how these teens coped with the tragic loss of a friend. The teen girls in this study demonstrated resilience in their ability to adequately "move on" with their lives. They remained achievement oriented and sustained meaningful relationships with family, valued friends, and others. Early, metaphysical, and motivational meaning constructions contributed to the teens' resilience. PMID- 20712141 TI - Mediating effects of social and personal religiosity on the psychological well being of widowed elderly people. AB - Spousal death is one the most stressful life events that seriously affects the psychological well being of widowed. This study examined the mediating effects of social and personal religiosity on the psychological well being of widowed elderly people. The sample for this study was comprised of 1367 widowed and married elderly Muslims from Malaysia. Psychological well being, religiosity, and physical health were measured using WHO-5 Well being Index, Intrinsic Extrinsic religiosity scale, and a checklist of 16 physical health problems, respectively. Data analysis was conducted using the Statistical Package for Social Sciences (version-13). As expected, bivariate correlation analysis revealed that widowhood is statistically and negatively associated with psychological well being. Results of multiple hierarchical regression analyses and Sobel test showed that only the indirect effect of widowhood through personal religiosity was statistically significant (Sobel = -2.79, p < .01). Sobel test for social religiosity was not significant (Sobel = -1.54, p > .05). The results of this study confirmed earlier studies, which found that widowhood negatively affects psychological well being of elderly people. Overall, the findings show that the potential solace provided by religiosity can decrease the negative effects of widowhood on the psychological well being of widowed elderly people. PMID- 20712142 TI - Bereavement interventions for adults with intellectual disabilities: what works? AB - Examination of the theory base for bereavement and loss is currently just beginning for adults with intellectual disabilities (ID). Yet, as life spans increase for individuals with ID, these adults experience more and more loss and bereavement events. Practitioners, especially grief counselors, are finding it increasingly critical for them to understand best practice principles for working with bereaved adults with ID in their daily work. Practitioners also are asked to guide families and care providers regarding grief and death education. This article provides counselors and other professionals with a review of existing bereavement intervention research for adults with ID. Practice recommendations are made on three levels: informal support; formal intervention; and community education. PMID- 20712144 TI - Toward a deeper understanding of the harms caused by partner stalking. AB - This study examined stalking prevalence, patterns, and harm among 210 women with civil protective orders (PO) against violent male partners or ex-partners. Results suggest that stalking is associated with PO violations and almost every other type of partner violence. Also, women who have been stalked by violent partners report significantly more distress and harm than even women who experience PO violations but not stalking. Results of key informant perceptions suggest many victim service (n=116) and criminal justice professionals (n=72) do not seem to understand the extent or gravity of the harms caused by partner stalking especially when contrasted with victim reports of harm. Furthermore, key informant reports of their advice to women being stalked by an ex-partner were not consistent with recommendations for stalking victims in general. PMID- 20712143 TI - Effects of early exposure and lifetime exposure to intimate partner violence (IPV) on child adjustment. AB - Children exposed to overwhelming and potentially traumatic events early in their lives are considered at-risk for problems in adjustment. Yet it is not known whether it is the age of first exposure (AFE) to violence or the amount of violence that the child witnessed in their lifetime that has the greatest impact on adjustment. For a sample of 190 children ages 6 to 12 exposed to intimate partner violence, their mothers reported that the average length of their abusive relationship was 10 years. The majority of children were first exposed to family violence as infants (64%), with only 12% first exposed when school-aged. Both the AFE and an estimate of the cumulative amount of violence were significantly and negatively related to children's behavioral problems. However, in regression analyses controlling for child sex, ethnicity, age, and family environment variables, cumulative violence exposure accounted for greater variance in adjustment than did AFE. Furthermore, cumulative violence exposure mediated the relationship between AFE and externalizing behavior problems, indicating that the cumulative exposure to IPV outweighed the AFE in its effect on child adjustment. PMID- 20712145 TI - Examining the link between posttraumatic stress disorder symptoms and dating aggression perpetration. AB - This study examined the role of posttraumatic stress disorder (PTSD) symptoms with respect to dating aggression perpetration among a sample of 199 undergraduates. Almost one-third of the overall sample reported physical dating aggression perpetration in the past year, and approximately 80% reported engaging in psychological dating aggression. Structural equation modeling (SEM) analyses indicated that the effects of trauma exposure on dating aggression were fully indirect via PTSD symptoms. PTSD symptoms were associated with psychological dating aggression in part through its association with anger, and alcohol problems were also directly related to this outcome. Results generalize findings from other populations suggesting the salience of trauma and PTSD symptoms in intimate relationship aggression and point to possible etiological pathways for these associations. PMID- 20712146 TI - Child neglect, social context, and educational outcomes: examining the moderating effects of school and neighborhood context. AB - Research on child neglect has found that neglected children are more likely to experience worse developmental outcomes than non-neglected children. These negative outcomes include antisocial behavior as well as poor school performance. Eco-developmental theory has found that adverse social contexts often worsen these outcomes for neglected and maltreated youths. However, little research has been done on the educational outcomes of neglected children and none of it has employed a national, longitudinal, community sample with an examination of social context. We do so in our research and find that several types of child neglect significantly predict a variety of poor educational outcomes at the bivariate level and that physical and educational neglect were significantly associated with a composite measure of school problems in multivariate analysis. We offer several explanations for our findings and future directions for research. PMID- 20712147 TI - The effectiveness of parent-child interaction therapy for victims of interparental violence. AB - This study compares the effectiveness of Parent-Child Interaction Therapy (PCIT) in reducing behavior problems (e.g., aggression, defiance, anxiety) of 62 clinic referred, 2- to 7-year-old, maltreated children exposed to interparental violence (IPV) with a group of similar children with no exposure to IPV (N=67). Preliminary analyses showed that IPV-exposed dyads were no more likely to terminate treatment prematurely than non IPV-exposed dyads. Results of repeated measures MANCOVAs showed significant decreases in child behavior problems and caregivers' psychological distress from pre- to posttreatment for IPV-exposed and IPV nonexposed groups, and no significant variation by exposure to IPV. Stress in the parent role related to children's difficult behaviors and the parent-child relationship decreased from pre- to posttreatment, but parental distress did not decrease significantly over the course of PCIT. Results of an analysis testing the benefits of a full course of treatment over the first phase of treatment showed that dyads completing the full course of treatment reported significantly greater improvements in children's behavior problems than those receiving only the first phase of treatment. PMID- 20712148 TI - Sexual revictimization and interpersonal effectiveness. AB - This study utilized a cross-sectional design in order to explore the relationship between interpersonal effectiveness, defined as level of assertiveness, social perception, and perceived self-efficacy, and repeated sexual victimization in adolescence and adulthood. In addition, we compared global versus situation specific measures of interpersonal effectiveness. Results indicated that global measures of interpersonal effectiveness failed to differentiate victim groups, and there were also no group differences in social perception. However, on situation-specific measures, revictimized women were significantly lower than nonvictims on sexual assertiveness and sexual self-efficacy. These results support the hypothesis that interpersonal functioning is related to sexual revictimization and highlight the need to measure interpersonal functioning specifically in sexual situations as it relates to women's sexual assault history. PMID- 20712149 TI - Classes of childhood sexual abuse and women's adult couple relationships. AB - The current study assessed if childhood sexual abuse (CSA) can be meaningfully classified into classes, based on the assumption that abuse by a close family member differs in important ways from other abuse, and whether abuse classes were differentially associated with couple relationship problems. The childhood experiences and adult relationships of 1335 Australian women (18-41 years) were assessed. Latent class analysis identified three classes of CSA: that perpetrated by a family member, friend, or stranger, which differed markedly on most aspects of the abuse. Family abuse was associated with the highest risk for adult relationship problems, with other classes of CSA having a significant but weaker association with adult relationship problems. CSA is heterogeneous with respect the long-term consequences for adult relationship functioning. PMID- 20712150 TI - External barriers to help-seeking encountered by Canadian gay and lesbian victims of intimate partner abuse: an application of the barriers model. AB - While understanding of intimate partner abuse (IPA) in gay and lesbian relationships has increased within the past decade, there remain several gaps in the help-seeking research. In particular, research examining the external barriers to help-seeking encountered by gay and lesbian victims of IPA has been largely atheoretical. To address this gap, an application of The Barriers Model was undertaken. This mixed-methods study surveyed 280 gay, lesbian, and/or queer participants living in Canada. Findings revealed that victims encountered external barriers in the environment (i.e., Layer 1 of the model), such as lack of availability of gay and lesbian specific services. Results also suggested that barriers due to family/socialization/role expectations (i.e., Layer 2 of the model), such as concealment of sexual orientation, had an impact on help-seeking. PMID- 20712151 TI - Preventing interpersonal violence in emergency departments: practical applications of criminology theory. AB - Over the past two decades, rates of violence in the workplace have grown significantly. Such growth has been more prevalent in some fields than others, however. Research shows that rates of violence against healthcare workers are continuously among the highest of any career field. Within the healthcare field, the overwhelming majority of victims of workplace violence are hospital employees, with those working in emergency departments (EDs) experiencing the lion's share of violent victimization. Though this fact is well-known by medical researchers and practitioners, it has received relatively little attention from criminal justice researchers or practitioners. Unfortunately, this oversight has severely limited the use of effective crime prevention techniques in hospital EDs. The goal of this analysis is to utilize techniques of situational crime prevention to develop an effective and easily applicable crime prevention strategy for hospital EDs. PMID- 20712152 TI - IQ variations across time, race, and nationality: an artifact of differences in literacy skills. AB - A body of data on IQ collected over 50 years has revealed that average population IQ varies across time, race, and nationality. An explanation for these differences may be that intelligence test performance requires literacy skills not present in all people to the same extent. In eight analyses, population mean full scale IQ and literacy scores yielded correlations ranging from .79 to .99. In cohort studies, significantly larger improvements in IQ occurred in the lower half of the IQ distribution, affecting the distribution variance and skewness in the predicted manner. In addition, three Verbal subscales on the WAIS show the largest Flynn effect sizes and all four Verbal subscales are among those showing the highest racial IQ differences. This pattern of findings supports the hypothesis that both secular and racial differences in intelligence test scores have an environmental explanation: secular and racial differences in IQ are an artifact of variation in literacy skills. These findings suggest that racial IQ distributions will converge if opportunities are equalized for different population groups to achieve the same high level of literacy skills. Social justice requires more effective implementation of policies and programs designed to eliminate inequities in IQ and literacy. PMID- 20712154 TI - Buyer-seller negotiations: a comparison of domestic and international conditions in a pilot study with international business students. AB - This study examined the differences and similarities between domestic and international negotiations, using Kelley's Negotiation Game to measure the profit achieved. There were 58 participants in the international negotiation sample, 29 Turkish and 29 European students. There were 62 Turkish students in the domestic negotiations. All participants studied business or related topics at a university in Izmir. Student t tests indicated statistically significant differences in scores on misrepresentation of information, interpersonal attraction, peer evaluation of misrepresentation information, and satisfaction between domestic and international negotiations. PMID- 20712153 TI - Google earth as a source of ancillary material in a history of psychology class. AB - This article discusses the use of Google Earth to visit significant geographical locations associated with events in the history of psychology. The process of opening files, viewing content, adding placemarks, and saving customized virtual tours on Google Earth are explained. Suggestions for incorporating Google Earth into a history of psychology course are also described. PMID- 20712155 TI - Personality disorders and premature dropout from psychological treatment for smoking cessation. AB - The relation between personality disorders and premature dropout (attending half of the sessions or fewer) from a psychological treatment for giving up smoking was examined in a sample of 202 smokers. Percent of premature dropout was significantly higher for smokers with personality disorder in general, specifically for smokers with dependent personality disorder and with Cluster C personality disorder, than in smokers without such psychopathology. PMID- 20712156 TI - Equity on national school achievement tests: a multicultural perspective in Kenya. AB - The study examined the differences in performance on the national Kiswahili achievement tests administered in 2005, 2006, and 2007 among three cohorts of primary school children from two different linguistic backgrounds in Kenya. The analysis showed the test favored children from Kiswahili-speaking communities; those whose mother tongue had no linguistic relation with Kiswahili scored lower. Results are discussed in terms of language effects on performance and cognition. PMID- 20712157 TI - Sex differences in self-reported risk-taking propensity on the Evaluation of Risks scale. AB - The Evaluation of Risks scale was recently developed as a self-report inventory for assessing risk-taking propensity, but further validation is necessary because most studies have predominantly included male subjects. Because males commonly exhibit greater risk-taking propensity than females, evidence of such a sex difference on the scale would further support its construct validity. 29 men and 25 women equated for age (range: 18 to 36 years) completed the scale. Internal consistency of the scale was generally modest, particularly among women. Men scored significantly higher than women on four of nine indices of risk-taking propensity, including Danger Seeking, Energy, Invincibility, and Total Risk Propensity. Factors measuring thrill seeking and danger seeking correlated positively with a concurrent measure of sensation seeking. Although the higher scores exhibited by men are consistent with prior research on other measures of risk-taking, further research on this scale with samples including women is warranted. PMID- 20712158 TI - The behavior and social communication of honey bees (Apis mellifera carnica Poll.) under the influence of alcohol. AB - In this study, the effects of ethanol on honey bee social communication and behavior within the hive were studied to further investigate the usefulness of honey bees as an ethanol-abuse model. Control (1.5 M sucrose) and experimental (1.5 M sucrose, 2.5% w/v ethanol) solutions were directly administered to individual forager bees via proboscis contact with glass capillary tubes. The duration, frequency, and proportion of time spent performing social and nonsocial behaviors were the dependent variables of interest. No differences in the relative frequency or proportion of time spent performing the target behaviors were observed. However, ethanol consumption significantly decreased bouts of walking, resting, and the duration of trophallactic (i.e., food-exchange) encounters. The results of this study suggest that a low dose of ethanol is sufficient to disrupt both social and nonsocial behaviors in honey bees. In view of these results, future behavioral-genetic investigations of honey bee social behavior are encouraged. PMID- 20712159 TI - Predictors of national suicide rates: a reply to Voracek (2004, 2006, 2009). AB - Voracek (2004, 2006a, 2006b, 2009) reported that cognitive ability predicts national suicide rates, even after plausible controls. Yet, national IQs were not a significant predictor of suicide rates when regressed with indices of national religiousness and perceptions of personal health. PMID- 20712160 TI - Factor analysis of a scale to assess state self-monitoring in adolescents during interview: a pilot study. AB - Self-monitoring is the extent to which individuals regulate self-presentation for the sake of desired public appearances. Snyder developed a Self-Monitoring Scale to measure individual differences on this construct. Since the measure could be insensitive to situational influences, it is uncertain whether the short-term self-monitoring elicited by certain social interactions could be examined. The present study explored the factor structures of a state self-monitoring scale which was adapted from 10 items of the Self-Monitoring Scale. Participants took part in an individual interview with an unfamiliar authority, and then completed the State Self-Monitoring Scale. Two samples of adolescents (N=98 and N=95) were tested. Exploratory factor analysis and confirmatory factor analysis using the two samples indicated that the 9-item State Self-Monitoring Scale had two stable factors. There was a statistically significant difference on State Self monitoring between adolescents with high and low academic achievement, supporting the validity of the scale. PMID- 20712161 TI - Notes on the determinants of suicide rates in Italy's regions: a reply to Voracek (2009). AB - This article is a review of Voracek's report (2009) of aggregate intelligence and suicide rates in Italy's regions, contending some findings and proposing new evidence and suggestions for further research. Voracek did not use intelligence data, but educational attainment, which in Italy's regions is affected by sharp imbalances in the quality of public schools and may not reflect differences in intelligence. The statistical analyses were inadequate given the small number of cases; the resulting correlation could be meaningless or even misleading. The paper shows that when the analysis is extended to other variables (latitude) or historical periods (1911) the correlations reported by Voracek are not significant. This criticism is based on perspectives among different branches of psychology and cognitive sciences, economic and social history, and economic geography. PMID- 20712162 TI - Influence of brand personality-marker attributes on purchasing intention: the role of emotionality. AB - Marketing researchers employ the Five-Factor Model to describe branded products using attributes of human personality. "Marker attributes" used to elicit these brand personality attributes may be related to consumers' intention to purchase. Two connected studies, carried out on two samples of 91 and 557 participants, respectively, indicated that brand personality-marker attributes predict intention to purchase, but only to the extent that such attributes are "vivid" and, in particular, when they elicit emotional responses (i.e., when they are emotionally interesting). These findings have several implications for people involved in developing strategies for advertising. PMID- 20712163 TI - Further validating the two-factor structure of the personal need for structure scale: comment on Shi, Wang, and Chen (2009). AB - Shi, Wang, and Chen's 2009 study validated the Personal Need for Structure Scale in Chinese. The two-factor structure can be further validated by examining the different functions of its components, i.e., "Desire for Structure" and "Response to Lack of Structure". This validation will help researchers and practitioners explore the different attributes, functions, and foundations of the two factors, and also help cultivate the use of the scale in the most appropriate situations. PMID- 20712164 TI - From proactive personality to organizational citizenship behavior: mediating role of harmony. AB - The objective of the present study was to examine the moderating role of interpersonal harmony in the relation of proactive personality with organizational citizenship behavior. 158 employees in Chinese state-owned companies completed the Proactive Personality Scale (Bateman & Crant, 1993), Harmony scale, and Organizational Citizenship Behavior Questionnaire. Proactive personality had insignificant correlation with job dedication. The correlation between interpersonal facilitation and proactive personality was significant but quite low. Results of the hierarchical regression analyses indicated that when demographic variables were controlled, Harmony had significant moderating effects on the relations of proactive behavior and job dedication/interpersonal facilitation. In the high Harmony group, the correlation between proactive personality and organizational citizenship behavior was significant; whereas in the low Harmony group, this correlation was not significant. PMID- 20712165 TI - Comment on Merydith and Phelps (2009): "Convergent validity of the MMPI-A and MACI Scales of Depression. AB - In 2009, Merydith and Phelps reported convergent validity of scales in the Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-A) and the Millon Adolescent Clinical Inventory (MACI) that assess depression with a sample of adolescent psychiatric inpatients. This comment addresses analysis of these data, cites selected research on sex and the two inventories, and restates the recommendation that researchers routinely examine such data separately by sex before proceeding with combined-sex analyses. PMID- 20712166 TI - Changes in the images of teaching, teachers, and children expressed by student teachers before and after student teaching. AB - The purpose of this study was to investigate how education majors' images of teaching, teachers, and children change before and after student teaching, with special attention to the grade level (Grades 1-2, 3-4, 5-6) taught by the student teachers at primary school in Japan. A total of 126 student teachers from an education faculty (49 men, 77 women) participated in this study using metaphor questionnaires before and after student teaching. For images of teaching, responses to the factors Dull Event and Live Event changed, suggesting that students started to develop more positive, active, and clear images of teaching. For images of teachers, responses on the factor Performer changed, suggesting that students started to develop more active images of teachers. For images of children, responses on the factors Critic and Pure-minded Person changed, suggesting that student teachers started to develop more realistic images of children. However, grade level taught had no significant effect. PMID- 20712167 TI - Nearly lethal resuscitated suicide attempters have no low serum levels of cholesterol and triglycerides. AB - To verify the hypothesis that suicide attempts are associated with lower serum cholesterol and triglyceride levels of patients with mood disorders, 26 patients with mood disorders (bipolar disorder and major depressive disorder) were admitted after a medically serious suicide attempt to the emergency department and then hospitalized in the psychiatric unit of the Sant' Andrea Hospital (Rome, Italy). Controls were 87 patients who had not made a recent suicide attempt. Attempters and nonattempters did not differ in the levels of serum cholesterol or triglycerides. Indeed, attempters had nonsignificantly higher serum levels of cholesterol and lower serum levels of triglycerides. The use of biologic indicators such as levels of serum cholesterol and triglycerides in the prediction of suicide risk in mood disorders was not fully supported from this small sample. PMID- 20712168 TI - The final hours: a linguistic analysis of the final words of a suicide. AB - A journal, two suicide notes, and two tape recordings from a young man who took his own life were analyzed by applying a computer program to analyze texts. The analysis indicates a calming trend from the journal entries to the suicide notes to the tape recordings, with an additional increase in positive emotions expressed from the first recorded message to the second recording made just an hour or two before his death. The usefulness of this approach for understanding the psychodynamics of suicidal behavior is discussed. PMID- 20712169 TI - Undergraduates' intentions to take a second language proficiency test: a comparison of predictions from the theory of planned behavior and social cognitive theory. AB - English competency has become essential for obtaining a better job or succeeding in higher education in Taiwan. Thus, passing the General English Proficiency Test is important for college students in Taiwan. The current study applied Ajzen's theory of planned behavior and the notions of outcome expectancy and self efficacy from Bandura's social cognitive theory to investigate college students' intentions to take the General English Proficiency Test. The formal sample consisted of 425 undergraduates (217 women, 208 men; M age = 19.5 yr., SD = 1.3). The theory of planned behavior showed greater predictive ability (R2 = 33%) of intention than the social cognitive theory (R2 = 7%) in regression analysis and made a unique contribution to prediction of actual test-taking behavior one year later in logistic regression. Within-model analyses indicated that subjective norm in theory of planned behavior and outcome expectancy in social cognitive theory are crucial factors in predicting intention. Implications for enhancing undergraduates' intentions to take the English proficiency test are discussed. PMID- 20712170 TI - Poems by a suicide: Sara Teasdale. AB - An analysis of trends over time in the poems of Sara Teasdale as the time of her suicide approached identified a decrease in positive emotions and fewer references to the self and to others. These trends are different from those previously identified from studies of letters and diaries written by suicides. PMID- 20712171 TI - Emotion and the humors: scoring and classifying major characters from Shakespeare's comedies on the basis of their language. AB - The theory of humors, which was the prevalent theory of affect in Shakespeare's day, was used to explain both states (moods, emotions) and traits (personalities). This article reports humoral scores appropriate to the major characters of Shakespeare's comedies. The Dictionary of Affect in Language was used to score all words (N = 180,243) spoken by 105 major characters in 13 comedies in terms of their emotional undertones. These were translated into humoral scores. Translation was possible because emotional undertones, humor, and personality (e.g., Eysenck's model) are defined by various axes in the same two dimensional space. Humoral scores differed for different types of characters, e.g., Shakespeare's lovers used more Sanguine language and his clowns more Melancholy language than other characters. A study of Kate and Petruchio from The Taming of the Shrew demonstrated state-like changes in humor for characters as the play unfolded. PMID- 20712172 TI - Are empathic abilities impaired in posttraumatic stress disorder? AB - Trauma survivors with PTSD show social interaction and relationship impairments. It is hypothesized that traumatic experiences lead to known PTSD symptoms, empathic ability impairment, and difficulties in sharing affective, emotional, or cognitive states. A PTSD group (N=16) and a nontraumatized Control group (N=16) were compared on empathic abilities, namely the Empathic Resonance Test, Reading the Mind in the Eyes Test, and Faux Pas Test. The Interpersonal Reactivity Index as a self-report measure of empathy and measures of non-social cognitive functions, namely the Verbal Fluency Test, the Five-Point Test, and the Stroop Test, were also administered. The PTSD group showed lower empathic resonance. No clear indications of other impairments in social cognitive functions were found. The PTSD group had significantly higher personal distress. Empathic resonance impairments did not correlate with subjective severity of PTSD symptomatology. This article discusses whether impaired empathic resonance in PTSD trauma survivors is a consequence of trauma itself or a protective coping strategy. PMID- 20712173 TI - Perceptions of a tattooed college instructor. AB - 128 undergraduates' perceptions of tattoos on a model described as a college instructor were assessed. They viewed one of four photographs of a tattooed or nontattooed female model. Students rated her on nine teaching-related characteristics. Analyses indicated that the presence of tattoos was associated with some positive changes in ratings: students' motivation, being imaginative about assignments, and how likely students were to recommend her as an instructor. PMID- 20712174 TI - Reactions to waiting online by men and women. AB - The goal of the present study was to identify factors which may affect the difference between the actual time participants expected to wait for downloading a web page and the perceived waiting time, i.e., the online waiting-time gap. The findings from an experiment in which the music tempo (fast vs. slow) and waiting duration information (presence vs. absence) were manipulated showed that sex moderated the relation between the manipulated variables and waiting-time gap; emotional response was more important between the manipulated variables and waiting-time gap than was cognitive response. The type of emotional response with an effect on waiting-time gap varied by sex: pleasure for women and arousal for men. For women, pleasure was affected by their cognitive response, while cognitive response played no significant role for men. For both sexes, information on waiting duration increased the perceived waiting time. This study leads to reconsidering the role of emotional response and sex in evaluating waiting time. PMID- 20712175 TI - A reliability analysis of the revised competitiveness index. AB - This study examined the reliability of the Revised Competitiveness Index by investigating the test-retest reliability, interitem reliability, and factor structure of the measure based on a sample of 280 undergraduates (200 women, 80 men) ranging in age from 18 to 28 years (M = 20.1, SD = 2.1). The findings indicate that the Revised Competitiveness Index has high test-retest reliability, high inter-item reliability, and a stable factor structure. The results support the assertion that the Revised Competitiveness Index assesses competitiveness as a stable trait rather than a dynamic state. PMID- 20712176 TI - Religion in America--1972-2006: religious affiliation, attendance, and strength of faith. AB - The present study used data from the General Social Survey, collected between 1972 and 2006 (N = 45,463) to analyze changes over time in three aspects of religion among American adults: religious affiliation, frequency of attending religious services, and strength of faith. The last two measures were analyzed only for survey participants who had a religious affiliation. Ordinary least squares regression confirmed a significant decrease in religious affiliation over time, after controlling for socio-demographic variables that are known to be associated with religion. A significant decrease in attending religious services was found among those survey participants who were religiously affiliated. As expected, participants who were African American, female, older, and from the South were more religious according to all three measures. No effect of birth cohort was found for any religious measure. The results are discussed in the context of Stark and Bainbridge's 1996 theory of religion. PMID- 20712177 TI - Predicting long-term citation impact of articles in social and personality psychology. AB - The citation impact of a comprehensive sample of articles published in social and personality psychology journals in 1998 was evaluated. Potential predictors of the 10-yr. citation impact of 1580 articles from 37 journals were investigated, including number of authors, number of references, journal impact factor, author nationality, and article length, using linear regression. The impact factor of the journal in which articles appeared was the primary predictor of the citations that they accrued, accounting for 30% of the total variance. Articles with greater length, more references, and more authors were cited relatively often, although the citation advantage of longer articles was not proportionate to their length. A citation advantage was also enjoyed by authors from the United States of America, Canada, and the United Kingdom. 37% of the variance in the total number of citations was accounted for by the study variables. PMID- 20712178 TI - The structure of Thalbourne's brief Manic-Depressive scale. AB - Data from 1376 respondents on a 1994 scale to measure depressive and manic experiences devised by Thalbourne, Delin, and Bassett (1994) were analyzed. Internal consistency reliability estimates for the Total scale (.66), the Depressive subscale (.63), and the Manic subscale (.45) were poor to marginal, and a confirmatory factor analysis did not support the two-subscale structure of the scale. These results, considered in conjunction with those of previous psychometric analyses of the Manic-Depressive Scale, cast doubt on its usefulness for research and clinical use. PMID- 20712179 TI - Subjective ratings of prospective memory deficits in chronic alcohol users. AB - Previous research showing everyday memory is impaired by heavy alcohol use may have underestimated the cognitive impairment of heavy users because drinkers consuming over the recommended limits for safe drinking have often been treated as a homogeneous group, often with a low threshold for inclusion. The current study investigated whether the reported linear relationship applies to participants consuming alcohol significantly above recommended limits. The everyday memory of 80 participants (43 men; modal age, 31-35 years) was investigated using the Prospective Memory Questionnaire. Participants also detailed their average weekly intake of alcohol and other substances. Current heavy users of alcohol (who consumed on average over 25 units per week) reported more memory problems than low (1-9 units per week) or medium users (10-25 units per week). Participants undergoing counselling for alcohol use reported more deficits than low or medium drinkers, but fewer than current heavy drinkers. Possible reasons for this were discussed. Strengths and limitations of subjective approaches to memory assessment were discussed as well as suggestions for future research. PMID- 20712180 TI - Smoking cessation: case study of a client with probable borderline personality disorder. AB - This report concerns the case of a female client with a probable borderline personality disorder who requested psychological treatment for the cessation of smoking. After six sessions, this client gave up smoking and remained abstinent at follow-up after 1, 3, 6, and 12 months. The presence of a probable borderline personality disorder did not interfere in the cessation of tobacco use or in the maintenance of abstinence. PMID- 20712181 TI - Problem-solving style and multicultural personality dispositions: a study of construct validity. AB - This exploratory study examined the relationship between problem-solving styles and multicultural personality dispositions among 91 graduate students enrolled in an urban university located in the northeast United States. Problem-solving style was assessed with the three dimensions of the VIEW: an Assessment of Problem Solving Style. Multicultural personality was assessed with the five-factor Multicultural Personality Questionnaire (MPQ); its factors of Cultural Empathy, Open-mindedness, Social Initiative, and Flexibility correlated significantly with Explorer and External problem-solving styles, as predicted. The Emotional Stability subscale also correlated significantly with scores on Explorer style, suggesting that individuals who prefer "thinking in new directions" in problem solving are more likely to report remaining calm under stressful situations. Collectively, study results provided additional evidence of construct validity for the VIEW. PMID- 20712182 TI - Comment on Kesici and Sahin (2009): measurement of negative consequences of Internet use. AB - In an ongoing discussion regarding use of the concept of Internet addiction, it does not seem reasonable to use the concept in studies which are conducted in nonclinical settings and describe negative situations experienced by the general population during Internet use. It may be more appropriate to discuss problematic Internet use. Dimensional rather than categorical measures would be more appropriate than Young's diagnostic criteria alone to specify whether Internet use is within a healthy range. PMID- 20712183 TI - The four-point scoring system for the clock drawing test does not differentiate between Alzheimer's disease and vascular dementia. AB - The purpose of this study was to explore the sensitivity and specificity of the Clock Drawing Test by using a widely employed four-point scoring system to discriminate between patients with Alzheimer's disease or vascular dementia. Receiver operating characteristic analysis indicated that the Clock Drawing Test was able to distinguish between normal elders and those with a dementia diagnosis. The cutoff score for differentiating patients with Alzheimer's disease from normal participants was < or =3. The cutoff score for differentiating those with vascular disease from normal participants was < or =3. Overall, the four point scoring system demonstrated good sensitivity and specificity for identifying cognitive dysfunction associated with dementia; however, the current findings do not support the utility of the four-point scoring system in discriminating Alzheimer's disease and vascular dementia. PMID- 20712184 TI - Economic and cultural correlates of subjective wellbeing in countries using data from the Organisation for Economic Co-Operation and Development (OECD). AB - The correlations among indicators of objective well-being, cultural dimensions, and subjective well-being were investigated using Organisation for Economic Co operation and Development (OECD) data from 35 countries. The subjective well being measures included life satisfaction as well as six positive and six negative indexes of experience. Positive and negative experience scores were subjected to principal component analysis, and two positive experience components (labeled as "positive experiences" and "time management") and two negative experience components (labeled as "pain, worry, and sadness" and "anger and boredom") were extracted. Objective well-being included economic indicators, education, and health. The cultural variables included Hofstede's and Schwartz's cultural dimensions, national Big Five personality scores, and national IQs. High life satisfaction was positively related to Gross Domestic Product, life expectancy, education, individualism, affective and intellectual autonomy, egalitarianism, and conscientiousness, whereas low life satisfaction was related to unemployment, unequal income distribution, power distance, masculinity uncertainty avoidance, embeddedness, hierarchy, and neuroticism. PMID- 20712185 TI - Danger. EHRs can replace one set of medical errors with another. PMID- 20712186 TI - Bridging the gap. PMID- 20712188 TI - Military might. PMID- 20712187 TI - Tension over relaxation. PMID- 20712189 TI - Cash crunch. PMID- 20712190 TI - Test pilot. Interview by Elizabeth Gardner. PMID- 20712191 TI - The year of the spill. PMID- 20712192 TI - Scissoring through barriers. PMID- 20712193 TI - Hazmat training: preparing for the worst. PMID- 20712194 TI - Preparing for the turnaround. PMID- 20712195 TI - FR clothing: important tool as OSHA expectations get tougher. PMID- 20712196 TI - Cleaning the Gulf. PMID- 20712197 TI - Foundations of hand protection. PMID- 20712198 TI - Providing a solid foundation. PMID- 20712199 TI - Best Practices 101. PMID- 20712200 TI - A serious subject. Dealing with erectile dysfuntion. PMID- 20712201 TI - Drink up. How you hydrate yourself makes a difference. PMID- 20712202 TI - Baby talk. For a healthy pregnancy, the planning starts now. PMID- 20712203 TI - You, pregnant. The science of pregnancy and diabetes. PMID- 20712204 TI - How to build a terrific taco. PMID- 20712205 TI - Boards recognise role of nursing in raising quality. PMID- 20712206 TI - National guidance on last offices would prevent family distress. PMID- 20712207 TI - The high impact actions for nursing and midwifery 1: keeping nourished--getting better. AB - Approximately one in four patients in NIIS hospitals are either malnourished or at risk of malnurition and as much as 70% of malnutrition in acute hospital admission is unrecognised and unmanaged. Although most of those who are malnourished live in the community, malnutrition and dehydration are key challenges for NHS organisations. Well hydrated and nourished patients get better more quickly, have a shorter length of stay and a more positive experience of care. Ensuring patients receive all of the nutrients they need is vital to the delivery of good care. This article, the second in our series on the high impact actions for nursing and midwifery, looks at how nurses can reduce malnutrition in their patients. PMID- 20712208 TI - Embracing the opportunity to make sustainable improvements to nutritional care in all settings. AB - The enactment of the Health and Social Care Act 2008 represents a watershed moment in the history of the delivery of high quality nutritional care. The problem of undernutrition has been an intractable issue in health and social care for decades. This new act comes at the same time as a range of new initiatives, such as the high impact actions for nursing and midwifery, which include an action to stop inappropriate weight loss and dehydration in NHS care. Poor nutritional care equals poor quality care; it is an expensive waste of resources that the NHS can ill afford as we meet the challenge of delivering comprehensive healthcare in this financial climate. PMID- 20712209 TI - Ensuring reusable equipment meets patients' needs and infection prevention guidelines. AB - This article describes the processes used by an infection prevention and control team to identify a commode chair that would meet the needs of patients in an acute teaching hospital, and could be easily cleaned and disinfected. Some of the strategies used to ensure the commode was fit for purpose could be applied when searching for other reusable equipment for patient use. PMID- 20712210 TI - How nurses working in acute care can help to ensure patients achieve a good death. PMID- 20712211 TI - After death 1: caring for bereaved relatives and being aware of cultural differences. AB - This first in a two part unit on bereavement and last offices discusses relatives' grief reactions and caring for deceased patients, taking into account spiritual and cultural differences. PMID- 20712213 TI - Training without change is a waste of time and money. PMID- 20712212 TI - What are the differences in nurse practitioner training and scope of practice in the US and UK? AB - In the US, the role of the nurse practitioner is long established. In the UK, the role is not as well developed and there is neither a separate registry nor a recordable qualification to recognise NPs on the Nursing and Midwifery Council register. This has hindered the development of NPs as there is no specified level of training or scope of practice that applies to all nurses in posts labelled "nurse practitioner". This article examines the differences in NP training, licensing and practice between the US and the UK; recommendations are made for using the lessons learnt in the US to help promote the development of NPs in the UK. PMID- 20712215 TI - The epidemic of diabetes for SC. PMID- 20712216 TI - Diabetes self-management education. PMID- 20712217 TI - Diabetes-related hospitalizations--A challenge for South Carolina hospitals and nurses. PMID- 20712218 TI - Diabetes community outreach efforts in South Carolina. PMID- 20712219 TI - Lateral violence update: we are still listening & we thank you. PMID- 20712220 TI - The new CEO. PMID- 20712221 TI - Clinical integration: fast forward. PMID- 20712222 TI - Accepting the governance challenge of health care reform. PMID- 20712223 TI - The right stuff. AB - The interviews with board members at 10 high-performing community health systems revealed many other factors that, in the opinions of some, have contributed to their system's strong operating performance; for example, prudent investments in facilities and services, new technology and strategic mistakes by competitors. On the whole, however, the trustees perceived the six factors outlined above as being most influential in their organizations' successful performance in recent years. The table on Page 21 provides a summary of the trustees' views. Numerous factors contribute in varying degrees to organizational performance. Board leaders and CEOs should assess their organization and, as objectively as possible, identify those which are truly pivotal in determining its operating performance. Allocating proper attention and resources to them and monitoring the results on an on-going basis are among the main responsibilities of governing boards in today's challenging health care environment. PMID- 20712224 TI - Striking a balance. PMID- 20712225 TI - How reform can empower trustees. PMID- 20712226 TI - Reform, investor scrutiny and succession planning imperatives. PMID- 20712227 TI - Trustee engagement and hospital success. PMID- 20712229 TI - The complexities of grounded theory: a commentary. PMID- 20712228 TI - CEO retirement benefits: the board's dilemma. PMID- 20712230 TI - The role and place of knowledge and literature in grounded theory. AB - Grounded theory has existed for more than 40 years and has proved a successful and rigorous general inductive research method. However, it is apparent in the literature that novice researchers, or those new to interpretative studies, struggle to understand and defend the use of existing knowledge and the literature in a grounded theory study. While the engagement with and the role of the literature in grounded theory are documented in many texts, there are apparently contradictory perspectives. In addition, for the novice researcher undertaking grounded theory in an era of evidence-based practice, it can be a considerable challenge to understand and defend the role of the literature, substantive knowledge of the area and the place of a theoretical framework in grounded theory. The purpose of this paper is to consider these issues using salient arguments in the literature to guide novice researchers in considering their theoretical and philosophical positions. PMID- 20712231 TI - Choosing between Glaser and Strauss: an example. AB - Choosing between Glaserian and Straussian grounded theory when selecting a methodological approach can be challenging, but few papers consider this decision making process. This paper explores the Glaser-Strauss debate using an example of a study which explored whether older people experience a sense of home in residential settings. PMID- 20712232 TI - Practical strategies to avoid the pitfalls in grounded theory research. AB - How can grounded theory researchers develop integrated conceptual analysis? In this paper, the authors use lessons learnt during a study of clinical judgment in nursing to offer practical strategies that avoid some of the pitfalls commonly encountered during grounded theory research. PMID- 20712233 TI - Classic grounded theory: a framework for contemporary application. AB - While undertaking a qualitative exploration of the role of lecturers in helping with problem-based learning, the author used an adapted form of classic grounded theory as a guiding methodology. This paper outlines the reasons for the suitability of classic grounded theory for this research and why adaptations were necessary to use it in practice. PMID- 20712234 TI - Participant overexposure and the role of researcher judgement. AB - Ethical conduct discussion often focuses on decisions made before and during the research process. In contrast, this paper offers a reflective and personal post factum critique of two distinct elements of ethical practice that emerged from a recent study of aspects of activity at a hospice in England. First, it is suggested that researcher judgement in protecting participants from 'overexposure' may have been insufficiently developed. Second, it is proposed that an unnecessarily individualist (biomedical) model of ethical good practice was uncritically accepted and that assumptions inherent in this approach should have been more thoroughly questioned. In conducting this study 'usual' measures were taken to protect from harm the individuals and organisation taking part. Before collecting data, which took the form of interview transcripts and notes made by the researcher in his role as staff nurse (participant observation), ethical approval was secured. Interviewees were known to the interviewer prior to interview. PMID- 20712235 TI - Exploring how Heideggerian philosophy underpins phenomenolgical research. AB - This paper demonstrates the methodological implications of using Heideggerian philosophy to inform a phenomenological study of the experience of memory loss. In particular, it addresses the methodological implications in relation to forestructure and pre-understanding, gaining entry into the hermeneutic circle and the process of data analysis, by considering their influences on the research. PMID- 20712237 TI - The concept analysis of therapeutic misconception. AB - The concept of therapeutic misconception is explored following the Wilson method of concept analysis. The phenomenon, identified in the early 1980s, was first observed during interviews with psychiatric patients who had consented to research, but believed the study in which they were agreeing to participate was for their benefit. The concept has more recently been identified in oncology research subjects, primarily those participating in phase I trials. Using the Wilson method, the investigator identified four elements present in therapeutic misconception in which subjects: Confuse research with treatment. Believe they will receive physical benefit from study participation. Fail to list altruism and contribution to science as motives for participating. PMID- 20712236 TI - Development of a violence tool in the emergency hospital setting. AB - Violence against nurses is an on-going issue in healthcare settings, and is regularly documented in the literature. Assessing the potential for violence against nurses in the emergency department is essential to maintain their safety. The aim of this study was to develop a violence assessment tool by refining a list of predictive cues identified from both a previous study and existing literature. Using the Delphi technique, a panel of 11 expert nurse academics and clinicians developed a 37-item questionnaire and used three rounds of Delphi to refine the violence assessment questionnaire. The resulting tool comprises 17 cues of potential violence that can be easily observed and requires no prior knowledge of the perpetrators' medical history. PMID- 20712239 TI - [Genetic base of heart diseases]. AB - Progress in understanding of human genome enables the researches to reveal genetic basis of many disorders, including genetic heart diseases--defects developed by genetic disorders. The most frequent causes of genetic diseases are defects of many genes (e.g., a correlation has been observed between arterial hypertension and mutations in ACE and ADD1 genes). Moreover, a defect of single gene can be connected with several disorders (e.g., mutations in preseniline genes observed in Alzheimer disease and dilated cardiomyopathy). On the other hand, mutations in genes coding elements of particular signaling pathway can cause similar disorders (mutations in different components of RAS-MAPK pathway cause such disorders as Noonan syndrome, LEOPARD syndrome, Costello syndrome and CFC). The ability to identify genetic markers connected with heart diseases may contribute to the improvement of diagnostic and treatment of such disorders. PMID- 20712238 TI - Attention to the fundamentals of nursing care. PMID- 20712240 TI - [Smoking and clinical manifestation, lung function impairment, resulting comorbidities]. AB - Smoking cigarettes is an illness and it constitutes one of the major health risks. Although the consumption of cigarettes has been on the decline since 1990s, the smoking habit is still widespread. According to WHO statistics, Poland is among the countries in which smoking and smoking-related diseases are very common. MATERIAL AND METHODS: 1026 patients (83.8% of the patients registered in one of the health care centers in Bytom) were examined and the prevalence of smoking and the relation between chronic tobacco smoking and the clinical symptoms, lung function tests and concurrent diseases were assessed. RESULTS: The study revealed that the majority of the patients examined were either current or former smokers (567 persons, 55.3% study population). 343 persons (33.4%) were current smokers; 200 men (58.3%) and 143 women (41.7%), while former smokers were 224 persons (21.8%): 135 men (60.3%) and 89 women (39.7%). Correlation between smoking habit and dyspnoea, morning cough, sputum production and wheezing was confirmed. It was established that lung function (FEV1, FEV1%FVC) decreases with increasing number of pack-years. Moreover, smokers were more likely to develop such diseases as systemic hypertension, coronary disease and COPD. CONCLUSIONS: Tobacco smoking is related to such demographic factors as age, sex, education and financial status. Although the Poles' attitude towards tobacco smoking has changed for the better, the smoking habit still remains a significant epidemiological problem, particularly among young women. The incidence of cardiovascular diseases and COPD are statistically significantly related to smoking habit. PMID- 20712241 TI - [Plasma matrix metalloproteinases MMP-2 and MMP-9 and tissue inhibitors TIMP-1 and TIMP-2 in children treated for acute lymphoblastic leukemia]. AB - THE AIM OF THE STUDY: An analysis of changes in plasma levels of MMP-2 and MMP-9 as well as the tissue inhibitors TIMP-1 and TIMP-2 in children diagnosed for acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: In 21 children aged from 1 to 15 with ALL (17 with pre-B ALL and 4 with T-ALL) we made the analysis: at diagnosis (point I), after induction remission (point II) and after the end of intensive treatment (point III). Control group was composed of 47 healthy persons. RESULTS: At diagnosis, the mean plasma values of MMP-2, MMP-9, TIMP-2 were lower than in control group, whereas TIMP-1 levels were similar. During and after the treatment we found the increase of MMP-2 comparing to the values at diagnosis (relatively p = 0.003 and p = 0.008). Plasma MMP-9 was higher at point III of analysis than at point II. The levels of TIMP-2 increased in following points of the study We did not found the influence of immunophenotype, initial LDH levels and leukocytosis on MMPs and TIMPs values. At diagnosis, the ratio MMP 2/TIMP-1 was at the same level as in the control but it was higher during and after the intensive treatment. At diagnosis as well as during the treatment the ratios MMP-9/TIMP-2 and MMP-9/TIMP-1 were lower than in control. At diagnosis we found a positive correlation between MMP-2 and TIMP-2 (r = 0.679, p = 0.001) and between TIMP-1 and TIMP-2 (r = 0.482, p = 0.027), whereas during the treatment- only a positive correlation between MMP-2 and TIMP-2 was observed (r = 0.766, p = 0.001). CONCLUSIONS: The differences in plasma matrix metalloproteinases and their tissue inhibitors between leukemic patients and control group, as well as in patients during the treatment, suggest their probable role in the development of leukemic process. The analysis conducted in the bigger group of patients, establishing simultaneously levels of these markers in plasma and in leukemic cells, would be advisable. PMID- 20712242 TI - [A comparison of serum concentrations of biochemical bone turnover markers in patients with osteosarcoma with good and poor prognosis]. AB - Osteosarcoma is a primary malignant bone tumor, whose peak incidence occurs in the second decade of life during the adolescent growth spurt. Complex oncological treatment consisted of chemotherapy combined with surgery which substantially increased the cure rate of patients with osteosarcoma, but it is very important to identify patients with poor prognosis and to treat them with more aggressive therapy. THE AIM OF THIS STUDY: To assess serum biochemical bone turnover markers as prognostic indicators in patients with osteosarcoma. MATERIAL AND METHODS: We studied 55 patients from age 5 to 20 years with diagnosed osteosarcoma treated at the Institute of Mother and Child in Warsaw. The studied group was divided into 2 subgroups consisted of 27 patients with favorable (disease remission) and 28 patients with unfavorable (disease progression) prognosis. Venous blood was collected from patients in the morning hours at time of diagnosis, during anticancer treatment and after completion of treatment. Serum osteocalcin (OC), bone alkaline phosphatase (BALP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were analyzed by immunoenzymatic methods. RESULTS: At time of diagnosis, in patients with unfavorable prognosis concentration of bone formation markers were higher (OC by 30% and BALP by 60%) than in those with good prognosis, however, CTX level was similar in both groups of patients. During chemotherapy in patients with poor prognosis we observed higher levels of bone turnover markers in comparison to subjects with favorable prognosis. After the completion of therapy, in patients with progression median values of bone formation markers were over twofold and bone resorption marker about 50% higher as compared to patients with remission of disease. These differences were statistically significant at p < 0.05 for OC, p < 0.001 for BALP and p < 0.01 for CTX. CONCLUSIONS: Our results suggest that bone turnover markers, especially bone alkaline phosphatise may be useful in the monitoring and in the assessment of the efficacy of therapy in children with osteosarcoma. Higher rates of bone formation and resorption during treatment and after its completion are associated with unfavorable prognosis and may indicate progression of disease. PMID- 20712243 TI - [Characteristic of the patients' gait with recurrent lateral patella dislocation]. AB - Recurrent lateral patella dislocation, as a kind of patellofemoral malalignment, significantly influences knee biomechanics by the changing patellofemoral movement during flexion and during gait. So far other papers doesn't describe characteristic of the patients' gait with recurrent lateral patella dislocation. THE AIM OF THIS STUDY: To evaluate gait pattem patients with recurrent lateral patella luxation in comparison to normal gait pattern. MATERIAL AND METHODS: There have been 10 patients involved in evaluation. Those patients have been diagnosed recurrent lateral patella luxation. All of the patients were subjected analysis using objective system of movement analysis VICON 460. RESULTS: The results of gait parameters analysis revealed significant changes in comparison with normal pattern gait. CONCLUSIONS: Gait pattern patients with recurrent lateral patella luxation unlike normal gait pattern characterizes itself with decrease of gait speed, steps frequency reduction and hyperextension of the knee during foot of gait phase. PMID- 20712244 TI - [Changes in gait pattern in patients with recurrent patella dislocations after tibial tuberosity transfer by modified Elmsllie-Trillat procedure]. AB - Recurrent lateral patella dislocation, as a kind of patellofemoral malalignment, significantly influences knee biomechanics by the changing patellofemoral movement during flexion and during gait. So far other papers doesn't describe characteristic of the patients' gait with recurrent lateral patella dislocation. THE AIM OF THIS STUDY: To evaluate gain pattern patients with recurrent lateral patella luxation in comparison to normal gait pattern. MATERIAL AND METHODS: There have been 6 patients involved in evaluation. Those patients have been diagnosed recurrent lateral patella luxation. All of the patients were subjected analysis using objective system of movement analysis VICON 460. RESULTS: The results of gait parameters analysis revealed significant changes in comparison with normal pattern gait. CONCLUSIONS: Gait pattern patients with recurrent lateral patella luxation unlike normal gain pattern characterizes itself with decrease of gait speed, steps frequency reduction and hyperextension of the knee during foot of gait phase. PMID- 20712245 TI - [Gender psychological of psychiatrically hospitalized persons with a history of suicide attempt]. AB - Suicide is a major social problem. Annually as a result of suicide, almost one million people are killed and many more unsuccessful attempt to take his own life. Knowledge of risk factors is one of the first steps of prevention of this phenomenon. THE AIM OF THE STUDY: To know the personality determinants of gender found in people after a suicide attempt. MATERIAL AND METHODS: The study included 37 people after a suicide attempt, psychiatric hospital and a control group (healthy people) well-matched for age and education. Questionnaire method used to study selected personality variables. RESULTS AND CONCLUSIONS: Psychological gender--masculinity dimension to significantly differentiate a person from the study group and controls. People after a suicide attempt is characterized by a higher level of anxiety (as a state and as a feature). In less able to cope effectively with stress. PMID- 20712246 TI - [Health economic impact of viral respiratory infections and pneumonia diseases on the elderly population in Poland]. AB - Respiratory diseases and particularly those linked to pneumonia and influenza infections are a leading cause of serious illness. Streptococcus pneumoniae is responsible for 30 to 50% of all community-acquired pneumonia. It is also a common bacterial complication of influenza, especially in the frail populations, such as the elderly. There are scarce data reporting the medical and economic burden of these infections in Poland. Polish authorities recommend influenza and pneumococcal vaccinations for subjects aged 65 years and over but there is not public vaccination program in place for covering immunization. Elderly vaccination rates against influenza and pneumonia in Poland remain far below the World Health Organization's recommendations. THE AIMS OF THE STUDY: To assess the mean economic costs of influenza and pneumococcal diseases in the Polish elderly population, treated in outpatient and inpatient settings. Costs were estimated from the public payer and societal perspectives. MATERIAL AND METHODS: Data were collected retrospectively from 2007 to 2009 in three different sites: a general practitioner Family clinic for outpatient data and two hospitals in Warsaw for inpatient data. Resource use linked to pneumonia orinfluenza treatments were collected from each site. Microcosting calculation method was used to estimate the outpatient costs. Inpatient costs were measured using the Ministry of Health patient's payment for each diagnosis group (DRG) but also using each subject's treatment inpatient costs added to the cost of hospital stay. RESULTS: Mean outpatient cost for treating an outpatient was 101 PLN for influenza (1 euro = 4 PLN) and 186 PLN for community-acquired pneumonia. Mean total hospitalization cost including treatment cost and cost of stay was 7633 PLN among P&I patients whereas the DRG cost for this diagnosis was 1885 PLN. Similarly, the mean total inpatient cost was estimated to be 7162 PLN for Streptococcal bacteremia (DRG payment: 7140 PLN) and 4104 PLN for meningitis (DRG payment: 3804 PLN). CONCLUSIONS: This study highlights the significant economic impact of influenza and pneumococcal diseases in the Polish population aged 65 years and over. Complications of influenza and pneumonia diseases contribute to weight down this burden as they often lead to hospitalizations in these frail populations. This first economic assessment is a 1st step in the measurement of the value of preventing these diseases through vaccination. PMID- 20712247 TI - [Venous thrombosis as a clinical problem after pacemaker implantation--case report]. AB - Although transvenous pacing is a safe treatment modality for bradyarrhythmias, serious thrombotic and embolic complications are reported to occur in 0.6-3.5% of cases. We describe a case of pacemaker-associated thrombosis, with an axillary and subclavia veins thrombosis. The patient was treated with subcutaneous heparin which proved successful as the sole treatment. PMID- 20712248 TI - [Feeding disorders, ALTE syndrome, Sandifer syndrome and gastroesophageal reflux disease in the course of food hypersensitivity in 8-month old infant]. AB - This paper describes the occurrence of feeding disorders, atopic dermatitis, life threatening symptoms, Sandifer syndrome, and gastroesophageal reflux disease in 8 month old infant in the course of food hypersensitivity. Used in the treatment of cow's milk protein hydrolysates with a considerable degree of hydrolysis, omeprazole, Cisapride. It was not until the introduction of elemental diet based on free amino acids resulted in the withdrawal of life-threatening child's symptoms. PMID- 20712249 TI - [Macroprolactinaemia]. AB - Hyperprolactinaemia is one of the most common endocrinological disorders affecting the hypothalamic-pituitary axis. The increase of prolactin level in the blood interrupts the pulsatile GnRH secretion and in turn causes hypoestrogenism. Hyperprolactinaemia can occur in physiological and pathological conditions. Prolactin has 3 different isoforms: little prolactin, big prolactin and big-big prolactin. Macroprolactin is a complex of little prolactin and an immunoglobulin G antibody and the weight of the complex is more than 150 kDa. In physiological condition macroprolactin comprises up to 1% of all circulating prolactin in the serum blood. In pathological condition percentage of macroprolactin can increase in the serum blood. The prevalence of macroprolactinaemia is found in around 10 26% of all patients with hyperprolactinaemia. Women with high serum prolactin concentration in should be screened for macroprolactinaemia. Confirmation the presence of macroprolactinaemia doesn't require any pharmacological treatment or other medical procedures. PMID- 20712250 TI - [Current trends in the treatment of incisional hernia in patients after kidney transplantation]. AB - The incidence of incisional hernia following abdominal surgery varies between 2 and 13%, the rate of incisional hernia after renal transplantation varies between 1.1 and 3.8%. There are no evidence based guidelines regarding the treatment of incisional hernias in renal transplant recipients. The aim of this study was to compare results of surgical repair of incisional hernia in patients after renal transplantation depending on the treatment method. A Pubmed was searched for articles related to the treatment of patients with incisional hernia after renal transplantation. Finally five articles were used for review. The analyzed papers report a total of 5606 patients in a time period between 1965-2004. Hernia mesh repairs were similar - primary approximation of the fascial borders and polypropylene mesh reinforcement, mainly by on lay technique or by suturing the mesh to fascial edges. Hernia repairs without mesh were diverse: simple closure, component separation technique, tensor fascia late grafts, split thickness skin grafting. Although all authors are concerned about prosthetic mesh use for hernia repair in transplant patients, four of them advise this method. Surprisingly, the incidence of incisional hernia in transplant recipients (1.83%) is no higher than in normal population (2-13%). Hernia recurrence in the analyzed group was 2% for prosthetic mesh repair, and 25% for no mesh repair. Prosthetic mesh repair of incisional hernias after kidney transplantation is a safe technique and starting to displace other methods of treatment. PMID- 20712251 TI - [The usefulness of nicotinamide in radioiodine therapy in patients with toxic and nontoxic large goitres]. AB - Nicotinamide (niacin) is very useful substance in treatment of many kinds of diseases. For the decades the main indications for application of niacin were lipid disorders. There are studies confirming that niacin increases thyroid radiosensitivity to 1-131. The radioiodine therapy is common method of treatment of hyperthyroidism (Graves' disease, toxic nodular goitre), large euthyroid goitre and differentiated thyroid cancer. In some studies with Wistar rats there is shown that niacin potentiates the effect of 1-131 by increasing thyroid blood flow, what results better effects of radioiodine treatment. Moreover niacin in therapeutic doses decreases serum thyroid hormone levels (mainly total thyroxine and thyroxine-binding globuline). In case of large goitre, when the calculated radioisotope dose exceeds ambulatory limits, the patient must be hospitalized. There are patients with low radioiodine uptake and radiosensitivity of thyroid, radiosensitizers can be utilized for this purpose. Recently obtained results of studies are showing that niacin can be used as radiosensitizer. It is making possible ambulatory treatment of patients with large goitres and low radioiodine sensitive thyroid. The radioiodine therapy with niacin could become shorter, less expensive and more safety for patients. PMID- 20712252 TI - [Natural history of polycyclic ovary syndrome]. AB - Polycystic Ovary Syndrome (PCOS) occurs in 3-6% women of reproductive age. The Rotterdam 2003 criteria for PCOS diagnosis include: oligo or anovulation, hyperandrogenism and a typical clinical picture of polycystic ovaries in the USG image when other causes of hypoestrogenism are excluded. The etiology of the syndrome remains largely unknown. In 30-60% cases of women with PCOS, obesity is observed. The aim of the present study was to track the natural history of PCOS by observing the disorders in different stages of the female patient's life starting with infancy through childhood and adolescence, then full sexual maturity period, which is the best known one and up to around menopause period. Each of these life stages is characterized by different specificity of disorders. In the fetal and infant period the focus should be placed on the influence of hormonal disorders in mother on PCOS induction. Childhood is the period when the observation is focused on fenotypical features that may indicate the risk of PCOS development. In the reproductive period, which is the most widely known, the focus is understandably on fertility disorders, however metabolic disorders are also quite often manifested. In PCOS patients around menopause, metabolic disorders are of primary focus for exemple mostly the risk of the development of diabetes type 2 as well ascardiovascular system diseases. Such versatility of coexistent disorders in one syndrome and variability depending on a woman's age call for closer examination of these relations and dependencies. PMID- 20712253 TI - [Diabetic macular edema--modern diagnostics and treatment]. AB - Diabetic macular edema is very important medical and social problem and major cause of severe and permanent visual acuity depression in the working-age population. Rapid diagnostics with optical coherence tomography, color fundus photography, fluorescein angiography and appropriate treatment in patients with diabetes stops or retards progress of diabetic macular edema. PMID- 20712254 TI - [Effectiveness of trazodone in the treatment of sexual dysfunctions]. AB - Sexual dysfunctions may be main cause of social disability. The knowledge of the rates of occurrence of sexual dysfunctions in the general population and the primary risk factors for these conditions is very important to assist in assessing the risk and planning treatment. Sexual dysfunctions are highly prevalent in our society worldwide, and that the occurrence of sexual dysfunctions increases directly with age for both men and women. Specific medical conditions and health behaviors represent major risk factors for sexual disorders. Trazodone is sedative antidepressant drug, which is effective, safe, fast acting, with a few side effects, with proved efficiency in the treatment of sexual dysfunction. PMID- 20712255 TI - [The shaken baby syndrome as a kind of domestic abuse]. AB - In the recent decades research on child abuse has grown impressively. Four types of child abuse: physical, psychological (emotional), sexual, and neglect have been clinically observed and defined. In 1972, John Caffey, a pediatric radiologist, published an article on the theory and practice of the abusive shaking of infants. This was followed, in 1974, with a second article on the whiplash shaken baby syndrome (SBS). Shaken baby syndrome, is caused by the violent shaking of a child with or without contact between the child's head and a hard surface. Such contact may result in head trauma, including subdural hematoma, diffuse axonal injury and retinal hemorrhage. The annual estimated rate of inflicted traumatic brain injury is 30 cases per 100,000 children aged 1 year of younger. Shaken baby syndrome often occurs after shaking in response to crying bouts. In 2001, an estimated 903,000 children were victims of SBS. Additionally, 1300 children were fatally injured from SBS the same year. The ability to detect SBS is difficult secondary to under reporting and misdiagnosis. There is no established set of symptoms that indicate SBS. PMID- 20712256 TI - Atorvastatin restores the balance between pro-inflammatory and anti-inflammatory mediators in rats with acute myocardial infarction. AB - BACKGROUND: Pro- and anti-inflammatory cytokines play a major role in the development of acute myocardial infarction (AMI). This paper tests the hypothesis that atorvastatin may attenuate the severity of myocardial ischemic injury by restoring the balance between pro-inflammatory and anti-inflammatory mediators. MATERIALS AND METHODS: Sixty adult male albino rats were used. Experimental AMI was induced by subcutaneous injection of isoprenaline. Atorvastatin was given for five days, then, it was combined with isoprenaline in the last two days of treatment protocol. Rats without any treatment were used as controls. Rats were subjected to ECG tracing, assessment of Creatine phosphokinase (CPK) and CPK-MB, measurements of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF alpha), interleukin-10 (IL-10), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: Induction of AMI by isoprenaline resulted in a significant elevation of ST segment, elevation of CPK and CPK-MB. CRP, TNF-alpha and plasma PAI-1 were significantly elevated in the AMI rats compared to the control groups. On the other hand, the level of the anti-inflammatory cytokine IL-10 was significantly reduced. Treatment with atorvastatin prior to induction of AMI was associated with a significant reduction of serum CRP, TNF-alpha, plasma PAI-1 and an increase of serum IL-10. CONCLUSIONS: This study suggests the usefulness of atorvastatin as an attenuating agent against AMI. Atorvastatin restores the balance between the pro-inflammatory and the anti-inflammatory mediators and modulates the fibrinolysis by reducing the levels of PAI-1. PMID- 20712257 TI - Effects of developmental fluoride exposure on rat ultrasonic vocalization, acoustic startle reflex and pre-pulse inhibition. AB - Rats receiving fluoride during the whole pregnancy up to the 9th day of lactation showed, when isolated at 10th day of life, a reduced rate of ultrasonic vocalizations (UV) in male pups (NaF 5.0 mg) and, in 90th days male rats, an increase of the Pre-Pulse Inhibition (PPI) with a reduction of the Peak response to the Startle stimulus given alone. Newborn rat reactivity could represent a useful and validated model in anxiety studies which could be moored with the Acoustic Startle Reflex (ASR) and PPI, appropriate models to study, in adulthood, particular neurological and psychiatric disorders showing deficits in attention and sensory-motor gating (Tourettes' syndrome, obsessive compulsive disorders, Huntington's disease and schizophrenia). PMID- 20712258 TI - Efficient "one-pot" synthesis of novel 3-azabicyclic spiro-1',2',4'-triazolidin 3'-thiones catalyzed by potassium superoxide and their in vitro antibacterial and antifungal activities. AB - A new series of novel 3-azabicyclic spiro 1',2',4'-triazolidin-3'-thiones 15-21 catalyzed by potassium superoxide under microwave irradiation have been synthesized and studied for their in vitro microbiological evaluation on clinically isolated bacterial strains namely Micrococcus luteus, Bacillus subtilis, Bacillus cereus, Pseudomonas aeuroginosa and fungal strains namely Aspergillus niger, Candida albicans, Candida 6 and Candida 51. Results of the in vitro microbiological evaluation of the synthesized compounds are discussed. PMID- 20712259 TI - Relation of phase angle tertiles with blood adipocytokines levels, insulin resistance and cardiovascular risk factors in obese women patients. AB - BACKGROUND: Few studies have evaluated the relation between phase angle (PA) and metabolic syndrome. As long as we know, there are not studies of association between phase angle and adipocytokines. The aim of our study was to evaluate the association of adipocytokines levels and classical cardiovascular risk factors with tertiles of phase angle in obese women. MATERIAL AND METHODS: A cross sectional study was designed to establish whether phase angle from 228 adult female patients with obesity are related with adipocitokynes and cardiovascular risk factors. These patients were studied in a Nutrition Clinic Unit after signed informed consent. All patients with a 2 weeks weight-stabilization period before recruitment were enrolled. Weight, blood pressure, basal glucose, C-reactive protein (CRP), insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides blood and adypocitokines (leptin, adiponectin, resistin Interleukin 6 and TNF-alpha) levels were measured. The phase angle alpha was determined by bioimpedance with the equation [PA degrees =(Xc/R)x(180 degrees/pi)]. RESULTS: Two hundred and twenty-eight females gave informed consent and were enrolled in the study. The mean age was 38.2 +/- 14.7 years and the mean BMI 35.27 +/- 6.5. Patients were divided by tertiles of phase angle. Fat mass was higher in first tertile than third tertile (43.6 +/- 12.6 vs 40.9 +/- 15 kg: p<0.05). HOMA (2.4 +/- 1.6 vs 1.46 +/- 1.6: p<0.05), insulin (14.4 +/- 8.5 vs 11.3 +/- 9.4 mUI/L: p<0.05) and glucose (102.1 +/- 20 vs 90 +/- 19.5 mg/dl: p<0.05) levels were higher in first tertile than second and third tertiles. Leptin (167.3 +/- 98 vs 104.5 +/- 80 ng/ml: p<0.05) and IL-6 (3.84 +/- 5.7 vs 1.8 +/- 2.9 pg/ml: p<0.05) levels were higher in first phase angle tertile than third tertile phase angle. CONCLUSION: Obese women with a low PA tertile have high fat mass with a secondary high level of glucose, HOMA, IL-6 and leptin. Perhaps, a low tertile of phase angle could be a new subrogate cardiovascular risk factor to categorize the obese patients. PMID- 20712260 TI - Relationship between oxidative stress, ferritin and insulin resistance in sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by hemolytic anemia. The oxidative phenomena play a significant role in its pathophysiology. Blood transfusions are a therapeutic mainstay in SCD and repeated transfusions can result in iron overload. There is little direct information available to confirm the correlation between the oxidative stress, iron overload and insulin resistance in SCD patients. OBJECTIVE: To investigate the relationship between iron overload, the disorders of antioxidants and insulin levels in blood of SCD patients and their matched controls. METHODS: The antioxidant activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as the malondialdehyde (MDA, the membrane lipid peroxidation products) and carbonyl contents (the oxidative products of proteins) were estimated spectrophotometrically in erythrocytes of patients and control subjects of matched sex and ages. In addition, fasting blood glucose (FBG), ferritin and insulin levels were estimated in the sera of the same subjects. RESULTS: The mean activity values of SOD, CAT and GSH-Px were significantly decreased, whereas the average values of MDA and carbonyl contents were significantly increased in erythrocytes of SCD patients in comparison to the corresponding values of the control subjects. The average levels of FBS, ferritin, insulin and homeostasis model assessment of insulin resistance (HOMA IR) were significantly elevated in the sera of SCD patients as compared to the controls. In addition, both serum ferritin, and oxidative products (expressed as MDA and carbonyl levels) were significantly correlated with blood glucose, insulin level, and HOMA-IR. CONCLUSION: These findings may explain the role of elevated ferritin and oxidative products (i.e. MDA & carbonyl contents) in the development of insulin resistance and high glucose levels in SCD patients. PMID- 20712261 TI - Levobupivacaine vs. racemic bupivacaine in peribulbar anaesthesia: a randomized double blind study in ophthalmic surgery. AB - AIMS: The Authors examine the employement of a new anaesthetic agent, levobupivacaine 0.50% (S - enantiomer of racemic mixture of bupivacaine), for peribulbar anaesthesia in a randomized double blind study vs. racemic bupivacaine 0.50% alone or in association with hyaluronidase 10 IU x ml(-1). MATERIALS AND METHODS: 120 patients were divided into four groups of 30 each: group L (levobupivacaine 0.50%), group B (racemic bupivacaine 0.50%), group LH (levobupivacaine-hyaluronidase 10 IU x ml(-1)), group BH (racemic bupivacaine hyaluronidase 10 IU x ml(-1)). RESULTS: The onset-time (14 +/- 3.2 min vs. 13 +/- 4.8 min) and the duration of anaesthesia (195 +/- 34.2 vs. 204 +/- 37.6) were similar. The ocular akinesia was evaluated with an 8 point system: it was considered sufficient for surgery with values of less than 5 points. The association with hyaluronidase increased the spread of local anaesthetics (76.6% of group LH, 73.3% of group BH) with local anaesthetics alone (60% of group L, 56.6% of group B). Moderate hypotension (<30% baseline) was reported in 3 patients (10%) of group L, 2 (6.6%) of group B, 1 (3.3%) of group LH and 2 (6.6%) of group BH. Statistical analysis (Student-Newman-Keuls test) was significant between group L vs. BH, B vs. BH and LH vs. BH as regards onset-time of anaesthesia; between group B vs. LH, B vs. BH and L vs. LH for the duration of anaesthesia. Chi square test for the general akinesia score showed significant results in group L vs. LH (p=0.043) and B vs. LH 8P =0.018); as regards the score 0, test reported significant values between groups B vs. LH (p=0.004) and B vs. BH (p=0.017). CONCLUSIONS: In conclusion levobupivacaine, a longlasting local anaesthetic with limited cardio and neurotoxicity, might be useful for vitreoretinal surgery in elderly patients, compared with general anaesthesia. PMID- 20712262 TI - Isolation, identification and molecular characterization of Vibrio parahaemolyticus from fish samples in Kolkata. AB - Vibrio parahaemolyticus is a marine bacterium which is also responsible for acute diarrhoeal illness in human beings. Eating raw seafish or contaminated seafood is responsible for acute gastroenteritis. The aim of this study was to investigate the isolation, identification and molecular characterization of Vibrio parahaemolyticus from the fish samples in Kolkata, India. MATERIALS AND METHODS: In this study 90 fish samples were collected from 8 different market places in Kolkata, India. Fish samples collected were shrimp, prawn, bhetki, pamfret and hilsa. VP-toxR PCR was performed to confirm the presence of species specific toxR. tdh and trh genes PCR for detection of virulence genes were performed separately. GS-PCR was performed in tdh, trh gene positive strains to determine whether they belong to pandemic genotype. Serotyping was also done on the tdh, trh positive strains. RESULTS: Out of the 90 fish samples collected from different local fish markets 60 were positive for Vibrio parahaemolyticus. 21 (35%) out of 60 Vibrio parahaemolyticus isolates from fish samples harboured the tdh gene. 1 (1.7%) out of 60 Vibrio parahaemolyticus isolates from fish samples carried trh gene. Out of 22 isolates only 2 were positive for GS-PCR. O10:KUT was the serovar maximum isolated. CONCLUSION: Considerable percentage of Vibrio parahaemolyticus carrying the virulence genes and pandemic genotype among fish in Kolkata indicates that there is potential reservoir in Kolkata and consumption of sea fish or contaminated fish might cause Vibrio parahaemolyticus mediated diarrhea in this region. PMID- 20712263 TI - Seroconversion of HBsAg in HBeAg positive and HBeAg negative patients with chronic HBV treated with entecavir: a case series. AB - We report a case series of three HBeAg positive and five HBeAg negative patients (7 males, mean age 50.6 +/- 14.6 years) with chronic HBV infection experiencing seroconversion after treatment with entecavir (0.5 mg/day or 1 mg/day), initiated in 2007. Overall, the mean time to HBsAg clearance was 9.4 +/- 4.5 months. Seroconversion occurred in all patients, after a mean time of 8.0 +/- 3.7 months. In HBeAg negative patients, mean time to HBsAg clearance and to seroconversion were 9.2 +/- 5.9 and 6.8 +/- 4.0 months, respectively. In HBeAg positive patients, mean time to HBsAg clearance and to seroconversion were 9.7 +/- 0.6 months and 10.0 +/- 2.6 months, respectively. In this case series, seroconversion was maintained and was observed both in HBeAg positive patients and in HBeAg negative patients. Therefore, it may be preliminarily suggested that treatment with entecavir could be associated to HBsAg seroconversion in a short period of time, in both HBeAg positive and HBeAg negative HBV patients. PMID- 20712264 TI - Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles. A prospective, clinical trial. AB - OBJECTIVE: The aim of the study was to evaluate the efficacy of a treatment with myo-inositol plus folic acid plus melatonin compared with myo-inositol plus folic acid alone on oocyte quality in women underwent in vitro fertilization (IVF) cycles. DESIGN: A prospective, clinical trial. MATERIALS AND METHODS: Starting on the day of GnRH administration, 65 women undergoing IVF cycles were randomized in two groups to receive myo-inositol plus folic acid plus melatonin (32 women, group A), and myo-inositol plus folic acid (33 women, group B), administered continuously. Primary endpoints were number of morphologically mature oocytes retrieved (MII oocytes), embryo quality, and pregnancy rate. Secondary endpoints were the total number of oocytes retrieved (immature and mature oocytes), fertilization rate per number of retrieved oocytes and embryo cleavage rate. RESULTS: The mean number of oocytes retrieved did not differ between the two groups (7.88 +/- 1.76 vs 7.67 +/- 1.88; P=0.65). Whereas the group cotreated with melatonin reported a significantly greater mean number of mature oocytes (6.56 +/ 1.64 vs 5.76 +/- 1.56; P=0.047) and a lower mean number of immature oocytes (1.31 +/- 0.74 vs. 1.91 +/- 0.68; P=0.001). The mean number of embyos of top quality (class 1 and 2) resulted higher in the group A (1.69 +/- 0.64 vs 1.24 +/- 0.75; P=0.01). Fertilization rate did not differ between the two groups. A total of 22 pregnancies were obtained (13 in group A and 9 in group B; P=0.26). Clinical pregnancy rate and implantation rate were in tendency higher in the group cotreated with melatonin, although the differences did not reach statistical significance. Biochemical pregnancy rate and abortion rate were similar in both groups. CONCLUSION: melatonin ameliorates the activity of myo inositol and folic acid by improving oocyte quality and pregnancy outcome in women with low oocyte quality history. PMID- 20712265 TI - New trends in breast reconstructive surgery: "Florentine Lily" reductive mastoplasty. AB - BACKGROUND: To describe a mammoplasty technique that we called "Florentine Lily" because of the shape of the pre-operative drawings similarity with the symbol lily Florentine. METHODS: In a group of 190 women who underwent reductive mammoplasty, 23 women affected by severe enlarged breasts were selected. Main selection requirements were: 18-30 cm rising of the Areola-Nipple Complex (NAC). RESULTS: to obtain a functional and cosmetic result; preservation of mammary gland function; vitality of the areola-nipple complex and its sensitivity. We describe the case of 35 years old woman affected by severe enlargement of the breast and no pathologies. CONCLUSION: We didn't observe necrosis of the skin flaps and NAC in any case. In one case (rising of Nipple-Areola Complex >25 cm) NAC showed NAC 2 days post-surgery, which spontaneously resolved. Minor complications (edema and ematoma) developed in 20 cases. No infections were observed. PMID- 20712266 TI - Prevalence of celiac disease and symptoms in relatives of patients with celiac disease. AB - BACKGROUND AND OBJECTIVES: We determined the prevalence and clinical features of celiac disease (CD) in family-members (FMs) of a population-based cohort of index cases. MATERIALS AND METHODS: We recruited 108 CD index cases: mean age at diagnosis, 23.0 years (range, 1.5-45.2 years); 81 (75%) female. Three-hundred twelve (mean age, 41.6 years; 219 [70%] female) of FMs were analyzed. 153 (49%) were parents, 24 (7.7%) were children, 69 (22.2%) were siblings, 66 (21.1%) were second degree FMs. RESULTS: CD was diagnosed in 63 subjects (20.1%, 21 males and 42 females, mean age 34.24 years, range 2-81 years). Classic, subclinical, and silent forms of CD were recognized in 18 [28.6% (6 siblings, 6 parents, 3 child, 3 second-degree FMs)], in 27 [45.8% (9 siblings, 3 parent, 15 second-degree FMs)], and in 18 [28.6% (6 siblings, 6 parents, 6 second-degree FMs)] cases, respectively. Most of patients suffering from "classical" (18/63 patients, 28.7%) and "subclinical" (27/63 patients, 42.9%) form of CD were older than patients suffering from "silent " CD (18/63 patients, 28.7%) (p=0.01). Most of patients suffering from subclinical disease showed autoimmune diseases (Hashimoto's thyroiditis, and psoriasis), and other atypical symptoms, as gastroesophageal reflux disease (GERD), were also recorded. CONCLUSIONS: We found an high prevalence of CD between CD FMs, and most of them were olygo- or asymptomatic. PMID- 20712267 TI - Giant lipoma of descending colon diagnosed at CT: report of a case. AB - Colonic lipomas are rare benign lesions, detected accidentally. These are often asymptomatic, but large lipoma may produce symptoms as abdominal pain, nausea, weight loss, diarrhea, constipation, hemorrhage, and intussusception. Colonic lipomas are more often localized in the ascending colon: literature reports less than 20 symptomatic cases situated in the descending colon. We report the case of a young man with a colonic giant lipoma diagnosed at Computed Tomography, who presented with rectum bleeding and 5-kg weight loss. The case was interesting because of the patient's young age, the tumor's location in the left side of the colon and the giant size (5.5 cm). PMID- 20712268 TI - Value of unstructured patient narratives. Current EHRs capture most information- patient demographics, medications and problem lists--as structured data, and often codify the details to support billing instead of clinical activities. PMID- 20712270 TI - IT infrastructure convergence key to managed network services. Multiplicity of infrastructures and management has led to increased complexity installing, maintaining and troubleshooting technology-based applications and systems. PMID- 20712269 TI - HIEs: The future is now. PMID- 20712271 TI - Rural healthcare system drops AR days and cleans up claims. RCM system has led to dramatic reductions in AR days, denied claims, and billing backlogs while supporting the organization's move to a new central business office. PMID- 20712272 TI - Impact of meaningful-use criteria on EMR developers. Insights from the 2010 MSP/Andrew EMR Benchmark. PMID- 20712274 TI - How to boost operational efficiency in the enterprise radiology environment. Until a few years ago, many of North Shore-Long Island Jewish Health System's radiology departments continued to operate partially or entirely on paper-based documentation systems. PMID- 20712273 TI - PACS helps medical center reduce turnaround time from hours to minutes. As technology becomes an ever-increasing driver to ensuring a smooth and efficient healthcare environment, a well-run collaboration can hold the key to success. PMID- 20712275 TI - Healthcare's survival in the information age. PMID- 20712276 TI - It's far from over. PMID- 20712277 TI - What does the vision mean for health ministry? PMID- 20712278 TI - A rich tapestry, weaving in commitment. PMID- 20712279 TI - Cultural competence, an ongoing quest. PMID- 20712280 TI - Six months and counting. PMID- 20712281 TI - Managing diversity, a look at where we are. PMID- 20712282 TI - Programs groom managers and candidates for boards. PMID- 20712283 TI - Medical interpreters can save money, lives. Certification remains unresolved. PMID- 20712284 TI - What's that you said? Sometimes it's not the words, it's the accent. PMID- 20712285 TI - Welcoming all, honoring their beliefs. PMID- 20712286 TI - Beyond accommodation: diversity is part of who we are. PMID- 20712287 TI - A parish nurse works with refugees from Burundi. 'God brought Africa to me'. PMID- 20712289 TI - Lamentation: the ethics/gospel divide. PMID- 20712288 TI - Teaching in Africa: medical ethics Zimbabwe-style. PMID- 20712290 TI - An American history lesson: are lay leaders paying attention? PMID- 20712291 TI - What did Jesus do? Lessons for health care leaders. PMID- 20712293 TI - Leadership formation: what difference is it making? PMID- 20712292 TI - Slower is faster: it takes time to align cultures. PMID- 20712294 TI - Feet on the street. PMID- 20712295 TI - The ethical and religious directives as particular law. PMID- 20712297 TI - Lipid bilayer-assisted release of an enediyne antibiotic from neocarzinostatin chromoprotein. AB - The nine-membered enediyne class has drawn extensive interest because of extremely high antitumor potency and intricate interactions with its carrier protein. While the drug-induced DNA cleavage reactions have been mostly elucidated, the critical release-transport process of the labile enediyne molecule in cellular environment remained obscure. Using neocarzinostatin chromoprotein as a model, we demonstrated a lipid bilayer-assisted release mechanism. The in vitro enediyne release rate under aqueous conditions was found to be too slow to account for its efficient DNA cleavage action. Via the presence of lipid bilayers, chaotropic agents, or organic solvents, we found the release was substantially enhanced. The increased rate was linearly dependent on the lipid bilayer concentration and the dielectric value of the binary organic solvent mixtures. While lipid bilayers provided a low surrounding dielectricity to assist in drug release, there were no major conformational changes in the apo and holo forms of the carrier protein. In addition, the lifespan of the released enediyne chromophore was markedly extended through partitioning of the chromophore in the hydrophobic bilayer phase, and the lipid bilayer-stabilized enediyne chromophore significantly enhanced DNA cleavage in vitro. Collectively, we depicted how a lipid bilayer membrane efficiently enhanced dissociation of the enediyne chromophore through a hydrophobic sensing release mechanism and then acted as a protector of the released enediyne molecule until its delivery to the target DNA. The proposed membrane-assisted antibiotic release-transport model might signify a new dimension to our understanding of the modus operandi of the antitumor enediyne drugs. PMID- 20712298 TI - Salt-induced modulation of the pathway of amyloid fibril formation by the mouse prion protein. AB - To investigate how the heterogeneity inherent in the formation of worm-like amyloid fibrils by the mouse prion protein is modulated by a change in aggregation conditions, as well as to determine how heterogeneity in reaction leads to heterogeneity in structure, the amyloid fibril formation reaction of the protein at low pH was studied in the presence of various salts. It is shown that beta-rich oligomers of different sizes and structures are formed at low and high NaCl concentrations, as determined by Fourier transfer infrared (FTIR) spectroscopy and dynamic light scattering (DLS). The worm-like fibrils formed from the beta-rich oligomers at low and high NaCl concentrations also differ in their internal structure, as determined by FTIR measurements. The apparent rate constant for the formation of the worm-like amyloid fibrils shows a very steep sigmoidal dependence on NaCl concentration, suggesting that the effect occurs because of the binding of many ions. The effect of salt in modulating the kinetics of worm-like fibril formation occurs at ionic strengths below 200 mM, over different concentration ranges for different salts, and is shown to depend not only on the ionic strength but also on the nature of the anion. The ability of different anions to promote worm-like fibril formation does not follow the Hofmeister series but instead follows the electroselectivity series for anion binding. Hence, it appears that the effect of salt is because of the linkage of the aggregation reaction to anion binding to the protein. A comparison of the apparent rate constants measured from the changes in thioflavin T fluorescence, circular dichroism, and DLS, which occur during worm-like fibril formation, suggests that conformational conversion follows fibril elongation at low NaCl concentration and follows fibril formation at high NaCl concentration. PMID- 20712300 TI - New protocol for oligonucleotide microarray fabrication using SU-8-coated glass microslides. AB - Microarray technology has become an important tool for detection and analysis of nucleic acid targets. Immobilization of modified and unmodified oligonucleotides on epoxy-functionalized glass surfaces is often used in microarray fabrication. Here, we demonstrate a protocol that employs coating of SU-8 (glycidyl ether of bisphenol A) onto glass microslides to obtain high density of epoxy functions for efficient immobilization of aminoalkyl-, thiophosphoryl-, and phosphorylated oligonucleotides with uniform spot morphology. The resulting microarrays exhibited high immobilization (~65%) and hybridization efficiency (30-36%) and were sufficiently stable over a range of temperature and pH conditions. The prominent feature of the protocol is that spots can be visualized distinctly at 0.05 MUM probe (a 20-mer oligonucleotide) concentration. The constructed microarrays were subsequently used for detection of base mismatches and bacterial diseases (meningitis and typhoid). PMID- 20712299 TI - Cysteine sulfenic acid as an intermediate in disulfide bond formation and nonenzymatic protein folding. AB - As a posttranslational protein modification, cysteine sulfenic acid (Cys-SOH) is well established as an oxidative stress-induced mediator of enzyme function and redox signaling. Data presented herein show that protein Cys-SOH forms spontaneously in air-exposed aqueous solutions of unfolded (disulfide-reduced) protein in the absence of added oxidizing reagents, mediating the oxidative disulfide bond formation process key to in vitro, nonenzymatic protein folding. Molecular oxygen (O(2)) and trace metals [e.g., copper(II)] are shown to be important reagents in the oxidative refolding process. Cys-SOH is also shown to play a role in spontaneous disulfide-based dimerization of peptide molecules containing free cysteine residues. In total, the data presented expose a chemically ubiquitous role for Cys-SOH in solutions of free cysteine-containing protein exposed to air. PMID- 20712301 TI - Regioselective synthesis of 1-bromo-1,4-dienes by free-radical-mediated bromoallylation of activated acetylenes. AB - The free-radical-mediated bromoallylation of acetylenes proceeded efficiently in the presence of V-65 (2,2-azobis(2,4-dimethylvaleronitrile)) as the radical initiator. The regioselective reaction, which yields 1-bromo-2-substituted 1,4 dienes, is complementary to the Pd-catalyzed bromoallylation reaction previously reported by Kaneda. The products of the free-radical-mediated bromoallylation of acetylenes could be converted into a variety of substituted dienes by subsequent Pd-catalyzed reactions. PMID- 20712302 TI - Synthesis of sulfuric macrocycles and a rotaxane through thiol-yne click and dithiol coupling reactions. AB - A macrocycle and a rotaxane were constructed by virtue of the thiol-yne click reaction under the irradiation of light in high yield, which can proceed at ambient temperature and humidity under an air atmosphere. Two disulfide macrocycles were synthesized through a simple dithiol coupling reaction, which exhibited high stability and a weak assembly interaction with a dialkylammonium ion. PMID- 20712303 TI - Substituted pyrroles via olefin cross-metathesis. AB - Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-gamma-aminoenones. When exposed to either acid or Heck arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this chemistry is demonstrated by its application to the tetrasubstituted pyrrole subunit of Atorvastatin. PMID- 20712304 TI - Total synthesis and anticancer activities of (-)- and (+)-thespesone. AB - The natural p-naphthoquinone (-)-thespesone 1 and its (+)-enantiomer were synthesized for the first time by bisacylation of a 5-lithiodihydrobenzofuran 2' with 4-methyl-3-tert-butoxycyclobut-3-ene-1,2-dione 3. The racemate of the required 2-arylpropan-1-ol precursor 10 was kinetically resolved by an enzyme catalyzed acetylation exclusively of the (S)-enantiomer. Saponification of this acetate mediated by the same enzyme, porcine pancreas lipase (PPL), afforded the (S)-2-arylpropan-1-ol in 96% ee. Its unreacted (R)-enantiomer could be obtained with 77% ee. (-)-(S)-thespesone was far more efficacious against a panel of six cancer cell lines including multiresistant ones than its (+)-enantiomer and also when compared to thymoquinone, an established natural antitumoral p-quinone from Nigella sativa. Unlike the latter, (-)-thespesone was well tolerated by nonmalignant fibroblasts. PMID- 20712305 TI - A solid-state (17)O NMR study of L-tyrosine in different ionization states: implications for probing tyrosine side chains in proteins. AB - We report experimental characterization of (17)O quadrupole coupling (QC) and chemical shift (CS) tensors for the phenolic oxygen in three l-tyrosine (l-Tyr) compounds: l-Tyr, l-Tyr.HCl, and Na(2)(l-Tyr). This is the first time that these fundamental (17)O NMR tensors are completely determined for phenolic oxygens in different ionization states. We find that, while the (17)O QC tensor changes very little upon phenol ionization, the (17)O CS tensor displays a remarkable sensitivity. In particular, the isotropic (17)O chemical shift increases by approximately 60 ppm upon phenol ionization, which is 6 times larger than the corresponding change in the isotropic (13)C chemical shift for the C(zeta) nucleus of the same phenol group. By examining the CS tensor orientation in the molecular frame of reference, we discover a "cross-over" effect between delta(11) and delta(22) components for both (17)O and (13)C CS tensors. We demonstrate that the knowledge of such "cross-over" effects is crucial for understanding the relationship between the observed CS tensor components and chemical bonding. Our results suggest that solid-state (17)O NMR can potentially be used to probe the ionization state of tyrosine side chains in proteins. PMID- 20712306 TI - Structural relationships in 2,3-bis-n-decyloxyanthracene and 12-hydroxystearic acid molecular gels and aerogels processed in supercritical CO(2). AB - Supercritical carbon dioxide is used to prepare aerogels of two reference molecular organogelators, 2,3-bis-n-decyloxyanthracene (DDOA) (luminescent molecule) and 12-hydroxystearic acid (HSA). Electron microscopy reveals the fibrillar morphology of the aggregates generated by the protocol. SAXS and SANS measurements show that DDOA aerogels are crystalline materials exhibiting three morphs: (1) arrangements of the crystalline solid (2D p6m), (2) a second hexagonal morph slightly more compact, and (3) a packing specific of the fibers in the gel. Aggregates specific of the aerogel (volume fraction being typically phi approximately 0.60) are developed over larger distances (approximately 1000 A) and bear fewer defaults and residual strains than aggregates in the crystalline and gel phases. Porod, Scherrer and Debye-Bueche analyses of the scattering data have been performed. The first five diffraction peaks show small variations in position and intensity assigned to the variation of the number of fibers and their degree of vicinity within hexagonal bundles of the related SAFIN according to the Oster model. Conclusions are supported by the guidelines offered by the analysis of the situation in HSA aerogels for which the diffraction pattern can be described by two coexisting lamellar-like arrangements. The porosity of the aerogel, as measured by its specific surface extracted from the scattering invariant analysis, is only 1.8 times less than that of the swollen gel and is characteristic of a very porous material. PMID- 20712307 TI - NMR relaxation and self-diffusion study at high and low magnetic fields of ionic association in protic ionic liquids. AB - NMR relaxation and diffusion characterization of several protic ionic liquids at high and low magnetic fields are reported. The dynamics of cations and anions were similar at both frequencies, with similar trends and magnitudes for a fixed component paired with oppositely charged species. An Arrhenius relationship was displayed between the molecular motion and the glass transition temperature. The diffusion of ions showed a strong degree of ion correlation between cation and anion, and Arrhenius plots of relaxation and diffusion indicated that the ions diffused as a pair. At high field diffusion was dominated by mobile species that followed Stokes-Einstein behavior. Conversely, diffusion observed at low field emphasized relatively immobile species that displayed fractional Stokes-Einstein behavior. No evidence was found to indicate the influence of magnetic field on structural and dynamic properties of the studied ILs; however, variation between diffusion coefficients at different magnetic fields indicated dynamic heterogeneities (or temporal aggregates) within the ionic liquid. PMID- 20712308 TI - De novo design of peptide-calcite biomineralization systems. AB - Many organisms produce complex, hierarchically structured, inorganic materials via protein-influenced crystal growth--a process known as biomineralization. Understanding this process would shed light on hard-tissue formation and guide efforts to develop biomaterials. We created and tested a computational method to design protein-biomineralization systems. The algorithm folds a protein from a fully extended structure and simultaneously optimizes the fold, orientation, and sequence of the protein adsorbed to a crystal surface. We used the algorithm to design peptides (16 residues) to modify calcite (CaCO(3)) crystallization. We chemically synthesized six peptides that were predicted to bind different states of a calcite growth plane. All six peptides dramatically affected calcite crystal growth (as observed by scanning electron microscopy), and the effects were dependent on the targeted state of the {001} growth plane. Additionally, we synthesized and assayed scrambled variants of all six designed peptides to distinguish cases where sequence composition determines the interactions versus cases where sequence order (and presumably structure) plays a role. Scrambled variants of negatively charged peptides also had dramatic effects on calcite crystallization; in contrast, scrambled variants of positively charged peptides had a variable effect on crystallization, ranging from dramatic to mild. Special emphasis is often placed on acidic protein residues in calcified tissue mineralization; the work presented here suggests an important role for basic residues as well. In particular, this work implicates a potential role for basic residues in sequence-order specificity for peptide-mineral interactions. PMID- 20712309 TI - Quantized folding of plasmid DNA condensed with block catiomer into characteristic rod structures promoting transgene efficacy. AB - Highly regulated folding of plasmid DNA (pDNA) through polyion complexation with the synthetic block catiomer, poly(ethylene glycol)-block-poly(L-lysine) (PEG PLys), was found to occur in such a way that rod structures are formed with a quantized length of 1/2(n + 1) of the original pDNA length folding by n times. The folding process of pDNA was elucidated with regard to rigidity of the double stranded DNA structure and topological restriction of the supercoiled closed circular form, and a mechanism based on Euler's buckling theory was proposed. Folded pDNA exhibited higher gene expression efficiency compared to naked pDNA in a cell-free transcription/translation assay system, indicating that the packaging of pDNA into a polyion complex core surrounded by a PEG palisade is a promising strategy for constructing nonviral gene carrier systems. Extension of this finding may provide a reasonable model to further understand the packaging mechanism of supercoiled DNA structures in nature. PMID- 20712310 TI - Indium-mediated catalytic enantioselective allylation of N-benzoylhydrazones using a protonated chiral amine. AB - A catalytic enantioselective indium-mediated allylation of N-benzoylhydrazones in conjunction with a protonated chiral amine affording enantioenriched homoallylic amines with an extremely high level of enantioselectivity and chemical yield was developed. PMID- 20712311 TI - Antifreeze glycoprotein activity correlates with long-range protein-water dynamics. AB - Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) enable the survival of organisms living in subfreezing habitats and serve as preservatives. Although their function is known, the underlying molecular mechanism was not understood. Mutagenesis experiments questioned the previous assumption of hydrogen bonding as the dominant mechanism. We use terahertz spectroscopy to show that antifreeze activity is directly correlated with long-range collective hydration dynamics. Our results provide evidence for a new model of how AFGPs prevent water from freezing. We suggest that antifreeze activity may be induced because the AFGP perturbs the aqueous solvent over long distances. Retarded water dynamics in the large hydration shell does not favor freezing. The complexation of the carbohydrate cis-hydroxyl groups by borate suppresses the long-range hydration shell detected by terahertz absorption. The hydration dynamics shift toward bulk water behavior strongly reduces the AFGP antifreeze activity, further supporting our model. PMID- 20712312 TI - Iron(II)-thiolate S-oxygenation by O2: synthetic models of cysteine dioxygenase. AB - The synthesis of structural and functional models of the active site of the nonheme iron enzyme cysteine dioxygenase (CDO) is reported. A bis(imino)pyridine ligand scaffold was employed to synthesize a mononuclear ferrous complex, Fe(II)(LN(3)S)(OTf) (1), which contains three neutral nitrogen donors and one anionic thiolato donor. Complex 1 is a good structural model of the Cys-bound active site of CDO. Reaction of 1 with O(2) results in oxygenation of the thiolato sulfur, affording the sulfonato complex Fe(II)(LN(3)SO(3))(OTf) (2) under mild conditions. Isotope labeling studies show that O(2) is the sole source of O atoms in the product and that the reaction proceeds via a dioxygenase-type mechanism for two out of three O atoms added, analogous to the dioxygenase reaction of CDO. The zinc(II) analog, Zn(LN(3)S)(OTf) (4), was prepared and found to be completely unreactive toward O(2), suggesting a critical role for Fe(II) in the oxygenation chemistry observed for 1. To our knowledge, S-oxygenation mediated by an Fe(II)-SR complex and O(2) is unprecedented. PMID- 20712314 TI - Rhodium-catalyzed oxidative C-H arylation of 2-arylpyridine derivatives via decarbonylation of aromatic aldehydes. AB - A new concept for aryl-aryl coupling that involves oxidative decarbonylative coupling of aryl C-H bonds and readily available aldehydes has been developed, achieving the aryl-aryl union with complete control of reaction sites. PMID- 20712313 TI - High-fidelity hydrophilic probe for two-photon fluorescence lysosomal imaging. AB - The synthesis and characterization of a novel two-photon-absorbing fluorene derivative, LT1, selective for the lysosomes of HCT 116 cancer cells, is reported. Linear and nonlinear photophysical and photochemical properties of the probe were investigated to evaluate the potential of the probe for two-photon fluorescence microscopy (2PFM) lysosomal imaging. The cytotoxicity of the probe was investigated to evaluate the potential of using this probe for live two photon fluorescence biological imaging applications. Colocalization studies of the probe with commercial Lysotracker Red in HCT 116 cells demonstrated the specific localization of the probe in the lysosomes with an extremely high colocalization coefficient (0.96). A figure of merit was introduced to allow comparison between probes. LT1 has a number of properties that far exceed those of commercial lysotracker probes, including higher two-photon absorption cross sections, good fluorescence quantum yield, and, importantly, high photostability, all resulting in a superior figure of merit. 2PFM was used to demonstrate lysosomal tracking with LT1. PMID- 20712315 TI - Atomic structure of Au-Pd bimetallic alloyed nanoparticles. AB - Using a two-step seed-mediated growth method, we synthesized bimetallic nanoparticles (NPs) having a gold octahedron core and a palladium epitaxial shell with controlled Pd-shell thickness. The mismatch-release mechanism between the Au core and Pd shell of the NPs was systematically investigated by high-resolution transmission electron microscopy. In the NPs coated with a single atomic layer of Pd, the strain between the surface Pd layer and the Au core is released by Shockley partial dislocations (SPDs) accompanied by the formation of stacking faults. For NPs coated with more Pd (>2 nm), the stacking faults still exist, but no SPDs are found. This may be due to the diffusion of Au atoms into the Pd shell layers to eliminate the SPDs. At the same time, a long-range ordered L1(1) AuPd alloy phase has been identified in the interface area, supporting the assumption of the diffusion of Au into Pd to release the interface mismatch. With increasing numbers of Pd shell layers, the shape of the Au-Pd NP changes, step by step, from truncated-octahedral to cubic. After the bimetallic NPs were annealed at 523 K for 10 min, the SPDs at the surface of the NPs coated with a single atomic layer of Pd disappeared due to diffusion of the Au atoms into the surface layer, while the stacking faults and the L1(1) Au-Pd alloyed structure remained. When the annealing temperature was increased to 800 K, electron diffraction patterns and diffraction contrast images revealed that the NPs became a uniform Au-Pd alloy, and most of the stacking faults disappeared as a result of the annealing. Even so, some clues still support the existence of the L1(1) phase, which suggests that the L1(1) phase is a stable, long-range ordered structure in Au-Pd bimetallic NPs. PMID- 20712316 TI - Synthesis of monodispersed wurtzite structure CuInSe2 nanocrystals and their application in high-performance organic-inorganic hybrid photodetectors. AB - A new facile solution method for the synthesis of high-quality CuInSe(2) nanocrystals with monodispersed size and uniform hexagonal shape was developed. A high-performance hybrid photodetector based on a hybrid film of CuInSe(2) nanocrystals and poly(3-hexylthiophene) was constructed. The device showed distinct "ON" and "OFF" states with a ratio of >100 in photocurrents responding to outside illumination. The high sensitivity and stability of the hybrid device revealed a broad prospect for use of the hybrid material in light detection and signal magnification for the development of large-area, low-cost, lightweight, and foldable products. PMID- 20712318 TI - Effect of methyl jasmonate in combination with ethanol treatment on postharvest decay and antioxidant capacity in Chinese bayberries. AB - The effects of methyl jasmonate (MeJA) in combination with ethanol (EtOH) treatment on green mold rot caused by Penicillium citrinum , natural decay, and antioxidant capacity in harvested Chinese bayberries were investigated. MeJA at 10 micromol L(-1) in combination with EtOH at 22.32 micromol L(-1) was most effective in reducing green mold rot and natural decay. This combined treatment also significantly inhibited spore germination and germ tube elongation of the pathogen in vitro compared with MeJA alone or control. Meanwhile, the combination treated bayberries exhibited highest reducing power, scavenging activities against superoxide, hydroxyl, and 1,1-diphenyl-2-picrylhydrazyl radicals, and contents of total phenolics, flavonoids, and anthocyanins as well as individual phenolic compounds. Fruit quality parameters were not significantly affected by these treatments. These results suggest that the combination of MeJA and EtOH had an additive effect in reducing postharvest decay and improving antioxidant capacity in Chinese bayberries. PMID- 20712319 TI - Gene expression enabling synthetic diversification of natural products: chemogenetic generation of pacidamycin analogs. AB - Introduction of prnA, the halogenase gene from pyrrolnitrin biosynthesis, into Streptomyces coeruleorubidus resulted in efficient in situ chlorination of the uridyl peptide antibotic pacidamycin. The installed chlorine provided a selectably functionalizable handle enabling synthetic modification of the natural product using mild cross-coupling conditions in crude aqueous extracts of the culture broth. PMID- 20712321 TI - Simultaneous determination of 346 multiresidue pesticides in grapes by PSA-MSPD and GC-MS-SIM. AB - The article demonstrates a method of simultaneous determination for 352 pesticide residues in grapes using primary-secondary amine (PSA) matrix solid phase dispersion (MSPD) cleanup and gas chromatography-mass spectrometry-selected ion monitoring (GC-MS-SIM). Grape samples (15 g) were mixed with 6 g of anhydrous magnesium sulfate and 1.5 g of sodium chloride, and then extracted with acetonitrile (15 mL) and cleaned up with 0.3 g of dispersive PSA. The analytes were determined by GC-MS-SIM. Four injections for one sample were acquired to cover a total of 352 pesticides. The limit of detection (LOD) for the method was 0.0017-0.2667 mg kg(-1), depending on the nature of compounds. The linear correlation coefficient (r) was equal to or greater than 0.95; at low, medium, and high fortification levels, recoveries ranged from 45% to 136% for 352 pesticides, among which the recoveries between 60%-120% accounted for 97%. The pesticides for which the relative standard deviations (RSD) were equal to or below 20% accounted for 95%. A positive of nine varieties of grape samples was detected out, one of which was abtained Changli city, Hebei province, China. Pesticides were identified by the retention time, molecule ions, fragment ions, and the abundance ratio of the selected ions. The analytical method was rugged, quick, cheap and effective, and suitable for the determination of a wide scope of 346 pesticides in grapes. PMID- 20712320 TI - Facile C-H bond cleavage via a proton-coupled electron transfer involving a C H...Cu(II) interaction. AB - The present study provides mechanistic details of a mild aromatic C-H activation effected by a copper(II) center ligated in a triazamacrocylic ligand, affording equimolar amounts of a Cu(III)-aryl species and Cu(I) species as reaction products. At low temperatures the Cu(II) complex 1 forms a three-center, three electron C-H...Cu(II) interaction, identified by pulse electron paramagnetic resonance spectroscopy and supported by density functional theory calculations. C H bond cleavage is coupled with copper oxidation, as a Cu(III)-aryl product 2 is formed. This reaction proceeds to completion at 273 K within minutes through either a copper disproportionation reaction or, alternatively, even faster with 1 equiv of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), quantitatively yielding 2. Kinetic studies of both reactions strongly implicate a rate-limiting proton coupled electron transfer as the key C-H activation step, a mechanism that does not conform to the C-H activation mechanism in a Ni(II) analogue or to any previously proposed C-H activation mechanisms. PMID- 20712322 TI - New approaches to prepare hydride silica. AB - Two synthetic schemes to produce a hydride-modified support that serves as an intermediate for the preparation of bonded phases for liquid chromatography (LC) and capillary electrophoresis (CE) are investigated. The strategies differ in the silane reagent utilized (trichlorosilane (TCS) or triethoxysilane (TES)) and the manner water is incorporated into the reaction. In the first approach, TCS in toluene reacts with a previously humidified silica substrate so that the reaction is confined to the silica surface. In the second approach, TES and a small amount of aqueous HCl are dissolved in THF, and this hydrolysate is diluted by a great factor in cyclohexane, prior to reaction with the silica substrate. Atomic force microscopy (AFM) images of the hydride film on wafers revealed that, unlike the traditional approach that produced a patchy coating, both new methods provided a homogeneous layer on the substrate's surface. IR and NMR spectra from porous silica particles clearly confirmed a successful surface modification. AFM and water contact angles (WCA) were used to examine the effect of dilution of the TES hydrolysate in cyclohexane on the trend of the film to polymerize on wafers and found that a dilution factor of at least 100 is required to attain a molecularly thin hydride layer. WCA and CE also revealed a strong susceptibility of the hydride silica intermediate to hydrolyze, even at low pH. Compared to TCS, the lower reactivity and volatility of TES resulted in a much more desirable experimental approach. PMID- 20712323 TI - Direct voltammetric detection of DNA and pH sensing on epitaxial graphene: an insight into the role of oxygenated defects. AB - In this paper, we carried out detailed electrochemical studies of epitaxial graphene (EG) using inner-sphere and outer-sphere redox mediators. The EG sample was anodized systematically to investigate the effect of edge plane defects on the heterogeneous charge transfer kinetics and capacitive noise. We found that anodized EG, consisting of oxygen-related defects, is a superior biosensing platform for the detection of nucleic acids, uric acids (UA), dopamine (DA), and ascorbic acids (AA). Mixtures of nucleic acids (A, T, C, G) or biomolecules (AA, UA, DA) can be resolved as individual peaks using differential pulse voltammetry. In fact, an anodized EG voltammetric sensor can realize the simultaneous detection of all four DNA bases in double stranded DNA (dsDNA) without a prehydrolysis step, and it can also differentiate single stranded DNA from dsDNA. Our results show that graphene with high edge plane defects, as opposed to pristine graphene, is the choice platform in high resolution electrochemical sensing. PMID- 20712324 TI - Mesoporous TiO(2) nanocrystal clusters for selective enrichment of phosphopeptides. AB - Protein phosphorylation plays a key role in most cellular processes. Studying phosphopeptides in complex biological samples has been a great challenge due to their low abundance as well as the coexistence of excessive amounts of salts or surfactants. In this work we demonstrate a general approach for selective separation of phosphopeptides using a class of novel mesoporous nanostructured materials. TiO(2) nanocrystals are first self-assembled into submicrometer clusters containing relatively uniform mesoscale pores and then stabilized by coating with a thin layer of silica. Calcination of the materials at high temperatures connects the neighboring nanocrystals together and enhances the mechanical stability of the clusters and at the same time removes the organic surfactants and makes the TiO(2) surface fully accessible to phosphopeptides. By coating the nanocrystal clusters with a layer of silica before calcination and removing it afterward through chemical etching, we have been able to make the cluster surface hydrophilic and negatively charged, thus enhancing the water dispersibility of the clusters and eventually their accessibility to phosphopeptides. The high selectivity and capacity of these mesoporous TiO(2) clusters have been demonstrated by effectively enriching phosphopeptides from digests of phosphoprotein (alpha- or beta-casein), protein mixtures of beta casein and bovine serum albumin, milk, and human serum samples. We also demonstrate that the self-assembly process brings the flexibility of incorporation of multiple components, such as superparamagnetic nanocrystals, to further facilitate the peptide separation. PMID- 20712326 TI - Cohesive force change induced by polyperoxide degradation for application to dismantlable adhesion. AB - Polyperoxides containing peroxy bonds as the main-chain repeating units are a new class of degradable polymers because of significant changes in their molecular weight and physical properties during a degradation process. In this study, the application of linear and network polyperoxides to dismantlable adhesion was investigated. When the linear polyperoxide obtained from methyl sorbate and oxygen (PP-MS) was used as a pressure-sensitive adhesive (PSA), its shear holding power and 180 degrees peel strength immediately decreased upon heating at 70 degrees C or under UV irradiation. Low-molecular-weight products, which were generated by the degradation of PP-MS, behaved as a plasticizer to effectively reduce the cohesive force. The adhesive properties of two types of polyperoxides based network polymers, the cross-linking point and main-chain degradable network polymers, were evaluated. A cross-linking point degradable network polymer was produced by the oxygen cross-linking of dienyl-functionalized poly(ethylene glycol). A main-chain degradable network polymer was formed by the diisocyanate cross-linking of a hydroxy-functionalized polyperoxide. Both network polymers showed a higher adhesive strength than PP-MS due to their three-dimensional network structure. Noteworthy, the adhesive strength of the main-chain degradable network polymer was varied from the level of PSA to structural adhesives by increasing the added amount of the diisocyanate cross-linker. After heating at 110 degrees C, the cohesive and adhesive strengths significantly decreased. The linear and network polyperoxides are shown to be promising materials for dismantlable adhesion. PMID- 20712325 TI - Analysis of isoaspartic Acid by selective proteolysis with Asp-N and electron transfer dissociation mass spectrometry. AB - A ubiquitous yet underappreciated protein post-translational modification, isoaspartic acid (isoAsp, isoD, or beta-Asp), generated via the deamidation of asparagine or isomerization of aspartic acid in proteins, plays a diverse and crucial role in aging, as well as autoimmune, cancer, neurodegeneration, and other diseases. In addition, formation of isoAsp is a major concern in protein pharmaceuticals, as it may lead to aggregation or activity loss. The scope and significance of isoAsp have, up to now, not been fully explored, as an unbiased screening of isoAsp at low abundance remains challenging. This difficulty is due to the subtle difference in the physicochemical properties between isoAsp and Asp, e.g., identical mass. In contrast, endoprotease Asp-N (EC 3.4.24.33) selectively cleaves aspartyl peptides but not the isoaspartyl counterparts. As a consequence, isoaspartyl peptides can be differentiated from those containing Asp and also enriched by Asp-N digestion. Subsequently, the existence and site of isoaspartate can be confirmed by electron transfer dissociation (ETD) mass spectrometry. As little as 0.5% of isoAsp was detected in synthetic beta-amyloid and cytochrome c peptides, even though both were initially assumed to be free of isoAsp. Taken together, our approach should expedite the unbiased discovery of isoAsp. PMID- 20712327 TI - Virtual screening of selective multitarget kinase inhibitors by combinatorial support vector machines. AB - Multitarget agents have been increasingly explored for enhancing efficacy and reducing countertarget activities and toxicities. Efficient virtual screening (VS) tools for searching selective multitarget agents are desired. Combinatorial support vector machines (C-SVM) were tested as VS tools for searching dual inhibitors of 11 combinations of 9 anticancer kinase targets (EGFR, VEGFR, PDGFR, Src, FGFR, Lck, CDK1, CDK2, GSK3). C-SVM trained on 233-1,316 non-dual-inhibitors correctly identified 26.8%-57.3% (majority >36%) of the 56-230 intra-kinase-group dual-inhibitors (equivalent to the 50-70% yields of two independent individual target VS tools), and 12.2% of the 41 inter-kinase-group dual-inhibitors. C-SVM were fairly selective in misidentifying as dual-inhibitors 3.7%-48.1% (majority <20%) of the 233-1,316 non-dual-inhibitors of the same kinase pairs and 0.98% 4.77% of the 3,971-5,180 inhibitors of other kinases. C-SVM produced low false hit rates in misidentifying as dual-inhibitors 1,746-4,817 (0.013%-0.036%) of the 13.56 M PubChem compounds, 12-175 (0.007%-0.104%) of the 168 K MDDR compounds, and 0-84 (0.0%-2.9%) of the 19,495-38,483 MDDR compounds similar to the known dual-inhibitors. C-SVM was compared to other VS methods Surflex-Dock, DOCK Blaster, kNN and PNN against the same sets of kinase inhibitors and the full set or subset of the 1.02 M Zinc clean-leads data set. C-SVM produced comparable dual inhibitor yields, slightly better false-hit rates for kinase inhibitors, and significantly lower false-hit rates for the Zinc clean-leads data set. Combinatorial SVM showed promising potential for searching selective multitarget agents against intra-kinase-group kinases without explicit knowledge of multitarget agents. PMID- 20712328 TI - Correlation between structural and semiconductor-metal changes and extreme conditions materials chemistry in Ge-Sn. AB - High pressure and temperature experiments on Ge-Sn mixtures to 24 GPa and 2000 K reveal segregation of Sn from Ge below 10 GPa whereas Ge-Sn agglomerates persist above 10 GPa regardless of heat treatment. At 10 GPa Ge reacts with Sn to form a tetragonal P4(3)2(1)2 Ge(0.9)Sn(0.1) solid solution on recovery, of interest for optoelectronic applications. Using electron diffraction and scanning electron microscopy measurements in conjunction with a series of tailored experiments promoting equilibrium and kinetically hindered synthetic conditions, we provide a step by step correlation between the semiconductor-metal and structural changes of the solid and liquid states of the two elements, and whether they segregate, mix or react upon compression. We identify depletion zones as an effective monitor for whether the process is moving toward reaction or segregation. This work hence also serves as a reference for interpretation of complex agglomerates and for developing successful synthesis conditions for new materials using extremes of pressure and temperature. PMID- 20712329 TI - Using the voids. Evidence for an antenna effect in dye-sensitized mesoporous TiO2 thin films. AB - Composite structures of Ru(bpy)(2)(4,4'-(PO(3)H(2))(2)bpy)(2+) surface bound to nanocrystalline TiO(2) with an overlayer of Ru(bpy)(3)(2+) ion exchanged into Nafion, FTO|nanoTiO(2)-[Ru(bpy)(2)(4,4' (PO(3)H(2))(2)bpy)](2+)/Nafion,Ru(bpy)(3)(2+) (FTO = fluorine-doped tin oxide), have been prepared and characterized. Steady-state emission and time-resolved lifetime measurements demonstrate that energy transfer occurs from Nafion,Ru(bpy)(3)(2+*) to adsorbed Ru(bpy)(2)(4,4'-(PO(3)H(2))(2)bpy)(2+) with an efficiency of ~0.49. Energy transfer sensitizes photoinjection by the adsorbed metal-to-ligand charge transfer (MLCT) excited state by an "antenna effect." PMID- 20712330 TI - Adsorption of binary gas mixtures in heterogeneous carbon predicted by density functional theory: on the formation of adsorption azeotropes. AB - Classical density functional theory (DFT) was used to predict the adsorption of nine different binary gas mixtures in a heterogeneous BPL activated carbon with a known pore size distribution (PSD) and in single, homogeneous, slit-shaped carbon pores of different sizes. By comparing the heterogeneous results with those obtained from the ideal adsorbed solution theory and with those obtained in the homogeneous carbon, it was determined that adsorption nonideality and adsorption azeotropes are caused by the coupled effects of differences in the molecular size of the components in a gas mixture and only slight differences in the pore sizes of a heterogeneous adsorbent. For many binary gas mixtures, selectivity was found to be a strong function of pore size. As the width of a homogeneous pore increases slightly, the selectivity for two different sized adsorbates may change from being greater than unity to less than unity. This change in selectivity can be accompanied by the formation of an adsorption azeotrope when this same binary mixture is adsorbed in a heterogeneous adsorbent with a PSD, like in BPL activated carbon. These results also showed that the selectivity exhibited by a heterogeneous adsorbent can be dominated by a small number of pores that are very selective toward one of the components in the gas mixture, leading to adsorption azeotrope formation in extreme cases. PMID- 20712331 TI - Application of high surface area tin-doped indium oxide nanoparticle films as transparent conducting electrodes. AB - Metal complex derivatized, optically transparent nanoparticle films of Sn(IV) doped In(2)O(3) (nanoITO) undergo facile interfacial electron transfer allowing for rapid, potential controlled color changes, direct spectral (rather than current) monitoring of voltammograms, and multilayer catalysis of water oxidation. PMID- 20712332 TI - Study of conformation effects on the retention of small peptides in reversed phase chromatography by thermodynamic analysis and molecular dynamics simulation. AB - Chromatographic behavior of a small peptide in RP-HPLC can generally be correlated with the summation of the hydrophobic contribution from its composed amino acid residues. But this approach fails to predict the retention deviation between two sequence shuffled peptides. One set of 11-residue peptides was designed to study the conformation effect. The two sequence shuffled peptides had different conformations and showed different retention behaviors in a C18 column. The retention factors of the relatively helical peptide GELELKLKLEG (GELE) were consistently lower than those of the peptide GELKLELKLEG (GELK) at all conditions under investigation. All atom molecular dynamics (MD) simulation was performed to study the origin of the deviation in column retention. Circular dichroism spectra and MD simulation confirmed that the structure of GELE is more helical and the energy of GELE in solution is lower than that of GELK. The deformation energies calculated from MD described well the concentration effect on DeltaC(P) obtained from column retention data. After analyzing the desolvation, deformation, and interaction energies after the adsorption of these two sequence shuffled peptides on C18 self assembly monolayer (SAM), it was found that the longer retention of GELK in the column was not due to its higher accessibility toward the hydrophobic stationary phase. The structurally rigid peptide, i.e., the low potential energy one, owned a lower retention time because its ability to minimize the overall adsorption energy was limited. This result suggested that the overall potential energy of peptide in solution calculated from MD simulation may be used to quantify the conformation effect. PMID- 20712333 TI - Diastereoselective synthesis of 6-trifluoromethyl-5,6-dihydropyrans via phosphine catalyzed [4 + 2] annulation of alpha-benzylallenoates with ketones. AB - The highly diastereoselective synthesis of 6-trifluoromethyl-5,6-dihydropyrans was realized by the phosphine-catalyzed [4 + 2] annulation of ethyl alpha benzylallenoates and trifluoromethyl ketones. PMID- 20712334 TI - Searching for the Nik operon: how a ligand-responsive transcription factor hunts for its DNA binding site. AB - Transcription factors regulate a wide variety of genes in the cell and play a crucial role in maintaining cellular homeostasis. A major unresolved issue is how transcription factors find their specific DNA binding sequence in the vast expanse of the cell and how they do so at rates that appear faster than the diffusion limit. Here, we relate an atomic-detail model that has been developed to describe the transcription factor NikR's mechanism of DNA binding to the broader theories of how transcription factors find their binding sites on DNA. NikR is the nickel regulatory transcription factor for many bacteria, and NikR from Escherichia coli is one of the best studied ligand-mediated transcription factors. For the E. coli NikR protein, there is a wide variety of structural, biochemical, and computational studies that provide significant insight into the NikR-DNA binding mechanism. We find that the two models, the atomic-level model for E. coli NikR and the cellular model for transcription factors in general, are in agreement, and the details laid out by the NikR system may lend additional credence to the current models for transcription factors searching for DNA. PMID- 20712335 TI - Infrared spectra of a species of potential prebiotic and astrochemical interest: cyanoethenethiol (NC-CH=CH-SH). AB - Cyanoethenethiol (NC-CH=CH-SH) was obtained in a 8:1 Z:E ratio by flash vacuum thermolysis of the t-butylsulfide derivative. Density functional theory (DFT) and G3 ab initio calculations predict the existence of Z-and E-isomers, each of which exhibits two rotamers as a function of the relative position of the SH group. All these rotameric forms are planar (C(s) symmetry) and correspond to synperiplanar and antiperiplanar conformations. Calculations indicate that the synperiplanar Z isomer is the more stable. In pure form, the cyanoethenethiol rapidly decomposes at room temperature, even at low pressure and partially condenses on the wall of the cell. To record its spectrum, a long optical path of 136 m was necessary, and several successive fillings of the cell were required. On the basis of the calculated harmonic and anharmonic vibrational frequencies, a complete and unambiguous assignment of the experimental spectrum has been carried out. PMID- 20712336 TI - UV/thermally driven rewritable wettability patterns on TiO2-PDMS composite films. AB - Composite films of TiO2 and polydimethylsiloxane (PDMS) are prepared by a sol-gel method, cured with UV irradiation, and then treated in hot water to crystallize the TiO2 in the film. The presence of anatase TiO2 contributes to the photoinduced superhydrophilicity of the film under UV irradiation. Contact angle studies reveal that the TiO2-PDMS composite film recovers its original hydrophobic state. Hydrophobic-superhydrophilic patterns are successfully formed on the films. The wettability patterns can be erased by UV irradiation and thermal treatment. New wettability patterns can be reconstructed, demonstrating that the film exhibits rewritable wettability without the need for organic chemicals. PMID- 20712338 TI - Dissociation behavior of methane--ethane mixed gas hydrate coexisting structures I and II. AB - Dissociation behavior of methane-ethane mixed gas hydrate coexisting structures I and II at constant temperatures less than 223 K was studied with use of powder X ray diffraction and solid-state (13)C NMR techniques. The diffraction patterns at temperatures less than 203 K showed both structures I and II simultaneously convert to Ih during the dissociation, but the diffraction pattern at temperatures greater than 208 K showed different dissociation behavior between structures I and II. Although the diffraction peaks from structure II decreased during measurement at constant temperatures greater than 208 K, those from structure I increased at the initial step of dissociation and then disappeared. This anomalous behavior of the methane-ethane mixed gas hydrate coexisting structures I and II was examined by using the (13)C NMR technique. The (13)C NMR spectra revealed that the anomalous behavior results from the formation of ethane rich structure I. The structure I hydrate formation was associated with the dissociation rate of the initial methane-ethane mixed gas hydrate. PMID- 20712337 TI - Efficient marginalization to compute protein posterior probabilities from shotgun mass spectrometry data. AB - The problem of identifying proteins from a shotgun proteomics experiment has not been definitively solved. Identifying the proteins in a sample requires ranking them, ideally with interpretable scores. In particular, "degenerate" peptides, which map to multiple proteins, have made such a ranking difficult to compute. The problem of computing posterior probabilities for the proteins, which can be interpreted as confidence in a protein's presence, has been especially daunting. Previous approaches have either ignored the peptide degeneracy problem completely, addressed it by computing a heuristic set of proteins or heuristic posterior probabilities, or estimated the posterior probabilities with sampling methods. We present a probabilistic model for protein identification in tandem mass spectrometry that recognizes peptide degeneracy. We then introduce graph transforming algorithms that facilitate efficient computation of protein probabilities, even for large data sets. We evaluate our identification procedure on five different well-characterized data sets and demonstrate our ability to efficiently compute high-quality protein posteriors. PMID- 20712339 TI - Laserspray ionization-ion mobility spectrometry-mass spectrometry: baseline separation of isomeric amyloids without the use of solvents desorbed and Ionized directly from a surface. AB - The ability of laserspray ionization (LSI) to produce multiply charged ions by laser ablation from the solid state, directly from a surface, and at atmospheric pressure allows protein analysis on an ion mobility spectrometry (IMS)-mass spectrometry (MS) instrument (SYNAPT G2) having a mass-to-charge limit of 8000. The matrix, 2,5-dihydroxyacetophenone, lowers the thermal requirements for desolvation of matrix/analyte clusters to produce the highly charged LSI ions under gentle conditions to retain structural integrity of the proteins. Examples include cytochrome C and lysozyme. The solvent-free IMS gas-phase separation is used to baseline separate in the drift time dimension the isomeric solubility restricted beta-amyloid (1-42) from the reversed (42-1). The LSI process is shown to be sufficiently soft to preserve structural integrity and permit separation according to the different shapes. These results suggest that LSI-IMS-MS potentially combines speed of analysis and imaging capability common to matrix assisted laser desorption/ionization and multiple charging with the potential for structural analysis common to electrospray ionization. PMID- 20712340 TI - Modular elastic patches: mechanical and biological effects. AB - A modular approach to engineering cross-linked elastic biomaterials is presented for fine-tuning of material mechanical and biological properties. The three components, soluble elastin, hyaluronic acid, and silk fibroin, contribute with different features to the overall properties of the final material system. The elastic biomaterial is chemically cross-linked via interaction between primary amine groups naturally present on the two proteins, silk and elastin, or chemically introduced on hyaluronan and N-succinimide functionalities of the cross-linker. The materials obtained by cross-linking the three components in different ratios have Young's moduli ranging from ~ 100 to 230 kPa, strain to failure between ~ 15-40% and ultimate tensile strengths of ~ 30 kPa. The biological effects and enzymatic degradation rates of the different composites are also different based on material composition. These findings further underline the strength of modular, multicomponent systems in creating a range of biomaterials, targeted tissue engineering, and regenerative medicine applications, with application-tailored mechanical and biological properties. PMID- 20712341 TI - Rapid flexible docking using a stochastic rotamer library of ligands. AB - Existing flexible docking approaches model the ligand and receptor flexibility either separately or in a loosely coupled manner, which captures the conformational changes inefficiently. Here, we propose a flexible docking approach, MedusaDock, which models both ligand and receptor flexibility simultaneously with sets of discrete rotamers. We developed an algorithm to build the ligand rotamer library "on-the-fly" during docking simulations. MedusaDock benchmarks demonstrate a rapid sampling efficiency and high prediction accuracy in both self- (to the cocrystallized state) and cross-docking (to a state cocrystallized with a different ligand), the latter of which mimics the virtual screening procedure in computational drug discovery. We also perform a virtual screening test of four flexible kinase targets, including cyclin-dependent kinase 2, vascular endothelial growth factor receptor 2, HIV reverse transcriptase, and HIV protease. We find significant improvements of virtual screening enrichments when compared to rigid-receptor methods. The predictive power of MedusaDock in cross-docking and preliminary virtual-screening benchmarks highlights the importance to model both ligand and receptor flexibility simultaneously in computational docking. PMID- 20712342 TI - Postprocessing of protein-ligand docking poses using linear response MM-PB/SA: application to Wee1 kinase inhibitors. AB - Prediction of the binding strength of untested ligands is a central issue in structure-based drug design. In order to rapidly screen large compound databases, simple scoring schemes are often used in target-based virtual screening. The resulting scores often correlate poorly with biological affinities. More rigorous scoring methods, such as MM-PB/SA, correlate better with biological data by considering solvation effects and protein flexibility in the calculation of the binding free energy of a ligand. Here we describe the performance of a modified MM-PB/SA method on 222 Wee1 kinase inhibitors (48 pyridopyrimidine and 174 pyrrolocarbazole derivatives). Docking of these inhibitors into the available Wee1 kinase crystal structure yielded a consistent binding mode, and the derived MM-PB/SA models showed a significant correlation between calculated and experimental data (r(2) values between 0.64 and 0.67). Further study of these models on external test sets of Wee1 kinase inhibitors and structurally related decoys showed that a model based on a single kinase-inhibitor conformation can discriminate the active inhibitors from decoys. We also tested whether the linear interaction energy method with continuum electrostatics (LIECE) yields comparable results to MM-PB/SA and whether the LIECE and MM-PB/SA models can be applied for virtual screening of compound libraries. PMID- 20712343 TI - Theoretical investigations of the time-resolved photodissociation dynamics of IBr(-). AB - The role of laser pulse width as well as other quantum mechanical effects in the interpretation of the observed time-resolved photoelectron spectra (TRPES) of IBr(-) are investigated using conditions that are chosen to reproduce those used for the experimental study of Mabbs et al. [ J. Chem. Phys. 2005 , 122 , 174305 ]. In that study, it was shown that one could correlate shifts in the frequency of the maximum in signal as a function of time to differences between the potential energies of the electronic states that are accessed by the pump and probe lasers. While this classical picture is attractive, it is based on a single trajectory with an initial I-Br separation that is ~0.3 A longer than the equilibrium value. In addition, it does not include the role of the pulse widths and other possible quantum effects. In the present work, the six lowest energy electronic states of IBr(-) were calculated at the MR-SO-CISD/aug-cc-pVDZ level of theory/basis set as a function of the I-Br distance. The TRPES of IBr(-) were calculated in three pulse regimes: an infinitesimally short pulse, an intermediate pulse that has a temporal full width at half-maximum (fwhm) of 300 fs, which was chosen to match the experimental value, and one that is 3 times longer than the experimental value. The resulting spectra are qualitatively different, and the sources of these differences are discussed. The intermediate pulse provides very good agreement with experiment with the introduction of no adjustable parameters. The origins of the features of the experimental signal are discussed in terms of this fully quantum mechanical picture. PMID- 20712344 TI - Universal chemical gradient platforms using poly(methyl methacrylate) based on the biotin-streptavidin interaction for biological applications. AB - This article describes a simple method for the construction of a universal surface chemical gradient platform based on the biotin-streptavidin model. In this approach, surface chemical gradients were prepared in poly(methyl methacrylate) (PMMA), a biocompatible polymer, by a controlled hydrolysis procedure. The physicochemical properties of the resulting modified surfaces were extensively characterized. Chemical analysis carried out via time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) showed the formation of a smooth, highly controllable carboxylic acid gradient of increasing concentration along the sample surface. Atomic force microscopy (AFM) and contact angle (CA) results indicate that, in contrast with most of the chemical gradient methods published in the literature, the chemical modification of the polymer surface barely affects its physical properties. The introduction of carboxylic acid functionality along the surface was then used for biomolecule anchoring. For this purpose, the surface was activated and derivatized first with biotin and finally with streptavidin (SAV) in a directed orientation fashion. The SAV gradient was qualitatively assessed by fluorescence microscopy analysis and quantified by surface plasmon resonance (SPR) in order to establish a quantitative relationship between SAV surface densities and the surface location. The usefulness of the fabrication method described for biological applications was tested by immobilizing biotinylated bradykinin onto the SAV gradient. This proof-of-concept application shows the effectiveness of the concentration range of the gradient because the effects of bradykinin on cell morphology were observed to increase gradually with increasing drug concentrations. The intrinsic characteristics of the fabricated gradient platform (absence of physicochemical modifications other than those due to the biomolecules included) allow us to attribute cell behavior unequivocally to the biomolecule surface density changes. PMID- 20712345 TI - Reconstruction of conjugated oligoelectrolyte electron injection layers. AB - Surface reconstruction of electron injection layers based on conjugated oligoelectrolytes atop an electroluminescent layer occurs in the presence of air. The proposed mechanism involves hydration and concomitant increase of the interfacial energy with the underlying hydrophobic surface followed by dewetting via a nucleation process. No such changes are observed in the case of a conjugated polyelectrolyte, presumably because the lower mobility of the polymer chains leads to a kinetically locked bilayer. PMID- 20712346 TI - Discovery of pyridazinopyridinones as potent and selective p38 mitogen-activated protein kinase inhibitors. AB - The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats. PMID- 20712347 TI - Biotransformation of the diphenyl ether herbicide lactofen and purification of a lactofen esterase from Brevundimonas sp. LY-2. AB - The diphenyl ether herbicide lactofen is commonly used to control broadleaf weeds. Once released into the environment, this herbicide is subject to microbial reactions. This study describes the biotransformation of lactofen by Brevundimonas sp. LY-2 isolated from enrichment cultures inoculated with soil sample. This strain degraded about 80% of 50 mg L(-1) lactofen in 5 days of incubation in flasks. The metabolic behaviors of the herbicide in the media are described. The results show a transformation pathway of lactofen by the bacterium leading to the formation of 1-(carboxy)ethyl-5-(2-chloro-4 (trifluoromethyl)phenoxy)-2-nitrobenzoate and ethanol. An esterase, which could cleave the right ester bond of the alkanoic side chain of lactofen, was purified 113.3-fold to homogeneity with 6.83% recovery. The current results suggested that Brevundimonas sp. LY-2 degraded lactofen via the ester bond cleavage catalyzed by esterase. PMID- 20712349 TI - One pot hemimicellar synthesis of amphiphilic Janus gold nanoclusters for novel electronic attributes. AB - A one-pot hemimicellar synthesis of oriented, amphiphilic, and fluorescent Janus gold clusters, establishing the Janus character in terms of ligand asymmetry and distribution, has been demonstrated. The method was based on the efficient Langmuir strategy, where the in situ two-dimensional (2D) reduction of Au(3+) in the sprayed micellar electrostatic complex, TOA(+)-AuCl(4)(-), was accomplished by subphase tryptophan that acted as the hydrophilic protecting ligand on one hemisphere of the spherical gold cluster. In contrast to the reported micelle assisted Janus cluster formation, here the cluster growth occurred inside the surface pressure driven hemimicelles, which rapidly formed 2D cluster arrays without any interfacial reorientation. The Janus structure was validated using angle dependent polarized Fourier Transform Infrared Reflection-Absorption Spectroscopy (FT-IRRAS), where orientation dependent vibrational changes in the adsorbed ligand functionalities were detected. Electrochemical impedance measurements of the transferred Janus layers onto hydrophobized ITO revealed the heterogeneous electron transfer rate constant k(ET) to show a clear orientational odd-even parity effect with the odd layers showing much higher rates. Isobaric area relaxation investigations further evidenced toward a hemispherical instantaneous nucleation with edge growth mechanism of the nanoclusters formed at the tryptophan subphase. Surface pressure as a thermodynamic variable effectively controlled the interparticle separation; intercluster electron coupling exhibited insulator-metal transition in the Janus cluster monolayers through scanning electrochemical microscopy investigations. PMID- 20712350 TI - Drying of a solution in a meniscus: a model coupling the liquid and the gas phases. AB - A model simulating the drying of a solution in a meniscus in contact with a moving substrate is developed. It takes into account the hydrodynamics in the solution in the framework of the lubrication approximation, the vapor diffusion in the gas phase, and the variation of physical properties during drying. The free surface profile and spatial evaporation flux are not imposed a priori but result from the simulation of the mass transfer in the liquid/gas system (1.5 sided model). Several regimes are observed depending on the substrate velocity. For a large substrate velocity, the classical Landau-Levich regime is obtained. For smaller velocities, a drying front appears that is characterized by a strong concentration gradient and a peak in the evaporation flux. The coupling between the evaporation flux and the meniscus shape in this regime is analyzed. Another regime appears at a very low substrate velocity and seems to be driven by a competition between advection and diffusion. This macroscopic model simulates recent experimental results, namely, the dependence of the deposit thickness on the substrate velocity, which scales as 1/V in the regime dominated by evaporation. PMID- 20712348 TI - Electrospray droplet exposure to gaseous acids for the manipulation of protein charge state distributions. AB - The exposure of electrospray droplets to acid vapors can significantly affect protein charge state distributions (CSDs) derived from unbuffered solutions. Such experiments have been conducted by leaking acidic vapors into the counter-current nitrogen drying gas of an electrospray interface. On the basis of changes in protein CSDs, protein folding and unfolding phenomena are implicated in these studies. Additionally, noncovalently bound complexes are preserved, and transient intermediates are observed, such as high charge state ions of holomyoglobin. CSDs of proteins containing disulfide bonds shift slightly, if at all, with acid vapor leak-in, but when these disulfide bonds are reduced in solution, charge states higher than the number of basic sites (Lys, Arg, His, and N-terminus) are observed. Since there is no observed change in the CSD of buffered proteins exposed to acidic vapors, this novel multiple charging phenomenon is attributed to a pH effect. Thus, this acid vapor leak-in approach can be used to reverse "wrong-way-round" nanoelectrospray conditions by altering solution pH in the charged droplets relative to the pH in bulk solution. In general, the exposure of electrospray droplets to acidic vapors provides means for altering protein CSDs independent of bulk unbuffered solution pH. PMID- 20712351 TI - Manipulation of the elastic modulus of polymers at the nanoscale: influence of UV ozone cross-linking and plasticizer. AB - The mechanical stability of polymeric nanostructures is critical to the processing, assembly, and performance of numerous existing and emerging technologies. A key predictor of mechanical stability is the elastic modulus. However, a significant reduction in modulus has been reported for thin films and nanostructures when the thickness or size of the polymer material decreases below a critical length scale. Routes to mitigate or even eliminate this reduction in modulus, and thus enhancing the mechanically stability of polymeric nanostructures, would be extremely valuable. Here, two routes to modulate the mechanical properties of polymers at the nanoscale are described. Exposure to ultraviolet light and ozone (UVO) cross-links the near surface region of high molecular mass PS films, rendering the elastic modulus independent of thickness. However, UVO cannot eliminate the decrease in modulus of low molecular mass PS or PMMA due to limited reaction depth and photodegradation, respectively. Alternatively, the thickness dependence of the elastic modulus of both PS and PMMA can be eliminated by addition of dioctyl phthalate (DOP) at 5% by mass. Furthermore, an increase in modulus is observed for films with thicknesses less than 30 nm with 5% DOP by mass in comparison to neat PS. Although DOP acts as a plasticizer for both PS and PMMA in the bulk, evidence indicates that DOP acts as an antiplasticizer at the nanoscale. By maintaining or even increasing the elastic modulus of polymers at the nanoscale, these methods could lead to improved stability of polymeric nanostructures and devices. PMID- 20712352 TI - Creating biomimetic polymeric surfaces by photochemical attachment and patterning of dextran. AB - In this work, we report the preparation of photoactive dextran and demonstrate its utility by photochemically attaching it onto various polymeric substrates. The attachment of homogeneous and patterned dextran films was performed on polyurethane and polystyrene, with detailed analysis of surface morphology, swelling behavior, and the protein resistance of these substrates. The described photoactive dextran and attachment procedure is applicable to a wide variety of substrates while accommodating surfaces with complex surface geometries. Dextran with azide content between 22 and 0.3 wt % was produced by esterification with p azidobenzoic acid. Dextran (1.2 wt % azide) was photografted onto plasma oxidized polyurethane and polystyrene and displayed thicknesses of 5 +/- 3 and 7 +/- 3 nm, respectively. The patterned dextran on oxidized polyurethane was patchy with a nominal height difference between dextranized and nondextranized regions. The azidated dextran on oxidized polystyrene exhibited a distinct step in height. In the presence of phosphate buffered saline (PBS), the dextranized regions became smoother and more uniform without affecting the height difference at the oxidized polyurethane boundary. However, the dextranized regions on oxidized polyurethane were observed to swell by a factor of 3 relative to the dried thickness. These dissimilarities were attributed to hydrogen bonding between the dextran and oxidized polyurethane and were confirmed by the photoimmobiliization in the presence of LiCl. The resulting surface was the smoothest of all the azidated dextran samples (R(rms) = 1 +/- 0.3 nm) and swelled up to 2 times its dried thickness in PBS. The antifouling properties of dextran functionalized surfaces were verified by the selective adsorption of FITC-labeled human albumin only on the nondextranized regions of the patterned polyurethane and polystyrene substrates. PMID- 20712354 TI - Synthesis of organo cobalt-aluminum layered double hydroxide via a novel single step self-assembling method and its use as flame retardant nanofiller in PP. AB - Synthesis of polypropylene/organo-layered double hydroxide (PP/OLDH) has been carried out based on self-assembled organocobalt-aluminum LDH (O-CoAl-LDH). The novel method of synthesizing self-assembled CoAl-LDH and its characterization have also been reported in details. This method is proven to be very efficient way of producing OLDH in a single step with homogeneous composition and structure. As flame-retardant nanofiller, O-CoAl-LDH shows significant decrease in heat release rate (HRR), the total heat release (THR) and the heat release capacity (HRC) of the PP composites, though the thermal stability of the compounds decreases slightly compared to the base polymer. Morphological analyses show that the LDH particles are dispersed in PP matrix in a partially exfoliated form. The activation energy calculation based on the Kissinger method reveals that O-CoAl-LDH has a positive effect on the activation energy of thermal decomposition of PP. However, in the presence of this filler, decomposition of the composites starts at an earlier stage than that of pure PP. PMID- 20712353 TI - Pickering-type water-in-oil-in-water multiple emulsions toward multihollow nanocomposite microspheres. AB - Multihollow hydroxyapatite (HAp)/poly(L-lactic acid) (PLLA) nanocomposite microspheres were readily fabricated by solvent evaporation from a "Pickering type" water-in-(dichloromethane solution of PLLA)-in-water multiple emulsion stabilized with HAp nanoparticles. The multiple emulsion was stabilized with the aid of PLLA molecules used as a wettability modifier for HAp nanoparticles, although HAp nanoparticles did not work solely as particulate emulsifiers for Pickering-type emulsions consisting of pure dichloromethane and water. The interaction between PLLA and HAp nanoparticles at the oil-water interfaces plays a crucial role toward the preparation of stable multiple emulsion and multihollow microspheres. PMID- 20712355 TI - Dichalcogenide bonding in seven alkali-metal actinide chalcogenides of the KTh2Se6 structure type. AB - The solid-state compounds CsTh(2)Se(6), Rb(0.85)U(1.74)S(6), RbU(2)Se(6), TlU(2)Se(6), Cs(0.88)(La(0.68)U(1.32))Se(6), KNp(2)Se(6), and CsNp(2)Se(6) of the AAn(2)Q(6) family (A = alkali metal or Tl; An = Th, U, Np; Q = S, Se, Te) have been synthesized by high-temperature techniques. All seven crystallize in space group Immm of the orthorhombic system in the KTh(2)Se(6) structure type. Evidence of long-range order and modulation were found in the X-ray diffraction patterns of TlU(2)Se(6) and CsNp(2)Se(6). A 4a * 4b supercell was found for TlU(2)Se(6) whereas a 5a * 5b * 5c supercell was found for CsNp(2)Se(6). All seven compounds exhibit Q-Q interactions and, depending on the radius ratio R(An)/R(A), disorder of the A cation over two sites. The electrical conductivity of RbU(2)Se(6), measured along [100], is 6 * 10(-5) S cm(-1) at 298 K. The interatomic distances, including those in the modulated structure of TlU(2)Se(6), and physical properties suggest the compounds may be formulated as containing tetravalent Th or U, but the formal oxidation state of Np in the modulated structure of CsNp(2)Se(6) is less certain. The actinide contraction from Th to U to Np is apparent in the interatomic distances. PMID- 20712356 TI - Direct measurement of interface anisotropy of bicontinuous structures via 3D image analysis. AB - A very important morphological parameter in two-phase fluids is the interface anisotropy, which can be quantified using the interface tensor, q(ij). However, the computation of this tensor for complex interfaces is not straightforward. A novel method (the local cross product method, LCPM) to compute the interface tensor of two-phase fluids using 3D imaging coupled with differential geometry is presented here. The method was used to evaluate the degree of anisotropy of phase separated systems with bicontinuous morphologies subjected to uniaxial and shear deformation fields. A model bicontinuous structure (i.e., the gyroid surface) was used to assess the accuracy and precision of the method. The method was then used to track the anisotropy changes of an immiscible polymer blend with cocontinuous morphology, during uniaxial deformation and subsequent retraction. It was found that the dependence of the anisotropy on the Hencky strain of both the gyroid surface and the cocontinuous blend follow the same trend. The retraction of the blend after uniaxial extension is accompanied by an exponential decay of the second invariant of q(ij), which obeys the relation: |II(q)|/Q(2) approximately e(-0.129t). PMID- 20712357 TI - Effect of jet stretch and particle load on cellulose nanocrystal-alginate nanocomposite fibers. AB - Alginate fibers have found many applications such as the preparation of dressings to treat exuding wounds, drug delivery, enzyme immobilization, etc.; however, their use is limited due to poor mechanical properties. Cellulose nanocrystals (CNCs) were isolated from cotton and introduced into calcium alginate fibers with the goal of improving their strength and modulus. The isolated CNCs are elongated nanoparticles of crystalline cellulose with an average length of 130 nm with a standard deviation (s) of 63 nm, an average width of 20.4 nm (s = 7.8 nm), and an average height of 6.8 nm (s = 3.3 nm). The CNCs were mixed with an aqueous sodium alginate dope solution and wet spun into a CaCl(2) bath to form fibers. It was found that if the apparent jet stretch (ratio of the fiber draw velocity to extrusion velocity) is kept constant, addition of the nanocrystals reduces the tensile strength and modulus of the material; however, a small concentration of CNCs in the dope solution increases the tensile energy to break and enables an increase in the fiber spinning apparent jet stretch ratio by nearly 2-fold at up to 25% CNCs load; the maximum ratio of 4.6 is observed at 25 wt % CNC loading as compared to a maximum of 2.4 for the native alginate. Mechanical testing showed a 38% increase in tenacity and a 123% increase in tensile modulus with 10 wt % CNCs loading and an apparent jet stretch of 4.2. The data suggest that alignment of the nanocrystals in the composites is a key factor influencing the mechanical properties. CNCs have potential to become a biocompatible, renewable, and cost effective solution to reinforce alginate fibers. PMID- 20712358 TI - Swelling, mechanical, and barrier properties of albedo-based films prepared in the presence of phaseolin cross-linked or not by transglutaminase. AB - Edible films were obtained from Citrus paradisi grapefruit albedo homogenates and bean protein phaseolin modified or not by the enzyme transglutaminase. Swelling capability, barrier performance to water vapor, oxygen and carbon dioxide, and mechanical properties of such films were investigated. The addition of the protein, mostly in the presence of transglutaminase, provide films less swellable at pH values above 5 compared to films made by albedo homogenates only, whereas the action of the enzyme clearly improves mechanical properties producing more stretchable and elastic films. Moreover, transglutaminase-mediated cross-linking of phaseolin gives rise to films less permeable to carbon dioxide and able to offer a high barrier to water vapor. These findings suggest that albedo-phaseolin film prepared in the presence of transglutaminase can be a promising candidate to be used as food edible wrap. PMID- 20712359 TI - All-nitrogen coordinated amidinato/imido complexes of molybdenum and tungsten: syntheses and characterization. AB - The first all-nitrogen coordinated bis(alkylamidinato)/bis(alkylimido) complexes of molybdenum and tungsten, [Mo(NtBu)(2){(iPrN)(2)CMe}(2)]and [W(NtBu)(2){(iPrN)(2)CMe}(2)], have been synthesized and fully characterized by (1)H and (13)C NMR spectroscopy, elemental analyses, high-resolution electron impact mass spectrometry, and Fourier transform infrared spectroscopy. Density functional theory calculations of the tungsten complex allow for geometry optimization and structural characterization by assignment of the NMR data, in particular a comparison of the experimental (13)C NMR signals with the calculated ones. Both compounds sublime without decomposition at 130 degrees C and 1 mTorr and show rapid decomposition above 250 degrees C, hence representing promising vapor-phase deposition routes for metal nitride based thin-film materials. PMID- 20712360 TI - Polyethylenimine based magnetic iron-oxide vector: the effect of vector component assembly on cellular entry mechanism, intracellular localization, and cellular viability. AB - The order of assembly of a magnetic nanoparticle (MNP) vector comprised of the same components (MNP, PEI, and plasmid DNA) on entry mechanism, intracellular localization, and viability of BHK21 cells was investigated. Cellular uptake measurements under four different uptake inhibiting conditions, such as low temperature, depleted cellular ATP, nystatin treatment, and hypertonic environment, show that the cellular entry mechanism of the MNP vector was mediated via clathrin endocytosis. Despite different vector component assembly, all MNP vectors were taken up by the cells through the same mechanism. Labeling and intracellular tracking of the MNP vectors using epi-fluorescence and confocal laser scanning microscopy showed localization of MNP vector within the lysosomes when DNA was assembled on the outer layer of vector. Conversely, when PEI was on the surface of the vector, such that it enclosed both magnetic nanoparticles and the DNA, vector localization in the cell nucleus was observed. The microscopy results demonstrated that the configuration of the MNP vectors dictate the vector's final intracellular target location, and thus the efficiency of transfection. The cellular viability assessment using three different assays further showed that the cellular viability of MNP vector was dose-dependent and varied with the assembly of vector component. All viability assays found negligible toxicity when DNA was on the outer layer of MNP vector except at the highest vector loading. In contrast, attachment of PEI on MNP vector surface induced a significant decrease in cellular viability, due to the ability of PEI on the MNP vector to rupture the lysosomal vesicles. PMID- 20712361 TI - Efflorescence of ammonium sulfate and coated ammonium sulfate particles: evidence for surface nucleation. AB - Using optical microscopy, we investigated the efflorescence of ammonium sulfate (AS) in aqueous AS and in aqueous 1:1 and 8:1 (by dry weight) poly(ethylene glycol)-400 (PEG-400)/AS particles deposited on a hydrophobically coated slide. Aqueous PEG-400/AS particles exposed to decreasing relative humidity (RH) exhibit a liquid-liquid phase separation below approximately 90% RH with the PEG-400-rich phase surrounding the aqueous AS inner phase. Pure aqueous AS particles effloresced in the RH range from 36.3% to 43.7%, in agreement with literature data (31-48% RH). In contrast, aqueous 1:1 (by dry weight) PEG-400/AS particles with diameters of the AS phase from 7.2 to 19.2 mum effloresced between 26.8% and 33.9% RH and aqueous 8:1 (by dry weight) PEG-400/AS particles with diameters of the AS phase from 1.8 to 7.3 mum between 24.3% and 29.3% RH. Such low efflorescence relative humidity (ERH) values have never been reached before for AS particles of this size range. We show that these unprecedented low ERHs of AS in PEG-400/AS particles could not possibly be explained by the presence of low amounts of PEG-400 in the aqueous AS phase, by a potential inhibition of water evaporation via anomalously slow diffusion through the PEG coating, or by different time scales between various experimental techniques. High-speed photography of the efflorescence process allowed the development of the AS crystallization fronts within the particles to be monitored with millisecond time resolution. The nucleation sites were inferred from the initial crystal growth sites. Analysis of the probability distribution of initial sites of 31 and 19 efflorescence events for pure AS and 1:1 (by dry weight) PEG-400/AS particles, respectively, showed that the particle volume can be excluded as the preferred nucleation site in the case of pure AS particles. For aqueous 1:1 (by dry weight) PEG-400/AS particles preferential AS nucleation in the PEG phase and at the PEG/AS/substrate contact line can be excluded. On the basis of this probability analysis of efflorescence events together with the AS ERH values of pure aqueous AS and aqueous PEG-400/AS particles aforementioned, we suggest that in pure aqueous AS particles nucleation starts at the surface of the particles and attribute the lower ERH values observed for aqueous PEG-400/AS particles to the suppression of the surface-induced nucleation process. Our results suggest that surface-induced nucleation is likely to also occur during the efflorescence of atmospheric AS aerosol particles, possibly constituting the dominating nucleation pathway. PMID- 20712362 TI - A fluorogenic reaction based on heavy-atom removal for ultrasensitive DNA detection. AB - Fluorogenic reactions have recently emerged as a powerful tool for detection, diagnostics, and biosensing applications in a chemical and biological context. However, conventional fluorogenic systems reported to date rely on energy- or photoinduced electron transfer within the probes. Our communication demonstrates a conceptually new approach for generating a strong fluorescence signal through chemical bond formation mediated by a heavy-atom removal process. This method has favorable photophysical properties such as exceptional quantum yield and very low limits of fluorogenic DNA detection. PMID- 20712363 TI - Sequence-specific detection of short-length DNA via template-dependent surface hybridization events. AB - Short-length DNA and RNA, such as mature small RNA, which contains only 17-25 nucleotides, are always a problem in hybridization-based detection assays. In this paper, we report a proof-of-concept for a new short-length DNA detection technology which encompasses a design strategy whereby capture and reporter probes that do not hybridize to each other at 20 degrees C can be made to anneal to each other in the presence of a template via the formation of a stable three component complex. The thermodynamics of this magnetic bead-based DNA biosensor was then investigated in detail by monitoring chemiluminescence (CL) changes in the absence and presence of targets over a temperature profile. The data show that this new biosensor offers the possibility of highly selective and sensitive detection of the short-length target DNA. In view of these advantages, this template-dependent surface-hybridization assay, as a new CL strategy, might create a universal technology for developing simple biosensors in sensitive and selective detection of short-length DNA and RNA. PMID- 20712364 TI - Pentacyclic triterpenoids from olive fruit and leaf. AB - This work establishes a new procedure for the extraction and analysis of pentacyclic triterpenes, with which fruits and leaves from three Spanish olive cultivars ("Picual", "Hojiblanca", and "Arbequina") has been studied. The leaf contains important amounts of oleanolic acid (3.0-3.5% DW), followed by significant concentrations of maslinic acid and minor levels of ursolic acid, erythrodiol, and uvaol. The abundance and profile of triterpenoids change during the leaf ontogeny. In the fruit, triterpenes are exclusively located in the epicarp at concentrations 30-fold lower than that in the leaf. Maslinic acid is the main triterpenoid, only accompanied of oleanolic acid. Along the ripening the levels of these triterpenes decreased. All the analyzed leaves and fruits come from the same agricultural estate, with identical climate and culturing conditions. For this reason, the found differences could majorly be attributable to the genetic factors of the olive cultivars. PMID- 20712365 TI - Quantification of chemically reducing species in the phosphate ion catalyzed degradation of reducing sugars. AB - Chemically reducing species formed during phosphate ion catalyzed degradation of reducing sugars were directly quantified by titration with 2,6-dichloroindophenol (Tillman's reagent) and by measurement of open circuit electrical redox potentials. Both techniques demonstrated a time-dependent increased production of chemically reducing species in 0.1 M phosphate buffer at 100 degrees C and the increasingly negative redox potentials observed were consistent with the formation of reductones. Cyclic voltammetry (CV) was investigated in an attempt to generate and observe the sugar-derived highly reactive reducing species in situ. CV analysis of a model Amadori compound, N-(1-deoxyfructos-1-yl)piperidine, indicated oxidative waves consistent with reductone formation, but chemical instability of the oxidation products formed precluded the electrochemical detection of highly electrophilic reducing species such as reductones. PMID- 20712366 TI - Cobalt-catalyzed hydroarylation of alkynes through chelation-assisted C-H bond activation. AB - Ternary catalytic systems consisting of cobalt salts, phosphine ligands, and Grignard reagents promote addition of arylpyridines and imines to unactivated internal alkynes with high regio- and stereoselectivities. Deuterium-labeling experiments suggest that the reaction involves chelation-assisted oxidative addition of the aryl C-H bond to the cobalt center and insertion of the C-C triple bond into the Co-H bond, followed by reductive elimination of the resulting diorganocobalt species. PMID- 20712367 TI - Innovative high-surface-area CuO pretreated cotton effective in bacterial inactivation under visible light. AB - This study presents the first report on enhanced bacterial inactivation of E. coli by RF-plasma pretreated cotton with high-surface-area CuO powders compared with nonpretreated cotton textiles. The high-surface-area CuO (65 m/g) powder was fully characterized. The E. coli inactivation proceeded in the dark and was accelerated under visible and sunlight irradiation even at very low levels of visible light irradiation. The effect the RF-plasma pretreatment of the cotton on the binding of CuO, applied light dose, the amount of CuO loading and initial E. coli concentration on the inactivation kinetics of E. coli is reported in detail. PMID- 20712368 TI - Multitiered 2D pi-stacked conjugated polymers based on pseudo-geminal disubstituted [2.2]paracyclophane. AB - Interchain interactions between pi-systems have a strong effect on the electronic structure of conjugated organic materials. This influence has previously been explored by the spectroscopic and electrochemical characterization of molecules in which pairs of conjugated oligomers are held in a stacked fashion by attachment to a rigid scaffold. We have prepared a new polymer which uses a pseudo-geminal disubstituted [2.2]paracyclophane scaffold to hold 1,4 bis(phenylethynyl)-2,5-dialkoxybenzene (PE(3)) chromophores in a pi-stacked fashion over their entire length and in an extended multitier arrangement. Solutions of this new polymer display a Stokes shift of 171 nm, compared to just ca. 30 nm for previous models in which only the terminal phenyl rings of the PE(3) chromophore are held in a stacked arrangement. This suggests that interchain interactions of pi-systems over their entire length in a multitier assembly provides for relaxation of the excited state to a stable "phane" electronic state which is responsible for emission. This stabilization is not available in the stacked dimer or other regioisomers of the polymer which possess lesser degrees of overlap. Thus, the architecture of the soluble polymer mimics that of segments of conjugated polymers in semiconducting thin films and will provide a platform for the exploration of the nature of charge carriers and excitons in these important materials. PMID- 20712369 TI - Thermochemical properties of exo-tricyclo[5.2.1.0(2,6)]decane (JP-10 jet fuel) and derived tricyclodecyl radicals. AB - exo-Tricyclo[5.2.1.0(2,6)]decane (TCD) or exo-tetrahydrodicyclopentadiene is the principal component of the high-energy density hydrocarbon fuel commonly identified as JP-10. Thermodynamic parameters for the parent TCD molecule and of all the tricyclodecyl radicals corresponding to the loss of hydrogen atoms from different carbons sites (TCD-Ri with i indicating the given carbon center) are determined using several density functional theory and G3MP2B3 and CBS-QB3 higher level composite computational chemistry methods. Five isodesmic work reactions, three involving bridged hydrocarbon reference molecules with similar ring strains, are employed to produce a cancelation of systematic calculation errors in evaluation of standard, gas-phase formation enthalpies at 298 K. Delta(f)H degrees (298) for TCD is found to be -19.5 +/- 1.3 kcal mol(-1), which is several kcal mol(-1) lower than the commonly used values. C(i)-H bond energies for corresponding TCD carbon sites are evaluated as follows: TCD-R1, 107.2; TCD-R2, 100.1; TCD-R3, 98.0; TCD-R4, 98.5; TCD-R9, 98.7; TCD-R10, 104.1 kcal mol(-1). Results from use of five different DFT methods are in very good agreement with composite level values for all work reactions used for the radicals. The exo and endo isomers of TCD are both determined to have chair and boat conformers. PMID- 20712370 TI - Lyotropic hexagonal columnar liquid crystals of large colloidal gibbsite platelets. AB - We report the formation of hexagonal columnar liquid crystal phases in suspensions of large (570 nm diameter), sterically stabilized, colloidal gibbsite platelets in organic solvent. In thin cells these systems display strong iridescence originating from hexagonally arranged columns that are predominantly aligned perpendicularly to the cell walls. Small angle X-ray scattering and polarization microscopy indicate the presence of orientational fluctuations in the hexagonal columnar liquid crystal phase. The presence of decoupling of the average platelet orientation and the column axis as well as column undulations leading to a decrease of the effective column diameter are discussed. The fact that these phenomena are particularly pronounced in the vertical direction and are enhanced toward the bottom part of the system points to the role of gravitational compaction on the structure. PMID- 20712371 TI - Iron porphyrins with different imidazole ligands. A theoretical comparative study. AB - A theoretical comparative study of a series of five- and six-coordinate iron porphyrins, FeP(L) and FeP(L)(O(2)), has been carried out using DFT methods, where P = porphine and L = imidazole (Im), 1-methylimidazole (1-MeIm), 2 methylimidazole (2-MeIm), 1,2-dimethylimidazole (1,2-Me(2)Im), 4-ethylimidazole (4-EtIm), or histidine (His). Two ligated "picket-fence" iron porphyrins, FeTpivPP(2-MeIm) and FeTpivPP(2-MeIm)(O(2)), were also included in the study for comparison. A number of density functionals were employed in the computations to obtain reliable results. The performance of functionals and basis set effects were investigated in detail on FeP, FeP(Im), and FeP(Im)(O(2)), for which certain experimental information is available and there are some previous calculations in the literature for comparison. Many subtle distinctions in the effects of the different imidazole ligands on the structures and energetics of the deoxy- and oxy iron porphyrins are revealed. While FeP(2-MeIm) is identified to be high spin (S = 2), the ground state of FeP(1-MeIm) may be an admixture of a high-spin (S = 2) and an intermediate-spin (S = 1) state. The ground state of FeP(L)(O(2)) may be different with different L. A weaker Fe-L bond more likely leads to an open shell singlet ground state for the oxy complex. The 2-methyl group in 2-MeIm, which increases steric contact between the ligand and the porphyrinato skeleton, weakens the Fe-O(2) bond, and thus iron porphyrins with 2-MeIm mimic T-state (low affinity) hemoglobin. The calculated FeP(2-MeIm)-O(2) bonding energy is comparable to the FeTpivPP(2-MeIm)-O(2) one, in agreement with the fact that the picket-fence iron porphyrin binds O(2) with affinity similar to that of myoglobin but different from the result obtained by the CPMD scheme. Im and 4-EtIm closely resemble His, the biologically axial base, and so future computations on hemoprotein models can be simplified safely by using Im. PMID- 20712372 TI - Borylene-based functionalization of iron-alkynyl-sigma-complexes and stepwise reversible metal-boryl-to-borirene transformation: synthesis, characterization, and density functional theory studies. AB - Thermally induced chemoselective borylene transfer from [(OC)(5)Mo=BN(SiMe(3))(2)] (2a) to the carbon-carbon triple bond of an iron dicarbonyl alkynyl complex [(eta(5)-C(5)Me(5))Fe(CO)(2)C=CPh] (3) led to the isolation of an iron aminoborirene complex [(eta(5)-C(5)Me(5))(OC)(2)Fe{MU BN(SiMe(3))(2)C=C}Ph] (4) in satisfactory yield. Room temperature photolysis of 4 resulted in an unprecedented rearrangement and a concurrent decarbonylation, affording the novel C(2) side-on coordinated iron boryl complex [(eta(5) C(5)Me(5))(OC)FeBN(SiMe(3))(2)(eta(2)-CC)Ph] (5). Carbonylation of 5 under CO atmosphere at ambient temperature yielded [(eta(5) C(5)Me(5))(OC)(2)FeBN(SiMe(3))(2)CCPh] (6), which is an isomer of 4. Decarbonylation of 6 at 80 degrees C led to 5, which could be upon introduction of CO gas further converted into 4 under same conditions. Reaction of 5 with PMe(3) at 80 degrees C yielded the phosphane complex [(eta(5) C(5)Me(5))(OC)(PMe(3))Fe{MU-BN(SiMe(3))(2)C=C}Ph] (7). All above-mentioned iron complexes 4-7 were isolated as air and moisture sensitive crystalline solids in good yields and have been fully characterized in solution and by X-ray crystallography. Quantum chemical calculations using density functional theory (DFT) have been carried out to understand the mechanisms of the experimentally observed reactions and to analyze the bonding situation in the molecules 4-7. PMID- 20712373 TI - Laser desorption postionization mass spectrometry of antibiotic-treated bacterial biofilms using tunable vacuum ultraviolet radiation. AB - Laser desorption postionization mass spectrometry (LDPI-MS) with 8.0-12.5 eV vacuum ultraviolet synchrotron radiation is used to single photon ionize antibiotics and extracellular neutrals that are laser desorbed both from neat and intact bacterial biofilms. Neat antibiotics are optimally detected using 10.5 eV LDPI-MS but can be ionized using 8.0 eV radiation, in agreement with prior work using 7.87 eV LDPI-MS. Tunable vacuum ultraviolet radiation also postionizes laser desorbed neutrals of antibiotics and extracellular material from within intact bacterial biofilms. Different extracellular material is observed by LDPI MS in response to rifampicin or trimethoprim antibiotic treatment. Once again, 10.5 eV LDPI-MS displays the optimum trade-off between improved sensitivity and minimum fragmentation. Higher energy photons at 12.5 eV produce significant parent ion signal, but fragment intensity and other low mass ions are also enhanced. No matrix is added to enhance desorption, which is performed at peak power densities insufficient to directly produce ions, thus allowing observation of true VUV postionization mass spectra of antibiotic treated biofilms. PMID- 20712374 TI - Associative and dissociative mechanisms in the formation of phthalazine bridged organodiplatinum(II) complexes. AB - The reaction of phthalazine with the binuclear organoplatinum complexes [Me(2)Pt(MU-SMe(2))(MU-dppm)PtR(2)], R = Me, Ph, 4-tolyl or R(2) = (CH(2))(4), dppm = bis(diphenylphosphino)methane, gives the corresponding complexes [Me(2)Pt(MU-phthalazine)(MU-dppm)PtR(2)] by displacement of the bridging dimethylsulfide ligand. The structures of [Me(2)Pt(MU-SMe(2))(MU-dppm)PtMe(2)] and [Me(2)Pt(MU-phthalazine)(MU-dppm)PtMe(2)] have been determined. Kinetic studies show that the reactions occur mostly by a second order reaction when R = Me or R(2) = (CH(2))(4) but entirely by a first order reaction when R = Ph or 4 tolyl. Evidence is presented that the reactions when R = Me or R(2) = (CH(2))(4) can occur by either associative or dissociative mechanisms but that the reactions when R = Ph or 4-tolyl occur only by an unusual dissociative mechanism involving formation of an intermediate with a donor-acceptor Pt-Pt bond. PMID- 20712375 TI - Systematic analysis of helical protein interfaces reveals targets for synthetic inhibitors. AB - Synthetic inhibitors of protein-protein interactions are being discovered despite the inherent challenge in targeting large contact surfaces with small molecules. An analysis of available examples identifies common features of complexes that make them tractable for small molecules. We deduced that relative disposition and energetic contributions of "hot spot" residues provide a predictive scale for the potential of protein-protein interactions to be inhibited by small molecules. On the basis of this model, we analyzed the full set of helical protein interfaces in the Protein Data Bank to identify those that are potentially suitable candidates for synthetic ligands. PMID- 20712376 TI - Characterization of the interactions of vMIP-II, and a dimeric variant of vMIP II, with glycosaminoglycans. AB - Chemokines are important immune proteins, carrying out their function by binding to glycosaminoglycans (GAGs) on the endothelial surface and to cell surface chemokine receptors. A unique viral chemokine analogue, viral macrophage inflammatory protein-II (vMIP-II), encoded by human herpesvirus-8, has garnered interest because of its ability to bind to multiple chemokine receptors, including both HIV coreceptors. In addition, vMIP-II binds to cell surface GAGs much more tightly than most human chemokines, which may be the key to its anti inflammatory function in vivo. The goal of this work was to determine the mechanism of binding of GAG by vMIP-II. The interaction of vMIP-II with a heparin derived disaccharide was characterized using NMR. Important binding sites were further analyzed by mutagenesis studies, in which corresponding vMIP-II mutants were tested for GAG binding ability using heparin chromatography and NMR. We found that despite having many more basic residues than some chemokines, vMIP-II shares a characteristic binding site similar to that of its human analogues, utilizing basic residues R18, R46, and R48. Interestingly, a particular mutation (Leu13Phe) caused vMIP-II to form a pH-dependent CC chemokine-type dimer as determined by analytical ultracentrifugation and NMR. To the best of our knowledge, this is the first example of engineering a naturally predominantly monomeric chemokine into a dissociable dimer by a single mutation. This dimeric vMIP-II mutant binds to heparin much more tightly than wild-type vMIP-II and provides a new model for studying the relationship between chemokine quaternary structure and various aspects of function. Structural differences between monomeric and dimeric vMIP-II upon GAG binding were characterized by NMR and molecular docking. PMID- 20712378 TI - Coenzyme B12-dependent diol dehydratase is a potassium ion-requiring calcium metalloenzyme: evidence that the substrate-coordinated metal ion is calcium. AB - The X-ray analyses of coenzyme B(12)-dependent diol dehydratase revealed two kinds of electron densities that correspond to metal ions in the active site. One is directly coordinated by substrate [Shibata, N., et al. (1999) Structure 7, 997 1008] and the other located near the adenine ring of the coenzyme adenosyl group [Masuda, J., et al. (2000) Structure 8, 775-788]. Both have been assigned as potassium ions, although the coordination distances of the former are slightly shorter than expected. We examined the possibility that the enzyme is a metalloenzyme. Apodiol dehydratase was strongly inhibited by incubation with EDTA and EGTA in the absence of substrate. The metal analysis revealed that the enzyme contains approximately 2 mol of tightly bound calcium per mole of enzyme. The calcium-deprived, EDTA-free apoenzyme was obtained by the EDTA treatment, followed by ultrafiltration. The activity of the calcium-deprived apoenzyme was dependent on Ca(2+) when assayed with 1 mM substrate. The K(m) for Ca(2+) evaluated in reconstitution experiments was 0.88 muM. These results indicate that the calcium is essential for catalysis. Ca(2+) showed a significant stabilizing effect on the calcium-deprived apoenzyme as well. It was thus concluded that the substrate-coordinated metal ion is not potassium but calcium. The potassium ion bound near the adenine ring would be the essential one for the diol dehydratase catalysis. Therefore, this enzyme can be considered to be a metal-activated metalloenzyme. PMID- 20712377 TI - Changes in small-angle X-ray scattering parameters observed upon binding of ligand to rabbit muscle pyruvate kinase are not correlated with allosteric transitions. AB - Protein fluorescence and small-angle X-ray scattering (SAXS) have been used to monitor effector affinity and conformational changes previously associated with allosteric regulation in rabbit muscle pyruvate kinase (M(1)-PYK). In the absence of substrate [phosphoenolpyruvate (PEP)], SAXS-monitored conformational changes in M(1)-PYK elicited by the binding of phenylalanine (an allosteric inhibitor that reduces the affinity of M(1)-PYK for PEP) are similar to those observed upon binding of alanine or 2-aminobutyric acid. Under our assay conditions, these small amino acids bind to the protein but elicit a minimal change in the affinity of the protein for PEP. Therefore, if changes in scattering signatures represent cleft closure via domain rotation as previously interpreted, we can conclude that these motions are not sufficient to elicit allosteric inhibition. Additionally, although PEP has similar affinities for the free enzyme and the M(1)-PYK-small amino acid complexes (i.e., the small amino acids have minimal allosteric effects), PEP binding elicits different changes in the SAXS signature of the free enzyme versus the M(1)-PYK-small amino acid complexes. PMID- 20712380 TI - Selective targeting of G-quadruplex using furan-based cyclic homooligopeptides: effect on c-MYC expression. AB - Quadruplex-specific molecules can serve as suitable drugs in cancer therapy. We have synthesized a pair of furan-based cyclic homooligopeptides, ligand 1 and ligand 2, to specifically target G-quadruplexes. We have shown by CD spectroscopy and UV melting that these ligands can effectively induce G-quadruplex structures in the G-rich 22-mer c-MYC DNA sequence and further stabilize the structure. Equilibrium binding constants measured by isothermal titration calorimeter methods indicate a high affinity of the ligands for the quadruplex structures (K ~ 10(7) M(-1)) and no affinity for the duplex DNA, demonstrating that these ligands are selective for G-quadruplex structures. Surface plasmon resonance was also used to compute the binding while fluorescence resonance energy transfer based assay was additionally used to confirm the selectivity. Moreover, using real time PCR we observed up to 90% downregulation of c-MYC transcripts after 24 h of ligand treatment in HeLa cells. Using a luciferase assay we show the downregulation of the protein levels. Fluorescent-assisted cell sorter-based cell cycle analysis showed a prominent arrest of cells in the sub-G1 stage upon treatment of ligands that leads toward apoptosis. Altogether, these experiments support the hypothesis that the present molecules are effective in specifically binding and stabilizing quadruplexes and provide a suitable scaffold to develop into a quadruplex-targeting therapeutic agent. PMID- 20712379 TI - Integrated proteomic and cytological study of rice endosperms at the storage phase. AB - The endosperm at the storage phase undergoes a series of coordinated cellular and metabolic events, including starchy endosperm cell death, starch synthesis, and starch granule packaging, which leads to efficient accumulation of starch. However, the mechanism underlying the interconnections remains unknown. We used integrated proteomic and cytological approaches to probe the interconnections in rice (Oryza sativa) endosperm at the storage phase from 12 to 18 days after flowering (DAF). Starch granule packaging was completed first in the inner part of endosperm at 15 DAF and spread to almost the entire endosperm at 18 DAF. Programmed starchy endosperm cell death occurred after the starch granule packaging. Endogenous H(2)O(2) was detectable in the inner part of endosperm at 12 DAF and the region beyond the inner part at 15 DAF, with an H(2)O(2) burst at 15 DAF. Proteomics analysis with 2-D fluorescent difference gel electrophoresis and matrix-assisted laser-desorption ionization time-of-flight/time-of-flight mass spectrometry revealed 317 proteins, including almost all known antioxidants, differentially expressed throughout the 3 stages of the developmental phase. More than two-thirds of the 317 proteins were potential thioredoxin targets, with a preferential skew toward central carbon metabolism, alcoholic fermentation, starch metabolism, amino acid metabolism, and protein synthesis or folding. These proteins implicated in starch synthesis and gluconeogenesis were upregulated, whereas those involved in anabolism of biomacromolecules such as proteins, lipids, and cell wall components were downregulated, with upregulated expression of proteins involved in catabolism of these biomacromolecules, which suggests remobilization of nutrients for starch synthesis. These data suggested important roles of the H(2)O(2)-antioxidant interface in coordinating starch accumulation, programmed cell death of starchy endosperm, and remobilization of nutrients during the cell death. PMID- 20712381 TI - Self-assembled boronic ester cavitand capsule as a photosensitizer and a guard nanocontainer against photochemical reactions of 2,6-diacetoxyanthracene. AB - The optical properties of 2,6-diacetoxyanthracene 4 encapsulated in the self assembled boronic ester cavitand capsule 3 in C(6)H(6) are described. Upon excitation at 285 nm, the encapsulated 4 showed strong fluorescence emission as a result of the energy transfer from the excited 3 to the encapsulated 4, while 4 alone in C(6)H(6) exhibited very weak emission. Upon photoirradiation at 365 nm, the encapsulated 4 also showed strong fluorescence emission and remained almost intact, whereas 4 alone in C(6)H(6) gradually underwent photodimerization and photooxygenation to afford photodimers 5 and 5' and 9,10-anthraquinone 6 via 9,10 endoperoxide 7, respectively. Thus, the capsule 3 serves as a photosensitizer for the encapsulated 4 as well as a guard nanocontainer to protect against the photochemical reactions of 4. PMID- 20712382 TI - Ultrafast spectroscopy of oxyhemoglobin during photodissociation. AB - Ultrafast time-resolved pump-probe spectroscopy was studied to clarify the detailed mechanism in the photodissociation process of oxyhemoglobin in the visible spectral range. The photodissociation had not been time-resolved and only the upper limit of the time needed for the dissociation process was claimed to be faster than 50 fs; it was time-resolved to be 45 +/- 5 fs with 10 fs time resolution. The broadband spectrum of the visible laser pulses enabled us to observe the signal over a broad spectral range. A broadband multichannel detector array was used to simultaneously obtain the pump-probe signal at all probe frequencies. Thus, we obtained for the first time the spectra of the ultrashort lifetime electronic excited state of HbO(2) in the visible range from 523 nm (19 109 cm(-1)) to 719 nm (13 914 cm(-1)). After the photodissociation, subpicosecond time constant was found and attributed to the dynamics of the photolyzed Hb. Time resolved difference absorption spectra in 0-100 fs showed oscillatory motion reflecting wavepacket motion in the potential energy surface of the photoexcited HbO(2) during the ultrafast photolysis. PMID- 20712384 TI - Liquid crystalline phases of the amphiphilic ionic liquid N-hexadecyl-N methylpyrrolidinium bromide formed in the ionic liquid ethylammonium nitrate and in water. AB - The phase behavior of a surfactant-like ionic liquid, N-hexadecyl-N methylpyrrolidinium bromide (C(16)MPB), was studied in both water and a room temperature ionic liquid, ethylammonium nitrate (EAN). Polarized optical microscopy (POM) and small-angle X-ray scattering (SAXS) measurements were employed to investigate the phase behavior of the two systems and to determine which lyotropic liquid crystalline (LC) phases were formed. With increasing C(16)MPB concentration, an isotropic solution phase, a hexagonal (H(1)) phase, and a cubic phase (V(2)) are all present in either EAN or H(2)O. The structural parameters of the H(1) phase were calculated from SAXS patterns, which show the structural changes as a function of the amount of C(16)MPB. The rheological results reveal that the H(1) phase constructed by C(16)MPB in EAN displays a typical Maxwell behavior, whereas the H(1) phase formed by C(16)MPB in water shows a gel-like behavior, unlike traditional cationic surfactants. POM and differential scanning calorimetry (DSC) results demonstrate that the lyotropic LC phase in EAN has a higher thermal stability than that formed in H(2)O, which may be important to extend the applications of the LC phase. PMID- 20712383 TI - Spontaneous formation of water droplets at oil-solid interfaces. AB - We report observations of spontaneous formation of micrometer-sized water droplets within micrometer-thick films of a range of different oils (isotropic and nematic 4-cyano-4'-pentylbiphenyl (5CB) and silicone, olive and corn oil) that are supported on glass substrates treated with octadecyltrichlorosilane (OTS) and immersed under water. Confocal imaging was used to determine that the water droplets nucleate and grow at the interface between the oils and OTS treated glass with a contact angle of approximately 130 degrees. A simple thermodynamic model based on macroscopic interfacial energetic arguments consistent with the contact angle of 130 degrees, however, fails to account for the spontaneous formation of the water droplets. zeta-potential measurements performed with OTS-treated glass (-59.0 +/- 16.4 mV) and hydrophobic monolayers formed on gold films (2.0 +/- 0.7 mV), when combined with the observed absence of droplet formation under films of oil supported on the latter surfaces, suggest that the charge of the oil-solid interface promotes partitioning of water to the interfacial region. The hydrophobic nature of the OTS-treated glass promotes dewetting of water accumulated in the interfacial region into droplets (a thin film of water is seen to form on bare glass). The inhibitory effect on droplet formation of both salt (NaCl) and sucrose (0.1-500 mM) added to the aqueous phase was similar, indicating that both solutes lower the chemical potential of the bulk water (osmotic effect) sufficiently to prevent partitioning of the water to the interface between the oil and supporting substrates. These results suggest that charged, hydrophobic surfaces can provide routes to spontaneous formation of surface-supported, water-in-oil emulsions. PMID- 20712385 TI - Photophysical properties of dipeptides containing substituted 3-(quinoxalin-6-yl) alanine. Spectroscopic studies and theoretical calculations. AB - The photophysical properties of excited states of two hybrid dipeptides [N-(3 (2,3-diphenylquinoxaline-6-ylo)alanylo) glycine], Pe-DPhQ, and [N-(3-(2,3 (pirydine-2-ylo) quinoxaline-6-ylo)alanylo) glycine], Pe-DPiQ, have been investigated by a combined solution-state study (absorption, emission) and quantum-mechanical (ab initio, DFT) calculations. The RHF and DFT B3LYP/6-31G (d,p) computations of the ground-state isomers of Pe-DPiQ dipeptide (open, half closed, and closed) indicate that the most stable is the "open"-type structure with approximately equal (-44.43 degrees , -43.05 degrees ) dihedral angles describing rotation of the aromatic side rings with respect to the quinoxaline framework. This agrees with the literature findings that synthetic peptides are mostly unfolded. The experiments show that emission of Pe-DPiQ dipeptide is strongly temperature dependent, and at ambient and elevated temperatures the fluorescence is prevailing while the phosphorescence dominated emission spectra are observed at 77 K. On the basis of the decay curves that in the broad temperature range (rt-77 K) are biexponential (2 and 9 ns), it was concluded that at least its two major excited-state conformations may interconvert on the nanosecond time scale. The third component, of a small amplitude (10%) and a long time constant (25 ns), appears only in a new fluorescence band (570 nm) that grows up with the temperature increase. Analysis of the CIS/6-31G(d,p) results of the excited-state isomers of Pe-DPiQ supports the interpretation of experimental emission spectra and enables one to assign two excited-state conformations, demonstrating a tendency to keep one of their two side rings coplanar relative to the central quinoxaline plane, as Pe-DPiQ-I* (41.9 degrees , 6.3 degrees ) and Pe DPiQ-II* (40.1 degrees , 4.5 degrees ) isomers contributing to the room temperature (403 nm) and 363 K (570 nm) fluorescence bands, respectively. The calculations also explain the electronic character of the corresponding S(1)<- >S(0) transitions and show that the state ordering of Pe-DPiQ resembles that of other diazines where the first singlet is of the npi* character while the S(2) and T(1) are the pipi* states. The reason for a strong phosphorescence is assigned to an effective spin-orbit coupling of appropriate singlet and triplet states that leads to ISC transitions and in result to population of the T(1) state and a phosphorescence from the T(1) state. From the present study, it was concluded that incorporation of quinoxaline moiety into the model peptides does not change the useful spectroscopic properties of the fluorophore and allows one to design its new analogues with improved activity and specificity. PMID- 20712386 TI - An olmesartan medoxomil-based treatment algorithm is effective in achieving 24 hour BP control in patients with type 2 diabetes mellitus, regardless of age, race, sex, or severity of hypertension: subgroup analysis of the BENIFICIARY study. AB - BACKGROUND: Hypertension often occurs concomitantly with diabetes mellitus, such that >50% of adults with type 2 diabetes have hypertension. These individuals are at a greater risk of developing renal and cardiovascular disease. The currently recommended BP goal of <130/80 mmHg for patients with type 2 diabetes is achieved in only 37.5% of treated patients with diabetes and hypertension. METHODS: The antihypertensive efficacy of olmesartan medoxomil (OM) +/- hydrochlorothiazide (HCTZ) was investigated in prespecified subgroups (age <65/>=65 years, Blacks/non Blacks, males/females, or stage 1/stage 2 hypertension) of patients with hypertension and type 2 diabetes enrolled in an open-label, single-arm study (n = 192). Patients started treatment with OM 20 mg/day and were uptitrated at 3-week intervals to OM 40, OM/HCTZ 40/12.5, and OM/HCTZ 40/25 mg/day if BP was >=120/70 mmHg. The primary endpoint was the change in mean 24-hour ambulatory SBP from baseline to week 12, assessed by mean 24-hour ambulatory BP monitoring. Secondary endpoints included changes in mean 24-hour ambulatory DBP, mean daytime ambulatory BP, mean nighttime ambulatory BP, and mean office seated BP, and the proportions of patients achieving prespecified ambulatory BP targets. SETTING: This was a multicenter study (24 sites) that took place between November 2006 and November 2007 in the US. RESULTS: BP reductions were significant (p < 0.0001) and similar among subgroups of patients with type 2 diabetes. Following dose titration to OM/HCTZ 40/25 mg/day, similar proportions of patients in the age, race, and sex subgroups (approximately 60-64% across these subgroups) achieved an ambulatory BP target of <130/80 mmHg. A larger proportion of patients with type 2 diabetes and stage 1 hypertension achieved this same goal compared with patients with stage 2 hypertension (75% vs 46.3%). The combination of OM/HCTZ was well tolerated in all patient subgroups irrespective of age, race, sex, or hypertension severity. CONCLUSIONS: In this open-label study, OM/HCTZ combination therapy was efficacious and well tolerated in subgroups of patients with diabetes and hypertension. [Clinical Trials Registry Number: NCT00403481]. PMID- 20712387 TI - Comparative effectiveness of long-acting risperidone in New Zealand: a report of resource utilization and costs in a 12-month mirror-image analysis. AB - BACKGROUND: Schizophrenia affects approximately 1% of the population and is associated with a considerable economic burden to society. The healthcare costs of the disorder are high and are compounded by substantial productivity losses. Failure to adhere to medication regimens, with subsequent relapse and hospitalization, is a key driver of these costs. A long-acting injectable formulation of the second generation antipsychotic risperidone (risperidone long acting injection [risperidone LAI]) was licensed in New Zealand and received full government funding in October 2005. Second generation antipsychotics may have some efficacy advantages, be associated with fewer adverse effects and could improve adherence. However, the acquisition cost of risperidone LAI is higher than that of first generation antipsychotics and healthcare decision makers need information that allows them to determine whether risperidone LAI represents a cost-effective investment in terms of improved outcomes. OBJECTIVES: To explore real-world outcomes and costs of patients treated with risperidone LAI within New Zealand. METHODS: A mirror-image retrospective study was conducted comparing outcomes and costs 12 months post- versus 12 months pre-initiation of risperidone LAI in all adults receiving approval for risperidone LAI between 1 October 2005 and 31 October 2006 in five health services. Continuation rates, compulsory treatment status, psychiatric hospitalization (admission number, bed-stay and cost) and treatment data were collected from clinical files and patient information systems for the 12 months on either side of the first risperidone LAI prescription. Hospitalization costs were valued using estimates for cost per admission and cost per hospital day ($NZ, year 2009 values). RESULTS: 58.3% of patients remained on risperidone LAI 12 months after initiation. Compared with the pre-risperidone LAI treatment period the mean number of admissions for the total study population was significantly lower in the post-risperidone LAI treatment period (1.38 vs 0.61, p<0.001) but the mean length of bed-stay increased (37.2 vs 53.3 days, p<0.001), as did compulsory treatment use. Overall hospital bed-nights (hospitalization days) increased by 6877 in the post-index period, driven mostly by those who discontinued treatment. Patients who continued risperidone LAI had fewer admissions and days in hospital post-risperidone LAI than patients who discontinued risperidone LAI use in the first year. The reduction in total hospital admission rates between the two treatment periods was significantly greater in the continuation group and mean difference in bed-days between the two treatment periods was significantly less for continuers (5.4 vs 31.1 days, p<0.001). Applying a cost per admission, hospitalization costs reduced by approximately $NZ1.7 million in the post risperidone LAI-period. Applying a daily hospitalization cost resulted in an increase of approximately $NZ3.5 million in the post-risperidone LAI period. CONCLUSION: This study suggests that patients have reduced hospital admissions but longer bed-stay after starting risperidone LAI. Longer admissions were driven by those that discontinued treatment and continuation was associated with improved resource and cost outcomes compared with those who discontinued. These findings have potential implications for payers, providers and patients that require further investigation over a longer time frame. PMID- 20712388 TI - Statin therapy for elevated hsCRP: what are the public health implications? PMID- 20712389 TI - Statin therapy for elevated hsCRP: more evidence is needed. PMID- 20712390 TI - Antihypertensive medication adherence and subsequent healthcare utilization and costs. AB - OBJECTIVES: To evaluate the relationship between adherence to antihypertensive medications (AHMs) and subsequent hospitalizations, emergency department (ED) visits, and costs of care. STUDY DESIGN: Retrospective analysis of a national pharmacy benefits database of deidentified pharmacy and medical claims among patients with a diagnosis of hypertension. Adherence was estimated using the medication possession ratio (MPR). METHODS: Multivariate logistic and 2-part general linear models were estimated to study the relationship between adherence level (estimated by the MPR) and subsequent association with healthcare costs and cardiovascular (CV)-related hospitalizations and ED visits. RESULTS: We identified 625,620 patients with at least 2 claims for AHMs and divided them into 3 cohorts based on year 1 MPR of less than 60% (62,388 patients with low adherence), 60% to 79% (96,226 patients with moderate adherence), and 80% or higher (467,006 patients with high adherence). Patients with high adherence to AHMs were more likely to be older and male, have higher chronic disease scores and lower AHM copayments, and fill a greater percentage of prescriptions by mail order. Year 2 total mean (SD) adjusted healthcare costs were significantly lower for patients with an MPR of 80% or higher ($7182 [$27]) vs 60% to 79% ($7560 [$59]) or less than 60% ($7995 [$73]) (P <.001 for both). In addition, patients with low or moderate adherence had higher age- and sex-adjusted odds of CV related hospitalizations (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.25-1.41) and ED visits (OR, 1.45; 95% CI, 1.33-1.58) (P <.001 for both). CONCLUSION: Adherence to AHMs is associated with significantly lower total healthcare costs and with significantly lower odds of CV-related hospitalizations and ED visits. PMID- 20712391 TI - Clinical and economic outcomes after introduction of drug-eluting stents. AB - BACKGROUND: In clinical trials, drug-eluting stents (DES) improve clinical outcomes but are more expensive than bare-metal stents (BMS). OBJECTIVE: To assess clinical and economic outcomes of all percutaneous coronary intervention (PCI) procedures in a general interventional cardiology practice before and after DES introduction in 2003. METHODS: We identified all patients undergoing PCI in 2000-2002 (early cohort, pre-DES era) and from 2004 through April 31, 2006 (late cohort, DES era) in a large PCI registry. Logistic and Cox proportional hazard models estimated the risk of adverse events; generalized linear modeling predicted economic outcomes. RESULTS: We compared 4303 early-cohort patients with 3422 late-cohort patients. Most early-cohort patients (90%) had BMS implanted; the rest had atherectomy or balloon angioplasty only. Among late-cohort patients, 83% had DES, 14% BMS, and 6% balloon angioplasty or atherectomy only. In-hospital adverse-event rates and incidence of death or myocardial infarction (during a median follow-up of 22 months) were similar. Follow-up procedures were significantly fewer in the later era (hazard ratio for target lesion revascularization: 0.58; 95% confidence interval [CI], 0.50-0.68). Although catheterization lab supply costs were higher in the DES era, length of stay following index PCI and overall practice costs were reduced, on average, 0.40 days and $2053 in the late cohort (95% bootstrapped CI of adjusted mean difference, -$2937 to -$1197). Follow-up cardiac hospitalization costs were similar at 1 year. CONCLUSIONS: Patients undergoing PCI following DES introduction experienced improved clinical outcomes during follow-up and reduced overall procedural costs, despite higher stent acquisition costs. PMID- 20712392 TI - Cost sharing, adherence, and health outcomes in patients with diabetes. AB - OBJECTIVES: To assess the relationship between cost sharing and adherence to antidiabetic medications in patients with type 2 diabetes and to examine the relationship between medication adherence and outcomes, including complication rates, medical service utilization, and workplace productivity measures. STUDY DESIGN: A retrospective, cross-sectional study analyzing the healthcare experience of patients with type 2 diabetes on oral antidiabetic medication (OAD) with or without insulin (n = 96,734) and patients on OAD only (n = 55,356) with employer-sponsored insurance in the 2003-2006 MarketScan Database. METHODS: Using a 2-stage residual inclusion model, the first stage estimated the effects of cost sharing on adherence to antidiabetic medications in an 18-month time frame (January 2003 through June 2004). Adherence was determined from the percentage of days covered. The second stage estimated the effects of adherence on complication rates (eg, retinopathy, neuropathy, peripheral vascular disease), medical service utilization rates, and measures of productivity (absence days and short-term disability days) in the subsequent 2 years (July 2004 through June 2006). RESULTS: A $10 increase in the patient cost-sharing index resulted in a 5.4% reduction in adherence to antidiabetic medications for patients on OAD only and a 6.2% reduction in adherence for patients on OAD with or without insulin. Adherence was associated with lower rates of complications (eg, amputation/ulcers, retinopathy) and also was associated with fewer emergency department visits and short-term disability days. CONCLUSIONS: Medical plans, employers, and policy makers should consider implementing interventions targeted to improve antidiabetic medication adherence, which may translate to better outcomes. PMID- 20712393 TI - Relationship between quality improvement processes and clinical performance. AB - OBJECTIVES: To examine the association between performance on clinical process measures and intermediate outcomes and the use of chronic care management processes (CMPs), electronic medical record (EMR) capabilities, and participation in external quality improvement (QI) initiatives. STUDY DESIGN: Cross-sectional analysis of linked 2006 clinical performance scores from the Integrated Healthcare Association's pay-for-performance program and survey data from the 2nd National Study of Physician Organizations among 108 California physician organizations (POs). METHODS: Controlling for differences in PO size, organization type (medical group or independent practice association), and Medicaid revenue, we used ordinary least squares regression analysis to examine the association between the use of CMPs, EMR capabilities, and external QI initiatives and performance on the following 3 clinical composite measures: diabetes management, processes of care, and intermediate outcomes (diabetes and cardiovascular). RESULTS: Greater use of CMPs was significantly associated with clinical performance: among POs using more than 5 CMPs, we observed a 3.2-point higher diabetes management score on a performance scale with scores ranging from 0 to 100 (P <.001), while for each 1.0-point increase on the CMP index, we observed a 1.0-point gain in intermediate outcomes (P <.001). Participation in external QI initiatives was positively associated with improved delivery of clinical processes of care: a 1.0-point increase on the QI index translated into a 1.4-point gain in processes-of-care performance (P = .02). No relationship was observed between EMR capabilities and performance. CONCLUSION: Greater investments in CMPs and QI interventions may help POs raise clinical performance and achieve success under performance-based accountability schemes. PMID- 20712394 TI - Value and the medical home: effects of transformed primary care. AB - BACKGROUND: The primary care medical home has been promoted to integrate and improve patient care while reducing healthcare spending, but with little formal study of the model or evidence of its efficacy. ProvenHealth Navigator (PHN), an intensive multidimensional medical home model that addresses care delivery and financing, was introduced into 11 different primary care practices. The goals were to improve the quality, efficiency, and patient experience of care. OBJECTIVE: To evaluate the ability of a medical home model to improve the efficiency of care for Medicare beneficiaries. STUDY DESIGN: Observational study using regression modeling based on preintervention and postintervention data and a propensity-selected control cohort. METHODS: Four years of claims data for Medicare patients at 11 intervention sites and 75 control groups were analyzed to compute hospital admission and readmission rates, and the total cost of care. Regression modeling was used to establish predicted rates and costs in the absence of the intervention. Actual results were compared with predicted results to compute changes attributable to the PHN model. RESULTS: ProvenHealth Navigator was associated with an 18% (P <.01) cumulative reduction in inpatient admissions and a 36% (P = .02) cumulative reduction in readmissions across the total population over the study period. CONCLUSIONS: Investing in the capabilities of primary care practices to serve as medical homes may increase healthcare value by improving the efficiency of care. This study demonstrates that the PHN model is capable of significantly reducing admissions and readmissions for Medicare Advantage members. PMID- 20712395 TI - Insomnia risks and costs: health, safety, and quality of life. AB - The effect of insomnia on next-day functioning, health, safety, and quality of life results in a substantial societal burden and economic cost. The annual direct cost of insomnia has been estimated in the billions of US dollars and is attributed to the association of insomnia with the increased risk of certain psychiatric and medical comorbidities that result in increased healthcare service utilization. It is well known that psychiatric conditions, anxiety and depression in particular, are comorbid with insomnia. However, emerging data have shown links with several common and costly medical conditions such as heart disease and diabetes. Furthermore, studies show that patients who have insomnia have more emergency department and physician visits, laboratory tests, and prescription drug use than those who do not have insomnia, increasing direct and indirect consumption of healthcare resources. Insomnia also has been shown to negatively affect daytime functioning, including workplace productivity, as well as workplace and public safety. These daytime effects of insomnia are translated into indirect costs that are reportedly higher than the direct costs of this disorder. These observations have significant implications for managed care organizations and healthcare providers. Improvements in diagnosing and treating insomnia can significantly reduce the healthcare cost of insomnia and its comorbid disorders, while providing additional economic benefits from improved daytime functioning and from increased productivity. PMID- 20712396 TI - Prospects and perspectives in primate aging research. AB - As improvements in standard of living and advances in medicine have resulted in greater life expectancy, the relative proportion of elderly has continued to increase in human populations across the globe. The primary goal of aging research is to gain a better understanding of the series of events that lead to increased frailty and disease vulnerability with age. The direct study of human aging is an active area of research; however, the opportunity to conduct mechanistic studies and gain insights into the underlying biology is limited. In this special forum issue of Antioxidant & Redox Signaling, we present a selection of articles and reviews that illustrate some of the recent advances in primate aging research. The overarching goal of this work is to underscore the potential for mechanistic discovery that is presented by nonhuman primate models, and to promote studies that validate novel approaches and techniques in nonhuman primates before their adaptation for human health care. PMID- 20712397 TI - Amyloid beta-peptide oligomers stimulate RyR-mediated Ca2+ release inducing mitochondrial fragmentation in hippocampal neurons and prevent RyR-mediated dendritic spine remodeling produced by BDNF. AB - Soluble amyloid beta-peptide oligomers (AbetaOs), increasingly recognized as causative agents of Alzheimer's disease (AD), disrupt neuronal Ca(2+) homeostasis and synaptic function. Here, we report that AbetaOs at sublethal concentrations generate prolonged Ca(2+) signals in primary hippocampal neurons; incubation in Ca(2+)-free solutions, inhibition of ryanodine receptors (RyRs) or N-methyl-d aspartate receptors (NMDARs), or preincubation with N-acetyl-l-cysteine abolished these signals. AbetaOs decreased (6 h) RyR2 and RyR3 mRNA and RyR2 protein, and promoted mitochondrial fragmentation after 24 h. NMDAR inhibition abolished the RyR2 decrease, whereas RyR inhibition prevented significantly the RyR2 protein decrease and mitochondrial fragmentation induced by AbetaOs. Incubation with AbetaOs (6 h) eliminated the RyR2 increase induced by brain-derived nerve factor (BDNF) and the dendritic spine remodeling induced within minutes by BDNF or the RyR agonist caffeine. Addition of BDNF to neurons incubated with AbetaOs for 24 h, which had RyR2 similar to and slightly higher RyR3 protein content than those of controls, induced dendritic spine growth but at slower rates than in controls. These combined effects of sublethal AbetaOs concentrations (which include redox sensitive stimulation of RyR-mediated Ca(2+) release, decreased RyR2 protein expression, mitochondrial fragmentation, and prevention of RyR-mediated spine remodeling) may contribute to impairing the synaptic plasticity in AD. PMID- 20712398 TI - Brain nitric oxide inactivation is governed by the vasculature. AB - The mechanisms underlying nitric oxide ((*)NO) synthesis and inactivation in the brain are essential determinants of (*)NO neuroactivity. Although (*)NO production is well characterized, the pathways of inactivation in vivo remain largely unknown. Here, we characterize the kinetics and the major mechanism of (*)NO inactivation in the rat brain cortex and hippocampus in vivo by measuring locally applied (*)NO with carbon-fiber microelectrodes (CFMs) and ceramic-based microelectrode arrays (MEAs). An apparent first-order clearance was observed in both brain regions, with decay rate constants (k) of (*)NO signals of 0.67 to 0.84 per second, significantly higher than the k obtained in agarose gel (0.099 per second), used as a (*)NO diffusion-control medium. (*)NO half-life in vivo, estimated by mathematical modeling, was 0.42 to 0.75 s. Experiments using MEAs support that the (*)NO diffusion radius is heterogeneous and related to local metabolic activity and vascular density. After global ischemia, k decreased to control values of diffusion in gel, but during anoxia, k decreased only 21%. Additionally, k in brain slices was threefold to fivefold lower than that in vivo, and hemorrhagic shock induced a 53% decrease in k. Overall, the results support that (*)NO scavenging by circulating erythrocytes constitutes the major (*)NO-inactivation pathway in the brain. PMID- 20712400 TI - Magnetic resonance spectroscopy study of the antioxidant defense system in schizophrenia. AB - Accumulating evidence suggests that oxidative stress associated with impaired metabolism of the antioxidant glutathione (GSH) plays a key role in the pathophysiology of schizophrenia. Magnetic resonance spectroscopy (MRS) is one of the brain-imaging techniques that can quantitatively measure bioactive substances such as GSH in the intact human brain. Four different measurement sequences including double quantum coherence (DQC) filtering, MEscher-GArwood Point RESolved Spectroscopy (MEGA-PRESS), Stimulated Echo Acquisition Mode (STEAM), and PRESS have been used to evaluate the (1)H-MRS measurement of GSH in the brains of patients with schizophrenia. Although the results of these studies were somewhat diverse, a negative correlation between brain GSH levels and the severity of negative symptoms in schizophrenia patients suggests that increasing the brain GSH levels might be beneficial for schizophrenia patients with negative symptoms. Moreover, a recent double-blind, placebo-controlled study demonstrated that add on of N-acetyl-l-cysteine (NAC), a precursor of GSH, to antipsychotics improved the negative symptoms and reduced the side effects (akathisia) in patients with chronic schizophrenia. MRS study of the antioxidant defense system in schizophrenia still remains in the infantile stage; future studies are needed to examine the brain GSH level before and after NAC treatment, and thereby to provide direct evidence of the induced production of GSH in the living brain. PMID- 20712401 TI - Signal transducers and activators of transcription: STATs-mediated mitochondrial neuroprotection. AB - Cerebral ischemia is defined as little or no blood flow in cerebral circulation, characterized by low tissue oxygen and glucose levels, which promotes neuronal mitochondria dysfunction leading to cell death. A strategy to counteract cerebral ischemia-induced neuronal cell death is ischemic preconditioning (IPC). IPC results in neuroprotection, which is conferred by a mild ischemic challenge prior to a normally lethal ischemic insult. Although many IPC-induced mechanisms have been described, many cellular and subcellular mechanisms remain undefined. Some reports have suggested key signal transduction pathways of IPC, such as activation of protein kinase C epsilon, mitogen-activated protein kinase, and hypoxia-inducible factors, that are likely involved in IPC-induced mitochondria mediated-neuroprotection. Moreover, recent findings suggest that signal transducers and activators of transcription (STATs), a family of transcription factors involved in many cellular activities, may be intimately involved in IPC induced ischemic tolerance. In this review, we explore current signal transduction pathways involved in IPC-induced mitochondria mediated neuroprotection, STAT activation in the mitochondria as it relates to IPC, and functional significance of STATs in cerebral ischemia. PMID- 20712403 TI - Oncosuppressive functions of autophagy. AB - Macroautophagy (herein referred to as autophagy) constitutes a phylogenetically old mechanism leading to the lysosomal degradation of cytoplasmic structures. At baseline levels, autophagy exerts homeostatic functions by ensuring the turnover of potentially harmful organelles and long-lived aggregate-prone proteins. Moreover, the autophagic flow can be dramatically upregulated in response to a plethora of stressful conditions, including glucose, amino acid, oxygen, or growth factor deprivation, accumulation of unfolded proteins in the endoplasmic reticulum, and invasion by intracellular pathogens. In some experimental settings, stress-induced autophagy has been shown to contribute to programmed cell death. Nevertheless, autophagy most often confers cytoprotection by providing cells with new metabolic substrates or by ridding them of noxious intracellular entities including protein aggregates and invading organisms. Thus, autophagy has been implicated in an ever-increasing number of human diseases including cancer. Autophagy inhibition accelerates the demise of tumor cells that are subjected to chemo- or radiotherapy, thereby constituting an interesting target for the development of anticancer strategies. However, several oncosuppressor proteins and oncoproteins have been recently shown to stimulate and inhibit the autophagic flow, respectively, suggesting that autophagy exerts bona fide tumor-suppressive functions. In this review, we will discuss the mechanisms by which autophagy may prevent oncogenesis. PMID- 20712402 TI - Inhibition of Na+/H+ exchanger isoform 1 is neuroprotective in neonatal hypoxic ischemic brain injury. AB - We investigated the role of Na(+)/H(+) exchanger isoform 1 (NHE-1) in neonatal hypoxia/ischemia (HI). HI was induced by unilateral ligation of the left common carotid artery in postnatal day 9 (P9) mice, and subsequent exposure of animals to 8% O(2) for 55 min. A pre/posttreatment group received a selective and potent NHE-1 inhibitor HOE 642 (0.5 mg/kg, intraperitoneally) 5 min before HI, then at 24 and 48 h after HI. A posttreatment group received HOE 642 (0.5 mg/kg) at 10 min, 24 h, and 48 h after HI. Saline injections were used as vehicle controls. The vehicle-control brains at 72 h after HI exhibited neuronal degeneration in the ipsilateral hippocampus, striatum, and thalamus, as identified with Fluoro Jade C positive staining and loss of microtubule-associated protein 2 (MAP2) expression. NHE-1 protein was upregulated in glial fibrillary acidic protein positive reactive astrocytes. In HOE 642-treated brains, the morphologic hippocampal structures were better preserved and displayed less neurodegeneration and a higher level of MAP2 expression. Motor-learning deficit was detected at 4 weeks of age after HI in the vehicle control group. Inhibition of NHE-1 in P9 mice not only reduced neurodegeneration during the acute stage of HI but also improved the striatum-dependent motor learning and spatial learning at 8 weeks of age after HI. These findings suggest that NHE-1-mediated disruption of ionic homeostasis contributes to striatal and CA1 pyramidal neuronal injury after neonatal HI. PMID- 20712399 TI - Animal, in vitro, and ex vivo models of flow-dependent atherosclerosis: role of oxidative stress. AB - Atherosclerosis is an inflammatory disease preferentially occurring in curved or branched arterial regions, whereas straight parts of the arteries are protected, suggesting a close relationship between flow and atherosclerosis. However, evidence directly linking disturbed flow to atherogenesis is just emerging, thanks to the recent development of suitable animal models. In this article, we review the status of various animal, in vitro, and ex vivo models that have been used to study flow-dependent vascular biology and atherosclerosis. For animal models, naturally flow-disturbed regions such as branched or curved arterial regions as well as surgically created models, including arterio-venous fistulas, vascular grafts, perivascular cuffs, and complete, incomplete, or partial ligation of arteries, are used. Although in vivo models provide the environment needed to mimic the complex pathophysiological processes, in vitro models provide simple conditions that allow the study of isolated factors. Typical in vitro models use cultured endothelial cells exposed to various flow conditions, using devices such as cone-and-plate and parallel-plate chambers. Ex vivo models using isolated vessels have been used to bridge the gap between complex in vivo models and simple in vitro systems. Here, we review these flow models in the context of the role of oxidative stress in flow-dependent inflammation, a critical proatherogenic step, and atherosclerosis. PMID- 20712404 TI - Regulation of autophagy in the heart: "you only live twice". AB - Autophagy is a highly orchestrated cellular process by which proteins and organelles are degraded via an elaborate lysosomal pathway to generate free amino acids and sugars for ATP during metabolic stress. At present, the exact role of autophagy in the heart is highly debated but suggested to play a key role in regulating cell turnover in cardiomyopathies and heart failure. The signaling pathways and molecular effectors that govern autophagy are incomplete, as are the mechanisms that determine whether autophagy promotes or prevents cell death. The mitochondrion has been identified as a key organelle centrally involved in regulating autophagy. Certain members of the Bcl-2 gene family, including Beclin 1, Bcl-2 nineteen kilodaltons interacting protein (Bnip3), and Nix/Bnip3L, provoke mitochondrial perturbations leading to permeability transition pore opening, resulting in apoptosis, autophagy, or both. These and other aspects of autophagy processes have been discussed. PMID- 20712405 TI - Autophagosome formation and molecular mechanism of autophagy. AB - Autophagy (macroautophagy), or the degradation of large numbers of cytoplasmic components, is induced by extracellular and intracellular signals, including oxidative stress, ceramide, and endoplasmic reticulum stress. This dynamic process involves membrane formation and fusion, including autophagosome formation, autophagosome-lysosome fusion, and the degradation of intra autophagosomal contents by lysosomal hydrolases. Autophagy is associated with tumorigenesis, neurodegenerative diseases, cardiomyopathy, Crohn's disease, fatty liver, type II diabetes, defense against intracellular pathogens, antigen presentation, and longevity. Among the proteins and multimolecular complexes that contribute to autophagosome formation are the PI(3)-binding proteins, the PI3 phosphatases, the Rab proteins, the Atg1/ULK1 protein-kinase complex, the Atg9*Atg2-Atg18 complex, the Vps34-Atg6/beclin1 class III PI3-kinase complex, and the Atg12 and Atg8/LC3 conjugation systems. Two ubiquitin-like modifications, the Atg12 and LC3 conjugations, are essential for membrane elongation and autophagosome formation. Recent findings have revealed that processes of selective autophagy, including pexophagy, mitophagy, ERphagy (reticulophagy), and the p62-dependent degradation of ubiquitin-positive aggregates, are physiologically important in various disease states, whereas "classical" autophagy is considered nonselective degradation. Processes of selective autophagy require specific Atg proteins in addition to the "core" Atg complexes. Finally, methods to monitor autophagic activity in mammalian cells are described. PMID- 20712406 TI - Role of MnSOD and p66shc in mitochondrial response to p53. AB - Control of intracellular redox balance has emerged as a primary function of the p53 network, with crucial implications for tumor suppression, aging, and cell metabolism. Mitochondria are central to redox homeostasis, produce energy, and trigger apoptosis and senescence: not surprisingly, many "old" and "new" functions of p53 appear to be based in mitochondria. Genetic and biomolecular evidence indicates that generation of reactive oxygen species (ROS) in mitochondria can be a deliberate and finely regulated cell response on which signaling by environmental stressors, oncogenes, and nutrients converge. p53 orchestrates mitochondrial redox signaling by the coordinated control of at least two key effectors: the superoxide scavenger MnSOD, and the ROS generator p66shc. This review presents recent evidence and emerging questions regarding the p53 MnSOD-p66shc connection, and discusses how dissection of a circuitry comprising a tumor suppressor, an antioxidant, and a molecule regulating cell survival and mammalian lifespan can provide a framework to address important aspects related to the intricate connection between metabolism, aging, and cancer. PMID- 20712408 TI - Mitochondrial liaisons of p53. AB - Mitochondria play a central role in cell survival and cell death. While producing the bulk of intracellular ATP, mitochondrial respiration represents the most prominent source of harmful reactive oxygen species. Mitochondria participate in many anabolic pathways, including cholesterol and nucleotide biosynthesis, yet also control multiple biochemical cascades that contribute to the programmed demise of cells. The tumor suppressor protein p53 is best known for its ability to orchestrate a transcriptional response to stress that can have multiple outcomes, including cell cycle arrest and cell death. p53-mediated tumor suppression, however, also involves transcription-independent mechanisms. Cytoplasmic p53 can physically interact with members of the BCL-2 protein family, thereby promoting mitochondrial membrane permeabilization. Moreover, extranuclear p53 can suppress autophagy, a major prosurvival mechanism that is activated in response to multiple stress conditions. Thirty years have passed since its discovery, and p53 has been ascribed with an ever-increasing number of functions. For instance, p53 has turned out to influence the cell's redox status, by transactivating either anti- or pro-oxidant factors, and to regulate the metabolic switch between glycolysis and aerobic respiration. In this review, we will analyze the mechanisms by which p53 affects the balance between the vital and lethal functions of mitochondria. PMID- 20712407 TI - Critical role of the nitric oxide/reactive oxygen species balance in endothelial progenitor dysfunction. AB - Endothelial injury and dysfunction are critical events in the pathogenesis of cardiovascular disease. During these processes, an impaired balance of nitric oxide bioavailability and oxidative stress is mechanistically involved. Circulating angiogenic cells (including early and late outgrowth endothelial progenitor cells (EPC)) contribute to formation of new blood vessels, neovascularization, and homeostasis of the vasculature, and are highly sensitive for misbalance between NO and oxidative stress. We here review the role of the endothelial nitric oxide synthase and oxidative stress producing enzyme systems in EPC during cardiovascular disease. We also focus on the underlying molecular mechanisms and potential emerging drug- and gene-based therapeutic strategies to improve EPC function in cardiovascular diseased patients. PMID- 20712409 TI - The origins of oxidant stress in Parkinson's disease and therapeutic strategies. AB - Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease. PMID- 20712411 TI - Cardiac postconditioning. AB - In the heart, ischemia/reperfusion damage occurs mainly during the first minutes of reperfusion. Recently, it has been shown that the heart can be protected against the extension of ischemia/reperfusion injury if brief coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called postconditioning (PostC). It can also be elicited by pharmacological intervention, that is, pharmacological PostC. In particular, PostC limits infarct size, apoptosis, endothelial dysfunction, neutrophil adherence, and arrhythmias. Similar to preconditioning, PostC may trigger signaling pathways, including reperfusion injury salvage kinase and survivor activating factor enhancement pathways. PostC-induced protection also involves intracellular acidosis and early redox-sensitive mechanisms. However, controversies exist on the nature of receptors and main pathway(s) involved in PostC. Protective pathways activated by PostC appear to converge on mitochondria and, in particular, on mitochondrial permeability transition pores. Preliminary clinical data indicate that drugs targeting mitochondrial permeability transition pore or reperfusion injury salvage kinases may confer benefits to patients with acute myocardial infarction above that provided by myocardial reperfusion alone. Future studies must define the principal protective cascades, the interdependence of the signaling pathways, and the optimal pharmacological target and agent(s) for protection. These studies must also consider the possible confounding effects of comorbidities and their drug treatments. PMID- 20712410 TI - Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. AB - The tumor suppressor p53 protects organisms from most types of cancer through multiple mechanisms. The p53 gene encodes a stress-activated transcriptional factor that transcriptionally regulates a large set of genes with versatile functions. These p53-activated genes mitigate consequences of stress regulating cell viability, growth, proliferation, repair, and metabolism. Recently, we described a novel antioxidant function of p53, which is important for its tumor suppressor activity. Among the many antioxidant genes activated by p53, Sestrins (Sesns) are critical for suppression of reactive oxygen species (ROS) and protection from oxidative stress, transformation, and genomic instability. Sestrins can regulate ROS through their direct effect on antioxidant peroxiredoxin proteins and through the AMP-activated protein kinase-target of rapamycin signaling pathway. The AMP-activated protein kinase-target of rapamycin axis is critical for regulation of metabolism and autophagy, two processes associated with ROS production, and deregulation of this pathway increases vulnerability of the organism to stress, aging, and age-related diseases, including cancer. Recently, we have shown that inactivation of Sestrin in fly causes accumulation of age-associated damage. Hence, Sestrins can link p53 with aging and age-related diseases. PMID- 20712412 TI - The role of macroautophagy in development of filamentous fungi. AB - Autophagy (macroautophagy) is a bulk degradative pathway by which cytoplasmic components are delivered to the vacuole for recycling. This process is conserved from yeast to human, where it is implicated in cancer and neurodegenerative diseases. During the last decade, many ATG genes involved in autophagy have been identified, initially in Saccharomyces cerevisiae. This review summarizes the knowledge on the molecular mechanisms of autophagy using yeast as model system. Although many of the core components involved in autophagy are conserved from yeast to human, there are, nevertheless, significant differences between these organisms, for example, during autophagy initiation. Autophagy also plays an essential role in filamentous fungi especially during differentiation. Remarkably, in these species autophagy may reflect features of both yeast and mammals. This is exemplified by the finding that filamentous fungi lack the S. cerevisiae clade-specific Atg31 protein, but contain Atg101, which is absent in this clade. A reappraisal of genome data further suggests that, similar to yeast and mammals, filamentous fungi probably also contain two distinct phosphatidylinositol 3-kinase complexes. This review also summarizes the state of knowledge on the role of autophagy in filamentous fungi during differentiation, such as pathogenic development, programmed cell death during heteroincompatibility, and spore formation. PMID- 20712413 TI - Bacillithiol, a new player in bacterial redox homeostasis. AB - Bacillithiol (BSH), the alpha-anomeric glycoside of l-cysteinyl-d-glucosamine with l-malic acid, plays a dominant role in the cytosolic thiol redox chemistry of the low guanine and cytosine (GC) Gram-positive bacteria (phylum Firmicutes). BSH is functionally analogous to glutathione (GSH) but differs sufficiently in chemical structure that cells have evolved a distinct set of enzymes that use BSH as cofactor. BSH was discovered in Bacillus subtilis as a mixed disulfide with the redox-sensing repressor OhrR and in B. anthracis by biochemical analysis of pools of labeled thiols. The structure of BSH was determined after purification from Deinococcus radiodurans. Similarities in structure between BSH and mycothiol (MSH) facilitated the identification of biosynthetic genes for BSH in the model organism B. subtilis. Phylogenomic analyses have identified several candidate BSH using or associated proteins, including a BSH reductase, glutaredoxin-like thiol dependent oxidoreductases (bacilliredoxins), and a BSH-S-transferase (FosB) involved in resistance to the epoxide antibiotic fosfomycin. Preliminary results implicate BSH in cellular processes to maintain cytosolic redox balance and for adaptation to reactive oxygen, nitrogen, and electrophilic species. BSH also is predicted to chelate metals avidly, in part due to the appended malate moiety, although the implications of BSH for metal ion homeostasis have yet to be explored in detail. PMID- 20712414 TI - Redox signaling in an in vivo murine model of low magnitude oscillatory wall shear stress. AB - Wall Shear Stress (WSS) has been identified as an important factor in the pathogenesis of atherosclerosis. We utilized a novel murine aortic coarctation model to acutely create a region of low magnitude oscillatory WSS in vivo. We employed this model to test the hypothesis that acute changes in WSS in vivo induce upregulation of inflammatory proteins, mediated by reactive oxygen species (ROS). Superoxide generation and VCAM-1 expression both increased in regions of low magnitude oscillatory WSS. WSS-dependent superoxide formation was attenuated by tempol treatment, but was unchanged in p47 phox knockout (ko) mice. However, in both the p47 phox ko mice and the tempol-treated mice, low magnitude oscillatory WSS produced an increase in VCAM-1 expression comparable to control mice. Additionally, this same VCAM-1 expression was observed in ebselen-treated mice and catalase overexpressing mice. These results suggest that although the redox state is important to the overall pathogenesis of atherosclerosis, the initial WSS-dependent inflammatory response leading to lesion localization is not dependent on ROS. PMID- 20712415 TI - Reduction of cysteine sulfinic acid in eukaryotic, typical 2-Cys peroxiredoxins by sulfiredoxin. AB - The eukaryotic, typical 2-Cys peroxiredoxins (Prxs) are inactivated by hyperoxidation of one of their active-site cysteine residues to cysteine sulfinic acid. This covalent modification is thought to enable hydrogen peroxide-mediated cell signaling and to act as a functional switch between a peroxidase and a high molecular-weight chaperone. Moreover, hyperoxidation has been implicated in a variety of disease states associated with oxidative stress, including cancer and aging-associated pathologies. A repair enzyme, sulfiredoxin (Srx), reduces the sulfinic acid moiety by using an unusual ATP-dependent mechanism. In this process, the Prx molecule undergoes dramatic structural rearrangements to facilitate repair. Structural, kinetic, mutational, and mass spectrometry-based approaches have been used to dissect the molecular basis for Srx catalysis. The available data support the direct formation of Cys sulfinic acid phosphoryl ester and protein-based thiosulfinate intermediates. This review discusses the role of Srx in the reversal of Prx hyperoxidation, the questions raised concerning the reductant required for human Srx regeneration, and the deglutathionylating activity of Srx. The complex interplay between Prx hyperoxidation, other forms of Prx covalent modification, and the oligomeric state also are discussed. PMID- 20712416 TI - The impact of stroke: are people with aphasia different to those without? AB - PURPOSE: Stroke rehabilitation programmes aim to improve functional outcomes and quality of life. This study explored long-term outcomes in a cohort of people admitted to two acute stroke units with stroke. Comparisons were drawn between people with aphasia (PWA) and people without aphasia. METHODS: People admitted to hospital with a first stroke were assessed at 2-weeks, 3-months and 6-months post stroke. Measures included: the Barthel Index for Activities of Daily Living (ADL), the Frenchay Aphasia Screening Test, the General Health Questionnaire-12 for emotional well-being and the Stroke and Aphasia Quality of Life Scale-39g. Extended ADL and social support were also measured at 3 and 6 months, with the Frenchay Activities Index and the Social Support Survey, respectively. RESULTS: Of 126 eligible participants, 96(76%) took part and 87(69%) were able to self report. Self-report data are reported here. Although outcomes improved significantly across time, at 6 months people continued to experience substantial functional limitations (16% aphasic; 32% dependent on basic ADL); participation limitations (79% <=30 on the FAI); high psychological distress (45%) and compromised quality of life (54% <=4 on the SAQOL-39g). Levels of social support remained relatively stable. Though at 3-months post-stroke PWA were significantly more likely to experience high psychological distress (93% versus 50% for those without), across time, there were no significant differences between PWA and those without on psychological distress and also ADL and social support. There were, however, significant differences on extended ADL (F(1,68) = 7.80, p < 0.01) and quality of life (F(1,69) = 6.30, p < 0.05). CONCLUSION: PWA participated in fewer activities and reported worse quality of life after stroke than people without aphasia, even when their physical abilities, well-being and social support were comparable. Implications for clinical practice and future research are discussed. PMID- 20712417 TI - Application of resorbable poly(lactide-co-glycolide) with entangled hyaluronic acid as an autograft extender for posterolateral intertransverse lumbar fusion in rabbits. AB - Facilitating fusion between bony segments in a reliable and reproducible manner using a synthetic bone graft material has a number of benefits for the surgeon as well as the patient. Although autograft remains the gold standard, associated comorbidities continue to drive the development of new biomaterials for use in spinal fusion. The ability of autograft alone and autograft combined with a radiolucent biomaterial composed of resorbable osteoconductive poly(lactide-co glycolide) with entangled hyaluronic acid to facilitate fusion was examined in a single-level noninstrumented posterolateral intertransverse lumbar fusion model in New Zealand White rabbits. Progressive bone formation was demonstrated radiographically for the extender group (synthetic biomaterial plus autograft) between 3 and 6 months. Computed tomography revealed a new cortical shell in the fusion mass at 3 and 6 months for both study groups. Tensile testing at 6 months demonstrated that the quality of bone formed between the intertransverse space was equivalent for both study groups. Histologic evaluation of the fusion mass revealed new bone on and adjacent to the transverse processes with the synthetic biomaterial group that extended laterally, supporting the osteoconductive nature of the material. Histological evidence of endochondral bone growth in the intertransverse space was observed for the autograft plus synthetic biomaterial group. Bone remodeling, new marrow spaces, and peripheral cortices were observed for each study group at 3 months that matured by 6 months. These findings support the use of a radiolucent biosynthetic material comprising poly(lactide-co glycolide) with integrated hyaluronic acid as an autograft extender for lumbar intertransverse fusion. PMID- 20712418 TI - Micron-scale spatially patterned, covalently immobilized vascular endothelial growth factor on hydrogels accelerates endothelial tubulogenesis and increases cellular angiogenic responses. AB - Spontaneous formation of endothelial tubules was restricted to patterned micron scale regions presenting cell adhesion ligands and angiogenic signaling protein on poly(ethylene glycol) hydrogels. Arginine-glycine-aspartic acid-serine (RGDS), an integrin ligand, and vascular endothelial growth factor (VEGF), a rate limiting signaling protein involved in angiogenesis, were covalently bound through photopolymerization via laser scanning lithography to the surface of poly(ethylene glycol) hydrogels in patterned micron-scale regions. Endothelial cells cultured in this restricted environment underwent accelerated tubulogenesis, forming endothelial tubes within 2 days, whereas cells cultured on larger patterned areas remained spread and did not form tubules by day 2. Tubules formed in 2 days on RGDS and VEGF patterns were observed to possess lumens; however, tubule-like structures formed in 2 days on RGDS-only control patterns did not have observable lumens. Additionally, tubules that formed on restricted areas of RGDS and VEGF expressed more VEGF receptor 1, VEGF receptor 2, and ephA7 surface markers, in addition to higher expression of laminin, than cells remaining spread on wide patterned lines. This work reports spatial control and acceleration of endothelial tubule formation using biocompatible hydrogel materials to allow the formation of highly organized vascularized tissues. PMID- 20712420 TI - Role of 5'-adenosine monophosphate-activated protein kinase in cell survival and death responses in neurons. AB - 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of cellular energy status. AMPK signaling regulates energy balance at the cellular, organ, and whole-body level. More recently, it has become apparent that AMPK plays also an important role in long-term decisions that determine cell fate, in particular cell cycle progression and apoptosis activation. Here, we describe the diverse mechanisms of AMPK activation and the role of AMPK in the regulation of cellular energy balance. We summarize recent studies implicating AMPK activation in the regulation of neuronal survival and as a key player during ischemic stroke. We also suggest that AMPK activation may have dual functions in the regulation of neuronal survival: AMPK provides a protective effect during transient energy depletion as exemplified in a model of neuronal Ca(2+) overloading, and this effect is partially mediated by the activation of neuronal glucose transporter 3. Prolonged AMPK activation, on the contrary, can lead to neuronal apoptosis via the transcriptional activation of the proapoptotic Bcl-2 family member, bim. Molecular switches that determine the protective versus cell death-inducing effects of AMPK activation are discussed. PMID- 20712419 TI - Maturation state-dependent alterations in meniscus integration: implications for scaffold design and tissue engineering. AB - The knee meniscus is a crucial component of the knee that functions to stabilize the joint, distribute load, and maintain congruency. Meniscus tears and degeneration are common, and natural healing is limited. Notably, few children present with meniscus injuries and other related fibrocartilaginous tissues heal regeneratively in immature animals and in the fetus. In this work, we evaluated fetal, juvenile, and adult bovine meniscus properties and repair capacity in vitro. Although no changes in cell behavior (migration and proliferation) were noted with age, drastic alterations in the density and distribution of the major components of meniscus tissue (proteoglycan, collagen, and DNA) occurred with development. Coincident with these marked tissue changes, the in vitro healing capacity of the tissue decreased with age. Fetal and juvenile meniscus formed a robust repair over 8 weeks on both a histological and mechanical basis, despite a lack of vascular supply. In contrast, adult meniscus did not integrate over this period. However, integration was improved significantly with the addition of the growth factor transforming growth factor-beta 3. Finally, to evaluate engineered scaffold integration in the context of aging, we monitored cellular infiltration from native tissue into engineered nanofibrous constructs. Our findings suggest that maturation processes that enable load bearing in the adult limit endogenous healing potential and identify new metrics for the development of tissue engineered meniscus implants. PMID- 20712421 TI - The role of the occupational therapist in Jordan: a survey of the members of the healthcare team exploring their knowledge about occupational therapy in rehabilitation hospitals. AB - PURPOSE: Occupational therapy (OT) is a developing profession that has only been introduced to Jordanian hospitals 18 years ago. The main objective of this study was to explore the level of knowledge the healthcare team members in Jordanian rehabilitation hospitals have about OT. METHOD: Two hundred and fifty questionnaires were distributed to different members in the healthcare team in three major hospitals in Jordan. One hundred fifty-three questionnaires were returned and used for analysis. RESULTS: Collectively, the results revealed a fair knowledge level about OT among the healthcare team members in rehabilitation, who stated that the main responsibilities of this profession were rehabilitation for activities of daily living, hand therapy and increasing the quality of life for disabled people. Furthermore, the majority of the respondents agreed that OT is a vital profession that plays an important role in rehabilitation teams, and expressed their expectations of developing standards and regulations for this profession. CONCLUSION: Actions should be channelled towards educating members of the team about OT through university curriculum. It is critical that the Jordanian Ministry of Health establishes specific statements and regulations which clarify the role of the OT within different settings of the healthcare system. PMID- 20712422 TI - Vascular wall as a reservoir for different types of stem and progenitor cells. AB - Tissue regeneration and several diseases such as tumor and atherosclerosis depend on new vessel formation by both angiogenesis and vasculogenesis. Endothelial cells (ECs) are widely considered to be the active cellular component in these processes, followed by contractile cells such as pericytes and smooth muscle cells. The best known sources providing these cell types or their progenitors are ECs lining the vessel lumen and bone marrow. As easily evident, the vessel wall was recognized as being a passive player to a great extent except ECs of the vascular intima. Particularly, the vascular adventitia has been considered as a passive layer rather than an active part of the vessel wall. But results provided during the last few years have led to a revision of this classical view because of an apparent stem cell niche function of the vascular adventitia. This review aims to sum up findings identifying the vessel wall as an important stem cell reservoir and discusses its impact on health and disease. PMID- 20712423 TI - Relationship of leptin, resting metabolic rate, and body composition in premenopausal hispanic and non-Hispanic White women. AB - OBJECTIVE: The purpose was to evaluate the relationships between fasting serum leptin, resting metabolic rate (RMR), and body composition in premenopausal Hispanic and non-Hispanic White (White) women. METHODS: Participants were 67 Hispanic and 43 White women who arrived at the laboratory in a fasted state for measurement of RMR by indirect calorimetry, bone mineral content measured by dual energy X-ray absorptiometry, and body density measured by hydrodensitometry. Serum leptin levels were determined by EIA. RESULTS: Multiple regression analysis revealed that body mass and lean body mass were the best predictors of RMR. Leptin was not a significant predictor of RMR. CONCLUSION: Further research needs to be done to examine the role of leptin on metabolism, especially in ethnic groups predisposed to development of obesity and related disorders. PMID- 20712424 TI - Relationship between leptin, adiponectin, bone mineral density, and measures of adiposity among pre-menopausal Hispanic and Caucasian women. AB - OBJECTIVE: The purpose of this study was to examine the relationship between fasting serum leptin and adiponectin levels with bone mineral density (BMD) and body composition in pre-menopausal, middle-aged Hispanic and Caucasian women. OBJECTIVE: Participants' (68 Hispanic and 36 Caucasian) BMD and bone mineral content were measured by dual-energy X-ray absorptiometry, and body density was measured by hydrodensitometry. Serum leptin was determined by enzyme immunoassay and adiponectin by ELISA. RESULTS: Hispanic women had significantly higher leptin, BMD, and fat mass (FM), and lower adiponectin than Caucasian women. There was no significant correlation between leptin and BMD for Hispanic or Caucasian women; adiponectin was inversely correlated with BMD in Caucasian women only (p = 0.01). In both Hispanic and Caucasian women, lean body mass and adiponectin best explained the variance in BMD (r(2) = 0.25, p < 0.001). CONCLUSION: These data demonstrate no significant relationship between leptin and BMD of pre-menopausal, middle-aged Hispanic and Caucasian women, and a significant inverse relationship between adiponectin and BMD in Caucasian women. The role of adipocytokines in the regulation of BMD remains inconclusive and may vary across ethnic groups. PMID- 20712425 TI - Comparative study of Misgav-Ladach and Pfannenstiel-Kerr cesarean techniques: a randomized controlled trial. AB - AIM: To compare Pfannenstiel-Kerr (PKM) and Misgav-Ladach (MLM) methods in terms of operation-related features and neonatal outcome in primary cesarean deliveries. METHODS: A total of 180 pregnant women randomized into PKM (n = 90) or MLM (n = 90) groups were included in this study. Primary outcome measures were total operative and extraction times, Apgar score, blood loss, wound complications, and the suture use. Secondary outcome measures were wound seroma and infection incidence, time of bowel restitution, and the perceived pain. RESULTS: Total operation and extraction times were significantly shorter and less suture material was used in the MLM group than the PKM group (p < 0.001). Initially, higher scores obtained for 6 h-VAS in the MLM group (p < 0.05) were normalized after 24 h of the operation. PKM and MLM were similar in terms of preoperative and postoperative levels of hemoglobin and hematocrit, wound complication, bowel restitution, fever, seroma, infection, wound dehiscence and the need for transfusion, antibiotic, and analgesics. CONCLUSION: The operation related morbidity of the MLM and PKM for primary C/S seem to be comparable; however, the MLM seems to be superior in terms of operation time and the amount of suture usage but inferior in pain scores in the early postoperative period. PMID- 20712426 TI - Differential effects of pioglitazone on metabolic parameters in newly diagnosed, drug-naive Japanese patients with type 2 diabetes with or without metabolic syndrome. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of pioglitazone on metabolic parameters in drug-naive Japanese type 2 diabetic patients with (Diabetes Mellitus Metabolic Syndrome [DMMS] group, n = 36) and without (Diabetes Mellitus non-Metabolic Sundrome [DMNMS] group, n = 36) metabolic syndrome. PATIENTS AND METHODS: The patients received monotherapy of 15-30 mg/day pioglitazone for 3 months. The baseline levels of metabolic parameters were compared with the levels after 3 months. RESULTS: At baseline, the two groups showed no significant difference in HbA1c (10.05 vs. 9.81%, n.s.) or systolic blood pressure (134.5 vs. 133.0 mmHg, n.s.), but had significant differences in diastolic blood pressure (84.7 vs. 78.9 mmHg, p < 0.05), insulin (14.96 vs. 7.09 microU/mL, p < 0.001), homeostasis model assessment insulin resistance index (HOMA-R) (8.49 vs. 3.96, p < 0.001), triglyceride (TG) (231.4 vs. 131.5 mg/dL, p < 0.0005), high-density lipoprotein (HDL)-C (46.6 vs. 56.1 mg/dL, p < 0.005), body weight (BW) (77.97 vs. 62.52 kg, p < 0.001), and body mass index (BMI) (28.14 vs. 22.86, p < 0.00001). In the DMMS group, significant changes of HbA1c (from 10.05 to 8.01%, p < 0.00001), insulin (-22.7%, p < 0.05), HOMA-R (-48.9%, p < 0.0002), TG (-20.8 %, p < 0.05), HDL-C (+12.0%, p < 0.00001), BW (+1.0 kg/+1.3%, p < 0.05), and BMI (+1.4%, p < 0.02) were observed after 3 months. In the DMNMS group, the reduction of HbA1c (from 9.81 to 8.33%, p < 0.00001) was similar to that in the DMMS group, but the changes of insulin (-4.7%, n.s.), HOMA R (-15.6%, n.s.), and TG (-12.9%, n.s.) were smaller and not significant. Significant increases of HDL-C (+9.2%, p < 0.02), BW (+0.64 kg/+1.0%, p < 0.05), and BMI (+1.0%, p < 0.02) were observed, but these changes were also smaller than the respective changes in the DMMS group. Based on the change of each parameter relative to its baseline value, significant intergroup differences were found for TG, insulin, or HOMA-R, whereas no such differences were observed for HDL-C, BW, and BMI. No subjects showed any clinically significant adverse events. CONCLUSIONS: These results suggest that the glucose-lowering effect of pioglitazone is comparable in patients with type 2 diabetes with or without metabolic syndrome, but that the drug has different effects on nonglycemic parameters including TG, insulin and HOMA-R in the two groups of patients. PMID- 20712427 TI - Ghrelin expression of endometrium hyperplasia and endometrioid carcinoma. AB - BACKGROUND: Endometrium carcinoma ranks fourth among female carcinomas. Therefore, early diagnosis of endometrium pre-malignant lesions is emphasised, and attempts are made to identify the risk factors. Since hyperplasias, particularly those with atypia, are held responsible for the development of the most common endometrium carcinomas, it is important to definitely distinguish between well-differentiated carcinomas and hyperplasia with atypia. In the present study, we aimed to explore whether ghrelin expression had a role in distinguishing between benign, pre-malignant and malignant lesions of endometrium. METHODS: Tissue ghrelin expressions of a total of 60 cases, who were diagnosed in the Pathology Department Laboratory of Firat University Medical School, and of whom 10 were in the proliferation phase, 10 had simple hyperplasia without atypia, 10 had simple hyperplasia with atypia, 10 had complex hyperplasia without atypia, 10 had complex hyperplasia with atypia and 10 had endometrioid carcinoma cases, were examined using immunohistochemical method. Additionally, tissue samples were homogenised to analyse tissue ghrelin levels in the supernatants according to RIA method. Samples from the parotid glands were used as positive control for ghrelin. Cells that exhibited cytoplasmic staining with ghrelin antibody were evaluated as positive. RESULTS: Immunohistochemical examination showed that ghrelin expression increased markedly in the proliferation phase, relative to hyperplasias and carcinoma. These results were parallel to ghrelin levels in tissue supernatants. Immunohistochemical and RIA analysis results indicate that ghrelin expression either markedly decreases or is entirely depleted in endometrial carcinomas. CONCLUSIONS: Therefore, we think that ghrelin expression can be useful in differentiating not only endometrium carcinomas from benign lesions but also complex hyperplasias with atypia, which pose diagnostic difficulties. PMID- 20712428 TI - New insights into the pathophysiology of endometriosis: from chronic inflammation to danger signal. AB - BACKGROUND: Various theories try to explain the development and progression of endometriosis, however, no single theory can explain all aspects of this disorder. Gene expression profiling studies might reveal factors that explain variability in disease development and progression, which can serve as specific biomarkers for endometriosis and novel drug development. We have recently showed that the upregulated genes were predominantly clustered in stress and detoxification, providing a mechanistic explanation for the oxidative stress and chronic inflammatory response in endometriosis. OBJECTIVE: This review aims: (1) to analyse the published data, with the aim of identifying pathways consistently regulated by the endometriosis genotype and (2) to summarise the findings of specific genes, which are involved in the process of oxidative stress and inflammation. METHODS: We identified gene array and proteomics studies whose data were accessible in PubMed. RESULTS: A major finding is the increased expressions of several markers including heat shock protein, S100, fibronectin, and neutrophil elastase, which might be involved in the process of Toll-like receptor (TLR)-dependent sterile inflammation. The study reviews a convergence in the main pathogenic process, where the TLR-mediated inflammation occurs possibly through the endogenous ligands. CONCLUSIONS: In conclusion, a circulus vitiosus of both the oxidative stress pathway and the TLR pathways is generated when the process becomes chronic (danger signal spiral). PMID- 20712429 TI - Change in cytokine levels after administration of saikokaryuukotsuboreito or testosterone in patients with symptoms of late-onset hypogonadism. AB - The purpose of this study was to evaluate plasma cytokine levels after treatment with saikokaryukotsuboreito (SKRBT), which is a herbal medicine, or androgen replacement treatment (ART), for patients with late-onset hypogonadism (LOH) related symptoms. Thirty-one patients over 40 years of age with LOH-related symptoms were included in this study. SKRBT was given orally three times daily to a total of 7.5 g/day for 15 eugonadal patients and ART was give to 16 hypogonadal patients by intramuscular injection of testosterone enanthate at 125 mg each time every 2 weeks. Plasma levels of testosterone and 18 cytokines, as well as LOH related symptoms scored according to the Aging Males' Symptoms (AMS) scale, were compared before and more than 2 months after treatment. In the ART group, the total AMS score was decreased and testosterone was increased significantly after treatment. No cytokine variables were altered significantly after the treatment. In the SKRBT group, although the total AMS score was significantly decreased, testosterone did not change. From the evaluation of cytokines, a significant increase was found in interleukin (IL)- 8, IL-13, interferon-gamma and tumour necrosis factor-alpha. We conclude that SKRBT might improve LOH-related symptoms in eugonadal patients through the beneficial effect of cytokines, a mechanism that is quite different from ART. PMID- 20712430 TI - Possible role of vitamin E, coenzyme Q10 and rutin in protection against cerebral ischemia/reperfusion injury in irradiated rats. AB - PURPOSE: To investigate the possible role of vitamin E, coenzyme Q10 and rutin in ameliorating the biochemical changes in brain and serum induced by cerebral ischemia/reperfusion (I/R) in whole body gamma-irradiated rats. MATERIALS AND METHODS: Cerebral ischemia was induced in male Wistar rats (either irradiated or non-irradiated) followed by reperfusion. RESULTS: I/R increased brain content of malondialdehyde (MDA) and depleted its glutathione (GSH) content with a compensatory elevation in cytosolic activities of glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes. It also raised brain cytosolic lactate dehydrogenase (LDH) activity and calcium (Ca(2+)) level. Furthermore, I/R provoked an inflammatory response reflected by an increment in serum levels of the proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interlukin-1beta (IL-1beta). Moreover, induction of I/R in irradiated rats resulted in a further increase in brain oxidative stress and cytosolic LDH activity, disturbed brain Ca(2+) homeostasis and exaggerated the inflammatory reaction. During irradiation, administration of each of vitamin E, coenzyme Q10 (CoQ10) and rutin to irradiated rats before induction of I/R, alleviated the brain oxidative stress. Moreover, these antioxidants caused attenuation of the rise of the cytosolic activities of GPx and GR. A lowering effect of the cytosolic LDH activity and Ca(2+) level were caused by treatment with antioxidants. Each of vitamin E and rutin revealed an anti-inflammatory action of these antioxidants, while CoQ10 had no effect on serum levels of TNF-alpha and IL 1beta. CONCLUSION: These findings indicate that supplementation with either vitamin E, CoQ10 or rutin ameliorated most of the biochemical changes induced by I/R in irradiated rat brain and serum. PMID- 20712432 TI - When tumor repopulation starts? The onset time of prostate cancer during radiation therapy. AB - PURPOSE: To analyze published clinical data and provide a preliminary estimate of tumor repopulation rate and its onset time during radiation therapy for prostate cancer. METHODS: Data on prostate cancer treated with external beam radiotherapy (EBRT) by Perez et al. (2004), Amdur et al. (1990) and Lai et al. (1991) were analyzed in this study. The stage-combined pelvic control rate from Perez et al. was calculated to be 0.95+/-0.01, 0.87+/-0.02, and 0.72+/-0.04 for patients treated <=7 weeks, 7.1-9 weeks, and >9 weeks respectively. Based on the Linear Quadratic model, extended to account for tumor repopulation, the least chi2 method was used to fit the clinical data and derive the onset time (T(k)) and effective doubling time (T(d)) for prostate cancer. Similar analysis was performed for the other two datasets. RESULTS: Best fit was achieved with onset time T(k)=34+/-7 days and doubling time T(d)=12+/-2 days. These parameters were independent of the choice of the alpha/beta values currently published in the literature. Analyses of the other two datasets showed T(k)=42+/-7 days with T(d)=9 +/- 3 days, and T(k)=34+/-6 days with T(d)=34+/-5 days, respectively. T(k) was found to be dependent on tumor stage. CONCLUSIONS: Consistent values for onset time T(k) were obtained from different datasets, while the range of doubling time T(d) was large. Tumor repopulation starts no later than 58 days (at 90% confidence level) in the course of EBRT for prostate cancer. PMID- 20712431 TI - Longitudinal studies of patients with ANCA vasculitis demonstrate concurrent reactivity to complementary PR3 protein segments cPR3m and cPR3C and with no reactivity to cPR3N. AB - Antibodies recognizing the complement of the middle of PR3 (cPR3m) occur in ~30% of PR3-anti-neutrophil cytoplasmic autoantibodies (ANCA)-vasculitis patients and immunization of animals with a peptide complementary to the middle of PR3 (cPR3m) induces not only anti-complementary PR3 antibodies, but also anti-PR3 antibodies derived through an anti-idiotypic response. PR3 epitopes recognized by patient ANCA, however, are not restricted to the middle of PR3. This prompted us to test for antibodies that react with proteins complementary to the terminal regions of PR3 (cPR3C and cPR3N) in PR3-ANCA patients. Anti-cPR3C reactivity was detected in 28% of patients but anti-cPR3N reactivity in only 15%. Ranked anti-cPR3C and anti cPR3m reactivity correlated in the cohort, whereas there was no significant relationship between cPR3C and cPR3N reactivity. Serial samples from 3 patients' revealed that anti-cPR3C and anti-cPR3m reactivity followed a similar pattern over time. Serial samples from a fourth patient demonstrated an anti-cPR3N response without concurrent cPR3m or cPR3C reactivity. Epitope determination by mass spectrometry identified a 13-amino acid sequence on cPR3C that contained a common binding site recognized by antibodies from three patients. This peptide sequence contains a "PHQ" motif which was reported to be the basis for cross reactivity of anti-cPR3m antibodies with plasminogen. Why these antibodies are detected in only ~30% of the patients remains unclear. The data reveal that it is not due to lack of inclusion of flanking regions of complementary PR3 during screening. Instead, quite unexpectedly, the data demonstrate that patients' antibodies react with a restricted epitope that exists in both cPR3m and cPR3C. PMID- 20712433 TI - Allergic laryngitis as a cause of dysphonia: a preliminary report. AB - OBJECTIVES: To investigate the relationship between air-borne allergen exposure and Voice Handicap Index scores in patients seeking medical treatment for rhinitis. METHODS: As we had previously identified a higher-than-expected incidence of allergy in patients presenting to a voice clinic, we undertook a prospective audit of patients without specific voice-related complaints presenting to a rhinology clinic to see if these patients might have unrecognized vocal dysfunction. To this end 70 consecutive patients with no pre-reported voice related symptoms presenting to a teaching hospital rhinology clinic underwent skin prick testing to common air-borne allergens and completed the Voice Handicap Index (VHI) questionnaire. Discriminant performances in the Voice Handicap Index and its individual domains and questions were determined using analysis of variance. An allergy-specific subset of the VHI was constructed and tested using receiver operating characteristic (ROC) statistics. RESULTS: There were 30 males and 40 females. Mean age was 36 +/- 12 years. Dust mite (83%), house dust mite (55%), and grass pollen (40%) were the commonest allergens, and 23 patients did not react to common allergens. Mean VHI score was 23.7 +/- 20.1 in patients with >= 4 allergens, 10.8 +/- 21.3 in patients with fewer than 4 allergies, and 7.8 +/ 8.5 in non-allergics (P = 0.044; analysis of variance). Nine VHI questions best discriminated between allergic and non-allergic patients (P < 0.05), and the combined VHI-9 score had a ROC area under the curve of 0.85. CONCLUSIONS: Patients with more air-borne allergies have a higher incidence of undiagnosed vocal dysfunction, as determined by the raised Voice Handicap Index score, than those with fewer or no such allergies. As noted, earlier work has shown that, conversely, patients with vocal dysfunction have a high incidence of undiagnosed allergy. PMID- 20712435 TI - Central administration of kisspeptin-10 inhibits water and sodium excretion of anesthetized male rats and the involvement of arginine vasopressin. AB - AIM: To investigate the effect of hypothalamus kisspeptin on water and sodium excretion and the possible mechanism. METHOD: The intracerebroventricular (icv) administration and radioimmunoassay were used to observe the effect of kisspeptin 10 on urine flow, sodium and potassium excretion, plasma arginine vasopressin (AVP), and atrial natriuretic peptide (ANP) concentrations in anesthetized male rats. The mediation of renal sympathetic nerve was also investigated by studies conducted on rats with bilateral renal sympathetic denervation. RESULTS: The urine flow, sodium excretion, and free water clearance decreased significantly by icv injection of 5 nmol kisspeptin-10 (p < 0.05) from 30 to 60 min post injection. Meanwhile, plasma AVP concentrations increased significantly 30 min after the icv injection of 5 nmol kisspeptin-10 (p < 0.05), whereas the equal dose of kisspeptin-10 did not significantly change plasma ANP concentrations. The mean arterial blood pressure, heart rate, and potassium excretion did not significantly change during the experiment. Furthermore, pretreatment with 5 nmol kisspeptin-10 could still significantly decrease urine flow and sodium excretion in renal sympathetic denervated rats. CONCLUSION: Central administration of kisspeptin-10 could inhibit sodium excretion and urine flow in anesthetized male rats, which is probably mediated by increasing the plasma AVP concentration and is independent of plasma ANP concentration and renal sympathetic nerve activity. PMID- 20712434 TI - Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-beta receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. AB - We have investigated whether systemic delivery of an oncolytic adenovirus, Ad.sTbetaRFc, expressing the soluble form of transforming growth factor-beta receptor II fused with human immunoglobulin Fc fragment (sTGFbetaRIIFc), could inhibit breast cancer bone metastasis in a mouse model. MDA-MB-231 (human breast cancer) cells were inoculated into the left heart ventricles of nude mice. Once the skeletal tumors were visible by X-rays, mice were intravenously injected with either buffer, Ad.sTbetaRFc, Ad(E1-).sTbetaRFc (a replication-deficient adenovirus expressing sTGFbetaRIIFc), or Ad.luc2 (a replicating adenovirus expressing firefly luciferase gene). On days 2 and 7 after viral injections, viral replication and sTGFbetaRIIFc expression were detected in the skeletal tumors in Ad.sTbetaRFc-treated group; only viral replication in Ad.luc2 group, and sTGFbetaRIIFc expression in the Ad(E1-).sTbetaRFc group, were detected. To examine the therapeutic effects, buffer or various viral vectors were administered on days 4 and 7 after intracardiac injection of MDA-MB-231 cells. On day 28, X-ray radiography showed a highly significant reduction in lesion size by Ad.sTbetaRFc, a significant reduction by Ad.luc2, and some reduction by Ad(E1 ).sTbetaRFc. Goldner's trichrome and hematoxylin-eosin staining of the bone sections revealed a significant reduction of tumor burden in the Ad.sTbetaRFc group, but not in the Ad(E1-).sTbetaRFc or Ad.luc2 group. There were significant reductions in free calcium levels by Ad.sTbetaRFc, Ad(E1-).sTbetaRFc, and Ad.luc2; however, only in the Ad.sTbetaRFc group were calcium levels reduced to the normal values. These results suggest that concomitant viral replication and sTGFbetaRIIFc production are important to inhibit bone metastasis and osteolysis, and that Ad.sTbetaRFc could be developed for targeting breast cancer bone metastases. PMID- 20712437 TI - Immediate implant placement into infected sites: bacterial studies of the Hydroacoustic effects of the YSGG laser. AB - This article describes the use of an erbium laser to use photoacoustics to reduce the bacteria in osteotomy sites that were infected by apical pathology. The author shows reduced bacterial counts by performing bacterial cultures following laser treatment. Swabs were taken after the extraction of the tooth and then after the laser was placed into the osteotomy site. The results showed a noticeable reduction of bacteria and no traces of virulent bacteria. PMID- 20712436 TI - The hypothalamic-pituitary-adrenal axis in women with differentiated thyroid cancer. AB - INTRODUCTION: We studied the function of hypothalamic-pituitary-adrenal (HPA) axis in females with differentiated thyroid cancer (DTC) and its sequelae on metabolism and cardiovascular risk. METHODS AND RESULTS: Sixteen women were investigated with (1) morning, evening, and midnight cortisol and adrenocortophic hormone, (2) cortisol after overnight 1 mg dexamethasone suppression test, (3) cortisol after corticotropin releasing hormone test, (4) oral glucose tolerance test with glucose and insulin estimations, and (5) ultrasound for carotid intima media thickness. A matched control group underwent similar investigations. None of the parameters was significantly different between patients and controls. CONCLUSION: Females with DTC have normal HPA-axis function and similar insulin sensitivity and cardiovascular risk compared to controls. PMID- 20712438 TI - Relationships between the gonial angle and mandibular ramus morphology in dentate subjects: a panoramic radiophotometric study. AB - Analysis of dental panoramic radiographs (DPRs) is an indispensable diagnostic tool for dental implants both pre and post operation. Many studies on linear and angular morphometry of the mandibular body have been conducted, but those on the mandibular ramus have not yet been reported. The purpose of this study was to investigate the differences in the morphometric parameters of the mandibular ramus between high and low gonial angles (GAs) on DPRs as well as between genders, and to determine the relationships between GA and variables of the mandibular ramus morphometry. The DPRs of 156 dentate subjects (78 for each gender) with more than 15 teeth present, a mean age of 49.54 years, and a mean number of teeth of 26.20 were examined. The films were divided into the following 2 groups of GA: less than 120 degrees (low gonial angle, LGA) and more than 125 degrees (high gonial angle, HGA) in both the right and left sides. The parameters for Ar'-Go, MaF-Go, RW, and RD in the LGA group were significantly larger than those in the HGA group in both men and women, but that for the ramus angle (RA) was significantly smaller in the LGA group than in the HGA group. Significant gender differences in the 2 GA groups were recognized with respect to the Ar'-Go, MaF-Go, RW, and RD parameters. Significant negative low and moderate correlations were found between GA and the Ar'-Go, MaF-Go, RW, and RD variables, whereas significant positive low correlation was found between GA and the RA variable. Within the limits of this study, the analysis of the mandibular ramus morphometry on DPRs in terms of GA size and gender was found to be useful for devising a highly predictive and strategic plan for implant-supported oral rehabilitation. PMID- 20712439 TI - Microstrains around standard and mini implants supporting different bridge designs. AB - The purpose of the study was to analyze microstrains around small- versus standard-diameter implants used in restoration of thin wiry ridge through different bridge designs. Additionally, influence of the site of occlusal vertical loading was evaluated using strain gauges. Two models simulating mandibular unilateral free-end saddle were fabricated. Two standard-size implants (3.75 * 13 mm) were inserted in one model in the position of the second premolar and first molar to support 2 3-unit cantilever bridges (NiCr alloy). On the other model, a standard implant and a mini implant (3.0 * 13 mm) were inserted in the position of the second premolar and second molar, respectively, to support 2 fixed-fixed 3-unit NiCr bridges. Four strain gauges were mounted buccally, lingually, mesially, and distally adjacent to each implant. The prostheses were temporarily cemented. A 300 N vertical load was applied on the middle of the horizontal runner bar connecting the prosthetic units and on the center of the pontics. Microstrains were recorded and analyzed. Cantilever bridges recorded higher microstrains than fixed-fixed bridges for both loading conditions. Yet, for both designs, loading on the horizontal runner bars, which apply an equal load on all bridge units simultaneously, resulted in significantly lower microstrain values than applying the load only on the pontics. Mini implant revealed greater strain values than standard implant supporting the same fixed partial denture. The best treatment option that produced the least microstrains was the fixed-fixed bridge with a mini implant as a terminal abutment. Mini implants induced higher microstrains than standard implants. PMID- 20712440 TI - Marginal bone loss around implants supporting fixed restorations. AB - A key criterion of success following dental implants is the marginal bone level. Long-term clinical and radiographic evaluation is necessary to test the results of in vitro studies investigating how cantilevering of restorations or implant size affect bone level changes around implants. There is no consensus on the effect of several variables such as age, gender, implant size, and cantilever prostheses on marginal bone levels around fixed dentures supported by dental implants. Patients who received cemented, fixed restorations supported by implants and who were examined in routine recall sessions 6, 12, 24, and 36 months after loading were included in the study group. Comparative bone level measurements were obtained from images of radiographs at *20 magnification using the CorelDraw 11.0 software program. Statistical analysis was performed using the Student t test and 1-way analysis of variance. In the 36-month observation period, there were no incidences of implant failure, excessive bone loss around implants, or peri-implant inflammation. One hundred twenty-six implants in 36 patients were evaluated, and the effect of several factors on marginal bone loss (MBL) during the 36 months after loading was analyzed statistically. There was no significant relationship between MBL and implant length or diameter, whereas age, gender, and cantilevers affected bone loss rates. MBL was elevated in older and female patients as well as in patients who received cantilevers. In cases of limiting anatomic conditions, short and/or narrow implants should be preferred over cantilever extensions. PMID- 20712441 TI - Estimation of the safe distance between the implant and an adjacent tilted implant using trigonometry. PMID- 20712442 TI - A comparison of peripheral marginal bone loss at dental implants measured with conventional intraoral film and digitized radiographs. AB - The purpose of the present study was to examine the effects of conventional and bone-condensing implantation techniques and time (6 and 12 months after implantation) on levels of marginal bone surrounding implants and to assess the level of agreement between measurements made using digitized intraoral images and film. The study group consisted of 14 healthy patients (9 female, 5 male; age range, 23-59 years; mean age, 41.1 years) with 28 single-tooth dental implants. In each patient, an implant was placed on one side using a conventional technique and on the opposite side using a bone-condensing technique. Film radiographs were taken at 6 and 12 months following implant placement and were digitized at 300 dpi and 600 dpi using a laser scanner. All scanned images were stored as both TIFF and JPEG files. A single observer twice measured distal and mesial marginal bone loss from film and digitized images. At the mesial site, there was a significant main effect of time (6 and 12 months after implantation) on the measurement of bone loss, F(1, 26) = 6.08, P = .02, but no significant main effect of implantation technique, F(1, 26) = 1.56, P = .223, and no significant interaction between time and technique, F(1, 26) = 2.09, P = .160. Similarly, at the distal site, there was a significant main effect of time on the measurement of bone loss, F(1, 26) = 14.1, P = .001, but no significant main effect of implantation technique, F(1, 26) = 1.21, P = .281. However, in contrast to the mesial site, there was also significant interaction between technique and time on the distal site, F(1, 26) = 4.974, P = .035. Intraobserver intraclass correlation coefficients and repeatability measurements showed high agreement for all image types. The bone-condensing technique resulted in greater marginal bone loss. Marginal bone measurements made using digitized intraoral images and conventional film showed high levels of agreement. PMID- 20712443 TI - Comparative stress distribution of implant-retained mandibular ball-supported and bar-supported overlay dentures: a finite element analysis. AB - Implant-retained mandibular ball-supported and bar-supported overlay dentures are the two most common treatment options for the edentulous mandible. The superior option in terms of strain distribution should be determined. The three dimensional model of mandible (based on computerized tomography scan) and its overlying implant-retained bar-supported and ball-supported overlay dentures were simulated using SolidWorks, NURBS, and ANSYS Workbench. Loads A (60 N) and B (60 N) were exerted, respectively, in protrusive and laterotrusive motions, on second molar mesial, first molar mesial, and first premolar. The strain distribution patterns were assessed on (1) implant tissue, (2) first implant-bone, and (3) second implant-bone interfaces. Protrusive: Strain was mostly detected in the apical of the fixtures and least in the cervical when bar design was used. On the nonworking side, however, strain was higher in the cervical and lower in the apical compared with the working side implant. Laterotrusive: The strain values were closely similar in the two designs. It seems that both designs are acceptable in terms of stress distribution, although a superior pattern is associated with the application of bar design in protrusive motion. PMID- 20712444 TI - Should the implant fit the patient or should the patient fit the implant? PMID- 20712446 TI - Effect of surgical guide design and surgeon's experience on the accuracy of implant placement. AB - Implant position is a key determinant of esthetic and functional success. Achieving the goal of ideal implant position may be affected by case selection, prosthodontically driven treatment planning, site preparation, surgeon's experience and use of a surgical guide. The combined effect of surgical guide design, surgeon's experience, and size of the edentulous area on the accuracy of implant placement was evaluated in a simulated clinical setting. Twenty-one volunteers were recruited to participate in the study. They were divided evenly into 3 groups (novice, intermediate, and experienced). Each surgeon placed implants in single and double sites using 4 different surgical guide designs (no guide, tube, channel, and guided) and written instructions describing the ideal implant positions. A definitive typodont was constructed that had 3 implants in prosthetically determined ideal positions of single and double sites. The position and angulation of implants placed by the surgeons in the duplicate typodonts was measured using a computerized coordinate measuring machine and compared to the definitive typodont. The mean absolute positional error for all guides was 0.273, 0.340, 0.197 mm in mesial-distal, buccal-lingual, vertical positions, respectively, with an overall range of 0.00 to 1.81 mm. The mean absolute angle error for all guides was 1.61 degrees and 2.39 degrees in the mesial-distal and buccal-lingual angulations, respectively, with an overall range of 0.01 degrees to 9.7 degrees . Surgical guide design had a statistically significant effect on the accuracy of implant placement regardless of the surgeon's experience level. Experienced surgeons had significantly less error in buccal-lingual angulation. The size of the edentulous sites was found to affect both implant angle and position significantly. The magnitude of error in position and angulation caused by surgical guide design, surgeon's experience, and site size reported in this study are possibly not large enough to be clinically significant; however, it is likely that errors would be magnified in clinical practice. Future research is recommended to evaluate the effect of surgical guide design in vivo on implant angulation and position error. PMID- 20712447 TI - Esthetic and functional reconstruction of the posttumoral interrupted mandible with double-barrel fibular free flap graft: rationale for a microsurgical and prosthodontic approach. AB - Reconstruction after substantial osseous, cutaneous, and muscular tissue loss following a mandibular resection is a challenge. The use of a fibular free flap is an outstanding, but delicate, treatment option. These grafts, using the double barrel technique, can achieve an almost complete reconstruction of the mandibular defect. The challenge posed by these treatments is to achieve an end result that is both functional and esthetically pleasing-an endeavor that requires a defined prosthetic plan prior to complete microsurgical reconstruction. Using a detailed clinical case, this article discusses the importance of planning the mandible reconstruction with double-barrel fibular graft in view of an implant-supported fixed partial denture. Immediate implant loading was even possible in this case. This approach allows improvement of the final esthetic and functional result of such a complex rehabilitation. Maxillofacial reconstructive surgery should seek to establish a near-as-normal anatomic situation that will allow a permanent implant rehabilitation that is both esthetic and durable. PMID- 20712450 TI - Sources of variability in ketoconazole inhibition of human cytochrome P450 3A in vitro. AB - Despite the extensive use of ketoconazole as an index inhibitor of human cytochrome P450 3A (CYP3A) isoforms in vitro, literature reports of the quantitative inhibitory potency of ketoconazole are highly variable. In 51 published studies reporting 76 values of ketoconazole inhibition constants (K(i)) versus in vitro clearance of 31 different CYP3A substrates, the K(i) values ranged from 0.001 uM to 25 uM. The geometric mean was 0.1 uM (90% confidence interval: 0.07 to 0.15 uM), and the median was 0.08 uM. Even for one specific substrate metabolized to one specific metabolite (midazolam alpha-hydroxylation), variability was still extensive (K(i) range: 0.004-0.18 uM). Only about 20% of overall variability in K(i) was explained by a combination of incubation, duration, and microsomal protein concentration. The remaining variation is unexplained, but could be attributable to factors such as: in vitro clearance by non-CYP3A pathways; incorrect assignment of inhibition mechanism; and variable relative content of CYP3A4 and CYP3A5 in different microsomal preparations. However, the role of these factors still is not established. Until sources of variation are more clearly defined, variability can be minimized by use of low microsomal protein concentrations, short incubation periods, and data analysis procedures that use untransformed reaction velocities and inhibition models that allow for mixed competitive-noncompetitive mechanisms. PMID- 20712449 TI - Human foreskin fibroblasts exert immunomodulatory properties by a different mechanism to bone marrow stromal/stem cells. AB - Human bone marrow mesenchymal stromal/stem cells (BMSCs) have been reported to possess immunomodulatory functions with the capacity to suppress immune reactions partly mediated by immunosuppressive factors, indoleamine 2,3-dioxygenase and nitric oxide, and suggested to be potentially applicable for therapeutic use. More recently, other fibroblast-like cells have been reported to possess similar properties. Here we demonstrate that human foreskin fibroblasts (HFFs) express an MSC-like immunophenotype and possess immunosuppressive properties similar to BMSCs but lack the capacity for osteogenic and adipogenic differentiation. HFFs suppressed human peripheral blood mononuclear cells (PBMC) proliferation stimulated with mitogen or in an allogeneic mixed lymphocyte reaction comparable to BMSCs. However, HFFs showed undetectable levels of indoleamine 2,3-dioxygenase and inducible nitric oxide synthase expression, in contrast to BMSCs when cocultured with activated PBMCs. To identify HFF specific immunosuppressive factors, we performed array profiling of common cytokines expressed by HFFs and BMSCs alone or when cocultured with activated PBMCs. Real-time polymerase chain reaction analysis confirmed that multiple factors were upregulated in HFFs cocultured with activated PBMCs compared with HFFs alone or BMSCs cultured under the same conditions. Functional assays identified interferon-alpha as the major immunosuppressive mediator expressed by HFFs. These results suggest that the HFFs possess immunosuppressive properties, which are mediated by alternate mechanisms to that reported for BMSCs. PMID- 20712451 TI - Cell free DNA detected by a novel method in acute ST-elevation myocardial infarction patients. AB - BACKGROUND: High levels of circulating cell free DNA (CFD) have been associated with poor prognosis in various diseases. Data pertaining to CFD in acute myocardial infarction (MI) are scarce. The available data have been obtained by either electrophoresis or polymerase chain reaction. We evaluated a novel method for the detection of CFD in patients with ST elevation myocardial infarction (STEMI) and examined its correlation with established markers of necrosis and ventricular function. METHODS: Serum concentrations of CFD, troponin-T and creatine kinase (CK) were measured simultaneously in 16 randomly selected acute STEMI patients upon admission and at three more time points. 47 healthy subjects served as a control group. CFD was quantified by a novel rapid fluorometric assay. Ejection fraction (EF) was assessed by echocardiography. RESULTS: Peak CFD levels were significantly higher in patients compared with controls (P = 0.001) and correlated with peak levels of CK and troponin-T (R = 0.79, P <0.001); R = 0.65, P = 0.006, respectively). Peak CFD levels tended to be associated with lower EF (P = 0.075). CONCLUSION: With this method, CFD levels correlated with the levels of established markers of myocardial necrosis but not with EF. The kinetic pattern of CFD release after STEMI and its prognostic value require further investigation. PMID- 20712452 TI - Prognosis and high-risk complication identification in unselected patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. AB - AIMS: The aim of this study was to evaluate treatment with primary percutaneous coronary intervention (PCI) in unselected patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We registered complication and mortality rates in all patients with STEMI admitted for primary PCI at a high-volume center over a two-year period (2004 to 2006). RESULTS: We included 1022 consecutive patients (mean age 64 years; 69% men). In-hospital and one-year mortality were 8% and 12%, respectively. Cardiac arrest, cardiogenic shock, left ventricular ejection fraction or =15 IU/mL. The mean rubella antibody concentration measured by both assays was >37 IU/mL; however, 10% of our study participants had low concentrations of circulating rubella-specific antibodies. These findings might indicate a need for additional monitoring of antibody levels as these children reach child-bearing age, or potentially a need for a third dose of vaccine to increase seroconversion. PMID- 20712480 TI - Characterization of Anti-HCV Antibodies in IL-10-Treated Patients. AB - There is limited information on the direct role of the neutralizing antibody responses against hepatitis C virus (HCV) infection or methodologies to study them. Previously we have demonstrated that interleukin-10 (IL-10) administered to chronic hepatitis patients led to a decrease in disease activity, but an increase in HCV viral burden. The mechanism behind this is unknown. The objective of this study was to examine the antibody response in IL-10-treated patients. To establish a neutralization antibody assay, HCV-positive and HCV-negative sera were collected and incubated with HCV strain JFH-1 particles before culture with Huh 7.5 cells. Viral replication was measured a week later by either indirect immunofluorescence assay (iIFA) or real-time reverse transcriptase polymerase chain reaction (RT-PCR). After validation of the methodology, the sera from 30 previously-described subjects of a group previously treated with IL-10 were tested for the neutralization capacity of their antibodies. The amount of total anti-HCV antibody in the sera was also measured by direct staining of HCV full length replicon cells. With this validated neutralization assay for anti-HCV antibodies we found that HCV-neutralizing antibodies are universally present, but with significantly different titers. In patients who were treated with IL-10, the total anti-HCV antibody titers appear to be constant, but with significantly decreased antibody neutralization activity. Our study validates an assay to quantitatively determine the presence and strength of HCV-specific neutralizing antibodies. We have found that IL-10-treated patients have significantly lower HCV antibodies, but maintain the total anti-HCV antibody titer, suggesting a novel mechanism by which IL-10 treatment increases viral load in patients. PMID- 20712481 TI - Antibody-dependent enhancement of coxsackievirus B3 infection of primary CD19+ B lymphocytes. AB - Coxsackievirus B3 (CVB3) is associated with several different acute and chronic forms of human disease, including myocarditis, aseptic meningitis, and pancreatitis. Moreover, CVB3 also infects immune cells like CD19+ B lymphocytes, but the viral uptake mechanism into these cells is not well understood. Therefore, primary murine and human CD19+ B cells were isolated by magnetic activated cell separation technology and analyzed for virus receptor expression, antibody-dependent enhancement of viral infection, and different cellular surface proteins, that might be involved in mechanisms of viral uptake. Western blot analysis of these cells revealed no significant expression of the coxsackievirus adenovirus receptor CAR. But incubation of CVB3 with serum dilutions, which exhibited binding but not neutralizing characteristics, increased viral uptake and replication significantly in a dose-dependent manner. Viral entry was reduced when Fc portions of immunoglobulins were blocked by protein A treatment. Moreover, the classical complement system rather than Fc-gamma-receptor-mediated mechanisms could be involved in viral uptake. Taken together, these data suggest an antibody-dependent enhancement of CVB3 infection of primary murine and human CD19+ B cells. PMID- 20712482 TI - Both systemic and mucosal LCMV immunization generate robust viral-specific IgG in mucosal secretions, but elicit poor LCMV-specific IgA. AB - Immunoglobulins in secretions play a critical role in protection at mucosal surfaces. We examined the generation of viral-specific IgG and IgA in plasma and mucosal secretions of mice following systemic or mucosal immunization with lymphocytic choriomeningitis virus (LCMV), a widely used experimental model of viral infection. While there are early differences in humoral responses depending on the route of viral entry, we show that both routes generate comparably robust viral-specific IgG in plasma, vaginal, lung, and nasal secretions of immune mice. In contrast, LCMV elicited poor viral-specific IgA responses. Mice that were infected IN showed elevated viral-specific IgA in nasal and lung washes compared to IP-infected mice; however, LCMV-specific IgG overwhelmingly contributed to the humoral response in all mucosal secretions examined. Thus similarly to HIV-1, and several other mucosally-encountered microbial infections, these data suggest that LCMV infection fails to induce vigorous viral-specific IgA responses. PMID- 20712483 TI - Expression and serological characterization of polyomavirus WUPyV and KIPyV structural proteins. AB - The polyomaviruses WUPyV and KIPyV were recently discovered. We expressed their structural proteins VP1, VP2, and VP3, and the corresponding proteins of BKV and JCV, for immunoblotting of IgG antibodies from 115 wheezing young children and 25 asymptomatic adults. Furthermore, nasopharyngeal aspirates (NPA) and sera from the children were examined by PCR for viral DNA. The overlapping minor proteins VP2 and VP3 of WUPyV and KIPyV were more reactive in immunoblots than the major protein VP1; of 100 NPA PCR-negative wheezing children aged < or = 4 y, 31 (31%) and 31 (31%) were positive for WUPyV and KIPyV VP2/VP3, compared to only 3 (3%) and 5 (5%) for VP1, respectively. For comparison, the respective WUPyV and KIPyV IgG seroprevalences as determined by immunofluorescence assay (IFA) with nondenatured VP1 were 80% and 54%, respectively, among 50 NPA PCR-negative children aged < or = 2 y. This difference shows the importance of conformational VP1 antigenicity. Of the 25 adults, 52% and 68% were IgG-positive in immunoblots for VP2/VP3 of WUPyV and KIPyV, and 8% and 12% were for VP1, respectively. Of the 192 NPA samples studied by PCR, 7 (3.6%) were positive for WUPyV, and 3 (1.5%) were positive for KIPyV DNA. Unlike the NPA samples, none of the corresponding 443 sera contained WUPyV or KIPyV DNA. Together with the high VP2/VP3 IgG prevalence, this points to a paucity or brevity of KIPyV and WUPyV viremias among immunocompetent children. Our results indicate the significance of protein conformation in immunoreactivity of VP1, and show the antigenic importance of the WUPyV and KIPyV minor proteins VP2 and VP3. The high and rapidly increasing IgG prevalence rates observed in this study for WUPyV and KIPyV support the notion that these novel polyomaviruses are widespread and are acquired early in childhood. PMID- 20712484 TI - Protection of ferrets from infection by swine-origin 2009 A (H1N1) influenza virus by the inactivated vaccine. AB - Swine-origin pandemic 2009 A (H1N1) influenza viruses are still infecting humans, and humans are currently being vaccinated with the inactivated vaccine of 2009 A (H1N1) influenza virus. We wanted to determine the efficacy of 2009 A (H1N1) inactivated vaccine in ferrets. Ferrets immunized with one dose (7.5 microg) of 2009 A (H1N1) inactivated vaccine were not protected from infections of either pandemic H1N1 or seasonal H1N1 influenza viruses, while ferrets immunized with two doses of 2009 A (H1N1) inactivated vaccine were protected from infections of pandemic H1N1, but not seasonal H1N1 influenza viruses. IgG subtype of antibody was dominantly detected in tissues of immunized ferrets. Our study suggests that pandemic H1N1 vaccine may not elicit the antibody cross-reactive to the seasonal H1N1 influenza virus. PMID- 20712485 TI - A variable region in GP4 of European-type porcine reproductive and respiratory syndrome virus induces neutralizing antibodies against homologous but not heterologous virus strains. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) can induce severe reproductive failure in sows, and is involved in the porcine respiratory disease complex. The glycoprotein GP4 of the European prototype PRRSV strain Lelystad virus (LV) contains a linear neutralizing epitope that is located in a highly variable region. The current study aimed to evaluate the antibody response against this and other epitopes on GP4 to infection of pigs with European-type PRRSV. It was shown that three virus strains, differing in the region that corresponds to the neutralizing epitope on GP4 of LV, strongly induce antibodies against this area. Antibodies against the epitopes of the different virus strains were purified from polyclonal swine sera, and used in virus-neutralization tests on primary alveolar macrophages. This revealed that antibodies against the variable region in GP4 of different virus strains are able to neutralize infection with homologous but not heterologous virus strains. PMID- 20712486 TI - Detection of anti-HPV11-L1 antibodies in immune sera from patients suffering from recurrent respiratory papillomatosis using ELISA. AB - Infection with human papillomaviruses (mostly HPV6 and HPV11) may lead to recurrent respiratory papillomatosis (RRP), a chronic disease affecting 2 4/100,000 people. Papillomas have to be removed surgically so patients can breathe normally. Papillomas often grow back and some patients are subjected to a number of operations. In general, asymptomatic HPV-positive people have low levels of antiviral antibodies in their sera, as the human humoral response is weak due to HPV's biology. In patients suffering from RRP who have undergone multiple surgeries, a blood-epithelium barrier breach stimulates the production of anti-HPV antibodies. Our study's aim was to produce HisTag-HPV11-L1 major capsid protein in E. coli cells, and to purify it. We also sought to detect anti HPV11-L1 antibodies in antisera obtained from RRP patients using ELISA. Clinical samples were collected from 47 patients with RRP (antisera and papillomas), and from 32 controls (sera and oral swabs), from the Wielkopolska region of Poland. Antisera and control sera were used to coat microplates, HisTag-HPV11-L1 antigen was applied, and antibody-antigen complexes were detected by anti-HisTag monoclonal antibody in an ELISA assay. Simultaneously, total cellular DNA was extracted from papillomas and oral squamous cells obtained from controls. All DNA samples were screened for HPV DNA using MY-PCR. All patients were HPV-positive (30% for HPV6 and 70% for HPV11). Statistically significant correlations were found between the amount of anti-HPV11-L1 antibodies in the sera of RRP patients and the number of surgical procedures they underwent. Although HPV virus-like particles are most often used for anti-HPV antibody detection, the ELISA method presented herein is another viable option for use in RRP patients. PMID- 20712487 TI - Interleukin-10 antisense oligodeoxynucleotide suppresses IL-10 expression and effects on proinflammatory cytokine responses to porcine reproductive and respiratory syndrome virus. AB - Upregulation of interleukin-10 (IL-10) expression has been suggested to be the mechanism by which the porcine reproductive and respiratory syndrome virus (PRRSV) suppresses the innate and adaptive immune response in infected pigs. In this study we evaluated the potential of phosphorothioate-modified IL-10 antisense oligodeoxynucleotide specific to the translation initiation region of porcine IL-10 mRNA (IL-10AS) in enhancing proinflammatory cytokine responses to PRRSV. Naive peripheral blood mononuclear cells from eight PRRSV-seronegative pigs were transfected with IL-10AS in vitro prior to PRRSV inoculation and phorbol 12-myristate 13-acetate plus ionomycin or concanavalin A stimulation. The effects of IL-10AS on mRNA expression of IL-10, interferon-gamma (IFN-gamma), IFN alpha, tumor necrosis factor-alpha (TNF-alpha), IL-2, and IL-4 were tested by real-time PCR. The percentages of IFN-gamma-producing T-cell subsets were determined by flow cytometry. Compared to the controls, the levels of IL-10 and IL-2 mRNA were significantly reduced, while those of IFN-gamma mRNA were increased, and TNF-alpha, IFN-alpha, and IL-4 mRNA were unchanged. An increase in the percentage of the IFN-gamma+ population was also observed in lymphocytes and CD8beta+ T cells. Our results suggest that IL-10AS has the potential to enhance proinflammatory cytokine responses to PRRSV infection. PMID- 20712488 TI - Characterization of a variant virus from ascitic fluid of subacute granulomatous serositis in interferon-gamma-deficient C57BL/6 mice persistently infected with murine coronavirus strain JHM. AB - Previously, we showed that intraperitoneal infection with murine coronavirus strain JHM (JHMV) established a persistent infection with subacute granulomatous serositis in interferon-gamma-deficient C57BL/6 (B6-GKO) mice. Herein, we characterize a variant virus from B6-GKO mice persistently infected with JHMV. Viruses were isolated from ascites at 25 d post-infection and cloned by limiting dilution on DBT cells; one variant was named 25V16G. To compare pathogenicity in vivo, we inoculated 25V16G and JHMV intraperitoneally into 8- to 12-week-old B6 GKO mice. Whereas nearly all of the B6-GKO mice infected with JHMV survived over 14 d, all of those infected with 25V16G died by 9 d post-infection. Histopathological examination revealed that 25V16G induced acute fulminant hepatitis in B6-GKO mice, whereas JHMV caused severe but focal hepatitis. The virus titer of 25V16G in the liver was 50- and 250-fold higher than that of JHMV at 5 and 7 d post-infection, respectively. However, there was no significant difference in viral growth between 25V16G and JHMV in cell lines cultured in vitro. Nucleotide sequencing of the S gene of 25V16G and JHMV revealed a deletion of 29 amino acids encompassing S(511-539), which covers a major cytotoxic T lymphocyte (CTL) epitope in C57BL/6 mice, and two point mutations resulting in amino acid changes in the S protein of 25V16G. One explanation for the greater pathogenicity of 25V16G is that 25V16G escapes CTL-mediated protection in B6-GKO mice. This experimental model may be used to assess the role of IFN-gamma in viral persistence in vivo. PMID- 20712489 TI - Association between mannose-binding lectin gene polymorphism and pediatric cytomegalovirus infection. AB - Mannose-binding lectin (MBL) is an important constituent of the human innate immune system, and can bind to a wide range of pathogens, including viruses such as influenza A, HIV, herpes simplex 2, and SARS-CoV. MBL deficiency results from single nucleotide polymorphisms (SNPs) in exon 1, and the promoter region of the human MBL2 gene has been found to be associated with susceptibility to a number of infections. However, studies on the interactions between MBL and CMV infection are limited. In this study, we investigated 104 children suffering from HCMV infection, in an effort to find any association between MBL and HCMV infection of children in China. We analyzed the genotypes of 104 HCMV patients and 105 healthy controls, and investigated the distributions of polymorphisms at -550(H/L), 221(Y/X), and +4(P/Q), together with their structural variants. Although there was no significant difference in the distribution of B alleles between HCMV patients and healthy controls, the frequencies of the high-MBL-level related genotype of YA type in HCMV patients were significantly lower than those seen in healthy controls, while low-level related genotypes of XB type were more common in HCMV patients. In addition, CMV-DNA quantification revealed higher viral loads of the XB type in HCMV patients. Thus we can speculate that as an acute response protein and a pattern-recognition molecule of the innate immune system, MBL may play a role in protecting against HCMV infection in children, and MBL gene mutations may be a significant risk factor for the development of infantile HCMV infection. PMID- 20712490 TI - High frequency of variant alleles of the mannose-binding lectin 2 (MBL2) gene are associated with patients infected by hepatitis B virus. AB - Patients with hepatitis B virus (HBV) infection may develop severe chronic liver disease. Carriers of HBV have an increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Worldwide an estimated 350 million people are infected with HBV, and 15-40% will develop serious sequelae in their lifetime. In our study we investigated the association of single nucleotide polymorphisms (SNPs) in the first exon and promoter region of the mannose-binding lectin gene 2 (MBL2) situated on chromosome 10, with susceptibility to HBV infection. One-hundred and two patients infected with HBV were included in this study, and 232 uninfected individuals were used as healthy controls. Genotyping of the first exon (alleles A/O) was performed using a melting temperature assay. Genotyping of the promoter region (-550 H/L; -221 Y/X) was performed using the Taqman PCR technique. In the HBV-infected group we found a significantly increased frequency of haplotypes associated with low serum MBL. Our findings may indicate that MBL has a protective role against HBV infection in the studied population. PMID- 20712491 TI - Highlights from the August 2010 issue of DNA and Cell Biology. PMID- 20712492 TI - Using objective measures prepares psychologists for a brain-based taxonomy. PMID- 20712493 TI - Self-presentation 2.0: narcissism and self-esteem on Facebook. AB - Online social networking sites have revealed an entirely new method of self presentation. This cyber social tool provides a new site of analysis to examine personality and identity. The current study examines how narcissism and self esteem are manifested on the social networking Web site Facebook.com . Self esteem and narcissistic personality self-reports were collected from 100 Facebook users at York University. Participant Web pages were also coded based on self promotional content features. Correlation analyses revealed that individuals higher in narcissism and lower in self-esteem were related to greater online activity as well as some self-promotional content. Gender differences were found to influence the type of self-promotional content presented by individual Facebook users. Implications and future research directions of narcissism and self-esteem on social networking Web sites are discussed. PMID- 20712494 TI - Conflict management in online relationships. AB - With the diffusion of networked technology, personal relationships can be easily formed and maintained online today. Similar to a face-to-face situation, conflict is also seen in these online relationships. Early theories suggested that computer-mediated communication (CMC) tends to increase conflicts because of the lack of social-context cues, and CMC is not rich enough to manage conflict. As CMC has become part of our daily life, we often face conflict online, and thus we need to understand how people manage conflict online. This study explored how online users manage interpersonal conflict. Self-report survey data from 159 university students were analyzed to examine their conflict-management styles in association with the perceived closeness of the online relationship and a future intention toward the relationship. The results indicated that online users select cooperative management styles to handle conflict in their close relationships. In addition, online users avoid less cooperative styles when they want to continue the relationship. PMID- 20712495 TI - Differentiation of Internet addiction risk level based on autonomic nervous responses: the Internet-addiction hypothesis of autonomic activity. AB - How high-risk Internet addiction (IA) abusers respond to different autonomic nervous activities compared with low-risk subjects may be a critical research goal with prevention and treatment implications. The aim of the present study was to address this issue by observing differences between high- and low-risk IA abusers in four physiological assessments when surfing the Internet: blood volume pulse (BVP), skin conductance (SC), peripheral temperature (PTEMP), and respiratory response (RESPR). Forty-two male and ten female participants aged 18 24 years were screened with the Chen Internet Addiction Scale (CIAS, 2003), and then separated into high- and low-risk IA groups. Using psychophysiology equipment, participants encountered a 3-minute adaptation period followed by a 6 minute testing period for surfing the Internet on baseline and testing phases. The present results indicate that: (a) the CIAS scores were positively and negatively correlated with the RESPR and the PTEMP; (b) the PTEMP and RESPR of high-risk IA abusers were respectively weaker and stronger than those of low-risk IA abusers; the BVP and SC of high-risk IA abusers were respectively augmented and decreased relative to low-risk IA abusers. Thus we suggest that four autonomic responses may be differentially sensitive to abusers' potency in terms of the IA hypothesis of autonomic activity. The stronger BVP and RESPR responses and the weaker PTEMP reactions of the high-risk IA abusers indicate the sympathetic nervous system was heavily activated in these individuals. However, SC activates parasympathetic responses at the same time in the high-risk IA abusers. The paradoxical responses between the sympathetic and parasympathetic actions are addressed in the discussion. PMID- 20712496 TI - Predictive factors of excessive online poker playing. AB - Despite the widespread rise of online poker playing, there is a paucity of research examining potential predictors for excessive poker playing. The aim of this study was to build on recent research examining motives for Texas Hold'em play in students by determining whether predictors of other kinds of excessive gambling apply to Texas Hold'em. Impulsivity, negative mood states, dissociation, and boredom proneness have been linked to general problem gambling and may play a role in online poker. Participants of this study were self-selected online poker players (N = 179) who completed an online survey. Results revealed that participants played an average of 20 hours of online poker a week and approximately 9% of the sample was classified as a problem gambler according to the Canadian Problem Gambling Index. Problem gambling, in this sample, was uniquely predicted by time played, dissociation, boredom proneness, impulsivity, and negative affective states, namely depression, anxiety, and stress. PMID- 20712497 TI - Internet-usage patterns of immigrants in the process of intercultural adaptation. AB - This paper investigates Internet-usage patterns of immigrants, and seeks to identify the correlation between Internet use and intercultural adaptation. The study focuses on mainland Chinese immigrants in Singapore, and was conducted via a nationwide telephone survey. The results show that immigrants tend to change their preferences on Internet use to reflect their residence in the host country. In particular, the longer an immigrant resides in the host country, the less likely they would be to surf their original country's websites and the more likely they would be to communicate with local people via the Internet. More importantly, differences in Internet usage are found to have a significant impact on immigrants' intercultural adaptation. In an online environment, the social communication in the host country is a critical component that can facilitate or impede immigrants' successful adaptation to the host country, whereas ethnic social communication also plays a role at the initial stage of transition. PMID- 20712498 TI - Mental health, personality, and parental rearing styles of adolescents with Internet addiction disorder. AB - The objectives of this study were to compare the personality profiles of adolescent males with and without Internet addiction disorder (IAD), and to determine if IAD is associated with specific parental rearing behaviors. A total of 304 subjects (204 IAD positive and 100 IAD negative controls) completed three instruments: Symptom Checklist-90-revision (SCL-90-R), Eysenck Personality Questionnaire Revised (EPQ-R), and Egna Minnen av Barndoms Uppfostran--'My Memories of Upbringing' (EMBU). SCL-90-R profiles of adolescents with IAD revealed comparatively higher mean scores for all of the nine domains, and significantly higher scores for obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, and paranoid ideation; the mean global symptom index of adolescents with IAD was also significantly higher by approximately 10%. EPQ profiles of adolescents with IAD showed that Internet-dependent individuals tended to exhibit a significantly lower degree of extraversion and a significantly higher degree of psychoticism when compared with the control group. EMBU profiles revealed that adolescents with IAD generally rated both maternal and paternal rearing practices as lacking in emotional warmth, being over involved, rejecting, and punitive (mothers only). The results of this study confirm that IAD often occurs concurrently with mental symptoms and personality traits such as introversion and psychoticism. Adolescents with IAD consistently rated parental rearing behaviors as being over-intrusive, punitive, and lacking in responsiveness. These findings suggest that the influences of parenting style and family function are important factors in the development of Internet dependency. PMID- 20712499 TI - An Internet-based self-help treatment for fear of public speaking: a controlled trial. AB - This study offers data about the efficacy of "Talk to Me," an Internet-based telepsychology program for the treatment of fear of public speaking that includes the most active components in cognitive-behavior therapy (CBT) for social phobia (exposure and cognitive therapies). One hundred twenty-seven participants with social phobia were randomly assigned to three experimental conditions: (a) an Internet-based self-administered program; (b) the same program applied by a therapist; (c) a waiting-list control group. Results showed that both treatment conditions were equally efficacious. In addition, Talk to Me and the same treatment applied by a therapist were more efficacious than the waiting-list condition. Treatment gains were maintained at 1-year follow-up. The results from this study support the utility of Internet-delivered CBT programs in order to reach a higher number of people who could benefit from CBT. Internet-delivered CBT programs could also play a valuable role in the dissemination of CBT. PMID- 20712500 TI - Effect of herd cues and product involvement on bidder online choices. AB - Previous works have shown that consumers are influenced by others in decision making. Herd behavior is common in situations in which consumers infer product quality from other consumer choices and incorporate that information into their own decision making. This research presents two studies examining herd effect and the moderating role of product involvement on bidder choices in online auctions. The two studies addressed the influence on bidder online choices of herd cues frequently found in online auctions, including feedback ratings and number of questions and answers. The experimental results demonstrated that bidders use online herd cues when making decisions in online auctions. Additionally, the effects of herd cues on bidder online choices were stronger in high-involvement than low-involvement participants. Results and implications are discussed. PMID- 20712501 TI - Virtual reality induces dissociation and lowers sense of presence in objective reality. AB - This study utilizes an innovative experimental paradigm to investigate the effects of virtual reality (VR) on dissociative experience and the sense of presence. A nonclinical sample of 30 people were administered measures of dissociation, sense of presence, and immersion before and after an immersion in a virtual environment. Results indicate an increase in dissociative experience (depersonalization and derealization), including a lessened sense of presence in objective reality as the result of exposure to VR. Higher preexisting levels of dissociation and a tendency to become more easily absorbed or immersed were associated with higher increases in dissociative symptoms resulting from VR immersion. Results are discussed in terms of imaginative processes underlying the dissociative experience and potential implications to the treatment of anxiety disorders with VR. PMID- 20712502 TI - Comparison of human anxiety based on different cultural backgrounds. AB - This work conceptualizes human behavior on the Internet. The study was conducted with 10 university participants representing two different cultural backgrounds, Asian and Western. The participants were asked to visit any Web page on the Internet for 15 minutes, for 30 minutes, and for 1 hour. The results showed that participants displayed no signs of anxiousness during the 15-minute task and very little anxiousness during the 30-minute task. Western participants showed overall more anxiousness than Asian participants. However, all participants showed anxiousness during the 1-hour task. Data on comparative human anxiety were collected on the basis of a literature review of social fun, online belonging, and community on the Internet. Only the limited set of data of the participant is discussed in this article. PMID- 20712503 TI - Storming the servers: a social psychological analysis of the First Internet War. AB - In April 2007, the First Internet War began. Owing to the relocation of a World War II-era Soviet war memorial in Estonia, angry protestors, primarily of Russian descent, engaged in a month-long series of coordinated online attacks on Estonia's Internet infrastructure that disabled it for several days. We analyze this real-world event from a social psychological perspective. Specifically, we review the details surrounding the event and examine why protest manifested in this form of online attack and discuss how it was successfully orchestrated from a framework provided by social psychology, the science of human social interaction. We argue that the psychological principles of loss, relative anonymity of online interaction, group membership and adherence to group norms, social validation, and contagion all contributed to the success of the attacks. PMID- 20712504 TI - College counselors' use of informal language online: student perceptions of expertness, trustworthiness, and attractiveness. AB - The purpose of this study was to examine language formality and informality in online counseling sessions. Specifically, the author compared undergraduate student (n = 224) perceptions of college counselors' use of informal language and mirroring of client's formality in four mock online counseling scenarios. A multivariate analysis of covariance found significant differences between conditions. Pairwise analyses revealed that counselors who used informal language following their client's formal expressions were perceived as having less expertise. However, language mirroring seemed to moderate perceptions of expertise when counselors followed their client's informal language use. PMID- 20712505 TI - The roles of regulatory focus and medical recommendation avatars' trustworthiness in virtual environment-based e-health. AB - This study examined the influence of regulatory focus and medical recommendation avatars' trustworthiness in avatar-based e-health within 3D virtual environments (VEs). Drawing on Higgins's regulatory focus theory and the existing literature on self-construal, a 2 x 2 (regulatory focus: promotion vs. prevention by interdependent self-construal: low vs. high) between-participants factorial design experiment tested the moderating role of health consumers' interdependent self-construal in determining the effects of regulatory focus in VE-based e health. Results showed an interaction effect of regulatory focus and interdependent self-construal such that VE users with a dominant interdependent self-construal indicated greater issue familiarity and involvement when exposed to a prevention-focused e-health intervention than when exposed to a promotion focused e-health intervention, whereas the effects of regulatory focus on issue familiarity and involvement among users low in interdependent self-construal demonstrated the opposite pattern. A path analysis further revealed that VE users' evaluation of a medical recommendation avatar's trustworthiness mediated the effects regulatory focus had on their perceived informational and educational values of the health messages. Theoretical contributions and practical implications for VE-based e-health applications are discussed. PMID- 20712506 TI - "I can be happy even when I lose the game": the influence of chronic regulatory focus and primed self-construal on exergamers' mood. AB - This research explored the effects of priming interdependent self-construals (collective self ) versus independent self-construals (private self ) on exergame players' mood in response to negative performance feedback. An experiment was conducted to test the interaction effects of self-construal priming as a situational factor and game players' chronic regulatory focus as an individual difference factor. To this end, the author leveraged a video-game console (Wii) and an exergame (Dance Dance Revolution) in a controlled, randomized 2 x 2 (experimental priming: interdependent self-construal vs. independent self construal x game players' chronic promotion regulatory focus: low vs. high) between-subjects factorial design experiment (N = 58). The results of a two-way analysis of variance demonstrated the proposed interaction effect between primed self-construal and game players' chronic regulatory focus on the game players' mood in response to negative performance. The theoretical mechanism underlying the two-way interaction is explicated by regulatory focus and the primed self construals is explicated by regulatory focus theory and two-basket theory. Practical implications for game developers and theoretical contributions to video game research are discussed. PMID- 20712509 TI - Recent FDA approvals and changes. PMID- 20712510 TI - Center for AIDS research planned for Washington, DC. PMID- 20712511 TI - Enzyme-like replication de novo in a microcontroller environment. AB - The desire to start evolution from scratch inside a computer memory is as old as computing. Here we demonstrate how viable computer programs can be established de novo in a Precambrian environment without supplying any specific instantiation, just starting with random bit sequences. These programs are not self-replicators, but act much more like catalysts. The microcontrollers used in the end are the result of a long series of simplifications. The objective of this simplification process was to produce universal machines with a human-readable interface, allowing software and/or hardware evolution to be studied. The power of the instruction set can be modified by introducing a secondary structure-folding mechanism, which is a state machine, allowing nontrivial replication to emerge with an instruction width of only a few bits. This state-machine approach not only attenuates the problems of brittleness and encoding functionality (too few bits available for coding, and too many instructions needed); it also enables the study of hardware evolution as such. Furthermore, the instruction set is sufficiently powerful to permit external signals to be processed. This information-theoretic approach forms one vertex of a triangle alongside artificial cell research and experimental research on the creation of life. Hopefully this work helps develop an understanding of how information-in a similar sense to the account of functional information described by Hazen et al. is created by evolution and how this information interacts with or is embedded in its physico-chemical environment. PMID- 20712512 TI - Globe preservation surgery for a paranasal tumor with orbital extension. AB - Orbital exenteration is a rare radical procedure used for the treatment of locally invasive or potentially life threatening orbital tumors. The procedure results in significant visual and psychosocial disability. Recently there has been a shift toward a subtotal extenteration with maximum preservation of orbital tissue and globe in appropriate cases. We describe the management dilemma of a patient with orbital extension of a frontal sinus squamous cell carcinoma. The patient underwent combined craniofacial and transnasal macroscopic excision with globe preservation. Traditional approach for a sinus tumor that has invaded the orbit would be an exenteration. The favorable outcome of the case reported here raises the possibility of considering this approach more frequently. PMID- 20712514 TI - Different types of conjunctival papilloma presenting in the same eye. AB - A 31-year-old Black man presented with two oval masses in his right conjunctiva. The tumors were completely excised and histology showed that the inferior lesion was a conjunctival squamous papilloma with pigmentation while the superior one was an inverted conjunctival papilloma, which grew in an endophytic manner. Follow up examination one year later showed no recurrence. Literature search revealed no previous report of simultaneous appearance of these types of papilloma in the same eye. Management of conjunctival squamous papillomas is difficult and is complicated by multiple recurrences in contrast to inverted conjunctival papillomas where no recurrences have been reported after complete excision. Thus, histopathology is an absolute necessity even when papillomas appear in the same eye. PMID- 20712513 TI - Bacteriological evaluation of adult dacryocystitis in Iran. AB - PURPOSE: To examine the microbiology and antibiogram of specimens from patients with dacryocystitis. METHODS: A total of 66 samples from lacrimal sac contents of 61 consecutive patients with acute and chronic dacryocystitis were obtained. These specimens were cultured for bacteria with a routine microbiological technique. Antibiograms were acquired from positive cultures. RESULTS: A total of 61 patients (12 patients with acute and 49 patients with chronic dacryocystitis) were included in this investigation with the average age of 40 (12-85) years (female = 74% and male = 26%). Five patients were culture-negative and five patients had mixed gram-positive cultures (a total of 66 samples were obtained). The total prevalence of gram-positive, gram-negative, and culture-negative samples were 71.2%, 21.2%, and 7.6%, respectively. The prevalence of gram positive, gram-negative, and culture-negative samples were 77.4%, 18.9%, and 3.8% in the chronic and 46.2%, 30.8%, and 23.1% in the acute groups, respectively. The most prevalent pathogen in both groups was Staphylococcus epidermis. In 38% of patients the culture results were similar to those of the contralateral conjunctival flora. Gram-negative bacteria had a high sensitivity to ciprofloxacin and cephalexin while the gram-positive ones were highly sensitive to ceftriaxone and ampicillin. CONCLUSION: The responsible pathogens in acute and chronic dacryocystitis are significantly different. Because of the high prevalence of gram-negative bacteria and also culture-negative samples and considering the necessity of treatment in acute dacryocystitis, selecting an appropriate antibiotic with a good coverage of gram-negative and gram-positive bacteria seems essential. PMID- 20712515 TI - Independent cultural evolution of two song traditions in the chestnut-sided warbler. AB - In oscine songbirds, song phenotypes arise via gene-culture coevolution, in which genetically transmitted learning predispositions and culturally transmitted song forms influence one another's evolution. To assess the outcome of this process in a population of chestnut-sided warblers (Dendroica pensylvanica), we recorded songs at intervals over a 19-year period. These recordings revealed the pattern of cultural evolution of songs in our study area, from which we inferred likely learning predispositions and mechanisms of cultural transmission. We found that the species' two song categories form two distinct cultural traditions, each with its own pattern of change over time. Unaccented-ending songs have undergone continual, rapid turnover of song and element types, consistent with a model of neutral cultural evolution. Accented-ending songs, in contrast, persisted virtually unchanged for the entire study period, with extraordinarily constant song form and only one appearance of a new song type. Our results indicate that in songbirds, multiple independent cultural traditions and probably multiple independent learning predispositions can evolve concurrently, especially when different signal classes have become specialized for different communicative functions. PMID- 20712516 TI - Intra- and intersexual trade-offs between testosterone and immune system: Implications for sexual and sexually antagonistic selection. AB - Parasites indirectly affect life-history evolution of most species. Combating parasites requires costly immune defenses that are assumed to trade off with other life-history traits. In vertebrate males, immune defense is thought to trade off with reproductive success, as androgens enhancing sexual signaling can suppress immunity. The phenotypic relationship between male androgen levels and immune function has been addressed in many experimental studies. However, these do not provide information on either intra- or intersex genetic correlations, necessary for understanding sexual and sexually antagonistic selection theories. We measured male and female humoral antibody responses to a novel antigen (bovine gamma globulin), total immunoglobulin G, and the male testosterone level of a laboratory population of the bank vole (Myodes glareolus). Although we studied five traits, factor-analytic modeling of the additive genetic (co)variance matrix within a restricted maximum likelihood-animal model supported genetic variation in three dimensions. Sixty-five percent of the genetic variation contrasted testosterone with both immune measures in both sexes; consequently, selection for the male trait (testosterone) will have correlated effects on the immune system not only in males but also in females. Thus, our study revealed an intra- and intersexual genetic trade-off between immunocompetence and male reproductive effort, of which only indirect evidence has existed so far. PMID- 20712517 TI - Birds and anthropogenic noise: are urban songs adaptive? AB - In cities with intense low-frequency traffic noise, birds have been observed to sing louder and at a higher pitch. Several studies argue that higher song pitch is an adaptation to reduce masking from noise, and it has even been suggested that the song divergence between urban and nonurban songs might lead to reproductive isolation. Here we present models of signal transmission to compare the benefits of raised song amplitude and song pitch in terms of sound transmission. We chose two bird species that sing with higher pitch in urban areas, the great tit (Parus major) and the blackbird (Turdus merula). For both species, we calculated communication distances in response to different levels of urban noise and in their natural forest habitats. We found that an increase in vocal pitch increased communication distance only marginally. In contrast, vocal amplitude adjustments had a strong and significantly larger effect. Our results indicate that frequency changes of urban songs are not very effective in mitigating masking from traffic noise. Increased song pitch might not be an adaptation to reduce signal masking but a physiological side effect of singing at high amplitudes or an epiphenomenon of urbanization that is not related to signal transmission. PMID- 20712518 TI - Occupational performance, pain, and global quality of life in women with upper extremity fractures. AB - To examine pain, occupational performance problems, and quality of life (QoL) and possible associations between these variables, 41 elderly women with acute pain due to a fracture of the upper extremity were assessed with COPM, DASH, validated questions on pain, and a global question on QoL. The participants reported 802 performance problems: 38% within self-care, 52% within productivity, and 10% within leisure. Strength demanding bilateral activities in cleaning, hygiene, and cooking were most frequently reported. The median COPM performance and satisfaction scores were 2.8 and 3.4; the mean DASH score was 44.27. Pain frequency and intensity as well as QoL correlated moderately with the number of performance problems on the COPM. QoL was in general not very reduced and correlated only negligibly with pain. The DASH score correlated moderately with the total number of performance problems on the COPM and with the COPM satisfaction score, and it can be argued that a finding of a low DASH score in elderly women with upper extremity fractures should be followed up by a referral to occupational therapy. Future studies, preferably follow-up studies, are called for to further explore the multiple factors leading to performance problems in women with fractures of the upper extremity and to explore possible associations between activity performance and QoL. PMID- 20712519 TI - "Rescue allocation offers" in liver transplantation: is there any reason to reject "unwanted" organs? AB - To increase the number of transplanted organs, the Eurotransplant foundation uses a so-called "rescue-organ-allocation" procedure for organs that had been rejected by at least three consecutive transplant centers for medical reasons. The transplant center that finally accepts such an organ can then freely choose a patient from its own waiting list, without being bound to regular allocation criteria. Almost 30% of deceased donor livers are now allocated through this process in the Eurotransplant region. We report our results of 38 "rescue allocation" livers (RA livers) transplanted at our institution (2003-2007), compared to a group of 115 regularly allocated organs within the same period. From our data, RA livers have the same results as regularly allocated livers. Type and frequency of postoperative morbidity did not differ between both groups, though the analysis of subgroups showed a tendency toward reduced survival of RA livers in patients with viral hepatitis. Interestingly, the Donor Risk Index (DRI) showed no difference between RA livers and regularly allocated livers. Although preliminary due to small numbers, we conclude that RA livers can be safely transplanted without increased mortality or morbidity. However, no donor specific criteria which would justify rejecting a RA liver were found. This highly challenges the applicability of the RA procedure in its current form. PMID- 20712520 TI - Interstitial concentration of serotonin is increased in myalgic human trapezius muscle during rest, repetitive work and mental stress - an in vivo microdialysis study. AB - OBJECTIVES: The pathophysiology of trapezius myalgia is not fully elucidated. Serotonin (5-HT) is involved in modulation of nociception and hyperalgesia. Our aim was to compare the interstitial 5-HT levels of the trapezius muscle in women with chronic trapezius myalgia and in pain-free controls. MATERIALS AND METHODS: Microdialysate of the trapezius muscle collected every 20 minutes during rest, work (100 min) and stress (20 min) was used to study the dynamics of 5-HT in women with chronic trapezius myalgia (MYA; n=18) and in pain-free controls (CON; n=30). RESULTS: MYA had higher levels of 5-HT than CON at baseline, during repetitive work, during mental stress and during recovery. There were no significant time effects on 5-HT levels. CONCLUSION: 5-HT has the potential of a biomarker of chronic myalgia. Elevated levels of 5-HT may be involved in maintenance of habitual chronic pain and might contribute to increased pain during exercise by facilitating the effect of released algesic substances linked to such muscle demands. PMID- 20712521 TI - Vicriviroc, a new CC-chemokine receptor 5 inhibitor for treatment of HIV: properties, promises and challenges. AB - IMPORTANCE OF THE FIELD: Although HIV has become a treatable disease with near to normal life expectancy, the quest for the development of better tolerated drugs with simple dosing schedules and a high barrier to the emergence of drug resistance remains. Vicriviroc is a small-molecule chemokine receptor antagonist that inhibits the binding of R5-tropic HIV-1 to host cells at the CC-chemokine receptor 5 (CCR5) co-receptor, thus, preventing viral entry. CCR5 inhibitors are believed to possibly decrease inflammation from the immune system and thereby offer additional properties further to their antiretroviral efficacy. AREAS COVERED IN THIS REVIEW: This review is based on a PubMed search covering the years 2005 - 2010 for pharmacokinetic, pharmacological and clinical data of vicriviroc. WHAT THE READER WILL GAIN: In this review, the pharmacokinetic, pharmacological and clinical data of vicriviroc are presented. Moreover, the potential role of vicriviroc in the growing HIV armamentarium is discussed. TAKE HOME MESSAGE: Vicriviroc is being developed to be administered in combination with a ritonavir-boosted protease inhibitor for patients with R5-tropic virus. Early clinical trials have established the safety of vicriviroc in both treatment naive and -experienced R5-tropic HIV-1 infected individuals. Recently, two Phase III clinical trials in treatment-experienced patients failed to prove its superiority over available HIV medications. Phase III trials for treatment-naive patients are still under planning. Clearly, more favorable study results are needed to move vicriviroc into drug registration and approval. PMID- 20712522 TI - Cancer pharmacogenomics: do cancer cell lines have the right stuff? PMID- 20712524 TI - Genetic variation in three candidate genes and nicotine dependence, withdrawal and smoking cessation in hospitalized patients. AB - AIMS: This study evaluates the relationship of six polymorphisms found in the CHRNA3, DRD2 and COMT genes with nicotine dependence, the ability to quit smoking and the occurrence of withdrawal symptoms after short-term use of nicotine patch in hospitalized patients. MATERIALS & METHODS: The study included 233 participants from a double-blind, placebo-controlled trial of nicotine patch substitution with a 6-month follow-up period. Nicotine dependence was assessed by the Fagerstrom Test for Nicotine Dependence (FTND) questionnaire, withdrawal symptoms by the Minnesota Nicotine Withdrawal Scale questionnaire and smoking cessation by self-reported abstinence at 1 week, 1 month and 6 months after treatment. RESULTS: After correcting for multiple testing, three polymorphisms in the DRD2 gene (Taq1A, Taq1B and Pro319Pro) were significantly associated with nicotine dependence (p = 0.018, p = 0.048 and p = 0.006, respectively). Using a cutoff point for the FTND score, the CHRNA3 Tyr215Tyr (rs1051730) polymorphism was also associated with nicotine dependence (p = 0.037 and p = 0.074 after correction for multiple testing). No association of any of the studied polymorphisms was observed with either smoking cessation or the occurrence of withdrawal symptoms. CONCLUSION: This study confirms the reported association of the CHRNA3 locus with nicotine dependence and shows the involvement of two independent DRD2 polymorphisms in nicotine dependence. PMID- 20712525 TI - Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction. AB - AIMS: Genetic variability within the SLCO1B1 and ABCB1 transporter genes has been associated with modification of statin effectiveness in cholesterol management. MATERIALS & METHODS: We conducted a case-control study using a population-based registry of pharmacy records linked to the hospital discharge records. Within a hypercholesterolemic cohort, we included 668 myocardial infarction cases and 1217 controls. RESULTS: We tested 24 tagging SNPs and found two SNPs within ABCB1 (rs3789244, p = 0.01; rs1922242, p = 0.01) to interact with statin treatment. In addition, we found a nonsignificant haplotype-treatment interaction (p = 0.054). The odds ratio for subjects homozygous for SLCO1B1*1A was 0.49 (95% CI: 0.34 0.71) compared with 0.31 (95% CI: 0.24-0.41) for heterozygous or noncarriers of the *1A allele. CONCLUSION: This is the first study to demonstrate that common genetic variability within the SLCO1B1 and ABCB1 genes is associated with the modification of the effectiveness of statins in the prevention of the clinical outcome, myocardial infarction. PMID- 20712526 TI - Interethnic comparisons of important pharmacology genes using SNP databases: potential application to drug regulatory assessments. AB - BACKGROUND: The frequencies of alleles implicated in drug-response variability provide vital information for public health management. Differences in frequencies between genetically diverse groups of individuals can hamper drug assessments, particularly in populations where clinical data are not readily available. MATERIALS & METHODS: Making use of large, publicly available population genotype databases and population genetics tools, we developed a quick and efficient methodology to assess population divergence, which could be integrated into drug assessment and regulatory processes. To showcase its effectiveness, we present an analysis of population differences in a set of 42 important pharmacogenomics genes (PharmGKB) by utilizing allele frequencies of SNPs shared among three ethnic groups in the recently completed Singapore Genome Variation Project (Chinese, Malay and Indian) and four populations in the International HapMap project. RESULTS: The analyses facilitate comparisons across populations, such as identification of genes that exhibit moderate-to-high divergence between the main ethnic groups in Singapore and Caucasians, the dominant population in most drug-development programs. CONCLUSION: A potential use of the analyses is for regulators to develop a decision tree based on the extent of population divergence in key drug targets, metabolizing enzymes or transporter pathways when reviewing foreign clinical trial data. The methodology can be readily extended to other genes and countries with diverse ethnic groups. We continue to explore ways of integrating the information from these population genetics tools into stratifying the risk that the drug response established in one population could be translated to another. PMID- 20712527 TI - Characterization of the genetic profile of CYP2C19 in two South African populations. AB - AIMS: This study was aimed at elucidating the common sequence variation present in the CYP2C19 gene within the South African Xhosa population and comparing it with the Cape Mixed Ancestry (CMA) population for possible future pharmacogenetic applications. MATERIALS & METHODS: Common sequence variation was identified through the resequencing of 15 Xhosa individuals. The detected variants were prioritized for genotyping in an additional 85 Xhosa and 75 CMA individuals, while 5 -upstream variants were analyzed using dual luciferase reporter assays. RESULTS: Resequencing of the Xhosa population revealed 30 variants, including the novel CYP2C19*27 and CYP2C19*28 alleles. CYP2C19*27, characterized by -1041G>A, caused a twofold decrease in luciferase activity, while CYP2C19*28 is characterized by the nonsynonymous V374I variant. In addition, the previously characterized variants, CYP2C19*2, CYP2C19*9 and CYP2C19*17, were present in both populations, while CYP2C19*3 was only observed in the CMA population. CONCLUSION: Our data demonstrate that both the Xhosa and CMA populations exhibit unique genetic profiles that could influence the outcome of drug therapy in these populations. PMID- 20712528 TI - CUL2 and STK11 as novel response-predictive genes for neoadjuvant radiochemotherapy in esophageal cancer. AB - AIMS: Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since only patients with major histopathological response benefit from multimodality treatment, we profiled the genome of patients with esophageal cancer for markers indicating response or nonresponse. PATIENTS AND METHODS: Pretreatment biopsies of responding and nonresponding patients with locally advanced esophageal cancer, as well as the corresponding normal epithelium, were analyzed by human genome microarrays. Differential gene expression was associated with histomorphological tumor regression. Quantitative real-time reverse transcriptase-PCR was applied for verification of the predictive value of a panel of the identified marker genes, including 66 patients. RESULTS: We detected differentially expressed candidate genes with regard to response and nonresponse to neoadjuvant radiochemotherapy. The response-predictive impact of the novel markers, CUL2 and STK11, was confirmed by the verification study including 66 patients. Whereas CUL2 mRNA expression levels of greater than 1.7 was predictive for major response (p = 0.02) in adeno- and squamous cell carcinoma, STK11 was predominantly response predictive for adenocarcinomas. Downregulation of CUL2 (p = 0.04) and STK11 (p = 0.02) mRNA also correlated with a more favorable prognosis. CONCLUSION: We identified two novel markers, CUL2 and STK11, for response prediction in esophageal cancer. They will be applied to complement our panel of response-predictive markers to further individualize therapy. PMID- 20712529 TI - Tailored therapy of ACE inhibitors in stable coronary artery disease: pharmacogenetic profiling of treatment benefit. AB - Angiotensin-converting enzyme (ACE) inhibitors are among the most commonly used drugs in stable coronary artery disease as these agents have been proven to be effective for reducing the risk of cardiovascular morbidity and mortality. As with other drugs, individual variation in treatment benefit is likely. Such heterogeneity could be used to target ACE-inhibitor therapy to those patients most likely to benefit from treatment. However, prior attempts to target ACE inhibitor therapy to those patients who are most likely to benefit of such prophylactic treatment in secondary prevention using clinical characteristics or the level of baseline risk appeared not to be useful. A new approach of 'tailored therapy' could be to integrate more patient-specific characteristics, such as the genetic information of patients. Pharmacogenetic research of ACE inhibitors in coronary artery disease patients is at a formative stage, and studies are limited. The Perindopril Genetic association (PERGENE) study is a large pharmacogenetic substudy of the randomized placebo-controlled European trial On Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery disease (EUROPA) trial, aimed to assess the feasibility of pharmacogenetic profiling of ACE-inhibitor therapy by perindopril. This article summarizes the recent findings of the PERGENE study and pharmacogenetic research of the treatment benefit of perindopril in stable coronary artery disease. PMID- 20712530 TI - IFN-beta pharmacogenomics in multiple sclerosis. AB - Multiple sclerosis (MS) is a condition of the CNS marked by inflammation and neurodegeneration. Interferon (IFN)-beta was the first, and still is the main, immunomodulatory treatment for MS. Its clinical efficacy is limited, and a proportion of patients, ranging between 20-55%, do not respond to the therapy. Identification and subsequently, implementation in the clinic of biomarkers predictive for individual therapeutic response would facilitate improved patient care in addition to ensuring a more rational provision of this therapy. In this article, we summarize the main findings from studies addressing the pharmacogenomics of clinical response to IFN-beta in MS by either whole-genome association scans, candidate gene or transcriptomics studies. Whole-genome DNA association screens have revealed a high representation of brain-specific genes, and have hinted toward both extracellular ligand-gated ion channels and type I IFNs pathway genes as important categories of genetic IFN-beta response modifiers. One hit, glypican 5 (GPC5), was recently replicated in an independent study of IFN-beta responsiveness. Recent RNA transcriptomics studies have revealed the occurrence of a pre-existing type I IFN gene-expression signature, composed of genes that are predominantly induced by type I IFNs, as a potential contributing feature of poor response to therapy. Thus, while the outlines of a complex polygenic mechanism are gradually being uncovered, the main challenges for the near future will reside in the robust validation of identified response modifying genes as well as in the decipherment of the mechanistic relationships between these genes and clinical response to IFN-beta. PMID- 20712531 TI - Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice. AB - The implementation of genetic data for a better prediction of response to medications and adverse drug reactions is becoming a reality in some clinical fields. However, to be successful, personalized medicine should take advantage of an informational structured framework of genetic, phenotypic and environmental factors in order to provide the healthcare system with useful tools that can optimize the effectiveness of specific treatment. The impact of personalized medicine is potentially enormous, but the results that have so far been gathered are often difficult to translate into clinical practice. In this article we have summarized the most relevant applications of pharmacogenomics on diseases to which they have already been applied and fields in which they are currently emerging. The article provides an overview of the opportunities and shortcomings of the implementation of genetic information into personalized medicine and its full adoption in the clinic. In the second instance, it provides readers from different fields of expertise with an accessible interpretation to the barriers and opportunities in the use/adoption of pharmacogenomic testing between the different clinical areas. PMID- 20712532 TI - Detection of KRAS mutations in colorectal carcinoma patients with an integrated PCR/sequencing and real-time PCR approach. AB - AIMS: Patients with metastatic colorectal carcinoma (mCRC) carrying activating mutations of the KRAS gene do not benefit from treatment with anti-EGF receptor monoclonal antibodies. Therefore, KRAS mutation testing of mCRC patients is mandatory in the clinical setting to aid in the choice of appropriate therapy. MATERIALS & METHODS: We developed a cost-effective approach for the determination of KRAS mutations in codons 12 and 13 in clinical practice based on a sensitive PCR/sequencing technique and the commercially available real-time PCR-based Therascreen kit (DxS Ltd). RESULTS & CONCLUSION: The PCR/sequencing test was able to detect 10% mutant DNA in a background of wild-type DNA. By using this assay, we determined the mutational status of KRAS in 527 out of 540 (97.6%) formalin fixed paraffin-embedded tissues from mCRC patients. PCR/sequencing was not conclusive in 13 cases, in which low-intensity peaks suggestive of potential mutations were identified. The DxS assay, which showed a sensitivity of 1%, identified mutations in 11 out of 13 inconclusive cases. Interestingly, five of these 11 cases showed high levels of DNA fragmentation. No significant difference was found in the ability of PCR/sequencing and DxS to identify KRAS mutations within 160 cases with more than 30% tumor cells. However, in 24 samples with less than 30% tumor cells, DxS showed an higher sensitivity. In conclusion, our findings suggest that PCR/sequencing can be used for mutational analysis of the majority of tumor samples that have more than 30% tumor cell content, whereas more sensitive and expensive tests should be reserved for inconclusive cases and for samples with a low amount of tumor cells. PMID- 20712533 TI - NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss. AB - Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss. PMID- 20712534 TI - Synergistic angiogenic effect of codelivering fibroblast growth factor 2 and granulocyte-colony stimulating factor from fibrin scaffolds and bone marrow transplantation in critical limb ischemia. AB - Increasing evidence suggests that therapeutic angiogenesis strategies utilizing cytokines and stem cells are necessary to treat traumatic vascular events such as critical limb ischemia and peripheral artery disease. In this study, basic fibroblast growth factor 2 (FGF-2) and granulocyte-colony stimulating factor (G CSF) were immobilized in fibrin matrices and codelivered in combination with unfractionated bone marrow cells. Hindlimb ischemia was induced on young (6-7 weeks) Balb/C mice, and fibrin gels containing 100 ng/mL of FGF-2 and G-CSF were implanted adjacent to the ligation points. In addition, 1*10(6) bone marrow (BM) cells were injected into five locations in the ischemic muscle immediately after ligation and artery excision. Hindlimb reperfusion was determined by Laser Doppler Perfusion Imaging and immunohistochemistry for CD31+ and smooth muscle actin-positive cells at 2, 4, and 8 weeks postsurgery to identify capillary formation and maturation. A fluorescent vessel painting technique was also utilized to determine the extent of angiogenesis and arteriogenesis in the hindlimb at 8 weeks postsurgery. The codelivery of FGF-2 and G-CSF in combination with BM cells led to enhanced therapeutic recovery in critical limb ischemia Balb/C mice after 8 weeks of treatment with 87.2% blood flow recovery and a significant increase (p<0.05) in capillary formation in comparison to growth factor delivery or BM cell administration alone. PMID- 20712535 TI - Mitochondrial disease: recognising more than just the tip of the iceberg. AB - On 22 August 2010, the Australian Mitochondrial Disease Foundation will hold its annual Stay in Bed Day to raise awareness of a genetic disorder that robs thousands of Australians of their energy. PMID- 20712536 TI - Atypical femur fractures: a complication of prolonged bisphosphonate therapy? AB - Physicians need to be aware of this newly described complication. PMID- 20712537 TI - Asbestos still poses a threat to global health: now is the time for action. AB - Australia should support international bans on asbestos trade. PMID- 20712538 TI - Towards integrated care: Australia's new model of care for patients with glaucoma. AB - Using shared care to tackle the complexity of optimal patient management. PMID- 20712539 TI - Characteristics, management and outcomes of adults with major trauma taking pre injury warfarin in a Western Australian population from 2000 to 2005: a population-based cohort study. AB - OBJECTIVES: To describe the characteristics, management and outcomes of patients with major trauma who were taking warfarin; explore the use of rapid anticoagulation reversal; and assess the effect of reversal on outcomes. DESIGN AND SETTING: Retrospective cohort analysis of prospective data extracted from the trauma registries and patient charts of the two adult trauma referral hospitals with neurosurgical units in Western Australia, 2000 to 2005. Inclusion criteria were: major trauma (injury severity score > 15); first international normalised ratio (INR) after injury > 1.4; and documented (in registry or chart) warfarin use. RESULTS: Eighty patients were identified. Their mean age was 76.8 years. Forty-six were men; 34 were transferred from another hospital; 28 died; and the functional outcomes of 58 were worse at discharge from hospital than before injury. Intracranial haemorrhage (ICH) occurred in 62, of whom 25 died; the difference in mortality between those with ICH and those without ICH was insignificant. Warfarin reversal started 17.4 hours (mean) after injury and the documented period between injury and completion of reversal was 54.2 hours (mean). Multiple logistic regression models, controlling for age, sex, on-scene Glasgow Coma Scale (GCS), initial INR and progressive ICH, showed no independent survival benefit for rapid reversal. Factors associated with mortality were age (22% increase per year [95% CI, 17%-34%]) and progressive ICH on computed tomography scan (24 of the 36 patients with progressive ICH died v one of the 26 patients with stable ICH died). Every point increase in on-scene GCS > 8 increased survival likelihood by 215% (95% CI, 119%-388%). CONCLUSIONS: Patients with major trauma taking warfarin at the time of injury have high mortality rates, poor functional outcomes and long delays to initiation and completion of anticoagulation reversal. Rapid, appropriate warfarin reversal was rarely performed and was not independently associated with survival. Age, low on-scene GCS and progressive ICH were strongly associated with mortality, but presenting INR, ICH v no ICH, and sex were not. PMID- 20712540 TI - Door-to-balloon times are reduced in ST-elevation myocardial infarction by emergency physician activation of the cardiac catheterisation laboratory and immediate patient transfer. AB - OBJECTIVES: To assess whether a collaborative interdepartmental pathway involving emergency department (ED) physicians activating the cardiac catheterisation laboratory (CCL) with immediate patient transfer to the CCL reduces door-to balloon (DTB) times for patients with suspected ST-elevation myocardial infarction (STEMI). DESIGN, SETTING AND PARTICIPANTS: A quasi-experimental before and-after observational study using a prospective database, supplemented by chart review, of consecutive patients transferred from the ED to the CCL for suspected STEMI, from January 2007 to October 2009, at Sir Charles Gairdner Hospital, an adult tertiary-care hospital, Western Australia. MAIN OUTCOMES MEASURES: Median DTB time and proportion of patients with DTB time of < 90 minutes. Secondary outcomes, based on analysis of predefined subgroups, included door-to-activation time, activation-to-balloon time and false-positive activations of the CCL. RESULTS: Two hundred and thirty-four patients underwent emergency coronary angiography for suspected STEMI, with 188 (80%) undergoing percutaneous coronary intervention (118 before and 70 after implementation of the new pathway). Following implementation of the new pathway, median DTB time reduced from 97 to 77 minutes (P < 0.001), median door-to-activation time from 28 to 15 minutes (P = 0.002) and median activation-to-balloon time from 66 to 53 minutes (P < 0.001). The proportion of patients with recommended DTB time of < 90 minutes increased from 41% to 77% (P < 0.001) with no change in false positive CCL activation rates (12% v 11%; P = 0.38). CONCLUSION: ED physician activation of CCL with immediate patient transfer is associated with highly significant improvements in DTB time without increased false positive rates. PMID- 20712541 TI - Trends in anthropometry and severity of sleep-disordered breathing over two decades of diagnostic sleep studies in an Australian adult sleep laboratory. AB - OBJECTIVE: To document trends in subject demographics, anthropometry and sleep disorder severity over 21 years of diagnostic sleep studies. DESIGN, PARTICIPANTS AND SETTING: A retrospective observational study of consecutive subjects undergoing initial diagnostic polysomnography for investigation of possible sleep disorders in a university-affiliated tertiary public metropolitan hospital in the Hunter New England region of New South Wales between 1987 and 2007. MAIN OUTCOME MEASURES: Body weight, body mass index (BMI) and severity of sleep-related breathing disorders (apnoea-hypopnoea index [AHI]). RESULTS: Between 1987 and 2007, 14 648 new diagnostic sleep studies were performed. The median age of subjects (51 years; interquartile range, 41-61 years) did not change over time and the proportion of women increased from 20% to 39%. Median body weight increased from 89 kg to 99 kg for men (11%) and from 73 kg to 85 kg for women (16%), equating to a yearly increase in median BMI of 0.15 kg/m(2) for men and 0.14 kg/m(2) for women. The proportion of subjects who were morbidly obese (BMI > or = 40) increased from 3% in 1987 to 16% in 2007. Median AHI progressively increased from 1992-1995 to 2004-2007 (from 6.5 events/h to 14.3 events/h; P < 0.001), indicating increasing disease severity. Over the same period, for every unit increase in BMI, AHI increased by 5.5 events/h for men and by 2.8 events/h for women. About 80% of the observed variance in AHI over this period was attributable to variance in BMI. CONCLUSION: There is a continuing trend towards increasing body weight and BMI in people undergoing diagnostic sleep studies. Our data do not support the hypothesis that increased accessibility to diagnostic services and increased awareness of sleep disorders are resulting in a decline in disease severity. These findings are consistent with the premise that worsening severity in sleep-disordered breathing is primarily attributable to increasing obesity. PMID- 20712542 TI - Survival from haematological malignancy in childhood, adolescence and young adulthood in Australia: is the age-related gap narrowing? AB - OBJECTIVES: To examine 5-year survival from haematological malignancies in children, adolescents and young adults in Australia and determine if there has been any improvement in survival for the older age groups compared with children (the age-related "survival gap"). DESIGN, SETTING AND PARTICIPANTS: Population based study of all Australian children (aged 0-14 years), adolescents (15-19 years) and young adults (20-29 years) diagnosed with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma (HL) and non Hodgkin lymphoma (NHL) between 1982 and 2004, with follow-up to 2006. MAIN OUTCOME MEASURES: 5-year survival from ALL, AML, HL and NHL analysed for four periods of diagnosis (1982-1989, 1990-1994, 1995-1999 and 2000-2004). RESULTS: During 1982-2004, 13 015 people aged < or = 29 years were diagnosed with primary leukaemia or lymphoma in Australia. For those with ALL, 5-year survival for adolescents improved from 40% (1982-1989) to 74% (2000-2004); the improvement for young adults was smaller (31% to 47%), and both these groups still had lower survival than children, whose 5-year survival improved from 74% to 88%. There was a larger narrowing of the gap for AML: for cases diagnosed in 2000-2004, 5-year survival was similar for young adults (63%), adolescents (74%) and children (69%). For lymphoma cases diagnosed in 2000-2004, 5-year survival in all age groups was greater than 95% for HL and greater than 81% for NHL, although children fared better than adolescents and young adults. CONCLUSIONS: These Australian population-based data confirm an improvement in survival from haematological malignancies across all three age groups, but an age-related survival gap remains for adolescents and young adults compared with children, especially for young adults with ALL. Greater participation of adolescents and young adults in clinical trials and more detailed data collection are needed to provide evidence about optimal treatment regimens in these age groups. PMID- 20712543 TI - Trends in the incidence of hospitalisation for injuries resulting from non traffic crashes in New South Wales, July 1998 to June 2007. AB - OBJECTIVE: To describe changes in the incidence of hospitalised injury for New South Wales residents involved in non-traffic crashes for the period 1 July 1998 to 30 June 2007. DESIGN, SETTING AND PARTICIPANTS: This study identified 37 480 NSW residents admitted to hospitals for injuries resulting from non-traffic crashes from the NSW Admitted Patients Data Collection during the study period. Injury rates were calculated by applying 2001 census-derived estimates of NSW population figures as the denominator, and directly adjusting to the age distribution of the 2001 Australian population. The significance of trends in rates was assessed by the per cent change annualised estimator. MAIN OUTCOME MEASURES: Age-standardised rates of hospitalisation for injuries, and trends by inpatient demographics, travel mode and severity of injuries. RESULTS: The annual rate of hospitalisation for injury showed a significant increase of 0.7% per annum (95% CI, 0.2% to 1.2%) for NSW residents involved in non-traffic crashes over 10 years. Annual hospitalisation rates for serious injuries increased by 2.2% (95% CI, 0.9% to 3.6%). The hospitalised injury rate for motorcyclists and pedal cyclists increased significantly by 3.3% per annum (95% CI, 2.4% to 4.2%) and 3.7% (95% CI, 2.6% to 4.9%), respectively, but the rate declined significantly for car occupants and pedestrians by - 8.3% per annum (95% CI, - 9.5% to - 7.0%) and - 2.2% (95% CI, - 4.2% to - 0.2%) respectively. CONCLUSIONS: The rate of hospitalisation for injury from non-traffic crashes increased significantly over time for NSW residents from 1998-99 to 2007-08, especially for serious injuries and injuries to motorcyclists and pedal cyclists. These findings call for continuing and specific effort to prevent road non-traffic injuries. PMID- 20712544 TI - Contrasts in acute medicine: a comparison of the British and Australian systems for managing emergency medical patients. AB - Increasing numbers of patients are presenting for unscheduled medical admission to hospitals worldwide, prompting clinical redesign of "front-door" emergency medical services. In the United Kingdom, there has been considerable investment in the establishment of acute medical units (AMUs) and the training of acute medicine physicians. Some centres in Australia have established similar medical assessment units. While these initiatives have undoubtedly met with some success, the evidence base for their overall benefit remains elusive. We describe key aspects of the recent establishment of acute medical services in Britain and discuss the relevance of these experiences to Australia. Successful models of care in acute medicine have often been shared with other centres. The adaptation of existing models of care to meet local demands is superior to simply adopting an existing model. Once the desired clinical functionality of a service is determined, informed decisions can be made on staffing requirements, skill mix, and the structure of any new clinical unit. The functionality of the acute medical service, rather than simply the physicality of an AMU, should drive service design. PMID- 20712545 TI - Teaching hospital planning: a case study and the need for reform. AB - Academic teaching hospitals and their networks can best serve patients and other stakeholders by achieving critical mass and scope of clinical services, teaching and research. Successful hospital reconfigurations are associated with a convincing case and majority clinician buy-in. The inscrutable political decision to relocate services away from a major teaching hospital campus and into a merged Queensland Children's Hospital was determined without broad stakeholder consultation or a transparent and accountable business case. This compromised process poses a significant and enduring risk to patient care and Queensland's paediatric, perinatal, adolescent and obstetric academic teaching hospital services. As the proposed major stakeholder in Australia's public hospitals and medical workforce training, the federal government should review this decision using an effective methodology incorporating relevant criteria. National guidelines are needed to ensure best practice in the future planning and auditing of major health care projects. The medical profession is responsible for ensuring that health care policy complies with reliable evidence and good practice. PMID- 20712546 TI - Prehospital thrombolysis followed by early angiography and percutaneous coronary intervention where appropriate - an underused strategy for the management of STEMI. AB - Prompt myocardial reperfusion, particularly if achieved within 2 hours of the onset of symptoms, improves outcomes in patients with ST-elevation myocardial infarction (STEMI). Recent data suggest that ambulance-administered prehospital thrombolysis, if given within 2 hours of the onset of STEMI, produces superior outcomes to primary percutaneous coronary intervention (PCI); if given within 4 hours, the outcomes are similar. For optimal results after thrombolysis, patients require angiography (and PCI where appropriate) within 24 hours of the event. These developments have major implications for the practice of cardiology and for the organisation of health services in Australia. PMID- 20712547 TI - Legal and ethical aspects of refusing medical treatment after a suicide attempt: the Wooltorton case in the Australian context. AB - When a patient presents to hospital after a suicide attempt and appears to refuse treatment, clinicians should first assess if he or she should be treated under mental health legislation, regardless of competence to refuse treatment. When it is not possible or is inappropriate to treat under mental health legislation, the person's competence to refuse treatment should be assessed. If the patient is definitely competent, his or her decision to refuse treatment should probably be honoured. If an incompetent patient carries a document refusing treatment, clinicians must determine the validity of that document as an advance care directive - including whether or not the patient was competent at the time it was written. The law around the right to refuse treatment after a suicide attempt remains unclear and, if uncertain of what to do, clinicians should provide urgently required life-saving treatment and simultaneously seek an urgent court order to clarify how they should proceed. In all but extraordinary circumstances, a patient who refuses treatment after a suicide attempt can and should be given life-saving treatment, under either mental health legislation or the common law concept of necessity. PMID- 20712548 TI - Restricted career paths for overseas students graduating from Australian medical schools: legal and policy considerations. PMID- 20712549 TI - Inferior vena cava filters in trauma patients: who is responsible for their removal? PMID- 20712550 TI - Seizures related to praziquantel therapy in neurocysticercosis. PMID- 20712551 TI - Alarm about computed tomography scans is unjustified. PMID- 20712552 TI - What is the place of a student medical journal? PMID- 20712553 TI - Diagnosis and monitoring of bipolar disorder in general practice. AB - General practitioners are often consulted for first presentations of bipolar disorder and are well placed to coordinate patient care. They can assist with early identification of bipolar disorder and monitoring for manic and depressive episodes. Delayed and incorrect diagnoses are common in bipolar disorder, and unipolar depression is a frequent misdiagnosis. Characteristics that can be used to distinguish bipolar I depression from unipolar depression (when no clear prior manic episodes are evident) include the course of illness, symptoms, mental state signs and family history. Manic episodes can be caused by poor adherence to medication, substance misuse, antidepressants and stressful events, and are often preceded by early warning signs. Early warning signs are less commonly observed for depressive episodes. Daily mood charts are useful for providing an overview of patient progress and for identifying and managing early warning signs. Families and carers can also play an active role in supporting patients with bipolar disorder. PMID- 20712554 TI - Bipolar disorder in general practice: challenges and opportunities. AB - General practitioners are involved in the continuing care and shared care of patients with chronic mental illness, including bipolar disorder. Psychiatrists are particularly reliant on GPs to monitor and treat comorbidities as well as the psychiatric condition itself. Management of chronic mental illness is compromised by a number of factors, including problems with diagnosis, physical comorbidity, erratic attendance and poor compliance with treatment. Diagnosis of bipolar disorder is often delayed, and differential diagnoses to be considered include unipolar depression, anxiety disorder, drug and alcohol dependence, personality disorder, attention deficit hyperactivity disorder, and general medical and central nervous system diseases. New Medicare items have been introduced under the Better Access to Mental Health Care initiative. However, uptake for patients with chronic psychiatric illness, including bipolar disorder, is low. Patients with bipolar disorder may be prone to a range of comorbid psychological, social and physical problems, and GPs need to be vigilant to detect and manage comorbidity and social problems as part of the overall plan. This includes assistance with certification for sickness and unemployment benefits. GPs may become involved during crises affecting patients and this may pose significant problems for GPs who need to provide ongoing care following patient discharge from hospital. Despite these difficulties, opportunities exist for GPs to play a vital and ongoing role in the management of patients with bipolar disorder. PMID- 20712555 TI - Comorbidities in bipolar disorder: models and management. AB - Rates of conditions comorbid with bipolar disorder are very high, with anxiety disorders, impulse-control disorders, and drug and alcohol problems being the most distinctly over-represented conditions. Although the high rates of comorbid conditions may be overestimates--owing to measurement distortions in community surveys, and because definitions of comorbidity generally include antecedent and consequential conditions (not merely coterminous ones)--they are clinically distinctive. Clinical comorbidity can be explained by at least four different models, which each have clinical management implications. If the bipolar disorder and the comorbid conditions are deemed to be interdependent, two broad approaches are appropriate: hierarchical management strategies and sequential management strategies. Successful management of bipolar disorder often involves the development of a wellbeing plan that addresses comorbid issues iterative to the bipolar disorder. PMID- 20712556 TI - Risk assessment and management in bipolar disorders. AB - Bipolar affective disorders carry significant risks to the patient and sometimes others. The form of the illness relapse needs to be determined, and high-risk features such as psychosis and suicide considered. Gathering collateral information from others is invaluable. Mania brings particular risks of disinhibition, poor judgement, risk taking and sometimes aggression. Depression carries notable risks of suicidal behaviour, poor self-care and homicide. Both mania and depression bring risks of substance misuse and disrupted relationships. Management requires an optimal therapeutic alliance with good communication, appropriate treatment and sometimes compulsory care during crises. Preventive strategies are invaluable. PMID- 20712557 TI - The pharmacological treatment of bipolar disorder in primary care. AB - OBJECTIVE: To provide a practical overview of the pharmacological management of adults with bipolar disorder in primary care and the role of general practitioners in the pharmacotherapy of this complex disorder. DATA SOURCES: Published guidelines for the treatment of bipolar disorder, plus Cochrane reviews, meta-analyses, review articles and reports from randomised controlled trials that were published up to May 2009. STUDY SELECTION: Over 500 articles on the treatment of bipolar disorder were reviewed, with an emphasis on meta analyses and systematic reviews of randomised controlled trials. Where evidence was more limited, open trials and non-controlled data were also reviewed. DATA EXTRACTION: Key recommendations relevant to GPs were synthesised and rated according to National Health and Medical Research Council levels of evidence. DATA SYNTHESIS: Lithium, valproate and atypical antipsychotics are first-line treatment options for acute mania, and monotherapy is ideal if it produces an adequate response. For depressive episodes, recommendations are less definitive and the use of antidepressants is controversial. Most patients require maintenance treatment, during which pharmacotherapy should be used to prevent relapse, and psychological and social interventions should be considered. CONCLUSIONS: Bipolar disorder is a lifelong episodic illness that affects 1%-2% of the population, many of whom are principally managed by their GPs. Pharmacological treatment with mood-stabilising agents is the primary form of management, although this is ideally provided in conjunction with psychosocial interventions. PMID- 20712558 TI - Bipolar disorder: new understandings, emerging treatments. AB - The role of general practitioners in managing bipolar disorder is gaining increasing recognition. PMID- 20712559 TI - The role of psychotherapy in bipolar disorder. AB - Adjunctive psychosocial interventions for bipolar disorder target many of the issues that are not addressed by medication alone, including non-adherence, efficacy-effectiveness gap and functionality. Psychosocial interventions have been found to reduce relapse, particularly for the depressive pole, and improve functionality. Approaches such as psychoeducation, cognitive behaviour therapy, interpersonal and social rhythm therapy, and family therapy have shown benefits as adjunctive treatments. Each of the various psychosocial interventions has a unique emphasis, but they share common elements. These include: providing information and education; developing a personal understanding of the illness, such as triggers and early warning signs; having prepared strategies in place for early intervention, should symptoms of illness develop; and promoting a collaborative approach. Evidence to date supports the use of adjunctive psychosocial interventions in the management of bipolar disorder. PMID- 20712560 TI - From neuroprogression to neuroprotection: implications for clinical care. AB - Bipolar disorder follows a staged trajectory in which persistence of illness is associated with a number of clinical features such as progressive shortening of the inter-episode interval and decreased probability of treatment response. This neuroprogressive clinical process is reflected by both progressive neuroanatomical changes and evidence of cognitive decline. The biochemical foundation of this process appears to incorporate changes in inflammatory cytokines, cortisone, neurotrophins and oxidative stress. There is a growing body of evidence to suggest that these markers may differ between the early and late stages of the disorder. The presence of a series of tangible targets raises the spectre of development of rational neuroprotective strategies, involving judicious use of current therapies and novel agents. Most of the currently used mood stabilisers share effects on oxidative stress and neurotrophins, while novel potentially neuroprotective agents are being developed. These developments need to be combined with service initiatives to maximise the opportunities for early diagnosis and intervention. PMID- 20712561 TI - Bipolar disorder: diagnostic issues. AB - Bipolar disorders are cyclical mood disorders with clinical features including distinct sustained periods of mood elevation. Briefer (4 days or more), mild episodes of mood elevation define bipolar II disorder; lengthier (7 days or more), more severe episodes (or those requiring hospitalisation), with or without psychotic features, define bipolar I disorder. Depressive periods are more common and lengthier than manic or hypomanic states, and are the main cause of disability. Bipolar depression may respond poorly to antidepressants and these medications may destabilise the illness. The diagnosis of bipolar disorder should be considered when a patient with depression is treatment resistant. Irritability is a common symptom in bipolar disorder, particularly during mixed states (during which patients have features of mood elevation and depression concurrently) or when there is rapid cycling of mood (more than four episodes of mood disorder per year). Alcohol misuse and use of illicit drugs may simulate mood changes in bipolar disorder. Accurate diagnosis and assessment of bipolar disorder is essential for clinical decision making and determining prognosis and treatments. PMID- 20712562 TI - Macrocyclic G-quadruplex ligands. AB - G-quadruplex stabilizing compounds have recently received increased interest due to their potential application as anticancer therapeutics. A significant number of structurally diverse G-quadruplex ligands have been developed. Some of the most potent and selective ligands currently known are macrocyclic structures which have been modeled after the natural product telomestatin or from porphyrin based ligands discovered in the late 1990s. These two structural classes of G quadruplex ligands are reviewed here with special attention to selectivity and structure-activity relationships, and with focus on the recent developments. PMID- 20712563 TI - Genetic factors as a cause of miscarriage. AB - Aneuploidy in the conceptus or fetus, occurs in 5-10% of all pregnancies and is a common reproductive problem in humans. Most aneuploid conceptuses die in utero, resulting in early pregnancy loss. Causes of recurrent miscarriage may include abnormal chromosomes in either partner, particularly translocations, antiphospholipid antibodies and uterine anomalies. Chromosomal aberrations in parents are a major pre-disposing factor and causative of abortion if carried over to the embryo. The transmission rate in the embryo can be speculated to be about 50%. Embryo morphology, developmental rates, and maternal age are correlated with chromosomal abnormalities. Translocation in either partner is one of the most important causes of recurrent miscarriage and the prognosis of subsequent pregnancy in couples with abnormal embryonic karyotype is poorer than that in couples with normal chromosome karyotypes. As for parents whose karyotypes are normal, the frequency of normal embryonic karyotypes significantly increases with the number of previous abortions and a normal karyotype in a previous pregnancy is a predictor of subsequent miscarriage. Recently, many kinds of genetic polymorphisms have also been found to be associated with recurrent miscarriages. In contrast, preimplantation genetic diagnosis for aneuploidy screening is sometimes performed in patients with unexplained recurrent miscarriages. We review genetic factors as a cause of miscarriage. PMID- 20712564 TI - Medicinal chemistry of 2,2,4-substituted morpholines. AB - We have designed a number of 2-hydroxy (alkoxy)-2-aryl-4-alkyl-(5,6-alkyl) morpholines with interesting biological activities, i.e. sympathomimetic, analgesic, drug metabolizing enzyme modulating ability, antioxidant potential, anti-inflammatory and anti-dyslipidemic properties. They are synthesised by reaction of the proper 2-aminoethanol with aryl-bromomethyl-ketone. The intermediate hydroxyaminoketone is spontaneously cyclised to form the tetrahydro 1,4-oxazine ring. The produced 2-hydroxy substituted morpholines form the 2 alkoxy derivatives. The 2-hydroxy or 2-alkoxy-1,4-oxazine derivatives can lose water or alcohol, to give styrene-type products. The conditions for oxazine ring formation and water or alcohol abstraction are investigated. Ionisation constants and partition coefficients have been determined and related to structure and activity. The biological activities of these compounds are quite interesting: The 2-phenyl analogues acquire the structural requirements for sympathomimetic amines, and present a structure related to the pethidine-type analgesics. Indeed, they show central dopaminergic and analgesic, antagonized by naloxone, activities. They also affect drug metabolising enzymes. The 2- phenyl and especially the 2-biphenyl derivatives are good antioxidants, also possessing anti inflammatory and immunomodulating action. The later class of compounds reduces remarkably plasma triglycerides, total cholesterol and LDL-cholesterol in hyperlipidemic rats. Since NO plays a multiple role in atheromatosis and inflammation, some 2-nitroxy-alkoxy derivatives are synthesized and their NO liberating ability assessed. These nitric esters are also found to be potent hypolipidemic-hypocholesterolemic agents. In a mechanism elucidation attempt, it is indicated that these derivatives may act as squalene synthase inhibitors. PMID- 20712565 TI - Past, present and future drugs for the treatment of obsessive-compulsive disorder. AB - In the last decades, the treatment of obsessive-compulsive disorder (OCD) has been revolutioned by the introduction into the clinical practice of the selective serotonin (5-HT) reuptake inhibitors (SSRIs), following the observation of the unique response of OCD patients to clomipramine. However, if with no doubt the 5 HT system is central to the pharmacological treatment of OCD, it is unlikely that it represents the whole story. In fact, different studies suggest abnormalities of other neurotransmitters, neuropeptides or second messengers, so that it can be hypothesized that the possible heterogeneity of pathophysiological mechanisms might underlie the different clinical pictures and responses to treatment. Moreover, latest developments in the pharmacology of SSRIs have shown that they share the common property of 5-HT reuptake blockade, but, with the exception of citalopram and escitalopram, they do interact with other receptors and systems. In this paper, the latest findings on pharmacological treatments of OCD will be reviewed, together with a focus on putative targets for future drugs, such as the glutamate system or second messengers, and the problems related to treating OCD in different ages. PMID- 20712566 TI - Targeting protein-protein interactions: a promising avenue of anti-HIV drug discovery. AB - In recent years, the number of useful chemical biology information of protein protein interactions in the HIV life cycle and related inhibitors, is growing rapidly, which makes protein-protein interactions a new investigative area for antiviral drug intervention. This review will summarize recent work in this field, mainly focusing on the utilization of small molecules targeted against a variety of protein-protein interactions that have great therapeutic feasibility for HIV infection, and lastly outline some other important protein-protein interactions with a potential to advance into novel anti-HIV drug targets in future. PMID- 20712567 TI - Design and development of anti-hepatitis B virus agents. AB - Hepatitis B virus (HBV) infected hepatitis is the common infectious disease. In the World Conservative Estimate Plan, the number of persons chronically infected with HBV is more than 300 million. Current regimen of treatment is far from satisfactory, as it is associated with certain side effects and viral resistance capacity. Therefore, a serious attention has recently been paid to the design and development of new potent anti-HBV agents. A variety of drugs have been synthesized and screened for their anti-HBV effects. These include nucleosides, natural compounds, quinolines, benzodiazepines, indoles, etc. Many of them are in wide trend in current treatment regimen. In this review, we have presented the recent development on the design and development of all categories HBV inhibitors studied. PMID- 20712568 TI - Chemoprevention of lung pathologies by dietary n-3 polyunsaturated fatty acids. AB - Different intervention trials have been so far conducted and others are ongoing to evaluate the effect of increased intake of n-3 polyunsaturated fatty acids (PUFAs) in the prevention of several disorders affecting lungs and airways. They have been focused on chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, alteration of lung function in cystic fibrosis, as well as asthma and cachexia in lung cancer patients. Their outcomes are not always consistent, but, if beneficial effects were observed, they have been related mainly to the anti-inflammatory action of n 3 PUFAs. On the contrary, trials investigating their effects on the development and progression of lung cancer are still not available. This in spite of the huge number of equivalent studies performed on other kind of cancers (breast, colon and prostate cancer), which share with lung cancer the highest incidence in Western countries and an elevated sensitivity to chemoprevention. Contrasting results were also obtained by the few epidemiological studies available on lung cancer. However, different experimental studies, performed in vivo and in vitro, provided strong indications of the anti-tumor action of n-3 PUFAs against lung cancer, and identified molecular mechanisms for their action. In this review our effort will concentrate in critically reviewing the current evidence for the beneficial effect of n-3 PUFAs in inflammatory and neoplastic disorders of lungs and airways, and in identifying possible molecular mechanisms underlying their effects. PMID- 20712569 TI - Interleukin-18: biology and role in the immunotherapy of cancer. AB - Interleukin-18 (IL-18) is an immunostimulatory cytokine belonging to the IL-1 family. IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-gamma (IFN-gamma) production by NK cells, T cells, and possibly other cell types. Systemic administration of IL-18 has been shown to have significant antitumor activity in several preclinical animal models. Phase I clinical trials of recombinant human IL-18 have demonstrated that it can be safely administered to patients with advanced cancer. Biologic effects of IL-18 therapy include activation of monocytes, NK cells, and T cells and production of IFN-gamma as well as other cytokines in vivo. A phase II study of IL-18 in patients with metastatic melanoma confirmed its safety but suggested limited efficacy of IL-18 monotherapy in this setting. IL-18 appears to act predominantly as a costimulatory cytokine and its optimal use for cancer immunotherapy may be in combination with other immunostimulatory cytokines, vaccines, or monoclonal antibodies. PMID- 20712570 TI - The dual role of tumor necrosis factor (TNF) in cancer biology. AB - Tumor necrosis factor (TNF) is a cytokine with well known anticancer properties and is being utilized as anticancer agent for the treatment of patients with locally advanced solid tumors. However, TNF role in cancer biology is debated. In fact, in spite of the wealth of evidence supporting its antitumor activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Furthermore, some preclinical findings suggest that TNF may even promote cancer development and progression. With this work we intend to summarize the molecular biology of TNF (with particular regard to its tumor-related activities) and review the experimental and clinical evidence currently available describing the complex and sometime apparently conflicting relationship between this cytokine, cancer biology and antitumor therapy. We also propose a model to explain the dual effect of TNF based on the exposure time and cytokine levels reached within the tumor microenvironment. Finally, we overview recent research findings that might lead to new ways for exploiting the anticancer potential of TNF in the clinical setting. PMID- 20712571 TI - The anticancer face of interferon alpha (IFN-alpha): from biology to clinical results, with a focus on melanoma. AB - Alpha interferons (IFN) are type I IFNs that have pleiotropic effects on cell functions. A wealth of evidence exists that these cytokines exhibit a variety of biological effects different from those on viral replication, including antitumor activity. IFNs-alpha represent the cytokines exhibiting the longest record of use in clinical oncology for the treatment of over a dozen of cancer types, including some hematological malignancies and solid tumors. Although targeted anticancer agents have recently replaced IFN-alpha in the treatment of certain hematological (e.g. chronic myeloid leukemia) and solid (e.g. renal cell carcinoma) malignancies, this cytokine is still used for the treatment of patients with specific tumor types, such as cutaneous melanoma. Despite the intense work in preclinical tumor models and considerable experience in the clinical use of IFN alpha, the mechanisms of action underlying tumor response is still a matter of open debate. In this review we describe the evidence supporting the main mechanisms underlying IFN-alpha anticancer effects using both preclinical and clinical findings; moreover, we focus on the results of IFN-alpha for the treatment of patients with high-risk cutaneous melanoma, one of the malignancies most resistant to conventional chemotherapy. PMID- 20712572 TI - IL-24: physiological and supraphysiological effects on normal and malignant cells. AB - IL-24, previously known as melanoma differentiation antigen 7 (mda-7), is a member of the IL-10 family of cytokines and is mainly produced by Th2 cells and activated monocytes. Binding of IL-24 to either of its two heterodimeric receptors IL-20R1/IL-20R2 and IL-22R/IL-20R2 triggers phosphorylation and consequently activation of STAT3 and/or STAT1 in target tissues such as lung, testis, ovary, keratinocytes and skin. There is accumulating evidence that skin represents a major target tissue for IL-24 and related cytokines such as IL-19, 20, and -22. To date, the physiological properties of IL-24 are incompletely understood but available data indicate that it affects epidermal functions by increasing proliferation of dermal cells, suggestive of a possible role in psoriasis. However, the initial interest in IL-24 did not arise from its physiological signalling properties through its cognate receptors but rather because this cytokine has been reported to efficiently kill cancer cells independent of receptor expression and Jak-STAT signaling. These potentially intriguing properties have led to the development of adenovirally expressed IL 24, which was reported to induce selective cancer cell death in many different malignancies by activation or deactivation of a continuously growing list of distinct signaling pathways without harming surrounding healthy cells. In the present review we critically revisit and discuss the potential of IL-24 to become a selective and cancer cell-specific oncolytic drug and put these tentative properties into context with recent data on the physiological properties of this cytokine. PMID- 20712573 TI - TRAIL: a sword for killing tumors. AB - Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent that selectively triggers apoptosis in various cancer cells by interacting with its proapoptotic receptors DR4 and KILLER/DR5. The intensive studies of TRAIL signaling pathways over the past decade have provided clues for understanding the molecular mechanisms of TRAIL-induced apoptosis in carcinogenesis and identified an array of therapeutic responses elicited by TRAIL and its receptor agonists. Preclinical and clinical studies have shown that recombinant TRAIL and the agonistic mono-antibodies targeting TRAIL receptors exhibit potent tumoricidal activities as monotherapies and that the combinatorial therapies of these agents in conjunction with other anticancer modalities such as chemo or radiotherapy amplify the activities of anticancer agents and widen the therapeutic window by overcoming tumor resistance to apoptosis and driving cancer cells to self-destruction. The identification of a number of biomarkers that predict tumor sensitivity of patients to TRAIL-based therapy shed a new light on the personalized therapeutic strategies targeting the TRAIL/TRAIL receptor pathway. PMID- 20712575 TI - Interleukin 2 in cancer therapy. AB - Cancer immunotherapy with interleukin-2 (IL-2) has demonstrated long term disease control in metastatic renal cell carcinoma and malignant melanoma. With introduction of novel kinase inhibitors, immunomodulatory molecules, cytokines, and vaccines for treatment of cancer there is an increased interest in combining these therapeutic strategies with IL-2. Here we discuss toxicity and established activity of IL-2 in the management of advanced malignancies, and speculate on future use of this cytokine for treatment of cancer. PMID- 20712574 TI - Anticancer properties of the IL-12 family--focus on colorectal cancer. AB - The prominent role of interleukin (IL)-12 in inflammatory responses, especially in TH1 T cell differentiation, is well established. Moreover, in murine models of tumorigenesis, IL-12 displays remarkable antitumor properties that are mainly mediated by interferon (IFN)-gamma secretion by CD4+, CD8+ T cells, natural killer (NK) or NK-T cells. Importantly, IL-12 through IFN- gamma -dependent induction of the antiangiogenic factors interferon-inducible protein (IP) 10 and monokine induced by gamma interferon (MIG) contributes to tumor eradication. Recently, the structurally similar but functionally different cytokines IL-23 and IL-27 were discovered and related to the IL-12 family of cytokines. Each of those cytokines has its own specific effects on tumor growth. Similarly to IL12p70, antitumor effects of IL-27 are mediated via the IFN gamma -IP10/MIG-axis and tumor-specific increase of cytotoxic T-lymphocyte activity. Additionally, IL-27 itself may mimic the function of IFN- gamma due to the similarity in usage of JAK/STAT signalling molecules such as STAT1. The role of IL-23 in tumor growth to date is controversial. Whether IL-23 acts pro- or anticancerogenic seems to depend on a critical balance of STAT3 signalling in both the tumor and the immune cellular microenvironment of the tumor. At least for solid tumors the promising results from preclinical studies of systemic and on-site IL-12-based therapy did not prevail in clinical studies. In future combinatorial approaches using IL-12 together with other cytokines or antiangiogenic molecules have to be evaluated. This review focuses on anticancer effects of the IL-12 family in preclinical and clinical studies with an emphasis on colorectal cancer. PMID- 20712576 TI - Cytokines as anti-cancer agents rational, results and perspectives. PMID- 20712577 TI - Update on MDS therapy: from famine to feast. AB - Myelodysplastic syndromes (MDS) are acquired hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cellular dysfunction and increased risks of transformation into acute myeloid leukemia. The natural history of the disease remains variable and depend upon multiple prognostic factors at the time of initial diagnosis. The current prognostic models are helpful to determine the outcome of individual patients but they remain imperfect. Earlier, the most frequent treatment given for patients with MDS was supportive with transfusion of blood products and administration of erythropoietic stimulating agents and iron chelation therapy. Now, there is an arsenal of therapies available and the landscape for the treatment of MDS is rapidly evolving. There are several FDA approved therapies available for this disorder that makes this review particularly timely and relevant. PMID- 20712578 TI - Major challenges for gene therapy of thalassemia and sickle cell disease. AB - Gene therapy utilizing retroviral vectors is being postulated as a real therapeutic alternative for many hemopoietic inherited diseases, such as beta thalassemia or sickle cell disease. A major limitation of current vectors is their inability to achieve efficient gene transfer into quiescent cells, such as human CD34+ cells that reside in the Go phase of the cell cycle and are highly enriched in hemopoietic stem cells. For that reason, lentiviral vectors (LVs) were proven to be more efficient than oncoretroviral vectors. Additional problems of these vectors are a) the low titers observed due to regulatory elements of the beta-globin locus, used for the improvement of the transgene's expression b) the eventual silencing of the transgene and c) the toxicity posed on CD34+ cells due to the usage of VSV-G as an envelope protein. These facts hamper their application for gene therapy of hematopoietic cells. Thus, the major current drawbacks of the field affecting therapeutic efficacy, include 1) insufficient transduction efficiency of the target hemopoietic stem cells, 2) inconsistent expression of the transgene, 3) putative aberrant expression near integration sites raising safety issues and 4) lack of long term expression of the transgene exhibiting eventual silencing. This review presents the current status of globin gene therapy for the hemoglobin disorders, reviews the recent results and discusses how the knowledge gained from these trials can be used to develop a safe and effective gene therapy approach for the treatment of beta-thalassemia and SCD. PMID- 20712579 TI - Gene therapeutic approaches for dominant retinopathies. AB - Over the past two decades, significant progress has been made in defining the molecular pathogenesis of hereditary retinal degenerations. Many of these are characterised by immense genetic heterogeneity. For example, in retinitis pigmentosa (RP), the most common form of this group of disorders, over 50 disease causing genes have been implicated, 20 of which are inherited in an autosomal dominant manner. Knowledge of the underlying genetic pathogenesis together with the availability of animal models and vectors for delivery has enabled exploration of gene-based therapies for inherited retinopathies. Notably, many studies have focused on treatment of recessive forms of these disorders and significant progress including ongoing clinical trials have been achieved. Progress in developing gene therapies for dominant retinopathies has been slower. One reason for this is that gene therapies for many dominant diseases, which are targeted to correcting the primary genetic defect, are likely to require suppression of the mutant gene. Alternative therapeutic approaches, which involve modulating secondary features associated with the disease pathology (such as ER stress or apoptosis) are also being explored. This review is focused on the development of gene-based therapies for dominantly inherited retinopathies. The main topics discussed are suppression technologies, preclinical animal models, retinal gene delivery and therapeutic strategies. PMID- 20712580 TI - AAV-mediated gene supply for treatment of degenerative and neovascular retinal diseases. AB - Common blinding diseases that are currently untreatable include conditions characterized by progressive neuronal degeneration, such as retinitis pigmentosa, leber congenital amaurosis or glaucoma, or characterized by ocular neovascularization, like wet age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. The pathogenic mechanisms underlying either neuronal degeneration or new vessel formation may be similar and independent of the mutation underlying the disease, thus allowing to test therapeutic strategies acting downstream of the primary causative event. Gene supply is the delivery of a gene that can prevent or arrest disease progression without being directly implicated in the disease pathogenesis. To this end, one of the most efficient and safe retinal gene delivery vehicles derives from the small adeno-associated virus (AAV). We review studies on AAV-mediated gene supply of: neurotrophic/antiapoptotic factors to prevent retinal neurons degeneration, and anti-angiogenic molecules to inhibit retinal neovascularization. Successful gene supply may represent a one-fit-all treatment for inherited and acquired blinding diseases. PMID- 20712581 TI - Retinal blinding disorders and gene therapy--molecular and clinical aspects. AB - Retinal blinding disorders together have a prevalence of 1 in 2000 humans world wide and represent a significant impact on the quality of life as well as the possibility to attain personal achievements. Mutations in genes that are expressed either in RPE cells, photoreceptors or bipolar cells can cause varying forms of degenerative or stationary retinal disorders, as the presence of the encoded proteins is crucial for normal function, maintenance and synaptic interaction. The degree of damage caused by different mutations depends upon the type of mutation within the gene, resulting in either total absence or the presence of a non-functional or potentially toxic protein. Potential treatment strategies require the identification of the cell type, in which the mutated gene is expressed for later targeting by viral vector mediated gene transfer. In the first part of this review, the authors present different cellular pathways that take place either in the RPE, photoreceptors, or bipolar cells. Furthermore, the authors demonstrate why genetic and molecular testing methods, which clearly identify the disease causing mutations, are crucial for attaining the correct diagnosis in order to identify patients suitable to be treated by upcoming new therapeutic methods. In the second part, a short clinical classification of the most important forms of retinal blinding disorders is given, together with clinical aspects concerning the problems that arise when facing low residual visual perception and the enormous heterogeneity of symptoms within these disorders. PMID- 20712582 TI - Manufacturing and regulatory strategies for clinical AAV2-hRPE65. AB - Recombinant adeno-associated virus (AAV) -based vectors expressing therapeutic gene products have shown great promise for human gene therapy. A recent milestone has been the safety and efficacy observed using recombinant AAV2 expressing retinal pigment epithelial associated 65KDa protein for Leber Congenital Amaurosis. This review summarizes manufacturing and characterization of 'AAV2 hRPE65v2', the vector used in one completed Phase I/II clinical trial. Regulatory challenges and strategies that were successfully used for this groundbreaking trial are described. PMID- 20712584 TI - Discovery of novel cell proliferation-enhancing gene by random siRNA library based combinatorial screening. AB - Bone remodeling is tightly controlled by the actions of osteoblast and osteoclast. Impaired osteoblast proliferation and differentiation may disrupt the balance and lead to pathological symptom such as osteoporosis. To help understand the molecular mechanism of osteoblast proliferation, we performed a phenotype driven high throughput screening with a random siRNA library, in search of novel genes that can accelerate murine preosteoblast MC3T3-E1 cell proliferation. Three siRNAs screened from the library were able to enhance MC3T3-E1 cell proliferation significantly. One of the proliferation-enhancing siRNAs (B7) was further subjected to expression profiling to pinpoint genes that putatively act down stream of it. A number of genes were regulated in response to proliferation enhancing siRNA B7. Among these genes, Tmed2, which has never been reported yet in cell proliferation, was verified to be able to enhance MC3T3-E1 cell proliferation when over-expressed. Our screening process with random siRNA library provided an alternative strategy in addition to gene-specific siRNA library, in search of novel functional genes in genome scale. PMID- 20712585 TI - Metformin and energy metabolism in breast cancer: from insulin physiology to tumour-initiating stem cells. AB - A whole new area of investigation has emerged recently with regards to the anti diabetic drug metformin and breast cancer. Metformin's anti-breast cancer actions, observed in population studies, in rodents and in cultured tumour cells, are especially encouraging because they attack not only the most common bulk of the tumour cells but also the more rare tumour-initiating stem cells. Here, we illustrate the multifaceted and redundant mechanisms through which metformin reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease. PMID- 20712583 TI - AAV's anatomy: roadmap for optimizing vectors for translational success. AB - Adeno-Associated Virus based vectors (rAAV) are advantageous for human gene therapy due to low inflammatory responses, lack of toxicity, natural persistence, and ability to transencapsidate the genome allowing large variations in vector biology and tropism. Over sixty clinical trials have been conducted using rAAV serotype 2 for gene delivery with a number demonstrating success in immunoprivileged sites, including the retina and the CNS. Furthermore, an increasing number of trials have been initiated utilizing other serotypes of AAV to exploit vector tropism, trafficking, and expression efficiency. While these trials have demonstrated success in safety with emerging success in clinical outcomes, one benefit has been identification of issues associated with vector administration in humans (e.g. the role of pre-existing antibody responses, loss of transgene expression in non-immunoprivileged sites, and low transgene expression levels). For these reasons, several strategies are being used to optimize rAAV vectors, ranging from addition of exogenous agents for immune evasion to optimization of the transgene cassette for enhanced therapeutic output. By far, the vast majority of approaches have focused on genetic manipulation of the viral capsid. These methods include rational mutagenesis, engineering of targeting peptides, generation of chimeric particles, library and directed evolution approaches, as well as immune evasion modifications. Overall, these modifications have created a new repertoire of AAV vectors with improved targeting, transgene expression, and immune evasion. Continued work in these areas should synergize strategies to improve capsids and transgene cassettes that will eventually lead to optimized vectors ideally suited for translational success. PMID- 20712588 TI - From nanotechnology to nanomedicine: applications to cancer research. AB - Scientific advances have significantly improved the practice of medicine by providing objective and quantitative means for exploring the human body and disease states. These innovative technologies have already profoundly improved disease detection, imaging, treatment and patient follow-up. Today's analytical limits are at the nanoscale level (one-billionth of a meter) enabling a detailed exploration at the level of DNA, RNA, proteins and metabolites which are in fact nano-objects. This translational review aims at integrating some recent advances from micro- and nano-technologies with high potential for improving daily oncology practice. PMID- 20712589 TI - Nanotechnology in cancer therapy: targeting the inhibition of key DNA repair pathways. AB - Cancer therapy has been changing over the decades as we move away from the administration of broad spectrum cytotoxic drugs and towards the use of therapy targeted for each tumor type. After the induction of DNA damage through chemotherapeutic agents, tumor cells can survive due to their proficient DNA repair pathways, some of which are dysregulated in cancer. Latest improvements in nanotechnology and drug discovery has led to the discovery of some very unique, highly specific and innovative drugs as inhibitors of various DNA repair pathways like base excision repair and double strand break repair. In this review we look at the efficacy and potency of these small chemical molecules to target the processing of DNA damage induced by standard therapeutic agents. Emphasis is given to those drugs currently under clinical trials. We also discuss the future directions of using this nanotechnology to increase the therapeutic ratio in cancer treatment. PMID- 20712586 TI - SnoN: bridging neurobiology and cancer biology. AB - The transcriptional regulator SnoN has been the subject of growing interest due to its diverse functions in normal and pathological settings. A large body of evidence has established a fundamental role for SnoN as a modulator of signaling and responses by the transforming growth beta (TGFbeta) family of cytokines, though how SnoN regulates TGFbeta responses remains incompletely understood. In accordance with the critical and complex roles of TGFbeta in tumorigenesis and metastasis, SnoN may act as a tumor promoter or suppressor depending on the stage and type of cancer. Beyond its role in cancer, SnoN has also been implicated in the control of axon morphogenesis in postmitotic neurons in the mammalian brain. Remarkably, signaling pathways that control SnoN functions in the divergent cycling cells and postmitotic neurons appear to be conserved. Identification of novel SnoN regulatory and effector mechanisms holds the promise of advances at the interface of cancer biology and neurobiology. PMID- 20712590 TI - Medullary thyroid cancer: a promising model for targeted therapy. AB - In recent years, the clinical validation of molecular targeted therapies inhibiting the action of pathogenic tyrosine kinase (TK) has been one of the most exciting developments in cancer research. In this context, medullary thyroid carcinoma (MTC) represents a promising model. It is well known that in MTC, the RET receptor TK and its signal transduction pathways, lead to subsequent neoplastic transformation. Several strategies aimed at blocking the activation and signaling of RET have been preclinically tested. The most advanced results have been obtained by competitive inhibition of RET-TK activity by tyrosine kinases inhibitors (TKI). However, although the inhibition of the RET pathway is actually one of the most studied for therapeutic purposes, other signal transduction pathways have been recognized to contribute to the growth and functional activity of MTC and are considered attractive therapeutic targets. To date, surgery represents the only curative treatment of MTC. Despite promising initial results, studies on targeted agents are in early stages and several issues regarding preclinical evaluations and clinical trials of new targeted agents in MTC are still unresolved. Now, available mouse models bearing mutations of RET or other genes, which spontaneously develop MTC, promise to improve preclinical evaluation of activity of targeted compounds. Furthermore, the rarity of the disease and the number of patients available for enrollment may lessen the relevance of clinical trials. A major effort needs to be made by endocrinologists and oncologists to refer their patients for multi-institutional trials in order to optimize them, perform translational studies and expedite the availability of novel beneficial selective therapies. PMID- 20712587 TI - Hypoxia and fetal heart development. AB - Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although "normal" hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart's development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long term changes in gene expression are not clear, but likely involve variation in epigenetic regulation. PMID- 20712591 TI - The role of beverage congeners in hangover and other residual effects of alcohol intoxication: a review. AB - Congeners are minor compounds other than ethanol that occur naturally in alcohol beverages as a result of distilling and fermenting processes. While ethanol itself is the main source of hangover (subjective distress) and other residual effects of alcohol (cognitive and behavioral), the role of the congeners is of interest due to the potential toxicity of many of them despite their minute quantities. Survey studies, while comparing beer to liquor to wine, have generally not addressed beverage effects that clearly differ in congener content. The few experimental studies indicate that the highest congener beverage (bourbon) results in more severe hangover ratings than does the beverage with essentially no congeners (vodka), although ethanol effects per se had a considerably stronger effect on hangover than did congener content. Safety sensitive performance that was affected by alcohol intoxication the previous night (vigilance with reaction time; ataxia) was not differentially affected by bourbon versus vodka. The paucity of studies indicates more work is needed in order to have confidence in these results. PMID- 20712592 TI - Cognitive and psychomotor performance during alcohol hangover. AB - The consequences of alcohol consumption have risen high on health and social agendas in recent years. Although much work has focused on the physical problems associated with alcohol use, one theme that has emerged in alcohol research has been a focus on the effects of hangovers on functioning. This brief literature review specifically examines recent empirical investigations of the relationship between alcohol hangover and psychological performance and is tabled as an update to our earlier review of similar research (Stephens et al., 2008). A literature search generated 75 results on hangover and cognition (and synonyms) since the last published review. However, of these, only 4 met all inclusion criteria, such as establishing that BAL (Blood Alcohol Level) was zero at testing. Taking the findings of these newer studies with those that we reviewed previously, there appears to be real evidence of convergence of findings. There are now four rigorous laboratory studies, two less rigorous laboratory studies lacking placebo control and two rigorous naturalistic studies that indicate specific cognitive decrements in attention and memory during the hangover phase of alcohol consumption. Given this convergence, research agendas for increasing understanding of the cognitive effects of alcohol hangover should now switch from studies that routinely assess many cognitive functions to studies assessing the attention and memory deficits of hangover in greater detail. PMID- 20712594 TI - Treatment and prevention of alcohol hangover. AB - The search for alcohol hangover cures is as old as alcohol itself. Many cures and prophylactic agents are available, but scientific evidence for their effectiveness is generally lacking. This review summarizes and discusses the limited number of studies that examined the effectiveness of alcohol hangover treatments. From these studies it must be concluded that most remedies do not significantly reduce overall hangover severity. Some compounds reduce specific symptoms such as vomiting and headache, but are not effective in reducing other common hangover symptoms such as drowsiness and fatigue. Hangover cures that showed positive effects were those inhibiting prostaglandin synthesis or accelerating alcohol metabolism. Future studies should elucidate the pathology of alcohol hangover. Until then, it is unlikely that an effective hangover cure will be developed. PMID- 20712593 TI - The alcohol hangover research group consensus statement on best practice in alcohol hangover research. AB - Alcohol-induced hangover, defined by a series of symptoms, is the most commonly reported consequence of excessive alcohol consumption. Alcohol hangovers contribute to workplace absenteeism, impaired job performance, reduced productivity, poor academic achievement, and may compromise potentially dangerous daily activities such as driving a car or operating heavy machinery. These socioeconomic consequences and health risks of alcohol hangover are much higher when compared to various common diseases and other health risk factors. Nevertheless, unlike alcohol intoxication the hangover has received very little scientific attention and studies have often yielded inconclusive results. Systematic research is important to increase our knowledge on alcohol hangover and its consequences. This consensus paper of the Alcohol Hangover Research Group discusses methodological issues that should be taken into account when performing future alcohol hangover research. Future research should aim to (1) further determine the pathology of alcohol hangover, (2) examine the role of genetics, (3) determine the economic costs of alcohol hangover, (4) examine sex and age differences, (5) develop common research tools and methodologies to study hangover effects, (6) focus on factor that aggravate hangover severity (e.g., congeners), and (7) develop effective hangover remedies. PMID- 20712595 TI - The application of minerals in managing alcohol hangover: a preliminary review. AB - Despite the high prevalence and economic burden, biological mechanisms and effective treatments of alcohol hangover are not well understood. We have focused on oxidative stress and inflammatory responses which would substantially contribute to hangover physiology and symptoms based on preexisting research data. And, it is considered that minerals are one of the important components and influencing factors in antioxidant and anti-inflammatory system. Moreover, mineral deficient conditions show similar symptoms that occur in alcohol hangover. Herein we review some possible implications of various minerals, such as selenium, zinc, copper, vanadium, iron, and magnesium, according to suggested mechanisms and symptoms of alcohol hangover. Although, noticeable considerations and controlled trials will be required for general recommendations, we hope that our preliminary speculation would pave the way for further understanding and managing alcohol hangover. PMID- 20712596 TI - The pathology of alcohol hangover. AB - Research on human subjects analyzing blood and urine samples determined biological correlates that may explain the pathology of alcohol hangover. These analyses showed that concentrations of various hormones, electrolytes, free fatty acids, triglycerides, lactate, ketone bodies, cortisol, and glucose were not significantly correlated with reported alcohol hangover severity. Also, markers of dehydration (e.g., vasopressin) were not significantly related to hangover severity. Some studies report a significant correlation between blood acetaldehyde concentration and hangover severity, but most convincing is the significant relationship between immune factors and hangover severity. The latter is supported by studies showing that hangover severity may be reduced by inhibitors of prostaglandin synthesis. Several factors do not cause alcohol hangover but can aggravate its severity. These include sleep deprivation, smoking, congeners, health status, genetics and individual differences. Future studies should more rigorously study these factors as well as biological correlates to further elucidate the pathology of alcohol hangover. PMID- 20712597 TI - A review of the next day effects of alcohol on subjective mood ratings. AB - Alcohol-induced hangover is commonly experienced after excessive alcohol consumption. This paper presents a critical review of literature on the next day effects of excessive alcohol consumption on subjective ratings of mood. The review has identified 7 comprehensive studies which have followed either the pharmacological approach or the naturalistic approach to investigating the mood state of the individual during the post intoxication hangover phase. There is diversity in the tools used to assess mood and in the aspects of mood measured, this needs to be addressed in future research however there is a general finding that mood is decreased during hangover. PMID- 20712599 TI - Spatial organization of the transforming MHC class II compartment. AB - BACKGROUND INFORMATION: DC (dendritic cells) continuously capture pathogens and process them into small peptides within the endolysosomal compartment, the MIIC (MHC class II-containing compartment). In MIICs peptides are loaded on to MHC class II and rapidly redistributed to the cell surface. This redistribution is accompanied by profound changes of the MIICs into tubular structures. An emerging concept is that MIIC tubulation provides a means to transport MHC class II peptide complexes to the cell surface, either directly or through vesicular intermediates. To obtain spatial information on the reorganization of the MIICs during DC maturation, we performed electron tomography on cryo-immobilized and freeze-substituted mouse DCs after stimulation with LPS (lipopolysaccharide). RESULTS: In non-stimulated DCs, MIICs are mostly spherical. After 3 h of LPS stimulation, individual MIICs transform into tubular structures. Three dimensional reconstruction showed that the MIICs frequently display fusion profiles and after 6 h of LPS stimulation, MIICs become more interconnected, thereby creating large MIIC reticula. Microtubules and microfilaments align these MIICs and reveal physical connections. In our tomograms we also identified a separate population of MIIC-like intermediates, particularly at extended ends of MIIC tubules and in close proximity to the trans-Golgi network. No fusion events were captured between reticular MIICs and the plasma membrane. CONCLUSIONS: Our results indicate that MIICs have the capacity to fuse together, whereby the cytoskeleton possibly provides a scaffold for the MIIC shape change and directionality. MIIC-like intermediates may represent MHC class II carriers. PMID- 20712600 TI - At the heart of tissue: endothelin system and end-organ damage. AB - ET (endothelin)-1 was first described as a potent vasoconstrictor. Since then, many other deleterious properties mediated via its two receptors, ETA and ETB, have been described, such as inflammation, fibrosis and hyperplasia. These effects, combined with a wide tissue distribution of the ET system, its up regulation in pathological situations and a local autocrine/paracrine activity due to a high tissue receptor binding, make the tissue ET system a key local player in end-organ damage. Furthermore, ET-1 interacts in tissues with other systems such as the RAAS (renin-angiotensin-aldosterone system) to exert its effects. In numerous genetically modified animal models, non-specific or organ targeted ET-1 overexpression causes intense organ damage, especially hypertrophy and fibrosis, in the absence of haemodynamic changes, confirming a local activity of the ET system. ET receptor antagonists have been shown to prevent and sometimes reverse these tissue alterations in an organ-specific manner, leading to long-term benefits and an improvement in survival in different animal models. Potential for such benefits going beyond a pure haemodynamic effect have also been suggested by clinical trial results in which ET receptor antagonism decreased the occurrence of new digital ulcers in patients with systemic sclerosis and delayed the time to clinical worsening in patients with PAH (pulmonary arterial hypertension). The tissue ET system allows therapeutic interventions to provide organ selectivity and beneficial effects in diseases associated with tissue inflammation, hypertrophy or fibrosis. PMID- 20712601 TI - The transferability of valuing lost productivity across jurisdictions. differences between national pharmacoeconomic guidelines. AB - For at least two decades, there has been an intense debate on whether and how to include the value of lost productivity in economic evaluations. This debate is often reflected in pharmacoeconomic guidelines, which have been developed to indicate the methods and requirements for the design, execution, and reporting of economic evaluations in a particular country. OBJECTIVE: To examine what various national pharmacoeconomic guidelines recommend regarding the identification, measurement, and valuation of lost productivity. METHODS: First, the theoretical framework on how lost productivity can be identified, measured, and valued is described. Second, a summary sheet has been used to identify various pharmacoeconomic guidelines recommendations regarding the value of lost productivity. RESULTS: Twenty-two of the 30 guidelines identified recommend performing economic evaluations using the societal perspective. Nevertheless, even if the societal perspective is recommended, it is not always clear how the value of lost productivity should be taken into account. Most guidelines recommend including the costs of absenteeism from paid and/or unpaid work. In addition, although no agreement exists on how lost productivity should be valued, none of the guidelines recommended using the US panel approach for the valuation of lost productivity. DISCUSSION: The different recommendations hinder international transferability of the value of lost productivity. This difficulty is mainly caused by different recommendations regarding identification and valuation. These differences result from the debate and lack of consensus on including the value of lost productivity losses in economic evaluations. It will become easier to transfer data across jurisdictions if all data are reported transparently. PMID- 20712598 TI - Hangover and risk for alcohol use disorders: existing evidence and potential mechanisms. AB - Hangover may be related to propensity to develop alcohol use disorders (AUDs). However, the etiological role, if any, played by hangover in AUD is unclear. From a motivational perspective, hangover can be construed as either a deterrent to future alcohol consumption or a setting event for negative reinforcement that could promote deviant drinking practices (e.g., "hair-of-the-dog" drinking). Hangover could be related to AUD risk even if it does not play a direct role in promoting or inhibiting near-term drinking. For example, measures of hangover might serve as symptoms of AUD or as markers of individual differences that more directly account for AUD risk. Empirical evidence (though usually indirect) exists to support contentions that hangover is related to both risk for and protection from AUD. In this article, we briefly address variation in assessment strategies in existing hangover research because measures of hangover frequency and hangover susceptibility may prove to have different correlates. Next, we review the existing, limited evidence on relations between hangover and AUD risk. Finally, we sketch a variety of theoretically-informed hypotheses that might help delineate productive lines of inquiry for this emerging field. PMID- 20712602 TI - A cost-utility analysis of microwave endometrial ablation versus thermal balloon endometrial ablation. AB - OBJECTIVE: To evaluate the cost-effectiveness of microwave endometrial ablation (MEA) and thermal balloon endometrial ablation (TBALL) for heavy menstrual bleeding. METHODS: A cost-utility analysis performed alongside a pragmatic RCT in a single hospital within Scotland on women undergoing MEA and TBALL. Resource use data collected from all 314 trial participants were combined with study specific and published unit cost data to estimate a cost per patient. Quality-adjusted life-years (QALYs) were based on EQ-5D responses at baseline, 2 weeks, 6 and 12 months. The incremental cost per QALY of TBALL versus MEA was calculated and bootstrapping was performed to determine the likelihood that a treatment would be cost-effective at different threshold values for society's willingness to pay for a QALY. RESULTS: The mean cost of TBALL (10 years equipment life, 100 uses annually) of reusable equipment was pound181 (95% confidence interval [CI] pound70-434) greater than MEA. There were no statistically significant differences between the total nonhealth costs and health benefits of the two arms. On average, MEA provided more QALYs after adjusting for baseline EQ-5D score (0.017; 95% CI 0.017-0.051). In terms of mean incremental cost per QALY, MEA was, on average, dominant (less costly and at least as effective) and there was over a 90% chance that MEA would be considered cost-effective at a pound20,000 threshold of a cost per QALY. CONCLUSIONS: MEA is likely to be more cost-effective than TBALL at 1 year. Further longer-term follow-up is, however, needed. PMID- 20712603 TI - A valuation of infusion therapy to preserve islet function in type 1 diabetes. AB - OBJECTIVES: Recent advances in monoclonal antibody therapies offer the prospect of the prevention or amelioration of type 1 diabetes mellitus (T1DM). The present study was designed to capture UK (English and Scottish) preference weights for the process of undergoing infusion therapy and the likely outcomes of treatment for children (8-12 years), adolescents (13-17 years), and adults. METHODS: Vignette descriptions of T1DM health states (describing infusion therapy and reduced insulin need) were constructed based on qualitative interviews with people with type 1 diabetes, clinicians and findings from a literature review. Utilities were elicited for each health state using the standard gamble interview from the general public, adults with diabetes, and parents of children with diabetes. Participants also completed other outcome measures-EQ-5D, Pediatric Quality-of-Life Inventory, and Hyperglycemic Fear Survey. Mixed model analyses were used to estimate the influence on utility of different participant characteristics. RESULTS: Self-report questionnaires indicated the nature and degree of impact of T1DM on adults', adolescents', and children's quality of life, with adolescents reporting the lowest health-related quality-of-life profile of all groups. The mixed model analysis indicated that each health state was a significant predictor of utility and the T1DM participants gave significantly higher utilities compared with the general public (P = 0.02). CONCLUSION: The general public and people with diabetes (or parents of children with diabetes) all place significant value on reducing the need for insulin injections; also, all recognize the disutility of undergoing infusion cycles. These values are suitable for supporting estimates of cost-effectiveness of infusion therapies in T1DM. PMID- 20712605 TI - Comparison of two different methods for physiologic dead space measurements in ventilated dogs in a clinical setting. AB - OBJECTIVE: To compare physiologic dead space (V(D)) and physiologic dead space to tidal volume (V(T)) ratio (V(D)/V(T)) obtained by an automated single breath test for carbon dioxide (CO(2)) (method SBT) and a manual calculation (method MC) in ventilated healthy dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: Twenty client-owned dogs, ASA I and II undergoing anaesthesia for clinical purposes. METHODS: Following pre-medication, induction of anaesthesia, and intubation of the trachea, intermittent positive pressure ventilation was commenced. Mixed expired CO(2) partial pressure (PeCO(2)) was measured by two methods: method MC by analysis, using an infrared capnograph, of the expired gas collected in a mixing box and method SBT which calculated it automatically by a device consisting of a mainstream capnograph and a pneumotachograph. At four time points arterial partial pressure of CO(2) (PaCO(2)) was measured. Physiologic dead space variables (V(D) and V(D)/V(T)) were calculated manually (method MC) or automatically (method SBT) using the Bohr-Enghoff equation. Method MC and SBT were compared using Bland-Altman plots and linear regression. Intra-class correlation coefficient (ICC) was used to measure consistency of each method. RESULTS: Four measurement pairs were obtained in all 20 dogs for method SBT and MC. The bias was -1.15 mmHg, 7.97 mL and 0.02 for PeCO(2), V(D) and V(D)/V(T), respectively. Linear regression analysis revealed a correlation coefficient (r(2)) of 0.79, 0.94, and 0.83 for PeCO(2), V(D) and V(D)/V(T), respectively. The ICC revealed an excellent consistency for both methods. CONCLUSIONS: The single breath test (SBT) can be used for clinical evaluation of V(D) and V(D)/V(T) in anaesthetized ventilated dogs. CLINICAL RELEVANCE: Through measuring V(D) and V(D)/V(T) important information about lung ventilation can be obtained and the SBT is an easy method to use for this purpose. PMID- 20712606 TI - Comparison between two methods for cardiac output measurement in propofol anesthetized dogs: thermodilution and Doppler. AB - OBJECTIVE: To compare cardiac output (CO) measured by Doppler echocardiography and thermodilution techniques in spontaneously breathing dogs during continuous infusion of propofol. To do so, CO was obtained using the thermodilution method (CO(TD)) and Doppler evaluation of pulmonary flow (CO(DP)) and aortic flow (CO(DA)). STUDY DESIGN: Prospective cohort study. ANIMALS: Eight adult dogs weighing 8.3 +/- 2.0 kg. METHODS: Propofol was used for induction (7.5 +/- 1.9 mg kg(-1) IV) followed by a continuous rate infusion at 0.7 mg kg(-1) minute(-1). The animals were positioned in left lateral recumbency on an echocardiography table that allowed for positioning of the transducer at the 3rd and 5th intercostal spaces of the left hemithorax for Doppler evaluation of pulmonary and aortic valves, respectively. CO(DP) and CO(DA) were calculated from pulmonary and aortic velocity spectra, respectively. A pulmonary artery catheter was inserted via the jugular vein and positioned inside the lumen of the pulmonary artery in order to evaluate CO(TD). The first measurement of CO(TD), CO(DP) and CO(DA) was performed 30 minutes after beginning continuous infusion (T0) and then at 15 minute intervals (T15, T30, T45 and T60). Numeric data were submitted to two-way anova for repeated measurements, Pearson's correlation coefficient and Bland & Altman analysis. Data are presented as mean +/- SD. RESULTS: At T0, CO(TD) was lower than CO(DA). CO(DA) was higher than CO(TD) and CO(DP) at T30, T45 and T60. The difference between the CO(TD) and CO(DP), when all data were included, was 0.04 +/- 0.22 L minute(-1) and Pearson's correlation coefficient (r) was 0.86. The difference between the CO(TD) and CO(DA) was -0.87 +/- 0.54 L minute(-1) and r = 0.69. For CO(TD) and CO(DP), the difference was -0.82 +/- 0.59 L minute(-1) and r = 0.61. CONCLUSION: Doppler evaluation of pulmonary flow was a clinically acceptable method for assessing the CO in propofol-anesthetized dogs. PMID- 20712607 TI - Incidence of elevation of cardiac troponin I prior to and following routine general anaesthesia in dogs. AB - OBJECTIVE: To estimate the incidence of raised cTnI after general anaesthesia in dogs and to explore major risk factors influencing this. STUDY DESIGN: Prospective clinical study. Animals A total of 107 (ASA physical status 1-2) dogs, 63% male and 37% female, median age 5 years (range 0.3-13.4), median weight 24.4 kg (range 4.2-66.5 kg) undergoing anaesthesia for clinical purposes. METHODS: Venous blood samples were taken within 24 hours prior to induction and 24 hours after the termination of anaesthesia. Serum concentrations of cardiac troponin I were measured using a chemiluminescent enzyme immunometric assay with a lower level of detection of 0.20 ng mL(-1) (below this level <0.20 ng mL(-1)). Continuous data were assessed graphically for normality and paired and unpaired data compared with the Wilcoxon signed ranks and Mann-Whitney U-tests respectively. Categorical data were compared with the Chi squared or Fisher's exact test as appropriate (p < 0.05). RESULTS: Of the 107 dogs recruited, 100 had pre- and post-anaesthetic cTnI measured. The median pre-anaesthesia cTnI was '<0.20' ng mL(-1) (range '<0.20'-0.43 ng mL(-1)) and the median increase from pre anaesthesia level was 0.00 ng mL(-1) (range -0.12 to 0.61 ng mL(-1)). Fourteen dogs had increased cTnI after anaesthesia relative to pre-anaesthesia (14%, 95% CI 7.2-20.8%, range of increase 0.03-0.61 ng mL(-1)). Six animals had cTnI levels that decreased (range 0.02-0.12 ng mL(-1)). Older dogs were more likely to have increased cTnI prior to anaesthesia (OR = 5.32, 95% CI 1.35-21.0, p = 0.007) and dogs 8 years and over were 3.6 times as likely to have an increased cTnI after anaesthesia (95% CI 1.1-12.4, p = 0.028). CONCLUSION AND CLINICAL RELEVANCE: Increased cTnI after anaesthesia relative to pre-anaesthesia levels was observed in a number of apparently healthy dogs undergoing routine anaesthesia. PMID- 20712609 TI - Romifidine as a constant rate infusion in isoflurane anaesthetized horses: a clinical study. AB - OBJECTIVE: To evaluate the effects of a constant rate infusion (CRI) of romifidine on the requirement of isoflurane, cardiovascular performance and recovery in anaesthetized horses undergoing arthroscopic surgery. STUDY DESIGN: Randomized blinded prospective clinical trial. ANIMALS: Thirty horses scheduled for routine arthroscopy. METHODS: After premedication (acepromazine 0.02 mg kg( 1), romifidine 80 microg kg(-1), methadone 0.1 mg kg(-1)) and induction (midazolam 0.06 mg kg(-1) ketamine 2.2 mg kg(-1)), anaesthesia was maintained with isoflurane in oxygen. Horses were assigned randomly to receive a CRI of saline (group S) or 40 microg kg(-1) hour(-1) romifidine (group R). The influences of time and treatment on anaesthetic and cardiovascular parameters were evaluated using an analysis of variance. Body weight (t-test), duration of anaesthesia (t-test) and recovery score (Wilcoxon Rank Sum Test) were compared between groups. Significance was set at p < 0.05. RESULTS: All but one horse were positioned in the dorsal recumbent position and ventilated from the start of anaesthesia. End tidal isoflurane concentrations were similar in both groups at similar time points and over the whole anaesthetic period. Cardiac output was significantly lower in horses of the R group, but there were no significant differences between groups in cardiac index, body weight or age. All other cardiovascular parameters were similar in both groups. Quality of recovery did not differ significantly between groups, but more horses in group R stood without ataxia at the first attempt. One horse from group S had a problematic recovery. CONCLUSIONS AND CLINICAL RELEVANCE: No inhalation anaesthetic sparing effect or side effects were observed by using a 40 microg kg(-1) hour(-1) romifidine CRI in isoflurane anaesthetized horses under clinical conditions. Cardiovascular performance remained acceptable. Further studies are needed to identify the effective dose of romifidine that will induce an inhalation anaesthetic sparing effect in anaesthetized horses. PMID- 20712608 TI - Sedative and cardiorespiratory effects of dexmedetomidine and buprenorphine administered to cats via oral transmucosal or intramuscular routes. AB - OBJECTIVE: To determine if buprenorphine plus dexmedetomidine administered via the oral transmucosal route produces sufficient sedation in cats so that students can insert intravenous catheters. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: Eighty-seven shelter-owned female cats aged 4-48 months, weighing 1.1-4.9 kg. METHODS: Cats were randomly allocated to two treatment groups based on route of drug administration: oral transmucosal (OTM), or intramuscular (IM). Buprenorphine (20 microg kg(-1)) plus dexmedetomidine (20 microg kg(-1)) were administered as pre-medicants via one of these two routes. Prior to and 20 minutes after drug administration, heart and respiratory rates, systolic arterial pressure, and posture were measured and recorded. Twenty minutes after drug administration the same variables plus each cat's response to clipper sound, clipping, and restraint were recorded; higher scores indicated more sedation. RESULTS: There were no significant differences between the two groups prior to pre-medication. Within each treatment group heart rate was significantly lower 20 minutes after treatment, but it did not differ significantly between the two groups. Twenty minutes after treatment, respiratory rate was significantly less in the OTM group, but did not differ significantly between the two groups. Systolic arterial pressure did not differ within or between the two groups at either time. Scores for posture increased significantly within both groups, and cats in the IM group had higher scores after treatment. Twenty minutes after treatment, cats in the IM group had higher scores for clipping and restraint than OTM cats. Ketamine (IM) was necessary to facilitate catheterization in 25% and 16% of cats in the OTM and IM groups, respectively, but this was not significantly different. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of dexmedetomidine plus buprenorphine by the OTM route is easy to perform, but produces less sedation than the IM route for IV catheterization in cats. PMID- 20712610 TI - Comparison of an implantable telemetry device and an oscillometric monitor for measurement of blood pressure in anaesthetized and unrestrained green iguanas (Iguana iguana). AB - OBJECTIVE: The objective of this study was to compare an implanted direct blood pressure monitor and a non-invasive oscillometric unit for use in anesthetized and awake green iguanas. STUDY DESIGN: Prospective experimental trial. ANIMALS: Four male and four female adult green iguanas (Iguana iguana) weighing 1833 +/- 534 g. METHODS: For each animal, the carotid artery was surgically exposed and the catheter tip of the pressure transducer was placed in the aortic arch. Non invasive blood pressure was measured using a cuff over the left femoral region. Pulse rate, respiratory rate and arterial blood pressure (ABP) measurements were taken every 5 minutes. Direct ABP measurements consisted of recording numerical values and graphic output. Simultaneous direct and indirect measurements were repeated in awake animals. RESULTS: The oscillometric device failed to provide a reading in over 80% of attempts, and failed to provide readings that correlated with direct measurements. The implanted direct transducer was capable of detecting blood pressures throughout all ABP ranges examined. CONCLUSIONS: The implantable transducer was a reliable means of determining blood pressure in this study, while the oscillometric device was unreliable and often failed to provide any reading. CLINICAL RELEVANCE: We do not recommend using the oscillometric device as described in a research or clinical setting for green iguanas. The advantages of an implantable device include the ability to monitor awake and anesthetized subjects remotely and continuously. These monitors are small, biocompatible and function across a wide range of ABP. PMID- 20712611 TI - Evaluation of cardiovascular, respiratory and biochemical effects, and anesthetic induction and recovery behavior in horses anesthetized with a 5% micellar microemulsion propofol formulation. AB - OBJECTIVE: To characterize cardiovascular, respiratory and biochemical effects and recovery behavior associated with a 3-hour continuous infusion of a micellar microemulsion propofol formulation in horses. STUDY DESIGN: Prospective experimental trial. ANIMALS: Six healthy adult horses, 9 +/- 2 years old and weighing 557 +/- 14 kg. METHODS: All horses received xylazine (1 mg kg(-1), IV) 5 minutes prior to anesthetic induction. Each horse was anesthetized on two occasions with a 5% micellar microemulsion propofol formulation (2 mg kg(-1), IV); first as a single bolus (phase I) and then as a 3-hour continuous infusion (phase II). Propofol pharmacokinetics were obtained from phase I and used to determine the starting infusion rates in phase II. Anesthetic induction and recovery characteristics were quantitatively and qualitatively assessed. Cardiovascular, respiratory and biochemical parameters were monitored during anesthesia and recovery. RESULTS: Induction quality varied, ranging from good to poor. Standing and overall recovery quality scores were consistently excellent in phase I but more variability was observed among horses in phase II. Heart rate (HR) and mean arterial pressure (MAP) were adequately maintained but marked hypoventilation developed. There were only minimal changes in blood biochemical analytes following anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: The micellar microemulsion propofol formulation, administered as a 3-hour continuous infusion, showed similar results compared to those previously described with a commercially available propofol preparation. However, based on present findings, use of propofol as a primary anesthetic in horses for prolonged periods of anesthesia requires further study to determine the limits of safety and clinical applicability. PMID- 20712612 TI - Segmental dorsolumbar epidural analgesia via the caudal approach using multiple port catheters with ketamine or lidocaine or in combination in cattle. AB - OBJECTIVE: To determine the analgesic and systemic effects of epidural administration of ketamine, lidocaine or a combination of ketamine/lidocaine in standing cattle. STUDY DESIGN: Prospective, randomized, experimental trial. ANIMALS: Six healthy male cattle weighing between 335 and 373 kg. METHODS: The animals received 0.5 mg kg(-1) of ketamine (K), 0.2 mg kg(-1) of 2% lidocaine (L) or 0.25 mg kg(-1) ketamine plus 0.1 mg kg(-1) lidocaine (KL). All the drugs were injected into the dorsolumbar epidural space via a caudal approach through a non styletted multiple-port catheter. Each animal received each treatment at random. Evaluations of analgesia, sedation, ataxia, heart rate, arterial pressure, respiratory rate, skin temperature and rectal temperature were obtained at 0 (basal), 5, 10, 15, 30, 45, 60, 75, 90 minutes after epidural injection, and then at 30-minute intervals until loss of analgesia occurred. Skin temperature was taken at these intervals up to 60 minutes. All the animals received a standard noxious stimulus; a 4-point scale was used to score the response. A second scale was used to score ataxia and a third for sedation. RESULTS: The duration of analgesia in the upper and lower flanks in cattle was 140 +/- 15, 50 +/- 14 and 80 +/- 22 minutes (mean +/- SD) after dorsolumbar epidural KL, K or L, respectively. The cardiovascular changes were within acceptable limits in these clinically healthy cattle. CONCLUSIONS: Dorsolumbar epidural administration of KL to cattle resulted in longer duration of analgesia of the upper and lower flanks in standing conscious cattle, than the administration of K or L alone. CLINICAL RELEVANCE: Further research is necessary to determine whether this combination using this technique provides sufficient analgesia for flank surgery in standing cattle. PMID- 20712613 TI - Ultrasound-guided nerve blocks of the pelvic limb in dogs. AB - OBJECTIVES: To evaluate the efficacy of ultrasound-guidance in nerve blockade of the sciatic and saphenous nerves in dogs and to determine if this technique could allow lower anaesthetic doses to be used with predictable onset and duration of effect. STUDY DESIGN: Prospective randomized (for dose and leg) blinded experimental crossover trial with 10 day washout period. ANIMALS: Six healthy female Hound dogs aged 12.3 +/- 0.5 (mean +/- SD) months and weighing 18.7 +/- 0.8 (mean +/- SD) kg. METHODS: An ultrasound-guided, perineural injection was used with saline at 0.2 mL kg(-1) (Sal) or bupivacaine 0.5% at 0.05 (low dose; LD), 0.1 (medium dose; MD), or 0.2 (high dose; HD) mL kg(-1), divided 2/3 at the sciatic nerve and 1/3 at the saphenous nerve. Blocks were performed using dexmedetomidine sedation with atipamezole reversal immediately after completion of the injections. Motor/proprioceptive and sensory functions were scored using a 0-8 and a 0-2 scale, respectively. Clinically relevant blocks were defined as a motor score > or =2 and sensory score > or =1. Nonparametric methods were used for statistical analysis. RESULTS: No adverse effects were noted. There was a significant difference between the treatments with bupivacaine and the saline control, but not between the three bupivacaine treatments. Success rates of clinically relevant sciatic and saphenous blocks were both 67% (CI 95% 0.22 0.96). Onset and duration of the blocks were variable; 20-160 and 20-540 minutes, respectively. CONCLUSION AND CLINICAL RELEVANCE: None of the bupivacaine doses was significantly superior, though there was a tendency for a better block with the high bupivacaine dose. Either the technique or the doses used need further modification before this method will be useful in clinical practice. PMID- 20712614 TI - Suspected acute meperidine toxicity in a dog. AB - OBSERVATIONS: A 22-month-old male neutered Coton De Tulear dog was presented for upper gastrointestinal endoscopy under general anesthesia. The anesthetic plan included premedication with intramuscular meperidine (4 mg kg(-1)) but meperidine was inadvertently administered at ten-fold this dose. Within 5 minutes, the dog was unresponsive to external stimulation, and by 10 minutes post-injection developed generalized signs of central nervous system (CNS) excitement. Initial therapy included inspired oxygen supplementation, and single intravenous (IV) doses of diazepam (0.68 mg kg(-1)) and naloxone (0.03 mg kg(-1)) to no effect. A second dose of diazepam (0.46 mg kg(-1), IV) abolished most of the signs of CNS excitement. General anesthesia was induced and the endoscopy performed. Time to extubation was initially prolonged, but administering naloxone (final dose 0.1 mg kg(-1), IV) to effect enabled extubation. After naloxone, the dog became agitated, noise sensitive, and had leg and trunk muscle twitches. Diazepam (0.30 mg kg(-1), IV) abolished these signs and the dog became heavily sedated and laterally recumbent. Naloxone administration was continued as a constant rate infusion (0.02 mg kg(-1) hour(-1), IV) until approximately 280 minutes post meperidine injection, at which time the dog suddenly sat up. Occasional twitches of the leg and trunk muscles were observed during the night. The dog was discharged the next day appearing clinically normal. CONCLUSIONS: Given that the CNS excitatory effects of normeperidine are not a mu opioid receptor effect, the use of naloxone should be considered carefully when normeperidine excitotoxicity is suspected. Benzodiazepines may be beneficial in ameliorating clinical signs of normeperidine excitotoxicity. PMID- 20712615 TI - Dynamics and regulation of plant membrane transport. PMID- 20712616 TI - Modelling polar auxin transport in developmental patterning. AB - Auxin interacts with its own polar transport to influence cell polarity and tissue patterning. Research over the past decade has started to deliver new insights into the molecular mechanisms that drive and regulate polar auxin transport. The most prominent auxin efflux protein, PIN1, has subsequently become a crucial component of auxin transport models because it is now known to direct auxin flow and maintain local auxin gradients. Recent molecular and genetic experiments have allowed the formulation of conceptual models that are able to interpret the role of (i) auxin, (ii) its transport, and (iii) the dynamics of PIN1 in generating temporal and spatial patterns. Here we review the current mathematical models of patterning in two specific developmental contexts: lateral shoot and vein formation, focusing on how these models can help to untangle the details of auxin transport-mediated patterning. PMID- 20712617 TI - An update on the ABCC transporter family in plants: many genes, many proteins, but how many functions? AB - The ABCC subfamily of the ATP binding cassette (ABC) transporters, which were formerly known as multidrug resistance-related proteins (MRPs), consists of closely related members found in all eukaryotic organisms. Although more than a decade of intensive research has elapsed since the first MRP protein was functionally characterised in Arabidopsis thaliana, knowledge of this particular transporter family is still limited in plants. Although ABCC proteins were originally defined as vacuolar pumps of glutathione-S (GS) conjugates, evidence, as well as speculation, on their endogenous functions inside the cell ranges from detoxification and heavy metal sequestration, to chlorophyll catabolite transport and ion channel regulation. The characterisation of knockout mutants in Arabidopsis has been pivotal for elucidation of different roles of ABCC transporters. However, a functional annotation for the majority of these transport proteins is still lacking, even in this model plant. On the one hand, this problem seems to be caused by functional redundancy between family members, which might lead to physiological complementation by a highly homologous gene in the mutant lines. On the other hand, there is growing evidence that the functional diversity of ABCC genes in Arabidopsis and other plants is far greater than previously assumed. For example, analysis of microarray expression data supports involvement of ABCC transporters in the response to biotic stress: particular changes in ABCC transcript levels are found, which are pathogen specific and evoke distinct signalling cascades. Current knowledge about plant ABCC transporters indicates that novel and unexpected functions and substrates of these proteins are still waiting to be elucidated. PMID- 20712618 TI - Nucleoside transport and associated metabolism. AB - Nucleosides are intermediates of nucleotide metabolism. Nucleotide de novo synthesis generates the nucleoside monophosphates AMP and UMP, which are further processed to all purine and pyrimidine nucleotides involved in multiple cellular reactions, including the synthesis of nucleic acids. Catabolism of these substances results in the formation of nucleosides, which are further degraded by nucleoside hydrolase to nucleobases. Both nucleosides and nucleobases can be exchanged between cells and tissues through multiple isoforms of corresponding transport proteins. After uptake into a cell, nucleosides and nucleobases can undergo salvage reactions or catabolism. Whereas energy is preserved by salvage pathway reactions, catabolism liberates ammonia, which is then incorporated into amino acids. Keeping the balance between nitrogen consumption during nucleotide de novo synthesis and ammonia liberation by nucleotide catabolism is essential for correct plant development. Senescence and seed germination represent situations in plant development where marked fluctuations in nucleotide pools occur. Furthermore, extracellular nucleotide metabolism has become an immensely interesting research topic. In addition, selected aspects of nucleoside transport in yeast, protists and humans are discussed. PMID- 20712619 TI - The Arabidopsis sugar transporter (AtSTP) family: an update. AB - The Arabidopsis sugar transporter (AtSTP) family is one of the best characterised families within the monosaccharide transporter (MST)-like genes. However, several aspects are still poorly investigated or not yet addressed experimentally, such as post-translational modifications and other factors affecting transport activity. This mini-review summarises recent advances in the AtSTP family as well as objectives for future studies. PMID- 20712620 TI - The plant PRAT proteins - preprotein and amino acid transport in mitochondria and chloroplasts. AB - The membrane proteins of the plant preprotein and amino acid transporter (PRAT) superfamily all share common structural elements, such as four membrane-spanning alpha-helices. Interestingly they display diverse localisation to outer and inner membranes of chloroplasts and mitochondria. Furthermore, they fulfil different functions in preprotein translocation as well as amino acid transport across these membranes. This review summarises current knowledge on precursor protein import and amino acid transport in plastids and mitochondria and provides an overview of the distinct tasks and features of members of the PRAT superfamily in the model plant Arabidopsis thaliana. PMID- 20712621 TI - Roles of tandem-pore K+ channels in plants - a puzzle still to be solved. AB - The group of voltage-independent K(+) channels in Arabidopsis thaliana consists of six members, five tandem-pore channels (TPK1-TPK5) and a single K(ir)-like channel (KCO3). All TPK/KCO channels are located at the vacuolar membrane except for TPK4, which was shown to be a plasma membrane channel in pollen. The vacuolar channels interact with 14-3-3 proteins (also called General Regulating Factors, GRFs), indicating regulation at the level of protein-protein interactions. Here we review current knowledge about these ion channels and their genes, and highlight open questions that need to be urgently addressed in future studies to fully appreciate the physiological functions of these ion channels. PMID- 20712622 TI - Light-induced modification of plant plasma membrane ion transport. AB - Light is not only the driving force for electron and ion transport in the thylakoid membrane, but also regulates ion transport in various other membranes of plant cells. Light-dependent changes in ion transport at the plasma membrane and associated membrane potential changes have been studied intensively over the last century. These studies, with various species and cell types, revealed that apart from regulation by chloroplasts, plasma membrane transport can be controlled by phytochromes, phototropins or channel rhodopsins. In this review, we compare light-dependent plasma membrane responses of unicellular algae (Eremosphaera and Chlamydomonas), with those of a multicellular alga (Chara), liverworts (Conocephalum), mosses (Physcomitrella) and several angiosperm cell types. Light-dependent plasma membrane responses of Eremosphaera and Chara are characterised by the dominant role of K(+) channels during membrane potential changes. In most other species, the Ca(2+)-dependent activation of plasma membrane anion channels represents a general light-triggered event. Cell type specific responses are likely to have evolved by modification of this general response or through the development of additional light-dependent signalling pathways. Future research to elucidate these light-activated signalling chains is likely to benefit from the recent identification of S-type anion channel genes and proteins capable of regulating these channels. PMID- 20712623 TI - Physiology and biophysics of plant ligand-gated ion channels. AB - Small molecules and metabolites often act as intra- or extracellular messengers in signal transduction pathways. Ligand-gated ion channels provide a mean to transduce those biochemical signals at the membrane into electrical events and ion fluxes. In plants, cyclic nucleotides and glutamate represent intra- and extracellular signalling ligands, respectively. While the former have been shown to regulate voltage-dependent ion channels and are supposed to activate cyclic nucleotide gated (CNG) channels, the latter are perceived by ionotropic glutamate receptors (GLRs). This review summarises our current knowledge about CNG channels and glutamate receptors in plants and their proposed roles in plant development and adaptation to biotic and abiotic stresses. PMID- 20712624 TI - Plants and fungi in the era of heterogeneous plasma membranes. AB - Examples from yeast and plant cells are described that show that their plasma membrane is laterally compartmented. Distinct lateral domains encompassing both specific lipids and integral proteins coexist within the plane of the plasma membrane. The compartments are either spatially stable and include distinct sets of proteins, or they are transiently formed to accomplish diverse functions. They are not related to lipid rafts or their clusters, as defined for mammalian cells. This review summarises only well-documented compartments of plasma membranes from plants and fungi, which have been recognised using microscopic approaches. In several cases, physiological functions of the membrane compartmentation are revealed. PMID- 20712625 TI - Trafficking, lateral mobility and segregation of the plant K channel KAT1. AB - Functioning of ion channels depends not only on the control of their activity but also on their density and lateral organisation in the membrane. The two latter aspects have recently attracted increasing attention. Here, we summarize studies on trafficking and plasma membrane distribution of the plant K(+) channel KAT1 from Arabidopsis thaliana. In guard cells, KAT1 was found to be subject to constitutive and pressure-driven turnover and ABA-stimulated endocytosis. These results point to a role of exo- and endocytosis in regulating KAT1 density and thus ion transport during guard cell functioning. Recent studies indicate that KAT1 density can also be adjusted at the site of ER export. Efficient ER export of KAT1 was shown to depend on an acidic motif that interacts with Sec24, a component of ER-derived vesicles. Surface expression of ER export mutants of KAT1 can be rescued through heterotetrameric assembly with wild-type KAT1, implying that not all subunits of the channel tetramer need to carry an ER export motif. Analysis of the distribution of KAT1 in the plasma membrane revealed segregation of the channel into microdomains, and low lateral mobility in both plant and mammalian cells. In plant cells, SNAREs have been shown to be involved in anchoring KAT1 in the plasma membrane. Studies on guard cells imply a role for the cell wall in organisation of KAT1 microdomains. Together, these findings underline the importance of investigating mechanisms of KAT1 trafficking and lateral organisation in order to fully understand channel functioning. PMID- 20712626 TI - Expression of the AtSUC1 gene in the female gametophyte, and ecotype-specific expression differences in male reproductive organs. AB - Based on analyses in Arabidopsis thaliana ecotype C24, the AtSUC1 protein was previously characterised as a male gametophyte-specific H(+)/sucrose symporter. Later, expression analyses in ecotype Columbia-0 (Col-0) identified AtSUC1 expression also in trichomes (not detected in trichome-less C24 plants) and roots, suggesting ecotype-specific differences in AtSUC1 expression. Here, we present data on additional ecotype-specific differences in AtSUC1 expression in other tissues. Using different AtSUC1 promoter-reporter gene lines, we performed comparative analyses of AtSUC1 expression in floral tissues of C24 and Col-0 plants, and using an AtSUC1-specific antiserum, we performed immunohistochemical analyses on tissue sections from C24, Col-0, Landsberg erecta (Ler) and Wassilewskaija (Ws) ecotypes. We show that AtSUC1 expression occurs in the funicular epidermis of C24, Ler and Ws, but not in Col-0. In contrast, we observed high levels of AtSUC1 protein in pollen grains of Col-0, lower levels in pollen of C24 and Ler, and no AtSUC1 protein in Ws pollen. Moreover, our reporter gene analyses identified a previously undetected expression of AtSUC1 in the female gametophyte, and revealed that AtSUC1 expression in the funicular epidermis is absent from unpollinated siliques and is induced upon successful pollination. The impact of these findings on the potential physiological role of AtSUC1 is discussed. PMID- 20712627 TI - The role of plastidial glucose-6-phosphate/phosphate translocators in vegetative tissues of Arabidopsis thaliana mutants impaired in starch biosynthesis. AB - Arabidopsis thaliana mutants impaired in starch biosynthesis due to defects in either ADP glucose pyrophosphorylase (adg1-1), plastidic phosphoglucose mutase (pgm) or a new allele of plastidic phosphoglucose isomerase (pgi1-2) exhibit substantial activity of glucose-6-phosphate (Glc6P) transport in leaves that is mediated by a Glc6P/phosphate translocator (GPT) of the inner plastid envelope membrane. In contrast to the wild type, GPT2, one of two functional GPT genes of A. thaliana, is strongly induced in these mutants during the light period. The proposed function of the GPT in plastids of non-green tissues is the provision of Glc6P for starch biosynthesis and/or the oxidative pentose phosphate pathway. The function of GPT in photosynthetic tissues, however, remains obscure. The adg1-1 and pgi1-2 mutants were crossed with the gpt2-1 mutant defective in GPT2. Whereas adg1-1/gpt2-1 was starch-free, residual starch could be detected in pgi1-2/gpt2-1 and was confined to stomatal guard cells, bundle sheath cells and root tips, which parallels the reported spatial expression profile of AtGPT1. Glucose content in the cytosolic heteroglycan increased substantially in adg1-1 but decreased in pgi1-2, suggesting that the plastidic Glc6P pool contributes to its biosynthesis. The abundance of GPT2 mRNA correlates with increased levels of soluble sugars, in particular of glucose in leaves, suggesting induction by the sugar-sensing pathway. The possible function of GPT2 in starch-free mutants is discussed in the background of carbon requirement in leaves during the light-dark cycle. PMID- 20712628 TI - Kinetic analyses of plant water relocation using deuterium as tracer - reduced water flux of Arabidopsis pip2 aquaporin knockout mutants. AB - Due to reduced evaporation and diffusion of water molecules containing heavier isotopes, leaf water possesses an elevated (18)O or (2)H steady-state content. This enrichment has been exploited in plant physiology and ecology to assess transpiration and leaf water relations. In contrast to these studies, in this work the (2)H content of the medium of hydroponically grown Arabidopsis thaliana was artificially raised, and the kinetics of (2)H increase in the aerial parts recorded during a short phase of 6-8 h, until a new equilibrium at a higher level was reached. A basic version of the enrichment models was modified to establish an equation that could be fitted to measured leaf (2)H content during uptake kinetics. The fitting parameters allowed estimation of the relative water flux q(leaf) into the Arabidopsis rosette. This approach is quasi-non-invasive, since plants are not manipulated during the uptake process, and therefore, offers a new tool for integrated analysis of plant water relations. The deuterium tracer method was employed to assess water relocation in Arabidopsis pip2;1 and pip2;2 aquaporin knockout plants. In both cases, q(leaf) was significantly reduced by about 20%. The organ and cellular expression patterns of both genes imply that changes in root hydraulic conductivity, as previously demonstrated for pip2;2 mutants, and leaf water uptake and distribution contributed in an integrated fashion to this reduced flux in intact plants. PMID- 20712629 TI - Expression, localisation and phylogeny of a novel family of plant-specific membrane proteins. AB - In a screen for senescence-associated genes in Arabidopsis thaliana, a novel, highly up-regulated membrane protein was identified. It is a member of an uncharacterised, strictly plant-specific gene family and was named AtDMP1 (Arabidopsis thaliana DUF679 domain membrane protein 1). The AtDMP proteins are predicted to have four transmembrane spans, with cytosolic amino- and carboxy termini. In this study, we investigated the phylogenetic distribution of DMP proteins, their tissue-specific expression and subcellular localisation in A. thaliana. The Chlamydomonas reinhardtii and Physcomitrella patens genomes in dicots contain only a single DMP gene copy, whereas there are five to 13 DMP genes and 11-16 in monocots, many of which supposedly result from recent gene duplications. The ubiquitous occurrence of DMP proteins in green plants and their absence from other kingdoms suggest a role in plant-specific processes. In A. thaliana, expression of nine out of ten DMP genes was detected. The expression patterns were found to be markedly tissue- and development-specific; thus, functional redundancy of most proteins is unlikely. The occurrence of several AtDMPs in tissues undergoing senescence (AtDMP1, -3, -4), dehiscence (AtDMP7) or abscission (AtDMP2, -4, -7) suggests involvement of DMPs in different types of programmed cell death. AtDMP-eGFP fusion proteins were found to localise either to the endoplasmic reticulum, the tonoplast or, under certain conditions, to both membrane systems. Further investigations are in progress to elucidate functions of the AtDMP proteins. PMID- 20712630 TI - Host-parasite interactions in periodontitis: microbial pathogenicity and innate immunity. PMID- 20712632 TI - Porphyromonas gingivalis cell-induced hemagglutination and platelet aggregation. PMID- 20712634 TI - Bioactive mechanism of Porphyromonas gingivalis lipid A. PMID- 20712631 TI - Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins. PMID- 20712635 TI - Aggregatibacter (Actinobacillus) actinomycetemcomitans: a triple A* periodontopathogen? PMID- 20712633 TI - Contribution of Porphyromonas gingivalis lipopolysaccharide to periodontitis. PMID- 20712637 TI - Virulence factors of Treponema denticola. PMID- 20712636 TI - Virulence mechanisms of Tannerella forsythia. PMID- 20712638 TI - Genotyping to distinguish microbial pathogenicity in periodontitis. PMID- 20712639 TI - Cytokine regulation of immune responses to Porphyromonas gingivalis. PMID- 20712642 TI - Molecular dissection of Porphyromonas gingivalis-related arteriosclerosis: a novel mechanism of vascular disease. PMID- 20712640 TI - Epithelial cell-derived antimicrobial peptides are multifunctional agents that bridge innate and adaptive immunity. PMID- 20712643 TI - Osteoclastic bone resorption induced by innate immune responses. PMID- 20712641 TI - Periodontal innate immune mechanisms relevant to atherosclerosis and obesity. PMID- 20712644 TI - Mucosal regulatory cells in the gastrointestinal tract and periodontium. PMID- 20712645 TI - Mouse models of gastric tumors: Wnt activation and PGE2 induction. AB - Accumulating evidence has suggested that cooperation of oncogenic activation and the host responses is important for cancer development. In gastric cancer, activation of Wnt signaling appears to be a major oncogenic pathway that causes tumorigenesis. In the chronic gastritis caused by Helicobacter pylori infection, cyclooxigenase-2 induces prostaglandin E(2) (PGE(2)) biosythesis, which plays an important role in tumorigenesis. We constructed a series of mouse models and investigated the role of each pathway in the gastric tumorigenesis. Wnt activation in gastric epithelial cells suppresses differentiation, and induces development of preneoplastic lesions. On the other hand, induction of the PGE(2) pathway in gastric mucosa induces development of spasmolytic polypeptide expressing metaplasia (SPEM), which is a possible preneoplastic metaplasia. Importantly, simultaneous activation of Wnt and PGE(2) pathways leads to dysplastic gastric tumor development. Moreover, induction of the PGE(2) pathway also promotes gastric hamartoma development when bone morphogenetic protein (BMP) signaling is suppressed. These results indicate that alteration in the Wnt or BMP signaling impairs epithelial differentiation, and the PGE(2) pathway accelerates tumor formation regardless of the types of oncogenic pathways. We review the phenotypes and gene expression profiles of the respective models, and discuss the cooperation of oncogenic pathways and host responses in gastric tumorigenesis. PMID- 20712646 TI - Diagnostic utility of EWS break-apart fluorescence in situ hybridization in distinguishing between non-cutaneous melanoma and clear cell sarcoma. AB - Clear cell sarcoma (CCS) is a rare soft tissue sarcoma with morphological similarities to malignant melanoma (MM), but with a distinct genetic background that includes the chromosomal translocation t(12;22)(q13;q12). Clear cell sarcoma is often misdiagnosed as MM because of similarities in target locations and immunophenotypes. Eighteen cases with MM in non-cutaneous sites were subjected to fluorescence in situ hybridization (FISH) to assess EWS gene breakage. Tissue microarrays were constructed using formalin-fixed, paraffin-embedded tissue and the EWSR1 (22q12) dual-color, break-apart rearrangement probe (Vysis) was used. Two patients were classified as CCS with EWS gene rearrangement, with a mean of 67.5% positive cells per sample according to break-apart FISH. The remaining 16 patients lacked break-apart signals of the EWS gene. The presence of type 1 (EWS exon 8-ATF1 exon 4) fusion transcripts was confirmed in FISH-positive patients by RT-PCR. Retrospective analysis revealed that the masses were located in the foot and buttock, respectively. Morphologically, tumor cells were not typical for those of CCS or MM. Break-apart FISH is an accurate and convenient method for differentiating between MM and CCS. Molecular detection of EWS gene rearrangement, either by break-apart FISH or RT-PCR, is mandatory in subjects with melanotic tumors of soft tissue. PMID- 20712647 TI - Glyoxalase I Ala111Glu gene polymorphism: No association with breast cancer risk but correlated with absence of progesterone receptor. AB - The aim of the present study was to evaluate the association between the Glyoxalase I (GLOI) Ala111Glu polymorphism and breast cancer risk among the major Malaysian ethnic groups, the Malays, Chinese and Indians, as well as clinico pathological characteristics of these patients. Genotyping of GLOI gene was performed on blood samples obtained from 387 patients and 252 normal healthy women who had no history of any malignancy using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The genotype and allele frequencies of GLOI polymorphism were not significantly different between the patients and normal individuals among the Malays (P= 0.721, 0.402), Chinese (P= 0.208, 0.079) and Indians (P= 0.612, 0.349), respectively. The Malay, Chinese and Indian women who were Glu/Glu homozygotes (P= 0.419, 0.093, 0.367), Ala/Glu heterozygotes (P= 0.648, 0.182, 0.402) and carriers of Glu allele (P= 0.402, 0.079, 0.349), respectively, were not associated with breast cancer risk. The Glu allele genotype was significantly associated with absence of progesterone receptor (P= 0.036). Thus, the polymorphic variant of the GLOI gene might not be a useful genetic marker to identify Malaysian Malay, Chinese or Indian women who could be at greater risk of developing breast cancer. PMID- 20712648 TI - Gastric plexiform angiomyxoid myofibroblastic tumor. AB - Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a relatively recently described gastric tumor with a peculiar plexiform growth pattern. PAMT is typified by a myofibroblastic immunophenotype that distinguishes it from the more common gastrointestinal stromal tumors and the rarely documented fibromyxomas. We report an additional PAMT, the seventh tumor with this label, which was an incidental finding on abdominal computed tomography scan of a 35-year-old Indian female. The tumor measured 4 x 3 x 2 cm and demonstrated plexiform architecture, myxoid stroma, prominent vasculature and spindled cells with myofibroblastic differentiation. The clinicopathological features, progesterone immunopositivity, hitherto undocumented, and mimicry of other primary and secondary gastric mesenchymal tumors, including endometrial stromal sarcoma, are discussed. PMID- 20712649 TI - Identification of MPO-positive capillaries of the pleura by immunohistochemistry in MPO-ANCA associated vasculitis. AB - We present a case of a middle-aged woman with myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis that demonstrated immunohistochemically positive MPO capillaries of the pleura. The patient initially presented with proteinuria and microscopic hematuria at the age of 38. Acute progressive glomerulonephritis and pulmonary hemorrhage occurred 4 years later, and a high serum titer of MPO-ANCA was detected therefore a diagnosis of microscopic polyangiitis was made. Steroid-pulse therapy was performed and the pulmonary shadow improved, but the renal failure did not improve, thus, hemodialysis was initiated. Thereafter, an 18-year asymptomatic phase followed, but high serum levels of MPO-ANCA persisted during this period. Chronic pulmonary hemorrhage was discovered at the age of 60, and video-assisted thoracoscopic surgery was performed. Resected tissue revealed diffuse aloveolar hemorrhage accompanied by marked hemosiderin deposition, whereas MPO-immunopositive capillaries were identified only in the pleura. To our knowledge, this is the first report demonstrating MPO-positive capillaries in a disease other than glomerulonephritis. Judging from this unique case, MPO-positive endothelial cells may appear only during the hyperacute stage before hemorrhage, and may diminish thereafter, thus, may be associated with the trigger of microscopic polyangiitis. PMID- 20712650 TI - A potential case of intraductal tubulopapillary neoplasms of the bile duct. AB - Intraductal tubulopapillary neoplasm (ITPN) has been recently reported in pancreas. We experienced an unusual intraductal growing bile duct tumor, which showed the same histopathologic and immunostaining profiles as ITPN of pancreas. A 72-year-old female patient visited hospital due to intrahepatic stone. The hilar bile duct tumor was detected and incidental lung mass was found in systemic evaluation. The histopathologic finding of the two biopsy lesions was different. The lung tumor was an adenocarcinoma, and the bile duct tumor showed poorly differentiated carcinoma with eosinophilic cytoplasm. Lung lobectomy and hemihepatectomy were performed under the impression of double primary neoplasms of the lung adenocarcinoma and oncocytic variant of the biliary papillary tumor. However the histopathologic findings and immunostaining profiles of the two resected tumors were the same. Both the lung and bile duct tumors showed a tubulopapillary pattern with high-grade nuclear atypia. Pathologic findings were the same as a recently reported ITPN of the pancreas. Eosinophilic cytoplasm of the bile duct tumor was not oncocytic cytoplasm but pyknotic change due to necrosis. Here, we report the first case of ITPN of the bile duct with lung metastasis. The tumor in this case does not fit with any categories in the current biliary tumor classification. We speculate that this may be the first case of biliary ITPN. PMID- 20712651 TI - Endometrioid adenocarcinoma of the vagina with a microglandular pattern arising from endometriosis after hysterectomy. AB - Primary endometrioid adenocarcinoma rarely occurs in the vagina. Occasionally, endometrioid adenocarcinoma has a microglandular pattern. Herein, a case of primary endometrioid adenocarcinoma of the vagina with a microglandular pattern arising from pre-existing endometriosis long after a hysterectomy, is described. A 57-year-old postmenopausal woman developed a vaginal discharge over one decade after undergoing a hysterectomy. Microscopic examination of the vaginal smear and a biopsy specimen demonstrated an atypical glandular proliferation composed of columnar cells with occasional intracytoplasmic mucin and bland nuclear morphology, showing microcysts and numerous neutrophils within and around cysts. Immunohistochemically, the neoplastic cells were diffusely positive for CK7, MUC1, ER, and PR, and focally positive for vimentin, CEA, CK5/6, p63, p16(INK4a), and p53. A portion of residual endometrioid adenocarcinoma was identified adjacent to foci of endometriosis in the vaginectomy specimen. The patient has done well without evidence of recurrent disease for 1 year after surgery. Pathologists are encouraged to be aware of the occurrence of endometrioid adenocarcinoma associated with endometriosis in the vaginal stump after hysterectomy, and microglandular morphology which might be a source of misinterpretation. PMID- 20712652 TI - Study of CD21-positive FDC-like structures in MALT lymphoma: Does it provide helpful information for histopathological diagnosis? PMID- 20712653 TI - Primary rhabdoid tumor of thyroid gland. Description of a rare entity with molecular study. PMID- 20712656 TI - International migration versus National health-care. PMID- 20712654 TI - Renal oncocytoma with diffuse and prominent intraneoplastic xanthomatous reaction. PMID- 20712657 TI - Ambivalence and the experience of China-educated nurses working in Australia. AB - Ambivalence and the experience of China-educated nurses working in Australia The last decade has seen an increase in research on the experience of immigrant nurses. There are two prevailing approaches in this body of work. One is a focus on the positive or negative aspects of the experience, and the other, a depiction of the experience as a linear movement from struggle to a comfortable state. Based on our study findings on the experience of China-educated nurses working in Australia, this study proposes that the concept of ambivalence is more appropriate in portraying the experience of immigrant nurses. Several sources of ambivalence experienced by the participants are represented: a disparity between expectation and reality, conflicting social and cultural norms, the dual reference points of comparison, divergent interests within families, and a sense that although it is unsatisfactory, it is hard to go back. We argue that immigration generates various forms of ambivalence and immigrant nurses must live with more or less ambivalence. The notion of ambivalence can explain a range of behaviours and situations beyond the scope of rational-choice explanations. To date, ambivalence as a theoretical concept in understanding the experience of immigrant nurses has been either ignored or insufficiently addressed in the literature. PMID- 20712658 TI - From 'part of ' to 'partnership': the changing relationship between nurse education and the National Health Service. AB - Worldwide, many countries have moved towards incorporating nurse education into the higher education sector and this inevitably has implications for the relationship between nurse education providers and local health service providers. This study explores the changes to the relationship in the UK between nurse education providers and the UK National Health Service over the past 20 years and demonstrates how two political ideologies have been central to those changes. The two ideologies of interest are the introduction of internal markets to the National Health Service by the Conservative government at the end of the 1980s and the New Labour response to the fragmentation of public services caused by Conservative neoliberal policy, which was to introduce the notion of 'partnership working'. This study reviews the wider debate around partnership policy and applies that debate to evaluate the way that nurse education providers and the National Health Service are working in partnership to provide clinical practice placements for nursing students. PMID- 20712659 TI - Continuing nursing education policy in China and its impact on health equity. AB - The aim of this study was to evaluate the mandatory continuing nursing education (MCNE) policy in China and to examine whether or not the policy addresses health equity. MCNE was instituted in 1996 in China to support healthcare reform was to include producing greater equity in health-care. However, the literature increasingly reports inequity in participation in MCNE, which is likely to have had a detrimental effect on the pre-existing discrepancies of education in the nursing workforce, and thereby failing to really address health equity. Despite a growing appeal for change, there is lack of critical reflection on the issues of MCNE policy. Critical ethnography underpinned by Habermas' Communicative Action Theory and Giddens' Structuration Theory were used to guide this study. Findings are presented in four themes: (i) inaccessibility of learning programs for nurses; (ii) undervaluation of workplace-based learning; (iii) inequality of the allocation of resources; and (iv) demands for additional support in MCNE from non tertiary hospitals. The findings strongly suggest the need for an MCNE policy review based on rational consensus with stakeholders while reflecting the principles of health equity. PMID- 20712661 TI - Applying a realist(ic) framework to the evaluation of a new model of emergency department based mental health nursing practice. AB - Evaluation has become progressively popular within public health and healthcare programme research, with an emphasis on outcomes and a desire to improve practice and service delivery. Mixed methods approaches are consequently being employed to capture the multidimensional characteristics of programmes that aim to address problematic situations affecting targeted populations. This paper provides an overview of critical realism, a modern philosophical perspective that seeks contextualised causal understandings of social phenomena. Realistic evaluation, a research methodology adapted from critical realism, is highlighted as a means of obtaining a deeper appreciation of how complex programmes work, for whom they work, and under what circumstances. The evaluation of a mental health nurse practitioner outpatient service based in the emergency department of a large teaching hospital in Sydney Australia is used to illustrate the application of a realist perspective to research in nursing practice. PMID- 20712660 TI - A critical analysis of health promotion and 'empowerment' in the context of palliative family care-giving. AB - Traditionally viewed as in opposition to palliative care, newer ideas about 'health-promoting palliative care' increasingly infuse the practices and philosophies of healthcare professionals, often invoking ideals of empowerment and participation in care and decision-making. The general tendency is to assume that empowerment, participation, and self-care are universally beneficial for and welcomed by all individuals. But does this assumption hold for everyone, and do we fully understand the implications of health-promoting palliative care for family caregivers in particular? In this study, we draw on existing literature to highlight potential challenges arising from the application of 'family empowerment' strategies in palliative home-care nursing practice. In particular, there is a risk that empowerment may be operationalized as transferring technical and medical-care tasks to family caregivers at home. Yet, for some family caregivers, a sense of security and support, as well as trust in professionals, may be equally if not more important than empowerment. Relational and role concerns may also at times take precedence over a desire for empowerment. The potential implications of 'family empowerment' are explored in this regard. 'Family empowerment' approaches need to be accompanied by a strong understanding of how to best support individual palliative family caregivers. PMID- 20712662 TI - Representations of people with dementia - subaltern, person, citizen. AB - This study traces shifts in health professional representations of people with dementia. The concepts of subaltern, personhood and citizenship are used to draw attention to issues around visibility, voice and inclusion. Professional discourses and practices draw upon, and are shaped by historical and contemporary representations. Until recently, people with dementia were subaltern in nursing and medical discourses; marginalised and silenced. The incorporation of contemporary representations foregrounding personhood and citizenship into health professional accounts provide space for transformative styles of care. Privileging personhood centralises the person with dementia in social networks, focusing on their experiences and relationships. Respecting citizenship involves challenging discrimination and stigma: nursing from a rights-based approach necessitates listening and being responsive to the needs of the person with dementia. Incorporating contemporary representations in health professional practice requires the discarding of the historically dominant elite and authoritarian accounts of dementia still apparent in some nursing texts along with, perhaps, the historically burdened term of dementia itself. PMID- 20712663 TI - Dignity in health-care: a critical exploration using feminism and theories of recognition. AB - Growing concerns over undignified health-care has meant the concept of dignity is currently much discussed in the British National Health Service. This has led to a number of policies attempting to reinstate dignity as a core ethical value governing nursing practice and health-care provision. Yet these initiatives continue to draw upon a concept of dignity which remains reliant upon a depoliticised, ahistorical and decontexualised subject. In this paper, we argue the need to revise the dignity debate through the lens of feminism and theories of recognition. Postmodern feminist theories provide major challenges to what remain dominant liberal approaches as they pay attention to the contingent, reflexive, and affective aspects of care work. Theories of recognition provide a further critical resource for understanding how moral obligations and responsibilities towards others and our public and private responses to difference arise. This re-situates dignity as a highly contested and politicised concept involving complex moral deliberations and diverse political claims of recognition. The dignity debate is thus moved beyond simplistic rational injunctions to care, or to care more, and towards critical discussions of complex politicised, moral practices infused with power that involve the recognition of difference in health-care. PMID- 20712664 TI - The meaning of middle-aged female spouses' lived experience of the relationship with a partner who has suffered a stroke, during the first year postdischarge. AB - Stroke consequences present a great long-term challenge to the spouses of the stroke sufferer. A longitudinal study with a phenomenological hermeneutic approach was used to illuminate the meanings of middle-aged female spouses' lived experience of their relationship with a partner who has suffered a stroke, during the first year postdischarge. Four middle-aged female spouses of stroke sufferers participated in the study. Narrative interviews were conducted 1, 6 and 12 month postdischarge (total of 12 interviews), audio-taped and transcribed verbatim to a text and interpreted by a phenomenological hermeneutic method inspired by Ricoeur. The findings showed a process over time during which spouses come to know, recognize and acknowledge the residual changes in their partners' cognitive and emotional conditions and the impact on their relationship. Spouses showed grief due to the loss of the marital relationship they once had and anxiety that they would not be able to continue in an undesired relationship in the future. Even if the partner is still alive, there is a loss to grieve and to be understood, an important meaning of the transition process in the relationship during the first year after the partner's discharge. PMID- 20712665 TI - 'Health equity through action on the social determinants of health': taking up the challenge in nursing. AB - Reducing health inequities is a priority issue in Canada and worldwide. In this paper, we argue that nursing has a clear mandate to ensure access to health and health-care by providing sensitive empowering care to those experiencing inequities and working to change underlying social conditions that result in and perpetuate health inequities. We identify key dimensions of the concept of health (in)equities and identify recommendations to reduce inequities advanced in key global and Canadian documents. Using these documents as context, we advocate a 'critical caring approach' that will assist nurses to understand the social, political, economic and historical context of health inequities and to tackle these inequities through policy advocacy. Numerous societal barriers as well as constraints within the nursing profession must be acknowledged and addressed. We offer recommendations related to nursing practice, education and research to move forward the agenda of reducing health inequities through action on the social determinants of health. PMID- 20712666 TI - Palliative critical care is not an oxymoron. PMID- 20712667 TI - Organ donation: we can solve the shortage. PMID- 20712668 TI - International dialogue on end of life: challenges in the UK and USA. AB - AIM: The aim of this paper was to increase international collaboration on end of life care (EoLC) in critical care. Objectives included highlighting key challenges for critical care nurses in EoLC through a transcribed interview between a clinician, an educationalist and a researcher who all hold an EoLC focus. BACKGROUND: EoLC continues to hold high profile within international health care arenas, including critical care units. Whilst end of life care remains well debated, it still presents many challenges for everyday practitioners. Dialogue with international colleagues and disciplines may provide opportunity for further understanding of this complex and sensitive area. CONCLUSIONS: A key issues to arise from this venture of shared learning was that futility of treatment is problematic for all. This is further complicated in the USA where the concept of (family) autonomy strongly shapes EoLC decision making. RELEVANCE TO CLINICAL PRACTICE: This paper demonstrates that there are opportunities for nurses within health care teams which could be addressed through education and professional development initiatives. Furthermore, knowledge from other disciplines can provide a useful lens through which to improve our understanding of EoLC. PMID- 20712669 TI - Family witnessed resuscitation - experience and attitudes of German intensive care nurses. AB - AIM: To explore German intensive care nurses' experiences and attitudes toward family witnessed resuscitation (FWR). BACKGROUND: The subject of FWR has fuelled much controversy among health professionals. Typically studies involving European critical and cardiac nurses' under-represent the perspective of individual countries. Arguably research exploring the experiences and attitudes of nurses by country may expand understanding and embrace cultural values. DESIGN: Descriptive survey. METHODS: Three hundred and ninety-four German intensive care nurses attending a conference were invited to complete a 36-item questionnaire on their experiences and attitudes towards FWR. Participants were also invited to share, in writing, other thoughts relevant to the study. Data was analysed using descriptive statistics. RESULTS: A total of 166 (42.1%) questionnaires were returned completed. Seventy participants had experiences with family members being present and for 46 (65.7%) these were negative. Participants (68%) did not agree that family members should have the option to be with loved ones during resuscitation. Over half (56.0%) were concerned that family presence may adversely influence staff performance during resuscitation procedures. There was a lack of certainty about the outcomes of the practice, although 61% agreed that family presence could facilitate better understanding among relatives. Qualitative responses where characterized by four broad themes relating to individualized decision-making, supporting families, threats of violence and family involvement. CONCLUSIONS: German intensive care nurses have guarded attitudes towards FWR because of their experiences and concerns for the well being of relatives and staff. Introducing this topic within nursing curricula, as part of resuscitation training and by wider professional debate will help challenge and resolve practitioner concerns and objections. RELEVANCE TO CLINICAL PRACTICE: Health professionals have anxieties about possible consequences of FWR, strategies involving education and simulation training may improve attitudes. PMID- 20712670 TI - Prevention of nosocomial infections in intensive care patients. AB - BACKGROUND: Changes in patient profile, and in the health care environment, altering socioeconomic conditions and advances in science and information technology challenge the nursing profession, in particular intensive care nursing. All these changes will undoubtedly affect the way we will practice in the (near) future. A comprehensive understanding of these factors is therefore essential if nursing is to meet the challenges presented by tomorrow's critical care environment. Precisely because of the often expensive high-tech evolutions that have occurred at a rapid pace and are to be further expected, a continued focus on the basics of nursing, the core role of care, as well as maintaining confidence in the capacity to deliver safe, high-quality, and evidence-based patient care will increasingly be a challenge to critical care nurses. In particular, basic nursing skills and knowledge remain a key prerequisite in the prevention of nosocomial infections, which is a continuing major complication and threat to intensive care unit patients. However, critical care nurses' knowledge about the evidence-based consensus recommendations for infection prevention and control has been found to be rather poor. It has nevertheless been demonstrated that a meticulous implementation of such preventive bundles may result in significantly better patient and process outcomes. Moreover, many preventive strategies are considered to be easy to implement and inexpensive. As such, a first and critical step should be to increase critical care nurses' adherence to the recommendations of the Centers for Disease Control and Prevention. AIM: In this article, an up-to-date assessment of evidence-based recommendations for the prevention of nosocomial infections, with special focus on catheter-related bloodstream infections and strategies relevant for nurses working in critical care environments, will be provided. Additionally, we will detail on a number of approaches advocated to translate the internationally accepted consensus recommendations to the needs and expectations of critical care nurses, and to consequently enhance the likelihood of successful implementation and adherence. These steps will help critical care nurses in their striving towards excellence in their profession. SUMMARY: Intensive care nurses can make a significant contribution in preventing nosocomial infections by assuming full responsibility for quality improvement measures such as evidence-based infection prevention and control protocols. However, as general knowledge of the preventive measures has been shown to be rather poor, nurses' education should include supplementary support from evidence-based recommendations. PMID- 20712671 TI - Increasing positive end expiratory pressure at extubation reduces subglottic secretion aspiration in a bench-top model. AB - AIM: To estimate the ability of simulated tracheal suction, adjusting the positive end expiratory pressure (PEEP) settings on the ventilator or compressing a self-inflating bag to minimize aspiration during cuff deflation and extubation in a bench-top model. BACKGROUND: During intubation, colonized secretions accumulate in the subglottic space above the endotracheal tube (ETT) cuff. Consequently, during cuff deflation and extubation, there is a risk of aspiration of the secretions. This may result in pneumonitis or pneumonia. There are a number of techniques used during cuff deflation and extubation to prevent secretion aspiration. METHOD: A model trachea was intubated and the proximal end of the ETT was attached to a mechanical ventilator. Ten millilitres of water was placed above the inflated cuff and then nine test protocols were implemented in a random order to simulate tracheal suction, adjusting the PEEP settings on the ventilator or compressing a self-inflating bag. The volume of water 'aspirated' by the model was determined by weighing the apparatus pre- and post-extubation. Statistical analysis was performed using regression analysis and heteroscedastic t tests with a Bonferroni correction. RESULTS: The level of PEEP was negatively correlated with the volume of fluid aspirated [co-efficient -0.24 (99% confidence interval -0.31 to -0.17), R(2) = 0.75]. Significantly less fluid was aspirated when a PEEP of 35 cmH(2)O was applied when compared with competing techniques. DISCUSSION AND CONCLUSIONS: This study suggests that applying PEEP during cuff deflation and extubation is protective against aspiration. We conclude that unless there is a contraindication, the application of PEEP should be considered when extubating patients. PMID- 20712672 TI - Extracorporeal membrane oxygenation in a Scottish intensive care unit. AB - I reflected on the training I had on an extraordinary treatment for profound respiratory failure. The result of training enabled us to successfully treat a young female with the influenza A virus with extracorporeal membrane oxygenation (ECMO). I report the positive outcome that occurred, while continuing to run a busy general intensive care unit (ICU). She was the first of six patients who were all successfully treated with ECMO. Ten trained and experienced critical care nurses and two doctors attended the ECMO training course provided by the national centre in the UK. Five patients had already received ECMO therapy in the Scottish specialist unit (over the period of 8 years). As our Scottish specialist unit purchased exactly the same equipment as the national centre, it was easier for the multidisciplinary team to utilize their new-found knowledge and treat future patients with ECMO. With the predicted swine flu (H1N1) pandemic and the subsequent demand for critical care beds, funding was obtained to facilitate ECMO training. The potential need for increased provision of ECMO therapies was highlighted by recent events in Australia and New Zealand. Their most recent winter produced 68 patients requiring ECMO, whereas the previous year had manifested only three. Using our new equipment and adapted protocols from the national centre, we used these new skills to treat our first patient in October 2009. Johns' reflective practice tool was used to evaluate the care provided. Our patient was on ECMO for 9 days. She went on to make a remarkable recovery and was discharged from the ICU 1 week after ECMO was discontinued. She was discharged to the cardiothoracic high-dependency unit, where she was successfully rehabilitated. We were able to successfully treat a young lady, while providing the care for all other patients. This was a complex treatment, one that uses many resources including time and finance. Now that we have all the equipment, the necessary training and the knowledge, we can continue to deliver this service to the public in our locality. PMID- 20712673 TI - What's in this issue? PMID- 20712675 TI - Does information for patients and relatives help? PMID- 20712679 TI - Determinants of depressive symptoms in Jordanian working women. AB - Depressive symptoms are an epidemic problem affecting different subgroups of women in clinical and non-clinical settings. However, depressive symptoms experienced by working women have rarely been studied. This study aimed at identifying depressive symptoms and their determinants in a sample of 101 Jordanian working women recruited from a higher educational institution. Data about women's depressive symptoms, their educational level, presence of children, sharing a job with an intimate partner, health status, diagnosis with chronic illnesses, and complaints of spousal abuse were collected. Logistic regression analysis was used to test for the significance of the selected factors on women's experiences of depressive symptoms. Findings indicated that 51.2% (n = 42) women complained of moderate and severe levels of depressive symptoms. Factors identified as significant in predicting depressive symptoms were women's experiences of spousal abuse (odds ratio adjusted = 3.5, 95% confidence interval = 1.05-11.7) and being diagnosed with chronic illnesses (odds ratio adjusted = 7.09, 95% confidence interval = 1.2-42.2). It was concluded that causes of women's depressive symptoms were imbedded in their familial and social environment, rather than their job per se. Mental health nurses can change the practice of nursing to better standards. Being familiarized with causes of depressive symptoms can empower nurses to be active advocates for depressed women. PMID- 20712680 TI - Writing the reflexive self: an autoethnography of alcoholism and the impact of psychotherapy culture. AB - Experimental ethnography enables the use of fictionalized accounts that celebrate partial truths and challenge realist and positivist ethnographic authority. Literary devices drawn from fiction arguably allow social researchers to better portray real events. Fiction, which should not be regarded as synonymous with falsehood, enables the telling of tales in dramatic and enjoyable ways. In this account - an autoethnography of alcoholism and the impact of therapy culture - the author's intention is not to make claims for a final word or closure on the topics raised, and juxtaposed with appropriate social theory. It is rather hoped that the text will trigger further meaning creation on the part of the reader and, in terms of praxis, contribute towards creating a kinder and more humane mental health nursing and therapy practice and in the 'off duty' world. PMID- 20712681 TI - Using systemic reflective practice to treat couples and families with alcohol problems. AB - In the UK, an adult with a drinking problem is generally treated from an individual perspective with minimal involvement of carers and relatives. In response to this gap in service provision, a systemic reflecting intervention was introduced to assist couples and families experiencing alcohol-related difficulties. The article documents the background and development of this initiative. Findings from evaluation and clinical outcome studies are reviewed and demonstrate how the use of the approach proved to be effective in facilitating positive change both in drinking and family behaviour. In conclusion, the paper explores the implications of how systemic reflective practice with family groups may be extended and be usefully used in wider addiction, diverse mental and general health-care settings. PMID- 20712682 TI - Experiences of instructors delivering the Mental Health First Aid training programme: a descriptive qualitative study. AB - Mental health literacy among the public is often poor, and although people frequently encounter others experiencing mental distress in their workplace, families and communities, they may be ill-equipped to provide appropriate support. 'Mental Health First Aid' (MHFA), a 12-h mental health promotion programme seeks to address this, training people in the knowledge and skills needed to engage with someone experiencing mental health problems. Research relating to the MHFA programme has centred on course attendees, with a paucity of research surrounding the delivery of basic mental health training programmes. Understanding experiences of instructors delivering such programmes is key to the success of future delivery. This study sought to identify the views and experiences of instructors delivering the MHFA programme in Wales. Fourteen MHFA instructors participated in semi-structured audio-recorded interviews, with the transcripts analysed to identify key themes. This paper explores two of the identified themes namely prerequisite skills and support required by instructors. The study highlighted that because of the ensuing emotional labour experienced by instructors, universal mental health training programmes must put in place a clear infrastructure to train, support and monitor those delivering them, for programme roll-out to be effective. PMID- 20712683 TI - Psychotropic medication adherence in correctional facilities: a review of the literature. AB - Despite the high percentage of incarcerated persons with mental illness, surprisingly little is known about effective ways to increase psychotropic medication adherence in prison and upon release. Currently, there are limited definitive data regarding psychotropic medication adherence patterns among incarcerated persons, and the data that exist often miss specific information on changes in behaviour, symptom management and adherence patterns over the length of a person's sentence, which has implications for post-release ability to live in the community. This paper presents the current literature regarding psychotropic medication adherence among mentally ill persons who are incarcerated. The factors identified in support of medication adherence, future clinical research and care strategies are provided. PMID- 20712684 TI - The Broset Violence Checklist: clinical utility in a secure psychiatric intensive care setting. AB - Violence towards health-care workers, especially in areas such as mental health/psychiatry, has become increasingly common, with nursing staff suggesting that a fear of violence from their patients may affect the quality of care they provide. Structured clinical tools have the potential to assist health-care providers in identifying patients who have the potential to become violent or aggressive. The Broset Violence Checklist (BVC), a six-item instrument that uses the presence or absence of three patient characteristics and three patient behaviours to predict the potential for violence within a subsequent 24-h period, was trialled for 3 months on an 11-bed secure psychiatric intensive care unit. Despite the belief on the part of some nurses that decisions related to risk for violence and aggression rely heavily on intuition, there was widespread acceptance of the tool. During the trial, use of seclusion decreased suggesting that staff were able to intervene before seclusion was necessary. The tool has since been implemented as a routine part of patient care on two units in a 92-bed psychiatric centre. Five-year follow-up data and implications for practice are presented. PMID- 20712685 TI - Does the currently accepted RADS-2 factor structure apply to LGBTIQ youth? AB - First-stage measures of depressive symptoms need to demonstrate accuracy in capturing depression in diverse populations of youth. The research question in this study asked, 'How is the Reynolds Adolescent Depression Scale-2nd Edition (RADS-2) factor structure expressed in a sample of lesbian, gay, bisexual, transgender, intersex or queer adolescent students?' Reliability, validity and principal components with orthogonal rotation factor analysis testing were conducted on a sample of 265 school-based adolescents in grades 7-12, including 72 girls and 193 boys, who sought guidance for sexual orientation or gender identity issues in this secondary data analysis. Four factors were identified that each demonstrates adequate internal consistency reliability. The RADS-2 effectively captures the features of depressive symptoms in sexual minority adolescents. PMID- 20712686 TI - The efficacy of a cognitively orientated carers group in an early intervention in psychosis service--a pilot study. AB - A significant amount of evidence has demonstrated that families and carers play an important role in an individual's recovery from a first episode of psychosis (FEP) and can significantly reduce relapse rates. This, in addition to the fact that caring for an individual experiencing their FEP can be incredibly stressful, suggests that the development of appropriate support for carers must be an integral part of any Early Intervention in Psychosis Service (EIPS). This study examines the efficacy of a closed structured group designed for carers of individuals experiencing their FEP based in Southampton city. A 12-session cognitively orientated group programme covering a range of areas was attended by 18 carers over a 6-month period. Following the group, a significant decrease was found in the carer's negative appraisals of the impact of psychosis, feelings of burden, depression and anxiety rates as measured by the Experience of Caregiving Inventory (ECI), Caregiver Burden Inventory (CBI), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). A significant positive correlation was also found between carer's negative appraisals and their anxiety and depression rates, although further research is needed to clarify the causality of this relationship. PMID- 20712687 TI - Forensic psychiatric nursing: a description of the role of the psychiatric nurse in a high secure psychiatric facility in Ireland. AB - The Central Mental Hospital is one of the oldest high secure mental health services in Europe dating back to 1845 but has been one of the last to introduce (forensic) psychiatric nurses. This paper describes the role of psychiatric nurses working in this high secure psychiatric facility in Ireland. The United Kingdom Central Council competency framework was considered to be a prudent starting point for beginning to understand this role in an Irish context. The study received a response rate of 74% and found that the Irish Forensic Mental Health Nurse experiences many of the same challenges as their international colleagues. A high proportion of nursing practice is focused on assessment, communication and creating a therapeutic environment based very much in keeping with the mainstream role in mental health nursing. Skills in specialist assessments and addressing offending behaviour were considered important but deficient at that time. The importance of recovery and human rights were considered paramount but challenged by the need for risk management and security. PMID- 20712688 TI - The impact of basing mental health liaison nurses in an emergency department at night. PMID- 20712689 TI - The development and implementation of a nurse-led hepatitis C protocol for people with serious mental health problems. AB - Hepatitis C (HCV) is a significant health issue for people with serious mental health problems (SMHP). Factors associated with this include high rates of substance use, injecting drug use, and lack of knowledge regarding the transmission and prevention of HCV. This population are at higher risk of experiencing conditions where transmission rates are high, e.g. night shelters and homelessness. People with SMHP also often have factors associated with acceleration of the disease, including excessive alcohol use and poor physical health. Nurses across services collaborated to develop and implement a protocol to address the needs of clients of an Assertive Outreach Team with or at risk of HCV. It has been successful in developing an effective approach to addressing the needs of people with or at risk of HCV and serious mental health problems. It guides staff in providing a flexible, accessible service for clients delivered across organizational boundaries. It has demonstrated improved health outcomes for clients. It is believed that this project can be used as a template to address other health needs of this client group for example diet, obesity and smoking. PMID- 20712690 TI - Attitudes and perceptions of mental health nurses towards borderline personality disorder clients in acute mental health settings: a review of the literature. PMID- 20712695 TI - Motivational correlates of physical activity in persons with an intellectual disability: a systematic literature review. AB - BACKGROUND: The purpose of this study is to systematically retrieve, examine and discuss scientific studies focusing on motivational correlates that both contribute to, and can be assumed to be effects of, participation in sport, recreation, or health-related physical activities in persons with intellectual disability (ID). METHODS: A systematic analysis of the literature retrieved through electronic databases and other resources was performed, covering articles published from 1980 through 2009. Inclusion criteria were based on terms referring to the participants, the psychosocial correlates and the type of activity. RESULTS: Twenty-three articles satisfied the inclusion criteria, and were divided into four categories of studies: (1) cross-sectional designs, (2) experimental prospective one-group designs, (3) longitudinal comparative intervention designs, and (4) qualitative designs. The level of quality regarding the intervention studies was assessed using four different scales, and on average they depicted a moderate level of evidence. CONCLUSIONS: Both exercise and sport related activities seem to contribute to well-being. Improved physical fitness and elevated skill level gained during exercise and sport activities appear to serve as mediators for increased perceptions of self-efficacy and social competence. Peer modelling, as well as video and audio reinforcement, appear to be important modalities in maintaining compliance to exercise programmes. PMID- 20712696 TI - Identifying facilitators and barriers to physical activity for adults with Down syndrome. AB - BACKGROUND: Adults with Down syndrome are typically sedentary, and many do not participate in the recommended levels of physical activity per week. The aim of this study was to identify the facilitators and barriers to physical activity for this group. METHOD: Semi-structured interviews were conducted to elicit the views of adults with Down syndrome and their support people about what factors facilitate physical activity and what factors are barriers to activity. A sample of 18 participants (3 men, 15 women) was recruited through two agencies providing services for adults with disabilities; six participants were adults with Down syndrome and 12 participants were support people (four were parents of adults with Down syndrome and eight participants were employed by day programmes attended by the adults with Down syndrome). The interviews were recorded, transcribed verbatim and independently coded by two researchers. RESULTS: Three themes around facilitators to physical activity were identified: (1) support from others; (2) that the physical activity was fun or had an interesting purpose; and (3) routine and familiarity. Three themes around barriers were also identified: (1) lack of support; (2) not wanting to engage in physical activity; and (3) medical and physiological factors. CONCLUSIONS: The results suggest that support people play a key role, both as facilitators and barriers, in the participation by adults with Down syndrome in physical activity. Many of the barriers and facilitators of activity for adults with Down syndrome indentified are similar to those reported for adults without impairment. Our findings are also consistent with established theories in the field of health behaviour change. PMID- 20712697 TI - Why some adults with intellectual disability consult their general practitioner more than others. AB - BACKGROUND: This research identifies factors affecting why some adults with intellectual disability (AWIDs) consult their general practitioner (GP) more than others. Little is known about these factors, despite AWIDs having higher health needs and reduced longevity. Current barriers to accessing health care need to be understood and overcome to achieve improved health outcomes. METHODS: A secondary analysis of data obtained from a stratified randomised sample of AWIDs participating in a cluster randomised trial of hand held health records. The number of GP consultations was obtained retrospectively for the year preceding initial health interviews from GP records. AWIDs and their carers were given separate health interviews using identical/adapted questions where possible. RESULTS: Two hundred and one AWIDs and or their carers from 40 practices participated (response rate 64.6%) with GP consultation data extracted for 187 AWIDs. Overall consulting levels were low, 3.2 per annum for women and 2.2 for men. Increased age, gender (women) and type of carer (paid) were all significantly associated with increased consultations. Carers reporting health problems, medications reported by AWIDs, medications recorded in GP records, and pain reported by AWIDs were also significant factors affecting consultations to GP practices after adjustment for age and type of carer. CONCLUSIONS: Overall consultation rates were lower than expected, and affected by age, gender and type of carer. Targeted interventions are needed to improve attendance and promote health. PMID- 20712698 TI - Standard care and telecare services: comparing the effectiveness of two service systems with consumers with intellectual disabilities. AB - BACKGROUND: Onsite standard care and remote telecare supports were provided to adults with intellectual disabilities living in integrated community settings and evaluated in terms of effectiveness as consumers completed a series of novel household activities. METHODS: Using an alternating treatment design with baseline and follow-up conditions in this single-case study, investigators compared the prompting effectiveness provided by onsite standard care staff and a remote telecare provider. RESULTS: While both types of supports resulted in consumers completing tasks, results indicated consumers achieved slightly more independence when prompted by the telecare support provider. Additionally, telecare supports resulted in greater duration for task completion per consumer. CONCLUSIONS: Although consumers completed tasks with greater independence using telecare supports, caution should be used when interpreting results due to the small number of participants. The potential for this technology certainly exists in supporting consumers in their own homes thus, suggestions for future investigations are provided. PMID- 20712699 TI - The Attitudes to Disability Scale (ADS): development and psychometric properties. AB - BACKGROUND: This paper describes the development of an Attitudes to Disability Scale for use with adults with physical or intellectual disabilities (ID). The aim of the research was to design a scale that could be used to assess the personal attitudes of individuals with either physical or ID. METHOD: The measure was derived following standard WHOQOL methodology as part of an international trial. In the pilot phase of the study, 12 centres from around the world carried out focus groups with people with physical disabilities, people with ID, with their carers, and with relevant professionals in order to identify themes relevant for attitudes to disability. Items generated from the focus groups were then tested in a pilot study with 1400 respondents from 15 different centres worldwide, with items being tested and reduced using both classical and modern psychometric methods. A field trial study was then carried out with 3772 respondents, again with the use of both classical and modern psychometric methods. RESULTS: The outcome of the second round of data collection and analysis is a 16-item scale that can be used for assessment of attitudes to disability in physically or intellectually disabled people and in healthy respondents. CONCLUSIONS: The Attitudes to Disability Scale is a new psychometrically sound scale that can be used to assess attitudes in both physically and intellectually disabled groups. The scale is also available in both personal and general forms and in a number of different language versions. PMID- 20712700 TI - EADV preceptorship: advances in dermatology. PMID- 20712701 TI - The socket-shield technique: a proof-of-principle report. AB - AIM: Clinical studies have suggested that retaining roots of hopeless teeth may avoid tissue alterations after tooth extraction. Therefore, the objective of this proof-of-principle experiment was to histologically assess a partial root retention (socket-shield technique) in combination with immediate implant placement. MATERIAL AND METHODS: In one beagle dog, the third and fourth mandibular pre-molar were hemisected and the buccal fragment of the distal root was retained approximately 1 mm coronal to the buccal bone plate. Following application of enamel matrix derivate, a titanium implant was placed lingual to that tooth fragment either with or without contact to the buccal tooth fragment and a healing abutment was connected. Four months after implant placement, histological evaluation, and backscatter scanning electron microscopy were performed. RESULTS: All four implants were osseointegrated without any histologic inflammatory reaction and the tooth fragment was devoid of any resorptional processes. On the buccal side, the tooth fragment was attached to the buccal bone plate by a physiologic periodontal ligament. On the lingual side of the fragment, newly formed cementum could be detected. In the areas where the implant was placed into the fragment, newly formed cementum was demonstrated directly on the implant surface. CONCLUSIONS: Retaining the buccal aspect of the root during implant placement does not appear to interfere with osseointegration and may be beneficial in preserving the buccal bone plate. PMID- 20712702 TI - A manually controlled new device for punctuate mechanical stimulation of teeth during functional magnetic resonance imaging studies. AB - AIM: To design a simple and affordable device that could apply standardized mechanical punctuate stimuli to trigger the periodontal mechanoreceptors during functional magnetic resonance imaging (fMRI). MATERIAL AND METHODS: A new manually controlled device using von Frey monofilaments was tested on a phantom and on eight volunteers. Four block design paradigms with different timing were compared. Teeth 11, 12, 13, 21, 22, 23 and the thumb were stimulated. RESULTS: The device did not induce any artefacts in MR images. The most efficient protocol included an epoch duration of 24 s and stimuli delivered at 1 Hz. When stimulating the teeth, activations of the primary (S1) and secondary (S2) somatosensory areas were consistently obtained, either on the ipsilateral, contra lateral or both sides. Stimulation of the thumb led to activations of the contra lateral S1 area and either ipsilateral or contra-lateral S2 area. CONCLUSION: The use of this innovative tool should allow to perform fMRI studies aimed to unveil the neural correlates of periodontal neural receptors, and to understand their plasticity induced by tooth loss and their eventual replacement by endosseous oral implants. PMID- 20712706 TI - Human breast milk is a rich source of multipotent mesenchymal stem cells. AB - Putative stem cells have been isolated from various tissue fluids such as synovial fluid, amniotic fluid, menstrual blood, etc. Recently the presence of nestin positive putative mammary stem cells has been reported in human breast milk. However, it is not clear whether they demonstrate multipotent nature. Since human breast milk is a non-invasive source of mammary stem cells, we were interested in examining the nature of these stem cells. In this pursuit, we could succeed in isolating and expanding a mesenchymal stem cell-like population from human breast milk. These cultured cells were examined by immunofluorescent labeling and found positive for mesenchymal stem cell surface markers CD44, CD29, SCA-1 and negative for CD33, CD34, CD45, CD73 confirming their identity as mesenchymal stem cells. Cytoskeletal protein marker analysis revealed that these cells expressed mesenchymal stem cells markers, namely, nestin, vimentin, smooth muscle actin and also manifests presence of E-Cadherin, an epithelial to mesenchymal transition marker in their early passages. Further we tested the multipotent differentiation potential of these cells and found that they can differentiate into adipogenic, chondrogenic and oesteogenic lineage under the influence of specific differentiation cocktails. This means that these mesenchymal stem cells isolated from human breast milk could potentially be "reprogrammed" to form many types of human tissues. The presence of multipotent stem cells in human milk suggests that breast milk could be an alternative source of stem cells for autologous stem cell therapy although the significance of these cells needs to be determined. PMID- 20712707 TI - Detection of genomic DNA methylation with denaturing high performance liquid chromatography. AB - DNA methylation contributes to the epigenetic control of gene expression. Variations in the methylation status can result in the silencing of genes. DNA methyltransferase converts cytosine to 5-methyl cytosine in CpG islands located in the promoter regions of genes. When CpG islands are hypermethylated, the gene is repressed/silenced, and similarly when it is hypomethylated, transcription can take place and the gene is expressed. The classical methods to detect DNA methylation require labor-intensive and time-consuming steps. As a result of large-scale expression profiling studies, high-throughput techniques are needed to screen for alterations in the methylation patterns. Denaturing high performance liquid chromatography (DHPLC) is a reliable, highly sensitive technique for mutation discovery. In the present study we examined the suitability of DHPLC technology to detect alterations in methylation pattern of the promoter regions of several genes. We report reliable and reproducible results in distinguishing methylated and unmethylated promoter regions of human PCDHGB6, c-MYC, MGMT1, CDKN2A/p16, and ATM genes. These DHPLC profiles were independently confirmed with bisulfite genomic sequencing. In conclusion, DHPLC technology serves as a rapid screening tool to monitor the genomic DNA methylation and could be used to increase the throughput efficiency of methylation analysis. PMID- 20712708 TI - Establishment of a primary human sarcoma model in athymic nude mice. AB - Improvement of soft tissue sarcoma patient outcome requires well-characterized animal models in which to evaluate novel therapeutic options. Xenograft sarcoma models are frequently used, but commonly with established cell lines rather than with primary human sarcoma cells. The objective of the present study was to establish a reproducible xenograft model of primary human soft tissue sarcoma in athymic nude mice. Primary soft tissue sarcoma cells from four resected human sarcomas were isolated, cultured until the third passage and injected subcutaneously into athymic nude mice. The sarcoma xenograft was further analyzed by histological and immunohistochemical staining. In two out of four sarcomas tumor growth could successfully be established leading to solid tumors of up to 540 mm(3) volume. Histological and immunohistochemical staining confirmed the mouse xenograft as identical sarcoma compared with the original patient's tissue. In the present study a reproducible xenograft model of primary human soft tissue sarcoma in athymic nude mice was established. This animal model is of great interest for the study of sarcomogenesis and therapy. PMID- 20712709 TI - Establishment and characterization of a novel cell line derived from a human small cell lung carcinoma that secretes parathyroid hormone, parathyroid hormone related protein, and pro-opiomelanocortin. AB - There are few case reports describing small cell lung carcinoma (SCLC), which secrete parathyroid hormone (PTH)-related protein (PTHrP) and result in hypercalcemia. We have established a novel cell line, derived from a 37-year-old woman with SCLC, which produced PTH, PTH-rP, and a part of proopiomelanocortin (POMC), and led to hypercalcemia. The cell line, named SS-1, was grown as floating cell clusters in DMEM/F12 medium supplemented with 10% fetal bovine serum and had a population doubling time of 72 h. The modal chromosome number was 47 (88%); marker chromosomes were not observed. The SS-1 cell line secreted not only PTHrP but also PTH, and both were decreased by CaCl(2) administration. Decreasing the concentration of Ca(++) in the growth medium stimulated the secretion of both PTHrP and PTH. The cell line had calcium sensing receptor (Cas R). Since PTHrP and PTH secretion from the SS-1 cells was related to Ca(++) concentration in the growth medium, the cell line might be useful for the study of PTH-rP and PTH regulation as well as for SCLC analysis. In addition, the cells secreted N terminal POMC, the precursor of adrenocorticotropic hormone, in response to stimulation with corticotropin releasing hormone. In summary, we established a novel cell line, SS-1 from SCLC, which produced PTHrP, PTH and N terminal POMC. PMID- 20712711 TI - Key words and their role in information retrieval. AB - As any good library or information worker knows the accurate and consistent application of keywords can serve to enhance the content representation and retrieval of literature. Research has demonstrated that this aspect of the library and information science evidence base is particularly well represented. Drawing on the thesauri of the Library & Science Abstracts, Library, Information Science & Technology Abstracts and medline databases, the Health Information and Libraries Journal (HILJ) has recently updated and expanded the HILJ keyword list. Based on the content of reviews and original articles published in HILJ over the past 4 years, the keyword list will be used by submitting authors to represent the content of the manuscripts and enable more accurate matching of manuscript to HILJ referees. PMID- 20712710 TI - Establishment and characterization of the rhabdomyosarcoma cell line designated NUTOS derived from the human tongue sarcoma: Special reference to the susceptibility of anti-cancer drugs. AB - Primary alveolar type of rhabdomyosarcoma (RMS) tumor tissue was collected from the tongue of a 17-year-old Japanese woman and used to successfully establish a rhabdomyosarcoma cell line, which has been designated NUTOS. The chromosomal distribution revealed that the NUTOS cell line was hyper-tetraploid with chromosomal translocation. The cells were grown in Dulbecco's modified eagle medium/F12 supplemented with 15% fetal bovine serum, 0.1% non-essential amino acids solution (NEAA), 50 microg of streptomycin, 50 U/mL of penicillin and 0.25 microg /mL of Fungizone. The NUTOS shapes included small spindles, large spindles and long, thick multinucleated cells. All three cell types were immunostained with anti-desmin antibody, which is a marker protein for middle sized myofilaments. Furthermore, immunocytochemical staining revealed that the cells were positively immunostained with anti-MyoD, myogenin, alpha-sarcomeric actin, myosin and troponin T. Mitotic figures were only observed in the small spindle cells. These cells were coadunated with each other at the lateral portion of the apex of the cells. Subsequently, these cells grew into large multinucleated cells. Autonomic contractions (approximately 20 times/min) were observed in both the large spindle cells and the large multinucleated cells. NUTOS cells incorporated serotonin from the serum in the growth medium. Histopathological observations of the NUTOS cell grafts in the subcutis of nude mice exhibited characteristics similar to those seen for the primary rhabdomyosarcoma of the tongue. Susceptibility tests for the anti-cancer drugs revealed that NUTOS cells were susceptive to cisplatin, paclitaxel, and docetaxel, but not to adriacin. PMID- 20712713 TI - The impact of information skills training on independent literature searching activity and requests for mediated literature searches. AB - BACKGROUND: Most NHS library services routinely offer both mediated searches and information skills training sessions to their users. We analyse the impact of these two services on the amount of literature searching demonstrated by users of hospital- based library services in the north-west of England. METHODS: Data for (1) mediated literature searches, (2) number of library users attending information skills training sessions, (3) amount of library staff time devoted to information skills training, and (4) number of Athens-authenticated log-ins to databases were obtained from statistical returns for 2007, and analysed for significant correlations. RESULTS: There was evidence of quite strong correlations between the two measures of training activity and the number of mediated literature searches performed by library staff. There was weaker evidence of correlation between training activity and total literature searching activity. DISCUSSION: Attending training sessions may make some library users aware of the difficulty of complex literature searches and actually reduce their confidence to perform their own complex searches independently. The relationships between information skills training, mediated literature searches, and independent literature searching activity remain complex. PMID- 20712712 TI - Sources of information on adverse effects: a systematic review. AB - BACKGROUND: Systematic reviews can provide accurate and timely information on adverse effects. An essential part of the systematic review process is a thorough search of the literature. This often requires searching many different sources. However, it is unclear which sources are most effective at providing information on adverse effects. OBJECTIVE: To identify and summarise studies that have evaluated sources of information on adverse effects. METHODS: Studies were located by searching in 10 databases as well as by reference checking, hand searching, citation searching and contacting experts. RESULTS: A total of 6218 citations were retrieved yielding 19 studies which met the inclusion criteria. The included studies tended to focus on the adverse effects of drug interventions and compare the relative value of different sources using the number of relevant references retrieved from searches of each source. However, few studies were conducted recently with a large sample of references. CONCLUSIONS: This review suggests that embase, Derwent Drug File, medline and industry submissions may potentially provide the greatest number of relevant references for information on adverse effects of drugs. However, a systematic evaluation of the current value of different sources of information for adverse effects is urgently required. PMID- 20712714 TI - The SPECTRAL project: a training needs analysis for providers of clinical question answering services. AB - PURPOSE: To characterise the training needs of those providing clinical question answering services (CQAS). PARTICIPANTS: Seventeen specialist UK staff working in CQAS, 21 from general health library UK staff and eight international respondents. METHODOLOGY: A literature review examined documented training needs for CQAS staff. A follow-up questionnaire examined prior training and experience and identified training needs for the surveyed staff. RESULTS/OUTCOMES: Ninety per cent of CQAS staff had worked in health services for 3 years or longer. Training received in preparation for the CQAS role comprised literature searching (including the PRECEPT/ADEPT and cochrane library courses) and critical appraisal. Skills considered 'essential' for clinical question answering were 'literature searching' (100%), 'understanding the context of clinical questions', 'bibliographic databases', 'evidence-based sources' and 'the Internet' (all 93%). Main training needs for specialist CQAS staff include management and organisation of CQAS and technical skills in interpretation and presentation. DISCUSSION/CONCLUSION: CQAS staff require a formal training programme. Most CQAS staff considered that this should be a mandatory requirement. PMID- 20712715 TI - Pharmacists' online information literacy: an assessment of their use of Internet based medicines information. AB - INTRODUCTION: Pharmacists need effective skills in accessing and using Internet based medicines information (IBMI) for themselves and their consumers. However, there is limited information regarding how pharmacists use the Internet. OBJECTIVES: To develop and use a research instrument to measure pharmacists' Internet knowledge, search skills, evaluation of and opinions about using IBMI. METHODS: A structured questionnaire examining general Internet knowledge, ability to search for and select pertinent IBMI, evaluation of IBMI, opinions about using IBMI and current Internet use was developed. Exploratory factor analysis was performed to analyse IBMI evaluation. RESULTS: 208 pharmacists responded (response rate 20.6%). There was a large variation in pharmacists' scores. Mean scores were low for General Internet Knowledge (mean 7.91 +/- 3.62; scale 0-16), Search and Selection of IBMI (4.98 +/- 2.91; 0-10) and Opinions on IBMI (44.51 +/ 9.61; 0-80). Four factors [Professionalism of website (4 items; factor loading 0.62-0.87; Cronbach's alpha 0.84), Disclosure (5; 0.37-0.79; 0.73), Appropriateness of content (5; 0.32-0.50; 0.65), Standard of information (6; 0.31 0.48; 0.58)] were extracted from the evaluation scale, explaining 36.89% of the total variance. CONCLUSIONS: A tool was developed to evaluate pharmacists' skills and opinions in using IBMI. A wide range of skills and opinions highlighted the need for training in online information literacy. PMID- 20712716 TI - Integrating the hospital library with patient care, teaching and research: model and Web 2.0 tools to create a social and collaborative community of clinical research in a hospital setting. AB - BACKGROUND: Research in hospital settings faces several difficulties. Information technologies and certain Web 2.0 tools may provide new models to tackle these problems, allowing for a collaborative approach and bridging the gap between clinical practice, teaching and research. OBJECTIVES: We aim to gather a community of researchers involved in the development of a network of learning and investigation resources in a hospital setting. METHODS: A multi-disciplinary work group analysed the needs of the research community. We studied the opportunities provided by Web 2.0 tools and finally we defined the spaces that would be developed, describing their elements, members and different access levels. MODEL DESCRIPTION: WIKINVESTIGACION is a collaborative web space with the aim of integrating the management of all the hospital's teaching and research resources. It is composed of five spaces, with different access privileges. The spaces are: Research Group Space 'wiki for each individual research group', Learning Resources Centre devoted to the Library, News Space, Forum and Repositories. CONCLUSIONS: The Internet, and most notably the Web 2.0 movement, is introducing some overwhelming changes in our society. Research and teaching in the hospital setting will join this current and take advantage of these tools to socialise and improve knowledge management. PMID- 20712717 TI - Developing and testing of search filters for the new European Union Member States' research. AB - BACKGROUND: To develop and apply search filters retrieving the scientific output (SO) after 2000 focusing on Public Health (PH) of the new European Union (EU) Member States after the 2004 and 2007 enlargements. METHODS: Twelve geographical filters (GFs) were designed and applied to retrieve references added since 2001 in Medline (accessed through PubMed) and originated in the new EU countries. The PH area was accessed using Medical Subject Heading terms. The filters were evaluated through a manual check and the agreement/non-agreement percentages were calculated. RESULTS: A number of 99 912 articles revealing the total SO and 6502 articles focusing on PH were retrieved. More than 66% were published abroad and more than 80% in English. The evaluation revealed an average agreement percentage of 98.97%. The results were compared with those obtained by using simple search strategies. CONCLUSIONS: Twelve GFs applied to medline retrieved references belonging to twelve countries for a specific period of time. The evaluation of the GFs through the manual check demonstrated effectiveness of these filters. Complementary studies would be advisable to focus on the development of search filters to retrieve complete and accurate information. PMID- 20712719 TI - The state of medical libraries in the former Soviet Union. PMID- 20712718 TI - Caption-based topical descriptors for microscopic images as published in academic papers. AB - BACKGROUND: Visual findings summarized in the figures and tables of academic papers are invaluable sources for biomedical researchers. Captions associated with the visual findings are often neglected while retrieving biomedical images in published academic papers. OBJECTIVES: This study is to assess caption-based topical descriptors for microscopic images of breast neoplasms, as published in academic papers retrieved through the PubMed Central database. METHOD: Human indexers as well as an automatic keyword finder called TAPoR generated the topical descriptors from collected captions. The study then compared the human generated descriptors to machine-generated descriptors. Finally, a set of core descriptors was developed from both sets and automatically mapped into the Unified Medical Language System's (UMLS) Metathesaurus through a MetaMap Transfer engine. RESULTS: Major topical descriptors included histologic disease names, laboratory procedures, genetic functions and components. Human indexers provided more relevant descriptors than TAPoR. The UMLS Metathesaurus identified several semantic types including Indicator, Reagent, or Diagnostic Aid; Organic Chemical; Laboratory Procedure; Spatial Concept; Qualitative Concept; and Quantitative Concept. DISCUSSION: The findings suggest that caption-based descriptors can complement title or abstract-based literature indexing for figure image retrieval in articles. With respect to forming a metadata framework for online microscopic image description, the semantic types can be used as a core metadata set. In this regard, this finding can be used for standardising a microscopic image description protocol to train medical students. CONCLUSIONS: It is incumbent upon libraries and other information agencies to promote and maintain an interest in the opportunities and challenges associated with biomedical imaging. PMID- 20712720 TI - Beyond the library: reflections from a librarian in an academic faculty. PMID- 20712721 TI - Upon reflection: five mirrors of evidence-based practice. PMID- 20712722 TI - Frederick (Freddie) Martin Sutherland 1921-2010. PMID- 20712723 TI - Antipsychotic treatment of UHR ('prodromal') individuals. PMID- 20712724 TI - Correlation between attenuated psychotic experiences and depressive symptoms among Japanese students. AB - AIMS: To examine the emergence of attenuated psychotic experiences, self disturbance or affective symptoms among younger subjects in the general population and to investigate the intergroup differences on each symptom between adolescents and post-adolescents. METHODS: A total of 781 participants, 496 university students (mean age: 19.3 +/- 1.1 years) and 285 high school students (mean age: 16.0 +/- 0.3 years), were administered self-reported questionnaires. Psychotic prodromal symptoms were evaluated using the PRIME Screen-Revised (PS R), a 12-item self-reported questionnaire. To measure the cognitive, emotional and physical symptoms associated with depression, the Zung Self-rating Depression Scale (ZSDS), a 20-item self-reported questionnaire, was administered. RESULTS: There were no intergroup differences on the factor score of the PS-R, except the self-demarcation factor (post-adolescents > adolescents), whereas there were significant differences in the factor score of the ZSDS, except for the anxiety factor. Among the post-adolescents, the factors of the PS-R showed a moderate correlation to the cognitive factor on the ZSDS; among the adolescents, the PS-R factors showed a greater correlation to the anxiety factor on the ZSDS than other factors. There were no differences in the distribution of each item of the PS-R between the two groups. CONCLUSIONS: The disturbance of self results in difficulty to precisely objectify, especially among adolescents, which would induce more primitive reactions such as agitation, irritability or anxiety; probably, the self disturbance would become an explicit symptom from an implicit experience with advancing age of the subject. Although these data are only preliminary, they could explain the pathway of progression prior to the onset of psychosis, from disturbance within the self to exaggerated self-absorption. PMID- 20712725 TI - Psychotic-like experiences (PLEs) and mental health status in twin and singleton Japanese high school students. AB - AIM: Studying what factors and behaviours to work on may be a key to develop the effective prevention of future mental disorder in both high-risk and general young subjects. This study aimed to investigate whether twins are more vulnerable to mental health problems including psychotic-like experiences (PLEs) than singletons and what factors on lifestyle and social environment are associated with poor mental health. METHODS: Subjects comprised 341 Japanese high-school students (173 males and 168 females) including 62 twins. We examined PLEs, general psychological distress, length and regularity of sleep, domestic violence, being bullied and other environmental factors using questionnaires including the 12-item General Health Questionnaire (GHQ-12). The variables were compared between twins and singletons. Whether variables on lifestyle and social environment affect PLEs and GHQ-12 scores were studied by logistic regression. RESULTS: Significant difference was observed in PLEs and GHQ-12 between twins and singletons. Experiencing PLEs was negatively associated with being a twin (OR = 0.293, 95% CI = 0.101-0.847) and length of sleep (OR = 0.685, 95% CI = 0.519 0.903). GHQ-12 > 4 was significantly associated with irregular sleep schedule (OR = 3.042, 95% CI = 1.818-5.090), being bullied (OR = 3.677, 95% CI = 1.317-10.266) and having no people to confide in (OR = 2.615, 95% CI = 1.249-5.475). CONCLUSION: Poor mental health status including experiencing PLEs might be less frequent in twins than in singletons. Problems in sleep length, its schedule and human relationships were significantly associated with mental health in high school students as we hypothesized. Early identification programmes and mental health education focused on these factors may be helpful. PMID- 20712726 TI - Early intervention for psychosis in Hong Kong--the EASY programme. AB - AIM: This article aims to describe the Hong Kong experience in developing and implementing an early psychosis programme. METHODS: In 2001, the Early Assessment Service for Young People with Psychosis programme was launched in Hong Kong, providing both educational and service components. Public education includes promotion of timely help-seeking, accessible channels to service and knowledge of psychosis. The 2-year phase-specific intervention includes intensive medical follow-up and individualized psychosocial intervention. The programme has adopted the case-management approach, in which case managers provide protocol-based psychosocial intervention. The programme collaborates with non-governmental organizations and community networks in the provision of rehabilitation service. RESULTS: An average of over 600 young patients enter the programme for intensive treatment each year. Based on preliminary data from a 3-year outcome study, patients in the programme have remarkable reductions in hospital stay accompanied by improvements in vocational functioning. CONCLUSIONS: The results suggested that the programme improved patients' outcome. Additional costs such as extra medical staff and medications may be offset by the shortened hospital stay. Further directions in early intervention are also discussed. PMID- 20712728 TI - Impaired verbal memory in young adults with unipolar and bipolar depression. AB - AIM: Early stages of severe mood disorders may be accompanied by neurocognitive changes. Specifically, deficits in verbal memory have been linked to depression in young people. This study examined whether young adults with unipolar compared with bipolar depression showed similar neurocognitive deficits. METHODS: A total of 57 young adults (16-32 years) were assessed in this study. Twenty with unipolar and 20 with bipolar depression, all currently depressed, were compared with 17 healthy controls. Neuropsychological assessment included psychomotor speed, attention for routine mental operations, attentional switching, executive control and verbal learning and memory. RESULTS: Both unipolar and bipolar subjects showed significant impairments in verbal memory and attentional switching compared with controls. Both mood disorder groups showed no impairments in psychomotor speed, attention for routine mental operations and executive control. Effects size calculations show that the unipolar and bipolar groups do not differ from each other across a range of neurocognitive measures. CONCLUSION: Neurocognitive deficits in young adults with current depressive syndromes appear to differ from those typically seen in older patients. In early adulthood, both unipolar and bipolar depression may be distinguished by poor verbal memory, despite intact speed of processing, attention and executive functions. This study suggests that there is utility in neuropsychological testing for young adults in the early stages of severe mood disorders. In order to prevent neurobiological changes inherent to the disease, pharmacological and non-pharmacological interventions that target verbal memory deficits may be optimally delivered early in the disease course. PMID- 20712727 TI - Treatment history in the psychosis prodrome: characteristics of the North American Prodrome Longitudinal Study Cohort. AB - AIM: Early identification and better characterization of the prodromal phase of psychotic illness can lead to targeted treatment and, perhaps, prevention of many of the devastating effects of a first psychotic episode. The primary aim of this manuscript is to describe the treatment histories of a large cohort of individuals who entered into one of seven prodromal research programs in a North American Prodrome Longitudinal Study consortium. METHODS: Treatment histories from 372 clinical high-risk subjects are described along with demographic, symptom, diagnostic and functional variables that may have contributed to treatment decisions for this group of individuals. RESULTS: Of all subjects included, 82.1% had received psychosocial and/or pharmacologic treatment prior to entry. Psychosocial interventions were more common in the attenuated psychotic syndrome prodromal sample, especially those with more negative, disorganized or general symptoms and more impaired functioning. Psychotropic medication had been administered to individuals with a history of Axis I disorders. CONCLUSIONS: Given the many potential clinical presentations, treatments and ethical issues connected with the psychosis-risk syndrome, it is not surprising that clinicians administered a broad range of interventions to study participants prior to their entry into the various research programs. Those individuals with milder and non specific symptoms were more likely to have received psychosocial treatments, whereas those with more severe symptoms received pharmacologic intervention. Clinical treatment research is needed that addresses the complexities of these psychosis-risk states and helps to specify appropriate treatment at different stages of the psychosis prodrome. PMID- 20712729 TI - Sexual risk behaviour in young people with first episode psychosis. AB - AIM: Previous studies have consistently reported high rates of risky behaviour for sexually transmitted infections (STIs) amongst individuals with persistent psychosis. Whether such behaviours are evident from the first presentation or relate to a chronic illness course remains largely undetermined, with limited research conducted amongst young people with first episode psychosis. The aim of the current study was to compare engagement in sexual risk behaviour amongst young people with first episode psychosis with their peers. METHODS: Sixty-seven sexually active young people with first episode psychosis and 48 healthy control participants (aged 18-29 years) closely matched on sociodemographic characteristics completed a detailed questionnaire assessing a comprehensive range of sexual risk behaviours. RESULTS: There were few differences in the rates of sexual risk behaviour reported by the first episode sample and their peers. Compared with control participants, young people with first episode psychosis reported significantly more inconsistent condom use, less condom-related preparatory behaviour, more concern about HIV/STIs when sex was unprotected, less confidence discussing condom use and increased substance use by their last sexual partner. CONCLUSIONS: The sexual behaviour of young people with first episode psychosis appears similar to their peers. However, group differences, particularly increased frequency of unprotected sex amongst the first episode sample, suggest that those with psychosis are at increased STI risk and have distinct needs. The findings support the call for early intervention strategies that target reduction of sexual risk behaviour in the context of persistent mental illness. PMID- 20712730 TI - Reshaping an enduring sense of self: the process of recovery from a first episode of schizophrenia. AB - AIM: Although advances in the treatment of schizophrenia have been made, little is known about the process of recovery from first episode of schizophrenia (FES). To date, the study of recovery in the field of mental health has focused on long term mental illness. This qualitative study addresses ways in which individuals with FES describe their process of recovery and how identified individuals (e.g. family members) describe their perceptions of and roles in the participant's process of recovery. METHODS: Charmaz's constructivist grounded theory methodology was used to interview 10 young adults twice who self-identified as recovering from FES. In addition, 10 individuals were identified who had influenced their recovery and were interviewed once, for a total of 30 interviews. Data collection sources included in-depth semi-structured interviews. Data analysis methods were consistent with Charmaz's methodology and included coding, and constant comparison of data. RESULTS: The results provide a substantive theory of the process of recovery from FES that is comprised of the following phases: 'Who they were prior to the illness', 'Lives interrupted: Encountering the illness', 'Engaging in services and supports', 'Re-engaging in life', 'Envisioning the future'; and the core category, 'Re-shaping an enduring sense of self', that occurred throughout all phases. A prominent feature of this model is that participants' enduring sense of self were reshaped rather than reconstructed throughout their recovery. CONCLUSIONS: This model of recovery from FES is unique, and as such, provides implications for clinical care, research and policy development for these young adults and their families. PMID- 20712731 TI - Cognitive-behaviour therapy for medication-resistant positive symptoms in early psychosis: a case series. AB - INTRODUCTION: Cognitive-behaviour therapy (CBT) for psychosis reduces the severity of medication-resistant positive symptoms in chronic schizophrenia, but its efficacy for early psychosis outpatients with a similar profile has not been established. OBJECTIVE: This paper describes an uncontrolled evaluation of CBT, added to medication and comprehensive care in an early psychosis program, in a group of stable outpatients. PATIENTS: The sample was drawn from 24 consecutive referrals. Fourteen were eligible, i.e. had positive symptom(s) and had been on the same medication regime for 3 months. TREATMENT: Patients received an average of 16 individual sessions with a senior psychologist. MEASURES: Symptom severity was assessed both by an independent rater, and by patient self-report. RESULTS: Eleven of 14 patients completed treatment. Both clinician and self-report post treatment ratings of positive symptoms were significantly reduced following CBT. For positive symptom totals, effect sizes ranged from d = 1.0 to 1.3. Clinically significant changes were apparent in at least eight of 11 patients. DISCUSSION: While case-series studies have significant limitations, the large effect sizes described here suggest that CBT shows promise for effectiveness with early psychosis patients. A randomized trial is needed to establish both the effect size over and above a control condition, and the durability of gains of CBT for medication-resistant symptoms in early psychosis. PMID- 20712732 TI - At-risk mental state (ARMS) detection in a community service center for early attention to psychosis in Barcelona. AB - AIM: To describe the strategy and some results in at-risk mental state (ARMS) patient detection as well as some of the ARMS clinical and socio-demographical characteristics. The subjects were selected among the patients visited by an Early Care Equipment for patients at high risk of psychoses, in Barcelona (Spain) during its first year in operation. METHODS: Descriptive study of the community team relations, selection criteria and intervention procedure. Description of patient's socio-demographic and symptomatic characteristics according to the different instruments used in detection and diagnoses, taking account of four principal origins of referrals: mental health services, primary care services, education services and social services. RESULTS: Twenty of 55 referred people fulfilled the at-risk mental state criteria, showing an incidence of 2.4 cases per 10,000 inhabitants. They were mainly adolescent males referred from health, education and social services. Overall, negative symptoms were predominant symptoms and the more frequent specific symptoms were decrease of motivation and poor work and school performance, decreased ability to maintain or initiate social relationships, depressed mood and withdrawal. CONCLUSIONS: It is possible to detect and to provide early treatment to patients with prodromal symptoms if the whole matrix of the community--including the social services--contributes to the process. The utilization of a screening instrument and a two-phase strategy- the second carried out by the specialized team--seems to be an appropriate approach for early psychosis and ARMS detection. PMID- 20712733 TI - Paranoid thinking as a heuristic. AB - Paranoid thinking can be viewed as a human heuristic used by individuals to deal with uncertainty during stressful situations. Under stress, individuals are likely to emphasize the threatening value of neutral stimuli and increase the reliance on paranoia-based heuristic to interpreter events and guide their decisions. Paranoid thinking can also be activated by stress arising from the possibility of losing a good opportunity; this may result in an abnormal allocation of attentional resources to social agents. A better understanding of the interplay between cognitive heuristics and emotional processes may help to detect situations in which paranoid thinking is likely to exacerbate and improve intervention for individuals with delusional disorders. PMID- 20712734 TI - Individual differences in language development: relationship with motor skill at 21 months. AB - Language development has long been associated with motor development, particularly manual gesture. We examined a variety of motor abilities - manual gesture including symbolic, meaningless and sequential memory, oral motor control, gross and fine motor control - in 129 children aged 21 months. Language abilities were assessed and cognitive and socio-economic measures controlled for. Oral motor control was strongly associated with language production (vocabulary and sentence complexity), with some contribution from symbolic abilities. Language comprehension, however, was associated with cognitive and socio-economic measures. We conclude that symbolic, working memory, and mirror neuron accounts of language-motor control links are limited, but that a common neural and motor substrate for nonverbal and verbal oral movements may drive the motor-language association. PMID- 20712735 TI - Ophthalmological, cognitive, electrophysiological and MRI assessment of visual processing in preterm children without major neuromotor impairment. AB - Many studies report chronic deficits in visual processing in children born preterm. We investigated whether functional abnormalities in visual processing exist in children born preterm but without major neuromotor impairment (i.e. cerebral palsy). Twelve such children (< 33 weeks gestation or birthweight < 1000 g) without major neuromotor impairment and 12 born full-term controls were assessed at 8-12 years of age by means of ophthalmological assessment (visual acuity, colour vision, stereopsis, stereoacuity, visual fields, ocular motility, motor fusion), cognitive tests of visual-motor, visual-perceptual and visual spatial skills and pattern-reversal visual evoked potentials (PR-VEPs). All participants also underwent magnetic resonance imaging (MRI) of the brain and neuromotor assessments. No significant differences were found between the groups on the ophthalmological, visual cognitive, neurological, neuromotor or MRI measures. The P100 component of the PR-VEP showed a significantly shorter latency in the preterm compared with the full-term participants. Whilst this P100 finding suggests that subtle abnormalities may exist at the neurophysiological level, we conclude that visual dysfunction is not systematically associated with preterm birth in the context of normal neurological status. PMID- 20712736 TI - The role of competition in word learning via referent selection. AB - Previous research suggests that competition among the objects present during referent selection influences young children's ability to learn words in fast mapping tasks. The present study systematically explored this issue with 30-month old children. Children first received referent selection trials with a target object and either two, three or four competitor objects. Then, after a short delay, children were tested on their ability to retain the newly fast-mapped names. Overall, the number of competitors did not affect children's ability to form the initial name-object mappings. However, only children who encountered few competitors during referent selection demonstrated significant levels of retention. Results and implications are discussed in terms of the role of competition in studies of children's fast mapping. The relationship between referent selection and full word learning is also discussed. PMID- 20712737 TI - The Ebbinghaus illusion deceives adults but not young children. AB - The sensitivity of size perception to context has been used to distinguish between 'vision for action' and 'vision for perception', and to study cultural, psychopathological, and developmental differences in perception. The status of that evidence is much debated, however. Here we use a rigorous double dissociation paradigm based on the Ebbinghaus illusion, and find that for children below 7 years of age size discrimination is much less affected by surround size. Young children are less accurate than adults when context is helpful, but more accurate when context is misleading. Even by the age of 10 years context-sensitivity is still not at adult levels. Therefore, size contrast as shown by the Ebbinghaus illusion is not a built-in property of the ventral pathway subserving vision for perception but a late development of it, and low sensitivity to the Ebbinghaus illusion in autism is not primary to the pathology. Our findings also show that, although adults in Western cultures have low context sensitivity relative to East Asians, they have high context-sensitivity relative to children. Overall, these findings reveal a gradual developmental trend toward ever broader contextual syntheses. Such developments are advantageous, but the price paid for them is that, when context is misleading, adults literally see the world less accurately than they did as children. PMID- 20712738 TI - Lexical and articulatory interactions in children's language production. AB - Traditional models of adult language processing and production include two levels of representation: lexical and sublexical. The current study examines the influence of the inclusion of a lexical representation (i.e. a visual referent and/or object function) on the stability of articulation as well as on phonetic accuracy and variability in typically developing children and children with specific language impairment (SLI). A word learning paradigm was developed so that we could compare children's production with and without lexical representation. The variability and accuracy of productions were examined using speech kinematics as well as traditional phonetic accuracy measures. Results showed that phonetic forms with lexical representation were produced with more articulatory stability than phonetic forms without lexical representation. Using more traditional transcription measures, a paired lexical referent generally did not influence segmental accuracy (percent consonant correct and type token ratio). These results suggest that lexical and articulatory levels of representation are not completely independent. Implications for models of language production are discussed. PMID- 20712739 TI - Increasing task difficulty enhances effects of intersensory redundancy: testing a new prediction of the Intersensory Redundancy Hypothesis. AB - Prior research has demonstrated intersensory facilitation for perception of amodal properties of events such as tempo and rhythm in early development, supporting predictions of the Intersensory Redundancy Hypothesis (IRH). Specifically, infants discriminate amodal properties in bimodal, redundant stimulation but not in unimodal, nonredundant stimulation in early development, whereas later in development infants can detect amodal properties in both redundant and nonredundant stimulation. The present study tested a new prediction of the IRH: that effects of intersensory redundancy on attention and perceptual processing are most apparent in tasks of high difficulty relative to the skills of the perceiver. We assessed whether by increasing task difficulty, older infants would revert to patterns of intersensory facilitation shown by younger infants. Results confirmed our prediction and demonstrated that in difficult tempo discrimination tasks, 5-month-olds perform like 3-month-olds, showing intersensory facilitation for tempo discrimination. In contrast, in tasks of low and moderate difficulty, 5-month-olds discriminate tempo changes in both redundant audiovisual and nonredundant unimodal visual stimulation. These findings indicate that intersensory facilitation is most apparent for tasks of relatively high difficulty and may therefore persist across the lifespan. PMID- 20712742 TI - Early development of spatial-numeric associations: evidence from spatial and quantitative performance of preschoolers. AB - Numeric magnitudes often bias adults' spatial performance. Partly because the direction of this bias (left-to-right versus right-to-left) is culture-specific, it has been assumed that the orientation of spatial-numeric associations is a late development, tied to reading practice or schooling. Challenging this assumption, we found that preschoolers expected numbers to be ordered from left to-right when they searched for objects in numbered containers, when they counted, and (to a lesser extent) when they added and subtracted. Further, preschoolers who lacked these biases demonstrated more immature, logarithmic representations of numeric value than preschoolers who exhibited the directional bias, suggesting that spatial-numeric associations aid magnitude representations for symbols denoting increasingly large numbers. PMID- 20712740 TI - Medial temporal lobe memory in childhood: developmental transitions. AB - The medial temporal lobes (MTL) support declarative memory and mature structurally and functionally during the postnatal years in humans. Although recent work has addressed the development of declarative memory in early childhood, less is known about continued development beyond this period of time. The purpose of this investigation was to explore MTL-dependent memory across middle childhood. Children (6 -10 years old) and adults completed two computerized tasks, place learning (PL) and transitive inference (TI), that each examined relational memory, as well as the flexible use of relational learning. Findings suggest that the development of relational memory precedes the development of the ability to use relational knowledge flexibly in novel situations. Implications for the development of underlying brain areas and ideas for future neuroimaging investigations are discussed. PMID- 20712741 TI - Sex differences in language first appear in gesture. AB - Children differ in how quickly they reach linguistic milestones. Boys typically produce their first multi-word sentences later than girls do. We ask here whether there are sex differences in children's gestures that precede, and presage, these sex differences in speech. To explore this question, we observed 22 girls and 18 boys every 4 months as they progressed from one-word speech to multi-word speech. We found that boys not only produced speech + speech (S+S) combinations ('drink juice') 3 months later than girls, but they also produced gesture + speech (G+S) combinations expressing the same types of semantic relations ('eat' + point at cookie) 3 months later than girls. Because G+S combinations are produced earlier than S+S combinations, children's gestures provide the first sign that boys are likely to lag behind girls in the onset of sentence constructions. PMID- 20712743 TI - 'I bet you know more and are nicer too!': what children infer from others' accuracy. AB - Research has shown that preschoolers monitor others' prior accuracy and prefer to learn from individuals who have the best track record. We investigated the scope of preschoolers' attributions based on an individual's prior accuracy. Experiment 1 revealed that 5-year-olds (but not 4-year-olds) used an individual's prior accuracy at labelling to predict her knowledge of words and broader facts; they also showed a 'halo effect' predicting she would be more prosocial. Experiment 2 confirmed that, overall, 4-year-olds did not make explicit generalizations of knowledge. These findings suggest that an individual's prior accuracy influences older preschoolers' expectations of that individual's broader knowledge as well as their impressions of how she will behave in social interactions. PMID- 20712744 TI - Synergies between processing and memory in children's reading span. AB - Previous research has established the relevance of working memory for cognitive development. Yet the factors responsible for shaping performance in the complex span tasks used to assess working memory capacity are not fully understood. We report a study of reading span in 7- to 11-year-old children that addresses several contemporary theoretical issues. We demonstrate that both the timing and the accuracy of recall are affected by the presence or absence of a semantic connection between the processing requirement and the memoranda. Evidence that there can be synergies between processing and memory argues against the view that complex span simply measures the competition between these activities. We also demonstrate a consistent relationship between the rate of completing processing operations (sentence reading) and recall accuracy. At the same time, the shape and strength of this function varies with the task configuration. Taken together, these results demonstrate the potential for reconstructive influences to shape working memory performance among children. PMID- 20712745 TI - Imprinted numbers: newborn chicks' sensitivity to number vs. continuous extent of objects they have been reared with. AB - Newborn chicks were tested for their sensitivity to number vs. continuous physical extent of artificial objects they had been reared with soon after hatching. Because of the imprinting process, such objects were treated by chicks as social companions. We found that when the objects were similar, chicks faced with choices between 1 vs. 2 or 2 vs. 3 objects chose the set of objects of larger numerosity, irrespective of the number of objects they had been reared with. Moreover, when volume, surface or contour length were controlled for using sets of 1 vs. 4, 1 vs. 6 or 1 vs. 3 objects, chicks resorted to choosing the larger object, rather than the familiar numerosity. When, however, chicks were reared with objects differing in their aspect (colour, size, and shape) and then tested with completely novel objects (of different colour and shape but controlled for continuous extent), they chose to associate with the same number of objects they had been reared with. These results suggest that identification of objects as different and separate individuals is crucial for the computation of number rather than continuous extent in numerical representation of small numerosities and provide a striking parallel with results obtained in human infants. Early availability of small numerosity discrimination by chicks strongly suggests that these abilities are in place at birth. PMID- 20712746 TI - Twelve- to 14-month-old infants can predict single-event probability with large set sizes. AB - Previous research has revealed that infants can reason correctly about single event probabilities with small but not large set sizes (Bonatti, 2008; Teglas et al., 2007). The current study asks whether infants can make predictions regarding single-event probability with large set sizes using a novel procedure. Infants completed two trials: A preference trial to determine whether they preferred pink or black lollipops and a test trial where infants saw two jars, one containing mostly pink lollipops and another containing mostly black lollipops. The experimenter removed one occluded lollipop from each jar and placed them in two separate opaque cups. Seventy-eight percent of infants searched in the cup that contained a lollipop from the jar with a higher proportion of their preferred color object, significantly better than chance. Thus infants can reason about single-event probabilities with large set sizes in a choice paradigm, and contrary to most findings in the infant literature, the prediction task used here appears a more sensitive measure than the standard looking-time task. PMID- 20712747 TI - Circadian rhythms and sleep in bipolar disorder. AB - OBJECTIVE: Biological rhythm pathways are highlighted in a number of etiological models of bipolar disorder, and the management of circadian instability appears in consensus treatment guidelines. There are, however, significant conceptual and empirical limitations on our understanding of a hypothesised link between circadian, sleep, and emotion regulation processes in bipolar disorder. The aim of this article is to articulate the limits of scientific knowledge in relation to this hypothesis. METHODS: A critical evaluation of various literatures was undertaken. The basic science of circadian and sleep processes, their involvement in normal emotion regulation, and the types of evidence suggesting circadian/sleep involvement in bipolar disorder are reviewed. RESULTS: Multiple lines of evidence suggest that circadian and sleep-wake processes are causally involved in bipolar disorder. These processes demonstrably interact with other neurobiological pathways known to be important in bipolar disorder, but are unique in that they are open to behavioural manipulation. CONCLUSION: Further research into biological rhythm pathways to bipolar disorder is warranted. Person environment feedback loops are fundamental to circadian adaptation, and models of circadian pathogenesis (and treatment) should recognize this complexity. PMID- 20712748 TI - Functioning and disability in bipolar disorders: a systematic review of literature using the ICF as a reference. AB - OBJECTIVES: To systematically identify and examine the frequency of use of concepts contained in outcome variables across bipolar disorder (BD) studies using the International Classification of Functioning, Disability and Health (ICF) as a reference. METHODS: Original studies published between 2000 and 2006 were located on the MEDLINE and PsycINFO databases and selected according to predetermined criteria. Outcome variables were extracted, and concepts contained therein were linked to the ICF. RESULTS: A total of 109 final studies were included. The concepts contained in these studies were linked to 145 different ICF categories. ICF category b152, emotional functions, was the most frequently represented category, appearing in 94% of the publications, followed by b126, temperament and personality functions (73%). E110, products or substances for personal consumption, and e580, health services, systems, and policies, appeared in 68% of the studies. CONCLUSIONS: The present systematic review reflects the research focus of the literature on BD in recent years. Most of the studies performed concentrate on body functions rather than activities and participation domains. Experimental studies are mostly pharmacological, reflecting the need to study nonpharmacological interventions. Furthermore, our study shows that outcome variables used in studies with persons with BD can, to a large extent, be mapped to the ICF. PMID- 20712749 TI - Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6). AB - OBJECTIVES: In industry-generated pivotal studies, lamotrigine has been found to be superior to placebo and comparable to lithium in the maintenance treatment of bipolar I disorder. Here, we directly compared lamotrigine to lithium under conditions similar to clinical routine conditions. METHODS: Adult bipolar I disorder patients with at least two episodes within the last five years and an index episode requiring treatment were randomized to lithium (n = 78; doses adjusted to obtain serum levels of 0.5-1.0 mmol/L) or to lamotrigine (n = 77; up titrated to 400 mg/day) as maintenance treatments. Randomization took place when clinically appropriate, and comedication was allowed within the first six months after randomization. The patients were enrolled from March 2001 to December 2005, and observations were censored December 2006, allowing a subgroup of patients to be followed for more than five years. The primary outcome measure was time to predefined endpoints indicating insufficient maintenance treatment, and the major secondary outcome measure was time to any study endpoint. Data were analyzed primarily by Cox proportional regression models. RESULTS: For the primary outcome measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was 0.92 [95% confidence interval (CI): 0.60-1.40]. When the primary endpoints were broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and depression were, respectively, 1.91 (95% CI: 0.73-5.04) and 0.69 (95% CI: 0.41 1.22). There was no between-group difference in terms of staying in study [HRR: 0.85 (95% CI: 0.61-1.19)]. Most treatment failures occurred within the first 1.5 years of treatment, and, among patients followed for at least five years, practically no patients were maintained successfully on monotherapy with either of the drugs. The lithium-treated patients reported diarrhea, tremor, polyuria, and thirst more frequently. Two cases, probably lamotrigine-related, of benign rash occurred. CONCLUSIONS: No differences in maintenance effectiveness between lithium and lamotrigine could be demonstrated. Lamotrigine was better tolerated than lithium, but apparently this did not influence the outcome. PMID- 20712750 TI - Clinical course of children with a depressive spectrum disorder and transient manic symptoms. AB - OBJECTIVE: To assess rates of conversion to bipolar spectrum disorder (BPSD) and risk factors associated with conversion in children with depressive spectrum disorders (DSD) and transient manic symptoms (TMS) over 18 months. TMS are manic like symptoms of insufficient duration or number to warrant a diagnosis of BPSD. METHODS: Participants were 165 children (mean = 9.9 years, SD = 1.3) with mood disorders from the Multi-Family Psychoeducational Psychotherapy (MF-PEP) treatment study: 37 with DSD+TMS, 13 with DSD, and 115 with BPSD. All were assessed with standardized instruments on four occasions over 18 months, with half receiving MF-PEP after their baseline assessment and half receiving MF-PEP after a one-year wait-list condition. RESULTS: At baseline, the Children's Global Assessment Scale scores did not differ significantly between the DSD+TMS, DSD, and BPSD groups. Conversion rates to BPSD were significantly higher for the DSD+TMS group (48.0%) compared to the DSD group (12.5%). Conversion was significantly more frequent for participants in the one-year wait-list control group (60%) compared to the immediate treatment group (16%). Clinical presentation, family environment, and family history did not differ significantly between the small subset of DSD+TMS participants who did convert to BPSD at follow-up and those who did not convert. Baseline functional impairment was greater for the converted group than the non-converted group. CONCLUSIONS: Transient manic symptoms are a risk factor for eventual conversion to BPSD; psychoeducational psychotherapy may be protective. As this exploratory study had a small sample size and did not correct for multiple comparisons, additional studies with larger sample sizes are needed. PMID- 20712752 TI - Fibromyalgia and bipolar disorder: a potential problem? AB - OBJECTIVE: To screen patients with fibromyalgia for bipolar disorder and to determine if there were any clinical clues, other than the Mood Disorders Questionnaire (MDQ), which might suggest a diagnosis of comorbid bipolar disorder. METHODS: A total of 128 consecutive new fibromyalgia patients referred to a tertiary care center rheumatology practice were enrolled and assessed using a standard clinical protocol that included the completion of four screening questionnaires: (i) MDQ for bipolar disorder, (ii) Beck Depression Inventory (BDI) for depression, (iii) Epworth Sleepiness Scale (ESS) for daytime sleepiness, and (iv) Fibromyalgia Impact Questionnaire Disability Index (FIQ-DI) to assess for functional capacity. RESULTS: A quarter of the fibromyalgia subjects, 25.19%, had a positive screen for bipolar disorder (MDQ >or= 7); 78.12% were clinically depressed (BDI >or= 10); and 52.13% reported daytime sleepiness (ESS >or= 10). Fibromyalgia subjects who screened positive for bipolar disorder had more severe depression than those with a negative screen [median BDI: 26.0 (19.0, 32.0) versus 15.0 (9.0, 24.0), p < 0.001]. CONCLUSIONS: We report a high prevalence of positive testing for bipolar disorder in this fibromyalgia cohort. Clinical data and questionnaire instruments other than nonspecific high depression severity failed to identify these patients. Since the norepinephrine serotonin reuptake inhibitors duloxetine and milnacipran have been recently approved by the U.S. Food and Drug Administration for the treatment of fibromyalgia, and because patients with bipolar disorder may experience destabilization of mood when treated with such agents, patients with fibromyalgia should be systematically screened for bipolar disorder prior to treatment. PMID- 20712753 TI - The interactive computer interview for mania. AB - OBJECTIVES: The Interactive Computer Interview for Mania (ICI-M) is a computer administered interview that presents probes to assess symptom severity and utilizes a scoring algorithm to select follow-up questions and rate subject responses in accordance with rating scale anchor points. The current study examines the acceptability, feasibility, and reliability of the ICI-M as a potential method for evaluating the performance of human raters. METHODS: Participants with a diagnosis of bipolar I or II disorder completed both a live interview of the Young Mania Rating Scale with a human rater (LR) and the ICI-M. A panel of three expert raters reviewed each videotaped LR and assigned a consensus rating (CR). Participants completed a modified version of the Client Satisfaction Questionnaire to assess each method. RESULTS: Intraclass correlation coefficients were 0.91 between the ICI-M and CR and 0.97 between the LR and CR (n = 100), providing empirical support for the inter-rater reliability of each approach. Coefficient alphas indicated comparable internal consistency reliability: ICI-M = 0.82, LR = 0.83, and CR = 0.84. The ICI-M was significantly more sensitive in detecting symptomatology than the LR (p < 0.001) and the CR (p < 0.001), and resulted in significantly higher ratings than CR on mood, speech, psychotic content, and disruptive-aggressive behavior. While participants endorsed significantly higher overall satisfaction with LR, no significant differences emerged between ICI-M and LR regarding willingness to participate again or ability to understand the questions. CONCLUSIONS: The ICI-M is a well accepted and reliable method for assessing manic symptoms. The ICI-M is a tool with adequate sensitivity to elicit symptoms and rate severity and is recommended as a tool to monitor and improve rater performance, not as a replacement of a human rater. PMID- 20712751 TI - Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus. AB - OBJECTIVE: Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD. METHODS: Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women. RESULTS: As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity. CONCLUSIONS: Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed. PMID- 20712754 TI - Performance of the Bipolar Spectrum Diagnostic Scale in psychiatric outpatients. AB - OBJECTIVES: Recent research has suggested that bipolar disorder, when defined to include milder variants such as bipolar II disorder and bipolar disorder not otherwise specified (NOS), is more prevalent than had been previously reported and often underrecognized. Recommendations for improving the detection of bipolar disorder have included careful clinical evaluations inquiring about a history of mania and hypomania and the use of screening questionnaires. The Bipolar Spectrum Diagnostic Scale (BSDS) was designed to be particularly sensitive to the milder variants of bipolar disorder. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we examined the operating characteristics of the BSDS in a large sample of psychiatric outpatients presenting for treatment. METHODS: A total of 1,100 psychiatric outpatients were interviewed with the Structured Clinical Interview for DSM-IV and asked to complete the BSDS. Missing data on the BSDS reduced the sample size to 961, approximately 10% (n = 90) of whom were diagnosed with bipolar disorder. RESULTS: The sensitivity of the BSDS was similar for bipolar I disorder, bipolar II disorder, and bipolar disorder NOS/cyclothymia. A receiver operating curve (ROC) analysis indicated that cutoffs of 11 and 12 maximized the sum of sensitivity and specificity for the entire group of patients with bipolar disorder (area under curve = 0.80, p < 0.001). The cutoff point associated with 90% sensitivity for the entire sample of patients with bipolar disorder was 8. At this cutoff the specificity of the scale was 51.1% and positive predictive value was 16.0%. We compared the patients with and without bipolar disorder on each of the BSDS symptom items. The odds ratios were higher for the items assessing hypomanic/manic symptoms than items assessing depressive symptoms. We therefore examined the performance of a subscale composed only of the hypomania/mania items. The area under the curve in the ROC analysis was nearly identical to that of the entire scale (0.81, p < 0.001). CONCLUSIONS: With its high negative predictive value, the BSDS was excellent at ruling out a diagnosis of bipolar disorder; however, the low positive predictive value indicates that it is not good at ruling in the diagnosis. These data raise questions about the use of the BSDS as a screening measure in routine clinical psychiatric practice. PMID- 20712755 TI - Ruling in and ruling out 'caseness' in the bipolar spectrum: implications for initial screening. PMID- 20712756 TI - Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. AB - OBJECTIVES: Several magnetic resonance imaging studies have found changes in amygdala volumes in adults with mood disorders. The cellular basis for these changes has not been explored in detail. Specifically, it is not known whether differences in the density and/or volume of neurons or glial cells contribute to tissue volume changes seen on magnetic resonance images. METHODS: Postmortem amygdala samples were obtained from the Stanley Foundation Neuropathology Consortium from subjects diagnosed with bipolar disorder (n = 10), major depressive disorder (n = 11), and schizophrenia (n = 9), and from normal controls (n = 14). Samples were first stained with glial fibrillary acidic protein (GFAP) and counter-stained with hematoxylin to ascertain neuron and glia (astrocyte) densities. RESULTS: No significant differences in neuronal densities were found between groups. However, a reduction in the density of GFAP immunoreactive astrocytes was observed in the amygdala of subjects with major depressive disorder compared to the bipolar disorder, schizophrenia, and normal control postmortem samples. CONCLUSIONS: A decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies. PMID- 20712757 TI - Assessing oxidative pathway genes as risk factors for bipolar disorder. AB - OBJECTIVES: There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. METHODS: Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals). RESULTS: Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global chi(2) = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, chi(2) = 9.526, p = 0.002, corrected p = 0.029). CONCLUSIONS: Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder. PMID- 20712758 TI - Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. AB - OBJECTIVE: To determine if the repeated occurrence of manic episodes in bipolar I disorder (BD-I) patients is associated with reduced cognitive performance, which could in turn imply a worsening in the disorder's evolution. METHOD: Cognitive performance in euthymic patients was assessed using attention, memory, and executive function tests on 24 BD-I patients who had experienced only 1 manic episode, on 27 BD-I patients with 2 manic episodes, on 47 BD-I patients with 3 or more manic episodes, and on 66 healthy control subjects. RESULTS: In BD-I patients, number of manic episodes was positively associated with poorer performance on neurocognitive tests, an association that was not accounted for by depression, disease chronicity, onset, or medication. Significant differences in attention and executive function were found between patients and controls and in those patients who had had just 1 manic episode compared to those who had 3 or more. CONCLUSION: The number of manic episodes predicted poor cognitive performance, suggesting that the recurrence of mania may have a long-term neuropsychological impact. Prospective follow-up studies need to be completed to explore this effect further as better treatment adherence may have a protective effect on neurocognitive function. PMID- 20712759 TI - Bipolar affective disorder in the postnatal period: investigating the role of sleep. AB - OBJECTIVES: Psychotic disorders have a high rate of relapse in the postpartum period for reasons that are unclear, but may be related to changes in sleep patterns that occur during pregnancy and after birth. Understanding of the influence of sleep on postpartum psychosis presentation is limited. The aim of the current study was to investigate changes in sleep/wake activity during pregnancy and the postpartum period in women with a history of psychosis. METHODS: Women with a history of bipolar disorder and/or postpartum psychosis (HxW) were recruited (n = 23) together with a control population (CtW) (n = 15). Data on demographic and psychosocial factors, mental health status, and sleep/wake activity were collected at seven timepoints-the last week of each trimester of pregnancy and four times during the postpartum (weeks 1, 4, and 8, and at month 6). Longitudinal data were analysed using an HLM version 6 repeated measures multilevel model. RESULTS: No significant differences were noted in sleep/wake activity between HxW and CtW. None of the HxW who were taking a mood stabilizer during their pregnancy, including at delivery, relapsed during the study. Of those taking an antidepressant or antipsychotic, or no medication, 3 relapsed within the first six months and 2 within the first two months. HxW were more likely to report a poor partner relationship than CtW. CONCLUSION: Results suggest that during the perinatal period, there is no difference in sleep/wake activity in women with a history of a psychotic disorder. Use of mood stabilizer during pregnancy and at delivery appears important in preventing psychotic relapse in the postpartum. PMID- 20712760 TI - Association analysis of DAOA and DAO in bipolar disorder: results from two independent case-control studies. PMID- 20712761 TI - Depression not related to lower religious involvement in bipolar disorders? PMID- 20712763 TI - Preface to Cooley's Anemia: Ninth Symposium. PMID- 20712764 TI - Clinical trials in thalassemia: insights from the patient community. PMID- 20712765 TI - Pathogenesis and management of iron toxicity in thalassemia. AB - In thalassemia major, iron overload is the joint outcome of multiple blood transfusions and an inappropriately increased iron absorption associated with ineffective erythropoiesis. Threshold values for iron toxicity are a liver iron concentration exceeding 440 mmoles/g dry weight, serum ferritin >2500 ng/mL, DFO urinary iron excretion >20 mg/day, and transferrin saturation >75%. The outpouring of catabolic iron that exceeds the iron-carrying capacity of transferrin results in the emergence of non-transferrin-bound iron (NTBI). NTBI is cleared preferentially by the liver and myocardium at a rate exceeding 200 times that of transferrin iron. NTBI catalyzes the formation of free radicals, resulting in oxidative stress and damage to mitochondria, lysosomes, lipid membranes, proteins, and DNA. The long-term consequences of iron toxicity, including cirrhosis, myocardiopathy, and endocrine disorders, are preventable and mostly reversible by effective iron chelation therapy. Recent technologic advances in the documentation of organ-specific siderosis and the improved efficiency of iron chelating programs resulted in a spectacular improvement in the prevention of iron-induced end-organ failure and improved survival in thalassemic patients. PMID- 20712766 TI - The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia. AB - On the basis of all the presented data, one can conclude that oxidative stress plays a major role in the pathophysiology of thalassemia and other congenital and acquired hemolytic anemias. Free extracellular (labile plasma iron, LPI) and intracellular (labile iron pool, LIP) iron species that have been identified in thalassemic blood cells are responsible for generation of oxidative stress by catalyzing formation of oxygen radicals over the antioxidant capacity of the cell. Consequently, there is a rationale for iron chelation to eliminate the free iron species, which in this respect, act like antioxidants. In addition, antioxidants such as vitamin E and polyphenols are also capable of ameliorating increased oxidative stress parameters and, given together with iron chelators, may provide a substantial improvement in the pathophysiology of hemolytic anemias and particularly in thalassemia. PMID- 20712767 TI - Thalassemia as a global health problem: recent progress toward its control in the developing countries. AB - The thalassemias, together with sickle cell anemia and its variants, are by far the most common monogenic diseases. They occur at their highest frequency in countries of the developing world where their control and management is hampered by a lack of knowledge of their true prevalence, adequate services for their management and control, and support by their governments and international health agencies. However, there has been some progress recently in addressing these problems and there are several ways in which the lot of children with thalassemia in poor countries could be improved in the future. Over the last 20 years there has been considerable improvement in the control and management of the thalassemias in the richer countries of the world. Unfortunately, however, this is not the case for many of the developing countries, where there have been few improvements in the control of the numbers of births of babies with thalassemia or in the care of thalassemic children since the frequency of the problem started to become evident in the 1960s. Here, I will try to assess the current situation in these countries and examine some of the potential approaches for improving the current situation. PMID- 20712768 TI - Iron metabolism and ineffective erythropoiesis in beta-thalassemia mouse models. AB - beta-thalassemia is a disease associated with decreased beta-globin production leading to anemia, ineffective erythropoiesis, and iron overload. New mechanisms associated with modulation of erythropoiesis and iron metabolism have recently been discovered in thalassemic mice, improving our understanding of the pathophysiology of this disease. These discoveries have the potential to be translated into clinically-relevant therapeutic options to reduce ineffective erythropoiesis and iron overload. A new generation of therapies based on limiting ineffective erythropoiesis, iron absorption, and the correction of iron maldistribution could be on the way, possibly complementing and improving the current standard of patient care. PMID- 20712770 TI - Therapy for beta-globinopathies: a brief review and determinants for successful and safe correction. AB - Gene therapy for beta-globinopathies, particularly beta-thalassemia and sickle cell anemia, hold much promise for the future, as a one time cure for these common and debilitating disorders. Correction of the beta-globinopathies using lentivirus vectors (LV) carrying the beta- or gamma-globin genes and elements of the locus control region has been well established in murine models, and a good idea of "what it will take to cure these diseases" has been developed in the first decade of the twenty-first century. A clinical trial using one such vector has been initiated in France while other trials are in development. Vector improvements to enhance the safety and efficiency of LV are being explored, while newer strategies, like homologous recombination in induced pluripotent cells for correction of sickle cell anemia, has been shown as a proof-of-concept. Here we provide a review of current progress in genetic correction of beta-globin disorders. PMID- 20712769 TI - Hepcidin in beta-thalassemia. AB - Iron overload is the principal cause of morbidity and mortality in beta thalassemia with or without transfusion dependence. Iron homeostasis is regulated by the hepatic peptide hormone hepcidin. Hepcidin controls dietary iron absorption, plasma iron concentrations, and tissue iron distribution. A deficiency in this hormone is the main or contributing factor of iron overload in iron-loading anemias such as beta-thalassemia. Hepcidin deficiency results from a strong suppressive effect of the high erythropoietic activity on hepcidin expression. Although in thalassemia major patients iron absorption contributes less to the total iron load than transfusions, in non-transfused thalassemia, low hepcidin, and the consequent hyperabsorption of dietary iron is the major cause of systemic iron overload. Hepcidin diagnostics and future therapeutic agonists may help in management of patients with beta-thalassemia. PMID- 20712771 TI - Humanized mouse models of Cooley's anemia: correct fetal-to-adult hemoglobin switching, disease onset, and disease pathology. AB - beta thalassemia major or Cooley's Anemia (CA) has been difficult to model in mice due to their lack of a fetal hemoglobin gene equivalent. This summary describes novel preclinical humanized mouse models of CA that survive on human fetal hemoglobin at birth and are blood-transfusion dependent for life upon completion of their human fetal-to-adult hemoglobin switch after birth. These CA models are the first to recapitulate the temporal onset of the disease in human patients. These novel humanized CA disease models are useful for the study of the regulation of globin gene expression, synthesis, and switching; examining the onset of disease pathology; development of transfusion and iron chelation therapies; induction of fetal hemoglobin synthesis; and the testing of novel genetic and cell-based therapies for the correction of thalassemia. PMID- 20712772 TI - Strategy for a multicenter phase I clinical trial to evaluate globin gene transfer in beta-thalassemia. AB - Globin gene transfer in autologous hematopoietic stem cells offers a potentially curative treatment option for patients suffering from beta-thalassemia major who lack an HLA-matched hematopoietic stem cell donor. Based on extensive preclinical investigation, we are initiating a phase I clinical trial using G-CSF mobilized, autologous CD34(+) cells transduced with a vector similar to the original TNS9 vector. Our first mobilizations in adult beta-thalassemic subjects have been well tolerated and yielded the required CD34(+) cell dose. To minimize toxicity to enrolled subjects, and in the absence of a demonstrated requirement for myeloablative conditioning, our trial will use a reduced intensity conditioning regimen. Because low vector titers may adversely affect efficacy and safety, we have focused on vector manufacturing processes. We are now in a position to transfer our globin lentiviral vectors in a clinically relevant dosage (averaging 0.8 vector copy per cell in bulk CD34(+) cells) and to supply clinical grade vector to collaborating centers in the U.S.A. and in Europe. We anticipate that the first U.S. trial of globin gene transfer will start in 2010. PMID- 20712773 TI - Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease. AB - Effective gene therapy for hemoglobinopathies will require high numbers of autologous gene-engineered hematopoetic stem cells to be reintroduced into the patients. Stem cell mobilization using G-CSF is the most convenient and effective approach to achieve this goal, but it can have severe side effects in sickle cell anemia and be potentially harmful in the case of severe thalassemia. Hence, the optimal way of collection of hematopoetic stem cells from patients with thalassemia and sickle cell disease needs to be determined. In this paper, we review the possible risks of G-CSF mobilization in hemoglobinopathies and we outline the approaches used in an on-going clinical trial in which pretreatment with hydroxyurea is used to reduce potential risks of G-CSF administration to patients with severe beta thalassemia. PMID- 20712774 TI - Transcriptional silencing of fetal hemoglobin by BCL11A. AB - The beta-thalassemia syndromes are a major global health problem. Increased levels of fetal hemoglobin (HbF) ameliorate the clinical symptoms seen in this disease. By taking advantage of the natural variation in the level of HbF in various populations, we and others identified several common genetic variants in three major loci that regulate HbF levels. One of these variants resides in the gene BCL11A. We have studied the role of this gene product and established that BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. Moreover, we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients. PMID- 20712775 TI - The challenge of obtaining therapeutic levels of genetically modified hematopoietic stem cells in beta-thalassemia patients. AB - Hematopoietic stem cells (HSCs) function to provide the individual with a continuing supply of blood cells over many decades. To this end, HSCs have evolved unique mechanisms for self-preservation, including resistance to viral infection. Unfortunately, this characteristic may impede the ability to achieve high levels of gene transfer mediated by HIV-based lentiviral vectors. This is an important consideration for gene therapy efforts being undertaken for beta thalassemia. In particular, the study of beta-thalassemia patients that underwent allogeneic stem cell transplantation and developed stable, long-term mixed chimerism suggests that HSC gene transfer levels of greater than 25% will be needed for a robust therapeutic effect in such patients. Available pre-clinical and clinical trial lentiviral gene transfer studies suggest that improvements are needed to achieve this goal. Here, we review what level of gene transfer is needed in the context of varying degrees of beta-globin deficiency, what level is currently achievable, and the areas of research which may be fruitful in improving the likelihood of success for patients with the severest forms of beta thalassemia. PMID- 20712776 TI - Deferiprone. AB - Deferiprone (DFP) has been evaluated in a wide range of disorders, but most data come from transfusion-dependent thalassemia. The safety and tolerability profile includes gastrointestinal complaints, liver enzymes elevation, weight gain, arthropathy, neutropenia, and agranulocytosis. The last requires close monitoring of blood count and precludes the use of DFP in conditions with bone marrow abnormalities. The efficacy profile is similar among the three available chelators. For DFP, the choice of dosage is crucial to optimize the effect on liver iron concentration, according to the iron load degree and transfusional iron input. Growing evidence indicates that DFP, alone or in combination with deferoxamine, is effective in removing cardiac iron and preventing cardiac iron load. The available data consolidate an important role of DFP in the management of iron overload. There is a need to compare directly the relative value of the available chelators in the long-term prevention of iron toxicity by well-designed randomized controlled trials. PMID- 20712777 TI - Combined iron chelation therapy. AB - Patients with thalassemia major accumulate body iron over time as a consequence of continuous red blood cell transfusions which cause hepatic, endocrine, and cardiac complications. Despite the availability of three iron chelators, some patients fail to respond adequately to monotherapy with any of them. Combination therapy, consisting in the use of two chelators on the same day, has been introduced to increase the efficacy and to induce negative iron balance in patients with severe iron overload. Extensive long-term experience has shown that combined chelation with deferiprone and deferoxamine (DFO) rapidly reduces liver iron, serum ferritin, and myocardial siderosis, improves cardiac function, reverses and prevents endocrine complications, reduces cardiac mortality, and improves survival. Side effects, though significant, are manageable if properly monitored. Preliminary promising results have been obtained using combined chelation with deferasirox and DFO. As more drug combination regimes are evaluated, it should be possible to better tailor iron chelation to the needs of the patients, minimizing toxicity and maximizing efficacy throughout life. PMID- 20712778 TI - Deferasirox--current knowledge and future challenges. AB - Since the last Cooley's symposium in 2005, our knowledge and clinical experience with deferasirox had advanced considerably. This has been based on prospective multicenter clinical trials, on a scale hitherto unprecedented for chelation therapy, now totalling over 7,400 patients. Here, current knowledge about the clinical effects of deferasirox is described in key areas, namely, the pharmacokinetics and its relevance to mechanisms of action; effects on iron balance; effects on serum ferritin; long-term tolerability; and effects on cardiac iron removal. Challenges for future research include a better understanding of the relationship of serum ferritin to iron balance; the optimal target level and rate of decrease in serum ferritin to achieve a "soft landing," as ferritin values fall below 500-1,000 microg/L; the use of surrogate markers, such as mT2*, to infer the likely effects on long-term survival; and the safety and efficacy of deferasirox when combined with other chelators. PMID- 20712779 TI - Monitoring the efficiency of iron chelation therapy: the potential of nontransferrin-bound iron. AB - The major ligands of nontransferrin-bound iron (NTBI) are suggested to be citrate and albumin. The proportion of iron binding to albumin is influenced by the degree of oxidation and glycation of the protein. LC-ICP-MS is demonstrated to be a useful technique for the speciation of NTBI, with unprocessed serum being subjected to analysis. Ferritin iron, citrate iron, and ferrioxamine can be quantified using this technique. This review describes the use of a new fluorescent probe for NTBI quantification. PMID- 20712780 TI - Critical appraisal of growth retardation and pubertal disturbances in thalassemia. AB - Growth and pubertal disturbances are the commonest endocrinopathies in homozygous thalassemia, accounting for significant morbidity in 70-80% children and adolescents globally. This review focuses on the pathophysiology of the endocrinopathy from a historical perspective and altered natural history induced by better care due to transfusion and chelation therapy. We have also discussed clinical features, diagnosis, and management strategies of growth retardation, sexual infantilism, pubertal aberrations, and scope of growth hormone, sex steroids, and other endocrine therapies. The article also emphasizes current and future strategies for screening, monitoring of growth and pubertal disturbances, and early intervention for the restoration of fertility potential and bone mass in the affected individuals. PMID- 20712782 TI - Predicting pituitary iron and endocrine dysfunction. AB - Patients with thalassemia major (TM) require lifelong transfusion therapy to survive, leading to toxic iron overload in the endocrine glands and heart. The pituitary gland is one of the most vulnerable targets, leading to irreversible hypogonadotropic hypogonadism in approximately half of patients. Improvements in magnetic resonance imaging (MRI) technology and understanding have allowed earlier recognition of preclinical iron deposition in the heart, pancreas, and liver; prior work also supports a similar role for the pituitary. The purpose of this study is threefold, (1) to develop age-specific nomograms for pituitary iron and volume metrics; (2) to determine the prevalence, severity, and age of onset of pituitary iron deposition and volume loss in TM patients, and (3) to determine whether deferasirox monotherapy can modify the trajectory of pituitary iron accumulation and damage over a two-year period. This article outlines relevant background studies and methodological details as well as providing preliminary results from our first two aims. PMID- 20712781 TI - Magnetic resonance assessment of iron overload by separate measurement of tissue ferritin and hemosiderin iron. AB - With transfusional iron overload, almost all the excess iron is sequestered intracellularly as rapidly mobilizable, dispersed, soluble ferritin iron, and as aggregated, insoluble hemosiderin iron for long-term storage. Established magnetic resonance imaging (MRI) indicators of tissue iron (R(2), R(2)*) are principally influenced by hemosiderin iron and change slowly, even with intensive iron chelation. Intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool that can change rapidly with iron chelation. We have developed a new MRI method to separately measure ferritin and hemosiderin iron, based on the non-monoexponential signal decay induced by aggregated iron in multiple-spin-echo sequences. We have initially validated the method in agarose phantoms and in human liver explants and shown the feasibility of its application in patients with thalassemia major. Measurement of tissue ferritin iron is a promising new means to rapidly evaluate the effectiveness of iron-chelating regimens. PMID- 20712783 TI - Better survival and less cardiac morbidity in female patients with thalassemia major: a review of the literature. AB - Female patients with thalassemia and other hemoglobinopathies enjoy a longer survival when compared to males. We report data from the literature and from our own studies on gender differences in survival of thalassemia patients, and also examine this phenomenon in animals and in the general population. Some of the more widely accepted hypotheses that try to explain the differences in longevity between males and females are reviewed. The oxidative stress hypothesis is commonly accepted by the researchers on ageing, although further support for it is needed. In conclusion, it appears that male and female patients with transfusion-dependent thalassemia major are at the same risk of accumulating iron, but females survive longer and develop less cardiac disease because they tolerate iron toxicity better, possibly as an effect of increased tolerance to chronic oxidative stress. PMID- 20712784 TI - A preclinical approach for gene therapy of beta-thalassemia. AB - Lentiviral-mediated beta-globin gene transfer successfully treated beta thalassemic mice. Based on this result, clinical trials were initiated. To date, however, no study has investigated the efficacy of gene therapy in relation to the nature of the different beta-globin mutations found in patients. Most mutations can be classified as beta(0) or beta(+), based on the amount of beta globin protein produced. Therefore, we propose that a screening in vitro is necessary to verify the efficacy of gene transfer prior to treatment of individual patients. We used a two-phase liquid culture system to expand and differentiate erythroid progenitor cells (ErPCs) transduced with lentiviral vectors. We propose the use of this system to test the efficiency of lentiviral vectors carrying the human beta-globin gene, to correct the phenotype of ErPCs from patients preparing for gene therapy. This new approach might have profound implications for designing gene therapy and for understanding the genotype/phenotype variability observed in Cooley's anemia patients. PMID- 20712785 TI - The role of reduced intensity preparative regimens in patients with thalassemia given hematopoietic transplantation. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) still remains the only curative treatment for patients with thalassemia major (TM). However, HSCT is associated with a non-negligible risk of both transplantation-related mortality (TRM) and morbidity. Great interest and relevant expectations have been raised by the introduction in the clinical practice of reduced-intensity preparative regimens, which may represent an effective strategy to reduce the toxicity of transplantation and may also help reduce the incidence of late effects. Although some reports have documented the feasibility of using reduced-intensity preparative regimens for successfully treating patients with TM, a high incidence of graft failure has been frequently reported. Recently, treosulfan-based myeloablation has been demonstrated to be associated with limited extra-medullary toxicity and a high rate of sustained donor engraftment. This novel approach is a promising alternative for reducing the risk of life-threatening complications and increasing the number of TM patients successfully cured with an allograft. PMID- 20712786 TI - Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia. AB - Allogeneic hemopoietic stem cell transplantation (HSCT) represents one of the best cures for thalassemia. Currently, HSCT for thalassemia consists of allogeneic stem cell gene therapy and still awaits autologous genetically modified stem cell transplantation. HSCT for thalassemia has substantially improved over the last two decades, due in large part to improvements in preventive strategies, the effective control of transplant-related complications, and the development of new preparative regimens. A risk classes-based approach to transplantation in thalassemia has led to disease-free survival probability of 87, 85, and 80% in classes 1, 2, and 3 patients, respectively. Adult thalassemia patients, who are higher risk patients for transplant-related toxicity due to an advanced phase of the disease, have a cure rate of 65% with current treatment protocol. Patients who do not have matched family or unrelated donors could benefit from haploidentical mother-to-child transplantation. Overall, the results of this type of transplantation appear encouraging. PMID- 20712787 TI - Emerging insights in the management of hemoglobin E beta thalassemia. AB - Globally, hemoglobin (Hb) E beta thalassemia accounts for approximately half the severe forms of beta thalassemia. Because of its wide clinical diversity and the ability of patients with this condition to adapt unusually well to low hemoglobin levels, the management of Hb E beta thalassemia, particularly the decision to instigate regular blood transfusion, is particularly difficult. Here, we present a summary of our work in patients with this condition, which attempts to define clinical, adaptive, and genetic factors of possible value in determining the early management of this condition. PMID- 20712789 TI - Detection of the cardiovascular complications of thalassemia by echocardiography. AB - The thalassemia syndromes are associated with cardiovascular complications, which differ with the varying phenotypes encountered. The well-recognized paradigm of heart failure induced by myocardial iron overload, in thalassemia major (TM), has now been joined by pulmonary arterial hypertension (mostly seen in thalassemia intermedia) among other more subtle disorders of the cardiovascular system, including endothelial dysfunction. Cardiovascular magnetic resonance (T2*) has allowed cardiac iron load to be quantified noninvasively, and the routine measurement of T2* has been associated with a marked improvement in the outlook for patients with TM, in particular. Echocardiography remains an indispensable tool in the cardiovascular assessment of patients, it provides many insights into cardiovascular function, and its use allows improved management of patients. It is particularly suited to assess diastolic function, diagnose intracardiac masses (usually thrombus), and assess right ventricular function and pulmonary pressure. PMID- 20712788 TI - Fetal globin gene inducers: novel agents and new potential. AB - Inducing expression of endogenous fetal globin (gamma-globin) gene expression to 60-70% of alpha globin synthesis produces beta-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced gamma-globin expression in beta-thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as seven years. However, prior generation inducers were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic, sodium 2,2 dimethylbutyrate, is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of three major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used worldwide. PMID- 20712790 TI - Cardiovascular MRI in thalassemia major. AB - MRI assessment of myocardial iron and function has revolutionized the treatment of thalassemia major patients. While knowledge of somatic iron stores is vital for iron chelation management, it does not adequately monitor cardiac risk. MRI monitoring of cardiac T2* allows preclinical recognition of myocardial iron, stratifies prospective cardiac risk, and tracks response to modifications in iron chelation therapy. MRI assessment of cardiac function complements T2* measurements by offering highly accurate and reproducible assessments of ventricular function. This manuscript describes the historical context of cardiac toxicity in thalassemia major, the introduction of cardiac T2* methods in the early 2000s, and the impact of these techniques on patient care as well as our fundamental understanding of iron cardiomyopathy. Technical details regarding T2* image acquisition and postprocessing are also discussed. As barriers to widespread implementation are being overcome, cardiac T2* is rapidly transitioning from a clinical research tool to the standard of care. PMID- 20712791 TI - Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. AB - Alpha thalassemia, the most common genetic disorder of hemoglobin synthesis, affects up to 5% of the world's population. It represents a group of conditions with reduced or absent synthesis of one to all four of alpha globin genes. Deletional or nondeletional mutations occur on chromosome 16. Its severity ranges from asymptomatic to fatal in utero. Hemoglobin H disease, a mutation of three alpha globin genes, is more severe than previously recognized. Anemia, hypersplenism, hemosiderosis, growth failure, and osteoporosis are commonly noted as the patient ages. Alpha thalassemia major, a usually fatal in utero disease, is now recognized to have a complex molecular and phenotypic expression with increasing births being reported. Surviving newborns without intrauterine transfusion often have congenital anomalies and neurocognitive injury. Serious maternal complications often accompany pregnancy. Doppler ultrasonography with intrauterine transfusion ameliorates these complications. The high incidence in many populations mandates population screening and prenatal diagnosis of at-risk couples. Universal newborn screening has been adopted in several regions with DNA confirmatory testing. These advances have resulted in ethical dilemmas for the family and the provider. PMID- 20712792 TI - Nutritional deficiencies in patients with thalassemia. AB - Optimal nutritional status is imperative for growth, development, immune function, and bone health. Patients with thalassemia are known to have poor growth, altered puberty, and immune function as well as reduced bone mineral acquisition. The etiology of these comorbidites is typically ascribed to the toxic effects of transfusion-related iron-overload. Recently, our group and others have observed marked nutritional deficiencies in key fat and water-soluble vitamins as well as important essential minerals. Depressed circulating levels of nutrients have been observed despite seemingly adequate dietary intake. This disconnect between intake and circulating levels suggests that patients with thalassemia may have increased needs for certain nutrients due to either poor nutrient absorption, elevated losses, or increased nutrient turnover. Randomized controlled clinical trials are needed to test the efficacy of nutritional therapies toward improving the overall health in thalassemia, as well as decreasing long-term comorbidities such as reduced bone mass. PMID- 20712793 TI - Ferritin iron minerals are chelator targets, antioxidants, and coated, dietary iron. AB - Cellular ferritin is central for iron balance during transfusions therapies; serum ferritin is a small fraction of body ferritin, albeit a convenient reporter. Iron overload induces extra ferritin protein synthesis but the protein is overfilled with the extra iron that damages ferritin, with conversion to toxic hemosiderin. Three new approaches that manipulate ferritin to address excess iron, hemosiderin, and associated oxidative damage in Cooley's Anemia and other iron overload conditions are faster removal of ferritin iron with chelators guided to ferritin gated pores by peptides; more ferritin protein synthesis using ferritin mRNA activators, by metal complexes that target mRNA 3D structures; and determining if endocytotic absorption of iron from legumes, which is mostly ferritin, is regulated during iron overload to prevent excess iron entry while providing protein. More of a focus on ferritin features, including protein cage structure, iron mineral, regulatable mRNA, and specific gut absorption properties, will achieve the three novel experimental goals for managing iron homeostasis with transfusion therapies. PMID- 20712794 TI - Pulmonary hypertension in thalassemia. AB - Pulmonary hypertension (PH) is common in thalassemia and contributes to mortality. Advancing age and a history of splenectomy are major risk factors in this population. The etiology of PH is multifactorial, involving a complex interaction of platelets, the coagulation system, erythrocytes, and endothelial cells along with inflammatory and vascular mediators. The long-term effect of splenectomy, red cell membrane pathology, coagulation abnormalities, low nitric oxide (NO) bioavailability, excess arginase activity, platelet activation, oxidative stress, iron overload, and chronic hemolysis play a role. The process of hemolysis disables the arginine-NO pathway through the simultaneous release of erythrocyte arginase and cell-free hemoglobin. Both NO and its obligate substrate arginine are rapidly consumed. The biological consequences of hemolysis on NO bioavailability ultimately translate into the clinical manifestations of PH. Guidelines for the management of PH in thalassemia have not yet been established; however, clinical trials are ongoing in an effort to guide future therapy. PMID- 20712795 TI - The natural history of thalassemia intermedia. AB - The severity of thalassemia intermedia depends on the degree of imbalance between alpha and non-alpha chains as well as other genetic and environmental factors that modify the natural history of the disease. By definition, the patients spontaneously maintain hemoglobin at or above 7 g/dL, sometimes at the price of intense hyperplasia of the bone marrow that is in turn responsible for bone deformities, osteoporosis, and extramedullary erythropoietic masses that often characterize thalassemia intermedia. Transfusion may become necessary with advancing age, during infection and pregnancy, and when hypersplenism develops. Splenectomy is often needed. Iron overload in nontransfused patients is due to increased gastrointestinal absorption and involves mainly the liver. Complications affecting the lives of patients with thalassemia intermedia include pulmonary hypertension, leg ulcers, pseudoxanthoma elasticum, gallstones, hepatocellular carcinoma, and thromboembolic events. PMID- 20712796 TI - Hepcidin and Hfe in iron overload in beta-thalassemia. AB - Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with beta-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in beta-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in beta-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries. PMID- 20712797 TI - Fertility potential in thalassemia major women: current findings and future diagnostic tools. AB - Preserving fertility, preventing early menopause, and predicting reproductive ability have become crucial for many adult thalassemia major females. Luteinizing hormone/follicle-stimulating hormone (LH/FSH) and estradiol, commonly used for assessment of fertility potential in thalassemia, have a poor predictive value. Current reproductive practice uses markers of ovarian reserve testing, which were not yet studied in thalassemia women. We explored the relationship between liver iron concentration (LIC) and fertility status in 26 females (mean 30 years old). Seventeen (65%) of them experienced primary or secondary amenorrhea. Levels of LH/FSH and estradiol were low or undetectable in 48% and 35% of patients, respectively and did not correlate with age, presence of amenorrhea, and LIC. This further addresses the need for utilization of current available methods for assessment of fertility capacity in thalassemia, which will also allow future correlation with pituitary iron measures by MRI as well as early intervention for fertility preservation. PMID- 20712798 TI - Redefining thalassemia as a hypercoagulable state. AB - As the life expectancy of beta-thalassemia patients has markedly improved over the last decade, several new complications are being recognized. The presence of a high incidence of thromboembolic events, mainly in thalassemia intermedia patients, has led to the identification of a hypercoagulable state in thalassemia. In this review, the molecular and cellular mechanisms leading to hypercoagulability in thalassemia are highlighted, and the current clinical experience is summarized. Recommendations for thrombosis prophylaxis are also discussed. PMID- 20712799 TI - Treatment options for thalassemia patients with osteoporosis. AB - Osteoporosis represents a prominent cause of morbidity in patients with thalassemia. The delay in sexual maturation, the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the progressive marrow expansion, the iron toxicity on osteoblasts, the iron chelators, and the deficiency of growth hormone or insulin growth factors have been identified as major causes of osteoporosis in thalassemia. Adequate hormonal replacement, effective iron chelation, improvement of hemoglobin levels, calcium and vitamin D administration, physical activity, and smoking cessation are the main to-date measures for the management of the disease. During the last decade, novel pathogenetic data suggest that the reduced osteoblastic activity, which is believed to be the basic mechanism of bone loss in thalassemia, is accompanied by a comparable or even greater increase in bone resorption. Therefore, the role of bisphosphonates, potent inhibitors of osteoclast activation, arises as a major factor in the management of osteoporosis in thalassemia patients. PMID- 20712800 TI - Health care transition in thalassemia: pediatric to adult-oriented care. AB - Improved technology and medical advances have increased the lifespan for people with thalassemia. As thalassemia is no longer exclusively a pediatric blood disorder, consideration must now be given to transition planning from pediatric to adult care. The complexity of thalassemia disease, coupled with the changing face of U.S. health care, creates barriers to transitional planning. Additional barriers develop because this chronic disease is less common in adults, leaving caregivers unprepared to facilitate proper adult treatment. This paper will discuss two common U.S. health care settings where care is provided to adults with thalassemia. It will also offer health care administrators, providers, policy makers, and the thalassemia community at large some recommendations on the provision of comprehensive, quality care to assure the best possible outcomes no matter what setting is available to adult patients living with thalassemia. PMID- 20712801 TI - Ninth Cooley's Anemia Symposium: summary and perspective. AB - The Ninth Cooley's Symposium provided an outstanding summary of progress in the field. Highlights of the conference included the report of clinical benefit in one of two patients treated in a gene therapy trial. Another major breakthrough was the report that the transcriptional factor, BCL11A, is a key molecular component of the gamma-globin silencing mechanism that results in the fetal to adult perinatal switch. The ability to evaluate tissue iron is becoming increasingly more sophisticated, with results presented at this conference indicating that independent measurement of cardiac ferritin and hemosiderin can be achieved with specific MRI sequences. The three available iron chelators, deferoxamine, deferiprone, and deferasirox, provide a potent therapeutic armamentarium so that effective chelation regimens can be devised for most individual patients. Unfortunately, compliance remains a significant issue despite the availability of oral chelators. Modification of conditioning regimens and the use of alternative donor sources have made stem cell transplantation available to an increasing number of patients with progressive improvement in outcome. Despite many advances, the global burden of disease for the thalassemias remains very high, with many challenges that still need to be addressed in order to optimize treatment for the majority of patients. PMID- 20712802 TI - Regional distribution and relative frequency of gastrointestinal endocrine cells in the ddN mice: an immunohistochemical study. AB - The distributions and frequencies of some endocrine cells in the eight portions of the gastrointestinal (GI) tract - fundus, pylorus, duodenum, jejunum, ileum, cecum, colon and rectum of the ddN mouse, were studied with immunohistochemical method using seven types of antisera against chromogranin (Cg) A serotonin, somatostatin, glucagon, gastrin, cholecystokinin (CCK)-8 and human pancreatic polypeptide (hPP). In the GI tract of ddN mice, CgA, serotonin, somatostatin, glucagon, gastrin, CCK-8 immunoreactive (IR) cells were identified with various frequencies, but hPP-IR cells were not observed in this study. Most of IR cells in the intestinal portion were generally spherical or spindle in shape (open type cell) whereas cells showing round in shape (close type cell) were found in the intestinal gland and stomach regions occasionally. They showed the highest frequency in the pylorus or colon. CgA-IR cells were observed from the pylorus to ileum. Serotonin-IR cells were detected throughout the whole GI tract except for the fundus. Somatostatin-IR cells were demonstrated throughout the whole GI tract except for the cecum and colon. Gastrin and CCK-8-IR cells were restricted to the pylorus and duodenum. In addition, a few glucagon-IR cells were restricted to the fundus and rectum. In conclusion, the general distribution patterns and relative frequency of GI endocrine cells of the ddN mouse was similar to that of other strains of mice. However, some strain and/or species-dependent unique distributions and frequencies of endocrine cells were also observed in the present study. PMID- 20712803 TI - Branching patterns of the subclavian arteries in German Shepherd dogs. AB - This study is the first report of the branching pattern of the four major branches of the subclavian artery in German Shepherd dogs. A total 116 subclavian artery casts made of silicon under mean arterial pressure were analysed. The casts were classified according to their branching order and the pattern of the first two branches of the vertebral artery and costocervical trunk. The three subtypes of each major type were based on the branching order or level of the next two branches (the superficial cervical artery and internal thoracic artery). Eleven of 12 possible subtypes were found in the samples. The number of dogs having the same branching subtype of the left and right subclavian arteries was not greater than those having a different subtype. The distance between the first and last branches of the subclavian artery was always longer on the left side than on the right. However, gender-based differences were identified neither in the subtype patterns nor in the distance between the branches. These results suggest a variable branching of the subclavian arteries with frequent differences of the branching pattern on the left and right sides in German Shepherds. PMID- 20712804 TI - Monitoring of intra-operative nociception: skin conductance and surgical stress index versus stress hormone plasma levels. AB - 'Surgical Stress Index' and the 'Number of Fluctuations in Skin Conductance.s-1, use different methods to analyse sympathetic tone and so provide an estimate of peri-operative analgesia. The aim of our study was to investigate the relationship between these methods and stress hormone plasma levels. In 20 patients scheduled for elective surgery, values of the two methods, mean arterial blood pressure, heart rate and blood samples (to measure plasma levels of adrenaline, noradrenaline, adrenocorticotrophic hormone and cortisol) were obtained at five time points. Changes in Surgical Stress Index and the Number of Fluctuations in Skin Conductance.s-1 only partially reflected changes in plasma noradrenaline levels. Surgical Stress Index, heart rate and blood pressure, but not the 'Number of Fluctuations in Skin Conductance.s-1 changed in response to changes in depth of analgesia by showing significant differences between before and after a bolus of fentanyl. However, the overall predictive ability of both methods was poor. PMID- 20712805 TI - A comparison of the respiratory effects of oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation. AB - Oxycodone's respiratory profile (particularly the extent of respiratory depression in comparison to morphine) remains to be fully characterised in the peri-operative period. We randomly assigned ASA 1-2 adults for elective surgery under general anaesthesia to receive saline, morphine 0.1 mg.kg-1, or oxycodone 0.05 mg.kg-1, 0.1 mg.kg-1, or 0.2 mg.kg(-1) . Results were obtained from six patients in the saline group, 12 patients in the groups receiving morphine 0.1 mg.kg-1, oxycodone 0.05 mg.kg-1 and 0.1 mg.kg-1, and from 10 patients who received oxycodone 0.2 mg.kg-1. Patients were breathing spontaneously and minute ventilation monitored with a wet wedge spirometer for 30 min. All active groups demonstrated significant respiratory depression compared to saline (p < 0.0001 for all groups). The mean (SD) reduction in minute volume from baseline was 22.6% (10.4%) for the morphine 0.1 group and 53.3% (27.2%), 74.4% (12.9%) and 88.6% (13.5%) for the oxycodone 0.05, 0.1 and 0.2 groups, respectively, with significant dose dependent differences between oxycodone groups (p = 0.0007). The extent and speed of onset of oxycodone induced respiratory depression was dose dependent and greater than an equivalent dose of morphine. PMID- 20712806 TI - Thyroid autoimmunity and its association with cellular and humoral immunity in women with reproductive failures. AB - PROBLEM: thyroid autoimmunity (TAI), which is T helper (Th)1-cell-mediated autoimmunity to thyrocytes, is associated with increased risk of miscarriages and highly prevalent in women with infertility. We aim at investigating the prevalence of TAI in women with recurrent spontaneous abortions (RSA) or unexplained infertility (UI) and its relationship with cellular and humoral immune abnormalities. METHOD OF STUDY: prevalence of antiphospholipid antibodies, anti-nuclear antibody, other non-organ-specific antibodies (NOSAs; anti-dsDNA, anti-ssDNA, anti-histone, anti-Scl70), peripheral blood natural killer (NK) cell levels (%) and cytotoxicity, and CD3(+) /CD4(+) Th1/Th2 cell ratios were compared in women with and without TAI. Thyroid functional tests (TFT) were analyzed in both groups before and after pregnancy. RESULTS: tumor necrosis factor-alpha/IL 10 expressing CD3(+) /CD4(+) cell ratios (P < 0.05), CD56(+) NK cell levels (P < 0.05), the prevalence of anticardiolipin antibodies (P < 0.05) and other NOSAs (P < 0.005) were significantly higher in women with TAI when compared to women without TAI. Changes in thyroid-stimulating hormone levels between before and after pregnancy in women with TAI were significantly higher when compared to those of women without TAI (P < 0.05). CONCLUSION: TAI is associated with impaired cellular and humoral immune responses in women with RSA or UI. In women with TAI, serial TFT is recommended when pregnancy is established. PMID- 20712807 TI - IL-11 expression in human term placental macrophages. AB - PROBLEM: IL-11 is a cytokine with pleiotropic activities, including gestational effects. Whereas IL-11 production by maternal reproductive tissues is extensively studied, there is poor information about IL-11 sources in the fetal counterpart of the maternal-fetal unit. METHOD OF STUDY: We investigated the expression of IL 11 in the purified human term placenta macrophages, using flow cytometry and immunoenzyme assay. RESULTS: Intracellular IL-11 was detected in a substantial proportion of cultured CD68(+) cells (median 38%). IL-11 secretion by the placental macrophages was observed after 23-hr cultivation (median 4.3 pg/10(5) cells). Stimulation with lipopolysaccharide did not significantly change both intracellular expression and secretion of the cytokine. CONCLUSION: Demonstrated IL-11 expression by placental macrophages suggests that non-trophoblast cells contribute to IL-11 production at the maternal-fetal interface and thus account for the reproductive effects of the cytokine. PMID- 20712809 TI - Immunological paradigms and the pathogenesis of ovine chlamydial abortion. AB - Successful mammalian pregnancy involves complex immunological interactions between the mother and foetus that are not yet fully understood. A number of immunological paradigms have been established to explain the failure of the maternal immune system to reject the semi-allogeneic foetus, mainly based on studies in mice and humans. However, as placental structure, gestation periods and number of concepti per pregnancy can vary greatly between mammals, it is not always clear how applicable these immunological paradigms are to reproduction in other species. Here, we discuss the predictions of three important immunological paradigms in relation to the pathogenesis of ovine enzootic abortion (OEA), a common cause of infectious abortion in sheep and other ruminants. OEA is caused by the intracellular Gram-negative bacterium Chlamydophila abortus that exhibits a tropism for placental trophoblast. The paradigms of particular relevance to the pathogenesis of OEA are as follows: (i) intracellular bacterial infections are controlled by T(H)1-type CD4(+ve) T cells; (ii) indoleamine 2,3-dioxygenase is expressed in the placenta to prevent immunological rejection of the semi allogeneic foetus; and (iii) pregnancy is a maternal T(H)2-type phenomenon. We discuss the relevance and validity of these paradigms for chlamydial abortion and reproductive immunology in sheep. PMID- 20712808 TI - Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis. AB - PROBLEM: Among pregnant women, acquired viral infections with a concurrent bacterial infection is a detrimental factor associated to poor prognosis. We evaluate the effect of a viral infection that does not lead to pre-term labor on the response to low doses of lipopolysaccharide (LPS). Our objectives were (i) to characterize the effect of a viral infection concurrent with exposure to microbial products on pregnancy outcome and (ii) to characterize the placental and fetal immune responses to the viral sensitization to LPS. METHOD: C57B/6 wild type mice were injected with murine gammaherpesvirus 68 (MHV68) at E8.5. Either PBS or LPS was injected i.p. at E15.5. Pregnancy outcome and cytokine/chemokine profile from implantation sites were analyzed by multiplex. RESULTS: LPS treatment of MHV-68-infected animals induced pre-term delivery and fetal death in 100% of the mice. Pre-term labor was characterized by a upregulation of pro inflammatory cytokines and chemokines in both placenta and decidua. Similar profiles were observed from MHV-68-infected human primary trophoblast and trophoblast cell lines in response to LPS. CONCLUSION: We describe for the first time that a sub-clinical viral infection in pregnant mice might sensitize to a bacterial infection leading to pre-term delivery. We propose the 'Double Hit Hypothesis' where the presence of a viral infection enhances the effect of bacterial products during pregnancy leading not only to pre-term labor but likely larger adverse outcomes. PMID- 20712810 TI - The interface of the immune and reproductive systems in the ovary: lessons learned from the corpus luteum of domestic animal models. AB - The dynamic changes that characterize the female reproductive system are regulated by hormones. However, local cell-to-cell interactions may mediate responsiveness of tissues to hormonal signals. The corpus luteum (CL) is an excellent model for understanding how immune cells are recruited into tissues and the role played by those cells in regulating tissue homeostasis or demise. Leukocytes are recruited into the CL throughout its lifespan, and leukocyte derived cytokines have been found in corpora lutea of all species examined. The proinflammatory cytokines inhibit gonadotropin-stimulated steroidogenesis, profoundly stimulate prostaglandin synthesis by luteal cells, and promote apoptosis. However, there is mounting evidence that leukocytes and luteal cells communicate in different ways to maintain homeostasis within the functional CL. Domestic animals have provided important information regarding the presence and role of immune cells in the CL. PMID- 20712811 TI - Are educators at high risk of sub-fertility? A multicenter study. AB - PROBLEM: A high percentage of women schoolteachers having fertility problems were observed by three independent teams. METHOD: Expected percentage of educators was calculated in 4650 sub-fertile women and 2,062,891 women at reproductive age. To explore the possibility that schoolteachers' contact with childhood viral infections results in alterations of peripheral blood natural killer (NK) cells, a multiple linear regression analysis for profession, age, difficulty to conceive, number of abortions/implantation failures (predictor variables) was performed in childless educators (210) and housewives (184). RESULTS: The difference between observed and expected percentage of sub-fertile schoolteachers was statistically significant (17.6% vs 6.86%, P < 0.0001). The mean percentage of PB NK cells was slightly higher in educators compared to housewives (12.48% vs 11.56%, P = 0.10), and the multiple linear regression analysis revealed that the profession (schoolteacher or not) was the only predictive variable for higher NK% values (P = 0.044). CONCLUSION: Teachers' sub-fertility appears as an 'occupational disease'. Tauhe possibility that results from their exposure to childhood viral infections has to be further explored. PMID- 20712812 TI - Peripheral blood cytokine profiling during pregnancy and post-partum periods. AB - PROBLEM: Pregnancy requires that the maternal immune system adapt to prevent rejection of the fetal semi-allograft. This immunologic adaptation may contribute to pregnancy-related alterations in disease susceptibility and severity of infections from viral pathogens such as influenza virus. METHOD OF STUDY: As part of a larger study investigating the maternal systemic immune response during pregnancy, peripheral blood was collected three times during pregnancy and twice post-partum to measure serum levels of 23 cytokines, chemokines, and growth factors. This longitudinal study design allowed each woman's post-partum blood draw to serve as her own comparison, thus controlling for interpersonal variability in expression levels. RESULTS: When compared to the post-partum samples, significant pregnancy-related changes in IFNgamma, TNFalpha, VEGF, GCSF, Eotaxin, and MCP-1 expression were observed. These changes have significant immunologic effects in vivo and in culture. CONCLUSION: Pregnancy-associated changes to steady state serum cytokines may have important immunologic consequence. PMID- 20712813 TI - Political and systemic barriers increasing risk of HIV for injecting drug users in East Africa. PMID- 20712814 TI - Agonist treatment in substance use disorders. PMID- 20712815 TI - Conversation with Jim Orford. PMID- 20712816 TI - Conversation with Martin Jarvis. PMID- 20712817 TI - Sun-downing and integration for the advancement of science and therapeutics: the National Institute on Substance Use Disorders (NISUD). AB - The National Institutes of Health (NIH) is the most prominent funding source for scientific research in the world. It is also a complex and diverse organization, having multiple institutes, centers and offices. NIH emphasizes the need for innovation and collaboration in research to discover critical knowledge, enhance health and prevent disease. Advancement in science requires not only sophisticated methods, but also logical organization. Here, an overview of 'behavioral research' (writ large) at NIH is presented, focusing upon the common trinity of 'alcohol, tobacco/nicotine and other drugs' and programmatic overlap across entities. Consideration is also given to the origins of institutes and their historical movement across organizational boundaries. Specific issues, concerns and advantages of integration of the National Institute on Drug Abuse and National Institute on Alcoholism and Alcohol Abuse are addressed. It is concluded that advances in understanding, treating and preventing substance use disorders would best be served by (1)review and integration of all related research throughout NIH, (2) logical placement of leadership for this activity in a single institute, here entitled the National Institute on Substance Use Disorders, and (3) close collaboration of this institute with its complementary partner, the National Institute on Mental Health. Thus, NIH can establish an organizational structure and collaborations reflecting the realities of the scientific and disease/health domains. This would make a prominent statement to the world scientific and health communities regarding NIH recognition of the need for innovation (scientific and organizational) and focus upon these myriad interrelated and costly problems. PMID- 20712818 TI - Losses disguised as wins in modern multi-line video slot machines. AB - AIMS: Players can wager on multiple lines of modern slot machines. When they spin and fail to gain any credits, the machine goes into a state of relative quiet. By contrast, when they spin and win, these spins are accompanied by reinforcing sights and sounds. Such reinforcement also occurs when the amount won is less than the spin wager. We sought to show that these 'losses disguised as wins', or LDWs, would be as arousing as wins, and more arousing than regular losses. MEASUREMENT AND PARTICIPANTS: We measured skin conductance response (SCR) amplitudes and heart-rate changes following wins, LDWs and losses for 40 novices playing a multi-line slot machine. FINDINGS: SCR amplitudes were similar for wins and LDWs-both were significantly larger than for regular losses. CONCLUSIONS: For novice players, the reinforcing sights and sounds of the slot machine triggered arousal on wins, where the number of credits gained was greater than the spin wager, but also on 'losses disguised as wins' where the amount 'won' was less than the spin wager. Despite the fact that players lost money on these spins, these outcomes were more arousing than regular losses where no credits were gained. Although these findings involve novice players, the heightened arousal associated with these losses may have implications for the development of problem gambling, as arousal has been viewed as a key reinforcer in gambling behaviour. PMID- 20712819 TI - Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. AB - AIMS: Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health care system. METHODS: Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. RESULTS: Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0-29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). CONCLUSION: Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts. PMID- 20712820 TI - Validity of suspected alcohol and drug violations in aviation employees. AB - AIMS: In the United States, transportation employees who are suspected of using alcohol and drugs are subject to reasonable-cause testing. This study aims to assess the validity of suspected alcohol and drug violations in aviation employees. METHODS: Using reasonable-cause testing and random testing data from the Federal Aviation Administration for the years 1995-2005, we calculated the positive predictive value (PPV) and positive likelihood ratio (LR+) of suspected alcohol and drug violations. The true status of violations was based on testing results, with an alcohol violation being defined as a blood alcohol concentration of >=0.04 mg/dl and a drug violation as a test positive for marijuana, cocaine, amphetamines, phencyclidine or opiates. RESULTS: During the 11-year study period, a total of 2284 alcohol tests and 2015 drug tests were performed under the reasonable-cause testing program. The PPV was 37.7% [95% confidence interval (CI), 35.7-39.7%] for suspected alcohol violations and 12.6% (95% CI, 11.2-14.1%) for suspected drug violations. Random testing revealed an overall prevalence of 0.09% for alcohol violations and 0.6% for drug violations. The LR+ was 653.6 (95% CI, 581.7-734.3) for suspected alcohol violations and 22.5 (95% CI, 19.6-25.7) for suspected drug violations. CONCLUSION: The discriminative power of reasonable cause testing suggests that, despite its limited positive predictive value, physical and behavioral observation represents an efficient screening method for detecting alcohol and drug violations. The limited positive predictive value of reasonable-cause testing in aviation employees is due in part to the very low prevalence of alcohol and drug violations. PMID- 20712821 TI - Case studies of tobacco dependence treatment in Brazil, England, India, South Africa and Uruguay. AB - AIMS: The aims of this study are to describe the tobacco dependence treatment systems in five countries at different stages of development of their systems, and from different income levels and regions of the world, and to draw some lessons from their experiences that might be useful to other countries. METHODS AND DATA SOURSES: Data were drawn from an earlier survey of treatment services led by M.R. and A.M., from Party reports to the Secretariat of the Framework Convention on Tobacco Control, and from correspondents in the five countries. These data were entered onto a standard template by the authors, discussed with the correspondents to ensure they were accurate and to help us interpret them, and then the templates were used as a basis to write prose descriptions of the countries' treatment systems, with additional summary data presented in tables. RESULTS: Two of the middle-income countries have based their treatment on specialist support and both consequently have very low population coverage for treatment. Two countries have integrated broad-reach approaches, such as brief advice with intensive specialist support; these countries are focusing currently upon monitoring performance and guaranteeing quality. Cost is a significant barrier to improving treatment coverage and highlights the importance of using existing infrastucture as much as possible. CONCLUSIONS: Perhaps not surprisingly the greatest challenges appear to be faced by large, lower-income countries that have prioritized more intensive but low-reach approaches to treatment, rather than developing basic infrastructure, including brief advice in primary care and quitlines. PMID- 20712822 TI - Empirical support for a multi-dimensional model of sensations experienced by youth during their initial smoking episodes. AB - AIMS: To examine the dimensionality of sensations experienced during initial tobacco smoking. DESIGN: Cross-sectional survey. SETTING: Thirteen secondary schools located in British Columbia, Canada. PARTICIPANTS: Data from 1187 adolescents who responded 'yes' to the question: 'Have you ever tried cigarette smoking, even one or two puffs?'. MEASUREMENTS: Participants answered questions about their demographic characteristics, tobacco smoking history and sensations experienced during their initial smoking episodes. FINDINGS: The sensations appear to represent the following three separate but modestly correlated dimensions: a pleasant dimension defined by feeling good and relaxed; an unpleasant dimension defined by coughing, feeling sick and nervous; and a 'buzz' dimension defined by feeling high and dizzy. The three factors made statistically significant contributions to the prediction of transition to regular smoking (defined as having smoked at least 100 cigarettes in one's life-time) after adjusting for age, sex and age at first puff. CONCLUSIONS: The results suggest that three relatively distinct physiological systems appear to explain the relationship between initial smoking sensations and probability of becoming a regular smoker. Researchers examining sensations experienced during initial tobacco smoking episodes should consider using a three-dimensional profile of symptoms composed of pleasant, unpleasant and buzz dimensions. PMID- 20712823 TI - Dopamine release in ventral striatum of pathological gamblers losing money. AB - OBJECTIVE: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). METHOD: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). RESULTS: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. CONCLUSION: Our findings suggest a dopaminergic basis of monetary losses in pathological gambling, which might explain loss-chasing behavior. The findings may have implications for the understanding of dopamine dysfunctions and impaired decision-making in pathological gambling and substance-related addictions. PMID- 20712824 TI - Childhood trauma and increased stress sensitivity in psychosis. AB - OBJECTIVE: The notion that traumatic experiences in childhood may predict later psychotic outcomes would be strengthened if a plausible mechanism could be demonstrated. Because increased stress sensitivity is part of the behavioural expression of psychosis liability, the possible mediating role of childhood trauma was investigated. METHOD: Fifty patients with psychosis were studied with the experience sampling method to assess stress reactivity in daily life, defined as emotional and psychotic reactivity to stress. Traumatic experiences in childhood were assessed with the Childhood Trauma Questionnaire. RESULTS: A significant interaction was found between stress and CT on both negative affect (event stress: beta = 0.04, P < 0.04; activity stress: beta = 0.12, P < 0.001) and psychotic intensity (event stress: beta = 0.06, P < 0.001; activity stress: beta = 0.11, P < 0.001), showing that a history of CT is associated with increased sensitivity to stress. CONCLUSION: A history of childhood trauma in patients with psychosis is associated with increased stress reactivity later in life, suggestive for an underlying process of behavioural sensitization. PMID- 20712825 TI - Three-year course of clinical symptomatology in young people at ultra high risk for transition to psychosis. AB - OBJECTIVE: The investigation into the course of ultra high risk (UHR) symptomatology of those patients who eventually do not meet the psychosis threshold criteria within the 3-year timeframe of the study. METHOD: The course of UHR symptoms, GAF score and employment status was investigated in 57 patients who did not make a transition to psychosis and who were examined within the Dutch Prediction of Psychosis Study in Amsterdam, the Netherlands. RESULTS: At the 3 year follow-up, 75% of the patients who did not make a transition to psychosis had remitted from UHR status. With a Generalized Estimation Equation Model it was shown that this group recovered from positive (F = 52.7, P < 0.0001), negative (F = 24.3, P < 0.0001), disorganization (F = 14.4, P < 0.0001) and general symptoms (F = 25.0, P < 0.0001) within the timeframe of the study. In addition, the level of global functioning and likelihood of having a job and/or education significantly improved. The largest improvements occurred within the first year. UHR symptoms did not re-occur after improvement. CONCLUSION: With the current UHR criteria, a large percentage of the included subjects appear to have transitory complaints and dysfunctioning. A refinement of the UHR criteria may diminish the chance of including 'false positives' in future UHR studies. PMID- 20712826 TI - Manic episodes are associated with grey matter volume reduction - a voxel-based morphometry brain analysis. AB - OBJECTIVE: To investigate whether the lifetime number of affective episodes or illness duration is associated with changes in local grey matter volume, in patients with bipolar I disorder without comorbid conditions. METHOD: Magnetic resonance imaging scans of 55 patients with bipolar I disorder were analysed using VBM. RESULTS: Smaller grey matter volume in the inferior frontal gyri of the dorsolateral prefrontal cortices (DLPFC) correlated significantly to the lifetime number of manic episodes. No association between local grey matter volume and the lifetime number of depression episodes or illness duration was found. CONCLUSION: We found strong evidence for a linear correlation between a decrease in DLPFC volume and the lifetime number of manic episodes in patients with bipolar I disorder. Interestingly, DLPFC is known to be important for executive functions and the findings in this study might hence be linked to the executive cognitive deficits associated with bipolar disorder. PMID- 20712827 TI - Disrupted theory of mind network processing in response to idea of reference evocation in schizophrenia. AB - OBJECTIVE: This study examined the neural pathophysiology of the theory of mind network by eliciting self-referential processing during an idea of reference evocating situation in patients with schizophrenia. METHOD: Functional MRI was conducted on 14 schizophrenic in-patients with the idea of reference and 15 healthy participants while viewing video vignettes of referential conversations, non-referential conversations or no conversations between two people, which were filmed at varying distances of 1, 5 or 10 m. RESULTS: The patient group did not show normal patterns of superior temporal sulcus activation to conversational context, and reciprocal deactivation and activation of the ventromedial and dorsomedial prefrontal cortex to referential conversational context. Instead, the patient group showed overall greater ventromedial prefrontal activities across different conversational contexts and inverse correlation between superior temporal sulcus activity and delusional severity. Differential activations of the temporal pole and its posterior extension to varying distances were observed in the control group but not in the patient group. CONCLUSION: The present study demonstrates that theory of mind-related responses of the medial prefrontal superior temporal network are attenuated during the self-referential processing in patients with schizophrenia and that these abnormalities may be related to the formation of their referential or persecutory delusion. PMID- 20712828 TI - Experience sampling research in individuals with mental illness: reflections and guidance. AB - OBJECTIVE: The experience sampling method (ESM) represents a valuable way of assessing clinical phenomena in real world settings and across time. Despite its theoretical advantages, using this methodology in psychiatric populations is challenging. This paper acts as a guide to researchers wishing to employ this approach when investigating mental illness. METHOD: The contents represent the opinions of researchers around the United Kingdom and the Netherlands who are experienced at using the ESM. RESULTS: In ESM studies, participants are required to fill in questions about their current thoughts, feelings and experiences when prompted by an electronic device (e.g. a wristwatch, PDA). Entries are typically made at fixed or random intervals over 6 days. This article outlines how to design and validate an ESM diary. We then discuss which sampling procedure to use and how to increase compliance through effective briefing and telephone sessions. Debriefing, data management and analytical issues are considered, before suggestions for future clinical uses of the ESM are made. CONCLUSION: The last decade has seen an increase in the number of studies employing the ESM in clinical research. Further research is needed to examine the optimal equipment and procedure for different clinical groups. PMID- 20712829 TI - Vaccination of children--a systematic review. PMID- 20712831 TI - Antiangiogenic combination therapy after local radiotherapy with topotecan radiosensitizer improved quality of life for children with inoperable brainstem gliomas. PMID- 20712830 TI - Presumed and definite bacteremia in extremely low gestational age newborns. AB - AIM: To explore risk patterns for presumed and definite, early and late neonatal bacteremia. METHODS: We studied 1106 extremely low gestational age newborns who survived until postnatal day 28. We defined early definite bacteremia as a positive bacterial culture in the first week and definite late bacteremia as a positive bacterial culture in week 2, 3 or 4. Bacteremia was presumed if antibiotics were given for more than 72 h despite negative blood cultures. RESULTS: Risk patterns did not differ much for presumed and definite bacteremia in the first postnatal month. While maternal and pregnancy characteristics were associated with early bacteremia, neonatal comorbidities, especially NEC, were the main antecedents/correlates of late bacteremia. All four categories of bacteremia were associated with younger gestational age and lower birth weight. Infants with presumed and definite bacteremia had similar distributions of days of ventilation and oxygenation. CONCLUSION: Definite and presumed late bacteremias have rather similar risk patterns, while those of early and late bacteremia differ appreciably. PMID- 20712832 TI - Paracetamol - accumulating reports of an association with allergy and asthma. PMID- 20712833 TI - Newborn behaviour to locate the breast when skin-to-skin: a possible method for enabling early self-regulation. AB - AIM: The aim of this study was to provide a more detailed analysis of the infant's behavioural sequence that begins immediately after birth and terminates with grasping the nipple, suckling and then falling asleep. METHOD: Twenty-eight full-term infants were videotaped immediately after birth. A video protocol was developed to examine infant behaviours identified from five random videotapes. RESULTS: When birth crying had stopped, the babies showed a short period of relaxation and then successively became alert. They went through an 'awakening phase', an 'active phase' with movements of limbs, rooting activity and looking at the mother's face, a 'crawling phase' with soliciting sounds, a 'familiarization phase' with licking of the areola, and a 'suckling phase' and last a 'sleeping phase'. Five factors related to the time spent to locate the breast: more number of looks at the breast 10-20 min after birth (p < 0.0001); and exposure to meperidine (p = 0.0006) related to increased time. Early start of crawling (p = 0,0040); increased number of 'soliciting sounds' (p = 0.0022); and performing hand-breast-mouth movements (p = 0.0105) related to shorter time. CONCLUSION: Inborn breastfeeding reflexes were depressed at birth, possibly because of a depressed sensory system. It is hypothesized that when the infant is given the option to peacefully go through the nine behavioural phases birth cry, relaxation, awakening, activity, crawling, resting, familiarization, suckling and sleeping when skin-to-skin with its mother this results in early optimal self regulation. PMID- 20712835 TI - Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report. AB - Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3-7 days and recurring every 4-6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C-reactive protein are elevated during the episode, and in addition, high levels of interleukine-1 (IL-1), IL-6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF-alpha inhibitor, and three children with anakinra, IL-1 receptor antagonist. CONCLUSION: This review summarizes currently available data on the use biological medicines for HIDS in children. A Finnish 1.5-year-old patient with disease onset at 6 months of age, treated successfully with anakinra, is presented. PMID- 20712838 TI - Current empirical research in neonatal bioethics. AB - Ethical dilemmas in neonatology can be analysed using both the theoretical tools of analytic philosophy and the empirical tools of clinical epidemiology and health services research. Both yield important insights into ways to think about the ethical issues that arise in clinical neonatology. In this paper, we review recent empirical research in neonatal bioethics. Studies published in the last 5 years shed light on issues that arise in prenatal consultation, prognostication, outcomes, quality-of-life and cost-effectiveness in neonatal intensive care. These studies show ways in which doctors vary in their decisions from country to country, hospital to hospital and for babies and children with different conditions but similar prognoses. Empirical research in bioethics can answer questions about what doctors and parents think and do. It does not answer questions about what they ought to do. CONCLUSION: Good ethics starts with good facts, even if good facts are not sufficient to get us to good ethics. PMID- 20712837 TI - The clustering of disorders in infants born before the 28th week of gestation. AB - AIM: To see whether disorders prevalent in infants born extremely preterm cluster. DESIGN: Observational cohort study. SETTING: University-affiliated newborn intensive care nurseries. SUBJECTS: One thousand two hundred and twenty three infants born before the 28th week of gestation who survived until 36 weeks postmenstrual age when the diagnosis of bronchopulmonary dysplasia (BPD) could be made. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Cerebral white matter damage (an echolucent lesion, or moderate or severe ventriculomegaly on a protocol cranial ultrasound scan), BPD, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and early and late bacteremia. RESULTS: After adjustment for gestational age, children who had severe NEC (Bell stage IIIb) were at increased risk of cerebral white matter damage, severe ROP (stage 3+), and severe BPD (defined as both oxygen and ventilator dependent). Children who had early bacteremia were at increased risk of late bacteremia and severe ROP. Those who had severe ROP were at increased risk of severe BPD and both early and late bacteremia. CONCLUSIONS: Necrotizing enterocolitis is the disorder common to most of the clusters, but we do not know if its onset occurred before the others. Organ-damage-promoting substances, however, have been found in the circulation of newborn animals with bowel inflammation, supporting the view that NEC contributes to the damage of other organs. PMID- 20712839 TI - High-frequency ventilation with the Drager Babylog 8000plus: measuring the delivered frequency. AB - BACKGROUND: Ventilator frequency is one of the determinants of tidal volume delivery during high-frequency ventilation. Clinicians increasingly use data on ventilator displays to inform their decisions. AIM: To measure the frequencies delivered by the Drager Babylog 8000plus ventilator when used in high-frequency mode. METHODS: Ventilator waveforms using a test lung were recorded at the full range of settings 5-20 Hz using Spectra software at 1000 Hz. The changes in frequency produced by a 1-Hz change in set frequency were calculated. Actual and displayed frequencies were compared. RESULTS: For settings up to 12 Hz, median (range) difference between set and delivered frequencies was 0 (-0.4 to +0.1) Hz. Above 12 Hz, delivered frequency varied by -0.3 (-1.9 to +0.3) Hz. For 1-Hz changes in frequency settings, in the range 5-12 Hz, 1-Hz changes produced a change in delivered frequency of 1.0 (0.6-1.4) Hz. Above 12 Hz, the corresponding changes were 0.7 (0-2.9) Hz. The ventilator displays the set frequency during operation rather than the delivered frequency. CONCLUSION: At 12 Hz and below, the differences between set and delivered frequencies were relatively small compared with those at 13 Hz and higher. Above 13 Hz, the difference between set and delivered frequencies was up to 2.9 Hz. Some frequency setting changes did not result in a change in delivered frequency. PMID- 20712840 TI - Change in prevalence of overweight and obesity in Finnish children - comparison between 1974 and 2001. AB - OBJECTIVE: To analyse the possible changes in the prevalence of overweight and obesity comparing birth cohorts from four different decades in Finland. DESIGN: A retrospective longitudinal growth study. METHODS: The subjects representing five birth cohorts: 1974 (n = 1109), 1981 (n = 987), 1991 (n = 586), 1995 (n = 856) and 2001 (n = 766) in the city of Tampere and three rural municipalities in Finland. Data included five consecutive height and weight measurements from 2 to 15 years of age. Normal weight, overweight and obesity at the time points were classified by body mass index (BMI, kg/m(2) ) according to international age- and gender-specific BMI cut-off points. The chi-square test was used to analyse the differences in the between birth cohorts. RESULTS: The combined prevalence of overweight and obesity decreased significantly in 2-year-old boys (p = 0.009) and girls (p = 0.002) from 1974 to 2001. Insignificant fluctuation was seen in 5- and 7-year-old children. Both the prevalence of obesity and the combined prevalence of overweight and obesity showed a significant increase in 12- (p = 0.031 and p < 0.001) and 15-year-old boys (p < 0.001 in both) from the 1970s to 2000s. In girls, the prevalence of obesity as well as the combined prevalence of overweight and obesity increased significantly in the age group of 12 years (p = 0.023), but not in that of 15 years. CONCLUSIONS: During the last three decades, overweight and obesity have become clearly more prevalent in Finnish young adolescents. This trend has been more obvious in boys than in girls. At the same time, 2-year-old children have shown an opposite trend. PMID- 20712841 TI - Acute pancreatitis and child sexual abuse. PMID- 20712842 TI - Coma after spinal anaesthesia in a patient with an unknown intracerebral tumour. AB - Spinal anaesthesia is contraindicated in patients with elevated intracranial pressure or space-occupying intracranial lesions. Drainage of the lumbar cerebrospinal fluid (CSF) can increase the pressure gradient between the spinal, supratentorial and infratentorial compartments. This can result in rapid herniation of the brain stem or occluding hydrocephalus. We present a case of a female patient with an occult brain tumour who received a spinal anaesthesia for an orthopaedic procedure. The primary course of anaesthesia was uneventful. Several hours after surgery, the patient became increasingly disoriented and agitated. The next day, she was found comatose. A computed tomogram of the head revealed herniation of the brain stem, resulting in an occluding hydrocephalus due to a prior not known infratentorial mass. By acute relieving of the intracranial pressure by external CSF drainage, the mass was removed 2 days later. The further post-operative course was uneventful and the patient was discharged from the hospital without neurological deficit 3 weeks after the primary surgery. PMID- 20712843 TI - Ketamine reduce left ventricular systolic and diastolic function in patients with ischaemic heart disease. AB - OBJECTIVE: Ketamine may be followed by a general increase in haemodynamics and oxygen consumption, which may be of concern in patients with ischaemic heart disease. The purpose of this study was to evaluate the effect of ketamine on left ventricular (LV) systolic and diastolic function by different modalities of echocardiography and tissue Doppler imaging in patients with ischaemic heart disease. METHODS AND RESULTS: Prospective observational study of 11 patients acting as own control based on echocardiographic imaging before and after bolus ketamine 0.5 mg/kg. Simpson's 2 D-volumetric method was used to quantify left ventricular volume and ejection fraction. General global LV deformation was assessed by Speckle tracking ultrasound, systolic LV longitudinal displacement was assessed by Tissue Tracking score index and the diastolic function was evaluated from changes in early-(E') and atrial (A') peak velocities during diastole. Average heart rate (34%) and blood pressure (35%) increased significantly after ketamine (P<0.0001). Mean tissue tracking score index decreased from 11.2 +/- 2.3 to 8.3 +/- 2.6 (P=0.005) and Global Speckle tracking 2D strain from 17.7 +/- 2.7 to 13.7 +/- 3.6 (P=0.0014) indicating a decrease in LV global systolic function. The E'/A' ratio decreased from 1.11 +/- 0.43 to 0.81 +/- 0.46 (P=0.044) indicating impaired relaxation. CONCLUSION: Different modalities of echocardiography in combination with tissue Doppler indicate both diminished systolic and diastolic function after ketamine administration in patients with ischaemic heart disease. PMID- 20712844 TI - The effects of methylene blue on ovine post-pneumonectomy pulmonary oedema. AB - BACKGROUND: We recently reported that post-pneumonectomy pulmonary oedema (PPO) occurs after ventilating the remaining lung with excessive tidal volumes. Studies in small animals have indicated that nitric oxide (NO) release increases in hyper inflated lungs, but confirmatory evidence from larger animals is still lacking. We hypothesized that PPO could be prevented by methylene blue (MB), an inhibitor of NO synthase. METHODS: Sheep were subjected to a right-sided pneumonectomy (PE) and randomly assigned to a protectively ventilated group ((PROTV group, n=7) with tidal volumes of 6 ml/kg at 20 inflations/min and a positive end-expiratory pressure (PEEP) of 2 cmH(2)O, and two groups undergoing 'injurious ventilation' (INJV) with tidal volumes of 12 ml/kg and zero end-expiratory pressure (ZEEP), a control group (INJV group, n=7) and a treatment group subjected to MB 1 h after PE (INJV+MB group, n=7). Haemodynamic variables, lung mechanics, blood gases and plasma nitrites and nitrates (NOx) were determined. RESULTS: PE reduced pulmonary blood volume, extravascular lung water (EVLWI) and quasistatic lung compliance in all groups, in parallel with a rise in peak airway pressure (P<0.05). In the INJV group, pulmonary arterial pressure, EVLWI and pulmonary vascular permeability index increased and arterial oxygenation decreased towards cessation of the experiments. These changes were not antagonized by MB. Plasma NOx increased in all the groups compared with baseline, but with no intergroup difference. CONCLUSION: MB did not reduce PPO and accumulation of NOx in sheep subjected to ventilation with excessive tidal volumes and ZEEP. PMID- 20712852 TI - Observer and subject bias: lessons from procrustes. PMID- 20712854 TI - Sleep and recovery in physicians on night call: a longitudinal field study. AB - BACKGROUND: It is well known that physicians' night-call duty may cause impaired performance and adverse effects on subjective health, but there is limited knowledge about effects on sleep duration and recovery time. In recent years occupational stress and impaired well-being among anaesthesiologists have been frequently reported for in the scientific literature. Given their main focus on handling patients with life-threatening conditions, when on call, one might expect sleep and recovery to be negatively affected by work, especially in this specialist group. The aim of the present study was to examine whether a 16-hour night-call schedule allowed for sufficient recovery in anaesthesiologists compared with other physician specialists handling less life-threatening conditions, when on call. METHODS: Sleep, monitored by actigraphy and Karolinska Sleep Diary/Sleepiness Scale on one night after daytime work, one night call, the following first and second nights post-call, and a Saturday night, was compared between 15 anaesthesiologists and 17 paediatricians and ear, nose, and throat surgeons. RESULTS: Recovery patterns over the days after night call did not differ between groups, but between days. Mean night sleep for all physicians was 3 hours when on call, 7 h both nights post-call and Saturday, and 6 h after daytime work (p < 0.001). Scores for mental fatigue and feeling well rested were poorer post-call, but returned to Sunday morning levels after two nights' sleep. CONCLUSIONS: Despite considerable sleep loss during work on night call, and unexpectedly short sleep after ordinary day work, the physicians' self-reports indicate full recovery after two nights' sleep. We conclude that these 16-hour night duties were compatible with a short-term recovery in both physician groups, but the limited sleep duration in general still implies a long-term health concern. These results may contribute to the establishment of safe working hours for night-call duty in physicians and other health-care workers. PMID- 20712855 TI - Downregulation of metastasis suppressor 1(MTSS1) is associated with nodal metastasis and poor outcome in Chinese patients with gastric cancer. AB - BACKGROUND: The putative tumor metastasis suppressor 1(MTSS1) is an actin-binding scaffold protein that has been implicated to play an important role in carcinogenesis and cancer metastasis, yet its role in the development of gastric cancer has not been well illustrated. In this study, we detected MTSS1 expression and explored its clinical significance in gastric cancer. METHODS: Immunohistochemistry was performed using tissue microarrays containing gastric adenocarcinoma specimens from 1,072 Chinese patients with normal adjacent mucosa, primary gastric cancer and lymph node (LN) metastasis and specific antibody against MTSS1. MTSS1 mRNA and protein expression were detected by reverse transcription-polymerase chain reaction and Western blotting. The clinical follow up was done in the 669 patients living in Shanghai that was chose from the 1072 cases. RESULTS: Complete loss of MTSS1 expression was observed in 751 cases (70.1%) of the 1,072 primary tumors and 103 (88%) of 117 nodal metastases; and loss of MTSS1 expression was significantly associated with poorly differentiated tumors, large tumor size, deep invasion level, the presence of nodal metastases and advanced disease stage. Moreover, multivariate analysis demonstrated that loss of MTSS1 expression correlated significantly with poor survival rates (RR = 0.194, 95% CI = 0.144-0.261, P < 0.001). CONCLUSIONS: MTSS1 expression decreased significantly as gastric cancer progressed and metastasized, suggesting MTSS1 may serve as a useful biomarker for the prediction of outcome of gastric cancer. PMID- 20712856 TI - Confusion after spine injury: cerebral fat embolism after traumatic rupture of a Tarlov cyst: case report. AB - BACKGROUND: Acute low back pain is a very common symptom and reason for many medical consultations. In some unusual circumstances it could be linked to a rare aetiology. CASE PRESENTATION: We report a 70-year-old man with an 8-month history of left posterior thigh and leg pain who had sudden confusion after a fall from standing. It was due to cerebral fat embolism suspected by computed tomography scan, later confirmed by brain magnetic resonance imaging (MRI). A spinal MRI scan was then performed and revealed a sacral fracture which drained into an unknown perineurial cyst (Tarlov cyst). Under medical observation the patient fully recovered within three weeks. CONCLUSIONS: Sacral perineurial cysts are rare, however they remain a potential cause of lumbosacral radiculopathy. PMID- 20712857 TI - Recent patterns in chronic disease mortality in remote living Indigenous Australians. AB - BACKGROUND: Despite the well-recognised Indigenous-non-Indigenous health disparity, some reports suggest improvements in Indigenous mortality. Our aim was to quantify Indigenous mortality in Outer Regional (OR), Remote (R), and Very Remote (VR) areas in New South Wales, Queensland, South Australia, Western Australia, and the Northern Territory and changes in mortality from 1998 to 2005. METHODS: We calculated rates, standardized mortality ratios (SMRs) and percentage change in annual rates of Indigenous cardiovascular, diabetes and renal mortality mentioned anywhere on the death certificate by using ICD-10 codes and the 2001 total Australian population as the reference population. RESULTS: In 1998-2001, Indigenous SMRs for all-cause mortality were 241%, 421% and 220% in OR, R and VR, respectively. In 2001-03, corresponding SMRs were 202%, 331% and 176%. Percentage changes (95% confidence interval) in annual all-cause mortality were -3.0% ( 5.3%, -0.7%) in OR, -4.2% (-7.4%, -0.9%) in R and -0.5 (-9.1%, -0.7%) in VR. In 2002-2005, compared with 1998-2001, changes in the number of Indigenous deaths were -147, -195, and -197 in OR, R and VR, respectively. Similar patterns and trends were observed for cardiovascular mortality. CONCLUSIONS: Mortality was elevated about 2-fold in OR, 4-fold in R and 2-fold in VR areas. The downward trend in mortality regardless of remoteness of residence was partly attributable to a decrease in the absolute number of deaths. These patterns were observed for each of the states/territories individually. PMID- 20712858 TI - Repeated reunions and splits feature the highly dynamic evolution of 5S and 35S ribosomal RNA genes (rDNA) in the Asteraceae family. AB - BACKGROUND: In flowering plants and animals the most common ribosomal RNA genes (rDNA) organisation is that in which 35S (encoding 18S-5.8S-26S rRNA) and 5S genes are physically separated occupying different chromosomal loci. However, recent observations established that both genes have been unified to a single 35S 5S unit in the genus Artemisia (Asteraceae), a genomic arrangement typical of primitive eukaryotes such as yeast, among others. Here we aim to reveal the origin, distribution and mechanisms leading to the linked organisation of rDNA in the Asteraceae by analysing unit structure (PCR, Southern blot, sequencing), gene copy number (quantitative PCR) and chromosomal position (FISH) of 5S and 35S rRNA genes in approximately 200 species representing the family diversity and other closely related groups. RESULTS: Dominant linked rDNA genotype was found within three large groups in subfamily Asteroideae: tribe Anthemideae (93% of the studied cases), tribe Gnaphalieae (100%) and in the "Heliantheae alliance" (23%). The remaining five tribes of the Asteroideae displayed canonical non linked arrangement of rDNA, as did the other groups in the Asteraceae. Nevertheless, low copy linked genes were identified among several species that amplified unlinked units. The conserved position of functional 5S insertions downstream from the 26S gene suggests a unique, perhaps retrotransposon-mediated integration event at the base of subfamily Asteroideae. Further evolution likely involved divergence of 26S-5S intergenic spacers, amplification and homogenisation of units across the chromosomes and concomitant elimination of unlinked arrays. However, the opposite trend, from linked towards unlinked arrangement was also surmised in few species indicating possible reversibility of these processes. CONCLUSIONS: Our results indicate that nearly 25% of Asteraceae species may have evolved unusual linked arrangement of rRNA genes. Thus, in plants, fundamental changes in intrinsic structure of rDNA units, their copy number and chromosomal organisation may occur within relatively short evolutionary time. We hypothesize that the 5S gene integration within the 35S unit might have repeatedly occurred during plant evolution, and probably once in Asteraceae. PMID- 20712859 TI - Effect of candesartan monotherapy on lipid metabolism in patients with hypertension: a retrospective longitudinal survey using data from electronic medical records. AB - BACKGROUND: Studies focusing on the add-on effects of angiotensin II type 1 receptor blockers (ARBs) other than their antihypertensive effect are receiving attention. However, the effects of prolonged administration of ARBs on lipid metabolism in clinical cases are unclear. Our aims were to survey the changes in plasma lipid profile in patients with hypertension over a one-year period, and to examine the correlations between these values and the time after the start of ARB monotherapy with candesartan. METHODS: We carried out candesartan monotherapy in patients with mild to moderate hypertension and examined the longitudinal changes in plasma lipid profile. Data from 405 patients for triglyceride (TG), 440 for total cholesterol (TC), 313 for high density lipoprotein cholesterol (HDL-C) and 304 for low density lipoprotein cholesterol (LDL-C) were obtained from the electronic medical records (EMRs) in the Clinical Data Warehouse (CDW) of Nihon University School of Medicine (NUSM). The inverse probability of treatment weighting (IPTW) method (calculated from the inverse of the propensity score) was used to balance the covariates and reduce bias in each treatment duration. Linear mixed effects models were used to analyse the relationship between these longitudinal data of blood examinations and covariates of patient sex, age, diagnosis of diabetes mellitus (DM) and duration of candesartan monotherapy. RESULTS: Plasma HDL-C level was associated with sex, duration of treatment, and interaction of sex and treatment duration, but not with age or diagnosis of DM. HDL-C level was significantly decreased during the 6 approximately 9 months period (p = 0.0218) compared with baseline. TG and TC levels were associated with sex, but not with age, diagnosis of DM or treatment duration. LDL-C level was not associated with any covariate. Analysis of the subjects divided by sex revealed a decrease in HDL-C in female subjects (during the 6 approximately 9 months period: p = 0.0054), but not in male subjects. CONCLUSIONS: Our study revealed that administration of candesartan slightly decreased HDL-C in female subjects. However, TG, TC and LDL-C levels were not influenced by candesartan monotherapy. Candesartan may be safely used for patients with hypertension with respect to lipid metabolism, because the effect of candesartan on lipids may be small. PMID- 20712861 TI - EasyModeller: A graphical interface to MODELLER. AB - BACKGROUND: MODELLER is a program for automated protein Homology Modeling. It is one of the most widely used tool for homology or comparative modeling of protein three-dimensional structures, but most users find it a bit difficult to start with MODELLER as it is command line based and requires knowledge of basic Python scripting to use it efficiently. FINDINGS: The study was designed with an aim to develop of "EasyModeller" tool as a frontend graphical interface to MODELLER using Perl/Tk, which can be used as a standalone tool in windows platform with MODELLER and Python preinstalled. It helps inexperienced users to perform modeling, assessment, visualization, and optimization of protein models in a simple and straightforward way. CONCLUSION: EasyModeller provides a graphical straight forward interface and functions as a stand-alone tool which can be used in a standard personal computer with Microsoft Windows as the operating system. PMID- 20712860 TI - Fetal and life course origins of serum lipids in mid-adulthood: results from a prospective cohort study. AB - BACKGROUND: During the past two decades, the hypothesis of fetal origins of adult disease has received considerable attention. However, critique has also been raised regarding the failure to take the explanatory role of accumulation of other exposures into consideration, despite the wealth of evidence that social circumstances during the life course impact on health in adulthood. The aim of the present prospective cohort study was to examine the contributions of birth weight and life course exposures (cumulative socioeconomic disadvantage and adversity) to dyslipidemia and serum lipids in mid-adulthood. METHODS: A cohort (effective n = 824, 77%) was prospectively examined with respect to self-reported socioeconomic status as well as stressors (e.g., financial strain, low decision latitude, separation, death or illness of a close one, unemployment) at the ages of 16, 21, 30 and 43 years; summarized in cumulative socioeconomic disadvantage and cumulative adversity. Information on birth weight was collected from birth records. Participants were assessed for serum lipids (total cholesterol, low- and high-density lipoprotein cholesterol and triglycerides), apolipoproteins (A1 and B) and height and weight (for the calculation of body mass index, BMI) at age 43. Current health behavior (alcohol consumption, smoking and snuff use) was reported at age 43. RESULTS: Cumulative life course exposures were related to several outcomes; mainly explained by cumulative socioeconomic disadvantage in the total sample (independently of current health behaviors but attenuated by current BMI) and also by cumulative adversity in women (partly explained by current health behavior but not by BMI). Birth weight was related only to triglycerides in women, independently of life course exposures, health behaviors and BMI. No significant association of either exposure was observed in men. CONCLUSIONS: Social circumstances during the life course seem to be of greater importance than birth weight for dyslipidemia and serum lipid levels in adulthood. PMID- 20712862 TI - Who benefits most from mild therapeutic hypothermia in coronary intervention era? A retrospective and propensity-matched study. AB - INTRODUCTION: The aim of the present study was to investigate the impact of the time interval from collapse to return of spontaneous circulation (CPA-ROSC) in cardiac arrest patients and the types of patients who will benefit from therapeutic hypothermia. METHODS: Four hundred witnessed adult comatose survivors of out-of-hospital cardiac arrest of cardiac etiology were enrolled in the study. The favorable neurological outcome was defined as category 1 or 2 on the five point Pittsburgh cerebral performance scale at the time of hospital discharge. A matching process based on the propensity score was performed to equalize potential prognostic factors in the hypothermia and normothermia groups, and to formulate a balanced 1:1 matched cohort study. RESULTS: The rate of favorable neurological outcome was higher (P < 0.05) in the hypothermia group (n = 110) than in the normothermia group in patients with CPA-ROSC of 15 to 20 minutes (64% vs. 17%), 20 to 25 minutes (70% vs. 8%), 25 to 30 minutes (50% vs. 7%), 35 to 40 minutes (27% vs. 0%) and 40 to 45 minutes (29% vs. 2%). A similar association was observed in a propensity-matched cohort, but the differences were not significant. There was no significant difference in the rate of favorable neurological outcome between the hypothermia-matched group and the normothermia matched group. In the patients whose CPA-ROSC was greater than 15 minutes, however, the rate of favorable neurological outcome was higher in the hypothermia matched group than in the normothermia-matched group (27% vs. 4%, P < 0.001). In multivariate analysis, the CPA-ROSC was an independent predictor of favorable neurological outcome (every 1 minute: odds ratio = 0.89, 95% confidence interval = 0.85 to 0.92, P < 0.001). CONCLUSIONS: The CPA-ROSC is an independent predictor of neurological outcome. Therapeutic hypothermia is more beneficial in comatose survivors of cardiac arrest with CPA-ROSC greater than 15 minutes. PMID- 20712863 TI - Integration of metabolic databases for the reconstruction of genome-scale metabolic networks. AB - BACKGROUND: Genome-scale metabolic reconstructions have been recognised as a valuable tool for a variety of applications ranging from metabolic engineering to evolutionary studies. However, the reconstruction of such networks remains an arduous process requiring a high level of human intervention. This process is further complicated by occurrences of missing or conflicting information and the absence of common annotation standards between different data sources. RESULTS: In this article, we report a semi-automated methodology aimed at streamlining the process of metabolic network reconstruction by enabling the integration of different genome-wide databases of metabolic reactions. We present results obtained by applying this methodology to the metabolic network of the plant Arabidopsis thaliana. A systematic comparison of compounds and reactions between two genome-wide databases allowed us to obtain a high-quality core consensus reconstruction, which was validated for stoichiometric consistency. A lower level of consensus led to a larger reconstruction, which has a lower quality standard but provides a baseline for further manual curation. CONCLUSION: This semi automated methodology may be applied to other organisms and help to streamline the process of genome-scale network reconstruction in order to accelerate the transfer of such models to applications. PMID- 20712864 TI - Deoxysphingoid bases as plasma markers in diabetes mellitus. AB - BACKGROUND: Sphingoid bases are formed from the precursors L-serine and palmitoyl CoA-a reaction which is catalyzed by the serine-palmitoyltransferase (SPT). SPT metabolizes, besides palmitoyl-CoA also other acyl-CoAs but shows also variability towards the use of other amino acid substrates. The enzyme is also able to metabolize alanine, which results in the formation of an atypical deoxy sphingoid base (DSB). This promiscuous activity is greatly increased in the case of the sensory neuropathy HSAN1, and pathologically elevated DSB levels have been identified as the cause of this disease. Clinically, HSAN1 shows a pronounced similarity to the diabetic sensory neuropathy (DSN), which is the most common chronic complication of diabetes mellitus. Since serine and alanine metabolism is functionally linked to carbohydrate metabolism by their precursors 3 phosphoglycerate and pyruvate, we were interested to see whether the levels of certain sphingoid base metabolites are altered in patients with diabetes. RESULTS: In a case-control study we compared plasma sphingoid base levels between healthy and diabetic individuals. DSB levels were higher in the diabetic group whereas C16 and C18 sphingoid bases were not significantly different. Plasma serine, but not alanine levels were lower in the diabetic group. A subsequent lipoprotein fractionation showed that the DSBs are primarily present in the LDL and VLDL fraction. CONCLUSION: Our results suggest that DSBs are a novel category of plasma biomarkers in diabetes which reflect functional impairments of carbohydrate metabolism. Furthermore, elevated DSB levels as we see them in diabetic patients might also contribute to the progression of the diabetic sensory neuropathy, the most frequent complication of diabetes. PMID- 20712865 TI - Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness. AB - INTRODUCTION: In this study we aimed to investigate whether there are indications of premature atherosclerosis, as measured by endothelial dependent flow-mediated dilation (ED-FMD) and intima media thickness (IMT), in patients with very early RA, and to analyze its relation to biomarkers of endothelial dysfunction, taking inflammation and traditional cardiovascular disease (CVD) risk factors into account. METHODS: Patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study of CVD co-morbidity. Of these, all patients aged <=60 years were consecutively included in this survey of CVD risk factors (n = 79). Forty-four age and sex matched controls were included. IMT of common carotid artery and ED-FMD of brachial artery were measured using ultrasonography. Blood was drawn for analysis of lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA)-mass, VonWillebrand factor (VWF), soluble intercellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), sE-selectin, sL-selectin and monocyte chemotactic protein-1 (MCP-1). In a subgroup of 27 RA patients and their controls the ultrasound measurements were reanalysed after 18 months. RESULTS: There were no significant differences between RA patients and controls in terms of IMT or ED-FMD at the first evaluation. However after 18 months there was a significant increase in the IMT among the patients with RA (P < 0.05). Patients with RA had higher levels of VWF, sICAM-1 (P < 0.05) and of MCP-1 (P = 0.001) compared with controls. In RA, IMT was related to some of the traditional CVD risk factors, tPA-mass, VWF (P < 0.01) and MCP-1 and inversely to sL-selectin (P < 0.05). In RA, ED-FMD related to sL-selectin (P < 0.01). DAS28 at baseline was related to PAI-1, tPA-mass and inversely to sVCAM-1 (P < 0.05) and sL-selectin (P = 0.001). CONCLUSIONS: We found no signs of atherosclerosis in patients with newly diagnosed RA compared with controls. However, in patients with early RA, IMT and ED-FMD were, to a greater extent than in controls, related to biomarkers known to be associated with endothelial dysfunction and atherosclerosis. After 18 months, IMT had increased significantly in RA patients but not in controls. PMID- 20712866 TI - Factors associated with underutilization of antenatal care services in Indonesia: results of Indonesia Demographic and Health Survey 2002/2003 and 2007. AB - BACKGROUND: Antenatal care aims to prevent maternal and perinatal mortality and morbidity. In Indonesia, at least four antenatal visits are recommended during pregnancy. However, this service has been underutilized. This study aimed to examine factors associated with underutilization of antenatal care services in Indonesia. METHODS: We used data from Indonesia Demographic and Health Survey (IDHS) 2002/2003 and 2007. Information of 26,591 singleton live-born infants of the mothers' most recent birth within five years preceding each survey was examined. Twenty-three potential risk factors were identified and categorized into four main groups, external environment, predisposing, enabling, and need factors. Logistic regression models were used to examine the association between all potential risk factors and underutilization of antenatal services. The Population Attributable Risk (PAR) was calculated for selected significant factors associated with the outcome. RESULTS: Factors strongly associated with underutilization of antenatal care services were infants from rural areas and from outer Java-Bali region, infants from low household wealth index and with low maternal education level, and high birth rank infants with short birth interval of less than two years. Other associated factors identified included mothers reporting distance to health facilities as a major problem, mothers less exposed to mass media, and mothers reporting no obstetric complications during pregnancy. The PAR showed that 55% of the total risks for underutilization of antenatal care services were attributable to the combined low household wealth index and low maternal education level. CONCLUSIONS: Strategies to increase the accessibility and availability of health care services are important particularly for communities in rural areas. Financial support that enables mothers from poor households to use health services will be beneficial. Health promotion programs targeting mothers with low education are vital to increase their awareness about the importance of antenatal services. PMID- 20712867 TI - Determination of reference genes for circadian studies in different tissues and mouse strains. AB - BACKGROUND: Circadian rhythms have a profound effect on human health. Their disruption can lead to serious pathologies, such as cancer and obesity. Gene expression studies in these pathologies are often studied in different mouse strains by quantitative real time polymerase chain reaction (qPCR). Selection of reference genes is a crucial step of qPCR experiments. Recent studies show that reference gene stability can vary between species and tissues, but none has taken circadian experiments into consideration. RESULTS: In the present study the expression of ten candidate reference genes (Actb, Eif2a, Gapdh, Hmbs, Hprt1, Ppib, Rn18s, Rplp0, Tbcc and Utp6c) was measured in 131 liver and 97 adrenal gland samples taken from three mouse strains (C57BL/6JOlaHsd, 129Pas plus C57BL/6J and Crem KO on 129Pas plus C57BL/6J background) every 4 h in a 24 h period. Expression stability was evaluated by geNorm and NormFinder programs. Differences in ranking of the most stable reference genes were observed both between individual mouse strains as well as between tissues within each mouse strain. We show that selection of reference gene (Actb) that is often used for analyses in individual mouse strains leads to errors if used for normalization when different mouse strains are compared. We identified alternative reference genes that are stable in these comparisons. CONCLUSIONS: Genetic background and circadian time influence the expression stability of reference genes. Differences between mouse strains and tissues should be taken into consideration to avoid false interpretations. We show that the use of a single reference gene can lead to false biological conclusions. This manuscript provides a useful reference point for researchers that search for stable reference genes in the field of circadian biology. PMID- 20712868 TI - Combined measurement of soluble and cellular ICAM-1 among children with Plasmodium falciparum malaria in Uganda. AB - BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a cytoadhesion molecule implicated in the pathogenesis of Plasmodium falciparum malaria. Elevated levels of soluble ICAM-1 (sICAM-1) have previously been reported with increased malaria disease severity. However, studies have not yet examined both sICAM-1 concentrations and monocyte ICAM-1 expression in the same cohort of patients. To better understand the relationship of soluble and cellular ICAM-1 measurements in malaria, both monocyte ICAM-1 expression and sICAM-1 concentration were measured in children with P. falciparum infection exhibiting a spectrum of clinical severity. METHODS: Samples were analysed from 160 children, aged 0.5 to 10.8 years, with documented P. falciparum malaria in Kampala, Uganda. The patients belonged to one of three pre-study defined groups: uncomplicated malaria (UM), severe non-fatal malaria (SM-s), and fatal malaria (SM-f). Subset analysis was done on those with cerebral malaria (CM) or severe malaria anaemia (SMA). Monocyte ICAM-1 was measured by flow cytometry. sICAM-1 was measured by enzyme immunoassay. RESULTS: Both sICAM-1 and monocyte cell-surface ICAM-1 followed a log-normal distribution. Median sICAM-1 concentrations increased with greater severity-of-illness: 279 ng/mL (UM), 462 ng/mL (SM-s), and 586 ng/mL (SM-f), p < 0.0001. sICAM-1 levels were not statistically different among children with CM compared to SMA. Monocyte ICAM-1 expression was significantly higher in cases of UM compared with SM-s or SM-f (p < 0.001) and was higher among the subset of patients with CM compared with SMA, p < 0.0014. The combination of sICAM-1 and cellular ICAM-1 identified distinct categories of patients (UM with low sICAM-1 and higher monocyte ICAM-1, CM with both sICAM-1 and monocyte ICAM-1 high, and SMA with sICAM-1 high but monocyte ICAM-1 low). CONCLUSION: In this cohort of children with P. falciparum malaria, sICAM-1 levels were associated with severity of-illness. Patients with UM had higher monocyte ICAM-1 expression consistent with a role for monocyte ICAM-1 in immune clearance during non-severe malaria. Among the subsets of patients with either SMA or CM, monocyte ICAM-1 levels were higher in CM, consistent with the role of ICAM-1 as a marker of cytoadhesion. Categories of disease in pediatric malaria may exhibit specific combinations of soluble and cellular ICAM-1 expression. PMID- 20712869 TI - Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. AB - BACKGROUND: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment. METHODS: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit. RESULTS: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] or = 15 cm2 (92.3% vs. 73.7%; P = 0.009). They also had a greater 3-year distant metastasis-free survival (94% vs.75%; P = 0.034). CONCLUSION: The predictive ability of BDMprn was validated in a separate NPC cohort. A BDMprn of 15 cm2 can be used to separate NPC patients into high- and low-risk groups and predict survival rates and metastasis potential. It can, therefore, be used as a reference to design clinical trials, predict prognosis, and make treatment decisions. PMID- 20712872 TI - The correlation of osteoporosis to clinical features: a study of 4382 female cases of a hospital cohort with musculoskeletal symptoms in southwest China. AB - BACKGROUND: By analyzing the clinical features and risk factors in female patients with musculoskeletal symptoms of Southwest China, this report presents the initial analysis of characteristics in this region and compared with international evaluative criteria. METHODS: Diagnosis of osteoporosis (OP) was made in female hospital patients age > or = 18 years admitted from January 1998 to December 2008 according to WHO definition. Case data were analyzed by symptoms, age, disease course and risk factors to reveal correlation with diagnosis of OP. Logistic regression was used to identify the risks of osteoporosis. RESULTS: A total of 4382 patients were included in the analysis of the baseline characteristics, among which 1455 in the OP group and 2927 in the non-OP group. The morbidity of OP is significantly increased in females' > or = 50 years. Both groups had symptoms related to pain and numbness; no significant difference was found in reported upper and lower back pain, or leg pain between two groups (p > 0.05). Neck, shoulder and arm pain, leg and arm numbness were more common in the non-osteoporosis group (p < 0.05, OR < 1, and upper limit of 95% CI of OR < 1). Hypertension, diabetes, hyperostosis were major risk factors for the patients with OP. The most common lifestyle-related risk factors for osteoporosis were smoking, body mass index, lack of physical activity and menopause. CONCLUSIONS: The present study offers the first reference data of the relationship between epidemiologic distribution of osteoporosis and associated factors in adults Chinese women. These findings provide a theoretical basis for its prevention and treatment in developing country. PMID- 20712873 TI - Exploring the impact of mentoring functions on job satisfaction and organizational commitment of new staff nurses. AB - BACKGROUND: Although previous studies proved that the implementation of mentoring program is beneficial for enhancing the nursing skills and attitudes, few researchers devoted to exploring the impact of mentoring functions on job satisfaction and organizational commitment of new nurses. In this research we aimed at examining the effects of mentoring functions on the job satisfaction and organizational commitment of new nurses in Taiwan's hospitals. METHODS: We employed self-administered questionnaires to collect research data and select new nurses from three regional hospitals as samples in Taiwan. In all, 306 nurse samples were obtained. We adopted a multiple regression analysis to test the impact of the mentoring functions. RESULTS: Results revealed that career development and role modeling functions have positive effects on the job satisfaction and organizational commitment of new nurses; however, the psychosocial support function was incapable of providing adequate explanation for these work outcomes. CONCLUSION: It is suggested in this study that nurse managers should improve the career development and role modeling functions of mentoring in order to enhance the job satisfaction and organizational commitment of new nurses. PMID- 20712874 TI - Sperm protein 17 is highly expressed in endometrial and cervical cancers. AB - BACKGROUND: Sperm protein 17 (Sp17) is a highly conserved mammalian protein in the testis and spermatozoa and has been characterized as a tumor-associated antigen in a variety of human malignancies. Many studies have examined the role of Sp17 in tumorigenesis and the migration of malignant cells. It has been proposed as a useful target for tumor-vaccine strategies and a novel marker to define tumor subsets and predict drug response. This study aimed to investigate the expression of Sp17 in endometrial and cervical cancer specimens, its possible correlation with the pathological characteristics, and its value in the diagnosis and immunotherapy of the related cancers. METHODS: The monoclonal antibodies against human Sp17 were produced as reagents for the analysis and immunohistochemistry was used to study two major kinds of paraffin-embedded gynecological cancer specimens, including 50 cases of endometrial cancer (44 adenous and 6 adenosquamous) and 31 cases of cervical cancer (15 adenous and 16 squamous). Normal peripheral endometrial and cervical tissues were used as controls. RESULTS: Sp17 was found in 66% (33/50) of the patients with endometrial cancer and 61% (19/31) of those with cervical cancer. Its expression was found in a heterogeneous pattern in the cancer tissues. The expression was not correlated with the histological subtype and grade of malignancy, but the staining patterns were different in endometrial and cervical cancers. The hyperplastic glands were positive for Sp17 in the normal peripheral endometrial and cervical tissues in 10% (8/81) of the patients. CONCLUSIONS: Sp17 is highly expressed in human endometrial and cervical cancers in a heterogeneous pattern. Although the expression frequency of Sp17 is not correlated with the histological subtype, the staining pattern may help to define endometrial and cervical cancers. Sp17 targeted immunotherapy of tumors needs more accurate validation. PMID- 20712875 TI - PET-CT staging of the neck in cancers of the oropharynx: patterns of regional and retropharyngeal nodal metastasis. AB - OBJECTIVE: To study the retropharyngeal lymph node status (RPLN) by pretreatment PET-CT imaging in patients with squamous cell carcinomas of the oropharynx (OPSCC). STUDY DESIGN: Retrospective. METHODS: 101 patients with a biopsy proven OPSCC were identified. 53 patients meeting inclusion criteria were further analyzed. RESULTS: The frequency of RPLN was 20.8% (11/53). Advanced T stage cancer (OR = 5.6250, 95% CI: 1.06 - 29.80, p = 0.0410) and advanced clinical N stage cancer (i.e. N2+) had higher odds (OR = 3.9773, 95% CI: 0.9628 - 16.4291) of being RPLN positive as compared to N0-1 patients. CONCLUSIONS: Pre-treatment PET-CT can be used as a staging tool to aid in treatment planning of OPSCC, as rates of RPLN and nodal metastasis are consistent with those reported in the literature. Advanced T and N stage are associated with a greater odds ratio of being RPLN positive by PET-CT imaging. PMID- 20712876 TI - Examining appropriate diagnosis and treatment of malaria: availability and use of rapid diagnostic tests and artemisinin-based combination therapy in public and private health facilities in south east Nigeria. AB - BACKGROUND: Rapid diagnostic tests (RDTs) and Artemisinin-based combination therapy (ACT) have been widely advocated by government and the international community as cost-effective tools for diagnosis and treatment of malaria. ACTs are now the first line treatment drug for malaria in Nigeria and RDTs have been introduced by the government to bridge the existing gaps in proper diagnosis. However, it is not known how readily available these RDTs and ACTs are in public and private health facilities and whether health workers are actually using them. Hence, this study investigated the levels of availability and use of RDTs and ACTs in these facilities. METHODS: The study was undertaken in Enugu state, southeast Nigeria in March 2009. Data was collected from heads of 74 public and private health facilities on the availability and use of RDTs and ACTs. Also, the availability of RDTs and the types of ACTs that were available in the facilities were documented. RESULTS: Only 31.1% of the health facilities used RDTs to diagnose malaria. The majority used the syndromic approach. However, 61.1% of healthcare providers were aware of RDTs. RDTs were available in 53.3% of the facilities. Public health facilities and health facilities in the urban areas were using RDTs more and these were mainly bought from pharmacy shops and supplied by NGOs. The main reasons given for non use are unreliability of RDTs, supply issues, costs, preference for other methods of diagnosis and providers' ignorance. ACTs were the drug of choice for most public health facilities and the drugs were readily available in these facilities. CONCLUSION: Although many providers were knowledgeable about RDTs, not many facilities used it. ACTS were readily available and used in public but not private health facilities. However, the reported use of ACTs with limited proper diagnosis implies that there could be high incidence of inappropriate case management of malaria which can also increase the economic burden of illnesses. Government and donors should ensure constant availability of RDTs in both public and private facilities, so that every treatment with ACTs is accompanied with proper diagnosis. PMID- 20712877 TI - Idiopathic toe walking and sensory processing dysfunction. AB - BACKGROUND: It is generally understood that toe walking involves the absence or limitation of heel strike in the contact phase of the gait cycle. Toe walking has been identified as a symptom of disease processes, trauma and/or neurogenic influences. When there is no obvious cause of the gait pattern, a diagnosis of idiopathic toe walking (ITW) is made. Although there has been limited research into the pathophysiology of ITW, there has been an increasing number of contemporary texts and practitioner debates proposing that this gait pattern is linked to a sensory processing dysfunction (SPD). The purpose of this paper is to examine the literature and provide a summary of what is known about the relationship between toe walking and SPD. METHOD: Forty-nine articles were reviewed, predominantly sourced from peer reviewed journals. Five contemporary texts were also reviewed. The literature styles consisted of author opinion pieces, letters to the editor, clinical trials, case studies, classification studies, poster/conference abstracts and narrative literature reviews. Literature was assessed and graded according to level of evidence. RESULTS: Only one small prospective, descriptive study without control has been conducted in relation to idiopathic toe walking and sensory processing. A cross-sectional study into the prevalence of idiopathic toe walking proposed sensory processing as being a reason for the difference. A proposed link between ITW and sensory processing was found within four contemporary texts and one conference abstract. CONCLUSION: Based on the limited conclusive evidence available, the relationship between ITW and sensory processing has not been confirmed. Given the limited number and types of studies together with the growing body of anecdotal evidence it is proposed that further investigation of this relationship would be advantageous. PMID- 20712878 TI - Bioelectrical impedance analysis in clinical practice: implications for hepatitis C therapy BIA and hepatitis C. AB - BACKGROUND: Body composition analysis using phase angle (PA), determined by bioelectrical impedance analysis (BIA), reflects tissue electrical properties and has prognostic value in liver cirrhosis. Objective of this prospective study was to investigate clinical use and prognostic value of BIA-derived phase angle and alterations in body composition for hepatitis C infection (HCV) following antiviral therapy. METHODS: 37 consecutive patients with HCV infection were enrolled, BIA was performed, and PA was calculated from each pair of measurements. 22 HCV genotype 3 patients treated for 24 weeks and 15 genotype 1 patients treated for 48 weeks, were examined before and after antiviral treatment and compared to 10 untreated HCV patients at 0, 24, and 48 weeks. Basic laboratory data were correlated to body composition alterations. RESULTS: Significant reduction in body fat (BF: 24.2 +/- 6.7 kg vs. 19.9 +/- 6.6 kg, genotype 1; 15.4 +/- 10.9 kg vs. 13.2 +/- 12.1 kg, genotype 3) and body cell mass (BCM: 27.3 +/- 6.8 kg vs. 24.3 +/- 7.2 kg, genotype 1; 27.7 +/- 8.8 kg vs. 24.6 +/- 7.6 kg, genotype 3) was found following treatment. PA in genotype 3 patients was significantly lowered after antiviral treatment compared to initial measurements (5.9 +/- 0.7 degrees vs. 5.4 +/- 0.8 degrees). Total body water (TBW) was significantly decreased in treated patients with genotype 1 (41.4 +/- 7.9 l vs. 40.8 +/- 9.5 l). PA reduction was accompanied by flu-like syndromes, whereas TBW decline was more frequently associated with fatigue and cephalgia. DISCUSSION: BIA offers a sophisticated analysis of body composition including BF, BCM, and TBW for HCV patients following antiviral regimens. PA reduction was associated with increased adverse effects of the antiviral therapy allowing a more dynamic therapy application. PMID- 20712880 TI - Gene-knockdown in the honey bee mite Varroa destructor by a non-invasive approach: studies on a glutathione S-transferase. AB - BACKGROUND: The parasitic mite Varroa destructor is considered the major pest of the European honey bee (Apis mellifera) and responsible for declines in honey bee populations worldwide. Exploiting the full potential of gene sequences becoming available for V. destructor requires adaptation of modern molecular biology approaches to this non-model organism. Using a mu-class glutathione S-transferase (VdGST-mu1) as a candidate gene we investigated the feasibility of gene knockdown in V. destructor by double-stranded RNA-interference (dsRNAi). RESULTS: Intra haemocoelic injection of dsRNA-VdGST-mu1 resulted in 97% reduction in VdGST-mu1 transcript levels 48 h post-injection compared to mites injected with a bolus of irrelevant dsRNA (LacZ). This gene suppression was maintained to, at least, 72 h. Total GST catalytic activity was reduced by 54% in VdGST-mu1 gene knockdown mites demonstrating the knockdown was effective at the translation step as well as the transcription steps. Although near total gene knockdown was achieved by intra haemocoelic injection, only half of such treated mites survived this traumatic method of dsRNA administration and less invasive methods were assessed. V. destructor immersed overnight in 0.9% NaCl solution containing dsRNA exhibited excellent reduction in VdGST-mu1 transcript levels (87% compared to mites immersed in dsRNA-LacZ). Importantly, mites undergoing the immersion approach had greatly improved survival (75-80%) over 72 h, approaching that of mites not undergoing any treatment. CONCLUSIONS: Our findings on V. destructor are the first report of gene knockdown in any mite species and demonstrate that the small size of such organisms is not a major impediment to applying gene knockdown approaches to the study of such parasitic pests. The immersion in dsRNA solution method provides an easy, inexpensive, relatively high throughput method of gene silencing suitable for studies in V. destructor, other small mites and immature stages of ticks. PMID- 20712881 TI - High-throughput SNP discovery and assay development in common bean. AB - BACKGROUND: Next generation sequencing has significantly increased the speed at which single nucleotide polymorphisms (SNPs) can be discovered and subsequently used as molecular markers for research. Unfortunately, for species such as common bean (Phaseolus vulgaris L.) which do not have a whole genome sequence available, the use of next generation sequencing for SNP discovery is much more difficult and costly. To this end we developed a method which couples sequences obtained from the Roche 454-FLX system (454) with the Illumina Genome Analyzer (GA) for high-throughput SNP discovery. RESULTS: Using a multi-tier reduced representation library we discovered a total of 3,487 SNPs of which 2,795 contained sufficient flanking genomic sequence for SNP assay development. Using Sanger sequencing to determine the validation rate of these SNPs, we found that 86% are likely to be true SNPs. Furthermore, we designed a GoldenGate assay which contained 1,050 of the 3,487 predicted SNPs. A total of 827 of the 1,050 SNPs produced a working GoldenGate assay (79%). CONCLUSIONS: Through combining two next generation sequencing techniques we have developed a method that allows high-throughput SNP discovery in any diploid organism without the need of a whole genome sequence or the creation of normalized cDNA libraries. The need to only perform one 454 run and one GA sequencer run allows high-throughput SNP discovery with sufficient sequence for assay development to be performed in organisms, such as common bean, which have limited genomic resources. PMID- 20712879 TI - The dominant Anopheles vectors of human malaria in the Americas: occurrence data, distribution maps and bionomic precis. AB - BACKGROUND: An increasing knowledge of the global risk of malaria shows that the nations of the Americas have the lowest levels of Plasmodium falciparum and P. vivax endemicity worldwide, sustained, in part, by substantive integrated vector control. To help maintain and better target these efforts, knowledge of the contemporary distribution of each of the dominant vector species (DVS) of human malaria is needed, alongside a comprehensive understanding of the ecology and behaviour of each species. RESULTS: A database of contemporary occurrence data for 41 of the DVS of human malaria was compiled from intensive searches of the formal and informal literature. The results for the nine DVS of the Americas are described in detail here. Nearly 6000 occurrence records were gathered from 25 countries in the region and were complemented by a synthesis of published expert opinion range maps, refined further by a technical advisory group of medical entomologists. A suite of environmental and climate variables of suspected relevance to anopheline ecology were also compiled from open access sources. These three sets of data were then combined to produce predictive species range maps using the Boosted Regression Tree method. The predicted geographic extent for each of the following species (or species complex*) are provided: Anopheles (Nyssorhynchus) albimanus Wiedemann, 1820, An. (Nys.) albitarsis*, An. (Nys.) aquasalis Curry, 1932, An. (Nys.) darlingi Root, 1926, An. (Anopheles) freeborni Aitken, 1939, An. (Nys.) marajoara Galvao & Damasceno, 1942, An. (Nys.) nuneztovari*, An. (Ano.) pseudopunctipennis* and An. (Ano.) quadrimaculatus Say, 1824. A bionomics review summarising ecology and behaviour relevant to the control of each of these species was also compiled. CONCLUSIONS: The distribution maps and bionomics review should both be considered as a starting point in an ongoing process of (i) describing the distributions of these DVS (since the opportunistic sample of occurrence data assembled can be substantially improved) and (ii) documenting their contemporary bionomics (since intervention and control pressures can act to modify behavioural traits). This is the first in a series of three articles describing the distribution of the 41 global DVS worldwide. The remaining two publications will describe those vectors found in (i) Africa, Europe and the Middle East and (ii) in Asia. All geographic distribution maps are being made available in the public domain according to the open access principles of the Malaria Atlas Project. PMID- 20712883 TI - Guilt by association - what is the true risk of malignancy in children treated with etanercept for JIA? AB - Recently, the Food and Drug Administration placed a "black box" label on etanercept, and other tumor necrosis factor inhibitors used to treat childhood arthritis, warning of the risk of malignancies. The Food and Drug Administration made their decision based on a review of 48 cases of malignancies identified worldwide in children treated with tumor necrosis factor inhibitors for inflammatory bowel disease, sarcoidosis, and juvenile idiopathic arthritis. Recently, an article in Pediatric Rheumatology demonstrated that there may not be an increased risk of cancer in children with juvenile idiopathic arthritis treated specifically with the tumor necrosis factor receptor fusion protein, etanercept. There are many confounding issues regarding whether or not etanercept increases the risk of malignancy, specifically lymphomas, above the background rate of cancer in children with juvenile idiopathic arthritis who are not being treated with biologic agents. Whether or not it was appropriate for the Food and Drug Administration to lump cancer patients with underlying granulomatous diseases (inflammatory bowel disease and sarcoidosis) with children with juvenile idiopathic arthritis is explored herein. Moreover, the amalgamation of etanercept with anti-tumor necrosis factor monoclonal antibodies (adalimumab and infliximab) is another point of contention. What is clear is that there is much that is currently unknown to be able to convincingly demonstrate a substantial risk of cancer in children with juvenile idiopathic arthritis treated with etanercept. Conversely, there is ample evidence demonstrating remarkable benefit of etanercept in treating juvenile idiopathic arthritis. Physicians treating childhood arthritis should weigh these potential risks and benefits with patients and their families discussing the current limitations in available data regarding the risk of cancer in children treated with etanercept for juvenile idiopathic arthritis. PMID- 20712882 TI - Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations. AB - INTRODUCTION: Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers. METHODS: We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data. RESULTS: Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma. CONCLUSIONS: These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features. PMID- 20712884 TI - Thyroid function tests in patients taking thyroid medication in Germany: Results from the population-based Study of Health in Pomerania (SHIP). AB - BACKGROUND: Studies from iodine-sufficient areas have shown that a high proportion of patients taking medication for thyroid diseases have thyroid stimulating hormone (TSH) levels outside the reference range. Next to patient compliance, inadequate dosing adjustment resulting in under- and over-treatment of thyroid disease is a major cause of poor therapy outcomes. Using thyroid function tests, we aim to measure the proportions of subjects, who are under- or over-treated with thyroid medication in a previously iodine-deficient area. FINDINGS: Data from 266 subjects participating in the population-based Study of Health in Pomerania (SHIP) were analysed. All subjects were taking thyroid medication. Serum TSH levels were measured using immunochemiluminescent procedures. TSH levels of < 0.27 or > 2.15 mIU/L in subjects younger than 50 years and < 0.19 or > 2.09 mIU/L in subjects 50 years and older, were defined as decreased or elevated, according to the established reference range for the specific study area. Our analysis revealed that 56 of 190 (29.5%) subjects treated with thyroxine had TSH levels outside the reference range (10.0% elevated, 19.5% decreased). Of the 31 subjects taking antithyroid drugs, 12 (38.7%) had TSH levels outside the reference range (9.7% elevated, 29.0% decreased). These proportions were lower in the 45 subjects receiving iodine supplementation (2.2% elevated, 8.9% decreased). Among the 3,974 SHIP participants not taking thyroid medication, TSH levels outside the reference range (2.8% elevated, 5.9% decreased) were less frequent. CONCLUSION: In concordance with previous studies in iodine-sufficient areas, our results indicate that a considerable number of patients taking thyroid medication are either under- or over-treated. Improved monitoring of these patients' TSH levels, compared to the local reference range, is recommended. PMID- 20712885 TI - Body weight, metabolism and clock genes. AB - Biological rhythms are present in the lives of almost all organisms ranging from plants to more evolved creatures. These oscillations allow the anticipation of many physiological and behavioral mechanisms thus enabling coordination of rhythms in a timely manner, adaption to environmental changes and more efficient organization of the cellular processes responsible for survival of both the individual and the species. Many components of energy homeostasis exhibit circadian rhythms, which are regulated by central (suprachiasmatic nucleus) and peripheral (located in other tissues) circadian clocks. Adipocyte plays an important role in the regulation of energy homeostasis, the signaling of satiety and cellular differentiation and proliferation. Also, the adipocyte circadian clock is probably involved in the control of many of these functions. Thus, circadian clocks are implicated in the control of energy balance, feeding behavior and consequently in the regulation of body weight. In this regard, alterations in clock genes and rhythms can interfere with the complex mechanism of metabolic and hormonal anticipation, contributing to multifactorial diseases such as obesity and diabetes. The aim of this review was to define circadian clocks by describing their functioning and role in the whole body and in adipocyte metabolism, as well as their influence on body weight control and the development of obesity. PMID- 20712886 TI - Final results of a phase I/II pilot study of capecitabine with or without vinorelbine after sequential dose-dense epirubicin and paclitaxel in high-risk early breast cancer. AB - BACKGROUND: The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC) could improve efficacy, but this combination was not examined in this context so far. METHODS: Patients with stage II/IIIA EBC (four or more positive lymph nodes) received post-operative intensified dose-dense sequential epirubicin (150 mg/m(2) every 2 weeks) and paclitaxel (225 mg/m(2) every 2 weeks) with filgrastim and darbepoetin alpha, followed by capecitabine alone (dose levels 1 and 3) or with vinorelbine (dose levels 2 and 4). Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively). Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4). RESULTS: Fifty-one patients were treated. There was one dose-limiting toxicity (DLT) at dose level 1. At dose level 2 (capecitabine and vinorelbine), five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy) was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively. CONCLUSIONS: Administration of capecitabine monotherapy after sequential dose dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs. PMID- 20712887 TI - Cadmium suppresses the proliferation of piglet Sertoli cells and causes their DNA damage, cell apoptosis and aberrant ultrastructure. AB - OBJECTIVE: Very little information is known about the toxic effects of cadmium on somatic cells in mammalian testis. The objective of this study is to explore the toxicity of cadmium on piglet Sertoli cells. METHODS: Sertoli cells were isolated from piglet testes using a two-step enzyme digestion and followed by differential plating. Piglet Sertoli cells were identified by oil red O staining and Fas ligand (FasL) expression as assayed by immunocytochemistry and expression of transferrin and androgen binding protein by RT-PCR. Sertoli cells were cultured in DMEM/F12 supplemented with 10% fetal calf serum in the absence or presence of various concentrations of cadmium chloride, or treatment with p38 MAPK inhibitor SB202190 and with cadmium chloride exposure. Apoptotic cells in seminiferous tubules of piglets were also performed using TUNEL assay in vivo. RESULTS: Cadmium chloride inhibited the proliferation of Piglet Sertoli cells as shown by MTT assay, and it increased malondialdehyde (MDA) but reduced superoxide dismutase (SOD) and Glutathione peroxidase (GSH-Px) activity. Inhibitor SB202190 alleviated the proliferation inhibition of cadmium on piglet Sertoli cells. Comet assay revealed that cadmium chloride caused DNA damage of Piglet Sertoli cells and resulted in cell apoptosis as assayed by flow cytometry. The in vivo study confirmed that cadmium induced cell apoptosis in seminiferous tubules of piglets. Transmission electronic microscopy showed abnormal and apoptotic ultrastructure in Piglet Sertoli cells treated with cadmium chloride compared to the control. CONCLUSION: cadmium has obvious adverse effects on the proliferation of piglet Sertoli cells and causes their DNA damage, cell apoptosis, and aberrant morphology. This study thus offers novel insights into the toxicology of cadmium on male reproduction. PMID- 20712889 TI - An in vivo evaluation of bone response to three implant surfaces using a rabbit intramedullary rod model. AB - Our study was designed to evaluate osseointegration among implants with three surface treatments: plasma-sprayed titanium (P), plasma-sprayed titanium with hydroxyapatite (PHA), and chemical-textured titanium with hydroxyapatite (CHA). Average surface roughness (Ra) was 27 microns for the P group, 17 microns for the PHA group, and 26 microns for the CHA group. Bilateral distal intramedullary implants were placed in the femora of thirty rabbits. Histomorphometry of scanning electron microscopy images was used to analyze the amount of bone around the implants at 6 and 12 weeks after implantation. Greater amounts of osseointegration were observed in the hydroxyapatite-coated groups than in the noncoated group. For all implant surfaces, osseointegration was greater at the diaphyseal level compared to the metaphyseal level. No significant differences were seen in osseointegration between the 6 and 12 week time points. Although the average surface roughness of the P and the CHA groups was similar, osseointegration of the CHA implants was significantly greater. The results of this in vivo lapine study suggest that the presence of an hydroxyapatite coating enhances osseointegration despite similarities in average surface roughness. PMID- 20712888 TI - Genotypes and haplotypes of the VEGF gene and survival in locally advanced non small cell lung cancer patients treated with chemoradiotherapy. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving in carcinogenesis, including lung cancer. We hypothesized that VEGF polymorphisms may affect survival outcomes among locally advanced non small cell lung cancer (LA-NSCLC) patients. METHODS: We genotyped three potentially functional VEGF variants [-460 T > C (rs833061), -634 G > C (rs2010963), and +936 C > T (rs3025039)] and estimated haplotypes in 124 Caucasian patients with LA-NSCLC treated with definitive radiotherapy. We used Kaplan-Meier log-rank tests, and Cox proportional hazard models to evaluate the association between VEGF variants and overall survival (OS). RESULTS: Gender, Karnofsky's performance scores (KPS) and clinical stage seemed to influence the OS. The variant C genotypes were independently associated with significantly improved OS (CT+CC vs. TT: adjusted hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.37-0.92, P = 0.022), compared with the VEGF -460 TT genotype. CONCLUSIONS: Our study suggests that VEGF -460 C genotypes may be associated with a better survival of LA-NSCLC patients after chemoradiotherapy. Large studies are needed to confirm our findings. PMID- 20712890 TI - Analysis of genetic copy number changes in cervical disease progression. AB - BACKGROUND: Cervical dysplasia and tumorigenesis have been linked with numerous chromosomal aberrations. The goal of this study was to evaluate 35 genomic regions associated with cervical disease and to select those which were found to have the highest frequency of aberration for use as probes in fluorescent in-situ hybridization. METHODS: The frequency of gains and losses using fluorescence in situ hybridization were assessed in these 35 regions on 30 paraffin-embedded cervical biopsy specimens. Based on this assessment, 6 candidate fluorescently labeled probes (8q24, Xp22, 20q13, 3p14, 3q26, CEP15) were selected for additional testing on a set of 106 cervical biopsy specimens diagnosed as Normal, CIN1, CIN2, CIN3, and SCC. The data were analyzed on the basis of signal mean, % change of signal mean between histological categories, and % positivity. RESULTS: The study revealed that the chromosomal regions with the highest frequency of copy number gains and highest combined sensitivity and specificity in high-grade cervical disease were 8q24 and 3q26. The cytological application of these two probes was then evaluated on 118 ThinPrep samples diagnosed as Normal, ASCUS, LSIL, HSIL and Cancer to determine utility as a tool for less invasive screening. Using gains of either 8q24 or 3q26 as a positivity criterion yielded specificity (Normal +LSIL+ASCUS) of 81.0% and sensitivity (HSIL+Cancer) of 92.3% based on a threshold of 4 positive cells. CONCLUSIONS: The application of a FISH assay comprised of chromosomal probes 8q24 and 3q26 to cervical cytology specimens confirms the positive correlation between increasing dysplasia and copy gains and shows promise as a marker in cervical disease progression. PMID- 20712891 TI - Quantitative in vitro and in vivo pharmacological profile of CE-178253, a potent and selective cannabinoid type 1 (CB1) receptor antagonist. AB - BACKGROUND: Cannabinoid 1 (CB1) receptor antagonists exhibit pharmacological properties favorable for the treatment of obesity and other related metabolic disorders. CE-178253 (1-[7-(2-Chlorophenyl)-8-(4-chlorophenyl)-2 methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid hydrochloride) is a recently discovered selective centrally-acting CB1 receptor antagonist. Despite a large body of knowledge on cannabinoid receptor antagonists little data exist on the quantitative pharmacology of this therapeutic class of drugs. The purpose of the current studies was to evaluate the quantitative pharmacology and concentration/effect relationships of CE-178253 based on unbound plasma concentration and in vitro pharmacology data in different in vivo preclinical models of FI and energy expenditure. RESULTS: In vitro, CE 178253 exhibits sub-nanomolar potency at human CB1 receptors in both binding (Ki = 0.33 nM) and functional assays (Ki = 0.07 nM). CE-178253 has low affinity (Ki > 10,000 nM) for human CB2 receptors. In vivo, CE-178253 exhibits concentration dependent anorectic activity in both fast-induced re-feeding and spontaneous nocturnal feeding FI models. As measured by indirect calorimetry, CE-178253 acutely stimulates energy expenditure by greater than 30% in rats and shifts substrate oxidation from carbohydrate to fat as indicated by a decrease the respiratory quotient from 0.85 to 0.75. Determination of the concentration-effect relationships and ex vivo receptor occupancy in efficacy models of energy intake and expenditure suggest that a greater than a 2-fold coverage of the Ki (50-75% receptor occupancy) is required for maximum efficacy. Finally, in two preclinical models of obesity, CE-178253 dose-dependently promotes weight loss in diet induced obese rats and mice. CONCLUSIONS: We have combined quantitative pharmacology and ex vivo CB1 receptor occupancy data to assess concentration/effect relationships in food intake, energy expenditure and weight loss studies. Quantitative pharmacology studies provide a strong a foundation for establishing and improving confidence in mechanism as well as aiding in the progression of compounds from preclinical pharmacology to clinical development. PMID- 20712892 TI - Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment. AB - BACKGROUND: High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen. METHODS: Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. RESULTS: Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-alpha 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b. CONCLUSIONS: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present. PMID- 20712893 TI - XIAP gene expression and function is regulated by autocrine and paracrine TGF beta signaling. AB - BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) is often overexpressed in cancer cells, where it plays a key role in survival and also promotes invasiveness. To date however, the extracellular signals and intracellular pathways regulating its expression and activity remain incompletely understood. We have previously showed that exposure to each of the three TGF-beta (transforming growth factor beta) isoforms upregulates XIAP protein content in endometrial carcinoma cells in vitro. In the present study, we have investigated the clinical relevance of TGF-beta isoforms in endometrial tumours and the mechanisms through which TGF-beta isoforms regulate XIAP content in uterine cancer cells. METHODS: TGF-beta isoforms immunoreactivity in clinical samples from endometrial tumours was assessed using immunofluorescence. Two model cancer cell lines (KLE endometrial carcinoma cells and HeLa cervical cancer cells) and pharmacological inhibitors were used to investigate the signalling pathways regulating XIAP expression and activity in response to autocrine and paracrine TGF-beta in cancer cell. RESULTS: We have found immunoreactivity for each TGF beta isoform in clinical samples from endometrial tumours, localizing to both stromal and epithelial/cancer cells. Blockade of autocrine TGF-beta signaling in KLE endometrial carcinoma cells and HeLa cervical cancer cells reduced endogenous XIAP mRNA and protein levels. In addition, each TGF-beta isoform upregulated XIAP gene expression when given exogenously, in a Smad/NF-kappaB dependent manner. This resulted in increased polyubiquitination of PTEN (phosphatase and tensin homolog on chromosome ten), a newly identified substrate for XIAP E3 ligase activity, and in a XIAP-dependent decrease of PTEN protein levels. Although each TGF-beta isoform decreased PTEN content in a XIAP- and a Smad-dependent manner, decrease of PTEN levels in response to only one isoform, TGF-beta3, was blocked by PI3-K inhibitor LY294002. CONCLUSIONS: XIAP gene expression and function is positively regulated by exposure to the three TGF-beta isoforms in a Smad dependent manner, similar to constitutive XIAP gene expression which depends on autocrine TGF-beta/Smad signalling. PMID- 20712894 TI - Dynamics of long-term genomic selection. AB - BACKGROUND: Simulation and empirical studies of genomic selection (GS) show accuracies sufficient to generate rapid gains in early selection cycles. Beyond those cycles, allele frequency changes, recombination, and inbreeding make analytical prediction of gain impossible. The impacts of GS on long-term gain should be studied prior to its implementation. METHODS: A simulation case-study of this issue was done for barley, an inbred crop. On the basis of marker data on 192 breeding lines from an elite six-row spring barley program, stochastic simulation was used to explore the effects of large or small initial training populations with heritabilities of 0.2 or 0.5, applying GS before or after phenotyping, and applying additional weight on low-frequency favorable marker alleles. Genomic predictions were from ridge regression or a Bayesian analysis. RESULTS: Assuming that applying GS prior to phenotyping shortened breeding cycle time by 50%, this practice strongly increased early selection gains but also caused the loss of many favorable QTL alleles, leading to loss of genetic variance, loss of GS accuracy, and a low selection plateau. Placing additional weight on low-frequency favorable marker alleles, however, allowed GS to increase their frequency earlier on, causing an initial increase in genetic variance. This dynamic led to higher long-term gain while mitigating losses in short-term gain. Weighted GS also increased the maintenance of marker polymorphism, ensuring that QTL-marker linkage disequilibrium was higher than in unweighted GS. CONCLUSIONS: Losing favorable alleles that are in weak linkage disequilibrium with markers is perhaps inevitable when using GS. Placing additional weight on low-frequency favorable alleles, however, may reduce the rate of loss of such alleles to below that of phenotypic selection. Applying such weights at the beginning of GS implementation is important. PMID- 20712896 TI - Survival associated pathway identification with group Lp penalized global AUC maximization. AB - It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p < 1) (with its special implementation entitled adaptive LASSO) is asymptotic unbiased and has oracle properties 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS). This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times. PMID- 20712897 TI - Utilisation of priority traditional medicinal plants and local people's knowledge on their conservation status in arid lands of Kenya (Mwingi District). AB - Mwingi District lies within the Kenyan Arid and Semiarid lands (ASALs) in Eastern Province. Although some ethnobotanical surveys have been undertaken in some arid and semiarid areas of Kenya, limited studies have documented priority medicinal plants as well as local people's awareness of conservation needs of these plants. This study sought to establish the priority traditional medicinal plants used for human, livestock healthcare, and those used for protecting stored grains against pest infestation in Mwingi district. Further, the status of knowledge among the local people on the threat and conservation status of important medicinal species was documented. This study identified 18 species which were regarded as priority traditional medicinal plants for human health. In terms of priority, 8 were classified as moderate, 6 high, while 4 were ranked highest priority species. These four species are Albizia amara (Roxb.) Boiv. (Mimosacaeae), Aloe secundiflora (Engl. (Aloaceae), Acalypha fruticosa Forssk. (Euphorbiaceae) and Salvadora persica L. (Salvadoraceae). In regard to medicinal plants used for ethnoveterinary purposes, eleven species were identified while seven species were reported as being important for obtaining natural products or concoctions used for stored grain preservation especially against weevils. The data obtained revealed that there were new records of priority medicinal plants which had not been documented as priority species in the past. Results on conservation status of these plants showed that more than 80% of the respondents were unaware that wild medicinal plants were declining, and, consequently, few of them have any domesticated species. Some of the species that have been conserved on farm or deliberately allowed to persist when wild habitats are converted into agricultural lands include: Croton megalocarpus Hutch., Aloe secundiflora, Azadirachta indica A. Juss., Warburgia ugandensis Sprague, Ricinus communis L. and Terminalia brownie Fresen. A small proportion of the respondents however, were aware of the threats facing medicnal plants. Some of the plants reported as declining include, Solanum renschii Vatke (Solanaceae), Populus ilicifolia (Engl.) Rouleau (Salicaceae), Strychnos henningsii Gilg (Loganiaceae) and Rumex usambarensis (Dammer) Dammer (Polygonaceae). Considering the low level of understanding of conservation concerns for these species, there is need therefore, to build capacity among the local communities in this area particularly in regard to sustainable use of natural resources, conservation methods as well as domestication processes. PMID- 20712895 TI - Functional effects of spinocerebellar ataxia type 13 mutations are conserved in zebrafish Kv3.3 channels. AB - BACKGROUND: The zebrafish has been suggested as a model system for studying human diseases that affect nervous system function and motor output. However, few of the ion channels that control neuronal activity in zebrafish have been characterized. Here, we have identified zebrafish orthologs of voltage-dependent Kv3 (KCNC) K+ channels. Kv3 channels have specialized gating properties that facilitate high-frequency, repetitive firing in fast-spiking neurons. Mutations in human Kv3.3 cause spinocerebellar ataxia type 13 (SCA13), an autosomal dominant genetic disease that exists in distinct neurodevelopmental and neurodegenerative forms. To assess the potential usefulness of the zebrafish as a model system for SCA13, we have characterized the functional properties of zebrafish Kv3.3 channels with and without mutations analogous to those that cause SCA13. RESULTS: The zebrafish genome (release Zv8) contains six Kv3 family members including two Kv3.1 genes (kcnc1a and kcnc1b), one Kv3.2 gene (kcnc2), two Kv3.3 genes (kcnc3a and kcnc3b), and one Kv3.4 gene (kcnc4). Both Kv3.3 genes are expressed during early development. Zebrafish Kv3.3 channels exhibit strong functional and structural homology with mammalian Kv3.3 channels. Zebrafish Kv3.3 activates over a depolarized voltage range and deactivates rapidly. An amino terminal extension mediates fast, N-type inactivation. The kcnc3a gene is alternatively spliced, generating variant carboxyl-terminal sequences. The R335H mutation in the S4 transmembrane segment, analogous to the SCA13 mutation R420H, eliminates functional expression. When co-expressed with wild type, R335H subunits suppress Kv3.3 activity by a dominant negative mechanism. The F363L mutation in the S5 transmembrane segment, analogous to the SCA13 mutation F448L, alters channel gating. F363L shifts the voltage range for activation in the hyperpolarized direction and dramatically slows deactivation. CONCLUSIONS: The functional properties of zebrafish Kv3.3 channels are consistent with a role in facilitating fast, repetitive firing of action potentials in neurons. The functional effects of SCA13 mutations are well conserved between human and zebrafish Kv3.3 channels. The high degree of homology between human and zebrafish Kv3.3 channels suggests that the zebrafish will be a useful model system for studying pathogenic mechanisms in SCA13. PMID- 20712898 TI - Whole ovary immunohistochemistry for monitoring cell proliferation and ovulatory wound repair in the mouse. AB - BACKGROUND: Ovarian surface epithelial cells are thought to be a precursor cell type for ovarian carcinoma. It has been proposed that an increased rate of ovarian surface epithelial cell proliferation during ovulatory wound repair contributes to the accumulation of genetic changes and cell transformation. The proliferation of ovarian surface epithelial cells during ovulatory wound repair has been studied primarily using immunohistochemical staining of paraffin embedded ovary sections. However, such analyses require complex reconstruction from serially-cut ovary sections for the visualization and quantification of the cells on the ovarian surface. In order to directly visualize the proliferation and organization of the ovarian surface epithelial cells, we developed a technique for immunohistochemical staining of whole mouse ovaries. Using this method, we analyzed cell proliferation and morphologic changes in mouse ovarian surface epithelial cells during follicle growth and ovulatory wound repair. METHODS: Three-week old FVB/N female mice were superovulated by sequential administration of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). Ten hours after hCG administration, mice were given 5-bromo-2 deoxyuridine (BrdU) and euthanized two hours after BrdU administration for ovary isolation. The levels of incorporated BrdU in the ovarian surface epithelial cells were measured by staining paraffin-embedded ovary sections and whole ovaries with the BrdU antibody. Re-epithelialization of the ovarian surface after ovulatory rupture was visualized by immunohistochemical staining with E-cadherin and Keratin 8 in paraffin-embedded ovary sections and whole ovaries. RESULTS: We determined that active proliferation of ovarian epithelial surface cells primarily occurs during antral follicle formation and, to a lesser extent, in response to an ovulatory wound. We also demonstrated that ovarian surface epithelial cells exhibit a circular organization around the wound site CONCLUSION: Whole ovary immunohistochemistry enables efficient and comprehensive three-dimensional visualization of ovarian surface epithelial cells without the need for laborious reconstruction from immunohistochemically-stained serial ovary sections. PMID- 20712899 TI - Use of manual and powered wheelchair in children with cerebral palsy: a cross sectional study. AB - BACKGROUND: Mobility is important for the cognitive and psychosocial development of children. Almost one third of children with cerebral palsy (CP) are non ambulant. Wheelchairs can provide independent mobility, allowing them to explore their environment. Independent mobility is vital for activity and participation and reduces the dependence on caregivers. The purpose of this study was to describe the use of manual and powered wheelchair indoors and outdoors in relation to the degree of independent wheelchair mobility or need for assistance in a total population of children with CP. METHODS: A cross-sectional study was performed including all children aged 3-18 years with CP living in southern Sweden during 2008. Data was extracted from a register and health care programme for children with CP (CPUP). There were a total of 562 children (326 boys, 236 girls) in the register. Information on the child's use of manual and powered wheelchair indoors and outdoors and the performance in self-propelling or need for assistance were analysed related to age, CP subtype and gross motor function. RESULTS: Wheelchairs for mobility indoors were used by 165 (29%) of the 562 children; 61 used wheelchair for independent mobility (32 using manual only, 12 powered only, 17 both) and 104 were pushed by an adult. For outdoor mobility wheelchairs were used by 228 children (41%); 66 used a wheelchair for independent mobility (18 using manual only, 36 powered only, 12 both) and 162 were pushed. The use of wheelchair increased with age and was most frequent in the spastic bilateral and dyskinetic subtypes. Most powered wheelchairs were operated by children at GMFCS level IV. CONCLUSION: In this total population of children with CP, aged 3-18 years, 29% used a wheelchair indoors and 41% outdoors. A majority using manual wheelchairs needed adult assistance (86%) while powered wheelchairs provided independent mobility in most cases (86%). To achieve a high level of independent mobility, both manual and powered wheelchairs should be considered at an early age for children with impaired walking ability. PMID- 20712900 TI - p53 nuclear accumulation and ERalpha expression in ductal hyperplasia of breast in a cohort of 215 Chinese women. AB - INTRODUCTION: Women with ductal hyperplasia including usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH) have an increased risk of developing invasive ductal carcinoma (IDC) of breast. The importance of several molecular markers in breast cancer has been of considerable interest during recent years such as p53 and estrogen receptor alpha (ERalpha). However, p53 nuclear accumulation and ERalpha expression have not been assessed in ductal hyperplasia co-existing with ductal carcinoma in situ (DCIS) or IDC versus pure ductal hyperplasia without DCIS or IDC. MATERIALS AND METHODS: We investigated p53 nuclear accumulation and ERalpha expression in breast ductal hyperplasia in a cohort of 215 Chinese women by immunohistochemistry (IHC), which included 129 cases of pure ductal hyperplasia, 86 cases of ductal hyperplasia co-existing with DCIS (41 cases) or IDC (45 cases). RESULTS: Nuclear p53 accumulation was identified in 22.8% of ADH (31/136), 41.5% of DCIS (17/41) and 42.2% of IDC (19/45), and no case of UDH (0/79). No difference in nuclear p53 accumulation was observed between pure ADH and ADH co-existing with DCIS (ADH/DCIS) or IDC (ADH/IDC) (P>0.05). The positive rate of ERalpha expression was lower in ADH (118/136, 86.8%) than that in UDH (79/79, 100%) (P<0.001), but higher than that in DCIS (28/41, 68.3%) or IDC (26/45, 57.8%) respectively (P<0.001). The frequency of ERalpha expression was lower in ADH/DCIS (23/29, 79.31%) and ADH/IDC (23/30, 76.67%) than that in pure ADH (72/77, 93.51%) respectively (P<0.05). There was a negative weak correlation between p53 nuclear accumulation and ERalpha expression as for ADH (coefficient correlation -0.51; P<0.001). CONCLUSIONS: Different pathological types of ductal hyperplasia of breast are accompanied by diversity in patterns of nuclear p53 accumulation and ERalpha expression. At least some pure ADH is molecularly distinct from ADH/CIS or ADH/IDC which indicated the two types of ADH are molecularly distinct entities although they have the same morphological appearance. PMID- 20712901 TI - A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells. AB - BACKGROUND: Targeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells. RESULTS: FLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-gamma. CONCLUSION: Our findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling. PMID- 20712902 TI - Successful enteral nutrition in the treatment of esophagojejunal fistula after total gastrectomy in gastric cancer patients. AB - BACKGROUND: Esophagojejunal fistula is a serious complication after total gastrectomy in gastric cancer patients. This study describes the successful conservative management in 3 gastric cancer patients with esophagojejunal fistula after total gastrectomy using total enteral nutrition. METHODS: Between January 2004 to December 2008, 588 consecutive patients with a proven diagnosis of gastric cancer were taken to the operation room to try a curative treatment. Of these, 173 underwent total gastrectomy, 9 of them had esophagojejunal fistula (5.2%). In three selected patients a trans-anastomotic naso-enteral feeding tube was placed under fluoroscopic vision when the fistula was clinically detected and a complete polymeric enteral formula was used. RESULTS: The complete closing of the esophagojejunal fistula was obtained in day 8, 14 and 25 respectively. CONCLUSION: In some selected cases it is possible to make a successful enteral nutrition using a feeding tube distal to the leak area inserted with the help of fluoroscopic vision. The specialized management of a gastric surgery unit and nutritional therapy unit are highlighted. PMID- 20712903 TI - Obesity and diabetes genes are associated with being born small for gestational age: results from the Auckland Birthweight Collaborative study. AB - BACKGROUND: Individuals born small for gestational age (SGA) are at increased risk of rapid postnatal weight gain, later obesity and diseases in adulthood such as type 2 diabetes, hypertension and cardiovascular diseases. Environmental risk factors for SGA are well established and include smoking, low pregnancy weight, maternal short stature, maternal diet, ethnic origin of mother and hypertension. However, in a large proportion of SGA, no underlying cause is evident, and these individuals may have a larger genetic contribution. METHODS: In this study we tested the association between SGA and polymorphisms in genes that have previously been associated with obesity and/or diabetes. We undertook analysis of 54 single nucleotide polymorphisms (SNPs) in 546 samples from the Auckland Birthweight Collaborative (ABC) study. 227 children were born small for gestational age (SGA) and 319 were appropriate for gestational age (AGA). RESULTS AND CONCLUSION: The results demonstrated that genetic variation in KCNJ11, BDNF, PFKP, PTER and SEC16B were associated with SGA and support the concept that genetic factors associated with obesity and/or type 2 diabetes are more prevalent in those born SGA compared to those born AGA. We have previously determined that environmental factors are associated with differences in birthweight in the ABC study and now we have demonstrated a significant genetic contribution, suggesting that the interaction between genetics and the environment are important. PMID- 20712904 TI - Resveratrol differentially modulates inflammatory responses of microglia and astrocytes. AB - BACKGROUND: Inflammatory responses in the CNS mediated by activated glial cells play an important role in host-defense but are also involved in the development of neurodegenerative diseases. Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect microglia and astrocyte from inflammatory insults and explored mechanisms underlying different inhibitory effects of resveratrol on microglia and astrocytes. METHODS: A murine microglia cell line (N9), primary microglia, or astrocytes were stimulated by LPS with or without different concentrations of resveratrol. The expression and release of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, MCP-1) and iNOS/NO by the cells were measured by PCR/real-time PCR and ELISA, respectively. The phosphorylation of the MAP kinase superfamily was analyzed by western blotting, and activation of NF-kappaB and AP-1 was measured by luciferase reporter assay and/or electrophoretic mobility shift assay. RESULTS: We found that LPS stimulated the expression of TNF-alpha, IL-1beta, IL-6, MCP-1 and iNOS in murine microglia and astrocytes in which MAP kinases, NF-kappaB and AP-1 were differentially involved. Resveratrol inhibited LPS-induced expression and release of TNF-alpha, IL-6, MCP-1, and iNOS/NO in both cell types with more potency in microglia, and inhibited LPS-induced expression of IL-1beta in microglia but not astrocytes. Resveratrol had no effect on LPS-stimulated phosphorylation of ERK1/2 and p38 in microglia and astrocytes, but slightly inhibited LPS-stimulated phosphorylation of JNK in astrocytes. Resveratrol inhibited LPS-induced NF-kappaB activation in both cell types, but inhibited AP-1 activation only in microglia. CONCLUSION: These results suggest that murine microglia and astrocytes produce proinflammatory cytokines and NO in response to LPS in a similar pattern with some differences in signaling molecules involved, and further suggest that resveratrol exerts anti-inflammatory effects in microglia and astrocytes by inhibiting different proinflammatory cytokines and key signaling molecules. PMID- 20712905 TI - Incidence of type 2 diabetes in Aboriginal Australians: an 11-year prospective cohort study. AB - BACKGROUND: Diabetes is an important contributor to the health inequity between Aboriginal and non-Aboriginal Australians. This study aims to estimate incidence rates of diabetes and to assess its associations with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) among Aboriginal participants in a remote community. METHODS: Six hundred and eighty six (686) Aboriginal Australians aged 20 to 74 years free from diabetes at baseline were followed for a median of 11 years. During the follow-up period, new diabetes cases were identified through hospital records. Cox proportional hazards models were used to assess relationships of the incidence rates of diabetes with IFG, IGT and body mass index (BMI). RESULTS: One hundred and twenty four (124) new diabetes cases were diagnosed during the follow up period. Incidence rates increased with increasing age, from 2.2 per 1000 person-years for those younger than 25 years to 39.9 per 1000 person-years for those 45-54 years. By age of 60 years, cumulative incidence rates were 49% for Aboriginal men and 70% for Aboriginal women. The rate ratio for developing diabetes in the presence of either IFG or IGT at baseline was 2.2 (95% CI: 1.5, 3.3), adjusting for age, sex and BMI. Rate ratios for developing diabetes were 2.2 (95% CI: 1.4, 3.5) for people who were overweight and 4.7 (95% CI: 3.0, 7.4) for people who were obese at baseline, with adjustment of age, sex and the presence of IFG/IGT. CONCLUSIONS: Diabetes incidence rates are high in Aboriginal people. The lifetime risk of developing diabetes among Aboriginal men is one in two, and among Aboriginal women is two in three. Baseline IFG, IGT and obesity are important predictors of diabetes. PMID- 20712906 TI - A comparison of physicians and medical assistants in interpreting verbal autopsy interviews for allocating cause of neonatal death in Matlab, Bangladesh: can medical assistants be considered an alternative to physicians? AB - OBJECTIVE: This study assessed the agreement between medical physicians in their interpretation of verbal autopsy (VA) interview data for identifying causes of neonatal deaths in rural Bangladesh. METHODS: The study was carried out in Matlab, a rural sub-district in eastern Bangladesh. Trained persons conducted the VA interview with the mother or another family member at the home of the deceased. Three physicians and a medical assistant independently reviewed the VA interviews to assign causes of death using the International Classification of Diseases - Tenth Revision (ICD-10) codes. A physician assigned cause was decided when at least two physicians agreed on a cause of death. Cause-specific mortality fraction (CSMF), kappa (k) statistic, sensitivity, specificity, and positive predictive values were applied to compare agreement between the reviewers. RESULTS: Of the 365 neonatal deaths reviewed, agreement on a direct cause of death was reached by at least two physicians in 339 (93%) of cases. Physician and medical assistant reviews of causes of death demonstrated the following levels of diagnostic agreement for the main causes of deaths: for birth asphyxia the sensitivity was 84%, specificity 93%, and kappa 0.77. For prematurity/low birth weight, the sensitivity, specificity, and kappa statistics were, respectively, 53%, 96%, and 0.55, for sepsis/meningitis they were 48%, 98%, and 0.53, and for pneumonia they were 75%, 94%, and 0.51. CONCLUSION: This study revealed a moderate to strong agreement between physician- assigned and medical assistant- assigned major causes of neonatal death. A well-trained medical assistant could be considered an alternative for assigning major causes of neonatal deaths in rural Bangladesh and in similar settings where physicians are scarce and their time costs more. A validation study with medically confirmed diagnosis will improve the performance of VA for assigning cause of neonatal death. PMID- 20712907 TI - Lipid ratios and appropriate cut off values for prediction of diabetes: a cohort of Iranian men and women. AB - BACKGROUND: Dyslipidemia is a risk factor for incident type 2 diabetes; however, no study has specifically assessed the lipid ratios (i.e. total cholesterol (TC)/high density lipoprotein cholesterol (HDL-C) and triglyceride (TG)/HDL-C) as predictors of diabetes. We aimed to compare the independent association between the different lipid measures with incident diabetes over a median follow up of 6.4 years in Iranian men and women. METHOD: The study population consisted of 5201 non diabetic (men = 2173, women = 3028) subjects, aged > or =20 years. The risk factor adjusted odds ratios (ORs) for diabetes were calculated for every 1 standard deviation (SD) change in TC, log-transformed TG, HDL-C, non-HDL-C, TC/HDL-C and log-transformed TG/HDL-C using multivariate logistic regression analysis. Receiver operator characteristic (ROC) curve analysis was used to define the points of the maximum sum of sensitivity and specificity (MAXss) of each lipid measure as a predictor of diabetes. RESULT: We found 366 (146 men and 220 women) new diabetes cases during follow-up. The risk-factor-adjusted ORs for a 1 SD increase in TG, TC/HDL-C and TG/HDL-C were 1.23, 1.27 and 1.25 in men; the corresponding risks in females were 1.36, 1.14, 1.39 respectively (all p < 0.05, except TC/HDL-C in females which was marginally significant, p = 0.07). A 1 SD increase of HDL-C only in women decreased the risk of diabetes by 25% [0.75(0.64 0.89)]. In both genders, there was no difference in the discriminatory power of different lipid measures to predict incident diabetes in the risk factor adjusted models (ROC approximately 82%). TG cutoff values of 1.98 and 1.66 mmol/l; TG/HDL C cutoff values of 4.7 and 3.7, in men and women, respectively, TC/HDL-C cutoff value of 5.3 in both genders and HDL-C cutoff value of 1.18 mmol/l in women yielded the MAXss for defining the incidence of diabetes. CONCLUSION: TC/HDL-C and TG/HDL-C showed similar performance for diabetes prediction in men population however; among women TG/HDL-C highlighted higher risk than did TC/HDL-C, although there was no difference in discriminatory power. Importantly, HDL-C had a protective effect for incident diabetes only among women. PMID- 20712909 TI - Schizophrenia in Thailand: prevalence and burden of disease. AB - BACKGROUND: A previous estimate of the burden of schizophrenia in Thailand relied on epidemiological estimates from elsewhere. The aim of this study is to estimate the prevalence and disease burden of schizophrenia in Thailand using local data sources that recently have become available. METHODS: The prevalence of schizophrenia was estimated from a community mental health survey supplemented by a count of hospital admissions. Using data from recent meta-analyses of the risk of mortality and remission, we derived incidence and average duration using DisMod software. We used treated disability weights based on patient and clinician ratings from our own local survey of patients in contact with mental health services and applied methods from Australian Burden of Disease and cost effectiveness studies. We applied untreated disability weights from the Global Burden of Disease (GBD) study. Uncertainty analysis was conducted using Monte Carlo simulation. RESULTS: The prevalence of schizophrenia at ages 15-59 in the Thai population was 8.8 per 1,000 (95% CI: 7.2, 10.6) with a male-to-female ratio of 1.1-to-1. The disability weights from local data were somewhat lower than the GBD weights. The disease burden in disability-adjusted life years was similar in men (70,000; 95% CI: 64,000, 77, 000) and women (75,000; 95% CI: 69,000, 83,000). The impact of using the lower Thai disability weights on the DALY estimates was small in comparison to the uncertainty in prevalence. CONCLUSIONS: Prevalence of schizophrenia was more critical to an accurate estimate of burden of disease in Thailand than variations in disability weights. PMID- 20712908 TI - The microfloral analysis of secondary caries biofilm around Class I and Class II composite and amalgam fillings. AB - BACKGROUND: Secondary caries is responsible for 60 percent of all replacement restorations in the typical dental practice. The diversity of the bacterial sources and the different types of filling materials could play a role in secondary caries. The aim of this study was to determine and compare the microbial spectrum of secondary caries biofilms around amalgam and composite resin restorations. METHODS: Clinical samples were collected from freshly extracted teeth diagnosed with clinical secondary caries. Samples were categorized into four groups according to the types of restoration materials and the classification of the cavity. Biofilms were harvested from the tooth restoration interface using a dental explorer and after dilution were incubated on special agars. The bacteria were identified using the biochemical appraisal system. Statistical calculations were carried out using SPSS11.5 software to analyze the prevalence of the bacteria involved in secondary caries. RESULTS: Samples from a total of four groups were collected: two groups were collected from amalgam restorations, each had 21 samples from both Class I and Class II caries; and the other two groups were from composite resin restorations, each had 13 samples from both class I and class II caries. Our results showed: (1) Anaerobic species were dominant in both restoration materials. (2) In terms of the types of individual bacteria, no significant differences were found among the four groups according to the geometric mean of the detected bacteria (P > 0.05). However, there were significant differences among the detected bacteria within each group (P < 0.05). The composition of each bacterium had no statistical difference among the four groups (P > 0.05), but showed significant differences among the detected bacteria in each group (P < 0.05). (3) Among the four groups, there were no significant differences for the detection rate of each bacterium (P > 0.05), however, the detection rate of each bacterium within each group was statistically different among the detected bacteria (P < 0.05). CONCLUSIONS: The proportion of obligatory anaerobic species was much greater than the facultative anaerobic species in the biofilm of secondary caries. Statistically, the materials of restoration and the location of secondary caries did not show any significant effects on the composition of the microflora. PMID- 20712910 TI - Ethnobotanical study of wild edible plants of Kara and Kwego semi-pastoralist people in Lower Omo River Valley, Debub Omo Zone, SNNPR, Ethiopia. AB - BACKGROUND: The rural populations in Ethiopia have a rich knowledge of wild edible plants and consumption of wild edible plants is still an integral part of the different cultures in the country. In the southern part of the country, wild edible plants are used as dietary supplements and a means of survival during times of food shortage. Therefore, the aim of this study is to document the wild edible plants gathered and consumed by Kara and Kwego people, and to analyze patterns of use between the two people. METHODS: A cross sectional ethnobotanical study of wild edible plant species was conducted from January 2005 to March 2007. About 10% of each people: 150 Kara and 56 Kwego were randomly selected to serve as informants. Data were collected using semi-structured questionnaire and group discussions. Analysis of variance (alpha = 0.05) was used to test the similarity of species richness of wild edible plants reported by Kara and Kwego people; Pearson's Chi-square test (alpha = 0.05) was used to test similarity of growth forms and plant parts of wild edible plants used between the two people. RESULTS: Thirty-eight wild plant species were reported as food sources that were gathered and consumed both at times of plenty and scarcity; three were unique to Kara, five to Kwego and 14 had similar local names. The plant species were distributed among 23 families and 33 genera. The species richness: families, genera and species (p > 0.05) were not significantly different between Kara and Kwego. Nineteen (50%) of the reported wild edible plants were trees, 11 (29%) were shrubs, six (16%) were herbs and two (5%) were climbers. Forty plant parts were indicated as edible: 23 (58.97%) fruits, 13 (33.33%) leaves, 3 (7.69%) roots and one (2.56%) seed. There was no difference between wild edible plants growth forms reported (Pearson's Chi-square test (d.f. = 3) = 0.872) and plant parts used (Pearson's Chi-square test (d.f. = 3) = 0.994) by Kara and Kwego people. The majority of wild edible plants were gathered and consumed from 'Duka' (March) to 'Halet' (May) and from 'Meko' (August) to 'Tejo' (November). Sixteen (41%) of the plant parts were used as a substitute for cultivated vegetables during times of scarcity. The vegetables were chopped and boiled to make 'Belesha' (sauce) or as a relish to 'Adano' (porridge). The ripe fruits were gathered and consumed fresh and some were made into juices. The seeds and underground parts were only consumed in times of famine. Thirty-seven percent of the wild edible plants were used as medicine and 23.6% were used for other functions. CONCLUSIONS: The wild edible plants were used as supplements to the cultivated crops and as famine foods between harvesting seasons. But information on the nutritional values and possible toxic effects of most of the wild edible plants reported by Kara and Kwego, and others in different part of Ethiopia is not available. Therefore, the documented information on the wild edible plants may serve as baseline data for future studies on nutritional values and possible side effects, and to identify plants that may improve nutrition and increase dietary diversity. Some of these wild edible plants may have the potential to be valuable food sources (if cultivated) and could be part of a strategy in tackling food insecurity. PMID- 20712911 TI - Physician nutrition and cognition during work hours: effect of a nutrition based intervention. AB - BACKGROUND: Physicians are often unable to eat and drink properly during their work day. Nutrition has been linked to cognition. We aimed to examine the effect of a nutrition based intervention, that of scheduled nutrition breaks during the work day, upon physician cognition, glucose, and hypoglycemic symptoms. METHODS: A volunteer sample of twenty staff physicians from a large urban teaching hospital were recruited from the doctors' lounge. During both the baseline and the intervention day, we measured subjects' cognitive function, capillary blood glucose, "hypoglycemic" nutrition-related symptoms, fluid and nutrient intake, level of physical activity, weight, and urinary output. RESULTS: Cognition scores as measured by a composite score of speed and accuracy (Tput statistic) were superior on the intervention day on simple (220 vs. 209, p = 0.01) and complex (92 vs. 85, p < 0.001) reaction time tests. Group mean glucose was 0.3 mmol/L lower (p = 0.03) and less variable (coefficient of variation 12.2% vs. 18.0%) on the intervention day. Although not statistically significant, there was also a trend toward the reporting of fewer hypoglycemic type symptoms. There was higher nutrient intake on intervention versus baseline days as measured by mean caloric intake (1345 vs. 935 kilocalories, p = 0.008), and improved hydration as measured by mean change in body mass (+352 vs. -364 grams, p < 0.001). CONCLUSIONS: Our study provides evidence in support of adequate workplace nutrition as a contributor to improved physician cognition, adding to the body of research suggesting that physician wellness may ultimately benefit not only the physicians themselves but also their patients and the health care systems in which they work. PMID- 20712912 TI - Dental problems delaying the initiation of interferon therapy for HCV-infected patients. AB - BACKGROUND: There has been little discussion about the importance of oral management and interferon (IFN) therapy, although management of the side effects of therapy for chronic hepatitis C has been documented. This study determined whether dental problems delayed the initiation of IFN therapy for hepatitis C virus (HCV)-infected patients. RESULTS: We analyzed 570 HCV-infected patients who were admitted to our hospital from December 2003 to June 2010 for treatment consisting of pegylated IFN (Peg-IFN) monotherapy or Peg-IFN/ribavirin combination therapy. The group comprised 274 men and 296 women with a mean age 57.2 years. Of the 570 patients, six could not commence Peg-IFN therapy, despite their admission, because of dental problems such as periodontitis, pupitis, and pericoronitis. The ages of six whose dental problems delayed the initiation of Peg-IFN ranged from 25 to 67 years, with a mean age of 47.3 +/- 15.2 years. IFN therapy was deferred for 61.3 +/- 47.7 days. Among the six subjects for whom IFN treatment was delayed, only one had a salivary flow that was lower than the normal value. CONCLUSIONS: Treatment of dental infections is required before IFN therapy for HCV infection can be started. To increase the depth of understanding of oral health care, it is hoped that dentists and medical specialists in all areas will hold discussions to generate cooperation. PMID- 20712913 TI - The interpretation of brain natriuretic peptide in critical care patients; will it ever be useful? AB - The measurement of B-type natriuretic peptide (BNP) is recommended for the diagnosis of decompensated heart failure, the prognosis of chronic heart failure is worse if BNP is increased and studies suggest that BNP is useful to guide therapy. A study by Di Somma and colleagues adds to the body of evidence showing that patients with a marked decrease in BNP concentrations during their hospital admission are less likely to be readmitted with a further adverse cardiac event than patients in whom BNP fails to decrease. However, the wider interpretation of BNP concentrations in critically ill patients with other conditions remains uncertain. PMID- 20712914 TI - [A woman with cutaneous diphtheria]. AB - A 67-year-old woman had multiple ulcers due to cutaneous diphtheria, following a trip to the Philippines. PMID- 20712915 TI - UK Food Standards Agency Workshop Consensus Report: the choice of method for measuring 25-hydroxyvitamin D to estimate vitamin D status for the UK National Diet and Nutrition Survey. AB - The consensus workshop, organised on behalf of the Food Standards Agency, was convened to recommend the most appropriate and secure method for measuring vitamin D status in the UK. Workshop participants (the Expert Panel) were invited on the basis of expertise in current 25-hydroxyvitamin D (25OHD) assays, or expertise in vitamin D nutrition and metabolism or detailed knowledge and experience in the National Diet and Nutrition Survey (NDNS). A decision support matrix, which set out the particular criteria by which the different options were scored and evaluated, was used to structure the discussion. The Expert Panel agreed that five methods for measuring 25OHD should be evaluated according to eleven criteria, selected on the basis of their relevance to the NDNS. All three of the evaluating subgroups of the Expert Panel produced similar total scores over the eleven criteria for the different methods; they scored LC-MS/MS and HPLC UV similarly highly, while the scores for the immunoassay methods were lower. The Expert Panel recommended that an LC-MS/MS method should be the preferred method for the NDNS. A detailed specification for the method will be required to ensure comparability between NDNS and the National Health and Nutrition Examination Survey in the US facilitating future comparisons. The Expert Panel also recommended that the method should be carried out in a laboratory with appropriate expertise, competency and history of records of good performance. The method should be standardised against the National Institute of Standards and Technology SRM 972. If the recommended LC-MS/MS is adopted, the Expert Panel indicated that the method should be able to discriminate the C-3 epimer of 25OHD(3), especially if used to measure 25OHD in young infants in the forthcoming Diet and Nutrition Survey of Infants and Young Children, who are known to have high circulating concentrations of the C-3 epimer. PMID- 20712916 TI - A state-level analysis of life expectancy in Mexico (1990-2006). AB - Using a methodology similar to that proposed by Barro & Sala-i-Martin (1995), it is found that, in the period 1990-2006, there was strong convergence among state level life expectancy series, but a distancing in life expectancy in the Mexican Republic compared with more developed countries, especially during the new millennium. The interior convergence had taken place at the expense of the exterior; that is, not so much as a result of an improvement in living conditions in the poorer states, but more due to the low performance of the richer states. The causes of this situation are explained using the concept of 'epidemiological transition'. PMID- 20712917 TI - Housing concerns of vulnerable older Canadians. AB - Preparing for the future housing needs of older adults is imperative in countries with an aging population, but little is known about these issues among vulnerable older adults. This study used a qualitative approach to identify key housing concerns in this group. A total of 84 vulnerable older adults including Aboriginal elders, those with various disabilities, and ethnic minorities participated in 10 focus groups. The Canadian Mortgage and Housing Corporation's (CMHC's) standards of core housing need provided a framework for data analysis, along with the identification of additional key housing themes across and within groups of vulnerable older adults. The results provide insight into preferred housing characteristics, regardless of housing form. Additionally, the results provide insight into how to support vulnerable older adults who choose to remain in their homes and communities and how to help ensure that appropriate housing is developed that meets the needs of this diverse population. PMID- 20712918 TI - White Americans' opposition to affirmative action: group interest and the harm to beneficiaries objection. AB - We focused on a powerful objection to affirmative action - that affirmative action harms its intended beneficiaries by undermining their self-esteem. We tested whether White Americans would raise the harm to beneficiaries objection particularly when it is in their group interest. When led to believe that affirmative action harmed Whites, participants endorsed the harm to beneficiaries objection more than when led to believe that affirmative action did not harm Whites. Endorsement of a merit-based objection to affirmative action did not differ as a function of the policy's impact on Whites. White Americans used a concern for the intended beneficiaries of affirmative action in a way that seems to further the interest of their own group. PMID- 20712922 TI - Effects of minimally invasive procedures for removal of intracranial hematoma on matrix metalloproteinase expression and blood-brain barrier permeability in perihematomal brain tissues. AB - OBJECTIVE: To observe the effects of minimally invasive removal of intracerebral hematoma on perihematomal matrix metalloproteinase (MMP)-9 expressions and permeability of blood-brain barrier (BBB). METHODS: Twenty-four rabbits of 2.8 3.4 kg body weight (regardless of male and female) were selected and randomly divided into a control group and a minimally invasive group, and the model of intracranial hemorrhage (ICH) was established in the two groups by injecting fresh autologous non-anticoagulant blood into the brain basal ganglia of rabbits. The minimally invasive procedures for removal of intracranial hematoma were performed 6 hours after the model of ICH was established successfully. All the animals were killed on the first, third, and seventh days after the model of ICH was established, and the perihematomal brain tissues were extracted to observe MMP-9 expressions by immunohistochemical methods. The permeability of BBB was detected by Evans blue (EB) as a tracer. RESULTS: The numbers of neurons with expression of MMP-9 in perihematomal brain tissues on the first, third, and seventh days after minimally invasive removal of hematoma were 5.00+/-2.94, 13.75+/-7.89, and 8+/-6.98 respectively, while in model control group were 25.25+/-6.85, 39.01+/-10.68, and 23.12+/-5.72 respectively. Expression of MMP-9 in the minimally invasive group decreased significantly as compared with that of model control group, and a significant difference was observed. The content of EB in perihematomal brain tissues on the first, third and seventh days was 28.41+/ 0.72, 34.04+/-1.48, and 26.30+/-0.78 MUg respectively in minimally invasive group, and 31.24+/-1.02, 37.13+/-1.57, and 28.72+/-0.23 MUg in the control group. A significant decrease in EB content in minimally invasive group was observed in the brain tissue around the hematoma as compared with that of control group, suggesting that the BBB permeability was reduced. CONCLUSIONS: The minimally invasive procedure for removal of intracranial hematoma could decrease the MMP-9 expression and BBB permeability in perihematomal brain tissues. It might be helpful in reducing secondary brain damages after intracerebral hemorrhage. PMID- 20712923 TI - Internal carotid artery agenesis: diagnosis, clinical spectrum, associated conditions and its importance in the era of stroke interventions. AB - BACKGROUND: Internal carotid artery (ICA) agenesis has been usually reported as an asymptomatic condition in association with other congenital anomalies. However, it is less well described in the context of clinical neurological syndromes. METHOD: Five cases of ICA agenesis are reviewed. The diagnosis of ICA agenesis was based on the absence of bony carotid canal on computed tomography. Brain CT and magnetic resonance image (MRI) scans were done in all the patients and four vessels digital angiograms were obtained in two. Clinical presentation, coexistent radiological findings and associated abnormalities are reviewed. FINDINGS: The initial presentations were pulsatile tinnitus, ischemic stroke, migraine, Horner's syndrome, and subarachnoid hemorrhage. Collateral circulation was supplied via the posterior communicating artery and the anterior communicating artery. Ophthalmic artery was supplied by meningeal arteries. On CT, all cases demonstrated agenesis of the bony carotid canal. Smaller cavernous sinus were detected in all cases, enlargement of the foramen spinosum was found in three patients and hyper-pneumatization of the petrous apex was detected in two cases. In one patient a cerebral aneurysms was detected and treated with an endovascular approach. Other associated vascular abnormalities were aortic origin of the vertebral artery in two patients, ICA coiling in two cases and fenestration of basilar artery in one case. CONCLUSION: ICA agenesis is usually asymptomatic but occasionally may be associated with ischemic stroke. Collateral supply is usually effective in preventing stroke but may become inefficient leading to ischemia. Associated anomalies such as cerebral aneurysms are commonly depicted on the same side as the ICA agenesis and may represent a potential life threatening condition. PMID- 20712924 TI - L-arginine reactivity in cerebral vessels after severe traumatic brain injury. AB - OBJECTIVES: Traumatic brain injury (TBI) causes an early reduction of cerebral blood flow (CBF). The purpose was to study cerebrovascular endothelial function by examining the reactivity of cerebral vessels to L-arginine. METHODS: Fifty-one patients with severe TBI were prospectively studied by measuring cerebral hemodynamics before and after the administration of L-arginine, 300 mg/kg at 12 hours and at 48 hours after injury. These hemodynamic measurements, using transcranial Doppler techniques, included internal carotid flow volume as an estimate of hemispheric CBF, flow velocity in intracranial vessels, CO(2) reactivity, and dynamic pressure autoregulation using thigh cuff deflation and carotid compression methods. Changes in the hemodynamics with L-arginine administration were analyzed using a general linear mixed model. RESULTS: L arginine produced no change in mean arterial pressure, intracranial pressure, or brain oxygenation. Overall, L-arginine induced an 11.3% increase in internal carotid artery flow volume (P=0.0190). This increase was larger at 48 hours than at 12 hours (P=0.0045), and tended to be larger in the less injured hemisphere at both time periods. The response of flow velocity in the intracranial vessels was similar, but smaller differences with administration of L-arginine were observed. There was a significant improvement in CO(2) reactivity with L-arginine, but no change in dynamic pressure autoregulation. DISCUSSION: The low response of the cerebral vessels to L-arginine at 12 hours post-injury with improvement at 48 hours suggests that dysfunction of cerebrovascular endothelium plays a role in the reduced CBF observed after TBI. PMID- 20712925 TI - Leptomeningeal collateral and cerebral hemodynamics in patients with ICA and MCA steno-occlusion. AB - OBJECTIVES: The purpose of our study was to evaluate the correlation between fluid-attenuated inversion recovery (FLAIR) images of hyperintense vessel (HV), a representative of leptomeningeal vessels (LMVs), and cerebral vascular hemodynamic status in patients with steno-occlusive disease of the internal carotid artery (ICA) and middle cerebral artery (MCA). METHODS: Sixty-eight patients with unilateral ICA or MCA stenosis or occlusion were enrolled. Correlations between hyperintense vessel (HV) on FLAIR images and hemodynamic status measured by quantitative single-photon emission computed tomography data were evaluated in four groups: affected (A) and non-affected (B) hemispheres in HV-positive patients, and affected (C) and non-affected (D) hemispheres in HV negative patients. RESULTS: The presence of HV was most frequently seen on affected hemispheres in patients with MCA and ICA occlusions. HV was significantly higher in the anterior communicating artery (AcomA) (-), posterior communicating artery (PcomA) (-) group than in other groups, which included either or both AcomA and PcomA (P = 0.008). The presence of HV had a significant correlation with transdural anastomosis (P = 0.046) and LMV (P = 1.64*10(-9)). No significant difference was observed in resting regional cerebral blood flow among the four groups. Vascular reserve in group A was significantly less compared to other groups (P = 0.021). CONCLUSIONS: HV is related to the hemisphere with severe ICA and MCA steno-occlusion when the circle of Willis is insufficient. The HV-positive hemisphere on the steno-occlusive side shows a lower vascular reserve than that in the contralateral hemisphere or HV-negative hemispheres. PMID- 20712926 TI - Adaptively controlling deep brain stimulation in essential tremor patient via surface electromyography. AB - OBJECTIVES: We present patient test outcomes to show that on-off control of deep brain stimulation sequences in essential tremor patients is achievable in a self adaptive manner via non-invasive surface-electromyography, to prevent tremors in these patients. METHOD: In our study, an essential tremor patient, who underwent bilateral deep brain stimulation implantation 8 years earlier, was subjected to deep brain stimulation at 130 pulses/second, with a 90-microsecond pulse-width, in packets of durations from 20 to 73 seconds and was monitored with surface electromyography. RESULTS: At the end of these stimulation packets, tremor-free intervals followed, averaging over 20 seconds, before tremor reappeared. Wavelet analysis of the eletromyographic signals allowed predicting onset of tremors at the end of the tremor-free intervals and was successful in all test cycles. Furthermore, once stimulation was restarted, the tremors disappeared within 0.5 seconds on average. When restarting stimulation approximately 2 seconds ahead of the end of tremor-free post-simulation intervals as predicted by visual inspection of unprocessed electromyograms, no tremors occurred during three successive cycles of stimulation-on and stimulation-off. Maximal ratio of tremor free duration to stimulation duration was computed, to determine a best DBS (deep brain stimulation) duration range (20-35 seconds). CONCLUSIONS: We show existence of a tremor-free interval averaging over 20 seconds that follows applying stimulation packets of 20-35 seconds and that surface electomyogram allows predicting onset of tremor to facilitate activation of a next stimulation packet before tremor reappears. This establishes the feasibility of electromyographic based predictive on-off control of deep brain stimulation in certain essential tremor patients. Best tremor-free duration to stimulation duration ratio may differ over the progression of the disorder and from patient to patient. PMID- 20712927 TI - Accountability metrics and paying for performance in education and health care. AB - The track record in paying for performance in education is not good; nevertheless, emphasis on accountability and performance has gained momentum in the last 25 years. This emphasis includes systems of merit pay, career ladders, and national board certification. The general failures of these efforts have led some reformers to suggest that teacher pay be directly related to student value added performance. This suggestion remains controversial but is also the hottest topic in paying for performance in education. Although many similarities exist between education and health care, major differences may make it even harder to install pay-for-performance systems in health than in education. If those systems are to be tried, experiments should begin in a bottom-up fashion at the unit level, rather than being imposed systemwide. PMID- 20712928 TI - Population health rankings as policy indicators and performance measures. AB - Population health rankings can be used by various actors for different purposes. This article examines those potential uses and concludes that the chief promise of population health rankings lies in 2 areas. The first is to help set agendas - stimulating awareness, motivation, and debate over means to improved health outcomes. The second is to help establish broad responsibility for population health and the need for multisectoral collaboration to improve outcomes. A new performance regime based on rankings will require more research to establish causal pathways and relative determinants of health, as well as stronger evidence about the effects of public and private interventions to guide investment strategies. Finally, leaders who develop and promote population health rankings must further develop the technical community needed to translate the response to the rankings into constructive public debate and policy development. PMID- 20712929 TI - Learning from the European experience of using targets to improve population health. AB - Health targets have become a widely used instrument to promote population health. We describe the experience in England, where the use of targets has reached the most advanced stage of development, and other European countries. The experience demonstrates that targets may change the behavior of a health system, probably to a larger extent than many other policy instruments, if incentives are aligned correctly and if measures to deal with unintended effects are put in place. PMID- 20712930 TI - Reach and effectiveness of a weight loss intervention in patients with prediabetes in Colorado. AB - INTRODUCTION: Although lifestyle interventions are effective in delaying the onset of diabetes, translating these lessons to routine health care settings remains a challenge. We investigated the effectiveness of a theory-based, brief, small-group weight loss intervention for diabetes prevention. A secondary purpose was to determine the potential reach of the intervention. METHODS: A total of 14,379 members of an integrated health care organization newly diagnosed with prediabetes were potentially eligible to participate in this matched cohort longitudinal study. Of this group, 1,030 attended a 90-minute, small-group session that targeted personal action planning for healthful eating, physical activity, and weight management. We accessed electronic medical records to select 1 to 2 controls (matched on impaired fasting glucose measurement, sex, age, and body mass index) for each member who attended the small-group session (n = 760). Weight change, as recorded in the medical record, was the primary outcome. Mixed models analyses were used to adjust for matching variables and covariates and to account for individual random effects over time. RESULTS: Small-group participants lost significantly more weight than did their matched controls. A significantly higher proportion of small-group participants lost at least 5% of their body weight compared with controls. CONCLUSION: A brief, small-group weight loss intervention was effective. However, it did not reach broadly into the population that was at risk for diabetes. PMID- 20712931 TI - Residence in a distressed county in Appalachia as a risk factor for diabetes, Behavioral Risk Factor Surveillance System, 2006-2007. AB - INTRODUCTION: We compared the risk of diabetes for residents of Appalachian counties to that of residents of non-Appalachian counties after controlling for selected risk factors in states containing at least 1 Appalachian county. METHODS: We combined Behavioral Risk Factor Surveillance System data from 2006 and 2007 and conducted a logistic regression analysis, with self-reported diabetes as the dependent variable. We considered county of residence (5 classifications for Appalachian counties, based on economic development, and 1 for non-Appalachian counties), age, sex, race/ethnicity, education, household income, smoking status, physical activity level, and obesity to be independent variables. The classification "distressed" refers to counties in the worst 10%, compared with the nation as a whole, in terms of 3-year unemployment rate, per capita income, and poverty. RESULTS: Controlling for covariates, residents in distressed Appalachian counties had 33% higher odds (95% confidence interval, 1.10-1.60) of reporting diabetes than residents of non-Appalachian counties. We found no significant differences between other classifications of Appalachian counties and non-Appalachian counties. CONCLUSION: Residents of distressed Appalachian counties are at higher risk of diabetes than are residents of other counties. States with distressed Appalachian counties should implement culturally sensitive programs to prevent diabetes. PMID- 20712932 TI - Effects of perceived neighborhood characteristics and use of community facilities on physical activity of adults with and without disabilities. AB - INTRODUCTION: Using data from the 2004 Texas Behavioral Risk Factor Surveillance System, we investigated whether the physical activity behaviors of people with disabilities are related to their perceptions of the characteristics of the built environment and whether this relationship differs from that of people without disabilities. METHODS: The research questions were, "Are perceived neighborhood characteristics and reported use of community facilities associated with reported leisure-time physical activity for adults aged 18 to 64 years with disabilities?"; "Are perceived neighborhood characteristics and reported use of community facilities associated with reported moderate to vigorous physical activity for adults with disabilities?"; and "To what extent do perceived neighborhood characteristics, reported use of community facilities, reported leisure-time physical activity, and reported moderate to vigorous physical activity differ between adults with disabilities and without disabilities?" We used logistic regression to analyze the responses. RESULTS: People with disabilities were less likely to engage in leisure-time physical activity and meet recommendations for physical activity than people without disabilities. Participation of people with disabilities in leisure-time physical activity had significant correlations with positive perceptions of neighbors, physical activity, trails, parks, playgrounds, or sports fields, and with their use of private or membership-only recreation facilities. The presence of sidewalks was significantly related to whether people with disabilities met recommended levels of physical activity. CONCLUSION: Although people with disabilities engaged in less leisure-time physical activity and physical activity than people without disabilities, perceptions of the built environment and use of community facilities similarly affected people with and without disabilities. PMID- 20712933 TI - Differences in health and health behaviors between state employees and other employed adults in Oregon, 2007. AB - INTRODUCTION: Worksite health promotion and interventions have gained popularity among state agencies. We studied the health behaviors and health characteristics of adults employed in state agencies in Oregon and compared those state employees with the statewide population of employed, insured adults. METHODS: We used data from the Oregon Behavioral Risk Factor Surveillance System (BRFSS) and a modified BRFSS survey administered to state employees. State employees were compared with employed, insured BRFSS respondents in total and then separately for men and women. RESULTS: The prevalence of healthy weight was lower among state employees compared with the statewide population of employed, insured adults (29% vs 35%), and the prevalence of obesity was higher (35% vs 26%). State employees were also less likely to meet physical activity recommendations (44% vs 56%). Diabetes prevalence was higher among state employees (7% vs 5%), and self-reported excellent or very good health status was lower (54% vs 64%). CONCLUSION: State employees differ from the statewide population of employed, insured adults on a number of health behaviors and conditions. These differences suggest obesity prevention and diabetes control as priority areas for state agency worksite interventions. PMID- 20712934 TI - Commute times, food retail gaps, and body mass index in North Carolina counties. AB - INTRODUCTION: The prevalence of obesity is higher in rural than in urban areas of the United States, for reasons that are not well understood. We examined correlations between percentage of rural residents, commute times, food retail gap per capita, and body mass index (BMI) among North Carolina residents. METHODS: We used 2000 census data to determine each county's percentage of rural residents and 1990 and 2000 census data to obtain mean county-level commute times. We obtained county-level food retail gap per capita, defined as the difference between county-level food demand and county-level food sales in 2008, from the North Carolina Department of Commerce, and BMI data from the 2007 North Carolina Behavioral Risk Factor Surveillance System. To examine county-level associations between BMI and percentage of rural residents, commute times, and food retail gap per capita, we used Pearson correlation coefficients. To examine cross-sectional associations between individual-level BMI (n = 9,375) and county level commute times and food retail gap per capita, we used multilevel regression models. RESULTS: The percentage of rural residents was positively correlated with commute times, food retail gaps, and county-level BMI. Individual-level BMI was positively associated with county-level commute times and food retail gaps. CONCLUSION: Longer commute times and greater retail gaps may contribute to the rural obesity disparity. Future research should examine these relationships longitudinally and should test community-level obesity prevention strategies. PMID- 20712935 TI - Using multiple sources of data to assess the prevalence of diabetes at the subcounty level, Duval County, Florida, 2007. AB - INTRODUCTION: Diabetes rates continue to grow in the United States. Effectively addressing the epidemic requires better understanding of the distribution of disease and the geographic clustering of factors that influence it. Variations in the prevalence of diabetes at the local level are largely unreported, making understanding the disparities associated with the disease more difficult. Diabetes death rates during the past 15 years in Duval County, Florida, have been disproportionately high compared with the rest of the state. METHODS: We analyzed multiple sources of secondary data related to diabetes illness and death in Duval County, including data on hospital discharge, emergency department (ED) use, and vital statistics. We accessed diabetes and diabetes-related ED use and hospitalization and death data by using codes from the International Classification of Diseases versions 9 and 10. We analyzed data from the Behavioral Risk Factor Surveillance System survey for Duval County and adapted Centers for Disease Control and Prevention weighting formulas for subcounty analysis. We used relative risk-type disease ratios and geographic information systems mapping to analyze data. RESULTS: The urban, mostly minority, low socioeconomic area of Duval County had twice the rate of diabetes-related illness and death as other areas of the county, and the inner-city, poor area of the county had almost 3 times the rate of hospitalization and ED use for diabetes and diabetes-related conditions compared with the other areas of the county. CONCLUSION: Our analyses show that diabetes-related disparities affect not only people and their families but also the community that absorbs the costs associated with the disproportionate health care use that results from these disparities. Analyzing data at the subcounty level has implications for health care planning and public health policy development at the local level. PMID- 20712936 TI - Cost-effectiveness analysis of efforts to reduce risk of type 2 diabetes and cardiovascular disease in southwestern Pennsylvania, 2005-2007. AB - INTRODUCTION: We assessed the cost-effectiveness of a community-based, modified Diabetes Prevention Program (DPP) designed to reduce risk factors for type 2 diabetes and cardiovascular disease. METHODS: We developed a Markov decision model to compare costs and effectiveness of a modified DPP intervention with usual care during a 3-year period. Input parameters included costs and outcomes from 2 projects that implemented a community-based modified DPP for participants with metabolic syndrome, and from other sources. The model discounted future costs and benefits by 3% annually. RESULTS: At 12 months, usual care reduced relative risk of metabolic syndrome by 12.1%. A modified DPP intervention reduced relative risk by 16.2% and yielded life expectancy gains of 0.01 quality-adjusted life-years (3.67 days) at an incremental cost of $34.50 ($3,420 per quality adjusted life-year gained). In 1-way sensitivity analyses, results were sensitive to probabilities that risk factors would be reduced with or without a modified DPP and that patients would enroll in an intervention, undergo testing, and acquire diabetes with or without an intervention if they were risk-factor positive. Results were also sensitive to utilities for risk-factor-positive patients. In probabilistic sensitivity analysis, the intervention cost less than $20,000 per quality-adjusted life-year gained in approximately 78% of model iterations. CONCLUSION: We consider the modified DPP delivered in community and primary care settings a sound investment. PMID- 20712937 TI - Evaluating a preventive services index to adjust for healthy behaviors in observational studies of older adults. AB - INTRODUCTION: Analysis of outcome measures from nonrandomized, observational studies of people participating or not participating in health programs may be suspect because of selection bias. For example, fitness programs may preferentially enroll people who are already committed to healthy lifestyles, including use of preventive services. Some of our earlier studies have attempted to account for this potential bias by including an ad hoc preventive services index created from the patient's number of earlier clinical preventive services, to adjust for health-seeking behaviors. However, this index has not been validated. We formally evaluated the performance of this preventive services index by comparing it with its component parts and with an alternative index derived from principal component analysis by using the weighted sums of the principal components. METHODS: We used data from a cohort of 38,046 older adults. We used the following variables from the administrative database of a health maintenance organization to create this index: fecal occult blood test, flexible sigmoidoscopy, screening mammogram, prostate cancer screening, influenza vaccination, pneumococcal vaccination, and preventive care office visits. RESULTS: The preventive services index was positively correlated with each of the following components: colon cancer screening (r = .752), screening mammogram (r = .559), prostate cancer screening (r = .592), influenza vaccination (r = .844), pneumococcal vaccination (r = .487), and preventive care office visits (r = .737). An alternative preventive services index, created by using principal component analysis, had similar performance. CONCLUSION: A preventive services index created by using administrative data has good face validity and construct validity and can be used to partially adjust for selection bias in observational studies of cost and use outcomes. PMID- 20712938 TI - Achieving a high response rate with a health care provider survey, Washington State, 2006. AB - BACKGROUND: Growing evidence of deficiencies in patient safety, health outcomes, cost, and overall quality of care in the United States has led to proposed initiatives and conceptual frameworks for improvement. A means for feasible, valid, and ongoing measurement of health care quality is necessary for planning and evaluating such initiatives. COMMUNITY CONTEXT: We sought to assess and improve health care quality for the management of chronic diseases in Washington State. We used the Chronic Care Model to develop a survey for health care providers and systems that measured quality of care and monitored improvement for multiple chronic conditions. METHODS: We surveyed a random sample of primary care providers and their clinic managers. We used 2 complementary tools: a provider questionnaire (administered by mail) and a clinic manager questionnaire (administered by telephone) to measure intermediate indicators of health care quality. OUTCOME: We achieved high response rates (78% for physicians, 82% for physician assistants, and 71% for clinic managers). INTERPRETATION: Our survey administration methods, or modified versions of these methods, may be effective for obtaining high response rates as part of ongoing monitoring of health care quality. PMID- 20712939 TI - Can incentives improve population health? An interview with Bridget Booske, PhD. Interview by Fran Kritz. PMID- 20712940 TI - Observations on incentives to improve population health. PMID- 20712941 TI - Creating incentives to improve population health. PMID- 20712942 TI - Principles to guide the development of population health incentives. AB - Improving population health is not simple. Many instruments are available for changing behavior and consequent outcomes. However, the following basic principles should guide development of any incentive arrangement: 1) identify the desired outcome, 2) identify the behavior change that will lead to this outcome, 3) determine the potential effectiveness of the incentive in achieving the behavior change, 4) link a financial incentive directly to this outcome or behavior, 5) identify the possible adverse effects of the incentive, and 6) evaluate and report changes in the behavior or outcome in response to the incentive. A wide range of financial and nonfinancial incentives is available to encourage efficient behaviors and discourage costly and unproductive ones. Evidence for the beneficial effects of incentive programs has been slow to emerge, partly because such evidence must show how behaviors have changed because of the incentive. Nevertheless, the potential for incentive programs in health care seems large, and research should support their design and assess their effect. PMID- 20712943 TI - Understanding the production of population health and the role of paying for population health. AB - This article considers 2 related themes that address population health outcomes and the contributions to those outcomes by time, place, individual behaviors and choices, and activities of various social sectors. First, what does it mean to "produce" population health, and how can the production of health be understood empirically? Second, through what processes can incentives be modified to improve population health? Among the issues that arise are understanding the mechanisms through which paying for population health works and how the health-producing incentives materialize in various sectors, especially those whose primary functions are not generally viewed as fostering better population health. PMID- 20712944 TI - Using social marketing to manage population health performance. AB - Population health can be affected by implementing pay-for-performance measures with key players. From a social marketing perspective, people (both consumers and managers) have choices and will do what they perceive enhances their own self interest. The bottom-up focus of social marketing begins with an understanding of the people whose behaviors are targeted. Desired behavior results when people perceive that they will get more value than the cost of behaving and when the resulting offer is perceived to be better than what is obtainable through alternative choices. Incentives should be offered to consumers; managers should receive motivation for their own behavior and understand how to motivate relevant consumers. Pay can be monetary or nonmonetary, tangible or intangible. Everyone is paid for performance. Some are paid well enough to behave as desired; others are offered a poor rate of pay and choose not to behave. PMID- 20712945 TI - Making better use of the policies and funding we already have. AB - The potential for population health reform could be enhanced by assessing whether we have made the most of policies and resources already available. Opportunities to promote population health independent of major changes in resources or public authority include the following: enforcing laws already in effect; clarifying and updating the application of long-standing policies; leveraging government's and the private sector's purchasing and investment clout; facilitating access to programs by everyone who is eligible for them; evaluating the effectiveness of population health programs, agencies, and policies; and intervening to stop agencies and policies from operating at cross-purposes. PMID- 20712946 TI - Paying for performance in population health: lessons from health care settings. AB - The appeal of pay-for-performance in health care derives from the conceptual view that paying doctors and hospitals more to deliver better care will encourage them to deliver better care. What lessons can be learned from the successes and failures of pay-for-performance in health care settings that apply to pay-for performance in population health? We argue that pay-for-performance requires conditions that are not easily met in population health settings. Pay-for performance has focused on narrow clinical problems whose success depends on identifiable actors with the motivation and resources to change clinical processes or outcomes. In contrast, population health has broad goals, many antecedents, and no single, identifiable fiduciary (a person who holds assets in trust for a beneficiary). Nevertheless, with careful attention, conditions for successful pay-for-performance in population health might be met. PMID- 20712948 TI - [New year wishes.]. PMID- 20712949 TI - Targeting Signal Pathways active in Cancer Stem Cells to Overcome Drug Resistance. PMID- 20712947 TI - Realizing and allocating savings from improving health care quality and efficiency. AB - International efforts to increase the quality and efficiency of health care services may be creating financial savings that can be used to improve population health. This article examines evidence that such savings (ie, a quality/efficiency or value dividend) are accruing and how they have been allocated and assesses the prospects for reallocating future savings to improve population health. Savings have resulted mainly from reducing the number of inappropriate or harmful interventions, managing care of people with chronic disease more effectively, and implementing health information technology. Savings to date have accrued to the revenues of public and private collective purchasers of care and large provider organizations, but none seem to have been reallocated to address other determinants of health. Furthermore, improved quality sometimes increases spending. PMID- 20712950 TI - DNA expression profiles of non-small cell lung cancer. AB - DNA expression profi ling using microarray technology has been applied to studies on the molecular classifi cation of lung cancers, pathogenetic alterations in gene expressions and cellular pathways, prediction of prognosis and metastasis, customized therapies, and drug development. Due to the wide variation in technical factors, different cohorts of patients and biological heterogeneity, the major hurdle to successful clinical application is lack of robustness, reliability and reproducibility of data. With better standardization and better analytic approaches to cut down the noises from the high dimensionality of data, microarray technologies may be ready to make its way to the doctor's offi ce with contribution to personalized treatment of lung cancer in the future. PMID- 20712951 TI - [Detection of IFN Response of Non-Specific Effects on RNAi.]. AB - BACKGROUND: The RNA interference (RNAi) approach is an efficient and widely used method for silencing specific genes and exploring their functions. However, numerous studies have highlighted the non-specific effects of RNAi experiments and the IFN response is one of the most common non-specific effects. In this research, we will study how to detect the IFN response in RNAi experiments. METHODS: Five different FLJ20420 siRNAs was transfected into human lung adenocarinoma cell line A549 using LipofectamineTM2000. The alternation of the interferon stimulated genes (ISGs) expression profile was analysed by real-time PCR and microarray assay. RESULTS: (1) Different FLJ20420 siRNA had different effect on silencing FLJ20420 mRNA expression in A549 cells, and FLJsiRNA-1 and -4 had the better effects to knockdown the expression of FLJ20420 (80% and 90% down regulation, respectively); (2) In analyzed 16 major ISGs, the expression of 14 of these genes was significantly increased in A549-FLJsiRNA-1 cells (P <0.05), while only 2 of these genes had a significant change in A549-FLJ-siRNA-4 cells. These results indicated an IFN response existed in A549-FLJ-siRNA-1 cells. (3) Microarray assay indicated that the expression of 51 ISGs were increased over 2 times in A549-FLJ-siRNA-1 cells, while only the expression of 6 ISGs were over 2 time in A549-FLJ-siRNA-4 cells. These results confirmed that there was an IFN response of non-specific effects of RNAi in A549 cells transfected with FLJ-siRNA 1. CONCLUSIONS: In RNAi experiments, siRNA can not only silence the target genes, but also may activate IFN response. The analysis of the expression change of the major ISGs by real-time PCR is a useful approach to explore the IFN response in RNAi experiments. PMID- 20712952 TI - [Construction, Expression and Purification of Wild and Mutant Type of nm23-H1 in Prokaryotic Expression System.]. AB - BACKGROUND: Nm23-H1 is a metastasis-suppressor gene. However, its molecular mechanism of suppressing metastasis is unknown until now. The aim of this study is to construct prokaryotic expression vector of wild and mutant type of nm23-H1 (WT, P96S, H118F), and then express and purify the proteins. METHODS: wild and mutant type of nm23-H1 fragments were amplified by PCR. The prokaryotic expression vectors of pET28anm23-H1 were constructed by gene recombination technique and verified by restriction enzyme analysis and sequencing. The positive clones were transformed into E. coli BL21 (DE3) and soluble analysis of the expression was conducted in this system. The proteins were purified by nickel column chromatography and identified by Western blot RESULTS: The sequences and open read frames of all the pET28a-nm23-H1 plasmids were completely correct. After transforming, these plasmids can express the target proteins. The protein production was very high, and all the proteins were soluble expression. The molecular weight of wild and mutant type of nm23-H1 was 20 kDa detected by Western blot, which was as the same as the objective protein. CONCLUSIONS: We have succeeded in constructing the prokaryotic expression vectors of pET28a-nm23 H1 (WT, P96S, H118F) and the proteins which expressed can be used in following studies. PMID- 20712953 TI - [Relationship between Mutations of the Epidermal Growth Factor Receptor Gene and Drug-Resistance to Gefitinib in Human Lung Cancer in vitro.]. AB - BACKGROUND: To explore cell lines' difference of drug-resistance to gefitinib and the underlying mechanism. METHODS: Human lung cancer cell lines of PC9, PC9/AB2, PC9/AB11, PC9/BB4 were treated in vitro, exons 18-21 of EGFR gene were sequenced and EGFR gene mRNA levels were measured. RESULTS: Four cell lines' drug resistance difference of gefitinib were validated. All the four cell lines had the 15 bp deletion at exon 19, and AB11 had A to G point-mutation at exon 20. PC9 EGFR gene in the sensitive cell line was expressed much higher than that in 3 resistance cell lines by real-time PCR. CONCLUSIONS: There is significant difference of drug-resistance to gefitinib existed among the lung cancer cell lines PC9, PC9/AB2, PC9/AB11 and PC9/BB4. The mutations changes of expressive level of EGFR gene might be correlated with the acquired drug-resistance to gefitinib in lung cancer cell lines. PMID- 20712954 TI - [The Effect of Endostatin and Radiotherapy on Human Lung Cancer Cell Line A549 and the Impact of HIF-1 Expression after Therapy.]. AB - BACKGROUND: It has been proven that radiotherapy can induce tumor cells over expressing HIF-1. The aim of this work is to investigate the effect of endostatin and radiotherapy on human lung cancer cell line A549 and the impact of HIF-1 expression after therapy. METHODS: Analysed the cell proliferation periods of the A549 cells after treated by endostatin. The A549 cells were treated with endostatin (ES) and/or radiotherpy (RT), and then the cell growth inhibiting rate was detected by methyl thiazolyl tetrazolium (MTT), the expression of HIF-1 was determined by enzyme linked immunosorbent assay (Elisa). RESULTS: Every treatments can inhibit the growth of A549 cells, but the cells treated with endostatin and radiotherapy were inhibited more obviously. Endostatin had the function of block cell periods on A549, it stoped the A549 cells at G2/M and S periods. Treatment of endostatin and radiotherapy can reduce the expression of HIF-1 induced by radiotherapy. CONCLUSIONS: Endostatin was synergistical with the effect of radiotherapy on inhibiting the growth rate of the A549 cells. This synergism may come from: endostatin can make A549 cells accumulated in G2-M and S transition, thereby inhibiting the proliferation of the A549 cells. HIF-1 is a important factor in resistant of cemotherapy and radiotherapy. Endostatin can inhibite the producing of HIF-1 by cells itself or induced by radiation, so increasing the treatment effect of radiotherapy. PMID- 20712955 TI - [A Meta-Analysis of Platinum Plus Gemcitabine or Vinorelbine for Advanced Non small Cell Lung Cancer.]. AB - BACKGROUND: Platinum plus the third-generation agent doublet chemotherapy is the standard regimens and first line chemotherapy for advanced non-small cell lung cancer (NSCLC). The aim of this study is to determine the benefits and harms of platinum plus gemcitabine or vinorelbine for advanced NSCLC. METHODS: The databases PubMed, CENTRAL, EMBASE and Chinese Biomedical Literature database were retrieved by using the key words "non small cell lung cancer" or "Carcinoma, Non Small Cell Lung" so as to search the studies about the randomized controlled clinical trials (RCT) that had compared the gemcitabine plus platinum versus vinorelbine plus platinum for advanced NSCLC. A meta-analysis was conducted. RESULTS: Nine randomized controlled trials, with total 2 186 patients, were included. The overall response rate and one-year survival rate of the gemcitabine group were not significantly different from that of vinorelbine regimen (RR=0.91, 95%CI: 0.81-1.03, P =0.15; RR=1.06, 95%CI: 0.96-1.18, P =0.27, respectively). The incidence rate of grade 3-4 netropenia, constipation, phlebitis and grade 1-4 neuropathy were higher in vinorelbine group, just like higher incidence rate of grade 3-4 thrombocytopenia in the gemcitabine group. CONCLUSIONS: The curative effects of the gemcitabine or vinorelbine plus platinum regimens are similar. The choice of gemcitabine or vinorelbine depends on the toxicity of the drugs and patients' tolerance. PMID- 20712956 TI - [The study of prethrombotic state in patients with lung cancer.]. AB - BACKGROUND: The prethrombotic state can be observed in advanced lung cancer patients. The aim of this study is to investigate the relationship between coagulation and fibrinolysis marks on pathophysiological characteristics and prognosis in patients with lung cancer. METHODS: The coagulation and fibgrinolysis marks were detected in sixty patients with lung cancer and twenty normal controls. RESULTS: The D-dimer, fibrinogen degradation products, plasma fibrinogen were significantly higher than those of normal controls. The plasma antithrombin III was significantly lower than those of normal controls. All marks in patients with lung cancer were not related to age, sex, histological classification, the size of the primary tumors, P-TNM stages, distant metastasis. The plasma levels of D-dimer and fibrinogen in patients with lung cancer were negatively correlated to survival. CONCLUSIONS: The patients with lung cancer have abnormal coagulation and fibrinolysis state, these contribute to hypercoagulability state and thrombi. The plasma levels of D-dimer and fibrinogen in patients with lung cancer were correlated with prognosis. The anticoagulability medicine treatment are benefit for the patients with lung cancer. PMID- 20712957 TI - [Relationship between Expression of beta-tubulin-III Plus Stathmin in Advanced Non-Small Cell Lung Cancer and its Sensitivity to Venorelbine Chemotherapy.]. AB - BACKGROUND: Vinorelbine plus cisplatin/carboplatin (NP) is one of the standard combination chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The aim of this study is to investigate the relationship between expression of Stathmin and beta-tubulin-III in NSCLC biopsies and sensitivity to Vinorelbine, which would provide a basis of the proper medicine choice for the patients' tailored chemotherapy. METHODS: Western blot was used to investigate the expression of Stathmin and beta-tubulin-III protein in the biopsies from stage IIIB-IV NSCLC patients. All the cases were divided into 4 groups according to the level of the two proteins, of which L represented both protein expressed lowly, B showed beta-tubulin-III lowly expressed group, while S showed Stathmin lowly, and H represented both protein highly expressed. At the same time, all the patients accepted NP chemotherapy for 2 or 4 cycles according to the responses to this regimen. The responses rate (RR), media survival time (MST), time to progress (TTP) were observed. RESULTS: A total of 90 stage IIIB-IV NSCLC patients were divided into 4 groups, 22 in L group, 23 in B and S group while 22 in H group respectively. The RR of the groups were 68.2%, 26.1%, 30.4% and 22.7% respectively. There were statistically significant differences between L group and other 3 groups (P <0.05). The MST were 377, 305, 321 and 271 days respectively, and the TTP were 240, 182, 190 and 166 days in the 4 groups. Statistically significant differences between L group and other 3 groups (P <0.05) can be seen in both MST and TTP. CONCLUSIONS: The expression of beta tubulin-III and Stathmin in advanced NSCLC biopsies had relationship with the sensitivity to NP chemotherapy regimen in the patients. Cases with high level of these two proteins would have poor responses to this cytotoxic drug. PMID- 20712958 TI - [Selective Expression of Calcium-Binding Protein S100A7 in Lung Cancer.]. AB - BACKGROUND: S100A7 is a member of S100 family and its overexpression has been previously associated with carcinogenesis of certain cancers. The aim of this study is to explore the expression of calcium-binding protein S100A7 in lung cancer. METHODS: In the present study, RT-PCR, Western-blot and immunohistochemistry were used to analyze the different expression of S100A7 in lung cancer tissues and paired noncancerous lung tissues. RESULTS: The specific expression of S100A7 was found in squamous cell carcinomas and large cell lung carcinomas, whereas it was not detected in adenocarcinomas, small cell carcinomas, other cell types of lung cancer and normal lung tissues as well as paired noncancerous lung tissues. CONCLUSIONS: S100A7 was selectively expressed in squamous cell carcinomas and large cell lung carcinomas and may serve as a potential marker for lung cancer diagnosis. PMID- 20712959 TI - [Role of NKG2D-Expressing NK Cells and sMICA in Immune Surveillance of Advanced Lung Cancer.]. AB - BACKGROUND: NKG2D-expressing NK cells and soluble major histocompatibility complex class I-related chain A (sMICA) is one of aroused general interests in tumor research area recently. The aim of the study is to investigate the levels of NKG2D-expressing NK cells and sMICA in peripheral blood of advanced lung cancer which are remarkably related to clinical significance and analyse the role of NKG2D-expressing NK cells and sMICA in immune surveillance. METHODS: Flow cytometry was used to determine the percentage of NKG2D-expressing NK cells, T cell subsets, NK cells, and ELISA was used to mesure the levels of sMICA in peripheral blood of 115 advanced lung cancer patients and 50 healthy controls. RESULTS: Compared with control group, the levels of sMICA, CD8+T cells, NK cells increased, while the levels of NKG2D-expressing NK cells, CD3+ T cells, CD4+ T cells, CD4+ T/CD8+ T in experimental group decreased. NKG2D-expressing NK cells had a perfect negative correlation with sMICA (r =-0.319, P <0.05). NKG2D expressing NK cells had positive correlation with CD4+ T cells, CD4+ T/CD8+ T and negative correlation with CD8+ T cells (P <0.05), sMICA had negative correlation with CD4+ T cells, CD4+ T/CD8+ T and positive correlation with CD8+ T cells (P <0.05), they had no significant correlation with CD3+ T cells, NK cells respectively (P <0.05). CONCLUSIONS: Accumulation of sMICA in serum may lead to the down-modulation of NKG2D-expressing NK which has been proposed to be a novel mechanism used by cancer cells to evade the tumor immunosurveillance. They may be potential indicators investigating immune functions and helpful in the evaluation of their happening and proceeding. PMID- 20712960 TI - [A case control study of lung cancer among workers in dagang oil field, tianjin, china.]. AB - BACKGROUND: To investigate the risk factors of lung cancer among the employees who had worked in Dagang oil field, Tianjin, China. METHODS: A matched case control study was conducted to analyse the association between some exposures and lung cancer risk by univariate and multiple Logistic regression method. RESULTS: According to the results from univariate and multiple analysis, smoking and previous lung disease increase lung cancer risk with adjusted OR of 1.52 (95%CI: 1.18-1.94) and 3.37 (95%CI: 1.88-7.16) respectively, while the adjusted OR for occupational chemical toxic substance and dust exposure is 0.73 (95%CI: 0.69 1.30) and 0.84 (95%CI: 0.62-1.15) respectively, and there is no significant association between family history of cancer and lung cancer risk in this study. CONCLUSIONS: Smoking and previous lung disease are the independent risk factors for lung cancer among workers in Dagang oil field, yet due to some potential epidemiological bias, the association between occupational exposure and lung cancer needs further investigation. PMID- 20712961 TI - [Protein kinase C inhibitor and treatment of non-small cell lung cancer.]. PMID- 20712962 TI - [Diagnosis and treatment of malignant pleural mesothelioma.]. PMID- 20712963 TI - [Advances of 8-hydroxy-2-deoxyguanosine Expression in Lung Cancer.]. PMID- 20712964 TI - [ERCC1 and Class III beta-tubulin Protein Expression in Relation to Tumour Response and Survival of Stage IIIB/IV NSCLC Patients Treated with TP/NP Chemotherapy Regimens.]. PMID- 20712965 TI - [A case report and literature review of double primary cancer in nasopharynx and lung.]. PMID- 20712966 TI - [Brochoscopic intervention for rare airway tumor.]. PMID- 20712967 TI - Tear dysfunction from lacrimal gland to LASIK. PMID- 20712968 TI - The first definition of Sjogren's syndrome. PMID- 20712969 TI - A lacrimal gland is a lacrimal gland, but rodent's and rabbit's are not human. AB - Research into the physiological processes governing both normal and abnormal functions of the lacrimal gland has used animal models to provide insights that might be applied to improving our understanding of human disease and designing of beneficial therapeutic interventions. Animal models most frequently used are mice, rats, and rabbits. As participants in research into normal and abnormal lacrimal gland function, the authors have observed significant differences between the various animal models, and these differences must be considered in investigational studies. This review summarizes a wide range of topics, including structural organization of the lacrimal gland and the immunological, secretomotor and hormonal processes regulating lacrimal gland function in all three animal models. In addition, comparisons with relevant aspects of the human lacrimal gland are included where permitted by available data. PMID- 20712971 TI - Techniques for culture and assessment of limbal stem cell grafts. AB - The therapeutic use of limbal cultures for the permanent regeneration of corneal epithelium in patients with limbal stem cell deficiency (LSCD) has been reported in many studies. According to the guidelines for good manufacturing practice (GMP), strictly regulated procedures and stringent quality control tests are now required to manipulate stem cells as "medicinal products" and make engraftment safer and eventually more successful. This paper describes techniques for optimal preparation of limbal stem cell grafts, including 1) a reliable impression cytology assay for the grading of LSCD, 2) culture methods that maintain high percentages of limbal stem cells, 3) the use of specific markers for the detection of corneal, conjunctival, and limbal stem cells, namely keratin 12, mucin 1, and DeltaNp63alpha, and 4) assays to assess the presence of contaminants, such as murine fibroblasts, endotoxins, mycoplasmae, and viral particles, in the cultured graft. The use of some of these assays allowed us to obtain a regenerated normal corneal epithelium in approximately 80% of 166 LSCD patients who received transplants from 2004 to 2008. PMID- 20712970 TI - Post-LASIK tear dysfunction and dysesthesia. AB - Symptoms of tear dysfunction after laser in situ keratomileusis (LASIK) occur in nearly all patients and resolve in the vast majority. Although dry eye complaints are a leading cause of patient discomfort and dissatisfaction after LASIK, the symptoms are not uniform, and the disease is not a single entity. Post-LASIK tear dysfunction syndrome or dry eye is a term used to describe a spectrum of disease encompassing transient or persistent post-operative neurotrophic disease, tear instability, true aqueous tear deficiency, and neuropathic pain states. Neural changes in the cornea and neuropathic causes of ocular surface discomfort may play a separate or synergistic role in the development of symptoms in some patients. Most cases of early post-operative dry eye symptoms resolve with appropriate management, which includes optimizing ocular surface health before and after surgery. Severe symptoms or symptoms persisting after 9 months rarely respond satisfactorily to traditional treatment modalities and require aggressive management. This review covers current theories of post-LASIK dry eye disease, pathophysiology, risk factors, and management options for this disease spectrum of post-LASIK tear dysfunction and neuropathic pain. PMID- 20712972 TI - Personal profile. Mark B. Abelson, MD, CM, FRCSC. PMID- 20712973 TI - Personalized medicine and the ocular surface. PMID- 20712974 TI - [The occlusion-orthodontics relationship: an interview with Jean-Daniel Orthlieb]. PMID- 20712975 TI - [Dentofacial Orthopedics to treat facial asymmetries before six years of age. How to balance craniofacial growth and enhance temporomandibular function]. AB - Minor facial asymmetries that can be detected in newborn infants indicate that facial growth for this child will also be asymmetric. When practitioners observe a displacement of the mandible in temporary dentition it probably indicates the presence of asymmetric masticatory function and they should look for an inter temporal axial asymmetry by tracing cutaneous landmarks in the vicinity of the external ears. If they find the possible presence of asymmetric remodeling of glenoid fossas, they have to anticipate future temporo-mandibular disorders. By using a measurement grid (Orthogrille type) placed on the teeth of the upper plaster cast, they can assess sagittal and transverse status of the temporary teeth. If indicated, they can use acrylic plates fitted with sectional distalizing or expansion screws designed for full or partial arch correction. They can also modify the upper occlusal plane inclination by using acrylic bite blocks that keep all of the teeth from occluding and thus allow the displaced mandible to return to symmetrical movements during mastication and at the same time allow the temporal bones to remodel symmetrically. Finally, they can re center the two dental arches and their midlines with a Frankel re-centering device that will also restore harmony to respiratory and vocalization functions. Thanks to this type of orthopedic treatment carried out for patients before they reach the age of six the asymmetric direction of their facial growth will become normal and the functioning of their temporo-mandibular joints will become optimal. PMID- 20712976 TI - [Aesthetic repercussions of the class II treatment on the profile: comparative study Distal Activ Concept (DAC)/Extra-Oral Force (EOF)]. AB - In the past orthodontists frequently used extra-oral force to slow down skeletal growth in their treatment of Class II malocclusions; more modern practice relies less on applying distal force to the maxilla than on stimulating forward growth of the mandible. Does this change in therapeutic design have any repercussions in facial esthetics? To evaluate the impact of treatment on the appearance of the profile, we conducted a study with 64 patients in the adolescent dentition stage with a Class II, division 1 malocclusions. None had teeth extracted or preliminary orthodontic treatment. We divided them into two sections; we treated the first group of 33 patients with the Distal Active Concept (DAC), which encourages forward movement and growth of the mandible, and we treated the second group of 31 patients with Extra-Oral Force (EOF) in combination with a full banded appliance. Comparing the results with cephalometric profile analyses, we found that the soft tissue contour of the lower part of the face showed considerably more sagittal development in the children treated by DAC than those treated by EOF. PMID- 20712977 TI - [About retention]. AB - The aim of temporary retention is not to eliminate every causes of relapse and to ensure the stability of treatment, but to eliminate one cause of relapse: the periodontal reactions consecutive to the orthodontic displacement of teeth. The other causes of relapse must be eliminated by the treatment itself, and not by retention. To be effective the retention must be immediate, complete and prolonged. The most used temporary retainers are: the Hawley retainer, the vacuum retainers and the bonded retainers. None of which is perfect. Only the permanent retention can ensure the stability whatever the cause of relapse. The risks of permanent retainers are not yet well known. PMID- 20712978 TI - [Supraclusion origins]. AB - Orthodontists often observe the clinical sign of supraclusion, or deep overbite, in their patients, a condition that is difficult to correct and that relapses frequently. In order to treat it with the most appropriate therapy, orthodontists should have a precise understanding of its etiology, which can be skeletal, neuromuscular, or dental and may often result from an intricate web of factors. In preparing their diagnoses, orthodontists should examine the possible mechanisms of its installation and evaluate them in an architectural cephalometric analysis of the oral prehensile complex. PMID- 20712979 TI - [Study of asymmetries in the severe antero-posterior disharmonies]. AB - Using the Treil 14 points cephalometric model orthodontists can prepare a complete cranio-facial anatomic assessment at three analytic levels: the framework or envelope, the basal bone and the alveolo-dental arcade. The assessment of border-line surgical antero-posterior dysmorphosis can elucidate interesting depictions of asymmetries, their relation to other malformities, and their genesis. Asymmetry arises from over-growth of one side of the face in all three dimensions of space even if, clinically, it often appears that one dimension is predominately affected. The ortho-morphic cases of Angle Class I present a little right excess or "natural" asymmetry. The Class III cases present a severe excess on the right side, while the Class II cases present an excess on the left side comparing with reference sample. PMID- 20712980 TI - [Early treatment of Class III: a long-term cohort study]. AB - The aim of this comparative retrospective short- and long-term study was to evaluate the interceptive treatment in Class III malocclusion in daily orthodontic practice. The sample was composed of 69 children divided into two groups according to the interceptive treatment applied: 31 children in group F (facial mask) and 38 in group M (interceptive fixed appliance). A Pancherz cephalometric analysis was carried out on the lateral head films at the start of the study (t(0), after the active treatment (t(1) and 29 months after t(1) (t(2). The two groups were compared at the beginning of the study by t-test and chi squared test: there were no difference between groups M and F except for facial divergence, which was greater in group M. Long-term comparison (interceptive and post-interceptive stage i.e. six years) showed that (i) overjet was corrected in each group: molar discrepancy was stable in both groups, (ii) alveolar discrepancy was stable and (iii) antero-posterior discrepancy was not improved in either group. At t(2) there were no differences, either qualitative or quantitative between groups M and F. In the end, more than 80% of the children did not need an orthognathic surgery. PMID- 20712981 TI - High mobility of bicoid captured by fluorescence correlation spectroscopy: implication for the rapid establishment of its gradient. AB - The Bicoid (Bcd) morphogen is essential for pattern formation in fruit flies. It forms an exponential concentration gradient along the embryo AP axis and turns on cascades of target genes in distinct anterior domains. The most commonly accepted model for gradient formation assumes that Bcd travels by simple diffusion and is uniformly degraded across syncytial embryos, yet several recent studies have challenged these ideas. Here, the question of Bcd mobility was investigated using fluorescence correlation spectroscopy in live Drosophila melanogaster embryos. Bcd-EGFP molecules were found to be highly mobile in the cytoplasm during cycles 12-14, with a diffusion coefficient approximately 7 microm(2)/s. This value is large enough to explain the stable establishment of the Bcd gradient simply by diffusion before cycle 8, i.e., before the onset of zygotic transcription. PMID- 20712982 TI - Mitochondrial free [Ca2+] increases during ATP/ADP antiport and ADP phosphorylation: exploration of mechanisms. AB - ADP influx and ADP phosphorylation may alter mitochondrial free [Ca2+] ([Ca2+](m)) and consequently mitochondrial bioenergetics by several postulated mechanisms. We tested how [Ca2+](m) is affected by H2PO4(-) (P(i)), Mg2+, calcium uniporter activity, matrix volume changes, and the bioenergetic state. We measured [Ca2+](m), membrane potential, redox state, matrix volume, pH(m), and O2 consumption in guinea pig heart mitochondria with or without ruthenium red, carboxyatractyloside, or oligomycin, and at several levels of Mg2+ and P(i). Energized mitochondria showed a dose-dependent increase in [Ca2+](m) after adding CaCl2 equivalent to 20, 114, and 485 nM extramatrix free [Ca2+] ([Ca2+](e)); this uptake was attenuated at higher buffer Mg2+. Adding ADP transiently increased [Ca2+](m) up to twofold. The ADP effect on increasing [Ca2+](m) could be partially attributed to matrix contraction, but was little affected by ruthenium red or changes in Mg2+ or P(i). Oligomycin largely reduced the increase in [Ca2+](m) by ADP compared to control, and [Ca2+](m) did not return to baseline. Carboxyatractyloside prevented the ADP-induced [Ca2+](m) increase. Adding CaCl2 had no effect on bioenergetics, except for a small increase in state 2 and state 4 respiration at 485 nM [Ca2+](e). These data suggest that matrix ADP influx and subsequent phosphorylation increase [Ca2+](m) largely due to the interaction of matrix Ca2+ with ATP, ADP, P(i), and cation buffering proteins in the matrix. PMID- 20712983 TI - The effects of replacing Sst2 with the heterologous RGS4 on polarization and mating in yeast. AB - RGS proteins stimulate the deactivation of heterotrimeric G-proteins. The yeast RGS protein Sst2 is regulated at both the transcriptional and posttranscriptional levels. We replaced the SST2 gene with the distantly related human RGS4 gene, which consists of the catalytic domain and an N-terminal membrane attachment peptide, and replaced the native promoter (P(SST2)) with the heterologous tetracycline-repressible promoter (P(TET)). We then measured the effect of the substitutions on pheromone sensitivity, mating, and polarization. Although the pheromone sensitivity was essentially normal, there were differences in mating and polarization. In particular, the RGS4-substituted strains did not form multiple mating projections at high levels of alpha-factor, but instead formed a single malformed projection, which frequently gave rise to a bud. We provide evidence that this phenotype arose because unlike Sst2, RGS4 did not localize to the projection. We use mathematical modeling to argue that localization of Sst2 to the projection prevents excess G-protein activation during the pheromone response. In addition, modeling and experiments demonstrate that the dose of Sst2 influences the frequency of mating projection formation. PMID- 20712984 TI - Hydrodynamics of sperm cells near surfaces. AB - Sperm are propelled by an actively beating tail, and display a wide variety of swimming patterns. When confined between two parallel walls, sperm swim either in circles or on curvilinear trajectories close to the walls. We employ mesoscale hydrodynamics simulations in combination with a mechanical sperm model to study the swimming behavior near walls. The simulations show that sperm become captured at the wall due to the hydrodynamic flow fields which are generated by the flagellar beat. The circular trajectories are determined by the chiral asymmetry of the sperm shape. For strong (weak) chirality, sperm swim in tight (wide) circles, with the beating plane of the flagellum oriented perpendicular (parallel) to the wall. For comparison, we also perform simulations based on a local anisotropic friction of the flagellum. In this resistive force approximation, surface adhesion and circular swimming patterns are obtained as well. However, the adhesion mechanism is now due to steric repulsion, and the orientation of the beating plane is different. Our model provides a theoretical framework that explains several distinct swimming behaviors of sperm near and far from a wall. Moreover, the model suggests a mechanism by which sperm navigate in a chemical gradient via a change of their shape. PMID- 20712985 TI - Gating of two mechanoelectrical transducer channels associated with a single tip link. AB - Although gating of mechanoelectrical transducer (MET) channels has been successfully described by assuming that one channel is associated with a tip link in the hair bundle, recent reports indicate that a single tip link is associated with more than one channel. To address the consistency of the model with the observations, gating of MET channels is described here by assuming that each tip link is associated with two identical MET channels, which are connected either in series or in parallel. We found that series connection does not lead to a single minimum of stiffness with respect to hair bundle displacement unless the minimum is above a certain positive value. Thus, negative stiffness must appear in pairs in the displacement axis. In contrast, parallel connection of the two channels predicts gating compliance similar to that predicted by the one-channel-per-tip link model of channel gating, within the physiological range of parameters. Parallel connection of MET channels is, therefore, a reasonable assumption to explain most experimental observations. However, the compatibility with series connection cannot be ruled out for experimental data on turtle hair cells. PMID- 20712986 TI - Architecture-dependent robustness and bistability in a class of genetic circuits. AB - Understanding the relationship between genotype and phenotype is a challenge in systems biology. An interesting yet related issue is why a particular circuit topology is present in a cell when the same function can supposedly be obtained from an alternative architecture. Here we analyzed two topologically equivalent genetic circuits of coupled positive and negative feedback loops, named NAT and ALT circuits, respectively. The computational search for the oscillation volume of the entire biologically reasonable parameter region through large-scale random samplings shows that the NAT circuit exhibits a distinctly larger fraction of the oscillatory region than the ALT circuit. Such a global robustness difference between two circuits is supplemented by analyzing local robustness, including robustness to parameter perturbations and to molecular noise. In addition, detailed dynamical analysis shows that the molecular noise of both circuits can induce transient switching of the different mechanism between a stable steady state and a stable limit cycle. Our investigation on robustness and dynamics through examples provides insights into the relationship between network architecture and its function. PMID- 20712987 TI - A microscopic formulation for the actin-driven motion of listeria in curved paths. AB - Using a generalized Brownian ratchet model that accounts for the interactions of actin filaments with the surface of Listeria mediated by proteins like ActA and Arp2/3, we have developed a microscopic model for the movement of Listeria. Specifically, we show that a net torque can be generated within the comet tail, causing the bacteria to spin about its long axis, which in conjunction with spatially varying polymerization at the surface leads to motions of bacteria in curved paths that include circles, sinusoidal-like curves, translating figure eights, and serpentine shapes, as observed in recent experiments. A key ingredient in our formulation is the coupling between the motion of Listeria and the force-dependent rate of filament growth. For this reason, a numerical scheme was developed to determine the kinematic parameters of motion and stress distribution among filaments in a self-consistent manner. We find that a 5-15% variation in polymerization rates can lead to radii of curvatures of the order of 4-20 microm, measured in experiments. In a similar way, our results also show that most of the observed trajectories can be produced by a very low degree of correlation, <10%, among filament orientations. Since small fluctuations in polymerization rate, as well as filament orientation, can easily be induced by various factors, our findings here provide a reasonable explanation for why Listeria can travel along totally different paths under seemingly identical experimental conditions. Besides trajectories, stress distributions corresponding to different polymerization profiles are also presented. We have found that although some actin filaments generate propelling forces that push the bacteria forward, others can exert forces opposing the movement of Listeria, consistent with recent experimental observations. PMID- 20712988 TI - RhoA regulates calcium-independent periodic contractions of the cell cortex. AB - When microtubules are depolymerized in spreading cells, they experience morphological oscillations characterized by a period of about a minute, indicating that normal interactions between the microfilament and microtubule systems have been significantly altered. This experimental system provides a test bed for the development of both fine- and coarse-grained models of complex motile processes, but such models need to be adequately informed by experiment. Using criteria based on Fourier transform analysis, we detect spontaneous oscillations in spreading cells. However, their amplitude and tendency to operate at a single frequency are greatly enhanced by microtubule depolymerization. Knockdown of RhoA and addition of various inhibitors of the downstream effector of RhoA, Rho kinase, block oscillatory behavior. Inhibiting calcium fluxes from endoplasmic reticulum stores and from the extracellular medium does not significantly affect the ability of cells to oscillate, indicating that calcium plays a subordinate regulatory role compared to Rho. We characterized the dynamic structure of the oscillating cell by light, fluorescence, and electron microscopy, showing how oscillating cells are dynamically polarized in terms of their overall morphology, f-actin and phosphorylated myosin light chain distribution, and nuclear position and shape. Not only will these studies guide future experiments, they will also provide a framework for the development of refined mathematical models of the oscillatory process. PMID- 20712989 TI - Tectorial membrane morphological variation: effects upon stimulus frequency otoacoustic emissions. AB - The tectorial membrane (TM) is widely believed to play an important role in determining the ear's ability to detect and resolve incoming acoustic information. While it is still unclear precisely what that role is, the TM has been hypothesized to help overcome viscous forces and thereby sharpen mechanical tuning of the sensory cells. Lizards present a unique opportunity to further study the role of the TM given the diverse inner-ear morphological differences across species. Furthermore, stimulus-frequency otoacoustic emissions (SFOAEs), sounds emitted by the ear in response to a tone, noninvasively probe the frequency selectivity of the ear. We report estimates of auditory tuning derived from SFOAEs for 12 different species of lizards with widely varying TM morphology. Despite gross anatomical differences across the species examined herein, low-level SFOAEs were readily measurable in all ears tested, even in non TM species whose basilar papilla contained as few as 50-60 hair cells. Our measurements generally support theoretical predictions: longer delays/sharper tuning features are found in species with a TM relative to those without. However, SFOAEs from at least one non-TM species (Anolis) with long delays suggest there are likely additional micromechanical factors at play that can directly affect tuning. Additionally, in the one species examined with a continuous TM (Aspidoscelis) where cell-to-cell coupling is presumably relatively stronger, delays were intermediate. This observation appears consistent with recent reports that suggest the TM may play a more complex macromechanical role in the mammalian cochlea via longitudinal energy distribution (and thereby affect tuning). Although significant differences exist between reptilian and mammalian auditory biophysics, understanding lizard OAE generation mechanisms yields significant insight into fundamental principles at work in all vertebrate ears. PMID- 20712990 TI - A molecular dynamics investigation of vinculin activation. AB - Vinculin activation plays a critical role in focal adhesion initiation and formation. In its native state, vinculin is in an autoinhibitory conformation in which domain 1 prevents interaction of the vinculin tail domain with actin by steric hindrance. Once activated, vinculin is able to interact with both actin and talin. Several hypotheses have been put forth addressing the mechanisms of vinculin activation. One set of studies suggests that vinculin interaction with talin is sufficient to cause activation, whereas another set of studies suggests that a simultaneous interaction with several binding partners is necessary to achieve vinculin activation. Using molecular-dynamics (MD) simulations, we investigate the mechanisms of vinculin activation and suggest both a trajectory of conformational changes leading to vinculin activation, and key structural features that are likely involved in stabilizing the autoinhibited conformation. Assuming that the simultaneous interaction of vinculin with both actin and talin causes a stretching force on vinculin, and that vinculin activation results from a removal of steric hindrance blocking the actin-binding sites, we simulate with MD the stretching and activation of vinculin. The MD simulations are further confirmed by normal-mode analysis and simulation after residue modification. Taken together, the results of these simulations suggest that bending of the vinculin-binding-site region in vinculin away from the vinculin tail is the likely trajectory of vinculin activation. PMID- 20712991 TI - A mechanochemical model explains interactions between cortical microtubules in plants. AB - Microtubules anchored to the two-dimensional cortex of plant cells collide through plus-end polymerization. Collisions can result in rapid depolymerization, directional plus-end entrainment, or crossover. These interactions are believed to give rise to cellwide self-organization of plant cortical microtubules arrays, which is required for proper cell wall growth. Although the cell-wide self organization has been well studied, less emphasis has been placed on explaining the interactions mechanistically from the molecular scale. Here we present a model for microtubule-cortex anchoring and collision-based interactions between microtubules, based on a competition between cross-linker bonding, microtubule bending, and microtubule polymerization. Our model predicts a higher probability of entrainment at smaller collision angles and at longer unanchored lengths of plus-ends. This model addresses observed differences between collision resolutions in various cell types, including Arabidopsis cells and Tobacco cells. PMID- 20712992 TI - Actin filament length tunes elasticity of flexibly cross-linked actin networks. AB - Networks of the cytoskeletal biopolymer actin cross-linked by the compliant protein filamin form soft gels that stiffen dramatically under shear stress. We demonstrate that the elasticity of these networks shows a strong dependence on the mean length of the actin polymers, unlike networks with small, rigid cross links. This behavior is in agreement with a model of rigid filaments connected by multiple flexible linkers. PMID- 20712993 TI - Ion-dependent dynamics of DNA ejections for bacteriophage lambda. AB - We studied the control parameters that govern the dynamics of in vitro DNA ejection in bacteriophage lambda. Previous work demonstrated that bacteriophage DNA is highly pressurized, and this pressure has been hypothesized to help drive DNA ejection. Ions influence this process by screening charges on DNA; however, a systematic variation of salt concentrations to explore these effects has not been undertaken. To study the nature of the forces driving DNA ejection, we performed in vitro measurements of DNA ejection in bulk and at the single-phage level. We present measurements on the dynamics of ejection and on the self-repulsion force driving ejection. We examine the role of ion concentration and identity in both measurements, and show that the charge of counterions is an important control parameter. These measurements show that the mobility of ejecting DNA is independent of ionic concentrations for a given amount of DNA in the capsid. We also present evidence that phage DNA forms loops during ejection, and confirm that this effect occurs using optical tweezers. PMID- 20712994 TI - Phosphatidylinositol-4,5-bisphosphate (PIP(2)) stabilizes the open pore conformation of the Kv11.1 (hERG) channel. AB - Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is a phospholipid that has been shown to modulate several ion channels, including some voltage-gated channels like Kv11.1 (hERG). From a biophysical perspective, the mechanisms underlying this regulation are not well characterized. From a physiological perspective, it is critical to establish whether the PIP(2) effect is within the physiological concentration range. Using the giant-patch configuration of the patch-clamp technique on COS-7 cells expressing hERG, we confirmed the activating effect of PIP(2). PIP(2) increased the hERG maximal current and concomitantly slowed deactivation. Regarding the molecular mechanism, these increased amplitude and slowed deactivation suggest that PIP(2) stabilizes the channel open state, as it does in KCNE1-KCNQ1. We used kinetic models of hERG to simulate the effects of the phosphoinositide. Simulations strengthened the hypothesis that PIP(2) is more likely stabilizing the channel open state than affecting the voltage sensors. From the physiological aspect, we established that the sensitivity of hERG to PIP(2) comes close to that of KCNE1-KCNQ1 channels, which lies in the range of physiological PIP(2) variations. PMID- 20712995 TI - Cholesterol displaces palmitoylceramide from its tight packing with palmitoylsphingomyelin in the absence of a liquid-disordered phase. AB - A set of different biophysical approaches has been used to explore the phase behavior of palmitoylsphingomyelin (pSM)/cholesterol (Chol) model membranes in the presence and absence of palmitoylceramide (pCer). Fluorescence spectroscopy of di-4-ANEPPDHQ-stained pSM/Chol vesicles and atomic force microscopy of supported planar bilayers show gel L(beta)/liquid-ordered (L(o)) phase coexistence within the range X(Chol) = 0-0.25 at 22 degrees C. At the latter compositional point and beyond, a single L(o) pSM/Chol phase is detected. In ternary pSM/Chol/pCer mixtures, differential scanning calorimetry of multilamellar vesicles and confocal fluorescence microscopy of giant unilamellar vesicles concur in showing immiscibility, but no displacement, between L(o) cholesterol-enriched (pSM/Chol) and gel-like ceramide-enriched (pSM/pCer) phases at high pSM/(Chol + pCer) ratios. At higher cholesterol content, pCer is unable to displace cholesterol at any extent, even at X(Chol) < 0.25. It is interesting that an opposite strong cholesterol-mediated pCer displacement from its tight packing with pSM is clearly detected, completely abolishing the pCer ability to generate large microdomains and giving rise instead to a single ternary phase. These observations in model membranes in the absence of the lipids commonly used to form a liquid-disordered phase support the role of cholesterol as the key determinant in controlling its own displacement from L(o) domains by ceramide upon sphingomyelinase activity. PMID- 20712996 TI - Modeling smooth muscle myosin's two heads: long-lived enzymatic roles and phosphorylation-dependent equilibria. AB - Smooth muscle myosin has two heads, each capable of interacting with actin to generate force and/or motion as it hydrolyzes ATP. These heads are inhibited when their associated regulatory light chain is unphosphorylated (0P), becoming active and hydrolyzing ATP maximally when phosphorylated (2P). Interestingly, with only one of the two regulatory light chains phosphorylated (1P), smooth muscle myosin is active but its ATPase rate is <2P. To explain published 1P single ATP turnover and steady-state ATPase activities, we propose a kinetic model in which 1P myosin exists in an equilibrium between being fully active (2P) and inhibited (0P). Based on the single ATP turnover data, we also propose that each 2P head adopts a hydrolytic role distinct from its partner at any point in time, i.e., one head strongly binds actin and hydrolyzes ATP at its actin-activated rate while the other weakly binds actin. Surprisingly, the heads switch roles slowly (<0.1 s( 1)), suggesting that their activities are not independent. The phosphorylation dependent equilibrium between active and inhibited states and the hydrolytic role that each head adopts during its interaction with actin may have implications for understanding regulation and mechanical performance of other members of the myosin family of molecular motors. PMID- 20712997 TI - Bending the rules of transcriptional repression: tightly looped DNA directly represses T7 RNA polymerase. AB - From supercoiled DNA to the tight loops of DNA formed by some gene repressors, DNA in cells is often highly bent. Despite evidence that transcription by RNA polymerase (RNAP) is affected in systems where DNA is deformed significantly, the mechanistic details underlying the relationship between polymerase function and mechanically stressed DNA remain unclear. Seeking to gain additional insight into the regulatory consequences of highly bent DNA, we hypothesize that tightly looping DNA is alone sufficient to repress transcription. To test this hypothesis, we have developed an assay to quantify transcription elongation by bacteriophage T7 RNAP on small, circular DNA templates approximately 100 bp in size. From these highly bent transcription templates, we observe that the elongation velocity and processivity can be repressed by at least two orders of magnitude. Further, we show that minicircle templates sustaining variable levels of twist yield only moderate differences in repression efficiency. We therefore conclude that the bending mechanics within the minicircle templates dominate the observed repression. Our results support a model in which RNAP function is highly dependent on the bending mechanics of DNA and are suggestive of a direct, regulatory role played by the template itself in regulatory systems where DNA is known to be highly bent. PMID- 20712998 TI - The microrheology of sickle hemoglobin gels. AB - Sickle cell disease is a rheological disease, yet no quantitative rheological data exist on microscopic samples at physiological concentrations. We have developed a novel method for measuring the microrheology of sickle hemoglobin gels, based on magnetically driven compression of 5- to 8-microm-thick emulsions containing hemoglobin droplets approximately 80 microm in diameter. Using our method, by observing the expansion of the droplet area as the emulsion is compressed, we were able to resolve changes in thickness of a few nanometers with temporal resolution of milliseconds. Gels were formed at various initial concentrations and temperatures and with different internal domain structure. All behaved as Hookean springs with Young's modulus from 300 to 1500 kPa for gels with polymerized hemoglobin concentration from 6 g/dl to 12 g/dl. For uniform, multidomain gels, Young's modulus mainly depended on the terminal concentration of the gel rather than the conditions of formation. A simple model reproduced the quadratic dependence of the Young's modulus on the concentration of polymerized hemoglobin. Partially desaturated samples also displayed quadratic concentration dependence but with a smaller proportionality coefficient, as did samples that were desaturated in steps; such samples were significantly less rigid than gels formed all at once. The magnitude of the Young's modulus provides quantitative support for the dominant models of sickle pathophysiology. PMID- 20712999 TI - Thermal and structural stability of adsorbed proteins. AB - Experimental evidence suggests that proteins adsorbed to hydrophobic surfaces at low coverages are stabilized relative to the bulk. For larger coverages, proteins unfold and form beta-sheets. We performed computer simulations on model proteins and found that: 1), For weakly adsorbing surfaces, unfolded conformations lose more entropy upon adsorption than folded ones. 2), The melting temperature, both in the bulk and at surfaces, decreases with increasing protein concentration because of favorable interprotein interactions. 3), Proteins in the bulk show large unfolding free energy barriers; this barrier decreases at stronger adsorbing surfaces. We conjecture that typical experimental temperatures appear to be below the bulk melting temperature for a single protein, but above the melting temperature for concentrated protein solutions. Purely thermodynamic factors then explain protein stabilization on adsorption at low concentrations. However, both thermodynamic and kinetic factors are important at higher concentrations. Thus, proteins in the bulk do not denature with increasing concentration due to large kinetic barriers, even though the aggregated state is thermodynamically preferred. However, they readily unfold upon adsorption, with the surface acting as a heterogeneous catalyst. The thermal behavior of proteins adsorbed to hydrophobic surfaces thus appears to follow behavior independent of their chemical specificity. PMID- 20713000 TI - Triphasic force dependence of E-selectin/ligand dissociation governs cell rolling under flow. AB - During inflammation, flowing leukocytes tether to and roll on vascular surfaces through the association and dissociation of selectin/ligand bonds. The interactions of P- and L- selectins with their respective ligands exhibit catch slip bonds, such that increasing force initially prolongs and then shortens bond lifetimes. In addition, catch-slip bonds have been shown to govern L-selectin mediated cell rolling. Using a flow chamber and biomembrane force probe, we show a triphasic force dependence of E-selectin/ligand dissociation that initially behaves as slip bonds, then transitions to catch bonds, and finally transitions again to slip bonds as the force increases. These transitions govern the velocities of neutrophils, HL-60 cells, and Colo-205 cells rolling on E-selectin, as evidenced by the fact that their velocities exhibited a triphasic force dependence that inversely matched the triphasic lifetime-force relationship. At low forces, slip bonds may also precede catch bonds for interactions of P- and L selectin with their ligands. PMID- 20713001 TI - Squeezing protein shells: how continuum elastic models, molecular dynamics simulations, and experiments coalesce at the nanoscale. AB - The current rapid growth in the use of nanosized particles is fueled in part by our increased understanding of their physical properties and ability to manipulate them, which is essential for achieving optimal functionality. Here we report detailed quantitative measurements of the mechanical response of nanosized protein shells (viral capsids) to large-scale physical deformations and compare them with theoretical descriptions from continuum elastic modeling and molecular dynamics (MD). Specifically, we used nanoindentation by atomic force microscopy to investigate the complex elastic behavior of Hepatitis B virus capsids. These capsids are hollow, approximately 30 nm in diameter, and conform to icosahedral (5-3-2) symmetry. First we show that their indentation behavior, which is symmetry-axis-dependent, cannot be reproduced by a simple model based on Foppl von Karman thin-shell elasticity with the fivefold vertices acting as prestressed disclinations. However, we can properly describe the measured nonlinear elastic and orientation-dependent force response with a three-dimensional, topographically detailed, finite-element model. Next, we show that coarse-grained MD simulations also yield good agreement with our nanoindentation measurements, even without any fitting of force-field parameters in the MD model. This study demonstrates that the material properties of viral nanoparticles can be correctly described by both modeling approaches. At the same time, we show that even for large deformations, it suffices to approximate the mechanical behavior of nanosized viral shells with a continuum approach, and ignore specific molecular interactions. This experimental validation of continuum elastic theory provides an example of a situation in which rules of macroscopic physics can apply to nanoscale molecular assemblies. PMID- 20713002 TI - Flow-induced beta-hairpin folding of the glycoprotein Ibalpha beta-switch. AB - Flow-induced shear has been identified as a regulatory driving force in blood clotting. Shear induces beta-hairpin folding of the glycoprotein Ibalpha beta switch which increases affinity for binding to the von Willebrand factor, a key step in blood clot formation and wound healing. Through 2.1-micros molecular dynamics simulations, we investigate the kinetics of flow-induced beta-hairpin folding. Simulations sampling different flow velocities reveal that under flow, beta-hairpin folding is initiated by hydrophobic collapse, followed by interstrand hydrogen-bond formation and turn formation. Adaptive biasing force simulations are employed to determine the free energy required for extending the unfolded beta-switch from a loop to an elongated state. Lattice and freely jointed chain models illustrate how the folding rate depends on the entropic and enthalpic energy, the latter controlled by flow. The results reveal that the free energy landscape of the beta-switch has two stable conformations imprinted on it, namely, loop and hairpin--with flow inducing a transition between the two. PMID- 20713003 TI - The mechanism of VWF-mediated platelet GPIbalpha binding. AB - The binding of Von Willebrand Factor to platelets is dependent on the conformation of the A1 domain which binds to platelet GPIbalpha. This interaction initiates the adherence of platelets to the subendothelial vasculature under the high shear that occurs in pathological thrombosis. We have developed a thermodynamic strategy that defines the A1:GPIbalpha interaction in terms of the free energies (DeltaG values) of A1 unfolding from the native to intermediate state and the binding of these conformational states to GPIbalpha. We have isolated the intermediate conformation of A1 under nondenaturing conditions by reduction and carboxyamidation of the disulfide bond. The circular dichroism spectrum of reduction and carboxyamidation A1 indicates that the intermediate has approximately 10% less alpha-helical structure that the native conformation. The loss of alpha-helical secondary structure increases the GPIbalpha binding affinity of the A1 domain approximately 20-fold relative to the native conformation. Knowledge of these DeltaG values illustrates that the A1:GPIbalpha complex exists in equilibrium between these two thermodynamically distinct conformations. Using this thermodynamic foundation, we have developed a quantitative allosteric model of the force-dependent catch-to-slip bonding that occurs between Von Willebrand Factor and platelets under elevated shear stress. Forced dissociation of GPIbalpha from A1 shifts the equilibrium from the low affinity native conformation to the high affinity intermediate conformation. Our results demonstrate that A1 binding to GPIbalpha is thermodynamically coupled to A1 unfolding and catch-to-slip bonding is a manifestation of this coupling. Our analysis unites thermodynamics of protein unfolding and conformation-specific binding with the force dependence of biological catch bonds and it encompasses the effects of two subtypes of mutations that cause Von Willebrand Disease. PMID- 20713004 TI - Facilitated DNA search by multidomain transcription factors: cross talk via a flexible linker. AB - More than 70% of eukaryotic proteins are composed of multiple domains. However, most studies of the search for DNA focus on individual protein domains and do not consider potential cross talk within a multidomain transcription factor. In this study, the molecular features of the DNA search mechanism were explored for two multidomain transcription factors: human Pax6 and Oct-1. Using a simple computational model, we compared a DNA search of multidomain proteins with a search of isolated domains. Furthermore, we studied how manipulating the binding affinity of a single domain to DNA can affect the overall DNA search of the multidomain protein. Tethering the two domains via a flexible linker increases their affinity to the DNA, resulting in a higher propensity for sliding along the DNA, which is more significant for the domain with the weaker DNA-binding affinity. In this case, the domain that binds DNA more tightly anchors the multidomain protein to the DNA and, via the linker, increases the local concentration of the weak DNA-binding domain (DBD). The tethered domains directly exchange between two parallel DNA molecules via a bridged intermediate, where intersegmental transfer is promoted by the weaker DBD. We found that, in general, the relative affinity of the two domains can significantly affect the cross talk between them and thus their overall capability to search DNA efficiently. The results we obtained by examining various multidomain DNA-binding proteins support the necessity of discrepancies between the DNA-binding affinities of the constituent domains. PMID- 20713005 TI - Mechanism of cohesin loading onto chromosomes: a conformational dynamics study. AB - The structure-function relationship of cohesin, an essential chromosome maintenance protein, is investigated by analyzing its collective dynamics and conformational flexibility, enhancing our understanding of the sister chromatid cohesion process. A three-dimensional model of cohesin has been constructed by homology modeling using both crystallographic and electron microscopy image data. The harmonic dynamics of the cohesin structure are calculated with a coarse grained elastic network model. The model shows that the bending motion of the cohesin ring is able to adopt a head-to-tail conformation, in agreement with experimental data. Low-frequency conformational changes are observed to deform the highly conserved glycine residues at the interface of the cohesin heterodimer. Normal mode analysis further reveals that, near large globular structures such as nucleosome and accessory proteins docked to cohesin, the mobility of the coiled-coil regions is notably affected. Moreover, fully solvated molecular dynamics calculations, performed specifically on the hinge region, indicate that hinge opening starts from one side of the dimerization interface, and is coordinated by highly conserved glycine residues. PMID- 20713006 TI - Chemomechanical regulation of SNARE proteins studied with molecular dynamics simulations. AB - SNAP-25B is a neuronal protein required for neurotransmitter (NT) release and is the target of Botulinum Toxins A and E. It has two SNARE domains that form a four helix bundle when combined with syntaxin 1A and synaptobrevin. Formation of the three-protein complex requires both SNARE domains of SNAP-25B to align parallel, stretching out a central linker. The N-terminal of the linker has four cysteines within eight amino acids. Palmitoylation of these cysteines helps target SNAP-25B to the membrane; however, these cysteines are also an obvious target for oxidation, which has been shown to decrease SNARE complex formation and NT secretion. Because the linker is only slightly longer than the SNARE complex, formation of a disulfide bond between two cysteines might shorten it sufficiently to reduce secretion by limiting complex formation. To test this idea, we have carried out molecular dynamics simulations of the SNARE complex in the oxidized and reduced states. Indeed, marked conformational differences and a reduction of helical content in SNAP-25B upon oxidation are seen. Further differences are found for hydrophobic interactions at three locations, crucial for the helix helix association. Removal of the linker induced different conformational changes than oxidation. The simulations suggest that oxidation of the cysteines leads to a dysfunctional SNARE complex, thus downregulating NT release during oxidative stress. PMID- 20713007 TI - Asymmetry as the key to clathrin cage assembly. AB - The self-assembly of clathrin proteins into polyhedral cages is simulated for the first time (to our knowledge) by introducing a coarse-grain triskelion particle modeled after clathrin's characteristic shape. The simulations indicate that neither this shape, nor the antiparallel binding of four legs along the lattice edges, is sufficient to induce cage formation from a random solution. Asymmetric intersegmental interactions, which probably result from a patchy distribution of interactions along the legs' surfaces, prove to be crucial for the efficient self assembly of cages. PMID- 20713008 TI - A yeast toxic mutant of HET-s((218-289)) prion displays alternative intermediates of amyloidogenesis. AB - Amyloids are thought to be involved in various types of neurodegenerative disorders. Several kinds of intermediates, differing in morphology, size, and toxicity, have been identified in the multistep amyloidogenesis process. However, the mechanisms explaining amyloid toxicity remain unclear. We previously generated a toxic mutant of the nontoxic HET-s((218-289)) amyloid in yeast. Here we report that toxic and nontoxic amyloids differ not only in their structures but also in their assembling process. We used multiple and complementary methods to investigate the intermediates formed by these two amyloids. With the methods used, no intermediates were observed for the nontoxic amyloid; however, under the same experimental conditions, the toxic mutant displayed visible oligomeric and fibrillar intermediates. PMID- 20713009 TI - Solid-state NMR spectroscopy of membrane-associated myelin basic protein- conformation and dynamics of an immunodominant epitope. AB - Myelin basic protein (MBP) maintains the tight multilamellar compaction of the myelin sheath in the central nervous system through peripheral binding of adjacent lipid bilayers of oligodendrocytes. Myelin instability in multiple sclerosis (MS) is associated with the loss of positive charge in MBP as a result of posttranslational enzymatic deimination. A highly-conserved central membrane binding fragment (murine N81-PVVHFFKNIVTPRTPPP-S99, identical to human N83-S101) represents a primary immunodominant epitope in MS. Previous low-resolution electron paramagnetic resonance measurements on the V83-T92 fragment, with Cys mutations and spin-labeling that scanned the epitope, were consistent with it being a membrane-associated amphipathic alpha-helix. Pseudodeimination at several sites throughout the protein, all distal to the central segment, disrupted the alpha-helix at its amino-terminus and exposed it to proteases, representing a potential mechanism in the autoimmune pathogenesis of MS. Here, we have used magic-angle spinning solid-state NMR spectroscopy to characterize more precisely the molecular conformation and dynamics of this central immunodominant epitope of MBP in a lipid milieu, without Cys-substitution. Our solid-state NMR measurements have revealed that the alpha-helix present within the immunodominant epitope is shorter than originally modeled, and is independent of the pseudodeimination, highlighting the importance of the local hydrophobic effects in helix formation and stability. The main effect of pseudodeimination is to cause the cytoplasmic exposure of the fragment, potentially making it more accessible to proteolysis. These results are the first, to our knowledge, to provide atomic-level detail of a membrane-anchoring segment of MBP, and direct evidence of decreased MBP membrane interaction after posttranslational modification. PMID- 20713010 TI - In situ muGISAXS: I. Experimental setup for submicron study of protein nucleation and growth. AB - In this study, we used microbeam grazing-incidence small-angle x-ray scattering (muGISAXS) to investigate in situ protein nucleation and crystal growth assisted by a protein nanotemplate, and introduced certain innovations to improve the method. Our aim was to understand the protein nanotemplate method in detail, as this method has been shown to be capable of accelerating and increasing crystal size and quality, as well as inducing crystallization of proteins that are not crystallizable by classical methods. The nanotemplate experimental setup was used for drops containing growing protein crystals at different stages of nucleation and growth. Two model proteins, lysozyme and thaumatin, were used under unique flow conditions to differentially probe protein crystal nucleation and growth. PMID- 20713011 TI - In situ muGISAXS: II. Thaumatin crystal growth kinetic. AB - The formation of thaumatin crystals by Langmuir-Blodgett (LB) film nanotemplates was studied by the hanging-drop technique in a flow-through cell by synchrotron radiation micrograzing-incidence small-angle x-ray scattering. The kinetics of crystallization was measured directly on the interface of the LB film crystallization nanotemplate. The evolution of the micrograzing-incidence small angle x-ray scattering patterns suggests that the increase in intensity in the Yoneda region is due to protein incorporation into the LB film. The intensity variation suggests several steps, which were modeled by system dynamics based on first-order differential equations. The kinetic data can be described by two processes that take place on the LB film, a first, fast, process, attributed to the crystal growth and its detachment from the LB film, and a second, slower process, attributed to an unordered association and conversion of protein on the LB film. PMID- 20713012 TI - Development of cellular magnetic dipoles in magnetotactic bacteria. AB - Magnetotactic bacteria benefit from their ability to form cellular magnetic dipoles by assembling stable single-domain ferromagnetic particles in chains as a means to navigate along Earth's magnetic field lines on their way to favorable habitats. We studied the assembly of nanosized membrane-encapsulated magnetite particles (magnetosomes) by ferromagnetic resonance spectroscopy using Magnetospirillum gryphiswaldense cultured in a time-resolved experimental setting. The spectroscopic data show that 1), magnetic particle growth is not synchronized; 2), the increase in particle numbers is insufficient to build up cellular magnetic dipoles; and 3), dipoles of assembled magnetosome blocks occur when the first magnetite particles reach a stable single-domain state. These stable single-domain particles can act as magnetic docks to stabilize the remaining and/or newly nucleated superparamagnetic particles in their adjacencies. We postulate that docking is a key mechanism for building the functional cellular magnetic dipole, which in turn is required for magnetotaxis in bacteria. PMID- 20713013 TI - Three-color spectral FRET microscopy localizes three interacting proteins in living cells. AB - FRET technologies are now routinely used to establish the spatial relationships between two cellular components (A and B). Adding a third target component (C) increases the complexity of the analysis between interactions AB/BC/AC. Here, we describe a novel method for analyzing a three-color (ABC) FRET system called three-color spectral FRET (3sFRET) microscopy, which is fully corrected for spectral bleedthrough. The approach quantifies FRET signals and calculates the apparent energy transfer efficiencies (Es). The method was validated by measurement of a genetic (FRET standard) construct consisting of three different fluorescent proteins (FPs), mTFP, mVenus, and tdTomato, linked sequentially to one another. In addition, three 2-FP reference constructs, tethered in the same way as the 3-FP construct, were used to characterize the energy transfer pathways. Fluorescence lifetime measurements were employed to compare the relative relationships between the FPs in cells producing the 3-FP and 2-FP fusion proteins. The 3sFRET microscopy method was then applied to study the interactions of the dimeric transcription factor C/EBPalpha (expressing mTFP or mVenus) with the heterochromatin protein 1alpha (HP1alpha, expressing tdTomato) in live-mouse pituitary cells. We show how the 3sFRET microscopy method represents a promising live-cell imaging technique to monitor the interactions between three labeled cellular components. PMID- 20713014 TI - Microfiberoptic measurement of extracellular space volume in brain and tumor slices based on fluorescent dye partitioning. AB - The fractional volume occupied by extracellular space in tissues, termed alpha, is an important parameter of tissue architecture that affects cellular functions and drug delivery. We report a technically simple fluorescent dye partitioning method to measure alpha in tissue slices based on microfiberoptic detection of dye fluorescence in tissue versus overlying solution. Microfiberoptic tip geometry and dyes were selected for alpha determination from fluorescence intensity ratios, without the need to correct for illumination profile, light scattering/absorption, or dye binding. The method was validated experimentally using cell-embedded gels of specified alpha-values and optical properties. In mouse brain slices, alpha was strongly location-dependent, ranging from 0.16 in thalamus to 0.22 in brainstem, and was sensitive to cell volume changes. Aquaporin-4 water channel gene deletion caused significant extracellular space expansion, with alpha = 0.181 +/- 0.002 in cortex in wild-type mice and 0.211 +/- 0.003 in Aquaporin-4 knockout mice. In slices of LLC1 cell tumors grown in mice to approximately 5 mm diameter, alpha decreased remarkably from approximately 0.45 in superficial tumor to <0.25 in deeper (>100 mum) tumor. Fluorescent dye partitioning with microfiberoptic detection permits rapid, accurate, and anisotropy-insensitive determination of alpha-values in tissue slices. PMID- 20713015 TI - Quantitative guidelines for force calibration through spectral analysis of magnetic tweezers data. AB - Single-molecule techniques are powerful tools that can be used to study the kinetics and mechanics of a variety of enzymes and their complexes. Force spectroscopy, for example, can be used to control the force applied to a single molecule and thereby facilitate the investigation of real-time nucleic acid protein interactions. In magnetic tweezers, which offer straightforward control and compatibility with fluorescence measurements or parallel tracking modes, force-measurement typically relies on the analysis of positional fluctuations through video microscopy. Significant errors in force estimates, however, may arise from incorrect spectral analysis of the Brownian motion in the magnetic tweezers. Here we investigated physical and analytical optimization procedures that can be used to improve the range over which forces can be reliably measured. To systematically probe the limitations of magnetic tweezers spectral analysis, we have developed a magnetic tweezers simulator, whose outcome was validated with experimental data. Using this simulator, we evaluate methods to correctly perform force experiments and provide guidelines for correct force calibration under configurations that can be encountered in typical magnetic tweezers experiments. PMID- 20713016 TI - Dynamic superresolution imaging of endogenous proteins on living cells at ultra high density. AB - Versatile superresolution imaging methods, able to give dynamic information of endogenous molecules at high density, are still lacking in biological science. Here, superresolved images and diffusion maps of membrane proteins are obtained on living cells. The method consists of recording thousands of single-molecule trajectories that appear sequentially on a cell surface upon continuously labeling molecules of interest. It allows studying any molecules that can be labeled with fluorescent ligands including endogenous membrane proteins on living cells. This approach, named universal PAINT (uPAINT), generalizes the previously developed point-accumulation-for-imaging-in-nanoscale-topography (PAINT) method for dynamic imaging of arbitrary membrane biomolecules. We show here that the unprecedented large statistics obtained by uPAINT on single cells reveal local diffusion properties of specific proteins, either in distinct membrane compartments of adherent cells or in neuronal synapses. PMID- 20713018 TI - Anomalous diffusion reports on the interaction of misfolded proteins with the quality control machinery in the endoplasmic reticulum. AB - A multitude of transmembrane proteins enters the endoplasmic reticulum (ER) as unfolded polypeptide chains. During their folding process, they interact repetitively with the ER's quality control machinery. Here, we have used fluorescence correlation spectroscopy to probe these interactions for a prototypical transmembrane protein, VSVG ts045, in vivo. While both folded and unfolded VSVG ts045 showed anomalous diffusion, the unfolded protein had a significantly stronger anomaly. This difference subsided when unfolded VSVG ts045 was in a complex with its chaperone calnexin, or when a mutant form of VSVG ts045 with only one glycan was used. Our experimental data and accompanying simulations suggest that the folding sensor of the quality control (UGT1) oligomerizes unfolded VSVG ts045, leading to a more anomalous/obstructed diffusion. In contrast, calnexin dissolves the oligomers, rendering unfolded VSVG ts045 more mobile, and hence prevents poisoning of the ER. PMID- 20713017 TI - Mapping dynamic protein interactions to insulin secretory granule behavior with TIRF-FRET. AB - Biological processes are governed by extensive networks of dynamic molecular interactions. Yet, establishing a spatial and temporal map of these interactions and their direct relationship to specific cell functions has remained a challenge. Here, we implement sensitized emission Forster resonance energy transfer (FRET) stoichiometry under total internal reflection fluorescence (TIRF) microscopy. We demonstrate through quantitative analysis and modeling that evanescent fields must be precisely matched between FRET excitation wavelengths to isolate dynamic interactions between bimolecular FRET pairs that are not entirely membrane-delimited. We then use TIRF-FRET to monitor the behavior of individual insulin-containing secretory granules at the plasma membrane of living cells, while simultaneously tracking the dynamic interaction between the GTPase Rab27A and its effector Slp4A, on those same granules. Notably, insulin granules that underwent exocytosis demonstrated a specific increase in Rab27A-GTP/Slp4A FRET in the 5 s before membrane fusion, which coincided temporally with an increase in granule displacement and mobility. These results demonstrate an initial spatiotemporal mapping of a dynamic protein-protein interaction on individual secretory granules that is linked to a specific granule behavior in living cells. PMID- 20713019 TI - Effects of the antimalarial drug primaquine on the dynamic structure of lipid model membranes. AB - Primaquine (PQ) is a potent therapeutic agent used in the treatment of malaria and its mechanism of action still lacks a more detailed understanding at a molecular level. In this context, we used differential scanning calorimetry (DSC), pressure perturbation calorimetry (PPC), and electron spin resonance (ESR) to investigate the effects of PQ on the lipid phase transition, acyl chain dynamics, and on volumetric properties of lipid model membranes. DSC thermograms revealed that PQ stabilizes the fluid phase of the lipid model membranes and interacts mainly with the lipid headgroups. This result was revealed by the great effect on the pretransition of phosphatidylcholines and the destabilization of the inverted hexagonal phase of a phosphatidylethanolamine bilayer. Spin probes located at different positions along the lipid chain were used to monitor different membrane regions. ESR results indicated that PQ is effective in changing the acyl chain ordering and dynamics of the whole chain of dimyristoylphosphatidylcholine (DMPC) phospholipid in the rippled gel phase. The combined ESR and PPC results revealed that the slight DMPC volume changes at the main phase transition induced by the presence of PQ is probably due to a less dense lipid gel phase. At physiological pH, the cationic amphiphilic PQ strongly interacts with the lipid headgroup region of the bilayers, causing considerable disorganization in the hydrophobic core. These results shed light on the molecular mechanism of primaquine-lipid interaction, which may be useful in the understanding of the complex mechanism of action and/or the adverse effects of this antimalarial drug. PMID- 20713020 TI - Dimerization and ligand binding affect the structure network of A(2A) adenosine receptor. AB - G protein Coupled Receptors (GPCRs) are allosteric proteins whose functioning fundamentals are the communication between the two poles of the helix bundle. The representation of GPCR structures as networks of interacting amino acids can be a meaningful way to decipher the impact of ligand and of dimerization/oligomerization on the molecular communication intrinsic to the protein fold. In this study, we predicted likely homodimer architectures of the A(2A)R and investigated the effects of dimerization on the structure network and the communication paths of the monomeric form. The results of this study emphasize the roles of helix 1 in A(2A)R dimerization and of highly conserved amino acids in helices 1, 2, 6 and 7 in maintaining the structure network of the A(2A)R through a persistent hub behavior as well as in the information flow between the extracellular and intracellular poles of the helix bundle. The arginine of the conserved E/DRY motif, R3.50, is not involved in the communication paths but participates in the structure network as a stable hub, being linked to both D3.49 and E6.30 like in the inactive states of rhodopsin. A(2A)R dimerization affects the communication networks intrinsic to the receptor fold in a way dependent on the dimer architecture. Certain architectures retain the most recurrent communication paths with respect to the monomeric antagonist bound form but enhancing path numbers and frequencies, whereas some others impair ligand-mediated communication networks. Ligand binding affects the network as well. Overall, the communication network that pertains to the functional dynamics of a GPCR is expected to be influenced by ligand functionality, oligomeric order and architecture of the supramolecular assembly. PMID- 20713021 TI - Specific inhibition of a pathogenic receptor tyrosine kinase by its transmembrane domain. AB - The transmembrane (TM) domains of receptor tyrosine kinases (RTKs) are believed to be important players in RTK signal transduction. However, the degree of specificity and promiscuity of RTK TM domain lateral interactions in mammalian membranes has not been assessed in detail in the literature. A technique to probe the occurrence of interactions between TM domains and their biological significance is to evaluate the propensity for formation of heterodimers of a full-length RTK and its TM domain. Here we examine if the inhibition of two RTK pathogenic mutants, Neu/V664E and FGFR3/A391E, can be achieved by the TM domains of Neu, Neu/V664E, FGFR3 and FGFR3/A391E. We show that the TM domain of Neu/V664E specifically inhibits the phosphorylation of full-length Neu/V664E, while the wild-type Neu TM domain does not. In addition, Neu/V664E TM domain does not affect the phosphorylation levels of full-length FGFR3/A391E. The results suggest that TM domain peptides could be exploited in the future for the development of specific inhibitors of mutant RTKs. PMID- 20713022 TI - Mitochondrial Na+/Ca2+ exchanger, a new target for neuroprotection in rat hippocampal slices. AB - We tested here the hypothesis that the pharmacological modulation of the mitochondrial Na(+)/Ca(2+) exchanger (mNCX) could be a new neuroprotective strategy to rescue stressed vulnerable neurons from death. We used rat hippocampal slices incubated with veratridine to cause neuronal death through a mechanism involving Na(+) and Ca(2+) overload. CGP37157 (CGP), an inhibitor of the mNCX, rescued veratridine vulnerable neurons from death, showing an EC(50) of 5 MUM. This neuroprotection was associated to mitigation of veratridine-elicited overproduction of free radicals and to inhibition of the p38 MAPK-linked apoptotic pathway. These results suggest that the mNCX could become a new target to develop compounds with potential therapeutic neuroprotective actions in neurodegenerative diseases. PMID- 20713023 TI - Early-life stress and neurometabolites of the hippocampus. AB - We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA)-an amino acid considered reflective of neuronal density/functional integrity-using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N=10) or control rearing conditions (N=9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted. PMID- 20713025 TI - Correlations between soluble alpha/beta forms of amyloid precursor protein and Abeta38, 40, and 42 in human cerebrospinal fluid. AB - Cerebrospinal fluid (CSF) biomarkers are now widely used for diagnosis of Alzheimer disease (AD) in atypical clinical forms, for differential and early diagnosis, or for stratification of patients in clinical trials. Among these biomarkers, different forms of amyloid peptides (Abeta) produced by the cleavage of a transmembrane precursor protein called APP (amyloid precursor protein) have a major role. Abeta peptides exist in different length the most common ones having 40 (Abeta40), 42 (Abeta42), or 38 (Abeta38) amino acids in length. APP processing by gamma-secretase releases also an amino-terminal secreted fragment called sAbetaPP-beta while an alternative nonamyloidogenic cleavage of APP, through an alpha-secretase, liberates another fragment called sAbetaPP-alpha. To decipher the molecular and pathological mechanisms leading to the production and the detection of these entities is essential for the comprehension and the prevention of AD. In this report, we present the results of the multiplex measurement of CSF Abeta38, Abeta40, Abeta42, sAbetaPP-alpha, and sAbetaPP-beta in 60 patients mostly with dementia eventually segregated between neurochemical dementia diagnostic (NDD) positive and negative groups. The NDD classification was based on our routine Tau, P-tau(181), and Abeta(42) cutoff values. We confirmed previous findings regarding the correlation between sAbetaPP-alpha and sAbetaPP-beta, as well as the potential interest of these new biomarkers. We also studied the correlation between sAbetaPPs and Abeta peptides, as well as between Abeta peptides themselves. We observed a strong correlation between Abeta38 and sAbetaPP-beta which suggested that the production of this peptide was in direct relation with beta secretase activities. We also reported a strong correlation between Abeta38 and Abeta40, while Abeta42 was correlated to these fragments only in nonpathological situations. These results enlighten the complex relationships between these molecular markers in both physiological and pathological situations. Our results are important for the further use of these analytes for AD diagnosis as well as for validating the cell biological hypotheses of APP processing and Abeta fragment production. PMID- 20713024 TI - (1)H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2. AB - BACKGROUND AND AIM: Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias. However, brain metabolism in these disorders is poorly characterized and biomarkers of the disease progression are lacking. We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases. METHODS: Short-echo, single-voxel proton ((1)H) magnetic resonance spectroscopy data were acquired from 8 volunteers with FRDA, 9 volunteers with AOA2, and 38 control volunteers at 4T. Disease severity was assessed by the Friedreich's Ataxia Rating Scale (FARS). RESULTS: Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p<0.01). CONCLUSION: Distinct neurochemical patterns were observed in the two patient populations, warranting further studies with larger patient populations to determine if the alterations in metabolite levels observed here may be utilized to monitor disease progression and treatment. PMID- 20713026 TI - Characterization of the in vitro propagation of epileptiform electrophysiological activity in organotypic hippocampal slice cultures coupled to 3D microelectrode arrays. AB - Dynamic aspects of the propagation of epileptiform activity have so far received little attention. With the aim of providing new insights about the spatial features of the propagation of epileptic seizures in the nervous system, we studied in vitro the initiation and propagation of traveling epileptiform waves of electrophysiological activity in the hippocampus by means of substrate three dimensional microelectrode arrays (MEAs) for extracellular measurements. Pharmacologically disinhibited hippocampal slices spontaneously generate epileptiform bursts mostly originating in CA3 and propagating to CA1. Our study specifically addressed the activity-dependent changes of the propagation of traveling electrophysiological waves in organotypic hippocampal slices during epileptiform discharge and in particular our question is: what happens to the epileptic signals during their propagation through the slice? Multichannel data analysis enabled us to quantify an activity-dependent increase in the propagation velocity of spontaneous bursts. Moreover, through the evaluation of the coherence of the signals, it was possible to point out that only the lower-frequency components (<95Hz) of the electrical activity are completely coherent with respect to the activity originating in the CA3, while components at higher frequencies lose the coherence, possibly suggesting that the cellular mechanism mediating propagation of electrophysiological activity becomes ineffective for those firing rates exceeding an upper bound or that some noise of neuronal origin was added to the signal during propagation. PMID- 20713027 TI - Regional calcineurin subunit B isoform expression in rat hippocampus following a traumatic brain injury. AB - Calcineurin subunit isoforms are implicated in long term potentiation, long term depression, and structural plasticity. Calcineurin inhibitors benefit axonal damage, cellular dysfunction, and cognitive outcomes in animal models of traumatic brain injury (TBI). Distribution of the catalytic calcineurin A subunit is altered and calcineurin activity increased following fluid percussion injury. Alterations in calcineurin subunit A isoform distribution within the hippocampus also occur post controlled cortical impact (CCI) demonstrating a reduction in catalytic subunit distribution in CA1-2 dendritic fields. Furthermore the effect of TBI on the regulatory subunit, calcineurin B, is unknown. Understanding the role of both subunits is necessary to effectively target alterations in calcineurin signaling as current calcineurin inhibitors, such as cyclosporin A and FK-506, rely upon binding sites on both subunits for complete inhibition. The effect of moderate CCI on the expression and distribution of calcineurin B isoforms within the hippocampus was examined at 2h and 2weeks post injury. Calcineurin B isoforms showed increased expression throughout the CA1 and CA2 while there was a decrease in expression within the ipsilateral dentate gyrus. Alterations in CnB isoform expression within the CA1, CA1-2, and dentate gyrus have significant implications for persistent hippocampal dysfunction following TBI. Regional changes in regulatory subunit expression may alter the effect of calcineurin inhibitors regionally following a traumatic brain injury. PMID- 20713029 TI - Differential responses of sympathetic premotor neurons in the rostral ventrolateral medulla to stimulation of the dorsomedial hypothalamus in rabbits. AB - Electrical stimulation of the posterior dorsomedial hypothalamus (DMH) elicits a defense response, including vasodilation in the skeletal muscles and vasoconstriction in the viscera. To examine whether sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) participate in these differential vascular responses, RVLM neuron activity, renal sympathetic nerve activity (RSNA), renal vessel conductance (RVC), skeletal muscular vessel conductance (MVC), arterial pressure (AP), and heart rate (HR) were simultaneously measured in urethane-anesthetized, vagotomized, and immobilized rabbits. Electrical stimulation of the DMH increased RSNA, MVC, AP, and HR but decreased RVC. The RVLM neurons were classified into three groups according to their responses to tetanic (10s) stimulation of the DMH. Twenty neurons (Type I) were excited, 17 (Type II) were inhibited, and 2 (Type III) did not respond. To the short-train (100 ms) stimulation, all of the Type I neurons showed excitation; in contrast, 12 Type II neurons showed biphasic response that was early excitation followed by inhibition. The remainder showed only inhibition. Type III neurons also did not respond to the short-train stimulation. These results indicated that regional differences in responses of sympathetic nerves in the defense response are supported by functional differentiation of sympathetic premotor neurons in the RVLM. PMID- 20713028 TI - Olfactory discrimination varies in mice with different levels of alpha7-nicotinic acetylcholine receptor expression. AB - Previous studies have shown that schizophrenics have decreased expression of alpha7-nicotinic acetylcholine (alpha7) receptors in the hippocampus and other brain regions, paranoid delusions, disorganized speech, deficits in auditory gating (i.e., inability to inhibit neuronal responses to repetitive auditory stimuli), and difficulties in odor discrimination and detection. Here we use mice with decreased alpha7 expression that also show a deficit in auditory gating to determine if these mice have similar deficits in olfaction. In the adult mouse olfactory bulb (OB), alpha7 expression localizes in the glomerular layer; however, the functional role of alpha7 is unknown. We show that inbred mouse strains (i.e., C3H and C57) with varying alpha7 expressions (e.g., alpha7 wild type [alpha7+/+], alpha7 heterozygous knock-out [alpha7+/-] and alpha7 homozygous knock-out mice [alpha7-/-]) significantly differ in odor discrimination and detection of chemically-related odorant pairs. Using [(125)I] alpha-bungarotoxin (alpha-BGT) autoradiography, alpha7 expression was measured in the OB. As previously demonstrated, alpha-BGT binding was localized to the glomerular layer. Significantly more expression of alpha7 was observed in C57 alpha7+/+ mice compared to C3H alpha7+/+ mice. Furthermore, C57 alpha7+/+ mice were able to detect a significantly lower concentration of an odor in a mixture compared to C3H alpha7+/+ mice. Both C57 and C3H alpha7+/+ mice discriminated between chemically-related odorants sooner than alpha7+/- or alpha7-/- mice. These data suggest that alpha7-nicotinic-receptors contribute strongly to olfactory discrimination and detection in mice and may be one of the mechanisms producing olfactory dysfunction in schizophrenics. PMID- 20713030 TI - Current status of clinical 25-hydroxyvitamin D measurement: an assessment of between-laboratory agreement. AB - BACKGROUND: Historically, methodological differences and lack of standardization led to between-laboratory variability in 25(OH)D results. Recent observations raised concern about persisting variability. This quality assurance exercise investigated 25(OH)D result comparability between laboratories. METHODS: Serum pools (n=25) were prepared to contain endogenous 25(OH)D(2) and 25(OH)D(3) at 25(OH)D concentrations from ~12 to 150 nmol/l (5-60 ng/ml). Aliquots were sent to 8 laboratories utilizing various 25(OH)D assay methods including high performance liquid chromatography with ultraviolet detection (LC-UV), LC with tandem mass spectroscopy detection (LC-MS/MS) or an automated immunoassay (Diasorin Liaison). The LC-UV results were selected as a referent to which all others were compared using linear regression and Bland-Altman analysis. RESULTS: Good correlation (R(2)=0.87 to 0.97) was observed for all laboratories. Modest systematic bias was observed for some laboratories ranging from a positive mean bias of 10.5 nmol/l (4.2 ng/ml) to a negative mean bias of 3.5 nmol/l (1.4 ng/ml). For the laboratory with the greatest bias, 22/25 results were numerically higher (mean +15.7%) than LC-UV results. For Liaison, the primary error was likely random, whereas the major LC-MS/MS assay error source was biases likely due to calibration issues. CONCLUSIONS: Modest inter-laboratory variability persists in serum 25(OH)D measurement. The National Institute of Standards and Technology 25(OH)D Standard Reference and calibration materials will further improve between-laboratory agreement for chromatography-based assays. PMID- 20713031 TI - The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction. AB - BACKGROUND: Immune activation and inflammation participate in the progression of chronic heart failure (CHF), and T helper (Th) lymphocytes play critical roles in it. Th17 cells and CD4(+)CD25(+) regulatory T (Treg) cells both come from naive Th cells, share reciprocal development pathways but exhibit opposite effects, and the balance between them controls inflammation and autoimmune diseases. We hypothesized that the Th17/Treg balance was impaired in patients with CHF. METHODS: To assess our hypothesis, patients with CHF were divided into 2 groups: heart failure with normal ejection fraction (HFNEF) group and heart failure with reduced ejection fraction (HFREF) group. Peripheral Th17 and Treg frequencies were analyzed by flow cytometry. RESULTS: Patients with HFNEF and HFREF both revealed significant increase in the frequencies of Th17 and obvious decrease in the frequencies of Treg compared with the controls. CONCLUSION: The results indicate that the Th17/Treg imbalance exists in patients with CHF, suggesting the imbalance potentially plays a role in the pathogenesis, and the Th17/Treg balance may be a promising therapeutic approach in patients with CHF. PMID- 20713032 TI - Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) regulates the level of SMN expression through ubiquitination in primary spinal muscular atrophy fibroblasts. AB - BACKGROUND: Spinal muscular atrophy (SMA), a lethal hereditary disease caused by mutations of the survival of motor neuron 1 (SMN1) gene, is the leading genetic cause of infant mortality. Its severity directly correlates to the expression level of SMN protein in patients with SMA, but the regulatory mechanisms of SMN protein expression remain incompletely defined. In the present study, we aimed to identify candidate proteins to distinguish SMA fibroblasts from normal fibroblasts. METHODS: To identify cellular targets regulating the expression of SMN, we initially utilized a proteomics approach combining 2D electrophoresis and LC-MS/MS, wherein the total proteins extracted from type I SMA patients and normal skin fibroblast cells were compared. RESULTS: Our initial proteomics analysis discovered significant increase of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in type I SMA fibroblasts when compared to normal fibroblasts. Significantly, UCHL1 proteins directly interacted with SMN protein, as determined by immunoprecipitation and immunofluorescence assays in P19 and NSC34 cells. Over expression of UCHL1 in P19 and NSC34 cells significantly reduced the level of SMN proteins in vivo, and, in fact, purified UCHL1 was shown to be able to enhance, in a dose-dependent manner, the level of ubiquitinated SMN in vitro. Further, inhibition of UCHL1 activity by UCHL1 inhibitor (LDN-57444) increased cellular SMN protein and gems number in the nucleus in NSC34 and SMA skin fibroblasts. The same results were observed in cells with UCHL1-specific knockdown. CONCLUSIONS: These results suggested that UCHL1 may be a critical regulator in controlling cellular SMN protein turnover, and that it may serve as an attractive therapeutic target for SMA. PMID- 20713033 TI - Flow injection analysis vs. ultra high performance liquid chromatography coupled with tandem mass spectrometry for determination of imatinib in human plasma. AB - BACKGROUND: The aim of this study was to develop, validate and compare flow injection analysis (FIA) and ultra-high-performance liquid chromatography (LC)/tandem mass spectrometry methods for the determination of imatinib in plasma from patients with chronic myeloid leukemia. METHODS: The plasma for analysis by both methods was deproteinated by methanol containing d8-imatinib. The separation was achieved on a 1.7 MUm C18 column with a linear gradient (4 mM ammonium formiate and acetonitrile, pH 3.2). FIA was performed at flow rate of 0.03 mL/min (0.1% formic acid in methanol). Multiple reaction monitoring mode on the tandem mass spectrometer (API 4000, AB Sciex) in positive ESI were used for detection. RESULTS: The total analysis times were 3.2 (LC) and 0.75 min (FIA). Both methods were successfully validated and applied to the plasma patients samples. The limits of quantification were 4.1 and 30.8 ng/mL; imprecisions were less than 5.7% and recovery ranged between 93 and 105%, for the LC and FIA, respectively. The methods revealed an agreement with a mean difference of 1.46 ng/mL (SD 28.95 ng/mL). CONCLUSIONS: The high-throughput methods that were developed are suitable for the therapeutic drug monitoring of imatinib in plasma. They can be used in routine clinical practice. PMID- 20713034 TI - Sensitive detection of Epstein-Barr virus-derived latent membrane protein 1 based on CdTe quantum dots-capped silica nanoparticle labels. AB - BACKGROUND: The detection of Epstein-Barr virus-derived latent membrane protein 1 (LMP-1) is essential for understanding its contribution to the development of malignancy in epithelial cells and the early screening of nasopharyngeal carcinoma tumors. It is important to explore novel means for enhancing detection sensitivity of LMP-1. METHODS: The current strategy for enhancing sensitivity is based on signal amplification of LMP-1/cadmium telluride (CdTe) quantum dots (QDs) functionalized silica nanosphere labels (Si/QD/Ab2). Si/QD/Ab2 was fabricated by covalently binding LMP-1 antibody (denoted Ab2) to CdTe QDs, which have been previously coated onto the surface of silica nanoparticles with EDC Chemistry. The as-prepared Si/QD/Ab2 label can be brought to a modified gold slice by a "sandwiched" immunoreaction, which was confirmed by SEM images and detected by square wave voltammetry (SWV). RESULTS: The amount of captured Si/QD/Ab2 by sandwiched immunoreaction was related to the concentration of LMP-1 in the incubation solution. The calibration range for LMP-1 detection was found to be 0.001 to 10 ng/ml with a correlation coefficient of 0.9897 and the lowest detectable concentration of 0.001 ng/ml. Compared with traditional sandwich immunoassay, the detection sensitivity of presented approach was enhanced largely due to the large surface area of silica nanoparticle carriers, which increased in CdTe QDs loading per sandwiched immunoreaction. CONCLUSION: The ease of functionalization, good monodispersed sizes and uniformity of the silica nanoparticles allows the QDs coated silica nanospheres to be highly suited for immunological labeling of trace protein analysis. The proposed method is simple, selective, reproducible, and can be extended to study protein-protein, peptide protein, and DNA-protein interaction. PMID- 20713035 TI - Diagnosis of FVII Padua (Arg304Gln) by means of simple clotting tests. PMID- 20713036 TI - The effect of obesity on testicular function by insulin-like factor 3, inhibin B, and leptin concentrations in obese adolescents according to pubertal stages. AB - OBJECTIVES: The aim of the present study is to investigate the effect of obesity on testicular function by evaluating reproductive hormones, inhibinB, insulin like 3(INSL3), and leptin, in obese and non-obese adolescents according to pubertal Tanner stages. DESIGN AND METHODS: Eighty adolescent boys were grouped (n=20) as; Group1: obese-Tanner2, Group2: non-obese-Tanner2, Group3: obese Tanner4, Group4: non-obese-Tanner4. Serum INSL3, luteinizing hormone, follicle stimulating hormone, total testosterone, free testosterone, estradiol, sex hormone binding globulin, inhibin B and leptin levels were assessed in all groups. RESULTS: INSL3 levels were significantly lower in obese adolescents compared to non-obese boys (p=0.003, Tanner2) and (p=0.031, Tanner4). There was a negative correlation between INSL3 and leptin (r=-0.468, p=0.001). The negative correlation between INSL3 and BMISDS indicates that pubertal obesity leads to Leydig cell impairment. CONCLUSIONS: This study demonstrated for the first time in the literature that obesity effects testicular Leydig cell function starting from Tanner stage 2. PMID- 20713038 TI - Tracer-based metabolomics: concepts and practices. AB - Tracer-based metabolomics is a systems biology tool that combines advances in tracer methodology for physiological studies, high throughput "-omics" technologies and constraint based modeling of metabolic networks. It is different from the commonly known metabolomics or metabonomics in that it is a targeted approach based on a metabolic network model in cells. Because of its complexity, it is the least understood among the various "-omics." In this review, the development of concepts and practices of tracer-based metabolomics is traced from the early application of radioactive isotopes in metabolic studies to the recent application of stable isotopes and isotopomer analysis using mass spectrometry; and from the modeling of biochemical reactions using flux analysis to the recent theoretical formulation of the constraint based modeling. How these newer experimental methods and concepts of constraint-based modeling approaches can be applied to metabolic studies is illustrated by examples of studies in determining metabolic responses of cells to pharmacological agents and nutrient environment changes. PMID- 20713037 TI - Optimization and robustness of blood tests for liver fibrosis and cirrhosis. AB - OBJECTIVES: To optimize the performance and feasibility of fibrosis blood tests and evaluate their robustness. DESIGN AND METHODS: The derivation population included 1056 HCV patients with liver biopsy and blood markers. Validation populations included 984 patients with various viral hepatitis causes, and Fibroscan and/or liver biopsy and/or blood markers. RESULTS: The bootstrap method validated the markers of the original FibroMeter(2G), but not those of Fibrotest and Hepascore, and provided a hyaluronate-free FibroMeter(3G). AUROCs for significant fibrosis were: FibroMeter(2G): 0.853 vs. FibroMeter(3G): 0.851, p=0.489. Compared to FibroMeter(2G), FibroMeter(3G) had a significantly higher patient rate with predictive values >=90% for significant fibrosis. Accuracy for fibrosis stage classification was: Fibrotest: 37.9%, FibroMeter(2G): 74.9%, and FibroMeter(3G): 86.9% (p<10(-3)). CONCLUSION: The bootstrap method validated FibroMeter(2G) and provided a cheaper and more feasible hyaluronate-free FibroMeter(3G) with comparable performance. Compared to binary diagnosis, fibrosis stage classification increased discrimination, with an increased accuracy to 87% for FibroMeter(3G). PMID- 20713039 TI - Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages after chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide. AB - OBJECTIVES: Breast carcinoma is related to the increase of lipid peroxidation in plasma with concomitant decrease of antioxidant (AO) defense capacity in blood cells, which becomes more pronounced during aging of the patients. This work evaluated the potential age-related effect of chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) on the level of lipid hydroperoxides (LP), glutathione (GSH), AO enzyme activities of copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in breast cancer patients. The level of CuZnSOD protein was assessed after the FAC therapy and radiotherapy of breast cancer. DESIGN AND METHODS: AO parameters were measured in the blood of 58 breast cancer patients and 60 healthy age-matched healthy subjects by biochemical and Western blot analyses. RESULTS: Increased oxidative stress (LP: p<0.05) and decreased AO enzyme activities (CuZnSOD: p<0.01, GPx: p<0.05, GR: p<0.01) and GSH level (p<0.01) in the blood of breast cancer patients in response to FAC chemotherapy seem not to be age-dependent. CuZnSOD enzyme expression decreased after the FAC chemotherapy (p<0.05), while it increased after the radiotherapy of breast cancer (p<0.05). CONCLUSION: FAC chemotherapy and radiotherapy promote further oxidative shift, which potentiate already existing chronic oxidative stress linked to breast cancer. In these effects, impaired capacity for H(2)O(2) detoxification (CAT, GPX and GSH) seems to have major contribution. PMID- 20713040 TI - Potential adverse interaction of human cardiac calsequestrin. AB - Calsequestrin (CASQ) is a major Ca(2+) storage protein within the sarcoplasmic reticulum (SR) of both cardiac and skeletal muscles. CASQ reportedly acts as a Ca(2+) buffer and Ca(2+)-channel regulator through its unique Ca(2+)-dependent oligomerization, maintaining the free Ca(2+) concentration at a low level (0.5 1mM) and the stability of SR Ca(2+) releases. Our approach, employing isothermal titration calorimetry and light scattering in parallel, has provided valuable information about the affinity of human cardiac CASQ (hCASQ2) for a variety of drugs, which have been associated with heart- or muscle-related side effects. Those strongly binding drugs included phenothiazines, anthracyclines and Ca(2+) channel blockers, such as trifluoperazine, thioridazine, doxorubicin, daunorubicin, amlodipine and verapamil, having an average affinity of ~18 MUM. They exhibit an inhibitory effect on in vitro Ca(2+)-dependent polymerization of hCASQ2 in a manner proportional to their binding affinity. Therefore accumulation of such drugs in the SR could significantly hinder the Ca(2+)-buffering capacity of the SR and/or the regulation of the Ca(2+) channel, RyR2. These effects could result in serious cardiac problems in people who have genetically impaired hCASQ2, defects in other E-C coupling components or problems with metabolism and clearance of those drugs. PMID- 20713041 TI - Binocular lens treatment in tree shrews: Effect of age and comparison of plus lens wear with recovery from minus lens-induced myopia. AB - We examined normal emmetropization and the refractive responses to binocular plus or minus lenses in young (late infantile) and juvenile tree shrews. In addition, recovery from lens-induced myopia was compared with the response to a similar amount of myopia produced with plus lenses in age-matched juvenile animals. Normal emmetropization was examined with daily noncycloplegic autorefractor measures from 11 days after natural eye-opening (days of visual experience [VE]) when the eyes were in the infantile, rapid growth phase and their refractions were substantially hyperopic, to 35 days of VE when the eyes had entered the juvenile, slower growth phase and the refractions were near emmetropia. Starting at 11 days of VE, two groups of young tree shrews wore binocular +4 D lenses (n=6) or -5 D lenses (n=5). Starting at 24 days of VE, four groups of juvenile tree shrews (n=5 each) wore binocular +3 D, +5 D, -3 D, or -5 D lenses. Non cycloplegic measures of refractive state were made frequently while the animals wore the assigned lenses. The refractive response of the juvenile plus-lens wearing animals was compared with the refractive recovery of an age-matched group of animals (n=5) that were myopic after wearing a -5 D lens from 11 to 24 days of VE. In normal tree shrews, refractions (corrected for the small eye artifact) declined rapidly from (mean+/-SEM) 6.6+/-0.6 D of hyperopia at 11 VE to 1.4+/-0.2 D at 24 VE and 0.8+/-0.4 D at 35 VE. Plus 4 D lens treatment applied at 11 days of VE initially corrected or over-corrected the young animals' hyperopia and produced a compensatory response in most animals; the eyes became nearly emmetropic while wearing the +4 D lenses. In contrast, plus-lens treatment starting at 24 days of VE initially made the juvenile eyes myopic (over correction) and, on average, was less effective. The response ranged from no change in refractive state (eye continued to experience myopia) to full compensation (emmetropic with the lens in place). Minus-lens wear in both the young and juvenile groups, which initially made eyes more hyperopic, consistently produced compensation to the minus lens so that eyes reached age-appropriate refractions while wearing the lenses. When the minus lenses were removed, the eyes recovered quickly to age-matched normal values. The consistent recovery response from myopia in juvenile eyes after minus-lens compensation, compared with the highly variable response to plus lens wear in age-matched juvenile animals suggests that eyes retain the ability to detect the myopic refractive state, but there is an age-related decrease in the ability of normal eyes to use myopia to slow their elongation rate below normal. If juvenile human eyes, compared with infants, have a similar difficulty in using myopia to slow axial elongation, this may contribute to myopia development, especially in eyes with a genetic pre-disposition to elongate. PMID- 20713042 TI - ICAM-1 mediates surface contact between neutrophils and keratocytes following corneal epithelial abrasion in the mouse. AB - Corneal epithelial abrasion elicits an inflammatory response involving neutrophil (PMN) recruitment from the limbal vessels into the corneal stroma. These migrating PMNs make surface contact with collagen and stromal keratocytes. Using mice deficient in PMN integrin CD18, we previously showed that PMN contact with stromal keratocytes is CD18-dependent, while contact with collagen is CD18 independent. In the present study, we wished to extend these observations and determine if ICAM-1, a known ligand for CD18, mediates PMN contact with keratocytes during corneal wound healing. Uninjured and injured right corneas from C57Bl/6 wild type (WT) mice and ICAM-1(-/-) mice were processed for transmission electron microscopy and imaged for morphometric analysis. PMN migration, stromal thickness, and ICAM-1 staining were evaluated using light microscopy. Twelve hours after epithelial abrasion, PMN surface contact with paralimbal keratocytes in ICAM-1(-/-) corneas was reduced to ~ 50% of that observed in WT corneas; PMN surface contact with collagen was not affected. Stromal thickness (edema), keratocyte network surface area and keratocyte shape were similar in ICAM-1(-/-) and WT corneas. WT keratocyte ICAM-1 expression was detected at baseline and ICAM-1 staining intensity increased following injury. Since ICAM-1 is readily detected on mouse keratocytes and PMN-keratocyte surface contact in ICAM-1(-/-) mice is markedly reduced, the data suggest PMN adhesive interactions with keratocyte-stromal networks is in part regulated by keratocyte ICAM-1 expression. PMID- 20713043 TI - Deficits in bladder function following spinal cord injury vary depending on the level of the injury. AB - Loss of bladder function is an important consequence of a spinal cord injury (SCI) but is rarely assessed in animal studies of SCI. Here, we use a simple outcome measure (volume of retained urine) to assess bladder dysfunction over time following moderate contusion injuries at 3 different thoracic levels (T1, T4, or T9) and complete crush injuries (T1 vs. T9). The volume of urine retained in the bladder was measured daily for fourteen days post injury by anesthetizing the animals with isoflurane, expressing the bladder, and weighing the urine. To compare bladder deficits with the degree of impairment of hindlimb motor function, locomotion was assessed using the BBB open field rating scale. Rats with contusions at T4 and T9 exhibited bladder impairments reflected by increased urine retention from 1 to 12 days post injury. In contrast, rats with contusions at T1 exhibited minimal deficits (smaller volumes of retained urine). Lesion size and overall functional impairment were comparable between groups based on quantitative assessments of lesion area at the epicenter and BBB locomotor scores. Moreover, a sector analysis of sparing of different portions of the white matter revealed no differences in sparing of different funiculi between the groups. Injections of Fluorogold into lumbar segments led to retrograde labeling of a larger number of neurons in the pontine micturition center (PMC) following T1 injury when compared to T4 or T9. Thus, moderate contusion lesions at T1 spare a critical descending pathway able to mediate at least reflex voiding in rats. PMID- 20713044 TI - Experience-dependent reactivation of ocular dominance plasticity in the adult visual cortex. AB - A crucial issue in neurobiology is to understand the main mechanisms restricting neural plasticity to brief windows of early postnatal life. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. The closure of one eye (monocular deprivation, MD) causes a marked ocular dominance (OD) shift of neurons in the primary visual cortex only during the critical period. Here, we report that environmental enrichment (EE), a condition of increased sensory-motor stimulation, reactivates OD plasticity in the adult visual cortex, as assessed with both visual evoked potentials and single-unit recordings. This effect is accompanied by a marked increase in cerebral serotonin (5-HT) levels. Blocking 5-HT enhancement in the visual cortex of EE rats completely prevents the OD shift induced by MD. We also found that EE leads to a reduced intracortical GABAergic inhibition and an increased BDNF expression and that the modulation of these molecular factors is neutralized by cortical infusion of the 5-HT synthesis inhibitor pCPA. Our results show that EE rejuvenates the adult visual cortex and that 5-HT is a crucial factor in this process, triggering a cascade of molecular events that allow the reinstatement of neural plasticity. The non-invasive nature of EE makes this paradigm particularly eligible for clinical application. PMID- 20713045 TI - Monitoring dyskinesia with Zif. PMID- 20713046 TI - Sleep alterations in an environmental neurotoxin-induced model of parkinsonism. AB - Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non motor symptom, may provide potential therapeutic interventions in the treatment of PD. PMID- 20713047 TI - The effects of levodopa and ongoing deep brain stimulation on subthalamic beta oscillations in Parkinson's disease. AB - Local field potentials (LFPs) recorded through electrodes implanted in the subthalamic nucleus (STN) for deep brain stimulation (DBS) in patients with Parkinson's disease (PD) show that oscillations in the beta frequency range (8-20 Hz) decrease after levodopa intake. Whether and how DBS influences the beta oscillations and whether levodopa- and DBS-induced changes interact remains unclear. We examined the combined effect of levodopa and DBS on subthalamic beta LFP oscillations, recorded in nine patients with PD under four experimental conditions: without levodopa with DBS turned off; without levodopa with DBS turned on; with levodopa with DBS turned on; and with levodopa with DBS turned off. The analysis of STN-LFP oscillations showed that whereas levodopa abolished beta STN oscillations in all the patients (p=0.026), DBS significantly decreased the beta oscillation only in five of the nine patients studied (p=0.043). Another difference was that whereas levodopa completely suppressed beta oscillations, DBS merely decreased them. When we combined levodopa and DBS, the levodopa-induced beta disruption prevailed and combining levodopa and DBS induced no significant additive effect (p=0.500). Our observations suggest that levodopa and DBS both modulate LFP beta oscillations. PMID- 20713048 TI - Reactive astrocytosis, microgliosis and inflammation in rats with neonatal hydrocephalus. AB - The deleterious effects of hydrocephalus, a disorder that primarily affects children, include reactive astrocytosis, microgliosis and inflammatory responses; however, the roles that these mechanisms play in the pathophysiology of hydrocephalus are still not clear in terms of cytopathology and gene expression. Therefore we have examined neuroinflammation at both the cellular and the molecular levels in an experimental model of neonatal obstructive hydrocephalus. On post-natal day 1, rats received an intracisternal injection of kaolin to induce hydrocephalus; control animals received saline injections. Prior to sacrifice on post-natal day 22, animals underwent magnetic resonance imaging to quantify ventricular enlargement, and the parietal cortex was harvested for analysis. Immunohistochemistry and light microscopy were performed on 5 hydrocephalic and 5 control animals; another set of 5 hydrocephalic and 5 control animals underwent molecular testing with Western blots and a gene microarray. Scoring of immunoreactivity on a 4-point ranking scale for GFAP and Iba-1 demonstrated an increase in reactive astrocytes and reactive microglia respectively in the hydrocephalic animals compared to controls (2.90+/-0.11 vs. 0.28+/-0.26; 2.91+/-0.11 vs. 0.58+/-0.23, respectively). Western blots confirmed these results. Microarray analysis identified significant (1.5-fold) changes in 1729 of 33,951 genes, including 26 genes out of 185 genes (26/185) in the cytokine-cytokine receptor interaction pathway, antigen processing and presentation pathways (15/66), and the apoptosis pathway (10/69). Collectively, these results demonstrate alterations in normal physiology and an up-regulation of the inflammatory response. These findings lead to a better understanding of neonatal hydrocephalus and begin to form a baseline for future treatments that may reverse these effects. PMID- 20713049 TI - Dissociation of motor symptoms during deep brain stimulation of the subthalamic nucleus in the region of the internal capsule. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be an effective treatment for the motor symptoms of Parkinson's disease. The therapeutic benefits are voltage-dependent and, in many cases, limited by the appearance of side effects, including muscle contractions. We have observed a number of clinical cases where improvements in rigidity were accompanied by a worsening of bradykinesia. Considering the anatomic position of STN and current approaches to implantation of the DBS lead, we hypothesized that this dissociation of motor symptoms arises from activation of pyramidal tract fibers in the adjacent internal capsule. The objective of this study was to assess the physiological basis for this dissociation and to test our hypothesis that the underlying etiology of this paradox is activation of fibers of the internal capsule. The effect of STN DBS at 80% of motor threshold for each of the four contacts was evaluated for its effect on rigidity, bradykinesia, and akinesia in a single primate with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Consistent with our observations in humans, this near-threshold stimulation was found to improve rigidity while bradykinesia and akinesia worsened. Worsening bradykinesia in the face of improvement of other motor signs in Parkinson's disease (PD) patients is suggestive of activation of pyramidal tract (PT) fibers during stimulation. This phenomenon may occur without overt muscle contraction and improved rigidity. PMID- 20713050 TI - Interaction of olfactory ensheathing cells with other cell types in vitro and after transplantation: glial scars and inflammation. AB - Olfactory ensheathing cells (OECs) have been investigated extensively as a therapy to promote repair in the injured CNS, with variable efficacy in numerous studies over the previous decade. In many studies that report anatomical and functional recovery, the beneficial effects have been attributed to the ability of OECs to cross the PNS-CNS boundary, their production of growth factors, cell adhesion molecules and extracellular matrix proteins that promote and guide axon growth, and their ability to remyelinate axons. In this brief review, we focus on the interaction between OECs and astrocytes in vivo and in vitro, in the context of how OECs may be overcoming the deleterious effects of the glial scar. Drawing from a selection of different experimental models of spinal injury, we discuss the morphological alterations of the glial scar associated with OEC transplants, and the in vitro research that has begun to elucidate the interaction between OECs and the cell types that compose the glial scar. We also discuss recent research showing that OECs bear properties of immune cells and the consequent implication that they may modulate neuroinflammation when transplanted into CNS injury sites. Future studies in unraveling the molecular interaction between OECs and other glial cells may help explain some of the variability in outcomes when OECs are used as transplants in CNS injury and more importantly, contribute to the optimization of OECs as a cell-based therapy for CNS injury. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20713051 TI - Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor beta1 is enhanced after co-infusion in rats. AB - The objective was to analyze functional effects of the combination of GDNF and TGF-beta1 in the retrograde model of Parkinsonism in rats, based on the intrastriatal infusion of 6-hydroxydopamine, which leads to protracted and progressive cell death in the substantia nigra. Hemiparkinsonian rats were implanted with osmotic minipumps 2 months after striatal lesion, pumps delivering GDNF alone (10 ng/day), TGF-beta1 alone (2 ng/day), or a GDNF and TGF-beta1 combination. The findings confirmed that GDNF alone has potent dopaminotrophic effects but they also revealed, for the first time, that GDNF and TGF-beta1 co infusion led to stronger trophic effects relative to the infusion of GDNF alone. TGF-beta1 allowed further reducing dopamine receptor hypersensitivity, and potentiated GDNF-mediated effects. This cooperation could be accounted for by the recruitment of GFRalpha1 on striatal membranes, and by enhanced expression and activation of TH through augmented pSer31TH and pSer40TH. Co-infusion induced striatal sprouting, as revealed by augmentation of p21-Arc, stathmin, and synaptophysin, and led to a reliable recovery of phenotypic expression of TH in surviving nigral neurons. Functional recovery and improvement of TH signal in the nigrostriatal system were long-lasting and sustained, remaining after cessation of trophic infusion. PMID- 20713052 TI - Increased subventricular zone-derived cortical neurogenesis after ischemic lesion. AB - In adult rodents stroke enhances neurogenesis resulting in the addition of neurons to forebrain regions such as striatum or cortex where postnatal neurogenesis under normal conditions plays a negligible role. In the cortex, new neurons are generated either from local cortical precursors that are activated by stroke or from precursors residing in the subventricular zone (SVZ) of lateral ventricles that under normal conditions supply neuroblasts by and large only for the olfactory bulb. In this study we used 5HT3A-EGFP transgenic mice in which all neuroblasts originating in the SVZ are EGFP-labeled. We induced stroke in these mice and by combination of EGFP detection with BrdU injections we labeled all post-stroke-generated SVZ-derived neuroblasts. We showed an increase in SVZ derived neuroblasts 14 and 35 days after stroke in the ipsilateral hemisphere. Post-stroke-generated SVZ-derived neuroblasts migrated to the cortex and survived for at least 35 days representing 2% of BrdU-positive cells in peri-infarct area where they differentiate into mature neurons. Thus, stroke enhances SVZ neurogenesis and attracts newborn neurons to the injury zone. PMID- 20713053 TI - Leishmania amazonensis META2 protein confers protection against heat shock and oxidative stress. AB - The META cluster of Leishmania amazonensis contains both META1 and META2 genes, which are upregulated in metacyclic promastigotes and encode proteins containing the META domain. Previous studies defined META2 as a 48.0-kDa protein, which is conserved in other Leishmania species and in Trypanosoma brucei. In this work, we demonstrate that META2 protein expression is regulated during the Leishmania life cycle but constitutive in T. brucei. META2 protein is present in the cytoplasm and flagellum of L. amazonensis promastigotes. Leishmania META2-null replacement mutants are more sensitive to oxidative stress and, upon heat shock, assume rounded morphology with shortened flagella. The increased susceptibility of null parasites to heat shock is reversed by extra-chromosomal expression of the META2 gene. Defective Leishmania promastigotes exhibit decreased ability to survive in macrophages. By contrast, META2 expression is decreased by 80% in RNAi-induced T. brucei bloodstream forms with no measurable effect on survival or resistance to heat shock. PMID- 20713054 TI - ARF-dependent regulation of ATM and p53 associated KZNF (Apak) protein activity in response to oncogenic stress. AB - The KRAB-type zinc-finger protein Apak (ATM and p53 associated KZNF protein) specifically suppresses p53-mediated apoptosis. Upon DNA damage, Apak is phosphorylated and inhibited by ATM kinase, resulting in p53 activation. However, how Apak is regulated in response to oncogenic stress remains unknown. Here we show that upon oncogene activation, Apak is inhibited in the tumor suppressor ARF dependent but ATM-independent manner. Oncogene-induced ARF protein directly interacts with Apak and competes with p53 to bind to Apak, resulting in Apak dissociation from p53. Thus, Apak is differentially regulated in the ARF and ATM dependent manner in response to oncogenic stress and DNA damage, respectively. PMID- 20713056 TI - A glycine residue essential for high ivermectin sensitivity in Cys-loop ion channel receptors. AB - Ivermectin exerts its anthelmintic effect by activating nematode Cys-loop glutamate-gated receptors. Here we show that a glycine residue at a specific transmembrane domain location is essential for high ivermectin sensitivity in both glycine- and glutamate-gated Cys-loop receptors. We also show that ivermectin sensitivity can be conferred on an ivermectin-insensitive receptor by introducing a glycine at this position. Furthermore, comparison of amino acid sequences of ivermectin-sensitive and -resistant receptors reveals that the presence of a glycine reliably predicts ivermectin sensitivity. By providing a means of identifying ivermectin-sensitive receptors, this finding should help in characterising ivermectin-resistance mechanisms and identifying new anthelmintic targets. PMID- 20713057 TI - Survival rate and expression of Heat-shock protein 70 and Frost genes after temperature stress in Drosophila melanogaster lines that are selected for recovery time from temperature coma. AB - In this study, we investigated the physiological mechanisms underlying temperature tolerance using Drosophila melanogaster lines with rapid, intermediate, or slow recovery from heat or chill coma that were established by artificial selection or by free recombination without selection. Specifically, we focused on the relationships among their recovery from heat or chill coma, survival after severe heat or cold, and survival enhanced by rapid cold hardening (RCH) or heat hardening. The recovery time from heat coma was not related to the survival rate after severe heat. The line with rapid recovery from chill coma showed a higher survival rate after severe cold exposure, and therefore the same mechanisms are likely to underlie these phenotypes. The recovery time from chill coma and survival rate after severe cold were unrelated to RCH-enhanced survival. We also examined the expression of two genes, Heat-shock protein 70 (Hsp70) and Frost, in these lines to understand the contribution of these stress-inducible genes to intraspecific variation in recovery from temperature coma. The line showing rapid recovery from heat coma did not exhibit higher expression of Hsp70 and Frost. In addition, Hsp70 and Frost transcription levels were not correlated with the recovery time from chill coma. Thus, Hsp70 and Frost transcriptional regulation was not involved in the intraspecific variation in recovery from temperature coma. PMID- 20713055 TI - Estrogen receptor-alpha gene expression in the cortex: sex differences during development and in adulthood. AB - 17beta-estradiol is a hormone with far-reaching organizational, activational and protective actions in both male and female brains. The organizational effects of early estrogen exposure are essential for long-lasting behavioral and cognitive functions. Estradiol mediates many of its effects through the intracellular receptors, estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta). In the rodent cerebral cortex, estrogen receptor expression is high early in postnatal life and declines dramatically as the animal approaches puberty. This decline is accompanied by decreased expression of ERalpha mRNA. This change in expression is the same in both males and females in the developing isocortex and hippocampus. An understanding of the molecular mechanisms involved in the regulation of estrogen receptor alpha (ERalpha) gene expression is critical for understanding the developmental, as well as changes in postpubertal expression of the estrogen receptor. One mechanism of suppressing gene expression is by the epigenetic modification of the promoter regions by DNA methylation that results in gene silencing. The decrease in ERalpha mRNA expression during development is accompanied by an increase in promoter methylation. Another example of regulation of ERalpha gene expression in the adult cortex is the changes that occur following neuronal injury. Many animal studies have demonstrated that the endogenous estrogen, 17beta-estradiol, is neuroprotective. Specifically, low levels of estradiol protect the cortex from neuronal death following middle cerebral artery occlusion (MCAO). In females, this protection is mediated through an ERalpha-dependent mechanism. ERalpha expression is rapidly increased following MCAO in females, but not in males. This increase is accompanied by a decrease in methylation of the promoter suggesting a return to the developmental program of gene expression within neurons. Taken together, during development and in adulthood, regulation of ERalpha gene expression in the cortex can occur by DNA methylation and in a sex-dependent fashion in the adult brain. PMID- 20713058 TI - High gamma-aminobutyric acid content, a novel component associated with resistance to abamectin in Tetranychus cinnabarinus (Boisduval). AB - An abamectin-resistant strain of Tetranychus cinnabarinus (Boisduval) (Rf=25.3) was selected in laboratory. We compared the gamma-aminobutyric acid (GABA) content in abamectin-susceptible T. cinnabarinus individuals with that in resistant individuals and investigated its relationship to abamectin resistance. High performance liquid chromatography (HPLC) was used to ascertain GABA content in abamectin-susceptible (SS) and resistant (AR) strains of T. cinnabarinus. The results indicate that GABA content in the AR was significantly higher than that in the SS (1.39-fold). AR individuals treated with a sublethal dose of abamectin did not show significant differences in GABA levels compared with AR individuals that were not treated with abamectin. However in the SS, abamectin treated individuals had a significantly higher GABA content than those that were untreated (1.52-fold). Individuals in the SS that survived from selection with LC(95) of abamectin (SS-AR) showed significantly higher GABA levels compared to SS (1.41-fold). Similarly, progenies of the SS-AR parental generation (SS-ARF(1)) also showed increased GABA levels (1.51-fold) compared to SS. In addition, behavioral observations have shown that all individuals from the AR, SS-AR and SS ARF(1), which had more GABA content than the SS, demonstrated a significant decrease in crawling speed compared with SS individuals. This observation is consistent with excessive GABA levels had inhibitory effect on the central nervous system. Thus, we postulate that increasing GABA content in T. cinnabarinus is associated with resistance against abamectin. PMID- 20713059 TI - Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. AB - Myocardial infarction caused by vascular occlusion results in the formation of nonfunctional fibrous tissue. Cumulative evidence indicates that cell therapy modestly improves cardiac function; thus, novel cell sources with the potential to repair injured tissue are actively sought. Here, we identify and characterize a cell population of cardiac adipose tissue-derived progenitor cells (ATDPCs) from biopsies of human adult cardiac adipose tissue. Cardiac ATDPCs express a mesenchymal stem cell-like marker profile (strongly positive for CD105, CD44, CD166, CD29 and CD90) and have immunosuppressive capacity. Moreover, cardiac ATDPCs have an inherent cardiac-like phenotype and were able to express de novo myocardial and endothelial markers in vitro but not to differentiate into adipocytes. In addition, when cardiac ATDPCs were transplanted into injured myocardium in mouse and rat models of myocardial infarction, the engrafted cells expressed cardiac (troponin I, sarcomeric alpha-actinin) and endothelial (CD31) markers, vascularization increased, and infarct size was reduced in mice and rats. Moreover, significant differences between control and cell-treated groups were found in fractional shortening and ejection fraction, and the anterior wall remained significantly thicker 30days after cardiac delivery of ATDPCs. Finally, cardiac ATDPCs secreted proangiogenic factors under in vitro hypoxic conditions, suggesting a paracrine effect to promote local vascularization. Our results indicate that the population of progenitor cells isolated from human cardiac adipose tissue (cardiac ATDPCs) may be valid candidates for future use in cell therapy to regenerate injured myocardium. PMID- 20713060 TI - Context-dependent remodeling of structure in two large protein fragments. AB - Protein folding involves the formation of secondary structural elements from the primary sequence and their association with tertiary assemblies. The relation of this primary sequence to a specific folded protein structure remains a central question in structural biology. An increasing body of evidence suggests that variations in homologous sequence ranging from point mutations to substantial insertions or deletions can yield stable proteins with markedly different folds. Here we report the structural characterization of domain IV (D4) and DeltaD4 (polypeptides with 222 and 160 amino acids, respectively) that differ by virtue of an N-terminal deletion of 62 amino acids (28% of the overall D4 sequence). The high-resolution crystal structures of the monomeric D4 and the dimeric DeltaD4 reveal substantially different folds despite an overall conservation of secondary structure. These structures show that the formation of tertiary structures, even in extended polypeptide sequences, can be highly context dependent, and they serve as a model for structural plasticity in protein isoforms. PMID- 20713061 TI - Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7. AB - Ubiquitin-specific protease 7 (USP7) catalyzes the deubiquitination of several substrate proteins including p53 and Hdm2. We have previously shown that USP7, and more specifically its amino-terminal domain (USP7-NTD), interacts with distinct regions on p53 and Hdm2 containing P/AxxS motifs. The ability of USP7 to also deubiquitinate and control the turnover of HdmX was recently demonstrated. We utilized a combination of biochemistry and structural biology to identify which domain of USP7 interacts with HdmX as well as to identify regions of HdmX that interact with USP7. We showed that USP7-NTD recognized two of six P/AxxS motifs of HdmX ((8)AQCS(11) and (398)AHSS(401)). The crystal structure of the USP7-NTD:HdmX(AHSS) complex was determined providing the molecular basis of complex formation between USP7-NTD and the HdmX(AHSS) peptide. The HdmX peptide interacted within the same residues of USP7-NTD as previously demonstrated with p53, Hdm2, and EBNA1 peptides. We also identified an additional site on Hdm2 ((397)PSTS(400)) that interacts with USP7-NTD and determined the crystal structure of this complex. Finally, analysis of USP7-interacting peptides on filter arrays confirmed the importance of the serine residue at the fourth position for the USP7-NTD interaction and showed that phosphorylation of serines within the binding sequence prevents this interaction. These results lead to a better understanding of the mechanism of substrate recognition by USP7-NTD. PMID- 20713062 TI - DNA minor groove induced dimerization of heterocyclic cations: compound structure, binding affinity, and specificity for a TTAA site. AB - With the increasing number and variations of genome sequences available, control of gene expression with synthetic, cell-permeable molecules is within reach. The variety of sequence-specific binding agents is, however, still quite limited. Many minor groove binding agents selectivity recognize AT over GC sequences but have less ability to distinguish among different AT sequences. The goal with this article is to develop compounds that can bind selectively to different AT sequences. A number of studies indicate that AATT and TTAA sequences have significantly different physical and interaction properties and different requirements for minor groove recognition. Although it has been difficult to get minor groove binding at TTAA, DB293, a phenyl-furan-benzimidazole diamidine, was found to bind as a strong, cooperative dimer at TTAA but with no selectivity over AATT. In order to improve selectivity, we made modifications to each unit of DB293. Binding affinities and stoichiometries obtained from biosensor-surface plasmon resonance experiments show that DB1003, a furan-furan-benzimidazole diamidine, binds strongly to TTAA as a dimer and has selectivity (K(TTAA)/K(AATT)=6). CD and DNase I footprinting studies confirmed the preference of this compound for TTAA. In summary, (i) a favorable stacking surface provided by the pi system, (ii) H-bond donors to interact with TA base pairs at the floor of the groove provided by a benzimidazole (or indole) -NH and amidines, and (iii) appropriate curvature of the dimer complex to match the curvature of the minor groove play important roles in differentiating the TTAA and AATT minor grooves. PMID- 20713063 TI - Thermodynamic characterization of ppGpp binding to EF-G or IF2 and of initiator tRNA binding to free IF2 in the presence of GDP, GTP, or ppGpp. AB - In addition to their natural substrates GDP and GTP, the bacterial translational GTPases initiation factor (IF) 2 and elongation factor G (EF-G) interact with the alarmone molecule guanosine tetraphosphate (ppGpp), which leads to GTPase inhibition. We have used isothermal titration calorimetry to determine the affinities of ppGpp for IF2 and EF-G at a temperature interval of 5-25 degrees C. We find that ppGpp has a higher affinity for IF2 than for EF-G (1.7-2.8 MUM K(d)versus 9.1-13.9 MUM K(d) at 10-25 degrees C), suggesting that during stringent response in vivo, IF2 is more responsive to ppGpp than to EF-G. We investigated the effects of ppGpp, GDP, and GTP on IF2 interactions with fMet tRNA(fMet) demonstrating that IF2 binds to initiator tRNA with submicromolar K(d) and that affinity is altered by the G nucleotides only slightly. This--in conjunction with earlier reports on IF2 interactions with fMet-tRNA(fMet) in the context of the 30S initiation complex, where ppGpp was suggested to strongly inhibit fMet-tRNA(fMet) binding and GTP was suggested to strongly promote fMet tRNA(fMet) binding--sheds new light on the mechanisms of the G-nucleotide regulated fMet-tRNA(fMet) selection. PMID- 20713064 TI - Magnesium-dependent interaction of PKR with adenovirus VAI. AB - Protein kinase R (PKR) is an interferon-induced kinase that plays a pivotal role in the innate immunity pathway for defense against viral infection. PKR is activated to undergo autophosphorylation upon binding to RNAs that contain duplex regions. Activated PKR phosphorylates the alpha-subunit of eukaryotic initiation factor 2, thereby inhibiting protein synthesis in virus-infected cells. Viruses have evolved diverse PKR-inhibitory strategies to evade the antiviral response. Adenovirus encodes virus-associated RNA I (VAI), a highly structured RNA inhibitor that binds PKR but fails to activate. We have characterized the stoichiometry and affinity of PKR binding to define the mechanism of PKR inhibition by VAI. Sedimentation velocity and isothermal titration calorimetry measurements indicate that PKR interactions with VAI are modulated by Mg(2+). Two PKR monomers bind in the absence of Mg(2+), but a single monomer binds in the presence of divalent ion. Known RNA activators of PKR are capable of binding multiple PKR monomers to allow the kinase domains to come into close proximity and thus enhance dimerization. We propose that VAI acts as an inhibitor of PKR because it binds and sequesters a single PKR in the presence of divalent cation. PMID- 20713065 TI - Binding of sodium channel inhibitors to hyperpolarized and depolarized conformations of the channel. AB - Sodium channels are inhibited by a chemically diverse group of compounds. In the last decade entirely new structural classes with superior properties have been discovered, and novel therapeutic uses of sodium channel inhibitors (SCIs) have been suggested. Many promising novel drug candidates have been described and characterized. Published structure-activity relationship studies, pharmacophore models, and mutagenesis studies seem to lag behind, dealing with only a limited group of inhibitor compounds. The abundance of novel compounds requires an organized comparison of drug potencies. The affinity of sodium channel inhibitors can vary typically ten- to thousand-fold depending on the voltage protocol; therefore comparison of electrophysiology data is difficult. In this study we describe a method for standardization of these data with the help of a simple model of state-dependence. We derived hyperpolarized (resting) and depolarized (generally termed "inactivated") state affinities for the studied drugs, which made the measurements comparable. We show a rank order of SCIs based on resting and inactivated affinity values. In an attempt to define basic chemical requirements for sodium channel inhibitor activity we investigated the dependence of both resting and inactivated state affinities on individual chemical descriptors. Lipophilicity (most often expressed by the logP value) is the single most important determinant of SCI potency. We investigated the independent impact of several other calculated chemical properties by standardizing drug potencies for logP values. By combining these two approaches: standardization of affinity values, and standardization of potencies, we concluded that while resting affinity is mostly determined by lipophilicity, inactivated state affinity is determined by a more complex interaction of chemical properties, including hydrogen bond acceptors, aromatic rings, and molecular weight. PMID- 20713066 TI - 3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels. AB - Pentameric ligand-gated ion channels mediate rapid chemo-electric signal transduction in animals. The active site of this family of proteins is their ion channel pore, which is located at the center of the transmembrane domain. The opening/closing motions of the channel pore are governed by the binding of neurotransmitter to the extracellular domain, but also by allosteric effectors acting within the transmembrane domain. Here, we review the structure of the transmembrane domain as well as its role in the allosteric modulation of pentameric ligand-gated ion channel function. We focus on two examples: the interactions of nicotinic ACh receptors with lipids, for which a novel "uncoupled" state has been proposed, and the interactions of GABA(A) and Glycine receptors with allosteric modulators, such as general anesthetics, ethanol and neurosteroids. We revisit these data in light of the recently solved X-ray structures of bacterial members of the family, which provide atomic-resolution insight into the structures of both the transmembrane domain and associated lipids. PMID- 20713067 TI - The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics. AB - Ligands acting at the same receptor can differentially activate distinct signal transduction pathways, which in turn, can have diverse functional consequences. Further, receptors expressed in different tissues may utilize intracellular signaling proteins in response to a ligand differently as well. The mu opioid receptor (MOR), which mediates many of the pharmacological actions of opiate therapeutics, is also subject to differential signaling in response to diverse agonists. To study the effect of diverse agonists on MOR signaling, we examined the effects of chronic opiate treatment on two distinct physiological endpoints, antinociceptive tolerance and physical dependence, in mice lacking the intracellular regulatory molecule, betaarrestin2. While betaarrestin2 knockout (betaarr2-KO) mice do not become tolerant to the antinociceptive effects of chronic morphine in a hot plate test, tolerance develops to the same degree in both wild type and betaarr2-KO mice following chronic infusion with methadone, fentanyl, and oxycodone. Studies here also assess the severity of withdrawal signs precipitated by naloxone following chronic infusions at three different doses of each opiate agonist. While there are no differences in withdrawal responses between genotypes at the highest dose of morphine tested (48 mg/kg/day), the betaarr2-KO mice display several less severe withdrawal responses when the infusion dose is lowered (12 or 24 mg/kg/day). Chronic infusion of methadone, fentanyl, and oxycodone all lead to equivalent naloxone-precipitated withdrawal responses in both genotypes at all doses tested. These results lend further evidence that distinct agonists can differentially impact on opioid mediated responses in vivo in a betaarrestin2-dependent manner. PMID- 20713068 TI - Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems. AB - Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl} N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT(2A/C) receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111. PMID- 20713069 TI - Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators. AB - Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. These receptors play an important role for the development and function of the nervous system, and are essential in learning and memory. However, iGluRs are also implicated in or have causal roles for several brain disorders, e.g. epilepsy, Alzheimer's disease, Parkinson's disease and schizophrenia. Their involvement in neurological diseases has stimulated widespread interest in their structure and function. Since the first publication in 1998 of the structure of a recombinant soluble protein comprising the ligand binding domain of GluA2 extensive studies have afforded numerous crystal structures of wildtype and mutant proteins including different ligands. The structural information obtained combined with functional data have led to models for receptor activation and desensitization by agonists, inhibition by antagonists and block of desensitization by positive allosteric modulators. Furthermore, the structural and functional studies have formed a powerful platform for the design of new selective compounds. PMID- 20713070 TI - The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors. AB - In the human genome, 22 genes are coding for the class C G protein-coupled receptors that are receptors for the two main neurotransmitters glutamate and gamma-aminobutyric acid, for Ca(2+) and for sweet and amino acid taste compounds. In addition to the GPCR heptahelical transmembrane domain responsible for G protein activation, class C receptors possess a large extracellular domain that is responsible for ligand recognition. Recent studies had revealed that class C receptors are homo- or heterodimers with unique mechanism of activation. In the present review, we present an up-to-date view of the structures and activation mechanism of these receptors in particular the metabotropic glutamate and GABA(B) receptors. We show how the complexity of functioning of these transmembrane proteins can be used for the development of therapeutics to modulate their activity. We emphasize on the new approaches and drugs that could potentially become important in the future pharmacology of these receptors. PMID- 20713071 TI - Top-down control of MEG alpha-band activity in children performing Categorical N Back Task. AB - Top-down cognitive control has been associated in adults with the prefrontal parietal network. In children the brain mechanisms of top-down control have rarely been studied. We examined developmental differences in top-down cognitive control by monitoring event-related desynchronization (ERD) and event-related synchronization (ERS) of alpha-band oscillatory activity (8-13 Hz) during anticipation, target detection and post-response stages of a visual working memory task. Magnetoencephalography (MEG) was used to record brain oscillatory activity from healthy 10-year-old children and young adults performing the Categorical N-Back Task (CNBT). Neuropsychological measures assessing frontal lobe networks were also acquired. Whereas adults showed a modulation of the ERD at the anticipatory stages of CNBT and ERS at the post-response stage, children displayed only some anticipatory modulation of ERD but no ERS at the post response stage, with alpha-band remaining at a desynchronized state. Since neuropsychological and prior neuroimaging findings indicate that the prefrontal parietal networks are not fully developed in 10-year olds, and since the children performed as well as the adults on CNBT and yet displayed different patterns of ERD/ERS, we suggest that children may be using different top-down cognitive strategies and, hence, different, developmentally apt neuronal networks. PMID- 20713073 TI - Why don't you feel how I feel? Insight into the absence of empathy after severe traumatic brain injury. AB - Although the existence of empathy deficits in people with traumatic brain injury (TBI) is generally well accepted, it has been a topic of limited investigation. The current study examined the relationship between self-reported emotional and cognitive empathy and psychophysiological responding to emotionally evocative pictures in 20 patients with severe TBI and 22 control participants. Eighteen pictures with alternating pleasant, unpleasant and neutral content selected from the International Affective Picture System (IAPS) were presented whilst facial muscle responses, skin conductance, and valence and arousal ratings were measured. Self-reported emotional and cognitive empathy questionnaires were also administered. In comparison to control participants, those in the TBI group displayed a reduction in the ability to empathize both emotionally and cognitively, and evidence that these two aspects of empathy may be interconnected was established. Further, TBI participants showed reduced facial responding to unpleasant pictures, while also rating them as less unpleasant and arousing than controls. In addition, they exhibited lowered autonomic arousal to all pictures, regardless of affective valence. Interestingly, hypoarousal to pleasant pictures in particular was found to be related to the absence of empathy observed after TBI, and is consistent with the view that impaired emotional responsivity is associated with impairment to the empathy network. The results represent a further step towards understanding what processes shape empathy. PMID- 20713072 TI - Motion-onset visual evoked potentials predict performance during a global direction discrimination task. AB - The relationship between cognitive processing stages and event-related potential components has been extensively researched for single components, but even the simplest task comprises multiple electrophysiological and cognitive components. Here we examined the relationship between behavioral measures and several visual evoked potentials (VEPs) related to global motion onset during a visual motion discrimination task. In addition to reaction time and accuracy, the EZ diffusion model was used to characterize elements of the decision process. Results showed that latencies, but not amplitudes, from three VEP components reliably predicted about 40% of the variance in reaction times for motion discrimination. These included the latency from stimulus motion onset to N2 onset, the latency from N2 onset to N2 peak, and the latency from the N2 peak to the peak of a late positive potential. These latencies were also able to predict the rate of information accumulation during the decision process and the duration of non-decision processes, but not the observer's threshold (boundary) for making a response. This pattern of results is consistent with an interpretation of these three latencies as reflecting a non-specific visual perceptual process, a motion specific process, and a decision process, respectively. The relationship between the earliest interval and drift rate estimated with the EZ model also supports the notion that early perceptual processing might be a constituent part of the decision process itself. PMID- 20713074 TI - Orbital prefrontal cortex volume correlates with social cognitive competence. AB - Intentionality, or Theory of Mind, is the ability to explain and predict the behaviour of others by attributing to them intentions and mental states and is hypothesised to be one of several social cognitive mechanisms which have impacted upon brain size evolution. Though the brain activity associated with processing this type of information has been studied extensively, the neuroanatomical correlates of these abilities, e.g. whether subjects who perform better have greater volume of associated brain regions, remain to be investigated. Because social abilities of this type appear to have evolved relatively recently, and because the prefrontal cortex (PFC) was the last brain region to develop both phylogenetically and ontogenetically, we hypothesised a relationship between PFC volume and intentional competence. To test this, we estimated the volume of four regional prefrontal subfields in each cerebral hemisphere, in 40 healthy adult humans by applying stereological methods on T(1)-weighted magnetic resonance images. Our results reveal a significant linear relationship between intentionality score and volume of orbital PFC (p=0.01). Since this region is known to be involved in the processing of social information our findings support the hypothesis that brain size evolution is, at least in part, the result of social cognitive mechanisms supporting social cohesion. PMID- 20713075 TI - Defensive engagement and perceptual enhancement. AB - We tested whether visual cortical sensitivity to external cues in the context of an acute defensive reaction is heightened or attenuated. A strong cardiac defense (fear) response was elicited by presenting an abrupt, loud acoustic stimulus following a 10-min period of quiescence. Electrocortical responses to aversive and neutral pictures following defensive stimulus onset were measured using dense array EEG. Pictures were flickered at 12.5 Hz to evoke steady-state visual evoked potentials (ssVEP), which can be reliably extracted on the basis of single trials. Visual cortical activity indexing perceptual processing was substantially heightened when pictures were shown in temporal proximity to (i.e., 5s after) the defense stimulus. Replicating previous studies, aversive visual stimuli were associated with enhanced ssVEP amplitude, compared to neutral stimuli. Acute defense facilitates visual perception of external cues and preserves accurate discrimination between threatening and safe cues. PMID- 20713076 TI - Changes of behavioral parameters during long-term food restriction in middle-aged Wistar rats. AB - Food restriction (FR) has a beneficial effect on aging process and exerts a significant effect on the responses of rodents to standard behavioral tasks. The aim of this study was to assess the cumulative influence of FR on the behavioral and biochemical parameters in Wistar rats. Six-month-old rats were subjected to restrictive feeding (50% of the daily food intake, every-other-day feeding regimen) for one month or for six months until ages of 7 and 12months, respectively. We examined the habituation of exploratory movement, amphetamine (AMPH)-induced motor activity, as well as changes in serum corticosterone (CORT) and glucose levels. The results obtained from FR animals were compared with ad libitum (AL)-fed age-matched control rats. Habituation of motor activity was only affected by six months of restrictive feeding. The sensitization of the motor response to AMPH that was observed in animals exposed to FR for one month was not observed in animals that were exposed to the same feeding regimen for six months. Serum CORT was increased and serum glucose was decreased in both FR groups. These results clearly show that despite the similarity of the biochemical changes that were induced by one and six months of FR, the nature of the changes in motor activities in these two groups of animals during habituation and after AMPH treatment was different. Our findings indicate that long-term FR has complex behavioral consequences that need to be carefully evaluated with respect to animal age, duration of FR and severity of the diet. PMID- 20713077 TI - Fullerenol cytotoxicity in kidney cells is associated with cytoskeleton disruption, autophagic vacuole accumulation, and mitochondrial dysfunction. AB - Water soluble fullerenes, such as the hydroxylated fullerene, fullerenol (C60OHx), are currently under development for diagnostic and therapeutic biomedical applications in the field of nanotechnology. These molecules have been shown to undergo urinary clearance, yet there is limited data available on their renal biocompatibility. Here we examine the biological responses of renal proximal tubule cells (LLC-PK1) exposed to fullerenol. Fullerenol was found to be cytotoxic in the millimolar range, with viability assessed by the sulforhodamine B and trypan blue assays. Fullerenol-induced cell death was associated with cytoskeleton disruption and autophagic vacuole accumulation. Interaction with the autophagy pathway was evaluated in vitro by Lysotracker Red dye uptake, LC3-II marker expression and TEM. Fullerenol treatment also resulted in coincident loss of cellular mitochondrial membrane potential and ATP depletion, as measured by the Mitotracker Red dye and the luciferin-luciferase assays, respectively. Fullerenol-induced ATP depletion and loss of mitochondrial potential were partially ameliorated by co-treatment with the autophagy inhibitor, 3 methyladenine. In vitro fullerenol treatment did not result in appreciable oxidative stress, as measured by lipid peroxide and glutathione content. Based on these data, it is hypothesized that cytoskeleton disruption may be an initiating event in fullerenol cytotoxicity, leading to subsequent autophagy dysfunction and loss of mitochondrial capacity. As nanoparticle-induced cytoskeleton disruption, autophagic vacuole accumulation and mitochondrial dysfunction are commonly reported in the literature, the proposed mechanism may be relevant for a variety of nanomaterials. PMID- 20713078 TI - The role of vitamin D3 upregulated protein 1 in thioacetamide-induced mouse hepatotoxicity. AB - Thioacetamide (TA) is a commonly used drug that can trigger acute hepatic failure (AHF) through generation of oxidative stress. Vitamin D3 upregulated protein 1 (VDUP1) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. In this study, we investigated the role of VDUP1 in AHF using a TA-induced liver injury model. VDUP1 knockout (KO) and wild-type (WT) mice were subjected to a single intraperitoneal TA injection, and various parameters of hepatic injury were assessed. VDUP1 KO mice displayed a significantly higher survival rate, lower serum alanine aminotransferase and aspartate aminotransferase levels, and less hepatic damage, compared to WT mice. In addition, induction of apoptosis was decreased in VDUP1 KO mice, with the alteration of caspase-3 and -9 activities, Bax-to-Bcl-2 expression ratios, and mitogen activated protein kinase (MAPK) signaling pathway. Importantly, analysis of TA bioactivation revealed lower plasma clearance of TA and covalent binding of [14C]TA to liver macromolecules in VDUP1 KO mice. Furthermore, the level of oxidative stress was significantly less in VDUP1 KO mice than in their WT counterparts, as evident from lipid peroxidation assay. These results collectively indicate that VDUP1 deficiency protects against TA-induced acute liver injury via lower bioactivation of TA and antioxidant effects. PMID- 20713080 TI - Audit on prevention and early diagnosis of chronic kidney disease in patients admitted to medical wards in a district hospital in the UK. PMID- 20713079 TI - The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food reinforced behavior. AB - Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors, and may be useful clinically as appetite suppressants. However, there may also be undesirable side effects (e.g., nausea, malaise, anxiety, and depression) that are produced by the current generation of CB1 inverse agonists such as rimonabant and taranabant. For that reason, it is important to continue research on novel cannabinoid antagonists. The present studies examined the effects of the novel compound AM6545, which is a neutral antagonist of CB1 receptors that is thought to have relatively poor penetrability into the central nervous system. Intraperitoneal administration of AM6545 significantly reduced food-reinforced operant responding at doses of 4.0, 8.0 and 16.0 mg/kg. AM6545 also produced a strong suppression of the intake of high-carbohydrate and high fat diets in the same dose range, but only produced a mild suppression of lab chow intake at the highest dose (16.0 mg/kg). Although AM6545 did not affect food handling, it did reduce time spent feeding and feeding rate. Taken together, these results suggest that AM6545 is a compound that warrants further study as a potential appetite suppressant drug. PMID- 20713081 TI - Chemical and thermal cross-linking of collagen and elastin hydrolysates. AB - Chemical and thermal cross-linking of collagen soluble in acetic acid and elastin hydrolysates soluble in water have been studied. Solutions of collagen and elastin hydrolysates were treated using variable concentrations of 1-ethyl-3(3 dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). Moreover, diepoxypropylether (DEPE) has been used as cross-linking agent. Films made of collagen and elastin hydrolysates were also treated with temperature at 60 degrees C and 100 degrees C to get additional cross-links. The effect of cross linking has been studied using FTIR spectroscopy, thermal analysis, AFM and SEM microscopy. Mechanical and surface properties of materials have been studied after cross-linking. It was found that thermal and mechanical properties of collagen and elastin materials have been altered after thermal treatment and after the reactions with EDC/NHS and/or DEPE. Surface properties of collagen materials after chemical cross-linking have been modified. Thermal and chemical cross-linking of collagen films lead to alteration of polarity of the surface. PMID- 20713082 TI - Peptidoglycan activation of the proPO-system without a peptidoglycan receptor protein (PGRP)? AB - Recognition of microbial polysaccharide by pattern recognition receptors triggers the prophenoloxidase (proPO) cascade, resulting in melanin synthesis and its deposition on the surface of invading pathogens. Several masquerade-like proteins and serine proteinase homologues have been shown to be involved in the proPO activation in insects. In this study, a novel serine proteinase homologue, Pl SPH2, was found and isolated as a 30kDa protein from hemocytes of the freshwater crayfish, Pacifastacus leniusculus, by its binding property to a partially lysozyme digested or TCA-treated insoluble Lysine (Lys)-type peptidoglycan (PGN) and soluble polymeric Lys-type PGN. Two other proteins, the Pl-SPH1 and lipopolysaccharide- and beta-1,3-glucan-binding protein (LGBP) were also found in the several different PGN-binding assays. However no PGRP homologue was detected. Neither was any putative PGRP found after searching available crustacean sequence databases. If RNA interference of Pl-SPH2, Pl-SPH1 or LGBP in the crayfish hematopoietic tissue cell culture was performed, it resulted in lower PO activity following activation of the proPO-system by soluble Lys-type PGN. Taken together, we report for the first time that Lys-type PGN is a trigger of proPO-system activation in a crustacean and that two Pl-SPHs are involved in this activation possibly by forming a complex with LGBP and without a PGRP. PMID- 20713083 TI - Peptidoglycan recognition protein of Chlamys farreri (CfPGRP-S1) mediates immune defenses against bacterial infection. AB - Peptidoglycan recognition protein (PGRP) is an essential molecule in innate immunity for both invertebrates and vertebrates, owing to its prominent ability in detecting and eliminating the invading bacteria. Several PGRPs have been identified from mollusk, but their functions and the underlined mechanism are still unclear. In the present study, the mRNA expression profiles, location, and possible functions of PGRP-S1 from Zhikong scallop Chlamys farreri (CfPGRP-S1) were analyzed. The CfPGRP-S1 protein located in the mantle, gill, kidney and gonad of the scallops. Its mRNA expression in hemocytes was up-regulated extremely after PGN stimulation (P<0.01), while moderately after the stimulations of LPS (P<0.01) and beta-glucan (P<0.05). The recombinant protein of CfPGRP-S1 (designated as rCfPGRP-S1) exhibited high affinity to PGN and moderate affinity to LPS, but it did not bind beta-glucan. Meanwhile, rCfPGRP-S1 also exhibited strong agglutination activity to Gram-positive bacteria Micrococcus luteus and Bacillus subtilis and weak activity to Gram-negative bacteria Escherichia coli. More importantly, rCfPGRP-S1 functioned as a bactericidal amidase to degrade PGN and strongly inhibit the growth of E. coli and Staphyloccocus aureus in the presence of Zn(2+). These results indicated that CfPGRP-S1 could not only serve as a pattern recognition receptor recognizing bacterial PGN and LPS, but also function as a scavenger involved in eliminating response against the invaders. PMID- 20713084 TI - A hardware-algorithm co-design approach to optimize seizure detection algorithms for implantable applications. AB - Implantable neural prostheses that deliver focal electrical stimulation upon demand are rapidly emerging as an alternate therapy for roughly a third of the epileptic patient population that is medically refractory. Seizure detection algorithms enable feedback mechanisms to provide focally and temporally specific intervention. Real-time feasibility and computational complexity often limit most reported detection algorithms to implementations using computers for bedside monitoring or external devices communicating with the implanted electrodes. A comparison of algorithms based on detection efficacy does not present a complete picture of the feasibility of the algorithm with limited computational power, as is the case with most battery-powered applications. We present a two-dimensional design optimization approach that takes into account both detection efficacy and hardware cost in evaluating algorithms for their feasibility in an implantable application. Detection features are first compared for their ability to detect electrographic seizures from micro-electrode data recorded from kainate-treated rats. Circuit models are then used to estimate the dynamic and leakage power consumption of the compared features. A score is assigned based on detection efficacy and the hardware cost for each of the features, then plotted on a two dimensional design space. An optimal combination of compared features is used to construct an algorithm that provides maximal detection efficacy per unit hardware cost. The methods presented in this paper would facilitate the development of a common platform to benchmark seizure detection algorithms for comparison and feasibility analysis in the next generation of implantable neuroprosthetic devices to treat epilepsy. PMID- 20713085 TI - Rotating disk electrode voltammetric measurements of serotonin transporter kinetics in synaptosomes. AB - Altered serotonin (5-HT) signaling is implicated in several neuropsychiatric disorders, including depression, anxiety, obsessive-compulsive disorder, and autism. The 5-HT transporter (SERT) modulates 5-HT neurotransmission strength and duration. This is the first study using rotating disk electrode voltammetry (RDEV) to measure 5-HT clearance. SERT kinetics were measured in whole brain synaptosomes. Uptake kinetics of exogenous 5-HT were measured using glassy carbon electrodes rotated in 500 MUL glass chambers containing synaptosomes from SERT knockout (-/-), heterozygous (+/-), or wild-type (+/+) mice. RDEV detected 5-HT concentrations of 5nM and higher. Initial velocities were kinetically resolved with K(m) and V(max) values of 99+/-35 standard error of regression (SER) nM and 181+/-11 SER fmol/(s*mg protein), respectively in wild-type synaptosomes. The method enables control over drug and chemical concentrations, facilitating interpretation of results. Results are compared in detail to other techniques used to measure SERT kinetics, including tritium labeled assays, chronoamperometry, and fast scan cyclic voltammetry. RDEV exhibits decreased 5-HT detection limits, decreased vulnerability to 5-HT oxidation products that reduce electrode sensitivity, and also overcomes diffusion limitations via forced convection by providing a continuous, kinetically resolved signal. Finally, RDEV distinguishes functional differences between genotypes, notably, between wild type and heterozygous mice, an experimental problem with other experimental approaches. PMID- 20713086 TI - Autogenic EMG-controlled functional electrical stimulation for ankle dorsiflexion control. AB - Our objectives were to develop and test a new system for the potential for stable, real-time cancellation of residual stimulation artefacts (RSA) using surface electrode autogenic electromyography-controlled functional electrical stimulator (aEMGcFES). This type of closed-loop FES could be used to provide more natural, continuous control of lower extremity paretic muscles. We built upon work that has been done in the field of FES with one major technological innovation, an adaptive Gram-Schmidt filtering algorithm, which allowed us to digitally cancel RSA in real-time. This filtering algorithm resulted in a stable real-time estimation of the volitional intent of the stimulated muscle, which then acted as the direct signal for continuously controlling homonymous muscle stimulation. As a first step toward clinical application, we tested the viability of our aEMGcFES system to continuously control ankle dorsiflexion in a healthy subject. Our results indicate positively that an aEMGcFES device with adaptive filtering can respond proportionally to voluntary EMG and activate forceful movements to assist dorsiflexion during controlled isometric activation at the ankle. We also verified that normal ankle joint range of movement could be maintained while using the aEMGcFES system. We suggest that real-time cancellation of both primary and RSA is possible with surface electrode aEMGcFES in healthy subjects and shows promising potential for future clinical application to gait pathologies such as drop foot related to hemiparetic stroke. PMID- 20713087 TI - Automatic mosaicking and volume assembly for high-throughput serial-section transmission electron microscopy. AB - We describe a computationally efficient and robust, fully-automatic method for large-scale electron microscopy image registration. The proposed method is able to construct large image mosaics from thousands of smaller, overlapping tiles with unknown or uncertain positions, and to align sections from a serial section capture into a common coordinate system. The method also accounts for nonlinear deformations both in constructing sections and in aligning sections to each other. The underlying algorithms are based on the Fourier shift property which allows for a computationally efficient and robust method. We demonstrate results on two electron microscopy datasets. We also quantify the accuracy of the algorithm through a simulated image capture experiment. The publicly available software tools include the algorithms and a Graphical User Interface for easy access to the algorithms. PMID- 20713088 TI - Spatio-temporal dual effects of IkappaBzeta dictates the caution on visual disturbance resulting from IkappaBzeta deficiency. PMID- 20713089 TI - Development of a simple system for screening anti-hepatitis C virus drugs utilizing mutants capable of vigorous replication. AB - Replication of infectious hepatitis C virus in Huh7 cells, a human hepatocyte cell line, has become possible due to the unique properties of the JFH1 isolate. Developing reporter virus systems for a simple titration has been attempted by integrating heterologous reporter genes into the JFH1 genome, resulting in a big infectivity reduction that limits the usefulness of such reporter systems. To overcome this problem, JFH1-infected Huh7 cells were cultured continuously for 2 years to obtain Huh7-adapted JFH1 variants capable of yielding up to 1000-fold higher titers. Sequence analysis of variant genome RNA suggested that this adapted population consisted mainly of two variants. By joining the 5'-half of the obtained representative viral complementary DNA (cDNA) fragments of the variants with the 3'-half of the wild-type's, two prototype clones, A/WT and B/WT, were constructed. Replication of A/WT and B/WT viruses in Huh7 cells showed up to 100-1000-fold higher titers than the wild-type. A Renilla luciferase cDNA was inserted into the Nonstructural Protein 5A region of the A/WT and B/WT cDNA to generate A/WT-Rluc and B/WT-Rluc, respectively. Transfection of Huh7 cells with in vitro-transcribed A/WT-Rluc and B/WT-Rluc RNA resulted in production of infectious viruses with approximately 15- and 25-fold higher titers, respectively, than the wild-type RNA. The replication of A/WT-Rluc and B/WT-Rluc viruses was more vigorous than the wild-type even with insertion of the luciferase cDNA showing a good correlation of luciferase activities with infectious titers. Furthermore, interferon-alpha inhibited the replication of A/WT-Rluc and B/WT-Rluc viruses in a dose-dependent manner as determined by a luciferase assay. These results imply that our system is potentially a tool useful for screening anti-hepatitis C virus drugs in a simple and time/cost saving manner. PMID- 20713090 TI - Drastic decrease of transcription activity due to hypermutated long terminal repeat (LTR) region in different HIV-1 subtypes and recombinants. AB - Transcriptional activation of HIV-1 gene expression is partially controlled by the interaction between viral and cellular transcription factors acting at HIV-1 long terminal repeat (LTR) sequences. HIV-1 subtyping at LTR region and nucleotide LTR variability from clinical samples in 48 subjects carrying different HIV-1 subtypes (9A, 5C, 3D, 3F, 21G, 2H, 3J and 2 undefined) at the protease (PR) gene, were performed. LTR sequences from each HIV-1 clade were cloned in luciferase-expression vectors to determine basal and Tat-induced transcriptional activities in the presence and absence of PMA stimulation. A high number (37.8%) of recombinants at LTR/PR regions were identified. All HIV-1 promoters presented low basal transcriptional activity that was nevertheless induced by Tat and PMA. LTR activity was similar across the majority of HIV-1 variants in response to Tat and cell activation. Only subtype C and CRF01_AE LTRs presented higher basal and induced-PMA transcription activities than HXB2 clade B promoter. No basal or Tat/PMA induced activity was found in those promoters presenting G to A hypermutation compared to the wild type promoter activities. G to A hypermutation at some important transcription binding-factor sites within LTR compromised the activity of the viral promoter, decreasing the in vitro viral transcription of the luciferase gene. PMID- 20713091 TI - The potent inhibitory effect of tipepidine on marble-burying behavior in mice. AB - Our previous study revealed that centrally acting non-narcotic antitussives inhibited G-protein-coupled inwardly rectifying K(+) (GIRK) channel currents in brain neurons, and that the tipepidine antitussives had a novel antidepressive like effect on rats. Furthermore, the antitussives revealed multiplexed ameliorating actions on intractable brain disease models. This study evaluated the therapeutic potential of tipepidine in obsessive-compulsive disorder (OCD) subjects using marble-burying behavior (MBB) tests in mice. In fact, OCD is classified as an anxiety disorder characterized by obsession or compulsion. Although selective 5-HT reuptake inhibitors (SSRIs) are considered first choice agents for the pharmacological treatment of OCD, 50% of patients with OCD failed to respond to SSRIs. The burying of harmless objects such as marbles by mice might reflect the formation of compulsive behavior. The results show that tipepidine reduced MBB in a dose-dependent manner. The effect of tipepidine was significant even at a dosage as small as 5 mg/kg. The tipepidine at 10 mg/kg s.c. nearly abolished MBB without reducing the locomotor activity in mice. It is particularly interesting that the dopamine D2 antagonist or 5-HT(1A) antagonist partly inhibited the effect of tipepidine on MBB. The results suggest that tipepidine has more of a potent inhibitory effect on MBB, compared with known drugs used for the treatment of OCD, and that the tipepidine action mechanism might differ from that of known drugs. PMID- 20713092 TI - Manganese-enhanced magnetic resonance imaging (MEMRI) of rat brain after systemic administration of MnCl2: hippocampal signal enhancement without disruption of hippocampus-dependent behavior. AB - Manganese (Mn(2+))-enhanced magnetic resonance (MR) imaging (MEMRI) in rodents offers unique opportunities for the longitudinal study of hippocampal structure and function in parallel with cognitive testing. However, Mn(2+) is a potent toxin and there is evidence that it can interfere with neuronal function. Thus, apart from causing adverse peripheral side effects, Mn(2+) may disrupt the function of brain areas where it accumulates to produce signal enhancement and, thereby, Mn(2+) administration may confound cognitive testing. Here, we examined in male adult Lister hooded rats if a moderate systemic dose of MnCl2 (200 MUmol/kg; two intraperitoneal injections of 100 MUmol/kg separated by 1 h) that produces hippocampal MR signal enhancement would disrupt hippocampal function. To this end, we used a delayed-matching-to-place (DMP) watermaze task, which requires rapid allocentric place learning and is highly sensitive to interference with hippocampal function. Tested on the DMP task 1 h and 24 h after MnCl2 injection, rats did not show any impairment in indices of memory performance (latencies, search preference) or any sensorimotor effects. However, MnCl2 injection caused acute peripheral effects (severe ataxia and erythema, i.e. redness of paws, ears, and nose) which subsided over 30 min. Additionally, rats injected with MnCl2 showed reduced weight 1 day after injection and failed to reach the normal weight-growth curve of control rats within the 16 days monitored. Our results indicate that 200 MUmol/kg MnCl2 produces hippocampal MR signal enhancement without disrupting hippocampus-dependent behavior on a rapid place learning task, even though attention must be paid to peripheral side effects. PMID- 20713093 TI - The effect of propranolol dose and novelty of the reactivation procedure on the reconsolidation of a morphine place preference. AB - Previously consolidated memories may become labile when they are reactivated and require reconsolidation. It has been suggested that when novel information is present at the time of memory reactivation reconsolidation is engaged but when no new information is present, reconsolidation may not occur, and extinction may be the dominant process instead. To test this idea we trained rats to associate a context with the rewarding properties of morphine (5 mg/kg, sc) over four conditioning pairings. Following training, animals were reactivated by a 30-min test session, once a day for 3 days. Rats were injected with the amnestic drug propranolol (10 or 40 mg/kg, sc) following reactivation either on the first or on the second day. They received saline on the alternate day. Propranolol disrupted reconsolidation for a conditioned place preference only when given on the first reactivation day, and this effect was more robust following the higher dose of propranolol. In contrast, animals given propranolol on the second reactivation day still displayed a preference for the morphine-paired context on the final test day. These results support the view that for memory to return to a labile state, the situation that evokes reactivation needs to be novel in some way. If the reactivation situation is familiar, reconsolidation may not occur. PMID- 20713094 TI - Progressive motor and respiratory metabolism deficits in post-weaning Mecp2-null male mice. AB - The methyl-CpG binding protein 2 (Mecp2) gene encodes a nuclear transcriptional modulator highly expressed in post-mitotic neurons. Mutations of this gene cause a large spectrum of neurological disorders in humans. Several lines of mice harboring a constitutional deletion of Mecp2 are available. The use of these models is crucial to understand the basis of Mecp2-related pathologies. However, most of the studies performed using these lines focused on different postnatal time points. The aim of the present study was to provide a more complete description of the behavioral phenotype of the Mecp2(tm1.1Bird) mice. To this aim, we used a modified version of the SHIRPA protocol and a set of sensorimotor tests and respiratory metabolism measurements, in a longitudinal study of the Mecp2-null male mice (Mecp2(-/y)) from three weeks (weaning) to eight weeks of age. Our data document, for the first time, the sequential appearance of the in vivo deficits in this mouse line. The observed deficits initially concern major parameters (such as body weight), and are followed by involuntary and sensitive defects (reflexes). Subsequently, motor functions and respiratory metabolism are severally impaired. A detailed description of these gradual defects may help to identify their neuronal origin and to elaborate novel therapeutic strategies. PMID- 20713095 TI - Apoptogenic factors released from mitochondria. AB - When cells kill themselves, they usually do so by activating mechanisms that have evolved specifically for that purpose. These mechanisms, which are broadly conserved throughout the metazoa, involve two processes: activation in the cytosol of latent cysteine proteases (termed caspases), and disruption of mitochondrial functions. These processes are linked in a number of different ways. While active caspases can cleave proteins in the mitochondrial outer membrane, and cleave and thereby activate certain pro-apoptotic members of the Bcl-2 family, proteins released from the mitochondria can trigger caspase activation and antagonise IAP family proteins. This review will focus on the pro apoptotic molecules that are released from the mitochondria of cells endeavouring to kill themselves. This article is part of a Special Issue entitled Mitochondria: the deadly organelle. PMID- 20713097 TI - Can a regular context induce temporal orienting to a target sound? AB - It has been shown recently (Lange, 2009) that the N1 of the auditory event related potential (ERP) is attenuated when the eliciting stimulus predictably follows a regular vs. an irregular sequence. This may be a sign of temporal orienting induced by the regular sequence. Alternatively, the attenuated N1 may have been due to sensory predictability of target timing. The present study investigated whether presenting a regular sequence still attenuates target N1 when target timing is unpredictable. A regular (vs. irregular) tone sequence was presented prior to a target tone, which appeared unpredictably at one of three different time points after the sequence. For the regular sequence, targets either continued regularity (on-time targets) or were early or late with respect to this regular time point. ERPs to on-time targets were compared as a function of sequence regularity. Consistent with the assumption that N1 attenuation reflects sensory predictability of target timing, an attenuated N1 was not observed in the present study, where target timing was uncertain. PMID- 20713096 TI - Long-range synchrony of gamma oscillations and auditory hallucination symptoms in schizophrenia. AB - Phase locking in the gamma-band range has been shown to be diminished in patients with schizophrenia. Moreover, there have been reports of positive correlations between phase locking in the gamma-band range and positive symptoms, especially hallucinations. The aim of the present study was to use a new methodological approach in order to investigate gamma-band phase synchronization between the left and right auditory cortex in patients with schizophrenia and its relationship to auditory hallucinations. Subjects were 18 patients with chronic schizophrenia (SZ) and 16 healthy control (HC) subjects. Auditory hallucination symptom scores were obtained using the Scale for the Assessment of Positive Symptoms. Stimuli were 40-Hz binaural click trains. The generators of the 40Hz ASSR were localized using eLORETA and based on the computed intracranial signals lagged interhemispheric phase locking between primary and secondary auditory cortices was analyzed. Current source density of the 40 ASSR response was significantly diminished in SZ in comparison to HC in the right superior and middle temporal gyrus (p<0.05). Interhemispheric phase locking was reduced in SZ in comparison to HC for the primary auditory cortices (p<0.05) but not in the secondary auditory cortices. A significant positive correlation was found between auditory hallucination symptom scores and phase synchronization between the primary auditory cortices (p<0.05, corrected for multiple testing) but not for the secondary auditory cortices. These results suggest that long-range synchrony of gamma oscillations is disturbed in schizophrenia and that this deficit is related to clinical symptoms such as auditory hallucinations. PMID- 20713098 TI - Analysis of expression and glycosylation of avian metapneumovirus attachment glycoprotein from recombinant baculoviruses. AB - Recently, we reported the expression and glycosylation of avian metapneumovirus attachment glycoprotein (AMPV/C G protein) in eukaryotic cell lines by a transient-expression method. In the present study, we investigated the biosynthesis and O-linked glycosylation of the AMPV/C G protein in a baculovirus expression system. The results showed that the insect cell-produced G protein migrated more rapidly in SDS-PAGE as compared to LLC-MK2 cell-derived G proteins owing to glycosylation differences. The fully processed, mature form of G protein migrated between 78 and 86 kDa, which is smaller than the 110 kDa mature form of G expressed in LLC-MK2 cells. In addition, several immature G gene products migrating at 40-48 and 60-70 kDa were also detected by SDS-PAGE and represented glycosylated intermediates. The addition of the antibiotic tunicamycin, which blocks early steps of glycosylation, to insect cell culture resulted in the disappearance of two glycosylated forms of the G protein and identified a 38 kDa unglycosylated precursor. The maturation of the G protein was completely blocked by monensin, suggesting that the O-linked glycosylation of G initiated in the trans-Golgi compartment. The presence of O-linked sugars on the mature protein was further confirmed by lectin Arachis hypogaea binding assay. Furthermore, antigenic features of the G protein expressed in insect cells were evaluated by ELISA. PMID- 20713099 TI - Sustained delivery of human growth hormone using a polyelectrolyte complex-loaded thermosensitive polyphosphazene hydrogel. AB - A combined system of polyelectrolyte complex (PEC) and injectable, biodegradable and thermosensitive poly(organophosphazene) hydrogel has been suggested as an injectable depot for a controlled and sustained delivery of human growth hormone (hGH) to improve patient compliance. PEC was prepared by mixing polycations with hGH to suppress diffusion of hGH from the hydrogel through an enlargement of the hydrodynamic size of hGH. Among the polycations, poly-L-arginine (PLA) formed a large complex with hGH and its size increased as the amount of PLA increased. When PLA and/or zinc were added to hGH, the time-dependent stability of hGH increased more than that of native-hGH. The polymer solution containing PECs formed a gel at 37 degrees C. PLA decreased the initial release rate of hGH in proportion to the amount of PLA in vitro and in vivo. Zinc increased the released amount of hGH from the PEC-loaded hydrogel in vitro and in vivo. In a pharmacokinetic study in rats, a single administration of PEC-loaded hydrogel resulted in the sustained release of hGH for 5days. These results suggest that injectable, biodegradable, and thermosensitive PEC-loaded poly(organophosphazene) hydrogel has great potential to be used as an effective delivery system for a sustained release of hGH with improved patient compliance. PMID- 20713101 TI - Impact of vaccinating boys and men against HPV in the United States. AB - We assessed the public health impact and value of vaccinating boys and men with the quadrivalent HPV vaccine in the United States. We used mathematical population models, accounting for both the direct and indirect protective effects of vaccination. Inputs for the models were obtained from public data sources, published literature, and analyses of clinical trial data. Compared with a program of vaccinating girls and women only, including boys and men 9-26 years of age would further decrease the cumulative mean number of genital wart cases, cervical intraepithelial neoplasia 2/3 cases, cancer cases, and cancer deaths by 5,146,000, 708,000, 116,000, and 40,000, respectively, within 100 years. The mean cost-effectiveness ratio (2008 US $) of this strategy was $25,700 (range: 13,600 48,800) per QALY gained if vaccination protects against all HPV 6/11/16/18 associated diseases, and $69,000 (range: 37,700-152,300)/QALY if it only protects against diseases currently in the vaccine indication. Vaccinating boys and men age 9-26 against all HPV 6/11/16/18-associated diseases provides substantial public health benefits and is cost-effective at commonly cited thresholds. PMID- 20713103 TI - Lipopeptide induces apoptosis in fungal cells by a mitochondria-dependent pathway. AB - Bacillus amyloliquefaciens WH1 inhibit the growth of fungi by producing a new surfactin called as WH1fungin. WH1fungin plays an anti-fungal role by two models: high concentration to elicit pores on cell membrane and low concentration to induce apoptosis. WH1fungin can also inhibits the glucan synthase resulting in a decreased synthesis of callose on fungal cell wall. Further detection revealed that classical apoptotic markers such as reactive oxygen species (ROS) accumulation, phosphatidylserine (PS) externalization, DNA strand breaks and caspase-like activities could be found in fungal cells after treated by WH1fungin. Oligomycin was used as an inhibitor to block the mitochondria dependent apoptosis in fungal cells, and results showed it could not inhibit but enhance the apoptosis induced by WH1fungin. After isolation by affinity chromatography, WH1fungin was found to bind with ATPase on the mitochondrial membrane and result in a decreased ATPase activity in fungal cells. This was further verified by treating fungal cells with FITC-labeled WH1fungin, which could bind to the mitochondrial membrane showing green fluorescence in fungal cells. After that, cytochrome C was released from the mitochondria, which then acted with caspase 9 to induce apoptosis by an intracellular pathway. High caspase 8 activity was also detectable in apoptotic fungal cells, indicating that an extracellular pathway might also be responsible for apoptosis induced by WH1fungin. Taken together, we report that lipopeptide can induce apoptosis in fungal cells, and induction of apoptosis by lipopeptide might be a common anti fungal mechanism of Bacillus in the natural habitat. PMID- 20713104 TI - Novel peptide ligands that bind specifically to mouse embryonic stem cells. AB - The search for new ES cell markers is critical not only for identification, isolation and visualization of embryonic stem (ES) cells, but also for potential clinical treatment as a targeting agent. Here, by using phage display technology, 12-mer peptide ligands that bind specifically to mouse ES cells were isolated. After four rounds of negative-positive selection, nine sequences in 20 random samples from the chosen clones were selected. Enzyme-linked immunosorbent assay results suggested the Seq2 peptide (KHMHWHPPALNT) had high affinity and specificity to the mouse ES cells. The binding capability of the Seq2 phage could be matched with that of a chemically synthesized peptide with a sequence identical to that displayed by the phage, indicating that this ability was due to the peptide sequence itself. Immunofluorescence analysis confirmed that Seq2 phage selectively bound to the mouse ES cells but not to the differentiated mouse ES cells. Western blot analysis proved the Seq2 phage was bound to two mouse ES membrane proteins which were about 18/20KD, suggesting that the selected peptide targeted to a unique receptor expressed on the mouse ES cells with specificity. Peptides obtained from the study may provide a way to label, identify, and characterize ES cells. PMID- 20713100 TI - TLR-based immune adjuvants. AB - This work describes the nature and strength of the immune response induced by various Toll-like receptor ligands and their ability to act as vaccine adjuvants. It reviews the various ligands capable of triggering individual TLRs, and then focuses on the efficacy and safety of those agents for which clinical results are available. PMID- 20713105 TI - Neuroprotective effects of stanniocalcin 2 following kainic acid-induced hippocampal degeneration in ICR mice. AB - Stanniocalcin 2 (STC2), the paralog of STC1, has been shown to act as a novel target of the mammalian unfolded protein response. We investigated the potential neuroprotective actions of STC2 against kainic acid toxicity in the hippocampus of ICR mice. STC2-treated mice experienced less neuronal cell loss in the CA3 area of the hippocampus. Also, microglial activation and heme oxygenase 1 expression were attenuated in the hippocampus of STC2-treated mice. To confirm whether STC2 regulates microglial activation directly, nitric oxide levels were measured in BV2 cells cultured with and without 10nM STC2. STC2 decreased the level of nitric oxide induced by lipopolysaccharide (LPS) treatment significantly. Also, STC2 pretreatment significantly decreased TNF-alpha and IL 1beta expression induced by LPS treatment. These observations demonstrated that STC2 exerts neuroprotective actions against excitotoxic insults through the inhibition of microglial activation. PMID- 20713102 TI - Nonviral gene transfer as a tool for studying transcription regulation of xenobiotic metabolizing enzymes. AB - Numerous xenobiotic metabolizing enzymes are regulated by nuclear receptors at transcriptional level. The challenge we currently face is to understand how a given nuclear receptor interacts with its xenobiotics, migrates into nucleus, binds to the xenobiotic response element of a target gene, and regulates transcription. Toward this end, new methods have been developed to introduce the nuclear receptor gene into appropriate cells and study its activity in activating reporter gene expression under the control of a promoter containing xenobiotic response elements. The goal of this review is to critically examine the gene transfer methods currently available. We concentrate on the gene transfer mechanism, advantages and limitations of each method when employed for nuclear receptor-mediated gene regulation studies. It is our hope that the information provided highlights the importance of gene transfer in studying the mechanisms by which our body eliminates the potentially harmful substances and maintains the homeostasis. PMID- 20713106 TI - In vitro activity of pacifastin-like inhibitors in relation to their structural characteristics. AB - Information on the structural characteristics and inhibitory activity of the pacifastin family is restricted to a handful of locust pacifastin-related inhibitors. In this report the optimization of a bacterial recombinant expression system is described, resulting in the high yield production of pacifastin-like inhibitors of the desert locust. Subsequently, the relative inhibitory activity of these peptides towards mammalian, locust and caterpillar digestive peptidases has been compared. In general, the enzyme specificity of locust pacifastin-like inhibitors towards trypsin- or chymotrypsin-like peptidases corresponds to the nature of the P1-residue at the reactive site. In addition, other structural characteristics, including specific core interactions, have been reported to result in a different affinity of pacifastin members towards digestive trypsin like enzymes from mammals and arthropods. One remarkable observation in this study is a specifically designed pacifastin-like peptidase inhibitor, which, unlike other inhibitors of the same family, does not display this specificity and selectivity towards digestive enzymes from different animals. PMID- 20713108 TI - Antimicrobial activity of human hepcidin 20 and 25 against clinically relevant bacterial strains: effect of copper and acidic pH. AB - Hepcidin 25 (hep-25) is a peptide primarily produced by human liver with a central role in iron homeostasis. Its isoform, hepcidin 20 (hep-20), has an unknown function and lacks the first five aminoacids of the amino-terminal portion. This sequence is crucial for iron regulation by hep-25 and contains a molecular motif able to bind metals. Aim of this study, was to evaluate the antibacterial properties of both peptides in vitro, against a wide range of bacterial clinical isolates and in different experimental conditions. Although both peptides were found to be bactericidal against a variety of clinical isolates with different antibiotic resistance profiles, hep-20 was active at lower concentrations than hep-25, in most of the cases. Killing kinetics, carried on in sodium-phosphate buffer at pH 7.4, demonstrated that bactericidal activity occurred not earlier than 30-90 min of incubation. Bactericidal activity of hep 25 was slightly enhanced in the presence of copper, while the same metal did not affect the activity of hep-20. Interestingly, bactericidal activity of both hepcidins was highly enhanced at acidic pH. Acidic pH (pH 5.0 and 6.6) not only reduced the microbicidal concentrations of hepcidins, but also shortened the killing times of both peptides, as compared to pH 7.4. Combining hep-20 and hep 25 at pH 5.0 a bactericidal effect could be obtained at very low concentrations of both peptides. These results render hepcidins interesting for the design of new drugs for the treatment of infections occurring in body districts with physiologic acidic pH. PMID- 20713107 TI - Cost-effective expression and purification of antimicrobial and host defense peptides in Escherichia coli. AB - Cationic antimicrobial host defense peptides (HDPs) combat infection by directly killing a wide variety of microbes, and/or modulating host immunity. HDPs have great therapeutic potential against antibiotic-resistant bacteria, viruses and even parasites, but there are substantial roadblocks to their therapeutic application. High manufacturing costs associated with amino acid precursors have limited the delivery of inexpensive therapeutics through industrial-scale chemical synthesis. Conversely, the production of peptides in bacteria by recombinant DNA technology has been impeded by the antimicrobial activity of these peptides and their susceptibility to proteolytic degradation, while subsequent purification of recombinant peptides often requires multiple steps and has not been cost-effective. Here we have developed methodologies appropriate for large-scale industrial production of HDPs; in particular, we describe (i) a method, using fusions to SUMO, for producing high yields of intact recombinant HDPs in bacteria without significant toxicity and (ii) a simplified 2-step purification method appropriate for industrial use. We have used this method to produce seven HDPs to date (IDR1, MX226, LL37, CRAMP, HHC-10, E5 and E6). Using this technology, pilot-scale fermentation (10L) was performed to produce large quantities of biologically active cationic peptides. Together, these data indicate that this new method represents a cost-effective means to enable commercial enterprises to produce HDPs in large-scale under Good Laboratory Manufacturing Practice (GMP) conditions for therapeutic application in humans. PMID- 20713109 TI - Peripheral antinociceptive effects of the cyclic endomorphin-1 analog c[YpwFG] in a mouse visceral pain model. AB - We previously described a novel cyclic endomorphin-1 analog c[Tyr-D-Pro-D-Trp-Phe Gly] (c[YpwFG]), acting as a mu-opioid receptor (MOR) agonist. This study reports that c[YpwFG] is more lipophilic and resistant to enzymatic hydrolysis than endomorphin-1 and produces preemptive antinociception in a mouse visceral pain model when injected intraperitoneally (i.p.) or subcutaneously (s.c.) before 0.6% acetic acid, employed to evoke abdominal writhing (i.p. ED(50)=1.24 mg/kg; s.c. ED(50)=2.13 mg/kg). This effect is reversed by the selective MOR antagonist beta funaltrexamine and by a high dose of the mu(1)-opioid receptor-selective antagonist naloxonazine. Conversely, the kappa-opioid receptor antagonist nor binaltorphimine and the delta-opioid receptor antagonist naltrindole are ineffective. c[YpwFG] produces antinociception when injected i.p. after acetic acid (ED(50)=4.80 mg/kg), and only at a dose of 20mg/kg did it elicit a moderate antinociceptive response in the mouse, evaluated by the tail flick assay. Administration of a lower dose of c[YpwFG] (10mg/kg i.p.) apparently produces a considerable part of antinociception on acetic acid-induced writhes through peripheral opioid receptors as this action is fully prevented by i.p. naloxone methiodide, which does not readily cross the blood-brain barrier; whereas this opioid antagonist injected intracerebroventricularly (i.c.v.) is not effective. Antinociception produced by a higher dose of c[YpwFG] (20mg/kg i.p.) is partially reversed by naloxone methiodide i.c.v. administered. Thus, only at the dose of 20mg/kg c[YpwFG] can produce antinociception through both peripheral and central opioid receptors. In conclusion, c[YpwFG] displays sufficient metabolic stability to be effective after peripheral administration and demonstrates the therapeutic potential of endomorphin derivatives as novel analgesic agents to control visceral pain. PMID- 20713110 TI - Exposure-based waiving under REACH. AB - Within the REACH framework, but also within OECD, there is understanding that for reasons of animal welfare, costs and logistics, it is important to limit the number of tests to be conducted. Exposure-based waiving (EBW) is a potentially important element in testing strategies. This publication describes criteria for exposure-based waiving as foreseen in the REACH regulation and gives more detail to the REACH requirements for exposure-based waiving The principle behind any EBW is that there are situations when human or environmental exposures are so low or infrequent that there is a very low probability that the acquisition of additional effect information may lead to an improvement in the ability to manage risk. EBW therefore is risk-based and needs thorough knowledge on exposure as well as on effects criteria. Both elements are discussed: exposure models are analysed and the uncertainty in their predictions discussed as well as no-effect criteria such as the threshold of toxicological concern. Examples of EBW are provided for environmental, consumer and worker exposure. REACH only allows EBW in a limited number of cases with constraints on tonnage levels, types of tests to be waived and the need for a thorough ES and exposure assessment throughout the life cycle of a chemical and for all human exposure routes and environmental pathways. EBW will only be considered a real option by industry if a cost-benefit analysis shows an advantage, which may heavily depend on the weighing factor one applies for the non-use of experimental animals. PMID- 20713111 TI - Acute and sub-chronic oral toxicological evaluations of quinocetone in Wistar rats. AB - To provide a detailed toxicity with wide spectrum of doses for quinocetone, a new antimicrobial growth promoting agent, acute and sub-chronic toxicological studies were conducted. For acute study, quinocetone was administered singly by oral gavage to Wistar rats and Kunming mice. Calculated LD50 was 8687.31 mg/kg b.w./day in rats and 15848.93 mg/kg b.w./day in mice. In sub-chronic study, quinocetone was fed to Wistar rats at dietary levels of 0, 50, 300 and 1800 mg/kg or olaquindox (300 mg/kg), approximately equivalent to quinocetone 5, 30, 180 or olaquindox 30 mg/kg b.w./day. There was significant decrease in body weight in both genders, total protein and creatinine in females and alkaline phosphatase in males fed with 1800 mg/kg diet, while alkaline aminotransferase values decreased in all treated groups. Significant increase in relative weights of liver and kidneys in both genders and testis in male rats were noted at 1800 mg/kg diet. Histopathological observations revealed that 1800 mg/kg quinocetone diet and 300 mg/kg olaquindox diet could induce proliferation of bile canaliculi in the portal area. In conclusion, quinocetone can induce hepatic histological changes as well as leaking of different serum enzymes. The no-observed-adverse-effect level of quinocetone was considered to be 300 mg/kg diet. PMID- 20713112 TI - Sex differences in the association of weight gain and risperidone efficacy among schizophrenic patients. PMID- 20713113 TI - The increase in theta/beta ratio on resting-state EEG in boys with attention deficit/hyperactivity disorder is mediated by slow alpha peak frequency. AB - Attention-deficit/hyperactivity disorder (ADHD) was found to be characterized by a deviant pattern of electrocortical activity during resting state, particularly increased theta and decreased beta activity. The first objective of the present study is to confirm whether individuals with slow alpha peak frequency contribute to the finding of increased theta activity in ADHD. The second objective is to explore the relation between resting-state brain oscillations and specific cognitive functions. From 49 boys with ADHD and 49 healthy control boys, resting state EEG during eyes open and eyes closed was recorded, and a variety of cognitive tasks were administered. Theta and beta power and theta/beta ratio were calculated using both fixed frequency bands and individualized frequency bands. As expected, theta/beta ratio, calculated using fixed frequency bands, was significantly higher in ADHD children than control children. However, this group effect was not significant when theta/beta ratio was assessed using individualized frequency bands. No consistent relation was found between resting state brain oscillations and cognition. The present results suggest that previous findings of increased theta/beta ratio in ADHD may reflect individuals with slow alpha peak frequencies in addition to individuals with true increased theta activity. Therefore, the often reported theta/beta ratio in ADHD can be considered a non-specific measure combining several distinct neurophysiological subgroups such as frontal theta and slowed alpha peak frequencies. Future research should elucidate the functional role of resting-state brain oscillations by investigating neurophysiological subgroups, which may have a clearer relation to cognitive functions than single frequency bands. PMID- 20713114 TI - Synergism of theophylline and anticholinergics to inhibit haloperidol-induced catalepsy: a potential treatment for extrapyramidal syndromes. AB - Extrapyramidal syndromes (EPS) impose a heavy burden on patients receiving antipsychotic therapy. Anticholinergics are the drugs of choice for preventing EPS, but they also produce many adverse reactions. Using the EPS model of haloperidol-induced catalepsy we evaluated the potential therapeutic value of a mixture of low doses of the non-selective adenosine antagonist theophylline (0.93 and 1.86 mg/kg), and the muscarinic antagonists benztropine (0.134 and 0.268 mg/kg) and ethopropazine (0.116 and 0.232 mg/kg). In rats pretreated with vehicle (distilled water), the cumulative catalepsy time over 5 h was 4199+/-228 s, and the mean latency was 67.5+/-7.8 min. Applied separately, neither of the drugs at the doses used caused significant changes of catalepsy intensity vs. control rats. However, the combination of the larger doses of theophylline and benztropine caused a significant reduction of catalepsy intensity (-41+/-10%) compared with the effects of the vehicle, vs. the lower dose of benztropine, and vs. both doses of theophylline alone. The mixture of the larger doses of theophylline and benztropine also delayed catalepsy onset (156+/-21 min) as compared with the lower doses of these same drugs applied alone. In the case of theophylline plus ethopropazine, only the association of the larger doses showed a non-significant tendency to inhibit catalepsy (-21+/-8%) and to prolong its latency (108+/-13 min). Further, neither catalepsy intensity nor its latency was affected by a combination of the selective A(1)R antagonist DPCPX (1 mg/kg), with the larger doses of both anticholinergics. In contrast, the anticholinergics showed synergism with a subthreshold dose of the selective A(2A)R antagonist ZM 241395 (0.5 mg/kg), causing a significant reduction of catalepsy intensity (ethopropazine, -27+/-5%; benztropine, -35+/-9%) and prolonging its latency (ethopropazine, 65+/-9 min; benztropine, 78+/-11 min), compared with the effect of their respective vehicle (DMSO plus mineral oil: catalepsy time, 5100+/-196 s; latency, 17.5+/-2.5 min). These findings suggest that neuroleptic-induced EPS could be effectively controlled by a combination of lower doses of theophylline and anticholinergics, with the advantage of maximizing their efficacy and minimizing their adverse reactions. PMID- 20713115 TI - Inhibitory effect of berberine on the motivational effects of ethanol in mice. AB - It is believed that drug-induced rewarding effects play an important role in the development of substance dependence. Recently, berberine was reported to inhibit the rewarding effects of drugs of abuse such as cocaine, morphine, and nicotine. Berberine is also demonstrated to modulate the activity of several neurotransmitter systems like, dopamine, nitric oxide, serotonin, and NMDA, which are implicated in rewarding effects of ethanol. Hence, we hypothesized that berberine may modulate the ethanol-induced rewarding effects. Therefore, we studied the effect of berberine on locomotor sensitization, conditioned place preference (CPP), and ethanol drinking preference in mice. The results revealed that acute administration of berberine (2.5, 5, and 10 mg/kg, i.p.) dose dependently reduced locomotor stimulant effect of acute ethanol and expression of sensitization to locomotor stimulant effect of ethanol. Further, pretreatment with berberine (2.5, 5, and 10 mg/kg, i.p.) prior to each dose of ethanol, blocked the development as well as expression of sensitization to locomotor stimulant effect of ethanol. In another set of experiment, treatment with berberine (5 and 10 mg/kg, i.p.) reduced the induction and expression of ethanol induced CPP in mice. In addition, berberine in these doses also reduced preference to ethanol drinking over water, but did not alter the general reward. In conclusion, the results of the present study revealed that berberine attenuates ethanol-induced rewarding effects in mice and that could be attributed to its neuro-modulatory action. PMID- 20713116 TI - Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains. AB - Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [(3)H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all p<0.05); however 10 mg/kg/day simvastatin increased H1 receptor density only in the medial amygdaloid nucleus (Mep) (p<0.05), but had no significant effect in other regions examined. The 6-OHDA lesion did not alter H1 receptor binding density in most brain areas, except a trend decrease in the hippocampus (p=0.07) and a trend increase in the cingulate cortex (p=0.06). These results suggested that simvastatin has different effects on the H1 receptors in different rat brain regions depending on the doses. Therefore, simvastatin can modulate histaminergic neurotransmission in the brain, and support the role of H1 receptors in psychoneurological disorders. PMID- 20713117 TI - A 10-year retrospective study of the survival rate of teeth restored with metal prefabricated posts versus cast metal posts and cores. AB - OBJECTIVE: The aim of this retrospective study was to compare the cumulative survival rate of teeth restored with prefabricated posts and with cobalt-chrome cast post-cores. METHODS: 112 endodontically treated teeth restored with prefabricated post and cobalt-chrome cast post-and-cores were evaluated. Teeth were considered as failures when were objective or radiologic sign of endodontic failure, post or root fracture, or when they had been extracted at the moment of the evaluation. Kaplan-Meier's method was used to reconstruct the survival curves of the restorations and to test the variable type of post-and-core restoration. RESULTS: 93 of the posts were still in function without clinical or radiographic signs of failure at the time of the examination resulting in a survival rate of 83.03% after a mean follow-up period of 10.08 years. When comparing the two techniques, prefabricated posts showed a slightly higher survival rate: 84.6% versus 82.6%.Focusing on tooth-type, maxillary premolars (n=30) had the highest failure rate (30%) and also the lowest mean lifetime, with 6-and-a-half years. Maxillary incisors (n=20) showed the highest success rate (5%) with only one case of failure. CONCLUSIONS: The results showed no significant difference between both groups after a 10-year average follow-up. PMID- 20713118 TI - Lack of cytotoxicity by Trustwater EcasolTM used to maintain good quality dental unit waterline output water in keratinocyte monolayer and reconstituted human oral epithelial tissue models. AB - We previously showed that residual treatment of dental chair unit (DCU) supply water using the electrochemically-activated solution Trustwater EcasolTM (2.5 ppm) provided an effective long-term solution to the problem of dental unit waterline (DUWL) biofilm resulting in DUWL output water quality consistently superior to potable water. OBJECTIVES: To investigate the cytoxicity of Ecasol using cultured keratinocyte monolayers and reconstituted human oral epithelial (RHE) tissue and to extend the study of Ecasol's effectiveness in maintaining the microbiological quality of DUWL output water. METHODS: TR146 human keratinocyte monolayers and RHE tissues were exposed to Ecasol (2.5-100 ppm) for 1h periods after removal of growth medium and washing with phosphate-buffered saline (PBS). Experiments were repeated using Ecasol that had been exposed for 30 min to 1 2mg/mL bovine serum albumin (BSA), equivalent to protein concentrations in saliva. To quantitatively determine cytotoxic effects on monolayers following Ecasol exposure, the Alamar Blue proliferation assay (assesses cell viability) and the Trypan Blue exclusion assay (assesses plasma membrane integrity), were used. Cytotoxicity effects on RHE tissues were assessed by the Alamar Blue assay and by histopathology. RESULTS: Ecasol at >5.0 ppm resulted in significant (P<0.001) cytotoxicity to keratinocyte monolayers following a 1h exposure. These effects, however, were completely negated by BSA pretreatment of Ecasol. No cytotoxicity was observed in the more complex RHE tissue at any of the Ecasol concentrations tested. In a 60-week study of 10 DCUs, tested weekly, the average density of aerobic heterotrophic bacteria in Ecasol-treated (2.5 ppm) DCU supply water was <1cfu/mL and in DUWL output water was 6.5cfu/mL. CONCLUSIONS: Ecasol present as a residual disinfectant in DUWL output water is very unlikely to have adverse effects on human oral tissues at levels effective in maintaining DUWL output water quality at better than potable standard water quality. PMID- 20713119 TI - A potent potassium channel blocker from Mesobuthus eupeus scorpion venom. AB - Scorpion venom-derived peptidyl toxins are valuable pharmacological tools for investigating the structure-function relationship of ion channels. Here, we report the purification, sequencing and functional characterization of a new K(+) channel blocker (MeuKTX) from the venom of the scorpion Mesobuthus eupeus. Effects of MeuKTX on ten cloned potassium channels in Xenopus oocytes were evaluated using two-electrode voltage-clamp recordings. MeuKTX is the orthologue of BmKTX (alpha-KTx3.6), a known Kv1.3 blocker from the scorpion Mesobuthus martensii, and classified as alpha-KTx3.13. MeuKTX potently blocks rKv1.1, rKv1.2 and hKv1.3 channels with 50% inhibitory concentration (IC(50)) of 203.15 +/- 4.06 pM, 8.92 +/- 2.3 nM and 171 +/- 8.56 pM, respectively, but does not affect rKv1.4, rKv1.5, hKv3.1, rKv4.3, and hERG channels even at 2 MUM concentration. At this high concentration, MeuKTX is also active on rKv1.6 and Shaker IR. Our results also demonstrate that MeuKTX and BmKTX have the same channel spectrum and similar pharmacological potency. Analysis of the structure-function relationships of alpha-KTx3 subfamily toxins allows us to recognize several key sites which may be useful for designing toxins with improved activity on hKv1.3, an attractive target for T-cell mediated autoimmune diseases. PMID- 20713120 TI - Targeting human Rad51 by specific DNA aptamers induces inhibition of homologous recombination. AB - Human Rad51 (HsRad51), a key element of the homologous recombination repair pathway, is related to the resistance of cancer cells to chemo- and radio therapies. This protein is thus a good target for the development of anti-cancer treatments. We have searched for new inhibitors directed against HsRad51 using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach. We have selected three aptamers displaying strong effects on strand exchange activity. Analysis by circular dichroism shows that they are highly structured DNA molecules. Our results also show that they affect the first step of the strand exchange reaction by promoting the dissociation of DNA from the ATP/HsRad51/DNA complex. Moreover, these inhibitors bind only weakly to RecA, a prokaryotic ortholog of HsRad51. Both the specificity and the efficiency of their inhibition of recombinase activity offer an analytical tool based on molecular recognition and the prospect of developing new therapeutic agents. PMID- 20713121 TI - Hormonal and nutritional regulation of SCD1 gene expression. AB - Stearoyl-CoA Desaturase 1 (SCD1) is the rate limiting enzyme catalyzing the biosynthesis of monounsaturated fatty acids preferentially from palmitoyl-CoA and stearoyl-CoA forming respectively palmitoleyl-CoA and oleyl-CoA. These monounsaturated fatty acids are the key components of triglycerides and membrane phospholipids. Studying the regulation of SCD1 is of particular interest since alterations in phospholipids composition have been implicated in a variety of diseases including cancers, diabetes and cardiovascular disorders. Furthermore, oleic acid, the main product of SCD1 reaction, is the predominant fatty acid of human adipose tissue triacylglycerols, associating SCD1 with the development of obesity and the metabolic syndrome. In light of the key role of SCD1 in general metabolism, it is not surprising to observe a very tight and complex regulation of SCD1 gene expression in response to various parameters including hormonal and nutrient factors. In this review we analyze the anatomy and index the transcription factors that have been characterized to bind the SCD1 promoter. Then we present the current knowledge on how hormones regulate SCD1 expression with a particular interest on the role of insulin and leptin. We also describe how nutrients especially polyunsaturated fatty acids and carbohydrates modulate SCD1 gene expression. PMID- 20713122 TI - Polygonatum cyrtonema lectin induces murine fibrosarcoma L929 cell apoptosis and autophagy via blocking Ras-Raf and PI3K-Akt signaling pathways. AB - Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding lectin, has been reported to display remarkable anti-proliferative and apoptosis-inducing activities toward a variety of cancer cells; however, the precise molecular mechanisms by which PCL induces cancer cell death are still elusive. In the current study, we found that PCL could induce apoptosis and autophagy in murine fibrosarcoma L929 cells. Subsequently, we demonstrated that inhibition of Ras could promote L929 cell death, suggesting that Ras-Raf signaling pathway plays the key negative regulator in PCL-induced apoptosis. And, we showed that Ras-Raf signaling pathway was also involved in PCL-induced autophagy as the negative regulator. In addition, we found that class I phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway could play the negative regulator in PCL-induced apoptosis and autophagy. Taken together, these results demonstrate that PCL induces murine fibrosarcoma L929 cell apoptosis and autophagy via blocking Ras Raf and PI3K-Akt signaling pathways. PMID- 20713123 TI - Human liver peroxisomal alanine:glyoxylate aminotransferase: Different stability under chemical stress of the major allele, the minor allele, and its pathogenic G170R variant. AB - The sensitivity to denaturant stress of the major (AGT-Ma) and the minor (AGT-Mi) allele of alanine:glyoxylate aminotransferase and P11L mutant has been examined by studying their urea-induced equilibrium unfolding processes with various spectroscopic and analytical techniques. AGT-Ma loses pyridoxal 5'-phosphate (PLP) and unfolds completely without exposing significant hydrophobic clusters through a two-state model (C(m) ~ 6.9 M urea). Instead, the unfolding of AGT-Mi and P11L variant proceeds in two steps. The first transition (C(m) ~ 4.6 M urea) involves PLP release, dimer dissociation and exposure of hydrophobic patches leading to a self-associated intermediate which is converted to an unfolded monomer in the second step. The unfolding pathways of apoAGT-Mi and apoP11L are similar to each other, but different from that of apoAGT-Ma. Notably, the monomerization step in apoAGT-Mi and apoP11L occurs with a C(m) value (~1.6 M urea) lower than in apoAGT-Ma (~2.4 M urea). These data indicate that Pro11 is relevant for the stability of both the dimeric structure and the PLP binding site of AGT. Moreover, to understand the pathogenic consequences of G170R mutation on AGT-Mi at the protein level, G170R-Mi has been characterized. HoloG170R-Mi exhibits spectroscopic and catalytic features and urea unfolding profiles comparable to those of AGT-Mi, while the apo form monomerizes with a C(m) of ~1.1 M urea. These biochemical results are discussed in the light of the characteristics of the enzymatic phenotype of PH1 patients bearing G170R mutation in AGT-Mi and the positive response of these patients to pyridoxine treatment. PMID- 20713124 TI - Modulation of hypoxia-inducible factor-1alpha expression by mitochondrial NADP+ dependent isocitrate dehydrogenase. AB - The transcription factor hypoxia-inducible factor-1 (HIF-1) is an important regulator of the tumor response to hypoxia, including increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. In the current study, small interfering RNA (siRNA)-mediated knockdown of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) suppressed hypoxia-induced stimulation of HIF 1alpha protein expression in PC3 human prostate cancer cells. Treatment with the 26S proteasome inhibitor MG132 failed to abrogate the suppression of HIF-1alpha accumulation induced by IDPm knockdown, whereas HIF-1alpha levels were reduced by cycloheximide treatment in both control and IDPm siRNA-transfected cells. These results suggested that the suppression of HIF-1alpha accumulation by IDPm knockdown in PC3 cells was due to an inhibition of HIF-1alpha transcription. Inactivation of the phosphoinsotide-3 kinase (PI3K)/Akt pathway decreased HIF 1alpha expression through inactivation of Sp1. Thus, IDPm siRNA functioned as a potentially useful agent for targeting chemo- and radio-resistant hypoxic cells within solid tumors through inhibition of HIF-1alpha expression. PMID- 20713125 TI - Regulation of local translation at the synapse by BDNF. AB - The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in synaptic plasticity, in part due to changes in local protein synthesis. Activation of TrkB (tropomyosin-related kinase B) receptors for BDNF triggers several parallel signaling pathways, including the Ras/ERK, the phosphatidylinositol 3-kinase (PI3-K) and the phospholipase C-gamma pathways. Recent studies have elucidated some of the signaling mechanisms that contribute to the regulation of translation activity by BDNF, through modulation of initiation and elongation phases, but the resulting changes in the proteome are not yet fully characterized. The proteins synthesized in response to activation of TrkB receptors by BDNF depend on the mRNAs that are available locally, after delivery and transport along dendrites. Recent studies have shown that BDNF may also play a regulatory role at this level. Furthermore, BDNF regulates transcription activity, thereby affecting the array of mRNAs available to be transported along dendrites. This review highlights the recent advances in the understanding of the diversity of mechanisms that contribute to the regulation of the synaptic proteome by BDNF, which may account for its role in synaptic plasticity. PMID- 20713127 TI - Prevention and treatment of drug addiction by environmental enrichment. AB - Environmental enrichment (EE) has been shown to have powerful beneficial effects on a variety of physiological and pathological processes. Accumulating evidence indicates that EE can mimic positive life experiences and prevent the development of drug addiction. More recently, EE has also been shown to eliminate already developed addiction-related behaviors and to reduce the risks of relapse. These preventive and "curative" effects of EE are associated with dramatic plastic changes in several brain areas such as the hippocampus, the frontal cortex and the striatum. EE alters neurotransmitter systems, produces changes in gene expression and transcription factors, induces chromatin rearrangement, and stimulates hippocampal neurogenesis. Here we review the existent literature on behavioral, neurochemical, cellular and molecular effects of EE and we discuss different possible ways in which EE-induced neuroadaptations result in decreased vulnerability to addiction and relapse. We propose a unified theoretical framework in which EE is seen as a functional opposite of stress. On the one hand, the antistress effects of EE would reduce the reinforcing effects of drugs and their ability to induce long-lasting neuroplastic changes and, thus, they would prevent the development of drug addiction. On the other hand, permanent or transient restoration of the normal, pre-drug functioning of the stress system would facilitate resisting prepotent desire to take drug and it would decrease the risks of relapse. This theoretical framework highlights the importance of stress in each phase of drug addiction and strongly suggests that life conditions of abstinent addicts should be considered as part of their treatment. PMID- 20713128 TI - Mathematical modeling of microtubule dynamics: insights into physiology and disease. AB - Computer models of microtubule dynamics have provided the basis for many of the theories on the cellular mechanics of the microtubules, their polymerization kinetics, and the diffusion of tubulin and tau. In the three-dimensional model presented here, we include the effects of tau concentration and the hydrolysis of GTP-tubulin to GDP-tubulin and observe the emergence of microtubule dynamic instability. This integrated approach simulates the essential physics of microtubule dynamics in a cellular environment. The model captures the structure of the microtubules as they undergo steady state dynamic instabilities in this simplified geometry, and also yields the average number, length, and cap size of the microtubules. The model achieves realistic geometries and simulates cellular structures found in degenerating neurons in disease states such as Alzheimer disease. Further, this model can be used to simulate microtubule changes following the addition of antimitotic drugs which have recently attracted attention as chemotherapeutic agents. PMID- 20713126 TI - Preclinical and clinical research on inflammation after intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise. PMID- 20713129 TI - Decitabine increases fetal hemoglobin in Papio anubis by increasing gamma-globin gene transcription. AB - OBJECTIVE: The mechanism responsible for increased fetal hemoglobin levels following decitabine treatment remains controversial. These experiments were performed to evaluate the role of transcriptional vs. translational mechanisms in the ability of decitabine to increase fetal hemoglobin levels in vivo. MATERIALS AND METHODS: Three normal, nonanemic baboons were treated with decitabine subcutaneously (0.5 mg/kg/d) for 10 days. The effect of decitabine on globin chain synthesis and globin messenger RNA levels was measured in pre- and posttreatment bone marrow aspirates by biosynthetic radiolabeling with [(3)H] leucine followed by separation of globin chains by high-performance liquid chromatography, and real-time polymerase chain reaction, respectively. The effect on DNA methylation of the E- and gamma-globin gene promoters was determined by bisulfite sequence analysis. RESULTS: Decitabine treatment of normal, nonanemic baboons induced similar increases in the gamma/gamma+beta chain synthetic ratio and the gamma/total beta-like globin RNA ratio and also increased expression of E globin transcripts. Increased expression of E- and gamma-globin was associated with decreased DNA methylation of the E- and gamma-globin gene promoters. CONCLUSIONS: Decitabine increases fetal hemoglobin in vivo by transcriptional activation of the gamma-globin gene. PMID- 20713130 TI - Aging-related changes in auditory and visual integration measured with MEG. AB - As noted in the aging literature, processing delays often occur in the central nervous system with increasing age, which is often attributable in part to demyelination. In addition, differential slowing between sensory systems has been shown to be most discrepant between visual (up to 20ms) and auditory systems (<5ms). Therefore, we used MEG to measure the multisensory integration response in auditory association cortex in young and elderly participants to better understand the effects of aging on multisensory integration abilities. Results show a main effect for reaction times (RTs); the mean RTs of the elderly were significantly slower than the young. In addition, in the young we found significant facilitation of RTs to the multisensory stimuli relative to both unisensory stimuli, when comparing the cumulative distribution functions, which was not evident for the elderly. We also identified a significant interaction between age and condition in the superior temporal gyrus. In particular, the elderly had larger amplitude responses (~100ms) to auditory stimuli relative to the young when auditory stimuli alone were presented, whereas the amplitude of responses to the multisensory stimuli was reduced in the elderly, relative to the young. This suppressed cortical multisensory integration response in the elderly, which corresponded with slower RTs and reduced RT facilitation effects, has not been reported previously and may be related to poor cortical integration based on timing changes in unisensory processing in the elderly. PMID- 20713131 TI - Mutational analysis of NHAoc/NHA2 in Saccharomyces cerevisiae. AB - BACKGROUND: NHAoc/NHA2 is highly and selectively expressed in osteoclasts and plays a role(s) in normal osteoclast differentiation, apoptosis and bone resorptive function in vitro. Extensive mutational analysis of a bacterial homologue, NhaA, has revealed a number of amino acid residues essential for its activity. Some of these residues are evolutionarily conserved and have been shown to be essential not only for activity of NhaA in bacteria, but also of NHAoc/NHA2 in eukaryotes. METHODS: The salt-sensitive Saccharomyces cerevisiae strain BW31a was used for heterologous expression of mutants of NHAoc/NHA2. Membrane expression of NHAoc/NHA2 was confirmed by confocal microscopy. Intracellular concentration of Na+ (a measure of Na+ antiporter activity) was estimated by atomic absorption spectroscopy. The growth phenotypes of cells expressing NHAoc/NHA2 mutants were studied on YNB agar supplemented with NaCl and by growth curves in YNB broth. RESULTS: Mutations in amino acid residues V161 and F357 reduced the ability of transfected BW31a cells to remove intracellular sodium and to grow in NaCl-containing medium. Yeast expressing the double mutant F357 F437 cannot grow in 0.4M NaCl, suggesting that these residues are also essential for antiporter activity. CONCLUSIONS: Evolutionarily conserved amino acids are required for full antiporter function. GENERAL SIGNIFICANCE: Mutations in these amino acid residues may impact NHAoc activity and therefore osteoclast function in vitro and in vivo. PMID- 20713132 TI - Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease mutation carriers compared with mutation-negative first-degree controls. AB - Neurodegeneration in Huntington's disease (HD) occurs in various brain regions including the hypothalamus. In this cross-sectional study, hypothalamic-pituitary adrenal (HPA) axis functioning was studied in 26 presymptomatic and 58 symptomatic HD mutation carriers, and 28 controls. HPA axis functioning was measured through salivary cortisol in the day curve, the cortisol awakening response (CAR), the area under the curve (AUC), the morning rise, and the dexamethasone suppression test (DST). Only the CAR was statistically different between the three groups, being explained by higher cortisol concentrations at 45 and 60 min post-awakening for presymptomatic mutation carriers compared to both symptomatic mutation carriers and controls. No differences were found for the AUC, evening and post-DST cortisol concentrations. Our study indicates a mild disturbance in morning cortisol secretion in HD mutation carriers that precedes the onset of motor symptoms. PMID- 20713133 TI - Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae). AB - Inhibition of Acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease. Many plant derived alkaloids (such as galantamine and rivastigmine) are known for their AChE inhibitory activity. Recently, other classes of natural compounds such as terpenoids, sesquiterpene glycosides and coumarins have been studied as new AChE inhibitors, with the aim to discover less toxic compounds compared to alkaloidal ones. The Ferulago campestris roots dichloromethane extract was used for a bioassay-guided fractionation for the search of AChE inhibitors. Three coumarin derivatives (umbelliprenin 1, coladonin 2 and coladin 3), three daucane ester derivatives (siol anisate 4, ferutinin 5 and 1-acetyl-5-angeloyl lapiferol 6), two phenol derivatives (2-epilaserine 7 and epielmanticine 8) and one polyacetylene (9-epoxyfalcarindiol 9) were isolated by the bioassay-guided approach. Their structures were characterized on the basis of spectral methods (1D and 2D NMR, and MS spectroscopy). All the isolated compounds were able to inhibit the AChE (IC(50) 1.2-0.1mM) although at higher doses if compared to galantamine (6.7 MUM) measured in the same conditions. The most active compounds were the daucane derivative siol anisate 4 and the epielmanticine 8, with IC(50) of 0.172 and 0.175 mM respectively. PMID- 20713134 TI - Plasmodium falciparum Tudor Staphylococcal Nuclease interacting proteins suggest its role in nuclear as well as splicing processes. AB - Tudor Staphylococcal Nuclease (p100 or SND1), a member of the micronuclease family is a multifunctional protein that plays a key role(s) in transcription and splicing processes in many eukaryotic cells. PfTudor-SN, a Plasmodium homolog of the human p100 protein is a structurally conserved protein; however molecular details of its function are not yet understood. Our previous studies have shown that PfTudor-SN binds RNA and it is possible to selectively inhibit parasite growth by PfTudor-SN specific drugs. In the present study, we identified the molecular interactions between Plasmodium falciparum Tudor-SN and twelve Plasmodium proteins such as Histone h2A, SPT2 (a transcriptional regulator), a Cold-shock DNA binding protein in a bacterial two-hybrid screen. To get further insight into some of these interactions, we mapped the interaction domain in PfTudor-SN protein using the yeast two-hybrid system. Of these proteins, Plasmodium N-methyl-d-aspartate receptor associated protein, PfUbiquitin conjugating enzyme and Cold-shock DNA binding protein showed interaction with the SN domains of PfTudor-SN. Immuno-localization studies of the interacting proteins showed their presence predominantly in the nucleus, which inevitably suggests the molecular interactions between these proteins and PfTudor-SN. Furthermore, we also identified a molecular interaction between the Tudor domain of PfTudor-SN protein and Plasmodium spliceosomal Sm protein, PfSmD1 advocating the role of PfTudor-SN in the spliceosome assembly. Together, these results suggest multiple role(s) for PfTudor-SN protein mainly in nuclear and splicing processes at asexual blood stages of the malaria parasite. PMID- 20713136 TI - Prediction of the contact sensitizing potential of chemicals using analysis of gene expression changes in human THP-1 monocytes. AB - The aim of this study was to find differentially regulated genes in THP-1 monocytic cells exposed to sensitizers and nonsensitizers and to investigate if such genes could be reliable markers for an in vitro predictive method for the identification of skin sensitizing chemicals. Changes in expression of 35 genes in the THP-1 cell line following treatment with chemicals of different sensitizing potential (from nonsensitizers to extreme sensitizers) were assessed using real-time PCR. Verification of 13 candidate genes by testing a large number of chemicals (an additional 22 sensitizers and 8 nonsensitizers) revealed that prediction of contact sensitization potential was possible based on evaluation of changes in three genes: IL8, HMOX1 and PAIMP1. In total, changes in expression of these genes allowed correct detection of sensitization potential of 21 out of 27 (78%) test sensitizers. The gene expression levels inside potency groups varied and did not allow estimation of sensitization potency of test chemicals. Results of this study indicate that evaluation of changes in expression of proposed biomarkers in THP-1 cells could be a valuable model for preliminary screening of chemicals to discriminate an appreciable majority of sensitizers from nonsensitizers. PMID- 20713137 TI - Amphiphilic PHA-mPEG copolymeric nanocontainers for drug delivery: preparation, characterization and in vitro evaluation. AB - Amphiphilic biodegradable core-shell nanoparticles were prepared by emulsification-solvent evaporation technique from diblock copolymers which were synthesized by chemical coupling of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) P(3HB-co-3HV) or poly(3-hydroxybutyrate-co-4-hydroxybutyrate) P(3HB-co-4HB) to monomethoxy poly(ethylene glycol) (mPEG) through transesterification reaction. The nanoparticles were found to be assembled in aqueous solution into an outer hydrophilic shell of mPEG connected to the interior hydrophobic polyhydroxyalkanoate (PHA) copolymer core, which was identified by a comparative analysis of enzymatic degradation of the mPEG-coupled and non-coupled PHA nanoparticles. Morphological examination under atomic force microscope showed the formation of smooth spherically shaped nanoparticles. The average particle sizes and zeta potentials of amphiphilic nanoparticles were in the range of 112-162 nm and -18 to -27 mV, respectively. A hydrophobic drug thymoquinone was encapsulated in the nanoparticles and its release kinetics was studied. The in vitro cytotoxicity evaluation of the nanoparticles on prenatal rat neuronal hippocampal and fibroblast cells revealed that biocompatibility of the amphiphilic nanoparticles was generally independent of the ratio of comonomer units in the PHA block. In conclusion, the amphiphilic nanoparticles contained the hydrophobic PHA segments buried in the core and could thus be used as safe carriers for the controlled release of variety of hydrophobic drugs. PMID- 20713135 TI - Identification of novel families and classification of the C2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes. AB - Eukaryotes contain an elaborate membrane system, which bounds the cell itself, nuclei, organelles and transient intracellular structures, such as vesicles. The emergence of this system was marked by an expansion of a number of structurally distinct classes of lipid-binding domains that could throw light on the early evolution of eukaryotic membranes. The C2 domain is a useful model to understand these events because it is one of the most prevalent eukaryotic lipid-binding domains deployed in diverse functional contexts. Most studies have concentrated on C2 domains prototyped by those in protein kinase C (PKC-C2) isoforms that bind lipid in a calcium-dependent manner. While two other distinct families of C2 domains, namely those in PI3K-C2 and PTEN-C2 are also recognized, a complete picture of evolutionary relationships within the C2 domain superfamily is lacking. We systematically studied this superfamily using sequence profile searches, phylogenetic and phyletic-pattern analysis and structure-prediction. Consequently, we identified several distinct families of C2 domains including those respectively typified by C2 domains in the Aida (axin interactor, dorsalization associated) proteins, B9 proteins (e.g. Mks1 (Xbx-7), Stumpy (Tza 1) and Tza-2) involved in centrosome migration and ciliogenesis, Dock180/Zizimin proteins which are Rac/CDC42 GDP exchange factors, the EEIG1/Sym-3, EHBP1 and plant RPG/PMI1 proteins involved in endocytotic recycling and organellar positioning and an apicomplexan family. We present evidence that the last eukaryotic common ancestor (LECA) contained at least 10 C2 domains belonging to 6 well-defined families. Further, we suggest that this pre-LECA diversification was linked to the emergence of several quintessentially eukaryotic structures, such as membrane repair and vesicular trafficking system, anchoring of the actin and tubulin cytoskeleton to the plasma and vesicular membranes, localization of small GTPases to membranes and lipid-based signal transduction. Subsequent lineage specific expansions of Zizimin-type C2 domains and functionally linked CDC42/Rac GTPases occurred independently in eukaryotes that evolved active amoeboid motility. While two lipid-binding regions are likely to be shared by majority of C2 domains, the actual constellation of lipid-binding residues (predominantly basic) are distinct in each family potentially reflective of the functional and biochemical diversity of these domains. Importantly, we show that the calcium dependent membrane interaction is a derived feature limited to the PKC-C2 domains. Our identification of novel C2 domains offers new insights into interaction between both the microtubular and microfilament cytoskeleton and cellular membranes. PMID- 20713138 TI - Third generation solid dispersions of ferulic acid in electrospun composite nanofibers. AB - Third generation solid dispersions (SDs) of ferulic acid (FA) in composite nanofibers were prepared using electrospinning. The spinning liquids involved co dissolving solutions of FA, polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS) and sucralose in 75% ethanol aqueous solutions. FESEM observations showed that the nanofibers were assembled in a homogeneous web structure that had a smooth cross-section and surface with an average diameter of 254+/-32 nm. Results from DSC and XRD suggested that FA, SDS and sucralose were distributed in the PVP fibers in an amorphous manner and this is due to their compatibility resulting through a second-order interactions, as demonstrated by ATR-FTIR spectra. In vitro dissolution and permeation tests showed that the nanofiber-based SDs could release all the contained FA within 1 min and had a 13-fold higher permeation rate across sublingual mucosa compared to crude FA particles. The casting films have the same compositions as the nanofibers and belong to the third generation SDs, they gave the same solubility of FA as the nanofibers, and also exhibited a much faster dissolution rate than pure FA particles. It felt that electrospinning can be taken to prepare new generation SDs with structural characteristics that enhancing absorbance of poorly soluble drugs. PMID- 20713139 TI - Effect and mechanism of penetration enhancement of organic base and alcohol on glycyrrhetinic acid in vitro. AB - The aim of the present study was to explore the effects of organic bases and alcohols on the percutaneous absorption of Glycyrrhetinic acid (GA). GA is a metabolite of Glycyrrhizic acid (GL), a major active ingredient of Glycyrrhizae (Gancao) Radices. Skin penetration parameters of GA were obtained via in vitro penetration experiments using intact and stripped mice back skin. Non-aqueous solvent comprising isopropyl myristate (IPM) and alcohols (ethanol, butanol, octanol and dodecanol) loaded with organic base (triethanolamine or triethylamine) were applied to improve the penetration of GA. In order to further confirm the mechanism by which the organic bases enhanced the penetration of GA, conductivity measurement, (1)H NMR spectroscopy and FT-IR analysis were used to observe the formation of ion pair between GA and organic base. The formation of ion pair increased the solubility of GA in the stratum corneum (SC) and its partition into the viable skin, and therefore enhanced the penetration of GA in skin. PMID- 20713140 TI - Effects of Red Ginseng extract on allergic reactions to food in Balb/c mice. AB - AIM OF THE STUDY: Red Ginseng roots (Panax ginseng C.A. Meyer) have traditionally been thought to have anti-allergic effects, but their influence on food-induced allergic responses is unclear. MATERIALS AND METHODS: This study examined the effects of a Red Ginseng extract on an ova-albumin (OVA)-evoked allergic reaction in mice. RESULTS AND CONCLUSIONS: The orally administered extract significantly inhibited the increase in OVA-specific IgG(1) (Th(2)) levels in OVA-sensitized mice, but had no effect on OVA-specific IgE (Th(2)) levels. The extract prevented a reduction in IL-12 production and the ratio of IFN-gamma (Th(1)) to IL-4 (Th(2)) in splenocytes, and enhanced small intestinal CD8-, IFN-gamma-, and IgA positive cell numbers in the OVA-sensitized mice. These findings suggest that Red Ginseng inhibits allergic reactions to food by preventing reductions in the ratio of IFN-gamma to IL-4 and in IL-12 production induced by dietary antigens in spleen cells, and/or increasing the expression of CD8 and IFN-gamma in the small intestine. It may also protect against sensitization to antigens as an immunomodulator by increasing intestinal IgA secretion without affecting antigen specific IgE levels. In conclusion, Red Ginseng roots may be a natural preventative of food allergies. PMID- 20713142 TI - An ethnobotanical survey of medicinal plants in Sivrice (Elazig-Turkey). AB - AIM OF THE STUDY: This study aimed to identify wild plants collected for medical purposes by the local people of Sivrice County, located in the Eastern Anatolia Region of Turkey, and to establish the uses and local names of these plants. MATERIALS AND METHODS: Field study was carried out over a period of approximately two years (2005-2006). During this period, 146 vascular plant specimens were collected. In addition, the relative importance value of the species was determined and informant consensus factor (FIC) was calculated for the medicinal plants included in the study. RESULTS: A total of 81 medical plants belonging to 32 families were identified in the region. 9 plants out of 81 were recorded to be used for curative purposes for the first time. It was determined that the local names of five different kinds of plants used in Sivrice were same as the different kinds of plants used in different regions. The most encountered medicinal plant families were Asteraceae (>19% of use-reports), Rosaceae and Urticaceae (>17%), Lamiaceae and Fabaceae (>11%), Polygonaceae (>8%), Poaceae (>5%); the most common preparations were infusion and decoction. Urtica dioica L. was found out to be the plant most commonly used by the local people. Thymus haussknechtii Velen, Mentha spicata L. subsp. spicata, Malva neglecta Wallr., Rosa canina L., Hypericum perforatum L., Rheum ribes L., Rubus discolor Weihe & Nees, Portulaca oleracea L. were the other plants commonly used for curative purposes. The medicinal uses of Echinophora tenuifolia L. subsp. sibthorpiana (Guss.) Tutin, Onopordum tauricum Willd., Vaccaria pyramidata Medik. var. grandiflora (Fisch. ex DC.) Cullen, Astragalus gummifer Lab, Quercus pubescens Willd, Erodium cicutarium (L.) L'Herit. subsp. cicutarium, Scutellaria orientalis L., Rumex scutatus L., Rubus discolor Weihe & Nees were recorded for the first time. CONCLUSION: These plants, used in the treatment of many different diseases, are freely harvested in this region at abundant amounts. Plants which are used in different parts of the world for the treatment of similar diseases may be deemed to be effective in pharmacological terms. PMID- 20713141 TI - Anti-inflammatory and antioxidant effects of a hypoglycemic fructan fraction from Psacalium peltatum (H.B.K.) Cass. in streptozotocin-induced diabetes mice. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: Psacalium peltatum (H.B.K.) Cass. (Asteraceae) is used medicinally to treat diabetes, rheumatic pains, as well as gastrointestinal and kidney ailments. Previous pharmacological and chemical assays have demonstrated that an aqueous fraction from Psacalium peltatum (AP fraction) contains a carbohydrate-type compound with hypoglycemic activity. Nevertheless, studies have not yet considered the hypoglycemic action of the AP faction by sub-chronic administration nor on other healing properties, some of which might be associated with DM2 and other inflammatory processes. AIM OF STUDY: To determine whether a hypoglycemic carbohydrate fraction (AP-fraction) from Psacalium peltatum roots has antioxidant and anti-inflammatory effects in streptozotocin-induced diabetes mice. MATERIAL AND METHODS: Healthy mice received either saline, the AP-fraction with a high content of fructans, or pioglitazone (a positive control) daily by gavage. After 15 days of treatment, these animals received a single intraperitoneal administration of streptozotocin and all treatments were continued for additional 33 days. The antioxidant and anti inflammatory properties of the AP-fraction were evaluated through the quantification of biomarkers of oxidative stress (glutathione (GSH) and malondialdehyde (MDA)) and inflammation (interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), and IL-10). RESULTS: The AP-fraction reduced glycemia and the glycated hemoglobin. Furthermore, animals treated with the AP-fraction had increased GSH, while MDA was decreased in the liver and the heart, without changes in the kidneys and the pancreas. The AP fraction significantly reduced TNF-alpha serum levels but did not modify IL-6; in addition, this fraction increased IFN-gamma and IL-10 levels. The increase in IL 10 levels may indicate an inhibition of the production of pro-inflammatory cytokines such as TNF-alpha, whereas the increase in IFN-gamma might be indicative of a beneficial effect on the immune system. CONCLUSIONS: The AP fraction hypoglycemic fructans from Psacalium peltatum roots showed antioxidant and anti-inflammatory properties in mice with streptozotocin-induced diabetes. The Psacalium peltatum hypoglycemic fructans may be valuable in preventing insulin resistance, as well as the development and progression of diabetic complications caused by chronic inflammation. PMID- 20713143 TI - The protective effects of total saponins from Ornithogalum saundersiae (Liliaceae) on acute hepatic failure induced by lipopolysaccharide and D galactosamine in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study examined the protective effects of total saponins from Ornithogalum saundersiae (Liliaceae) on D-galactosamine (D GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure. MATERIALS AND METHODS: Total saponins of Ornithogalum saundersiae (Liliaceae) (OC) were prepared with ethyl alcohol extract from bulbs of the plant. Mice were given an intraperitoneal injection of D-GalN (700 mg/kg)/LPS (10 MUg/kg). OC (100 mg/kg, 200 mg/kg and 300 mg/kg) was administered orally for 3 days continuously, and at the last day at 1 h before the D-GalN/LPS injection. Mice were sacrificed at 8 h after the D-GalN/LPS injection. The liver injury was assessed biochemically, investigating aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), glutathione (GSH) activities, and the expressions of caspase-3 and hypoxia inducible factor-1alpha (HIF-1alpha) as well. Tumor necrosis factor (TNF-alpha) content was measured after D-GalN/LPS induced 1 h by ELISA assay. The survival rates after application of OC in 24 h also were observed. RESULTS: D-GalN/LPS increased the serum aminotransferase levels and lipid peroxidation, while decreased the reduced glutathione level. The pretreatment with OC attenuated these changes in a dose-dependent manner. Elevation of TNF-alpha level and activation of caspase-3, HIF-1alpha were observed in the D-GalN/LPS group, which was attenuated by OC. The survival rate of the OC groups was significantly higher than that of the D-GalN/LPS group. CONCLUSIONS: Protection afforded by OC against D-GalN/LPS-induced fulminant hepatic failure is the result of reduced oxidative stress, inhibited expression of caspase-3, HIF-1alpha, and anti-apoptotic activity. PMID- 20713144 TI - Fundamental studies on the inhibitory action of Acanthopanax senticosus Harms on glucose absorption. AB - AIM OF THE STUDY: Acanthopanax senticosus Harms extract (ASE) is used as an ingredient of over-the-counter drugs and functional foods, such as health supplements, in Japan. ASE exhibits a hypoglycemic effect; however, the mechanism of the hypoglycemic effect is not clear. In the present study, we investigated whether ASE has a glucose absorption inhibitory action. MATERIALS AND METHODS: We examined the effects of ASE on alpha-amylase and alpha-glucosidase activities, and on glucose uptake in Caco-2 cells. We also examined the effects of ASE oral administration on glucose tolerance in type 2 diabetes mellitus model db/db mice. RESULTS: The addition of ASE inhibited alpha-glucosidase activity but not alpha amylase activity. The alpha-glucosidase inhibitory activity of ASE was approximately 1/13 of that of acarbose. The addition of ASE inhibited 2'-deoxy-D glucose (DG) uptake in human intestinal Caco-2 cells, and the inhibitory activity of ASE was approximately 1/40 of that of phloretin. Kinetic analysis of glucose uptake indicated that ASE has no effects on DG uptake through passive diffusion, but that ASE inhibits intracellular DG uptake chiefly by inhibiting transport via a glucose transporter. In the glucose tolerance study, db/db mice orally administered ASE for 3 days showed significantly lower plasma glucose level than the control group 30 min after sucrose loading, without affecting plasma insulin levels. In addition, ASE oral administration significantly inhibited alpha glucosidase activity in the small intestine mucosa extirpated from the mice. CONCLUSION: These findings indicate that ASE may be useful as an ingredient of functional foods to improve postprandial hyperglycemia and prevent type II diabetes mellitus. PMID- 20713145 TI - The relation between clinical effects of Tokishakuyakusan and the identity of Paeonia lactiflora materials. AB - AIM OF THE STUDY: To investigate the relation between the clinical effects and the quality of crude drugs, we focused on Tokishakuyakusan (TS), consisted of 6 crude drugs. MATERIALS AND METHODS: We prepared two kinds of TS containing either medicinal cultivar of Paeonia lactiflora (MTS) or ornamental one (OTS). Other components were the same. First, we assessed the clinical effects of two TS formulations by cross-over study among the anemia patients. Second, we investigated the chemical differences between them by using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Mossbauer analysis. RESULTS: The clinical effects of these formulations (3 g/day for 8 weeks) were tested in the cross-over study consisted of 12 women patients who were diagnosed as having anemia (Hb <= 11 g/dl) and consented to participate to this study. Both TS formulations were effective for anemia symptoms as shown by the improvement of several hematological parameters, whereas their comprehensive effects were distinguishable by Genetic Algorithm Partial Least Squares (GA-PLS) analysis. There were no significant differences in organic ingredients and Fe content measured by ultra performance liquid chromatography (UPLC) and ICP-MS, respectively. Interestingly, Mossbauer spectra of Fe ion were remarkably different between two formulations. Fe ion in MTS was only one form, but that in OTS was at least two forms. CONCLUSIONS: This study suggested that clinical effects of TS formulation reflect the quality of Paeoniae Radix. PMID- 20713146 TI - Application of bioactivity database of Chinese herbal medicine on the therapeutic prediction, drug development, and safety evaluation. AB - AIM OF THE STUDY: Chinese herbal medicine has been used for the treatments of various diseases for years. However, it is often difficult to analyze their biological activities and molecule mechanisms because of their complex nature. In this study, we applied DNA microarray to analyze the biological events induced by herbal formulae, predict the therapeutic potentials of formulae, and evaluate the safety of formulae. MATERIALS AND METHODS: Mice were administrated orally with 15 formulae for 7 consecutive days, and the gene expression profiles in liver or kidney were further analyzed by transcriptomic tools. RESULTS: Our data showed that most formulae altered the metabolic pathways, such as glutathione metabolism and oxidative phosphorylation, and regulatory pathways, such as antigen processing and presentation and insulin-like growth factor signaling pathway. By comparing the gene expression signatures of formulae with those of disease states or drugs, we found that mice responsive to formula treatments might be related to disease states, especially metabolic and cardiovascular diseases, and drugs, which exhibit anti-cancer, anti-inflammatory, and anti-oxidative effects. Moreover, most formulae altered the expression levels of cytochrome p450, glutathione S-transferase, and UDP glycosyltransferase genes, suggesting that caution should be paid to possible drug interaction of these formulae. Furthermore, the similarities of gene expression profiles between formulae and toxic chemicals were low in kidney, suggesting that these formulae might not induce nephrotoxicities in mice. CONCLUSIONS: This report applied transcriptomic tools as a novel platform of translational medicine for Chinese herbal medicine. This platform will not only for understanding the therapeutic mechanisms involving herbal formulae and gene interactions, but also for the new theories in drug discovery. PMID- 20713147 TI - Olive (Olea europaea L.) leaf extract elicits antinociceptive activity, potentiates morphine analgesia and suppresses morphine hyperalgesia in rats. AB - AIM OF THE STUDY: Olive (Olea europaea) leaves are used as anti-rheumatic, anti inflammatory, antinociceptive, antipyretic, vasodilatory, hypotensive, antidiuretic and hypoglycemic agents in traditional medicine. Recently, it has been shown that olive leaf extract (OLE) has calcium channel blocker property; however, its influences on nociceptive threshold and morphine effects have not yet been clarified. MATERIALS AND METHODS: All experiments were carried out on male Wistar rats. The tail-flick, hot-plate and formalin tests were used to assess the effect of OLE on nociceptive threshold. To determine the effect of OLE on analgesic and hyperalgesic effects of morphine, OLE (6, 12 and 25 mg/kg i.p.) that had no significant nociceptive effect, was injected concomitant with morphine (5 mg/kg and 1 MUg/kg i.p., respectively). The tail-flick test was used to assess the effect of OLE on anti- and pro-nociceptive effects of morphine. RESULTS: The data showed that OLE (50-200 mg/kg i.p.) could produce dose dependent analgesic effect on tail-flick and hot-plate tests. Administration of 200 mg/kg OLE (i.p.) caused significant decrease in pain responses in the first and the second phases of formalin test. In addition, OLE could potentiate the antinociceptive effect of 5 mg/kg morphine and block low-dose morphine-induced hyperalgesia. CONCLUSION: Our results indicate that olive leaf extract has analgesic property in several models of pain and useful influence on morphine analgesia in rats. Therefore, it can be used for the treatment and/or management of painful conditions. PMID- 20713148 TI - Vascular relaxation by ethanol extract of Xanthoceras sorbifolia via Akt- and SOCE-eNOS-cGMP pathways. AB - AIM OF THE STUDY: The aim of the present study was to define the effect of Xanthoceras sorbifolia extracts (XS) on vascular tension and responsible mechanisms in rat thoracic aortic rings. MATERIALS AND METHODS: Ethanol extract of the leaves of XS (EXS) was examined for their vascular relaxant effects in isolated phenylephrine-precontracted rat thoracic aorta. RESULTS: EXS (0.1-100 MUg/ml) induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Endothelium-denudation abolished EXS-induced vasorelaxation. Pretreatment of the endothelium-intact aortic rings with N(G) nitro-L-arginine methylester (L-NAME) and 1H-[1,2,4]-oxadiazolo-[4,3-alpha] quinoxalin-1-one (ODQ) inhibited EXS-induced vasorelaxation. Inhibition of Ca(2+) entry via L-type Ca(2+) channels failed to block the EXS-induced vasorelaxation. Extracellular Ca(2+) depletion significantly attenuated EXS-induced vasorelaxation. Modulators of the store-operated Ca(2+) entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate (2-APB) and Gd(3+), and an inhibitor of Akt, wortmannin, markedly attenuated the EXS-induced vasorelaxation. EXS increased cGMP levels of the aortic rings in a concentration-dependent manner and the effect was blocked by L-NAME, ODQ, thapsigargin, Gd(3+), 2-APB, and wortmannin. Further, EXS-induced vasorelaxation was significantly attenuated by tetraethylammonium, a non-selective K(ca) channels blocker, but not by glibenclamide, an ATP-sensitive K(+) channels inhibitor. Inhibition of cyclooxygenase with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on EXS-induced vasorelaxation. CONCLUSIONS: The present study suggests that EXS relaxes vascular smooth muscle via endothelium-dependent NO-cGMP signaling through activation of the Akt- and SOCE-eNOS-sGC pathways, which may, at least in part, be related to the function of K(+) channels. PMID- 20713149 TI - Curculigoside attenuates human umbilical vein endothelial cell injury induced by H2O2. AB - AIM OF THE STUDY: Vessel endothelium injury caused by reactive oxygen species (ROS) including H(2)O(2) plays a critical role in the pathogenesis of cardiovascular disorders. Therefore, agents or antioxidants that can inhibit production of ROS has highly clinical values in cardiovascular therapy. Curculigoside is the major bioactive compounds present in Curculigo orchioides, and possess potent antioxidant properties against oxidative stress insults through undefined mechanism(s). The present study was designed to test the hypothesis that curculigoside can inhibit H(2)O(2)-induced injury in human umbilical vein endothelial cells. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with curculigoside in the presence/absence of hydrogen peroxide (H(2)O(2)). The protective effects of curculigoside OP-D against H(2)O(2) were evaluated. RESULTS: HUVECs incubated with 400 MUM H(2)O(2) had significantly decreased the viability of endothelial cells, which was accompanied with apparent cells apoptosis, the activation of caspase-3 and the upregulation of p53 mRNA expression. In addition, H(2)O(2) treatment induced a marked increase of MDA, LDH content and in intracellular ROS, decreased the content of nitric oxide (NO) and GSH-Px activities in endothelial cells. However, pretreatment with 0.5.5,10 MUM curculigoside resulted in a significant recovery from H(2)O(2)-induced cell apoptosis. Also, it decreased other H(2)O(2)-induced damages in a concentration-dependent manner. Furthermore, pretreatment with curculigoside decreased the activity of caspase-3 and p53 mRNA expression, which was known to play a key role in H(2)O(2)-induced cell apoptosis. CONCLUSION: The present study shows that curculigoside can protect endothelial cells against oxidative injury induced by H(2)O(2), suggesting that this compound may constitute a promising intervention against cardiovascular disorders. PMID- 20713150 TI - Post-ischemic administration of nimodipine following focal cerebral ischemic reperfusion injury in rats alleviated excitotoxicity, neurobehavioural alterations and partially the bioenergetics. AB - The present study focuses on the temporal calcium significance in middle cerebral artery occluded (2 h ischemia)-reperfused (70 h reperfusion) rats treated with nimodipine (NM) through concurrent measurements of excitotoxicity, bioenergetics and neurobehavioural paradigms. Further, the suitable therapeutic time window of calcium channel antagonism in stroke was also ascertained. NM (5 mg/kg, i.p.) was administered at pre (30 min before the induction of ischemia), during (1 h following occlusion of MCA) and post-ischemic (3 h after begin of reperfusion) states. The magnitude of neuroprotection in terms of excitotoxicity (glutamate, glutamine synthetase, Na(+)K(+)ATPase), bioenergetics (ATP, NAD(+)) and neurobehavioural paradigms (neurological score and open field exploratory behaviour) were measured and compared to ensure the therapeutic time-window of NM in stroke. Middle cerebral artery occlusion-reperfusion (MCAO/R) was found to elevate glutamate, glutamine synthetase levels and deplete Na(+)K(+)ATPase activity in the vehicle treated group (IR group). Significant decrease in bioenergetics such as ATP and NAD(+) levels was also observed. Further, IR group demonstrated grievous oxidative stress (increase in lipid peroxidation, protein carbonyl content, nitrite/nitrate levels and decrease in superoxide dismutase and glutathione levels) along with anxiogenic behaviour, neurological deficits and neuronal damage and decreased nuclear to cytoplasm ratio in CA1 hippocampal region. Post-ischemic NM administration reversed the excitotoxicity, neurobehavioural and histopathological alterations significantly, but it restored bioenergetics level in MCAO/R rats only partially. These findings were further confirmed with the combination treatment (CT) of post-ischemic NM and pre ischemic memantine (MN) administration, since MN showed protective effect in the pre-ischemic administration (Babu and Ramanathan, 2009). The failure of NM to forefend the neurodegeneration on pre- and during-ischemic administration suggests that the initial phase damages in ischemic-reperfusion (IR) might be mediated through other mechanism(s) such as glutamergic overstimulation or reverse operation of glutamate transporters. From the present study, it is concluded that calcium plays a crucial role in post-ischemic status and the suitable therapeutic time window of calcium antagonism is the post-ischemic state. PMID- 20713151 TI - PriProET based melting point analyses on PRRSV positive field samples. AB - A one-step real time RT-PCR method has previously been developed for the simultaneous detection of both genotypes of porcine reproductive and respiratory syndrome virus (PRRSV). For further evaluation of the assay and a detailed characterization of the probe binding sites a collection of 24 PRRSV positive field samples from Hungary, Serbia, Austria, a highly pathogenic strain from Bhutan and commercially available MLV vaccine strains were collected and sequenced from the terminal part of ORF6 to the 3' end UTR. The regions that were targeted by the probe were analyzed in detail, and their sequences were compared to that of the probe. Each sample showed a positive result with the PriProET assay, and the samples that showed nucleotide mismatches on the probe binding region had shifted melting points compared to the perfectly matching Lelystad strain. Based on the melting temperatures the strains were classified into 8 groups ranging from 62.4 degrees C to 75.5 degrees C. The samples with the lowest melting temperatures were Type I strains which had less mismatches on the probe binding site than Type II strains. However, these mutations were closer to the 3' end of the probe. It can be speculated that mismatches near the 5' end of the probe had lower influence on the melting temperature. PMID- 20713152 TI - Stem cell potential in Parkinson's disease and molecular factors for the generation of dopamine neurons. AB - Parkinson's disease (PD) involves the loss of dopamine (DA) neurons, making it the most expected neurodegenerative disease to be treated by cell replacement therapy. Stem cells are a promising source for cell replacement therapy due to their ability to self-renew and their pluripotency/multipotency that allows them to generate various types of cells. However, it is challenging to derive midbrain DA neurons from stem cells. Thus, in this review, I will discuss the molecular factors that are known to play critical roles in the generation and survival of DA neurons. The developmental process of DA neurons and functions of extrinsic soluble factors and homeodomain proteins, forkhead box proteins, proneural genes, Nurr1 and genes involved in epigenetic control are discussed. In addition, different types of stem cells that have potential for future cell replacement therapy are reviewed. PMID- 20713153 TI - High-molecular weight hyaluronan reduced renal PKC activation in genetically diabetic mice. AB - The cluster determinant (CD44) seems to play a key role in tissues injured by diabetes type 2. CD44 stimulation activates the protein kinase C (PKC) family which in turn activates the transcriptional nuclear factor kappa B (NF-kappaB) responsible for the expression of the inflammation mediators such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-18 (IL-18), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMPs). Regulation of CD44 interaction with its ligands depends greatly upon PKC. We investigated the effect of the treatment with high-molecular weight hyaluronan (HA) on diabetic nephropathy in genetically diabetic mice. BKS.Cg-m+/+Lepr(db) mice had elevated plasma insulin from 15 days of age and high blood sugar levels at 4 weeks. The severe nephropathy that developed was characterized by a marked increased in CD44 receptors, protein kinase C betaI, betaII, and epsilon (PKC(betaI), PKC(betaII), and PKCepsilon) mRNA expression and the related protein products in kidney tissue. High levels of mRNA and related protein levels were also detected in the damaged kidney for NF-kappaB, TNF-alpha, IL-6, IL-18, MMP-7, and iNOS. Chronic daily administration of high-molecular mass HA for 2 weeks significantly reduced CD44, PKC(betaI), PKC(betaII), and PKCalpha gene expression and the related protein production in kidney tissue and TNF-alpha, IL-6, IL-18, MMP-7, and iNOS expression and levels also decreased. Histological analysis confirmed the biochemical data. However, blood parameters of diabetes were unchanged. These results suggest that the CD44 and PKC play an important role in diabetes and interaction of high-molecular weight HA with these proteins may reduce inflammation and secondary pathologies due to this disease. PMID- 20713154 TI - Aldosterone: a cardiovascular risk factor? AB - The hormone aldosterone has a well-recognized physiological role in epithelial fluid and electrolyte homeostasis, and more recently defined pathophysiological roles in the cardiovascular system. The term "risk factor" implies an active role in pathophysiology, with levels lower (e.g. HDL) or higher (e.g. LDL, BP) than normal contributing to an increased likelihood of morbidity and/or mortality. In this regard, primary aldosteronism represents a classic illustration of aldosterone as a cardiovascular risk factor. In this syndrome of (relatively) autonomous aldosterone secretion, the effects of elevated hormone levels are on a range of organs and tissues-the heart, blood vessels and brain, inter alia. In other cardiovascular disorders (e.g. CCF, EH) while an elevation of aldosterone levels is often regarded as a risk factor, it is more correctly a response to the severity of disease (or to treatment intervention), rather than necessarily a risk factor with a primary role in disease progression. An enduring enigma relevant to any discussion of aldosterone as a risk factor is that very high levels of aldosterone in response to chronic sodium deficiency have homeostatic (and protective of cardiovascular) functions, while the considerably lower levels commonly seen in primary aldosteronism are incontrovertibly damaging. A final section of the paper will thus propose a mechanism which might solve this enigma, based on the commonalities-and a single crucial difference-in the factors stimulating the secretion of aldosterone and endogenous ouabain from the zona glomerulosa of the adrenal gland. PMID- 20713155 TI - Silencing of two alternative splicing-derived mRNA variants of chitin synthase 1 gene by RNAi is lethal to the oriental migratory locust, Locusta migratoria manilensis (Meyen). AB - Chitin synthases are crucial enzymes responsible for chitin biosynthesis in fungi, nematodes and arthropods. We characterized two alternative splicing derived variants of chitin synthase 1 gene (LmCHS1) from the oriental migratory locust, Locusta migratoria manilensis (Meyen). Each cDNA of the two variants (LmCHS1A and LmCHS1B) consists of 5116 nucleotides that include a 4728-nucleotide open reading frame (ORF) encoding 1576 amino acid residues, and 67- and 321-bp non-coding regions at the 5'- and 3'-ends of the cDNA, respectively. The two variants differ only in one exon consisting of 177 nucleotides that encode 59 amino acid residues. The amino acid sequences within this alternative splicing region are 75% identical between the two variants. Both variants were expressed in all the developmental stages. However, LmCHS1A was predominately expressed in the integument whereas LmCHS1B was mainly expressed in the trachea. Our RNAi based gene silencing study resulted in a dramatic reduction in the levels of the corresponding mRNA in the locust nymphs injected with dsRNA of LmCHS1, or either of its two variants, LmCHS1A and LmCHS1B. Consequentially, 95, 88 and 51% of mortalities were observed in the locusts injected with the LmCHS1, LmCHS1A and LmCHS1B dsRNA, respectively. The phenotypes resulted from the injection of LmCHS1A dsRNA were similar to those from the injection of LmCHS1 dsRNA, whereas the locusts injected with LmCHS1B dsRNA exhibited crimpled cuticle phenotype. Our results suggest that both variants of chitin synthase 1 are essential for insect growth and development. PMID- 20713156 TI - In vitro and in vivo immunomodulatory effects of cobalt protoporphyrin administered in combination with immunosuppressive drugs. AB - BACKGROUND: Immunosuppressive strategies are designed to take advantage of potential synergies between drugs to possibly decrease the risk of side-effects. In the present study, the ability of Cobalt protoporphyrin (CoPP) to potentiate the effect of the immunosuppressive drugs mycophenolate sodium (MPS) or cyclosporin A (CsA) was explored in vitro and in vivo. METHODS: In vitro analyses of proliferation and apoptosis were performed on primate T cell cultures, following incubation with the immunosuppressive drugs MPS or CsA, alone or in combination with CoPP. In vivo the effect of CoPP and CsA combination therapy was assessed in a rat heterotopic cardiac allotransplantation model. RESULTS: In vitro results suggest that co-administration of CoPP with CsA or MPS increases immunosuppressive effects of these drugs when combined with CoPP. In particular, the co-administration of CoPP with CsA resulted in the synergistic induction of lymphocyte apoptosis. In vivo, animals immunosuppressed with CsA (1.5 mg/kg) or CoPP (20 mg/kg) alone, had a median survival of 7 or 8 days, respectively. In contrast, animals immunosuppressed with CsA (1.5 mg/kg) combined with CoPP (20 mg/kg) had significantly prolonged median survival (12 days), compared to recipients treated with CsA or CoPP alone (p<0.05). CONCLUSION: Our in vitro and in vivo studies demonstrate that CoPP can potentiate the immunomodulatory effects of CsA, ultimately extending allograft survival. PMID- 20713157 TI - Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia. AB - Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets. The caudate-putamen of normal monkeys contained numerous fine and smooth TPH positive fibres and numerous varicose fibres, but a marked hyperinnervation of TPH positive fibres characterised by a significant increase in the number and diameter of TPH positive axon varicosities was noted in the dorsal caudate and putamen of MPTP-intoxicated monkeys but not the globus pallidus. In MPTP-intoxicated marmosets that had received chronic levodopa treatment to induce dyskinesia, a further increase in the number and enlargement of TPH positive axonal varicosities in both caudate nucleus and putamen was evident. Following LID induction, a similar pattern of increase was also observed in the external segment of the globus pallidus, but only a significant varicosity enlargement was seen in the internal pallidal segment. These results confirm that striatal 5-HT hyperinnervation follows nigro-striatal pathway loss and provide the first evidence in primates that chronic levodopa treatment and the onset of dyskinesia are associated with a marked hypertrophy of striatal 5-HT axonal varicosities. These findings support the concept that altered 5-HT function may contribute to the genesis or expression of LID. PMID- 20713158 TI - Use of RNA-bound Tb3+ as a FRET donor. AB - Lanthanide ions such as Tb(3+) and Eu(3+) have long been used to probe RNA and protein structures due to their luminescence properties and their steric and chemical similarities to biological metal ions such as Mg(2+) and Ca(2+). In this article, we introduce a method that utilizes the enhanced Tb(3+) luminescence upon site-binding to RNA molecules as a FRET donor. Using this method, it is possible to identify specific metal ion-binding locations within a folded RNA molecule. Applications of this method include introducing FRET donors into molecules of interest by engineering RNA loops or bulges as Tb(3+)-binding pockets. PMID- 20713159 TI - Molecular cloning and characterization of interferon regulatory factor 7 (IRF-7) in Japanese flounder, Paralichthys olivaceus. AB - Interferon regulatory factor (IRF) 7 in mammals is known to be a key player in regulating the type I interferon (IFN) response to viral infection as a transcription activator of IFNs and IFN-stimulated genes (ISGs). In this study, a full-length cDNA of Japanese flounder, Paralichthys olivaceus, (Po)IRF-7 was cloned and characterized. PoIRF-7 is 2032 bp in length, with an open reading frame (ORF) of 1293 bp that encodes 430 amino acid residues. The putative amino acid sequence shows the highest homology to fish IRF-7 with 51.5-76.3% identity and possesses a DNA-binding domain (DBD), an IRF association domain (IAD) and a serine-rich domain of vertebrate IRF-7. In addition, the tryptophan cluster of PoIRF-7 DBD consists of only four tryptophans, which is a characteristic unique to all fish IRF-7 members. The PoIRF-7 was expressed constitutively in all tested tissues of healthy flounders, with high levels in head kidney, spleen, gill, intestine and skin, and moderately expressed in FG9307 cells, a flounder gill epithelial cell line. Using a luciferase assay, PoIRF-7 was proved to be capable of activating fish type I IFN promoter in FG9307 cells. A quantitative real time PCR assay was employed to monitor the gene expression of PoIRF-7 and Mx in FG9307 cells and flounder head kidney and gill. Both genes were up-regulated by polyinosinic:polycytidylic acid (poly I:C) and lymphocystis disease virus (LCDV) though to a much lesser extent in FG9307 cells. Further, their transcription kinetics were similar in fish organs but different in FG9307 cells. These data provide insights into the functions of PoIRF-7 and imply a difference in PoIRF-7 related signaling pathways in antiviral response between cultured cells and live fish. PMID- 20713160 TI - Characterization of two novel ADP ribosylation factors from the shrimp Marsupenaeus japonicus. AB - ADP-ribosylation factors (Arfs) that play an essential role in intracellular trafficking and organelle structure are small GTP-binding proteins, which have been identified recently to be involved in virus infection. However, little is known about the Arfs and their relationships with viral infection in the economically important crustaceans to date. In the present study, two novel members of the Arf family, designated as MjArf1 and MjArfn respectively, were cloned from the shrimp Marsupenaeus japonicus. Sequence and phylogenetic analysis showed that MjArf1 belongs to Class I Arf, which has very high homology in sequence to the known Arf 79F of insects and Arf1 of other animals (96-99%), whereas MjArfn is an unidentified Arf, which has only 62-66% identity to other known Arfs. In High Five cells, the distribution of MjArf1 was dependent on its GDP/GTP binding state but the distribution of MjArfn was not affected by that. Both Arfs were ubiquitously expressed in examined tissues. Further investigation with real-time quantitative PCR revealed that MjArf1 and MjArfn were significantly up-regulated after WSSV challenge. In virus-resistant shrimps, however, no distinct fluctuation of MjArf1 expression was found and MjArfn was even found to be notably repressed. These results suggested that MjArf1 and MjArfn might be involved in the shrimp innate immune response in WSSV infection and MjArfn might play a role in WSSV invasion. These studies may contribute to a better understanding of host defense and/or virus invasion interaction and for the control of marine crustacean diseases. PMID- 20713162 TI - What information must measures provide to demonstrate the problems in knee alignment and osteoarthritis? PMID- 20713163 TI - One in four people may develop symptomatic hip osteoarthritis in his or her lifetime. AB - OBJECTIVE: To estimate the lifetime risk of symptomatic hip osteoarthritis (OA). DESIGN: We analyzed data from the Johnston County Osteoarthritis Project [a longitudinal population-based study of OA in North Carolina, United States (n=3068)]. The weighted baseline sample comprised 18% blacks and 54% women, and the mean age was 63 years (range=45-93). Symptomatic hip OA was defined as a Kellgren-Lawrence (K-L) radiographic score of >= 2 (anterior-posterior pelvis X rays) and pain, aching or stiffness on most days, or groin pain, in the same hip. Lifetime risk, defined as the proportion who developed symptomatic hip OA in at least one hip by age 85, among people who live to age 85, was modeled using logistic regression with repeated measures (through generalized estimating equations). RESULTS: Lifetime risk of symptomatic hip OA was 25.3% [95% confidence interval (CI)=21.3-29.3]. Lifetime risk was similar by sex, race, highest educational attainment, and hip injury history. We studied lifetime risk by body mass index (BMI) in three forms: at age 18; at baseline and follow-up; and at age 18, baseline and follow-up and found no differences in estimates. CONCLUSION: The burden of symptomatic hip OA is substantial with one in four people developing this condition by age 85. The similar race-specific estimates suggest that racial disparities in total hip replacements are not attributable to differences in disease occurrence. Despite increasing evidence that obesity predicts an increased risk of both hip OA and joint replacement, we found no association between BMI and lifetime risk. PMID- 20713165 TI - Combined effects of interleukin-7 and stem cell factor administration on lymphopoiesis after murine bone marrow transplantation. AB - The decreased ability of the thymus to generate T cells after bone marrow transplantation (BMT) is a clinically significant problem. Interleukin (IL)-7 and stem cell factor (SCF) induce proliferation, differentiation, and survival of thymocytes. Although previous studies have shown that administration of recombinant human IL-7 (rhIL-7) after murine and human BMT improves thymopoiesis and immune function, whether administration of SCF exerts similar effects is unclear. To evaluate independent or combinatorial effects of IL-7 and SCF in post BMT thymopoiesis, bone marrow (BM)-derived mesenchymal stem cells transduced ex vivo with the rhIL-7 or murine SCF (mSCF) genes were cotransplanted with T cell depleted BM cells into lethally irradiated mice. Although rhIL-7 and mSCF each improved immune reconstitution, the combination treatment had a significantly greater effect than either cytokine alone. Moreover, the combination treatment significantly increased donor-derived common lymphoid progenitors (CLPs) in BM, suggesting that transplanted CLPs expand more rapidly in response to IL-7 and SCF and may promote immune reconstitution. Our findings demonstrate that IL-7 and SCF might be therapeutically useful for enhancing de novo T cell development. Furthermore, combination therapy may allow the administration of lower doses of IL-7, thereby decreasing the likelihood of IL-7-mediated expansion of mature T cells. PMID- 20713164 TI - CTLA-4 blockade following relapse of malignancy after allogeneic stem cell transplantation is associated with T cell activation but not with increased levels of T regulatory cells. AB - Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of T cell activation and proliferation. Ipilimumab is a human monoclonal antibody that specifically blocks the binding of CTLA-4 to its ligand. To test the hypothesis that blockade of CTLA-4 by ipilimumab could augment graft-versus malignancy (GVM) effects without a significant impact on graft-versus-host disease (GVHD), we conducted a phase I clinical trial of ipilimumab infusion in patients with relapsed malignancy following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report the analysis of peripheral blood T lymphocyte reconstitution, T regulatory cell (Treg) expression, and T cell activation markers after a single dose of ipilimumab in 29 patients. Peripheral blood samples were collected from all patients before and after ipilimumab infusion. Lymphocyte immunophenotyes, including levels of CD4(+)CD25(high) cells and T cell activation markers, were analyzed in all cases. Levels of CD4(+)CD25(high)Foxp3(+) cells and intracellular CTLA-4 in CD4(+) T cells also were evaluated in the last 11 cases. We found lower baseline levels of CD4(+) and CD45RO(+) T cells in patients compared with normal controls. More than 50% of the patients had abnormally low lymphocyte counts (CD4 or/and CD8 T cells), and some had no circulating B lymphocytes. The percentages of both CD4(+)CD25(high) and CD4(+)CD25(high)Foxp3(+) T cells were significantly higher in patients before ipilimumab infusion than in healthy donors. Twenty of 29 patients exhibited an elevated level of CD4(+)CD25(low) activated T cells at baseline, compared with only 3 of 26 healthy donors. Both CD4(+) and CD8(+) T lymphocyte counts were significantly increased after ipilimumab infusion. There was no consistent change in absolute lymphocyte count or in the number of T cells expressing the activation marker CD69. However, increases in CD4(+)CD25(low) T cells were seen in 20 of 29 patients and increases in CD4(+)HLA-DR(+) T cells were seen in the last 10 patients in the first 60 days after ipilimumab infusion. Although the percentages of both CD4(+)CD25(high) and CD4(+)CD25(high)Foxp3(+) T cells decreased significantly during the observation period, the absolute cell counts did not change. Intracellular CTLA-4 expression in CD4(+)CD25(lo/-) T cells increased significantly after ipilimumab infusion. We conclude that CTLA-4 blockade by a single infusion of ipilimumab increased CD4(+) and CD4(+)HLA-DR(+) T lymphocyte counts and intracellular CTLA-4 expression at the highest dose level. There was no significant change in Treg cell numbers after ipilimumab infusion. These data demonstrate that significant changes in T cell populations occur on exposure to a single dose of ipilimumab. Further studies with multiple doses are needed to explore this phenomenon further and to correlate changes in lymphocyte subpopulations with clinical events. PMID- 20713166 TI - Characterization of the Aspergillus nidulans biotin biosynthetic gene cluster and use of the bioDA gene as a new transformation marker. AB - The genes involved in the biosynthesis of biotin were identified in the hyphal fungus Aspergillus nidulans through homology searches and complementation of Escherichia coli biotin-auxotrophic mutants. Whereas the 7,8-diaminopelargonic acid synthase and dethiobiotin synthetase are encoded by distinct genes in bacteria and the yeast Saccharomyces cerevisiae, both activities are performed in A. nidulans by a single enzyme, encoded by the bifunctional gene bioDA. Such a bifunctional bioDA gene is a genetic feature common to numerous members of the ascomycete filamentous fungi and basidiomycetes, as well as in plants and oomycota. However, unlike in other eukaryota, the three bio genes contributing to the four enzymatic steps from pimeloyl-CoA to biotin are organized in a gene cluster in pezizomycotina. The A. nidulans auxotrophic mutants biA1, biA2 and biA3 were all found to have mutations in the 7,8-diaminopelargonic acid synthase domain of the bioDA gene. Although biotin auxotrophy is an inconvenient marker in classical genetic manipulations due to cross-feeding of biotin, transformation of the biA1 mutant with the bioDA gene from either A. nidulans or Aspergillus fumigatus led to the recovery of well-defined biotin-prototrophic colonies. The usefulness of bioDA gene as a novel and robust transformation marker was demonstrated in co-transformation experiments with a green fluorescent protein reporter, and in the efficient deletion of the laccase (yA) gene via homologous recombination in a mutant lacking non-homologous end-joining activity. PMID- 20713168 TI - Role of heme oxygenase in preserving vascular bioactive NO. AB - Beyond its vasodilator role, vascular nitric oxide (NO), which is synthesized by endothelial NO synthase (eNOS) via its activation, has been shown to play a number of other beneficial roles in the vascular system; it inhibits proliferation of vascular smooth muscle cells, prevents platelet aggregation, and regulates endothelial apoptosis. Such beneficial roles have been shown to be implicated in the regulation of endothelial functions. A loss of NO bioavailability that may result either from decreased eNOS expression and activity or from increased NO degradation is associated with endothelial dysfunction, a key factor in the development of vascular diseases. Heme oxygenase 1 (HO-1), an inducible enzyme, catalyzes the oxidative degradation of heme to free iron, carbon monoxide, and biliverdin, the latter being subsequently converted into bilirubin. In the vascular system, HO-1 and heme degradation products perform important physiological functions, which are ultimately linked to the protection of vascular cells. Studies have shown that HO-1 and heme degradation products exert vasodilatory, antioxidant, anti-inflammatory, antiproliferative and anti-apoptotic effects on vascular cells. Interestingly, these effects of HO-1 and its by-products are similar, at least in part, to those of eNOS-derived NO; this similarity may prompt investigators to study a possible relationship between eNOS-derived NO and HO-1 pathways. Many studies have been reported, and accumulating evidence suggests that HO-1 and heme degradation products can improve vascular function, at least in part, by compensating for the loss of NO bioavailability. This paper will provide the possible pathway explaining how HO-1 and heme degradation products can preserve vascular NO. PMID- 20713167 TI - A new method for sustained generation of ultra-pure nitric oxide-containing gas mixtures via controlled UVA-photolysis of nitrite solutions. AB - Exogenous gaseous nitric oxide (gNO) is an FDA approved drug for treatment of a variety of human pathologies like Persistent Pulmonary Hypertension in neonates and premature babies, skin lesions and fungal dermatophyte infections. Substantial disadvantages of current gNO-based therapies are the high therapy costs, high storage costs of the gas cylinders, and the rapid contamination of compressed NO gases with various decomposition products. Here we describe a new, very simple, and inexpensive photolytic generator of uncontaminated NO-containing gas mixtures at therapeutic concentrations. The new method bases on UVA-induced and redox-assisted decomposition of nitrite ions in aqueous solutions. NO formation via UVA-induced photolysis of nitrite is accompanied by an OH radical dependent production of NO(2) that beside its toxic character additionally strongly reduces the NO yield by consuming NO in its reaction to N(2)O(3). During the UVA-induced photodecomposition process both, inhibition of NO(2) formation or NO(2) depletion by antioxidants hinders the NO-consuming reaction with NO(2) and ensured a maximal purity and maximal yield of NO-containing gas mixtures. Therefore, NO-containing gas mixtures generated by the described method are suitable for medical applications like inhalation or gassing of chronic non healing wounds. Control of temperature, UVA intensity and composition of the reaction mixture allows facile control over the final NO level in the carrier gas over a wide concentration range. We demonstrate the sustained and stable release of NO over a wide dynamic range (10-5000 ppm NO) for many hours. The method avoids contamination-prone long time storage of NO gas. As such, it appears particularly relevant for applications involving the additional presence of oxygen (e.g. inhalation). PMID- 20713169 TI - Effect of pigment dispersing hormone on the electrical activity of crayfish visual photoreceptors during the 24-h cycle. AB - Visual photoreceptors are structures involved in the expression and synchronization of crayfish circadian rhythm of sensitivity to light (electroretinogram, ERG). Considering the relevant role of Pigment dispersing hormone (PDH) in the invertebrate circadian system organization, we study the effect of this substance on the electrical activity of crayfish visual photoreceptors during the 24-h cycle. The study demonstrates that: (1) PDH affects the electrical response to light of crayfish visual photoreceptor cells in a circadian time-dependent manner. (2) The kinetics of the light-elicited current of crayfish visual photoreceptor cells, as well as the ionic permeability underlying the electrical response to light vary over the 24-h cycle. (3) PDH modifies the kinetics and ionic permeability underlying the light-elicited current of crayfish visual photoreceptor cells in a circadian time-dependent manner. PMID- 20713170 TI - Sex-, morph- and size-specific susceptibility to stress measured by haematological variables in captive common wall lizard Podarcis muralis. AB - In polymorphic species of animals, colour morphs may show alternative physiological properties, and hence evolve or be maintained as an indirect response to selection exerted on these physiological attributes. In this study, we investigated if different colour morphs (white, red and yellow) of the polymorphic common wall lizard differed in their physiological responses to a long-term stress by determining variation between capture and release in leukocytes profiles, haemoparasite loads and body condition of male and females maintained in captivity throughout the breeding season. We found that most blood parameters of lizards varied significantly following captivity, and this variation was sex-, morph- and size-dependent. In particular, the heterophil:lymphocyte ratio (H:L), a sensitive measure of immunodepression and long-term stress, varied significantly among yellow females, larger individuals significantly increasing and smaller individuals decreasing their H:L ratio after captivity. This trend was reversed in red females, where smaller individuals presented raised H:L index at release. Our study indicated that response to long term stressful conditions, such as those induced by captivity, differed among common wall lizard colour morphs, implying a sex-, size-(i.e. age) and morph specific sensitivity to stress, and hence a different physiological profile of colour morphs, which may contribute to the maintenance of colour polymorphism in this species. PMID- 20713171 TI - Impact of CRF01_AE-specific polymorphic mutations G335D and A371V in the connection subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on susceptibility to nucleoside RT inhibitors. AB - Certain mutations in the connection subdomain and RNase H domain of reverse transcriptase (RT) of subtype B HIV-1 contribute to resistance to nucleoside reverse transcriptase inhibitors (NRTIs). However, the impact of non-B subtype polymorphisms in this region on drug resistance remains unclear. In this study, we determined the frequencies of drug resistance mutations of the entire RT in patients with treatment failure from a cohort of Circulating recombinant form (CRF) 01_AE HIV-1-infected patients in Hanoi, Viet Nam. Subsequently, we assessed the impact of CRF01_AE polymorphisms G335D and A371V with or without thymidine analogue mutations (TAMs) on susceptibility to NRTI with recombinant viruses. In 49 patients with treatment failure, resistance mutations to NRTIs in the N terminal half of RT were observed in 89.8%. In the C-terminal half, G335D (100%), N348I (36.8%), A371V (100%), A376S (5.3%) and A400T (97.4%) were detected, although G335D, A371V and A400T were considered polymorphisms of CRF01_AE. Drug susceptibility showed G335D, A371V, or both did not confer resistance by themselves but conferred significant resistance to NRTIs with TAMs, especially in mutants containing G335D, A371V and TAM type 2. Our results suggest the important role of CRF01_AE polymorphisms in the C-terminal half of RT in drug resistance. PMID- 20713172 TI - Intracerebral vaccination suppresses the spread of rabies virus in the mouse brain. AB - To investigate the efficacy of intracerebral (IC) immunization in preventing viral spread in the brain, we immunized mice with inactivated rabies virus via the subcutaneous (SC) or IC route, followed by administration of a lethal dose of rabies virus (challenge virus standard strain), directly into the brains of immunized mice. Progressive paralytic neurological signs were observed in control and 75% of SC immunized mice, whereas only 20% of IC immunized mice exhibited symptoms. Neutralizing antibody titers in blood plasma were significantly elevated in SC and IC immunized mice, with the highest levels seen in IC immunized mice. Analysis of whole brain lysates revealed a strong induction of immunoglobulin in the brains of IC immunized mice that had virus neutralizing activity. Histopathological examination of brain tissue revealed mild encephalitis and disseminated viral antigen in control and SC immunized mice, but rare in IC immunized mice. These results suggest that IC immunization induces a preventive humoral immune response against intracerebrally inoculated rabies virus. Induction of neutralizing antibody in cerebrospinal fluid represents a putative therapeutic measure for the treatment of rabid animals and humans. PMID- 20713174 TI - Fruits and vegetables protect against the genotoxicity of heterocyclic aromatic amines activated by human xenobiotic-metabolizing enzymes expressed in immortal mammalian cells. AB - Heterocyclic aromatic amines (HAAs) can be formed during the cooking of meat and fish at elevated temperatures and are associated with an increased risk for cancer. On the other hand, epidemiological findings suggest that foods rich in fruits and vegetables can protect against cancer. In the present study three teas, two wines, and the juices of 15 fruits and 11 vegetables were investigated for their protective effect against the genotoxic effects of 2-amino-3 methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP). To closely mimic the enzymatic activation of these HAAs in humans, genetically engineered V79 Chinese hamster fibroblasts were employed that express human cytochrome P450-dependent monooxygenase (hCYP) 1A2 (responsible for the first step of enzymatic activation) and human N(O)-acetyltransferase (hNAT) 2*4 or human sulfotransferase (hSULT)1A1*1 (responsible for the second step of enzymatic activation): V79-hCYP1A2-hNAT2*4 for IQ activation and V79-hCYP1A2 hSULT1A1*1 for PhIP activation. HAA genotoxicity was determined by use of the comet assay. Black, green and rooibos tea moderately reduced the genotoxicity of IQ (IC(50)=0.8-0.9%), whereas red and white wine were less active. From the fruit juices, sweet cherry juice exhibited the highest inhibitory effect on IQ genotoxicity (IC(50)=0.17%), followed by juices from kiwi fruit, plum and blueberry (IC(50)=0.48-0.71%). The juices from watermelon, blackberry, strawberry, black currant, and Red delicious apple showed moderate suppression, whereas sour cherry, grapefruit, red currant, and pineapple juices were only weakly active. Granny Smith apple juice and orange juice proved inactive. Of the vegetable juices, strong inhibition of IQ genotoxicity was only seen with spinach and onion juices (IC(50)=0.42-0.54%). Broccoli, cauliflower, beetroot, sweet pepper, tomato, chard, and red-cabbage juices suppressed IQ genotoxicity only moderately, whereas cucumber juice was ineffective. In most cases, fruits and vegetables inhibited PhIP genotoxicity less strongly than IQ genotoxicity. As one possible mechanism of antigenotoxicity, the inhibition of activating enzymes was studied either indirectly with diagnostic substrates or directly by measuring CYP1A2 inhibition. Only sour cherry, blueberry, and black currant juices suppressed the first step of HAA enzymatic activation, whereas most plant-derived beverages inhibited the second step. PMID- 20713173 TI - Adjudin-mediated Sertoli-germ cell junction disassembly affects Sertoli cell barrier function in vitro and in vivo. AB - Adjudin, an analogue of lonidamine, affects adhesion between Sertoli and most germ cells, resulting in reversible infertility in rats, rabbits and dogs. Previous studies have described the apical ectoplasmic specialization, a hybrid type of Sertoli cell-elongating/elongated spermatid adhesive junction, as a key target of adjudin. In this study, we ask if the function of the blood-testis barrier which is constituted by co-existing tight junctions, desmosome-gap junctions and basal ectoplasmic specializations can be maintained when the seminiferous epithelium is under assault by adjudin. We report herein that administration of a single oral dose of adjudin to adult rats increased the levels of several tight junction and basal ectoplasmic specialization proteins during germ cell loss from the seminiferous epithelium. These findings were corroborated by a functional in vitro experiment when Sertoli cells were cultured on MatrigelTM-coated bicameral units in the presence of adjudin and transepithelial electrical resistance was quantified across the epithelium. Indeed, the Sertoli cell permeability barrier was shown to become tighter after adjudin treatment as evidenced by an increase in transepithelial electrical resistance. Equally important, the blood-testis barrier in adjudin-treated rats was shown to be intact 2 weeks post-treatment when its integrity was monitored following vascular administration of inulin-fluorescein isothiocyanate which failed to permeate past the barrier and enter into the adluminal compartment. These results illustrate that a unique mechanism exists to maintain blood-testis barrier integrity at all costs, irrespective of the presence of germ cells in the seminiferous epithelium of the testis. PMID- 20713175 TI - Evaluation of male germ cell toxicity in rats: correlation between sperm head morphology and sperm comet assay. AB - The present study was aimed to investigate the germ cell toxicity of doxorubicin and find out the possible correlation between sperm head morphological evaluation and sperm comet assay, which are used to assess male germ cell toxicity. The correlation between these two assays was validated using a potent germ cell toxicant, doxorubicin, in male Sprague-Dawley rats. Doxorubicin was administered intra-peritionally at the doses of 1.25, 2.5 and 5mg/kg weekly once for a period of 5 weeks and all the animals were sacrificed after 1 week of receiving the last dose. The germ cell toxicity of doxorubicin was assessed using oxidative stress parameters, sperm head morphology, sperm comet assay, halo assay and histology in testes as the end point of evaluation. A significant increase in the % abnormality in sperm head was found in the animals treated with 2.5 and 5mg/kg/week doxorubicin. Doxorubicin treatment significantly increased the DNA damage of sperm in a dose-dependent manner as observed by sperm comet assay parameters. A strong positive correlation was observed between the sperm head morphological evaluation and the sperm comet assay. Therefore, it can be concluded that the damage in genetic material of sperm may result into abnormalities in the sperm head morphology. The sperm head morphological evaluation is considered to be essential for the assessment of male germ cell toxicity by several regulatory bodies like the Organization for Economic Cooperation and Development (OECD) and the International Conference on Harmonization (ICH). However, acceptance of the sperm comet assay by regulatory authorities as a standard genotoxicity test for assessing male germ cell toxicity still requires further validation of the assay. PMID- 20713176 TI - Anterograde and retrograde transport of neutral sphingomyelinase-2 between the Golgi and the plasma membrane. AB - The activation of neutral sphingomyelinase-2 (nSMase2) and consequent ceramide production are implicated in many stress-induced signaling pathways. Trafficking of nSMase2 from the Golgi compartment to the plasma membrane (PM) in response to signaling stimuli has been described. However, the precise mechanisms of transport remain unknown. This study aimed to investigate the trafficking of nSMase2 between the Golgi and the PM. We show here that V5-nSMase2 localizes at the PM and Golgi in MCF-7 cells and confirm relocalization of nSMase2 to the PM at confluence. Although cycloheximide (CHX) treatment partially inhibited the Golgi localization of GFP-nSMase2, recovery of GFP-nSMase2 to an intracellular compartment was still observed after photobleaching. Moreover, in the presence of CHX, GFP- and V5-nSMase2 co-localized with endosomal/recycling markers. In HEK293 cells, activation of either protein kinase C-alpha or betaII, with the phorbol ester PMA led to relocalization of both wild-type and inactive nSMase2 to the pericentrion, a PKC-dependent subset of recycling endosomes. Finally, inhibition of nSMase2 endocytosis by K+depletion reduced the intracellular pool of nSMase2 and increased nSMase2 activity resulting in elevated ceramide levels. Altogether, these results suggest that nSMase2 traffics from the Golgi to the PM as a membrane protein en route to the cell surface and recycles back to the Golgi through the endosomal/recycling compartment. Moreover, the recycling of nSMase2 from the PM is important for its catalytic regulation. PMID- 20713177 TI - The influence of nutritional conditions on metal uptake by the mixotrophic dual symbiosis harboring vent mussel Bathymodiolus azoricus. AB - The vent mussel Bathymodiolus azoricus, host thioautotrophic and methanotrophic bacteria, in their gills and complementary, is able to digest suspended organic matter. But the involvement of nutritional status in metal uptake and storage remains unclear. The influence of B. azoricus physiological condition on its response to the exposure of a mixture of metals in solution is addressed. Mussels from the Menez Gwen field were exposed to 50 MUgL(-1) Cd, plus 25 MUgL(-1) Cu and 100 MUgL(-1) Zn for 24 days. Four conditions were tested: (i) mussels harboring both bacteria but not feed, (ii) harboring only methanotrophic bacteria, (iii) without bacteria but fed during exposure and (iv) without bacteria during starvation. Unexposed mussels under the same conditions were used as controls. Eventual seasonal variations were assessed. Metal levels were quantified in subcellular fractions in gills and digestive gland. Metallothionein levels and condition indices were also quantified. Gill sections were used for fluorescence in situ hybridization (FISH) to assess the temporal distribution of symbiotic associations. Starvation damages metal homeostasis mechanisms and increase the intracellular Zn and MT levels function. There is a clear metallic competition for soluble and insoluble intracellular ligands at each condition. Seasonal variations were observed at metal uptake and storage. PMID- 20713178 TI - Prevalence and challenges of liver diseases in patients with chronic hepatitis C virus infection. AB - Hepatitis C virus (HCV) infections pose a growing challenge to health care systems. Although chronic HCV infection begins as an asymptomatic condition with few short-term effects, it can progress to cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and death. The rate of new HCV infections is decreasing, yet the number of infected people with complications of the disease is increasing. In the United States, people born between 1945 and 1964 (baby boomers) are developing more complications of infection. Men and African Americans have a higher prevalence of HCV infection. Progression of fibrosis can be accelerated by factors such as older age, duration of HCV infection, sex, and alcohol intake. Furthermore, insulin resistance can cause hepatic steatosis and is associated with fibrosis progression and inflammation. If more effective therapies are not adopted for HCV, more than 1 million patients could develop HCV related cirrhosis, hepatic decompensation, or HCC by 2020, which will impact the US health care system. It is important to recognize the impact of HCV on liver disease progression and apply new therapeutic strategies. PMID- 20713179 TI - A 30-year, population-based study shows improved management and prognosis of hepatocellular carcinoma. AB - BACKGROUND & AIMS: Little is known about the impact of changes in the management of hepatocellular carcinoma (HCC) over time. We assessed trends in the pattern of care and in prognosis at a population level. METHODS: Data on diagnostic conditions, treatment, and prognosis from 1976-2005 were collected by the population-based digestive cancer registry of Burgundy (France). A nonconditional logistic regression was used to identify factors associated with treatment for cure. A multivariate relative survival analysis was also performed. RESULTS: The context of HCC diagnosis has changed; the proportion of asymptomatic patients increased from 5.6% (1976-1985) to 37.2% (1996-2005). The proportion of cases diagnosed on the basis of morphologic criteria increased from 14% during 1976 1985 to 35.6% during 1996-2005, whereas histologically verified cases decreased from 62.2% to 41.2% between the same time periods. The proportion of patients who were treated with intent to cure increased from 2.7% (1976-1985) to 19.6% (1996 2005). This increase was associated with improvements in relative survival from 4.7% (1976-1985) to 32.8% (1996-2005) at 1 year and from 1.4% to 10.0% at 5 years. The 5-year relative survival of patients treated with curative intent increased, reaching 46.6% for the 1996-2005 period. In the multivariate relative survival analysis, age, period of diagnosis, clinical presentation, alpha fetoprotein level, and treatment were independent prognostic factors. CONCLUSIONS: During a 30-year period, there was an increase in the number of HCCs diagnosed in asymptomatic subjects that was associated with the development of new effective therapies; this association might account for improvements in prognosis of patients with HCC. PMID- 20713180 TI - Assessing the success probability of a Phase III clinical trial based on Phase II data. AB - Assessing the probability that a Phase III clinical trial will demonstrate clinically relevant efficacy based on Phase II data is an important topic in clinical drug development. An accurate estimate of how likely a Phase III trial will succeed based on available data will inform the decision on whether to move an experimental medicine forward to Phase III testing. Bayesian and likelihood methodologies have been developed in the literature to assess the probability of reproducibility in clinical trials for parametric models. A class of approaches that combines the Bayesian and likelihood approaches is proposed to evaluate the success probability of a Phase III trial based on Phase II data, which applies to the parametric, semi-parametric, and non-parametric settings and includes the Bayesian and likelihood approaches as special cases. PMID- 20713181 TI - A comparative analysis of recruitment methods used in a randomized trial of diabetes education interventions. AB - Recruitment methods heavily impact budget and outcomes in clinical trials. We conducted a post-hoc examination of the efficiency and cost of three different recruitment methods used in Journey for Control of Diabetes: the IDEA Study, a randomized controlled trial evaluating outcomes of group and individual diabetes education in New Mexico and Minnesota. Electronic databases were used to identify health plan members with diabetes and then one of the following three methods was used to recruit study participants: 1. Minnesota Method 1--Mail only (first half of recruitment period). Mailed invitations with return-response forms. 2. Minnesota Method 2--Mail and selective phone calls (second half of recruitment period). Mailed invitations with return-response forms and subsequent phone calls to nonresponders. 3. New Mexico Method 3--Mail and non-selective phone calls (full recruitment period): Mailed invitations with subsequent phone calls to all. The combined methods succeeded in meeting the recruitment goal of 623 subjects. There were 147 subjects recruited using Minnesota's Method 1, 190 using Minnesota's Method 2, and 286 using New Mexico's Method 3. Efficiency rates (percentage of invited patients who enrolled) were 4.2% for Method 1, 8.4% for Method 2, and 7.9% for Method 3. Calculated costs per enrolled subject were $71.58 (Method 1), $85.47 (Method 2), and $92.09 (Method 3). A mail-only method to assess study interest was relatively inexpensive but not efficient enough to sustain recruitment targets. Phone call follow-up after mailed invitations added to recruitment efficiency. Use of return-response forms with selective phone follow-up to non-responders was cost effective. PMID- 20713182 TI - Feasibility of a longitudinal study of women anticipating first pregnancy and assessed by multiple pelvic exams: recruitment and retention challenges. AB - OBJECTIVE: To better understand the relationship between childbirth and pelvic floor disorders the ideal study design would begin with data collection prior to but close in time to first pregnancy and follow participants through postpartum. We conducted a feasibility study to determine the following: a) whether women desiring to get pregnant would agree to pre-pregnancy data collection including a one-time urethral catheter measure and repeat pelvic exams to ascertain a baseline within 6 months of pregnancy; b) effectiveness of various recruitment and retention methods, c) number achieving pregnancy, and then d) number expressing willingness to continue follow-up through pregnancy and postpartum. METHODS: Advertising included newspaper ads, targeted emails and flyers. Post enrollment, four data collection visits were scheduled and occurred every 6 months or until pregnant. If pregnancy occurred, women were asked to indicate their willingness to continue assessments. RESULTS: The most successful advertising strategy for both recruitment and retention was local newspaper ads. Ninety-four women inquired about the study, 30 enrolled. Post-baseline retention was 23 women at 6 months, 17 at 12 months, and 13 at 18 months. Nine of the 30 women achieved pregnancy; two remained eligible and willing to participate through pregnancy and postpartum. CONCLUSIONS: This study provides data on feasibility of recruiting women to establish near-pregnancy clinical baseline measures that include pelvic exams. Close to 30% reached pregnancy within 2 years of study start and within 6 months of most recent pelvic exam measure. Of those who became pregnant, 22% expressed willingness to continue follow-up into the childbearing year. PMID- 20713183 TI - Identification of in vivo released products of Onchocerca with diagnostic potential, and characterization of a dominant member, the OV1CF intermediate filament. AB - A sensitive and specific test for the routine diagnosis of active Onchocerca infection is currently lacking. A major drawback in the development of such a test has been the paucity of knowledge of suitable parasite antigens that can serve as targets in antigen-detection assays. In the present investigation, we employed mass spectrometry, bioinformatics and molecular techniques to identify and characterize several potentially diagnostic Onchocerca antigens in the in vivo nodular fluid, which is being investigated for the first time. The majority of the 27 identified antigens lacked a secretory signal. One of them, also identified and characterized in greater detail with the aid of previously developed monoclonal antibodies (Mabs), was a dominant circulating cytoplasmic intermediate filament protein, previously identified and named, OV1CF. Although OV1CF lacks a secretory signal in its amino acid sequence and is not detected in the pure 42 h in vitro released products, it is easily detected in the in vivo nodular fluid. We conclude that these in vivo released products offer promise as diagnostics markers in onchocerciasis. PMID- 20713184 TI - A large, systematic molecular-genetic study of G6PD in Indian populations identifies a new non-synonymous variant and supports recent positive selection. AB - Malaria has been endemic in India. G6PD deficiency is known to confer resistance to malaria. Many G6PD deficiency variants, some of which are India-specific, are known to occur in high frequencies in India. This is the first systematic molecular-genetic study in multiple populations from India drawn from diverse ethnic, socio-cultural and geographical backgrounds. Resequencing of the G6PD gene was carried out in 80 males and then the polymorphic variants were genotyped in 400 individuals of both genders, drawn from 10 ethnic groups of India. Our study has identified one new exonic variant (M159I; exon-5), occurring in multiple populations, that is predicted to result in G6PD deficiency. A strong geographical sub-structuring of known G6PD variants has also been established. We have compared all available data from public-domain resources with those generated in this study to identify the nature and extent of natural selection. Our results (a) provide indication of weak negative selection, and (b) reveal signals of recent positive selection for the G6PD Orissa and G6PD Coimbra mutation bearing haplotypes. These inferences have been interpreted in the light of malarial protection to the populations that have been long exposed to plasmodium infection. PMID- 20713186 TI - Modern diagnosis of autoimmune blistering skin diseases. AB - The diagnostic gold standard of autoimmune bullous diseases is the detection of autoantibodies in skin or mucous membranes by direct immunofluorescence microscopy of a perilesional biopsy. The molecular characterisation of several target antigens within the last 10 years has, however, fostered the development of sensitive and specific diagnostic tools that allow the serological diagnosis in about 90% of patients. Based on the recombinant immunodominant portions of the target antigens, ELISA systems are commercially available for the detection of circulating antibodies against desmoglein 1, desmoglein 3, envoplakin, BP180, and BP230. Autoantibodies against the soluble ectodomain of BP180 (LAD-1), laminin 332, type VII collagen, and most recently, laminin gamma1 can be detected by Western blotting with recombinant or cell-derived forms of these proteins. The definite differentiation between the various immunobullous disorders that comprise about a dozen entities is increasingly important since more diverse treatment options are employed. Exact diagnosis is also pivotal for the prognosis, since some autoimmune bullous diseases may indicate an underlying tumor. Association with a malignancy has been shown in paraneoplastic pemphigus (in 100%) and anti-laminin 332 mucous pemphigoid (in 25%) In pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid, autoantibodies to desmoglein 3, desmoglein 1, and BP180, respectively, have been shown to correlate with the disease activity. The detection of serum autoantibodies during the course of the disease may thus be helpful in guiding treatment decisions in these patients. PMID- 20713187 TI - Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. AB - Although the pathogenesis of systemic sclerosis (SSc) remains unknown, cytokine production and release are key events in this autoimmune disease, characterized by T cell activation and auto-antibodies production leading to microvascular damage, inflammation and fibrosis. We review herein experimental and clinical data, aiming to analyze the relationship between cytokine release and SSc pathogenesis. Measurement of circulating or in situ cytokine levels provides evidence for a balance between "Th1/Th2" or "Th17/Treg" cytokines in the development of SSc. Indeed, the Th2 cytokine response, with the production of IL 4, IL-10 and TGF-beta, leads to tissue fibrosis, whereas Th1 and Th17 cytokines promote inflammation in SSc patients. Thus, cytokine levels have been assessed as diagnostic or prognostic markers in SSc patients. Restoration of the Th1/Th2/Th17/Treg balance is one of the hallmarks of treatment effectiveness and development of cytokine modulators could be considered for new therapeutic approaches in SSc patients. PMID- 20713185 TI - Preferential killing of cancer cells with mitochondrial dysfunction by natural compounds. AB - Mitochondria play essential roles in cellular metabolism, redox homeostasis, and regulation of cell death. Emerging evidences suggest that cancer cells exhibit various degrees of mitochondrial dysfunctions and metabolic alterations, which may serve as a basis to develop therapeutic strategies to preferentially kill the malignant cells. Mitochondria as a therapeutic target for cancer treatment is gaining much attention in the recent years, and agents that impact mitochondria with anticancer activity have been identified and tested in vitro and in vivo using various experimental systems. Anticancer agents that directly target mitochondria or indirectly affect mitochondrial functions are collectively classified as mitocans. This review article focuses on several natural compounds that preferentially kill cancer cells with mitochondrial dysfunction, and discusses the possible underlying mechanisms and their therapeutic implications in cancer treatment. Mitocans that have been comprehensively reviewed recently are not included in this article. Important issues such as therapeutic selectivity and the relevant biochemical basis are discussed in the context of future perspectives. PMID- 20713190 TI - Distal gastrectomy via minilaparotomy for non-overweight patients with T1N0-1 gastric cancer: initial experience of 30 cases. AB - Minilaparotomy is considered to be a useful treatment alternative to laparoscopic assisted surgery from the viewpoint of minimal invasiveness, although it has several limitations for the resection of malignant tumors. We evaluated the usefulness of distal gastrectomy via minilaparotomy for non-overweight patients with clinically diagnosed T1N0-1 gastric cancer. Clinicopathological and surgical data on 30 patients attempted to undergo distal gastrectomy via minilaparotomy (skin incision, <=7cm) without laparoscopic assistance were analyzed. Inclusion criteria were clinically (preoperatively) diagnosed T1N0-1 gastric cancer that was not suitable for endoscopic mucosal resection located in the middle- or lower third of the stomach and the patient body mass index <= 25.0 kg/m(2). The minilaparotomy approach was successful in 27 patients (90%), while laparoscopic assistance was required to accomplish the procedures in three patients (10%). The type of lymph node dissection was D1 + alpha in 23 patients and D1 + beta in 7 patients. The duration of surgery was 105-170 min (median, 143.5 min) and blood loss was 25-520 mL (median, 152.5 mL). Pathological stage was stage IA in 26 patients, IB in two patients, and stage II in two patients. Postoperative complications were wound infection in one patient, bleeding in one patient, and anastomotic ulcer in one patient. The length of postoperative stay was 7-41 (median, 11) days. With a median follow-up of 31 months, there was no recurrence. Distal gastrectomy via minilaparotomy seems feasible and safe in the majority of non-overweight patients with clinically diagnosed T1N0 gastric cancer. PMID- 20713188 TI - Role of ROS signaling in differential hypoxic Ca2+ and contractile responses in pulmonary and systemic vascular smooth muscle cells. AB - Hypoxia causes a large increase in [Ca2+]i and attendant contraction in pulmonary artery smooth muscle cells (PASMCs), but not in systemic artery SMCs. The different responses meet the respective functional needs in these two distinct vascular myocytes; however, the underlying molecular mechanisms are not well known. We and other investigators have provided extensive evidence to reveal that voltage-dependent K+ (KV) channels, canonical transient receptor potential (TRPC) channels, ryanodine receptor Ca2+ release channels (RyRs), cyclic adenosine diphosphate-ribose, FK506 binding protein 12.6, protein kinase C, NADPH oxidase and reactive oxygen species (ROS) are the essential effectors and signaling intermediates in the hypoxic increase in [Ca2+]i in PASMCs and HPV, but they may not primarily underlie the diverse cellular responses in pulmonary and systemic vascular myocytes. Hypoxia significantly increases mitochondrial ROS generation in PASMCs, which can induce intracellular Ca2+ release by opening RyRs, and may also cause extracellular Ca2+ influx by inhibiting KV channels and activating TRPC channels, leading to a large increase in [Ca2+]i in PASMCs and HPV. In contrast, hypoxia has no or a minor effect on mitochondrial ROS generation in systemic SMCs, thereby causing no change or a negligible increase in [Ca2+]i and contraction. Further preliminary work indicates that Rieske iron-sulfur protein in the mitochondrial complex III may perhaps serve as a key initial molecular determinant for the hypoxic increase in [Ca2+]i in PASMCs and HPV, suggesting its potential important role in different cellular changes to respond to hypoxic stimulation in pulmonary and systemic artery myocytes. All these findings have greatly improved our understanding of the molecular processes for the differential hypoxic Ca2+ and contractile responses in vascular SMCs from distinct pulmonary and systemic circulation systems. PMID- 20713191 TI - Effect of bovine amniotic fluid on intra-abdominal adhesion in male rats. AB - BACKGROUND: A wide variety of treatments have been proposed in order to deal with prevention of postoperative adhesions formation, but, no definitive results have been achieved. In the present study, bovine amniotic fluid (BAF) has been investigated as a possible option. MATERIALS AND METHODS: 84 male Wistar rats were undergone a laparotomy. After 2 weeks, adhesions were scaled grossly. Bovine amniotic fluid (in whole combination, without cells or without cells and proteins) extracted from cows carried either male or female calves was then applied to treated groups 2 weeks later during the second laparotomy. Adhesions were rescored 2 weeks later during a third laparotomy. RESULTS AND CONCLUSION: A significant reduction (P<0.05) in adhesions formation was observed only in rats treated with male bovine amniotic fluid without cells and proteins. Therefore, BAF could be used in treatment of adhesion formation because it is inexpensive, readily available, and has minimal side effects. PMID- 20713192 TI - Allan-Herndon-Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH. AB - Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan-Herndon Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343-1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations. PMID- 20713189 TI - Hypoxia-induced changes in pulmonary and systemic vascular resistance: where is the O2 sensor? AB - Pulmonary arteries (PA) constrict in response to alveolar hypoxia, whereas systemic arteries (SA) undergo dilation. These physiological responses reflect the need to improve gas exchange in the lung, and to enhance the delivery of blood to hypoxic systemic tissues. An important unresolved question relates to the underlying mechanism by which the vascular cells detect a decrease in oxygen tension and translate that into a signal that triggers the functional response. A growing body of work implicates the mitochondria, which appear to function as O2 sensors by initiating a redox-signaling pathway that leads to the activation of downstream effectors that regulate vascular tone. However, the direction of this redox signal has been the subject of controversy. Part of the problem has been the lack of appropriate tools to assess redox signaling in live cells. Recent advancements in the development of redox sensors have led to studies that help to clarify the nature of the hypoxia-induced redox signaling by reactive oxygen species (ROS). Moreover, these studies provide valuable insight regarding the basis for discrepancies in earlier studies of the hypoxia-induced mechanism of redox signaling. Based on recent work, it appears that the O2 sensing mechanism in both the PA and SA are identical, that mitochondria function as the site of O2 sensing, and that increased ROS release from these organelles leads to the activation of cell-specific, downstream vascular responses. PMID- 20713193 TI - Development of artificial conidia for ecological studies of Rhizoctonia solani in soil. AB - Artificial conidia of Rhizoctonia solani were developed by releasing protoplasts from young mycelia with lytic enzymes and by inducing cell wall formation in stabilizer solution. Conidia produced in this way were spherical with sizes ranging from 10 to 20MUm in diameter. Artificial conidia were sensitive to soil fungistasis. Young hyphae originated from artificial conidia were also sensitive to fungistasis and mycolysis in soils. These results demonstrate that the previously reported insensitivity of R. solani to fungistasis and mycolysis in soils is due to special ability of propagules used rather than the inherited nature of the organism. Germination rates of artificial conidia on soils were inversely correlated with the amount of fungicide Flutolanil added. When germination of artificial conidia was used to detect suppressive soils, 3 out of 30 soil samples collected from different parts of Taiwan were suppressive to R. solani and all these suppressive soils were low in pH. Using artificial conidia for assay of fungicide activity in soil and detection of suppressive soils has the advantages of being fast and precise in comparison with relative hyphal growth. However, preparation of artificial conidia at this stage is tedious and time-consuming. PMID- 20713194 TI - NAD: a master regulator of transcription. AB - Cellular processes such as proliferation, differentiation and death are intrinsically dependent upon the redox status of a cell. Among other indicators of redox flux, cellular NAD(H) levels play a predominant role in transcriptional reprogramming. In addition to this, normal physiological functions of a cell are regulated in response to perturbations in NAD(H) levels (for example, due to alterations in diet/metabolism) to maintain homeostatic conditions. Cells achieve this homeostasis by reprogramming various components that include changes in chromatin structure and function (transcription). The interdependence of changes in gene expression and NAD(H) is evolutionarily conserved and is considered crucial for the survival of a species (by affecting reproductive capacity and longevity). Proteins that bind and/or use NAD(H) as a co-substrate (such as, CtBP and PARPs/Sirtuins respectively) are known to induce changes in chromatin structure and transcriptional profiles. In fact, their ability to sense perturbations in NAD(H) levels has been implicated in their roles in development, stress responses, metabolic homeostasis, reproduction and aging or age-related diseases. It is also becoming increasingly clear that both the levels/activities of these proteins and the availability of NAD(H) are equally important. Here we discuss the pivotal role of NAD(H) in controlling the functions of some of these proteins, the functional interplay between them and physiological implications during calorie restriction, energy homeostasis, circadian rhythm and aging. PMID- 20713196 TI - Radical trachelectomy for clear cell carcinoma of the cervix in a 6-year old: a case report, review, and description of the surgical technique. AB - Clear cell carcinoma is a rare pediatric cervical cancer, seen primarily in the setting of in utero diethylstilbesterol exposure. Historically, this type of cancer has been treated with radical hysterectomy and lymph-node dissection, rendering patients incapable of carrying a pregnancy in the future. We describe a young patient with clear cell carcinoma of the cervix who, through a multidisciplinary collaboration, was managed by a fertility-sparing alternative surgical approach--a radical trachelectomy. We present the surgical technique and review the current evidence regarding the use of radical trachelectomy as a fertility-sparing procedure in young patients with cervical cancer. PMID- 20713195 TI - Activation of beta-catenin signaling in MLO-Y4 osteocytic cells versus 2T3 osteoblastic cells by fluid flow shear stress and PGE2: Implications for the study of mechanosensation in bone. AB - The osteocyte is hypothesized to be the mechanosensory cell in bone. However, osteoblastic cell models have been most commonly used to investigate mechanisms of mechanosensation in bone. Therefore, we sought to determine if differences might exist between osteocytic and osteoblastic cell models relative to the activation of beta-catenin signaling in MLO-Y4 osteocytic, 2T3 osteoblastic and primary neonatal calvarial cells (NCCs) in response to pulsatile fluid flow shear stress (PFFSS). beta-catenin nuclear translocation was observed in the MLO-Y4 cells at 2 and 16 dynes/cm(2) PFFSS, but only at 16 dynes/cm(2) in the 2T3 or NCC cultures. The MLO-Y4 cells released high amounts of PGE(2) into the media at all levels of PFFSS (2-24 dynes/cm(2)) and we observed a biphasic pattern relative to the level of PFFSS. In contrast PGE(2) release by 2T3 cells was only detected during 16 and 24 dynes/cm(2) PFFSS starting at >1h and never reached the levels produced by the MLO-Y4 cells. Exogenously added PGE(2) was able to induce beta catenin nuclear translocation in all cells suggesting that the differences between the cell lines observed for beta-catenin nuclear translocation were associated with the differences in PGE(2) production. To investigate a possible mechanism for the differences in PGE(2) release by the MLO-Y4 and 2T3 cells we examined the regulation of Ptgs2 (Cox-2) gene expression by PFFSS. 2T3 cell Ptgs2 mRNA levels at both 0 and 24h after 2h of PFFSS showed biphasic increases with peaks at 4 and 24 dynes/cm(2) and 24-hour levels were higher than zero-hour levels. MLO-Y4 cell Ptgs2 expression was similarly biphasic; however at 24-hour post-flow Ptgs2 mRNA levels were lower. Our data suggest significant differences in the sensitivity and kinetics of the response mechanisms of the 2T3 and neonatal calvarial osteoblastic versus MLO-Y4 osteocytic cells to PFFSS. Furthermore our data support a role for PGE(2) in mediating the activation of beta-catenin signaling in response to the fluid flow shear stress. PMID- 20713197 TI - Induction of life-threatening supraventricular tachycardia during central venous catheter placement: an unusual complication. AB - Cardiac arrhythmias during central venous catheter (CVC) insertion are typically transient events with no hemodynamic repercussions. Pediatric reports on this condition are scarce and fail to describe potentially life-threatening complications. CASE: A 14-day-old boy was admitted to the pediatric intensive care unit presenting with septic shock. During CVC insertion, the patient developed supraventricular tachycardia (SVT), which was unresponsive to vagal maneuvers or adenosine. Chest roentgenogram control revealed the tip of the catheter positioned in the midportion of the superior vena cava. After 30 minutes, the patient had a heart rate of 215 beats/min (bpm) and signs of hemodynamic compromise. The SVT eventually reverted to a sinus rhythm with synchronized cardioversion. The patient was discharged in good health. CONCLUSION: Awareness of this potential complication of CVC insertion warrants a high level of concern by pediatric surgeons performing these procedures. Patients with sepsis and/or cardiac dysfunction who present SVT during catheter insertion can represent a therapeutic challenge for surgeons. PMID- 20713198 TI - Aposthia: a case report. AB - Aposthia is a very rare congenital abnormality in which the prepuce is missing. The prepuce is a common anatomical covering of the glans penis. There are some reports on boys being born without a prepuce among Jews and Muslims, but this is more likely to actually be hypospadias. We present a boy with an actual natural circumcision or aposthia. PMID- 20713199 TI - Laparoscopic management of neonatal paraesophageal hernia with intrathoracic gastric volvulus. AB - Intrathoracic gastric volvulus associated with neonatal paraesophageal hernia is very rare in the newborn period. We report a case of a 3-week-old term infant who presented to the hospital with a history of non-bilious vomiting. Workup for hypertrophic pyloric stenosis eventually revealed the presence of a congenital hiatal hernia and intrathoracic gastric volvulus requiring urgent surgical management. The infant underwent successful laparoscopic repair. We discuss the diagnosis and management of this extremely rare surgical cause of neonatal nonbilious emesis. PMID- 20713200 TI - Multiple segmental absence of intestinal musculature presenting as spontaneous isolated perforation in an extremely low-birth-weight infant. AB - Defect of the intestinal musculature is a rare condition. It may cause intestinal perforation or obstruction. It manifests itself mainly in the neonatal period and usually affects preterm infants. We describe one such case, which was first diagnosed as a spontaneous isolated intestinal perforation. Emergency laparotomy was performed and showed multiple perforations, with accompanying peritonitis and ascites. Pathologic examination showed partial or complete absence of the musculature, particularly of the inner circular layer, with fibrous tissue in the regions of missing muscle, and abnormal vasculature. The myenteric plexus was absent in areas of muscle loss but present in other sites. These findings suggest that the absence of muscle may not represent a congenital malformation but may be secondary to ischemic injury. PMID- 20713201 TI - Multiple intestinal atresia and congenital bilateral perisylvian syndrome in a surviving monochorionic twin with intrauterine death of the co-twin. AB - This report presents a case of a surviving monochorionic twin with multiple intestinal atresia and congenital bilateral perisylvian syndrome, which developed after the intrauterine death of the cotwin. The pathology of the placenta demonstrated vein-to-vein communication between the twins and multiple intravascular thrombi in the dead cotwin. PMID- 20713202 TI - Mucinous cystadenoma arising 3 years after ovarian-sparing surgery for mature teratoma in a child. AB - We report the case of a 15-year-old girl diagnosed with mucinous cystadenoma 3 years after ovarian-sparing surgery for a mature teratoma located in the same ovary. Ovarian teratoma is the most common ovarian neoplasm in children, whereas mucinous cystadenoma is extremely rare during childhood. PMID- 20713203 TI - The feasibility of using an endoluminal device for intestinal lengthening. AB - PURPOSE: Prior studies demonstrating the ability to lengthen intestinal segments with mechanical force required devices with extracorporeal components. The feasibility of using a completely implantable device for in vivo intestinal lengthening was evaluated in this study. METHODS: Biocompatible Nitinol springs capable of 5-fold expansions were compressed using absorbable sutures and were implanted into isolated segments of proximal jejunum in rats. Springs compressed with nonabsorbable sutures served as controls. The animals were observed with serial abdominal x-rays until the springs became fully expanded. Intestinal segments were then retrieved for histologic analysis. Two-tailed and paired Student's t tests were used for statistical analysis. RESULTS: Intestinal segments were successfully lengthened in the experimental group from 1.3 +/- 0.3 cm to 4.4 +/- 0.5 cm (P < .001). Maximum spring length was achieved on postoperative day 36 (range, 16-50 days). In the control group, there was also an increase in intestinal lengths, from 1.6 +/- 0.04 cm to 2.9 +/- 0.4 cm (P < .001) (Fig. 4). In percentages, a 250% increase in length was observed in the experimental group vs an 85% increase in the control group (P < .001). Microscopic evaluation of both control and experimental segments revealed gross preservation of intestinal architecture; however, muscular layer hypertrophy and villous atrophy were noted. CONCLUSIONS: Continuous mechanical force with an implantable spring successfully lengthened isolated segments of small bowel in an animal model. Although similar results have been demonstrated using other devices, the current device is totally implantable and may be deployed endoscopically. PMID- 20713204 TI - Morphological and functional changes in the colon after massive small bowel resection. AB - PURPOSE: Anecdotal evidence suggests that the colon plays an important role after small bowel resection (SBR). However, colonic changes have not previously been studied. The aim of this study was to characterize morphological and functional changes within the colon after SBR and elucidate the influence of diet complexity on adaptation. METHOD: In study 1, 4-week-old piglets underwent a 75% SBR or sham operation and were studied at 2, 4, and 6 weeks postoperation to allow analysis of early and late adaptation responses. Piglets received a polymeric infant formula (PIF). In study 2, SBR piglets received an elemental diet and were studied at 6 weeks postoperation and compared with SBR + PIF piglets from study 1. For both studies, immunohistochemistry was used to quantitate intestinal cell types. Changes in functional proteins were measured by Western blot, enteroendocrine/peptide YY (PYY), enterocyte/liver fatty acid binding protein (L FABP), and goblet cells/trefoil factor 3 (TFF3). RESULTS: In study 1, early and late adaptation-related changes were observed after SBR. Early adaptation included increased numbers of enterocytes (P = .0001), whereas late adaptation included increased proliferative cell numbers (P = .02). Enteroendocrine, goblet, and apoptotic cells numbers were significantly elevated in the resected group at all time-points studied (P < .05). Functional changes included increased levels of L-FABP (P = .04) and PYY (P = .03). There was no change in TFF3 expression. In study 2, feeding with an elemental diet resulted in suboptimal adaptation as evidenced by reduced rate of weight gain and significant reductions in total cell numbers (P = .0001), proliferative (P = .0001) and apoptotic cells (P = .04), enteroendocrine cells (P = .001), and PYY expression (P .004). CONCLUSION: These findings indicate that significant morphological and functional changes occur in the colon after massive SBR and that these occur as early and late adaptation responses. Elemental diet was associated with suboptimal adaptation suggesting an effect of diet complexity on colonic adaptation. PMID- 20713205 TI - NOD2 mutations predict the risk for surgery in pediatric-onset Crohn's disease. AB - BACKGROUND/PURPOSE: Three common mutations of the NOD2/CARD15 gene have been associated with Crohn disease (CD), ileal disease location, and fibrostenotic behavior. The aim of this study was to investigate the effect of these mutations on disease manifestation and the risk of surgery in a cohort of German childhood onset CD patients. METHODS: Genotyping for the NOD2 mutations p.Arg702Trp, p.Gly908Arg, and p.1007fs was performed in 171 CD children (onset of disease <17 years; mean 11.8 years) and in 253 controls. NOD2 mutation status was correlated with the need for surgery during childhood. RESULTS: Seventy-eight children (45.6%) were carriers of at least 1 NOD2 mutation versus 36 (14.2%) in the control group (P < .0001). NOD2 mutations were highly associated with CD and stricturing behavior (P < .0001), with the p.1007fs mutation also conferring a risk for isolated ileal disease (P = .003). Thirty-two children (18.7%) needed an intestinal resection with a significant association between the need of surgery and NOD2 carrier status. Surgery occurred at an earlier stage of disease in children with p.1007fs mutations. CONCLUSIONS: In children with pediatric-onset CD, the need for surgical therapy younger than 17 years is associated with the NOD2 genotype. Genetic testing therefore may identify children with CD who are at risk. PMID- 20713206 TI - Meta-analysis: the clinical features of the duodenal duplication cyst. AB - BACKGROUND: Duplication cyst of the duodenum is rare. This study describes a case of duodenal duplication and evaluates its clinical features through a literature review. METHODS: A case of duodenal duplication is reported, and related articles published from 1999 to 2009 on PubMed were reviewed. Clinical manifestations, diagnostic examinations, and methods of management were analyzed. RESULTS: Including this report, there had been 38 citations in literature that provide adequate descriptions of 47 cases of duodenal duplication cysts. Nineteen (40.4%) were discovered before 10 years of age, whereas 10 (21.3%) were found in the second decade. The remaining 18 patients (38.3%) were older than 20 years. The case number decreased as age increased. Overall, 80% of cases presented with abdominal pain, and 53% were complicated with pancreatitis. CONCLUSIONS: The most common symptom in duodenal duplication cysts is abdominal pain with or without nausea or vomiting. The most common complication is pancreatitis. Differential diagnoses of pancreatitis, hepatitis, cholestasis, or intussusception should include duplication cyst of the duodenum. PMID- 20713207 TI - 15-Year experience in the treatment of rectal prolapse in children. AB - BACKGROUND: Rectal prolapse is a common and usually self-limited condition in children. Several surgical techniques have been advocated for refractory prolapse. We reviewed our experience with treatment and the outcome of refractory rectal prolapse. METHODS: Retrospective review was conducted on patients undergoing surgery for rectal prolapse from January 1993 to March 2009. Patients with imperforate anus/cloacal abnormalities, Hirschsprung disease, spina bifida, or prior pull-through were excluded. RESULTS: Twenty patients underwent 23 procedures for rectal prolapse. There were 10 posterior sagittal rectopexies, 6 transabdominal rectopexies, 5 laparoscopic rectopexies, 1 hypertonic saline injection, and 1 anal cerclage. The mean duration of symptoms was 1.6 years (range, 1-10 years). The mean age at operation was 6.8 years (range, 4 months-19 years), with a 5:1 male predominance. There was no operative or perioperative mortality. Median length of follow-up was 7.2 months; 2 patients were lost to follow-up. The overall recurrence rate was 35%. All recurrences followed posterior sagittal rectopexies, which had a 70% recurrence rate. Four patients required reoperation, all done transabdominally (2 open and 2 laparoscopically). None of the 3 remaining patients with mild recurrences required reoperation. CONCLUSIONS: A variety of options for management of refractory rectal prolapse in children exist. Laparoscopic rectopexy seems to be safe and a comparatively successful option in these children. PMID- 20713208 TI - Role of RET codonic mutations in the surgical management of medullary thyroid carcinoma in pediatric age multiple endocrine neoplasm type 2 syndromes. AB - PURPOSE: Hereditary medullary thyroid carcinoma (MTC) therapy is surgical resection. Because the genetic screening was available, the early diagnosis of the disease has been possible. The purpose of this study was to evaluate the role of the genetic test in the management of these children and to draw some information about the surgical timing. METHODS: Thirteen patients underwent total thyroidectomy at our institute between 1995 and 2007. Seven patients underwent a curative thyroidectomy, and 6 patients underwent a prophylactic thyroidectomy. Two patients were operated with a minimally invasive video-assisted technique. We studied the following parameters: age, risk level associated to the RET gene mutations, aim of surgery (curative or prophylactic), tumor histopathologic features, lymph node involvement, and distal metastases. RESULTS: We found a statistical association between cancer maximum diameter and some parameters analyzed: age of patients, aim of surgery, single or multifocal MTC, and number of organs involved by distal metastases. Cancer diameter at the moment of diagnosis seems to increase according to the aggressiveness of RET gene mutation found. CONCLUSIONS: The best strategy to cure MTC is to prevent it. Genetic screening could be a fundamental tool in the management of multiple endocrine neoplasm type 2 children. An improvement of scientific knowledge regarding RET gene alterations and an early and appropriate use of genetic tests could allow a better understanding of the correct surgical timing and a wider use of less aggressive surgical procedures. PMID- 20713209 TI - Cytoreductive surgery associated to hyperthermic intraperitoneal chemoperfusion for desmoplastic round small cell tumor with peritoneal carcinomatosis in young patients. AB - PURPOSE: Desmoplastic round small cell tumor (DRSCT) is a rare intraabdominal mesenchymal tissue neoplasm in young patients and spreads through the abdominal cavity. Its prognosis is poor despite a multimodal therapy including chemotherapy, radiotherapy, and surgical cytoreduction (CS). hyperthermic intraperitoneal chemotherapy (HIPEC) is considered as an additional strategy in the treatment of peritoneal carcinomatosis; for this reason, we planned to treat selected cases of children with DRSCT using CS and HIPEC. METHODS: Peritoneal disease extension was evaluated according to Gilly classification. Surgical cytoreduction was considered as completeness of cytoreduction-0 when no macroscopic nodule was residual; HIPEC was performed according to the open technique. RESULTS: We described 3 cases: the 2 first cases were realized for palliative conditions and the last one was operated on with curative intent. There was no postoperative mortality. One patient was reoperated for a gallbladder perforation. There was no other complication related to HIPEC procedure. CONCLUSIONS: Surgical cytoreduction and HIPEC provide a local alternative approach to systemic chemotherapy in the control of microscopic peritoneal disease in DRSCT, with an acceptable morbidity, and may be considered as a potential beneficial adjuvant waiting for a more specific targeted therapy against the fusion protein. PMID- 20713210 TI - Thoracic neuroblastoma: a retrospective review of our institutional experience with comparison of the thoracoscopic and open approaches to resection. AB - PURPOSE: Neuroblastoma is the most common extracranial solid tumor in children. Twenty percent of all neuroblastomas arise in the thorax. This study evaluates the open vs thoracoscopic resection of thoracic neuroblastoma. METHODS: A retrospective chart review was conducted from the medical records of all children undergoing resection of a thoracic neuroblastoma from 1990 to 2007 at our institution. We evaluated patients who underwent open vs thoracoscopic resection and compared demographics, pathologic condition, stage, operative details, complications, and outcomes between the 2 groups. RESULTS: A total of 149 cases of neuroblastoma were identified during the study period, 36 (24%) of which had tumor located in the thorax. Thirty-six of these patients underwent 37 operations for primary thoracic neuroblastoma. Open thoracotomy was used in 26 cases with the thoracoscopic approach to resection used in the remaining 11. We observed no differences in patient demographics including mean age, sex, or ethnicity. Tumors in both groups were of similar histologic condition, location, surgical margin, lymph node status, and stage. The length of operation was similar between the 2 groups, but length of stay was shorter in the thoracoscopic group (2.0 days; range, 1-7 days vs 3.5 days; range, 2-8 for the open group; P = .01). Estimated blood loss was also less in the minimally invasive group (median, 10 mL; range, 0 75 mL vs 25 mL; 5-650 mL in the open group; P = .02). Review of outcomes showed no significant difference in complications, recurrence, survival, or disease-free survival between these 2 groups. CONCLUSIONS: This retrospective review of thoracic neuroblastoma for an 18-year period shows that thoracoscopic resection is an effective approach to this tumor and offers shorter length of stay and decreased blood loss when compared to open thoracotomy. PMID- 20713211 TI - Sclerotherapy with bleomycin does not adversely affect facial nerve function in children with cervicofacial cystic lymphatic malformation. AB - BACKGROUND AND PURPOSE: Sclerotherapy with bleomycin sulfate (BS) is currently used in the management of cervicofacial cystic lymphatic malformations in children. Neurotoxic adverse effects of BS after intraventricular or intracavitary administration have been reported; however, the effects of intralesionally administered BS on the adjacent peripheral neural structures have not been previously investigated. The authors conducted a clinical experimental study to evaluate facial nerve function in children who have undergone BS sclerotherapy for cervicofacial cystic lymphatic malformation. MATERIALS AND METHODS: Twelve patients who underwent BS sclerotherapy for cervicofacial lymphatic malformation were included in the study. The hospital records were reviewed, and the following data were recorded: age at admission and at the time of motor nerve conduction study (MNCS) and electromyography (EMG) study, sex, time elapsed between sclerotherapy and the EMG study, and the outcome. The MNCS/EMG study was performed by neurologists blinded to the side of sclerotherapy. Bilateral facial MNCS and needle-EMG study of the orbicularis oris muscle on the treated side were performed. The previously treated and untreated sides constituted the study and control groups, respectively. In the MNCS, compound muscle action potential (CMAP) amplitude and distal latencies were recorded from the orbicularis oculi and orbicularis oris muscles on both sides, and needle-EMG of the orbicularis oris muscle was performed on the treated side. RESULTS: The male-to-female ratio was 2, and age at the time of sclerotherapy ranged from 1 month to 16 years (median, 19.5 months). The lymphatic malformations were located in the right submandibular (n = 5), left submandibular (n = 6), and in the right buccal (n = 1) areas. Bleomycin sulfate was injected 1 to 4 times, and the time elapsed between injections varied from 1 to 6 months. The results of sclerotherapy were excellent, with residual disease observed in only 1 patient. The MNCS/EMG study was performed 6 months to 10 years after completion of sclerotherapy, and ages of the patients at the time of the study ranged from 4 to 17 years. Side-to-side CMAP amplitude difference did not exceed 50% for orbicularis oculi and orbicularis oris muscles. The mean CMAP amplitude of orbicularis oculi and orbicularis oris muscles on the treated and untreated sides (1219.0 +/- 842.0 vs 1202.4 +/- 923.8 microV and 1866.3 +/- 911.5 vs 1921.0 +/- 910.0 microV, respectively) did not differ between groups (P = .76 and P = .80). Distal latencies recorded from orbicularis oculi and orbicularis oris muscles on treated and untreated sides (2.64 +/- 0.46 vs 2.68 +/- 0.47 milliseconds and 3.10 +/- 0.35 vs 3.10 +/- 0.25 milliseconds, respectively) also did not differ between groups (P = .71 and P = .80). Needle-EMG orbicularis oris muscle (n = 11) on the treated side showed normal findings at rest, and there was no spontaneous activity. During mild voluntary contraction, the amplitude and duration of motor unit action potentials were within normal limits except in one case. Interference patterns were also normal in all cases. CONCLUSION: Bleomycin sulfate did not adversely affect facial nerve function in children who underwent sclerotherapy for cervicofacial cystic lymphatic malformation when it was applied according to our protocol. PMID- 20713212 TI - Predicting the severity of congenital high airway obstruction syndrome. AB - BACKGROUND: Congenital high airway obstruction syndrome (CHAOS) is caused by complete or near-complete obstruction of the fetal airway. Obstruction sets in motion a sequence of events that can ultimately lead to fetal demise. However, on rare occasions in utero airway decompression occurs, reversing syndromic findings and improving the prognosis. In our relatively large series of CHAOS patients, we have observed a spectrum of clinical severity. The aim of this study was to identify the prenatal characteristics of CHAOS predictive of a milder postnatal course. METHODS: The medical charts of all fetuses observed at our institution with the diagnosis of CHAOS were reviewed for radiologic findings, delivery information, perinatal course, autopsy or discharge report, and long-term follow up. RESULTS: Between 1996 and 2008, 12 fetuses with CHAOS were identified. Four fetuses had no evidence of hydrops on initial imaging. Of the 8 fetuses displaying hydrops, 3 were terminated, 2 died in utero, and 1 with multiple anomalies died at birth. Six fetuses were delivered via the ex utero intrapartum therapy procedure for attempted salvage, and 5 of the 6 survived the neonatal period including all 4 fetuses without hydrops. Serial prenatal imaging demonstrated less severe signs of CHAOS in 3 fetuses, and in 2 of them, direct laryngoscopy revealed a tiny opening in the airway. All 3 fetuses that showed improvement on serial imaging survived the neonatal period and were discharged home by 2-10 weeks of age. CONCLUSIONS: Although the natural history of CHAOS is variable, trends in prenatal ultrasound findings are highly predictive of postnatal outcome and are a valuable guide to prenatal counseling. PMID- 20713213 TI - Functional outcome after operation for Hirschsprung disease--transanal vs transabdominal approach. AB - BACKGROUND: It has been hypothesized that the extensive transanal dissection in transanal endorectal pull-through (TEPT) for Hirschsprung disease (HD) can impair the anal sphincters in neonates and thereby cause incontinence. Theoretically, transabdominal endorectal pull-through might have less impact on the sphincters. The aim of this study was to compare functional outcome in HD patients operated with either TEPT or laparotomy-assisted endorectal pull-through (LEPT) with particular focus on soiling and fecal incontinence. PATIENTS AND METHODS: Anorectal function in 52 children older than 3 years is reported. The patients were operated for HD with either TEPT (n = 28) or LEPT (n = 24) and followed prospectively. Functional outcome was recorded by standardized interviews. The Krickenbeck criteria were used to classify voluntary bowel movements, soiling, and constipation. RESULTS: The median age at follow-up was 5.7 years (3.1-13.2) for TEPT and 10.1 years (7.7-16.2) for LEPT. Twenty-nine patients reported soiling at final follow-up. There was no difference in the rate of soiling between children operated with TEPT (54%) or LEPT (58%). Constipation was reported in 11 children (TEPT, 25%; LEPT, 17%). CONCLUSIONS: The functional outcome and in particular the rate of soiling did not differ between patients operated with LEPT or TEPT. PMID- 20713214 TI - Disruption of noncanonical Wnt/CA2+ pathway in the cadmium-induced omphalocele in the chick model. AB - PURPOSE: Cadmium (Cd) has been found to cause ventral body wall defects (VBWDs) in the chick embryo similar to human omphalocele. The earliest detectable histologic changes in Cd-induced VBWD chick model have been observed 4 hours posttreatment. The exact mechanism by which Cd acts in the early embryogenesis remains unclear. Wnt proteins play a key role during embryogenesis, and altered Wnt signaling has been linked to developmental defects. Noncanonical Wnt/Ca(2+) pathway has been implicated in regulating embryogenesis by controlling cell movement and adhesion. Wnt11 can activate protein kinase C (PKC) and calcium/calmodulin-dependent kinase II (CaMKII) in the Wnt/Ca(2+) pathway. We hypothesized that the Wnt11, PKCalpha, and CaMKII gene expression is downregulated in the Cd-induced VBWD during early embryogenesis. METHODS: After 60 hours of incubation, chick embryos were harvested 1 hour (1H), 4H, and 8H after treatment of saline or cadmium and divided into 2 groups: control and Cd (n = 8 at each time-point, respectively). Real-time polymerase chain reaction was performed to evaluate the messenger RNA (mRNA) expression of Wnt11, PKCalpha, and CaMKII in the Cd-induced VBWD chick model. RESULTS: The mRNA expression levels of Wnt11, PKCalpha, and CaMKII were significantly decreased at 1H in Cd group compared to controls (P < .05). However, there were no significant differences in the other time-points. CONCLUSION: Downregulation of Wnt11, PKCalpha, and CaMKII gene expression during the narrow window of early embryogenesis may cause VBWD, interfering with cell movement and adhesion, disrupting Wnt/Ca(2+) pathway. PMID- 20713215 TI - Bile duct ligation in developing rats: temporal progression of liver, kidney, and brain damage. AB - PURPOSE: Cholestatic liver disease may result in progressive end-stage liver disease and other extrahepatic complications. We explored the temporal progression of bile duct ligation (BDL)-induced cholestasis in developing rats, focusing on brain cognition and liver and kidney pathology, to elucidate whether these findings were associated with asymmetric dimethylarginine and oxidative stress alterations. MATERIALS AND METHODS: Three groups of young male Sprague Dawley rats were studied: one group underwent laparotomy (sham), another group underwent laparotomy and BDL for 2 weeks (BDL2), and a third group underwent laparotomy and BDL for 4 weeks (BDL4). RESULTS: The effect of BDL on liver was represented by transforming growth factor beta1 levels and histology activity index scores, which were worse in the BDL4 rats than in the BDL2 rats. BDL4 rats also exhibited more severe spatial memory deficits than BDL2 rats. In addition, renal injury was more progressive in BDL4 rats than in BDL2 rats because BDL4 rats displayed higher Cr levels, elevated tubulointerstitial injury scores, neutrophil gelatinase-associated lipocalin, and symmetric dimethylarginine levels. CONCLUSIONS: Our findings highlight the fact that young BDL rats exhibit similar trends of progression of liver, kidney, and brain damage. Further studies are needed to better delineate the nature of progression of organ damage in young cholestatic rats. PMID- 20713216 TI - Surrogate markers of cholesterol metabolism in children with native liver after successful portoenterostomy for biliary atresia. AB - PURPOSE: Cholestasis gradually ensues after portoenterostomy for biliary atresia (BA) and may deteriorate liver function. Cholesterol metabolism and its relationships with serum markers of liver function were evaluated in children living with native liver after successful portoenterostomy for BA. SUBJECTS AND METHODS: Serum lipids, noncholesterol sterol ratios to cholesterol, that is, surrogate markers of cholesterol metabolism, and liver function were cross sectionally studied in 17 consecutive children after successful (postoperative bilirubin <20 micromol/L) portoenterostomy for BA with native liver and a mean age of 5.2 years. The results were compared with healthy age-matched controls. RESULTS: Mean serum total and low-density lipoprotein cholesterol and campesterol ratio were 18%, 43%, and 26% less than those of controls, respectively (P < .01 for all). Despite low serum cholesterol and campesterol (marker of cholesterol absorption) levels, serum lathosterol (marker of cholesterol synthesis) was decreased by 34% (P < .0001) from control levels and reflected serum prealbumin (r = 0.666) and cholestanol (r = -0.515, P < .05 for both). Cholestanol, twice higher than those of controls (P < .0001), reflected abnormally high serum alkaline phosphatase, glutamyl transferase, and bile acids (r = 0.558-0.711, P < .05). Serum campesterol was inversely related with lathosterol (r = -0.238, P < .05) in controls, but not in patients (r = -0.039). CONCLUSION: Children living with native liver after portoenterostomy for BA are inclined to low serum concentration and absorption of cholesterol. Cholesterol homeostasis was disturbed so that low cholesterol absorption was not associated with compensatory increase in cholesterol synthesis that decreased together with worsening of cholestasis. PMID- 20713217 TI - Early outcomes of laparoscopic surgery for biliary atresia. AB - AIM: The aim of the study was to present early outcomes of the laparoscopic technique for biliary atresia with some technical modifications. MATERIALS AND METHODS: We reviewed charts of all patients with biliary atresia who underwent laparoscopic portoenterostomy from July to December 2008. There were 11 patients with biliary atresia, including 5 boys and 6 girls. The operation was carried out using 4 trocars. The liver was elevated by 2 transcutaneous stay sutures: one on the round ligament and the other on the gallbladder remnant. The left and right hepatic arteries and portal veins were dissected and retracted laterally by 2 transcutaneous sutures to expose the liver hilum. A stay suture was placed on fibrotic tissue at the liver hilum to facilitate its maximal removal. A jejunal end-to-side anastomosis was constructed extracorporeally. Portoenterostomy was carried out laparoscopically. RESULTS: Mean operative time was 245 +/- 31 minutes. No patient required conversion. There were no operative deaths. Blood loss during operation was minimal. One patient died on day 65 after operation because of intractable hepatic liver. Follow-up after discharge from 10 to 16 months revealed that 6 patients still survived and 4 patients died. One patient died because of milk aspiration at 12 months of age. Three patients died because of repeated cholangitis and liver failure at 10, 10, and 14 months, respectively. CONCLUSION: With a modified laparoscopic technique, good early outcomes of laparoscopic surgery for biliary atresia were achieved. PMID- 20713218 TI - Biliary reconstruction in pediatric live donor liver transplantation: duct-to duct or Roux-en-Y hepaticojejunostomy. AB - BACKGROUND: Duct-to-duct biliary reconstruction (DD) is currently a standard procedure in adult live donor liver transplantation (LDLT). Its pediatric feasibility, however, has rarely been reported. The goal of this study is to assess the incidence and treatment of biliary complication after pediatric LDLT with DD or Roux-en-Y hepaticojejunostomy (RY). METHOD: Sixty children received LDLT between November 2005 and June 2008, and their database was reviewed. RESULTS: Biliary reconstruction was achieved with DD in 14 patients and with RY in 46 patients with mean follow-up period of 26.0 and 22.3 months, respectively. The incidence of biliary leakage in the DD and RY groups was 7.1% and 8.7%, respectively, and that of stricture was 28.6% and 10.9%, respectively; but the differences were not statistically significant. Biliary stricture in the DD group tended to require revision surgery with RY and longer treatment with percutaneous transhepatic cholangiodrainage compared with that in the RY group. CONCLUSION: Theoretical advantages of DD over RY were not confirmed in this study. Duct-to duct biliary reconstruction tended to encounter more biliary complications, especially stricture, with more difficulty in treating it than RY. Roux-en-Y hepaticojejunostomy seems preferable to DD in the setting of pediatric LDLT, but DD must be considered when making new Roux-en-Y limb seems impossible or troublesome owing to abdominal dense adhesion or short bowel syndrome. PMID- 20713219 TI - Portal vascular anomalies in Down syndrome: spectrum of clinical presentation and management approach. AB - PURPOSE: The occurrence of portal vascular anomalies in Down syndrome has been sporadically reported in the literature. These rare disorders have a wide spectrum of anatomical and clinical presentations. The aim of this communication was to describe the clinical course, imaging features, and management approaches in patients with this association. METHODS: We conducted a comprehensive search of the databases of the Vascular Anomalies Center and the Department of Radiology at Children's Hospital Boston for patients with Down syndrome and portal vascular anomalies. Medical records and imaging studies of varying modalities were reviewed. RESULTS: Three children with Down syndrome and portal anomalies (portosystemic shunt, simple arterioportal shunt, complex arterioportal shunt) were managed at our institution. The portosystemic shunt was clinically insignificant and resolved without any intervention. The simple arterioportal shunt was successfully treated with embolization. The complex arterioportal shunt was associated with major congenital cardiac defects and the child ultimately expired despite a decrease in the arterioportal shunting after embolization. CONCLUSIONS: Three is a wide spectrum of clinical and anatomical features of portal vascular shunts in Down syndrome. The management approach should be tailored based on the severity of symptoms. Percutaneous embolization can offer a safe, effective, and minimally invasive alternative to the surgical approach in selective cases. PMID- 20713220 TI - Institutional experience with laparoscopic partial splenectomy for hereditary spherocytosis. AB - BACKGROUND/PURPOSE: Moderate to severe hereditary spherocytosis (HS) is treated with splenectomy. However, total splenectomy leads to decreased immunologic function with the risk of overwhelming postsplenectomy sepsis. Splenic preservation is postulated as a method to avoid this potentially fatal complication. Although mainly performed through laparotomy, we report our experience with a laparoscopic approach to partial splenectomy for HS. METHODS: A retrospective review was conducted on 9 laparoscopic partial splenectomies performed for HS at our institution. Follow-up was from 1 to 3.5 years. Data included preoperative and postoperative hemoglobin, absolute reticulocyte count, splenic size, operative time, complications, and length of stay. RESULTS: All patients successfully underwent laparoscopic partial splenectomy with a radiologically determined upper-pole remnant of 10% to 30% and preservation of the blood supply through the upper short gastric arteries. The mean preoperative spleen length was 13 cm. Mean hospital stay was 3.6 days (range, 1-6 days). There was 1 intraoperative complication (a small bowel tear during spleen extraction) and 2 minor postoperative complications (ileus and wound infection). One patient underwent completion total splenectomy 2 years after partial splenectomy. CONCLUSION: Laparoscopic partial splenectomy is a feasible and effective procedure that addresses the hematologic consequences of HS while retaining a portion of functional spleen, in addition to conferring the advantages of laparoscopy. PMID- 20713221 TI - Pericardial effusion and cardiac tamponade associated with central venous catheters in children: an uncommon but serious and treatable condition. AB - PURPOSE: Pericardial effusion (PCE) resulting in cardiac tamponade (CT) is a rare complication associated with central venous catheters (CVCs) in children. The goal of this study was to determine the demographics, presenting clinical picture and CVC characteristics in children developing CT as a result of a CVC. METHODS: An institutional review board-approved retrospective review of children treated at a tertiary-care pediatric hospital from 1998 to 2007 was conducted. Patients were identified through institutional database search for diagnostic codes of PCE and simultaneously assigned patient codes for the presence of CVC. Patients with incidentally discovered effusions, those with recent cardiac surgery, or those with causative factors other than a CVC were excluded. RESULTS: Over the 10-year study period, 463 patients were identified using the search criteria. Six cases of CVC-associated PCE causing CT were identified (1.3%). Corrected postgestational age at diagnosis ranged from 34 to 41 weeks with a median corrected postgestational age of 38.5 weeks (median, 38.5 weeks). The median time from CVC placement to diagnosis was 2.5 days (range, 0-6 days). Radiographs obtained before diagnosis demonstrated CVC tip to be overlying the cardiac silhouette in 5 patients (83%). Five (83%) of the 6 patients were receiving hyperalimentation via the CVC at the time of PCE. All patients presented with clinical signs of cardiorespiratory distress and/or cardiac arrest. Pericardiocentesis was performed in 5 patients (83%) and resulted in rapid stabilization. All CVCs were removed at diagnosis. There was 1 mortality (17%). CONCLUSIONS: Pericardial effusion and CT associated with CVC is rare and is chiefly a concern among infants. Characteristics of CVCs including infusate and tip position may be associated with increased risk of PCE. This diagnosis should be considered in any infant with a CVC who experiences acute respiratory distress or cardiovascular collapse. PMID- 20713222 TI - Short and long-term quality of life after reconstruction of bladder exstrophy in infancy: preliminary results of the QUALEX (QUAlity of Life of bladder EXstrophy) study. AB - PURPOSE: The aim of the study was to assess quality of life (QOL) of patients born with bladder exstrophy (BE) and reconstructed during early childhood in 7 French university hospitals (QUALEX study: QUAlity of Life of bladder EXstrophy). METHODS: Patients from 6 to 42 years old answered self-administered Short-Form 36 (SF-36), VSP-A (Vecu et Sante Percue de l'Adolescent), VSP-AE (Vecu et Sante Percue de l'Enfant), AUQUIE (AUto-QUestionnaire Image de l'Enfant), and general questionnaires about functional and socioeconomic data. Dimension scores were compared between adults and adolescents using SF-36 and adolescents and children using VSP-AE. Scores were also compared to the general French population. RESULTS: Among the 134 eligible patients, 36 adults, 18 adolescents, and 17 children answered the questionnaire. There was no difference between responders and nonresponders in reconstruction criteria. Continence was achieved in 77% of adults, 65% of adolescents, and 12% of children. Adolescent QOL was globally superior to adults and children. Adult QOL was globally lower than the general population except on the physical dimension. Children's QOL was also globally lower than the general population except for relations with family and school work. Adolescents' scores on SF-36 were superior to the general population but lower on half of the dimensions with VSP-AE. CONCLUSION: Patients presenting with reconstructed BE have impaired QOL, and functional results seem to be the most likely predictive factor of health-related QOL score. PMID- 20713223 TI - Long-term follow-up and management of prenatally detected, isolated hydronephrosis. AB - PURPOSE: The aim of the study was to determine the outcome and management of infants with isolated hydronephrosis, detected prenatally and confirmed postnatally. MATERIALS AND METHODS: Between January 1988 and January 2008, the files of 629 children (492 males and 137 females), who were diagnosed prenatally with isolated, unilateral hydronephrosis, and the diagnosis was confirmed postnatally, were retrospectively reviewed. The median follow-up time was 142 months. Serial ultrasonography and isotope diuretic renography nuclear imaging were performed. Hydronephrosis was assessed and classified according to the Society of Fetal Urology (SFU) grading system. RESULTS: Initially, all of the children were treated conservatively. Stabilization occurred in all children with grade 1 hydronephrosis, in 87% of children (144) with grade 2 hydronephrosis, and in 30% of children (37) with grade 3 hydronephrosis. However, 13% of children (21) with grade 2 hydronephrosis, 70% of children (85) with grade 3 hydronephrosis, and 100% of children with grade 4 hydronephrosis received surgical intervention according to our predetermined criteria. Ninety-five patients (late pyeloplasty group) were treated for a reduction for a differential renal function (DRF) to less than 40%, and 80 children (early pyeloplasty group) underwent surgery for a DRF more than 40%, but hydronephrosis progressed to higher grades or failed to improve and had poor radiotracer clearance. Significant improvements after pyeloplasty were noted in both groups with respect to the DRF and the ratio of the depth of the calyces to the thickness of the parenchyma (C/P ratio; P < .0001). The improvement in DRF was greater in the late pyeloplasty group than the early pyeloplasty group (P = .044), whereas the improvement in the C/P ratio was greater in the early pyeloplasty group than the late pyeloplasty group (P = .001). The ipsilateral DRF was preserved in the early pyeloplasty group, whereas the ipsilateral DRF was still less than 40% in the late pyeloplasty group. The improvement in DRF was significant during the first year postoperatively and became stable thereafter. The C/P ratio was inversely correlated with the DRF in the patients before and after pyeloplasty (r = -0.257; P = .01; and r = -0.616; P = .001, respectively). CONCLUSIONS: All infants with SFU-1 and most infants with SFU-2 hydronephrosis have relatively benign conditions and do not need an invasive procedure. Although greater improvement occurred in patients with an initial DRF less than 40%, the reduced DRF did not recover to the predeterioration level postoperatively. Earlier surgical intervention after a short period of strict clinical surveillance is beneficial for preserving renal function for patients with persistent SFU-3 or SFU-4 hydronephrosis. PMID- 20713224 TI - Primary osteomyelitis of the acetabulum resulting in septic arthritis of the hip and obturator internus abscess diagnosed as acute appendicitis. AB - The misdiagnosis of acute appendicitis is not uncommon. Rarely does infection of the triradiate cartilage imitate this entity. This case highlights an uncommon presentation of acetabular osteomyelitis as acute appendicitis and the severity of its sequelae. Like septic arthritis of the hip, acute appendicitis overtreatment is acceptable in part because of the complications resulting from delayed diagnosis and treatment. However, this case demonstrates the need to consider pelvic osteomyelitis and peripelvic infection in the differential diagnosis of appendicitis. PMID- 20713225 TI - True thymic hyperplasia in an infant. AB - True thymic hyperplasia is a very rare entity. We present an instance of idiopathic true massive thymic hyperplasia in a 9-month-old girl with a very large left-sided mediastinal mass noted on diagnostic imaging. Percutaneous biopsy revealed normal thymic tissue. Steroids were administered with no response. Surgery may be required in patients with respiratory distress unresponsive to steroids. PMID- 20713226 TI - Laparoscopic-assisted sigmoid resection for colonic ectasia in a neonate. AB - A 2.7-kg, 2-day-old girl was diagnosed to have a colonic ectasia and malrotation. She underwent laparoscopic resection of the ectatic segment and Ladd procedure. To our knowledge, such a laparoscopic resection of a colonic ectasia in a neonate has not been reported previously in the English literature. The clinical features, management, and surgical technique will be discussed in this report. PMID- 20713227 TI - Isolated retroperitoneal hydatid cyst in a child: a rare cause of acute scrotal swelling? AB - Hydatidosis affects almost every region of the body. Although adults are mostly affected, children also suffer from the disease especially in endemic areas. The usual affected location is the liver, lung, spleen, brain, and kidney. We report a hydatid cyst located in a retroperitoneal location presenting with a sudden scrotal extension in a 7-year-old child. The finding presented a diagnostic dilemma vis-a-vis obstructed inguinal hernia. PMID- 20713228 TI - Difficult extraction of long-term central venous catheters in children--case report. AB - Although many publications address the complications associated with insertion of long-term, indwelling central venous catheters, there are only scattered reports of problems related to their removal. We report 4 cases of pediatric patients in whom the lines could not be pulled from the vein by standard methods, requiring 2 intraperiosteal clavicle resections with venorrhaphy, 1 femoral vein exploration and reconstruction, and 1 jugular venorrhaphy. Despite their relative biocompatibility, long-term silicone lines may become fixed in the vein. The rare and unpredictable occurrence of this problem may present the surgeon with unexpected intraoperative dilemmas. Before attempting localized extraction, surgeons should consider what venue, equipment, and anesthesia support may be required to successfully remove these catheters. PMID- 20713229 TI - Gastroschisis with Hirschsprung's disease: a therapeutic dilemma. AB - The authors report a case of a neonate with gastroschisis, which, after repair, was further complicated by the diagnosis of Hirschsprung's disease. The authors discuss the diagnostic and management dilemmas posed by the coexistence of these two conditions for the clinician. PMID- 20713230 TI - Neonatal care in patients with giant ompholocele: arduous management but favorable outcomes. AB - OBJECTIVES: The objectives of the study were to provide a review of patients with giant omphalocele managed in a single institution (2001-2006), focusing on medical management in the neonatal period, and to evaluate short-term outcomes. METHODS: Data from 14 neonates with giant ompholocele (abdominal wall defect >5 cm and/or containing liver) and the absence of malformation and chromosomal anomalies during fetal screening were retrospectively reviewed. All were intubated and sedated before surgical treatment. Initial management consisted of progressive reduction of the herniated organs by gentle compression. After sequential reduction, abdominal wall closure was attempted at the skin and fascia level and, when necessary, with a Gore-Tex patch. RESULTS: Median gestational age was 39 weeks (38-40), and median birth weight was 3100 g (2470-3700). Median age at closure was 6 days (0-20). A central Gore-Tex patch was inserted in 10 cases. Median ventilation length was 26 days (2-78). Full enteral diet was achieved after an average of 33 days (8-82), and median time until discharge from the intensive care unit was 24.5 days (11-85). Nine patients developed sepsis in the postoperative course. In 10 patients, at least 1 associated malformation was diagnosed in the postnatal course, among which cardiac and diaphragmatic defects were the most common. Survival rate was 85.7%. CONCLUSION: Mortality rate of giant omphalocele without chromosomal anomaly or major malformations is low when treated by gradual reduction of the contents. Parents should be informed of the long hospitalization in the intensive care unit at birth, the potential nonthreatening associated malformations to be diagnosed after birth, and the high risk of sepsis. PMID- 20713231 TI - Usefulness of magnetic resonance imaging for congenital prepubic fistula. AB - Congenital prepubic fistula is a rare congenital anomaly. Complete removal of the fistular tract remains challenging because of the complicated course. Although conventional fistulography has been used widely as a diagnostic tool for congenital prepubic fistula, more detailed information such as accurate localization of the fistular end or relative position to the urinary tract cannot be preoperatively obtained because the conventional contrast studies have insufficient capability. In this article, we reported the complete removal of congenital prepubic fistula based on preoperative magnetic resonance imaging findings, especially T2-weighted imaging. Magnetic resonance imaging clearly displayed not only the tract of the prepubic fistula originating from a subcutaneous cyst but also the tract extending and ending near the top of the urinary bladder. PMID- 20713232 TI - Pyogenic osteomyelitis of the vertebral arch in children. AB - Vertebral infection represents 2% to 4% of all cases of osteomyelitis in children. Extension of vertebral osteomyelitis into the vertebral arch is rare; and exclusive pyogenic involvement is exceedingly rare, especially in children. A review of the literature revealed less than 25 combined cases, most of them reported in the beginning of the 20th century without cross-sectional imaging. The unusual location creates difficulties in distinguishing vertebral osteomyelitis from neoplasm and arthritic conditions. We present 2 cases of infection of the posterior vertebral elements. Most useful in identifying the presence and extent of infection were a sudden onset of nonspecific back pain, elevated inflammatory parameters, and magnetic resonance imaging. Antibiotic therapy with or without surgical intervention provided successful management. With the recurrence observed in 1 child, the most optimal treatment of this condition might still be unknown. PMID- 20713233 TI - The Ventral V-plasty: a simple procedure for the reconstruction of a congenital megaprepuce. AB - A buried penis secondary to a megaprepuce is defined clinically by a phimosis, failure of the corporal bodies to inhabit a variably deficient penile shaft skin and a basal hemispheric ballooning of the penis during micturition. Anatomically, it describes a condition in which a normal phallus is trapped within normal prepubic connective tissue by the excessive skin of a megaprepuce and a variable abundance of dartos fascia. Many surgical procedures have been described to correct this deformity, suggesting that no single method has a clear advantage. Most of them rely on relatively complex skin flaps or on the abnormal megapreputial tissue for reconstruction of the deficient ventral shaft skin. Herein, the authors describe an alternative technique for ventral skin coverage, the Ventral V-plasty. This surgical procedure allowed for the favorable reconstruction of 10 consecutive children with a buried penis secondary to a megaprepuce. This technique is distinguished by its simplicity and consistent, pleasing cosmetic results. PMID- 20713234 TI - Thoracoscopic treatment of chylothorax after patch repair of congenital diaphragmatic hernia. PMID- 20713235 TI - Meniere's disease: 150 years and still elusive. PMID- 20713236 TI - Current epidemiology of Meniere's syndrome. AB - The burden of Meniere syndrome (MS) is substantial, especially when considering the significant impact on the quality of life of those affected. Reported estimates of incidence and prevalence have varied widely due to methodological differences between studies, changes in criteria for diagnosis of MS, and differences in populations studied. Reported prevalence rates for MS range from 3.5 per 100,000 to 513 per 100,000. A recent study using health claims data for more than 60 million patients in the United States found prevalence of 190 per 100,000 with a female:male ratio of 1.89:1. The prevalence of MS increases with increasing age. PMID- 20713238 TI - Physiologic effects on the vestibular system in Meniere's disease. AB - Meniere syndrome is an inner ear disorder characterized by spontaneous attacks of vertigo, fluctuating low-frequency sensorineural hearing loss, aural fullness and tinnitus. When the syndrome is idiopathic and cannot be attributed to any other cause (eg, syphilis, immune-mediated inner ear disease, surgical trauma), it is referred to as Meniere disease. This article reviews the physiologic effects of Meniere disease on vestibular function, as measured by caloric, head impulse, and vestibular-evoked myogenic potential testing. PMID- 20713239 TI - Audiovestibular testing in patients with Meniere's disease. AB - In this article, the present state of the art with respect to audiovestibular testing for Meniere's disease (MD) is reviewed. There is no gold standard for MD diagnosis, and the classic dictum is that even the "best" tests yield positive results in only two-thirds of patients with MD. Still, we advocate the use and further investigation of advanced audiovestibular testing in patients with MD in an attempt to answer the questions that confront any clinician who cares for patients with audiovestibular symptoms. PMID- 20713237 TI - Endolymphatic hydrops: pathophysiology and experimental models. AB - It is well established that endolymphatic hydrops plays a role in Meniere disease, even though the precise role is not fully understood and the presence of hydrops in the ear does not always result in symptoms of the disease. It nevertheless follows that a scientific understanding of how hydrops arises, how it affects the function of the ear, and how it can be manipulated or reversed could contribute to the development of effective treatments for the disease. Measurements in animal models in which endolymphatic hydrops has been induced have given numerous insights into the relationships between hydrops and other pathologic and electrophysiological changes, and how these changes influence the function of the ear. The prominent role of the endolymphatic sac in endolymph volume regulation, and the cascade of histopathological and electrophysiological changes that are associated with chronic endolymphatic hydrops, have now been established. An increasing number of models are now available that allow specific aspects of the interrelationships to be studied. The yclical nature of Meniere symptoms gives hope that treatments can be developed to maintain the ear in permanent state of remission, possibly by controlling endolymphatic hydrops, thereby avoiding the rogressive damage and secondary pathologic changes that may also contribute to the patient's symptoms. PMID- 20713240 TI - Clinical hints and precipitating factors in patients suffering from Meniere's disease. AB - Meniere disease is one of the most fascinating and most vexing of all clinical conditions encountered by the otolaryngologist. Operationally speaking, a Meniere ear is a fragile ear. In fact, Meniere disease can and should be redefined as a degenerating inner ear that has impairment of one or more homeostatic systems, resulting in instability of hearing and balance function. This updated definition is a valuable guide to the clinical epidemiology and presentation of Meniere disease and to understanding the effects of conservative treatments. In the absence of a definitive test for Meniere disease, the greatest challenge for the clinician may be differentiating this condition from migraine. Ultimately, Meniere vertigo attacks are controllable in more than 99% of cases, but hearing loss and other auditory symptoms tend to be unresponsive to treatment. PMID- 20713241 TI - Hypothetical mechanism for vertigo in Meniere's disease. AB - Past theories that have been proposed to account for the attacks of vertigo during the course of Meniere disease are reviewed. In the past, vascular theories and theories of perilymph and endolymph mixing due to ruptures or leakages were proposed. Recent research concerning the basic mechanisms of the inner ear anatomy and function cast doubt on these theories. The anatomy, physiology, and pathophysiology of the inner ear, and in particular of the endolymphatic sac and endolymphatic duct are reviewed. Recent studies suggest that in people the endolymph ionic content is replenished without any flow of fluid and that longitudinal endolymph flow only occurs in response to volume excess. Furthermore audiological and electrophysiological studies have revealed little or no change in the cochlear function during episodes of vertigo. The longitudinal drainage theory attempts to encompass the recent research findings. The theory hypothesizes that endolymph draining too rapidly from the cochlear duct (pars inferior) causes attacks of vertigo. The endolymph overfills the endolymphatic sinus and overflows into the utricle (pars superior), stretching the cristae of the semicircular canals, causing the attacks of vertigo. PMID- 20713242 TI - Premenstrual exacerbation of Meniere's disease revisited. AB - Some women with Meniere disease demonstrate exacerbation of symptoms during the premenstrual period. It is believed that the hormonal stress of the premenstrual period acts on the volatile inner ear with Meniere disease to result in dysfunction. Migraine, Meniere disease, and the premenstrual period may be a complex interaction leading to exacerbation of symptoms. Having patients maintain a daily calendar of symptoms, diet, and menses can be helpful in understanding the disease as well as instigating treatment monitoring. Most patients can be effectively managed with dietary sodium restriction and a loop diuretic. PMID- 20713243 TI - Meniere's disease in the elderly. AB - Meniere disease usually begins in adults from 20 to 60 years old, and occurs in more than 10% of patients older than 65. The treatment of Meniere disease in the elderly represents a challenge because of polymedication. Antivertiginous drugs such as betahistine and cinnarizin give good results with minor secondary effects. In contrast, major vestibular suppressor drugs such as thiethylperazin must be avoided as long-term treatment because of their side effects. Definitive vestibular surgical deafferentations such as labyrinthectomy and selective vestibular neurectomy represent optional procedures but must be carefully evaluated from case to case. Ablative procedures remain the efficient treatment of drop attacks, which represent a high potential risk of severe injuries by older patients sometimes with important social consequences. PMID- 20713244 TI - Allergy and its relation to Meniere's disease. AB - Meniere's disease (MD), which by definition is idiopathic, has been ascribed to various causes, including inhalant and food allergies. Patients with MD report higher rates of allergy history and positive skin or in vitro tests compared with a control group of patients with other otologic diseases and to the general public. Recent immunologic studies have shown higher rates of circulating immune complexes, CD4, and other immunologic components in patients with MD compared with normal controls. Published treatment results have shown benefit from immunotherapy and/or dietary restriction for symptoms of MD in patients who present with allergy and MD. PMID- 20713245 TI - Magnetic resonance imaging of the inner ear in Meniere's disease. AB - Recent magnetic resonance imaging (MRI) techniques have made it possible to examine the compartments of the cochlea using gadolidium-chelate (GdC) as a contrast agent. As GdC loads into the perilymph space without entering the endolymph in healthy inner ears, the technique provides possibilities to visualize the different cochlear compartments and evaluate the integrity of the inner ear barriers. This critical review presents the recent advancements in the inner ear MRI technology, contrast agent application and the correlated ototoxicity study, and the uptake dynamics of GdC in the inner ear. GdC causes inflammation of the mucosa of the middle ear, but there are no reports or evidence of toxicity-related changes in vivo either in animals or in humans. Intravenously administered GdC reached the guinea pig cochlea about 10 minutes after administration and loaded the scala tympani and scala vestibuli with the peak at 60 minutes. However, the perilymphatic loading peak was 80 to 100 minutes in mice after intravenous administration of GdC. In healthy animals the scala media did not load GdC. In mice in which GdC was administered topically onto the round window, loading of the cochlea peaked at 4 hours, at which time it reached the apex. The initial portions of the organ to be filled were the basal turn of the cochlea and vestibule. In animal models with endolymphatic hydrops (EH), bulging of the Reissner's membrane was observed as deficit of GdC in the scala vestibuli. Histologically the degree of bulging correlated with the MR images. In animals with immune reaction-induced EH, MRI showed that EH could be limited to restricted regions of the inner ear, and in the same inner ear both EH and leakage of GdC into the scala media were visualized. More than 100 inner ear MRI scans have been performed to date in humans. Loading of GdC followed the pattern seen in animals, but the time frame was different. In intravenous delivery of double-dose GdC, the inner ear compartments were visualized after 4 hours. The uptake pattern of GdC in the perilymph of humans between 2 hours and 7 hours after local delivery needs to be clarified. In almost all patients with probable or suspected Meniere's disease, EH was verified. Specific algorithms with a 12 pole coil using fluid attenuation inversion recovery sequences are recommended for initial imaging in humans. PMID- 20713246 TI - Medical and noninvasive therapy for Meniere's disease. AB - Nonoperative therapy continues to be the mainstay of treatment of patients suffering from Meniere disease. Despite extensive research, the exact pathogenesis of Meniere disease remains elusive. The poorly understood nature of this condition has made it nearly impossible to develop treatments that are curative. Most modern treatments are aimed at controlling symptoms. This article reviews the various nonoperative treatments that have been used to treat Meniere disease historically as well as outlining the authors' clinical treatment paradigm. PMID- 20713247 TI - Endolymphatic sac shunt, labyrinthectomy, and vestibular nerve section in Meniere's disease. AB - Medical treatment for Meniere's disease is effective in controlling vertigo for approximately 85% of patients. However, when disabling vertigo continues, surgical therapy is indicated. Several surgical approaches are performed to control the symptoms of peripheral vestibular disorders refractory to medical measures, each procedure having many technical variations. Surgery is usually reserved for patients with disabling vertigo. Here, the authors discuss surgical options for vertigo control in Meniere's disease and review the literature on outcomes of these management options. The authors discuss endolymphatic sac shunt (ie, endolymphatic mastoid shunt), vestibular nerve section, cochleosacculotomy, and labyrinthectomy. When looking at data based on patient ratings, the authors find that surgery improves vertigo in endolymphatic sac shunt, vestibular nerve section, and labyrinthectomy groups and improves imbalance for the endolymphatic sac shunt and vestibular nerve section groups. Labyrinthectomy and translabyrinthine vestibular nerve section both offer excellent control of intractable vertigo. However, patients undergoing translab yrinthine vestibular nerve section are more likely to show improvement in imbalance and functional disability. This outcome is more likely for diagnoses other than Meniere's disease. There are potential prognostic factors that can be helpful in the preoperative or postoperative counseling of patients undergoing surgical treatment of vertigo. Patients who rate themselves as more disabled before surgery are less likely to achieve the best outcomes. Several other factors, such as duration of disease, contralateral tinnitus, eye disease, and allergy, may play a role. PMID- 20713248 TI - Early vestibular physical therapy rehabilitation for Meniere's disease. AB - Meniere disease includes symptoms of fluctuating hearing loss, tinnitus, and subjective ear fullness accompanied by episodic vertigo. Along with these symptoms, patients with chronic Meniere often develop symptoms of disequilibrium and unsteadiness that extend beyond the episodic attacks and contribute to the total disability and reduced quality of life attributed to the disease. Vestibular rehabilitation physical therapy has been used only after vestibular ablation has stabilized the vestibular loss, and for patients stably managed on medical therapy who exhibit no fluctuation in symptoms. This article reviews the data substantiating current applications of vestibular therapy, including improvements in subjective and objective balance outcome measures, and explores the possible extension of vestibular rehabilitation to treatment of patients exhibiting continued fluctuating vestibular loss. PMID- 20713249 TI - Genetic investigations of Meniere's disease. AB - Meniere's disease remains a disorder of unknown origin despite the collective efforts to determine the pathogenesis, although experts have long recognized that disease development likely has some heritable component. Although genetic studies of Meniere's disease have been inconclusive, increasing knowledge of human genetic structure and mutation and investigative techniques have potential to further understanding of this disorder. PMID- 20713250 TI - Silicon effects on photosynthesis and antioxidant parameters of soybean seedlings under drought and ultraviolet-B radiation. AB - Silicon (Si) may be involved in metabolic, physiological, and/or structural activity in higher plants exposed to abiotic and biotic stresses. This has not yet been determined due to the absence of direct evidence that it is part of the molecule of an essential plant constituent or metabolite. The aim of this study was to investigate the effect of silicon on soybean seedlings under drought and ultraviolet-B (UV-B) radiation stresses. The relative leaf water content (RWC), which was the main factor resulting in reduced growth in response to drought, increased 19.0% and 30.0% with Si application under drought and drought+UV-B stresses, respectively. Under UV-B radiation, the anthocyanin and phenol levels decreased 91.5% and 10.0% in the treatment of Si. Ultraviolet-B radiation and drought stress caused great membrane damage, as assessed by lipid peroxidation and osmolyte leakage, but Si application significantly reduced the membrane damage. Catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and hydrogen peroxide were observed under stress conditions. Proline increased primarily in drought-stressed seedlings and may be the drought-induced factor with a protective role in response to UV-B and silicon. Photosynthesis (P(N)) increased following Si application by 21.0%, 18.3% and 21.5% under UV-B radiation, drought and the combination, respectively. The physiological and biochemical parameters measured indicated that the UV-B light had more adverse effects on growth of soybean seedlings than drought, but the data also showed that Si could alleviate seedling damage under these stress conditions. PMID- 20713251 TI - Adjuvant systems educational supplement. Introductory editorial. PMID- 20713252 TI - Principles of vaccine design-Lessons from nature. AB - Microbial pathogens have developed complex and efficient ways of counteracting and evading innate and adaptive immune mechanisms. The strategies used by pathogens determine strongly the type of immune response a vaccine should elicit and how the vaccine should be formulated. Improved knowledge of immune response mechanisms has brought successes in the development of vaccines that protect against challenging pathogens as well as vaccines that can be used in immunocompromised and elderly populations. This includes the production of highly purified antigens that provide a better reactogenicity and safety profile than some of the early whole-pathogen vaccines. Successful attempts to improve antigen purity, however, can result in weakened immunogenicity. The search for approaches to overcome this has led to new technologies, such as live vector vaccines, DNA vaccines and novel adjuvant formulations, which have been based on growing knowledge of the interplay between innate and adaptive immune systems and the central role played by antigen-presenting cells. Of these technologies, one of the most promising to date is based on the use of innovative adjuvants combined with careful antigen selection. Vaccine design has therefore become more tailored, and in turn has opened up the potential of extending its application in immunotherapies to tackle diseases such as cancer, Alzheimer disease and immune mediated disorders. PMID- 20713253 TI - Key concepts in immunology. AB - Vertebrates have developed systems of immune defence enabling them to cope with the constant threat posed by environmental pathogens. The mammalian immune system represents a multilayered defence system comprising both innate and adaptive immune responses, characterized by the increasing complexity of their antigen recognition systems. The discovery of the intimate relationship between innate and adaptive responses has paved the way to a novel understanding of the basic mechanisms governing the regulation of an immune response. The purpose of the present review is to briefly describe the basic immunological concepts that constitute the founding principles of modern vaccinology in humans. PMID- 20713254 TI - Unmet needs in modern vaccinology: adjuvants to improve the immune response. AB - The key objective of vaccination is the induction of an effective pathogen specific immune response that leads to protection against infection and/or disease caused by that pathogen, and that may ultimately result in its eradication from humanity. The concept that the immune response to pathogen antigens can be improved by the addition of certain compounds into the vaccine formulation was demonstrated about one hundred years ago when aluminium salts were introduced. New vaccine technology has led to vaccines containing highly purified antigens with improved tolerability and safety profiles, but the immune response they induce is suboptimal without the help of adjuvants. In parallel, the development of effective vaccines has been facing more and more important challenges linked to complicated pathogens (e.g. malaria, TB, HIV, etc.) and/or to subjects with conditions that jeopardize the induction or persistence of a protective immune response. A greater understanding of innate and adaptive immunity and their close interaction at the molecular level is yielding insights into the possibility of selectively stimulating immunological pathways to obtain the desired immune response. The better understanding of the mechanism of 'immunogenicity' and 'adjuvanticity' has prompted the research of new vaccine design based on new technologies, such as naked DNA or live vector vaccines and the new adjuvant approaches. Adjuvants can be used to enhance the magnitude and affect the type of the antigen-specific immune response, and the combination of antigens with more than one adjuvant, the so called adjuvant system approach, has been shown to allow the development of vaccines with the ability to generate effective immune responses adapted to both the pathogen and the target population. This review focuses on the adjuvants and adjuvant systems currently in use in vaccines, future applications, and the remaining challenges the field is facing. PMID- 20713255 TI - Putting the puzzle pieces together: the dynamic landscape of influenza vaccine and policy. PMID- 20713256 TI - Seasonal influenza vaccinations: specialized products for different target groups. AB - Traditionally, inactivated influenza vaccines have all been treated as virtually identical, at least in terms of recommendations for use. This has mostly been the case since their development over 60 years ago. The concept, still often quoted, that they are 70-90% protective against laboratory-confirmed clinical influenza comes from multiple studies carried out with different preparations in the US military; studies which ended in 1969 [1]. During this period, there were only gradual advances in improved potency and purity of the vaccines, so that it was appropriate to consider them as being comparable. However, we are currently witnessing a change, which started slowly, but is now accelerating, in which very different types of vaccine are becoming available. This has already begun in some parts of the world, but will soon be universal. The process is being accelerated by questions concerning the actual effectiveness of the current vaccines in specific risk groups. In this paper, we will take a look at the developments in the formulation of the vaccine to address the needs that have been identified. We will also consider different strategies for vaccine use which might be applied to traditional or future vaccines to improve population protection. PMID- 20713257 TI - New emerging technologies and the intradermal route: the novel way to immunize against influenza. AB - Influenza-related illness is an enormous health burden in all age groups. Immunization remains the best method of prevention, yet despite the availability of a safe and effective vaccine, many individuals go unvaccinated each season. Intradermal (ID) vaccination represents an alternative approach to standard intramuscular (IM) vaccination and takes advantage of the immunologically active dermis capable of producing a robust immune response. Enhanced immunogenicity with ID vaccination compared with standard IM vaccination has been observed in several groups with a history of poor vaccine response rates, such as older adults and haemodialysis patients. In addition, these methods of delivery may increase acceptability in children and persons with needle phobias, thus addressing some of the present barriers to influenza immunization. PMID- 20713258 TI - The 2009-2010 influenza pandemic: effects on pandemic and seasonal vaccine uptake and lessons learned for seasonal vaccination campaigns. AB - Individual and national/cultural differences were apparent in response to the 2009-2010 influenza pandemic. Overall pandemic influenza immunization rates were low across all nations, including among healthcare workers. Among the reasons for the low coverage rates may have been a lack of concern about the individual risk of influenza, which may translate into a lack of willingness or urgency to be vaccinated, particularly if there is mistrust of information provided by public health or governmental authorities. Intuitively, a link between willingness to be vaccinated against seasonal influenza and against pandemic influenza exists, given the similarities in decision-making for this infection. As such, the public is likely to share common concerns regarding pandemic and seasonal influenza vaccination, particularly in the areas of vaccine safety and side effects, and personal risk. Given the public's perception of the low level of virulence of the recent pandemic influenza virus, there is concern that the perception of a lack of personal risk of infection and risk of vaccine side effects could adversely affect seasonal vaccine uptake. While governments are more often concerned about public anxiety and panic, as well as absenteeism of healthcare and other essential workers during a pandemic, convincing the public of the threat posed by pandemic or seasonal influenza is often the more difficult, and underappreciated task. Thus, appropriate, timely, and data-driven health information are very important issues in increasing influenza vaccine coverage, perhaps even more so in western societies where trust in government and public health reports may be lower than in other countries. This article explores what has been learned about cross-cultural responses to pandemic influenza, and seeks to apply those lessons to seasonal influenza immunization programs. PMID- 20713259 TI - Seasonal influenza and vaccination coverage. AB - Seasonal influenza represents a considerable public health burden, and annual vaccination represents the most effective preventive strategy for amelioration of this problem. Certain groups are at greatest risk, such as the young, the elderly, pregnant women, and those with chronic underlying medical conditions: the high-risk groups. Traditionally, annual vaccination has been targeted to people classified as being at high risk, particularly the elderly, but in recent years, there has been a broadening of vaccination recommendations to target larger numbers of people. This has recently culminated in the recommendation of "universal vaccination" in the USA (everyone over 6 months of age is recommended to receive the seasonal influenza vaccine). In this review, we will look at coverage rates in Europe and the USA, changes in vaccination guidelines, and the rationale for broadening vaccination recommendations. It is clear that often only modest improvements in vaccination coverage have occurred recently, with programs targeting risk groups, but some substantial increases in coverage have followed the broadening of USA vaccination recommendations to all persons under 18 years and to middle-aged healthy adults (> or =50 years). It is likely, however, that some of these increases may be because of the increased awareness related to the recent pandemic. It is unclear if increases in coverage will translate into public health benefits, but perhaps results will be similar to experiments with universal vaccination in Ontario, Canada, where increased coverage may have provided some reductions in healthcare use, fewer influenza-associated deaths, and even financial benefits. PMID- 20713260 TI - The need for quadrivalent vaccine against seasonal influenza. AB - Seasonal influenza epidemics represent a substantial public health burden, causing significant morbidity and mortality. Influenza in humans can be caused by influenza type A and type B viruses, and although influenza A is responsible for the majority of seasonal influenza infections, influenza B disease is common in children and young adults, and causes seasonal epidemics every 2-4 years. Influenza strains circulating during a seasonal epidemic may be influenza type A strains A/H1N1 and A/H3N2, strains of influenza B lineages B/Victoria and B/Yamagata, or any combination of these. The morbidity and mortality burden of influenza infections means that public health agencies worldwide recommend vaccination to try and protect against seasonal epidemics. The World Health Organization (WHO) and, in the United States of America (USA), the Food and Drug Administration (FDA), recommend trivalent seasonal influenza vaccines containing the two main influenza type A strains and, due to its lesser but still important prevalence, one influenza type B strain. There is little or no cross-reactive protection between the influenza B lineages: this means that good protection against the circulating virus relies on correctly predicting the prevalent influenza B lineage in any season. This has proved to be reliant on chance, and little or no protection has been provided in the USA by the trivalent vaccines against the circulating influenza B virus in 5 of the 10 seasons between 2001 and 2010. There is, therefore, a clear need for a quadrivalent influenza vaccine, containing influenza A/H1N1, A/H3N2, and B/Victoria and B/Yamagata lineage strains, to improve protection against influenza B virus and reduce the morbidity of influenza B infection. PMID- 20713261 TI - Preface: Alveolar bone grafting techniques for dental implant preparation. PMID- 20713263 TI - Principles of bone grafting. AB - This article reviews the principles of bone healing and bone grafting. There are many different ways to reach the same goal when bone grafting procedures are performed. With all of the available methods and materials, a clear understanding of these basic principles will assist in the selection of a technique for each individual patient. PMID- 20713262 TI - Genetic and transcriptional control of bone formation. AB - An exquisite interplay of developmental cues, transcription factors, and coregulatory and signaling proteins support formation of skeletal elements of the jaw during embryogenesis and dynamic remodeling of alveolar bone in postnatal life. These molecules promote initial condensation of the mesenchyme, commitment of the mesenchymal progenitor to osteogenic lineage cells, and differentiation of committed osteoblasts to mature osteocytes within mineralized bone. Parallel regulatory networks promote formation of the functional osteoclast from mononuclear cells to support continuous bone remodeling within the alveolar bone. With an ever expanding list of new regulatory factors, the complexities of the molecular mechanisms that control gene expression in skeletal cells are being further appreciated. This article examines the multifunctional roles of prominent nuclear proteins, cytokines, hormones, and paracrine factors that control osteogenesis. PMID- 20713264 TI - Bone graft harvesting from distant sites: concepts and techniques. AB - Bony augmentation of the moderately to severely resorbed alveolus in preparation for endosseous dental implant placement can be challenging for the oral and maxillofacial surgeon. Autogenous bone remains the gold standard for alveolar grafting. Multiple extraoral bone graft sources can be used to help meet this challenge, including the iliac crest, proximal tibia, and calvarium. This article reviews the anatomy, harvest techniques, and morbidity associated with each of these donor sites. PMID- 20713265 TI - Bone graft harvesting from regional sites. AB - Bone grafts are widely used in the reconstruction of osseous defects in the oral and maxillofacial region. Successful osseointegration of dental implants requires sufficient bone surrounding the implant. Although bone substitutes and augmentation techniques offer viable prognoses for achieving the required amount of hard tissue augmentation, autologous bone is the gold standard with regard to quantity, quality, and an uneventful healing. Autogenous bone grafts are generally obtained from the ilium, the rib, and the calvarium. Alternative sources for local harvesting in the mandible can be evaluated by careful clinical and radiographic examinations of the patient. This article discusses the various sources of grafts and the techniques used to harvest bone. PMID- 20713266 TI - Osteoperiosteal flaps and local osteotomies for alveolar reconstruction. AB - This article focuses on the emergence of the small edentulous osteoperiosteal flap. PMID- 20713267 TI - Bone materials available for alveolar grafting. AB - The restoration of bony defects has followed an interesting course through history. From the early use of animal materials to bone grown in the laboratory, the goal of restoring bony defects has generated ingenuity in solving these significant clinical challenges. PMID- 20713268 TI - Vertical ridge augmentation using titanium mesh. AB - With tooth loss, there is increased bone loss of the alveolus. In some cases alveolar bone loss can be severe. Severe bone loss may cause difficulty for patients wearing a conventional prosthesis or being restored with dental implants. Severe alveolar bone loss can result in malnutrition, poor self-esteem, multiple dental visits for failed prosthesis, and jaw fracture. In many cases, patients with loss of alveolar bone height or width may require reconstructive procedures. Vertical ridge augmentation remains a challenge in the reconstruction of the atrophic maxilla and mandible. The main problem arises from the need to expand the soft-tissue envelope and achieve the proper bony architecture. Techniques that have been developed to solve or circumvent this problem include onlay bone grafting with particulate bone graft, block bone graft, barrier techniques with permanent or resorbable membranes, distraction osteogenesis, vascularized ridge splitting techniques, sinus lifts, nerve repositioning techniques, short implants, and angled implants. All of these techniques have advantages and disadvantages. This article focuses on augmentation procedures using titanium mesh, which acts as a barrier and physical support of the soft tissue over the bone graft. PMID- 20713269 TI - Alveolar distraction osteogenesis for dental implant preparation: an update. AB - Alveolar distraction is a constantly evolving technique. A review of the literature within the past 14 years reveals that there are clear indications for its use, with outcomes similar to and sometimes even more predictable than traditional bone grafting techniques in preparation for implant placement. Although complications exist with alveolar distraction, it seems that most are minor and easy to manage. Appropriate patient selection and a better understanding of the technique are paramount to successful bone regeneration with alveolar distraction osteogenesis. This article discusses newer research and provides clinical advice on the practice of alveolar distraction osteogenesis for dental implant preparation. PMID- 20713270 TI - Soft tissue considerations in implant site development. AB - Healthy soft tissue surrounding a dental implant is essential for health, function, and esthetics. The development of the tooth includes the formation of a biologic connection between the living tissues that has to be created during the healing process after placement of the implant. The success of dental implants is dependent on the establishment of a soft-tissue barrier that is able to shelter the underlying osseous structures and the osseointegration surrounding the implant body. The esthetics of a dental implant prosthesis depends on the health and stability of the peri-implant mucosa. Understanding of soft-tissue healing and maintenance around dental implants is paramount for implant success. This article discusses the soft-tissue interface, aspects of soft-tissue health, and esthetics during treatment planning and therapy. PMID- 20713271 TI - Dental implants after reconstruction with free tissue transfer. AB - The transfer of composite tissue flaps by microvascular techniques has become the standard for reconstructing complex defects of the oral and maxillofacial regions. Despite advances in these techniques, sites reconstructed by free tissue transfer (free flaps) are often compromised by scarring, bulky tissue, and altered architecture. Dental rehabilitation is often impossible without endosseous implants to aid in stabilization and retention of prostheses. The most commonly used free flaps, however, have significant shortcomings with regard to implant placement, prosthetics, and maintenance. This article describes some site development and prosthetic techniques that can be applied to improve outcomes when dental implants are used in conjunction with free flap reconstruction. PMID- 20713272 TI - Retrieval and analysis of explanted and in situ implants including bone grafts. AB - This article briefly explains the process of, and provides examples from, dental surgical implant device retrieval and analysis. Study results of three areas where unique and new information has been or is being published within professional journals are summarized. An analysis of past and current activities strongly supports opportunities for more in-depth investigations of explanted and postmortem-type specimens. It seems that these types of protocols will be supportive of more fully investigating the clinical applications for successful and unsuccessful outcomes of evolving tissue-engineered medical products as alternatives to some types of synthetic-origin implant devices. PMID- 20713273 TI - The 11th International Congress on Shoulder and Elbow Surgery. PMID- 20713274 TI - Locked intramedullary fixation vs plating for displaced and shortened mid-shaft clavicle fractures: a randomized clinical trial. AB - BACKGROUND: Recent literature supports surgical intervention for shortened, displaced, mid-shaft clavicle fractures. We present the results of a randomized clinical trial comparing locked intramedullary fixation and plate fixation for short, displaced, mid-shaft clavicle fractures. MATERIALS AND METHODS: Local ethical approval was obtained and power analysis and sample size calculations were performed prior to commencement. Patients randomized to 2 groups to be treated with either locked intramedullary fixation or plating. Patients regularly followed up to clinical and radiographic union. The primary outcome measure was the Constant score, secondary outcome measures included the Oxford shoulder score, union rate, and complication rates. RESULTS: Seventeen patients were randomized to locked intramedullary fixation and 15 randomized to plating. Mean age was 29.3 years. Mean follow-up was 12.4 months. There was no significant difference in either Constant scores (P = .365) or Oxford scores (P = .773). There was 100% union in both groups. In the intramedullary group, 1 case of soft tissue irritation settled after the pin removal; 1 pin backed out and was revised. Three superficial wound infections resulted in plate removal and 8 plates (53%) were removed. DISCUSSION: Intramedullary fixation has the theoretical advantage of preserving the periosteal blood supply, but carries the morbidity of pin removal. Clavicle plates are not routinely removed but require greater exposure and may compromise periosteal blood supply. CONCLUSION: Both locked intramedullary fixation and plating produce good functional results; however, metalwork may need to be removed as a second procedure. PMID- 20713275 TI - Bicipital groove morphology on MRI has no correlation to intra-articular biceps tendon pathology. AB - BACKGROUND: Multiple authors have debated the contribution of intertubercular groove morphology to biceps tendon pathology. It has been proposed that the shallow groove, combined with the supertubercular ridge of Meyer, predisposes patients to bicipital disease. In this study we hypothesized that there would be a correlation between bicipital groove morphology and the intraoperative finding of biceps pathology. METHODS: Seventy-five consecutive patients (average age of 63) undergoing arthroscopic rotator cuff repair surgery had their biceps tendons and intertubercular groove morphologies prospectively evaluated on closed MRI T1 axial cut images. The opening angle and medial wall angle of the bicipital groove was measured for each patient. At the time of surgery, the biceps tendon was classified as normal, inflamed, partially ruptured, or ruptured and the findings correlated to the bicipital groove measurements. RESULTS: The average opening angle was 81 degrees for normal biceps tendons and 77 degrees for torn biceps tendons. The average medial wall angle was 47 degrees for normal biceps tendons and 49 degrees for torn biceps tendons. Using Chi-square analysis, we found no statistically significant correlation between the bicipital groove average opening angle and medial wall angle on MRI and intraoperative biceps tendon pathology. CONCLUSION: This study does not support any correlation between intraarticular biceps tendon pathology and bicipital groove morphology. PMID- 20713276 TI - Intermediate biomechanical analysis of the effect of physiotherapy only compared with capsular shift and physiotherapy in multidirectional shoulder instability. AB - HYPOTHESIS: This study compared the kinematic parameters and activity pattern of muscles around the glenohumeral joint in multidirectional instability (MDI) treated by only physiotherapy and by capsular shift and physiotherapy, before and after treatment, to test the hypothesis that the surgery group would demonstrate better kinematic and muscle activity than the physiotherapy group. MATERIALS AND METHODS: The study comprised 32 patients with MDI treated with only physiotherapy, 19 patients with MDI treated by capsular shift and physiotherapy, and 50 healthy shoulders as the control group. The investigated kinematic parameters were the range of humeral elevation in the scapular plane, the scapulothoracic and glenohumeral angle, the scapulothoracic and glenohumeral rhythms, and relative displacement between the rotational centers of the humerus and the scapula. The muscle activity was modeled by the on-off pattern of muscles around the shoulder. RESULTS: Before treatment, increased relative displacement between the rotational centers of the scapula and the humerus and different regression lines were observed in MDI patients. The physiotherapy strengthened the muscles, but regression lines remained monolinear. Capsular shift and physiotherapy resulted in bilinear regression lines and normal relative displacement between the rotation center of scapula and humerus was restored. After surgery and physiotherapy the activity pattern of muscles was almost normal. CONCLUSION: The significant alterations in kinematic parameters in MDI patients cannot be completely normalized by physiotherapy only. After the capsular shift and postoperative physiotherapy, the bilinear regression lines (angulation at 60 degrees ), the normal relative displacement between the rotational centers of scapula and humerus, and the normal muscular activity pattern were restored to normal ranges and maintained for at least 4 years. PMID- 20713277 TI - Electromyographic activity of selected scapular stabilizers during glenohumeral internal and external rotation contractions. AB - HYPOTHESIS: An important synergistic relationship exists between the scapular stabilizers and the glenohumeral rotators. Information on the relative contribution of the scapular stabilizers to glenohumeral rotation would be useful for exercise prescription for overhead athletes and for patients with shoulder pathology. We hypothesized that the scapular stabilizers would be highly active during both maximal and submaximal internal and external rotation. MATERIALS AND METHODS: Eight healthy male volunteers (16 shoulders) performed internal and external glenohumeral rotation testing at maximal and submaximal intensities. They also performed a scapular retraction rowing exercise at maximal and submaximal levels. Electromyographic (EMG) signals were recorded from the infraspinatus, pectoralis major, serratus anterior, and middle trapezius. Values were compared among muscle groups, among individual muscles at different intensity levels, and among individual muscles at different points in the arc of motion. RESULTS: For submaximal glenohumeral internal rotation, activity in the scapular stabilizers was not different (P = .1-.83) from activity in the internal rotator throughout the range of motion. For the initial two-thirds of maximal internal rotation, middle trapezius activity and pectoralis major activity were higher (P < .05) than serratus anterior activity. For submaximal external rotation, activity in the scapular stabilizers during the middle phase of the motion was higher (P < .05) than activity in the external rotators. For maximal external rotation these differences were present throughout the motion with middle trapezius activity exceeding 100% maximal voluntary contraction. CONCLUSIONS: The scapular stabilizers functioned at a similar or higher intensity than the glenohumeral rotators during internal and external rotation. This highlights the importance of training the scapular stabilizers in upper extremity athletes and in patients with shoulder pathology. PMID- 20713278 TI - Instrumented Bone Preserving elbow prosthesis in rheumatoid arthritis: 2-8 year follow-up. AB - BACKGROUND: The aim of this study was to analyze the clinical and radiological results of elbow arthroplasty using the instrumented Bone Preserving (iBP) elbow prosthesis, which is the 6(th) iteration of the Kudo prosthesis, in patients with rheumatoid arthritis. METHODS: From December 1999 to August 2006, 20 total elbow replacements in 19 patients with rheumatoid arthritis were performed by 2 surgeons using the iBP. The humeral component is uncemented and the ulnar component cemented. There were 14 women and 5 men. The period of follow-up was 2 8 years, with a mean of 49 months. The mean age at time of operation was 62 years (range, 32-80). The Larsen grade and The Mayo Elbow Performance Score were used. Possible radiolucent lines or displacement of the components were evaluated yearly. RESULTS: The preoperative radiographs showed that all of the involved elbows were in grade 3-5 with an average of 4.1. All patients had a poor elbow before operation. Two elbows were moderately unstable. Three complications occurred: 1 intraoperative fracture of the medial condyl, 1 postoperative dislocation, and 1 persistent sensory ulnar neuropathy. After surgery, at the last follow-up, 3 patients had fair results, 5 good, and 12 excellent. In 6 cases, radiographic loosening of the ulnar component was observed without any clinical symptoms; none around the humeral component. CONCLUSION: The iBP elbow prosthesis in patients with rheumatoid arthritis shows good to excellent clinical results, despite radiolucency around the cemented ulnar component in some cases. PMID- 20713279 TI - Delayed treatment of elbow pain and dysfunction following Essex-Lopresti injury with metallic radial head replacement: a case series. AB - BACKGROUND: Chronic longitudinal radioulnar dissociation has been associated with unpredictable and generally unfavorable outcomes. Metallic radial head replacement may address this treatment deficiency. METHODS: Eight patients were treated with a metallic radial head replacement for chronic longitudinal radioulnar dissociation. The average treatment delay was 3.3 years. All eight patients were seen for a clinical and radiographic assessment. RESULTS: Five of the 8 failed after a mean of 3 years (range, 1-5.7). Revision to bipolar metallic radial head replacement was successful in the short term in 2 of 3 that failed from aseptic loosening. One of 2 failures due to painful radiocapitellar arthritis was salvaged with a capitellar replacement. DISCUSSION: Reconstruction for symptoms following an Essex-Lopresti injury remains problematic. A metallic radial head implant appears to be an effective adjunct, but not a perfect solution in all patients. Recognition of the negative impact of residual lateral ulnar collateral ligament laxity is an important observation and should be specifically addressed with the reconstructive procedure. CONCLUSION: Metallic monoblock radial head replacement did not reliably address the functional deficiency from chronic radioulnar dissociation primarily due to malalignment and implant loosening. A cemented bipolar radial head implant may provide a better alternative as a long-term solution. Regardless, ligamentous integrity at the elbow should also be addressed at the time of the reconstruction. PMID- 20713280 TI - Rotator cuff tears with cervical radiculopathy. PMID- 20713281 TI - LigAlign: flexible ligand-based active site alignment and analysis. AB - Ligand-based active site alignment is a widely adopted technique for the structural analysis of protein-ligand complexes. However, existing tools for ligand alignment treat the ligands as rigid objects even though most biological ligands are flexible. We present LigAlign, an automated system for flexible ligand alignment and analysis. When performing rigid alignments, LigAlign produces results consistent with manually annotated structural motifs. In performing flexible alignments, LigAlign automatically produces biochemically reasonable ligand fragmentations and subsequently identifies conserved structural motifs that are not detected by rigid alignment. PMID- 20713282 TI - Three dimensional medical imaging: from dream to reality. PMID- 20713283 TI - Protein for preterm infants: how much is needed? How much is enough? How much is too much? AB - Preterm infants require considerably more protein to achieve normal intrauterine growth rates than is commonly fed to them during their first postnatal days. Continuing protein nutrition to maintain normal growth rates often is not achieved until several weeks after birth. Most very preterm infants do not receive the protein necessary to produce the 2-3 kilograms of body mass over a 12 16 week period of NICU care and, as a result, end up growth restricted by term, in lean body mass more than fat. This article reviews the requirements for protein and amino acids necessary to achieve normal growth and development of preterm infants. Protein requirements at 24-30 weeks' gestation are as high as 4 g/kg/day, decreasing to 2-3 g/kg/day by term. Individual amino acids are important not just as building blocks for protein synthesis and net protein balance, but also as essential signalling molecules for normal cellular function. Perhaps most importantly, brain growth and later life cognitive function are directly related to protein intake during the neonatal period in preterm infants. Data are reviewed that document successful increase in protein balance in preterm infants achieved with higher than usual rates of amino acid and protein nutrition, noting that positive protein balance requires at least 1.5 g/kg/day, but there still is increased protein balance up to 4 g/kg/day. Further research is necessary to determine optimal amounts and mixtures of protein and amino acids for both intravenous and enteral feeding to improve growth, development, and functional capacity of preterm infants. PMID- 20713284 TI - Clinical manifestations of symptomatic intracranial hemorrhage in term neonates: 18 years of experience in a medical center. AB - BACKGROUND: Intracranial hemorrhage (ICH) is an uncommon but important cause of morbidity and mortality in term neonates. We conducted a retrospective analysis of the clinical characteristics and developmental outcomes of symptomatic ICH in term neonates. METHODS: A retrospective chart review was conducted of all term neonates (less than 1 month old) diagnosed with ICH and admitted to the neonatal intensive care unit of Kaohsiung Chang Gung Hospital from December 1991 to December 2008. Demographic characteristics, mode of delivery, laboratory data, clinical presentation, and developmental status were recorded. RESULTS: Data for 24 term neonates (17 boys and 7 girls) with a diagnosis of ICH were collected for analysis. The clinical manifestations of ICH included anemia (13/24, 54%), seizure (11/24, 46%), cyanosis (7/24, 29%), tachypnea (5/24, 21%), fever (1/24, 4%), hypothermia (1/24, 4%), and poor feeding (1/24, 4%). Age at symptom onset ranged from 2 hours to 11 days following birth. The most common type of ICH was subdural hemorrhage. All ICHs resolved, except in one infant, who died from hypoxicischemic encephalopathy at 25 days. Ten children with symptomatic ICH were reported to have normal development, while the remainder (13/23, 57%) showed developmental delays or disabilities. CONCLUSION: Unexplained anemia, seizure, and cyanosis were the major presenting signs in infants with symptomatic ICH. A diagnosis of ICH should be considered in term neonates who present with one or more of these signs. Although the mortality in term infants with symptomatic ICH was low, more than half. PMID- 20713285 TI - Effects of flow rate on delivery of bubble continuous positive airway pressure in an in vitro model. AB - BACKGROUND: There has been concern over the effect of vigorous bubbling on the delivery pressure during the operation of the bubble nasal continuous positive airway pressure (CPAP) system. We investigated the relationship between intra tubing pressure changes and flow rates in a closed bubble CPAP system in vitro. METHODS: Using an experimental (in vitro) model, the distal connecting tube of the CPAP system was immersed under the water seal to a depth of 5 cm. Sixteen different flow rates, ranging from 2 L/min to 20 L/min, were tested. The procedure was repeated 10 times at each flow rate, and the intra-tubing pressure was recorded. RESULTS: The intra-tubing pressure within the model increased as the air flow rates were adjusted from 2 L/min to 20 L/min. The relationship was represented by the following equation, pressure (cmH(2)O) = 5.37 + 0.15 x flow rate (L/min) (R(2) = 0.826, p < 0.001). CONCLUSION: These results demonstrated that the intra-tubing pressure in a bubble CPAP system was highly correlated with flow rate in vitro. PMID- 20713287 TI - Role of multi-slice and three-dimensional computed tomography in delineating extracardiac vascular abnormalities in neonates. AB - BACKGROUND: Recent advances in multi-slice computed tomography (MSCT) and three dimensional computed tomography (3D CT) provide good-resolution images and short scan time for complete diagnosis of congenital heart disease (CHD). In the present study, we found that MSCT rapidly provides clinically relevant information for diagnosing extracardiac vascular anatomy in neonates with CHD. It is less invasive, necessitating only minimum or no sedation and a relatively small amount of contrast material. These advantages are crucial, especially for critically ill neonates. METHODS: Between January 2007 and December 2008, MSCT scans were conducted on 41 neonates who were admitted to our neonatal intensive care unit. All the neonates were suspected to have complex CHD after an initial echocardiography examination. The scans were focused on detecting extracardiac vascular anatomy and abnormalities. All the image data sets were sent to image processing workstations for multiplanar interactive viewing and 3D reconstruction. RESULTS: High-resolution MSCT scan images were obtained from 41 patients. Reported indications and findings of extracardiac abnormalities and related structural anatomy pertaining to congenital heart disease from MSCT and 3D CT findings were confirmed by clinical and surgical findings by a team of multidisciplinary congenital heart disease specialists. CONCLUSION: Based on clinical and surgical confirmation of the MSCT scan results from a multidisciplinary congenital heart disease specialist team, we concluded that adequate information on CHD, specifically that regarding extracardiac abnormalities of the anatomy, can be obtained and MSCT can be used to replace cardiac catheterization. PMID- 20713286 TI - Acute pathophysiological effects of intratracheal instillation of budesonide and exogenous surfactant in a neonatal surfactant-depleted piglet model. AB - BACKGROUND: Chronic lung disease continues to be a major complication in premature infants with severe respiratory distress syndrome (RDS). This is despite having advanced ventilatory care, prenatal corticosteroids, and postnatal surfactant therapies. The combined use of intratracheal corticosteroids and surfactant may not only recruit the lungs, but also alleviate pulmonary inflammation in severe RDS. METHODS: Fifteen newborn piglets received repeated pulmonary saline lavage to induce surfactant-depleted lungs, mimicking neonatal RDS. They were randomly divided into three groups: control group receiving no treatment; surfactant (Surf) group, treated with standard intratracheally instilled surfactant (100 mg/kg); and Budesonide plus surfactant (Bude + Surf) group, treated with intratracheally administered mixed suspension of budesonide (0.5 mg/kg) and surfactant (100 mg/kg). Blood samples were taken every 30 minutes for 4 hours. Lung tissue was examined after the experiment. RESULTS: Significantly better oxygenation with higher PaO(2) and alveolar-arterial oxygen difference was noted in the Surf and Bude + Surf groups, compared with the control group (p < 0.05), but there were no significant differences between the Surf and Bude + Surf groups. Pulmonary histologic damage was also markedly alleviated in both the Surf and Bude + Surf groups, compared with the control group, and lung injury scores were significantly decreased in the Surf and Bude + Surf groups, compared with the control group (p < 0.05). CONCLUSIONS: Intratracheal instillation of surfactant or surfactant plus budesonide can improve oxygenation and pulmonary histologic outcome in neonatal surfactant depleted lungs. The additional use of budesonide does not disturb the function of the exogenous surfactant. Intratracheal administration of a corticosteroid combined with surfactant may be an effective method for alleviating local pulmonary inflammation in severe RDS. PMID- 20713288 TI - Relationship between birth weight and time of first deciduous tooth eruption in 143 consecutively born infants. AB - BACKGROUND: Deciduous teeth play an important role in the proper alignment, spacing and occlusion of permanent teeth. The calcification of deciduous teeth begins during the fourth prenatal month, and calcification of all deciduous teeth begin by the end of the sixth prenatal month. The eruption date varies and is genetically influenced. Delayed eruption of deciduous teeth, especially the first teeth, causes nutritional problems for the infants. It also results in parental concerns. In this study, we compared the timing of eruption of the first deciduous teeth in infants in relation to their birth weight. METHODS: A total of 143 infants born at Shariati Hospital in Tehran from December 2004 to December 2005 were included in the study. Data on sex, birth weight, gestational age, and time of first tooth eruption were collected. RESULTS: The mean birth weight was 3220 +/- 420 g with 5.5% of infants weighing less than 2500 g, and 19.9% weighing more than 3500 g. Patients were monitored weekly from the third month of age until the time of first tooth eruption. The mean age of first tooth eruption was 7.68 +/- 1.84 months. CONCLUSION: There was a negative linear correlation between the time of first deciduous tooth eruption and birth weight, suggesting that delayed tooth eruption may be related to lower birth weight. PMID- 20713289 TI - Calcinosis cutis complicated by compartment syndrome following extravasation of calcium gluconate in a neonate: a case report. AB - Hypocalcemia most frequently occurs in premature neonates. It is usually treated by intravenous (iv) calcium supplementation. However, complications caused by extravasation of iv calcium gluconate include localized soft tissue calcification, necrosis, cellulitis, osteomyelitis, and even compartment syndrome. We present a rare case of iatrogenic calcinosis cutis complicated by compartment syndrome secondary to extravasation of iv calcium gluconate in a neonate. Emergent fasciotomy was performed twice for decompression of compartment syndrome. Histologic findings revealed necrosis and calcification. Appropriate antibiotics were administered to control secondary infection. To the best of our knowledge, there were no previous case reports of calcinosis cutis with compartment syndrome in infants. Although iatrogenic calcinosis cutis is generally a benign entity, the early recognition of the presentation of extravasation of calcium gluconate is important to avoid severe complications and possible medical malpractice disputes. This report aims to raise doctors' awareness of the presentation, course, and management of this relatively rare iatrogenic complication. PMID- 20713290 TI - Late-onset group B streptococcal meningitis in a neonate with early antibiotic prophylaxis. AB - An otherwise healthy female baby who had received early postnatal antibiotic prophylaxis because of maternal vaginal group B streptococcal (GBS) colonization died of late-onset GBS meningitis. GBS was isolated from blood and cerebrospinal fluid. Genotyping using pulsed-field gel electrophoresis confirmed that the GBS isolates from the patient were identical to those from her mother's vagina. Susceptibility tests demonstrated no antibiotic resistance. This report provides additional microbiologic evidence indicating that early postnatal antibiotic prophylaxis is not effective in preventing late-onset GBS infections in neonates born to mothers with GBS colonization. PMID- 20713291 TI - Neonate with severe heart failure related to vein of Galen malformation. AB - We report a full-term female neonate who presented with respiratory distress and severe heart failure soon after birth. Heart failure secondary to perinatal infection was initially suspected. Subsequent echocardiography revealed aortic runoff, which led to consideration of an intracranial vascular abnormality. Ultrasound and magnetic resonance imaging of the brain confirmed a diagnosis of vein of Galen aneurismal malformation (VGAM). Endovascular coil embolization of the vascular anomaly was performed, resulting in improvement of heart failure. VGAM should be considered in the differential diagnosis of neonatal congestive heart failure with a structurally normal heart. Urgent endovascular embolization and aggressive medical treatment of heart failure improve prognosis in neonatal VGAM. PMID- 20713292 TI - Neonatal intracranial aneurysm rupture treated by endovascular management: a case report. AB - Pediatric intracranial aneurysm rupture is rare, and is traditionally managed by surgical clipping. To the best of our knowledge, endovascular embolization of aneurysms in neonates has not previously been reported in Taiwan. We report a 9 day-old boy with intracranial aneurysms who underwent endovascular embolization, representing the youngest reported case in Taiwan. The 9-day-old boy presented with non-specific symptoms of irritable crying, seizure and respiratory distress. Computed tomography disclosed intraventricular hemorrhage, subarachnoid hemorrhage and focal intracranial hemorrhage around the right cerebellum. Subsequent computed tomographic angiography showed two sequential fusiform aneurysms, measuring 3 mm, located in the right side posterior inferior cerebellar artery (PICA). The patient underwent endovascular embolization because of the high risk of aneurysm re-rupture and the impossibility of surgical clipping due to the fusiform nature of the aneurysms. A postembolization angiogram revealed complete obliteration of the right distal PICA and proximal aneurysm. The distal PICA aneurysm was revascularized from the collateral circulation, but demonstrated a slow and delayed filling pattern. The patient's condition remained stable over the following week, and he was discharged without anticonvulsant therapy. No significant developmental delay was noted at follow-up at when he was 3 months old. This case emphasizes the need for clinical practitioners to consider a diagnosis of intracranial hemorrhage in neonates with seizure and increased intracranial pressure. Neonatal intracranial aneurysms can be treated safely by endovascular treatment. PMID- 20713293 TI - Effects of method of uterine repair on surgical outcome of cesarean delivery. AB - OBJECTIVE: To compare the rates of intraoperative and postoperative complications of uterine repair when performed in situ or extra-abdominally following cesarean delivery. METHODS: In this prospective randomized study 4925 women who underwent cesarean delivery were randomly assigned to in situ (n = 2462) or extra-abdominal (n = 2463) uterine repair (group 1 and group 2, respectively). The study compares drop in hemoglobin concentration (as a measure of intraoperative blood loss). It also compares operating time, time to return of bowel sound, and duration of hospitalization as well as rates of uterine atony, blood transfusion, intraoperative complications, additional use postoperative analgesics, endometritis, and wound infection. RESULTS: Uterine atony developed in 96 women (3.8%) in group 1 and 226 women (9.1%) in group 2 (P = 0.001). Moreover, the operating time and the time to return of bowel sound were shorter and the rates of both additional use of postoperative analgesics and wound infection were lower in group 1 (P = 0.001, P = 0.002, P = 0.001, and P = 0.003, respectively). CONCLUSION: Fewer cases of uterine atony, a shorter operating time, a faster return of bowel function, a lesser need for postoperative analgesics, and lower rates of additional use of postoperative analgesics and wound infections suggest that in-situ uterine repair ought to be preferred to extra-abdominal uterine repair following cesarean delivery. PMID- 20713294 TI - Outcomes and causes of death in children on home mechanical ventilation via tracheostomy: an institutional and literature review. AB - OBJECTIVE: To describe outcomes and causes of death in children on chronic positive-pressure ventilation via tracheostomy. STUDY DESIGN: We conducted a retrospective observational cohort analysis of 228 children enrolled in an university-affiliated home mechanical ventilation (HMV) program over 22 years (990 person-years). Cumulative incidences of survival and liberation from HMV are presented. Time-to-events were compared by reason for chronic respiratory failure (CRF) and age and date of HMV initiation with Kaplan-Meier and Cox regression analyses. Circumstances of death are described. RESULTS: Of our cohort, 47 of 228 children died, and 41 children were liberated from HMV. The 5-year cumulative incidences of survival and liberation were 80% and 24%, respectively. Being placed on HMV for chronic pulmonary disease was independently associated with liberation from HMV (hazard ratio, 7.38; 95% CI, 3.0-18.2; P < .001). Neither age nor reasons for CRF were associated with shortened survival. Progression of underlying condition accounted for only 34% of deaths; 49% of deaths were unexpected. CONCLUSION: Most children on HMV survive or were weaned off. However, a sizable number of children in our cohort died, and many deaths were unexpected and from causes not directly related to their primary reason for CRF. PMID- 20713295 TI - Cuban healthcare providers in Venezuela: a case study. AB - Approximately 31,000 Cuban healthcare providers reside in Venezuela as part of an initiative to increase Venezuelans' access to health care. The concept began in 1999 as part of the new constitution, and has grown steadily to include 6000 clinics, health promotion and prevention programmes, an integrated healthcare system, and a vision to train and deploy community public health physicians selected from and trained within the neighbourhood. In the case study described herein, physician-patient consultations increased from 3.5 million to 17 million, and the numbers of primary care physicians, nurses and dentists increased dramatically. Furthermore, in Caracas, there has been a 30% reduction in the use of emergency rooms at public hospitals. Estimates are provided for preventive services and potential lives saved. As health care is a politically-laden issue in many countries, all approaches to reducing healthcare disparities are worth analysing for their potential contributions to population health improvement. PMID- 20713296 TI - Control of start-up and operation of anaerobic biofilm reactors: an overview of 15 years of research. AB - Anaerobic biofilm reactors have to be operated in a way that optimizes on one hand the start-up period by a quick growth of an active biofilm, on the other hand the regular operation by an active control of the biofilm to avoid diffusion limitations and clogging. This article is an overview of the research carried out at INRA-LBE for the last 15 years. The start-up of anaerobic biofilm reactors may be considerably shortened by applying a short inoculation period (i.e. contact between the inoculum and the support media). Then, the increase of the organic loading rate should be operated at a short hydraulic retention time and low hydrodynamic constraints in order to favor biofilm growth. After the start-up period, biofilm growth should be controlled to maintain a high specific activity and prevent clogging. This can be done in particulate biofilm systems by using hydrodynamics to increase or decrease shear forces and attrition but is much more difficult in anaerobic fixed bed reactors. PMID- 20713297 TI - Background bisphenol A in experimental materials and its implication to low-dose in vitro study. AB - In vitro low-dose studies are important to understand the mechanisms of bisphenol A (BPA) action. BPA doses used in current in vitro studies varied considerably, and doses as low as 10(-15)M have been reported. The actual doses of BPA used in the in vitro low-dose studies were rarely checked analytically, and the background BPA levels in experimental materials, which will determine the lowest BPA dose to be used, should be investigated or considered. In this study, the background BPA levels in various materials typically used in in vitro low-dose studies for BPA were investigated. Background BPA levels from the use of disposable pipettes and pipette tips were low (<0.20 ng mL(-1) or 0.88 nM). BPA was also detected in several commercial buffer solutions at levels close to the method limit of quantification (LOQ) (0.02 ng mL(-1); 0.088 nM). However, BPA was detected in all cell culture media obtained from various sources at levels ranging from 0.080 to 4.26 ng mL(-1) (or 0.35 to 19 nM) with an average of 0.83 ng mL(-1) (3.5 nM). We suggest that culture media used for low-dose BPA studies should be analysed for background BPA levels prior to use, and the medium with the lowest BPA levels should be used. PMID- 20713298 TI - Statistical estimate of mercury removal efficiencies for air pollution control devices of municipal solid waste incinerators. AB - Although representative removal efficiencies of gaseous mercury for air pollution control devices (APCDs) are important to prepare more reliable atmospheric emission inventories of mercury, they have been still uncertain because they depend sensitively on many factors like the type of APCDs, gas temperature, and mercury speciation. In this study, representative removal efficiencies of gaseous mercury for several types of APCDs of municipal solid waste incineration (MSWI) were offered using a statistical method. 534 data of mercury removal efficiencies for APCDs used in MSWI were collected. APCDs were categorized as fixed-bed absorber (FA), wet scrubber (WS), electrostatic precipitator (ESP), and fabric filter (FF), and their hybrid systems. Data series of all APCD types had Gaussian log-normality. The average removal efficiency with a 95% confidence interval for each APCD was estimated. The FA, WS, and FF with carbon and/or dry sorbent injection systems had 75% to 82% average removal efficiencies. On the other hand, the ESP with/without dry sorbent injection had lower removal efficiencies of up to 22%. The type of dry sorbent injection in the FF system, dry or semi-dry, did not make more than 1% difference to the removal efficiency. The injection of activated carbon and carbon-containing fly ash in the FF system made less than 3% difference. Estimation errors of removal efficiency were especially high for the ESP. The national average of removal efficiency of APCDs in Japanese MSWI plants was estimated on the basis of incineration capacity. Owing to the replacement of old APCDs for dioxin control, the national average removal efficiency increased from 34.5% in 1991 to 92.5% in 2003. This resulted in an additional reduction of about 0.86Mg emission in 2003. Further study using the methodology in this study to other important emission sources like coal-fired power plants will contribute to better emission inventories. PMID- 20713299 TI - Cost-effectiveness of using human papillomavirus 16/18 genotype triage in cervical cancer screening. AB - OBJECTIVE: Testing for human papillomavirus (HPV) 16 and 18 genotypes, which are known to cause approximately 65-70% of invasive cervical cancer cases, may allow clinicians to identify women at highest risk for underlying cervical intraepithelial neoplasia missed by Pap cytology. Our objective was to determine the cost-effectiveness of adding HPV-16 and 18 genotype triage to current cervical cancer screening strategies in the United States. METHODS: We developed a lifetime Markov model to assess the cost-effectiveness of the following cervical cancer screening algorithms: (1) liquid-based cytology (LBC), (2) LBC+HPV triage, (3) HPV+LBC triage, (4) co-screening, (5) co-screening+HPV genotyping, and (6) HPV only+HPV genotyping. Costs were estimated from a payer perspective in 2007 U.S. dollars. Outcome measures included lifetime risk of cervical cancer, quality-adjusted life years saved (QALYs), and incremental cost effectiveness ratios (ICERs). RESULTS: In our model, the use of HPV genotyping strategies prevented 51-73 deaths per 100,000 women screened compared to screening using LBC followed by HPV triage and 4-26 deaths compared to co screening with LBC and high-risk HPV. Use of HPV genotyping to triage all high risk HPV-positive women every three years had an ICER of $34,074 per QALY compared to HPV and LBC co-screening. HPV genotyping with co-screening was the most effective strategy and had an ICER of $33,807 per QALY compared to HPV genotyping for all high-risk HPV-positive women. CONCLUSION: The addition of HPV 16 and -18 genotype triage to HPV and LBC co-screening was a cost-effective screening strategy in the United States. PMID- 20713300 TI - Are rhinoviral proteinases responsible for mixed T(H)1 and T(H)2 immunity in chronic obstructive pulmonary disease? PMID- 20713303 TI - Rare earth elements in fly ashes created during the coal burning process in certain coal-fired power plants operating in Poland - Upper Silesian Industrial Region. AB - The subject of the study covered volatile ashes created during hard coal burning process in ash furnaces, in power plants operating in the Upper Silesian Industrial Region, Southern Poland. Coal-fired power plants are furnished with dust extracting devices, electro precipitators, with 99-99.6% combustion gas extracting efficiency. Activity concentrations ofTh-232, Ra-226, K-40, Ac-228, U 235 and U-238 were measured with gamma-ray spectrometer. Concentrations of selected rare soil elements (La, Ce, Nd, Sm, Y, Gd, Th, U) were analysed by means of instrumental neutron activation analysis (INAA). Mineral phases of individual ash particles were identified with the use of scanning electron microscope equipped with EDS attachment. Laser granulometric analyses were executed with the use of Analyssette analyser. The activity of the investigated fly-ash samples is several times higher than that of the bituminous coal samples; in the coal, the activities are: 226Ra - 85.4 Bq kg(-1), 40 K-689 Bq kg(-1), 232Th - 100.8 Bq kg( 1), 235U-13.5 Bq kg(-1), 238U-50 Bq kg(-1) and 228Ac - 82.4 Bq kg(-1). PMID- 20713304 TI - Confronting maternal mortality, controlling birth in Nepal: the gendered politics of receiving biomedical care at birth. AB - One way of reducing maternal mortality in developing countries is to ensure that women have a referral system at the local level that includes access to emergency obstetric care. Using a 13-month ethnographic study from 2003 to 2005 of women's social positions and maternal health in a semi-urban community of Hindu-caste women in the Kathmandu Valley, this paper identifies impediments to receiving obstetric care in a context where the infrastructure and services are in place. As birth in Nepal predominantly takes place at home, this paper identifies the following areas for potential improvement in order to avoid the loss of women's lives during childbirth: the frequency of giving birth unaided, minimal planning for birth or obstetric complications, and delayed responses at the household level to obstetric emergencies. Focusing particularly on the last item, this study concludes that women do not have the power to demand biomedical services or emergency care, and men still viewed birth as the domain of women and remained mostly uninvolved in the process. As the cultural construction of birth shifts from a "natural" phenomenon that did not require human regulation toward one that is located within the domain of biomedical expertise and control, local acceptance of a biomedical model does not necessarily lead to the utilization of services if neither women nor men are in a culturally-defined position to act. PMID- 20713302 TI - The prostaglandin D2 receptor CRTH2 is important for allergic skin inflammation after epicutaneous antigen challenge. AB - BACKGROUND: Cutaneous prostaglandin (PG) D2 levels increase after scratching. Chemoattractant receptor-homologous molecule expressed on receptor on T(H)2 cells (CRTH2) mediates chemotaxis to PGD2 and is expressed on T(H)2 cells and eosinophils, which infiltrate skin lesions in patients with atopic dermatitis. OBJECTIVE: We sought to examine the role of CRTH2 in a murine model of atopic dermatitis. METHODS: CRTH2(-/-) mice and wild-type control animals were epicutaneously sensitized by means of repeated application of ovalbumin (OVA) to tape-stripped skin for 7 weeks and then challenged by means of OVA application to tape-stripped previously unsensitized skin for 1 week. Skin histology was assessed by means of hematoxylin and eosin staining and immunohistochemistry. Cytokine mRNA expression was examined by means of quantitative RT-PCR. Levels of PGD2, antibody, and cytokines were measured by means of ELISA. RESULTS: PGD2 levels significantly increased in skin 24 hours after tape stripping, although not in skin subjected to repeated sensitization with OVA. Allergic skin inflammation developed normally at sites of chronic epicutaneous sensitization with OVA in CRTH2(-/-) mice but was severely impaired in previously unsensitized skin challenged with OVA, as evidenced by significantly decreased skin infiltration with eosinophils and CD4(+) cells and impaired T(H)2 cytokine mRNA expression. Impaired skin inflammation at sites of acute OVA challenge in CRTH2( /-) mice was not due to an impaired systemic response to epicutaneous sensitization because OVA-specific IgG1 and IgE antibody levels and OVA-driven splenocyte secretion of cytokines in these mice were comparable with those seen in wild-type control animals. CONCLUSIONS: CRTH2 promotes allergic skin inflammation in response to cutaneous exposure to antigen in previously sensitized mice. PMID- 20713305 TI - Medical image analysis with artificial neural networks. AB - Given that neural networks have been widely reported in the research community of medical imaging, we provide a focused literature survey on recent neural network developments in computer-aided diagnosis, medical image segmentation and edge detection towards visual content analysis, and medical image registration for its pre-processing and post-processing, with the aims of increasing awareness of how neural networks can be applied to these areas and to provide a foundation for further research and practical development. Representative techniques and algorithms are explained in detail to provide inspiring examples illustrating: (i) how a known neural network with fixed structure and training procedure could be applied to resolve a medical imaging problem; (ii) how medical images could be analysed, processed, and characterised by neural networks; and (iii) how neural networks could be expanded further to resolve problems relevant to medical imaging. In the concluding section, a highlight of comparisons among many neural network applications is included to provide a global view on computational intelligence with neural networks in medical imaging. PMID- 20713306 TI - Physical proximity in anticipation of meeting someone with schizophrenia: the role of explicit evaluations, implicit evaluations and cortisol levels. AB - It has been suggested that the study of the stigma of mental illness should include more behavioral measures and further investigation of the possible importance of implicit evaluations in predicting responses to those with such illness. In the current paper, we report a study testing the relationship of implicit and explicit evaluations to physical proximity and cortisol levels in anticipation of meeting someone with schizophrenia. The results showed that both explicit evaluations and cortisol levels independently predicted physical proximity. Implicit evaluations were not related to either physical proximity or cortisol levels. The findings suggest that there are aspects of emotional response to those with mental illness that are not reflected in explicit measures of evaluation and that these, as well as explicit responses, can contribute to the prediction of behavior. PMID- 20713307 TI - Healthcare waste management practices and risk perceptions: findings from hospitals in the Algarve region, Portugal. AB - The management of healthcare wastes is receiving greater attention because of the risks to both human health and the environment caused by inadequate waste management practices. In that context, the objective of this study was to analyse the healthcare waste management practices in hospitals of the Algarve region, Portugal, and in particular to assess the risk perceptions of, and actual risk to, healthcare staff. The study included three of the six hospitals in the region, covering 41% of the bed capacity. Data were collected via surveys, interviews, and on-site observations. The results indicate that waste separation is the main deficiency in healthcare waste practice, with correct separation being positively related to the degree of daily contact with the waste. Risk perceptions of healthcare staff show the highest levels for the environment (4.24) and waste workers (4.08), and the lowest for patients (3.29) and visitors (2.80), again being positively associated with the degree of daily contact. Risk perceptions of healthcare staff are related to the difficulties of the correct separation of wastes and the lack of knowledge concerning the importance of that separation. The risk of infection with needlesticks/sharps is higher during patient care than during waste handling, and the frequency of these injuries is related to the daily tasks of each healthcare group (doctors, nurses, and housekeepers). Furthermore, legislative definitions and classifications of healthcare wastes appear to have conditioned the management practices associated with, and the perceptions of risk concerning, healthcare wastes. PMID- 20713308 TI - Production and characterization of a biodegradable poly (hydroxybutyrate-co hydroxyvalerate) (PHB-co-PHV) copolymer by moderately haloalkalitolerant Halomonas campisalis MCM B-1027 isolated from Lonar Lake, India. AB - Several microorganisms produce polyhydroxyalkanoates (PHA). They are accumulated intracellularly as energy storage compounds. The PHAs are of interest because of their potential in biomedical applications. Halophilic bacteria and archaea are known to produce polyhydroxybutyrate (PHB). This paper describes production of a biodegradable copolymer, PHB-co-PHV by a moderately haloalkalitolerant Halomonas campisalis, isolated from Lonar Lake, India. The production of PHA was in the range of 45-81% on dry cell weight basis when the organism was grown in a production medium containing 1% (w/v) maltose and 0.1% (w/v) yeast extract, at pH ranging from 6 to 9 with an inoculum density of 10(5)-10(7) cells/ml of medium, for incubation period of 15-30 h and at 37 degrees C. The polymer produced by the organism is a hydroxyester with molecular weight of 1.3014 x 10(6). Its melting temperature was 171 degrees C. The (1)H NMR analysis revealed that the polymer was a copolymer of PHB-co-PHV. This could be achieved by providing simple carbon source viz. maltose. PMID- 20713309 TI - Esterification activity and conformation studies of Burkholderia cepacia lipase in conventional organic solvents, ionic liquids and their co-solvent mixture media. AB - In this work, experiments were carried out to evaluate the esterification activity and conformation of lipase from Burkholderia cepacia in the selected conventional organic solvents, ionic liquids and their co-solvent mixture media. The results revealed that the activity of esterification of B. cepacia lipase was mostly highest in co-solvent mixture of ionic liquids-organic solvents, followed by conventional organic solvents and ionic liquids. Hence, co-solvent mixture was a high-effective strategy to enhance the activity of B. cepacia lipase for non aqueous enzymology reaction. Conformational studies via circular dichroism spectroscopy indicated that the secondary structure of B. cepacia lipase was variant in the above-mentioned media, especially the content of alpha-helix, which was probably responsible for lipase activity difference. PMID- 20713310 TI - MECs use bacteria on the anode, and either chemical catalysts or bacteria on the cathode. Preface. PMID- 20713311 TI - Bile acid toxicity structure-activity relationships: correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A). AB - The molecular mechanisms and interactions underlying bile acid cytotoxicity are important to understand for intestinal and hepatic disease treatment and prevention and the design of bile acid-based therapeutics. Bile acid lipophilicity is believed to be an important cytotoxicity determinant but the relationship is not well characterized. In this study we prepared new azido and other lipophilic BAs and altogether assembled a panel of 37 BAs with good dispersion in lipophilicity as reflected in RPTLC RMw. The MTT cell viability assay was used to assess cytotoxicity over 24 h in the HET-1A cell line (oesophageal). RMw values inversely correlated with cell viability for the whole set (r2=0.6) but this became more significant when non-acid compounds were excluded (r2=0.82, n=29). The association in more homologous subgroups was stronger still (r2>0.96). None of the polar compounds were cytotoxic at 500 microM, however, not all lipophilic BAs were cytotoxic. Notably, apart from the UDCA primary amide, lipophilic neutral derivatives of UDCA were not cytotoxic. Finally, CDCA, DCA and LagoDCA were prominent outliers being more toxic than predicted by RMw. In a hepatic carcinoma line, lipophilicity did not correlate with toxicity except for the common naturally occurring bile acids and their conjugates. There were other significant differences in toxicity between the two cell lines that suggest a possible basis for selective cytotoxicity. The study shows: (i) azido substitution in BAs imparts lipophilicity and toxicity depending on orientation and ionizability; (ii) there is an inverse correlation between RMw and toxicity that has good predictive value in homologous sets; (iii) lipophilicity is a necessary but apparently not sufficient characteristic for BA cytocidal activity to which it appears to be indirectly related. PMID- 20713312 TI - Immunisation of pigs with a major envelope protein sub-unit vaccine against porcine reproductive and respiratory syndrome virus (PRRSV) results in enhanced clinical disease following experimental challenge. AB - Disease exacerbation was observed in pigs challenged with virulent porcine reproductive and respiratory syndrome virus (PRRSV) following immunisation with a recombinant GP5 sub-unit PRRSV vaccine (rGP5) produced in E. coli. Eighteen animals were divided into three experimental groups: group A were immunised twice IM with rGP5, 21 days apart; group B acted as positive controls (challenged but not immunised); and group C were negative controls. Pigs in groups A and B were challenged 21 days after the second immunisation of the group A animals. Following challenge, three pigs given rGP5 exhibited more severe clinical signs than the positive controls, including respiratory distress and progressive weight loss. Although not statistically significant, the more severe disease exhibited by group A animals may suggest previous immunisation as a contributory factor. The mechanisms of these findings remain unclear and no association could be established between the severity of disease, non-neutralising antibody concentrations and tissue viral loads. PMID- 20713313 TI - Task-based performance analysis of FBP, SART and ML for digital breast tomosynthesis using signal CNR and Channelised Hotelling Observers. AB - We assess the performance of filtered backprojection (FBP), the simultaneous algebraic reconstruction technique (SART) and the maximum likelihood (ML) algorithm for digital breast tomosynthesis (DBT) under variations in key imaging parameters, including the number of iterations, number of projections, angular range, initial guess, and radiation dose. This is the first study to compare these algorithms for the application of DBT. We present a methodology for the evaluation of DBT reconstructions, and use it to conduct preliminary experiments investigating trade-offs between the selected imaging parameters. This investigation includes trade-offs not previously considered in the DBT literature, such as the use of a stationary detector versus a C-arm imaging geometry. A real breast CT volume serves as a ground truth digital phantom from which to simulate X-ray projections under the various acquisition parameters. The reconstructed image quality is measured using task-based metrics, namely signal CNR and the AUC of a Channelised Hotelling Observer with Laguerre-Gauss basis functions. The task at hand is the detection of a simulated mass inserted into the breast CT volume. We find that the image quality in limited view tomography is highly dependent on the particular acquisition and reconstruction parameters used. In particular, we draw the following conclusions. First, we find that optimising the FBP filter design and SART relaxation parameter yields significant improvements in reconstruction quality from the same projection data. Second, we show that the convergence rate of the maximum likelihood algorithm, optimised with paraboloidal surrogates and conjugate gradient ascent (ML-PSCG), can be greatly accelerated using view-by-view updates. Third, we find that the optimal initial guess is algorithm dependent. In particular, we obtained best results with a zero initial guess for SART, and an FBP initial guess for ML-PSCG. Fourth, when the exposure per view is constant, increasing the total number of views within a given angular range improves the reconstruction quality, albeit with diminishing returns. When the total dose of all views combined is constant, there is a trade-off between increased sampling using a larger number of views and increased levels of quantum noise in each view. Fifth, we do not observe significant differences when testing various access ordering schemes, presumably due to the limited angular range of DBT. Sixth, we find that adjusting the z resolution of the reconstruction can improve image quality, but that this resolution is best adjusted by using post-reconstruction binning, rather than by declaring lower-resolution voxels. Seventh, we find that the C-arm configuration yields higher image quality than a stationary detector geometry, the difference being most outspoken for the FBP algorithm. Lastly, we find that not all prototype systems found in the literature are currently being run under the best possible system or algorithm configurations. In other words, the present study demonstrates the critical importance (and reward) of using optimisation methodologies such as the one presented here to maximise the DBT reconstruction quality from a single scan of the patient. PMID- 20713314 TI - EEG-based neonatal seizure detection with Support Vector Machines. AB - OBJECTIVE: The study presents a multi-channel patient-independent neonatal seizure detection system based on the Support Vector Machine (SVM) classifier. METHODS: A machine learning algorithm (SVM) is used as a classifier to discriminate between seizure and non-seizure EEG epochs. Two post-processing steps are proposed to increase both the temporal precision and the robustness of the system. The resulting system is validated on a large clinical dataset of 267 h of EEG data from 17 full-term newborns with seizures. RESULTS: The performance of the system using event-based metrics is reported. The system showed the best up-to-date performance of a neonatal seizure detection system. The system was able to achieve an average good detection rate of ~89% with one false seizure detection per hour, ~96% with two false detections per hour, or ~100% with four false detections per hour. An analysis of errors revealed sources of misclassification in terms of both missed seizures and false detections. CONCLUSIONS: The results obtained with the proposed SVM-based seizure detection system allow for its practical application in neonatal intensive care units. SIGNIFICANCE: The proposed SVM-based seizure detection system can greatly assist clinical staff, in a neonatal intensive care unit, to interpret the EEG. The system allows control of the final decision by choosing different confidence levels which makes it flexible for clinical needs. The obtained results may provide a reference for future seizure detection systems. PMID- 20713316 TI - Deep inferior epigastric perforators do not correlate between sides of the body: the role for preoperative imaging. PMID- 20713315 TI - White matter is altered with parental family history of Alzheimer's disease. AB - BACKGROUND: Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E (APOE) varepsilon4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE varepsilon4 on brain integrity, in addition to assessing possible additive effects of these two risk factors. METHODS: Diffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE varepsilon4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (lambda1, lambda2, lambda3) to provide potential additional insight on underlying tissue differences. RESULTS: Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE varepsilon4; however, there was an additive effect of family history and APOE varepsilon4 in which family history-positive participants who were also APOE varepsilon4 carriers had the lowest FA compared with the other groups. CONCLUSIONS: The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset. PMID- 20713317 TI - Primary and secondary neoplasms of the spleen. AB - With the exception of lymphoma involving the spleen, other primary and secondary neoplasms are rare and infrequently encountered. Primary malignant neoplasms involving the spleen are lymphoma and angiosarcoma. Primary benign neoplasms involving the spleen include hemangioma, lymphangioma, littoral cell angioma and splenic cyst and solid lesions such as hamartoma and inflammatory pseudotumor. PMID- 20713318 TI - Treatment monitoring of paranasal sinus tumors by magnetic resonance imaging. AB - Treatment monitoring of paranasal tumors is crucial, given the high rate of local and regional relapses that impairs the overall prognosis of patients. Magnetic resonance imaging (MRI) is the technique of choice to detect changes in the submucosa and deep spaces of the suprahyoid neck, inaccessible at clinical and endoscopic assessment. Correct interpretation of MRI requires detailed knowledge of the treatment applied and of the changes treatments are supposed to produce on macroscopic anatomy and tissue signals. Once such background of information is obtained, detection of recurrences is a less challenging task. PMID- 20713319 TI - Effects of feeding diets contaminated with Fusarium mycotoxins on blood biochemical parameters of broiler chickens. AB - This study was conducted to investigate the effects of deoxynivalenol (DON) and zearalenone (ZEA) on some biochemical indices of broiler chickens. Twenty-four Ross 308 hybrid broiler chickens of both sexes were fed diets containing maize contaminated with Fusarium mycotoxins. The diets included a control diet (DON 0.60 mg/kg feed; ZEA 0.07 mg/kg feed), an experimental 1 diet (DON 3.4 mg kg-1 feed; ZEA 3.4 mg kg-1 feed), and an experimental 2 diet (DON 8.2 mg kg-1 feed; ZEA 8.3 mg kg-1 feed). Contaminated diets were fed from 14 days of age for 14 days. Blood samples were collected from 4-week-old birds. Chicks fed a diet containing a low level of contaminated maize (experimental 1) had decreased plasma potassium, magnesium, phosphorus, total protein, albumin, triglycerides, free glycerol concentrations and increased cholesterol and calcium levels as well as alkaline phosphatase (ALP) and aspartate aminotransferase (AST) enzyme activities as compared to the control. Feeding a diet contaminated with high levels of mycotoxins (experimental 2) resulted in decreased plasma potassium, magnesium, total protein, albumin, triglycerides, free glycerol concentrations and increased plasma ALP, alanine aminotransferase (ALT) and AST enzyme activities. The effect of mycotoxin-contaminated diets on ALP activity was dose dependent. Chloride concentration was not affected by the diets. It can be concluded that feeding diets contaminated with both levels of Fusarium mycotoxins significantly affected protein, lipid and mineral metabolism as well as AST and ALP enzyme activities in broiler chickens. PMID- 20713320 TI - Phenotyping and genotyping of streptococci in bovine milk in Argentinean dairy herds. AB - Most veterinary and milk hygiene laboratories identify streptococci and enterococci based on serological and biochemical tests. The analysis of 16S rDNA was suggested to be used for more exact identification; however, its use has not been considered so far in monitoring studies. The objective of the present study was to compare a conventional phenotypic method with restriction fragment length polymorphism analysis of 16S rDNA (16S rDNA RFLP) for identification of streptococci isolated from composite milk samples collected in connection with intramammary infection (IMI) in six Argentinean dairy farms. Composite milk samples (n = 1223) from cows belonging to six herds were collected for bacteriological analysis. Twelve reference strains and fifty streptococci or streptococcuslike isolates were identified to species level by the API 20 Strep system, conventional biochemical tests and 16S rDNA RFLP in a blind assay. The remaining streptococci or streptococcus-like isolates (n = 40) were identified to the species level both by 16S rDNA RFLP and conventional biochemical tests. As indicated by Kappa values, agreement between the 16S rDNA RFLP and the conventional scheme for identification of Streptococcus agalactiae, S. dysgalactiae, S. uberis, S. equinus and Enterococcus faecalis was 0.91, 0.73, 0.92, 0.81 and 0.85, respectively. Together with the less frequently isolated streptococcal species, the conventional scheme correctly identified 77 out of 90 isolates (85.5%). Thus, the use of 16S rDNA RFLP is considered valuable for monitoring studies due to its affordable cost for standard laboratories. PMID- 20713321 TI - Genetic diversity of Mycoplasma hyopneumoniae isolates from conventional farrow to-finish pig farms in Serbia. AB - Mycoplasma hyopneumoniae is a primary agent associated with mycoplasma pneumonia and the porcine respiratory disease complex (PRDC). Various reports have indicated that different strains of M. hyopneumoniae are circulating in the swine population. Lysates from lung swabs from naturally infected pigs of different ages were tested according to a new variable number of tandem repeats (VNTR) genetic typing method based on the polyserine repeat motif of the P146 lipoproteoadhesin, which can be applied directly on clinical material without isolation of M. hyopneumoniae. The aim was to determine the diversity of M. hyopneumoniae isolates from conventional farrow-to-finish pig farms located in different geographical areas of Serbia. PCR amplification was carried out using M. hyopneumoniae -specific designed, conserved primers (p146MH-L and p146MH-R) flanking the region encoding the repeat motif, followed by sequencing and cluster analysis. Five groups of M. hyopneumoniae with thirteen to twenty-four serine repeats were observed. Analysis of three samples from each farm indicated that the specific isolate is ubiquitous in pigs of different ages. Furthermore, seven clusters were observed within 27 tested samples. The results indicated a considerable diversity among M. hyopneumoniae field isolates in the swine population from conventional farrow-to-finish farms in Serbia and suggest close genetic relatedness of the corresponding isolates. PMID- 20713322 TI - Vaginal rupture and evisceration in a dog. AB - A 1.5-year-old German Shepherd mixed breed dog was admitted with mild haemorrhage from the vulva and a perineal mass of 24-hour duration, which had been first observed immediately after parturition. Parturition had occurred at low ambient temperature, and only one puppy survived out of the seven oversized fetuses. The dog was in poor body condition, dehydrated, hypothermic, depressed, non ambulatory and in a state of shock. Intestinal loops, the urinary bladder and the uterine horns and body were protruding from the vulva. A true vaginal prolapse was also observed. The abdominal viscera were flushed with warm sterile saline solution, protected and maintained wet. The laboratory findings included moderate anaemia, leukocytosis, hypoalbuminaemia, azotaemia and elevated liver enzyme activities. Stabilisation of the dog's general condition was attempted before surgery. Antimicrobial and analgesic drugs were also administered. After exploratory laparotomy the protruding organs, which were in good condition, were reduced. A recent rupture in the vaginal wall, approximately 6 cm long, was observed. Ovariohysterectomy and partial vaginectomy were performed. The preoperative course of therapy was continued, but the bitch died 12 hours later. The probable cause of vaginal rupture and evisceration in this bitch was tenesmus and/or trauma due to the oversized fetuses. PMID- 20713323 TI - Assessment of the mineral density and mineral content of the equine third metacarpal and first phalanx bone by dual energy x-ray absorptiometry. AB - In the first part of this methodological study eleven metacarpi of 9 skeletally normal horses were examined from 4 directions by dual energy x-ray absorptiometry (DXA). The differences between the dorsopalmar-palmarodorsal and lateromedial mediolateral (opposite sites) bone mineral density (BMD) values were found to be nonsignificant. In the second part of the study the precision of the Norland XR 26 densitometer was tested by measuring 34 metacarpal bones and 34 proximal phalanges, each of them three times, from a single direction. The difference between the individual measurements of the first phalanges and of the metacarpal bones originating from the right or the left side of the same horse were not significant, nor did the age or breed have a significant effect on BMD or bone mineral content (BMC). However, both BMD and BMC are greater in the metacarpal bones than in the proximal phalanges and are higher in geldings than in mares or to stallions, while the BMD or BMC values of mares and stallions did not differ from each other significantly. These data point to the necessity of further BMD studies in a higher number of patients. PMID- 20713324 TI - Claudin-5-positive angioleiomyoma in the uterus of a degu (Octodon degus ). AB - A 5-year-old female degu (Octodon degus ) showed the clinical sign of metrorrhagia. During ovariohysterectomy a circumscribed tumoural lesion was found in the right uterine horn. The histopathological diagnosis of this soft tissue mass was primary benign cavernous angioleiomyoma of the uterus. During immunohistochemical analysis the neoplastic endothelial cells of this mixed mesenchymal tumour showed strong membrane positivity for the endothelial marker claudin-5 but were negative for CD31 (another endothelial marker). The endothelial cells of the internal positive control tissues such as intact peritumoural vessels were positive for claudin-5 but negative for the CD31 endothelial marker. As it has been described also in other species, it seems that claudin-5 is a better endothelial marker than CD31 for the detection of normal and neoplastic endothelial cells in different tissues of degus. PMID- 20713325 TI - Microbiological and pathological examination of fatal calf pneumonia cases induced by bacterial and viral respiratory pathogens. AB - The infectious origin of fatal cases of calf pneumonia was studied in 48 calves from 27 different herds on postmortem examination. Lung tissue samples were examined by pathological, histological, bacterial culture, virus isolation and immunohistochemical methods for the detection of viral and bacterial infections. Pneumonia was diagnosed in 47/48 cases and infectious agents were found in 40/47 (85%) of those cases. The presence of multiple respiratory pathogens in 23/40 (57.5%) cases indicated the complex origin of fatal calf pneumonia. The most important respiratory pathogens were Mannheimia-Pasteurella in 36/40 (90%) cases, followed by Arcanobacterium pyogenes in 16/40 (40%) cases, Mycoplasma bovis in 12/40 (30%) cases, and bovine respiratory syncytial virus in 4/40 (10%) cases. Histophilus somni was detected in 2/40 (5%) cases, while bovine herpesvirus-1, bovine viral diarrhoea virus and parainfluenza virus-3 were each found in 1/40 (2.5%) case. Mastadenovirus, bovine coronavirus, influenza A virus or Chlamydiaceae were not detected. PMID- 20713326 TI - Effects of enrofloxacin, flunixin meglumine and dexamethasone on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activity in endotoxaemia in rats. AB - The aim of this study was to determine the effects of drugs used in the treatment of endotoxaemia on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activities in endotoxaemic rats. Rats were divided into seven groups. Lipopolysaccharide (LPS) was injected into all groups, including the positive control group. The other six groups received the following drugs: enrofloxacin (ENR), flunixin meglumine (FM), low-dose dexamethasone (DEX), high dose DEX, ENR + FM + low-dose DEX, and ENR + FM + high-dose DEX. After the treatments, serum and plasma samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 hours (h). A coagulometer was used to determine the levels of coagulation values, while ELISA was used to assay serum cytokines and adenosine deaminase (ADA). Low-dose DEX alone and combined treatments depressed the levels of cytokines and ADA (from 371 to 70 IU/L at 6 h) significantly and inhibited the decrease of coagulation values (antithrombin from 67 to 140% at 6 h, fibrinogen from 54 to 252 mg/dL at 6 h). In summary, FM + high-dose DEX may be the preferred treatment of endotoxaemia because of its highest effectiveness. FM plus high-dose DEX may be a new therapy for endotoxaemic domestic animals. PMID- 20713327 TI - HET-CAM test for determining the possible eye irritancy of pesticides. AB - Agrochemicals and veterinary products must undergo numerous toxicological tests before registration. The use of animals in these studies is a controversial issue. The Draize eye irritation test is one of the most criticised methods because of the injuries inflicted on the test animals. Several in vitro methods have been used to investigate the toxicity of potential eye irritants with a view to replacing in vivo eye irritation testing. One of these alternative methods is the Hen's Egg Test--Chorioallantoic Membrane (HET-CAM) test. In the present studies comparative screening was performed with a set of agrochemicals to establish parallel data on in vitro (HET-CAM) and in vivo (Draize) results. The examined materials were: Totril (ioxynil), Omite 57 E (propargit), Actellic 50 EC (pyrimiphos-methyl), Stomp 330 EC (pendimethalin), Mospilan 3 EC (acetamiprid), Alirox 80 EC (EPTC), Match 050 EC (lufenuron), Nonit (dioctyl sulphosuccinate sodium), Perenal (haloxyfop-R methyl ester), Pyrinex 48 EC (chlorpyrifos). These experiments showed good correlation between results obtained by the HET-CAM test and those of the Draize rabbit eye test in most cases. The present form of the HET-CAM test can be proposed as a pre-screening method for the determination of eye irritative potential, therefore the number of test animals can be reduced and/or experimental animals can be replaced. PMID- 20713328 TI - Blood gas values and pulmonary hypertension as affected by dietary sodium source in broiler chickens reared at cool temperature in a high-altitude area. AB - One hundred and twenty day-old male chicks (Ross 308) reared at a cool temperature at high altitude were subjected to the following two treatments in a completely randomised design: (1) a group for which the sodium requirements were supplied by sodium chloride from day-old age and regarded as control, (2) a group similar to the control but for which 50% of the sodium requirements was supplied by sodium bicarbonate from day-old age. Provision of sodium equally from NaCl and NaHCO3 significantly (P < 0.05) increased the partial pressure of oxygen and the saturation of haemoglobin with oxygen, and significantly (P < 0.05) decreased the heterophil to lymphocyte ratio. The right ventricle to total ventricles ratio shifted to lower values as a result of substituting NaHCO3 for NaCl as a sodium source. Growth performance and carcass characteristics were not affected significantly by the dietary sodium source. PMID- 20713329 TI - Distribution and chemical coding of sympathetic neurons in the caudal mesenteric ganglion projecting to the ovary in sexually mature gilts. AB - The distribution and co-localisation patterns of dopamine-beta-hydroxylase (DbetaH), neuropeptide Y (NPY), somatostatin (SOM) and galanin (GAL) were investigated by use of retrograde neuronal tracing and double-labelling immunofluorescence techniques in the caudal mesenteric ganglion (CaMG) neurons supplying the ovary of adult pigs. The existence and density of nerve fibres that are immunoreactive (IR) for the above-mentioned neuroactive substances were also evaluated. Injections of a fluorescent tracer (Fast Blue; FB) into the ovaries revealed the presence of small- (76.38%) and large-sized (23.62%) FB-positive postganglionic neurons in the CaMG. Noradrenergic FB-positive cells were simultaneously NPY- (43.38%), SOM- (18.77%) and GAL- (18.31%) IR. Of the examined FB-positive neurons, 53.49% were DbetaH-IR but NPY-immunonegative (IN), 79.06% were DbetaH-IR but SOM-IN, and 77.16% were DbetaH-IR but GAL-IN. Small- or large sized subsets of traced neurons were supplied by only one or a few nerve fibres, exhibiting DbetaH-, NPY-, SOM- and/or GAL-IR. Our data show the specific morphological as well as immunochemical structural organisation of the sympathetic neurons in the CaMG in adult gilts. The occurrence of an abundant population of noradrenergic perikarya in the CaMG may suggest their important physiological role in the regulation of gonadal function(s) in these animals. PMID- 20713331 TI - Endocrine hypertension: then and now. AB - OBJECTIVE: To review the first reported cases of successfully treated pheochromocytoma and primary aldosteronism and to document the diagnostic and therapeutic advances that have occurred since the initial descriptions. METHODS: The original case descriptions and the subsequent pertinent literature were reviewed. RESULTS: The successful management of the initial cases of pheochromocytoma in 1926 and primary aldosteronism in 1954 was highlighted by keen clinical observation, clinical intuition, and application of scientific principles. Since those prismatic case descriptions, the technological advances in laboratory-based diagnosis, radiology-based tumor localization, and surgical approaches to the adrenal glands have been truly remarkable. CONCLUSIONS: The evolution in the diagnosis and treatment of pheochromocytoma will continue to progress as we identify more genetic causes, develop biochemical markers for "preclinical" pheochromocytoma, identify better markers for malignant disease, and develop more effective treatment options for malignant pheochromocytoma. Over the next decade, we hope to determine the pathophysiology for bilateral idiopathic hyperaldosteronism, develop less invasive and less technically demanding tests to distinguish between unilateral aldosterone-producing adenoma and bilateral idiopathic hyperaldosteronism, determine where low renin hypertension stops and primary aldosteronism starts, and determine the impact of genetic and environmental factors on aldosterone secretion in patients with and without primary aldosteronism. PMID- 20713332 TI - Efficacy of high-fiber diets in the management of type 2 diabetes mellitus. AB - OBJECTIVE: To review outcomes of randomized controlled clinical trials exploring the efficacy of different types of diets containing various amounts of fiber in the management of type 2 diabetes mellitus. METHODS: We searched PubMed, Medline, and Google Scholar for published data from the past decade (through December 2009) on dietary patterns and risk of type 2 diabetes mellitus. Only randomized controlled trials investigating the effect of whole grains, fiber, or vegetarian diets on type 2 diabetes were included. Search criteria included whole grain, fruit, vegetable, fiber, and meat intake regarding insulin sensitivity and glycemic responses in healthy, prediabetic, and diabetic persons. RESULTS: A total of 14 randomized clinical trials were included. Addition of insoluble or soluble fiber to meals, increased consumption of diets rich in whole grains and vegetables, and vegan diets improve glucose metabolism and increase insulin sensitivity. The greatest improvement in blood lipids, body weight, and hemoglobin A(1c) level occurred in participants following low-fat, plant-based diets. CONCLUSIONS: Increased consumption of vegetables, whole grains, and soluble and insoluble fiber is associated with improved glucose metabolism in both diabetic and nondiabetic individuals. Improvements in insulin sensitivity and glucose homeostasis were more evident in participants following a plant-based diet compared with other commonly used diets. PMID- 20713333 TI - Visual vignette. Steroid-induced exophthalmos. PMID- 20713334 TI - Failure of multiple therapies in the treatment of a type 1 diabetic patient with insulin allergy: a case report. AB - OBJECTIVE: To describe the clinical manifestations of insulin allergy and explain a systematic management approach. METHODS: We present the clinical, laboratory, and pathologic findings of a type 1 diabetic patient with allergy to subcutaneous insulin and briefly review the related literature. RESULTS: An 18-year old woman with type 1 diabetes mellitus had an insulin allergy and developed subcutaneous nodules after insulin administration. Human and analogue insulins were used, but painful nodule formation persisted. Treatment with antihistamines, steroids, and omalizumab and insulin desensitization were ineffective. The patient required pancreatic transplant because glycemic control could not be achieved due to the insulin allergy. CONCLUSIONS: Insulin allergy is not a common condition and can be challenging in patients with type 1 diabetes. Therefore, identifying patients with true insulin allergy and applying a stepwise approach to their treatment is important. PMID- 20713335 TI - Visual vignette. PMID- 20713336 TI - Relationship between insulin sensitivity and long-term weight change in adults. AB - OBJECTIVE: To determine whether insulin resistance is associated with reduced risk of weight gain. METHODS: In this retrospective study, we reviewed medical records of volunteers who had undergone a euglycemic, hyperinsulinemic clamp in research studies at Mayo Clinic between October 20, 1986, and January 30, 2002. Data from volunteers who had at least 1 year of followup were analyzed, which included height, weight, date of birth, ethnicity, body composition (percentage body fat and kilograms of fat-free mass), waist-to-hip ratio, date of insulin clamp, fasting plasma glucose and insulin, average plasma glucose and insulin concentrations during the final 30 minutes of each insulin clamp step, and average glucose infusion rate (MUmol.kg fat free mass-1.min-1) during the final 30 minutes of each insulin clamp step. We abstracted the following for each medical encounter: date of visit, height, weight, diagnoses, procedures, and medication use. For the purposes of statistical analysis, the diagnoses, procedures, and medications were then converted into Current Procedural Terminology codes and National Drug Codes. RESULTS: One hundred sixteen patients had at least 1 year of follow-up. The average baseline body mass index was 29.4 +/- 5.3 kg/m2, and the follow-up time averaged 8.1 +/- 5.9 years. We found no significant correlation between baseline insulin action and annual weight change or overall weight change (P = .60 and P = .11, respectively) or between log transformed insulin action and annual weight gain (P = .61). CONCLUSION: These results suggest that in free-living, healthy, white adults, there is not a clinically meaningful relationship between insulin action and subsequent weight change. PMID- 20713337 TI - Visual vignette. PMID- 20713338 TI - Ectopic acromegaly due to a pancreatic neuroendocrine tumor producing growth hormone-releasing hormone. AB - OBJECTIVE: To present a case of acromegaly due to ectopic growth hormone releasing hormone (GHRH) secretion from a pancreatic neuroendocrine tumor in the context of multiple endocrine neoplasia type 1 (MEN 1). METHODS: We describe the clinical, imaging, and pathologic findings of the study patient. RESULTS: A 46 year-old woman presented with clinical and biochemical findings diagnostic of acromegaly. Magnetic resonance imaging showed a 1.2-cm sellar mass. Following resection of the macroadenoma, serum insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels remained unchanged. Pathologic examination revealed adenomatous changes, including a nonsecretory focus and a prolactin immunopositive area (GH stain negative in both). Octreotide long-acting release was ineffective. Search for an ectopic tumor included normal octreoscan and abdominal computed tomography. GHRH was greater than 1000 pg/mL. Repeated abdominal computed tomography documented a 6.2-cm mass in the tail and body of the pancreas. Distal pancreatectomy revealed a pancreatic neuroendocrine tumor that stained positive for GHRH. Postoperatively, serum GHRH and IGF-1 normalized. Re-evaluation of the initial pituitary pathologic specimen revealed additional somatotroph hyperplasia of the adjacent, normal pituitary gland. Primary hyperparathyroidism was diagnosed, and multigland parathyroid hyperplasia was noted at surgery. Genetic testing was positive for a mutation in the MEN1 gene. CONCLUSION: This patient's acromegaly was resistant to somatostatin analogue therapy, reflecting the negative octreoscan imaging. In addition, this case is novel because the patient presented with pituitary adenomatous changes, which were presumably associated with MEN 1 and/or possibly the elevated GHRH levels. PMID- 20713339 TI - Usage patterns of devices designed to support diabetes management: an educational needs assessment. AB - OBJECTIVE: To determine knowledge, competence, and attitudinal issues among diabetes specialists and primary care providers (PCPs) regarding the use of insulin delivery devices such as insulin pens and insulin pumps and the role of glucose monitoring devices and systems in the care of patients with diabetes. METHODS: A quantitative survey tool was developed that contained 51 questions directed to diabetes specialists and 49 questions directed to PCPs. A 5-point, Likert-type scale or multiple-choice format was used. Data were collected from attendees at live symposia across the United States. Results were analyzed for frequency of response and significant relationships among the variables. RESULTS: The survey was completed by 136 specialists and 418 PCPs. There were higher usage rates for insulin pens among specialists than PCPs, although there were higher usage rates among more experienced PCPs. Regarding glucose monitoring, most specialists and PCPs did not recommend "block checking," which has been commonly thought of as a reasonable compromise checking schedule for patients with type 2 diabetes not using insulin. PCPs who were more experienced and used outside educational resources, such as a certified diabetes educator, and specialists who saw more patients on a weekly basis were more likely to prescribe the use of continuous glucose monitoring. There was a general underuse of continuous glucose monitoring in eligible patients. CONCLUSIONS: These findings underscore the discordance between PCPs and specialists with regard to advanced knowledge and confidence required for the use of newer technologies for glucose monitoring and insulin replacement. We have identified important remedial opportunities for quality- and performance-based educational interventions. PMID- 20713340 TI - Hyponatremia: mechanisms and newer treatments. AB - OBJECTIVE: To review the neural and renal mechanisms of osmotic homeostasis, provide a rationale for the sensitivity of the central nervous system to hyponatremia, and outline modern approaches to therapy of acute and chronic hyponatremia. METHODS: Review of relevant literature with focus on physiologic mechanisms. RESULTS: With careful monitoring, acute hyponatremia can be managed, while minimizing risks both of continued hyponatremia and the osmotic demyelination that can occur with overly rapid correction of severe hyponatremia. Chronic hyponatremia due to disorders of volume regulation (congestive heart failure or cirrhosis) or to syndrome of inappropriate antidiuretic hormone release can be managed effectively with vasopressin V2 receptor antagonists, but there is no evidence that controlling the hyponatremia enhances survival associated with the underlying diseases. CONCLUSIONS: Therapy in the acute setting balances the risk of the osmotic disturbance with the risk of overly rapid correction. The V2 receptor antagonist tolvaptan has enhanced our ability to improve chronic hyponatremia in conditions such as congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone hypersecretion. PMID- 20713341 TI - Tumor-induced osteomalacia: a single center experience. AB - OBJECTIVE: To describe the clinical presentation, localization modalities, and management of patients with tumor-induced osteomalacia (TIO). METHODS: We performed a retrospective analysis of case records of patients diagnosed with TIO between January 1996 and March 2010 at our institution in Mumbai, India. RESULTS: Nine patients (6 female and 3 male) with a mean age of 37.5 +/- 17.5 years with biochemical and imaging evidence of TIO were included in the study. Overall, patients presented with proximal muscle weakness and pain. Three patients had neurofibromatosis 1, one had isolated schwannoma, and one had epidermal nevus syndrome. The mean delay in diagnosis was 7.67 years. Biochemical studies revealed normal serum calcium (mean, 9.2 +/- 0.8 mg/dL), low serum phosphorus (mean, 1.36 +/- 0.54 mg/dL), and low maximal tubular reabsorption of phosphorus factored for glomerular filtration rate (mean, 0.94 +/- 0.49 mg/dL). Fibroblast growth factor-23 was increased in 3 of the patients without neurofibromatosis but was normal or near-normal in all the patients with neurofibromas. A fludeoxyglucose F 18 positron emission tomography (FDG PET) scan helped to localize the tumors in 4 of the 5 patients with diagnoses other than neurofibromatosis. Three patients underwent surgical excision and were cured. One patient underwent biopsy and partial excision. Histopathologic findings were suggestive of phosphaturic mesenchymal tumor, benign fibrous histiocytoma, nonossifying fibroma, and sciatic nerve schwannoma. CONCLUSION: There is a well known delay in the diagnosis of TIO. FDG PET is a useful modality for localization of tumors. Preoperative localization increases the odds for cure after surgical excision. PMID- 20713342 TI - Cystic lymph nodes in the lateral neck as indicators of metastatic papillary thyroid cancer. AB - OBJECTIVE: To determine whether radiographic findings portend to metastatic disease in patients with papillary thyroid carcinoma (PTC) and whether cystic lymph node metastasis can be recognized by preoperative, ultrasound-guided fine needle aspiration (FNA). METHODS: We performed a retrospective review of patients with cystic lymph nodes in the lateral neck identified on preoperative ultrasonography between March 1996 and December 2009. Factors examined included demographic information; stage; cytologic and final pathologic findings; and imaging characteristics including location, size, and presence of vascularity and calcifications. Time of cystic node identification in relationship to initial diagnosis was also recorded. RESULTS: Thirty patients had cystic lymph nodes in the lateral neck on cervical ultrasonography during the study period. Among this group, 28 (93%) had PTC, 1 (3%) had papillary serous carcinoma of the ovary, and 1 (3%) had poorly differentiated thyroid cancer. Median age at initial cancer diagnosis was 41 years (range, 16-64 years). Twenty-one patients (70%) were women, and median lymph node size was 1.8 cm (range, 0.6-4.8 cm). Twenty-three patients (77%) had a solitary cystic lymph node, and the remainder had more than 1 cystic lymph node. Cystic lymph nodes were identified at initial presentation in 11 patients (37%), while cystic lymph nodes were discovered in 19 patients (63%) after the initial operation. FNA was performed on the cystic lymph nodes of 23 patients (77%). Cytologic findings were positive for metastatic disease in 18 of 23 patients (78%). Among the 5 of 23 patients with negative cytologic findings, thyroglobulin aspirate was obtained in 1 patient, confirming metastatic PTC. Final pathologic review after surgical resection of cystic lymph nodes with negative cytologic findings from FNA was consistent with metastatic disease in 4 of 5 patients (80%). CONCLUSIONS: In patients with PTC, the presence of a cystic lymph node by ultrasonographic examination is highly suggestive of locally metastatic disease. Confirmation of metastatic PTC may sometimes be achieved with thyroglobulin aspirate from cystic lymph nodes when cytologic findings are negative. Clinicians should strongly consider surgical lymph node resection of cystic lymph nodes regardless of the preoperative cytologic findings by FNA. PMID- 20713343 TI - Management of well-differentiated thyroid cancer in 2010: perspectives of a head and neck surgical oncologist. AB - OBJECTIVE: To review the terminology and controversy regarding the performance of prophylactic lymph node dissection for patients without evidence suggestive of pathologic adenopathy. METHODS: Terminology of lymph node levels in the neck and chest, and the issues regarding lymph node dissection, are reviewed. In addition, differences between lymph nodes are reviewed and discussed. RESULTS: Management of lymph nodes in this disease process has become the most contentious aspect of surgical decision-making due to the ambiguity of their prognostic significance and the prevalence of nodal metastases in very early primary tumors. Performance of prophylactic central compartment node dissection is not technically any more difficult than therapeutic node dissection when clinically significant nodes are encountered. It is therefore reasonable to consider this technique as an important adjunct to a total thyroidectomy for the purpose of enhanced disease staging, prevention of nodal recurrence, and avoidance of having to re-enter the previously operated central compartment. A recent study is reviewed and discussed in detail. The literature regarding the prognostic significance of extracapsular spread in lymph nodes is also presented. CONCLUSIONS: Morphologic characteristics of metastatic lymph nodes in thyroid cancer vary greatly. However, the reporting of these differences is lacking. The presence of extracapsular extension in a lymph node has prognostic significance. The clinician should be aware of these variations and the impact that they may have on recurrence risk and disease specific survival. PMID- 20713344 TI - Incidental radiologic finding of an anterior superior mediastinal mass masquerading as metastatic thyroid cancer in patients with treated thyroid cancer. AB - OBJECTIVE: To demonstrate that an anterior superior mediastinal mass on radiologic imaging may represent an incidental finding and not metastases in patients with a history of treated well-differentiated thyroid cancer. METHODS: We report the clinical presentation and outcomes of 4 patients with a history of thyroid cancer who were incidentally found to have anterior superior mediastinal masses on imaging. We also review the relevant literature. RESULTS: Four young adults with a history of stage I papillary thyroid cancer treated with total thyroidectomy and radioiodine were incidentally found to have thymic enlargement on imaging studies within a 3-year posttreatment window. In each case, this enlargement was believed to be secondary to thymic hyperplasia and not metastatic disease, and each patient has exhibited a benign clinical course. Review of the literature revealed few reports of an association between thymic hyperplasia and thyroid cancer. CONCLUSIONS: Thymic hyperplasia may be discovered on posttreatment imaging studies in patients with a history of well-differentiated thyroid cancer, particularly in young adults who have received radioiodine therapy. Recognition of the possible coexistence of this incidental finding in patients with thyroid cancer may help to avoid unnecessary invasive procedures and treatments. PMID- 20713345 TI - A comparison of twice-daily biphasic insulin aspart 70/30 and once-daily insulin glargine in persons with type 2 diabetes mellitus inadequately controlled on basal insulin and oral therapy: a randomized, open-label study. AB - OBJECTIVE: To compare efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) with insulin (glargine) in type 2 diabetic patients who were not maintaining glycemic control on basal insulin and oral antidiabetic drugs. METHODS: In a 24 week, open-label, parallel-group trial, type 2 diabetic patients who were not maintaining glycemic control on basal insulin (glargine or neutral protamine Hagedorn) + oral antidiabetic drugs were randomly assigned to twice-daily BIAsp 30 + metformin or once-daily glargine + metformin + secretagogues (secretagogues were discontinued in the BIAsp 30 arm). RESULTS: One hundred thirty-seven patients were randomly assigned to the BIAsp 30 group and 143 patients were randomly assigned to the glargine group. Of 280 patients randomized, 229 (81.8%) completed the study. End-of-trial hemoglobin A1c reductions were -1.3% (BIAsp 30) vs -1.2% (glargine) (treatment difference: 95% confidence interval, -0.06 [-0.32 to 0.20]; P = .657). Of patients taking BIAsp 30, 27.3% reached a hemoglobin A1c level <7.0% compared with 22.0% of patients taking glargine (treatment difference: P = .388). Glucose increment averaged over 3 meals was lower in the BIAsp 30 arm (treatment difference: -17.8 mg/dL, P = .001). Fasting plasma glucose reductions from baseline were -13.8 mg/dL (BIAsp 30) vs -42.5 mg/dL (glargine) (P = .0002). Final minor hypoglycemia rate, insulin dose, and weight change were higher in the BIAsp 30 arm (6.5 vs 3.4 events/patient per year, P<.05; 1.19 vs 0.63 U/kg; and 3.1 vs 1.4 kg, P = .0004, respectively). CONCLUSIONS: Despite not receiving secretagogues, patients taking BIAsp 30 + metformin achieved similar hemoglobin A1c levels and lower postprandial plasma glucose compared with those receiving glargine + metformin + secretagogues. The large improvement in the glargine group suggests the patients were not true basal failures at randomization. While switching to BIAsp 30 improves glycemic control in this patient population, remaining on basal insulin and optimizing the dose may be equally effective in the short term. PMID- 20713346 TI - Thyrotoxicosis due to ectopic lateral thyroid tissue presenting 5 years after total thyroidectomy. AB - OBJECTIVE: To describe a patient who, 5 years after total thyroidectomy to treat Graves disease, presented with thyrotoxicosis due to nonmalignant lateral ectopic thyroid tissue. METHOD: We describe the laboratory, imaging, and physical findings of the study patient and review the relevant literature. RESULTS: A 32 year-old white woman with a history of Graves disease presented with recurrent hyperthyroidism 5 years after total thyroidectomy. A radioactive iodine scan was performed, which revealed elevated uptake (40%) and positive imaging in the left mid-neck. Ultrasonography examination of the neck confirmed the absence of any thyroid tissue within the thyroid bed, but documented 2 nodular, hypoechoic left upper-neck masses with punctuate hyperlucency. Contrast-enhanced computed tomography was performed to precisely localize the nodules, which were excised surgically via selective neck dissection. Histopathologic examination revealed chronic lymphocytic inflammatory infiltrate with focal thyroid hyperplasia and papillary infoldings and no evidence of malignancy. CONCLUSIONS: To our knowledge, this represents the first report of ectopic benign thyroid tissue as the sole cause of hyperthyroid symptoms, and this entity should be considered in patients who have undergone thyroidectomy and have persistent hyperthyroidism. PMID- 20713347 TI - Reduction of false-negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotropin measurement. AB - OBJECTIVE: To investigate the value of prolactin as an independent marker of catheter placement to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with corticotropin-dependent Cushing syndrome. METHODS: In this retrospective cohort study, we reviewed hospital records of patients who underwent IPSS procedures at the Cleveland Clinic between 1997 and 2009. Serum prolactin and plasma corticotropin levels were measured prospectively in peripheral and inferior petrosal sinus (IPS) samples. RESULTS: Forty-one patients underwent 42 IPSS procedures at our institution during the study period. Among 35 patients with Cushing disease, 1 patient had erroneous IPSS results: all pre-corticotropin-releasing hormone (CRH) and post-CRH IPS to peripheral (IPS:P) ACTH ratios were less than 2 and less than 3, respectively. Despite radiologic evidence of appropriate IPS catheter placement, concurrent IPS:P prolactin ratios indicated that successful IPS venous sampling was not achieved. A second case with equivocal IPSS results could also be explained by corresponding IPS:P prolactin ratios. During IPSS, all patients with an identifiable ACTH-staining adenoma localizing to 1 side of the pituitary gland (n = 22) who demonstrated absent IPS:P ACTH gradients (<2 before or <3 after CRH administration) on the ipsilateral side of the corticotroph adenoma had corresponding IPS:P prolactin ratios less than 1.3. CONCLUSIONS: Measurement of prolactin during IPSS testing may reduce false-negative results in patients with Cushing disease who do not demonstrate an appropriate central-to-peripheral ACTH gradient. In our series, all false-negative IPS:P ACTH ratios had a corresponding IPS:P prolactin ratio less than 1.3. PMID- 20713348 TI - Thyroid function and 3,3'-diiodothyronine sulfate cross-reactive substance (compound W) in maternal hyperthyroidism with antithyroid treatment. AB - OBJECTIVE: To test whether the serial measurement of maternal levels of compound W, a 3,3'-diiodothyronine sulfate cross-reactive substance, can serve as a potential indicator of fetal thyroid function in pregnant women receiving antithyroid medication. METHODS: Compound W was measured repeatedly in serum of pregnant women with hyperthyroidism treated with antithyroid medication. Free thyroxine levels of mothers and serum thyroid-stimulating hormone levels of 1-day old neonates were analyzed by local clinical or state laboratories. RESULTS: Use of minimal antithyroid medication impaired the progressive increase of compound W seen in euthyroid mothers during pregnancy. At term, depressed compound W levels in maternal serum were found in 7 of 22 pregnancies; in 1 case, maternal compound W was suppressed and newborn thyroid-stimulating hormone was elevated. Seven mothers with treated hyperthyroidism failed to show an increase in serum levels of compound W after midterm. CONCLUSION: Normal progression of maternal serum compound W may be an index of normal fetal thyroid development in mothers with hyperthyroidism treated with necessary antithyroid medication. PMID- 20713349 TI - Iatrogenic osteoporosis, bilateral HIP osteonecrosis, and secondary adrenal suppression in an HIV-infected man receiving inhaled corticosteroids and ritonavir-boosted highly active antiretroviral therapy. AB - OBJECTIVE: To report the first case of severe osteoporosis associated with a vertebral pathologic fracture and osteonecrosis of femoral heads in an HIV infected man receiving inhaled corticosteroids and ritonavir-boosted antiretroviral therapy. METHODS: We describe an HIV-infected man with severe osteoporosis, bilateral hip osteonecrosis, and secondary adrenal suppression, including detailed clinical, laboratory, and radiographic data, and review the related literature. RESULTS: A 60-year-old man with a 15-year history of HIV infection and a medical history of long-standing bronchiectasis treated with inhaled corticosteroids and hypogonadism treated with testosterone was referred to the endocrinology clinic after experiencing an osteoporotic vertebral fracture. He was taking ritonavir-boosted antiretroviral therapy. Osteonecrosis of both hips was also diagnosed, which required total hip replacement therapy. Laboratory evaluation revealed adrenal insufficiency due to increased effect of exogenous inhaled steroids and no other secondary causes of osteoporosis. A bone densitometry study showed osteoporosis of both hips and the lumbar spine. He was treated with intravenous pamidronate. During treatment, he developed bilateral femoral fractures after minor trauma. CONCLUSIONS: Given the potential for increased serum levels of inhaled corticosteroids in patients taking ritonavir boosted highly active antiretroviral therapy, attention must be paid to the risk of bone loss in HIV-infected patients taking inhaled corticosteroids. Prescribing calcium and vitamin D supplementation and considering early osteoporosis screening are reasonable measures for this patient population. Interaction between inhaled corticosteroids and ritonavir may increase risk of hypothalamus pituitary-adrenal axis suppression. PMID- 20713350 TI - Primary menopausal insomnia: definition, review, and practical approach. AB - OBJECTIVE: To present a case of primary menopausal insomnia with hot flashes to introduce recent changes in technology and nomenclature of sleep medicine and to review presentation, diagnosis, and therapies for menopausal insomnia. METHODS: Clinical findings and results of sleep evaluation in the menopausal study patient are presented with details about polysomnography performed before and after therapy with pregabalin. RESULTS: A 56.5-year-old female athlete with severe hot flashes and insomnia of 12 years' duration was treated with pregabalin, which ameliorated the hot flashes and sweats and improved sleep quality and architecture. Menopause is associated with hormonal and metabolic changes that disrupt sleep. Disruption of sleep can in turn lead to morbidity and metabolic sequelae. Hormonal treatment, although effective, carries risks unacceptable to many patients and physicians. To date, nonhormonal therapies of symptomatic menopause have not been objectively studied for effects on sleep efficiency and architecture. Primary menopausal insomnia is insomnia associated with menopause and not attributable to secondary causes. Polysomnographically, it seems characterized by a high percentage of slow-wave (N3) sleep, decreased rapid eye movement sleep, cyclic alternating pattern, and arousals. CONCLUSIONS: Primary menopausal insomnia is probably mediated through a mechanism separate from hot flashes, and one can occur without the other. Thermal dys-regulation and sleep abnormalities of menopause are probably related to more general changes mediated through loss of estrogenic effects on neuronal modulation of energy metabolism, and more clinical direction is expected as this research field develops. Identification of sleep disorders in menopausal women is important, and polysomnographic evaluation is underused in both clinical and research evaluations of metabolic disturbances. PMID- 20713352 TI - RB.E2F1 complex mediates DNA damage responses through transcriptional regulation of ZBRK1. AB - RB plays an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that the ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6, together with chromatin remodeling proteins CtIP and CtBP to form a repression complex that suppresses ZBRK1 transcription. Furthermore, loss of RB-mediated transcriptional repression led to an increase in ZBRK1 transcript levels, correlating with increased sensitivity to ultraviolet (UV) and methyl methanesulfonate-induced DNA damage. Taken together, these results suggest that the RB.CtIP (CtBP interacting protein)/CtBP (C terminus-binding protein) /E2F1 complex plays a critical role in ZBRK1 transcriptional repression, and loss of this repression may contribute to cellular sensitivity of DNA damage, ultimately leading to carcinogenesis. PMID- 20713353 TI - Phosphorylation and activation of androgen receptor by Aurora-A. AB - Aurora-A kinase is frequently overexpressed/activated in various types of human malignancy, including prostate cancer. In this study, we demonstrate elevated levels of Aurora-A in androgen-refractory LNCaP-RF but not androgen-sensitive LNCaP cells, which prompted us to examine whether Aurora-A regulates the androgen receptor (AR) and whether elevated Aurora-A is involved in androgen-independent cell growth. We show that ectopic expression of Aurora-A induces AR transactivation activity in the presence and absence of androgen. Aurora-A interacts with AR and phosphorylates AR at Thr(282) and Ser(293) in vitro and in vivo. Aurora-A induces AR transactivation activity in a phosphorylation-dependent manner. Ectopic expression of Aurora-A in LNCaP cells induces prostate-specific antigen expression and cell survival, whereas knockdown of Aurora-A sensitizes LNCaP-RF cells to apoptosis and cell growth arrest. These data indicate that AR is a substrate of Aurora-A and that elevated Aurora-A could contribute to androgen-independent cell growth by phosphorylation and activation of AR. PMID- 20713354 TI - Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E deficient mice. AB - Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) markedly attenuated the cholesterol ester accumulation in oxidized low density lipoprotein-loaded macrophages. Notably, AICAR treatment significantly increased ATP-binding cassette transporters G1 (Abcg1) mRNA and protein levels without affecting mRNA and protein expression of ABCA1, scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI (SR-BI), and cholesterol synthesis related genes. The up-regulation of Abcg1 by AICAR was independent of the liver X receptor/retinoid X receptor pathway but dependent on ERK activation. AICAR elevates Abcg1 expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the Abcg1 mRNA 3'-UTR responsible for the regulatory effect of AICAR. Prevention of ABCG1 expression by small interfering RNA abolished the AICAR-mediated attenuation on foam cell formation. Furthermore, increased ABCG1 expression and reduced lipid accumulation were demonstrated in AICAR-treated macrophages isolated from apolipoprotein E-deficient mice (apoE(-/-) mice). AICAR treatment also inhibited atherosclerotic plaque formation in apoE(-/-) mice. Our findings elucidate a precise mechanism involved in the prevention of atherogenesis by AMPK. PMID- 20713355 TI - Interdependent phosphorylation within the kinase domain T-loop Regulates CHK2 activity. AB - Chk2 is a critical regulator of the cellular DNA damage repair response. Activation of Chk2 in response to IR-induced damage is initiated by phosphorylation of the Chk2 SQ/TQ cluster domain at Ser(19), Ser(33), Ser(35), and Thr(68). This precedes autophosphorylation of Thr(383)/Thr(387) in the T-loop region of the kinase domain an event that is a prerequisite for efficient kinase activity. We conducted an in-depth analysis of phosphorylation within the T-loop region (residues 366-406). We report four novel phosphorylation sites at Ser(372), Thr(378), Thr(389), and Tyr(390). Substitution mutation Y390F was defective for kinase function. The substitution mutation T378A ablated the IR induction of kinase activity. Interestingly, the substitution mutation T389A demonstrated a 6-fold increase in kinase activity when compared with wild-type Chk2. In addition, phosphorylation at Thr(389) was a prerequisite to phosphorylation at Thr(387) but not at Thr(383). Quantitative mass spectrometry analysis revealed IR-induced phosphorylation and subcellular distribution of Chk2 phosphorylated species. We observed IR-induced increase in phosphorylation at Ser(379), Thr(389), and Thr(383)/Thr(389). Phosphorylation at Tyr(390) was dramatically reduced following IR. Exposure to IR was also associated with changes in the ratio of chromatin/nuclear localization. IR-induced increase in chromatin localization was associated with phosphorylation at Thr(372), Thr(379), Thr(383), Thr(389), Thr(383)/Thr(387), and Thr(383)/Thr(389). Chk2 hyper phosphorylated species at Thr(383)/Thr(387)/Thr(389) and Thr(383)/Thr(387)/Thr(389)/Tyr(390) relocalized from almost exclusively chromatin to predominately nuclear expression, suggesting a role for phosphorylation in regulation of chromatin targeting and egress. The differential impact of T-loop phosphorylation on Chk2 ubiquitylation suggests a co-dependence of these modifications. The results demonstrate that a complex interdependent network of phosphorylation events within the T-loop exchange region regulates dimerization/autophosphorylation, kinase activation, and chromatin targeting/egress of Chk2. PMID- 20713356 TI - Characterization of hMTr1, a human Cap1 2'-O-ribose methyltransferase. AB - Cellular eukaryotic mRNAs are capped at their 5' ends with a 7-methylguanosine nucleotide, a structural feature that has been shown to be important for conferring mRNA stability, stimulating mRNA biogenesis (splicing, poly(A) addition, nucleocytoplasmic transport), and increasing translational efficiency. Whereas yeast mRNAs have no additional modifications to the cap, called cap0, higher eukaryotes are methylated at the 2'-O-ribose of the first or the first and second transcribed nucleotides, called cap1 and cap2, respectively. In the present study, we identify the methyltransferase responsible for cap1 formation in human cells, which we call hMTr1 (also known as FTSJD2 and ISG95). We show in vitro that hMTr1 catalyzes specific methylation of the 2'-O-ribose of the first nucleotide of a capped RNA transcript. Using siRNA-mediated knockdown of hMTr1 in HeLa cells, we demonstrate that hMTr1 is responsible for cap1 formation in vivo. PMID- 20713357 TI - Maspin regulates endothelial cell adhesion and migration through an integrin signaling pathway. AB - Maspin has been identified as a potent angiogenesis inhibitor. However, the molecular mechanism responsible for its anti-angiogenic property is unclear. In this study, we examined the effect of maspin on endothelial cell (EC) adhesion and migration in a cell culture system. We found that maspin was expressed in blood vessels ECs and human umbilical vein endothelial cells (HUVECs). Maspin significantly enhanced HUVEC cell adhesion to various matrix proteins. This effect was dependent on the activation of integrin beta(1), which subsequently led to distribution pattern changes of vinculin and F-actin. These results indicated that maspin affects cell adhesion and cytoskeleton reorganization through an integrin signal transduction pathway. Analysis of HUVECs following maspin treatment revealed increased integrin-linked kinase activities and phosphorylated FAK levels, consistent with increased cell adhesion. Interestingly, when HUVECs were induced to migrate by migration stimulatory factor bFGF, active Rac1 and cdc42 small GTPase levels were decreased dramatically at 30 min following maspin treatment. Using phosphorylated FAK at Tyr(397) as an indicator of focal adhesion disassembly, maspin-treated HUVECs had elevated FAK phosphorylation compared with the mock treated control. The results were a reduction in focal adhesion disassembly and the retardation in EC migration. This study uncovers a mechanism by which maspin exerts its effect on EC adhesion and migration through an integrin signal transduction pathway. PMID- 20713358 TI - Post-transcriptional up-regulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-{beta}-induced collagen expression in kidney cells. AB - Increased accumulation of extracellular matrix proteins and hypertrophy induced by transforming growth factor-beta1 (TGF-beta) in renal mesangial cells (MC) are hallmark features of diabetic nephropathy. Although the post-transcriptional regulation of key genes has been implicated in these events, details are not fully understood. Here we show that TGF-beta increased microRNA-216a (miR-216a) levels in mouse MC, with parallel down-regulation of Ybx1, a miR-216a target and RNA-binding protein. TGF-beta also enhanced protein levels of Tsc-22 (TGF-beta stimulated clone 22) and collagen type I alpha-2 (Col1a2) expression in MC through far upstream enhancer E-boxes by interaction of Tsc-22 with an E-box regulator, Tfe3. Ybx1 colocalized with processing bodies in MC and formed a ribonucleoprotein complex with Tsc-22 mRNA, and this complex formation was reduced by TGF-beta, miR-216a mimics, or Ybx1 shRNA to increase Tsc-22 protein levels but enhanced by miR-216a inhibitor oligonucleotides. Chromatin immunoprecipitation (ChIP) assays revealed that TGF-beta could increase the occupancies of Tsc-22 and Tfe3 on enhancer E-boxes of Col1a2. Co immunoprecipitation assays revealed that TGF-beta promoted the interaction of Tsc 22 with Tfe3. These results demonstrate that post-transcriptional regulation of Tsc-22 mediated through Ybx1, a miR-216a target, plays a key role in TGF-beta induced Col1a2 in MC related to the pathogenesis of diabetic nephropathy. PMID- 20713360 TI - Mixed methods research: a design for emergency care research? AB - This paper follows previous publications on generic qualitative approaches, qualitative designs and action research in emergency care by this group of authors. Contemporary views on mixed methods approaches are considered, with a particular focus on the design choice and the amalgamation of qualitative and quantitative data emphasising the timing of data collection for each approach, their relative 'weight' and how they will be mixed. Mixed methods studies in emergency care are reviewed before the variety of methodological approaches and best practice considerations are presented. The use of mixed methods in clinical studies is increasing, aiming to answer questions such as 'how many' and 'why' in the same study, and as such are an important and useful approach to many key questions in emergency care. PMID- 20713359 TI - Ubiquitin proteasome-dependent degradation of the transcriptional coactivator PGC 1{alpha} via the N-terminal pathway. AB - PGC-1alpha is a potent, inducible transcriptional coactivator that exerts control on mitochondrial biogenesis and multiple cellular energy metabolic pathways. PGC 1alpha levels are controlled in a highly dynamic manner reflecting regulation at both transcriptional and post-transcriptional levels. Here, we demonstrate that PGC-1alpha is rapidly degraded in the nucleus (t(1/2 0.3 h) via the ubiquitin proteasome system. An N-terminal deletion mutant of 182 residues, PGC182, as well as a lysine-less mutant form, are nuclear and rapidly degraded (t(1/2) 0.5 h), consistent with degradation via the N terminus-dependent ubiquitin subpathway. Both PGC-1alpha and PGC182 degradation rates are increased in cells under low serum conditions. However, a naturally occurring N-terminal splice variant of 270 residues, NT-PGC-1alpha is cytoplasmic and stable (t(1/2>7 h), providing additional evidence that PGC-1alpha is degraded in the nucleus. These results strongly suggest that the nuclear N terminus-dependent ubiquitin proteasome pathway governs PGC-1alpha cellular degradation. In contrast, the cellular localization of NT-PCG-1alpha results in a longer-half-life and possible distinct temporal and potentially biological actions. PMID- 20713361 TI - Range of elbow movement as a predictor of bony injury in children. AB - BACKGROUND: The aim of this study was to determine whether a normal range of elbow movement can be used as a rule out tool for significant injury after blunt trauma in the paediatric population. METHODS: A prospective observational study was set up in an Australian tertiary paediatric emergency department. Patients from 3 to 16 years old were included. Active range of elbow movement (flexion, extension, supination and pronation) was recorded as either normal or abnormal. All participants received standard elbow x-rays. Range of movement (ROM) was compared to the radiologist's final x-ray report. An x-ray was considered abnormal if it showed a fracture, dislocation or isolated elbow effusion. RESULTS: 177 patients were included in the study, of which all received elbow x rays. 146 had a restricted ROM (82%). 106 x-rays were reported as abnormal (60%). An abnormal ROM had a sensitivity of 93.4% (95% CI 86.9% to 97.3%), specificity 33.8% (95% CI 23.0% to 46.0%) and negative predictive value of 77.4% (95% CI 58.9% to 90.4%) for an abnormal x-ray. There were seven false-negative results in this group. Clinical management was changed in four of these patients due to abnormalities seen on x-ray. CONCLUSION: In the setting of blunt trauma resulting in elbow injury in children, a normal ROM does not rule out a significant injury and should not be used as a screening tool. PMID- 20713362 TI - Emergency department abdominal x-rays have a poor diagnostic yield and their usefulness is questionable. AB - OBJECTIVE: To determine the prevalence and nature of new clinically significant abdominal x-ray (AXR) findings and the proportion of patients receiving additional imaging in the emergency department (ED). METHODS: This was a retrospective audit of consecutive adult patients, who presented to a tertiary referral ED (annual census 70,000) between September and December 2008. Data were extracted from radiologist reports and the medical records of patients with new significant AXR findings. The electronic radiology record was further interrogated to determine which patients received additional imaging and whether this correlated with the original AXR findings. RESULTS: Of 997 cases that met the inclusion criteria, 121 (12.1%, 95% CI 10.2 to 14.4) and 43 (4.3%, 95% CI 3.2 to 5.8) had new clinically significant and insignificant AXR findings, respectively. Among the significant findings, the predominant diagnoses were bowel obstruction (72.7%), renal calculi (14.0%) and sigmoid volvulus (5.0%). Patient signs and symptoms were poorly associated with significant AXR findings. In all, 334 (33.5%, 95% CI 30.6 to 36.5) cases had additional imaging after the AXR. However, more patients with clinically significant AXR findings went on to have additional imaging (difference in proportions 23.0%, 95% CI 13.2 to 32.9, p<0.001). CONCLUSIONS: The yield for clinically useful information from the AXR is low and this investigation may be overused. Positive findings are associated mostly with bowel obstruction. As the proportion of patients ordered additional imaging was considerable, the utility of the preliminary AXR is questionable, especially in cases where the diagnosis is clear. Guidelines for AXR imaging are recommended to assist clinicians with investigation ordering. PMID- 20713363 TI - Is paper-based documentation in an emergency medical service adequate for retrospective scientific analysis? An evaluation of a physician-run service. AB - OBJECTIVE: To investigate if paper-based documentation in the authors' emergency medical service (EMS) satisfies scientific requirements. METHODS: From 1 July 2007 to 28 February 2008, data from all paper-based protocols of a physician-run EMS in Aachen, Germany, were transferred to a SQL database (n=4815). Database queries were conducted after personal data had been anonymised. Documentation ratios of 11 individual parameters were analysed at two points in time (T1, scene; T2, arrival in emergency department). The calculability of the Mainz Emergency Evaluation Score (MEES, embracing seven vital parameters) was investigated. The calculability of the Revised Trauma Score (RTS) was also determined for all trauma patients (n=408). Fisher's exact test was used to compare differences in ratios at T1 versus T2. RESULTS: The documentation ratios of vital parameters ranged from 99.33% (Glasgow Coma Scale, T1) to 40.31% (respiratory rate, T2). The calculability of the MEES was poor (all missions: 28.31%, T1; 22.40%, T2; p<0.001). In missions that required cardiopulmonary resuscitation (n=87), the MEES was calculable in 9.20% of patients at T1 and 29.89% at T2 (p<0.001). In trauma missions, the RTS was calculable in 37.26% at T1 and 27.70% at T2 (p=0.004). CONCLUSIONS: Documentation of vital parameters is carried out incompletely, and documentation of respiratory rate is particularly poor, making calculation of accepted emergency scores infeasible for a significant fraction of a given test population. The suitability of paper-based documentation is therefore limited. Electronic documentation that includes real time plausibility checks might improve data quality. Further research is warranted. PMID- 20713364 TI - Analysis of recreational drug samples obtained from patients presenting to a busy inner-city emergency department: a pilot study adding to knowledge on local recreational drug use. AB - INTRODUCTION: Routine toxicological screening is not undertaken in individuals presenting to emergency departments (ED) with acute recreational drug toxicity, because it does not usually alter an individual patient's management. Localised information on the types of recreational drugs being used is often not available. The pilot study described here looks at the analysis of presumed recreational drugs in the possession of individuals presenting to the ED with acute recreational drug toxicity. METHODS: Suspected recreational drug samples were handled as controlled drugs and transported to a Home Office approved laboratory. Samples were initially categorised on the basis of their physical appearance; liquid samples were analysed by infrared spectrophotometry and non-liquid samples were analysed by gas chromatography-mass spectrometry. RESULTS: A total of 33 (12 liquid and 21 non-liquid) samples was analysed in this pilot study. Liquid samples were shown to contain either gamma-butyrolactone or isopropyl nitrite. 19% of non-liquid samples (12% of total samples) did not contain any drugs and 23% contained legal pharmaceutical agents. Of the remaining samples, they contained both 'classic' and 'novel' recreational drugs. Only 33.3% of crystalline substances contained methamphetamine. DISCUSSION: This pilot study has shown that analysing samples obtained in the ED can contribute to clinicians' knowledge of local drug epidemiology. Extension of this approach in areas with a high prevalence of recreational drug use, with appropriate funding, may be useful in monitoring drug trends and detecting novel emerging drugs. PMID- 20713365 TI - Impact of implementing an exclusively dedicated respiratory isolation room in a Brazilian tertiary emergency department. AB - BACKGROUND: Occupational risk due to airborne disease challenges healthcare institutions. Environmental measures are effective but their cost-effectiveness is still debatable and most of the capacity planning is based on occupational rates. Better indices to plan and evaluate capacity are needed. GOAL: To evaluate the impact of installing an exclusively dedicated respiratory isolation room (EDRIR) in a tertiary emergency department (ED) determined by a time-to-reach facility method. METHODS: A group of patients in need of respiratory isolation were first identified--group I (2004; 29 patients; 44.1+/-3.4 years) and the occupational rate and time intervals (arrival to diagnosis, diagnosis to respiratory isolation indication and indication to effective isolation) were determined and it was estimated that adding an EDRIR would have a significant impact over the time to isolation. After implementing the EDRIR, a second group of patients was gathered in the same period of the year--group II (2007; 50 patients; 43.4+/-1.8 years) and demographic and functional parameters were recorded to evaluate time to isolation. Cox proportional hazard models adjusted for age, gender and inhospital respiratory isolation room availability were obtained. RESULTS: Implementing an EDRIR decreased the time from arrival to indication of respiratory isolation (27.5+/-9.3 * 3.7+/-2.0; p=0.0180) and from indication to effective respiratory isolation (13.3+/-3.0 * 2.94+/-1.06; p=0.003) but not the respiratory isolation duration and total hospital stay. The impact on crude isolation rates was very significant (8.9 * 75.4/100.000 patients; p<0.001). The HR for effective respiratory isolation was 26.8 (95% CI 7.42 to 96.9) p<0.001 greater for 2007. CONCLUSION: Implementing an EDRIR in a tertiary ED significantly reduced the time to respiratory isolation. PMID- 20713366 TI - Ultrasound measurement of optic nerve sheath diameter in patients with a clinical suspicion of raised intracranial pressure. AB - BACKGROUND: To assess if ultrasound measurement of the optic nerve sheath diameter (ONSD) can accurately predict the presence of raised intracranial pressure (ICP) and acute pathology in patients in the emergency department. METHODS: This 3-month prospective observational study used ultrasound to measure the ONSD in adult patients who required CT from the emergency department. The mean ONSD from both eyes was measured using a 7.5 MHz ultrasound probe on closed eyelids. A mean ONSD value of >0.5 cm was taken as positive. Two radiologists independently assessed CT scans from patients in the study population for signs of raised ICP and signs of acute pathology (cerebrovascular accident, subarachnoid, subdural or extradural haemorrhage and tumour). Specificity, sensitivity and kappa values, for interobserver variability between reporting radiologists, were generated for the study data. RESULTS: In all, 26 patients were enrolled into the study. The ONSD measurement was 100% specific (95% CI 79% to 100%) and 86% sensitive (95% CI 42% to 99%) for raised ICP. For any acute intracranial abnormality the value of ONSD was 100% specific (95% CI 76% to 100%) and 60% sensitive (95% CI 27% to 86%). kappa Values were 0.91 (95% CIs 0.73 to 1) for identification of raised ICP on CT and 0.84 (95% CIs 0.62 to 1) for any acute pathology on CT, between the radiologists. CONCLUSIONS: This study shows that ultrasound measurement of ONSD is sensitive and specific for raised ICP in the emergency department. Further observational studies are needed but this emerging technique could be used to focus treatment in unstable patients. PMID- 20713367 TI - Pharmacological diagnosis of Horner's syndrome in the emergency department. PMID- 20713368 TI - Early goal-directed therapy: can the emergency department deliver. PMID- 20713369 TI - The whirl sign. PMID- 20713370 TI - Expectations of patients, nurses and physicians in geriatric nursing home emergencies. AB - OBJECTIVES: To determine contentment with the performance of primary mission emergency care providers. METHODS: A prospective cohort study was conducted using key informant interviews to assess quality of life and self-rated degree of contentment with care in geriatric emergencies. RESULTS: Interviews concerning a total of 152 geriatric emergency cases in nursing homes were conducted with patients in 13 (8.6%) cases, geriatric nurses in 132 (86.8%) cases and emergency physicians in 116 (76.3%) cases within a 3-month period. All responding patients as well as the majority of nurses (96.2%) and physicians (79.4%) were content with the quality of emergency care, but showed less contentment with communication (57.6% of nurses; 22.4% of physicians) and with cooperation on-site (57.6% of nurses; 20.7% of physicians). CONCLUSIONS: Participants perceived a deficit in communication and cooperation on-site. There is a need for intensified education in managing geriatric emergency patients, especially with regard to communication and psychosocial issues. PMID- 20713371 TI - Heavy drinking in early adulthood and outcomes at mid life. AB - BACKGROUND: Heavy drinking in early adulthood among Blacks, but not Whites, has been found to be associated with more deleterious health outcomes, lower labor market success and lower educational attainment at mid-life. This study analysed psychosocial pathways underlying racial differences in the impact of early heavy alcohol use on occupational and educational attainment at mid-life. METHODS: Outcomes in labor market participation, occupational prestige and educational attainment were measured in early and mid-adulthood. A mixture model was used to identify psychosocial classes that explain how race-specific differences in the relationship between drinking in early adulthood and occupational outcomes in mid life operate. Data came from Coronary Artery Risk Development in Young Adults, a longitudinal epidemiologic study. RESULTS: Especially for Blacks, heavy drinking in early adulthood was associated with a lower probability of being employed in mid-life. Among employed persons, there was a link between heavy drinking for both Whites and Blacks and decreased occupational attainment at mid-life. We grouped individuals into three distinct distress classes based on external stressors and indicators of internally generated stress. Blacks were more likely to belong to the higher distressed classes as were heavy drinkers in early adulthood. Stratifying the data by distress class, relationships between heavy drinking, race and heavy drinking-race interactions were overall weaker than in the pooled analysis. CONCLUSIONS: Disproportionate intensification of life stresses in Blacks renders them more vulnerable to long-term effects of heavy drinking. PMID- 20713373 TI - Huge thymolipoma. PMID- 20713372 TI - Occupational, social, and relationship hazards and psychological distress among low-income workers: implications of the 'inverse hazard law'. AB - BACKGROUND: Few studies have simultaneously included exposure information on occupational hazards, relationship hazards (eg, intimate partner violence) and social hazards (eg, poverty and racial discrimination), especially among low income multiracial/ethnic populations. METHODS: A cross-sectional study (2003 2004) of 1202 workers employed at 14 worksites in the greater Boston area of Massachusetts investigated the independent and joint association of occupational, social and relationship hazards with psychological distress (K6 scale). RESULTS: Among this low-income cohort (45% were below the US poverty line), exposure to occupational, social and relationship hazards, per the 'inverse hazard law,' was high: 82% exposed to at least one occupational hazard, 79% to at least one social hazard, and 32% of men and 34% of women, respectively, stated they had been the perpetrator or target of intimate partner violence (IPV). Fully 15.4% had clinically significant psychological distress scores (K6 score >= 13). All three types of hazards, and also poverty, were independently associated with increased risk of psychological distress. In models including all three hazards, however, significant associations with psychological distress occurred among men and women for workplace abuse and high exposure to racial discrimination only; among men, for IPV; and among women, for high exposure to occupational hazards, poverty and smoking. CONCLUSIONS: Reckoning with the joint and embodied reality of diverse types of hazards involving how people live and work is necessary for understanding determinants of health status. PMID- 20713374 TI - Acupuncture for dysphagia after chemoradiation therapy in head and neck cancer: a case series report. AB - BACKGROUND: Dysphagia is a common side effect following chemoradiation therapy (CRT) in patients with head and neck cancer (HNC). METHODS: In this retrospective case series, 10 patients with HNC were treated with acupuncture for radiation induced dysphagia and xerostomia. All patients were diagnosed with stage III/IV squamous cell carcinoma. In all, 7 of 10 patients were percutaneous endoscopic gastrostomy (PEG) tube dependent when they began acupuncture. Manual acupuncture and electroacupuncture were used once a week. RESULTS: A total of 9 of 10 patients reported various degrees of subjective improvement in swallowing functions, xerostomia, pain, and fatigue levels. Overall, 6 (86%) of 7 PEG tube dependent patients had their feeding tubes removed after acupuncture, with a median duration of 114 days (range 49 to 368 days) post CRT. One typical case is described in detail. CONCLUSIONS: A relatively short PEG tube duration and reduced symptom severity following CRT were observed in these patients. Formal clinical trials are required to determine the causality of the observations. PMID- 20713375 TI - Enhancement of the response of B16F1 melanoma to fractionated radiotherapy and prolongation of survival by withaferin A and/or hyperthermia. AB - Withaferin A (WA), isolated from Indian medicinal plant Withania somnifera has weak antitumor and radiosensitizing property. The present investigation was planned to evaluate the tumor sensitizing effect of WA with or without local hyperthermia on the response of B16F1 melanoma to fractionated and acute radiotherapy. C57BL mice bearing tumors of 100 +/- 10 mm3 were treated with fractionated radiotherapy (RT, 2 Gy x 5 days/week, 4 weeks), withaferin A (15 mg/kg, i.p., 5 days/ week, 3 weeks), local hyperthermia (HT, 43 degrees C once a week, 3 weeks) and their combinations, or acute RT (40 Gy), WA (40 mg/kg), HT (43 degrees C, 30 min) and their combinations. Treatment response was studied by tumor regression, growth delay and animal survival. Acute RT+HT produced 50% partial response which increased to 62.5% with combination of WA. In fractionated regimen, trimodality combination resulted in 100% PR. Acute RT+HT and WA+RT produced similar increase in growth delay (GD) compared to RT alone which further increased in trimodality treatment. Fractionated WA+RT+HT for 3 weeks produced a higher GD and survival than all other treatments. In conclusion, WA is a better radiosensitizer than HT in fractionated regimen and the response of radioresistant tumors like melanoma can be significantly enhanced by combining nontoxic doses of WA with fractionated RT, with or without HT, allowing decrease in radiation dose. PMID- 20713376 TI - In vitro and in vivo apoptosis-inducing antileukemic effects of Mucuna macrocarpa stem extract on HL-60 human leukemia cells. AB - Mucuna macrocarpa Wallich (Leguminosae) is believed to hold blood circulation activating effects, and has been used as a folk remedy in Southeast Asia for the treatment of various hematologic and circulatory-related ailments. The objective of this study was to investigate whether crude methanolic extract of M macrocarpa (CMEMM) possessed antileukemic effects on HL-60, human leukemia cells. CMEMM was prepared from dried stems of this plant, and its apoptosis-inducing effects were investigated using HL-60 cells in vitro and in vivo. With treatment of 25 to 75 MUg/mL CMEMM, the in vitro antiproliferative effect on HL-60 cells increased in a dose- and time-dependent manner during the 72-hour treatment period. The concentration of CMEMM that exhibited a 50% growth inhibition (IC(50)) for 72 hour exposure was 36.4 MUg/mL. Apoptosis triggered by CMEMM in HL-60 cells was confirmed by the following observations: ( a) characteristic apoptotic nuclear fragmentation, (b) dose-dependent accumulation of sub-G(1) phase in cell cycle analyses, (c) increased percentages of annexin V-positive apoptotic cells, and (d) dose-dependent elevation of active caspase-3. Furthermore, an in vivo tumor growth suppression effect by CMEMM (500 mg/kg/d intraperitoneally) was observed in mouse xenografts. The results suggest that CMEMM exerts antileukemic effects via an apoptotic pathway in HL-60 cells, and could be a candidate for developing antileukemic agents in the future. PMID- 20713377 TI - Effects of sesquiterpenes isolated from largehead atractylodes rhizome on growth, migration, and differentiation of B16 melanoma cells. AB - The aims of this study were to isolate sesquiterpene compounds from the largehead atractylodes rhizome (LAR) and to investigate their effects on B16 cancer cells. A total of 8 sesquiterpenes from LAR were identified, of which eudesm-4 (15), 7 diene-9alpha, 11-diol (7) was isolated for the first time. All 8 compounds inhibited growth of B16 cells, and atractylenolide I (AT-I), atractylenolide II (AT-II), and atractylenolactam (ATR) were the most potent, with IC(50) values of 76.46, 84.02, and 54.88 MUMU, respectively. Monomer lactone or lactam structures in the 8 compounds appeared to be critical for their antiproliferative activities. In addition, AT-I, AT-II, and ATR could induce cell differentiation and inhibit cell migration. Western blot analysis indicated that 2 of the compounds, AT-I and AT-II, could inactivate ERK, where all 3 inhibited AKT activation, suggesting that Ras/ERK and PI3K/AKT signaling pathways are involved in the action mechanisms of the LAR sesquiterpene compounds. PMID- 20713382 TI - Global food and farming futures. PMID- 20713383 TI - The future of the global food system. AB - Although food prices in major world markets are at or near a historical low, there is increasing concern about food security-the ability of the world to provide healthy and environmentally sustainable diets for all its peoples. This article is an introduction to a collection of reviews whose authors were asked to explore the major drivers affecting the food system between now and 2050. A first set of papers explores the main factors affecting the demand for food (population growth, changes in consumption patterns, the effects on the food system of urbanization and the importance of understanding income distributions) with a second examining trends in future food supply (crops, livestock, fisheries and aquaculture, and 'wild food'). A third set explores exogenous factors affecting the food system (climate change, competition for water, energy and land, and how agriculture depends on and provides ecosystem services), while the final set explores cross-cutting themes (food system economics, food wastage and links with health). Two of the clearest conclusions that emerge from the collected papers are that major advances in sustainable food production and availability can be achieved with the concerted application of current technologies (given sufficient political will), and the importance of investing in research sooner rather than later to enable the food system to cope with both known and unknown challenges in the coming decades. PMID- 20713384 TI - Dimensions of global population projections: what do we know about future population trends and structures? AB - The total size of the world population is likely to increase from its current 7 billion to 8-10 billion by 2050. This uncertainty is because of unknown future fertility and mortality trends in different parts of the world. But the young age structure of the population and the fact that in much of Africa and Western Asia, fertility is still very high makes an increase by at least one more billion almost certain. Virtually, all the increase will happen in the developing world. For the second half of the century, population stabilization and the onset of a decline are likely. In addition to the future size of the population, its distribution by age, sex, level of educational attainment and place of residence are of specific importance for studying future food security. The paper provides a detailed discussion of different relevant dimensions in population projections and an evaluation of the methods and assumptions used in current global population projections and in particular those produced by the United Nations and by IIASA. PMID- 20713385 TI - Food consumption trends and drivers. AB - A picture of food consumption (availability) trends and projections to 2050, both globally and for different regions of the world, along with the drivers largely responsible for these observed consumption trends are the subject of this review. Throughout the world, major shifts in dietary patterns are occurring, even in the consumption of basic staples towards more diversified diets. Accompanying these changes in food consumption at a global and regional level have been considerable health consequences. Populations in those countries undergoing rapid transition are experiencing nutritional transition. The diverse nature of this transition may be the result of differences in socio-demographic factors and other consumer characteristics. Among other factors including urbanization and food industry marketing, the policies of trade liberalization over the past two decades have implications for health by virtue of being a factor in facilitating the 'nutrition transition' that is associated with rising rates of obesity and chronic diseases such as cardiovascular disease and cancer. Future food policies must consider both agricultural and health sectors, thereby enabling the development of coherent and sustainable policies that will ultimately benefit agriculture, human health and the environment. PMID- 20713386 TI - Urbanization and its implications for food and farming. AB - This paper discusses the influences on food and farming of an increasingly urbanized world and a declining ratio of food producers to food consumers. Urbanization has been underpinned by the rapid growth in the world economy and in the proportion of gross world product and of workers in industrial and service enterprises. Globally, agriculture has met the demands from this rapidly growing urban population, including food that is more energy-, land-, water- and greenhouse gas emission-intensive. But hundreds of millions of urban dwellers suffer under-nutrition. So the key issues with regard to agriculture and urbanization are whether the growing and changing demands for agricultural products from growing urban populations can be sustained while at the same time underpinning agricultural prosperity and reducing rural and urban poverty. To this are added the need to reduce greenhouse gas emissions and to build resilience in agriculture and urban development to climate change impacts. The paper gives particular attention to low- and middle-income nations since these have more than three-quarters of the world's urban population and most of its largest cities and these include nations where issues of food security are most pressing. PMID- 20713387 TI - Income distribution trends and future food demand. AB - This paper surveys the theoretical literature on the relationship between income distribution and food demand, and identifies main gaps of current food modelling techniques that affect the accuracy of food demand projections. At the heart of the relationship between income distribution and food demand is Engel's law. Engel's law establishes that as income increases, households' demand for food increases less than proportionally. A consequence of this law is that the particular shape of the distribution of income across individuals and countries affects the rate of growth of food demand. Our review of the literature suggests that existing models of food demand fail to incorporate the required Engel flexibility when (i) aggregating different food budget shares among households; and (ii) changing budget shares as income grows. We perform simple simulations to predict growth in food demand under alternative income distribution scenarios taking into account nonlinearity of food demand. Results suggest that (i) distributional effects are to be expected from changes in between-countries inequality, rather than within-country inequality; and (ii) simulations of an optimistic and a pessimistic scenario of income inequality suggest that world food demand in 2050 would be 2.7 per cent higher and 5.4 per cent lower than distributional-neutral growth, respectively. PMID- 20713388 TI - Possible changes to arable crop yields by 2050. AB - By 2050, the world population is likely to be 9.1 billion, the CO(2) concentration 550 ppm, the ozone concentration 60 ppb and the climate warmer by ca 2 degrees C. In these conditions, what contribution can increased crop yield make to feeding the world? CO(2) enrichment is likely to increase yields of most crops by approximately 13 per cent but leave yields of C4 crops unchanged. It will tend to reduce water consumption by all crops, but this effect will be approximately cancelled out by the effect of the increased temperature on evaporation rates. In many places increased temperature will provide opportunities to manipulate agronomy to improve crop performance. Ozone concentration increases will decrease yields by 5 per cent or more. Plant breeders will probably be able to increase yields considerably in the CO(2) enriched environment of the future, and most weeds and airborne pests and diseases should remain controllable, so long as policy changes do not remove too many types of crop-protection chemicals. However, soil-borne pathogens are likely to be an increasing problem when warmer weather will increase their multiplication rates; control is likely to need a transgenic approach to breeding for resistance. There is a large gap between achievable yields and those delivered by farmers, even in the most efficient agricultural systems. A gap is inevitable, but there are large differences between farmers, even between those who have used the same resources. If this gap is closed and accompanied by improvements in potential yields then there is a good prospect that crop production will increase by approximately 50 per cent or more by 2050 without extra land. However, the demands for land to produce bio-energy have not been factored into these calculations. PMID- 20713389 TI - Livestock production: recent trends, future prospects. AB - The livestock sector globally is highly dynamic. In developing countries, it is evolving in response to rapidly increasing demand for livestock products. In developed countries, demand for livestock products is stagnating, while many production systems are increasing their efficiency and environmental sustainability. Historical changes in the demand for livestock products have been largely driven by human population growth, income growth and urbanization and the production response in different livestock systems has been associated with science and technology as well as increases in animal numbers. In the future, production will increasingly be affected by competition for natural resources, particularly land and water, competition between food and feed and by the need to operate in a carbon-constrained economy. Developments in breeding, nutrition and animal health will continue to contribute to increasing potential production and further efficiency and genetic gains. Livestock production is likely to be increasingly affected by carbon constraints and environmental and animal welfare legislation. Demand for livestock products in the future could be heavily moderated by socio-economic factors such as human health concerns and changing socio-cultural values. There is considerable uncertainty as to how these factors will play out in different regions of the world in the coming decades. PMID- 20713390 TI - Food security and marine capture fisheries: characteristics, trends, drivers and future perspectives. AB - World population is expected to grow from the present 6.8 billion people to about 9 billion by 2050. The growing need for nutritious and healthy food will increase the demand for fisheries products from marine sources, whose productivity is already highly stressed by excessive fishing pressure, growing organic pollution, toxic contamination, coastal degradation and climate change. Looking towards 2050, the question is how fisheries governance, and the national and international policy and legal frameworks within which it is nested, will ensure a sustainable harvest, maintain biodiversity and ecosystem functions, and adapt to climate change. This paper looks at global fisheries production, the state of resources, contribution to food security and governance. It describes the main changes affecting the sector, including geographical expansion, fishing capacity building, natural variability, environmental degradation and climate change. It identifies drivers and future challenges, while suggesting how new science, policies and interventions could best address those challenges. PMID- 20713391 TI - Inland capture fisheries. AB - The reported annual yield from inland capture fisheries in 2008 was over 10 million tonnes, although real catches are probably considerably higher than this. Inland fisheries are extremely complex, and in many cases poorly understood. The numerous water bodies and small rivers are inhabited by a wide range of species and several types of fisher community with diversified livelihood strategies for whom inland fisheries are extremely important. Many drivers affect the fisheries, including internal fisheries management practices. There are also many drivers from outside the fishery that influence the state and functioning of the environment as well as the social and economic framework within which the fishery is pursued. The drivers affecting the various types of inland water, rivers, lakes, reservoirs and wetlands may differ, particularly with regard to ecosystem function. Many of these depend on land-use practices and demand for water which conflict with the sustainability of the fishery. Climate change is also exacerbating many of these factors. The future of inland fisheries varies between continents. In Asia and Africa the resources are very intensely exploited and there is probably little room for expansion; it is here that resources are most at risk. Inland fisheries are less heavily exploited in South and Central America, and in the North and South temperate zones inland fisheries are mostly oriented to recreation rather than food production. PMID- 20713392 TI - Aquaculture: global status and trends. AB - Aquaculture contributed 43 per cent of aquatic animal food for human consumption in 2007 (e.g. fish, crustaceans and molluscs, but excluding mammals, reptiles and aquatic plants) and is expected to grow further to meet the future demand. It is very diverse and, contrary to many perceptions, dominated by shellfish and herbivorous and omnivorous pond fish either entirely or partly utilizing natural productivity. The rapid growth in the production of carnivorous species such as salmon, shrimp and catfish has been driven by globalizing trade and favourable economics of larger scale intensive farming. Most aquaculture systems rely on low/uncosted environmental goods and services, so a critical issue for the future is whether these are brought into company accounts and the consequent effects this would have on production economics. Failing that, increased competition for natural resources will force governments to allocate strategically or leave the market to determine their use depending on activities that can extract the highest value. Further uncertainties include the impact of climate change, future fisheries supplies (for competition and feed supply), practical limits in terms of scale and in the economics of integration and the development and acceptability of new bio-engineering technologies. In the medium term, increased output is likely to require expansion in new environments, further intensification and efficiency gains for more sustainable and cost-effective production. The trend towards enhanced intensive systems with key monocultures remains strong and, at least for the foreseeable future, will be a significant contributor to future supplies. Dependence on external feeds (including fish), water and energy are key issues. Some new species will enter production and policies that support the reduction of resource footprints and improve integration could lead to new developments as well as reversing decline in some more traditional systems. PMID- 20713393 TI - The roles and values of wild foods in agricultural systems. AB - Almost every ecosystem has been amended so that plants and animals can be used as food, fibre, fodder, medicines, traps and weapons. Historically, wild plants and animals were sole dietary components for hunter-gatherer and forager cultures. Today, they remain key to many agricultural communities. The mean use of wild foods by agricultural and forager communities in 22 countries of Asia and Africa (36 studies) is 90-100 species per location. Aggregate country estimates can reach 300-800 species (e.g. India, Ethiopia, Kenya). The mean use of wild species is 120 per community for indigenous communities in both industrialized and developing countries. Many of these wild foods are actively managed, suggesting there is a false dichotomy around ideas of the agricultural and the wild: hunter gatherers and foragers farm and manage their environments, and cultivators use many wild plants and animals. Yet, provision of and access to these sources of food may be declining as natural habitats come under increasing pressure from development, conservation-exclusions and agricultural expansion. Despite their value, wild foods are excluded from official statistics on economic values of natural resources. It is clear that wild plants and animals continue to form a significant proportion of the global food basket, and while a variety of social and ecological drivers are acting to reduce wild food use, their importance may be set to grow as pressures on agricultural productivity increase. PMID- 20713394 TI - Competition for water for the food system. AB - Although the global agricultural system will need to provide more food for a growing and wealthier population in decades to come, increasing demands for water and potential impacts of climate change pose threats to food systems. We review the primary threats to agricultural water availability, and model the potential effects of increases in municipal and industrial (M&I) water demands, environmental flow requirements (EFRs) and changing water supplies given climate change. Our models show that, together, these factors cause an 18 per cent reduction in the availability of worldwide water for agriculture by 2050. Meeting EFRs, which can necessitate more than 50 per cent of the mean annual run-off in a basin depending on its hydrograph, presents the single biggest threat to agricultural water availability. Next are increases in M&I demands, which are projected to increase upwards of 200 per cent by 2050 in developing countries with rapidly increasing populations and incomes. Climate change will affect the spatial and temporal distribution of run-off, and thus affect availability from the supply side. The combined effect of these factors can be dramatic in particular hotspots, which include northern Africa, India, China, parts of Europe, the western US and eastern Australia, among others. PMID- 20713395 TI - Competition for land. AB - A key challenge for humanity is how a future global population of 9 billion can all be fed healthily and sustainably. Here, we review how competition for land is influenced by other drivers and pressures, examine land-use change over the past 20 years and consider future changes over the next 40 years. Competition for land, in itself, is not a driver affecting food and farming in the future, but is an emergent property of other drivers and pressures. Modelling studies suggest that future policy decisions in the agriculture, forestry, energy and conservation sectors could have profound effects, with different demands for land to supply multiple ecosystem services usually intensifying competition for land in the future. In addition to policies addressing agriculture and food production, further policies addressing the primary drivers of competition for land (population growth, dietary preference, protected areas, forest policy) could have significant impacts in reducing competition for land. Technologies for increasing per-area productivity of agricultural land will also be necessary. Key uncertainties in our projections of competition for land in the future relate predominantly to uncertainties in the drivers and pressures within the scenarios, in the models and data used in the projections and in the policy interventions assumed to affect the drivers and pressures in the future. PMID- 20713396 TI - Ecosystem services and agriculture: tradeoffs and synergies. AB - Agricultural ecosystems provide humans with food, forage, bioenergy and pharmaceuticals and are essential to human wellbeing. These systems rely on ecosystem services provided by natural ecosystems, including pollination, biological pest control, maintenance of soil structure and fertility, nutrient cycling and hydrological services. Preliminary assessments indicate that the value of these ecosystem services to agriculture is enormous and often underappreciated. Agroecosystems also produce a variety of ecosystem services, such as regulation of soil and water quality, carbon sequestration, support for biodiversity and cultural services. Depending on management practices, agriculture can also be the source of numerous disservices, including loss of wildlife habitat, nutrient runoff, sedimentation of waterways, greenhouse gas emissions, and pesticide poisoning of humans and non-target species. The tradeoffs that may occur between provisioning services and other ecosystem services and disservices should be evaluated in terms of spatial scale, temporal scale and reversibility. As more effective methods for valuing ecosystem services become available, the potential for 'win-win' scenarios increases. Under all scenarios, appropriate agricultural management practices are critical to realizing the benefits of ecosystem services and reducing disservices from agricultural activities. PMID- 20713397 TI - Implications of climate change for agricultural productivity in the early twenty first century. AB - This paper reviews recent literature concerning a wide range of processes through which climate change could potentially impact global-scale agricultural productivity, and presents projections of changes in relevant meteorological, hydrological and plant physiological quantities from a climate model ensemble to illustrate key areas of uncertainty. Few global-scale assessments have been carried out, and these are limited in their ability to capture the uncertainty in climate projections, and omit potentially important aspects such as extreme events and changes in pests and diseases. There is a lack of clarity on how climate change impacts on drought are best quantified from an agricultural perspective, with different metrics giving very different impressions of future risk. The dependence of some regional agriculture on remote rainfall, snowmelt and glaciers adds to the complexity. Indirect impacts via sea-level rise, storms and diseases have not been quantified. Perhaps most seriously, there is high uncertainty in the extent to which the direct effects of CO(2) rise on plant physiology will interact with climate change in affecting productivity. At present, the aggregate impacts of climate change on global-scale agricultural productivity cannot be reliably quantified. PMID- 20713398 TI - Energy and the food system. AB - Modern agriculture is heavily dependent on fossil resources. Both direct energy use for crop management and indirect energy use for fertilizers, pesticides and machinery production have contributed to the major increases in food production seen since the 1960s. However, the relationship between energy inputs and yields is not linear. Low-energy inputs can lead to lower yields and perversely to higher energy demands per tonne of harvested product. At the other extreme, increasing energy inputs can lead to ever-smaller yield gains. Although fossil fuels remain the dominant source of energy for agriculture, the mix of fuels used differs owing to the different fertilization and cultivation requirements of individual crops. Nitrogen fertilizer production uses large amounts of natural gas and some coal, and can account for more than 50 per cent of total energy use in commercial agriculture. Oil accounts for between 30 and 75 per cent of energy inputs of UK agriculture, depending on the cropping system. While agriculture remains dependent on fossil sources of energy, food prices will couple to fossil energy prices and food production will remain a significant contributor to anthropogenic greenhouse gas emissions. Technological developments, changes in crop management, and renewable energy will all play important roles in increasing the energy efficiency of agriculture and reducing its reliance of fossil resources. PMID- 20713399 TI - Globalization's effects on world agricultural trade, 1960-2050. AB - Recent globalization has been characterized by a decline in the costs of cross border trade in farm and other products. It has been driven primarily by the information and communication technology revolution and-in the case of farm products-by reductions in governmental distortions to agricultural production, consumption and trade. Both have boosted economic growth and reduced poverty globally, especially in Asia. The first but maybe not the second of these drivers will continue in coming decades. World food prices will depend also on whether (and if so by how much) farm productivity growth continues to outpace demand growth and to what extent diets in emerging economies move towards livestock and horticultural products at the expense of staples. Demand in turn will be driven not only by population and income growth, but also by crude oil prices if they remain at current historically high levels, since that will affect biofuel demand. Climate change mitigation policies and adaptation, water market developments and market access standards particularly for transgenic foods will add to future production, price and trade uncertainties. PMID- 20713400 TI - Food price volatility. AB - The high food prices experienced over recent years have led to the widespread view that food price volatility has increased. However, volatility has generally been lower over the two most recent decades than previously. Variability over the most recent period has been high but, with the important exception of rice, not out of line with historical experience. There is weak evidence that grains price volatility more generally may be increasing but it is too early to say. PMID- 20713401 TI - Agricultural R&D, technology and productivity. AB - The relationships between basic and applied agricultural R&D, developed and developing country R&D and between R&D, extension, technology and productivity growth are outlined. The declining growth rates of public R&D expenditures are related to output growth and crop yields, where growth rates have also fallen, especially in the developed countries. However, growth in output value per hectare has not declined in the developing countries and labour productivity growth has increased except in the EU. Total factor productivity has generally increased, however it is measured. The public sector share of R&D expenditures has fallen and there has been rapid concentration in the private sector, where six multinationals now dominate. These companies are accumulating intellectual property to an extent that the public and international institutions are disadvantaged. This represents a threat to the global commons in agricultural technology on which the green revolution has depended. Estimates of the increased R&D expenditures needed to feed 9 billion people by 2050 and how these should be targeted, especially by the Consultative Group on International Agricultural Research (CGIAR), show that the amounts are feasible and that targeting sub Saharan Africa (SSA) and South Asia can best increase output growth and reduce poverty. Lack of income growth in SSA is seen as the most insoluble problem. PMID- 20713402 TI - Managing uncertainty: a review of food system scenario analysis and modelling. AB - Complex socio-ecological systems like the food system are unpredictable, especially to long-term horizons such as 2050. In order to manage this uncertainty, scenario analysis has been used in conjunction with food system models to explore plausible future outcomes. Food system scenarios use a diversity of scenario types and modelling approaches determined by the purpose of the exercise and by technical, methodological and epistemological constraints. Our case studies do not suggest Malthusian futures for a projected global population of 9 billion in 2050; but international trade will be a crucial determinant of outcomes; and the concept of sustainability across the dimensions of the food system has been inadequately explored so far. The impact of scenario analysis at a global scale could be strengthened with participatory processes involving key actors at other geographical scales. Food system models are valuable in managing existing knowledge on system behaviour and ensuring the credibility of qualitative stories but they are limited by current datasets for global crop production and trade, land use and hydrology. Climate change is likely to challenge the adaptive capacity of agricultural production and there are important knowledge gaps for modelling research to address. PMID- 20713403 TI - Food waste within food supply chains: quantification and potential for change to 2050. AB - Food waste in the global food supply chain is reviewed in relation to the prospects for feeding a population of nine billion by 2050. Different definitions of food waste with respect to the complexities of food supply chains (FSCs)are discussed. An international literature review found a dearth of data on food waste and estimates varied widely; those for post-harvest losses of grain in developing countries might be overestimated. As much of the post-harvest loss data for developing countries was collected over 30 years ago, current global losses cannot be quantified. A significant gap exists in the understanding of the food waste implications of the rapid development of 'BRIC' economies. The limited data suggest that losses are much higher at the immediate post-harvest stages in developing countries and higher for perishable foods across industrialized and developing economies alike. For affluent economies, post-consumer food waste accounts for the greatest overall losses. To supplement the fragmentary picture and to gain a forward view, interviews were conducted with international FSC experts. The analyses highlighted the scale of the problem, the scope for improved system efficiencies and the challenges of affecting behavioural change to reduce post-consumer waste in affluent populations. PMID- 20713404 TI - Feeding the world healthily: the challenge of measuring the effects of agriculture on health. AB - Agricultural production, food systems and population health are intimately linked. While there is a strong evidence base to inform our knowledge of what constitutes a healthy human diet, we know little about actual food production or consumption in many populations and how developments in the food and agricultural system will affect dietary intake patterns and health. The paucity of information on food production and consumption is arguably most acute in low- and middle income countries, where it is most urgently needed to monitor levels of under nutrition, the health impacts of rapid dietary transition and the increasing 'double burden' of nutrition-related disease. Food availability statistics based on food commodity production data are currently widely used as a proxy measure of national-level food consumption, but using data from the UK and Mexico we highlight the potential pitfalls of this approach. Despite limited resources for data collection, better systems of measurement are possible. Important drivers to improve collection systems may include efforts to meet international development goals and partnership with the private sector. A clearer understanding of the links between the agriculture and food system and population health will ensure that health becomes a critical driver of agricultural change. PMID- 20713405 TI - European Surveillance of Antibiotic Consumption (ESAC) point prevalence survey 2008: paediatric antimicrobial prescribing in 32 hospitals of 21 European countries. AB - BACKGROUND: Antimicrobials are the most common medicines prescribed to children, but very little is known about patterns of hospital paediatric antimicrobial prescribing. This study aimed at describing paediatric antimicrobial prescribing in European hospitals to identify targets for quality improvement. METHODS: The European Surveillance of Antibiotic Consumption (ESAC) project (www.esac.ua.ac.be) collected data during 2 calendar weeks between May and June 2008 in 32 hospitals of 21 European countries with paediatric departments, using a standardized method. The ESAC point prevalence survey included all inpatient beds and identified all patients who were receiving systemic antimicrobials on the day of the survey or had received antimicrobial surgical prophylaxis on the previous day. RESULTS: Of 1799 children, 583 (32%) received one or more antimicrobials (range 17%-100%). The indications were therapeutic in 71%, prophylactic in 26% and both indications in 3% of patients. The parenteral route was used in 82% of therapeutic indications and in 63% of prophylactic indications. Third-generation cephalosporins were the most prescribed antimicrobials for therapeutic indications (18%). A high proportion of treated children received antimicrobial combinations (37%). The most commonly treated diagnosis site was the respiratory tract for both therapeutic use (30%) and prophylaxis (25%). The duration of surgical prophylaxis was >1 day in 67%. CONCLUSIONS: Targets identified for quality improvement of antimicrobial use in children included excessive use of antimicrobial combinations and a high proportion of parenteral antimicrobials, both of which require further investigation. Surgical prophylaxis for >1 day should also be curbed in order to achieve quality improvement. PMID- 20713406 TI - Efficacy, safety and pharmacokinetics of 900/100 mg of darunavir/ritonavir once daily in treatment-experienced patients. AB - OBJECTIVES: To evaluate the virological efficacy, safety, tolerability and pharmacokinetics of a regimen containing 900/100 mg of ritonavir-boosted darunavir once daily in patients with antiretroviral experience but no darunavir resistance. PATIENTS AND METHODS: An observational, prospective, multicentre study was conducted. Patients were included if 900/100 mg of darunavir/ritonavir once daily and at least one other active drug had been started due to virological failure, simplification or toxicity. Minimum follow-up was 24 weeks, or less if there was premature discontinuation of any drug or loss to follow-up. In a subgroup of patients, a complete 24 h pharmacokinetic study was performed by HPLC. RESULTS: One hundred and three patients (47 switch strategies, 56 early salvage therapies) were included. After 6 months, 85/103 (83%; 95% CI: 74%-89%) and 85/93 (91%; 95% CI: 84%-97%) patients had <50 copies/mL HIV-RNA by intention to-treat and on-treatment analyses, respectively. The respective values were 42/47 (89%; 95% CI: 72%-96%) and 42/43 (98%; 95% CI: 88%-100%) in switch therapy, and 43/56 (77%; 95% CI: 64%-87%) and 43/50 (86%; 95% CI: 73%-94%) in salvage therapy. There was a significant increase in CD4 cell counts [+73 cells/mm(3) (95% CI: 43%-102%), P<0.001]. There were no interruptions due to rash or liver toxicity. Significant decreases in cholesterol and triglycerides were seen in patients with abnormal lipids at baseline. Ten patients discontinued antiretrovirals (5 were lost to follow-up and 5 due to side effects). Twenty-five patients were included in the pharmacokinetic study. All patients had trough plasma concentrations >0.05 MUg/mL. CONCLUSIONS: Darunavir/ritonavir at 900/100 mg once daily is highly effective, safe and well tolerated in treatment experienced patients with no darunavir resistance, both in early salvage and switch strategies. Adequate drug plasma levels were achieved in all patients. PMID- 20713407 TI - Mode of action of hydrogen peroxide and other oxidizing agents: differences between liquid and gas forms. AB - OBJECTIVES: Antimicrobials such as chlorine dioxide, peracetic acid and hydrogen peroxide (H(2)O(2)) share a basic mechanism of action (chemical oxidation of cellular components), but profound differences arise in their efficacy against microorganisms. Optimization of activity requires an understanding of their interaction with microbial targets and a clear differentiation between the chemical efficacies of each oxidative biocide. This study aimed to elucidate the biochemical mechanisms of action of oxidizing biocides at a macromolecular level, using amino acids, protein and an enzyme as model substrates for the action of each biocide. METHODS: The interactions of a number of oxidising agents (liquid and gaseous H(2)O(2), ClO(2), peracetic acid formulations) with amino acids, proteins (bovine serum albumin and aldolase) and enzymes were investigated by spectrophotometry, SDS-PAGE and alkaline phosphatase activity measurements. RESULTS: Biocide reactions yielded different types of oxidative structural change and different degrees of oxidation to amino acids and proteins, and differences in activity against a microbial enzyme. In particular there was a marked difference in the interactions of liquid H(2)O(2) and gaseous H(2)O(2) with the macromolecules, the latter causing greater oxidation; these results explain the dramatic differences in antimicrobial efficacy between liquid and gas peroxide. CONCLUSIONS: These results provide a comprehensive understanding of the differences in interactions between a number of oxidizing agents and macromolecules commonly found in microbial cells. Biochemical mechanistic differences between these oxidative biocides do exist and lead to differential effects on macromolecules. This in turn could provide an explanation as to their differences in biocidal activity, particularly between liquid and gas peroxide. PMID- 20713408 TI - Neurocognitive outcome 12 months following cerebellar mutism syndrome in pediatric patients with medulloblastoma. AB - The aim is to prospectively assess early neurocognitive outcome of children who developed cerebellar mutism syndrome (CMS) following surgical resection of a posterior fossa embryonal tumor, compared with carefully matched control patients. Children who were enrolled on an ongoing IRB-approved protocol for treatment of embryonal tumors, were diagnosed with postoperative CMS, and had completed prospectively planned neuropsychological evaluation at 12 months postdiagnosis were considered eligible. The cognitive outcomes of these patients were examined in comparison to patients without CMS from the same treatment protocol and matched with regard to primary diagnosis, age at diagnosis, and risk/corresponding treatment (n = 22 pairs). Seventeen were also matched according to gender, and 14 were also matched according to race. High-risk patients received 36-39.6 Gy CSI and 3D conformal boost to the primary site to 55.8-59.4 Gy. Average-risk patients received 23.4 Gy CSI and 3D conformal boost to the primary site to 55.8 Gy. Significant group differences were found on multiple cognitive outcomes. While the matched control patients exhibited performance in the average range, patients who developed CMS postsurgery were found to have significantly lower performance in processing speed, attention, working memory, executive processes, cognitive efficiency, reading, spelling, and math. Patients treated for medulloblastoma who experience postoperative CMS show an increased risk for neurocognitive impairment, evident as early as 12 months following diagnosis. This study highlights the need for careful follow-up with neuropsychological evaluation and for obtaining critical support for patients and their families. PMID- 20713410 TI - Functional beta-propeller lectins by tandem duplications of repetitive units. AB - Internal symmetry in proteins is likely to be the footprint of evolution by gene duplication and fusion. Like other symmetrical proteins, beta-propellers, which are made of 4-10 beta-sheet units (blades) circularly arranged around a central tunnel, have probably evolved by duplication and fusion of a rudimentary repetitive unit. However, reproducing the evolution of functional beta-propellers by duplication and fusion of repeated units remains a challenge, in particular, because the repeated units must jointly pack to form one hydrophobic core while maintaining intact active sites. As model for generating repeat propellers, we chose tachylectin-2--a highly symmetrical five-bladed beta-propeller lectin with five sugar-binding sites. We report the engineering of folded and functional lectins by duplication and fusion of repetitive sequence modules taken from tachylectin-2. The repeated modules comprise three strands of one blade plus one strand of the next blade, thus enabling the closure of the propeller's ring via strand-strand Velcro-like interactions. Duplication and fusion of five modules with the same sequence gave rise to a highly aggregated protein, yet its soluble fraction exhibited lectin function. Subsequently, a library of diversified sequence modules fused in tandem was selected by phage display for glycoprotein binding. A range of new lectins were isolated with binding and biophysical properties that resemble those of wild-type tachylectin-2. These results demonstrate the ability to construct folded and functional globular repeat proteins, and support the role of duplication and fusion of elementary modules in the evolutionary routes that led to the beta-propellers fold. PMID- 20713409 TI - The polynuclear platinum BBR3610 induces G2/M arrest and autophagy early and apoptosis late in glioma cells. AB - BBR3610 is a polynuclear platinum compound, in which two platinums are linked by a spermine-like linker, and studies in a variety of cancers, including glioma, have shown that it is more potent than conventional platinums and works by different means. Identifying the mechanism of action of BBR3610 would help in developing the drug further for clinical use. Previous work showed that BBR3610 does not induce immediate apoptosis but results in an early G2/M arrest. Here, we report that BBR3610 induces early autophagy in glioma cells. Increased autophagy was also seen in intracranial xenografts treated with BBR3610. Interestingly, upon attenuation of autophagy by RNAi-mediated knockdown of ATG5 or ATG6/BECN1, no change in cell viability was observed, suggesting that the autophagy is neither an effective protection against BBR3610 nor an important part of the mechanism by which BBR3610 reduces glioma cell viability. This prompted a multimodal analysis of 4 cell lines over 2 weeks posttreatment with BBR3610, which showed that the G2/M arrest occurred early and apoptosis occurred later in all cell lines. The cells that survived entered a senescent state associated with mitotic catastrophe in 2 of the cell lines. Together, our data show that the response to treatment with a single agent is complex and changes over time. PMID- 20713411 TI - Rational engineering of Lactobacillus acidophilus NCFM maltose phosphorylase into either trehalose or kojibiose dual specificity phosphorylase. AB - Lactobacillus acidophilus NCFM maltose phosphorylase (LaMP) of the (alpha/alpha)(6)-barrel glycoside hydrolase family 65 (GH65) catalyses both phosphorolysis of maltose and formation of maltose by reverse phosphorolysis with beta-glucose 1-phosphate and glucose as donor and acceptor, respectively. LaMP has about 35 and 26% amino acid sequence identity with GH65 trehalose phosphorylase (TP) and kojibiose phosphorylase (KP) from Thermoanaerobacter brockii ATCC35047. The structure of L. brevis MP and multiple sequence alignment identified (alpha/alpha)(6)-barrel loop 3 that forms the rim of the active site pocket as a target for specificity engineering since it contains distinct sequences for different GH65 disaccharide phosphorylases. Substitution of LaMP His413-Glu421, His413-Ile418 and His413-Glu415 from loop 3, that include His413 and Glu415 presumably recognising the alpha-anomeric O-1 group of the glucose moiety at subsite +1, by corresponding segments from Ser426-Ala431 in TP and Thr419-Phe427 in KP, thus conferred LaMP with phosphorolytic activity towards trehalose and kojibiose, respectively. Two different loop 3 LaMP variants catalysed the formation of trehalose and kojibiose in yields superior of maltose by reverse phosphorolysis with (alpha1, alpha1)- and alpha-(1,2) regioselectivity, respectively, as analysed by nuclear magnetic resonance. The loop 3 in GH65 disaccharide phosphorylase is thus a key determinant for specificity both in phosphorolysis and in regiospecific reverse phosphorolysis. PMID- 20713412 TI - Mass media barriers to social marketing interventions: the example of sun protection in the UK. AB - The role of the mass media in communicating health-related information to the wider population is the focus of this paper. Using the example of sun protection within the UK, we highlight some of the major challenges to raising awareness of steadily increasing melanoma rates and of effective sun protection strategies. The implications of potential barriers to official sun protection messages via conflicting messages in the media are discussed in terms of editorial on sun protection and in the way in which television programme content portrays the issues. Implications for public policy and future research conclude the paper. PMID- 20713413 TI - Family functioning, parental psychological distress, child behavioural problems, socio-economic disadvantage and fruit and vegetable consumption among 4-12 year old Victorians, Australia. AB - The aim of this analysis was to assess relationships between family functioning, parental psychological distress, child behaviour difficulties and fruit and vegetable (F&V) consumption among 4-12-year-old children in Victoria, Australia. We used the 2006 Victorian Child's Health and wellbeing data set that included 3370 randomly selected primary caregivers of 4-12-year-old children interviewed between October 2005 and March 2006. Behavioural problems were measured using the Strengths and Difficulties Questionnaire; level of family functioning was measured using the McMaster Family Assessment Device-General Functioning Scale and parental psychological distress was measured using the Kessler-6 scale. The mean number of servings consumed per day was 2.2 (95% CI: 2.1, 2.3) for fruit and 2.0 (95% CI: 1.9, 2.1) for vegetables. The proportion of children meeting the minimum daily age-specific recommendation was 87.8% (95% CI: 86.4, 89.1%) for fruit and 36.5% (95% CI: 34.5, 38.5) for vegetables. Children with behaviour difficulties, low levels of prosocial behaviours and from poorly functioning households consumed fewer servings of F&V than children who did not experience any environment stressors or behavioural problems. Although parental psychological distress was not associated with fruit intake, daughters of parents who reported higher levels of psychological distress consumed fewer servings of vegetables than daughters of parents who reported lower levels of psychological distress. Child behavioural problems and family functioning and to some extent parental psychological distress were associated with F&V consumption. Programmes aimed at promoting F&V consumption in children should target those families with children experiencing behavioural problems or poorly functioning households. PMID- 20713414 TI - PGD for fragile X syndrome: ovarian function is the main determinant of success. AB - BACKGROUND: PGD for fragile X syndrome (FRAX) is inefficient, probably owing to fewer oocytes, poor embryo quality and difficulties in genetic analysis. We investigated IVF-PGD in FRAX mutation carriers compared with controls, looking at the effects of oocyte and embryo number/quality on live birth outcome. METHODS: We performed IVF-PGD in 27 patients with the FRAX mutation and 33 controls with other genetic diseases. Genetic testing was by multiplex PCR. RESULTS: Seventy nine and 108 IVF-PGD cycles were started in FRAX mutation carriers and controls, respectively. Twenty-two patients had a premutation (CGG repeat number 60-200) and five had a full mutation (300-2000 CGG repeats). FRAX patients required higher doses of gonadotrophins (6788 +/- 2379 versus 4360 +/- 2330, P< 0.001) but had lower peak serum estradiol levels (8166 +/- 5880 versus 10 211 +/- 4673, P = 0.03) and fewer oocytes retrieved (9.8 +/- 6 versus 14 +/- 8, P = 0.01). The cancellation rate (unsatisfactory ovarian response) was higher in the FRAX group than in the control group (13 versus 1%, P < 0.001). When embryos were transferred, ongoing pregnancy/live birth rates per transfer were similar (29 versus 36%, P = 0.54). CONCLUSIONS: Ovarian dysfunction in FRAX carriers is more prevalent and profound than previously appreciated, with a high cancelation rate and reduced efficiency of PGD. The main determinant for successful PGD for FRAX is ovarian dysfunction. When embryo transfer is possible, the results are comparable to PGD for other monogenic diseases. PMID- 20713415 TI - High risk men's perceptions of pre-implantation genetic diagnosis for hereditary breast and ovarian cancer. AB - BACKGROUND: Pre-implantation genetic diagnosis (PGD) is an assisted reproductive technology procedure which provides parents with the option of conducting genetic analyses to determine if a mutation is present in an embryo. Though studies have discussed perceptions of PGD from a general population, couples or high-risk women, no studies to date have specifically examined PGD usage among men. This study sought to explore perceptions and attitudes towards PGD among males who either carry a BRCA mutation or have a partner or first degree relative with a BRCA mutation. METHODS: A cross-sectional survey was conducted among 228 men visiting the Facing Our Risk of Cancer Empowered or Craigslist website. Eligibility criteria included men who self-reported they had been tested for a BRCA mutation or had a partner or first degree relative tested for a BRCA mutation. A 41-item survey assessed socio-demographic, clinical characteristics, PGD knowledge and attitudinal factors and consideration of the use of PGD. Differences in proportions of subgroups were tested using the Monte Carlo exact test for categorical data. A multiple logistic regression model was then built through a backward elimination procedure. RESULTS: Although 80% of men reported being previously unfamiliar with PGD, after learning the definition of PGD, 34% of the 228 respondents then said they would 'ever consider the use of PGD'. Respondents who thought of PGD only in terms of 'health and safety' were almost three times more likely (OR = 2.82; 95% 1.19-6.71) to 'ever consider the use of PGD' compared with respondents who thought of PGD in terms of both 'health and safety', and 'religion and morality'. CONCLUSIONS: As with other anonymous web based surveys, we cannot verify clinical characteristics that may impact consideration of PGD use. Our findings indicate high-risk men need more information about PGD and may benefit from educational materials to assist them in reproductive decision-making. PMID- 20713416 TI - Silencing of cofilin-1 gene attenuates biological behaviours of stromal cells derived from eutopic endometria of women with endometriosis. AB - BACKGROUND: Eutopic endometria with endometriosis (EMs) differ dramatically from normal endometria, physiologically and biochemically, yet the pathogenesis of EMs remains unclear. Cofilin-1 (CFL1), a critical modulator of the actin cystoskeleton, is associated with tumour progression, cell motility, cell adhesion, cell invasion and angiogenesis. Although eutopic endometria with EMs exhibit many malignant-like behaviours and a higher expression of CFL1 than normal endometria, the effects of CFL1 on the pathogenesis of EMs are unknown. The aim of this study was to explore the role of CFL1 expression in proliferation, apoptosis, adhesion, invasion, angiogenesis and ultrastructure of endometrial cells. METHODS: We isolated and cultured stromal cells derived from the eutopic endometria of 30 patients with advanced ovarian EMs (ESCs, Stromal Cells of eutopic endometria in Endometriosis patients) and 30 control patients without EMs (NSCs, Stromal Cells of eutopic endometria in Non-endometriosis patients), and evaluated their proliferation, apoptosis, adhesion, invasion and expression of markers of adhesion, invasion and angiogenesis in vitro. In addition, these functions were examined after short hairpin RNA (shRNA) was used to silence the CFL1 gene in ESCs, and pEGFP-N1-CFL recombinant plasmid was transiently transfected into NSCs to up-regulate CFL1 expression. RESULTS: Under basal conditions, CFL1 mRNA and protein were overexpressed in ESCs. Proliferation, adhesion, invasion and markers of adhesion, invasion and angiogenesis were enhanced in ESCs compared with NSCs; in contrast, the apoptosis rate was lower in ESCs than in NSCs. Silencing the CFL1 gene in ESCs markedly attenuated proliferation, adhesion, invasion and expression of the markers, but enhanced apoptosis. Conversely, up-regulation of CFL1 in NSCs increased proliferation, adhesion, invasion and expression of the markers but reduced apoptosis. CONCLUSIONS: The overexpression of CFL1 in ESCs is associated with enhanced proliferation, adhesion, invasion and angiogenesis and reduced apoptosis in EMs. These malignant-like behaviours of ESCs in EMs can be attenuated by inducing CFL1 gene silencing with shRNA interference. PMID- 20713417 TI - Fertility preservation for girls and young women with cancer: what are the remaining challenges? PMID- 20713418 TI - Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma. AB - BACKGROUND: In a phase II, open-label, multicentre Japanese study, sunitinib demonstrated antitumour activity and acceptable tolerability in metastatic renal cell carcinoma patients. Final survival analyses and updated results are reported. METHODS: Fifty-one Japanese patients with a clear-cell component of metastatic renal cell carcinoma (25 treatment-naive; 26 cytokine-refractory) received sunitinib 50 mg orally, once daily (Schedule 4/2). Overall and progression-free survivals were estimated by the Kaplan-Meier method. Objective response rate (per Response Evaluation Criteria in Solid Tumours) and safety were assessed with an updated follow-up. RESULTS: First-line and pretreated patients received a median 6.0 and 9.5 treatment cycles, respectively. Investigator assessed, end-of-study objective response rate was 52.0, 53.8 and 52.9% in first line, pretreated and overall intent-to-treat populations, respectively. The median progression-free survival was 12.2 and 10.6 months in first-line and pretreated patients, respectively. Fourteen patients per group died (56 and 54%), and the median overall survival was 33.1 and 32.5 months, respectively. The most common treatment-related Grade 3 or 4 adverse events and laboratory abnormalities were fatigue (24%), hand-foot syndrome (18%), decreased platelet count (55%), decreased neutrophil count (53%) and increased lipase (49%). No Grade 5 treatment related adverse events occurred. Forty patients (78%) required dose reduction, and 13 (25%) discontinued, due to treatment-related adverse events. CONCLUSIONS: With the median overall survival benefit exceeding 2.5 years, and acceptable tolerability, in first-line and pretreated Japanese metastatic renal cell carcinoma patients with Eastern Cooperative Oncology Group performance status 0/1, sunitinib showed a favourable risk/benefit profile, similar to Western studies. However, there was a trend towards greater efficacy and more haematological adverse events in Japanese patients. PMID- 20713419 TI - Supported reporting of first person accounts: assisting people who have mental health challenges in writing and publishing reports about their lived experience. PMID- 20713420 TI - How to follow up advanced-stage borderline tumours? Mode of diagnosis of recurrence in a large series stage II-III serous borderline tumours of the ovary. AB - BACKGROUND: The aim of this study was to describe how recurrences were diagnosed in the largest series of patients treated for an advanced-stage serous borderline ovarian tumour. PATIENTS AND METHODS: From 1973 to 2006, 45 patients with a serous borderline tumour and peritoneal implants relapsed among 162 patients with a follow-up exceeding 1 year. Data concerning recurrences and the mode of diagnosis were reviewed. RESULTS: The median follow-up interval was 8.2 years (range 19-286 months). The mode of diagnosis of recurrences was imaging (n = 19), clinical symptoms (n = 8), cancer antigen (CA) 125 elevation (n = 7), secondary surgery (n = 5) and unknown (n = 6). The median time to recurrence was 31 months (range 4-242 month). The type of recurrence was invasive low-grade serous carcinoma in 14 patients. Five patients died of recurrent tumour. Among the 39 patients with a known mode of diagnosis of recurrence, the most frequent diagnostic method for invasive recurrences was blood CA 125 elevation (6 of 13) and the majority of noninvasive recurrences were diagnosed by imaging (16 of 23). CONCLUSIONS: This study demonstrates that ultrasound is the most relevant follow up procedure in this context. Nevertheless, the blood CA 125 test is of particular interest for detecting invasive recurrent disease, which is the most crucial event. PMID- 20713421 TI - Code status discussions at hospital admission are not associated with patient and surrogate satisfaction with hospital care: results from the multicenter hospitalist study. AB - BACKGROUND: Physicians may avoid code status discussions for fear of decreasing patient or surrogate satisfaction. METHODS: Charts of patients admitted to medical services at 6 university hospitals were reviewed for documentation of a code status discussion in the first 24 hours of admission. Satisfaction with care provided during the hospitalization was assessed by telephone 1 month after discharge. RESULTS: Of the 11 717 patients with 1-month follow-up, 1090 (9.3%) had a code status discussion documented. Patient or surrogate satisfaction did not differ by whether a discussion was documented. The lack of association persisted after adjusting for patient's severity of illness and using propensity adjustment for likelihood of having a discussion. CONCLUSIONS: Discussing code status on admission to the inpatient setting did not affect patient or surrogate satisfaction. PMID- 20713422 TI - Managing cardiac devices near the end of life: a survey of hospice and palliative care providers. AB - Implantable cardioverter defibrillators (ICDs) and pacemakers may change the character of an individual's eventual death. The objective of this study was to explore hospice and palliative care provider attitudes and experience in managing ICDs and pacemakers for patients near the end of life. A voluntary survey was distributed to session attendees at a national conference. Doctors and nurses surveyed overwhelmingly agreed it is appropriate to disable these devices in a terminally ill patient who does not wish to be resuscitated or prolong life. However, respondents emphasized a less defined burden for pacemakers. Respondents also reported limited involvement in such cases and few institutional protocols. As more terminal patients have these devices, research and education on device management protocols/guidelines and on provider communication skills are critical. PMID- 20713424 TI - The inventory of motivations for hospice palliative care volunteerism: a tool for recruitment and retention. AB - Given the essential role of volunteers in hospice palliative care, it would be beneficial to have a recruitment and retention tool that is reliable and valid. To address this gap, the current investigation sought to adapt and extend the Inventory of Motivations for Palliative Care Volunteerism (IMPCV) of Claxton Oldfield, Jefferies, Fawcett, Wasylkiw, and Claxton-Oldfield.(1) The purpose of study 1 was to address methodological concerns of the IMPCV using 141 undergraduate students. After conceptually relevant items were added to the IMPCV, participants indicated the degree of influence each of the motivations would have on their, and another person's, decision to become a hospice palliative care volunteer. In both cases, 5 internally consistent subscales were identified through principal components analysis: altruism, civic responsibility, self-promotion, leisure, and personal gain. Convergent and discriminant validity were demonstrated using an established measure of empathy. In study 2, 141 hospice palliative care volunteers completed the revised and renamed Inventory of Motivations for Hospice Palliative Care Volunteerism (IMHPCV). Confirmatory factor analysis provided support for the 5-factor structure of the IMHPCV. The authors encourage other researchers to use the IMHPCV as a measurement tool in studying the motivations of hospice palliative care volunteers. PMID- 20713423 TI - Prevalence of opioid-related dysuria in patients with advanced cancer having pain. AB - The aim of this study was to assess the prevalence of opioid-induced dysuria in patients with advanced cancer having pain and to evaluate the possible factors associated. A consecutive sample of cancer patients admitted to an acute pain relief and palliative care unit during 8 months was surveyed. Most patients (147, 86.5%) were receiving opioids at admission. The mean age was 65.1 (SD 12.2) and 106 patients were males. Twenty-five patients presented with dysuria at admission (of which 22 were taking opioids, 14.9%). Eleven patients were inserted a bladder catheter at admission for urine monitoring and 18 patients had urinary incontinence. During admission, 31 patients presented dysuria (19% of population was taking opioids). The prevalence of dysuria was more frequent in males, in patients presenting pelvic masses or who had pelvic surgery, and patients with neurological deficits. Opioid switching during admission was correlated to the occurrence of dysuria. Patients with chronic cancer pain receiving opioid therapy present a prevalence of bladder dysfunction of about 15%, which is influenced by several concomitant factors. Given the complex clinical picture of advanced cancer patients, further studies should be performed to explore the presence of dysuria in patients with no pain and not receiving opioids to know the real weight of opioid therapy with respect to other variables. PMID- 20713425 TI - Evaluating causes for unplanned hospital readmissions of palliative care patients. AB - This study evaluated reasons why palliative care patients were readmitted within 30 days of discharge. A secondary purpose was to determine whether length of stay (LOS) was different between readmission reasons. From July 2006 to June 2007, 156 palliative care readmissions were identified. Codes were assigned to each readmission and included compliance issues, discharge planning, disease process, new diagnosis, premature discharge, surgical complications, and other. Results demonstrated that disease progression (63%) and development of new co-morbidities (17%) were the primary readmission causes. No significant differences among readmission causes for LOS were identified. As the primary reason for readmission was the disease process, a closer look at the most common disease processes and the specific complications that resulted in a readmission would be helpful in planning patient care. PMID- 20713426 TI - Validation of a new automatic smoking machine to study the effects of cigarette smoke in newborn lambs. AB - The aim of this study was to describe the characteristics and validate the use of a new, custom-built automatic smoking machine (ASM), primarily designed to study the effects of an environmental tobacco smoke surrogate (ETS surrogate) exposure in animals of various sizes, including large animals. The equipment includes a programmable ASM coupled to a vented whole body chamber, where animals can be exposed to both mainstream and sidestream smoke. The user-friendly interface allows for full programming of puff volume (1-60 mL), time interval between two puffs (1-60 s) and between two cigarettes (1-60 min). Eight newborn lambs were exposed to either 10 (4 lambs, C10 group) or 20 (4 lambs, C20 group) cigarettes, 8 h per day for 15 days. Four additional control, lambs were exposed to air (C0 group). Weight gain was identical in all three groups of lambs. Urinary cotinine/creatinine ratio increased with the number of cigarettes smoked (C0: 11 +/- 7 ng/mg; C10: 961 +/- 539 ng/mg; C20: 1821 +/- 312 ng/mg), with levels in the C10 and C20 groups in keeping with values published in infants exposed to ETS. Overall, results show that our new ASM is especially well suited for ETS surrogate exposure in non-restrained, non-anaesthetized large animals such as sheep. PMID- 20713428 TI - The effects of urethane on the isoflurane minimum alveolar concentration in rats. AB - Urethane is often used as a sole anaesthetic agent for non-recovery studies in laboratory animals. However, the use of urethane is controversial, in part, because the electroencephalogram after urethane administration is similar to the electroencephalogram recorded from unanaesthetized animals. Here, we assessed the minimum alveolar concentration (MAC)-sparing effects of urethane by measuring the effect of two doses of urethane on the MAC of isoflurane in male Sprague Dawley rats. Isoflurane MAC was measured before and after intravenous administration of urethane at 1.0 g/kg (Group G1, n = 6) and 1.5 g/kg (Group G1.5, n = 6), or an equal volume of 0.9% saline (Group Gs, n = 6). Baseline isoflurane MAC was not statistically different between groups (isoflurane concentration: 1.47 +/- 0.08%, 1.40 +/- 0.19% and 1.42 +/- 0.12% for G1, G1.5 and Gs, respectively). Intravenous injection of saline did not alter isoflurane MAC (post-saline MAC: 1.43 +/- 0.11%). After urethane administration, isoflurane MAC decreased in a dose dependent manner (new MAC G1: 0.19 +/- 0.06%; G1.5: 0.03 +/- 0.01%; P < 0.05). The isoflurane MAC after 1.5 g/kg urethane was not significantly different from room air isoflurane concentrations (0.01 +/- 0.01%), demonstrating a 100% MAC reduction at this dose. In conclusion, high-dose urethane (1.5 g/kg intravenously) was suitable as a sole anaesthetic agent to prevent gross purposeful movement during the conditions of the study, whereas low-dose urethane (1.0 g/kg intravenously) was not. PMID- 20713427 TI - Family relationship of female breeders reduce the systematic inter-individual variation in the gut microbiota of inbred laboratory mice. AB - The gut microbiota (GM) may influence disease expression in several animal models for inflammatory diseases. It may therefore seem reasonable to pursue reduction in the number of animals used for individual studies by reducing the variation in the GM. Previous studies have shown that the composition of the GM is related to genetics to a certain extent. We hypothesized that the GM similarity in a group of mice born by mothers not being sisters would be lower than that in a group born by mothers being sisters. The lower similarity could lead to clustering of the GM of mice born by non-sisters according to their mothers, while such clustering would not be visible if the mothers were sisters. We used 16S rRNA gene (V3 region) polymerase chain reaction-derived amplicon profiling by denaturing gradient gel electrophoresis (DGGE) to study the GM composition in caecum samples of 33 eight-week-old C57BL/6Sca mice from a breeding set-up with dam breeders that were sisters, as well as caecum samples of 35 eight-week-old C57BL/6Sca mice from a breeding set-up with dam breeders that were not sisters. Principal component analysis revealed a significant difference between the litters from the breeding set-up with dam breeders that were not sisters, whereas no significant difference between the litters based on the breeding set-up with dam breeders that were sisters was observed. The results obtained indicate that the systematic variation in the GM of inbred mice can be reduced by increasing the family relatedness of the breeding pairs. PMID- 20713429 TI - Removal of the toxic effects of chlormadinon acetate on the development of Drosophila melanogaster via the use of nordihydroguaiaretic acid. AB - In this study, the effects of chlormadinon acetate (CMA) and CMA + nordihydroguaiaretic acid (NDGA) on various developmental stages of Drosophila melanogaster were investigated. Different concentrations of CMA (1.0; 3.0; 5.0 and 10.0 MUM/100 mL medium) and CMA + NDGA as the concentrations of CMA (1.0 + 1.0; 3.0 + 3.0; 5.0 + 5.0 and 10.0 + 10.0 MUM/100 mL medium) were carried out during the developmental periods of the flies. When F(1) progeny of control and application groups were compared, CMA was found to extend the process of metamorphosis and decrease the total offspring numbers. However, these negative effects were inhibited by NDGA treatment at different concentrations. These results suggest that NDGA could effectively inhibit CMA-induced abnormalities in developmental stages of D. melanogaster. It was found that the difference between the groups was significantly important (p < 0.05). PMID- 20713430 TI - Food contaminant acrylamide increases expression of Cox-2 and nitric oxide synthase in breast epithelial cells. AB - Acrylamide has been discovered in foods cooked at high temperature. A potentially harmful effect of this dietary component has been suggested by data indicating its association with increased breast cancer. This study investigated the potential effects of acrylamide in nontumorigenic breast cells by assessing expression levels of inducible nitric oxide synthase (iNOS) and cycloogenase-2 (Cox-2) and NOS activity, which are known to be early molecular changes in disease formation. Treatment of cells with acrylamide increased levels of iNOS (both expression and activity) and Cox-2. Its potent metabolite, glycidamide, also induced both iNOS and Cox-2, with induction of iNOS occurring at a lower concentration. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), another food-borne carcinogen, was found to induce Cox-2 expression. Combining acrylamide with PhIP did not result in a further increase. These studies suggest that further research is needed to determine the role of carcinogens formed from cooking foods in inducing early molecular changes associated with breast cancer. PMID- 20713431 TI - Effects of extremely low magnetic field on the production of invertase by Rhodotorula glutinis. AB - Invertase is an important enzyme used in many fields especially in food industry to produce fructose syrups. The current study focused on increasing invertase production by exposing Rhodotorula glutinis to extremely low magnetic fields (ELMF; 0 and 7 mT). For this purpose, the microorganism was allowed to grow in normal magnetic field and ELMF for 72 hours at the same temperature (24 +/- 2 degrees C). The fermentation was carried out in submerged culture for 120 hours. The results showed that invertase production is strongly dependent on the growth conditions of the microorganism. Both of the different magnetic fields applied to R. glutinis increased invertase production ranged from 48%-67% when compared with the control. On the other hand, ELMF treatment increased biomass formation about 14%-28% when compared with the control. As a result, magnetic field treatment could effectively be used in the production of invertase by R. glutinis. PMID- 20713432 TI - Antagonistic effects of Zingerone, a phenolic alkanone against radiation-induced cytotoxicity, genotoxicity, apoptosis and oxidative stress in Chinese hamster lung fibroblast cells growing in vitro. AB - Zingerone (ZO), a dietary phenolic compound was investigated for its ability to protect against radiation-induced oxidative stress and DNA damage in Chinese hamster fibroblast cells (V79). Cells treated with optimal dose of ZO (25 MUg/ml), 1 h prior radiation exposure resulted in a significant (P<0.01) elevation of cell survival and decreased the genotoxicity (micronuclei and comet assays). Further, pretreatment with ZO significantly reduced radiation-induced oxidative stress as indicated by decreased reactive oxygen species levels and inhibition of mitochondrial depolarisation. The experiments conducted to evaluate the intracellular antioxidant activity in ZO-pretreated cells demonstrated a significant (P<0.01) increase in the various antioxidants like glutathione, gluthione-S-transferase, superoxide dismutase, catalase and a significant (P<0.01) decrease in malondialdehyde levels versus irradiation alone. Further, ZO scavenged various free radicals generated in vitro (OH., O(2)., DPPH., ABTS.(+) and NO.) in a dose-dependent manner. The anti-apoptotic effect of ZO pretreatment was by the inhibition of the activation of capase-3, by upregulating Bcl-2 and down-regulating Bax proteins. Our study demonstrates the antagonistic effect of ZO against radiation-induced cytotoxicity. Further, ZO rendered anti-genotoxic, anti-apoptotic and anti-lipid peroxidative potency, plausibly ascribable to its antioxidant/free radical scavenging ability and also by the suppression of radiation-induced oxidative stress. PMID- 20713433 TI - DNA damage and repair activity after broccoli intake in young healthy smokers. AB - Cruciferous vegetables contain compounds with antioxidant properties (e.g. carotenoids, vitamin C and folates) and can alter the activity of xenobiotic metabolism (i.e. isothiocyanates). These constituents may be particularly important for subjects who are exposed to free radicals and genotoxic compounds, including smokers. The aim of the study was to evaluate the effect of broccoli intake on biomarkers of DNA damage and repair. Twenty-seven young healthy smokers consumed a portion of steamed broccoli (250 g/day) or a control diet for 10 days each within a crossover design with a washout period. Blood was collected before and after each period. The level of oxidatively damaged DNA lesions (formamidopyrimidine DNA glycosylase-sensitive sites), resistance to ex vivo H(2)O(2) treatment and repair of oxidised DNA lesions were measured in peripheral blood mononuclear cells (PBMCs). We also measured mRNA expression levels of repair and defence enzymes: 8-oxoguanine DNA glycosylase (OGG1), nucleoside diphosphate linked moiety X-type motif 1 (NUDT1) and heme oxygenase 1 (HO-1). After broccoli consumption, the level of oxidised DNA lesions decreased by 41% (95% confidence interval: 10%, 72%) and the resistance to H(2)O(2)-induced DNA strand breaks increased by 23% (95% CI: 13%, 34%). Following broccoli intake, a higher protection was observed in subjects with glutathione S-transferase (GST) M1-null genotype. The expression level and activity of repair enzymes was unaltered. In conclusion, broccoli intake was associated with increased protection against H(2)O(2)-induced DNA strand breaks and lower levels of oxidised DNA bases in PBMCs from smokers. This protective effect could be related to an overall improved antioxidant status. PMID- 20713434 TI - Comparing endurance- and resistance-exercise training in people with multiple sclerosis: a randomized pilot study. AB - OBJECTIVE: The purpose of this study was to compare adaptations in functional and quality of life measures following endurance- and resistance-exercise training in people with multiple sclerosis. DESIGN: Cross-over design with an eight-week washout period. SETTING: Community health centre. SUBJECTS: Sixteen individuals with multiple sclerosis. INTERVENTION: Subjects completed both an eight-week endurance- and an eight-week resistance-exercise training programme in a randomized order. The exercise training comprised individualized progressive programmes that were completed twice weekly in a supervised group setting. MAIN MEASURES: Grip strength, functional reach, four step square, timed up and go and six-minute walk tests, Multiple Sclerosis Impact and Modified Fatigue Impact Scales, Becks Depression Inventory and the Health Status Questionnaire Short Form 36. RESULTS: Sixteen of 21 (76%) subjects completed the study. Subjects attended 13.2 +/- 1.6 endurance- and 15.8 +/- 1.9 resistance-exercise training sessions. No adverse events were reported. No significant differences (P < 0.05) in any outcome measures were observed between the two exercise training programmes either at baseline or following the completion of both training programmes. CONCLUSION: Both endurance- and resistance-exercise training were well tolerated and appear to provide similar effects for people with multiple sclerosis, but larger studies are required to confirm these findings. PMID- 20713435 TI - Deriving a Barthel Index from the Northwick Park Dependency Scale and the Functional Independence Measure: are they equivalent? AB - OBJECTIVE: to examine the extent of agreement between Barthel Index scores derived from Northwick Park Dependency Scores (NPDS) and the Functional Independence Measure (FIM) ratings, in an inpatient setting. DESIGN AND SETTING: previously described conversion criteria were applied in a secondary analysis of a large existing dataset, gathered in a tertiary specialist inpatient neurorehabilitation unit. SUBJECTS: patients with neurological disabilities (N = 1347), mainly following acquired brain injury. MAIN MEASURES: comparison of Barthel scores derived from the NPDS (rated by nursing staff) and from parallel FIM scores (rated by the therapy team). RESULTS: very strong intraclass correlations were observed between the total scores (0.93, P<0.001); 95% limits of agreement ranged from -3.53 to 4.90. Item-by-item agreement (linear-weighted Cohen's kappa coefficients) ranged from 0.41 to 0.77, which represents 'moderate' to 'substantial' agreement. A significant bias towards lower NPDS-derived scores (median 10 (interquartile range (IQR) 6-16) compared with median 11 (IQR 7-16) for the FIM-derived score; Wilcoxon z 11.60, P<0.001) was considered most likely to reflect actual differences in patient performance observed by therapy and nursing staff. CONCLUSIONS: this study demonstrates good overall agreement between the Barthel Index ratings derived from NPDS and FIM scores. However, scores may be affected by differential performance with nursing and therapy staff, and should not automatically be regarded as equivalent. PMID- 20713436 TI - 'Getting back to real living': A qualitative study of the process of community reintegration after stroke. AB - OBJECTIVES: To examine the process of community reintegration over the first year following stroke, from the patient's perspective. DESIGN: Qualitative, longitudinal, grounded theory study involving ten participants. During the first year post discharge from inpatient rehabilitation, 46 one-on-one semi-structured interviews were conducted with ten participants. Interviews were completed with participants before discharge from inpatient stroke rehabilitation and in their homes at two weeks, three months, six months and one year post discharge. Analysis was guided by grounded theory methods described by Corbin and Strauss. SUBJECTS: Four women and six men (mean age 59.6 +/- 18.0, all with left hemiparesis and without aphasia) who had sustained their first hemispheric stroke and were returning to the community following inpatient rehabilitation. RESULTS: The process of community reintegration after stroke involved transitioning through a series of goals: gaining physical function, establishing independence, adjusting expectations and getting back to real living. The ultimate challenge for stroke survivors during this process of community reintegration was to create a balance between their expectations of themselves and their physical capacity to engage in meaningful roles. CONCLUSIONS: Over the first year after stroke, participants reported that the process of community reintegration was marked by ongoing changes in their goals. Formal and informal caregivers need to work with stroke survivors living in the community to facilitate realistic and achievable goal setting. Tools which identify meaningful activities should also be incorporated to provide stroke survivors with the opportunity to contribute and engage with others in the community. PMID- 20713437 TI - Cognitive stimulation therapy in the treatment of neuropsychiatric symptoms in Alzheimer's disease: a randomized controlled trial. AB - OBJECTIVE: to determine the efficacy of cognitive stimulation therapy (CST) in the treatment of neuropsychiatric symptoms in patients with Alzheimer's disease. DESIGN: a randomized, controlled, rater-blind clinical trial. SETTING: the military sanatorium. SUBJECTS: thirty-two patients with mild to moderate Alzheimer's disease exhibiting marked neuropsychiatric symptoms were included in the study. INTERVENTION: all 32 patients were randomly assigned to a cognitive stimulation therapy group (n = 16) or a control group (n = 16) for 10 weeks. MAIN MEASURE: the efficacy measures included the Mini Mental State Examination and the Neuropsychiatric Inventory. RESULTS: patients receiving cognitive stimulation therapy showed a greater improvement in the Neuropsychiatric Inventory total score (mean change - 2.06 points versus 0.00 points, t = -4.766, P<0.001) and in the Mini Mental State Examination total score (mean change 0.81 points versus 0.19 points, t =3.106, P =0.004) compared to control at week 10. Analysis of the individual Neuropsychiatric Inventory domains revealed a statistically significant benefit for cognitive stimulation therapy-treated patients in the areas of apathy (mean change -1.06 points versus -0.31 points, P =0.017) and depression/dysphoria (mean change -0.50 points versus 0.06 points, P =0.047). There were no statistically significant benefits for cognitive stimulation therapy-treated patients in the other individual Neuropsychiatric Inventory domains or in the caregiver distress score. CONCLUSIONS: cognitive stimulation therapy has significant efficacy in lowering apathy and depression symptomatology and in the Mini Mental State Examination in patients with mild to moderate Alzheimer's disease. PMID- 20713438 TI - Evaluation of an exercise concept focusing on eccentric strength training of the rotator cuff for patients with subacromial impingement syndrome. AB - OBJECTIVE: To evaluate the effect on pain intensity and function of an exercise concept focusing on specific eccentric strength training of the rotator cuff in patients with subacromial impingement syndrome. DESIGN: Single-subject research design with baseline and treatment phases (AB design). SETTING: Home-based training programme supervised and supported by visits to physiotherapy clinic. SUBJECTS: Ten patients, mean (SD) age 54 (8.6) years, symptom duration 12 (9.1) months. INTERVENTION: Daily eccentric strengthening exercises of the rotator cuff during 12 weeks. MAIN MEASURES: PRIMARY OUTCOME MEASURES: Pain intensity, assessed with a visual analogue scale, and function, using the Patient-Specific Functional Scale. SECONDARY OUTCOME MEASURES: Shoulder function evaluated with the Constant score, and shoulder-related quality of life evaluated with the Western Ontario Rotator Cuff Index. RESULTS: Pain intensity decreased significantly in eight of the ten subjects. Function improved significantly in all ten subjects. Constant score increased in nine subjects and Western Ontario Rotator Cuff Index increased in seven subjects. Mean Constant score for the whole group increased significantly from 44 to 69 points (P = 0.008). Mean Western Ontario Rotator Cuff Index increased from 51 to 71% (P = 0.021). CONCLUSION: A 12 week eccentric strengthening programme targeting the rotator cuff and incorporating scapular control and correct movement pattern can be effective in decreasing pain and increasing function in patients with subacromial impingement syndrome. A randomized controlled trial is necessary to provide stronger evidence of the method. PMID- 20713439 TI - Effects of disinhibitory transcutaneous electrical nerve stimulation and therapeutic exercise on sagittal plane peak knee kinematics and kinetics in people with knee osteoarthritis during gait: a randomized controlled trial. AB - OBJECTIVE: to determine whether sensory transcutaneous electrical nerve stimulation (TENS) augmented with therapeutic exercise and worn for daily activities for four weeks would alter peak gait kinetics and kinematics, compared with placebo electrical stimulation and exercise, and exercise only. DESIGN: randomized controlled trial. SETTING: motion analysis laboratory. SUBJECTS: thirty-six participants with radiographically assessed knee osteoarthritis and volitional quadriceps activation below 90% were randomly assigned to electrical stimulation, placebo and comparison (exercise-only) groups. INTERVENTIONS: participants in all three groups completed a four-week quadriceps strengthening programme directed by an experienced rehabilitation clinician. Active electrical stimulation units and placebo units were worn in the electrical stimulation and placebo groups throughout the rehabilitation sessions as well as during all activities of daily living. MAIN MEASURES: peak external knee flexion moment and angle during stance phase were analysed at a comfortable walking speed before and after the intervention. FINDINGS: Comfortable walking speed increased for all groups over time (TENS 1.16 +/- 0.15 versus 1.32 +/- 0.16 m/s; placebo 1.21 +/- 0.34 versus 1.3 +/- 0.24 m/s; comparison 1.27 +/- 0.18 versus 1.5 +/- 0.14 m/s), yet no group differences in speed were found. No differences were found for peak flexion moment or angle between groups overtime. CONCLUSIONS: TENS in conjunction with therapeutic exercise does not seem to affect peak flexion moment and angle during stance over a four-week period in participants with tibiofemoral osteoarthritis. PMID- 20713440 TI - The comparative effectiveness of clinic, work-site, phone, and Web-based tobacco treatment programs. AB - INTRODUCTION: Tobacco treatment programs may be offered in clinical settings, at work-sites, via telephone helplines, or over the Internet. Little comparative data exist regarding the real-world effectiveness of these programs. This paper compares the reach, effectiveness, and costs of these different modes of cessation assistance. METHODS: This is an observational study of cohorts of participants in Minnesota's QUITPLAN programs in 2004. Cessation assistance was provided in person at 9 treatment centers, using group counseling at 68 work sites, via a telephone helpline, or via the Internet. The main outcomes of the study are enrollment by current smokers, self-reported 30-day abstinence, and cost per quit. Reach was calculated statewide for the helpline and Web site, regionally for the treatment centers, and for the employee population for work site programs. RESULTS: Enrollment was greatest for the Web site (n = 4,698), followed by the helpline (n = 2,351), treatment centers (n = 616), and work-sites (n = 479). The Web site attracted younger smokers. Smokers at treatment centers had higher levels of nicotine dependence. The helpline reached more socially disadvantaged smokers. Responder 30-day abstinence rates were higher for the helpline (29.3%), treatment centers (25.8%), and work-sites (19.6%) compared with the online program (12.5%). These differences persisted after controlling for baseline differences in participant characteristics and use of pharmacological therapy. The cost per quit was lowest for the Web site program ($291 per quit, 95% CI = $229-$372). DISCUSSION: Treatment center, work-site, helpline, and Web site programs differ in their reach, effectiveness, and estimated cost per quit. Each program plays a part in assisting populations of tobacco users in quitting. PMID- 20713441 TI - Breast feeding is associated with postpartum smoking abstinence among women who quit smoking due to pregnancy. AB - INTRODUCTION: The purpose of this study was to characterize the relationship between breast feeding and postpartum smoking abstinence among women who quit smoking due to pregnancy and who were participating in a randomized clinical trial of an intervention designed to prevent postpartum relapse. METHODS: A total of 251 women were enrolled in the intervention between 30 and 33 weeks postpartum and were followed through 26 weeks postpartum. Participant characteristics were assessed at the prepartum baseline visit, any breast feeding was assessed at 8 weeks postpartum, and smoking abstinence was assessed at 8 and 26 weeks postpartum. RESULTS: Although 79.1% of participants intended to breast feed, only 40.2% reported breast feeding at 8 weeks postpartum. Characteristics associated with breast feeding at 8 weeks postpartum included Caucasian race/ethnicity, greater education, higher household income, and being married/living with a significant other. Logistic regression analysis indicated that breast feeding at 8 weeks postpartum was significantly associated with smoking abstinence at 8 weeks postpartum, odds ratio (OR) = 7.27 (95% CI = 3.27, 16.13), p < .001. Breast feeding at 8 weeks postpartum was also associated with abstinence at 26 weeks postpartum after controlling for smoking status at 8 weeks postpartum, OR = 2.64 (95% CI = 1.14, 6.10), p = .02. DISCUSSION: Encouraging breast feeding among women who quit smoking due to pregnancy may facilitate postpartum smoking abstinence while increasing adherence to current infant feeding guidelines. PMID- 20713443 TI - Molecular dissection of telomeric repeat-containing RNA biogenesis unveils the presence of distinct and multiple regulatory pathways. AB - Telomeres are transcribed into telomeric repeat-containing RNA (TERRA), large, heterogeneous, noncoding transcripts which form part of the telomeric heterochromatin. Despite a large number of functions that have been ascribed to TERRA, little is known about its biogenesis. Here, we present the first comprehensive analysis of the molecular structure of TERRA. We identify biochemically distinct TERRA complexes, and we describe TERRA regulation during the cell cycle. Moreover, we demonstrate that TERRA 5' ends contain 7 methylguanosine cap structures and that the poly(A) tail, present on a fraction of TERRA transcripts, contributes to their stability. Poly(A)(-) TERRA, but not poly(A)(+) TERRA, is associated with chromatin, possibly reflecting distinct biological roles of TERRA ribonucleoprotein complexes. In support of this idea, poly(A)(-) and poly(A)(+) TERRA molecules end with distinct sequence registers. We also determine that the bulk of 3'-terminal UUAGGG repeats have an average length of 200 bases, indicating that the length heterogeneity of TERRA likely stems from its subtelomeric regions. Finally, we find that TERRA is regulated during the cell cycle, being lowest in late S phase and peaking in early G(1). Our analyses offer the basis for investigating multiple regulatory pathways that affect TERRA synthesis, processing, turnover, and function. PMID- 20713442 TI - Lysine-specific demethylase 1 regulates the embryonic transcriptome and CoREST stability. AB - Lysine-specific demethylase 1 (LSD1), which demethylates mono- and dimethylated histone H3-Lys4 as part of a complex including CoREST and histone deacetylases (HDACs), is essential for embryonic development in the mouse beyond embryonic day 6.5 (e6.5). To determine the role of LSD1 during this early period of embryogenesis, we have generated loss-of-function gene trap mice and conditional knockout embryonic stem (ES) cells. Analysis of postimplantation gene trap embryos revealed that LSD1 expression, and therefore function, is restricted to the epiblast. Conditional deletion of LSD1 in mouse ES cells, the in vitro counterpart of the epiblast, revealed a reduction in CoREST protein and associated HDAC activity, resulting in a global increase in histone H3-Lys56 acetylation, but not H3-Lys4 methylation. Despite this biochemical perturbation, ES cells with LSD1 deleted proliferate normally and retain stem cell characteristics. Loss of LSD1 causes the aberrant expression of 588 genes, including those coding for transcription factors with roles in anterior/posterior patterning and limb development, such as brachyury, Hoxb7, Hoxd8, and retinoic acid receptor gamma (RARgamma). The gene coding for brachyury, a key regulator of mesodermal differentiation, is a direct target gene of LSD1 and is overexpressed in e6.5 Lsd1 gene trap embryos. Thus, LSD1 regulates the expression and appropriate timing of key developmental regulators, as part of the LSD1/CoREST/HDAC complex, during early embryonic development. PMID- 20713444 TI - Srs2 plays a critical role in reversible G2 arrest upon chronic and low doses of UV irradiation via two distinct homologous recombination-dependent mechanisms in postreplication repair-deficient cells. AB - Differential posttranslational modification of proliferating cell nuclear antigen (PCNA) by ubiquitin or SUMO plays an important role in coordinating the processes of DNA replication and DNA damage tolerance. Previously it was shown that the loss of RAD6-dependent error-free postreplication repair (PRR) results in DNA damage checkpoint-mediated G(2) arrest in cells exposed to chronic low-dose UV radiation (CLUV), whereas wild-type and nucleotide excision repair-deficient cells are largely unaffected. In this study, we report that suppression of homologous recombination (HR) in PRR-deficient cells by Srs2 and PCNA sumoylation is required for checkpoint activation and checkpoint maintenance during CLUV irradiation. Cyclin-dependent kinase (CDK1)-dependent phosphorylation of Srs2 did not influence checkpoint-mediated G(2) arrest or maintenance in PRR-deficient cells but was critical for HR-dependent checkpoint recovery following release from CLUV exposure. These results indicate that Srs2 plays an important role in checkpoint-mediated reversible G(2) arrest in PRR-deficient cells via two separate HR-dependent mechanisms. The first (required to suppress HR during PRR) is regulated by PCNA sumoylation, whereas the second (required for HR-dependent recovery following CLUV exposure) is regulated by CDK1-dependent phosphorylation. PMID- 20713446 TI - Regulation of nucleolar chromatin by B23/nucleophosmin jointly depends upon its RNA binding activity and transcription factor UBF. AB - Histone chaperones regulate the density of incorporated histone proteins around DNA transcription sites and therefore constitute an important site-specific regulatory mechanism for the control of gene expression. At present, the targeting mechanism conferring this site specificity is unknown. We previously reported that the histone chaperone B23/nucleophosmin associates with rRNA chromatin (r-chromatin) to stimulate rRNA transcription. Here, we report on the mechanism for site-specific targeting of B23 to the r-chromatin. We observed that, during mitosis, B23 was released from chromatin upon inactivation of its RNA binding activity by cdc2 kinase-mediated phosphorylation. The phosphorylation status of B23 was also shown to strongly affect its chromatin binding activity. We further found that r-chromatin binding of B23 was a necessary condition for B23 histone chaperone activity in vivo. In addition, we found that depletion of upstream binding factor (UBF; an rRNA transcription factor) decreased the chromatin binding affinity of B23, which in turn led to an increase in histone density at the r-chromatin. These two major strands of evidence suggest a novel cell cycle-dependent mechanism for the site-specific regulation of histone density via joint RNA- and transcription factor-mediated recruitment of histone chaperones to specific chromosome loci. PMID- 20713445 TI - The transcriptional mediator subunit MED1/TRAP220 in stromal cells is involved in hematopoietic stem/progenitor cell support through osteopontin expression. AB - MED1/TRAP220, a subunit of the transcriptional Mediator/TRAP complex, is crucial for various biological events through its interaction with distinct activators, such as nuclear receptors and GATA family activators. In hematopoiesis, MED1 plays a pivotal role in optimal nuclear receptor-mediated myelomonopoiesis and GATA-1-induced erythropoiesis. In this study, we present evidence that MED1 in stromal cells is involved in supporting hematopoietic stem and/or progenitor cells (HSPCs) through osteopontin (OPN) expression. We found that the proliferation of bone marrow (BM) cells cocultured with MED1 knockout (Med1(-/-)) mouse embryonic fibroblasts (MEFs) was significantly suppressed compared to the control. Furthermore, the number of long-term culture-initiating cells (LTC-ICs) was attenuated for BM cells cocultured with Med1(-/-) MEFs. The vitamin D receptor (VDR)- and Runx2-mediated expression of OPN, as well as Mediator recruitment to the Opn promoter, was specifically attenuated in the Med1(-/-) MEFs. Addition of OPN to these MEFs restored the growth of cocultured BM cells and the number of LTC-ICs, both of which were attenuated by the addition of the anti-OPN antibody to Med1(+/+) MEFs and to BM stromal cells. Consequently, MED1 in niche appears to play an important role in supporting HSPCs by upregulating VDR- and Runx2-mediated transcription on the Opn promoter. PMID- 20713447 TI - Tetrahymena telomerase protein p65 induces conformational changes throughout telomerase RNA (TER) and rescues telomerase reverse transcriptase and TER assembly mutants. AB - The biogenesis of the Tetrahymena telomerase ribonucleoprotein particle (RNP) is enhanced by p65, a La family protein. Single-molecule and biochemical studies have uncovered a hierarchical assembly of the RNP, wherein the binding of p65 to stems I and IV of telomerase RNA (TER) causes a conformational change that facilitates the subsequent binding of telomerase reverse transcriptase (TERT) to TER. We used purified p65 and variants of TERT and TER to investigate the conformational rearrangements that occur during RNP assembly. Nuclease protection assays and mutational analysis revealed that p65 interacts with and stimulates conformational changes in regions of TER beyond stem IV. Several TER mutants exhibited telomerase activity only in the presence of p65, revealing the importance of p65 in promoting the correct RNP assembly pathway. In addition, p65 rescued TERT assembly mutants but not TERT activity mutants. Taken together, these results suggest that p65 stimulates telomerase assembly and activity in two ways. First, by sequestering stems I and IV, p65 limits the ensemble of structural conformations of TER, thereby presenting TERT with the active conformation of TER. Second, p65 acts as a molecular buttress within the assembled RNP, mutually stabilizing TER and TERT in catalytically active conformations. PMID- 20713448 TI - Downregulation of thrombomodulin, a novel target of Snail, induces tumorigenesis through epithelial-mesenchymal transition. AB - The expression of thrombomodulin (TM), a calcium-dependent adhesion molecule, is frequently downregulated in various cancer types. However, the mechanism responsible for the low expression level of TM in tumorigenesis is unknown. Here, an inverse expression of TM and Snail was detected in different cancer cell lines. We further confirmed this inverse relation using the epithelial mesenchymal transition cell model in HaCaT and A431 cells. We demonstrated that Snail suppressed TM expression by binding to E-box (CACCTG) in TM promoter. Moreover, TM knockdown by short hairpin RNA disrupted E-cadherin-mediated cell junctions and contributed to tumorigenesis. In the calcium switch assay, E cadherin lost the ability to associate with beta-catenin and accumulated in cytoplasm in TM knockdown cells. Meanwhile, wound healing and invasive assays showed that TM knockdown promoted cell motility. A subcutaneous injection of TM knockdown transfectants into immunocompromised mice induced squamous cell carcinoma-like tumors. Besides, forced expression of murine TM in TM knockdown cells made the cells reassume epithelium-like morphology and increased calcium dependent association of E-cadherin and beta-catenin. In conclusion, TM, a novel downstream target of Snail in epithelial-mesenchymal transition, is required for maintaining epithelial morphology and functions as a tumor suppressor. PMID- 20713450 TI - A proteomic analysis reveals differential regulation of the sigma(S)-dependent yciGFE(katN) locus by YncC and H-NS in Salmonella and Escherichia coli K-12. AB - The stationary phase sigma factor sigma(S) (RpoS) controls a regulon required for general stress resistance of the closely related enterobacteria Salmonella and Escherichia coli. The sigma(S)-dependent yncC gene encodes a putative DNA binding regulatory protein. Application of the surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) ProteinChip technology for proteome profiling of wild-type and mutant strains of Salmonella enterica serovar Typhimurium revealed potential protein targets for YncC regulation, which were identified by mass spectrometry, and subsequently validated. These proteins are encoded by the sigma(S)-dependent operon yciGFEkatN and regulation of their expression by YncC operates at the transcriptional level, as demonstrated by gene fusion analyses and by in vitro transcription and DNase I footprinting experiments with purified YncC. The yciGFE genes are present (without katN) in E. coli K-12 but are poorly expressed, compared with the situation in Salmonella. We report that the yciGFE(katN) locus is silenced by the histone-like protein H-NS in both species, but that sigma(S) efficiently relieves silencing in Salmonella but not in E. coli K-12. In Salmonella, YncC acts in concert with sigma(S) to activate transcription at the yciG promoter (pyciG). When overproduced, YncC also activated sigma(S)-dependent transcription at pyciG in E. coli K-12, but solely by countering the negative effect of H-NS. Our results indicate that differences between Salmonella and E. coli K-12, in the architecture of cis-acting regulatory sequences upstream of pyciG, contribute to the differential regulation of the yciGFE(katN) genes by H-NS and YncC in these two enterobacteria. In E. coli, this locus is subject to gene rearrangements and also likely to horizontal gene transfer, consistent with its repression by the xenogeneic silencer H-NS. PMID- 20713449 TI - Replication factor C recruits DNA polymerase delta to sites of nucleotide excision repair but is not required for PCNA recruitment. AB - Nucleotide excision repair (NER) operates through coordinated assembly of repair factors into pre- and postincision complexes. The postincision step of NER includes gap-filling DNA synthesis and ligation. However, the exact composition of this NER-associated DNA synthesis complex in vivo and the dynamic interactions of the factors involved are not well understood. Using immunofluorescence, chromatin immunoprecipitation, and live-cell protein dynamic studies, we show that replication factor C (RFC) is implicated in postincision NER in mammalian cells. Small interfering RNA-mediated knockdown of RFC impairs upstream removal of UV lesions and abrogates the downstream recruitment of DNA polymerase delta. Unexpectedly, RFC appears dispensable for PCNA recruitment yet is required for the subsequent recruitment of DNA polymerases to PCNA, indicating that RFC is essential to stably load the polymerase clamp to start DNA repair synthesis at 3' termini. The kinetic studies are consistent with a model in which RFC exchanges dynamically at sites of repair. However, its persistent localization at stalled NER complexes suggests that RFC remains targeted to the repair complex even after loading of PCNA. We speculate that RFC associates with the downstream 5' phosphate after loading; such interaction would prevent possible signaling events initiated by the RFC-like Rad17 and may assist in unloading of PCNA. PMID- 20713451 TI - Proteome-wide alterations in Escherichia coli translation rates upon anaerobiosis. AB - Enzyme reprofiling in bacteria during adaptation from one environmental condition to another may be regulated by both transcription and translation. However, little is known about the contribution of translational regulation. Recently, we have developed a pulse labeling method using the methionine analog azidohomoalanine to determine the relative amounts of proteins synthesized by Escherichia coli in a brief time frame upon a change in environmental conditions. Here we present an extension of our analytical strategy, which entails measuring changes in total protein levels on the same time scale as new protein synthesis. This allows identification of stable and labile proteins and demonstrates that altered levels of most newly synthesized proteins are the result of a change in translation rate rather than degradation rate. With this extended strategy, average relative translation rates for 10 min immediately after a switch from aerobiosis to anaerobiosis were determined. The majority of proteins with increased synthesis rates upon an anaerobic switch are involved in glycolysis and pathways aimed at preventing glycolysis grinding to a halt by a cellular redox imbalance. Our method can be used to compare relative translation rates with relative mRNA levels at the same time. Discrepancies between these parameters may reveal genes whose expression is regulated by translation rather than by transcription. This may help unravel molecular mechanism underlying changes in translation rates, e.g. mediated by small regulatory RNAs. PMID- 20713452 TI - Involvement of cytoskeleton-associated proteins in the commitment of C3H10T1/2 pluripotent stem cells to adipocyte lineage induced by BMP2/4. AB - The developmental pathway that gives rise to mature adipocytes involves two distinct stages: commitment and terminal differentiation. Although the important proteins/factors contributing to terminal adipocyte differentiation have been well defined, the proteins/factors in the commitment of mesenchymal stem cells to the adipocyte lineage cells have not. In this study, we applied proteomics analysis profiling to characterize differences between uncommitted C3H10T1/2 pluripotent stem cells and those that have been committed to the adipocyte lineage by BMP4 or BMP2 with the goal to identify such proteins/factors and to understand the molecular mechanisms that govern the earliest stages of adipocyte lineage commitment. Eight proteins were found to be up-regulated by BMP2, and 27 proteins were up-regulated by BMP4, whereas five unique proteins were up regulated at least 10-fold by both BMP2/4, including three cytoskeleton associated proteins (i.e. lysyl oxidase (LOX), translationally controlled tumor protein 1 (TPT1), and alphaB-crystallin). Western blotting further confirmed the induction of the expression of these cytoskeleton-associated proteins in the committed C3H10T1/2 induced by BMP2/4. Importantly, knockdown of LOX expression totally prevented the commitment, whereas knockdown of TPT1 and alphaB-crystallin expression partially inhibited the commitment. Several published reports suggest that cell shape can influence the differentiation of partially committed precursors of adipocytes, osteoblasts, and chondrocytes. We observed a dramatic change of cell shape during the commitment process, and we showed that knockdown of these cytoskeleton-associated proteins prevented the cell shape change and restored F-actin organization into stress fibers and inhibited the commitment to the adipocyte lineage. Our studies indicate that these differentially expressed cytoskeleton-associate proteins might determine the fate of mesenchymal stem cells to commit to the adipocyte lineage through cell shape regulation. PMID- 20713453 TI - Quantitative proteomics discloses MET expression in mitochondria as a direct target of MET kinase inhibitor in cancer cells. AB - Cancer cells with MET overexpression are paradoxically more sensitive to MET inhibition than cells with baseline MET expression. The underlying molecular mechanisms are incompletely understood. Here, we have traced early responses of SNU5, a MET-overexpressing gastric cancer cell line, exposed to sublethal concentration of PHA-665752, a selective MET inhibitor, using iTRAQ-based quantitative proteomics. More than 1900 proteins were quantified, of which >800 proteins were quantified with at least five peptides. Proteins whose expression was perturbed by PHA-665752 included oxidoreductases, transfer/carrier proteins, and signaling proteins. Strikingly, 38% of proteins whose expression was confidently assessed to be perturbed by MET inhibition were mitochondrial proteins. Upon MET inhibition by a sublethal concentration of PHA-665752, mitochondrial membrane potential increased and mitochondrial permeability transition pore was inhibited concomitant with widespread changes in mitochondrial protein expression. We also showed the presence of highly activated MET in mitochondria, and striking suppression of MET activation by 50 nm PHA 665752. Taken together, our data indicate that mitochondria are a direct target of MET kinase inhibition, in addition to plasma membrane MET. Effects on activated MET in the mitochondria of cancer cells that are sensitive to MET inhibition might constitute a novel and critical noncanonical mechanism for the efficacy of MET-targeted therapeutics. PMID- 20713455 TI - Physical disability trajectories in older Americans with and without diabetes: the role of age, gender, race or ethnicity, and education. AB - PURPOSE: This research combined cross-sectional and longitudinal data to characterize age-related trajectories in physical disability for adults with and without diabetes in the United States and to investigate if those patterns differ by age, gender, race or ethnicity, and education. DESIGN AND METHODS: Data were examined on 20,433 adults aged 51 and older from the 1998 to 2006 Health and Retirement Study. Multilevel models and a cohort-sequential design were applied to quantitatively depict the age norm of physical disability after age 50. RESULTS: Adults with diabetes not only experience greater levels of physical disability but also faster rates of deterioration over time. This pattern is net of attrition, time-invariant sociodemographic factors, and time-varying chronic disease conditions. Differences in physical disability between adults with and without diabetes were more pronounced in women, non-White, and those of lower education. The moderating effects of gender and education remained robust even after controlling for selected covariates in the model. IMPLICATIONS: This study highlighted the consistently greater development of disability over time in adults with diabetes and particularly in those who are women, non-White, or adults of lower education. Future studies are recommended to examine the mechanisms underlying the differential effects of diabetes on physical disability by gender and education. PMID- 20713456 TI - Validity and reliability of the Brazilian version of the psychosocial impact of dental aesthetics questionnaire. AB - Oral health-related quality of life (OHRQoL) is an important aspect of health outcomes and its assessment should be made using validated instruments. The psychosocial impact of dental aesthetics questionnaire (PIDAQ) is an OHRQoL instrument that assesses the psychosocial impact of dental aesthetics was developed and validated for use on young adults. The aim of the present study was to assess the reliability, validity, and applicability of the PIDAQ for young adults in Brazil. After translation and cross-cultural adaptation, the questionnaire was completed by 245 individuals (124 males and 121 females) aged 18-30 years from the city of Belo Horizonte, Brazil. In order to test discriminant validity, the subjects were examined for the presence or absence of malocclusion based on the dental aesthetic index criteria. Dental examinations were carried out by a previously calibrated examiner [weighted kappa = 0.64-1.00, intraclass correlation coefficient (ICC) = 0.78-1.00]. Internal consistency measured by Cronbach's alpha of the subscales was between 0.75 and 0.91 and test retest reliability was assessed using the ICC, which ranged from 0.89 to 0.99 for dental self-confidence and social impact, thereby revealing satisfactory reliability. Discriminant validity revealed that subjects without malocclusion had different PIDAQ scores when compared with those with malocclusion. The results suggest that the Brazilian version of the PIDAQ has satisfactory psychometric properties and is thus applicable to young adults in Brazil. Further research is needed to assess these properties in population studies. PMID- 20713457 TI - Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy. AB - BACKGROUND: CD4(+) regulatory T cells are a specialized subset of T cells that actively control immune responses. Several experimental protocols have been used to expand natural regulatory T cells and to generate adaptive type 1 regulatory T cells for regulatory T-cell-based therapies. DESIGN AND METHODS: The ability of exogenous recombinant human interleukin-10 to induce alloantigen-specific anergy in T cells was investigated and compared to that of interleukin-10 derived from tolerogenic dendritic cells, in mixed lymphocyte cultures. A detailed characterization of the effector functions of the resulting anergized T cells is reported. RESULTS: Interleukin-10, whether exogenous or derived from tolerogenic dendritic cells, induces a population of alloantigen-specific T cells (interleukin-10-anergized T cells) containing type 1 regulatory T cells, which are anergic and actively suppress alloantigen-specific effector T cells present within the mixed population. Interleukin-10-induced anergy is transforming growth factor-beta independent, and is associated with a decreased frequency of alloantigen-specific cytotoxic T lymphocyte precursors, but interleukin-10 anergized T cells are still responsive to third-party, bacterial, and viral antigens. Tolerogenic dendritic cells are more powerful than exogenous interleukin-10 in generating type 1 regulatory T-cell precursors, and are also effective in the context of HLA-matched donors. CONCLUSIONS: Based on these studies, we have developed an efficient and reproducible in vitro method to generate antigen-specific type 1 regulatory T-cell precursors starting from total peripheral blood cells with minimal cell manipulation and suitable for generating type 1 regulatory T cells for regulatory T-cell-based therapies. PMID- 20713458 TI - Immunoassay for human serum hemojuvelin. AB - BACKGROUND: Hemojuvelin, a critical regulator of iron homeostasis, is involved in the regulation of hepcidin expression and iron homeostasis. It is expressed both as a membrane-bound form and as a soluble one. Serum hemojuvelin can be produced by secretion following furin cleavage or by proteolytic cleavage of the membrane bound form by matriptase 2 (TMPRSS6). These forms contribute to down-regulation of hepcidin expression upon iron deficiency or hypoxia. This study describes the development and validation of the first enzyme-linked immunosorbent assay for hemojuvelin in human serum. DESIGN AND METHODS: This assay is based on the use of a recombinant human repulsive guidance molecule-c peptide and a polyclonal antibody against hemojuvelin able to recognize the recombinant peptide and the native soluble hemojuvelin by immunoprecipitation. RESULTS: The enzyme-linked immunosorbent assay was validated and appeared to be a robust method with intra- and inter-coefficients of variance ranging from 2.6% to 15%. The assay was able to quantify hemojuvelin levels in a control population within a range from 0.88 to 1.14 mg/L. Patients with iron-refractory iron-deficiency anemia with a mutation in the TMPRSS6 gene were found to have lower levels of circulating hemojuvelin than those in healthy patients. The enzyme-linked immunosorbent assay also showed that soluble hemojuvelin levels were significantly higher in patients with anemia of chronic disease than in control individuals. CONCLUSIONS: This enzyme-linked immunosorbent assay has a good specificity and sensitivity for the quantification of soluble hemojuvelin in human serum and could be a valuable aid to understanding the physiological role of this protein. PMID- 20713459 TI - Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors. AB - BACKGROUND: Cytokine-induced killer cells are ex vivo-expanded cells with potent antitumor activity. The infusion of cytokine-induced killer cells in patients with acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplant is well tolerated, but limited clinical responses have been observed. To improve their effector functions against acute myeloid leukemia, we genetically modified cytokine-induced killer cells with chimeric receptors specific for the CD33 myeloid antigen. DESIGN AND METHODS: SFG-retroviral vectors coding for anti-CD33-zeta and anti-CD33-CD28-OX40-zeta chimeric receptors were used to transduce cytokine-induced killer cells. Transduced cells were characterized in vitro for their ability to lyse leukemic targets (4-hour (51)chromium-release and 6-day co-cultures assays on human stromal mesenchymal cells), to proliferate ((3)H-thymidine-incorporation assay) and to secrete cytokines (flow cytomix assay) after contact with acute myeloid leukemia cells. Their activity against normal CD34(+) hematopoietic progenitor cells was evaluated by analyzing the colony-forming unit capacity after co-incubation. RESULTS: Cytokine-induced killer cells were efficiently transduced with the anti CD33 chimeric receptors, maintaining their native phenotype and functions and acquiring potent cytotoxicity (up to 80% lysis after 4-hour incubation) against different acute myeloid leukemia targets, as also confirmed in long-term killing experiments. Moreover, introduction of the anti-CD33 chimeric receptors was accompanied by prominent CD33-specific proliferative activity, with the release of high levels of immunostimulatory cytokines. The presence of CD28-OX40 in chimeric receptor endodomain was associated with a significant amelioration of the anti-leukemic activity of cytokine-induced killer cells. Importantly, even though the cytokine-induced killer cells transduced with anti-CD33 chimeric receptors showed toxicity against normal hematopoietic CD34(+) progenitor cells, residual clonogenic activity was preserved. CONCLUSIONS: Our results indicate that anti-CD33 chimeric receptors strongly enhance anti-leukemic cytokine-induced killer cell functions, suggesting that cytokine-induced killer cells transduced with these molecules might represent a promising optimized tool for acute myeloid leukemia immunotherapy. PMID- 20713460 TI - Protein expression analysis of chronic lymphocytic leukemia defines the effect of genetic aberrations and uncovers a correlation of CDK4, P27 and P53 with hierarchical risk. AB - BACKGROUND: Chronic lymphocytic leukemia has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms that are poorly understood. In particular it remains unclear whether the prognostic subgroups of chronic lymphocytic leukemia are characterized by different levels of leukemogenic proteins. DESIGN AND METHODS: Expression of 23 proteins involved in apoptosis, proliferation, DNA damage, and signaling or whose genes map to chromosomal regions known to be critical in chronic lymphocytic leukemia was quantified in 185 cytogenetically well characterized cases of chronic lymphocytic leukemia using immunoblotting. Cases were categorized hierarchically into deletion(17p), deletion(11q), trisomy 12, deletion(13q) as sole abnormality or normal karyotype. Statistical analysis was performed for expression differences between these subgroups. In addition, the expression levels of CDK4, P27 and P53 were quantified over the clinical course and compared to levels in immunopurified B cells from healthy individuals. RESULTS: In subgroups with a good prognosis, differential expression was mainly seen for proteins that regulate apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, differential expression was mostly detected for proteins that control DNA damage and proliferation. Expression levels of CDK4, P27 and P53 were higher compared to those in B cells from healthy individuals and significantly correlated with increasing hierarchical risk. In addition, no significant longitudinal changes of expression levels of CDK4, P27 and P53 could be detected in chronic lymphocytic leukemia patients. CONCLUSIONS: Differences in expression levels of apoptosis- and proliferation-controlling proteins define distinct prognostic subgroups of chronic lymphocytic leukemia and uncover a correlation of levels of CDK4, P27 and P53 proteins with higher hierarchical risk. PMID- 20713461 TI - Vascularization predicts overall survival and risk of transformation in follicular lymphoma. AB - Follicular lymphoma patients display heterogeneous overall survival and variable risk of transformation. Recent studies have highlighted the role of the microenvironment. The contribution of microvessel density to follicular lymphoma survival remains controversial. We used a quantitative tumor mapping approach to determine whether the degree of vascularization correlated with outcome in a uniformly treated cohort. Whole-tissue sections of diagnostic biopsies from 84 cases were stained for CD34 and tumor-to-vessel-distance that encompassed 90% of the tumor (TVD(90)) was determined using image analysis. Twenty-one cases with lower TVD(90) showed inferior overall survival (P=0.0001) and high risk of transformation (P=0.01). These cases significantly correlated with increased Lymphoma-Associated Macrophages (chi(2)=0.025). In multivariate analysis macrophages content, IPI and TVD(90) were independent predictors of overall survival (P=0.05, P=0.001 and P=0.01, respectively) and IPI and TVD(90) predicted risk of transformation (P=0.008 and P=0.08, respectively). Increased angiogenesis is an independent marker of inferior survival and may promote transformation. PMID- 20713462 TI - Co-expression of the collagen receptors leukocyte-associated immunoglobulin-like receptor-1 and glycoprotein VI on a subset of megakaryoblasts. AB - BACKGROUND: The collagen receptor glycoprotein VI generates activating signals through an immunoreceptor tyrosine-based activating motif on the co-associated Fc receptor gamma chain. Leukocyte-associated immunoglobulin-like receptor-1 also ligates collagen but generates inhibitory signals through immunoreceptor tyrosine based inhibitory motifs. Thus far, the cellular expression of glycoprotein VI and leukocyte-associated immunoglobulin-like receptor-1 appears mutually exclusive. DESIGN AND METHODS: Using flow cytometry, we studied expression of collagen receptors on differentiating human megakaryocytes. CD34(+) cells were isolated from umbilical cord blood and matured to megakaryocytes in vitro. Freshly isolated bone marrow cells were used to study primary megakaryocytes. Upon cell sorting, cytospins were made to examine cytological characteristics of differentiation. RESULTS: Megakaryocyte maturation is accompanied by up regulation of glycoprotein VI and down-regulation of leukocyte-associated immunoglobulin-like receptor-1. Interestingly, both in cultures from hematopoietic stem cells and primary cells obtained directly from bone marrow, we identified a subset of morphologically distinct megakaryocytes which co-express glycoprotein VI and leukocyte-associated immunoglobulin-like receptor-1. CONCLUSIONS: This is the first report of a primary cell that co-expresses these collagen receptors with opposite signaling properties. Since megakaryocytes mature in the collagen-rich environment of the bone marrow, these findings may point to a role for leukocyte-associated immunoglobulin-like receptor-1 in the control of megakaryocyte maturation/migration. PMID- 20713463 TI - High concentrations of Na+ and Cl- ions in soil solution have simultaneous detrimental effects on growth of faba bean under salinity stress. AB - Despite the fact that most plants accumulate both sodium (Na(+)) and chloride (Cl(-)) ions to high concentration in their shoot tissues when grown in saline soils, most research on salt tolerance in annual plants has focused on the toxic effects of Na(+) accumulation. There have also been some recent concerns about the ability of hydroponic systems to predict the responses of plants to salinity in soil. To address these two issues, an experiment was conducted to compare the responses to Na(+) and to Cl(-) separately in comparison with the response to NaCl in a soil-based system using two varieties of faba bean (Vicia faba), that differed in salinity tolerance. The variety Nura is a salt-sensitive variety that accumulates Na(+) and Cl(-) to high concentrations while the line 1487/7 is salt tolerant which accumulates lower concentrations of Na(+) and Cl(-). Soils were prepared which were treated with Na(+) or Cl(-) by using a combination of different Na(+) salts and Cl(-) salts, respectively, or with NaCl. While this method produced Na(+)-dominant and Cl(-)-dominant soils, it unavoidably led to changes in the availability of other anions and cations, but tissue analysis of the plants did not indicate any nutritional deficiencies or toxicities other than those targeted by the salt treatments. The growth, water use, ionic composition, photosynthesis, and chlorophyll fluorescence were measured. Both high Na(+) and high Cl(-) reduced growth of faba bean but plants were more sensitive to Cl(-) than to Na(+). The reductions in growth and photosynthesis were greater under NaCl stress and the effect was mainly additive. An important difference to previous hydroponic studies was that increasing the concentrations of NaCl in the soil increased the concentration of Cl(-) more than the concentration of Na(+). The data showed that salinity caused by high concentrations of NaCl can reduce growth by the accumulation of high concentrations of both Na(+) and Cl(-) simultaneously, but the effects of the two ions may differ. High Cl(-) concentration reduces the photosynthetic capacity and quantum yield due to chlorophyll degradation which may result from a structural impact of high Cl(-) concentration on PSII. High Na(+) interferes with K(+) and Ca(2+) nutrition and disturbs efficient stomatal regulation which results in a depression of photosynthesis and growth. These results suggest that the importance of Cl(-) toxicity as a cause of reductions in growth and yield under salinity stress may have been underestimated. PMID- 20713464 TI - Genetic mapping of natural variation in a shade avoidance response: ELF3 is the candidate gene for a QTL in hypocotyl growth regulation. AB - When plants become shaded by neighbouring plants, they perceive a decrease in the red/far-red (R/FR) ratio of the light environment, which provides an early and unambiguous warning of the presence of competing vegetation. The mechanistic bases of the natural genetic variation in response to shade signals remain largely unknown. This study demonstrates that a wide range of genetic variation for hypocotyl elongation in response to an FR pulse at the end of day (EOD), a light signal that simulates natural shade, exists between Arabidopsis accessions. A quantitative trait locus (QTL) mapping analysis was done in the Bayreuth*Shahdara recombinant inbred line population. EODINDEX1 is the most significant QTL identified in response to EOD. The Shahdara alleles at EODINDEX1 caused a reduced response to shade as a consequence of an impaired hypocotyl inhibition under white light, and an accelerated leaf movement rhythm, which correlated positively with the pattern of circadian expression of clock genes such as PRR7 and PRR9. Genetic and quantitative complementation analyses demonstrated that ELF3 is the most likely candidate gene underlying natural variation at EODINDEX1. In conclusion, ELF3 is proposed as a component of the shade avoidance signalling pathway responsible for the phenotypic differences between Arabidopsis populations in relation to adaptation in a changing light environment. PMID- 20713465 TI - Nicotiana attenuata NaHD20 plays a role in leaf ABA accumulation during water stress, benzylacetone emission from flowers, and the timing of bolting and flower transitions. AB - Homeodomain-leucine zipper type I (HD-Zip I) proteins are plant-specific transcription factors associated with the regulation of growth and development in response to changes in the environment. Nicotiana attenuata NaHD20 was identified as an HD-Zip I-coding gene whose expression was induced by multiple stress associated stimuli including drought and wounding. To study the role of NaHD20 in the integration of stress responses with changes in growth and development, its expression was silenced by virus-induced gene silencing (VIGS), and control and silenced plants were metabolically and developmentally characterized. Phytohormone profiling showed that NaHD20 plays a positive role in abscisic acid (ABA) accumulation in leaves during water stress and in the expression of some dehydration-responsive genes including ABA biosynthetic genes. Moreover, consistent with the high levels of NaHD20 expression in corollas, the emission of benzylacetone from flowers was reduced in NaHD20-silenced plants. Additionally, bolting time and the opening of the inflorescence buds was decelerated in these plants in a specific developmental stage without affecting the total number of flowers produced. Water stress potentiated these effects; however, after plants recovered from this condition, the opening of the inflorescence buds was accelerated in NaHD20-silenced plants. In summary, NaHD20 plays multiple roles in N. attenuata and among these are the coordination of responses to dehydration and its integration with changes in flower transitions. PMID- 20713466 TI - Pollen density on the stigma affects endogenous gibberellin metabolism, seed and fruit set, and fruit quality in Pyrus pyrifolia. AB - To clarify the relationship between pollen density and gametophytic competition in Pyrus pyrifolia, gametophytic performance, gibberellin metabolism, fruit set, and fruit quality were investigated by modifying P. pyrifolia pollen grain number and density with Lycopodium spores. Higher levels of pollen density improved seed viability, fruit set, and fruit quality. Treatments with the highest pollen density showed a significantly increased fruit growth rate and larger fruit at harvest. High pollen density increased germination rate and gave a faster pollen tube growth, both in vivo and in vitro. Endogenous gibberellin (GA) concentrations increased in pollen tubes soon after germination and the concentration of two growth-active GAs, GA(3), and GA(4), was positively correlated to final fruit size, cell numbers in the mesocarp, and pollen tube growth rate. These two GAs appear to be biosynthesized de novo in pollen tube and are the main pollen-derived bioactive GAs found after pollen germination. GA(1) levels in the pollen tube appear to be related to a pollen-style interaction that occurred after the pollen grains landed on the stigma. PMID- 20713467 TI - OB-fold domain of KREPA4 mediates high-affinity interaction with guide RNA and possesses annealing activity. AB - KREPA4, also called MP24, is an essential mitochondrial guide RNA (gRNA)-binding protein with a preference for the 3' oligo(U) tail in trypanosomes. Structural prediction and compositional analysis of KREPA4 have identified a conserved OB (oligonucleotide/oligosaccharide-binding)-fold at the C-terminal end and two low compositional complexity regions (LCRs) at its N terminus. Concurrent with these predictions, one or both of these regions in KREPA4 protein may be involved in gRNA binding. To test this possibility, deletion mutants of KREPA4 were made and the effects on the gRNA-binding affinities were measured by quantitative electrophoretic mobility shift assays. The gRNA-binding specificities of these mutants were evaluated by competition experiments using gRNAs with U-tail deletions or stem-loop modifications and uridylated nonguide RNAs or heterologous RNA. Our results identified the predicted OB-fold as the functional domain of KREPA4 that mediates a high-affinity interaction with the gRNA oligo(U) tail. An additional contribution toward RNA-binding function was localized to LCRs that further stabilize the binding through sequence-specific interactions with the guide secondary structure. In this study we also found that the predicted OB-fold has an RNA annealing activity, representing the first report of such activity for a core component of the RNA editing complex. PMID- 20713468 TI - Large-scale mtDNA screening reveals a surprising matrilineal complexity in east Asia and its implications to the peopling of the region. AB - In order to achieve a thorough coverage of the basal lineages in the Chinese matrilineal pool, we have sequenced the mitochondrial DNA (mtDNA) control region and partial coding region segments of 6,093 mtDNAs sampled from 84 populations across China. By comparing with the available complete mtDNA sequences, 194 of those mtDNAs could not be firmly assigned into the available haplogroups. Completely sequencing 51 representatives selected from these unclassified mtDNAs identified a number of novel lineages, including five novel basal haplogroups that directly emanate from the Eurasian founder nodes (M and N). No matrilineal contribution from the archaic hominid was observed. Subsequent analyses suggested that these newly identified basal lineages likely represent the genetic relics of modern humans initially peopling East Asia instead of being the results of gene flow from the neighboring regions. The observation that most of the newly recognized mtDNA lineages have already differentiated and show the highest genetic diversity in southern China provided additional evidence in support of the Southern Route peopling hypothesis of East Asians. Specifically, the enrichment of most of the basal lineages in southern China and their rather ancient ages in Late Pleistocene further suggested that this region was likely the genetic reservoir of modern humans after they entered East Asia. PMID- 20713469 TI - Contrasting evolutionary patterns of the Rp1 resistance gene family in different species of Poaceae. AB - Disease-resistance genes (R-genes) in plants show complex evolutionary patterns. We investigated the evolution of the Rp1 R-gene family in Poaceae, and 409 Rp1 fragments were sequenced from 21 species. Our data showed that the common ancestor of Poaceae had two Rp1 loci, but the number of Rp1 locus in extant species varies from one to five. Some wheat and Zea genotypes have dozens of Rp1 homologues in striking contrast to one or two copies in Brachypodium distachyon. The large number of diverse Rp1 homologues in Zea was the result of duplications followed by extensive sequence exchanges among paralogues, and all genes in maize have evolved in a pattern of Type I R-genes. The high frequency of sequence exchanges did not cause concerted evolution in Zea species, but concerted evolution was obvious between Rp1 homologues from genera Zea and Sorghum. Differentiation of Type I and Type II Rp1 homologues was observed in Oryza species, likely occurred in their common ancestor. One member (Type II R-gene) in the Oryza Rp1 cluster did not change sequences with its paralogues, whereas the other paralogues (Type I R-genes) had frequent sequence exchanges. The functional Pi37 resistance gene in rice was generated through an unequal crossover between two neighboring paralogues followed by four point mutations. The Rp1 homologues in wheat and barley were most divergent, probably due to lack of sequence exchanges among them. Our results shed more light on R-gene evolution, particularly on the differentiation of Type I and Type II R-genes. PMID- 20713470 TI - Alu monomer revisited: recent generation of Alu monomers. AB - Alu is a predominant short interspersed element (SINE) family in the human genome and consists of two monomer units connected by an A-rich linker. At present, dimeric Alu elements are active in humans, but Alu monomers are present as fossilized sequences. A comparative genome analysis of human and chimpanzee genomes revealed eight recent insertions of Alu monomers. One of them was a retroposed product of another Alu monomer with 3' transduction. Further analysis of 1,404 loci of the Alu monomer in the human genome revealed that some Alu monomers were recently generated by recombination between the internal and 3' A rich tracts inside of dimeric Alu elements. The data show that Alu monomers were generated by 1) retroposition of other Alu monomers and 2) recombination between two A-rich tracts. PMID- 20713471 TI - Toxicogenomics applied to in vitro carcinogenicity testing with Balb/c 3T3 cells revealed a gene signature predictive of chemical carcinogens. AB - Information on the carcinogenic potential of chemicals is primarily available for High Production Volume (HPV) products. Because of the limited knowledge gain from routine cancer bioassays and the fact that HPV chemicals are tested only, there is the need for more cost-effective and informative testing strategies. Here we report the application of advanced genomics to a cellular transformation assay to identify toxicity pathways and gene signatures predictive for carcinogenicity. Specifically, genome-wide gene expression analysis and quantitative real time polymerase chain reaction (qRT-PCR) were applied to untransformed and transformed mouse fibroblast Balb/c 3T3 cells that were exposed to either 2, 4 diaminotoluene, benzo(a)pyrene, 2-acetylaminoflourene, or 3-methycholanthrene at IC20 conditions for 24 and 120 h, respectively. Then, bioinformatics was applied to define toxicity pathways and a gene signature predictive of the carcinogenic risk of these chemicals. Although bioinformatics revealed distinct differences for individual chemicals at the gene-level pathway, analysis identified common perturbation that resulted in an identification of 14 genes whose regulation in cancer tissue had already been established. Strikingly, this gene signature was identified in short-term (24 and 120 h) untransformed and transformed cells (3 weeks), therefore demonstrating robustness for its predictive power. The developed testing strategy thus identified commonly regulated carcinogenic pathways and a gene signature that predicted the risk for carcinogenicity for three well-known carcinogens. Overall, the testing strategy warrants in-depth validation for the prediction of carcinogenic risk of industrial chemicals in in vitro carcinogenicity assay. PMID- 20713472 TI - Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells. AB - The current report examines the interactions of silver nanoparticles (Ag-NPs) with the cerebral microvasculature to identify the involvement of proinflammatory mediators that can increase blood-brain barrier (BBB) permeability. Primary rat brain microvessel endothelial cells (rBMEC) were isolated from adult Sprague Dawley rats for an in vitro BBB model. The Ag-NPs were characterized by transmission electron microscopy (TEM), dynamic light scattering, and laser Doppler velocimetry. The cellular accumulation, cytotoxicity (6.25-50 MUg/cm(3)) and potential proinflammatory mediators (interleukin [IL]-1beta, IL-2, tumor necrosis factor [TNF] alpha, and prostaglandin E(2) [PGE(2)]) of Ag-NPs (25, 40, or 80 nm) were determined spectrophotometrically, cell proliferation assay (2,3 bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide) and ELISA. The results show Ag-NPs-induced cytotoxic responses at lower concentrations for 25 and 40 nm when compared with 80-nm Ag-NPs. The proinflammatory responses in this study demonstrate both Ag-NPs size and time-dependent profiles, with IL-1B preceding both TNF and PGE(2) for 25 nm. However, larger Ag-NPs (40 and 80 nm) induced significant TNF responses at 4 and 8 h, with no observable PGE(2) response. The increased fluorescein transport observed in this study clearly indicates size-dependent increases in BBB permeability correlated with the severity of immunotoxicity. Together, these data clearly demonstrate that larger Ag-NPs (80 nm) had significantly less effect on rBMEC, whereas the smaller particles induced significant effects on all the end points at lower concentrations and/or shorter times. Further, this study suggests that Ag-NPs may interact with the cerebral microvasculature producing a proinflammatory cascade, if left unchecked; these events may further induce brain inflammation and neurotoxicity. PMID- 20713473 TI - Parental BMI and childhood undernutrition in India: an assessment of intrauterine influence. AB - OBJECTIVE: The objective of this study was to examine the influence of parental BMI on childhood undernutrition in India. METHODS: The study population was a nationally representative cross-sectional sample of singleton children (n = 15976) who were aged 0 to 59 months from the 2005-2006 Indian National Family Health Survey. Information was obtained by a face-to-face interview with the mother with a 94.5% response rate. Modified Poisson regression models that account for multistage survey design and sampling weights were applied to estimate the associations between parental BMI and childhood undernutrition. The outcome measures were child underweight, stunting, and wasting; parental BMI was the primary exposure. RESULTS: In mutually adjusted models, an increase in 1 unit of maternal BMI was associated with a lower relative risk (RR) for childhood undernutrition (underweight RR: 0.957 [95% confidence interval [CI]: 0.947 0.967]; stunting RR: 0.985 [95% CI: 0.977-0.993]; wasting RR: 0. 941 [95% CI: 0.926-0.958]). The association between paternal BMI and childhood undernutrition was similar to that observed for maternal BMI (underweight RR: 0.961 [95% CI: 0.951-0.971]; stunting RR: 0.986 [95% CI: 0.978-0.995]; wasting RR: 0.965 [95% CI: 0.947-0.982]). CONCLUSIONS: Similarity in the association between paternal/maternal BMI and childhood undernutrition suggests that intergenerational associations in nutritional status are not driven by maternal intrauterine influences. PMID- 20713474 TI - Shoulder height labeling of child restraints to minimize premature graduation. AB - OBJECTIVE: We hypothesized that parents and caregivers would make better judgments about child restraint fit if shoulder height labeling was used to communicate appropriate child restraint transition times. METHODS: Participants were recruited at a shopping center in New South Wales, Australia, and were observed choosing restraints, with and without shoulder height labels indicating appropriate restraint fit, for each of 2 test mannequins (representing a 3-year old child and a 5-year-old child). Demographic and child restraint use experience data also were collected. Generalized estimating equations were used to examine associations between labeling condition and participant's judgment of restraint appropriateness. RESULTS: Participants (N=86) made significantly fewer errors in judging restraint appropriateness for the test mannequins when the restraints included shoulder height labels (P<.001). Depending on label format, the odds that a participant would always make the correct decision were 5.2 (95% confidence interval: 2.7-9.8) to 3.7 (95% confidence interval: 2.0-6.9) times greater when shoulder height labels were included than when they were not. CONCLUSION: The use of shoulder height labels on child safety seats and booster seats is an effective means of communicating child restraint fit to parents and caregivers. PMID- 20713475 TI - Once- vs twice-daily budesonide/formoterol in 6- to 15-year-old patients with stable asthma. AB - OBJECTIVE: To assess efficacy/tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide pMDI (primary) and twice-daily budesonide/formoterol (secondary) in children/adolescents with asthma stabilized with twice-daily budesonide/formoterol. METHODS: This 12-week multicenter, double-blind randomized controlled study (www.clinicaltrials.gov identifier NCT00646321) included 521 patients aged 6 to 15 years with mild/moderate persistent asthma. Patients stabilized during a 4- to 5-week run-in with twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily) received twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily), once-daily budesonide/formoterol pMDI 80/4.5 microgx2 inhalations (160/9 microg daily; evening), or once-daily budesonide pMDI 80 microgx2 inhalations (160 microg daily; evening). RESULTS: Once- or twice daily budesonide/formoterol was more effective than budesonide for evening peak expiratory flow (primary variable) at the end of the 24-hour once-daily dosing interval (Por=16. RESULTS: The prevalence of depressive symptoms was 22.5% for boys and 31.2% for girls. For boys, fish intake was inversely associated with depressive symptoms (adjusted odds ratio [OR] for depressive symptoms in the highest [compared with the lowest] quintile of intake: 0.73 [95% confidence interval (CI): 0.55-0.97]; P for trend=.04). EPA intake showed an inverse association with depressive symptoms (OR: 0.71 [95% CI: 0.54-0.94]; P=.04). DHA intake also showed a similar inverse, albeit nonsignificant, association (OR: 0.79 [95% CI: 0.59-1.05]; P=.11). In addition, intake of EPA plus DHA was inversely associated with depressive symptoms (OR: 0.72 [95% CI: 0.55-0.96]; P=.08). Conversely, no such associations were observed among girls. CONCLUSIONS: Higher intake of fish, EPA, and DHA was independently associated with a lower prevalence of depressive symptoms in early male, but not female, adolescents. PMID- 20713477 TI - Disparities in the evaluation and diagnosis of abuse among infants with traumatic brain injury. AB - OBJECTIVE: To evaluate in a national database the association of race and socioeconomic status with radiographic evaluation and subsequent diagnosis of child abuse after traumatic brain injury (TBI) in infants. METHODS: We conducted a retrospective study of infants with non-motor vehicle-associated TBI who were admitted to 39 pediatric hospitals from January 2004 to June 2008. Logistic regression controlling for age, type, and severity of TBI and the presence of other injuries was performed to examine the association of race and socioeconomic status with the principal outcomes of radiographic evaluation for suspected abuse and diagnosis of abuse. Regression coefficients were transformed to probabilities. RESULTS: After adjustment for type and severity of TBI, age, and other injuries, publicly insured/uninsured infants were more likely to have had skeletal surveys performed than were privately insured infants (81% vs 59%). The difference in skeletal survey performance for infants with public or no insurance versus private insurance was greater among white (82% vs 53%) infants than among black (85% vs 75%) or Hispanic (72% vs 55%) infants (P=.022). Although skeletal surveys were performed in a smaller proportion of white than black or Hispanic infants, the adjusted probability for diagnosis of abuse among infants evaluated with a skeletal survey was higher among white infants (61%) than among black (51%) or Hispanic (53%) infants (P=.009). CONCLUSIONS: National data suggest continued biases in the evaluation for abusive head trauma. The conflicting observations of fewer skeletal surveys among white infants and higher rates of diagnosis among those screened elicit concern for overevaluation in some infants (black or publicly insured/uninsured) or underevaluation in others (white or privately insured). PMID- 20713478 TI - Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To test the efficacy of Lactobacillus reuteri on infantile colic and to evaluate its relationship to the gut microbiota. STUDY DESIGN: Fifty exclusively breastfed colicky infants, diagnosed according to modified Wessel's criteria, were randomly assigned to receive either L reuteri DSM 17 938 (10(8) colony-forming units) or placebo daily for 21 days. Parental questionnaires monitored daily crying time and adverse effects. Stool samples were collected for microbiologic analysis. RESULTS: Forty-six infants (L reuteri group: 25; placebo group: 21) completed the trial. Daily crying times in minutes/day (median [interquartile range]) were 370 (120) vs 300 (150) (P=.127) on day 0 and 35.0 (85) vs 90.0 (148) (P=.022) on day 21, in the L reuteri and placebo groups, respectively. Responders (50% reduction in crying time from baseline) were significantly higher in the L reuteri group versus placebo group on days 7 (20 vs 8; P=.006), 14 (24 vs 13; P=.007), and 21 (24 vs 15; P=.036). During the study, there was a significant increase in fecal lactobacilli (P=.002) and a reduction in fecal Escherichia coli and ammonia in the L reuteri group only (P=.001). There were no differences in weight gain, stooling frequency, or incidence of constipation or regurgitation between groups, and no adverse events related to the supplementation were observed. CONCLUSION: L. reuteri DSM 17 938 at a dose of 10(8) colony-forming units per day in early breastfed infants improved symptoms of infantile colic and was well tolerated and safe. Gut microbiota changes induced by the probiotic could be involved in the observed clinical improvement. PMID- 20713479 TI - Prediction of death for extremely premature infants in a population-based cohort. AB - OBJECTIVE: Although gestational age (GA) is often used as the primary basis for counseling and decision-making for extremely premature infants, a study of tertiary care centers showed that additional factors could improve prediction of outcomes. Our objective was to determine how such a model could improve predictions for a population-based cohort. METHODS: From 2005 to 2008, data were collected prospectively for the California Perinatal Quality Care Collaborative, which encompasses 90% of NICUs in California. For infants born at GAs of 22 to 25 weeks, we assessed the ability of the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5-factor model to predict survival rates, compared with a model using GA alone. RESULTS: In the study cohort of 4527 infants, 3647 received intensive care. Survival rates were 53% for the whole cohort and 66% for infants who received intensive care. In multivariate analyses of data for infants who received intensive care, prenatal steroid exposure, female sex, singleton birth, and higher birth weight (per 100-g increment) were each associated with a reduction in the risk of death before discharge similar to that for a 1-week increase in GA. The multivariate model increased the ability to group infants in the highest and lowest risk categories (mortality rates of >80% and <20%, respectively). CONCLUSIONS: In a population-based cohort, the addition of prenatal steroid exposure, sex, singleton or multiple birth, and birth weight to GA allowed for improved prediction of rates of survival to discharge for extremely premature infants. PMID- 20713480 TI - Nebulized hypertonic saline without adjunctive bronchodilators for children with bronchiolitis. AB - OBJECTIVE: The goal was to determine an adverse event rate for nebulized hypertonic saline solution administered without adjunctive bronchodilators for infants with bronchiolitis. METHODS: This was a retrospective cohort study of the use of nebulized 3% saline for children<2 years of age who were hospitalized with the primary diagnosis of bronchiolitis at a single academic medical center. The medical records of study participants were analyzed for the use of nebulized 3% saline solution and any documented adverse events related to this therapy. Other clinical outcomes evaluated included respiratory distress scores, timing of the use of bronchodilators in relation to 3% saline solution, transfer to a higher level of care, and readmission within 72 hours after discharge. RESULTS: A total of 444 total doses of 3% saline solution were administered, with 377 doses (85%) being administered without adjunctive bronchodilators. Four adverse events occurred with these 377 doses, for a 1.0% adverse event rate (95% confidence interval: 0.3%-2.8%). Adverse events were generally mild. One episode of bronchospasm was documented, for a rate of 0.3% (95% confidence interval: <0.01% 1.6%). CONCLUSIONS: The use of 3% saline solution without adjunctive bronchodilators for inpatients with bronchiolitis had a low rate of adverse events in our center. Additional clinical trials of 3% saline solution in bronchiolitis should evaluate its effectiveness in the absence of adjunctive bronchodilators. PMID- 20713481 TI - The role of pediatricians in the coordinated national effort to address childhood obesity. PMID- 20713482 TI - Disparities in peaks, plateaus, and declines in prevalence of high BMI among adolescents. AB - OBJECTIVES: The objective of this study was to investigate trends in prevalence of high BMI from 2001 to 2008 and examine racial/ethnic disparities. METHODS: Records for a total of 8 283 718 fifth-, seventh-, and ninth-grade students who underwent California's school-based BMI screening between 2001 and 2008 were included. Logistic regression identified trends in prevalence of high BMI (>or=85th, >or=95th, >or=97th, and >or=99th percentiles). RESULTS: For 3 of 4 BMI cut points, prevalence continued to increase for black and American Indian girls through 2008, Hispanic girls plateaued after 2005, non-Hispanic white girls declined to 2001 prevalence levels after peaking in 2005, and Asian girls showed no increases. Non-Hispanic white boys peaked in 2005, then declined to 2001 prevalence levels for all BMI cut points; Hispanic and Asian boys declined after 2005 (for 3 lowest BMI cut points only) but remained above 2001 levels; and American Indian boys peaked later (2007) and declined only for BMI>or=95th. No girls and few boys showed a decline after peaking in prevalence of BMI>or=99th percentile. In 2008, disparities in prevalence were greatest for BMI>or=99th percentile, with prevalence of 4.9% for American Indian girls and 4.6% for black girls versus 1.3% for non-Hispanic white girls. CONCLUSIONS: On the basis of statewide California data, prevalence of high BMI is declining for some groups but has not declined for American Indian and black girls. These trends portend greater disparities over time, particularly in severe obesity. Interventions and policies that are tailored to the highest risk groups should be pursued. PMID- 20713483 TI - Bicalutamide and third-generation aromatase inhibitors in testotoxicosis. AB - Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization. PMID- 20713484 TI - Brain activation of children with developmental coordination disorder is different than peers. AB - OBJECTIVES: Children with developmental coordination disorder (DCD) struggle to learn new motor skills, demonstrating more variable performance than typically developing (TD) children. The purpose of this study was to determine whether patterns of brain activity differed between children with and without DCD while performing a motor task. METHODS: Using functional MRI, we measured brain activation patterns in 7 children with DCD and 7 age-matched peers (aged 8-12 years) during a fine-motor, trail-tracing task. RESULTS: Despite similar levels of behavioral motor performance, different patterns of brain activity were noted between the 2 groups. The group with DCD showed significantly more activation than control subjects in left inferior parietal lobule, right middle frontal gyrus, right supramarginal gyrus, right lingual gyrus, right parahippocampal gyrus, right posterior cingulate gyrus, right precentral gyrus, right superior temporal gyrus, and right cerebellar lobule VI. These results suggest that the group with DCD relied on visuospatial processing to complete the task. The TD group demonstrated significantly more activation than the group with DCD in left precuneus, left superior frontal gyrus, right superior temporal gyrus/insula, left inferior frontal gyrus, and left postcentral gyrus; these regions have been associated with spatial processing, motor control and learning, and error processing. CONCLUSIONS: Children with DCD activate different brain regions from typical children when performing the same trail-tracing task. Despite the small sample size, our results contribute to a growing body of literature suggesting that children with DCD exhibit differences in neural networks and patterns of brain activation relative to same-age peers. PMID- 20713485 TI - Partial thrombus resolution with trofiban in a pregnant woman with mechanical prosthetic mitral valve thrombosis. AB - We present a 15-week pregnant woman who developed mechanical mitral valve thrombosis on a fixed dose of enoxaparin therapy 60 mg twice daily. No reductions were observed in the thrombus size or mean mitral gradient on transesophageal echocardiography (TEE) with 1 week of unfractioned heparin therapy. As the thrombus on TEE imaging was hypermobile and fragile, in addition to a higher dose of enoxaparin (80 mg twice daily), trofiban infusion 0.20 ug/kg per minute was administered for another 1 week. The thrombus on the valve was reduced in size, mobility and fragility of the thrombus diminished, and mean valve gradient decreased on TEE. As complete thrombus resolution was not observed and limitation of valve mobility continued, tissue plasminogen activator (tPA) was given to the patient. A complete thrombus resolution was observed on this therapy. The patient is presented for being the first case in literature whose valvular thrombus reduced with trofiban therapy. PMID- 20713486 TI - The clinical outcome of 260 pediatric ITP patients in one center. AB - In the current study, clinical and laboratory findings and treatment modalities of children with acute and chronic immune thrombocytopenic purpura (ITP) were evaluated retrospectively. Our purpose was to determine clinical outcome of children with ITP and their responses to different treatment regimes. Total of 260 children with ITP were enrolled in the study. The mean age of patients was 76.8 +/- 48.1 months. The therapy responses of high-dose methylprednisolone (HDMP; n = 134), standard dose methylprednisolone (n = 32), and intravenous immunoglobulin (IVIG; n = 15) treatments were similar. Two (0.8%) of the 260 ITP patients had intracranial bleeding. None of the patients died due to hemorrhage. Of all the patients with ITP, 191 (73.5%) completely resolved within 6 months after initiation of the disease and therefore they were diagnosed as acute ITP; 69 patients (26.5%) had progressed into chronic ITP. The therapy responses of HDMP, standard dose methylprednisolone, and IVIG treatments are similar. PMID- 20713487 TI - Resemblance to vWD types and laboratory diagnosis of obligatory carriers of type 3 von Willebrand disease. AB - OBJECTIVES: It is important to diagnose obligatory carrier (OC) type 3 von Willebrand Disease (vWD) in countries, such as Turkey, where marriages between relatives is common. However, mild bleeding or no bleeding in such patients complicates the diagnosis of the disease. It is not clear how the diagnosis of OC type 3 vWD will be made based on FVIII:C (Factor VIII activity), vWF:Ag (von Willebrand factor antigen), vWF:RCo (von Willebrand factor ristocetin cofactor activity), and PFA (platelet function analyzer )-100 parameters. Therefore, the purpose of the study is to investigate how OC type 3 vWD diagnoses may be established by studying laboratory phenotypes of close relatives of patients with diagnosed 3 vWD. PATIENTS AND METHODS: 8 patients with type 3 vWD (index cases) and 20 patients who were defined as OCs type 3 vWD were enrolled into the study. RESULT: 10 cases had similarity with mild type VWD, 4 cases had similarity with moderate type 1 vWD, 4 other cases had type 1 or 2 vWD similarities, 1 case had similarity with severe type 1 vWD, and 1 case also had similarity with severe type 1 or type 2 vWD; regarding their laboratory phenotypic characteristics. CONCLUSION: we identified that OC type 3 vWD is similar specifically to type 1 vWD in terms of laboratory phenotypic character, and we suggest that it may be used with PFA-100 as an easy and fast method in screening relatives. PMID- 20713489 TI - Incomplete removal of great saphenous vein is the most common cause for recurrent varicose veins. AB - OBJECTIVE: Hie-tie and great saphenous vein (GSV) stripping decreases recurrence of varicose veins (VVs). However, varying lengths of residual-GSV are observed in patients with previous GSV stripping. This may explain high recurrence rates of VVs. The proportion of recurrent VV occurring secondary to suboptimal GSV stripping is calculated. METHODS: Patients with recurrent VV (CEAP-class > C2) underwent venous duplex-ultrasound. RESULTS: 419 limbs were investigated in 298 patients (189 women and 109 men); median age for women and men was 60 and 61 years, respectively; 32.2% had reflux in residual-GSV; 30.3% had groin-reflux; 20% had reflux in sapheno-popliteal confluence (SPC); 10.2% had primary segmental deep-venous incompetence (DVI), and 6.9% had reflux at multiple sites. The frequency of reflux in the residual-GSV was significantly greater than that of reflux in the SPC (P < .0001) and DVI (P < .0001) but not groin (P = .3652). CONCLUSION: Residual-GSV is an important cause for recurrent VV. PMID- 20713488 TI - Serum inflammatory and immune marker response after bare-metal or drug-eluting stent implantation following percutaneous coronary intervention. AB - We assessed the changes in serum antiheat shock protein (HSP)-27 antibody and high-sensitivity C-reactive protein (hsCRP) levels, following the placement of a drug-eluting stent (DES) or bare-metal stent (BMS) in patients with stable coronary artery disease. Either a BMS or DES was implanted in 137 patients (82 BMS; 55 DES). Anti-HSP27 and hsCRP levels were measured 24 hours before and 24 hours after stenting. Median hsCRP serum levels increased significantly to 60.78 (10.13-84.87) and 77.80 (50.00-84.84) mg/L for BMS and DES groups (P = .006 and P = .000, respectively); this increase did not differ significantly between the 2 groups. Median anti-HSP27 antibody levels decreased to 0.26 (0.17-0.49) and 0.21 (0.16-0.29) absorbency units in BMS and DES groups (P = .045 and P = < 0.001, respectively). The changes in anti-HSP27 antibody titers were significant between the 2 groups (P = .015). Bare-metal stent and DES differ in stimulation of immune rather than inflammatory responses. Less stent restenosis after DES compared with BMS implantation could, in part, be attributed to differences in immune responses. PMID- 20713490 TI - General anaesthesia for external electrical cardioversion of atrial fibrillation: experience of an exclusively cardiological procedural management. AB - AIMS: External electrical cardioversion (EC) usually requires brief general anaesthesia involving anaesthetists. The aim of this study was to evaluate the feasibility and safety of inducing anaesthesia for EC of atrial fibrillation (AF) exclusively by the cardiologic team with anaesthetists on-hand. METHODS AND RESULTS: A retrospective analysis of 624 elective EC, over a 6-year period, was made. No patients were excluded due to the severity of pathology or comorbidities. The protocol of the intravenous anaesthesia was 5 mg bolus of midazolam and subsequent increasing doses of propofol starting from 20 mg to achieve the desired sedation level. After delivering DC shock, a direct observation period followed in order to assess the post-sedation recovery and to detect the procedure-related complications. Electrical cardioversion was effective in 98.9% of the cases. General anaesthesia was effective in 100% of cases with a dosage of propofol, ranging between 20 mg to a maximum of 80 mg, after 5 mg of midazolam was administered. All patients generally showed a fast recovery waking up in a few minutes. The anaesthesiology team was never called for assistance. All the procedures were carried out by the cardiologic team as planned. No thrombo-embolic and allergic complications were observed. Arrhythmic complications were uncommon and essentially bradyarrhythmias. CONCLUSION: A general anaesthesia for outpatient EC of AF can be safely handled by a cardiologist having adequate experience with anaesthetical agents. Moreover, the association of midazolam and a very small dosage of propofol, given their synergic action, is effective and safe in inducing anaesthesia. Arrhythmic complications are rare and limited to bradyarrhythmias. PMID- 20713491 TI - HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase. AB - Fatty acid synthase (FAS) and focal adhesion kinase (FAK), which are overexpressed in a variety of human epithelial tumors, play a key role in the migration and invasion of cancer cells. Hence, strategies targeted at inhibiting the FAS/FAK proteins may have therapeutic potential for cancer treatment. The goal of the present study was to determine the effect of HO-3867, a synthetic compound, on the migratory ability of ovarian cancer cells and to understand the mechanistic pathways including the involvement of FAS, FAK, and associated signaling proteins. The study was done using two established human ovarian cancer cell lines, A2780 and SKOV3. Incubation with 10 MUmol/L HO-3867 for 24 hours significantly inhibited the native as well as the vascular endothelial growth factor (VEGF)-mediated migration and invasion of the cells. HO-3867 significantly attenuated FAS and FAK protein levels apparently through accelerated ubiquitin dependent degradation, as shown by a clear downregulation of isopeptidase USP2a. Exposure of cells to HO-3867 also significantly inhibited FAS activity and mRNA levels and a number of downstream proteins, including phospho-extracellular signal-regulated kinase 1/2, phospho-human epidermal growth factor receptor 1, sterol regulatory element binding protein 1, VEGF, and matrix metalloproteinase 2. Western blot and immunohistochemical analyses of A2780 xenograft tumors in mice treated with HO-3867 showed significant reduction in FAS, FAK, VEGF, and downstream protein levels when compared with the untreated control. Collectively, the results showed that HO-3867 suppressed the migration and invasion of ovarian cancer cells by inhibiting the expression or activity of FAS and FAK proteins. The study suggests that molecular targeting of FAS and FAK by HO-3867 may be a potential strategy for ovarian cancer therapy. PMID- 20713492 TI - Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. AB - Methuosis is a unique form of nonapoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively active Ras. This study identifies the small GTPases, Rac1 and Arf6, and the Arf6 GTPase-activating protein, GIT1, as key downstream components of the signaling pathway underlying Ras-induced methuosis. The extent to which graded expression of active H-Ras(G12V) triggers cytoplasmic vacuolization correlates with the amount of endogenous Rac1 in the active GTP state. Blocking Rac1 activation with the specific Rac inhibitor, EHT 1864, or coexpression of dominant-negative Rac1(T17N), prevents the accumulation of vacuoles induced by H-Ras(G12V). Coincident with Rac1 activation, H-Ras(G12V) causes a decrease in the amount of active Arf6, a GTPase that functions in the recycling of clathrin-independent endosomes. The effect of H-Ras(G12V) on Arf6 is blocked by EHT 1864, indicating that the decrease in Arf6-GTP is directly linked to the activation of Rac1. Constitutively active Rac1(G12V) interacts with GIT1 in immunoprecipitation assays. Ablation of GIT1 by short hairpin RNA prevents the decrease in active Arf6, inhibits vacuolization, and prevents loss of cell viability in cells expressing Rac1(G12V). Together, the results suggest that perturbations of endosome morphology associated with Ras-induced methuosis are due to downstream activation of Rac1 combined with reciprocal inactivation of Arf6. The latter seems to be mediated through Rac1 stimulation of GIT1. Further insights into this pathway could suggest opportunities for the induction of methuosis in cancers that are resistant to apoptotic cell death. PMID- 20713494 TI - Shell shock, trauma, and the First World War: the making of a diagnosis and its histories. AB - During the First World War, thousands of soldiers were treated for "shell shock," a condition which encompassed a range of physical and psychological symptoms. Shell shock has most often been located within a "genealogy of trauma," and identified as an important marker in the gradual recognition of the psychological afflictions caused by combat. In recent years, shell shock has increasingly been viewed as a powerful emblem of the suffering of war. This article, which focuses on Britain, extends scholarly analyses which question characterizations of shell shock as an early form of post-traumatic stress disorder. It also considers some of the methodological problems raised by recasting shell shock as a wartime medical construction rather than an essentially timeless manifestation of trauma. It argues that shell shock must be analyzed as a diagnosis shaped by a specific set of contemporary concerns, knowledges, and practices. Such an analysis challenges accepted understandings of what shell shock "meant" in the First World War, and also offers new perspectives on the role of shell shock in shaping the emergence of psychology and psychiatry in the early part of the twentieth century. The article also considers what relation, if any, might exist between intellectual and other histories, literary approaches, and perceptions of trauma as timeless and unchanging. PMID- 20713493 TI - New strategies in hepatocellular carcinoma: genomic prognostic markers. AB - Accurate prognosis prediction in oncology is critical. In patients with hepatocellular carcinoma (HCC), unlike most solid tumors, the coexistence of two life-threatening conditions, cancer and cirrhosis, makes prognostic assessments difficult. Despite the usefulness of clinical staging systems for HCC in routine clinical decision making (e.g., Barcelona-Clinic Liver Cancer algorithm), there is still a need to refine and complement outcome predictions. Recent data suggest the ability of gene signatures from the tumor (e.g., EpCAM signature) and adjacent tissue (e.g., poor-survival signature) to predict outcome in HCC (either recurrence or overall survival), although independent external validation is still required. In addition, novel information is being produced by alternative genomic sources such as microRNA (miRNA; e.g., miR-26a) or epigenomics, areas in which promising preliminary data are thoroughly explored. Prognostic models need to contemplate the impact of liver dysfunction and risk of subsequent de novo tumors in a patient's life expectancy. The challenge for the future is to precisely depict genomic predictors (e.g., gene signatures, miRNA, or epigenetic biomarkers) at each stage of the disease and their specific influence to determine patient prognosis. PMID- 20713495 TI - Low back pain symptoms show a similar pattern of improvement following a wide range of primary care treatments: a systematic review of randomized clinical trials. AB - OBJECTIVES: To assess overall responses to treatments among non-specific low back pain (NSLBP) patients in clinical trials to examine the pattern following a wide range of treatments. METHODS: We conducted a systematic review of published trials on NSLBP and meta-analysis of within-group responses to treatments calculated as the standardized mean difference (SMD). We included randomized controlled trials that investigated the effectiveness of primary care treatments in NSLBP patients aged>=18 years. Outcome measures included the visual analogue scale for pain severity, Roland Morris Disability Questionnaire and Oswestry Disability Index for physical functioning. RESULTS: One hundred and eighteen trials investigating a wide range of primary care treatment for NSLBP were included. Plots of response to treatments showed that there was a similar pattern of initial improvement at 6 weeks followed by smaller improvement for both pain and functional disability at long-term follow-up. This was also shown by the pooled SMD for pain which was 0.86 (95% CI 0.65, 1.07) at 6 weeks, 1.07 (95% CI 0.87, 1.27) at 13 weeks, 1.03 (95% CI 0.82, 1.25) at 27 weeks and 0.88 (95% CI 0.60, 1.1) at 52 weeks. There was a wide heterogeneity in the size of improvement. This heterogeneity, however, was not explained by differences in the type of treatment classified as active, placebo, usual care or waiting list controls or as pharmacological or non-pharmacological treatment. CONCLUSIONS: NSLBP symptoms seem to improve in a similar pattern in clinical trials following a wide variety of active as well as inactive treatments. It is important to explore factors other than the treatment, that might influence symptom improvement. PMID- 20713496 TI - Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. AB - OBJECTIVE: MTX is a prodrug producing anti-arthritic effects through a folylpolyglutamate synthase-mediated activation to MTX polyglutamates (MTXPGs). Our objective was to characterize the pharmacokinetics of intracellular MTXPGs and the factors associated with their accumulation in adult RA patients treated with MTX weekly. METHODS: MTX pharmacokinetics were evaluated in 47 MTX-naive patients enrolled in an MTX dose-escalation study for an average of 20 weeks and 223 patients enrolled in a cross-sectional study under long-term MTX therapy. Short-chain (MTXPG1-2), long-chain (MTXPG3) and very long-chain (MTXPG4-5) concentrations were measured in circulating red blood cells using liquid chromatography. Statistical analyses consisted of non-linear mixed models, multivariate regression analyses and Wilcoxon signed-rank test. RESULTS: The accumulation of MTXPG1-5 was sigmoidal and steady-state concentrations were achieved after 7 weeks of therapy. However, additional exposure and MTX dosage escalation produced a selective redistribution towards longer chain MTXPGs at the expense of shorter chain MTXPGs. Age, glomerular filtration rate and route of MTX administration were the most important predictors of MTXPG accumulation. In 10 patients, a switch from oral to parenteral MTX was associated with a 37% increase in long-chain MTXPGs, a 132% increase in very long-chain MTXPGs and a concomitant 31% reduction in disease activity (P<0.02). CONCLUSION: The selective emergence of long-chain MTXPGs is function of dose, time of exposure and hence dosage intensity. Switching from oral to parenteral MTX produces a selective accumulation of longer chain MTXPGs that are known to be more potent inhibitors of de novo purine biosynthesis than shorter chain MTXPGs. PMID- 20713497 TI - The effects of antidepressant step therapy protocols on pharmaceutical and medical utilization and expenditures. AB - OBJECTIVE: This study examined the effects of step therapy for antidepressants on prescription drug and other medical utilization and spending. Step therapy is a type of pharmaceutical benefit design that requires that patients try certain specified medications (typically generic medications) prior to using alternative, more expensive medications within the same medication class. Step therapy is not the same as generic substitution. METHOD: Using the 2003-2006 Thomson Reuters MarketScan claims databases, antidepressant users enrolled in employer plans that implemented antidepressant step therapy were compared with antidepressant users enrolled in employer plans that had not implemented step therapy. Multivariate generalized estimating equation models were used to analyze the relationship between step therapy for antidepressants and 1) pharmacy and medical utilization and 2) spending. RESULTS: Antidepressant days supplied and medication costs decreased after step therapy was implemented, relative to the comparison group. However, overall and mental health-specific inpatient and emergency room utilization and costs increased. CONCLUSIONS: Step therapy may have the unintended effect of reducing overall antidepressant use and increasing medical use and costs. PMID- 20713498 TI - Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. AB - OBJECTIVE: There is growing clinical and epidemiologic evidence that major mood disorders form a spectrum from major depressive disorder to pure mania. The authors examined the prevalence and clinical correlates of major depressive disorder with subthreshold bipolarity compared with pure major depressive disorder in the National Comorbidity Survey Replication (NCS-R). METHOD: The NCS R is a nationally representative face-to-face household survey of the U.S. population conducted between February 2001, and April 2003. Lifetime history of mood disorders, symptoms, and clinical indicators of severity were collected using version 3.0 of the World Health Organization's Composite International Diagnostic Interview. RESULTS: Nearly 40% of study participants with a history of major depressive disorder had a history of subthreshold hypo-mania. This subgroup had a younger age at onset, more episodes of depression, and higher rates of comorbidity than those without a history of hypomania and lower levels of clinical severity than those with bipolar II disorder. CONCLUSIONS: These findings demonstrate heterogeneity in major depressive disorder and support the validity of inclusion of subthreshold mania in the diagnostic classification. The broadening of criteria for bipolar disorder would have important implications for research and clinical practice. PMID- 20713500 TI - Androgen-mediated down-regulation of CYP1A subfamily genes in the pig liver. AB - In Meishan and Landrace pigs, sex differences in the constitutive expression of hepatic cytochrome P4501A (CYP1A) subfamily enzymes were examined in terms of their mRNA, protein, and enzyme activity. All the results from the real-time RT PCR, western blotting, and enzyme assays for CYP1A subfamily enzymes indicated that, in 5-month-old Meishan pigs, the expression levels of CYP1A1 and CYP1A2 in males were significantly low as compared with those in females. In contrast, there were no such significant sex differences in Landrace pigs. Castration of male Meishan pigs led to a female-type expression of the CYP1A subfamily enzymes, whereas no such effect was observed in male Landrace pigs after castration. In both breeds of pigs, the administration of testosterone propionate to the females and castrated males led to marked decreases in the expression levels of mRNAs and proteins in the CYP1A subfamily enzymes, and also in their enzyme activities. Furthermore, the correlation analyses between the serum testosterone level and the gene expression levels of CYP1A subfamily enzymes in different sex-matured (1 5-month-old) male pigs revealed that the clear decrease in expression levels of hepatic CYP1A subfamily enzymes occurred at concentrations of more than 33 ng/ml of serum testosterone. Incidentally, the mean concentrations of serum testosterone in 5-month-old Landrace and Meishan pigs were around 18 and 50 ng/ml respectively. In conclusion, we demonstrated for the first time that the serum testosterone level is one of the physiological factors which regulate constitutive expression of hepatic CYP1A1 and CYP1A2 in pigs. PMID- 20713499 TI - Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. AB - OBJECTIVE: Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. METHOD: The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. RESULTS: The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. CONCLUSIONS: This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses. PMID- 20713501 TI - Prenatal androgen exposure programs metabolic dysfunction in female mice. AB - Polycystic ovary syndrome (PCOS) is a common fertility disorder with metabolic sequelae. Our laboratory previously characterized reproductive phenotypes in a prenatally androgenized (PNA) mouse model for PCOS. PNA mice exhibited elevated testosterone and LH levels, irregular estrous cycles, and neuroendocrine abnormalities suggesting increased central drive to the reproductive system. In this study, we examined metabolic characteristics of female PNA mice. PNA mice exhibited increased fasting glucose and impaired glucose tolerance (IGT) that were independent of age and were not associated with changes in body composition or peripheral insulin sensitivity. IGT was associated with defects in pancreatic islet function leading to an impaired response to high glucose, consistent with impaired insulin secretion. Exposure of isolated pancreatic islets to androgen in vitro demonstrated an impaired response to glucose stimulation similar to that in PNA mice, suggesting androgens may have activational in addition to organizational effects on pancreatic islet function. PNA mice also exhibited increased size of visceral adipocytes, suggesting androgen-programed differences in adipocyte differentiation and/or function. These studies demonstrate that in addition to causing reproductive axis abnormalities, in utero androgen exposure can induce long-term metabolic alterations in female mice. PMID- 20713503 TI - Hand modulation of visual, preparatory, and saccadic activity in the monkey frontal eye field. AB - Behavioral studies have shown that hand position influences saccade characteristics. This study examined the neuronal changes that could underlie this behavioral observation. Single neurons were recorded in the frontal eye field (FEF) of 2 monkeys as they executed a visually guided saccade task, while holding their hand at given locations on a touch screen. The task was performed with the hand either visible or invisible, in order to assess the relative contribution of visual and proprioceptive information on hand position. Among the 224 neurons tested, the visual, saccadic and/or preparatory activity of more than half of them was modulated by hand position, whether the hand was visible or invisible. Comparison of lower (hand's workspace) and upper (out of reach) visual targets showed that hand modulation was predominant in the hand's workspace. Finally, some cells preferred congruency of hand and target in space, others preferred incongruency. Interestingly, hand modulation of saccadic activity correlated with hand position effects on saccade reaction times. We conclude that visual and proprioceptive signals derived from the hand are integrated by FEF neurons. These signals can modulate target selection through attention and allow the oculomotor system to use hand-related somatosensory signals for the initiation of visually guided saccades. PMID- 20713502 TI - Timing of cortical interneuron migration is influenced by the cortical hem. AB - Cerebral cortical gamma-aminobutyric acid (GABA)ergic interneurons originate from the basal forebrain and migrate into the cortex in 2 phases. First, interneurons cross the boundary between the developing striatum and the cortex to migrate tangentially through the cortical primordium. Second, interneurons migrate radially to their correct neocortical layer position. A previous study demonstrated that mice in which the cortical hem was genetically ablated displayed a massive reduction of Cajal-Retzius (C-R) cells in the neocortical marginal zone (MZ), thereby losing C-R cell-generated reelin in the MZ. Surprisingly, pyramidal cell migration and subsequent layering were almost normal. In contrast, we find that the timing of migration of cortical GABAergic interneurons is abnormal in hem-ablated mice. Migrating interneurons both advance precociously along their tangential path and switch prematurely from tangential to radial migration to invade the cortical plate (CP). We propose that the cortical hem is responsible for establishing cues that control the timing of interneuron migration. In particular, we suggest that loss of a repellant signal from the medial neocortex, which is greatly decreased in size in hem-ablated mice, allows the early advance of interneurons and that reduction of another secreted molecule from C-R cells, the chemokine SDF-1/CXCL12, permits early radial migration into the CP. PMID- 20713504 TI - Puberty influences medial temporal lobe and cortical gray matter maturation differently in boys than girls matched for sexual maturity. AB - Sex differences in age- and puberty-related maturation of human brain structure have been observed in typically developing age-matched boys and girls. Because girls mature 1-2 years earlier than boys, the present study aimed at assessing sex differences in brain structure by studying 80 adolescent boys and girls matched on sexual maturity, rather than age. We evaluated pubertal influences on medial temporal lobe (MTL), thalamic, caudate, and cortical gray matter volumes utilizing structural magnetic resonance imaging and 2 measures of pubertal status: physical sexual maturity and circulating testosterone. As predicted, significant interactions between sex and the effect of puberty were observed in regions with high sex steroid hormone receptor densities; sex differences in the right hippocampus, bilateral amygdala, and cortical gray matter were greater in more sexually mature adolescents. Within sex, we found larger volumes in MTL structures in more sexually mature boys, whereas smaller volumes were observed in more sexually mature girls. Our results demonstrate puberty-related maturation of the hippocampus, amygdala, and cortical gray matter that is not confounded by age, and is different for girls and boys, which may contribute to differences in social and cognitive development during adolescence, and lasting sexual dimorphisms in the adult brain. PMID- 20713505 TI - Flexible cerebral connectivity patterns subserve contextual modulations of pain. AB - The perception of pain can be significantly modulated by the behavioral context. Here, we investigated how contextual modulations of pain are subserved in the human brain. We independently modulated the attentional and emotional context of painful stimuli and recorded brain activity by using functional magnetic resonance imaging. Our results confirm that attention to pain and a negative emotional context increases pain perception and this is concomitantly associated with increased neural activity in the anterior insular cortex. Connectivity analyses further reveal that during attentional and emotional modulations of pain, the anterior insula selectively and flexibly connects to attentional and emotional brain networks in frontoparietal and medial temporal lobe areas, respectively. We conclude that the flexible functional connectivity of the anterior insula to other functional systems of the brain, for example, attentional and emotional brain networks, subserves the extraordinary sensitivity of the pain experience to contextual modulations. PMID- 20713506 TI - Treatment options in Cheyne-Stokes respiration. AB - About half of the patients suffering from heart failure present with sleep disordered breathing. In most cases obstructive and central breathing disturbances (including Cheyne-Stokes respiration [CSR]) coexist. CSR is defined by a waxing and waning pattern of the tidal volume. While its pathophysiology has not been elucidated completely, increased ventilatory sensitivity for CO(2) and therefore an imbalance of the respiratory drive and effort, a chronic hyperventilatory state, and changes of the apnoeic threshold are considered to play a relevant role. However, CSR in heart failure impairs survival and quality of life of the patients and is therefore a major challenge of respiratory sleep medicine. If CSR persists despite optimal medical and interventional therapy of the underlying cardiac disorder, oxygen supply, continuous positive airway pressure (CPAP), and bilevel pressure are often trialled. However, there is insufficient evidence to recommend oxygen or bilevel treatment. CPAP has proven to improve left ventricular function. In addition, retrospective analyses suggested a reduction of mortality under CPAP in heart failure patients with CSR. However, these findings could not be reproduced in the prospective controlled CanPAP trial. More recently, adaptive servoventilation (ASV) has been introduced for treatment of CSR or coexisting sleep-related breathing disorders. ASV devices aim at counterbalancing the ventilatory overshoot and undershoot by applying variable pressure support with higher tidal volume (TV) during hypoventilation and reduced TV during hyperventilation. ASV has proven to be superior to CPAP but the long-term efficacy and the influences on cardiac parameters and survival are still under investigation. PMID- 20713507 TI - Structural basis for methylarginine-dependent recognition of Aubergine by Tudor. AB - Piwi proteins are modified by symmetric dimethylation of arginine (sDMA), and the methylarginine-dependent interaction with Tudor domain proteins is critical for their functions in germline development. Cocrystal structures of an extended Tudor domain (eTud) of Drosophila Tudor with methylated peptides of Aubergine, a Piwi family protein, reveal that sDMA is recognized by an asparagine-gated aromatic cage. Furthermore, the unexpected Tudor-SN/p100 fold of eTud is important for sensing the position of sDMA. The structural information provides mechanistic insights into sDMA-dependent Piwi-Tudor interaction, and the recognition of sDMA by Tudor domains in general. PMID- 20713508 TI - Functional microdomains in bacterial membranes. AB - The membranes of eukaryotic cells harbor microdomains known as lipid rafts that contain a variety of signaling and transport proteins. Here we show that bacterial membranes contain microdomains functionally similar to those of eukaryotic cells. These membrane microdomains from diverse bacteria harbor homologs of Flotillin-1, a eukaryotic protein found exclusively in lipid rafts, along with proteins involved in signaling and transport. Inhibition of lipid raft formation through the action of zaragozic acid--a known inhibitor of squalene synthases--impaired biofilm formation and protein secretion but not cell viability. The orchestration of physiological processes in microdomains may be a more widespread feature of membranes than previously appreciated. PMID- 20713511 TI - A telephone-linked computer system for home enteral nutrition. AB - We studied the effect of telephone-linked computer (TLC) communication in patients being treated with home enteral nutrition. A total of 290 patients were enrolled in the study which compared two groups of patients who were recruited at different times (control: 193, TLC: 97). At baseline there were no significant differences in characteristics or clinical practice between the two groups. Over a three-month period, 823 automatic telephone calls were dialled out to the TLC patients and in 787 of the calls (96%) there were complete responses to all questions. A total of 205 alert messages were generated for the 823 calls. Less than 10% were false alerts. All health outcome measures, the EQ-5D and three components of the SF-36 improved slightly with time in both groups, but there was no significant difference between the groups. The patients' body mass index increased slightly in both groups, but the change was not significant. Home enteral nutrition prevented weight loss and improved some components of the QOL scores. The TLC system detected a high number of abnormal nutritional symptoms. PMID- 20713509 TI - Canonical and alternate functions of the microRNA biogenesis machinery. AB - The canonical microRNA (miRNA) biogenesis pathway requires two RNaseIII enzymes: Drosha and Dicer. To understand their functions in mammals in vivo, we engineered mice with germline or tissue-specific inactivation of the genes encoding these two proteins. Changes in proteomic and transcriptional profiles that were shared in Dicer- and Drosha-deficient mice confirmed the requirement for both enzymes in canonical miRNA biogenesis. However, deficiency in Drosha or Dicer did not always result in identical phenotypes, suggesting additional functions. We found that, in early-stage thymocytes, Drosha recognizes and directly cleaves many protein coding messenger RNAs (mRNAs) with secondary stem-loop structures. In addition, we identified a subset of miRNAs generated by a Dicer-dependent but Drosha independent mechanism. These were distinct from previously described mirtrons. Thus, in mammalian cells, Dicer is required for the biogenesis of multiple classes of miRNAs. Together, these findings extend the range of function of RNaseIII enzymes beyond canonical miRNA biogenesis, and help explain the nonoverlapping phenotypes caused by Drosha and Dicer deficiency. PMID- 20713510 TI - Cotranscriptional recruitment of She2p by RNA pol II elongation factor Spt4 Spt5/DSIF promotes mRNA localization to the yeast bud. AB - Pre-mRNA processing is coupled with transcription. It is still unclear if the transcription machinery can also directly affect the cytoplasmic fate of a transcript, such as its intracellular localization. In yeast, the RNA-binding protein She2p binds several mRNAs and targets them for localization at the bud. Here we report that She2p is recruited cotranscriptionally to the nascent bud localized ASH1, IST2, and EAR1 mRNA. She2p interacts in vivo with the elongating forms of RNA polymerase II (pol II) via the transcription elongation factor Spt4 Spt5. Mutations in either SPT4 or SPT5 reduce the cotranscriptional recruitment of She2p on the ASH1 gene, disrupt the proper localization of ASH1 mRNA at the bud tip, and affect Ash1p sorting to the daughter cell nucleus. We propose that She2p is recruited by the RNA pol II machinery prior to its transfer to nascent bud-localized mRNAs. Indeed, She2p is present with RNA pol II on genes coding for localized or nonlocalized transcripts, but is associated with nascent mRNA only on genes coding for bud-localized transcripts. Moreover, a She2p mutant defective in RNA binding still associates with RNA pol II transcribed genes. This study uncovers a novel mechanism for the cotranscriptional assembly of mRNP complexes primed for localization in the cytoplasm. PMID- 20713512 TI - How serious are the symptoms of callers to a telephone triage call centre? AB - Adverse events such as deaths following telephone triage calls are rare, suggesting that the process is basically safe. However, if calls tend to concern mostly minor illnesses, then adverse events following calls would be uncommon even if the triage process itself was flawed. We investigated hospitalization rates following triage calls and compared them to hospitalization following two other types of medical access, emergency department (ED) visits and office visits. For the Ask Mayo Clinic telephone triage centre, hospitalization rates for adult calls concerning chest pain and abdominal pain were each 13%. Based on national survey data, hospitalization for adult ED visits concerning the same symptoms were 33% (chest pain) and 19% (abdominal pain). Office visits had hospitalization rates significantly lower than triage calls in all age groups, while ED visits had higher hospitalization rates than triage calls in all age groups. There are both qualitative and quantitative similarities between triage calls and ED visits and, using hospitalization as an indicator, some subgroups of triage calls are nearly as serious as ED visits. PMID- 20713513 TI - Merlin in organ size control and tumorigenesis: Hippo versus EGFR? AB - The role of the NF2 gene as a tumor suppressor has been well established. In this issue of Genes & Development, Benhamouche and colleagues (pp. 1718-1730) demonstrate that NF2 is also involved in the regulation of organ size control in mammals. Conditional knockout of Nf2 in the mouse liver results in massive organ enlargement and eventual tumor development, which is attributed to the specific expansion of oval cells. Here we discuss these findings and the proposed molecular mechanisms involved within the context of our current understanding of the pathways regulated by NF2. PMID- 20713514 TI - Expanded roles of the Fanconi anemia pathway in preserving genomic stability. AB - Studying rare human genetic diseases often leads to a better understanding of normal cellular functions. Fanconi anemia (FA), for example, has elucidated a novel DNA repair mechanism required for maintaining genomic stability and preventing cancer. The FA pathway, an essential tumor-suppressive pathway, is required for protecting the human genome from a specific type of DNA damage; namely, DNA interstrand cross-links (ICLs). In this review, we discuss the recent progress in the study of the FA pathway, such as the identification of new FANCM binding partners and the identification of RAD51C and FAN1 (Fanconi-associated nuclease 1) as new FA pathway-related proteins. We also focus on the role of the FA pathway as a potential regulator of DNA repair choices in response to double strand breaks, and its novel functions during the mitotic phase of the cell cycle. PMID- 20713515 TI - Early abscisic acid signal transduction mechanisms: newly discovered components and newly emerging questions. AB - The plant hormone abscisic acid (ABA) regulates many key processes in plants, including seed germination and development and abiotic stress tolerance, particularly drought resistance. Understanding early events in ABA signal transduction has been a major goal of plant research. The recent identification of the PYRABACTIN (4-bromo-N-[pyridin-2-yl methyl]naphthalene-1-sulfonamide) RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family of ABA receptors and their biochemical mode of action represents a major breakthrough in the field. The solving of PYR/RCAR structures provides a context for resolving mechanisms mediating ABA control of protein-protein interactions for downstream signaling. Recent studies show that a pathway based on PYR/RCAR ABA receptors, PROTEIN PHOSPHATASE 2Cs (PP2Cs), and SNF1-RELATED PROTEIN KINASE 2s (SnRK2s) forms the primary basis of an early ABA signaling module. This pathway interfaces with ion channels, transcription factors, and other targets, thus providing a mechanistic connection between the phytohormone and ABA-induced responses. This emerging PYR/RCAR-PP2C-SnRK2 model of ABA signal transduction is reviewed here, and provides an opportunity for testing novel hypotheses concerning ABA signaling. We address newly emerging questions, including the potential roles of different PYR/RCAR isoforms, and the significance of ABA-induced versus constitutive PYR/RCAR-PP2C interactions. We also consider how the PYR/RCAR-PP2C SnRK2 pathway interfaces with ABA-dependent gene expression, ion channel regulation, and control of small molecule signaling. These exciting developments provide researchers with a framework through which early ABA signaling can be understood, and allow novel questions about the hormone response pathway and possible applications in stress resistance engineering of plants to be addressed. PMID- 20713516 TI - Constitutively active NF-kappaB triggers systemic TNFalpha-dependent inflammation and localized TNFalpha-independent inflammatory disease. AB - NF-kappaB is well established as a key component of the inflammatory response. However, the precise mechanisms through which NF-kappaB activation contributes to inflammatory disease states remain poorly defined. To test the role of NF-kappaB in inflammation, we created a knock-in mouse that expresses a constitutively active form of NF-kappaB p65 dimers. These mice are born at normal Mendelian ratios, but display a progressive, systemic hyperinflammatory condition that results in severe runting and, typically, death 8-20 d after birth. Examination of homozygous knock-in mice demonstrates significant increases in proinflammatory cytokines and chemokines. Remarkably, crossing this strain with mice lacking TNF receptor 1 (TNFR1) leads to a complete rescue of the hyperinflammatory phenotype. However, upon aging, these rescued mice begin to display chronic keratitis accompanied by increased corneal expression of TNFalpha, IL-1beta, and MMP-9, similar to that seen in human keratoconjunctivitis sicca (KCS) or "dry eyes." Therefore, our results show that, while constitutively active NF-kappaB can trigger systemic inflammation, it does so indirectly, through increased TNF production. However, certain inflammatory disease states, such as keratitis or KCS, a condition that is seen in Sjogren's syndrome, are dependent on NF-kappaB, but are independent of TNFR1 signaling. PMID- 20713517 TI - Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. AB - Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention. PMID- 20713518 TI - Foxp1 coordinates cardiomyocyte proliferation through both cell-autonomous and nonautonomous mechanisms. AB - Cardiomyocyte proliferation is high in early development and decreases progressively with gestation, resulting in the lack of a robust cardiomyocyte proliferative response in the adult heart after injury. Little is understood about how both cell-autonomous and nonautonomous signals are integrated to regulate the balance of cardiomyocyte proliferation during development. In this study, we show that a single transcription factor, Foxp1, can control the balance of cardiomyocyte proliferation during development by targeting different pathways in the endocardium and myocardium. Endocardial loss of Foxp1 results in decreased Fgf3/Fgf16/Fgf17/Fgf20 expression in the heart, leading to reduced cardiomyocyte proliferation. This loss of myocardial proliferation can be rescued by exogenous Fgf20, and is mediated, in part, by Foxp1 repression of Sox17. In contrast, myocardial-specific loss of Foxp1 results in increased cardiomyocyte proliferation and decreased differentiation, leading to increased myocardial mass and neonatal demise. We show that Nkx2.5 is a direct target of Foxp1 repression, and Nkx2.5 expression is increased in Foxp1-deficient myocardium. Moreover, transgenic overexpression of Nkx2.5 leads to increased cardiomyocyte proliferation and increased ventricular mass, similar to the myocardial-specific loss of Foxp1. These data show that Foxp1 coordinates the balance of cardiomyocyte proliferation and differentiation through cell lineage-specific regulation of Fgf ligand and Nkx2.5 expression. PMID- 20713519 TI - Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis. AB - Profound epigenetic differences exist between genomes derived from male and female gametes; however, the nature of these changes remains largely unknown. We undertook a systematic investigation of chromatin reorganization during gametogenesis, using the model eukaryote Saccharomyces cerevisiae to examine sporulation, which has strong similarities with higher eukaryotic spermatogenesis. We established a mutational screen of histones H3 and H4 to uncover substitutions that reduce sporulation efficiency. We discovered two patches of residues-one on H3 and a second on H4-that are crucial for sporulation but not critical for mitotic growth, and likely comprise interactive nucleosomal surfaces. Furthermore, we identified novel histone post-translational modifications that mark the chromatin reorganization process during sporulation. First, phosphorylation of H3T11 appears to be a key modification during meiosis, and requires the meiotic-specific kinase Mek1. Second, H4 undergoes amino tail acetylation at Lys 5, Lys 8, and Lys 12, and these are synergistically important for post-meiotic chromatin compaction, occurring subsequent to the post-meiotic transient peak in phosphorylation at H4S1, and crucial for recruitment of Bdf1, a bromodomain protein, to chromatin in mature spores. Strikingly, the presence and temporal succession of the new H3 and H4 modifications are detected during mouse spermatogenesis, indicating that they are conserved through evolution. Thus, our results show that investigation of gametogenesis in yeast provides novel insights into chromatin dynamics, which are potentially relevant to epigenetic modulation of the mammalian process. PMID- 20713520 TI - Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling. AB - Eukaryotic translation initiation begins with ribosomal recruitment of aminoacylated initiator tRNA (Met-tRNA(Met)(i)) by eukaryotic initiation factor eIF2. In cooperation with eIF3, eIF1, and eIF1A, Met-tRNA(Met)(i)/eIF2/GTP binds to 40S subunits yielding 43S preinitiation complexes that attach to the 5' terminal region of mRNAs and then scan to the initiation codon to form 48S initiation complexes with established codon-anticodon base-pairing. Stress activated phosphorylation of eIF2alpha reduces the level of active eIF2, globally inhibiting translation. However, translation of several viral mRNAs, including Sindbis virus (SV) 26S mRNA and mRNAs containing hepatitis C virus (HCV)-like IRESs, is wholly or partially resistant to inhibition by eIF2 phosphorylation, despite requiring Met-tRNA(Met)(i). Here we report the identification of related proteins that individually (Ligatin) or together (the oncogene MCT-1 and DENR, which are homologous to N-terminal and C-terminal regions of Ligatin, respectively) promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes, if attachment of 40S subunits to the mRNA places the initiation codon directly in the P site, as on HCV-like IRESs and, as we show here, SV 26S mRNA. In addition to their role in initiation, Ligatin and MCT 1/DENR can promote release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated dissociation of post-termination ribosomes. PMID- 20713521 TI - The homeodomain protein hmbx-1 maintains asymmetric gene expression in adult C. elegans olfactory neurons. AB - Differentiated neurons balance the need to maintain a stable identity with their flexible responses to dynamic environmental inputs. Here we characterize these opposing influences on gene expression in Caenorhabditis elegans olfactory neurons. Using transcriptional reporters that are expressed differentially in two olfactory neurons, AWC(ON) and AWC(OFF), we identify mutations that affect the long-term maintenance of appropriate chemoreceptor expression. A newly identified gene from this screen, the conserved transcription factor hmbx-1, stabilizes AWC gene expression in adult animals through dosage-sensitive interactions with its transcriptional targets. The late action of hmbx-1 complements the early role of the transcriptional repressor gene nsy-7: Both repress expression of multiple AWC(OFF) genes in AWC(ON) neurons, but they act at different developmental stages. Environmental signals are superimposed onto this stable cell identity through at least two different transcriptional pathways that regulate individual chemoreceptor genes: a cGMP pathway regulated by sensory activity, and a daf-7 (TGF-beta)/daf-3 (SMAD repressor) pathway regulated by specific components of the density-dependent C. elegans dauer pheromone. PMID- 20713522 TI - Tbr2-positive intermediate (basal) neuronal progenitors safeguard cerebral cortex expansion by controlling amplification of pallial glutamatergic neurons and attraction of subpallial GABAergic interneurons. AB - Little is known about how, during its formidable expansion in development and evolution, the cerebral cortex is able to maintain the correct balance between excitatory and inhibitory neurons. In fact, while the former are born within the cortical primordium, the latter originate outward in the ventral pallium. Therefore, it remains to be addressed how these two neuronal populations might coordinate their relative amounts in order to build a functional cortical network. Here, we show that Tbr2-positive cortical intermediate (basal) neuronal progenitors (INPs) dictate the migratory route and control the amount of subpallial GABAergic interneurons in the subventricular zone (SVZ) through a non cell-autonomous mechanism. In fact, Tbr2 interneuron attractive activity is moderated by Cxcl12 chemokine signaling, whose forced expression in the Tbr2 mutants can rescue, to some extent, SVZ cell migration. We thus propose that INPs are able to control simultaneously the increase of glutamatergic and GABAergic neuronal pools, thereby creating a simple way to intrinsically balance their relative accumulation. PMID- 20713523 TI - Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer. AB - Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86 21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy. PMID- 20713524 TI - miR-335 directly targets Rb1 (pRb/p105) in a proximal connection to p53-dependent stress response. AB - Loss-of-function mutations of retinoblastoma family (Rb) proteins drive tumorigenesis by overcoming barriers to cellular proliferation. Consequently, factors modulating Rb function are of great clinical import. Here, we show that miR-335 is differentially expressed in human cancer cells and that it tightly regulates the expression of Rb1 (pRb/p105) by specifically targeting a conserved sequence motif in its 3' untranslated region. We found that by altering Rb1 (pRb/p105) levels, miR-335 activates the p53 tumor suppressor pathway to limit cell proliferation and neoplastic cell transformation. DNA damage elicited an increase in miR-335 expression in a p53-dependent manner. miR-335 and p53 cooperated in a positive feedback loop to drive cell cycle arrest. Together, these results indicate that miR-335 helps control proliferation by balancing the activities of the Rb and p53 tumor suppressor pathways. Further, they establish that miR-335 activation plays an important role in the induction of p53-dependent cell cycle arrest after DNA damage. PMID- 20713526 TI - Tipping the balance: Cdk2 enables Myc to suppress senescence. AB - Intrinsic tumor-suppressor pathways protect healthy cells from transformation by activated oncogenes like MYC or RAS through induction of apoptosis or cellular senescence, respectively. However, when expressed together, MYC and RAS evade these barriers and initiate tumorigenesis. Although Ras suppresses Myc-induced apoptosis, the role of Myc in this cooperation has remained undefined. In a recent report, we showed that Myc represses Ras-induced senescence, thereby overcoming the second major barrier of tumorigenesis. Inhibition of Ras-induced senescence required specific phosphorylation of Myc by cyclin-dependent kinase 2 (Cdk2) and was abrogated by pharmacologic Cdk2 inhibitors, urging a reevaluation of this kinase as a therapeutic target in Myc- or Ras-driven tumors. PMID- 20713525 TI - Chromatin remodeling is required for gene reactivation after decitabine-mediated DNA hypomethylation. AB - The DNA hypomethylating drug decitabine (DAC) reactivates silenced gene expression in cancer and is approved for the treatment of the myelodysplastic syndrome. Gene reactivation after DAC is variable and incompletely understood. Here, we established a cell line system (YB5) derived from the SW48 colon cancer cell line to study DAC-induced reactivation. YB5 contains a hypermethylated cytomegalovirus promoter driving green fluorescent protein (GFP), and the locus is transcriptionally silent. GFP reexpression can be achieved by DAC treatment, but the expression level of individual cells is heterogeneous. DAC-treated YB5 cells were separated into GFP-positive and GFP-negative subpopulations. By comparing DAC-treated sorted GFP-positive and GFP-negative cells, we found that their methylation levels were similarly decreased but that histone modifications and histone H3 densities were remarkably different. Despite a similar degree of (incomplete) DNA hypomethylation, GFP-positive cells reverted to an active chromatin structure marked by higher H3K9 acetylation, lower H3K27 trimethylation, and lower promoter nucleosome density. GFP-negative cells had histone modifications and promoter nucleosome density, similar to parental cells. On DAC withdrawal, gradual resilencing and remethylation occurred in both GFP positive and GFP-negative cells, and the resilencing correlated with a gradual increase in nucleosome occupancy in GFP-positive cells. These data show that hypomethylation alone after DAC is insufficient for gene expression induction, and that chromatin resetting to an active state including nucleosome eviction is required for activation of protein expression. Our findings suggest that gene expression is the key in optimizing DAC treatment strategies in the clinic. PMID- 20713527 TI - ZIC1 overexpression is oncogenic in liposarcoma. AB - Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for liposarcoma is surgical excision because liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of liposarcoma compared with normal fat, and in liposarcoma cell lines compared with adipose-derived stem cells. Here, we show that ZIC1 contributes to the pathogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either adipose-derived stem cells or in a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for liposarcoma. PMID- 20713528 TI - FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to mesenchymal transition in human prostate cancer cells. AB - TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active beta(1)-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active beta(1)-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion. PMID- 20713529 TI - Recruitment of phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates. AB - Protein accumulation at DNA double-strand breaks (DSB) is essential for genome stability; however, the mechanisms governing these events are not fully understood. Here, we report a new role for the nucleophosmin protein NPM1 in these mechanisms. Thr199-phosphorylated NPM1 (pT199-NPM1) is recruited to nuclear DNA damage foci induced by ionizing radiation (IR). Foci formation is impaired by depletion of the E3 ubiquitin ligases RNF8 and RNF168 or the E2 Ubc13, and pT199 NPM1 binds to Lys63-linked ubiquitin polymers in vitro. Thus, phosphorylated NPM1 may interact with RNF8-dependent ubiquitin conjugates at sites of DNA damage. The interaction was found to rely on T199 phosphorylation, an acidic tract, and an adjacent ubiquitin-interacting motif-like domain. Depletion of the breast cancer suppressor BRCA1 or its partner, RAP80, enhanced IR-induced NPM1 foci and prolonged persistence of the foci, possibly implicating BRCA1 in pT199-NPM1 action and dynamics. Replacement of endogenous NPM1 with its nonphosphorylable T199A mutant prolonged persistence of IR-induced RAD51 foci accompanied by unrepaired DNA damage. Collectively, our findings suggest that phosphorylated NPM1 is a novel component in DSB repair that is recruited by ubiquitin conjugates downstream of RNF8 and RNF168. PMID- 20713530 TI - Association of human cytochrome P450 1A1 (CYP1A1) and sulfotransferase 1A1 (SULT1A1) polymorphisms with differential metabolism and cytotoxicity of aminoflavone. AB - Aminoflavone (AF), a clinically investigational novel anticancer agent, requires sequential metabolic activation by CYP1A1 and SULT1A1 to exert its antitumor activities. The purpose of this study was to determine the functional significance of common polymorphisms of human CYP1A1 and SULT1A1 on the metabolism and cytotoxicity of AF. To this end, Chinese Hamster V79 cells were genetically engineered to stably express human CYP1A1*1 (wild-type), CYP1A1*2C (I462V), or CYP1A1*4 (T461N) and coexpress human CYP1A1*1 with human SULT1A1*1 (wild-type), SULT1A1*2 (R213H), or SULT1A1*3 (M223V). The metabolism and cytotoxicity of AF were evaluated in these cellular models. All common variants of CYP1A1 and SULT1A1 were actively involved in the metabolic activation of AF, but with a varying degree of activity. Whereas CYP1A1 I462V variant exhibited a superior activity (mainly caused by a significantly higher V(max)) for hydroxylations of AF, expression of different CYP1A1 variants did not confer cell differential sensitivity to AF. The cells coexpressing CYP1A1*1 with SULT1A1*1, SULT1A1*2, or SULT1A1*3 displayed SULT1A1 allele-specific sensitivity to AF: SULT1A1*3 exhibited the highest sensitivity (IC(50), 0.01 MUmol/L), followed by SULT1A1*1 (IC(50), 0.5 MUmol/L), and SULT1A1*2 showed the lowest sensitivity (IC(50), 4.4 MUmol/L). These data suggest that the presence of low-activity SULT1A1*2 may predict poor response to AF, whereas the presence of high-activity CYP1A1/SULT1A1 alleles, especially combination of CYP1A1*2C and SULT1A1*3 or SULT1A1*1, may be beneficial to patients receiving AF. The present study provides a foundation for future clinical investigations of potential genetic biomarkers that may enable selection of patients for the greatest potential benefit from AF treatment. PMID- 20713532 TI - The right to treatment for self-inflicted conditions. AB - The increasing awareness of personal health responsibility had led to the claim that patients with 'self-inflicted' conditions have less of a right to treatment at the public's expense than patients whose conditions arose from 'uncontrollable' causes. This paper suggests that regardless of any social decision as to the limits and scope of individual responsibility for health, the moral framework for discussing this issue is equality. In order to reach a consensus, discourse should be according to the common basis of all theories of justice, Aristotle's formal principle of justice: 'equals must be treated equally and unequals must be treated unequally, in proportion to the relevant inequality'. This paper deals with the question of whether and under what circumstances risk-taking behaviour could be regarded as a 'relevant inequality' with respect to the right to health care. Following a discussion of the relevant inequalities in health care, the conclusion is reached that the fact that the condition was avoidably caused by the patient and is therefore his or her fault can not be regarded necessarily as a relevant inequality. Therefore, the issue is one of societal support for health care; after defining relevant inequalities in this respect, the paper attempts to apply them to self-inflicted conditions. This analysis reveals that, in theory, it may be just to restrict societal support in such cases. However, the application of this conclusion requires proof of many factual claims-for which there is often very limited evidence. PMID- 20713531 TI - Multigene expression-based predictors for sensitivity to Vorinostat and Velcade in non-small cell lung cancer. AB - The ability to predict the efficacy of molecularly targeted therapies for non small cell lung cancer (NSCLC) for an individual patient remains problematic. The purpose of this study was to identify, using a refined "coexpression extrapolation (COXEN)" algorithm with a continuous spectrum of drug activity, tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat, a histone deacetylase inhibitor, and Velcade, a proteasome inhibitor. Using our refined COXEN algorithm, biomarker prediction models were discovered and trained for Vorinostat and Velcade based on the in vitro drug activity profiles of nine NSCLC cell lines (NCI-9). Independently, a panel of 40 NSCLC cell lines (UVA-40) were treated with Vorinostat or Velcade to obtain 50% growth inhibition values. Genome-wide expression profiles for both the NCI-9 and UVA-40 cell lines were determined using the Affymetrix HG-U133A platform. Modeling generated multigene expression signatures for Vorinostat (45-gene; P = 0.002) and Velcade (15-gene; P = 0.0002), with one overlapping gene (CFLAR). Examination of Vorinostat gene ontogeny revealed a predilection for cellular replication and death, whereas that of Velcade suggested involvement in cellular development and carcinogenesis. Multivariate regression modeling of the refined COXEN scores significantly predicted the activity of combination therapy in NSCLC cells (P = 0.007). Through the refinement of the COXEN algorithm, we provide an in silico method to generate biomarkers that predict tumor sensitivity to molecularly targeted therapies. Use of this refined COXEN method has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost. PMID- 20713533 TI - Morality and moral conflicts in hospice care: results of a qualitative interview study. AB - Hospices consider themselves places that practise a holistic form of terminal care, encompassing physical and psychological symptoms, and also the social and spiritual support for a dying patient. So far, the underlying ethical principles have been treated predominantly in terms of a normative theoretical discussion. The interview study discussed in this paper is a qualitative investigation into general and hospice-related conceptions of morality among full-time and voluntary workers in German inpatient hospices. It examines moral conflicts and efforts leading to their solution. The main ideas identified include moral neutrality towards the patients and their requests, the capability of acceptance, the idea of self-restraint with respect to the dying patient and the principle of respect for the natural course of dying. Essential triggers for moral conflicts were the inadequate education of patients, problems of acceptance in view of incurable disease, and disagreements between members of patients' families. The interviewees expressed their scepticism towards formal institutions of ethical counselling. The study has shown a type of virtue ethics that forms an integral part of the overall concept of hospice care, which cannot be treated separately from a holistic idea of care at the end of life. PMID- 20713534 TI - Parental attitudes towards and perceptions of their children's participation in clinical research: a developing-country perspective. AB - BACKGROUND: Paediatric clinical research faces unique challenges that compromise optimal recruitment of children into clinical trials. A main barrier to enrolment of children is parental misconceptions about the research process. In developing countries, there is a knowledge gap regarding parental perceptions of and attitudes towards their children's participation in clinical trials. OBJECTIVE: To explore such perceptions and attitudes in Lebanese parents. STUDY DESIGN: 33 in-depth interviews were conducted with parents with and without previous research experience. Interviews were tape-recorded, transcribed in colloquial Arabic, and later subjected to thematic analysis. RESULTS: Benefit/risk ratio assessment was a major determinant of parental consent. Fear of adverse events or painful procedures in research was a recurring theme in most interviews. Whereas perception of direct benefit to the child, trust in the physician or institution, financial gains or having a positive previous experience in research facilitated consent, a complex informed consent form and misunderstanding of the term 'randomisation' hindered parental approval of participation. CONCLUSION: Lebanese parents have perceptions of and attitudes towards children's participation in clinical trials that are similar to those reported from the industrialised world. Improving communication with parents and building trust between researchers and parents is important for successful recruitment. Investigators planning to conduct paediatric trials in developing countries need to simplify consent forms and devise new ways to explain randomisation. PMID- 20713535 TI - The use of vignettes within a Delphi exercise: a useful approach in empirical ethics? AB - There has been an increase in recent years in the use of empirical methods in healthcare ethics. Appeals to empirical data cannot answer moral questions, but insights into the knowledge, attitudes, experience, preferences and practice of interested parties can play an important part in the development of healthcare ethics. In particular, while we may establish a general ethical principle to provide explanatory and normative guidance for healthcare professionals, the interpretation and application of such general principles to actual practice still requires interpretation and judgement. And many situations in healthcare practice are complex and may involve a variety of principles, each of which may conflict with the others. Simple surveys or interview studies may not be sufficient if we wish to develop a nuanced approach to ethical practice that can be set out in guidelines, codes or directives. We do not resolve moral questions by plebiscite. In this paper, the authors argue for the use of consensus methods to develop shared understanding of ethical practice, and they argue further for the combination of the Delphi method with the use of vignettes to illustrate the kind of situations that may occur in practice. They develop their argument in part by reference to their experience of using this approach in their recent research. PMID- 20713536 TI - The risk of arrhythmias following coronary artery bypass surgery: do smokers have a paradox effect? AB - Smoking is reported to increase the risk of arrhythmias. However, there are limited data on its effects on arrhythmias following coronary artery bypass graft (CABG). This is a retrospective review of a prospective database of all CABG patients over an eight-year period. Our cohort (n=2813) was subdivided into: current (n=1169), former (n=837), and non-smokers (n=807). Predictors of arrhythmias following CABG in relation to smoking status were analysed. Atrial arrhythmias occurred in 942 patients (33%). Ventricular arrhythmias occurred in 48 patients (2%) and high-grade atrioventricular block occurred in five patients (0.2%). Arrhythmias were lower in current smokers than former and non-smokers (29% vs. 40% vs. 39%, respectively P<0.001). Logistic regression analysis showed 30% arrhythmia risk reduction in smokers compared to non-smokers [odds ratio (OR) 0.7, 95% confidence intervals (CI) 0.5-0.8] and this effect persisted after accounting for potential confounders while former smokers had the same risk as non-smokers (OR 1.04, CI 0.9-1.3). There were no significant differences in mortality. Smokers are less prone to develop arrhythmias following CABG. This paradox effect is lost in former smokers. This effect is possibly due to a lower state of hyper adrenergic stimulation observed in smokers than non-smokers following the stress of surgery. PMID- 20713537 TI - What type of valve replacement should be used in patients with endocarditis? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'in patients undergoing a surgery for endocarditis is a biological valve or mechanical valve superior for achieving long-term low rates of reinfection?' Altogether more than 41 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Out of the studies that include statistical comparisons, in mechanical valve replacement the average endocarditis recurrence rate ranged from approximately 3 to 9% and in biological valves from approximately 7 to 29%. Out of the studies that specifically compared the outcomes of the two valves, 50% concluded there to be no significant difference when separated from other risk factors and 50% recommended a mechanical valve for lower recurrence and higher survival rates. The Euro Heart Survey found that 63% of valve replacements were mechanical, due to young age (90%) and physician preference (75%) and only 21% bioprosthetic. Current guidelines from American College of Cardiology/American Heart Association (ACC/AHA) recommend a mechanical valve in patients <65 years old and a bioprosthetic valve if >65, without risk factors for thromboembolism, but this is based on class II evidence (conflicting evidence or opinion). These guidelines are not specific to patients with infective endocarditis, so it is vital to review the literature related to this. Three of the studies in the search specify that for patients under 60-65 years old, a mechanical valve has greater benefit, but this was not found to be true for the over 65 years. It can be concluded that for patients under 65 years old, a mechanical valve may offer greater freedom from reoperation and increased long-term survival when compared to a bioprosthetic valve (assuming no other co-morbidities), although this divide is narrowing with the use of newer generation bioprosthetic valves and has to be off-set against potential bleeding risks. For patients over 65 years, other important variants need to be considered including patient choice, correct protocols of antibiotics and radical debridement. PMID- 20713538 TI - New indication for preoperative marking of small peripheral pulmonary nodules in thoracoscopic surgery. AB - The aim of this work was to analyze parameters to determine the possibility for detection of tumor location, and clarify the indication for preoperative marking of small peripheral pulmonary nodules in thoracoscopic resection. In a series of 97 patients who underwent video-assisted thoracoscopic surgery, information on standard uptake values (SUVs) and the detectability of tumor location was assessed. In patients whose lesions were <15 mm in diameter and where the distance to the pleura was >10 mm, lesions were not detected. Multivariate analysis to determine the factors related to the possibility of detecting tumor localization revealed that the distance to the pleural surface (P=0.0001), and the ratio of solid portion (P=0.0104) were statistically significant. In the non solid tumor group, we should perform preoperative marking for tumors located more than 3 mm in depth from the visceral pleura. In the solid tumor group, the linear function (depth=0.4*size-0.9) may be used to separate detectable and undetectable groups. However, the sensitivity was 90.3% even if this formula was applied. Here we advocate the algorithm for detection of indication for preoperative marking using the ratio of solid portion, tumor size and SUV of fluorodeoxyglucose positron emission tomography. PMID- 20713541 TI - Long-acting beta-agonist step-up therapy is more likely to provide best response, compared to inhaled corticosteroid or leukotriene-receptor antagonist step-up in children with uncontrolled asthma receiving inhaled corticosteroids. PMID- 20713542 TI - Administration of annual oral high-dose vitamin D to community-dwelling older women in autumn and winter months increases risk of falls and fractures. PMID- 20713543 TI - Low-dose and high-dose colchicine have comparable efficacy in the treatment of acute gout, but high dose carries significantly greater risk of adverse effects. PMID- 20713544 TI - Health effects of the Gulf oil spill. PMID- 20713545 TI - Airway surface liquid depth imaged by surface laser reflectance microscopy. AB - The thin layer of liquid at the surface of airway epithelium, the airway surface liquid (ASL), is important in normal airway physiology and in the pathophysiology of cystic fibrosis. At present, the best method to measure ASL depth involves scanning confocal microscopy after staining with an aqueous-phase fluorescent dye. We describe here a simple, noninvasive imaging method to measure ASL depth by reflectance imaging of an epithelial mucosa in which the surface is illuminated at a 45-degree angle by an elongated 13-microm wide rectangular beam produced by a 670-nm micro-focus laser. The principle of the method is that air liquid, liquid-liquid, and liquid-cell interfaces produce distinct specular or diffuse reflections that can be imaged to give a micron-resolution replica of the mucosal surface. The method was validated using fluid layers of specified thicknesses and applied to measure ASL depth in cell cultures and ex vivo fragments of pig trachea. In addition, the method was adapted to measure transepithelial fluid transport from the dynamics of fluid layer depth. Compared with confocal imaging, ASL depth measurement by surface laser reflectance microscopy does not require dye staining or costly instrumentation, and can potentially be adapted for in vivo measurements using fiberoptics. PMID- 20713546 TI - Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells. AB - Plasma membrane large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels and sarcoplasmic reticulum inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) are expressed in a wide variety of cell types, including arterial smooth muscle cells. Here, we studied BK(Ca) channel regulation by IP(3) and IP(3)Rs in rat and mouse cerebral artery smooth muscle cells. IP(3) activated BK(Ca) channels both in intact cells and in excised inside-out membrane patches. IP(3) caused concentration-dependent BK(Ca) channel activation with an apparent dissociation constant (K(d)) of approximately 4 microM at physiological voltage (-40 mV) and intracellular Ca(2+) concentration ([Ca(2+)](i); 10 microM). IP(3) also caused a leftward-shift in BK(Ca) channel apparent Ca(2+) sensitivity and reduced the K(d) for free [Ca(2+)](i) from approximately 20 to 12 microM, but did not alter the slope or maximal P(o). BAPTA, a fast Ca(2+) buffer, or an elevation in extracellular Ca(2+) concentration did not alter IP(3)-induced BK(Ca) channel activation. Heparin, an IP(3)R inhibitor, and a monoclonal type 1 IP(3)R (IP(3)R1) antibody blocked IP(3)-induced BK(Ca) channel activation. Adenophostin A, an IP(3)R agonist, also activated BK(Ca) channels. IP(3) activated BK(Ca) channels in inside-out patches from wild-type (IP(3)R1(+/+)) mouse arterial smooth muscle cells, but had no effect on BK(Ca) channels of IP(3)R1-deficient (IP(3)R1(-/-)) mice. Immunofluorescence resonance energy transfer microscopy indicated that IP(3)R1 is located in close spatial proximity to BK(Ca) alpha subunits. The IP(3)R1 monoclonal antibody coimmunoprecipitated IP(3)R1 and BK(Ca) channel alpha and beta1 subunits from cerebral arteries. In summary, data indicate that IP(3)R1 activation elevates BK(Ca) channel apparent Ca(2+) sensitivity through local molecular coupling in arterial smooth muscle cells. PMID- 20713547 TI - Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node. AB - The sympathetic nervous system increases heart rate by activating beta adrenergic receptors and increasing cAMP levels in myocytes in the sinoatrial node. The molecular basis for this response is not well understood; however, the cardiac funny current (I(f)) is thought to be among the end effectors for cAMP signaling in sinoatrial myocytes. I(f) is produced by hyperpolarization-activated cyclic nucleotide-sensitive (HCN4) channels, which can be potentiated by direct binding of cAMP to a conserved cyclic nucleotide binding domain in the C terminus of the channels. beta Adrenergic regulation of I(f) in the sinoatrial node is thought to occur via this direct binding mechanism, independent of phosphorylation. Here, we have investigated whether the cAMP-activated protein kinase (PKA) can also regulate sinoatrial HCN4 channels. We found that inhibition of PKA significantly reduced the ability of beta adrenergic agonists to shift the voltage dependence of I(f) in isolated sinoatrial myocytes from mice. PKA also shifted the voltage dependence of activation to more positive potentials for heterologously expressed HCN4 channels. In vitro phosphorylation assays and mass spectrometry revealed that PKA can directly phosphorylate at least 13 sites on HCN4, including at least three residues in the N terminus and at least 10 in the C terminus. Functional analysis of truncated and alanine-substituted HCN4 channels identified a PKA regulatory site in the distal C terminus of HCN4, which is required for PKA modulation of I(f). Collectively, these data show that native and expressed HCN4 channels can be regulated by PKA, and raise the possibility that this mechanism could contribute to sympathetic regulation of heart rate. PMID- 20713549 TI - How is the heart rate regulated in the sinoatrial node? Another piece to the puzzle. PMID- 20713548 TI - Paradoxical buffering of calcium by calsequestrin demonstrated for the calcium store of skeletal muscle. AB - Contractile activation in striated muscles requires a Ca(2+) reservoir of large capacity inside the sarcoplasmic reticulum (SR), presumably the protein calsequestrin. The buffering power of calsequestrin in vitro has a paradoxical dependence on [Ca(2+)] that should be valuable for function. Here, we demonstrate that this dependence is present in living cells. Ca(2+) signals elicited by membrane depolarization under voltage clamp were compared in single skeletal fibers of wild-type (WT) and double (d) Casq-null mice, which lack both calsequestrin isoforms. In nulls, Ca(2+) release started normally, but the store depleted much more rapidly than in the WT. This deficit was reflected in the evolution of SR evacuability, E, which is directly proportional to SR Ca(2+) permeability and inversely to its Ca(2+) buffering power, B. In WT mice E starts low and increases progressively as the SR is depleted. In dCasq-nulls, E started high and decreased upon Ca(2+) depletion. An elevated E in nulls is consistent with the decrease in B expected upon deletion of calsequestrin. The different value and time course of E in cells without calsequestrin indicate that the normal evolution of E reflects loss of B upon SR Ca(2+) depletion. Decrement of B upon SR depletion was supported further. When SR calcium was reduced by exposure to low extracellular [Ca(2+)], release kinetics in the WT became similar to that in the dCasq-null. E became much higher, similar to that of null cells. These results indicate that calsequestrin not only stores Ca(2+), but also varies its affinity in ways that progressively increase the ability of the store to deliver Ca(2+) as it becomes depleted, a novel feedback mechanism of potentially valuable functional implications. The study revealed a surprisingly modest loss of Ca(2+) storage capacity in null cells, which may reflect concurrent changes, rather than detract from the physiological importance of calsequestrin. PMID- 20713550 TI - Thapsigargin induces expression of activating transcription factor 3 in human keratinocytes involving Ca2+ ions and c-Jun N-terminal protein kinase. AB - Thapsigargin is a specific inhibitor of the sarco/endoplasmic reticulum Ca(2+) ATPase of the endoplasmic reticulum. Here, we show that stimulation of human HaCaT keratinocytes with nanomolar concentrations of thapsigargin triggers expression of activating transcription factor (ATF) 3, a basic-region leucin zipper transcription factor. ATF3 expression was also up-regulated in thapsigargin-stimulated glioma cells, hepatoma cells, retinal pigment epithelial cells, and airway epithelial cells. Thapsigargin-induced up-regulation of ATF3 expression in keratinocytes was attenuated by BAPTA-acetoxymethyl ester or by expression of the Ca(2+)-binding protein parvalbumin in the cytosol of HaCaT cells but not by a panel of pharmacological agents that chelate extracellular Ca(2+) (EGTA) or inhibit either ryanodine receptors (dantrolene) or voltage-gated Ca(2+) channels (nifedipine). Hence, elevated levels of intracellular Ca(2+), released from intracellular stores, are essential for the effect of thapsigargin on the biosynthesis of ATF3. The thapsigargin-induced signaling pathway was blocked by expression of either mitogen-activated protein kinase phosphatase-1 or -5. Experiments involving pharmacological and genetic tools revealed the importance of c-Jun N-terminal protein kinase (JNK) within the signaling cascade, whereas inhibition of extracellular signal-regulated protein kinase or p38 protein kinase did not attenuate thapsigargin-induced expression of ATF3. Functional studies showed that treatment of HaCaT keratinocytes with thapsigargin led to a 2-fold induction of caspase-3/7 activity. The up-regulation of caspase 3/7 activity in thapsigargin-stimulated HaCaT cells was attenuated by inhibition of JNK. Together, these data show that stimulation of HaCaT cells with thapsigargin induces a specific signaling pathway in keratinocytes involving activation of JNK, biosynthesis of ATF3, and up-regulation of caspase-3/7 activity. PMID- 20713551 TI - Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1. AB - The transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p glycoprotein), which plays an important role in the efflux from the target cell of many anticancer agents. We recently showed that a Forkhead box-containing protein of the O subfamily 1 (FoxO1) is a key regulator of MDR1 gene transcription. Because nuclear localization of FoxO1 is regulated by silent information regulator two ortholog 1 (SIRT1) deacetylase, we wondered whether SIRT1 dominates MDR1 gene expression in breast cancer cells. Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. In addition, SIRT1 inhibition reduced both nuclear FoxO1 levels and MDR1 expression in doxorubicin-resistant breast cancer cells (MCF 7/ADR) cells. A potent SIRT1 inhibitor, amurensin G (from Vitis amurensis), was identified by screening plant extracts and bioassay-guided fractionation. The compound suppressed FoxO1 activity and MDR1 expression in MCF-7/ADR cells. Moreover, pretreatment of MCF-7/ADR cells with 1 MUg/ml amurensin G for 24 h increased cellular uptake of doxorubicin and restored the responsiveness of MCF 7/ADR cells to doxorubicin. In xenograft studies, injection of 10 mg/kg i.p. amurensin G substantially restored the ability of doxorubicin to inhibit MCF 7/ADR-induced tumor growth. These results suggest that SIRT1 is a potential therapeutic target of MDR1-mediated chemoresistance and that it may be possible to develop amurensin G as a useful agent for chemoresistance reversal. PMID- 20713552 TI - Design considerations in migraine with aura trials: learning from experience. PMID- 20713553 TI - Pain sensitivity in children with frequent episodic tension type headache. PMID- 20713554 TI - On the methodology of drug trials in migraine with aura. AB - INTRODUCTION: Specific problems occur in clinical treatment trials for migraine with aura that differ from those encountered in treatment trials for migraine without aura. DISCUSSION: Based on our experience with four such trials, we point to a number of possible solutions and outline areas for future inquiry. We make recommendations about subject selection; the choice, definition and assessment of outcome measures; optimal treatments in relation to aura and headache; and we provide samples of study report forms used to record occurrence of aura and headache in this population. PMID- 20713555 TI - Bilateral, wide-spread, mechanical pain sensitivity in children with frequent episodic tension-type headache suggesting impairment in central nociceptive processing. AB - INTRODUCTION: The aim was to investigate bilateral, wide-spread pressure pain hyperalgesia in symptomatic (trigeminocervical) and non-symptomatic (pain-free distant) regions in children with frequent episodic tension-type headache (FETTH). METHODS: Twenty-five children, 6 boys and 19 girls (mean age, 8.9 +/- 1.8 years) with FETTH and 50 age- and sex-matched healthy children (12 boys, 38 girls; mean age: 8.8 +/- 1.7 years) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over temporalis muscle, upper trapezius muscle, second metacarpal and tibialis anterior muscles in a blinded design. RESULTS: The results showed that PPT levels were significantly decreased bilaterally over the temporalis, upper trapezius and tibialis muscles, and the second metacarpal in children with FETTH as compared to controls (all sites, P < 0.001). No significant differences in the magnitude of PPT decrease between the upper trapezius muscle, second metacarpal and tibialis anterior muscles were found. PPT over both upper trapezius muscles were negatively correlated with the history and intensity of headache (r(s) = -0.415; P = 0.045). CONCLUSIONS: The findings revealed bilateral, wide-spread pressure pain hypersensitivity in children with FETTH suggesting that wide-spread central sensitisation is involved in children with this headache pain condition. PMID- 20713556 TI - Primary headaches in childhood--a population-based study. AB - The aim of this study was to estimate the prevalence of primary headaches in pre adolescent children, as well as headache frequency and days of treatment in this population. Sample consisted of 1994 children (aged 5-12 years). Parents were interviewed by a paediatric headache specialist using a questionnaire that allowed the classification of headaches using the criteria of the Second Edition of the International Classification of Headache Disorders. The most severe headache type was classified (mutually-exclusive diagnoses). Prevalence and prevalence ratios were calculated overall, as well as by age, gender and race. The overall prevalence of migraine was 3.76%, non-significantly higher in boys (3.9%) than in girls (3.6%). Prevalence of probable migraine was significantly higher than the prevalence of migraine for all ages (overall prevalence of 17.1%). Chronic migraine (CM) happened in 0.8% (girls, 1.15%; boys, 0.5%). Infrequent episodic tension-type headache (ETTH) happened in 2.3% of the sample while prevalence of frequent ETTH was 1.6%. Probable TTH happened in 13.5%. Most children with migraine had consulted a medical doctor because of their headaches, and the proportion was higher among children with CM (93.7%). Prevalence of primary headaches is high in young children. Probable diagnoses are more common than full diagnoses. Consultation rates are elevated. PMID- 20713557 TI - Migraine prevalence by age and sex in the United States: a life-span study. AB - The present study assessed age- and sex-specific patterns of migraine prevalence in a US population of 40,892 men, women, and children who participated in the 2003 National Health Interview Survey. Gaussian mixture models characterised the relationship between migraine, age, and sex. Migraine prevalence was 8.6% (males), 17.5% (females), and 13.2% (overall) and showed a bimodal distribution in both sexes (peaking in the late teens and 20s and around 50 years of age). Rate of change in migraine prevalence for both sexes increased the fastest from age 3 years to the mid-20s. Beyond the age of 10 years, females had a higher prevalence of migraine than males. The prevalence ratio for females versus males was highest during the female reproductive/child-bearing years, consistent with a relationship between menstruation and migraine. After age 42 years, the prevalence ratio was approximately 2-fold higher in women. PMID- 20713558 TI - Migraine symptomatology and major depressive disorder. AB - INTRODUCTION AND OBJECTIVE: Migraine and major depressive disorder (MDD) frequently co-occur, but it is unclear whether depression is associated with a specific subtype of migraine. The objective of this study was to investigate whether migraine is qualitatively different in MDD patients (N = 1816) and non depressed controls (N = 3428). METHODS: Migraine symptom data were analyzed using multi-group Latent Class Analysis, and a qualitative comparison was made between the symptom profiles of MDD patients and controls, while allowing for differences in migraine prevalence and severity between groups. RESULTS: In both groups, three migrainous headache classes were identified, which differed primarily in terms of severity. Both mild and severe migrainous headaches were two to three times more prevalent in MDD patients. Migraine symptom profiles showed only minor qualitative differences in the MDD and non-MDD groups: in the severe migrainous headache class, significant differences were observed only in the prevalence of aggravation by physical activity (83% and 91% for the non-MDD and MDD groups, respectively) and aura (42% vs. 53%, respectively). CONCLUSION: The similar overall symptom profiles observed in the MDD and non-MDD subjects suggest that a similar disease process may underlie migraine in both groups. PMID- 20713559 TI - Development and validation of the EUROLIGHT questionnaire to evaluate the burden of primary headache disorders in Europe. AB - We developed a 103-item self-reporting questionnaire to assess the burden of primary headache disorders on those affected by them, including headache characteristics, associated disability, co-morbidities, disease-management and quality of life. We validated the questionnaire in five languages with 426 participants (131 in UK, 60 in Italy, 107 in Spain, 83 in Germany/Austria, and 45 in France). After a linguistic and a face-content validation, we tested the questionnaire for comprehensibility, internal consistency and test-retest reliability at an interval of one month. In the different countries, response rates were between 73% and 100%. Test-retest reliability varied between -0.27 to 1.0 depending of the nature of the expected agreement. The internal consistency was between 0.69 and 0.91. The EUROLIGHT questionnaire is suitable for evaluating the burden of primary headache disorders, and can be used in English, German, French, Italian and Spanish. PMID- 20713560 TI - Cortical hyperexcitability and mechanism of medication-overuse headache. AB - The present study was conducted to determine the effect of acute (1 h) and chronic (daily dose for 30 days) paracetamol administration on the development of cortical spreading depression (CSD), CSD-evoked cortical hyperaemia and CSD induced Fos expression in cerebral cortex and trigeminal nucleus caudalis (TNC). Paracetamol (200 mg/kg body weight, intraperitonealy) was administered to Wistar rats. CSD was elicited by topical application of solid KCl. Electrocorticogram and cortical blood flow were recorded. Results revealed that acute paracetamol administration substantially decreased the number of Fos-immunoreactive cells in the parietal cortex and TNC without causing change in CSD frequency. On the other hand, chronic paracetamol administration led to an increase in CSD frequency as well as CSD-evoked Fos expression in parietal cortex and TNC, indicating an increase in cortical excitability and facilitation of trigeminal nociception. Alteration of cortical excitability which leads to an increased susceptibility of CSD development can be a possible mechanism underlying medication-overuse headache. PMID- 20713561 TI - Functional and molecular characterization of prostaglandin E2 dilatory receptors in the rat craniovascular system in relevance to migraine. AB - INTRODUCTION: Migraine pain is thought to involve an increase in trigeminal nerve terminal activity around large cerebral and meningeal arteries, leading to vasodilatation. Because prostaglandin E(2) (PGE(2)) is elevated in cephalic venous blood during migraine attacks, and is also capable of inducing headache in healthy volunteers, we hypothesize that PGE(2) dilatory receptors, EP(2) and EP(4), mediate the response. MATERIALS AND METHODS: By the use of specific agonists and antagonists, the dilatory effect of PGE(2) was characterized in rat cranial arteries by use of in vivo and in vitro methods. Furthermore, EP(2) and EP(4) quantitative messenger RNA (mRNA) receptor expression was studied in the rat craniovascular system. RESULTS: Our results suggest that EP(4), and to a lesser degree EP(2), receptors mediate the dilatory effect of PGE(2) in the craniovascular system in rats. Thus, antagonism of these receptors might be of therapeutic relevance in migraine. PMID- 20713562 TI - Ten years of chronic cluster--attacks still cluster. AB - The chronic variant can be found in 10-20% of all cluster headache patients. While circadian and circannual rhythmicity are characteristic of the episodic variant, little is known on chronobiology in chronic cluster headache. We report a patient with chronic cluster evolved from episodic who recorded a total of 5447 attacks over 10 years. After spectral analysis, cosinor models were calculated within the frequency ranges of 23-25 h (circadian) and 11-13 months (circannual), respectively. Significant results (P < 0.01) were found for 24-h periods, but not for circannual intervals (12 months). However, with regard to circannual periodicity, a semi-circannual rhythm (5-7 months) was suitable for curve fit and yielded significant results in the cosinor analysis at 6 months (P < 0.05). This remarkable long observation period of 10 years shows that, at least for secondary chronic cluster headache which evolved from the episodic form, a typical circadian and circannual rhythmicity comparable to that of episodic cluster headache exists. PMID- 20713563 TI - Reversible cerebral vasoconstriction syndrome associated with hormone therapy for intrauterine insemination. AB - INTRODUCTION: Reversible cerebral vasoconstriction syndrome (RCVS) comprises a heterogeneous group of acute neurological diseases which are characterized by thunderclap headache and evidence of reversible multifocal constriction of cerebral arteries. A number of precipitating factors have been described in the literature, including recent childbirth and use of vasoactive substances. CASE DESCRIPTION: Here we present the case of a female patient with RCVS which occurred in the setting of hormonal ovarian stimulation for intrauterine insemination. DISCUSSION: This case possibly contributes to the understanding of the pathophysiological mechanisms underlying reversible cerebral vasoconstriction. PMID- 20713564 TI - A case review of the MRI features in alternating Tolosa-Hunt syndrome. AB - Tolosa-Hunt syndrome (THS) consists of a painful ophthalmoplegia with typical features in magnetic resonance imaging (MRI). The recurring nature of this affliction has been known since its first description. However, compromise of the contralateral cavernous sinus, known as alternating THS, is very rare and has never been examined using MRI. We report clinical data, laboratory data and imaging features of a patient with alternating THS. According to our literature review, this is the first MRI study of THS. PMID- 20713565 TI - Secondary hypnic headache or symptomatic nocturnal hypertension? Two case reports. PMID- 20713566 TI - The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series. PMID- 20713567 TI - Comments on results of Scher et al. pertaining to nonprescription caffeine containing combination analgesics. PMID- 20713568 TI - Almotriptan efficacy in migraine with allodynia: a rebuttal to Burstein and Jakubowski's critique of Schoenen et al. PMID- 20713569 TI - Atrial myxoma as a trigger of migraine with aura--pathophysiological considerations. PMID- 20713570 TI - Nummular headache dramatically responsive to indomethacin. PMID- 20713573 TI - The hypocrisy of Canada's prostitution legislation. PMID- 20713572 TI - Mathematical models and cost-effective screening strategies for colorectal cancer. PMID- 20713575 TI - Harlequin colour change: unilateral erythema in a newborn. PMID- 20713576 TI - Short-term mortality associated with failure to receive home care after hemiarthroplasty. AB - BACKGROUND: Hemiarthroplasty is often the treatment of choice after hip fracture, particularly in frail elderly patients. Such patients may benefit from home care after discharge. We assessed factors associated with the receipt of home care and evaluated the risk of death within three months after discharge. METHODS: We obtained administrative data for patients 65 years or older in the province of Quebec who were discharged alive from hospital after hemiarthroplasty during the period 1997-2004. We evaluated destination after discharge and mortality within three months after discharge. RESULTS: Of 11 326 study patients, 5.6% were discharged home with home care, 29.9% home without home care, 2.0% to a rehabilitation centre, 24.2% to a nursing home and 38.3% to another hospital. Among patients who were discharged home, those who were older, had osteoarthritis, had an emergent admission and were admitted to a high-volume hospital were less likely to receive home care. Discharge with home care was most likely among patients admitted to teaching hospitals, those in hospital for more than seven days, those with atrial fibrillation and those with acute renal failure. Patients who received home care were at lower risk of death than those discharged home without care (hazard ratio 0.57, 95% confidence interval 0.39 0.85). INTERPRETATION: Less than 16% of the patients discharged home after hemiarthroplasty received home care. Those who received such care had a lower risk of death within three months after discharge. PMID- 20713577 TI - On the streets at the G20. PMID- 20713578 TI - Uncertainties surround new funding for "Most Responsible Physicians". PMID- 20713579 TI - Nordion retreats from defamation lawsuit. PMID- 20713580 TI - The fear factor in health fundraising. PMID- 20713581 TI - United States war Veterans gain access to medicinal marijuana. PMID- 20713582 TI - Widespread variations exist in bike helmet laws across Canada. PMID- 20713584 TI - A guide to imaging for common neurological problems. PMID- 20713585 TI - Acromegaly. PMID- 20713586 TI - Patient groups must reveal corporate sponsorship, urges campaign group. PMID- 20713588 TI - Australian health authorities' response criticised after adverse events related to influenza vaccination in children. PMID- 20713583 TI - Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients. AB - OBJECTIVE: To evaluate the relative effectiveness of hysterectomy, endometrial destruction (both "first generation" hysteroscopic and "second generation" non hysteroscopic techniques), and the levonorgestrel releasing intrauterine system (Mirena) in the treatment of heavy menstrual bleeding. DESIGN: Meta-analysis of data from individual patients, with direct and indirect comparisons made on the primary outcome measure of patients' dissatisfaction. DATA SOURCES: Data were sought from the 30 randomised controlled trials identified after a comprehensive search of the Cochrane Library, Medline, Embase, and CINAHL databases, reference lists, and contact with experts. Raw data were available from 2814 women randomised into 17 trials (seven trials including 1359 women for first v second generation endometrial destruction; six trials including 1042 women for hysterectomy v first generation endometrial destruction; one trial including 236 women for hysterectomy v Mirena; three trials including 177 women for second generation endometrial destruction v Mirena). Eligibility criteria for selecting studies Randomised controlled trials comparing hysterectomy, first and second generation endometrial destruction, and Mirena for women with heavy menstrual bleeding unresponsive to other medical treatment. RESULTS: At around 12 months, more women were dissatisfied with outcome with first generation hysteroscopic techniques than with hysterectomy (13% v 5%; odds ratio 2.46, 95% confidence interval 1.54 to 3.9, P<0.001), but hospital stay (weighted mean difference 3.0 days, 2.9 to 3.1 days, P<0.001) and time to resumption of normal activities (5.2 days, 4.7 to 5.7 days, P<0.001) were longer for hysterectomy. Unsatisfactory outcomes were comparable with first and second generation techniques (odds ratio 1.2, 0.9 to 1.6, P=0.2), although second generation techniques were quicker (weighted mean difference 14.5 minutes, 13.7 to 15.3 minutes, P<0.001) and women recovered sooner (0.48 days, 0.20 to 0.75 days, P<0.001), with fewer procedural complications. Indirect comparison suggested more unsatisfactory outcomes with second generation techniques than with hysterectomy (11% v 5%; odds ratio 2.3, 1.3 to 4.2, P=0.006). Similar estimates were seen when Mirena was indirectly compared with hysterectomy (17% v 5%; odds ratio 2.2, 0.9 to 5.3, P=0.07), although this comparison lacked power because of the limited amount of data available for analysis. CONCLUSIONS: More women are dissatisfied after endometrial destruction than after hysterectomy. Dissatisfaction rates are low after all treatments, and hysterectomy is associated with increased length of stay in hospital and a longer recovery period. Definitive evidence on effectiveness of Mirena compared with more invasive procedures is lacking. PMID- 20713590 TI - Trust missed breast cancer in eight women, review finds. PMID- 20713592 TI - Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. AB - Recent studies have shown that a carbohydrate-binding protein, galectin-3, is a novel pro-angiogenic molecule. The mechanism by which galectin-3 promotes angiogenesis remains unknown. We demonstrate here that galectin-3 is a mediator of vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenic response. Angiogenesis assays revealed that galectin-3 inhibitors, beta-lactose and dominant-negative galectin-3, reduce VEGF- and bFGF mediated angiogenesis in vitro and that VEGF- and bFGF-mediated angiogenic response is reduced in galectin-3 knockdown cells and Gal3(-/-) animals. Integrin alphavbeta3 was identified as the major galectin-3-binding protein and anti alphav, -beta3, and -alphavbeta3 integrin function-blocking antibodies significantly inhibited the galectin-3-induced angiogenesis. Furthermore, galectin-3 promoted the clustering of integrin alphavbeta3 and activated focal adhesion kinase. Knockdown of GnTV, an enzyme that synthesizes high-affinity glycan ligands for galectin-3, substantially reduced: (a) complex N-glycans on alphavbeta3 integrins and (b) VEGF- and bFGF-mediated angiogenesis. Collectively, these data suggest that galectin-3 modulates VEGF- and bFGF-mediated angiogenesis by binding via its carbohydrate recognition domain, to the GnTV synthesized N glycans of integrin alphavbeta3, and subsequently activating the signaling pathways that promote the growth of new blood vessels. These findings have broad implications for developing novel, carbohydrate-based therapeutic agents for inhibition of angiogenesis. PMID- 20713593 TI - A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function. AB - Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnA(loxP/loxP) females with GATA1-Cre males. FlnA(loxP/y) GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIbalpha because they lack the normal cytoskeletal linkage of GPIbalpha to underlying actin filaments. This results in approximately 70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like-mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased alpha-granule secretion, integrin alphaIIbbeta3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C-gamma2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA-Syk interaction, as Syk binds to FlnA at immunoglobulin like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like-containing receptor signaling and platelet function. PMID- 20713594 TI - The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation. AB - Human cytomegalovirus (HCMV) encodes an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, US10, expressed early in the replicative cycle of HCMV as part of the same cluster that encodes the known immunoevasins US2, US3, US6, and US11. We show that US10 down-regulates cell surface expression of HLA-G, but not that of classical class I MHC molecules. The unique and short cytoplasmic tail of HLA-G (RKKSSD) is essential in its role as a US10 substrate, and a tri leucine motif in the cytoplasmic tail of US10 is responsible for down-regulation of HLA-G. Both the kinetics of HLA-G degradation and the mechanisms responsible appear to be distinct from those used by the US2 and US11 pathways, suggesting the existence of a third route of protein dislocation from the ER. We show that US10-mediated degradation of HLA-G interferes with HLA-G-mediated NK cell inhibition. Given the role of HLA-G in protecting the fetus from attack by the maternal immune system and in directing the differentiation of human dendritic cells to promote the evolution of regulatory T cells, HCMV likely targets the HLA G-dependent axis of immune recognition no less efficiently than it interferes with classical class I MHC-restricted antigen presentation. PMID- 20713595 TI - Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice. AB - The current epidemic of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections has caused significant human morbidity, but a protective vaccine is not yet available. Prior infection with S. aureus is not associated with protective immunity. This phenomenon involves staphylococcal protein A (SpA), an S. aureus surface molecule that binds to Fcgamma of immunoglobulin (Ig) and to the Fab portion of V(H)3-type B cell receptors, thereby interfering with opsonophagocytic clearance of the pathogen and ablating adaptive immune responses. We show that mutation of each of the five Ig-binding domains of SpA with amino acid substitutions abolished the ability of the resulting variant SpA(KKAA) to bind Fcgamma or Fab V(H)3 and promote B cell apoptosis. Immunization of mice with SpA(KKAA) raised antibodies that blocked the virulence of staphylococci, promoted opsonophagocytic clearance, and protected mice against challenge with highly virulent MRSA strains. Furthermore, SpA(KKAA) immunization enabled MRSA-challenged mice to mount antibody responses to many different staphylococcal antigens. PMID- 20713596 TI - Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation. AB - End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft. PMID- 20713597 TI - Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. AB - Autophagy is a catabolic process that allows cells to digest their cytoplasmic constituents via autophagosome formation and lysosomal degradation. Recently, an autophagy-specific phosphatidylinositol 3-kinase (PI3-kinase) complex, consisting of hVps34, hVps15, Beclin-1, and Atg14L, has been identified in mammalian cells. Atg14L is specific to this autophagy complex and localizes to the endoplasmic reticulum (ER). Knockdown of Atg14L leads to the disappearance of the DFCP1 positive omegasome, which is a membranous structure closely associated with both the autophagosome and the ER. A point mutation in Atg14L resulting in defective ER localization was also defective in the induction of autophagy. The addition of the ER-targeting motif of DFCP1 to this mutant fully complemented the autophagic defect in Atg14L knockout embryonic stem cells. Thus, Atg14L recruits a subset of class III PI3-kinase to the ER, where otherwise phosphatidylinositol 3-phosphate (PI3P) is essentially absent. The Atg14L-dependent appearance of PI3P in the ER makes this organelle the platform for autophagosome formation. PMID- 20713598 TI - Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors: a possible link to Rho family GTPases. AB - Cell migration requires the coordinated spatiotemporal regulation of actomyosin contraction and cell protrusion/adhesion. Nonmuscle myosin II (MII) controls Rac1 and Cdc42 activation, and cell protrusion and focal complex formation in migrating cells. However, these mechanisms are poorly understood. Here, we show that MII interacts specifically with multiple Dbl family guanine nucleotide exchange factors (GEFs). Binding is mediated by the conserved tandem Dbl homology pleckstrin homology module, the catalytic site of these GEFs, with dissociation constants of approximately 0.3 microM. Binding to the GEFs required assembly of the MII into filaments and actin-stimulated ATPase activity. Binding of MII suppressed GEF activity. Accordingly, inhibition of MII ATPase activity caused release of GEFs and activation of Rho GTPases. Depletion of betaPIX GEF in migrating NIH3T3 fibroblasts suppressed lamellipodial protrusions and focal complex formation induced by MII inhibition. The results elucidate a functional link between MII and Rac1/Cdc42 GTPases, which may regulate protrusion/adhesion dynamics in migrating cells. PMID- 20713601 TI - BAG-6 is essential for selective elimination of defective proteasomal substrates. AB - BAG-6/Scythe/BAT3 is a ubiquitin-like protein that was originally reported to be the product of a novel gene located within the human major histocompatibility complex, although the mechanisms of its function remain largely obscure. Here, we demonstrate the involvement of BAG-6 in the degradation of a CL1 model defective protein substrate in mammalian cells. We show that BAG-6 is essential for not only model substrate degradation but also the ubiquitin-mediated metabolism of newly synthesized defective polypeptides. Furthermore, our in vivo and in vitro analysis shows that BAG-6 interacts physically with puromycin-labeled nascent chain polypeptides and regulates their proteasome-mediated degradation. Finally, we show that knockdown of BAG-6 results in the suppressed presentation of MHC class I on the cell surface, a procedure known to be affected by the efficiency of metabolism of defective ribosomal products. Therefore, we propose that BAG-6 is necessary for ubiquitin-mediated degradation of newly synthesized defective polypeptides. PMID- 20713600 TI - Regulation of the autophagy protein LC3 by phosphorylation. AB - Macroautophagy is a major catabolic pathway that impacts cell survival, differentiation, tumorigenesis, and neurodegeneration. Although bulk degradation sustains carbon sources during starvation, autophagy contributes to shrinkage of differentiated neuronal processes. Identification of autophagy-related genes has spurred rapid advances in understanding the recruitment of microtubule-associated protein 1 light chain 3 (LC3) in autophagy induction, although braking mechanisms remain less understood. Using mass spectrometry, we identified a direct protein kinase A (PKA) phosphorylation site on LC3 that regulates its participation in autophagy. Both metabolic (rapamycin) and pathological (MPP(+)) inducers of autophagy caused dephosphorylation of endogenous LC3. The pseudophosphorylated LC3 mutant showed reduced recruitment to autophagosomes, whereas the nonphosphorylatable mutant exhibited enhanced puncta formation. Finally, autophagy-dependent neurite shortening induced by expression of a Parkinson disease-associated G2019S mutation in leucine-rich repeat kinase 2 was inhibited by dibutyryl-cyclic adenosine monophosphate, cytoplasmic expression of the PKA catalytic subunit, or the LC3 phosphorylation mimic. These data demonstrate a role for phosphorylation in regulating LC3 activity. PMID- 20713602 TI - Oxidative status of muscle is determined by p107 regulation of PGC-1alpha. AB - Mice lacking p107 exhibit a white adipose deficiency yet do not manifest the metabolic changes typical for lipodystrophy, and instead exhibit low levels of serum triglycerides and a normal liver phenotype. When fed a high fat diet, p107 null mice still did not accumulate fat in the liver, and display markedly elevated energy expenditures together with an increased energy preference for lipids. Skeletal muscle was therefore examined, as this is normally the major tissue involved in whole body lipid metabolism. Notably, p107-deficient muscle express increased levels of peroxisome proliferator-activated receptor gamma co activator-1alpha (PGC-1alpha) and contained increased numbers of the pro oxidative type I and type IIa myofibers. Chromatin immunoprecipitation revealed binding of p107 and E2F4 to the PGC-1alpha proximal promoter, and this binding repressed promoter activity in transient transcription assays. Ectopic expression of p107 in muscle tissue in vivo results in a pronounced 20% decrease in the numbers of oxidative type IIa myofibers. Lastly, isolated p107-deficient muscle tissue display a threefold increase in lipid metabolism. Therefore, p107 determines the oxidative state of multiple tissues involved in whole body fat metabolism, including skeletal muscle. PMID- 20713603 TI - Identification of novel filament-forming proteins in Saccharomyces cerevisiae and Drosophila melanogaster. AB - The discovery of large supramolecular complexes such as the purinosome suggests that subcellular organization is central to enzyme regulation. A screen of the yeast GFP strain collection to identify proteins that assemble into visible structures identified four novel filament systems comprised of glutamate synthase, guanosine diphosphate-mannose pyrophosphorylase, cytidine triphosphate (CTP) synthase, or subunits of the eIF2/2B translation factor complex. Recruitment of CTP synthase to filaments and foci can be modulated by mutations and regulatory ligands that alter enzyme activity, arguing that the assembly of these structures is related to control of CTP synthase activity. CTP synthase filaments are evolutionarily conserved and are restricted to axons in neurons. This spatial regulation suggests that these filaments have additional functions separate from the regulation of enzyme activity. The identification of four novel filaments greatly expands the number of known intracellular filament networks and has broad implications for our understanding of how cells organize biochemical activities in the cytoplasm. PMID- 20713604 TI - Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. AB - Autophagy is an evolutionarily conserved pathway responsible for degradation of cytoplasmic material via the lysosome. Although autophagy has been reported to contribute to cell death, the underlying mechanisms remain largely unknown. In this study, we show that autophagy controls DNA fragmentation during late oogenesis in Drosophila melanogaster. Inhibition of autophagy by genetically removing the function of the autophagy genes atg1, atg13, and vps34 resulted in late stage egg chambers that contained persisting nurse cell nuclei without fragmented DNA and attenuation of caspase-3 cleavage. The Drosophila inhibitor of apoptosis (IAP) dBruce was found to colocalize with the autophagic marker GFP Atg8a and accumulated in autophagy mutants. Nurse cells lacking Atg1 or Vps34 in addition to dBruce contained persisting nurse cell nuclei with fragmented DNA. This indicates that autophagic degradation of dBruce controls DNA fragmentation in nurse cells. Our results reveal autophagic degradation of an IAP as a novel mechanism of triggering cell death and thereby provide a mechanistic link between autophagy and cell death. PMID- 20713606 TI - Benign anterior temporal epidural hematoma: indolent lesion with a characteristic CT imaging appearance after blunt head trauma. AB - PURPOSE: To study the incidence, pathogenesis, imaging characteristics, and clinical importance of a unique subtype of epidural hematoma (EDH) associated with blunt head trauma. MATERIALS AND METHODS: This study was reviewed and approved by the hospital's Institutional Review Board and was compliant with HIPAA. Informed consent was waived. The investigation was a retrospective study of 200 patients with acute supratentorial EDH, defined as a biconvex, high attenuating, extraaxial hematoma. A subgroup of 21 patients in whom the EDH was located at the anterior aspect of the middle cranial fossa was defined. Computed tomographic images and inpatient medical records of these 21 patients were evaluated for imaging characteristics of the EDH, presence or absence of associated fracture, presence or absence of midline shift and/or mass effect, additional intracranial injury, and hospital clinical course. RESULTS: Twenty-one (10.5%) of 200 traumatic EDHs localized to the anterior middle cranial fossa. All of these 21 anterior temporal EDHs were juxtaposed to the sphenoparietal sinus, and all but one were limited laterally by the sphenotemporal suture and medially by the orbital fissure; none extended above the lesser sphenoid wing. Maximum thickness was less than 1 cm in 13 (62%) of 21 and less than 2 cm in 20 (95%) of 21 patients. Isolated fractures of the greater sphenoid wing and ipsilateral zygomaticomaxillary fractures were present in 12 (57%) of 21 and nine (43%) of 21 patients, respectively. Concomitant intracranial injury was identified in 15 (71%) of 21 patients. Twenty (95%) of 21 lesions were present at the admission study, and all 21 were stable or smaller at follow-up imaging. No patient required neurosurgical intervention of their anterior temporal EDH. CONCLUSION: Acute EDHs isolated to the anterior aspect of the middle cranial fossa constitute a subgroup of traumatic EDHs with a benign natural history. It is postulated that they arise from venous bleeding due to disruption of the sphenoparietal sinus. PMID- 20713607 TI - Renal cell carcinoma: diffusion-weighted MR imaging for subtype differentiation at 3.0 T. AB - PURPOSE: To assess the usefulness of apparent diffusion coefficients (ADCs) for characterizing renal cell carcinoma (RCC) subtypes at 3.0 T. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective study, and informed consent was waived. Eighty-three patients underwent diffusion-weighted (DW) magnetic resonance (MR) imaging of 85 renal masses. In each patient, precontrast single-shot spin-echo echo-planar DW imaging was performed with b values of 0 and 500 and 0 and 800 sec/mm(2) by using a 3.0-T MR imaging system. Differences in ADCs between the RCC lesions and uninvolved renal parenchyma were tested by using a paired-samples t test. One-way analysis of variance was used to compare ADCs of the various RCC subtypes. Receiver operating characteristic (ROC) curve analysis was used to test the ability of ADCs in differentiating clear cell from non-clear cell RCCs. RESULTS: Pathologic diagnoses of the 85 tumors (median diameter, 4.4 cm) in the 83 patients (54 men, 29 women; age range, 23-75 years; mean age, 49.4 years) were clear cell RCC for 49 tumors, papillary RCC for 22 tumors, and chromophobic RCC for 14 tumors. With b values of 0 and 500 sec/mm(2), clear cell RCCs showed a significantly higher mean ADC (1.849 * 10(-3) mm(2)/sec) than papillary (1.087 * 10(-3) mm(2)/sec) and chromophobic (1.307 * 10(-3) mm(2)/sec) RCCs (P < .001); however, the difference between papillary and chromophobic RCCs was not significant (P = .068). With b values of 0 and 800 sec/mm(2), clear cell RCC showed the largest mean ADC (1.698 * 10(-3) mm(2)/sec) of the three subtypes, and the difference between each pair of subtypes was significant (P < .001). ADCs obtained with b values of 0 and 800 sec/mm(2) were more effective for distinguishing clear cell from non-clear cell RCC (area under the ROC curve, 0.973): A threshold value of 1.281 * 10(-3) mm(2)/sec permitted distinction with high sensitivity (95.9%) and specificity (94.4%). CONCLUSION: DW imaging with b values of 0 and 800 sec/mm(2) allows sensitive and specific differentiation of clear cell, papillary, and chromophobic RCCs, suggesting that DW imaging may be useful in the preoperative characterization of RCC. PMID- 20713605 TI - Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells. AB - Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells. PMID- 20713608 TI - 23Na MR imaging at 7 T after knee matrix-associated autologous chondrocyte transplantation preliminary results. AB - PURPOSE: To evaluate the feasibility of sodium 7-T magnetic resonance (MR) imaging in repaired tissue and native cartilage of patients after matrix associated autologous chondrocyte transplantation (MACT) and compare results with delayed gadolinium-enhanced MR imaging of cartilage (dGEMRIC) at 3 T. MATERIALS AND METHODS: Ethical approval was provided by the local ethics committee; written informed consent was obtained from all patients. Six women and six men (mean age, 32.8 year +/- 8.2 [standard deviation] and 32.3 years +/- 12.7, respectively) were included. Mean time between MACT and MR was 56 months +/- 28. A variable three-dimensional (3D) gradient-echo (GRE) dual-flip-angle technique was used for T1 mapping before and after contrast agent administration at 3 T. All patients were also examined at 7 T (mean delay, 70.5 days +/- 80.1). A sodium 23-only transmit-receive knee coil was used with the 3D GRE sequence. A statistical analysis of variance and Pearson correlation were applied. RESULTS: Mean signal to-noise ratio (SNR) was 24 in native cartilage and was 16 in transplants (P < .001). Mean sodium signal intensities normalized with the reference sample were 174 +/- 53 and 267 +/- 42 for repaired tissue in the cartilage transplant and healthy cartilage, respectively (P < .001). Mean postcontrast T1 values were 510 msec +/- 195 and 756 msec +/- 188 for repaired tissue and healthy cartilage, respectively (P = .005). Mean score of MR observation of cartilage repair tissue was 75 +/- 14. Association between postcontrast T1 and normalized sodium signal values showed a high Pearson correlation coefficient (R) of 0.706 (P = .001). A high correlation of R = 0.836 (P = .001) was found between ratios of normalized sodium values and ratios of T1 postcontrast values. CONCLUSION: With the modified 3D GRE sequence at 7 T, a sufficiently high SNR in sodium images was achieved, allowing for differentiation of repaired tissue from native cartilage after MACT. A strong correlation was found between sodium imaging and dGEMRIC in patients after MACT. PMID- 20713609 TI - Quantitative analysis of clinical dynamic contrast-enhanced MR imaging for evaluating treatment response in human breast cancer. AB - PURPOSE: To develop a method that combines a fixed-T1, fuzzy c-means (FCM) technique with a reference region (RR) model (T1-FCM method) to estimate pharmacokinetic parameters without measuring the arterial input function or baseline T1, or T1(0), and to demonstrate its feasibility in the assessment of treatment response to neoadjuvant chemotherapy (NAC) in patients with breast cancer by using data from dynamic contrast material-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the human investigation committees of the two participating institutions. All patients gave written informed consent. A conventional dual-flip-angle gradient-echo method was used to evaluate the effects of noise and the T1 in the tissue itself on the accuracy of T1 estimation. Both conventional RR and fixed-T1 methods were used to evaluate the effects of noise and preselected T1(0) on the estimation of pharmacokinetic parameters by means of a simulation study. Thirty-three women (age range, 32-66 years; mean age, 45 years) with pathologically proved breast tumors were examined to evaluate the feasibility of using the T1-FCM method as a means of assessing treatment response to NAC. A nonparametric Mann-Whitney U test was used to assess the difference in each of the MR imaging parameters between patients with a major histologic response to treatment and those with a nonmajor histologic response. RESULTS: With use of the dual-flip-angle method, the accuracy and distribution of T1 estimation are dependent on the T1 in the tissue itself. The T1-FCM method is more accurate than other methods and is relatively insensitive to the effects of noise and incorrect T1(0) selection. Preliminary clinical data revealed a significant difference (P < .01) in the change of the volume transfer constant after two cycles of NAC between the major and nonmajor histologic response groups. CONCLUSION: Results of the simulation study demonstrate that the T1-FCM method appears to be relatively insensitive to noisy dynamic contrast-enhanced MR imaging data. This method could prove useful in the evaluation of breast cancer therapy. PMID- 20713610 TI - Gastroesophageal junction: structure and function as assessed by using MR imaging. AB - PURPOSE: To develop and validate magnetic resonance (MR) imaging protocols for quantitative assessment of the structural and functional properties of the gastroesophageal junction (GEJ) and to compare MR imaging detection of reflux events against concurrent manometry as a reference method. MATERIALS AND METHODS: The local ethics committee approved this study, and written informed consent was obtained. Twelve healthy volunteers were examined. Three-dimensional models of the GEJ and proximal portion of the stomach were reconstructed from high-spatial resolution anatomic MR images to assess the insertion angle of the esophagus into the stomach and proximal stomach distention before and after ingestion of a large test meal. A linear mixed-effects model was used to detect differences in the insertion angle and proximal stomach distention with respect to the respiratory cycle and gastric filling. Additionally, dynamic MR imaging at high temporal resolution was used to detect reflux events. RESULTS: The esophageal insertion angle, given in units of plane angle (radians), was more acute in expiration than in inspiration (0.57 vs 0.73 radian, P = .004) but was not affected by feeding. Progressive distention of the proximal stomach was observed from baseline compared with the postprandial period (0.95 vs 0.65 radian(-1), P < .05). Eighteen reflux events detected by using MR imaging were also detected by using manometry. CONCLUSION: MR imaging methods were developed and validated for the assessment of GEJ structure and function (a) to describe the effects of respiration and feeding on the reflux barrier and (b) to detect reflux events in real time. Anatomic and dynamic MR imaging may be useful techniques in the assessment of GEJ physiology and reflux. PMID- 20713611 TI - Does coronary calcium score predict future cardiac function? Association of subclinical atherosclerosis with left ventricular systolic and diastolic dysfunction at MR imaging in an elderly cohort. AB - PURPOSE: To evaluate subclinical atherosclerosis measured by using coronary artery calcium (CAC) as a predictor of future left ventricular (LV) systolic and diastolic function in asymptomatic elderly participants. MATERIALS AND METHODS: The institutional review boards of the University of Southern California and the Harbor University of California Los Angeles Research and Education Institute (where the South Bay Heart Watch study was initially conducted) approved this HIPAA-compliant study of 386 participants (mean age, 75.2 years) from among the original 1461 participants in the longitudinal South Bay Heart Watch prospective investigation of subclinical atherosclerosis. CAC at computed tomography was correlated with LV ejection fraction (LVEF), regional wall motion abnormalities (RWMAs), and peak filling rate (PFR) assessed a mean of 11.4 years +/- 0.6 (standard deviation) later with cardiac magnetic resonance imaging. Analysis of variance and covariance testing was performed with the Wald test, testing for trends across the CAC groups. Covariates included age, level of total cholesterol, level of high-density lipoprotein cholesterol, systolic blood pressure, use of lipid-lowering medication, and smoking status. RESULTS: Mean LVEF was 60.3% +/- 9.9, with 11 (2.8%) of 386 participants having an LVEF of less than 40%. Forty-six (11.9%) of 386 participants had RWMAs. Higher CAC scores were associated with slightly lower LVEF (P for trend = .04) and a greater percentage of participants with decreased PFR (P for trend = .47) and RWMAs (P for trend = .01). After age- and risk factor-adjustment, only RWMA (P = .05) was associated with higher CAC. RWMAs were associated with significantly (P < .001) lower mean LVEF and PFR. Nineteen (41%) of 46 participants with RWMAs had documented Q-wave myocardial infarction, and three (7%) underwent coronary revascularization. CAC scores of 100 or greater were associated with a 2.2-fold (95% confidence interval: 1.30, 3.75) increase in RWMA (P < .001). CONCLUSION: Subclinical atherosclerosis assessed by using CAC is associated with an increased future likelihood of RWMA, as a marker of previous and possible subclinical coronary artery disease. PMID- 20713612 TI - Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes. AB - PURPOSE: To assess adipose body compartments with magnetic resonance (MR) imaging and MR spectroscopy during a lifestyle intervention program that included optimized nutrition and controlled physical activity in subjects at increased risk for type 2 diabetes to determine factors that may help predict an increase in insulin sensitivity following the intervention. MATERIALS AND METHODS: This prospective study was approved by the local review board. All participants gave written informed consent. MR imaging and MR spectroscopy were performed in 243 subjects (99 men and 144 women) before and 9 months after enrollment in a lifestyle intervention program. The results of whole-body MR imaging were used to calculate tissue profiles, differentiating between adipose tissue--especially visceral adipose tissue--and lean tissue. The concentration of hepatic lipids and intramyocellular lipids in the anterior tibial and soleus muscles was determined with MR spectroscopy, and insulin sensitivity was estimated by using an oral glucose tolerance test. The Student t test was used to assess differences between groups, and multivariate regression models were used to assess the value of adipose tissue compartments in the prediction of insulin sensitivity. RESULTS: Compared with women, men had almost twice the amount of visceral adipose tissue and a smaller amount of total adipose tissue (25.9% for men and 36.9% for women) at baseline. In addition, their insulin sensitivity was significantly lower than that of women. The most pronounced changes in adipose tissue were detected for visceral adipose tissue (from 4.9 L to 4.1 L [ie, -15.1%] in men and from 2.3 L to 1.9 L [ie, -15.8%] in women) and hepatic lipids (from 8.6% to 5.4% [ie, 36.8%] in men and from 5.1% to 4.3% [ie, -16.5%] in women). The mean insulin sensitivity improved significantly (from 11.3 arbitrary units [au] to 14.6 au [ie, +29.9%] in men and from 13.6 au to 14.6 au [ie, +7.5%] in women), with 70 of the 99 men (71%) and 84 of 144 women (58%) showing an increase in insulin sensitivity. In men, low concentrations of visceral adipose tissue, hepatic lipids, and abdominal subcutaneous fat at baseline were predictive of successful intervention in terms of changes in insulin sensitivity; in women, only low hepatic lipid levels were significantly predictive of successful intervention. CONCLUSION: Visceral adipose tissue and hepatic lipids, as assessed with MR imaging and MR spectroscopy, can be significantly reduced during lifestyle intervention. Their baseline values emerged as predictive factors for an improvement of insulin sensitivity. PMID- 20713613 TI - Women with anorexia nervosa: finite element and trabecular structure analysis by using flat-panel volume CT. AB - PURPOSE: To use finite element modeling based on flat-panel volume computed tomography (CT) and bone mineral density (BMD) provided by dual-energy x-ray absorptiometry (DXA) to compare bone failure load, stiffness, and trabecular structure in women with anorexia nervosa (AN) and age-matched normal-weight control subjects. MATERIALS AND METHODS: The study was approved by the institutional review board and complied with HIPAA guidelines. Informed consent was obtained. Fourteen women, eight with AN (mean age, 26.6 years) and six control subjects (mean age, 26.3 years), underwent flat-panel volume CT of the distal radius to determine apparent trabecular bone volume fraction (BV/TV), apparent trabecular number (TbN), apparent trabecular thickness (TbTh), and apparent trabecular separation (TbSp). Bone strength and stiffness were calculated from uniaxial compression tests by using finite element models created from flat-panel volume CT. DXA was used to determine BMD of the radius, lumbar spine, and hip. Means +/- standard deviations of all variables were calculated for both groups and compared (Student t test). Univariate regression analysis and stepwise regression modeling were performed. RESULTS: Patients with AN had lower values for stiffness (284.77 kN/mm +/- 76.14 vs 389.97 kN/mm +/- 84.90, P = .04), failure load (4.98 kN +/- 1.23 vs 7.01 kN +/- 1.52, P = .02), BV/TV (0.32% +/- 0.09 vs 0.44% +/- 0.02, P = .007), and TbN (1.15 mm(-3) +/- 0.20 vs 1.43 mm(-3) +/- 0.13, P = .008) and higher values for TbSp (0.62 mm +/- 0.20 vs 0.40 mm +/- 0.04, P = .02) compared with normal-weight control subjects. TbTh was lower in women with AN (P = .1). BMD measurements were significantly lower for the AN group. BMD measurements and trabecular parameters (except TbTh) correlated with stiffness and failure load (r = 0.58 to 0.83). CONCLUSION: Failure load and stiffness are abnormal in women with AN compared with those in normal-weight control subjects and correlate with BMD and trabecular parameters. PMID- 20713614 TI - Cross-sectional study of tracheomegaly in children after fetal tracheal occlusion for severe congenital diaphragmatic hernia. AB - PURPOSE: To measure tracheal dimensions in children with congenital diaphragmatic hernia (CDH) who had undergone fetoscopic endoluminal tracheal occlusion (FETO) or were treated expectantly during gestation. MATERIALS AND METHODS: The study was approved by the local ethics committee. Computed tomography was performed in 23 patients (14 boys and nine girls) aged 1 month to 6.5 years, and the anteroposterior diameter, width, area, and perimeter of the trachea were determined. Seven of the 23 patients had undergone FETO and 16 had been treated expectantly. The relative difference of each parameter between the two most proximal concentric sections of the trachea, just below the larynx, and the two sections on which the trachea was the largest was compared between both groups (Mann-Whitney U test). Regression statistics were applied to maximum and mean tracheal areas as a function of age. Each trachea was divided into quartiles, and mean areas normalized to 3 years of age were analyzed for each quartile as a function of its relative position on the trachea (Student t test). RESULTS: Tracheal width, area, and perimeter were significantly different between both groups. A linear relationship was observed between the maximum and mean tracheal areas and age for both the FETO group (maximum tracheal area: R(2) = 0.83, P = .0045; mean tracheal area: R(2) = 0.92, P = .0005) and the non-FETO group (maximum tracheal area: R(2) = 0.66, P = .0001; mean trachea area: R(2) = 0.66, P = .0001). The maximum tracheal area in both groups tended to decrease toward the age of 5 years. Significantly different mean tracheal areas per tracheal quartile (P < .05) were found for all quartiles except for the proximal one-fourth. CONCLUSION: The relative difference between proximal and largest tracheal width, area, and perimeter was significantly larger in patients who underwent FETO than in those treated expectantly, demonstrating tracheal dilatation in the former. Measurements of tracheal dimensions at different levels indicate a maximum dilatation in the lower half of the trachea, which tends to level off toward the age of 5 years. PMID- 20713615 TI - Pancreatic duct stenosis secondary to small endocrine neoplasms: a manifestation of serotonin production? AB - PURPOSE: To determine if serotonin production by pancreatic endocrine neoplasms is associated with the pancreatic duct stenosis seen in patients with stenosis that is out of proportion to the size of the tumors seen on computed tomographic images. MATERIALS AND METHODS: Institutional approval was obtained for this HIPAA compliant study. Informed consent was waived. Clinical and radiologic findings in six patients were reviewed. Gross and histologic findings in the resected pancreata were also assessed. Formalin-fixed paraffin-embedded tumor sections were immunolabeled with antibodies to serotonin. Tissue microarrays constructed from 47 pancreatic endocrine neoplasms from the institutional tissue bank served as controls. Histologic and serotonin immunoreactivity findings were compared between the two groups. The Fisher exact test was used to compare serotonin immunoreactivity. RESULTS: Only one of the six study patients had a large dominant tumor (4 cm in the pancreatic head). All others were 2.5 cm or smaller. Four of the six pancreatic endocrine neoplasms with associated pancreatic duct stricture had prominent stromal fibrosis. Serotonin immunoreactivity was present in five (83%) patients, and this labeling was strong and diffuse in the four patients with prominent fibrosis. By contrast, stromal fibrosis was minimal in the nonimmunoreactive case. Only three (6%) of the 47 control pancreatic endocrine neoplasms were immunoreactive for serotonin (P < .01, Fisher exact test). CONCLUSION: These data suggest that serotonin produced by pancreatic endocrine neoplasms may be associated with local fibrosis and stenosis of the pancreatic duct. Clinicians should be aware that small pancreatic endocrine neoplasms can produce pancreatic duct stenosis resulting in ductal dilatation and/or upstream pancreatic atrophy out of proportion to the size of the tumor. PMID- 20713616 TI - Coexpression analysis identifies Rice Starch Regulator1, a rice AP2/EREBP family transcription factor, as a novel rice starch biosynthesis regulator. AB - Starch biosynthesis is important for plant development and is a critical factor in crop quality and nutrition. As a complex metabolic pathway, the regulation of starch biosynthesis is still poorly understood. We here present the identification of candidate regulators for starch biosynthesis by gene coexpression analysis in rice (Oryza sativa). Starch synthesis genes can be grouped into type I (in seeds; sink tissues) and type II (in vegetative tissues; source tissues), and 307 and 621 coexpressed genes are putatively involved in the regulation of starch biosynthesis in rice seeds and vegetative tissues, respectively. Among these genes, Rice Starch Regulator1 (RSR1), an APETALA2/ethylene-responsive element binding protein family transcription factor, was found to negatively regulate the expression of type I starch synthesis genes, and RSR1 deficiency results in the enhanced expression of starch synthesis genes in seeds. Seeds of the knockout mutant rsr1 consistently show the increased amylose content and altered fine structure of amylopectin and consequently form the round and loosely packed starch granules, resulting in decreased gelatinization temperature. In addition, rsr1 mutants have a larger seed size and increased seed mass and yield. In contrast, RSR1 overexpression suppresses the expression of starch synthesis genes, resulting in altered amylopectin structure and increased gelatinization temperature. Interestingly, a decreased proportion of A chains in rsr1 results in abnormal starch granules but reduced gelatinization temperature, whereas an increased proportion of A chains in RSR1 overexpressing plants leads to higher gelatinization temperatures, which is novel and different from previous reports, further indicating the complicated regulation of starch synthesis and determination of the physicochemical properties of starch. These results demonstrate the potential of coexpression analysis for studying rice starch biosynthesis and the regulation of a complex metabolic pathway and provide informative clues, including the characterization of RSR1, to facilitate the improvement of rice quality and nutrition. PMID- 20713617 TI - Tethering factors required for cytokinesis in Arabidopsis. AB - At the end of the cell cycle, the nascent cross wall is laid down within a transient membrane compartment referred to as the cell plate. Tethering factors, which act by capturing vesicles and holding them in the vicinity of their target membranes, are likely to play an important role in the first stages of cell plate assembly. Factors required for cell plate biogenesis, however, remain to be identified. In this study, we used a reverse genetic screen to isolate tethering factors required for cytokinesis in Arabidopsis (Arabidopsis thaliana). We focused on the TRAPPI and TRAPPII (for transport protein particle) tethering complexes, which are thought to be required for the flow of traffic through the Golgi and for trans-Golgi network function, as well as on the GARP complex, thought to be required for the tethering of endocytotic vesicles to the trans Golgi network. We found weak cytokinesis defects in some TRAPPI mutants and strong cytokinesis defects in all the TRAPPII lines we surveyed. Indeed, four insertion lines at the TRAPPII locus AtTRS120 had canonical cytokinesis-defective seedling-lethal phenotypes, including cell wall stubs and incomplete cross walls. Confocal and electron microscopy showed that in trs120 mutants, vesicles accumulated at the equator of dividing cells yet failed to assemble into a cell plate. This shows that AtTRS120 is required for cell plate biogenesis. In contrast to the TRAPP complexes, we found no conclusive evidence for cytokinesis defects in seven GARP insertion lines. We discuss the implications of these findings for the origin and identity of cell plate membranes. PMID- 20713618 TI - The B-3 ethylene response factor MtERF1-1 mediates resistance to a subset of root pathogens in Medicago truncatula without adversely affecting symbiosis with rhizobia. AB - The fungal necrotrophic pathogen Rhizoctonia solani is a significant constraint to a range of crops as diverse as cereals, canola, and legumes. Despite wide ranging germplasm screens in many of these crops, no strong genetic resistance has been identified, suggesting that alternative strategies to improve resistance are required. In this study, we characterize moderate resistance to R. solani anastomosis group 8 identified in Medicago truncatula. The activity of the ethylene- and jasmonate-responsive GCC box promoter element was associated with moderate resistance, as was the induction of the B-3 subgroup of ethylene response transcription factors (ERFs). Genes of the B-1 subgroup showed no significant response to R. solani infection. Overexpression of a B-3 ERF, MtERF1 1, in Medicago roots increased resistance to R. solani as well as an oomycete root pathogen, Phytophthora medicaginis, but not root knot nematode. These results indicate that targeting specific regulators of ethylene defense may enhance resistance to an important subset of root pathogens. We also demonstrate that overexpression of MtERF1-1 enhances disease resistance without apparent impact on nodulation in the A17 background, while overexpression in sickle reduced the hypernodulation phenotype. This suggests that under normal regulation of nodulation, enhanced resistance to root diseases can be uncoupled from symbiotic plant-microbe interactions in the same tissue and that ethylene/ERF regulation of nodule number is distinct from the defenses regulated by B-3 ERFs. Furthermore, unlike the stunted phenotype previously described for Arabidopsis (Arabidopsis thaliana) ubiquitously overexpressing B-3 ERFs, overexpression of MtERF1-1 in M. truncatula roots did not show adverse effects on plant development. PMID- 20713619 TI - Invasion of bovine peripheral blood mononuclear cells and erythrocytes by Mycoplasma bovis. AB - Mycoplasma bovis is a small, cell wall-less bacterium that contributes to a number of chronic inflammatory diseases in both dairy and feedlot cattle, including mastitis and bronchopneumonia. Numerous reports have implicated M. bovis in the activation of the immune system, while at the same time inhibiting immune cell proliferation. However, it is unknown whether the specific immune cell population M. bovis is capable of attaching to and potentially invading. Here, we demonstrate that incubation of M. bovis Mb1 with bovine peripheral blood mononuclear cells (PBMC) resulted in a significant reduction in their proliferative responses while still remaining viable and capable of gamma interferon secretion. Furthermore, we show that M. bovis Mb1 can be found intracellularly (suggesting a role for either phagocytosis or attachment/invasion) in a number of select bovine PBMC populations (T cells, B cells, monocytes, gammadelta T cells, dendritic cells, NK cells, cytotoxic T cells, and T-helper cells), as well as red blood cells, albeit it at a significantly lower proportion. M. bovis Mb1 appeared to display three main patterns of intracellular staining: diffuse staining, an association with the intracellular side of the cell membrane, and punctate/vacuole-like staining. The invasion of circulating immune cells and erythrocytes could play an important role in disease pathogenesis by aiding the transport of M. bovis from the lungs to other sites. PMID- 20713620 TI - Escherichia coli subtilase cytotoxin induces apoptosis regulated by host Bcl-2 family proteins Bax/Bak. AB - Subtilase cytotoxin (SubAB) was first isolated from a Shiga toxigenic Escherichia coli (STEC) strain that was responsible for an outbreak of hemolytic-uremic syndrome and is the prototype of a new family of AB(5) cytotoxins. SubAB is a subtilase-like serine protease, and upon uptake by host cells, it is trafficked to the endoplasmic reticulum (ER), where it cleaves the essential ER chaperone BiP (GRP78) with high specificity. Previous work has shown that BiP cleavage by SubAB initiates ER stress-signaling pathways in host cells that eventuate in cell death associated with DNA fragmentation, a hallmark of apoptosis. The present study has investigated the role of the Bcl-2 protein family, which has been shown to regulate ER stress-induced apoptosis in other model systems. Examination of the cytotoxicity of SubAB for wild-type and bax(-/-)/bak(-/-) mouse embryonic fibroblasts and comparison of apoptotic markers in these cells revealed that SubAB cytotoxicity can be predominantly attributed to the activation of apoptotic pathways activated by Bax/Bak. The results of the present study further our understanding of the molecular mechanism whereby SubAB kills eukaryotic cells and contributes to STEC pathogenesis, in addition to consolidating the roles of Bcl-2 family members in the regulation of ER stress-induced apoptosis. PMID- 20713621 TI - Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF kappaB-dependent responses and peptidoglycan delivery in epithelial cells. AB - Infection with Helicobacter pylori cag pathogenicity island (cagPAI)-positive strains is associated with more destructive tissue damage and an increased risk of severe disease. The cagPAI encodes a type IV secretion system (TFSS) that delivers the bacterial effector molecules CagA and peptidoglycan into the host cell cytoplasm, thereby inducing responses in host cells. It was previously shown that interactions between CagL, present on the TFSS pilus, and host alpha(5)beta(1) integrin molecules were critical for CagA translocation and the induction of cytoskeletal rearrangements in epithelial cells. As the alpha(5)beta(1) integrin is found in cholesterol-rich microdomains (known as lipid rafts), we hypothesized that these domains may also be involved in the induction of proinflammatory responses mediated by NOD1 recognition of H. pylori peptidoglycan. Indeed, not only did methyl-beta-cyclodextrin depletion of cholesterol from cultured epithelial cells have a significant effect on the levels of NF-kappaB and interleukin-8 (IL-8) responses induced by H. pylori bacteria with an intact TFSS (P < 0.05), but it also interfered with TFSS mediated peptidoglycan delivery to cells. Both of these effects could be restored by cholesterol replenishment of the cells. Furthermore, we demonstrated for the first time the involvement of alpha(5)beta(1) integrin in the induction of proinflammatory responses by H. pylori. Taking the results together, we propose that alpha(5)beta(1) integrin, which is associated with cholesterol-rich microdomains at the host cell surface, is required for NOD1 recognition of peptidoglycan and subsequent induction of NF-kappaB-dependent responses to H. pylori. These data implicate cholesterol-rich microdomains as a novel platform for TFSS-dependent delivery of bacterial products to cytosolic pathogen recognition molecules. PMID- 20713622 TI - LT-IIc, a new member of the type II heat-labile enterotoxin family encoded by an Escherichia coli strain obtained from a nonmammalian host. AB - Two families of bacterial heat-labile enterotoxins (HLTs) have been described: the type I HLTs are comprised of cholera toxin (CT) of Vibrio cholerae, LT-I of Escherichia coli, and several related HLTs; the type II HLTs are comprised of LT IIa and LT-IIb. Herein, we report LT-IIc, a new type II HLT encoded from an enterotoxigenic E. coli (ETEC) strain isolated from an avian host. Using a mouse Y1 adrenal cell bioassay, LT-IIc was shown to be less cytotoxic than CT, LT-IIa, or LT-IIb. Cytotoxicity of LT-IIc was partially neutralized by antisera recognizing LT-IIa or LT-IIb but not by anti-CT antiserum. Genes encoding putative A polypeptide and B polypeptides of LT-IIc were arranged in an operon which was flanked by potential prophage sequences. Analysis of the nucleotide and predicted amino acid sequences demonstrated that the A polypeptide of LT-IIc has moderate homology to the A polypeptides of CT and LT-I and high homology to the A polypeptides of LT-IIa and LT-IIb. The B polypeptide of LT-IIc exhibited no significant homology to the B polypeptides of CT and LT-I and only moderate homology to the B polypeptides of LT-IIa and LT-IIb. The binding pattern of LT IIc for gangliosides was distinctive from that of either LT-IIa or LT-IIb. The data suggest that other types of the type II HLT subfamily are circulating in the environment and that host specificity of type II HLT is likely governed by changes in the B polypeptide which mediate binding to receptors. PMID- 20713624 TI - CD28 exerts protective and detrimental effects in a pulmonary model of paracoccidioidomycosis. AB - T-cell immunity has been claimed as the main immunoprotective mechanism against Paracoccidioides brasiliensis infection, the most important fungal infection in Latin America. As the initial events that control T-cell activation in paracoccidioidomycosis (PCM) are not well established, we decided to investigate the role of CD28, an important costimulatory molecule for the activation of effector and regulatory T cells, in the immunity against this pulmonary pathogen. Using CD28-deficient (CD28(-/-)) and normal wild-type (WT) C57BL/6 mice, we were able to demonstrate that CD28 costimulation determines in pulmonary paracoccidioidomycosis an early immunoprotection but a late deleterious effect associated with impaired immunity and uncontrolled fungal growth. Up to week 10 postinfection, CD28(-/-) mice presented increased pulmonary and hepatic fungal loads allied with diminished production of antibodies and pro- and anti inflammatory cytokines besides impaired activation and migration of effector and regulatory T (Treg) cells to the lungs. Unexpectedly, CD28-sufficient mice progressively lost the control of fungal growth, resulting in an increased mortality associated with persistent presence of Treg cells, deactivation of inflammatory macrophages and T cells, prevalent presence of anti-inflammatory cytokines, elevated fungal burdens, and extensive hepatic lesions. As a whole, our findings suggest that CD28 is required for the early protective T-cell responses to P. brasiliensis infection, but it also induces the expansion of regulatory circuits that lately impair adaptive immunity, allowing uncontrolled fungal growth and overwhelming infection, which leads to precocious mortality of mice. PMID- 20713623 TI - New candidate vaccines against blood-stage Plasmodium falciparum malaria: prime boost immunization regimens incorporating human and simian adenoviral vectors and poxviral vectors expressing an optimized antigen based on merozoite surface protein 1. AB - Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in adjuvant vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well as cross-strain humoral immunity to P. falciparum MSP-1. PMID- 20713625 TI - CsrA and Cra influence Shigella flexneri pathogenesis. AB - Shigella flexneri is a facultative intracellular pathogen that invades and disrupts the colonic epithelium. In order to thrive in the host, S. flexneri must adapt to environmental conditions in the gut and within the eukaryotic cytosol, including variability in the available carbon sources and other nutrients. We examined the roles of the carbon consumption regulators CsrA and Cra in a cell culture model of S. flexneri virulence. CsrA is an activator of glycolysis and a repressor of gluconeogenesis, and a csrA mutant had decreased attachment and invasion of cultured cells. Conversely, Cra represses glycolysis and activates gluconeogenesis, and the cra mutant had an increase in both attachment and invasion compared to the wild-type strain. Both mutants were defective in plaque formation. The importance of the glycolytic pathway in invasion and plaque formation was confirmed by testing the effect of a mutation in the glycolysis gene pfkA. The pfkA mutant was noninvasive and had cell surface alterations as indicated by decreased sensitivity to SDS and an altered lipopolysaccharide profile. The loss of invasion by the csrA and pfkA mutants was due to decreased expression of the S. flexneri virulence factor regulators virF and virB, resulting in decreased production of Shigella invasion plasmid antigens (Ipa). These data indicate that regulation of carbon metabolism and expression of the glycolysis gene pfkA are critical for synthesis of the virulence gene regulators VirF and VirB, and both the glycolytic and gluconeogenic pathways influence steps in S. flexneri invasion and plaque formation. PMID- 20713626 TI - RssAB-FlhDC-ShlBA as a major pathogenesis pathway in Serratia marcescens. AB - Serratia marcescens has long been recognized as an important opportunistic pathogen, but the underlying pathogenesis mechanism is not completely clear. Here, we report a key pathogenesis pathway in S. marcescens comprising the RssAB two-component system and its downstream elements, FlhDC and the dominant virulence factor hemolysin ShlBA. Expression of shlBA is under the positive control of FlhDC, which is repressed by RssAB signaling. At 37 degrees C, functional RssAB inhibits swarming, represses hemolysin production, and promotes S. marcescens biofilm formation. In comparison, when rssBA is deleted, S. marcescens displays aberrant multicellularity favoring motile swarming with unbridled hemolysin production. Cellular and animal infection models further demonstrate that loss of rssBA transforms this opportunistic pathogen into hypervirulent phenotypes, leading to extensive inflammatory responses coupled with destructive and systemic infection. Hemolysin production is essential in this context. Collectively, a major virulence regulatory pathway is identified in S. marcescens. PMID- 20713627 TI - CD4+ CD25+ Foxp3+ regulatory T cells, dendritic cells, and circulating cytokines in uncomplicated malaria: do different parasite species elicit similar host responses? AB - Clearing blood-stage malaria parasites without inducing major host pathology requires a finely tuned balance between pro- and anti-inflammatory responses. The interplay between regulatory T (Treg) cells and dendritic cells (DCs) is one of the key determinants of this balance. Although experimental models have revealed various patterns of Treg cell expansion, DC maturation, and cytokine production according to the infecting malaria parasite species, no studies have compared all of these parameters in human infections with Plasmodium falciparum and P. vivax in the same setting of endemicity. Here we show that during uncomplicated acute malaria, both species induced a significant expansion of CD4(+) CD25(+) Foxp3(+) Treg cells expressing the key immunomodulatory molecule CTLA-4 and a significant increase in the proportion of DCs that were plasmacytoid (CD123(+)), with a decrease in the myeloid/plasmacytoid DC ratio. These changes were proportional to parasite loads but correlated neither with the intensity of clinical symptoms nor with circulating cytokine levels. One-third of P. vivax-infected patients, but no P. falciparum-infected subjects, showed impaired maturation of circulating DCs, with low surface expression of CD86. Although vivax malaria patients overall had a less inflammatory cytokine response, with a higher interleukin-10 (IL-10)/tumor necrosis factor alpha (TNF-alpha) ratio, this finding did not translate to milder clinical manifestations than those of falciparum malaria patients. We discuss the potential implications of these findings for species-specific pathogenesis and long-lasting protective immunity to malaria. PMID- 20713628 TI - Gelatinase contributes to the pathogenesis of endocarditis caused by Enterococcus faecalis. AB - The Gram-positive pathogen Enterococcus faecalis is a leading agent of nosocomial infections, including urinary tract infections, surgical site infections, and bacteremia. Among the infections caused by E. faecalis, endocarditis remains a serious clinical manifestation and unique in that it is commonly acquired in a community setting. Infective endocarditis is a complex disease, with many host and microbial components contributing to the formation of bacterial biofilm-like vegetations on the aortic valve and adjacent areas within the heart. In the current study, we compared the pathogenic potential of the vancomycin-resistant E. faecalis V583 and three isogenic protease mutants (DeltagelE, DeltasprE, and DeltagelE DeltasprE mutants) in a rabbit model of enterococcal endocarditis. The bacterial burdens displayed by GelE(-) mutants (DeltagelE and DeltagelE DeltasprE mutants) in the heart were significantly lower than those of V583 or the SprE(-) mutant. Vegetations on the aortic valve infected with GelE(-) mutants (DeltagelE and DeltagelE DeltasprE mutants) also showed a significant increase in deposition of fibrinous matrix layer and increased chemotaxis of inflammatory cells. In support of a role for proteolytic modulation of the immune response to E. faecalis, we also demonstrate that GelE can cleave the anaphylatoxin complement C5a and that this proteolysis leads to decreased neutrophil migration in vitro. In vivo, a decreased heterophil (neutrophil-like cell) migration was observed at tissue sites infected with GelE-producing strains but not at those infected with SprE-producing strains. Taken together, these observations suggest that of the two enterococcal proteases, gelatinase is the principal mediator of pathogenesis in endocarditis. PMID- 20713629 TI - Identification of three novel superantigen-encoding genes in Streptococcus equi subsp. zooepidemicus, szeF, szeN, and szeP. AB - The acquisition of superantigen-encoding genes by Streptococcus pyogenes has been associated with increased morbidity and mortality in humans, and the gain of four superantigens by Streptococcus equi is linked to the evolution of this host restricted pathogen from an ancestral strain of the opportunistic pathogen Streptococcus equi subsp. zooepidemicus. A recent study determined that the culture supernatants of several S. equi subsp. zooepidemicus strains possessed mitogenic activity but lacked known superantigen-encoding genes. Here, we report the identification and activities of three novel superantigen-encoding genes. The products of szeF, szeN, and szeP share 59%, 49%, and 34% amino acid sequence identity with SPEH, SPEM, and SPEL, respectively. Recombinant SzeF, SzeN, and SzeP stimulated the proliferation of equine peripheral blood mononuclear cells, and tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) production, in vitro. Although none of these superantigen genes were encoded within functional prophage elements, szeN and szeP were located next to a prophage remnant, suggesting that they were acquired by horizontal transfer. Eighty-one of 165 diverse S. equi subsp. zooepidemicus strains screened, including 7 out of 15 isolates from cases of disease in humans, contained at least one of these new superantigen-encoding genes. The presence of szeN or szeP, but not szeF, was significantly associated with mitogenic activity in the S. equi subsp. zooepidemicus population (P < 0.000001, P < 0.000001, and P = 0.104, respectively). We conclude that horizontal transfer of these novel superantigens from and within the diverse S. equi subsp. zooepidemicus population is likely to have implications for veterinary and human disease. PMID- 20713630 TI - The Inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. AB - The secretion of aspartic proteases (Saps) has long been recognized as a virulence-associated trait of the pathogenic yeast Candida albicans. In this study, we report that different recombinant Saps, including Sap1, Sap2, Sap3, and Sap6, have differing abilities to induce secretion of proinflammatory cytokines by human monocytes. In particular Sap1, Sap2, and Sap6 significantly induced interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and IL-6 production. Sap3 was able to stimulate the secretion of IL-1beta and TNF-alpha. All Saps tested were able to induce Ca(2+) influx in monocytes. Treatment of these Saps with pepstatin A did not have any effect on cytokine secretion, indicating that their stimulatory potential was independent from their proteolytic activity. The capacity of Saps to induce inflammatory cytokine production was also independent from protease-activated receptor (PAR) activation and from the optimal pH for individual Sap activity. The interaction of Saps with monocytes induced Akt activation and phosphorylation of IkappaBalpha, which mediates translocation of NF-kappaB into the nucleus. Overall, these results suggest that individual Sap proteins can induce an inflammatory response and that this phenomenon is independent from the pH of a specific host niche and from Sap enzymatic activity. The inflammatory response is partially dependent on Sap denaturation and is triggered by the Akt/NF-kappaB activation pathway. Our data suggest a novel, activity-independent aspect of Saps during interactions of C. albicans with the host. PMID- 20713631 TI - Interleukin-4 regulates the expression of CD209 and subsequent uptake of Mycobacterium leprae by Schwann cells in human leprosy. AB - The ability of microbial pathogens to target specific cell types is a key aspect of the pathogenesis of infectious disease. Mycobacterium leprae, by infecting Schwann cells, contributes to nerve injury in patients with leprosy. Here, we investigated mechanisms of host-pathogen interaction in the peripheral nerve lesions of leprosy. We found that the expression of the C-type lectin, CD209, known to be expressed on tissue macrophages and to mediate the uptake of M. leprae, was present on Schwann cells, colocalizing with the Schwann cell marker, CNPase (2',3'-cyclic nucleotide 3'-phosphodiesterase), along with the M. leprae antigen PGL-1 in the peripheral nerve biopsy specimens. In vitro, human CD209 positive Schwann cells, both from primary cultures and a long-term line, have a higher binding of M. leprae compared to CD209-negative Schwann cells. Interleukin 4, known to be expressed in skin lesions from multibacillary patients, increased CD209 expression on human Schwann cells and subsequent Schwann cell binding to M. leprae, whereas Th1 cytokines did not induce CD209 expression on these cells. Therefore, the regulated expression of CD209 represents a common mechanism by which Schwann cells and macrophages bind and take up M. leprae, contributing to the pathogenesis of leprosy. PMID- 20713632 TI - Anti-expression aftereffects reveal prototype-referenced coding of facial expressions. AB - Adaptation is a powerful experimental technique that has recently provided insights into how people encode representations of facial identity. Here, we used this approach to explore the visual representation of facial expressions of emotion. Participants were adapted to anti-expressions of six facial expressions. The participants were then shown an average face and asked to classify the face's expression using one of six basic emotion descriptors. Participants chose the emotion matching the anti-expression they were adapted to significantly more often than they chose any other emotion (e.g., if they were adapted to antifear, they classified the emotion on the average face as fear). The strength of this aftereffect of adaptation decreased as the strength of the anti-expression adapter decreased. These findings provide evidence that visual representations of facial expressions of emotion are coded with reference to a prototype within a multidimensional framework. PMID- 20713633 TI - I feel your voice. Cultural differences in the multisensory perception of emotion. AB - Cultural differences in emotion perception have been reported mainly for facial expressions and to a lesser extent for vocal expressions. However, the way in which the perceiver combines auditory and visual cues may itself be subject to cultural variability. Our study investigated cultural differences between Japanese and Dutch participants in the multisensory perception of emotion. A face and a voice, expressing either congruent or incongruent emotions, were presented on each trial. Participants were instructed to judge the emotion expressed in one of the two sources. The effect of to-be-ignored voice information on facial judgments was larger in Japanese than in Dutch participants, whereas the effect of to-be-ignored face information on vocal judgments was smaller in Japanese than in Dutch participants. This result indicates that Japanese people are more attuned than Dutch people to vocal processing in the multisensory perception of emotion. Our findings provide the first evidence that multisensory integration of affective information is modulated by perceivers' cultural background. PMID- 20713634 TI - Attention affects visual perceptual processing near the hand. AB - Specialized, bimodal neural systems integrate visual and tactile information in the space near the hand. Here, we show that visuo-tactile representations allow attention to influence early perceptual processing, namely, figure-ground assignment. Regions that were reached toward were more likely than other regions to be assigned as foreground figures, and hand position competed with image-based information to bias figure-ground assignment. Our findings suggest that hand position allows attention to influence visual perceptual processing and that visual processes typically viewed as unimodal can be influenced by bimodal visuo tactile representations. PMID- 20713635 TI - The effect of creative labor on property-ownership transfer by preschool children and adults. AB - Recognizing property ownership is of critical importance in social interactions, but little is known about how and when this attribute emerges. We investigated whether preschool children and adults believe that ownership of one person's property is transferred to a second person following the second person's investment of creative labor in that property. In our study, an experimenter and a participant borrowed modeling-clay objects from each other to mold into new objects. Participants were more likely to transfer ownership to the second individual after he or she invested creative labor in the object than after any other manipulations (holding the object, making small changes to it). This effect was significantly stronger in preschool children than in adults. Duration of manipulation had no effect on property-ownership transfer. Changes in the object's identity acted only as a secondary cue for children. We conclude that ownership is transferred after an investment of creative labor and that determining property ownership may be an intuitive process that emerges in early childhood. PMID- 20713636 TI - Infant attachment security and the timing of puberty: testing an evolutionary hypothesis. AB - Life-history theories of the early programming of human reproductive strategy stipulate that early rearing experience, including that reflected in infant parent attachment security, regulates psychological, behavioral, and reproductive development. We tested the hypothesis that infant attachment insecurity, compared with infant attachment security, at the age of 15 months predicts earlier pubertal maturation. Focusing on 373 White females enrolled in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, we gathered data from annual physical exams from the ages of 91/2 years to 151/2 years and from self-reported age of menarche. Results revealed that individuals who had been insecure infants initiated and completed pubertal development earlier and had an earlier age of menarche compared with individuals who had been secure infants, even after accounting for age of menarche in the infants' mothers. These results support a conditional adaptational view of individual differences in attachment security and raise questions about the biological mechanisms responsible for the attachment effects we discerned. PMID- 20713637 TI - Color channels, not color appearance or color categories, guide visual search for desaturated color targets. AB - In this article, we report that in visual search, desaturated reddish targets are much easier to find than other desaturated targets, even when perceptual differences between targets and distractors are carefully equated. Observers searched for desaturated targets among mixtures of white and saturated distractors. Reaction times were hundreds of milliseconds faster for the most effective (reddish) targets than for the least effective (purplish) targets. The advantage for desaturated reds did not reflect an advantage for the lexical category "pink," because reaction times did not follow named color categories. Many pink stimuli were not found quickly, and many quickly found stimuli were not labeled "pink." Other possible explanations (e.g., linear-separability effects) also failed. Instead, we propose that guidance of visual search for desaturated colors is based on a combination of low-level color-opponent signals that is different from the combinations that produce perceived color. We speculate that this guidance might reflect a specialization for human skin. PMID- 20713638 TI - ICU staffing: the South American perspective. PMID- 20713639 TI - Impact of intensivist staffing on patient care and trainee education: a Canadian perspective. PMID- 20713640 TI - Does asbestos exposure (asbestosis) cause (clinical) airway obstruction (small airway disease)? PMID- 20713641 TI - Pulmonary alveolar proteinosis in workers at an indium processing facility. PMID- 20713642 TI - The quest for the holy grail: a dead lock. PMID- 20713643 TI - Anatomy of lateral patellar instability: trochlear dysplasia and tibial tubercle trochlear groove distance is more pronounced in women who dislocate the patella. AB - BACKGROUND: A trend toward young women being at greatest risk for primary and recurrent dislocation of the patella is evident in the current literature. However, a causative factor is missing, and differences in the anatomical risk factors between men and women are less defined. PURPOSE: To identify differences between the sexes in the anatomy of lateral patellar instability. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Knee magnetic resonance images were collected from 100 patients treated for lateral patellar instability. Images were obtained from 157 patients without patellar instability who served as controls. Using 2-way analyses of variance, the influence of patellar dislocation, gender, and their interaction were analyzed with regard to sulcus angle, trochlear depth, trochlear asymmetry, patellar height, and the tibial tubercle-trochlear groove (TT-TG) distance. Mechanisms of injury of first-time dislocations were divided into high-risk, low-risk, and no-risk pivoting activities and direct hits. RESULTS: For all response variables, a significant effect was observed for the incidence of patellar dislocation (all P < .01). In addition, sulcus angle, trochlear asymmetry, and trochlear depth depended significantly on gender (all P < .01) but patellar height did not (P = .13). A significant interaction between patellar dislocation and gender was observed for the TT-TG distance (P = .02). The mean difference in TT-TG distance between study and control groups was 4.1 mm for women (P < .01) and 1.6 mm for men (P = .05). Low-risk and no-risk pivoting injuries were most common in women, whereas first time dislocations in men occurred mostly during high-risk pivoting activities (P < .01). CONCLUSION: The data from this study indicate that trochlear dysplasia and the TT-TG distance is more prominent in women who dislocate the patella. Both factors might contribute to an increased risk of lateral patellar instability in the female patient as illustrated by the fact that dislocations occurred most often during low-risk or no-risk pivoting activities in women. PMID- 20713644 TI - Knee function and prevalence of knee osteoarthritis after anterior cruciate ligament reconstruction: a prospective study with 10 to 15 years of follow-up. AB - BACKGROUND: Few prospective long-term studies of more than 10 years have reported changes in knee function and radiologic outcomes after anterior cruciate ligament (ACL) reconstruction. PURPOSE: To examine changes in knee function from 6 months to 10 to 15 years after ACL reconstruction and to compare knee function outcomes over time for subjects with isolated ACL injury with those with combined ACL and meniscal injury and/or chondral lesion. Furthermore, the aim was to compare the prevalence of radiographic and symptomatic radiographic knee osteoarthritis between subjects with isolated ACL injuries and those with combined ACL and meniscal and/or chondral lesions 10 to 15 years after ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Follow-up evaluations were performed on 221 subjects at 6 months, 1 year, 2 years, and 10 to 15 years after ACL reconstruction with bone-patellar tendon-bone autograft. Outcome measurements were KT-1000 arthrometer, Lachman and pivot shift tests, Cincinnati knee score, isokinetic muscle strength tests, hop tests, visual analog scale for pain, Tegner activity scale, and the Kellgren and Lawrence classification. RESULTS: One hundred eighty-one subjects (82%) were evaluated at the 10- to 15-year follow-up. A significant improvement over time was revealed for all prospective outcomes of knee function. No significant differences in knee function over time were detected between the isolated and combined injury groups. Subjects with combined injury had significantly higher prevalence of radiographic knee osteoarthritis compared with those with isolated injury (80% and 62%, P = .008), but no significant group differences were shown for symptomatic radiographic knee osteoarthritis (46% and 32%, P = .053). CONCLUSION: An overall improvement in knee function outcomes was detected from 6 months to 10 to 15 years after ACL reconstruction for both those with isolated and combined ACL injury, but significantly higher prevalence of radiographic knee osteoarthritis was found for those with combined injuries. PMID- 20713645 TI - Animal models of soft-tissue sarcoma. AB - Soft-tissue sarcomas (STSs) are rare mesenchymal tumors that arise from muscle, fat and connective tissue. Currently, over 75 subtypes of STS are recognized. The rarity and heterogeneity of patient samples complicate clinical investigations into sarcoma biology. Model organisms might provide traction to our understanding and treatment of the disease. Over the past 10 years, many successful animal models of STS have been developed, primarily genetically engineered mice and zebrafish. These models are useful for studying the relevant oncogenes, signaling pathways and other cell changes involved in generating STSs. Recently, these model systems have become preclinical platforms in which to evaluate new drugs and treatment regimens. Thus, animal models are useful surrogates for understanding STS disease susceptibility and pathogenesis as well as for testing potential therapeutic strategies. PMID- 20713646 TI - Combined zebrafish-yeast chemical-genetic screens reveal gene-copper-nutrition interactions that modulate melanocyte pigmentation. AB - Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu(2+)) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect copper metabolism with yeast chemical genetic profiles to identify pathways that are sensitive to copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to hypopigmentation in low-copper environmental conditions. Because trafficking pathways are essential for copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in copper metabolism for the small-molecule MEK kinase inhibitor U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks. PMID- 20713647 TI - Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. AB - The Mouse Metabolic Phenotyping Center (MMPC) Consortium was established to address the need to characterize the growing number of mouse models of metabolic diseases, particularly diabetes and obesity. A goal of the MMPC Consortium is to propose standard methods for assessing metabolic phenotypes in mice. In this article, we discuss issues pertaining to the design and performance of various tests of glucose metabolism. We also propose guidelines for the description of methods, presentation of data and interpretation of results. The recommendations presented in this article are based on the experience of the MMPC Consortium and other investigators. PMID- 20713648 TI - Effects of reproductive stage and 11-ketotestosterone on LPL mRNA levels in the ovary of the shortfinned eel. AB - To understand the dynamics of lipid uptake into the ovary and the potential role that lipoprotein lipase plays in this event, changes in LPL transcript abundance during oogenesis were measured in both wild-caught and pituitary homogenate induced artificially maturing eels. Also, the effects of 11-ketotestosterone (11 KT) on LPL mRNA levels were investigated in vivo and in vitro. Normalized ovarian LPL transcript abundance increased as oogenesis advanced, and it rose particularly rapidly during midvitellogenesis, corresponding to pronounced increases in ovarian lipid deposits and LPL activity. Furthermore, LPL mRNA levels were dramatically increased following 11-KT treatment in vivo, findings that were reinforced as trends in ovarian tissue incubated in vitro. Ovarian LPL appears to be directly involved in the uptake of lipids into the eel ovary, an involvement that appears to be controlled, at least in part, by the androgen 11 KT. PMID- 20713650 TI - Postprandial lipemia enhances the capacity of large HDL2 particles to mediate free cholesterol efflux via SR-BI and ABCG1 pathways in type IIB hyperlipidemia. AB - Lipid and cholesterol metabolism in the postprandial phase is associated with both quantitative and qualitative remodeling of HDL particle subspecies that may influence their anti-atherogenic functions in the reverse cholesterol transport pathway. We evaluated the capacity of whole plasma or isolated HDL particles to mediate cellular free cholesterol (FC) efflux, cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester (CE) transfer, and selective hepatic CE uptake during the postprandial phase in subjects displaying type IIB hyperlipidemia (n = 16). Postprandial, large HDL2 displayed an enhanced capacity to mediate FC efflux via both scavenger receptor class B type I (SR-BI)-dependent (+12%; P < 0.02) and ATP binding cassette transporter G1 (ABCG1)-dependent (+31%; P < 0.008) pathways in in vitro cell systems. In addition, the capacity of whole postprandial plasma (4 h and 8 h postprandially) to mediate cellular FC efflux via the ABCA1 dependent pathway was significantly increased (+19%; P < 0.0003). Concomitantly, postprandial lipemia was associated with elevated endogenous CE transfer rates from HDL2 to apoB lipoproteins and with attenuated capacity (-17%; P < 0.02) of total HDL to deliver CE to hepatic cells. Postprandial lipemia enhanced SR-BI and ABCG1-dependent efflux to large HDL2 particles. However, postprandial lipemia is equally associated with deleterious features by enhancing formation of CE enriched, triglyceride-rich lipoprotein particles through the action of CETP and by reducing the direct return of HDL-CE to the liver. PMID- 20713649 TI - Shedding new light on lipid biology with coherent anti-Stokes Raman scattering microscopy. AB - Despite the ubiquitous roles of lipids in biology, the detection of lipids has relied on invasive techniques, population measurements, or nonspecific labeling. Such difficulties can be circumvented by a label-free imaging technique known as coherent anti-Stokes Raman (CARS) microscopy, which is capable of chemically selective, highly sensitive, and high-speed imaging of lipid-rich structures with submicron three-dimensional spatial resolution. We review the broad applications of CARS microscopy to studies of lipid biology in cell cultures, tissue biopsies, and model organisms. Recent technical advances, limitations of the technique, and perspectives are discussed. PMID- 20713652 TI - Importance of macrophage cholesterol content on the flux of cholesterol mass. AB - Net flux of cholesterol represents the difference between efflux and influx and can result in net cell-cholesterol accumulation, net cell-cholesterol depletion, or no change in cellular cholesterol content. We measured radiolabeled cell cholesterol efflux and cell-cholesterol mass using cholesterol-normal and enriched J774 and elicited mouse peritoneal macrophage cells. Net cell cholesterol effluxes were observed when cholesterol-enriched J774 cells were incubated with 3.5% apolipoprotein (apo) B depleted human serum, HDL(3), and apo A-I. Net cell-cholesterol influxes were observed when cholesterol-normal J774 cells were incubated with the same acceptors except apo A-I. When incubated with 2.5% individual sera, cholesterol mass efflux in free cholesterol (FC)-enriched J774 cells correlated with the HDL-cholesterol (HDL-C) concentrations (r(2) = 0.4; P=0.003), whereas cholesterol mass influx in cholesterol-normal J774 cells correlated with the LDL cholesterol (LDL-C) concentrations (r(2) = 0.6; P<0.0001) of the individual sera. A positive correlation was observed between measurements of [(3)H]cholesterol efflux and reductions in cholesterol mass (r(2) = 0.4; P=0.001) in FC-enriched J774 cells. In conclusion, isotopic efflux measurements from cholesterol-normal or cholesterol-enriched cells provide an accurate measurement of relative ability of an acceptor to remove labeled cholesterol under a specific set of experimental conditions, i.e., efflux potential. Moreover, isotopic efflux measurements can reflect changes in cellular cholesterol mass if the donor cells are enriched with cholesterol. PMID- 20713651 TI - Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low fat high-carbohydrate diet. AB - Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) [Lp(a)], a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles. PMID- 20713654 TI - High-throughput simultaneous analysis of five urinary metabolites of areca nut and tobacco alkaloids by isotope-dilution liquid chromatography-tandem mass spectrometry with on-line solid-phase extraction. AB - BACKGROUND: Areca nut and tobacco are commonly used drugs worldwide and have been frequently used in combination. We describe the use of on-line solid-phase extraction and isotope-dilution liquid chromatography-tandem mass spectrometry for the simultaneous measurement of five major urinary metabolites of both areca nut and tobacco alkaloids, namely, arecoline, arecaidine, N-methylnipecotic acid, nicotine, and cotinine. METHODS: Automated purification of urine was accomplished with a column-switching device. After the addition of deuterium-labeled internal standards, urine samples were directly analyzed within 13 minutes. This method was applied to measure urinary metabolites in 90 healthy subjects to assess areca nut/tobacco exposure. Urinary time course of arecoline, arecaidine, and N methylnipecotic acid was investigated in five healthy nonchewers after oral administration of areca nut water extracts. RESULTS: The limits of detection were 0.016 to 0.553 ng/mL. Interday and intraday imprecision were <10%. Mean recoveries of five metabolites in urine were 97% to 114%. Mean urinary concentrations of arecoline, arecaidine, N-methylnipecotic acid, nicotine, and cotinine in regular areca nut chewers also smokers were 23.9, 5,816, 1,298, 2,635, and 1,406 ng/mg creatinine, respectively. Time course study revealed that after administration of areca nuts extracts, the major urinary metabolite was arecaidine with a half-life of 4.3 hours, followed by N-methylnipecotic acid with a half-life of 7.9 hours, and very low levels of arecoline with a half-life of 0.97 hour. CONCLUSIONS: This on-line solid-phase extraction liquid chromatography tandem mass spectrometry method firstly provides high-throughput direct analysis of five urinary metabolites of areca nut/tobacco alkaloids. IMPACT: This method may facilitate the research into the oncogenic effects of areca nut/tobacco exposure. PMID- 20713653 TI - Vasoprotective effects of life span-extending peripubertal GH replacement in Lewis dwarf rats. AB - In humans, growth hormone deficiency (GHD) and low circulating levels of insulin like growth factor 1 (IGF-1) significantly increase the risk for cerebrovascular disease. Genetic growth hormone (GH)/IGF-1 deficiency in Lewis dwarf rats significantly increases the incidence of late-life strokes, similar to the effects of GHD in elderly humans. Peripubertal treatment of Lewis dwarf rats with GH delays the occurrence of late-life stroke, which results in a significant extension of life span. The present study was designed to characterize the vascular effects of life span-extending peripubertal GH replacement in Lewis dwarf rats. Here, we report, based on measurements of dihydroethidium fluorescence, tissue isoprostane, GSH, and ascorbate content, that peripubertal GH/IGF-1 deficiency in Lewis dwarf rats increases vascular oxidative stress, which is prevented by GH replacement. Peripubertal GHD did not alter superoxide dismutase or catalase activities in the aorta nor the expression of Cu-Zn-SOD, Mn SOD, and catalase in the cerebral arteries of dwarf rats. In contrast, cerebrovascular expression of glutathione peroxidase 1 was significantly decreased in dwarf vessels, and this effect was reversed by GH treatment. Peripubertal GHD significantly decreases expression of the Nrf2 target genes NQO1 and GCLC in the cerebral arteries, whereas it does not affect expression and activity of endothelial nitric oxide synthase and vascular expression of IGF-1, IGF-binding proteins, and inflammatory markers (tumor necrosis factor alpha, interluekin-6, interluekin-1beta, inducible nitric oxide synthase, intercellular adhesion molecule 1, and monocyte chemotactic protein-1). In conclusion, peripubertal GH/IGF-1 deficiency confers pro-oxidative cellular effects, which likely promote an adverse functional and structural phenotype in the vasculature, and results in accelerated vascular impairments later in life. PMID- 20713655 TI - The influence of a spirituality-based intervention on quality of life, depression, and anxiety in community-dwelling adults with cardiovascular disease: a pilot study. AB - PURPOSE AND DESIGN: The specific aims of this pre-experimental pilot study were to determine the feasibility and preliminary efficacy of an individualized spirituality-based intervention on health-related outcomes (quality-of-life [QOL], depression, and anxiety) in community-dwelling patients with cardiovascular disease (CVD). METHODS: Self-reported QOL, depression, and anxiety data were provided by cardiac patients recruited from three community-based organizations, ( N = 27) at baseline and one month later. The Spirituality Scale developed by the principal investigator assessed study participants' level of spirituality and scoring on the subscales activated one or more of three spirituality-based interventions. Repeated measures analysis of variance was used to evaluate temporal changes. FINDINGS: Patients who participated in the 1-month intervention demonstrated a significant modest increase in overall QOL. There was a trend toward lower depression scores but this was not significant. No significant changes were seen in anxiety scores. Content analysis of patients' perceptions of feasibility supports the acceptability of the intervention. CONCLUSION: Results from this small pilot study provide preliminary evidence that the individualized spirituality-based intervention used in this study holds promise as an addition to traditional cardiac care and has the potential to improve QOL in community-dwelling adults with CVD. PMID- 20713656 TI - Metabolism of 1'- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7. AB - Midazolam undergoes oxidative hydroxylation by CYP3A to its metabolites, which are excreted mainly as glucuronidated conjugates into the urine. In this study, we examined the glucuronidation of hydroxymidazolam in human liver microsomes (HLMs) and characterized the UDP-glucuronosyltransferases (UGTs) involved in 1'- and 4-hydroxymidazolam glucuronidation. Among the 12 UGT isoforms tested, the O- and N-glucuronidation of 1'-hydroxymidazolam was mediated by UGT2B4/2B7 and 1A4, respectively. In contrast, the glucuronidation of 4-hydroxymidazolam was mediated by UGT1A4. Consistent with these observations, the UGT1A4 inhibitor hecogenin and the UGT2B7 substrate diclofenac potently inhibited the N- and O-glucuronidation of 1'-hydroxymidazolam in HLMs, respectively. A correlation analysis of UGT enzymatic activity and the formation rate of glucuronide metabolites from 1'- and 4-hydroxymidazolam in 25 HLMs showed that hydroxymidazolam glucuronidation is correlated with UGT1A4-mediated lamotrigine glucuronidation and UGT2B7-mediated diclofenac glucuronidation activity. Taken together, these findings indicate that UGT1A4, 2B4, and 2B7 are major isoforms responsible for glucuronide conjugate formation from 1'- and 4-hydroxymidazolam, which are the two major oxidative metabolites of midazolam. PMID- 20713657 TI - Sulfated derivatives of Escherichia coli K5 capsular polysaccharide are potent inhibitors of human cytomegalovirus. AB - To date, there are few drugs licensed for the treatment of human cytomegalovirus (HCMV) infections, most of which target the viral DNA polymerase and suffer from many drawbacks. Thus, there is still a strong need for new anti-HCMV compounds with novel mechanisms of action. In this study, we investigated the anti-HCMV activity of chemically sulfated derivatives of Escherichia coli K5 capsular polysaccharide. These compounds are structurally related to cellular heparan sulfate and have been previously shown to be effective against some enveloped and nonenveloped viruses. We demonstrated that two derivatives, i.e., K5-N,OS(H) and K5-N,OS(L), are able to prevent cell infection by different strains of HCMV at concentrations in the nanomolar range while having no significant cytotoxicity. Studies performed to elucidate the mechanism of action of their anti-HCMV activity revealed that these compounds do not interact with either the host cell or the viral particle but need a virus-cell interaction to exert antiviral effects. Furthermore, these K5 derivatives were able to inhibit the attachment step of HCMV infection, as well as the viral cell-to-cell spread. Since the mode of inhibition of these compounds appears to differ from that of the available anti-HCMV drugs, sulfated K5 derivatives could represent the basis for the development of a novel class of potent anti-HCMV compounds. Interestingly, our studies highlight that small variations of the K5 derivatives structure can modulate the selectivity and potency of their activities against different viruses, including viruses belonging to the same family. PMID- 20713658 TI - Frequency of spontaneous resistance to fosfomycin combined with different antibiotics in Pseudomonas aeruginosa. PMID- 20713659 TI - Efficacy of calcium-EDTA as an inhibitor for metallo-beta-lactamase in a mouse model of Pseudomonas aeruginosa pneumonia. AB - In this study, we have evaluated the efficacy of calcium-EDTA (Ca-EDTA) as an inhibitor of bacterial metalloenzymes, such as metallo-beta-lactamase (MBL) and other proteases, in a mouse model of Pseudomonas aeruginosa pneumonia. The simultaneous presence of Ca-EDTA (32 MUg/ml) reduced the MICs of imipenem (IPM) in all MBL-producing P. aeruginosa isolates (IMP-1, -2, -7, and -10 and VIM-2) but not non-MBL-producing strains. In the pneumonia model, mice were intranasally infected with MBL-producing P. aeruginosa and then kept under conditions of hyperoxia to mimic ventilator-associated pneumonia. With both intranasal and subcutaneous administrations, Ca-EDTA significantly potentiated survival benefits of IPM compared to those of IPM alone. Ca-EDTA combination therapy induced a significant reduction of the bacterial burden in the lungs (P < 0.05). Furthermore, the inhibition activity of Ca-EDTA against MBL activity was confirmed by using the purified IMP-1 enzyme, which was characterized by a 50% inhibitory concentration (IC(50)) of 55 +/- 8.2 MUM. Finally, the protective effects of Ca-EDTA were demonstrated by culture supernatant-induced epithelial cell damage and acute lung injury in mice. These data suggest the therapeutic potential of Ca-EDTA not only by the blocking of MBLs but also by neutralizing tissue-damaging metalloproteases in P. aeruginosa infections. PMID- 20713660 TI - ampG gene of Pseudomonas aeruginosa and its role in beta-lactamase expression. AB - In enterobacteria, the ampG gene encodes a transmembrane protein (permease) that transports 1,6-GlcNAc-anhydro-MurNAc and the 1,6-GlcNAc-anhydro-MurNAc peptide from the periplasm to the cytoplasm, which serve as signal molecules for the induction of ampC beta-lactamase. The role of AmpG as a transporter is also essential for cell wall recycling. Pseudomonas aeruginosa carries two AmpG homologues, AmpG (PA4393) and AmpGh1 (PA4218), with 45 and 41% amino acid sequence identity, respectively, to Escherichia coli AmpG, while the two homologues share only 19% amino acid identity. In P. aeruginosa strains PAO1 and PAK, inactivation of ampG drastically repressed the intrinsic beta-lactam resistance while ampGh1 deletion had little effect on the resistance. Further, deletion of ampG in an ampD-null mutant abolished the high-level beta-lactam resistance that is associated with the loss of AmpD activity. The cloned ampG gene is able to complement both the P. aeruginosa and the E. coli ampG mutants, while that of ampGh1 failed to do so, suggesting that PA4393 encodes the only functional AmpG protein in P. aeruginosa. We also demonstrate that the function of AmpG in laboratory strains of P. aeruginosa can effectively be inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP), causing an increased sensitivity to beta-lactams among laboratory as well as clinical isolates of P. aeruginosa. Our results suggest that inhibition of the AmpG activity is a potential strategy for enhancing the efficacy of beta-lactams against P. aeruginosa, which carries inducible chromosomal ampC, especially in AmpC-hyperproducing clinical isolates. PMID- 20713661 TI - TelA contributes to the innate resistance of Listeria monocytogenes to nisin and other cell wall-acting antibiotics. AB - Nisin is a class I bacteriocin (lantibiotic), which is employed by the food and veterinary industries and exhibits potent activity against numerous pathogens. However, this activity could be further improved through the targeting and inhibition of factors that contribute to innate nisin resistance. Here we describe a novel locus, lmo1967, which is required for optimal nisin resistance in Listeria monocytogenes. The importance of this locus, which is a homologue of the tellurite resistance gene telA, was revealed after the screening of a mariner random mutant bank of L. monocytogenes for nisin-susceptible mutants. The involvement of telA in nisin resistance was confirmed through an analysis of a nonpolar deletion mutant. In addition to being 4-fold-more susceptible to nisin, the DeltatelA strain was also 8-fold-more susceptible to gallidermin and 2-fold more susceptible to cefuroxime, cefotaxime, bacitracin, and tellurite. This is the first occasion upon which telA has been investigated in a Gram-positive organism and also represents the first example of a link being established between a telA gene and resistance to cell envelope-acting antimicrobials. PMID- 20713662 TI - Bactericidal potencies of new regimens are not predictive of their sterilizing potencies in a murine model of tuberculosis. AB - TMC207, rifapentine, and moxifloxacin are in clinical testing for the treatment of tuberculosis. Five experimental regimens with various combinations of TMC207, rifapentine, moxifloxacin, and pyrazinamide were tested for their bactericidal and sterilizing potencies in Swiss mice intravenously inoculated with Mycobacterium tuberculosis bacilli. TMC207 had the strongest bactericidal efficacy, while rifapentine was the strongest contributor to sterilizing efficacy. The rank order of sterilizing potencies was different from the rank order of bactericidal potencies, underlining the importance of prioritizing new regimens designed to shorten the treatment duration by their sterilizing potencies rather than by their bactericidal potencies. Both 3 months of treatment with a regimen combining TMC207, pyrazinamide, and rifapentine and 5 months of treatment with a regimen combining TMC207, pyrazinamide, and moxifloxacin resulted in relapse rates similar to the rate obtained by 6 months of treatment with rifampin-isoniazid-pyrazinamide. PMID- 20713663 TI - A chimeric protein that functions as both an anthrax dual-target antitoxin and a trivalent vaccine. AB - Effective measures for the prophylaxis and treatment of anthrax are still required for counteracting the threat posed by inhalation anthrax. In this study, we first demonstrated that the chimeric protein LFn-PA, created by fusing the protective antigen (PA)-binding domain of lethal factor (LFn) to PA, retained the functions of the respective molecules. On the basis of this observation, we attempted to develop an antitoxin that targets the binding of lethal factor (LF) and/or edema factor (EF) to PA and the transportation of LF/EF. Therefore, we replaced PA in LFn-PA with a dominant-negative inhibitory PA (DPA), i.e., PA(F427D). In in vitro models of anthrax intoxication, the LFn-DPA chimera showed 3-fold and 2-fold higher potencies than DPA in protecting sensitive cells against anthrax lethal toxin (LeTx) and edema toxin (EdTx), respectively. In animal models, LFn-DPA exhibited strong potency in rescuing mice from lethal challenge with LeTx. We also evaluated the immunogenicity and immunoprotective efficacy of LFn-DPA as an anthrax vaccine candidate. In comparison with recombinant PA, LFn DPA induced significantly higher levels of the anti-PA immune response. Moreover, LFn-DPA elicited an anti-LF antibody response that could cross-react with EF. Mice immunized with LFn-DPA tolerated a LeTx challenge that was 5 times its 50% lethal dose. Thus, LFn-DPA represents a highly effective trivalent vaccine candidate for both preexposure and postexposure vaccination. Overall, we have developed a novel and dually functional reagent for the prophylaxis and treatment of anthrax. PMID- 20713664 TI - 1-O-hexadecyloxypropyl cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular epithelial cells. AB - Antiviral drugs for treating polyomavirus BK (BKV) replication in polyomavirus associated nephropathy or hemorrhagic cystitis are of considerable clinical interest. Unlike cidofovir, the lipid conjugate 1-O-hexadecyloxypropyl cidofovir (CMX001) is orally available and has not caused detectable nephrotoxicity in rodent models or human studies to date. Primary human renal proximal tubular epithelial cells were infected with BKV-Dunlop, and CMX001 was added 2 h postinfection (hpi). The intracellular and extracellular BKV DNA load was determined by quantitative PCR. Viral gene expression was examined by quantitative reverse transcription-PCR, Western blotting, and immunofluorescence microscopy. We also examined host cell viability, proliferation, metabolic activity, and DNA replication. The titration of CMX001 identified 0.31 MUM as the 90% effective concentration (EC(90)) for reducing the extracellular BKV load at 72 hpi. BKV large T antigen mRNA and protein expression was unaffected at 24 hpi, but the intracellular BKV genome was reduced by 90% at 48 hpi. Late gene expression was reduced by 70 and 90% at 48 and 72 hpi, respectively. Comparisons of CMX001 and cidofovir EC(90)s from 24 to 96 hpi demonstrated that CMX001 had a more rapid and enduring effect on BKV DNA and infectious progeny at 96 hpi than cidofovir. CMX001 at 0.31 MUM had little effect on overall cell metabolism but reduced bromodeoxyuridine incorporation and host cell proliferation by 20 to 30%, while BKV infection increased cell proliferation in both rapidly dividing and near-confluent cultures. We conclude that CMX001 inhibits BKV replication with a longer-lasting effect than cidofovir at 400* lower levels, with fewer side effects on relevant host cells in vitro. PMID- 20713665 TI - Reductions in skin and systemic parasite burdens as a combined effect of topical paromomycin and oral miltefosine treatment of mice experimentally infected with Leishmania (Leishmania) amazonensis. AB - This study aimed to investigate the activity of a combination of topical paromomycin gel and oral miltefosine for the treatment of experimental cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis. The efficacy of the combination, evaluated by measuring lesion size and parasite burden in the skin and spleen, was assessed in BALB/c mice infected by L. (L.) amazonensis. The miltefosine was administered orally at 10 mg/kg of body weight/day for 10 days, while 10% paromomycin gel was applied topically twice a day for 20 days. Treatment of the experimentally infected animals with a topical paromomycin-oral miltefosine combination induced a statistically significant reduction in lesion size and parasite burden in the skin and spleen, with complete healing of ulcers, compared with those treated with a placebo group. A combination of topical paromomycin gel and oral miltefosine provided enhanced efficacy in the treatment of L. (L.) amazonensis-infected mice, showing activity higher than that observed for the monotherapeutic regimens. PMID- 20713666 TI - A novel galacto-glycerolipid from Oxalis corniculata kills Entamoeba histolytica and Giardia lamblia. AB - Oxalis corniculata is a naturally occurring weed that has been used in traditional medicine for the cure of dysentery and diarrhea in India. One of the common causes of dysentery is due to infection by the protist pathogen Entamoeba histolytica. Bioactivity profiling of extracts from O. corniculata identified several compounds that showed antiamoebic activity in axenic cultures of E. histolytica. These were characterized by nuclear magnetic resonance, infrared, and mass spectrometry as (i) Oc-1, a mixture of saturated fatty acids C24 to C28; (ii) Oc-2, a mixture of long-chain alcohols C18 to C28; and (iii) Oc-3, a single compound that was a galacto-glycerolipid (GGL). Of the different compounds that were obtained, the strongest antiamoebic activity was found in GGL. The addition of GGL to E. histolytica xenic cultures containing other microbial flora from the large intestine did not affect its antiamoebic activity. Amoebicidal concentrations of GGL had no effect on intestinal microbial flora or on the mammalian cell line HEK-293. GGL was also found to be equally effective in killing another protist pathogen, Giardia lamblia, that causes diarrhea in humans. The importance of this study is based on the identification of novel natural products and the possibility of developing these compounds as active agents to treat at least two pathogenic parasitic intestinal infections endemic to tropical regions. PMID- 20713667 TI - Genetic and functional variability of AmpC-type beta-lactamases from Acinetobacter baumannii. AB - The incidence of naturally occurring AmpC beta-lactamases with extended activities toward several cephalosporins was evaluated among 17 ceftazidime (CAZ) resistant Acinetobacter baumannii isolates. Five AmpC beta-lactamases (named ADC beta-lactamases) were identified, among which those possessing the Val208Ala (inside the omega-loop) or Asn283Ser (helix H-10) substitution conferred higher levels of resistance (4- to 64-fold higher) to CAZ and to cefotaxime in Escherichia coli. This study demonstrates that peculiar AmpCs playing a role in resistance to broad-spectrum cephalosporins in A. baumannii may be identified. PMID- 20713669 TI - Subinhibitory concentrations of protein synthesis-inhibiting antibiotics promote increased expression of the agr virulence regulator and production of phenol soluble modulin cytolysins in community-associated methicillin-resistant Staphylococcus aureus. AB - Tetracycline, clindamycin, and other protein synthesis inhibitors at subinhibitory concentrations significantly increased the expression of the pivotal virulence regulator agr and production of the agr-regulated cytolytic phenol-soluble modulins in the community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300. Our results suggest that such protein synthesis inhibitors may exacerbate the progression of CA-MRSA disease when applied at concentrations that are too low or when treating infections caused by strains resistant to those antibiotics. PMID- 20713668 TI - Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. AB - Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. PMID- 20713671 TI - Demonstration of conjugative transposon (Tn5397)-mediated horizontal gene transfer between Clostridium difficile and Enterococcus faecalis. AB - Antibiotic-resistant Enterococcus faecalis and Clostridium difficile are responsible for nosocomial infections in humans, in which they inhabit the same niche. Here, we demonstrate transfer of the conjugative transposon Tn5397 from C. difficile 630 to E. faecalis JH2-2, the first reported gene transfer between these two bacteria. Furthermore, transfer from the E. faecalis EF20A transconjugant to the epidemic ribotype 027 C. difficile strain R20291 was also demonstrated. Tn5397 was shown to use a single specific target site in E. faecalis; it also has specific target sites in C. difficile. These experiments highlight the importance of continual monitoring for emerging resistances in these bacteria. PMID- 20713670 TI - Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds. AB - Bradyzoite-to-tachyzoite conversion plays a role in the pathogenesis of recrudescence of ocular toxoplasmosis and disease in immunocompromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous study showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. The present study shows that FR235222 can target in vitro-converted cysts and bradyzoites. Moreover, the compound is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compound is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compound impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target, T. gondii HDAC3, to synthesize new FR235222 derivative compounds. We identified two new molecules that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach. These results identify FR235222 and its derivatives as new lead compounds in the range of therapeutics available for acute and chronic toxoplasmosis. PMID- 20713672 TI - Diversity of staphylococcal cassette chromosome mec elements in predominant methicillin-resistant Staphylococcus aureus clones in a small geographic area. AB - Recent population genetic studies suggest that staphylococcal cassette chromosome mec (SCCmec) was acquired much more frequently than previously thought. In the present study, we aimed to investigate the diversity of SCCmec elements in a local methicillin-resistant Staphylococcus aureus (MRSA) population. Each MRSA isolate (one per patient) recovered in the Vaud canton of Switzerland from January 2005 to December 2008 was analyzed by the double-locus sequence typing (DLST) method and SCCmec typing. DLST analysis indicated that 1,884/2,036 isolates (92.5%) belong to four predominant clones. As expected from the local spread of a clone, most isolates within clones harbored an identical SCCmec type. However, three to seven SCCmec types have been recovered in every predominant DLST clone, suggesting that some of these elements might have been acquired locally. This pattern could also be explained by distinct importations of related isolates into the study region. The addition of a third highly variable locus to further increase the discriminatory power of typing as well as epidemiological data suggested that most ambiguous situations were explained by the second hypothesis. In conclusion, our study showed that even if the acquisition of new SCCmec elements at a local level likely occurs, it does not explain all the diversity observed in the study region. PMID- 20713673 TI - The initial 96 hours of invasive pulmonary aspergillosis: histopathology, comparative kinetics of galactomannan and (1->3) beta-d-glucan and consequences of delayed antifungal therapy. AB - Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1->3)-beta-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1->3)-beta-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1->3)-beta-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1->3)-beta-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at >=48 h postinoculation is associated with suboptimal therapeutic outcomes. PMID- 20713674 TI - In vitro and in vivo efficacy of florfenicol for treatment of Francisella asiatica infection in tilapia. AB - Francisella asiatica is a recently described, Gram-negative, facultative intracellular fish pathogen, known to be the causative agent of francisellosis in warm-water fish. Francisellosis outbreaks have increased in frequency among commercial aquaculture operations and have caused severe economic losses in every case reported. The lack of effective treatments for piscine francisellosis led us to investigate the potential efficacy of florfenicol for inhibition of F. asiatica in vitro and as an oral therapeutic agent in vivo. The MIC of florfenicol for F. asiatica, as determined by the broth dilution method, was 2 MUg/ml, which indicates its potential efficacy as a therapeutic agent for treatment of francisellosis. The intracellular susceptibility of the bacterium to florfenicol in tilapia head kidney-derived macrophages (THKDM) was also investigated. Addition of florfenicol to the medium at 10 MUg/ml was sufficient to significantly reduce bacterial loads in the THKDM in vitro. Cytotoxicity assays done in infected THKDM also demonstrated drug efficacy in vivo, as determined by lactate dehydrogenase (LDH) release. Levels of LDH released from infected THKDM were significantly lower in macrophages treated with florfenicol (P < 0.001) than in untreated cells. In medicated-feed trials, fish were fed 15 mg of florfenicol/kg of fish body weight for 10 days, and the feeding was initiated at either 1, 3, or 6 days postchallenge. Immersion challenges resulted in 30% mean percent survival in nontreated fish, and fish receiving medicated feed administered at 1 and 3 days postinfection showed higher mean percent survival (100% and 86.7%, respectively). A significant decrease (P < 0.001) in bacterial numbers (number of CFU/g of spleen tissue) was observed in treated groups compared to nontreated infected fish at both 1 and 3 days postchallenge. There were no differences in bacterial burden in the spleens between fish treated 6 days postchallenge and untreated controls. In conclusion, if florfenicol is administered during early stages of infection, it has the potential for effectively treating piscine francisellosis, including the capacity for intracellular penetration and bacterial clearance. PMID- 20713675 TI - Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania. AB - The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model. PMID- 20713676 TI - blaROB-1 presence on pB1000 in Haemophilus influenzae is widespread, and variable cefaclor resistance is associated with altered penicillin-binding proteins. AB - Plasmid pB1000 is a small replicon recently identified as bearing bla(ROB-1) in animal and human Pasteurellaceae in Spain. We identified pB1000 in 11 bla(ROB-1) positive Australian and North American Haemophilus influenzae isolates, suggesting a wider role for pB1000 in disseminating bla(ROB-1). Native H. influenzae conjugative elements can mobilize plasmids similar to pB1000 at a low frequency of 10(-8), and this might account for the infrequency of bla(ROB-1) compared to the rate of occurrence of bla(TEM-1). Altered penicillin-binding protein 3 was associated with an increased cefaclor MIC in 3 isolates. PMID- 20713677 TI - Low frequency of intermittent HIV-1 semen excretion in patients treated with darunavir-ritonavir at 600/100 milligrams twice a day plus two nucleoside reverse transcriptase inhibitors or monotherapy. AB - HIV-1 RNA level and darunavir concentration in the genital tract were measured in 45 men receiving darunavir-ritonavir mono- or tritherapy. At week 48, a low frequency (3/45) of HIV-1 RNA shedding was observed in patients (1 on monotherapy and 2 on triple therapy), although they had undetectable HIV-1 RNA in plasma. The median darunavir seminal plasma concentration was close to the blood plasma free fraction, demonstrating a good penetration of darunavir into the male genital tract. PMID- 20713678 TI - Synergy testing by Etest, microdilution checkerboard, and time-kill methods for pan-drug-resistant Acinetobacter baumannii. AB - Pan-drug-resistant (PDR) Acinetobacter baumannii is an important nosocomial pathogen that poses therapeutic challenges. Tigecycline alone or in combination with agents such as colestimethate, imipenem, and/or amikacin is being used clinically to treat PDR A. baumannii infections. The purpose of this study was to compare in vitro susceptibility testing by epsilometric (Etest) methods and the checkerboard (CB) method with testing by time-kill analysis. PDR A. baumannii clinical strains representing eight unique pulsed-field gel electrophoresis clones selected from a total of 32 isolates were tested in vitro with tigecycline, colestimethate, imipenem, and amikacin in single- and two-drug combinations by using two different methods of Etest (with a fixed ratio method [method 1] and with the incorporation of the active drug in medium [method 2]) and by using CB. The three-drug combination of imipenem, tigecycline, and amikacin was also tested by CB. These results were compared to time-kill results. Synergy was consistently detected with the imipenem plus colestimethate and tigecycline plus imipenem combinations. The Etest method with active drug incorporated into the agar allowed us to detect synergy even in the presence of the active drug and was more comparable to CB and time-kill tests. Synergy was detected with the three-drug combination of imipenem, tigecycline, and amikacin by both CB and time-kill methods among several tested clones. These findings indicate the utility of synergy testing to predict activity of specific antibiotic combinations against PDR A. baumannii. PMID- 20713679 TI - Emergence and molecular characterization of extensively drug-resistant Mycobacterium tuberculosis clinical isolates from the Delhi Region in India. AB - We screened 194 Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in Delhi and neighboring regions in India to identify the prevalence of extensive drug resistance (XDR) in clinical isolates. Among these, 104 isolates were found to be multidrug resistant (MDR), and 6 were identified as XDR isolates, which was later confirmed by antimicrobial susceptibility testing against the respective drug screening panel. Genotyping was carried out by amplifying and sequencing the following genes: rpoB (rifampin), katG (isoniazid), gyrA (fluoroquinolones), and rrs (amikacin, kanamycin, and capreomycin). Our analyses indicated that mutations at the hot spots of these genes were positively correlated with drug resistance in clinical isolates. The key mutation observed for rpoB was in the codon for amino acid position 531 (S531L), and other mutations were seen in the hot spot, including those encoding Q510P, L511H, D516V, and H526Y mutations. We identified S315T and R463L substitutions encoded in the katG locus. An S95T substitution encoded in the gyrA locus was the most common mutation observed in fluoroquinolone-resistant isolates. In addition, we saw D94G and D94N mutations encoded in the QRDR region. The 16S rRNA (rrs) gene encoded mainly the A1401G mutation and an additional mutation, G1484T, resulting in ribosomal modifications. Taken together, the data in this report clearly establish the presence of phenotypically distinct XDR strains in India by molecular profiling and further identify specific mutational hot spots within key genes of XDR-TB strains. PMID- 20713680 TI - Emergence and Distribution of Plasmids Bearing the blaOXA-51-like gene with an upstream ISAba1 in carbapenem-resistant Acinetobacter baumannii isolates in Taiwan. AB - The bla(OXA-51)-like gene with an upstream ISAba1 (ISAba1-bla(OXA-51)-like gene) was originally found on the chromosomes of carbapenem-resistant or -susceptible Acinetobacter baumannii isolates. However, a plasmid-borne ISAba1-bla(OXA-51) like gene has recently been identified in Acinetobacter genomic species 13TU and several A. baumannii isolates in Taiwan, and all of the isolates are carbapenem resistant. This study aimed to characterize the plasmids bearing the ISAba1 bla(OXA-51)-like gene and their significance in A. baumannii. Among the 117 ISAba1-bla(OXA-51)-like-harboring isolates collected from 10 hospitals in Taiwan, 58 isolates (49.6%) from 24 clones had the genes located on plasmids that likely originated from a common progenitor. Among the 58 isolates, four had additional copy of the ISAba1-bla(OXA-51)-like gene on their chromosomes. Based on the analysis of these four isolates, the plasmid-located ISAba1-bla(OXA-51)-like gene appeared to be acquired via one-ended transposition (Tn6080). The isolates with a plasmid bearing the ISAba1-bla(OXA-51)-like gene had higher rates of resistance to imipenem (98% versus 46.6%; P < 0.001) and meropenem (98% versus 69%; P = 0.019) than those with the genes chromosomally encoded, which is most likely due to increased gene dosage provided by the higher copy number of associated plasmids. Transformation with a recombinant plasmid harboring only the ISAba1 bla(OXA-51)-like gene was enough to confer a high level of carbapenem resistance to A. baumannii, eliminating the possible contribution of other factors on the original plasmids. This study demonstrated that the carbapenem resistance associated plasmids carrying the ISAba1-bla(OXA-51)-like gene are widespread in A. baumannii strains in Taiwan. PMID- 20713681 TI - Characterization of two newly identified genes, vgaD and vatH, [corrected] conferring resistance to streptogramin A in Enterococcus faecium. AB - We characterized two new streptogramin A resistance genes from quinupristin dalfopristin-resistant Enterococcus faecium JS79, which was selected from 79 E. faecium isolates lacking known genes encoding streptogramin A acetyltransferase. A 5,650-bp fragment of HindIII-digested plasmid DNA from E. faecium JS79 was cloned and sequenced. The fragment contained two open reading frames carrying resistance genes related to streptogramin A, namely, genes for an acetyltransferase and an ATP efflux pump. The first open reading frame comprised 648 bp encoding 216 amino acids with a predicted left-handed parallel beta-helix domain structure; this new gene was designated vatH. [corrected] The second open reading frame consisted of 1,575 bp encoding 525 amino acids with two predicted ATPase binding cassette transporters comprised of Walker A, Walker B, and LSSG motifs; this gene was designated vgaD. vgaD is located 65 bp upstream from vatH, [corrected] was detected together with vatH [corrected] in 12 of 179 quinupristin dalfopristin-resistant E. faecium isolates, and was located on the same plasmid. Also, the 5.6-kb HindIII-digested fragment which was observed in JS79 was detected in nine vgaD- and vatH-containing [corrected] E. faecium isolates by Southern hybridization. Therefore, it was expected that these two genes were strongly correlated with each other and that they may be composed of a transposon. Importantly, vgaD is the first identified ABC transporter conferring resistance to streptogramin A in E. faecium. Pulsed-field gel electrophoresis patterns and sequence types of vgaD- and vatH-containing [corrected] E. faecium isolates differed for isolates from humans and nonhumans. PMID- 20713682 TI - A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease. AB - OBJECTIVE: Type 2 diabetes and obesity are increasingly affecting human populations around the world. Our goal was to identify early molecular signatures predicting genetic risk to these metabolic diseases using two strains of mice that differ greatly in disease susceptibility. RESEARCH DESIGN AND METHODS: We integrated metabolic characterization, gene expression, protein-protein interaction networks, RT-PCR, and flow cytometry analyses of adipose, skeletal muscle, and liver tissue of diabetes-prone C57BL/6NTac (B6) mice and diabetes resistant 129S6/SvEvTac (129) mice at 6 weeks and 6 months of age. RESULTS: At 6 weeks of age, B6 mice were metabolically indistinguishable from 129 mice, however, adipose tissue showed a consistent gene expression signature that differentiated between the strains. In particular, immune system gene networks and inflammatory biomarkers were upregulated in adipose tissue of B6 mice, despite a low normal fat mass. This was accompanied by increased T-cell and macrophage infiltration. The expression of the same networks and biomarkers, particularly those related to T-cells, further increased in adipose tissue of B6 mice, but only minimally in 129 mice, in response to weight gain promoted by age or high-fat diet, further exacerbating the differences between strains. CONCLUSIONS: Insulin resistance in mice with differential susceptibility to diabetes and metabolic syndrome is preceded by differences in the inflammatory response of adipose tissue. This phenomenon may serve as an early indicator of disease and contribute to disease susceptibility and progression. PMID- 20713683 TI - Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. AB - OBJECTIVE: Fibrosis is a newly appreciated hallmark of the pathological alteration of human white adipose tissue (WAT). We investigated the composition of subcutaneous (scWAT) and omental WAT (oWAT) fibrosis in obesity and its relationship with metabolic alterations and surgery-induced weight loss. RESEARCH DESIGN AND METHODS: Surgical biopsies for scWAT and oWAT were obtained in 65 obese (BMI 48.2 +/- 0.8 kg/m(2)) and 9 lean subjects (BMI 22.8 +/- 0.7 kg/m(2)). Obese subjects who were candidates for bariatric surgery were clinically characterized before, 3, 6, and 12 months after surgery, including fat mass evaluation by dual energy X-ray absorptiometry. WAT fibrosis was quantified and characterized using quantitative PCR, microscopic observation, and immunohistochemistry. RESULTS: Fibrosis amount, distribution and collagen types (I, III, and VI) present distinct characteristics in lean and obese subjects and with WAT depots localization (subcutaneous or omental). Obese subjects had more total fibrosis in oWAT and had more pericellular fibrosis around adipocytes than lean subjects in both depots. Macrophages and mastocytes were highly represented in fibrotic bundles in oWAT, whereas scWAT was more frequently characterized by hypocellular fibrosis. The oWAT fibrosis negatively correlated with omental adipocyte diameters (R = -0.30, P = 0.02), and with triglyceride levels (R = 0.42, P < 0.01), and positively with apoA1 (R = 0.25, P = 0.05). Importantly, scWAT fibrosis correlated negatively with fat mass loss measured at the three time points after surgery. CONCLUSIONS: Our data suggest differential clinical consequences of fibrosis in human WAT. In oWAT, fibrosis could contribute to limit adipocyte hypertrophy and is associated with a better lipid profile, whereas scWAT fibrosis may hamper fat mass loss induced by surgery. PMID- 20713684 TI - Accelerated progression from mild cognitive impairment to dementia in people with diabetes. AB - OBJECTIVE: The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI and accelerate the progression from MCI to dementia. RESEARCH DESIGN AND METHODS: In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 with amnestic MCI [aMCI] and 182 with other cognitive impairment no dementia [oCIND]) age >= 75 years were identified at baseline. The two cohorts were followed for 9 years to detect the incident MCI and dementia following international criteria. Diabetes was ascertained based on a medical examination, hypoglycemic medication use, and random blood glucose level >= 11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8-11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models. RESULTS: During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30-6.34) for diabetes, and 4.96 (2.27-10.84) for pre-diabetes. In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre diabetes were neither cross-sectionally nor longitudinally associated with MCI. CONCLUSIONS: Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. The association of diabetes with the development of MCI is less evident in old people. PMID- 20713686 TI - Association between higher serum fetuin-A concentrations and abnormal albuminuria in middle-aged and elderly chinese with normal glucose tolerance. AB - OBJECTIVE: To study the association of serum fetuin-A as a potential risk factor with abnormal albuminuria in Chinese individuals with normal glucose tolerance (NGT). RESEARCH DESIGN AND METHODS: The cross-sectional analysis included 607 men and 1,042 women aged 40 or older with NGT. RESULTS: Women with combined microalbuminuria and macroalbuminuria (n=68) had significantly higher serum fetuin-A concentrations than those with normal albumin excretion (n=974) (314.3 vs. 280.4 mg/l, P=0.007). Compared with the lowest quartile, the highest quartile of serum fetuin-A had 40% increased risk of abnormal albuminuria after the multiple adjustments in women (Pfor trend=0.02). However, the associations were not detected in men. CONCLUSIONS: Higher serum fetuin-A was associated with abnormal albuminuria independent of BMI, waist circumference, homeostasis model assessment of insulin resistance, blood pressure, and other determinants of albuminuria in middle-aged and elderly Chinese women with NGT. PMID- 20713685 TI - Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. AB - OBJECTIVE: Regional differences among adipose depots in capacities for fatty acid storage, susceptibility to hypoxia, and inflammation likely contribute to complications of obesity. We defined the properties of endothelial cells (EC) isolated from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) biopsied in parallel from obese subjects. RESEARCH DESIGN AND METHODS: The architecture and properties of the fat tissue capillary network were analyzed using immunohistochemistry and flow cytometry. CD34(+)/CD31(+) EC were isolated by immunoselection/depletion. Expression of chemokines, adhesion molecules, angiogenic factor receptors, as well as lipogenic and senescence-related genes were assayed by real-time PCR. Fat cell size and expression of hypoxia-dependent genes were determined in adipocytes from both fat depots. RESULTS: Hypoxia related genes were more highly expressed in VAT than SAT adipocytes. VAT adipocytes were smaller than SAT adipocytes. Vascular density and EC abundance were higher in VAT. VAT-EC exhibited a marked angiogenic and inflammatory state with decreased expression of metabolism-related genes, including endothelial lipase, GPIHBP1, and PPAR gamma. VAT-EC had enhanced expression of the cellular senescence markers, IGFBP3 and gamma-H2AX, and decreased expression of SIRT1. Exposure to VAT adipocytes caused more EC senescence-associated beta galactosidase activity than SAT adipocytes, an effect reduced in the presence of vascular endothelial growth factor A (VEGFA) neutralizing antibodies. CONCLUSIONS: VAT-EC exhibit a more marked angiogenic and proinflammatory state than SAT-EC. This phenotype may be related to premature EC senescence. VAT-EC may contribute to hypoxia and inflammation in VAT. PMID- 20713687 TI - Physical activity, adiposity, and diabetes risk in middle-aged and older Chinese population: the Guangzhou Biobank Cohort Study. AB - OBJECTIVE: Physical activity may modify the association of adiposity with type 2 diabetes. We investigated the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose, and type 2 diabetes in a Chinese population. RESEARCH DESIGN AND METHODS: Middle-aged and older Chinese (n=28,946, >=50 years, 72.4%women) from the Guangzhou Biobank Cohort Study were examined in 2003-2008. Multivariable regression was used in a cross-sectional analysis. RESULTS: BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with type 2 diabetes after multiple adjustment, most strongly for WHR with odds ratio (OR) of 3.99 (95% CI 3.60-4.42) for highest compared with lowest tertile. Lack of moderate-to-vigorous physical activity, but not walking, was associated with diabetes with an OR of 1.29 (1.17 1.41). The association of moderate-to-vigorous activity with fasting glucose varied with WHR tertiles (P=0.01 for interaction). Within the high WHR tertile, participants who had a lack of moderate-to-vigorous activity had an OR of 3.87 (3.22-4.65) for diabetes, whereas those who were active had an OR of 2.94 (2.41 3.59). CONCLUSIONS: In this population, WHR was a better measure of adiposity related diabetes risk than BMI or waist circumference. Higher moderate-to vigorous activity was associated with lower diabetes risk, especially in abdominally obese individuals. PMID- 20713688 TI - Estimating indirect genetic effects: precision of estimates and optimum designs. AB - Social interactions among individuals are abundant both in natural and domestic populations. Such social interactions cause phenotypes of individuals to depend on genes carried by other individuals, a phenomenon known as indirect genetic effects (IGE). Because IGEs have drastic effects on the rate and direction of response to selection, knowledge of their magnitude and relationship to direct genetic effects (DGE) is indispensable for understanding response to selection. Very little is known, however, of statistical power and optimum experimental designs for estimating IGEs. This work, therefore, presents expressions for the standard errors of the estimated (co)variances of DGEs and IGEs and identifies optimum experimental designs for their estimation. It also provides an expression for optimum family size and a numerical investigation of optimum group size. Designs with groups composed of two families were optimal and substantially better than designs with groups composed at random with respect to family. Results suggest that IGEs can be detected with ~1000-2000 individuals and/or ~250 500 groups when using optimum designs. Those values appear feasible for agriculture and aquaculture and for the smaller laboratory species. In summary, this work provides the tools to optimize and quantify the required size of experiments aiming to identify IGEs. An R-package SE.IGE is available, which predicts SEs and identifies optimum family and group sizes. PMID- 20713689 TI - Multilevel selection 4: modeling the relationship of indirect genetic effects and group size. AB - Indirect genetic effects (IGE) occur when individual trait values depend on genes in others. With IGEs, heritable variance and response to selection depend on the relationship of IGEs and group size. Here I propose a model for this relationship, which can be implemented in standard restricted maximum likelihood software. PMID- 20713690 TI - Changes in the nuclear envelope environment affect spindle pole body duplication in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae nuclear membrane is part of a complex nuclear envelope environment also containing chromatin, integral and peripheral membrane proteins, and large structures such as nuclear pore complexes (NPCs) and the spindle pole body. To study how properties of the nuclear membrane affect nuclear envelope processes, we altered the nuclear membrane by deleting the SPO7 gene. We found that spo7Delta cells were sickened by the mutation of genes coding for spindle pole body components and that spo7Delta was synthetically lethal with mutations in the SUN domain gene MPS3. Mps3p is required for spindle pole body duplication and for a variety of other nuclear envelope processes. In spo7Delta cells, the spindle pole body defect of mps3 mutants was exacerbated, suggesting that nuclear membrane composition affects spindle pole body function. The synthetic lethality between spo7Delta and mps3 mutants was suppressed by deletion of specific nucleoporin genes. In fact, these gene deletions bypassed the requirement for Mps3p entirely, suggesting that under certain conditions spindle pole body duplication can occur via an Mps3p-independent pathway. These data point to an antagonistic relationship between nuclear pore complexes and the spindle pole body. We propose a model whereby nuclear pore complexes either compete with the spindle pole body for insertion into the nuclear membrane or affect spindle pole body duplication by altering the nuclear envelope environment. PMID- 20713691 TI - A genomic imprinting defect in mice traced to a single gene. AB - Mammalian androgenones have two paternally or sperm-derived genomes. In mice (Mus musculus) they die at peri-implantation due to the misexpression of imprinted genes-the genes that are expressed monoallelically according to the parent of origin. The misexpressions involved are poorly defined. To gain further insight, we examined the causes of midgestation death of embryos with paternal duplication (PatDp) of distal chromosome 7 (dist7), a region replete with imprinted genes. PatDp(dist7) embryos have a similar phenotype to mice with a knockout of a maternally expressed imprinted gene, Ascl2 [achaete-scute complex homolog-like 2 (Drosophila)], and their death at midgestation could result from two inactive paternal copies of this gene. However, other dist7 misexpressions could duplicate this phenotype, and the potential epistatic load is undefined. We show that an Ascl2 transgene is able to promote the development of PatDp(dist7) embryos to term, providing strong evidence that Ascl2 is the only imprinted gene in the genome for which PatDp results in early embryonic death. While some of the defects in perinatal transgenic PatDp(dist7) fetuses were consistent with known misexpressions of dist7 imprinted genes, the overall phenotype indicates a role for additional undefined misexpressions of imprinted genes. This study provides implications for the human imprinting-related fetal overgrowth disorder, Beckwith Wiedemann syndrome. PMID- 20713692 TI - Yin and Yang of histone H2B roles in silencing and longevity: a tale of two arginines. AB - In budding yeast, silent chromatin is defined at the region of telomeres, rDNA loci, and silent mating loci. Although the silent chromatin at different loci shows structural similarity, the underlying mechanism to establish, maintain, and inherit these structures may be fundamentally different. In this study, we found two arginine residues within histone H2B, which are specifically required to maintain either the telomeric or the rDNA silenct chromatin. Arginine 95 (R95) plays a specific role at telomeres, whereas arginine 102 (R102) is required to maintain the silent chromatin at rDNA and to ensure the integrity of rDNA loci by suppressing recombination between rDNA repeats. R95 mutants show enhanced rDNA silencing but a paradoxically low Sir2 protein abundance. Furthermore weakened silencing at telomeres in R95 mutants can be suppressed by a specific SIR3 allele, SIR3-D205N, which increases the affinity of Sir proteins to telomeres, suggesting H2B-R95 may directly mediate telomeric Sir protein-nucleosome interactions. Double mutations of R95 and R102 lead to desilencing of both rDNA and telomeres, indicating both arginines are necessary to ensure integrity of silent chromatin at these loci. Furthermore, mutations of R102 cause accumulation of extrachromosomal rDNA circles and reduce life span, suggesting that histone H2B contributes to longevity. PMID- 20713693 TI - Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM. AB - Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O(2)(*-). ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3 deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m(3)) to 6 mo (100 mg/m(3) total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema. PMID- 20713694 TI - High-throughput screens in diploid cells identify factors that contribute to the acquisition of chromosomal instability. AB - Chromosomal instability and the subsequent genetic mutations are considered to be critical factors in the development of the majority of solid tumors, but the mechanisms by which a stable diploid cell loses the ability to maintain genomic integrity are not well characterized. We have approached this critical issue through the use of high-throughput screens in untransformed diploid epithelial cells. In a screen of a cDNA library, we identified 13 kinases whose overexpression leads to increased ploidy. In a series of shRNA screens, we identified 16 kinases whose loss leads to increased ploidy. In both cDNA and shRNA screens, the majority of hits have not been linked previously to genomic stability. We further show that sustained loss of the shRNA screening hits leads to multipolar spindles and heterogeneous chromosome content, two characteristics of chromosomal instability. Loss of several of the kinases leads to loss of contact inhibition and to anchorage-independent growth, vital traits acquired during tumor development. We anticipate that this work will serve as a template for the comprehensive identification of pathways whose dysregulation can drive tumorigenesis through impaired karyotypic maintenance. PMID- 20713695 TI - Nucleoside diphosphate kinase Nm23-H1 regulates chromosomal stability by activating the GTPase dynamin during cytokinesis. AB - Chromosomal instability and the subsequent genetic mutations are considered to be critical factors in the development of the majority of solid tumors. Here, we describe how the nucleoside diphosphate kinase Nm23-H1, a protein with a known link to cancer progression, regulates a critical step during cytokinesis. Nm23-H1 acts to provide a local source of GTP for the GTPase dynamin. Loss of Nm23-H1 in diploid cells leads to cytokinetic furrow regression, followed by cytokinesis failure and generation of tetraploid cells. Loss of dynamin phenocopies loss of Nm23-H1, and ectopic overexpression of WT dynamin complements the loss of Nm23 H1. In the absence of p53 signaling, the tetraploid cells resulting from loss of Nm23-H1 continue cycling and develop classic hallmarks of tumor cells. We thus provide evidence that the loss of Nm23-H1, an event suspected to promote metastasis, may additionally function at an earlier stage of tumor development to drive the acquisition of chromosomal instability. PMID- 20713696 TI - Temperatures and cyclones strongly associated with economic production in the Caribbean and Central America. AB - Understanding the economic impact of surface temperatures is an important question for both economic development and climate change policy. This study shows that in 28 Caribbean-basin countries, the response of economic output to increased temperatures is structurally similar to the response of labor productivity to high temperatures, a mechanism omitted from economic models of future climate change. This similarity is demonstrated by isolating the direct influence of temperature from that of tropical cyclones, an important correlate. Notably, output losses occurring in nonagricultural production (-2.4%/+1 degrees C) substantially exceed losses occurring in agricultural production (-0.1%/+1 degrees C). Thus, these results suggest that current models of future climate change that focus on agricultural impacts but omit the response of workers to thermal stress may underestimate the global economic costs of climate change. PMID- 20713697 TI - NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. AB - NAD(P)H oxidases (Noxs) produce O(2)(-) and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4(-/-) (c-Nox4(-/-)) mice. Nox4 expression was inhibited in c-Nox4(-/-) mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4(-/-) mice. In response to pressure overload (PO), however, increases in Nox4 expression and O(2)(-) production in mitochondria were abolished in c-Nox4(-/-) mice, and c-Nox4(-/-) mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4(-/-) mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO. PMID- 20713698 TI - Herbivore physiological response to predation risk and implications for ecosystem nutrient dynamics. AB - The process of nutrient transfer through an ecosystem is an important determinant of production, food-chain length, and species diversity. The general view is that the rate and efficiency of nutrient transfer up the food chain is constrained by herbivore-specific capacity to secure N-rich compounds for survival and production. Using feeding trials with artificial food, we show, however, that physiological stress-response of grasshopper herbivores to spider predation risk alters the nature of the nutrient constraint. Grasshoppers facing predation risk had higher metabolic rates than control grasshoppers. Elevated metabolism accordingly increased requirements for dietary digestible carbohydrate-C to fuel heightened energy demands. Moreover, digestible carbohydrate-C comprises a small fraction of total plant tissue-C content, so nutrient transfer between plants and herbivores accordingly becomes more constrained by digestible plant C than by total plant C:N. This shift in herbivore diet to meet the altered nutrient requirement increased herbivore body C:N content, the C:N content of the plant community from which grasshoppers select their diet, and grasshopper fecal C:N content. Chronic predation risk thus alters the quality of animal and plant tissue that eventually enters the detrital pool to become decomposed. Our results demonstrate that herbivore physiology causes C:N requirements and nutrient intake to become flexible, thereby providing a mechanism to explain context dependence in the nature of trophic control over nutrient transfer in ecosystems. PMID- 20713699 TI - Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering. AB - Soluble oligomeric aggregates of the amyloid-beta peptide (Abeta) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Abeta within these aggregates is not known, a beta hairpin conformation is known to be accessible to monomeric Abeta. Here we show that this beta-hairpin is a building block of toxic Abeta oligomers by engineering a double-cysteine mutant (called Abetacc) in which the beta-hairpin is stabilized by an intramolecular disulfide bond. Abeta(40)cc and Abeta(42)cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation specific antibodies used to detect Abeta aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Abetacc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that beta-sheet-containing Abeta(42)cc oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Abeta(42), in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Abeta oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Abeta(42) is more toxic than the shorter Abeta(40), and why certain inherited mutations are linked to protofibril formation and early onset AD. PMID- 20713700 TI - Social interactions, information use, and the evolution of collective migration. AB - Migration of organisms (or cells) is typically an adaptive response to spatiotemporal variation in resources that requires individuals to detect and respond to long-range and noisy environmental gradients. Many organisms, from wildebeest to bacteria, migrate en masse in a process that can involve a vast number of individuals. Despite the ubiquity of collective migration, and the key function it plays in the ecology of many species, it is still unclear what role social interactions play in the evolution of migratory strategies. Here, we explore the evolution of migratory behavior using an individual-based spatially explicit model that incorporates the costs and benefits of obtaining directional cues from the environment and evolvable social interactions among migrating individuals. We demonstrate that collective migratory strategies evolve under a wide range of ecological scenarios, even when social encounters are rare. Although collective migration appears to be a shared navigational process, populations typically consist of small proportions of individuals actively acquiring directional information from their environment, whereas the majorities use a socially facilitated movement behavior. Because many migratory species face severe threat through anthropogenic influences, we also explore the microevolutionary response of migratory strategies to environmental pressures. We predict a gradual decline of migration due to increasing habitat destruction and argue that much greater restoration is required to recover lost behaviors (i.e., a strong hysteresis effect). Our results provide insights into both the proximate and ultimate factors that underlie evolved migratory behavior in nature. PMID- 20713701 TI - Profile of Michael Lynch. PMID- 20713702 TI - Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3 kinase function through the catalytic subunit p110alpha. AB - Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85alpha, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85alpha. The mutant proteins are still able to bind to the catalytic subunits p110alpha and p110beta. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110alpha, and p110alpha is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85alpha and p110alpha while preserving the stabilizing interaction between p85alpha iSH2 and the adapter-binding domain of p110alpha. PMID- 20713703 TI - miR-204 is required for lens and retinal development via Meis2 targeting. AB - MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in the regulation of gene expression. The roles of individual miRNAs in controlling vertebrate eye development remain, however, largely unexplored. Here, we show that a single miRNA, miR-204, regulates multiple aspects of eye development in the medaka fish (Oryzias latipes). Morpholino-mediated ablation of miR-204 expression resulted in an eye phenotype characterized by microphthalmia, abnormal lens formation, and altered dorsoventral (D-V) patterning of the retina, which is associated with optic fissure coloboma. Using a variety of in vivo and in vitro approaches, we identified the transcription factor Meis2 as one of the main targets of miR-204 function. We show that, together with altered regulation of the Pax6 pathway, the abnormally elevated levels of Meis2 resulting from miR-204 inactivation are largely responsible for the observed phenotype. These data provide an example of how a specific miRNA can regulate multiple events in eye formation; at the same time, they uncover an as yet unreported function of Meis2 in the specification of D-V patterning of the retina. PMID- 20713704 TI - Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating modifier. AB - The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators. In contrast, the voltage sensing domain (VSD) was practically not exploited for therapeutic purposes, although it is the target of various toxins. We recently designed unique diphenylamine carboxylates that are powerful Kv7.2 voltage-gated K(+) channel openers or blockers. Here we show that a unique Kv7.2 channel opener, NH29, acts as a nontoxin gating modifier. NH29 increases Kv7.2 currents, thereby producing a hyperpolarizing shift of the activation curve and slowing both activation and deactivation kinetics. In neurons, the opener depresses evoked spike discharges. NH29 dampens hippocampal glutamate and GABA release, thereby inhibiting excitatory and inhibitory postsynaptic currents. Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the external groove formed by the interface of helices S1, S2, and S4 in a way that stabilizes the interaction between two conserved charged residues in S2 and S4, known to interact electrostatically, in the open state of Kv channels. Results indicate that NH29 may operate via a voltage-sensor trapping mechanism similar to that suggested for scorpion and sea anemone toxins. Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels, a feature similar to that of tarantula toxins. Our data provide a structural framework for designing unique gating-modifiers targeted to the VSD of voltage-gated cation channels and used for the treatment of hyperexcitability disorders. PMID- 20713705 TI - beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression. AB - Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of beta1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional beta1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated erbB2 (herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the beta1-integrin-deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as beta1-integrin-null. Animals bearing beta1-integrin-deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, beta1-integrin-deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although beta1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression. PMID- 20713706 TI - Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. AB - Disregulated Wnt/beta-catenin signaling has been linked to various human diseases, including cancers. Inhibitors of oncogenic Wnt signaling are likely to have a therapeutic effect in cancers. LRP5 and LRP6 are closely related membrane coreceptors for Wnt proteins. Using a phage-display library, we identified anti LRP6 antibodies that either inhibit or enhance Wnt signaling. Two classes of LRP6 antagonistic antibodies were discovered: one class specifically inhibits Wnt proteins represented by Wnt1, whereas the second class specifically inhibits Wnt proteins represented by Wnt3a. Epitope-mapping experiments indicated that Wnt1 class-specific antibodies bind to the first propeller and Wnt3a class-specific antibodies bind to the third propeller of LRP6, suggesting that Wnt1- and Wnt3a class proteins interact with distinct LRP6 propeller domains. This conclusion is further supported by the structural functional analysis of LRP5/6 and the finding that the Wnt antagonist Sclerostin interacts with the first propeller of LRP5/6 and preferentially inhibits the Wnt1-class proteins. We also show that Wnt1 or Wnt3a class-specific anti-LRP6 antibodies specifically block growth of MMTV-Wnt1 or MMTV-Wnt3 xenografts in vivo. Therapeutic application of these antibodies could be limited without knowing the type of Wnt proteins expressed in cancers. This is further complicated by our finding that bivalent LRP6 antibodies sensitize cells to the nonblocked class of Wnt proteins. The generation of a biparatopic LRP6 antibody blocks both Wnt1- and Wnt3a-mediated signaling without showing agonistic activity. Our studies provide insights into Wnt-induced LRP5/6 activation and show the potential utility of LRP6 antibodies in Wnt-driven cancer. PMID- 20713707 TI - Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only gene egl-1 in Caenorhabditis elegans. AB - The decision of a cell to undergo programmed cell death is tightly regulated during animal development and tissue homeostasis. Here, we show that the Caenorhabditis elegans Six family homeodomain protein C. elegans homeobox (CEH 34) and the Eyes absent ortholog EYA-1 promote the programmed cell death of a specific pharyngeal neuron, the sister of the M4 motor neuron. Loss of either ceh 34 or eya-1 function causes survival of the M4 sister cell, which normally undergoes programmed cell death. CEH-34 physically interacts with the conserved EYA domain of EYA-1 in vitro. We identify an egl-1 5' cis-regulatory element that controls the programmed cell death of the M4 sister cell and show that CEH-34 binds directly to this site. Expression of the proapoptotic gene egl-1 in the M4 sister cell requires ceh-34 and eya-1 function. We conclude that an evolutionarily conserved complex that includes CEH-34 and EYA-1 directly activates egl-1 expression through a 5' cis-regulatory element to promote the programmed cell death of the M4 sister cell. We suggest that the regulation of apoptosis by Six and Eya family members is conserved in mammals and involved in human diseases caused by mutations in Six and Eya. PMID- 20713708 TI - Tracking, tuning, and terminating microbial physiology using synthetic riboregulators. AB - The development of biomolecular devices that interface with biological systems to reveal new insights and produce novel functions is one of the defining goals of synthetic biology. Our lab previously described a synthetic, riboregulator system that affords for modular, tunable, and tight control of gene expression in vivo. Here we highlight several experimental advantages unique to this RNA-based system, including physiologically relevant protein production, component modularity, leakage minimization, rapid response time, tunable gene expression, and independent regulation of multiple genes. We demonstrate this utility in four sets of in vivo experiments with various microbial systems. Specifically, we show that the synthetic riboregulator is well suited for GFP fusion protein tracking in wild-type cells, tight regulation of toxic protein expression, and sensitive perturbation of stress response networks. We also show that the system can be used for logic-based computing of multiple, orthogonal inputs, resulting in the development of a programmable kill switch for bacteria. This work establishes a broad, easy-to-use synthetic biology platform for microbiology experiments and biotechnology applications. PMID- 20713709 TI - Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. AB - Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding beta(1)-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective beta(1)-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on beta(1) receptors on the ghrelin secreting cells of the stomach. PMID- 20713710 TI - Noninvasive molecular imaging of c-Myc activation in living mice. AB - The cytoplasmic Myc protein (c-Myc) regulates various human genes and is dysregulated in many human cancers. Phosphorylation mediates the protein activation of c-Myc and is essential for the function of this transcription factor in normal cell behavior and tumor growth. To date, however, the targeting of Myc as a therapeutic approach for cancer treatment has been achieved primarily at the nonprotein level. We have developed a molecular imaging sensor for noninvasive imaging of c-Myc activity in living subjects using a split Firefly luciferase (FL) complementation strategy to detect and quantify the phosphorylation-mediated interaction between glycogen synthase kinase 3beta (GSK3beta) and c-Myc. This sensor system consists of two fusion proteins, GSK 35 433-CFL and NFL-c-Myc, in which specific fragments of GSK3beta and c-Myc are fused with C-terminal and N-terminal fragments of the split FL, respectively. The sensor detects phosphorylation-specific GSK3beta-c-Myc interaction, the imaging signal of which correlates with the steady-state and temporal regulation of c-Myc phosphorylation in cell culture. The sensor also detects inhibition of c-Myc activity via differential pathways, allowing noninvasive monitoring of c-Myc targeted drug efficacy in intact cells and living mice. Notably, this drug inhibition is detected before changes in tumor size are apparent in mouse xenograft and liver tumor models. This reporter system not only provides an innovative way to investigate the role of functional c-Myc in normal and cancer related biological processes, but also facilitates c-Myc-targeted drug development by providing a rapid quantitative approach to assessing cancer response to therapy in living subjects. PMID- 20713711 TI - Megafaunal meiolaniid horned turtles survived until early human settlement in Vanuatu, Southwest Pacific. AB - Meiolaniid or horned turtles are members of the extinct Pleistocene megafauna of Australia and the southwest Pacific. The timing and causes of their extinction have remained elusive. Here we report the remains of meiolaniid turtles from cemetery and midden layers dating 3,100/3,000 calibrated years before present to approximately 2,900/2,800 calibrated years before present in the Teouma Lapita archaeological site on Efate in Vanuatu. The remains are mainly leg bones; shell fragments are scant and there are no cranial or caudal elements, attesting to off site butchering of the turtles. The new taxon differs markedly from other named insular terrestrial horned turtles. It is the only member of the family demonstrated to have survived into the Holocene and the first known to have become extinct after encountering humans. PMID- 20713712 TI - Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. AB - Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3 deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala-related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention. PMID- 20713713 TI - Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. AB - The epithelial-to-mesenchymal transition (EMT) produces cancer cells that are invasive, migratory, and exhibit stem cell characteristics, hallmarks of cells that have the potential to generate metastases. Inducers of the EMT include several transcription factors (TFs), such as Goosecoid, Snail, and Twist, as well as the secreted TGF-beta1. Each of these factors is capable, on its own, of inducing an EMT in the human mammary epithelial (HMLE) cell line. However, the interactions between these regulators are poorly understood. Overexpression of each of the above EMT inducers up-regulates a subset of other EMT-inducing TFs, with Twist, Zeb1, Zeb2, TGF-beta1, and FOXC2 being commonly induced. Up regulation of Slug and FOXC2 by either Snail or Twist does not depend on TGF beta1 signaling. Gene expression signatures (GESs) derived by overexpressing EMT inducing TFs reveal that the Twist GES and Snail GES are the most similar, although the Goosecoid GES is the least similar to the others. An EMT core signature was derived from the changes in gene expression shared by up-regulation of Gsc, Snail, Twist, and TGF-beta1 and by down-regulation of E-cadherin, loss of which can also trigger an EMT in certain cell types. The EMT core signature associates closely with the claudin-low and metaplastic breast cancer subtypes and correlates negatively with pathological complete response. Additionally, the expression level of FOXC1, another EMT inducer, correlates strongly with poor survival of breast cancer patients. PMID- 20713714 TI - Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle. AB - The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKalpha2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle. PMID- 20713715 TI - Heterodimeric integrin complexes containing beta1-integrin promote internalization and lethality of anthrax toxin. AB - To kill macrophages, the lethal factor component of Bacillus anthracis toxin binds to a carrier protein (PA), which then interacts with the CMG2 receptor protein on the cell surface and is endocytosed into the cytoplasm. CMG2, as well as TEM8, a second PA receptor not present on macrophages, contain a von Willebrand A domain that is crucial for toxin binding. Here we report that integrin beta1, another cell surface von Willebrand A domain protein, can mediate and potentiate anthrax toxin endocytosis. By using microarray-based analysis to globally correlate gene expression profiles with toxin sensitivity, we associated toxin effects with the integrin-activating proteins osteopontin and CD44. Further study showed that PA binds to alpha4beta1- and alpha5beta1-integrin complexes, leading to their conjoint endocytosis, and also interacts-weakly relative to CMG2 but comparably to TEM8--with purified alpha5beta1 complex in vitro. Monoclonal antibody directed against beta1-integrin or its alpha integrin partners reduced PA/integrin endocytosis and anthrax toxin lethality, and hyaluronic acid--which interferes with CD44-mediated integrin activation--had similar effects. Remarkably, whereas deficiency of CMG2 protected macrophages from rapid killing by large toxin doses (>50 ng/mL), by 24 h the toxin-treated cells were dead. Such late killing of CMG2-deficient cells by high dose toxin as well as the late death observed during exposure of CMG2-producing macrophages to low-dose toxin (<1 ng/mL), was dependent on integrin function. Effects of inactivating both CMG2 and integrin were synergistic. Collectively, our findings argue strongly that beta1 integrin can both potentiate CMG2-mediated endocytosis and serve independently as a low-affinity PA receptor. PMID- 20713716 TI - Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection. AB - Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast, S. Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknown Salmonella virulence determinants, including Salmonella Pathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication of S. Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights into S. Typhi pathogenesis and devise strategies for the prevention of typhoid fever. PMID- 20713717 TI - Short-term meditation induces white matter changes in the anterior cingulate. AB - The anterior cingulate cortex (ACC) is part of a network implicated in the development of self-regulation and whose connectivity changes dramatically in development. In previous studies we showed that 3 h of mental training, based on traditional Chinese medicine (integrative body-mind training, IBMT), increases ACC activity and improves self-regulation. However, it is not known whether changes in white matter connectivity can result from small amounts of mental training. We here report that 11 h of IBMT increases fractional anisotropy (FA), an index indicating the integrity and efficiency of white matter in the corona radiata, an important white-matter tract connecting the ACC to other structures. Thus IBMT could provide a means for improving self-regulation and perhaps reducing or preventing various mental disorders. PMID- 20713718 TI - Uterine FK506-binding protein 52 (FKBP52)-peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress. AB - Immunophilin FK506-binding protein 52 (FKBP52) is a cochaperone that binds to the progesterone receptor (PR) to optimize progesterone (P(4))-PR signaling. We recently showed that Fkbp52-deficient (Fkbp52(-/-)) mice have reduced uterine PR responsiveness and implantation failure which is rescued by excess P(4) supplementation in a genetic background-dependent manner. This finding led us to hypothesize that FKBP52 has functions in addition to optimizing PR activity. Using proteomics analysis, we found that uterine levels of peroxiredoxin-6 (PRDX6), a unique antioxidant, are significantly lower in Fkbp52(-/-) mice than in WT and PR-null (Pgr(-/-)) mice. We also found that Fkbp52(-/-) mice with reduced uterine PRDX6 levels are susceptible to paraquat-induced oxidative stress (OS), leading to implantation failure even with P(4) supplementation. The same dose of paraquat did not interfere with implantation in WT mice. Moreover, treatment with antioxidants alpha-tocopherol and N-acetylcysteine (NAC) attenuated paraquat-induced implantation failure in P(4)-treated Fkbp52(-/-) mice. Functional analyses using mouse embryonic fibroblasts show that Fkbp52 deficiency associated with reduced PRDX6 levels promotes H(2)O(2)-induced cell death, which is reversed by the addition of NAC or by forced expression of PRDX6, suggesting that Fkbp52 deficiency diminishes the threshold against OS by reducing PRDX6 levels. These findings provide evidence that heightened uterine OS in Fkbp52(-/-) females with reduced PRDX6 levels induces implantation failure even in the presence of excess P(4). This study shows that FKBP52-PRDX6 signaling protects pregnancy from overt OS. PMID- 20713719 TI - Neuropeptide receptor positive allosteric modulation in epilepsy: galanin modulation revealed. PMID- 20713720 TI - Myonuclei acquired by overload exercise precede hypertrophy and are not lost on detraining. AB - Effects of previous strength training can be long-lived, even after prolonged subsequent inactivity, and retraining is facilitated by a previous training episode. Traditionally, such "muscle memory" has been attributed to neural factors in the absence of any identified local memory mechanism in the muscle tissue. We have used in vivo imaging techniques to study live myonuclei belonging to distinct muscle fibers and observe that new myonuclei are added before any major increase in size during overload. The old and newly acquired nuclei are retained during severe atrophy caused by subsequent denervation lasting for a considerable period of the animal's lifespan. The myonuclei seem to be protected from the high apoptotic activity found in inactive muscle tissue. A hypertrophy episode leading to a lasting elevated number of myonuclei retarded disuse atrophy, and the nuclei could serve as a cell biological substrate for such memory. Because the ability to create myonuclei is impaired in the elderly, individuals may benefit from strength training at an early age, and because anabolic steroids facilitate more myonuclei, nuclear permanency may also have implications for exclusion periods after a doping offense. PMID- 20713722 TI - Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. AB - Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5' exon (P = 1.097E(-12) to 1.445E(-15)). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association. PMID- 20713723 TI - TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. AB - The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N'-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to mesenchymal transition (EMT). We showed that activation of TGF-beta-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-beta-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-beta are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR. PMID- 20713724 TI - Public perceptions of energy consumption and savings. AB - In a national online survey, 505 participants reported their perceptions of energy consumption and savings for a variety of household, transportation, and recycling activities. When asked for the most effective strategy they could implement to conserve energy, most participants mentioned curtailment (e.g., turning off lights, driving less) rather than efficiency improvements (e.g., installing more efficient light bulbs and appliances), in contrast to experts' recommendations. For a sample of 15 activities, participants underestimated energy use and savings by a factor of 2.8 on average, with small overestimates for low-energy activities and large underestimates for high-energy activities. Additional estimation and ranking tasks also yielded relatively flat functions for perceived energy use and savings. Across several tasks, participants with higher numeracy scores and stronger proenvironmental attitudes had more accurate perceptions. The serious deficiencies highlighted by these results suggest that well-designed efforts to improve the public's understanding of energy use and savings could pay large dividends. PMID- 20713725 TI - Profile of Charles M. Newman. PMID- 20713726 TI - Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. AB - Both increase and decrease of cardiac inward rectifier current (I(K1)) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease I(K1) (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide induced increase of the current generated by Kir2.1 channels (I(Kir2.1)) and I(K1) recorded in ventricular myocytes. Flecainide increases outward I(Kir2.1) generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase I(Kir2.2) and I(Kir2.3), because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification. PMID- 20713727 TI - Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice. AB - Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are a leading cause of untreatable blindness with substantive impact on the quality of life of affected individuals and their families. Mouse mutants with retinal dystrophies have provided a valuable resource to discover human disease genes and helped uncover pathways critical for photoreceptor function. Here we show that the rd11 mouse mutant and its allelic strain, B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by degeneration of both rods and cones. Using linkage analysis, we mapped the rd11 locus to mouse chromosome 13. We then identified a one-nucleotide insertion (c.420-421insG) in exon 3 of the Lpcat1 gene. Subsequent screening of this gene in the B6-JR2845 strain revealed a seven-nucleotide deletion (c.14-20delGCCGCGG) in exon 1. Both sequence changes are predicted to result in a frame-shift, leading to premature truncation of the lysophosphatidylcholine acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoylphosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 and B6-JR2845 mice showed substantially reduced DPPC levels compared with C57BL/6J control mice, suggesting a causal link to photoreceptor dysfunction. A follow-up screening of LPCAT1 in retinitis pigmentosa and Leber congenital amaurosis patients did not reveal any obvious disease-causing mutations. Previously, LPCAT1 has been suggested to be critical for the production of lung surfactant phospholipids and biosynthesis of platelet-activating factor in noninflammatory remodeling pathway. Our studies add another dimension to an essential role for LPCAT1 in retinal photoreceptor homeostasis. PMID- 20713728 TI - Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein. AB - Fragile X syndrome is caused by the absence of functional fragile X mental retardation protein (FMRP), an RNA binding protein. The molecular mechanism of aberrant protein synthesis in fmr1 KO mice is closely associated with the role of FMRP in mRNA transport, delivery, and local protein synthesis. We show that GFP labeled Fmr1 and CaMKIIalpha mRNAs undergo decelerated motion at 0-40 min after group I mGluR stimulation, and later recover at 40-60 min. Then we investigate targeting of mRNAs associated with FMRP after neuronal stimulation. We find that FMRP is synthesized closely adjacent to stimulated mGluR5 receptors. Moreover, in WT neurons, CaMKIIalpha mRNA can be delivered and translated in dendritic spines within 10 min in response to group I mGluR stimulation, whereas KO neurons fail to show this response. These data suggest that FMRP can mediate spatial mRNA delivery for local protein synthesis in response to synaptic stimulation. PMID- 20713729 TI - Quantitative phosphoproteomic analysis reveals cAMP/vasopressin-dependent signaling pathways in native renal thick ascending limb cells. AB - Quantitative mass spectrometry was used to identify hormone-dependent signaling pathways in renal medullary thick ascending limb (mTAL) cells via phosphoproteomic analysis. Active transport of NaCl across the mTAL epithelium is accelerated by hormones that increase cAMP levels (vasopressin, glucagon, parathyroid hormone, and calcitonin). mTAL suspensions from rat kidneys were exposed (15 min) to a mixture of these four hormones. Tryptic phosphopeptides (immobilized metal affinity chromatography-enriched) were identified and quantified by mass spectrometry (LTQ-Orbitrap) using label-free methodology. We quantified a total of 654 phosphopeptides, of which 414 were quantified in three experimental pairs (hormone vs. vehicle). Of these phosphopeptides, 82% were statistically unchanged in abundance in response to the hormone mixture. In contrast, 48 phosphopeptides were significantly increased, whereas 28 were significantly decreased. The population of up-regulated phosphopeptides was highly enriched in basophilic kinase substrate motifs (AGC or calmodulin sensitive kinase families), whereas the down-regulated sites were dominated by "proline-directed" motifs (cyclin-dependent or MAP kinase families). Bioinformatic classification uncovered overrepresentation of transmembrane transporters, protein phosphatase regulators, and cytoskeletal binding proteins among the regulated proteins. Immunoblotting with phospho-specific antibodies confirmed cAMP/vasopressin-dependent phosphorylation at Thr96, Ser126, and Ser874 of the Na(+):K(+):2Cl(-) cotransporter NKCC2, at Ser552 of the Na(+):H(+) exchanger NHE3, and at Ser552 of beta-catenin. Vasopressin also increased phosphorylation of NKCC2 at both Ser126 (more than fivefold) and Ser874 (more than threefold) in rats in vivo. Both sites were phosphorylated by purified protein kinase A during in vitro assays. These results support the view that, although protein kinase A plays a central role in mTAL signaling, additional kinases, including those that target proline-directed motifs, may be involved. PMID- 20713730 TI - New strategy for the synthesis of chemically modified RNA constructs exemplified by hairpin and hammerhead ribozymes. AB - The CuAAC reaction (click chemistry) has been used in conjunction with solid phase synthesis to produce catalytically active hairpin ribozymes around 100 nucleotides in length. Cross-strand ligation through neighboring nucleobases was successful in covalently linking presynthesized RNA strands with high efficiency (trans-ligation). In an alternative strategy, intrastrand click ligation was employed to produce a functional hammerhead ribozyme containing a novel nucleic acid backbone mimic at the catalytic site (cis-ligation). The ability to synthesize long RNA strands by a combination of solid-phase synthesis and click ligation is an important addition to RNA chemistry. It is compatible with a plethora of site-specific modifications and is applicable to the synthesis of many biologically important RNA molecules. PMID- 20713731 TI - Dynamical organization of the cytoskeletal cortex probed by micropipette aspiration. AB - Bleb-based cell motility proceeds by the successive inflation and retraction of large spherical membrane protrusions ("blebs") coupled with substrate adhesion. In addition to their role in motility, cellular blebs constitute a remarkable illustration of the dynamical interactions between the cytoskeletal cortex and the plasma membrane. Here we study the bleb-based motions of Entamoeba histolytica in the constrained geometry of a micropipette. We construct a generic theoretical model that combines the polymerization of an actin cortex underneath the plasma membrane with the myosin-generated contractile stress in the cortex and the stress-induced failure of membrane-cortex adhesion. One major parameter dictating the cell response to micropipette suction is the stationary cortex thickness, controlled by actin polymerization and depolymerization. The other relevant physical parameters can be combined into two characteristic cortex thicknesses for which the myosin stress (i) balances the suction pressure and (ii) provokes membrane-cortex unbinding. We propose a general phase diagram for cell motions inside a micropipette by comparing these three thicknesses. In particular, we theoretically predict and experimentally verify the existence of saltatory and oscillatory motions for a well-defined range of micropipette suction pressures. PMID- 20713732 TI - A family of diiron monooxygenases catalyzing amino acid beta-hydroxylation in antibiotic biosynthesis. AB - The biosynthesis of chloramphenicol requires a beta-hydroxylation tailoring reaction of the precursor L-p-aminophenylalanine (L-PAPA). Here, it is shown that this reaction is catalyzed by the enzyme CmlA from an operon containing the genes for biosynthesis of L-PAPA and the nonribosomal peptide synthetase CmlP. EPR, Mossbauer, and optical spectroscopies reveal that CmlA contains an oxo-bridged dinuclear iron cluster, a metal center not previously associated with nonribosomal peptide synthetase chemistry. Single-turnover kinetic studies indicate that CmlA is functional in the diferrous state and that its substrate is L-PAPA covalently bound to CmlP. Analytical studies show that the product is hydroxylated L-PAPA and that O(2) is the oxygen source, demonstrating a monooxygenase reaction. The gene sequence of CmlA shows that it utilizes a lactamase fold, suggesting that the diiron cluster is in a protein environment not previously known to effect monooxygenase reactions. Notably, CmlA homologs are widely distributed in natural product biosynthetic pathways, including a variety of pharmaceutically important beta-hydroxylated antibiotics and cytostatics. PMID- 20713733 TI - Direct mapping of nanoscale compositional connectivity on intact cell membranes. AB - Lateral segregation of cell membranes is accepted as a primary mechanism for cells to regulate a diversity of cellular functions. In this context, lipid rafts have been conceptualized as organizing principle of biological membranes where underlying cholesterol-mediated selective connectivity must exist even at the resting state. However, such a level of nanoscale compositional connectivity has been challenging to prove. Here we used single-molecule near-field scanning optical microscopy to visualize the nanolandscape of raft ganglioside GM1 after tightening by its ligand cholera toxin (CTxB) on intact cell membranes. We show that CTxB tightening of GM1 is sufficient to initiate a minimal raft coalescence unit, resulting in the formation of cholesterol-dependent GM1 nanodomains < 120 nm in size. This particular arrangement appeared independent of cell type and GM1 expression level on the membrane. Simultaneous dual color high-resolution images revealed that GPI anchored and certain transmembrane proteins were recruited to regions proximal (< 150 nm) to CTxB-GM1 nanodomains without physical intermixing. Together with in silico experiments, our high-resolution data conclusively demonstrate the existence of raft-based interconnectivity at the nanoscale. Such a linked state on resting cell membranes constitutes thus an obligatory step toward the hierarchical evolution of large-scale raft coalescence upon cell activation. PMID- 20713734 TI - Comparative surface dynamics of amorphous and semicrystalline polymer films. AB - The surface dynamics of amorphous and semicrystalline polymer films have been measured using helium atom scattering. Time-of-flight data were collected to resolve the elastic and inelastic scattering components in the diffuse scattering of neutral helium atoms from the surface of a thin poly(ethylene terephthalate) film. Debye-Waller attenuation was observed for both the amorphous and semicrystalline phases of the polymer by recording the decay of elastically scattered helium atoms with increasing surface temperature. Thermal attenuation measurements in the specular scattering geometry yielded perpendicular mean square displacements of 2.7*10(-4) A(2) K(-1) and 3.1*10(-4) A(2) K(-1) for the amorphous and semicrystalline surfaces, respectively. The semicrystalline surface was consistently ~15% softer than the amorphous across a variety of perpendicular momentum transfers. The Debye-Waller factors were also measured at off-specular angles to characterize the parallel mean-square displacements, which were found to increase by an order of magnitude over the perpendicular mean-square displacements for both surfaces. In contrast to the perpendicular motion, the semicrystalline state was ~25% stiffer than the amorphous phase in the surface plane. These results were uniquely accessed through low-energy neutral helium atom scattering due to the highly surface-sensitive and nonperturbative nature of these interactions. The goal of tailoring the chemical and physical properties of complex advanced materials requires an improved understanding of interfacial dynamics, information that is obtainable through atomic beam scattering methods. PMID- 20713735 TI - PCNA function in the activation and strand direction of MutLalpha endonuclease in mismatch repair. AB - MutLalpha (MLH1-PMS2) is a latent endonuclease that is activated in a mismatch-, MutSalpha-, proliferating cell nuclear antigen (PCNA)-, replication factor C (RFC)-, and ATP-dependent manner, with nuclease action directed to the heteroduplex strand that contains a preexisting break. RFC depletion experiments and use of linear DNAs indicate that RFC function in endonuclease activation is limited to PCNA loading. Whereas nicked circular heteroduplex DNA is a good substrate for PCNA loading and for endonuclease activation on the incised strand, covalently closed, relaxed circular DNA is a poor substrate for both reactions. However, covalently closed supercoiled or bubble-containing relaxed heteroduplexes, which do support PCNA loading, also support MutLalpha activation, but in this case cleavage strand bias is largely abolished. Based on these findings we suggest that PCNA has two roles in MutLalpha function: The clamp is required for endonuclease activation, an effect that apparently involves interaction of the two proteins, and by virtue of its loading orientation, PCNA determines the strand direction of MutLalpha incision. These results also provide a potential mechanism for activation of mismatch repair on nonreplicating DNA, an effect that may have implications for the somatic phase of triplet repeat expansion. PMID- 20713736 TI - Accelerated warming of the Southern Ocean and its impacts on the hydrological cycle and sea ice. AB - The observed sea surface temperature in the Southern Ocean shows a substantial warming trend for the second half of the 20th century. Associated with the warming, there has been an enhanced atmospheric hydrological cycle in the Southern Ocean that results in an increase of the Antarctic sea ice for the past three decades through the reduced upward ocean heat transport and increased snowfall. The simulated sea surface temperature variability from two global coupled climate models for the second half of the 20th century is dominated by natural internal variability associated with the Antarctic Oscillation, suggesting that the models' internal variability is too strong, leading to a response to anthropogenic forcing that is too weak. With increased loading of greenhouse gases in the atmosphere through the 21st century, the models show an accelerated warming in the Southern Ocean, and indicate that anthropogenic forcing exceeds natural internal variability. The increased heating from below (ocean) and above (atmosphere) and increased liquid precipitation associated with the enhanced hydrological cycle results in a projected decline of the Antarctic sea ice. PMID- 20713737 TI - An explanation for conflicting records of Triassic-Jurassic plant diversity. AB - Macrofossils (mostly leaves) and sporomorphs (pollen and spores) preserve conflicting records of plant biodiversity during the end-Permian (P-Tr), Triassic Jurassic (Tr-J), and end-Cretaceous (K-T) mass extinctions. Estimates of diversity loss based on macrofossils are typically much higher than estimates of diversity loss based on sporomorphs. Macrofossils from the Tr-J of East Greenland indicate that standing species richness declined by as much as 85% in the Late Triassic, whereas sporomorph records from the same region, and from elsewhere in Europe, reveal little evidence of such catastrophic diversity loss. To understand this major discrepancy, we have used a new high-resolution dataset of sporomorph assemblages from Astartekloft, East Greenland, to directly compare the macrofossil and sporomorph records of Tr-J plant biodiversity. Our results show that sporomorph assemblages from the Tr-J boundary interval are 10-12% less taxonomically diverse than sporomorph assemblages from the Late Triassic, and that vegetation composition changed rapidly in the boundary interval as a result of emigration and/or extirpation of taxa rather than immigration and/or origination of taxa. An analysis of the representation of different plant groups in the macrofossil and sporomorph records at Astartekloft reveals that reproductively specialized plants, including cycads, bennettites and the seed fern Lepidopteris are almost absent from the sporomorph record. These results provide a means of reconciling the macrofossil and sporomorph records of Tr-J vegetation change, and may help to understand vegetation change during the P-Tr and K-T mass extinctions and around the Paleocene-Eocene Thermal Maximum. PMID- 20713738 TI - Amphiphile regulation of ion channel function by changes in the bilayer spring constant. AB - Many drugs are amphiphiles that, in addition to binding to a particular target protein, adsorb to cell membrane lipid bilayers and alter intrinsic bilayer physical properties (e.g., bilayer thickness, monolayer curvature, and elastic moduli). Such changes can modulate membrane protein function by altering the energetic cost (DeltaG(bilayer)) of bilayer deformations associated with protein conformational changes that involve the protein-bilayer interface. But amphiphiles have complex effects on the physical properties of lipid bilayers, meaning that the net change in DeltaG(bilayer) cannot be predicted from measurements of isolated changes in such properties. Thus, the bilayer contribution to the promiscuous regulation of membrane proteins by drugs and other amphiphiles remains unknown. To overcome this problem, we use gramicidin A (gA) channels as molecular force probes to measure the net effect of amphiphiles, at concentrations often used in biological research, on the bilayer elastic response to a change in the hydrophobic length of an embedded protein. The effects of structurally diverse amphiphiles can be described by changes in a phenomenological bilayer spring constant (H(B)) that summarizes the bilayer elastic properties, as sensed by a bilayer-spanning protein. Amphiphile-induced changes in H(B), measured using gA channels of a particular length, quantitatively predict changes in lifetime for channels of a different length--as well as changes in the inactivation of voltage-dependent sodium channels in living cells. The use of gA channels as molecular force probes provides a tool for quantitative, predictive studies of bilayer-mediated regulation of membrane protein function by amphiphiles. PMID- 20713739 TI - Proton and cation transport activity of the M2 proton channel from influenza A virus. AB - The M2 protein is a small, single-span transmembrane (TM) protein from the influenza A virus. This virus enters cells via endosomes; as the endosomes mature and become more acidic M2 facilitates proton transport into the viral interior, thereby disrupting matrix protein/RNA interactions required for infectivity. A mystery has been how protons can accumulate in the viral interior without developing a large electrical potential that impedes further inward proton translocation. Progress in addressing this question has been limited by the availability of robust methods of unidirectional insertion of the protein into virus-like vesicles. Using an optimized procedure for reconstitution, we show that M2 has antiporter-like activity, facilitating K(+) or Na(+) efflux when protons flow down a concentration gradient into the vesicles. Cation efflux is very small except under conditions mimicking those encountered by the endosomally entrapped virus, in which protons are flowing through the channel. This proton/cation exchange function is consistent with the known high proton selectivity of the channel. Thus, M2 acts as a proton uniporter that occasionally allows K(+) to flow to maintain electrical neutrality. Remarkably, as the pH inside M2-containing vesicles (pH(in)) decreases, the proton channel activity of M2 is inhibited, but its cation transport activity is activated. This reciprocal inhibition of proton flux and activation of cation flux with decreasing pH(in) first allows accumulation of protons in the early stages of acidification, then trapping of protons within the virus when low pH(in) is achieved. PMID- 20713743 TI - The distinction between recoding and codon reassignment. PMID- 20713740 TI - Mechanism for pH-dependent gene regulation by amino-terminus-mediated homooligomerization of Bacillus subtilis anti-trp RNA-binding attenuation protein. AB - Anti-TRAP (AT) is a small zinc-binding protein that regulates tryptophan biosynthesis in Bacillus subtilis by binding to tryptophan-bound trp RNA-binding attenuation protein (TRAP), thereby preventing it from binding RNA, and allowing transcription and translation of the trpEDCFBA operon. Crystallographic and sedimentation studies have shown that AT can homooligomerize to form a dodecamer, AT(12), composed of a tetramer of trimers, AT(3). Structural and biochemical studies suggest that only trimeric AT is active for binding to TRAP. Our chromatographic and spectroscopic data revealed that a large fraction of recombinantly overexpressed AT retains the N-formyl group (fAT), presumably due to incomplete N-formyl-methionine processing by peptide deformylase. Hydrodynamic parameters from NMR relaxation and diffusion measurements showed that fAT is exclusively trimeric (AT(3)), while (deformylated) AT exhibits slow exchange between both trimeric and dodecameric forms. We examined this equilibrium using NMR spectroscopy and found that oligomerization of active AT(3) to form inactive AT(12) is linked to protonation of the amino terminus. Global analysis of the pH dependence of the trimer-dodecamer equilibrium revealed a near physiological pK(a) for the N-terminal amine of AT and yielded a pH-dependent oligomerization equilibrium constant. Estimates of excluded volume effects due to molecular crowding suggest the oligomerization equilibrium may be physiologically important. Because deprotonation favors "active" trimeric AT and protonation favors "inactive" dodecameric AT, our findings illuminate a possible mechanism for sensing and responding to changes in cellular pH. PMID- 20713742 TI - Mutagenesis as a genetic research strategy. AB - Morgan's three students (Muller, Sturtevant, and Bridges) introduced reductionist empirical methods to the study of the chromosomal theory of heredity. Herman J. Muller concentrated on mutations, namely changes in the heterocatalytic properties of genes, without losing their autocatalytic (self-replication) properties. Experimental induction of mutations allowed quantitative analyses of genes' parameters, but hopes to deduce their chemicophysical character were never fulfilled. Once the model for DNA structure was proposed, the reductionist notions of mutation analysis were successfully applied to the molecular genes. However, it was soon realized that the concept of the particulate gene was inadequate. The more the molecular analysis of the genome advanced, the clearer it became that the entities of heredity must be conceived within systems' perspectives, for which special tools for handling large number of variables were developed. Analytic mutagenesis, however, continues to be a major strategy for the study of the cellular and chromosomal mechanisms that control mutation inductions. PMID- 20713744 TI - Genetics computer teaching simulation programs: promise and problems. PMID- 20713746 TI - Male sexual assault and rape: who seeks counseling? AB - This work rests on responses from 219 male sexual assault and rape victims who self-reported their victimization in the 1994-1996 Violence and Threats of Violence Against Women and Men in the United States survey. The authors expected that men who reported being severely assaulted would be more likely than others to seek counseling. They defined severely assaulted as having been penetrated, assaulted with a weapon, threatened, self-reported sustaining physical injuries, sought medical care, and/or reported the assault to the police. However, in their logistic model that explores who sought counseling, only one variable was significant. The odds of seeking counseling for men who reported being penetrated had significantly lower odds of seeking counseling all else equal. PMID- 20713747 TI - A trial of voluntary polygraphy testing in 10 english probation areas. AB - Sex offenders taking part in treatment programs in 10 probations areas of England were asked to undertake polygraph testing on a voluntary basis. Over a 2-year period 347 offenders attended for testing (43% of those eligible). Outcome was compared with offenders from four probation areas where polygraphy was not introduced. Case managers of polygraphed offenders reported new disclosures relevant to supervision being made in 70% of first tests, compared with 14% of case managers of nonpolygraphed offenders who reported new disclosures in the preceding months (odds ratio [OR] = 14.4, confidence interval [CI] = 8.5, 24.5). Of the disclosures made during polygraph testing, 27% were rated as being of "medium" severity and 10% "high." Polygraph and nonpolygraph case managers reported making revisions in risk assessment with similar frequency, but nonpolygraph case managers were much more likely to consider risk to have reduced while changes in risk assessment made by polygraph case managers were usually upwards (OR = 5.0, CI = 1.7, 14.6). Case managers of polygraph offenders reported more treatment changes than case managers of the comparison group (OR = 3.1, CI = 1.6, 6.0), which were attributable to the polygraph test. Case managers rated polygraphy as "somewhat" or "very" helpful after 93% of tests for which we had information. PMID- 20713749 TI - Victims' routine activities and sex offenders' target selection scripts: a latent class analysis. AB - This study investigates target selection scripts of 72 serial sex offenders who have committed a total of 361 sex crimes on stranger victims. Using latent class analysis, three target selection scripts were identified based on the victim's activities prior to the crime, each presenting two different tracks: (1) the Home script, which includes the (a) intrusion track and the (b) invited track, (2) the Outdoor script, which includes the (a) noncoercive track and the (b) coercive track, and (3) the Social script, which includes the (a) onsite track and the (b) off-site track. The scripts identified appeared to be used by both sexual aggressors of children and sexual aggressors of adults. In addition, a high proportion of crime switching was found among the identified scripts, with half of the 72 offenders switching scripts at least once. The theoretical relevance of these target selection scripts and their practical implications for situational crime prevention strategies are discussed. PMID- 20713748 TI - Sexual murderers with adult or child victims: are they different? AB - This study investigates characteristics differentiating sexually motivated murderers targeting child victims (CV; n = 35) from those with only adult victims (AV; n = 100). In the initial phase, psychiatric court reports were evaluated using standardized instruments (SCID-II, PCL-R, HCR-20, SVR-20, Static-99). In the second phase, data on duration of detention and reconviction rates were obtained from German federal criminal records. The CV group showed more often diagnostic criteria of pedophilia (43% vs. 4%) and less often alcohol abuse and drug dependency (31% vs. 55%), sexual dysfunctions (9% vs. 29%) and narcissistic personality disorder (0% vs. 13%). No significant differences were found regarding PCL-R and total risk assessment scores. Child victim perpetrators were more likely to have committed acts of sexual child abuse before the sexual homicide (46% vs. 16%) but were less likely to have committed rape or sexual assault (17% vs. 42%) or caused bodily injury (26% vs. 50%). The CV group was detained more frequently in forensic psychiatric hospitals (59% vs. 26%), but the two groups showed the same rates of release and reconviction for sexual (22% for both groups), nonsexual violent (CV 25% vs. AV 15%) and nonviolent offenses (CV 63% vs. AV 59%). Although well-known differences between nonhomicidal sexual child abusers and rapists were replicated in this study on sexual homicide perpetrators, the groups showed more similarities than differences. The high prevalence of violence and antisocial personality disorder in both groups seem to be important risk factors for committing a (sexual) homicide and might have outweighed other differences. PMID- 20713751 TI - Dexamethasone administration and postoperative bleeding risk in children undergoing tonsillectomy. AB - OBJECTIVE: To assess whether administration of dexamethasone during tonsillectomy is associated with a dose-dependent increased rate of postoperative tonsillectomy hemorrhage. DESIGN: Retrospective review of 2788 children and adolescents who underwent tonsillectomy with or without adenoidectomy for sleep-disordered breathing or infectious tonsillitis and received perioperative dexamethasone between January 1, 2002, and March 3, 2009. Patients underwent 1 of 3 methods of tonsillectomy, including extracapsular electrosurgical tonsillectomy, extracapsular radiofrequency ablation tonsillectomy, or intracapsular microdebrider tonsillotomy. SETTING: Massachusetts Eye and Ear Infirmary. PATIENTS: Two thousand seven hundred eighty-eight children and adolescents aged 2 to 18 years (hereinafter referred to as children) who underwent tonsillectomy with or without adenoidectomy. INTERVENTIONS: Each child received 1 of 2 distinct intravenous doses of perioperative dexamethasone (0.5 mg/kg or 1.0 mg/kg) based on the protocol of the surgeon who performed the tonsillectomy; other aspects of care, including anesthetic technique, perioperative analgesia, and postoperative care, were equivalent between children. MAIN OUTCOME MEASURES: Occurrence of postoperative hemorrhage based on 3 severity stratification levels. RESULTS: Ninety-four of the 2788 children experienced 104 episodes of postoperative hemorrhage. After adjusting for age, sex, primary diagnosis, and surgical technique, the odds ratio of experiencing a postoperative hemorrhage of any severity in children who received the 1.0-mg/kg compared with the 0.5-mg/kg dose was 0.66 (95% confidence interval [CI], 0.42-1.05). Children requiring readmission with or without the need for operative intervention demonstrated an adjusted odds ratio of 0.83 (95% CI, 0.51-1.36). An adjusted odds ratio of 0.71 (95% CI, 0.39-1.28) was seen in children requiring operative intervention. CONCLUSION: In this observational review of children undergoing tonsillectomy or adenotonsillectomy, perioperative dexamethasone administration is not associated with a dose-dependent elevation of postoperative hemorrhage rates after adjusting for age, sex, primary diagnosis, and surgical technique. PMID- 20713752 TI - Short hospital stay following neck dissection. AB - OBJECTIVES: To review the clinical characteristics of patients who had a short hospital stay (<24 hours) following neck dissection, and to assess the incidence and type of complications in this patient group. DESIGN: Case series. SETTING: University-based academic medical center. PATIENTS: All patients who underwent neck dissection at our institution from July 2004 through June 2008 and were discharged within 24 hours postoperatively (short stay) were included. MAIN OUTCOME MEASURES: Patient demographics, cancer site and type, and details of the procedures performed were quantified. In addition, medical records were reviewed for complications requiring readmission within 30 days postoperatively. RESULTS: Review of a prospectively maintained surgical database identified 122 consecutive neck dissections performed at our institution from July 1, 2004, to June 30, 2008. Of these 122 procedures, 71 involved a subsequent postoperative stay of less than 24 hours. These 71 procedures were performed in 69 patients; they had a mean age of 59 years and a sex distribution that was 33% female and 67% male. Neck dissection alone was performed in 22 of the 71 short-stay cases (31%). The most commonly performed concurrent procedures included limited oral cavity or oropharyngeal resections (21 patients) and parotidectomy (13 patients). Modified radical neck dissection was performed in 22 of the 71 cases (31%); the remaining procedures were selective neck dissections. Cranial nerve XI, the internal jugular vein, and the sternocleidomastoid muscle were all preserved in 57 cases (80%). Of the 71 short-stay cases, only 2 (3%) required readmission for a surgical complication within 30 days of their procedure. CONCLUSIONS: In carefully selected patients, discharge within 24 hours following neck dissection seems to be safe and appropriate. Given the potential for substantial cost savings, short stay should be studied further in this patient population. PMID- 20713753 TI - Foregut duplication cysts in the head and neck: presentation, diagnosis, and management. AB - OBJECTIVE: To review the presentation, diagnosis, and management of foregut duplication cysts of the head and neck in our institution. DESIGN: An institutional review board-approved retrospective review of all patients treated for foregut duplication cysts of the head and neck over an 18-year period. SETTING: Pediatric otolaryngology tertiary referral center. PATIENTS: Twenty-two patients with 23 pathologically confirmed foregut duplication cysts of the head and neck were identified. Fourteen patients (64%) were male. The median age at diagnosis was 1.5 years (age range, 5 days to 7 years). MAIN OUTCOME MEASURES: Clinical data, including age, presenting symptoms, anatomical site(s), evaluation, treatment, and complication, were recorded and analyzed. RESULTS: Presentation varied depending on anatomical site of involvement, with 12 patients (55%) being asymptomatic. The cysts were found in the oral cavity (n = 12), oropharynx (n = 6), supraglottis (n = 2), and neck (n = 3). Imaging, which was performed in 13 patients and consisted of magnetic resonance imaging (n = 8), computed tomography (n = 5), and ultrasonography (n = 1), demonstrated the cystic nature of the lesions. All patients underwent surgical excision, which focused on excising the cyst, while preserving surrounding normal tissues. No patient demonstrated recurrence at follow-up. CONCLUSIONS: Foregut duplication cysts of the head and neck, although uncommon, should be included in the differential diagnosis of cystic head and neck lesions. Preoperative imaging is recommended to differentiate these lesions from other congenital head and neck masses. Surgical excision biopsy with complete removal of the mucosal lining is curative, with no instances of recurrence in our series. PMID- 20713754 TI - Consequence of dysphagia in the hospitalized patient: impact on prognosis and hospital resources. AB - OBJECTIVE: To determine if comorbid dysphagia in all hospitalized patients has the potential to prolong hospital stay and increase morbidity. Dysphagia is increasingly prevalent with age and comorbid medical conditions. Our research group has previously shown that dysphagia is a bad prognostic indicator in patients with stroke. DESIGN: Analysis of national database. MAIN OUTCOME MEASURES: The National Hospital Discharge Survey (NHDS), 2005-2006, was evaluated for presence of dysphagia and the most common comorbid medical conditions. Patient demographics, associated disease, length of hospital stay, morbidity and mortality were also evaluated. RESULTS: There were over 77 million estimated hospital admissions in the period evaluated, of which 271,983 were associated with dysphagia. Dysphagia was most commonly associated with fluid or electrolyte disorder, esophageal disease, stroke, aspiration pneumonia, urinary tract infection, and congestive heart failure. The median number of hospitalization days for all patients with dysphagia was 4.04 compared with 2.40 days for those patients without dysphagia. Mortality increased substantially in patients with dysphagia associated with rehabilitation, intervertebral disk disorders, and heart diseases. CONCLUSIONS: Dysphagia has a significant impact on hospital length of stay and is a bad prognostic indicator. Early recognition of dysphagia and intervention in the hospitalized patient is advised to reduce morbidity and length of hospital stay. PMID- 20713755 TI - Intralesional endoscopy of advanced lymphatic malformations of the head and neck: a new diagnostic approach and a potential therapeutic tool. AB - OBJECTIVES: To evaluate the morphologic properties of advanced lymphatic malformations of the head and neck and to investigate possible therapeutic interventions by intralesional endoscopy. DESIGN: This case study analyzes the outcome of intralesional endoscopy of lymphatic malformations of the head and neck and discusses the results of this approach. SETTING: Academic medical center. PATIENTS: Endoscopy was performed on 4 patients with cervicofacial lymphatic malformations. INTERVENTIONS: Endoscopy of lymphatic malformations. RESULTS: The endoscopic inspection and assessment of the lesions revealed detailed information about morphologic aspects like the structure of intralesional septa, internal vascularization, and intercystic correspondence and channel networks. Anatomic landmarks could be followed on their intralesional courses. CONCLUSIONS: Intralesional endoscopy of lymphatic malformations provides insight into the morphologic properties of the lesion and is a useful supplementary tool during conventional surgical intervention and for sclerosing therapy. The technique allows a detailed assessment of these lesions and opens a broad spectrum of therapeutic options. PMID- 20713756 TI - Rupatadine and levocetirizine for seasonal allergic rhinitis: a comparative study of efficacy and safety. AB - OBJECTIVE: To determine the better agent among rupatadine fumarate and levocetirizine dihydrochloride for seasonal allergic rhinitis. Although treating and ensuring a decent quality of life to patients is challenging, an increasing understanding of pathomechanisms has revealed the potentiality of new-generation antihistamines in the treatment of seasonal allergic rhinitis. DESIGN: A 2-week, single-center, randomized, open, parallel group comparative clinical study between rupatadine and levocetirizine in patients with seasonal allergic rhinitis. SETTING: A tertiary care center. PATIENTS: Following inclusion and exclusion criteria, 60 patients were assigned to either the rupatadine or levocetirizine group. INTERVENTIONS: Two-week treatment with rupatadine or levocetirizine. MAIN OUTCOME MEASURES: After 2 weeks, all postdrug symptoms were listed, baseline laboratory investigations (total and differential leukocyte count and IgE level) were repeated, and clinical improvement was assessed in terms of change in Total Nasal Symptom Score, Rhinoconjunctivitis Quality of Life Questionnaire score, and laboratory parameters. RESULTS: Differential count (P = .01) and absolute eosinophil count (P = .009) was significantly lowered by both drugs, but rupatadine was found to be superior. In the rupatadine group there was a significantly higher reduction (P = .004) in IgE level and Total Nasal Symptom Score (P < .001) compared with the levocetirizine group. There was a decrease of 18.08% (P = .02) in Rhinoconjunctivitis Quality of Life Questionnaire score in the rupatadine group, which was significantly greater compared with the levocetirizine group. Incidence of adverse effects was less in the rupatadine group compared with the levocetirizine group. CONCLUSION: Rupatadine is a better choice for seasonal allergic rhinitis compared with levocetirizine because of its better efficacy and safety profile. PMID- 20713757 TI - Impact of IgE-mediated hypersensitivity on nasal mucociliary clearance. AB - OBJECTIVE: To evaluate the effect of IgE-mediated hypersensitivity on mucociliary clearance time (MCCT) and clinical severity, as indicated by total nasal symptoms score (TNSS) and peak expiratory flow index (PEFI). DESIGN: A prospective cross sectional study. SETTING: Tertiary medical center. PARTICIPANTS: One hundred twenty-nine patients with rhinitis and 48 healthy control subjects. MAIN OUTCOME MEASURES: Results of an allergy skin prick test in the patients with rhinitis categorized them as allergic (AR) or nonallergic (non-AR). We evaluated TNSS and PEFI in the patient group and assessed MCCTs from the patients in the rhinitis groups and the healthy controls. RESULTS: The AR group patients had the longest MCCT, followed by patients in the non-AR group and the healthy controls (mean MCCTs, 14.36, 10.87, and 6.55 minutes, respectively). The AR group patients had significantly higher TNSS and worse PEFI compared with patients in the non-AR group (P = .002 and P = .03, respectively). We found a significant positive correlation of MCCTs with TNSS, and MCCTs showed a tendency to be inversely correlated with PEFI (rho = 0.43 [P < .001] and r = -0.22 [P = .05], respectively). In AR group patients, the wheal responses to Dermatophagoides pteronyssinus, Dermatophagoides farinae, American cockroach, and Bermuda grass were fairly correlated with the MCCTs (r = 0.39 [P = .001], r = 0.40 [P = .001], r = 0.34 [P = .01], and r = 0.36 [P = .02], respectively). The maximal wheal response among various positive allergen responses was well correlated with the MCCTs (r = 0.54 [P < .001]). CONCLUSION: A prolonged MCCT, significant correlation between MCCTs and the magnitude of allergen reactivity, and clinical severity suggest an impact of IgE-mediated hypersensitivity on mucociliary clearance function. PMID- 20713758 TI - Development of an animal model for wound healing in chronic rhinosinusitis. AB - OBJECTIVE: To develop a model for sinonasal wounding and evaluation during healing in mice with chronic eosinophilic inflammation. DESIGN: Exploratory controlled study in which chronic eosinophilic nasal and sinus inflammation was established in mice followed by wounding of the sinonasal cavity. Histologic features and gene expression were then studied. SETTING: University of Utah Center for Comparative Medicine. SUBJECTS: Chronic eosinophilic inflammation was established in mice. They were then wounded and humanely killed at days 3, 7, and 14 after wounding. MAIN OUTCOME MEASURES: Inflammation was assayed by light microscopic examination. Polymerase chain reaction analysis of transforming growth factor-beta1b, insulinlike growth factor (IGF)-1, matrix metalloproteinase (MMP)-7, MMP-9, tissue inhibitor of metalloproteinase 1 (TIMP-1), and prostaglandin E receptor EP4 expression was performed as well. Uninflamed mice were wounded and examined using the same protocol. RESULTS: Chronically inflamed mice showed higher histologic inflammatory scores before and after wounding. Expression of IGF-1, TIMP-1, and MMP-9 was also higher prior to wounding and during healing. Continued stimulation appears necessary for the chronic eosinophilic inflammation to persist. CONCLUSIONS: We successfully constructed a model in which wound healing in a setting of chronic eosinophilic inflammation can be studied. In this exploratory pilot, we demonstrated the feasibility of reproducibly wounding the sinonasal cavity of chronically inflamed mice and examining histologic and gene expression effects of the inflammatory response after wounding. PMID- 20713759 TI - Anatomical variability of the maxillary artery: findings from 100 Asian cadaveric dissections. AB - OBJECTIVE: To describe the anatomical variability of the maxillary artery. DESIGN: Anatomical study. SETTING: Academic institution. SUBJECTS: One hundred midsagittal sections of randomly selected adult cadaver heads with intact maxillary sinuses, pterygopalatine fossa, and surrounding structures. MAIN OUTCOME MEASURES: The location of the proximal portion of the maxillary artery in relation to the lateral pterygoid muscle, the branches of the mandibular division of the trigeminal nerve, and the branching patterns of the third section of the maxillary artery. RESULTS: The first and second sections of the maxillary artery most commonly traveled through the lateral aspect of the lateral pterygoid muscle, with the inferior alveolar nerve, lingual nerve, and buccal nerve on the medial side of the maxillary artery (61.0%). The course and branching type of the third section of the maxillary artery were classified into 3 patterns: loop (61.0%), bifurcated (19.0%), and straight (18.0%). In most cases (62.0%), the division point of the maxillary artery was located on the superior and medial thirds of the posterior wall of the maxilla. CONCLUSION: This study provides detailed information concerning the anatomical variability of the maxillary artery, which we hope will help prevent the arterial bleeding that may occur during mandibular or maxillary osteotomy or maxillectomy for ligation of the sphenopalatine artery. PMID- 20713760 TI - MUC5AC expression in human middle ear epithelium of patients with otitis media. AB - OBJECTIVE: To compare levels of middle ear (ME) MUC5AC expression in patients with otitis media (OM) with patients without OM. Mucin gene 5AC has been identified as a major secretory mucin in the ME and is fundamentally important in the development of ME mucoid effusions, hearing loss and also provides ME mucosal protection and bacterial clearance. DESIGN: Case control. SETTING: Tertiary, academic, pediatric otolaryngology practice. PATIENTS: Patients 9 months to 7 years old undergoing routine tympanostomy tube (TT) insertion for recurrent otitis media (RecOM) or chronic otitis media with effusion (COME) were compared with control patients without a history of OM undergoing cochlear implantation. METHODS: During routine TT placement or cochlear implantation, a 1-mm biopsy sample of the ME epithelium was obtained. RNA was extracted, and real-time reverse transcriptase-polymerase chain reaction was used to quantify levels of MUC5AC expression. RESULTS: Twenty-three patients with OM (12 with RecOM and with 11 COME) were evaluated using 5 controls. Mean age was not different between groups. In the RecOM group, mean expression of MUC5AC was 25.92 times greater than in controls. In the COME group, the mean expression was 155.40 times greater than in controls. CONCLUSIONS: Levels of MUC5AC expression in the human ME are significantly increased in patients with RecOM and COME compared with controls. This study demonstrates MUC5AC gene changes in patients with OM and highlights the need for greater understanding of the molecular responses in OM; particularly that of mucin. A thorough exploration of these factors will provide opportunities to develop novel interventions for the extremely common problem of OM. PMID- 20713761 TI - Vocal fold injection as a treatment for glottic insufficiency: pro. PMID- 20713762 TI - Vocal fold injection as a treatment for glottic insufficiency: con. PMID- 20713763 TI - Vocal fold injection as a treatment for glottic insufficiency. Commentary. PMID- 20713764 TI - Cystic pilomatrixoma: a diagnostic challenge. PMID- 20713765 TI - The spheno-ostio-choanal polyp: a rare and curious entity. PMID- 20713767 TI - Radiology quiz case 2. Hemorrhagic vestibular schwannoma. PMID- 20713766 TI - Radiology quiz case 1. Sinonasal idiopathic inflammatory pseudotumor (IIP) with orbital invasion. PMID- 20713768 TI - Pathology quiz case 1. Diffuse large B-cell lymphoma (DLBCL). PMID- 20713769 TI - Pathology quiz case 2. Calcifying fibrous pseudotumor (CFT) of the oral cavity. PMID- 20713770 TI - The vulnerable atherosclerotic plaque: scope of the literature. AB - The scope of recent literature on the concept of "vulnerable plaque" was reviewed by examining 463 abstracts of primary and review articles identified through MEDLINE (2003 to April 2010). Proposed definition criteria of vulnerable plaque included active inflammation, a thin cap with a large lipid core, endothelial denudation, fissured cap, severe stenosis, or combinations of these findings. In 242 primary studies, histopathology, biomarkers, and imaging of carotid and coronary artery plaques were evaluated for features suggestive of vulnerability. Notably, 89% of these studies were cross-sectional in design and were exclusively conducted in patients with known cardiovascular disease. None of the imaging studies documented whether the identified lesions were responsible for cardiovascular events. Cross-sectional design precludes evaluation of the predictive utility of biomarkers. Because vulnerable plaque is not an established medical diagnosis, no studies have been done that explicitly evaluate the treatment of vulnerable plaques. Few studies examined potential systemic treatments (for example, statins) to modify vulnerability features. Large prospective studies in patients with and without previous cardiovascular events during long follow-up are required to validate this concept. PMID- 20713771 TI - Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. AB - OBJECTIVES: To investigate the expression profile of programmed death-1 (PD-1) on T cells derived from patients with cutaneous T-cell lymphoma (CTCL), analyze a potential mechanism responsible for upregulation of PD-1, and assess the correlation between blockade of its signaling pathway and improvement in immunological function. DESIGN: Translation research study. SETTING: University medical center. PARTICIPANTS: Patients with Sezary syndrome, patients with mycosis fungoides, and healthy volunteers. MAIN OUTCOME MEASURES: Programmed death-1 expression on T cells by flow cytometry and interferon gamma (IFN-gamma) production by enzyme-linked immunosorbent assay. RESULTS: We report significantly increased PD-1 expression on CD4(+) T cells from patients with Sezary syndrome compared with CD4(+) T cells from patients with mycosis fungoides and healthy volunteers. Both CD26(-) and CD26(+) populations of CD4(+) T cells demonstrated increased expression of PD-1, which was upregulated by the engagement of the T cell receptor with anti-CD3/CD28 antibodies. In addition, blockade of the signaling pathway with blocking antibodies to PD-1 or its ligand PD-L1 led to an increase in the capacity to produce IFN-gamma among some patients. Finally, longitudinal studies of 1 patient revealed a progressive decrease in PD-1 expression on CD4(+) T cells with improvement of clinical disease. CONCLUSION: Our data imply that increased PD-1 expression in Sezary syndrome may play a role in attenuating the immune response and provide further insight into the immunosuppressive nature of CD4(+) T cells in Sezary syndrome and suggest another potential means of targeted therapy for these patients. PMID- 20713773 TI - Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases. AB - OBJECTIVE: To investigate the clinical and pathologic features of patients with drug reaction with eosinophilia and systemic symptoms (DRESS) in Taiwan. DESIGN: Case series and retrospective analysis. SETTING: A medical referral center in Northern Taiwan. PATIENTS: Sixty cases of DRESS occurring from June 1998 to May 2008. MAIN OUTCOME MEASURES: Clinical characteristics for specific drugs and important prognostic factors in DRESS. RESULTS: Patients ranged in age from 6 to 90 years (mean age, 51 years). The female to male ratio was 1.3 to 1. The most common culprit drugs were allopurinol, phenytoin, and dapsone. Exanthematous eruption was the most common skin manifestation, but purpurae and blisters were also observed. Hepatic (80%), renal (40%), and pulmonary (33%) involvement were also common. The overall mortality rate was 10%. Allopurinol-induced DRESS was characterized by preceding chronic renal insufficiency and frequent renal involvement. Pancytopenia indicated a poor prognosis. CONCLUSIONS: Drug reaction with eosinophilia and systemic symptoms has a variable clinical presentation, and its definition requires clarification. It may be a heterogeneous syndrome with some particular patterns related to different drugs. Early diagnosis and prompt discontinuation of offending drug regimens are essential. PMID- 20713772 TI - Alcohol intake and risk of incident psoriasis in US women: a prospective study. AB - OBJECTIVES: To evaluate the independent association between alcohol consumption and risk of developing psoriasis and to determine if this risk is associated with different types of alcoholic beverages. DESIGN: A prospective study of female nurses who were followed up from 1991 to 2005. SETTING: Nurses' Health Study II, a cohort of 116,671 US women aged 27 to 44 years in 1991. PARTICIPANTS: The study population included 82,869 women who reported amount and type of alcohol intake on biennial questionnaires. We excluded participants with a history of psoriasis prior to 1991. MAIN OUTCOME MEASURE: Self-report of incident physician-diagnosed psoriasis. For a sensitivity analysis, we had a subset of confirmed psoriasis cases. RESULTS: There were 1150 cases of incident psoriasis, 1069 of which were used for analysis. Compared with women who did not drink alcohol, the multivariate relative risk (RR) of psoriasis was 1.72 (95% confidence interval [CI], 1.15-2.57) for an alcohol consumption of 2.3 drinks/wk or more. When examined by type of alcoholic beverage, there was an association between psoriasis and nonlight beer intake (multivariate RR for >= 5 drinks/wk, 1.76; 95% CI, 1.15-2.69); light beer, red wine, white wine, and liquor were not significantly associated with psoriasis risk. The association with nonlight beer intake became stronger in a subset of confirmed psoriasis cases (multivariate RR for >= 5 drinks/wk, 2.29; 95% CI, 1.36-3.85). CONCLUSIONS: Nonlight beer intake is associated with an increased risk of developing psoriasis among women. Other alcoholic beverages did not increase the risk of psoriasis in this study. PMID- 20713774 TI - Atypical fibroxanthoma with regional lymph node metastasis: report of a case and review of the literature. AB - BACKGROUND: Atypical fibroxanthoma (AFX) is a low-grade sarcoma usually occurring on sun-damaged skin of the head and neck in elderly patients. Metastatic disease has been reported very rarely. The potential aggressiveness of AFX is controversial. OBSERVATIONS: We describe herein a patient who developed metastatic disease in cervical lymph nodes. Our patient was an 87-year-old man with a 7-week history of a rapidly growing AFX presenting as a 1.5-cm sessile nodule on his right mandible. Two months following excision, the patient developed cervical lymphadenopathy. Histopathologic analysis of the cervical lymph nodes revealed spindle-cell tumors with histologic characteristics identical to those of the primary AFX, and the tumors were immunonegative for cytokeratin MNF-116 and S-100. In addition, we review and analyze cases from the literature and articles related to immunohistochemical stains used to diagnose AFX. CONCLUSIONS: Atypical fibroxanthoma is a diagnosis of exclusion, and only a small number of metastatic AFX cases have been reported. A review of the literature pertaining to immunohistochemical stains suggests the potential benefit of use of CD10, procollagen I, CD99, CD117, p63, and LN-2 in differentiating AFX from other spindle-cell tumors. The metastatic potential of AFX may not be fully appreciated, and clinicians should be reminded of its potential aggressive behavior. PMID- 20713775 TI - Association of hearing loss with PHACE syndrome. AB - BACKGROUND: PHACE syndrome describes a spectrum of anomalies associated with large facial infantile hemangiomas and characterized by posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. With improved recognition and imaging practices of infants with PHACE syndrome, additional associations have been identified. To our knowledge, the potential association of ipsilateral hearing loss and PHACE syndrome has not been previously emphasized. OBSERVATIONS: We describe 6 patients, 4 with definite and 2 with probable PHACE syndrome, according to the new diagnostic criteria, and associated auditory deficiencies. One patient had isolated conductive hearing loss; 2 patients had isolated sensorineural hearing loss; 1 patient had mixed hearing loss (both conductive and sensorineural components); and 1 patient had hearing loss that was inconclusive at the time. Also, 1 patient had conductive loss and auditory neuropathy and auditory dyssynchrony. Four of the 6 patients had magnetic resonance imaging features of lesions consistent with intracranial hemangiomas involving auditory structures. All 6 patients had facial hemangiomas in a nearly identical distribution ipsilateral to the ear with the hearing loss, with involvement of the proposed facial segments S1 and S3, the affected ear, the periauricular region, and the midoccipital area of the scalp. CONCLUSIONS: There is an underrecognized risk of hearing loss in patients with PHACE syndrome, although the exact nature of such deficiencies can vary. Patients with PHACE syndrome who have cutaneous hemangiomas involving the ear should be evaluated for intracranial hemangiomas and monitored for hearing loss. Early detection and therapy of intracranial hemangiomas may slow or stop tumor growth, resultant hearing loss, and structural damage. PMID- 20713776 TI - Summaries for patients. Does admitting mistakes to patients lead to more lawsuits? PMID- 20713777 TI - ACP Journal Club. Dexamethasone did not reduce mortality or neurologic sequelae in bacterial meningitis. PMID- 20713778 TI - ACP Journal Club. HbA1c levels < or = 5.5% ruled out, and levels > or = 7.0% ruled in, type 2 diabetes in clinical and community populations. PMID- 20713779 TI - ACP Journal Club. Review: Clinical pathways reduce in-hospital complications but not in-hospital mortality or readmissions. PMID- 20713780 TI - ACP Journal Club. Review: Some instruments predict development of persistent, disabling low back pain. PMID- 20713781 TI - ACP Journal Club. Review: Joint lavage does not reduce pain or improve function in knee osteoarthritis. PMID- 20713782 TI - ACP Journal Club. Review: Therapy guided by B-type natriuretic peptide levels reduces mortality in chronic heart failure. PMID- 20713783 TI - ACP Journal Club. Lenient rate control is as effective as strict rate control for preventing cardiovascular events in AF. PMID- 20713784 TI - ACP Journal Club. Low-dose computed tomography was associated with higher risk for false-positive lung cancer screening than chest radiography. PMID- 20713785 TI - ACP Journal Club. Amylmetacresol and 2, 4-dichlorobenzyl alcohol lozenges were better than placebo lozenges for relief of acute sore throat. PMID- 20713786 TI - ACP Journal Club. Telaprevir combination therapy induced a sustained virologic response in nonresponsive chronic HCV infection. PMID- 20713787 TI - ACP Journal Club. Rifaximin maintained remission from hepatic encephalopathy longer than placebo in patients with cirrhosis. PMID- 20713788 TI - ACP Journal Club. Early tracheotomy did not reduce ventilator-associated pneumonia in adults ventilated for acute respiratory failure. PMID- 20713789 TI - Liability claims and costs before and after implementation of a medical error disclosure program. AB - BACKGROUND: Since 2001, the University of Michigan Health System (UMHS) has fully disclosed and offered compensation to patients for medical errors. OBJECTIVE: To compare liability claims and costs before and after implementation of the UMHS disclosure-with-offer program. DESIGN: Retrospective before-after analysis from 1995 to 2007. SETTING: Public academic medical center and health system. PATIENTS: Inpatients and outpatients involved in claims made to UMHS. MEASUREMENTS: Number of new claims for compensation, number of claims compensated, time to claim resolution, and claims-related costs. RESULTS: After full implementation of a disclosure-with-offer program, the average monthly rate of new claims decreased from 7.03 to 4.52 per 100,000 patient encounters (rate ratio [RR], 0.64 [95% CI, 0.44 to 0.95]). The average monthly rate of lawsuits decreased from 2.13 to 0.75 per 100,000 patient encounters (RR, 0.35 [CI, 0.22 to 0.58]). Median time from claim reporting to resolution decreased from 1.36 to 0.95 years. Average monthly cost rates decreased for total liability (RR, 0.41 [CI, 0.26 to 0.66]), patient compensation (RR, 0.41 [CI, 0.26 to 0.67]), and non compensation-related legal costs (RR, 0.39 [CI, 0.22 to 0.67]). LIMITATIONS: The study design cannot establish causality. Malpractice claims generally declined in Michigan during the latter part of the study period. The findings might not apply to other health systems, given that UMHS has a closed staff model covered by a captive insurance company and often assumes legal responsibility. CONCLUSION: The UMHS implemented a program of full disclosure of medical errors with offers of compensation without increasing its total claims and liability costs. PRIMARY FUNDING SOURCE: Blue Cross Blue Shield of Michigan Foundation. PMID- 20713790 TI - Steroid pretreatment of organ donors to prevent postischemic renal allograft failure: a randomized, controlled trial. AB - BACKGROUND: Posttransplantation acute renal failure (ARF) occurs in roughly 25% of recipients of organs from deceased donors. Inflammation in the donor organ is associated with risk for ARF. OBJECTIVE: To determine whether administering corticosteroids to deceased organ donors reduces the incidence and duration of ARF in organ recipients more than placebo. DESIGN: Parallel, blocked randomized trial, performed between February 2006 and November 2008, with computer-generated randomization and centralized allocation. Investigators were masked to group assignment. (Controlled-trials.com registration number: ISRCTN78828338) SETTING: 3 renal transplantation centers in Austria and Hungary. PATIENTS: 306 deceased heart-beating donors and 455 renal transplant recipients. INTERVENTIONS: Organ donors were administered an intravenous infusion of either 1000 mg of methylprednisolone (136 donors) or placebo (0.9% saline) (133 donors) at least 3 hours before organ harvesting. MEASUREMENTS: Incidence of ARF, defined as more than 1 dialysis session in the first week after transplantation, was the primary end point. Secondary and other end points included duration of ARF and trajectories of serum creatinine level. The suppression of immune response and inflammation by the intervention was assessed in the donor organ on a genome-wide basis. RESULTS: 52 of 238 recipients (22%) of kidneys from steroid-treated donors and 54 of 217 recipients (25%) of kidneys from placebo-treated donors had ARF (difference, 3 percentage points [95% CI, -11 to 5 percentage points]). One graft was lost on day 1 in each group, and 1 recipient in the placebo group died of cardiac arrest on day 2. The median duration of ARF was 5 days (interquartile range, 2 days) in the steroid group and 4 days (interquartile range, 2 days) in the placebo group (P = 0.31). The groups had similar trajectories of serum creatinine level in the first week (P = 0.72). Genomic analysis showed suppressed inflammation and immune response in kidney biopsies from deceased donors who received corticosteroids. LIMITATION: Donors and recipients were mainly white, and all were from 3 transplantation centers in central Europe, which may limit generalizability. CONCLUSION: Systemic suppression of inflammation in deceased donors by corticosteroids did not reduce the incidence or duration of posttransplantation ARF in allograft recipients. PRIMARY FUNDING SOURCE: Austrian Science Fund and Austrian Academy of Science. PMID- 20713791 TI - Quality of care in patients with chronic hepatitis C virus infection: a cohort study. AB - BACKGROUND: Medicare has proposed quality-of-care indicators for chronic hepatitis C virus (HCV) infection. The extent to which these standards are met in practice is largely unknown. OBJECTIVE: To evaluate the quality of health care that patients with HCV receive and the factors associated with receipt of quality care. DESIGN: Retrospective cohort study. SETTING: Nationwide U.S. health insurance company research database. PARTICIPANTS: 10 385 patients with HCV enrolled in the database between 2003 and 2006. Patients were included if they were eligible for at least 1 quality indicator. MEASUREMENTS: Quality of HCV care received by patients, as measured by 7 explicit quality indicators included in Medicare's 2009 Physician Quality Reporting Initiative. RESULTS: Proportions of patients meeting quality indicators varied, ranging from 21.5% for vaccination to 79% for the HCV genotype testing indicator. Overall, 18.5% of patients (95% CI, 18% to 19%) received all recommended care. Older age and presence of comorbid conditions were associated with lower quality, whereas elevated liver enzyme levels, cirrhosis, and HIV infection were associated with higher quality. Patients who saw both generalists and specialists received the best care (odds ratio of receiving care for which a patient is eligible: specialists alone, 0.79 [CI, 0.66 to 0.95]; primary care physician alone, 0.44 [CI, 0.40 to 0.48]). LIMITATIONS: The study had an observational retrospective design, used a convenience sample, and had no information on patient ethnicity. It may be that the indicators or the reporting of the indicators of HCV care--and not the care itself--is suboptimum. CONCLUSION: Health care quality, based on Medicare criteria, is suboptimum for HCV. Care that included both specialists and generalists is associated with the best quality. Our results support the development of specialist and primary care collaboration to improve the quality of HCV care. PRIMARY FUNDING SOURCE: Saint Louis University Liver Center. PMID- 20713792 TI - Narrative review: ventilator-induced respiratory muscle weakness. AB - Clinicians have long been aware that substantial lung injury results when mechanical ventilation imposes too much stress on the pulmonary parenchyma. Evidence is accruing that substantial injury may also result when the ventilator imposes too little stress on the respiratory muscles. Through adjustment of ventilator settings and administration of pharmacotherapy, the respiratory muscles may be rendered almost (or completely) inactive. Research in animals has shown that diaphragmatic inactivity produces severe injury and atrophy of muscle fibers. Human data have recently revealed that 18 to 69 hours of complete diaphragmatic inactivity associated with mechanical ventilation decreased the cross-sectional areas of diaphragmatic fibers by half or more. The atrophic injury seems to result from increased oxidative stress leading to activation of protein-degradation pathways. Scientific understanding of ventilator-induced respiratory muscle injury has not reached the stage where meaningful controlled trials can be done, and thus, it is not possible to give concrete recommendations for patient management. In the meantime, clinicians are advised to select ventilator settings that avoid both excessive patient effort and excessive respiratory muscle rest. The contour of the airway pressure waveform on a ventilator screen provides the most practical indication of patient effort, and clinicians are advised to pay close attention to the waveform as they titrate ventilator settings. Research on ventilator-induced respiratory muscle injury is in its infancy and portends to be an exciting area to follow. PMID- 20713795 TI - My moment. PMID- 20713794 TI - Patient compensation without litigation: a promising development. PMID- 20713793 TI - Redefining the "planning" in advance care planning: preparing for end-of-life decision making. AB - The traditional objective of advance care planning has been to have patients make treatment decisions in advance so that clinicians can attempt to provide care consistent with their goals. The authors contend that the objective for advance care planning ought to be the preparation of patients and surrogates to participate with clinicians in making the best possible in-the-moment medical decisions. They provide practical steps for clinicians to help patients and surrogate decision makers achieve this objective in the outpatient setting. Preparation for in-the-moment decision making shifts the focus from having patients make premature decisions based on incomplete information to preparing them and their surrogates for the types of decisions and conflicts they may encounter when they do have to make in-the-moment decisions. Advance directives, although important, are just one piece of information to be used at the time of decision making. PMID- 20713796 TI - Fresh eyes. PMID- 20713797 TI - Further perspectives on concierge medicine. PMID- 20713798 TI - Further perspectives on concierge medicine. PMID- 20713799 TI - Further perspectives on concierge medicine. PMID- 20713800 TI - Further perspectives on concierge medicine. PMID- 20713801 TI - Further perspectives on concierge medicine. PMID- 20713802 TI - Further perspectives on concierge medicine. PMID- 20713803 TI - Population strategies to decrease sodium intake. PMID- 20713804 TI - Population strategies to decrease sodium intake. PMID- 20713805 TI - Errors in meta-analysis regarding the 3CPO trial. PMID- 20713807 TI - Delayed complications from exposure to improvised explosive devices. PMID- 20713809 TI - The ice diet. PMID- 20713811 TI - In situ photoimmunotherapy: a surgery- and limb-sparing approach to the treatment of cutaneous metastases in advanced melanoma. PMID- 20713812 TI - Extending the sun safety recommendations: emphasizing eye protection for patients taking sun-sensitizing medications. PMID- 20713813 TI - The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland. AB - OBJECTIVES: To determine whether narrowband UV-B (NB-UV-B) may mediate its beneficial effect on psoriasis by increasing vitamin D levels, and to assess the effect of NB-UV-B on vitamin D status in patients with psoriasis in wintertime. DESIGN: A prospective controlled study from October 2008 to February 2009. SETTING: A dermatology outpatient department at a university teaching hospital. PATIENTS: Thirty consecutive patients with psoriasis treated with NB-UV-B and 30 control patients with psoriasis were recruited. Control patients were recruited within 1 week of treated patients to control for seasonal variation of serum 25 hydroxyvitamin D [25(OH)D] levels. One patient with photo aggravated psoriasis was withdrawn from the study. INTERVENTION: Narrowband UV-B was administered 3 times per week. MAIN OUTCOME MEASURE: Serum 25(OH)D was measured at baseline, after 4 weeks and at completion of treatment. RESULTS: Levels of serum 25(OH)D increased significantly(P< .001) from a median (range) of 23 (9-46)ng/mL at baseline to 51 [rather than 59, as given in the originally published article] (32 112) ng/mL at the end of NB-UV-B treatment compared with no change in the control group [corrected]. The change in serum 25(OH)D level correlated with the number of exposures of NB-UV-B (r = 0.61; P < .001) and cumulative UV-B dose (r = 0.47; P = .01) but not with treatment response. At the end of the study, all patients in the treatment group were vitamin D sufficient, but 75% of the control group had vitamin D insufficiency [serum 25(OH)D level <20 ng/mL]. In a multiple regression model, prior phototherapy was the sole predictor of baseline serum 25(OH)D level (r(2) = 0.13; P = .006), whereas the number of exposures of NB-UV-B predicted change in serum 25(OH)D level (r(2) = 0.38; P = .001). CONCLUSIONS: Narrowband UV-B effectively increases serum 25(OH)D level while clearing psoriasis. Up to 75% of Irish patients with psoriasis were shown to be vitamin D insufficient during wintertime. PMID- 20713814 TI - Confocal laser scanning microscopy vs 3-dimensional histologic imaging in basal cell carcinoma. AB - OBJECTIVE: To compare ex vivo confocal laser scanning microscopy (CLSM), which offers rapid images without the need for tissue processing, vs 3-dimensional histologic imaging, the criterion standard treatment for basal cell carcinomas in high-risk areas of the face. DESIGN: Single-center prospective trial. SETTING: Dermatosurgical unit of a university hospital. Patients Seventy-two consecutive surgically removed basal cell carcinomas were examined using CLSM vs standard paraffin-embedded 3-dimensional histologic imaging. Interventions A total of 312 images, including 73 midsections, 196 lateral margins, 23 "muffins," and 20 "bread loaf sections," were obtained using CLSM. Immediately after surgery, the CLSM images were evaluated by the surgeon. The following day, the 3-dimensional histologic slides were evaluated and compared with the CLSM images. MAIN OUTCOME MEASURES: Diagnostic accuracy of ex vivo CLSM to detect tumor strands of basal cell carcinomas and the practicality of using CLSM vs 3-dimensional histologic slides in micrographic surgery. RESULTS: The sensitivity of CLSM reached 94.0% in midsections, 73.7% in lateral margins, 80.0% in muffins, and 80.0% in bread loaf sections. The CLSM images were evaluated by the surgeon within 7.5 minutes. CONCLUSIONS: Confocal laser scanning microscopy lacks high sensitivity to detect small tumor strands of basal cell carcinomas. In the future, CLSM may represent a time-saving and less expensive alternative to cryostat histopathologic examination. PMID- 20713815 TI - Risk factors for single and multiple basal cell carcinomas. AB - OBJECTIVE: To investigate the incidence of single and multiple basal cell carcinoma (BCC) lesions and associated risk factors. DESIGN: A prospective, population-based cohort study (from January 1, 1990, through December 31, 2007). SETTING: Two cohorts of 10 994 Dutch people, 55 years or older, were studied in 1990 (first cohort) and 1999 (second cohort). PATIENTS: Patients with BCC lesions were identified from the Dutch national pathology laboratories network, hospitals, and general practices. MAIN OUTCOME MEASURES: The associations between determinants and single and multiple BCC lesions were studied by estimating odds ratios (ORs) and hazards ratios, using multivariate logistic regression and Andersen-Gill models, respectively. RESULTS: Of the eligible 10 820 cohort members, 524 (4.8%) had BCC, of whom 361 had single and 163 (31.1%) had multiple lesions. Age and red hair were significant risk factors for a first BCC lesion in a multivariate model. In the Andersen-Gill model, people who developed a first BCC lesion after 75.0 years of age were significantly less likely to develop multiple lesions (> or =75.0 years adjusted OR, 0.58; 95% confidence interval [CI], 0.47-0.71). Red hair (adjusted OR, 1.43; 95% CI, 1.05-1.94), high educational level (1.42; 1.12-1.81), and a first BCC lesion located on the upper extremities (1.49; 1.02-2.15) were associated with a significantly increased risk of developing multiple lesions. CONCLUSION: Patients who are relatively young at their first BCC diagnosis, those with red hair, those with higher socioeconomic status, and/or those with a BCC lesion on their upper extremities have a higher risk of developing multiple lesions and require closer follow-up over time. PMID- 20713817 TI - Development and validation of Skindex-Teen, a quality-of-life instrument for adolescents with skin disease. AB - OBJECTIVE: To develop and validate a quality-of-life index for adolescents with skin disease. DESIGN: Prospective, longitudinal cohort study taking place from July 15, 2005, through February 29, 2008. SETTING: Academic pediatric dermatology practice. PATIENTS: A total of 205 patients between the ages of 12 and 17 years with a skin condition. MAIN OUTCOME MEASURES: Participants completed the Skindex Teen questionnaire, reported sociodemographic data, and answered clinical questions at enrollment. Four weeks later, they completed Skindex-Teen and responded to clinical questions again. Forty patients also completed Skindex-Teen 48 hours after baseline. RESULTS: Of 205 patients, 200 (97.6%) completed all enrollment materials; 125 (62.5%) of these returned follow-up materials, of which 115 (57.5%) were complete. Twenty-three of 40 participants (57.5%) completed the 48-hour-after-initial-answers materials. The mean (SD) age of the patients was 15.3 (1.4) years (range, 12.9-18.0 years). Approximately half reported their skin condition as poor (26 [13.0%]) or fair (67 [33.5%]); most rated their general health as very good (62 [31.0%]) or excellent (80 [40.0%]). The dimensionality of the items was evaluated using factor analysis; results suggested 2 factors, termed physical symptoms (5 items) and psychosocial functioning (16 items). Both scales demonstrated excellent internal consistency. All item-scale reliabilities were greater than 0.4. Fit of items to the measurement model was supported by Rasch analysis. Test-retest reliability was supported by intraclass correlation coefficients (0.82-0.94) for total scores, physical symptoms, and psychosocial functioning scales. At 4 weeks, 16 (13.9%) reported worsening of their skin condition, 57 (19.6%) reported it had remained unchanged, and 42 (36.5%) reported improvement. Significant mean differences were present between the improved and worsened groups for the psychosocial functioning scale and total scores. CONCLUSIONS: These data provide evidence of construct, content, and face validity for Skindex-Teen, a new quality-of-life instrument for adolescents with skin disease. Test-retest reliability was verified, and responsiveness at 4 weeks was shown for total scores and the psychosocial functioning scale scores. PMID- 20713818 TI - The dermatopathology ward round: a tribute to the multiheaded microscope. PMID- 20713816 TI - Advanced biological therapies for diabetic foot ulcers. AB - OBJECTIVE: To assess the clinical use of advanced biological therapies in treating diabetic foot ulcers in practice and the effect of these therapies on time to healing. DESIGN: A retrospective cohort study. SETTING: A validated wound care database from January 1, 2001, through December 31, 2004. PARTICIPANTS: Two thousand five hundred seventeen patients with diabetic neuropathic foot ulcers. INTERVENTION: Patients who received advanced biological therapy (ie, Apligraf, Regranex, or Procuren). MAIN OUTCOME MEASURE: Time to healing after initial use of advanced biological therapy. This was derived using Kaplan-Meier estimates and the Ederer least squares method after adjusting for covariates, which were assessed using generalized estimating equations and Cox proportional hazards regression modeling. RESULTS: Advanced biological therapy was used, on average, within 28 days from the first wound clinic visit and associated with a median time to healing of 100 days. Regardless of the advanced biological therapy used, wounds with larger wound area, more severe wound grades, longer duration of wound prior to the first visit, and prolonged time to treatment with advanced biological therapies were significantly associated with longer time to healing. Wounds treated with engineered skin as the first advanced biological therapy were 31.2% more likely to heal than wounds first treated with topical recombinant growth factor (P < .001), and 40.0% more likely to heal than those first treated with platelet releasate (P = .01). Wound size, wound grade, duration of wound, and time to initiation of advanced biological therapy affected the time to healing. CONCLUSIONS: Advanced biological therapies were used, on average, within 1 month, and improved healing of refractory diabetic foot ulcers. Differences on outcomes among advanced biological therapies were noted. PMID- 20713819 TI - Viral-associated trichodysplasia of immunosuppression: report of a pediatric patient with response to oral valganciclovir. AB - BACKGROUND: Viral-associated trichodysplasia of immunosuppression is an increasingly recognized entity characterized by follicular-based papules, primarily in the central part of the face, that produce variable degrees of alopecia and dysmorphic features. It has been primarily described in transplant recipients but has recently been recognized in patients receiving chemotherapy for leukemia and lymphoma. It is associated with distinctive histologic features such as dilated anagen hair follicles, absent hair papillae, and abrupt cornification of the inner root sheath. OBSERVATIONS: A 5-year-old boy presented with spiny follicular papules that caused thickening of the skin of the face 1 year after cardiac transplantation. He had been exposed to several immunosuppressive agents, including mycophenolate mofetil, tacrolimus, intravenous immunoglobulin, rituximab, cylcophosphamide, and prednisone. Despite the failure of multiple topical treatments, our patient's eruption improved with systemic valganciclovir therapy. CONCLUSIONS: We describe the youngest patient (to our knowledge) with viral-associated trichodysplasia of immunosuppression and discuss the characteristic clinicopathologic features. Our report supports the theory that immunosuppression is the predisposing factor to a folliculotropic papovavirus that alters follicular maturation. PMID- 20713820 TI - Lipoatrophic panniculitis: case report and review of the literature. AB - BACKGROUND: Lipoatrophic panniculitis (LP) is a rare disease of childhood characterized by eruption of tender erythematous nodules and plaques followed by circumferential bands of lipoatrophy often seen on the arms and legs. This condition has also been known as lipophagic panniculitis of childhood, annular atrophy of the ankles, and partial lipodystrophy. OBSERVATIONS: A previously healthy 8-year-old boy was evaluated for tender, raised plaques on the ankles, which progressed to circumferential atrophy of the distal lower extremities. Biopsy specimen analysis revealed a dense mixed infiltrate extending into the subcutaneous tissue as well as lipophages within the fatty lobules. A diagnosis of LP was made, and the patient began treatment with prednisone and hydroxychloroquine. Methotrexate was added later to the regimen as a steroid sparing agent, and the dose was increased over the course of 3 months, by which time the cutaneous disease progression was nearly halted. However, the patient continued to have lower leg pain with bone changes demonstrated on magnetic resonance imaging. CONCLUSIONS: We report this case and review of the literature to call attention to the clinical features of LP and its association with skeletal changes. Our patient's response to combination therapy is of interest and contributes to the limited literature about management of this disease. PMID- 20713821 TI - Subcutaneous fat necrosis as a complication of whole-body cooling for birth asphyxia. AB - BACKGROUND: Subcutaneous fat necrosis (SCFN) of the newborn is a form of panniculitis that affects full-term neonates who often have suffered either birth asphyxia or hypothermia. The induction of hypothermia in newborns is becoming frequently used to reduce the neurologic sequelae associated with birth asphyxia. The risk of SCFN in neonates undergoing this therapy is unknown. Observation We describe a neonate who developed an abscess-like presentation of SCFN and subsequent asymptomatic hypercalcemia after undergoing whole-body cooling for hypoxic-ischemic encephalopathy. CONCLUSIONS: Hypothermia protocols may be placing newborns at increased risk for the development of SCFN. Clinicians should recognize this association, and newborns who undergo therapeutic cooling should have frequent dermatologic assessments. PMID- 20713824 TI - Retrospective analysis of the association between Demodex infestation and rosacea. AB - OBJECTIVES: To explore the association between Demodex infestation and rosacea and the pathogenesis of demodicosis rosacea by means of a meta-analysis. DATA SOURCES: Electronic searches of the ISI Web of Knowledge (Science Citation Index, ISTP [Index to Scientific & Technical Proceedings], Journal Citation Reports, BP [BIOSIS Preview], INSPEC [Ination Service in Physics, Electronics Technology, and Computer and Control], and DII [Derwent Innovation Index]), MEDLINE, and CNKI (China National Knowledge Infrastructure) databases (January 1, 1950, to December 31, 2009). We also performed hand searches of reference lists and conference proceedings. STUDY SELECTION: Predefined selection criteria were applied to all published case-control studies that analyzed the association between Demodex infestation and rosacea. DATA EXTRACTION: Two of us independently extracted data from the included studies. For disputed articles, a third party mediated whether to include the study. DATA SYNTHESIS: Forty-eight English- and Chinese-language articles, which covered 10 different countries and 28 527 participants, were eligible. The pooled odds ratio in random-effects models is 7.57 (95% confidence interval, 5.39-10.62). Stability is good according to sensitivity analysis. The fail-safe number is 18 456 in the quantitative analysis of publication bias. CONCLUSIONS: A significant association exists between Demodex infestation and the development of rosacea. Demodex infestation is a vital risk factor for rosacea according to the time-to-event relationship, and the degree of infestation played a more important role than did the mite infestation rate in the development of rosacea. PMID- 20713825 TI - What is the evidence for effective treatments of acquired epidermodysplasia verruciformis in HIV-infected patients? PMID- 20713823 TI - The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. AB - OBJECTIVE: To determine the incidence of depression, anxiety, and suicidality in patients with psoriasis compared with the general population. DESIGN: A population-based cohort study using data collected as part of patient's electronic medical record from 1987 to 2002. SETTING: General Practice Research Database. PATIENTS: Analyses included 146 042 patients with mild psoriasis, 3956 patients with severe psoriasis, and 766 950 patients without psoriasis. Five controls without psoriasis were selected from the same practices and similar cohort entry dates as patients with psoriasis. MAIN OUTCOME MEASURE: Clinical diagnoses of depression, anxiety, and suicidality among patients. RESULTS: The adjusted hazard ratios (HRs) for receiving a diagnosis of depression, anxiety, and suicidality in patients with psoriasis compared with controls were 1.39 (95% confidence interval [CI], 1.37-1.41), 1.31 (95% CI, 1.29-1.34), and 1.44 (95% CI, 1.32-1.57), respectively. The adjusted HR of depression was higher in severe (HR, 1.72; 95% CI, 1.57-1.88) compared with mild psoriasis (HR, 1.38; 95% CI, 1.35 1.40). Younger patients with psoriasis had elevated HRs of outcomes compared with older patients with psoriasis. CONCLUSIONS: Patients with psoriasis have an increased risk of depression, anxiety, and suicidality. We estimate that in the United Kingdom, in excess of 10 400 diagnoses of depression, 7100 diagnoses of anxiety, and 350 diagnoses of suicidality are attributable to psoriasis annually. It is important for clinicians to evaluate patients with psoriasis for these conditions to improve outcomes. Future investigation should determine the mechanisms by which psoriasis is associated with psychiatric outcomes as well as approaches for prevention. PMID- 20713826 TI - Phototherapy and vitamin D. PMID- 20713827 TI - Optical biopsy at the bedside. PMID- 20713828 TI - Subungual tumor in a 66-year-old woman. Onychomatricoma. PMID- 20713829 TI - Multiple papules and nodules of the scalp. Angiolymphoid hyperplasia with eosinophilia (ALHE). PMID- 20713830 TI - Recurrent erythematous vulvar nodule on a 33-year-old woman. Aggressive angiomyxoma. PMID- 20713831 TI - Pruritic natal cleft plaque. Porokeratosis ptychotropica. PMID- 20713832 TI - Increased IL-23 expression in palmoplantar psoriasis and hyperkeratotic hand dermatitis. PMID- 20713833 TI - A cost-effectiveness comparison of liquor carbonis distillate solution and calcipotriol cream in the treatment of moderate chronic plaque psoriasis. PMID- 20713834 TI - An Internet-delivered video intervention for skin self-examination by patients with melanoma. PMID- 20713835 TI - Actinic keratosis on a continuum with squamous cell carcinoma. PMID- 20713836 TI - Polyalkylimide implant: critical evaluation of a clinical study. PMID- 20713837 TI - "Pruritis" redux. PMID- 20713838 TI - Papulopustular eruption associated with panitumumab. PMID- 20713839 TI - Livedoid vasculopathy in a pediatric patient with elevated lipoprotein(a) levels: prompt response to continuous low-molecular-weight heparin. PMID- 20713840 TI - Bacillary angiomatosis after skin autografting in a patient without human immunodeficiency virus who was treated with interferon alfa. PMID- 20713841 TI - Traction alopecia in a ballerina: clinicopathologic features. PMID- 20713842 TI - Human papillomavirus typing of verrucae in a patient with WHIM syndrome. PMID- 20713843 TI - Perforated ischiogluteal bursitis mimicking a gluteal decubitus ulcer in patients with spinal cord injury: report of 2 cases. PMID- 20713844 TI - Lymphomatoid contact dermatitis to baby wipes. PMID- 20713845 TI - Dermoscopic patterns of purpuric lesions. PMID- 20713847 TI - Astrocytoma in a breast cancer lineage: part of the BRCA2 phenotype? PMID- 20713848 TI - Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. AB - PURPOSE: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 * 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5 year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT. PMID- 20713850 TI - Early treatment failure in intermediate-risk rhabdomyosarcoma: results from IRS IV and D9803--a report from the Children's Oncology Group. AB - PURPOSE: The goal of this study was to determine the frequency and clinical features of early treatment failure during induction chemotherapy before protocol radiation therapy for children with intermediate-risk rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Patients with intermediate-risk RMS enrolled onto the Intergroup Rhabdomyosarcoma Study-IV and the Children's Oncology Group D9803 study were reviewed for an early treatment failure. Early failure was defined as failure caused by progressive disease, death as a result of progressive disease, or death as a result of other causes occurring fewer than 120 days from study entry. Patients with parameningeal site RMS with high-risk features who received radiation therapy at week 1 were excluded from analysis. Overall survival (OS) was estimated using the Kaplan-Meier method. Fisher's exact test was used to compare differences between groups. Cumulative incidence of progression was estimated. RESULTS: Of 916 patients, 20 (2.2%) were found to have an early disease progression and did not receive planned protocol radiotherapy. Three additional early failures resulted from treatment-related death without progression. Median time to failure was 48 days (range, 7 to 106 days). Nineteen (95%) of the 20 patients experienced progression at their primary site. Five-year OS was 32% (95% CI, 12% to 54%) for patients experiencing an early progression. CONCLUSION: A small proportion of patients with intermediate-risk RMS suffer an early failure as a result of early progression (2.2%) or treatment-related mortality (0.3%). The majority of patients with early progression had a local failure. Earlier radiotherapy could potentially improve outcome by preventing early local progression. PMID- 20713852 TI - Prognostic significance of molecular remission in follicular lymphoma. PMID- 20713849 TI - Vitamin D insufficiency and prognosis in non-Hodgkin's lymphoma. AB - PURPOSE: Vitamin D insufficiency is common in the United States, with low levels linked in some studies to higher cancer incidence, including non-Hodgkin's lymphoma (NHL). Recent data also suggest that vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data for NHL. PATIENTS AND METHODS: We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)(2)D levels were associated with better EFS and OS, suggesting that any putative tumor 1-alpha-hydroxylase activity did not explain the 25(OH)D associations. CONCLUSION: 25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials. PMID- 20713853 TI - Pretreatment quality of life as a predictor of distant metastasis and survival for patients with nasopharyngeal carcinoma. AB - PURPOSE: The purpose of this study was to examine the prognostic value of pretreatment quality of life (QoL) data on locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: A total of 347 new patients with NPC, who were curatively treated by conformal radiotherapy from March 2003 to December 2007, were recruited. The Taiwan Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 was completed before treatment. Multivariate Cox's proportional hazards models were used to analyze the impact of clinical and QoL variables on the treatment results. RESULTS: The 5-year LRC, DMFS, and OS rates were 72.9%, 79.1%, and 68.4%, respectively. After adjusting the clinical variables, 10 QoL variables were observed to be significantly (P < .05) related to OS, and four QoL variables were related to DMFS. No QoL variable was predictive of LRC. Among the QoL variables that significantly predicted OS and DMFS, physical functioning was the most powerful predictor. A 10-point increase in the physical functioning score was associated with a 23% (95% CI, 12% to 34%) reduction in the likelihood of death and a 22% (95% CI, 9% to 36%) reduction in the likelihood of distant metastasis. CONCLUSION: Our findings indicate that pretreatment QoL variables, especially physical functioning, provide easily available prognostic value for distant metastasis and survival in patients with NPC. PMID- 20713854 TI - Refractory anemia with ringed sideroblasts: more than meets the eye. PMID- 20713855 TI - Qualitative assessment of the progesterone receptor and HER2 improves the Nottingham Prognostic Index up to 5 years after breast cancer diagnosis. AB - PURPOSE: To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS). PATIENTS AND METHODS: The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively. RESULTS: In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer-related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI - PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group. CONCLUSION: The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care. PMID- 20713856 TI - Posteriori conformal radiotherapy using three-dimensional dosimetric reconstitution in a survivor of adult-onset Hodgkin's disease for definitive diagnosis of lower motor neuron disease. PMID- 20713857 TI - Living in the moment. PMID- 20713858 TI - Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease. PMID- 20713859 TI - Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. AB - PURPOSE: The current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) in the setting of R-CHOP chemotherapy is not well reported. This retrospective analysis is an attempt to clarify this role. PATIENTS AND METHODS: Subjects were 469 patients with histologically confirmed DLBCL treated between January 2001 and December 2007. Variables including age, sex, Ann Arbor disease stage, bulky disease status, standardized uptake values (SUVs) on positron emission tomography (PET), International Prognostic Index (IPI), and Ki67 staining (proliferation). RESULTS: Of 469 patients, 190 (40.5%) had stage I or II disease and 279 (59.5%) had stage III or IV disease, 327 (70%) had at least six cycles of R-CHOP, and 142 (30.2%) had involved-field RT (dose, 30 to 39.6 Gy) after complete response to chemotherapy. Median follow-up was 36 months (range, 8 to 85 months). Multivariate analysis showed that RT (P < .0001), IPI score (P = .001), response to therapy (P = .001), use of six to eight cycles of R-CHOP (P < .001), and combined presence (P = .006) or absence (P = .025) of high Ki67, high PET SUV, and bulky disease influenced overall survival (OS) and progression-free survival (PFS). Matched-pair analyses of patients who received six to eight cycles of R CHOP with stage I or II disease (44 pairs) and all stages (74 pairs) indicated that RT improved OS (hazard ratio [HR], 0.52 and 0.29, respectively) and PFS (HR, 0.45 and 0.24, respectively) compared with no RT. CONCLUSION: This study showed significant improvements in OS and PFS among patients who received consolidation RT after R-CHOP chemotherapy for DLBCL. PMID- 20713860 TI - Pitfalls of using composite primary end points in the presence of competing risks. PMID- 20713861 TI - Uncommon reason for high fluorodeoxyglucose positron emission tomography uptake. PMID- 20713862 TI - Parenchymal versus nonparenchymal target lesion response in clinical trials for metastatic medullary thyroid cancer. PMID- 20713863 TI - Perforated rectal cancer presenting as Fournier's gangrene. PMID- 20713864 TI - Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study. AB - PURPOSE: To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m(2) to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed during the first two courses. Expression of the four ERBB receptors and downstream signaling elements in tumor tissue was evaluated by immunohistochemistry. RESULTS: Fifty-nine patients were enrolled (stratum I, n = 32; stratum II, n = 27). Of 29 patients evaluable for toxicity in stratum I, one experienced a DLT (diarrhea) at 520 mg/m(2) twice daily, and all three receiving 1,150 mg/m(2) twice daily experienced DLTs (one each of rash, diarrhea, and fatigue). Two of 21 patients evaluable for toxicity in stratum II experienced DLTs of rash at 900 mg/m(2) twice daily. Lapatinib dosage was related linearly to area under the [concentration-time] curve from start time to 12 hours later (AUC(0-12)) and dose-normalized maximum serum concentration and AUC values for patients in stratum II were both significantly higher (P = .001) than those for patients in stratum I. Frequent, high-level expression of activated (phosphorylated) EGFR and ERBB2 receptors and downstream signal intermediates were observed in tumors, particularly in ependymomas that displayed prolonged stable disease on lapatinib therapy. CONCLUSION: Lapatinib is well tolerated in children with recurrent CNS malignancies, with rash, diarrhea, and fatigue identified as DLTs. The recommended phase II dose, regardless of steroid use, is 900 mg/m(2) twice daily. PMID- 20713865 TI - Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. AB - PURPOSE: Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid. PATIENTS AND METHODS: Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid <= 7.5 mg/dL during days 3 to 7. RESULTS: Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol. CONCLUSION: In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol. PMID- 20713866 TI - Hematopoietic neoplasm of the stomach. PMID- 20713867 TI - Detecting functional impairment in older patients with cancer: is vulnerable elders survey-13 the right prescreening tool? An open question. PMID- 20713868 TI - Early-stage favorable Hodgkin's lymphoma: is chemotherapy alone sufficient? PMID- 20713869 TI - Papillary thyroid cancer associated with light-chain amyloidosis initially presenting with small-bowel bleeding and protein-losing enteropathy. PMID- 20713871 TI - Unusual presentation of granulosa cell tumor of the ovary. PMID- 20713872 TI - Cancer patients' roles in treatment decisions: do characteristics of the decision influence roles? AB - PURPOSE: Patients with more active roles in decisions are more satisfied and may have better health outcomes. Younger and better educated patients have more active roles in decisions, but whether patients' roles in decisions differ by characteristics of the decision itself is unknown. PATIENTS AND METHODS: We surveyed a large, population-based cohort of patients with recently diagnosed lung or colorectal cancer about their roles in decisions regarding surgery, radiation therapy, and/or chemotherapy. We used multinomial logistic regression to assess whether characteristics of the decision, including evidence about the treatment's benefit, whether the decision was likely preference-sensitive (palliative therapy for metastatic cancer), and treatment modality, influenced patients' roles in that decision. RESULTS: Of 10,939 decisions made by 5,383 patients, 38.9% were patient controlled, 43.6% were shared, and 17.5% were physician controlled. When there was good evidence to support a treatment, shared control was greatest; when evidence was uncertain, patient control was greatest; and when there was no evidence for or evidence against a treatment, physician control was greatest (overall P < .001). Decisions about treatments for metastatic cancers tended to be more physician controlled than other decisions (P < .001). CONCLUSION: Patients making decisions about treatments for which no evidence supports benefit and decisions about noncurative treatments reported more physician control, which suggests that patients may not want the responsibility of deciding on treatments that will not cure them. Better strategies for shared decision making may be needed when there is no evidence to support benefit of a treatment or when patients have terminal illnesses that cannot be cured. PMID- 20713873 TI - Isolated bowel relapse in acute promyelocytic leukemia: an unusual site of extramedullary recurrence. PMID- 20713874 TI - Radiation therapy after R-CHOP for diffuse large B-cell lymphoma: the gain remains. PMID- 20713877 TI - Metastatic pancreatic adenocarcinoma presenting as a large pelvic mass mimicking primary osteogenic sarcoma: a series of two patient cases. PMID- 20713876 TI - Patients' experiences with care for lung cancer and colorectal cancer: findings from the Cancer Care Outcomes Research and Surveillance Consortium. AB - PURPOSE: To assess patients' experiences with cancer care, ratings of their quality of care, and correlates of these assessments. PATIENTS AND METHODS: For 4,093 patients with lung cancer and 3,685 patients with colorectal cancer in multiple US regions and health care delivery systems, we conducted telephone surveys of patients or their surrogates in English, Spanish, or Chinese at 4 to 7 months after diagnosis. The surveys assessed ratings of the overall quality of cancer care and experiences with three domains of interpersonal care (physician communication, nursing care, and coordination and responsiveness of care). RESULTS: English-speaking Asian/Pacific Islander patients and Chinese-speaking patients and those in worse health reported significantly worse adjusted experiences with all three domains of interpersonal care, whereas white, black, and Hispanic patients reported generally similar experiences with interpersonal care. The overall quality of cancer care was rated as excellent by 44.4% of patients with lung cancer and 53.0% of patients with colorectal cancer, and these ratings were most strongly correlated with positive experiences with coordination and responsiveness of care (Spearman rank coefficients of 0.49 and 0.42 for lung and colorectal cancer, respectively). After multivariate adjustment, excellent ratings were less common for each cancer among black patients, English-speaking Asian/Pacific Islander patients, Chinese-speaking patients, and patients reporting worse health status (all P <= .05). CONCLUSION: Patients' reports and ratings of care differed significantly by race, language, and health status. Efforts to improve patients' experiences with cancer care should focus on problems affecting Asian and Pacific Islander patients and those in worse health. PMID- 20713878 TI - Hodgkin's lymphoma: Richter's transformation of chronic lymphocytic leukemia involving the liver. PMID- 20713879 TI - Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab refractory metastatic colorectal cancer. AB - PURPOSE: To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer. METHODS: A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R. RESULTS: Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients). CONCLUSION: IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors. PMID- 20713880 TI - T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. AB - Cell-mediated adaptive immunity is very important in tumor immune surveillance and tumor vaccination. However, the genetic program underlying an effective adaptive antitumor immunity is elusive. T-bet and Eomesodermin (Eomes) have been suggested to be master regulators of Th1 cells and CD8(+) T cells. However, whether they are important for T cell-mediated antitumor immunity is controversial. In this paper, we show that the combined germline deletion of T bet and T cell-specific deletion of Eomes resulted in profound defects in adaptive antitumor immune responses. T-bet and Eomes drive Tc1 differentiation by preventing alternative CD8(+) T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against cancer cells. Instead, T-bet and Eomes are crucial for tumor infiltration by CD8(+) T cells. This study defines T-bet and Eomes as critical regulators of T cell-mediated immune responses against tumor. PMID- 20713881 TI - Restricted TCR-alpha CDR3 diversity disadvantages natural regulatory T cell development in the B6.2.16 beta-chain transgenic mouse. AB - To date, analysis of mice expressing TCR-beta transgenes derived from CD4(+) T cell clones has demonstrated equivalent or higher TCR diversity in naturally occurring regulatory CD4(+) T cells (Tregs) versus conventional CD4(+) T cells (Tcons). However, TCR-alpha-chain diversity in these mice may be influenced by the inherent bias toward the CD4(+) lineage in the selected repertoires. We wished to determine whether the choice of TCR-beta-chain influences the relative diversity of the Treg and Tcon repertoires, examining as a model the B6.2.16beta transgenic mouse, in which the fixed beta-chain is derived from a CD8(+) T cell clone. B6.2.16beta Treg thymocytes showed significantly lower TRAV17 (AV9) CDR3 sequence diversity than both syngeneic Tcon thymocytes, and Treg and Tcon thymocytes from wild-type C57BL/6 (B6) mice. The ratio of single-positive CD4(+)/single-positive CD8(+) thymocytes in B6.2.16beta mice was similar to that in B6, yet both the proportional frequency and absolute number of CD4(+)Foxp3(+) cells was significantly lower in the thymi and peripheral lymph nodes of B6.2.16beta mice. Furthermore, B6 + B6.2.16beta-->B6 mixed bone marrow chimeras revealed that the transgenic beta-chain disadvantaged Treg development in a competitive environment. These data underline the importance of the beta-chain in assessments of Treg alpha-chain diversity and provide further support for the notion that interclonal competition for entry into the Treg lineage is a significant factor in determining the composition of this lineage. PMID- 20713882 TI - TGF-beta is required to maintain the pool of immature Langerhans cells in the epidermis. AB - The pivotal role of TGF-beta in Langerhans cell (LC) development has been previously established in TGF-beta-deficient mice, which lack epidermal LCs. As to whether TGF-beta also governs LC homeostasis and function remains elusive. To assess the role of TGF-beta-mediated control of cutaneous dendritic cells (DCs) in vivo, we generated mice with a conditional knockout of the TGF-beta receptor 1 (TbetaR1) under a DC-specific promoter (DC-TbetaR1(del) mice). While initial LC seeding occurred in DC-TbetaR1(del) mice, the cells disappeared from the epidermis during the first week of life. TbetaR1-deficient LCs demonstrated spontaneous maturation and gained migratory potential based on increased surface expression of MHC class II, costimulatory molecules, and CCR7 and downregulation of E-cadherin. In parallel to their early loss from the epidermis, migrating LCs were reduced in the dermis and skin-draining lymph nodes of adult DC-TbetaR1(del) mice, whereas the number of Langerin(+) dermal DCs was similar to wild-type. In the absence of LCs, low-dose contact hypersensitivity in DC-TbetaR1(del) mice was significantly diminished. In contrast, ear swelling was restored to wild-type levels when a higher hapten dose was applied to efficiently target TbetaR1 deficient dermal DCs. In conclusion, TGF-beta inhibits in vivo LC maturation and migratory phenotype, identifying TGF-beta as a critical factor controlling LC homeostasis in the steady state. PMID- 20713883 TI - Nonsteroidal anti-inflammatory drugs increase TNF production in rheumatoid synovial membrane cultures and whole blood. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity and hence PG production. However, the ability of NSAIDs to ameliorate pain and tenderness does not prevent disease progression in rheumatoid arthritis, a disease whose pathogenesis is linked to the presence of proinflammatory cytokines, such as TNF-alpha. To understand this observation, we have examined the effect of NSAIDs on the production of clinically validated proinflammatory cytokines. We show that a variety of NSAIDs superinduce production of TNF from human peripheral blood monocytes and rheumatoid synovial membrane cultures. A randomized, double-blinded, crossover, placebo-controlled trial in healthy human volunteers also revealed that the NSAID drug celecoxib increased LPS-induced TNF production in whole blood. NSAID-mediated increases in TNF are reversed by either the addition of exogenous PGE(2) or by a PGE(2) EP2 receptor agonist, revealing that PGE(2) signaling via its EP2 receptor provides a valuable mechanism for controlling excess TNF production. Thus, by reducing the level of PGE(2), NSAIDs can increase TNF production and may exacerbate the proinflammatory environment both within the rheumatoid arthritis joint and the systemic environment. PMID- 20713885 TI - TCR-induced activation of Ras proceeds at the plasma membrane and requires palmitoylation of N-Ras. AB - Ras transmits manifold signals from the TCR at various crossroads in the life of a T cell. For example, selection programs in the thymus or the acquisition of a state of hypo-responsiveness known as anergy are just some of the T cell features known to be controlled by TCR-sparked signals that are intracellularly propagated by Ras. These findings raise the question of how Ras can transmit such a variety of signals leading to the shaping of equally many T cell traits. Because Ras proteins transit through endomembrane compartments on their way to the plasma membrane (PM), compartmentalized Ras activation at distinct subcellular sites represents a potential mechanism for signal diversification in TCR signaling. This hypothesis has been nurtured by studies in T cells engineered to overexpress Ras that reported distinct activation of Ras at the PM and Golgi. Contrary to this scenario, we report in this study that activation of endogenous Ras, imaged in live Jurkat T cells using novel affinity probes for Ras-GTP, proceeds only at the PM even upon enforced signal flux through the diacylglycerol/RasGRP1 pathway. Physiological engagement of the TCR at the immunological synapse in primary T cells caused focalized Ras-GTP accumulation also only at the PM. Analysis of palmitoylation-deficient Ras mutants, which are confined to endomembranes, confirmed that the TCR does not activate Ras in that compartment and revealed a critical function for palmitoylation in N-Ras/H-Ras activation. These findings identify the PM as the only site of TCR-driven Ras activation and document that endomembranes are not a signaling platform for Ras in T cells. PMID- 20713884 TI - IL-10 restricts memory T cell inflation during cytomegalovirus infection. AB - The beta-herpesvirus CMV induces a substantial and progressive expansion of virus specific memory CD8 T cells, which protect the host against viral reactivation from latency. In this paper, we report that this expansion, or "inflation," of memory T cells is amplified dramatically during mouse CMV infection of IL-10 knockout (IL-10(-/-)) mice. T cells from IL-10(-/-) mice were oligoclonal, exhibited a highly activated phenotype, expressed antiviral cytokines, and degranulated in response to cognate Ag encounter ex vivo. Moreover, latent viral load was reduced in IL-10(-/-) mice. Importantly, these results were recapitulated by IL-10R blockade during chronic/latent infection of wild-type mice. These data demonstrate that regulatory immune mechanisms can influence CMV specific T cell memory and suggest a possible rationale for the acquisition of functional IL-10 orthologs by herpesviruses. PMID- 20713886 TI - In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages. AB - Macrophages are part of the tumor microenvironment and have been associated with poor prognosis in uveal melanoma. We determined the presence of macrophages and their differentiation status in a murine intraocular melanoma model. Inoculation of B16F10 cells into the anterior chamber of the eye resulted in rapid tumor outgrowth. Strikingly, in aged mice, tumor progression depended on the presence of macrophages, as local depletion of these cells prevented tumor outgrowth, indicating that macrophages in old mice had a strong tumor-promoting role. Immunohistochemistry and gene expression analysis revealed that macrophages carried M2-type characteristics, as shown by CD163 and peroxisome proliferator activated receptor gamma expression, and that multiple angiogenic genes were heavily overrepresented in tumors of old mice. The M2-type macrophages were also shown to have immunosuppressive features. We conclude that tumor-associated macrophages are directly involved in tumor outgrowth of intraocular melanoma and that macrophages in aged mice have a predisposition for an M2-type profile. PMID- 20713888 TI - Directly transfected langerin+ dermal dendritic cells potentiate CD8+ T cell responses following intradermal plasmid DNA immunization. AB - Dendritic cells (DCs) play a critical role in CD8(+) T cell priming following DNA vaccination. In contrast to other DNA injection routes or immunization with viral vectors, Ag presentation is delayed following needle injection of plasmid DNA into the skin. The contribution of various skin DC subsets to this process is not known. In this study, we show that dermal CD11c(+) cells are the most important transgene-expressing cells following immunization. Using langerin- diphtheria toxin receptor mice we demonstrated that langerin(+) dermal DCs (Ln(+) dDCs) were crucial for generating an optimal CD8(+) T cell response. Blocking migration of skin cells to the lymph node (LN) ablated immunogenicity, suggesting that migration of dDC subsets to the LN is essential for generating immunity. This migration generated a weak Ag-presenting activity in vivo until day 5 postimmunization, which then increased dramatically. We further found that Ln(+) dDCs and dDCs were the only DC populations directly presenting Ag to CD8(+) T cells ex vivo during the initial 8-d period postimmunization. This activity changed on the following days, when both skin DCs and LN-resident DCs were able to present Ag to CD8(+) T cells. Taken together, our in vivo and ex vivo results suggest that activation of CD8(+) T cells following intradermal plasmid DNA immunization depends on directly transfected Ln(+)dDCs and dDCs. Moreover, the type of DCs presenting Ag changed over time, with Ln(+)dDCs playing the major role in potentiating the initial CD8(+) T cell response. PMID- 20713887 TI - Tyrosine kinase 2 controls IL-1beta production at the translational level. AB - IL-1beta is an important proinflammatory cytokine with a major role in several inflammatory diseases. Expression of IL-1beta is tightly regulated at the level of transcription, mRNA stability, and proteolytic processing. In this study, we report that IL-1beta expression in response to LPS is also regulated at the translational level. LPS-induced IL-1beta protein levels in macrophages derived from murine bone marrow are markedly increased in the absence of tyrosine kinase 2 (Tyk2). Increased IL-1beta is found intra- and extracellularly, irrespective of the efficiency of IL-1beta processing. We show that the absence of Tyk2 results both in higher translational rates and in enhanced association of IL-1beta mRNA with polysomes. Induction and stability of IL-1beta mRNA are not affected by the lack of Tyk2. We show further that the Tyk2-dependent translational inhibition is mediated by autocrine/paracrine type I IFN signaling and requires signal transducer and activator of transcription 1. Enhanced IL-1beta production in Tyk2 and IFN receptor 1-deficient macrophages is also observed following Listeria monocytogenes infection. Taken together, the data describe a novel mechanism for the control of IL-1beta synthesis. PMID- 20713890 TI - TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. AB - TLR9 plays an important role in innate defense against viruses by the detection of CpG motifs of foreign DNA within intracellular compartments. In this study, we evaluated the ability of EBV to promote monocyte and plasmacytoid dendritic cell (pDC) activation and cytokine release through TLR9 activation. We demonstrated that treatment of primary monocytes with EBV and with purified EBV DNA induced the release of IL-8 through TLR9. Activation of TLR9 by viral DNA requires endosomal maturation because pretreatment of monocytes with chloroquine strongly reduced IL-8 secretion. However, pretreatment of monocytes with siRNA directed against TLR2, with inhibitory ODN (iODN) or with a combination of both inhibitors strongly reduced the secretion of IL-8, providing evidence of a dual action of TLR2 and TLR9 in EBV recognition by monocytes. In contrast, production of MCP-1 and IL-10 in EBV-treated monocytes was mainly regulated through TLR2. Although EBV does not establish infection in pDCs, challenge with either live EBV particles or isolated EBV DNA was found to induce the release of IFN-alpha through TLR9, as supported by blockage of TLR9 activity with iODN or chloroquine. The role of TLR9 in the recognition of EBV by pDCs appears to be dominant, as confirmed by the marked inhibitory effect of iODN observed on the synthesis of IFN-alpha, IL-6, and IL-8 by pDCs. These results demonstrate that recognition of EBV by TLR9 is differently orchestrated in primary monocytes and pDCs to optimize viral recognition and antiviral response. PMID- 20713889 TI - Ethylenecarbodiimide-treated splenocytes carrying male CD4 epitopes confer histocompatibility Y chromosome antigen transplant protection by inhibiting CD154 upregulation. AB - In humans and certain strains of laboratory mice, male tissue is recognized as nonself and destroyed by the female immune system via recognition of histocompatibility Y chromosome Ag (Hya). Male tissue destruction is thought to be accomplished by CTLs in a helper-dependent manner. We show that graft protection induced with the immunodominant Hya-encoded CD4 epitope (Dby) attached to female splenic leukocytes (Dby-SPs) with the chemical cross-linker ethylenecarbodiimide significantly, and often indefinitely, prolongs the survival of male skin graft transplants in an Ag-specific manner. In contrast, treatments with the Hya CD8 epitopes (Uty-/Smcy-SPs) failed to prolong graft survival. Dby SP-tolerized CD4(+) T cells fail to proliferate, secrete IFN-gamma, or effectively prime a CD8 response in recipients of male grafts. Ag-coupled splenocyte treatment is associated with defective CD40-CD40L interactions as demonstrated by the observation that CD4 cells from treated animals exhibit a defect in CD40L upregulation following in vitro Ag challenge. Furthermore, treatment with an agonistic anti-CD40 Ab at the time of transplantation abrogates protection from graft rejection. Interestingly, anti-CD40 treatment completely restores the function of Dby-specific CD4 cells but not Uty- or Smcy-specific CD8 cells. PMID- 20713891 TI - Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets. AB - A pivotal role for tertiary lymphoid structures (TLSs) in promoting Ag-specific humoral responses during chronic inflammation is emerging in several autoimmune conditions, including rheumatoid arthritis, Sjogren's syndrome, and autoimmune thyroiditis. However, there is limited evidence on the cellular and molecular mechanisms underlying TLS formation and their contribution to autoimmunity in the pancreas during autoimmune insulitis. In this study, we performed a detailed and comprehensive assessment of the evolution of TLSs during autoimmune insulitis in 126 female NOD mice from 4 to 38 wk of age. We demonstrated that during progression from peri- to intrainsulitis in early diabetic mice, T and B cell infiltration follows a highly regulated process with the formation of lymphoid aggregates characterized by T/B cell segregation, follicular dendritic cell networks, and differentiation of germinal center B cells. This process is preceded by local upregulation of lymphotoxins alpha/beta and lymphoid chemokines CXCL13 and CCL19, and is associated with infiltration of B220(+)/IgD(+)/CD23(+)/CD21(-) follicular B cells expressing CXCR5. Despite a similar incidence of insulitis, late diabetic mice displayed a significantly reduced incidence of fully organized TLSs and reduced levels of lymphotoxins/lymphoid chemokines. Upon development, TLSs were fully functional in supporting in situ autoreactive B cell differentiation, as demonstrated by the expression of activation-induced cytidine deaminase, the enzyme required for Ig affinity maturation and class switching, and the presence of CD138(+) plasma cells displaying anti-insulin reactivity. Overall, our work provides direct evidence that TLSs are of critical relevance in promoting autoimmunity and chronic inflammation during autoimmune insulitis and diabetes in NOD mice. PMID- 20713892 TI - Cutting edge: proteolytic inactivation of poly(ADP-ribose) polymerase 1 by the Nlrp3 and Nlrc4 inflammasomes. AB - Caspase-mediated cleavage of the DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP1) is a hallmark of apoptosis. However, it remains unclear whether PARP1 is processed during pyroptosis, a specialized cell-death program that occurs upon activation of caspase-1 in inflammasome complexes. In this article, we show that activation of the Nlrp3 and Nlrc4 inflammasomes induces processing of full-length PARP1 into a fragment of 89 kDa in a stimulus-dependent manner. Macrophages deficient for caspase-1 and those lacking the inflammasome adaptors Nlrp3, Nlrc4, and ASC were highly resistant to cleavage, whereas macrophages lacking the downstream inflammasome effector caspase-7 were partially protected. A modest, but statistically significant, reduction in Nlrp3 inflammasome-induced pyroptosis was observed in PARP1 knockout macrophages. Thus, protease-mediated inactivation of PARP1 is a shared feature of apoptotic, necrotic, and pyroptotic cells. PMID- 20713894 TI - Hold the patty, not the lettuce: processing foods for over a quarter century in the Nurses' Health Study. PMID- 20713893 TI - Internalization and coreceptor expression are critical for TLR2-mediated recognition of lipoteichoic acid in human peripheral blood. AB - Lipoteichoic acid (LTA), a ubiquitous cell wall component of Gram-positive bacteria, represents a potent immunostimulatory molecule. Because LTA of a mutant Staphylococcus aureus strain lacking lipoproteins (Deltalgt-LTA) has been described to be immunobiologically inactive despite a lack of ascertained structural differences to wild-type LTA (wt-LTA), we investigated the functional requirements for the recognition of Deltalgt-LTA by human peripheral blood cells. In this study, we demonstrate that Deltalgt-LTA-induced immune activation critically depends on the immobilization of LTA and the presence of human serum components, which, to a lesser degree, was also observed for wt-LTA. Under experimental conditions allowing LTA-mediated stimulation, we found no differences between the immunostimulatory capacity of Deltalgt-LTA and wt-LTA in human blood cells, arguing for a limited contribution of possible lipoprotein contaminants to wt-LTA-mediated immune activation. In contrast to human blood cells, TLR2-transfected human embryonic kidney 293 cells could be activated only by wt-LTA, whereas activation of these cells by Deltalgt-LTA required the additional expression of TLR6 and CD14, suggesting that activation of human embryonic kidney 293 cells expressing solely TLR2 is probably mediated by residual lipoproteins in wt-LTA. Notably, in human peripheral blood, LTA-specific IgG Abs are essential for Deltalgt-LTA-mediated immune activation and appear to induce the phagocytic uptake of Deltalgt-LTA via engagement of FcgammaRII. In this study, we have elucidated a novel mechanism of LTA-induced cytokine induction in human peripheral blood cells that involves uptake of LTA and subsequent intracellular recognition driven by TLR2, TLR6, and CD14. PMID- 20713895 TI - The ideal conduit for surgical revascularization: the quest for the holy grail continues. PMID- 20713896 TI - Aortic root remodeling over the adult life course: longitudinal data from the Framingham Heart Study. AB - BACKGROUND: Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course. METHODS AND RESULTS: We used serial routine echocardiograms in participants of the Framingham Heart Study to track aortic root diameter over 16 years in mid to late adulthood and to determine its short-term (4 years; n=6099 observations in 3506 individuals) and long-term (16 years; n=14,628 observations in 4542 individuals) clinical correlates by multilevel modeling. Age, sex, body size, and blood pressure were principal correlates of aortic remodeling in both short- and long-term analyses (all P < or = 0.01). Aortic root diameter increased with age in both men and women but was larger in men at any given age. Each 10-year increase in age was associated with a larger aortic root (by 0.89 mm in men and 0.68 mm in women) after adjustment for body size and blood pressure. A 5-kg/m(2) increase in body mass index was associated with a larger aortic root (by 0.78 mm in men and 0.51 mm in women) after adjustment for age and blood pressure. Each 10 mm Hg increase in pulse pressure was related to a smaller aortic root (by 0.19 mm in men and 0.08 mm in women) after adjustment for age and body size. CONCLUSIONS: These longitudinal community-based data show that aortic root remodeling occurs over mid to late adulthood and is principally associated with age, sex, body size, and blood pressure. The underlying basis for these differences and implications for the development of cardiovascular events deserve further study. PMID- 20713898 TI - Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. AB - BACKGROUND: Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes. METHODS AND RESULTS: We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics. CONCLUSIONS: This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH. PMID- 20713897 TI - Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown. METHODS AND RESULTS: We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function. CONCLUSIONS: CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model. PMID- 20713899 TI - Int6/eIF3e silencing promotes functional blood vessel outgrowth and enhances wound healing by upregulating hypoxia-induced factor 2alpha expression. AB - BACKGROUND: We previously identified INT6/eIF3e as a novel regulator of hypoxia inducible factor 2alpha (HIF2alpha) activity. Small interfering RNA (siRNA)-Int6 adequately stabilized HIF2alpha, even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo. METHODS AND RESULTS: We demonstrated a 6- to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure of the injury. HIF2alpha accumulation caused by siRNA Int6 was confirmed as the unequivocal cause of the angiogenesis by an in vivo angiogenesis assay. Further analysis of the Int6 silencing-induced neoangiogenesis revealed that a negative feedback regulation of HIF2alpha stability was caused by HIF2alpha-induced transcription of Int6 via hypoxia response elements in its promoter. Thus, siRNA-Int6 temporarily facilitates an accumulation of HIF2alpha protein, leading to hypoxia-independent transcription of angiogenic factors and concomitant neoangiogenesis. CONCLUSIONS: We suggest that the pathway involving INT6/HIF2alpha acts as a hypoxia-independent master switch of functional angiogenesis; therefore, siRNA-Int6 application might be of clinical value in treating ischemic diseases such as heart and brain ischemia, skin injury, and diseases involving obstructed vessels. PMID- 20713900 TI - Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multi institutional study. AB - BACKGROUND: The arrhythmia burden in tetralogy of Fallot, types of arrhythmias encountered, and risk profile may change as the population ages. METHODS AND RESULTS: The Alliance for Adult Research in Congenital Cardiology (AARCC) conducted a multicenter cross-sectional study to quantify the arrhythmia burden in tetralogy of Fallot, to characterize age-related trends, and to identify associated factors. A total of 556 patients, 54.0% female, 36.8+/-12.0 years of age were recruited from 11 centers. Overall, 43.3% had a sustained arrhythmia or arrhythmia intervention. Prevalence of atrial tachyarrhythmias was 20.1%. Factors associated with intraatrial reentrant tachycardia in multivariable analyses were right atrial enlargement (odds ratio [OR], 6.2; 95% confidence interval [CI], 2.8 to 13.6), hypertension (OR, 2.3; 95% CI, 1.1 to 4.6), and number of cardiac surgeries (OR, 1.4; 95% CI, 1.2 to 1.6). Older age (OR, 1.09 per year; 95% CI, 1.05 to 1.12), lower left ventricular ejection fraction (OR, 0.93 per unit; 95% CI, 0.89 to 0.96), left atrial dilation (OR, 3.2; 95% CI, 1.5 to 6.8), and number of cardiac surgeries (OR, 1.5; 95% CI, 1.2 to 1.9) were jointly associated with atrial fibrillation. Ventricular arrhythmias were prevalent in 14.6% and jointly associated with number of cardiac surgeries (OR, 1.3; 95% CI, 1.1 to 1.6), QRS duration (OR, 1.02 per 1 ms; 95% CI, 1.01 to 1.03), and left ventricular diastolic dysfunction (OR, 3.3; 95% CI, 1.5 to 7.1). Prevalence of atrial fibrillation and ventricular arrhythmias markedly increased after 45 years of age. CONCLUSIONS: The arrhythmia burden in adults with tetralogy of Fallot is considerable, with various subtypes characterized by different profiles. Atrial fibrillation and ventricular arrhythmias appear to be influenced more by left- than right-sided heart disease. PMID- 20713901 TI - Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. AB - BACKGROUND: Endomyocardial biopsy (EMB) represents the gold standard for diagnosing myocarditis and nonischemic cardiomyopathies. This study focuses on the risk of complications and the respective diagnostic performance of left ventricular (LV), right ventricular (RV), or biventricular EMB in patients with suspected myocarditis and/or cardiomyopathy of unknown origin. METHODS AND RESULTS: In this 2-center study, 755 patients with clinically suspected myocarditis (n=481) and/or cardiomyopathy of nonischemic origin including those with infiltrative or connective tissue disease (n=274) underwent either selective LV-EMB (n=265; 35.1%), selective RV-EMB (n=133; 17.6%), or biventricular EMB (n=357; 47.3%) after coronary angiography and exclusion of significant coronary artery disease. Cardiovascular magnetic resonance, including late gadolinium enhancement, imaging was performed in 540 patients (71.5%). The major complication rate for LV-EMB was 0.64% and for RV-EMB, 0.82%. Considering postprocedural pericardial effusion that occurred after biventricular EMB, the minor complication rate for LV-EMB varied between 0.64% to 2.89% and for RV-EMB, between 2.24% and 5.10%. Diagnostic EMB results were achieved significantly more often in those patients who underwent biventricular EMBs (79.3%) compared to those who underwent either selective LV-EMB or selective RV-EMB (67.3%; P<0.001). In patients with biventricular EMB, myocarditis was diagnosed in LV-EMB samples in 18.7% and in RV-EMB samples in 7.9% (P=0.002) , and it was diagnosed in both ventricles in 73.4%. There were no differences in the number of positive LV-EMB, RV-EMB, or LV- and RV-EMB findings when related to the site of cardiovascular magnetic resonance-based late gadolinium enhancement. CONCLUSIONS: Both LV-EMB and RV-EMB are safe procedures if performed by experienced interventionalists. The diagnostic yield of EMB may be optimized when samples from both ventricles are available. Preferential biopsy in regions showing late gadolinium enhancement on cardiovascular magnetic resonance does not increase the number of positive diagnoses of myocarditis. PMID- 20713902 TI - Major dietary protein sources and risk of coronary heart disease in women. AB - BACKGROUND: With the exception of fish, few major dietary protein sources have been studied in relation to the development of coronary heart disease (CHD). Our objective was to examine the relation between foods that are major dietary protein sources and incident CHD. METHODS AND RESULTS: We prospectively followed 84,136 women aged 30 to 55 years in the Nurses' Health Study with no known cancer, diabetes mellitus, angina, myocardial infarction, stroke, or other cardiovascular disease. Diet was assessed by a standardized and validated questionnaire and updated every 4 years. During 26 years of follow-up, we documented 2210 incident nonfatal infarctions and 952 deaths from CHD. In multivariable analyses including age, smoking, and other risk factors, higher intakes of red meat, red meat excluding processed meat, and high-fat dairy were significantly associated with elevated risk of CHD. Higher intakes of poultry, fish, and nuts were significantly associated with lower risk. In a model controlling statistically for energy intake, 1 serving per day of nuts was associated with a 30% (95% confidence interval, 17% to 42%) lower risk of CHD compared with 1 serving per day of red meat. Similarly, compared with 1 serving per day of red meat, a lower risk was associated with 1 serving per day of low fat dairy (13%; 95% confidence interval, 6% to 19%), poultry (19%; 95% confidence interval, 3% to 33%), and fish (24%; 95% confidence interval, 6% to 39%). CONCLUSIONS: These data suggest that high red meat intake increases risk of CHD and that CHD risk may be reduced importantly by shifting sources of protein in the US diet. PMID- 20713903 TI - Vascular reactivity and flow characteristics of radial artery and long saphenous vein coronary bypass grafts: a 5-year follow-up. AB - BACKGROUND: Radial artery (RA) aortocoronary bypass grafts anastomosed to a branch of the circumflex coronary artery have significantly better patency rates than saphenous vein (SV) grafts at 5 years, but the physiological characteristics and mechanisms involved are not clearly defined. We compared RA and SV graft vasomotor and flow responses to endothelium-dependent and -independent stimuli 5 years after surgery in a subgroup of patients enrolled in the Radial artery versus Saphenous Vein Patency (RSVP) trial. METHODS AND RESULTS: Twenty-seven patients were included in the study (RA, n=15; SV, n=12). Graft blood flow was calculated from flow velocity, measured by intracoronary Doppler, and luminal diameter, measured by quantitative coronary angiography, before and after intragraft infusions of adenosine, acetylcholine, and isosorbide dinitrate. At rest, RA luminal diameters were significantly smaller than SV luminal diameters (P=0.029), blood flow velocity was greater in RA than SV (P=0.008), and volume blood flows were similar. RA but not SV dilated in response to adenosine and isosorbide dinitrate (all P<0.05, RA versus SV, percent change from baseline), and there were no significant differences in the diameter responses to acetylcholine. Volume blood flow responses to adenosine, acetylcholine, and isosorbide dinitrate were comparable. CONCLUSIONS: Five years after surgery, RA coronary bypass conduits grafted to a single coronary territory demonstrated preserved flow-mediated vasodilatation, whereas SV grafts did not. Our results may provide insight into the more favorable patency of RA grafts over SV grafts. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00139399. PMID- 20713904 TI - Chocolate intake and incidence of heart failure: a population-based prospective study of middle-aged and elderly women. AB - BACKGROUND: Randomized clinical trials have shown that chocolate intake reduces systolic and diastolic blood pressure, and observational studies have found an inverse association between chocolate intake and cardiovascular disease. The aim of this study was to investigate the association between chocolate intake and incidence of heart failure (HF). METHODS AND RESULTS: We conducted a prospective cohort study of 31,823 women aged 48 to 83 years without baseline diabetes or a history of HF or myocardial infarction who were participants in the Swedish Mammography Cohort. In addition to answering health and lifestyle questions, participants completed a food-frequency questionnaire. Women were followed from January 1, 1998, through December 31, 2006, for HF hospitalization or death through the Swedish inpatient and cause-of-death registers. Over 9 years of follow-up, 419 women were hospitalized for incident HF (n=379) or died of HF (n=40). Compared with no regular chocolate intake, the multivariable-adjusted rate ratio of HF was 0.74 (95% CI, 0.58 to 0.95) for women consuming 1 to 3 servings of chocolate per month, 0.68 (95% CI, 0.50 to 0.93) for those consuming 1 to 2 servings per week, 1.09 (95% CI, 0.74 to 1.62) for those consuming 3 to 6 servings per week, and 1.23 (95% CI, 0.73 to 2.08) for those consuming >=1 servings per day (P=0.0005 for quadratic trend). CONCLUSIONS: In this population, moderate habitual chocolate intake was associated with a lower rate of HF hospitalization or death, but the protective association was not observed with intake of >=1 servings per day. PMID- 20713905 TI - Bronchogenic cyst masquerading as pericarditis. PMID- 20713906 TI - Letter by Violi et al regarding article, "Association of cyclooxygenase-1 dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization". PMID- 20713907 TI - Letter by Giglio and Mangiola regarding article, "Cardiomyopathy in Duchenne muscular dystrophy carrier and her diseased son: similar pattern revealed by cardiovascular MRI". PMID- 20713908 TI - Series on exercise in cardiovascular disease. PMID- 20713909 TI - Physical activity and cardiovascular health: lessons learned from epidemiological studies across age, gender, and race/ethnicity. PMID- 20713910 TI - Gargantuan pseudoaneurysm of the left ventricle. PMID- 20713911 TI - Positive relationship between plasma leptin levels and hypertension from an epidemiological perspective. PMID- 20713912 TI - Hemodynamic determinants of myocardial B-type natriuretic peptide release: relative contributions of systolic and diastolic wall stress. AB - Although B-type natriuretic peptide (BNP) is widely used as a biomarker for heart failure, the in vivo mechanical stimulus for its cardiac release remains poorly defined. We aimed to characterize the hemodynamic determinants of the transcardiac BNP gradient as a measure of myocardial BNP release by performing a detailed hemodynamic assessment in subjects with a broad spectrum of systolic and diastolic left ventricular dysfunction. Forty-two subjects underwent a detailed transthoracic echocardiographic study, right heart catheterization, and simultaneous BNP measurement in arterial and coronary sinus plasma. The transcardiac BNP gradient was lowest in subjects with normal left ventricular ejection fraction/high peak early diastolic annular velocity (n=11), intermediate in those with normal left ventricular ejection fraction/low peak early diastolic annular velocity (n=13), and highest in those with low left ventricular ejection fraction/low peak early diastolic annular velocity (n=18; 29 ng/L (range: 15 to 78 ng/L) versus 88 ng/L (range: 34 to 172 ng/L) versus 1566 ng/L (range: 624 to 2349 ng/L; P<0.001). Across the range of patients, left ventricular end-systolic wall stress (r(2)=0.51) and peak systolic mitral annular velocity (r(2)=0.47) showed the strongest correlation with higher transcardiac BNP gradient. In contrast, the transcardiac BNP gradient was weakly related to indices of diastolic load, including pulmonary capillary wedge pressure (r(2)=0.27) and left ventricular end-diastolic wall stress (r(2)=0.21). Across this spectrum of pathophysiology, left ventricular end-systolic wall stress appears to be the key mechanical stimulus influencing cardiac BNP release. PMID- 20713913 TI - Trait antagonism and the progression of arterial thickening: women with antagonistic traits have similar carotid arterial thickness as men. AB - A large body of evidence links antagonism-related traits with cardiovascular outcomes, but less is known about how psychological traits are associated with intermediate markers of cardiovascular disease. Using a large, community-based sample from Sardinia, Italy (n=5614), this study examined how trait antagonism (low agreeableness) and its facets are associated with carotid artery intima media thickness, a measure of arterial thickening. Controlling for demographic and cardiovascular risk factors, low agreeableness and, in particular, low straightforwardness and low compliance, were associated with greater carotid thickening, measured concurrently and prospectively, and with increases in intima media thickness over 3 years. Indeed, those in the bottom 10% of agreeableness had a 40% increase in risk for elevated intima-media thickness. Although men have thicker arterial walls, women with antagonistic traits had similar carotid thickening as antagonistic men. Antagonistic individuals, especially those who are manipulative and aggressive, have greater increases in arterial thickening, independent of traditional cardiovascular risk factors. PMID- 20713914 TI - Impaired 3',5'-cyclic adenosine monophosphate-mediated signaling in immediate early responsive gene X-1-deficient vascular smooth muscle cells. AB - Gene-targeted deletion of the immediate early responsive gene X-1 (IEX-1) results in a significant increase in systemic arterial blood pressure, but the underlying mechanism is not understood. Studies of arterial reactivity in isolated aortas revealed normal endothelium-dependent and -independent vasorelaxation and vasoconstriction but reduced cAMP-dependent vasorelaxation in the absence of IEX 1. This defect in cAMP signaling was also evident in endothelium-denuded aortic rings, consistent with the enhancement of mitochondrial O2.- production only in IEX-1-deficient vascular smooth muscle cells, not in endothelial cells. Excessive production of reactive oxygen species at mitochondria augmented the expression of Galpha(i2), suppressing cAMP production in vascular smooth muscle cells. The role of mitochondrial reactive oxygen species in the upregulation of Galpha(i2) leading to the development of hypertension was supported by the ability of antioxidant or pertussis toxin to restore the cAMP-dependent vasorelaxation to a normal level and reverse established hypertension in IEX-1 homozygous knockout mice. Our results suggest that hypertension in IEX-1 knockout mice may arise primarily from impaired cAMP signaling induced by overproduction of mitochondrial reactive oxygen species in vascular smooth muscle cells and demonstrate a causal relationship between mitochondrial dysfunction and cAMP-dependent vasorelaxation. PMID- 20713915 TI - Dietary fatty acids and the risk of hypertension in middle-aged and older women. AB - Dietary intake of various fats may have different effects on blood pressure. We conducted a prospective cohort study to examine the association between intake of subtype and individual fatty acids (FAs) and the risk of developing hypertension among 28 100 US women aged >=39 years and free of cardiovascular disease and cancer. Baseline intake of FAs was assessed using semiquantitative food frequency questionnaires. Incident hypertension was identified from annual follow-up questionnaires based on self-reported physician diagnosis, medication use, and blood pressure levels. A total of 13 633 women developed incident hypertension during 12.9 years of follow-up. After adjusting for demographic, lifestyle, and other dietary factors, intake of saturated FAs, monounsaturated FAs, and trans unsaturated FAs (trans FAs) was positively associated with the risk of hypertension. The multivariable relative risks and 95% CIs of hypertension in the highest compared with the lowest quintile of intake were 1.12 (1.05 to 1.20) for saturated FAs, 1.11 (1.04 to 1.18) for monounsaturated FAs, and 1.15 (1.08 to 1.22) for trans FAs. After additional adjustment for body mass index and history of diabetes mellitus and hypercholesterolemia, these associations were attenuated and remained statistically significant only for trans FAs (relative risk in the highest quintile: 1.08; 95% CI: 1.01 to 1.15). Intake of polyunsaturated FAs, including omega3 and omega6 polyunsaturated FAs, was not significantly associated with the risk of hypertension. In conclusion, higher intake of saturated FAs, monounsaturated FAs, and trans FAs was each associated with increased risk of hypertension among middle-aged and older women, whereas only association for trans FAs remained statistically significant after adjustment for obesity-related factors. PMID- 20713917 TI - Cerebrovascular damage in late-life depression is associated with structural and functional abnormalities of subcutaneous small arteries. AB - Late-life depression is increasingly viewed as a vascular illness because of patients exhibiting characteristic white matter brain lesions and in vivo large artery endothelial dysfunction. However, the "vascular depression" hypothesis pertains to the microvasculature, and this circulation has not been studied in this context. Our objective was to examine structure and function of small subcutaneous arteries in patients with late-life depression. Thus, 16 patients aged 71.8+/-4.0 years with late-life depression were compared with 15 control participants aged 72.1+/-5.9 years. There were similar cardiovascular profiles between the 2 groups. All of the participants underwent MRI brain scans and subcutaneous gluteal fat biopsy from which small arteries were isolated and studied using pressure myography. Cerebral microvascular damage in depressed patients was confirmed by assessment of basal ganglia Virchow-Robin space scores (depressed patients 3.9+/-1.7 versus controls: 2.5+/-1.6; P=0.01). Contractility to norepinephrine was equivalent in both groups, but relaxation of the small arteries to acetylcholine was significantly reduced in depressed patients (84.0+/ 4.0%) compared with control participants (96.0+/-1.4%; P=0.012). This difference in arterial relaxation was reduced but not entirely eliminated when NO synthase was inhibited. Depressed patients also exhibited hypertrophic wall growth with an increase in medial cross-sectional area (P=0.035, multiple ANOVA and wall thickness; P=0.04, multiple ANOVA). In conclusion, despite similar cardiovascular profiles, depressed patients with cerebral microvascular damage show abnormalities of subcutaneous small artery structure and function. PMID- 20713916 TI - Angiotensin (1-7) receptor antagonism equalizes angiotensin II-induced hypertension in male and female spontaneously hypertensive rats. AB - Females are less sensitive to the hypertensive effects of angiotensin II compared with males, although the molecular mechanisms responsible are unknown. We hypothesize that differential activation of angiotensin II, angiotensin (1-7), angiotensin II type 1, angiotensin II type 2, and mas levels in the renal cortex of male and female spontaneously hypertensive rats contribute to sex differences in the blood pressure response to angiotensin II infusion. Males had a greater increase in blood pressure after angiotensin II infusion than females (males: 150+/-2 to 186+/-3 mm Hg; females: 137+/-3 to 160+/-4 mm Hg; P<0.05). Angiotensin II infusion resulted in comparable increases in plasma and renal cortical angiotensin II levels in both sexes. Renal cortical angiotensin (1-7) levels were higher in female rats under basal conditions (195+/-10 versus 67+/-11 ng/g of cortex; P<0.05) and after angiotensin II infusion (281+/-25 versus 205+/-47 ng/g of cortex; P<0.05) compared with male rats. In the renal cortex of male rats, angiotensin II infusion decreased angiotensin II type 1 protein expression and increased angiotensin II type 2 expression with no change in mas expression. In female rats there was an increase in mas receptor protein expression with angiotensin II infusion, although angiotensin II type 1 and angiotensin II type 2 expressions were unchanged. Male and female rats were then treated with the angiotensin (1-7) mas receptor antagonist A-779 in the absence and presence of angiotensin II. A-779 equalized the blood pressure response to angiotensin II in males and females (blood pressure at the end of treatment: males, 166+/-4 mm Hg; females, 164+/-5 mm Hg). In conclusion, angiotensin (1-7) contributes to the sex difference in angiotensin II-induced increases in blood pressure in spontaneously hypertensive rats. PMID- 20713918 TI - Decreased activity of the Na+/H+ exchanger by phosphodiesterase 5A inhibition is attributed to an increase in protein phosphatase activity. AB - The beneficial effect of phosphodiesterase 5A inhibition in ischemia/reperfusion injury and cardiac hypertrophy is well established. Inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1) exerts beneficial effects on these same conditions, and a possible link between these therapeutic strategies was suggested. Experiments were performed in isolated cat cardiomyocytes to gain insight into the intracellular pathway involved in the reduction of NHE-1 activity by phosphodiesterase 5A inhibition. NHE-1 activity was assessed by the rate of intracellular pH recovery from a sustained acidic load in the absence of bicarbonate. Phosphodiesterase 5A inhibition with sildenafil (1 MUmol/L) did not affect basal intracellular pH; yet, it did decrease proton efflux (J(H); in millimoles per liter per minute) after the acidic load (proton efflux: 6.97+/ 0.43 in control versus 3.31+/-0.58 with sildenafil; P<0.05). The blockade of both protein phosphatase 1 and 2A with 100 nmol/L of okadaic acid reverted the sildenafil effect (proton efflux: 6.77+/-0.82). In contrast, selective inhibition of protein phosphatase 2A (1 nmol/L of okadaic acid or 100 MUmol/L of endothall) did not (3.86+/-1.0 and 2.61+/-1.2), suggesting that only protein phosphatase 1 was involved in sildenafil-induced NHE-1 inhibition. Moreover, sildenafil prevented the acidosis-induced increase in NHE-1 phosphorylation without affecting activation of the extracellular signal-regulated kinase 1/2-p90(RSK) pathway. Our results suggest that phosphodiesterase 5A inhibition decreases NHE-1 activity, during intracellular pH recovery after an acidic load, by a protein phosphatase 1-dependent reduction in NHE-1 phosphorylation. PMID- 20713919 TI - Positive relationship between plasma leptin level and hypertension. AB - Leptin is an adipose tissue-derived hormone shown to be related to metabolic, inflammatory, and hemostatic factors involved in hypertension development. Animal studies suggest that higher leptin levels may activate the sympathetic nervous system and cause elevations in blood pressure (BP). However, few studies have examined the association between leptin and hypertension in humans. Also it is not clear whether this association is present among women as well as men. Therefore, we examined the association between plasma leptin levels and hypertension in a representative sample of US adults. We examined the third National Health and Nutrition Examination Survey participants >20 years of age (n=5599; 54.7% women). Plasma leptin levels were categorized into quartiles (women: <7.68, 7.68 to 13.18, 13.19 to 21.70, >21.70 fg/L; men: <2.64, 2.64 to 4.36, 4.37 to 7.12, >7.12 fg/L). Hypertension was defined as BP-reducing medication use or having systolic BP >=140 mm Hg and/or diastolic BP >=90 mm Hg. We found that higher plasma leptin levels were positively associated with hypertension after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index, diabetes mellitus, serum cholesterol, and C reactive protein. Compared with quartile 1 of leptin (referent), the odds ratio (95% CI) of hypertension associated with quartile 4 was 1.89 (1.24 to 2.09; P for trend=0.0036). Subgroup analyses examining the relation between leptin and hypertension by sex and body mass index categories also showed a consistent positive association. In conclusion, higher plasma leptin levels are associated with hypertension both among women as well as men in a representative sample of US adults. PMID- 20713920 TI - Globalization of surgery: let's get serious. PMID- 20713921 TI - Bilateral robotic-assisted transaxillary surgery. AB - HYPOTHESIS: Robotic-assisted transaxillary surgery (RATS) for the removal of thyroid glands is feasible by surgeons in the United States. DESIGN: Case report. SETTING: Academic research. Patient A 53-year-old woman. INTERVENTION: Total thyroidectomy via the transaxillary approach. MAIN OUTCOME MEASURE: Successful completion thyroidectomy using bilateral RATS. RESULTS: Right thyroid lobectomy was performed via RATS to remove a 2.2-cm Hurthle cell neoplasm of the thyroid gland per cytologic analysis. Final pathologic analysis was consistent with minimally invasive follicular thyroid carcinoma. The patient then underwent completion thyroidectomy via left-sided RATS. There were no complications. CONCLUSIONS: Bilateral RATS to perform total thyroidectomy is a feasible option in properly selected patients. To our knowledge, this is the first reported use of this technique in the United States. PMID- 20713922 TI - Operative mortality in resource-limited settings: the experience of Medecins Sans Frontieres in 13 countries. AB - OBJECTIVE: To determine operative mortality in surgical programs from resource limited settings. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of 17 surgical programs in 13 developing countries by 1 humanitarian organization, Medecins Sans Frontieres, was performed between January 1, 2001, and December 31, 2008. Participants included patients undergoing surgical procedures. MAIN OUTCOME MEASURE: Operative mortality. Determinants of mortality were modeled using logistic regression. RESULTS: Between 2001 and 2008, 19,643 procedures were performed on 18,653 patients. Among these, 8329 procedures (42%) were emergent; 7933 (40%) were for obstetric-related pathology procedures and 2767 (14%) were trauma related. Operative mortality was 0.2% (31 deaths) and was associated with programs in conflict settings (adjusted odds ratio [AOR] = 4.6; P = .001), procedures performed under emergency conditions (AOR = 20.1; P = .004), abdominal surgical procedures (AOR = 3.4; P = .003), hysterectomy (AOR = 12.3; P = .001), and American Society of Anesthesiologists classifications of 3 to 5 (AOR = 20.2; P < .001). CONCLUSIONS: Surgical care can be provided safely in resource limited settings with appropriate minimum standards and protocols. Studies on the burden of surgical disease in these populations are needed to improve service planning and delivery. Quality improvement programs are needed for the various stakeholders involved in surgical delivery in these settings. PMID- 20713923 TI - Medication utilization and annual health care costs in patients with type 2 diabetes mellitus before and after bariatric surgery. AB - OBJECTIVE: To examine the relationship of bariatric surgery with the use of diabetes medications and with total health care costs in patients with type 2 diabetes mellitus. DESIGN: We studied 2235 adults with type 2 diabetes and commercial health insurance who underwent bariatric surgery in the United States during a 4-year period from January 1, 2002, through December 31, 2005. We used administrative claims data to measure the use of diabetes medications at specified time intervals before and after surgery and total median health care costs per year. SETTING: Seven states in the Blue Cross/Blue Shield Obesity Care Collaborative. PATIENTS: Two thousand two hundred thirty-five patients with type 2 diabetes mellitus who underwent bariatric surgery. RESULTS: Surgery was associated with elimination of diabetes medication therapy in 1669 of 2235 patients (74.7%) at 6 months, 1489 of 1847 (80.6%) at 1 year, and 906 of 1072 (84.5%) at 2 years after surgery. Reduction of use was observed in all classes of diabetes medications. The median cost of the surgical procedure and hospitalization was $29,959. In the 3 years following surgery, total annual health care costs per person increased by 9.7% ($616) in year 1 but then decreased by 34.2% ($2179) in year 2 and by 70.5% ($4498) in year 3 compared with a preoperative annual cost of $6376 observed from 1 to 2 years before surgery. CONCLUSIONS: Bariatric surgery is associated with reductions in the use of medication and in overall health care costs in patients with type 2 diabetes. Health insurance should cover bariatric surgery because of its health and cost benefits. PMID- 20713924 TI - Effect of physician ownership of specialty hospitals and ambulatory surgery centers on frequency of use of outpatient orthopedic surgery. AB - BACKGROUND: Physician-owned specialty hospitals and ambulatory surgery centers have become commonplace in many markets throughout the United States. Little is known about whether the financial incentives linked to ownership affect frequency of outpatient surgery. OBJECTIVE: To evaluate if financial incentives linked to physician ownership influence frequency of outpatient orthopedic surgical procedures. DESIGN AND SETTING: We analyzed 5 years of claims data from a large private insurer in Idaho to compare frequency by orthopedic surgeon owners and nonowners of surgical procedures that could be performed in either ambulatory surgery centers or hospital outpatient surgery departments. MAIN OUTCOME MEASURE: Frequency of use, calculated as number of patients treated with the specific diagnoses who received the surgical procedure of interest divided by the number of patients with such diagnoses treated by each physician. RESULTS: Age- and sex adjusted odds ratios indicate that the likelihood of having carpal tunnel repair was 54% to 129% higher for patients of surgeon owners compared with surgeon nonowners. For rotator cuff repair, the adjusted odds ratios of having surgery were 33% to 100% higher for patients treated by physician owners. The age- and sex-adjusted probability of arthroscopic surgery was 27% to 78% higher for patients of surgeon owners compared with surgeon nonowners. CONCLUSION: The consistent finding of higher use rates by physician owners across time clearly suggests that financial incentives linked to ownership of either specialty hospitals or ambulatory surgery centers influence physicians' practice patterns. PMID- 20713925 TI - Impact of mesh use on morbidity following ventral hernia repair with a simultaneous bowel resection. AB - OBJECTIVE: To evaluate the impact of mesh use on outcomes following ventral hernia repairs and simultaneous bowel resection. DESIGN: Retrospective review. SETTING: Teaching academic hospital. PATIENTS: We studied 177 patients who underwent a ventral hernia repair with a bowel resection between May 1, 1992, and May 30, 2007. A prosthesis was used in 51 repairs (mesh group), while 126 repairs were primary (mesh-free group). MAIN OUTCOME MEASURES: Demographic characteristics, comorbidities, mesh type, bowel resection type (colon vs small bowel), defect size, drain use, and length of hospital stay were compared between groups with Fisher exact test and multivariate analysis. RESULTS: There were no statistically significant differences between patient characteristics and relevant comorbidities. The incidence of postoperative infection (superficial or deep) was 22% in the mesh group vs 5% in the mesh-free group (P = .001). Other complications (fistula, seroma, hematoma, bowel obstruction) occurred in 24% of patients in the mesh group vs 8% of patients in the mesh-free group (P = .009). Focusing on the patients who developed an infection, prosthetic mesh use was the only significant risk factor on multivariate regression analysis, irrespective of drain use, defect size, and type of bowel resection. CONCLUSIONS: We recommend caution in using mesh when performing a ventral hernia repair with a simultaneous bowel resection because of significantly increased postoperative infectious complications. Drain use, defect size, and bowel resection type did not influence outcomes. PMID- 20713926 TI - Laparoscopic ileostomy in severe, obscure gastrointestinal hemorrhage: diagnostic laparoscopic ileostomy. AB - HYPOTHESIS: Laparoscopic diverting ileostomy should help define whether a severe, obscure gastrointestinal hemorrhage is in the upper or lower gastrointestinal tract in preparation for subtotal resection without increasing risk of patient morbidity and mortality. DESIGN: Case reports. SETTING: University hospital. PATIENTS: Patient 1 is an 83-year-old woman. Patient 2 is a 75-year-old woman. Both were admitted to the hospital for massive gastrointestinal hemorrhage, which required multiple blood transfusions. Extensive workup revealed multiple diverticula in the small and large intestines without identification of any source of active bleeding in either patient. INTERVENTION: Laparoscopic exploration of the abdominal cavity was performed. The terminal ileum at the ileocecal valve was identified and, 5 cm proximal to the ileocecal valve, the small bowel was transected. The distal end staple line was secured in end-to-side fashion to the proximal end, and the proximal end was brought out as an end ileostomy. Patients were then observed for bleeding into the ostomy bag or in the rectum. MAIN OUTCOME MEASURE: Localization of the source of bleeding as upper or lower, occurrence of surgical complications, and clinical outcome. RESULTS: No intraoperative complications occurred in either patient. Patient 1 had significant bleeding into her ileostomy bag on postoperative day 1. She was taken back to the operating room for empirical small bowel resection. She was discharged, had no further bleeding, and underwent closure of the ileostomy 2 months later. The postoperative course of patient 2 was complicated by a small parastomal abscess that resolved with percutaneous drainage and antibiotics. Patient 2 returned on postoperative day 22 with bleeding in the rectum. She was taken to the operating room for laparoscopic total colectomy with ileosigmoid anastomosis and ileostomy closure. Both patients recovered uneventfully and had no recurrent bleeding. CONCLUSIONS: Our experience with these 2 patients suggests that in cases in which the risk of blind resection appears ill-advised, laparoscopic compartmentalization of the small bowel from the colon via end ileostomy may be safely performed. PMID- 20713927 TI - Surgery in the Horn of Africa: a 1-year experience of an American-sponsored surgical residency in Eritrea. AB - OBJECTIVE: To describe the 1-year experience of a unique postgraduate medical education program set in Eritrea, a recently war-torn country. DESIGN: The Partnership for Eritrea, a cooperative between The George Washington University Medical Center, Physicians for Peace, and the Eritrean Ministry of Health, formed a surgical residency program, launched January 2, 2008, in Asmara, Eritrea, to train native Eritrean surgeons. No prior residency program (to our knowledge) had existed in Eritrea. SETTING: Eritrea, a country in the Horn of Africa. PATIENTS: Five Eritrean physicians participated in the surgical residency. MAIN OUTCOME MEASURES: The number of operations performed, length of stay, antibiotic use, and intravenous fluid use. RESULTS: The number of operations increased and resource use decreased because of improved and standardized clinical management. CONCLUSIONS: The Partnership for Eritrea established a general surgical residency program that improved clinical care in a resource-poor country that previously had lacked postgraduate training. The program experience suggests a model that can be reproduced in other developing countries. PMID- 20713928 TI - Bile duct injuries associated with laparoscopic cholecystectomy: timing of repair and long-term outcomes. AB - OBJECTIVES: To report on a large experience with laparoscopic cholecystectomy associated bile duct injuries (LC-BDIs) and examine factors influencing outcomes. DESIGN: A retrospective medical record review. Univariate statistical analysis was used to identify risk factors for postoperative complications. SETTING: Two university-affiliated hospitals. PATIENTS: Sixty-nine patients who underwent surgical repair of LC-BDI between January 1, 1992, and December 31, 2007. MAIN OUTCOME MEASURES: Outcomes following repair of LC-BDI, relationship between timing of LC-BDI repair and outcomes, complications, and long-term results following LC-BDI repair. RESULTS: Thirteen immediate repairs (0-72 hours post LC), 34 intermediate repairs (72 hours-6 weeks), and 22 late repairs (>6 weeks) were performed. The LC-BDIs were Strasberg type A in 1 patient (1%), D in 2 patients (3%), E1 in 22 patients (32%), E2 in 16 patients (23%), E3 in 22 patients (32%), E4 in 4 patients (6%), and E5 in 2 patients (3%). Forty-one hepaticojejunostomies (59%), 24 choledochojejunostomies (35%), 3 right hepatic hepatectomies with biliary reconstruction (4%), and 1 primary common bile duct repair (1%) were performed. The overall morbidity rate was 30% (21 patients). The mortality rate was 1% (1 patient). Twelve patients (17%) developed short-term postoperative complications. There were no factors found to be associated with early postoperative morbidity. The most common long-term complication was biliary stricture, which occurred in 10 patients (14%). Patients whose BDIs were repaired in the intermediate period were more likely to develop biliary stricture than patients with repairs performed in the immediate or late periods (P = .03). CONCLUSIONS: Our results suggest that the timing of LC-BDI repair is an important determinant of long-term outcome. Repairs in the intermediate period were significantly associated with biliary stricture. Thus, repairs should be undertaken either in the immediate (0-72 hours) or delayed (>6 weeks) periods after LC. PMID- 20713929 TI - Surgical decompression for abdominal compartment syndrome in severe acute pancreatitis. AB - HYPOTHESIS: In patients with severe acute pancreatitis and abdominal compartment syndrome, establishment of the indications and optimal time for surgical decompression may avoid exacerbation of multiple-organ dysfunction syndrome. DESIGN: Retrospective study. SETTING: Tertiary care university teaching hospital. PATIENTS: Twenty-six consecutive patients with severe acute pancreatitis and abdominal compartment syndrome treated by surgical decompression between January 1, 2002, and December 31, 2007. INTERVENTION: Surgical decompression of the abdomen. MAIN OUTCOME MEASURES: Morbidity, mortality, and organ dysfunction before and after surgical decompression. RESULTS: At the time of surgical decompression, the median sequential organ failure assessment score among patients was 12 (interquartile range, 10-15), and the median intra-abdominal pressure was 31.5 (interquartile range, 27-35) mm Hg. After surgical decompression, renal or respiratory function was improved in 14 patients (54%). The overall hospital mortality was 46%, but mortality was 18% among 17 patients in whom surgical decompression was performed within the first 4 days after disease onset. CONCLUSIONS: Patients with severe acute pancreatitis and abdominal compartment syndrome managed by surgical decompression had severe multiple-organ dysfunction syndrome and high mortality. Surgical decompression may improve renal or respiratory function. Early surgical decompression is associated with reduced mortality in patients with severe acute pancreatitis, early multiple-organ dysfunction syndrome, and abdominal compartment syndrome. PMID- 20713930 TI - Gossypiboma: tales of lost sponges and lessons learned. AB - OBJECTIVE: To review the details surrounding cases of patients found to have retained laparotomy sponges after surgical procedures and share policy changes that have led to process improvements at one academic medical center. DESIGN: Retrospective medical record review as part of a quality improvement process. SETTING: Single academic medical center. PATIENTS: Patients identified through the quality improvement process as having had retained foreign bodies after surgery. CONCLUSIONS: Sentinel events such as retained foreign bodies after surgery require intensive review to identify systems problems. This can lead to protocol changes to improve the process. After a series of incidents, protocol changes at our institution have led to no further incidents of retained foreign bodies. PMID- 20713931 TI - Impact of race and socioeconomic status on presentation and management of ventral hernias. AB - OBJECTIVE: To assess for disparity in presentation and management of ventral hernias. DESIGN: Retrospective review. SETTING: Academic center. PATIENTS: Three hundred twenty-one patients who underwent ventral hernia repair from 2005 to 2008. MAIN OUTCOME MEASURES: Disparity in ventral hernia presentation, management, and outcome. Univariate analysis was conducted by unpaired t test and chi(2) test. RESULTS: Black individuals were more likely than white individuals to present with acute hernia complications requiring emergent surgery (11% vs 4%; P < .01). This finding persisted after controlling for socioeconomic status (SES). Assessment by SES demonstrated patients with Medicaid were more likely to present with incarcerated or strangulated hernias (39% vs 25%; P < .001) and had longer hospital stays (4.7 vs 3 days; P < .05) as compared with patients with private insurance. Patients classified as low income had increased 30-day readmission rates as compared with average- or high-income patients (32% vs 9% vs 7%, respectively; P < .01). No difference in use of minimally invasive technique, performance of primary vs mesh repair, or postoperative morbidity or mortality was demonstrated. Twelve-month follow-up demonstrated no difference in recurrence rate by race or SES. CONCLUSIONS: Our study demonstrates the existence of disparity in patient presentation with complicated ventral hernia. Despite clear disparity by race and SES, at our institution, disparate presentation did not equate to disparate treatment or postoperative complications. No difference was demonstrated by use of operative technique, perioperative outcome, or 12-month recurrence rate. This study illustrates the need for long-term measures directed at reevaluation of organizational and institutional factors that perpetuate inequality. PMID- 20713932 TI - Robotic posterior retroperitoneal adrenalectomy: operative technique. AB - OBJECTIVE: To describe a robotic technique for posterior retroperitoneal (PR) adrenalectomy. DESIGN: Prospective study. SETTING: Academic hospital. PATIENTS: Twenty-three patients had robotic adrenalectomy within a year. Of these, 8 cases were done using a PR approach. MAIN OUTCOME MEASURES: Feasibility of the robotic approach, patient and tumor characteristics, operative time, and complications. RESULTS: There were 5 women and 3 men (mean age, 52 years). There were no conversions to laparoscopic or open surgery. Pathology included benign adrenocortical adenoma in 3 patients, aldosteronoma in 2, and pheochromocytoma, subclinical Cushing syndrome, and lymphangioma in 1 patient each. The right and left sides were each involved in 4 patients. The mean (SD) tumor size was 2.9 (1.7) cm. The procedures were done using 3 trocars and 5-mm robotic instruments. The mean (SD) operative time was 214.8 (40.8) minutes; docking time, 21.7 (16.6) minutes; and console time, 97.1 (24.2) minutes. Estimated blood loss was 24 (35) mL. All patients were discharged to home in 24 hours. There were no complications. Subjectively, the dissection was felt to be easier with the robotic technique compared with the laparoscopic approach owing to the improved dexterity of the instruments. CONCLUSIONS: To our knowledge, this is the first article describing robotic PR adrenalectomy, and we have demonstrated the technique to be feasible and safe. Owing to the limitations of a conventional laparoscopic PR approach, we believe that use of the robot is a refinement of the technique. PMID- 20713933 TI - Asian race/ethnicity as a risk factor for bile duct injury during cholecystectomy. AB - Iatrogenic bile duct injury (BDI) is an uncommon but serious complication of cholecystectomy, with identified risk factors of acute cholecystitis, male sex, older age, and aberrant biliary anatomy. The Nationwide Inpatient Sample (1998 2006) was queried for cholecystectomy performed on hospital day 0 or 1. Bile duct injury repair procedure codes were used as a surrogate for BDI. We identified 377,424 patients who underwent cholecystectomy, with 1124 BDIs (0.3%). On multivariate logistic regression analysis, Asian race/ethnicity was a significant risk factor for BDI (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.59 3.23; P < .001). This persisted for laparoscopic (OR, 2.62; 95% CI, 1.28-5.39; P = .009) and open (2.21; 1.59-3.07; P < .001) cholecystectomies. No other race/ethnicity was identified as a risk factor for BDI. We report a new finding that Asian race/ethnicity is a significant risk factor for BDI in laparoscopic and open cholecystectomies. PMID- 20713934 TI - Uninformed consent for children undergoing operations. PMID- 20713935 TI - Image of the month. Emphysematous gastritis. PMID- 20713936 TI - Image of the month. Metastasis from leiomyosarcoma in the head of the pancreas. PMID- 20713937 TI - ERCP vs laparoscopic common bile duct exploration for common bile duct stones: are the 2 techniques truly equivalent? PMID- 20713938 TI - ERCP or laparoscopic exploration for the treatment of suspected choledocholithiasis? PMID- 20713939 TI - Is laparoscopic surgery for early gallbladder cancer less invasive or dangerous? PMID- 20713940 TI - Laparoscopic cholecystectomy for early gallbladder carcinoma. PMID- 20713941 TI - Association with a high number of lymph nodes and microsatellite instability in colorectal cancer. PMID- 20713942 TI - Never say never: understanding Centers for Medicare and Medicaid Services policy on usually preventable harm. PMID- 20713943 TI - Clinical reasoning: a 75-year-old woman with visual disturbances and unilateral ataxia. PMID- 20713944 TI - Teaching NeuroImages: methotrexate leukoencephalopathy mimicking a transient ischemic attack. PMID- 20713946 TI - Primary progressive aphasia: New insights paving the way toward clinical research tools. PMID- 20713947 TI - Why are patients with progressive nonfluent aphasia nonfluent? AB - OBJECTIVE: To investigate the cognitive and neural basis for nonfluent speech in progressive nonfluent aphasia (PNFA). BACKGROUND: Nonfluent speech is the hallmark feature of PNFA, and this has been attributed to impairments in syntactic processing, motor-speech planning, and executive functioning that also occur in these patients. Patients with PNFA have left inferior frontal atrophy. METHODS: A large semi-structured speech sample and neuropsychological measures of language and executive functioning were examined in 16 patients with PNFA, 12 patients with behavioral-variant frontotemporal dementia (bvFTD), and 13 age matched controls. Speech fluency was quantified as words per minute (WPM) in the semi-structured speech sample. Stepwise linear regression analyses were used to relate WPM to grammatic, motor-speech planning, and executive aspects of patient functioning. These measures were then related to cortical thickness in 8 patients with PNFA and 7 patients with bvFTD using structural MRI. RESULTS: WPM was significantly reduced in patients with PNFA relative to controls and patients with bvFTD. Regression analyses revealed that only grammatic measures predicted WPM in PNFA, whereas executive measures were the only significant predictor of WPM in bvFTD. Cortical thinning was significant in PNFA relative to controls in left inferior frontal and anterior-superior temporal regions, and a regression analysis related this area to reduced WPM in PNFA. Significant cortical thinning associated with limited grammatic processing also was seen in the left inferior frontal-superior temporal region in PNFA, and this overlapped with the area of frontal-temporal thinning related to reduced WPM. CONCLUSION: Nonfluent speech in PNFA may be due in part to difficulty with grammatic processing associated with left inferior frontal and anterior-superior temporal disease. PMID- 20713948 TI - Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia. AB - OBJECTIVE: Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are hypothesized to cause clinically distinct forms of primary progressive aphasia (PPA) that predominantly affect expressive speech. AD is thought to cause logopenic progressive aphasia (LPA), and FTLD may cause progressive nonfluent aphasia (PNFA). We sought to determine the value of clinical characterization, neuropsychological analysis, and MRI atrophy in predicting pathology of LPA and PNFA. METHODS: Patients with LPA (n = 19) and patients with PNFA (n = 19) were evaluated with neuropsychological assessments, structural MRI, CSF analysis, and neuropathologic examination. RESULTS: Twelve of 19 patients with LPA (63%) and 6 of 19 patients with PNFA (32%) had neuropathologic findings or CSF biomarkers consistent with AD. Neuropsychological testing showed that naming was more impaired in patients with AD, and letter-guided fluency was more affected in patients with a non-AD disorder. Voxel-based morphometry analysis revealed that in patients with AD, patients with LPA and PNFA had significant posterior superior temporal atrophy; in patients with non-AD, patients with LPA had peri Sylvian atrophy and patients with PNFA had dorsolateral prefrontal and insular atrophy. Receiver operator characteristic curve analysis showed that combining neuropsychological testing with MRI atrophy pattern had 90% specificity for pathology or CSF biomarkers consistent with AD, and combining clinical features with neuropsychological analysis had 100% sensitivity for pathology or CSF biomarkers consistent with AD. CONCLUSIONS: Neither PPA phenotyping nor imaging alone is a reliable predictor of pathology. Multimodal predictors, such as combining neuropsychological testing with MRI analysis, can improve noninvasive prediction of underlying pathology in nonfluent forms of PPA. PMID- 20713949 TI - Syndromes of nonfluent primary progressive aphasia: a clinical and neurolinguistic analysis. AB - BACKGROUND: Despite recent work, the nosology of nonfluent primary progressive aphasia (PPA) remains unresolved. METHODS: We describe a clinical and neurolinguistic cross-sectional analysis of a cohort of 24 patients with nonfluent PPA. Patients were initially classified based on analysis of spontaneous speech into 4 groups: apraxia of speech (AOS)/agrammatism (10 patients); AOS/no agrammatism (4 patients); no AOS/agrammatism (3 patients); no AOS/no agrammatism (7 patients). These groups were further characterized using a detailed neurolinguistic and neuropsychological battery. Parkinsonism was present in 3/10 patients in the AOS/agrammatism group. All patients in the no AOS/agrammatism group had mutations in the progranulin (GRN) gene, while 5/7 cases in the no AOS/no agrammatism group had CSF findings compatible with Alzheimer disease. RESULTS: The groups without AOS showed more severe neurolinguistic impairments for a given disease stage, and sentence comprehension, speech repetition, and reading were impaired in all groups. Prolonged word-finding pauses and impaired single word comprehension were salient features in the no AOS/agrammatism group. Additional impairments of executive function and praxis were present in both groups with agrammatism, and impaired episodic memory was a feature of the no AOS/no agrammatism group. CONCLUSION: PPA with AOS is aligned with the syndrome previously designated progressive nonfluent aphasia; agrammatism may emerge as the syndrome evolves, or alternatively, the pure AOS group may be pathophysiologically distinct. PPA without AOS resembles the syndrome designated logopenic/phonologic aphasia; however, there is evidence for a distinct subsyndrome of GRN-associated aphasia. The findings provide a rationale for further longitudinal studies with pathologic correlation. PMID- 20713951 TI - Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder. AB - BACKGROUND: Myotonia is unusual in infants, and not well-known. METHODS: We describe neonatal life-threatening features of myotonia caused by de novo mutations in the muscle sodium channel gene SCN4A. RESULTS: Three male neonates initially displayed episodic laryngospasms, with face and limb myotonia appearing later. We found SCN4A de novo mutations in these neonates: p.Gly1306Glu in 2 unrelated cases and a novel mutation p.Ala799Ser in the third. Two patients survived their respiratory attacks and were efficiently treated by sodium channel blockers (mexiletine, carbamazepine) following diagnosis of myotonia. CONCLUSION: Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers. PMID- 20713950 TI - HLA B*44: protective effects in MS susceptibility and MRI outcome measures. AB - OBJECTIVE: In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele (HLA DRB1*1501), investigations of the MHC have implicated several class I MHC loci (HLA A, HLA B, and HLA C) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A*02, HLA B*44, and HLA C*05. METHODS: Subjects include a clinic-based patient sample with a diagnosis of either MS or a clinically isolated syndrome (n = 532), compared to subjects in a bone marrow donor registry (n = 776). All subjects have 2-digit HLA data. Logistic regression was used to determine the independence of each allele's effect. We used linear regression and an additive model to test for correlation between an allele and MRI and clinical measures of disease course. RESULTS: After accounting for the effect of HLA DRB1*1501, both HLA A*02 and HLA B*44 are validated as susceptibility alleles (p(A*02) 0.00039 and p(B*44) 0.00092) and remain significantly associated with MS susceptibility in the presence of the other allele. Although A*02 is not associated with MS outcome measures, HLA B*44 demonstrates association with a better radiologic outcome both in terms of brain parenchymal fraction and T2 hyperintense lesion volume (p = 0.03 for each outcome). CONCLUSION: The MHC class I alleles HLA A*02 and HLA B*44 independently reduce susceptibility to MS, but only HLA B*44 appears to influence disease course, preserving brain volume and reducing the burden of T2 hyperintense lesions in subjects with MS. PMID- 20713952 TI - Protocadherin 19 mutations in girls with infantile-onset epilepsy. AB - OBJECTIVE: To explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy. METHODS: We studied a cohort of 117 female patients with febrile seizures (FS) and a wide spectrum of epilepsy phenotypes including focal and generalized forms with either sporadic or familial distribution. RESULTS: PCDH19 screening showed point mutations in 13 probands (11%). Mean age at seizure onset was 8.5 months; 8 patients (62%) presented with FS, 4 (33%) with cluster of focal seizures, and 1 with de novo status epilepticus (SE). Subsequent seizure types included afebrile tonic-clonic, febrile, and afebrile SE, absences, myoclonic, and focal seizures. Seven patients (54%) had a clinical diagnosis consistent with Dravet syndrome (DS); 6 (46%) had focal epilepsy. In most patients, seizures were particularly frequent at onset, manifesting in clusters and becoming less frequent with age. Mental retardation was present in 11 patients, ranging from mild (7; 64%) to moderate (1; 9%) to severe (3; 27%). Five patients (38%) had autistic features in association to mental retardation. Mutations were missense (6), truncating (2), frameshift (3), and splicing (2). Eleven were new mutations. Mutations were inherited in 3 probands (25%): 2 from apparently unaffected fathers and 1 from a mother who had had generalized epilepsy. CONCLUSIONS: PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented. PMID- 20713954 TI - Acetylcholine in the cerebral cortex: effects and clinical implications. PMID- 20713953 TI - Neurocysticercosis: unraveling the nature of the single cysticercal granuloma. AB - A single enhancing lesion in the brain parenchyma, also called an inflammatory granuloma, is a frequent neurologic diagnosis. One of the commonest causes of this lesion is human neurocysticercosis, the infection by the larvae of the pork tapeworm, Taenia solium. Following the demonstration that viable cysticercosis cysts survive in good conditions for several years in the human brain, single cysticercal granulomas have been consistently interpreted as representing late degeneration of a long-established parasite. On the basis of epidemiologic, clinical, and laboratory evidence detailed in this article, we hypothesize that in most cases these inflammatory lesions correspond to parasites that die in the early steps of infection, likely as the natural result of the host immunity overcoming mild infections. PMID- 20713955 TI - Influenza a/h1n1 encephalitis. PMID- 20713956 TI - Different meaning of vessel signs in acute cerebral infarction. PMID- 20713957 TI - Cognitive decline in incident Alzheimer disease in a community population. PMID- 20713958 TI - Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the quality standards subcommittee of the american academy of neurology and the practice committee of the child neurology society. PMID- 20713959 TI - Sex differences in presentation, severity, and management of stroke in a population-based study. PMID- 20713960 TI - The incidence of chronic lymphocytic leukemia in Taiwan, 1986-2005: a distinct increasing trend with birth-cohort effect. AB - The incidence of chronic lymphocytic leukemia (CLL) in Taiwan is markedly lower than that in Western countries, but we have seen a drastically increasing trend. We explored this distinct incidence trend of CLL for Taiwanese. The epidemiologic data of CLL for Taiwanese and Caucasian Americans during 1986 to 2005 were obtained from the Taiwan National Cancer Registry and Surveillance, Epidemiology, and End Results Program, respectively. The individual effects of time period and birth cohort on the incidence trends were analyzed using an age-period-cohort model. Although there was a weak period effect corresponding to the increased applications of immunophenotyping in 1991 to 1995 in Taiwan, evidences suggested that the age-adjusted incidence rate of CLL for Taiwanese was continuously increasing during the 20-year period while that for Caucasian Americans remained steady. In addition, a much stronger birth-cohort effect was identified for Taiwanese but not for Caucasian Americans. This effect corresponded to the westernization of lifestyle in Taiwan since 1960. We conclude that, in addition to the ethnic difference of incidence, there is distinct increasing incidence trend of CLL in Taiwan. The strong birth-cohort effect underlying this increasing trend indicates that lifestyles and environmental factors may play a role in the development of CLL for Taiwanese. PMID- 20713961 TI - Eosinophils in the zebrafish: prospective isolation, characterization, and eosinophilia induction by helminth determinants. AB - Eosinophils are granulocytic leukocytes implicated in numerous aspects of immunity and disease. The precise functions of eosinophils, however, remain enigmatic. Alternative models to study eosinophil biology may thus yield novel insights into their function. Eosinophilic cells have been observed in zebrafish but have not been thoroughly characterized. We used a gata2:eGFP transgenic animal to enable prospective isolation and characterization of zebrafish eosinophils, and demonstrate that all gata2(hi) cells in adult hematopoietic tissues are eosinophils. Although eosinophils are rare in most organs, they are readily isolated from whole kidney marrow and abundant within the peritoneal cavity. Molecular analyses demonstrate that zebrafish eosinophils express genes important for the activities of mammalian eosinophils. In addition, gata2(hi) cells degranulate in response to helminth extract. Chronic exposure to helminth- related allergens resulted in profound eosinophilia, demonstrating that eosinophil responses to allergens have been conserved over evolution. Importantly, infection of adult zebrafish with Pseudocapillaria tomentosa, a natural nematode pathogen of teleosts, caused marked increases in eosinophil number within the intestine. Together, these observations support a conserved role for eosinophils in the response to helminth antigens or infection and provide a new model to better understand how parasitic worms activate, co-opt, or evade the vertebrate immune response. PMID- 20713962 TI - Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. AB - Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg twice daily for 1 year during an open-label phase 2 study (Blood. 2010;116(6):893-899). We report further improvements after 2 years of treatment in 20 patients (11 females, 9 males; mean age, 33 years) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (P < .001) percentage improvements from baseline occurred in platelet count (mean +/- SD, 81% +/- 56%), hemoglobin level (20% +/- 15%), spleen volume ( 52% +/- 11%), and liver volume (-24% +/- 13%). Mean platelet count increased ~ 50 000/mm(3). Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for >= 3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8% +/- 10.6% (P = .01) and T-score 0.6 +/- 0.8 (P = .012), with major gains in osteoporotic and osteopenic patients. Magnetic resonance imaging assessment showed that bone marrow infiltration by Gaucher cells was decreased (8/18 patients) or stable (10/18 patients). No safety-related trends emerged during 2 years of treatment. This multisite, open-label, single-arm phase 2 study is registered at www.clinicaltrials.gov as NCT00358150. PMID- 20713963 TI - Low-strength T-cell activation promotes Th17 responses. AB - We show that the strength of T-cell stimulation determines the capability of human CD4(+) T cells to become interleukin-17 (IL-17) producers. CD4(+) T cells received either high- (THi) or low (TLo)-strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1beta, transforming growth factor beta, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells. Titration of anti CD3 revealed that low TCR signaling promoted Th17 cells, but only in the presence of anti-CD28. Impaired IL-17 production in THi cells could not be explained by high levels of Foxp3 or transforming growth factor beta-latency-associated peptide expressed by THi cells. Nuclear factor of activated T cells was translocated to the nucleus in both THi and TLo cells, but only bound to the proximal region of the IL-17 promoter in TLo cells. The addition of a Ca(2+) ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca(2+) signaling impairs Th17 development. Although our data do not distinguish between priming of naive T cells versus expansion/differentiation of memory T cells, our results clearly establish an important role for the strength of T-cell activation in regulating Th17 responses. PMID- 20713964 TI - LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. AB - Lysophosphatidic acid (LPA) is a potent lipid mediator with a wide variety of biological actions mediated through G protein-coupled receptors (LPA(1-6)). LPA(4) has been identified as a G(13) protein-coupled receptor, but its physiological role is unknown. Here we show that a subset of LPA(4)-deficient embryos did not survive gestation and displayed hemorrhages and/or edema in many organs at multiple embryonic stages. The blood vessels of bleeding LPA(4) deficient embryos were often dilated. The recruitment of mural cells, namely smooth muscle cells and pericytes, was impaired. Consistently, Matrigel plug assays showed decreased mural cell coverage of endothelial cells in the neovessels of LPA(4)-deficient adult mice. In situ hybridization detected Lpa4 mRNA in the endothelium of some vasculatures. Similarly, the lymphatic vessels of edematous embryos were dilated. These results suggest that LPA(4) regulates establishment of the structure and function of blood and lymphatic vessels during mouse embryogenesis. Considering the critical role of autotaxin (an enzyme involved in LPA production) and Galpha(13) in vascular development, we suggest that LPA(4) provides a link between these 2 molecules. PMID- 20713965 TI - Prevalence of t(12;21)[ETV6-RUNX1]-positive cells in healthy neonates. AB - t(12;21)(p13;q22)[ETV6-RUNX1] is the most common chromosomal translocation in childhood acute lymphoblastic leukemia, and it can often be backtracked to Guthrie cards supporting prenatal initiation and high levels of circulating t(12;21)-positive cells at birth. To explore the prevalence of ETV6-RUNX1 positive cells in healthy neonates, mononuclear cells from 1417 umbilical cord blood samples were isolated within 24 hours from birth and subsequently screened for ETV6-RUNX1 transcripts using a highly sensitive real-time reverse transcription polymerase chain reaction assay. In first-run polymerase chain reaction, 14 samples were positive at levels below 10(-5), of which specific hybridization reflecting the relevant genetic region was positive in 9 cases. Repeated analyses using stored mRNA and flowcytometric sorting of a CD19(+), CD8(+), and CD19(-)/CD8(-) subpopulations from cryopreserved mononuclear cells from the same cord blood samples (mean sorted: 18 * 10(6) cells) revealed no positive findings, which demonstrates that the level and/or frequency of ETV6 RUNX1-positive cells is markedly lower than suggested in previous studies. PMID- 20713966 TI - Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. AB - In the bone marrow, hematopoietic stem cells (HSCs) reside in specific niches near osteoblast-lineage cells at the endosteum. To investigate the regulation of these endosteal niches, we studied the mobilization of HSCs into the bloodstream in response to granulocyte colony-stimulating factor (G-CSF). We report that G CSF mobilization rapidly depletes endosteal osteoblasts, leading to suppressed endosteal bone formation and decreased expression of factors required for HSC retention and self-renewal. Importantly, G-CSF administration also depleted a population of trophic endosteal macrophages (osteomacs) that support osteoblast function. Osteomac loss, osteoblast suppression, and HSC mobilization occurred concomitantly, suggesting that osteomac loss could disrupt endosteal niches. Indeed, in vivo depletion of macrophages, in either macrophage Fas-induced apoptosis (Mafia) transgenic mice or by administration of clodronate-loaded liposomes to wild-type mice, recapitulated the: (1) loss of endosteal osteoblasts and (2) marked reduction of HSC-trophic cytokines at the endosteum, with (3) HSC mobilization into the blood, as observed during G-CSF administration. Together, these results establish that bone marrow macrophages are pivotal to maintain the endosteal HSC niche and that the loss of such macrophages leads to the egress of HSCs into the blood. PMID- 20713968 TI - Mechanotransduction in rat myometrium: coordination of contractions of electrically and chemically isolated tissues. AB - The generally accepted mechanism for global uterine coordination is propagation of electrical activity. Mechanotransduction mechanisms were briefly considered as a secondary mechanism 40 years ago, but scant data have appeared. Here, we provide evidence that tissue strips are capable of functionally interacting solely by mechanical mechanisms. We mechanically linked, in series, 2 rat myometrial strips of similar size. Strips were placed in separate baths to ensure they were electrically and chemically isolated. A force transducer was used to measure force production. We precisely determined when each tissue contracted by simultaneously measuring each strip's electrical activity using contact electrodes. We observed both in-phase and out-of-phase contraction patterns from the tissues. To determine whether modulation of the electrical properties of the tissue is involved in the mechanotransduction mechanism, we briefly stretched single tissue strips during alternate contractions. This technique provided a control contraction for each test contraction. The duration of the contraction that was stretched measured longer than the control in 33 of 35 pairs (P = .0001, Wilcoxon signed-rank test for paired data). Interestingly, briefly slackening the tissue also prolonged the force-producing phase of that contraction (39 of 42 pairs; P = .0006). Because our data show that mechanotransduction mechanisms coordinate tissue-level contractions, we speculate that mechanotransduction mechanisms may contribute to organ-level coordination of contractions. PMID- 20713969 TI - Estrogen promotes parvalbumin expression in arcuate nucleus POMC neurons. AB - We have found that estrogen promotes suppression of feeding and a lean body mass while activating the arcuate nucleus proopiomelanocortin (POMC)-expressing neurons. These neurons, when activated, suppress appetite and increase energy expenditure. Because the increased activation of POMC neurons by estradiol was associated with increased glutamate receptor presence that enable calcium influx, we analyzed the expression of the calcium-binding protein, parvalbumin, in these hypothalamic neurons. We observed that estrogen treatment of female mice resulted in induction of parvalbumin-immunoreactivity in arcuate nucleus neurons, a large number of which was POMC-expressing. These data indicate that the increased excitatory activity induced by estradiol in the arcuate nucleus in support of suppression of appetite is associated with calcium overload of these neurons. Although parvalbumin may protect these cells from calcium overload-associated neuronal degeneration, maintenance of calcium entry may lead to increased vulnerability of POMC neurons during the course of sustained satiety. PMID- 20713970 TI - Gonadotropin-releasing hormone fibers contact POMC neurons in the hypothalamic arcuate nucleus. AB - The metabolic state has long been shown to affect reproduction. Peripheral signals and hormones from the reproductive organs are also known to regulate energy metabolism and feeding and energy expenditure. Much attention has been paid to determine the signaling flow from key hypothalamic neuronal populations, including those producing the anorexigenic proopiomelanocortin (POMC) derivate, alpha-melanocyte stimulating hormone (alpha-MSH), to the medial preoptic area gonadotropin-releasing hormone (GnRH) neurons, cells that are the drivers of ovulation and reproduction in general. In this study, the authors explored whether a reverse signaling modality may also exist. Specifically, the authors analyzed GnRH efferents in the arcuate nucleus with particular emphasis on their anatomical proximity to arcuate nucleus melanocortin perikarya. Using correlated light and electron microscopy, the authors observed direct apposition between GnRH-containing axon terminals and POMC cell bodies. These data provide the first experimental evidence to suggest that GnRH may have a direct influence on feeding, energy expenditure, and glucose homeostasis, independent of the activity of the gonadal axis. PMID- 20713971 TI - Emergent behaviors in a deterministic model of the human uterus. AB - The human birth process is powered by uterine contractions that have observable patterns that depend on the physiology of muscular activity. We explored a previously designed model(1) simulating the uterus to assess global contractile patterns. The model is a cellular automaton that simulates the complexities of uterine activity from a few simple rules of cellular interaction and uterine geometry. Multiple experiments using the cellular automaton involved different uterine shapes, cell numbers, and initial distributions of active and resting cells. Results demonstrate complex contraction patterns similar to those observed in human labor. At least 2 modes of behavior appear in the simulations, one consistent with effective labor and one not. Experiments with cellular automata provide insights into stereotypic and disordered labor patterns that produce patient discomfort without progress in labor. We hypothesize that complex uterine contraction patterns may have other roles in the preparation for labor and birth. PMID- 20713972 TI - Nitric oxide inhibits ACTH-induced cortisol production in near-term, long-term hypoxic ovine fetal adrenocortical cells. AB - We previously reported that in the sheep fetus, long-term hypoxia (LTH) resulted in elevated basal plasma adrenocorticotropic hormone (ACTH(1- 39)) whereas the cortisol levels were not different from normoxic controls. We also showed that LTH enhances endothelial nitric oxide synthase (eNOS) expression in the fetal adrenal. This study was designed to determine the effect of NO on cortisol production in adrenocortical cells from LTH fetal sheep. Ewes were maintained at high altitude (3820 m) from ~40 days' gestation (dG) to near term. Between 138 and 141 dG, fetal adrenal glands were collected from LTH and age-matched normoxic control fetuses. Adrenal cortical cells were pretreated with sodium nitroprusside (SNP), nitro-L-arginine methyl ester (L-NAME), L-arginine, or diethyleneamine NO (DETA-NO) and then challenged with 10 nmol/L ACTH. Cortisol responses were compared after 1 hour. Adrenocorticotropic hormone -induced cortisol secretion was significantly higher in LTH versus control (P < .01). Enhancement of NO with L-arginine resulted in a significant reduction of ACTH-mediated cortisol production in the LTH group. DETA-NO also caused a significant decrease in ACTH mediated cortisol production (P < .05). Inhibition of NOS with L-NAME significantly increased cortisol production in the LTH group (P < .05 compared to ACTH alone), whereas the effect on the control group was not significant. Nitric oxide synthase activity was significantly higher in the LTH group compared to control, but this difference was eliminated following ACTH treatment. These data indicate that LTH enhances adrenal cortical sensitivity to the inhibitory effects of NO on cortisol production. Nitric oxide may, therefore, play an important role in regulating ACTH-induced cortisol production in the LTH fetal adrenal. PMID- 20713973 TI - Elevated plasma osteopontin level is associated with pelvic inflammatory disease. AB - Our purpose here was to detect the association among plasma osteopontin concentration, single nucleotide polymorphisms (SNPs) of osteopontin gene, and pelvic inflammatory disease (PID). The enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were respectively used to measure the plasma osteopontin level and its gene polymorphisms. The level of plasma osteopontin was elevated in patients with PID as compared to that of healthy women and decreased significantly after treatment. Plasma osteopontin concentration was significantly correlated with white blood cell (WBC) and neutrophil counts and plasma C-reactive protein (CRP) level in patients with PID. No significant difference was found in the genotypes or alleles distribution of osteopontin SNPs, rs1126616 or rs9138, between patients with PID and normal controls. Plasma osteopontin concentration was not associated with osteopontin polymorphism. When the cutoff level of the plasma osteopontin concentration was set to be 58.53 ng/mL, the adjusted odds ratio of plasma osteopontin for PID risk was 3.87 (95% confident interval: 1.30-11.51). Plasma osteopontin level may act as a prediction marker for PID. PMID- 20713974 TI - Prevalence of monoclonal gammopathy of undetermined significance: a systematic review. AB - Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that is associated with a lifelong risk of multiple myeloma. We conducted a systematic review of all studies investigating the prevalence and incidence of MGUS in the online database PubMed. The review was conducted from January 6, 2009, through January 15, 2010. The following MeSH search headings were used: monoclonal gammopathy, benign and prevalence; monoclonal gammopathy, benign and incidence; paraproteinemia and prevalence; and paraproteinemia and incidence. Articles were limited to those written in English and published by January 2009. Fourteen studies that met prespecified criteria were included and systematically assessed to identify the most accurate prevalence estimates of MGUS based on age, sex, and race. On the basis of our systematic review, we estimate that the crude prevalence of MGUS in those older than 50 years is 3.2% in a predominantly white population. Studies in white and Japanese populations demonstrate a clear increase in prevalence with age. The prevalence is also affected by sex: 3.7% and 2.9% in white men and women, respectively; and 2.8% and 1.6% in Japanese men and women, respectively. Additionally, MGUS is significantly more prevalent in black people (5.9%-8.4%) than in white people (3.0%-3.6%). We conclude that MGUS is a common premalignant plasma cell disorder in the general population of those older than 50 years. The prevalence increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. These results are important for counseling, clinical care, and the design of clinical studies in high-risk populations. PMID- 20713975 TI - The finding of reduced estimated glomerular filtration rate is associated with increased mortality in a large UK population. AB - BACKGROUND: CKD as defined by KDIGO/KDOQI has been shown to affect ~ 8.5% of the UK population. The prevalence of CKD in the UK is similar to that in the USA, yet incident dialysis rates are dramatically different. This retrospective cohort study investigates the association between reduced kidney function and mortality in a large UK population. METHODS: All serum creatinine results covering Northern Ireland's 1.7 million population were collected between 1 January 2001 and 31 December 2002. Estimated glomerular filtration rates (eGFR) were calculated for all serum creatinine measurements using four-variable MDRD equation (IDMS aligned). Patients were followed up for both all-cause and cardiovascular mortality data until the end of December 2006. Patients on renal replacement therapy were excluded. Subgroup analysis in the 75,345 subjects enrolled within a parallel primary care study permitted additional survival analysis with adjustment for traditional cardiovascular risk factors. RESULTS: A total of 1,967,827 serum creatinine results from 533,798 patients were collected. During the period of follow-up, 59,980 deaths occurred. In multivariate survival analysis, using eGFR as a time-varying covariate, a graded association between CKD (defined by eGFR) and all-cause mortality was identified. Compared with participants with an eGFR of > 60 mL/min/1.73 m(2), the adjusted hazard ratios (and 95% confidence intervals) for participants with an eGFR of 45-59 mL/min/1.73 m(2) was 1.02 (0.99-1.04), an eGFR of 30-44 mL/min/1.73 m(2) was 1.44 (1.40 1.47), an eGFR of 15-29 mL/min/1.73 m(2) was 2.12 (2.05-2.20) and an eGFR of < 15 mL/min/1.73 m(2) was 3.46 (3.24-3.70). Significantly, increased all-cause mortality was associated with an eGFR < 45 mL/min/1.73 m(2) following adjustment for age and gender. The association between cardiovascular mortality and reduced renal function continued to be significant for participants with an eGFR of 45-65 mL/min/1.73 m(2). Subgroup analysis in 75,345 individuals with more detailed clinical information available confirmed this association following adjustment for traditional cardiovascular risk factors in addition to age and gender. CONCLUSIONS: This study demonstrates a graded association between reduced renal function as represented by eGFR and mortality in a UK population. The all-cause and cardiovascular mortality risk increases sharply when estimated GFR falls < 45 mL/min/1.73 m(2). The association between an eGFR measured between 45 and 65 mL/min/1.73 m(2) and cardiovascular mortality persists in this cohort and highlights the ongoing uncertainty in accurately categorizing renal dysfunction. PMID- 20713976 TI - Peritoneal dialysis fluids can alter HSP expression in human peritoneal mesothelial cells. AB - BACKGROUND: Acute exposure of mesothelial cells to peritoneal dialysis fluid (PDF) has been shown not only to result in injury but also to induce cytoprotective heat shock proteins (HSP). The aim of the present study was to evaluate the expression of HSP in a more chronic in vitro PDF exposure system, searching for a role of glucose degradation products (GDP). METHODS: Human peritoneal mesothelial cells (HPMC) were chronically incubated in filter- or heat sterilized PDF (mixed 1:1 with cell culture medium), or in control cell culture medium. After incubation periods of 1, 3 and 10 days, cell extract was assessed for Ezrin, Hsp27 and Hsp72, and supernatant for IL-6 and IL-8. After 24-h exposure to the GDP 3.4-di-deoxyglucosone-3-ene (3.4-DGE), HPMC were assessed for expression of Hsp27 and Hsp72, and for release of LDH, IL-6 and IL-8. RESULTS: In vitro PDF exposure for more than 1 day resulted in reduced cell mass, lower expression of the epithelial marker Ezrin and depressed cellular levels of both HSP, associated with increased IL-6 and IL-8 release. These effects occurred earlier and stronger with heat-sterilized than with filter-sterilized PDF. Exposure of HPMC to 3.4-DGE resulted in suppression of HSP, and increased release of LDH, IL-6 and IL-8. CONCLUSION: Our data show that GDP (dys)regulate the mesothelial cell stress response. This was associated with reduced cell mass, loss of the epithelial phenotype and sterile cellular inflammation following extended exposure to heat-sterilized PDF. Toxic effects of PDF might thus be extended to reduced mesothelial cell stress responses. PMID- 20713977 TI - The predictive value of anthropometric parameters on mortality in haemodialysis patients. AB - BACKGROUND: Since protein-calorie malnutrition is a common factor influencing morbidity and mortality of haemodialysis patients, assessing their nutritional status is important. The aim of this study was to investigate the predictive value of anthropometric parameters on mortality and their interrelationship. METHODS: The study included a cohort of 242 patients. The analysis involved baseline data obtained during the first calendar year after the patients entered the study (1994-2001) and repeated measurements for up to 132 months of follow-up (until 2004). Anthropometric measurements were made during the winter season and included skinfolds, mid-arm circumference (MAC), body height and weight. The percentage of body fat (%fat) was calculated from triceps (TSF), biceps, subscapular and suprailiac skinfolds (Disease Outcomes Quality Initiative (DOQI) guidelines) and mid-arm muscle circumference (MAMC) from MAC and TSF. Body mass index (BMI), Kt/V, normalized protein catabolic rate (NPCR) and cardiovascular co morbidity were also determined and laboratory analyses undertaken. RESULTS: Strong correlations were found among the anthropometric parameters. Extended Cox regression analysis selected %fat, MAC, MAMC and TSF in addition to age, ischaemic heart disease, congestive heart failure, Kt/V, haemoglobin, creatinine, albumin and NPCR as potential predictors of mortality. The same anthropometric parameters were found to be independent mortality predictors in corresponding models. The most predictive anthropometric factor was MAC. BMI was not a risk factor. CONCLUSION: Percentage of body fat, MAC, MAMC and TSF were independent predictors of mortality of haemodialysis patients, and MAC was the most predictive one. PMID- 20713978 TI - Screening for proteinuria in kidney transplant recipients. AB - BACKGROUND: Proteinuria is a predictor of graft loss and death in kidney transplant recipients. This study examines the clinical significance of albumin to-creatinine (ACR) and protein-to-creatinine (PCR) ratios compared with conventional dipstick measures of proteinuria. METHODS: At this single centre, 500 adult patients with a functioning kidney transplant > 4 months provided a urine sample for dipstick, ACR and PCR. The primary end point was defined as death-censored graft loss. Associations between proteinuria and graft loss were examined by concordance statistics and multivariate Cox models. RESULTS: There were 32 graft losses over a mean 2.98 years follow-up. PCR (c = 0.82, P < 0.001) and ACR (c = 0.83, P < 0.001) demonstrated similar concordance with events, and both scored higher than dipstick (c = 0.76, P < 0.001). ACR cut points of 30 and 300 mg/g for grading albuminuria were equivalent to 130 and 490 mg/g for PCR. Moderate grades of proteinuria by ACR and PCR were predicted of adverse events in a multivariate analysis. CONCLUSIONS: ACR and PCR are probably equivalent in predicting adverse events. Conventional dipstick is also predictive but does not appear to be as sensitive. PMID- 20713979 TI - Do sea stars have low ADMA levels? High ADMA and low EPC count--duo infernal for the kidney. PMID- 20713980 TI - Plant immunity triggered by microbial molecular signatures. AB - Pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) are recognized by host cell surface-localized pattern-recognition receptors (PRRs) to activate plant immunity. PAMP-triggered immunity (PTI) constitutes the first layer of plant immunity that restricts pathogen proliferation. PTI signaling components often are targeted by various Pseudomonas syringae virulence effector proteins, resulting in diminished plant defenses and increased bacterial virulence. Some of the proteins targeted by pathogen effectors have evolved to sense the effector activity by associating with cytoplasmic immune receptors classically known as resistance proteins. This allows plants to activate a second layer of immunity termed effector-triggered immunity (ETI). Recent studies on PTI regulation and P. syringae effector targets have uncovered new components in PTI signaling. Although MAP kinase (MAPK) cascades have been considered crucial for PTI, emerging evidence indicates that a MAPK-independent pathway also plays an important role in PTI signaling. PMID- 20713981 TI - Immunohistochemical expression of cell cycle/apoptosis regulators and epidermal growth factor receptor in pediatric intracranial ependymomas. AB - Intracranial ependymomas are the third most common primary brain tumor in children. We set out to investigate the expression of p-53, p-27, bcl-2, and epidermal growth factor receptor in 13 pediatric infratentorial ependymomas, in correlation with Ki-67/ MIB-1 proliferation index and prognosis. The median progression-free survival was 37.5 months, and the 5-year overall survival was 50%. There was a statistically significant higher expression of Ki-67 and p-53 index in anaplastic tumors. There was also a higher expression of p-27, bcl-2, and epidermal growth factor receptor in anaplastic tumors, but the difference was not statistical significant. No significant correlation was found between overall survival and level of expression of Ki-67, p-53, p-27, bcl-2, and epidermal growth factor receptor. Epidermal growth factor receptor detection in a considerable number of ependymomas probably reflects its role in the neoplastic transformation and can serve as a therapeutic target. PMID- 20713982 TI - Expression of serum amyloid a in human ovarian epithelial tumors: implication for a role in ovarian tumorigenesis. AB - Serum amyloid A (SAA) is an acute phase protein which is expressed primarily in the liver as a part of the systemic response to various injuries and inflammatory stimuli; its expression in ovarian tumors has not been described. Here, we investigated the expression of SAA in human benign and malignant ovarian epithelial tumors. Non-radioactive in situ hybridization applied on ovarian paraffin tissue sections revealed mostly negative SAA mRNA expression in normal surface epithelium. Expression was increased gradually as epithelial cells progressed through benign and borderline adenomas to primary and metastatic adenocarcinomas. Similar expression pattern of the SAA protein was observed by immunohistochemical staining. RT-PCR analysis confirmed the overexpression of the SAA1 and SAA4 genes in ovarian carcinomas compared with normal ovarian tissues. In addition, strong expression of SAA mRNA and protein was found in the ovarian carcinoma cell line OVCAR-3. Finally, patients with ovarian carcinoma had high SAA serum levels, which strongly correlated with high levels of CA-125 and C reactive protein. Enhanced expression of SAA in ovarian carcinomas may play a role in ovarian tumorigenesis and may have therapeutic application. PMID- 20713983 TI - Immunohistochemical analysis of the effects of cross-innervation of murine thyroarytenoid and sternohyoid muscles. AB - This work uses cross-innervation of respiratory muscles of different developmental origins to probe myogenic and neurogenic mechanisms regulating their fiber types. The thyroarytenoid (TA) originates from the sixth branchial arch, whereas the sternohyoid (SH) is derived from somitic mesoderm. Immunohistochemical analysis using highly specific monoclonal antibodies to myosin heavy chain (MyHC) isoforms reveals that normal rat SH comprises slow, 2a, 2x, and 2b fibers, as in limb fast muscles, whereas the external division of the TA has only 2b/eo fibers coexpressing 2B and extraocular (EO) MyHCs. Twelve weeks after cross-innervation with the recurrent laryngeal nerve, the SH retained slow and 2a fibers, greatly increased the proportion of 2x fibers, and their 2b fibers failed to express EO MyHC. In the cross-innervated TA, the SH nerve failed to induce slow and 2A MyHC expression and failed to suppress EO MyHC expression in 2b/eo fibers. However, 2x fibers amounting to 4.2% appeared de novo in the external division of the TA. We conclude that although MyHC gene expression in these muscles can be modulated by neural activity, the patterns of response to altered innervation are largely myogenically determined, thus supporting the idea that SH and TA differ in muscle allotype. PMID- 20713985 TI - Time-resolved ultrastructural detection of phosphatidylinositol 3-phosphate. AB - Phosphatidylinositol 3-phosphate [PtdIns(3)P] plays an important role in recruitment of various effector proteins in the endocytic and autophagic pathways. In an attempt to follow the distribution of PtdIns(3)P at the ultrastructural level, we are using the Fab1, YOTB, Vac1, and EEA1 (FYVE) domain, which is a zinc finger motif specifically binding to PtdIns(3)P. To follow PtdIns(3)P trafficking during a defined time window, here we have used a monomeric dimerizable FYVE probe, which binds with high avidity to PtdIns(3)P only after rapalog-induced dimerization. The probe localized to early and late endocytic compartments according to the time period of dimerization, which indicates that PtdIns(3)P is turned over via the endocytic machinery. In the functional context of epidermal growth factor (EGF) stimulation, we observed that dimerization of the probe led to clustering of mainly early endocytic structures, leaving most of the probe localized to the limiting membrane of endosomes. Interestingly, these clustered endosomes contained coats positive for the PtdIns(3)P-binding protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), indicating that the probe did not displace Hrs binding. We conclude that the dimerizer-inducible probe is useful for the time-resolved detection of PtdIns(3)P at the ultrastructural level, but its effects on endosome morphology after EGF stimulation need to be taken into account. PMID- 20713984 TI - Expression and localization of angiogenic growth factors in developing porcine mesonephric glomeruli. AB - The development and growth of renal glomeruli is regulated by specific angiogenic growth factors, including vascular endothelial growth factor (VEGF) and the angiopoietins (ANGPT1 and ANGPT2). The expression of these factors has already been studied during metanephric glomerulogenesis, but it remains to be elucidated during the development of the embryonic mesonephros, which can function as an interesting model for glomerular development and senescence. In this study, the presence of the angiogenic growth factors was studied in developing porcine mesonephroi, using IHC and real-time RT-qPCR on laser capture microdissected glomeruli. In addition, mesonephric glomerular growth was measured by using stereological methods. ANGPT2 remained upregulated during maturation of glomeruli, which may be explained by the continuous growth of the glomeruli, as observed by stereological examination. The mRNA for VEGFA was expressed in early developing and in maturing glomeruli. The VEGF receptor VEGFR1 was stably expressed during the whole lifespan of mesonephric glomeruli, whereas VEGFR2 mRNA was only upregulated in early glomerulogenesis, suggesting that VEGFR2 is important for the vascular growth but that VEGFR1 is important for the maintenance of endothelial fenestrations. PMID- 20713986 TI - Phosphorylation of fascin decreases the risk of poor survival in patients with esophageal squamous cell carcinoma. AB - Phosphorylation of fascin at serine 39 (phospho-S39-fascin) could inhibit its actin-binding and actin-bundling activities and decrease filopodia formation. However, the relationship between phospho-S39-fascin expression and clinicopathological parameters in tumors is still unknown. Here, Western blot analysis and IHC applied to tissue microarray technology were performed to examine the expression status of non-phosphorylated fascin (fascin) and phospho S39-fascin and their impacts on the prognosis of patients with esophageal squamous cell carcinoma (ESCC). Fascin and phospho-S39-fascin expressions were tested by cytoplasmic staining. Among the 254 patients, 90 cases showed high expression of fascin and 87 cases showed high expression of phospho-S39-fascin. Survival analysis showed that high expression of fascin was significantly associated with a poor prognosis of the patients with ESCC (p=0.004). In contrast, high expression of phospho-S39-fascin correlated significantly with an improved outcome of patients (p=0.020). Multivariate analysis showed that both fascin and phospho-S39-fascin were independent prognostic factors. In a combined analysis, the patients with high expression of fascin and low expression of phospho-S39-fascin tumors had a shorter overall survival than those with high expression of both fascin and phospho-S39-fascin tumors (5-year overall survival rate: 28.7% vs 48.3%, p=0.068). Our results suggest that high expression of fascin correlates with poor outcome and that high expression of phospho-S39 fascin decreases the risk of poor prognosis in ESCC. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. PMID- 20713987 TI - Obesity predicts differential response to cancer prevention interventions among African Americans. AB - Wellness for African Americans Through Churches was a randomized trial that tested the effectiveness of tailored print and video (TPV) and/or lay health advisors (LHA) at increasing recreational physical activity (RPA), fruit and vegetable (F&V) consumption, and colorectal cancer (CRC) screening in African American churches. Baseline data revealed lower screening and RPA rates among obese individuals but no weight-related differences in F&V consumption. This analysis examined if intervention effectiveness was also moderated by participant weight group. Regression analyses tested for interactions between intervention and weight group for screening and RPA. Weight group was found to be a moderator of intervention effectiveness (p = .02); normal and overweight individuals receiving the LHA intervention increased RPA more, whereas obese individuals responded better to TPV. For CRC screening, the interaction term was not significant; weight alone was related to screening at follow-up (p = .049), with obese individuals reporting less screening. These results suggest that weight tailoring may improve the effectiveness of behavior change interventions. PMID- 20713988 TI - Development of a no-wash assay for mitochondrial membrane potential using the styryl dye DASPEI. AB - Mitochondrial dysfunction is a hallmark of several diseases and may also result from drugs with unwanted side effects on mitochondrial biochemistry. The mitochondrial membrane potential is a good indicator of mitochondrial function. Here, the authors have developed a no-wash mitochondrial membrane potential assay using 2-(4-(dimethylamino)styryl)-N-ethylpyridinium iodide (DASPEI), a rarely used mitochondrial potentiometric probe, in a 96-well format using a fluorescent plate reader. The assay was validated using 2 protonophores (CCCP, DNP), which are known uncouplers, and the neuroleptic thioridazine, which is a suspected mitochondrial toxicant. CCCP and DNP have short-term depolarizing effects, and thioridazine has long-term hyperpolarizing effects on the mitochondrial membrane potential of Chinese hamster ovary (CHO) cells. The assay also detected changes of the mitochondrial membrane potential in CHO cells exposed to cobalt (mimicking hypoxia) and in PC12 cells exposed to amyloid beta, demonstrating that the assay can be used in cellular models of hypoxia and Alzheimer's disease. The assay needs no washing steps, has a Z' value >0.5, can be used on standard fluorometers, has good post liquid-handling stability, and thus is suitable for large-scale screening efforts. In summary, the DASPEI assay is simple and rapid and may be of use in toxicological testing, drug target discovery, and mechanistic models of diseases involving mitochondrial dysfunction. PMID- 20713989 TI - The Latin American Association for the Study of the Liver in its meeting on diagnosis, management and treatment of hepatitis C. PMID- 20713990 TI - Latin American Association for the Study of the Liver Practice Guidelines. Diagnosis, management, and treatment of hepatitis C. PMID- 20713991 TI - Epidemiology of HCV infection in Latin America. AB - Hepatitis C virus is one of the most common causes of chronic liver disease and one of the principal indications for liver transplantation. The prevalence and incidence worldwide is variable, although there may be some similarities among different regions. Worldwide prevalence has been estimated around 3.1% or 170 million infected people. The Latin America region has one of the lowest prevalence around the world with an overall prevalence estimated around 1.23%, nevertheless it varies from country to country and even between regions of the same country. Although the principal route of transmission continues being blood transfusion, the epidemiological change around the world is affecting our region, increasing the virus transmission among intravenous drugs users. Also in Latin America the most prevalent genotype is 1 different from other regions like Africa and Asia. The knowledge of epidemiology of Hepatitis C in our region is basic for the prevention and treatment of this arising disease, and further research with greater general population based studies must be carried out. PMID- 20713992 TI - Routes of transmission of hepatitis C virus. AB - Hepatitis C is one of the most common causes of chronic liver disease in Latin America. It is essential to understand the different mechanisms of transmission of the infection in order to design control measures. The pattern of transmission of the infection in our region suggests that the peak of the infection occurred 30 to 50 years ago. While most infections in Latin America seem to be the result of blood transfusion and unsafe therapeutic injection practices in the past, there is still a need to identify and notify infected blood donors. Intravenous drug use and sexually transmitted hepatitis C virus among human immunodeficiency virus-positive patients are current problems that need to be addressed. PMID- 20713993 TI - Diagnosis of patients with suspected chronic hepatitis C infection. AB - The current optimal approach to detecting hepatitis C virus (HCV) infection involves screening people for risk factors and only testing selected individuals at risk. Blood transfusion from infectious donors, unsafe therapeutic injection practices, and illegal intravenous drug use have been the predominant modes of transmission of HCV infection. Virological markers that are currently used for the clinical management of patients with hepatitis C include serologic assays (ELISA or immunoblot assays), which detect specific antibodies (IgG) to HCV, and virological assays, which detect serum HCV RNA, by highly sensitive qualitative and quantitative techniques. The applicability of these tests is for the diagnoses and monitoring of the treatment but they have no role in the assessment of disease severity or prognosis. Patients diagnosed with HCV infection must be educated in order to avoid the spread of the disease to other people. PMID- 20713994 TI - Usefulness of liver biopsy in chronic hepatitis C. AB - Major requirements for performance of liver biopsy (LB) are the benefits for the patient and the impossibility of having the same information by less invasive procedures. In the last two decades physicians have faced the difficult task of convincing a patient positive for hepatitis C, with minimal clinical or laboratory alterations to be submitted to LB in order to evaluate the status of the disease for therapeutic management. The characteristics of the needle used for percutaneous LB interferes with the accuracy of diagnosis. In chronic hepatitis C (CHC), validity is achieved with liver fragments about 25 mm in length containing more than 10 portal tracts. Morbidity due to LB is mainly related to bleeding but death is very rare. Severe complications are also uncommon, increasing with number of passes and decreasing with experience of operator and ultrasound guidance. Although CHC is a diffuse disease, the various areas of the liver may not be equally affected and sampling errors are possible. Another potential limitation of LB is the discordance between pathologists in its interpretation. To replace LB, many panels of surrogate markers have been described, aiming to identify extent of fibrosis and inflammation. All of them have used LB as their gold standard. Liver biopsy continues to be the most reliable method to evaluate the possibility of therapy for CHC. Universal treatment of all patients with diagnosis of CHC would be ideal. But, there are mainly three drawbacks. Overall efficacy is as low as 50%, side effects are common and may be severe and treatment is prolonged and expensive. The acceptability of the biopsy by the patient is highly dependent on the physicians conviction of its usefulness. PMID- 20713995 TI - Noninvasive markers of liver fibrosis in Latin America and Mexico. PMID- 20713996 TI - Indications for treatment in chronic HCV infection. AB - HCV Infection is a global burden disease and it is related to the development of progressive liver fibrosis, cirrhosis and hepatocellular carcinoma. At least 80% of the persons that have an acute infection evolve to chronicity. This event affects the patient and their contacts for the risk of acquiring the infection. Once chronic HCV is present some factors accelerate progression: older age, obesity, alcohol consumption, etc. Severity of fibrosis is one of the most important factors to be analyzed before deciding to treat a patient. Pegylated interferon and ribavirin is the .standard of care. for this disease, however, it has many side effects, some of them life threatening. That is the reason why this treatment must be indicated in the right moment in the right patient. A complete medical evaluation must be done previously to initiate treatment. Other concurrent problems must be ruled out or treated. Decompensated cirrhosis, autoimmune diseases or other uncontrolled disease are contraindication to HCV treatment. Previous failure to treatment for HCV must be analyzed to identify the reasons for that event and consider retreatment. Cryoglobulinemia and membranoproliferative glomerulonephritis are indications for treatment independent from the severity of liver disease.
PMID- 20713997 TI - Predictors of response to chronic hepatitis C treatment. AB - Nowadays the standard of care for hepatitis C therapy is based on pegylated interferon alpha and ribavirin (Peg IFN/RBV). This combination has led to a sustained virological response rate (SVR) of 50 to 80% depending on genotype. This is still low, considering the side effects, overall costs and duration of therapy. So far, strategies to foresee SVR have been described such as genotype, fibrosis stage, viral load and gammaglutamyltransferase.In addition, new data has recently been provided on predictive factors of SVR like genetic polymorphism related to race, insulin resistance and viral kinetics. This review aims to discuss these predictive factors of therapy that might help the decision about starting or discontinuing therapy in chronic HCV infected patients. PMID- 20713998 TI - Characteristics of hepatitis C treatment with pegylated interferons and ribavirin. AB - The effect of interferon alfa against hepatitis C virus has been well documented. However, clinical efficacy is low due to the short interferon residence in the body. To prolong half-life, interferon molecules have been bound to the biologically inert polymer, polyethyleneglycol. Pegylated interferons exhibit a longer residence time with an improved clinical efficacy, although the rate of therapeutic failure is still important. Addition of ribavirin to interferon, either pegylated or not, significantly increases efficacy. Therefore, the combination of a pegylated interferon with ribavirin has become the standard treatment of chronic hepatitis C. As the efficacy and safety of such combinations are not yet optimal, different drugs, including other types of long-acting interferons and ribavirin analogs, are presently been investigated. PMID- 20713999 TI - Chronic hepatitis C treatment in naive patients. AB - Hepatitis C (HCV) is a major public health problem worldwide and it is considered that there are about 180 millions of infected people. The natural history of hepatitis C shows that, of those individuals affected by a primo-infection, 55 to 95% evolve into chronicity. The objective of treatment for chronic hepatitis C is to prevent in the long term the complications and death that this disease may cause. In a short term the most important aim is the sustained virological response (SVR), considered a virological response, normalization of the serum ALT level, histological improvement, improvement in patients. quality of life and the risk of transmission reduction. The association Peginterferon alpha. Ribavirin (PEG IFNa-RBV), at the moment, is the standard of care of patients with chronic hepatitis C and compensated cirrhosis. Two PEG IFNa are licensed, PEG IFNa 2a and PEG IFNa 2b. Pegylation is a procedure that allows the union of polyethylene glycol moieties (PEG) to pharmacologic active proteins; in this case, IFNa. Pegylation of the IFNa 2a and 2b provoke important modifications in these proteins: slower absorption, different distribution, slower elimination, and longer half life with major exposure to the drug and lesser antigenicity. The two pegylated interferons available are dissimilar between them. The SVR in chronic hepatitis C patients who were treated with PEG IFNa-RBV in registration trials was 54 to 61%. Patients with genotypes 1 and 4 must be treated 48 weeks and those with genotypes 2 and 3, 24 weeks. In some situations patients could be treated lesser or longer time. Results obtained from the association of PEG IFNa - RBV - Amantadine in chronic hepatitis C patients are controversial. Meta-analysis comparing both PEG IFNs alpha shows a better SVR with PEG IFNa 2a. Therapies in patients with mild chronic hepatitis C have a similar SVR that those with more advanced liver disease and could be treated in this phase of the disease.
PMID- 20714000 TI - Clinical approach to the patient with chronic hepatitis C infection and normal aminotransferases. AB - Approximately 30% of patients with chronic HCV infection have persistently normal alanine aminotransferase levels (PNALT). Most of these patients have minimal or mild inflammation and absent or minimal fibrosis, although occasionally cirrhosis and hepatocarcinoma may be seen. Overall, liver histology is significantly less severe than in patients with elevated ALT levels, and most follow-up studies have reported stability of the disease, with minimal fibrosis progression over years, and thus a disease with a favorable prognosis. Nevertheless, a few studies have shown more recently that many patients with PNALT, may have elevations in ALT over time, and almost 20-30% have a significant progression of fibrosis, being eligible for antiviral therapy. During the last decade it has been demonstrated that in chronic HCV infection with PNALT, combination antiviral therapy with peg interferon-alpha plus ribavirin is efficacious, safe, and associated with significant improvements in health-related quality of life, and the decision whether to treat or not this patients should be based on multiple factors including: age, HCV genotype, histology, patients motivation and adherence, symptoms and comorbidity, rather than on ALT levels alone. PMID- 20714001 TI - Treatment of HCV infection in patients with cirrhosis. AB - The treatment of patients with cirrhosis has the following purposes: to prevent the complications of the disease; to allow for the regression of cirrhosis; and to prevent reinfection in the graft in patients undergoing liver transplantation. When the sustained viral response is evaluated in patients with cirrhosis, especially in those with decompensated disease, it is noted to be lower than that of patients with chronic hepatitis, and with a higher possibility of complications of the treatment. Based on a review of the literature, we conclude that we should treat patients with compensated cirrhosis, probably also those with portal hypertension, and patients with decompensated cirrhosis only when included on the transplant list, as long as Child B with HCV genotype 2 (possibly 3) and preferably after clinical compensation. PMID- 20714002 TI - Treatment of recurrent hepatitis C post-liver transplantation. AB - Recurrent hepatitis C after liver transplantation is universal. Graft reinfection occurs rapidly, with chronic hepatitis and rapid evolution from end-stage liver disease. Within 5 years until 30% of patients with recurrent disease ultimately progress to cirrhosis, and survival of transplanted patients with recurrent hepatitis C virus has been shown to be lower than of patients transplanted for other indications. Antiviral therapy in this patient population is generally recommended, but indication, optimal timing, dose and duration of therapy are not clearly defined. There are two major indications of therapy in that patients: pre transplant antiviral therapy aiming to prevent reinfection, and post-transplant therapy with the goal of eradicating the recurrent infection. The first is limited by poor tolerance and drug side effects, and the second achieves only sustained virologic response in 25-45% of patients. Combination therapy with PEG INF and ribavirin showed the better results. Dose reduction and interruption of therapy occurs in 30 to 60% by side effects. There are no prospective randomized trials with confidence of results. More efficacious and better tolerable antiviral therapies are needed. PMID- 20714003 TI - The management of HCV-infected pregnant women. AB - Hepatitis C is, at present, a worldwide health problem and is the most common cause of liver transplantation. Its prevalence in pregnant women is similar to that of the general population. In the absence of cirrhosis and portal hypertension, most HCV-infected pregnant women do not have obstetric complications. Screening of pregnant women that are asymptomatic and do not have risk factors is not cost effective. A high hepatitis C viral load reportedly increases vertical transmission and is higher in women who are coinfected with HIV or who are intravenous drug users. Prolonged rupture of the membrane for more than 6 h, amniocentesis, and perineal lacerations increase the potential risk of perinatal transmission. Although the hepatitis C virus can be transmitted intrapartum, prevention by caesarean delivery is not generally indicated. The HCV virus can be found in maternal milk; however, breast feeding is not contraindicated. In conclusion, there are no antiviral treatment recommendations for HCV-infected women during pregnancy, or guidelines for the prevention of vertical transmission. PMID- 20714004 TI - Management of hepatitis C virus infection in childhood. AB - Infection with hepatitis C virus (HCV) is a worldwide health problem with more than 170 million infected individuals. In children, since 1992 almost all infections occurred through vertical transmission from an infected mother to her newborn infant. Natural history of HCV infection in children is not yet well defined, most children are asymptomatic and may remain so for decades. Most infected individuals (60-80%), regardless of their age at infection, become chronically infected with HCV. Spontaneous resolution in children appears to be infrequent. Positive HCV antibody implicate that patient has been exposed to the virus (EIA test). To discriminate between active or resolved HCV viral infection it is necessary to perform HCV RNA (PCR). Liver biopsy assess degree of liver injury and exclude concurrent diseases. HCV chronic infection is slow progressive in childhood. Progression of fibrosis seems to be a function of infection duration. Treatment objective is clearance of HCVRNA. IFNa is recognized as the drug approved for hepatitis C treatment in pediatric population. Combination therapy with IFNa or pegylated IFNa plus ribavirin is recently approved by US FDA and EMEA and clinical trials are in progress. PMID- 20714005 TI - Treatment of HCV infected patients and renal disease. AB - Hepatitis C signifies a highly prevalent infection in patients with end stage renal disease. Most frequently it is associated to glomerulonephritis, patients on hemodialysis and renal transplants. The prevalence of HCV antibodies in hemodialysis patients varies between 5-70% depending on the geographical location of the patients. Factors associated with the prevalence of anti HCV in patients with hemodialysis include: age, blood transfusions, tattoos, use of illegal drugs, time in hemodialysis, more than two hospitalizations, treatment in multiple hemodialysis units or a kidney transplant. In some of the reported outbreaks of hepatitis in hemodialysis units, the phylogenetic analysis indicate that the transmission of HCV could relate to failures or breaches in general precautions in the management of these type of patients resulting in nosocomial transmission owed to sharing equipment or instruments employed in the hemodialysis or by transmission from professional members of the hemodialysis units. Antiviral treatment may be affected by a number of co-factors and co morbidities, it consist mainly of non pegylated interferon or pegylated interferon. The treatment with interferon after a renal transplant is associated with an increase in the number of rejections; reason enough to recommended that treatment should be administered before the transplant. PMID- 20714006 TI - Acute hepatitis C treatment. AB - There are no well established treatment guidelines about acute hepatitis C (AHC), leaving physicians to make several challenging decisions, such whether to treat, when to treat and what treatment regimens to use. This article examines the diagnosis of acute infection and critically appraises the various treatment regimens. PMID- 20714008 TI - Hepatitis C and hepatocellular carcinoma. AB - Chronic hepatitis C virus infection is a well-recognized risk factor for occurrence of hepatocellular carcinoma (HCC). In Europe, Oceania and America, chronic hepatitis C and alcoholic cirrhosis are the main risk factors for HCC. In Latin America, a few retrospective and one prospective study have also shown the predominant role played by hepatitis C in this setting. Furthermore, the incidence of HCC has been increasing in industrialized countries in the last decades; partially as a consequence of the increase in HCV-related cirrhosis (as the long-term sequel of the peak of infections occurring 2-4 decades ago). The main risk factor for HCC development in patients with hepatitis C is the presence of cirrhosis. Among patients with hepatitis C and cirrhosis, the annual incidence rate of HCC ranges between 1-8%, being higher in Japan (4-8%) intermediate in Italy (2-4%) and lower in USA (1.4%). Some studies have also found that HCC may be the first complication to develop and the more frequent cause of death in the compensated HCV-associated cirrhosis. Other risk factors for HCC occurrence are older age at infection, male gender, decreased platelet count, esophageal varices, presence of porphyria cutanea tarda, liver steatosis or diabetes, infection with genotype 1b, coinfection with hepatitis B virus or with HIV and chronic alcoholism. Many studies and also meta-analysis have reported that antiviral therapy based on interferon may reduce the incidence of HCC in chronic hepatitis C, especially in patients with sustained virologic response. Patients with HCV-related cirrhosis should undergo surveillance for HCC. PMID- 20714007 TI - Insulin resistance, hepatic steatosis and hepatitis C: a complex relationship with relevant clinical implications. AB - Insulin resistance (IR) is a common pathophysiological condition where higher than-normal concentrations of insulin are needed to maintain a normal glycemia and adequate glucose utilization in insulin target tissues. A high proportion (50 80%) of patients chronically infected with the hepatitis C virus (HCV) exhibit evidence of IR. Basic and clinical studies have disclosed a complex bidirectional relationship between IR and HCV infection that has important clinical implications. HCV infection may promote IR through direct viral-dependent mechanisms or due to activation of the inflammatory response resulting in increased production of tumor necrosis factor-a and other cytokine-related molecules. These abnormalities may act synergistically with pre-existing metabolic risk factors and result in the development of hepatic steatosis and type 2 diabetes mellitus (T2DM) which are frequently found in the setting of HCV infection. Moreover, in addition to underlying metabolic abnormalities leading to its development hepatic steatosis also exhibit genotype-specific pathogenic mechanisms. A number of studies have shown that hepatic steatosis is associated to fibrosis progression in patients with HCV and that IR has a negative impact on the response rates to interferon-a-based therapy. Thus, modification of these factors through life-style changes or pharmacological agents may represent an undervalued specific target of therapy aiming to improve sustained virological response rates and reduce HCV related-morbidity and mortality. PMID- 20714009 TI - On the cusp of change: new therapeutic modalities for HCV. AB - We are at the cusp of significant new alternatives for the treatment of chronic hepatitis C. Among more than 100 drugs in development, some are ready to be approved and in the market as soon as next year. The protease inhibitors telaprevir and boceprevir, will change the SOC treatment to triple therapy, (combined with peg IFN and RBV), with duration of treatment guided by rapid virological response. In this article we present the data supporting the approval of telaprevir and boceprevir, and information on polymerase inhibitors and IFN free proof of concept trials. Finally we discuss which patients should wait for DAA based therapies and which should be considered for peg IFN/RBV now. In the next 5 years our patients can expect higher response rates and truncated duration of therapy. They can expect drug cocktails or combos but for the next years these novel drugs will still require peg IFN and RBV. Also, a new era of resistance as a barrier to therapy will require sub typing and more viral monitoring. Overall, improved outcomes will come at the expense of more adverse events and increased costs of treatment. PMID- 20714010 TI - Hepatitis C virus infection in health-care settings: medical and ethical implications. AB - Hepatitis C is a major public health issue. It infects about 200 million people worldwide and is a major cause of chronic liver disease. Its transmission in medical facilities is a topic of increased concern, as outbreaks of the disease had raised the attention of media and medical authorities. To date, evidence suggests that infection from in which a health-care worker is involved is mostly result of bad injecting practices as well as the result of shared medical devices. Furthermore, the infection caused by physicians is rare and very few well documented cases exist on the literature. Among countries, different definitions and legislation exist, in that mode that the responsibility of this issue almost is an obligation of individual institutions. Nonetheless, Hepatitis C virus transmission in medical facilities is an important source of new cases, and as treatments options are very limited, it's recommendable that institutions as well as governments implement policies to avoid Hepatitis C spread in a almost fully preventable setting. PMID- 20714011 TI - Efficient 3D geometric and Zernike moments computation from unstructured surface meshes. AB - This paper introduces and evaluates a fast exact algorithm and a series of faster approximate algorithms for the computation of 3D geometric moments from an unstructured surface mesh of triangles. Being based on the object surface reduces the computational complexity of these algorithms with respect to volumetric grid based algorithms. In contrast, it can only be applied for the computation of geometric moments of homogeneous objects. This advantage and restriction is shared with other proposed algorithms based on the object boundary. The proposed exact algorithm reduces the computational complexity for computing geometric moments up to order N with respect to previously proposed exact algorithms, from N(9) to N(6). The approximate series algorithm appears as a power series on the rate between triangle size and object size, which can be truncated at any desired degree. The higher the number and quality of the triangles, the better the approximation. This approximate algorithm reduces the computational complexity to N(3). In addition, the paper introduces a fast algorithm for the computation of 3D Zernike moments from the computed geometric moments, with a computational complexity N(4), while the previously proposed algorithm is of order N(6). The error introduced by the proposed approximate algorithms is evaluated in different shapes and the cost-benefit ratio in terms of error, and computational time is analyzed for different moment orders. PMID- 20714012 TI - Distance-driven skeletonization in voxel images. AB - A distance-driven method to compute the surface and curve skeletons of 3D objects in voxel images is described. The method is based on the use of the <3,4,5> weighted distance transform, on the detection of anchor points, and on the application of topology preserving removal operations. The obtained surface and curve skeletons are centered within the object, have the same topology as the object, and have unit thickness. The object can be almost completely recovered from the surface skeleton since this includes almost all of the centers of maximal balls of the object. Hence, the surface skeleton is a faithful representation. In turn, though only partial recovery is possible from the curve skeleton, this still provides an appealing representation of the object. PMID- 20714013 TI - Visually inspecting specular surfaces: A generalized image capture and image description approach. AB - Image capturing and image content description can be regarded as the two major steps of a computer vision process. This paper focuses on both within the field of specular surface inspection, by generalizing a previously defined stripebased inspection method to free-form surfaces on the basis of a specific stripe illumination technique and by outlining a general feature-based stripe image characterization approach by means of new theoretical concepts. One major purpose of this paper is to propose a general stripe image interpretation approach on the basis of a three-step procedure: 1) comparison of different image content description techniques, 2) fusion of the most appropriate ones, and 3) selection of the optimal features. It is shown that this approach leads to an increase in the classification rates of more than 2 percent between the initial fused set and the selected one. The new contributions encompass 1) the generalization of a cylindrical specular surface enhancement technique to more complex specular geometries, 2) the generalization of the previously defined stripe image description by using the same number of features for the bright and the dark stripes, and 3) the definition of an optimal, in terms of classification rates and computational costs, stripe feature set. PMID- 20714014 TI - Action recognition using mined hierarchical compound features. AB - The field of Action Recognition has seen a large increase in activity in recent years. Much of the progress has been through incorporating ideas from single frame object recognition and adapting them for temporal-based action recognition. Inspired by the success of interest points in the 2D spatial domain, their 3D (space-time) counterparts typically form the basic components used to describe actions, and in action recognition the features used are often engineered to fire sparsely. This is to ensure that the problem is tractable; however, this can sacrifice recognition accuracy as it cannot be assumed that the optimum features in terms of class discrimination are obtained from this approach. In contrast, we propose to initially use an overcomplete set of simple 2D corners in both space and time. These are grouped spatially and temporally using a hierarchical process, with an increasing search area. At each stage of the hierarchy, the most distinctive and descriptive features are learned efficiently through data mining. This allows large amounts of data to be searched for frequently reoccurring patterns of features. At each level of the hierarchy, the mined compound features become more complex, discriminative, and sparse. This results in fast, accurate recognition with real-time performance on high-resolution video. As the compound features are constructed and selected based upon their ability to discriminate, their speed and accuracy increase at each level of the hierarchy. The approach is tested on four state-of-the-art data sets, the popular KTH data set to provide a comparison with other state-of-the-art approaches, the Multi-KTH data set to illustrate performance at simultaneous multiaction classification, despite no explicit localization information provided during training. Finally, the recent Hollywood and Hollywood2 data sets provide challenging complex actions taken from commercial movie sequences. For all four data sets, the proposed hierarchical approach outperforms all other methods reported thus far in the literature and can achieve real-time operation. PMID- 20714015 TI - Textual query of personal photos facilitated by large-scale web data. AB - The rapid popularization of digital cameras and mobile phone cameras has led to an explosive growth of personal photo collections by consumers. In this paper, we present a real-time textual query-based personal photo retrieval system by leveraging millions of Web images and their associated rich textual descriptions (captions, categories, etc.). After a user provides a textual query (e.g., "water"), our system exploits the inverted file to automatically find the positive Web images that are related to the textual query "water" as well as the negative Web images that are irrelevant to the textual query. Based on these automatically retrieved relevant and irrelevant Web images, we employ three simple but effective classification methods, k-Nearest Neighbor (kNN), decision stumps, and linear SVM, to rank personal photos. To further improve the photo retrieval performance, we propose two relevance feedback methods via cross-domain learning, which effectively utilize both the Web images and personal images. In particular, our proposed crossdomain learning methods can learn robust classifiers with only a very limited amount of labeled personal photos from the user by leveraging the prelearned linear SVM classifiers in real time. We further propose an incremental cross-domain learning method in order to significantly accelerate the relevance feedback process on large consumer photo databases. Extensive experiments on two consumer photo data sets demonstrate the effectiveness and efficiency of our system, which is also inherently not limited by any predefined lexicon. PMID- 20714016 TI - Improving offline handwritten text recognition with hybrid HMM/ANN models. AB - This paper proposes the use of hybrid Hidden Markov Model (HMM)/Artificial Neural Network (ANN) models for recognizing unconstrained offline handwritten texts. The structural part of the optical models has been modeled with Markov chains, and a Multilayer Perceptron is used to estimate the emission probabilities. This paper also presents new techniques to remove slope and slant from handwritten text and to normalize the size of text images with supervised learning methods. Slope correction and size normalization are achieved by classifying local extrema of text contours with Multilayer Perceptrons. Slant is also removed in a nonuniform way by using Artificial Neural Networks. Experiments have been conducted on offline handwritten text lines from the IAM database, and the recognition rates achieved, in comparison to the ones reported in the literature, are among the best for the same task. PMID- 20714017 TI - Connectedness of random walk segmentation. AB - Connectedness of random walk segmentation is examined, and novel properties are discovered, by considering electrical circuits equivalent to random walks. A theoretical analysis shows that earlier conclusions concerning connectedness of random walk segmentation results are incorrect, and counterexamples are demonstrated. PMID- 20714018 TI - Greedy learning of binary latent trees. AB - Inferring latent structures from observations helps to model and possibly also understand underlying data generating processes. A rich class of latent structures is the latent trees, i.e., tree-structured distributions involving latent variables where the visible variables are leaves. These are also called hierarchical latent class (HLC) models. Zhang and Kocka proposed a search algorithm for learning such models in the spirit of Bayesian network structure learning. While such an approach can find good solutions, it can be computationally expensive. As an alternative, we investigate two greedy procedures: the BIN-G algorithm determines both the structure of the tree and the cardinality of the latent variables in a bottom-up fashion. The BIN-A algorithm first determines the tree structure using agglomerative hierarchical clustering, and then determines the cardinality of the latent variables as for BIN-G. We show that even with restricting ourselves to binary trees, we obtain HLC models of comparable quality to Zhang's solutions (in terms of cross-validated log likelihood), while being generally faster to compute. This claim is validated by a comprehensive comparison on several data sets. Furthermore, we demonstrate that our methods are able to estimate interpretable latent structures on real-world data with a large number of variables. By applying our method to a restricted version of the 20 newsgroups data, these models turn out to be related to topic models, and on data from the PASCAL Visual Object Classes (VOC) 2007 challenge, we show how such treestructured models help us understand how objects co-occur in images. For reproducibility of all experiments in this paper, all code and data sets (or links to data) are available at http://people.kyb.tuebingen.mpg.de/harmeling/code/ltt-1.4.tar. PMID- 20714019 TI - SIFT flow: dense correspondence across scenes and its applications. AB - While image alignment has been studied in different areas of computer vision for decades, aligning images depicting different scenes remains a challenging problem. Analogous to optical flow, where an image is aligned to its temporally adjacent frame, we propose SIFT flow, a method to align an image to its nearest neighbors in a large image corpus containing a variety of scenes. The SIFT flow algorithm consists of matching densely sampled, pixelwise SIFT features between two images while preserving spatial discontinuities. The SIFT features allow robust matching across different scene/object appearances, whereas the discontinuity-preserving spatial model allows matching of objects located at different parts of the scene. Experiments show that the proposed approach robustly aligns complex scene pairs containing significant spatial differences. Based on SIFT flow, we propose an alignment-based large database framework for image analysis and synthesis, where image information is transferred from the nearest neighbors to a query image according to the dense scene correspondence. This framework is demonstrated through concrete applications such as motion field prediction from a single image, motion synthesis via object transfer, satellite image registration, and face recognition. PMID- 20714020 TI - Large displacement optical flow: descriptor matching in variational motion estimation. AB - Optical flow estimation is classically marked by the requirement of dense sampling in time. While coarse-to-fine warping schemes have somehow relaxed this constraint, there is an inherent dependency between the scale of structures and the velocity that can be estimated. This particularly renders the estimation of detailed human motion problematic, as small body parts can move very fast. In this paper, we present a way to approach this problem by integrating rich descriptors into the variational optical flow setting. This way we can estimate a dense optical flow field with almost the same high accuracy as known from variational optical flow, while reaching out to new domains of motion analysis where the requirement of dense sampling in time is no longer satisfied. PMID- 20714021 TI - Describing reflectances for color segmentation robust to shadows, highlights, and textures. AB - The segmentation of a single material reflectance is a challenging problem due to the considerable variation in image measurements caused by the geometry of the object, shadows, and specularities. The combination of these effects has been modeled by the dichromatic reflection model. However, the application of the model to real-world images is limited due to unknown acquisition parameters and compression artifacts. In this paper, we present a robust model for the shape of a single material reflectance in histogram space. The method is based on a multilocal creaseness analysis of the histogram which results in a set of ridges representing the material reflectances. The segmentation method derived from these ridges is robust to both shadow, shading and specularities, and texture in real-world images. We further complete the method by incorporating prior knowledge from image statistics, and incorporate spatial coherence by using multiscale color contrast information. Results obtained show that our method clearly outperforms state-of-the-art segmentation methods on a widely used segmentation benchmark, having as a main characteristic its excellent performance in the presence of shadows and highlights at low computational cost. PMID- 20714022 TI - Closed-Loop Feedback Illumination for Optical Inverse Tone-Mapping in Light Microscopy. AB - In this paper, we show that optical inverse tone-mapping (OITM) in light microscopy can improve the visibility of specimens, both when observed directly through the oculars and when imaged with a camera. In contrast to previous microscopy techniques, we premodulate the illumination based on the local modulation properties of the specimen itself. We explain how the modulation of uniform white light by a specimen can be estimated in real time, even though the specimen is continuously but not uniformly illuminated. This information is processed and back-projected constantly, allowing the illumination to be adjusted on the fly if the specimen is moved or the focus or magnification of the microscope is changed. The contrast of the specimen's optical image can be enhanced, and high-intensity highlights can be suppressed. A formal pilot study with users indicates that this optimizes the visibility of spatial structures when observed through the oculars. We also demonstrate that the signal-to-noise (S/N) ratio in digital images of the specimen is higher if captured under an optimized rather than a uniform illumination. In contrast to advanced scanning techniques that maximize the S/N ratio using multiple measurements, our approach is fast because it requires only two images. This can improve image analysis in digital microscopy applications with real-time capturing requirements. PMID- 20714023 TI - Approximate Boolean Operations on Large Polyhedral Solids with Partial Mesh Reconstruction. AB - We present a new approach to compute the approximate Boolean operations of two freeform polygonal mesh solids efficiently with the help of Layered Depth Images (LDIs). After applying the LDI sampling-based membership classification, the most challenging part, a trimmed adaptive contouring algorithm, is developed to reconstruct the mesh surface from the LDI samples near the intersected regions and stitch it to the boundary of the retained surfaces. Our method of approximate Boolean operations holds the advantage of numerical robustness as the approach uses volumetric representation. However, unlike other methods based on volumetric representation, we do not damage the facets in nonintersected regions, thus preserving geometric details much better and speeding up the computation as well. We show that the proposed method can successfully compute the Boolean operations of free-form solids with a massive number of polygons in a few seconds. PMID- 20714024 TI - Beautification of Design Sketches Using Trainable Stroke Clustering and Curve Fitting. AB - We propose a new sketch parsing and beautification method that converts digitally created design sketches into beautified line drawings. Our system uses a trainable, sequential bottom-up and top-down stroke clustering method that learns how to parse input pen strokes into groups of strokes each representing a single curve, followed by point-cloud ordering that facilitates curve fitting and smoothing. This approach enables greater conceptual freedom during visual ideation activities by allowing designers to develop their sketches using multiple, casually drawn strokes without requiring them to indicate the separation between different stroke groups. With the proposed method, raw sketches are seamlessly converted into vectorized geometric models, thus, facilitating downstream assessment and editing activities. PMID- 20714025 TI - Regular networks can be uniquely constructed from their trees. AB - A rooted acyclic digraph N with labeled leaves displays a tree T when there exists a way to select a unique parent of each hybrid vertex resulting in the tree T. Let Tr(N) denote the set of all trees displayed by the network N. In general, there may be many other networks M, such that Tr(M) = Tr(N). A network is regular if it is isomorphic with its cover digraph. If N is regular and D is a collection of trees displayed by N, this paper studies some procedures to try to reconstruct N given D. If the input is D = Tr(N), one procedure is described, which will reconstruct N. Hence, if N and M are regular networks and Tr(N) = Tr(M), it follows that N = M, proving that a regular network is uniquely determined by its displayed trees. If D is a (usually very much smaller) collection of displayed trees that satisfies certain hypotheses, modifications of the procedure will still reconstruct N given D. PMID- 20714026 TI - 3D shape reconstruction of loop objects in X-ray protein crystallography. AB - Knowledge of the shape of crystals can benefit data collection in X-ray crystallography. A preliminary step is the determination of the loop object, i.e., the shape of the loop holding the crystal. Based on the standard set-up of experimental X-ray stations for protein crystallography, the paper reviews a reconstruction method merely requiring 2D object contours and presents a dedicated novel algorithm. Properties of the object surface (e.g., texture) and depth information do not have to be considered. The complexity of the reconstruction task is significantly reduced by slicing the 3D object into parallel 2D cross-sections. The shape of each cross-section is determined using support lines forming polygons. The slicing technique allows the reconstruction of concave surfaces perpendicular to the direction of projection. In spite of the low computational complexity, the reconstruction method is resilient to noisy object projections caused by imperfections in the image-processing system extracting the contours. The algorithm developed here has been successfully applied to the reconstruction of shapes of loop objects in X-ray crystallography. PMID- 20714027 TI - Estimating genome-wide gene networks using nonparametric Bayesian network models on massively parallel computers. AB - We present a novel algorithm to estimate genome-wide gene networks consisting of more than 20,000 genes from gene expression data using nonparametric Bayesian networks. Due to the difficulty of learning Bayesian network structures, existing algorithms cannot be applied to more than a few thousand genes. Our algorithm overcomes this limitation by repeatedly estimating subnetworks in parallel for genes selected by neighbor node sampling. Through numerical simulation, we confirmed that our algorithm outperformed a heuristic algorithm in a shorter time. We applied our algorithm to microarray data from human umbilical vein endothelial cells (HUVECs) treated with siRNAs, to construct a human genome-wide gene network, which we compared to a small gene network estimated for the genes extracted using a traditional bioinformatics method. The results showed that our genome-wide gene network contains many features of the small network, as well as others that could not be captured during the small network estimation. The results also revealed master-regulator genes that are not in the small network but that control many of the genes in the small network. These analyses were impossible to realize without our proposed algorithm. PMID- 20714028 TI - Rearrangement phylogeny of genomes in contig form. AB - There has been a trend in increasing the phylogenetic scope of genome sequencing while decreasing the quality of the published sequence for each genome. With reduced finishing effort, there is an increasing number of genomes being published in contig form. Rearrangement algorithms, including gene order-based phylogenetic tools, require whole genome data on gene order, segment order, or some other marker order. Items whose chromosomal location is unknown cannot be part of the input. The question we address here is, for gene order-based phylogenetic analysis, how can we use rearrangement algorithms to handle genomes available in contig form only? Our suggestion is to use the contigs directly in the rearrangement algorithms as if they were chromosomes, while making a number of corrections, e.g., we correct for the number of extra fusion/fission operations required to make contigs comparable to full assemblies. We model the relationship between contig number and genomic distance, and estimate the parameters of this model using insect genome data. With this model, we use distance matrix methods to reconstruct the phylogeny based on genomic distance and numbers of contigs. We compare this with methods to reconstruct ancestral gene orders using uncorrected contig data. PMID- 20714029 TI - Toward a robust search method for the protein-drug docking problem. AB - Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this paper is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time, the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 A. PMID- 20714030 TI - [Limbic encephalitis--history,symptoms,and the latest classification]. AB - The concept of limbic encephalitis has changed over time. Since the introduction of "limbic encephalitis" (LE) in 1968, LE was thought to almost always be associated with carcinoma; this belief led to the coining of the term "paraneoplastic limbic encephalitis" (PLE). In the 1990s, antineuronal antibodies, including anti-Hu and anti-Ta/Ma2, were detected; this supported the hypothesis of an autoimmune mechanism for PLE. The prognosis of patients with PLE was, however, poor. Since 2001, there have been reports of patients with LE exhibiting antibodies to the voltage-gated potassium channel; this observation is intriguing because in such cases the encephalitis was usually independent of carcinoma, and its clinical course was often reversible. Since the 1990s, cases of non-herpetic acute limbic encephalitis have been reported in Japan. In some of these cases, an autoantibody to GluRepsilon2 (NR2B) has been detected; GluRepsilon2 is a subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor found in the limbic forebrain. A postulated pathophysiologic role of this antibody led to the concept of autoantibody-mediated acute reversible LE (AMED ARLE). In 2007, some patients with ovarian teratoma developed encephalitis and exhibited antibodies to the NMDA receptor; this antibody is thought to recognize NR1/NR2 heteromers. Later, anti-NMDA receptor antibodies were also detected in some Japanese patients who had been previously diagnosed with juvenile acute non herpetic encephalitis. Currently, limbic encephalitis is categorized into 3 groups: limbic encephalitis caused by virus infection, autoantibody-mediated limbic encephalitis (AMLE), and limbic encephalitis with autoimmune disease. In AMLE, antibodies to cytoplasmic antigens cause classical PLE (type I). In contrast, antibodies to cell membrane antigens often cause reversible limbic encephalitis in patients with (PLE type II) or without tumors (AMED-ARLE). PMID- 20714031 TI - [Antibodies to glutamate receptor in limbic encephalitis]. AB - N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR), is an important molecule, which contributes to the pathophysiological processes of various neurological diseases by various molecular mechanisms. Antibodies against NMDA type GluR (NR) are detected by immunoblot analysis, enzyme-linked immunosorbent assay (ELISA), or immunocytochemical analysis (Dalmau's method). Immunoblot method uses whole molecules of GluRepsilon2 (NR2B), which are synthesized in NIH3T3 cells by using tetracycline system as antigens. In ELISA, synthesized peptides of each domain of GluRepsilon2 and GluRtheta1 (NR1) are used. Immunocytochemical method uses human embryonic kidney (HEK) cells transfected by expression vectors for NR1+NR2B/2A. In non-paraneoplastic, non-herpetic acute limbic encephalitis (NHALE), serum antibodies to GluRepsilon2 (NR2B) were detected in approximately 60% of the patients from acute to chronic stages further, these antibodies in the cerebrospinal fluid (CSF) were detected in 50% (acute stage), 40% (recovery stage), and 30% (chronic stage) of the patients. The antibodies against GluRepsilon2 seemed to increase in the sera after infection and infiltrate the central nervous system through the blood-brain barrier (BBB), which was damaged by cytokines, etc. The antibodies against GluRepsilon2 recognize broad regions of GluRepsilon2 as epitopes. In NHALE patients with ovarian teratoma, antibodies to NR recognize epitopes on GluRepsilon2 (NR2B) and GluRtheta1 (NR1). Pathophysiology of antibodies against NR is estimated to cause internalization of NR on surface of neurons, resulting in inhibition of NR function. PMID- 20714032 TI - [Anti-Ma2-associated encephalitis and paraneoplastic limbic encephalitis]. AB - Anti-Ma2-associated encephalitis (or anti-Ma2 encephalitis) is a paraneoplastic neurological syndrome (PNS) characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. Anti-Ma2 antibodies detected in the serum or cerebrospinal fluid of patients are highly specific for this disease entity and belong to a group of well-characterized onconeuronal antibodies (or classical antibodies). The corresponding antigen, Ma2 is selectively expressed intracellularly in neurons and tumors as is the case with other onconeuronal antigens targeted by classical antibodies. However, in most cases the clinical pictures are different from those of classical PNS and this creates a potential risk of underdiagnosis. Although limbic dysfunction is the most common manifestation in patients with anti-Ma2 encephalitis which is one of the major causes of paraneoplastic limbic encephalitis (LE), it has been reported that less than 30% of the patients with anti-Ma2 LE exhibit clinical presentations typical of the classical description of LE. Of the remaining, many exhibit excessive daytime sleepiness, vertical ophthalmoparesis, or both associated with LE, because of frequent involvement of the diencephalon and/or upper brainstem. Anti Ma2 LE can also be manifested as a pure psychiatric disturbance such as obsessive compulsive disorder in a few cases. Some patients develop mesodiencephalic encephalitis with minor involvement of the limbic system, and some may manifest severe hypokinesis. About 40% of the patients with anti-Ma2 antibodies also have antibodies against different epitopes on Ma1, a homologue of Ma2. These patients may have predominant cerebellar and/or brainstem dysfunctions due to more extensive involvement of subtentorial structures. Anti-Ma2 encephalitis is outstanding among other PNS associated with classical antibodies in that the response rate to treatment is relatively high. While it can cause severe neurological deficits or death in a substantial proportion of the patients, approximately one-third show neurological improvement and another 20 - 40% stabilize in response to treatment, including immunotherapy and/or tumor treatment. Patients who have limited CNS involvement and testicular tumors with complete response to therapy are more likely to show neurological improvement. This fact emphasizes the importance of early diagnosis and prompt initiation of therapy. However, it should be noted that even carcinoma in situ, which is difficult to detect can cause severe neurological disorders. In this respect, it is useful to highlight that anti-Ma2 encephalitis is almost always associated with testicular germ cell tumors in men younger than 50 years. We experienced a 40-year-old patient with severe hypokinesis caused by anti-Ma2 encephalitis associated with bilateral intratubular germ-cell neoplasm of the testes. In older men and women, non-small-cell lung cancer is most common but various types of cancers are reported to be associated. In this study,in addition to reviewing the above case we have reviewed the significance of anti-Ma2 antibodies in the diagnosis of anti-Ma2 encephalitis and the clinical features of this disease. PMID- 20714033 TI - [Clinical characteristics of non-herpetic limbic encephalitis]. AB - In Japan,the prevalence of non-herpetic acute limbic encephalitis (NHALE),characterized by a lack of evidence of the herpes simplex virus (HSV) genome or enzyme-linked immunosorbent assay (ELISA) antibody,has shown an upward trend. The causes of NHALE include several anti-neural antibodies related NHALE. Among them,NHALE that is characterized by the onset of abnormal behavior and presence of anti-glutamate receptor epsilon2 (GluRepsilon2) antibody is gaining attention. NHALE was identified in 1994 during a survey of herpes simplex encephalitis in Kyushu District. This disease has not been reported in individuals belonging to countries other than Japan. In this review article,3 cases of NHALE patients with positive GluRepsilon2 antibody titers and ovarian teratoma-related anti-N-methyl-D-aspartate receptor (NMDAR) antibody-positive encephalitis are briefly described. In addition,the naming of this disease as well as its pathogenesis,clinical features, prognosis, and sequels are discussed in this report. Patients in the acute stage of NHALE frequently exhibited schizophrenic-like symptoms such as abnormal behavior, incoherence, delusions, and hallucinations followed by convulsive seizures, status epilepticus, and autonomic seizures. Mild signs of meningeal irritation were also detected. Magnetic resonance imaging (MRI) in these patients often revealed bilateral abnormalities in the limbic areas, including the hippocampus and amygdala. Examination of the cerebrospinal fluid (CSF) revealed mild pleocytosis, and sometimes, a lack of the pleocytosis. The CSF level of interferon-gamma remained unchanged, whereas that of interleukin-6 was increased. The prognostic outcome of the patients was rather favorable. Further, differential diagnosis for herpes simplex encephalitis is important in order to decide the initial treatment antiviral drug therapy or immunological therapy. The most commonly described sequel of this condition is memory impairment; however,patients should be monitored for personality or emotional changes. PMID- 20714034 TI - [Neuropathological findings of non-herpetic limbic encephalitis]. AB - In Japan,acute encephalitis similar to herpes simplex encephalitis (HSE) but with no evidence of herpes simplex virus (HSV) infection has been reported. Recently,this type of acute encephalitis has been termed as non-herpetic limbic encephalitis (NHLE) and is indicated to be a possible new subgroup of limbic encephalitis. Only 3 autopsy cases of NHLE have been reported because most patients had a good clinical outcome. However,the 3 autopsy patients who were diagnosed with NHLE on the basis of their typical clinical course died of complications. The neuropathological findings in these 3 cases were similar in that the lesions were exclusively limited to the hippocampus and amygdala. The macroscopic findings in their brains were unremarkable, except for mild swelling. No leptomeningitis, hemorrhagic necrosis, or evidence of any etiologic agent was detected microscopically. The rostral portion of the hippocampus showed small foci characterized by neuronal loss with neuronophagia coexisting with proliferation of microglias, macrophages, hypertrophic astrocytes, and a few lymphocytes. The caudal portion of the hippocampus and amygdala showed neuronal loss with astrocytosis and lymphocytic perivascular cuffing. The abnormal high intensity areas seen on the magnetic resonance imaging scans corresponded well with the regions with astrocytosis. These findings are more similar to those in the case of autoimmune limbic encephalitis than those in the case of HSE. It is likely that these mild neuropathological changes in the case of NHLE are reflective of a good clinical outcome. PMID- 20714035 TI - [Human herpesvirus 6 encephalitis]. AB - Primary human herpesvirus 6 (HHV-6) infection causes exanthem subitum,a common febrile illness,in infants. At the time of primary infection with HHV-6, the virus rarely causes encephalitis. Recently, various types of clinical features of patients with HHV-6 encephalitis have been reported. Therefore, appropriate procedures for the management of these patients should be established on the basis of the clinical features of the patients. In addition to primary infection with the virus, reactivation of HHV-6 can be associated with encephalitis in the case of immunocompromised patients. Numerous copies of the viral DNA were detected in the cerebrospinal fluid collected from the patients. This finding suggests that active viral replication possibly occurred in the brain tissues of these patients. A typical clinical feature of post transplant HHV-6 encephalitis, was the development of amnesia; further, abnormal magnetic resonance imaging (MRI) findings in the hippocampal regions were observed. Thus, HHV-6 is considered to be one of the causative agents for limbic encephalitis that develops in immunocompromised patients. On the basis of the results of in vitro analysis, it has been suggested that ganciclovir and foscarnet have antiviral effects against HHV-6. Although a double-blind control study has not been performed to elucidate the effectiveness of these 2 drugs in vivo, either of the 2 antiviral drugs should be used for the treatment of patients with HHV-6 encephalitis. PMID- 20714036 TI - [Investigating the "social brain" through Williams syndrome]. AB - Recent advances in social cognitive neuroscience have led to the concept of the "social brain". The social brain includes neural processes specialized for processing social information necessary for the recognition of self and others, and interpersonal relationships. Because of its unique behavioral phenotypic features which includes 'hypersociability', Williams syndrome has gained popularity among social cognitive neuroscientists. Individuals with Williams syndrome share the same genetic risk factor for cognitive-behavioral dysfunction utilizing brain imaging to elucidate endophenotype provides us with an unprecendented opportunity to study gene, brain and behavior relationships especially those related to social cognition. In this review, we provide an overview of neuroimaging studies on social cognition in Williams syndrome and discuss the neural basis of the social brain. PMID- 20714037 TI - [Amyotrophic lateral sclerosis--electrophysiologic aspects of its pathophysiology and new therapeutic options]. AB - It is essential to perform electromyography and nerve-conduction studies for diagnosis amyotrophic lateral sclerosis (ALS), but these conventional electrophysiologic methods cannot be used for studies on the mechanism underlying ALS. The recently developed nerve-excitability test can provide new insights into the pathophysiology of this disease. Fasciculation is one of the characteristic features of ALS. Ectopic firing of motor units originates usually from the motor nerve terminals and occasionally from the motor neurons, indicating a widespread abnormality in axonal excitability. ALS is a multifactorial disease in which some genetic abnormalities and environmental factors lead to cell death through a complex cascade, which includes oxidative stress, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. It is important to elucidate the pathophysiology of axonal excitability in ALS because increased axonal excitability enhances oxidative stress and excitotoxicity, ultimately contributing to motor neuron death. To date, 2 axonal ion channel abnormalities have been identified: (1) increased persistent sodium currents and (2) reduced potassium currents; both abnormalities cause an increase in axonal excitability and are responsible for fasciculations. The results for excitability testing in such patients are characterized by the following features: (1) a prolonged strength-duration time constant, which suggests increased persistent sodium currents; (2) greater threshold changes in depolarizing threshold electrotonus; and (3) greater supernormality, which suggests impaired potassium channels. The altered axonal properties in patients with ALS may provide new insights into the pathophysiology of ALS and have implications for the development of ion channel modulators as therapeutic options for patients with ALS. PMID- 20714038 TI - [Formed visual hallucination after excision of the right temporo parietal cystic meningioma--a case report]. AB - We report the case of a 64-year-old woman with cystic meningioma; this patients was otherwise healthy and experienced formed visual hallucinations after excision of the tumor. She experienced diplopia associated with metamorphopsia, which had persisted for 5 years only when she laid down and turned on her left side. After the excision of the convexity meningioma located in the right temporoparietal lobe, she experienced several types of formed visual hallucinations such as closet-like pictures, flowers sketched on stones, falling maple-like leaves, and moving or wriggling dwarves. She was alert and her visual field was normal; further, she did not experience delirium or seizures. She experienced these hallucinations only when she closed her eyes; these hallucinations persisted for 3 days after the operation. The patient illustrated her observations with beautiful sketches, and the mechanism of visual hallucinations was studied. PMID- 20714039 TI - [Optic nerve injury without optic canal fracture revealed by MR imaging with short inversion time inversion recovery sequences--a case report]. PMID- 20714040 TI - [One hundred books which built up neurology (44)-Charles-Edouard Brown-Sequard "Course of lectures on the physiology and pathology of the central nervous system" (1860)]. PMID- 20714041 TI - A GPU-based framework for modeling real-time 3D lung tumor conformal dosimetry with subject-specific lung tumor motion. AB - In this paper, we present a graphics processing unit (GPU)-based simulation framework to calculate the delivered dose to a 3D moving lung tumor and its surrounding normal tissues, which are undergoing subject-specific lung deformations. The GPU-based simulation framework models the motion of the 3D volumetric lung tumor and its surrounding tissues, simulates the dose delivery using the dose extracted from a treatment plan using Pinnacle Treatment Planning System, Phillips, for one of the 3DCTs of the 4DCT and predicts the amount and location of radiation doses deposited inside the lung. The 4DCT lung datasets were registered with each other using a modified optical flow algorithm. The motion of the tumor and the motion of the surrounding tissues were simulated by measuring the changes in lung volume during the radiotherapy treatment using spirometry. The real-time dose delivered to the tumor for each beam is generated by summing the dose delivered to the target volume at each increase in lung volume during the beam delivery time period. The simulation results showed the real-time capability of the framework at 20 discrete tumor motion steps per breath, which is higher than the number of 4DCT steps (approximately 12) reconstructed during multiple breathing cycles. PMID- 20714042 TI - Beam characteristics and radiation output of a kilovoltage cone-beam CT. AB - This study presents beam characteristics of five recently available x-ray beams produced by an on-board imager (OBI 1.4) for acquiring kilovoltage cone-beam computed tomography (kV-CBCT) and investigates suitable methods for the beam radiation output determination resulting from an image acquisition. Both are essential for commissioning an x-ray beam in a radiotherapy treatment planning system. The BEAM/DOSXYZnrc Monte Carlo codes were used in the investigation. The simulated beam data were benchmarked against measurements. Three different commercially available plastic phantom materials are investigated as liquid water substitutes in the beam radiation output determination. Ionization chambers are used for the measurements. Five kV-CBCT beam characteristics including photon fluence, average beam energy and photon spectra are generated from Monte Carlo simulations. The Monte Carlo calculated dose profiles are validated by measurements. The fluence of kV-CBCT beams is strongly dependent on the geometry of added filters as well as X and Y beam collimations. The potential errors of determining the beam output of a kV-CBCT beam in Solid Water and PMMA phantoms may approach 8% and 20%, respectively, for use in a conventional treatment planning system, whereas using the Plastic Water low-energy range (PW-LR) phantom results in errors within 2%. The Monte Carlo simulation is essential in providing the parameters of an x-ray beam which are needed for the commissioning of a kV CBCT beam in a radiotherapy treatment planning system. The PW-LR phantom is a suitable liquid water substitute in the beam output determination resulting from a kV-CBCT acquisition. PMID- 20714043 TI - Motion management with phase-adapted 4D-optimization. AB - Cancer treatment with ionizing radiation is often compromised by organ motion, in particular for lung cases. Motion uncertainties can significantly degrade an otherwise optimized treatment plan. We present a spatiotemporal optimization method, which takes into account all phases of breathing via the corresponding 4D CTs and provides a 4D-optimal plan that can be delivered throughout all breathing phases. Monte Carlo dose calculations are employed to warrant for highest dosimetric accuracy, as pertinent to study motion effects in lung. We demonstrate the performance of this optimization method with clinical lung cancer cases and compare the outcomes to conventional gating techniques. We report significant improvements in target coverage and in healthy tissue sparing at a comparable computational expense. Furthermore, we show that the phase-adapted 4D-optimized plans are robust against irregular breathing, as opposed to gating. This technique has the potential to yield a higher delivery efficiency and a decisively shorter delivery time. PMID- 20714044 TI - The influence of lateral beam profile modifications in scanned proton and carbon ion therapy: a Monte Carlo study. AB - Scanned ion beam delivery promises superior flexibility and accuracy for highly conformal tumour therapy in comparison to the usage of passive beam shaping systems. The attainable precision demands correct overlapping of the pencil-like beams which build up the entire dose distribution in the treatment field. In particular, improper dose application due to deviations of the lateral beam profiles from the nominal planning conditions must be prevented via appropriate beam monitoring in the beamline, prior to the entrance in the patient. To assess the necessary tolerance thresholds of the beam monitoring system at the Heidelberg Ion Beam Therapy Center, Germany, this study has investigated several worst-case scenarios for a sensitive treatment plan, namely scanned proton and carbon ion delivery to a small target volume at a shallow depth. Deviations from the nominal lateral beam profiles were simulated, which may occur because of misaligned elements or changes of the beam optic in the beamline. Data have been analysed with respect to the lateral penumbra, homogeneity and coverage of the dose deposition in the target volume. The results indicate that homogeneity is not seriously compromised by extremely narrow profiles for the standard planning choices of the lateral raster scan stepping and dose grid. Differently, broad beam distributions can significantly deteriorate the conformality of the dose delivery and too large increases (above approximately 150-200% of the nominal spotsize) must be prevented. PMID- 20714045 TI - A Monte Carlo tool to simulate breast cancer screening programmes. AB - A Monte Carlo tool which permits the simulation of screening mammography programmes is developed. Various statistical distributions describing different parameters involved in the problem are used: the characteristics of the population under study, a tumour growth model and a model for tumour detection based on parameters such as sensitivity and specificity which depends on the woman's age. We reproduce results of different actual programmes. The model enables us to find out the configuration (the age of the women who attend the screening trials and screening frequency) which produces maximum benefits with minimum risks. In addition, the model has permitted us to validate some of the assumed hypothesis, such as the probability distribution of the tumour detection as a function of the tumour size, the frequency of the histological types and the transition probability between different histological types. PMID- 20714046 TI - Evaluation of image reconstruction for mouse brain imaging with synthetic collimation from highly multiplexed SiliSPECT projections. AB - We have performed a theoretical study to explore the potential and limitations of synthetic collimation for SPECT imaging with stacked-detector acquisition (dual magnification). This study will be used to optimize SiliSPECT, a small-animal SPECT for imaging small volumes such as a mouse brain at high sensitivity and resolution. The synthetic collimation enables image reconstruction with a limited number of camera views and in the presence of significant multiplexing. We also developed a new formulation to quantify the multiplexed object sensitivity and investigated how this changes for different acquisition parameters such as number of pinholes and combinations of front and back detector distances for imaging objects as small as the mouse brain. In our theoretical studies, we were not only able to demonstrate better reconstruction results by incorporating two detector magnifications in comparison to either one alone, but also observed an improved image reconstruction by optimizing the detector-collimator distances to change the multiplexing ratio between the front and back detectors. PMID- 20714047 TI - The feasibility of using microwave-induced thermoacoustic tomography for detection and evaluation of renal calculi. AB - Imaging of renal calculi is important for patients who suffered a urinary calculus prior to treatment. The available imaging techniques include plain x ray, ultrasound scan, intravenous urogram, computed tomography, etc. However, the visualization of a uric acid calculus (radiolucent calculi) is difficult and often impossible by the above imaging methods. In this paper, a new detection method based on microwave-induced thermoacoustic tomography was developed to detect the renal calculi. Thermoacoustic images of calcium oxalate and uric acid calculus were compared with their x-ray images. The microwave absorption differences among the calcium oxalate calculus, uric acid calculus and normal kidney tissue could be evaluated by the amplitude of the thermoacoustic signals. The calculi hidden in the swine kidney were clearly imaged with excellent contrast and resolution in the three orthogonal thermoacoustic images. The results indicate that thermoacoustic imaging may be developed as a complementary method for detecting renal calculi, and its low cost and effective feature shows high potential for clinical applications. PMID- 20714048 TI - Interphantom and interscanner variations for Hounsfield units--establishment of reference values for HU in a commercial QA phantom. AB - In computer tomography (CT) diagnostics, the measured Hounsfield units (HU) are used to characterize tissue and are in that respect compared to nominal HU values found in the radiological literature. Quality assurance (QA) phantoms are commercially available with a variety of tissue substitutes and materials to test the HU values in CT. It is however recognized from CT physics that the HU for a given material is energy dependent and may vary substantially between scanners. The aim of this study is to analyze the characteristics of a commonly used QA phantom, the Catphan 500/600 (The Phantom Laboratory, NY). Four CT phantoms were scanned on one CT scanner to examine possible interphantom variations in HU values. Secondly, one selected phantom was scanned at three kVp levels on eight different CT scanners. The interphantom variations in HU values were small, in the range 2-5 HU. The interscanner variations were however substantial, in the range 7-56 HU depending on energy and material. Varying the x-ray energy produced a shift in the measured HU of up to 79 HU on one scanner. Reference HU values for the eight sensitometric test materials in Catphan are provided for eight CT scanner models from four vendors. The reference HU values are provided for 80, 120 and 140 kVp. Our results suggest that scanner-independent threshold levels for HU should be used only with extreme caution. Tissue characterization can be used provided that a scanner-specific data set for normal and abnormal is determined. PMID- 20714050 TI - Nanopore formation by low-energy focused electron beam machining. AB - The fabrication of nanopores in thin silicon nitride and aluminum oxide membranes by water vapor assisted, low-energy (0.2-20 kV) electron beam machining using a scanning electron microscope (SEM) is described. Using this technique, pores with diameters ranging in size from < 5 to 20 nm are easily formed. The nanopores are characterized by SEM, transmission electron microscopy (TEM) and atomic force microscopy (AFM). The mechanism of etching is briefly discussed. PMID- 20714049 TI - An efficient analysis of nanomaterial cytotoxicity based on bioimpedance. AB - In the emerging nanotechnology field, there is an urgent need for the development of a significant and sensitive method that can be used to analyse and compare the cytotoxicities of nanomaterials such as carbon nanotubes (CNTs) and gold nanoparticles (AuNPs), since such materials can be applied as contrast agents or drug delivery carriers. The bioimpedance system possesses great potential in many medical research fields including nanotechnology. Electric cell-substrate impedance sensing (ECIS) is a particular bioimpedance system that offers a real time, non-invasive, and quantitative measurement method for the cytotoxicity of various materials. The present work compared the cytotoxicity of AuNPs to that of purchased single-walled carbon nanotubes (SWCNTs). The size-controlled and monodispersed AuNPs were synthesized under autoclaved conditions and reduced by ascorbic acid (AA) whereas the purchased SWCNTs were used without any surface modifications. Bioimpedance results were validated by conventional WST-1 and trypan blue assays, and transmission electron microscopy (TEM) and field emission scanning electron microscopy (FE-SEM) were performed to examine nanomaterials inside the VERO cells. This research evaluates the ability of the ECIS system compared to those of conventional methods in analyzing the cytotoxicity of AuNPs and SWCNTs with higher sensitivity under real-time conditions. PMID- 20714051 TI - Self-assembled ZnS nanowire arrays: synthesis, in situ Cu doping and field emission. AB - Well-aligned single-crystalline ZnS nanowire arrays have been grown on highly conductive Cu substrates through controlling the morphology evolution of self patterned ZnS nanoparticles. The ZnS nanowires have sharp tips with an average size of approximately 30 nm and a length of approximately 3 microm. Field emission measurements demonstrated that the aligned ZnS nanowires grown on Cu substrates are excellent field emitters having a turn-on field as low as 2.92 V microm(-1) and a field-enhancement factor as high as 3400. The use of highly conductive metal substrate may promote the commercial applications of ZnS-based emitters in flat panel displays and other optoelectronic devices. PMID- 20714052 TI - Facile synthesis of hollow nano-spheres and hemispheres of cobalt by polyol reduction. AB - The hydrophilic hollow nano-spheres and hemispheres of Co are synthesized via ethylene glycol reduction of cobalt acetate in the presence of PVP and Pd nano particle seeds. The dimensions of the hollow core can be tuned from 100 to 300 nm by controlling the amount of Pd nano-particle seeds. The morphology of the hollow materials strongly depends on the molar ratio of the amide unit in PVP over Co and the M(w) of PVP. The hollow structure is formed when the ratio falls in the range 1-1.5 and the M(w) is over 40,000. Based on the experimental data, a possible formation mechanism of Co hollow spheres is proposed. PMID- 20714053 TI - Comment on 'Fabrication of uniform core-shell structural calcium and titanium precipitation particles and enhanced electrorheological activities'. AB - This comment is an analysis of the static yield stress of core-shell structured SiO(2)-calcium-titanium precipitation (CTP) particle-based electrorheological (ER) suspensions under various applied electric field strengths. We find that our previously published universal yield stress equation covers both polarization and conduction regions while the polar-molecule-based linearity mechanism becomes dominant for the giant ER fluid beyond the second critical electric field strength. PMID- 20714054 TI - Sulfur-doped gallium phosphide nanowires and their optoelectronic properties. AB - Sulfur-doped gallium phosphide nanowires were synthesized in a high yield by a facile sublimation of ball-milled mixture powders in a confined reaction zone. The nanowires have diameters in the range of 50-200 nm and lengths up to tens of micrometers. They consist of single-crystalline zinc blende structure crystals with a (111) growth direction. Electron energy-loss spectroscopy reveals that the sulfur doping occurs in the uniform forms of the body. Amorphous Ga-O containing a self-catalyst growth mechanism is proposed based on the detailed characterizations. Photoluminescence shows strong visible emissions at room temperature, indicating their potential applications in light sources, laser or light emitting display devices. PMID- 20714055 TI - Fibrous CdS/CdSe quantum dot co-sensitized solar cells based on ordered TiO2 nanotube arrays. AB - A new kind of fibrous quantum dot sensitized solar cell has been designed and fabricated by using CdS and CdSe co-sensitized TiO(2) nanotubes on Ti wire as the photoanode and highly active Cu(2)S as the counter electrode. By optimizing the CdSe deposition time and the length of the nanotube, a power conversion efficiency of 3.18% has been obtained under AM 1.5 illumination (100 mW cm(-2)). The potential application of this kind of solar cell has also been discussed in this paper. PMID- 20714056 TI - Trends in cerebellar research. PMID- 20714058 TI - A preliminary characterisation of cognition and social cognition in spinocerebellar ataxia types 2, 1, and 7. AB - Over the last decade, studies have implicated the cerebellum not only in motor functioning, but also in cognition and social cognition. Although some aspects of cognition have been explored in the five most common forms of Spinocerebellar Ataxia (SCA), social cognition in these patients has rarely been examined. The present study provides a preliminary characterisation of the severity of cognitive and social cognitive impairments in patients with SCA2, SCA1 and SCA7 using an identical battery to the one previously used in SCA3 and SCA6 patients for comparison. The cognitive profiles of SCA1 and SCA7 patients were comparable to that of SCA6 patients; SCA1 patients had relatively intact profiles, while SCA7 patients demonstrated only some selective deficits. In contrast, SCA2 patients showed the greatest impairments, similarly to SCA3 patients. On tests of social cognition, SCA2 and SCA7 patients were impaired on a task of emotion attribution, whereas one SCA1 patient had a Theory of Mind deficit, which has also been documented in SCA3 and SCA6. We provide preliminary evidence that the neuropsychological profiles of SCA patients correspond well with the severity of pathological and clinical features. Moreover, these patients may also have social cognition impairments. Overall, we suggest that there is a degree of heterogeneity in the types of cognitive and social cognitive impairments in SCA patients. PMID- 20714057 TI - The contribution of the cerebellum to cognition in Spinocerebellar Ataxia Type 6. AB - This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (Wechsler Adult Intelligence Scale-III, Wechsler Memory Scale-III, Delis and Kaplan Executive Function System, Brixton Spatial Anticipation test). The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance. PMID- 20714059 TI - Lateralized cerebellar contributions to word generation: a phonemic and semantic fluency study. AB - Impairment on verbal fluency tasks has been one of the more consistently reported neuropsychological findings after cerebellar lesions, but it has not been uniformly observed and the possible underlying cognitive basis has not been investigated. We tested twenty-two patients with chronic, unilateral cerebellar lesions (12 Left, 10 Right) and thirty controls on phonemic and semantic fluency tasks. We measured total words produced, words produced in the initial 15 seconds, errors and strategy switches. In the phonemic fluency task, the right cerebellar lesion (RC) group produced significantly fewer words compared to the left cerebellar lesion (LC) group and healthy controls, particularly over the first 15 seconds of the task with no increase in errors and significantly fewer switches over the entire task. In the semantic fluency task there was only a modest decrease in total words in the RC group compared to controls. RC lesions impair fluency with many of the same performance characteristics as left prefrontal lesions. This supports the hypotheses of a prefrontal-lateral cerebellar system for modulation of attention/executive or strategy demanding tasks. PMID- 20714060 TI - Cerebellar information processing in relapsing-remitting multiple sclerosis (RRMS). AB - Recent research has characterized the anatomical connectivity of the cortico cerebellar system - a large and important fibre system in the primate brain. Within this system, there are reciprocal projections between the prefrontal cortex and Crus II of the cerebellar cortex, which both play important roles in the acquisition and execution of cognitive skills. Here, we propose that this system also plays a particular role in sustaining skilled cognitive performance in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), in whom advancing neuropathology causes increasingly inefficient information processing. We scanned RRMS patients and closely matched healthy subjects while they performed the Paced Auditory Serial Addition Test (PASAT), a demanding test of information processing speed, and a control task. This enabled us to localize differences between conditions that change as a function of group (group-by-condition interactions). Hemodynamic activity in some patient populations with CNS pathology are not well understood and may be atypical, so we avoided analysis strategies that rely exclusively on models of hemodynamic activity derived from the healthy brain, using instead an approach that combined a 'model-free' analysis technique (Tensor Independent Component Analysis, TICA) that was relatively free of such assumptions, with a post-hoc 'model-based' approach (General Linear Model, GLM). Our results showed group-by-condition interactions in cerebellar cortical Crus II. We suggest that this area may have in role maintaining performance in working memory tasks by compensating for inefficient data transfer associated with white matter lesions in MS. PMID- 20714061 TI - Modality specific cerebro-cerebellar activations in verbal working memory: an fMRI study. AB - Verbal working memory (VWM) engages frontal and temporal/parietal circuits subserving the phonological loop, as well as, superior and inferior cerebellar regions which have projections from these neocortical areas. Different cerebro cerebellar circuits may be engaged for integrating aurally- and visually presented information for VWM. The present fMRI study investigated load (2, 4, or 6 letters) and modality (auditory and visual) dependent cerebro-cerebellar VWM activation using a Sternberg task. FMRI revealed modality-independent activations in left frontal (BA 6/9/44), insular, cingulate (BA 32), and bilateral inferior parietal/supramarginal (BA 40) regions, as well as in bilateral superior (HVI) and right inferior (HVIII) cerebellar regions. Visual presentation evoked prominent activations in right superior (HVI/CrusI) cerebellum, bilateral occipital (BA19) and left parietal (BA7/40) cortex while auditory presentation showed robust activations predominantly in bilateral temporal regions (BA21/22). In the cerebellum, we noted a visual to auditory emphasis of function progressing from superior to inferior and from lateral to medial regions. These results extend our previous findings of fMRI activation in cerebro-cerebellar networks during VWM, and demonstrate both modality dependent commonalities and differences in activations with increasing memory load. PMID- 20714063 TI - How consistent are cognitive impairments in patients with cerebellar disorders? AB - Many human lesion und functional brain imaging studies suggest involvement of the cerebellum in cognitive functions. However, negative and inconsistent findings are rarely discussed. It is still an open question as to which areas of cognition the cerebellum contributes, as well as how, and to what extent. Frequently cited earlier findings in one area of cognition have been challenged in more recent studies, that is the cerebellum may not be directly involved in attention. Furthermore, disorders in patients with acquired cerebellar disease are frequently mild and less severe compared to lesions of the corresponding areas of the cerebral cortex. Patients with cerebellar disease often perform within the normal range of neuropsychological test norms. This pattern is illustrated based on general intelligence and verbal working memory, which have been assessed by a large number of authors using comparable tests. Findings, however, appear to be more pronounced in individual cases with acute onset cerebellar disorders and in children, in particular with congenital disease. The review suggests that the inconsistencies in cognitive impairments may offer clues as to the nature of cerebellar cognitive involvement. PMID- 20714064 TI - Brain stimulation and brain repair--rTMS: from animal experiment to clinical trials--what do we know? AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of stimulating the brain that changes excitability at the site of stimulation as well as at distant anatomically connected sites. Since the effects can outlast the period of stimulation for minutes or hours and are thought to be depend, at least in part, on changes in the efficiency of synaptic connections in the cortex, the method has generated much interest as a potential therapeutic intervention in a wide range of neurological and psychiatric conditions. A symposium on brain stimulation and brain recovery was held in Greifswald (Germany) in 2010 to exchange of state-of-the-art knowledge about rTMS effects from animal experiments to clinical trials in conditions such as stroke, Parkinson disease, and depression. There was enormous interest in the effects of rTMS and signs of therapeutic success in mainly small clinical trials. However, it was also clear that some of our models of the effects of rTMS, such as upregulation or downregulation of specific brain areas may need further development if they are to account for all the observations that have been made so far. The results of the symposium are made available by lab reviews of members of the symposium's faculty. This editorial provides an overview. PMID- 20714062 TI - An fMRI study of intra-individual functional topography in the human cerebellum. AB - Neuroimaging studies report cerebellar activation during both motor and non-motor paradigms, and suggest a functional topography within the cerebellum. Sensorimotor tasks activate the anterior lobe, parts of lobule VI, and lobule VIII, whereas higher-level tasks activate lobules VI and VII in the posterior lobe. To determine whether these activation patterns are evident at a single subject level, we conducted functional magnetic resonance imaging (fMRI) during five tasks investigating sensorimotor (finger tapping), language (verb generation), spatial (mental rotation), working memory (N-back), and emotional processing (viewing images from the International Affective Picture System). Finger tapping activated the ipsilateral anterior lobe (lobules IV-V) as well as lobules VI and VIII. Activation during verb generation was found in right lobules VII and VIIIA. Mental rotation activated left-lateralized clusters in lobules VII VIIIA, VI-Crus I, and midline VIIAt. The N-back task showed bilateral activation in right lobules VI-Crus I and left lobules VIIB-VIIIA. Cerebellar activation was evident bilaterally in lobule VI while viewing arousing vs. neutral images. This fMRI study provides the first proof of principle demonstration that there is topographic organization of motor execution vs. cognitive/emotional domains within the cerebellum of a single individual, likely reflecting the anatomical specificity of cerebro-cerebellar circuits underlying different task domains. Inter-subject variability of motor and non-motor topography remains to be determined. PMID- 20714065 TI - Cortical cellular actions of transcranial magnetic stimulation. AB - Transcranial magnetic stimulation (TMS) can be used in two different ways to manipulate cortical information processing, either by applying a single pulse around the time point of expected task processing or by persistently shifting cortical excitability by repetitive stimulation (rTMS). Single pulses applied when specific cortical processing takes place always impair cortical function due to increased noise or enhanced inhibition, both resulting in decreased signal-to noise ratio, while repetitive stimulation may allow to weaken or improve cortical processing depending on the type of stimulation. The opposite effects of low- ( approximately 1 Hz) and high-frequency rTMS (5-20 Hz), as well as the opposing effects of continuous versus intermittent theta-burst trains, lowering or raising cortical excitability respectively, have mainly been attributed to synaptic plasticity. As reviewed in this article, in a series of electrophysiological, immunohistochemical and molecular-biological animal experiments we obtained evidence for modulation of inhibitory cortical activity as a further reason of changing cortical excitability following rTMS. PMID- 20714066 TI - Quadripulse stimulation--a new patterned rTMS. AB - A new patterned repetitive transcranial magnetic stimulation (rTMS) protocol, quadripulse stimulation (QPS), can produce a broad range of motor cortical plasticity ranging from MEP suppression to MEP facilitation depending on the interval of the pulses within a burst. In addition to inducing lasting cortical plastic changes, QPS can also be used to evaluate priming effects: when used as a priming stimulation, which does not induce an LTP- or LTD-like phenomena itself, it can nevertheless change the threshold for LTP- or LTD-like plasticity caused by a consecutive stimulation. This enables us to examine metaplasticity theory in more details in humans. Another application of QPS might be to induce symptomatic relief in patients with neurological or psychiatric disorders, such as Parkinson's disease, depression, or intractable pain. PMID- 20714067 TI - Imaging the effects of rTMS-induced cortical plasticity. AB - Repetitive Transcranial Magnetic Stimulation (rTMS) paradigms are showing increasing promise as tools for neurorehabilitation in a variety of chronic neurological and psychiatric conditions. However, the mechanisms by which they modulate cortical activation are still not completely understood. In this review we summarize what non-invasive magnetic resonance imaging techniques can tell us about the cortical effects of rTMS - from changes at a cellular level within the stimulated motor cortex, to modulating activation patterns within the wider motor network. We discuss how variation in these effects in stroke patients may inform our understanding of how rTMS could improve function in these patients. PMID- 20714068 TI - Effect of slow repetitive TMS of the motor cortex on ipsilateral sequential simple finger movements and motor skill learning. AB - BACKGROUND: Disruption of a cortical region can paradoxically improve behavior. After unilateral damage to the primary motor cortex (M1), increased excitability of the unaffected M1 has been shown. The M1 plays a critical role in motor performance and also early aspects of motor skill learning. Repetitive transcranial magnetic stimulation (rTMS) of one motor cortex can lead a temporary reduction in cortical excitability. We hypothesize that unilateral suppression of one M1 by rTMS may increase excitability of the unaffected motor cortex and thus improve motor performance and motor skill learning with the ipsilateral hand by releasing the contralateral motor cortex from transcallosal inhibition. METHODS: Forty healthy volunteers participated in our study; 16 for the experiment I and 24 for the experiment II. In the experiment I, after practicing a sequential simple key-pressing task with the index finger, their motor performance was monitored before and after slow-frequency (1Hz) rTMS, applied on the M1 ipsilateral or contralateral to the hand, ipsilateral premotor area or vertex (Cz). In the experiment II, participants were randomly divided into three stimulation groups: i) ipsilateral M1; ii) contralateral M1; and iii) Cz. rTMS was applied before the initiation of practice and learning of a simple motor skill. Mean execution time and error rate were recorded in 4 sessions distributed over 2 days. RESULTS: In experiment I: rTMS of M1 shortened execution time of the motor task with the ipsilateral hand, without affecting performance with the contralateral hand. This effect outlasted rTMS by at least 10 min, and was most prominent for M1 stimulation. In experiment II, disruption of M1 with rTMS slowed down skill acquisition with the contralateral hand, but paradoxically accelerated learning with the ipsilateral hand. This effect was evident during the first of 2 days of practice in the group with rTMS over the ipsilateral M1 compared to the other two groups (Cz and contralateral M1). CONCLUSIONS: Our results support the notion of an interhemispheric competition, and demonstrate the utility of rTMS to explore the functional facilitation of the un-stimulated counterpart M1 with effects on motor execution and learning, which may have implications for neurorehabilitation. PMID- 20714069 TI - The modulation of cortical motor circuits and spinal reflexes using theta burst stimulation in healthy and dystonic subjects. AB - Repetitive electrical stimulation has been applied to induce long-term changes in synaptic strength in animal preparations. It is generally believed that such changes in synapses form the basis of neural plasticity. Recently, several techniques, including repetitive transcranial magnetic stimulation (rTMS), have been developed to attempt to replicate similar plasticity effects in the brains of conscious humans. However, traditional paradigms of rTMS usually require lengthy stimulation and relatively high stimulus intensity. In light of these problems, a novel rTMS paradigm- theta burst stimulation (TBS) - was developed. TBS is able to produce plasticity-like effects more efficiently and powerfully than traditional protocols. The excitability of circuits within the motor cortex can be modified not only by TBS over the primary motor cortex but also when it is delivered to the premotor area. Moreover, TBS over the premotor cortex modifies aspects of spinal reflexes. Studies using TBS over the motor and premotor cortices provide further understanding of dystonia, and the results also distinguish the different mechanisms of the effects of TBS given to the primary motor and premotor cortices. In addition, some data also support the hypothesis that TBS is a potential candidate technique to help restore damaged motor functions through brain stimulation. PMID- 20714070 TI - The response to repetitive stimulation of human motor cortex is influenced by the history of synaptic activity. AB - Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), can modify cortical excitability in a lasting fashion. The modification can be bi-directional in nature and holds considerable therapeutic promise for a number of neurological conditions. However, the effectiveness of these techniques is currently limited by large intra- and inter subject variability in the response. A number of factors that contribute to response variability have now been identified, with one of the most important being the history of synaptic activity within the cortical region being targeted by stimulation. In this review we discuss what is currently known about the influence of behaviourally, or experimentally, induced changes in synaptic activity in the cortical (or interconnected) region being targeted by stimulation on the response to rTMS techniques. Understanding such influences is a critical step in the development of effective therapeutic paradigms employing such techniques. PMID- 20714071 TI - Functional lesions of the motor system with TMS--a challenge for individual functional mapping. AB - Applying functional lesions using functional magnetic resonance imaging (fMRI) navigated transcranial magnetic stimulation (TMS) is a powerful method for investigation of the functional relevance of a given activation site for motor performance in healthy individuals, and also for investigation of the temporal interactions of particular areas during movement preparation. In patients with good cognitive compliance, this procedure may be useful for detection of functional reorganisation or to plan individual therapy directions. Different protocols for applying functional lesions are presented here and their relevance and usage in different applications are explained. PMID- 20714072 TI - Effects of transcranial theta-burst stimulation on acute pain perception. AB - Transcranial stimulation of the primary motor cortex (M1) for the treatment of pain has attracted much interest in recent years. Non-invasive low frequency and high frequency repetitive transcranial magnetic stimulation (rTMS) over the M1 was reported to reduce both experimentally induced acute and chronic pain. In this paper we summarize the results of several studies from our laboratory and report the antinociceptive effects of a special rTMS paradigm, theta-burst stimulation (TBS). We have applied excitatory (iTBS) and inhibitory (cTBS) paradigms over two cortical locations (M1 and the primary somatosensory cortex (S1)). As evaluation criteria a pain rating scale and the recording of laser evoked potentials (LEPs) were used. Reduced subjective pain perception after cTBS could be objectified by alterations of LEPs that reflect pain related activations in the pain processing in the operculo-insular and anterior cingulate cortex. The stimulation of S1 had physiological effects (LEPs), but did not induce significant reduction in acute pain perception. We believe that the application of cTBS over M1 in pain research has a great potential and as a method it can contribute to a more efficient manipulation of the brain plasticity for therapeutic purposes, for example in chronic pain. Nevertheless, the effectiveness of other types of TBS paradigms should also be tested. PMID- 20714073 TI - Using non-invasive brain interference as a tool for mimicking spatial neglect in healthy volunteers. AB - Visuospatial processing refers to the spatial perception, recognition and analysis of visual input. Human functional brain imaging studies have consistently revealed the involvement of fronto-parietal brain areas during the execution of visuospatial tasks. Just as the execution of these tasks activates fronto-parietal regions in the healthy brain, lesions to those structures, e.g. after stroke or brain injury, cause specific spatial deficits. The most prominent of these is known as spatial neglect. There are several competing theories on the neural mechanisms underlying spatial neglect. Although each of these theories postulates different underlying physiological mechanisms, they all account in their own way for the fact that the prevalence of neglect is much higher following right hemisphere lesions. This makes it difficult to distinguish between the different models at a behavioural level. Until today, it was impossible to empirically address these matters and to provide direct and conclusive empirical evidence in favour of one of the competing theories of spatial neglect. This review article describes the neural correlates of intact visuospatial processing as revealed by non-invasive functional brain imaging studies. It subsequently focuses on the approach of using the non-invasive brain inference technique of transcranial magnetic brain stimulation (TMS) to transiently and reversibly disrupt neural activity in these visuospatial processing-related brain regions. Using this approach, we can now imitate specific spatial deficits and neglect-like symptoms in healthy volunteers. Mimicking and manipulating the spatial deficits following unilateral brain lesions, under controlled experimental conditions, may allow for the development of new therapeutic interventions for parietal stroke patients suffering from real spatial neglect. The perspective is to use non-invasive brain interference to guide and promote functional recovery on a brain-system level in stroke and neglect patients, based on knowledge directly derived from fundamental brain research in healthy volunteers. PMID- 20714074 TI - Treatment of hemispatial neglect by means of rTMS--a review. AB - Hemispatial neglect - defined as the failure to attend, explore, and act upon the contralesional side of space - is a frequent and disabling neurological syndrome. Interhemispheric rivalry is considered as a major pathophysiological mechanism underlying hemispatial neglect. According to this account, the contralesional, intact hemisphere undergoes a pathological hyperactivity due to a deficient transcallosal inhibition from the damaged hemisphere. This model offers a framework for possible therapeutic interventions with repetitive transcranial magnetic stimulation (rTMS), i.e. a reduction of the pathological hyperactivity with a rTMS protocol that has lasting inhibitory effects. In the present work, we will first review evidence for the interhemispheric rivalry account coming from animals and humans. We will then describe studies showing the possibility to perturb and to restore interhemispheric balance in healthy subjects as a proof of concept for therapeutic rTMS application. Finally, we will consider studies applying rTMS as a therapeutic approach in hemispatial neglect. We conclude that rTMS is a promising approach to reduce the interhemispheric imbalance in neglect patients and to ameliorate symptoms. Newly developed protocols such as Theta Burst Stimulation (TBS) - with short stimulation times and long offline effects - seem to be particularly convenient. However, future studies should assess stimulation effects not only in clinical testing, but also on disability, considering combination with traditional therapies as well. PMID- 20714076 TI - Noninvasive brain stimulation and motor recovery after stroke. AB - PURPOSE: Upper limb function is the best predictor of long-term disability after stroke. Despite extensive rehabilitation, recovery of upper limb motor function is frequently incomplete after stroke. METHODS: We review the pertinent literature on functional reorganization within the cerebral motor network after stroke and noninvasive techniques to modulate brain function towards beneficial plasticity. RESULTS: Direct current stimulation and repetitive transcranial magnetic stimulation are powerful tools to (i) modulate cortical excitability, (ii) induce remote changes within the cortical motor system and (iii) thereby improve upper limb motor function after stroke. Today no relevant side effects have been reported. CONCLUSIONS: Neuromodulation, by means of noninvasive brain stimulation techniques, has been shown to be a safe, feasible and effective method to promote recovery of motor function after stroke. However, several methodological and theoretical issues remain to be addressed in future work. PMID- 20714075 TI - Research with rTMS in the treatment of aphasia. AB - This review of our research with rTMS to treat aphasia contains four parts: Part 1 reviews functional brain imaging studies related to recovery of language in aphasia with emphasis on nonfluent aphasia. Part 2 presents the rationale for using rTMS to treat nonfluent aphasia patients (based on results from functional imaging studies). Part 2 also reviews our current rTMS treatment protocol used with nonfluent aphasia patients, and our functional imaging results from overt naming fMRI scans, obtained pre- and post- a series of rTMS treatments. Part 3 presents results from a pilot study where rTMS treatments were followed immediately by constraint-induced language therapy (CILT). Part 4 reviews our diffusion tensor imaging (DTI) study that examined white matter connections between the horizontal, midportion of the arcuate fasciculus (hAF) to different parts within Broca's area (pars triangularis, PTr; pars opercularis, POp), and the ventral premotor cortex (vPMC) in the RH and in the LH. Part 4 also addresses some of the possible mechanisms involved with improved naming and speech, following rTMS with nonfluent aphasia patients. PMID- 20714077 TI - Short- and long-term effect of rTMS on motor function recovery after ischemic stroke. AB - This review discusses the clinical results that were obtained by applying rTMS in acute and chronic ischemic stroke patients. These studies included only the recovery of motor disability and dysphagia. In summary, two approaches have been used when employing rTMS as a potential therapy for the treatment of stroke. The most direct approach involves applying rTMS directly over the affected hemisphere in an attempt to increase excitability and plasticity of damaged circuits to improve motor function. The second approach has taken advantage of the concept of interhemispheric balance in which damage to the stroke hemisphere is exacerbated by increased inhibition from the intact non-stroke hemisphere. In this case, inhibitory rTMS is applied to the non-stroke hemisphere with the intention of reducing interhemispheric inhibition and restoring the balance of excitation between the motor cortices.The overall procedure remains to be optimized, in particular regarding the number of rTMS sessions, frequency and intensity of stimulation and the exact timing of rTMS application after stroke. Cortical stimulation is an effective method for improving functional recovery of acute and chronic stroke. PMID- 20714078 TI - rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for effective cortical targets. AB - Long-term therapy with levodopa and dopamine agonists in Parkinson's disease (PD) patients is complicated by the development of fluctuations in motor response, such as levo-dopa induced dyskinesia (LID). Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently put forward as a possible therapeutic tool able to LID in PD. Trains of 1 Hz rTMS applied either over the supplementary motor area (SMA) or the primary motor cortex (M1) were able to induce a transient reduction in the severity of LID, confirming that an over-activity of these areas plays a crucial role in the pathophysiology of LID. However, repeated sessions of rTMS were not effective in inducing persistent beneficial clinical effects. Functional or metabolic changes have been reported in the cerebellum in studies in PD patients treated with procedures known to alleviate LID, such as deep brain stimulation. Therefore, the effects of rTMS applied over the lateral cerebellum has been recently tested in patients with LID. A two-week course of bilateral cerebellar rTMS induced persistent clinical beneficial effects, reducing peak dose LID for up to four weeks after the end of the daily stimulation period. These findings demonstrate that rTMS is a potential tool in individuating the best cortical targets and the optimal parameters of stimulation able to improve LID in dyskinetic PD patients. PMID- 20714079 TI - Transcranial magnetic stimulation in depression--lessons from the multicentre trials. AB - Looking at novelties and advances in medicine in particular in the treatment of major depressive disorder no principally new antidepressant treatment strategy has been established in clinical routine in the last fifty years. However, regarding the considerable issue of treatment resistance in depression, new therapeutic strategies are urgently required. In this context, repetitive transcranial magnetic stimulation above the dorsolateral prefrontal cortex has been proposed as a potential new treatment option for depression; furthermore, in October 2008 a first rTMS-device (NeuroStar TMS Therapy System) was approved by the FDA for the treatment of treatment resistant major refractory depression in adults. Yet, despite now nearly two decades of research in this field, no final answer concerning its validity for antidepressant treatment in the clinical practice is given. Numerous studies with small sample sizes and heterogeneous designs have been performed in this field yielding to different results. These were subjected to meta-analyses, assessing the antidepressant effect of rTMS, which are briefly summarized in this article. Further, multicentre-trials with larger numbers of patients were performed, which are presented and critically discussed here in more detail. This short review shall thus provide an overview of the current status of knowledge concerning rTMS in depression and it also provides some recommendations for future research in this field. PMID- 20714080 TI - Influence of repetitive transcranial magnetic stimulation on special symptoms in depressed patients. AB - Since various studies, including multi-centre studies, investigating the effect of repetitive transcranial magnetic stimulation (rTMS) in depression have shown different results, it is now important to research, which symptoms of depression are most responsive to this kind of non-invasive brain stimulation. Furthermore, an increasing interest of rTMS as a potential tool for treatment of neurological and psychiatric disorders should be recorded. Therefore, it is critical to investigate dopaminergic functional interactions in the prefrontal cortex, and in particular, the effect of dorsolateral prefrontal cortex stimulation on clinical symptoms depending on dopaminergic concentrations in various brain regions. This short review summarizes important preliminary data, which focus on the symptom oriented effects of rTMS in depression. PMID- 20714082 TI - Fast hybrid CPU- and GPU-based CT reconstruction algorithm using air skipping technique. AB - This paper presents a fast hybrid CPU- and GPU-based CT reconstruction algorithm to reduce the amount of back-projection operation using air skipping involving polygon clipping. The algorithm easily and rapidly selects air areas that have significantly higher contrast in each projection image by applying K-means clustering method on CPU, and then generates boundary tables for verifying valid region using segmented air areas. Based on these boundary tables of each projection image, clipped polygon that indicates active region when back projection operation is performed on GPU is determined on each volume slice. This polygon clipping process makes it possible to use smaller number of voxels to be back-projected, which leads to a faster GPU-based reconstruction method. This approach has been applied to a clinical data set and Shepp-Logan phantom data sets having various ratio of air region for quantitative and qualitative comparison and analysis of our and conventional GPU-based reconstruction methods. The algorithm has been proved to reduce computational time to half without losing any diagnostic information, compared to conventional GPU-based approaches. PMID- 20714083 TI - Differentiation of diffusion coefficients to distinguish malignant and benign tumor. AB - Taking advantage of Diffusion Weighted Imaging (DWI) to characterize the random movement of water molecules in biological tissue, this article intends to review the Intravoxel Incoherent Motion (IVIM) theory as a valuable method to find the differentiation between malignant and benign tumor based on the microcirculation of blood in the capillaries. IVIM is measured by means of a parameter called apparent diffusion coefficient (ADC). Through the application of IVIM to the imaging processing software, it will be possible to set up an expert system with screening, discrimination, staging and therapeutic evaluation function of tumor. PMID- 20714081 TI - Human embryonic stem cells: derivation, culture, and differentiation: a review. AB - The greatest therapeutic promise of human embryonic stem cells (hESC) is to generate specialized cells to replace damaged tissue in patients suffering from various degenerative diseases. However, the signaling mechanisms involved in lineage restriction of ESC to adopt various cellular phenotypes are still under investigation. Furthermore, for progression of hESC-based therapies towards clinical applications, appropriate culture conditions must be developed to generate genetically stable homogenous populations of cells, to hinder possible adverse effects following transplantation. Other critical challenges that must be addressed for successful cell implantation include problems related to survival and functional efficacy of the grafted cells. This review initially describes the derivation of hESC and focuses on recent advances in generation, characterization, and maintenance of these cells. We also give an overview of original and emerging differentiation strategies used to convert hESC to different cell types. Finally, we will discuss transplantation studies of hESC derived cells with respect to safety and functional recovery. PMID- 20714084 TI - Enhancement of in-plane spatial resolution in volumetric Computed Tomography with focal spot wobbling - overcoming the constraint on number of projection views per gantry rotation. AB - The spatial resolution of diagnostic Computed Tomography (CT) has increased substantially, and 3D isotropic sub-millimeter spatial resolution in both axial and helical scan modes is routinely available in the clinic. However, driven by advanced clinical applications, the pursuit for higher spatial resolution and free of aliasing artifacts in diagnostic CT has never stopped. A method to accommodate focal spot wobbling at an arbitrary number of projection views per gantry rotation in CT is presented and evaluated here. The method employs a beta correction scheme in the row-wise fan-to-parallel rebinning to transform the native cone beam geometry into the cone-parallel geometry under which existing 3D weighted cone beam filtered backprojection algorithms can be utilized for image reconstruction. The experimental evaluation shows that the row-wise fan-to parallel rebinning with the beta-correction can increase the quantitative in plane spatial resolution (Modulation Transfer Function) substantially, while the visual spatial resolution can be enhanced significantly. Consequently, the architectural designers of CT scanners are no longer constrained to choosing the number of projection views per rotation determined by gantry geometry. Instead, they can choose the number of projection views per rotation to optimize the trade offs between in-plane spatial resolution and noise characteristics. Therefore, the presented method is of practical relevance in the architectural design of state-of-the-art diagnostic CT. PMID- 20714085 TI - A new iterative reconstruction algorithm for 2D exterior fan-beam CT. AB - The exterior computed tomography (CT) problem is one kind of truncation problem. It is very ill-posed, so that accurate reconstruction of the attenuation function is hardly possible from real data. Based on projection onto convex sets (POCS) algorithm, total variation minimization (TVM) methods, and C-V model, we develop and investigate a new iterative reconstruction algorithm, which is referred to as subregion-averaged-TVM-POCS (SA-TVM-POCS). Numerical simulations are presented to illustrate the efficiency of the algorithm. The results of this paper can be easily applied to other x-ray CT reconstruction problems. PMID- 20714086 TI - Improving visibility of X-ray phase-contrast imaging with Wiener filtering. AB - To investigate the degrading effects of the physical parameters on the in-line X ray phase-contrast imaging (XPCi), a simulation tool based on the Fresnel/Kirchhoff diffraction integral was firstly developed with comprehensively considering effects of the source-to-sample (S-S) and sample-to-detector (S-D) distances, the practical characteristics of a polychromatic and finite size source, the point spread function (PSF) of the fluorescent screen and the spatial resolution of the detector on the theoretical phase-contrast pattern. By a comparison between the simulative profile and the experimental one under the commonly-used parameters, an acceptable consistency has been demonstrated in despite of the deviation between the theoretically-predicted contrast (0.188) and the original experimental one (0.12). From the simulations, it is apparently observed that the fine interference pattern has been severely degraded by the finite spatial resolution, and will inevitably be further deteriorated by the system noise in practice. Since the image quality of the X-ray phase-contrast imaging is strongly dependent on the physical parameters of the system, a model based deblurring procedure to upgrade the image visibility is preferably desired. As a simple restoration way, a Wiener filter was then introduced to offer an optimal tradeoff between the contrast preservation and the noise suppression. Finally, to minimize the deviation resulting from the finite spatial resolution, one-dimensional interpolation was performed by positioning the set square at a tiny angle to the vertical direction. The result after the Wiener-filtering-based deblurring has shown a considerably improved profile visibility: the processed experimental contrast (0.156) increased by 30% as compared to the original one (0.12) in company with the increase in the signal-to-noise ratio (SNR) by 0.9dB. With the trend of the post-filtered experimental contrast to the theoretical one, it could be motivated that higher visibility would be achieved with the introduction of more precise blurring mask and noise spectrum estimation. PMID- 20714087 TI - Taxol induces concentration-dependent apoptotic and paraptosis-like cell death in human lung adenocarcinoma (ASTC-a-1) cells. AB - Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors such as ovarian, breast, non-small-cell lung tumors, and some head and neck carcinomas. Different concentrations of taxol trigger distinct effects on cell death forms. In present study, cell counting kit (CCK-8) assay, confocal fluorescence microscopy imaging, flow cytometry (FCM) and western blotting (WB) analysis were used to analyze the characteristics of cell death induced by low (35 nM) and high (70 microM) concentration of taxol respectively in human lung adenocarcinoma (ASTC-a-1) cells. Our results showed that low concentration of taxol induced cell death dominantly in apoptotic fashion associated with nuclear fragmentation, protein synthesis, phosphatidylserine (PS) externalization, G2/M cell cycle arrest, Bax translocation into mitochondria and caspase-3 activation, whereas high concentration of this drug induced significant cytoplasm vacuolization, mitochondria swelling and paraptosis-like cell death form without protein synthesis that is necessary for paraptosis. Although the mechanism of high concentration of taxol-induced paraptosis-like cell death has not been clear, this finding might have a potential implication for cancer therapy, especially for apoptosis-resistant cancer. PMID- 20714088 TI - Clinical implementation of an empirical method for electron output factor determination. AB - The objective of this work has been to develop and implement an empirical calculation method for the determination of clinical electron output factors. Electron beams with various energies, field sizes, and source to surface distances using cutouts of varying radii were used to measure dose output at the depth of maximum dose in water. A 30 cm x 30 cm x 17.8 cm water equivalent phantom with a 0.125 cc cylindrical ion-chamber (PTW Model 31010) was used. The calculation model predicted the output factor as a product of the cone factor, radius dependent cutout factor, the effective source to surface distance factor and the area dependent aspect ratio factor. A comparative analysis of clinical cutout output factors, determined through both empirical calculation and direct measurement was performed to evaluate the clinical viability of the calculation method before its implementation in our clinic. A total of 643 output factors for 294 different cutout shapes were determined through both traditional measurement and predictive calculation. Predictive calculation differed from definitive measurement by at most 3.5% for all cases, a majority of cases falling within 1%. The method developed successfully predicts electron output factors on the basis of cutout geometry with accuracy better than 96% for all cases and better then 98% for most cases. This ability holds true for all practical SSD, electron energy, cone, and irregular shape combinations. The method has been clinically implemented and in use at our center since 2007. PMID- 20714089 TI - Quantitative evaluation of increase in surface dose by immobilization thermoplastic masks and superficial dosimetry using Gafchromic EBT film and Monte Carlo calculations. AB - PURPOSE: To investigate the increase in surface dose under immobilization thermoplastic masks by measurements and calculation in the build-up region using Gafchromic films and Monte Carlo simulation. MATERIALS AND METHODS: Surface doses were measured underneath three thermoplastic masks in open fields using 6 and 18 MV photon beams. These masks are used to immobilize patients for head and neck (H&N), pelvis and thoracic treatment. Gafchromic EBT films were placed on the top of the flat surface of a phantom partially underneath the mask and exposed in open 10 x 10 cm2 photon fields. The depth doses were calculated using BEAMnrc Monte Carlo code for water-equivalent film detectors with different layers of thickness ranging from 50 microm to 2.5 mm and compared with film measurements. RESULTS: Surface dose increased by a factor of 3 to 4 underneath the mask relative to the open areas and 6 MV beam delivers more skin dose than 18 MV. H&N mask increased surface dose by a factor of 3 using 18 MV and a factor of 4 using 6 MV. In addition, increase in surface dose depended on the type of the mask, the size of openings, and the amount of stretching performed during the mask preparation. The measured depth doses were compared with BEAMnrc Monte Carlo calculation for water-equivalent detectors using different sizes. The calculated depth dose depended significantly on the thickness of film detector and varies by more than 15% using layer thickness of 2.5 mm compared to 50 microm. Surface doses measured by Gafchromic EBT films agreed within 3% with the Monte Carlo calculations using a small detector layer of 50 microm. CONCLUSION: Thermoplastic masks used for patient immobilization can significantly increase skin doses by up to a factor of 4 more than that without the mask using 6 MV beams. The skin reactions resulting from thermoplastic masks should be monitored and corrective measures should be taken during treatment such as partially removing the mask over skin areas with complications and optimizing the skin dose in IMRT planning. Gafchromic EBT films provide accurate skin dosimetry which agrees within 3% with Monte Carlo calculations. Gafchromic EBT film makes an excellent tool for measuring depth doses in the buildup region and these data can be applied for treatment planning calculations and IMRT optimization. PMID- 20714090 TI - Synchrotron-based scattered radiation from phantom materials used in X-ray CT. AB - Synchrotron-based scattered radiation form low-contrast phantom materials prepared from polyethylene, polystyrene, nylon, and Plexiglas is used as test objects in X-ray CT was examined with 8, 10 and 12 keV X-rays. These phantom materials of medical interest will contains varying proportions of low atomic number elements. The assessment will allowed us to estimate the fluorescence to total scattered radiation. Detected the fluorescence spectra and the associated scattered radiation from calcium hydroxyapatite phantom with 8, 10 and 12 keV synchrotron X-rays. Samples with Bonefil (60% and 70% of calcium hydroxyapatite) and Bone cream (35 approximately 45% of calcium hydroxyapatite), were used. Utilized the X-ray micro-spectroscopy beamline facility, X27A, available at NSLS, BNL, USA. The primary beam with a spot size of the order of approximately 10 mum, has been used for focusing. With this spatial resolution and high flux throuput, the synchrotron-based scattered radiation from the phantom materials were measured using a liquid-nitrogen-cooled 13-element energy-dispersive high-purity germanium detector. PMID- 20714091 TI - Executive function in the workplace. PMID- 20714092 TI - The use of visual imagery to enhance sequencing of work tasks. AB - OBJECTIVES: This case study report investigated the use of visual imagery to enhance sequencing of a work task in an individual with executive functioning impairment due to Asperger's Syndrome. PARTICIPANT: This individual's job was at risk due to his inability to correctly sequence his assigned work task in a busy pizza parlor. METHODS: Visual imagery training was administered to the client at work by a therapist employed as a job coach. RESULTS: After six 15 minute daily sessions of visual imagery training, the client was able to perform the work task independently. CONCLUSIONS: The use of visual imagery may have been associated with the ability of this individual to perform more independently on this job task. PMID- 20714093 TI - A metacognitive contextual approach for facilitating return to work following acquired brain injury: three descriptive case studies. AB - OBJECTIVE: To describe the implementation of a metacognitive contextual approach for facilitating return to work for individuals with acquired brain injury (ABI). PARTICIPANTS: Participants included three individuals with ABI (one male aged 33 years with head injury, one male aged 51 years with stroke, and one female aged 43 years with head injury) who were 3-7 years post-injury and were experiencing long-term unemployment. METHODS: Individuals participated in a 16-week metacognitive contextual intervention in the community that emphasized executive strategy training and enhancement of social contextual factors in the return to work process. RESULTS: Each participant met their employment goals, achieving a paid work placement within a 3-16 week period following the intervention with durable outcomes. The participant with a less positive employment prognosis attained a faster work placement than the other participants but required more intensive on-the-job support. CONCLUSIONS: This study provides preliminary support regarding the efficacy of a metacognitive contextual approach in vocational rehabilitation following ABI. PMID- 20714094 TI - Cognitive executive functions and work: advancing from job jeopardy to success following a brain aneurysm. AB - Cognitive executive functions have significant implications for quality of life and succeeding at home, in the community and at work. This paper reviews the return to work of an internationally acclaimed professional who was medically treated for the physical effects of a brain aneurysm, but whose resulting cognitive deficits were not identified until he experienced failure at work and accompanying depression and anxiety. Review of the Occupational Therapy Work Services includes the accommodations, strategies and client-centered collaborative efforts that led to enduring success at home, the community and work. PMID- 20714095 TI - Assistive technology: a compensatory strategy for work production post mild brain injury. AB - This case study describes the changes in the quantity of work production of a 32 year-old male paralegal secondary to a mild brain injury from a racquetball racket blow to the frontal lobe area. The case illustrates how a work analysis can serve as an effective evaluation tool and how the utilization of assistive technology can circumvent executive functioning challenges and improve work production and client self-reported self-esteem. This evaluative and intervention process may be highly effective in mild-brain injury where executive functioning disorders cannot be identified through typical methods. Yet a detailed comparison of work productivity pre and post injury through work samples, interviews, and observations may be a powerful system to differentiate changes in executive functioning. PMID- 20714096 TI - Feasibility of using the EFPT to detect executive function deficits at the acute stage of stroke. AB - OBJECTIVE: The goal of this study was to test the feasibility of administering subtests of the EFPT to stroke survivors in the acute phase of stroke to detect executive function deficits. PARTICIPANTS: A population of adults with mild to moderate stroke (N=20). METHODS: This study employed a cross-sectional design using the EFPT and a neuropsychological battery immediately post-stroke. RESULTS: Overall EFPT performance significantly correlated with 3 of the 13 DKEFS scaled scores: Sorting (r = -0.511, p = 0.030), Verbal Fluency (r = -0.474, p = 0.035) and Color-Word Interference (r = -0.566, p = 0.011) and the Short Blessed Test (r = 0.548, p = 0.012). Multiple significant correlations were also found between EFPT-bill paying and cooking subtests and DKEFS subtests. CONCLUSIONS: Performance on the EFPT one-week post stroke was very similar to what was found in a prior study validating the EFPT in stroke survivors at 6-months post-onset. The results of this study provide evidence to the support conducting a follow-up study in the acute care setting using the bill paying subtest of the EFPT along with a neuropsychological battery, to augment discharge planning. PMID- 20714097 TI - Executive dysfunction, severity of traumatic brain injury, and IQ in workers with disabilities. AB - OBJECTIVE: To study whether severity of traumatic brain injury and the intelligence quotient are related to executive dysfunction. PARTICIPANTS: Sixty two adults with brain injury who were referred for a work capacity evaluation. METHODS: Retrospective review of severity of traumatic brain injury, intelligence quotient from a previously-conducted neuropsychological evaluation, determination of executive function status from the neuropsychological evaluation, and both self-report and informant-report executive dysfunction scores from the Behavior Rating Inventory of Executive Function. RESULTS: Executive dysfunction and the intelligence quotient are related to severity of traumatic brain injury, but executive dysfunction and the intelligence quotient are not related to each other. Executive dysfunction as determined by a neuropsychological evaluation was not consistent with clients' self-reports but was consistent with informant reported executive dysfunction. Five types of executive dysfunction were reported by knowledgeable informants, with significant elevations on the Shift, Plan/Organize, Task Monitor, Organization of Materials, and Working Memory BRIEF clinical scales. CONCLUSIONS: The intelligence quotient is not a useful indicator of executive dysfunction. Informant-report executive dysfunction is a reliable and potentially useful adjunct to a neuropsychological evaluation. Working memory is the most severe type of executive dysfunction and may not be adequately measured by current neuropsychological evaluation methods. PMID- 20714098 TI - Development and pilot-testing of a work readiness assessment battery. AB - OBJECTIVE: To develop a work readiness assessment battery that can be used in the course of work rehabilitation and to pilot test the battery to determine its ability to measure the effectiveness of work rehabilitation treatment. PARTICIPANTS: All participants were recruited from the patient population at the Occupational Performance Center (OPC) at The Rehabilitation Institute of St. Louis (TRISL) (n = 7). METHODS: A work readiness assessment battery was constructed using the Readiness to Return to Work theory and then pilot-tested using a repeated-measures design. RESULTS: Participants showed significant improvement on all measures including in the battery with the exception of the depression measure. CONCLUSIONS: These results demonstrate that it is feasible to construct a work readiness battery of assessments using the Readiness to Return to Work theory and that the measures included capture the effect of work rehabilitation on the constructs identified in the literature to effect work performance. Further investigation is necessary to validate this form of assessment for use in a work rehabilitation setting. PMID- 20714099 TI - Return to work after acquired brain injury: facilitators and hindrances observed in a sub-acute rehabilitation setting. AB - OBJECTIVES: There is great variability in the rate of return to work for persons who have suffered from brain injury. The aims of this study was: 1) to describe employment status of persons with stroke or traumatic brain injury, one year after the incident and 2) to investigate the impact of injury/stroke severity, length of stay, the ability to perform activities of daily living and cognitive function on return to work. PARTICIPANTS AND METHODS: Information was collected from 72 persons; 48 with a diagnosis of stroke and 24 with a traumatic brain injury. All patients had attended to a Rehabilitation Centre with inpatient and outpatient facilities. Data of the above mentioned variables was gathered retrospectively and information about employment status was retrieved from the medical records. RESULTS: After one year, 13 persons (approximately 18%), 5 with a stroke and 8 with a traumatic brain injury (one with mild brain injury, 9 with moderate and 3 persons with severe injuries) had returned to work. They had significantly shorter length of stay at the rehabilitation hospital and were younger than those that did not return to work. Somewhat better results at the neuropsychological screening were seen among those that returned to work, although with a significant difference only in the subscale assessing affect. Some persons with severe injury returned to work, while a majority of those with mild brain injury did not. CONCLUSION: Traumatic brain injury, younger age and less need of rehabilitation were associated with a higher rate of returning to work. Patients with stroke were older and seem to need more support in order to be successful in work return. It is of importance to reach primary rehabilitation goals, such as being ADL independent, as this was also favourable for work return. The impact of injury severity seemed complex and should to be further explored. Persons with mild brain injury should be followed-up with respect to work return. An important cognitive factor was ability to perceive and express affective responses, reflecting the need of social skills in today's work-life. PMID- 20714100 TI - Determining work outcomes in mild to moderate stroke survivors. AB - OBJECTIVE: To assess the work outcomes of individuals who have a mild to moderate stroke. PARTICIPANTS: Individuals who (1) experienced a mild to moderate stroke as determined by the National Institutes of Health Stroke Scale (NIHSS) scores (range 0-16); (2) were working full time prior to their stroke; and (3) were between the ages of 30-65. METHODS: Participants were contacted and provided verbal consent to complete the Occupational Outcome Questionnaire (OOQ) over the telephone at 6 months post-stroke to determine their work outcomes. RESULTS: Of the 98 participants recruited for this study, 37% (n = 36) never returned to work following stroke. Of the 63% (n = 62) who did return to work, 90% (n = 56) returned immediately to their previous jobs at their previous level. Of those returning to work, 56% (n = 35) of individuals reported performing at 75% of their ability or less. Further, the majority of all participants reported chronic symptoms from their strokes. CONCLUSIONS: The current assumption in the literature is that individuals experiencing mild to moderate strokes are returning to work even in the absence of work rehabilitation services. The assumptions of previous literature can be disputed with the results of the current study. PMID- 20714101 TI - A model to guide the rehabilitation of high-functioning employees after mild brain injury. AB - Impairment in executive functioning can occur after mild stroke, mild Traumatic Brain Injury, and neurodegenerative disease, and this can have deleterious effects on employment outcomes, occupational functioning, and general quality of life. What is not as well identified is the symbiotic relationship between executive functioning and other important psychosocial constructs inherent in successful employees ("Employee Performance Enablers"), and how various aspects of the employment environment can enable or inhibit the success of the employee with executive functioning deficits in meeting their essential job functions ("Workplace Ecology"). From an extensive review of the literature and the author's practice experience, a clinical model was developed to elucidate these two critical variables, as well as to provide guidance for organizing, planning, and implementing interventions that will address both employee enablers and workplace ecology to affect positive return to work outcomes for individuals with mild brain injury. PMID- 20714102 TI - Participation in work: the necessity of addressing executive function deficits. PMID- 20714103 TI - Reconstructing neural circuits using transplanted neural stem cells in the injured spinal cord. AB - Traumatic spinal cord injury is one of the most common causes of disability in young adults. Restoring independent ambulation in such patients is considered one of the biggest challenges in regenerative medicine because repair of spinal cord injury involves the complex processes of axonal regeneration, remyelination, and formation of new synaptic connections. In this issue of the JCI, Abematsu et al. report their attempts to rise to this challenge, showing in a mouse model of severe spinal cord injury that spinal neuronal circuits can be restored by neural stem cell transplantation, leading to impressive functional recovery in the hind limbs. PMID- 20714104 TI - Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. AB - The body's capacity to restore damaged neural networks in the injured CNS is severely limited. Although various treatment regimens can partially alleviate spinal cord injury (SCI), the mechanisms responsible for symptomatic improvement remain elusive. Here, using a mouse model of SCI, we have shown that transplantation of neural stem cells (NSCs) together with administration of valproic acid (VPA), a known antiepileptic and histone deacetylase inhibitor, dramatically enhanced the restoration of hind limb function. VPA treatment promoted the differentiation of transplanted NSCs into neurons rather than glial cells. Transsynaptic anterograde corticospinal tract tracing revealed that transplant-derived neurons reconstructed broken neuronal circuits, and electron microscopic analysis revealed that the transplant-derived neurons both received and sent synaptic connections to endogenous neurons. Ablation of the transplanted cells abolished the recovery of hind limb motor function, confirming that NSC transplantation directly contributed to restored motor function. These findings raise the possibility that epigenetic status in transplanted NSCs can be manipulated to provide effective treatment for SCI. PMID- 20714105 TI - Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. AB - Antineutrophil cytoplasmic autoantibody (ANCA) causes vascular injury that leads to small-vessel vasculitis. Patients with ANCA aberrantly express neutrophil granule-encoding genes, including 2 that encode autoantigens: proteinase 3 (PR3) and myeloperoxidase (MPO). To uncover a potential transcriptional regulatory mechanism for PR3 and MPO disrupted in patients with ANCA vasculitis, we examined the PR3 and MPO loci in neutrophils from ANCA patients and healthy control individuals for epigenetic modifications associated with gene silencing. We found that levels of the chromatin modification H3K27me3, which is associated with gene silencing, were depleted at PR3 and MPO loci in ANCA patients compared with healthy controls. Interestingly, in both patients and controls, DNA was unmethylated at a CpG island in PR3, whereas in healthy controls, DNA was methylated at a CpG island in MPO. Consistent with decreased levels of H3K27me3, JMJD3, the demethylase specific for H3K27me3, was preferentially expressed in ANCA patients versus healthy controls. In addition, we describe a mechanism for recruiting the H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) to PR3 and MPO loci mediated by RUNX3. RUNX3 message was decreased in patients compared with healthy controls, and may also be under epigenetic control. DNA methylation was increased at the RUNX3 promoter in ANCA patients. These data indicate that epigenetic modifications associated with gene silencing are perturbed at ANCA autoantigen-encoding genes, potentially contributing to inappropriate expression of PR3 and MPO in ANCA patients. PMID- 20714106 TI - New players in the sepsis-protective activated protein C pathway. AB - Recombinant activated protein C (aPC) improves the survival of patients with severe sepsis, but the precise molecular and cellular targets through which it mediates this effect remain incompletely understood. In this issue of the JCI, Kerschen et al. show that endothelial cell protein C receptor (EPCR) is specifically expressed by mouse CD8+ dendritic cells and that these coordinators of host responses to systemic infection are required for aPC to provide protection against the lethality of sepsis. An additional study, by Cao and colleagues, recently published in the JCI, implicates the leukocyte integrin CD11b in the pathways by which aPC mediates antiinflammatory effects in the context of lethal sepsis in mice, suggesting a common thread of synergistic control of innate immune responses by life-saving aPC therapy. PMID- 20714107 TI - Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis. AB - Allergic bronchopulmonary aspergillosis (ABPA) is caused by a dominant Th2 immune response to antigens derived from the opportunistic mold Aspergillus, most commonly Aspergillus fumigatus. It occurs in 4%-15% of patients with cystic fibrosis (CF); however, not all patients with CF infected with A. fumigatus develop ABPA. Therefore, we compared cohorts of A. fumigatus-colonized CF patients with and without ABPA to identify factors mediating tolerance versus sensitization. We found that the costimulatory molecule OX40 ligand (OX40L) was critical in driving Th2 responses to A. fumigatus in peripheral CD4+ T cells isolated from patients with ABPA. In contrast, CD4+ T cells from the non-ABPA cohort did not mount enhanced Th2 responses in vitro and contained a higher frequency of TGF-beta-expressing regulatory T cells. Heightened Th2 reactivity in the ABPA cohort correlated with lower mean serum vitamin D levels. Further, in vitro addition of 1,25 OH-vitamin D3 substantially reduced DC expression of OX40L and increased DC expression of TGF-beta. This in vitro treatment also resulted in increased Treg TGF-beta expression and reduced Th2 responses by CD4+ T cells from patients with ABPA. These data provide rationale for a therapeutic trial of vitamin D to prevent or treat ABPA in patients with CF. PMID- 20714109 TI - Public understanding of risks from gene-environment interaction in common diseases: implications for public communications. AB - BACKGROUND/AIMS: Public understanding of the relationship between health behaviors and genes is likely to affect the motivational impact of learning information about one's own genes. Extant research has featured difficulty measuring public understandings of this relationship. This essay explores public understanding of the relationship between genes and behavior, especially with regard to the mathematical relationships to risk concept. It contributes a psychometrically valid scale for measuring beliefs about gene- behavior relationships. METHODS: Three population representative surveys (n = 633, 658, 1,218) were conducted using the Knowledge Networks panel platform. RESULTS: Interpretations of risk vary depending on whether genes and behavior are conceived of as health-damaging (loss frame) or health-protecting (gain frame). In the loss frame, the majority of the population adopts an additive model of the relationship with approximately one-third adopting an amplificative model. In the gain frame, beliefs are divided roughly equally among additive, amplificative and sub-additive models. Scores on the nonmathematically based scale indicate higher belief in the existence of interaction than scores on the more concrete question format. CONCLUSIONS: The existence of different interpretations of gene-behavior relationships based on gain/loss frame and abstract/concrete modes indicates the need to select frame and mode carefully in both teaching and research. Research is needed to identify optimal configurations for teaching and presenting this relatively complex material. PMID- 20714108 TI - Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. AB - Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset of CD8+ conventional dendritic cells. Adoptive transfer of splenic CD11chiPDCA-1- dendritic cells from wild-type mice into animals with hematopoietic EPCR deficiency restored the therapeutic efficacy of aPC, whereas transfer of EPCR deficient CD11chi dendritic cells or wild-type CD11chi dendritic cells depleted of EPCR+ cells did not. In addition, 5A-aPC inhibited the inflammatory response of conventional dendritic cells independent of EPCR and suppressed IFN-gamma production by natural killer-like dendritic cells. These data reveal an essential role for EPCR and PAR1 on hematopoietic cells, identify EPCR-expressing dendritic immune cells as a critical target of aPC therapy, and document EPCR-independent antiinflammatory effects of aPC on innate immune cells. PMID- 20714110 TI - Oxidative stress and aminopeptidases in Parkinson's disease patients with and without treatment. AB - BACKGROUND/OBJECTIVE: Mitochondrial dysfunction, oxidative stress and protein metabolism impairment are the main molecular events underlying the pathogenesis of Parkinson's disease (PD). However, only few studies have addressed the changes produced by these phenomena in the blood of PD patients. Our purpose was to compare oxidative stress between newly diagnosed PD patients (ntPD) and PD patients under treatment (tPD). We also analyzed changes in plasma activity of several aminopeptidases (AP) involved in the metabolism of various active peptides. METHODS: Plasma lipid peroxide (LPO) and lactate (LAC) concentrations were measured by colorimetric methods, and plasma AP activities were determined by fluorometric assay. RESULTS: LPO and LAC concentrations were significantly elevated in ntPD and tPD patients versus controls, but there were no differences between the PD groups. Alanine-, cystine- and aspartate-AP activities were significantly lower in tPD versus ntPD patients. Nondenaturing electrophoresis and Western blot results confirmed these findings. CONCLUSIONS: The plasma LPO and LAC levels were high in both PD groups, indicating that they are elevated at an early stage of PD and are not affected by anti-PD treatment. The higher AP activities in ntPD versus tPD patients suggest that anti-PD treatment may improve protein metabolism while not altering oxidative stress. A therapy directed to reduce oxidative stress and normalize AP activity may be useful in the treatment of PD. PMID- 20714111 TI - Heavy-chain complementarity-determining regions determine conformation selectivity of anti-abeta antibodies. AB - BACKGROUND/AIMS: Amyloid-beta (Abeta) protofibrils are neurotoxic soluble intermediates in the Abeta aggregation process eventually forming senile plaques in Alzheimer's disease. This Abeta species is a potential biomarker for Alzheimer's disease and also a promising target for immunotherapy. In this study, we investigated the characteristics of conformation-dependent Abeta antibodies specific for Abeta protofibrils. METHODS: Mice were immunized with Abeta protofibrils to generate hybridomas producing Abeta-specific monoclonal antibodies. Binding of antibodies to different Abeta conformations was investigated with inhibition ELISA. The antibodies' complementarity-determining region (CDR) sequences were determined and compared. RESULTS: A majority of the antibodies were of the IgM class, all selectively binding to aggregated Abeta. Two IgG antibodies were generated: one with selective affinity for Abeta protofibrils and the other bound Abeta in all conformations. A high degree of similarity between the heavy-chain CDRs of the conformation-dependent antibodies was found, and all high-affinity Abeta antibodies displayed a high degree of sequence similarity in the light-chain CDRs. CONCLUSION: Sequence similarity in the heavy-chain CDRs is associated with conformation selectivity of the antibodies, while sequence similarity in the light-chain CDRs correlates with the affinity for Abeta. PMID- 20714112 TI - Lack of activation of the unfolded protein response in mouse and cellular models of Niemann-Pick type C disease. AB - BACKGROUND: Niemann-Pick type C (NPC) disease is a fatal lysosomal storage disease related to progressive neurodegeneration secondary to abnormal intracellular accumulation of cholesterol. Signs of endoplasmic reticulum (ER) stress have been reported in other lipidoses. Adaptation to ER stress is mediated by the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates stress or triggers apoptosis of irreversibly damaged cells. OBJECTIVE: To investigate the possible engagement of ER stress responses in NPC models. METHODS: We used NPC1 deficient mice and an NPC cell-based model by knocking down the expression of NPC1 to measure several UPR markers through different approaches. RESULTS: Despite expectations that the UPR will be activated in NPC, our results indicate a lack of ER stress reactions in the cerebellum of symptomatic mice. Similarly, knocking down NPC1 in Neuro2a cells leads to clear cholesterol accumulation without evidence of UPR activation. CONCLUSION: Our results suggest that cholesterol overload and neuronal dysfunction in NPC is not associated with ER stress, which contrasts with recent reports suggesting the activation of the UPR in other lysosomal storage diseases. PMID- 20714113 TI - Ethical principles for the management of infants with disorders of sex development. AB - The Fifth World Congress on Family Law and Children's Rights (Halifax, August 2009) adopted a resolution endorsing a new set of ethical guidelines for the management of infants and children with disorders of sex development (DSD) [www.lawrights.asn.au/index.php?option = com_content&view = article&id = 76&Itemid = 109]. The ethical principles developed by our group were the basis for the Halifax Resolution. In this paper, we outline these principles and explain their basis. The principles are intended as the ethical foundation for treatment decisions for DSD, especially decisions about type and timing of genital surgery for infants and young children. These principles were formulated by an analytic review of clinician reasoning in particular cases, in relation to established principles of bioethics, in a process consistent with the Rawlsian concept of reflective equilibrium as the method for building ethical theory. The principles we propose are: (1) minimising physical risk to child; (2) minimising psychosocial risk to child; (3) preserving potential for fertility; (4) preserving or promoting capacity to have satisfying sexual relations; (5) leaving options open for the future, and (6) respecting the parents' wishes and beliefs. PMID- 20714114 TI - Regional and temporal profiles of calpain and caspase-3 activities in postnatal rat brain following repeated propofol administration. AB - Exposure of newborn rats to a variety of anesthetics has been shown to induce apoptotic neurodegeneration in the developing brain. We investigated the effect of the general anesthetic propofol on the brain of 7-day-old (P7) Wistar rats during the peak of synaptic growth. Caspase and calpain protease families most likely participate in neuronal cell death. Our objective was to examine regional and temporal patterns of caspase-3 and calpain activity following repeated propofol administration (20 mg/kg). P7 rats were exposed for 2, 4 or 6 h to propofol and killed 0, 4, 16 and 24 h after exposure. Relative caspase-3 and calpain activities were estimated by Western blot analysis of the proteolytic cleavage products of alpha-II-spectrin, protein kinase C and poly(ADP-ribose) polymerase 1. Caspase-3 activity and expression displayed a biphasic pattern of activation. Calpain activity changed in a region- and time-specific manner that was distinct from that observed for caspase-3. The time profile of calpain activity exhibited substrate specificity. Fluoro-Jade B staining revealed an immediate neurodegenerative response that was in direct relationship to the duration of anesthesia in the cortex and inversely related to the duration of anesthesia in the thalamus. At later post-treatment intervals, dead neurons were detected only in the thalamus 24 h following the 6-hour propofol exposure. Strong caspase-3 expression that was detected at 24 h was not followed by cell death after 2- and 4-hour exposures to propofol. These results revealed complex patterns of caspase-3 and calpain activities following prolonged propofol anesthesia and suggest that both are a manifestation of propofol neurotoxicity at a critical developmental stage. PMID- 20714115 TI - Growth patterns in the first three years of life in children with classical congenital adrenal hyperplasia diagnosed by newborn screening and treated with low doses of hydrocortisone. AB - BACKGROUND: Linear growth is the best clinical parameter for monitoring metabolic control in classical congenital adrenal hyperplasia (CAH). OBJECTIVE: to analyze growth patterns in children with CAH diagnosed by newborn screening and treated with relatively low doses of hydrocortisone during the first year of life. PATIENTS AND METHODS: 51 patients (27 females) were diagnosed with classical CAH by newborn screening. All patients were treated with relatively low doses of hydrocortisone (9-15 mg/m(2) body surface area). 47 patients were additionally treated with fludrocortisone. RESULTS: at birth, height SDS (H-SDS) was 1.1 +/- 1 in girls and 0.9 +/- 1.5 in boys. After 3 months, H-SDS decreased to 0.4 +/- 0.9 in girls and to 0.1 +/- 1.3 in boys. Over the 3-year period, H-SDS further decreased to -0.4 +/- 1.8 in girls and to -0.8 +/- 1 in boys and approached the genetic height potential (target H-SDS of girls -0.5 +/- 0.3 and target H-SDS of boys -0.9 +/- 0.7). During the first 9 months of age, growth velocity was slightly decreased in girls (18.2 +/- 1.9 cm) and boys (17.3 +/- 1.6 cm) when compared to a healthy reference population (girls 19.0 +/- 3.9 cm and boys 18.7 +/- 4.7 cm). At the age of 3 years, bone age was appropriate for chronological age in both girls (2.7 +/- 0.5 years) and boys (2.9 +/- 0.5 years). CONCLUSION: birth length is above average in children with classical CAH, which might be the result of untreated hyperandrogenism in utero. With relatively low doses of hydrocortisone treatment, growth velocity decreases slightly during the first 9 months and H-SDS then approaches the genetic height potential. PMID- 20714116 TI - Morgagni hernia with massive pericardial effusion diagnosed in the second trimester: prenatal diagnosis and perinatal management. AB - Morgagni hernia is an extremely rare form of congenital diaphragmatic hernia. Only 6 cases of this condition have been reported in the English literature, as diagnosed prenatally. The prognosis of the disease is determined by the severity of the pulmonary hypoplasia and associated anomalies. Here we report a case of Morgagni hernia with massive pericardial effusion diagnosed by ultrasonography and MRI during the second trimester, enabling planning of appropriate treatment in the pre- and perinatal periods. PMID- 20714117 TI - Peripheral B cells may serve as a reservoir for persistent hepatitis C virus infection. AB - A recent study by our group indicated that peripheral B cells in chronic hepatitis C (CHC) patients are infected with hepatitis C virus (HCV). This raised the logical question of how HCV circumvents the antiviral immune responses of B cells. Because type I interferon (IFN) plays a critical role in the innate antiviral immune response, IFNbeta expression levels in peripheral B cells from CHC patients were analyzed, and these levels were found to be comparable to those in normal B cells, which suggested that HCV infection failed to trigger antiviral immune responses in B cells. Sensing mechanisms for invading viruses in host immune cells involve Toll-like receptor-mediated and retinoic acid-inducible gene I (RIG-I)-mediated pathways. Both pathways culminate in IFN regulatory factor-3 (IRF-3) translocation into the nucleus for IFNbeta gene transcription. Although the expression levels of RIG-I and its adaptor molecule, IFN promoter-stimulator 1, were substantially enhanced in CHC B cells, dimerization and subsequent nuclear translocation of IRF-3 were not detectable. TANK-binding kinase-1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) are essential for IRF-3 phosphorylation. Constitutive expression of both kinases was markedly enhanced in CHC B cells. However, reduced expression of heat shock protein of 90 kDa, a TBK1 stabilizer, and enhanced expression of SIKE, an IKKepsilon suppressor, were observed in CHC B cells, which might suppress the kinase activity of TBK1/IKKepsilon for IRF-3 phosphorylation. In addition, the expression of vesicle-associated membrane protein-associated protein-C, a putative inhibitor of HCV replication, was negligible in B cells. These results strongly suggest that HCV utilizes B cells as a reservoir for persistent infection. PMID- 20714118 TI - Interaction of kisspeptin and the somatotropic axis. AB - Kisspeptin, a regulator of gonadotropin-releasing hormone, has been hypothesized as an integrator of nutrition and hormones critical to metabolism and the regulation of reproduction. Growth hormone (GH) is necessary for optimal reproduction and recent evidence suggests that its secretion may be influenced by kisspeptin. The objectives of this study were to determine whether the effect of kisspeptin to stimulate GH release is due to an interaction with growth hormone releasing hormone (GHRH) or somatostatin (SS), or an effect at the hypothalamus. Intravenous injection and infusion of kisspeptin [500 pmol/kg BW (650 ng/kg)/h * 5 h] to cows (n = 5) increased serum concentrations of luteinizing hormone (LH) but not GH. Pretreatment with kisspeptin injection and infusion in cows (n = 5) reduced the stimulatory effect of GHRH (0.05 MUg/kg BW) on GH secretion. However, the magnitude of the GH response to GHRH (assessed by incremental AUC) was not affected by kisspeptin. In these same cows, administration of kisspeptin prevented the increase in GH induced by SS infusion (0.5 MUg/kg BW/ h * 1.5 h) withdrawal. Peripheral administration of kisspeptin [200 and 1,000 pmol/kg BW (260 and 1,300 ng/kg)] increased serum concentrations of LH but not GH in ewes (n = 8). However, concentrations of GH were stimulated by central kisspeptin treatment [100 and 200 pmol/kg BW (130 and 260 ng/kg)] in ewes. In addition to activating the gonadotropic axis, kisspeptin can activate the somatotropic axis in ruminants. Present data support the concept of a central site of action for this effect. PMID- 20714119 TI - Cocaine use and abuse triggering sporadic young-onset amyotrophic lateral sclerosis. AB - To our knowledge, we describe for the first time the case of a male patient with sporadic young-onset amyotrophic lateral sclerosis, most likely attributed to chronic regular cocaine use and abuse. Our case supports the view that cocaine use and abuse may trigger a process of motor neuron degeneration by mechanisms implicating alterations in the neurobiology of the excitatory neurotransmitter glutamate and its receptors. PMID- 20714120 TI - Perinatal outcomes of fetal abdominal cysts and comparison of prenatal and postnatal diagnoses. AB - INTRODUCTION: The differential diagnosis of an abdominal cyst can be challenging, and an accurate diagnosis is crucial for optimal antenatal management. The aim of this study was to compare the ante- and postnatal diagnoses of cases with abdominal cyst and to determine the diagnostic accuracy of ultrasonography. MATERIAL AND METHODS: A database review was performed regarding the diagnosis of fetal abdominal cyst covering the period 2002-2009. Structural characteristics and localizations of the cysts in the abdomen were recorded. Ante- and postnatal diagnoses were classified into systems according to the origin of the cyst and were compared. Perinatal outcomes were obtained for all cases. RESULTS: 71 cases with an abdominal cyst were identified. The mean gestational age at the time of diagnosis was 25 +/- 5.1 weeks. In 9 cases, there were extra-fetal structural abnormalities, and in 5 cases a chromosomal abnormality was determined. Seven pregnancies were terminated. Overall spontaneous mortality was 11/64 (17%). In 12/64 cases (18%), the cyst resolved at birth. After birth, nearly half of the cases required surgical correction and of these, 20% died. Sensitivity, specificity and positive predictive value of ultrasonography in identifying the system of origin were 88.1, 95.7 and 92.0%, respectively, with a 4.1% false positive rate. CONCLUSION: Incorporation of different disciplines in the counseling, management and postpartum follow-up is crucial. Postnatal physical examination of fetuses with an abdominal cyst will help to prevent unnecessary surgery. PMID- 20714121 TI - First and second trimester markers of fetal aneuploidy in pregnant women with HIV infection. AB - OBJECTIVE: To evaluate if levels of pregnancy-associated plasma protein-A (PAPP A), free beta-hCG and nuchal translucency (NT) used in first trimester aneuploidy screening and alpha-fetoprotein (AFP), unconjugated oestriol (UE3) and free beta hCG in the second trimester are altered in pregnancies with human immunodeficiency virus (HIV) infection. METHODS: Median MoM values of biochemical markers and delta-NT in 92 women with HIV infection in the first trimester were compared with those from 912 HIV-seronegative controls. In the second trimester, biochemical marker levels were compared in 52 women with HIV infection and 378 HIV-seronegative controls. RESULTS: First trimester free beta-hCG median MoM levels in HIV-infected pregnancies were not different to controls (0.978 vs. 0.981, p = 1.000), as were PAPP-A levels (1.190 vs. 1.102, p = 0.099) and delta NT (0.1374 vs. 0.0445, p = 0.0631). Second trimester levels of free beta-hCG were not significantly different (1.0575 vs. 0.9619, p = 0.1827), as was AFP (0.9734 vs. 0.9350, p = 0.6576), although UE3 was significantly lower (0.970 vs. 1.110, p = 0.0005). CONCLUSIONS: In the first trimester, marker levels are not affected by the presence of HIV infection, and risks for aneuploidy are likely to be accurate in this group. Further studies are required to evaluate if UE3 levels continue to be low in HIV-infected women since this may have an impact on screening in the second trimester. PMID- 20714122 TI - Oligoarray (105K) CGH analysis of chromosome microdeletions within 10q22.1q24.32. AB - To populate the chromosome 10 genetic landscape with clinical correlations we describe 3 non-overlapping, nearly contiguous deletions within chromosome 10q22.1q24.32. Three cases were studied by oligoarray comparative genomic hybridization (CGH), cytogenetics, and/or fluorescence in situ hybridization. The array CGH showed de novo deletions: arr 10q22.1q22.2(74,115,795-77,077,025)*1dn, arr 10q22.3q23.2(81,437,039-89,144,374)*1dn and arr 10q23.33q24.32(94,894,780 103,144,781)*1dn. Developmental delay, speech impairment and growth retardation were observed in all 3 patients. Facial palsy and renal dysplasia were the other notable findings. The renal dysplasia was ascribed to the loss of a PAX2 gene in the 10q23.33q24.32 deletion patient (OMIM *167409). The facial palsy was seen in the case with a deletion of 10q22.1q22.2. One of three 10q22.3q23.2 deletions involved low copy repeats. We have described the phenotype specific to the chromosome region involved within 10q22.1-q24.32. The oligoarray analysis improved the clinical management of the patients and enabled counseling for deleted genes. PMID- 20714123 TI - Penile incarceration secondary to a ring. AB - Penile incarceration by foreign objects for sexual stimulation purposes is a situation described in universal literature, however it is a rare situation that the urologist must face in the emergency room. A 75-year-old male is presented to whom his sexual partner had placed a ring in the coronal sulcus. PMID- 20714125 TI - Use of competency-based metrics to determine effectiveness of a postgraduate thoracoscopy course. AB - BACKGROUND: Despite the paradigm shift from process to competency-based education, no study has explored how competency-based metrics might be used to assess short-term effectiveness of thoracoscopy-related postgraduate medical education. OBJECTIVES: To assess the use of a single-group, pre-/post-test model comprised of multiple-choice questions (MCQ) and psychomotor skill measures to ascertain the effectiveness of a postgraduate thoracoscopy program. METHODS: A 37 item MCQ test of cognitive knowledge was administered to 17 chest physicians before and after a 2-day continued medical education-approved program. Pre- and post-course technical skills were assessed using rigid videothoracoscopy simulation stations. Competency-based metrics (mean relative gain, mean absolute gain, and class-average normalized gain ) were calculated. A >30% was used to determine curricular effectiveness. RESULTS: Mean cognitive knowledge score improved significantly from 20.9 to 28.7 (7.8 +/- 1.3 points, p < 0.001), representing a relative gain of 37% and an absolute gain of 21%. Mean technical skill score improved significantly from 5.20 to 7.82 (2.62 +/- 0.33 points, p < 0.001), representing a relative gain of 50% and an absolute gain of 33%. Non parametric testing confirmed t test results (p < 0.001). Class-average normalized gains were 48 and 92%, respectively. CONCLUSION: Competency-based metrics, including class-average normalized gain, can be used to assess course effectiveness and to determine if a program meets predesignated objectives of knowledge acquisition and psychomotor technical skill. PMID- 20714124 TI - Interactions of corticotropin-releasing factor, urocortin and citalopram in a primate model of stress-induced amenorrhea. AB - BACKGROUND/AIMS: We established a cynomolgus macaque model of stress-induced amenorrhea in which the application of combined metabolic and psychosocial stress suppressed ovulation in stress-sensitive (SS) individuals, but not in highly stress-resilient (HSR) individuals. We previously reported that SS monkeys have deficits in global serotonin release and serotonin-related gene expression in the raphe nucleus, and that administration of the selective serotonin reuptake inhibitor S-citalopram increased estrogen and progesterone production in SS monkeys. In this study, we questioned whether there was a difference in corticotropin-releasing factor (CRF) or urocortin (UCN) stress-related peptide systems in the midbrain raphe region when HSR and SS monkeys treated with placebo or S-citalopram are compared. METHODS: Monkeys characterized as HSR or SS were administered placebo or S-citalopram for 15 weeks. CRF fibers in the dorsal raphe were detected with an antibody against human CRF. UCN1 fibers were immunostained in an area rostral to the dorsal raphe. The fibers were quantified by stereology and analyzed by two-way ANOVA. UCN1 cell bodies were counted in the supraoculomotor area near the Edinger-Westphal nucleus. RESULTS: S-citalopram significantly decreased the CRF fiber density in SS animals, but not in HSR animals. SS monkeys had a significantly lower UCN1 fiber density compared to HSR monkeys, but S-citalopram treatment did not alter the UCN1 fiber density. SS animals treated with S-citalopram tended to have a higher number of UCN1-positive cell bodies than the other groups. CONCLUSION: S-citalopram decreased CRF fiber density and appears to increase the production of UCN1 in SS individuals, indicating the likelihood that serotonin is involved in regulating CRF and UCN1 in individuals who are sensitive to the effects of serotonin. PMID- 20714126 TI - New insight into the mechanism of Lonomia obliqua envenoming: toxin involvement and molecular approach. AB - Despite the nearly worldwide distribution of Lepidoptera, there are few species with clear documentation of adverse reactions in humans. Most syndromes caused by Lepidoptera are consequences of direct contact with the hairs or setae of caterpillars. In most instances, the adverse effects caused by moth and caterpillars are self-limited and the treatment is based on the removal of hairs, application of topical antipruritics and, in some cases, the use of oral antihistamines. However, in the case of envenoming by South American Lonomiaobliqua caterpillars, the antilonomic serum produced at Instituto Butantan in Brazil is the only effective treatment to re-establish the physiological coagulation parameters in poisoned patients and to abolish the complications seen in severe cases (e.g. consumptive coagulopathy, intracerebral hemorrhage, and acute renal failure). Many studies have been carried out to understand the pathophysiological mechanism of envenoming by L. obliqua. Several toxic principles were found in bristle extract and the hemolymph, probably related to the envenoming. An interesting fact is that some toxins from the venom usually have more than one function. With the advent of molecular biology techniques it has become possible to analyze these processes at a molecular level, thus giving rise to hypotheses on the molecular basis of envenomation. This review contributes to enhance our understanding of the dramatic alterations that hemorrhagic syndrome causes in patients, current treatment, and the diversity of the molecules involved in this pathology. PMID- 20714127 TI - Primary synovial sarcoma of the lung with intra-cardiac extension. AB - Synovial sarcomas are a distinct clinical entity occurring most often in the lower extremities. They account for 10-14% of all soft tissue sarcomas. Pulmonary synovial sarcomas are quite rare and account for less than 0.5% of all intra thoracic neoplasms. We present the first reported case of primary pulmonary synovial sarcoma with intra cardiac extension in a 53-year-old male who presented with chronic cough. Imaging revealed a large right upper lobe mass extending through the superior pulmonary veins into the left atrium. The patient underwent a right total pneumonectomy with extraction of the left atrial mass and left atrial reconstruction. Pathology and immunohistochemistry was diagnostic of primary pulmonary synovial sarcoma positive for SYT-SSX1 gene fusion transcription. PMID- 20714128 TI - Level of kidney function correlates with cognitive decline. AB - BACKGROUND: Early stage chronic kidney disease has been related to cognitive decline recently, while the association between them has never been explored in a Chinese population. METHODS: This prospective study included a 1,351 community based Chinese population >40 years and with estimated glomerular filtration rate (eGFR) >30 ml/min/ 1.73 m(2). Kidney function was assessed by eGFR at baseline; cognitive function was evaluated by Mini-Mental State Examination (MMSE) both at baseline and 4 years later, and MMSE score decreased < or =2 was defined as cognitive decline using analysis of Reliable Change Indices. There were 1,243 participants (92.0%) with valid data of MMSE at the second visit. RESULTS: Altogether there were 66 (5.3%) incident cognitive decline cases during 4 years of follow-up. After adjusting for potential confounders including urinary albumin to-creatinine ratio, the odds ratio of developing cognitive decline was 1.35 (95% CI 0.69-2.65) among participants with eGFR 60-89 ml/min/1.73 m(2) and was 2.73 (95% CI 1.00-7.56) among participants with eGFR 30-59 ml/min/1.73 m(2), compared to those with eGFR > or =90 ml/min/1.73 m(2). CONCLUSION: Our prospective study suggests that kidney function is associated with a cognitive decline in a Chinese population and the relation is independent of urinary albumin excretion. PMID- 20714129 TI - Lipoxin A(4) inhibits transition of epithelial to mesenchymal cells in proximal tubules. AB - BACKGROUND: Previous studies showed that connective tissue growth factor (CTGF) induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A(4) (LXA(4)). It is speculated that LXA(4) could modulate the CTGF-induced epithelial to mesenchymal transition. METHODS: The expressions of alpha-smooth muscle actin (alpha-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of alpha-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2). RESULTS: Pretreatment of HK-2 cells with LXA(4) inhibited the morphological fibroblast-like changes and alpha SMA expression induced by CTGF but not by transforming growth factor-beta(1) (TGF beta(1)). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-beta(1) were increased by LXA(4). LXA(4) inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA(4) did not affect TGF-beta(1)-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2's binding to Smad-4 and subsequent nuclear translocation. CONCLUSION: LXA(4) inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-beta(1), via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF. PMID- 20714130 TI - Increased low-density lipoprotein S-homocysteinylation in chronic kidney disease. AB - BACKGROUND: Since low-density lipoprotein (LDL) S-homocysteinylation has been recently reported to enhance atherogenicity of lipoprotein, we have investigated the levels of homocysteine (Hcy) linked to LDL in chronic proteinuric patients in which lipid abnormalities highly contribute to the excess of morbidity and mortality. METHODS: We used capillary electrophoresis to measure LDL-bound thiol Hcy, cysteine (Cys), cysteinylglycine (Cys-Gly), glutathione (GSH), and glutamylcysteine (Glu-Cys) in 30 chronic kidney disease (CKD) individuals and 60 healthy volunteers. RESULTS: We found more elevated levels of total plasma Hcy, Cys, GSH and Glu-Cys in patients than in controls and also found that Hcy and Cys bound to LDL were significantly increased in nephropathic subjects. By multiple linear regression, we found that in healthy people, total Hcy was the most important determinant of LDL-bound Hcy and Cys-Gly was negatively associated with apoB-Hcy concentrations. In CKD the most important determinant of homocysteinylation was creatinine while total plasma Hcy is weakly associated with apoB-Hcy. CONCLUSIONS: The increased levels in Hcy-LDL observed in CKD patients might account, at least in part, for the excess of cardiovascular risk; thus LDL S-homocysteinylation can be considered a key marker of risk for cardiovascular disease in these individuals. PMID- 20714131 TI - Osteopontin overproduction is associated with progression of glomerular fibrosis in a rat model of anti-glomerular basement membrane glomerulonephritis. AB - BACKGROUND: Glomerular fibrosis is the common end result of glomerulonephritis (GN) regardless of etiology. In our rat model for anti-glomerular basement membrane GN, severe fibrosis follows glomerular inflammation. We investigated the association between expression of extracellular matrix (ECM) proteins and progression of glomerular fibrosis. METHODS: Expression of ECM genes in glomeruli was determined at RNA and protein levels. Immunofluorescence was applied to identify cell sources for the molecules. RESULTS: DNA microarray for ECM genes, quantitative RT-PCR and Western blot revealed significant upregulation of osteopontin (OPN), a multifunctional molecule, in the glomeruli only after onset of glomerular fibrosis. Two-dimensional electrophoresis showed that the expressed OPN was in three major isoforms. Immunofluorescence showed that fibrotic tissues in glomeruli accumulated massive deposits of extracellular OPN. Both in vivo and in vitro experiments showed that a novel population of multinucleated alpha smooth muscle actin(+)CD90(-) myofibroblast-like cells, which surrounded fibrotic tissue, was the main source of OPN during progression of fibrosis. Since senescence-associated beta-galactosidase activity was detected in those cells both in vitro and in vivo, these cells probably were terminally differentiated senescent myofibroblasts. CONCLUSION: OPN has been implicated in fibrosis in several organs. Our results suggest potential roles of OPN and its main source, the senescent myofibroblasts, in glomerular fibrosis. PMID- 20714132 TI - Acute responses of gastrointestinal hormones to both oral and parenteral intradialytic nutrition. AB - INTRODUCTION: Intradialytic nutrition (IDN) has been used to improve the nutritional status of malnourished hemodialysis (HD) patients. OBJECTIVE: To evaluate the different effects of parenteral IDN (IDPN) and oral IDN (IDON) on nutrition-related gastrointestinal hormones. PATIENTS AND METHODS: Seven clinically stable HD patients with malnutrition were included. All patients were treated for 1 month with either IDPN or IDON, with a 4-week period of no nutritional support between each type of therapy. On the first day of each nutritional support (IDON or IDPN) we analyzed the acute responses of insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). We compared the areas under the secretory curves (AUC) and the maximum peaks of serum glucose, insulin, ghrelin, and GLP-1. A group of 6 clinically stable HD patients without any type of IDN served as the control group. RESULTS: The acute responses of glucose and insulin to IDN were significantly higher with IDPN than with IDON. The AUC of glucose (602 +/- 81 vs. 495 +/- 81 mg/dl/h, p < 0.01) and insulin (232 +/- 103 vs. 73.8 +/- 69 MUU/ml/h, p < 0.01) as well as the maximum peaks of glucose (228 +/- 41 vs. 177 +/- 47 mg/dl, p < 0.05) and insulin (104 +/- 46 vs. 29 +/- 24 MUU/ml, p < 0.01) were significantly higher after IDPN than after IDON. Ghrelin decreased after both IDPN and IDON; however, the decrease was significantly higher with IDPN compared to IDON. The ghrelin nadir was significantly lower in IDPN than in IDON (0.77 +/- 0.5 vs. 1.5 +/- 0.3, p < 0.05) although the AUC of ghrelin was not significantly different. GLP-1 was significantly increased at 1 h after starting both IDPN and IDON with no significant differences between the groups. CONCLUSION: IDPN induces a higher increase in serum glucose and insulin levels and a greater reduction in serum ghrelin concentrations compared with an equivalent orally administered nutritional supplement. PMID- 20714133 TI - Association of four genetic loci with uric acid levels and reduced renal function: the J-SHIPP Suita study. AB - BACKGROUND: Recent genome-wide association studies have identified several genetic variants as susceptibility loci for serum uric acid (UA) levels. We also identified a common nonsense mutation, W258X, responsible for renal hypouricemia. Here, we investigated clinical implications of these genetic variants by cross sectional and longitudinal genetic epidemiological analysis. METHODS: The study enrolled 5,165 Japanese subjects aged 64 +/- 12 years from the general population. Clinical parameters were obtained from the personal health records, evaluated at medical checkups. RESULTS: Serum UA levels were significantly different between the SLC22A12 rs11231825 (CC/CT/TT: 4.5 +/- 1.6, 5.0 +/- 1.4, 5.3 +/- 1.4 mg/dl; p = 7.6 * 10(-20)), SLC2A9 rs1014290 (TT/TG/GG: 4.9 +/- 1.4, 5.1 +/- 1.4, 5.3 +/- 1.4 mg/dl; p = 3.1 * 10(-11)) and ABCG2 rs2231142 (TT/TG/GG: 5.3 +/- 1.5, 5.2 +/- 1.4, 5.1 +/- 1.4 mg/dl; p = 2.0 * 10(-5)) genotypes. During 9.4 years of follow-up, 87 new cases of hyperuricemia were diagnosed. Multiple logistic regression analysis identified the accumulation of risk alleles as a significant determinant of future development of hyperuricemia (OR = 7.94; 95% CI: 1.97-53.6). In contrast, subjects with nonsense mutation predominantly showed lower UA levels (XX/XW/WW: 1.3 +/- 1.7, 3.6 +/- 1.0, 5.2 +/- 1.4 mg/dl; p = 9.3 * 10(-82)). However, these subjects showed significantly reduced renal function (beta = -0.111; p < 0.001) independently of possible covariates. CONCLUSION: Accumulation of risk genotypes was an independent risk factor for future development of hyperuricemia. Genetically developed hypouricemia was an independent risk factor for decreased renal function. PMID- 20714134 TI - Intrauterine growth restriction following ligation of the uterine arteries leads to more severe glomerulosclerosis after mesangioproliferative glomerulonephritis in the offspring. AB - BACKGROUND: Low birth weight is a risk factor for the development of a more severe course of secondary renal diseases. We tested the hypothesis that experimental mesangioproliferative glomerulonephritis (GN) shows an aggravated course in rats inflicted with experimental uteroplacental insufficiency during gestation. METHODS: Intrauterine growth restriction (IUGR) was induced by ligation of both uterine arteries on day 19 in pregnant Wistar rat dams. GN was induced in male offspring at the age of 9 weeks by intravenous injection of an anti-Thy-1.1 antibody. At day 14 of GN, kidneys were taken and analyzed for glomerular morphometry, markers of inflammation, glomerulosclerosis and tubulointerstitial fibrosis. RESULTS: Despite a similar extent of mesangiolysis, former IUGR animals presented with a higher level of glomerulosclerosis and increased deposition of glomerular collagens I and IV compared to nephritic control animals. Arterial blood pressure, renal function, and proteinuria after 14 days of GN were not influenced by former IUGR. CONCLUSION: Ligation of the uterine arteries in the rat leads to more pronounced sclerotic changes in the glomerulus in the offspring suffering from acute GN. This finding supports the hypothesis that former IUGR increases the susceptibility for a more severe course of secondary renal diseases. PMID- 20714135 TI - Implantable defibrillators improve survival in end-stage renal disease: results from a multi-center registry. AB - BACKGROUND: Small retrospective analyses suggest that end-stage renal disease (ESRD) patients do not obtain as much of a survival benefit from an implantable cardioverter-defibrillator (ICD) as non-ESRD patients do. We aimed to assess the survival effect of an ICD in ESRD patients with left ventricular dysfunction. METHODS: Data from two registries identified ESRD patients with an ICD and ESRD patients with left ventricular dysfunction (defined as ejection fraction <0.35). Cox proportional hazards regression was performed, including certain predefined covariates to assess the effect of an ICD on survival. RESULTS: Overall survival in the full cohort was a median of 4.7 years with 20 deaths in the ICD group and 29 deaths in the no-ICD group. The median survival in the ICD group was 8.0 years and 3.1 years in the no-ICD group. Crude analysis showed a better survival in the ICD group as compared to the no-ICD group (p = 0.016). The multivariable analysis confirmed that the ICD group had significantly less all-cause mortality compared to the no-ICD group (HR: 0.40; 95% CI: 0.19, 0.82; p = 0.013). CONCLUSION: An ICD is associated with a higher survival in ESRD patients with left ventricular dysfunction. This result merits further study in a larger cohort of patients. PMID- 20714136 TI - Hepatitis C increases the risk of progression of chronic kidney disease in patients with glomerulonephritis. AB - BACKGROUND/AIMS: We have shown that hepatitis C does not increase the risk of developing chronic kidney disease (CKD), but it is not known if hepatitis C worsens progression of existing CKD. METHODS: We retrospectively identified patients with primary glomerulonephritis on biopsy over 4 years, evaluating the progression of CKD over time. RESULTS: The cohort consisted of 111 patients: 21% were positive for hepatitis C, 61% were negative for hepatitis C and 18% were not tested. The hepatitis C-positive subjects were more likely to be African American (p = 0.031), followed for fewer days (p = 0.007) and have diabetes and focal segmental glomerulosclerosis on biopsy (p < 0.001). Longitudinal follow-up of CKD progression using multiple creatinine measures analyzed by repeated measures ANCOVA demonstrated that patients with hepatitis C had a worsening creatinine over time compared to the hepatitis C-negative and not tested groups (p < 0.001). By Cox hazards regression analyses, risk of death/end-stage renal disease (ESRD) was decreased in patients who tested negative for hepatitis C compared to testing positive (0.46, CI 0.27-0.88), but this became nonsignificant after adjustment for mean arterial pressure and hemoglobin. CONCLUSION: Our results support that infection with hepatitis C in patients with glomerulonephritis is associated with an increased risk of progression of CKD. Prospective studies are required to confirm these observations. PMID- 20714137 TI - Increasing Dietary alpha-linolenic acid enhances tissue levels of long-chain n-3 PUFA when linoleic acid intake is low in hamsters. AB - BACKGROUND/AIMS: We tested whether feeding hamsters diets varying in alpha linolenic acid (ALA) content and low in linoleic acid (LA) could increase the tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) to the same extent as a fish oil-supplemented diet. METHODS: For 5 weeks, 60 hamsters were fed 1 of the following 5 diets containing 2% of total dietary energy (TE) as LA and either 0.5% (diet A), 1% (diets B and E), 2% (diet C), or 4% (diet D) ALA of TE, so that the ratio of LA/ALA was 4:1, 2:1, 1:1, or 1:2. Diet E was supplemented with fish oil at the level of 0.2% of total energy intake. At the end of the study, overnight-fasted hamsters were sacrificed, and blood and tissues were collected. RESULTS: Tissue levels of ALA, EPA, DPA, and DHA rose in proportion to the increase in the dietary ALA level (p < 0.01); however, the levels of DHA reached a plateau at ALA intakes above 1% (p < 0.01). These changes were accompanied by decreases in arachidonic acid with or without increases in LA levels (p < 0.01). Hamsters fed diet D had similar or higher EPA, DPA, and DHA tissue levels to those fed diet E (p < 0.01). CONCLUSIONS: In hamsters, diets containing 4% energy as ALA and 2% energy as LA can increase the tissue levels of EPA, DPA, and DHA to the same extent as feeding 0.2% energy as fish oil. PMID- 20714138 TI - Metabolic and appetite hormone responses of hyperinsulinemic normoglycemic males to meals with varied macronutrient compositions. AB - AIMS: The aim of this study was to investigate the appetite hormones and metabolic responses of hyperinsulinemic subjects to high-protein (HP) meals as compared to high-carbohydrate (HC) and high-fat (HF) meals. DESIGN: Fifteen hyperinsulinemic normoglycemic men received, on 3 separate occasions, HP, HC, or HF meals in a randomized crossover design. Blood samples were collected before and after the ingestion of each meal. Postprandially, acylated ghrelin, PYY(3 36), insulin, glucose, and triglycerides were measured. RESULTS: While the HC meal induced an acutely greater postprandial ghrelin decrease below baseline, the HP meal maintained this decline significantly more than the HF meal at 240 min. Postprandial PYY(3-36) responses did not significantly vary with time and meal composition. Postprandial insulin and glucose peaks were significantly lower following the HP and HF meals in comparison to the HC meal, whereas triglyceride responses were significantly higher following the HF meal. Significant correlations, negative between acylated ghrelin and insulin and positive between PYY(3-36) and insulin, were observed. CONCLUSIONS: In hyperinsulinemic normoglycemic men, HP meals ensure a longer-lasting suppression of circulating ghrelin levels and result in more favorable metabolic responses, characterized by a lower surge of postprandial insulin and glucose and a reduced postprandial triglyceride response, as compared to both HC and HF meals. PMID- 20714139 TI - Multiple symmetric lipomatosis: substantial subcutaneous adipose tissue accumulation did not induce glucose and lipid metabolism dysfunction. AB - OBJECTIVE: To study whether substantial subcutaneous adipose tissue (SCAT) can induce glucose and lipid metabolism dysfunction and possible underlying mechanisms. METHODS: We report a male patient with multiple symmetrical lipomatosis (MSL) suffering from increased adipose tissue accumulation in abdomen and back for 7 years, accompanied by the gradual expansion of excess adipose tissue to the nuchal region, upper thorax, upper arms and shoulders. Four obese male adults of similar age and body mass index were chosen as controls (only 4 subjects consented to blood and tissue sampling).Blood samples were collected before anesthesia in the early morning after overnight fasting, and tissue samples from all subjects and the patient were obtained under general anesthesia. Glucose tolerance, insulin resistance in the oral glucose tolerance test and insulin-releasing test were studied. A pathologic examination was made and expression of SCAT-related genes was determined. RESULTS: Although adipose tissue mainly accumulated in SCAT, the patient had no impaired glucose tolerance, insulin resistance and dyslipidemia. Importantly, the circulating adiponectin concentration was higher than in the control group (50.3 +/- 3.2 vs. 28.4 +/- 2.2 microg/ml, p < 0.05). Accordingly, adiponectin and leptin mRNA expression in SCAT was higher than in the control group (1.83 and 3.75 times, p < 0.05) but TNF alpha and IL-6 mRNA levels were lower (decreased by 79 and 45%, p < 0.05). Furthermore, pathologically, adipocyte size in the patient's SCAT was smaller than in the control group (66.2 +/- 6.1 vs. 78.9 +/- 6.6 and 98.6 +/- 12.8 microm in SCAT and omentum adipose tissue, respectively, p < 0.05). CONCLUSION: In spite of the patient's SCAT accumulation, glucose and lipid metabolism dysfunction was absent. The mechanism may involve the interaction of different factors, including the subcutaneous formation of small adipocytes, the secretion of protective adipokines such as adiponectin and anti-inflammatory effects of SCAT. PMID- 20714140 TI - Association of polymorphisms of heat shock protein 70 with susceptibility to noise-induced hearing loss in the Taiwanese population. AB - Noise-induced hearing loss (NIHL) is the major cause of adult sensorineural hearing loss. It is a complex disease caused by the interaction of environmental and genetic factors. Previous studies found that heat shock proteins (HSPs) were associated with the development of NIHL. Specifically, polymorphisms in the heat shock protein 70 (HSP70) gene family are associated with a susceptibility to NIHL. In this study, three single nucleotide polymorphisms (SNPs) of the HSP70 family (SNP1: rs2075800; SNP2: rs1043618; SNP3: rs2763979) were genotyped in 349 noise-exposed Taiwanese workers. The subjects were categorized into noise susceptible (NS; n = 27) and general susceptibility (GS; n = 322) groups by the change of a 4K-weighted audiometric average in an interval of 5 years. The G/C genotype of SNP2 was found to be associated with NIHL susceptibility (adjusted OR = 2.634; 95% CI = 1.096-6.328). No significant association was found for SNP1 and SNP3 with NIHL susceptibility. Analysis of haplotypes composed of these three SNPs revealed a significant association between NIHL susceptibility and haplotype CCC (OR = 2.197; 95% CI = 1.110-4.370). In conclusion, the genetic polymorphisms in the HSP70 genes seem to be associated with the individual's susceptibility to NIHL in the Taiwanese population. These findings could be used as a reference in the understanding and prevention of NIHL. PMID- 20714141 TI - Do differences in dialysis prescription impact on KDOQI bone mineral targets? The Pan Thames Renal Audit. AB - BACKGROUND AND OBJECTIVES: Patients achieving the Kidney Disease Outcomes Quality Initiative (KDOQI) bone mineral clinical practice guidelines have been reported to have improved survival. Many factors affecting calcium and phosphate control are not modifiable; however, we wished to determine whether differences in dialysis treatment could affect achievement of KDOQI clinical guideline targets. METHODS: We audited pre-mid-week session calcium and phosphate levels in 5,324 adult patients receiving thrice weekly dialysis in the 14 Pan Thames centres: 60% male, mean age 62 +/- 16 years, median dialysis vintage 29 months (14-58), 84% treated by haemodialysis, 16% by online haemodiafiltration, median session time 4.0 h (3.5-4.0). RESULTS: Patients achieving the KDOQI guidelines varied between the centres: 23.4-60% for calcium, 31.7-56.7% for phosphate, 60-87.3% for calcium phosphate product, 17.1-46.8% for parathyroid hormone (PTH) and 1.8-10.8% for all 4 targets. Those centres which used the highest dialysate calcium concentrations (1.5 mmol/l, 3 mEq/l) had more patients above the KDOQI serum calcium and more below the PTH target, than those centres using the lowest calcium dialysates (1 mmol/l, 2 mEq/l), with chi(2) = 85.1 and chi(2) = 52.4, p < 0.001, respectively. On logistic regression analysis, serum phosphate was negatively associated with duration of dialysis session time (F = 21.4, p = 0.000) and haemodiafiltration (F = 9.6, p = 0.000), respectively. CONCLUSIONS: Although many of the factors determining calcium and phosphate control in haemodialysis patients are unmodifiable, dialysate calcium concentration, the duration of the dialysis session and haemodiafiltration all had an impact on calcium, phosphate and PTH. PMID- 20714142 TI - Enhanced paracetamol clearance with molecular adsorbents recirculating system (MARS(r)) in severe autointoxication. PMID- 20714143 TI - Acute kidney injury in a Chinese hospitalized population. AB - OBJECTIVES: This study's objective was to determine the incidence and mortality rate of acute kidney injury (AKI) among hospitalized adult patients in a tertiary metropolitan hospital of China, and to evaluate the impact of AKI on in-hospital mortality, cost and length of stay (LOS). METHODS: Patients who were admitted to Zhongshan Hospital, Fudan University, Shanghai, China between September 1st, 2004 and June 30th, 2008 were involved. The presence and severity of AKI were assessed using absolute and relative increases from baseline to peak serum creatinine concentration during hospitalization. AKI was defined as a relative 50% increase or an absolute increment of 0.3 mg/dl (26.5 MUmol/l) in serum creatinine within 48 h. After screening the computer-based data on kidney function, patients with AKI were identified and further history reviews were performed to obtain information regarding patients' demography, prognosis, severity of kidney injury and causes of AKI. RESULTS: There were 176,155 admissions during the study period and 5,619 met the diagnostic criteria of AKI. The overall incidence rate of AKI was 3.19%. Cardiovascular diseases followed by urogenital diseases and malignancy were the most common admission diagnoses. In-hospital mortality rate was 2.84% in all discharges and 19.68% in patients with AKI. Of AKI patients, old age, intensive care unit admission, Acute Kidney Injury Network score, need for renal replacement therapy and organ system failure number were independent predictors of hospital mortality according to forward conditional logistic regression. CONCLUSIONS: AKI is prevalent in the Chinese hospitalized patients. Slight elevations of serum creatinine are associated with significantly increased mortality, LOS and hospital cost. Moreover, outcomes are related directly to the severity of AKI characterized by percent changes in serum creatinine. PMID- 20714144 TI - Catalytic therapy of cancer by ascorbic acid involves redox cycling of exogenous/endogenous copper ions and generation of reactive oxygen species. AB - Catalytic therapy is a cancer treatment modality based on the generation of reactive oxygen species (ROS) through administration of ascorbate/medicinal herbal extracts and copper. It is known that antioxidants such as ascorbate also exhibit prooxidant activity in the presence of transition metals such as copper. Based on our work and that in the literature, in this review we propose a mechanism for the cytotoxic action of ascorbate against cancer cells. It involves redox cycling of exogenous/endogenous copper ions and the consequent generation of ROS leading to oxidative DNA breakage. Using human peripheral lymphocytes and the Comet assay, we have shown that ascorbic acid is able to cause oxidative breakage in cellular DNA. Such DNA degradation is inhibited by neocuproine (a Cu(I) sequestering agent) and scavengers of ROS indicating that the cellular DNA breakage involves the generation of Cu(I) and formation of ROS. Similar results are also obtained with plant polyphenol antioxidants that are important constituents of medicinal herbal extracts. Copper is an essential component of chromatin and can take part in redox reactions. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Therefore, cancer cells may be more subject to electron transfer between copper ions and ascorbate/plant polyphenols to generate ROS. In this review we cite evidence to indicate that in catalytic therapy cytotoxic action against cancer cells involves redox cycling of exogenous/endogenous copper ions. PMID- 20714145 TI - A multicenter, randomized controlled clinical study on biapenem and imipenem/cilastatin injection in the treatment of respiratory and urinary tract infections. AB - BACKGROUND: Biapenem is an injectable carbapenem antibiotic. A clinical study was designed to evaluate its efficacy and safety in the treatment of respiratory and urinary infections compared to imipenem/cilastatin. METHODS: A total of 216 patients with respiratory or urinary tract infections were enrolled into this multicenter, open-label, randomized controlled clinical study. Each patient was randomly assigned to either the treatment or control group; 106 patients in each group were included in the ITT analyses. The patients were given biapenem 300 mg or imipenem/cilastatin 500 mg/500 mg two or three times daily, i.v. g.t.t. for 7 14 days according to their conditions. RESULTS: The cure and effective rates were 67.92 and 88.68% in the biapenem group and 76.02 and 93.40% in the imipenem/cilastatin group, the bacterial eradication rates were 93.83 and 98.82%, and the adverse-event rates were 6.54 and 7.41%, respectively. There were no significant differences between the two groups (p > 0.05). CONCLUSION: Biapenem is as effective and well-tolerated as imipenem/cilastatin for the treatment of intermediate and severe bacterial infections. PMID- 20714146 TI - PINCH protein expression in normal endometrium, atypical endometrial hyperplasia and endometrioid endometrial carcinoma. AB - BACKGROUND: Particularly interesting new cysteine-histidine rich protein (PINCH), as an adapter protein of the LIM family for signal transduction in the integrin and growth factor pathway, is upregulated in the stroma of several common types of cancers and involved in promoting tumor progression. In the present study, we examined PINCH expression in normal endometrium, atypical endometrial hyperplasia and endometrioid carcinoma, and further studied the relationships of PINCH expression with clinicopathological variables in cancer patients. METHODS: PINCH expression was examined by immunohistochemistry in 23 normal endometrial samples, 18 atypical endometrial hyperplasias and 48 endometrioid endometrial carcinomas. RESULTS: The PINCH expression in the stroma of cancer (71%) was significantly increased compared to either normal endometrium (17%, p < 0.0001) or atypical hyperplasia (39%, p = 0.017), along with 9 cancers that had stronger PINCH expressions at the invasive margin of the cancers compared to the inner cancers. PINCH expression in cancer was higher in the patients with hypertension (p = 0.041) and estrogen exposure time >30 years (p = 0.021). On the other hand, PINCH expression was not related to menopausal status, gravid status, blood sugar/lipid, family background of cancer, histological grade, myometrial invasion, cervical involvement, lymph nodal metastases, growth pattern, estrogen and progestogen receptors (p > 0.05). conclusion: The results suggest that PINCH seems to play a role, presently unknown, in the tumorigenesis and development of endometrial cancer that merits further study. PMID- 20714147 TI - Effect of vitamin C on lipidperoxidation and antioxidant status in tamoxifen treated breast cancer patients. AB - BACKGROUND: Vitamin C is a water-soluble chain-breaking antioxidant that has beneficial effects on lipid-metabolizing enzymes. In the present study, the level of thiobarbituric acid (TBA) substances and antioxidant enzymes such as catalase, superoxide dismutase (SOD), glutathione peroxidase and glutathione-S-transferase were assayed. METHODS: The level of TBA substances and antioxidant enzymes was determined in plasma and RBC hemolysates, respectively, in 60 postmenopausal women with breast cancer. RESULTS: The data obtained from the study revealed that the levels of TBA and the antioxidant enzymes catalase, SOD, glutathine peroxidase and glutathine-S-transferse were significantly normalized by vitamin C treatment in the RBC hemolysate. CONCLUSION: The results compared vitamin C treated breast cancer patients with normal individuals and showed that co administration of vitamin C is more beneficial in breast cancer patients treated with tamoxifen. PMID- 20714148 TI - Synergistic cytotoxicity and molecular interaction on drug targets of sorafenib and gemcitabine in human pancreas cancer cells. AB - BACKGROUND: Current treatments have a modest impact on survival of pancreatic cancer patients and this study investigates the interaction between sorafenib and gemcitabine and the molecular pharmacodynamics of this combination. METHODS: The pancreatic cancer cells were treated with sorafenib and gemcitabine, alone or in combination. The effects of treatments were evaluated on cell proliferation, cell cycle, apoptosis, phosphorylation of Akt, c-Kit, ERK and VEGFR2, and expression of genes related to drug activity. RESULTS: Gemcitabine and sorafenib synergistically interacted on the inhibition of cell proliferation, and assessment of apoptosis demonstrated that drug associations increased the apoptotic index. Sorafenib reduced c-Kit, ERK and VEGFR2 activation and on the other hand, gemcitabine inhibited Akt phosphorylation. Moreover, quantitative PCR showed that sorafenib modulated the expression of genes related to gemcitabine activity, while gemcitabine induced the expression of RKIP. CONCLUSION: These data demonstrate that gemcitabine and sorafenib combination displays a synergistic effect in pancreatic cancer cells. PMID- 20714149 TI - Genetic polymorphisms associated with 5-Fluorouracil-induced neurotoxicity. AB - BACKGROUND: Encephalopathy is a rare drug toxicity of fluorouracil therapy. Toxicity from fluorouracil therapy is known to be associated with the individual genetic background of the enzymes, thymidylate synthase and dihydropyrimidine dehydrogenase. METHODS: Two patients with advanced gastric cancer and metastatic pancreatic cancer who received 5-fluorouracil-based chemotherapy presented with acute mental change and hyperammonemia. To evaluate the genetic background of the fluorouracil-associated hyperammonemic encephalopathy, analysis of the polymorphisms of the TYMS, DPYD and MTHFR genes was performed. RESULTS: The patients revealed to be TYMS suppressors showing homogenous deletion of 6 bp in the 3'-UTR and 3RC/3RC genotype in the promoter enhancer region (TSER), respectively. CONCLUSION: Genetic polymorphisms of the TYMS gene would contribute to the 5-fluorouracil-associated hyperammonemic encephalopathy. The prospective validation of the clinical implication of TYMS gene polymorphisms is warranted. PMID- 20714150 TI - Dimers of nostocarboline with potent antibacterial activity. AB - OBJECTIVES: In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived from the cyanobacterial alkaloid nostocarboline were investigated. The mechanism of action and selectivity to bacteria were studied and compared to the cationic antiseptic chlorhexidine. METHODS: Minimal inhibitory concentrations were determined against clinical isolates and against a panel of microbial reference strains using the CLSI microdilution method. Bacterial membrane damage was addressed by measuring ATP leakage and the mode of action was investigated in Escherichia coli reporter strains. Selectivity was tested by a cytotoxicity assay using MTS. RESULTS: The antimicrobial potency of dimers varied with length of the hydrophobic linker. The most potent compounds, NCD9 and NCD10, had a C10 and C12 linker, respectively, and showed strong activity against Gram-positive bacteria, notably methicillin-resistant Staphylococcus aureus strains. Similar to chlorhexidine, these compounds showed a rapid concentration-dependent bactericidal effect, which correlated with membrane damage as indicated by ATP leakage. NCD9, in contrast to NCD10 and chlorhexidine, lacked activity against yeast strains and showed low cytotoxicity in CHO cells indicating a high degree of selectivity. In E. coli reporter strains, NCD9 induced the DegP response pathway as well as the SOS response, suggesting interaction with both the cell envelope and DNA metabolism. CONCLUSIONS: The results presented in this report indicate the potential of this new class of cationic antimicrobial compounds for the design of potent and selective antibacterials with low cytotoxicity. PMID- 20714151 TI - Are there options to prevent early occurring deaths in acute myocardial infarction: prospective evaluation of all <24 h in-hospital deaths, 2004-2006- the MONICA/KORA Augsburg Infarction Registry. AB - OBJECTIVES: To provide valid clinical data of early in-hospital deaths with presumed acute myocardial infarction (AMI) who are often not included in clinical trials or registries. METHODS: From August 2004 to August 2006 all patients (age 25-84 years) dying within 24 h after hospitalization in a large tertiary care academic teaching hospital were screened regarding an underlying cardiovascular cause of death. RESULTS: After validation, 79 out of 1,352 patients remained with a final diagnosis of AMI. Sixty-six percent of these experienced prehospital cardiac arrest or shock. In 37% no resuscitation attempts were performed in hospital, the most common reason being multimorbidity. Only 23% could be transferred to coronary angiography for revascularisation attempts. An independent panel of clinicians judged that only in one patient would another management strategy have been promising. Of interest, 33% of the deceased patients had typical or atypical chest pain the days before the lethal event. CONCLUSION: A large percentage of AMI patients who died soon after hospitalization were in critical circulatory state directly before hospitalization. In 37%, in-hospital resuscitation attempts were omitted for understandable reasons. Options for improvement in acute care in the investigated setting were not found. However, in one third of the cases earlier preventive measures might have been reasonable. PMID- 20714152 TI - Caries experience and quantification of Streptococcus mutans and Streptococcus sobrinus in saliva of Sudanese schoolchildren. AB - Streptococcus mutans and Streptococcus sobrinus are among the most commonly isolated bacterial species implicated as etiological agents of dental caries. Details of the composition of the oral microflora related to dental caries should aid in assessing the prevalence and risk of disease at an individual level. The aim of the present study was to determine the presence and relative amounts of S. mutans and S. sobrinus in the saliva samples obtained from schoolchildren in Khartoum State, the Sudan, and to study the association of the amounts of S. mutans and S. sobrinus with caries experience, socioeconomic status and sugar sweetened snacks in this population. 140 samples, 30 of which were from individuals with caries experience, were examined using quantitative real-time polymerase chain reaction (qRT-PCR) with specific oligonucleotide primers. The mean ratio of fold differences of S. mutans to S. sobrinus was 0.77 (SD 5.4) and 2.29 (SD 6.0) for samples obtained from caries-free and caries-active individuals, respectively. This suggested that the proportion of S. sobrinus was higher than S.mutans in the caries-active group when compared to the caries-free group. An association was found between children with caries-active lesions and the frequent consumption of sticky desserts and higher socioeconomic status. S. sobrinus seems to be associated with caries experience in the studied population. A proposal of caries screening programs designed to test for S. sobrinus in this population may be developed. PMID- 20714153 TI - Infiltration of natural caries lesions with experimental resins differing in penetration coefficients and ethanol addition. AB - Resin infiltration of enamel caries lesions requires materials optimized for penetration into the capillary structures of the lesion body. With increasing penetration coefficients (PC) improved penetration and caries-inhibiting properties of low-viscosity resins (infiltrants) could be observed in artificial caries lesions. The aim of the present in vitro study was to compare the penetrativity of experimental resins varying in PC and ethanol addition into natural caries lesions using this technique. Extracted human molars and premolars showing proximal white spot lesions (International Caries Detection and Assessment System: code 2) were etched for 2 min using 15% hydrochloric acid gel. After drying, the lesions were stained with tetramethylrhodamine isothiocyanate and 1 of 4 experimental resins (PC63; PC185; PC204; PC391) was applied for 5 min. The materials consisted of bisphenol-A-glycidyl-methacrylate (B), tri-ethylene glycol-dimethacrylate (T) and ethanol (E) in ratios (B:T:E) of PC63: 25:75:0; PC185: 20:60:20; PC204: 0:100:0; PC391: 0:80:20. Excess material was removed before light curing. The teeth were sectioned perpendicularly to the lesion surfaces and unbound dye was bleached by immersion in hydrogen peroxide. The remaining lesion pores were stained with fluorescein solution. Lesion and penetration depths were analyzed using confocal microscopy (n = 60). At deep lesion sites the percentage penetration of PC204 was significantly higher compared to PC63 and PC391 (p < 0.05; Mann-Whitney test) but only slightly higher than PC185 (p > 0.05). It can be concluded that materials with high PC (infiltrants) are capable of penetrating almost completely into enamel parts of natural caries lesions in vitro. A solvent-free resin mainly consisting of triethylene glycol dimethacrylate seems to be preferable. PMID- 20714154 TI - Genetic association between PLTP gene polymorphisms and Alzheimer's disease in a Japanese population. AB - BACKGROUND/AIMS: A recent paper reported that the phospholipid transfer protein (PLTP) reduces phosphorylation of tau in human neuronal cells. In addition, patients with Alzheimer's disease (AD) have significantly higher levels of PLTP in brain tissue and significantly lower PLTP-mediated phospholipid transfer activity in cerebrospinal fluid. PLTP also affects apolipoprotein E (APOE) secretion from glial cells. This study aimed to investigate whether single nucleotide polymorphisms (SNPs) of the PLTP gene are associated with AD. METHODS: Five SNPs, genotyped using TaqMan technology, were analyzed using a case-control study design. Furthermore, we also checked for a synergetic association between the PLTP gene, APOE and AD. Our case-control dataset consisted of 180 AD patients and 130 age-matched controls. RESULTS: None of the SNPs showed a statistically significant association. We could not confirm any synergetic association between the SNPs and APOE in our AD patients. CONCLUSION: Our results indicate that there is no genetic association between PLTP and AD. Due to the relatively small sample size and the incomplete coverage of the region surrounding the PLTP gene of this study, larger genetic studies covering the entire PLTP gene region are needed. PMID- 20714155 TI - Awareness of memory abilities in community-dwelling older adults with suspected dementia and mild cognitive impairment. AB - AIMS: To examine awareness of memory abilities by groups (healthy control, suspected dementia/mild cognitive impairment, MCI, and diagnosed dementia/MCI), and to describe group differences in the relationship between awareness and cognitive performance in a community sample. METHODS: In a cross-sectional design, 183 subjects were evaluated in a community setting and categorized into 3 groups based on their cognitive performance and reported medical history. Awareness of memory abilities was quantified using a published anosognosia ratio (AR) comparing the estimated to the objective memory performance by subjects. Each group was further categorized into 'overestimators', 'accurate estimators', and 'underestimators' based on their AR scores. RESULTS: The suspected and diagnosed dementia/MCI groups had significantly higher AR scores than the controls. The suspected group also had a significantly larger proportion (96.2%) of overestimators than the diagnosed (73.3%) and control groups (26.1%). Impaired awareness in overestimators of the suspected and diagnosed groups was correlated with deficits in executive function, language or global cognition. CONCLUSION: Impaired awareness of memory abilities was prevalent in community-dwelling older adults with suspected and diagnosed dementia or MCI. Those with suspected dementia or MCI were more likely to overestimate their memory abilities than their diagnosed counterparts, suggesting that limited awareness of deficits may hinder utilization of dementia diagnostic services. PMID- 20714156 TI - A trophic role for serotonin in the development of a simple feeding circuit. AB - Correct differentiation and positioning of individual synapses during development is fundamental to the normal function of neuronal circuits. While classical transmitters such as serotonin (5-HT) play a critical trophic role in neurogenesis in addition to their functions as transmitters in the mature nervous system, this process is not well understood. We used a simple model to assess both development and function of a specific behavioral circuit in the larval stage of the fruit fly (Drosophila melanogaster). We show that, as in all other species examined, the neurotransmitter actions of 5-HT depress feeding, and decreased neuronal 5-HT levels increase appetite. However, using transgenic tools, we show that constitutive knockdown of neuronal 5-HT synthesis to reduce 5 HT levels during central nervous system (CNS) development results in increased branching of the serotonergic fibers projecting to the gut, as well as increased size and number of varicosities along the neurite length. As larvae, these animals display decreased feeding rates relative to controls, and, when given exogenous 5-hydroxytryptophan, feeding is significantly enhanced. Late-stage wild type embryos exposed to 5-HT to augment 5-HT levels during CNS development display, as mature larvae, a significant decrease in gut fiber branching and total varicosity number, as well as increased feeding and a hyposensitivity to the effects of 5-HT. Exposure of embryos unable to synthesize neuronal serotonin to 5-HT during late embryogenesis results in rescue of the feeding behavior and abnormalities in the 5-HT gut fiber architecture. These results demonstrate an inverse relationship between developmental 5-HT levels and complexity of the fiber architecture projecting to gut tissue, which results in a perturbed feeding pattern. We conclude that 5-HT is tightly regulated during CNS development to direct the normal architecture and mature function of this neural circuit. PMID- 20714157 TI - Association of internal border zone infarction with middle cerebral artery steno occlusion. AB - BACKGROUND: Demonstrating the precise anatomical area of the internal border zone (IB) by brain imaging has been unclear, and it is not well known which relevant arteries are associated with IB infarction. METHODS: Patients with IB infarctions were selected from 748 consecutive patients with acute ischemic stroke. The IB infarctions were identified by coronal diffusion-weighted imaging, excluding lesions over the upper pole of the lateral ventricle. The angiographic findings of the internal carotid artery (ICA) and middle cerebral artery (MCA), on contrast-enhanced MRA, were evaluated in the patients with and without IB infarction. RESULTS: Thirty patients met the criteria for an IB infarction: 7 had MCA steno-occlusion without ICA disease, and 23 had ICA steno-occlusion. Sixty one patients had ICA steno-occlusion without IB infarction. The multiple logistic regression analysis showed that a more than moderate degree of steno-occlusion of the MCA was a significant factor (OR, 11.32; p = 0.006) associated with IB infarction; whereas that of the ICA was not significant (OR, 2.19; p = 0.298). CONCLUSION: The results of this study suggest that IB infarctions were associated with MCA steno-occlusion. ICA disease resulting in IB infarctions would be expected to have significant MCA steno-occlusion causing hemodynamic compromise. PMID- 20714158 TI - Symptomatic hemorrhagic transformation and its predictors in acute ischemic stroke with atrial fibrillation. AB - BACKGROUND AND PURPOSE: Patients with acute cardioembolic stroke frequently show hemorrhagic transformation (HTr). We attempted to identify predictors of symptomatic HTr in acute ischemic stroke with atrial fibrillation (AF). METHODS: Of the consecutive acute ischemic stroke patients with AF at 12 hospitals in Korea, patients with posterior circulation stroke or thrombolytic therapy were excluded. Immediate anticoagulation was recommended to all patients, except those with: (1) large infarcts, 50% or more of the middle cerebral artery territory, (2) significant HTr on initial imaging, or (3) other safety concerns. Symptomatic HTr was defined as cerebral hemorrhage temporally related to neurological deterioration. RESULTS: Of the 389 included patients (mean age 71 years), 260 (67%) were treated with anticoagulation within 1 week from the onset. Symptomatic HTr occurred in 4.6%. Large infarct (OR 6.38, 95% CI 1.16-35.14), previous hemorrhagic stroke (OR 10.67, 1.77-64.25), and low platelet count (OR per 10(4) increase 0.87, 0.79-0.97) were independent predictors of symptomatic HTr. hsCRP values tended to be higher in patients with symptomatic HTr (p = 0.055). CONCLUSIONS: Caution is needed in anticoagulation treatment of acute cardioembolic stroke patients with a large infarct, previous hemorrhagic stroke, low platelet count, or a high hsCRP level. PMID- 20714159 TI - Molecular systematics and phylogeography of the genus Lagothrix (Atelidae, Primates) by means of the mitochondrial COII gene. AB - We propose the first molecular systematic hypothesis on the origin and evolution of Lagothrix taxa based on an analysis of 720 base pairs of the cytochrome c oxidase subunit II mitochondrial gene in 97 Lagothrix specimens. All the current Lagothrix forms probably descended from the ancestor L. poeppigii or perhaps (less probably) that of L. lugens. We detected at least 2 lineages in L. poeppigii. L. cana and L. lagotricha were determined to be monophyletic and had lower gene diversity levels compared to L. poeppigii and L. lugens. The most basal ancestors of the current L. poeppigii lineages diverged from the other Lagothrix taxa around 2.5 million years ago, at the end of the Pliocene or at the beginning of the Pleistocene. Clearly, L. cana and L. lagotricha were the 2 most recently derived Lagothrix taxa. The diversification within L. lugens and L. poeppigii may coincide with the first and second Pleistocene glacial periods, respectively, while the diversification within L. cana and L. lagotricha could have occurred in the last 400,000 years, coinciding with the climatological changes provoked by the Illinois-Riss (third) and Wisconsin-Wurm (fourth) glaciations. PMID- 20714160 TI - Feeding ecology, food availability and ranging patterns of wild hamadryas baboons at Filoha. AB - Most hamadryas baboons rely on Acacia species for subsistence in their semidesert habitats. Unlike other hamadryas sites, palm forests at Filoha in Awash National Park, Ethiopia, provide the baboons with a preferred food resource close to a commonly used sleeping site. The baboons are expected to feed on doum palm trees when fruit is available, and this resource use should play a role in ranging patterns. This paper describes the feeding ecology, food availability and ranging patterns of a band of wild hamadryas baboons at Filoha from March 2005 to February 2006. Data on feeding and ranging behavior derive from band scans during all-day follows of baboons, and data on food availability derive from monthly phenological monitoring of frequently consumed food species. The baboons fed predominantly on palms when fruit was available, and preferred the flowers of Acacia senegal to its leaves. There was no relationship between daily path length and the proportion of palm fruit in the baboons' diet, but changes in the availability of fruit across the Filoha region appear to mirror the baboons' shifting use of its home range. The large band sizes at Filoha may obscure the effects doum palm fruit might have on ranging patterns. PMID- 20714161 TI - Using a pharmacokinetic model to relate an individual's susceptibility to alcohol dependence to genotypes. AB - BACKGROUND/AIMS: Population-based studies have successfully identified genes affecting common diseases, but have not provided a molecular mechanism. We describe an approach for alcohol dependence connecting a mechanistic model at the molecular level with disease risk at the population level, and investigate how this model implies statistical gene-gene interactions that affect disease risk. METHODS: We develop a pharmacokinetic model describing how genetic variations in ADH1B, ADH1C, ADH7, ALDH2, and TAS2R38 affect consumption behavior, and alcohol and acetaldehyde levels over time in various tissues of individuals with a particular genotype to predict their susceptibility to alcohol dependence. RESULTS: We show that there is good agreement between the observed genotype/haplotype frequencies and those predicted by the model among cases and controls. Based on this framework, we show that we expect to observe statistical interactions among these genes for a reasonably large sample size when logistic regression models are used to relate genotype effects and disease risk. CONCLUSION: Our model exemplifies mechanistic modeling of how genes interact to influence an individual's susceptibility to alcohol dependence. We anticipate that this general approach could also be applied to study other diseases at the molecular level. PMID- 20714162 TI - Cinacalcet - clinical and laboratory effectiveness, concomitant treatment patterns and treatment cost: could we do better and how? AB - BACKGROUND: The cost and effectiveness patterns in the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients in the Czech Republic are unknown. METHODS: 52 dialysis patients from 17 centers were followed up in a multicenter prospective study of laboratory and clinical (hospitalization rate, clinical complaints questionnaire) responses to 12-month cinacalcet treatment. Treatment patterns and cost (including phosphate binders, vitamin D, and cinacalcet) were evaluated. RESULTS: The mean s-Ca dropped significantly from 2.36 +/- 0.24 to 2.21 +/- 0.20 mmol/l, s-P from 2.45 +/- 0.54 to 2.01 +/- 0.53 mmol/l, Ca*P from 5.79 +/- 1.25 to 4.42 +/- 1.13 mmol2/l2, and iPTH dropped from 919.0 +/- 465.6 to 372.1 +/- 294.6 pg/ml. The mean cinacalcet dose reached 44.1 +/- 23.0 mg/day after 12 months. Itching intensity decreased significantly. No change in hospitalization rate was observed. The direct cost of daily SHPT treatment rose significantly from EUR 8.77 +/- 9.59 to 20.62 +/- 9.22. CONCLUSIONS: Cinacalcet decreased elevated s-Ca, s-P, Ca*P, and iPTH, alleviated itching, and significantly raised the SHPT treatment cost. A minority of patients reached K/DOQI targets, especially due to poor phosphate control caused by insufficient phosphate binder treatment, cinacalcet underdosing, and advanced SHPT. PMID- 20714163 TI - Change in augmentation index during NOS inhibition, an index of basal NO production, is an independent determinant of large-artery function. AB - BACKGROUND/AIMS: Arterial wave reflection, measured as augmentation index (AIx), and central pulse pressure (PP) closely predict cardiovascular events. We hypothesized that basal nitric oxide (NO) production would be a determinant of AIx and central PP. METHODS: AIx and central PP were assessed at baseline by pulse wave analysis in 86 male subjects across a wide range of age, blood pressure and lipid values. The basal NO production in the cardiovascular system was then determined as change in AIx during NO synthase blockade with N(G) monomethyl-L-arginine (L-NMMA, 3.25 mg/kg). RESULTS: AIx increased from 17.5 +/- 14.6 to 23.1 +/- 14.2 during L-NMMA infusion (p < 0.001). The increase in AIx during NO synthase blockade, an index of basal NO production, was inversely related to baseline central AIx and PP, and positively to PP amplification. Multiple linear regression analyses disclosed that in addition to age and mean blood pressure, change of AIx to L-NMMA is a strong and independent determinant of baseline central AIx, central PP and PP amplification. CONCLUSION: Greater change of AIx to L-NMMA, an index of basal NO production, is associated with better large-artery function. Therefore, therapeutic interventions which increase the basal NO production might be particularly effective in reducing cardiovascular risk. PMID- 20714164 TI - Albuminuria is the stronger risk factor for peripheral arterial disease than eGFR decline in a type 2 diabetic Taiwanese population. AB - BACKGROUND: Several studies have shown the identified risk factors for peripheral arterial disease in individuals with diabetes, but relatively little information has been provided regarding the risk factors for peripheral arterial disease especially in individuals with renal insufficiency and albuminuria. AIMS: In our study, we attempted to determine whether peripheral arterial disease is related to the reduction of estimated glomerular filtration rate (eGFR) or albuminuria in type 2 diabetic patients if both were measured. METHODS: We included 478 type 2 diabetic patients that were more than 50 years old in this study and determined their urine albumin to creatinine ratio and eGFR. The ankle-brachial index was measured. RESULTS: We found a prevalence of peripheral arterial disease of 12 and 11.7% in the normoalbuminuria and >90 ml/min/1.73 m2 eGFR group. Simple logistic regression analysis showed that both macroalbuminuria and eGFR <60 ml/min/1.73 m2 were significantly associated with peripheral arterial disease individually, but most interestingly in the multiple logistic regression analysis, macroalbuminuria and age are independent factors for peripheral arterial disease with a p value of 0.012 (beta = 1.014) and <0.001 (beta = 0.107), respectively. CONCLUSION: In summary, our study indicates that macroalbuminuria is a stronger indicator for peripheral arterial disease than eGFR <60 ml/min/1.73 m2 in a type 2 diabetic population older than 50 years of age. PMID- 20714165 TI - Cystatin C as a parameter of glomerular filtration rate in patients with ovarian cancer. AB - AIMS: To evaluate the potential role of serum cystatin C as a marker of renal function in patients with ovarian cancer. METHODS: Treatment of consecutive ovarian cancer patients who were eligible for chemotherapy with paclitaxel (135 mg/m2/24 h) and cisplatin (75 mg/m2) every 3 weeks in 6 cycles. Glomerular filtration rate (GFR) markers, i.e. serum levels of creatinine and cystatin C, estimated by the Cockcroft-Gault and Modification of Diet in Renal Disease formulas, were recorded before each cycle and 3 weeks after the 6th course. RESULTS: The median age of 34 patients was 54 years. In the initial stage of treatment, we did not observe any correlation between cystatin C and other GFR markers. We noted a significant association between cystatin C and tumor extent on spiral CT scans (diameter: >1 cm) performed at baseline (p = 0.004), and after the 1st (p = 0.03) and 2nd cycle (p = 0.026). We observed a correlation between cystatin C and CA-125 level before chemotherapy (R = 0.4; p = 0.02) and after the 1st cycle (R = 0.43; p = 0.04). CONCLUSION: The results of our study suggest that cystatin C is not a reliable marker of the GFR in ovarian cancer patients, probably due to its nature as a cysteine protease inhibitor. PMID- 20714166 TI - Effect of sevelamer hydrochloride exposure on carotid intima media thickness in hemodialysis patients. AB - BACKGROUND: Elevated phosphorus (P) and calcium (Ca)-P product (Ca * P) are associated with vascular calcification and cardiovascular disease (CVD) morbidity and CVD and all-cause mortality. OBJECTIVES: This study examined the effect of sevelamer hydrochloride exposure (regardless of calcium carbonate exposure) on carotid and femoral intima media thickness (IMT), reliable surrogate measures of prospective intimal thickening, in end-stage renal disease patients on maintenance hemodialysis. METHODS: The present cross-sectional study is nested in the Sevelamer hydrochloride and ultrasound-measured femoral and carotid intima media thickness progression in end-stage renal disease (SUMMER) clinical trial. Carotid and femoral arteries were visualized in B-mode ultrasonography. Log transformed IMT was compared by sevelamer hydrochloride exposure and modeled using multiple linear regression. RESULTS: Forty-five subjects were exposed to sevelamer hydrochloride and 130 were not. Exposed subjects had significantly lower carotid IMT, an association which persisted in the multiple linear regression model even after controlling for potentially confounding variables including serum Ca, history of CVD and body weight. Exposed subjects had lower low-density lipoprotein cholesterol levels and significantly higher parathyroid hormone, but no differences in P, Ca and Ca * P. CONCLUSIONS: Sevelamer hydrochloride was associated with lower carotid IMT. This association may be mediated through reduction in Ca load, low-density lipoprotein cholesterol lowering or some other pleiotropic effect. PMID- 20714167 TI - C-reactive protein and mortality in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). AB - BACKGROUND: We examined associations of C-reactive protein (CRP) levels with mortality in Japanese hemodialysis patients and trends in prevalence of CRP measurement at hemodialysis facilities internationally. To assess whether measurement of CRP may influence outcomes, we examined associations of facility prevalence of CRP measurement with mortality. METHODS: CRP measurements were from a cross-section of patients in the international Dialysis Outcomes and Practice Patterns Study (n = 610 facilities, 16,355 patients). Cox proportional hazards models assessed associations of mortality with CRP in Japan, and with a facility's frequency of measuring CRP internationally, (except in the USA and Canada). RESULTS: From 2002-2004, CRP was measured in 0-19% of patients in each country, except Japan (55%). From 2005-2007, CRP was measured in >= 50% of country patients except in Canada (15%) and the USA (2%). After multivariable adjustment, the hazard ratio (HR) of death was 1.6- to 2.4-fold higher (p < 0.05) for various categories of CRP levels >3 mg/l (vs. <1.0 mg/l). Cardiovascular mortality risk was lower in facilities measuring CRP for >= 50% of patients (HR = 0.72, p = 0.01) in multivariable-adjusted analyses. CONCLUSIONS: CRP is informative regarding mortality risk beyond that provided by other inflammatory and nutritional markers, with significantly higher risk seen at CRP >3 mg/l. Greater use of CRP may lead to improved patient care as suggested by the association of greater CRP measurement with lower cardiovascular mortality. PMID- 20714168 TI - Serum adiponectin, TNF-alpha, IL-12p70, and IL-13 levels in multiple sclerosis and the effects of different therapy regimens. AB - OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory disease of the human central nervous system. In the present study, we aimed to determine adiponectin, tumor necrosis factor-alpha, interleukin (IL)-12p70, and IL-13 levels in the sera of patients with MS and to investigate the effects of interferon (IFN), glatiramer acetate (GA), and immunosuppressive treatment regimens on these parameters. METHODS: Fifty-seven patients with MS and 34 healthy controls were enrolled into the study. Serum cytokine levels were measured using enzyme immunoassay. RESULTS: Significantly elevated levels of IL 12p70 and IL-13 were found in the sera of patients with MS, but decreased adiponectin levels were found in patients' sera compared to healthy controls. The levels of IL-12p70 and IL-13 in the IFN therapy group were higher than those of the healthy controls. However, the IL-12p70 and IL-13 levels in the GA therapy group were not different from those of the healthy controls. There were no differences with regard to adiponectin levels among the subgroups of patients with MS according to therapy regimen and the healthy controls. At the end of a 2 year follow-up period, Expanded Disability Status Scale (EDSS) values were found to be increased in the IFN therapy group but unchanged in the GA therapy group. CONCLUSIONS: These findings suggest that adiponectin, IL-12p70, and IL-13 may play a role in the pathogenesis of MS. Additionally, GA therapy regimens in MS are more effective than IFN therapy with respect to decreasing the levels of IL 12p70 and IL-13 and stabilizing the EDSS value. PMID- 20714169 TI - Associations between brain-derived neurotrophic factor plasma levels and severity of the illness, recurrence and symptoms in depressed patients. AB - BACKGROUND: There is increasing evidence that the brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of mood disorders and that its peripheral levels represent a reliable mirror of its concentration in the brain. The aim of the present study was to measure BDNF plasma levels in patients affected by major depression and to explore the possible relationship between the biological parameter and characteristics of the illness. METHOD: BDNF plasma levels were evaluated in 30 inpatients suffering from major depression, according to DSM-IV criteria, by means of a commonly employed ELISA method. The clinical characteristics were assessed by the Hamilton Rating Scale for Depression (HRSD) and the Clinical Global Impression Scale. RESULTS: BDNF plasma levels were significantly lower in the patients with the severest illness compared with the others, and the same was true for patients with dissociative symptoms, severe sleep disturbance and recurrent depression. A significant and negative correlation was observed between the biological parameter and the retardation factor score of the HRSD. CONCLUSION: These findings suggest that low BDNF levels are related to both recurrence and severity of depression, as well as to symptoms typical of dysfunctions of the hypothalamic-pituitary-adrenal axis. PMID- 20714170 TI - Electropharmacograms of rasagiline, its metabolite aminoindan and selegiline in the freely moving rat. AB - BACKGROUND: Rasagiline and selegiline are classified as monoamine oxidase B (MAO B) inhibitors. The present investigation deals with time-dependent electrical frequency changes (electropharmacograms) induced by these, as well as by aminoindan, the major metabolite of rasagiline. METHOD: Adult rats (day-night converted, >5 months old) were fitted with 4 bipolar concentric steel electrodes connected to a small base plate, which was positioned stereotactically for insertion of the electrodes into the frontal cortex, hippocampus, striatum and reticular formation. The plate carried a small plug to receive a telemetric device during the experimental session. Changes in field potentials were recorded during a pre-drug reference period of 45 min, followed by intraperitoneal administration and 5 h of recording thereafter. Data were transmitted wirelessly for frequency analysis. Data from 10 animals treated within a crossover design were averaged. RESULTS: A dose of 0.25 mg/kg i.p. rasagiline produced statistically significant decreases in spectral alpha2 and beta1 power. Higher dosages showed a linear enhancement of this effect. A similar pattern was obtained after administration of aminoindan (2-10 mg/kg), but of shorter duration. Selegiline produced a similar pattern only for the first 1-2 h. After this, statistically significant increases in delta and theta power were observed. CONCLUSION: Despite the feature of MAO-B inhibition in both drugs and its reflection in the initial changes of the frequency pattern during the first hour, the pharmacological action of selegiline during the following hours differs profoundly from that of rasagiline, presumably due to the toxicity of its major metabolites methamphetamine and amphetamine. PMID- 20714171 TI - Gender differences in cognitive ability associated with genetic variants of NLGN4. AB - Neuroligin-4 (NL4), encoded by the NLGN4 gene on the X chromosome, is a neuronal specific brain membrane protein which plays an important role in the formation of functional presynaptic elements and axon specialization. The genetic variants of NLGN4 affect the biological function of NL4, resulting in the manifestation of different psychiatric disorders. The present study investigates the influence of these genetic variants on cognitive performance. The cognitive abilities of 351 subjects were evaluated using the Chinese Wechsler Intelligence Scale Children. The haplotypes were assigned with the PHASE program. The ANOVA method was applied to investigate the relationship between single SNP, the identified target haplotypes and cognitive performance in a random sample. We observed that the X(C) allele of rs5916271 and X(A) allele of the re6638575 carriers had significantly higher cognitive ability performances than the noncarrier boys (p < 0.05). The target haplotype composed of 2 allele (X(CA+)) carriers also displayed a higher cognitive performance than that of the noncarriers boys. The genetic polymorphism of NLGN4 also had a significant effect on the boys' cognitive ability and other intelligence factors. Future research will involve determining the relationship between NLGN4 and personal cognitive ability. PMID- 20714172 TI - Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy. AB - AIM: The aim of the study was to evaluate serum brain-derived neurotrophic factor (BDNF) levels in a group of euthymic bipolar patients on long-term prophylactic lithium treatment and to delineate putative relationships between lithium efficacy and BDNF concentrations. METHODS: 141 euthymic bipolar patients (51 male, 90 female) on long-term lithium treatment were studied. Three categories of prophylactic lithium response were delineated: excellent lithium responders (ER; 30 patients), partial lithium responders (PR; 61 patients) and lithium nonresponders (NR; 50 patients). The control group consisted of 75 age- and gender-matched healthy subjects. RESULTS: The lithium-treated patients as a whole group had lower BDNF levels compared to the healthy controls. However, after breaking down the patients into ER, PR and NR, it appeared that only NR had significantly lower BDNF levels compared with the healthy control subjects. No association between the age of the patients, duration of bipolar illness, and serum lithium and BDNF levels was found. CONCLUSION: The results point to a relationship between lithium prophylactic efficacy and plasma BDNF levels in euthymic bipolar patients where lithium NR had reduced BDNF levels. These findings suggest that serum BDNF is associated with lithium efficacy in bipolar disorder. PMID- 20714173 TI - When faces signal danger: event-related potentials to emotional facial expressions in animal phobics. AB - Attentional bias research indicates that specific phobics prioritize the processing of disorder-relevant stimuli, although the time course of attentional allocation to the phobic threat remains unclear. The present study employed event related potentials (ERPs) to investigate whether a processing bias also exists towards specific facial expressions that are able to signal potential phobic cues in the environment. Fifteen women with snake phobia and 15 healthy controls performed an attention-shifting task in which angry, fearful, disgusted and neutral faces were presented as emotional cues. ERP to facial expressions and reaction times to target stimuli were collected during the task. The P200 amplitude was significantly lower in phobics than in controls, specifically in response to facial expressions of fear and disgust. Such reduction in cortical activity may reflect reduced processing associated with rapid cognitive avoidance. Such an avoidance response would not be determined by the threat value of the face stimuli per se, but rather by the ability of fearful and disgusted faces to avert attention by signaling a possible phobic threat in the surrounding area. In addition, phobics showed relatively greater positivity to negative than neutral facial expressions in the later processing stages, indicating a general hypervigilant processing mode. PMID- 20714174 TI - Steroids and management of macular edema. Introduction. PMID- 20714175 TI - Diagnosis of macular edema. AB - Macular edema may be intracellular or extracellular. Intracellular accumulation of fluid (cytotoxic edema) is an alteration of the cellular ionic distribution. Extracellular accumulation of fluid is more frequent and clinically more relevant, and is directly associated with an alteration of the blood-retinal barrier. Fluorescein angiography has been critical for detecting macular edema and currently remains the 'gold standard' for its diagnosis by identifying the characteristic stellar pattern of cystoid macular edema, also providing a qualitative assessment of vascular leakage essential for identifying treatable lesions. The clinical diagnosis of macular edema, recognition of its main etiologies and its treatment have greatly improved due to multiple and remarkable advances in modern imaging technologies. By correlating results from fluorescein angiography and optical coherence tomography (OCT), fluid accumulation within and under the sensory retina can be confirmed and located. We are now able to measure changes in retinal thickness and use noninvasive instrumentation in a clinical setting to identify macular edema. Moreover, spectral-domain OCT can characterize the presence and integrity of the external limiting membrane and the photoreceptor inner and outer segments, which is useful information for prognosis as well as a guide for treatment. The diagnosis of macular edema and its clinical forms is now based primarily on the correlation of these imaging techniques. PMID- 20714176 TI - Pathophysiology of macular edema. AB - Macular edema is defined as an accumulation of fluid in the outer plexiform layer and the inner nuclear layer as well as a swelling of Muller cells of the retina. It consists of a localized expansion of the retinal extracellular space (sometimes associated with the intracellular space) in the macular area. Macular edema is a common cause of a sudden or chronic decrease in visual acuity occurring in many ocular diseases such as age-related macular degeneration, diabetic retinopathy and retinal vein occlusion. As a nonspecific sign of many intraocular and systemic diseases, macular edema represents a common final pathway. The existence of the blood-retinal barrier (BRB) formed by intercellular junctions is the precondition required to maintain this physiological status. This status may become severely disturbed by many diseases, finally resulting in macular edema. In this article, the development of macular edema will also be classified by its pathophysiological and pathobiochemical pathways. Vascular components, the dysfunctional BRB, the role of proteins and water fluxes as well as the role of several inflammatory mediators (e.g. angiotensin II, vascular endothelial growth factor, prostaglandins) in the retina will be discussed as responsible mechanisms leading to the development of macular edema. PMID- 20714178 TI - Differentiating intraocular glucocorticoids. AB - BACKGROUND: Natural corticosteroids (e.g. hydrocortisone) and synthetic selective glucocorticoid (GC) agonists have been used by ophthalmologists for decades to treat various forms of ocular inflammation. More recently, increased clinical use of locally delivered GC has shown significant benefit for the treatment of multiple retinal indications including macular edema associated with uveitis, retinal vascular occlusions and diabetes. Our current understanding of the clinical utility of specific intraocular GC far surpasses our knowledge of their biologic and pharmacologic activities in the eye. OBJECTIVE: To present an update on GC receptor (GR) biology in general and as it applies to the eye, and discuss the pharmacokinetics, delivery and pharmacology of the commonly used intraocular GC dexamethasone (DEX), triamcinolone acetonide (TA) and fluocinolone acetonide (FA). RESULTS: DEX, TA and FA are structurally similar but significantly differentiated by their aqueous and lipid solubility, delivery system requirements, pharmacokinetics and interactions with functional GR. Culture of human trabecular meshwork cells and full transcriptome microarray analysis reveals that DEX, TA and FA generate unique gene transactivation and repression profiles as well as potentially distinct biologic responses that are not only steroid structure dependent, but also dose and time dependent. Finally, DEX and FA markedly protect photoreceptors from degenerating in animal models of excessive light and retinitis pigmentosa, respectively. CONCLUSION: It is tempting to speculate that the unique pharmacokinetic and pharmacologic profiles of the commonly used intraocular steroids and novel future drugs may reveal significant differences in their therapeutic value in patients with macular edema or other inflammatory disease, in their ocular adverse side effect profile, and their ability to normalize glial and neuronal function in diseased retina. PMID- 20714177 TI - The multifactorial nature of retinal vascular disease. AB - Retinal vascular disease is the most common cause of macular edema (ME). While there are several etiologies of vascular compromise and subsequent macular leakage, diabetic retinopathy is the most prevalent and continues to challenge ophthalmologists and frustrate patients due to its refractory nature. In response to this epidemic, diabetic ME (DME) along with cystoid ME (CME) have been areas of active investigation both in the clinic and the laboratory. Several decades of basic science research have revealed a growing and complex array of cytokine growth factors and proinflammatory mediators which are capable of inciting the cellular changes that result in accumulation of fluid within the retina. Much of this new molecular foundation provides the current and fundamental scaffold for understanding the pathologic process of ME while simultaneously identifying potential therapeutic targets. Whereas CME has classically been treated with corticosteroids and nonsteroidal antiinflammatory drugs, recent clinical studies have demonstrated improved visual outcomes for DME treatment with light focal/grid laser, corticosteroids and anti-vascular endothelial growth factor antibodies. Yet, each of these treatments has differential effects on the multifactorial mechanisms of ME. This article reviews the anatomical, cellular and molecular derangements associated with ME and highlights specific pathways targeted by current treatments. PMID- 20714179 TI - Steroids and the management of macular edema. AB - Macular edema (ME) is a condition which is usually secondary to an underlying disease process. It is most commonly seen following venous occlusive disease, diabetic retinopathy and posterior segment inflammatory disease. The treatment of ME varies, depending upon the underlying etiology, and has led to varying degrees of success. Traditionally, the main treatment options have included topical and systemic steroids, due to their known antiangiogenic, antiedematous, antiinflammatory and antiproliferative effects. This comprehensive review outlines the current use of steroids and highlights the ever-growing indications for steroids in ME secondary to various ocular conditions as well as the recent breakthrough results of the efficacy of this treatment. PMID- 20714180 TI - Steroids as part of combination treatment: the future for the management of macular edema? AB - Diabetic macular edema (DME), defined as a retinal thickening involving or approaching the center of the macula, plays a major role in vision loss related to diabetic retinopathy. This article presents an in-depth analysis of therapeutic perspectives on DME by means of an approach based on combination therapy with steroids. Corticosteroid drugs have been demonstrated to both inhibit the expression of vascular endothelial growth factor (VEGF) and the VEGF gene, and to have antiinflammatory properties. A treatment algorithm is provided regarding the management of DME. While grid laser photocoagulation remains the first-line therapy for focal vasogenic DME, diffuse DME can be effectively treated by means of intravitreal injections of corticosteroids. Recalcitrant DME can also be managed beneficially with intravitreal steroids. The management of DME is complex, and often multiple treatment approaches are needed. Each form of DME should be properly classified and specifically treated. The combination treatment has still an important role in the combined treatment options for DME. PMID- 20714181 TI - New developments in corticosteroid therapy for uveitis. AB - Corticosteroids remain the mainstay of the management of patients with uveitis. Topical corticosteroids are effective in the control of anterior uveitis, but vary in strength, ocular penetration and side effect profile. Systemic corticosteroids are widely used for the management of posterior segment inflammation which requires treatment, particularly when it is associated with systemic disease or when bilateral ocular disease is present. However, when ocular inflammation is unilateral, or is active in one eye only, local therapy has considerable advantages, and periocular injections of corticosteroid are a useful alternative to systemic medication and are very effective in controlling mild or moderate intraocular inflammation. More recently, the injection of intraocular corticosteroids such as triamcinolone have been found to be effective in reducing macular oedema and improving vision in uveitic eyes which have proved refractory to systemic or periocular corticosteroids. The effect is usually transient, lasting around 3 months, but can be repeated although the side effects of cataract and raised intraocular pressure are increased in frequency with intraocular versus periocular corticosteroid injections. This has led to the development of new intraocular corticosteroid devices which are designed to deliver sustained-release drugs and obviate the need for systemic immunosuppressive treatment. The first such implant was Retisert, which is surgically implanted (in the operating theatre) and is designed to release fluocinolone over a period of about 30 months. More recently, Ozurdex, a 'bioerodible' dexamethasone implant which can be inserted in an office setting, has completed phase III clinical trials in patients with intermediate and posterior uveitis. This implant lasts approximately 6 months, and has been found to be effective with a much better side effect profile than Retisert or intravitreal triamcinolone injection, at least for one injection. PMID- 20714182 TI - Association of the preoperative photoreceptor layer defect as assessed by optical coherence tomography with the functional outcome after macular hole closure: a long follow-up study. AB - BACKGROUND: to evaluate the correlation between the extent of the inner/outer segment (IS/OS) defect preoperatively and improvement in postoperative best corrected visual acuity (BCVA) associated with IS/OS line restoration. METHODS: forty-six eyes (46 patients) with successfully operated idiopathic full-thickness macular holes were studied using Stratus OCT3 with a mean follow-up of 34.7 months (range 24-60 months). The preoperative extent of the IS/OS junction defect, macular hole base diameter (MHBD) and BCVA were studied before surgery. The degree of IS/OS line restoration, macular thickness and BCVA were measured after treatment. RESULTS: the mean preoperative MHBD and IS/OS defect size were 783 and 1,973 MUm, respectively. Postoperative continuity of the IS/OS junction was observed in 11 of 46 cases 12 months after treatment. In the remaining 35 patients, the IS/OS line was interrupted at 12 months of follow-up. The size of the preoperative IS/OS defect line was negatively correlated with the size of the postoperative IS/OS line and BCVA at 6 months and 12 months only (p < 0.0001). In all 46 eyes, the mean BCVA before and 12 months after treatment was 10 and 36.7 letters, respectively. BCVA remained almost unchanged after the first postoperative year of observation. CONCLUSIONS: the degree of reorganization of the photoreceptor layer after successful macular hole closure varies and is mostly related to the preoperative extent of the IS/OS defect line and the MHBD. A small-sized IS/OS preoperative defect favors improvement and restoration of the IS/OS line after treatment. The IS/OS junction line and BCVA are mostly restored during the first 12 months after treatment. PMID- 20714183 TI - The prognostic value of the wuerzburg bleb classification score for the outcome of trabeculectomy. AB - BACKGROUND: the Wuerzburg bleb classification score (WBCS) aims at an objective and standardized assessment of the developing filtering bleb after trabeculectomy, in order to detect and treat bleb scarring at the earliest possible stage of development. The purpose of this retrospective study was to evaluate the prognostic value of the early postoperative WBCS for the long-term outcome of trabeculectomy. METHODS: the WBCS is a grading system for clinical bleb morphology. It evaluates the following parameters: vascularization, corkscrew vessels, encapsulation and microcysts. The WBCS of 113 eyes of 113 consecutive patients after trabeculectomy was determined 1 day, 1 and 2 weeks, 3, 6 and 12 months after surgery. Complete success was defined as an intra-ocular pressure (IOP) <21 mm Hg and >20% pressure reduction without glaucoma medication after 1 year. RESULTS: a complete success rate of 73.9% and a qualified success rate of 82.4% were achieved 1 year after surgery. The average total bleb score during follow-up in the success group was always higher than in the failure group, but there was no statistically significant difference at any time. The bleb average score for eyes with an IOP of <= 12 mm Hg after 2 weeks was significantly higher (p = 0.005) than for eyes with an IOP >= 13 mm Hg at the end of follow-up. CONCLUSION: patients with a higher early WBCS postoperatively had a significantly lower IOP 1 year after surgery. However, the study could not reveal a certain prognostic value of the early total bleb score using the WBCS for the long-term complete success of trabeculectomy. PMID- 20714184 TI - Use of the double-pass technique to quantify ocular scatter in patients with uveitis: a pilot study. AB - PURPOSE: to assess whether the double-pass technique can be employed to quantify the amount of light scattering in patients with uveitis. METHODS: 56 eyes of 44 patients with intraocular inflammation were consecutively recruited from the uveitis clinic over 9 months. The degree of intraocular inflammation was recorded according to the Standardization of Uveitis Nomenclature criteria and the eyes were grouped as having anterior, intermediate, posterior or panuveitis. Objective scatter index (OSI) was assessed using a double-pass technique with the Optical Quality Analysis System II. RESULTS: twenty-four eyes had anterior uveitis, 9 eyes had intermediate uveitis, 10 eyes had posterior uveitis and 13 eyes had panuveitis. The OSI was significantly different between all 4 groups (p = 0.0005). The mean OSI was highest in eyes with anterior uveitis (2.6 +/- 3.1) and lowest in posterior uveitis (1.9 +/- 1.3). Anterior chamber cells significantly correlated with OSI (R(2) = 0.8726, p = 0.007), unlike posterior chamber cells (R(2) = 0.0189, p = 0.588) and flare (R(2) = 0.0048, p = 0.471). CONCLUSION: patients with anterior uveitis have more ocular scatter, and anterior chamber cells scatter more light. This pilot study opens new avenues for research in use of the double-pass technique to assess light scattering in uveitis. PMID- 20714185 TI - Bone marrow-derived cells in neovascular age-related macular degeneration: contribution and potential application. AB - Neovascular age-related macular degeneration, characterized by the formation of choroidal neovascularization (CNV), is a predominant cause of serious loss of vision. The pathogenesis of CNV is complex and still imperfectly understood. Prior studies have shown that bone marrow-derived cells (BMC) play a role in CNV. In this review article, we describe the contribution of BMC to CNV development, and discuss the potential use of BMC in the anticipation and treatment of CNV associated diseases as well as research needs in the future. PMID- 20714186 TI - Chemokine expression of intraocular lymphocytes in patients with Behcet uveitis. AB - BACKGROUND: To compare the expression of chemokines in the aqueous humor and chemokine receptors in intraocular lymphocytes from Behcet and non-Behcet uveitis patients. METHODS: A total of 95 uveitis patients were included in this study. We studied 39 Behcet and 56 non-Behcet uveitis patients. Flow cytometric analysis was performed using lymphocytes from the aqueous humor and the peripheral blood during the active phase of intraocular inflammation. We compared the expression of CXCR1, CXCR3, and CCR5 in CD4+ and CD8+ T lymphocytes and the concentration of intraocular CXCL8, CXCL10 and CCL5 in Behcet and non-Behcet patients. RESULTS: The CD4+ cell population was higher in the aqueous humor of non-Behcet patients, whereas the CD8+ cell population was higher in the aqueous humor of Behcet patients. The expressions of CXCR1 and CCR5 were not significantly different between the two groups, whereas the intraocular expression of CXCR3 was higher in the CD4+ cells of non-Behcet and in the CD8+ cells of Behcet uveitis patients. Intraocular CXCL8 and CXCL10 levels were higher in Behcet than they were in non Behcet patients. CCL5 levels were not different between the groups. CONCLUSIONS: This suggests that the expression of chemokines and chemokine receptors in intraocular lymphocytes is different in Behcet compared to non-Behcet uveitis patients, which might be related to the differential phenotypes of intraocular lymphocytes among different uveitis etiologies. PMID- 20714187 TI - Bevacizumab (Avastin) as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy: a prospective case series. AB - PURPOSE: To evaluate the role of preoperative intravitreal bevacizumab as an adjunct to vitrectomy in diabetic eye disease. METHODS: Twenty eyes of 18 patients were recruited and underwent a single intravitreal injection of bevacizumab 1.25 mg 1 week prior to vitrectomy. Fundus fluorescein angiography (FFA) was done before and 1 week after injections. Best corrected visual acuity (BCVA) and ophthalmic evaluation were done before, 1 week after injections, 1 day, 1 week and monthly for 3 months after vitrectomy. RESULTS: The mean age was 47.7 +/- 10.39 years. The male:female ratio was 2:3. Mean preinjection BCVA (logMAR) was 1.460 +/- 0.439. FFA showed a dramatic reduction in dye leakage 1 week after injection. Intraoperative bleedings were minimal in most cases (85%, n = 17). Postoperatively, 16 patients had no bleeding (80%), 4 had minimal bleeding (20%), and 1 had recurrent fibrovascular proliferation (5%). The mean BCVA on day 1, week 1, months 2 and 3 after surgery were 1.645 +/- 0.422, 1.300 +/- 0.413, 1.065 +/- 0.538 and 1.065 +/- 0.538 logMAR, respectively (p = 0.078, 0.123, 0.002 and 0.002, respectively). CONCLUSION: Bevacizumab administered prior to vitrectomy was well tolerated and was particularly useful during surgery. PMID- 20714188 TI - Serum concentration of bevacizumab after intravitreal injection in experimental branch retinal vein occlusion. AB - AIM: To compare the serum concentration of bevacizumab after intravitreal injection of bevacizumab (IVB) in an experimental model of branch retinal vein occlusion (BRVO) with control injections in albino rats. METHODS: BRVO was created in one eye of each of the 24 albino rats. Another 24 rats served as controls. The BRVO was generated by argon laser photothrombosis after intravenous injection with Rose Bengal. Three days later, IVB (5 MUl) was administered to both BRVO and control eyes. The serum concentration of bevacizumab was examined at baseline, 6 h, 1 day, 3 days, 7 days, 14 days, and 28 days after IVB. RESULTS: At baseline, no serum bevacizumab was detected in either group. The serum concentration of bevacizumab reached a peak concentration at 1 day with 5,020 +/- 1,602 ng/ml in the BRVO group and 4,103 +/- 1,790 ng/ml in the control group (p < 0.001). The concentration decreased subsequently on days 3, 7, 14 and 28. The serum concentration of bevacizumab was significantly higher in BRVO rats up to 28 days after IVB. CONCLUSIONS: The serum concentration of bevacizumab after IVB reached its peak on day 1 in both BRVO and control eyes. This value was significantly higher in BRVO rats than in control rats up to 28 days after intravitreal injection. PMID- 20714189 TI - Is prevalence of retinopathy related to the age of onset of diabetes? Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Report No. 5. AB - AIM: To compare the prevalence of diabetic retinopathy (DR) and risk factors in patients with a known onset of diabetes before 40 years and after 40 years of age. METHODS: This is a population-based study for which 1,414 diabetics were recruited. The fundi were photographed using 45-degree 4-field stereoscopic digital photography. The diagnosis of DR was based on Klein's classification of the Early Treatment Diabetic Retinopathy Study scales. RESULTS: The prevalence of DR was 33.3% (95% confidence interval, CI: 26.6-39.9) in known onset of diabetes (<= 40 years) compared to 15.6% (95% CI: 13.6-17.6) in those with late onset (> 40 years; p < 0.0001). In the group with age of known onset of diabetes <= 40 years, the risk factors, associated with any DR, were poor glycemic control (odds ratio, OR: 1.36 for every g% increase in glycosylated hemoglobin), insulin use (OR: 4.21), increasing known duration of diabetes (OR: 1.10 for increase of every year in known duration of diabetes) and presence of macroalbuminuria (OR: 13.39). In the late onset of diabetes group, besides the above-mentioned risk factors, the presence of microalbuminuria (OR: 2.08), male gender (OR: 1.67), presence of anemia (OR: 1.89) and increased systolic blood pressure (OR: 1.01) were the risk factors for DR. CONCLUSION: The prevalence of DR was almost twice more in those subjects who developed diabetes before the age of 40 years than those who developed it later. PMID- 20714190 TI - Effects of propofol and isoflurane anesthesia on the intraocular pressure and hemodynamics of pigs. AB - To determine the conditions under which anesthetized pigs can be used in acute noninvasive investigations of ocular hydro- and hemodynamics, the intraocular pressure (IOP) of adult pigs was recorded under the following conditions: (1) after intravenous injection of propofol plus ketamine; (2) during inhalation of isoflurane, and (3) 2 h after topical administration of bimatoprost or (4) timolol. Propofol/ketamine and isoflurane induced significant decreases in the IOP. The pulsation of the ophthalmic artery appeared at a significantly higher IOP in animals anesthetized with isoflurane than in those anesthetized with propofol/ketamine. Bimatoprost and timolol did not significantly decrease the IOP within 2 h after topical administration. It is concluded that different techniques for the acute noninvasive investigation of ocular hydro- and hemodynamics are applicable in anesthetized pigs. To test the effects of antiglaucoma agents, investigation periods longer than 2 h are required. We recommend the use of intravenous propofol/ketamine anesthesia rather than isoflurane anesthesia in future experiments using pigs. PMID- 20714191 TI - Association between changes in visual acuity and vision-related quality of life in Japanese patients with low vision. AB - PURPOSE: To investigate the association between vision-related quality of life (VRQOL) and changes in visual acuity (VA). METHODS: We examined the VA in 100 patients for > 1 year and evaluated the degree of its impact on VRQOL using the National Eye Institute Visual Function (VF) Questionnaire (VFQ-25; Japanese version). Before determining VFQ-25, we monitored the changes in VA in these patients for 1 year and classified them into the following two groups depending on VA changes. Patients exhibiting a decline of > 3 steps in VA, as assessed by the logarithm of the minimum angle of resolution scale, were placed in the 'decline' group (47.0%) and patients exhibiting no change in VA were placed in the 'no change' group (53.0%). We compared the VFQ-25 scores between both groups in all patients with glaucoma (GLA) and macular degeneration (MD). RESULTS: The total score of the decline was 34.9 +/- 13.6 and that of the no change group was 44.6 +/- 13.9: the difference in the scores between both groups was statistically significant (p = 0.006). Similar results were obtained for patients with GLA and MD (p = 0.007 and 0.003, respectively). CONCLUSION: VRQOL differed between patients with constant VA and those with reduced VA, even though VA values were equal at a certain time point. PMID- 20714192 TI - Association of strength of religious adherence with attitudes regarding glaucoma or ocular hypertension. AB - BACKGROUND: To evaluate the impact of religious adherence on a patient's outlook on disease in a glaucoma population. METHODS: A prospective survey analysis of patients with open-angle glaucoma or ocular hypertension evaluating self-reported global religious adherence, adherence to specific basic activities and knowledge of faith ('maturity') and 'comfort' (ability to cope, attitude toward glaucoma, motivation to take medication and God's concern). This specific analysis was limited to self-professed Christians. RESULTS: 248 patients were included and religious adherence was correlated to religious activity and knowledge (p < 0.0001). Patients who scored as adherent on at least 1 of 4 maturity questions had greater benefit than less adherent patients from each of the 5 comfort questions (p < 0.0001). We found an increased statistical separation on each of the 5 comfort questions between religiously adherent and less adherent individuals for patients who scored as adherent on any 2 (n = 40), 3 (n = 50) or all 4 (n = 57) of the maturity questions (p < 0.001). CONCLUSIONS: This study suggests, at least for the Christian faith, that religious patients are subjectively more prone to cope with treatment and that religiosity increases the self-confidence, and possibly the quality of life, of patients with glaucoma or ocular hypertension. Whether this necessarily translates into better glaucoma practices remains to be demonstrated by further studies. PMID- 20714193 TI - Gene expression profile determination in rat retinal tissue after ocular hypertension through oligo microarray. AB - Increased intraocular pressure is the main cause of glaucoma development. However, the systemic information of genes related to ocular hypertension has not yet been clarified. In the present study, oligomicroarray determined the profile of gene expression in the retina after ocular hypertension. A rat ocular hypertension model was constructed through photocoagulation by diode lasers. On postoperative days 7, 35, 60, 90, 180 and 360, the intraocular pressure and the gene expression profile were determined using an ophthalmotonometer and an Oligochip containing 35,000 oligonucleotides, respectively. Oligochip reliability was verified by real-time PCR, and the Oligochip data were analyzed through functional distribution analysis. In our study, we found that the intraocular pressure was significantly increased in a time-dependent manner but returned to the normal level on postoperative day 360. We also found that 1,692 genes were differentially expressed, including 719 upregulated and 973 downregulated genes. The chi2 value of gene clusters related to transport function is significantly higher than that of other gene clusters as determined through function distribution analysis, suggesting that this group of genes plays an important role in the repair process of the optical nerve. In conclusion, the gene expression pattern at different time points of ocular hypertension was determined, which may contribute to clarify the molecular mechanism of glaucoma and to establish better therapeutic strategies to treat glaucoma. PMID- 20714195 TI - Epidemiology of diabetic retinopathy in Egypt: a hospital-based study. AB - PURPOSE: To determine the prevalence and determinants of diabetic retinopathy (DR) in patients >=18 years at the Cairo University and Sixth of October University hospitals. PATIENTS AND METHODS: This is a cross-sectional survey among known diabetic patients attending diabetic clinics. Patients were randomly selected to complete an interviewer-administered questionnaire and a medical assessment. All patients had a dilated fundus examination for evidence of DR using slit-lamp biomicroscopy. RESULTS: A sample of 1,325 patients was selected with a mean age of 49 years (SD +/-12.9). DR was found in 20.5% of patients. Most patients (82%) were not aware of the hazards of diabetes mellitus for the eyes. The prevalence of DR was statistically significantly higher in females (22 vs.17%, p < 0.05), with longer diabetes disease duration (p < 0.001), hypertension (p < 0.001) and absence of hypertension control (p < 0.001), especially proliferative DR. Increasing age and poor glycemic control were associated with a nonsignificant increase in the rate of DR (p = 0.340 and p = 0.444, respectively). CONCLUSION: The prevalence of DR in our study population is 20.5%. Regular screening is highly recommended for early detection of DR where timely laser photocoagulation is known to reduce the risk of visual loss in these patients. PMID- 20714196 TI - Where does essential reporting stop and where does 'l'art pour l'art' begin while imaging the middle ear? PMID- 20714194 TI - Genistein blunts the negative effect of ischaemia to the retina caused by an elevation of intraocular pressure. AB - AIMS: Deduce whether the isoflavone genistein blunts the effect of ischaemia to the retina. METHODS: Ischaemia was induced in rats by raising the intraocular pressure (120 mm Hg) for 50 min. Genistein (10 mg/kg) was injected intraperitoneally 1 h before and after ischaemia. Seven days after ischaemia, the level of mRNAs for neurofilament light (NF-L), caspase 3, caspase 8, glial fibrillary acidic protein (GFAP), poly-ADP ribose polymerase (PARP), Thy-1 and proteins (GFAP, NF-L, PARP) in whole retinas were determined. NF-L and tubulin proteins in optic nerves were also determined. Retinas were also processed for the localization of choline acetyltransferase (ChAT) and GFAP immunoreactivities. RESULTS: Ischaemia caused a significant reduction in ganglion cell proteins in the optic nerve (NF-L and tubulin) and retina (NF-L). Retinal Thy-1 (mRNA and protein) and NF-L (mRNA) were also reduced while mRNAs of caspase 3, caspase 8, PARP and GFAP (also protein) were increased. Changes in the mRNAs and proteins induced by ischaemia were significantly blunted by genistein with the exception of the increase in GFAP and PARP protein/mRNA levels. Ischaemia-induced changes in the localization of ChAT were also clearly attenuated by genistein treatment. CONCLUSIONS: Genistein blunts most of the damaging effects caused to the retina by ischaemia. PMID- 20714197 TI - Clinical guidelines and professional liability: a short comment from the legal side. AB - The paper explores the relationship between clinical guidelines and medical liability. In order to ascertain the standard of care required for example in ear surgery, courts rely on expert opinions and on existing clinical guidelines from medical societies. They assume that clinical guidelines express the reasonable standard of care that, when followed, insulates surgeons from liability. But judges keep the right to find that a set of clinical guidelines does not sufficiently protect the patient's health interests. If in contrast clinical guidelines are overly cautious (e.g. by requiring a scientifically questionable examination), there is no incentive stemming from the legal rules on medical liability to deter surgeons from following the guidelines. However, a growing concern about health costs may in the future influence professional behaviour as much as fear of a malpractice suit today. PMID- 20714198 TI - Clinical indication as an ethical appraisal: the example of imaging before middle ear surgery. AB - PURPOSE OF THE STUDY: Asking whether imaging is indicated before middle ear surgery requires us to examine the question of indication more generally. PROCEDURES: Clinical indication integrates different levels, which are distinguished in this paper. As deciding whether or not an intervention is indicated requires different approaches on each of these levels, these approaches are also explored. RESULTS: Even when sufficient data are available to determine whether an intervention brings some benefit, knowing whether or not this intervention is indicated still requires us to answer 3 additional questions: (1) Is the intervention sufficiently beneficial to be clinically relevant? (2) Is the intervention 'reasonable' in terms of its opportunity costs? (3) How are we to decide which interventions 'make the cut', and which do not? Although we may all have an informed opinion on this topic, the question of the thresholds we ought to apply to very marginal benefits is one where the best answer can only be the one we have all agreed on. This requires a guideline integrating elements of procedural fairness, developed in conditions of protection from the risks of conflicts of interests. CONCLUSION: Although some of these questions integrate considerations of costs, not all do. However, all integrate value judgements, making clinical indication in part a question of ethical appraisal. PMID- 20714199 TI - What the surgeon cannot see and needs to see before middle ear surgery. AB - OBJECTIVE: To define the utility of imaging prior to middle ear surgery. METHODS: Different middle ear pathologies are subsequently described: conductive hearing loss with a normal tympanic membrane, labyrinthine fistulae, tegmen anomalies, opacified tympanic membrane, cholesteatoma, temporal bone fractures and glomus tumors. We discuss the indications and benefits of imaging in each of these pathologies. RESULTS: Preoperative imaging shows interesting features and can be very helpful in the differential diagnosis and in surgical decision-making and planning. However, it is not mandatory and should not be systematic in every middle ear surgery. CONCLUSION: The modern radiological era provides the otological surgeon with numerous imaging technologies. Yet, these techniques should by no means replace the surgeon's anatomical knowledge, clinical sense and surgical skills. PMID- 20714200 TI - Quality management in middle ear surgery: controversies regarding preoperative imaging. AB - Today a large variety of different imaging techniques are available for middle ear investigation. However, imaging is not suitable to give essential information in every case on the surgical strategy to be chosen. This article discusses the most frequent indications for preoperative imaging and the relevant techniques. CT scanning, MRI and rotational tomography are taken into consideration as well as traditional X-ray investigations like e.g. 'Schuller's view'. In general, preoperative imaging should only be performed in a patient if certain specific questions can be answered. The experience of the investigator to interpret the images may influence the choice of imaging as well as the equipment he has access to. PMID- 20714201 TI - Why do we include CT scanning in the evaluation of otosclerosis patients? PMID- 20714202 TI - The use of radiology in middle ear and temporal bone surgery. AB - A nationwide survey was performed in Sweden regarding the way that practicing otosurgeons utilize radiological imaging before and after performing surgery of the middle ear and temporal bone. Sixty-six surgeons from 30 different otorhinolaryngology departments participated in the study. These represented all hospitals in Sweden where ear surgery is performed to some degree. A questionnaire was designed consisting of 18 questions that were assigned to 4 different groups. Questions in group 1 assessed the general conditions regarding imaging services in the local hospital. Questions in group 2 illuminated the level of tuition and competence development when it comes to judging radiological examinations. Group 3 questions mirrored the clinical routines when ordering various specific investigations. In group 4, the questions were aimed at describing which type of information the surgeons wanted to obtain from the imaging investigations. The answers gave a good picture of how Swedish otosurgeons use the services offered by their local radiological departments. One of the conclusions is that, although there is consensus regarding certain types of examinations in specific conditions, there is a great variation in how surgeons utilize radiological imaging in many of the most common clinical conditions. It is obvious that the routines regarding the use of radiology in conjunction with ear surgery vary from place to place and also between different surgeons. Whether a consensus can be reached in the future regarding this issue remains to be seen. PMID- 20714203 TI - Do we need imaging before middle ear surgery? When is imaging useful, when is it mandatory and when is it only interesting, profitable or defensive? AB - This article summarizes an opinion on preoperative imaging based upon a personal composite of observations and experience in otological and skull base surgery that spans 35 years in several Swiss and US academic centers and 10 years in private practice. PMID- 20714204 TI - General comments on this issue: how much good does it take to make a real difference? PMID- 20714205 TI - Idiopathic phantosmia: outcome and clinical significance. AB - BACKGROUND/AIM: Little is known about the clinical significance of phantosmia. The literature on phantosmia indicates that this symptom has a wide range of differential diagnoses. However, most cases of phantosmia remain of unknown origin. Our goal was to follow up patients with idiopathic phantosmia, with special regard to improvement rates and possible severe health conditions preceded by phantosmia of unknown origin. METHODS: Forty-four patients with idiopathic phantosmia which had consulted our Ear-Nose-Throat Smell and Taste Clinic over the last 10 years were contacted by telephone and underwent a structured medical interview. RESULTS: None of the patients had developed any severe health condition or Parkinson's disease. More than 5 years after the occurrence of phantosmia, more than 50% of the patients experienced disappearance (31.8%) or improvement (25%). In the remaining cases, phantosmia did not change (38.7%) or became worse (<5%). CONCLUSION: The main findings of the present study were that idiopathic phantosmia improves or disappears in almost two thirds of the patients after more than 5 years, and that idiopathic phantosmia seems to be more likely a harmless symptom rather than a reliable predictor of early Parkinson's disease or other severe diseases. PMID- 20714206 TI - An alternative approach to determine oral bioavailability of drugs that follow Michaelis-Menten elimination: a case study with voriconazole. AB - BACKGROUND/AIMS: the determination of oral bioavailability of drugs which follow nonlinear pharmacokinetics is difficult and few methods are available. In this work, an alternative approach to determine oral bioavailability of voriconazole (VRC), used as a model drug, is presented. METHODS: VRC pharmacokinetics was investigated in Wistar rats after p.o. (40 mg/kg) and i.v. administration (2.5, 5 and 10 mg/kg). VRC elimination showed saturation in all doses investigated, except the lower i.v. dose in which case a 3-compartment model with linear elimination adequately fitted the data. Data for the 2 higher i.v. doses were best described by a 3-compartment model with Michaelis-Menten elimination. A 1 compartment disposition with a saturable metabolic elimination model described the oral profile. VRC absolute oral bioavailability was determined by simultaneous fitting of the i.v. and oral profiles. RESULTS: the Michaelis constant and the maximum velocity estimated after 5 and 10 mg/kg i.v. dosing were 0.54 +/- 0.25 microg/ml and 2.53 +/- 0.54 microg/h, and 0.62 +/- 0.12 microg/ml and 2.74 +/- 0.84 microg/h, respectively. VRC oral bioavailability was determined to be 82.8%. CONCLUSION: the approach presented is an alternative for determining the bioavailability of drugs with similar nonlinear behavior. PMID- 20714207 TI - Nicotinic ligands modulate ethanol-induced dopamine function in mice. AB - The aim of the present study was to examine the effects of two neuronal nicotinic acetylcholine receptor ligands on acute ethanol-induced dopamine (DA) function in the C57BL/6J mouse ventral striatumusing an ex vivo assay and high-performance liquid chromatography coupled with electrochemicaldetection. Acute systemic injection of ethanol (2.5 g/kg) significantly increased the DA and dihydroxyphenylacetic acid (DOPAC) content in the ventral striatum. Pretreatment with lobeline (1 or 10 mg/kg) inhibited the ethanol-induced increase in the tissue DA and DOPAC content in the ventral striatum. Similarly, pretreatment with cytisine (0.5 or 3 mg/kg) also reduced the ethanol-induced increase in the tissue DA and DOPAC content in the ventral striatum. However, when given alone lobeline or cytisine did not produce significant effect on the DA or DOPAC content in the ventral striatum compared with controls. These findings provide evidence that lobeline and cytisine modulate ethanol-induced DA function by targeting nicotinic acetylcholine receptors in the ventral striatum, a reward-relevant brain region implicated in ethanol dependence. PMID- 20714208 TI - Differential effects of ICA-27243 on cloned K(V)7 channels. AB - BACKGROUND/AIMS: the neuronal K(V)7 family members (K(V)7.2-5) are important regulators of neuronal excitability. K(V)7 channel openers are therefore attractive drug candidates for the treatment of several hyperexcitability disorders. While most described K(V)7 channel openers discriminate poorly between K(V)7.2-5, Icagen's N-(6-chloropyridin- 3-yl)-3,4-difluorobenzamide (ICA-27243) is more potent at K(V)7.2/3 than at K(V)7.4 and K(V)7.3/5 and offers some progress towards subtype selectivity. We have investigated its mode of action on K(V)7.2 and K(V)7.4, compared its effect to that of retigabine and studied the combinatorial effect of retigabine and ICA-27243, as these two compounds recognize different binding sites in the channels. METHODS: the effects of ICA 27243 and retigabine were studied using voltage-clamp electrophysiology in Xenopus laevis oocytes and rubidium flux in Chinese hamster ovary cells. RESULTS: we found that in contrast to retigabine's voltage-dependent action on K(V)7.2, ICA-27243 induced a voltage-independent current on this subtype, which was not observed on K(V)7.4. Additionally, the combined treatment of K(V)7.2 and K(V)7.4 with retigabine and ICA-27243 revealed that the effect of ICA-27243 on K(V)7.2 dominates that of retigabine, while the compounds act additively and synergistically on K(V)7.4. CONCLUSIONS: these results offer further detailed insight into pharmacological activation of K(V)7 channels and offer evidence of differential functional and subtype-specific effects by activation of different binding sites in the K(V)7 channels. PMID- 20714210 TI - Less is more: adaptation of voltage after battery replacement in deep brain stimulation for dystonia. AB - BACKGROUND: To maintain the efficacy of deep brain stimulation (DBS) on dystonic symptoms, slight incremental increase in voltage may be necessary over years after a steady state has been reached following the initial programming of optimal settings. So far however, no data are available regarding the adjustment of voltage after implantable pulse generator (IPG) replacement to achieve sustained optimal control of dystonia with the least side effects. METHODS: We analyzed stimulation settings before and after IPG replacement for battery depletion (n = 61) in 18 patients with chronic DBS of the globus pallidus internus or the ventral intermediate nucleus of the thalamus for dystonia. RESULTS: The stimulation intensity could be significantly reduced by 24.8% after IPG replacement. The amount of voltage reduction was equal between bipolar and monopolar stimulation modes (24.9 vs. 24.3%, p = 0.89) and significantly correlated with the magnitude of stimulation intensity before IPG replacement (rho = 0.429, p = 0.001). CONCLUSIONS: After IPG replacement, in patients with DBS for segmental dystonia the voltage can be reduced by approximately 25%. This phenomenon might be explained by a gradual decrease in the electrical energy effectively delivered by the IPG in the course of the lifetime of the battery or neuroplastic processes in particular in the period around battery replacement. PMID- 20714211 TI - Stereotactic radiosurgery for spine tumors: review of current literature. AB - Stereotactic radiosurgery (SR) is increasingly utilized for the treatment of intracranial and extracranial pathology. It is considered an important adjuvant to surgery, chemotherapy or fractionated radiotherapy, and the role of SR as a primary treatment modality continues to be explored. Although SR for spinal lesions is in its infancy, there is a growing body of literature supporting its efficacy. The purpose of this review is to summarize the pertinent literature regarding the use of SR for lesions of the spine and spinal cord. Particular emphasis will be placed on large clinical series of both primary and secondary spine tumors. PMID- 20714212 TI - A case of mania following deep brain stimulation for obsessive compulsive disorder. AB - Deep brain stimulation (DBS) of the basal ganglia is an effective treatment for select movement disorders, including Parkinson's disease, essential tremor and dystonia. Based on these successes, DBS has been explored as an experimental treatment for medication-resistant neuropsychiatric disease. During a multiyear experience employing DBS to treat patients for obsessive compulsive disorder (OCD) we encountered several unanticipated stimulation-induced psychiatric side effects. We present a case of a young woman treated for OCD with DBS of the anterior limb of the internal capsule and nucleus accumbens region, who subsequently manifested a manic episode. We aim to discuss the case details, treatment and potential neuroanatomical underpinnings of this response. PMID- 20714214 TI - DNA oxidation drives Myc mediated transcription. AB - Myc oncogene is a transcription factor that contributes to the genesis of a wide variety of tumors by regulating proliferation, differentiation and apoptosis. Despite being one of the first isolated oncogene, the biochemical mechanisms of Myc mediated transcriptional regulation remain unclear. Myc has been found to govern different aspects of gene expression, from chromatin remodeling to basal transcription and processive RNAPII elongation. Myc binding to targets genes depends on the presence of the E-box binding motif and the presence of histone H3K4me3 lysines. Here, we summarize recent findings regarding the function of Myc in orchestrating different steps in transcription, and we propose a model that links histone H3 methylation code to Myc target genes. Myc upon binding to the E box triggers a series of events that assembles the transcription initiation complex, recruits the demethylating enzyme LSD1, induces DNA oxidation and chromating looping. Once started RNAPII still needs Myc assistance during transcription elongation. Myc seems to modulate at least two crucial steps in transcription. i.e., chromatin modifications for initiation and RNAPII pause release for productive elongation. PMID- 20714213 TI - Differential response of dystonia and parkinsonism following globus pallidus internus deep brain stimulation in X-linked dystonia-parkinsonism (Lubag). AB - BACKGROUND: X-linked dystonia-parkinsonism (XDP; DYT3; Lubag) is an adult-onset hereditary progressive dystonia/parkinsonism which is typically minimally responsive to pharmacological treatment. CASE REPORT: We report a 63- year-old man with a diagnosis of XDP who underwent bilateral globus pallidus internus deep brain stimulator (GPi-DBS) placement. His course initially began with right hand tremor and dystonia at age 57 and progressed to also include bradykinesia and rigidity. The patient tolerated the procedure without significant complications. GPi-DBS improved his right hand dystonia, but did not significantly improve his parkinsonism. CONCLUSION: DBS may be a therapeutic option for select cases of XDP, but its specific indications must be carefully discussed, as the available cases have had mixed responses. Whether other targets may be more effective is not known. PMID- 20714215 TI - Rethinking the role of cyclooxygenase-1 in neuroinflammation: more than homeostasis. PMID- 20714217 TI - A new role for Cdks in the DNA damage response. PMID- 20714218 TI - Development of a novel multiplex in vitro binding assay to profile p53-DNA interactions. AB - The p53 tumor suppressor plays a critical role in cancer biology, functioning as a transcription factor capable of directing cell fate. It interacts with specific DNA response elements (REs) to regulate the activity of target genes. We describe here a novel, non-radioactive assay to measure p53-DNA binding which involves the sequential use of in vitro transcription/ translation (IVT), immunoprecipitation and real-time PCR. The method reliably enables the detection of sequence-specific DNA binding of full-length p53 at low concentrations of physiologically relevant REs (<5 nM). Furthermore, we demonstrate multiplexing of 4 different REs in a single binding reaction. The use of IVT precludes the requirement for purified protein, enabling rapid characterization of the binding properties of p53 variants. Uniquely, it also offers the opportunity to add compounds during translation that might modulate and activate p53. When compared to prevailing protein-DNA binding assays, this method exhibits comparable or higher sensitivity, in addition to an expansive dynamic range afforded by the use of real-time PCR. A further extrapolation of its utility is demonstrated when the addition of a peptide known to activate p53 increased its binding to a consensus RE, consistent with published data. PMID- 20714216 TI - The perivascular niche microenvironment in brain tumor progression. AB - Glioblastoma, the most frequent and aggressive malignant brain tumor, has a very poor prognosis of approximately 1-year. The associated aggressive phenotype and therapeutic resistance of glioblastoma is postulated to be due to putative brain tumor stem-like cells (BTSC). The best hope for improved therapy lies in the ability to understand the molecular biology that controls BTSC behavior. The tumor vascular microenvironment of brain tumors has emerged as important regulators of BTSC behavior. Emerging data have identified the vascular microenvironment as home to a multitude of cell types engaged in various signaling that work collectively to foster a supportive environment for BTSCs. Characterization of the signaling pathways and intercellular communication between resident cell types in the microvascular niche of brain tumors is critical to the identification of potential BTSC-specific targets for therapy. PMID- 20714219 TI - Cyclin T1 overexpression induces malignant transformation and tumor growth. AB - Human PTE Fb is a protein kinase composed by CDK9 and Cyclin T that controls the elongation phase of RNA Pol II. This complex also affects the activation and differentiation program of lymphoid cells. In this study we found that several head and neck tumor cell lines overexpress PTE Fb. We also established that Cyclin T1 is able to induce transformation in vitro, as we determined by foci and colony formation assays. Nu/nu mice s.c. injected with stable transfected Cyclin T1 cells (NIH 3T3 Cyclin T1) developed tumors faster than animals injected with control cells (NIH 3T3 beta-gal). In vitro, NIH 3T3 Cyclin T1 cells show increased proliferation and CDK4-Rb phosphorylation. Even more, silencing E2F1 expression (shRNA E2F1) in NIH 3T3 cells resulted in a dramatic inhibition of Cyclin T1-induced foci. All these data demonstrate for the first time the Cyclin T1 oncogenic function and suggest a role for this protein in controlling cell cycle probably via Rb/E2F1 pathway. PMID- 20714220 TI - Linking tRNA localization with activation of nutritional stress responses. AB - Cells respond to nutrient deprivation a variety of ways. In addition to global downregulation of cap-dependent protein synthesis mediated by the GCN2 and mTORC1 signaling pathways, a catabolic process autophagy is upregulated to provide internal building blocks and energy needed to sustain viability. It has recently been shown that during nutrient deprivation tRNAs accumulate in the nucleus, but the functional role of this accumulation remains unknown. This study investigates whether subcellular localization of tRNAs plays a role in signaling nutritional stress and autophagy. We report that human fibroblasts that accumulate tRNA in the nucleus due to downregulation of their transportin, Xpo-t, show reduced mTORC1 activity and upregulated autophagy. This suggests that subcellular localization of tRNAs may regulate an intracellular response to starvation independently of the cellular nutritional status. PMID- 20714221 TI - Parole terms for a killer: directing caspase3/CAD induced DNA strand breaks to coordinate changes in gene expression. AB - In a series of discoveries over the preceding decade, a number of laboratories have unequivocally established that apoptotic proteins and pathways are well conserved cell fate determinants, which act independent of a cell death response. Within this context, the role for apoptotic proteins in the induction of cell differentiation has been widely documented. Despite these discoveries, little information has been forthcoming regarding a conserved mechanism by which apoptotic proteins achieve this non-death outcome. In the following discussion, we will explore the premise that the penultimate step in apoptosis, genome wide DNA damage/strand breaks act as a conserved genomic reprogramming event necessary for cell differentiation (Larsen et al. Proc Natl Acad Sci USA 2010; 107:4230-5). Moreover, we hypothesis that directed DNA damage, as mediated by known apoptotic proteins, may participate in numerous forms of regulated gene expression. PMID- 20714222 TI - Deciphering the chromatin landscape induced around DNA double strand breaks. AB - DNA double strand breaks (DSBs) are among the most deleterious forms of lesions and deciphering the details of the chromatin landscape induced around DSBs represents a great challenge for molecular biologists. Chromatin Immunoprecipitation, followed by microarray hybridisation (ChIP-chip) or high throughput sequencing (ChIP-seq), are powerful techniques that provide high resolution maps of protein-genome interactions. However, applying these techniques to study chromatin changes induced around DSBs was previously hindered due to a lack of suitable DSB induction techniques. We have recently developed an experimental system utilizing a restriction enzyme fused to a modified oestrogen receptor ligand binding domain (AsiSI-ER), which generates multiple, sequence specific and unambiguously positioned DSBs across the genome upon induction with 4-hydroxytamoxifen (4OHT).(1) Cell lines expressing this construct represent a powerful tool to study specific chromatin changes during DSB repair, enabling high-resolution profiling of DNA repair complexes and chromatin modifications induced around DSBs. Using this system, we have recently produced the first map of gammaH2AX, a DSB-induced chromatin modification, on two human chromosomes and have investigated its spreading properties.(1) Here we provide additional data characterizing the cell lines, present a genome-wide profile of gammaH2AX obtained by ChIP-seq, and discuss the potential of our system towards investigations of previously uncharacterized aspects of DSB repair. PMID- 20714223 TI - Clb2 and the APC/C(Cdh1) regulate Swe1 stability. AB - Swe1/Wee1 regulates mitotic entry by inhibiting Clb2-Cdk1 and its accumulation is involved in stress induced G(2) arrest. The APC/C(Cdh1) substrates Cdc5, Clb2 and Hsl1 regulate Swe1 degradation. We observed that clb2Deltacdh1Delta double mutant S. cerevisiae does not express any detectable levels of Swe1, presumably due to its constitutive degradation. This effect of Cdh1 inactivation is due to stabilization of Cdc5 and Hsl1, as expression of the non-degradable Cdc5(T29A) in clb2Delta cells prevented Swe1 accumulation. Strikingly, expression of non degradable Hsl1(mdb/mkb) prevented Swe1 accumulation even in wild type Clb2 cells. Interestingly Swe1 accumulation could be reconstituted in all these mutants by eliciting a replication fork stress with hydroxyurea. Cells expressing the Clb2(ME) mutant, that cannot bind Swe1, behaved like clb2Delta cells, and failed to accumulate Swe1 in the absence of Cdh1 or the presence of Cdc5(T29A). This suggests that for Swe1 to accumulate it must interact with Clb2. We further show that in the absence of Clb2, Hsl1 is no longer essential for Swe1 degradation. We hypothesize that Clb2-Cdk1 protects Swe1 from premature degradation until its Hsl1 mediated de-protection, which enables its Cdc5 mediated degradation. Swe1 levels are thus regulated by monitoring the levels of three major mitotic regulators. PMID- 20714224 TI - Finding the midzone: the role of ubiquitination for CPC localization during anaphase. PMID- 20714225 TI - Fast, repetitive light-activation of CaV3.2 using channelrhodopsin 2. AB - Channelrhodopsin-2 (ChR2) is a light-gated ion channel that is successfully used in neurosciences to depolarize cells with blue light. In this regard control of membrane voltage with light opens new perspectives for the characterization of ion channels and the search for inhibitors or modulators. Here, we report a control of membrane potential with ChR2 and the potassium channel mTrek for the purpose of screening for ion channel specific drugs. To verify principle we have chosen the voltage gated calcium channel Ca(V)3.2 as potential drug target. For this purpose we transfected the ChR2 gene into a HEK293T-cell line that permanently expresses Ca(V)3.2 and the K-channel mTrek. The resting potential was adjusted with low concentration of extracellular potassium ions whereas transient depolarization was achieved by activation of ChR2 with short pulses of blue light. Calcium ion influx through Ca(V)3.2 was monitored by observing fura-2 fluorescence. This approach allowed a repetitive activation of Ca(V)3.2. The Ca(2+) influx was specifically blocked by the inhibitor mibefradil. Since this assay is genetically-encoded, it may be employed for a variety of voltage-gated calcium channels and should be applicable to multi-well reader formats for high throughput screening. PMID- 20714226 TI - The Golgi complex as a source for yeast autophagosomal membranes. AB - Today, more than 50 years after the discovery of autophagy, the origin of the autophagosomal membranes remains for the most part elusive. Many sources for the lipid bilayers have been proposed, but no conclusive evidence has been found to support one particular origin. The lipids do not appear to be generated at the site of autophagosome formation, the phagophore assembly site (PAS), since so far no lipid synthesizing enzyme has been found at this location. The current consensus is also that the autophagosomes do not directly bud off from a pre existing compartment, and recent evidence in mammalian cells has revealed that the nascent autophagosome could expand through a lipid transfer mechanism from an adjacent organelle. In yeast, such an event has never been observed and data from our and other laboratories suggest that the Golgi complex could be a key player in mediating the expansion of the phagophore. PMID- 20714227 TI - Association between acute and chronic life events on acute coronary syndrome: a case-control study. AB - BACKGROUND AND OBJECTIVES: Some studies have shown that acute and chronic psychological stressors are associated with acute coronary syndromes (ACSs). The aim of the present study was to assess the association between acute and chronic psychological stressors and ACS in an Iranian population. METHOD: In an age-sex frequency-matched, case-control study, 78 hospitalized patients with ACS as the case group were compared with 146 patients with chronic stable angina (CSA) as the control group. Chronic stable angina was confirmed by positive angiographic findings. Acute stressors were examined through a semistructured interview and the acute life event checklist, regarding stressful events during 48 hours before interview. To assess chronic stress, the occurrence of 46 stressful events in a period of 6 months prior to the interview was examined using the stress inventory questionnaire. RESULTS: The average acute stressor counts were 4.80 (SD, 2.87) and 3.97 (SD, 2.2) in ACS and CSA groups, respectively (P = .028). Chronic stressor counts were 9.91 (SD, 5.86) and 6.58 (SD, 3.16) in case and control groups (<.001), respectively. Odds ratios for acute and chronic stressor counts were 1.14 (95% confidence interval [95% CI], 1.02-1.28) and 1.84 (95% CI, 1.10 1.26), respectively; when the associations were adjusted for traditional risk factors, they become 1.12 (95% CI, 0.99-1.27) and 1.20 (95% CI, 1.10-1.30), respectively. CONCLUSION: Acute stress did not contribute significantly in the models including chronic stress. Acute stressful events in the recent 48 hours, independent of traditional risk factors, can have a triggering effect on ACS occurrence. Nevertheless, this happens in the context of high chronic stress. In addition, chronic stress count was moderately associated with ACS even when it was adjusted for traditional risk factors (ALEACE study). PMID- 20714228 TI - Clinical events in coronary heart disease patients with an ejection fraction of 40% or less: 3-year follow-up results. AB - BACKGROUND AND RESEARCH OBJECTIVE: It is unclear whether lifestyle changes can delay the need for surgical procedures in coronary heart disease (CHD) patients with asymptomatic reduced left ventricular ejection fraction (LVEF). The aim of this pilot study was to examine whether lifestyle changes can delay the need for surgical procedures in this population. SUBJECTS AND METHODS: We compared 3-year clinical events in 27 CHD patients eligible to receive revascularization (by insurance standards), but underwent lifestyle changes (low-fat diet, exercise, stress management) instead (intervention group [IG], LVEF < or =40%), with those of a historically matched (age, gender, LVEF, and stenosis of the 3 major coronary arteries) control group receiving usual care (UCG; n = 13) who received revascularization at study entry. Both IG and UCG patients were enrolled in the health insurance companies participating in the Multicenter Lifestyle Demonstration Project, an insurance-sponsored, community-based, secondary prevention study implemented at 8 hospital sites in the United States. RESULTS AND CONCLUSION: At 3 months, there were more cardiac events in the UCG (6 events) than in the IG (1 event; P < .006; odds ratio = 13.27; confidence interval = 1.57 111.94). This difference was maintained over 3 years (P < .06; odds ratio = 2.75; confidence interval = 1.05-7.19). Of the 26 surviving (1 cardiac death) IG patients, 23 did not require primary revascularization. In conclusion, CHD patients with asymptomatic reduced LVEF may be able to safely delay revascularization by making changes in lifestyle with no increased risk for cardiac events or overt heart failure over 3 years. PMID- 20714231 TI - Dietary sodium reduction: a public health approach to decreasing hypertension. PMID- 20714233 TI - Summaries of nursing care-related systematic reviews from the Cochrane library: exercise-based rehabilitation for coronary heart disease. PMID- 20714234 TI - Summaries of nursing care-related systematic reviews from the Cochrane library: erythropoiesis-stimulating agents for anemia in chronic heart failure patients. PMID- 20714235 TI - Do cognitive coping and goal adjustment strategies used shortly after myocardial infarction predict depressive outcomes 1 year later? AB - RESEARCH OBJECTIVE: The aim of this study was to examine the extent to which cognitive and goal-related coping strategies used shortly after myocardial infarction predicted depressive outcomes 1 year later. SUBJECT AND METHODS: The sample consisted of 88 persons who had experienced a myocardial infarction 3 to 12 months before first data assessment. Cognitive coping and goal adjustment strategies were assessed at time 1 by the Cognitive Emotion Regulation Questionnaire and the Goal Obstruction Questionnaire, respectively. Depressive symptoms were assessed at both time 1 and time 2 by the Hospital Anxiety and Depression Scale. RESULTS AND CONCLUSIONS: The results showed that cognitive coping strategies (rumination, catastrophizing, and positive refocusing) and goal adjustment strategies predicted 39% of the variance in depressive symptoms at follow-up. In addition, little change in depressive symptom scores was observed after 1 year. The results with regard to the prospective relationships between coping and depressive symptoms provide important targets for intervention. PMID- 20714236 TI - Cognitive impairment predicts functional capacity in dementia-free patients with cardiovascular disease. AB - BACKGROUND AND RESEARCH OBJECTIVE: A high proportion of elderly people with cardiovascular diseases and risk factors have mild forms of cognitive impairment, the functional impact of which is poorly understood. The aim of this study was to determine whether subtle cognitive impairment contributes to limitations in instrumental activities of daily living in this group and whether this association is independent of physical comorbidity and other potentially confounding factors. SUBJECTS AND METHODS: Two hundred and nineteen nondemented patients were recruited from cardiovascular and diabetic hospital outpatient clinics. Functional dependence was assessed using the self-report version of the instrumental activities of daily living scale. Cognitive ability was assessed using the Montreal Cognitive Assessment (MoCA). Demographic and clinical information was collected via interview and a review of hospital records. Standard logistic regression was performed to identify factors independently associated with functional status. RESULTS: Five variables (sex, cardiovascular disease burden, non-cardiovascular disease burden, cognitive status, and age) were independently associated with an increased likelihood of requiring assistance with 1 or more everyday activities. The likelihood of needing assistance increased 2.05 times (95% confidence interval [CI], 1.59-2.79) for each additional cardiovascular diagnosis present and 1.12 times (95% CI, 1.01 1.27) for every point lower on MoCA. Thus, in comparison to a person with a perfect MoCA score, a person who scored in the cognitively impaired range (<23) was 7.7 (CI, 7.07-8.89) times more likely to report that he/she required assistance with an everyday activity. CONCLUSION: Cognitive impairments appear to reduce the ability to independently carry out routine daily tasks in patients with cardiovascular diseases and risk factors. Cognition should therefore be considered along with physical symptoms when assessing and responding to the support needs of this group. PMID- 20714237 TI - Determining psychosocial research priorities for adolescents with implantable cardioverter defibrillators using Delphi methodology. AB - BACKGROUND AND RESEARCH OBJECTIVE: Adolescents with implantable cardioverter defibrillators (ICDs) have unique psychosocial needs that are not currently addressed in the literature. To prioritize these issues into a concise cardiovascular nursing research agenda, the objective of this study was to identify current psychosocial issues in this population by obtaining expert consensus from experienced pediatric dysrhythmia clinicians. SUBJECTS AND METHODS: A 3-round electronic Delphi study was conducted. A multidisciplinary purposive sample was drawn from 2 international organizations of pediatric and young adult cardiovascular caregivers who specialize in rhythm disturbances in this patient population. Round 1 included an open-ended question in which respondents were asked to provide as many psychosocial issues as desired, but at least 5. Round 2 included the 10 most frequent issues, which participants were asked to rank (1 = most important, 10 = least important). Round 3 included the collective ranking of the respondents using mean values; respondents were asked to indicate agreement/disagreement with the final ranking. If they disagreed, they were asked to re-rank the items. RESULTS AND CONCLUSIONS: The top 10 psychosocial issues identified by the panel included, in order of importance: fear of being shocked, sports participation/activity restrictions, feeling different from peers/peer acceptance, depression, adjustment problems, fear of death, medication noncompliance, acting out, body change/weight gain, and issues related to planning for adulthood. There was 90% agreement among the expert panel members. Ascertaining the opinions and consensus of pediatric cardiovascular dysrhythmia experts has led to the development of a concise research agenda for the psychosocial issues faced by children and adolescents with ICDs. The identification of these issues will allow nurse researchers to incorporate these findings into future studies in which interventions aimed at promoting positive adjustment to the ICD in the child and adolescent age group can be tested. PMID- 20714238 TI - Low blood pressure and preserved systolic function in elders with heart failure. AB - This literature review was performed to evaluate the relationship of systolic blood pressure (SBP) and preserved systolic function on morbidity and mortality in individuals older than 65 years with heart failure (HF). When prolonged, high SBP, defined as measurements greater than 140 to 160 mm Hg, is associated with increased risk of developing HF. Medications to lower SBP measurements to Joint National Committee VII goals of less than 140 mm Hg are often prescribed on the assumption that treatment guidelines result from a systematic analysis of clinical trials and efficacy of drug treatments. Lower limits of SBP are less defined in current guidelines optimizing HF. The electronic databases PubMed, CINAHL, and Google Scholar are searched for keywords heart failure, prognosis, preserved systolic function, and blood pressure (BP). Five scholarly research articles investigated the effects of variables, notably SBP and confirmed preserved systolic function, on HF, published in the English language between July 2006 and January 2009. Inclusion criteria were study samples consisting of individuals 65 years and older referred in this article as elders, with the diagnosis of HF with a focus on variables measuring SBP and systolic function when assessing outcomes. Low SBP is a risk factor for adverse outcomes in HF elders. Additionally, female elders more commonly had preserved systolic function, but presented with less classic symptoms of HF and were less likely to receive cardiology consultation. Considerations for future research are the inclusion of participants presenting with SBP of less than 110 mm Hg in clinical trials and updated evidence-based guidelines, defining acceptable increased target BP ranges, for sex- and age-adjusted HF patients with preserved systolic function. PMID- 20714240 TI - Human responses to pulmonary arterial hypertension: review of the literature. AB - Pulmonary arterial hypertension (PAH) is a devastating disease characterized by elevation in pulmonary artery pressures causing progressive symptoms that lead to functional decline and poor quality of life. There are multiple causes of PAH including familial disease, connective tissue disease, and HIV. The estimated life expectancy is 4 years after onset of symptoms and approximately 6 to 7 years with PAH treatment. Much of the current research has focused on pharmacological treatments to improve functional status and decrease mortality. A comprehensive literature review was conducted using the CINAHL, PubMed, and MEDLINE to identify and synthesize current studies on human responses to PAH organized by emotional responses and physical functioning. Eight studies fulfilled the search criteria. Patients with PAH were learning to cope and live with uncertainty and treatment. Pulmonary arterial hypertension produced the emotional responses of anxiety, depression, and panic attacks along with impairments in cognition and memory as well as reductions in physical functioning. PMID- 20714239 TI - Predictors of depressive symptoms in caregivers of patients with heart failure. AB - BACKGROUND: Millions of family members deliver informal care and support to patients with heart failure (HF). Caregivers of patients with HF experience depressive symptoms, but factors associated with depressive symptoms are unknown. The purposes of this study were (1) to examine differences between caregivers with and without depressive symptoms in patients' characteristics and caregivers' functional status, caregiving burden (time devoted to caregiving, difficulty of caregiving tasks, and overall perceived caregiving distress), and perceived control; and (2) to determine predictors of depressive symptoms of caregivers. METHOD: A total of 109 caregivers (mean age of 57 years; spousal caregiver, 79%) and patients with HF participated in this study. Depressive symptoms, perceived control, and functional status of both patients and caregivers were assessed using the Beck Depression Inventory II, the Control Attitudes Scale-Revised, and the Duke Activity Status Index, respectively. Caregivers' burden (time and difficulty of caregiving tasks and burden) were assessed using the Oberst Caregiving Burden Scale and the Zarit Burden Interview. RESULTS: The 27.5% of HF caregivers with depressive symptoms (Beck Depression Inventory II score > or =14) had poorer functional status, lower perceived control, and higher perceived caregiving distress; experienced more caregiving difficulty; and spent more time in caregiving tasks than did caregivers without depressive symptoms. Controlling for age and sex in a multiple regression, caregivers' own functional disability (standard beta [sbeta] = -.307, P < .001), perceived control (sbeta = -.304, P < .001), and caregiver burden (sbeta = .316, P = .002) explained 45% of the variance in caregivers' depressive symptoms. Patients' New York Heart Association class and functional status did not predict caregivers' depressive symptoms. CONCLUSION: Caregivers' poor functional status, overall perception of caregiving distress, and perceived control were associated with depressive symptoms. Depressed caregivers of patients with HF may benefit from interventions that improve caregivers' perceived control, address the caregiving burden, and improve or assist with caregivers' functional status. PMID- 20714241 TI - Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat. AB - BACKGROUND: Hypoxia inducible factors (HIFs) are transcription factors that are regulated by HIF-prolyl 4-hydroxylases (PHDs) in response to changes in oxygen tension. Once activated, HIFs play an important role in angiogenesis, erythropoiesis, proliferation, cell survival, inflammation, and energy metabolism. We hypothesized that GSK360A, a novel orally active HIF-PHD inhibitor, could facilitate local and systemic HIF-1 alpha signaling and protect the failing heart after myocardial infarction (MI). METHODS AND RESULTS: GSK360A is a potent (nanomolar) inhibitor of HIF-PHDs (PHD1>PHD2 = PHD3) capable of activating the HIF-1 alpha pathway in a variety of cell types including neonatal rat ventricular myocytes and H9C2 cells. Male rats treated orally with GSK360A (30 mg x kg x d) had a sustained elevation in circulating levels of erythropoietin and hemoglobin and increased hemoxygenase-1 expression in the heart and skeletal muscle. In a rat model of established heart failure with systolic dysfunction induced by ligation of left anterior descending coronary artery, chronic treatment with GSK360A for 28 days prevented the progressive reduction in ejection fraction, ventricular dilation, and increased lung weight, which were observed in the vehicle-treated animals, for up to 3 months. In addition, the microvascular density in the periinfarct region was increased (>2 fold) in GSK360A-treated animals. Treatment was well tolerated (survival was 89% in the GSK360A group vs. 82% in the placebo group). CONCLUSIONS: Chronic post myocardial infarction treatment with a selective HIF PHD inhibitor (GSK360A) exerts systemic and local effects by stabilizing HIF-1 alpha signaling and improves long-term ventricular function, remodeling, and vascularity in a model of established ventricular dysfunction. These results suggest that HIF-PHD inhibitors may be suitable for the treatment of post-MI remodeling and heart failure. PMID- 20714245 TI - Reducing readmissions of patients with heart failure. PMID- 20714250 TI - Patient education series. Seasonal influenza (the flu). PMID- 20714252 TI - Medical emergency at 30,000 feet. PMID- 20714253 TI - ERCP: much ado about blockages. Update your knowledge about the diagnostic and therapeutic uses for endoscopic regrograde cholangiopancreatography. PMID- 20714254 TI - Nursing students on the unit: what's your role? PMID- 20714255 TI - 10 tips for documenting domestic violence. PMID- 20714256 TI - Targeting the red-hot danger of inflammatory breast cancer. PMID- 20714257 TI - Managing hypernatremia. PMID- 20714258 TI - Negative pressure wound therapy: Use with care. PMID- 20714259 TI - Dengue returns to the United States. PMID- 20714260 TI - Asthma drugs. PMID- 20714261 TI - Acute myocardial infarction in pregnancy. PMID- 20714262 TI - The ongoing challenge of sepsis in Latin America. PMID- 20714263 TI - Neutrophil paralysis in sepsis. AB - Sepsis develops when the initial host response is unable to contain the primary infection, resulting in widespread inflammation and multiple organ dysfunction. The impairment of neutrophil migration into the infection site, also termed neutrophil paralysis, is a critical hallmark of sepsis, which is directly related to the severity of the disease. Although the precise mechanism of this phenomenon is not fully understood, there has been much advancement in the understanding of this field. In this review, we highlight the recent insights into the molecular mechanisms of neutrophil paralysis during sepsis. PMID- 20714264 TI - Hemodynamic and perfusion end points for volemic resuscitation in sepsis. AB - Sepsis is the systemic inflammatory response syndrome secondary to a local infection, and severe sepsis and septic shock are the more devastating scenarios of this disease. In the last decade, considerable achievements were obtained in sepsis knowledge, and an international campaign was developed to improve the treatment of this condition. However, sepsis is still one of the most important causes of death in intensive care units. The early stages of sepsis are characterized by a variety of hemodynamic derangements that induce a systemic imbalance between tissue oxygen supply and demand, leading to global tissue hypoxia. This dysfunction, which may occur in patients presenting normal vital signs, can be accompanied by a significant increase in both morbidity and mortality. The early identification of high-risk sepsis patients through tissue perfusion markers such as lactate and venous oxygen saturation is crucial for prompt initiation of therapeutic support, which includes early goal-directed therapy as necessary. The purpose of this article was to review the most commonly used hemodynamic and perfusion parameters for hemodynamic optimization in sepsis, emphasizing the physiological background for their use and the studies that demonstrated their effectiveness as goals of volemic resuscitation. PMID- 20714266 TI - What's new in Shock September 2010? PMID- 20714265 TI - Early fluid resuscitation in sepsis: evidence and perspectives. AB - Hemodynamic instability plays a major role in the pathogenesis of systemic inflammation, tissue hypoxia, and multiple organ dysfunction in sepsis. Aggressive fluid replacement is one of the key interventions for the hemodynamic support in severe sepsis. In this scenario, the ability to restore the imbalance between tissue oxygen demand and supply, the heterogeneity in microcirculation, and endothelial dysfunction in the early stages of sepsis are associated with reduced mortality. In 2001, a single-center randomized controlled trial showed impressive reductions in hospital mortality when patients presenting to the emergency department with severe sepsis were treated with an aggressive protocol of fluids, blood transfusion, and inotropes aiming to improve tissue perfusion. However, external validation of this trial remains to be carried out. To date, there is no unequivocal evidence that such strategy is both universally feasible and effective. In the present article, we review the current evidence and comment on the future perspectives on early fluid resuscitation in severe sepsis. PMID- 20714268 TI - Re: Cristante AF, de Souza FI, Barros Filho TE, et al. Lead poisoning by intradiscal firearm bullet: a case report. Spine 2010;35:E140-3. PMID- 20714269 TI - Re: Richardson TD, Pineda SJ, Strenge KB, et al. Serum titanium levels after instrumented spinal arthrodesis. Spine 2008;33:792-6. PMID- 20714271 TI - Time for "test and treat" in prevention of mother-to-child transmission programs in low- and middle-income countries. AB - Significant progress has been made in the prevention of mother-to-child transmission (PMTCT) of HIV. In 2008, an estimated 1.4 million pregnant women living with HIV in low- and middle-income countries (LMIC) gave birth and almost half of these accessed antiretroviral drugs to prevent HIV transmission to their infants, which ranged from single-dose nevirapine to full combination antiretroviral therapy (ART). Although this represents a significant increase in ART coverage, much more remains to be done in terms of HIV testing and counseling, establishment of ART eligibility, and postnatal treatment and care. In November 2009, the World Health Organization issued new PMTCT guidelines for LMIC, stressing the benefits of earlier initiation of ART during pregnancy and its continuation throughout the delivery and the breastfeeding periods. A key recommendation of these guidelines is to start ART for all HIV-positive pregnant women with a CD4 count below 350 cells/mm, irrespective of clinical stage. This makes access to CD4 testing more crucial than ever for the successful implementation of PMTCT programs, since clinical staging performs poorly in identifying pregnant women eligible for ART. However, there are still many barriers to accessing CD4 testing in remote health structures implementing antenatal care services, particularly in countries with a high HIV prevalence. In these settings, universal ART initiation among HIV-positive pregnant women, irrespective of CD4 cell count or clinical staging, is a potentially superior strategy for the prevention of vertical transmission and the improvement of mothers' health. PMID- 20714270 TI - Fibroblast response to gadolinium: role for platelet-derived growth factor receptor. AB - OBJECTIVE: The purpose of this study was to assess the effects of gadolinium (Gd3+), provided as gadolinium chloride, on fibroblast function. MATERIALS AND METHODS: Human dermal fibroblasts in monolayer culture and intact skin in organ culture were exposed to the lanthanide metal (1-20 MUM). RESULTS: Increased proliferation was observed, in association with upregulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1, without an apparent increase in production of type I procollagen. A platelet-derived growth factor (PDGF) receptor-blocking antibody inhibited fibroblast proliferation in response to Gd3+ as did inhibitors of signaling pathways--that is, mitogen activated protein kinase and phosphatidylinositol-3 kinase pathways--that are activated by PDGF. CONCLUSION: The responses to gadolinium chloride are similar to responses previously seen with chelated Gd3+ in clinically used magnetic resonance imaging contrast agents. Fibroblast responses appear to reflect Gd3+ induced PDGF receptor activation and downstream signaling. Increased dermal fibroblast proliferation in conjunction with effects on matrix metalloproteinase 1 and tissue inhibitor of metalloproteinases-1 could contribute to the fibroplastic/fibrotic changes seen in the lesional skin of individuals with nephrogenic systemic fibrosis. PMID- 20714272 TI - Acceptance of HIV testing for children ages 18 months to 13 years identified through voluntary, home-based HIV counseling and testing in western Kenya. AB - BACKGROUND: Home-based voluntary counseling and testing (HCT) presents a novel approach to early diagnosis. We sought to describe uptake of pediatric HIV testing, associated factors, and HIV prevalence among children offered HCT in Kenya. METHODS: The USAID-Academic Model Providing Access to Healthcare Partnership conducted HCT in western Kenya in 2008. Children 18 months to 13 years were offered HCT if their mother was known to be dead, her living status was unknown, mother was HIV infected, or of unknown HIV status. This retrospective analysis describes the cohort of children encountered and tested. RESULTS: HCT was offered to 2289 children and accepted for 1294 (57%). Children were more likely to be tested if more information was available about a suspected or confirmed maternal HIV infection [for HIV-infected living mothers odds ratio (OR) = 3.20, 95% confidence interval (CI): 1.64 to 6.23), if parents were not in household (OR = 1.50, 95% CI: 1.40 to 1.63), if they were grandchildren of head of household (OR = 4.02, 95% CI: 3.06 to 5.28), or if their father was not in household (OR = 1.41, 95% CI: 1.24 to 1.56). Of the eligible children tested, 60 (4.6%) were HIV infected. CONCLUSIONS: HCT provides an opportunity to identify HIV among high-risk children; however, acceptance of HCT for children was limited. Further investigation is needed to identify and overcome barriers to testing uptake. PMID- 20714273 TI - Comparison of home and clinic-based HIV testing among household members of persons taking antiretroviral therapy in Uganda: results from a randomized trial. AB - OBJECTIVE: Due to high rates of undiagnosed and untreated HIV infection in Africa, we compared HIV counseling and testing (VCT) uptake among household members of patients receiving antiretroviral therapy. METHODS: HIV-infected persons attending an AIDS clinic were randomized to a home-based or clinic-based antiretroviral therapy program including VCT for household members. Clinic arm participants were given free VCT vouchers and encouraged to invite their household members to the clinic for VCT. Home arm participants were visited, and their household members offered VCT using a 3-test rapid finger-stick testing algorithm. VCT uptake and HIV prevalence were compared. FINDINGS: Of 7184 household members, 3974 (55.3%) were female and 4798 (66.8%) were in the home arm. Home arm household members were more likely to receive VCT than those from the clinic arm (55.8% vs. 10.9%, odds ratio: 10.41, 95% confidence interval: 7.89 to 13.73; P < 0.001), although the proportion of HIV-infected household members was higher in the clinic arm (17.3% vs. 7.1%, odds ratio: 2.76, 95% confidence interval: 1.97 to 3.86, P < 0.001). HIV prevalence among all household members tested in the home arm was 56% compared with 27% in the clinic arm. Of 148 spouses of HIV-infected patients, 69 (46.6%) were uninfected. Persons aged 15-24 were less likely to test than other age groups, and in the home arm, women were more likely to test than men. CONCLUSIONS: Home-based VCT for household members of HIV-infected persons was feasible, associated with lower prevalence, higher uptake, and increased identification of HIV-infected persons than clinic-based provision. PMID- 20714274 TI - Pneumatic retinopexy for retinal detachment associated with severe choroidal detachment. AB - PURPOSE: The purpose of this study was to evaluate the role of pneumatic retinopexy as an initial management of retinal detachment associated with hypotony, severe choroidal detachment, and vitritis. METHODS: Retrospective, interventional, noncomparative case series. We included nine eyes from nine patients (six women and three men) with retinal detachment associated with hypotony, severe choroidal detachment, and vitritis managed with pneumatic retinopexy (either SF6 or C3F8) as their initial management between January 1, 1992, and December 31, 2007. RESULTS: Hypotony and choroidal detachment were rapidly and significantly improved 1 to 3 days after pneumatic retinopexy in all patients. The extent of retinal detachment was decreased in five patients. After vitreoretinal surgery for these five patients, all had attached retina. Complete reattachment of the retina was noted in four patients after pneumatic retinopexy. Two of these patients did not require further surgery because the entire retina remained attached at 6 months and 16 months postoperatively. CONCLUSION: Pneumatic retinopexy is a useful initial procedure in managing retinal detachment associated with hypotony, severe choroidal detachment, and vitritis. By rapidly resolving the hypotony and choroidal detachments, it facilitates subsequent surgical repair of this complicated retinal detachment. In addition, complete retinal reattachment after pneumatic retinopexy alone was initially achieved in 33% of eyes. PMID- 20714275 TI - Outcomes following nonoperative and operative treatment for cervical disc herniations in National Football League athletes. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the performance based outcomes in elite athletes of the National Football League (NFL) after a cervical disc herniation. SUMMARY OF BACKGROUND DATA: Because outcomes after the treatment of cervical disc herniations (CDH) in elite athletes are currently unknown, the treatment decisions for this injury in professional football players are often controversial. METHODS: NFL players diagnosed with a CDH were identified through previously published protocols using team injury reports and newspaper archives. The "Performance Score" for each player was calculated on the basis of pertinent statistical data, before and after diagnosis of CDH. Data analysis was performed for players with at least a 2-year follow-up. RESULTS: A total of 99 NFL athletes met the inclusion criteria. In the operative group, on average, 38 of 53 (72%) players successfully returned to play for 29 games over a 2.8-year period, which was significantly greater than that of the nonoperative group, in which only 21 of 46 (46%) players successfully returned to the field to play after treatment for 15 games over a 1.5-year period (P < 0.04). Performance scores and the percentage of games started were not statistically significantly different for either cohort, before and after treatment. Notably, defensive backs had a significantly poorer outcome after treatment for CDH than any other position, playing in only 10 games over a 1.2-year period compared with all others (P < 0.0008). Age at diagnosis demonstrated a negative effect on career longevity after treatment. CONCLUSION: The data in this study suggest that players have higher return-to-play rates and longer careers after operative treatment than players treated with nonoperative means. Although confounding variables such as concomitant cervical stenosis could have affected these data, these performance-based outcomes after surgical treatment for CDH are better than previously thought. Defensive backs have a poorer prognosis after CDH compared with players of all other positions. PMID- 20714276 TI - Surgical management of primary bone tumors of the spine: validation of an approach to enhance cure and reduce local recurrence. AB - STUDY DESIGN: Multicenter ambispective cohort analysis. OBJECTIVE: The purpose of this study is to determine whether applying Enneking's principles to surgical management of primary bone tumors of the spine significant decreases local recurrence and/or mortality. SUMMARY OF BACKGROUND DATA: Oncologic management of primary tumors of spine has historically been inconsistent, controversial, and open to individual interpretation. METHODS: A multicenter ambispective cohort analysis from 4 tertiary care spine referral centers was done. Patients were analyzed in 2 cohorts, "Enneking Appropriate" (EA), surgical margin as recommended by Enneking, and "Enneking Inappropriate" (EI), surgical margin not recommended by Enneking. Benign tumors were not included in mortality analysis. RESULTS: Two cohorts represented an analytic dataset with 147 patients, 86 male, average age 46 years (range: 10-83). Median follow-up was 4 (2-7) years in the EA and 6 (5.5-15.5) years in the EI. Seventy-one patients suffered at least 1 local recurrence during the study, 57 of 77 in the EI group and 14 of 70 in the EA group. EI surgical approach caused higher risk of first local recurrence (P < 0.0001). There were 48 deaths in total; 29 in the EI group and 19 in the EA. There was a strong correlation between the first local recurrence and mortality with an odds ratio of 4.69, (P < 0.0001). EI surgical approach resulted in a higher risk of mortality with a hazard ratio of 3.10, (P = 0.0485) compared to EA approach. CONCLUSION: Surgery results in a significant reduction in local recurrence when primary bone tumors of the spine are resected with EA margins. Local recurrence has a high concordance with mortality in resection of these tumors. A significant decrease in mortality occurs when EA surgery is used. PMID- 20714277 TI - Spontaneous slip reduction of low-grade isthmic spondylolisthesis following circumferential release via bilateral minimally invasive transforaminal lumbar interbody fusion: technical note and short-term outcome. AB - STUDY DESIGN.: Retrospective clinical data analysis. OBJECTIVE.: To investigate and verify our philosophy of spontaneous slip reduction following circumferential release via bilateral minimally invasive transforaminal lumbar interbody fusion (Mini-TLIF) for treatment of low-grade symptomatic isthmic spondylolisthesis. SUMMARY OF BACKGROUND DATA.: Symptomatic isthmic spondylolisthesis usually requires surgical intervention, and the most currently controversial focus is on method and degree of reduction; and Mini-TLIF is an attractive surgical procedure for isthmic spondylolisthesis. METHODS.: Between February 2004 and June 2008, 21 patients with low-grade isthmic spondylolisthesis underwent Mini-TLIF in our institute. Total resection of the scar around the pars interarticularis liberated the nerve roots, achieving posterior release as well. The disc was thoroughly resected, and the disc space was gradually distracted and thoroughly released with sequential disc shavers until rupture of anulus conjunct with anterior longitudinal ligament, accomplishing anterior release, so as to insert Cages. Because of circumferential release, the slipped vertebrae would tend to obtain spontaneous reduction, and with pedicle screw fixation, additional reduction would be achieved without any application of posterior translation force. Radiographs, Visual Analogue Scale, and Oswestry Disability Index were documented. All the cases were followed up for 10 to 26 months. RESULTS.: Slip percentage was reduced from 24.2% +/- 6.9% to 10.5% +/- 4.0%, and foraminal area percentage increased from 89.1% +/- 3.0% to 93.6% +/- 2.1%. Visual Analogue Scale and Oswestry Disability Index decreased from 7.8 +/- 1.5 to 2.1 +/- 1.1 and from 53.3 +/- 16.2 to 17.0 +/- 7.8, respectively. No neurologic complications were encountered. There were no signs of instrumentation failure. The fusion rate approached 100%. CONCLUSION.: Slip reduction is based on circumferential release. The procedure can be well performed via Mini-TLIF, the outcome of which is equally gratifying to that of instrumented slip reduction and traditional midline approach. There is no need to fully reduce the slipped vertebrae. Circumferential release contributes to achieving spontaneous slip reduction partially, which aids sufficiently in the surgical treatment of low-grade isthmic spondylolisthesis. PMID- 20714278 TI - Aorta movement in patients with scoliosis after posterior surgery. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To evaluate movement of the aorta in patients with scoliosis who have undergone the posterior correction and fusion. SUMMARY OF BACKGROUND DATA: Surgeons check preoperative imaging for pedicle screw placement, but past analyses indicated that the aorta shifts after scoliosis surgery. Few studies, however, evaluated the aorta movement in detail. METHODS: A total of 22 patients with a right thoracic curve underwent posterior instrumentation and fusion. The average age at surgery was 17.2 years. The average of the preoperative Cobb angle was 65.2 degrees which decreased to 20.0 degrees .Computed-tomographic data were analyzed by multiplanar reconstruction. In our coordinate system, the middle of the base of the left superior facet was set as the origin and a line connecting the middle points of both bases of the superior facets was defined as the X-axis. We defined the angle and the distance to describe the aorta position and analyzed the movement of the aorta relative to the spine. Deformity parameters were examined to determine their correlation with the aorta parameters.We simulated variable pedicle screw placement and defined a warning pedicle when the aorta enters the expected area of the screw and examined them in 24 scenarios. RESULTS: The aorta moved 4.7 +/- 3.0 mm on an average. The aorta had a tendency to migrate in the anteromedial direction and this movement correlated with preoperative apical vertebral translation, preoperative sagittal alignment, and change of sagittal alignment. The ratio of warning pedicles at the middle thoracic level (T7-T9) increased after deformity correction. CONCLUSION: The aorta moved anteromedially relative to the spine after the posterior correction and the risk of the aorta by a pedicle screw increased by correction of the deformity at the middle thoracic spine. Surgeons are recommended to anticipate the aorta movement in the surgical planning. PMID- 20714279 TI - Less invasive posterior lumbar interbody fusion and obesity: clinical outcomes and return to work. AB - STUDY DESIGN: Single-center retrospective study. OBJECTIVE: The purpose of this study was to examine the relationship between obesity (body mass index [BMI] >30) and the incidence of perioperative complications, outcome of surgery, and return to work in a cohort of patients undergoing elective less invasive posterior lumbar interbody fusion (LI-PLIF) of the lumbar spine for low back pain and leg pain. SUMMARY OF BACKGROUND DATA: Spine surgery in the obese is challenging and an increasing problem. There are few reported studies that have assessed the incidence of perioperative complications in obese patients undergoing elective lumbar fusion procedures. To our knowledge, the effect of obesity on LI-PLIF and return to work has not been evaluated in the published data. METHODS: We identified 15 patients with BMI >30 who underwent LI-PLIF by reviewing the clinical notes and the preoperative admission sheet between April 2005 and March 2007. Patients who had suffered chronic low back pain for a minimum of 2 years that had proven unresponsive to conservative treatment were included. All patients underwent pre- and postoperative evaluations for Oswestry Disability Index, short-form 36, and visual analogue scores. Minimum follow-up was for 12 months. RESULTS: Blood loss was dependent on BMI, number of levels, and surgical time. Postoperative complication was 33.3%, which was more in the morbidly obese group than the in the obese group. Ten patients (66.6%) returned to their normal preoperative employment within 12 months of the index procedure. There was a significant improvement in the Oswestry Disability Index (14.78 +/- 6.0, P = 0.03), in the visual analogue scores for back pain (3.2 +/- 0.76, P = 0.001). Length of hospital stay was a mean of 3.35 days (range, 1-7). CONCLUSION: Surgical decision-making in the obese and morbidly obese patient is a challenge for the operating surgeon. Although surgery is technically more demanding, our experience with less invasive posterior interbody fusion has shown less incidence of postoperative complication, less intraoperative blood loss, and short in patient hospital stay. Furthermore (66.6%) returned to their normal preoperative employment within 12 months of the index procedure. We conclude that a high BMI should not be a contraindication to surgery in patients with degenerative low back pain. PMID- 20714280 TI - Region-dependent aggrecan degradation patterns in the rat intervertebral disc are affected by mechanical loading in vivo. AB - STUDY DESIGN: Immunoblotting study to evaluate aggrecan degradation patterns in rat intervertebral discs (IVDs) subjected to mechanical overload. OBJECTIVE: To evaluate the effects of in vivo dynamic compression overloading on aggrecan degradation products associated with matrix metalloproteinase (MMP) and aggrecanase activity in different regions of the IVD. SUMMARY OF BACKGROUND DATA: Aggrecan cleavage at the MMP and aggrecanase sites is an important event in human IVD aging, with distinct cleavage patterns in the anulus and nucleus regions.No such information is available on regional variations in rat IVDs, nor on how such cleavage is affected by mechanical loading. METHODS: Sprague-Dawley rats were instrumented with an Ilizarov-type device and subjected to dynamic compression (1 MPa and 1 Hz for 8 hours per day for 8 weeks). Control, sham, and overloaded IVDs were separated by disc region and analyzed for aggrecan degradation products using immunoblotting techniques, with antibodies specific for the aggrecanase and MMP cleavage sites in the interglobular domain of aggrecan. RESULTS: Control IVDs exhibited strong regional variation in aggrecan degradation patterns with minimal degradation products being present in the nucleus pulposus, degradation products associated with aggrecanase cleavage predominating in the inner anulus fibrosus (AF), and degradation products associated with MMP cleavage predominating in the outer AF. Dynamic compression overloading increased the amount of aggrecan degradation products associated with MMP cleavage not only in the AF but also in the nucleus pulposus. Degradation profiles of sham IVDs were similar to control. CONCLUSION: Aggrecan G1 regions resulting from proteolysis were found to have a strong regionally specific pattern in the rat IVD, which was altered under excessive loading. The shift from aggrecanase to MMP-induced degradation products with dynamic compression overloading suggests that protein degradation and loss can precede major structural disruption in the IVD, and that MMP-induced aggrecan degradation may be a marker of mechanically induced disc degeneration. PMID- 20714281 TI - Inflammatory cytokine and chemokine expression is differentially modulated acutely in the dorsal root ganglion in response to different nerve root compressions. AB - STUDY DESIGN: Inflammatory proteins were quantified in bilateral dorsal root ganglions (DRGs) at 1 hour and 1 day using a multiplexed assay after 2 different unilateral nerve root compression injuries. OBJECTIVE: To quantify cytokines and a chemokine in the DRG after nerve root compression with and without a chemical injury to determine contributing inflammatory factors in the DRG that may mediate radicular nociception in clinically relevant nerve root pathologies. SUMMARY OF BACKGROUND DATA: Inflammatory cytokines are known to relate to the behavioral hypersensitivity induced after injuries to the nerve root. However, the relative expression of these proteins in the DRG after cervical nerve root compression are not known. METHODS: The right C7 nerve root underwent transient compression (10 gf) or transient compression with a chemical irritation (10 gf + chr). The chemical injury was also given alone (chr), and the nerve root was exposed (sham), providing 2 types of controls. Mechanical allodynia was measured to assess behavioral outcomes. Interleukin (IL)-1b, IL-6, tumor necrosis factor-a, and macrophage inflammatory protein 3 (MIP3) were quantified in bilateral DRGs at 1 hour and 1 day using a multiplexed assay. RESULTS: Ipsilateral allodynia at day 1 after 10 gf + chr was significantly increased over both 10 gf and chr (P < 0.049). Cytokines and MIP3 were not statistically increased over sham at 1 hour. By day 1 after 10 gf + chr, all proteins (IL-1beta, IL-6, tumor necrosis factor a, MIP3) were significantly increased over both normal and sham in the ipsilateral DRG (P < 0.036), and the cytokines were also significantly increased over chr (P < 0.029). Despite allodynia at day 1, cytokines at that time were not increased over normal or sham after either 10 gf or chr. CONCLUSION: Nerve root compression alone may not be sufficient to induce early increases in proinflammatory cytokines in the DRG after radiculopathy and this early protein response may not be directly responsible for nociception in this type of injury. PMID- 20714282 TI - Involvement of calcitonin gene-related peptide innervation in the promoting effect of low-intensity pulsed ultrasound on spinal fusion without decortication. AB - STUDY DESIGN: A prospective left-right comparison designed experiment using a rabbit posterolateral intertransverse process fusion model. OBJECTIVE: To investigate the involvement of calcitonin gene-related peptide (CGRP) innervation in the promoting effect of low intensity pulsed ultrasound stimulation (LIPUS) on spinal fusion without decortication. SUMMARY OF BACKGROUND DATA: Sensory neuropeptide CGRP is involved in bone repair and ectopic ossification. Comparison of CGRP innervations in ectopic bone between sham LIPUS and LIPUS sides can help us to understand the relationship between sensory nerve innervation and LIPUS. METHODS: A total of 27 New Zealand white rabbits underwent bilateral posterolateral intertransverse process fusion with implantation of porous poly D,L-lactic acid blocks loaded with 1.25 MUg recombinant human bone morphogenetic protein-4 solution. One side was provided LIPUS daily whereas the other side served as control. Animals were killed and the operated lumbar vertebrae were harvested for histomorphologic evaluation at 3 days (n = 3), 1 week (n = 6), 3 weeks (n = 6), 7 weeks (n = 6), and 12 weeks (n = 6) following surgery, respectively. RESULTS: LIPUS accelerated the invasion of CGRP-positive nerve fibers during ectopic ossification spatially and temporally. Spatially, CGRP positive nerve fibers were also observed in the new formed cartilage and bone tissues on LIPUS side, whereas they were only detected in the fibrous tissue and bone marrow on sham LIPUS side. Temporally, the density of CGRP-positive nerve fibers was significantly higher on the LIPUS side when compared with the sham LIPUS side. CONCLUSION: LIPUS promoted the invasion of CGRP sensory nerve in ectopic bone, which may in turn contribute to the promoting effect of LIPUS on ectopic ossification. PMID- 20714284 TI - Cooperative signaling for angiogenesis and neovascularization by VEGF and HGF following islet transplantation. AB - BACKGROUND: Delayed angiogenesis remains a significant challenge to the survival of transplanted islets. In this study, using a murine model of subcutaneous islet transplantation with matrigel basement membrane matrix, we determined the role of the proangiogenic growth factors in enhancing the islet engraftment. METHODS: BALB/c islets were transplanted subcutaneously in growth factor reduced (GFR) or growth factor supplemented (GFS) matrigel into diabetic severe combined immunodeficient mice. GFS matrigel was prepared by supplementing GFR with proangiogenic factors, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The functioning grafts were harvested at 15 days and vessel formation was analyzed histopathologically. RESULTS: Our results demonstrate that suboptimal (250) islet equivalents in GFS-VEGF+HGF were able to restore normoglycemia, whereas those transplanted in GFR failed to reverse diabetes. Histopathology of the GFS-VEGF+HGF graft revealed 12+/-3 blood vessels per field, whereas GFR, GFS-VEGF, and GFS-HGF grafts had only 3+/-1, 6+/-2, and 4+/-1 blood vessels, respectively. Insulin staining demonstrated increased number of islets in matrigel supplemented with VEGF and HGF. Protein and mRNA analysis demonstrated enhanced intercellular adhesion molecule and vascular cell adhesion molecule within the islets when supplemented with both VEGF+HGF suggesting stable blood vessel formation. Transcription factors focal adhesion kinase phosphorylation and extracellular signal-regulated kinase1/2 phosphorylation were also increased (8-fold and 4.6-fold, respectively) when both the growth factors were present. There was weak expression of transcription factors when VEGF or HGF were supplemented alone. CONCLUSION: We conclude that proangiogenic growth factors, VEGF and HGF, synergistically enhance angiogenesis after islet transplantation leading to stable engraftment. PMID- 20714283 TI - Behavioral signs of chronic back pain in the SPARC-null mouse. AB - STUDY DESIGN: Secreted Protein, Acidic, and Rich in Cysteine (SPARC)-null mice were examined for behavioral signs of chronic low back and/or radicular pain. OBJECTIVE: to assess SPARC-null mice as an animal model of chronic low back and/or radicular pain caused by degenerative disc disease. SUMMARY OF BACKGROUND DATA: degeneration of intervertebral discs is a major cause of chronic low back and adicular pain in humans. Inactivation of the SPARC gene in mice results in premature intervertebral disc degeneration. The effect of disc degeneration on behavioral measures of chronic pain has not been evaluated in this model. METHODS: cohorts of young and old (3 and 6-12 months, respectively) SPARC-null and wild-type control mice were screened for behavioral indices of low back and/or radiating pain. Sensitivity to mechanical, cold and heat stimuli, locomotor impairment, and movement-evoked hypersensitivity were determined. Animals were challenged with 3 analgesic agents with different mechanisms: morphine, dexamethasone, and gabapentin. RESULTS: SPARC-null mice showed signs of movement-evoked discomfort as early as 3 months of age. Hypersensitivity to cold stimuli on both the lower back and hindpaws developed with increasing age. SPARC null mice had normal sensitivity to tactile and heat stimuli, and locomotor skills were not impaired. The hypersensitivity to cold was reversed by morphine, but not by dexamethasone or gabapentin. CONCLUSION: SPARC-null mice display behavioral signs consistent with chronic low back and radicular pain that we attribute to intervertebral disc degeneration. We hypothesize that the SPARC-null mouse is useful as a model of chronic back pain due to degenerative disc disease. PMID- 20714285 TI - The protective effects of the active fraction of Shaofu Zhuyu decoction on hydrogen peroxide-induced oxidative injury in vascular smooth muscle cells. AB - In this paper, the protective effects of the active fraction (SF-7) from Shaofu Zhuyu decoction (SFZYD) were tested on a hydrogen peroxide (H(2)O(2))-induced rat vascular smooth muscle cells (VSMCs) oxidative injury model. This active fraction (SF-7) shows potent antioxidant properties. The cell viability and oxidative damage markers of VSMCs were determined after exposure to H(2)O(2) for 16 hours. It was observed that SF-7 significantly increased cell survival and reduced apoptosis of H(2)O(2)-injured VSMCs. Moreover, SF-7 could markedly increase intracellular superoxide dismutase (SOD) activity and decrease the malondialdehyde (MDA) level in H(2)O(2)-injured VSMCs, and suppress the generation of intracellular reactive oxygen species (ROS), as well as intracellular Ca2+ concentration. Thus, SF-7 exhibits protective effects against H(2)O(2)-injury on VSMCs, which may be associated with its antioxidant properties. It is suggested that SF may be useful in the treatment of blood stasis syndrome in which oxidative injury is mainly implicated. PMID- 20714286 TI - Functionality pattern matching as an efficient complementary structure/reaction search tool: an open-source approach. AB - An open-source software package for creating and operating web-based structure and/or reaction databases is presented. Besides standard search capabilities (text, structure/substructure/similarity), the system offers a fast additional search option, entirely based on binary pattern matching, which uses automatically assigned functional group descriptors. PMID- 20714287 TI - Identification of two polysaccharides from Prunella vulgaris L. and evaluation on their anti-lung adenocarcinoma activity. AB - Prunella vulgaris L. (PV) has been used for tumor therapy in Traditional Chinese Medicine for centuries, however, systematic research on extracted PV polysaccharides believed to possess various biological activities, as well as their preventive and anti-tumor effects on lung cancer has not been reported. In this study, two polysaccharides (P31 and P32) were isolated from the aqueous extract of PV and purified through ethanol precipitation, followed by deproteination using DEAE-52 gel-filtration chromatography. The main monosaccharide composition of polysaccharide P32 was analyzed by GC. It was found that polysaccharide P32 consisted of rhamnose, arabinose, xylose, mannose, glucose and galactose in a molar ratio of 3.46:49.32:58.91:0.43:2.64: 3.11, respectively. In order to evaluate polysaccharide P32's anti-lung adenocarcinoma activities and immunomodulation effects, a C57BL/6 mouse-Lewis lung carcinoma (LLC) model was established and investigated. Our results showed that polysaccharides of PV had anti-lung cancer activity and could increase the thymus index and the spleen index in tumor-bearing mice, suggesting possible immunomodulation effects. PMID- 20714288 TI - Synthesis and odor evaluation of five new sulfur-containing ester flavor compounds from 4-ethyloctanoic acid. AB - Five sulfur-containing flavor compounds were synthesized for the first time by the reaction of 4-ethyloctanoyl chloride with sulfur-containing alcohols or mercaptans. The synthesized compounds are 3-(methylthio)propyl 4-ethyloctanoate, 2-methyl-3-tetrahydro-furanthiol 4-ethyloctanoate, 4-methyl-5-thiazoleethanol 4 ethyloctanoate, 2-furan-methanethiol 4-ethyloctanoate and 2-methyl-3-furanthiol 4 ethyloctanoate. These five synthetic sulfur-containing ester flavor compounds all have meaty odor and might be used in foods if approved for this purpose in the future. PMID- 20714289 TI - Synthesis and antiviral bioactivity of chiral thioureas containing leucine and phosphonate moieties. AB - A series of novel chiral thioureas 3a-n bearing leucine and phosphonate moieties were synthesized in excellent yields. The structures of the compounds were completely characterized by elemental analysis, IR, 1H-, 13C-, 31P- and 19F-NMR spectral data. A half-leaf method was used to determine the in vivo protective and curative efficacies of the title products against tobacco mosaic virus (TMV). The compounds 3l and 3n displayed good in vivo protection and curative effects against TMV with inhibitory rates of 60.1, 62.8% (protection) and 56.7, 53.6% (curative) at 0.5 mg/mL, respectively. To the best of our knowledge, this is the first report on the antiviral activity of chiral thioureas containing leucine and phosphonate moieties. PMID- 20714291 TI - Hydrogenation of ethyl acetate to ethanol over Ni-based catalysts obtained from Ni/Al hydrotalcite-like compounds. AB - A series of Ni-based catalysts were prepared using hydrogen reduction of Ni/Al hydrotalcite-like compounds (Ni/Al HTlcs) synthesized by coprecipitation. The physico-chemical properties of Ni/Al hydrotalcite-like compounds and the corresponding Ni-based catalysts were characterized using inductively coupled plasma (ICP), BET surface areas, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) techniques. The results indicated that Ni/Al HTlcs with layered structures could be successfully prepared by the coprecipitation method, and the characteristic HTlcs reflections were also observed in the XRD analysis. The NiO and Ni0 phases were identified in all Ni-based catalysts, which displayed randomly interconnected pores and no layer structures. In addition, the studies also found the Ni/Al HTlcs and Ni-based catalysts had high specific surface areas, low pore volumes and low pore diameters. The catalytic hydrogenation of ethyl acetate to ethanol with Ni-based catalysts was also investigated. Among the studied catalysts, RE1NASH-110-3 showed the highest selectivity and yield of ethyl acetate to ethanol, which were 68.2% and 61.7%, respectively. At the same time, a major by product, butyl acetate, was formed due to an ester-exchange reaction. A proposed hydrogenation pathway for ethyl acetate over Ni-based catalysts was suggested. PMID- 20714290 TI - Antiplatelet aggregation and platelet activating factor (PAF) receptor antagonistic activities of the essential oils of five Goniothalamus species. AB - Nine essential oils, hydrodistilled from different parts of five Goniothalamus species (G. velutinus Airy-Shaw, G. woodii Merr., G. clemensii Ban, G. tapis Miq. and G. tapisoides Mat Salleh) were evaluated for their ability to inhibit platelet aggregation in human whole blood using an electrical impedance method and their inhibitory effects on platelet activating factor (PAF) receptor binding with rabbit platelets using 3H-PAF as a ligand. The chemical composition of the oils was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The bark oil of G. velutinus was the most effective sample as it inhibited both arachidonic acid (AA) and ADP-induced platelet aggregation with IC(50) values of 93.6 and 87.7 microg/mL, respectively. Among the studied oils, the bark oils of G. clemensii, G. woodii, G. velutinus and the root oil of G. tapis showed significant inhibitory effects on PAF receptor binding, with IC(50 )values ranging from 3.5 to 10.5 microg/mL. The strong PAF antagonistic activity of the active oils is related to their high contents of sesquiterpenes and sesquiterpenoids, and the individual components in the oils could possibly produce a synergistic effect in the overall antiplatelet activity of the oils. PMID- 20714292 TI - Synthesis of beta-maltooligosaccharides of glycitein and daidzein and their anti oxidant and anti-allergic activities. AB - The production of beta-maltooligosaccharides of glycitein and daidzein using Lactobacillus delbrueckii and cyclodextrin glucanotransferase (CGTase) as biocatalysts was investigated. The cells of L. delbrueckii glucosylated glycitein and daidzein to give their corresponding 4'- and 7-O-beta-glucosides. The beta glucosides of glycitein and daidzein were converted into the corresponding beta maltooligosides by CGTase. The 7-O-beta-glucosides of glycitein and daidzein and 7-O-beta-maltoside of glycitein showed inhibitory effects on IgE antibody production. On the other hand, beta-glucosides of glycitein and daidzein exerted 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging activity and supeoxide-radical scavenging activity. PMID- 20714293 TI - Characterization of dextrins with different Dextrose Equivalents. AB - Dextrins are widely used for their functional properties and prepared by partial hydrolysis of starch using acid, enzymes, or combinations of both. The physiochemical properties of dextrins are dependent on their molecular distribution and oligosaccharide profiles. In this study, scanning electron microscopy (SEM), X-ray diffractometry (XRD), rapid viscoanalysis (RVA), high performance Liquid Chromatography (HPLC) and gel permeation chromatography (GPC) were used to characterize dextrins prepared by common neutral and thermostable alpha-amylase hydrolysis. The dextrin granules displayed irregular surfaces and were badly damaged by the enzyme treatment. They displayed A-type X-ray diffraction patterns with a decrease of intensity of the characteristic diffraction peaks. The RVA profiles showed that the viscosity of dextrin decreased with the increase of its Dextrose Equivalent (DE) value. According to HPLC analysis, the molecular weight, degree of polymerization and the composition of oligosaccharides in dextrins were different. PMID- 20714294 TI - Chemistry of nitroquinolones and synthetic application to unnatural 1-methyl-2 quinolone derivatives. AB - The 1-methyl-2-quinolone (MeQone) framework is often found in alkaloids and recently attention was drawn to unnatural MeQone derivatives with the aim of finding new biologically active compounds, however, low reactivity of the MeQone framework prevents the syntheses of versatile derivatives. A nitro group is one of the useful activating groups for this framework that enables a concise chemical transformation. Among nitroquinolones, 1-methyl-3,6,8-trinitro-2 quinolone (TNQ) exhibits unusual reactivity favoring region-selective cine substitutions that afford 4-substituted 1-methyl-6,8-dinitro-2-quinolones upon treatment with nucleophilic reagents. Contrary to this, 1-methyl-3,6-dinitro-2 quinolone (3,6-DNQ) does not undergo any reaction under the same conditions. The unusual reactivity of TNQ is caused by steric repulsion between the methyl group at the 1-position and the nitro group at the 8-position, which distorts the MeQone framework. As a result, the pyridone ring of TNQ loses aromaticity and acts rather as an activated nitroalkene. Indeed, the pyridone moiety of TNQ undergoes cycloaddition with electron-rich alkenes or dienes under mild conditions, whereby a new fused ring is constructed on the [c]-face of the MeQone. Consequently, TNQ can be used as a new scaffold leading to versatile unnatural MeQone derivatives. PMID- 20714295 TI - Photochemistry of flavonoids. AB - Flavonoids and their photochemical transformations play an important role in biological processes in nature. Synthetic photochemistry allows access to molecules that cannot be obtained via more conventional methods. This review covers all published synthetic photochemical transformations of the different classes of flavonoids. It is first comprehensive review on the photochemistry of flavonoids. PMID- 20714296 TI - Pre-ischemic treadmill training induces tolerance to brain ischemia: involvement of glutamate and ERK1/2. AB - Physical exercise has been shown to be beneficial in stroke patients and animal stroke models. However, the exact mechanisms underlying this effect are not yet very clear. The present study investigated whether pre-ischemic treadmill training could induce brain ischemic tolerance (BIT) by inhibiting the excessive glutamate release and event-related kinase 1/2 (ERK1/2) activation observed in rats exposed to middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into three groups (n = 12/group): sham surgery without prior exercise, MCAO without prior exercise and MCAO following three weeks of exercise. Pre-MCAO exercise significantly reduced brain infarct size (103.1 +/- 6.7 mm3) relative to MCAO without prior exercise (175.9 +/- 13.5 mm3). Similarly, pre-MCAO exercise significantly reduced neurological defects (1.83 +/- 0.75) relative to MCAO without exercise (3.00 +/- 0.63). As expected, MCAO increased levels of phospho ERK1/2 (69 +/- 5%) relative to sham surgery (40 +/- 5%), and phospho-ERK1/2 levels were normalized in rats exposed to pre-ischemic treadmill training (52 +/- 6%) relative to MCAO without exercise (69% +/- 5%). Parallel effects were observed on striatal glutamate overflow. This study suggests that pre-ischemic treadmill training might induce neuroprotection by inhibiting the phospho-ERK1/2 over-activation and reducing excessive glutamate release. PMID- 20714297 TI - Catalytic conversion of cellulose to levulinic acid by metal chlorides. AB - The catalytic performance of various metal chlorides in the conversion of cellulose to levulinic acid in liquid water at high temperatures was investigated. The effects of reaction parameters on the yield of levulinic acid were also explored. The results showed that alkali and alkaline earth metal chlorides were not effective in conversion of cellulose, while transition metal chlorides, especially CrCl(3), FeCl(3) and CuCl(2) and a group IIIA metal chloride (AlCl(3)), exhibited high catalytic activity. The catalytic performance was correlated with the acidity of the reaction system due to the addition of the metal chlorides, but more dependent on the type of metal chloride. Among those metal chlorides, chromium chloride was found to be exceptionally effective for the conversion of cellulose to levulinic acid, affording an optimum yield of 67 mol % after a reaction time of 180 min, at 200 degrees C, with a catalyst dosage of 0.02 M and substrate concentration of 50 wt %. Chromium metal, most of which was present in its oxide form in the solid sample and only a small part in solution as Cr3+ ion, can be easily separated from the resulting product mixture and recycled. Finally, a plausible reaction scheme for the chromium chloride catalyzed conversion of cellulose in water was proposed. PMID- 20714298 TI - 2-(penta-1,3-diynyl)-5-(3,4-dihydroxybut-1-ynyl)thiophene, a novel NQO1 inducing agent from Echinops grijsii Hance. AB - A natural alkynol group-substituted thiophene, 2-(penta-1,3-diynyl)-5-(3,4 dihydroxybut-1-ynyl)-thiophene (PDDYT), was isolated from the roots of Echinops grijsii Hance. It possessed potent NAD(P)H: quinone oxidoreductase1 (NQO1) inducing activity and could activate Keap1-Nrf2 pathway effectively in murine hepatoma Hepa 1c1c7 cells. Further investigations indicated that the activation of Keap1-Nrf2 pathway by PDDYT might be attributed to the activation of Akt and depleting the cellular glutathione (GSH). PMID- 20714300 TI - Chalcones and dihydrochalcones augment TRAIL-mediated apoptosis in prostate cancer cells. AB - Chalcones and dihydrochalcones exhibit chemopreventive and antitumor activity. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a natural endogenous anticancer agent. We examined the cytotoxic and apoptotic effect of chalcones and dihydrochalcones on TRAIL-mediated apoptosis in LNCaP prostate cancer cells. The cytotoxicity was evaluated by the MTT and LDH assays. The apoptosis was detected using annexin V-FITC by flow cytometry and fluorescence microscopy. The DeltaPsim was evaluated using DePsipher staining by fluorescence microscopy. Our study showed that two tested chalcones (chalcone and 2',6'dihydroxy-4'-methoxychalcone) and three dihydrochalcones (2',6'-dihydroxy 4'4-dimethoxydihydrochalcone, 2',6'-dihydroxy-4'-methoxydihydro- chalcone, and 2',4',6'-trihydroxydihydrochalcone, called phloretin) markedly augmented TRAIL induced apoptosis and cytotoxicity in LNCaP cells and confirmed the significant role of chalcones in chemoprevention of prostate cancer. PMID- 20714299 TI - Solid-phase synthesis of N-substituted glycine oligomers (alpha-peptoids) and derivatives. AB - Peptoids (N-substituted polyglycines and extended peptoids with variant backbone amino-acid monomer units) are oligomeric synthetic polymers that are becoming a valuable molecular tool in the biosciences. Of particular interest are their applications to the exploration of peptoid secondary structures and drug design. Major advantages of peptoids as research and pharmaceutical tools include the ease and economy of synthesis, highly variable backbone and side-chain chemistry possibilities. At the same time, peptoids have been demonstrated as highly active in biological systems while resistant to proteolytic decay. This review with 227 references considers the solid-phase synthetic aspects of peptoid preparation and utilization up to 2010 from the instigation, by R. N. Zuckermann et al., of peptoid chemistry in 1992. PMID- 20714301 TI - Effects of time point measurement on the reconstruction of gene regulatory networks. AB - With the availability of high-throughput gene expression data in the post-genomic era, reconstruction of gene regulatory networks has become a hot topic. Regulatory networks have been intensively studied over the last decade and many software tools are currently available. However, the impact of time point selection on network reconstruction is often underestimated. In this paper we apply the Dynamic Bayesian network (DBN) to construct the Arabidopsis gene regulatory networks by analyzing the time-series gene microarray data. In order to evaluate the impact of time point measurement on network reconstruction, we deleted time points one by one to yield 11 distinct groups of incomplete time series. Then the gene regulatory networks constructed based on complete and incomplete data series are compared in terms of statistics at different levels. Two time points are found to play a significant role in the Arabidopsis gene regulatory networks. Pathway analysis of significant nodes revealed three key regulatory genes. In addition, important regulations between genes, which were insensitive to the time point measurement, were also identified. PMID- 20714302 TI - Highly efficient procedure for the synthesis of fructone fragrance using a novel carbon based acid. AB - The novel carbon based acid has been synthesized via one-step hydrothermal carbonization of furaldehyde and hydroxyethylsulfonic acid. A highly efficient procedure for the synthesis of fructone has been developed using the novel carbon based acid. The results showed that the catalyst possessed high activity for the reaction, giving a yield of over 95%. The advantages of high activity, stability, reusability and low cost for a simple synthesis procedure and wide applicability to various diols and beta-keto esters make this novel carbon based acid one of the best choices for the reaction. PMID- 20714303 TI - Simultaneous determination of flavonoids in different parts of Citrus reticulata 'Chachi' fruit by high performance liquid chromatography-photodiode array detection. AB - Flavonoids are important polyphenolic secondary metabolites in plant. Citrus reticulata 'Chachi' fruit are rich in flavonoids and are being used as functional antioxidant ingredients for the treatment of atherosclerosis and cancer, etc. A high performance liquid chromatography-photodiode array detection system was used to analyze five flavonoids, namely, naringin, hesperidin, didymin, tangeretin and nobiletin, in different parts of C. reticulata 'Chachi' fruit. The chromatographic analysis was performed on a C(18) column with a gradient elution of acetonitrile and water at a flow rate of 1.0 mL/min. Detection was carried out using a photodiode array detector at 280 nm. The calibration curves for the determination of all analytes showed good linearity over the investigated ranges (R2 > 0.9995). Precision and reproducibility were evaluated by six replicated analyses, and the R.S.D. values were less than 0.9% and 2.7%. The recoveries were between 98.37 and 103.89%. This method is promising to improve the quality control of different parts of C. reticulata 'Chachi' fruit. PMID- 20714305 TI - Using topological indices to predict anti-Alzheimer and anti-parasitic GSK-3 inhibitors by multi-target QSAR in silico screening. AB - Plasmodium falciparum, Leishmania, Trypanosomes, are the causers of diseases such as malaria, leishmaniasis and African trypanosomiasis that nowadays are the most serious parasitic health problems worldwide. The great number of deaths and the few drugs available against these parasites, make necessary the search for new drugs. Some of these antiparasitic drugs also are GSK-3 inhibitors. GSKI-3 are candidates to develop drugs for the treatment of Alzheimer's disease. In this work topological descriptors for a large series of 3,370 active/non-active compounds were initially calculated with the ModesLab software. Linear Discriminant Analysis was used to fit the classification function and it predicts heterogeneous series of compounds like paullones, indirubins, meridians, etc. This study thus provided a general evaluation of these types of molecules. PMID- 20714304 TI - Hammerhead ribozymes: true metal or nucleobase catalysis? Where is the catalytic power from? AB - The hammerhead ribozyme was first considered as a metalloenzyme despite persistent inconsistencies between structural and functional data. In the last decade, metal ions were confirmed as catalysts in self-splicing ribozymes but displaced by nucleobases in self-cleaving ribozymes. However, a model of catalysis just relying on nucleobases as catalysts does not fully fit some recent data. Gathering and comparing data on metal ions in self-cleaving and self splicing ribozymes, the roles of divalent metal ions and nucleobases are revisited. Hypothetical models based on cooperation between metal ions and nucleobases are proposed for the catalysis and evolution of this prototype in RNA catalysis. PMID- 20714307 TI - Antioxidant activity of butyl- and phenylstannoxanes derived from 2-, 3- and 4 pyridinecarboxylic acids. AB - In vitro antioxidant activity for 12 stannoxanes derived from Ph(3)SnCl (compounds 1-3), Ph(2)SnCl(2) (compounds 4-6), Bu(3)SnCl (compounds 7-9), and Bu(2)SnCl(2) (compounds 10-12), was assayed qualitatively by the chromatographic profile with 1,1-diphenyl-2-picrylhydrazil (DPPH) method and by two quantitative methods: the DPPH radical scavenging activity and Ferric-Reducing Antioxidant Power (FRAP) assays. The results were compared with those obtained with the starting materials 2-pyridine- carboxylic acid (I), 3-pyridinecarboxylic acid (II) and 4-pyridinecarboxylic acid (III), as well as with standard compounds, such as vitamin C and vitamin E, respectively. The in vitro antiradical activity with DPPH of diphenyltin derivative 5 showed a very similar behavior to vitamin C at a 20 microg/mL concentration, whereas according to the FRAP method, compound 8 was better. This difference is due to the mechanism of the antioxidant process. The Structure-Activity Relationships (SAR) for both methods is also reported. PMID- 20714306 TI - Molecular evolution of functional nucleic acids with chemical modifications. AB - Nucleic acids are attractive materials for creating functional molecules that have applications as catalysts, specific binders, and molecular switches. Nucleic acids having such functions can be obtained by random screening, typically using in vitro selection methods. These methods have helped explore the potential abilities of nucleic acids and steadily contributed to their evolution, i.e., creation of RNA/DNA enzymes, aptamers, and aptazymes. Chemical modification would be a key means to further increase their performance, e.g., expansion of function diversity, enhancement of activity, and improvement of biostability for biological use. Indeed, in the past two decades, random screening involving chemical modification, post-SELEX chemical modification, and rational design methods have been advanced, and combining and integrating these methods may produce a new class of functional nucleic acids. This review focuses on the effectiveness of chemical modifications on the evolution of nucleic acids as functional molecules and the outlook for related technologies. PMID- 20714309 TI - Preparation of Tyrian purple (6,6'-dibromoindigo): past and present. AB - Over the past century, various synthetic approaches have been suggested to the most famous dye of antiquity, Tyrian purple (6,6'-dibromoindigo). These synthetic routes have been exhaustively surveyed and critically evaluated from the perspective of convenience, cost, safety and yield. PMID- 20714308 TI - The application of ribozymes and DNAzymes in muscle and brain. AB - The discovery of catalytic nucleic acids (CNAs) has provided scientists with valuable tools for the identification of new therapies for several untreated diseases through down regulation or modulation of endogenous gene expression involved in these ailments. These CNAs aim either towards the elimination or repair of pathological gene expression. Ribozymes, a class of CNAs, can be mostly used to down-regulate (by RNA cleavage) or repair (by RNA trans-splicing) unwanted gene expression involved in disease. DNAzymes, derived by in vitro selection processes are also able to bind and cleave RNA targets and therefore down-regulate gene expression. The purpose of this review is to present and discuss several applications of ribozymes and DNAzymes in muscle and brain. There are several diseases which affect muscle and brain and catalytic nucleic acids have been used as tools to target specific cellular transcripts involved in these groups of diseases. PMID- 20714310 TI - Seasonal variation, chemical composition, and analgesic and antimicrobial activities of the essential oil from leaves of Tetradenia riparia (Hochst.) Codd in southern Brazil. AB - The seasonal variation of the chemical composition of the essential oil from fresh leaves of Tetradenia riparia (Hochst.) Codd grown in southern Brazil was analyzed by GC-MS, and the analgesic and antimicrobial activities of this oil were assayed. The yield of essential oil ranged from 0.17% to 0.26%, with the maximum amount in winter and the minimum in spring. The results obtained from principal components analysis (PCA) revealed the existence of high chemical variability in the different seasons. The samples were clearly discriminated into three groups: winter, autumn, and spring-summer. Samples collected during winter contained the highest percentages of calyculone (24.70%), abietadiene (13.54%), and viridiflorol (4.20%). In autumn, the major constituents were ledol (8.74%) and cis-muurolol-5-en-4-alpha-ol (13.78%). Samples collected in spring-summer contained the highest percentages of fenchone (12.67%), 14-hydroxy-9-epi caryophyllene (24.36%), and alpha-cadinol (8.33%). Oxygenated sesquiterpenes were predominant in all the samples analyzed. The observed chemovariation might be environmentally determined by a seasonal influence. The essential oil, when given orally at a dose of 200 mg/kg, exhibited good analgesic activity on acetic acid induced writhing in mice, inhibiting the constrictions by 38.94% to 46.13%, and this effect was not affected by seasonal variation. The antimicrobial activity of the essential oil against the bacterial strains: Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, Morganella morganii, and Enterobacter cloacae, and the pathogenic fungus Candida albicans was assessed by the disc diffusion method and determination of the minimum inhibitory concentration. The results obtained, followed by measurement of the minimum inhibitory concentration (MIC), indicated that S. aureus, B. subtilis, and Candida albicans were the most sensitive microorganisms, showing largest inhibition, and the lowest MIC values varied from 15.6 to 31.2 microg/mL, 7.8 to 15.6 microg/mL, and 31.2 to 62.5 microg/mL, respectively. PMID- 20714311 TI - Nanofabrication of nonfouling surfaces for micropatterning of cell and microtissue. AB - Surface engineering techniques for cellular micropatterning are emerging as important tools to clarify the effects of the microenvironment on cellular behavior, as cells usually integrate and respond the microscale environment, such as chemical and mechanical properties of the surrounding fluid and extracellular matrix, soluble protein factors, small signal molecules, and contacts with neighboring cells. Furthermore, recent progress in cellular micropatterning has contributed to the development of cell-based biosensors for the functional characterization and detection of drugs, pathogens, toxicants, and odorants. In this regards, the ability to control shape and spreading of attached cells and cell-cell contacts through the form and dimension of the cell-adhesive patches with high precision is important. Commitment of stem cells to different specific lineages depends strongly on cell shape, implying that controlled microenvironments through engineered surfaces may not only be a valuable approach towards fundamental cell-biological studies, but also of great importance for the design of cell culture substrates for tissue engineering. To develop this kind of cellular microarray composed of a cell-resistant surface and cell attachment region, micropatterning a protein-repellent surface is important because cellular adhesion and proliferation are regulated by protein adsorption. The focus of this review is on the surface engineering aspects of biologically motivated micropatterning of two-dimensional surfaces with the aim to provide an introductory overview described in the literature. In particular, the importance of non-fouling surface chemistries is discussed. PMID- 20714312 TI - Chemical constituents with free-radical-scavenging activities from the stem of Microcos paniculata. AB - The free-radical-scavenging activities of various solvent extracts of Microcos paniculata were evaluated through in vitro model systems, such as 1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS) and Co (II) EDTA-induced luminol chemiluminescence by flow injection. In all three of these systems the ethyl acetate (EtOAc) extract showed the highest free radical-scavenging activity compared with the other three (n-BuOH, water and petroleum ether) extracts. Free-radical-scavenging assay-guided chromatographic separation of the EtOAc extract, using a normal-phase and reverse-phase silica gel column chromatography yielded five compounds: a new triterpene named methyl 3beta-O-p-hydroxy-E-cinnamoyloxy-2alpha,23-dihydroxyolean-12-en-28-oate (1), whose spectral data are presented for the first time, together with four known compounds, epicatechin (2), 3-trans-feruloyl maslinic acid (3), maslinic acid (4) and sucrose (5). All of the compounds were isolated from Microcos paniculata for the first time. The compounds were identified by spectroscopic methods. Among them, compound 2 displayed significant free-radical-scavenging activity which is similar to that of standard antioxidant ascorbic acid (V(C)) and therefore may be a promising natural antioxidant. PMID- 20714313 TI - A simple, safe and efficient synthesis of Tyrian purple (6,6'-dibromoindigo). AB - 6,6'-Dibromoindigo is a major component of the historic pigment Tyrian purple, arguably the most famous dye of antiquity. Over the last century, chemists have been interested in developing practical syntheses of the compound We describe herein a new, reasonably simple and efficient synthesis of Tyrian purple which opens the way to the production of large quantities of the dye with minimal hazards and at low cost. PMID- 20714315 TI - Enantioselctive syntheses of sulfur analogues of flavan-3-Ols. AB - The first enantioselective syntheses of sulfur flavan-3-ol analogues 1-8 have been accomplished, whereby the oxygen atom of the pyran ring has been replaced by a sulfur atom. The key steps were: (a) Pd(0) catalyzed introduction of -S t-butyl group, (b) Sharpless enantioselective dihydroxylation of the alkene, (c) acid catalyzed ring closure to produce the thiopyran ring, and (d) removal of benzyl groups using N,N-dimethylaniline and AlCl(3). The compounds were isolated in high chemical and optical purity. PMID- 20714316 TI - Synthesis and characterization of azo compounds and study of the effect of substituents on their liquid crystalline behavior. AB - In this paper we present six select mesomorphic azo compounds distinguished by the presence of diverse substituents on a central benzene nucleus. All the synthesized compounds exhibit enantiotropic mesophases. The mesomorphic properties of the substituted compounds were compared with those of the unsubstituted parent compound to evaluate the effect of the nature and position of the substituents on mesomorphism. PMID- 20714314 TI - Emerging biological importance of central nervous system lanthionines. AB - Lanthionine (Lan), the thioether analog of cystine, is a natural but nonproteogenic amino acid thought to form naturally in mammals through promiscuous reactivity of the transsulfuration enzyme cystathionine-beta-synthase (CbetaS). Lanthionine exists at appreciable concentrations in mammalian brain, where it undergoes aminotransferase conversion to yield an unusual cyclic thioether, lanthionine ketimine (LK; 2H-1,4-thiazine-5,6-dihydro-3,5-dicarboxylic acid). Recently, LK was discovered to possess neuroprotective, neuritigenic and anti-inflammatory activities. Moreover, both LK and the ubiquitous redox regulator glutathione (gamma-glutamyl-cysteine-glycine) bind to mammalian lanthionine synthetase-like protein-1 (LanCL1) protein which, along with its homolog LanCL2, has been associated with important physiological processes including signal transduction and insulin sensitization. These findings begin to suggest that Lan and its downstream metabolites may be physiologically important substances rather than mere metabolic waste. This review summarizes the current state of knowledge about lanthionyl metabolites with emphasis on their possible relationships to LanCL1/2 proteins and glutathione. The potential significance of lanthionines in paracrine signaling is discussed with reference to opportunities for utilizing bioavailable pro-drug derivatives of these compounds as novel pharmacophores. PMID- 20714317 TI - Synthesis and biological evaluation of 2,5-bis(alkylamino)-1,4-benzoquinones. AB - A series of twelve 2,5-bis(alkylamino)-1,4-benzoquinones were prepared in yields ranging from 9-58% via the reaction between p-benzoquinone and various amines. The structures of the synthesized compounds were confirmed by IR, 1H- and 13C-NMR and MS analyses. The phytotoxicity of the 2,5-bis(alkylamino)-1,4-benzoquinones was evaluated against two crop species, Cucumis sativus and Sorgum bicolor, at 1.0 x 10(-3) mol/L. In general, the quinones displayed inhibitory effects on the dicotyledonous species C. sativus (7-74%). On the other hand stimulatory effects were observed on S. bicolor (monocotyledonous). Similar results were observed in the biological assays carried out with the weed species Ipomoea grandifolia (dicotyledonous) and Brachiaria decumbens (monocotyledonous). In addition, the cytotoxicity of the 2,5-bis(alkylamino)-1,4-benzoquinones was assayed against HL 60 (leukemia), MDA-MB-435 (melanoma), SF-295 (brain) and HCT-8 (colon) human cancer cell lines and human peripheral blood mononuclear cells (PBMC), as representatives of healthy cells, using a MTT and an Alamar Blue assay. Compound 12 was the most active, displaying cytotoxicity against all cancer cell lines tested. PMID- 20714318 TI - Study of cyclic quaternary ammonium bromides by B3LYP calculations, NMR and FTIR spectroscopies. AB - N,N-dioctyl-azepanium, -piperidinium and -pyrrolidinium bromides 1-3, have been obtained and characterized by FTIR and NMR spectroscopy. DFT calculations have also been carried out. The optimized bond lengths, bond angles and torsion angles calculated by B3LYP/6-31G(d,p) approach have been presented. Both FTIR and Raman spectra of 1-3 are consistent with the calculated structures in the gas phase. The screening constants for 13C and 1H atoms have been calculated by the GIAO/B3LYP/6-31G(d,p) approach and analyzed. Linear correlations between the experimental 1H and 13C chemical shifts and the computed screening constants confirm the optimized geometry. PMID- 20714319 TI - Antioxidant tannins from stem bark and fine root of Casuarina equisetifolia. AB - Structures of condensed tannins from the stem bark and fine root of Casuarina equisetifolia were identified using MALDI-TOF MS and HPLC analyses. The condensed tannins from stem bark and fine root consist predominantly of procyanidin combined with prodelphinidin and propelargonidin, and epicatechin is the main extension unit. The condensed tannins had different polymer chain lengths, varying from trimers to tridecamer for stem bark and to pentadecamer for fine root. The antioxidant activities were measured by two models: 1,1-diphenyl-2- picrylhydrazyl (DPPH) radical scavenging activity and ferric reducing/ antioxidant power (FRAP). The condensed tannins extracted from C. equisetifolia showed very good DPPH radical scavenging activity and ferric reducing/ antioxidant power, suggesting that these extracts may be considered as new sources of natural antioxidants for food and nutraceutical products. PMID- 20714320 TI - Synthesis, identification and anti-cancer activity of 1-(4-methylpent-2-enyl)-2 (4-phenylbut-2-enyl)disulfane. AB - In this study, we synthesized 1-(4-methylpent-2-enyl)-2-(4-phenylbut-2- enyl)disulfane using sodium sulfide, 1-bromine-4-methyl-2-amylene and 1-(4 bromine-2- butylene)benzene as raw materials. The yield rate of target product was 84%. The structure of the target product was confirmed by GC-MS, 1H-NMR and elemental analysis. The results of anti-cancer activity experiments showed that 1 (4-methylpent-2-enyl)-2-(4- phenylbut-2-enyl)disulfane could significantly inhibit the proliferation, induce the apoptosis of CNE2 cells in a dose dependent manner, and could significantly enhance the activity of XIAP. PMID- 20714322 TI - Vascular corrosion casting: analyzing wall shear stress in the portal vein and vascular abnormalities in portal hypertensive and cirrhotic rodents. AB - Vascular corrosion casting is an established method of anatomical preparation that has recently been revived and has proven to be an excellent tool for detailed three-dimensional (3D) morphological examination of normal and pathological microcirculation. In addition, the geometry provided by vascular casts can be further used to calculate wall shear stress (WSS) in a vascular bed using computational techniques. In the first part of this study, the microvascular morphological changes associated with portal hypertension (PHT) and cirrhosis in vascular casts are described. The second part of this study consists of a quantitative analysis of the WSS in the portal vein in casts of different animal models of PHT and cirrhosis using computational fluid dynamics (CFD). Microvascular changes in the splanchnic, hepatic and pulmonary territory of portal hypertensive and cirrhotic mice are described in detail with stereomicroscopic examination and scanning electron microscopy. To our knowledge, our results are the first to report the vascular changes in the common bile duct ligation cirrhotic model. Calculating WSS using CFD methods is a feasible technique in PHT and cirrhosis, enabling the differentiation between different animal models. First, a dimensional analysis was performed, followed by a CFD calculation describing the spatial and temporal WSS distributions in the portal vein. WSS was significantly different between sham/cirrhotic/pure PHT animals with the highest values in the latter. Up till now, no techniques have been developed to quantify WSS in the portal vein in laboratory animals. This study showed for the first time that vascular casting has an important role not only in the morphological evaluation of animal models of PHT and cirrhosis, but also in defining the biological response of the portal vein wall to hemodynamic changes. CFD in 3D geometries can be used to describe the spatial and temporal variations in WSS in the portal vein and to better understand the forces affecting mechanotransduction in the endothelium. PMID- 20714321 TI - An intronic LINE-1 element insertion in the dystrophin gene aborts dystrophin expression and results in Duchenne-like muscular dystrophy in the corgi breed. AB - Duchenne muscular dystrophy (DMD) is a dystrophin-deficient lethal muscle disease. To date, the catastrophic muscle wasting phenotype has only been seen in dystrophin-deficient humans and dogs. Although Duchenne-like symptoms have been observed in more than a dozen dog breeds, the mutation is often not known and research colonies are rarely established. Here, we report an independent canine DMD model originally derived from the Pembroke Welsh corgi breed. The affected dogs presented clinical signs of muscular dystrophy. Immunostaining revealed the absence of dystrophin and upregulation of utrophin. Histopathologic examination showed variable fiber size, central nucleation, calcification, fibrosis, neutrophil and macrophage infiltration and cardiac focal vacuolar degeneration. Carrier dogs also displayed mild myopathy. The mutation was identified as a long interspersed repetitive element-1 (LINE-1) insertion in intron 13, which introduced a new exon containing an in-frame stop codon. Similar mutations have been seen in human patients. A colony was generated by crossing carrier females with normal males. Affected puppies had a normal birth weight but they experienced a striking growth delay in the first 5 days. In summary, the new corgi DMD model offers an excellent opportunity to study DMD pathogenesis and to develop novel therapies. PMID- 20714323 TI - Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action. AB - Population studies suggest putative links between vitamin D (VD)-deficiency and risk of cancer and diabetes. The insulin/IGF-I receptor represents a signaling target of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) that is implicated in both diabetes and cancer, therefore we hypothesized that VD actions may be mediated through this adhesion molecule. In this study, we show that 1,25 vitamin D3 and its analogues EB1089 and KH1060 potently inhibit CEACAM1 expression in cancer cells. This effect was associated with significant reductions in mRNA and protein levels, resulting from transcriptional and posttranslational actions respectively. Insulin/IGF-I-mediated IRS-1 and Akt activation were enhanced by VD treatment. Similarly, CEACAM1 downregulation significantly upregulated the insulin and IGF-I receptors and mimicked the effect of VD-mediated enhanced insulin/IGF-I receptor signaling. Despite improved insulin/IGF-I signaling, the anti-proliferative actions of VD were preserved in the absence or presence of forced CEACAM1 expression. Forced CEACAM1, however, abrogated the anti-invasive actions of VD. Our findings highlight CEACAM1 as a target of VD action. The resulting inhibition of CEACAM1 has potentially beneficial effects on metabolic disorders without necessarily compromising the anticancer properties of this vitamin. PMID- 20714324 TI - Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse. AB - In this study, we investigated the involvement of dystrophin-associated proteins (DAPs) and their relationship with the perivascular basement membrane in the brains of mdx mice and controls at the age of 2 months. We analyzed (1) the expression of glial DAPs alpha-beta-dystroglycan (DG), alpha-syntrophin, aquaporin-4 (AQP4) water channel, Kir 4.1 and dystrophin isoform (Dp71) by immunocytochemistry, laser confocal microscopy, immunogold electron microscopy, immunoblotting and RT-PCR; (2) the ultrastructure of the basement membrane and expression of laminin and agrin; and (3) the dual immunofluorescence colocalization of AQP4/alpha-beta-DG, and of Kir 4.1/agrin. The following results were observed in mdx brain as compared with controls: (1) a significant reduction in protein content and mRNA expression of DAPs; (2) ultrastructurally, a thickened and discontinuous appearance of the basement membrane and a significant reduction in laminin and agrin; and (3) a molecular rearrangment of alpha-beta DG, coupled with a parallel loss of agrin and Kir 4.1 on basement membrane and glial endfeet. These data indicate that in mdx brain the deficiency in dystrophin and dystrophin isoform (Dp71) is coupled with a reduction of DAP components, coupled with an altered anchoring to the basement membrane. PMID- 20714325 TI - EGF signaling activates proliferation and blocks apoptosis of mouse and human intestinal stem/progenitor cells in long-term monolayer cell culture. AB - The homeostatic renewal of the intestinal epithelium depends on regulation of proliferation and differentiation of stem/progenitor cells residing in a specific site, called the 'stem cell niche.' Thus, the reconstitution of the microenvironment of the stem cell niche may allow us to maintain intestinal stem/progenitor cells in culture for a longer period. Although epidermal growth factor (EGF) is conventionally used as a supplement of intestinal epithelial cell culture, little has been known regarding a role of EGF signaling in a stem/progenitor cell population. In this study, we attempted to clarify the role of EGF signaling in intestinal stem/progenitor cells, and to establish a culture system in which these cells could be maintained with normal differentiation potential. We first examined the expression pattern of EGF and its receptor, EGFR, and inhibited EGF signaling in mouse intestines. Next, we cultured intestinal cells isolated from mouse and human intestines in the presence of EGF and analyzed the function of EGF signaling in cultured cells. In both embryonic and adult mouse intestines, EGFR and EGF were expressed in immature epithelial cells and adjacent fibroblasts, respectively, and EGF signaling was essential to activate proliferation and inhibit apoptosis of intestinal stem/progenitor cells. Activation of EGF signaling also stimulated proliferation and suppressed apoptosis, both of which are necessary to maintain mouse and human intestinal epithelial cells in culture. Moreover, in these cultured epithelial cells, putative intestinal stem/progenitor cells persisted longer, and gave rise to different types of differentiated intestinal epithelial cells. We conclude that EGF signaling is indispensable for activation of proliferation and inhibition of unexpected cell death, not only in the intestinal stem cell niche, but also in culture of primitive intestinal epithelial cells. PMID- 20714326 TI - An essential role for mast cells as modulators of neutrophils influx in collagen induced arthritis in the mouse. AB - Mast cells are involved in immune disorders so that many of the proinflammatory and tissue destructive mediators produced by these cells have been implicated in the pathogenesis of rheumatoid arthritis. This scenario prompted us to investigate the correlation between mast cell degranulation and neutrophil influx within the digits and knees joints of arthritic mice assessing what could be the functional role(s) of joint mast cells in the response to collagen immunization. DBA/1J mice were submitted to collagen-induced arthritis and disease was assessed on day 21, 32 and 42 post-immunization. Pharmacological treatment with the glucocorticoid prednisolone, commonly used in the clinic, and nedocromil, a mast cell stabilizer, was performed from day 21 to 30. Arthritis develop after immunization, gradually increased up to day 42. Neutrophil infiltration peaked on day 32 and 21, in the digits and knees, respectively, showing an unequal pattern of recruitment between these tissues. This difference emerged for mast cells: they peaked in the digits on day 21, but a higher degree of degranulation could be measured in the knee joints. Uneven modulation of arthritis occurred after treatment of mice with prednisolone or nedocromil. Neutrophils migration to the tissue was reduced after both therapies, but only prednisolone augmented mast cell migration to the joints. Nedocromil exerted inhibitory properties both on mast cell proliferation and migration, more effectively on the digit joints. Thus, collagen induced an inflammatory process characterized by tissue mast cells activation and degranulation, suggesting a potential driving force in propagating inflammatory circuits yielding recruitment of neutrophils. However, the different degree of affected joint involvement suggests a time-related implication of digits and knees during collagen-induced arthritis development. These results provide evidence for local alterations whereby mast cells contribute to the initiation of inflammatory arthritis and may be targeted in intervention strategies. PMID- 20714327 TI - High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response. AB - Previously, we reported that extracellular high-mobility group box 1 (HMGB1) functions as an innate alarmin implicated in cardiac allograft acute rejection. We now present evidence suggesting that HMGB1 is pivotal in inducing interleukin 17 (IL-17)-producing alloreactive T cells by stimulating dendritic cells secretion of IL-6. Those IL-17(+) T cells are likely to be the major effector cells responsible for the early stage of cardiac allograft rejection through mediating an influx of neutrophils into allografts, and therefore, blockade of IL 17A significantly prolonged murine cardiac allograft survival. In contrast to the classical model for a dominant role of IFN-gamma(+)-Th1 cells have in acute allograft rejection, our data suggest that IFN-gamma(+)-Th1 cells are responsible for the late stage of graft destruction by inducing monocyte infiltration when IL 17(+) T-cell response recedes. Blockade of HMGB1 significantly decreased splenic alloreactive Th17 cells and IFN-gamma-producing CD8(+) T cells in the recipients, leading to less infiltration of neutrophils along with lower IL-6 and IL-17 expression levels in the grafts as well as prolongation of cardiac allograft survival. Together, these data support a novel model in which HMGB1 induces IL-17 producing alloreactive T cells to mediate early stage of allograft rejection, whereas IFN-gamma-producing alloreactive Th1 cells provoke graft destruction after Th17 response recedes. PMID- 20714328 TI - Effects of central administration of distinct fatty acids on hypothalamic neuropeptide expression and energy metabolism. AB - OBJECTIVE: To investigate the differential effects of acute central administration of distinct fatty acids (FA) on food intake, body weight and energy metabolism. DESIGN: Male Sprague-Dawley rats were treated with bolus intracerebroventricular injections of control hydroxypropyl-beta-cyclodextrin (HPB) or HPB complexed with 30 nmol of saturated palmitic acid (PA), monounsaturated oleic acid (OA) or polyunsaturated omega-3 docosahexaenoic acid (DHA). Food intake, body weight, neuropeptide expression and various serum parameters were assessed. RESULTS: When compared with controls, rats injected with either OA or DHA had significantly reduced food intake and body weight for 48 h following injections. No significant changes in food intake or body weight were observed in the PA group. In conjunction with reduced food intake, hypothalamic anorexigenic pro-opiomelanocortin (POMC) gene expression was significantly augmented in the OA and DHA groups, with essentially no changes observed in the PA group. Changes in serum measures of energy metabolism also changed coinciding with the observed differences in food intake. Moreover, central administration of SHU9119, a melanocortin-4-receptor (MC4R) antagonist, completely abolished the anorexigenic actions of OA, suggesting a role for OA induced augmentation of hypothalamic POMC expression in mediating its central inhibition of food intake. CONCLUSIONS: The hypothalamus differentially senses FA and, specifically, that OA and DHA, but not PA, reduce food intake and body weight, which may be mediated through POMC/MC4R signaling. PMID- 20714330 TI - Abdominal diameter index and 12-year cardiovascular disease incidence in male bridge and tunnel workers. AB - BACKGROUND: A recent study has suggested that abdominal diameter index (ADI), that is, the supine sagittal abdominal diameter divided by thigh circumference, may be a better measure of the increased risk of abdominal adiposity for prevalent ischemic cardiovascular disease (CVD) than body mass index or waist circumference. The risk associated with all of these measures is believed to arise from the link between visceral obesity and insulin resistance. METHODS: Male bridge and tunnel workers in New York City without ischemic CVD in the highest and lowest quartiles of ADI (n=218) in a 1993-1994 cross-sectional study of risk factors and prevalent coronary heart disease were administered telephone follow-up questionnaires after 12 years (2005-2006) to assess incident ischemic CVD (new-onset angina, coronary revascularization, myocardial infarction, stroke, peripheral vascular disease and cardiovascular death). RESULTS: In the univariate analysis of 111 participants able to be contacted, study members in the highest quartile vs the lowest quartile of ADI had a significantly increased cumulative incidence of ischemic CVD (Relative risk (RR)=7.9, P=0.002). In a logistic regression analysis controlling for other cardiovascular risk factors including age, smoking, total cholesterol, high-density lipoprotein cholesterol, triglycerides, blood pressure and glucose, ADI lost statistical significance (RR=4.37, P=0.063), suggesting that ADI may be an anthropometric surrogate for these cardiovascular risk factors. CONCLUSIONS: ADI is a powerful anthropometric index for 12-year cumulative incidence of ischemic CVD in working men in New York City. PMID- 20714331 TI - Sleep duration and body-weight development during puberty in a Dutch children cohort. AB - BACKGROUND: Short sleep duration is associated with obesity during childhood and adulthood. OBJECTIVE: The objective of our study was to investigate the relationship between sleep duration and body mass index (BMI) from Tanner stages 1 to 5 in a Dutch children cohort. DESIGN: In 98 children, anthropometric measurements and leptin concentrations were measured from age 7 to 16 years; body composition, physical activity (Baecke questionnaire), hours television viewing and self-reported sleep duration were measured yearly from age 12 to 16 years. Moreover, the polymorphisms of the FTO gene (rs9939609) and parental BMI's were determined. RESULTS: At Tanner stages 1-5 sex differences were observed in height, body weight, waist circumference, fat mass per squared meter height and leptin concentrations per kg fat mass. Inverse relationships were observed between the change in BMI (kg m(-2)) and the change in hours of sleep per night (h) from Tanner stages 1 to 4 (r=-0.68, P<0.001), from Tanner stages 2 to 5 (r= 0.35, P<0.05) and from Tanner stages 1 to 5 (r=-0.33, P<0.05). Univariate analysis of variance showed that with progressive Tanner stages, BMI increases and sleep duration decreases in an interrelated way independent of possible confounders (R(2)=0.38, P<0.02). CONCLUSION: Changes in BMI during puberty were inversely related to changes in sleep duration, independent of possible confounders. PMID- 20714329 TI - C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. AB - CONTEXT: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C reactive protein (CRP) is disputed. OBJECTIVE: Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique. PARTICIPANTS AND METHODS: The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them. RESULTS: Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in log CRP of 1.03 kg m(-2) (95% confidence interval (95% CI): 1.00, 1.07), P<0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in log CRP of -0.24 kg m(-2) (95% CI: -0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006). CONCLUSIONS: Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components. PMID- 20714332 TI - A free-choice high-fat high-sugar diet induces glucose intolerance and insulin unresponsiveness to a glucose load not explained by obesity. AB - OBJECTIVES: In diet-induced obesity, it is not clear whether impaired glucose metabolism is caused directly by the diet, or indirectly via obesity. This study examined the effects of different free-choice, high-caloric, obesity-inducing diets on glucose metabolism. In these free-choice diets, saturated fat and/or a 30% sugar solution are provided in an addition to normal chow pellets. METHOD: In the first experiment, male rats received a free-choice high-fat high-sugar (HFHS), free-choice high-fat (HF) or a chow diet. In a second experiment, male rats received a free-choice high-sugar (HS) diet or chow diet. For both experiments, after weeks 1 and 4, an intravenous glucose tolerance test was performed. RESULTS: Both the HFHS and HF diets resulted in obesity with comparable plasma concentrations of free fatty acids. Interestingly, the HF diet did not affect glucose metabolism, whereas the HFHS diet resulted in hyperglycemia, hyperinsulinemia and in glucose intolerance because of a diminished insulin response. Moreover, adiposity in rats on the HF diet correlated positively with the insulin response to the glucose load, whereas adiposity in rats on the HFHS diet showed a negative correlation. In addition, total caloric intake did not explain differences in glucose tolerance. To test whether sugar itself was crucial, we next performed a similar experiment in rats on the HS diet. Rats consumed three times as much sugar when compared with rats on the HFHS diet, which resulted in obesity with basal hyperinsulinemia. Glucose tolerance, however, was not affected. CONCLUSION: Together, these results suggest that not only obesity or total caloric intake, but the diet content also is crucial for the glucose intolerance that we observed in rats on the HFHS diet. PMID- 20714333 TI - Long-term follow-up of patients with spinal cord injury with a new ICF-based tool. AB - STUDY DESIGN: To develop a computer program that supports the overview of a follow-up care process in people with spinal cord injury (SCI) in daily clinical practice. OBJECTIVES: To create a new electronic tool based on the International Classification of Functioning, Disability and Health (ICF) that enables information to be registered and visualized, including the use of a net-diagram ('spider') to show a patient's long-term development. This diagram helps the clinician to recognize predispositions over time, as well as making information accessible to the patient, so as to involve him as a participant in defining current and future treatment options. Furthermore, guidelines for the prevention of common diseases, based on the recommendations of internal medicine, rehabilitation medicine and findings in the SCI literature, were implemented to provide enhanced health coaching in the area of preventative care. METHODS: In an outpatient setting, four perspectives were assessed: patient, physician, occupational therapist and physiotherapist for a comprehensive bio-psycho-social consideration. All categories were assessed and graphically visualized with the electronic tool, on the basis of the ICF domains: body function, activities/participation and environmental factors. RESULTS: The assessed data were summarized and graphically represented using three spider charts. CONCLUSION: The tool facilitates the patient counselling and the interdisciplinary work in daily clinical practice. Such a visual report helps to recognize predispositions over time. Furthermore, it helps to explain the clinical and patient-related findings accessible to the patients, to involve them as participants in defining the goals and the treatment plan. PMID- 20714334 TI - Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury. AB - STUDY DESIGN: Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). OBJECTIVES: To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. METHODS: Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. RESULTS: There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. CONCLUSION: Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered. PMID- 20714335 TI - Hemodynamic responses to head-up tilt after spinal cord injury support a role for the mid-thoracic spinal cord in cardiovascular regulation. AB - BACKGROUND: Data showing a role for the mid-thoracic spinal cord (SC) in the control of hemodynamic changes is scarce despite existing evidence for its involvement in autonomic regulation. STUDY DESIGN: On the basis of the open label prospective series comparing three groups. OBJECTIVE: To determine whether the mid-thoracic SC has a role in hemodynamic regulation during head-up tilt (HUT). SETTING: Spinal Research Laboratory, Loewenstein Rehabilitation Hospital. METHODS: A total of 13 healthy control subjects, 10 patients with T(4)-T(6) paraplegia and 11 with C(4)-C(7) tetraplegia were examined during supine rest and during HUT. Heart rate (HR), blood pressure (BP), HR spectral components (lower frequency fluctuation (LF), higher frequency fluctuations (HF) and LF/HF) and cerebral blood flow velocity (CBFV) were continuously measured or calculated. RESULTS: BP response to HUT differed among these groups (P<0.02). During HUT, BP decreased markedly in the tetraplegia group (from a mean value of 81.65 to 67.69 mm Hg), and increased in the control groups (from 92.89 to 95.44 mm Hg) and in the T(4)-T(6) paraplegia group (from 96.24 to 97.86 mm Hg). Significant correlation was found in the control and tetraplegia groups between increases in HR LF/HF and HR at HUT (r>0.7; P<0.01). No such correlation was found in the paraplegia group. HUT effect on HR and CBFV was significant in all groups (P<0.001), but group differences were statistically non-significant. CONCLUSION: Findings were generally compatible with those of comparable previously published studies, but they also support a role for the mid-thoracic SC in hemodynamic regulation, which should be considered in clinical setting and in research. PMID- 20714336 TI - Clinicians' and patients' impressions of change in motor performance as potential outcome measures for clinical trials. AB - STUDY DESIGN: A cross-sectional descriptive study was undertaken. OBJECTIVES: The overall objective was to explore the potential usefulness of clinicians' and patients' impressions of change in motor performance for clinical trials. Specifically, the aim was to compare clinicians' and patients' impressions of change in motor performance with standardized outcome measures in people with spinal cord injury (SCI). SETTING: Spinal injury units, Sydney, Australia. METHODS: Thirty people undergoing rehabilitation after recent SCI were recruited. They were assessed on two occasions separated by between 1 and 5 months. On both occasions, patients were assessed sitting unsupported (n = 25), transferring (n = 23) and walking (n = 12) using standardized outcome measures. On the second occasion, patients rated their impressions of change in each of the three motor tasks since their initial assessment. A 15-point scale was used. In addition, patients were videoed performing the three motor tasks on the two occasions. Two clinicians with SCI experience independently viewed the pairs of videos and rated their impressions of change using the same 15-point scale. Clinicians' and patients' impressions of change were compared with each other and to the standardized objective measures. RESULTS: Clinicians' and patients' impressions of change were greater than change measured with standardized objective measures for all three motor tasks (P<0.01). In addition, patients' impressions of change were greater than clinicians' impressions of change for transferring, but comparable for unsupported sitting and walking. CONCLUSION: Clinicians' and patients' impressions of change in motor performance may have potential for evaluating treatment effectiveness in clinical trials. PMID- 20714338 TI - A new role for interleukin-10 in immune regulation. PMID- 20714337 TI - Leisure-time physical activity and diet quality are not associated in people with chronic spinal cord injury. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To determine the association between leisure-time physical activity (LTPA) and adherence to Eating Well with Canada's Food Guide (CFG) in community-dwelling adults with chronic Spinal Cord Injury (SCI). SETTING: Ontario, Canada. METHODS: Participants were recruited as part of the Study of Health and Activity in People with SCI (SHAPE-SCI). Dietary data were collected using 24-h recalls and analysed for adherence to CFG recommendations by age group and gender. LTPA was assessed using the Physical Activity Recall Assessment for Persons with SCI. Statistical analysis comprised correlations, multiple regression and chi(2). RESULTS: We studied 75 adults (n=61 M; 42.4+/-11.8 years; 25.5+/-5.2 kg m(-2)) with chronic (>=1-year post-injury) SCI. Of these, 37% of participants were inactive, 29% were low-active and 33% were high-active. Fewer than 5% of participants were 100% adherent with CFG; 85% were adherent to <=50%. Activity level and overall adherence to CFG were not correlated (r=-0.052, P=0.666). Although there were no associations between LTPA and vegetables and fruit, grain products, milk and alternatives, or other foods (all P>0.05), high activity was associated with consuming less than the minimum number of recommended servings of meat and alternatives (phi=-0.258, P=0.026). CONCLUSION: Clinicians need to be aware of the poor diet quality, and low levels of physical activity, of people with chronic SCI. They should not assume that those who are more active consume better quality diets than those who are low active or inactive. SPONSORSHIP: Canadian Institutes of Health Research. PMID- 20714339 TI - Interleukin 10 decreases MICA expression on melanoma cell surface. AB - Natural-killer group 2, member D (NKG2D) binds to a variety of ligands, including the major histocompatibility complex (MHC) class I chain-related proteins (MIC) and UL16-binding proteins (ULBP). It is regarded as a co-activating receptor on NK cells, having an important role in the cell-mediated immune response to tumours. We studied the influence of interleukin (IL)-10 on the regulation of MIC and ULBP expression on melanoma cells, and its effect on the cytotoxic function of NK cells in vitro. Here, we show that, in the presence of IL-10, FMS mel and BL mel cell lines decreased MICA and ULBP2 surface expression, whereas MHC class I did not change substantially on the cell surface. MICA mRNA levels decreased in IL-10-treated FMS and IL-10-transduced BL cell lines. Interestingly, we observed that MICB surface expression and its mRNA levels increased upon IL-10 treatment in a melanoma cell line. These changes in NKG2D ligands surface expression patterns owing to IL-10 treatment resulted in an effect on lysis susceptibility mediated by lymphocyte-activated killer cells, as tumour cell lines that displayed a higher decrease of MICA on their surface had lower levels of lysis. In addition, expression of CD107a was downregulated on the surface of NK cells following stimulation with IL-10-treated FMS cells. Our results suggest a novel function for IL-10 in the modulation of NKG2D ligand expression and in the control of cytotoxicity mediated by NKG2D/NKG2D ligand axis. PMID- 20714340 TI - Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic induced weight gain. AB - Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic induced weight gain in chronic schizophrenia patients. PMID- 20714341 TI - Incidence of insignificant prostate cancer using free/total PSA: results of a case-finding protocol on 14,453 patients. AB - To evaluate prostate cancer (PCa) detection and incidence of pathologically insignificant PCa (pIPCa) tumour using percent-free PSA (%f-PSA) in patients with total PSA <= 10 ng ml(-1). From February 2002 to October 2009, 14,453 patients (median 60.5 years) were enrolled in a case-finding protocol for the early diagnosis of PCa. Indications to biopsy were suspicious digital rectal examination; PSA >10 ng ml(-1); PSA <= 2.5 ng ml(-1), included between 2.6-4 and 4.1-10 ng ml(-1) with %f-PSA <15, <20 and <25%, respectively. A median of 18 and 26 cores in case of primary and repeated biopsy were determined; 2123 men underwent prostate biopsy, of whom 1589 (74.8%) had a PSA <= 10 ng ml(-1). A PCa was found in 777 (36.6%) and in 35 (23.3%) patients at primary and repeated biopsy: 459 and 26 men had PSA <= 10 ng ml(-1) and 419 and 26 patients underwent surgery, respectively, 244 (58.3%) and 18 (69.2%) had an organ-confined PCa with a pIPCa incidence equal to 1.4 and 7.7%, respectively. Cancer detection rate of 28.8% in patients with PSA <= 10 ng ml(-1) associated with a low incidence of pIPCa should induce to introduce %f-PSA in screening programmes to reduce the risk of overdiagnosis. PMID- 20714342 TI - The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. AB - The epithelial-mesenchymal transition (EMT) converts epithelial tumor cells into invasive and metastatic cancer cells, leading to mortality in cancer patients. Although TWIST is a master regulator of EMT and metastasis for breast and other cancers, the mechanisms responsible for TWIST-mediated gene transcription remain unknown. In this study, purification and characterization of the TWIST protein complex revealed that TWIST interacts with several components of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, MTA2, RbAp46, Mi2 and HDAC2, and recruits them to the proximal regions of the E-cadherin promoter for transcriptional repression. Depletion of these TWIST complex components from cancer cell lines that depend on TWIST for metastasis efficiently suppresses cell migration and invasion in culture and lung metastasis in mice. These findings not only provide novel mechanistic and functional links between TWIST and the Mi2/NuRD complex but also establish new essential roles for the components of Mi2/NuRD complex in cancer metastasis. PMID- 20714343 TI - Treating prostate cancer with radiotherapy. AB - This Review focuses on the adverse effects of radical radiotherapy for localized prostate cancer. The adverse effects are described in the context of alternative treatment modalities. First, we consider the methodological issues that make comparison between the different treatment modalities problematic. Such issues include differences in baseline levels of urinary, bowel and sexual dysfunction, the importance of using patient-reported outcomes and the distinction between actuarial and prevalence rates of treatment-related toxic effects. Second, we describe the pattern of adverse effects that occur over time after radiotherapy. Here, we focus on evidence for a beneficial effect of radiotherapy on some urinary symptoms, and the controversy regarding the risk of secondary malignancy. Third, predictors of radiation toxicity are discussed. Accurate prediction of radiotherapy toxicity would be an invaluable tool for treatment individualization. It is noteworthy that the data on the adverse effects of prostate radiotherapy necessarily relate to treatment as it was delivered in the past. It is likely that recent technical advances, such as intensity modulation and image guidance, will further improve the toxicity profile of prostate radiotherapy. PMID- 20714344 TI - Informativeness and learning: Response to Gauthier and colleagues. PMID- 20714345 TI - Correction: Activation of Akt signaling reduces the prevalence and intensity of malaria parasite infection and lifespan in Anopheles stephensi mosquitoes. AB - Malaria (Plasmodium spp.) kills nearly one million people annually and this number will likely increase as drug and insecticide resistance reduces the effectiveness of current control strategies. The most important human malaria parasite, Plasmodium falciparum, undergoes a complex developmental cycle in the mosquito that takes approximately two weeks and begins with the invasion of the mosquito midgut. Here, we demonstrate that increased Akt signaling in the mosquito midgut disrupts parasite development and concurrently reduces the duration that mosquitoes are infective to humans. Specifically, we found that increased Akt signaling in the midgut of heterozygous Anopheles stephensi reduced the number of infected mosquitoes by 60-99%. Of those mosquitoes that were infected, we observed a 75-99% reduction in parasite load. In homozygous mosquitoes with increased Akt signaling parasite infection was completely blocked. The increase in midgut-specific Akt signaling also led to an 18-20% reduction in the average mosquito lifespan. Thus, activation of Akt signaling reduced the number of infected mosquitoes, the number of malaria parasites per infected mosquito, and the duration of mosquito infectivity. PMID- 20714346 TI - Surgical management of hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory disease of skin, characterized by recurrent draining sinuses and abscesses, predominantly in skin folds carrying terminal hairs and apocrine glands. METHOD: This study reviewed 54 sites in 27 patients with moderate to extensive chronic inflammatory skin lesions treated surgically in our hospital from 2004 through 2009, with a follow-up of at least 6 months. RESULT: A total number of 54 operative procedures were performed during the study period with 42% (23 sites) involving the axilla, 20% (11 sites) involving the gluteal area, %24 (13 sites) involving the perineal area and 12% (7 sites) involving the inguinal region. CONCLUSION: Conservative treatment methods have little or no effects especially on gluteal, perineal/perianal, axillary hidradenitis suppurativa. The morbidity associated with the established form of this disease is significant, and the only successful treatment is wide surgical excision. PMID- 20714347 TI - Conserved role of unc-79 in ethanol responses in lightweight mutant mice. AB - The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt), disrupts the homolog of the Caenorhabditis elegans (C. elegans) unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca 2 double mutants suggests a novel conserved pathway that might influence alcohol related behaviors in humans. PMID- 20714348 TI - Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. AB - Mitochondrial dysfunction has been observed in skeletal muscle of people with diabetes and insulin-resistant individuals. Furthermore, inherited mutations in mitochondrial DNA can cause a rare form of diabetes. However, it is unclear whether mitochondrial dysfunction is a primary cause of the common form of diabetes. To date, common genetic variants robustly associated with type 2 diabetes (T2D) are not known to affect mitochondrial function. One possibility is that multiple mitochondrial genes contain modest genetic effects that collectively influence T2D risk. To test this hypothesis we developed a method named Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA; http://www.broadinstitute.org/mpg/magenta). MAGENTA, in analogy to Gene Set Enrichment Analysis, tests whether sets of functionally related genes are enriched for associations with a polygenic disease or trait. MAGENTA was specifically designed to exploit the statistical power of large genome-wide association (GWA) study meta-analyses whose individual genotypes are not available. This is achieved by combining variant association p-values into gene scores and then correcting for confounders, such as gene size, variant number, and linkage disequilibrium properties. Using simulations, we determined the range of parameters for which MAGENTA can detect associations likely missed by single marker analysis. We verified MAGENTA's performance on empirical data by identifying known relevant pathways in lipid and lipoprotein GWA meta-analyses. We then tested our mitochondrial hypothesis by applying MAGENTA to three gene sets: nuclear regulators of mitochondrial genes, oxidative phosphorylation genes, and approximately 1,000 nuclear-encoded mitochondrial genes. The analysis was performed using the most recent T2D GWA meta-analysis of 47,117 people and meta analyses of seven diabetes-related glycemic traits (up to 46,186 non-diabetic individuals). This well-powered analysis found no significant enrichment of associations to T2D or any of the glycemic traits in any of the gene sets tested. These results suggest that common variants affecting nuclear-encoded mitochondrial genes have at most a small genetic contribution to T2D susceptibility. PMID- 20714349 TI - The human fungal pathogen Cryptococcus neoformans escapes macrophages by a phagosome emptying mechanism that is inhibited by Arp2/3 complex-mediated actin polymerisation. AB - The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin 'flashes' occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism. PMID- 20714350 TI - The pneumococcal serine-rich repeat protein is an intra-species bacterial adhesin that promotes bacterial aggregation in vivo and in biofilms. AB - The Pneumococcal serine-rich repeat protein (PsrP) is a pathogenicity island encoded adhesin that has been positively correlated with the ability of Streptococcus pneumoniae to cause invasive disease. Previous studies have shown that PsrP mediates bacterial attachment to Keratin 10 (K10) on the surface of lung cells through amino acids 273-341 located in the Basic Region (BR) domain. In this study we determined that the BR domain of PsrP also mediates an intra species interaction that promotes the formation of large bacterial aggregates in the nasopharynx and lungs of infected mice as well as in continuous flow-through models of mature biofilms. Using numerous methods, including complementation of mutants with BR domain deficient constructs, fluorescent microscopy with Cy3 labeled recombinant (r)BR, Far Western blotting of bacterial lysates, co immunoprecipitation with rBR, and growth of biofilms in the presence of antibodies and competitive peptides, we determined that the BR domain, in particular amino acids 122-166 of PsrP, promoted bacterial aggregation and that antibodies against the BR domain were neutralizing. Using similar methodologies, we also determined that SraP and GspB, the Serine-rich repeat proteins (SRRPs) of Staphylococcus aureus and Streptococcus gordonii, respectively, also promoted bacterial aggregation and that their Non-repeat domains bound to their respective SRRPs. This is the first report to show the presence of biofilm-like structures in the lungs of animals infected with S. pneumoniae and show that SRRPs have dual roles as host and bacterial adhesins. These studies suggest that recombinant Non repeat domains of SRRPs (i.e. BR for S. pneumoniae) may be useful as vaccine antigens to protect against Gram-positive bacteria that cause infection. PMID- 20714351 TI - Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection. AB - The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3-4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3(GFP) reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3(+) Treg suppressive potency. In complementary experiments using Foxp3(DTR) mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection. PMID- 20714353 TI - Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-gamma and MyD88 signaling. AB - The development of classically activated monocytic cells (M1) is a prerequisite for effective elimination of parasites, including African trypanosomes. However, persistent activation of M1 that produce pathogenic molecules such as TNF and NO contributes to the development of trypanosome infection-associated tissue injury including liver cell necrosis in experimental mouse models. Aiming to identify mechanisms involved in regulation of M1 activity, we have recently documented that during Trypanosoma brucei infection, CD11b(+)Ly6C(+)CD11c(+) TNF and iNOS producing DCs (Tip-DCs) represent the major pathogenic M1 liver subpopulation. By using gene expression analyses, KO mice and cytokine neutralizing antibodies, we show here that the conversion of CD11b(+)Ly6C(+) monocytic cells to pathogenic Tip-DCs in the liver of T. brucei infected mice consists of a three-step process including (i) a CCR2-dependent but CCR5- and Mif-independent step crucial for emigration of CD11b(+)Ly6C(+) monocytic cells from the bone marrow but dispensable for their blood to liver migration; (ii) a differentiation step of liver CD11b(+)Ly6C(+) monocytic cells to immature inflammatory DCs (CD11c(+) but CD80/CD86/MHC-II(low)) which is IFN-gamma and MyD88 signaling independent; and (iii) a maturation step of inflammatory DCs to functional (CD80/CD86/MHC II(high)) TNF and NO producing Tip-DCs which is IFN-gamma and MyD88 signaling dependent. Moreover, IL-10 could limit CCR2-mediated egression of CD11b(+)Ly6C(+) monocytic cells from the bone marrow by limiting Ccl2 expression by liver monocytic cells, as well as their differentiation and maturation to Tip-DCs in the liver, showing that IL-10 works at multiple levels to dampen Tip-DC mediated pathogenicity during T. brucei infection. A wide spectrum of liver diseases associates with alteration of monocyte recruitment, phenotype or function, which could be modulated by IL-10. Therefore, investigating the contribution of recruited monocytes to African trypanosome induced liver injury could potentially identify new targets to treat hepatic inflammation in general, and during parasite infection in particular. PMID- 20714352 TI - Dynamic chromatin organization during foregut development mediated by the organ selector gene PHA-4/FoxA. AB - Central regulators of cell fate, or selector genes, establish the identity of cells by direct regulation of large cohorts of genes. In Caenorhabditis elegans, foregut (or pharynx) identity relies on the FoxA transcription factor PHA-4, which activates different sets of target genes at various times and in diverse cellular environments. An outstanding question is how PHA-4 distinguishes between target genes for appropriate transcriptional control. We have used the Nuclear Spot Assay and GFP reporters to examine PHA-4 interactions with target promoters in living embryos and with single cell resolution. While PHA-4 was found throughout the digestive tract, binding and activation of pharyngeally expressed promoters was restricted to a subset of pharyngeal cells and excluded from the intestine. An RNAi screen of candidate nuclear factors identified emerin (emr-1) as a negative regulator of PHA-4 binding within the pharynx, but emr-1 did not modulate PHA-4 binding in the intestine. Upon promoter association, PHA-4 induced large-scale chromatin de-compaction, which, we hypothesize, may facilitate promoter access and productive transcription. Our results reveal two tiers of PHA 4 regulation. PHA-4 binding is prohibited in intestinal cells, preventing target gene expression in that organ. PHA-4 binding within the pharynx is limited by the nuclear lamina component EMR-1/emerin. The data suggest that association of PHA-4 with its targets is a regulated step that contributes to promoter selectivity during organ formation. We speculate that global re-organization of chromatin architecture upon PHA-4 binding promotes competence of pharyngeal gene transcription and, by extension, foregut development. PMID- 20714354 TI - Bacteriophage lysin mediates the binding of streptococcus mitis to human platelets through interaction with fibrinogen. AB - The binding of bacteria to human platelets is a likely central mechanism in the pathogenesis of infective endocarditis. We have previously found that platelet binding by Streptococcus mitis SF100 is mediated by surface components encoded by a lysogenic bacteriophage, SM1. We now demonstrate that SM1-encoded lysin contributes to platelet binding via its direct interaction with fibrinogen. Far Western blotting of platelets revealed that fibrinogen was the major membrane associated protein bound by lysin. Analysis of lysin binding with purified fibrinogen in vitro confirmed that these proteins could bind directly, and that this interaction was both saturable and inhibitable. Lysin bound both the Aalpha and Bbeta chains of fibrinogen, but not the gamma subunit. Binding of lysin to the Bbeta chain was further localized to a region within the fibrinogen D fragment. Disruption of the SF100 lysin gene resulted in an 83+/-3.1% reduction (mean +/- SD) in binding to immobilized fibrinogen by this mutant strain (PS1006). Preincubation of this isogenic mutant with purified lysin restored fibrinogen binding to wild type levels. When tested in a co-infection model of endocarditis, loss of lysin expression resulted in a significant reduction in virulence, as measured by achievable bacterial densities (CFU/g) within vegetations, kidneys, and spleens. These results indicate that bacteriophage encoded lysin is a multifunctional protein, representing a new class of fibrinogen-binding proteins. Lysin appears to be cell wall-associated through its interaction with choline. Once on the bacterial surface, lysin can bind fibrinogen directly, which appears to be an important interaction for the pathogenesis of endocarditis. PMID- 20714355 TI - The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. AB - Recurrent and/or metastatic squamous cell carcinoma of the head and neck (HNSCC) continues to be a source of significant morbidity and mortality worldwide. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated beneficial effects in this setting. Cetuximab, a monoclonal antibody against the EGFR, improves locoregional control and overall survival when used as a radiation sensitizer in patients with locoregionally advanced HNSCC undergoing definitive radiation therapy with curative intent. Cetuximab is also active as monotherapy in patients whose cancer has progressed on platinum-containing therapy. In the first-line setting for incurable HNSCC, cetuximab added to platinum-based chemotherapy significantly improves overall survival compared with standard chemotherapy alone. These positive results have had a significant impact on the standard of care for advanced HNSCC. In this review, we will discuss the mechanism of action, clinical data and common toxicities that pertain to the use of cetuximab in the treatment of advanced incurable HNSCC. PMID- 20714356 TI - Rationale for targeted therapies and potential role of pazopanib in advanced renal cell carcinoma. AB - Advanced renal cell carcinoma (RCC) remains a challenging, major health problem. Recent advances in understanding the fundamental biology underlying one form of RCC, ie, clear cell (or conventional) RCC, have opened the door to a series of targeted agents, such as the tyrosine kinase inhibitors (TKIs), which have become the standard of care in managing advanced clear cell RCC. Among the newest of these agents to receive Food and Drug Administration approval in this disease is pazopanib. This review will summarize what is known about the fundamental biology that underlies clear cell RCC, the data surrounding the previously approved targeted agents for this disease, including not only the TKIs but also the mTOR inhibitors and the vascular endothelial growth factor-specific agent, bevacizumab, and the newest TKI, pazopanib. It will also explore the potential role for pazopanib relative to the other available agents and where it may fit into the armamentarium for treatment of advanced/metastatic RCC. PMID- 20714357 TI - Detection and characterization of liver lesions using gadoxetic acid as a tissue specific contrast agent. AB - The value of cross-sectional liver imaging is evaluated by the accuracy, sensitivity, and specificity of the specific imaging technique. Magnetic resonance imaging (MRI) has become a key technique for the characterization and detection of focal and diffuse liver disease. More recently, gadoxetic acid, the hepatocyte-specific MR contrast agent, was clinically approved and introduced in many countries. Gadoxetic acid may be considered a "molecular imaging" probe because the compound is actively taken into hepatocytes via the ATP-dependent organic anion transport system in the plasma membrane for the hepatic uptake. The transport of gadoxetic acid from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S-transferase. Gadoxetic acid enhances hepatocyte-containing lesions and improves detection of lesions devoid of normal hepatocytes, such as metastases. Innovative rapid MR acquisition techniques with near isotropic 3D pulse sequences with fat saturation parallel the technical progress made by multidetector computed tomography combined with an impressive improvement in tumor-liver contrast when used for gadoxetic acid enhanced MRI. The purpose of this review is to provide an overview of the development, clinical testing, and applications of this novel MR contrast agent. PMID- 20714360 TI - Beals-Hecht syndrome and choroidal neovascularization. AB - PURPOSE: To describe a case of choroidal neovascularization (CNV) in a female diagnosed with Beals-Hecht syndrome. METHODS: A retrospective, interventional case is described in a 26-year-old female complaining of metamorphopsia and visual loss in her left eye (counting fingers). The fluorescein angiogram and the optical coherence tomography supported the diagnosis of CNV. Intravitreal ranibizumab was administered. RESULTS: After the third intravitreal ranibizumab, her visual acuity improved to 0.8 and the morphology of the macular area was restored. CONCLUSIONS: To our knowledge this is the first report of CNV in Beals Hecht syndrome treated with ranibizumab. Self-monitoring by periodically performing Amsler grid test is strongly recommended in these patients in order to achieve an early diagnosis of eventual CNV and avoid visual acuity loss. PMID- 20714359 TI - New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride. AB - Oral administration of sapropterin hydrochloride, recently approved for use by the US Food and Drug Administration and the European Commission, is a novel approach for the treatment of phenylketonuria (PKU), one of the most common inborn errors of metabolism. PKU is caused by an inherited deficiency of the enzyme phenylalanine hydroxylase (PAH), and the pathophysiology of the disorder is related to chronic accumulation of the free amino acid phenylalanine in tissues. Contemporary therapy is based upon restriction of dietary protein intake, which leads to reduction of blood phenylalanine levels. This therapy is difficult to maintain throughout life, and dietary noncompliance is commonplace. Sapropterin dihydrochloride is a synthetic version of tetrahydrobiopterin, the naturally occurring pterin cofactor that is required for PAH-mediated phenylalanine hydroxylation. In a subset of individuals with PAH deficiency, sapropterin administration leads to reduction in blood phenylalanine levels independent of dietary protein. For these individuals, sapropterin is an effective novel therapy for PKU. PMID- 20714358 TI - Prevention of rotavirus gastroenteritis in infants and children: rotavirus vaccine safety, efficacy, and potential impact of vaccines. AB - Rotavirus infection is the most common cause of severe gastroenteritis globally, with greater than 86% of deaths occurring in low-income and middle-income countries. There are two rotavirus vaccines currently licensed in the United States and prequalified by the World Health Organization. RV1 is a monovalent attenuated human rotavirus strain, given orally in two doses. RV5 is a pentavalent human-bovine reassortant rotavirus vaccine, given orally in three doses. A third rotavirus vaccine, LLV, is a lamb rotavirus strain given orally as a single dose, which is currently available only in China. RV1 and RV5 have been shown to be highly efficacious in developed countries, and initial results from trials in Africa and Asia are promising as well. At least three other vaccines are in development, which are being developed by manufacturers of developing countries. Further studies are needed to clarify issues including administration of oral rotavirus vaccines with breastfeeding and other oral vaccines, and alterations in dosing schedule. Using new data on global diarrheal burden, rotavirus is estimated to cause 390,000 deaths in children younger than 5 years. Should rotavirus vaccines be introduced in the routine immunization programs of all countries, a potential of 170,000 deaths could be prevented annually. The largest impact on mortality would be seen in low-income and middle-income countries, despite poor immunization coverage and lower efficacy. Therefore, international efforts are needed to ensure that rotavirus vaccines reach the populations with highest burden of rotavirus disease. PMID- 20714361 TI - Multifocal visual evoked potentials in amblyopia due to anisometropia. AB - PURPOSE: To investigate multifocal visual evoked potentials (mfVEP) of the amblyopic and fellow eye in amblyopia due to anisometropia. METHODS: We recorded mfVEP in both eyes of 15 anisometropic amblyopic patients and 15 normal control subjects. The responses from the central 7.0 degrees arc of the visual field were measured, and changes in latency and amplitude were compared between the amblyopic, fellow, and normal control eyes. RESULTS: There was a significant difference in the latency and amplitude of mfVEP between the amblyopic and fellow eyes. The responses in the central region of the visual field (rings 1 and 2) had a longer latency and smaller amplitude in the amblyopic eye. In contrast, there was no difference in mfVEP latency or amplitude between the fellow eye and normal control eyes. CONCLUSION: These results suggest that mfVEP may be used as an alternative objective method for diagnosis and monitoring of anisometropic amblyopia. PMID- 20714362 TI - Clinical imaging and high-resolution ultrasonography in melanocytoma management. AB - PURPOSE: To demonstrate the utility of high resolution 20 MHz ophthalmic ultrasound in serial follow-up of optic nerve head melanocytoma patients. METHODS: This study is a retrospective review of 30 patients with melanocytoma of the optic nerve head studied with echography. All patients were evaluated with standard ophthalmic A-scan and B-scan ultrasonography and 10 (33%) underwent high resolution ultrasound. RESULTS: Sixty-two percent (62%) of patients had dome shaped lesions on ultrasound, twenty-eight percent (28%) presented with mild elevations. The maximum elevation of any lesion was 2.6 mm. The vast majority (89%) of lesions had medium or high internal reflectivity and 89% demonstrated avascularity. Mean follow-up for all patients was nearly 7 years. High-resolution ultrasound enabled enhanced accuracy for detection of lesion dimensions and documentation of growth and possible malignant transformation. CONCLUSIONS: In this study, we demonstrate a new and important role for the use of ultrasound in this disease as a complementary tool in identifying and following patients with high-risk growth characteristics. These tumor characteristics can be accurately detected with 10 MHz ultrasound in conjunction with standardized A-scan and better differentiated with the 20 MHz technology. Use of these modalities can aid in distinguishing the melanocytomas that grow from choroidal melanomas and can prevent unnecessary treatments. PMID- 20714363 TI - Cerebral and ocular congenital toxoplasmosis complicated by West syndrome. AB - We report a case of a child who presented cerebral and ocular congenital toxoplasmosis associated with West syndrome. He was seen and followed-up in the in patients pediatric and ophthalmologic units at the Gyneco-Obstetric and Pediatric Hospital of Yaounde in Cameroon between July 2008 and February 2010. PMID- 20714364 TI - The controversy over the association between statins use and progression of age related macular degeneration: a mini review. AB - OBJECTIVE: Age-related macular degeneration (AMD) is the leading cause of blindness in western societies. Statins comprise a class of pharmacological agents that reduce plasma cholesterol levels, and have been shown to prevent progression of atherosclerosis and reduce cardiovascular mortality. The relationship between these medications and AMD has been evaluated in several recent studies. Herein, we examine the current evidence for an association between statin use and risk of AMD. METHODS: Literature database search (Medline, Scopus, and Science Citation Index Expanded) for articles published up to March 2010, using particular search terms. RESULTS: From the current evidence available, it is not safe to conclude upon the assumption of a protective effect of statins against age-related maculopathy and AMD. CONCLUSION: There is a need for large scale prospective studies with a long follow-up period and accurate assessment of AMD to further explore this matter. PMID- 20714365 TI - Choroidal neovascularization due to punctate inner choroidopathy: long-term follow-up and review of literature. AB - INTRODUCTION: The aim of the article was to report on the long-term follow-up of choroidal neovascularization (CNV) cases secondary to punctate inner choroidopathy (PIC) either treated with photodynamic therapy (PDT) or followed without treatment. A comprehensive review of existing literature on the various treatment modalities is incorporated. METHODS: Nine eyes of 8 female patients with CNV due to PIC were followed retrospectively for an average of 105 months (range, 36-162 months). Mean age of the patient cohort on presentation was 28 years (range, 21-39). Four eyes were treated with PDT, whereas in 4 patients, including 1 with bilateral involvement, the disease followed its natural course without treatment. Snellen visual acuity and the extent of neovascularization and subretinal fibrosis were evaluated on presentation and at the end of the follow up period. RESULTS: Improvement of vision was observed in 6 eyes (66.7%), including all cases treated with PDT, and in 2 of 5 eyes left untreated. The size of the neovascular lesion, including both CNV and subretinal fibrosis, increased in all cases left untreated (55.6%) and remained stable in all cases treated with PDT (44.4%). CONCLUSION: Without treatment, the CNV due to PIC is slowly progressive. Our short cohort appears to have benefited from PDT in terms of maintaining visual acuity and stabilizing the extent of CNV and fibrosis. PMID- 20714367 TI - Selective laser trabeculoplasty reduces mean IOP and IOP variation in normal tension glaucoma patients. AB - PURPOSE: To evaluate the effect of selective laser trabeculoplasty (SLT) in normal tension glaucoma (NTG) patients. PATIENTS AND METHODS: A retrospective review was performed of NTG patients who had undergone SLT at the Duke University Eye Center between 12/2002 and 7/2005. For each eye of each patient at pre-laser and post-laser time points, the IOP measurements were summarized by mean, standard deviation, and range. Then for each of these descriptive statistics, the differences between pre-laser and post-laser values were obtained. Statistical analysis was performed using a random effects model. MAIN OUTCOME MEASURES: difference in mean IOP, standard deviation of IOP, and range of IOP. RESULTS: Thirty-one eyes of 18 patients were included for analysis. The average of the mean pre-operative IOP measurements was 14.3 +/- 2.6 mmHg compared to 12.2 +/- 1.7 mmHg (P < 0.001) post-operatively. The mean pre-operative standard deviation was 1.9 +/- 0.9 mmHg compared to 1.0 +/- 0.6 mmHg (P = 0.002) post-operatively while the mean IOP range prior to treatment was 4.5 +/- 2.5 mmHg compared to 2.5 +/- 1.9 mmHg (P = 0.017) after treatment. CONCLUSION: In this pilot study, SLT was found to lower mean IOP and intervisit IOP variation in NTG patients. Given the importance of IOP variation and its association with glaucoma progression, measurement of IOP variation following treatment with SLT may be considered. PMID- 20714366 TI - Efficacy and patient tolerability of travoprost BAK-free solution in patients with open-angle glaucoma and ocular hypertension. AB - The medical treatment of glaucoma has evolved significantly over the past several decades. The main driving forces behind this evolution are the safety profiles and efficacy of these medications. Prostaglandin (PG) analogues are shown to be superior to older drugs in both efficacy and tolerability. Though there are much fewer side effects that manifest after using PG analogues, the adherence and compliance to medication regimens are surprisingly lower than expected. A commonly sited reason is the ocular irritation and inflammation with these medications. Much of this inflammation can be attributed to the preservative, benzalkonium chloride (BAK). The chronic clinical and subclinical inflammation becomes increasingly detrimental when filtration surgery fails from bleb fibrosis secondary to this hypercellularity. A BAK-free formulation of a PG analogues recently became available. BAK-free travoprost is reviewed here. It has demonstrated equal efficacy and less ocular surface toxicity than its preserved counterparts. It is expected to serve as an instrumental resource in managing ocular hypertension and glaucoma in patients who demonstrate significant sensitivity to BAK. More randomized, controlled, double-blind studies are encouraged to evaluate its improved safety and tolerability. PMID- 20714368 TI - Low-dose aspirin as treatment for central serous chorioretinopathy. AB - PURPOSE: To evaluate the effectiveness of low-dose aspirin for the treatment of central serous chorioretinopathy (CSCR). PATIENTS AND METHODS: Patients with classical or multifocal CSCR were treated with aspirin 100 mg per day orally for 1 month followed by 100 mg on alternate days for 5 months. Treated patients were compared with historic controls consisting of patients with classical or multifocal CSCR previously followed up at our institution. RESULTS: Mean visual acuity in the group treated with aspirin started to improve after the first week of therapy and continued to improve throughout the following 3 months. Visual recovery was slower in the untreated control group than in the treated group and achieved better visual acuity between the first and third month from the onset of the disease. There were no adverse events related to the administration of aspirin. CONCLUSION: The results indicate that treatment with low-dose aspirin may result in more rapid visual rehabilitation with fewer recurrences in patient with CSCR compared with untreated historic controls. The effectiveness of treatment with aspirin supports our hypothesis regarding the role of impaired fibrinolysis and increased platelet aggregation in the choriocapillaris in the pathogenesis of CSCR. PMID- 20714369 TI - Micro-optofluidic Lenses: A review. AB - This review presents a systematic perspective on the development of micro optofluidic lenses. The progress on the development of micro-optofluidic lenses are illustrated by example from recent literature. The advantage of micro optofluidic lenses over solid lens systems is their tunability without the use of large actuators such as servo motors. Depending on the relative orientation of light path and the substrate surface, micro-optofluidic lenses can be categorized as in-plane or out-of-plane lenses. However, this review will focus on the tunability of the lenses and categorizes them according to the concept of tunability. Micro-optofluidic lenses can be either tuned by the liquid in use or by the shape of the lens. Micro-optofluidic lenses with tunable shape are categorized according to the actuation schemes. Typical parameters of micro optofluidic lenses reported recently are compared and discussed. Finally, perspectives are given for future works in this field. PMID- 20714370 TI - Elastic, dielectric, and piezoelectric constants of Pb(In(12)Nb(12))O(3) Pb(Mg(13)Nb(23))O(3)-PbTiO(3) single crystal poled along [011](c). AB - Ternary single crystals xPb(In(12)Nb(12))O(3)-(1-x-y)Pb(Mg(13)Nb(23))O(3) yPbTiO(3) (PIN-PMN-PT) poled along [011](c) showed remarkable electromechanical properties. We report complete sets of elastic, dielectric, and piezoelectric constants of PIN-PMN-28%PT and PIN-PMN-32%PT, measured by using combined resonance and ultrasonic methods. The electromechanical coupling coefficients k(15), k(32), and k(33) can reach 0.95, 0.90, and 0.92, and the piezoelectric strain coefficients d(15), d(32), and d(33) are as high as 3354 pCN, -1781 pCN, and 1363 pCN, respectively. These full matrix data sets provide the base for fundamental studies on domain engineering phenomena as well as urgently needed input data for the design of electromechanical devices using [011](c) poled PIN PMN-PT single crystals. PMID- 20714371 TI - Cost-effectiveness of combination fluticasone propionate-salmeterol 250/50 microg versus salmeterol in severe COPD patients. AB - OBJECTIVE: To estimate the cost-effectiveness of fluticasone propionate salmeterol combination (FSC) compared to salmeterol for maintenance therapy in severe chronic obstructive pulmonary disease (COPD). STUDY DESIGN: Pooled economic analysis. METHODS: We performed an economic analysis of pooled data from two randomized clinical trials (combined N = 1554) that evaluated the effect of maintenance therapy with FSC (250/50 microg twice daily) or salmeterol (50 microg twice daily) on exacerbation rates in patients with severe COPD. We calculated exacerbation rates and applied standardized costs to exacerbation-related health care utilization reported in the trials (office, urgent care, and emergency department visits; hospitalizations; and oral corticosteroids and antibiotics) to determine cost differences between FSC and salmeterol treatment outcomes. RESULTS: Annual rates of any exacerbation and moderate/severe exacerbation were lower in the FSC group than the salmeterol group (4.91 vs 5.78 and 1.32 vs 2.00 respectively, both P < 0.05). Total adjusted annual COPD related exacerbation and therapeutic costs were $4,842 (95% CI; $4,731-$4,952) in the FSC group and $5,066 (95% CI; $4,937-$5,195) in the salmeterol group. CONCLUSIONS: FSC combination therapy is associated with reduced risk of any exacerbation and moderate/severe exacerbation, and incurs lower annual COPD-related health care costs compared to treatment with salmeterol. This analysis demonstrates that FSC therapy may be advantageous from both a clinical and cost-benefit standpoint for patients with severe COPD. PMID- 20714372 TI - An overview of the benefits and drawbacks of inhaled corticosteroids in chronic obstructive pulmonary disease. AB - BACKGROUND: The benefit harm profile of inhaled corticosteroids, and their effect on patient oriented outcomes and comorbid pneumonia, osteoporosis and cardiovascular disease in patients with chronic obstructive pulmonary disease remain uncertain. METHODS: An overview of the evidence on the risks and benefits of inhaled corticosteroids (fluticasone and budesonide) in chronic obstructive pulmonary disease from recent randomized controlled trials and systematic reviews. Observational studies on adverse effects were also evaluated. RESULTS: Evidence from recent meta-analysis suggests a modest benefit from inhaled corticosteroid long-acting beta-agonist combination inhalers on the frequency of exacerbations, (rate ratio [RR], 0.82; 95% confidence interval [CI]: 0.78 to 0.88), in improvements in quality of life measures, and forced expiratory volume in one second when compared to long-acting beta-agonists alone. On the outcome of pneumonia, our updated meta-analysis of trials (n = 24 trials; RR, 1.56; 95% CI: 1.40-1.74, P < 0.0001) and observational studies (n = 4 studies; RR, 1.44; 95% CI: 1.20-1.75, P = 0.0001) shows a significant increase in the risk of pneumonia with the inhaled corticosteroids currently available (fluticasone and budesonide). Evidence for any intraclass differences in the risk of pneumonia between currently available formulations is inconclusive due to the absence of head to head trials. Inhaled corticosteroids have no cardiovascular effects. CONCLUSIONS: Among patients with chronic obstructive pulmonary disease, clinicians should carefully balance these long-term risks of inhaled corticosteroid against their symptomatic benefits. PMID- 20714374 TI - Changes in six-minute walking distance during pulmonary rehabilitation in patients with COPD and in healthy subjects. AB - BACKGROUND: The six-minute walking distance (6MWD) test has demonstrated validity and reliability to assess changes in functional capacity following pulmonary rehabilitation in patients with chronic obstructive lung disease. However, no attempt has been made to establish an iterative measurement of 6MWD during the overall period of pulmonary rehabilitation. Therefore, the aim of this study was to evaluate the impact of a twelve-week rehabilitation program on the iterative weekly measurement of 6MWD in chronic obstructive pulmonary disease (COPD) patients and healthy subjects. METHODS: Twenty-six patients with COPD and nine age-matched healthy subjects were studied. Measurements were taken at baseline and after twelve weeks except for the 6MWD. The exercise measurements included a six-minute walking test (6MWT) and an incremental exercise test. Oxygen saturation, heart rate, and dyspnea will be monitored during all these tests. RESULTS: At baseline there were significant differences between groups, except in age, body mass index, and oxygen saturation. After 12 weeks, there was no significant change in lung function in patients with COPD and healthy subjects. The 6MWD, peak oxygen uptake (.)VO(2peak) and anaerobic threshold increased significantly after training in both groups (P < 0.01). The averaged trace of the 6MWD of patients with COPD and healthy subjects was followed-up respectively by a logarithmic and linear fitting. 6MWD showed a plateau after eight weeks in patients with COPD, however, it increased continually overall in healthy subjects. CONCLUSION: Both patients with COPD and healthy subjects demonstrated functional responses to training but with somewhat different patterns in quality of the improvement of the 6MWD. PMID- 20714373 TI - Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. AB - Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versus placebo, inhaled via the Respimat Soft Mist Inhaler (SMI). The two studies were combined and had 4 co-primary endpoints (trough FEV(1) response, Mahler Transition Dyspnea Index [TDI] and St George's Respiratory Questionnaire scores all at week 48, and COPD exacerbations per patient-year). A total of 1990 patients with COPD participated (mean FEV(1): 1.09 L). The mean trough FEV(1) response of tiotropium 5 or 10 microg relative to placebo was 127 or 150 mL, respectively (both P < 0.0001). The COPD exacerbation rate was significantly lower with tiotropium 5 microg (RR = 0.78; P = 0.002) and tiotropium 10 microg (RR = 0.73; P = 0.0008); the health-related quality of life and Mahler TDI co primary endpoints were significantly improved with both doses (both P < 0.0001). Adverse events were generally balanced except anticholinergic class effects, which were more frequent with active treatment. Fatal events occurred in 2.4% (5 microg), 2.7% (10 microg), and 1.6% (placebo) of patients; these differences were not significant. Tiotropium Respimat SMI 5 microg demonstrated sustained improvements in patients with COPD relative to placebo and similar to the 10 microg dose but with a lower frequency of anticholinergic adverse events. PMID- 20714375 TI - Tumor necrosis factor-alpha serum levels in healthy smokers and nonsmokers. AB - BACKGROUND: Tobacco smoking is the most important risk factor for chronic obstructive pulmonary disease (COPD) development. Inhaled cigarette smoke can induce tumor necrosis factor-alpha (TNF-alpha) production by alveolar macrophages, which in turn may enhance the production of metalloproteinases (MMPs). MMPs have been involved in mediating airway inflammation and lung destruction. OBJECTIVES: We aimed to measure the TNF-alpha serum levels in healthy heavy smokers and healthy nonsmokers to determine the dose-response relationship based on the cigarette smoke exposure. SUBJECTS AND METHODS: We included in our study 43 healthy heavy smokers and 19 healthy nonsmokers (the control group). The smokers group was classified as less than one pack, one pack, and more than one pack per day. A clinical and paraclinical evaluation was performed in both groups, without any evidence of infection or COPD. The serum levels of TNF-alpha were assessed by ELISA. RESULTS: The TNF-alpha serum levels were significantly higher for the group of smokers compared to the group of nonsmokers (P < 0.004). We also noticed an increased TNF-alpha concentration in the serum of smokers with more than one pack per day compared with those with less than one pack per day (P < 0.03). There was a positive correlation between the serum level of TNF-alpha and tobacco smoke exposure. CONCLUSIONS: The high levels of TNF-alpha in the serum of smokers suggest an imbalance between the proinflammatory and anti-inflammatory factors as a result of tobacco smoke exposure. The concentration of TNF-alpha is elevated in the serum of healthy heavy smokers in a cigarette dose-dependent manner. We speculate that the serum level of TNF-alpha might be a useful biomarker for the selection of heavy smokers with a high risk of developing smoke induced pulmonary diseases. PMID- 20714376 TI - Nebulized formoterol: a review of clinical efficacy and safety in COPD. AB - A nebulized formulation of formoterol, Perforomist, 20 microg/2 ml, has been available since 2007 for the maintenance treatment of chronic obstructive pulmonary disease (COPD). We review the safety and efficacy data obtained during its development. In a dose-finding study, formoterol inhalation solution (FFIS) was similar to the formoterol originator, Foradil 12 microg DPI (FA) in patients with COPD. In a 12-week efficacy study, FFIS manifested a rapid onset of action and FEV(1) peak, AUC(0-12), and trough levels similar to FA. No loss of efficacy, tachyphylaxis, was observed over 12 weeks of regular administration. In placebo controlled studies in COPD patients receiving maintenance tiotropium, the addition of FFIS significantly augmented bronchodilation over the 6-week treatment duration, signifying that nebulized formoterol can further improve lung function in patients who are receiving tiotropium without an observed increase in adverse reactions. The safety profile of FFIS during 12-week and 1-year studies revealed adverse events that were similar to those of placebo and FA. Cardiac rhythm studies, including frequent ECGs and Holter monitoring, did not indicate any increase in rate or rhythm disturbances greater than placebo or FA. We conclude that maintenance use of Perforomist is appropriate for patients with COPD who require or prefer a nebulizer for management of their disease. PMID- 20714377 TI - Lung function and blood markers of nutritional status in non-COPD aging men with smoking history: a cross-sectional study. AB - PURPOSE: Cigarette smoking and advanced age are well known as risk factors for chronic obstructive pulmonary disease (COPD), and nutritional abnormalities are important in patients with COPD. However, little is known about the nutritional status in non-COPD aging men with smoking history. We therefore investigated whether reduced lung function is associated with lower blood markers of nutritional status in those men. SUBJECTS AND METHODS: This association was examined in a cross-sectional study of 65 Japanese male current or former smokers aged 50 to 80 years: 48 without COPD (non-COPD group), divided into tertiles according to forced expiratory volume in one second as percent of forced vital capacity (FEV(1)/FVC), and 17 with COPD (COPD group). RESULTS: After adjustment for potential confounders, lower FEV(1)/FVC was significantly associated with lower red blood cell count (RBCc), hemoglobin, and total protein (TP); not with total energy intake. The difference in adjusted RBCc and TP among the non-COPD group tertiles was greater than that between the bottom tertile in the non-COPD group and the COPD group. CONCLUSION: In non-COPD aging men with smoking history, trends toward reduced nutritional status and anemia may independently emerge in blood components along with decreased lung function even before COPD onset. PMID- 20714378 TI - Misdiagnosis of patients receiving inhaled therapies in primary care. AB - AIM: To analyze the accuracy of diagnosis in a population receiving inhaled therapies due to respiratory diseases in a primary care setting. METHOD: Noninterventional, multicenter, cross-sectional, observational epidemiologic study methodology. RESULTS: A total of 9752 subjects were evaluated. Of these, 4188 (42.9%) patients were diagnosed with asthma, 4175 (42.8%) with chronic obstructive pulmonary disease (COPD), and 1389 had a diagnosis of disease of unknown origin. Of those over the age of 40 years, 4079 (50.9%) had COPD and 2877 (35.9%) had asthma. Sixty percent of the subjects were men, and the proportion of men was higher in patients with COPD (83.2%) than in the group with asthma (39.8%, P < 0.0001). Of subjects with COPD, 17.3% had mild, 55.3% had moderate, 24.1% had severe, and 3.2% had very severe disease. With regard to the level of severity of asthma, 34.9% of subjects had intermittent, 34.6% had mild persistent, 27.1% had moderate persistent, and 3.5% had severe persistent disease. Only 13.9% of patients in the COPD group had all the characteristics of COPD based on the Global Initiative for Chronic Obstructive Lung Disease criteria and an absence of the characteristics of asthma. CONCLUSIONS: The majority of patients receiving inhaled therapy in primary care did not have an accurate diagnosis according to current international guidelines for COPD and asthma. More initiatives for improving diagnostic accuracy in respiratory diseases must be implemented in primary care. PMID- 20714379 TI - Clinical efficacy of farcosolvin syrup (ambroxol-theophylline-guaiphenesin mixture) in the treatment of acute exacerbation of chronic bronchitis. AB - BACKGROUND: Acute exacerbations of chronic bronchitis (AECB) are defined as recurrent attacks of worsening bronchial inflammation that are marked by an increase in the volume of daily sputum produced, a change in color of the expectorated sputum, and worsening dyspnea. Farcosolvin (Pharco Pharmaceuticals, Alexandria, Egypt) is a mixture of ambroxol (15 mg); theophylline (50 mg); and guaiphenesin (30 mg), per 5 mL syrup. OBJECTIVE: To test the clinical efficacy of Farcosolvin in the treatment of AECB in a randomized, single-blinded, controlled study design. PATIENTS AND METHODS: One hundred patients with AECB were randomized to either Farcosolvin or guaiphenesin treatment groups, in addition to the standard medical treatment for their cases. Baseline clinical symptomatolgy of breathlessness, cough, and sputum severity scoring were compared before and after 3 and 7 days of treatment in both groups and the differences compared between groups. Changes in perceived improvement were also compared between groups using the Clinical Global Impression of Improvement or Change Scale (CGIC). RESULTS: There were statistically significant improvements in breathlessness and cough scores in both groups (pretreatment versus posttreatment at day 3 and at day 7; P < 0.05). There were highly statistically significant differences between groups in improvement in breathlessness and cough scores, after 3 and 7 days treatment, in favor of the Farcosolvin treatment group (P < 0.001). Out of 50 patients, 48 (96%) in the Farcosolvin-treated group rated their improvement on the CGIC scale as "much" and "very much" improved, while only 41 patients (82%) reported such a degree of improvement in the control group. The difference was statistically significant (P < 0.05). CONCLUSION: We concluded from our study that Farcosolvin syrup might be safe and effective in improving symptoms in cases of acute exacerbation of chronic bronchitis. PMID- 20714380 TI - Inspiratory flows through dry powder inhaler in chronic obstructive pulmonary disease: age and gender rather than severity matters. AB - BACKGROUND: Dry powder inhalers (DPIs) are inspiratory flow driven and hence flow dependent. Most patients with chronic obstructive pulmonary disease (COPD) are elderly and have poor lung function. The factors affecting their inspiratory flows through inhalers are unclear. OBJECTIVE: To study peak inspiratory flows (PIFs) and their determinants through a DPI in COPD patients of varying age and severity. METHODS: Flow-volume spirometry was performed in 93 COPD patients. Maximum PIF rates were recorded through an empty Easyhaler (PIF(EH); Orion Corporation, Espoo, Finland), a DPI that provides consistent dose delivery at inhalation rates through the inhaler of 28 L/min or higher. RESULTS: The mean PIF(EH) was 54 L/min (range 26-95 L/min) with a coefficient of variation of 7%. All but two patients were able to generate a flow of > or = 28 L/min. In a general linear model, the independent determinants for PIF(EH) were age (P = 0.02) and gender (P = 0.01), and forced expiratory volume in 1 s (FEV(1)) expressed as percent predicted was not a significant factor. The regression model accounted only for 18% of the variation in PIF(EH). CONCLUSION: In patients with COPD, age and gender are more important determinants of inspiratory flow through DPIs than the degree of expiratory airway obstruction. Most COPD patients with varying age and severity are able to generate inspiratory flows through the test inhaler that is sufficient for optimal drug delivery to the lower airways. PMID- 20714382 TI - Effects of multicurve RGP contact lens use on topographic changes in keratoconus. AB - PURPOSE: To evaluate the effects of wearing rigid gas permeable (RGP) contact lenses on the topographic changes in keratoconus. METHODS: Seventy-seven keratoconic eyes that wore multicurve RGP contact lenses and 30 keratoconic eyes that wore no contact lenses were retrospectively analyzed. The mean follow-ups were 22.6 and 20.5 months in the lens-wearing and control groups, respectively. Visual acuity, comfort, daily wearing time, and corneal staining were evaluated for both groups. The changes in topographic indices were compared between the lens-wearing and control groups. RESULTS: Multicurve RGP lens corrected logarithm of the minimum angle of resolution visual acuity of the lens-wearing group significantly improved from -0.016+/-0.065 to -0.032+/-0.10 at follow-up (p=0.05). In the lens-wearing group with advanced keratoconus, the Sim Kmax, Sim Kmin, apical power, astigmatic index, and anterior elevation significantly decreased from 57.68+/-4.26 diopter (D), 50.50+/-2.32 D, 62.79+/-5.11 D, 7.20+/ 0.55 D and 67.36+/-16.30 microm to 55.51+/-4.28 D, 49.62+/-3.26 D, 60.31+/-5.41 D, 5.90+/-0.51 D and 60.61+/-16.09 microm, respectively (paired t-test, p<0.05). The irregularity index of 3 mm did not significantly change. Meanwhile, in the control group, the apical power and irregularity index increased from 55.56+/ 7.25 D and 3.06+/-1.68 D to 57.11+/-7.75 D and 3.25+/-1.71 D, respectively (paired t-test, p=0.008, p=0.01). CONCLUSIONS: Properly fitted multicurve RGP contact lenses are not likely to contribute to the progression of keratoconus. PMID- 20714381 TI - A comparison of posterior lamellar keratoplasty modalities: DLEK vs. DSEK. AB - PURPOSE: To compare clinical outcomes after deep lamellar endothelial keratoplasty (DLEK) with Descemet stripping endothelial keratoplasty (DSEK) performed as initial cases by a single surgeon. METHODS: Sixteen patients with corneal endothelial were enrolled. Eight patients (8 eyes) underwent DLEK and 8 patients (8 eyes) DSEK. We measured uncorrected visual acuity, best corrected visual acuity (BCVA), manifest refraction, corneal endothelial count, interface opacity via Schiempflug imaging, and contrast sensitivity, as well as tracked postoperative complications over the first postoperative year. RESULTS: Primary graft failure occurred in two DLEK cases and one DSEK case, all of which were excluded for further analysis. The average 12-month postoperative BCVA was 20/70 in the DLEK group and 20/50 in the DSEK group, with the difference not statistically significant. No significant differences were identified between the 2 groups in terms of mean spherical equivalent and refractive astigmatism, although individuals in the DSEK group tended toward hyperopia. The average endothelial cell count at postoperative month 12 was 1849+/-494 in the DLEK group and 1643+/-417 cells/mm(2) in the DSEK group, representing cell losses of 26.2% and 31.9%, respectively. No significant differences in endothelial cell count or endothelial cell loss were observed between groups. Early postoperative donor disc dislocation occurred in two eyes after DLEK and one eye after DSEK. Interface opacities and contrast sensitivities were similarly not significantly different between groups. CONCLUSIONS: No significant differences in any assessed clinical outcome were observed between individuals undergoing DLEK and DSEK, when performed as initial cases by a single surgeon. PMID- 20714383 TI - Long-term efficacy and rotational stability of AcrySof toric intraocular lens implantation in cataract surgery. AB - PURPOSE: To evaluate the long-term efficacy and rotational stability of the AcrySof toric intraocular lens (IOL) in correcting preoperative astigmatism in cataract patients. METHODS: This prospective observational study included 30 eyes from 24 consecutive patients who underwent implantation of an AcrySof toric IOL with micro-coaxial cataract surgery between May 2008 and September 2008. Outcomes of visual acuity, refractive and keratometric astigmatism, and IOL rotation after 1 day, 1 month, 3 months, and long-term (mean, 13.3+/-5.0 months) follow-up were evaluated. RESULTS: At final follow-up, 73.3% of eyes showed an uncorrected visual acuity of 20/25 or better. The postoperative keratometric value was not different from the preoperative value; mean refractive astigmatism was reduced to -0.28+/-0.38 diopter (D) from -1.28+/-0.48 D. The mean rotation of the toric IOL was 3.45+/-3.39 degrees at final follow-up. One eye (3.3%) exhibited IOL rotation of 10.3 degrees, the remaining eyes (96.7%) had IOL rotation of less than 10 degrees. CONCLUSIONS: Early postoperative and long-term follow-up showed that implantation of the AcrySof toric IOL is an effective, safe, and predictable method for managing corneal astigmatism in cataract patients. PMID- 20714384 TI - Central photoreceptor viability and prediction of visual outcome in patients with idiopathic macular holes. AB - PURPOSE: To identify the correlation between preoperative optical coherence tomography (OCT) features and postoperative visual outcomes in eyes with idiopathic macular holes (MHs). METHODS: Data from 55 eyes with idiopathic MHs which had been sealed by vitrectomy were retrospectively reviewed. Correlation analysis was conducted between postoperative visual acuity (V(postop), logarithm of the minimum angle of resolution [logMAR]) and preoperative factors, including four OCT parameters: the anticipated length (A) devoid of photoreceptors after hole closure, MH height (B), MH size (C), and the grading (D) of the viability of detached photoreceptors. Additionally, the formula for the prediction of visual outcome was deduced. RESULTS: V(postop) was determined to be significantly correlated with the preoperative visual acuity (V(preop)) and OCT parameters A, C, and D (p<0.001). Based on the correlation, the formula for the prediction of V(postop) was derived from the most accurate regression analysis: V(postop)=0.248xV(preop)+1.1x10(-6)xA(2)-0.121xD+0.19. CONCLUSIONS: The length and viability of detached photoreceptors are significant preoperative OCT features for predicting visual prognosis. This suggests that, regardless of the MH size and symptom duration, active surgical intervention should be encouraged, particularly if the MH exhibits good viability in the detached photoreceptor layer. PMID- 20714385 TI - Eye-preserving therapy in retinoblastoma: prolonged primary chemotherapy alone or combined with local therapy. AB - PURPOSE: To evaluate the efficacy of primary chemotherapy combined with local therapy in the treatment of retinoblastomas not treatable with a single therapeutic method. METHODS: We performed a retrospective chart review of 227 patients diagnosed with retinoblastoma. Sixty-five eyes in 52 patients had tumors not treatable with a single therapeutic method and received primary chemotherapy combined with local therapy as needed. RESULTS: Tumor control and eye salvage was achieved in 34 of the 65 eyes; the probability of ocular survival was 46.56% using the Kaplan-Meier method. Forty-three of the 65 eyes were group D or E tumors, in which tumor control and eye salvage was achieved in 16 eyes. Twenty eyes were treated with chemotherapy only, while 28 eyes received one additional modality of local therapy, and 17 eyes received two modalities of local therapy. Of the eyes treated with chemotherapy only, tumor control was achieved in 5 eyes. CONCLUSIONS: Primary chemotherapy combined with local therapy can be effective and safe in the treatment of retinoblastomas otherwise untreatable with other therapeutic methods, such as group D and E retinoblastomas. More vigorous treatment with more local therapeutic methods combined may yield even better results. PMID- 20714386 TI - Factors influencing the prevalence of amblyopia in children with anisometropia. AB - PURPOSE: To evaluate factors that can influence the prevalence of amblyopia in children with anisometropia. METHODS: We retrospectively reviewed the records of 63 children 2 to 13 years of age who had anisometropic amblyopia with a difference in the refractive errors between the eyes of at least two diopters (D). The type of anisometropia (myopia, hyperopia, and astigmatism), degree of anisometropia (<2-3 D, <3-4 D, or >4 D), best corrected visual acuity (BCVA) of the amblyopic eye at the time of initial examination, BCVA differences between sound and amblyopic eyes, whether or not occlusion therapy was performed, compliance with occlusion therapy, and the patient's age when eyeglasses were first worn were investigated. RESULTS: There was an increase in the risk of amblyopia with increased magnitude of anisometropia (p=0.021). The prevalence of amblyopia was higher in the BCVA <20/40 group and in patients with BCVA differences >4 lines between sound and amblyopic eyes (p=0.008 and p=0.045, respectively). There was no statistical relationship between the prevalence of amblyopia and the type of anisometropia or the age when eyeglasses were first worn. Poor compliance with occlusion therapy was less likely to achieve successful outcome (p=0.015). CONCLUSIONS: Eyes with poor initial visual acuities of <20/40, a high magnitude of anisometropia, and a >4 line difference in the BCVA between sound and amblyopic eyes at the initial visit may require active treatment. PMID- 20714387 TI - The effect of bevacizumab on corneal neovascularization in rabbits. AB - PURPOSE: To determine the efficacy of topical application and subconjunctival injection of bevacizumab in the treatment of corneal neovascularization. METHODS: Corneal neovascularization was induced with a silk suture of the corneal stroma in 12 rabbits (24 eyes). One week after suturing, four rabbits were treated with topical bevacizumab at 5 mg/mL (group A) and another four rabbits were treated with topical bevacizumab 10 mg/mL (group B) in the right eyes twice a day for two weeks. A subconjunctival injection of bevacizumab 1.25 mg/mL was done in the right eyes of four rabbits (group C). All of the left eyes (12 eyes) were used as controls. The area of corneal neovascularization was measured after one and two weeks, and the concentration of vascular endothelial growth factor (VEGF) in corneal tissue was measured after two weeks. RESULTS: The neovascularized area was smaller in all treated groups than in the control group (p<0.001). Upon analysis of the neovascularized area, there was no significant difference between groups A and B. However, the mean neovascularized area of group B was significantly smaller than that of group C after two weeks of treatment (p=0.043). The histologic examination revealed fewer new corneal vessels in all treated groups than the control group. The concentration of VEGF was significantly lower in all treated groups compared to the control group (p<0.01), but no difference was shown between treated groups. CONCLUSIONS: Topical and subconjunctival bevacizumab application may be useful in the treatment of corneal neovascularization and further study is necessary. PMID- 20714388 TI - Poliosis of eyelashes as an unusual sign of a halo nevus. AB - A 39-year-old man with poliosis of his lower eyelid lashes visited our clinic. He reported that his symptoms began with a few central lashes and then spread along the adjacent lashes during the ensuing 2 weeks. A pigmented nevus, approximately 4 mm in diameter, was identified just above the white lashes without surrounding skin depigmentation. No specific findings were identified with regard to the patient's general health or serologic and radiologic testing. Excisional biopsy of the pigmented nevus was performed. On histopathologic examination, infiltration of the dermis by numerous lymphocytes and melanophages was observed. The poliosis was ultimately diagnosed as a presenting sign of the halo phenomenon in the regressive stage of a melanocytic nevus. PMID- 20714389 TI - Two cases of corneal ulcer due to methicillin-resistant Staphylococcus aureus in high risk groups. AB - Considering the popular use of antibiotic-containing eyedrops in Korea, it is important to know the emerging antibiotic-resistant strains of bacteria before treating infectious eye diseases. This is especially important in high-risk groups because of the high incidence of resistant infections and the subsequent treatment requirements. We report two cases of methicillin-resistant Staphylococcus aureus (MRSA) corneal ulcers in high-risk groups. The first case involved a patient who had keratitis after using antibiotic- and steroid containing eyedrops to treat a corneal opacity that developed after repeated penetrating keratoplasty. The second case involved a patient who used antibiotic containing eyedrops and a topical lubricant on a regular basis for >1 month to treat exposure keratitis due to lagophthalmos. The second patient's problems, which included a persistent superficial infiltration, developed after brain tumor surgery. Both cases showed MRSA on corneal culture, and the corneal ulcers improved in both patients after the application of vancomycin-containing eyedrops. In conclusion, MRSA infection should be considered in corneal ulcers that have a round shape, mild superficial infiltration, and slow progression, especially in high-risk groups. This report includes descriptions of the characteristic features, antibiotic sensitivities, prevention, and successful treatment with vancomycin-containing eyedrops for MRSA corneal ulcers. PMID- 20714390 TI - Bilateral serous retinal detachment as a presenting sign of acute lymphoblastic leukemia. AB - We present a case of bilateral serous retinal detachment (SRD) as a presenting sign of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). A 45-year-old woman presented with decreased vision and was found to have bilateral serous retinal detachment. Peripheral blood smears revealed leukocytosis of 53.9x10(3)/microL with 64.6% lymphoblasts. A bone marrow aspirate revealed the presence of lymphoblasts. Cytogenetic and molecular genetic analysis detected a reciprocal translocation between chromosome 9 and 22, t(9;22) (q34;q11). A diagnosis of Ph(+) ALL was made. Following systemic chemotherapy, the bilateral SRD resolved completely with full recovery of vision. The sudden appearance of SRD should raise suspicion for leukemia. Prompt recognition of this disease is important for early systemic treatment and restoration of visual function. PMID- 20714391 TI - A case of bilateral endogenous Pantoea agglomerans endophthalmitis with interstitial lung disease. AB - We here in report a case of bilateral endogenous endophthalmitis caused by Pantoea agglomerans (P. agglomerans) in a patient who had interstitial lung disease and was treated with oral corticosteroids. A 72-year-old man presented with decreased visual acuity in both eyes nine days after he received oral corticosteroids. He had marked uveitis, cataracts, and vitreous opacities. Cultures were taken of blood, aqueous humor, and vitreous. We initially suspected a fungal etiology and treated him with antifungal drugs; however, the intraocular disease progressed without improvement. Vitreous culture was positive for P. agglomerans. The patient underwent pars plana vitrectomy with cataract surgery bilaterally, followed by a 2-week course of antibiotics. The final visual acuity was 20/25 in the right eye and 20/200 in the left eye. This is the first report of bilateral endogenous endophthalmitis caused by P. agglomerans in Korea; it is also the first case reported outside of the United States. PMID- 20714392 TI - Neovascular glaucoma following stereotactic radiosurgery for an optic nerve glioma: a case report. AB - A 13-year-old girl with a right intraorbital optic nerve glioma (ONG) was referred to our glaucoma clinic because of uncontrolled intraocular pressure (IOP) in her right eye. The IOP reached as high as 80 mmHg. Several months earlier, she had undergone stereotactic image-guided robotic radiosurgery using the CyberKnife for her ONG; the mass had become smaller after treatment. Her visual acuity was no light perception. Slit lamp examination revealed rubeosis iridis, a swollen pale optic disc, and vitreous hemorrhage. After medical treatment, the IOP decreased to 34 mmHg, and no pain was reported. Although the mass effect of an ONG can cause neovascular glaucoma (NVG), this case shows that stereotactic radiosurgery may also cause NVG, even after reducing the mass of the tumor. Patients who undergo radiosurgery targeting the periocular area should be followed carefully for complications. PMID- 20714393 TI - Optic neuropathy associated with Castleman disease. AB - A 44-year-old woman with Castleman disease presented with acute visual loss in the left eye. A full ophthalmologic examination and imaging were performed. Visual acuity was 20/20 in the right eye and 20/100 in the left eye. Total dyschromatopsia, a relative afferent pupillary defect, and a cecocentral scotoma were observed in the left eye. Mild disc edema, without leaking during fluorescein angiography, was also observed. Magnetic resonance imaging revealed a small cystic epidermoid-like lesion in the right prepontine and suprasellar cistern. Her visual acuity did not improve and deteriorated to 20/200 in the left eye at 22 months after the initial visual loss. Optic neuropathy may rarely be associated with Castleman disease and suggests a poor prognosis. PMID- 20714394 TI - Natural triterpenoid avicins selectively induce tumor cell death. AB - Avicins, a family of plant-derived triterpenoids, have been shown to possess pro apoptotic, anti-mutagenic and anti-inflammatory properties in mammalian cells. Through thiol binding, avicins can also mediate antioxidant defense. Accumulating evidence uncovered during the past several years suggests that avicins induce tumor cell death via multiple mechanisms. This review will focus on recent studies that provide insights into the cellular and molecular processes and pathways by which avicins induce tumor cell death, including the canonical intrinsic mitochondrial and the Fas-mediated apoptosis cascades as well as autophagy-associated non-apoptotic programmed cell death. PMID- 20714395 TI - Roles of membrane trafficking in nerve repair and regeneration. AB - Successful axonal repair following injury is critical for nerve regeneration and functional recovery. Nerve repair relies on three functionally distinct events involving membrane trafficking. First, axonally transported vesicles accumulate, while others are generated at the cut end to restore a selective barrier to the severed axon. Then, retrograde transport of vesicles along microtubules informs the cell body that damage has occurred in the distal axon. Finally, membrane addition to a newly formed growth cone, or to the axonal membrane is required to promote axonal re-growth and elongation. Yet, how these membrane trafficking events are regulated and what are the identities of the molecules and organelles involved remains largely unknown. Several potential factors have been recently identified. Members of the SNARE machinery appear to regulate fusion of vesicles in a calcium-dependent manner to promote axolemmal resealing. Retrograde transport of endosomes powered by the dynein-dynactin molecular motor complex represents a potential injury-signaling platform. Several classes of secretory and endocytic vesicles may coordinate axonal membrane extension and re-growth. Here we discuss recent advances in understanding the mechanisms of the membrane trafficking involved in nerve repair. PMID- 20714397 TI - The knowns and unknowns of chimpanzee culture. AB - Claims of culture in chimpanzees appeared soon after the launch of the first field studies in africa.1 The notion of chimpanzee 'material cultures' was coined,2 and this was followed by a first formal comparison, which revealed an astonishing degree of behavioural diversity between the different study communities, mainly in terms of tool use.3 Although this behavioural diversity is still undisputed, the question of chimpanzee cultures has remained controversial.4-6 The debate has less to do with the definition of culture (most animal behaviour researchers accept the notion for behaviour that is 'transmitted repeatedly through social or observational learning to become a population-level characteristic' 3), but more with whether some key criteria are met. PMID- 20714396 TI - Cellular bridges: Routes for intercellular communication and cell migration. AB - Cell-to-cell communication is the basis of all biology in multicellular organisms, allowing evolution of complex forms and viability in dynamic environments. Though biochemical interactions occur over distances, physical continuity remains the most direct means of cellular interactions. Cellular bridging through thin cytoplasmic channels-plasmodesmata in plants and tunneling nanotubes in animals-creates direct routes for transfer of signals and components, even pathogens, between cells. Recently, two new cellular connections, designated epithelial (EP) bridges, were discovered and found to be structurally distinct from other cellular channels. The first EP bridge type facilitates material transport between cells similar to plasmodesmata and tunneling nanotubes, the second EP bridge type mediates migration of cells between EP cell masses representing a novel form of cell migration. Here, we compare the structures and functions of EP bridges with other cellular channels and discuss biochemical and cellular interactions involved in EP bridge formation. Potential roles for EP bridges in health and disease are also presented. PMID- 20714398 TI - The role of calcium in neutrophil granule-phagosome fusion. AB - During phagocytosis, neutrophils kill microorganisms by delivering antimicrobial substances to the phagosome. For this, the intracellular targeting and fusion of granules must be strictly regulated and a dependence on the cytosolic concentration of free calcium has been suggested. New evidence show that different mechanisms regulate early and late stages of Fc receptor-mediated phagocytosis. The early fusion events are dependent on calcium but this is not the case for the fusion of azurophilic granules with phagosomes at later stages. Certain pathogens target the granule-phagosome fusion machinery in order to survive intracellularly; a deeper understanding of intracellular membrane traffic processes could allow new approaches for the eradication of pathogens that are harbored inside the cells of our immune system. PMID- 20714399 TI - Evolutionary conservation of the WASH complex, an actin polymerization machine involved in endosomal fission. AB - WASH is the Arp2/3 activating protein that is localized at the surface of endosomes, where it induces the formation of branched actin networks. This activity of WASH favors, in collaboration with dynamin, the fission of transport intermediates from endosomes, and hence regulates endosomal trafficking of several cargos. We have purified a novel stable multiprotein complex containing WASH, the WASH complex, and we examine here the evolutionary conservation of its seven subunits across diverse eukaryotic phyla. This analysis supports the idea that the invention of the WASH complex has involved the incorporation of an independent complex, the CapZ alpha/beta heterodimer, forming the so-called Capping Protein (CP), as illustrated by the yeasts S. cerevisiae and S. pombe, which possess the CP heterodimer but no other subunits of the WASH complex. The alignements of the orthologous genes that we have generated give a view on the conservation of the different subunits and on their organization into domains. Moreover, we propose here a unique nomenclature for the different subunits to prevent future confusions in the field. PMID- 20714400 TI - M-Sec: Emerging secrets of tunneling nanotube formation. AB - Tunneling nanotubes (TNT) are the latest addition to the array of strategies used for intercellular signaling. TNTs are continuous conduits of the plasma membrane that allow direct physical connection of plasma membranes and cytosol among remote cells. They are important for intercellular communication by mediating exchange of cellular components as well as signal transduction molecules. Despite ample evidence suggesting the pathophysiological importance of TNTs, virtually nothing is known about the molecular basis for their formation. With the lack of specific TNT markers, their study has relied solely on morphological analyses, and the precise identity of TNT and TNTlike structures have been difficult to define. We have now shown that M-Sec is a TNT marker and a central factor for TNT formation. In cooperation with the RalA small GTPase and the exocyst complex, M Sec can induce the formation of functional TNTs, indicating that the remodeling of the actin cytoskeleton is involved in M-Sec-mediated TNT formation. Discovery of the role of M-Sec will accelerate our understanding of TNTs, both at the molecular and physiological levels. PMID- 20714401 TI - Effects of loss of myosin VI no-insert isoform on clathrin-mediated endocytosis of plasma-membrane receptors. PMID- 20714402 TI - Pheromone-induced life-history shifts A novel approach to controlling invasive toads. AB - In a recent paper,1 we showed that recurrent exposure to alarm pheromones reduced development time and size at metamorphosis in larval cane toads (Bufo marinus). Subsequent measurements of post-metamorphic toads revealed larger parotoid glands relative to body size and increased amounts of bufalin (a toxic bufodienalide) in animals from the experimental treatment, suggesting increased investment in chemical defenses. These findings are of interest for evolutionary theory. But the study was also part of a larger conservation-based research program of which this pheromone work was an important component in the development of a management strategy for reducing the ecological impact of invasive cane toads in Australia. For example, our study1 aimed to quantify biochemical and life-history effects as well as assess the likely longterm impact of pheromone exposure on toads. In this addendum, I discuss the conservation potential of our research, with emphasis on exploiting alarm pheromones to induce viability reducing life-history shifts. PMID- 20714404 TI - The risk of predation favors cooperation among breeding prey. AB - Empirical studies have shown that animals often focus on short-term benefits under conditions of predation risk, which reduces the likelihood that they will cooperate with others. However, some theoretical studies predict that animals in adverse conditions should not avoid cooperation with their neighbors since it may decrease individual risks and increase long-term benefits of reciprocal help. We experimentally tested these two alternatives to find out whether increased predation risk enhances or diminishes the occurrence of cooperation in mobbing, a common anti-predator behavior, among breeding pied flycatchers, Ficedula hypoleuca. Our results show that birds attended mobs initiated by their neighbors more often, approached the stuffed predator significantly more closely, and mobbed it at a higher intensity in areas where the perceived risk of predation was experimentally increased. This study demonstrates a positive impact of predation risk on cooperation in breeding songbirds, which might help to explain the emergence and evolution of cooperation. PMID- 20714403 TI - Functional role of STIM1 and Orai1 in silkmoth (Bombyx mori) sex pheromone production. AB - Store-operated Ca(2+) influx has recently been shown to require the activation of two proteins, stromal interaction molecule 1 (STIM1) and Orai1. In mammals the putative channel ion selectivity filter is thought to comprise conserved charged residues in the first and third transmembrane domains of Orai1 in addition to three residues in the first extracellular loop. The latter residues, however, are not conserved in either of the Bombyx mori Orai1 variants or in most insects, suggesting that selectivity is a relatively recent evolutionary event. In B. mori, thapsigargin-mediated STIM1 redistribution is dependent on a cluster of highly conserved basic residues (amino acids 380-385) in the C terminus that likely interact with acidic residues in the Orai1 C terminus. BmSTIM1 redistribution in vitro also occurs downstream of pheromone biosynthesis activating neuropeptide receptor activation. Activation of in vivo RNA interference mechanisms confirmed the physiological role of BmSTIM1 and Orai1 in sex pheromone production. PMID- 20714405 TI - Neuronal JNK pathway activation by IL-1 is mediated through IL1RAPL1, a protein required for development of cognitive functions. AB - Interleukin-1-Receptor Accessory Protein Like 1 (IL1RAPL1) gene mutations are associated to cognitive impairment ranging from non-syndromic X-linked mental retardation to autism. Functionally IL1RAPL1 belongs to a novel family of Toll/IL 1 Receptors, but its ligand is unknown. In a recent study, we have shown that IL1RAPL1 is present in dendritic spine where it interacts with PSD-95, a major scaffold protein of excitatory post-synaptic density. We demonstrated that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling JNK (c-Jun terminal Kinase) activity and PSD-95 phosphorylation. Loss of IL1RAPL1 in mouse not only led to a reduction of excitatory synapses but also to specific deficits in hippocampal long-term synaptic plasticity. Here we report that activation of JNK pathway in neurons by Interleukin-1 (IL-1) is mediated by IL1RAPL1. The interaction of IL1RAPL1 with PSD-95 discloses a novel pathophysiological mechanism underlying cognitive impairment associated with alterations of the JNK pathway in response to IL-1 and leading to the mislocalization of PSD-95, that subsequently result in abnormal synaptic organization and function. PMID- 20714406 TI - Dispersion and colonisation by fungus-growing termites: Vertical transmission of the symbiont helps, but then...? AB - The fungus-growing termites (Macrotermitinae) have developed an obligate mutualistic symbiosis with fungi (Termitomyces) and, in most cases, the symbiotic partner is collected from the environment upon establishment of a new colony (horizontal transmission). The requirement that partners are able to find and recognize each other after independent reproduction is likely to severely constrain long distance dispersal. In support of this hypothesis, we have recently shown that a single colonisation of Madagascar by fungus-growing termites has occurred. The successful colonizers belong to the genus Microtermes, known to inherit their symbiont from the parental colony (vertical transmission). However, the fungal symbionts of Madagascar were not monophyletic, as expected under strict vertical transmission. Here we further discuss these findings, and we suggest further bottlenecks to dispersion and propose a transient window for horizontal transmission for the otherwise vertically transmitted Termitomyces strains. PMID- 20714407 TI - The long and the short of SAD-1 kinase. AB - The Ser/Thr SAD kinases are evolutionarily conserved, critical regulators of neural development. Exciting findings in recent years have significantly advanced our understanding of the mechanism through which SAD kinases regulate neural development. Mammalian SAD-A and SAD-B, activated by a master kinase LKB1, regulate microtubule dynamics and polarize neurons. In C. elegans, the sad-1 gene encodes two isoforms, namely the long and the short, which exhibit overlapping and yet distinct functions in neuronal polarity and synaptic organization. Surprisingly, our most recent findings in C. elegans revealed a SAD-1-independent LKB1 activity in neuronal polarity. We also found that the long SAD-1 isoform directly interacts with a STRADalpha pseudokinase, STRD-1, to regulate neuronal polarity and synaptic organization. We elaborate here a working model of SAD-1 in which the two isoforms dimer/oligomerize to form a functional complex, and STRD-1 clusters and localizes the SAD-1 complex to synapses. While the mechanistic difference between the vertebrate and invertebrate SAD kinases may be puzzling, a recent discovery of the functionally distinct SAD-B isoforms predicts that the difference likely arises from our incomplete understanding of the SAD kinase mechanism and may eventually be reconciled as the revelation continues. PMID- 20714408 TI - MT1-MMP: A novel component of the macrophage cell fusion machinery. AB - Mice deficient in the matrix metalloproteinase MT1-MMP display defects in tissue development and angiogenesis, together with a complex bone phenotype characterized by several skeletal abnormalities and osteopenia. OCs and giant cells are multinucleated cells arising from the fusion of myeloid progenitors/macrophages that specialize respectively in bone resorption and engulfment of pathogens and foreign bodies. Our work identifies MT1-MMP as a novel component of the macrophage fusion machinery during OC and giant cell formation in vitro and in vivo. MT1-MMP is required for the proper lamellipodia formation and motility required to achieve proximity between fusioncompetent myeloid cells; and roles of MT1-MMP in subsequent steps of the fusion process cannot be ruled out. For example, MT1-MMP might exert additional functions at fusion sites by forming molecular complexes with CD44 or tetraspanin proteins. Interestingly, the contribution of MT1-MMP to macrophage motility and fusion does not involve its catalytic activity. Instead, the MT1-MMP-cytosolic tail, in particular Tyr(573), is required to bind the adaptor protein p130Cas and regulate localized Rac1 activity in myeloid progenitors. Modulation of this novel MT1 MMPp130Cas- Rac1 signaling pathway in macrophages might have potential in the treatment of disorders involving increased OC activity or uncontrolled giant cell formation. PMID- 20714409 TI - Muscling in on GLUT4 kinetics. AB - Insulin triggers glucose uptake into muscle and adipose tissue by stimulating the translocation of the glucose transporter glut4 from intracellular vesicles to the plasma membrane (pm). insulin leads to a rapid increase in glut4 at the pm from approximately 5% to 40-50%. this effect is time and dose-dependent, reaching a new steady state after 30 min of insulin stimulation. previous kinetic analyses in adipocytes has revealed that this is regulated by two mechanisms-increasing the amount of glut4 in the endosomal recycling system and increasing the exocytosis rate constant. fazakerley et al.1 focuses on GLUT4 kinetics in the L6 skeletal muscle cell line. Despite displaying a similar redistribution of GLUT4 to the cell surface with insulin to that seen in adipocytes, the mechanism for this effect in L6 cells was completely different. Insulin had a modest effect to increase the amount of GLUT4 in the recycling system with the dominant effect being on reduction of the endocytosis rate constant. Similar findings were observed with AMPK agonists. These studies indicate that different cell types are capable of achieving the same cell biological endpoint but using completely distinct mechanisms. PMID- 20714410 TI - Fascin: Invasive filopodia promoting metastasis. AB - Fascin is an evolutionarily conserved actin bundling protein that localizes to microspikes, filopodia and actin-based protrusions underneath the plasma membrane. fascin has received a lot of attention among cytoskeletal proteins because multiple clinical studies have implicated its expression in cancer progression and metastasis. this may be because fascin is not normally expressed in epithelial tissues and when it is upregulated as a part of a program of cancer cell epithelial to mesenchymal progression it confers special motility and invasion properties on cancer cells. in normal adult tissues, fascin expression is high in neurons and dendritic cells; both cell types have striking large filopodia and are highly motile. it is not clear how fascin promotes invasive motility in cancer cells, but many studies have implicated filopodia formation in motility and we have recently provided new evidence that fascin stabilizes actin bundles in invasive foot structures termed invadopodia in cancer cells Figure 1.1 Here we review some of the evidence implicating fascin in motility, invasion and cancer aggressiveness, and we speculate that by stabilizing actin, fascin provides cells with powerful invasive properties that may confer increased metastatic potential. PMID- 20714411 TI - Are high-quality mates always attractive?: State-dependent mate preferences in birds and humans. AB - Sexual selection theory posits that females should choose mates in a way that maximizes their reproductive success. But what exactly is the optimal choice? Most empirical research is based on the assumption that females seek a male of the highest possible quality (in terms of the genes or resources he can provide), and hence show directional preferences for indicators of male quality. This implies that attractiveness and quality should be highly correlated. However, females frequently differ in what they find attractive. New theoretical and empirical insights provide mounting evidence that a female's own quality biases her judgement of male attractiveness, such that male quality and attractiveness do not always coincide. A recent experiment in songbirds demonstrated for the first time that manipulation of female condition can lead to divergent female preferences, with low-quality females actively preferring low-quality males over high-quality males. This result is in line with theory on state-dependent mate choice and is reminiscent of assortative mating preferences in humans. Here we discuss the implications of this work for the study of mate preferences. PMID- 20714412 TI - Customized notched music training reduces tinnitus loudness. AB - Chronic tinnitus is a symptom with high prevalence. There is evidence that the tinnitus perception is related to unfavorable cortical plastic changes. In our recent study we have developed and evaluated a customized music training strategy that appears capable of both reducing cortical tinnitus related neuronal activity and alleviating subjective tinnitus perception. We hypothesize that the regular and enjoyable music training reverses unprofitable cortical reorganization to a certain degree by means of the focused strengthening of auditory inhibitory neuronal networks. PMID- 20714413 TI - Reactive oxygen species as signaling molecules in neutrophil chemotaxis. AB - Neutrophil chemotaxis is a critical component in innate immunity. Recently, using a small-molecule functional screening, we identified NADPHoxidase- dependent Reactive Oxygen Species (ROS) as key regulators of neutrophil chemotactic migration. Neutrophils depleted of ROS form more frequent multiple pseudopodia and lost their directionality as they migrate up a chemoattractant concentration gradient. Here, we further studied the role of ROS in neutrophil chemotaxis and found that multiple pseudopodia formation induced by NADPH inhibitor diphenyleneiodonium chloride (DPI) was more prominent in relatively shallow chemoattractant gradient. It was reported that, in shallow chemoattractant gradients, new pseudopods are usually generated when existing ones bifurcate. Directional sensing is mediated by maintaining the most accurate existing pseudopod, and destroying pseudopods facing the wrong direction by actin depolymerization. We propose that NADPH-mediated ROS production may be critical for disruption of misoriented pseudopods in chemotaxing neutrophils. Thus, inhibition of ROS production will lead to formation of multiple pseudopodia. PMID- 20714414 TI - Curvaceous female bodies activate neural reward centers in men. AB - Facial symmetry, masculinity and shoulder-to-hip ratios in men convey information to mates about reproductive/genetic quality, the so-called "good genes" hypothesis. On the other hand waist-to-hip ratio conveys important reproductive information about women to men. Here using fMRI, men showed activation in neural reward centers when they viewed and rated the attractiveness of surgically optimally configured female bodies. PMID- 20714415 TI - Identification of tyrosine phosphatase ligands for contactin cell adhesion molecules. AB - The incessant tug of war between tyrosine kinases and tyrosine phosphatases regulates critical signaling events during embryogenesis and adulthood. Among these proteins, receptor protein tyrosine phosphatases (RPTPs) have emerged as an important class of neuronal receptors, seemingly capable of mediating cell adhesion and tyrosine dephosphorylation events. Indeed, these proteins combine extracellular domains that resemble those of cell adhesion molecules and tyrosine phosphatase domains that counter the activities of tyrosine kinases. However, the detailed mechanisms underlying RPTP-mediated cell adhesion and RPTP-mediated cell signaling continue to elude our understanding mainly because very few extracellular binding partners of RPTPs have been identified. We have recently characterized biochemically and structurally the interactions between members of the contactin family of neural recognition molecules and the homologous receptor protein tyrosine phosphatase zeta (PTPRZ) and gamma (PTPRG) that are expressed in the nervous system. Here, we present our main findings and we discuss their possible implication for the control of tyrosine dephosphorylation by contactin family members. PMID- 20714416 TI - Clocking perceptual processing speed: From chance to 75% correct in less than 30 milliseconds. AB - THE NEURAL BASIS OF CHOICE BEHAVIOR HAS BEEN INTENSELY STUDIED WITH LABORATORY TASKS IN WHICH A SUBJECT SEES A STIMULUS AND MAKES A CORRESPONDING MOTOR RESPONSE, BUT THE ISSUE OF TIMING HAS BEEN HARD TO TACKLE: How much time is necessary to make the perceptual judgment versus executing the motor report? When and how does a subject commit to a particular choice, and what neural mechanisms determine that? A major limitation has been that reaction times (RTs) are affected by sensory and motor factors (e.g., task difficulty, urgency, expectation) that can be covertly traded. Recently, we designed a task that overcomes these problems and allows us to construct a new curve that unambiguously reveals how a subject's perceptual judgment unfolds in time. Specifically, the slope of this "tachometric" curve depends on the perceptual difficulty of the task and the perceptual capacity of the subject, but not on motor execution. This technique shows that monkeys can make accurate color discriminations in less than 30 ms. More importantly, it provides a novel metric for correlating the time courses of pyschophysical and neuronal responses, opening up a new avenue for investigating choice behaviors in a wide variety of experimental conditions. PMID- 20714417 TI - Auditory-motor entrainment in vocal mimicking species: Additional ontogenetic and phylogenetic factors. AB - We have recently found robust evidence of motor entrainment to auditory stimuli in multiple species of non-human animal, all of which were capable of vocal mimicry. In contrast, the ability remained markedly absent in many closely related species incapable of vocal mimicry. This suggests that vocal mimicry may be a necessary precondition for entrainment. However, within the vocal mimicking species, entrainment appeared non-randomly, suggesting that other components besides vocal mimicry play a role in the capacity and tendency to entrain. Here we discuss potential additional factors involved in entrainment. New survey data show that both male and female parrots are able to entrain, and that the entrainment capacity appears throughout the lifespan. We suggest routes for future study of entrainment, including both developmental studies in species known to entrain and further work to detect entrainment in species not well represented in our dataset. These studies may shed light on additional factors necessary for entrainment in addition to vocal mimicry. PMID- 20714418 TI - Chitosan modification and pharmaceutical/biomedical applications. AB - Chitosan has received much attention as a functional biopolymer for diverse applications, especially in pharmaceutics and medicine. Our recent efforts focused on the chemical and biological modification of chitosan in order to increase its solubility in aqueous solutions and absorbability in the in vivo system, thus for a better use of chitosan. This review summarizes chitosan modification and its pharmaceutical/biomedical applications based on our achievements as well as the domestic and overseas developments: (1) enzymatic preparation of low molecular weight chitosans/chitooligosaccharides with their hypocholesterolemic and immuno-modulating effects; (2) the effects of chitin, chitosan and their derivatives on blood hemostasis; and (3) synthesis of a non toxic ion ligand--D-Glucosaminic acid from oxidation of D-Glucosamine for cancer and diabetes therapy. PMID- 20714421 TI - Carijoside A, a bioactive sterol glycoside from an octocoral Carijoa sp. (Clavulariidae). AB - A new bioactive sterol glycoside, 3beta-O-(3',4'-di-O-acetyl-beta-D arabinopyranosyl)-25xi-cholestane-3beta,5alpha,6beta,26-tetrol-26-acetate) (carijoside A, 1), was isolated from an octocoral identified as Carijoa sp. The structure of glycoside 1 was established by spectroscopic methods and by comparison with spectral data for the other known glycosides. Carijoside A (1) displayed significant inhibitory effects on superoxide anion generation and elastase release by human neutrophils and this compound exhibited moderate cytotoxicity toward DLD-1, P388D1, HL-60, and CCRF-CEM tumor cells. PMID- 20714419 TI - Chitin research revisited. AB - Two centuries after the discovery of chitin, it is widely accepted that this biopolymer is an important biomaterial in many aspects. Numerous studies on chitin have focused on its biomedical applications. In this review, various aspects of chitin research including sources, structure, biosynthesis, chitinolytic enzyme, chitin binding protein, genetic engineering approach to produce chitin, chitin and evolution, and a wide range of applications in bio- and nanotechnology will be dealt with. PMID- 20714422 TI - Palytoxin and analogs: biological and ecological effects. AB - Palytoxin (PTX) is a potent marine toxin that was originally found in soft corals from tropical areas of the Pacific Ocean. Soon after, its occurrence was observed in numerous other marine organisms from the same ecological region. More recently, several analogs of PTX were discovered, remarkably all from species of the dinoflagellate genus Ostreopsis. Since these dinoflagellates are also found in other tropical and even in temperate regions, the formerly unsuspected broad distribution of these toxins was revealed. Toxicological studies with these compounds shows repeatedly low LD50 values in different mammals, revealing an acute toxic effect on several organs, as demonstrated by different routes of exposure. Bioassays tested for some marine invertebrates and evidences from environmental populations exposed to the toxins also give indications of the high impact that these compounds may have on natural food webs. The recognition of its wide distribution coupled with the poisoning effects that these toxins can have on animals and especially on humans have concerned the scientific community. In this paper, we review the current knowledge on the effects of PTX and its analogs on different organisms, exposing the impact that these toxins may have in coastal ecosystems. PMID- 20714423 TI - Prebiotics from marine macroalgae for human and animal health applications. AB - The marine environment is an untapped source of bioactive compounds. Specifically, marine macroalgae (seaweeds) are rich in polysaccharides that could potentially be exploited as prebiotic functional ingredients for both human and animal health applications. Prebiotics are non-digestible, selectively fermented compounds that stimulate the growth and/or activity of beneficial gut microbiota which, in turn, confer health benefits on the host. This review will introduce the concept and potential applications of prebiotics, followed by an outline of the chemistry of seaweed polysaccharides. Their potential for use as prebiotics for both humans and animals will be highlighted by reviewing data from both in vitro and in vivo studies conducted to date. PMID- 20714424 TI - Cloning and comparative studies of seaweed trehalose-6-phosphate synthase genes. AB - The full-length cDNA sequence (3219 base pairs) of the trehalose-6-phosphate synthase gene of Porphyra yezoensis (PyTPS) was isolated by RACE-PCR and deposited in GenBank (NCBI) with the accession number AY729671. PyTPS encodes a protein of 908 amino acids before a stop codon, and has a calculated molecular mass of 101,591 Daltons. The PyTPS protein consists of a TPS domain in the N terminus and a putative TPP domain at the C-terminus. Homology alignment for PyTPS and the TPS proteins from bacteria, yeast and higher plants indicated that the most closely related sequences to PyTPS were those from higher plants (OsTPS and AtTPS5), whereas the most distant sequence to PyTPS was from bacteria (EcOtsAB). Based on the identified sequence of the PyTPS gene, PCR primers were designed and used to amplify the TPS genes from nine other seaweed species. Sequences of the nine obtained TPS genes were deposited in GenBank (NCBI). All 10 TPS genes encoded peptides of 908 amino acids and the sequences were highly conserved both in nucleotide composition (>94%) and in amino acid composition (>96%). Unlike the TPS genes from some other plants, there was no intron in any of the 10 isolated seaweed TPS genes. PMID- 20714425 TI - Structures, biological activities and phylogenetic relationships of terpenoids from marine ciliates of the genus Euplotes. AB - In the last two decades, large scale axenic cell cultures of the marine species comprising the family Euplotidae have resulted in the isolation of several new classes of terpenoids with unprecedented carbon skeletons including the (i) euplotins, highly strained acetylated sesquiterpene hemiacetals; (ii) raikovenals, built on the bicyclo[3.2.0]heptane ring system; (iii) rarisetenolides and focardins containing an octahydroazulene moiety; and (iv) vannusals, with a unique C30 backbone. Their complex structures have been elucidated through a combination of nuclear magnetic resonance spectroscopy, mass spectrometry, molecular mechanics and quantum chemical calculations. Despite the limited number of biosynthetic experiments having been performed, the large diversity of ciliate terpenoids has facilitated the proposal of biosynthetic pathways whereby they are produced from classical linear precursors. Herein, the similarities and differences emerging from the comparison of the classical chemotaxonomy approach based on secondary metabolites, with species phylogenesis based on genetic descriptors (SSU-rDNA), will be discussed. Results on the interesting ecological and biological properties of ciliate terpenoids are also reported. PMID- 20714426 TI - Neuroprotective properties of chitosan and its derivatives. AB - Neuronal cells are extremely vulnerable and have a limited capacity for self repair in response to injury. For those reasons, there is obvious interest in limiting neuronal damage. Mechanisms and strategies used in order to protect against neuronal injury, apoptosis, dysfunction, and degeneration in the central nervous system are recognized as neuroprotection. Neuroprotection could be achieved through several classes of natural and synthetic neuroprotective agents. However, considering the side effects of synthetic neuroprotective agents, the search for natural neuroprotective agents has received great attention. Recently, an increasing number of studies have identified neuroprotective properties of chitosan and its derivatives; however, there are some significant challenges that must be overcome for the success of this approach. Hence, the objective of this review is to discuss neuroprotective properties of chitosan and its derivatives. PMID- 20714427 TI - Preclinical pharmacology of BA-TPQ, a novel synthetic iminoquinone anticancer agent. AB - Marine natural products and their synthetic derivatives represent a major source of novel candidate anti-cancer compounds. We have recently tested the anti-cancer activity of more than forty novel compounds based on an iminoquinone makaluvamine scaffold, and have found that many of the compounds exert potent cytotoxic activity against human cancer cell lines. One of the most potent compounds, BA TPQ [(11,12),7-(benzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H) one], was active against a variety of human cancer cell lines, and inhibited the growth of breast and prostate xenograft tumors in mice. However, there was some toxicity noted in the mice following administration of the compound. In order to further the development of BA-TPQ, and in a search for potential sites of accumulation that might underlie the observed toxicity of the compound, we accomplished preclinical pharmacological studies of the compound. We herein report the in vitro and in vivo pharmacological properties of BA-TPQ, including its stability in plasma, plasma protein binding, metabolism by S9 enzymes, and plasma and tissue distribution. We believe these studies will be useful for further investigations, and may be useful for other investigators examining the use of similar compounds for cancer therapy. PMID- 20714428 TI - Cytotoxic cembranes from Indonesian specimens of the soft coral Nephthea sp. AB - Methanol extracts of two specimens of the soft coral Nephthea sp. collected from the Seribu Islands, Indonesia, were active in an anticancer bioassay. One new (1) and four known diterpenes (2-5) based on the cembrane carbon skeleton were isolated from these extracts, as was arachidonic acid (8). The structures of all compounds were elucidated using NMR, including 1,1-ADEQUATE and 1D gradient selective NOESY where applicable to determine the relative stereochemistry. Spectroscopic data, including 1H and 13C NMR, UV, IR and optical rotations are reported when enough material was available and where this has not been done previously. Inhibition assays employing three cancer cell lines; SF-268 (CNS), MCF-7 (breast), and H460 (lung) were used to guide the isolation of all compounds. PMID- 20714429 TI - The tetrodotoxin receptor of voltage-gated sodium channels--perspectives from interactions with micro-conotoxins. AB - Neurotoxin receptor site 1, in the outer vestibule of the conducting pore of voltage-gated sodium channels (VGSCs), was first functionally defined by its ability to bind the guanidinium-containing agents, tetrodotoxin (TTX) and saxitoxin (STX). Subsequent studies showed that peptide micro-conotoxins competed for binding at site 1. All of these natural inhibitors block single sodium channels in an all-or-none manner on binding. With the discovery of an increasing variety of micro-conotoxins, and the synthesis of numerous derivatives, observed interactions between the channel and these different ligands have become more complex. Certain micro-conotoxin derivatives block single-channel currents partially, rather than completely, thus enabling the demonstration of interactions between the bound toxin and the channel's voltage sensor. Most recently, the relatively small micro-conotoxin KIIIA (16 amino acids) and its variants have been shown to bind simultaneously with TTX and exhibit both synergistic and antagonistic interactions with TTX. These interactions raise new pharmacological possibilities and place new constraints on the possible structures of the bound complexes of VGSCs with these toxins. PMID- 20714430 TI - Bromopyrrole alkaloids as lead compounds against protozoan parasites. AB - In the present study, 13 bromopyrrole alkaloids, including the oroidin analogs hymenidin (2), dispacamide B (3) and dispacamide D (4), stevensine (5) and spongiacidin B (6), their derivatives lacking the imidazole ring bromoaldisin (7), longamide B (8) and longamide A (9), the dimeric oroidin derivatives sceptrin (10) and dibromopalau'amine (11), and the non-oroidin bromopyrrolohomoarginin (12), manzacidin A (13), and agelongine (14), obtained from marine sponges belonging to Axinella and Agelas genera have been screened in vitro against four parasitic protozoa, i.e., two Trypanosoma species (T. brucei rhodesiense and T. cruzi), Leishmania donovani and Plasmodium falciparum (K1 strain, a chloroquine resistant strain), responsible of human diseases with high morbidity and, in the case of malaria, high mortality. Our results indicate longamide B (8) and dibromopalau'amine (11) to be promising trypanocidal and antileishmanial agents, while dispacamide B (3) and spongiacidin B (6) emerge as antimalarial lead compounds. In addition, evaluation of the activity of the test alkaloids (2-14) against three different enzymes (PfFabI, PfFabG, PfFabZ) involved in the de novo fatty acid biosynthesis pathway of P. falciparum (PfFAS II) identified bromopyrrolohomoarginin (12) as a potent inhibitor of PfFabZ. The structural similarity within the series of tested molecules allowed us to draw some preliminary structure-activity relationships. Tests against the mammalian L6 cells revealed important clues on therapeutic index of the metabolites. This is the first detailed study on the antiprotozoal potential of marine bromopyrrole alkaloids. PMID- 20714431 TI - Multiple beneficial health effects of natural alkylglycerols from shark liver oil. AB - Alkylglycerols (alkyl-Gro) are ether lipids abundant in the liver of some elasmobranch fish species such as ratfishes and some sharks. Shark liver oil from Centrophorus squamosus (SLO), or alkyl-Gro mix from this source, have several in vivo biological activities including stimulation of hematopoiesis and immunological defences, sperm quality improvement, or anti-tumor and anti metastasis activities. Several mechanisms are suggested for these multiple activities, resulting from incorporation of alkyl-Gro into membrane phospholipids, and lipid signaling interactions. Natural alkyl-Gro mix from SLO contains several alkyl-Gro, varying by chain length and unsaturation. Six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0, 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro, were synthesized and tested for anti-tumor and anti-metastatic activities on a model of grafted tumor in mice (3LL cells). 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl- Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Multiple compounds and mechanisms are probably involved in the multiple activities of natural alkyl-Gro. PMID- 20714433 TI - Preparation and characterization of chitosan poly(acrylic acid) magnetic microspheres. AB - Spherical microparticles, capable of responding to magnetic fields, were prepared by encapsulating dextran-coated Fe3O4 nanoparticles into chitosan poly(acrylic acid) (PAA) microspheres template. The obtained magnetic microspheres were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and thermogravimetry (TG). The results showed that the microspheres were formed and demonstrated magnetic behavior in an applied magnetic field. In addition, magnetite particles were well encapsulated and the composite particles have high magnetite content, which was more than 40%. PMID- 20714434 TI - Post-traumatic glioma: report of one case and review of the literature. AB - We report one case of brain glioma that developed in the scar of an old brain trauma. A 45-year-old man who presented with seizures; MRI showed a large mass in the right temporal region. Surgical biopsy showed a glioblastoma multiforme. The patient had suffered a cranial trauma in a road accident 10 years previously with an intracerebral hematoma in the right temporal region. This case fulfills the established criteria for a traumatic origin of brain tumors and adds further support to the relationship between cranial trauma and the onset of glioma. As stated by other authors, an association between head trauma and brain tumor risk cannot be ruled out and should be studied further. PMID- 20714432 TI - Neurotoxic alkaloids: saxitoxin and its analogs. AB - Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs--each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids. PMID- 20714435 TI - Intrathecal siRNA against Toll-like receptor 4 reduces nociception in a rat model of neuropathic pain. AB - BACKGROUND: Neuropathic pain is characterized by hyperalgesia, allodynia and spontaneous pain. It often occurs as a result of injury to peripheral nerves, dorsal root ganglions (DRG), spinal cord, or brain. Recent studies have suggested that Toll-like receptor 4 (TLR4) might play a role in neuropathic pain. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the role of TLR4 in a rat chronic constriction injury (CCI) model and explored the feasibility of treating neuropathic pain by inhibiting TLR4. Our results demonstrated that intrathecal siRNA-mediated suppression of TLR4 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia through inhibiting the activation of NF-kappaB p65 and production of proinflammatory cytokines (e.g., TNF-alpha and IL-1 beta). CONCLUSIONS/SIGNIFICANCE: These findings suggest that suppression of TLR4 mediated by intrathecally administered siRNA may be a new strategy for the treatment of neuropathic pain. PMID- 20714436 TI - Changes of uterine blood flow after vaginal radical trachelectomy (VRT) in patients with early-stage uterine invasive cervical cancer. AB - BACKGROUND: Vaginal radical trachectomy (RT) ligates and cuts several arteries supplying the uterus. Changes of blood supply to the uterus in two patients who experienced pregnancy and delivery were studied by using 3-D CT scanning. Effects of changes of blood supply to the uterus on the pregnancy courses were also examined. METHODS: Vascular distribution in the uterus was studied in two patients who received vaginal RT after delivery. Effects of changes of vascular distribution after vaginal RT were studied with respect to pregnancy courses and cervical functions. RESULTS: New arterial vascularization from the ascending branches of uterine arteries or other arteries occurred, and these new vessels seemed to supply blood to the remaining cervix. Differences of fetal growth and histopathological changes in the placenta between the two patients could not be detected. CONCLUSION: Ligation and cutting of several supplying arteries by RT induces new arterial vascularization and it does not seem to affect fetal growth and placental function. PMID- 20714437 TI - Treatment of oroantral fistula with autologous bone graft and application of a non-reabsorbable membrane. AB - AIM: The aim of the current report is to illustrate an alternative technique for the treatment of oroantral fistula (OAF), using an autologous bone graft integrated by xenologous particulate bone graft. BACKGROUND: Acute and chronic oroantral communications (OAC, OAF) can occur as a result of inadequate treatment. In fact surgical procedures into the maxillary posterior area can lead to inadvertent communication with the maxillary sinus. Spontaneous healing can occur in defects smaller than 3 mm while larger communications should be treated without delay, in order to avoid sinusitis. The most used techniques for the treatment of OAF involve buccal flap, palatal rotation - advancement flap, Bichat fat pad. All these surgical procedures are connected with a significant risk of morbidity of the donor site, infections, avascular flap necrosis, impossibility to repeat the surgical technique after clinical failure, and patient discomfort. CASE PRESENTATION: We report a 65-years-old female patient who came to our attention for the presence of an OAF and was treated using an autologous bone graft integrated by xenologous particulate bone graft. An expanded polytetrafluoroethylene titanium-reinforced membrane (Gore-Tex) was used in order to obtain an optimal reconstruction of soft tissues and to assure the preservation of the bone graft from epithelial connection. CONCLUSIONS: This surgical procedure showed a good stability of the bone grafts, with a complete resolution of the OAF, optimal management of complications, including patient discomfort, and good regeneration of soft tissues. CLINICAL SIGNIFICANCE: The principal advantage of the use of autologous bone graft with an expanded polytetrafluoroethylene titanium-reinforced membrane (Gore-Tex) to guide the bone regeneration is that it assures a predictable healing and allows a possible following implant-prosthetic rehabilitation. PMID- 20714438 TI - Predictors of hepatic steatosis in HBeAg-negative chronic hepatitis B patients and their diagnostic values in hepatic fibrosis. AB - OBJECTIVE: To investigate predictors of hepatic steatosis in HBeAg-negative chronic hepatitis B (CHB) patients and their diagnostic values in hepatic inflammation and fibrosis. METHODS: A total of 106 HBeAg-negative CHB patients with clinically and pathologically proven steatosis and 98 patients without steatosis were recruited into this study. The levels of fasting blood glucose (FBG), fasting insulin (FINS), triglyceride (TG), cholesterol (CHOL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), globulin (Glb), HBV DNA, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR) and pathological changes of the liver in inflammation, fibrosis and fatty deposition were examined in all patients. RESULTS: The levels of BMI, HOMA-IR, FBG, insulin, TG, and CHOL were significantly higher in patients with steatosis than those without steatosis (all P<0.05). But ALT, AST and HBV DNA levels were significantly lower in patients with steatosis (all P<0.05). Logistic regression analysis showed that only FINS was a significant predictor for hepatic steatosis (P<0.05); FINS and Glb were significant predictors for hepatic inflammation (all P<0.05); BMI and TC were significant predictors for hepatic fibrosis (all P<0.05). CONCLUSIONS: Hepatic steatosis, a common disease in HBeAg-negative CHB patients, was positively associated with BMI, FBG, FINS, TG, TC, GGT, ALP and HOMA-IR. In these patients, the prevalence of hepatic inflammation and fibrosis was also increased. PMID- 20714439 TI - Subtle evolutionary changes in the distribution of N-glycosylation sequons in the HIV-1 envelope glycoprotein 120. AB - Many viruses are known to undergo rapid evolutionary changes under selective pressures. The HIV-1 envelope glycoprotein 120 (gp120) shows extreme selection for NXS/T sequons, the potential sites of N-glycosylation. Although the average number of sequons in gp120 appears to be relatively stable in the recent past, even slight changes in the distribution of sequons may potentially play crucial roles in protein interaction and viral infection. This study tracked the prevalence and distribution of NXS/T sequons in gp120 over a period of 29 years (from 1981 to 2009). The gp120 showed location specific distribution of sequons with higher density in the outer domain of the molecule. The NXT sequon density decreased in the outer domain (despite the increase in the sequon specific amino acid threonine), but increased in the inner domain. By contrast, the NXS sequon density increased specifically in the outer domain. Related changes were also seen in the distribution probabilities of sequons in two domains. The results indicate that the gp120, chiefly in subtype B, is redistributing NXS/T sequons within the molecule with specific selection for NXS sequons. The subtle evolution of sequons in gp120 may have implications in viral resistance and infection. PMID- 20714440 TI - Fluorouracil selectively enriches stem-like leukemic cells in a leukemic cell line. AB - Recent studies have reported that cancer stem cells (CSCs) could be isolated from solid cancer cell lines, in which the purity of CSCs was higher than that from tumor tissues. Separation of CSCs from leukemic cell lines was rarely reported. In this study, CD34(+)CD38(-)stem-like cell subsets in human KG-1a leukemic cell line were enriched by cytotoxic agent 5-fluorouracil (5-FU). After 4 days incubation of KG-1a cell line with 5-FU (50 microg/ml), the CD34(+)CD38(-) subpopulation of cell lines was enriched more than 10 times. The enriched cells had proliferate potential in vitro, low level of RNA transcription and Hoechst 33342 dye efflux ability, accompanied by high expression of ATP-binding cassette transporter protein ABCG2. Our findings suggest that treatment with 5-FU offers an easy method to isolate leukemic stem-like subpopulation. It can facilitate studies of leukemic stem cell biology and the development of new therapeutic strategies. PMID- 20714441 TI - Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression. AB - Our previous studies revealed that pregnancy associated breast cancer (PABC) had significantly reduced nuclear p63 expression in myoepithelia, while intense cytoplasmic p63 expression in associated epithelia. Our current study assessed these epithelia using immunohistochemistry with a panel of aggressiveness and invasiveness related markers and comparative genomic hybridization (array-CGH) with over 30,000 DNA probes. These epithelia showed several unique alterations, including (1) immunohistochemical and morphological resemblance to invasive cancer, (2) significant gain in copy numbers of DNA coding genes for morphogenesis, angiogenesis, and metastasis, and (3) significant loss in copy numbers of DNA coding genes for tumor suppressors, cell adhesion, and macromolecular complex assembly or intra-cellular trafficking. Detected array-CGH alterations correlated well with in vivo expression of a number of corresponding proteins tested. These findings suggest that aberrant sub-cellular localization of p63 expression in normal or hyperplastic appearing epithelial cells may significant contribute to increased invasiveness and aggressiveness of these cells. PMID- 20714442 TI - Substrate specificity and structural characteristics of the novel Rieske nonheme iron aromatic ring-hydroxylating oxygenases NidAB and NidA3B3 from Mycobacterium vanbaalenii PYR-1. AB - The Rieske nonheme iron aromatic ring-hydroxylating oxygenases (RHOs) NidAB and NidA3B3 from Mycobacterium vanbaalenii PYR-1 have been implicated in the initial oxidation of high-molecular-weight (HMW) polycyclic aromatic hydrocarbons (PAHs), forming cis-dihydrodiols. To clarify how these two RHOs are functionally different with respect to the degradation of HMW PAHs, we investigated their substrate specificities to 13 representative aromatic substrates (toluene, m xylene, phthalate, biphenyl, naphthalene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, benzo[a]pyrene, carbazole, and dibenzothiophene) by enzyme reconstitution studies of Escherichia coli. Both Nid systems were identified to be compatible with type V electron transport chain (ETC) components, consisting of a [3Fe-4S]-type ferredoxin and a glutathione reductase (GR)-type reductase. Metabolite profiles indicated that the Nid systems oxidize a wide range of aromatic hydrocarbon compounds, producing various isomeric dihydrodiol and phenolic compounds. NidAB and NidA3B3 showed the highest conversion rates for pyrene and fluoranthene, respectively, with high product regiospecificity, whereas other aromatic substrates were converted at relatively low regiospecificity. Structural characteristics of the active sites of the Nid systems were investigated and compared to those of other RHOs. The NidAB and NidA3B3 systems showed the largest substrate-binding pockets in the active sites, which satisfies spatial requirements for accepting HMW PAHs. Spatially conserved aromatic amino acids, Phe-Phe-Phe, in the substrate-binding pockets of the Nid systems appeared to play an important role in keeping aromatic substrates within the reactive distance from the iron atom, which allows each oxygen to attack the neighboring carbons. PMID- 20714443 TI - Reply to "Concerns about Recently Identified Widespread Antisense Transcription in Escherichia coli". PMID- 20714444 TI - Concerns about recently identified widespread antisense transcription in Escherichia coli. PMID- 20714445 TI - Microbial electrosynthesis: feeding microbes electricity to convert carbon dioxide and water to multicarbon extracellular organic compounds. AB - The possibility of providing the acetogenic microorganism Sporomusa ovata with electrons delivered directly to the cells with a graphite electrode for the reduction of carbon dioxide to organic compounds was investigated. Biofilms of S. ovata growing on graphite cathode surfaces consumed electrons with the reduction of carbon dioxide to acetate and small amounts of 2-oxobutyrate. Electrons appearing in these products accounted for over 85% of the electrons consumed. These results demonstrate that microbial production of multicarbon organic compounds from carbon dioxide and water with electricity as the energy source is feasible. PMID- 20714447 TI - Glycemic variability: too often overlooked in type 2 diabetes? AB - Look beyond the HbA1c average, and consider introducing insulin earlier in the disease process. PMID- 20714446 TI - Escherichia coli SRP, its protein subunit Ffh, and the Ffh M domain are able to selectively limit membrane protein expression when overexpressed. AB - The Escherichia coli signal recognition particle (SRP) system plays an important role in membrane protein biogenesis. Previous studies have suggested indirectly that in addition to its role during the targeting of ribosomes translating membrane proteins to translocons, the SRP might also have a quality control role in preventing premature synthesis of membrane proteins in the cytoplasm. This proposal was studied here using cells simultaneously overexpressing various membrane proteins and either SRP, the SRP protein Ffh, its 4.5S RNA, or the Ffh M domain. The results show that SRP, Ffh, and the M domain are all able to selectively inhibit the expression of membrane proteins. We observed no apparent changes in the steady-state mRNA levels or membrane protein stability, suggesting that inhibition may occur at the level of translation, possibly through the interaction between Ffh and ribosome-hydrophobic nascent chain complexes. Since E. coli SRP does not have a eukaryote-like translation arrest domain, we discuss other possible mechanisms by which this SRP might regulate membrane protein translation when overexpressed. PMID- 20714448 TI - Recurrent pleural effusions and a normal cardiac CT. AB - Our patient had the classic square root sign typical of constrictive pericarditis, but contrary to what we would have expected, his end-diastolic pressures did not equalize. PMID- 20714449 TI - Optimizing the clinical identification and management of patients at risk for anaphylaxis. AB - Anaphylaxis is a serious, systemic allergic reaction that is rapid in onset and can cause death. Anaphylaxis often occurs in the absence of a health care professional, so it is essential for patients at risk for anaphylaxis to be identified and prepared in the event of an emergency. Identifying at-risk patients goes beyond a history of anaphylaxis; it is important to identify patients who may be at risk for a more severe anaphylactic reaction. Patients at risk for anaphylaxis should be provided an epinephrine auto-injector and appropriately trained in its use in the community setting. PMID- 20714450 TI - Bittersweet transitions. PMID- 20714451 TI - Update on concussion: here's what the experts say. AB - Don't allow an athlete who has symptoms at rest or with exertion to return to play. Consider neuropsychological testing in conjunction with continued clinical assessment for objective measurements to assist in managing concussion. Recommend up-to-date protective equipment for athletes. Recent improvements, especially in football, have been shown to help decrease the incidence of concussion. PMID- 20714452 TI - PURLS: A-fib and rate control: don't go too low. AB - For patients with atrial fibrillation, more relaxed heart rate control is as effective as stricter control but, with fewer adverse effects. PMID- 20714453 TI - Give your sports physicals a performance boost. AB - Cover the 12 components of the preparticipation physical evaluation (PPE) recommended by the American Heart Association to screen young athletes for potentially life-threatening cardiovascular disease. Perform a genitourinary exam as part of the PPE for young men; assess young women for the criteria associated with the female athlete triad. Perform auscultation while the patient is squatting and while doing the Valsalva maneuver to determine whether any murmurs you detected on examination are associated with hypertrophic cardiomyopathy. PMID- 20714454 TI - Nonspecific low back pain: evaluation and treatment tips. AB - Avoid imaging in cases of uncomplicated low back pain (unless there are specific clinical indications). Use acetaminophen, nonsteroidal anti-inflammatory drugs, or muscle relaxants for short-term relief of acute nonspecific low back pain. Consider matching specific physical therapy options to the patient's history and exam findings. PMID- 20714455 TI - How best to manage dysfunctional uterine bleeding. AB - Irregular or unusually heavy periods are a common complaint. Most often, the condition is benign and can by managed conservatively. Assess postmenopausal women for cancer by endometrial biopsy, transvaginal ultrasound, or saline infusion sonohysterogram. Treat mild dysfunctional uterine bleeding (DUB) with nonsteroidal anti-inflammatory drugs, levonorgestrel intrauterine device (IUD), or danazol. Treat moderate DUB with oral contraceptive pills, levonorgestrel IUD, danazol, or tranexamic acid. PMID- 20714456 TI - Painful rash on face. AB - First came a sore throat. Then came a warm, erythematous rash on the patient's face. A 68-year-old woman came into the clinic for treatment of a painful, erythematous skin rash over the bridge of her nose. She'd had the rash for 4 days, and it was spreading to the malar area and up around her eyelids and forehead. PMID- 20714457 TI - Clinical inquiries: what is the most effective way to relieve symptoms of acute stress disorder? AB - Cognitive Behavioral Therapy (CBT) that emphasizes exposure-based treatment is the most effective intervention for adults with acute stress disorder (ASD). Exposure-based therapy reduces symptoms in adults with ASD more than CBT that focuses on cognitive restructuring; both therapies are better than no treatment at all. Avoid drug treatment within 4 weeks of appearance of symptoms, unless distress is too severe to be managed with psychological treatment alone. PMID- 20714458 TI - Clinical inquiries: what's the best way to manage upper extremity venous thrombosis? AB - Standard management is best: start with unfractionated heparin or low-molecular weight heparin and follow with long-term therapy with a vitamin K antagonist. Some evidence supports thrombolytic therapy, placement of a superior vena cava filter, or surgical thrombectomy in selected patients. Whether to remove venous catheters during initial treatment for catheter-induced venous thrombosis remains unclear, because limited studies address this issue specifically. PMID- 20714459 TI - Clinical inquiries: which women should we screen for gestational diabetes mellitus? AB - It's unclear which women we should screen. No randomized controlled trials (RCTs) demonstrate that either universal screening or risk factor screening for gestational diabetes mellitus (GDM) prevents maternal and fetal adverse outcomes. That said, the common practice of universal screening is more sensitive than screening based on risk factors. Historic risk factors are poor predictors of GDM in a current pregnancy. PMID- 20714463 TI - Synthesis and biological activity of naturally occurring alpha-glucosidase inhibitors. PMID- 20714464 TI - TiO(2) doping by hydroxyurea at the nucleation stage: towards a new photocatalyst in the visible spectral range. AB - We report an original method of preparation of OCN-doped TiO(2) for photocatalysis in the visible spectral range. The preparation is achieved by a sol-gel route using titanium tetraisopropoxide precursor. Special attention was paid to fluid micromixing, which enables homogeneous reaction conditions in the reactor bulk and monodispersity of the produced clusters/nanoparticles. The dopant hydroxyurea (HyU, CH(4)N(2)O(2)) is injected into the reactive fluid at the nucleation stage, which lasts tens of milliseconds. The doping results in a strong yellow coloration of the nanocolloids due to the absorption band in the spectral range 380-550 nm and accelerates the aggregation kinetics of both nuclei at the induction stage and sub-nuclei units (clusters) at the nucleation stage. FTIR, Raman and UV-visible absorption analyses show the formation of a stable HyU TiO(2) complex. EXAFS spectra indicate no appreciable changes of the first-shell Ti atom environment. The doping agent takes available surface sites of TiO(2) clusters/nanoparticles attaining ~10% molar loading. The reaction kinetics then accelerates due to a longer collisional lifetime between nanoparticles induced by the formation of a weak [double bond, length as m-dash]OTi bond. The OCN-group bonding to titanium atoms produces a weakening of the C[double bond, length as m dash]O double bond and a strengthening of the C-N and N-O bonds. PMID- 20714465 TI - Inositol polyphosphates, diphosphoinositol polyphosphates and phosphatidylinositol polyphosphate lipids: structure, synthesis, and development of probes for studying biological activity. PMID- 20714466 TI - Defensive strategies of Cladobranchia (Gastropoda, Opisthobranchia). PMID- 20714467 TI - Magnetic silicon fullerene. AB - A metal-encapsulating silicon fullerene, Eu@Si(20), has been predicted by density functional theory to be by far the most stable fullerene-like silicon structure. The Eu@Si(20) structure is a dodecahedron with D(2h) symmetry in which the europium atom occupies the center site. The calculated results show that the europium atom has a large magnetic moment of nearly 7.0 Bohr magnetons. In addition, it was found that a stable "pearl necklace" nanowire, constructed by concatenating a series of Eu@Si(20) units, with the central europium atom, retains the high spin moment. The magnetic structure of the nanowire indicates potential applications in the fields of spintronics and high-density magnetic storage. PMID- 20714468 TI - Molecularly tuned peptide assemblies at the liquid-solid interface studied by scanning tunneling microscopy. AB - We report here the modulation of a peptide assembly with a molecular template at the liquid-solid interface using scanning tunneling microscopy (STM). A lamella structure is observed for the assembly of pentapeptide 5Ala, and the introduction of the terpyridine derivative (BT-O-C16) gives rise to co-assembled molecular architectures with pentapeptide monomers and dimers encapsulated in the nanoscale cavities of the BT-O-C16 network. The selectivity of the molecular networks could allow for programmable construction of organic-peptide architectures. PMID- 20714469 TI - Kinetic studies of the heterogeneous oxidation of maleic and fumaric acid aerosols by ozone under conditions of high relative humidity. AB - In this paper, a kinetic study of the oxidation of maleic and fumaric acid organic particles by gas-phase ozone at relative humidities ranging from 90 to 93% is reported. A flow of single component aqueous particles with average size diameters in the range 2.6-2.9 um were exposed to a known concentration of ozone for a controlled period of time in an aerosol flow tube in which products were monitored by infrared spectroscopy. The results obtained are consistent with a Langmuir-Hinshelwood type mechanism for the heterogeneous oxidation of maleic/fumaric acid aerosol particles by gas-phase ozone, for which the following parameters were found: for the reaction of maleic acid aerosols, K(O(3)) = (9 +/- 4) * 10(-15) cm(3) molecule(-1) and k = (0.21 +/- 0.01) s(-1); for the reaction of fumaric acid aerosols, K(O(3)) = (5 +/- 2) * 10(-15) cm(3) molecule(-1) and k = (0.19 +/- 0.01) s(-1). From the pseudo-first-order coefficients, apparent uptake coefficient values were calculated for which a decreasing trend with increasing ozone concentrations was observed. Comparison with previous measurements of the same system under dry conditions reveals a direct effect of the presence of water on the mechanism of these reactions, in which the water is seen to increase the formation of CO(2) and formic acid (HCO(2)H) through increased levels of hydroxyacetyl hydroperoxide intermediate. PMID- 20714471 TI - Steroid-based anion receptors and transporters. AB - Anion binding and transport are important goals of supramolecular chemistry, especially in light of the potential for biological activity. Success depends on scaffolds which can preorganise polar functionality for anion recognition, and can maintain the right physical properties (e.g. solubility) to operate in the desired medium (e.g. a cell membrane). In this tutorial review we show how steroids, and in particular the bile acids, can provide good solutions to the problem. Not only do they provide rigid frameworks for mounting H-bond donor functionality, but their lipophilic nature ensures that they remain compatible with non-polar environments. Podands derived from cholic acid (cholapods) have proved especially useful, being tuneable, readily accessible and exceptionally powerful. For example, affinities up to 10(11) M(-1) have been measured for neutral cholapods binding chloride salts in chloroform. Steroid-based anion receptors can also display interesting selectivities, demonstrating the principle that discrimination improves with binding strength, and showing good enantioselectivities with chiral anions. The binding strength of cholapods and related systems allows them to act as transmembrane anion carriers. Again activity is exceptionally high, with measurable chloride transport at cholapod:lipid ratios of just 1:250,000 in vesicle membranes. These steroidal systems may present a real opportunity for the development of useful biological activity based on anion transport. PMID- 20714470 TI - The uses of supramolecular chemistry in synthetic methodology development: examples of anion and neutral molecular recognition. AB - The principles of supramolecular chemistry have successfully permeated through a broad range of organic chemistry subdisciplines. One subdiscipline that is not routinely associated with supramolecular chemistry is that of organic synthetic methodology. Though sometimes indiscernible, non-bonded and bonding supramolecular interactions play a large role in chemical reactions and catalysis. Many synthetic methods hinge on the creation of anionic charge, albeit just partial, at some step during this process, and hence are prime targets for molecular recognition interactions. Examples are artificial enzymes, biomimetic catalysis, organocatalysis, and many of the catalysts that are derived from a combinatorial screen. Further, supramolecular chemistry is playing an increasingly large role in high-throughput analytical techniques. This tutorial review ties together supramolecular approaches to methodology creation, combinatorial screening, and analytical protocols. The goal is to show, and further predict, that supramolecular chemistry will continually increase its impact in organic synthetic methodology development. PMID- 20714472 TI - Understanding the concept of randomness in inelastic electron tunneling excitations. AB - Inelastic electron tunneling excitation has been realized in the last decade as an effective way to probe reliably detailed atomic structures and control precisely behaviors of surface adsorbates at a single molecule level. A good understanding of rich and complex processes on the surface under inelastic electron excitations is of great importance, not only from a fundamental scientific point of view but also for potential practical applications. In this perspective paper, we give an overview of recent developments on excitations and characterizations of inelastic electron tunneling processes in surface adsorbates and molecular junctions. Special attention has been paid to the understanding of the randomness of the processes. A recently proposed general statistical model is introduced which has resolved a long-standing puzzle concerning the experimentally observed non-integer power law relationship between the rate of molecular conformation changes and the tunneling current. The success of the new model is highlighted by its applications for molecular switches. PMID- 20714473 TI - (2)H and (19)F solid-state NMR studies of the ionic liquid [C(2)Py][BTA]-d(10) confined in mesoporous silica materials. AB - Ionic liquids confined in porous materials are important solvents which allow a simple heterogenization of homogenous liquids. The perdeuterated ionic liquid N ethylpyridinium-bis(trifluoromethanesulfonyl)amide ([C(2)Py][BTA]-d(10)) was prepared and its bulk phase behavior was studied by differential scanning calorimetry (DSC) and temperature-resolved (2)H and (19)F solid-state NMR spectroscopy. Its bulk properties were compared to [C(2)Py][BTA]-d(10) confined in a mesoporous silica support material as model material usable in SILP catalysts. The line shape analysis of the temperature-dependent NMR spectra of the bulk material reveals two phase transitions, one at 287-289 K (solid II/solid I) and one extending over a temperature range of 298-306 K (solid I/liquid). While the first phase transition is caused by the onset of an intramolecular rotation of the ethyl group of the cation, the second is due to the melting of the ionic liquid. In the bulk material, a hysteresis between the transition temperatures in heating and cooling scans occurs. In confinement, the dynamics of the ionic liquid changes considerably: no hysteresis is observed for [C(2)Py][BTA]-d(10) confined in the mesopores. Instead, only a broad transition from solid II to the liquid state, which spans the temperature range of 215-245 K, is observed. This transition is identified as the result of a broad distribution of molecular environments of the confined ionic liquid, which thus forms an amorphous phase inside the pores. Hence, the behavior of the ionic liquid in confinement is similar to the behavior of non-ionic guest molecules in the mesoporous silica. Finally, it was found that the anion and cation of the ionic liquid exhibit the same dynamic behavior in confinement. PMID- 20714474 TI - Complex aggregation of TPPS and PEG-b-P4VP in confined space. AB - To explore the structure and property features of complex aggregates assembled by polymer and organic dye molecules in microcosmic soft confined space, a three dimensional microconfinement is constructed by W/O inverse emulsion as the site for the complex aggregation of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and poly(ethylene glycol)-block-poly(4-vinylpyridine) (PEG-b-P4VP). It is found that porphyrin molecules exist in emulsion droplets mainly as the deprotonated monomer form, even though the pH of the water phase is much lower than the pK(a) of TPPS in bulk (pK(a)~ 4.7). In spatially confined circumstances, upon blending of the single-component emulsions, complex aggregates are formed due to the thermodynamic collision of emulsion droplets and the subsequent electrostatic interaction between TPPS and polymer. The resultant novel complexes possess a relatively precise structure and homogenous core consisting of a porphyrin and P4VP block. Upon emulsion-breaking, the metastable complex kinetic intermediates generated in original acidic emulsion droplets display a remarkable trend of reaggregation within a certain period of time followed by a disassociation and redispersion. Complex aggregates with some novel morphologies are observed. The final product has a core-shell structure with the electrostatic complex of deprotonized porphyrin molecules homogenously dispersing in the P4VP clew as the core and the soluble PEG as the shell. However, those complexes produced in basic emulsion droplets exhibit a relatively higher stability against further aggregation after breakage of emulsion. PMID- 20714475 TI - Coordination-driven self-assembly of discrete and polymeric copper(ii) and dicopper(ii) supramolecular structures based on oxacalix[2]benzene[2]pyrazines. AB - The reaction of oxacalix[2]benzene[2]pyrazines and with copper(ii) nitrate, as well as dimeric copper(ii) tetraacetate are presented. Ligands and , both adopt 1,3-alternate conformation, with the two exo-Lewis basic sites spatially oriented outwards. Ligand reacts with copper(ii) ions generated a discrete molecular cage by bridging two ligands via two Cu(2+) ions in the equatorial region. While the reaction of with dicopper(ii) tetraacetate unit resulted in the formation of a discrete supramolecular complex with 1 : 2 stoichiometry between the dicopper(ii) unit and ligand , due to the larger size and axial coordination mode of the dicopper(ii) unit. The conformationally flexible nature of ligand facilitated the formation of coordination polymers and upon interaction with copper(ii) and dicopper(ii) units, respectively. Coordination polymer featured a zigzag structure of alternating ligand and Cu(2+) ion, while in coordination polymer , ligand serves as an axial 2-connected node, propagating the "paddlewheel" dicopper(ii) unit along the polymeric chain. PMID- 20714476 TI - Extension of the AMBER force-field for the study of large nitroxides in condensed phases: an ab initio parameterization. AB - The popular AMBER force-field has been extended to provide an accurate description of large and flexible nitroxide free-radicals in condensed phases. New atom types have been included, and relevant parameters have been fitted based on geometries, vibrational frequencies and potential energy surfaces computed at the DFT level for several different classes of nitroxides, both in vacuo and in different solvents. The resulting computational tool is capable of providing reliable structures, vibrational frequencies, relative energies and spectroscopic observables for large and flexible nitroxide systems, including those typically used as spin labels. The modified force field has been employed in the context of an integrated approach, based on classical molecular dynamics and discrete continuum solvent models, for the investigation of environmental and short-time dynamic effects on the hyperfine and gyromagnetic tensors of PROXYL, TEMPO and INDCO spin probes. The computed magnetic parameters are in very good agreement with the available experimental values, and the procedure allows for an unbiased evaluation of the role of different effects in tuning the overall EPR observables. PMID- 20714477 TI - Unprecedented H-atom transfer from water to ketyl radicals mediated by Cp(2)TiCl. AB - The H-atom transfer (HAT) from water to ketyl radicals, mediated by titanocene(iii) aqua-complexes, can explain the Ti(III)-promoted reduction of ketones in aqueous medium better than the conventional House mechanism. Moreover, we also report novel evidences supporting the existence of these titanocene(iii) aqua-complexes. PMID- 20714478 TI - Time-dependent density functional theory calculations of the spectroscopy of core electrons. AB - Recent advances in X-ray sources have led to a renaissance in spectroscopic techniques in the X-ray region. These techniques that involve the excitation of core electrons can provide an atom specific probe of electronic structure and provide powerful analytical tools that are used in many fields of research. Theoretical calculations can often play an important role in the analysis and interpretation of experimental spectra. In this perspective, we review recent developments in quantum chemical calculations of X-ray absorption spectra, focusing on the use of time-dependent density functional theory to study core excitations. The practical application of these calculations is illustrated with examples drawn from surface science and bioinorganic chemistry, and the application of these methods to study X-ray emission spectroscopy is explored. PMID- 20714479 TI - Fluorescence patterning in films of a photoswitchable BODIPY-spiropyran dyad. AB - A BODIPY-spiropyran dyad was embedded within poly(methyl methacrylate) films spin coated on glass slides. Visible illumination of the resulting materials excites selectively the BODIPY fragment, which then deactivates radiatively by emitting light in the form of fluorescence. Ultraviolet irradiation promotes the isomerization of the spiropyran component to the corresponding merocyanine. This photoinduced transformation activates electron and energy transfer pathways from the fluorescent to the photochromic fragment. Consistently, the BODIPY fluorescence is effectively suppressed within the photogenerated isomer. As a result, ultraviolet illumination with a laser, producing a doughnut-shaped spot on the sample, confines the fluorescent species within the doughnut hole. This behavior is an essential requisite for the implementation of super-resolution imaging schemes based on fluorescence photodeactivation. Thus, the operating principles governing the photochemical and photophysical response of this molecular switch can ultimately lead to the development of innovative probes for fluorescence nanoscopy. PMID- 20714480 TI - Facile fabrication of narrowly-distributed polymeric micelles via host-guest inclusion complexation of hyperbranched polymers and cyclodextrin and its two dimensional self-assembly. AB - A novel narrowly-distributed (ND) polymeric micelle obtained in combination with host-guest recognition and self-assembly is reported. First, the adamantyl terminated hyperbranched poly[3-ethyl-3-(hydroxymethyl)oxetane] (HBPO-AD) was synthesized by esterification of hyperbranched poly[3-ethyl-3 (hydroxymethyl)oxetane] (HBPO) with 1-adamantanecarbonyl chloride. Then the ND polymeric core-shell micelles, with the hydrophobic HBPO-AD cores and hydrophilic beta-cyclodextrin (beta-CD) shells, were prepared via host-guest inclusion complexation of HBPO-AD and beta-CD. The resultant polymer micelles were well characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Interestingly, after annealing at a temperature above the glass transition temperature (T(g)) for a certain time, the polymeric micelles can further self-assemble and fuse into two-dimensional (2D) sheets. The TEM, SEM and atomic force microscopy (AFM) characterization validate that the sheets are formed through stacking and fusion of tightly packed nanoparticles. In addition, the formation mechanism of polymeric complex micelles and 2D sheets has also been discussed. PMID- 20714481 TI - Conversion of C[triple bond]C to CO in alkynyl-metal complexes: oxidation of carbon chains capped by carbon-tricobalt clusters. AB - Treatment of Co(3)(mu(3)-CC[triple bond]CR)(mu-dppm)(CO)(7) with O(2) (air) in the presence of [FcH]PF(6) afforded Co(3){mu(3)-CC(O)R}(mu-dppm)(CO)(7) by the formal conversion -C[triple bond]C- + O-O --> >C-O + C[triple bond]O. In this way, complexes with R = Ph, Fc, and W(CO)(3)Cp, bis-clusters {Co(3)(mu dppm)(CO)(7)}(2){mu(3):mu(3)-[[triple bond]C(O)(C[triple bond]C)C[triple bond]]}, {Co(3)(mu-dppm)(CO)(7)}(2){mu(3):mu(3)-[[triple bond]C(O)(C[triple bond]C)(x)C(O)C[triple bond, length as m-dash]]} (x = 1, 2), and {Co(3)(mu dppm)(CO)(7)}(2){mu(3):mu(3)-[[triple bond]CC(O)C[triple bond, length as m dash]CC(6)H(4)C[triple bond]CC(O)C[triple bond]]}, and heterometallic bis clusters {Co(3)(mu-dppm)(CO)(7)}{mu(3):mu(3)-[[triple bond]CC(O)C[triple bond]CC[triple bond]]}{M(3)(mu-H)(3)(CO)(9)} (M = Ru, Os) have been prepared. Single-crystal XRD structure determinations of several products are reported together with that of precursor {Co(3)(mu-dppm)(CO)(7)}(2){mu(3):mu(3)-[[triple bond]C(C[triple bond]C)(2)C(6)H(4)(C[triple bond]C)(2)C[triple bond]]}. PMID- 20714482 TI - Oscillatory dynamics of the Belousov-Zhabotinsky system in the presence of a self assembling nonionic polymer. Role of the reactants concentration. AB - In the present study, the role played by the reactants concentration on the nonlinear response of a Belousov-Zhabotinsky (BZ) system to the addition of a self-assembling non-ionic polymer, poly(ethylene glycol) (PEG), has been assessed. The oscillatory parameters are influenced to an extent that significantly depends on the concentration of both the polymer and the Belousov Zhabotinsky components. The effects obtained were attributed to the reaction among some of the BZ key species and the backbone and the alcoholic functional groups of the polymer, both in its monomeric and aggregated forms.Support to the proposed perturbation mechanism has been provided by performing numerical simulations with the MBM model and by characterizing the physicochemical behavior of the PEG aqueous solution by means of viscosimetric and spectrofluorimetric measurements. PMID- 20714483 TI - Ligand design for site-selective installation of Pd and Pt centers to generate homo- and heteropolymetallic motifs. AB - The modular synthesis of a series of nitrogen-rich polydentate ligands that feature a common pincer-type framework is reported. These ligands allow for site selective installation of palladium and platinum to give rise to bi- and trimetallic complexes that have d(8)-d(8) interactions. PMID- 20714484 TI - One-dimensional supramolecular surface structures: 1,4-diisocyanobenzene on Au(111) surfaces. AB - One-dimensional supramolecular structures formed by adsorbing low coverages of 1,4-diisocyanobenzene on Au(111) at room temperature are obtained and imaged by scanning tunneling microscopy (STM) under ultrahigh vacuum (UHV) conditions. The structures originate from step edges or surface defects and arrange predominantly in a straight fashion on the substrate terraces along the <110> directions. They are proposed to consist of alternating units of 1,4-diisocyanobenzene molecules and gold atoms with a unit cell in registry with the substrate corresponding to four times the lattice interatomic distance. Their long 1-D chains and high thermal stability offer the potential to use them as conductors in nanoelectronic applications. PMID- 20714485 TI - Correlating Pt-P bond lengths and Pt-P coupling constants. AB - The X-ray structures of () cis-PtBr(2)(P(OMe)(3))(2), () cis PtBr(2)(P(OMe)(2)Ph)(2), () cis-PtBr(2)(P(OMe)Ph(2))(2), () cis PtBr(2)(PPh(3))(2), () cis-PtI(2)(P(OMe)(3))(2), () cis-PtI(2)(P(OMe)(2)Ph)(2), () cis-PtI(2)(P(OMe)Ph(2))(2) and () cis-PtI(2)(PPh(3))(2) are reported and compared with the previously reported chloride analogues. The magnitude of the J{Pt-P} varies linearly with the Pt-P bond length (l(Pt-P) = 2.421 -J/24255) for these 12 complexes. PMID- 20714486 TI - A numerical investigation into possible mechanisms by that the A629P mutant of ATP7A causes Menkes Disease. AB - We study in silico possible mechanisms by that the A629P mutant of ATP7A causes Menkes Disease. Our results indicate that the mutation does not have appreciable affects on the stability of copper-bound states but rather destabilizes the characteristic end-to-end beta-sheet. In this way, the mutation presumably increases the probability for aggregation and/or degradation leading to decreased concentration of the monomer. PMID- 20714487 TI - (15)N-Labeled ionic probes for bioanalytical mass spectrometry. AB - An effective La-complex-based probe ionization method is reported. Novel stable isotopically labeled probes containing the (15)N-labeled 2,6-bis(oxazolin-2 yl)pyridine (pybox) ligand, succinimide-tetramethylpybox (NHS-TMpybox), maleimide tetramethylpybox (Mal-TMpybox), and 4-(tetramethylpybox)-butyl bromoacetate (BrAc TMpybox), have been synthesized and their value in analyzing large complex molecules has been studied. The value of the (15)N-labeled pybox-La complex in ionizing various compounds, including bioactive peptides by cold-spray ionization mass spectrometry is emphasized. PMID- 20714488 TI - Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase. AB - A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations of transition state structures within a fully flexible molecular model, free downhill molecular dynamics trajectories have been performed at four different temperatures. The analysis of the reactive and non-reactive trajectories in the enzyme environment has allowed us to study the geometric and electronic coupling between the substrate, the cofactor and the protein. The results show how the contribution of dynamic effects to the rate enhancement measured by the transmission coefficients is, at the four studied temperatures, negligible. Nevertheless, the rare event trajectories performed have shown how the hydride transfer and the scission of the conserved active site cysteine residue (Cys146 in E. coli) take place in a concerted but asynchronous way; the latter takes place once the transfer has occurred. The analysis of the dynamics of the protein reveals also how the relative movements of some amino acids, especially Arg166, and a water molecule, promotes the departure of the Cys146 from the dUMP. Finally, it seems that the protein environment creates an almost invariant electric field in the active site of the protein that stabilizes the transition state of the reaction, thus reducing the free energy barrier. PMID- 20714489 TI - Dissociative recombination of the acetaldehyde cation, CH(3)CHO(+). AB - The dissociative recombination of the acetaldehyde cation, CH(3)CHO(+), has been investigated at the heavy ion storage ring CRYRING at the Manne Siegbahn Laboratory in Stockholm, Sweden. The dependence of the absolute cross section of the reaction on the relative kinetic energy has been determined and a thermal rate coefficient of k(T) = (1.5 +/- 0.2) * 10(-6) (T/300)(-0.70+/-0.02) cm(3) s( 1) has been deduced, which is valid for electron temperatures between ~10 and 1000 K. The branching fractions of the reaction were studied at ~0 eV relative kinetic energy and we found that breaking one of the bonds between two of the heavy atoms occurs in 72 +/- 2% of the reactions. In the remaining events the three heavy atoms stay in the same product fragment. While the branching fractions are fairly similar to the results from an earlier investigation into the dissociative recombination of the fully deuterated acetaldehyde cation, CD(3)CDO(+), the thermal rate coefficient is somewhat larger for CH(3)CHO(+). Astrochemical implications of the results are discussed. PMID- 20714490 TI - Infrared photodissociation spectroscopy of Co(+)(NH(3))(n) and Ni(+)(NH(3))(n): preference for tetrahedral or square-planar coordination. AB - Coordination structures of the Co(+)(NH(3))(n) and Ni(+)(NH(3))(n) ions are probed by infrared (IR) photodissociation spectroscopy with the aid of density functional theory (DFT) calculations. The IR spectra of N(2)-tagged Co(+)(NH(3))(n) (n = 1-4) exhibit two distinct bands assignable to the symmetric and antisymmetric NH stretches of the NH(3) molecules binding directly to Co(+). Size-dependent changes in the spectra of Co(+)(NH(3))(n) (n = 4-8) indicate that the first shell of Co(+) is filled with four NH(3) molecules and the resulting 4 coordinated structure forms the central core of further solvation. The spectra of Ni(+)(NH(3))(n) (n = 3-8) suggest that the coordination number of Ni(+) is also four, although a minor 3-coordinated isomer is identified for Ni(+)(NH(3))(4). Despite the same coordination number, the DFT calculations predict a distorted square-planar coordination for Ni(+)(NH(3))(4) and a distorted tetrahedral coordination for Co(+)(NH(3))(4). The coordination of Ni(+)(NH(3))(4) is explainable by using a simple model based on the geometry of a half-filled 3d orbital in Ni(+). This suggests that the Ni(+) ion gives priority to the minimization of the metal-ligand repulsion in accommodating four ligands in the first shell. On the other hand, the same model fails to explain the coordination of Co(+)(NH(3))(4). An interpretation for this is that the Co(+) ion gives priority to the minimization of the ligand-ligand repulsion. PMID- 20714491 TI - Determining the structure of alpha-phenylethyl isocyanide in chloroform by VCD spectroscopy and DFT calculations--simple case or challenge? AB - The present work provides a comprehensive theoretical and experimental study of the vibrational circular dichroism of (S)-alpha-phenylethyl isocyanide in chloroform. The structure in solution is investigated systematically by density functional theory calculations starting from the isolated molecule and then by considering solvent effects implicitly using the PCM and explicitly by taking into account molecular complexes of the isocyanide molecule and chloroform. Furthermore, the influence of dimerisation is evaluated, and it is finally found that the structure of (S)-alpha-phenylethyl isocyanide in chloroform is best described assuming a solvated dimer. These results are underlined by a quantitative correlation of the experimentally and theoretically obtained rotational strengths and a robust modes analysis. PMID- 20714492 TI - Comparing efficiencies of genetic and minima hopping algorithms for crystal structure prediction. AB - In this work several crystal structure prediction problems which have been studied by first-principles evolutionary algorithms recently are revisited. We increased the system size to see how the search efficiency changes with respect to problem size. We find that the relative performance and underlying mechanism of genetic algorithms in crystal structure searches for Al(x)Sc(1-x) strongly depend on the system composition as well as the size of the problem. Because of this strong dependence, caution should be taken in generalizing performance comparison from one problem to another even though they may appear to be similar. We also investigate the performance of the search algorithm for crystal structure prediction of boron with and without a priori knowledge of the lattice vectors. The results show that the degree of difficulty increases dramatically if the lattice vectors of the crystal are allowed to vary during the search. Comparison of the minima hopping algorithm with the genetic algorithm at small (<10 atoms) to larger problem sizes is also carried out. At the small sizes we have tested, both methods show comparable efficiency. But at large sizes the genetic algorithm becomes advantageous over minima hopping. PMID- 20714493 TI - Dynamics in the excited electronic state of periodic mesoporous biphenylylene silica studied by time-resolved diffuse reflectance and fluorescence spectroscopy. AB - The excited state dynamics of periodic mesoporous organosilica (powder) bearing biphenylylene moieties densely in the silica framework (Bp-PMO) is investigated for the first time using femtosecond time-resolved diffuse reflectance (TDR) and picosecond time-resolved fluorescence spectroscopies. The TDR spectra revealed the excitation-relaxation process of the biphenylylene moieties, including the relaxation of the twisted Frank-Condon (FC) state to the lowest singlet excited state (S(1)) with a time constant of 730 +/- 95 fs, and efficient quenching of the S(1) state by excimer (E) formations with two time constants of 7.0 +/- 0.2 ps (E(1): ca. 64%) and 170 +/- 47 ps (E(2) and E(3): ca. 36%). The individual absorption spectra of the FC, S(1), and E states were reconstructed by the TDR spectral analysis. The time-resolved fluorescence spectra showed that the excimers decayed with three time constants of 1.3 +/- 0.2 ns (E(1)), 8.2 +/- 0.7 ns (E(2)) and 27 +/- 2 ns (E(3)). The fluorescence quantum yields of the excimers are suggested to be almost zero for E(1), and unity for E(2) and E(3), which implies that the fluorescence quantum yield of Bp-PMO (Phi(F) = 0.38) can be explained by the fraction of the highly emissive excimers (E(2) and E(3)). The excited state dynamics of Bp-PMO is quite different from those of a solution of 4,4'-bis-(triethoxysilyl)biphenyl precursor and a biphenyl molecular crystal (powder). PMID- 20714494 TI - 5,5'-Dimethyl-3,3'-azoisoxazole as a new heterogeneous azo reagent for esterification of phenols and selective esterification of benzylic alcohols under Mitsunobu conditions. AB - 5,5'-Dimethyl-3,3'-azoisoxazole is used as a new efficient heterogeneous azo reagent for the highly selective esterification of primary and secondary benzylic alcohols and phenols with aliphatic and aromatic carboxylic acids via Mitsunobu protocols. The reaction is highly selective for primary benzylic alcohols versus secondary ones, aliphatic alcohols and also phenols. The isoxazole hydrazine byproduct can be simply isolated by filtration and recycled to its azoisoxazole by oxidation. PMID- 20714495 TI - Supercritical behavior in free radical polymerization of ethylene in the medium pressure range. AB - Free radical polymerization of ethylene in an intermediate pressure and temperature range (P(ethylene) < 250 bar and 50 degrees C < T < 90 degrees C) in the presence of an organic solvent has been studied. Under selected conditions (P, T) and according to the amount of organic solvent added, either a supercritical monophasic or a biphasic medium is obtained. In the case of a biphasic medium, polymerization occurred in the liquid phase in which radical initiator and ethylenes are dissolved. The transition between a monophasic to a biphasic medium has been predicted using thermodynamic calculations and has been related to experimental observations such as the dependence of polymerization activity versus solvent volume. PMID- 20714496 TI - Mechanosynthesized nanocrystalline BaLiF(3): The impact of grain boundaries and structural disorder on ionic transport. AB - The mechanosynthesis of highly pure nanocrystalline BaLiF(3) is reported. The product with mean crystallite diameter of about 30 nm was prepared by joint high energy ball-milling of the two binary fluorides LiF and BaF(2) at ambient temperature. Compared to coarse-grained BaLiF(3) with MUm-sized crystallites, which is available via conventional solid-state synthesis at much higher temperatures, the mechanosynthesized product exhibits a drastic increase of ionic conductivity by several orders of magnitude. This is presumably due to structural disorder introduced during milling and to the presence of a large volume fraction of interfacial regions in the nanocrystalline form of BaLiF(3) providing fast diffusion pathways for the charge carriers. Starting from mechanosynthesized nanocrystalline BaLiF(3) it is possible to tune the transport parameters in a well defined way by subsequent annealing. Changes of the electrical response of mechanosynthesized BaLiF(3) during annealing are studied in situ by impedance spectroscopy. The results are compared with those of a structurally well-ordered single crystal which clearly shows extrinsic and intrinsic regions of ionic conduction. PMID- 20714498 TI - Rational design of visible and NIR distyryl-BODIPY dyes from a novel fluorinated platform. AB - A new series of distyryl-BODIPY has been rationally designed and synthesised from a novel fluorinated platform, 8-pentafluorophenylBODIPY, which has enhanced reactivity in the presence of both electron rich, and for the first time, electron deficient aldehydes. The pentafluorobenzene leads to larger red shifts of absorption and emission compared to previously reported analogues. The reactivity and spectroscopic results have been rationalised with quantum mechanics calculation. The fluorescence sensitivity of one derivative to acidity is also presented. PMID- 20714497 TI - Biomolecular-motor-based autonomous delivery of lipid vesicles as nano- or microscale reactors on a chip. AB - We aimed to create an autonomous on-chip system that performs targeted delivery of lipid vesicles (liposomes) as nano- or microscale reactors using machinery from biological systems. Reactor-liposomes would be ideal model cargoes to realize biomolecular-motor-based biochemical analysis chips; however, there are no existing systems that enable targeted delivery of cargo-liposomes in an autonomous manner. By exploiting biomolecular-motor-based motility and DNA hybridization, we demonstrate that single-stranded DNA (ssDNA)-labeled microtubules (MTs), gliding on kinesin-coated surfaces, acted as cargo transporters and that ssDNA-labeled cargo-liposomes were loaded/unloaded onto/from gliding MTs without bursting at loading reservoirs/micropatterned unloading sites specified by DNA base sequences. Our results contribute to the development of an alternative strategy to pressure-driven or electrokinetic flow based microfluidic devices. PMID- 20714499 TI - Microfluidic perfusion system for culturing and imaging yeast cell microarrays and rapidly exchanging media. AB - High resolution live cell microscopy is increasingly used to detect cellular dynamics in response to drugs and chemicals, but it depends on complex and expensive liquid handling devices that have limited its wider adoption. Here, we present a microfluidic perfusion system that is built without using specialized microfabrication infrastructure, simple to use because only a pipette is needed for liquid handling, and yet allows for rapid media exchange and simultaneous fluorescence microscopy imaging. Yeast cells may be introduced from a culture, or spotted as arrays on a coverslip, and are sandwiched with a 20 mum thick track etched membrane. A second coverslip and a mesh with 120 mum porosity are placed on top, forming a microfluidic conduit for lateral flow of solutions by capillary effects. Solutions introduced through the inlet flow through the mesh and chemicals diffuse vertically across the membrane to the cells trapped below. Solutions are exchanged by adding a new sample to the inlet. Using this system, we studied the dynamic response of F-actin in living yeast expressing Sac6-EGFP-a protein associated with discrete F-actin structures called "patches"-to the drug latrunculin A, a well known inhibitor of actin polymerization. We observed that the patches disappeared in 85% of the cells within 5 min, and re-assembled in 45 min following exchange of the drug with media. The perfusion system presented here is a simple, inexpensive device suited for analysis of drug dose-response and regeneration of single cells and arrays of cells. PMID- 20714500 TI - Receptor expression changes as a basis for endothelial cell identification using microfluidic channels. AB - Microfluidic channels functionalized with adhesive ligands are versatile platforms for cell separation in a variety of applications. However, not much is known about how the adhesiveness of targeted cell types can vary within such channels due to the combined influence of fluid shear forces and exposure to ligands. Using microfluidic channels and the tetrapeptide ligand arg-glu-asp-val (REDV), we demonstrate how such dynamic changes can provide a basis for the identification of three distinct phenotypes of endothelial cells: human umbilical vein endothelial cells (HUVECs), human microvascular endothelial cells (HMVECs), and endothelial colony forming cells (ECFCs). This distinction is accomplished by characterizing changes in the adhesion profiles of the three cell types in REDV coated microfluidic channels induced by soluble REDV and fluid shear forces. The significance of this technique lies in the ability to distinguish very similar cell-types without fluorescent label-based staining or flow cytometry. PMID- 20714501 TI - Proteomic analysis of membrane proteins from a radioresistant and moderate thermophilic bacterium Deinococcus geothermalis. AB - Deinococcus geothermalis is a radioresistant and moderate thermophilic bacterium. Little was known about the membrane or membrane associated proteins of this bacterium. This study established the membrane subproteome profile of D. geothermalis, using 1-D PAGE and LC-MS/MS analysis following Triton X-114 detergent extraction. A total of 552 proteins from the membrane preparations were identified from two independent trials. In the total identified proteins, 117 were membrane subproteomic proteins, and 89 of them were described for the first time in D. geothermalis including fimbrial pilin (Dgeo_2038), cytochrome bd ubiquinol oxidase (Dgeo_2705) and multi-sensor (Dgeo_2096). The major membrane subproteomic proteins were distributed into 18 functional groups including nutrient transport and metabolism, energy production and conversion, cell wall/membrane biogenesis and a poorly characterized subclass. The identifications of Deinococcus-specific proteins, such as cell surface receptor IPT/TIG (Dgeo_1119) and four hypothetical proteins, demonstrated the special protein composition and functions in the cell membrane of Deinococcus. The results provide a basis for quantitative proteomic analysis, which will facilitate the understanding of the adaptation of this organism to different environmental stresses and the development of strategies for bioremediation of environmental waste. PMID- 20714502 TI - Band-offset engineering in organic/inorganic semiconductor hybrid structures. AB - Control over the electronic structure of organic/inorganic semiconductor interfaces is required to realize hybrid structures with tailored opto-electronic properties. An approach towards this goal is demonstrated for a layered hybrid system composed of p-sexiphenyl (6P) and ZnO. The molecular orientation can be switched from "upright-standing" to "flat-lying" by tuning the molecule-substrate interactions through aggregation on different crystal faces. The morphology change has profound consequences on the offsets between the molecular frontier energy levels and the semiconductor band edges. The combination of ZnO surface dipole modification through molecule adsorption and the orientation-dependence of the ionization energy of molecular layers shift these offsets by 0.7 eV. The implications for optimizing hybrid structures with regard to exciton and charge transfer are discussed. PMID- 20714503 TI - Undecahydro-closo-dodecaborates as good leaving groups in organic synthesis: generation of substituted styrenes via elimination of arylethyl dodecaborates. AB - New functionalized arylethyl undecahydro-closo-dodecaborates (S,S-disubstituted B(12)H(11)SH(2-), N,N-disubstituted B(12)H(11)NH(3)(-) and O-substituted B(12)H(11)OH(2-)) are prepared by a simple one-step reaction. Moderate to good yields are obtained in the presence of various functional aryl groups. The synthesis of functionalized styrene derivatives can be readily achieved by treating arylethyl undecahydro-closo-dodecaborates with various bases. The scope and limitations of this procedure are demonstrated by investigating an array of alkylated dodecaborates. Based on an E2 elimination reaction, we identify the mechanistic pathway for dealkylation of arylethyl dodecaborates. Mechanistic studies indicate the following essential requirements to promote the elimination reaction: (i) the presence of alpha-CH acidity of the phenethyl group; (ii) steric hindrance; (iii) a substituted heteroatom on the closo-B(12)H(11)(2-) cage and (iv) the presence of an electron-withdrawing group on the aromatic ring. PMID- 20714504 TI - Micropillar array chips toward new immunodiagnosis. AB - In this paper, we demonstrate the possibility to use a micropillar array to perform molecular immunodiagnosis. A polydimethylsiloxane (PDMS) microdevice consisting of a rectangular array of micropillars (45 um in height, 100 * 100 um square cross section) was used to replace microchannels or gels (polyacrylamide or agarose) to perform electrokinetic separation. This microarray was used to mimic highly diluted gel and to maintain electrolyte within the pillar zone by capillary effect. The electrolyte composition (glycerol and agarose content) was investigated in order to improve protein separation by isoelectric focusing (IEF). The influence of glycerol on focusing time and on the different evaporative contributions was further evaluated. In order to perform an immunodiagnostic of milk allergy, different surface treatments were optimized to prevent milk allergen adsorption on PDMS surface. Poly(dimethylacrylamide)-co allyl glycidyl ether (PDMA-AGE) as well as gelatin led to a satisfactory signal to noise ratio. Finally the possibility to perform protein mixture separation using this micropillar array chip followed by immunoblotting was demonstrated by using the serum from an allergic individual, confirming the great potential of this analytical platform in the field of immunodiagnosis. PMID- 20714505 TI - What is the conformation of physiologically-active dinucleoside polyphosphates in solution? Conformational analysis of free dinucleoside polyphosphates by NMR and molecular dynamics simulations. AB - Dinucleoside polyphosphates, or dinucleotides (Np(n)N'; N, N' = A, U, G, C; n = 2 7), are naturally occurring ubiquitous physiologically active compounds. Despite the interest in dinucleotides, and the relevance of their conformation to their biological function, the conformation of dinucleotides has been insufficiently studied. Therefore, here we performed conformational analysis of a series of Np(n)N' Na(+) salts (N = A, G, U, C; N' = A, G, U, C; n = 2-5) by various NMR techniques. All studied dinucleotides, except for Up(4/5)U, formed intramolecular base stacking interactions in aqueous solutions as indicated by NMR. The conformation around the glycosidic angle in Np(n)N's was found to be anti/high anti and the preferred conformation around the C4'-C5', C5'-O5' bonds was found to be gauche-gauche (gg). The ribose moiety in Np(n)N's showed a small preference for the S conformation, but when attached to cytosine the ribose ring preferred the N conformation. However, no predominant conformation was observed for the ribose moiety in any of the dinucleotides. Molecular dynamics simulations of Ap(2)A and Ap(4)A Na(+) salts supported the experimental results. In addition, three modes of base-stacking were found for Ap(2/4)A: alpha-alpha, beta-beta and alpha-beta, which exist in equilibrium, while none is dominant. We conclude that natural, free Np(n)N's (n = 2-5) at physiological pH exist mostly in a folded (stacked), rather than extended conformation, in several interconverting stacking modes. Intramolecular base stacking of Np(n)N's does not alter the conformation of each of the nucleotide moieties, which remains the same as that of the mononucleotides in solution. PMID- 20714506 TI - Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH2 and ABH3. AB - The human ABH2 and ABH3 proteins are functionally complementary in the oxidative demethylation of N(1)-methyl adenine (1-meA) and N(3)-methyl cytosine (3-meC) nucleotide bases. ABH3 displays higher activities with single-stranded DNA (ssDNA) in vitro, whereas ABH2 acts as the primary housekeeping enzyme in mammals for effectively repairing endogenously formed alkylated lesions in double stranded DNA (dsDNA). Structurally, their overall protein folding is quite similar, but the most significant differences occur in the nucleotide recognition lid and the beta-hairpin motif. We present here a site-directed mutational analysis and motif-swapping study to gain mechanistic insight into DNA substrate selection by ABH2 and ABH3. A V101A-F102A double mutant notably reduced ABH2 activity in dsDNA, indicating that this hydrophobic region appears to be important for damage searching and repair. The phenylalanine finger F102 is found to be crucial for ssDNA selection and repair as well; however, V101 shows reduced demethylating activity for only ssDNA and not dsDNA. The ABH2 R110A mutant completely loses the methyl base repair activity, suggesting that R110 is likely to be involved in the base flipping process. E175 and F124 contribute to nucleotide base specific selection and stabilization in the active site for repair. Additionally, swapping the RED residues in ABH3 to equivalent VFG residues in ABH2 endows ABH3 with activity in dsDNA repair as efficient as wild type ABH2. Surprisingly, by changing just a few residues, the ABH3 protein can have very different selectivity towards ssDNA or dsDNA. This result indicates that the RED motif most likely prevents ABH3 binding and repair of dsDNA. Consistently, swapped ABH3 cross-links with dsDNA very well, confirming the determining roles of these residues in the initial DNA strand recognition. Overall, this work has provided a detailed understanding of the structural features of the ssDNA and dsDNA preferences of ABH2 and ABH3. PMID- 20714507 TI - Towards proteomics-on-chip: the role of the surface. AB - Miniaturisation is revolutionary to high-throughput proteomics. These technologies have gained much interest in the past decade, as they allow for sensitive parallel analysis of small amounts of biological materials. This review describes the state of the art of proteomics-on-chip, with a particular focus on the fundamental proteomics-on-chip challenges. The important role of bio interfacial interactions and strategies to control them are presented. Various coating methodologies for on-chip protein/peptide separation are reviewed to provide an overview of the principles of protein-resistant and protein immobilisation coatings, and their effectiveness. PMID- 20714508 TI - Observing photophysical properties of quantum dots in air at the single molecule level: advantages in microarray applications. AB - Quantum dots (QDs) are promising fluorescent tags for microarrays. Because most microarrays are analyzed under dry conditions, it is necessary to examine the photo properties of QDs in air. We demonstrate that the photophysical characteristics of individual quantum dots are different at the liquid/solid interface compared with QDs at the air/solid interface by observing them through a wide-field fluorescence microscope. QDs in air show higher photo-stability, higher fluorescence signal, slower spectral blue shift rate, less blinking and shorter bulk fluorescence lifetime than those in solution. These beneficial properties indicate QDs are good alternative fluorescent probes for microarrays. PMID- 20714509 TI - Miniaturized multiple Fourier-horn ultrasonic droplet generators for biomedical applications. AB - Here we report micro-electro-mechanical system (MEMS)-based miniaturized silicon ultrasonic droplet generators of a new and simple nozzle architecture with multiple Fourier horns in resonance but without a central channel. The centimetre sized nozzles operate at one to two MHz and a single vibration mode which readily facilitates temporal instability of Faraday waves to produce monodisperse droplets. Droplets with diameter range 2.2-4.6 MUm are produced at high throughput of 420 MUl min(-1) and very low electrical drive power of 80 mW. We also report the first theoretical prediction of the droplet diameter. The resulting MHz ultrasonic devices possess important advantages and demonstrate superior performance over earlier devices with a central channel and thus have high potential for biomedical applications such as efficient and effective delivery of inhaled medications and encapsulated therapy to the lung. PMID- 20714511 TI - High-throughput sample introduction for droplet-based screening with an on-chip integrated sampling probe and slotted-vial array. AB - We developed a droplet-based microfluidic screening system with an on-chip sampling probe integrating multi-channels for sample introduction, reagent merging and nanolitre-scale droplet generation, and a slotted-vial array sample presenting system. The present system was applied in protein crystallization conditions screening with an ultra-high sampling throughput up to 6000 h(-1) for different samples. PMID- 20714510 TI - Residues 762-801 of PLD1 mediate the interaction with PED/PEA15. AB - The interaction of Phospholipase D1 (PLD1) by its C-terminal domain D4 with PED/PEA15 has been indicated as a target for type 2 diabetes. PED/PEA15 is overexpressed in several tissues of individuals affected by type 2 diabetes and its overexpression in intact cells and in transgenic animal models impairs insulin regulation of glucose transport by a mechanism mediated by the interaction with D4 and the consequent increase of protein kinase C-alpha activity. Expression of D4 or administration of a peptide mimicking the PED/PEA15 region involved in this interaction to cells stably overexpressing PED/PEA15 reduces its interaction with PLD1, thereby lowering PKC-alpha activation and restoring normal glucose transport mediated by PKC-zeta. By using D4 deletion mutants, we have restricted the PLD1 region involved in PED/PEA15 interaction to an N-terminal fragment named D4alpha (residues 712-818). This region binds PED/PEA15 with the same efficacy as D4 (K(D) approximately 0.7 microM) and, when transfected in different PED/PEA15-overexpressing cells, it is able to reduce PKC alpha activity and to restore the sensitivity of PKC-zeta to insulin stimulation, independently of the PI3K/Akt signalling. We also show that the effective disruption of the PED/PEA15-PLD1 interaction can restore the normal ERK1/2 signalling. Finally, using a set of overlapping peptides that cover the D4alpha region, we have further restricted the shortest PED/PEA15-binding site to a segment encompassing residues 762-801, suggesting that a quite limited binding interface mostly contributes to the interaction and can thus be a selective target for the design of effective antagonists. PMID- 20714512 TI - On-chip immunoprecipitation for protein purification. AB - Immunoprecipitation (IP) is one of the most widely used and selective techniques for protein purification. Here, a miniaturised, polymer-supported immunoprecipitation (uIP) method for the on-chip purification of proteins from complex mixtures is described. A 4 ul PDMS column functionalised with covalently bound antibodies was created and all critical aspects of the uIP protocol (antibody immobilisation, blocking of potential non-specific adsorption sites, sample incubation and washing conditions) were assessed and optimised. The optimised uIP method was used to obtain purified fractions of affinity-tagged protein from a bacterial lysate. PMID- 20714513 TI - Modifications induced by acetylacetone in properties of sol-gel derived Y(3)Al(5)O(12) : Tb(3+)- I: structural and morphological organizations. AB - Acetylacetone has been used as a chemical modifier for the synthesis of undoped and Tb(3+)-doped Y(3)Al(5)O(12) powders. A systematic investigation concerning its influence on the structural and morphological properties of amorphous and crystallized samples has been carried out. These properties have been comparatively studied by means of X-ray diffraction, infrared spectroscopy, SEM, XAS and SAXS. (27)Al NMR and EPR experiments have been performed to complete the study. The combined results have evidenced that acetylacetone promotes organic groups departure during calcination, entailing a better structural organization at lower temperatures compared with unmodified powders. Structuration has been proven to occur at short-scale range until a 600 degrees C heating treatment before being extended by coalescence at higher temperatures. Finally, the presence of acac ligands on the alkoxides leads to a monomer-cluster aggregation process, and thus to a more open network. PMID- 20714514 TI - Non scholae sed vitae discimus! PMID- 20714516 TI - Controllable preferential-etching synthesis of ZnO nanotube arrays on SiO2 substrate for solid-phase microextraction. AB - An improved route to obtain ZnO nanotube arrays and its first application to headspace solid-phase microextraction (HSSPME) as an adsorptive coating were described. The ZnO nanotube arrays were synthesized by a two-step chemical process including the hydrothermal synthesis of ZnO nanorod arrays on the surface of silica fiber (SiO(2)) in the first step, and the formation of ZnO nanotubes by selectively etching in NH(3).H(2)O solution in the second step. The influence of NH(3).H(2)O concentration, etching time, reaction temperature, and aging time in the ZnO nanotubes formation process was investigated, and arrays of ZnO nanotube with tailored dimensions (250 nm external diameters, 70 nm wall thicknesses and 2 MUm lengths) could be obtained by varying the conditions. In addition, the feasibility of ZnO nanotube arrays adopted for HSSPME was evaluated by extracting volatile organic compounds (VOCs) by use of benzene, toluene, ethylbenzene, o-, m and p-xylene (BTEX) as model compounds and the results showed that the coating has good extraction capability. The analytes were linear in the range of 10-600 MUg L(-1) (r > 0.9960) and the detection limits were about 0.005-0.01 MUg L(-1), lower than that obtained with ZnO nanorod arrays. The relative standard derivations (RSD) for the repeatability of single fiber and fiber-to-fiber were lower than 9.5% and 13.8%, respectively. The prepared coating showed good recoveries in the range of 87%-108% and long lifetime (more than 50 times), implying to be a potential absorbent for the VOCs in water samples. PMID- 20714515 TI - Detection of catechol using mixed Langmuir-Blodgett films of a phospholipid and phthalocyanines as voltammetric sensors. AB - The combination of metallic phthalocyanines (MPcs) and biomolecules has been explored in the literature either as mimetic systems to investigate molecular interactions or as supporting layers to immobilize biomolecules. Here, Langmuir Blodgett (LB) films containing the phospholipid dimyristoyl phosphatidic acid (DMPA) mixed either with iron phthalocyanine (FePc) or with lutetium bisphthalocyanine (LuPc(2)) were applied as ITO modified-electrodes in the detection of catechol using cyclic voltammetry. The mixed Langmuir films of FePc + DMPA and LuPc(2) + DMPA displayed surface-pressure isotherms with no evidence of molecular-level interactions. The Fourier Transform Infrared (FTIR) spectra of the multilayer LB films confirmed the lack of interaction between the components. The DMPA and the FePc molecules were found to be oriented perpendicularly to the substrate, while LuPc(2) molecules were randomly organized. The phospholipid matrix induced a remarkable electrocatalytic effect on the phthalocyanines; as a result the mixed LB films deposited on ITO could be used to detect catechol with detection limits of 4.30 * 10(-7) and 3.34 * 10(-7) M for FePc + DMPA and LuPc(2) + DMPA, respectively. Results from kinetics experiments revealed that ion diffusion dominated the response of the modified electrodes. The sensitivity was comparable to that of other non-enzymatic sensors, which is sufficient to detect catechol in the food industry. The higher stability of the electrochemical response of the LB films and the ability to control the molecular architecture are promising for further studies with incorporation of biomolecules. PMID- 20714517 TI - Electro-microchip DNA-biosensor for bacteria detection. AB - This paper presents a bacteria biosensor based on DNA hybridization detection with an electro-microchip transducer. Acinetobacter baumannii was chosen as DNA sample source, because the occurrence of bacteremia caused by Acinetobacter baumannii is high in hospitals worldwide. Our strategy is based on DNA hybridization of PCR amplified bacteria DNA with biotin labelled primers and detection enhancement using gold-streptavidin nanoparticles and Ag(+) hydroquinone solution. Gold nanoparticles catalyze silver ions reduction by hydroquinone. The gradually precipitated silver metal between the two electrodes of the electro-microchip allows electrons to pass. The detection limit for Acinetobacter baumannii genomic DNA sample is 0.825 ng mL(-1) (1.2 fM). Probe specificity was investigated by screening various species of bacteria, various strains of a single species and various species of a single genus. The proposed DNA hybridization method is easy, convenient, and rapid. Moreover, it has potential applications in detection of bacteria causing infections and clinical diagnosis. PMID- 20714518 TI - A valuable way for understanding the relationships between lysozyme and cephalosporin analogues by flow injection chemiluminescence. AB - The photochemical reaction mechanism of lysozyme with cephalosporin analogues was investigated with luminol used as a luminescence probe by flow injection chemiluminescence. It was found that Glu35 and Asp52 of lysozyme accelerated the rate of excited 3-aminophthalate electrons transferring and enhanced the chemiluminescence signal of luminol, producing steady-state chemiluminescence in the flow injection system with relative standard deviations less than 3.0%. It was also found that cephalosporin analogues could enter into the site of Trp62 in lysozyme forming 1 : 1 complex which leads to a conformational change of lysozyme, giving the effect of chemiluminescence quenching from luminol-lysozyme. Based on the photochemical behavior of luminol/lysozyme and cephalosporin, a model of lysozyme-cephalosporin interaction, lg[(I(0)-I)/I]=lgK(D) + nlg[D], was established. Using the proposed model, the interaction parameters and the binding ability of lysozyme with cephalosporin were successfully obtained, and the results agreed very well with the results obtained by fluorescence. PMID- 20714519 TI - Fast determination of the tetracyclines in milk samples by the aptamer biosensor. AB - A novel aptamer biosensor for fast tetracyclines determination was established and illustrated in this paper. The tetracyclines aptamer as a specific affinity molecule was immobilized on the surface of the glassy carbon (GC) electrodes. It can specifically bind tetracyclines quickly in milk and other samples without sample treatment. Subsequently, the electrochemical signals are produced and measured accurately. The linear relationship between the currents and the tetracyclines concentration is 0.1-100 ng ml(-1). The sensitivity limit of the device is 1 ng ml(-1). The detection time is 5 min. PMID- 20714520 TI - Gaining efficiency by parallel quantification and identification of iTRAQ-labeled peptides using HCD and decision tree guided CID/ETD on an LTQ Orbitrap. AB - Isobaric stable isotope labeling of peptides using iTRAQ is an important method for MS based quantitative proteomics. Traditionally, quantitative analysis of iTRAQ labeled peptides has been confined to beam-type instruments because of the weak detection capabilities of ion traps for low mass ions. Recent technical advances in fragmentation techniques on linear ion traps and the hybrid linear ion trap-orbitrap allow circumventing this limitation. Namely, PQD and HCD facilitate iTRAQ analysis on these instrument types. Here we report a method for iTRAQ-based relative quantification on the ETD enabled LTQ Orbitrap XL, which is based on parallel peptide quantification and peptide identification. iTRAQ reporter ion generation is performed by HCD, while CID and ETD provide peptide identification data in parallel in the LTQ ion trap. This approach circumvents problems accompanying iTRAQ reporter ion generation with ETD and allows quantitative, decision tree-based CID/ETD experiments. Furthermore, the use of HCD solely for iTRAQ reporter ion read out significantly reduces the number of ions needed to obtain informative spectra, which significantly reduces the analysis time. Finally, we show that integration of this method, both with existing CID and ETD methods as well as with existing iTRAQ data analysis workflows, is simple to realize. By applying our approach to the analysis of the synapse proteome from human brain biopsies, we demonstrate that it outperforms a latest generation MALDI TOF/TOF instrument, with improvements in both peptide and protein identification and quantification. Conclusively, our work shows how HCD, CID and ETD can be beneficially combined to enable iTRAQ-based quantification on an ETD-enabled LTQ Orbitrap XL. PMID- 20714522 TI - Surfactant bilayer coatings in narrow-bore capillaries in capillary electrophoresis. AB - The cationic surfactants didodecyldimethylammonium bromide (DDAB) and dioctadecyldimethyl-ammonium bromide (DODAB) have previously been shown to form semi-permanent coatings that effectively prevent adsorption of cationic proteins in fused silica capillaries with inner diameters of 25-75 um. This paper investigates the impact that narrower capillary diameters (<=25 um) have on the stability of surfactant bilayer coatings and the efficiency of separations of model cationic proteins and neurotransmitters. Using a DODAB-coated 5 um i.d. capillary 210 consecutive protein separations (1050 min) were performed without recoating the capillary between runs. Separation efficiencies of 1,400,000 2,000,000 plates per m (340,000-430,000 plates) were obtained. Migration time reproducibilites of 6.8% RSD were observed for 300 injections performed over a 30 day period without any regeneration of the coating. Neurotransmitters were separated with efficiencies ranging from 470,000-610,000 plates per m (110,000 140,000 plates) in a 5 um capillary. PMID- 20714521 TI - Glyco-biosensors: recent advances and applications for the detection of free and bound carbohydrates. AB - The field of biosensor development now encompasses several areas specifically geared toward the rapid and sensitive detection, identification, and quantification of target analytes. In contrast to the more mature research and development of nucleic acid and protein biosensors, the development of 'glyco biosensors' for detecting carbohydrates and conjugates of carbohydrates (glycoconjugates) is at a relatively nascent stage. The application of glyco biosensors aims to open novel analytical and diagnostic avenues, encompassing industrial bioprocesses, biomedical and clinical applications. This area of research has been greatly aided by advancement brought by interdisciplinary mergers of engineering, biology, chemistry and physical sciences and enabling the miniaturization of detection platforms. In this review, we briefly introduce the need for glyco-biosensors, discuss current analytical technologies, and examine advances in glyco-biosensor approaches aimed at the detection and/or quantification of glycoconjugates or carbohydrates derived from glycoconjugates since 2005. PMID- 20714523 TI - Electrochemical determination of nitrite using silver nanoparticles modified electrode. AB - In this work, we report the fabrication and characterization of silver nanoelectrode ensembles (Ag-NEEs) on a glassy carbon electrode. For this purpose, Ag nanoparticles (NPs) were anchored to the mercaptopropyl functionalized MCM-41 type silica spheres utilizing the chemisorption property of Ag NPs by -SH groups. The successful anchoring of Ag NPs into the silica matrix is characterized by several techniques including UV-vis diffuse reflectance and X-ray powder diffraction methods. The surface morphology of the Ag-NEEs was assessed by scanning and transmission electron microscopy (SEM and TEM respectively). Further, nitrite (NO(2)(-)) is electrocatalytically oxidized at Ag-NEEs, which leads to a sensitive determination of NO(2)(-). The fabrication, characterization, and efficient sensing of NO(2)(-) at the Ag-NEEs are presented. PMID- 20714525 TI - Simultaneous determination of four phthalate esters in bottled water using ultrasound-assisted dispersive liquid-liquid microextraction followed by GC-FID detection. AB - A simple and rapid sample pretreatment procedure based on ultrasound-assisted dispersive liquid-liquid microextraction is proposed for the determination of four phthalate esters (dibutyl phthalate, butyl benzyl phthalate, diisooctyl phthalate, dioctyl phthalate) in bottled water samples using gas chromatography flame ionization detection. An ultrasound-assisted process was applied to accelerate the formation of the fine cloudy solution using less disperser solvent, which markedly increased the extraction efficiency and reduced the equilibrium time. Under optimum conditions, the enrichment factor of the four analytes ranged from 490- to 530-fold and the recovery ranged from 84.8%~104.7%. A good linear relationship between the peak area and the concentration of analytes was obtained in the range of 6.9~444 MUg L(-1). Intra-assay and inter assay precision expressed as relative standard deviation (RSD) were in the range of 1.4~2.0% and 3.0~3.7%, respectively. This method offers a good alternative for routine analysis due to its simplicity and reliability. PMID- 20714524 TI - DNA as a target for anticancer compounds screening directly by resonance light scattering technique. AB - Anticancer drugs which selectively interact with DNA can change DNA's conformation and inhibit the duplication or transcription of DNA. An instrument based assay for directly screening DNA-targeted anticancer drugs using resonance light scattering (RLS) technique with a common spectrofluorometer was proposed. To monitor the proposed screening method, the interactions between three anticarcinogens (Adriamycin (ADM), Bleomycin A (BLMA), Actinomycin D (ACTD)) and DNA were studied. The sequence of binding constants for the three anticarcinogens obtained from RLS spectra is: K(RLS) (ACTD, 9.43 * 10(5) L mol(-1)) > K(RLS) (ADM, 6.67 * 10(5) L mol(-1)) > K(RLS) (BLMA, 8.88 * 10(3) L mol(-1)) and of binding numbers is: N(RLS) (ACTD, 3.36 mmol g(-1)) < N(RLS) (ADM, 3.81 mmol g( 1)) < N(RLS) (BLMA, 57.44 mmol g(-1)). From the results we got the sequence of combination intensity between these three drugs and DNA as follows: ACTD-DNA > ADM-DNA > BLMA-DNA, which was completely consistent with drug activity. The conclusion indicated that the present method was direct, rapid, reliable and was another important innovation of the application of RLS technique. PMID- 20714531 TI - Synthesis and characterization of gold-deposited red, green and blue fluorescent silica nanoparticles for biosensor application. AB - Fluorescent silica nanoparticles deposited with highly monodisperse gold nanoparticles (1-2 nm) were synthesized via the W/O method and intensive ultrasound irradiation. A large surface area of gold-doped fluorescent silica nanoparticle serves as a platform to immobilize a specific binding protein for biomolecules interaction in bioimaging applications. PMID- 20714532 TI - Single molecule magnet behaviour in robust dysprosium-biradical complexes. AB - A Dy-biradical complex was synthesized and characterized down to very low temperature. ac magnetic measurements reveal single molecule magnet behaviour visible without any application of dc field. The transition to the quantum tunneling regime is evidenced. Photophysical and EPR measurements provide evidence of the excellent stability of these complexes in solution. PMID- 20714533 TI - Fluorescent receptor-immobilized silica-coated magnetic nanoparticles as a general binding agent for histidine-tagged proteins. AB - The histidine-tagged protein binding capacity and purification efficiencies of TSMNPs (terpyridine receptor-immobilized silica-coated magnetic nanoparticles) is described. PMID- 20714534 TI - Thermodynamic and kinetic destabilization in LiBH4/Mg2NiH4: promise for borohydride-based hydrogen storage. AB - The reversible LiBH(4)/Mg(2)NiH(4) combined hydride system for hydrogen storage displays a concerted dehydrogenation reaction beginning at 250 degrees C with significantly low enthalpy (DeltaH = 15.4 +/- 2 kJ mol(-1) H(2)) and entropy (DeltaS = 62.2 +/- 3 J K(-1) mol(-1) H(2)). PMID- 20714535 TI - Preparation of hollow spheres with controllable interior structures by heterogeneous contraction. AB - We present a simple and effective heterogeneous contraction method to fabricate hollow spheres with controllable interior structures (ranging from solid, simple hollow to core-in-hollow-wall, double-wall hollow and core-in-double-hollow-wall spheres) by a non-equilibrium heat-treatment process of gel precursors with a high heating rate. PMID- 20714536 TI - High-spin supramolecular pair of Mn(II)/thiazyl radical complexes. AB - The Mn(hfac)(2) complex of the paramagnetic 4-(benzoxazol-2'-yl)-1,2,3,5 dithiadiazolyl ligand is reported (hfac = 1,1,1,5,5,5-hexafluoroacetylacetonato ). The Mn(ii) and radical ligand spins are coupled antiferromagnetically (AF) in the coordination complex. Short sulfur-oxygen contacts between molecules provide an efficient pathway for AF coupling between the radical ligand of one molecule and the Mn(ii) of a neighbouring molecule, resulting in a large total spin ground state (S(T) = 4) for a pair of molecules. PMID- 20714537 TI - Controllable formation of defect-rich Pd and Pd-Ag bimetallic nanocrystals through coalescence mechanism. AB - Pd and Pd-Ag bimetallic defect-rich nanocrystals were synthesized with iodobenzene as capping agent, followed by post-treatment with ice-cooled acetone. PMID- 20714538 TI - Controlled fabrication of uniform hollow core porous shell carbon spheres by the pyrolysis of core/shell polystyrene/cross-linked polyphosphazene composites. AB - Uniform carbon spheres with hollow core and porous shell structures were controllably fabricated through carbonizing fine core/shell particles of polystyrene/cross-linked poly(cyclotriphosphazene-co-4,4'-sulfonyldiphenol), obtained by a simple template approach. PMID- 20714539 TI - First determination of the rate constant for ring-closure of an azahexenoyl radical: 6-aza-7-ethyl-5-hexenoyl. AB - Competitive kinetic experiments utilising free radical carbonylation chemistry provide a first estimate for the rate constant for 6-endo cyclization of the 6 aza-7-ethyl-5-hexenoyl radical of (4.8 +/- 2.4) x 10(6) s(-1) at 90 degrees C in benzene, in good agreement with ONIOM-G3(MP2)-CC+COSMO-RS calculations (6.8 x 10(6) s(-1)). PMID- 20714540 TI - Mechanochemistry of magnesium oxide revisited: facile derivatisation of pharmaceuticals using coordination and supramolecular chemistry. AB - Liquid-assisted grinding allows the rapid, waste-free and one-pot synthesis of a variety of magnesium drug derivatives directly from the excipient MgO; such reactivity is relevant for the behaviour of ibuprofen formulations involving MgO and can be used for oxide-based mechanosynthesis of metal-organic salts, discrete complexes and carboxylate clusters involving magnesium and pharmaceutically active ingredients. PMID- 20714541 TI - Bioinspired fabrication of 3D hierarchical porous nanomicrostructures of calcium carbonate for bone regeneration. AB - Hierarchical calcium carbonate structures with multi-scale organization have been successfully fabricated covering the full range of pore sizes from nano-, to micro- to macrofeatures. The resulting 3D scaffolds, with a close resemblance to bone structures, have been evaluated in vitro and in vivo and showed great potential for bone regeneration. PMID- 20714542 TI - Aerobic oxidation of alcohols catalyzed by rhodium(III) porphyrin complexes in water: reactivity and mechanistic studies. AB - Selective oxidation of alcohol in water using molecular oxygen as the terminal oxidant is mediated by rhodium porphyrin complexes. Addition of methanol to an aqueous solution of (TSPP)Rh(III) resulted in observation of the key intermediate porphyrin rhodium(III) methoxide species. The activation parameters for betaC-H elimination of Rh-alkoxide were evaluated. PMID- 20714543 TI - Nanoparticle catalysed oxidation of sulfides to sulfones by in situ generated H2O2 in supercritical carbon dioxide/water biphasic medium. AB - In a one-pot reaction, hydrogen peroxide generated from H(2) and O(2) on a Pd catalyst was utilised as oxidant for the TiO(2) catalyzed conversion of a sulfide to a sulfone. This transformation, where two different nanoparticle catalysts were employed in a supercritical carbon dioxide/water biphasic system, demonstrates the potential of compartmentalising catalytic processes in consecutive reactions. PMID- 20714544 TI - Fabrication of uniform anatase TiO(2) particles exposed by {001} facets. AB - Uniform anatase TiO(2) particles exposed by {001} facets were successfully synthesized by using EDTA together with F as morphology controlling agents. The crystallographic structure as well as the growth mechanism of anatase TiO(2) particles was investigated systematically by XRD, SEM, TEM and XPS, respectively. PMID- 20714545 TI - Chitosan aerogel: a recyclable, heterogeneous organocatalyst for the asymmetric direct aldol reaction in water. AB - Aerogel microspheres of chitosan, an abundant biopolymer obtained from marine crustaceans, have been successfully applied to catalyze the asymmetric aldol reaction in water, providing the products in high yields and with good stereoselectivity (up to 93% ee) and recyclability (up to 4 runs). Yields were favourably affected by additives such as DNP and stearic acid. PMID- 20714546 TI - Assembling triple helical amide-to-amide hydrogen bonded columns of tris(4 halophenyl)benzene-1,3,5-tricarboxamides into porous materials via halogen...halogen interactions. AB - All the four halogen derivatives of tris(4-halophenyl)benzene-1,3,5 tricarboxamides were shown to form triple helical columns via N-H...O hydrogen bonds. These columns have shown the tendency to assemble into porous materials in case of iodo, bromo and chloro derivatives via halogenhalogen interactions. PMID- 20714547 TI - Fluoroglycoproteins: ready chemical site-selective incorporation of fluorosugars into proteins. AB - A tag-and-modify strategy allows the practical synthesis of homogenous fluorinated glyco-amino acids, peptides and proteins carrying a fluorine label in the sugar and allows access to first examples of directly radiolabelled ([(18)F] glyco)proteins. PMID- 20714548 TI - Synthesis of a mesoporous single crystal Ga2O3 nanoplate with improved photoluminescence and high sensitivity in detecting CO. AB - A new approach is proposed to synthesize a mesoporous single crystal Ga(2)O(3) nanoplate by heating a single crystal nanoplate of GaOOH, which involves an ion exchange between KGaO(2) and CH(3)COOH at room temperature for the formation of GaOOH and pseudomorphic and topotactic phase transformation from GaOOH to Ga(2)O(3). PMID- 20714549 TI - Visual and quantitative detection of copper ions using magnetic silica nanoparticles clicked on multiwalled carbon nanotubes. AB - Here we combine click chemistry and carbon nanotube peroxidase-like catalytic colour reaction together to develop a turn-on, highly sensitive and selective copper sensor. PMID- 20714550 TI - Dipole directed ring assembly of Ni-coated Au-nanorods. AB - We demonstrate the synthesis of novel core-shell nanoring superstructures consisting of non-dipolar Au nanorods coated with magnetic Ni shells. We show that the magnetic dipole induced self-assembly can be tuned by selective reduction of Ni on gold nanorods. Superstructures range from nanorings containing physically separated particles to solid rigid nanorings. PMID- 20714551 TI - Multi-component synthesis of trimetallic tetranuclear clusters [Cu(L)(H(2)O)](2)Ln(H(2)O)(2)Cr(C(2)O(4))(3).12H(2)O (H(2)L = 1,4,8,11 tetraazacyclotradecane-2,3-dione, Ln(3+) = Gd, Tb and Dy). AB - Novel tetranuclear Cu(ii)-Ln(iii)-Cr(iii) complexes with oxamidate and oxalate bridges have been prepared using [Cu(L)], LnCl(3).6H(2)O and K(3)[Cr(ox)(3)] components (ox(2-) = oxalate) during the development of new multimetallic complexes as molecular magnets. Overall ferromagnetic properties have been observed in the Cu(2)GdCr compound, and no single-magnet behavior has been found in the Cu(2)TbCr and Cu(2)DyCr compounds. PMID- 20714552 TI - Stability enhancement of ZnTPPS in acidic aqueous solutions by polymeric micelles. AB - Poly(ethyleneglycol)-b-poly(4-vinylpyridine) (PEG-b-P4VP) and zinc meso 5,10,15,20-tetrakis-(4-sulfonatophenyl)porphyrin (ZnTPPS) form complex micelles based on electrostatic interactions. The complex micelles have a core-shell structure that can effectively prevent the demetallization and aggregation of ZnTPPS in acidic aqueous solutions (pH < 4.0). PMID- 20714553 TI - Selective polymerization of polypyrrole in silica mesopores using an in situ generated oxidizing agent on a silica surface. AB - A novel method that selectively polymerizes pyrrole on the silica surface without inducing polymerization in bulk solution is developed, which is based on in situ generation of the NO(+) ion as an oxidant at the silica surface. PMID- 20714554 TI - Fabrication of novel hierarchically ordered porous magnetic nanocomposites for bio-catalysis. AB - Novel hierarchically ordered porous magnetic nanocomposites with interconnecting macroporous windows and meso-microporous walls containing well dispersed magnetic nanoparticles have been fabricated and used as a support to immobilise lipase for the efficient hydrolysis of ester. PMID- 20714555 TI - Pd nanoparticles in silica hollow spheres with mesoporous walls: a nanoreactor with extremely high activity. AB - A true nanoreactor composed of mesoporous silica hollow spheres and Pd nanoparticles residing inside the spheres shows superior activity in Suzuki coupling reactions with 99.5% yield in 3 min. PMID- 20714556 TI - Multi-colored dye sensitization of polymer/fullerene bulk heterojunction solar cells. AB - Multi-colored dye-sensitized polymer/fullerene solar cells with two different near-IR dyes, silicon phthalocyanine bis(trihexylsilyl oxide) (SiPc) and silicon naphthalocyanine bis(trihexylsilyl oxide) (SiNc), enhanced power conversion efficiency up to 4.3%, compared to that of the individual ternary blend solar cells with a single dye under AM1.5G illumination. PMID- 20714557 TI - Three different product types from reactions of lithiated cyclic aminals with trivalent organometal chlorides. AB - The reaction of 2-lithio-1,3,5-trimethyl-1,3,5-triazacyclohexane with YCp(2)Cl leads to the formation of a donor-functionalised mono-anionic amide ligand, 1,3,5 trimethyl-2-(methylamidomethyl)-1,3,5-triazacyclohexane, bonded to the YCp(2) unit. The reaction involves a cleavage of the 1,3,5-triazacyclohexane ring and such a cleavage is also observed in the analogous reaction with (Me(3)C)(2)GaCl, where a MeN[double bond, length as m-dash]CH(-) fragment is formed. No such cleavage occurs in the reaction of the related dilithiated bicyclic bis(3-methyl 1,3-diazacyclohex-1-yl)methane with YCpCl(2).3thf, which affords a mixed lithium yttrium organyl. PMID- 20714558 TI - A novel degradable polymeric carrier for selective release and imaging of magnetic nanoparticles. AB - A water-soluble, pH-responsive copolymer was synthesized successfully and used as a polymeric carrier to deliver hydrophobic paramagnetic nanoparticles into cells. In an acidic environment, the nanoparticles aggregate as the copolymer degrades, resulting in the enhancement of an in vitro MRI signal. PMID- 20714559 TI - Rosette nanotubes with 1.4 nm inner diameter from a tricyclic variant of the Lehn Mascal G--C base. AB - A new strategy to access rosette nanotubes with increased inner diameter is presented and demonstrated through the synthesis and self-assembly studies of a tricyclic variant of the Lehn-Mascal G--C base. PMID- 20714560 TI - Synthesis and characterization of phosphorescent three-coordinate Cu(I)-NHC complexes. AB - Cationic and neutral monomeric three-coordinate phosphorescent Cu(I) complexes were synthesized and characterized by XRD analysis, electrochemistry and photophysical studies in different environments. DFT calculations have aided the assignment of the electronic structure and excited state behavior of these complexes. PMID- 20714561 TI - Total synthesis of (+/-)-vertine with Z-selective RCM as a key step. AB - A concise total synthesis of the strained pentacyclic alkaloid (+/-)-Vertine has been achieved in eleven steps with the key steps being pelletierine condensation, Suzuki-Miyaura coupling, and ring-closing metathesis. PMID- 20714562 TI - A mass spectrometric investigation of novel quadruplex DNA-selective berberine derivatives. AB - ESI mass spectrometry was used to assess the binding of 13-substituted, 5-nitro-2 phenylindolyl- and 2-naphthalenyl-based berberine derivatives to inter- and intramolecular G-quadruplex DNA molecules. In contrast with the parent berberine, the compounds showed selectivity for quadruplex over duplex DNA and stabilised the quadruplex structure. They represent a new class of quadruplex DNA-selective ligands. PMID- 20714563 TI - Fe3O4-in-silica super crystal of defined interstices for single protein molecules entrapment under magnetic flux. AB - Confocal fluorescence demonstrates that single molecules of dye-labelled Cytochrome C or B5 containing paramagnetic Fe(III) can be magnetically placed into the interstices of super-crystal which is composed of three dimensional regular arrays of Fe(3)O(4) nanoparticles. PMID- 20714564 TI - Synthesis and catalytic properties of mesoporous, bifunctional, gallium-niobium mixed oxides. AB - Thermally stable mesoporous Ga-Nb mixed oxides, active in both acid-catalysed and redox reactions have been synthesized via self-assembly hydrothermal assisted approach. Methyl oleate, a major component of biodiesels, undergoes double bond and skeletal isomerisation as well as dehydrogenation over these novel mesophases. PMID- 20714565 TI - Synthesis of a 1-boratabenzene-(2,3,4,5-tetramethylphosphole): towards a planar monophosphole. AB - Novel boratabenzene-phosphole complexes have been prepared and structurally characterized. The electronic communication between the two heterocyclic rings linked by a P-B bond and the aromaticity of these systems were probed using crystallographic and density functional studies. PMID- 20714566 TI - A sequential direct arylation/Suzuki-Miyaura cross-coupling transformation of unprotected 2'-deoxyadenosine affords a novel class of fluorescent analogues. AB - Novel rigid 8-biaryl-2'-deoxyadenosines with tuneable fluorescent properties can be accessed by an efficient sequential catalytic Pd(0)-coupling approach. PMID- 20714567 TI - Pseudomorphic synthesis of mesoporous zeolite Y crystals. AB - A simple method for the conception of mesoporous zeolite Y crystals with a narrow intracrystalline mesopore size distribution is reported. It involves the pseudomorphic transformation of parent zeolite crystals by recrystallisation in the presence of surfactants, and leads to two interconnected pore systems in the zeolite crystals. PMID- 20714569 TI - Solution-phase synthesis of Au fibers using rod-shaped micelles as shape directing agents. AB - Au fibers with micron-scale lengths have been successfully prepared via a solution-phase synthetic method. Solubilization of salicylate ion into an aqueous CTAB solution forms rod-shaped micelles and becomes a key shape directing factor to generate one-dimensional Au structures. PMID- 20714568 TI - Alpha-synuclein in alpha-helical conformation at air-water interface: implication of conformation and orientation changes during its accumulation/aggregation. AB - Alpha-synuclein, a natively unstructured protein important in the neuropathology of Parkinson's disease, was found to form a Langmuir monolayer in an alpha helical conformation with its helical axis parallel to the air-water interface. This study sheds light on the role of vesicles in neuronal cells in the accumulation/aggregation of alpha-synuclein. PMID- 20714570 TI - Unexpected fluorescence properties in an axially sigma-bonded ferrocenyl containing porphyrin. AB - Molecular structure, redox, and unexpected fluorescence properties of a tetraphenylporphyrin tin(iv) complex axially sigma-bonded with two ferrocene substituents were investigated using UV-vis, MCD, electro- and spectroelectrochemical methods as well as DFT calculations and X-ray crystallography. PMID- 20714571 TI - Sulfhydryl-based dendritic chain reaction. AB - A new dendritic chain reaction probe system was demonstrated to produce exponential signal amplification for the detection of sulfhydryl compounds. PMID- 20714572 TI - Aerobic oxidation of thiols to disulfides using iron metal-organic frameworks as solid redox catalysts. AB - Aerobic oxidation of thiols to disulfides has been carried out using iron metal organic frameworks (MOFs) as solid redox catalysts with very high yield and selectivity in acetonitrile under mild reaction conditions. PMID- 20714573 TI - Continuous-flow homogeneous catalysis using the temperature-controlled solvent properties of supercritical carbon dioxide. AB - A fully integrated continuous process for homogeneous catalysed reactions in scCO(2) has been developed exploiting the tunable solvent properties of scCO(2). A heated condenser situated above the reaction zone leads to a phase split under isobaric conditions resulting in efficient catalyst retention and recirculation. Continuous isomerisation of allylic alcohols was carried out for over 200 hours time-on-stream demonstrating the viability of this approach. PMID- 20714574 TI - Organocatalytic diimide reduction of enamides in water. AB - Bridged flavinium organocatalysts have displayed efficacy in the diimide mediated reduction of enamides in aqueous conditions. This represents the first diimide reduction of an electron rich alkene and offers a clean alternative to the use of alkylating agents for N-alkylation. PMID- 20714575 TI - Structural disorder in alkaline earth metal doped Ba(x)Mn[Fe(CN)6](2(x+1)/3).zH2O molecular magnets: a reverse Monte Carlo study. AB - We report a detailed structural disorder study of the Ba(x)Mn[Fe(CN)(6)](2(x+1)/3).zH(2)O (x = 0 and 0.3) molecular magnets by carrying out Reverse Monte Carlo (RMC) simulations of neutron diffraction data. Both samples have also been investigated using X-ray diffraction, infrared spectroscopy and dc magnetization techniques. Rietveld refinement of X-ray and neutron diffraction patterns confirmed the single phase formation for both compounds in a face-centered cubic structure. IR spectral study establishes the presence of cyanide flipping in both compounds, thereby revealing inherent structural disorder in the compounds. A ferrimagnetic coupling of Mn(2+) (S = 5/2) spins and the Fe(3+) (S = 1/2) spins is found for both compounds. Results of RMC simulations of neutron diffraction data for both compounds show that: (i) around the coordinated oxygen atoms (located at the 24e crystallographic sites with [Fe(CN)(6)] vacancies), there are formations of small clusters of non coordinated oxygen atoms; and (ii) Ba substitution leads to a reduction in this structural disorder. The role of reduced water content as well as vacancies of [Fe(CN)(6)] towards the observed reduction in the structural disorder is discussed. PMID- 20714576 TI - Geometric correlations and infrared spectrum of adenine-uracil hydrogen bonds in CDCl(3) solution. AB - Hybrid QM/MM molecular dynamics simulations have been carried out for the Watson Crick base pair of 9-ethyl-8-phenyladenine and 1-cyclohexyluracil in deuterochloroform solution at room temperature. Trajectories are analyzed paying special attention to the geometric correlations within the N-HN and N-HO hydrogen bonds in the base pair. Even though the two hydrogen bonds are only approximately linear and the heterocycles are tilted with respect to each other, hydrogen bond and N-H lengths follow a simple empirical correlation based on Pauling's valence bond order model. In order to describe the IR line shape of the two NH-stretching vibrations, the correlation between their fundamental transition frequencies and the hydrogen bond lengths is exploited. This facilitates efficient evaluation of the fluctuating transition frequencies along the QM/MM trajectory which allows the determination of the line shape function. PMID- 20714577 TI - A new Phenol Red-modified porphyrin as efficient protein photocleaving agent. AB - Protein affinity is of importance for porphyrins in their application in photodynamic therapy (PDT). A new Phenol Red-modified porphyrin (R-TPP) was designed and synthesized to fully take advantage of the binding character of Phenol Red towards protein. Detailed comparisons of absorption spectra, fluorescence spectra, n-octanol/water partition coefficients, (1)O(2) quantum yields, as well as protein photocleaving abilities between R-TPP and its parent porphyrin Br-TPP clearly demonstrate the benefits stemming from the modification of Phenol Red. On one hand, the presence of Phenol Red moiety greatly enhances the binding affinity of R-TPP towards model proteins (bovine serum albumin and hen egg lysozyme), and therefore improves the availability of (1)O(2). On the other hand, the presence of Phenol Red moiety provides R-TPP with amphiphilic character, and therefore restricts aggregation and favors the generation of (1)O(2). As a result, R-TPP photocleaves proteins efficiently, showing promising application potential in PDT. PMID- 20714578 TI - The influence of orientations and external electric field on charge carrier mobilities in CuPc and F16CuPc films on highly ordered pyrolytic graphite and octane-1-thiol terminated Au(111) substrates. AB - The lying-down and standing-up CuPc and F(16)CuPc films on HOPG (highly ordered pyrolytic graphite) and C8-SAM/Au(111) (octane-1-thiol terminated Au(111)) substrates are investigated by using a hybrid strategy combing the molecular dynamic (MD) simulations with density functional theory (DFT) calculations, in order to understand the influence of packing orientation on charge carrier mobilities. On the basis of the periodic slab model and consistent-valence force field, MD simulations show the populations of various packing configurations and radial distribution of intermolecular distance in the films at room temperature. It is also demonstrated that the external electric field (parallel or perpendicular to the substrate) perturbs the intermolecular distances in CuPc and F(16)CuPc films, especially for the slipped edge-to-face stackings. DFT calculations are then used to evaluate two key charge-transfer parameters, reorganization energy and transfer integral. An electrostatics embedding model is employed to approximately consider the external electrostatics contributions to reorganization energy. The thermal-averaged mobility is consequently estimated by taking account of both electronic structures of charge-hopping pairs and dynamic fluctuations in film morphologies under various experimental conditions. It is found that CuPc has smaller reorganization energy and larger hole (electron) mobilities than F(16)CuPc. Under the external electric field of 10(4)-10(7) V cm( 1), both hole and electron mobilities of CuPc and F(16)CuPc films would decrease to 1-3 orders of magnitude. CuPc (F(16)CuPc) films show substantial orientation dependence of mobilities on the ratio of standing-up versus lying-down orientations falling in the range of 10-1000. PMID- 20714579 TI - Unravelling the atomic structure of cross-linked (1 * 2) TiO2(110). AB - The cross-linked (1 * 2) reconstruction of TiO(2)(110) is a frequently observed phase reflecting the surface structure of titania in a significantly reduced state. Here we resolve the atomic scale structure of the cross-linked (1 * 2) phase with dynamic scanning force microscopy operated in the non-contact mode (NC AFM). From an analysis of the atomic-scale contrast patterns of the titanium and oxygen sub-structures obtained by imaging the surface with AFM tips having different tip apex termination, we infer the hitherto most accurate model of the atomic structure of the cross-linked (1 * 2) phase. Our findings suggest that the reconstruction is based on added rows in [001] direction built up of Ti(3)O(6) units with an uninterrupted central string of oxygen atoms accompanied by a regular sequence of cross-links consisting of linear triples of additional oxygen atoms in between the rows. The new insight obtained from NC-AFM solves previous controversy about the cross-linked TiO(2)(110) surface structure, since previously proposed models based on cross-links with a lower O content do not appear to be consistent with the atom-resolved data presented here. Instead, our measurements strongly support the Ti(3)O(6) motif to be the structural base of the cross-linked (1 * 2) reconstruction of TiO(2)(110). PMID- 20714580 TI - The effect of PAMAM G6 dendrimers on the structure of lipid vesicles. AB - Dendrimers are polymers with unique properties that make them promising in a variety of applications such as potential drug and gene delivery systems. PAMAM dendrimers, in particular, have been widely investigated and are efficiently translocated into the cell. The mechanism of translocation, however, is still unknown. Recently it was proposed that PAMAM dendrimers are able to open holes in lipid bilayers by stealing lipid from the bilayer and forming "dendrisomes". The present work intends to contribute in the clarification of this question: why are dendrimers able to translocate into the cell? We create simple models for cell membranes by using small lipid vesicles that present a single lipid phase at physiologically relevant conditions. We then follow the effect that dendrimers have on the structure of the vesicles by using a combination of various techniques: dynamic light scattering, cryo-TEM and small angle X-ray scattering. We discuss our results with respect to the previous findings and reflect on their possible implications for real translocation in living cells. PMID- 20714581 TI - A multi-rate kinetic model for spontaneous oriented attachment of CdS nanorods. AB - A multi rate kinetic model to explain the spontaneous oriented attachment of CdS nanorods in the presence of an amine is presented. The model demonstrates the reasons that elongation is restricted to a maximum of quadruple, the starting rod length for rods of a certain aspect ratio (8 * 30 nm) with no elongation occurring for rods of a shorter aspect ratio. The rate constants for all possible attachment events are determined showing that elongation by attachment occurs sequentially by single rod addition alone. Both the reaction rate and the activation energy for subsequent attachment are found to increase as the rod lengthens. The increase in reaction rate correlates with increased dipole moment of longer rods which orients the rods end to end to maximize collision events. The two components of this reaction are alignment and fusion, with the former restricting attachment of low aspect ratio rods and the latter restricting attachment to higher aspect ratio rods. The model therefore predicts an aspect ratio "window" in which oriented attachment of nanorods is energetically possible. PMID- 20714582 TI - Influence of temperature on the structure and dynamics of the [BMIM][PF(6)] ionic liquid/graphite interface. AB - The influence of temperature on the structure and dynamics of the [BMIM][PF(6)] ionic liquid/graphite interface has been investigated by molecular dynamics simulations. The performed simulations cover a 100 K wide temperature interval, ranging from 300 K to 400 K. It was shown that the magnitudes of density peaks of anions in the vicinity of the surface decrease with increasing temperature while in the case of cations anomalous temperature behaviour of the density profile is observed: the magnitude of the second peak of cations increases with the increase of temperature. To characterize interface dynamics the local self-diffusion coefficients D(x) of ions in the normal direction to the surface and the residence time of ions in the first and second interfacial layer have been estimated. It was shown that the local self-diffusion coefficients in the vicinity of the surface correlate with the local ion density; the maxima of the function D(x)(x) for the cations (anions) coincide with the regions of reduced cation (anion) density and vice versa. Finally, the influence of temperature on the screening potential in the vicinity of a charged graphite surface has been studied. It was shown that the increase of temperature from 300 K to 400 K induces the decrease of the potential drop across the interface that implies the increase of the capacitance of the electrical double layer. PMID- 20714583 TI - Mapping of the organization of p-nitroaniline in SAPO-5 by second-harmonic generation microscopy. AB - Second-harmonic generation microscopy (SHGM) has been employed to study crystals of zeolite-like material SAPO-5 filled with p-nitroaniline (PNA). The SHG and 2 photon fluorescence response of PNA in the one-dimensional channels readily reveals the pore accessibility; intergrown crystallites containing hexagonal pyramidal components and internal diffusion barriers are found next to seemingly perfect crystals. The sensitivity of second-harmonic generation to molecular orientation allowed for mapping of the domains of differently organized PNA. Dense domains of highly aligned PNA alternate with dilute zones with loosely aligned PNA. PMID- 20714584 TI - Water structure at solid surfaces and its implications for biomolecule adsorption. AB - The ordered arrangement of water molecules at solid surfaces is a consequence of hydrogen-bonding opportunities, electrostatic and dipolar interactions, and specific interactions with the surface. This perspective highlights recent understanding of this water structure at the solid-liquid interface. We discuss findings from three experimental techniques (attenuated total internal reflection infrared spectroscopy, second harmonic generation spectroscopy, and vibrationally resonant sum-frequency generation spectroscopy) and two simulation approaches (molecular dynamics and Monte Carlo simulations). In each case, we also provide examples of how these techniques reveal the importance of interfacial water organization in rationalizing the structure of adsorbed biomolecules. PMID- 20714585 TI - Kinetics of the chemically activated HSO5 radical under atmospheric conditions--a master-equation study. AB - A detailed theoretical analysis of the HOSO(2) + O(2) reaction is performed, paying special attention to the kinetics of the intermediate HSO(5) radical. The possible formation of the monohydrated adduct, HSO(5).H(2)O, in the presence of water vapor is examined. For the binding energy of the most stable isomer at T = 0 K, a value of D(0)(HOSO(4)-H(2)O) = 51.7 kJ mol(-1) was obtained at the CCSD(T)/CBS level of theory; other energies were adopted from a recently published high-level quantum chemical study of our laboratory. Molecular geometries and vibrational frequencies of the reactants, intermediates, and products were obtained from B3LYP/cc-pVTZ calculations. Rate coefficients and lifetimes of the HSO(5) intermediate were calculated by solving a master equation with specific rate coefficients from statistical rate theory. The master equation is extended by a bimolecular sink term, which accounts for the HSO(5) + H(2)O reaction. The relation between thermal and chemical activation in this reaction system is examined. The results show that the lifetime of the HSO(5) intermediate under atmospheric conditions is too short for a bimolecular reaction with water to become important. Relative yields of HSO(5).H(2)O well below 1% were obtained, ruling out this reaction pathway as a relevant source for aerosols. PMID- 20714586 TI - A Langmuir-Schaefer approach for the synthesis of highly ordered organoclay thin films. AB - The Langmuir-Schaefer (LS) method has been investigated as a means to control the structure of hybrid organoclay thin films consisting of montmorillonite and dimethyldioctadecylammonium (DODA) cations. We observed a significant modification of the compression isotherms as a function of clay mineral concentration in the subphase, implying clay interaction with the alkylammonium monolayer. For a particular range of clay concentrations, LS hybrid monolayers could be readily prepared on a hydrophobic substrate. The structure of hybrid multilayers of DODA and clay platelets, prepared by repeated LS deposition, was found to be governed by the synthetic route: when the multilayer is fabricated by transferring the hybrid Langmuir films from the surface of the clay dispersion, the DODA-clay particles "flip over" while passing through the meniscus during the even cycles of the deposition, as demonstrated from the elemental analysis of the surface by X-ray photoelectron spectroscopy. In our new model for these multilayers, the structural building block consists therefore of two interdigited DODA layers and two clay layers held together by Na(+). Additionally, a minority phase forms, probably differing from the majority one in the conformation of the alkylammonium cations, and can be eliminated by annealing. This deposition procedure leads to a less ordered structure than an alternative route which combines LS deposition and self-assembly to produce a multilayer consisting of two interdigited DODA layers and one clay layer: here the hydrophilic surface of the transferred hybrid Langmuir film is converted to a hydrophobic surface by dipping into a solution of DODA cations before proceeding with the LS deposition of the next layer. PMID- 20714587 TI - Mechanistic insight into light-driven molecular rotors: a conformational search in chiral overcrowded alkenes by a pseudo-random approach. AB - Chiral overcrowded alkenes are capable of unidirectional rotation via a series of cis-trans photochemical and helix-inversion thermal steps. Using a pseudo-random conformational search we have located different ground state minima belonging to the potential energy surface of two different overcrowded alkenes that function as molecular rotors. The transition states connecting the minima allow identifying different reaction pathways which are possible in the thermal helix inversion steps. The mechanisms found for the two studied molecular rotors are different and provide a valuable insight into the conformational dynamics of the rotary cycle. While in one case the thermal step occurs via a single transition state, in the other, several intermediates are accessible. The associated energy barriers are in agreement with the experimental values, supporting the proposed mechanisms. PMID- 20714588 TI - Photodynamics in stable complexes composed of a zinc porphyrin tripod and pyridyl porphyrins assembled by multiple coordination bonds. AB - A tripod zinc porphyrin (TPZn(3)) forms a stable 1:1 complex with gold(III) tetra(4-pyridyl)porphyrin (AuTPyP(+)) and free-base tris(4-pyridyl)porphyrin (2H Py(3)P) in nonpolar solvents. The strong binding of TPZn(3) with AuTPyP(+) or 2H Py(3)P results from the encapsulation of AuTPyP(+) or 2H-Py(3)P inside the cavity of TPZn(3) through multiple coordination bonds, as indicated by UV-vis-NIR, ESI MS, (1)H NMR, electrochemistry and computational studies. The binding constants of monomer zinc porphyrin (MPZn) with AuTPyP(+) and 2H-Py(3)P drastically decrease as compared with TPZn(3). Detailed photophysical studies have been carried out on these composites using laser flash photolysis as well as emission spectroscopy. The efficient quenching of the singlet excited state of TPZn(3) occurs via a photoinduced electron-transfer pathway in the TPZn(3)-AuTPyP(+) complex. In contrast, energy transfer occurs in the TPZn(3)-2H-Py(3)P complex due to the smaller driving force of the photoinduced electron-transfer pathway. Neither electron transfer nor energy transfer occurs from MPZn to AuTPyP(+) under the same experimental conditions due to the small association constant of the monomer zinc porphyrin. PMID- 20714589 TI - Effect of interfacial curvature on the adsorption of copolymer stabilized nanoparticles of different copolymer compositions: a Brownian Dynamics study. AB - Block copolymer-stabilized nanoparticles placed in the presence of a curved oil water interface are described using Brownian Dynamics simulations. These simulations are targeted towards an exploration of the effect of geometry of the oil-water interface on the adsorption of the stabilized nanoparticle, and this goal is achieved by the systematic variation of the interfacial curvature, while exploring different block copolymer compositions. The contact angle, the order parameter and polymer density across the interface are used to assess the effect of a given block copolymer composition on the adsorption at the liquid-liquid interface. We find that the contact angle for a block-copolymer stabilized nanoparticle is affected by the curvature of the oil-water interface. This is a departure from earlier results of Komura et al. [J. Chem. Phys. 2006, 124, 241104], where the contact angle of a solid particle at a curved interface obeys the Young's formula for contact angle, in which case it is independent of the interfacial curvature. A part of the change of contact angle results from the increase of the radius of gyration of the nanoparticle due to the presence of the block copolymer. Furthermore, an investigation of the structure of the block copolymer and its distribution across the interface reveals changes as the curvature of the interface is changed, and those changes are reflected in different contact angle values. PMID- 20714590 TI - Methane activation by V3PO10(+) and V4O10(+) clusters: a comparative study. AB - A series of vanadium and phosphorus heteronuclear oxide cluster cations (V(x)P(y)O(z)(+)) are prepared by laser ablation and the reactions of V(3)PO(10)(+) and V(4)O(10)(+) with methane in a fast flow reactor under the same conditions are studied. A time of flight mass spectrometer is used to detect the cluster distribution before and after reactions. In addition to previously identified reaction of V(4)O(10)(+) + CH(4)-> V(4)O(10)H(+) + CH(3), the observation of hydrogen atom pickup cluster V(3)PO(10)H(+) suggests the reaction: V(3)PO(10)(+) + CH(4)-> V(3)PO(10)H(+) + CH(3). The rate of the reaction of V(4)O(10)(+) with CH(4) is approximately 2.5 times faster than that of V(3)PO(10)(+) with CH(4). Density functional theory (DFT) calculations predict that structure of V(3)PO(10)(+) is topologically similar to that of V(4)O(10)(+), as well as that of P(4)O(10)(+), which is very similar to V(4)O(10)(+) in terms of methane activation in previous studies. The facile methane activation by the homo- and hetero-nuclear oxide clusters can all be attributed to the presence of an oxygen-centered radical (O) in these clusters. Further theoretical study indicates that the O radical (or spin density of the cluster) can transfer within the high symmetry V(4)O(10)(+) and P(4)O(10)(+) clusters quite easily, and CH(4) molecule further enhances the rate of intra-cluster spin density transfer. In contrast, the intra-cluster spin density transfer within low symmetry V(3)PO(10)(+) is thermodynamically forbidden. The experimentally observed reactivity difference is consistent with the theoretical consideration of the intra-cluster spin density transfer. PMID- 20714591 TI - Density functional theory calculations on magnetic properties of actinide compounds. AB - We have performed a detailed analysis of the magnetic (collinear and non collinear) order and the atomic and electron structures of UO(2), PuO(2) and UN on the basis of density functional theory with the Hubbard electron correlation correction (DFT + U). We have shown that the 3-k magnetic structure of UO(2) is the lowest in energy for the Hubbard parameter value of U = 4.6 eV (and J = 0.5 eV) consistent with experiments when Dudarev's formalism is used. In contrast to UO(2), UN and PuO(2) show no trend for a distortion towards rhombohedral structure and, thus, no complex 3-k magnetic structure is to be anticipated in these materials. PMID- 20714592 TI - Direct electron transfer of glucose oxidase and biosensing of glucose on hollow sphere-nanostructured conducting polymer/metal oxide composite. AB - A hollow sphere-nanostructured conductive polymer/metal oxide composite was synthesized and used to investigate the electrochemical behavior of glucose oxidase, demonstrating a significantly enhanced direct electron transfer ability of glucose oxidase. In particular, the long-standing puzzle of whether enzymatic glucose sensing involves an enzyme direct electron transfer process was studied. The results indicate the mechanism is indeed a glucose oxidase direct electron transfer process with competitive glucose oxidation and oxygen reduction to detect glucose. A glucose biosensor with the glucose oxidase-immobilized nanomaterial was further constructed, demonstrating superior sensitivity and reliability, and providing great potential in clinical applications. PMID- 20714593 TI - Intramolecular competition in the photodissociation of C(3)D(3) radicals at 248 and 193 nm. AB - Motivated by recent experimental work, a theoretical study of the photodissociation of perdeuterated propargyl (D(2)CCD) and propynyl (D(3)CCC) radicals has been carried out, focusing on the C-C bond cleavage and D(2) loss channels. High-level ab initio calculations were carried out, and RRKM rate constants were calculated for isomerization and dissociation pathways. The resulting reaction barriers, microcanonical rate constants and product branching ratios are consistent with the experimental findings, supporting the overall mechanism of internal conversion followed by statistical dissociation on the ground state surface. We found loose transition states and very low exit barriers for two of the C-C bond cleavage channels and an additional CD(2) + CCD channel, which had not been reported previously. Our results probe the extent of propargyl and propynyl isomerization prior to dissociation at 248 and 193 nm and deliver a comprehensive picture of all ongoing molecular dynamics. PMID- 20714595 TI - A spiro-configured ambipolar host material for impressively efficient single layer green electrophosphorescent devices. AB - A spiro-configured bipolar molecule (CSC) that possesses high triplet energy, suitable energy levels, and balanced ambipolar carrier mobilities was successfully applied as an efficient host material, compatible with various iridium-based green phosphors, to realize highly efficient single-layer PhOLEDs of a maximum external quantum efficiency up to 8.3% (31.4 cd A(-1)) at a practical brightness of 1000 cd m(-2) (8 V). PMID- 20714594 TI - Studies of one and two component aerosols using IR/VUV single particle mass spectrometry: Insights into the vaporization process and quantitative limitations. AB - This paper presents the studies of one and two component particles using a CO(2) laser for vaporization and VUV ionization in an ion trap mass spectrometer. The degree of fragmentation for a one component system was demonstrated to be a function of CO(2) laser energy. In a two component system, the degree of fragmentation was shown to be a function of the particle composition. This observation indicates that the analysis of mixed particles may be far more complicated than anticipated for a two step process with soft vaporization. In addition to showing that fragmentation is a function of CO(2) laser energy and particle composition, we also show that a key parameter that determines the extent of fragmentation is the energy absorbed by the particle during desorption. The ionization delay profile in a one component system is also shown to be strongly dependent on the vaporization energy. In a two component system, the delay profile is shown to strongly depend on the composition of the particle. The combined data suggest that the key parameter that governs the delay profile is the energy absorbed by the particle during desorption. This finding has implications for potential field measurements. Finally, for a two component system where the absorption crosssections are different, the change in the degree of fragmentation with particle composition resulted in a non-linear dependence of ion signal on composition. This makes any attempt at quantification difficult. PMID- 20714596 TI - Hot plasmonic interactions: a new look at the photothermal efficacy of gold nanoparticles. AB - The photothermal (PT) outputs of individual gold nanoparticles (NP) were compared at room (cold) and high transient (hot) temperatures. High temperatures were induced in NPs by a single 0.5 ns laser pulse. All NPs with near-infrared plasmon resonances (rods, shells and bi-pyramids) exhibited a significant decrease in their photothermal output at the resonant wavelengths under high temperature, while non-resonant excitation of the same NPs provided several times higher PT efficacy of the hot NPs. This "inversion" of the PT efficacy of hot plasmonic NPs near their plasmon resonances might have been caused by damping of their resonances due to heating and surface melting. Therefore, photothermal output of plasmonic nanoparticles significantly depends upon their thermal state including the shift in excitation wavelength in hot nanoparticles. In particular, NPs with near-infrared resonances perform several times more efficiently at non-resonant excitation wavelengths rather than at the resonant ones. PMID- 20714597 TI - A numerical study of one-patch colloidal particles: from square-well to Janus. AB - We perform numerical simulations of a simple model of one-patch colloidal particles to investigate: (i) the behavior of the gas-liquid phase diagram on moving from a spherical attractive potential to a Janus potential and (ii) the collective structure of a system of Janus particles. We show that, for the case where one of the two hemispheres is attractive and one is repulsive, the system organizes into a dispersion of orientationally ordered micelles and vesicles and, at low temperature (T), the system can be approximated as a fluid of such clusters, interacting essentially via excluded volume. The stability of this cluster phase generates a very peculiar shape of the gas and liquid coexisting densities, with a gas coexistence density that increases on cooling, approaching the liquid coexistence density at very low T. PMID- 20714598 TI - Formation of magnetic nanotubes by the cooperative self-assembly of chiral amphiphilic molecules and Fe3O4 nanoparticles. AB - Single- and double-walled magnetic nanotubes are obtained in a one-step liquid phase reaction by the cooperative self-assembly of chiral amphiphiles and nanoparticles on cooling of heated mixtures of N-dodecanoyl-L-serine and Fe(3)O(4) nanoparticles in toluene. The nanotubes are composed of well-ordered, close-packed nanoparticle assemblies, and can be transformed into chiral magnetic nanostructures, such as helical coils, by subsequent calcination. The nanoparticle assemblies and their variations on calcination are attributed to the collective organization of the surfactant molecules adsorbed on the nanoparticles and the freely dispersed chiral molecules, and the dewetting effects guided by the primitive constitution of the chiral amphiphilic molecular assemblies. PMID- 20714599 TI - Inhibition of efflorescence in mixed organic-inorganic particles at temperatures less than 250 K. AB - It is now well recognized that mixed organic-inorganic particles are abundant in the atmosphere. While there have been numerous studies of efflorescence of mixed organic-inorganic particles close to 293 K, there are only a few at temperatures less than 273 K. Understanding the efflorescence properties of these particles at temperatures less than 273 K could be especially important for predicting ice nucleation in the upper troposphere. We studied the efflorescence properties of mixed citric acid-ammonium sulfate particles as a function of temperature to better understand the efflorescence properties of mixed organic-inorganic particles in the middle and upper troposphere. Our data for 293 K illustrate that the addition of citric acid decreases the ERH of ammonium sulfate, which is consistent with the trends observed with other systems containing highly oxygenated organic compounds. At low temperatures the trend is qualitatively the same, but efflorescence can be inhibited by smaller concentrations of citric acid. For example at temperatures <250 K an organic mass/(organic mass + sulfate mass) of only 0.33 is needed to inhibit efflorescence of ammonium sulfate. In the upper troposphere the organic mass/(organic mass + sulfate mass) can often be larger than this value. As a result, particles in the upper troposphere may be more likely to remain in the liquid state than previously thought and solid ammonium sulfate may be less likely to participate in heterogeneous ice nucleation in the upper troposphere. Additional studies are required on other model organic systems. PMID- 20714600 TI - Drop sizes and particle coverage in emulsions stabilised solely by silica nanoparticles of irregular shape. AB - We have investigated emulsions stabilised solely by partially-hydrophobised fumed silica particles which consist of a mixture of primary particles and irregularly shaped fused aggregates and larger agglomerates. The particle wettability is controlled by varying the extent of hydrophobisation of their surfaces. This, in turn, controls the contact angle between the oil-water interface and the particle surface (theta(ow)) which affects the particle adsorption energy and the type of emulsion formed (oil-in-water, o/w or water-in-oil, w/o). Progressive particle hydrophobisation causes transitional phase inversion of the emulsions from o/w to w/o which occurs when theta(ow) = 90 degrees and the energy of particle adsorption to the oil-water interface is maximally favourable. The key problem addressed here is to understand why the emulsion drop size passes through a minimum at the point of emulsion phase inversion. In principle, this effect could be the result of particle desorption, changes in the extent of close-packing of the adsorbed particle film (at constant particle orientation), particle re orientation or a combination of these processes. Using measurements of emulsion drop size and the extent of particle desorption, we have derived adsorbed particle surface concentrations as a function of the energy of desorption of the particles from the oil-water interface for a range of particle concentrations and different oil-water systems. The main conclusion is that the minimum in emulsion drop size through phase inversion is mainly caused by re-orientation of the particles from a high surface area orientation when the energy of desorption is high to a low surface area orientation when the energy of desorption is low. Some particle desorption occurs but this is a secondary effect. PMID- 20714602 TI - Kinetics and mechanism of the atmospheric reactions of atomic chlorine with 1 penten-3-ol and (Z)-2-penten-1-ol: an experimental and theoretical study. AB - Smog chamber/GC techniques were used to investigate the atmospheric degradation of two unsaturated alcohols, 1-penten-3-ol and (Z)-2-penten-1-ol, by oxidation with chlorine atoms at atmospheric pressure of N(2) or air, as a function of temperature. The rate coefficients at 298 K were (units in cm(3) molecule(-1) s( 1)): (2.35 +/- 0.31) * 10(-10) and (3.00 +/- 0.49) * 10(-10) for 1-penten-3-ol and (Z)-2-penten-1-ol, respectively. The identified and quantified gas-phase products (with molar yields in brackets) were carbonyl compounds such as chloroacetaldehyde (33 +/- 1%), propionaldehyde (39 +/- 1%), acetaldehyde (8 +/- 3%) and 1-penten-3-one (2%) from 1-penten-3-ol; and chlorobutyraldehyde (19 +/- 1%), propionaldehyde (27 +/- 1%), acetaldehyde (18 +/- 2%) and (Z)-2-pentenal (36 +/- 1%) from (Z)-2-penten-1-ol. A parallel theoretical study at the QCISD(T)6 311G**//MP2/6-311G** level was carried out to facilitate understanding of the reaction mechanism. Both the theoretical and experimental studies indicated that addition of Cl to the double bond of the unsaturated alcohol is the dominant reaction pathway, although the H-abstraction channel cannot be excluded. The atmospheric lifetimes of those unsaturated alcohols were calculated and the results are discussed. PMID- 20714601 TI - Formation dynamics and nature of tryptophan's primary photoproduct in aqueous solution. AB - The excited state quenching and photoproduct formation of tryptophan in water is studied by femtosecond transient absorption experiments covering the near-UV and Vis range of wavelengths. The quenching of the excited state absorption occurs simultaneously with the rise of a photoproduct characterized by two absorption bands at 350 nm and 425 nm. Both processes are characterized by the same biexponential kinetics, and the time constants found are in excellent agreement with previous time-resolved fluorescence measurements. By varying the pH and comparing with the transient spectra of Trp incorporated in a peptide where electron transfer is the dominant quenching mechanism, we suggest that the photoproduct is a zwitterionic form of Trp with the indole moiety protonated, formed via excited state proton transfer from the side chain amine group, in agreement with conclusions drawn from nanosecond experiments. The present work thus fills the gap between ultrafast fluorescence decay and nanosecond flash photolysis experiments, and pinpoints Trp's fluorescence quenching mechanism at acidic and neutral pH. PMID- 20714603 TI - Phase covariance in NMR signal. AB - To examine noisy nuclear-magnetic resonance (NMR) spectra, we have developed a novel signal analysis method based on phase correlation between the NMR signal and the excitation pulse. The new phase-covariance analysis is compatible with the conventional signal accumulation, and successful de-noising is demonstrated. PMID- 20714604 TI - Infrared spectra and quantum chemical characterization of weakly bound clusters of the benzoyl cation with Ar and H(2)O. AB - Weakly-bound clusters of the closed-shell benzoyl cation (C(6)H(5)CO(+), PhCO(+)) with Ar and H(2)O are investigated by infrared (IR) spectroscopy, mass spectrometry, and quantum chemical calculations in order to characterize the interaction of a closed shell aromatic cation with a nonpolar and a polar ligand. PhCO(+)-L dimers are produced by electron ionization of benzaldehyde in a supersonic plasma expansion. IR photodissociation (IRPD) spectra of PhCO(+)-L with L = Ar and H(2)O are analyzed in the C-O, C-H, and O-H stretch ranges (2000 3900 cm(-1)). The potential energy surface of the PhCO(+)-L dimers is characterized at the MP2/6-311++G(2df,2pd) level to locate the various minima and determine their energetic and vibrational properties. PhCO(+)-Ar prefers intermolecular pi-bonding to the aromatic ring with a bond energy of D(0) = 6 kJ mol(-1). The weak interaction implies that the IRPD spectrum of PhCO(+)-Ar is very close to the IR spectrum of bare PhCO(+). The detection of the C-H and C-O stretch fundamentals provides valuable information about the C-O and C-H bond strengths in this prototypical aromatic acylium ion. Moreover, a variety of weak combination and overtone bands are assigned. The global minimum on the PhCO(+) H(2)O potential has a planar charge-dipole configuration with D(0) = 41 kJ mol( 1) (with only the two H(2)O protons being out-of-plane), in which the lone pairs of H(2)O interact with the positive partial charges on the carbonyl carbon atom and the proton of the CH group in ortho position. The experimental IRPD spectra are in accord with the calculated global minima. The analysis of the charge distribution shows that the PhCO(+) cation is best represented as an oxocarbenium ion (Ph-C(+)[double bond, length as m-dash]O) with smaller contributions of the ketene structure (Ph(+)[double bond, length as m-dash]C[double bond, length as m dash]O). This view is supported by the geometrical and vibrational properties of PhCO(+) as well as the shape of the intermolecular PhCO(+)-L dimer potentials. PMID- 20714605 TI - Geminate recombination of hydrated electrons in liquid-to-supercritical water studied by ultrafast time-resolved spectroscopy. AB - Hydrated electrons were prepared by multi-photon ionization of neat water with 266 nm light. Using femtosecond pump-probe spectroscopy the dynamics of geminate recombination of the solvated electrons were studied over a wide temperature (296 K <=T<= 660 K) and density (0.18 g cm(-3)<=rho<= 1.00 g cm(-3)) range extending from the liquid well into the supercritical phase of water. The probability that hydrated electrons escape an initial recombination was found to strongly decrease with increasing temperature. In contrast, the isothermal density-dependence of this survival probability above the critical temperature was surprisingly weak. The peculiar dependence of the initial electron annihilation process on the thermodynamic state variables is discussed in terms of the Onsager model for initial recombination of ion pairs and an effective shielding of the electrostatic interactions of the recombining partners. A finite escape probability for a dielectric constant approaching unity can be interpreted by the existence of a minor fraction of highly mobile electrons created via autoionization. PMID- 20714606 TI - Influence of electrostatic fields on molecular electronic structure: insights for interfacial charge transfer. AB - Molecular and interfacial electronic structure at organic semiconductor interfaces shows a rich and subtle dependence on short- and long-range electrostatic interactions. Interface dipoles can be controlled making use of the anisotropic charge distribution at the interface, often with direct consequences also for the molecular electronic structure. In this Perspective, we will discuss the emerging understanding of how local and collective electrostatic effects control energy level alignment and molecular electronic structure at organic semiconductor interfaces and highlight some of the ramifications for interfacial charge-transfer dynamics. Attention is paid to the validity of the underlying assumptions inherent to the classical electrostatic approach. PMID- 20714607 TI - Specific cellular water dynamics observed in vivo by neutron scattering and NMR. AB - Neutron scattering, by using deuterium labelling, revealed how intracellular water dynamics, measured in vivo in E. coli, human red blood cells and the extreme halophile, Haloarcula marismortui, depends on the cell type and nature of the cytoplasm. The method uniquely permits the determination of motions on the molecular length (approximately angstrom) and time (pico- to nanosecond) scales. In the bacterial and human cells, intracellular water beyond the hydration shells of cytoplasmic macromolecules and membrane faces flows as freely as liquid water. It is not "tamed" by confinement. In contrast, in the extreme halophile archaeon, in addition to free and hydration water an intracellular water component was observed with significantly slowed down translational diffusion. The results are discussed and compared to observations in E. coli and Haloarcula marismortui by deuteron spin relaxation in NMR--a method that is sensitive to water rotational dynamics on a wide range of time scales. PMID- 20714608 TI - Themed issue on bioelectrochemistry. PMID- 20714609 TI - Unusual azobenzene/bipyridine palladacycles: structural, dynamical, photophysical and theoretical studies. AB - Two types of Pd(ii) azobenzene/bipyridine complexes with unusual coordination mode of azobenzenes, PdCl{(mu-Cl)(mu-R(1)C(6)H(3)N=NC(6)H(3)R(2))}Pd(bpy) 1a-4a and [(bpy)PdCl(mu-NH(2)C(6)H(3)N=NC(6)H(4))Pd(bpy)]Cl 3b were formed by the reaction of dicyclopalladated azobenzenes (DMF)PdCl(mu R(1)C(6)H(3)N=NC(6)H(3)R(2))PdCl(DMF) with excess of bpy, where bpy=2,2' bipyridine; R(2)=H and R(1)=H (1), CH(3) (2), NH(2) (3) or R(1)=N(CH(3))(2) and R(2)=NO(2) (4). Neutral species 1a-4a were obtained in acetone, while in DMSO or MeOH the ionic complex 3b was produced. When dissolved, 3b decomposes to 3a and free bpy; however in DMSO upon addition of bpy 3b crystallizes again. X-ray structures of all complexes confirmed breaking of one Pd-N bond in the initial precursors, thus allowing rotation of one phenyl ring and positioning of both Pd atoms on the same side of the azobenzene ligand. Two Pd atoms are connected by the azobenzene ligand and in neutral complexes additionally by the Cl-bridge. In all complexes in the solid-state azobenzenes act simultaneously as monodentate C- and bidentate C,N-donors while bpy acts as bidentate donor. Variable-temperature (1)H NMR experiments established that structures of 1a-4a in DMF and DMSO at ambient temperature are not consistent with solid-state structures due to the fast exchange of one of the bpy nitrogen atoms bound to the Pd atom with solvent molecules. Theoretical studies confirmed the experimental structures as the most stable isomers. Photoabsorption and photoemission properties of the new complexes have been measured and photoabsorption is rationalized by time dependent DFT calculations. The presence of bpy significantly increases the intensity of fluorescence either in the solution (4a) or in the solid state (3a, 4a, 3b) at ambient temperature. PMID- 20714610 TI - PdCl(2)-promoted reactions of diaryl-substituted methylenecyclopropanes. AB - The PdCl(2)-promoted reactions of methylenecyclopropanes (MCPs) 1 bearing diaryl substituents on the terminal double bond were carefully investigated. The solvents employed significantly affected the reaction outcomes. It was found that dimeric allylpalladium(ii) complexes 2a-2f can be obtained as the sole products in acceptable to good yields under mild reaction conditions with THF as the solvent, while dimeric allylpalladium(ii) complexes 2a-2f along with another type of dimeric allylpalladium(ii) complexes 4a-4e can be obtained in good to high total yields if N,N-dimethylacetamide (DMAc) was used as the solvent. Moreover, using N,N-dimethylformamide (DMF) as the solvent in the presence of water, it was found that water can also participate in the reaction to form another type of dimeric allylpalladium(ii) complex 6 as the minor product. All of these dimeric allylpalladium(ii) complexes reported in the paper have been characterized by X ray crystal structure diffraction. PMID- 20714611 TI - Reversible single-crystal to single-crystal transformations in a Hg(II) derivative. 1D-polymeric chain <=>2D-networking as a function of temperature. AB - Reactions of HgX(2) (X = Cl(-), Br(-), l(-)) with the ligand hep-H (hep-H = 2-(2 hydroxyethyl)pyridine) in methanol at 298 K result in 1D-polymeric chains of [(X)Hg(mu-X)(2)(hep-H)](infinity), 1-3, respectively, where hep-H binds to the Hg(ii) ions in a monodentate fashion exclusively with the pyridine nitrogen donor and the suitably ortho-positioned -(CH(2))(2)OH group of hep-H remains pendant. The packing diagrams of 1-3 exhibit extensive intramolecular and intermolecular hydrogen bonding interactions leading to hydrogen bonded 2D network arrangement in each case. Though the single crystal of either 2 (X = Br) or 3 (X = I) loses crystallinity upon heating, the single crystal of 1 selectively transforms to a 2D-polymeric network, 4 on heating at 383 K for 1.5 h. The polymeric 4 consists of central dimeric [Hg(mu(3)-Cl)(hep-H)Cl](2) units, which are covalently linked with the upper and lower layers of [-(mu-Cl)(2)-Hg-(mu-Cl)(2)-Hg(mu-Cl)(2)-](n). The packing diagram of 4 reveals the presence of O-H-Cl and C-H-Cl hydrogen bonding interactions which in effect yields hydrogen bonded 3D-network. Remarkably, the single crystals of 4 convert back to the single crystals of parent 1 on standing at 298 K for three days. PMID- 20714612 TI - Fluorinated dienes in transition-metal chemistry - the rich chemistry of electron poor ligands. AB - The coordination chemistry of alkenes is among the fundamentals of organometallic chemistry. However, despite the beneficial effects of fluorination to organic molecules, their fluorinated counterparts are rarely found in transition-metal complexes and most examples are limited to simple monoalkenes like tetrafluoroethene. The paucity of fluorodiene complexes is contrasted by their structural diversity. Seemingly similar dienes containing conjugated, isolated or cumulated double bonds exhibit largely different ligand properties. While the most prominent group, the conjugated fluorodienes, is very flexible in hapticity, their analogues bearing isolated double bonds behave more like monoalkenes. Fluorinated cumulenes in contrast are thermally labile, their chemistry is dominated by the stabilising effect of metal coordination. This review outlines the synthesis, structure and reactivity of transition-metal complexes derived from fluorinated dienes. PMID- 20714613 TI - Competition between histamine-like and poly-imidazole coordination sites for Cu(2+) and Zn(2+) ions in zebra-fish peptide of prion-like protein. AB - The fragment of the zebrafish prion-like protein (PrP-rel-2), encompassing residues 74-86 and unprotected at N-terminus (zf74-86) represents a good model to understand Cu(2+) and Zn(2+) binding to ligands containing multi-potential metal donor sites. Zf(74-86) contains four His and His-1 N-terminal amine groups which constitute both copper and zinc anchoring sites. The presence of His at the first position additionally provides the histamine-like binding mode which could compete with the multi-His binding mode. In this study the speciation profiles of the Cu(2+) and Zn(2+) complexes with zf74-86 have been obtained. The main species, dominating at physiological pH, have been fully characterized by using different spectroscopic techniques. The detected NMR chemical shift variations and line broadening enhancements, caused by Zn(2+) and Cu(2+) respectively, allowed to determine the metal binding sites. Both metal ions showed common binding donor atoms, being 2 or 3 His imidazoles and the N-terminal group involved in Cu(2+) and Zn(2+) binding. PMID- 20714614 TI - At the frontier between heterogeneous and homogeneous catalysis: hydrogenation of olefins and alkynes with soluble iron nanoparticles. AB - The use of non-supported Fe nanoparticles in the hydrogenation of unsaturated C-C bonds is a green catalytic concept at the frontier between homogeneous and heterogeneous catalysis. Iron nanoparticles can be obtained by reducing Fe salts with strong reductants in various solvents. FeCl(3) reduced by 3 equivalents of EtMgCl forms an active catalyst for the hydrogenation of a range of olefins and alkynes. Olefin hydrogenation is relatively fast at 5 bar using 5 mol% of catalyst. The catalyst is also active for terminal olefins and 1,1' and 1,2-cis disubstituted olefins while trans-olefins react much slower. 1-Octyne is hydrogenated to mixtures of 1-octene and octane. Kinetic studies led us to propose a mechanism for this latter transformation where octane is obtained by two different pathways. Characterization of the nanoparticles via TEM, magnetic measurements and poisoning experiments were undertaken to understand the true nature of our catalyst. PMID- 20714615 TI - Iron indenyl carbonyl compounds: CO-releasing molecules. AB - New CO-releasing molecules, CO-RMs, based on indenyl iron carbonyls have been identified. Half-lives for carbon monoxide (CO) release, (1)H NMR, (13)C NMR, IR, mass spectra, elemental analysis and biological data have been determined for the compounds. Limited correlations have been made between half-lives and DeltaG(?) for CO release and spectroscopic parameters, nu(CO) and delta((13)CO). X-ray structures have been determined for [Fe(eta(5)-C(9)H(7))(CO)(2)L][BF(4)] where L is CO, NCMe, PPh(3), P(OPh)(3), NC(5)H(5) or 1-methylimidazole. Improved preparations of [Fe(eta(5)-C(9)H(7))(CO)(2)](2) and [Fe(eta(5) C(9)H(7))(CO)(3)][BF(4)] are reported. PMID- 20714616 TI - Novel heterobimetallic thiocarboxylato complexes: synthesis, characterization and application as single source precursor for ternary chalcogenides. AB - Heterobimetallic complexes, (PPh(3))(2)M(mu-SCOPh)(2)Pb(SCOPh) [where, M = Cu(I) (1) or Ag(I) (2)] have been synthesized and characterized by FTIR, (1)H, (13)C and (31)P NMR spectroscopy. Molecular structures in solid state have been determined by single crystal X-ray diffraction. Electronic spectra of the compounds have been recorded and explained on the basis of TDDFT calculations. Luminescence and redox properties of the complexes have also been studied. Following the thermogravimetric analysis data the compounds were pyrolysed and one of the decomposition products has been characterized as Pb(4)Cu(5)O(22.6) (3) by SEM-EDX and X-ray diffraction studies. PMID- 20714617 TI - Intramolecular pi-stacking in copper(I) diketiminate phenanthroline complexes. AB - Diketimines N,N'-dibenzyl-2-amino-4-imino-pent-2-ene (1), S,S-N,N' di(phenylethyl)-2-amino-4-imino-pent-2-ene (2), N,N'-bis(3,4,5 trimethoxyphenylmethyl)-2-amino-4-imino-pent-2-ene (3), N,N' bis(pentafluorophenylmethyl)-2-amino-4-imino-pent-2-ene (4) and N,N'-diisobutyl-2 amino-4-imino-pent-2-ene (5) react with CuOtBu in the presence of 2,9-R2-1,10 phenanthroline to give the respective neutral, tetracoordinated diketiminate copper(I) phenanthroline complexes 1a+2a (R = H), 1b, 3b-5b (R = Me) and 1c+3c (R = Ph). Crystal structures were obtained for all complexes except 5b and intramolecular pi-stacking between the phenanthroline ligand and one or two N benzyl substituents were observed in 1a, 2a, 1b and 1c, or 3b and 4b, respectively. UV/vis absorption spectra show two transitions in the visible region, a diketiminate-based transition at 373-386 nm and a transition at 600-666 nm, tentatively assigned as an MLCT to phenanthroline. All complexes were weakly luminescent in the solid state at room temperature with lifetimes of less than 60 ns. Weak luminescence was also observed in solution with lambdamax = 720-830 nm for 1b, 1c, 3b, 4b and 5b and short luminescence lifetimes. Intramolecular pi stacking interactions, which prevent flattening distortions in the solid state, appear to have advantageous effects on luminescence intensities. PMID- 20714618 TI - The dehydrogenation of ammonia-borane catalysed by dicarbonylruthenacyclic(II) complexes. AB - The reactivity of ruthenacyclic compounds towards ammonia-borane's dehydrogenation was investigated by considering both hydrolytic and anhydrous conditions. The study shows that the highly soluble MU-chlorido dicarbonylruthenium(II) dimeric complex derived from 4-tert-butyl,2-(p tolyl)pyridine promotes, with an activation energy E(a) of 22.8 kcal mol(-1), the complete hydrolytic dehydrogenation of NH(3)BH(3) within minutes at ca. 40 degrees C. The release of 3 eq. of H(2) entails the formation of boric acid derivatives and the partly reversible protonolysis of the catalyst, which produces free 2-arylpyridine ligand and a series of isomers of "Ru(CO)(2)(H)(Cl)". Under anhydrous conditions, hydrogen gas release was found to be slower and the dehydrogenation of NH(3)BH(3) results in the formation of conventional amino-borane derivatives with concomitant protonolysis of the catalyst and release of isomers of "Ru(CO)(2)(H)(Cl)". The mechanism of the protonolysis of the ruthenacycle was investigated with state-of-the-art DFT-D methods. It was found to proceed by the concerted direct attack of the catalyst by NH(3)BH(3) leading either to the formation of a coordinatively unsaturated "Ru(CO)(2)(H)(Cl)" species. The key role of "Ru(CO)(2)(H)(Cl)" species in the dehydrogenation of ammonia-borane was established by trapping and quenching experiments and inferred from a comparison of the catalytic activity of a series of dicarbonylruthenium(II) complexes. PMID- 20714620 TI - 2-Pyridyl selenolates of antimony and bismuth: Synthesis, characterization, structures and their use as single source molecular precursor for the preparation of metal selenide nanostructures and thin films. AB - Reactions of SbCl(3) and BiCl(3) with M'Se-C(5)H(3)(R-3)N (M' = Li or Na; R = H or Me) gave homoleptic selenolate complexes of the general formula [M{Se C(5)H(3)(R-3)N}(3)] (M = Sb or Bi). The complexes were characterized by elemental analysis, UV-vis and NMR ((1)H, (13)C and (77)Se) spectroscopy. The single crystal X-ray analysis of [M{Se-C(5)H(3)(Me-3)N}(3)].nH(2)O (M/n = Sb/1.5 and Bi/0.5) revealed that the antimony complex adopts a trigonal pyramidal configuration with monodentate selenolate ligands while the bismuth analogue acquires a distorted square pyramidal configuration defined by two chelating and one monodentate selenolate groups. Pyrolysis of [M{Se-C(5)H(3)(Me-3)N}(3)] either in a furnace or in hexadecylamine (HDA) at different temperatures gave a variety of M(2)Se(3) nanostructures. Thin films of metal selenides have also been deposited on glass substrate by aerosol-assisted chemical vapor deposition (AACVD). Both nanostructures and thin films of metal selenides were characterized by UV-vis spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX) and transmission electron microscopy (TEM). PMID- 20714619 TI - C@ZnO nanorod array-based hydrazine electrochemical sensor with improved sensitivity and stability. AB - ZnO nanorod array grown directly on an inert alloy substrate has been modified with carbon by a simple immersion-calcination route and further used as the working electrode to construct a hydrazine sensor. The C@ZnO nanorod array-based sensor demonstrates a very high sensitivity of 9.4 muA muM(-1) cm(-2) and a low detection limit of 0.1 muM. The improved electrochemical properties are proposed to result from the synergy between the carbon layer and nanorod array, which can increase the ZnO electrocatalytic activity and promote the electron transport along the one-dimensional (1D) pathway, respectively. In particular, the carbon layer on ZnO nanorods also improves the sensor stability for successive usage due to the high chemical stability of carbon. The present study demonstrates the facile design of a promising electrode material for a hydrazine sensor and sheds light on the performance optimization of other electrochemical devices. PMID- 20714621 TI - ECL performance of ruthenium tris-bipyridyl complexes covalently linked with phenothiazine through different bridge. AB - Three ruthenium complexes 1a, 1b and 1c were synthesized, in which the phenothiazine moiety was covalently linked to the ruthenium complex through a 4 carbon chain and amide bond, respectively. The results demonstrate that one PTZ moiety is preferred to reach a good ECL performance, and the 4 carbon chain linked complex 1a exhibits the highest ECL enhancement (up to about 9 times), in comparison with the commonly utilized parent Ru(bpy)(3)(2+), permitting a lower detection limit of 1.0 x 10(-14) M with signal to noise of 3 for 20 mM DBAE at Au electrode. PMID- 20714622 TI - Two additive-induced isomeric aluminoborates templated by methylamine. AB - Two additive-induced isomeric aluminoborates, (CH(3)NH(3))(2)(H(2)O)(2)[Al(B(5)O(10))] (1) and (CH(3)NH(3))(H(2)O)[Al(B(5)O(10))] (2), have been obtained by using small methylamine molecules as structure directing agents (SDA) under solvothermal conditions and characterized by elemental analysis, IR, TGA, powder X-ray diffraction, single-crystal X-ray diffraction, NLO determination, UV-vis spectral investigation, electronic structure calculation and ion exchange. Different arrangements of B(5)O(10) units and AlO(4) tetrahedra results in two different structures with two pairs of helical channels along [100] and [010] directions, respectively. Interestingly, the two frameworks with noncentrosymmetric and chiral space groups separately exhibit the same diamond topologies and display good second harmonic generation efficiencies of about 2.0 times the value of KDP. PMID- 20714623 TI - The co-ordination chemistry of bis(2,2'-bipyrid-6'-yl)ketone with first row transition metals: the reversible interconversion of a mononuclear complex and a dinuclear hemiketal containing species. AB - Bis(2,2'-bipyrid-6'-yl)ketone has been shown to co-ordinate to Zn(II) to form either a dinuclear hemiketal complex in methanol solutions or mononuclear complexes in acetonitrile. The ligand readily complexes to the late transition metals in acetonitrile to yield mononuclear complexes (Mn(II), Co(II), Ni(II),Zn(II) and Cd(II)) however for Fe(II) only dinuclear complexes [Fe(2){(2 bipy)(2)C(OMe)O(-)}(2)][ClO(4)](2) could be isolated. The solid state structures of the mononuclear complexes exhibit varying degrees of distortion compared to an anticipated planar array of bipyridyl donors. PMID- 20714624 TI - Synthesis of N,N'-bis(thioether)-functionalized imidazolium salts: their reactivity towards Ag and Pd complexes and first S,C(NHC),S free carbene. AB - The synthesis of bis(thioether)-functionalized imidazolium salts, the characterisation of the first S,C(NHC),S free carbene ligand and the corresponding Ag(i) and Pd(ii) functional carbene complexes are reported. The latter have been prepared from the isolated Ag(i) carbene complexes using the transmetallation procedure or by reaction of the imidazolium salts with [PdCl(2)(COD)], followed by deprotonation of the intermediate in which both thioether functions are coordinated to Pd(ii). PMID- 20714625 TI - Rapid assembly of explicit, functional silicones. AB - The impressive surface activity of silicones can be enhanced by the incorporation of hydrophilic organic functional groups and polymers. Traditional routes to such compounds, which typically involve platinum-catalyzed hydrosilylation, suffer from incompatibility with certain functional groups. B(C(6)F(5))(3)-catalyzed condensation of hydrosilanes with alkoxysilanes offers new opportunities to prepare explicit silicone structures. We demonstrate here that conversion of alcohols to silyl ethers competes unproductively with alkoxysilane conversion to disiloxanes. By contrast, a wide range of structurally complex alkyl halide and oligovinyl compounds can be readily made in high yield. Thermal 3+2 cycloadditions and thiol-ene click reactions are used to convert these compounds into surface active materials. PMID- 20714626 TI - Oxidation of formic acid on the Pt(111) surface in the gas phase. AB - Formic acid (HCOOH) oxidation on Pt(111) under gas-phase conditions is a benchmark heterogeneous catalysis reaction used to probe electro-catalytic HCOOH conversion in fuel cells, itself an important reaction in energy conversion. We used density functional theory (DFT) calculations to elucidate the fundamental oxidation mechanisms of HCOOH in the gas phase, determining the relative strengths of chemical interactions between HCOOH oxidation intermediates and the Pt(111) surface. We focused on investigating how water and adsorption coverage affects reaction intermediate structures and transition states. Our results show that adsorbed HCOO is a reactive intermediate in gas phase, and co-adsorbed water plays a key role in HCOOH oxidation influencing the structure of reaction intermediates and reaction barriers on Pt(111). The simulations show the preferred catalytic pathway is qualitatively dependent on surface coverage. These results provide a conceptual basis to better interpret its complicated experimental reaction kinetics. PMID- 20714627 TI - An inconvenient influence of iridium(III) isomer on OLED efficiency. AB - The recently reported heteroleptic cyclometallated iridium(III) complex [Ir(2 phenylpyridine)(2)(2-carboxy-4-dimethylaminopyridine)] N984 and its isomer N984b have been studied more in detail. While photo- and electrochemical properties are very similar, DFT/TDDFT calculations show that the two isomers have different HOMO orbital characteristics. As a consequence, solution processed OLEDs made using a mixture of N984 and isomer N984b similar to vacuum processed devices show that the isomer has a dramatic detrimental effect on the performances of the device. In addition, commonly used thermogravimetric analysis is not suitable for showing the isomerization process. The isomer could impact performances of vacuum processed OLEDs using heteroleptic cyclometallated iridium(III) complexes as dopant. PMID- 20714628 TI - A strong red-emitting carbazole based europium(III) complex excited by blue light. AB - A novel 2-positional linked carbazole based beta-diketone with methoxyl in the 7 position (EMOCTFBD), and its europium(III) ternary complex Eu(EMOCTFBD)(3)phen were synthesized via a dexterously designed indirect routine, where EMOCTFBD was 1-(9-ethyl-7-methoxyl-9H-carbazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and phen was 1,10-phenanthroline. Eu(EMOCTFBD)(3)phen shows high thermal stability. The introduction of a methoxyl in the 7-position of the carbazole ring remarkably enhanced the excitation band intensity in the blue region, and the complex exhibited intense red emission under blue-light excitation. The lowest triplet state energy was measured and suggests the photoluminescence process as a ligand sensitized luminescence process (antenna effect). A bright red-emitting diode was fabricated by coating the complex phosphor onto a ~460 nm-emitting InGaN chip. All the results indicate that Eu(EMOCTFBD)(3)phen is an interesting red-emitting material excited by blue light, and therefore may be applied in many fields without UV radiation. PMID- 20714629 TI - Lanthanide doped Y6O5F8/YF3 microcrystals: phase-tunable synthesis and bright white upconversion photoluminescence properties. AB - High-quality Y(6)O(5)F(8)/YF(3) microcrystals have been synthesised by using a hydrothermal and subsequent calcination route. Upon changing the initial solution pH value, the as-prepared microcrystal can be well tuned from YF(3) octahedron microcrystals to YF(3) hollow spheres and finally to Y(6)O(5)F(8) microtubes. The as-obtained microcrystals have been characterised by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and photoluminescence (PL) spectra. When the Y(6)O(5)F(8):Ln(3+) microtubes are excited by a 980 nm continual wave laser diode, bright red, green, and blue room temperature upconversion PL emissions have been observed. A series of white light emissions have been obtained by precisely adjusting dopants concentration in Y(6)O(5)F(8) microtubes. PMID- 20714630 TI - Ferrocene-based multichannel molecular chemosensors with high selectivity and sensitivity for Pb(II) and Hg(II) metal cations. AB - The synthesis, electrochemical, optical and cation-sensing properties of ferrocene-imidazoquinoxaline dyads 6, are presented. Dyad 6a behaves as a highly selective redox, chromogenic and fluorescent chemosensor molecule for Pb(2+) cations in CH(3)CN solutions; the oxidation redox peak is anodically shifted (DeltaE(1/2) = 110 mV); in the absorption spectrum a new low-energy band appeared at lambda = 463 nm, and the emission band is red-shifted (Deltalambda = 31 nm) along with an important chelation-enhanced fluorescence factor (CHEF = 276), upon complexation with this metal cation. The dyad 6b, bearing two additional pyridine rings as substituents, has shown its ability for sensing Hg(2+) cations through three different channels: the oxidation peak is anodically higher shifted (DeltaE(1/2) = 300 mV), a new low-energy band appears in the absorption spectrum at lambda = 483 nm, and the emission band was also red-shifted (Deltalambda = 28 nm) and underwent an important chelation-enhanced fluorescent factor (CHEF = 227). The changes in their absorption spectra are accompanied by color changes from yellow to orange which allow their potential use for the "naked eye" detection of these metal cations. Linear sweep voltammetry revealed that Cu(2+) cations induced oxidation of the ferrocene unit in both dyads, which is accompanied by an important increase of the emission band. PMID- 20714631 TI - Solar fuels: thermodynamics, candidates, tactics, and figures of merit. AB - Inorganic chemistry has been and continues to be a central discipline in the field of renewable energy and solar fuels. A fundamental approach to storing solar energy is artificial photosynthesis, whereby uphill chemical reactions are driven by light, e.g. the water gas shift reaction, halogen acid splitting, or water splitting. This article endeavors to define a common context for these research topics, particularly by analyzing the thermodynamic boundaries of photosynthesis. Specifically, the generalized efficiency restrictions on both light absorption and energy storage are expounded, the analogous limitations for several individual photosynthetic strategies are stated, several synthetic catalyst architectures are highlighted, the advantages of molecular and macroscopic approaches are discussed, and key figures of merit are presented. PMID- 20714632 TI - Scorpionates bearing nitro substituents: mono-, bis- and tris-(3-nitro-pyrazol-1 yl)borate ligands and their copper(I) complexes. AB - Two scorpionates sodium trihydro(3-nitro-pyrazol-1-yl)borate (Na[H(3)B(3 (NO(2))pz)]) and sodium hydrotris(3-nitro-pyrazol-1-yl)borate (Na[HB(3 (NO(2))pz)(3)]), featuring electron withdrawing substituents, have been synthesized in high yield starting from 3(5)-nitropyrazole and sodium borohydride. The treatment of CuX (X = (CH(3)CN)(4)PF(6), Cl or I) with Na[H(3)B(3-(NO(2))pz)], Na[HB(3-(NO(2))pz)(3)] or the related bis(pyrazolyl)borate Na[H(2)B(3-(NO(2))pz)(2)] in the presence of triphenylphosphine or tert-butyl isocyanide afforded the corresponding (azolyl)borate supported copper(I) triphenylphosphine or tert-butyl isocyanide adducts. These compounds have been characterized by elemental analyses, FT-IR, ESI-MS and multinuclear NMR spectroscopy. X-Ray crystal structures of [H(3)B(3 (NO(2))pz)]Cu[P(C(6)H(5))(3)](2), [H(2)B(3-(NO(2))pz)]Cu(CNt-Bu)(2), and [HB(3 (NO(2))pz)(3)]Cu[P(C(6)H(5))(3)], as well as that of the {[HB(3 (NO(2))pz)(3)]Na}(4) are also reported. The latter displays a particularly interesting tetrameric structure with each tris(pyrazolyl)borate adopting an unusual inverted configuration and serves as a bridging ligand for three different sodium ions. PMID- 20714633 TI - Speciation of chloroindate(III) ionic liquids. AB - A range of chloroindate(iii) ionic liquid systems was prepared by mixing of 1 alkyl-3-methylimidazolium chloride with indium(iii) chloride in various ratios, expressed as the mol fraction of indium(iii) chloride, chi(InCl(3)). For chi(InCl(3)) 0.50, the products were biphasic (suspensions of a solid in an ionic liquid). Speciation of these chloroindate(iii) systems was carried out using a wide range of techniques: differential scanning calorimetry (DSC), polarised optical microscopy (POM), liquid-state and solid-state (115)In NMR spectroscopy, X-ray photoelectron spectroscopy (XPS) and extended X-ray absorption fine structure (EXAFS). Ionic liquids prepared using an excess of the organic chloride (chi(InCl(3)) < 0.5) contained [InCl(6)](3-), [InCl(5)](2-) and [InCl(4)](-) anions, in proportions dependent on the chi(InCl(3)) value. Equimolar mixtures yielded single compounds: 1-alkyl-3-methylimidazolium tetrachloroindates(iii). Systems containing an excess of indium(iii) chloride (chi(InCl(3)) > 0.5) contained indium(iii) chloride powder suspended in a neutral tetrachloroindate ionic liquid. PMID- 20714634 TI - Gas phase synthesis and reactivity of dimethylaurate. AB - A combination of multistage mass spectrometry experiments and DFT calculations were used to examine the synthesis and reactivity of dimethylaurate. Collision induced dissociation (CID) of [(CH(3)CO(2))(4)Au](-) proceeded via reductive elimination of acetylperoxide to yield the diacetate [CH(3)CO(2)AuO(2)CCH(3)](-), which in turn underwent sequential CID decarboxylation reactions to yield the organoaurates [CH(3)CO(2)AuCH(3)](-) and [CH(3)AuCH(3)](-). The unimolecular chemistry of the dimethylaurate proceeds via a combination of bond homolysis to yield the methyl aurate radical anion [CH(3)Au] (-) as well as formation of the gold dihydride [HAuH](-). DFT calculations reveal that the latter anion is formed via a 1,2-dyotropic rearrangement to yield the isomer [CH(3)CH(2)AuH](-), followed by a beta-hydride elimination reaction. Ion-molecule reactions of [CH(3)AuCH(3)](-) with methyl iodide did not yield any products even at relatively high concentrations of the neutral substrate and longer reaction times, indicating a reaction efficiency of less than 1 in 20 000 collisions. DFT calculations were carried out on two different potential energy surfaces (PES) for the reaction of [CH(3)AuCH(3)](-) with CH(3)I: (i) an S(N)2 mechanism proceeding via a side-on transition state; and (ii) a stepwise mechanism proceeding via oxidative addition followed by reductive elimination. Both pathways have significant endothermic barriers, consistent with the lack of C-C bond coupling products being formed in the experiments. Finally, the reactivity of [CH(3)AuCH(3)](-) is compared to the previously studied [CH(3)AgCH(3)](-) and [CH(3)CuCH(3)](-), as well as condensed phase studies on dimethylaurate salts. PMID- 20714635 TI - Ti and Zr complexes of ferrocenyl amidinates. AB - Preparation of a N-ferrocenyl-amidinate complex was achieved by employing (TMEDA)Li[(CpFeC(5)H(4))NC(Ph)NSiMe(3)] (1) to prepare Cp*Zr[(CpFeC(5)H(4))NC(Ph)NSiMe(3)]Cl(2) (2). Complex 2 exhibited poor polymerization activity and thus a series of C-ferrocenyl bis(amidinate) complexes of the type M(L)(2)Cl(2) (M = Zr, 4; M = Ti, 5; L = (CyNC(CpFeC(5)H(4))NCy) were synthesized via reaction of ferrocenyl-amidine, H(L) and M(NMe(2))(2)Cl(2) (M = Ti, Zr.2THF). Half sandwich mono(amidinate) complexes, Cp'ZrLCl(2) (Cp' = Cp, 7; Cp' = Cp*, 8), were prepared by the reaction of Cp'ZrCl(3) with Li(L) and subsequently alkylated to give M(L)(2)Me(2) (M = Zr, 9; M = Ti, 11), CpZr(L)(CH(2)Ph)(2) (12) and Cp*Zr(L)Me(2) (10) with the appropriate alkylating agent. Abstraction of a methyl group from 7 with B(C(6)F(5))(3) and [Ph(3)C][B(C(6)F(5))(4)] proceeded cleanly to give [{CyNC(CpFeC(5)H(4))NCy}(2)ZrMe][MeB(C(6)F(5))(3)] 13 and [{CyNC(CpFeC(5)H(4))NCy}(2)ZrMe][B(C(6)F(5))(4)] 14, respectively. Similarly, the analogous CpZr and Cp*Zr derivatives LZr{CyNC(CpFeC(5)H(4))NCy}CH(2)Ph] [PhCH(2)B(C(6)F(5))(3)] L = Cp 15, Cp* 17 and [LZr{CyNC(CpFeC(5)H(4))NCy}CH(2)Ph][B(C(6)F(5))(4)] L = Cp 16, Cp* 18 were prepared. Cyclic voltammetry studies on the metal complexes containing ferrocenyl amidinates reveal quasi reversible oxidation and reduction waves for the ferrocene/ferrocenium couple. The dichloride complexes (4-8) activated with MAO and dialkyl complexes (9,10) activated with B(C(6)F(5))(3) and [Ph(3)C][B(C(6)F(5))(4)] showed low ethylene polymerization activities. PMID- 20714636 TI - Bulky guanidinato and amidinato zinc complexes and their comparative stabilities. AB - The preparation of a series of amidinato and guanidinato zinc halide complexes incorporating ligands of varying steric bulk is described, and their thermal stabilities compared. Salt elimination reactions between [M(Giso)] (M = K or Li; Giso = [(ArN)(2)CNCy(2)](-), Ar = 2,6-diisopropylphenyl, Cy = cyclohexyl) and ZnX(2) (X = I or Br) have yielded the monomeric complexes [(Giso)ZnI] and [(Giso)Zn(mu-Br)(2)Li(OEt(2))(2)]. Both have been crystallographically characterised and the former shown to slowly decompose in solution at ambient temperature to give the carbodiimide, ArN[double bond, length as m-dash]C[double bond, length as m-dash]NAr. In contrast, reactions between alkali metal complexes of a less bulky guanidinate, [M(Priso)] (Priso = [(ArN)(2)CNPr(i)(2)](-)) and ZnX(2) have yielded [(IZn)(2)(mu-NPr(i)(2)){mu-N,N'-(NAr)(2)CH}] and [(Priso)Zn(mu-Br)(2)Li(OEt(2))(2)]. The latter decomposes in solution at ambient temperature, generating ArN[double bond, length as m-dash]C[double bond, length as m-dash]NAr, which was also produced in the preparation of the former. Analogies are drawn between the decomposition of [(Priso)Zn(mu Br)(2)Li(OEt(2))(2)] and the carbonic anhydrase catalysed dehydration of bicarbonate. Two bulky amidinato zinc complexes, [{(Piso)Zn(mu-Br)}(2)] and [Zn(Piso)(2)] (Piso = [(ArN)(2)CBu(t)](-)) have been prepared, structurally characterised and shown to be markedly more thermally stable than the zinc guanidinate compounds. Attempts to reduce several of the zinc(ii) halide complexes to dimeric zinc(i) compounds were so far unsuccessful, in all cases leading to the deposition of zinc metal. PMID- 20714637 TI - Re-determination of the structure of an anionic oxo-vanadium arsenate framework. AB - In this contribution we report the re-determination of the crystal structure of a previously reported anionic oxo-vanadium arsenate framework [(As(6)V(IV)(12)V(V)(3)O(51))(-9)](infinity) (1) with piperazinium counterions; we also present supporting spectroscopic and elemental data. PMID- 20714638 TI - An integrated micro-electro-fluidic and protein arraying system for parallel analysis of cell responses to controlled microenvironments. AB - Living cells have evolved sophisticated signaling networks allowing them to respond to a wide array of external stimuli. Microfluidic devices, facilitating the analysis of signaling networks through precise definition of the cellular microenvironment often lack the capacity of delivering multiple combinations of different signaling cues, thus limiting the throughput of the analysis. To address this limitation, we developed a microfabricated platform combining microfluidic definition of the cell medium composition with dielectrophoretic definition of cell positions and protein microarray-based presentation of diverse signaling inputs. Ligands combined at different concentrations were spotted along with an extracellular matrix protein onto a glass substratum in alignment with an electrode array. This substratum was combined with a polydimethylsiloxane chip for microfluidic control of the soluble medium components, in alignment with the electrode and protein arrays. Endothelial cells were captured by dielectrophoretic force, allowed to attach and spread on the protein spots; and the signaling output of the NF-kappaB pathway in response to diverse combinations of IGF1 and TNF was investigated, in the absence and presence of variable dose of the pathway inhibitor. The results suggested that cells can be potently activated by immobilized TNF with IGF1 having a modulating effect, and the response could be abolished to different degrees by the inhibitor. This study demonstrates considerable potential of combining precise cell patterning and liquid medium control with protein microarray technology for complex cell signaling studies in a high-throughput manner. PMID- 20714639 TI - Reagent-release capillary array-isoelectric focusing device as a rapid screening device for IEF condition optimization. AB - This report describes the fabrication and characterization of a simple and disposable capillary isoelectric focusing (cIEF) device containing a reagent release capillary (RRC) array and poly(dimethylsiloxane) (PDMS) platform, which allows rapid (within 10 min) screening of cIEF conditions by introducing a sample solution into plural RRCs by capillary action followed by electric field application. To prepare the RRC, covalent immobilization of poly(dimethylacrylamide) (PDMA) was conducted to suppress electro-osmotic flow (EOF), followed by physical adsorption of the mixture of carrier ampholyte (CA), surfactant, labeling reagent (LR), and other additives to the PDMA surface to construct a two-layer structure inside a square glass capillary. When the sample solution containing proteins was introduced into the RRC, physically adsorbed CA, surfactant, and LR can be dissolved and released into the sample solution. Then, complexation of LR with proteins, mixing with CA and surfactant, and exposure of the PDMA surface spontaneously occurs for the IEF experiments. Here, three different RRCs that immobilize different CAs were prepared, and simultaneous cIEF experiments involving hemoglobin AFSC mixtures for choosing the best CA demonstrated the proof of concept. PMID- 20714640 TI - Separation and metrology of nanoparticles by nanofluidic size exclusion. AB - A nanofluidic technology for the on-chip size separation and metrology of nanoparticles is demonstrated. A nanofluidic channel was engineered with a depth profile approximated by a staircase function. Numerous stepped reductions in channel depth were used to separate a bimodal mixture of nanoparticles by nanofluidic size exclusion. Epifluorescence microscopy was used to map the size exclusion positions of individual nanoparticles to corresponding channel depths, enabling measurement of the nanoparticle size distributions and validation of the size separation mechanism. PMID- 20714641 TI - Discovery and characterization of novel d-xylose-specific transporters from Neurospora crassa and Pichia stipitis. AB - Saccharomyces cerevisiae is considered one of the most promising organisms for ethanol production from lignocellulosic feedstock. Unfortunately, pentose sugars, which comprise up to 30% of lignocellulose, cannot be utilized by wild type S. cerevisiae. Heterologous pathways were introduced into S. cerevisiae to enable utilization of d-xylose, the most abundant pentose sugar. However, the resulting recombinant S. cerevisiae strains exhibited a slow growth rate and poor sugar utilization efficiency when grown on d-xylose as the sole carbon source. d-xylose uptake is the first step of d-xylose utilization. d-xylose can only enter yeast cells through hexose transporters, which have two orders of magnitude lower affinity towards d-xylose compared to hexoses. It was also shown that inefficient pentose uptake is the limiting step in some d-xylose metabolizing yeast strains. Here we report the cloning and characterization of two novel d-xylose-specific transporters from Neurospora crassa and Pichia stipitis. These two transporters were identified from a total of 18 putative pentose transporters. They were functionally expressed and properly localized in S. cerevisiae as indicated by HPLC analysis and fluorescence confocal microscopy, respectively. Kinetic parameters of the d-xylose-specific transporters were determined using a (14)C labeled sugar uptake assay. Use of pentose-specific transporters should improve d xylose consumption and ethanol production in fast d-xylose assimilating strains, thereby lowering the cost of lignocellulosic ethanol production. PMID- 20714642 TI - Yeast protein-protein interaction binding sites: prediction from the motif-motif, motif-domain and domain-domain levels. AB - Interacting proteins can contact with each other at three different levels: by a domain binding to another domain, by a domain binding to a short protein motif, or by a motif binding to another motif. In our previous work, we proposed an approach to predict motif-motif binding sites for the yeast interactome by contrasting high-quality positive interactions and high-quality non-interactions using a simple statistical analysis. Here, we extend this idea to more comprehensively infer binding sites, including domain-domain, domain-motif, and motif-motif interactions. In this study, we integrated 2854 yeast proteins that undergo 13 531 high-quality interactions and 3491 yeast proteins undergoing 578 459 high-quality non-interactions. Overall, we found 6315 significant binding site pairs involving 2371 domains and 637 motifs. Benchmarked using the iPfam, DIP CORE, and MIPS, our inferred results are reliable. Interestingly, some of our predicted binding site pairs may, at least in the yeast genome, guide researchers to assay novel protein-protein interactions by mutagenesis or other experiments. Our work demonstrates that by inferring significant protein-protein binding sites at an aggregate level combining domain-domain, domain-motif and motif-motif levels based on high-quality positive and negative datasets, this method may be capable of identifying the binding site pairs that mediate protein-protein interactions. PMID- 20714643 TI - In search of tetraploid wheat accessions reduced in celiac disease-related gluten epitopes. AB - Tetraploid wheat (durum wheat) is mainly used for the preparation of pasta. As a result of breeding, thousands of tetraploid wheat varieties exist, but also tetraploid landraces are still maintained and used for local food preparations. Gluten proteins present in wheat can induce celiac disease, a T-cell mediated auto-immune disorder, in genetically predisposed individuals after ingestion. Compared to hexaploid wheat, tetraploid wheat might be reduced in T-cell stimulatory epitopes that cause celiac disease because of the absence of the D genome. We tested gluten protein extracts from 103 tetraploid wheat accessions (obtained from the Dutch CGN genebank and from the French INRA collection) including landraces, old, modern, and domesticated accessions of various tetraploid species and subspecies from many geographic origins. Those accessions were typed for their level of T-cell stimulatory epitopes by immunoblotting with monoclonal antibodies against the alpha-gliadin epitopes Glia-alpha9 and Glia alpha20. In the first selection, we found 8 CGN and 6 INRA accessions with reduced epitope staining. Fourteen of the 57 CGN accessions turned out to be mixed with hexaploid wheat, and 5 out of the 8 selected CGN accessions were mixtures of two or more different gluten protein chemotypes. Based on single seed analysis, lines from two CGN accessions and one INRA accession were obtained with significantly reduced levels of Glia-alpha9 and Glia-alpha20 epitopes. These lines will be further tested for industrial quality and may contribute to the development of safer foods for celiac patients. PMID- 20714644 TI - Coevolution of PDZ domain-ligand interactions analyzed by high-throughput phage display and deep sequencing. AB - The determinants of binding specificities of peptide recognition domains and their evolution remain important problems in molecular systems biology. Here, we present a new methodology to analyze the coevolution between a domain and its ligands by combining high-throughput phage display with deep sequencing. First, from a library of PDZ domains with diversity introduced at ten positions in the binding site, we evolved domains for binding to 15 distinct peptide ligands. Interestingly, for a given peptide many different functional domains emerged, which exhibited only limited sequence homology, showing that many different binding sites can recognize a given peptide. Subsequently, we used peptide-phage libraries and deep sequencing to map the specificity profiles of these evolved domains at high resolution, and we found that the domains recognize their cognate peptides with high affinity but low specificity. Our analysis reveals two aspects of evolution of new binding specificities. First, we were able to identify some common features amongst domains raised against a common peptide. Second, our analysis suggests that cooperative interactions between multiple binding site residues lead to a diversity of binding profiles with considerable plasticity. The details of intramolecular cooperativity remain to be elucidated, but nonetheless, we have established a general methodology that can be used to explore protein evolution in a systematic yet rapid manner. PMID- 20714645 TI - Ingenuity pathways analysis of urine metabonomics phenotypes toxicity of gentamicin in multiple organs. AB - We introduce the use of Ingenuity Pathway Analysis to analyzing global metabonomics in order to characterize phenotypically biochemical perturbations and the potential mechanisms of the gentamicin-induced toxicity in multiple organs. A single dose of gentamicin was administered to Sprague Dawley rats (200 mg/kg, n = 6) and urine samples were collected at -24-0 h pre-dosage, 0-24, 24 48, 48-72 and 72-96 h post-dosage of gentamicin. The urine metabonomics analysis was performed by UPLC/MS, and the mass spectra signals of the detected metabolites were systematically deconvoluted and analyzed by pattern recognition analyses (Heatmap, PCA and PLS-DA), revealing a time-dependency of the biochemical perturbations induced by gentamicin toxicity. As result, the holistic metabolome change induced by gentamicin toxicity in the animal's organisms was characterized. Several metabolites involved in amino acid metabolism were identified in urine, and it was confirmed that gentamicin biochemical perturbations can be foreseen from these biomarkers. Notoriously, it was found that gentamicin induced toxicity in multiple organs system in the laboratory rats. The proof-of-knowledge based Ingenuity Pathway Analysis revealed gentamicin induced liver and heart toxicity, along with the previously known toxicity in kidney. The metabolites creatine, nicotinic acid, prostaglandin E2, and cholic acid were identified and validated as phenotypic biomarkers of gentamicin induced toxicity. Altogether, the significance of the use of metabonomics analyses in the assessment of drug toxicity is highlighted once more; furthermore, this work demonstrated the powerful predictive potential of the Ingenuity Pathway Analysis to study of drug toxicity and its valuable complementation for metabonomics based assessment of the drug toxicity. PMID- 20714647 TI - Monodispersity control in the synthesis of monometallic and bimetallic quasi spherical gold and silver nanoparticles. AB - In order for the nanoparticles of Au and Ag to be useful for a wide range of applications, the tailorability of the nanoparticle properties through controlled changes of composition, size, shape, and crystal structure is absolutely essential. Furthermore, these nanoparticle attributes must be delivered in high monodispersity to assure a consistent application performance. High monodispersity is also a requirement for the assembly of nanoparticles into extended nanostructures or mesoscale devices which may be needed for some applications. This article describes a variety of colloidal synthesis methods in use today for the preparation of monodisperse Au, Ag, and bimetallic Au-Ag nanoparticles. The emphasis is on the analysis of the efficacy of each method for tailoring the nanoparticle size and crystal structure. The scope of work surveyed is confined to quasi-spherical nanoparticles in the size range from sub-nanometre to several tens of nanometres. PMID- 20714646 TI - Controllable reflection properties of nanocomposite photonic crystals constructed by semiconductor nanocrystallites and natural periodic bio-matrices. AB - In this contribution, the subtle periodic nanostructures in butterfly wings and peacock feathers are applied as natural PhC matrices to in situ embed CdS nanocrystallites (nano-CdS) on the structure surface via a convenient solution process. The resulting nano-CdS/natural PhCs nanocomposites show typical 1D, quasi 1D and 2D PhC structures at the nanoscale, which is inherited from the corresponding natural periodic bio-matrices. Moreover, their reflection properties are investigated and show dependence on PhC type, structure parameter, loading amount, as well as collecting angle. This work suggests that natural periodic bio-structures could be perfect matrices to construct novel nanocomposite PhCs, whose photonic band structures are tunable and thus achieve controllable optical properties. Related ideas could inspire the design and synthesis of future nanocomposite PhCs. PMID- 20714648 TI - Inelastic electron tunneling spectra and vibronic coupling density analysis of 2,5-dimercapto-1,3,4-thiadiazole and tetrathiafulvalene dithiol. AB - We calculate inelastic electron tunneling (IET) spectra for 2,5-dimercapto-1,3,4 thiadiazole (DMcT) and tetrathiafulvalene dithiol (TTF-DT) sandwiched between two gold electrodes using non-equilibrium Green's function (NEGF) theory. The calculated peak positions are in reasonable agreement with the experimental data. We also calculate IET spectrum for thiophene dithiol (Th-DT) sandwiched between two gold electrodes and compare it with that for the Au/DMcT/Au junction. Th-DT and DMcT can be distinguished using the IET spectroscopy by the peak of the C-C stretching mode. The peak intensity in the IET spectra is analyzed using vibronic coupling density (VCD) analysis. For the Au/DMcT/Au junction, large distribution of electron-density difference Deltarho(HOMO) on the C-N bond is responsible for the intense peak of the C-N stretching mode; on the other hand, for Au/TTF-DT/Au junction, large distribution of Deltarho(HOMO) on the central C=C bond is responsible for the intense peak of the C=C stretching modes. PMID- 20714649 TI - Hydrophobic iron oxide and CdSe/ZnS nanocrystal loaded polyglutamate/polyelectrolyte micro- and nanocapsules. AB - A novel, simple and generic method for the preparation of hydrophobic nanocrystal loaded composite capsules is introduced. Firstly, magnetic Fe(3)O(4) nanocrystals prepared by pyrolysis of fatty acid iron salts in non-aqueous media were successfully incorporated into water-dispersible polyglutamate/polyelectrolyte capsules by combining an ultrasonic protocol and polyelectrolyte layer-by-layer (LBL) assembly. Then, inspired by the similar synthesis mechanism of oxide and semiconductor nanocrystals based on organometallic approaches in non-aqueous media, two kinds of fluorescent semiconductor quantum dots (zinc sulfide-capped cadmium selenide nanocrystals) were chosen as models to explore QD loaded composite capsules. With rhodamine B isothiocyanate (RBITC) tagging PEI as outer layers, fluorescence micrographs and confocal microscopy images indicate that CdSe/ZnS QDs were successfully incorporated into polyglutamate/polyelectrolyte capsules with almost unchanged optical properties and the color of RBITC tagging PEI shell can be changed under different excitation. Color transformation ascribed to spectral conversion of embedded QDs was also observed after the capsules were stored under day light for days. TEM, electron diffraction (ED), and ESEM revealed that the method leads to well-defined nanocrystal loaded composite nanocapsules and is simple and generic. PMID- 20714650 TI - Growth of pentatwinned gold nanorods into truncated decahedra. AB - The growth mechanism from pentatwinned (PTW) gold nanorods into truncated quasi decahedral particles when a gold salt (HAuCl4) is reduced by N, N dimethylformamide (DMF) in the presence of poly(vinylpyrrolidone), was elucidated through a combination of different techniques, including transmission and scanning electron microscopy, high resolution TEM and selected area electron diffraction. Particles with intermediate shapes between the original pentatwinned Au nanorods, used as seeds, and the final quasi-decahedral particles were obtained by simply tuning the [HAuCl4] to [seeds] ratio. From the thorough structural analysis of all the intermediate morphologies obtained, it was concluded that gradual morphology changes are related to the preferential growth of higher energy crystallographic facets. As a result of the particle growth and concomitant decreased anisotropy, a progressive blue-shift of the surface plasmon resonance bands of the nanoparticles was registered by vis-NIR extinction spectroscopy. PMID- 20714651 TI - Hydrothermal synthesis of novel Mn(3)O(4) nano-octahedrons with enhanced supercapacitors performances. AB - Uniform and single-crystalline Mn(3)O(4) nano-octahedrons have been successfully synthesized by a simple ethylenediaminetetraacetic acid disodium salt (EDTA-2Na) assisted hydrothermal route. The octahedron structures exhibit a high geometric symmetry with smooth surfaces and the mean side length of square base of octahedrons is ~160 nm. The structure is reckoned to provide superior functional properties and the nano-size achieved in the present work is noted to further facilitate the material property enhancement. The formation process was proposed to begin with a "dissolution-recrystallization" which is followed by an "Ostwald ripening" mechanism. The Mn(3)O(4) nano-octahedrons exhibited an enhanced specific capacitance of 322 F g(-1) compared with the truncated octahedrons with specific capacitances of 244 F g(-1), making them a promising electrode material for supercapacitors. PMID- 20714652 TI - Flow-directed assembly of nanostructured thin films from suspensions of anisotropic titania particles. AB - Nanostructured thin films are fabricated by directing the assembly of anisotropic titanium dioxide particles from a colloidal suspension by fixed blade flow coating. The titania particles (equatorial radius a = 24 +/- 4 nm, polar radius b = 130 +/- 31 nm, aspect ratio b/a = 5.4 +/- 0.9) undergo an isotropic-nematic (I N) transition at a volume fraction phi* ~ 0.40. For phi > phi* the deposited film has three structures depending on the substrate velocity, v. At a blade angle alpha = 25 degrees and a gap d = 200 MUm, nanoparticles orient either isotropically in the direction of the coating flow (v>= 350 MUm s(-1)), exhibit partially oriented "wavy" structures (100 < v < 300 MUm s(-1)), or are isotropically oriented (v < 100 MUm s(-1)). Below the I-N transition (phi < phi*), nanoparticles assemble into domains of uniform orientation with dimensions that increase with increasing v. Increasing the blade angle shifts these structural transitions to lower substrate velocities, consistent with an increasing extensional component of the flow. Established scaling relationships describe the film height dependence on phi and v. Overall, these results enable nanostructured films to be deposited with desired thickness and structure. PMID- 20714653 TI - Room temperature synthesis and optical properties of small diameter (5 nm) ZnO nanorod arrays. AB - We report a simple wet-chemical synthesis of ~5 nm diameter ZnO nanorod arrays at room temperature (20 degrees C) and normal atmospheric pressure (1 atm) and their optical properties. They were single crystalline in nature, and grew in the [001] direction. These small diameter ZnO nanorod arrays can also be synthesized at 0 degrees C. Control experiments were also conducted. On the basis of the results, we propose a mechanism for the spontaneous growth of the small diameter ZnO structures. The optical properties of the 5 nm diameter ZnO nanorod arrays synthesized using this method were probed by UV-Visible diffuse reflectance spectroscopy. A clear blue-shift, relative to the absorption band from 50 nm diameter ZnO nanorod arrays, was attributed to the quantum confinement effects caused by the small nanocrystal size in the 5 nm diameter ZnO nanorods. PMID- 20714654 TI - One-pot synthesis of triangular gold nanoplates allowing broad and fine tuning of edge length. AB - A photocatalytic approach was used to synthesize triangular nanoplates in aqueous solution. The synthesis is based on the reduction of a gold salt using a tin(iv) porphyrin as photocatalyst, cetyltrimethylammonium bromide (CTAB) as a stabilizing agent, and triethanolamine (TEA) as the final electron donor. The average edge length of the triangular nanoplates can be easily changed in the range 45-250 nm by varying the concentration of photocatalyst, and fine-tuning of the average edge length is achieved by varying the concentration of CTAB. Study of the mechanism of formation of the nanoplates by UV-vis and by transmission electron microscopy (TEM) shows that there is a first stage where formation of 5 nm seeds takes place, further growth is probably by fusion and by direct reduction of gold onto the preformed nanoparticles. The nanoparticles formed during the photocatalytic reduction of the gold precursor show an irregular shape that evolves to regular triangular nanoplates after ripening in solution for 24 h. PMID- 20714655 TI - In situ X-ray diffraction study of the hydrothermal crystallization of hierarchical Bi2WO6 nanostructures. AB - The hydrothermal crystallization of hierarchical Bi2WO6 nanostructures has been monitored with in situ energy-dispersive X-ray diffraction (EDXRD). The kinetic data analysis according to the Avrami-Erofe'ev model suggests that the formation of nanostructured Bi2(2)WO6 is diffusion controlled with Avrami exponents around 0.5 and that the growth mechanism is temperature independent in the interval from 150 to 180 degrees C. Furthermore, the reaction kinetics and the crystal structure of the resulting hydrothermal products depend on the pH value of the Bi(NO3)3.5H2O/K2WO4 hydrothermal system. PMID- 20714656 TI - Single-step synthesis and magnetic separation of graphene and carbon nanotubes in arc discharge plasmas. AB - The unique properties of graphene and carbon nanotubes made them the most promising nanomaterials attracting enormous attention, due to the prospects for applications in various nanodevices, from nanoelectronics to sensors and energy conversion devices. Here we report on a novel deterministic, single-step approach to simultaneous production and magnetic separation of graphene flakes and carbon nanotubes in an arc discharge by splitting the high-temperature growth and low temperature separation zones using a non-uniform magnetic field and tailor designed catalyst alloy, and depositing nanotubes and graphene in different areas. Our results are very relevant to the development of commercially-viable, single-step production of bulk amounts of high-quality graphene. PMID- 20714657 TI - Atomic-scale tuning of self-assembled ZnO microscopic patterns: from dendritic fractals to compact island. AB - How nature uses water molecules to create fascinating patterns ranging from snowflakes to ice cubes has intrigued mankind for centuries. Here we use ZnO to mimic nature's versatility in creating microscopic patterns with tunable morphology. During growth of ZnO on Zn-dominant spheres via chemical vapor deposition, highly regular and symmetric dendritic snowflake patterns and smooth compact islands can be obtained at different growth conditions. We reproduce the dendritic patterns using atomistic Monte Carlo simulations. These findings not only improve understanding of how water molecules form various patterns, but may also be instrumental in tailoring ZnO nanostructures for desirable functionality. PMID- 20714658 TI - In situ observations of fullerene fusion and ejection in carbon nanotubes. AB - We present in situ experimental observations of fullerenes seamlessly fusing to single-walled carbon nanotubes. The morphing-entry of a fullerene to the interior of a nanotube is also captured. The confined (1D) motion of the newly encapsulated fullerene within its host attests to the actual change from the exterior to interior. PMID- 20714659 TI - Efficient conversion of triacylglycerols and fatty acids to biodiesel in a microwave reactor using metal triflate catalysts. AB - We report that catalytic quantities of the Lewis acidic metal catalysts scandium triflate and bismuth triflate promote conversion of oleic, linoleic, palmitic and myristic acids and their glyceryl triesters to the corresponding methyl esters (biodiesel) in greater than 90% yield upon microwave heating. Additionally, both catalysts could be recovered and reused in esterification reactions at least six times. PMID- 20714660 TI - Two-photon fluorescence imaging of DNA in living plant turbid tissue with carbazole dicationic salt. AB - Three carbazole dicationic salts, namely 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), 9-ethyl-3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (9E-BMVC) and 9-ethyl-3,6-bis(1-hydroxyethyl-4-vinylpyridinium)carbazole diiodide (9E-BHVC), were synthesized successfully. Their photophysical properties were evaluated by absorption, one- and two-photon fluorescence spectra, and their higher fluorescence intensity and larger two-photon excited fluorescence action cross-sections (Phi*delta) in the presence of DNA than those in the absence of DNA give them good DNA two-photon light-switch properties. Furthermore, their ability to image nuclei in living plant cells and turbid tissues by using two photon excited fluorescence was carefully studied, and the experimental results indicate that these dicationic salts can exclusively label nuclei in intact living plant cells and tissues. In particular, 9E-BHVC exhibits optimized DNA labeling performance. Very importantly, compared to DAPI, 9E-BHVC can be used to carry out deeper observation using the same incident power, or can be used to obtain usable fluorescent images by using a lower incident power. PMID- 20714661 TI - Convenient and clean synthesis of imines from primary benzylamines. AB - The current syntheses of imines from benzylamines are often performed in organic solvents or under harsh reaction conditions. Clean oxidation of primary benzylamines to imines has been successfully achieved using H(2)O(2) in water at room temperature catalyzed by V(2)O(5). Among the 10 imine products, 5 of them precipitated from the reaction and led pure products after simple filtration. No organic solvents are needed in the whole process. The yields are good to quantitative. This represents an efficient and green procedure of the synthesis of imines. A similar green oxidation of benzylamines to aromatic aldehydes is also reported. A benzylic anion-involved mechanism is proposed based on the experiments. PMID- 20714662 TI - Mechanistic investigations of multidentate organocatalyst-promoted counterion catalysis for fast and enantioselective aza-Morita-Baylis-Hillman reactions at ambient temperature. AB - Kinetic experiments were performed on the catalytic cycle of a trifunctional organocatalyst-promoted counterion catalysis of asymmetric aza-Morita-Baylis Hillman reactions. The catalysis was found to be first order in the trifunctional catalyst with the Michael addition as the rate-limiting step. Temperature variation changed the rate of catalysis but not the enantioselectivity of the reaction. PMID- 20714663 TI - Tellurium: an element with great biological potency and potential. AB - Tellurium has long appeared as a nearly 'forgotten' element in Biology, with most studies focusing on tellurite, tellurate and a handful of organic tellurides. During the last decade, several discoveries have fuelled a renewed interest in this element. Bioincorporation of telluromethionine provides a new approach to add heavy atoms to selected sites in proteins. Cadmium telluride (CdTe) nanoparticles are fluorescent and may be used as quantum dots in imaging and diagnosis. The antibiotic properties of tellurite, long known yet almost forgotten, have attracted renewed interest, especially since the biochemical mechanisms of tellurium cytotoxicity are beginning to emerge. The close chemical relationship between tellurium and sulfur also transcends into in vitro and in vivo situations and provides new impetus for the development of enzyme inhibitors and redox modulators, some of which may be of interest in the field of antibiotics and anticancer drug design. PMID- 20714664 TI - Multicolor fluorescent switches in gel systems controlled by alkoxyl chain and solvent. AB - Two simple molecules, 1 and 2 with D-pi-A structure and alkoxyl groups, respectively, were designed and synthesized. Both compounds can gelatinize THF water and DMSO. And compound 2 forms gel in acetone by ultrasonic stimulus. Interestingly, these gels exhibit aggregation-induced emission (AIE) during the sol-gel phase transformation. Moreover, the molecular self-assembled and photophysical properties can be controlled by the number of the alkoxyl chains and the type of the solvents. For example, 1 has an identical packing model and fluorescent colour in THF-water and DMSO gels. Contrarily, the self-assembly of molecule 2 strongly depends on the solvent. Furthermore, the gel phases of 2 formed in three solvents possess different fluorescent colours. Such as, THF water gel emits yellow fluorescence, acetone gel has orange emission and red fluorescence appears in DMSO. PMID- 20714665 TI - Synthesis and characterization of an O(6)-2'-deoxyguanosine-alkyl-O(6)-2' deoxyguanosine interstrand cross-link in a 5'-GNC motif and repair by human O(6) alkylguanine-DNA alkyltransferase. AB - O(6)-2'-Deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand DNA cross-links (ICLs) with a four and seven methylene linkage in a 5'-GNC- motif have been synthesized and their repair by human O6-alkylguanine-DNA alkyltransferase (hAGT) investigated. Duplexes containing 11 base-pairs with the ICLs in the center were assembled by automated DNA solid-phase synthesis using a cross-linked 2' deoxyguanosine dimer phosphoramidite, prepared via a seven step synthesis which employed the Mitsunobu reaction to introduce the alkyl lesion at the O(6) atom of guanine. Introduction of the four and seven carbon ICLs resulted in no change in duplex stability based on UV thermal denaturation experiments compared to a non cross-linked control. Circular dichroism spectra of these ICL duplexes exhibited features of a B-form duplex, similar to the control, suggesting that these lesions induce little overall change in structure. The efficiency of repair by hAGT was examined and it was shown that hAGT repairs both ICL containing duplexes, with the heptyl ICL repaired more efficiently relative to the butyl cross-link. These results were reproducible with various hAGT mutants including one that contains a novel V148L mutation. The ICL duplexes displayed similar binding affinities to a C145S hAGT mutant compared to the unmodified duplex with the seven carbon containing ICLs displaying slightly higher binding. Experiments with CHO cells to investigate the sensitivity of these cells to busulfan and hepsulfam demonstrate that hAGT reduces the cytotoxicity of hepsulfam suggesting that the O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand DNA cross-link may account for at least part of the cytotoxicity of this agent. PMID- 20714666 TI - Manganese catalyzed cis-dihydroxylation of electron deficient alkenes with H(2)O(2). AB - A practical method for the multigram scale selective cis-dihydroxylation of electron deficient alkenes such as diethyl fumarate and N-alkyl and N-aryl maleimides using H(2)O(2) is described. High turnovers (>1000) can be achieved with this efficient manganese based catalyst system, prepared in situ from a manganese salt, pyridine-2-carboxylic acid, a ketone and a base, under ambient conditions. Under optimized conditions, for diethyl fumarate at least 1000 turnovers could be achieved with only 1.5 equiv. of H(2)O(2) with d/l-diethyl tartrate (cis-diol product) as the sole product. For electron rich alkenes, such as cis-cyclooctene, this catalyst provides for efficient epoxidation. PMID- 20714668 TI - The influence of a 1,1-diarylvinyl moiety on the photochromism of naphthopyrans. AB - 1,1,3-Triarylpent-4-en-1-yn-3-ols, efficiently obtained in two steps from 1,1,3 triarylprop-2-yn-1-ols by a Meyer-Schuster rearrangement and subsequent addition of lithium trimethylsilylacetylide, react with either a 1- or 2- naphthol to afford photochromic 1,1-diarylvinyl substituted naphtho[1,2-b]- or naphtho[2,1-b] pyrans respectively. Irradiation of solutions of these naphthopyrans results in reversible electrocyclic ring-opening to afford photomerocyanines which possess an extended conjugated system and show a bathochromically-shifted lambda(max) relative to the non-vinyl substituted analogues. PMID- 20714667 TI - Radical routes to interstellar glycolaldehyde. The possibility of stereoselectivity in gas-phase polymerization reactions involving CH(2)O and CH(2)OH. AB - A previous report that the interstellar molecule glycolaldehyde (HOCH(2)CHO) can be made from hydroxymethylene (HOCH:) and formaldehyde has been revisited at the CCSD(T)/6-311++G(3df,2p)//MP2/6-311++G(3df,2p) level of theory. This reaction competes with the formation of acetic acid and methylformate, molecules which have also been detected in interstellar clouds. Other possible modes of formation of glycolaldehyde by radical/radical reactions have been shown to be viable theoretically as follows: HO+CH2CHO -->HOCH2CHO [DeltaG(Gamma)(298K)=-303kJ mol 1] HOCH2+CHO-->HOCH2CHO (-259kJ mol-1). The species in these two processes are known interstellar molecules. Key radicals CH(2)CHO and CH(2)OH in these sequences have been shown to be stable for the microsecond duration of neutralization/reionization experiments in the dual collision cells of a VG ZAB 2HF mass spectrometer. The polymerization reaction HOCH(2)CHOH + nCH(2)O -> HOCH(2)[CH(OH)](n)CHOH (n = 1 to 3) has been studied theoretically and shown to be energetically feasible, as is the cyclization reaction of HOCH(2)[(CH(2)OH)(4)]CHOH (in the presence of one molecule of water at the reacting centre) to form glucose. The probability of such a reaction sequence is small even if polymerization were to occur in interstellar ice containing a significant concentration of CH(2)O. The large number of stereoisomers produced by such a reaction sequence makes the formation of a particular sugar, again for example glucose, an inefficient synthesis. The possibility of stereoselectivity occurring during the polymerization was investigated for two diastereoisomers of HOCH(2)[(CHOH)](2)CHOH. No significant difference was found in the transition state energies for addition of CH(2)O to these two diastereoisomers, but a barrier difference of 12 kJ mol(-1) was found for the H transfer reactions OCH(2)[(CHOH)](2)CH(2)OH -> HOCH(2)[(CHOH)(2)CHOH of the two diastereoisomers. PMID- 20714669 TI - Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer: generation of alpha-aminoalkyl radicals. AB - The extent to which deuterium can act as a protecting group to prevent unwanted 1,5-hydrogen atom transfer to aryl and vinyl radical intermediates was examined in the context of the generation of alpha-aminoalkyl radicals in a pyrrolidine ring. Intra- and intermolecular radical trapping following hydrogen atom transfer provides an illustration of the use of the primary kinetic isotope effect in directing the outcome of synthetic C-C bond-forming processes. PMID- 20714670 TI - Arenediazonium tetrafluoroborates in palladium-catalyzed C-P bond-forming reactions. Synthesis of arylphosphonates, -phosphine oxides, and -phosphines. AB - A novel palladium-catalyzed synthesis of arylphosphonates from arenediazonium tetrafluoroborates and triethylphosphite or diethylphosphite is presented. The reaction tolerates useful substituents including bromo, chloro, nitro, ether, cyano, keto, and ester groups, can be performed as a one-pot process from anilines omitting the isolation of arenediazonium salts, and can be extended to the preparation of arylphosphine oxides and arylphosphines. PMID- 20714671 TI - Copper-catalyzed aminobromination/elimination process: an efficient access to alpha,beta-unsaturated vicinal haloamino ketones and esters. AB - A novel copper-catalyzed aminobromination-elimination process has been developed, which provides an easy access to alpha,beta-unsaturated vicinal haloamindes derivatives from readily available alpha,beta-unsaturated ketones and esters in good to excellent yields. The isolated intermediate discloses that the current system proceeds through the aminobromination process. PMID- 20714672 TI - PUFAs enhance oxidative stress and apoptosis in tumour cells exposed to hypericin mediated PDT. AB - Since many studies have suggested the impact of dietary polyunsaturated fatty acids on cancer progression and prognosis, there is an assumption of possible pre sensitizing effects of their application in combined treatment. The present work evaluates modulation of photodynamic therapy (PDT) with hypericin by pre treatment with n-3 and n-6 fatty acids in HT-29 and HeLa tumour cells. We observed stimulation of cytotoxic effects by docosahexaenoic acid (n-3) and arachidonic acid (n-6) in several stages of action in both cell lines. Treatment with either fatty acids or photodynamic therapy alone induced apoptosis in a dose and time-dependent manner; however the effect was even more striking in mutual combination applied as pre-treatment with fatty acids prior to photodynamic therapy. Moreover, the combination also induced changes in membrane lipid composition leading to alteration in cell membrane fluidity. Increased toxicity of combined treatment was also confirmed by the presence of oxidative stress demonstrated by ROS production, RNS accumulation and increased presence of lipoperoxides. In conclusion, we suggest that pre-treatment with polyunsaturated fatty acids may contribute to cytotoxic effects induced by photodynamic therapy with hypericin. PMID- 20714673 TI - Optimizing photodynamic therapy by liposomal formulation of the photosensitizer pyropheophorbide-a methyl ester: in vitro and ex vivo comparative biophysical investigations in a colon carcinoma cell line. AB - Photodynamic therapy (PDT), induced by a photosensitizer (PS) encapsulated in a nanostructure, has emerged as an appropriate treatment to cure a multitude of oncological and non-oncological diseases. Pyropheophorbide-a methyl ester (PPME) is a second-generation PS tested in PDT, and is a potential candidate for future clinical applications. The present study, carried out in a human colon carcinoma cell line (HCT-116), evaluates the improvement resulting from a liposomal formulation of PPME versus free-PPME. Absorption and fluorescence spectroscopies, fluorescence lifetime measurements, subcellular imaging and co-localization analysis have been performed in order to analyze the properties of PPME for each delivery mode. The benefit of drug encapsulation in DMPC-liposomes is clear from our experiments, with a 5-fold higher intracellular drug delivery than that observed with free-PPME at similar concentrations. The reactive oxygen species (ROSs) produced after PPME-mediated photosensitization have been identified and quantified by using electron spin resonance spectroscopy. Our results demonstrate that PPME-PDT-mediated ROSs are composed of singlet oxygen and a hydroxyl radical. The small amounts of PPME inside mitochondria, as revealed by fluorescence co-localization analysis, could maybe explain the very low apoptotic cell death measured in HCT-116 cells. PMID- 20714674 TI - Urea-type ligand-modified CdSe quantum dots as a fluorescence "turn-on" sensor for CO3(2-) anions. AB - A new fluorescence "turn-on" nanosensor for carbonate determination was reported based on CdSe quantum dots (QDs) modified with thio ligands containing urea groups: N-(5-mercapto-1,3,4-thiadiazol-2-ylcarbamoyl)-2-(o-tolyloxy)acetamide (AASH-CdSe QDs). The AASH-CdSe QDs were prepared through a ligand exchange process and characterized by transmission electron microscopy (TEM), fluorescence spectroscopy, UV-vis spectroscopy and FT-IR spectroscopy. The synthesized AASH CdSe QDs allowed a selective fluorescence "turn-on" response towards carbonate. Under optimal conditions, the relative fluorescence intensity increases linearly with carbonate concentration in the range 1 x 10(-7)-1 x 10(-4) M with a detection limit of 2.3 x 10(-8) M. A Langmuir-type binding model was highly effective in describing the carbonate concentration dependence of the luminescence intensity of the AASH-CdSe QDs. The possible mechanism was discussed. PMID- 20714675 TI - Photoinduced ring opening reactions and subsequent thermal ring closure reactions in the thymine-ammonia system and related systems. AB - The photo-induced ring opening reactions of thymine (Thy) and 1-methylthymine (MeT) with ammonia and with methylamine (MA) at basic pH, and the subsequent ring closure reactions of the resulting adducts, have been studied. In the photo induced reaction of Thy with ammonia, the dominant product is the E form of N carbamoyl-3-amino-2-methylacrylamide (IIIa). Heating or acid treatment of aqueous IIIa results in rapid formation of Thy as final product, while allowing IIIa to stand at 4 degrees C produces Thy and two isomeric Thy hydrates, namely trans- and cis-6-hydroxy-5,6-dihydrothymine (Ia and IIa). The main products in the other reactions have analogous structures and undergo analogous ring closure reactions. Incubation of IIIa (and similar adducts) in phosphate buffer near pH 7 significantly enhances the rate of hydrate formation; other weak acid/conjugate base buffer systems also increase the rate of hydrate formation. A mechanism leading from opened ring adduct (e.g.IIIa) to hydrates (e.g.Ia and IIa) is proposed; ring closure leads initially to a dihydrothymine intermediate containing a 6-amino moiety, while further reaction with water produces the observed hydrates. The results described may be relevant to understanding the fate of cross-links generated by photo-induced reaction of thymine moieties in DNA with lysine residues in nuclear proteins (e.g. histones) when they are formed in a cellular environment. Decomposition of such cross-links, catalyzed by cellular phosphate, could lead to production of thymine hydrates attached to lysine residues contained in the protein partner and concurrent generation of an apyrimidinic site in the DNA partner. PMID- 20714676 TI - The effect of phenyl substitution on the fluorescence characteristics of fluorescein derivatives via intramolecular photoinduced electron transfer. AB - UV-vis absorption, steady state fluorescence emission, time-correlated single photon counting and laser flash photolysis methods were employed to examine the excited state properties of fluorescein derivatives to understand the mechanism that controls their fluorescence efficiency. The fluorescein derivatives contain amino, t-butyl, carboxyl or nitro on their phenyl moieties, respectively. These substituents are not directly connected to the fluorophore but still showed a very remarkable effect on the fluorescence properties. Compared to fluorescein, the introduction of nitro, a strong electron withdrawing group, or amino, a strong electron donating group, caused a substantial quenching of both the fluorescence quantum yield and lifetime. The presence of a t-butyl or carboxyl, on the other hand, caused a smaller decrease. The mechanism for the substituent effect is due to the involvement of an additional de-excitation process, i.e. intramolecular photoinduced electron transfer (PET). The thermodynamics and kinetics of PET were analyzed. Depending on the nature of the substituent, the xanthenic ring acts as an electron acceptor (or donor), while the phenyl moiety is the corresponding electron donor (or acceptor) in PET. The rate constant of PET for the amino case is larger than 4.79 x 10(9) s(-1), while for nitro substitution it is 0.67 x 10(9) s(-1). Both values are much larger than the radiation rate constant of 0.20 x 10(9) s(-1), meaning that PET plays important roles in the deactivation of S(1) for the two dyes. The charge transfer state generated by PET was observed by laser flash photolysis. PMID- 20714677 TI - Long-lived fluorescence of homopolymeric guanine-cytosine DNA duplexes. AB - The fluorescence spectrum of the homopolymeric double helix poly(dG) x poly(dC) is dominated by emission decaying on the nanosecond time-scale, as previously reported for the alternating homologue poly(dGdC) x poly(dGdC). Thus, energy trapping over long periods of time is a common feature of GC duplexes which contrast with AT duplexes. The impact of such behaviour on DNA photodamage needs to be evaluated. PMID- 20714678 TI - Cu and Ag catalyzed oxidative arylthiation of terminal acetylenes. AB - A mild Cu or Ag catalyzed oxidative arylthiation of terminal acetylenes is introduced. The process, featuring metal catalyzed C-H bond activation as a key step, leads to the formation of highly substituted mercaptoacetylenes under unprecedented neutral conditions. PMID- 20714680 TI - Presentation skills for healthcare professionals. PMID- 20714679 TI - Carnitine-acylcarnitine translocase deficiency. Clinical course of three Saudi children with a severe phenotype. AB - Carnitine-acylcarnitine translocase (CACT) deficiency (McKusick 212138) is a rare life threatening disorder characterized by hypoketotic hypoglycemia, hyperammonemia, encephalopathy, cardiomyopathy hepatopathy, and myopathy. Here, we present a detailed clinical course of 3 Saudi siblings with a severe phenotype. The third patient was described in more detail. Early medical intervention in the form of 25% dextrose intravenous infusion and carnitine supplement followed by a gradual introduction of a high carbohydrate low fat special formula resulted in a good clinical and biochemical response to the treatment in our patient. However, early nephrocalcinosis, severe hypotonia, and subsequently intravascular cerebral accident could not be prevented. He died at 18 months of age as a result of metabolic decompensation. This suggests that CACT deficiency is still a lethal disorder even with an early and aggressive medical intervention. PMID- 20714681 TI - Predominance of CTX-M genotype among extended spectrum beta lactamase isolates in a tertiary hospital in Saudi Arabia. AB - OBJECTIVE: To determine the molecular characterization of extended-spectrum beta lactamases (ESBL) isolates from a tertiary center in Saudi Arabia using multiplex polymerase chain reaction (PCR) technique and assess their antibiotic susceptibility pattern. METHODS: Prospective study conducted at the Saudi Aramco Dhahran Health Center, Dhahran, Saudi Arabia between April-December 2006. Extended-spectrum beta-lactamases phenotype of isolates identified by automated methods was confirmed using E-test. Multiplex PCR for the detection of blaTEM, blaSHV and blaCTX-M was performed. Susceptibility to a panel of antibiotics was determined. RESULTS: One hundred isolates (Escherichia coli [E.coli] n=84; Klebsiella pneumoniae [K. pneumoniae] n=16) were studied and 71% harbored the blaCTX-M gene. For E.coli isolates 43 (51%) harbored CTX-M+TEM combination and 21 (25%) had CTX-M alone. In contrast, only one K. pneumoniae isolate (6.2%) harbored the CTX-M+TEM combination and 3 (18.8%) isolates had CTX-M only. One E.coli and 7 K. pneumoniae isolates were blaSHV positive. The blaCTX-M gene was found predominantly in urinary isolates (n=63/71; 88.7%). The presence of blaCTX M was significantly higher in isolates from outpatients compared to inpatient (p<0.05). Sensitivity to imipenem was 100% and 78% to nitrofurantoin. Resistance to amoxicillin-sulbactam was significantly higher in blaCTX-M positive isolates (p<0.05). CONCLUSION: The findings indicate a high-level of blaCTX-M positive ESBL isolates circulating in our setting with the dissemination of these in the community. The trend of multidrug resistance profile associated with carriage of blaCTX-M gene is cause for concern. PMID- 20714682 TI - Biphasic effects of ankaferd blood stopper on renal tubular apoptosis in the rat partial nephrectomy model representing distinct levels of hemorrhage. AB - OBJECTIVE: To investigate the effect of Ankaferd Blood Stopper (ABS), on renal tubular apoptosis and on expressions of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and apoptosis protease-activating factor 1 (Apaf-1) in the ipsilateral kidney after an experimentally formed partial nephrectomy in a rat model. METHODS: The study was performed in 2009 at the Ankara Training and Research Hospital, Animal Laboratory Center, Ankara, Turkey. We divided 24 Wistar rats into the following 4 groups. Group I (GI) - partial nephrectomy (PN) with hilar control as the conventional technique, Group II (GII) the conventional technique with ABS, Group III (GIII) - received ABS application to the renal parenchyma and collecting duct with hilar control (non-sutured group). Group IV (GIV) - PN and ABS were performed without hilar control. The ABS solution (1 cc) was applied during the surgery to stop bleeding from resected renal tissue. At first month, all rats were sacrificed. Renal tubular apoptosis was investigated. RESULTS: The mean percentage of apoptotic cell counts in GI were 20% iNOS, 20% eNOS, and 10% Apaf-1. In GII they were 10% iNOS, 20% eNOS, 5% Apaf-1, in GIII they were 40% iNOS, 50% eNOS, 30% Apaf-1, and in GIV they were 5% iNOS, 5% eNOS, and 3% Apaf-1. There was no significant decrease in apoptotic cells in GII, GIII, and GIV, to which we applied ABS. The highest percentage of apoptosis was shown in GIII accompanied by significant inflammation. The lowest percentage was determined in GIV, the non-warm ischemia group. The ABS has a dual biphasic de novo effects on apoptosis. CONCLUSION: The challenge of severe hemorrhage in the renal tubular cellular micro-environment causes ABS-induced down-regulations in the expressions of apoptotic molecules, indicating that ABS may act as a topical biological response modifier. PMID- 20714683 TI - Effects of mobile phone radiation on serum testosterone in Wistar albino rats. AB - OBJECTIVE: To investigate the effects of electromagnetic field radiation generated by mobile phones on serum testosterone levels in Wistar albino rats. METHODS: This experimental interventional control study was conducted in the Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia during the period December 2006 to April 2008. A total of 34 male Albino rats [Wistar strain], 2 months of age, weighing 150-160 gm were used for the experiment. These animals were divided into 3 groups. The first group containing 6 rats was assigned as a control group. The second group containing 14 rats was exposed to mobile phone radiation for 30 minutes daily and the third group containing 14 rats was exposed to mobile phone radiation for 60 minutes daily for the total period of 3 months. At the end of experimental period, blood was collected into the container, and serum testosterone was analyzed using double-antibody radioimmunoassay method by Coat-A-Count. RESULTS: Exposure to mobile phone radiation for 60 minutes/day for the total period of 3 months significantly decrease the serum testosterone level [p=0.028] in Wistar Albino rats compared to their matched control. CONCLUSION: Long-term exposure to mobile phone radiation leads to reduction in serum testosterone levels. Testosterone is a primary male gender hormone and any change in the normal levels may be devastating for reproductive and general health. PMID- 20714684 TI - Morphological and morphometric study of cultured fibroblast from treated and untreated abnormal scar. AB - OBJECTIVE: To investigate the morphology of cultured fibroblasts derived from abnormal scars and compare it to those of human normal skin. METHODS: This study was carried out in the Surgical Clinic, Faculty of Medicine, King Abdul-Aziz University, Jeddah, Kingdom of Saudi Arabia between December 2008 and March 2010. Fifty-two samples of hypertrophic and keloid scar were collected. An in vitro study was conducted in which fibroblasts from normal foreskin; abnormal scars were cultured, studied morphologically and morphometrically. RESULTS: There was a highly significant increase in the length and breadth of fibroblasts from the hypertrophic and keloid scars, and highly significant decrease in the bipolarity index compared to control. There was a significant increase in the mean cell area, mean nuclear area and nuclear/cytoplasmic ratio of fibroblast of hypertrophic and keloid scars compared to control. There was a significant decrease in the mean cell area and mean nuclear area of the fibroblast of the treated keloid scar (with all used modalities) compared to untreated ones. Morphologically, abnormal scar fibroblasts has abundant spreading cytoplasm with numerous processes and large nuclei. The cytoplasm, of some cells, contained clumped granules in the peri-nuclear region, numerous vacuoles, and dense vesicles. CONCLUSION: Morphological and morphometric study showed that hyperactive cultured fibroblasts was a characteristic feature of abnormal scars and the studied modalities of treatment reduced, but not completely nullify this activity. PMID- 20714685 TI - Association of parental history of type 2 diabetes mellitus with leptin levels in Jordanian male youths. AB - OBJECTIVE: To investigate the association between high level serum leptin in male youths in relation to parental history of type 2 diabetes mellitus (T2DM) and body mass index (BMI). METHODS: This cross-sectional study was carried out at the Department of Medical Technology, Applied Science University, Amman, Jordan during the period from January to April 2009. One hundred and sixteen Jordanian male nursing students aged 18-24 years were divided into 4 groups according to parental history of T2DM and BMI. Fasting blood samples were measured for blood glucose, lipid profile, and serum leptin. RESULTS: Serum leptin levels in overweight and obese male youth diabetic patients with parental history of T2DM were significantly higher than in those overweight and obese without parental history (p<0.001). Of the 116 subjects, 83 (71.6%) had a positive parental history of T2DM. Compared with other groups, significant (p<0.001) elevation was observed in the mean cholesterol and triglyceride levels of obese T2DM. No significant differences were detected in high-density lipoprotein, low-density lipoprotein, and blood glucose levels among all study groups. CONCLUSION: High levels of leptin in overweight and obese Jordanian male youths were more likely associated with a positive parental family history of T2DM than BMI factor. PMID- 20714686 TI - The association of serum total cortisol and pneumonia severity index. AB - OBJECTIVE: To study the relation between severity of pneumonia and serum cortisol level in a cohort of Egyptian patients. METHODS: All consecutive adult patients with community acquired pneumonia (CAP) admitted to Mansoura University Hospital, Mansoura, Egypt between March 2008 and December 2008 were considered for study inclusion. Exclusion criteria were patients with HIV infection, impaired immune systems, collagen vascular disease, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), asthma requiring 10 mg of prednisolone at least daily, active malignant neoplasm, congestive heart failure (CHF), liver cirrhosis, or other causes of hypoproteinemia and septic shock. Pneumonia severity was scored at hospital admission according to pneumonia severity index (PSI) using the PORT criteria. The serum total cortisol was measured at hospital admission using ELISA. RESULTS: The present study comprised 23 adult patients with CAP: 14 male and 9 females with a mean age of 47 +/- 16.7 years. Total serum cortisol (mean 483.11 +/- 387.91 nmol/L) was positively correlated (p=0.012, R=0.576) with pneumonia severity as assessed by the PSI. Moreover, the total serum cortisol levels showed significantly negative correlation with arterial oxygen tension (R= 0.500, p=0.035), oxygen saturation % (R=0.450, p=0.029), and bicarbonate level (R=0.266, p=0.03), as well as a significant positive correlation with the extent of lung involvement (p=0.041). CONCLUSION: Total serum cortisol showed a significantly positive correlation with the severity of CAP assessed by the PORT index (PSI) in our study population. A single measurement of total serum cortisol may provide helpful information as the complex 20-variables, which are used in pneumonia severity index. PMID- 20714687 TI - Rotavirus and coeliac autoimmunity among adults with non-specific gastrointestinal symptoms. AB - OBJECTIVE: To determine celiac disease (CD) serology and rotavirus (RV) by polymerase reaction (PCR) in adults with non-specific gastrointestinal complaints. METHODS: The study comprised 5176 randomly selected individuals living in Tehran, Iran between September 2006 and September 2007. Six hundred and seventy individuals with GI symptoms were identified with a questionnaire and invited for a further study including stool sampling and blood tests. Stool samples were examined for detection of RV by amplification of specific gene (VP6) and by light microscopy and formalin-ether concentration methods for parasite detection. The subjects also tested for CD including anti-transglutaminase (tTG) antibodies and total immunoglobulin A (IgA). The study was carried out in the Research Center of Gastroentrology and Liver Disease, Taleghani Hospital, Tehran, Iran. RESULTS: The VP6 gene was detected in 150 (22.3%) individuals. Anti-tissue transglutaminase (tTG-IgA) was positive in 22 individuals (95% CI 2.3-5.1) and IgG-tTG antibody in 3 individuals who were IgA deficient. Amplification of VP6 gene was positive in 8/25 (32%) with positive CD serology and in 142/645 (22%) with negative CD serology. This difference was not statistically significant (p=0.2). CONCLUSION: This study shows that RV infection is common among Iranian patients with non-specific gastrointestinal symptoms. However, in contrast to studies in children, this study shows that the prevalence of active RV infection was not statistically significantly different between individuals who were tTG antibody positive and those who were tTG antibody negative. PMID- 20714688 TI - A comparison of red-green color vision deficiency between medical and non-medical students in Pakistan. AB - OBJECTIVE: To investigate the prevalence of red-green color vision deficiency (CVD) among medical and dental students compared with non-medical students. METHODS: This descriptive, cross-sectional study compared the prevalence of CVD between medical and non-medical Pakistani students. A total of 926 medical and dental students from Baqai Medical University, Karachi, Pakistan were compared with 7288 non-medical students from Nadirshaw Edulji Dinshaw University of Engineering and Technology, Karachi, Pakistan, and Pakistan Air Force (PAF) Public Schools (Muree and Sargodha), Pakistan. Standard Ishihara color vision charts were used, which provided an accurate assessment of CVD. More than 3 mistakes from plates 10-17 identified students as having red green CVD. The study was carried out from September 2003 to December 2008. RESULTS: The overall prevalence of CVD in the study population was 2.75%. They were no significant differences between male students in engineering college versus medical college (2.7% versus 4.4%, p=0.125), or between schools and universities (3.1% versus 3.1%, p=0.930). CONCLUSION: A small proportion of the Pakistani population suffers from red-green CVD, more prominent in males. We found no differences between students in engineering college versus medical college, or between schools and universities in different geographical locations within Pakistan. PMID- 20714689 TI - A preliminary study of endoscopic acoustic stapedial reflex in chronic otitis media. AB - OBJECTIVE: To introduce the endoscopic acoustic stapedial reflex (EASR) as a technique for assessing stapedial mobility in ears with chronic otitis media (COM). METHODS: This prospective study was performed from February 2008 to February 2009, patients with COM presented to the Otology Clinic, King Abdul-Aziz University Hospital, Riyadh, Kingdom of Saudi Arabia were examined with a rigid ear endoscope to visualize the stapedius tendon and the head of stapes. The reflex is elicited by pulsed sound stimuli. The stapedius muscle contraction and the mobility of the stapes are visualized during exposure ipsilaterally, and contralaterally to sound stimuli. RESULTS: Conventional tympanometry did not detect a stapedial reflex in any of the 10 patients. Acoustic stapedial reflex was detected in all ears. Despite a visible stapedial muscle contraction, one patient did not demonstrate stapes movement, and was confirmed to have stapes fixation at surgery. All patients tolerated the test with no complications, or side effects. CONCLUSION: The EASR was introduced for the first time. In addition to the well-known value of the stapedial reflex testing, it provides a safe, and reliable method for assessment of stapes mobility. PMID- 20714690 TI - Results of primary total hip replacement with special attention to technical difficulties encountered in a cohort of Saudi patients. AB - OBJECTIVE: To illustrate our experience and the difficulty faced in primary total hip replacement (THR) in Saudi patient population. METHODS: We retrospectively reviewed our database between February 2002 to December 2007 for primary THR cases at King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia and identified 58 hips (54 patients). Patients data were collected from patient's medical records, clinical examination, and x-ray films. Operative reports were examined for the difficulty encountered during surgery and was classified into femoral, acetabular, soft tissue and combined difficulties. Patients follow up was a minimum of 2 years. RESULTS: The indication of surgery was posttraumatic arthritis in 50%, sickle cell anemia related avascular necrosis in 16.6%, primary osteoarthritis in 9.2%, idiopathic avascular necrosis in 9.2%, rheumatoid arthritis in 7.4%, and other indications were 14.7%. The femoral obstacles included narrow femoral canal in 27.7% and proximally migrated femur in 5.5%. Acetabular obstacles included protrusio acetabuli in 14.8% and structural posterior acetabular bone defect in 5.5%. Soft tissue obstacles included tight capsule in 14.8% and muscle contracture in 11.1%. CONCLUSION: Our Saudi patient population has shown different pathology of their hip disease in which most of the hips being posttraumatic as compared to series published in the west. We advised those who intend to tackle THR in this population to perform extensive preoperative planning in order to be able to anticipate the difficulty demonstrated by our experience. PMID- 20714691 TI - Adverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-based study. AB - OBJECTIVE: To evaluate the side effects of methotrexate (MTX) in rheumatoid arthritis (RA) patients and to evaluate the possible predisposing variables. METHODS: A retrospective analysis conducted for all patients diagnosed with RA and treated with MTX over 3-years (January 2006 to December 2008) at King Abdul Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia. Frequency of MTX side effects and the predictive variables were recorded and analyzed statistically. RESULTS: Out of 116 RA patients, 71 patients used MTX. The most frequent side effect was gastrointestinal (GIT) disturbance in 31%, followed by central nervous system symptoms in 18%, hepatotoxicity in 14%, stomatitis and alopecia in 10% each, macrocytosis 7%, fever, malar rash and pancytopenia in 4%, and MTX-induced lung injury with increase in the size of rheumatoid nodule in 1% of patients. By Logistic regression analysis, renal impairment was the most significant variable increasing the risk of the side effects (OR=7.14, p<0.05). Other associated variables were male-gender, non-Saudi nationality, smoking, steroids use, hypoalbuminemia, and the presence of extra-articular manifestations. CONCLUSION: Methotrexate is the most commonly drug used in the treatment of RA. Gastrointestinal disturbances were the most common side effect while lung involvement was the least. The impact of each clinical variable on MTX side effects requires paying more attention on the disease management as not all variables can be considered as risk factors. PMID- 20714692 TI - Hypertensive crisis. Clinical presentation, comorbidities, and target organ involvement. AB - OBJECTIVE: To evaluate the clinical presentation and comorbidities of hypertensive crisis in our own population. METHODS: In this cohort based study, we investigate the clinical presentation and comorbidities of hypertensive crisis by evaluating the data collected between January and April 2009. We included 154 patients admitted with systolic and diastolic blood pressure of >179 mm Hg and >119 mm Hg (based on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria) in the Department of Internal Medicine, Salmaniya Medical Complex, Kingdom of Bahrain. RESULTS: In the study population, 64.3% had hypertensive urgency (blood pressure elevation without end organ damage) and 35.7% had hypertensive emergency (blood pressure elevation with end organ damage). The mean age group was 45-65 years (56% of the study population) and more men were affected than women (100:54). Shortness of breath and neurological deficits had a strong statistical association with hypertensive emergency, and headache and blurring of vision had the same tendency toward hypertensive urgency. Diabetes mellitus was an independent risk factor for hypertensive crisis. CONCLUSION: Most of the studied patients were known hypertensive. Diabetes mellitus is powerful predictor for hypertensive crisis. Dyspnea and neurological deficits have significant statistical correlation with hypertensive emergencies. PMID- 20714693 TI - Recurrent visits and admissions of children with asthma in central Saudi Arabia. AB - OBJECTIVE: To identify the pediatric age group and most affected gender by asthma, and to determine the significant predictors of severity of asthma, and assess the appropriateness of asthma medication administration. METHODS: This cross-sectional study was carried out at Emergency Department (ED) of children's Hospital at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia from January to March 2009. Interviews were carried out with the parents of 185 children, who presented to the Hospital with asthma exacerbation more than once over the last 6 months, to collect data of possible risk factors, and appropriateness of medication administration technique. RESULTS: Most patients were males 71.9%, aged 1-6 years (58.9%), and 8.1% of them presented to the ED because of asthma exacerbation more than once over the last 6 months. Approximately two-thirds (65.9%) of the parents explained the way of meter dose inhaler administration correctly. Infants were significantly the least affected group (p=0.02). Severity was significantly higher among appropriate users of medications (p=0.046). CONCLUSION: Appropriateness of medications administration was significantly associated with severity. However, this may not be considered a valid predictor of severity, as parents of children with recurrent attacks may have a better chance of being taught how to use medications. PMID- 20714694 TI - Patterns of referral in the Family Medicine Department in Southeastern Saudi Arabia. AB - OBJECTIVE: To assess the referral pattern and identify the appropriateness of the referral letter and consultants feedback. METHODS: This cross-sectional study was performed at the Family Medicine Department, Sharurah Armed Forces Hospital (SAFH), Sharurah, Kingdom of Saudi Arabia. The study population (sampled population) included all referrals in one month (June 2009). We obtained the appropriateness of the referral letter, consultants' feedback, and patients and physician's characteristics using research tools. The fieldwork was conducted during the period of August to September 2009 and the study was completed in January 2010. RESULTS: Overall, the referral rates was 16%. The percentage of referred male patients were 40.5% (n=183) and females were 59.5% (n=269). The variables of the administrative part of the referral letter (such as age, gender of the referred patient) were present and clear (readable) in most of the patients. Also, the scores of different administrative items of the referral letter were higher (> or =95%) than the clinical items (such as history taking and physical examination). Inappropriate consultant feedbacks (53%) were significantly higher than inappropriate primary health care referral letters (12%) ( p=0.008). CONCLUSION: The results of this study suggest that the quality standard of referral process needs to be improved as the received referrals letters and feedback reports were poor. PMID- 20714695 TI - Neurofibromatosis associated with hypertrophic cardiomyopathy. AB - We present a case of an 18-year-old boy with neurofibromatosis type 1 and hypertrophic cardiomyopathy with systolic anteward movement of the anterior leaflet of the mitral valve. Gradient in the left ventricular outflow was 85 mm Hg secondary to subvalvular aortic stenosis with left ventricular diastolic dysfunction. The possibility of a coincidence, or a causal relationship of these 2 conditions is mentioned. PMID- 20714696 TI - Magnetic resonance imaging assessment of the pectoralis major muscle rupture. PMID- 20714697 TI - Long-term results of phakic anterior chamber intraocular lens implantation in myopic eyes. PMID- 20714698 TI - Clinical profile of cystic fibrosis. Atypical presentation. PMID- 20714699 TI - Pediatric heart diseases in Madina, Saudi Arabia. Current status and future expectations. PMID- 20714700 TI - Prevalence of rubella IgG antibodies among Syrian females of childbearing age. PMID- 20714701 TI - [Preoperative evaluation and risk estimation in thoracic surgery]. AB - Preoperative evaluation of patients undergoing lung resection remains an interdisciplinary challenge. Despite substantial progress in anesthesiology, intensive care medicine and surgery, mortality of patients undergoing pneumonectomy remains high at 5-9%. Guidelines were developed to identify patients with an increased perioperative risk for morbidity and mortality. These guidelines are focused around the forced expiratory capacity (FEV) measured by spirometry, following further investigations in patients with limited FEV(1). Extended testing includes measurement of the diffusion capacity, calculation of postoperative predicted values of lung function and spiroergometry to determine maximal oxygen uptake. In this article the methods to measure parameters of lung function and gas exchange are described and evaluated in the context of the current guidelines. PMID- 20714702 TI - [Indocyanine green plasma disappearance rate: estimation of abdominal perfusion disturbances]. AB - Increased intraabdominal pressure (IAP) and abdominal compartment syndrome (ACS) are diseases which are often underestimated with respect to incidence and prognosis especially in critically ill patients. The clinical gold standard for the determination of IAP is the urinary bladder measurement technique. For assessment of hepatosplanchnic perfusion the indocyanine green plasma disappearance rate (ICG-PDR) has recently become a clinically attractive method. In this investigation a decrease in splanchnic perfusion caused by increased IAP was observed in critically ill patients with abdominal focused sepsis or postoperative systemic inflammatory response syndrome (SIRS). It was found that the reduction of ICG-PDR as a measure of splanchnic blood flow correlated with the increase of IAP, i.e. increased IAP is associated with lower ICG-PDR. Furthermore, the data suggest that a relevant decrease of splanchnic blood flow may appear even during lower IAP than previously assumed. PMID- 20714703 TI - Histone methyltransferases: regulation of transcription and contribution to human disease. AB - Histone modifications contribute to the precise regulation of transcription by recruiting non-histone proteins and controlling chromatin conformation. These covalent modifications are dynamically regulated by many enzymes that modify histones at specific residues in different ways. Histone modifiers contribute to development as well as cellular responses to extracellular stimuli. Mutations in the genes encoding them cause various diseases, including developmental disorders and certain malignancies. Haploinsufficiency for some histone methyltransferases, one of the principal modifiers of the histone modification network, are associated with particular congenital diseases, including Sotos syndrome, Wolf Hirschhorn syndrome, and 9q syndrome. In this review, we discuss the molecular function of the histone methyltransferases and the human diseases associated with their dysfunction. PMID- 20714704 TI - Mitochondria and aging in the vascular system. AB - This review focuses on mitochondrial abnormalities that occur in the vasculature during aging and explores the link between mitochondrial oxidative stress, chronic low-grade vascular inflammation, increased rate of endothelial apoptosis, and development of vascular diseases in the elderly. Therapeutic strategies targeting the mitochondria for prevention of age-associated vascular dysfunction and disease in old age are considered here based on emerging knowledge of the vasoprotective effects of caloric restriction, caloric restriction mimetics, the GH/IGF-1 axis, and mitochondria-targeted antioxidants. PMID- 20714705 TI - Genetical and molecular analysis reveals a cooperating relationship between cytoplasmic male sterility- and fertility restoration-related genes in Oryza species. AB - Although the characterization of genes associated with cytoplasmic male sterility (CMS) and fertility restoration (Rf) has been well documented, the evolutionary relationship between nuclear Rf and CMS factors in mitochondria in Oryza species is still less understood. Here, 41 accessions from 7 Oryza species with AA genome were employed for analyzing the evolutionary relationships between the CMS factors and Rf candidates on chromosome 10. The phylogenetic tree based on restriction fragment length polymorphism patterns of CMS-associated mitochondrial genes showed that these 41 Oryza accessions fell into 3 distinct groups. Another phylogenetic tree based on PCR profiles of the nuclear Rf candidates on chromosome 10 was also established, and three groups were distinctively grouped. The accessions in each subgroup/group of the two phylogenetic trees are well parallel to each other. Furthermore, the 41 investigated accessions were test crossed with Honglian (gametophytic type) and Wild-abortive (sporophytic type) CMS, and 5 groups were classified according to their restoring ability. The accessions in the same subgroup of the two phylogenetic trees shared similar fertility restoring pattern. Therefore, we conclude that the CMS-associated mitotypes are compatible to the Rf candidate-related nucleotypes, CMS and Rf have a parallel evolutionary relation in the Oryza species. PMID- 20714706 TI - Generic and crime type specific correlates of youth crime: a Finnish population based study. AB - OBJECTIVE: The aim of this study was to examine the psychosocial correlates of various crime types among adolescent males born in Finland in 1981. METHODS: Data on crime registered in the Finnish National Police Register between 1998 and 2001 were received for 2,866 boys, of whom 81% (n = 2,330) filled in a questionnaire at obligatory military call-up at age 18 in 1999. Crime was divided into five types: drug, violent, property, traffic, and drunk driving offences. RESULTS: Of the 2,866 boys, 23% had been registered for offending; 4% for drug, 7% for violent, 11% for property, 11% for traffic, and 5% for drunk driving offences during the 4-year period in late adolescence. All the crime types correlated with each other and shared many of the psychosocial problems. Small community size, parents' divorce, aggressiveness, daily smoking, and weekly drunkenness were generic correlates of crime, being independently related to various crime types. CONCLUSIONS: The results support general rather than specific accounts of youth crime. In particular, measures moderating the adverse effects of divorce, alleviating parental adversities and supporting parenthood, and tackling substance abuse seem relevant in social and criminal policy because they address psychosocial problems characterizing youth crime in general. PMID- 20714707 TI - [Gorham-Stout syndrome (GSS) with fulminant aseptic osteonecrosis of the shoulder]. AB - We report here a case of the rare Gorham-Stout syndrome (GSS) of the humerus. GSS is a disease in the course of which spontaneous idiopathic osteolysis occurs. We describe a case of a 46-year-old business economist who suffered an inadequate trauma and within 3 weeks developed self-limited idiopathic osteolysis of the left humerus head, also affecting the rotator cuff. This could be diagnosed especially on the basis of histopathological findings. Hereupon we indicated operative repair by means of inverted shoulder joint endoprosthesis. PMID- 20714708 TI - Juvenile stress attenuates the dorsal hippocampal postsynaptic 5-HT1A receptor function in adult rats. AB - RATIONALE: Traumatic events in early life are associated with an increased risk of psychiatric diseases in adulthood. 5-hydroxytryptamine (5-HT)(1A) receptors play a pivotal role in the 5-HTergic mechanisms associated with the etiology of stress-related disorders. OBJECTIVE: The goal of the present study was to investigate whether juvenile stress influences emotional control via postsynaptic 5-HT(1A) receptor in the hippocampus and amygdala using contextual fear conditioning test in adult rats. METHODS: The rats were subjected to aversive footshock (FS) during the third week of the postnatal period (3wFS group). During the postadolescent period (10-14 weeks postnatal), experiments were performed. RESULTS: The systemic administration of the 5-HT(1A) receptor agonist R-(+)-8 hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.2 mg/kg, i.p.) attenuated the freezing behavior in the non-FS group, but not in the 3wFS group. The bilateral local injection of 8-OH-DPAT (1 MUg/side) into the amygdala decreased the freezing behavior in the non-FS group and the 3wFS group. However, the local injection of 8-OH-DPAT (1 MUg/side) into the hippocampus decreased the freezing behavior in the non-FS group, but not in the 3wFS group. In a 5-HT(1A) receptor binding study, the Bmax of the 3wFS group decreased in the dorsal hippocampus, but not the amygdala in comparison with the non-FS group. CONCLUSIONS: The juvenile stress attenuated the hippocampal postsynaptic 5-HT(1A) receptor function in context-dependent conditioned fear. PMID- 20714709 TI - Effects of acute modafinil on cognition in trichotillomania. AB - RATIONALE: Individuals with trichotillomania often report significant difficulty resisting the urges and drive to pull hair. OBJECTIVES: The aim of this study is to examine whether modafinil improves motor inhibitory control, and other cognitive functions, in trichotillomania. METHODS: Eighteen subjects with trichotillomania (mean age 33.4 +/- 12.8 years; 78% female) received a single dose of modafinil (200 mg) and placebo in a crossover double-blind design. Neurocognitive performance was assessed using the stop-signal, pattern recognition, rapid visual information processing and Tower of London tasks. RESULTS: No effects of modafinil on cognition approached statistical significance on the test measures examined (all p > 0.10). CONCLUSIONS: These results suggest that modafinil may not be useful for targeting impulse dyscontrol in trichotillomania. However, it remains possible that relatively small effects of modafinil on cognition could exert larger downstream effects on overt behaviour. Further trials using modafinil and other pro-cognitive agents are warranted. PMID- 20714710 TI - Body posture affects tactile discrimination and identification of fingers and hands. AB - It is an unresolved question whether the posture of single fingers relative to each other is represented in the brain within an external frame of reference. In two experiments, we investigated postural influences on the processing of tactile stimuli at fingers and hands. Healthy subjects received two simultaneous tactile stimuli at the fingertips while the fingers of both hands were either interleaved or not. In speeded response tasks, they were asked to discriminate (experiment 1) or to identify (experiment 2) the touched body parts, either regarding hand laterality or finger type. The results demonstrate that both finger discrimination and finger identification are influenced by body posture. We conclude that the assumption of a solely somatotopic representation of fingers is not tenable and that an external reference system must be available for the detection of single fingers. The results are discussed in terms of a mental segmentation of external space, based on body posture and task requirements. PMID- 20714711 TI - Dual-task costs and benefits in anti-saccade performance. AB - It has been reported that anti-saccade performance is facilitated by diverting attention through a secondary task (Kristjansson et al. in Nat Neurosci 4:1037 1042, 2001). This finding supports the idea that the withdrawal of resources that would be taken up by the erroneous movement plan makes it easier to overcome the tendency to look towards the imperative stimulus. We first report an attempt to replicate this finding. Four observers were extensively tested in an anti-saccade paradigm. The luminance of the fixation point or peripheral target was briefly increased or decreased. In the dual-task condition observers signalled the direction of the luminance change. In the single-task condition the discrimination stimulus was presented, but could be ignored as it required no response. We found an overall dual-task cost in anti-saccade latency, although some facilitation was observed in the accuracy. The discrepancy between the two studies was attributed to performance in the single-task condition. For latency facilitation to occur, performance should not be affected by the discrimination stimulus when it is task-irrelevant. We show that naive, untrained observers could not ignore this irrelevant visual event. If it occurred before the imperative movement signal, the event acted as a warning signal, speeding up anti saccade generation. If it occurred after the imperative movement stimulus, it acted as a remote distractor and interfered with the generation of the correct movement. Under normal circumstances, these basic oculomotor effects operate in both single- and dual-task conditions. An overall dual-task cost rides on top of this latency modulation. This overall cost is best accounted for by an increase in the response criterion for saccade generation in the more demanding dual-task condition. PMID- 20714713 TI - Bilateral congenital midureteric strictures associated with multicystic dysplastic kidney and hydronephrosis: evaluation with MR urography. AB - We report a case of bilateral congenital midureteric strictures diagnosed using MR urography. The severity of obstruction differed in the two ureters, resulting in a multicystic dysplastic kidney (MCDK) with an atretic ureter on one side and hydronephrosis that worsened over time due to progressive stenosis on the other. Although midureteric strictures are usually misdiagnosed as ureteropelvic junction (UPJ) or ureterovesical junction (UVJ) obstruction on conventional imaging, MR urography was able to clearly demonstrate both the anatomical and functional abnormalities. Additionally, because of the excellent anatomical resolution, similarities in the underlying pathological lesions could be contrasted with the severity of the pathophysiological impact upon each kidney. PMID- 20714714 TI - Update on congenital nephrotic syndromes and the contribution of US. AB - The clinical classification of nephrotic syndrome (NS) is based on age at presentation. However, this classification is arbitrary because the majority of early onset NS has a genetic origin and has a widespread age of onset (from fetal life to several years). The aims of this review are to illustrate the knowledge accumulated on congenital nephrotic syndrome (CNS) in terms of genetics, classification, findings at histology and US-based on a review of the literature. PMID- 20714712 TI - Neglect dyslexia: a review of the neuropsychological literature. AB - Neglect dyslexia (ND) is reviewed, based on published single-patient and group studies. ND is frequently associated with right hemispheric damage and unilateral spatial neglect (USN), and typically involves the left side of the letter string. Left-brain-damaged patients showing ND, ipsilateral (left) or contralateral (right) to the side of the left-sided hemispheric lesion, have also been reported, as well as a few patients with bilateral damage, with more frequently left than right ND. As USN, ND is temporarily ameliorated by lateralized stimulations (vestibular caloric, visual prism adaptation). ND may occur independent of USN, suggesting the damage to specific visuospatial representational/attentional systems, supporting reading. ND errors comprise omission, substitution, and, less frequently, addition of letters on one side of the stimulus, resulting in words or nonwords, also with reference to the stimulus' linguistic features. Patients with ND may show preserved lexical morphological effects and implicit processing, up to the semantic level, of the misread string. This preserved processing is a feature of ND, shared with the USN syndrome. The mechanisms modulating error type and lexical-morphological effects are partly independent of each other. Different levels of representation of the letter string may be affected, giving rise to egocentric, stimulus-centred, and word-centred patterns of impairment. The anatomical correlates of ND include the temporo-parieto-occipital regions. PMID- 20714715 TI - Hepatocellular carcinoma and regenerating nodule in a 3-year-old child with Alagille syndrome. AB - In Alagille syndrome, routine follow-up imaging of the liver plays an important role in detecting early parenchymal changes and to evaluate portal hypertension. Modern contrast-enhanced imaging methods not only allow early detection of focal liver lesions, but also enable further characterization of their nature and guide biopsy procedures. We present the US and MR imaging findings of hepatocellular carcinoma and a regenerating nodule in a 3-year-old child with Alagille syndrome. PMID- 20714716 TI - Solitary osteochondroma: spontaneous regression. AB - Osteochondromas are the most common benign bone tumours. Nevertheless, their origin and biological behaviour are poorly understood. Rarely, spontaneous regression of osteochondromas may occur. We report the case of a 9-year-old girl with a solitary osteochondroma of the femur that regressed almost completely within 4 years, a fact that should be taken into account when deciding the management of these lesions, especially in young children. PMID- 20714717 TI - Transcriptional response of the catharanthine biosynthesis pathway to methyl jasmonate/nitric oxide elicitation in Catharanthus roseus hairy root culture. AB - Jasmonates and nitric oxide (NO) play important roles in the regulation of the signaling network leading to the biosynthesis of plant secondary metabolites. In this work, we explore the effect of constitutive overexpression of CrORCA3 (octadecanoid-responsive Catharanthus AP2/ERF domain), methyl jasmonate (MeJA), and sodium nitroprusside (SNP) on the differentiated tissue of Catharanthus roseus hairy roots. The changes in catharanthine concentration and in the levels of mRNA transcripts of pathway genes and regulators were tracked for 192 h. ORCA3 overexpression led to a slight decrease of the accumulation of catharanthine, while MeJA treatment caused a large increase in the levels of transcripts of pathway genes and the catharanthine concentration. SNP treatment alone or SNP in combination with MeJA treatment caused a dramatic decrease of the cathanranthine concentration, while at the same time the levels of transcripts of zinc finger binding proteins genes (ZCTs) increased. The latter treatment also caused a decrease of the levels of transcripts of type-I protein prenyltransferase gene (PGGT-I). This response of transcriptional repressors and pathway genes may explain the antagonistic effects of NO and MeJA on catharanthine biosynthesis in C. roseus hairy roots. PMID- 20714718 TI - Chemical and microbial community analysis during aerobic biostimulation assays of non-sulfonated alkyl-benzene-contaminated groundwater. AB - A chemical and microbial characterization of lab-scale biostimulation assays with groundwater samples taken from an industrial site in which the aquifer had been contaminated by linear non-sulfonate alkyl benzenes (LABs) was carried out for further field-scale bioremediation purposes. Two lab-scale biodegradability assays were performed, one with a previously obtained gas-oil-degrading consortium and another with the native groundwater flora. Results for the characterization of the groundwater microbial population of the site revealed the presence of an important LAB-degrading microbial population with a strong degrading capacity. Among the microorganisms identified at the site, the detection of Parvibaculum lavamentivorans, which have been described in other studies as alkyl benzene sulfonates degraders, is worth mentioning. Incubation of P. lavamentivorans DSMZ13023 with LABs as reported in this study shows for the first time the metabolic capacity of this strain to degrade such compounds. Results from the biodegradation assays in this study showed that the indigenous microbial population had a higher degrading capacity than the gas-oil-degrading consortium, indicating the strong ability of the native community to adapt to the presence of LABs. The addition of inorganic nutrients significantly improved the aerobic biodegradation rate, achieving levels of biodegradation close to 90%. The results of this study show the potential effectiveness of oxygen and nutrients as in situ biostimulation agents as well as the existence of a complex microbial community that encompasses well-known hydrocarbon- and LAS-degrading microbial populations in the aquifer studied. PMID- 20714719 TI - A new alpha-galactosidase from symbiotic Flavobacterium sp. TN17 reveals four residues essential for alpha-galactosidase activity of gastrointestinal bacteria. AB - The alpha-galactosidase gene, galA17, was cloned from Flavobacterium sp. TN17, a symbiotic bacterium isolated from the gut of Batocera horsfieldi larvae. The 2,205-bp full-length gene encodes a 734-residue polypeptide (GalA17) containing a putative 28-residue signal peptide and a catalytic domain belonging to glycosyl hydrolase family 36 (GH 36). The deduced amino acid sequence of galA17 was most similar to a putative alpha-galactosidase from Pedobacter sp. BAL39 (EDM38577; 66.6% identity) and a characterized alpha-galactosidase from Carnobacterium piscicola BA (AAL27305; 30.1%). Phylogenetic analysis revealed that GalA17 was similar to GH 36 alpha-galactosidases from symbiotic bacteria sharing two putative catalytic motifs, KWD and SDXXDXXXR, in which D480, S548, D549, and R556 were essential for alpha-galactosidase activity based on site-directed mutagenesis. Purified recombinant GalA17 showed apparent optimal activity at pH 5.5 and 45 degrees C; exhibited strong resistance to digestion by trypsin, alpha chymotrypsin, collagenase, and proteinase K; and efficiently hydrolyzed several synthetic and natural substrates (p-nitrophenyl-alpha-D-galactopyranoside, stachyose, melibiose, raffinose, soybean meal, locust bean gum, and guar gum). PMID- 20714720 TI - Development of a three-dimensional detection method of cam deformities in femoroacetabular impingement. AB - OBJECTIVE: The description of femoral head sphericity and related risk for femoroacetabularimpingement is currently limited to an angular estimate-the alpha angle-whose relevance and accuracy have been challenged. We developed a three dimensional approach for both automated digital measurement of the alpha angle and the detection of camdeformities. Accuracy and diagnostic relevance of the alpha angle estimated by means of the oblique axial and multiple radial plane protocol were compared with the computed results. MATERIALS AND METHODS: Using subject-specific statistical information of the femur head and mid-neck region, a method was developed to accurately compute the maximum alpha angle and to define aspherical eccentric areas at the femoral head-neck junction. The method was evaluated on 102 dry cadaver femur specimens. RESULTS: Average detection limit for bony prominences at the head-neck transition was 0.98 mm. Pixel size of the investigated CT data was 0.79 mm. Mean maximum computed alpha angle of the femurs with cam-type morphology as identified by the morphological method was 67.72 degrees (range 53.04-88.02 degrees ). Mean maximum computed alpha angle of the femurs without cam deformity was 47.65 degrees (range 38.67-59.81 degrees ). Alpha angle estimates obtained by means of the multiple radial plane protocol correlated better (R = 0.88) and showed higher diagnostic agreement (phi = 0.77) with the 3D computational analysis compared to the oblique axial protocol (R = 0.60; phi = 0.67). CONCLUSIONS: The alpha angle seems to be a relevant screening tool when obtained by 3D computed analysis or when estimated according to the multiple radial plane protocol. Estimates obtained by means of the oblique axial protocol have insufficient diagnostic and measurement accuracy. PMID- 20714721 TI - A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rgamma(null) mouse lymphoma model. AB - Engineering the Fc region of monoclonal antibodies (mAb) in order to enhance effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC) is likely to a be promising approach for next-generation mAb therapy. Here, we report on such an antibody, 113F, a novel CDC-enhancing variant of rituximab, and determine the tumor-associated factors influencing susceptibility to 113F-induced CDC. The latter included the quantity of complement inhibitors present, such as CD55 and CD59. We report that compared to rituximab, 113F mediated highly enhanced CDC against primary CD20-expressing lymphoma cells in vitro. Currently, a major problem in the field of immunotherapy research is the lack of suitable small animal models to evaluate human CDC in vivo. Therefore, we established a novel human tumor-bearing NOD/Shi-scid, IL 2Rgamma(null) mouse model, in which human complement functions as the CDC mediator. We demonstrated that rituximab exerted significant antitumor effects via human CDC in this humanized mouse. The finding of specific localization of human C1q on CD20-expressing tumor cell membranes was consistent with the observation that human CDC indeed contributed to the antitumor effect in this model. Moreover, 113F exerted significantly more potent antitumor effects than rituximab in this in vivo model. The detection of more abundant dense signals from C1q using 113F compared to rituximab was consistent with the concept that this reagent represented a CDC-enhancing mAb. In the near future, the efficacy of this type of CDC-enhancing antibody will be determined in clinical trials in humans. PMID- 20714722 TI - Primary mantle cell lymphoma of the testis. PMID- 20714723 TI - Cost-effectiveness of adenotonsillectomy in reducing obstructive sleep apnea, cerebrovascular ischemia, vaso-occlusive pain, and ACS episodes in pediatric sickle cell disease. AB - In children with sickle cell disease (SCD), adenotonsillar hypertrophy or recurrent tonsillitis are frequently linked with an increased risk of obstructive sleep apnea, cerebrovascular ischemia, or frequent pain episodes and often require an adenoidectomy and/or tonsillectomy. Interventions designed to prevent these complications, control vaso-occlusive pain episodes, and avoid hospitalizations may reduce the significant personal and economic burden of SCD. This study compares episode recurrence and treatment costs for cerebrovascular ischemia, vaso-occlusive pain, acute chest syndrome (ACS), and obstructive sleep apnea in children who had an adenotonsillectomy (A/T surgery, N = 256; 11.7%) and a matched cohort of those who did not (N = 512; 23.3%) from a cohort of 2,194 children and adolescents with SCD from South Carolina's Medicaid system. A/T surgery was associated with a significantly reduced rate of visits over time for obstructive sleep apnea and cerebrovascular ischemia (e.g., stroke, transient ischemic attacks), but not with any change in the rate of visits for vaso occlusive pain or ACS/pneumonia visits. The rate of mean acute (emergency and inpatient) service costs was significantly decreasing over time after an increase about the time the A/T surgery was performed. The cost-effectiveness of adenoidectomy and/or tonsillectomy for treating obstructive sleep apnea and preventing cerebrovascular ischemia without increasing vaso-occlusive pain episodes or long-term acute service costs in routine clinical practice settings was demonstrated. The matched control group of SCD patients without A/T surgery contained more patients with severe vaso-occlusive pain episodes, ACS visits, and higher mean total costs over time and appears to represent a different phenotype of children with SCD. PMID- 20714725 TI - Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal). AB - Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that results from mutations in the HFE gene. Almost all patients with hereditary hemochromatosis show a C282Y mutation in homozygosity or in compound heterozygosity with H63D. Also, the mutation S65C has been shown to be associated to a milder iron overload. Since allele and genotype frequencies of these three variants of the HFE gene vary between populations, the determination of their prevalence in Madeira Island will clarify the population susceptibility to hereditary hemochromatosis. One hundred and fifty-four samples from Madeira Island were genotyped for the three most common HFE gene mutations, H63D, C282Y, and S65C, by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results have shown a prevalence of 20.5%, 0.33%, and 1% for H63D, C282Y, and S65C, respectively. Accordingly to our estimates, both genotypes associated to hereditary hemochromatosis, C282Y homozygotes and C282/H63D compound heterozygotes, could be present in Madeira Island population in 1,648 individuals, which represents 0.65% of the total population. PMID- 20714724 TI - Resveratrol increases rate of apoptosis caused by purine analogues in malignant lymphocytes of chronic lymphocytic leukemia. AB - In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL 2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (gammaH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in gammaH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis. PMID- 20714726 TI - A phase II and pharmacokinetic study of first line S-1 for advanced gastric cancer in Taiwan. AB - PURPOSE: To evaluate the efficacy, safety and pharmacokinetic profiles of S-1, which composed of tegafur (FT, a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine and potassium oxonate (Oxo), in Taiwanese advanced gastric cancer (AGC) patients. METHODS: Patients with chemo-naive, histologically confirmed AGC were eligible. S 1 was given orally at dose of 40, 50 or 60 mg, twice daily for patients with body surface <1.25, 1.25-1.5 and >1.5 m(2), respectively, on day 1-28 every 42 days/cycle. RESULTS: Thirty-four patients were included. On intent-to-treat analysis, the overall response rate, median progression-free and overall survival were 35.3% [95% confidence interval (CI): 19.2-51.3%], 2.9 (95% CI: 2.4-5.8) months and 9.8 (95% CI: 6.1-NA) months, respectively. The most common grade 3-4 toxicities were anemia 23.5% and neutropenia 11.8%. There were two treatment related mortality, which occurred in patients with suboptimal renal function underestimated by serum creatinine level at study entry. Single-dose pharmacokinetic study showed trend toward lower AUC(5-FU), and higher AUC(FT) and AUC(Oxo) comparing to most Western reports. CONCLUSIONS: The efficacy, toxicity and pharmacokinetic profiles of S-1 in current study are compatible with those from other Asian populations. Accurate renal function assessment and more closely monitoring is mandatory for S-1 therapy in patients with low body mass. Literature review suggests that, besides AUC(5-FU), AUC(Oxo) may also attribute to the difference in the compliance to S-1 between Asian and Caucasian populations. PMID- 20714727 TI - Hibernation in warm hibernacula by free-ranging Formosan leaf-nosed bats, Hipposideros terasensis, in subtropical Taiwan. AB - The subtropical Formosan leaf-nosed bats, Hipposideros terasensis (Hipposideridae), show little activity during winter. It has never been determined whether in winter they exhibit hibernation and multi-day periods of low body temperature. The objectives of this study were to understand the winter activity pattern of H. terasensis and to examine whether it enters hibernation during winter. We monitored the skin temperature (T (sk)) of nine free-ranging H. terasensis by attaching temperature-sensitive transmitters during the winters of 2007-2008 and 2008-2009. The results showed that H. terasensis entered hibernation from late December to early March. H. terasensis, however, differs from temperate hibernating bats in several ways: (1) it is capable of hibernation at roost temperature (T (r)) and T (sk) > 20 degrees C; (2) hibernation at high T (r) and T (sk) does not lead to a relatively high arousal frequency; and (3) adults do not increase body mass in autumn prior to hibernation. To test the hypothesis that H. terasensis feeds frequently during the hibernation period to compensate for the high energetic demands of hibernating in warm hibernacula, we recorded the number and timing of bats that emerged from and entered into a hibernaculum, which contained more than 1,000 bats. From 30 December 2007 to 29 February 2008, an average of only 8.4 bats (<1%) per night (29 nights) emerged from the hibernaculum. Adult bats lost an average of 13-14% of body mass during an approximately 70-day hibernation period. We suggest that H. terasensis might have remarkably low torpid metabolic rates during hibernation. PMID- 20714728 TI - Thermal physiology and energetics in male desert hamsters (Phodopus roborovskii) during cold acclimation. AB - The adjustments in thermal physiology and energetics were investigated in male desert hamsters (Phodopus roborovskii) which were acclimated to 5 degrees C for 4 weeks. Mean core body temperature in cold acclimated animals decreased by 0.21 degrees C compared with controls. Further analysis revealed that the decrease mainly occurred in the scotophase, while in the photophase core body temperature remained constant during the whole cold acclimation. Thermogenic capacity, represented by resting metabolic rate and nonshivering thermogenesis increased in cold acclimated hamsters from initial values of 1.38 +/- 0.05 and 5.32 +/- 0.30 to 1.77 +/- 0.08 and 8.79 +/- 0.31 mlO(2) g(-1) h(-1), respectively. After cold acclimation, desert hamsters maintained a relative stable body mass of 21.7 +/- 0.1 g very similar to the controls kept at 23 degrees C (21.8 +/- 0.1 g). The mean values of food intake and digestible energy (metabolisable energy) in cold acclimated hamsters were 5.3 +/- 0.1 g day(-1) and 76.3 +/- 0.9 kJ day(-1) (74.8 +/- 0.9), respectively, which were significantly elevated by 76.7 and 80.4% compared to that in control group. The apparent digestibility was 81.0 +/- 0.3% in cold acclimated animals which was also higher than the 79.7 +/- 0.2% observed in controls. This increase corresponded with adaptive adjustments in morphology of digestive tracts with 20.2 and 36.8% increases in total length and wet mass, respectively. Body fat mass and serum leptin levels in cold acclimated hamsters decreased by 40.7 and 67.1%, respectively. The wheel running turns and the onset of wheel running remained unchanged. Our study indicated that desert hamsters remained very active during cold acclimation and displayed adaptive changes in thermal physiology and energy metabolism, such as enhanced thermogenic and energy processing capacities. PMID- 20714729 TI - Skip segment Hirschsprung's disease: a systematic review. AB - PURPOSE: Hirschsprung's disease is characterised by the congenital absence of ganglion cells beginning in the distal rectum and extending proximally for varying distances. 'Zonal aganglionosis' is a phenomenon involving a zone of aganglionosis occurring within normally innervated intestine. 'Skip segment' Hirschsprung's disease (SSHD) involves a 'skip area' of normally ganglionated intestine, surrounded proximally and distally by aganglionosis. While Hirschsprung's disease is believed to be the result of incomplete craniocaudal migration of neural crest-derived cells, the occurrence of SSHD has no clear embryological explanation. The aim of this study was to perform a systematic review of SSHD, reported in the literature between 1954 and 2009, in order to determine the clinical characteristics of this rare entity and its significance. METHODS: The first reported case of SSHD was published in 1954. A systematic review of SSHD cases in the literature, from 1954 to 2009, was carried out using the electronic database 'Pubmed'. Detailed information was recorded regarding the age, gender, presenting symptoms and location of the skip segment in each patient. RESULTS: 24 cases of SSHD have been reported in the literature to date. 18/24 (75%) of these cases were males and 6/24 (25%) were females. Of these, 22/24 (92%) were cases of total colonic aganglionosis (TCA), and 2/24 (8%) were rectosigmoid Hirschsprung's disease. Of the 22 TCA cases, 9 (41%) had a skip segment in the transverse colon, 6 (27%) in the ascending colon, 2 (9%) in the caecum and 5 (23%) had multiple skip segments. In both rectosigmoid Hirschsprung's disease cases, the skip segment was in the sigmoid colon. Overall, the length of the skip segment was variable, with the entire transverse colon ganglionated in some cases. CONCLUSION: SSHD occurs predominantly in patients with TCA. The existence of a skip area of normally innervated colon in TCA may influence surgical management, enabling surgeons to preserve and use the ganglionated skip area during pull-through operations. PMID- 20714730 TI - Delayed diagnosis of imperforate anus: an unacceptable morbidity. AB - PURPOSE: Diagnosis of imperforate anus is usually made shortly after birth with physical examination. Nonetheless, a significant number of patients have presented beyond the neonatal period without recognition of anorectal malformation. We reviewed our experience of anorectal malformations, with particular emphasis on the timing of diagnosis. METHODS: This retrospective study reviewed patients with imperforate anus between 1999 and 2009. Documentation included gender, time of diagnosis, complications, and classification. Delayed diagnosis was defined as diagnosis made >48 h of life. RESULTS: Ninety-nine patients with imperforate anus were managed, of whom 21 presented with delayed diagnosis. The condition was classified as perineal (n = 11), recto-urethral (n = 3), vestibular fistula (n = 3) and without fistula (n = 4). Patients showed at least one of the following symptoms: abdominal distension (61.9%), bilious vomiting (38.1%), delayed passage of meconium (19.0%), and sepsis (9.5%). Delayed diagnosis was made on day 4 in median (range 3-43). This delay was associated with bowel perforation in 9.5%. CONCLUSION: Despite routine physical examination postpartum, one in five neonates born with imperforate anus had a delayed diagnosis. This delay may lead to avoidable, serious morbidity. Therefore, we emphasise the practice of thorough perineal examination during the initial newborn examination to identify the presence of anorectal malformations. PMID- 20714731 TI - Colostomy closure: how to avoid complications. AB - PURPOSE: Colostomy is an operation frequently performed in pediatric surgery. Despite its benefits, it can produce significant morbidity. In a previous publication we presented our experience with the errors and complications that occurred during cases of colostomy creation. We now have focused in the morbidity related to the colostomy closure. The technical details that might have contributed to the minimal morbidity we experienced are described. METHODS: The medical records of 649 patients who underwent colostomy closure over a 28-year period were retrospectively reviewed looking for complications following these procedures. Our perioperative protocol for colostomy closure consisted in: clear fluids by mouth and repeated proximal stoma irrigations 24 h prior to the operation. Administration of IV antibiotics during anesthesia induction and continued for 48 h. Meticulous surgical technique that included: packing of the proximal stoma, plastic drape to immobilize the surgical field, careful hemostasis, emphasis in avoiding contamination, cleaning the edge of the stomas to allow a good 2-layer, end-to-end anastomosis with separated long-term absorbable sutures, generous irrigation of the peritoneal cavity and subsequent layers with saline solution, closure by layers to avoid dead space, and avoidance of hematomas. No drains and no nasogastric tubes were used. Oral fluids were started the day after surgery and patients were discharged 48-72 h after the operation. RESULTS: The original diagnoses of the patients were: anorectal malformation (583), Hirschsprung's disease (53), and others (13). 10 patients (1.5%) had complications: 6 had intestinal obstruction (5 due to small bowel adhesions, 1 had temporary delay of the function of the anastomosis due to a severe size discrepancy between proximal and distal stoma with a distal microcolon) and 4 incisional hernias. There were no anastomotic dehiscences or wound infection. There was no bleeding, no anastomotic stricture and no mortality. CONCLUSION: Based on this experience we believe that colostomy closure can be performed with minimal morbidity provided a meticulous technique is observed. PMID- 20714732 TI - Crohn's disease limited to the appendix: a case report in a pediatric patient. AB - In the original description of Crohn's disease, the appendix was not believed to be involved in the inflammatory process. Later on, case reports started to appear in publications demonstrating that the appendix could be involved in the inflammatory changes of Crohn's disease, and it could also be the primary or the sole manifestation of the disease. Being that appendectomies are one of the most common procedures performed by pediatric surgeons, the knowledge about this diagnosis, all be it rare, is important. Our aim was to report a case and discuss the results of our literature review in order to elucidate the probability of a pediatric patient subsequently developing full Crohn's disease and the follow up that is indicated in such patients. A 12-year-old male patient presented with a history of chronic abdominal pain (3-4 times per week) for 1 year, crampy in nature, localized in the left lower quadrant, and associated with diarrhea (2 episodes per day). There were no extraintestinal manifestations of Crohn's, such as arthralgia or uveitis. Important family history included two paternal uncles with ulcerative colitis both of whom currently have stomas. The only abnormal laboratory value in our patient was an elevated fecal calprotectin level. An esophagogastroduodenoscopy and colonoscopy were performed and found to be unremarkable except for the cecum where it appeared that an exudate was emanating from the appendiceal orifice. A magnetic resonance enterography was ordered and showed an enlarged enhancing appendix. An exploratory laparoscopy identified an appendix with macroscopic cobblestone or lymphoid reaction that histologically was consistent with Crohn's disease. It appears that the Crohn's appendix is more indolent than Crohn's disease of the ileum or colon, with a recurrence rate in the largest series of 8%. The interval time from diagnosis to recurrence varied from 1 to 48 months with an average of 19 months. Some authors debate the need of follow up at all in those patients, believing that the appendectomy alone is curative in the majority of patients. Others recommend follow up for up to 5 years. PMID- 20714734 TI - Port-site recurrence after laparoscopy-assisted low anterior resection: the sign of peritoneal dissemination. PMID- 20714733 TI - Anorectal malformations and neurospinal dysraphism: is this association a major risk for continence? AB - BACKGROUND/PURPOSE: Anorectal malformations (ARM) are a spectrum of defects ranging from the very minor ones, with an excellent functional prognosis, to those that are more complex, often associated with other anomalies, difficult to manage and with a poor functional outcome. A significant number of these children suffer from fecal and urinary incontinence despite major advances in the management of ARM patients have significantly improved the quality of life. The role of sacrovertebral anomalies/dysraphism (SD) and neurospinal cord anomalies/dysraphism (ND) associated with ARM on the continence of these patients is still controversial. The authors made a review of their experience in a period of 5 years, focusing on the role of neurospinal cord anomalies in patients with ARM. MATERIALS: At colorectal clinic of our department of pediatric surgery 215 patients who underwent a procedure of posterior sagittal anorectoplasty for ARM are followed-up in a multidisciplinary clinic. Among them 60 patients with either SD or ND were documented. In 37 patients the anomaly involved the spinal cord (ND). 12 of these 37 patients underwent neurosurgical treatment and 25 were managed conservatively. Data collected from their follow-up were analyzed and compared, focusing on their bowel and urinary continence. RESULTS: All 37 patients acquired regular bowel movements with an appropriate bowel management according to Pena's protocols. Urinary incontinence required clean intermittent catheterization in four cases. None of the patients who did not receive neurosurgical treatment developed acute complications due to the progression of the neurospinal anomaly, like acute urinary retention, orthopedic and motility problems or acute hydrocephalus. From literature review we were unable to find good evidence that the presence of ND worsens the functional prognosis of patients with ARM. We were also unable to find convincing evidence to support the practice of prophylactic neurosurgical procedures. CONCLUSIONS: The present study supports the theory that for ARM patients the prognosis in terms of continence depends mainly on the type of malformation and is not complicated by the association with ND. In our series neurosurgical treatments did not have any effect in improving the continence of ARM patients and a conservative management of ND did not expose the patients to the sequelae of progressive deterioration, reported elsewhere, requiring rescue neurosurgery. We believe that the correct practice of pediatric surgeons following-up ARM patients is a protocol which includes appropriate investigations to detect the presence of a SD or ND and, once these entities are detected, it is mandatory to manage the patient with a multidisciplinary team, where a conservative non-operative management is initially justified and advocated in the absence of neurosensorymotor symptoms. PMID- 20714736 TI - Endocervicosis of the rectum. PMID- 20714737 TI - Expression of the xenobiotic- and reactive oxygen species-detoxifying enzymes, GST-pi, Cu/Zn-SOD, and Mn-SOD in the endocrine cells of colorectal cancer. AB - BACKGROUND AND AIM: The aim of the present work was to analyze the expression of antioxidant enzymes GST-pi, SOD1, and SOD2 in endocrine cells of colorectal cancers and to evaluate the significance of the presence of thus labeled endocrine cells as prognostic factor. METHODS: The expression of chromogranin A (ChGA), GST-pi, SOD1, and SOD2 was determined in endocrine cells of 128 colorectal cancers using light and electron immunohistochemistry and double immunogold labeling method. RESULTS: Endocrine cells expressing at least one of the studied antioxidant enzymes were detected in a relatively small proportion of primary colorectal cancers (22 cases, 17%; 14% GST-pi-positive, 14% SOD1 positive, and 9% SOD2-positive). The double immunogold staining and the following electron microscopy showed that GST-pi, SOD1, and SOD2 were co-localized with ChGA to the granules of most endocrine cells. The survival analyses revealed that patients with endocrine cells in primary tumor tissues expressing GST-pi had worse prognosis after the surgical therapy than those without GST-pi-positive endocrine cells (median of 22.70 vs. 49.43 months, p < 0.05, Log-rank test). CONCLUSIONS: Most of the ChGA-positive endocrine cells in colorectal cancers also expressed some or all of the three studied antioxidant enzymes, GST-pi, SOD1, and SOD2. Moreover, patients having tumors with GST-pi-positive endocrine cells have an unfavorable prognosis. We suggest that not the neuroendocrine differentiation in general, but the presence in the tumors of endocrine cells with activated antioxidant defense and probably metabolically more active might determine a more aggressive type of cancer leading to worse prognosis for patients. PMID- 20714738 TI - An enhanced recovery programme reduces length of stay after rectal surgery. AB - PURPOSE: Enhanced Recovery Programmes (ERP) result in shorter hospital stay after colonic resection with no increase in complication, mortality or readmission rates. There is little data regarding the use of an ERP after rectal resection. We investigated the effect of introducing laparoscopic surgery and the ERP on outcomes in our unit. METHODS: From February 2007, elective patients undergoing rectal resection (laparoscopic or open) under the care of two colorectal surgeons were placed into the ERP. Length of stay (LOS) was recorded as total LOS, including readmissions. Comparison was made with a cohort of patients from 2004 2005 before the onset of laparoscopic surgery/ERP. RESULTS: Forty patients in the ERP group were compared with 42 patients from 2004-2005. Morbidity and mortality rates were similar. LOS was shorter in the ERP group cf. the retrospective group (median 7 days vs. 11 days; p=0.002). Median LOS was shorter in both laparoscopic ERP patients (6 days cf. 11 days; p= 0.004) and open ERP patients (7 days cf. 11 days; p=0.014) cf. the retrospective group. CONCLUSION: Patients having rectal resections benefit from a multimodal approach to surgery with significant reductions in LOS, but no change in morbidity or mortality. PMID- 20714739 TI - Dimensions of patient needs in dermatology: subscales of the patient benefit index. AB - Evaluation of patient-relevant treatment benefit gains importance for approval and reimbursement of therapeutic strategies. The 'Patient Benefit Index' (PBI) is the first questionnaire to measure patient-relevant treatment benefit in dermatology. Its global score is the average of benefits achieved after treatment, weighted by the individual importance of treatment needs. This study aimed to establish subscales of the PBI on the basis of independent and consistent treatment need dimensions. The PBI was used in a cross-sectional study involving n = 500 patients with ten distinct skin diseases, and in a longitudinal acne therapy study (n = 925). PBI dimensions were extracted by factor analysis and varimax rotation in both studies independently, using the longitudinal study data for replication. Factor analysis revealed largely similar need dimensions in both studies. The five-dimensional solution found in the cross-sectional study explained 63.0% of the variance. The need dimensions were named as reducing psychological impairments, reducing social impairments, reducing impairments due to therapy, reducing physical impairments, and building confidence into therapy. Using this factor solution, different patterns of need were found amongst the ten dermatological diseases. The PBI allows for a differential benefit assessment on five well distinguishable and interpretable subscales. The use of subscales as shown refines the interpretation of needs and benefits in dermatologic treatment. PMID- 20714740 TI - Fetal transverse cerebellar diameter measured by ultrasound does not differ between genders. AB - PURPOSE: The aim of this study was to determine the correlation between fetal transverse cerebellar diameter (TCD) and gestational age of male and female fetus in women under low-risk prenatal care between the 13th and 40th week of gestation. METHODS: A cross-sectional study was carried out with 184 pregnant women, at the age of 18 years or more, gestational age ranging from 13 to 40 weeks, with a single fetus. A single TCD measurement by ultrasound was used for each fetus. Correlations between fetal TCD and gestational age were determined for the whole sample and each gender separately. RESULTS: We identified 102 males and 82 female fetuses. A linear correlation was observed between fetal TCD and gestational age for the whole sample (r = 96.9%; p < 0.001). A significant linear correlation was also observed for both males (r = 97.0%; p < 0.001) and females (r = 96.9%; p < 0.001). Comparing the regression lines between genders, no significant difference was observed. CONCLUSIONS: The data of this study suggest TCD fetal ultrasound as a predictive biometric parameter of gestational age independently of fetal gender in the last two trimesters of a pregnancy. PMID- 20714741 TI - Are ATPase6 polymorphisms associated with primary ovarian insufficiency? PMID- 20714743 TI - Y chromosome homogeneity in the Korean population. AB - The distribution of Y-chromosomal variation from the 12 Y-SNP and 17 Y-STR markers was determined in six major provinces (Seoul-Gyeonggi, Gangwon, Chungcheong, Jeolla, Gyeongsang, and Jeju) to evaluate these populations' possible genetic structure and differentiation in Korea. As part of the present study, a 10-plex SNaPshot assay and two singleplex SNaPshot assays were developed. Based on the result of 12 Y-SNP markers (M9, M45, M89, M119, M122, M174, M175, M214, RPS4Y, P31, SRY465, and 47z), almost 78.9% of tested samples belonged to haplogroup O-M175 (including its subhaplogroups O3-M122: 44.3%, O2b* SRY465: 22.5%, O2b1-47z: 8.7%), and 12.6% of the tested samples belonged to haplogroup C-RPS4Y. A total of 475 haplotypes were identified using 17 Y-STR markers included in the Yfiler kit, among which 452 (95.2%) were individual specific. The overall haplotype diversity for the 17 Y-STR loci was 0.9997 and the discrimination capacity was 0.9387. Pairwise genetic distances and AMOVA of the studied Korean provinces reflected no patrilineal substructure in Korea, except for Jeju Island. Thus, this survey shows that the present data of Korean individuals could be helpful to establish a comprehensive forensic reference database for frequency estimation. PMID- 20714744 TI - Late onset of cervical dystonia in a 39-year-old patient following cerebellar hemorrhage. PMID- 20714745 TI - Fatigue, sleepiness, and physical activity in patients with multiple sclerosis. AB - Fatigue is a frequent and disabling symptom in patients with multiple sclerosis (MS). The objective of the study was to compare fatigue and sleepiness in MS, and their relationship to physical activity. Eighty patients with MS rated the extent of experienced fatigue (Fatigue Severity Scale, FSS) and sleepiness (Epworth Sleepiness Scale, ESS). The relationship between the scales was analysed for the scales as a whole and for single items. The clinical status of the patients was measured with the Extended Disability Status Scale (EDSS). In addition, physical activity was recorded continuously for 1 week by wrist actigraphy. The mean scores of fatigue and sleepiness were significantly correlated (FSS vs. ESS r=0.42). Single item analysis suggests that fatigue and sleepiness converge for situations that demand self-paced activation, while they differ for situations in which external cues contribute to the level of activation. While fatigue correlated significantly with age (r=0.40), disease severity (EDSS, r=0.38), and disease duration (r=0.25), this was not the case for sleepiness. Single patient analysis showed a larger scatter of sleepiness scores in fatigued patients (FSS>4) than in non-fatigued patients. Probably, there is a subgroup of MS patients with sleep disturbances that rate high on ESS and FSS. The amount of physical activity, which was measured actigraphically, decreased with disease severity (EDSS) while it did not correlate with fatigue or sleepiness. PMID- 20714746 TI - Pigment epithelium-derived factor and vascular endothelial growth factor in branch retinal vein occlusion with macular edema. AB - BACKGROUND: We investigated whether pigment epithelium-derived factor (PEDF) or vascular endothelial growth factor (VEGF) influence macular edema in patients with branch retinal vein occlusion (BRVO). This investigation aimed to clarify the influence of PEDF in the vitreous fluid on retinal vascular permeability in patients with macular edema secondary to BRVO. The findings were expected to be useful for the treatment of macular edema in BRVO patients. METHODS: This was a retrospective cross-sectional comparative case series. Thirty-three BRVO patients with macular edema and 24 control patients with nonischemic ocular diseases were enrolled. Retinal ischemia was evaluated by measuring the area of capillary nonperfusion on fluorescein angiography with Scion Image software. Macular edema was examined by optical coherence tomography. Vitreous fluid samples were obtained via pars plana vitrectomy, and the VEGF and PEDF levels were determined by enzyme-linked immunosorbent assay. RESULTS: The vitreous level of VEGF was significantly higher in BRVO patients than controls (P < 0.001). The vitreous PEDF level was significantly lower in BRVO patients than controls (P = 0.026). In BRVO patients, vitreous levels of PEDF and VEGF showed a significant negative correlation with each other (P < 0.001). Additionally, the vitreous VEGF level had a significant positive correlation (P < 0.001) and the vitreous PEDF level had a significant negative correlation (P < 0.001) with the nonperfused retinal area in BRVO patients. Furthermore, vitreous levels of VEGF and PEDF showed significant positive (P = 0.001) and negative (P = 0.014) correlations, respectively, with macular edema in BRVO patients. CONCLUSIONS: VEGF and PEDF may inversely influence retinal vascular permeability in patients with ischemic BRVO and macular edema. However, prospective validation will be needed to confirm these observations. PMID- 20714747 TI - Choroidal neovascularization in a patient with blunt trauma-caused traumatic retinopathy without choroidal rupture. AB - PURPOSE: To report a case of choroidal neovascularization (CNV) following blunt trauma without choroidal rupture, with past history of central serous chorioretinopathy (CSC). METHODS: A 43-year-old man with a nonperforating injury caused by a baseball that hit his right eye exhibited traumatic retinopathy. The damage was localized to the outer layer of the retina at the macula and there was no choroidal rupture. Five years prior to the accident, the patient suffered from a CSC attack with retinal pigment epithelium detachment. Two weeks after the blunt trauma, fundus examination revealed CNV extending into the subfoveal space, which led to an abrupt development of retinal hemorrhage and serous retinal detachment at the macula. Intravitreal injection of bevacizumab led to the resolution of retinal detachment 15 days later, with complete absorption of retinal hemorrhage 41 days later. Fluorescein angiography performed 2 months later revealed hyperfluorescent points with no leakage. CONCLUSION: CNV following blunt trauma in this case occurred in traumatic retinopathy, with the damage localized in the outer layer of the retina. This suggests that the retinal pigment epithelium-Bruch's membrane complex developed susceptibility to anteroposterior forces, which is subsequent to the spontaneous healing of CSC. Bevacizumab treatment also reduced exudation from CNV. PMID- 20714749 TI - Critical tests evaluating efficacy of moxidectin against small strongyles in horses from a herd for which reduced activity had been found in field tests in Central Kentucky. AB - Critical tests were performed in 2009 and 2010 in four 2-year-old horses naturally infected with internal parasites. The horses were from a herd (Farm MC) where reduced activity of ivermectin and moxidectin on small strongyles was demonstrated previously from EPG (eggs/gram of feces) data in field tests. Also, in critical tests in horses from the same herd, ivermectin was less effective on immature small strongyles in the lumen of the large intestine than when the drug was first marketed. The main interest in the present critical tests was to determine the efficacy of moxidectin (400 MUg/kg) on small strongyles. This was done to try and find indications of why there has been a return of strongyle EPG counts sooner after treatment in field tests than when moxidectin was first commercially available. Removal of adult small strongyles for the four treated horses was >99% to 100%. Efficacy on immature (L(4)) small strongyles was 82%, 96%, 98%, and >99% for the individual horses. Identification of small strongyles recovered from two of the horses revealed that three genera and 11 species were present. Specimens of Cylicocyclus ashworthi are reported for the first time in horses in Kentucky although eggs of this species have been identified. Moxidectin, in the present study, was excellent on removing adult small strongyles but was less effective on immatures (L(4)) in the intestinal contents. The question as to why moxidectin efficacy on small strongyles has declined in field tests may have been answered at least to a certain extent. It seems that a significant factor is "quick development" of a few remaining immatures in the gut lumen of horses. Also, possible activity may have decreased on encysted stages in the large intestinal lining. In any event, after treatment of some horses with moxidectin, the life cycle of small strongyles is shorter now than at the onset of usage of this compound. PMID- 20714748 TI - Angiostrongylus vasorum: the 'French Heartworm'. AB - Angiostrongylus vasorum which is commonly known as 'French heartworm' is a snail born parasitic disease affecting the members of the Canidae family. This parasite has a cosmopolitan distribution covering tropical, subtropical and temperate regions. However, its distribution is characterised by isolated endemic foci, with only sporadic occurrences outside this areas. During the last two decades, several sporadic occurrences in old and new endemic areas have been documented by the researchers. However, the spread of infection and dynamic consequences of this parasite in final host has not been clarified yet. Therefore, this review will focus on the morphology, biology, clinical significant as well as management of this parasitic disease. PMID- 20714750 TI - Cryptosporidium infection in herds with and without calf diarrhoeal problems. AB - A case-control study was designed to investigate the role of different Cryptosporidium spp. in Swedish dairy herds with and without calf diarrhoeal problems. Faecal samples were collected from preweaned calves, young stock and cows. Cryptosporidium oocysts were detected by sodium chloride flotation and epifluorescence microscopy. Molecular diagnostics were used to identify Cryptosporidium species. Samples containing C. parvum were further analysed to determine subtypes. Calf faecal samples were also analysed for rotavirus, coronavirus and Escherichia coli F5+. Total protein was assessed in 1- to 8-day old calves. A questionnaire was used to identify differences in management routines. Cryptosporidium infection was diagnosed in all herds, with equal prevalence in case and control herds in all three age groups. Cryptosporidium parvum, Cryptosporidium bovis, Cryptosporidium ryanae and Cryptosporidium andersoni were all identified, as were rotavirus, coronavirus and E. coli F5+. C. ryanae and C. andersoni were only detected in non-diarrhoeal samples, whereas the other pathogens were detected in both diarrhoeal and non-diarrhoeal samples. Diarrhoea was more common in case herd calves. Disinfection of single pens was more common in case herds and several other management routines seemed to differ although results were not significant. PMID- 20714751 TI - Assessment of skin penetration of third-stage larvae of Strongyloides ratti. AB - Strongyloides stercoralis infection is caused by skin penetration of third-stage larvae (L3s). We studied skin penetration of L3s of Strongyloides ratti using an in vitro assay that has been used previously to study Angiostrongylus cantonensis, an agarose membrane with a temperature gradient, and scanning electron microscopy. Our results revealed that skin penetration of L3s depended on host skin temperature. When the target temperature of the outer liquid was 37 degrees C, more than 80% of L3s penetrated the skin, but penetration was only 60% when the target temperature was 20 degrees C. Thirdstage larvae moved rapidly on the agarose membrane toward optimum temperature area for this parasite, which indicates that L3 has a sensor that is sensitive to temperature changes. Penetration rate for hosts such as cat (36%), dog (32%), and bird (13%) were significantly lower than that for rat (82%). Although we could not establish the reason, L3s seemed to have an ability to differentiate these hosts at the time of penetration. By using scanning electron microscopy, penetration of L3s could be observed within 10 min. We demonstrated thermotaxis of L3 of S. ratti, and this peculiar characteristic seemed to have a close relationship with the process of searching for the host. PMID- 20714752 TI - IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a low virulence mycobacterium, and the outcome of disease is dependent on the host genetics for either susceptibility per se or severity. The IFNG gene codes for interferon-gamma (IFN-gamma), a cytokine that plays a key role in host defense against intracellular pathogens. Indeed, single nucleotide polymorphisms (SNPs) in IFNG have been evaluated in several genetic epidemiological studies, and the SNP +874T>A, the +874T allele, more specifically, has been associated with protection against infectious diseases, especially tuberculosis. Here, we evaluated the association of the IFNG locus with leprosy enrolling 2,125 Brazilian subjects. First, we conducted a case-control study with subjects recruited from the state of Sao Paulo, using the +874 T>A (rs2430561), +2109 A>G (rs1861494) and rs2069727 SNPs. Then, a second study including 1,370 individuals from Rio de Janeiro was conducted. Results of the case-control studies have shown a protective effect for +874T carriers (OR(adjusted) = 0.75; p = 0.005 for both studies combined), which was corroborated when these studies were compared with literature data. No association was found between the SNP +874T>A and the quantitative Mitsuda response. Nevertheless, the spontaneous IFN-gamma release by peripheral blood mononuclear cells was higher among +874T carriers. The results shown here along with a previously reported meta-analysis of tuberculosis studies indicate that the SNP +874T>A plays a role in resistance to mycobacterial diseases. PMID- 20714753 TI - Neurological involvement in a child with atypical hemolytic uremic syndrome. AB - We report the case of a 4-year-old boy, diagnosed with atypical hemolytic uremic syndrome (HUS) due to a hybrid factor H. He progressed to end-stage renal failure despite plasmatherapy and underwent bilateral nephrectomy because of uncontrolled hypertension. Three days after, he had partial complex seizures with normal blood pressure, normal blood count and normal magnetic resonance imaging (MRI), which recurred 1 month later. Eight months later, he had a third episode of seizures, with hemoglobin of 10 g/dl without schizocytes, low haptoglobin of 0.18 g/l, and moderate thrombocytopenia (platelets 98 * 10(9)/l). He remained hypertensive and deeply confused for 2 days. The third MRI showed bilateral symmetrical hyperintensities of the cerebral pedunculas, caudate nuclei, putamens, thalami, hippocampi, and insulae suggesting thrombotic microangiopathy secondary to a relapse of HUS rather than reversible posterior leukoencephalopathy syndrome (RPLS), usually occipital and asymmetrical. Plasmatherapy led to a complete neurological recovery within 2 days although hypertension had remained uncontrolled. The fourth MRI 10 weeks after, on maintenance plasmatherapy, was normal and clinical examination remained normal, except for high blood pressure. In conclusion, brain MRI allows differentiating thrombotic microangiopathy lesions from RPLS in atypical HUS, which is crucial since lesions may be reversible with plasmatherapy. PMID- 20714754 TI - Animal models of the cancer anorexia-cachexia syndrome. AB - BACKGROUND AND AIMS: Cancer cachexia, a complex wasting syndrome, is common in palliative medicine. Animal models expand our understanding of its mechanisms. A review of cancer cachexia and anorexia animal models will help investigators make an informed choice of the study model. RESULTS AND DISCUSSION: Cancer-anorexia cachexia animal models are numerous. No one is ideal. The choice should depend on the research question. To investigate cancer-anorexia cachexia independent of pro inflammatory cytokine effects, the MAC16 ADK and XK1 are useful. MAC16 ADK helps study the host's tumor metabolic effects, independent of any anorexia or inflammation. XK1 is both anorectic and cachectic, but data about it is limited. All other models induce a host inflammatory response. The Walker 256 ADK and MCG 101 are best avoided due to excessive tumor growth. Since individual models do not address all aspects of the syndrome, use of a combination seems wise. Suggested combinations: MAC16-ADK (non-inflammatory and non-anorectic) with YAH 130 (inflammatory, anorectic, and cachectic), Lewis lung carcinoma (slow onset anorexia) or prostate adenocarcinoma (inflammatory, anorectic but not cachectic) with YAH-130. PMID- 20714755 TI - Arbuscular mycorrhizal propagules in soils from a tropical forest and an abandoned cornfield in Quintana Roo, Mexico: visual comparison of most-probable number estimates. AB - The present study was aimed at comparing the number of arbuscular mycorrhizal fungi (AMF) propagules found in soil from a mature tropical forest and that found in an abandoned cornfield in Noh-Bec Quintana Roo, Mexico, during three seasons. Agricultural practices can dramatically reduce the availability and viability of AMF propagules, and in this way delay the regeneration of tropical forests in abandoned agricultural areas. In addition, rainfall seasonality, which characterizes deciduous tropical forests, may strongly influence AMF propagules density. To compare AMF propagule numbers between sites and seasons (summer rainy, winter rainy and dry season), a "most probable number" (MPN) bioassay was conducted under greenhouse conditions employing Sorgum vulgare L. as host plant. Results showed an average value of 3.5 +/- 0.41 propagules in 50 ml of soil for the mature forest while the abandoned cornfield had 15.4 +/- 5.03 propagules in 50 ml of soil. Likelihood analysis showed no statistical differences in MPN of propagules between seasons within each site, or between sites, except for the summer rainy season for which soil from the abandoned cornfield had eight times as many propagules compared to soil from the mature forest site for this season. Propagules of arbuscular mycorrhizal fungi remained viable throughout the sampling seasons at both sites. Abandoned areas resulting from traditional slash and burn agriculture practices involving maize did not show a lower number of AMF propagules, which should allow the establishment of mycotrophic plants thus maintaining the AMF inoculum potential in these soils. PMID- 20714756 TI - The "X-Factor" index: a new parameter for the assessment of adolescent idiopathic scoliosis correction. AB - The correction rate (CR) and fulcrum bending correction index (FBCI) based on the fulcrum bending radiograph (FBR) were parameters introduced to measure the curve correcting ability; however, such parameters do not account for contributions by various, potential extraneous "X-Factors" (e.g. surgical technique, type and power of the instrumentation, anesthetic technique, etc.) involved in curve correction. As such, the purpose of the following study was to propose the concept of the "X-Factor Index" (XFI) as a new parameter for the assessment of the correcting ability of adolescent idiopathic scoliosis (AIS). A historical cohort radiographic analysis of the FBR in the setting of hook systems in AIS patients (Luk et al. in Spine 23:2303-2307, 1998) was performed to illustrate the concept of XFI. Thirty-five patients with AIS of the thoracic spine undergoing surgical correction were involved in the analysis. Plain posteroanterior (PA) plain radiographs were utilized and Cobb angles were obtained for each patient. Pre- and postoperative PA angles on standing radiograph and preoperative fulcrum bending angles were obtained for each patient. The fulcrum flexibility, curve CR, and FBCI were determined for all patients. The difference between the preoperative fulcrum bending angle and postoperative PA angle was defined as Angle(XF), which accounted for the correction contributed by "X-Factors". The XFI, designed to measure the curve correcting ability, was calculated by dividing Angle(XF) by the fulcrum flexibility. The XFI was compared with the curve CR and FBCI by re-evaluating the original data in the original paper (Luk et al. in Spine 23:2303-2307, 1998). The mean standing PA and FBR alignments of the main thoracic curve were 58.3 degrees and 24.5 degrees , respectively. The mean fulcrum flexibility was 58.8%. The mean postoperative standing PA alignment was 24.7 degrees . The mean curve CR was 58.0% and the mean FBCI was 101.1%. The mean XFI was noted as 1.03%. The CR was significantly positively correlated to curve flexibility (r = 0.66; p < 0.01).The FBCI (r = -0.47; p = 0.005) and the XFI (r = -0.45; p = 0.007) were significantly negatively correlated to curve flexibility. The CR was not correlated to Angle(XF) (r = 0.29; p = 0.089).The FBCI (r = 0.97; p < 0.01) and the XFI (r = 0.961; p < 0.01) were significantly positively correlated to Angle(XF). Variation in XFI was noted in some cases originally presenting with same FBCI values. The XFI attempts to quantify the curve correcting ability as contributed by "X-Factors" in the treatment of thoracic AIS. This index may be a valued added parameter to accompany the FBCI for comparing curve correction ability among different series of patients, instrumentation, and surgeons. It is recommended that the XFI should be used to document curve correction, compare between different techniques, and used to improve curve correction for the patient. PMID- 20714758 TI - Surgical treatment of a 180 degrees thoracolumbar fixed kyphosis in a young achondroplastic patient: a one-stage "in situ" combined fusion and spinal cord translocation. AB - An achondroplastic patient with a thoracolumbar kyphosis was first seen at the age of 16 at our institution. His only concern at that time was the aesthetic implication of his deformity. His physical examination was normal except for loss of the neurologic reflexes in the lower limbs. The radiographs showed a fixed 180 degrees thoracolumbar kyphosis with correct frontal and sagittal balances. No spinal cord anomaly was found on MRI. Two years later, he developed a progressive neurogenic claudication of the lower limbs. He was still neurologically intact at rest. The MRI showed an abnormal central spinal cord signal in front of the apex of the kyphosis associated with the narrow congenital spinal canal. In regards to this progressive neurological worsening, a surgical treatment was decided. We decided to perform a front and back arthrodesis combined with a spinal cord decompression without reduction of the deformity. A five-level hemilaminotomy was performed with a posterior approach at the kyphosis deformity. The spinal cord was individualised onto 10 cm and the left nerve roots were isolated. A decancellation osteotomy of the three apex vertebrae and a disc excision were performed. The posterior aspect of the vertebral body was then translated forward 2 cm and in association with the spinal cord. Two nerve roots were severed laterally to approach the anterior part of the kyphosis and a peroneal strut graft was inlayed anterolaterally. A complementary anterior and a right posterolateral fusion was made with cancellous bone. The patient was immobilised in a cast for 3 months relayed by a thoracolumbosacral orthosis for 6 months. At 3 years follow-up, the neurogenic claudication had disappeared. No worsening of the kyphosis was observed. His only complaint is violent electric shock in the lower limbs with any external sudden pressure on the spinal cord in the area uncovered by bone. PMID- 20714759 TI - The intracranial volume pressure response in increased intracranial pressure patients: Part 1. Calculation of the volume pressure indicator. AB - BACKGROUND: The intracranial pressure (ICP) is usually continuously monitored in the management of patients with increased ICP. The aim of this study was to discover a mathematic equation to express the intracranial pressure-volume (P-V) curve and a single indicator to reflect the status of the curve. METHODS: Patients with severe brain damage who had bilateral external ventricular drainage (EVD) from December 2008 to February 2010 were included in this study. The EVD was used as drainage of CSF and ICP monitor. The successive volume pressure response [6] values were obtained by successive drainage of CSF from ICP 20-25 to 10 mmHg. Parabolic, exponential, and linear regression models were designed to have a single parameter as the indicator to determine the P-V curves. RESULTS: The mean of parameter "a" in the exponential equation is 1.473 +/- 0.054; in the parabolic equation, it is 0.332 +/- 0.061; and in the linear equation, it is 1.717 +/- 0.209. All regression equations of P-V curves had statistical significance (p < 0.005). Parabolic and exponential equations are closer to the original ICP curve than linear equation (p < 0.005). There is no statistically significant difference between parabolic and exponential regressions. CONCLUSIONS: The P-V curve can be expressed with linear, parabolic, and exponential regression models in increased ICP patients. The parabolic and exponential equations are more accurate methods to represent the P-V curve. The single parameter in the three regression equations can be compared in different conditions of one patient in clinical practice. PMID- 20714760 TI - Pros and cons of permissive hypercapnia in patients with subarachnoid haemorrhage and ARDS. PMID- 20714761 TI - The SPO1-related bacteriophages. AB - A large and diverse group of bacteriophages has been termed 'SPO1-like viruses'. To date, molecular data and genome sequences are available for Bacillus phage SPO1 and eight related phages infecting members of other bacterial genera. Many additional bacteriophages have been described as SPO1-related, but very few data are available for most of them. We present an overview of putative 'SPO1-like viruses' and shall discuss the available data in view of the recently proposed expansion of this group of bacteriophages to the tentative subfamily Spounavirinae. Characteristics of SPO1-related phages include (a) the host organisms are Firmicutes; (b) members are strictly virulent myoviruses; (c) all phages feature common morphological properties; (d) the phage genome consists of a terminally redundant, non-permuted dsDNA molecule of 127-157 kb in size; and (e) phages share considerable amino acid homology. The number of phages isolated consistent with these parameters is large, suggesting a ubiquitous nature of this group of viruses. PMID- 20714762 TI - High doses of medroxyprogesterone as the cause of disappearance of adherence of the zona pellucida to an oocyte. AB - The zona pellucida (ZP) is an external glycoprotein membrane of oocytes of mammals and embryos in the early stage of their development. ZP first appears in growing ovarian follicles as an extracellular substance between the oocyte and granular cells. The zona pellucid markedly affects the development and maturation of the oocyte. The morphology of the ZP-oocyte complex allows a more precise determination of the oocyte maturity. According to numerous experimental studies, ZP is essential for preimplantation embryonic development of humans and other mammals. It prevents dispersion of blastomeres and enhances their mutual interactions. ZP is a dynamic structure responsible for the provision of nutrients to early forms of oocytes in mammals. The aim of the present study was untrastructural evaluation of the ZP-oocyte contact during inhibited ovulation. Female white rats (Wistar strain) received a suspension of medroxyprogesterone acetate (MPA) in incremental intramuscular bolus doses of 3.7 mg (therapeutic dose), 7.4 mg and 11.1 mg. The animals were decapitated 5 days after the administration of MPA. Ovarian sections were evaluated under a transmission electron microscope (TEM) Zeiss EM 900. Morphometric analysis of ZP was conducted using the cell imaging system by Olympus. In females exposed to therapeutic doses of MPA, ZP showed the structure of granular-fibrous reticulum of a medium electron density with single cytoplasmic processes originating from the surrounding structures. The oocyte cell membrane generated single, delicate processes directed toward ZP. Microvilli of the oocyte were short and thin. In the group receiving 7.4 mg of MPA, ZP had the structure of a delicate, loose granular-fibrous reticulum, and the oocyte cell membrane generated single microvilli directed toward ZP. In both those groups, the close ZP-oocyte contact was observed. Otherwise, in the group exposed to the highest MPA doses (11.1 mg), thicker and more numerous oocyte microvilli were found, which did not penetrate ZP matrix. They were dense, irregularly separated contour, forming a barrier between ZP and oocyte. The present findings are likely to suggest that MPA has inhibiting effects on the synthesis of binding proteins and causes the loss of the oocyte contact with ZP. PMID- 20714763 TI - Thrombin generation in ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with an increase in cardiovascular risk. Thrombin generation is associated with the risk of thrombosis, and the endogenous thrombin potential (ETP) has been proposed as a parameter for plasma-based hypercoagulability. The aim of the study was to evaluate the risk of thrombosis in a group of AS patients in comparison to healthy subjects and to look for factors associated with an increased risk. Patients with AS fulfilling revised New York criteria were included in the study. Age, sex, disease duration, presence of peripheral arthritis and of extra articular manifestation, and treatment were recorded, as well as HLA-B27 positivity, ESR, CRP, IgA, D-dimer levels, and bath ankylosing spondylitis disease activity index (BASDAI) score. Control patients were healthy blood donors. Patients with thrombosis history or with anti-thrombotic treatment were excluded. Endogenous thrombin generation was studied using a fluorometric technique (Technothrombin TGA kit, Technoclone, Austria). The thrombin generation parameters were ETP, corresponding to the area under the curve (nanomole per liter); lag time, corresponding to the initiation of the thrombin generation (minutes); maximal concentration of thrombin generated (Cmax, nanomole per liter); the time to reach the peak (Tmax, minutes); and the maximal rising slope of thrombin generation (velocity). Statistical analysis used Student's t test for comparisons, and Spearman's correlation test for the correlations; p values less than 0.05 were considered significant. Forty-six AS outpatients were included, 38 men with a mean (SD) age of 43.5 +/- 13.1 years and a mean disease duration of 14.1 +/- 8.4 years; ESR = 22.2 +/- 17.2 mm, CRP = 14.5 +/- 7.3 mg/l, and BASDAI = 37.8 +/- 21.7 mm. Twelve had peripheral arthritis, and 17 had extra-articular involvement (IBD, uveitis, and psoriasis). Thirty-nine are HLA-B27 positive, 28 are under NSAIDs alone, and 15 were under TNF blockers at time of evaluation. Control group was 24 healthy blood donors. There is no difference between AS and controls for ETP, Cmax, and velocity. There is an increase in lag time (p = 0.03) and T max (p = 0.04) in AS patients. There is no difference in thrombin generation parameters between axial and peripheric AS, or between anti-TNF treated and not treated patients. Correlations were found between ETP and ESR (p = 0.006), CRP (p = 0.05), and BASDAI (p = 0.01); between Cmax and ESR, CRP, and BASDAI; between velocity and ESR; and between D-dimers and ESR and CRP. Even if there are some correlations between thrombin generation parameters and biological and clinical activity, this study does not demonstrate an increase in thrombin generation in patients with AS compared with controls. Moreover, the findings of higher lag time and Tmax in the patients may argue for a delayed thrombin generation in AS. PMID- 20714764 TI - Correlations between coping styles and symptom expectation for rheumatoid arthritis. AB - BACKGROUND: In pain conditions, active coping has been found to be associated with less severe depression, increased activity level and less functional impairment. Studies indicate that there is a high expectation for chronic disability following a diagnosis of rheumatoid arthritis. The objective of this study was to compare both the expectations and the coping style for rheumatoid arthritis in disease-naive subjects. METHODS: The Vanderbilt Pain Management Inventory was administered to university students. Subjects who had not yet experienced rheumatoid arthritis (RA) and did not know a person with RA were given a vignette concerning a new onset diagnosis of RA and were asked to indicate how likely they were to have thoughts or behaviours indicated in the coping style questionnaire. Subjects also completed expectations regarding daily functioning according to the Stanford Health Assessment Questionnaire (HAQ) for RA. RESULTS: The mean active coping style score for RA was 27.3 +/- 4.6 (40 is the maximum score for active coping). The mean passive coping style score was 26.2 +/- 7.0 (50 is the maximum score for passive coping). Those with high passive coping styles had a higher mean expectation score (higher HAQ score) of disability from rheumatoid arthritis. The correlation between passive coping style score and expectation score was 0.48, while the correlation between active coping style score and expectation was -0.34. CONCLUSIONS: Both expectations and coping styles may interact or be co-modifiers in the outcomes of RA patients. Further studies of coping styles and expectations in RA are required. PMID- 20714765 TI - Risk of acquiring tick-borne infections in forestry workers from Lazio, Italy. AB - The seroprevalence of antibodies to Borrelia burgdorferi and tick-borne encephalitis (TBE) virus was evaluated in a group of forestry rangers in the Lazio region of Italy. One hundred and forty-five forestry rangers and 282 blood donors were examined by two-tiered serological tests for B. burgdorferi and TBE virus. Information on occupation, residence, tick bites, outdoor leisure activities and other risk factors was obtained. The prevalence of IgG/IgM antibodies to B. burgdorferi showed no statistical difference between the two groups, but there was a higher occurrence of IgM antibodies. There were significant differences between indoor and outdoor, urban and rural workplaces among the 145 exposed workers (chi2 test: p < 0.001), and a higher risk for outdoor rural than urban tasks was detected among the ten Western blot-tested forestry rangers positive to B. burgdorferi (chi2 test: p < 0.1). No seropositivity was observed for the TBE virus. Forestry rangers from the Lazio region did not have a higher risk of Borrelia infection than the blood donors, though an increase in the risk for outdoor tasks in a rural environment was observed. PMID- 20714766 TI - Adenine, guanine and pyridine nucleotides in blood during physical exercise and restitution in healthy subjects. AB - Maximal physical exertion is accompanied by increased degradation of purine nucleotides in muscles with the products of purine catabolism accumulating in the plasma. Thanks to membrane transporters, these products remain in an equilibrium between the plasma and red blood cells where they may serve as substrates in salvage reactions, contributing to an increase in the concentrations of purine nucleotides. In this study, we measured the concentrations of adenine nucleotides (ATP, ADP, AMP), inosine nucleotides (IMP), guanine nucleotides (GTP, GDP, GMP), and also pyridine nucleotides (NAD, NADP) in red blood cells immediately after standardized physical effort with increasing intensity, and at the 30th min of rest. We also examined the effect of muscular exercise on adenylate (guanylate) energy charge--AEC (GEC), and on the concentration of nucleosides (guanosine, inosine, adenosine) and hypoxanthine. We have shown in this study that a standardized physical exercise with increasing intensity leads to an increase in IMP concentration in red blood cells immediately after the exercise, which with a significant increase in Hyp concentration in the blood suggests that Hyp was included in the IMP pool. Restitution is accompanied by an increase in the ATP/ADP and ADP/AMP ratios, which indicates an increase in the phosphorylation of AMP and ADP to ATP. Physical effort applied in this study did not lead to changes in the concentrations of guanine and pyridine nucleotides in red blood cells. PMID- 20714767 TI - Thermoregulatory responses to ice-slush beverage ingestion and exercise in the heat. AB - We compared the effects of an ice-slush beverage (ISB) and a cool liquid beverage (CLB) on cycling performance, changes in rectal temperature (T (re)) and stress responses in hot, humid conditions. Ten trained male cyclists/triathletes completed two exercise trials (75 min cycling at ~60% peak power output + 50 min seated recovery + 75% peak power output * 30 min performance trial) on separate occasions in 34 degrees C, 60% relative humidity. During the recovery phase before the performance trial, the athletes consumed either the ISB (mean +/- SD 0.8 +/- 0.1 degrees C) or the CLB (18.4 +/- 0.5 degrees C). Performance time was not significantly different after consuming the ISB compared with the CLB (29.42 +/- 2.07 min for ISB vs. 29.98 +/- 3.07 min for CLB, P = 0.263). T (re) (37.0 +/- 0.3 degrees C for ISB vs. 37.4 +/- 0.2 degrees C for CLB, P = 0.001) and physiological strain index (0.2 +/- 0.6 for ISB vs. 1.1 +/- 0.9 for CLB, P = 0.009) were lower at the end of recovery and before the performance trial after ingestion of the ISB compared with the CLB. Mean thermal sensation was lower (P < 0.001) during recovery with the ISB compared with the CLB. Changes in plasma volume and the concentrations of blood variables (i.e., glucose, lactate, electrolytes, cortisol and catecholamines) were similar between the two trials. In conclusion, ingestion of ISB did not significantly alter exercise performance even though it significantly reduced pre-exercise T(re) compared with CLB. Irrespective of exercise performance outcomes, ingestion of ISB during recovery from exercise in hot humid environments is a practical and effective method for cooling athletes following exercise in hot environments. PMID- 20714768 TI - Changes in muscle fascicles of tibialis anterior during anisometric contractions are not associated with motor-output variability of the ankle dorsiflexors in young and old adults. AB - This study examined the associations between the fluctuations of foot acceleration during shortening and lengthening contractions with the electromyographic (EMG) activity of lower leg muscles and ultrasound measures of tibialis anterior fascicle length and pennation angle. Young (24.9 +/- 4.17 years) and old (74.8 +/- 3.31 years) adults lifted and lowered a submaximal load with the foot at different speeds (3 degrees /s-50 degrees /s). The standard deviation (SD) of foot acceleration normalized to the load lifted was similar for young (12.2 +/- 7.22 cm s(-2)/kg) and old adults (14.3 +/- 8.03 cm s(-2)/kg; P = 0.093). The changes in tibialis anterior muscle fascicle length and pennation angle were similar for young and old adults (P >= 0.233), but greater for shortening (fascicle length: 0.937 +/- 0.633 cm, pennation angle: 1.61 +/- 0.918o) than for lengthening contractions (fascicle length: 0.806 +/- 0.521 cm, pennation angle: 0.966 +/- 0.632o; P <= 0.014). The changes in fascicle length and pennation angle were not associated with the SD of foot acceleration (r(2) <= 0.031; P >= 0.092). The surface EMG of tibialis anterior was greater for the shortening contractions than for the lengthening contractions (P < 0.001), but triceps surae EMG was similar for the two types of contractions (P = 0.304). The results suggested that the influence of movement speed on variability in performance was similar for shortening and lengthening contractions with the dorsiflexor muscles; furthermore, old adults were able to match the performance of young adults. PMID- 20714769 TI - Dilated capillaries, disorganized collagen fibers and differential gene expression in periodontal ligaments of hypomorphic fibrillin-1 mice. AB - The periodontal ligaments (PDLs) are soft connective tissue between the cementum covering the tooth root surface and alveolar bone. PDLs are composed of collagen and elastic system fibers, blood vessels, nerves, and various types of cells. Elastic system fibers are generally formed by elastin and microfibrils, but PDLs are mainly composed of the latter. Compared with the well-known function of collagen fibers to support teeth, little is known about the role of elastic system fibers in PDLs. To clarify their role, we examined PDLs of mice under expressing fibrillin-1 (mgR mice), which is one of the major microfibrillar proteins. The PDLs of homozygous mgR mice showed one-quarter of the elastic system fibers of wild-type (WT) mice. A close association between the elastic system fibers and the capillaries was noted in WT, homozygous and heterozygous mgR mice. Interestingly, capillaries in PDLs of homozygous mice were dilated or enlarged compared with those of WT mice. A comparable level of type I collagen, which is the major collagen in PDLs, was expressed in PDL-cells of mice with three genotypes. However, multi-oriented collagen fiber bundles with a thinner appearance were noted in homozygous mice, whereas well-organized collagen fiber bundles were seen in WT mice. Moreover, there was a marked decrease in periostin expression, which is known to regulate the fibrillogenesis and crosslinking of collagen. These observations suggest that the microfibrillar protein, fibrillin 1, is indispensable for normal tissue architecture and gene expression of PDLs. PMID- 20714770 TI - Phase II study of carboplatin and gemcitabine as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer: a report from the Central Japan Lung Study Group, CJLSG 0503 trial. AB - BACKGROUND: The aim of this phase II study was to evaluate the feasibility and safety of a carboplatin and gemcitabine combination regimen in the treatment of completely resected non-small cell lung cancer (NSCLC). METHODS: Patients with completely resected pathologically documented stage IB, II or IIIA NSCLC were treated with carboplatin and gemcitabine. Chemotherapy consisted of 4 cycles of carboplatin at an area under the curve of 5 (level 1) or 4 (level 2) on day 1 combined with gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks. The primary endpoint of this study was the completion rate of 4 cycles. RESULTS: Twenty patients were treated, and the patient's demographics were: median age 61 years (range 51-74), gender male (n = 13, 65%)/female (n = 7, 35%), stage IB (n = 8, 40%), IIA (n = 1, 5%), IIB (n = 6, 30%), IIIA (n = 5, 25%). Seventeen patients (85%, 95% confidence interval 64.0-94.8) received the planned 4 cycles of the chemotherapy regimen at level 1 every 3 weeks. Among the 3 patients who failed to complete 4 cycles, the reasons for stopping were refusal (n = 1), thrombocytopenia (n = 1) and rash (n = 1). The main adverse effects were hematological toxicity as well as grade 3/4 neutropenia and thrombocytopenia (which occurred in 65% and 40% of the patients, respectively). CONCLUSIONS: Adjuvant chemotherapy with a carboplatin and gemcitabine combination regimen has an acceptable toxicity profile, and the majority of patients completed 4 cycles of therapy. PMID- 20714771 TI - Optimal port site placement. AB - Port (trocar) positioning is an important component of the successful completion of laparoscopic colorectal surgery. Although individual surgeons will vary the positions, the principles are well established. The type and positioning of ports will continue to evolve as technology advances. PMID- 20714772 TI - Comment on the article "Optimal port site placement" by R. W. Stitz. PMID- 20714773 TI - Renal allograft recipient with co-existing BK virus nephropathy and pulmonary histoplasmosis: report of a case. AB - Renal allograft recipients are prone to opportunistic infections, rarely multiple coexisting infections, due to the immunocompromised state. To the best of our knowledge, no case of a co-existing polyoma virus nephropathy and pulmonary histoplasmosis in a renal allograft recipient has been reported so far in the available literature. A 55-year-old male renal allograft recipient underwent graft biopsy for asymptomatic graft dysfunction. The graft biopsy showed features of polyoma virus nephropathy. Soon after, he developed fever with pulmonary nodules. Fine-needle aspiration from lung nodules showed intracellular yeast forms of histoplasma. The patient responded well to amphotericin B with subsidence of fever. The co-existence of renal allograft-limited infection like polyoma virus and systemic fungal infection such as histoplasmosis should be kept in mind in a transplant recipient with graft dysfunction and non-specific systemic symptoms. Prompt recognition of these infections permits the clinician to institute appropriate therapeutic modification and improved survival. PMID- 20714774 TI - Increased urinary levels of the leukocyte adhesion molecules ICAM-1 and VCAM-1 in human lupus nephritis with advanced renal histological changes: preliminary findings. AB - BACKGROUND: Leukocyte adhesion molecules are important for migration of the inflammatory cells into sites of inflammation. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin superfamily that are expressed in normal kidney. Their expression is up-regulated in the renal tissue of patients with lupus nephritis (LN). OBJECTIVES: We evaluated whether changes in urinary levels of ICAM-1 and VCAM-1 reflect renal tissue damage in LN. We related the levels of these molecules to other laboratory findings, especially complement C3/C4 levels. We also tested the hypothesis that changes in urinary levels of ICAM-1 and VCAM-1 reflect the severity of renal tissue damage in LN. PATIENTS AND METHODS: This study included 30 systemic lupus erythematosus (SLE) patients with LN (16 with mild histological changes, i.e., with World Health Organization (WHO) class I and II LN, and 14 with advanced histological changes, i.e., class III, IV, and V LN) and 20 with SLE without nephritis. In addition, 20 healthy individuals of comparable age were included as a control group. The levels of urinary ICAM-1 and VCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) and related to the clinical, laboratory [rheumatoid factor(RF), antinuclear antibodies (ANA), anti double-stranded DNA (anti-dsDNA), complements C3 and C4] and histological findings. RESULTS: Levels of urinary ICAM-1 and VCAM-l in LN patients with advanced histological changes (renal damage) were statistically significantly higher than those in other groups (LN patients with mild histological changes or SLE patients without nephritis and control group; p < 0.01). In contrast, serum levels of C3 and C4 in LN patients with advanced histological changes were significantly lower than those in other groups (p < 0.01). There was a significant negative correlation between the levels of urinary adhesion molecules and serum complement levels (p < 0.01). CONCLUSIONS: The significantly high urinary levels of the adhesion molecules in the LN group with advanced histological changes may reflect their renal tissue expression and therefore the severity of the nephritis. Renal tissue damage in these cases may be the result of transmigration of activated inflammatory cells, inducing serious tissue damage. The hypocomplementemia combined with increased urinary levels of adhesion molecules seems to be a useful biomarker of disease severity in LN. PMID- 20714775 TI - Airplane headache in pediatric age group: report of three cases. PMID- 20714776 TI - Effects of high-frequency repetitive transcranial magnetic stimulation of primary motor cortex on laser-evoked potentials in migraine. AB - The aim of this study was to examine the effects of high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex (M1) on subjective pain and evoked responses induced by laser stimulation (LEPs) of the contralateral hand and supraorbital zone in a cohort of migraine patients without aura during the inter-critical phase, and to compare the effects with those of non-migraine healthy controls. Thirteen migraine patients and 12 sex- and age-matched controls were evaluated. Each rTMS session consisted of 1,800 stimuli at a frequency of 5 Hz and 90% motor threshold intensity. Sham (control) rTMS was performed at the same stimulation position. The vertex LEP amplitude was reduced at the trigeminal and hand levels in the sham-placebo condition and after rTMS to a greater extent in the migraine patients than in healthy controls, while the laser pain rating was unaffected. These results suggest that HF rTMS of motor cortex and the sham procedure can both modulate pain-related evoked responses in migraine patients. PMID- 20714777 TI - Role of serum adiponectin level in the development of liver cirrhosis in patients with hepatitis C virus. AB - Adiponectin possesses anti-inflammatory and insulin-sensitizing properties. Little is known about the role of adiponectin in hepatitis-C-related liver disease. The aim of our study was to find a relationship between serum adiponectin levels and different grades of steatohepatitis in HCV-infected patients and to correlate it with the severity of liver disease. Sixty HCV infected patients were divided into two groups according to the presence/absence of steatosis proofed by abdominal ultrasonography and liver biopsy was selected. We evaluated the biochemical parameters for all patients including: ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, prothrombin time, CBC, lipid profile, fasting blood glucose, fasting insulin, and serum adiponectin; HOMA-IR was calculated as [fasting insulin (mIU/l) * fasting glucose (mmol/l)]/22.5. We found that adiponectin was significantly lower in HCV infected patients with steatosis than in those without steatosis. BMI, fasting blood glucose and HOMA-IR were significantly higher in HCV-infected patients with steatosis than in those without steatosis. Furthermore, it was found that steatosis correlates directly with fibrosis index, BMI, HOMA-IR, fasting blood glucose and ALT. Serum adiponectin levels inversely correlates with the grade of steatosis, histological activity index and the stage of fibrosis. PMID- 20714778 TI - Functions of disordered regions in mammalian early base excision repair proteins. AB - Reactive oxygen species, generated endogenously and induced as a toxic response, produce several dozen oxidized or modified bases and/or single-strand breaks in mammalian and other genomes. These lesions are predominantly repaired via the conserved base excision repair (BER) pathway. BER is initiated with excision of oxidized or modified bases by DNA glycosylases leading to formation of abasic (AP) site or strand break at the lesion site. Structural analysis by experimental and modeling approaches shows the presence of a disordered segment commonly localized at the N- or C-terminus as a characteristic signature of mammalian DNA glycosylases which is absent in their bacterial prototypes. Recent studies on unstructured regions in DNA metabolizing proteins have indicated their essential role in interaction with other proteins and target DNA recognition. In this review, we have discussed the unique presence of disordered segments in human DNA glycosylases, and AP endonuclease involved in the processing of glycosylase products, and their critical role in regulating repair functions. These disordered segments also include sites for posttranslational modifications and nuclear localization signal. The teleological basis for their structural flexibility is discussed. PMID- 20714780 TI - A genetic overhaul of Saccharomyces cerevisiae 424A(LNH-ST) to improve xylose fermentation. AB - Robust microorganisms are necessary for economical bioethanol production. However, such organisms must be able to effectively ferment both hexose and pentose sugars present in lignocellulosic hydrolysate to ethanol. Wild type Saccharomyces cerevisiae can rapidly ferment hexose, but cannot ferment pentose sugars. Considerable efforts were made to genetically engineer S. cerevisiae to ferment xylose. Our genetically engineered S cerevisiae yeast, 424A(LNH-ST), expresses NADPH/NADH xylose reductase (XR) that prefer NADPH and NAD(+)-dependent xylitol dehydrogenase (XD) from Pichia stipitis, and overexpresses endogenous xylulokinase (XK). This strain is able to ferment glucose and xylose, as well as other hexose sugars, to ethanol. However, the preference for different cofactors by XR and XD might lead to redox imbalance, xylitol excretion, and thus might reduce ethanol yield and productivity. In the present study, genes responsible for the conversion of xylose to xylulose with different cofactor specificity (1) XR from N. crassa (NADPH-dependent) and C. parapsilosis (NADH-dependent), and (2) mutant XD from P. stipitis (containing three mutations D207A/I208R/F209S) were overexpressed in wild type yeast. To increase the NADPH pool, the fungal GAPDH enzyme from Kluyveromyces lactis was overexpressed in the 424A(LNH-ST) strain. Four pentose phosphate pathway (PPP) genes, TKL1, TAL1, RKI1 and RPE1 from S. cerevisiae, were also overexpressed in 424A(LNH-ST). Overexpression of GAPDH lowered xylitol production by more than 40%. However, other strains carrying different combinations of XR and XD, as well as new strains containing the overexpressed PPP genes, did not yield any significant improvement in xylose fermentation. PMID- 20714781 TI - Bacteria-induced static batch fungal fermentation of the diterpenoid cyathin A(3), a small-molecule inducer of nerve growth factor. AB - Cyathin A(3), produced by the fungus Cyathus helenae, is a member of the cyathane family of diterpene natural products. While many of the cyathanes display antibacterial/antimicrobial activity or have cytotoxic activity against human cancer cell lines, their most exciting therapeutic potential is derived from their ability to induce nerve growth factor (NGF) release from glial cells, making the cyathanes attractive lead molecules for the development of neuroprotective therapeutics to prevent/treat Alzheimer's disease. To investigate if cyathin A(3) has NGF-inducing activity, we set out to obtain it using published C. helenae bench-scale fungal fermentations. However, to overcome nonproducing fermentations, we developed an alternative, bacteria-induced static batch fermentation approach to the production of cyathin A(3), as described in this report. HPLC, UV absorption spectra, and mass spectrometry identify cyathin A(3) in fungal fermentations induced by the timely addition of Escherichia coli K12 or Bacillus megabacterium. Pre-filtration of the bacterial culture abolishes cyathin A(3) induction, suggesting that bacteria-associated media changes or physical interaction between the fungus and bacteria underlie the induction mechanism. Through alteration of incubation conditions, including agitation, the timing of induction, and media composition, we optimized the fermentation to yield nearly 1 mg cyathin A(3)/ml media, a sixfold increase over previously described yields. Additionally, by comparison of fermentation profiles, we reveal that cyathin A(3) biosynthesis is regulated by carbon catabolite repression. We have used an enzyme-linked immunosorbent assay to illustrate that cyathin A(3) induces NGF release from cultured glial cells, and therefore cyathin A(3) warrants further examination in the development of neuroprotective therapeutics. PMID- 20714783 TI - American Association for Cancer Research Genetics and Biology of Brain Cancers 2009, December 13-15, 2009, San Diego, CA. AB - Molecularly targeted therapies promise to transform the treatment of cancer patients, including those with brain tumors. A deeper understanding of the biology of brain tumors has led to a palpable excitement that new and more effective treatments are on the horizon for these deadly diseases. This conference brought basic, genomic, and translational scientists together with clinicians to discuss how to develop more effective molecularly targeted therapies for brain tumor patients based on a mechanistic understanding of the molecular circuitry and biology of the disease. PMID- 20714782 TI - Meningiomas and neurofibromatosis. AB - Neurofibromatosis type 2 (NF2) is a rare genetic disorder predisposing to multiple benign tumors of the nervous system. Meningiomas occur in about half of NF2 patients, and are often multiple. Patients harboring seemingly isolated multiple meningiomas should be investigated to diagnose NF2 by careful familial history collection, detailed clinical examination (skin lesions and slit lamp examination of the lens), audiovestibular testing, and fine cranio-spinal Magnetic Resonance Imaging. Somatic mosaicism is frequent in NF2 and may explain a mild phenotype as, e.g. isolated multiple meningiomas. Neurofibromatosis type 1 is not associated with an increased risk of meningioma. Whether meningiomas are part of the schwannomatosis tumor phenotype or not remains debated. Meningiomas in NF2 patients are associated with a higher risk of mortality, and their treatment is challenging, but data about natural history of meningiomas in NF2 patients in the literature are sparse. Thus, knowledge of tumor behavior is essential in slow growing tumors like meningiomas, to balance the risk of treatment against the natural history of the disease, and to evaluate the efficiency of alternative therapeutics (radiation therapy or new drugs). PMID- 20714779 TI - Transgenic mouse models of multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system (CNS) and a frequent cause of neurological disability in young adults. Multifocal inflammatory lesions in the CNS white matter, demyelination, oligodendrocyte loss, axonal damage, as well as astrogliosis represent the histological hallmarks of the disease. These pathological features of MS can be mimicked, at least in part, using animal models. This review discusses the current concepts of the immune effector mechanisms driving CNS demyelination in murine models. It highlights the fundamental contribution of transgenesis in identifying the mediators and mechanisms involved in the pathophysiology of MS models. PMID- 20714784 TI - Complete reductive dechlorination of tetrachloroethene to ethene by anaerobic microbial enrichment culture developed from sediment. AB - A mixed, anaerobic microbial enrichment culture, AMEC-4P, was developed that uses lactate as the electron donor for the reductive dechlorination of tetrachloroethene (PCE) to ethene. AMEC-4P consistently and completely converted 2 mM PCE to cis-1,2-dichloroethene (cis-DCE) within 13 days, and the intermediate, cis-DCE, was then completely dechlorinated to ethene after 130 days. Dechlorination rates for PCE to cis-DCE, cis-DCE to VC, and VC to ethene were 243, 27, and 41 MUmol/l/day, respectively. Geobacter lovleyi and a Dehalococcoides sp. were identified from their 16S rRNA sequences to be the dominant phylotypes in AMEC-4P. PMID- 20714785 TI - The presence of ethics programs in critical access hospitals. AB - The purpose of this study was to assess the presence of ethics committees in rural critical access hospitals across the United States. Several studies have investigated the presence of ethics committees in rural health care facilities. The limitation of these studies is in the definition of 'rural hospital' and a regional or state focus. These limitations have created large variations in the study findings. In this nation-wide study we used the criteria of a critical access hospital (CAH), as defined by the Medicare Rural Hospital Flexibility Program (Flex Program, 2007), to bring consistency and clarity to the assessment of the presence of ethics committees in rural hospitals. The Flex Monitoring Team conducted a national telephone survey of 381 CAH administrators throughout the United States. The survey covered a wide variety of questions concerning hospitals' community benefit, impact activities, and whether the hospital had a formally established an ethics committee. About 230 (60%) of the respondents indicated they had a formally established ethics committee or ethics consultation program at their CAH. The prevalence of ethics committees declined as the CAH location became increasingly rural along a rural-urban continuum. Unlike CAHs, all rural Department of Veterans Affairs Medical Centers have ethics committees. The results of this study provide an understanding of the limited presence of ethics committee in rural America and the need to consider new approaches for providing ethics assistance. A virtual ethics committee network may be the most efficient and effective way of providing rural hospitals access to a knowledgeable ethics committee or consultant. PMID- 20714786 TI - The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells. AB - The process of carcinogenesis is complex and not easy to eliminate. It includes the initial occurrence of genetic alterations which can lead to the inactivation of tumor-suppressor genes and further accumulation of genetic alterations during tumor progression. Looking for food and food components with biological properties, collectively called nutraceuticals, that can hinder such alterations and prevent the inactivation of tumor-suppressor genes is a very promising area for cancer prevention. Proteins and peptides are one group of nutraceuticals that show potential results in preventing the different stages of cancer including initiation, promotion, and progression. In this review, we summarized current knowledge on the use of nutraceutical proteins and peptides in cancer prevention and treatment. We focused on the role of plant protease inhibitors, lactoferrin and lactoferricin, shark cartilage, plant lectins, and lunasin in the apoptosis, angiogenesis, and metastasis of cancer cells. Also included are studies on bioavailability and clinical trials conducted on these promising proteins and peptides. PMID- 20714787 TI - Nutraceutical use in late-stage cancer. AB - Access to a wealth of information on the internet has led many cancer patients to use complementary methods as an adjunct to traditional therapy for cancer, with, and more often, without informing their primary caregiver. Of the common complementary modalities, the use of dietary supplements appears to be highly prevalent in patients in active treatment for cancer, and later in cancer survivors. Emerging research suggests that some plant-based agents may, indeed, impact late-stage cancer, influencing molecular processes corrupted by tumor cells to evade detection, expand clonally, and invade surrounding tissues. The intent of this article is to review some of the current science underpinning the use of nutraceuticals in the latter stages of cancer. PMID- 20714789 TI - Cancer and metastasis: prevention and treatment by green tea. AB - Metastasis is the most deadly aspect of cancer and results from several interconnected processes including cell proliferation, angiogenesis, cell adhesion, migration, and invasion into the surrounding tissue. The appearance of metastases in organs distant from the primary tumor is the most destructive feature of cancer. Metastasis remains the principal cause of the deaths of cancer patients despite decades of research aimed at restricting tumor growth. Therefore, inhibition of metastasis is one of the most important issues in cancer research. Several in vitro, in vivo, and epidemiological studies have reported that the consumption of green tea may decrease cancer risk. (-)-Epigallocatechin 3-gallate, major component of green tea, has been shown to inhibit tumor invasion and angiogenesis which are essential for tumor growth and metastasis. This article summarizes the effect of green tea and its major polyphenolic compounds on cancer and metastasis against most commonly diagnosed cancer sites. PMID- 20714788 TI - Antimetastatic efficacy of silibinin: molecular mechanisms and therapeutic potential against cancer. AB - Cancer is a major health problem around the world. Research efforts in the last few decades have been successful in providing better and effective treatments against both early stage and localized cancer, but clinical options against advanced metastatic stage/s of cancer remain limited. The high morbidity and mortality in most of the cancers are attributed to their metastatic spread to distant organs. Due to its extreme clinical relevance, metastasis has been extensively studied and is now understood as a highly complex biological event that involves multiple steps including acquisition of invasiveness by cancer cells, intravasation into circulatory system, survival in the circulation, arrest in microvasculature, extravasation, and growth at distant organs. The increasing understanding of molecular underpinnings of these events has provided excellent opportunity to target metastasis especially through nontoxic and biologically effective nutraceuticals. Silibinin, a popular dietary supplement isolated from milk thistle seed extracts, is one such natural agent that has shown biological efficacy through pleiotropic mechanisms against a variety of cancers and is currently in clinical trials. Recent preclinical studies have also shown strong efficacy of silibinin to target cancer cell's migratory and invasive characteristics as well as their ability to metastasize to distant organs. Detailed mechanistic analyses revealed that silibinin targets signaling molecules involved in the regulation of epithelial-to-mesenchymal transition, proteases activation, adhesion, motility, invasiveness as well as the supportive tumor microenvironment components, thereby inhibiting metastasis. Overall, the long history of human use, remarkable nontoxicity, and preclinical efficacy strongly favor the clinical use of silibinin against advanced metastatic cancers. PMID- 20714790 TI - Novel female-specific splice form of dsx in the silkworm, Bombyx mori. AB - The Bombyx mori doublesex (Bmdsx), a homologue of doublesex of Drosophila, is the bottom most gene of the sex determination cascade. Bmdsx plays a very crucial role in somatic sexual development. Its pre-mRNA sex-specifically splices to generate two splice variants; one encodes female-specific and the other encodes male-specific polypeptides which differ only at their C-termini. The open reading frame of Bmdsx consists of 5 exons, of which exons 3 and 4 are female-specific and are skipped in males. In the present study, we have identified a third splice form of the Bmdsx which is specific only to females and differs from the previously reported Bmdsxf isoform by the presence of 15 bp sequence. This new female splice form is generated as a result of alternative 5' splice site selection in the third exon adding additional 15 bp sequence in exon 3 which results in alteration of the reading frame leading to incorporation of an early stop codon. Thus the protein encoded by this splice form is 20 aa shorter than the known BmDsxF. Initial results obtained from the study of dsx homologues in Saturniid silkmoths suggest that both the female-specific Dsx proteins are essential for female sexual differentiation. It remains to be seen whether female specific multiple splice forms of dsx are characteristic feature of only silkmoths or widespread among lepidopterans. The findings that sex determination mechanism is unique in lepidopterans offer an opportunity to develop genetic sexing methods in beneficial as well as economically destructive lepidopteran pests. PMID- 20714792 TI - Audience influence on EGM gambling: the protective effects of having others watch you play. AB - One component of social facilitation on gambling is the potential for an audience of people to observe the play of Electronic Gaming Machine (EGM) gamblers and influence their behaviour without participating directly in gambling themselves. An experiment was conducted with an audience of onlookers, purported to be students of research methods, taking notes while watching the participants play an EGM. Forty-three male and 82 female participants (N = 125), aged 18-79 (M = 49.2, SD = 15.6), played a laptop simulated 3-reel EGM using a $20 stake in three conditions: (1) alone, (2) watched by a simulated audience of six persons, or (3) watched by an audience of 26. Outcomes on the poker machine were rigged with a fixed sequence of five wins in the first 20 spins and indefinite losses thereafter. The results found smaller bet-sizes associated with larger audiences of onlookers, and this outcome is consistent with a hypothesized motivation to display more wins to the audience. Moreover, final payouts were greater in the audience conditions compared to the control, further suggesting that an audience may be a protective factor limiting player losses. PMID- 20714791 TI - Statins attenuate high mobility group box-1 protein induced vascular endothelial activation : a key role for TLR4/NF-kappaB signaling pathway. AB - High mobility group box-1 (HMGB1) has recently been implicated as a proinflammatory cytokine that plays critical roles in endothelial dysfunction and atherosclerosis. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, exerts anti-inflammatory effects in the cardiovascular system beyond its cholesterol-lowering property. The aim of our study was to investigate whether atorvastatin inhibits HMGB1-induced vascular endothelial activation, and elucidate the underlying molecular mechanism. In this study, we found that atorvastatin, at concentrations ranging from 0.1 to 10 MUM, effectively and in a dose-dependent manner inhibited HMGB1-induced endothelial cells (ECs) activation. Incubation of ECs with 10 MUM atorvastatin reduced adhesion molecules (ICAM-1 and E-selectin) expression concomitant with a significant inhibition in HMGB1-stimulated leukocyte-endothelial adhesion. Further experiments showed that atorvastatin markedly suppressed HMGB1-induced Toll like receptor 4 (TLR4) expression, Nuclear factor kappaB (NF-kappaB) nuclear translocation and DNA binding activity in ECs. Similar effects were also observed in ECs pretreated with the TLR4- specific inhibitor CLI-095, suggesting an important role of TLR4/NF-kappaB pathway. These findings indicate that atorvastatin attenuates HMGB1-induced vascular endothelial activation. The underlying mechanism involves, at least in part, inhibition of TLR4/NF-kappaB dependent signaling pathway, which provied the new evidence for therapeutic application of statins to target inflammatory processes in cardiovascular disease. PMID- 20714793 TI - A comparison of two algorithms for automated stone detection in clinical B-mode ultrasound images of the abdomen. AB - Ultrasound (US) imaging is an indispensible technique for detection of abdominal stones which are a serious health hazard. Segmentation of stones from abdominal ultrasound images presents a unique challenge because these images contain strong speckle noise and attenuated artifacts. In clinical situations where a large number of stones must be identified, traditional methods such as manual identification become tedious and lack reproducibility too. The necessity of obtaining high reproducibility and the need to increase efficiency motivates the development of automated and fast procedures that segment out stones of all sizes and shapes in medical images by applying image segmentation techniques. In this paper we present and compare two fully automatic and unsupervised methods for robust stone detection in B-mode ultrasound images of the abdomen. Our approaches are based on the marker controlled watershed segmentation, along with some pre processing and post-processing procedures that eliminate the inherent problems associated with medical ultrasound images. The first algorithm (Algorithm I) utilizes the advantage of the Speckle reducing anisotropic diffusion (SRAD) technique, along with unsharp filtering and histo- gram equalization for removal of speckle noise, and the second algorithm (Algorithm II) is based on the log decompression model which too serves as a tool for minimization of speckle. Experimental results obtained from processing a set of 50 ultrasound images ensure the robustness of both the proposed algorithms. Comparative results of both the algorithms based on efficiency and relative error in stone area have been provided. PMID- 20714794 TI - Up-regulation of beta1 integrin on tonsillar T cells and its induction by in vitro stimulation with alpha-streptococci in patients with pustulosis Palmaris et Plantaris. AB - Pustulosis palmaris et plantaris (PPP) is a tonsil-related disease that can be cured with tonsillectomy. Recent immunological studies have shown that hyperactivation of tonsillar T cells is caused by a hyperimmune response to alpha streptococci; recruitment of the T cells to lesions may be involved in the pathogenesis of PPP. beta1 integrin, expressed on T cells, not only provides a costimulatory signal for T-cell activation but also facilitates the accumulation of T cells in inflammatory skin lesions. In this study, we found that expression of beta1 integrin on both tonsillar and peripheral blood CD4-positive T cells was higher in PPP patients than in non-PPP patients. In vitro stimulation with alpha streptococcal antigen significantly enhanced beta1 integrin expression on tonsillar CD4-positive T cells in PPP patients, but not in non-PPP patients. The chemotactic response of tonsillar CD4-positive T cells to vascular cell adhesion molecule-1, the beta1 integrin ligand, was significantly better in PPP patients than in non-PPP patients. The percentage of beta1 integrin-positive peripheral blood CD4-positive T cells decreased after tonsillectomy in PPP patients. The numbers of beta1 integrin-positive T cells and the expression of vascular cell adhesion molecule-1 were more elevated in plantar PPP skin lesions than in normal skin. These results suggest that beta1 integrin may play a key role in the pathogenesis of PPP. PMID- 20714795 TI - Survey of tobacco control among Florida dentists. AB - Cigarette smoking contributes to the largest number of preventable deaths with a recent report estimating that nearly 5 million annual deaths worldwide and 400,000 in the United States were attributed to cigarette smoking. Dentists, in particular, are in a unique position to educate their patients about the health effects of tobacco. Tobacco cessation knowledge, behaviors, and compliance of Florida dentists were assessed using survey methodology. The survey was administered to a random sample of 6,000 dentists, which was provided by the Florida Department of Health. The survey inquired about (1) general demographic information, (2) Ask, Advise, Assess, Assist, and Arrange behaviors, (3) barriers to the incorporation of tobacco cessation activities, and (4) willingness to participate in further training. A large majority of dentists (88%) are not familiar with the concept of the Ask, Advise, Assess, Assist, and Arrange behaviors when asked directly. When asked about each individual component of this approach, however, dentists had much higher response rates. Dentists were best at routinely asking (59%), advising (46%), & assessing (32%) their patients about their smoking. However, they were much less helpful when assisting and arranging follow-up (70% stated that they never arrange follow-up). This study discovered that the majority of dentists who counsel patients spend only 1-4 min. Sixty-six percent of the dentists surveyed were willing to receive specific training, with 50% preferring an online course and 42% preferring a continued education course. PMID- 20714796 TI - TLR polymorphisms in FMF: association of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly, Thre399Ile) polymorphisms and myeloid cell TLR-2 and TLR-4 expression with the development of secondary amyloidosis in FMF. AB - Amyloidosis is the major complication of familial Mediterranean fever (FMF). Toll like receptors (TLR) are involved in the activation of an innate immune system TLR-2 and TLR-4 recognize lipoteichoic acid and lipopolysaccharides (LPS), respectively. While TLR-2 Arg753Gln polymorphism upregulates, TLR-4 Asp299Gly and Thre399Ile polymorphisms downregulate inflammation. We investigated the effect of these polymorphisms on the development of amyloidosis in FMF patients. We also investigated myeloid cell TLR-2 and TLR-4 expressions in these patients. We studied 26 FMF patients and 13 FMF patients with amyloidosis. TLR-2 Arg753Gln and TLR-4 Asp299Gly and Thr399Ile polymorphisms were analyzed with the polymerase chain reaction-restriction fragment length polymorphism method. Myeloid cell baseline TLR-2 and TLR-4 and LPS-induced TLR-4 expressions were evaluated. The TLR-2 and TLR-4 polymorphism rate was compared with the results of 100 healthy subjects in our previous study. In addition, 13 healthy controls were enrolled for leukocyte TLR-2 and TLR-4 expressions. Serum amyloid A (SAA) levels were measured in these 13 control cases and in FMF patients during attack-free periods. The frequency of TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms in healthy controls in our previous study were 1%, 3%, and 2%, respectively. The frequency of these polymorphisms were not different in FMF patients (with or without amyloidosis) compared to the control group. Likewise, myeloid cell TLR-2 and TLR-4 expressions were not different among the controls and FMF patients. However, LPS-induced TLR-4 expression in granulocytes was more prominent in FMF patients. There was no correlation between TLR-2 and TLR-4 expressions and SAA levels. Neither myeloid cell TLR-2 and TLR-4 expressions nor TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms seem to affect the development of secondary amyloidosis in FMF patients in our study population. PMID- 20714797 TI - Pharmacologic therapy for non ST-segment elevation acute coronary syndromes: focus on antithrombotic therapy. AB - Antithrombotic therapy constitutes the basis of the management of acute coronary syndromes. It combines antiplatelet and anticoagulant therapy. Antiplatelet agents should combine aspirin and agents acting through the ADP pathway such as clopidogrel; newer antiplatelet agents such as prasugrel or ticagrelor have superior anti-ischemic efficacy, compared with clopidogrel. Intravenous glycoprotein IIb/IIIa inhibitors may be used in selected patients at high risk undergoing percutaneous coronary interventions. Unfractionated heparin constitutes the reference anticoagulant treatment. Enoxaparin provides slightly better anti-ischemic efficacy. Newer agents, such as bivalirudin or fondaparinux, reduce bleeding complications, with no improvement in anti-ischemic efficacy. The combination of antiplatelet and anticoagulant agents should be chosen according to the patients' characteristics and the management strategy of the acute coronary syndrome. PMID- 20714798 TI - Using a Personal Digital Assistant to increase completion of novel tasks and independent transitioning by students with autism spectrum disorder. AB - The purpose of this study was to evaluate the use of a Personal Digital Assistant with multiple prompt levels to increase completion of novel task boxes and transitioning within and between tasks. The study used a multiple probe design across three sets of task boxes replicated with three students with a diagnosis of autism spectrum disorder. Results indicated that: task completion was higher for two of the students compared to baseline conditions using a picture-based task strip; all students were able to complete a greater number of between task transitions using the PDA; students performed within task transitions equally as well using the PDA and the task strip; and one student began to self-fade use of more intrusive prompt levels. PMID- 20714799 TI - Atypical disengagement from faces and its modulation by the control of eye fixation in children with autism spectrum disorder. AB - By using the gap overlap task, we investigated disengagement from faces and objects in children (9-17 years old) with and without autism spectrum disorder (ASD) and its neurophysiological correlates. In typically developing (TD) children, faces elicited larger gap effect, an index of attentional engagement, and larger saccade-related event-related potentials (ERPs), compared to objects. In children with ASD, by contrast, neither gap effect nor ERPs differ between faces and objects. Follow-up experiments demonstrated that instructed fixation on the eyes induces larger gap effect for faces in children with ASD, whereas instructed fixation on the mouth can disrupt larger gap effect in TD children. These results suggest a critical role of eye fixation on attentional engagement to faces in both groups. PMID- 20714800 TI - The effects of vitrification on gene expression in mature mouse oocytes by nested quantitative PCR. AB - PURPOSE: this study was conducted on the effects of vitrification cryotop method on gene expression of mature oocytes in Mus musculus. METHODS: transcript analyses of three mouse genes, namely Mater, Hook1 and Sod1, were performed upon non-vitrified and vitrified oocytes with different concentrations of dimethyl sulfoxide (DMSO) and ethylene glycol (EG),15%: 7.5% DMSO + 7.5% EG, and 30%: 15% DMSO + 15% EG, using cryotop following normalization of transcripts with Hprt1 by nested quantitative PCR. RESULTS: vitrification caused down-regulation of Mater and Hook1 and up-regulation of Sod1 when lower concentrations of cryoprotectants were used as opposed to the control group. The relative expression of Sod1 in vit(2) (30% v/v) was significantly higher than vit(1) (15% v/v)(.) Quantitative transcript analysis of Mater and Hook1 for the vit(2) condition failed to produce any data. Survival rates were the same for both vitrification treatments and significantly lower than control group. CONCLUSIONS: although vit(1) treatment had lower survival rate compared to control group, it demonstrated better stability comparing to vit(2) based on the transcript analysis. PMID- 20714801 TI - Non-specific (entropic) forces as major determinants of the structure of mammalian chromosomes. AB - Four specific forces (H-bonds, van der Waals forces, hydrophobic and charge interactions) shape the structure of proteins, and many biologists assume they will determine the shape of all structures in the cell. However, as the mass and contour length of a human chromosome are ~7 orders of magnitude larger than those of a typical protein, additional forces can become significant. We review evidence that additional non-specific (entropic) forces are major determinants of chromosomal shape and position. They are sufficient to drive the segregation (de mixing) of newly replicated DNA to the poles of bacterial cells, while an entropic centrifuge can both form human chromosomes into territories and position them appropriately in nuclei; more locally, a depletion attraction can loop bacterial and human genomes. PMID- 20714803 TI - Breast cancer during pregnancy. PMID- 20714802 TI - CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo. AB - Thus far the clinical benefits seen in breast cancer patients treated with drugs targeting the vascular endothelial growth factor (VEGF) pathway are only modest. Consequently, additional antiangiogenic approaches for treatment of breast cancer need to be investigated. Thrombospondin-2 (TSP-2) has been shown to inhibit tumor growth and angiogenesis with a greater potency than the related molecule TSP-1. The systemic effects of TSP-2 on tumor metastasis and the underlying molecular mechanisms of the antiangiogenic activity of TSP-2 have remained poorly understood. We generated a recombinant fusion protein consisting of the N terminal region of TSP-2 and the IgG-Fc1 fragment (N-TSP2-Fc) and could demonstrate that the antiangiogenic activity of N-TSP2-Fc is dependent on the CD36 receptor. We found that N-TSP2-Fc inhibited VEGF-induced tube formation of human dermal microvascular endothelial cells (HDMEC) on matrigel in vitro and that concurrent incubation of anti-CD36 antibody with N-TSP2-Fc resulted in tube formation that was comparable to untreated control. N-TSP2-Fc potently induced apoptosis of HDMEC in vitro in a CD36-dependent manner. Moreover, we could demonstrate a CD36 receptor-mediated loss of mitochondrial membrane potential and activation of caspase-3 in HDMEC in vitro. Daily intraperitoneal injections of N TSP2-Fc resulted in a significant inhibition of the growth of human MDA-MB-435 and MDA-MB-231 tumor cells grown in the mammary gland of immunodeficient nude mice and in reduced tumor vascularization. Finally, increased serum concentrations of N-TSP2-Fc significantly inhibited regional metastasis to lymph nodes and distant metastasis to lung as shown by quantitative real-time alu PCR. These results identify N-TSP2-Fc as a potent systemic inhibitor of tumor metastasis and provide strong evidence for an important role of the CD36 receptor in mediating the antiangiogenic activity of TSP-2. PMID- 20714804 TI - Spatial learning-induced egr-1 expression in telencephalon of gold fish Carassius auratus. AB - The immediate-early gene (egr-1) expression was used to examine the neuron's response in telencephalon of goldfish during spatial learning in small space. Fishes were pre-exposed in the experimental apparatus and trained to pick food from the tray in a rectangular-shaped arena. The apparatus was divided into identical compartments comprising three gates to provide different spatial tasks. After the fish learned to pass through the gate one, two more gates were introduced one by one. Fish made more number of attempts and took longer time (P < 0.05) to pass through the first gate than the gate two or three. This active learning induces the expression of egr-1 in telencephalon as established by western blot analysis. Subsequently, the fish learn quickly to cross the similar type of second and third gate and make fewer errors with a corresponding decline in the level of egr-1 expression. As the fish learned to pass through all the three gates, third gate was replaced by modified gate three. Interestingly, the level of egr-1 expression increased again, when the fish exhibit a high exploratory behavior to cross the modified gate three. The present study shows that egr-1 expression is induced in the telencephalon of goldfish while intensively acquiring geometric spatial information to pass through the gates. PMID- 20714805 TI - From Pichia anomala killer toxin through killer antibodies to killer peptides for a comprehensive anti-infective strategy. AB - "Antibiobodies", antibodies (Abs) with antibiotic activity, internal image of a Pichia anomala killer toxin (PaKT) characterized by microbicidal activity against microorganisms expressing beta-glucans cell-wall receptors (PaKTRs), were produced by idiotypic vaccination with a PaKT-neutralizing monoclonal Ab (PaKT like Abs) or induced by a protein-conjugated beta-glucan. Human natural PaKT-like Abs (PaKTAbs) were found in the vaginal fluid of women infected with KT-sensitive microorganisms. Monoclonal and recombinant PaKT-like Abs, and PaKTAbs proved to be protective against experimental candidiasis, cryptococcosis and aspergillosis. A killer decapeptide (KP), synthesized from the sequence of a recombinant PaKT like Ab or produced in transgenic plants, showed a microbicidal activity in vitro, neutralized by beta-glucans, a therapeutic effect in vivo, against experimental mucosal and systemic mycoses, and a prophylactic role in planta, against phytopathogenic microorganisms, respectively. KP showed fungicidal properties against all the defective mutants of a Saccharomyces cerevisiae library, inclusive of strains recognized to be resistant to conventional antifungal drugs. KP inhibited in vitro, ex vivo and/or in vivo HIV-1 and Influenza A virus replication, owing to down-regulation of CCR5 co-receptors, physical block of the gp120-receptor interaction and reduction in the synthesis of glycoproteins, HA and M1 in particular. KP modulated the expression of costimulatory and MHC molecules on murine dendritic cells, improving their capacity to induce lymphocyte proliferation. KP, proven to be devoid of cytotoxicity on human cells, showed self-assembly-releasing hydrogel-like properties, catalyzed by beta 1,3 glucan. PaKT's biotechnological derivatives may represent the prototypes of novel antifungal vaccines and anti-infective drugs characterized by different mechanisms of action. PMID- 20714806 TI - Adrenal incidentalomas and subclinical Cushing's syndrome. AB - The issue of cortisol secretion by adrenal masses discovered incidentally in the course of evaluation for an unrelated reason (Subclinical Cushing's Syndrome) is among the most controversial and contentious issues in clinical endocrine practice. This derives from our relatively poor ability to accurately determine clinically those at increased risk among the majority who are not, the significant limitations of available diagnostic tests, the lack of a gold standard for diagnosis or even universally agreed criteria for diagnosis. A consensus for diagnostic criteria would be a good first step on which to base the kinds of studies needed to address our uncertainties. In the meantime, we must be careful to recognize the limitations of the current evidence avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging and sophisticated laboratory testing. There remains an essential role for clinical judgment. PMID- 20714807 TI - A review of the International Atomic Energy Agency (IAEA) international standards for tissue banks. AB - The IAEA International Standards for Tissue Banks published in 2003 were based on the Standards then currently in use in the USA and the European Union, among others, and reflect the best practices associated with the operation of a tissue bank. They cover legal, ethical and regulatory controls as well as requirements and procedures from donor selection and tissue retrieval to processing and distribution of finished tissue for clinical use. The application of these standards allows tissue banks to operate with the current good tissue practice, thereby providing grafts of high quality that satisfy the national and international demand for safe and biologically useful grafts. The objective of this article is to review the IAEA Standards and recommend new topics that could improve the current version. PMID- 20714808 TI - The future role of the professional associations in the promotion of tissue banking activities in Asia and the Pacific and in the Latin America regions. AB - There are several important roles that the established professional associations [Asia-Pacific Association of Surgical Tissue Banking (APASTB) and Latin American Association of Tissue Banks (ALABAT)] could play for the promotion of tissue banking activities in Asia and the Pacific and in the Latin American regions in the future. The International Atomic Energy Agency (IAEA) and the World Health Organisation (WHO) could also play an important role in supporting the activities of both professional associations in the field of training, exchange of scientific information, the standardisation of national norms and regulations, the use of the IAEA documents, particularly the "Radiation Sterilisation of Tissue Allografts: Requirements for Validation and Routine Control. A Code of Practice", with the purpose to improve the quality of the activities carried out by the established tissue banks and the nuclear facilities in charge of the sterilisation of the processed tissues, and to increase tissue donations. The role of APASTB and ALABAT could be relevant and important for the improvement of the work of the established tissue banks in Asia and the Pacific and in the Latin American regions, and could increase the effectiveness and efficiency of their works, the improvement of management good practices and for increasing the awareness of the community on the importance of the activities carried out by the tissue banks, among others. PMID- 20714809 TI - Villa Metabolica - a center of excellence for the diagnosis and treatment of lysosomal storage disorders. AB - Lysosomal storage disorders are very rare diseases that are characterized by a great variability in their clinical presentation. In order to gain experience in this complex field, a center of excellence must be established that covers all aspects of these conditions such as diagnosis, treatment and research. The Villa Metabolica at the Children's Hospital of the University of Mainz is dedicated to provide diagnosis and multidisciplinary management for all patients affected by any of the about 50 known lysosomal storage disorders. This short communication will give an introduction of the activities of this institution. PMID- 20714810 TI - Levels of osteoprotegerin (OPG) and receptor activator for nuclear factor kappa B ligand (RANKL) in serum: are they of any help? AB - The coupling of bone formation and resorption is mediated through the OPG/RANK/RANKL system. OPG and RANKL are mainly produced by osteoblasts but also a variety of other tissues. The binding of RANKL to RANK, its natural receptor which is expressed by osteoclasts, accelerates bone resorption. OPG acts as decoy receptor and prevents the interaction of RANKL with RANK and therefore leads to a decrease in activity, survival and proliferation of osteoclasts. Since assays for measurements of serum OPG and RANKL have become commercially available, intense research focused on serum OPG/RANKL levels in context with underlying disease, age, co-morbidities, bone density, and fractures has derived. This review aims to provide an overview if and to which extent serum OPG and RANKL levels may reflect bone metabolism in patients with osteoporosis and metabolic bone disease. PMID- 20714811 TI - Laboratory and genetic evaluation of Gaucher disease. AB - Gaucher disease (GD) is an inherited lysosomal storage disorder due to deficiency of glucocerebrosidase. Diagnosis of GD may be suspected based on clinical symptoms and confirmed by the analysis of glucocerebrosidase in total white cells, mononuclear cells, fibroblasts and dried blood on filter paper. Low enzyme activities should be followed by molecular analysis of the GBA gene. Although there is no obvious genotype-phenotype correlation, the presence of p.N370S protects from neurological involvement whereas homozygosity of p.L444P mostly leads to a neuronopathic form of GD. Progressive storage of glucosylceramide in mononuclear cells and macrophages results in elevated levels of chitotriosidase and CCL18/PARC which may be used as biomarker to assess disease severity and efficacy of treatment. Chitotriosidase activities cannot be analysed in at least 6% of GD patients due to a null mutation in the corresponding gene. PMID- 20714812 TI - An antibody against RANKL for the treatment of osteoporosis, inflammatory and malignant bone diseases. AB - Over the years, the importance of receptor activator of nuclear factor kappaB ligand (RANKL) in bone physiology and pathophysiology has been thoroughly documented. Denosumab, also known as AMG 162, is a fully human monoclonal antibody against RANKL which is being studied in the treatment of metabolic, inflammatory, and malignant bone diseases. The purpose of this review is to analyze the potential role of denosumab in osteoporosis, rheumatoid arthritis, bone metastases and multiple myeloma. PMID- 20714813 TI - Glycitein decreases the generation of murine osteoclasts and increases apoptosis. AB - BACKGROUND: Phytoestrogens, especially genistein, have been shown to have bone beneficial effects in vitro and in vivo. However, the effect of glycitein on bone cells is not known. The aim of this study was to investigate the effects of glycitein on osteoclast differentiation and apoptosis in vitro. METHODS: Bone marrow-derived osteoclasts were cultured with various concentrations (0.01-100 nM) of glycitein. Osteoclast generation was assessed by the number of multinucleated, tartrate-resistant acid phosphatase (TRAP)-positive cells, and apoptosis by the activity of caspase 3/7. Bone-marrow-derived osteoblasts were cultured in the presence of 10 nM glycitein. Subsequently, gene expression levels of receptor activator of NFkappaB ligand (RANKL), osteoprotegerin (OPG), and interleukin-6 (IL-6) were determined by real-time PCR. RESULTS: Osteoclast generation was inhibited by glycitein in a biphasic-dose-dependent manner and showed the greatest inhibitory effects at 10 nM (-70%, p < 0.01). Glycitein increased caspase 3/7 activity by 15% at a concentration of 10 nM (p < 0.001). Further, 10 nM glycitein significantly decreased the expression of IL-6 (-53%, p < 0.05) and RANKL (-64%, p < 0.05) in osteoblasts but did not change mRNA levels of OPG. CONCLUSIONS: Our data demonstrate that glycitein suppresses osteoclast generation and induces osteoclast apoptosis in vitro to a similar extent as genistein and therefore suggests that glycitein may also exert bone beneficial effects in vivo. PMID- 20714814 TI - Cell biology of osteoimmunology. AB - Osteoimmunology is defined as the research area focusing on the crosstalk between the immune system and the muskoskeletal system. After nearly a decade of research, we are now beginning to understand the basic principles of this crosstalk. It seems that almost all immune cells are capable of communicating with osteoblasts, osteoclasts, and their respective progenitors - and vice versa. Diseases that fall into the category of osteoimmunology including osteoporosis, rheumatoid arthritis, and periodontal disease are of particular significance considering their implications in quality of life, their increased incidence in the population, and socioeconomic issues. To better understand the underlying pathogenesis, the main pathways of the crosstalk between the immune system and the muskoskeletal system need to be uncovered. Our current understanding has already provided the scientific basis for the development of targeted therapies. However, the challenge of future studies is to further decipher this crosstalk at cellular and molecular levels. PMID- 20714815 TI - [Hormonal contraception and breast cancer risk]. AB - The largest meta-analysis comprised a total of 54 epidemiologic studies (Collaborative Group on Hormonal Factors in Breast Cancer) and included 53,297 women with breast cancer and 100,239 controls. Women currently using hormonal contraceptives had a modestly elevated risk for breast cancer (RR 1.24). This risk continuously decreased over years and did not exist after discontinuation of the drugs after ten years. Women who had started on contraceptives before the age of 20, had an elevated risk for breast cancer over the subsequent years (relative risk = RR 1.95 until the 30th year of age, RR 1.54 between 30 and 34 years, and RR 1.27 between the age of 35 and 40 years, respectively) compared to those who started to use contraceptives after 20 years of age. There was no difference in the risk between the different dosages, combined or gestagen-based contraceptives. However, the proportion of women using gestagens only was small. Study data on the effect of oral contraceptives in women with BRCA1/2 mutation or women with a positive familial history are controversial. A recently published systematic overview of 10 studies including a pooled analysis of 54 studies did not reveal an elevated breast cancer risk for women carrying an elevated breast cancer risk taking contraceptives. PMID- 20714816 TI - [Biosurgical debridement using Lucilia sericata-maggots - an update]. AB - During the last years an increasing number of patients suffering from therapy refractory chronic wounds which are frequently infected by multi-resistant bacteria - e.g. methicillin-resistant Staphylococcus aureus - have led to an increasing interest in the treatment using larvae or maggots of the blow fly species Lucilia sericata. Maggots are responsible for necrectomy and they have antimicrobial activity in particular against grampositive bacteria like a disinfectant of the wound. It is concluded that maggots debridement therapy (MDT) using larvae of the species Lucilia sericata in non-healing chronic ulcers of the lower legs successfully leads to cleaning, debridement, reduced bacterial load, and improved wound granulation. A review is given on the clinical use of maggots, their mechanism of action and clinical efficacy for wound healing. PMID- 20714817 TI - gamma-Tocotrienol reduces squalene hydroperoxide-induced inflammatory responses in HaCaT keratinocytes. AB - Squalene hydroperoxide (SQ-OOH), the primary peroxidation product of squalene (SQ), accumulates at the surface of sunlight-exposed human skin. There are however only a few studies on the pathogenic actions (i.e., inflammatory stimuli) of SQ-OOH. Here, we evaluated whether SQ-OOH induced inflammatory responses in immortalized human keratinocytes (HaCaT). We found that SQ-OOH caused an increase in the expression of inflammatory genes such as the interleukins as well as cyclooxygenase-2 (COX-2). In concordance with the upregulation of COX-2 mRNA, SQ OOH enhanced reactive oxygen species generation, nuclear factor kappa B activation, COX-2 protein expression, and prostaglandin E2 production. Therefore, the pro-inflammatory effects of SQ-OOH may be mediated in part via COX-2. On the other hand, gamma-tocotrienol (gamma-T3, an unsaturated form of vitamin E) was found to ameliorate the SQ-OOH actions. These results suggest that SQ-OOH induces inflammatory responses in HaCaT, implying that SQ-OOH plays an important role in inflammatory skin disorders. As a preventive strategy, inflammation could be reduced via the use of gamma-T3. PMID- 20714818 TI - Lipid profiling reveals tissue-specific differences for ethanolamide lipids in mice lacking fatty acid amide hydrolase. AB - N-Acylethanolamines (NAE) are fatty acid derivatives, some of which function as endocannabinoids in mammals. NAE metabolism involves common (phosphatidylethanolamines, PEs) and uncommon (N-acylphosphatidylethanolamines, NAPEs) membrane phospholipids. Here we have identified and quantified more than a hundred metabolites in the NAE/endocannabinoid pathway in mouse brain and heart tissues, including many previously unreported molecular species of NAPE. We found that brain tissue of mice lacking fatty acid amide hydrolase (FAAH (-/-)) had elevated PE and NAPE molecular species in addition to elevated NAEs, suggesting that FAAH activity participates in the overall regulation of this pathway. This perturbation of the NAE pathway in brain was not observed in heart tissue of FAAH (-/-) mice, indicating that metabolic regulation of the NAE pathway differs in these two organs and the metabolic enzymes that catabolize NAEs are most likely differentially distributed and/or regulated. Targeted lipidomics analysis, like that presented here, will continue to provide important insights into cellular lipid signaling networks. PMID- 20714819 TI - Masculinity, medical mistrust, and preventive health services delays among community-dwelling African-American men. AB - BACKGROUND: The contribution of masculinity to men's healthcare use has gained increased public health interest; however, few studies have examined this association among African-American men, who delay healthcare more often, define masculinity differently, and report higher levels of medical mistrust than non Hispanic White men. OBJECTIVE: To examine associations between traditional masculinity norms, medical mistrust, and preventive health services delays. DESIGN AND PARTICIPANTS: A cross-sectional analysis using data from 610 African American men age 20 and older recruited primarily from barbershops in the North, South, Midwest, and West regions of the U.S. (2003-2009). MEASUREMENTS: Independent variables were endorsement of traditional masculinity norms around self-reliance, salience of traditional masculinity norms, and medical mistrust. Dependent variables were self-reported delays in three preventive health services: routine check-ups, blood pressure screenings, and cholesterol screenings. We controlled for socio-demography, healthcare access, and health status. RESULTS: After final adjustment, men with a greater endorsement of traditional masculinity norms around self-reliance (OR: 0.77; 95% CI: 0.60-0.98) were significantly less likely to delay blood pressure screening. This relationship became non-significant when a longer BP screening delay interval was used. Higher levels of traditional masculinity identity salience were associated with a decreased likelihood of delaying cholesterol screening (OR: 0.62; 95% CI: 0.45-0.86). African-American men with higher medical mistrust were significantly more likely to delay routine check-ups (OR: 2.64; 95% CI: 1.34-5.20), blood pressure (OR: 3.03; 95% CI: 1.45-6.32), and cholesterol screenings (OR: 2.09; 95% CI: 1.03-4.23). CONCLUSIONS: Contrary to previous research, higher traditional masculinity is associated with decreased delays in African-American men's blood pressure and cholesterol screening. Routine check-up delays are more attributable to medical mistrust. Building on African-American men's potential to frame preventive services utilization as a demonstration, as opposed to, denial of masculinity and implementing policies to reduce biases in healthcare delivery that increase mistrust, may be viable strategies to eliminate disparities in African-American male healthcare utilization. PMID- 20714820 TI - Outcomes of minimal and moderate support versions of an internet-based diabetes self-management support program. AB - OBJECTIVE: Internet and other interactive technology-based programs offer great potential for practical, effective, and cost-efficient diabetes self-management (DSM) programs capable of reaching large numbers of patients. This study evaluated minimal and moderate support versions of an Internet-based diabetes self-management program, compared to an enhanced usual care condition. RESEARCH DESIGN AND METHODS: A three-arm practical randomized trial was conducted to evaluate minimal contact and moderate contact versions of an Internet-based diabetes self-management program, offered in English and Spanish, compared to enhanced usual care. A heterogeneous sample of 463 type 2 patients was randomized and 82.5% completed a 4-month follow-up. Primary outcomes were behavior changes in healthy eating, physical activity, and medication taking. Secondary outcomes included hemoglobin A1c, body mass index, lipids, and blood pressure. RESULTS: The Internet-based intervention produced significantly greater improvements than the enhanced usual care condition on three of four behavioral outcomes (effect sizes [d] for healthy eating = 0.32; fat intake = 0.28; physical activity= 0.19) in both intent-to-treat and complete-cases analyses. These changes did not translate into differential improvements in biological outcomes during the 4 month study period. Added contact did not further enhance outcomes beyond the minimal contact intervention. CONCLUSIONS: The Internet intervention meets several of the RE-AIM criteria for potential public health impact, including reaching a large number of persons, and being practical, feasible, and engaging for participants, but with mixed effectiveness in improving outcomes, and consistent results across different subgroups. Additional research is needed to evaluate longer-term outcomes, enhance effectiveness and cost-effectiveness, and understand the linkages between intervention processes and outcomes. PMID- 20714821 TI - Statin utilization in nursing home patients after cardiac hospitalization. AB - BACKGROUND: Coronary artery disease (CAD) is highly prevalent in nursing home residents and is associated with a substantial clinical and economic burden. Statins reduce mortality and hospitalization rates in older patients with CAD. OBJECTIVES: To assess rates and predictors of statin use among high-risk patients with symptomatic coronary artery disease (CAD) admitted to nursing homes after acute cardiac hospitalization. DESIGN: Cohort study. PARTICIPANTS: Medicare beneficiaries enrolled in either a state-run drug assistance program or Medicaid in nursing homes in New Jersey from 1994 through 2005. MEASUREMENTS: Statin utilization within 60 days of nursing home admission was determined for patients recently hospitalized with symptomatic CAD in whom statins are indicated consisting of those with: acute coronary syndrome (ACS) without revascularization, ACS with revascularization and congestive heart failure (CHF) with revascularization. Predictors of statin use were evaluated with multivariate logistic regression models. RESULTS: While statin use over the 11-year period increased from 1.2% to 31.8%, overall utilization was very low. Predictors of greater statin use included prior cardiac hospitalization [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.13 to 1.57], prior statin use (OR 6.92, 95% CI 5.86 to 8.82) and receipt of a concurrent cardiac medication (range of odds ratios, 2.36-3.40). Older patients admitted for ACS with or without revascularization were less likely to receive a statin. Patients who had received anti-platelets or angiotensin-modifying agents prior to their hospitalization were less likely to receive statins after discharge. Renal disease, prior stroke, diabetes, hypertension and hyperlipidemia did not influence statin utilization. Predictors of treatment did not change when the cohort was dichotomized according to length of stay. CONCLUSIONS: Patients are infrequently treated with statins when discharged to nursing homes following hospitalization for a symptomatic cardiovascular event. Barriers to statin treatment in this setting require closer examination. PMID- 20714822 TI - Exploring the meaning of respect in medical student education: an analysis of student narratives. AB - BACKGROUND: Respect for others is recognized in the medical literature and society as an essential attribute of the good medical professional. However, the specific meaning of respect varies widely and is underexplored as a lived experience of physicians-in-training. OBJECTIVE: To describe third-year medical students' narratives of respect and disrespect [(dis)respect] during their internal medicine clerkship. DESIGN: Qualitative thematic analysis of 152 third year student narratives that 'taught them something about professionalism,' focusing on (dis)respect. APPROACH: Immersion/crystallization narrative analysis. RESULTS: We reviewed 595 professionalism narratives and found that one in four narratives involved (dis)respect. We then found that 2/3 of these narratives were negative (describing instances of disrespect rather than respect). In the other coded categories, the proportion of negative narratives was significantly lower. In order to better understand these results, we analyzed the content of the (dis)respect narratives and identified six primary themes: (1) content and manner of communication (including, appreciating or belittling, being sensitive or blunt and respecting privacy); (2) conduct: behaviors expressing (dis)respect; (3) patient centeredness: honoring others' preferences, decisions and needs; (4) treating others as equals; (5) valuing the other and their experience and/or problem; and (6) nurturing students' learning. CONCLUSIONS: Focusing on the lived experience of (dis)respect on wards broadens the concept of respect beyond any one type of act, behavior or attitude. Students perceive respect as a way of being that applies in all settings (private and public), with all participants (patients, family members, nurses, colleagues and students) and under all circumstances (valuing others' time, needs, preferences, choices, opinions and privacy). Respect seems to entail responding to a need, while disrespect involves ignoring the need or bluntly violating it. PMID- 20714823 TI - Study of lead level during pregnancy by application of synchrotron radiation micro XRF. AB - In order to study the daily Pb absorption in fetus and to monitor the main Pb sources in prenatal fetus, we have investigated several cases of Pb distribution along the longitudinal axis of fetal hair. The changes of Pb levels in the pregnancy period, even the daily changes of Pb levels can be detected in the hair. Therefore, by analyzing the Pb distribution curves in the fetal hair and the living habits of their mothers, the main sources of Pb in the prenatal fetus can be evaluated. In our study, the main sources of Pb in the two cases of prenatal fetus studied here should be from the polluted aquatics. PMID- 20714824 TI - Positron emission tomography with Pittsburgh compound B in diagnosis of early stage Alzheimer's disease. AB - In order to evaluate the role of positron emission tomography (PET) with N-methyl [(11)C]-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, also known as Pittsburgh compound B (PIB), in the early diagnosis of Alzheimer's disease (AD). Clinical data were collected, and PIB PET cerebral imaging was performed in patients with AD (n = 6), mild cognitive impairment (MCI) (n = 7), and elderly, mentally normal controls (NCs) (n = 7). PET images of the subjects were then analyzed. Visual analysis showed that the radioactivity clearance rate in AD patients was significantly different from that found in the NC group. Furthermore, the radioactivity clearance rate 45 min after PIB injection was significantly lower than the NC group. Images from the MCI group presented heterogeneous results, overlapping with those from both the AD and NC groups. Statistical analysis showed that the radioactivity clearance rate during 5-45 min post-injection was significantly lower in the AD group (41-77%) than the control group (75-81%) (P > 0.05) and the MCI group (59-77%). The radioactivity clearance rate in the bilateral parietal lobes, frontal, temporal, and right occipital lobes, and the bilateral corpora striata in MCI group were lower than that in control group (P < 0.05). PIB PET brain imaging can differentiate early AD patients from NCs and may have certain value in identifying patients progressing to MCI. PMID- 20714825 TI - Striatal dopaminergic fiber recovery after acute L-DOPA treatment in 6 hydroxydopamine (6-OHDA) lesioned rats. AB - In order to examine the acute effects of L: -DOPA treatment following 6 hydroxydopamine (6-OHDA) injection into rat medial forebrain bundle (MFB). Sprague-Dawley rats (n = 48) received either 6-OHDA, via intracranial unilateral injection, into the MFB (experimental group) or saline 0.9% (control group). Administration of L: -DOPA or saline 0.9% began 1 month after the 6-OHDA injection for 10 consecutive days. Within 3 days, an increase in the density of striatal tyrosine hydroxylase (TH) immunoreactive fibers within the striatum, when compared to the control group was observed. There was no difference in the loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons between. The greater density of TH fibers in the striatum following L: -DOPA may be related to recovery of the DA phenotype and/or sprouting of TH axon terminals. Only animals with severe cell loss in the SNpc experienced abnormal involuntary movements (AIMs) or "dyskinesias" in response to L: -DOPA, which did not correlate with striatal TH fiber density, suggesting that induction of TH positive fibers does not contribute to the occurrence of dyskinesia. The relationship between cell loss, fiber density and AIM to the abundance of markers of microglial activation were also examined. Iba-1, a microglial marker, immunoreactivity was not affected by L: -DOPA treatment, was not correlated with the severity of AIM indicating that microglial activation does not contribute to dyskinetic phenomena. PMID- 20714826 TI - Low-voltage direct-current stimulation is safe and promotes angiogenesis in rabbits with myocardial infarction. AB - This study evaluates safety and efficacy of low-voltage direct-current (DC) electrical stimulation of angiogenesis in rabbits with myocardial infarction (MI). Thirty Japanese rabbits were divided into treatment and control groups, and MI was induced by ligation of the left circumflex (LCX) artery. Two platinum electrodes were placed directly on the epicardium on either side of LCX artery. Low-voltage DC stimulation (4.0 V/cm, 30 min/day) was performed in the treatment group immediately after surgery until fourth week post-operatively. Cardio electrophysiological, respiratory, hematological, blood biochemical, histopathological, immunohistochemical parameters, as well as capillary density at the marginal zone of myocardial infarct were compared between treatment and control groups. Capillary density in the treatment group (63.1 +/- 2.2) was significantly higher (P < 0.01) than that in controls (45.4 +/- 3.9). Overall mortality was 6.7%, and the prevalences of pneumothorax and intraoperative arrhythmia were 3.3 and 6.7%, respectively. Transient hypotension, anemia, leukocytosis, hypoxemia, and a slight increase in myocardial enzymes levels were observed in both groups. Regarding electrical stimulation, no adverse reactions except a minor infiltration of inflammatory cells and mild degeneration were observed in the myocardium. It was, therefore, concluded that low-voltage DC stimulation in the MI rabbits was not only safe but also effective in promoting angiogenesis in the myocardium. PMID- 20714827 TI - The regenerative potential of the kidney: what can we learn from developmental biology? AB - Cell turnover in the healthy adult kidney is very slow but the kidney has a strong capacity for regeneration after acute injury. Although many molecular aspects of this process have been clarified, the source of the newly-formed renal epithelial cells is still being debated. Several studies have shown, moreover, that the repair of injured renal epithelium starts from mature tubular cells, which enter into an activated proliferative state characterized by the reappearance of mesenchymal markers detectable during nephrogenesis, thus pointing to a marked plasticity of renal epithelial cells. The regenerative potential of mature epithelial cells might stem from their almost unique morphogenetic process. Unlike other tubular organs, all epithelial and mesenchymal cells in the kidney derive from the same germ layer, the mesoderm. In a fascinating view of vertebrate embryogenesis, the mesoderm might be seen as a cell layer capable of oscillating between epithelial and mesenchymal states, thus acquiring a remarkable plasticity that lends it an extended potential for innovation and a better control of three-dimensional body organization. The renal papilla contains a population of cells with the characteristic of adult stem cells. Mesenchymal stromal stem cells (MSC) have been found to reside in the connective tissue of most organs, including the kidney. Recent studies indicate that the MSC compartment extends throughout the body postnatally as a result of its perivascular location. Developmental biology suggests that this might be particularly true of the kidney and that the papilla might represent the perivascular renal stem cell niche. The perivascular niche hypothesis fits well with the evolving concept of the stem cell niche as an entity of action. It is its dynamic capability that makes the niche concept so important and essential to the feasibility of regenerative medicine. PMID- 20714828 TI - Replacing synthetic with microbial surfactants as collectors in the treatment of aqueous effluent produced by acid mine drainage, using the dissolved air flotation technique. AB - Dissolved air flotation (DAF) is a well-established separation process employing micro bubbles as a carrier phase. The application of this technique in the treatment of acid mine drainage, using three yeast biosurfactants as alternative collectors, is hereby analyzed. Batch studies were carried out in a 50-cm high acrylic column with an external diameter of 2.5 cm. High percentages (above 94%) of heavy metals Fe(III) and Mn(II) were removed by the biosurfactants isolated from Candida lipolytica and Candida sphaerica and the values were found to be similar to those obtained with the use of the synthetic sodium oleate surfactant. The DAF operation with both surfactant and biosurfactants, achieved acceptable turbidity values, in accordance with Brazilian standard limits. The best ones were obtained by the biosurfactant from C. lipolytica, which reached 4.8 NTU. The results obtained with a laboratory synthetic effluent were also satisfactory. The biosurfactants removed almost the same percentages of iron, while the removal percentages of manganese were slightly higher compared with those obtained in the acid mine drainage effluent. They showed that the use of low-cost biosurfactants as collectors in the DAF process is a promising technology for the mining industries. PMID- 20714829 TI - Ectopic thyroid tissue within the gall bladder: case report and brief review of the literature. AB - In this brief report, we describe a case of ectopic thyroid tissue in the gallbladder wall. We review the literature on ectopia of the thyroid and its rare occurrence outside the usual path of the migration of the thyroid anlage from the foramen caecum to the mediastinum. The importance of distinguishing ectopic thyroid from metastatic thyroid carcinoma is emphasized. PMID- 20714830 TI - GNAq mutations are not identified in papillary thyroid carcinomas and hyperfunctioning thyroid nodules. AB - Activating mutations of GNAq protein in a hotspot at codon 209 have been recently described in uveal melanomas. Since these neoplasms share with thyroid carcinomas a high frequency of MAP kinase pathway-activating mutations, we hypothesized whether GNAq mutations could also play a role in the development of thyroid carcinomas. Additionally, activating mutations of another subtype of G protein (GNAS1) are frequently found in hyperfunctioning thyroid adenomas, making it plausible that GNAq-activating mutations could also be found in some of these nodules. To investigate thyroid papillary carcinomas and thyroid hyperfunctioning nodules for GNAq mutations in exon 5, codon 209, a total of 32 RET/PTC, BRAF, and RAS negative thyroid papillary carcinomas and 13 hyperfunctioning thyroid nodules were evaluated. No mutations were identified. Although plausible, GNAq mutations seem not to play an important role in the development of thyroid follicular neoplasms, either benign hyperfunctioning nodules or malignant papillary carcinomas. Our results are in accordance with the literature, in which no GNAq hotspot mutations were found in thyroid papillary carcinomas, as well as in an extensive panel of other tumors. The molecular basis for MAP-kinase pathway activation in RET-PTC/BRAF/RAS negative thyroid carcinomas remains to be determined. PMID- 20714831 TI - Readiness: the state of the science (or the lack thereof). AB - HIV treatment guidelines state that patients' readiness should be assessed before initiating highly active antiretroviral therapy (HAART) to assure adherence. None of the guidelines provide a way to measure readiness. Therefore, this article sought to review the literature on readiness to determine if there was a viable predictor of adherence. Twenty-seven articles were reviewed. Nine described studies that examined the relationship between a measure of readiness and HAART adherence. No readiness measure demonstrated clinical utility as a predictor of adherence. Study flaws included small sample sizes (only one study >100 patients), short follow-up periods (all <=1 year and six were <=5 months, four <=1 month), measures of readiness that related poorly to adherence, and inconsistent adherence measures (eight different measures were used by the researchers). Neither the guidelines nor the literature will help clinicians judge who should initiate HAART and who should delay treatment. PMID- 20714832 TI - Biomarkers in spondyloarthritis. AB - Key challenges in the management of spondyloarthritis focus on the lack of availability of measures of disease activity and the inability to predict joint damage or response to treatment, which is expensive and associated with potentially serious toxicity. Recent studies have focused on the possible contribution of soluble biomarkers, which have been selected based on current understanding of their role in inflammation and/or their association with turnover of joint matrix. Emerging candidates for disease activity markers include interleukin-6 and soluble cytotoxic T lymphocyte associated molecule-4. Potential predictors of damage include metalloproteinase-3 and sclerostin. Acute phase reactants C-reactive protein and serum amyloid A and interleukin-6 are currently the best predictors of treatment response. Significant study limitations are small sample size and the lack of multivariate analyses that can determine whether the biomarker contributes information that is independent of other clinical and laboratory variables used in routine care. PMID- 20714833 TI - Hemodynamic rounds: Ascending aortic dissection as a mechanism of hemodynamic instability. PMID- 20714834 TI - Pineal-adrenal-immune system relationship under thermal stress: effect on physiological, endocrine, and non-specific immune response in goats. AB - The purpose of the investigation was to observe the pineal-adrenal-immune system relationships and their influence on non-specific immune response in female goats under short-term thermal stress. Six female goats had been exposed to 40 degrees C and 60% relative humidity in the psychrometric chamber for 17 days. Blood samples were obtained on days 0 and 10 to establish control and thermal stress effects, respectively. Chemical adrenalectomy was achieved by injecting metyrapone (100 mg/kg body weight) followed by exogenous melatonin treatment (0.1 mg/kg body weight) from 11th to 17th day of experiment. Thermal stress significantly (P<=0.05) altered the physiological responses. Metyrapone and melatonin treatment significantly (P<=0.05) reduced the thermal-stress-induced increase in plasma concentrations of cortisol and corticosterone while significantly (P<=0.05) increased the plasma melatonin on days 11 and 17. Furthermore, these treatments significantly (P<0.05) increased the phagocytic activity of neutrophils as compared to both control and thermal exposure values from 11-17 days of experiment. The data generated from this study help us to understand the functional relationship between pineal, adrenal, and immune system, and how this relationship modifies the non-specific immune response for the well being of goats during thermal stress. PMID- 20714835 TI - [Imaging of the temporal bone]. AB - This article presents a review of diseases of the temporal bone which are relevant for radiologists in routine clinical practice. First the most prominent imaging methods will be briefly summarized with respect to the current state of the art and the most important aspects of cross-sectional anatomy of the temporal bone will be presented. This is followed by the presentation of various inflammatory diseases. Fractures (longitudinal, transverse and mixed fractures), auditory ossicle lesions and contusions of the labyrinth will be discussed in connection with injuries of the temporal bone. Tumors and tumor-like lesions and the clinical symptoms of otosclerosis and malformations will also be discussed. Finally the postoperative use of imaging methods will be presented. Special importance is given to the position of imaging techniques in the diagnostic chain and their evidential value. This is supplemented by special morphological imaging characteristics and aspects of differential diagnostics. PMID- 20714839 TI - Poor outcome following aborted orthotopic liver transplantation due to severe porto-pulmonary hypertension. AB - BACKGROUND/PURPOSE: The diagnosis of porto-pulmonary hypertension (PPHN) in patients with end-stage liver disease at the time of surgery is not an uncommon occurrence. The decision to proceed with orthotopic liver transplantation (OLT) in patients with severe PPHN is associated with high perioperative mortality. We sought to determine the progression of PPHN and patient outcome following aborted OLT. METHODS: A retrospective analysis of 2150 OLT cases was performed. RESULTS: The analysis revealed that six cases (0.3%) were cancelled due to severe PPHN at the time of surgery. The progression to severe PPHN occurred on median over a period of 82 days (range 10-229 days). Following aborted OLT, three patients (50%) expired shortly after. CONCLUSIONS: Cancellation of OLT due to severe pulmonary hypertension was also associated with high mortality. Moreover, this preliminary study reveals that once diagnosed, PPHN can progress to a more severe form over a short period of time. Therefore, we recommend more frequent monitoring of PPHN in this population of patients. PMID- 20714840 TI - Recurrent intrahepatic cholangiocarcinoma: single-center experience using repeated hepatectomy and radiofrequency ablation. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (IHC) is a rare liver malignancy with a rising incidence worldwide. Since no standard treatment has been established so far, the aim of this study was to assess the safety and efficacy of repeated liver resection and/or radiofrequency ablation (RFA) in selected cases with recurrent IHC. PATIENTS AND METHODS: The outcome of 13 patients who had been treated at least once for recurrent IHC by repeated liver resection and/or RFA was retrospectively analyzed. A total of 12 repeated liver resections and 8 radiofrequency ablations were performed in these patients between 2002 and 2008. RESULTS: After a median follow-up period of 28 months after primary liver resection (12-69 months), seven patients (54%) are still alive and three of these patients (23% of the entire cohort) are regarded as disease-free. The median survival for all patients was 51 months (12-69 months). One- and three-year survival after primary surgery was 92 and 52%, respectively, with an overall complication rate of 7.6%. CONCLUSION: According to the present data, repeated liver resection and radiofrequency ablation are feasible in select patients with recurrent IHC. Both procedures can be regarded as safe and might lead to a prolongation of patient survival. PMID- 20714841 TI - The distance of tumor spread in the main pancreatic duct of an intraductal papillary-mucinous neoplasm: where to resect and how to predict it. AB - BACKGROUND: The surgical decision regarding where to resect the pancreas is an important judgement that is directly linked to the surgical procedure. An appropriate surgical margin to resect intraductal papillary-mucinous neoplasm (IPMN) of the pancreas based on the distance of tumor spread (DTS) in the main pancreatic duct has not been adequately documented. We analyzed the appropriate surgical margin based on the DTS in the main pancreatic duct of IPMN and the positive rate at the pancreatic cut end margin. METHODS: Forty patients with main duct- or mixed-type IPMN diagnosed histopathologically who underwent surgery at Tokai University Hospital between 1991 and 2008 were retrospectively analyzed. The resection line was determined to achieve a 2-cm surgical margin in patients with main duct- or mixed-type IPMN and as limited a resection as possible to remove the dilated branch duct in patients with branch duct-type IPMN according to macroscopic type. The dysplastic state of the epithelium was judged as positive for carcinoma in situ (high-grade dysplasia) or adenoma (very low to moderate dysplasia) and judged as negative for hyperplasia or normal. RESULTS: The mean DTS in the main pancreatic duct was 41.6 +/- 30.0 mm, and that of the distance of tumor absence was 13.6 +/- 12.4 mm. The positive rate at the pancreatic cut end margin in frozen sections was 29.7%. The final positive rate at the pancreatic cut end margin was 26.2%. There has been no evidence of local recurrence in the remnant pancreas. DTS in the main pancreatic duct of IPMN was correlated with the maximum diameter of the duct (R = 0.678). CONCLUSION: Distance of tumor spread offered important insights about the appropriate site to resect the pancreas and the positive rate at the cut end margin in IPMN. PMID- 20714842 TI - Three-dimensional models of arteries constructed using multidetector-row CT images to perform pancreatoduodenectomy safely following dissection of the inferior pancreaticoduodenal artery. AB - BACKGROUND/PURPOSE: During a pancreatoduodenectomy (PD) it is important that the anatomy of the arcade of blood vessels in the head of the pancreas is fully understood before the surgery in order to reduce intraoperative bleeding. In most of the patients our group has treated, the inferior pancreaticoduodenal artery (IPDA), one of the efferent arteries of the head of the pancreas, has formed a short common trunk with the first jejunal artery (FJA). Thus, by first locating the origin of the FJA, it was easier to locate the IPDA. There are two ways to locate the IPDA: (1) by measuring the distance between the origin of the superior mesenteric artery (SMA) and that of the FJA; (2) by measuring the distance between the origin of the middle colic artery (MCA) and that of the FJA. Here, we report our measurements of both distances using three-dimensional (3D) models of arteries constructed with multidetector-row computed tomography (MD-CT) images and discuss which is the better measurement to determine the location of the IPDA during PD. METHODS: A total of 140 patients underwent 64-MD-CT imaging to acquire early and late arterial phase scans. The distance between the origin of the SMA and that of the FJA and the distance between the origin of the MCA and that of the FJA origin were measured. RESULTS: In patients whose IPDA formed either a common trunk with the FJA or arose directly from the SMA, the IPDA or the common truck was located in parallel with the SMA at a very short distance of approximately 18 mm from the MCA origin towards the center. The distance between the SMA origin and the IPDA was significantly longer (approximately 36 mm). Therefore, locating the MCA origin during PD helped determine the location of the IPDA. However, in patients whose anterior inferior pancreaticoduodenal artery (AIPDA) and posterior inferior pancreaticoduodenal artery (PIPDA) arose separately, the distance between the AIPDA origin and the MCA origin was approximately 18 mm, the distance between the AIPDA origin and the PIPDA origin was approximately 19 mm, and the distance between the PIPDA origin and the SMA origin was 19 mm. Thus, locating the SMA helped determine the location of the IPDA during PD in these patients. CONCLUSION: Based on our findings that the distance between the IPDA origin and the MCA origin was short, we have shown that it is effective to locate the MCA origin in order to determine the location of the IPDA. PMID- 20714843 TI - Disorders of tissue transformations of lysophosphatidylcholines at experimental pancreatic diabetes in white rats and peculiarities of the corrective effect of low-energy laser radiation of an extremely low intensity. PMID- 20714844 TI - Search for an optimal interfacing of subantennae in superantenna of photosynthetic green bacteria from Oscillochloridaceae family: model calculations. PMID- 20714845 TI - In vitro dimerization of telomerase protein Est3p is stimulated by magnesium cations. PMID- 20714846 TI - Free-radical oxidation of fibrinogen fragments D and E. PMID- 20714847 TI - The nature of mitochondrial monoamine oxidase from the seal (Phoca hispida ladogensis) liver. PMID- 20714848 TI - Stable isotope labelling of human histamine receptor H1R: prospects for structure based drug design. PMID- 20714849 TI - Evolution of carbon dioxide archaic chemoautotrophic fixation system in hydrothermal systems. PMID- 20714850 TI - Molecular-genetic identification of T4 bacteriophages in Lake Baikal. PMID- 20714851 TI - Fnr[4Fe-4S](2+) protein regulates the aidB gene expression in Escherichia coli cultured under anaerobic conditions. PMID- 20714852 TI - [PIN (+)]-dependent induction of protease-resistant amyloids by Ade2p protein fused with prionizing NM domain of Sup35 protein of the yeast Saccharomyces cerevisiae. PMID- 20714853 TI - Obtaining tomato plants transgenic for the preS2-S-HDEL gene, which synthesize the major hepatitis B surface antigen. PMID- 20714854 TI - Specific/nonspecific binding of TBP to promoter DNA of the auxin response factor genes in plants correlated with ARFs function on gene transcription (activator/repressor). PMID- 20714855 TI - Oligodimethylsiloxane reversible inhibitors of cholinesterases of some vertebrate and invertebrate animals. PMID- 20714856 TI - Biodegradable matrices from regenerated silk of Bombix mori. PMID- 20714857 TI - Analysis of Sus2 gene polymorphism in tomato varieties and related wild species. PMID- 20714858 TI - The role of translation termination factor eRF1 in the regulation of pseudohyphal growth in Saccharomyces cerevisiae cells. PMID- 20714859 TI - ENY2 protein forms a part of the THO complex of Drosophila melanogaster. PMID- 20714860 TI - Ornithine decarboxylase in the liver, spleen, and bone marrow of ground squirrels Spermophilus undulatus. PMID- 20714861 TI - Changes in the functional activity of membrane-bound guanylate cyclase forms in tissues of diabetic rats. PMID- 20714862 TI - Expression of Hsp27 and Hsp70 in lymphocytes and plasma in healthy workers and coal miners with lung cancer. AB - In coal mines, main occupational hazard is coal-mine dust, which can cause health problem including coal workers' pneumoconiosis and lung cancer. Some heat shock proteins (Hsps) have been reported as an acute response to a wide variety of stressful stimuli. Whether Hsps protect against chronic environmental coal-mine dust over years is unknown. It is also interesting to know that whether the expression of Hsp27 and Hsp70 proteins as a marker for exposure is associated risk of lung cancer among coal miners. We investigated the association between levels of Hsp27 and Hsp70 expression in lymphocytes and plasma and levels of coal mine dust exposure in workplace or risk of lung cancer in 42 cancer-free non-coal miners, 99 cancer-free coal miners and 51 coal miners with lung cancer in Taiyuan city in China. The results showed that plasma Hsp27 levels were increased in coal miners compared to non-coal miners (P<0.01). Except high cumulative coal-mine dust exposure (OR=13.62, 95%CI=6.05-30.69) and amount of smoking higher than 24 pack-year (OR=2.72, 95% CI=1.37-5.42), the elevated levels of plasma Hsp70 (OR=13.00, 95% CI=5.14-32.91) and plasma Hsp27 (OR=2.97, 95% CI=1.40-6.32) and decreased expression of Hsp70 in lymphocytes (OR=2.36, 95% CI=1.05-5.31) were associated with increased risk of lung cancer. These findings suggest that plasma Hsp27 may be a potential marker for coal-mine dust exposure. And the expression of Hsp27 and Hsp70 levels in plasma and lymphocytes may be used as biomarkers for lung cancer induced by occupational coal-mine dust exposure. PMID- 20714863 TI - Blockade of gammac signals in combination with donor-specific transfusion induces cardiac allograft acceptance in murine models. AB - The gammac cytokines play an important role in proliferation and survival of T cells. Blocking the gammac signals can cause the activated donor-reactive T cells losing the ability to proliferate, and getting into apoptosis pathway, which contributes to induction of the peripheral tolerance. In this study, we induced the transplant tolerance through blocking the gammac in combination with donor specific transfusion (DST) in the cardiac transplantation. Following DST, on the day 2, 4 and 6, C57BL/6 recipients received anti-gammac monoclonal antibodies (mAbs) injection, and those in control group were not given anti-gammac mAbs. On the day 7, Balb/c cardiac allografts were transplanted. All recipients in experimental group accepted cardiac allografts over 30 days, and two of them accepted allografts without rejection until sacrifice on the 120 day. Animals only receiving DST rejected grafts within 5 days, and the mice receiving cardiac transplantation alone rejected grafts within 9 days. Our study showed that blockade of gammac signaling combined with DST significantly prolonged allograft survival, which was probably associated with inhibition of antigen-specific T cell proliferation and induction of apoptosis. PMID- 20714864 TI - MCM3AP, a novel HBV integration site in hepatocellular carcinoma and its implication in hepatocarcinogenesis. AB - A novel HBV integration site involved in hepatocarcinogenesis was investigated. The HBV DNA integration sites were detected by Alu-PCR in hepatocellular carcinoma tissues, matched surrounding liver tissues in 30 patients with hepatitis B-related hepatocellular carcinoma (HCC) and 3 cases of normal liver tissues. The integration sites and flanking sequences in human genome were sequenced and blasted, and the expression of integrated HBV genes was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The influence of the up-regulated expression of integrated genes on hepatocarcinogenesis was analyzed. Nineteen integration sites of HBV DNA into HCC tissues were obtained by RT-PCR and sequencing. These genes encoding proteins were: LOC51030, LOC157777, minichromosome maintenance complex component 3 associated protein (MCM3AP), MCTP1, SH3 and multiple ankyrin repeat domains 2 isoform 2, CCDC40, similar to HCG2033532, mitochondrial ribosomal S5 pseudogene 4. One of them was integrated into the intron of MCM3AP. RT-PCR demonstrated that the expression levels of MCM3AP mRNA in HCC tissues, matched surrounding liver tissues and normal liver tissues were in a descendent order. The ratio of MCM3AP mRNA to the GAPDH mRNA in these three tissues was 1.07375, 0.21573, 0.06747 respectively, with the difference being statistically significant among them (P<0.05). Meanwhile, the expression levels of MCM3AP mRNA from HCC tissues in which HBV DNA integrated into MCM3AP were still significantly higher than those without HBV DNA integrated into MCM3AP. It was concluded that the HBV DNA integration sites into human genome were random, and MCM3AP was a new site. The up-regulated MCM3AP mRNA may affect flanking sequences which promote the hepatocarcinogenesis. PMID- 20714865 TI - Association between SNP rs10569304 on the second expressed region of hole gene and the congenital heart disease. AB - The correlation of single nucleotide polymorphism (SNP) rs10569304 on the second expressed region of hole gene and congenital heart disease (CHD) of human being, and the effect of hole gene on CHD were investigated. 179 patients with CHD as CHD group and 183 healthy people as control group were selected in the case control study. DNA was abstracted from the peripheral blood by phenol-chloroform method. Primer was designed for the flanking sequence of SNP rs10569304 on the second expressed region of hole gene. The genotype was identified by PCR degenerative acrylamide electrophoresis with amplification products. Then the three amplification products received sequencing. By chi-square test, the genotype frequency and allele frequency in CHD group and control group were analyzed. There was insertion-deletion (GCC/-) of SNP rs10569304 which corresponded to alleles of A and B in Southern Chinese people. The genotype frequency and allele frequency in control group and CHD group were met the Hardy Weinberg equilibrium. By chi-square test, in control group and CHD group, the genotype frequency of AA (insertion homozygous), AB (insertion-deletion heterozygous) and BB (deletion homozygous) was 21.31%, 54.09%, 24.59% and 16.75%, 46.36%, 36.87%, respectively. The distributional difference of genotype frequency had statistical significance (chi2=6.51, P<0.05); The allele frequency of A and B was 48.36% and 51.64% in control group, 39.94% and 60.06% in CHD group, respectively. The distributional difference of allele frequency had statistical significance (chi2=5.20, P<0.05). Meanwhile, by contrast with the control group, the BB genotype frequency and B allele frequency in CHD group was higher, but the AA and AB frequency was lower. There was higher risk to suffer from CHD involving B allele. BB genotype had 1.907-fold increased risk of developing CHD according to AA genotype (P<0.05). It is concluded that there is insertion-deletion (GCC/-) of SNP rs10569304 in the Southern Chinese people, and the people whose hole gene involving BB genotype have higher risk to suffering from CHD. PMID- 20714866 TI - Clinical significance of a myeloperoxidase gene polymorphism and inducible nitric oxide synthase expression in cirrhotic patients with hepatopulmonary syndrome. AB - The clinical significance of a myeloperoxidase (MPO) gene polymorphism and inducible nitric oxide synthase (iNOS) expression in cirrhotic patients with hepatopulmonary syndrome (HPS) was explored. Enrolled subjects were divided into three groups according to their disease/health conditions: the HPS group (cirrhotic patients with HPS; n=63), the non-HPS group (cirrhotic patients without HPS; n=182), and the control group (healthy subjects without liver disease; n=35). The distribution of the MPO -463 G/A genotype and its relationship with iNOS expression in a typical cell block from ascitic fluid were detected by immunohistochemistry and polymerase chain reaction-restricted fragment length polymorphism analysis (PCR-RFLP). In the HPS group, the partial pressure of oxygen in blood and ascitic fluid was significantly decreased (8.95+/ 1.58 kPa and 6.81+/-0.95 kPa, respectively; both P<0.01), while the partial pressure of carbon dioxide significantly increased (4.62+/-0.20 kPa and 5.92+/ 0.45 kPa, respectively; P<0.01). MPO and iNOS levels were significantly increased in the HPS group as compared with the non-HPS group. These increases were even more remarkable in ascitic fluid (41.36+/-11.62 and 13.23+/-4.81 microg/L; 10.27+/- 3.20 and 4.95+/-1.12 microg/L) than in blood (16.66+/-5.24 and 4.87+/ 1.73 microg/L; 5.79+/-2.31 and 2.35+/-0.84 microg/L). The distribution of the MPO genotypes GG, GA, and AA were 76.2%, 22.2% and 1.6% in the HPS group, and 57.7%, 37.9% and 4.4% in the non-HPS group (P<0.05). The expression of iNOS was significantly higher in patients with the G alleles (G/G and G/A) (61.54%, 48/78) than in patients with A alleles (G/A and A/A) (38.46%, 30/78) (P<0.01). It was suggested that the expression levels of iNOS and MPO were correlated with HPS induced hypoxemia. The MPO-463 G/A mutation might be a protective factor that prevents the development of HPS. The MPO might be involved in the regulation of iNOS expression. In humans, MPO pathways, the iNOS/NO system, and their interaction might have an impact on the occurrence and development of HPS. PMID- 20714867 TI - IL-17 contributes to autoimmune hepatitis. AB - The role of interleukin-17 (IL-17) in autoimmune hepatitis (AIH) was investigated. A mouse model of experimental autoimmune hepatitis was established, and the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally into adult male C57BL/6 mice. The IL-17 expression in serum and the livers of the mice models was detected by using ELISA and immunohistochemistry, respectively. IL-17 neutralizing antibody was used to study the biological effect of IL-17 in the experimental AIH. IL-17 neutralizing antibody in vivo administration alleviated the hepatic inflammation and ALT level in the AIH model. IL-17 in the peripheral blood mononuclear cells (PBMC) of AIH patients was measured by using real-time PCR method. The results showed that IL 17 level was significantly up-regulated in AIH patients and mice models. It was concluded that IL-17 contributed to the development of AIH and might be a potential therapeutic target of AIH. PMID- 20714868 TI - Use of rats mesenchymal stem cells modified with mHCN2 gene to create biologic pacemakers. AB - The possibility of rats mesenchymal stem cells (MSCs) modified with murine hyperpolarization-activated cyclic nucleotide-gated 2 (mHCN2) gene as biological pacemakers in vitro was studied. The cultured MSCs were transfected with pIRES2 EGFP plasmid carrying enhanced green fluorescent protein (EGFP) gene and mHCN2 gene. The identification using restriction enzyme and sequencing indicated that the mHCN2 gene was inserted to the pIRES2-EGFP. Green fluorescence could be seen in MSCs after transfection for 24-48 h. The expression of mHCN2 mRNA and protein in the transfected cells was detected by RT-PCR and Western blot, and the quantity of mHCN2 mRNA and protein expression in transfected MSCs was 5.31 times and 7.55 times higher than that of the non-transfected MSCs respectively (P<0.05, P<0.05). I(HCN2) was recorded by whole-cell patch clamp method. The effect of Cs+, a specific blocker of pacemaker current, was measured after perfusion by patch clamp. The results of inward current indicated that there was no inward current recording in non-transfected MSCs and a large voltage-dependent inward and Cs+-sensitive current activated on hyperpolarizations presented in the transfected MSCs. I(HCN2) was fully activated around -140 mV with an activation threshold of -60 mV. The midpoint (V50) was -95.1+/-0.9 mV (n=9). The study demonstrates that mHCN2 mRNA and protein can be expressed and the currents of HCN2 channels can be detected in genetically modified MSCs. The gene-modified MSCs present a novel method for pacemaker genes into the heart or other electrical syncytia. PMID- 20714869 TI - Antitumor effect of betulinic acid on human acute leukemia K562 cells in vitro. AB - The effects of betulinic acid (BA), a pentacyclic lupane-type triterpene, on the cell viability, cell cycle and apoptosis in human leukemia K562 cells were investigated. The effects of BA on the growth of K562 cells were studied by MTT assay. Apoptosis was assayed through Annexin V/propidium iodide (PI) double labeled cytometry. The effects of BA on the cell cycle of K562 cells were studied by a PI method. The expression of Bax and capase-3 was detected by using Western blot. The results showed that BA was cytotoxic to K562 cells with an IC50 of 21.26 microg/mL at 24 h. After treating K562 cells with 10 microg/mL BA for 72 h, the number of cells was reduced by 58%. BA induced apoptosis of K562 cells in a time- and dose-dependent manner. The proportion of cells in G0/G1 and G2/M phases was decreased and that in S phase was increased after K562 cells were treated with BA for 24 h. BA treatment also increased the expression of the pro-apoptotic proteins Bax and caspase-3. It suggested that BA could inhibit the proliferation of K562 cells through the induction of cell cycle arrest and apoptosis. The antitumor effects of BA were related with up-regulation of the expression of Bax and caspase-3 proteins. BA may qualify for the development of new therapies for leukemia. PMID- 20714870 TI - Plumbagin enhances TRAIL-mediated apoptosis through up-regulation of death receptor in human melanoma A375 cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent. However, emergence of drug resistance limits its potential use. Plumbagin is a natural quinonoid compound isolated from plant. In this study, induced apoptosis effect of the combined treatment with plumbagin and TRAIL on human melanoma A375 cell line was examined and possible mechanism was investigated. The cells were divided into four groups: control group, plumbagin group (plumbagin, 5 or 10 mumol/L), TRAIL group (TRAIL, 30 ng/mL) and plumbagin+TRAIL group (combined treatment group). The apoptosis, and the expression of DR4 and DR5 were detected by flow cytometry. The activities of caspase-8 and caspase-3 were determined by colorimetric assay. The results showed that the apoptosis rate was 8.3% in TRAIL group, 10.35%-16.94% in plumbagin group and 52.39%-65.39% in combined treatment group, respectively, with the difference being significant between combined treatment group and plumbagin or TRAIL group (P<0.05 for each). Moreover, plumbagin alone could markedly up-regulate DR5 mRNA and protein expression, and slightly increase DR4 mRNA and protein expression. Treatment of human melanoma A375 cells with plumbagin resulted in the activation of Caspase-3, but not Caspase-8. These results suggest that plumbagin might be useful for TRAIL-based treatment for melanoma. PMID- 20714871 TI - Effects of down-regulation of integrin-beta1 expression on migration and hepatic metastasis of human colon carcinoma. AB - Organ-specific tumor cell adhesion to extracellular matrix (ECM) components and cell migration into host organs often involve integrin-mediated cellular processes. Direct integrin-mediated cell adhesion to ECM components in the space of Disse appears to be required for the successful liver metastatic formation of colon cancer. In the present study, human colon cancer HT-29 cells were transfected by liposome with integrin-beta1 antisense oligodeoxynucleotide (ASODN). The integrin-beta1 gene expression in HT-29 cells was significantly down regulated. The migration of HT-29 cells was assayed using transwell cell culture chambers in vitro. The number of migrating HT-29 cells in experimental group was far less than that in control group (P<0.05). The models of hepatic metastasis in nude mice were established by the intrasplenic injection of transfected HT-29 cells. Thirty days later, the nude mice were killed and the average number of hepatic metastases (4.00+/-0.93 per mouse), average volume (10.10+/-6.50 mm3 per mouse), average weight (0.0440+/-0.0008 g per mouse) in experimental group were remarkably reduced as compared with those in control group (P<0.05). Integrin beta1 expression in the hepatic metastasis was studied by immunohistochemistry (SP). Positive cell percentage of hepatic metastases in experimental group was markedly decreased as compared with that in control group (P<0.05). It was concluded that integrin-beta1 may take part in hepatic metastasis, and down regulation of integrin-beta1 expression may play a key role in decreasing migration and hepatic metastasis of human colon carcinoma cells (HT-29). PMID- 20714872 TI - Frequent down-regulation and deletion of KLF6 in primary hepatocellular carcinoma. AB - Kruppel-like factor 6 (KLF6) was reported as tumor suppressor in multiple cancers. However, loss of chromosomal locus spanning KLF6 is relatively infrequent in previous published studies. To explore the role of KLF6 in hepatocellular carcinoma (HCC), we examined the gene for expression change, loss of heterozygosity (LOH) and mutation in 26 HCC samples. The expression levels of KLF6 were significantly down-regulated in HCCs, as detected by qRT-PCR. LOH occurred in 11 (52%) of 21 tumors, and all the samples with LOH showed KLF6 down regulation. The mutational frequency was 24%, and sequence changes located in activation domain of KLF6. Furthermore, MTT assay showed a significant antiproliferative effect of the wt KLF6 transfected in HepG2 hepatoblastoma cells. Fluorescence-activated cell sorting analysis revealed that KLF6 could induce apoptosis. These findings indicate that deregulation of KLF6, together with genetic abnormalities of allelic imbalance and mutations, may play a role in HCC pathogenesis. PMID- 20714873 TI - Mobilization efficiency of granulocyte colony-stimulating factor and stem cell factor to bone marrow mononuclear cells and mechanisms. AB - The mobilization efficiency of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) to bone marrow mononuclear cells (MNCs) in mice was observed, and the changes of CXCL12/CXCR4 signal were detected in order to find out the mobilization mechanism of stem cells. Kunming mice were randomly divided into two groups. The mice in treatment group were subjected to subcutaneous injection of G-CSF at a dose of 100 microg/kg and SCF at a dose of 25 microg/kg every day for 5 days, and those in control group were given isodose physiological saline. The MNCs were separated, counted and cultured, and the colony-forming unit-fibroblast (CFU-F) was evaluated. CD34+CXCR4+ MNCs were sorted by flow cytometry. The expression of CXCL12 protein in bone marrow extracellular fluid was detected by ELISA, and that of CXCL12 mRNA in bone marrow was measured by RT PCR. The results showed that the counts of MNCs in peripheral blood and bone marrow were increased after administration of G-CSF/SCF (P<0.01). The factors had a dramatic effect on the expansion capability of CFU-F (P<0.05). Flow cytometric of bone marrow MNCs surface markers revealed that CD34+CXCR4+ cells accounted for 44.6%+/-8.7% of the total CD34+ MNCs. Moreover, G-CSF/SCF treatment induced a decrease in bone marrow CXCL12 mRNA that closely mirrored the fall in CXCL12 protein. In this study, it is evidenced that G-CSF/SCF can effectively induce MNCs mobilization by disrupting the balance of CXCL12/CXCR4 signaling pathway in the bone marrow and down-regulating the interaction of CXCL12/CXCR4. PMID- 20714874 TI - Expression of PirB in normal and injured spinal cord of rats. AB - The expression of paired immunoglobulin-like receptor B (PirB) in normal and injured spinal cord of rats was investigated. The SD rat hemi-sectioned spinal cord injury (SCI) model was established. Before and 1, 3, 7, 10 days after SCI, the spinal cord tissues were harvested, and Western blot and immunohistochemistry were used to examine the expression and location of PirB. The results showed that the expression level of PirB in the normal spinal cord of SD rats was low. At the first day after SCI, the expression of PirB was obviously increased, and that in the injured spinal cord from the first day to the 10th day was significantly higher than in the normal spinal cord. The positive expression of PirB in neurons from different regions of gray matter of the injured spinal cord was seen. It was concluded that the expression of PirB in the normal spinal cord of rats was low. The expression of PirB in SCI was significantly increased till at least the 10th day. PMID- 20714876 TI - Effect of the artificial somato-autonomic neuroanastomosis on defecation after spinal cord injury and its underlying mechanisms. AB - A new artificial somatic-autonomic neuroanastomosis has been established in male rats with spinal cord injury (SCI). Anorectal manometry and neural retrograde tracing were conducted in this animal model to analyze the mechanisms and the effects on recovery of anorectal function. The left L4 ventral root (L4VR) was intradurally micro-anastomosed to the L6 ventral root (L6VR) to establish the new regenerated neural pathway. Three months later the spinal cord was completely transected at the T9-10 level. Eight weeks later the model rats were randomly divided into two groups. The rats in the group 1 (n=8) were applied for anorectal manometry, and those in the group 2 (n=4) were used for neural retrograde tracing study with fluorogold (FG) and dextran tetramethylrhodamine (TMR). The results of anorectal manometry showed the new reflex pathway could induce rectum to contract and simultaneously electric activity of external anal sphincter (EAS) to become weak or disappearing (indicating synergetic relaxation of EAS). FG and TMR dual labeled neurons with round and elliptical shape were mainly observed in L4 angulus anterior of model rats. The regenerated neural pathways were effective to improve the rectum external sphincter synergetic status and restore the anorectal function. PMID- 20714875 TI - Expression of angiotensin II receptors in aldosterone-producing adenoma of the adrenal gland and their clinical significance. AB - The expression of angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) in aldosterone-producing adenoma (APA) of the adrenal gland was detected, and their relationship with clinical indexes of APA was analyzed. The mRNA expression of AT1R and AT2R in 50 cases of APA and tissues adjacent to tumors and 12 cases of normal adrenal tissues was detected by using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of AT1R and AT2R proteins in paraffin-embedded slices of tissue was detected by immunohistochemistry. The expression of AT1R in adenoma, tissues adjacent to tumor, and normal tissues of the adrenal gland showed no significant differences. The expression of AT2R in APA tissue was lower than that in normal adrenal gland tissues (P<0.05). Correlation analysis of the mRNA expression level of AT2R and clinical data from patients demonstrated that AT2R expression was negatively related to plasma aldosterone concentration (PAC) (r=-0.467, P<0.05), but positively related with plasma renin activity (PRA) (r=0.604, P<0.05). It is concluded that down-regulation of the AT2R expression is possibly related with the tumorigenesis of APA. PMID- 20714877 TI - Relationship between the expression of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase and survival in epithelial ovarian cancer. AB - The mRNA and protein expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) and their relationship with prognosis were investigated. Real-time quantitative RT-PCR (Taqman) was used to detect the mRNA expression of TS, TP and DPD in formalin fixed and paraffin-embedded 106 samples of epithelial ovarian cancer and 29 normal ovaries. A TATA box-binding protein (TBP) was used as an endogenous reference gene. A relationship between TS, TP, DPD expression and clinicopathologic features was investigated. The protein location and expression of TS, TP and DPD was examined in the same patients by an avidin-biotin peroxidase immunohistochemistry. TS and TP mRNA expression levels were significantly higher in tumor group than in normal controls, with the average value of TS and TP mRNA being 6.14+/-0.62 and 0.59+/-0.06 in tumor tissue, and 0.71+/-0.14 and 0.16+/-0.04 in normal tissue, respectively. DPD mRNA expression levels were significantly lower in tumor group (0.11+/-0.02) than in normal controls (0.38+/-0.05). There was statistically significant difference in TS and TP mRNA expression levels among different pathological grades and clinical stages (P<0.05), but histological subtype was not significantly associated with TS and TP mRNA expression. DPD gene expression was not significantly associated with any clinicopathological parameters. Immunohistochemistry revealed that TP protein was mainly distributed in nucleus, and TS and DPD mainly in cytoplasm. The protein expression intensity of TS, TP and DPD was coincided with the mRNA expression levels. It was concluded that TS, TP mRNA and protein expression levels were significantly higher in epithelial ovarian cancer, and DPD mRNA and protein expression levels were significantly lower. The expression levels of TS and DPD were related to the patients' prognosis and survival. Combined gene expression levels of TS, TP and DPD represent a new variable to predict the clinical outcome in ovarian cancer. The association of TS, TP and DPD expression levels with survival suggests an importance of these genes for tumor occurrence and progression. PMID- 20714878 TI - Effect of different concentrations of neogenin on proliferation, apoptosis and related proliferative factors in human trophoblasts. AB - The underlying effect of different concentrations of neogenin on proliferation, apoptosis and the related proliferative factors in human trophoblasts was explored in order to understand the function of neogenin during placentation. TEV 1 cell line was cultured and the expression of netrin-1 was detected by using indirect cellular immunofluorescence. Exponentially growing TEV-1 cells were treated by different concentrations of neogenin (0, 1, 5, 10, 50 ng/mL) for 24 h. Cell viability was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. TEV-1 cell apoptosis was assessed by flow cytometry (FCM). The expression of netrin-1 mRNA and protein in TEV-1 cells was examined by using real-time PCR and Western blot, respectively. It was found that immunoreactivity for netrin-1 was observed in cytoplasm of the trophoblasts. Immediately after treatment with different concentrations of neogenin for 24 h, the netrin-1 expression began to increase. Real-time PCR revealed that the expression level of netrin-1 mRNA was 37.59+/-10.25 times higher than control group when TEV-1 cells were exposed to 50 ng/mL neogenin (P<0.01), and the same tendency was seen by using Western blot. MTT results showed that proliferation of TEV-1 cells was independent of neogenin. Meanwhile, apoptosis was significantly increased to (22.15+/-6.15)% at 50 ng/mL neogenin and (6.55+/-0.25)% without neogenin (P<0.01). It is suggested that neogenin regulates proliferation and apoptosis of TEV-1 cells. And it can enhance the ability of TEV-1 cells to express netrin-1 in a dose-dependent manner. Neogenin may play an important biological role in the normal human pregnancy and contribute to the physiological pregnancy process. PMID- 20714879 TI - Analysis of phosphatidylinositol 3-kinase activation in the adipose tissue of gestational diabetes mellitus patients and insulin resistance. AB - The P85 regulatory subunit protein and gene expression and P110 catalylic subunit activity of phosphatidylinositol 3-kinase (PI-3K) were investigated in adipose tissue of patients with gestational diabetes mellitus (GDM) in order to explore the molecular mechanisms of insulin resistance (IR) of GDM. Samples from patients with GDM (n=50), and controls (n=50) were collected. Fasting insulin (FIN) was determined by radioimmunoassay. Fasting plasma glucose (FPG) was measured by oxidase assay. Western blot technique was used to detect the levels of PI-3K P85 subunit in adipose tissues of patients with GDM. The mRNA expression of PI-3K P85 subunit was detected by reverse transcription polymerase chain reaction (RT-PCR) method in the adipose tissue. PI-3K activity was examined by immunoprecipitation, thin-layer chromatography and gamma scintillation counting. The results were analyzed statistically. It was found that the levels of FPG, FIN and HOMA-IR in GDM group were significantly higher than those in control group (all P<0.01). There was no significant difference in the protein and gene expression of PI-3K P85 subunit between GDM group and control group (P>0.05). PI-3K activity was significantly decreased to 82.89% in GDM group as compared with control group (P<0.01) and negatively correlated with HOMA-IR (r=-0.75, P<0.01). It was concluded that PI-3K in GDM patients may be involved in the insulin signaling pathway, resulting in IR of GDM. PMID- 20714880 TI - Dysregulation of E-cadherin in chronic rhinosinusitis with nasal polyps. AB - E-cadherin is a key epithelial protein and adhesive molecule. This study detected the E-cadherin expression in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and controls, and analyzed its possible role in the pathogenesis of CRSwNP. The expression of E-cadherin was detected by using Western blotting and immunohistochemistry in controls and patients with CRSwNP. Computed tomography (CT) scan findings were scored. The results showed that the E-cadherin expression was up-regulated in patients with CRSwNP as compared with controls (P=0.039) and the positive staining was predominantly localized on the epithelial cell membrane. E-cadherin level was correlated negatively with Lund-Mackay scores in patients with CRSwNP (r=-0.604, P=0.005). It is suggested that E-cadherin may be involved in the pathogenesis of CRSwNP and correlated with disease severity. PMID- 20714881 TI - Protective roles of alpha-lipoic acid in rat model of mitochondrial DNA4834bp deletion in inner ear. AB - The protective roles of alpha-lipoic acid in the rat model of mitochondrial DNA (mtDNA) 4834bp deletion in inner ear were investigated. Forty female Wistar rats at 4 weeks of age were divided into four groups: group A (D-galactose group, n=10), group B (D-galactose+alpha-lipoic acid group, n=10), group C (alpha-lipoic acid group, n=10), and group D (control group, n=10). Auditory brainstem response (ABR) was used to detect the hearing threshold. Colorimetry was used to analyze activity of superoxide dismutase (SOD) and concentration of malondialdehyde (MDA). The percentage of mtDNA4834bp deletion in inner ear was identified by real time PCR. There was no significant difference in ABR threshold shift among all groups. The percentage of mtDNA4834bp deletion in group A was higher than that in other groups, but there was no significant difference in percentage of mtDNA4834bp deletion among groups B, C, and D. The activity of SOD in group A was lower than that in other groups. The concentration of MDA in group A was higher than that in other groups. It was concluded that there was no significant hearing loss when the percentage of mtDNA4834bp deletion was lower than 12.5%. Alpha lipoic acid could prevent the reactive oxygen species (ROS)-induced mtDNA4834bp deletion in inner ear of rats. PMID- 20714882 TI - Effect of bone marrow mesenchymal stem cells transfected with rAAV2-bFGF on early angiogenesis of calvarial defects in rats. AB - The purpose of this study was to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) transfected with the basic fibroblast growth factor (bFGF) expressing recombinant adeno-associated virus vector (rAAV2-bFGF), on early angiogenesis of calvarial defects in rats. The MSCs were cultured and transfected with rAAV2-bFGF after differential adherence isolation. The transfection efficiency was detected by RT-PCR and Western blotting. The transfected MSCs were compounded with poly-DL-lactide/hydroxyapatite (PDLLA/HA) in vitro. The cranial defect models in 36 male SD rats were created. Nothing (group A), PDLLA/HA alone (group B), PDLLA/HA combined with MSCs (group C), and PDLLA/HA combined with rAAV2-bFGF transfected MSCs (group D) were implanted in rat calvarial defects. The specimens were harvested for hematoxylin-eosin staining on the day 1, 3 and 7 after implantation. Factor VIII immunohistochemical staining and histomorphometric analysis were carried out to evaluate neovascularization around the implantation. The results indicated that MSCs could indeed be successfully transfected with the rAAV2-bFGF vector. Histological and histomorphometric analysis revealed that the angiogenesis in group D was significantly enhanced as compared with the rest groups (P<0.05). These results strongly suggest that MSCs transfected with rAAV2-bFGF in combination with PDLLA/HA can effectively promote the early angiogenesis of calvarial defects in rats, which played an important role in creating an environment suitable for the survival and activity of transplanted cells for further applications in cranio-maxillofacial bone regeneration. PMID- 20714883 TI - Analysis of P53 mutation and invasion front grading in oral squamous cell carcinomas. AB - We examined P53 mutation and invasion front grading (IFG) in 30 cases of oral squamous cell carcinomas (OSCCs). The association of P53 mutation and IFG scores with clinicopathological parameters was evaluated. P53 mutation existed in exon 5 8 in 15 out of the 30 OSCCs (50%). The incidence of P53 mutation was not associated with age, gender, N value and TNM stage. However, there was a significant correlation between P53 mutation and T value (P=0.046). There were no statistically significant correlations among the clinicopathological parameters and IFG. Interestingly, The IFG score in OSCCs with P53 mutation was significantly higher than that in OSCCs without P53 mutation (P<0.001). These results suggest that the high incidence of P53 mutation is a major mechanism of OSCC carcinogenesis. The presence of P53 mutation indicates the most anaplastic fields in the invasive areas of the tumors, which may predict poor prognosis for the patients. PMID- 20714884 TI - Prognostic factors for patients after curative resection for proximal gastric cancer. AB - The factors influencing the long-term survival of patients with proximal gastric cancer (PGC) after curative resection were investigated. Data from 171 patients who underwent curative resection for PGC were retrospectively analyzed. The patients were grouped according to the clinicopathological factors and operative procedures. The tumor depth (T stage) and lymph node metastasis (pN stage) were graded according to the fifth edition of TNM Staging System published by UICC in 1997. The metastatic lymph node ratio (MLR) was divided into four levels: 0%, <10%, 10%-30% and >30%. The data of survival rate were analyzed by Kaplan-Meier method (log-rank test) and Cox regression model. The 5-year overall survival rate of 171 patients was 37.32%. The univariate analysis demonstrated that the survival time of the postoperative patients with PGC was related to tumor size (chi2=4.57, P=0.0325), gross type (chi2=21.38, P<0.001), T stage (chi2=27.91, P<0.001), pN stage (chi2=44.72, P<0.001), MLR (chi2=61.12, P<0.001), TNM stage (chi2=44.91, P<0.001), and range of gastrectomy (chi2=4.36, P=0.0368). Multivariate analysis showed that MLR (chi2=10.972, P=0.001), pN stage (chi2=6.640, P=0.010), TNM stage (chi2=7.081, P=0.007), T stage (chi2=7.687, P=0.006) and gross type (chi2=6.252, P=0.012) were the independent prognostic factors. In addition, the prognosis of patients who underwent total gastrectomy (TG) was superior to that of patients who underwent proximal gastrectomy (PG) for the cases of tumor>or=5 cm (chi2=6.31, P=0.0120), Borrmann III/IV (chi2=7.96, P=0.0050), T4 (chi2=4.57, P=0.0325), pN2 (chi2=5.52, P=0.0188), MLR 10%-30% (chi2=4.46, P=0.0347), MLR>30% (chi2=13.34, P=0.0003), TNM III (chi2=14.05, P=0.0002) or TNM IV stage (chi2=4.37, P=0.0366); and combining splenectomy was beneficial to the cases of T3 (chi2=5.68, P=0.0171) or MLR>30% (chi2=6.11, P=0.0134). It was concluded that MLR, pN stage, TNM stage, T stage, and gross type had advantages in providing a precise prognostic evaluation for patients undergoing curative resection for PGC, in which MLR was the most valuable index. TG and combining splenectomy were useful to improve the prognosis to patients with PGC of TNM III/IV stage, serosa invasion, or extensive regional lymph node metastasis. PMID- 20714885 TI - Noninvasive diagnosis of cardiac amyloidosis by MRI and echochardiography. AB - This study described the radiological features on echocardiography and MRI specific to cardiac amyloidosis confirmed on biopsy. Eleven cases of biopsy proven cardiac amyloidosis were retrospectively reviewed in this study. All patients underwent biopsy, cardiac MRI and echocardiography. The main echocardiography and MRI findings were as follows: diffuse ventricular and septum wall thickening, atrial enlargement, pericardial effusion, restricted left ventricular (LV) systolic and diastolic function, characteristic granular sparkling of myocardium. MRI revealed a characteristic pattern of global subendocardial late enhancement, extending in varying degrees into the neighboring myocardium. The findings agreed with the infiltration distribution of amyloid protein. Typical abnormalities seen on echocardiography and MRI should have important diagnostic and prognostic value of cardiac amyloidosis. MRI should be considered in the diagnosis of cardiac amyloidosis if echocardiographic features are suspicious. PMID- 20714886 TI - Quantitative analysis of cell tracing by in vivo imaging system. AB - In vivo imaging system (IVIS) is a new and rapidly expanding technology, which has a wide range of applications in life science such as cell tracing. By counting the number of photons emitted from a specimen, IVIS can quantify biological events such as tumor growth. We used B16F10-luc-G5 tumor cells and 20 Babl/C mice injected subcutaneously with B16F10-luc-G5 tumor cells (1x10(6) in 100 microL) to develop a method to quantitatively analyze cells traced by IVIS in vitro and in vivo, respectively. The results showed a strong correlation between the number of tumor cells and the intensity of bioluminescence signal (R2=0.99) under different exposure conditions in in vitro assay. The results derived from the in vivo experiments showed that tumor luminescence was observed in all mice by IVIS at all days, and there was significant difference (P<0.01) between every two days from day 3 to day 14. Moreover, tumor dynamic morphology could be monitored by IVIS when it was invisible. There was a strong correlation between tumor volume and bioluminescence signal (R2=0.97) by IVIS. In summary, we demonstrated a way to accurately carry out the quantitative analysis of cells using IVIS both in vitro and in vivo. The data indicate that IVIS can be used as an effective and quantitative method for cell tracing both in vitro and in vivo. PMID- 20714887 TI - Characterization of protein in old myocardial infarction by FTIR micro spectroscopy. AB - The aim of the present study was to assess whether Fourier transform infrared spectrometry (FTIR) micro-spectroscopy could produce distinct spectral information on protein of old myocardial infarction (OMI) and to set them as molecular markers to diagnose atypical OMI. Paraffin-embedded heart samples were derived from victims dying of OMI. In combination with histological stain, FTIR and infrared micro-spectroscopy, the characteristics of OMI were analyzed morphologically and molecularly. The most relevant bands identified were the amide A, B, I and, II showing crucial spectral differences between apparent normal region and OMI region, including the peak position blue shift and the increased intensity of OMI, moreover relative increase in alpha-helix and decrease in beta-sheet of protein secondary structures in OMI. Comparing to single spectral band, the I1650/I1550 ratio was increased and rationally used as a molecular marker for diagnosing OMI. These novel preliminary findings supported further exploration of FTIR molecular profiling in clinical or forensic study, and were in accordance with histopathology. PMID- 20714889 TI - Evaluation of standard and advanced preprocessing methods for the univariate analysis of blood serum 1H-NMR spectra. AB - Proton nuclear magnetic resonance ((1)H-NMR)-based metabolomics enables the high resolution and high-throughput assessment of a broad spectrum of metabolites in biofluids. Despite the straightforward character of the experimental methodology, the analysis of spectral profiles is rather complex, particularly due to the requirement of numerous data preprocessing steps. Here, we evaluate how several of the most common preprocessing procedures affect the subsequent univariate analyses of blood serum spectra, with a particular focus on how the standard methods perform compared to more advanced examples. Carr-Purcell-Meiboom-Gill 1D (1)H spectra were obtained for 240 serum samples from healthy subjects of the Asklepios study. We studied the impact of different preprocessing steps--integral (standard method) and probabilistic quotient normalization; no, equidistant (standard), and adaptive-intelligent binning; mean (standard) and maximum bin intensity data summation--on the resonance intensities of three different types of metabolites: triglycerides, glucose, and creatinine. The effects were evaluated by correlating the differently preprocessed NMR data with the independently measured metabolite concentrations. The analyses revealed that the standard methods performed inferiorly and that a combination of probabilistic quotient normalization after adaptive-intelligent binning and maximum intensity variable definition yielded the best overall results (triglycerides, R = 0.98; glucose, R = 0.76; creatinine, R = 0.70). Therefore, at least in the case of serum metabolomics, these or equivalent methods should be preferred above the standard preprocessing methods, particularly for univariate analyses. Additional optimization of the normalization procedure might further improve the analyses. PMID- 20714890 TI - Selective extraction of low molecular weight proteins by mesoporous silica particles with modified internal and external surfaces. AB - A new mesoporous silica material with modified external and internal surfaces (alkyl diol-vinyl-SiO(2)) was prepared and applied to selectively extract low molecular weight (LMW) proteins and peptides (less than 11 kDa) from biological samples. X-ray diffraction, N(2) adsorption, transmission electron microscopy, and Fourier transform infrared spectroscopy were used to characterize the alkyl diol-vinyl-SiO(2). This material was used to extract LMW proteins (peptides) from standard proteins, a mixture of peptides, and crude human plasma. We compared the amounts of different proteins adsorbed by alkyl diol-vinyl-SiO(2) and by vinyl SiO(2) (vinyl group on the internal surface of the mesoporous silica material). The desorption recovery of alkyl diol-vinyl-SiO(2) by different eluents was also investigated by using a standard protein (insulin) as a model LMW protein. The material could efficiently extract LMW proteins and peptides from a mixture of standard proteins and crude human plasma with good extraction efficiency and desorption recovery. Furthermore, the alkyl diol-vinyl-SiO(2) had much better extraction selectivity for LMW proteins and peptides than a commercial C(18) solid phase extraction material. PMID- 20714888 TI - Genetic variants affecting incretin sensitivity and incretin secretion. AB - Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The majority of these type 2 diabetes risk variants confer impaired pancreatic beta cell function. Though the molecular mechanisms by which common genetic variation within these loci affects beta cell function are not completely understood, risk variants may alter glucose-stimulated insulin secretion, proinsulin conversion, and incretin signals. In humans, the incretin effect is mediated by the secretion and insulinotropic action of two peptide hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. This review article aims to give an overview of the type 2 diabetes risk loci that were found to associate with incretin secretion or incretin action, paying special attention to the potential underlying mechanisms. PMID- 20714891 TI - Detection of bisphenol A using a novel surface plasmon resonance biosensor. AB - We present a compact surface plasmon resonance (SPR) biosensor for the detection of bisphenol A (BpA), an endocrine-disrupting chemical. The biosensor is based on an SPR sensor platform (SPRCD) and the binding inhibition detection format. The detection of BpA in PBS and wastewater was performed at concentrations ranging from 0.05 to 1,000 ng/ml. The limit of detection for BpA in PBS and wastewater was estimated to be 0.08 and 0.14 ng/ml, respectively. It was also demonstrated that the biosensor can be regenerated for repeated use. Results achieved with the SPR biosensor are compared with those obtained using ELISA and HPLC methods. PMID- 20714892 TI - Investigating the relationship between cell cycle stage and diosgenin-induced megakaryocytic differentiation of HEL cells using sedimentation field-flow fractionation. AB - Differentiation therapy could be one strategy for stopping cancer cell proliferation. A plant steroid, diosgenin, is known to induce megakaryocytic differentiation in human erythroleukemia (HEL) cells. In recent studies, the use of sedimentation field-flow fractionation (SdFFF) allowed the preparation of subpopulations that may differ in regard to sensitivity to differentiation induction. The specific goal of this study was to determine the relationship between cell cycle stage and sensitivity to megakaryocytic differentiation induction of HEL cells. After first confirming the capacity of diosgenin to specifically select targets, hyperlayer SdFFF cell sorting was used to prepare fractions according to cell cycle position from crude HEL cells. The sensitivities of these fractions to diosgenin-induced differentiation were then tested. The coupling of SdFFF cell separation to imaging flow cytometry showed that G1-phase cells were more sensitive to differentiation induction than S/G2M phase cells, confirming the relationship between cell status at the start of induction, the extent of the biological event, and the potential of SdFFF in cancer research. PMID- 20714893 TI - Bioactive molecules in Kalanchoe pinnata leaves: extraction, purification, and identification. AB - Kalanchoe pinnata (Lam.) Pers. (syn. Bryophyllum pinnatum; family Crassulaceae) is a popular plant used in traditional medicine in many temperate regions of the world and particularly in South America. In Guyana, the leaves are traditionally used as an anti-inflammatory and antiseptic to treat coughs, ulcers, and sores. The purpose of this study was to implement a method for targeting and identifying molecules with antimicrobial activity, which could replace chemical preservatives in cosmetic applications. The leaves were extracted by a method based on pressurized liquid extraction (PLE), using different solvents. A study of antimicrobial activity and cytotoxicity tests were performed to select the most interesting extract. To isolate one or more active molecules, the selected crude extract was fractionated by centrifugal partition chromatography (CPC) and then antimicrobial activity and cytotoxicity of each fraction were tested under the same procedure. The last step consisted of identifying the main compounds in the most active fraction by LC-MS/MS. PMID- 20714895 TI - Elective open versus laparoscopic sigmoid colectomy for diverticular disease: a meta-analysis with the Sigma trial. AB - BACKGROUND: A meta-analysis of published literature comparing open versus laparoscopic elective sigmoid resections for diverticular disease was conducted. METHODS: Electronic databases were searched for data from January 1991 to March 2009. A systematic review was performed to obtain a summative outcome. RESULTS: Twenty-two comparative studies involving 10,898 patients were analyzed; 1538 patients were in the laparoscopic group and 9360 were in the open group. The operative time for laparoscopic sigmoid resection (LSR) is longer than open resections (OSR) [random-effects model: SMD = 1.94, 95% CI = (1.14, 2.74), z = 4.74, p < 0.001]. However, patients who undergo LSR have earlier return to passage of feces [random-effects model: SMD = -1.01, 95% CI (-1.80, -0.22), z = 2.50, p = 0.013] and shorter hospital stay [random-effects model: SMD = -7.65, 95% CI (-10.96, -4.32), z = -4.52, p < 0.001]. Overall morbidity was higher in the OSR group [random-effects model: RR = 0.56, 95% CI (0.40, 0.80), z = -3.24, p < 0.001] and no difference in mortality rates was observed (p = 0.81). CONCLUSIONS: Laparoscopic sigmoid resection takes longer to perform than open procedures; however, it is safe and has lower overall morbidity, earlier return of bowel function, and shorter hospital stays. This approach should be considered for elective cases but more randomized controlled trials are required to strengthen the evidence. PMID- 20714896 TI - Outcomes of staple fixation of mesh versus nonfixation in laparoscopic total extraperitoneal inguinal repair: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Staple fixation of mesh during laparoscopic total extraperitoneal (TEP) inguinal repair is thought to be necessary to prevent recurrence. However, mesh fixation may increase surgical complications and pain. Therefore, a meta analysis of randomized controlled trials (RCTs) was conducted to compare the outcomes of nonfixation with fixation of mesh by metal tacks during TEP inguinal hernia repair. METHODS: The meta-analysis was conducted according to the Quality of Reporting of Meta-analyses (QUOROM) standards. The inclusion criteria were RCTs comparing stapled with unstapled mesh in TEP inguinal hernia repair. The primary outcome was incidence of recurrence, secondary outcomes were operative duration, postoperative pain score, number of analgesics consumed, in-hospital stay, time to return to normal activity, cost, and complications. RESULTS: Six trials were included with a total number of 932 patients (1086 hernias): the mesh was fixed in 463 (540 hernias) patients and not fixed in 469 (546 hernias). We found no difference between groups in the incidence of recurrence (OR = 2.01, 95% CI: 0.37-11.02), complications (OR = 0.73, 95% CI: 0.51-1.05), postoperative pain score [day 1 (p = 0.19), day 7 (p = 0.18) and month 1 (p = 0.47)] and number of analgesics consumed (WMD of -1.20, 95% CI: -3.08 to 0.68). The mean operative time (WMD of -3.86, 95% CI: -7.45 to -0.26) and hospital stay (WMD of -0.34, 95% CI: -0.50 to -0.18) were significantly higher in the mesh fixation group. Moreover, a net cost savings was realized for each hernia repair performed without stapled mesh. CONCLUSIONS: Elimination of tack fixation of mesh in TEP inguinal hernia repair is associated with decreased operative cost and significantly reduce operative time and in-hospital stay, but no difference in the risk of hernia recurrence, complications, and postoperative pain. For more detailed evaluation, further well-structured trials with improved standardization of hernia type, operative technique, and surgeon experience are necessary. PMID- 20714894 TI - DH and JH usage in murine fetal liver mirrors that of human fetal liver. AB - In mouse and human, the regulated development of antibody repertoire diversity during ontogeny proceeds in parallel with the development of the ability to generate antibodies to an array of specific antigens. Compared to adult, the human fetal antibody repertoire limits N addition and uses specifically positioned VDJ gene segments more frequently, including V6-1 the most D(H) proximal V(H,) DQ52, the most J(H)-proximal D(H), and J(H)2, which is D(H) proximal. The murine fetal antibody repertoire also limits the incorporation of N nucleotides and uses its most D(H) proximal V(H), V(H)81X, more frequently. To test whether D(H) and J(H) also follow the pattern observed in human, we used the scheme of Hardy to sort B lineage cells from BALB/c fetal and neonatal liver, RT PCR cloned and sequenced V(H)7183-containing VDJCMU transcripts, and then assessed V(H)7183-D(H)-J(H) and complementary determining region 3 of the immunoglobulin heavy chain (CDR-H3) content in comparison to the previously studied adult BALB/c mouse repertoire. Due to the deficiency in N nucleotide addition, perinatal CDR-H3s manifested a distinct pattern of amino acid usage and predicted loop structures. As in the case of adult bone marrow, we observed a focusing of CDR-H3 length and CDR-H3 loop hydrophobicity, especially in the transition from the early to late pre-B cell stage, a developmental checkpoint associated with expression of the pre-B cell receptor. However, fetal liver usage of J(H)-proximal D(H)Q52 and D(H)-proximal J(H)2 was markedly greater than that of adult bone marrow. Thus, the early pattern of D(H) and J(H) usage in mouse feta liver mirrors that of human. PMID- 20714897 TI - Survival after pancreaticoduodenectomy for ampullary cancer is not affected by age. AB - BACKGROUND: Although pancreaticoduodenectomy (PD) provides the best chance of survival for elderly patients with ampullary carcinoma, it is associated with considerable surgical risk. The aim of the present study was to compare the benefits and risks of pancreaticoduodenectomy as a treatment of ampullary carcinoma between young and elderly patients. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 171 consecutive patients treated at our hospital. Comparison of the biological aggressiveness of ampullary cancer between old and younger patients was also performed by immunohistochemical study of several prognostic biological markers, including MUC1, MUC2, CK17, and CDX2. RESULTS: For patients in whom ampullary carcinoma was presumed resectable preoperatively, actuarial survival was significantly poorer in 55 elderly patients because 9 of them did not have PD (the other 46 had PD) than in 101 younger patients (all had PD). Multivariate analysis indicated that PD was the only independent prognostic factor; age was not. There were no significant differences in MUC1, CK17, MUC2, and CDX2 immunohistochemical staining of ampullary carcinomas between elderly and young patients. In spite of increased co morbidities, PD could be performed as safely in elderly patients as in young patients. After PD, the actuarial survival was similar between old and young patients. CONCLUSIONS: Our data support the conclusion that ampullary cancers in elderly patients should be treated as aggressively as in younger patients. PMID- 20714898 TI - [Multilayer analysis of signal transduction and cell cycle control in GIST. Identifying new interaction partners with differential regulation]. AB - To identify new interactions as well as diagnostically, prognostically and therapeutically relevant differences in the regulation of gene expression in gastrointestinal stromal tumors (GISTs), we analyzed the methylation status, mRNA expression, microRNA expression, protein expression and protein phosphorylation in parallel in identical tumor tissue samples. The data were analyzed in a multilayer approach and were correlated to each other and to clinico-pathological parameters. Differentially regulated genes were mapped to signal transduction pathways which are already known to play a major role in GISTs. A functionally orientated overview of the different data layers was constructed, which enabled new insights into gene regulation in GISTs. PMID- 20714899 TI - [Opening address by the congress president of the German Society of Pathology]. PMID- 20714901 TI - Anatomical transverse patella double tunnel reconstruction of medial patellofemoral ligament with a hamstring tendon autograft for recurrent patellar dislocation. AB - INTRODUCTION: The purpose of this study was to describe our transverse patella double tunnel technique to reconstruct the medial patellofemoral ligament (MPFL) with a hamstring tendon autograft in patients who suffered recurrent dislocation of the patella, and to evaluate the intermediate-term outcomes of reconstruction treatment. MATERIALS AND METHODS: Fifty-nine consecutive knees (52 patients) with recurrent dislocation of the patella without marked predisposing anatomic abnormalities and radiographically documented moderate/severe osteochondral lesions were included in the study. Outcomes were assessed with physical and radiographic examination, the Kujala and the modified Cincinnati scores preoperatively and postoperatively at 3, 6, 12, 36, 60 and 84 months. RESULTS: There were 19 male and 33 female patients with up to 7.1-year follow-up (mean 5.7 years). The mean age was 24.3 years. A comparison of preoperative scores with those obtained at most recent follow-up revealed a significant improvement for all outcomes measured: range of motion (30 +/- 2 degrees vs. 125 +/- 5 degrees , P < 0.01), the mean Kujala scores (41.4 vs. 82.6, P < 0.001), the mean modified Cincinnati scores (50.6 vs. 88.7, P < 0.01), the mean congruence angle (12.2 degrees vs. -2.4 degrees , P < 0.01) and the mean tilt angle (11.4 degrees vs. 8.4 degrees , P < 0.05). No recurrent episodes of dislocation or subluxation were postoperatively reported, although there were seven knees with an occasional unstable feeling without redislocation. CONCLUSIONS: MPFL reconstruction with the double-transverse tunnels technique is safe and effective in patients of all ages, without marked predisposing anatomic abnormalities and moderate/severe osteochondral lesions, who suffered recurrent dislocation of the patella. PMID- 20714902 TI - Prevalence and etiological factors of sport-related groin injuries in top-level soccer compared to non-contact sports. AB - PURPOSE: Groin injuries and chronic pain are relatively common in soccer and other contact sports. Our aim was to define the gender-related frequency of both acute and chronic groin injuries in soccer compared to non-contact endurance sports. METHODS: A 12-month study of 613 professional athletes was conducted in 2006. Premier league soccer players (77 males and 90 females) answered retrospectively 70 multi-choice questions of sport injuries. Factors related to groin injuries were compared with corresponding data of elite-level swimmers (n = 154), long-distance runners (n = 143) and cross-country skiers (n = 149). RESULTS: In soccer, 125/167 players had 375 injuries (274 acute and 101 overuse injuries) and the number of acute injuries were 146/274 (53%) in males and 128/274 (47%) in females (p = 0.368). Acute groin injury was reported in 15/167 (9.0%) of elite soccer players compared to 3/154 (2.0%) in swimmers (p = 0.006) and 1.4% in both long-distance running (n = 2) and skiing (n = 2, p = 0.003). Male soccer players had acute groin injuries nearly three times more frequently than females. Chronic persistent groin pain was found in only one male and two female soccer players and no athletes in endurance sports. CONCLUSIONS: Almost every tenth soccer player had an acute groin injury. Long-standing groin pain was not frequent in soccer and it was not found in non-contact endurance sport at the elite-level. PMID- 20714900 TI - Molecular diagnostics of gliomas: state of the art. AB - Modern neuropathology serves a key function in the multidisciplinary management of brain tumor patients. Owing to the recent advancements in molecular neurooncology, the neuropathological assessment of brain tumors is no longer restricted to provide information on a tumor's histological type and malignancy grade, but may be complemented by a growing number of molecular tests for clinically relevant tissue-based biomarkers. This article provides an overview and critical appraisal of the types of genetic and epigenetic aberrations that have gained significance in the molecular diagnostics of gliomas, namely deletions of chromosome arms 1p and 19q, promoter hypermethylation of the O6 methylguanine-methyl-transferase (MGMT) gene, and the mutation status of the IDH1 and IDH2 genes. In addition, the frequent oncogenic aberration of BRAF in pilocytic astrocytomas may serve as a novel diagnostic marker and therapeutic target. Finally, this review will summarize recent mechanistic insights into the molecular alterations underlying treatment resistance in malignant gliomas and outline the potential of genome-wide profiling approaches for increasing our repertoire of clinically useful glioma markers. PMID- 20714903 TI - Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. AB - PURPOSE: Osteoarthritis (OA) is a highly prevalent, chronic, degenerative condition that generates a high expense. Alternative and co-adjuvant therapies to improve the quality of life and physical function of affected patients are currently being sought. METHODS: A total of 808 patients with knee pathology were treated with PRGF (plasma rich in growth factors), 312 of them with OA of the knee (Outerbridge grades I-IV) and symptoms of >3 months duration met the inclusion criteria and were evaluated to obtain a sample of 261 patients, 109 women and 152 men, with an average age of 48.39. Three intra-articular injections of autologous PRGF were administered at 2-week intervals in outpatient surgery. The process of obtaining PRGF was carried out following the Anitua Technique. Participants were asked to fill out a questionnaire with personal data and the following assessment instruments: VAS, SF-36, WOMAC Index and Lequesne Index before the first infiltration of PRGF and 6 months after the last infiltration. RESULTS: Statistically significant differences (P < 0.0001) between pre-treatment and follow-up values were found for pain, stiffness and functional capacity in the WOMAC Index; pain and total score, distance and daily life activities in the Lequesne Index; the VAS pain score; and the SF-36 physical health domain. There were no adverse effects related to PRGF infiltration. CONCLUSION: At 6 months following intra-articular infiltration of PRGF in patients with OA of the knee, improvements in function and quality of life were documented by OA-specific and general clinical assessment instruments. These favourable findings point to consider PRGF as a therapy for OA. PMID- 20714904 TI - Demographics and outcome of metatarsal fractures. AB - INTRODUCTION: Although metatarsal fractures are amongst the most common injuries of the foot, this is the first study on outcome after metatarsal fractures. METHOD: All consecutive patients with metatarsal fractures treated between January 2006 and September 2008 were re-evaluated. Patients aged 16 to 75 were sent a questionnaire consisting of the American Orthopaedic Foot Ankle Society midfoot score and a Visual Analogue Scale (VAS) for patient satisfaction. RESULTS: Four-hundred metatarsal fractures were identified in 322 patients. The fifth metatarsal was involved in more than 50% of patients. Most fractures were caused by an inversion injury or fall from height (75%). Out of 247 patients between 16 and 75 years, a total of 166 patients (67.2%) returned the questionnaire with a median follow-up of 33 months. All patients were treated conservatively. The median AOFAS score was 100 points (P(25)-P(75), 87-100), the median VAS was 9 points (P(25)-P(75), 8-10). The AOFAS and VAS scores correlated negatively with the body mass index (BMI) (R (s) = -0.409 and -0.305; p < 0.001). Patients with diabetes reported lower VAS (p = 0.010) and AOFAS scores (p = 0.020). Females reported a lower AOFAS score (p = 0.034). An increase in dislocation (>2 mm) resulted in a decrease in VAS score (p = 0.017). Multivariable analysis indicated that the VAS score was significantly affected by BMI and dislocation >2 mm (p = 0.013). The AOFAS score was affected by BMI (p = 0.011). CONCLUSION: This is the first investigation using two validated outcome scoring systems to determine functional outcome in metatarsal fractures. Overall outcome in metatarsal fractures is high, as almost all fractures healed without complaints at 33 months. Outcome is dependent on BMI, diabetes, gender, and dislocation at the fracture site. PMID- 20714905 TI - Strontium-90 and caesium-137 activity concentrations in bats in the Chernobyl exclusion zone. AB - Bats are a protected species and as such may be an object of protection in radiological assessments of the environment. However, there have previously been only few radioecological studies of species of bats. In this paper, results for >140 measurements of (90)Sr and (137)Cs in 10 species of bats collected within the Chernobyl zone are presented. There was some indication of a decreasing transfer of (90)Sr with increasing deposition, although this was inconsistent across species and explained little of the observed variability. There was no difference between male and female bats in the transfer (expressed as the ratio of whole-body activity concentrations to those in soil) of either radionuclide. There was considerable variability in transfer across all species groups. At two sites where there were sufficient data, Eptesicus serotinus was found to have higher transfer than other species. PMID- 20714906 TI - Variability in water temperature affects trait-mediated survival of a newly settled coral reef fish. AB - As animals with complex life cycles metamorphose from one stage to the next, carry-over effects from earlier stages can affect future mortality. To examine the relationship between early life history traits and survival, seven monthly cohorts of newly-settled bluehead wrasse Thalassoma bifasciatum were collected immediately after settlement and over sequential 3-day periods. Otolith analysis was used to quantify mean larval and juvenile growth rates, pelagic larval duration (PLD), and settlement size and condition of different age classes to identify the traits most important for survival. Overall, survivors tended to have shorter PLDs, to settle at smaller sizes and higher condition levels, and to exhibit faster early juvenile growth. Water temperature contributed to among cohort variability in traits as warmer water led to faster larval and juvenile growth and shorter PLDs. Trait-specific fitness functions demonstrated that temperature can influence fitness by changing the nature of selection on each trait. Estimates of selection intensity revealed that settlement condition contributed the most to variation in fitness across cohorts, followed by juvenile growth. Frequent loss of low settlement condition individuals and occasional loss of the very highest condition fish suggest that particularly high settlement condition during the warmest temperatures may be detrimental. Not only does the quality of settlers vary over time, but selective loss of individuals with particular phenotypic traits is not pervasive and can vary with environmental conditions such as temperature. PMID- 20714907 TI - Lymphotropic HCV strain can infect human primary naive CD4+ cells and affect their proliferation and IFN-gamma secretion activity. AB - BACKGROUND: Lymphotropic hepatitis C virus (HCV) infection of B and T cells might play an important role in the pathogenesis of hepatitis C. Recently, we showed that a lymphotropic HCV (SB strain) could infect established T-cell lines and B cell lines. However, whether HCV replication interferes with cell proliferation and function in primary T lymphocytes is still unclear. AIM: The aim of this study was to analyze whether HCV replication in primary T lymphocytes affected their development, proliferation, and Th1 commitment. METHODS: SB strain cell culture supernatant (2 * 10(4) copies/ml HCV) was used to infect several kinds of primary lymphocyte subsets. Mock, UV-irradiated SB-HCV, JFH-1 strain, and JFH-1 NS5B mutant, which could not replicate in T cells, were included as negative controls. Carboxyfluorescein succinimidyl ester (CFSE) and CD45RA double staining was used to evaluate the proliferative activity of CD4(+)CD45RA(+)CD45RO(-) naive CD4(+) cells. Interferon (IFN)-gamma and interleukin (IL)-10 secretion assays magnetic cell sorting (MACS) were carried out. RESULTS: Negative strand HCV RNA was detected in CD4(+), CD14(+), and CD19(+) cells. Among CD4(+) cells, CD4(+)CD45RA(+)RO(-) cells (naive CD4(+) cells) were most susceptible to replication of the SB strain. The levels of CFSE and CD45RA expression gradually declined during cell division in uninfected cells, while HCV-infected naive CD4(+) cells expressed higher levels of CFSE and CD45RA than Mock or UV-SB infected naive CD4(+) cells. Moreover, the production of IFN-gamma was significantly suppressed in SB-infected naive CD4(+) cells. CONCLUSIONS: Lymphotropic HCV replication suppressed proliferation and development, including that towards Th1 commitment, in human primary naive CD4(+) cells. PMID- 20714908 TI - Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model. AB - Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin-angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED(50) value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED(50) value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral. PMID- 20714909 TI - New diagnostic EEG markers of the Alzheimer's disease using visibility graph. AB - A new chaos-wavelet approach is presented for electroencephalogram (EEG)-based diagnosis of Alzheimer's disease (AD) employing a recently developed concept in graph theory, visibility graph (VG). The approach is based on the research ideology that nonlinear features may not reveal differences between AD and control group in the band-limited EEG, but may represent noticeable differences in certain sub-bands. Hence, complexity of EEGs is computed using the VGs of EEGs and EEG sub-bands produced by wavelet decomposition. Two methods are employed for computation of complexity of the VGs: one based on the power of scale-freeness of a graph structure and the other based on the maximum eigenvalue of the adjacency matrix of a graph. Analysis of variation is used for feature selection. Two classifiers are applied to the selected features to distinguish AD and control EEGs: a Radial Basis Function Neural Network (RBFNN) and a two-stage classifier consisting of Principal Component Analysis (PCA) and the RBFNN. After comprehensive statistical studies, effective classification features and mathematical markers were discovered. Finally, using the discovered features and a two-stage classifier (PCA-RBFNN), a high diagnostic accuracy of 97.7% was obtained. PMID- 20714910 TI - Effectiveness of autofluorescence to identify suspicious oral lesions--a prospective, blinded clinical trial. AB - Regular screening through white light inspection of the entire oral mucosa is the most important examination method to identify precancerous lesions and early oral carcinoma. Additionally, the physiologic autofluorescence of the oral mucosa has been described as a novel screening method for the detection of mucosal lesions that are not visible by white light. This study aimed to evaluate the sensitivity and specificity of the autofluorescence examination. Seventy-eight patients were examined in this study. All of them suffered from suspicious oral mucosal lesions. Two different investigation methods were applied: the standard examination by white light and an examination by a novel light source of 400 nm that evoked a green light emission (>500 nm) in normal mucosa. It was proposed that malignant oral mucosal lesions show different autofluorescence characteristics than the green autofluorescence of healthy mucosa. Red autofluorescence indicated SCC with a sensitivity of 20% and a specificity of 98%. The results showed that dysplasia and carcinoma could be identified with a sensitivity of 96% and a specificity of 18% by using the autofluorescence method. The sensitivity decreased according to the grade of mucosal keratosis and was influenced by the localisation of the lesion. In conclusion, benign as well as malignant oral lesions could not be distinguished by a diminished autofluorescence signal. A red autofluorescence signal, however, could indicate cancerous processes of the oral mucosa. PMID- 20714911 TI - The correlations between a proposed pathogenesis of syringomyelia and normal pressure hydrocephalus. PMID- 20714912 TI - Does the spread of hepatitis B virus genotype A increase the risk of intrafamilial transmission in Japan? AB - Recently, the prevalence of genotype A in patients with acute hepatitis B virus (HBV) infection has markedly increased in Japan. We encountered a 1-year-old infant who was infected with HBV genotype A and became an HBV carrier. His grandfather was identified as an HBV carrier; however, the grandfather was not aware of chronic HBV infection. This was a case of intrafamilial transmission. In addition, the child's father developed acute hepatitis B within 1 month of the infant's diagnosis. Molecular analysis revealed that the HBV isolates from the grandfather, the infant, and the father had identical sequences that belonged to genotypes A2/Ae. Compared with other HBV genotypes, genotype A has a significant association with chronic outcome. Therefore, prolonging hepatitis can increase the risk of transmitting the virus without realizing. The at-risk strategy of hepatitis B vaccination, which has been adopted in Japan, cannot prevent such intrafamilial transmission. Universal vaccination in childhood is only one way to prevent young children from unexpected HBV infection. PMID- 20714913 TI - An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication. AB - Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (>= 13 MUg/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was <2 MUg/mL). Each AUC was estimated using individual dose, creatinine clearance (CL(cr)), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 MUg h/mL for AUC from zero to 24 h (AUC(0-24 h)). Using published population pharmacokinetic parameters, the dose required to achieve the AUC(0-24 h) target was calculated as dose (mg) = 750 * (0.00498 * CL(cr) (mL/min) + 0.00426 * body weight (kg). For various combinations of CL(cr) and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin. PMID- 20714914 TI - The performance of the BD geneOhm MRSATM assay for MRSA isolated from clinical patients in Japan, including the effects of specimen contamination and ways to improve it. AB - The BD geneOhm MRSATM assay has been increasingly used in recent years, and it is possible to use it to screen and detect methicillin-resistant Staphylococcus aureus (MRSA) from a specimen within 2 h. The purpose of the present study was to evaluate the performance, i.e., the specificity and sensitivity, of the BD geneOhm MRSATM assay to detect MRSA. Its specificity was assessed to be 100% compared to bacterial culture methods, which are commonly used in medical laboratories. Its bacterial limit of detection was over 10 colony-forming units (cfu) per reaction, although MRSA was detected at a cfu below 10 per reaction in a few samples. Additionally, the effect of MRSA isolate contamination was examined. While contamination with protein or other bacteria did not affect the outcome, contamination with a high concentration of blood resulted in an unresolved outcome. To inactivate polymerase chain reaction (PCR) inhibitors, the DNA samples were freeze-thawed prior to the BD geneOhm MRSATM assay, which led to the sensitivity of the assay increasing. In summary, the BD geneOhm MRSATM assay is rapid and shows high specificity and sensitivity of cultured MRSA isolates. It will, therefore, be a valuable diagnostic tool for detecting MRSA in specimens from clinical patients. PMID- 20714916 TI - Magnetic resonance imaging research in sub-Saharan Africa: challenges and satellite-based networking implementation. AB - As part of an NIH-funded study of malaria pathogenesis, a magnetic resonance (MR) imaging research facility was established in Blantyre, Malawi to enhance the clinical characterization of pediatric patients with cerebral malaria through application of neurological MR methods. The research program requires daily transmission of MR studies to Michigan State University (MSU) for clinical research interpretation and quantitative post-processing. An intercontinental satellite-based network was implemented for transmission of MR image data in Digital Imaging and Communications in Medicine (DICOM) format, research data collection, project communications, and remote systems administration. Satellite Internet service costs limited the bandwidth to symmetrical 384 kbit/s. DICOM routers deployed at both the Malawi MRI facility and MSU manage the end-to-end encrypted compressed data transmission. Network performance between DICOM routers was measured while transmitting both mixed clinical MR studies and synthetic studies. Effective network latency averaged 715 ms. Within a mix of clinical MR studies, the average transmission time for a 256 * 256 image was ~2.25 and ~6.25 s for a 512 * 512 image. Using synthetic studies of 1,000 duplicate images, the interquartile range for 256 * 256 images was [2.30, 2.36] s and [5.94, 6.05] s for 512 * 512 images. Transmission of clinical MRI studies between the DICOM routers averaged 9.35 images per minute, representing an effective channel utilization of ~137% of the 384-kbit/s satellite service as computed using uncompressed image file sizes (including the effects of image compression, protocol overhead, channel latency, etc.). Power unreliability was the primary cause of interrupted operations in the first year, including an outage exceeding 10 days. PMID- 20714917 TI - Volume visualization: a technical overview with a focus on medical applications. AB - With the increasing availability of high-resolution isotropic three- or four dimensional medical datasets from sources such as magnetic resonance imaging, computed tomography, and ultrasound, volumetric image visualization techniques have increased in importance. Over the past two decades, a number of new algorithms and improvements have been developed for practical clinical image display. More recently, further efficiencies have been attained by designing and implementing volume-rendering algorithms on graphics processing units (GPUs). In this paper, we review volumetric image visualization pipelines, algorithms, and medical applications. We also illustrate our algorithm implementation and evaluation results, and address the advantages and drawbacks of each algorithm in terms of image quality and efficiency. Within the outlined literature review, we have integrated our research results relating to new visualization, classification, enhancement, and multimodal data dynamic rendering. Finally, we illustrate issues related to modern GPU working pipelines, and their applications in volume visualization domain. PMID- 20714918 TI - In vivo anti-lymphoma activity of an agonistic human recombinant anti-TRAIL-R2 minibody. AB - A new single-chain fragment variable (scFv) to TRAIL-R2 receptor produced as minibody (MB2.23) was characterized for anti-lymphoma activity in vivo. For this purpose, a disseminated lymphoma model was generated by intraperitoneal inoculation of BJAB cells in severe combined immunodeficiency mice. Two weekly injections with MB2.23 (10 mg/kg) were able to significantly increase the median survival time of lymphoma-bearing animals with respect to the vehicle-treated control mice, providing a rationale for further investigating the use of MB2.23 in anticancer therapy. PMID- 20714919 TI - A plant secretory signal peptide targets plastome-encoded recombinant proteins to the thylakoid membrane. AB - Plastids are considered promising bioreactors for the production of recombinant proteins, but the knowledge of the mechanisms regulating foreign protein folding, targeting, and accumulation in these organelles is still incomplete. Here we demonstrate that a plant secretory signal peptide is able to target a plastome encoded recombinant protein to the thylakoid membrane. The fusion protein zeolin with its native signal peptide expressed by tobacco (Nicotiana tabacum) transplastomic plants was directed into the chloroplast thylakoid membranes, whereas the zeolin mutant devoid of the signal peptide, Deltazeolin, is instead accumulated in the stroma. We also show that zeolin folds in the thylakoid membrane where it accumulates as trimers able to form disulphide bonds. Disulphide bonds contribute to protein accumulation since zeolin shows a higher accumulation level with respect to stromal Deltazeolin, whose folding is hampered as the protein accumulates at low amounts in a monomeric form and it is not oxidized. Thus, post-transcriptional processes seem to regulate the stability and accumulation of plastid-synthesized zeolin. The most plausible zeolin targeting mechanism to thylakoid is discussed herein. PMID- 20714920 TI - Color measurements as a reliable method for estimating chlorophyll degradation to phaeopigments. AB - The application of biocides is a traditional method of controlling biodecay of outdoor cultural heritage. Chlorophyll degradation to phaeopigments is used to test the biocidal efficacy of the antimicrobial agents. In the present study, the usefulness of color measurements in estimating chlorophyll degradation was investigated. An aeroterrestrial stone biofilm-forming cyanobacterium of the genus Nostoc was chosen as test organism, comparing its different behaviour in both planktonic and biofilm mode of growth against the isothiazoline biocide Biotin T(r). Changes in A(435 nm)/A(415 nm) and A(665 nm)/A(665a nm) and in the chlorophyll a and adenosine triphosphate (ATP) cell content were compared with the variations in the CIELAB color parameters (L*, a*, b*, C*(ab) and h(ab)). Our findings showed that both the phaeophytination indexes are useful in describing degradation of chlorophyl a to phaeopigments. Moreover, the CIELAB color parameters represented an effective tool in describing chlorophyll degradation. L* CIELAB parameter appeared to be the most informative parameter in describing the biocidal activity of Biotin T(r) against Nostoc sp. in both planktonic and biofilm mode of growth. PMID- 20714921 TI - Biodegradation of pyrene in sand, silt and clay fractions of sediment. AB - Microbial degradation is the dominant pathway for natural attenuation of PAHs in environmental compartments such as sediments, which in turn depends on the bioavailability of PAHs. The bioavailability of PAHs has seldom been studied at the sediment particle size scale. We evaluated biodegradation of pyrene by Mycobacterium vanbaalenii PYR-1 as a function of sediment particle sizes, and investigated the relationship between the rate of degradation on sand, silt and clay particles with their individual desorption kinetics measured with the Tenax extraction method. Regression analysis showed that the total organic carbon (TOC), black carbon (BC), and specific surface area (SSA) of the specific particle size fractions, instead of the particle size scale itself, were closely related (P<0.01) with the mineralization rate. While the fraction in the rapid desorption pool (F (rapid)) ranged from 0.11 to 0.38 for the whole sediments and different size groups, the fractions mineralized after 336-h incubation (0.52 to 0.72) greatly surpassed the F (rapid) values, suggesting utilization of pyrene in the slow desorption pool (F (slow)). A biodegradation model was modified by imbedding a two-phase desorption relationship describing sequential Tenax extractions. Model analysis showed that pyrene sorbed on silt and clay aggregates was directly utilized by the degrading bacteria. The enhanced bioavailability may be attributed to the higher chemical concentration, higher TOC or larger SSA in the silt and clay fractions, which appeared to overcome the reduced bioavailability of pyrene due to sorption, making pyrene on the silt and clay particles readily available to degrading microbes. This conjecture merits further investigation. PMID- 20714922 TI - High prevalence of obstructive sleep apnea in patients with resistant paroxysmal atrial fibrillation after pulmonary vein isolation. AB - OBJECTIVES: To address the question whether obstructive sleep apnea (OSA) is associated with the recurrence of paroxysmal atrial fibrillation (AF) in patients treated with >=2 pulmonary vein isolation procedures. PATIENTS AND METHODS: In this study, we included adults with therapy-resistant symptomatic paroxysmal AF, defined as AF recurring after >=2 PV-isolation procedures (n = 23). For comparison, we selected another cohort of patients being successfully treated by one PV isolation without AF recurrence within 6 months (n = 23). PV isolation was performed by radiofrequency with an open irrigated tip catheter. Each of the 46 participants completed an overnight polygraphic study. The two groups were matched for age, gender, and ejection fraction. Patients were late middle-aged (65 +/- 7 vs 63 +/- 10 years, P = 0.23), white (100%), and overweight (BMI 27.3 +/- 3.6 vs. 27.2 +/- 4.6 kg/m(2), P = 0.97). RESULTS: The prevalence of sleep apnea, defined as an apnea-hypopnea index (AHI) of >5 per hour of sleep, was 87% in patients with therapy-resistant AF compared to 48% in the control cohort (P = 0.005). In addition, OSA was more severe in the resistant AF group indicated by a significantly higher AHI (27 +/- 22 vs 12 +/- 16, P = 0.01). CONCLUSION: The extraordinarily high prevalence of sleep apnea in patients with recurrent paroxysmal AF supports its presumable role in the pathogenesis of AF and demands further controlled prospective trials. Moreover, OSA should inherently be considered in patients with therapy-resistant AF. PMID- 20714924 TI - Religion, relationships and reproduction: correlates of desire for a child among mothers living with HIV. AB - Despite challenges facing HIV-positive women in the U.S., some maintain strong desires and intentions for motherhood. We explore correlates of desire for another child-particularly current parenting experiences (number of children, parenting efficacy, parenting satisfaction, parenting practices, parental distress, and child-related quality of life), age, spirituality/religiosity, stress, coping, hopelessness, partner's desire for a child, social support, and stigma-among a sample of HIV-positive mothers (n = 96) in Alabama. Partner's desire for a child, participation in private religious practices, avoidant coping, and parity were significantly associated with desire for a child in multivariate models. Such findings indicate a need for reproductive counseling and education that is sensitive to the role of religious norms and values in fertility decision-making and suggest opportunities for partnership with faith based organizations. Further studies examining the impact of relationship dynamics on childbearing desires among U.S. women living with HIV/AIDS are also needed. PMID- 20714923 TI - Food insufficiency is a risk factor for suboptimal antiretroviral therapy adherence among HIV-infected adults in urban Peru. AB - We examined the relationship between food insufficiency and antiretroviral therapy (ART) adherence. A cohort of HIV-infected adults in urban Peru was followed for a two-year period after ART initiation. ART adherence was measured using a 30-day self-report tool and classified as suboptimal if <95% adherence was reported. We conducted a repeated measures cohort analysis to examine whether food insufficiency was more common during months of suboptimal adherence relative to months with optimal adherence. 1,264 adherence interviews were conducted for 134 individuals. Participants who reported food insufficiency in the month prior to interview were more likely to experience suboptimal adherence than those who did not (odds ratio [O.R.]:2.4; 95% confidence interval [C.I.]:1.4, 4.1), even after adjusting for baseline social support score (O.R. per 5 point increase:0.91; C.I.:[0.85, 0.98]) and good baseline adherence self-efficacy (O.R.:0.25; C.I.:[0.09, 0.69]). Interventions that ensure food security for HIV infected individuals may help sustain high levels of adherence. PMID- 20714925 TI - Assessment of the radiological impacts of utilizing coal combustion fly ash as main constituent in the production of cement. AB - The purpose of this study is to assess potential radiological impacts of utilizing pulverized fly ash (PFA) as a constituent in ordinary Portland cement. For this purpose, the activity concentrations of (226)Ra, (232)Th, and (40)K in samples of PFA and Portland cement containing 15%, 20%, and 25% by mass PFA were measured using gamma-ray spectrometry with HPGe detector. The mean activity concentrations of (226)Ra, (232)Th, and (40)K were found as 366.6, 113.7, and 460.2 Bq kg( - 1), 94.2, 25.9, and 215.3 Bq kg( - 1), 113.7, 34.3, and 238.3 Bq kg( - 1), and 124.2, 41.8, and 279.3 Bq kg( - 1) for the examined samples of PFA, Portland cement with 15%, 20%, and 25% by mass PFA, respectively. Radiological parameters such as radium equivalent activity, external exposure index (activity concentration index), internal dose index (alpha index), indoor absorbed gamma dose rate, and the corresponding the annually effective dose were assessed for Portland cement samples containing three percentages (15%, 20%, and 25%) by mass PFA. The results of assessment show that all Portland cement samples are within the safe limits recommended for building materials for dwellings. PMID- 20714926 TI - Development of a PCR protocol for the detection of Escherichia coli O157:H7 and Salmonella spp. in surface water. AB - Escherichia coli O157:H7 and Salmonella are pathogenic microorganisms that can cause severe gastrointestinal illness in humans. These pathogens may be transmitted in a variety of ways, including food and water. The presence of Salmonella and E. coli O157:H7 in surface waters constitutes a potential threat to human health when used for either drinking or recreation. As with most waterborne pathogens, Salmonella and E. coli O157:H7 are difficult to detect and enumerate with accuracy in surface waters due to methodological limitations. The aim of this study was to develop a protocol for the detection of Salmonella spp., E. coli O157:H7 and E. coli virulence genes (stx (1), stx (2) and eae) in water using a single enrichment step and PCR. In spiked water samples, PCR results showed high sensitivity (<3 CFU/L) for both microorganisms. The protocol developed in this study has been applied in different surface waters in association with microbiological and physical analysis. The frequency of PCR positive samples was 33% for Salmonella and 2% for E. coli O157:H7 producing intimin (eae) and Shiga-like toxin I (stx (1)). Moreover, the finding of amplicons corresponding to eae and stx (1) genes in the absence of E. coli O157:H7 suggested the possible presence of other pathogenic bacteria that carry these genes (e.g. EHEC, Shigella strains). The results obtained showed that the developed protocol could be applied as a routine analysis of surface water for the evaluation of microbiological risks. PMID- 20714927 TI - Polycyclic aromatic hydrocarbons in effluents from wastewater treatment plants and receiving streams in Tianjin, China. AB - Surface water, suspended particulate matter, pore water, and sediment samples were collected and analyzed for polycyclic aromatic hydrocarbons (PAHs) in Yongding New River, South Drainage Canal and North Drainage Canal, which receive most of wastewater from industrial city of Tianjin. PAH concentrations in effluent samples of wastewater treatment plants (WTP) discharging into the South Drainage Canal and North Drainage Canal were quantified for the first time. The results showed that the discharge of the WTPs recently only contributed to the PAH contamination in the canals near the outlets of the WTPs. PAH levels in sediments of the streams were greatly higher than those in soils by riverbank probably due to receiving large amounts of untreated wastewater. Unusually high benz[a] anthracene concentration strongly influenced the seasonal and spatial variation of total PAH concentrations in South Drainage Canal. Paired samples t test of ?Nap, Fl, Phe, Fluo and ?Nap, Phe, Fluo, Chry concentrations, which were dominant components in the air samples from non-heating and heating season, respectively, in the suspended particulate matters from the streams showed that PAH source from air deposition was more important for Yongding New River than that for South Drainage Canal and North Drainage Canal. Source apportionment based on PAH profiles indicated that coal combustion was the major PAH contamination source, and coke oven sources and wood combustion also contributed to the PAH contamination of the streams. This was further indicated by organic petrography analysis. PMID- 20714928 TI - Assessment of groundwater quality in Puri City, India: an impact of anthropogenic activities. AB - Puri City is situated on the east coast of India and receives water supply only from the groundwater sources demarcated as water fields. The objective of this paper is to assess and evaluate the groundwater quality due to impact of anthropogenic activities in the city. Groundwater samples were collected from the water fields, hand pumps, open wells, and open water bodies during post-monsoon 2006 and summer 2007. Groundwater quality was evaluated with drinking water standards as prescribed by Bureau of Indian Standards and Environmental Protection Agency to assess the suitability. The study indicated seasonal variation of water-quality parameters within the water fields and city area. Groundwater in the water fields was found to be suitable for drinking after disinfection. While in city area, groundwater quality was impacted by onsite sanitary conditions. The study revealed that groundwater quality was deteriorated due to the discharge of effluent from septic tanks, soak pits, pit latrines, discharges of domestic wastewater in leaky drains, and leachate from solid waste dumpsite. Based on observed groundwater quality, various mitigation measures were suggested to protect the water fields and further groundwater contamination in the city. PMID- 20714929 TI - Metal concentrations in monkfish, Lophius americanus, from the northeastern USA. AB - Concentrations of arsenic (As), selenium (Se), lead (Pb), zinc (Zn), cadmium (Cd), and total mercury (Hg) were analyzed in the muscle, liver, and gonads of the American monkfish, Lophius americanus, collected from Franklin Swell, Massachusetts; Mud Hole, New Jersey; and the Fingers, Maryland, in the northeastern US, by commercial gillnetters from February to May 2007. Results indicated that As and Hg concentrations were significantly higher in liver samples collected from the Fingers than from Mud Hole and Franklin Swell. The highest concentrations of Pb were found in muscle, liver, and gonads collected from Franklin Swell. L. americanus collected from the Fingers and Mud Hole had higher concentrations of Zn in the gonads and total Hg in the muscle than those collected from Franklin Swell. Significant differences were found in gonadal Cd concentrations among the three sites. A significant correlation was observed between hepatic Se and Hg molar concentrations in fish collected from Franklin Swell. The molar Se to Hg ratios were lowest in muscle and highest in gonads of L. americanus. With the exception of Hg, all metal concentrations were within the maximum permissible limit for human consumption. PMID- 20714930 TI - Assessment of cadmium exposure for neonates in Guiyu, an electronic waste pollution site of China. AB - This study aimed to determine the levels of placental cadmium (PCd) and cord blood cadmium (CBCd) and the resulting expression of placental metallothionein (MT) in neonates and to investigate cadmium (Cd) exposure levels in neonates and mothers who live in Guiyu, China, an electronic waste (e-waste) pollution site. Among the 423 mothers included in the study from 2004/2005 to 2007, 289 lived in Guiyu (exposed group) and 134 lived in Chaonan, located 10 km away from Guiyu (controls) and had never been exposed to e-waste pollution. CBCd and PCd levels were measured by atomic absorption spectrometry. Placental MT was examined by immunohistochemistry. Information on maternal and neonatal characteristics and exposure conditions was obtained from hospital records and by personal interviews. For the 3 years, the median CBCd was higher for Guiyu neonates than for controls (3.61 vs. 1.25 MUg/L), with 25.61% of Guiyu subjects exhibiting a median CBCd that exceeded the safety limit defined by the World Health Organization (5 MUg/L), as compared with 14.18% of control neonates (p < 0.01). In Guiyu, the mean PCd was higher than that for controls (0.17 +/- 0.48 vs. 0.10 +/- 0.11 MUg/g, p <= 0.01). The high levels of CBCd and PCd were significantly associated with parents' occupational and environmental exposure to e-waste recycling pollutants. Staining for MT was positive and dense for 67.00% (67/100) of Guiyu neonates as compared with 32.69% (17/52) of controls (p < 0.01). Exposure to e-waste recycling pollutants increased Cd exposure in neonates, which was accompanied by increased placental MT expression. PMID- 20714931 TI - Seasonal concentrations of some heavy metals (Cd, Pb, Zn, and Cu) in Ulva rigida J. Agardh (Chlorophyta) from Dardanelles (Canakkale, Turkey). AB - In this study, changes in heavy metal accumulation in U. rigida J. Agardh taxon and seawater have been investigated with respect to different stations and seasons. For this purpose, the severity of heavy metal pollution in the Dardanelles has been presented through the determination of Cu, Pb, Zn, and Cd concentrations in U. rigida macroalgae and seawater taken seasonally from the stations located on six different regions on the strait. While the metal concentrations in alga specimens were found to be high in spring and winter in all stations; the metal concentrations in the seawater, particularly the Pb concentration, were found to be high in all seasons. PMID- 20714932 TI - Initial evaluation of a biochemical cystic fibrosis newborn screening by sequential analysis of immunoreactive trypsinogen and pancreatitis-associated protein (IRT/PAP) as a strategy that does not involve DNA testing in a Northern European population. AB - BACKGROUND: Ethical concerns and disadvantages of newborn screening (NBS) for cystic fibrosis (CF) related to genetic testing have raised controversies and impeded implementation of CF NBS in some countries. In the present study, we used a prospective and sequential immunoreactive trypsinogene (IRT)/pancreatitis associated protein (PAP) strategy, with IRT as first and PAP as second tier, and validated this biochemical approach against the widely used IRT/DNA protocol in a population-based NBS study in southwest Germany. METHODS: Prospective quantitation of PAP and genetic analysis for the presence of four mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene most prevalent in southwest Germany (F508del, R553X, G551D, G542X) were performed in all newborns with IRT > 99.0th percentile. NBS was rated positive when either PAP was >=1.0 ng/mL and/or at least one CFTR mutation was detected. In addition, IRT > 99.9th percentile was also considered a positive rating. Positive rating led to referral to a CF centre for testing of sweat Cl(-) concentration. FINDINGS: Out of 73,759 newborns tested, 98 (0.13%) were positive with IRT/PAP and 56 (0.08%) with IRT/DNA. After sweat testing of 135 CF NBS-positive infants, 13 were diagnosed with CF. Detection rates were similar for both IRT/PAP and IRT/DNA. One of the 13 diagnosed CF newborns had a PAP concentration <1.0 ng/mL. CONCLUSIONS: Sequential measurement of IRT/PAP provides good sensitivity and specificity and allows reliable and cost-effective CF NBS which circumvents the necessity of genetic testing with its inherent ethical problems. PMID- 20714933 TI - Surgical model-view-controller simulation software framework for local and collaborative applications. AB - PURPOSE: Surgical simulations require haptic interactions and collaboration in a shared virtual environment. A software framework for decoupled surgical simulation based on a multi-controller and multi-viewer model-view-controller (MVC) pattern was developed and tested. METHODS: A software framework for multimodal virtual environments was designed, supporting both visual interactions and haptic feedback while providing developers with an integration tool for heterogeneous architectures maintaining high performance, simplicity of implementation, and straightforward extension. The framework uses decoupled simulation with updates of over 1,000 Hz for haptics and accommodates networked simulation with delays of over 1,000 ms without performance penalty. RESULTS: The simulation software framework was implemented and was used to support the design of virtual reality-based surgery simulation systems. The framework supports the high level of complexity of such applications and the fast response required for interaction with haptics. The efficacy of the framework was tested by implementation of a minimally invasive surgery simulator. CONCLUSION: A decoupled simulation approach can be implemented as a framework to handle simultaneous processes of the system at the various frame rates each process requires. The framework was successfully used to develop collaborative virtual environments (VEs) involving geographically distributed users connected through a network, with the results comparable to VEs for local users. PMID- 20714934 TI - Quantitative evaluation for accumulative calibration error and video-CT registration errors in electromagnetic-tracked endoscopy. AB - PURPOSE: Electromagnetic (EM)-guided endoscopy has demonstrated its value in minimally invasive interventions. Accuracy evaluation of the system is of paramount importance to clinical applications. Previously, a number of researchers have reported the results of calibrating the EM-guided endoscope; however, the accumulated errors of an integrated system, which ultimately reflect intra-operative performance, have not been characterized. To fill this vacancy, we propose a novel system to perform this evaluation and use a 3D metric to reflect the intra-operative procedural accuracy. METHODS: This paper first presents a portable design and a method for calibration of an electromagnetic (EM)-tracked endoscopy system. An evaluation scheme is then described that uses the calibration results and EM-CT registration to enable real-time data fusion between CT and endoscopic video images. We present quantitative evaluation results for estimating the accuracy of this system using eight internal fiducials as the targets on an anatomical phantom: the error is obtained by comparing the positions of these targets in the CT space, EM space and endoscopy image space. To obtain 3D error estimation, the 3D locations of the targets in the endoscopy image space are reconstructed from stereo views of the EM-tracked monocular endoscope. Thus, the accumulated errors are evaluated in a controlled environment, where the ground truth information is present and systematic performance (including the calibration error) can be assessed. RESULTS: We obtain the mean in-plane error to be on the order of 2 pixels. To evaluate the data integration performance for virtual navigation, target video-CT registration error (TRE) is measured as the 3D Euclidean distance between the 3D-reconstructed targets of endoscopy video images and the targets identified in CT. The 3D error (TRE) encapsulates EM-CT registration error, EM-tracking error, fiducial localization error, and optical-EM calibration error. CONCLUSION: We present in this paper our calibration method and a virtual navigation evaluation system for quantifying the overall errors of the intra-operative data integration. We believe this phantom not only offers us good insights to understand the systematic errors encountered in all phases of an EM-tracked endoscopy procedure but also can provide quality control of laboratory experiments for endoscopic procedures before the experiments are transferred from the laboratory to human subjects. PMID- 20714935 TI - Emergence of secondary resistance to imatinib in recurrent gastric GIST. PMID- 20714936 TI - Ethnicity influences lymph node resection in colon cancer. AB - The purpose of this study is to determine the association between ethnicity and lymph node retrieval after colon cancer resection. Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, patients who underwent colon cancer resection from 2000-2003 were evaluated. Subjects were classified as having <12 (N = 20,605) or >=12 (N = 12,358) lymph nodes examined. Multivariate models were used to analyze the relationship between lymph nodes resected and independent variables. Out of a total of 32,936 patients, 62.5% had fewer than 12 lymph nodes resected. In multivariate analysis, Hispanic ethnicity was associated with a significantly lower chance of having >=12 lymph nodes than the Caucasian population (OR = 0.61; CI, 0.50-0.74). Despite this, there was no understaging: the proportion of stage II and III diagnoses was the same. Both groups received the same rate of cancer-directed surgery and survival was equivalent. During this study period, a majority of colon cancer resections were inadequate based on the current standard of >=12 nodes. Hispanic patients were less likely to have an adequate node resection when compared to Caucasians. Despite fewer lymph nodes harvested, they had equivalent staging and survival. These results suggest that ethnicity influences the lymph node count. PMID- 20714938 TI - Damage control principles for pancreatic surgery. PMID- 20714937 TI - Pancreatoduodenectomy for ductal adenocarcinoma in the very elderly; is it safe and justified? AB - BACKGROUND: The outcomes of complex major surgery in the elderly are being scrutinized because of the demands on surgical services by an aging population and the concern whether such endeavors are justified. Pancreatoduodenectomy (PD) for pancreatic adenocarcinoma presents special challenges because of the high morbidity of the procedure, dismal prognosis of the disease, and the increasing incidence of pancreatic cancer with age. METHODS: All patients who underwent PD for pancreatic adenocarcinoma from 1981 to 2007 were analyzed for perioperative outcomes, tumor-related parameters, use of adjuvant therapy, and long-term survival. Specifically those aged >=80 years were compared with a control group aged <=80 years. Continuous variables are displayed as median and interquartile range (IQR); log-rank test and Cox's proportional hazards were used to determine survival and effect of age as an independent marker against other covariates. RESULTS: Fifty-three patients aged >=80 years underwent PD. Twenty-six (51%) developed complications, including delayed gastric emptying (nine, 17%), pancreatic leak (six, 11%), and postoperative bleeding (five, 9%). There was one in-hospital death (2%). The hospital stay was 13.5 days (IQR 9-19). Forty-one (79%) patients were discharged home; of the 11 (21%) patients who went to an outside health care facility (pancreatic leak/drains and feeding issues--five, delayed gastric emptying/nutritional--four, no home support--one), one died in a nursing home at 5 months while the other ten patients returned to their previous abode (median 4 weeks). The median disease-free and overall survivals were 11.8 (IQR 7.8-18.4) and 13.5 months (IQR 12-21.3). Compared to the non-octogenarians (n = 567), the older population had more poor risk patients with respect to ASA status (P < 0.0004), stayed longer as in-patients (P < 0.04), were more likely to develop complications (P < 0.001), and were less likely to receive adjuvant therapy (P < 0.0001). There was no difference in long-term disease-free or overall survival (log-rank P < 0.30 and P < 0.14), and age did not appear to be an independent marker of prognosis when analyzed (Cox's proportional hazards P < 0.26; chi-square, 1.25). CONCLUSIONS: In experienced institutions, PD for ductal adenocarcinoma is a viable option in the ambulatory octogenarian population who are deemed operative candidates for a PD. The trade off is a greater complication rate and the prospect of discharge (one in five) to a chronic care facility. The majority, however, can be discharged home with a reasonable functional status, and those discharged to temporary health care rehabilitation facilities are likely to make a recovery over a few weeks. PMID- 20714939 TI - Hypovitaminosis D in a healthy female population, aged from 40 to 85 years, in the west of Ireland. AB - BACKGROUND: Increasing attention has been focused on diseases associated with ageing, as the mean age of the population in developed countries increases. Vitamin D and parathyroid hormone play key roles in calcium homeostasis, which is integral to skeletal health. AIMS: To assess the vitamin D status of healthy, community dwelling, middle-aged and older females. METHODS: General biochemistry and bone profiles, including ALP, PTH and 25(OH)D, were determined. RESULTS: Of 143 healthy white women receiving no supplementation or bone modifying treatments, 47% were vitamin D insufficient (<50 nmol/L) and only 4% were sufficient for the time of year. There was no statically significant correlation between age and 25(OH)D concentrations; neither was there a statistically significant seasonal variation in 25(OH)D levels noted. CONCLUSION: Vitamin D status should be assessed more often in middle-aged and older females. Expected age-related and seasonal variations in 25(OH)D levels were not confirmed in this study. PMID- 20714940 TI - Microcarrier bioreactor culture system promotes propagation of human intervertebral disc cells. AB - BACKGROUND: Cell-based tissue engineering has emerged as a potential therapy for intervertebral disc degeneration. However, propagating and maintaining high quantity and quality of the seed cells remains a challenge. AIMS: To investigate the feasibility of culturing human disc cells using a microcarrier bioreactor system. METHODS: Cell counts, growth patterns, cell cycles and cellular viability were examined during the course of cell cultivation and compared between the microcarrier bioreactor culture system and the conventional monolayer culture. RESULTS: Cultures in the microcarrier bioreactor resulted in enhanced disc cell growth and satisfactory cell viability in comparison with the conventional monolayer culture. The cells in the microcarrier bioreactor cultivation exhibited higher S phase ratios, elevated mitotic index and persistent exponential growth. CONCLUSION: The microcarrier bioreactor culture system appears suitable for human disc cell propagation and may provide considerably more seeding cells for the tissue engineering process of intervertebral discs. PMID- 20714941 TI - Radiologic complete response with sirolimus and sorafenib in a hepatocellular carcinoma patient who relapsed after orthotopic liver transplantation. AB - BACKGROUND: No standard therapies have been established for the treatment of recurrent hepatocellular carcinoma (HCC) after liver transplantation. DISCUSSION: Sirolimus is a mTOR inhibitor which has been used as an immunosuppressive medication in patients who are at high risk of tumor reoccurrence after liver transplantation. Sorafenib is a multikinase inhibitor approved for the treatment of advanced HCC. However the role of sorafenib in patients with HCC reoccurrence after liver transplantation is unclear. RESULTS: Combination of sirolimus and sorafenib appears to have synergistic effect when treating HCC in preclinical settings. We report a case of a post-liver transplant patient treated with sorafenib and sirolimus for hepatic HCC recurrence who exhibited complete radiologic response after 5A months of therapy. PMID- 20714942 TI - FLANG salvage chemotherapy is an effective regimen that offers a safe bridge to transplantation for patients with relapsed or refractory acute myeloid leukemia. AB - The efficacy of fludarabine in combination with an intermediate dose of cytosine arabinoside, mitoxantrone, and G-CSF (FLANG; fludarabine 30 mg/m(2)/day, cytosine arabinoside 1 g/m(2)/day, mitoxantrone 10 mg/m(2)/day, and G-CSF 300 MUg/day for 5 days) was evaluated in patients with refractory or relapsed acute myelogenous leukemia (AML). Between January 2004 and December 2006, 27 patients with relapsed or refractory AML were enrolled in the present study. In total, 14 patients had experienced an early relapse, 10 had experienced a late relapse, and the remaining three (11%) had developed primary refractory leukemia at the time of study entry. Most patients (n = 17, 63%) had post-transplant relapse, and 10 of them relapsed after allogeneic hematopoietic stem cell transplantation (SCT). After FLANG treatment, 15 patients (56%) achieved a complete response (CR), and three patients died during reinduction chemotherapy. After achieving a CR, eight patients received SCT (seven allogeneic (sibling = 4, unrelated = 2, and haploidentical familial = 1) and one autologous SCT), one received donor lymphocyte infusion, three received consolidation chemotherapy, and the remaining three refused further therapy. Eight patients were alive during continuous CR, with an event-free survival (EFS) rate of 30% after a median follow-up of 42.1 months. The survival outcome of patients who received SCT was remarkable (EFS of 75%). Additionally, no toxicity severe enough to preclude transplantation was evident after or during FLANG. The findings of the present study suggest that FLANG salvage chemotherapy is an effective regimen and that it offers a safe bridge to SCT. Furthermore, this regimen prompts efforts to proceed to SCT as post-remission therapy for patients in greater than first CR. PMID- 20714943 TI - p14ARF promoter region methylation as a marker for gliomas diagnosis. AB - Methylation in the promoter region is one of the mechanisms through which tumor suppressors are inactivated, resulting in tumorigenesis and/or tumor progression. Herein, we studied the methylation status in the promoter region of the p14ARF tumor suppressor gene in 33 brain tissues isolated from glioma patients (astrocytomas) and compared to 12 brain tissues isolated from autopsy donors using methylation-specific polymerase chain reaction (MSP). The correlation between the expression of P14 and P53 was investigated using immunohistochemistry (IHC). The average percentage of methylation in the promoter region of p14ARF gene in brain samples from glioma patients is 39.4%, while 0 from autopsy donors. No difference in the methylation level between low-grade and high-grade gliomas was detected. The methylation status has no correlation with the prognosis in glioma patients. A significant correlation between the expression of mutant form of TP53 and the grade of the glioma was established. Furthermore, there was a negative correlation between methylation of the p14ARF promoter and the expression of the mutant form of TP53. Therefore, our data suggest that methylation in the promoter region of the p14ARF gene may be used as a biomarker for the diagnosis of gliomas. PMID- 20714944 TI - Serum cytokine levels in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. AB - To investigate whether expression of several cytokines affected clinical outcome in non-small cell lung cancer patients. A total of 86 stage IIIB/IV non-small cell lung cancer patients, treated with platinum-based doublets, were examined expression levels of IL-1, IL-2R, IL-5, IL-6, IFN-gamma, TNF-alpha pre- and post chemotherapy. Enzyme-linked immunosorbent assay technique was performed. Kaplan Meier analysis and Cox regression analyses were used to adjust for possible confounding variables. IL-6 expression levels were significantly decreased due to chemotherapy in patients with stable disease (P=0.041). IL-2R expression levels were significantly increased due to chemotherapy in patients with progression disease (P=0.010). Patients with high concentrations of TNF post-chemotherapy had a significantly longer survival (P=0.009, 17 months versus 11 months) than low levels. Multivariate analysis showed that sex, response rate, IL-1 and TNF-alpha were significantly predictive of the survival. Serum IL-6 and IL-2R levels correlated with chemoresponse in advanced non-small cell lung cancer, serum IL-1 and TNF-alpha can be predictive factors in advanced non-small cell lung cancer. PMID- 20714945 TI - Assessing the initiation and completion of adjuvant chemotherapy in a large nationwide and population-based cohort of elderly patients with stage-III colon cancer. AB - Randomized trials conducted in the 1980s have established the effectiveness of 5 fluorouracil-based adjuvant chemotherapy in treating stage-III colon cancer. However, the initiation of adjuvant chemotherapy is just the first step for survival improvement. Little is known about the actual completion rate of such a therapy in the community. The objectives of this study were to measure the initiation and completion rate of adjuvant chemotherapy and to identify the associated factors. We studied 12,265 patients aged 65+ diagnosed with stage-III colon cancer between 1991 and 2005 who were identified from the Surveillance, Epidemiology, and End Results-Medicare linked database. Chemotherapy initiation was defined as at least one claim indicating the use of chemotherapy. The first and last claims were used to measure the length of chemotherapy. A complete course of chemotherapy was defined as 8-13 months for 1991-1995 cohort and 5-7 months for 1996-2005 cohort according to clinical guideline. Of the 12,265 patients, 64.4% received adjuvant chemotherapy within 3 months after tumor resection. Among those who had chemotherapy initiated, 62.2% (or 38.0% of 12,265 patients) received a complete course of chemotherapy. Patient's age at diagnosis, marital status, and comorbidity score were the significant predictors for chemotherapy initiation. These variables remained significant in predicting chemotherapy completion after adjusting for year of diagnosis and other factors. In conclusion, initiation and completion of chemotherapy was largely influenced by patient's age, marital status and comorbidity. Further investigation is needed to explore the cause of these differences in adherence to standard treatment that is essential for better quality of cancer care. PMID- 20714948 TI - Comparison of carotid artery stenting performance between cardiologists and neuroradiologists: one medical center's experience. AB - PURPOSE: To report the experience of carotid artery angioplasty with stenting (CAS) by cardiologists (CV) and neuroradiologists (NR) in an area with less incidence of extracranial artery stenosis. METHODS: From 1999 to 2008, 210 patients with 231 stents were collected by claim records from the administrative office and reviewed by one independent neurologist. Outcome measures were peri procedural adverse events (AE), restenosis and recurrent ipsilateral stroke (RS) rate, categorized into treatment groups by either CV or NR. RESULTS: The average age was 69.0 years and 82.9 % of the patients were men. 63.8% of the patients with 62.8% stents were treated by CV and the remaining 36.2% of patients with 37.2% stents were done by NR. Symptomatic CAS was evident in 70.1% of the CV cases and 83.0% in NR treated patients (P = 0.017). The peri-procedural AE rate was 31.6%; 35.9% in CV group and 24.4% in the NR group (P = 0.071). RS rate was 4.8% in 663.3 days; 4.1% in 920.8 days in the CV group and 5.8% in 354.2 days in the NR group (P = 0.865). The restenosis rate was 10.9% in 630.5 days; 5.4% in the CV group in 224.8 days and 20.6% in the NR group in 817.8 days (P = 0.007). CONCLUSIONS: The restenosis and recurrent stroke rates after carotid artery stenting in Taiwan appears to be consistent with other published and well organized trials. Measures to minimize peri-procedural AR rates are definitely warranted. PMID- 20714946 TI - Fixed combination of oxycodone with naloxone: a new way to prevent and treat opioid-induced constipation. AB - Morphine and other opioids increase tone and reduce propulsive motility in several segments of the gut, enhance absorption of fluids, and inhibit secretion. This opioid-induced bowel dysfunction may present as infrequent stools, hard stools, difficult defecation, bloating, and sense of incomplete emptying of the bowels, but also dry mouth, gastroesophageal reflux, epigastric fullness, and abdominal cramping. It afflicts about one-third of patients on opioid treatment. Lifestyle measures, such as regular toilet visits, physical activity, and fiber rich diet, are very unlikely to be successful. Laxatives, such as bisacodyl, sodium picosulfate, sennosides, macrogols, and prucalopride, may relieve opioid induced constipation (OIC) in a proportion of patients only. A new approach to counteract OIC is the coadministration of an opioid antagonist devoid of the potential to penetrate the brain. In the EU, an oxycodonenaloxone combination has been approved for this purpose. Both components are included in an oral extended release preparation. Following its release, naloxone acts locally on the gut and antagonizes the inhibitory effect of the opioid. After being absorbed in parallel with oxycodone, naloxone is rapidly and completely inactivated by a high first pass effect in the liver. In a 2:1 dose ratio it may improve OIC without interfering with the analgesic effect. PMID- 20714949 TI - Risk factors for seizures after first-time ischemic stroke by magnetic resonance imaging. AB - BACKGROUND: Seizures are important neurological complications of ischemic stroke. There is a need to further clarify the risk factors of seizures following ischemic stroke and predict those who will require treatment. METHODS: One hundred and forty-three (143) first-time ischemic stroke patients were enrolled in this one-year (2002) retrospective study. Prognostic variables were analyzed based on the Cox's proportional hazards model after a minimum follow-up period of six years. RESULTS: Seizures occurred in 13 first-time ischemic stroke patients, including acute symptomatic seizures in two (1.4%) and unprovoked seizures in 11 (7.7%). Only one progressed to status epilepticus during hospitalization. After six years of follow-up, the median (inter-quartile range) Glasgow Outcome Scale (GOS) was 3 (3,4) for patients with seizures and 4 (3,4) for those without seizures. Regarding seizure control after discharge in the 13 cases, 12 were seizure-free with or without anti-epileptic drugs and one had 1-3 seizures per year. Only the presence of cortical distribution of ischemic infarction (p=0.009, OR=5.549, 95% CI=1.53-20.19) was independently associated with seizures by the Cox's proportional hazards model. DISCUSSION: The incidence of seizures following first-time ischemic stroke is low and may have delayed manifestation. Cortical distribution of the ischemic infarction is a risk factors for seizures. PMID- 20714950 TI - Brainstem auditory evoked potentials study in patients with diabetes mellitus. AB - OBJECTIVES: To analyze the correlation between brainstem-auditory evoked potentials (BAEP) and nerve conduction (NC) studies in patients with diabetes mellitus (DM). METHODS: We retrospectively reviewed the results from the subjects who received our neurological screening test including BAEP and NC studies. A DM group and a control group were applied. The DM group was subdivided 4 subgroups including neuropathy, non-neuropathy, infarct and non-infarct. RESULTS: A total of 43 DM patients and 43 control subjects were included. The inter-peak latencies (IPL) IIII and IPL I-V of the BAEP showed a statistical significance between the DM and control groups. In the IPL I-III study, the DM neuropathy subgroup showed a statistical significance in either the DM non-neuropathy or control subgroup. The IPL I-III showed moderate correlation (correlation coefficient- 0.334) with tibial motor NC velocity. CONCLUSION: Patients with DM have a prolongation in IPL I-III, especially in the neuropathy subgroup. This prolongation in IPL I-III would best be explained by acoustic neuropathy. The tibial motor, median sensory, and sural NC velocities correlated with the acoustic neuropathy in patients with DM. PMID- 20714951 TI - Thymic squamous cell carcinoma with multiple brain metastases. AB - Thymic carcinomas are rare epithelial malignancies with marked invasive tendency which can metastasize to distant organs, most commonly to the lung, bone, liver, kidney and extra-thoracic lymph nodes. Central nervous system metastasis is extremely rare and only 45 such cases have been reported in the English literature. We reported a 42-year-old male with thymic squamous cell carcinoma and lung and bones metastases. He underwent thymomectomy and pulmonary lobectomy with concurrent chemo-radiotherapy. Based on the clinical symptoms of severe headache and vomiting and the results of brain computed tomography and magnetic resonance imaging scans, 2 metastatic tumors with a cystic component were diagnosed. We resected the metastatic tumors and the signs of increased intracranial pressure subsided immediately after the operation. The patient underwent continuous chemotherapy systemically and whole brain irradiation for disease control. This presentation suggests that surgical resection with concurrent chemo-radiotherapy is the treatment of choice for thymic carcinomas with brain metastases. PMID- 20714952 TI - Isolated brainstem involvement in a patient with hypertensive encephalopathy. AB - Hypertensive encephalopathy (HE) is one of the acknowledged hypertensive emergencies. Isolated hypertensive brainstem encephalopathy (HBE) without concomitant typical parietooccipital lesion is unusual. Patients with HBE may or may not present with symptoms attributable to brainstem and the diagnosis is challenging in an emergency setting. The most important differential diagnosis in HBE is brainstem infarction, because the goals of blood pressure treatment are different. Evidence of vasogenic edema on magnetic resonance image, i.e. absence of high signal lesions on diffusion weighted images and increased value of apparent diffusion coefficient are diagnostic indicators of HBE, but not brainstem infarction. Prompt recognition of HBE and adequately lowering blood pressure offer the best outcomes. PMID- 20714953 TI - Role of early multimodal interventions in a case with autistic regression. AB - Autistic regression consists of paucity of social and emotional reciprocity, disorders of language and communication, and stereotyped behaviors that are noted after a period of normal or near-normal development for one or two years. We report a case who presented autistic regression symptoms but was improved with comprehensive multi-modal treatment approach in motor, language, and social domains, and also in the activities and skills of daily living. PMID- 20714954 TI - Cardiac cephalalgia presented with a thunderclap headache and an isolated exertional headache: report of 2 cases. AB - Headache could be the only manifestation of a myocardial infarction or angina pectoris. The recognition of myocardial ischemia as the cause of headache is important in clinical practice. We report two cases of cardiac cephalalgia, defined as headache attributed to myocardial ischemia. The first patient presented with a thunderclap headache probably secondary to a myocardial ischemia and the second patient presented with isolated headaches secondary to angina pectoris triggered by exertions. The clinical presentations of cardiac cephalalgia are highly variable and the most consistent feature is severe in intensity. Cardiac cephalalgia should be considered one of the differential diagnoses of exertional headache and thunderclap headache when the patient is older or has cardiovascular risk factors. PMID- 20714955 TI - [Tremor]. AB - Tremor is the most common involuntary movement disorder. It can be an isolated symptom or a symptom of another neurological disorder, such as dystonia, Parkinson disease, spinocerebellar ataxia et al. It is an unintentional, somewhat rhythmic, muscle movement involving to-and-fro movements of one or more parts of the body. It can affect the hands, arms, head, vocal cord, jaw, chin, and legs. Most tremors occur in the hands. Clinically, the most useful way to categorized tremor is whether it occurs mainly at rest, on postural, or during movement (kinetic tremor). Tremor is most common classified by different clinical features and cause or origin; include essential tremor, Parkinsonian tremor, cerebellar tremor, dystonic tremor, orthostatic tremor, physiologic tremor, and psychogenic tremor. Diagnosis need a detail history (include familial inheritance, drugs exposure, alcohol consumption or withdraw); complete physical examination and laboratory tests. Electromyography is also a simple and quick method with which to calculate tremor frequency and amplitude for assisting diagnosis. Treatment for majority of tremor syndrome is purely symptomatic, and is similar regardless of the underlying cause of the tremor. There are different medicines to try in order propranolol, clonazepam, primidome and gabapentin for limb tremors, or trihexyphenidyl for dystonic tremor. Focal botulinum toxin injection may be help in focal tremor. Neurosurgery is only indicated in severe tremor, such as deep brain stimulation (DBS) of subthalamic nucleus for primary or secondary parkinsonian tremor. PMID- 20714956 TI - [Beyond the psychometric assessments: the evaluation of patients with Alzheimer's disease]. AB - Alzheimer's disease is a neurodegenerative illness. The Mini Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI) and Clinical Dementia Rating (CDR) are applied to assess whether a person suffers Alzheimer's disease and determine its severity. There are many confounding factors within those assessments, medical professionals need to bear in mind the pitfalls when evaluating the data and the patient. PMID- 20714957 TI - Pathology and functional diagnosis of small-fiber painful neuropathy. AB - Small-fiber sensory neuropathy with neuropathic pain had been a diagnostic challenge for neurologists. We and several groups have developed skin biopsy with quantitation of intraepidermal nerve fiber (IENF) density as a diagnostic approach. In the skin with small-fiber sensory neuropathy, there are pathological hallmarks: reduced IENF density with degeneration of subepidermal nerve plexuses and dermal nerves. Skin denervation is a major presentation of diabetic neuropathy and inflammatory neuropathies including Guillain-Barr syndrome and chronic inflammatory demyelinating polyneuropathy. The skin biopsy approach also provides an opportunity to examine dermal vasculature and inflammatory vasculopathy is demonstrated in vasculitic neuropathy, systemic lupus erythematosus, and eosinophilia-associated neuropathy. In addition to neuropahtologic evidence, the functional consequences of cutaneous nerve degeneration can be assessed with quantitative sensory testing (QST), contact heat evoked potential (CHEP), and functional magnetic resonance imaging (fMRI). One major etiology of small-fiber sensory neuropathy is familial amyloid polyneuropathy caused by mutations of transthyretin (TTR). We recently conducted studies on a large cohort of unique TTR mutation on Ala97Ser in Taiwan. These patients had significant skin denervation in addition to motor and autonomic neuropathy. Taken together, the skin biopsy with quantitation of IENF density provides diagnostic utility for small-fiber sensory neuropathy and the combination of psychophysical, physiological, and neuroimaging examinations offer comprehensive assessments for patients with neuropathic pain due o cutaneous nerve degeneration. PMID- 20714958 TI - Changes in stroke awareness among undergraduate students after an educational intervention. AB - OBJECTIVE: This study investigated undergraduates'awareness about stroke, the effects of an educational intervention and the difference of measuring tests between recognition and recall. METHODS: We chose a convenient sample from two classes. One of the classes, the recognition group, was tested by a close-ended questionnaire with multiple choices. The other class, the recall group, was tested via an open-ended questionnaire. Participants completed their pretest and first posttest before and right after the education intervention. Twelve weeks after the intervention, participants were tested again to assess the knowledge retention over time. RESULTS: Fifty six participants in the recognition group and 53 participants in the recall group completed all three tests. Before the intervention, all respondents in the recognition group could recognize three or more risk factors and at least one warning sign, but in the recall group were only 32% and 72% respectively. After the intervention, the mean scores of first posttest and second posttest were all significant higher than that of pretest in both groups (P less 0.001). Comparisons of mean score of same items in both groups, the mean score of recognition group was significantly higher than that of recall group at each test (all P less 0.001). CONCLUSION: The intervention improved participants'knowledge towards stroke, even twelve weeks later. Participants obtained higher scores with a close-ended questionnaire than those with an open-ended questionnaire. PMID- 20714959 TI - Intravenous valproate for seizures in 137 Taiwanese children - valproate naive and non-naive. AB - PURPOSE: Valproate has been widely used in controlling various kinds of seizures. Intravenous forms of valproate control seizures in a more rapid and efficacious pattern than oral forms. We evaluated the effectiveness and adverse effects of intravenous valproate for controlling seizures in Taiwanese children under 18 years old. METHODS: Retrospective chart reviews were performed on 137 pediatric patients receiving valproate infusion from January 2003 to December 2006. Patients were divided into 4 groups as follows: (1) previous use of other antiepileptic drugs (AEDs) (n=59), (2) previous use of oral valproate (n=8), (3) previous use of other AEDs and valproate (n=32), (4) first time use of valproate (n=38). The indications for using intravenous valproate include status epilepticus, repetitive seizures, prophylactic use for brain operations or in cases where oral administration was not feasible due to medical problems. RESULTS: The mean age was 8+/-6.22 years old and the average dose was 31.2+/ 26.45 mg/kg/day. The mean duration of usage was 7.8+/-6.99 days. Eight patients failed to respond to intravenous valproate and the AED was shifted to other drugs. Thirty-two patients achieved successful seizure control after adding other AEDs following intravenous valproate. The seizure control rate in our study was 71%, and six patients died of complications associated with an underlying disorder. An allergic reaction (skin rash) was found in 1 patient, while no serious adverse effects were noted in our patients. CONCLUSION: Intravenous valproate is effective and safe in controlling seizures in children who are either valproate naive or not. PMID- 20714960 TI - Interleukin 10 gene polymorphism in Iranian patients with multiple sclerosis. AB - PURPOSE: IL-10 suppresses several activities of the immune response by inhibition of Th1 and Th2 cells. METHODS: We studied 110 Iranian patients with clinically definite multiple sclerosis (MS) and 100 ethnic and age matched controls. Three single-nucleotide polymorphisms in the proximal region of IL-10 promoter gene ( 1082/-819/-592) were analysed by amplification refractory mutation system (ARMS) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The -1082 (G/A), -819 (T/C) and -592 (A/C) genotypes were similarly distributed between MS patients and the controls. There was no statistically significant difference in the allelic and genotype distribution between patients and controls. In addition, gender, course and progression index did not reveal any statistically significant differences in the allele and genotype distribution of IL-10 polymorphisms. CONCLUSION: As a non-European patient population, according to our results, IL10 polymorphism is not associated with MS and its subtypes nor influences the disease progression. PMID- 20714961 TI - Gabapentin reduces neurovisceral pain of porphyria. AB - PURPOSE: Gabapentin is well known for pain control. Here, we report that gabapentin is a good adjunct for visceral pain in a porphyria patient. CASE REPORT: A young female was admitted due to acute abdomen. On admission, she was noted to have hyponatremia, tachycardia, and hypertension. Then, she had episodes of seizure and confusion. Gabapentin was prescribed for the control of seizure and pain before the diagnosis of acute intermittent porphyria was confirmed. Seizure did not occur after gabapentin. Pain severity also significantly reduced with visual analogue scale from 10 to 4. The severity of pain rebounded after gabapentin was withdrawn. When the diagnosis was proved, the neurovisceral pain further decreased with combination of morphine and gabapentin and subsided after treatment with hematin. CONCLUSION: Our report indicates that gabapentin can be considered in porphyria patients, especially when patients had seizures or acute abdomen, when morphine is not available or contraindicated, when abdomen pain transforms as chronic pattern, and when neuropathic pain occurs in extremities. PMID- 20714962 TI - Unilateral paresthesia after isolated infarct of the splenium: case report. AB - PURPOSE: We describe a patient who presented with unilateral paresthesia after acute isolated infarct of the splenium. CASE REPORT: A 74-year-old woman presented with acute onset of right sided numbness and tingling. MR imaging of the brain showed hypointensity on T1-weighted images and on apparent diffusion coefficient maps, and hyperintensity on T2-weighted and on diffusion-weighted images in the splenium, suggestive of acute infarction. MR angiography showed narrowing of left posterior cerebral artery with decreased branches. On detailed high cortical function assessment, she did not have frontal lobe dysfunction, alien hand syndrome, apraxia, optic ataxia, cortical sensation dysfunction, alexia, agraphia, visual field defect, nor color agnosia. CONCLUSION: Infarcts of the splenium are not common. Splenial lesion may be associated with altered mental status, ataxia, recent seizure, hemispheric disconnection, and dysarthria. The presentation of isolated unilateral paresthesia makes the patient different from those previously described. The paresthesia could be caused by selective lacunar infarcts in the diencephalic and mesencephalic regions or could be caused by the diaschisis in the parietal cortex. Single photon emission CT may be indicated to provide further information of central nervous system dysfunction in splenial lesion. PMID- 20714963 TI - Heterotopic ossification as a complication of carbon monoxide intoxication. AB - PURPOSE: Gait impairment due to encephalopathy and neuropathy has been reported in carbon monoxide (CO) intoxication. Heterotopic ossification (HO) as a cause of gait impairment after CO intoxication has never been reported. In this study we report a patient with HO after CO intoxication. CASE REPORT: A 21 year-old woman developed HO after CO intoxication, which resulted in progressive difficulties in ambulation. Bone scan 3 months later revealed HO around bilateral femoral joints and extended to proximal thighs. Selective involvement of bilateral iliopsoas, tensor fascia lata, rectus femoris, sartorius, and quadriceps muscles were found by muscle magnetic resonance imaging. Surgical intervention improved ambulation. A repeated bone scan 6 months after the operation showed no focal recurrence. CONCLUSION: CO intoxication can lead to HO through ischemic reperfusion injury. HO should be considered in patients with ambulation difficulties after CO intoxication. Excision of HO may be a treatment option to correct limitations in locomotion. PMID- 20714964 TI - Iron deficiency anemia - a rare etiology of sinus thrombosis in adults. AB - PURPOSE: Cerebral venous thrombosis (CVT) has a wide spectrum of symptoms and is therefore difficult to diagnose. CVT has been reported to be associated with various etiologies. There are, however, very few reported cases of CVT associated with iron deficiency anemia (IDA), especially in adults. CASE REPORT: We reported the case of a female patient with seizure and hemorrhagic infarction due to sagittal sinus thrombosis. She had severe hypochromic microcytic anemia due to iron deficiency, and had a good prognosis after iron supplementation and oral anticoagulation therapy. CONCLUSION: The present case indicates that iron deficiency is a risk factor for CVT. PMID- 20714965 TI - Transient attenuation of visual evoked potentials during focal status epilepticus in a patient with occipital lobe epilepsy. AB - PURPOSE: Seizures originating in the occipital areas are relatively uncommon. They are usually characterized by visual hallucinations and illusions or other symptoms related to the eyes and vision. CASE REPORT: In a 54-year-old woman with occipital lobe epilepsy, complex visual hallucinations, illusions, and migraine like headache constitute the major clinical manifestations. During focal status epilepticus, ictal electroencephalography revealed rhythmic focal spikes in the right occipital region, rapidly propagating to the right parietal and contralateral occipital areas. Ictal brain single-photon emission computed topography revealed hyperperfusion of the right occipital region. Using a full field pattern-shift visual evoked potential (VEP) study, we found that the P100 responses on both sides were markedly attenuated in amplitude during occipital focal status epilepticus, whereas the latencies of the VEPs were normal. The amplitude and morphology of P100 responses on both sides, however, returned to the normal range 7 days after cessation of the seizures. CONCLUSION: In addition to clinical seizure semiology, scalp EEG, SPECT and neuroimaging studies, VEP studies may be used as a supplementary examination tool to provide further information in the patients with occipital lobe seizures or epilepsies. PMID- 20714966 TI - [Neuroimaging guidelines in nonacute headaches]. AB - The Treatment Guideline Subcommittee of the Taiwan Headache Society evaluated the indication of neuroimaging for nonacute headache according to the principles of evidence-based medicine. We have assessed the qualities of studies, levels of evidence, and referred to other guidelines proposed by Western countries. After several panel discussions, we merged opinions from the subcommittee members and proposed a Taiwan consensus. Neuroimaging is not necessary for patients with nonacute and recurrent migraine or tension-type headache when there is no recent change of headache characteristics and neurological examinations are normal. Neuroimaging is suggested for patients who have headaches with abnormal neurological examinations. For patients who are diagnosed as having cluster headache and have never received neuroimaging studies, or patients whose headache characteristics are atypical for cluster headaches, neuroimaging studies should be considered. Neuroimaging is also recommended for patients with cough headache, exertional headache and headache associated with sexual activity. Although the resolution of MRI is superior to CT, evidence is insufficient to make recommendation regarding the choice of MRI or CT for the evaluation of nonacute headache patient. Clinicians should make a judgment by themselves according to the patient's specific conditions. PMID- 20714967 TI - Neurological manifestation of Swine flu: a brief note. AB - Swine flu is currently a problematic emerging infectious disease, and has reached pandemic proportions. Neurological manifestations of swine flu have been reported, but there is not much documentation. This note briefly summarizes what is known about the neurological manifestation of swine flu. PMID- 20714969 TI - Could schizophrenic subjects improve their social cognition abilities only with observation and imitation of social situations? AB - Schizophrenics display impairments in domains of social cognition such as theory of mind and emotion recognition. Recent studies, showing that the relationship of social cognition abilities with functional outcome is more significant than other neuro-cognitive functions, have considered these abilities as a target for intervention research. This article describes preliminary data from a new group based study focused on Emotion and ToM Imitation Training (ETIT), an imitation treatment aimed at improving social cognition and social functioning in schizophrenia. In the present study, 16 outpatients with schizophrenia completed ETIT assessment and were compared with 17 outpatients who participated to a Problem Solving Training group. Participants were assessed at pre- and post-test on measures of emotion recognition, theory of mind, cognition, flexibility and social functioning. We compared the rehabilitation training effects on neuro physiological activation through the event-related potentials (ERPs) method, which was recorded pre- and post-rehabilitation training. The results showed that when compared to the control group, ETIT participants improved on every social cognitive measure and showed better social functioning at post-test. Improvement in social cognition, in particular in emotion recognition, is also supported by ERP responses: we recorded an increase in electroactivity of medio-frontal areas only after ETIT treatment. Action observation and imitation could be regarded as a new frontier in rehabilitation. PMID- 20714970 TI - The relationship between therapist and client hope with therapy outcomes. AB - The current study examined whether clients' perceptions of hope and therapists' hope in their clients were associated with therapy outcomes. The authors conducted a naturalistic study of brief therapy with 10 therapists and 43 adult clients. Client-rated hope significantly increased after one session of therapy. However, no significant relationship was found between pretherapy client-rated hope and first-session symptom change. Further, client-rated hope at any point in therapy was not significantly related to therapy outcomes. Therapists' hope in their clients after the first and last sessions was significantly related to client outcomes. Implications for therapy practice and research are offered. PMID- 20714971 TI - [Voice disorders in asthma]. AB - Aasthma is one of the most common chronic diseases with a prevalence of 5% in Germany. Nearly half of the patients complain about permanent voice disorders. Mucosal changes due to the obstructive respiratory disease as well as mucus abnormalities and regularly accompanying chronic rhinosinusitis may explain these symptoms. The additional influence of laryngopharyngeal reflux is discussed controversially. Additionally, dysphonia may as well occur due to side effects of the therapy with inhaled corticosteroids: the ingredients as well as physical effects may be responsible for the development of chronic laryngitis. The concomitant therapy by an ENT specialist is important in asthma-related voice disorders to identify the basic cause of dysphonia systematically and to intervene at an early stage. PMID- 20714973 TI - [ENT-recommendations for tracheobronchoscopy]. AB - INTRODUCTION: Tracheobronchoscopy allows endoscopic inspection and management of the tracheobronchial system. MATERIAL: The recommendation was developed in 1997 and updated in 2004 and 2009. RESULTS: The recommendations comment on indications and contra-indications, instruments, anesthesia and complications of endoscopic tracheobronchoscopy. DISCUSSION: Rapid technical advances in endoscopy have led to changes in indications for different procedures, especially as pertains to rigid and flexible endoscopy. The recommendations are designed to provide guidance for ENT and affiliated specialties for choosing and processing instruments and sedation methods. PMID- 20714974 TI - [Preoperative patient information for goiter-relapse operation]. PMID- 20714975 TI - [Benign lesions of the larynx]. PMID- 20714978 TI - [Continuing education under test]. PMID- 20714979 TI - [Illness perceptions and functioning following total knee and hip arthroplasty]. AB - OBJECTIVE: In spite of the cumulating evidence for the prognostic relevance of illness perceptions regarding the course of disease and recovery of hip and knee joint patients, there are still no studies that examine the effects of these perceptions on postoperative functioning as assessed by clinical ratings. The aim of this inception cohort study was to describe the course of functioning following a hip or knee joint replacement over a period of one year and to analyse moderator-type effects of illness perceptions in order to develop strategies for preoperative counselling and postoperative rehabilitation. METHODS: The course of functioning following a hip joint replacement was assessed by the Harris hip score (HHS), the course of functioning following a knee joint replacement by the American Knee Society score (AKSS). Illness perceptions were assessed by the brief illness perception questionnaire. Due to the non-linear relationship of time and functional outcome, time was transformed using a log transformation. Moderator-type effects were analysed by interaction terms of log time and illness perceptions. RESULTS: For 135 patients the course of the HHS was analysed, for 127 patients the course of the AKSS. Results after one year confirmed a successful treatment for 82.3 % of the hip patients and 70.6 % of the knee patients. Hip patients expecting an enduring illness had lower scores on the HHS after one year (p = 0.026). The expectation that the treatment will be helpful was associated with a better outcome (p = 0.002). The outcome of knee patients was moderated by the degree how concerned they were about their illness (p = 0.016). CONCLUSION: The results confirmed the prognostic relevance of illness perceptions for the functional outcome and indicate the importance of preoperative counselling and the potential benefit of patient-oriented education that is aimed at modifying illness perceptions. PMID- 20714980 TI - [Metal ions: important co-players in aseptic loosening]. AB - AIM: The aims of this review were to discuss the different mechanisms of biocorrosion of orthopaedic metal implants in the human body, as well as the effects of the released metal ions on bone metabolism and the immune system in regard to their involvement in the pathophysiological mechanisms of aseptic loosening and metal hypersensitivity. Implant failure due to aseptic loosening is thought to occur in about 10-15% of cases. METHODS: A review of the literature (using PubMed with the search terms: biocorrosion, metal ions and bone metabolism) was performed. Additionally, we discuss our research results in the field of aseptic loosening. RESULTS: Despite a great effort in developing new implants, metal devices used in orthopaedic and trauma surgery remain prone to biocorrosion by several mechanisms including the direct corrosion by osteoclasts, leading to the production of significant amounts of wear particles and metal ions. In addition to the well documented increased osteolytic activity caused by large (in the nanometer range) wear particles, increasing evidence strongly suggests that the released metal ions contribute to the pathophysiological mechanism of aseptic loosening. Metal ions stimulate both the immune system and bone metabolism through a series of direct and indirect pathways leading to an increased osteolytic activity at the bone-implant interface. CONCLUSION: To date, revision surgery remains the only option for the treatment of a failed orthopaedic implant caused by aseptic loosening. A better understanding of the complex pathophysiological mechanisms (including the effects caused by the released metal ions) of aseptic loosening may have a significant potential in developing novel implants and therapies in order to reduce the incidence of this complication. PMID- 20714981 TI - [Is there a bone-preserving bone remodelling in short-stem prosthesis? DEXA analysis with the Nanos total hip arthroplasty]. AB - BACKGROUND: It has been suggested that the use of a short-stem prosthesis could conserve proximal bone by proximal load transfer. Proximal stress shielding should be reduced, a phenomenon that has been associated with bone resorption around traditional stems. Bone remodelling of a metaphyseal fixed stem (Nanos, Smith & Nephew Int.) was analysed by the dual-energy x-ray absorptiometry. PATIENTS AND METHOD: This study included 36 patients undergoing the total hip replacement using the Nanos short stem in comparison to 36 patients operated by a traditional long-stemmed femoral stem (Alloclassic). In all cases a threaded cup was inserted. Both groups were not different in regard to the BMI or in regard to the quality of bone (BMI). The average age of the group of patients with the short-stem prosthesis was slightly younger (average 54.2 years [range: 29 to 75]) than the patient group with the long-stem prosthesis (average 61.1 years [range: 39 to 71]). A prospective clinical analysis was done by the Harris hip score (HHS) and the Sutherland score to evaluate the social quality of life. With a minimum follow-up of 12 months in all cases, radiological changes in regard to stem subsidence, periprosthetic osteolysis or linear radiolucencies were analysed. The changes of periprosthetic bone density were examined with DEXA in all patients 3 and 12 months postoperatively. RESULTS: No patients required reoperation because of loosening or subsidence of the short-stem prosthesis. The HHS improved from a mean of 43.1 (range: 9 to 51) to 96.5 points (range: 79 to 100) in the short-stem group and to 91.3 points (range: 61 to 100) in the group of patients with long-stemmed femoral component. Radiographic follow-up revealed no evidence of component loosening or migration of the short-stem. Along the greater trochanter an osteolysis of the bone structure was found in two cases. A decrease of the proximal periprosthetic bone density (Gruen zone I, -6.4%) and in zone VII (-7.2%) were measured. An increase of the BMD in the lateral inferior region (Gruen zone II, +9.7%) superior to the polished tip of the short stem was observed over a period of one year after implantation. At the polished tip of the prosthesis a significant change of bone density in zone III (+1.03%) and in zone V (+0.7%) could not be observed. CONCLUSION: The desired proximal load transfer of a short-stemmed implant in the metaphyseal region of the proximal femur could not be reached with this device. On the basis of the excellent clinical results of the patients operated with the Nanos short-stem prosthesis we conclude that the component induces bone ingrowth in the lateral/distal region of the proximal femur. PMID- 20714982 TI - [Cementless femoral neck prosthesis CUT--clinical and radiological results after 5 years]. AB - AIM: With regard to total replacement of the hip, revision arthroplasty poses a challenge especially for younger patients. In spite of substantial improvements, new materials and operation techniques are still not able to prevent a shorter running life of prostheses in this group. The present work aims at evaluating clinical and radiological mid-term results of the femoral neck prosthesis CUT (ESKA Orthodynamics Lubeck) to answer the question of whether this implant is recommendable for younger patients. METHOD: Between 2001 and 2005 a consecutive series of 99 CUT prostheses was performed in 86 patients (50 female, 36 male) with a mean age of 50 (17-72) years and again evaluated clinically and radiologically after 5.4 (1.7-6.5) years. 84 cases were operated using a posterior approach and 15 cases were operated according to the anterolateral Watson-Jones approach. For clinical evaluation the Harris hip score and the visual analogue scale (VAS) for pain measurement were applied. Standard anteroposterior radiographs of the pelvis and lateral radiographs of the operated hip were compared to radiographs taken in the recovery room by two independent observers. Interobserver measurement discrepancy of the implant angle was 2.6 +/- 1.4 degrees. With 4 degrees being the maximum discrepancy, it was defined as the threshold of the normal range of 145 degrees (141-149 degrees). Additionally, the amount of femoral neck resection, the contact of the medial corticalis with the proximal stem, and the contact of the lateral corticalis with the distal part of the stem, periarticular ossifications and stable fixation by bone ingrowth according to Engh et al. were evaluated. Five delineated sections around the femoral component for evaluation of looseness or progressive loosening were used according to Gruen et al. Radiological evaluation of the cup was performed according to Charnley and DeLee. RESULTS: The survival rate according to Kaplan Meier was 98 % after on average 6.6 years. The Harris hip score significantly improved from 50 (16-83) points preoperatively to 98 (40-100) points at the time of follow-up (p < or = 0.05). 82 % achieved an excellent result (91-100 points), 10% a good (91-90 points), 4% had a moderate (71-80 points) and 4% had a bad (< 70 points) result. Six prostheses had to be revised. One of them had to be changed to a cementless standard stem after 5 years because of aseptic loosening. Another one had to be revised after 2.7 years because of chronic thigh pain. Two painful hips had a capsular revision. In one case the liner had to be changed and one case had an exchange of the femoral ball for a better femoral offset. The VAS revealed a significant reduction of pain in rest and under load (p < or = 0.05). 92% had a correct subcapital neck resection. The recommended implant angle of 145 degrees was seen in 72% while a valgus alignment in 18% and a varus alignment in 10% was measured. Undersizing of the CUT-prosthesis was seen in 27 cases. Nine of these cases developed a varus alignment. Osseous integration of the cup and stem was seen in 100% and in 95%, respectively. CONCLUSION: This study demonstrates the CUT prosthesis as a bone-preserving prosthesis with good functional and radiological results and therefore as an alternative joint replacement in younger patients. PMID- 20714983 TI - [Periprosthetic bone cement allocation at the femoral durom hip prosthesis. a pilot study: artificial bone models versus ex-vivo femura]. AB - INTRODUCTION: Despite controversial discussions, hip resurfacing at the moment seems to be the most bone-sparing surgical procedure of the femoral bone when implanting hip endoprostheses. Main risks are septic and aseptic loosening and necroses of the coxal end of the femoral bone mainly influenced by the periprosthetic allocation of bone cement. Because of a lack of radiation transparency of the hip resurfacing implant, this cement allocation cannot be sufficiently evaluated by common radiological procedures. A pilot study was conducted to describe and validate the macromechanical interdigitation of bone cement with spongy bone of anatomic specimens compared to artificial bone models and to evaluate whether artificial bones may be used for further interdigitation studies of different implantation techniques. METHODS: Plastic models of polyoxymethylene (POM) according to the inside geometry of the Metasul Durom hip prosthesis were implanted on ex vivo femora (n = 14) versus artificial bone models (n = 24) (Sawbones) of three different spongy densities (0.16; 0.20; 0.32 g/cm(3)) (each n = 8) in a clinically standardised surgical procedure and reproduced by highly resolving computed tomography. Afterwards a computer-based analysis of the cement allocation was accomplished. RESULTS: It could be shown that the Sawbones of the lower spongy densities (0.16 and 0.20 g/cm(3)) were similar to the ex vivo femora regarding the bone penetration of cement. No significant differences could be shown regarding interdigitation. According to our data, both groups of Sawbones may be used for further studies. PMID- 20714984 TI - [Perioperative morbidity in lumbar disc replacement]. AB - AIM: For several years now interbody fusion has been the gold standard procedure for treating degenerative disc disease. The problem of adjacent disc degeneration after interbody arthrodesis led to the development of non-fusion techniques. The device which best represents the philosophy of spine arthroplasty is the total lumbar disc replacement (TDR). An analysis of the perioperative morbidity of lumbar disc replacement was carried out in the current study. METHOD: 66 patients underwent lumbar disc replacement between 2001 and 2007. 78 protheses were implanted. Retrospectively patient-related variables (comorbidity, prior surgeries), perioperative blood loss, number and levels operated on, operation duration and technical and general complications were analysed. RESULTS: 54 patients had mono- and 12 patients bisegmental TDR. The mean operation time was 112 minutes with an average blood loss of 560 mL. Neither the type of comorbidity, prior surgery, operation duration, nor level operated on had an influence on the occurrence of perioperative morbidity. A significant influence could be shown for the number of levels operated on and the intraoperative blood loss. General complications were seen in 6 persons (9%) with urinary tract infection, technical complications occurred in 4 persons (6%) with severe blood loss (> 1500 mL) and erythrocyte/plasma substitution, 1 person (1.5%) with an injury of the iliac vein, 1 person (1.5%) with retrograde ejaculation and 1 person (1.5%) with dural tear and consecutive epidural infection. CONCLUSION: In our study the perioperative morbidity of lumbar disc replacement was similar to the data published so far and seems to be comparable with the perioperative morbidity of lumbar interbody fusion. PMID- 20714985 TI - [6 years after reformation of the specialty training reglementation--is there still room for improvement?]. AB - AIM: The specialty training reglementation in Germany is defined by a clear framework and aims regarding the obtainable specialty qualification. But its implementation is often difficult. The aim of the present study was to evaluate the demands of the new specialist qualification on the part of the trainers in Germany. METHOD: An e-mail questionnaire was distributed via the offices of DGU (German Society of Traumatology) and DGOOC (German Society of Orthopaedics and Orthopaedic Surgery) to 954 head physicians. Questions referred to abilities that are subject to concrete specialty training. Questions 1-3 referred to basic knowledge of the trained specialty. Questions 4 and 5 focused on self-reliant work, questions 6 and 7 touched aspects of conservative orthopaedics and multiple trauma management whereas questions 8-10 referred to the achieved surgical skills. RESULTS: 220 questionnaires were evaluated overall in a period of 6 weeks. 132 questionnaires were returned by the DGOOC and 88 by the DGU. Questions 1-3: basic knowledge regarding diagnostics and treatment of diseases and injuries of the musculoskeletal system as well as communication in adequate medical terminology were presumed by 97% and 85% respectively. 72% of the questioned trainers expected a brand new specialist to give a detailed and qualified description of an X-ray. Questions 4 and 5: 67% postulated that a brand new specialist should be capable of indicating a routine surgical intervention correctly. But only 30% expected a specialist to manage a consultation. Questions 6 and 7: the self-reliant conservative treatment of back pain patients was assumed by 60%, whereas the organisation of the medical care of multiple trauma patients is requested by 40%. Questions 8-10: referring to the surgical skills, 52% expected that one should handle the standard surgical approaches to the large extremity joints. Only 24% expected that after completing his training, a specialist can perform standard surgical procedures, which are required in the specialty training reglementation, without supervision. On the other hand they were expected to assist. CONCLUSION: Expectations of the head physicians concerning the skills of a new specialist did not match the expected skills defined in the specialty training reglementation regarding basic knowledge, self reliant work, surgical skills as well as conservative orthopaedics and multiple trauma management. A reasonable structuring is necessary in order to implement the requested contents of the specialty training reglementation. This can only be achieved if demands on aims are compliant. PMID- 20714986 TI - [Surgical therapy of distal biceps tendon ruptures]. AB - Ruptures of the distal biceps tendon are rare injuries which nearly exclusively occur in middle-aged men when eccentric load is applied to the flexed elbow. Operative treatment is supposed to be the most effective method to restore flexion and supination strength. However, there is a wide variety of potential surgical treatment methods. This article is aiming to present the anatomical, pathophysiological and epidemiological basics and to demonstrate the surgical techniques. Not only the approaches but also the differing fixation methods like bone tunnel fixation, endobutton- or suture anchor and interference screw are described in detail. Additionally, rehabilitation protocols and considerations concerning medical expertise are presented. PMID- 20714987 TI - [Osteolytic mass of the temporal bone]. PMID- 20714988 TI - [Unilateral degeneration of tissue of the tonsil in a patient with adeno carcinoma of the lung]. PMID- 20714989 TI - [Snoring by a bilateral protusion of the oro- and nasopharyngeal wall]. PMID- 20714990 TI - [A rare cause for supraclavicular lymph node metastases]. PMID- 20714991 TI - [Objective measurement of macular optical density]. AB - Determination of the optical density of the macular pigment may be used for an assessment of the efficacy of oral lutein supplementation in patients with dry AMD. Beside subjective methods like heterochrome flicker photometry, objective methods like the 2-wavelength auto-fluorescence method and the 1-wavelength reflection method are in clinical use today. Both methods show comparable results. For a long-term assessment of the efficacy of oral lutein supplementation, different parameters like mean and maximal optical density as well as the integral over optical density on all pixels ("volume") should be used. The parameter volume often increases also in cases in which other parameters do not change anymore. The 1-wavelength reflection method is used for the newly initiated LUTEGA study. This study will investigate the long-term effects of a fixed lutein/omega-3-fatty acid combination on the optical density in patients with dry AMD. PMID- 20714992 TI - [Corneal ulcers in systemic autoimmunologic diseases]. AB - BACKGROUND: Keratolysis is a rare severe complication following systemic autoimmunologic diseases. Despite of complex therapeutic treatments, the prognosis is very poor. PATIENTS: Ten eyes from seven patients with corneal ulcers were reported (age 45 - 73 years, mean 63 years; 6 women, 1 man). The corneal ulcer was perforated in 7 eyes. Five patients suffered from rheumatoid arthritis, and one patient developed a Sjogren's syndrome. Besides, one patient had shown both autoimmunologic diseases. After clinical attendance, visual acuity in the eyes with nonperforated ulcers was between 0.1 and 0.4, and in the eyes with perforated ulcers between light perception and 0.2. RESULTS: In 7 eyes with perforated corneal ulcers an emergency tectonic conjunctival plasty and, 1 - 2 days later, a keratoplasty had been performed. Postoperatively, local therapies had been initiated with antibiotic and immunosuppressive eyedrops as well as with conventional drops for dry-eye symptoms. Because of the autoimmunologic diseases of the patients, a systemic immunosuppressive therapy had been arranged. Follow up period had been between 4 weeks and 3,5 years (mean 16 months). In the three eyes with nonperforated ulcers which received an antibiotic and immunosuppressive treatment, visual acuity was found at 1 / 20 and 0.4. However, in spite of stabilized findings in the 5 eyes with perforated ulcers, the visual acuity was in this case only between light perception and 0.05. One patient with a perforated ulcer and one patient with a recurrent corneal perforation after keratoplasty refused further operative procedures. Finally, both eyes had to undergo evisceration. CONCLUSIONS: Despite of intensive local and systemic immunosuppressive as well as operative therapies, corneal ulcers associated with autoimmunologic diseases (rheumatoid arthritis, Sjogren's syndrome) may cause a marked decrease of visual acuity or the loss of an eye. With regard to the healthy eye, an immunosuppressive therapy for life is most important. PMID- 20714993 TI - [Slovenia's contribution to research in ophthalmology (1991 - 2009)]. AB - OBJECTIVE: The purpose of our study was to evaluate Slovenia's contribution to research in ophthalmology over a period of 18 years (1991 - 2009) including not only ophthalmologists but also other researchers. The aim of the study was to determine the relative contribution, quantitatively and qualitatively, to research in ophthalmology and to determine the trend over the period. The first authors as well as their institutes were evaluated. METHODS: A bibliometric analysis was performed using the database of the Institute for Scientific Information (ISI) 2007 report. All articles published in the top 45 ophthalmology journals listed in the ISI 2007 report were analysed. RESULTS: A total of 187 170 articles have been published in these journals in the given period of time. Slovenia's ophthalmologists and other researchers published 75 articles or 0.040 % of all publications. The articles were published in 21 of the 45 listed journals. Two were excluded from the study because they were only abstracts. In 8 articles the first author was not a Slovenian ophthalmologist. At the end, 65 articles remained in the study. 22 different Slovenian ophthalmologists were found as first author among these journals. Comparing ophthalmologists and other researchers, ophthalmologists produced 57 from 65 articles or 87.69 %. 13 from 22 ophthalmologists had published only one paper, accounting for 22.8 % (13 of 57) of total first authors. There were 47 articles with one or more co-authors (82.5 %) and 10 papers with a single author, which represent 17.5 % of total papers. There was only one first author who issued more than 10 articles (13 from 57 or 22.8 %). All the contribution came from two university clinical centres, Ljubljana (27 articles or 47.37 %) and Maribor (30 articles or 52.63 %). Three authors contributed to 45.6 % of all papers. Two-thirds of articles were published in English and one-third in German language. CONCLUSIONS: Although the number of articles published by Slovenia's ophthalmologists is increasing over the last 8 years there is a need to increase the quality and quantity of clinical research in ophthalmology and to involve more ophthalmologists in research work to support these trends. PMID- 20714994 TI - [Early manifestation of a pseudoexfoliation syndrom after a cornea transplantation]. PMID- 20714995 TI - AFLP markers for identification of Swertia species (Gentianaceae). AB - The genus Swertia is well known for its medicinal properties, as described in the Indian pharmacopoeia. Different members of this genus, although somewhat similar in morphology, differ widely in their pharmacological and therapeutic properties. The most important species of this genus, with maximal therapeutic properties, is S. chirayita, which is often adulterated with other less-potent Swertia spp. There is an existing demand in the herbal drug industry for an authentication system for Swertia spp, in order to enable their commercial use as genuine phytoceuticals. To this end, we used amplified fragment length polymorphism (AFLP) to produce DNA fingerprints for six Swertia species. Nineteen accessions (2 of S. chirayita, 3 of S. angustifolia, 2 of S. bimaculata, 5 of S. ciliata, 5 of S. cordata, and 2 of S. alata) were used in the study, which employed 64 AFLP selective primer pairs. Only 46 selective primer pairs were found to be useful for all the accessions. A total of 5312 fragments were produced by these 46 primer pairs. Species-specific markers were identified for all six Swertia species (131 for S. chirayita, 19 for S. angustifolia, 181 for S. bimaculata, 47 for S. ciliata, 94 for S. cordata, and 272 for S. alata). These AFLP fingerprints of the Swertia species could be used to authenticate drugs made with Swertia spp and to resolve adulteration-related problems faced by the commercial users of these herbs. PMID- 20714996 TI - Different responses to doxorubicin-induced chromosome aberrations in Brazilian deer species. AB - The tendency toward chromosome fragility is one of the theories that may explain chromosome variation in brocket deer species (genus Mazama). We tested doxorubicin as an inducer of chromosome aberrations in lymphocytes of three brocket deer species, Mazama gouazoubira, M. americana and M. nana, compared to the marsh deer, Blastocerus dichotomus. Doxorubicin, at a concentration of 0.25 microg/mL, induced chromosome aberrations and fragile sites in all four species; the highest frequencies were seen in M. gouazoubira; they were lowest in B. dichotomus and intermediate in M. americana and M. nana. These results were expected based on previous karyotypic studies, but they failed to explain the higher sensitivity seen in M. gouazoubira. This may be because not all the aberrations and fragile sites are related to chromosome evolution in brocket deer; other factors, such as environmental influences, may be involved in chromosome fragility. PMID- 20714997 TI - Genetic relationships among and within wild and cultivated olives based on RAPDs. AB - We examined genetic relationships among wild and cultivated olives, which is a very important crop in the economy of the Aegean region. We used RAPD analysis to evaluate relationships among and within 22 olive subspecies from Manisa, Mugla and Izmir provinces in Turkey. Twelve of the subspecies were wild and 10 were cultivated olives. Fifty-two primers were used (OP-Q 1-20, OP-I 1-20, OP-F 14-15 16-17, and OP-K 1-8) and 49 polymorphic bands were selected and used for analysis. The dendrogram based on unweighted pair-group cluster analysis using the Sorensen-Dice coefficient of similarity index indicated two major groups, dividing wild olives from cultivated olives. The patterns of genetic relationships among and within the different olives were analyzed by means of analysis of molecular variance. We found significant differences between wild and cultivated olives (Phi(st) = 0.1507; P < 0.001). In order to determine the genetic relationship among wild and cultivated olives, principal coordinate analysis was used to examine the variation among subspecies. The wild and cultivated olives formed two main groups, one on the right side and the other on the left side of the principal coordinates graph, respectively. This was compatible with the results we obtained from analysis of molecular variance. PMID- 20714998 TI - RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells. AB - Up-regulated gene 4 (URG4), stimulated by HBxAg, is a novel gene located on chromosome 7 (7p13). The full-length URG4 clone is 3.607 kb and encodes a polypeptide of 922 amino acids, with a molecular weight of 104 kDa (GeneID: 55665). It promotes cell growth, growth factor-independent survival, and anchorage-independent growth in HepG2 cells, and it accelerates tumor formation in nude mice. Hence, URG4 may be a natural effector of HBxAg and a putative oncogene that contributes to multi-step hepatocarcinogenesis. Cyclin D1 is frequently over-expressed in hepatocellular carcinoma, exhibiting a number of malignant phenotypes. We found that down-regulation of URG4 through RNA interference-mediated silencing suppressed cell proliferation in HepG2 cells. Over-expression of URG4 up-regulated cyclin D1 mRNA expression, whereas RNA interference-mediated URG4 silencing diminished cyclin D1 mRNA expression in HepG2 cells. The data suggest that URG4 may play an important role in the development of hepatocellular carcinoma by partially regulating the expression of cyclin D1 and has potential for use as a therapeutic target for hepatocellular carcinoma. PMID- 20714999 TI - Genetic diversity of eggplant (Solanum melongena) germplasm from Turkey assessed by SSR and RAPD markers. AB - Eggplant is a major crop in Turkey, which produces more of this crop than all of Europe; consequently, germplasm resources are of concern for the country. Molecular characterization of eggplant genotypes collected from different geographical regions of Turkey was carried out using SSR and RAPD markers. With amplification of five SSR loci, the number of alleles per microsatellite locus ranged from 2 to 10, with a total of 24 alleles. The greatest number of alleles was found at the emf21H22 locus (10 alleles); followed by emh11O01 and emf21C11 as five and four alleles, respectively. The average number of alleles per locus was 4.8. Using 11 decamer RAPD primers, 100 bands were amplified, among which 29 were polymorphic. The number of bands per primer ranged from seven (OPH10, OPH19, OPH20, OPH03) to 14 (OPB07). Primer OPB07 was the most polymorphic, generating 64% polymorphic bands; the rest of the primers gave less than 50% polymorphism. UPGMA dendrograms were used to examine the genetic relatedness of the genotypes. PMID- 20715000 TI - Tetraploidization in Wilms tumor in an infant. AB - Genetic instability is frequent in human cancer. Unscheduled tetraploidization can trigger cell transformation and tumorigenesis. We made a cytogenetic analysis by Giemsa-trypsin banding of a stage I, biphasic Wilms tumor diagnosed in a 10 month-old male. An evident karyotypic heterogeneity was found. Four different subclones of tumor cells were observed, with DNA content varying from diploid to near-tetraploid complements. The genetic events involved in the acquisition of aneuploidy in Wilms tumor remain unclear. We hypothesize that initial tetraploidization caused aberrant cell division, leading to abnormal chromosomal segregation, cell transformation and tumorigenesis. PMID- 20715001 TI - [Thrombocytopenia]. PMID- 20715003 TI - [Body weight related data: results of the 2007 Swiss Health Survey]. AB - The 2007 Swiss Health Survey is the fourth survey conducted on a random sample of nearly 19,000 adults, living in Switzerland. 37% are overweight or obese, but between 2002 and 2007 no increases in the prevalence of overweight and obesity were observed anymore. Overweight and obesity are associated with a number of socio-demographic and life-style factors. 9% of 15 to 34 years old women are underweight. Of the group of 15 to 49 years old men and women, 52% would like to change their body weight (to loose weight 87%, to gain weight 13%). 20% of them eat very irregularly and binge eating happens to 22%. In summary, life-style modifications are needed in relation to overweight, underweight and eating disorders. PMID- 20715004 TI - [Comment on rule of thumb 10. "A small pneumothorax less than 2 fingers wide will recover without drainage"]. PMID- 20715005 TI - [Craniopharyngioma--a "geographical malignant" tumour]. AB - The craniopharyngioma is a rare dysontogenetic tumour that originates from either scattered cells of the craniopharyngeal duct or from metaplastically mutated anterior pituitary parenchyma cells. Despite being classified as a WHO-Class-I tumour, the histologically benign craniopharyngioma may display an aggressive behaviour. Like other congenital tumours, it usually becomes manifest within the first two decades of life. Patients typically complain of headache and a chiasma syndrome with bitemporal hemianopsy may develop depending on tumour localisation. In children, anterior pituitary insufficiency often manifests as growth restriction. Additionally, diabetes insipidus and other hormonal disturbances may develop. Therapeutically either radical total removal or subtotal resection in combination with postoperative radiation is recommended. In cystic tumors, stereotactic cyst drainage and adjuvant radiation may be a possible alternative. The prognosis is best in patients who are diagnosed early. PMID- 20715006 TI - [Acute cough in adults]. PMID- 20715007 TI - [Successful treatment of a venous ulcer in an unusual manner]. AB - Wound treatment is increasingly becoming the domain of specially trained medical personal. The flood of diverse wound treatments and bandaging techniques grows continuously. Studies which compare the effectiveness deliver such a variety of results that medical personal are starting to doubt trusted methods. The presented case study shows how a non-medical measure, in this case a change in the person administering the treatment, or in other words the interpersonal relationship aspect, can significantly contribute to wound healing. PMID- 20715008 TI - [Biofeedback therapy in a traumatised migrant with chronic pain]. AB - We report on a 40-year-old Kurdish patient, who was imprisoned for six years for political reasons. The patient suffers from post-traumatic stress disorder and comorbid chronic pain. For a better pain management the patient was treated initially using biofeedback therapy. The intervention showed good effects on pain. Medical history, diagnosis, treatment plan and course of therapy are described. PMID- 20715009 TI - [Not Available]. PMID- 20715010 TI - [Not Available]. PMID- 20715013 TI - [Physician art and literature puzzle]. PMID- 20715014 TI - [Physician art column. In the face of things]. PMID- 20715015 TI - Bioactivity of essential oils from leaves and bark of Laurelia sempervirens and Drimys winteri against Acyrthosiphon pisum. AB - BACKGROUND: The pea aphid, Acyrthosiphon pisum (Harris), is a cosmopolitan pest that attacks a wide range of legume crops and vectors important plant virus diseases. In this project, essential oils from the leaf (L) and bark (B) of Laurelia sempervirens (Ruiz & Pavon) Tul. (L) and Drimys winteri JR Forster & G Forster (D) were extracted, and their deterrent and insecticidal activities were tested under laboratory conditions. RESULTS: By use of GC-MS, safrole was found as the main constituent in LL and LB oils, while the main constituents were more diverse in DL and DB oils. In the deterrent bioassays with A. pisum under choice conditions, the four oils were active, with LL being the most active, followed by LB, DB and DL. The respective deterrence indices were 1.0, 0.89, 0.87 and 0.46 when aphids were exposed for 24 h to 4 uL mL(-1) . Although there was no aphid mortality when oils were sprayed on faba bean leaves before aphid infestation, there was 58 and 42% mortality when settled aphids were directly sprayed with 4.0 uL mL(-1) of LL and LB respectively; DB and DL oils caused <=18% mortality. In a third series, the essential oils of LL and LB caused 100% mortality when applied at a dose of 64 uL L(-1) air by fumigation to faba bean plants infested with A. pisum; at the same dose, DB and DL oils caused 68 and 63% mortality respectively. When fumigation was limited to 2 h, the respective LC(50) values for LL and LB oils were 10.6-14.3 uL L(-1) air and 9.8-13.2 uL L(-1) air. CONCLUSION: Because of their high deterrent and insecticidal activities, the essential oils from leaf and bark of L. sempervirens may be explored as potential natural aphicides. PMID- 20715016 TI - Effects of six selected orchard insecticides on Neoseiulus fallacis (Acari: Phytoseiidae) in the laboratory. AB - BACKGROUND: Neoseiulus fallacis (Garman) is a key predator of tetranychid mites in integrated pest management (IPM) programs across Canada. This study identified compounds that would be recommended for tier-II field evaluations in an IPM program. RESULTS: The overall egg mortality caused by the six insecticides was negligible as it extended from 0 to 12.1%. Imidacloprid was classified as toxic to adults. The label rate was 7.73-fold the LC(50). Thiamethoxam was classified as moderately toxic to adults, and its label rate was 2.87-fold the LC(50). Acetamiprid and spinosad were classified as marginally toxic, and their label rates were respectively 0.99- and 0.45-fold the LC(50) for adults. Thiacloprid and methoxyfenozide were virtually innocuous to adults. CONCLUSION: Methoxyfenozide was totally harmless to all stages of N. fallacis, and it would be included in IPM programs immediately. Acetamiprid, spinosad and thiacloprid had varying degrees of mild toxicity to at least one growth stage of the predator. Therefore, they were recommended for tier-II field testing according to their label claims. Imidacloprid and thiamethoxam were toxic to moderately toxic to adults and had significant adverse effects on fecundity. Therefore, they would be field evaluated only if alternatives were unavailable. PMID- 20715017 TI - Improving detection probabilities for pests in stored grain. AB - BACKGROUND: The presence of insects in stored grain is a significant problem for grain farmers, bulk grain handlers and distributors worldwide. Inspection of bulk grain commodities is essential to detect pests and thereby to reduce the risk of their presence in exported goods. It has been well documented that insect pests cluster in response to factors such as microclimatic conditions within bulk grain. Statistical sampling methodologies for grain, however, have typically considered pests and pathogens to be homogeneously distributed throughout grain commodities. In this paper, a sampling methodology is demonstrated that accounts for the heterogeneous distribution of insects in bulk grain. RESULTS: It is shown that failure to account for the heterogeneous distribution of pests may lead to overestimates of the capacity for a sampling programme to detect insects in bulk grain. The results indicate the importance of the proportion of grain that is infested in addition to the density of pests within the infested grain. It is also demonstrated that the probability of detecting pests in bulk grain increases as the number of subsamples increases, even when the total volume or mass of grain sampled remains constant. CONCLUSION: This study underlines the importance of considering an appropriate biological model when developing sampling methodologies for insect pests. Accounting for a heterogeneous distribution of pests leads to a considerable improvement in the detection of pests over traditional sampling models. PMID- 20715018 TI - Characterization of the horseweed (Conyza canadensis) transcriptome using GS-FLX 454 pyrosequencing and its application for expression analysis of candidate non target herbicide resistance genes. AB - BACKGROUND: The de novo transcriptome sequencing of a weedy plant using GS-FLX 454 technologies is reported. Horseweed (Conyza canadensis L.) was the first broadleaf weed to evolve glyphosate resistance in agriculture, and also is the most widely distributed glyphosate-resistant weed in the United States and the world. However, available sequence data for this species are scant. The transcriptomic sequence should be useful for gene discovery, and to help elucidate the non-target-based glyphosate resistance mechanism and the genomic basis of weediness. RESULTS: Sequencing experiments yielded 411 962 raw reads, an average read length of 233 bp and a total dataset of 95.8 Mb (NCBI accession number SRA010952). After trimming and quality control, 379 152 high-quality sequences were retained and assembled into contigs. The assembly resulted in 31 783 unique transcripts, including 16 102 contigs and 15 681 singletons. The average coverage depth for each contig and each nucleotide position was 22-fold and 12-fold respectively. A total of 16 306 unique sequences were annotated by searching a custom plant protein database. The utility of the transcriptome data was demonstrated by further exploration of ABC transporters, which were previously hypothesized to play a role in non-target glyphosate resistance. Real time RT-PCR primers were designed from the transcriptome data, which made it possible to assess expression patterns of 17 ABC transporters from resistant and susceptible horseweed accessions from Tennessee, with and without glyphosate treatment. CONCLUSION: These results show that GS-FLX 454 sequencing is a powerful and cost-effective platform for the development of functional genomic tools for a weed species. PMID- 20715019 TI - Application of plant growth regulators mitigates chlorotic foliar injury by the black pecan aphid (Hemiptera: Aphididae). AB - BACKGROUND: Black pecan aphid, Melanocallis caryaefoliae (Davis) (Hemiptera: Aphididae), feeding elicits localized chlorotic injury to pecan foliage [Carya illinoinensis (Wangenh.) K Koch] and apparent acceleration of leaf senescence and defoliation. The ability of certain plant growth regulators (PGRs) (forchlorfenuron, gibberellic acid and aviglycine) to prevent M. caryaefoliae from triggering pecan leaf chlorosis and senescence-like processes was evaluated on two dates in both 2006 and 2007. Treatments were applied to orchard foliage and used in laboratory leaf-disc bioassays to assess possible reduction in aphid elicited chlorosis and concomitant effects on aphid mortality and development. RESULTS: Foliage pretreated with forchlorfenuron + gibberellic acid prior to being challenged with aphids resulted in significantly less aphid-elicited chlorosis than did control or aviglycine-treated leaf discs. No PGR affected aphid mortality; however, development time was increased by forchlorfenuron + gibberellic acid in 2006 and by aviglycine + gibberellic acid on one date in 2007. CONCLUSION: Certain PGRs possess the potential for usage on pecan to protect foliar canopies from M. caryaefoliae via changes in the susceptibility of the host leaf to senescence-like factors being introduced by feeding aphids. This protective effect on host foliage and the associated suppressive effect on development of feeding aphids might also be relevant to pest management programs on other aphid-crop systems in which aphid-elicited chlorosis and senescence-like processes can limit profitability. PMID- 20715020 TI - Prospective evaluation of a cognitive vulnerability-stress model for depression: the interaction of schema self-structures and negative life events. AB - This study tested the diathesis-stress component of Beck's (1967) cognitive theory of depression. Initially, participants completed measures assessing cognitive organization of the self-schema and depressive symptoms. One year later, participants completed measures assessing cognitive organization of the self-schema, depressive symptoms, and negative life events. Hierarchical multiple regression analyses, controlling for initial depression, indicated that more tightly interconnected negative content was associated with greater elevations in depressive symptoms following the occurrence of life events. More diffusely interconnected positive content for interpersonal self-referent information also interacted with life events to predict depressive symptoms. Cognitive organization dimensions showed moderate to high stability across the follow-up, suggesting that they may be trait-like vulnerability factors. Implications for the cognitive vulnerability-stress model of depression are discussed. PMID- 20715021 TI - A comparison of the millon behavioral medical diagnostic and millon behavioral health inventory with medical populations. AB - There is a lack of normative data on broadband omnibus types of personality tests with medical populations. In fact, the only two tests normed on medical populations are the Millon Behavioral Medicine Diagnostic (MBMD) and the Millon Behavioral Health Inventory (MBHI). The internal consistency, test-retest reliabilities, and validity studies of these instruments are reviewed and compared in an effort to aid clinicians in discerning their relative psychometric strengths and weaknesses. Due to the lack of validity studies with the MBMD and the fact that reliability limits the ceiling of validity coefficients, the MBMD has yet to meet the challenges it was designed to meet. Implications for practice are addressed. PMID- 20715022 TI - The clinical utility of a brief measure of perceived burdensomeness and thwarted belongingness for the detection of suicidal military personnel. AB - Perceived burdensomeness (PB) and thwarted belongingness (TB) are important indicators of suicide risk; however, limited research has investigated applicability to military populations, and no efforts have been initiated to translate these constructs into easily implemented clinical tools. The current study examined the structure and validity of a brief self-report survey of PB and TB, the 10-item Interpersonal Needs Questionnaire (INQ-10), among a sample of 219 deployed military personnel. Factor analysis confirmed that PB and TB are distinct, and are correlated with psychiatric symptomatology. Receiver operating characteristic analyses indicated the most useful cutoff scores were PB=1 and TB=3.2. Both scales significantly improved the ability to rule-in and rule-out current suicide ideation among deployed service members. PMID- 20715023 TI - Reynolds adolescent depression scale-second edition: a reliable and useful instrument. AB - The authors conducted two studies to address issues of the dimensionality, scale reliability, and psychometric properties of scores on the Reynolds Adolescent Depression Scale-Second Edition (RADS-2; Reynolds, 2002) in samples of adolescent psychiatric inpatients. In Study 1 (N=262), they used bifactor analysis to further evaluate the general and specific components of the RADS-2. In Study 2 (N=196), they used confirmatory factor analysis to evaluate the fit of a 1-factor model, the original 4-factor model, a second-order model, and a bifactor model to a new sample data. In both studies, the total RADS-2 and content-specific subscale scores showed acceptable estimates of reliability (i.e., scale reliability estimates >.80). Estimates of concurrent validity were also examined. Scores of the RADS-2 total and content-specific subscale scores were useful in differentiating between the responses of youth with mood disorder diagnoses and those with other primary psychiatric disorder diagnoses. The authors also conducted correlation analyses to identify potential correlates for the total RADS-2 scale and the proposed subscale scores. PMID- 20715024 TI - Laboratory evolution of stereoselective enzymes: a prolific source of catalysts for asymmetric reactions. AB - Asymmetric catalysis plays a key role in modern synthetic organic chemistry, with synthetic catalysts and enzymes being the two available options. During the latter part of the last century the use of enzymes in organic chemistry and biotechnology experienced a period of rapid growth. However, these biocatalysts have traditionally suffered from several limitations, including in many cases limited substrate scope, poor enantioselectivity, insufficient stability, and sometimes product inhibition. During the last 15 years, the genetic technique of directed evolution has been developed to such an extent that all of these long standing problems can be addressed and solved. It is based on repeated cycles of gene mutagenesis, expression, and screening (or selection). This Review focuses on the directed evolution of enantioselective enzymes, which constitutes a fundamentally new approach to asymmetric catalysis. Emphasis is placed on the development of methods to make laboratory evolution faster and more efficient, thus providing chemists and biotechnologists with a rich and non-ending source of robust and selective catalysts for a variety of useful applications. PMID- 20715025 TI - Metal triflimidates: better than metal triflates as catalysts in organic synthesis--the effect of a highly delocalized counteranion. AB - The continuously increasing need for novel and selective methods in organic synthesis to aid drug discovery and to address environmental concerns is a constant source of stimulation to develop novel and more efficient reaction systems. This has often resulted in a focus on transition metals, ligands, and additives, with much less attention paid to the counterion(s) of the metal cation. Recently, metal salts with one or more triflimidate counterion(s) have appeared as a unique class of catalysts that display outstanding sigma- and pi Lewis acid character. The highly delocalized nature of the triflimidate counterion, combined with its high steric hindrance results in virtually no nucleophilic behavior and an extremely high positive charge density on the metal cation, thus enhancing its Lewis acid character. Consequently, these metal triflimidates often outperform their metal halide or triflate analogues. This Review describes general methods for the preparation of metal triflimidate salts and their use as catalysts. PMID- 20715026 TI - Biotemplating of metal carbide microstructures: the magnetic leaf. PMID- 20715027 TI - A cleavable linker based on the levulinoyl ester for activity-based protein profiling. PMID- 20715028 TI - NMR-based protein potentials. PMID- 20715029 TI - Monodisperse gold-copper bimetallic nanocubes: facile one-step synthesis with controllable size and composition. PMID- 20715030 TI - An unexpected example of protein-templated click chemistry. PMID- 20715031 TI - Self-division of macroscopic droplets: partitioning of nanosized cargo into nanoscale micelles. PMID- 20715032 TI - Chiral mixed secondary phosphine-oxide-phosphines: high-performing and easily accessible ligands for asymmetric hydrogenation. PMID- 20715033 TI - Radiosynthesis and evaluation of [18F]Selectfluor bis(triflate). PMID- 20715034 TI - A nanoscale jigsaw-puzzle approach to large pi-conjugated systems. PMID- 20715035 TI - Interaction of propionylated and butyrylated histone H3 lysine marks with Brd4 bromodomains. PMID- 20715036 TI - Dual-color imaging of sodium/calcium ion activities with two-photon fluorescent probes. PMID- 20715037 TI - Two-chain insulin from a single-chain branched depsipeptide precursor: the end of a long journey. PMID- 20715039 TI - Two robust porous metal-organic frameworks sustained by distinct catenation: selective gas sorption and single-crystal-to-single-crystal guest exchange. AB - Assembly of copper(I) halide with a new tripodal ligand, benzene-1,3,5-triyl triisonicotinate (BTTP4), afforded two porous metal-organic frameworks, [Cu(2)I(2)(BTTP4)]?2CH(3)CN (1.2CH(3)CN) and [CuBr(BTTP4)]?(CH(3)CN.CHCl(3).H(2)O) (2.solvents), which have been characterized by IR spectroscopy, thermogravimetry (TG), single-crystal, and powder X-ray diffraction (PXRD) methods. Compound 1 is a polycatenated 3D framework that consists of 2D (6,3) networks through inclined catenation, whereas 2 is a doubly interpenetrated 3D framework possessing the ThSi(2)-type (ths) (10,3)-b topology. Both frameworks contain 1D channels of effective sizes 9*12 and 10*10 A(2), which amounts to 43 and 40% space volume accessible for solvent molecules, respectively. The TG and variable-temperature PXRD studies indicated that the frameworks can be completely evacuated while retaining the permanent porosity, which was further verified by measurement of the desolvated complex [Cu(2)I(2)(BTTP4)] (1'). The subsequent guest-exchange study on the solvent-free framework revealed that various solvent molecules can be adsorbed through a single-crystal-to-single-crystal manner, thus giving rise to the guest-captured structures [Cu(2)I(2)(BTTP4)]?C(6)H(6) (1.benzene), [Cu(2)I(2)(BTTP4)]?2C(7)H(8) (1.2 toluene), and [Cu(2)I(2)(BTTP4)]?2C(8)H(10) (1.2 ethylbenzene). The gas adsorption investigation disclosed that two kinds of frameworks exhibited comparable CO(2) storage capacity (86-111 mL g(-1) at 1 atm) but nearly none for N(2) and H(2), thereby implying its separation ability of CO(2) over N(2) and H(2). The vapor-adsorption study revealed the preferential inclusion of aromatic guests over nonaromatic solvents by the empty framework, which is indicative of selectivity toward benzene over cyclohexane. PMID- 20715038 TI - Alkyl-alkyl Suzuki cross-coupling of unactivated secondary alkyl chlorides. PMID- 20715040 TI - What kind of "soft materials" can we design from molecular gels? AB - Since their discovery, over the years, molecular gels have been constantly drawing the attention of chemists from various scientific fields. Their structural softness together with the orderliness at the molecular level provides such molecules immense potential for the amplification of their properties. Using this chemistry, one can easily realize a macroscopic outcome from a molecular level modulation. This phenomenon is governed by the principle of supramolecular interactions that introduce a unique "reversibility" to the system. The new generation of gel chemistry is now tending more towards the development of new attractive functions to create smart materials for achieving outstanding response or unprecedented selectivity over a process. However, for the successful implementation of this mission, it is really essential to correlate gel functions with their structures. This focus review is an attempt to find such a correlation, which can motivate and stimulate this existing field towards precisely designing molecular gels for the desired functions. PMID- 20715041 TI - Selective P-P and P-O-P bond formations through copper-catalyzed aerobic oxidative dehydrogenative couplings of H-phosphonates. PMID- 20715042 TI - Unified internal architecture and surface barriers for molecular diffusion of microporous crystalline aluminophosphates. PMID- 20715044 TI - A solution-processed air-stable perylene diimide derivative for N-type organic thin film transistors. AB - For future all-soluble organic thin film transistor (OTFT) applications, a new soluble n-type air-stable perylene diimide derivative semiconductor material with (trifluoromethyl)benzyl groups (TC-PDI-F) is synthesized. The film is formed by spin-coating in air and optimized for OTFT fabrications. The transistor characteristics and air-stability of the TC-PDI-F OTFTs is measured to investigate the feasibility of using solution-processed TC-PDI-F for future OTFT applications. For all-solution OTFT process applications, the transistor characteristics are demonstrated by using TC-PDI-F as an n-type semiconductor material and liquid-phase-deposited SiO(2) (LPD-SiO(2) ) as a gate dielectric material. All processes (except material synthesis and electrode deposition) and electrical measurements are conducted in air. PMID- 20715043 TI - Hydrogen peroxide activated matrix metalloproteinase inhibitors: a prodrug approach. PMID- 20715045 TI - Light on molecular machines. PMID- 20715046 TI - Direct synthesis of ethanol from dimethyl ether and syngas over combined H Mordenite and Cu/ZnO catalysts. AB - Ethanol was directly synthesized from dimethyl ether (DME) and syngas with the combined H-Mordenite and Cu/ZnO catalysts that were separately loaded in a dual catalyst bed reactor. Methyl acetate (MA) was formed by DME carbonylation over the H-Mordenite catalyst. Thereafter, ethanol and methanol were produced by MA hydrogenation over the Cu/ZnO catalyst. With the reactant gas containing 1.0% DME, the optimized temperature for the reaction was at 493 K to reach 100% conversion. In the products, the yield of methanol and ethanol could reach 46.3% and 42.2%, respectively, with a small amount of MA, ethyl acetate, and CO(2). This process is environmentally friendly as the main byproduct methanol can be recycled to DME by a dehydration reaction. In contrast, for the physically mixed catalysts, the low conversion of DME and high selectivity of methanol were observed. PMID- 20715047 TI - The intrinsic kinetics and heats of reactions for cellulose pyrolysis and char formation. PMID- 20715048 TI - Highly regioselective synthesis of bis-aziridino[60]fullerene with sulfilimine. AB - In the course of our study of the development of a synthetic methodology for the aziridination of fullerenes, we recently reported the photochemical [2+1] cycloaddition reaction of nitrene onto C(60) generated from sulfilimine. Sulfilimines with an electron-donating group on the N atom are well known to undergo Michael-type reactions, followed by concomitant elimination of sulfide to afford the corresponding aziridines. In these reactions, sulfilimines act as a nucleophile to the electrophilic olefins. Furthermore, C(60) has characteristic features of a low LUMO level and electron-accepting properties. Therefore, it can be an electrophilic olefin. In this context, sulfilimines might react with C(60) to afford the corresponding aziridinofullerenes. We have studied the thermal reaction of (S,S)-diphenylsulfilimines with C(60) and regioselectively synthesized bis- and tris-aziridinated fullerenes. These structures were determined through spectroscopic analyses. Among these, the structure of bis aziridinated[60]fullerene, C(60)(NCH(3))(2), was determined using single-crystal X-ray analysis. Results show that the multi-aziridination occurs exclusively at the same six-membered ring of C(60) to afford one isomer of the bis-adduct and tris-adduct. PMID- 20715049 TI - Graphene field-effect transistors: electrochemical gating, interfacial capacitance, and biosensing applications. AB - Single-layer graphene has received much attention because of its unique two dimensional crystal structure and properties. In this review, we focus on the graphene devices in solution, and their properties that are relevant to chemical and biological applications. We will discuss their charge transport, controlled by electrochemical gates, interfacial and quantum capacitance, charged impurities, and surface potential distribution. The sensitive dependence of graphene charge transport on the surrounding environment points to their potential applications as ultrasensitive chemical sensors and biosensors. The interfacial and quantum capacitance studies are directly relevant to the on-going effort of creating graphene-based ultracapacitors for energy storage. PMID- 20715050 TI - Dipyrenylcarbazole derivatives for blue organic light-emitting diodes. PMID- 20715051 TI - Structural origins of pH-dependent chemical shifts in the B1 domain of protein G. AB - We report chemical shifts for H(N), N, and C' nuclei in the His-tagged B1 domain of protein G (GB1) over a range of pH values from pH 2.0 to 9.0, which fit well to standard pH-dependent equations. We also report a 1.2 A resolution crystal structure of GB1 at pH 3.0. Comparison of this crystal structure with published crystal structures at higher pHs provides details of the structural changes in GB1 associated with protonation of the carboxylate groups, in particular a conformational change in the C-terminus of the protein at low pH. An additional change described recently is not seen in the crystal structure because of crystal contacts. We show that the pH-dependent changes in chemical shifts can be almost entirely understood based on structural changes, thereby providing insight into the relationship between structure and chemical shift. In particular, we describe through-bond effects extending up to five bonds, affecting N and C' but not H(N); through-space effects of carboxylates, which fit well to a simple electric field model; and effects due to conformational change, which have a similar magnitude to many of the direct effects. Finally, we discuss cooperative effects, demonstrating a lack of cooperative unfolding in the helix, and the existence of a beta-sheet "iceberg" extending over three of the four strands. This study therefore extends the application of chemical shifts to understanding protein structure. PMID- 20715052 TI - Sop-GPU: accelerating biomolecular simulations in the centisecond timescale using graphics processors. AB - Theoretical exploration of fundamental biological processes involving the forced unraveling of multimeric proteins, the sliding motion in protein fibers and the mechanical deformation of biomolecular assemblies under physiological force loads is challenging even for distributed computing systems. Using a C(alpha)-based coarse-grained self organized polymer (SOP) model, we implemented the Langevin simulations of proteins on graphics processing units (SOP-GPU program). We assessed the computational performance of an end-to-end application of the program, where all the steps of the algorithm are running on a GPU, by profiling the simulation time and memory usage for a number of test systems. The ~90-fold computational speedup on a GPU, compared with an optimized central processing unit program, enabled us to follow the dynamics in the centisecond timescale, and to obtain the force-extension profiles using experimental pulling speeds (v(f) = 1-10 MUm/s) employed in atomic force microscopy and in optical tweezers-based dynamic force spectroscopy. We found that the mechanical molecular response critically depends on the conditions of force application and that the kinetics and pathways for unfolding change drastically even upon a modest 10-fold increase in v(f). This implies that, to resolve accurately the free energy landscape and to relate the results of single-molecule experiments in vitro and in silico, molecular simulations should be carried out under the experimentally relevant force loads. This can be accomplished in reasonable wall-clock time for biomolecules of size as large as 10(5) residues using the SOP-GPU package. PMID- 20715054 TI - A structural dissection of amino acid substitutions in helical transmembrane proteins. AB - The evolution of protein folds is under strong constraints from their surrounding environment. Although folding in water-soluble proteins is driven primarily by hydrophobic forces, the nature of the forces that determine the folding and stability of transmembrane proteins are still not fully understood. Furthermore, the chemically heterogeneous lipid bilayer has a non-uniform effect on protein structure. In this article, we attempt to get an insight into the nature of this effect by examining the impact of various types of local structure environment on amino acid substitution, based on alignments of high-resolution structures of polytopic helical transmembrane proteins combined with sequences of close homologs. Compared to globular proteins, burying amino acid sidechains, especially hydrophilic ones, led to a lower increase in conservation in both the lipid-water interface region and the hydrocarbon core region. This observation is due to surface residues in HTM proteins especially in the HC region being relatively highly conserved, suggesting higher evolutionary constraints from their specific interactions with the surrounding lipid molecules. Polar and small residues, particularly Pro and Gly, show a noticeable increase in conservation as they are positioned more towards the centre of the membrane, which is consistent with their recognized key roles in structural stability. In addition, the examination of hydrogen bonds in the membrane environment identified some exposed hydrophilic residues being better conserved when not hydrogen-bonded to other residues, supporting the importance of lipid-protein sidechain interactions. The conclusions presented in this study highlight the distinct features of substitution matrices that take into account the membrane environment, and their potential role in improving sequence-structure alignments of transmembrane proteins. PMID- 20715055 TI - Dissection of the conformational cycle of the multidrug/lipidA ABC exporter MsbA. AB - Recent crystal structures of the multidrug ATP-binding cassette (ABC) exporters Sav1866 from Staphylococcus aureus, MsbA from Escherichia coli, Vibrio cholera, and Salmonella typhimurium, and mouse ABCB1a suggest a common alternating access mechanism for export. However, the molecular framework underlying this mechanism is critically dependent on assumed conformational relationships between nonidentical crystal structures and therefore requires biochemical verification. The structures of homodimeric MsbA reveal a pair of glutamate residues (E208 and E208') in the intracellular domains of its two half-transporters, close to the nucleotide-binding domains (NBDs), which are in close proximity of each other in the outward-facing state but not in the inward-facing state. Using intermolecular cysteine crosslinking between E208C and E208C' in E. coli MsbA, we demonstrate that the NBDs dissociate in nucleotide-free conditions and come close on ATP binding and ADP.vanadate trapping. Interestingly, ADP alone separates the half transporters like a nucleotide-free state, presumably for the following catalytic cycle. Our data fill persistent gaps in current studies on the conformational dynamics of a variety of ABC exporters. Based on a single biochemical method, the findings describe a conformational cycle for a single ABC exporter at major checkpoints of the ATPase reaction under experimental conditions, where the exporter is transport active. PMID- 20715057 TI - Explicit solvent dynamics and energetics of HIV-1 protease flap opening and closing. AB - An accurate description of the conformational dynamics of the beta-hairpin flaps of HIV-1 protease is of central importance in elucidating the functional recognition of the enzyme by ligands. Using all-atom molecular dynamics simulations in explicit solvent, with a total of 461 trajectories of ~50 ns each, we report the closed, semiopen, open, and wide-open flap conformation of the free wild-type protease. The free energy of flap opening and closing from the semiopen state is 0.9 +/- 0.2 and 2.4 +/- 0.4 kcal/mol, respectively. The mean relaxation time of opening is ~8 ns, in good agreement with NMR data. The explicit solvent simulations quantitatively confirm the hypothesis that the semiopen state is the dominant population in the free protease whilst fast flap tip fluctuations lead frequently to an open state. More pronounced flap rearrangements lead to a rare wide-open state with the catalytic site completely exposed to the solvent. The structures of the different flap conformations provided herein are of general interest for improved drug design of HIV-1 protease, in particular, the wide-open conformation could be favored by the large Gag and GagPol polyprotein chains. Strategies that take into account multiple flap-gating mechanisms may lead to more effective inhibitors. PMID- 20715056 TI - Docking by structural similarity at protein-protein interfaces. AB - Rapid accumulation of experimental data on protein-protein complexes drives the paradigm shift in protein docking from "traditional," template free approaches to template based techniques. Homology docking algorithms based on sequence similarity between target and template complexes can account for up to 20% of known protein-protein interactions. When highly homologous templates for the target complex are not available, but the structure of the target monomers is known, docking by local structural alignment may provide an adequate solution. Such an algorithm was developed based on the structural comparison of monomers to cocrystallized interfaces. A library of the interfaces was generated from cocrystallized protein-protein complexes in PDB. The partial structure alignment algorithm was validated on the DOCKGROUND benchmark sets. The optimal performance of the partial (interface) structure alignment was achieved with the interface residues defined by 12 A distance across the interface. Overall, the partial structure alignment yielded more accurate models than the full structure alignment. Most templates identified by the partial structure alignment had low sequence identity to the target, which makes them hard to detect by sequence based methods. The results indicate that the structure alignment techniques provide a much needed addition to the docking arsenal, with the combined structure alignment and template free docking success rate significantly surpassing that of the free docking alone. PMID- 20715058 TI - Dependence of blood R2 relaxivity on CPMG echo-spacing at 2.35 and 7 T. AB - The transverse relaxation rate (R(2)) of fresh human blood has been investigated at high and ultrahigh field, to characterize the R(2) dependency on blood sample oxygenation, hematocrit, and Carr-Purcell Meiboom-Gill sequence inter-echo spacing. Data were fitted to chemical exchange and diffusion models to assess their performance at different field strengths. The diffusion model gave a slightly superior fit at both field strengths, but the difference is unlikely to be relevant for the signal to noise ratio achieved in most in vivo experiments. Fitted model parameters were similar to those found in literature. PMID- 20715059 TI - Temporal resolution and SNR requirements for accurate DCE-MRI data analysis using the AATH model. AB - Dynamic contrast-enhanced MRI has been used in conjunction with tracer kinetics modeling in a wide range of tissues for treatment monitoring, oncology drug development, and investigation of disease processes. Accurate measurement of model parameters relies on acquiring data with high temporal resolution and low noise, particularly for models with large numbers of free parameters, such as the adiabatic approximation to the tissue homogeneity model for separate measurements of blood flow and vessel permeability. In this simulation study, accuracy of the adiabatic approximation to the tissue homogeneity model was investigated, examining the effects of temporal resolution, noise levels, and error in the measured arterial input function. A temporal resolution of 1.5 s and high SNR (noise sd = 0.05) were found to ensure minimal bias (<5%) in all four model parameters (extraction fraction, blood flow, mean transit time, and extravascular extracellular volume), and the sampling interval can be relaxed to 6 s, if the transit time need not be measured accurately (bias becomes >10%). A 10% error in the measured height of the arterial input function first pass peak resulted in an error of at most 10% in each model parameter. PMID- 20715060 TI - The enemy within: an epigenetic role of retrotransposons in cancer initiation. AB - This article proposes that cancers can be initiated by retrotransposon (RTN) activation through changes in the transcriptional regulation of nearby genes. I first detail the hypothesis and then discuss the nature of physiological stress(es) in RTN activation; the role of DNA demethylation in the initiation and propagation of new RTN states; the connection between ageing and cancer incidence and the involvement of activated RTNs in the chromosomal aberrations that feature in cancer progression. The hypothesis neither replaces nor invalidates other theories of cancer, in particular the somatic mutation theory, but helps clarify and unify much of the hitherto poorly integrated, complex phenomenology of cancer. PMID- 20715061 TI - Funding the frontier--the Human Frontier Science Program. PMID- 20715062 TI - Organic semiconductor growth and morphology considerations for organic thin-film transistors. AB - Analogous to conventional inorganic semiconductors, the performance of organic semiconductors is directly related to their molecular packing, crystallinity, growth mode, and purity. In order to achieve the best possible performance, it is critical to understand how organic semiconductors nucleate and grow. Clever use of surface and dielectric modification chemistry can allow one to control the growth and morphology, which greatly influence the electrical properties of the organic transistor. In this Review, the nucleation and growth of organic semiconductors on dielectric surfaces is addressed. The first part of the Review concentrates on small-molecule organic semiconductors. The role of deposition conditions on film formation is described. The modification of the dielectric interface using polymers or self-assembled mono-layers and their effect on organic-semiconductor growth and performance is also discussed. The goal of this Review is primarily to discuss the thin-film formation of organic semiconducting species. The patterning of single crystals is discussed, while their nucleation and growth has been described elsewhere (see the Review by Liu et. al).([1]) The second part of the Review focuses on polymeric semiconductors. The dependence of physico-chemical properties, such as chain length (i.e., molecular weight) of the constituting macromolecule, and the influence of small molecular species on, e.g., melting temperature, as well as routes to induce order in such macromolecules, are described. PMID- 20715063 TI - n-Type organic semiconductors in organic electronics. AB - Organic semiconductors have been the subject of intensive academic and commercial interest over the past two decades, and successful commercial devices incorporating them are slowly beginning to enter the market. Much of the focus has been on the development of hole transporting, or p-type, semiconductors that have seen a dramatic rise in performance over the last decade. Much less attention has been devoted to electron transporting, or so called n-type, materials, and in this paper we focus upon recent developments in several classes of n-type materials and the design guidelines used to develop them. PMID- 20715064 TI - Stable efficient solid-state white-light-emitting phosphor with a high scotopic/photopic ratio fabricated from fused CdSe-silica nanocomposites. PMID- 20715065 TI - Alkali metal doped organic molecules on insulators: charge impact on the optical properties. PMID- 20715066 TI - Three-dimensional carrier profiling of individual Si nanowires by scanning spreading resistance microscopy. PMID- 20715067 TI - Controlled in situ nanocavitation in polymeric materials. PMID- 20715068 TI - Cubic silsesquioxanes as a green, high-performance mold material for nanoimprint lithography. PMID- 20715069 TI - Electrically tunable optical switching of a Mott insulator-band insulator interface. PMID- 20715070 TI - Antireflection behavior of multidimensional nanostructures patterned using a conformable elastomeric phase mask in a single exposure step. PMID- 20715071 TI - Tetrakis(4-sulfonatophenyl)porphyrin-directed assembly of gold nanocrystals: tailoring the plasmon coupling through controllable gap distances. AB - It is known that universality and controllability over nanocrystal orientation must be accomplished to facilitate the potential applications of metal nanocrystals in the areas of photonics, electronics, and optics. The facile fabrication of linear chains of Au nanorods and bifurcated junctions of nanorods/nanospheres is achieved via the crosslinking of H-type tetrakis(4 sulfonatophenyl)porphyrin aggregates in solution. The tuning of the plasmon coupling between the Au nanocrystals is demonstrated by varying the porphyrin concentration and thus the interparticle gap distances. Finite-difference time domain calculations show that the red shift of the plasmon band exhibits a nearly exponential decay with increasing interparticle gap distances, thus giving rise to a "plasmon ruler equation." The gap distances determined according to this equation agree well with the experimental observations and further confirm the porphyrin-directed assembly process. The interaction mechanism between the Au nanorods and porphyrins is further investigated by a biological procedure using the dark-field light scattering technique. PMID- 20715072 TI - Layer-by-layer-assembled capsules and films for therapeutic delivery. AB - Polymeric materials formed via layer-by-layer (LbL) assembly have promise for use as drug delivery vehicles. These multilayered materials, both as capsules and thin fi lms, can encapsulate a high payload of toxic or sensitive drugs, and can be readily engineered and functionalized with specific properties. This review highlights important and recent studies that advance the use of LbL-assembled materials as therapeutic devices. It also seeks to identify areas that require additional investigation for future development of the field. A variety of drug loading methods and delivery routes are discussed. The biological barriers to successful delivery are identified, and possible solutions to these problems are discussed. Finally, state-of-the-art degradation and cargo release mechanisms are also presented. PMID- 20715073 TI - Transistors formed from a single lithography step using information encoded in topography. AB - This paper describes a strategy for the fabrication of functional electronic components (transistors, capacitors, resistors, conductors, and logic gates but not, at present, inductors) that combines a single layer of lithography with angle-dependent physical vapor deposition; this approach is named topographically encoded microlithography (abbreviated as TEMIL). This strategy extends the simple concept of 'shadow evaporation' to reduce the number and complexity of the steps required to produce isolated devices and arrays of devices, and eliminates the need for registration (the sequential stacking of patterns with correct alignment) entirely. The defining advantage of this strategy is that it extracts information from the 3D topography of features in photoresist, and combines this information with the 3D information from the angle-dependent deposition (the angle and orientation used for deposition from a collimated source of material), to create 'shadowed' and 'illuminated' regions on the underlying substrate. It also takes advantage of the ability of replica molding techniques to produce 3D topography in polymeric resists. A single layer of patterned resist can thus direct the fabrication of a nearly unlimited number of possible shapes, composed of layers of any materials that can be deposited by vapor deposition. The sequential deposition of various shapes (by changing orientation and material source) makes it possible to fabricate complex structures-including interconnected transistors-using a single layer of topography. The complexity of structures that can be fabricated using simple lithographic features distinguishes this procedure from other techniques based on shadow evaporation. PMID- 20715074 TI - Fabrication of carbon nanoscrolls from monolayer graphene. AB - A simple way of synthesizing carbon nanotube (CNT)/graphene (GN) nanoscroll core/shell nanostructures is demonstrated using molecular dynamics (MD) simulations. The simulations show that GN sheets can fully self-scroll onto CNTs when the CNT radius is larger than a threshold of about 10 A, forming a stable core/shell structure. Increasing the length of the GN sheet results in multilayered carbon nanoscroll (CNS) shells that exhibit a tubular structure similar to that of multiwall CNTs. The distances between the CNT and the GN wall or adjacent GN walls are about 3.4 A. It is found that the van der Waals force plays an important role in the formation of the CNT/GN nanoscroll core/shell composite nanostructures. However, the chirality of the CNT and the GN sheet does not affect the self-scrolling process, which thus provides a simple way of controlling the chirality and physical properties of the resulting core/shell structure. It is expected that this preparation method of CNT/GN nanoscroll core/shell composites will lead to further development of a broad new class of carbon/carbon core/shell composites with enhanced properties and even introduce new functionalities to composite materials. PMID- 20715075 TI - High-resolution, parallel patterning of nanoparticles via an ion-induced focusing mask. AB - An ion-induced focusing mask under the simultaneous injection of ions and charged aerosols generates invisible electrostatic lenses around each opening, through which charged nanoparticles are convergently guided without depositing on the mask surface. The sizes of the created features become significantly smaller than those of the mask openings due to the focusing capability. It is not only demonstrated that material-independent nanoparticles including proteins can be patterned as an ordered array on any surface regardless of the conductive, nonconductive, or flexible nature of the substrate, but also that the array density can be increased. Highly sensitive gas sensors based on these focused nanoparticle patterns are fabricated via the concept. PMID- 20715076 TI - A DNA-Origami chip platform for label-free SNP genotyping using toehold-mediated strand displacement. PMID- 20715077 TI - Rewritable and pH-sensitive micropatterns based on nanoparticle "inks". PMID- 20715078 TI - Hepatic transcription response to high-fat treatment in mice: microarray comparison of individual vs. pooled RNA samples. AB - Microarray analysis is an important tool in studying gene expression profiles in genomic research. Despite many concerns raised, mRNA samples are often pooled in microarray experiments to reduce the cost and complexity of analysis of transcript profiling. This study reports the results of microarray experiments designed to compare effects of pooling RNA samples and its impact on identifying profiles of mRNA transcripts and differentially expressed genes (DEGs) in the liver of C57BL/6J mice fed normal and high-fat diet. Pearson's correlation coefficient of transcripts between pooled and non-pooled RNA samples was 0.98 to 1.0. The impact of pooled vs. non-pooled RNA samples was also compared by number of transcripts or DEGs. Agreement of significant genes between pooled and non pooled sets was fairly desirable based on t-test <0.05 and/or signal intensity >= 2-fold. Biological process profile and the correlation coefficiency of fold change in the hepatic gene transcripts between pooled and non-pooled samples were also higher than 0.97. This suggests that pooling hepatic RNA samples can reflect the expression pattern of individual samples, and that properly constructed pools can provide nearly identical measures of transcription response to individual RNA sample. PMID- 20715079 TI - Linking obesity to colorectal cancer: application of nutrigenomics. AB - Diet is one of the most affective environmental factors in cancer development. Due to complicated nature of the diet, it has been very difficult to provide clear explanations for the role of dietary components in carcinogenesis. However, as high-throughput omics techniques became available, researchers are now able to analyze large sets of gene transcripts, proteins, and metabolites to identify molecules involved in disease development. Bioinformatics uses these data to perform network analyses and suggest possible interactions between metabolic processes and environmental factors. Obesity is known as one of the most closely related risk factors of colorectal cancer (CRC). Metabolic disturbances due to a positive energy balance may trigger and accelerate CRC development. In this review, we have summarized reports on genes, proteins and metabolites that are related to either obesity or CRC, and suggested candidate molecules linking obesity and CRC based on currently available literature. Possible application of bioinformatics for a large scale network analysis in studying cause-effect relationship between dietary components and CRC are suggested. PMID- 20715080 TI - Effective connectivity of the multiplication network: a functional MRI and multivariate Granger Causality Mapping study. AB - Developmental neuropsychology and functional neuroimaging evidence indicates that simple and complex mental calculation is subserved by a fronto-parietal network. However, the effective connectivity (connection direction and strength) among regions within the fronto-parietal network is still unexplored. Combining event related fMRI and multivariate Granger Causality Mapping (GCM), we administered a multiplication verification task to healthy participants asking them to solve single and double-digit multiplications. The goals of our study were first, to identify the effective connectivity of the multiplication network, and second, to compare the effective connectivity patterns between a low and a high arithmetical competence (AC) group. The manipulation of multiplication difficulty revealed a fronto-parietal network encompassing bilateral intraparietal sulcus (IPS), left pre-supplementary motor area (PreSMA), left precentral gyrus (PreCG), and right dorsolateral prefrontal cortex (DLPFC). The network was driven by an intraparietal IPS-IPS circuit hosting a representation of numerical quantity intertwined with a fronto-parietal DLPFC-IPS circuit engaged in temporary storage and updating of arithmetic operations. Both circuits received additional inputs from the PreCG and PreSMA playing more of a supportive role in mental calculation. The high AC group compared to the low AC group displayed a greater activation in the right IPS and based its calculation more on a feedback driven intraparietal IPS-IPS circuit, whereas the low competence group more on a feedback driven fronto-parietal DLPFC-IPS circuit. This study provides first evidence that multivariate GCM is a sensitive approach to investigate effective connectivity of mental processes involved in mental calculation and to compare group level performances for different populations. PMID- 20715082 TI - Inhibitory stimulation of the ventral premotor cortex temporarily interferes with musical beat rate preference. AB - Behavioral studies suggest that preference for a beat rate (tempo) in auditory sequences is tightly linked to the motor system. However, from a neuroscientific perspective the contribution of motor-related brain regions to tempo preference in the auditory domain remains unclear. A recent fMRI study (Kornysheva et al. [2010]: Hum Brain Mapp 31:48-64) revealed that the activity increase in the left ventral premotor cortex (PMv) is associated with the preference for a tempo of a musical rhythm. The activity increase correlated with how strongly the subjects preferred a tempo. Despite this evidence, it remains uncertain whether an interference with activity in the left PMv affects tempo preference strength. Consequently, we conducted an offline repetitive transcranial magnetic stimulation (rTMS) study, in which the cortical excitability in the left PMv was temporarily reduced. As hypothesized, 0.9 Hz rTMS over the left PMv temporarily affected individual tempo preference strength depending on the individual strength of tempo preference in the control session. Moreover, PMv stimulation temporarily interfered with the stability of individual tempo preference strength within and across sessions. These effects were specific to the preference for tempo in contrast to the preference for timbre, bound to the first half of the experiment following PMv stimulation and could not be explained by an impairment of tempo recognition. Our results corroborate preceding fMRI findings and suggest that activity in the left PMv is part of a network that affects the strength of beat rate preference. PMID- 20715081 TI - The effects of physical activity, education, and body mass index on the aging brain. AB - Normal human aging is accompanied by progressive brain tissue loss and cognitive decline; however, several factors are thought to influence brain aging. We applied tensor-based morphometry to high-resolution brain MRI scans to determine whether educational level or physical activity was associated with brain tissue volumes in the elderly, particularly in regions susceptible to age-related atrophy. We mapped the 3D profile of brain volume differences in 226 healthy elderly subjects (130F/96M; 77.9 +/- 3.6 SD years) from the Cardiovascular Health Study-Cognition Study. Statistical maps revealed the 3D profile of brain regions whose volumes were associated with educational level and physical activity (based on leisure-time energy expenditure). After controlling for age, sex, and physical activity, higher educational levels were associated with ~2-3% greater tissue volumes, on average, in the temporal lobe gray matter. After controlling for age, sex, and education, greater physical activity was associated with ~2-2.5% greater average tissue volumes in the white matter of the corona radiata extending into the parietal-occipital junction. Body mass index (BMI) was highly correlated with both education and physical activity, so we examined BMI as a contributing factor by including physical activity, education, and BMI in the same model; only BMI effects remained significant. This is one of the largest MRI studies of factors influencing structural brain aging, and BMI may be a key factor explaining the observed relationship between education, physical activity, and brain structure. Independent contributions to brain structure could not be teased apart as all these factors were highly correlated with one another. PMID- 20715083 TI - Strategic resource allocation in the human brain supports cognitive coordination of object and spatial working memory. AB - The ability to integrate different types of information (e.g., object identity and spatial orientation) and maintain or manipulate them concurrently in working memory (WM) facilitates the flow of ongoing tasks and is essential for normal human cognition. Research shows that object and spatial information is maintained and manipulated in WM via separate pathways in the brain (object/ventral versus spatial/dorsal). How does the human brain coordinate the activity of different specialized systems to conjoin different types of information? Here we used functional magnetic resonance imaging to investigate conjunction- versus single task manipulation of object (compute average color blend) and spatial (compute intermediate angle) information in WM. Object WM was associated with ventral (inferior frontal gyrus, occipital cortex), and spatial WM with dorsal (parietal cortex, superior frontal, and temporal sulci) regions. Conjoined object/spatial WM resulted in intermediate activity in these specialized areas, but greater activity in different prefrontal and parietal areas. Unique to our study, we found lower temporo-occipital activity and greater deactivation in temporal and medial prefrontal cortices for conjunction- versus single-tasks. Using structural equation modeling, we derived a conjunction-task connectivity model that comprises a frontoparietal network with a bidirectional DLPFC-VLPFC connection, and a direct parietal-extrastriate pathway. We suggest that these activation/deactivation patterns reflect efficient resource allocation throughout the brain and propose a new extended version of the biased competition model of WM. PMID- 20715084 TI - Emotion triggers executive attention: anterior cingulate cortex and amygdala responses to emotional words in a conflict task. AB - Coherent behavior depends on attentional control that detects and resolves conflict between opposing actions. The current functional magnetic resonance imaging study tested the hypothesis that emotion triggers attentional control to speed up conflict processing in particularly salient situations. Therefore, we presented emotionally negative and neutral words in a version of the flanker task. In response to conflict, we found activation of the dorsal anterior cingulate cortex (ACC) and of the amygdala for emotional stimuli. When emotion and conflict coincided, a region in the ventral ACC was activated, which resulted in faster conflict processing in reaction times. Emotion also increased functional connectivity between the ventral ACC and activation of the dorsal ACC and the amygdala in conflict trials. These data suggest that the ventral ACC integrates emotion and conflict and prioritizes the processing of conflict in emotional trials. This adaptive mechanism ensures rapid detection and resolution of conflict in potentially threatening situations signaled by emotional stimuli. PMID- 20715085 TI - Posttonsillectomy hemorrhage: blame on surgeons or genes? AB - OBJECTIVE: To investigate whether the insertion/deletion polymorphism ( 94ins/delATTG) in the promoter of NF kappa B1 is associated with the risk of bleeding after tonsillectomy. DESIGN AND SETTING: Retrospective study with genotyping performed from tonsillar tissue or blood. PATIENTS: One hundred forty eight patients having undergone tonsillectomy due to chronic tonsillitis, with or without posttonsillectomy hemorrhage. MEASUREMENTS AND RESULTS: DNA-extraction from paraffin-embedded tonsillectomy tissue or blood was followed by genotyping for the insertion/deletion (-94ins/delATTG) promoter NF kappa B1 polymorphism. Genotypes differed significantly between patients with (n = 56) and without (n = 92) posttonsillectomy hemorrhage, with the frequency of the homozygous deletion genotype carriers (DD) significantly increased in those with posttonsillectomy bleeding with an odds ratio (OR) for bleeding of 3.78 (95% confidence interval [CI] 1.2-11.7, P = .023) but not in homozygous (II) insertion and heterozygous (ID) genotype carriers (II/ID). Genotype distribution in patients was compatible with the Hardy Weinberg equilibrium. In contrast, there were no statistically significant differences between patients with or without posttonsillectomy hemorrhage with regard to demographic characteristics, different surgeons, postoperative medications like analgesics, antibiotics, anticoagulation therapy, or values of variables of pre- and postoperative coagulation studies. Likewise, these variables revealed no differences between genotypes. CONCLUSIONS: Carriers of the homozygous deletion allele were at an almost fourfold risk to develop posttonsillectomy hemorrhage compared to homozygous and heterozygous insertion allele carriers, independent of other risk factors. PMID- 20715086 TI - Endoscopic-assisted versus curettage adenoidectomy: a prospective, randomized, double-blind study with objective outcome measures. AB - OBJECTIVE: To establish whether there is both objectively and subjectively improved recovery in children receiving endoscopic-assisted adenoidectomy, compared with children receiving curettage adenoidectomy. STUDY DESIGN: Prospective, randomized, double-blinded study. METHODS: Thirty-eight patients who underwent adenoidectomy alone or in combination with tonsillectomy before the planned tympanomastoid surgery with an age range from 8 to 12 years were enrolled in the study. Children were prospectively and randomly assigned into two groups: the endoscopic-assisted adenoidectomy and the curettage adenoidectomy. The main subjective parameters were the nasopharyngoscopy and the symptom improvement scale, whereas the main objective parameter was the midsagittal reformatted images of the temporal bone computerized tomographies of patients who underwent adenoidectomy before the planned tympanomastoid surgery. To adequately compare the utility of one technique versus the other, blood loss and operative time were also reviewed. RESULTS: Evaluation of the temporal bone computerized tomographies of patients by adenoidal/nasopharyngeal ratios revealed a statistically significant difference with a mean ratio of 0.41 in the curettage and 0.30 in the endoscopic-assisted group. However, both groups had a significant improvement in the symptom improvement scale with no evidence for a significant difference between the endoscopic-assisted and curettage groups. CONCLUSIONS: Although, objective outcomes reveal that endoscopic-assisted adenoidectomy technique was superior to curettage adenoidectomy in reducing adenoidal size after surgery, subjectively no differences were noted between two methods. PMID- 20715087 TI - Posterior hyoid space as related to excision of the thyroglossal duct cyst. AB - OBJECTIVES/HYPOTHESIS: The anatomy of the anterior neck in the area of the hyoid, thyrohyoid membrane, and epiglottis is herein redescribed and compared to its classical depiction. The concept of the posterior hyoid space (PHS) is defined and substantiated through review of archived tissue and cadaver larynx dissection as well as by observation at many surgical dissections. The true anatomy of these relationships provides an insight into the effectiveness of the Sistrunk procedure. The author believes that recurrence of thyroglossal duct cysts (TGDC) occurs as a consequence of incomplete resection of: 1) microscopic suprahyoid ductules and/or 2) infra- and perihyoid tissue. STUDY DESIGN: The senior author has been using the concept of the posterior hyoid space as applied to the Sistrunk procedure for more than 20 years. A retrospective study was done on cases from April 2003 to August 2008, and outcome was reviewed and compared to historical controls to determine the impact of applying this anatomic concept. METHODS: A retrospective chart review was undertaken on 60 surgical cases performed for a 5-year period with clinical follow-up extended to an additional 7 months. Data collected included age at surgery, presenting symptoms, imaging characteristics, thyroid status, pathology results, and postoperative complications. All 60 were under the age of 18 who underwent a modified Sistrunk procedure and had a postoperative diagnosis of TGDC. Each patient had a minimum follow-up period of 4 months to check for recurrences. No revision was included in this study. RESULTS: Sixty patients met criteria for the study. There was one recurrence (1.67%); a complication rate of 6.67%. Complications were minor and wound related. Mean follow-up was 17 months. CONCLUSIONS: The technique of applying the concept of a PHS to ensure the complete resection of the middle third of the hyoid bone and offending tissues is believed to decrease recurrence of TGDC secondary to incomplete resection in the perihyoid area. PMID- 20715088 TI - Symptomatic maxillary sinus retention cysts: should they be removed? AB - OBJECTIVES/HYPOTHESIS: Recently, endoscopic sinus surgery (ESS) endoscopic sinus surgery (ESS) okay? has become the surgical procedure of choice for removing retention cysts from the maxillary sinus. The aim of our study was to determine the relationship between symptomatic relief and ESS with or without endoscopic excision of maxillary cysts. STUDY DESIGN: Prospective, randomized study. METHODS: Inclusion criteria were symptomatic maxillary cysts filling at least 50% of the sinus space. We conducted a prospective, randomized study comprising 80 patients. Of the patients, 41 underwent endoscopic ethmoidectomy, middle meatus antrostomy, and excision of the cysts (group A); and 39 underwent ethmoidectomy and antrostomy without cyst detachment (group B). During follow-up an attempt was made to correlate symptomatic failure with type of surgery, computed tomography (CT) score, cyst size, and ratio of cyst size/antral size. RESULTS: Symptomatic failure occurred in nine cases: four in the group A and five in group B. There was no relationship between success rates and type of surgery, CT score, cyst size, and ratio of cyst size/antral size. CONCLUSIONS: Endoscopic ethmoidectomy and middle meatus antrostomy without cyst detachment yielded similar outcomes with cyst extirpation through the antrostomy. Our treatment should be aimed in restoring ventilation and drainage of the dependent maxillary sinus. PMID- 20715089 TI - A computational study on the characteristics of airflow in bilateral abductor vocal fold immobility. AB - OBJECTIVES/HYPOTHESIS: To evaluate airway sufficiency and airflow dynamics in a group of patients who underwent a posterior transverse laser cordotomy (PTLC) procedure. STUDY DESIGN: Mixed methods research, university hospital setting. METHODS: Sixteen patients who underwent a PTLC procedure volunteered to be involved in this study. Dyspnea levels, voice, and glottic opening in indirect laryngoscopy were evaluated subjectively. The airway was evaluated objectively by pulmonary function tests, and glottic areas were measured from axial computed tomography (CT) images. The control group consisted of 63 subjects from the tomography archive. For computational fluid dynamics (CFD) analyses, two subjects from the study group were chosen on the basis of obstruction level, and a normal female subject was selected from the control group. Cartesian coordinates for airway boundaries were determined from axial CT images, and a three-dimensional computational model of the larynx was constructed. Flow simulations were performed with two different flow conditions during inspiration. Comparison of velocity, static pressure, turbulence intensity, and wall shear stress distribution values were made between selected cases and control. RESULTS: Pulmonary data varied widely and did not correlate with the size of the glottic area or dyspnea level. CFD analyses revealed that in addition to obstruction at the glottic level, aerodynamic properties of the larynx are altered due to loss in muscular tonus. Also, the contour of the glottic opening was found to be very important in determining the character of airflow as laminar or turbulent. CONCLUSIONS: Patients have considerable differences in their flow patterns and force distributions during respiration. Patient-specific models may help in evaluation and treatment planning. PMID- 20715090 TI - A prospective study of cardiovascular risk factors and incident hearing loss in men. AB - OBJECTIVES/HYPOTHESIS: Hearing loss is the most common sensory disorder in the United States, affecting more than 36 million people. Cardiovascular risk factors have been associated with the risk of hearing loss in cross-sectional studies, but prospective data are currently lacking. STUDY DESIGN: Prospective cohort study. METHODS: We prospectively evaluated the association between diagnosis of hypertension, diabetes mellitus, hypercholesterolemia, smoking, or body mass index (BMI) and incident hearing loss. Participants were 26,917 men in the Health Professionals Follow-up Study, aged 40 to 74 years at baseline in 1986. Study participants completed questionnaires about lifestyle and medical history every 2 years. Information on self-reported professionally diagnosed hearing loss and year of diagnosis was obtained from the 2004 questionnaire, and cases were defined as hearing loss diagnosed between 1986 and 2004. Multivariable-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression models. RESULTS: A total of 3,488 cases of hearing loss were identified. History of hypertension (HR 0.96; 95% confidence interval [CI], 0.88-1.03), diabetes mellitus (HR 0.92; 95% CI, 0.78-1.08), or obesity (HR 1.02; 95% CI, 0.90-1.15 for BMI >or=30 compared to normal range of 19-24.9) was not significantly associated with hearing-loss risk. Hypercholesterolemia (HR 1.10; 95% CI, 1.02-1.18) and past smoking history (HR 1.09; 95% CI, 1.01-1.17) were associated with a significantly increased risk of hearing loss after multivariate adjustment. CONCLUSIONS: A history of hypertension, diabetes mellitus, or obesity is not associated with increased risk of hearing loss; a history of past smoking or hypercholesterolemia has a small but statistically significant association with increased risk of hearing loss in adult males. PMID- 20715092 TI - Use of acoustic Doppler sonography to ascertain the feasibility of the pedicled nasoseptal flap after prior bilateral sphenoidotomy. AB - OBJECTIVES/HYPOTHESIS: Blood supply to the Hadad-Bassagasteguy pedicled nasoseptal flap may be interrupted by surgery of the pterygopalatine fossa, posterior septectomy, or large sphenoidotomies. This would preclude its use for reconstruction of skull base defects after expanded endonasal approaches (EEA). We present a novel method to ascertain the patency of the nasoseptal artery after prior surgery, and consequently the availability of the nasoseptal flap, using acoustic Doppler sonography. STUDY DESIGN: Retrospective clinical review. METHODS: Four patients who underwent EEAs were evaluated intraoperatively with acoustic Doppler sonography. The mucosa that covers the inferior aspect of the rostrum of the sphenoid sinus was scanned with the tip of the probe. Reflection of sound waves representing intravascular blood flow was assessed. RESULTS: In three patients, the artery was identified in at least one side. One remaining patient showed no acoustic signal suggesting loss of the nasoseptal artery bilaterally, therefore necessitating the use of a fat graft for the reconstruction. CONCLUSIONS: Acoustic Doppler sonography seems to be a feasible and effective way to ascertain the availability of the nasoseptal artery. It is a relatively inexpensive and simple technique that can be performed by any endoscopic surgeon. PMID- 20715091 TI - Role of tumor necrosis factor-alpha in wound repair in human vocal fold fibroblasts. AB - OBJECTIVES/HYPOTHESIS: Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine and apoptotic molecule that appears to be a mediator in inflammation and fibrosis. The objective of this investigation was to examine the effects of TNF alpha on 3D Carbylan-GSX in vitro cultured human vocal fold fibroblasts (hVFFs), to provide insight into the mechanism responsible for the improved vocal fold wound healing that has been previous reported with Carbylan-GSX treatment. STUDY DESIGN: In vitro cell culture. METHODS: hVFF were cultured in 3D Carbylan-GSX and on polystyrene with different dosages of TNF-alpha (0, 0.1, 1, 10, and 100 ng/mL) with and without 10% fetal bovine serum (FBS). hVFF response to TNF-alpha was characterized by morphology, proliferation rates, and gene transcript levels for matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 3 (TIMP3), collagen I, collagen III, fibronectin, and TNF-alpha receptor. RESULTS: In 3D Carbylan-GSX, TNF-alpha inhibited hVFF proliferation in a dose-dependent manner. TNF-alpha (0.1-100 ng/mL) was shown to significantly downregulate TIMP3 and extracellular matrix-related mRNA transcript levels for collagen III and fibronectin and to upregulate MMP1 and MMP2 expression, resulting in increased MMP/TIMP3 ratios. TNF-alpha receptor expression was significantly upregulated in Carbylan-GSX compared to control polystyrene. Responses were more marked in 10% FBS culture. CONCLUSIONS: After vocal fold injury, locally injected Carbylan-GSX can enhance the role of TNF alpha in remodeling the lamina propria layer of the vocal fold, accelerating wound healing. Carbylan-GSX has potential as a new therapeutic approach that may lead to better treatment of vocal fold wound healing. PMID- 20715093 TI - Inferior retrotympanum revisited: an endoscopic anatomic study. AB - OBJECTIVES/HYPOTHESIS: To describe the inferior retrotympanic anatomy from an endoscopic perspective. STUDY DESIGN: This was an anatomic study on a retrospective case series. METHODS: During November 2009 and December 2009, videos from endoscopic middle ear procedures carried out between June 2007 and November 2009 and stored in our database were retrospectively reviewed. Surgeries in which the inferior retrotympanic region was visualized were included in the study. Accurate descriptions of the anatomic findings were made for each ear included in the study group. RESULTS: The final study group consisted of 25 videos from 25 ear procedures. In 14/25 subjects, a bony ridge connecting the inferior portion of the styloid prominence to the anterior and inferior lip of the round window niche (Proctor's sustentaculum promontory) was identified and renamed the finiculus (from the Latin finis, -is: borderline), representing the ideal limit between the inferior retrotympanum and hypotympanum. In 14/25 patients, a complete sinus subtympanicus could be identified, lying between the subiculum and finiculus. CONCLUSIONS: Endoscopic exploration of the middle ear might guarantee a very good exposure of the inferior retrotympanum, allowing detailed anatomic descriptions of this hidden area. Improvement in our knowledge of its anatomy might decrease the possibility of residual disease during cholesteatoma surgery. PMID- 20715094 TI - Drug-induced autoimmune hepatitis caused by anti-tumor necrosis factor alpha agents. PMID- 20715095 TI - Glycolaldehyde-modified beta-lactoglobulin AGEs are unable to stimulate inflammatory signaling pathways in RAGE-expressing human cell lines. AB - SCOPE: Advanced glycation endproducts (AGEs) are suspected to stimulate inflammatory signaling pathways in target tissues via activation of the receptor for AGEs. Endotoxins are generally recognized as potential contamination of AGE preparations and stimulate biological actions that are very similar as or identical to those induced by AGEs. METHODS AND RESULTS: In our study, we used glycolaldehyde-modified beta-lactoglobulin preparations as model AGEs and employed two methods to remove endotoxin using either affinity columns or extraction with Triton X-114 (TX-114). Affinity column-purified AGEs retained their ability to stimulate inflammatory signaling as measured by mRNA expression of inflammatory cytokines in the human lung epithelial cell line Beas2b. However, glycolaldehyde-modified AGEs purified by extraction with TX-114 did not show any stimulation of mRNA expression of inflammatory cytokines. The presence of a cell stimulating endotoxin-like activity was demonstrated in the detergent phase after extraction with TX-114, thus indicating that not AGEs but a lipophilic contamination was responsible for the stimulation of inflammatory signaling. CONCLUSION: Our results demonstrate that glycolaldehyde-modified AGEs are unable to induce inflammatory signaling in receptor for AGE-expressing cells. The observed cell-activating activity can be ascribed to an endotoxin-like lipophilic contamination present in AGE preparations and affinity column purification was insufficient to remove this contamination. PMID- 20715096 TI - Dietary calcium decreases plasma cholesterol by down-regulation of intestinal Niemann-Pick C1 like 1 and microsomal triacylglycerol transport protein and up regulation of CYP7A1 and ABCG 5/8 in hamsters. AB - SCOPE: It has been shown that calcium supplementation favorably modifies plasma lipoprotein profile in postmenopausal women. The present study investigated the interaction of dietary calcium with genes of transporters, receptors and enzymes involved in cholesterol metabolism. METHODS AND RESULTS: Forty-eight ovariectomized hamsters were fed one of the four diets containing 0, 2, 6 and 8 g calcium per kg. Plasma total cholesterol (TC), triacylglycerols (TG), and non high density lipoprotein cholesterol were dose-dependently decreased, whereas high-density lipoprotein cholesterol (HDL-C) was dose-dependently increased with the increasing dietary calcium levels. Dietary calcium had no effect on protein mass of hepatic sterol regulatory element binding protein-2 (SREBP), liver X receptor-alpha (LXR), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), LDL receptor (LDLR) and cholesterol-7alpha-hydroxylase (CYP7A1). However, dietary calcium up-regulated the mRNA levels of hepatic CYP7A1 and intestinal ATP binding cassette transporters (ABCG5/8) whereas it down-regulated the intestinal Niemann Pick C1 like 1 (NPC1L1) and microsomal triacylglycerol transport protein (MTP). In addition, dietary calcium increased the activity of intestinal acyl coenzyme A: cholesterol acyltransferase 2, while it decreased plasma cholesteryl ester transport protein (CETP). CONCLUSION: Beneficial modification of lipoprotein profile by dietary calcium was mediated by sequestering bile acid absorption and enhancing excretion of fecal cholesterol, via up-regulation of mRNA CYP7A1 and intestinal ABCG 5/8 with down-regulation of mRNA NPC1L1 and MTP. PMID- 20715098 TI - An approach to evaluate the reliability of hybridization-based and sequencing based gene expression profiling technologies. AB - Hybridization-based and sequencing-based technologies have found a widespread application in gene expression profiling analysis but much ambiguity exists regarding their reliability. This study developed a framework based on three parameters: detection ability, repeatability, and accuracy to evaluate the reliability of gene expression profiling technologies. The fraction of coverage of detected transcript category, the degree of variance for the number of differentially expressed genes (DEGs), the consistency of DEG category, and suspected false discovery rate (sFDR) were first introduced as statistical indices. In order to validate the availability of these indices, based on the same RNA extract, the analysis was performed by comparing gene expression differences between wild-type and transgenic rice using deep sequencing and microarray. The results suggested that the parameters were available and showed advances in the determination of gene expression differences. Based on relative self-comparison design, suspected false positive genes were easily identified from all DEGs detected, which was difficult for quantitative real-time polymerase chain reaction (qRT-PCR) validation when the count of DEGs was enormous. In addition, sFDRs had advantages in the accuracy evaluation for previous datasets. PMID- 20715097 TI - Resveratrol (3,5,4'-trihydroxystilbene) protects pregnant mother and fetus from the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - SCOPE: The "fetal basis of adult disease" hypothesis proposes that prenatal exposure to environmental stress can lead to increased susceptibility to clinical disorders later in life. In utero exposure of fetus to 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) leads to alterations in T-cell differentiation in the thymus and increased susceptibility to autoimmune disease later in life. TCDD triggers toxicity through activation of aryl hydrocarbon receptor and severely affects maternal and fetal immune system during pregnancy. METHODS AND RESULTS: In this study, using a mouse model, we investigated if administration of resveratrol (RES; 3,5,4'-trihydroxystilbene) would inhibit immunotoxicity induced by TCDD during pregnancy in the mother and fetus. We observed that RES protected not only normal nonpregnant mice but also pregnant mothers and their fetuses from TCDD induced thymic atrophy, apoptosis, and alterations in the expression of T-cell receptor and costimulatory molecules as well as T-cell differentiation. In addition, there was significantly reduced expression of CYP1A1 in thymi of both the mother and the fetus when RES was used in vivo post-TCDD exposure. CONCLUSION: In conclusion, these studies demonstrate that consumption of RES, a natural plant product, during pregnancy, may afford protection to the mother and the fetus from the toxicity induced by environmental pollutants that mediate their effects through activation of aryl hydrocarbon receptor. PMID- 20715099 TI - Are abdominal prolegs serially homologous with the thoracic legs in Panorpidae (Insecta: Mecoptera)? Embryological evidence. AB - It is a long standing question whether the abdominal prolegs of holometabolous insect larvae are serially homologous with their thoracic legs. The histology and ultrastructure of proleg embryonic development in the scorpionfly Panorpa magna were studied using light and scanning electron microscopy. During the early embryonic development, paired primary abdominal appendages appeared laterally in line with the thoracic legs. Several hours later, a pair of proleg primordia arose along the midventral line on each of the first eight abdominal segments mesial to the primary abdominal appendages, which then ceased to grow and eventually degenerated into flat vestiges. Histological observation showed that the thoracic legs were obviously connected with lateral thoracic muscle cells, whereas the abdominal prolegs resembled secondary outgrowths. No apparent contact was observed between the lumen of abdominal prolegs and the hemocoel. After dorsal closure, each thoracic segment bore a pair of well-developed five-jointed legs, whereas the prolegs were unjointed, fleshy structure. The remnants of the primary abdominal appendages could still be clearly seen in the mature embryo. On the basis of the histological and morphological observation of the embryonic development, we confirm that the abdominal prolegs of Panorpidae lack the characters of the primary appendages; hence they are not serially homologous with the thoracic legs. The reasons why the primary abdominal legs are reduced in scorpionflies are briefly discussed. PMID- 20715100 TI - Limb development in the gekkonid lizard Gonatodes albogularis: A reconsideration of homology in the lizard carpus and tarsus. AB - Despite the attention squamate lizards have received in the study of digit and limb loss, little is known about limb morphogenesis in pentadactyl lizards. Recent developmental studies have provided a basis for understanding lizard autopodial element homology based on developmental and comparative anatomy. In addition, the composition and identity of some carpal and tarsal elements of lizard limbs, and reptiles in general, have been the theme of discussions about their homology compared to non-squamate Lepidosauromorpha and basal Amniota. The study of additional embryonic material from different lizard families may improve our understanding of squamate limb evolution. Here, we analyze limb morphogenesis in the gekkonid lizard Gonatodes albogularis describing patterns of chondrogenesis and ossification from early stages of embryonic development to hatchlings. Our results are in general agreement with previous developmental studies, but we also show that limb development in squamates probably involves more chondrogenic elements for carpal and tarsal morphogenesis, as previously recognized on the grounds of comparative anatomy. We provide evidence for the transitory presence of distal carpale 1 and intermedium in the carpus and tibiale, intermedium, distal centralia, and distal tarsale 2 in the tarsus. Hence, we demonstrate that some elements that were believed to be lost in squamate evolution are conserved as transitory elements during limb development. However, these elements do not represent just phylogenetic burden but may be important for the morphogenesis of the lizard autopodium. PMID- 20715101 TI - T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2. AB - The HER2 oncogene is frequently over-expressed in human cancers and a promising target for immune therapy. Previous studies have shown that over-expression of mouse or rat HER2 leads to markedly reduced levels of major histocompatibility complex (MHC) class I and molecules of the antigen processing and presentation machinery (APM), thus resulting in a phenotype promoting tumor escape from the immune system. Our study focuses on analyzing the effect of HER2 on MHC class I antigen presentation and sensitivity to tumor-antigen specific cytotoxic T lymphocytes (CTLs) in HLA-A2.1(+) melanoma cell lines. We demonstrate significant inverse correlations both between the expression of HER2 and total MHC class I surface expression as well as between HER2 and HLA-A2. A significant reduction of HLA-A2 levels was found when melanoma and carcinoma cell lines were transfected with a human HER2 gene. A signaling-competent HER2 molecule was crucial for the observed HLA-A2 down-regulation, as transfectants expressing high levels of HER2 mutated in the tyrosine signaling domain did not show altered HLA-A2 expression. Importantly, the human melanoma cell line EST049 demonstrated reduced HER2 and melanoma antigen-specific recognition by CTLs upon HER2 transfection. In addition, high expression of HER2 prevented both IFN-gamma mediated HLA-A2 up regulation and improved recognition by HLA-A2-restricted CTLs in treated cells. Moreover, key APM molecules were down-regulated by HER2. These findings implicate that HER2 over-expressing tumors may be more prone to escape from HLA-A2 restricted CTLs suggesting that immunotherapy approaches inducing an integrated humoral, cellular and innate immune response would be most effective. PMID- 20715102 TI - High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts. AB - Increasing evidence indicates that cancer development requires changes both in the precancerous cells and in their microenvironment. To study one aspect of the microenvironmental control, we departed from Michael Stoker's observation (Stroker et al, J Cell Sci 1966;1:297-310) that normal fibroblasts can inhibit the growth of admixed cancer cells (neighbour suppression). We have developed a high-throughput microscopy and image analysis system permitting the examination of live mixed cell cultures growing on 384-well plates, at the single cell level and over time. We have tested the effect of 107 samples of low passage number (<5) primary human fibroblasts from pediatric and adult donors, on the growth of six human tumor cell lines. Three of the lines were derived from prostate carcinomas, two from lung carcinomas and one was an EBV transformed lymphoblastoid line. Labeled tumor cells were grown in the presence of unlabeled fibroblasts. The majority of the tested fibroblasts inhibited the proliferation of the tumor cells, compared to the control cultures where labeled tumor cells were co-cultured with unlabeled tumor cells. The proliferation inhibiting effect of the fibroblasts differed depending on their site of origin and the age of the donor. Inhibition required direct cell contact. Mouse 3T3 fibroblasts inhibited the growth of SV40-transformed 3T3 cells and human tumor cells, showing that the inhibitory effect could prevail across the species barrier. Our high-throughput system allows the quantitative analysis of the inhibitory effect of fibroblasts on the population level and the exploration of differences depending on the source of the normal cells. PMID- 20715103 TI - The selective VEGFR1-3 inhibitor axitinib (AG-013736) shows antitumor activity in human neuroblastoma xenografts. AB - Tumor angiogenesis in childhood neuroblastoma is an important prognostic factor suggesting a potential role for antiangiogenic agents in the treatment of high risk disease. Within the KidsCancerKinome project, we evaluated the new oral selective pan-VEGFR tyrosine kinase inhibitor axitinib (AG-013736) against neuroblastoma cell lines and the subcutaneous and orthotopic xenograft model IGR N91 derived from a primary bone marrow metastasis. Axitinib reduced cell proliferation in a dose-dependent manner with IC(50) doses between 274 and >10,000 nmol/l. Oral treatment with 30 mg/kg BID for 2 weeks in advanced tumors yielded significant tumor growth delay, with a median time to reach five times initial tumor volume of 11.4 days compared to controls (p = 0.0006) and resulted in significant reduction in bioluminescence. Simultaneous inhibition of VEGFR downstream effector mTOR using rapamycin 20 mg/kg q2d*5 did not statistically enhance tumor growth delay compared to single agent activities. Axitinib downregulated VEGFR-2 phosphorylation resulting in significantly decreased microvessel density (MVD) and overall surface fraction of tumor vessels (OSFV) in all xenografts as measured by CD34 immunohistochemical staining (mean MVD +/- SD and OSFV at 14 days 21.27 +/- 10.03 in treated tumors vs. 48.79 +/- 17.27 in controls and 0.56% vs. 1.29%; p = 0.0006, respectively). We further explored the effects of axitinib on circulating mature endothelial cells (CECs) and endothelial progenitor cells (CEPs) measured by flow cytometry. While only transient modification was observed for CECs, CEP counts were significantly reduced during and up to 14 days after end of treatment. Axitinib has potent antiangiogenic properties that may warrant further evaluation in neuroblastoma. PMID- 20715104 TI - Pattern and clinical significance of cancer-testis gene expression in head and neck squamous cell carcinoma. AB - Cancer-testis (CT) antigens comprise families of tumor-associated antigens that are immunogenic in patients with various cancers. Their restricted expression makes them attractive targets for immunotherapy. The aim of this study was to determine the expression of several CT genes and evaluate their prognostic value in head and neck squamous cell carcinoma (HNSCC). The pattern and level of expression of 12 CT genes (MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, MAGE-C2, NY-ESO 1, LAGE-1, SSX-2, SSX-4, BAGE, GAGE-1/2, GAGE-3/4) and the tumor-associated antigen encoding genes PRAME, HERV-K-MEL, and NA-17A were evaluated by RT-PCR in a panel of 57 primary HNSCC. Over 80% of the tumors expressed at least 1 CT gene. Coexpression of three or more genes was detected in 59% of the patients. MAGE-A4 (60%), MAGE-A3 (51%), PRAME (49%) and HERV-K-MEL (42%) were the most frequently expressed genes. Overall, the pattern of expression of CT genes indicated a coordinate regulation; however there was no correlation between expression of MAGE-A3/A4 and BORIS, a gene whose product has been implicated in CT gene activation. The presence of MAGE-A and NY-ESO-1 proteins was verified by immunohistochemistry. Analysis of the correlation between mRNA expression of CT genes with clinico-pathological characteristics and clinical outcome revealed that patients with tumors positive for MAGE-A4 or multiple CT gene expression had a poorer overall survival. Furthermore, MAGE-A4 mRNA positivity was prognostic of poor outcome independent of clinical parameters. These findings indicate that expression of CT genes is associated with a more malignant phenotype and suggest their usefulness as prognostic markers in HNSCC. PMID- 20715105 TI - NADPH oxidase overexpression in human colon cancers and rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). AB - NADPH oxidase/dual-oxidase (Nox/Duox) family members have been implicated in nuclear factor kappa-B (NFkappaB)-mediated inflammation and inflammation associated pathologies. We sought to examine, for the first time, the role of Nox/Duox and NFkappaB in rats treated with the cooked meat heterocyclic amine carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In the PhIP induced colon tumors obtained after 1 year, Nox1, Nox4, NFkappaB-p50 and NFkappaB p65 were all highly overexpressed compared with their levels in adjacent normal looking colonic mucosa. Nox1 and Nox4 mRNA and protein levels also were markedly elevated in a panel of primary human colon cancers, compared with their matched controls. In HT29 human colon cancer cells, Nox1 knockdown induced G1 cell cycle arrest, whereas in Caco-2 cells there was a strong apoptotic response, with increased levels of cleaved caspase-3, -6, -7 and poly(ADP-ribose)polymerase. Nox1 knockdown blocked lipopolysaccharide-induced phosphorylation of IkappaB kinase, inhibited the nuclear translocation of NFkappaB (p50 and p65) proteins, and attenuated NFkappaB DNA binding activity. There was a corresponding reduction in the expression of downstream NFkappaB targets, such as MYC, CCND1 and IL1beta. The results provide the first evidence for a role of Nox1, Nox4 and NFkappaB in PhIP-induced colon carcinogenesis, including during the early stages before tumor onset. Collectively, the findings from this investigation and others suggest that further work is warranted on the role of Nox/Duox family members and NFkappaB in colon cancer development. PMID- 20715107 TI - Specific infiltration of langerin-positive dendritic cells in EBV-infected tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. AB - We report here the existence of a novel subset of langerin (CD207)-positive, immature dendritic cells (DCs) (CD83(neg) ) abundantly infiltrating Epstein Barr virus (EBV)-infected areas in tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. These CD207(+) DCs differ from conventional epidermal Langerhans cells in their lack of CD1a and CCR6 and their unusual tissue localization. CD207(+) DC infiltration strongly correlates with EBV infection because it was neither detected in EBV negative specimens nor in tissues infected with other human viruses. These immature DCs might represent good candidates for induction of the EBV-specific immune response. PMID- 20715108 TI - Dietary acrylamide intake and risk of esophageal cancer in a population-based case-control study in Sweden. AB - Acrylamide is a potential carcinogen, which commonly occurs in some food items. The relation between acrylamide and esophageal cancer deserves attention. In a Swedish nationwide, population-based case-control study, data were collected on diet among other variables in 1995-1997 through personal interviews. Included were 189 cases of esophageal adenocarcinoma (participation rate 88%), 262 cases of gastroesophageal junctional adenocarcinoma (84%), 167 cases of esophageal squamous cell carcinoma (73%), and 820 control participants (73%). Dietary intake of acrylamide exposure was assessed from a food-frequency questionnaire and categorized into quartiles based on the consumption among the control participants. Unconditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI), with multivariable adjustment for known risk factors. Among participants in the highest quartile of acrylamide exposure compared to the lowest, the adjusted risk of all esophageal tumors combined was increased (OR 1.23; 95% CI 1.02-1.75), particularly among overweight or obese persons (OR 1.88; 95% CI 1.06-3.34). Increased point risk estimates were found for each type of esophageal cancer, but the association with esophageal squamous cell carcinoma seemed stronger and was statistically significant, particularly among nonsmokers in the highest quartile of acrylamide exposure (adjusted OR 2.82; 95% CI 1.16-6.87). Regarding squamous cell carcinoma only, a dose-response association was identified (p for trend 0.01). Dietary intake of acrylamide might be a risk exposure for esophageal cancer, a stronger association among overweight or obese persons was indicated. PMID- 20715106 TI - Tumor infiltration by FcgammaRIII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma. AB - The prognostic significance of macrophage and natural killer (NK) cell infiltration in colorectal carcinoma (CRC) microenvironment is unclear. We investigated the CRC innate inflammatory infiltrate in over 1,600 CRC using two independent tissue microarrays and immunohistochemistry. Survival time was assessed using the Kaplan-Meier method and Cox proportional hazards regression analysis in a multivariable setting. Spearman's rank correlation tested the association between macrophage and lymphocyte infiltration. The Basel study included over 1,400 CRCs. The level of CD16+ cell infiltration correlated with that of CD3+ and CD8+ lymphocytes but not with NK cell infiltration. Patients with high CD16+ cell infiltration (score 2) survived longer than patients with low (score 1) infiltration (p = 0.008), while no survival difference between patients with score 1 or 2 for CD56+ (p = 0.264) or CD57+ cell (p = 0.583) infiltration was detected. CD16+ infiltrate was associated with improved survival even after adjusting for known prognostic factors including pT, pN, grade, vascular invasion, tumor growth and age [(p = 0.001: HR (95% CI) = 0.71 (0.6 0.9)]. These effects were independent from CD8+ lymphocyte infiltration [(p = 0.036: HR (95% CI) = 0.81 (0.7-0.9)] and presence of metastases [(p = 0.002: HR (95% CI) = 0.43 (0.3-0.7)]. Phenotypic studies identified CD16+ as CD45+CD33+CD11b+CD11c+ but CD64- HLA-DR-myeloid cells. Beneficial effects of CD16+ cell infiltration were independently validated by a study carried out at the University of Athens confirming that patients with CD16 score 2 survived longer than patients with score 1 CRCs (p = 0.011). Thus, CD16+ cell infiltration represents a novel favorable prognostic factor in CRC. PMID- 20715109 TI - The role of hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 in endometrial cancer. AB - Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) are Kunitz-type serine protease inhibitors that have a broad inhibitory spectrum against serine proteases. This is the first study to investigate the role of HAI-1 and HAI-2 in endometrial cancer. We investigated the biological functions of HAI-1 and HAI-2 using KLE and HEC-251 endometrial cancer cell lines, thus HAI-1 and HAI-2 were examined in uterine normal endometrium, endometrial hyperplasia and cancer specimens by immunohistochemistry. HAI-1 and HAI-2 showed potential inhibitory effects on cell proliferation, migration and cellular invasion by reduction of matriptase and hepsin expression. This in turn led to an increase in the levels of E-cadherin and Slug, and a reduction in the levels of Vimentin, SIP1, Snail and Twist, and hence ER and PR signal transduction in endometrial cancer cells. The levels of HAI-1 and HAI-2 expression were significantly decreased in endometrial cancer specimens relative to the corresponding normal endometrium specimens. Low HAI-1 and HAI-2 expression was a significant predictor for a poor prognosis compared with high HAI-1 and HAI-2 expression. These findings indicate that HAI-1 and HAI-2 could be considered as therapeutic targets and used as favorable prognosis markers for endometrial cancer. PMID- 20715110 TI - The B cell antigen receptor in atypical chronic lymphocytic leukemia with t(14;19)(q32;q13) demonstrates remarkable stereotypy. AB - The t(14;19)(q32;q13) is a recurrent chromosomal translocation reported in a variety of B-cell leukemias and lymphomas, including chronic lymphocytic leukemia (CLL). CLL cases associated with t(14;19) often have atypical morphologic and immunophenotypic features and unmutated immunoglobulin heavy chain (IGH) variable region (V) genes, associated with an aggressive clinical course. We analyzed IGHV somatic mutation status and gene use in 11 patients with t(14;19)-positive CLL. All cases were unmutated, and the IGHV genes in 10 cases showed minimal deviation from germline sequences. In 7 of 11 patients, we found homologous heavy chain rearrangements using IGHV4-39; light chain analysis revealed identical IGKV1-39 use. Corresponding V-(D)-J sequences demonstrated remarkable stereotypy of the immunoglobulin heavy and kappa light chain complementarity determining region 3 (H/K CDR3) genes. These findings raise the possibility that specific antigen drive is involved in the clonal development and/or selection of t(14;19)(q32;q13) positive CLL cells. Our findings support the hypothesis that stimulatory signals through specific antigen receptors may promote the expansion of either CLL precursor cells or CLL clones that harbor distinct chromosomal abnormalities. PMID- 20715111 TI - Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA-lesions. AB - Chronic alcohol consumption is a major risk factor for esophageal cancer. Various mechanisms may mediate carcinogenesis including the genotoxic effect of acetaldehyde and oxidative stress. Ethanol exerts its carcinogenic effect in the liver among others via the induction of cytochrome P450 2E1 (CYP2E1) and the generation of carcinogenic etheno-DNA adducts. Here we investigated if such effects can also be observed in the human esophagus. We studied nontumorous esophageal biopsies of 37 patients with upper aerodigestive tract cancer and alcohol consumption of 102.3 +/- 131.4 g/day (range: 15-600 g) as well as 16 controls without tumors (12 teetotalers and 4 subjects with a maximum of 25 g ethanol/day). CYP2E1, etheno-DNA adducts and Ki67 as a marker for cell proliferation were determined immunohistologically. Chronic alcohol ingestion resulted in a significant induction of CYP2E1 (p = 0.015) which correlated with the amount of alcohol consumed (r = 0.6, p < 0.001). Furthermore, a significant correlation between CYP2E1 and the generation of the carcinogenic exocyclic etheno-DNA adducts 1,N(6)-ethenodeoxyadenosine (r = 0.93, p < 0.001) and 3,N(4) ethenodeoxycytidine (r = 0.92, p < 0.001) was observed. Etheno-DNA adducts also correlated significantly with cell proliferation (p < 0.01), which was especially enhanced in patients who both drank and smoked (p < 0.001). Nonsmokers and nondrinkers had the lowest rate of cell proliferation, CYP2E1 expression and DNA lesions. Our data demonstrate for the first time an induction of CYP2E1 in the esophageal mucosa by ethanol in a dose dependent manner in man and may explain, at least in part, the generation of carcinogenic DNA lesions in this target organ. PMID- 20715112 TI - Transcriptional characteristics of familial non-BRCA1/BRCA2 breast tumors. AB - To better understand the alterations present in the group of the so-called BRCAX tumors, we have used a cDNA microarray containing genes related to tumorigenesis and analyzed a series of 49 tumors consisting of 13 BRCA1, 14 BRCAX and 22 sporadic. We have confirmed that the BRCAX tumors are heterogeneous and can be divided in at least two main subgroups, so-called A and B, transcriptionally distinguishable and with different altered pathways within each of the groups. We have found that BRCAX-A and B subgroups, can be classified as Luminal A and Luminal B, respectively, taking into account the intrinsic phenotypes defined for the sporadic breast tumors. We have found that, at the somatic level, the BRCAX-B tumors are identical to their sporadic Luminal B counterparts, whereas BRCAX-A, despite having a Luminal A phenotype, shows additional genomic alterations. We have found 21 deregulated genes in the BRCAX-A group that we have called "the BRCAX susceptibility pathway" and suggested it as a candidate to search for new genes involved in the inherited susceptibility underlying the disease in this group. PMID- 20715113 TI - Impact of platinum-based chemotherapy on circulating nucleic acid levels, protease activities in blood and disseminated tumor cells in bone marrow of ovarian cancer patients. AB - There is an unmet need for biomarkers for the prediction and monitoring of anticancer therapies. Here, we measured the concentrations of nucleosomes and DNA, protease and caspase activities in serum of 62 patients with ovarian cancer before and after first-line carboplatin/taxane-based chemotherapy and of 28 healthy individuals by Cell Death Detection ELISA, PicoGreen, Protease Fluorescent Detection Kit and Caspase-Glo3/7 Assay, respectively. By immunocytochemistry, we analyzed bone marrow (BM) aspirates for disseminated tumor cells (DTCs) using the monoclonal antibody A45-B/B3. The measurements in blood and BM were correlated to clinical outcome (median follow-up time: 18 months). Significant correlations between circulating nucleosome and DNA concentrations (p = 0.0001), nucleosome concentrations and caspase activities (p = 0.031) and circulating DNA concentrations and protease activities (p = 0.0001) were detected. Before therapy, the occurrence of DTCs correlated with increasing serum protease activities (p = 0.030) and higher tumor stages (p = 0.029), and after therapy, it correlated with a higher risk of relapse (p = 0.040). Higher protease activities in serum were associated with advanced tumor stages (p = 0.045). We observed a significant relationship between residual tumor load of >1 cm after primary surgery and serum DNA levels (p = 0.0001), and both parameters were associated with a higher risk of relapse (p = 0.0001 and p = 0.020, respectively) and a poorer overall survival (p = 0.021 and p = 0.010, respectively). These findings suggest that the residual tumor load might contribute to elevated DNA levels in blood. Serum DNA levels together with BM status for DTCs have the potential to become suitable biomarkers to predict the prognosis of ovarian cancer patients undergoing platinum-based chemotherapy. PMID- 20715114 TI - Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex. AB - Butyrate, a short-chain fatty acid produced by the colonic bacterial fermentation is able to induce cell growth inhibition and differentiation in colon cancer cells at least partially through its capacity to inhibit histone deacetylases. Since butyrate is expected to impact cellular metabolic pathways in colon cancer cells, we hypothesize that it could exert its antiproliferative properties by altering cellular metabolism. We show that although Caco2 colon cancer cells oxidized both butyrate and glucose into CO(2) , they displayed a higher oxidation rate with butyrate as substrate than with glucose. Furthermore, butyrate pretreatment led to an increase cell capacity to oxidize butyrate and a decreased capacity to oxidize glucose, suggesting that colon cancer cells, which are initially highly glycolytic, can switch to a butyrate utilizing phenotype, and preferentially oxidize butyrate instead of glucose as energy source to produce acetyl coA. Butyrate pretreated cells displayed a modulation of glutamine metabolism characterized by an increased incorporation of carbons derived from glutamine into lipids and a reduced lactate production. The butyrate-stimulated glutamine utilization is linked to pyruvate dehydrogenase complex since dichloroacetate reverses this effect. Furthermore, butyrate positively regulates gene expression of pyruvate dehydrogenase kinases and this effect involves a hyperacetylation of histones at PDK4 gene promoter level. Our data suggest that butyrate exerts two distinct effects to ensure the regulation of glutamine metabolism: it provides acetyl coA needed for fatty acid synthesis, and it also plays a role in the control of the expression of genes involved in glucose utilization leading to the inactivation of PDC. PMID- 20715115 TI - Analysis of tumor antigen-specific T cells and antibodies in cancer patients treated with radiofrequency ablation. AB - Radiofrequency (RF) ablation is a minimally invasive technique routinely applied for the treatment of primary and secondary liver tumors. It induces cell death by thermal coagulative necrosis of tumor tissues, whereas cellular metabolism can still take place in a transition zone surrounding the necrotic area. An increase in heat shock protein expression occurs shortly after treatment, suggesting that the induction of activating signals may stimulate the host immune system. In addition, various effects on immune effectors have also been observed, including stimulation of tumor-directed T lymphocytes. Here, we prospectively assessed the activation of tumor antigen-specific antibodies, as well as antigen-specific CD4(+) and CD8(+) T cells in patients suffering from primary or secondary malignancies and treated by RF ablation with or without concomitant chemotherapy. An increase of antibodies (in 4 patients of 49), CD4(+) T cells or CD8(+) T cells (in 2 patients of 49) could be detected several weeks to months following intervention. These findings suggest that in addition to the local control of tumor growth, RF ablation can provide the appropriate conditions for activating tumor-antigen specific immune responses. PMID- 20715116 TI - VEGF stimulates PKD-mediated CREB-dependent orphan nuclear receptor Nurr1 expression: role in VEGF-induced angiogenesis. AB - New vessel formation is critical for solid tumor growth and it is primarily stimulated by the most potent angiogenic factor vascular endothelial growth factor (VEGF or VEGF-A165). VEGF promotes endothelial cell proliferation by initiating signaling cascades to increase gene transcription. Recent works showed that VEGF potently and rapidly induces expression of orphan nuclear receptor Nurr1 in endothelial cells. However, the signaling pathway for VEGF-induced Nurr1 expression and its role in VEGF-induced endothelial cell proliferation and angiogenic response have not been examined. In our study, we first show that VEGF significantly induces expression of Nurr1 mRNA, protein and its promoter activity in cultured endothelial cells. Furthermore, the promoter analysis shows that deletion of the putative cAMP-responsive element binding protein (CREB) site in the proximal region of the promoter markedly reduces VEGF-induced promoter activity whereas deletion of the upstream NF-kappaB site has moderate effect. Transfection of a dominant negative CREB mutant (K-CREB) or mutation of this putative CREB site in the Nurr1 promoter attenuates VEGF-induced Nurr1 expression. VEGF also stimulates the binding of nuclear CREB protein to its site in the Nurr1 promoter in vitro and in vivo. Moreover, using pharmacological inhibitors and molecular approaches, we show that VEGF-induced CREB activation is largely mediated by protein kinase C-dependent protein kinase D activation. Finally, our data indicate that knockdown of endogenous Nurr1 expression attenuates VEGF-induced endothelial cell proliferation, migration and in vivo matrigel angiogenesis, suggesting its potential importance in mediating VEGF induced tumor angiogenesis. PMID- 20715117 TI - Performance of first-trimester serum screening for trisomy 21 before and from 11 + 0 weeks of gestational age in The Netherlands. PMID- 20715118 TI - Prenatal diagnosis and follow-up of 23 cases of cardiac tumors. AB - OBJECTIVE: To evaluate the prenatal characteristics and postnatal outcome of cardiac tumors diagnosed at two prenatal Polish cardiology centers. METHODS: Descriptive analysis of 23 fetuses with cardiac tumors (12 multiple and 11 single) diagnosed over 16 years (from 1993 to 2009). Congestive heart failure was diagnosed when the cardiovascular profile score was seven or less. RESULTS: Associated structural congenital heart defects were present in three fetuses, extracardiac anomalies in three, and chromosomal anomalies in two. Congestive heart failure developed in five cases. Perinatal survival was not different between cases with and without cardiac failure (2/5 vs 12/18, p = 0.28). The main ultrasonographic signs observed prenatally in association with cardiac tumors were cardiomegaly, left ventricular outflow tract obstruction, pericardial effusion, and hypokinesis. A diagnosis of tuberous sclerosis was eventually made in all 12 fetuses with multiple tumors. Perinatal death occurred in 4/11 cases with single tumors and in 5/12 with multiple tumors (p = 0.57). Surgical resection of the tumor was performed in 3/11 neonates with single tumors (histopathologically: rhabdomyoma, teratoma, and fibroma) and in 2/12 with multiple tumors (both rhabdomyomas). CONCLUSIONS: Survival is not different between neonates with single and multiple tumors and between those with and without congestive heart failure. PMID- 20715119 TI - HCMV seroprevalence and associated risk factors in pregnant women, Havana City, 2007 to 2008. AB - OBJECTIVE: To prenatally identify pregnant women at risk of developing congenital infection due to human cytomegalovirus (HCMV). METHODS: One thousand one hundred and thirty-one pregnant women from three municipalities from Havana City were serologically screened for HCMV infection (IgM/IgG, IgG avidity) from January 2007 to January 2008. Demographical, epidemiological, and clinical variables were correlated to serologic status to identify predictors of seroconversion in pregnancy. RESULTS: The majority of women were seropositive to HCMV (92.6%); 27 women (2.4%) developed HCMV active infection during pregnancy, defined by the detection of IgG+ and IgM+ (7 women), IgM+ and IgG- (2 women), and IgG seroconversion (18 women). Susceptibility of active HCMV infection during pregnancy was associated with maternal age < 20 years and nulligravidity. Primary infection was detected in 20 pregnant women (1.8%), whereas 7 patients (0.6%) had active non-primary infection. CONCLUSION: Although pregnant women in Cuba have high seroprevalence rates for HCMV, those younger than 20 years and nulligravidae are at risk of acquiring infection during pregnancy. PMID- 20715120 TI - Prevalence of steroid sulfatase deficiency in California according to race and ethnicity. AB - OBJECTIVE: Estimate steroid sulfatase deficiency (STSD) prevalence among California's racial/ethnic groups using data from a previous study focused on prenatal detection of Smith-Lemli-Opitz syndrome (SLOS). SLOS and STSD both have low maternal serum unconjugated estriol (uE3) levels. METHODS: Prevalence was estimated using three steps: listing clinically identified cases; modeling STSD frequency at three uE3 intervals using diagnostic urine steroid measurements; applying this model to determine frequency in pregnancies not providing urine. RESULTS: Overall, 2151 of 777 088 pregnancies (0.28%) were screen positive; 1379 of these were explained and excluded. Fifty-four cases were diagnosed clinically among 707 remaining pregnancies with a male fetus. Urine steroid testing identified 74 additional STSD cases: 66 (89.2%) at uE3 values < 0.15 MoM, 8 (10.8%) at 0.15-0.20 MoM, and 0 (0%) at > 0.20 MoM. Modeling estimated 107.5 STSD cases among 370 pregnancies without urine samples. In males, STSD prevalence was highest among non-Hispanic Whites (1:1230) compared to Hispanics (1:1620) and Asians (1:1790), but differences were not significant. No STSD pregnancies were found among 65 screen positive Black women. CONCLUSION: The overall prevalence estimate of 1:1500 males is consistent with published estimates and is reasonable for counseling, except among Black pregnancies where no reliable estimate could be made. PMID- 20715121 TI - A trend toward increased first trimester free beta-hCG and PAPP-A in monochorionic twins complicated by Twin-to-Twin Transfusion syndrome. PMID- 20715122 TI - Electrophoretic mapping of highly homologous keratins: a novel marker peptide approach. AB - Identification of the intermediate filament proteins (IFPs) in the wool proteome has formerly been hampered by limited sequence information, the high degree of IFP homology and their close proximity on 2-DE maps. This has been partially rectified by the recent acquisition of four new Type I and two Type II wool IFP sequences. Among closely migrating proteins, such as IFP clusters in a 2-DE map, proteins with higher sequence coverage will be assigned higher scores, but the identification of unique peptides in such tight clusters may distinguish these closely migrating proteins. Two approaches were adopted for the study of wool IFPs. In the first, searches were conducted for peptides known to be unique to each member of the family in each spot. In the second, MALDI imaging was employed to examine peptides bound to a PVDF membrane from a poorly resolved part of the Type I IFP region of the 2-DE map. As a result, a distinct picture has emerged of the distribution of the six Type I and four Type II IFPs across the 2-DE wool protein map. PMID- 20715123 TI - Protein phosphorylation in mitochondria --a study on fermentative and respiratory growth of Saccharomyces cerevisiae. AB - Phosphorylation as a posttranslational protein modification is a common subject of proteomic studies, but phosphorylation in mitochondria is still poorly investigated. The study presented here applied 2-DE to characterize phosphorylation in the yeast mitochondrial proteome and identified 59 spots corresponding to 34 phosphorylated mitochondrial or mitochondria-associated proteins. Most of these proteins presented putative substrates of mitogen activated protein and target of rapamycin kinases, cAMP-dependent protein kinase, cyclin-dependent kinases and Snf1p suggesting them as key players in the phosphorylation of mitochondrial or mitochondria-associated proteins. The dynamic behaviour of the phosphoproteome under a major metabolic change, the shift from fermentation to respiration (diauxic shift), was further studied. Eight proteins (Ald4p, Eft1p/2p, Eno1p, Eno2p, Om14p, Pda1p, Qcr2p, Sdh1p) had growth dependent changes in their phosphorylation, indicating a role of phosphorylation-dependent regulation of translation, metabolic pathways (e.g. glucose fermentation, tricarboxylic acid cycle, pyruvate dehydrogenase and its bypass) and respiratory chain. PMID- 20715124 TI - Construction of two fluorescence-labeled non-combined DNA index system miniSTR multiplex systems to analyze degraded DNA samples in the Chinese Han Population. AB - MiniSTR loci have been demonstrated to be an effective approach in recovering genetic information from degraded specimens, because of the reduced PCR amplicon sizes which improved the PCR efficiency. Eight non-combined DNA index system miniSTR loci suitable for the Chinese Han Population were analyzed in 300 unrelated Chinese Han individuals using two novel five fluorescence-labeled miniSTR multiplex systems(multiplex I: D10S1248, D2S441, D1S1677 and D9S2157; multiplex II: D9S1122, D10S1435, D12ATA63, D2S1776 and Amelogenin). The allele frequency distribution and forensic parameters in the Chinese Han Population were reported in this article. The Exact Test demonstrated that all loci surveyed here were found to be no deviation from Hardy-Weinberg equilibrium. The accumulated power of discrimination and power of exclusion for the eight loci were 0.999999992 and 0.98, respectively. The highly degraded DNA from artificially degraded samples and the degraded forensic case work samples was assessed with the two miniSTR multiplex systems, and the results showed that the systems were quite effective. PMID- 20715125 TI - Acute-phase proteins investigation based on lectins affinity capture prior to 2 DE separation: application to serum from multiple sclerosis patients. AB - Plasma acute-phase proteins (APPs) glyco-isoforms are important biomarkers of inflammatory processes such as those occurring in multiple sclerosis (MS). Specific analysis of these proteins is often hampered by sample biochemical complexity. The aim of our study was to set up a method to accurately visualize, identify and quantify APPs glyco-isoforms in human serum. An enrichment strategy based on affinity chromatography using the carbohydrate-binding proteins concanavalin A (ConA) and erythrina cristagalli lectin (ECL) was applied to pooled serum samples from 15 patients and 9 healthy individuals. Image analysis of 2-DE detected 30 spots with a fold change higher than 1.5. A total of 14 were statistically significant (p value<0.05): 7 up-regulated and 7 down-regulated in MS samples. ESI LC-Nanospray IT mass spectrometry analysis confirmed that all of them were APPs isoforms supporting the idea that the accurate analysis of differential glycosylation profiles in these biomarkers is instrumental to distinguish between MS patients and healthy subjects. Additionally, overlaps in ConA/ECL maps protein patterns suggest how the used lectins are able to bind sugars harbored by the same oligosaccharide structure. Among identified proteins, the presence of complex and/or hybrid type N-linked sugar structures is well known. Performing galectin-3 binding and Western blotting, we were able to demonstrate a correlation between hybrid type glyco-isoforms of beta-haptoglobin and MS. In conclusion, although the patho-physiological role of the identified species still remains unclear and further validations are needed, these findings may have a relevant impact on disease-specific marker identification approaches. PMID- 20715127 TI - Lamp-based wavelength-resolved fluorescence detection for protein capillary electrophoresis: setup and detector performance. AB - A lamp-based fluorescence detection (Flu) system for CE was extended with a wavelength-resolved (WR) detector to allow recording of full protein emission spectra. WRFlu was achieved using a fluorescence cell that employs optical fibres to lead excitation light from a Xe-Hg lamp to the capillary window and protein fluorescence emission to a spectrograph equipped with a CCD. A 280 nm band pass filter etc. together with a 300 nm short pass cut-off filter was used for excitation. A capillary cartridge was modified to hold the detection cell in a commercial CE instrument enabling WRFlu in routine CE. The performance of the WRFlu detection was evaluated and optimised using lysozyme as model protein. Based on reference spectral data, a signal-intensity adjustment was introduced to correct for transmission losses in the detector optics that occurred for lower protein emission wavelengths. CE-WRFlu of lysozyme was performed using BGEs of 50 mM sodium phosphate (pH 6.5 or 3.0) and a charged-polymer coated capillary. Using the 3-D data set, signal averaging over time and emission-wavelength intervals was carried out to improve the S/N of emission spectra and electropherograms. The detection limit for lysozyme was 21 nM, providing sufficient sensitivity to obtain spectral information on protein impurities. PMID- 20715126 TI - Electrokinetic supercharging focusing in capillary zone electrophoresis of weakly ionizable analytes in environmental and biological samples. AB - Five non-steroidal anti-inflammatory drugs, naproxen, fenoprofen, ketoprofen, diclofenac and piroxicam, were separated and analyzed by electrokinetic supercharging in CZE. Three different setups of the ITP technique were assayed for the separation and preconcentration of these five non-steroidal anti inflammatory drugs. For the setup that gave the best results, we evaluated the influence of different parameters on separation and preconcentration efficiency such as sample pH, concentration of the leading stacker, BGE composition, electrokinetic injection time, composition and hydrodynamic injection of the solvent plug and of the terminating stacker. In the selected setup, the BGE (10 mM Na(2)B(4)O(7) + 50 mM NaCl in 10% of MeOH aqueous solution) contained the leading electrolyte while the terminating electrolyte, hydrodynamically injected after the sample (50 mbar x 12 s), was 50 mM of CHES. Prior to sample injection at (700 s at -2 kV) a short plug of MeOH (50 mbar x 3 s) was hydrodynamically injected. The results show that this strategy enhanced detection sensitivity 2000 fold compared with normal hydrodynamic injection, providing detection limits of 0.08 MUg/L for standard samples with good repeatability (values of relative standard deviation, %RSD < 1.03%). Method validation with river water samples and human plasma demonstrated good linearity, with detection limits of 0.9 and 2 MUg/L for river water samples and human plasma samples, respectively (as well as satisfactory precision in terms of repeatability and reproducibility). PMID- 20715128 TI - Sulfoalkylbetaine-based monolithic column with mixed-mode of hydrophilic interaction and strong anion-exchange stationary phase for capillary electrochromatography. AB - A novel monolithic stationary phase with mixed mode of hydrophilic and strong anion exchange (SAX) interactions based on in situ copolymerization of pentaerythritol triacrylate (PETA), N,N-dimethyl-N-methacryloxyethyl N-(3 sulfopropyl) ammonium betaine (DMMSA) and a selected quaternary amine acrylic monomer was designed as a multifunctional separation column for CEC. Although the zwitterionic functionalities of DMMSA and hydroxy groups of PETA on the surface of the monolithic stationary phase functioned as the hydrophilic interaction (HI) sites, the quaternary amine acrylic monomer was introduced to control the magnitude of the EOF and provide the SAX sites at the same time. Three different quaternary amine acrylic monomers were tested to achieve maximum EOF velocity and highest plate count. The fabrication of the zwitterionic monolith (designated as HI and SAX stationary phase) was carried out when [2 (acryloyloxy)ethyl]trimethylammonium methylsulfate was used as the quaternary amine acrylic monomer. The separation mechanism of the monolithic column was discussed in detail. For charged analytes, a mixed mode of HI and SAX was observed by studying the influence of mobile phase pH and salt concentration on their retentions on the poly(PETA-co-DMMSA-co-[2 (acryloyloxy)ethyl]trimethylammonium methylsulfate) monolithic column. The optimized monolith showed good separation performance for a range of polar analytes including nucleotides, nucleic acid bases and nucleosides, phenols, estrogens and small peptides. The column efficiencies greater than 192 000 theoretical plates/m for estriol and 135 000 theoretical plates/m for charged cytidine were obtained. PMID- 20715129 TI - Sample stacking capillary electrophoretic microdevice for highly sensitive mini Y short tandem repeat genotyping. AB - Lab-on-a-chip provides an ideal platform for short tandem repeat (STR) genotyping due to its intrinsic low sample consumption, rapid analysis, and high-throughput capability. One of the challenges, however, in the forensic human identification on the microdevice is the detection sensitivity derived from the nanoliter volume sample handling. To overcome such a sensitivity issue, here we developed a sample stacking CE microdevice for mini Y STR genotyping. The mini Y STR includes redesigned primer sequences to generate smaller-sized PCR amplicons to enhance the PCR efficiency and the success rate for a low copy number and degraded DNA. The mini Y STR amplicons occupied in the 5- and 10-mm stacking microchannels are preconcentrated efficiently in a defined narrow region through the optimized sample stacking CE scheme, resulting in more than tenfold improved fluorescence peak intensities compared with that of a conventional cross-injection microcapillary electrophoresis method. Such signal enhancement allows us to successfully analyze the Y STR typing with only 25 pg of male genomic DNA, with high background of female genomic DNA, and with highly degraded male genomic DNA. The combination of the mini Y STR system with the novel sample stacking CE microdevice provides the highly sensitive Y STR typing on a chip, making it promising to perform high-performance on-site forensic human identification. PMID- 20715131 TI - Stem cell microenvironments--unveiling the secret of how stem cell fate is defined. AB - Stem cells are defined as unspecialized cells that are capable of long term self renewal and differentiation into specialized cell types. These unique properties make them an attractive cell source for regenerative medicine applications. Although the functions of various stem cells have been extensively studied in the development of organisms and in diseases, the specific factors and conditions that control stem cell fate, specifically the conditions that allow them to remain unspecialized, are not well studied. It has been suggested that adult stem cell survival and maintenance, as well as proliferation and differentiation, are controlled by the three-dimensional (3D) microenvironment, the so-called niche. Major functional niche components include supporting niche cells, growth modulating soluble factors stored within the niches, and the extracellular matrix (ECM). In this article, we review work highlighting the growing complexity of stem cell-ECM interactions and their impact on the fields of biomaterials research and regenerative medicine. PMID- 20715130 TI - Synthesis of linear polyamines with different amine spacings and their ability to form dsDNA/siRNA complexes suitable for transfection. AB - In this paper we report on the synthesis of diversified linear polyamine architectures with different chain lengths and compositions and their interaction with phosphate groups of DNA/siRNA. The polyplex formation between model nucleotide (dsDNA) and these linear polyamines has been determined at different nitrogen to phosphorus (N/P) ratios using small-angle neutron scattering (SANS) and atomic force microscopy (AFM) techniques. AFM images showed that while linear poly(ethylene imine) (PEI)/DNA complex results in bigger spherical aggregates, poly(propylene imine)s forms torroid and cigar shaped structures upon complexation with DNA. The poly(butylene imine)s (LPBI)s form compact and soluble DNA complexes with a radii range of R(g) = 15-30 nm. Among the studied linear polyamines, the LPBIs did show the best transfection efficiency. PMID- 20715132 TI - The use of fibrous, supramolecular membranes and human tubular cells for renal epithelial tissue engineering: towards a suitable membrane for a bioartificial kidney. AB - A bioartificial kidney, which is composed of a membrane cartridge with renal epithelial cells, can substitute important kidney functions in patients with renal failure. A particular challenge is the maintenance of monolayer integrity and specialized renal epithelial cell functions ex vivo. We hypothesized that this can be improved by electro-spun, supramolecular polymer membranes which show clear benefits in ease of processability. We found that after 7 d, in comparison to conventional microporous membranes, renal tubular cells cultured on top of our fibrous supramolecular membranes formed polarized monolayers, which is prerequisite for a well-functioning bioartificial kidney. In future, these supramolecular membranes allow for incorporation of peptides that may increase cell function even further. PMID- 20715133 TI - Comparative study of tumor hypoxia by diffuse optical spectroscopy and immunohistochemistry in two tumor models. AB - The capabilities of diffuse optical spectroscopy for noninvasive assessing of oxygen status in experimental tumors have been demonstrated. Specific features of the distribution of total hemoglobin, oxygenated hemoglobin, deoxygenated hemoglobin, and blood-oxygen saturation were shown on two tumor models having different histological structure and functional characteristics. The results obtained by the optical technique were verified by immunohistochemical study of tissue samples marked with exogenous marker of hypoxia--pimonidazole. PMID- 20715134 TI - High- and low-frequency mechanical properties of living starfish oocytes. AB - We studied the mechanical properties of living starfish oocytes belonging to two species, Astropecten Auranciacus and Asterina pectinifera, over a wide range of timescales. We monitored the Brownian motion of microspheres injected in the cytoplasm using laser particle-tracking (LPT) and video multiple-particle tracking (MPT) techniques, to explore high- and low-frequency response ranges, respectively. The analysis of the mean-square-displacements (MSD) allowed us to characterize the samples on different timescales. The MSD behavior is explained by three power-law exponents: for short times (tau < 1 ms) it reflects the semiflexible behavior of the actin network; for intermediate timescales (1 ms < tau < 1 s) it is similar to that of a soft-glass material; finally for long times (tau > 1 s) it behaves mainly like a viscous medium. We computed and compared the viscoelastic moduli using a recently proposed model describing the frequency response of the cell material. The large fluctuations found in the MSD over hundreds of trajectories indicate and confirm the significant cytoplasm heterogeneity. PMID- 20715135 TI - The impact of silica gel pore and particle sizes on HPLC column efficiency and resolution for an immobilized, cyclodextrin-based, chiral stationary phase. AB - In this study, the CD derivative, mono (6(A)-azido-6(A)-deoxy)-per(p chlorophenylcarbamonylated) beta-CD was chemically immobilized onto the surface of an amino-functionalized silica gel with different pore (100, 300, and 500A) and particle (3, 5, and 10 MUm) sizes to obtain novel chiral stationary phases. The impact of pore and particle size on the amount of immobilized Ph-beta-CD, column performance, and enantioselectivity was investigated by evaluating the separation of a variety of racemates in both the normal- and the reversed-phase modes. Experimental results revealed that the retention factor and resolution of racemates generally decreased with increasing pore size; the column prepared with the smallest (3 MUm) silica gel particle size gave the best column performance and enantioselectivity in both the normal- and the reversed-phase modes. PMID- 20715136 TI - A method of extracting ginsenosides from Panax ginseng by pulsed electric field. AB - The objective of this study was to develop and optimize a pulsed electric field (PEF) extraction method. Various experimental conditions, including electric field intensity and frequency, were evaluated against extraction methods. The content of six major ginsenosides (Rg(1), Re, Rb(1), Rc, Rb(2), and Rd) were quantified by HPLC. The results indicated that the highest yield of the ginsenoside is 12.69 mg/g by PEF using the conditions of 20 kV/cm electric field intensity, 6000 Hz frequency, 70% ethanol-water solution, and 150 L/h velocity. The yield of the ginsenoside of PEF extraction method is higher than the other five methods, such as microwave-assisted extraction, heat reflux extraction, ultrasonic-assisted extraction, accelerated solvent extraction, and ultrahigh pressure extraction, The whole extraction process of PEF takes less than 1 s, which is much less than the heat reflux extraction method for 6 h and even newly used technique ultrahigh pressure extraction method of 2 min. The high efficiency, shorter extraction times, and lower energy cost of PEF extraction method can be applied in the industrial production of saponins from Panax ginseng. The PEF extraction method is a promising and constructive method to extract ginsenosides. PMID- 20715138 TI - Extension of the C18 stationary phase knowledge by using the carotenoid test. AB - The carotenoid test for octadecylsiloxane-bonded stationary phases used in RPLC was developed some years ago. Additional experiments have now been performed with varied stationary phases. The effect of the bonding density and of the pore diameter on steric selectivity, polar surface activity and hydrophobicity was determined by using YMC series (J'Sphere and Pack ODSA). The test was also extended to estimate the phase evolution of several classical or hybrid silicas. The high loading phases were also studied, as well as the fused core silicas. The effect of the particle size reduction on the three previous phase properties was investigated in the goal to determine in which way this parameter could also modify the chemical properties of the phases. PMID- 20715137 TI - Simultaneous analysis of seven alkaloids in Coptis-Evodia herb couple and Zuojin pill by UPLC with accelerated solvent extraction. AB - A rapid, sensitive, and accurate ultra-performance liquid chromatography-UV detection method was developed and validated for simultaneous determination of seven active alkaloids, berberine, palmatine, coptisine, jatrorrhizine, epiberberine, evodiamine, and rutaecarpine, in the Coptis-Evodia herb couple and the Zuojin pill preparation. The original validated method had a total time of about 11 min, which was reduced to 4.7 min by further optimization of gradient elution conditions with eluent A comprising water/methanol/formic acid (v/v/v, 90:10:0.1) and eluent B ACN. An accelerated solvent extraction method was used for the rapid extraction of herb products and pill preparations. Linear behavior over the investigated concentration ranges was observed, with values of r(2) greater than 0.9987 for all analytes. Experiment results were satisfactory for both intra-day and inter-day precision, and method accuracy. Method recovery ranged from 95.7 to 103.5% based on pure reference standards. The validated method was successfully applied to determine amounts of bioactive alkaloid compounds in five samples, in the Coptis-Evodia herb couple, and the commercial Zuojin pill products. The developed method achieved baseline resolution for all seven main basic compounds and is suitable for use as a routine procedure for the rapid identification and quantification of basic compounds in the Coptis-Evodia herb couple and related products. PMID- 20715139 TI - Retention mechanism of the multifunctional solute on columns with different coverage densities using highly aqueous reversed-phase conditions. AB - A series of 11 homemade octadecyl bonded phases with different coverage densities were tested to determine the influence of the stationary phase on the retention in highly aqueous mobile phases. The concentrations of the organic modifiers (methanol and ACN) were in the range of 0-20%(v/v). The coverage density of bonded ligands and the presence of the end-capping have strong influence on the solute retention. Amoxicillin (AMO) was chosen as the test compound. Dual properties of AMO, which contain hydrophobic skeleton and polar groups (amino, hydroxyl and carbonyl), cause irregular changes of the retention over the stationary phase hydrophobicity and silanol activity at given mobile phase composition. Presented data show that application of non-standard low coverage density C18 phases allow to determine AMO in the RPLC condition with high retention. PMID- 20715140 TI - The influence of polymer concentration, applied voltage, modulation depth and pulse frequency on DNA separation by pulsed field CE. AB - DNA fragments (0.1-10 kbp (kbp, kilo base pair)) separation by square-wave pulsed field CE in hydroxyethylcellulose (HEC, 1300 K) polymer was performed in this work. The effects of polymer concentration, pulse field strength, pulse frequency and modulation depth were investigated. We found that low HEC (about 0.1%) concentration is suitable for the separation of small DNA fragments (<1 kbp), whereas higher HEC concentration (>0.5%) is appropriated for high-mass DNA molecular (>1 kbp) separation. The mobility of DNA fragments is nearly linearly related to average separation voltage under pulsed field conditions. Higher modulation depth is suited to separate the longer DNA fragments and lower modulation depth favors the resolution of short DNA fragments. Thus, the intermediate modulation depth (100%) and pulse frequency (about 31.3 Hz) are prerequisite for high-resolution DNA separation. PMID- 20715141 TI - Characterization of phenolic and other polar compounds in a lemon verbena extract by capillary electrophoresis-electrospray ionization-mass spectrometry. AB - In this study, a CE-MS method has been developed to carry out the qualitative characterization of a lemon verbena (Lippia citriodora) extract for the first time. The CE and ESI-MS parameters were optimized with respect to resolution, analysis time and peak shape in order to maximize the number of compounds detected and the sensitivity of their determination. The use of two different MS analyzers, TOF-MS and IT-MS, enabled the tentative identification of the major components of this extract. Thus, using this method, 16 compounds were determined. Some of them have been previously identified by HPLC methods, although four compounds were also found for the first time in lemon verbena such as asperuloside, tuberonic acid glucoside or 5'-hydroxyjasmonic acid 5'-O glucoside, shanzhiside and ixoside. These results demonstrate that CE-MS generates data complementary to those obtainable by HPLC-MS and it is particularly suited to the analysis of plant metabolites. PMID- 20715142 TI - Preparation of high-selective HPLC packing materials based on alternating copolymer-grafted silica. AB - Three alternating copolymer-grafted silica stationary phases for use in high selective RP-HPLC were prepared from two vinyl monomers selected from styrene, N methylmaleimide, N-octadecylmaleimide, and octadecyl acrylate; they were characterized by elemental analyses, thermogravimetric analysis, diffuse reflectance infrared Fourier transform spectroscopy, and (13)C cross-polarization magic-angle spinning NMR spectroscopy. Aspects of molecular-shape selectivity were evaluated for three different columns using Standard Reference Material 869b, Column Selectivity Test Mixture for Liquid Chromatography. The best selectivity for isomer separations was obtained for the stationary phase prepared with a copolymer of octadecyl acrylate and N-octadecylmaleimide, which was able to separate 16 polycyclic aromatic hydrocarbons (Standard Reference Material 1647e) in an isocratic elution. In this paper, the effectiveness of this phase is also demonstrated by separation of tocopherol isomers. PMID- 20715143 TI - Macroporous molecularly imprinted monolithic polymer columns for protein recognition by liquid chromatography. AB - Macroporous cytochrome c (cyc)-imprinted monolithic polyarylamide columns were prepared, and applied for the template protein recognition by HPLC. With cyc (18.8 mg) as template, the imprinted monolithic materials were in situ polymerized in an HPLC column tube, with methacrylamide (450 mg), methacrylic acid (15.8 mg), piperazine diacrylamide (720 mg) and ammonium sulfate (390 mg) dissolved in 5 mL of phosphate buffer (pH 7.4), initiated by ammonium persulfate and TEMED. After the reaction, cyc was removed with acetic acid (10%, v/v) containing 10% w/v SDS. The non-imprinted monolithic column was prepared under the same procedure except without cyc. Retention of cyc and its competitive protein, lysozyme (lys), on molecular-imprinting polymer (MIP) and non-imprinted polymer columns was studied. When the pH value of mobile phase was 4.0, on MIP column, the retention factors of cyc and lys were 2.0 and 1.3, respectively. However, those on non-imprinted polymer column were very similar, both as 1.1. Even in competitive environment, a mixture of cyc and lys could be separated on MIP column under gradient elution, with resolution as 1.2. These results indicate that protein-imprinted monolithic polymer columns could offer obvious affinity and specific recognition to the template protein. PMID- 20715144 TI - Simultaneous determination of rosiglitazone and its metabolites in rat liver microsomal fraction using hollow-fiber liquid-phase microextraction for sample preparation. AB - A three-phase hollow-fiber liquid-phase microextraction method for the analysis of rosiglitazone and its metabolites N-desmethyl rosiglitazone and rho-hydroxy rosiglitazone in microsomal preparations is described for the first time. The drug and metabolites HPLC determination was carried out using an X-Terra RP-18 column, at 22 degrees C. The mobile phase was composed of water, acetonitrile and acetic acid (85:15:0.5, v/v/v) and the detection was performed at 245 nm. The hollow-fiber liquid-phase microextraction procedure was optimized using multifactorial experiments and the following optimal condition was established: sample agitation at 1750 rpm, extraction for 30 min, hydrochloric acid 0.01 mol/L as acceptor phase, 1-octanol as organic phase, and donor phase pH adjustment to 8.0. The recovery rates, obtained by using 1 mL of microsomal preparation, were 47-70%. The method presented LOQs of 50 ng/mL and it was linear over the concentration range of 50-6000 ng/mL, with correlation coefficients (r) higher than 0.9960, for all analytes. The validated method was employed to study the in vitro biotransformation of rosiglitazone using rat liver microsomal fraction. PMID- 20715145 TI - Application of ultrasound-assisted matrix solid-phase dispersion extraction to the HPLC confirmatory determination of cephalosporin residues in milk. AB - Ultrasound-assisted matrix solid-phase dispersion (MSPD) was applied to isolate eight cephalosporins (cefadroxil, cefaclor, cephalexin, cefotaxime, cefazolin, cefuroxime, cefoperazone and ceftiofur) from milk. Multi-residue analysis was subsequently performed by HPLC-diode array detection. Extraction yield by matrix solid-phase dispersion using Nexus sorbent was higher than various investigated SPE protocols. Three analytical columns, two conventional silica based and one monolithic, were compared based on resolution, peak shape and retention time. The optimum method using Chromolith RP-18e (100*4.6 mm) achieved separation in less than 16 min. Method validation was performed according to the European Union Decision 2002/657/EC, determining linearity, selectivity, stability, decision limit, detection capability, accuracy and precision. RSD values observed were lower than 15.3%. Recovery rates of examined antimicrobials from milk ranged from 93.8 to 101.9% for cefadroxil, from 94.7 to 103.6% for cefaclor, from 93.4 to 106.6% for cephalexine, from 104.1 to 115.3% for cefotaxime, from 97.1 to 105.6% for cefazolin, from 97.4 to 108.6% for cefuroxime, from 98.8 to 103.4% for cefoperazone and from 95.5 to 103.6% for ceftiofur. Correlation coefficients ranged from 0.9926 to 0.9999. CC(b) values were in the range from 103.5 to 112.3 MUg/kg for analytes with a maximum residue limit of 100 MUg/kg and from 54.4 to 56.3 MUg/kg for those with a maximum residue limit of 50 MUg/kg. PMID- 20715146 TI - Unexpected enantioseparation of mandelic acids and their derivatives on 1,2,3 triazolo-linked quinine tert-butyl carbamate anion exchange-type chiral stationary phase. AB - Replacement of the flexible thioether linker for the novel, rigid 1,2,3-triazole spacer group in the course of immobilization of quinine tert-butyl carbamate onto a silica surface led to a chiral stationary phase (CSP) with enhanced enantioselectivity for the resolution of mandelic acid and derivatives thereof. These new CSPs allowed efficient resolution of a wide set of mandelic acids with alpha-values between 1.08 and 1.68. The high loadability of these chiral ion exchange type CSPs allows preparative separation in the milligram range on an analytical column of 100*4 mm id in a single run as it was demonstrated for 4 trifluoromethylmandelic, 2-naphthylglycolic and 3,4-methylenedioxymandelic acids. The chiral recognition process has been studied using a library of 25 diverse racemic probes. A tentative model suggests that the rigid 1,2,3-triazole group takes part in the formation of an enantioselective-binding pocket of the entire and immobilized selector moiety of the CSP. The primary interaction site is given by the ionizable quinuclidine group of the Cinchona alkaloid supported by possible pi-pi stabilization effects within the selector-selectand complex. PMID- 20715147 TI - Morphology and posthatching ontogeny of the autopodial skeleton of Bolitoglossa nicefori (Caudata: Plethodontidae). AB - Webbed foot morphology is a highly homoplastic character in species of Bolitoglossa and has been assumed to be pedomorphic. This study examines the morphology and posthatching ontogeny of the autopodial skeleton of Bolitoglossa nicefori and compares the descriptive and morphometric results with other species of the genus. We show that the autopodial morphology of B. nicefori coincides with the generalized pattern of the genus; webbed foot morphology is produced by pedomorphosis that affect the phalange length of the digits, resulting in a synchronized growth of digits (length and ossification rates) and the fleshy web. Although the webbed foot morphology of B. nicefori might be explained by the pervasive pedomorphic developmental trend observed in the genus, the large degree of variation encountered in the morphology of the distal phalanges indicates that the pedomorphic processes acting in this species are neither a simple truncation of the autopodial developmental program during early posthatching development nor a global process acting over the whole body plan. Instead, this morphological pattern is probably a result of the modular nature of limb development. PMID- 20715148 TI - Uterine and eggshell structure and histochemistry in a lizard with prolonged uterine egg retention (Lacertilia, Scincidae, Saiphos). AB - The eggshell of lizards is a complex structure composed of organic and inorganic molecules secreted by the oviduct, which protects the embryo by providing a barrier to the external environment and also allows the exchange of respiratory gases and water for life support. Calcium deposited on the surface of the eggshell provides an important nutrient source for the embryo. Variation in physical conditions encountered by eggs results in a tradeoff among these functions and influences eggshell structure. Evolution of prolonged uterine egg retention results in a significant change in the incubation environment, notably reduction in efficiency of gas exchange, and selection should favor a concomitant reduction in eggshell thickness. This model is supported by studies that demonstrate an inverse correlation between eggshell thickness and length of uterine egg retention. One mechanism leading to thinning of the eggshell is reduction in size of uterine shell glands. Saiphos equalis is an Australian scincid lizard with an unusual pattern of geographic variation in reproductive mode. All populations retain eggs in the uterus beyond the embryonic stage at oviposition typical for lizards, and some are viviparous. We compared structure and histochemistry of the uterus and eggshell of two populations of S. equalis, prolonged egg retention, and viviparous to test the hypotheses: 1) eggshell thickness is inversely correlated with length of egg retention and 2) eggshell thickness is positively correlated with size of shell glands. We found support for the first hypothesis but also found that eggshells of both populations are surprisingly thick compared with other lizards. Our histochemical data support prior conclusions that uterine shell glands are the source of protein fiber matrix of the eggshell, but we did not find a correlation between size of shell glands and eggshell thickness. Eggshell thickness is likely determined by density of uterine shell glands in this species. PMID- 20715149 TI - Thermally induced plasticity of body shape in adult zebrafish Danio rerio (Hamilton, 1822). AB - We examined the effect of temperature during the early development on the phenotypic plasticity of Danio rerio. The effect of temperature was examined during two different early developmental periods of 280 degrees d (the product of days * temperature) each, 28-308 degrees d or 280-560 degrees d, by subjecting the experimental populations to three different water temperatures (22 degrees C, 28 degrees C, and 32 degrees C). Before and after the end of the 280 degrees d period of the different thermal exposure, all populations were cultured in standard temperature (28 degrees C). Five to 10 months after exposure to the different thermal regimes, the body shape of the adults was analyzed by geometric morphometrics. In both ontogenetic windows and experimental repetitions, the results showed that developmental temperature and sex significantly affected the body shape of adult zebrafish. Thermally induced shape variation discriminated the fish that developed at 22 degrees C from those developed at 28 degrees C-32 degrees C. In the early developmental period (DP1, 28-308 degrees d postfertilization), dorsal, anal, and caudal fin structures differed between the animals that developed at 22 degrees C and 28 degrees C-32 degrees C. In the later developmental period (DP2, 280-560 degrees d postfertilization), caudal, anal, pectoral, and pelvic fins, as well as the gill cover and lower jaw, were affected when animals developed at different temperatures. These results show that thermal history during a short period of embryonic and larval life affects the body form of adult zebrafish with potentially functional consequences. Based on previous data on the effects of temperature on fish development, we suggest thermally induced muscle and bone remodelling as possible mechanism underlying the observed plasticity. PMID- 20715150 TI - Ultrastructure of spermiogenesis in the American alligator, Alligator mississippiensis (Reptilia, Crocodylia, Alligatoridae). AB - Testicular samples were collected to describe the ultrastructure of spermiogenisis in Alligator mississipiensis (American Alligator). Spermiogenesis commences with an acrosome vesicle forming from Golgi transport vesicles. An acrosome granule forms during vesicle contact with the nucleus, and remains posterior until mid to late elongation when it diffuses uniformly throughout the acrosomal lumen. The nucleus has uniform diffuse chromatin with small indices of heterochromatin, and the condensation of DNA is granular. The subacrosome space develops early, enlarges during elongation, and accumulates a thick layer of dark staining granules. Once the acrosome has completed its development, the nucleus of the early elongating spermatid becomes associated with the cell membrane flattening the acrosome vesicle on the apical surface of the nucleus, which aids in the migration of the acrosomal shoulders laterally. One endonuclear canal is present where the perforatorium resides. A prominent longitudinal manchette is associated with the nuclei of late elongating spermatids, and less numerous circular microtubules are observed close to the acrosome complex. The microtubule doublets of the midpiece axoneme are surrounded by a layer of dense staining granular material. The mitochondria of the midpiece abut the proximal centriole resulting in a very short neck region, and possess tubular cristae internally and concentric layers of cristae superficially. A fibrous sheath surrounds only the axoneme of the principal piece. Characters not previously described during spermiogenesis in any other amniote are observed and include (1) an endoplasmic reticulum cap during early acrosome development, (2) a concentric ring of endoplasmic reticulum around the nucleus of early to middle elongating spermatids, (3) a band of endoplasmic reticulum around the acrosome complex of late developing elongate spermatids, and (4) midpiece mitochondria that have both tubular and concentric layers of cristae. PMID- 20715151 TI - JNK phosphorylates Ser332 of doublecortin and regulates its function in neurite extension and neuronal migration. AB - Doublecortin (DCX) is expressed in young neurons and functions as a microtubule associated protein. DCX is essential for neuronal migration because humans with mutations in the DCX gene exhibit cortical lamination defects known as lissencephaly in males and subcortical laminar heterotopia (or double cortex syndrome) in females. Phosphorylation of DCX alters its affinity for tubulin and may modulate neurite extension and neuronal migration. Previous in vitro phosphorylation experiments revealed that cyclin-dependent kinase 5 (Cdk5) phosphorylates multiple sites of DCX, including Ser332, (S332). However, phosphorylation at only Ser297 has been shown in vivo. In the present study, we examined phosphorylation of S332 of DCX in the Cdk5-/- mouse brain and results found, unexpectedly, indicate an increased DCX phosphorylation at S332. We found that JNK, not Cdk5, phosphorylates DCX at S332 in vivo. To examine the physiological significance of S332 phosphorylation of DCX in neuronal cells, we transfected cells with either GFP, GFP-DCX-WT, or GFP-DCX-S332A and analyzed neurite extension and migration. Introduction of GFP-DCX-WT enhanced neurite extension and migration. These effects of DCX introduction were suppressed when we used GFP-DCX-S332A. Treatment of neurons with JNK inhibitor increased the amount of DCX that bound to tubulin. Interestingly, amount of DCX that bound to tubulin decreased in Cdk5-/- brain homogenates, which indicates that phosphorylation of DCX by JNK is critical for the regulation of DCX binding to tubulin. These results suggest the physiological importance of phosphorylation of DCX for its function. PMID- 20715152 TI - Progesterone, administered before kainic acid, prevents decrements in cognitive performance in the Morris Water Maze. AB - The nature of progesterone (P4)'s neuroprotective effects is of interest. We investigated effects of P4 when administered before, or after, kainic acid, which produces ictal activity and damage to the hippocampus, to mediate effects on spatial performance. The hypothesis was that P4, compared with vehicle, would reduce decrements in Morris Water Maze performance induced by kainic acid. Experiment 1: We examined the effects of kainic acid on plasma stress hormone, corticosterone, and progestogen (P4 and its metabolites) levels in plasma and the hippocampus after subcutaneous (s.c.) P4 administration to ovariectomized rats. Rats administered kainic acid had the highest corticosterone levels immediately following injection. P4 is 5alpha-reduced to dihydroprogesterone (DHP) and subsequently metabolized to 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) by 3alpha-hydroxysteroid dehydrogenase. The regimen of P4 used produced circulating and hippocampal levels of P4, DHP, and 3alpha,5alpha-THP within a physiological range, which declined at 14 hours postinjection and were not altered by kainic acid. Experiment 2: The physiological P4 regimen was administered to rats before, or after, kainic acid-induced seizures, and later effects on water maze performance were compared with that of rats administered vehicle. Rats administered kainic acid had significantly poorer performance in the water maze (i.e., increased latencies and distances to the hidden platform) than did rats administered vehicle. Administration of P4 before, but not after, kainic acid prevented these performance deficits. Thus, these data suggest that a physiological regimen of P4 can prevent some of the deficits in water maze performance produced by kainic acid. PMID- 20715153 TI - Segregation of the classical transmitters norepinephrine and acetylcholine and the neuropeptide Y in sympathetic neurons: modulation by ciliary neurotrophic factor or prolonged growth in culture. AB - Recent evidence has demonstrated that cotransmission from mammalian neurons is not uniquely achieved by costorage and corelease of transmitters and cotransmitters from single varicosities, but also by the concurrent release of mediators segregated in separate synapses of individual neurons. An important question to be addressed is whether neurons show defined patterns of segregation or whether this is a plastic feature. We addressed this question by exploring the segregation pattern of the classical sympathetic transmitters norepinephrine (NE) and acetylcholine (ACh) and the cotransmitter neuropeptide Y (NPY) in sympathetic ganglionic neurons cocultured with cardiac myocytes. Using antibodies against NPY and the vesicular NE and ACh transporters VMAT2 and vesicular acetylcholine transporter (VAChT), we investigated the effect of ciliary neurotrophic factor (CNTF) or long (three weeks) culture periods on the segregation of VMAT2, VAChT, and NPY to separate varicosities. We found that although ganglionic neurons showed cell body coexpression of all the markers examined after three days, VMAT2 was segregated from VAChT in 43% of the VAChT-positive varicosities. In contrast, VMAT2 was only segregated from NPY in 16.3% of the NPY-positive varicosities. Cotransmitter segregation and VAChT expression was potentiated by both CNTF and longer times in culture. We also found two types of varicosities: one was smaller and located further from neuronal somata, and the other was larger, proximal to neuronal somata and had a higher level of segregation. These data demonstrate segregation of classical transmitters in sympathetic neurons and plasticity of neurotransmitter segregation. Finally, we discuss a possible functional correlate of segregation in sympathetic neurons. PMID- 20715154 TI - delta-Catenin dysregulation in cancer: interactions with E-cadherin and beyond. AB - Stable E-cadherin-based adherens junctions are pivotal in maintaining epithelial tissue integrity and are the major barrier for epithelial cancer metastasis. Proteins of the p120(ctn) subfamily have emerged recently as critical players for supporting this stability. The identification of the unique juxtamembrane domain (JMD) in E-cadherin that binds directly to delta-catenin/NPRAP/neurojungin (CTNND2) and p120(ctn) (CTNND1) provides a common motif for their interactions. Recently, crystallographic resolution of the JMD of p120(ctn) further highlighted possibilities of intervening between interactions of p120(ctn) subfamily proteins and E-cadherin for designing anti-cancer therapeutics. For most epithelial cancers, studies have demonstrated a reduction of p120(ctn) expression or alteration of its subcellular distribution. On the other hand, delta-catenin, a primarily neural-enriched protein in the brain of healthy individuals, is up regulated in all cancer types that have been studied to date. Two research articles in the September 2010 issue of The Journal of Pathology increase our understanding of the involvement of these proteins in lung cancer. One reports the identification of rare p120(ctn) (CTNND1) gene amplification in lung cancer. One mechanism by which delta-catenin and p120(ctn) may play a role in carcinogenesis is their competitive binding to E-cadherin through the JMD. The other presents the first vigorous characterization of delta-catenin overexpression in lung cancer. Unexpectedly, the authors observed that delta catenin promotes malignant phenotypes of non-small cell lung cancer by non competitive binding to E-cadherin with p120(ctn) in the cytoplasm. Looking towards the future, the understanding of delta-catenin and p120(ctn) with and beyond their localization at the cell-cell junction should provide further insight into their roles in cancer pathogenesis. PMID- 20715155 TI - Evidence for multiple, developmentally regulated isoforms of Ptprq on hair cells of the inner ear. AB - Ptprq is a receptor-like inositol lipid phosphatase associated with the shaft connectors of hair bundles. Three lines of evidence suggest Ptprq is a chondroitin sulfate proteoglycan: (1) chondroitinase ABC treatment causes a loss of the ruthenium-red reactive, electron-dense particles associated with shaft connectors, (2) chondroitinase ABC causes an increase in the electrophoretic mobility of Ptprq, and (3) hair bundles in the developing inner ear of wild-type mice, but not those of Ptprq(-/-) mice, react with monoclonal antibody (mAb) 473 HD, an IgM that recognizes the dermatan-sulfate-dependent epitope DSD1. Two lines of evidence indicate that there may be multiple isoforms of Ptprq expressed in hair bundles. First, although Ptprq is expressed throughout the lifetime of most hair cells, hair bundles in the mouse and chick inner ear only express the DSD1 epitope transiently during development. Second, mAb H10, a novel mAb that recognizes an epitope common to several avian inner-ear proteins including Ptprq, only stains mature hair bundles in the extrastriolar regions of the vestibular maculae. MAb H10 does not stain mature hair bundles in the striolar regions of the maculae or in the basilar papilla, nor does it stain immature hair bundles in any organ. Three distinct, developmentally regulated isoforms of Ptprq may therefore be expressed on hair bundles of the chick inner ear. Hair bundles in the mature chick ear that do not express the H10 epitope have longer shaft connectors than those that do, indicating the presence or absence of the H10 epitope on Ptprq may modulate the spacing of stereocilia. PMID- 20715156 TI - Tandem dosing of samarium-153 ethylenediamine tetramethylene phosphoric acid with stem cell support for patients with high-risk osteosarcoma. AB - BACKGROUND: Samarium-153 ethylenediamine tetramethylene phosphoric acid (153Sm EDTMP) is a radiopharmaceutical that has been used to treat osteosarcoma. The authors conducted a phase 2 study to test safety and response of high-risk osteosarcoma to tandem doses of 153Sm-EDTMP and to determine correlation between radiation delivered by low and high administered activities. METHODS: Patients with recurrent, refractory osteosarcoma detectable on standard 99mTc bone scan received a low dose of 153Sm-EDTMP (37.0-51.8 MBq/kg), followed upon count recovery by a second, higher dose (222 MBq/kg). Fourteen days later, patients were rescued with autologous hematopoietic stem cells. The authors assessed response to therapy, performed dosimetry to determine the relationship between administered activity and tumor absorbed dose, and investigated whether changes in 2-(fluorine-18) fluoro-2-deoxy-d-glucose (18F-FDG) tumor uptake upon hematologic recovery reflected disease response. RESULTS: Nine patients were given tandem doses of 153Sm-EDTMP; 2 received only the initial dose because of disease progression. Six patients experienced radiographic disease stabilization, but this was not considered a response, so the study was terminated early. There was a linear relationship between administered activity and tumor absorbed dose, but there was no correlation between change in 18F-FDG positron emission tomography tumor uptake and tumor absorbed dose or time to progression. The median time to progression for the entire group was 79 days. CONCLUSIONS: Tandem doses of 153Sm-EDTMP were safe for this cohort of heavily pretreated patients with very high-risk disease. The strong correlation between absorbed dose and administered activity within each evaluable patient provides a methodology to individually tailor tandem doses of this agent. PMID- 20715158 TI - Overexpression of CD151 as an adverse marker for intrahepatic cholangiocarcinoma patients. AB - BACKGROUND: Previous studies have indicated that CD151, a hydrophobic protein, forms a functional complex with the proto-oncogene that encodes an N-methyl-N' nitro-N-nitroso-guanidine (MET) protein (c-Met), and CD151 overexpression reportedly is involved in metastasis/invasion of several tumors. The objective of the current study was to investigate the expression and role of CD151 and/or c Met in intrahepatic cholangiocarcinoma (ICC). METHODS: Sixty ICC tissues with matched nontumorous tissues and 20 normal liver tissues were used to analyze CD151 expression at the level of messenger RNA (mRNA) and protein. Then, the expression of CD151 in an ICC cell line was interrupted using a specific lentiviral-mediated small hairpin RNA (shRNA)-CD151, and the role of CD151 in the proliferation, metastasis, and invasion of ICC cells was assessed. The expression of CD151/c-Met was examined further by immunohistochemistry in a tissue microarray (TMA) that included 140 samples of ICC, and the prognostic role of CD151 and/or c-Met in ICC was evaluated in Kaplan-Meier and Cox regression analyses. RESULTS: The expression of CD151 in ICC tissues was much higher than that in nontumorous samples and normal liver; and, after the down-regulation of CD151, HCCC-9810 cells had decreased capability for metastasis/invasion in vitro. CD151 overexpression was correlated significantly with larger tumors, poor differentiation, multiple nodular, microvascular/bile duct invasion, and lymphatic metastasis (P<.05). The postoperative 2-year and 5-year overall survival (OS) rates for patients with low CD151 expression (<50% tumor staining) and/or low c-Met expression (<20% tumor staining) were higher than the rates for patients with high CD151 expression (>=50% tumor staining) and/or high c-Met expression (>=20% tumor staining). Multivariate analysis revealed that CD151 overexpression and c-Met overexpression were independent prognostic markers for ICC. CONCLUSIONS: Overexpression of CD151 was implicated in metastasis/invasion of ICC, and both CD151 overexpression and c-Met overexpression may be potential molecular therapeutic targets for ICC. PMID- 20715157 TI - The frameshift polymorphism CYP3A43_74_delA is associated with poor differentiation of breast tumors. AB - BACKGROUND: CYP3A enzymes, due to their role in the metabolism of steroid hormones, are suggested to affect carcinogenesis of hormone-related cancers. The purpose of the present study was to evaluate the association between polymorphisms located in CYP3A43, breast cancer risk, and tumor characteristics. METHODS: A 3-plex matrix-assisted laser desorption ionization time of flight mass spectrometry assay has been established for CYP3A43_74_delA (CYP3A43*2A), CYP3A43_1018_C>G (CYP3A43*3), and CYP3A43_1047_C>T (CYP3A43*1B) polymorphisms, and 1021 breast cancer cases and 1015 age-matched, population-based controls from the German GENICA collection have been genotyped. RESULTS: No differences in genotype frequencies between cases and controls were observed, indicating that CYP3A43_74_delA is not associated with breast cancer risk. Subgroup analyses showed an association between the CYP3A43_74_delA allele and high-grade tumors (odds ratio, 1.74; 95% confidence interval, 1.14-2.65 [P=.010 and Ptrend=.012]). CONCLUSIONS: The data support the notion that the CYP3A43_74_delA variant may result in decreased protein and/or activity levels, and this may further lead to increased hormone levels to promote tumor cell growth and hinder differentiation. PMID- 20715159 TI - The prevalence and assessment of ErbB2-positive breast cancer in Asia: a literature survey. AB - Overexpression of the epidermal growth factor receptor-related gene ErbB2 occurs in 18% to 25% of patients with breast cancer in Western countries and is associated with a poor prognosis. The prevalence of ErbB2-positive tumors in Asia is unclear, partly because data are limited. The objective of this review was to summarize the reported prevalence of ErbB2-positive tumors from a large sample of Asian patients and to examine ErbB2 assessment methods in Asia. From searches of MEDLINE, local language journals, and local and international conference proceedings as well as locoregional breast cancer experts' recommendations, the authors selected up to 5 studies each from India, Korea, Malaysia, the Philippines, Singapore, Taiwan, and Thailand that reported ErbB2 results based on assessment with immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). The reported prevalence of ErbB2-positive tumors in 22 studies on 24,671 patients, of whom 14,398 patients were assessed for ErbB2 status, varied widely (range, 6%-65%) as did the assessment methods used. Most studies (n=21) used IHC to assess ErbB2 status, but definitions for positivity varied. When robust assessment methods were used, the median prevalence was 19% based on strong IHC staining (IHC3+; n=9812 patients) and 25% based on FISH (n=681 patients). Data on the prevalence of ErbB2-positive breast cancer in Asia are limited. The current survey indicated that the prevalence in Asia may be similar to that in Western countries; thus, up to 1 in 4 Asian patients with breast cancer potentially could benefit from ErbB2-targeted treatment. A standard, reliable ErbB2 assessment method available to patients across Asia is urgently required. PMID- 20715160 TI - Risk of mortality in patients with cancer who experience febrile neutropenia. AB - BACKGROUND: Febrile neutropenia (FN) is a serious and potentially life threatening condition that may develop in patients with cancer who receive myelosuppressive chemotherapy. The risk of mortality from FN is not well characterized in current clinical practice. METHODS: Patients with cancer who were receiving chemotherapy in clinical practice were identified from a large US healthcare claims database, and mortality was confirmed using the National Death Index. Patients with FN had their propensity scores matched within tumor types of interest (non-Hodgkin lymphoma and breast, lung, colorectal, and ovarian cancers) to patients who did not experience FN. Study endpoints of overall mortality (anytime during follow-up), early mortality (during the first 12 months of the first chemotherapy course), and hospitalization were examined using univariate and multivariate techniques. RESULTS: Matched FN and control groups each included 5990 patients, and the average follow-up for both groups was 17.6 months. Crude incidence rates of early mortality were significantly higher for patients with FN compared with controls for all tumor types. Proportional hazards regression demonstrated a significant increase in the risk of overall and early mortality in patients with FN compared with controls (hazard ratio [HR], 1.15 [95% confidence interval, 1.02-1.29] and HR, 1.35 [95% confidence interval, 1.09-1.67], respectively). CONCLUSIONS: The adjusted risk of mortality in patients who experienced FN was at least 15% higher than in comparably matched patients without FN, supporting the inference that infectious complications because of neutropenia resulting from myelosuppressive chemotherapy are clinically important. PMID- 20715161 TI - Radiation-induced sarcoma in patients with nasopharyngeal carcinoma: a single institution study. AB - BACKGROUND: The increasing incidence of radiation-induced sarcoma (RIS) has become a significant problem that can limit long-term survival. The objective of the current study was to analyze the clinicopathologic characteristics, treatment outcomes, and prognostic factors of RIS after radiotherapy for nasopharyngeal carcinoma (NPC). METHODS: Institutional electronic medical records of patients with NPC who received definitive radiotherapy between February 1964 and 2003 were reviewed. Fifty-three patients who developed RIS and fulfilled the study criteria were included. RESULTS: The median follow-up after a diagnosis of RIS was 15.5 months (range, 0.4-90.3 months), and the median latency between radiotherapy for NPC and an RIS diagnosis was 9.3 years (range, 3.2-26.6 years). Fibrosarcoma was the most frequent histologic type observed, followed by osteosarcoma, and malignant fibrous histiocytoma. The 3-year overall survival (OS) rate for 49 patients who received treatment was 32.4%, and the median survival was 21.2 months (95% confidence interval, 8.7-33.8 months). The median OS was 41.3 months, 8.4 months, and 11 months for the complete resection group, the incomplete resection group, and the chemotherapy group, respectively (P<.0001). The only independent predictive factor that was associated with better OS was complete surgical resection. CONCLUSIONS: This retrospective study confirmed the rarity and poor prognosis of RIS in patients with NPC. Complete surgical resection was a significant prognostic factor for survival. The authors concluded that long-term follow-up is necessary for the early detection of RIS in patients with NPC. PMID- 20715162 TI - Prognostic value of lymph node evaluation in small bowel adenocarcinoma: analysis of the surveillance, epidemiology, and end results database. AB - BACKGROUND: The presence of distant metastases and the completeness of resection are important prognostic factors in patients with small bowel adenocarcinoma (SBA); however, the influence of lymph node metastasis on patient outcome has not been well characterized. The objective of the current study was to evaluate the impact of the number of positive and negative lymph nodes on survival after curative resection. METHODS: Patients who had SBA diagnosed between 1988 and 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) registry. Cox proportional hazards regression analyses were performed after adjusting for age, sex, race, tumor stage, tumor grade, and primary site. Five year disease-specific survival (DSS) was determined, all patients were categorized according to the total lymph nodes (TLNs) assessed, and patients with stage III disease also were categorized according to the number of positive lymph nodes (PLNs) and the PLN-to-TLN ratio (the lymph node ratio [LNR]). RESULTS: In total, 1991 patients (n=1216 with stage I/II SBA and n=775 with stage III SBA) were analyzed. Survival depended on the TLNs assessed. The 5-year DSS rate for patients with stage II disease was associated with the TLNs assessed (44%, 69%, and 83% for 0 TLNs, 1-7 TLNs, and>7 TLNs, respectively). The 5-year DSS for patients with stage III disease was associated with the number of PLNs (58% and 37% for <3 PLNs and >=3 PLNs, respectively). Among patients with stage III disease, the LNR was even more predictive of survival than stratification by the number of PLNs. CONCLUSIONS: Survival after surgical resection for stage I, II, and III SBA was associated with the TLNs assessed. Stratifying patients with stage III disease into those with <3 PLNs and >=3 PLNs significantly improved prognostication. PMID- 20715163 TI - Cationic polymer-mediated small interfering RNA delivery for P-glycoprotein down regulation in tumor cells. AB - BACKGROUND: Among the treatment options that have been developed for cancer, chemotherapy remains 1 of the leading clinical approaches. Chemotherapy can usually control tumor growth at the onset of disease, but its effectiveness becomes limited by the overexpression of transporter proteins responsible for drug efflux, leading to multidrug resistance (MDR). To overcome this obstacle, the authors explored the feasibility of down-regulating the main drug transporter, P-glycoprotein (P-gp), by using nonviral small interfering RNA (siRNA) delivery as means to enhance the accumulation of chemotherapeutic agents in drug-resistant cancer cells. METHODS: Several cationic carriers capable of siRNA complexation were investigated for P-gp down-regulation in the MDA435/LCC6 cell line and, consequently, increased cellular uptake of the chemotherapeutic agents doxorubicin and paclitaxel. RESULTS: Efficient siRNA delivery into tumor cells was demonstrated particularly using a palmitic-acid substituted poly(L lysine), with no apparent differences in siRNA delivery between the wild type (WT)-expressing and P-gp-expressing phenotype (MDR1) of the cells. Efficient siRNA delivery led to approximately 40% to 50% P-gp suppression (based on the average expression level of the protein), an approximately 3-fold increased DOX uptake, and increased cytotoxicity in MDR1 cells. CONCLUSIONS: The authors concluded that effective siRNA delivery with nonviral carriers can reduce the level of P-gp on cell surfaces and enhance the efficiency of chemotherapeutic agents in vitro. PMID- 20715164 TI - A novel null allele of mouse DSCAM survives to adulthood on an inbred C3H background with reduced phenotypic variability. AB - DSCAMs are cell adhesion molecules that play several important roles in neurodevelopment. Mouse alleles of Dscam identified to date do not survive on an inbred C57BL/6 background, complicating analysis of DSCAM-dependent developmental processes because of phenotypic variability related to the segregating backgrounds needed for postnatal survival. A novel spontaneous allele of Dscam, hereafter referred to as Dscam2(J), has been identified. This allele contains a four base pair duplication in exon 19, leading to a frameshift and truncation of the open reading frame. Mice homozygous for the Dscam2(J) mutant allele survive into adulthood on the C3H/HeJ background on which the mutation was identified. Using the Dscam2(J) allele, retinal phenotypes that have variable severity on a segregating background were examined. A neurite lamination defect similar to that described in chick was discovered in mice. These results indicate that, in the retina, additional DSCAM-dependent processes can be found by analysis of mutations on different genetic backgrounds. PMID- 20715165 TI - A comparison of client preferences for intervention empirical support versus common therapy variables. AB - Client preferences have been identified as an essential part of evidence-based practice in psychology. Further, client preferences have been found to play an important role in determining premature termination and therapy outcomes. However, our current understanding of this client variable is limited because of the methodologies that have previously been used to assess these preferences. In this study, 57 adult clients from a university-based psychology department clinic completed an instrument weighing preferences for intervention specific empirical support against preferences for 4 other common factor variables. These clients were found to discount a significant amount of intervention empirical support to ensure the following: (a) a satisfactory therapeutic relationship could be developed, (b) their therapist would be empathetic and accepting, (c) their therapist would have a greater level of experience, and (d) they, as clients, would do more of the talking during sessions. These findings suggest that clients prefer treatment decisions to be based on variables other than intervention empirical support alone. Recommendations are made for assessing and including client preferences to provide more individually tailored interventions. PMID- 20715166 TI - Isolated sleep paralysis and fearful isolated sleep paralysis in outpatients with panic attacks. AB - Isolated sleep paralysis (ISP) has received scant attention in clinical populations, and there has been little empirical consideration of the role of fear in ISP episodes. To facilitate research and clinical work in this area, the authors developed a reliable semistructured interview (the Fearful Isolated Sleep Paralysis Interview) to assess ISP and their proposed fearful ISP (FISP) episode criteria in 133 patients presenting for panic disorder treatment. Of these, 29.3% met lifetime ISP episode criteria, 20.3% met the authors' lifetime FISP episode criteria, and 12.8% met their recurrent FISP criteria. Both ISP and FISP were associated with minority status and comorbidity. However, only FISP was significantly associated with posttraumatic stress disorder, body mass, anxiety sensitivity, and mood and anxiety disorder symptomatology. PMID- 20715167 TI - Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. AB - The aim of our study was to provide population-based data on incidence and prognosis of synchronous peritoneal carcinomatosis and to evaluate predictors for its development. Diagnosed in 1995-2008, 18,738 cases of primary colorectal cancer were included. Predictors of peritoneal carcinomatosis were analysed by multivariable logistic regression analysis. Median survival in months was calculated by site of metastasis. In the study period, 904 patients were diagnosed with synchronous peritoneal carcinomatosis (4.8% of total, constituting 24% of patients presenting with M1 disease). The risk of peritoneal carcinomatosis was increased in case of advanced T stage [T4 vs. T1,2: odds ratio (OR) 4.7, confidence limits 4.0-5.6), advanced N stage [N0 vs. N1,2: OR 0.2 (0.1 0.2)], poor differentiation grade [OR 2.1 (1.8-2.5)], younger age [<60 years vs. 70-79 years: OR 1.4 (1.1-1.7)], mucinous adenocarcinoma [OR 2.0 (1.6-2.4)] and right-sided localisation of primary tumour [left vs. right: OR 0.6 (0.5-0.7)]. Median survival of patients with peritoneum as single site of metastasis remained dismal [1995-2001: 7 (6-9) months; 2002-2008: 8 (6-11) months], contrasting the improvement among patients with liver metastases [1995-2001: 8 (7-9) months; 2002 2008: 12 (11-14) months]. To conclude, synchronous peritoneal metastases from colorectal cancer are more frequent among younger patients and among patients with advanced T stage, mucinous adenocarcinoma, right-sided tumours and tumours that are poorly differentiated. The prognosis of synchronous peritoneal carcinomatosis remains poor with a median survival of 8 months and even worse if concomitant metastases in other organs are present. PMID- 20715168 TI - Decreased expression of updated NESG1 in nasopharyngeal carcinoma: its potential role and preliminarily functional mechanism. AB - Human NESG1 (CCDC19) gene was originally isolated in our laboratory from human nasopharynx tissue. However, the biological and clinical significances of this gene remain largely unknown. In this report, two errors in the originally submitted sequence of human NESG1 gene were found, and the open reading frame sequence of NESG1 (Accession number: NM_012337.1) was revised and updated in the NCBI database (Accession number: NM_012337.2). The antibody raised against the revised sequence of NESG1 detected a single band of 66 kD in human nasopharynx tissues. NESG1 transcripts were specifically expressed in the nasopharynx epithelium. Expression of NESG1 transcripts and protein was downregulated or absent in nasopharyngeal carcinoma (NPC) tissues and cell lines in comparison to that in the normal nasopharynx tissues. The levels of NESG1 protein were significantly greater in the low-grade NPC tissues than that in the high-grade NPC tissues. Induced expression of NESG1 in otherwise NESG1-negative 5-8F cells not only significantly decreased cell proliferation, G1-S phase transition, but also markedly inhibited the ability of cell migration and invasion as well as in vivo tumorigenesis. Furthermore, NESG1 also significantly regulated the expression of cell cycle regulator CCNA1 and p21. Our findings first provided evidence that NESG1 may act as a tumor suppressor by inhibiting cell proliferation, invasion and migration of NPC cells. PMID- 20715169 TI - Antitumor activities and on-target toxicities mediated by a TRAIL receptor agonist following cotreatment with panobinostat. AB - The recent development of novel targeted anticancer therapeutics such as histone deacetylase inhibitors (HDACi) and activators of the TRAIL pathway provide opportunities for the introduction of new treatment regimens in oncology. HDACi and recombinant TRAIL or agonistic anti-TRAIL receptor antibodies have been shown to induce synergistic tumor cell apoptosis and some therapeutic activity in vivo. Herein, we have used syngeneic preclinical models of human solid cancers to demonstrate that the HDACi panobinostat can sensitize tumor cells to apoptosis mediated by the anti-mouse TRAIL receptor antibody MD5-1. We demonstrate that the combination of panobinostat and MD5-1 can eradicate tumors grown subcutaneously and orthotopically in immunocompetent mice, while single agent treatment has minimal effect. However, escalation of the dose of panobinostat to enhance antitumor activity resulted in on-target MD5-1-mediated gastrointestinal toxicities that were fatal to the treated mice. Studies performed in mice with knockout of the TRAIL receptor showed that these mice could tolerate doses of the panobinostat/MD5-1 combination that were lethal in wild type mice resulting in superior tumor clearance. Given that clinical studies using HDACi and activators of the TRAIL pathway have been initiated, our preclinical data highlight the potential toxicities that could limit the use of such a treatment regimen. Our studies also demonstrate the power of using syngeneic in vivo tumor models as physiologically relevant preclinical systems to test the antitumor effects and identify potential side effects of novel anticancer regimens. PMID- 20715170 TI - Birth order and risk of childhood cancer: a pooled analysis from five US States. AB - The causes of childhood cancers are largely unknown. Birth order has been used as a proxy for prenatal and postnatal exposures, such as frequency of infections and in utero hormone exposures. We investigated the association between birth order and childhood cancers in a pooled case-control dataset. The subjects were drawn from population-based registries of cancers and births in California, Minnesota, New York, Texas and Washington. We included 17,672 cases <15 years of age who were diagnosed from 1980 to 2004 and 57,966 randomly selected controls born 1970 2004, excluding children with Down syndrome. We calculated odds ratios and 95% confidence intervals using logistic regression, adjusted for sex, birth year, maternal race, maternal age, multiple birth, gestational age and birth weight. Overall, we found an inverse relationship between childhood cancer risk and birth order. For children in the fourth or higher birth order category compared to first-born children, the adjusted OR was 0.87 (95% CI: 0.81, 0.93) for all cancers combined. When we examined risks by cancer type, a decreasing risk with increasing birth order was seen in the central nervous system tumors, neuroblastoma, bilateral retinoblastoma, Wilms tumor and rhabdomyosarcoma. We observed increased risks with increasing birth order for acute myeloid leukemia but a slight decrease in risk for acute lymphoid leukemia. These risk estimates were based on a very large sample size, which allowed us to examine rare cancer types with greater statistical power than in most previous studies, however the biologic mechanisms remain to be elucidated. PMID- 20715172 TI - Increased expression and serum levels of the stromal cell-secreted protein periostin in breast cancer bone metastases. AB - Periostin, a matricellular protein, is overexpressed in the stroma of several cancers. The aim of our study was to investigate more specifically whether periostin expression is associated with bone metastases from breast cancer and to determine its source in the affected bone. Nude mice were inoculated with human MDA-B02 breast cancer cells. Bone metastases-bearing mice were treated with zoledronic acid-an antiresorptive drug-or vehicle. Bone metastases were examined for tumor- and stroma-derived periostin expression by quantitative polymerase chain reaction with human- and mouse-specific primers and immunohistochemistry. Serum periostin and conventional bone turnover markers were also measured. MDA B02 cells did not express periostin both in vitro and in vivo. However, mouse derived periostin was markedly overexpressed (eightfold) in metastatic legs compared to noninoculated mice. Serum periostin levels were also markedly increased in metastatic mice and correlated with in situ expression levels. Immunostaining showed that periostin derived from the environing stromal cells of bone metastasis. Bone turnover blockade by zoledronic acid markedly decreased osteolytic lesions but only slightly modulated serum periostin levels. Bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells. Periostin could be a biochemical marker of the early stromal response associated to breast cancer bone metastasis formation. PMID- 20715171 TI - Fluid intake and the risk of urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow-up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking. When using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86-1.45, p-trend = 0.42) or with risk of prognostically high-risk UCC (HR 1.28; 95%CI 0.85-1.93, p-trend = 0.27) or prognostically low-risk UCC (HR 0.93; 95%CI 0.65-1.33, p-trend = 0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea and milk and other dairy beverages. For prognostically low-risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low-risk UCC with higher intake of fruit and vegetable juices. In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance, but further investigation of the role of all types of fluid is warranted. PMID- 20715173 TI - Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1alpha protein-dependent mechanism. AB - A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1alpha protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1alpha protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1alpha-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1alpha protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1alpha protein-dependent manner. In addition, pretreatment of cells with propranolol, a beta-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF 1alpha protein amount by NE in all of the tested cancer cells. However, treatment with the alpha1-AR blocker prazosin inhibited NE-induced HIF-1alpha protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1alpha protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis. PMID- 20715174 TI - RU486-inducible recombination in the salivary glands of lactoferrin promoter driven green fluorescent Cre transgenic mice. AB - When compared with the many tamoxifen-activated Cre mouse lines available for gene manipulation studies, relatively few RU486-inducible Cre mice are in use, due to leakiness issues. Here, we report the generation of an RU486-inducible triple fusion gene (GCrePR1e), consisting of green fluorescent protein, Cre, and the progesterone receptor ligand-binding domain (F642-L901). We sought to improve the GCrePR1e by selecting a truncated human lactoferrin (Lf) promoter to drive its expression, based on the promoter's low basal activity and innate sensitivity to RU486. The resulting vector displayed decreased leakiness and increased Cre induction by RU486 through transcriptional and posttranslational regulation in in vitro transfection assays. Inducible GCrePR1e expression was found in most organs of Lf-GCrePR1e transgenic mice and highly activated in the salivary gland, spleen, and lymph nodes. In the bigenic mouse generated by crossing the Lf GCrePR1e mouse and the Cre reporter mouse (R26R-LacZ), we found that RU486 induced LacZ expression only in the mucous acini and striated ducts of the salivary gland and had very low background recombination in the untreated mice. Our results demonstrated that the Lf-CrePR1e vector was suitable for in vitro recombination in culture models, and Lf-CrePR1e transgenic mice could mediate spatially restricted and RU486-induced gene manipulation in the salivary gland. PMID- 20715175 TI - Tamoxifen-inducible Cre-mediated recombination in adipocytes. AB - To generate a mouse line which allows inducible, Cre/loxP-dependent recombination in adipocytes, we used RedE/RedT-mediated recombineering to insert the CreER(T)2 transgene, which encodes a fusion protein of Cre and a mutated tamoxifen responsive estrogen receptor, into the start codon of the adipocyte-specific Adipoq gene. Adipoq encodes adiponectin, an adipokine specifically expressed in differentiated adipocytes. Tamoxifen treatment induced almost complete recombination in white adipose tissue of the AdipoqCreER(T)2 mouse line (97% 99%), while no recombination was seen in vehicle-treated animals. Recombination in brown adipose tissue was about 15%, whereas other organs and tissues did not undergo recombination. In addition, mice expressing CreER(T)2 in adipocytes did not show any alterations of metabolic functions like glucose tolerance, lipolysis, or energy expenditure compared to control mice. Therefore the AdipoqCreER(T)2 mouse line will be a valuable tool for studying the consequences of a temporally controlled deletion of floxed genes in white adipose tissue. PMID- 20715176 TI - A mouse tool for conditional mutagenesis in ovarian granulosa cells. AB - Here we describe the generation of an inducible Cre transgenic line allowing conditional mutagenesis in ovarian granulosa cells. We have expressed the tamoxifen inducible CreER(T)2 fusion protein from a Bacterial Artificial Chromosome (BAC) containing the regulatory elements of the hydroxysteroid (17 beta) dehydrogenase 1 (Hsd17b1) gene. Hsd17b1-iCreER(T)2 transgenic mice express the iCreER(T)2 fusion protein exclusively in ovarian granulosa cells. Recombination analysis at the genomic DNA level using mice with "floxed" Stat3 alleles showed no Cre activity in absence of tamoxifen whereas tamoxifen treatment induced Cre activity solely in the ovaries. Further characterization of Hsd17b1-iCreER(T)2 mice using a Cre reporter line demonstrated that Cre-mediated recombination was restricted to ovarian granulosa cells. Therefore, Hsd17b1 iCreER(T)2 mice should be a useful tool to analyze the gene functions in ovarian granulosa cells. PMID- 20715177 TI - Elevated cytokine production restores bone resorption by human Btk-deficient osteoclasts. AB - Mutations in Bruton's tyrosine kinase (Btk) cause the B-cell disorder X-linked agammaglobulinaemia (XLA) in humans, but the effect of Btk deficiency in human bone health has not been investigated previously. In this study, we show that human Btk-deficient osteoclasts are defective at resorption activity in vitro owing to a dysregulation of the actin cytoskeletal function. Contrary to expectation, XLA patients did not exhibit increased bone density or alterations in serum markers of bone turnover, indicating that a potential compensation mechanism normalizes bone homeostasis. In contrast to the bone turnover markers, the levels of inflammatory cytokines interleukin 6 (IL-6), IL-1beta, and tumor necrosis factor alpha (TNF-alpha) were significantly elevated in XLA patients' serum compared with control individuals. Supplementation of osteoclast cultures from normal and XLA subjects with serum from XLA patients or recombinant inflammatory cytokines IL-6, IL-1beta, and TNF-alpha resulted in a stimulation of osteoclast activity in vitro, whereas the addition of cytokine-neutralizing antibodies inhibited this stimulatory effect, confirming that elevated inflammatory cytokines in XLA serum heightened osteoclast activity in vitro. This study provides novel evidence that Btk signaling is crucial for optimal actin cytoskeletal organization and lacunar resorption in isolated osteoclasts. In XLA patients, however, these inherent osteoclast defects are corrected by increased inflammatory cytokine levels, restoring osteoclast activity and leading to the normalization of bone density. PMID- 20715178 TI - Real-time measurement of solute transport within the lacunar-canalicular system of mechanically loaded bone: direct evidence for load-induced fluid flow. AB - Since proposed by Piekarski and Munro in 1977, load-induced fluid flow through the bone lacunar-canalicular system (LCS) has been accepted as critical for bone metabolism, mechanotransduction, and adaptation. However, direct unequivocal observation and quantification of load-induced fluid and solute convection through the LCS have been lacking due to technical difficulties. Using a novel experimental approach based on fluorescence recovery after photobleaching (FRAP) and synchronized mechanical loading and imaging, we successfully quantified the diffusive and convective transport of a small fluorescent tracer (sodium fluorescein, 376 Da) in the bone LCS of adult male C57BL/6J mice. We demonstrated that cyclic end-compression of the mouse tibia with a moderate loading magnitude (-3 N peak load or 400 uepsilon surface strain at 0.5 Hz) and a 4-second rest/imaging window inserted between adjacent load cycles significantly enhanced (+31%) the transport of sodium fluorescein through the LCS compared with diffusion alone. Using an anatomically based three-compartment transport model, the peak canalicular fluid velocity in the loaded bone was predicted (60 um/s), and the resulting peak shear stress at the osteocyte process membrane was estimated (~5 Pa). This study convincingly demonstrated the presence of load induced convection in mechanically loaded bone. The combined experimental and mathematical approach presented herein represents an important advance in quantifying the microfluidic environment experienced by osteocytes in situ and provides a foundation for further studying the mechanisms by which mechanical stimulation modulates osteocytic cellular responses, which will inform basic bone biology, clinical understanding of osteoporosis and bone loss, and the rational engineering of their treatments. PMID- 20715179 TI - Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. AB - The development of methods to achieve efficient reprogramming of human cells while avoiding the permanent presence of reprogramming transgenes represents a critical step toward the use of induced pluripotent stem cells (iPSC) for clinical purposes, such as disease modeling or reconstituting therapies. Although several methods exist for generating iPSC free of reprogramming transgenes from mouse cells or neonatal normal human tissues, a sufficiently efficient reprogramming system is still needed to achieve the widespread derivation of disease-specific iPSC from humans with inherited or degenerative diseases. Here, we report the use of a humanized version of a single lentiviral "stem cell cassette" vector to accomplish efficient reprogramming of normal or diseased skin fibroblasts obtained from humans of virtually any age. Simultaneous transfer of either three or four reprogramming factors into human target cells using this single vector allows derivation of human iPSC containing a single excisable viral integration that on removal generates human iPSC free of integrated transgenes. As a proof of principle, here we apply this strategy to generate >100 lung disease-specific iPSC lines from individuals with a variety of diseases affecting the epithelial, endothelial, or interstitial compartments of the lung, including cystic fibrosis, alpha-1 antitrypsin deficiency-related emphysema, scleroderma, and sickle-cell disease. Moreover, we demonstrate that human iPSC generated with this approach have the ability to robustly differentiate into definitive endoderm in vitro, the developmental precursor tissue of lung epithelia. PMID- 20715181 TI - Undifferentiated embryonic cell transcription factor 1 regulates ESC chromatin organization and gene expression. AB - Previous reports showed that embryonic stem (ES) cells contain hyperdynamic and globally transcribed chromatin-properties that are important for ES cell pluripotency and differentiation. Here, we demonstrate a role for undifferentiated embryonic cell transcription factor 1 (UTF1) in regulating ES cell chromatin structure. Using chromatin immunoprecipitation-on-chip analysis, we identified >1,700 UTF1 target genes that significantly overlap with previously identified Nanog, Oct4, Klf-4, c-Myc, and Rex1 targets. Gene expression profiling showed that UTF1 knock down results in increased expression of a large set of genes, including a significant number of UTF1 targets. UTF1 knock down (KD) ES cells are, irrespective of the increased expression of several self-renewal genes, Leukemia inhibitory factor (LIF) dependent. However, UTF1 KD ES cells are perturbed in their differentiation in response to dimethyl sulfoxide (DMSO) or after LIF withdrawal and display increased colony formation. UTF1 KD ES cells display extensive chromatin decondensation, reflected by a dramatic increase in nucleosome release on micrococcal nuclease (MNase) treatment and enhanced MNase sensitivity of UTF1 target genes in UTF1 KD ES cells. Summarizing, our data show that UTF1 is a key chromatin component in ES cells, preventing ES cell chromatin decondensation, and aberrant gene expression; both essential for proper initiation of lineage-specific differentiation of ES cells. PMID- 20715180 TI - B-Myb is critical for proper DNA duplication during an unperturbed S phase in mouse embryonic stem cells. AB - A common feature of early embryo cells from the inner cell mass (ICM) and of ESCs is an absolute dependence on an atypical cell cycle in which the G1 phase is shortened to preserve their self-renewing and pluripotent nature. The transcription factor B-Myb has been attributed a role in proliferation, in particular during the G2/M phases of the cell cycle. Intriguingly, B-Myb levels in ICM/ESCs are greater than 100 times compared with those in normal proliferating cells, suggesting a particularly important function for this transcription factor in pluripotent stem cells. B-Myb is essential for embryo development beyond the preimplantation stage, but its role in ICM/ESCs remains unclear. Using a combination of mouse genetics, single DNA fiber analyses and high-resolution three-dimensional (3D) imaging, we demonstrate that B-Myb has no influence on the expression of pluripotency factors, but instead B-Myb ablation leads to stalling of replication forks and superactivation of replication factories that result in disorganization of the replication program and an increase in double-strand breaks. These effects are partly due to aberrant transcriptional regulation of cell cycle proliferation factors, namely c-Myc and FoxM1, which dictate normal S phase progression. We conclude that B-Myb acts crucially during the S phase in ESCs by facilitating proper progression of replication, thereby protecting the cells from genomic damage. Our findings have particular relevance in the light of the potential therapeutic application of ESCs and the need to maintain their genomic integrity. PMID- 20715182 TI - Neural induction intermediates exhibit distinct roles of Fgf signaling. AB - Formation of the neural plate is an intricate process in early mammalian embryonic development mediated by cells of the inner cell mass and involving a series of steps, including development of the epiblast. Here, we report on the creation of an embryonic stem (ES) cell-based system to isolate and identify neural induction intermediates with characteristics of epiblast cells and neural plate. We demonstrate that neural commitment requires prior differentiation of ES cells into epiblast cells that are indistinguishable from those derived from natural embryos. We also demonstrate that epiblast cells can be isolated and cultured as epiblast stem cell lines. Fgf signaling is shown to be required for the differentiation of ES cells into these epiblast cells. Fgf2, widely used for maintenance of both human ES cells and epiblast stem cells, inhibits formation of early neural cells by epiblast intermediates in a dose-dependent manner and is sufficient to promote transient self-renewal of epiblast stem cells. In contrast, Fgf8, the endogenous embryonic neural inducer, fails to promote epiblast self renewal, but rather promotes more homogenous neural induction with transient self renewal of early neural cells. Removal of Fgf signaling entirely from epiblast cells promotes rapid neural induction and subsequent neurogenesis. We conclude that Fgf signaling plays different roles during the differentiation of ES cells, with an initial requirement in epiblast formation and a subsequent role in self renewal. Fgf2 and Fgf8 thus stimulate self-renewal in different cell types. PMID- 20715183 TI - Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. AB - Human induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells represent a promising unlimited cell source for generating patient-specific cells for biomedical research and personalized medicine. As a first step, critical to clinical applications, we attempted to develop defined culture conditions to expand and differentiate human iPSCs into functional progeny such as dopaminergic neurons for treating or modeling Parkinson's disease (PD). We used a completely defined (xeno-free) system that we previously developed for efficient generation of authentic dopaminergic neurons from human embryonic stem cells (hESCs), and applied it to iPSCs. First, we adapted two human iPSC lines derived from different somatic cell types for the defined expansion medium and showed that the iPSCs grew similarly as hESCs in the same medium regarding pluripotency and genomic stability. Second, by using these two independent adapted iPSC lines, we showed that the process of differentiation into committed neural stem cells (NSCs) and subsequently into dopaminergic neurons was also similar to hESCs. Importantly, iPSC-derived dopaminergic neurons were functional as they survived and improved behavioral deficits in 6-hydroxydopamine-leasioned rats after transplantation. In addition, iPSC-derived NSCs and neurons could be efficiently transduced by a baculoviral vector delivering episomal DNA for future gene function study and disease modeling using iPSCs. We also performed genome-wide microarray comparisons between iPSCs and hESCs, and we derived NSC and dopaminergic neurons. Our data revealed overall similarity and visible differences at a molecular level. Efficient generation of functional dopaminergic neurons under defined conditions will facilitate research and applications using PD patient-specific iPSCs. PMID- 20715184 TI - Ascorbate promotes epigenetic activation of CD30 in human embryonic stem cells. AB - Human embryonic stem cells (hESCs) and induced pluripotent stem cells have the ability to adapt to various culture conditions. Phenotypic and epigenetic changes brought about by the culture conditions can, however, have significant impacts on their use in research and in clinical applications. Here, we show that diploid hESCs start to express CD30, a biomarker for malignant cells in Hodgkin's disease and embryonal carcinoma cells, when cultured in knockout serum replacement (KOSR) based medium, but not in fetal calf serum containing medium. We identify the commonly used medium additive, ascorbate, as the sole medium component in KOSR responsible for CD30 induction. Our data show that this epigenetic activation of CD30 expression in hESCs by ascorbate occurs through a dramatic loss of DNA methylation of a CpG island in the CD30 promoter. Analysis of the phenotype and transcriptome of hESCs that overexpress the CD30 signaling domain reveals that CD30 signaling leads to inhibition of apoptosis, enhanced single-cell growth, and transcriptome changes that are associated with cell signaling, lipid metabolism, and tissue development. Collectively, our data show that hESC culture media that contain ascorbate trigger CD30 expression through an epigenetic mechanism and that this provides a survival advantage and transcriptome changes that may help adapt hESCs to in vitro culture conditions. PMID- 20715185 TI - Novel hyperactive transposons for genetic modification of induced pluripotent and adult stem cells: a nonviral paradigm for coaxed differentiation. AB - Adult stem cells and induced pluripotent stem cells (iPS) hold great promise for regenerative medicine. The development of robust nonviral approaches for stem cell gene transfer would facilitate functional studies and potential clinical applications. We have previously generated hyperactive transposases derived from Sleeping Beauty, using an in vitro molecular evolution and selection paradigm. We now demonstrate that these hyperactive transposases resulted in superior gene transfer efficiencies and expression in mesenchymal and muscle stem/progenitor cells, consistent with higher expression levels of therapeutically relevant proteins including coagulation factor IX. Their differentiation potential and karyotype was not affected. Moreover, stable transposition could also be achieved in iPS, which retained their ability to differentiate along neuronal, cardiac, and hepatic lineages without causing cytogenetic abnormalities. Most importantly, transposon-mediated delivery of the myogenic PAX3 transcription factor into iPS coaxed their differentiation into MYOD(+) myogenic progenitors and multinucleated myofibers, suggesting that PAX3 may serve as a myogenic "molecular switch" in iPS. Hence, this hyperactive transposon system represents an attractive nonviral gene transfer platform with broad implications for regenerative medicine, cell and gene therapy. PMID- 20715186 TI - Influence of vertical trabeculae on the compressive strength of the human vertebra. AB - Vertebral strength, a key etiologic factor of osteoporotic fracture, may be affected by the relative amount of vertically oriented trabeculae. To better understand this issue, we performed experimental compression testing, high resolution micro-computed tomography (uCT), and micro-finite-element analysis on 16 elderly human thoracic ninth (T(9)) whole vertebral bodies (ages 77.5 +/- 10.1 years). Individual trabeculae segmentation of the uCT images was used to classify the trabeculae by their orientation. We found that the bone volume fraction (BV/TV) of just the vertical trabeculae accounted for substantially more of the observed variation in measured vertebral strength than did the bone volume fraction of all trabeculae (r(2) = 0.83 versus 0.59, p < .005). The bone volume fraction of the oblique or horizontal trabeculae was not associated with vertebral strength. Finite-element analysis indicated that removal of the cortical shell did not appreciably alter these trends; it also revealed that the major load paths occur through parallel columns of vertically oriented bone. Taken together, these findings suggest that variation in vertebral strength across individuals is due primarily to variations in the bone volume fraction of vertical trabeculae. The vertical tissue fraction, a new bone quality parameter that we introduced to reflect these findings, was both a significant predictor of vertebral strength alone (r(2) = 0.81) and after accounting for variations in total bone volume fraction in multiple regression (total R(2) = 0.93). We conclude that the vertical tissue fraction is a potentially powerful microarchitectural determinant of vertebral strength. PMID- 20715187 TI - Osteoblast-specific expression of MEF induces osteopenia through downregulation of osteoblastogenesis and upregulation of osteoclastogenesis. AB - In bone remodeling, various transcriptional factors are involved, and the deficiency or overexpression of some of these factors results in bone defects. Myeloid elf-1-like factor (MEF) is one of the Ets transcription factors that control the expression of genes that are critical for biologic processes such as cell proliferation, differentiation, and death. Previously, we reported that MEF promotes cell proliferation and functions as a negative regulator of osteogenic differentiation by interacting directly with Runx2 and suppressing its transcriptional activity. To investigate the in vivo function of MEF in bone formation and bone remodeling in vivo, we generated transgenic mice that overexpress MEF in osteoblasts under the control of the 2.3-kb Col1alpha1 promoter, named Col1alpha1-MEF. Femoral bone in Col1alpha1-MEF transgenic mice exhibited low bone mass with fewer trabecular bones and thinner and less developed cortical bones. The mineralized volume fraction (BV/TV) and bone forming rate (BFR) were remarkably decreased to about 63% and 40%, respectively, in 6-week-old MEF transgenic mice compared with wild-type mice. In addition, reduced bone mineral density was observed in lumbar vertebrae of Col1alpha1-MEF transgenic mice. The number of TRACP(+) osteoclasts was increased in Col1alpha1 MEF transgenic mice and MEF-overexpressing MC3T3-E1 cells. All these in vivo results suggest that MEF suppresses bone formation by osteoblasts and facilitates bone resorption by activating osteoclasts indirectly. PMID- 20715189 TI - Dethreading of deoxyribonucleotides through alpha-cyclodextrin. PMID- 20715188 TI - Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3 dioxygenase. AB - The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has become increasingly popular in pharmaceutical research as it was found to be involved in many physiological situations, including immune escape of cancer. More importantly, small-molecule inhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for the design of human IDO (hIDO) inhibitors is that they should be selective enough to avoid inhibition of TDO. In this work, we have used a combination of classical molecular dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basis that determine the differences in (a) the interactions of TDO and IDO with small ligands (CO/O(2)) and (b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in small ligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereo-specificity of TDO is achieved by the perfect fit of L-Trp, but not D-Trp, which exhibits weaker interactions with the protein matrix. For hIDO, the presence of multiple stable binding conformations for L/D Trp reveal the existence of a large and dynamic active site. Taken together, our data allow determination of key interactions useful for the future design of more potent hIDO-selective inhibitors. PMID- 20715191 TI - Electrically conductive hydrogen-bond-based supramolecular polymer with a tetrathiafulvalene moiety: modulation of electrical conductivity and flexibility of film by external stimulus. PMID- 20715190 TI - Solid-phase synthesis of a combinatorial methylated (+/-)-epigallocatechin gallate library and the growth-inhibitory effects of these compounds on melanoma B16 cells. AB - We report on the solid-phase synthesis of a combinatorial methylated (+/-) epigallocatechin gallate (EGCG) library and its biological evaluation. Epigallocatechin gallate (EGCG) and its methylated derivatives, which are members of the catechin family, exhibit various anti-cancer effects. The solid-phase synthesis of methylated EGCG involves the preparation of the alpha-acyloxyketone by the coupling of a solid-supported aldehyde with a ketone and an acid. The subsequent release and reductive etherification reaction of the solid-supported alpha-acyloxyketone provide the protected EGCG in good total yields. Sixty-four methylated EGCGs were successfully prepared. The growth-inhibitory effects of the methylated EGCG library were also examined. Although methylation of EGCG generally causes reduced growth inhibition, the growth-inhibitory effect of 7-OMe EGCGs was comparable to that of EGCG. The 7-OMe EGCGs are attractive drug candidates because of their enhanced bioavailability. PMID- 20715192 TI - Total synthesis of (-)-morphine. AB - We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1 one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N methyl-DNs-amide moiety. PMID- 20715193 TI - A joint experimental/theoretical investigation of the statistical olefin/conjugated diene copolymerization catalyzed by a hemi-lanthanidocene [(Cp*)(BH4)LnR]. AB - Statistical copolymerization of ethylene and isoprene was achieved by using a borohydrido half-lanthanidocene complex. Under copolymerization conditions, activation of [(Cp*)(BH(4))(2)Nd(thf)(2)] (Cp*=eta(5)-C(5)Me(5)) by an appropriate alkylating agent affords trans-1,4-poly-isoprene-co-ethylene. Analysis of the microstructure of the copolymer revealed the presence of successive short sequences of ethylene/ethylene, trans-1,4-isoprene/ethylene, and trans-1,4-isoprene/trans-1,4-isoprene. A small amount of 1,2-insertion of isoprene was observed, and no cyclic structures within the chain were characterized. Test runs showed that these catalysts are unable to copolymerize alpha-olefins (such as hex-1-ene) with isoprene. The probable initial steps in the copolymerization have been computed at the DFT level of theory. Analysis of the energy profile provides insight into the catalyst's activity and selectivity. Our theoretical results highlight the key role played by the allyl intermediate, in which diene insertion, and to a lesser extent olefin insertion, is the rate determining step of the process. These results also illustrate the coordination behavior of the allyl ligand during the insertion of an incoming monomer, which directly inserts, after pre-coordination to the metal center, into the eta(3) allyl ligand without inducing an eta(3) to eta(1) haptotropic shift. Finally, the inactivity of this family of catalysts towards the copolymerization of hex-1-ene was rationalized on the basis of the free-energy profile of the copolymerization. PMID- 20715194 TI - Site-specific investigation of the steady-state kinetics and dynamics of the multistep binding of bile acid molecules to a lipid carrier protein. AB - The investigation of multi-site ligand-protein binding and multi-step mechanisms is highly demanding. In this work, advanced NMR methodologies such as 2D (1)H (15)N line-shape analysis, which allows a reliable investigation of ligand binding occurring on micro- to millisecond timescales, have been extended to model a two-step binding mechanism. The molecular recognition and complex uptake mechanism of two bile salt molecules by lipid carriers is an interesting example that shows that protein dynamics has the potential to modulate the macromolecule ligand encounter. Kinetic analysis supports a conformational selection model as the initial recognition process in which the dynamics observed in the apo form is essential for ligand uptake, leading to conformations with improved access to the binding cavity. Subsequent multi-step events could be modelled, for several residues, with a two-step binding mechanism. The protein in the ligand-bound state still exhibits a conformational rearrangement that occurs on a very slow timescale, as observed for other proteins of the family. A global mechanism suggesting how bile acids access the macromolecular cavity is thus proposed. PMID- 20715195 TI - Expanded pyridiniums: bis-cyclization of branched pyridiniums into their fused polycyclic and positively charged derivatives--assessing the impact of pericondensation on structural, electrochemical, electronic, and photophysical features. AB - This study evaluates the impact of the extension of the pi-conjugated system of pyridiniums on their various properties. The molecular scaffold of aryl substituted expanded pyridiniums (referred to as branched species) can be photochemically bis-cyclized into the corresponding fused polycyclic derivatives (referred to as pericondensed species). The representative 1,2,4,6 tetraphenylpyridinium (1(H)) and 1,2,3,5,6-pentaphenyl-4-(p-tolyl)pyridinium (2(Me)) tetra- and hexa-branched pyridiniums are herein compared with their corresponding pericondensed derivatives, the fully fused 9 phenylbenzo[1,2]quinolizino[3,4,5,6-def]phenanthridinium (1(H)f) and the hitherto unknown hemifused 9-methyl-1,2,3-triphenylbenzo[h]phenanthro[9,10,1 def]isoquinolinium (2(Me)f). Combined solid-state X-ray crystallography and solution NMR experiments showed that stacking interactions are barely efficient when the pericondensed pyridiniums are not appropriately substituted. The electrochemical study revealed that the first reduction process of all the expanded pyridiniums occurs at around -1 V vs. SCE, which indicates that the lowest unoccupied molecular orbital (LUMO) remains essentially localized on the pyridinium core regardless of pericondensation. In contrast, the electronic and photophysical properties are significantly affected on going from branched to pericondensed pyridiniums. Typically, the number of absorption bands increases with extended activity towards the visible region (down to ca. 450 nm in MeCN), whereas emission quantum yields are increased by three orders of magnitude (at ca. 0.25 on average). A relationship is established between the observed differential impact of the pericondensation and the importance of the localized LUMO on the properties considered: predominant for the first reduction process compared with secondary for the optical and photophysical properties. PMID- 20715196 TI - Palladium membrane-installed microchannel devices for instantaneous Suzuki Miyaura cross-coupling. AB - Instantaneous catalytic carbon-carbon bond-forming reactions were achieved in catalytic membrane-installed microchannel devices that have a polymeric palladium complex membrane. The catalytic membrane-installed microchannel devices were provided inside the microchannels by means of coordinative and ionic molecular convolution at the interface between the organic and aqueous phases flowing laminarly, in which both non-crosslinked linear polymer ligands and palladium species dissolved. The palladium-catalyzed Suzuki-Miyaura reaction of aryl, heteroaryl, and alkenyl halides with arylboronic acids and sodium tetraarylborates was performed with the catalytic membrane-installed microchannel devices to give quantitative yields of biaryls, heterobiaryls, and aryl alkenes within 5 s of residence time in the defined channel region. These microchannel devices were applied to the instantaneous allylic arylation reaction of allylic esters with arylboron reagents under microflow conditions to afford the corresponding coupling products within 1 s of residence time. PMID- 20715197 TI - A "neck-formation" strategy for an antiquenching magnetic/upconversion fluorescent bimodal cancer probe. PMID- 20715198 TI - Do dynamic effects play a significant role in enzymatic catalysis? A theoretical analysis of formate dehydrogenase. AB - A theoretical study of the protein dynamic effects on the hydride transfer between the formate anion and nicotinamide adenine dinucleotide (NAD(+)), catalyzed by formate dehydrogenase (FDH), is presented in this paper. The analysis of free downhill molecular dynamic trajectories, performed in the enzyme and compared with the reaction in aqueous solution, has allowed the study of the dynamic coupling between the reacting fragments and the protein or the solvent water molecules, as well as an estimation of the dynamic effect contribution to the catalytic effect from calculation of the transmission coefficient in the enzyme and in solution. The obtained transmission coefficients for the enzyme and in solution were 0.46+/-0.04 and 0.20+/-0.03, respectively. These values represent a contribution to catalysis of 0.5 kcal mol(-1), which, although small, is not negligible keeping in mind the low efficiency of FDH. The analysis of the reactive trajectories also reveals how the relative movements of some amino acids, mainly His332 and Arg284, precede and promote the chemical reaction. In spite of these movements, the time-dependent evolution of the electric field created by the enzyme on the key atoms of the reaction reveals a permanent field, which reduces the work required to reach the transition state, with a concomitant polarization of the cofactor. Finally, application of Grote-Hynes theory has allowed the identification of the modes responsible for the substrate-environment coupling, showing how some protein motions take place simultaneously with the reaction. Thus, the equilibrium approach would provide, in this case, an overestimation of the catalyzed rate constant. PMID- 20715199 TI - General strategy for a large-scale fabric with branched nanofiber-nanorod hierarchical heterostructure: controllable synthesis and applications. AB - The preparation and characterization of a branched nanofiber-nanorod hierarchical heterostructure fabric (TiO(2)/NiO, TiO(2)/ZnO, and TiO(2)/SnO(2)) are described. The nanomaterial was synthesized on a large scale by an inexpensive, generalizable, facile, and controllable approach by combining the electrospinning technique with a hydrothermal method. The controllable formation process and factors (assistance by hexamethylenetetramine and metal oxide nuclei) influencing the morphology of the branched hierarchical heterostructure are discussed. In addition, photocurrent and photocatalytic studies suggest that the branched hierarchical heterostructure fabric shows higher mobility of charge carriers and enhanced photocatalytic activity relative to a bare TiO(2) nanofibrous mat and other heterostructures under irradiation by light. This work demonstrates the possibility of growing branched heterostructure fabrics of various uniform, one dimensional, functional metal oxide nanorods on a TiO(2) nanofibrous mat, which has a tunable morphology by changing the precursor. The study may open a new channel for building hierarchical heterostructure device fabrics with optical and catalytic properties, and allow the realization of a new class of nano heterostructure devices. PMID- 20715200 TI - Photolysis and thermolysis of platinum(IV) 2,2'-bipyridine complexes lead to identical platinum(II)-DNA adducts. AB - Two Pt(IV) and two Pt(II) complexes containing a 2,2'-bipyridine ligand were treated with a short DNA oligonucleotide under light irradiation at 37 degrees C or in the dark at 37 and 50 degrees C. Photolysis and thermolysis of the Pt(IV) complexes led to spontaneous reduction of the Pt(IV) to the corresponding Pt(II) complexes and to binding of Pt(II) 2,2'-bipyridine complexes to N7 of guanine. When the reduction product was [Pt(bpy)Cl(2)], formation of bis-oligonucleotide adducts was observed, whereas [Pt(bpy)(MeNH(2))Cl](+) gave monoadducts, with chloride ligands substituted in both cases. Neither in the dark nor under light irradiation was the reductive elimination process of these Pt(IV) complexes accompanied by oxidative DNA damage. This work raises the question of the stability of photoactivatable Pt(IV) complexes toward moderate heating conditions. PMID- 20715201 TI - Bufogargarizins A and B: two novel 19-norbufadienolides with unprecedented skeletons from the venom of Bufo bufo gargarizans. PMID- 20715202 TI - A flow microreactor system enables organolithium reactions without protecting alkoxycarbonyl groups. AB - A flow microreactor system consisting of micromixers and microtube reactors provides an effective tool for the generation and reactions of aryllithiums bearing an alkoxycarbonyl group at para-, meta-, and ortho-positions. Alkyl p- and m-lithiobenzoates were generated by the I/Li exchange reaction with PhLi. The Br/Li exchange reactions with sBuLi were unsuccessful. Subsequent reactions of the resulting aryllithiums with electrophiles gave the desired products in good yields. On the other hand, alkyl o-lithiobenzoates were successfully generated by the Br/Li exchange reaction with sBuLi. Subsequent reactions with electrophiles gave the desired products in good yields. PMID- 20715203 TI - Trifluoromethyl-substituted conjugated oligoelectrolytes. AB - Conjugated oligoelectrolytes (COEs) are being introduced into a variety of optical and electronic technologies, yet the dependence of their properties as a function of molecular structure remains poorly understood. In response, we designed, synthesized, and examined a new tetracationic COE, namely, 1,4 bis{9',9'-bis[6''-(N,N,N-trimethylammonium)hexyl]-2'-fluorenyl}-2,5 bis(trifluoromethyl)benzene tetrabromide (FPF-F6), which contains bulky electron withdrawing trifluoromethyl groups, and compared its properties with the unsubstituted counterpart 1,4-bis{9',9'-bis[6''-(N,N,N-trimethylammonium)hexyl] 2'-fluorenyl}benzene tetrabromide (FPF). The ground-state geometry of FPF-F6 is primarily twisted with little electronic communication between the aromatic units, as confirmed by single-crystal X-ray diffraction studies of the neutral precursor. However, absorption and photoluminescence spectroscopies reveal that the excited state of FPF-F6 displays strong intramolecular charge-transfer characteristics. Solution AFM in aqueous media shows that introduction of trifluoromethyl groups changes the size and aspect ratio of supramolecular aggregates that are brought together as a result of hydrophobic interactions. Furthermore, addition of ssDNA to FPF-F6 leads to interoligoelectrolyte complexes wherein the backbone is more planar; the environment the chromophore experiences under these conditions is also considerably less polar. These findings provide considerable insight into the complex photophysics of electronically conjugated materials in aqueous media. PMID- 20715204 TI - Investigation of Lewis acid versus Lewis base catalysis in asymmetric cyanohydrin synthesis. AB - The asymmetric addition of trimethylsilyl cyanide to aldehydes can be catalysed by Lewis acids and/or Lewis bases, which activate the aldehyde and trimethylsilyl cyanide, respectively. It is not always apparent from the structure of the catalyst whether Lewis acid or Lewis base catalysis predominates. To investigate this in the context of using salen complexes of titanium, vanadium and aluminium as catalysts, a Hammett analysis of asymmetric cyanohydrin synthesis was undertaken. When Lewis acid catalysis is dominant, a significantly positive reaction constant is observed, whereas reactions dominated by Lewis base catalysis give much smaller reaction constants. [{Ti(salen)O}(2)] was found to show the highest degree of Lewis acid catalysis, whereas two [VO(salen)X] (X=EtOSO(3) or NCS) complexes both displayed lower degrees of Lewis acid catalysis. In the case of reactions catalysed by [{Al(salen)}(2)O] and triphenylphosphine oxide, a non-linear Hammett plot was observed, which is indicative of a change in mechanism with increasing Lewis base catalysis as the carbonyl compound becomes more electron-deficient. These results suggested that the aluminium complex/triphenylphosphine oxide catalyst system should also catalyse the asymmetric addition of trimethylsilyl cyanide to ketones and this was found to be the case. PMID- 20715205 TI - The effect of ligand denticity in size-selective synthesis of calix[n]arene stabilized gold nanoparticles: a multitechnique approach. AB - A series of gold nanoparticles (AuNPs) stabilized by monodentate, bidentate, and tridentate thiolate calix[n]arene ligands 1-3 was prepared by using the Brust Schiffrin two-phase direct synthesis and characterized with NMR spectroscopy, elemental analysis, transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). The experimental data show that the particular multidentate structure of calix[n]arene derivatives 2 and 3 introduces a control element in the preparation of the gold nanoparticles that allows, in the particular experimental conditions here reported, to obtain very small (~1 nm) AuNPs. These are the first experimental findings that identify a role of ligand "denticity" in the determination of the nuclearity of nanoparticles. PMID- 20715206 TI - Chirally organized oligothiophenes: towards modeling interchain interactions within pi-conjugated systems. PMID- 20715208 TI - [Pd(Cl)2{P(NC5H10)(C6H11)2}2]--a highly effective and extremely versatile palladium-based Negishi catalyst that efficiently and reliably operates at low catalyst loadings. AB - [Pd(Cl)(2){P(NC(5)H(10))(C(6)H(11))(2)}(2)] (1) has been prepared in quantitative yield by reacting commercially available [Pd(cod)(Cl)(2)] (cod=cyclooctadiene) with readily prepared 1-(dicyclohexylphosphanyl)piperidine in toluene under N(2) within a few minutes at room temperature. Complex 1 has proved to be an excellent Negishi catalyst, capable of quantitatively coupling a wide variety of electronically activated, non-activated, deactivated, sterically hindered, heterocyclic, and functionalized aryl bromides with various (also heterocyclic) arylzinc reagents, typically within a few minutes at 100 degrees C in the presence of just 0.01 mol% of catalyst. Aryl bromides containing nitro, nitrile, ether, ester, hydroxy, carbonyl, and carboxyl groups, as well as acetals, lactones, amides, anilines, alkenes, carboxylic acids, acetic acids, and pyridines and pyrimidines, have been successfully used as coupling partners. Furthermore, electronic and steric variations are tolerated in both reaction partners. Experimental observations strongly indicate that a molecular mechanism is operative. PMID- 20715207 TI - An atomic-level strategy for unraveling gold nanocatalysis from the perspective of Au(n)(SR)m nanoclusters. AB - An atomic-level strategy is devised to gain insight into the origin of nanogold catalysis by using atomically monodisperse Au(n)(SR)(m) nanoclusters as well defined catalysts for styrene oxidation. The Au(n)(SR)(m) nanoclusters are emerging as a new class of gold nanocatalyst to overcome the polydispersity of conventional nanoparticle catalysts. The unique atom-packing structure and electronic properties of Au(n)(SR)(m) nanoclusters (<2 nm) are rationalized to be responsible for their extraordinary catalytic activity observed in styrene oxidation. An interesting finding is that quantum size effects of Au(n)(SR)(m) nanoclusters, rather than the higher specific surface area, play a major role in gold-catalyzed selective oxidation of styrene. For example, Au(25)(SR)(18) nanoclusters (~1 nm) are found to be particularly efficient in activating O(2), which is a key step in styrene oxidation, and hence, the ultrasmall Au(25) catalyst exhibits higher activity than do larger sizes. This atomic-level strategy has allowed us to obtain an important insight into some fundamental aspects of nanogold catalysis in styrene oxidation. The ultrasmall yet robust Au(n)(SR)(m) nanoclusters are particularly promising for studying the mechanistic aspects of nanogold catalysis and for future design of better catalysts with high activity and selectivity for certain chemical processes. PMID- 20715209 TI - Non-innocent behaviour of dithiocarboxylate ligands based on N-heterocyclic carbenes. PMID- 20715210 TI - Palladium(II)-catalyzed highly regio- and stereoselective synthesis of 2-chloro 1,3-diene derivatives from alkynols and alkenes. PMID- 20715211 TI - Enhanced anion binding from unusual coordination modes of bis(thiourea) ligands in platinum group metal complexes. AB - Treatment of a range of bis(thiourea) ligands with inert organometallic transition-metal ions gives a number of novel complexes that exhibit unusual ligand binding modes and significantly enhanced anion binding ability. The ruthenium(II) complex [Ru(eta(6)-p-cymene)(kappaS,S',N-L(3)-H)](+) (2b) possesses juxtaposed four- and seven-membered chelate rings and binds anions as both 1:1 and 2:1 host guest complexes. The pyridyl bis(thiourea) complex [Ru(eta(6)-p cymeme)(kappaS,S',N(py)-L(4))](2+) (4) binds anions in both 1:1 and 1:2 species, whereas the free ligand is ineffective because of intramolecular NH???N hydrogen bonding. Novel palladium(II) complexes with nine- and ten-membered chelate rings are also reported. PMID- 20715212 TI - Self-assembled nanostructures of tailored multi-metal complexes and morphology control by counter-anion exchange. PMID- 20715213 TI - 3,4-Dithiaphosphole and 3,3',4,4'-tetrathia-1,1'-biphosphole pi-conjugated systems: S makes the impact. AB - Conjugated systems based on phospholes and 1,1'-biphospholes bearing 3,4 ethylenedithia bridges have been prepared using the Fagan-Nugent route. The mechanism of this organometallic route leading to intermediate zirconacyclopentadienes has been investigated by using theoretical calculations. This study revealed that the oxidative coupling leading to zirconacyclopentadienes is favored over oxidative addition within the S-C=C bond both thermodynamically and kinetically. The impact of the presence of the S atoms on the optical and electrochemical behavior of the phospholes and 1,1' biphospholes has been systematically evaluated both experimentally and theoretically. A comparison with their "all-carbon" analogues is provided. Of particular interest, this comparative study revealed that the introduction of S atoms has an impact on the electronic properties of phosphole-based conjugated systems. A decrease of the HOMO-LUMO separation and a stabilization of the LUMO level were observed. These general trends are also observed with 1,1' biphospholes exhibiting sigma-pi conjugation. The P atom of the 3,4 ethylenedithiaphospholes can be selectively oxidized by S(8) or O(2). These P modifications result in a lowering of the HOMO-LUMO separation as well as an increase of the reduction and oxidation potentials. The S atoms of the 3,4 ethylenedithia bridge of the 2,5-phosphole have been oxidized using m chloroperoxybenzoic acid. The resulting 3,4-ethylenesulfoxide oxophosphole was characterized by an X-ray diffraction study. Experimental and theoretical studies show that this novel chemical manipulation results in an increase of the HOMO LUMO separation and an important decrease of the LUMO level. The electropolymerization of 2-thienyl-capped 3,4-ethylenedithiathioxophosphole and 1,1'-biphosphole is reported. The impact of the S substituents on the polymer properties is discussed. PMID- 20715214 TI - Scaling out by microwave-assisted, continuous flow organic synthesis (MACOS): multi-gram synthesis of bromo- and fluoro-benzofused sultams benzthiaoxazepine 1,1-dioxides. PMID- 20715215 TI - Nanographite impurities dominate electrochemistry of carbon nanotubes. PMID- 20715216 TI - Highly enantioselective Michael addition of malononitrile to vinylogous imine intermediates generated in situ from arylsulfonyl indoles. PMID- 20715217 TI - Total synthesis and antibiotic activity of dehydrohomoplatencin. PMID- 20715218 TI - Rhodium-catalysed intermolecular alkyne hydroacylation: the enantioselective synthesis of alpha- and beta-substituted ketones by kinetic resolution. PMID- 20715219 TI - The syntheses and structure of the vanadium(IV) and vanadium(V) binary azides V(N3)4, [V(N3)6]2-, and [V(N3)6]-. PMID- 20715220 TI - Exploiting cavities in supramolecular gels. AB - Endowing supramolecular gelators with cavities opens up a number of opportunities not possible with other gel systems. The well-established host-guest chemistry of cavitands can be utilized to build up and break down gel structures, introduce responsive functionalities, or enhance selectivity in applications such as catalysis and extraction. Cavity-containing gelators provide an excellent case study for how different aspects of supramolecular chemistry can be used intelligently to create responsive materials. PMID- 20715221 TI - Low-viscosity paramagnetic ionic liquids with doubly charged [Co(NCS)4]2- ions. PMID- 20715222 TI - Reversible self-assembly of metal chalcogenide/metal oxide nanostructures based on Pearson hardness. PMID- 20715223 TI - A unified pH scale for all phases. PMID- 20715224 TI - Supersensitive detection of explosives by silicon nanowire arrays. PMID- 20715225 TI - Access to extended polyphosphorus frameworks. PMID- 20715226 TI - Modular chemosensors from self-assembled vesicle membranes with amphiphilic binding sites and reporter dyes. PMID- 20715227 TI - Semiconductor nanocrystals with adjustable hole acceptors: tuning the fluorescence intensity by metal-ion binding. PMID- 20715228 TI - Fluidics meets electronics: carbon nanotubes as nanopores. PMID- 20715229 TI - Exceptional dielectric phase transitions in a perovskite-type cage compound. PMID- 20715230 TI - Nanopeapods by galvanic displacement reaction. PMID- 20715231 TI - Synchronized synthesis of peptide-based macrocycles by digital microfluidics. PMID- 20715232 TI - Aqueous dispersions of nonspherical polyethylene nanoparticles from free-radical polymerization under mild conditions. PMID- 20715233 TI - The measure of all rings--N-heterocyclic carbenes. AB - Quantification and variation of characteristic properties of different ligand classes is an exciting and rewarding research field. N-Heterocyclic carbenes (NHCs) are of special interest since their electron richness and structure provide a unique class of ligands and organocatalysts. Consequently, they have found widespread application as ligands in transition-metal catalysis and organometallic chemistry, and as organocatalysts in their own right. Herein we provide an overview on physicochemical data (electronics, sterics, bond strength) of NHCs that are essential for the design, application, and mechanistic understanding of NHCs in catalysis. PMID- 20715235 TI - Synthesis, structure, and photophysical properties of dibenzo[de,mn]naphthacenes. PMID- 20715236 TI - "Try and fall sick .."-the composer, chemist, and surgeon Aleksandr Borodin. PMID- 20715234 TI - Traceless ligation of cysteine peptides using selective deselenization. PMID- 20715237 TI - Zinc chloride enhanced arylations of secondary benzyl trifluoroacetates in the presence of beta-hydrogen atoms. PMID- 20715238 TI - Remarkable site difference of vibrational energy relaxation in benzene dimer: picosecond time-resolved IR-UV pump-probe spectroscopy. PMID- 20715239 TI - Metal-organic frameworks from edible natural products. PMID- 20715241 TI - A microchemical system with continuous recovery and recirculation of catalyst immobilized magnetic particles. PMID- 20715240 TI - Enantioselective phase-transfer catalysis: synthesis of pyrazolines. PMID- 20715242 TI - Pd adatom decorated (100) preferentially oriented Pt nanoparticles for formic acid electrooxidation. PMID- 20715243 TI - Deconstruction as a strategy for the design of libraries of self-assembling dendrons. PMID- 20715244 TI - Self-assembly of nanotriangle superlattices facilitated by repulsive electrostatic interactions. PMID- 20715245 TI - Biocatalytic desymmetrization of an atropisomer with both an enantioselective oxidase and ketoreductases. PMID- 20715246 TI - Carbodiylides C(ECp*)2 (E=B-Tl): another class of theoretically predicted divalent carbon(0) compounds. PMID- 20715247 TI - An isolable mixed P,S-bis(ylide) as an asymmetric carbon atom source. PMID- 20715248 TI - Insights into the chemistry of transient P-chlorophosphanyl complexes. PMID- 20715249 TI - Enhancing by weakening: electrooxidation of methanol on Pt3Co and Pt nanocubes. PMID- 20715250 TI - Backbone dynamics of cyclotide MCoTI-I free and complexed with trypsin. PMID- 20715251 TI - Cinchona alkaloid-metal complexes: noncovalent porous materials with unique gas separation properties. PMID- 20715252 TI - Mechanistic insights into direct amide bond formation catalyzed by boronic acids: halogens as Lewis bases. PMID- 20715253 TI - A catenated strut in a catenated metal-organic framework. PMID- 20715255 TI - Enantioselective formal alkenylations of imines catalyzed by axially chiral dicarboxylic acid using vinylogous aza-enamines. PMID- 20715254 TI - Direct structural determination of conformations of photoswitchable molecules by laser desorption-electron diffraction. PMID- 20715256 TI - Exploiting non-innocent ligands to prepare masked palladium(0) complexes. PMID- 20715258 TI - Albert Schenning. PMID- 20715264 TI - Modulation of Shank3 PDZ domain ligand-binding affinity by dimerization. PMID- 20715263 TI - Fluorous iminoalditols: a new family of glycosidase inhibitors and pharmacological chaperones. AB - A collection of new reversible glycosidase inhibitors of the iminoalditol type featuring N-substituents containing perfluorinated regions has been prepared for evaluation of physicochemical, biochemical and diagnostic properties. The vast variety of feasible oligofluoro moieties allows for modular approaches to customised structures according to the intended applications, which are influenced by the fluorine content as well as the distance of the fluorous moiety from the ring nitrogen. The first examples, in particular in the D-galacto series, exhibited excellent inhibitory activities. A preliminary screen with two human cell lines showed that, at subinhibitory concentrations, they are powerful pharmacological chaperones enhancing the activities of the catalytically handicapped lysosomal D-galactosidase mutants associated with GM1 gangliosidosis and Morquio B disease. PMID- 20715265 TI - Novel hybrid esterase-haloacid dehalogenase enzyme. PMID- 20715266 TI - Solution structure of the leader sequence of the patellamide precursor peptide, PatE1-34. AB - The solution structure of the leader sequence of the patellamide precursor peptide was analysed by using CD and determined with NOE-restrained molecular dynamics calculations. This leader sequence is highly conserved in the precursor peptides of some other cyanobactins harbouring heterocycles, and is assumed to play a role in targeting the precursor peptide to the post-translational machinery. The sequence was observed to form an alpha-helix spanning residues 13 28 with a hydrophobic surface on one side of the helix. This hydrophobic surface is proposed to be the site of the initial binding with modifying enzymes. PMID- 20715267 TI - Analysis of the sorangicin gene cluster reinforces the utility of a combined phylogenetic/retrobiosynthetic analysis for deciphering natural product assembly by trans-AT PKS. PMID- 20715269 TI - Experimental and theoretical study of the broadening and shifting of N2H+ rotational lines by helium. AB - Pressure broadening and pressure shift of N(2)H(+) rotational lines perturbed by collisions with He are studied for the first time using experiment and theory. Results are reported from measurements at 88 K for the rotational transitions j = 3<--2, 4<--3, 5<--4 and 6<--5 with frequencies ranging from 0.28 to 0.56 THz. The agreement between experiment and theoretical data derived from close coupling calculations confirms the reliability of a theoretical framework used for state to-state transition rates of interest in the interpretation of spectroscopic data from interstellar molecular clouds. The influence of hyperfine effects on shifts and widths of the rotational lines is discussed in detail. Although in principle possible, experiment and theoretical considerations lead to the conclusion that hyperfine effects only play a minor role. PMID- 20715268 TI - Membrane-surface anchoring of charged diacylglycerol-lactones correlates with biological activities. AB - Synthetic diacylglycerol-lactones (DAG-lactones) are effective modulators of critical cellular signaling pathways, downstream of the lipophilic second messenger diacylglycerol, that activate a host of protein kinase C (PKC) isozymes and other nonkinase proteins that share similar C1 membrane-targeting domains with PKC. A fundamental determinant of the biological activity of these amphiphilic molecules is the nature of their interactions with cellular membranes. This study examines the biological properties of charged DAG-lactones exhibiting different alkyl groups attached to the heterocyclic nitrogen of an alpha-pyridylalkylidene chain, and particularly the relationship between membrane interactions of the substituted DAG-lactones and their respective biological activities. Our results suggest that bilayer interface localization of the N alkyl chain in the R(2) position of the DAG-lactones inhibits translocation of PKC isoenzymes onto the cellular membrane. However, the orientation of a branched alkyl chain at the bilayer surface facilitates PKC binding and translocation. This investigation emphasizes that bilayer localization of the aromatic side residues of positively charged DAG-lactone derivatives play a central role in determining biological activity, and that this factor contributes to the diversity of biological actions of these synthetic biomimetic ligands. PMID- 20715270 TI - Spatially resolved ATR-FTIRS study of the formation of macroscopic domains and microislands during CO electrooxidation on Pt. AB - Electrooxidation of CO in CO-saturated sulfuric acid electrolyte solutions with controlled mass transport is investigated with spatially resolved attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy under galvanostatic and potentiostatic conditions. The reaction conditions are chosen such that steady states with intermediate current densities and intermediate average CO coverages are accessible. We demonstrate that under these conditions the reaction never proceeds uniformly on the electrode surface. Instead, macroscopic domains form spontaneously, composed of areas with high CO coverage and areas essentially free of adsorbed CO molecules. The average coverage within the CO-covered domains depends on the electrolyte concentration and the applied potential and can vary between saturation coverage and a few tenths of a monolayer. However, the absence of a red-shift of the CO vibrational band points to a further substructuring of the domains in densely packed CO microislands. These microislands most likely also form in the boundary layer between the CO rich and CO-free electrode domains. This hierarchical patterning of the electrode surface is attributed to the interplay of autocatalytic reaction steps, spatial coupling through migration or the galvanostatic control of the experiment, and molecular interactions between molecules co-adsorbed on the electrode surface. PMID- 20715271 TI - Metallization of ultra-thin, non-thiol SAMs with flat-lying molecular units: Pd on 1, 4-dicyanobenzene. AB - Self-assembled monolayers of 1,4-dicyanobenzene on Au(111) electrodes are studied by cyclic voltammetry, in-situ STM and ex-situ XPS. High-resolution STM images reveal a long-range order of propeller-like assemblies each of which consists of three molecules, all lying flat on the gold substrate with the cyano groups oriented parallel to the metal surface. It is demonstrated that both functional groups can act as complexation sites for metal ions from solution. Surprisingly, such arrangements still allow the metal to be deposited on top of the molecules by electrochemical reduction despite the close vicinity to the Au surface. The latter is demonstrated by angle-resolved XPS which unequivocally shows that the metal indeed resides on top of the organic layer rather than underneath, despite the flat arrangement of the molecules. PMID- 20715272 TI - Preparation of a functional GABARAP-lipid conjugate in nanodiscs and its investigation by solution NMR spectroscopy. PMID- 20715273 TI - Voltammetric manifestation of the ultraslow dynamics at the interface between water and an ionic liquid. AB - The ultraslow relaxation (on the order of minutes) of the electrical double-layer structure, related to a change in the phase-boundary potential across the interface between water (W) and the ionic liquid (IL) trioctylmethylammonium bis(nonafluorobutanesufonyl)amide ([TOMA(+)][C(4)C(4)N(-)]) (Y. Yasui et al., J. Phys. Chem. B. 2009, 113, 3273), appears to be invisible in the transfer of tetrapropylammonium ions across the [TOMA(+)][C(4)C(4)N(-)]|W interface, provided that the charging current, which shows an unusual dependence on the voltage scan rate, is subtracted to obtain the faradaic current. This counterintuitive observation can be explained by the differences in the timescales of the fast and slow components of the relaxation dynamics of the electrical double layer on the IL side (ms and min). In contrast, the effect of the slow dynamics becomes surfaced in ion-transfer voltammetry when the ion is surface-active. The transfer of pentadecafluorooctanoate across the [TOMA(+)][C(4)C(4)N(-)]|W interface is irreversible, which is attributable to the self-inhibition of pentadecafluorooctanoate ions transferred to the IL phase. This process is likely to be affected by the ultraslow structural change of the IL side of the interface. PMID- 20715274 TI - Effect of external pressure on the excitation energy transfer from [Cr(ox)3]3- to [Cr(bpy)3]3+ in [Rh(1-x)Cr(x)(bpy)3][NaM(1-y)Cr(y)(ox)3]ClO4. AB - Resonant excitation energy transfer from [Cr(ox)(3)](3-) to [Cr(bpy)(3)](3+) in the doped 3D oxalate networks [Rh(1-x)Cr(x)(bpy)(3)][NaM(III) (1 y)Cr(y)(ox)(3)]ClO(4) (ox=C(2)O(4) (-), bpy=2,2'-bipyridine, M=Al, Rh) is due to two types of interaction, namely super exchange coupling and electric dipole dipole interaction. The energy transfer probability for both mechanisms is proportional to the spectral overlap of the (2)E->(4)A(2) emission of the [Cr(ox)(3)](3-) donor and the (4)A(2)->(2)T(1) absorption of the [Cr(bpy)(3)](3+) acceptor. The spin-flip transitions of (pseudo-)octahedral Cr(3+) are known to shift to lower energy with increasing pressure. Because the shift rates of the two transitions in question differ, the spectral overlap between the donor emission and the acceptor absorption is a function of applied pressure. For [Rh(1 x)Cr(x)(bpy)(3)][NaM(1-y)Cr(y)(ox)(3)]ClO(4) the spectral overlap is thus substantially reduced on increasing pressure from 0 to 2.5 GPa. As a result, the energy transfer probability decreases with increasing pressure as evidenced by a decrease in the relative emission intensity from the [Cr(bpy)(3)](3+) acceptor. PMID- 20715275 TI - 1.7 nm platinum nanoparticles: synthesis with glucose starch, characterization and catalysis. AB - Monodisperse platinum nanoparticles (PtNPs) were synthesized by a green recipe. Glucose serves as a reducing agent and starch as a stabilization agent to protect the freshly formed PtNP cores in buffered aqueous solutions. Among the ten buffers studied, 2-(N-morpholino)ethanesulfonic acid (MES), ammonium acetate and phosphate are the best media for PtNP size control and fast chemical preparation. The uniform sizes of the metal cores were determined by transmission electron microscopy (TEM) and found to be 1.8 +/- 0.5, 1.7 +/- 0.2 and 1.6 +/- 0.5 nm in phosphate, MES and ammonium acetate buffer, respectively. The estimated total diameter of the core with a starch coating layer is 5.8-6.0 nm, based on thermogravimetric analysis (TGA). The synthesis reaction is simple, environmentally friendly, highly reproducible, and easy to scale up. The PtNPs were characterized electrochemically and show high catalytic activity for reduction of dioxygen and hydrogen peroxide as well as for oxidation of dihydrogen. The PtNPs can be transferred to carbon support materials with little demand for high specific surface area of carbon. This enables utilization of graphitized carbon blacks to prepare well-dispersed Pt/C catalysts, which exhibit significantly improved durability in the accelerated aging test under fuel cell mimicking conditions. PMID- 20715276 TI - From adlayer islands to surface alloy: structural and chemical changes on bimetallic PtRu/Ru(0001) surfaces. AB - The correlation between structural and chemical properties of bimetallic PtRu/Ru(0001) model catalysts and their modification upon stepwise annealing of a submonolayer Pt-covered Ru(0001) surface up to the formation of an equilibrated Pt(x)Ru(1-x)/Ru(0001) monolayer surface alloy was investigated by scanning tunneling microscopy and by the adsorption of CO and D(2) probe molecules. Both temperature-programmed desorption and IR measurements demonstrate the influence of the surface structure on the adsorption properties of the bimetallic surface, which can be explained by changes of the composition of the adsorption ensembles (ensemble effects) for D adsorption and by changes in the electronic interaction (ligand effects, strain effects) of the metallic constituents for CO and D adsorption upon alloy formation. PMID- 20715277 TI - Enhanced emission of silver nanoclusters through quantitative phase transfer. AB - Silver nanoclusters composed of only a few metal atoms present appealing properties such as fluorescence. We have previously reported on aqueous solutions of this fluorophore using poly(methacrylic acid) as scaffold and their sensing properties. Here we report on the preparation of organic solutions of fluorescent silver nanoclusters by quantitative transfer from aqueous solution to an immiscible organic solvent. The fluorescent silver nanoclusters in the organic phase present enhanced emission properties and increased purity, which may expand the range of applications of this promising fluorophore. PMID- 20715278 TI - In situ X-ray absorption analysis of ~1.8 nm dendrimer-encapsulated Pt nanoparticles during electrochemical CO oxidation. AB - We report an in situ X-ray absorption-fine structure (XAFS) spectroscopic analysis of ~1.8 nm Pt dendrimer-encapsulated nanoparticles (DENs) during electrocatalytic oxidation of CO. The results indicate that Pt nanoparticles encapsulated within poly(amidoamine) (PAMAM) dendrimers and immobilized on a carbon electrode retain their electrocatalytic activity and are structurally stable for extended periods during CO oxidation. This is a significant finding, because nanoparticles in this size range are good experimental models for comparison to first-principles calculations if they remain stable. PMID- 20715279 TI - Spin-orbit contributions in high-spin nitrenes/carbenes: a hybrid CASSCF/MRMP2 study of zero-field splitting tensors. AB - Zero-field splitting (ZFS) tensors (D tensors) of organic high-spin oligonitrenes/oligocarbenes up to spin-septet are quantitatively determined on the basis of quantum chemical calculations. The spin-orbit contributions, D(SO) tensors are calculated in terms of a hybrid CASSCF/MRMP2 approach, which was recently proposed by us. The spin-spin counterparts, D(SS) tensors are computed based on McWeeny-Mizuno's equation in conjunction with the RODFT spin densities. The present calculations show that more than 10% of ZFS arises from spin-orbit interactions in the high-spin nitrenes under study. Contributions of spin-bearing site-site interactions are estimated with the aid of a semi-empirical model for the D tensors and found to be ca. 5% of the D(SO) tensor. The analysis of intermediate states reveal that the largest contributions to the calculated D(SO) tensors are attributed to intra-site spin flip excitations and delocalized pi and pi* orbitals play an important role in the inter-site spin-orbit interactions. PMID- 20715280 TI - Rich self-assembly behavior from a simple amphiphile. PMID- 20715282 TI - Probing the peptidylglycine alpha-hydroxylating monooxygenase active site with novel 4-phenyl-3-butenoic acid based inhibitors. AB - Specific inhibition of the copper-containing peptidylglycine alpha-hydroxylating monooxygenase (PHM), which catalyzes the post-translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure-activity study of new compounds derived from a well-known PHM substrate analogue, the olefinic compound 4-phenyl-3-butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d, for example, bears a meta-benzyloxy substituent, and exhibits better inhibition features (K(i)=3.9 microM, k(inact)/K(i)=427 M(-1) s(-1)) than the parent PBA (K(i)=19 microM, k(inact)/K(i)=82 M(-1) s(-1)). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features. PMID- 20715283 TI - New halogenated water-soluble chlorin and bacteriochlorin as photostable PDT sensitizers: synthesis, spectroscopy, photophysics, and in vitro photosensitizing efficacy. AB - Chlorin and bacteriochlorin derivatives of 5,10,15,20-tetrakis(2-chloro-5 sulfophenyl)porphyrin have intense absorptions in the phototherapeutic window, high water solubility, high photostability, low fluorescence quantum yield, long triplet lifetimes, and high singlet oxygen quantum yields. Biological studies revealed their negligible dark cytotoxicity, yet significant photodynamic effect against A549 (human lung adenocarcinoma), MCF7 (human breast carcinoma) and SK MEL-188 (human melanoma) cell lines upon red light irradiation (cutoff lambda<600 nm) at low light doses. Time-dependent cellular accumulation of the chlorinated sulfonated chlorin reached a plateau at 2 h, as previously observed for the related porphyrin. However, the optimal incubation time for the bacteriochlorin derivative was significantly longer (12 h). The spectroscopic, photophysical, and biological properties of the compounds are discussed in relevance to their PDT activity, leading to the conclusion that the bacteriochlorin derivative is a promising candidate for future in vivo experiments. PMID- 20715281 TI - Chemistries for patterning robust DNA microbarcodes enable multiplex assays of cytoplasm proteins from single cancer cells. PMID- 20715284 TI - The influence of the acidity of ionic liquids on catalysis. PMID- 20715285 TI - A novel synthetic route for the anti-HIV drug MC-1220 and its analogues. PMID- 20715286 TI - 20S proteasome inhibition: designing noncovalent linear peptide mimics of the natural product TMC-95A. PMID- 20715287 TI - In situ infrared study of the role of PEG in stabilizing silica-supported amines for CO(2) capture. AB - The CO(2) capture capacity, adsorption mechanism, and degradation characteristics of two sorbents, silica-supported tetraethylenepentamine (TEPA/SiO(2)) and polyethylene-glycol-modified TEPA/SiO(2) (PEG/TEPA/SiO(2)), are studied by diffuse reflectance infrared Fourier transform spectroscopy and mass spectrometry. The CO(2) capture capacities of TEPA/SiO(2) and PEG/TEPA/SiO(2) are determined to be 2087 and 1110 micromol CO(2) g(-1) sorbent, respectively. Both sorbents adsorb CO(2) as hydrogen-bonding species, NH(2)--O, and carbamate/carboxylate species. The CO(2) adsorption half-time increases with the number of CO(2) capture cycles. Infrared results suggest that the increased adsorption half-time is a result of diffusion limitation, caused by accumulation of TEPA and PEG species on the surface of the sorbent particles. The degradation of TEPA/SiO(2) is found to correlate with the accumulation of carboxylate/carbamic species. The addition of PEG decreases the degradation rate of the sorbent and slows down the formation of carboxylate species. These carboxylate species can block CO(2) capture on amine (NH(2)/NH) sites. The stabilizing role of PEG on TEPA/SiO(2) can be attributed to hydrogen-bonding between TEPA (NH(2)/NH)and PEG (OH). PMID- 20715288 TI - ReplicOpter: a replicate optimizer for flexible docking. AB - We present a computationally efficient method for flexible refinement of docking predictions that reflects observed motions within a protein's structural class. Using structural homologs, we derive deformation models that capture likely motions. The models or "replicates" typically align along a rigid core, with a handful of flexible loops, linkers and tails. A few replicates can generate a much larger number of conformers, by exchanging each flexible region independently of the others. In this way, 10 replicates of a protein having 6 flexible regions can be used to generate a million conformations of a molecule. While this has obvious advantages in terms of sampling, the cost of assessing energies at every conformer is prohibitive, particularly when both molecules are flexible. Our approach addresses this combinatorial explosion, using key assumptions to compress the sampling by many orders of magnitude. ReplicOpter can perform hierarchical clustering from a list of rigid docking predictions and find nearby structures to any promising cluster representatives. These predicted complexes can then be refined and rescored. ReplicOpter's scoring function includes a Lennard-Jones potential softened using the Anderson-Chandler-Weeks decomposition, a desolvation term derived from the Atomic Contact Energy function, Coulombic electrostatics, hydrogen bonding, and terms to model pi-pi and pi-cation interactions. ReplicOpter has performed well on several recent CAPRI systems. We are presently benchmarking ReplicOpter on the complete docking benchmark set to fully establish its utility in refining rigid docking predictions and identifying near-native solutions. PMID- 20715289 TI - Generating stereochemically acceptable protein pathways. AB - We describe a new method for rapidly generating stereochemically acceptable pathways in proteins. The method, called geometric targeting, is publicly available at the webserver http://pathways.asu.edu, and includes tools for visualization of the pathway and creating movie files for use in presentations. The user submits an initial structure and a target structure, and a pathway between the two input states is generated automatically. Besides visualization, the structural quality of the pathways makes them useful as input pathways into pathway refinement techniques and further computations. The approach in geometric targeting is to gradually change the system's RMSD relative to the target structure while enforcing a set of geometric constraints. The generated pathways are not minimum free energy pathways, but they are geometrically plausible pathways that maintain good covalent bond distances and angles, keep backbone dihedral angles in allowed Ramachandran regions, avoid eclipsed side-chain torsion angles, avoid non-bonded overlap, and maintain a set of hydrogen bonds and hydrophobic contacts. Resulting pathways for over 20 proteins featuring a wide variety of conformational changes are reported here, including the very large GroEL complex. PMID- 20715290 TI - Binding site prediction and improved scoring during flexible protein-protein docking with ATTRACT. AB - The ATTRACT protein-protein docking program combined with a coarse-grained protein model has been used to predict protein-protein complex structures in CAPRI rounds 13-19. For six targets acceptable or better quality solutions have been submitted (high quality predictions for targets 32, 40, 41, and 42). The improved performance compared to previous rounds can be attributed in part to the inclusion of conformational flexibility during systematic searches and an optimized scoring function. In addition, a recently developed method for the prediction of putative protein binding sites based on the electrostatic penalty to place neutral low dielectric probes on the protein surface was applied to the most recent targets. The approach resulted in useful predictions of putative binding sites that can help to limit the systematic docking searches. Possible improvements of the docking approach in particular at the scoring and refinement steps are discussed. PMID- 20715293 TI - Surgeons and selection of adjuvant therapy for node-negative colonic cancer. PMID- 20715291 TI - Max CAPR: high-resolution 3D contrast-enhanced MR angiography with acquisition times under 5 seconds. AB - High temporal and spatial resolution is desired in imaging of vascular abnormalities having short arterial-to-venous transit times. Methods that exploit temporal correlation to reduce the observed frame time demonstrate temporal blurring, obfuscating bolus dynamics. Previously, a Cartesian acquisition with projection reconstruction-like (CAPR) sampling method has been demonstrated for three-dimensional contrast-enhanced angiographic imaging of the lower legs using two-dimensional sensitivity-encoding acceleration and partial Fourier acceleration, providing 1mm isotropic resolution of the calves, with 4.9-sec frame time and 17.6-sec temporal footprint. In this work, the CAPR acquisition is further undersampled to provide a net acceleration approaching 40 by eliminating all view sharing. The tradeoff of frame time and temporal footprint in view sharing is presented and characterized in phantom experiments. It is shown that the resultant 4.9-sec acquisition time, three-dimensional images sets have sufficient spatial and temporal resolution to clearly portray arterial and venous phases of contrast passage. It is further hypothesized that these short temporal footprint sequences provide diagnostic quality images. This is tested and shown in a series of nine contrast-enhanced MR angiography patient studies performed with the new method. PMID- 20715292 TI - High-field continuous arterial spin labeling with long labeling duration: reduced confounds from blood transit time and postlabeling delay. AB - In quantitative perfusion imaging using arterial spin labeling, variable blood transit times and postlabeling delays are two confounding factors that may compromise the accuracy of perfusion quantifications. In this study, theoretical analyses and experimental data at 9.4 T demonstrate that increasing labeling duration not only enhances the contrast of the arterial spin labeling signal but also minimizes the effect of variable postlabeling delays in multislice arterial spin labeling acquisitions. With a labeling duration of 6.4 sec, arterial spin labeling signal acquired in multislice mode (11 slices) is very similar to that acquired in single-slice mode. Previous studies have shown that inserting a delay between the spin labeling pulse and the image acquisition pulse could reduce confounds resulting from variable blood transit times at the expense of arterial spin labeling sensitivity. Our simulations suggest that enhancing the contrast of arterial spin labeling signal offers the opportunity for extending the postlabeling delay to a longer duration, minimizing systematic errors associated with a wide range of blood transit times, which could have significant implications for applying arterial spin labeling techniques to perfusion imaging of pathological conditions in animal models. PMID- 20715295 TI - Working and living: A difficult balance. PMID- 20715294 TI - Laws of plastic surgery. PMID- 20715296 TI - On being an editor. PMID- 20715297 TI - Someone out there loves you. PMID- 20715298 TI - How to survive your patients. PMID- 20715299 TI - A review of the costs associated with depression and treatment noncompliance: the potential benefits of online support. AB - This systematic review examines the economic and human costs of depression and the potential savings associated with improvement in patient adherence to treatment with antidepressants through the use of enhanced-care programs. A MEDLINE search was conducted for papers published on the health economics and costs of depression and compliance, adherence, and persistence. Compliance data collected through the online antidepressant compliance support website iCAN (www.ican.co.uk) were compared with data for patients with depression from the IMS Disease Analyzer UK database. Depression frequently causes unemployment, absenteeism, and presenteeism, which results in significantly reduced productivity. Indirect costs of depression accounted for more than $50 billion, whereas direct costs resulted in expenditure of $26 billion, in the US in 2000. Improving patients' compliance with their antidepressant medication results in improved outcomes and prolongs remission from depression, increasing work productivity, and thus reducing overall costs. The implementation of remote enhanced-care programs may improve compliance and reduce overall costs. Novel methods for delivering enhanced-care programs to assist in maintaining compliance have the potential to further reduce costs and should be a focus of future research. In conclusion, depression is a common disorder with a high economic impact. Enhanced-care programs may lower costs associated with depression and improve patients' lives. PMID- 20715300 TI - Mirtazapine in generalized social anxiety disorder: a randomized, double-blind, placebo-controlled study. AB - This study is aimed at investigating the efficacy and tolerability of mirtazapine in a generalized social anxiety disorder. Sixty patients with generalized social anxiety disorder were randomly allocated to receive mirtazapine (30-45 mg/day) (n= 30) or placebo (n= 30) for 12 weeks in a double-blind study design. Primary efficacy was assessed by the Liebowitz Social Anxiety Scale (LSAS) and response to treatment was defined as a reduction of 40% on the LSAS and an improvement on the Clinical Global Impression scale of 'much or very much improved'. An intent to-treat analysis showed no difference between mirtazapine and placebo on the absolute LSAS scores with a mean decrease of 13.5 +/- 16.9 and 11.2 +/- 17.8 respectively, and on the number of responders, 13 and 13%, respectively. In conclusion, mirtazapine (30-45 mg/day) failed to be effective in the generalized social anxiety disorder. PMID- 20715301 TI - An Asian case of fibroblastic rheumatism: clinical, radiological, and histological features. AB - We report a case of fibroblastic rheumatism (FR) in a 61-year-old woman. The patient showed sclerodactyly and polyarthritis that involved both her hands and feet joints. Levels of C-reactive protein and matrix metallopeptidase-3 were within normal range. We diagnosed her condition as FR according to both the clinical features characterized with the destructive change of multiple joints and the histological sample. This is the first FR published case of FR in an Asian individual, and 23 published cases were reviewed. PMID- 20715302 TI - Proceedings from IEEE International Conference on Bioinformatics and Biomedicine 2009, Washington, DC, USA . 1-4 November 2009. PMID- 20715303 TI - Why those critters bug you. PMID- 20715304 TI - Exact and approximate probability distributions of evidence-based bundle composite compliance measures. AB - Several studies recently have indicated that compliance with the medical evidence base across a wide range of chronic and acute conditions is dismally low. Partly in response, core measure sets and evidence-based "bundles" of care processes known to improve a patient's condition have become a common means for assessing and comparing the reliability of healthcare organizations to comply with best care practices. Compliance typically is estimated with a composite reliability statistic of the percent of all indicated bundle elements actually delivered to a sample of patients, which then is used to monitor, improve, rank, and reward organizations. Given these judgments inherently involve statistical concepts, we derive exact probability distributions of bundle reliability measures and illustrate how they can be used to develop appropriate statistical methods (confidence intervals, hypothesis tests, statistical process control charts, and probability ratio tests) for supporting process improvement and patient safety activities. Due to their computational complexity, we also discuss several accurate and fast approximations that can be useful in practice, including cumulant-based expansions, saddle point approximations, and probability generating function inversion. In contrast, we show that in some cases simple binomial or normal approximations can result in significant interpretation error and prolonged delays to detect process improvements or deteriorations. PMID- 20715305 TI - A data-integrated simulation-based optimization for assigning nurses to patient admissions. AB - The health care system in the United States has a shortage of nurses. A careful planning of nurse resources is needed to ease the health care system from the burden of the nurse shortage and standardize nurse workload. An earlier research study developed a data-integrated simulation to evaluate nurse-patient assignments (SIMNA) at the beginning of a shift based on a real data set provided by a northeast Texas hospital. In this research, with the aid of the same SIMNA model, two policies are developed to make nurse-to-patient assignments when new patients are admitted during a shift. A heuristic (HEU) policy assigns a newly admitted patient to the nurse who has performed the least assigned direct care among all the nurses. A partially-optimized (OPT) policy seeks to minimize the difference in workload among nurses for the entire shift by estimating the assigned direct care from SIMNA. Results comparing HEU and OPT policies are presented. PMID- 20715306 TI - Risk-adjusted number-between failures charting procedures for monitoring a patient care process for acute myocardial infarctions. AB - Risk-adjusted charts for monitoring a surgical or patient care process have recently gained prominence in the literature. To monitor a patient care process, especially to detect deterioration is crucial in saving patients' lives. In this paper, a new charting procedure is developed for monitoring a patient care process for patients admitted to a hospital with acute myocardial infarctions. This procedure is based on the number-between failures by taking the patients' risks into account. When there is a change in the risk distribution of incoming patients, it is demonstrated that this procedure will behave properly while the non-risk-adjusted counterpart will signal incorrectly that the patient care process has changed. The setting up of this chart to monitor a patient care process for patients with acute myocardial infarctions is described in detail. PMID- 20715307 TI - Money for nothing? The net costs of medical training. AB - One of the stages of medical training is the residency programme. Hosting institutions often claim compensation for the training provided. How much should this compensation be? According to our results, given the benefits arising from having residents among the house staff, no transfer (either tuition fee or subsidy) should be set to compensate the hosting institution for providing medical training. This paper quantifies the net costs of medical training, defined as the training costs over and above the wage paid. We jointly consider two effects. On the one hand, residents take extra time and resources from both the hosting institution and the supervisor. On the other hand, residents can be regarded as a less expensive substitute to nurses and/or graduate physicians, in the production of health care, both in primary care centres and hospitals. The net effect can be either positive or negative. We use the fact that residents, in Portugal, are centrally allocated to National Health Service hospitals to treat them as a fixed exogenous production factor. The data used comes from Portuguese hospitals and primary care centres. Cost function estimates point to a small negative marginal impact of residents on hospitals' (-0.02%) and primary care centres' (-0.9%) costs. Nonetheless, there is a positive relation between size and cost to the very large hospitals and primary care centres. Our approach to estimation of residents' costs controls for other teaching activities hospitals might have (namely undergraduate Medical Schools). Overall, the net costs of medical training appear to be quite small. PMID- 20715308 TI - Planning and scheduling of semi-urgent surgeries. AB - This paper investigates the trade-off between cancellations of elective surgeries due to semi-urgent surgeries, and unused operating room (OR) time due to excessive reservation of OR time for semi-urgent surgeries. Semi-urgent surgeries, to be performed soon but not necessarily today, pose an uncertain demand on available hospital resources, and interfere with the planning of elective patients. For a highly utilized OR, reservation of OR time for semi urgent surgeries avoids excessive cancellations of elective surgeries, but may also result in unused OR time, since arrivals of semi-urgent patients are unpredictable. First, using a queuing theory framework, we evaluate the OR capacity needed to accommodate every incoming semi-urgent surgery. Second, we introduce another queuing model that enables a trade-off between the cancelation rate of elective surgeries and unused OR time. Third, based on Markov decision theory, we develop a decision support tool that assists the scheduling process of elective and semi-urgent surgeries. We demonstrate our results with actual data obtained from a department of neurosurgery. PMID- 20715309 TI - Length of stay and imminent discharge probability distributions from multistage models: variation by diagnosis, severity of illness, and hospital. AB - Multistage models have been effective at describing length of stay (LOS) distributions for diverse patient groups. Our study objective was to determine whether such models could be used for patient groups restricted by diagnosis, severity of illness, or hospital in order to facilitate comparisons conditioned on these factors. We performed a retrospective cohort study using data from 317,876 hospitalizations occurring over 2 years in 17 hospitals in a large, integrated health care delivery system. We estimated model parameters using data from the first year and validated them by comparing the predicted LOS distribution to the second year of data. We found that 3- and 4-stage models fit LOS data for either the entire hospital cohort or for subsets of patients with specific conditions (e.g. community-acquired pneumonia). Probability distributions were strongly influenced by the degree of physiologic derangement on admission, pre-existing comorbidities, or a summary mortality risk combining these with age, sex, and diagnosis. The distributions for groups with greater severity of illness were shifted slightly to the right, but even more notable was the increase in the dispersion, indicating the LOS is harder to predict with greater severity of illness. Multistage models facilitate computation of the hazard function, which shows the probability of imminent discharge given the elapsed LOS, and provide a unified method of fitting, summarizing, and studying the effects of factors affecting LOS distributions. Future work should not be restricted to expected LOS comparisons, but should incorporate examination of LOS probability distributions. PMID- 20715310 TI - Previous research in operating room scheduling and staffing. PMID- 20715313 TI - Opening the closed ribosome-binding site of the lysis cistron of bacteriophage MS2. AB - In prokaryotes gene expression is mainly regulated at the levels of transcription and translation. An important form of translational control operates at the initiation of protein synthesis. For instance the translation of an existing mRNA can be prevented by features in the mRNA structure that prohibit binding of ribosomes. This type of control is frequently applied to polycistronic mRNA to forestall translation of a downstream cistron until the 5' neighbouring cistron has been read (1-7). Such translational coupling or sequential reading also facilitates the shutting off of several cistrons from one control point(6). An interesting example of a nontranslatable message is the lysis (L) cistron, present as an overlapping gene in the RNA bacteriophage MS2 (refs 8-10; Fig. 1). The start of the L cistron is not directly accessible to ribosomes. Instead its translation is strictly coupled to the passage of ribosomes over the preceding coat cistron(2). We have now analysed which features in the MS2 RNA structure deny ribosomes access to the start of the L message. We report here that small deletions, introduced about 40 nucleotides 5' to the start codon of the L gene, remove the initiation barrier and open the cistron to independent translation. An RNA secondary structure accounting for the closed state of the ribosome binding site is proposed. PMID- 20715314 TI - Where we are and where we need to be: keeping our focus on clinical practice. PMID- 20715315 TI - "None Must Meddle Betueene Man and Wife": assessing family and the fluidity of public and private in early modern Scotland. AB - The physical and ideological boundaries between public and private in early modern Scotland were constantly contested, resulting in a shifting reality of what was public and private. This fluidity has been recognized by historians, but how, when, and why the shifting took place is not as clear. The moral church courts (Kirk Sessions) of Reformation Scotland allow a unique opportunity to begin to understand the largely elusive boundaries between public and private in the early modern era. PMID- 20715316 TI - Abandoned in Brussels, delivered in Paris: long-distance transports of unwanted children in the eighteenth century. AB - The study uses examinations and other documents produced in the course of a large scale investigation undertaken by the central authorities of the Austrian Netherlands in the 1760s on the transportation of about thirty children from Brussels to the Parisian foundling house by a Brussels shoemaker and his wife. It combines the rich archival evidence with sparse indications in the literature to demonstrate that long-distance transports of abandoned children were a common but historiographically neglected by-product of the ambiguities of foundling policies in eighteenth-century Europe and provides insight into the functioning of the associated networks and the motives of parents, doctors, midwives, transporters, and local officials involved. PMID- 20715317 TI - The "afterlife" of parenting: memory, parentage, and personal identity in Britain c. 1760-1830. AB - Remembering parentage and parents in life writings in Britain c. 1760-1830 served four functions. First, recounting parentage enabled the writer to situate himself or herself in terms of social status, personal value, and worth. Second, memories of parents helped an individual understand and make meaning of the path his or her life had taken. Third, the process was bound up with a range of emotions, which gave parents power after childhood and had repercussions and meaning throughout the writer's life. Finally, the memories selected and accorded specific significance were often those from times of emotional crisis and disruption and recalling them may have enabled writers to impose some stability upon the insecurities of life. Overall, such memories offer insights into attitudes toward family, indicate the emotional significance of the role that parents played in their offsprings' lives from childhood to old age, and were important in the formation of personal identities. PMID- 20715318 TI - Sex and the city in decline: Midnight Cowboy (1969) and Klute (1971). AB - This essay looks at two popular and influential films of the late 1960s and early 1970s, which were both shot in New York City: Midnight Cowboy (1969) and Klute (1971). It places them in film history, New York City history, and U.S. urban history more generally, finding that they offer an update on earlier century narratives of the connections between urban areas and deviant sexuality. In this modern version, it is not just a moral tale but also an economic one, where, because of the historical decline of the U.S. city and of New York in particular, sex work becomes a plausible, if unsettling means of support. These films find both narrative and spatial terms for advancing the contemporary antiurban narrative, envisioning New York as an impinging vertical space and seeing possible redemption only in the protagonists leaving the city. PMID- 20715319 TI - The shantytowns of Central Park West: fin de siecle squatting in American cities. AB - This article argues that the scope and importance of squatting has been greatly understated in discussions of nineteenth-century urban development. Period newspapers reported often on the struggle of cities and titleholders across North America to evict squatters, indicating that squatters were a common and persistent component of the city landscape. Evidence also suggests that many, if not most, squatters believed that they would eventually win clear title to their homes. PMID- 20715320 TI - The construction of the idea of the city in Early Modern Europe: Perez de Herrera and Nicolas Delamare. AB - With the economic and social changes in Europe at the end of the sixteenth century and the formation and consolidation of an urban network throughout the continent, questions such as poverty, sanitation, and hygiene began to pose acute problems in the cities of the age. A new school of thought, known in Spain as Ciencia de Policia and in the Mediterranean area as Policy Science, proposed solutions for these problems and tested them through practical interventions inside the urban setting. In this article the author compares the work of two thinkers: Cristobal Perez de Herrera, a Spaniard, and Nicolas Delamare, a Frenchman. Writing in the late sixteenth and early seventeenth centuries, Perez de Herrera examined the organization of Madrid, the newly founded (though still not firmly established) capital of Spain. Delamare based his study on the Paris of the early eighteenth century. The author stresses the coincidences in some of the ideas of both thinkers and shows how their writings begin to embody a new idea of the city, many aspects of which have survived until the present day. PMID- 20715321 TI - Norms and customs: causally important or causally impotent? AB - In this article, I argue that norms and customs, despite frequently being described as being causes of behavior in the social sciences and ordinary conversation, cannot really cause behavior. Terms like "norms" and the like seem to refer to philosophically disreputable disjunctive properties. More problematically, even if they do not, or even if there can be disjunctive properties after all, I argue that norms and customs still cannot cause behavior. The social sciences would be better off without referring to properties like norms and customs as if they could be causal. PMID- 20715322 TI - The regulation of prostitution in Beyoglu (1875-1915). AB - This study examines the development and nature of the regulation of prostitution in Beyoglu during the late Ottoman Empire with special emphasis on the way the regulationist regime reinforced existing patterns of class and gender domination. The regulation of prostitution became a matter of urgency in the last decades of the nineteenth century in Istanbul, particularly in Beyoglu, the cosmopolitan centre of the city. Through this process, the protests of the local residents of the area objecting to the proliferation of prostitution in their neighbourhoods played a crucial role in prompting the governmental authorities to tighten the regulations. PMID- 20715323 TI - The women preachers of the secular state: the politics of preaching at the intersection of gender, ethnicity and sovereignty in Turkey. AB - This article analyzes the politics of preaching in Turkey in the last decade by focusing on the appointment of women as preachers and vice-muftis by the Turkish Presidency of Religious Affairs (Diyanet), a state institution established for the protection of secular foundations through religious service. It asks what happens when women wearing headscarves become civil servants and give religious guidance in a secular state, which prohibits headscarves in public offices and schools. It shows that the context, the use and the interlocutors of preaching make ordinary religious activity a complicated political practice that interacts with gender, ethnicity and state sovereignty. It argues that exceptional integration of headscarved women into public offices would seem to be an achievement given the long lasting political activism of women over the headscarf, but in the final analysis it serves the sovereign power of the state, which aims to absorb both Islamist and Kurdish challenges by mobilizing women preachers. PMID- 20715324 TI - The New Negro era and the Great African American Transformation. PMID- 20715325 TI - As Canadian as possible ... under what circumstances?: Public opinion on national identity in Canada outside Quebec. AB - Public opinion on national identity in Canada is changing. Using data from the International Social Science Programme, this essay presents evidence that most Canadians have a strong national identity rooted in universal conceptions that everyone can share, such as citizenship. Data also show, however, that a growing number of Canadians define their national identity narrowly, such as through birthplace and religion. Drawing on research from social psychology, the essay suggests that theories of Canadian identity need to take into account the fact that many Canadians have strong national identities that do not fit cleanly into the civic/ethnic theoretical dichotomy. PMID- 20715326 TI - Linking traditional knowledge and environmental practice in Ontario. AB - Beginning in the late 1980s with the release of Our Common Future by the World Commission on Environment and Development, followed by the development of international accords such as the 1992 Convention on Biological Diversity, international pressure to resolve Indigenous rights issues has been steadily mounting. Successive Canadian governments have been striving increasingly to recognize and incorporate Aboriginal traditional knowledge into resource management planning. Following more than a decade of such efforts, the question of how to achieve such incorporation appropriately remains inadequately answered. This essay contributes to the resolution of this issue by first clarifying some key differences between Aboriginal and non-Aboriginal definitions of "traditional knowledge." Then, three Ontario case studies are briefly described that highlight the most and least successful aspects of previous undertakings. Among the lessons learned are the need to value traditional knowledge on a par with Western science while recognizing the particular capabilities of each system, and the requirement that Aboriginal peoples and their knowledge participate on a mutually respectful basis. PMID- 20715327 TI - "But what is the object of educating these children, if it costs their lives to educate them?": federal Indian education policy in western Canada in the late 1800s. AB - Debates in the Canadian House of Commons in the last two decades of the nineteenth century revealed persistent differences between the Conservatives and the Liberals over federal Indian education policy and the administration of industrial schools. Until their defeat in 1896, the Conservatives supported a denominational industrial school system and a policy of rapid assimilation. The Liberals generally opposed denominational schools and believed the industrial school system was too costly and was not leading to rapid assimilation. After gaining power, the Liberals stopped construction of industrial schools in favour of boarding and day schools, but denominational influence remained strong. The Conservative emphasis on assimilation was replaced by measures that supported reserve-based segregation as earlier hopes for rapid assimilation diminished. Despite policy differences, neither the Conservatives nor the Liberals held Aboriginal cultures in high regard, and debates regarding the means and intent of Indian education played out against well-known, high mortality rates and often abysmal conditions in the schools. PMID- 20715328 TI - Fragments and absences: language and loss in Miriam Toews's A complicated kindness. AB - Miriam Toews resists the conventional narrative of the adolescent leaving the small town, proposing instead that the community deserts Nomi Nickel. Nomi, facing maternal absence and the loss of her mother tongue, attempts to use linguistic and material fragments to connect word and world. Suffering from multiple and inexplicable desertions, she rejects the community's intolerance but values its kindness. Her contradictory responses to Plautdietsch, which is both deserting her and being rejected by her, complicate and challenge the concrete words and signs of adolescent protest and rebellion. Binaries separating word and world, kindness and judgement, margin and centre are challenged and collapsed in the course of Nomi's narrative. PMID- 20715329 TI - Jewish immigrant encounters with Canada's Native Peoples: Yiddish writings on Tekahionwake. AB - During the mass Jewish immigration of Eastern-European Jews to Canada in the first decades of the twentieth century, Yiddish publications offered a primary forum for a group of local writers to negotiate with their new identities as Canadian Jews. Within this wider process, Montreal writers H.M. Caiserman and B.G. Sack authored studies of Canadian literature in the early 1920s centred on Mohawk-English writer E. Pauline Johnson (Tekahionwake). What these essays show is that, despite the long-standing association of Canada's Jewish population with the country's dominant English culture, their status as "other" impelled leading members of the local Yiddish cultural milieu to seek out literary models among other historically marginalized groups. For Caiserman and Sack, Johnson's Native heritage offered a model for resistance to assimilation into Canada's dominant culture. In contrast, the advent of literature responding to the Nazi Holocaust by A.M. Klein and Eli Mandel, Native peoples became a symbol of loss and vanished landscapes. PMID- 20715330 TI - The aping apes of Poe and Wright: race, animality, and mimicry in The murders in the rue morgue and Native son. PMID- 20715331 TI - The slaveries of sex, race, and mind: Harriet Beecher Stowe's Lady Byron vindicated. PMID- 20715332 TI - Anti-Interiority: compulsiveness, objectification, and identity in infinite jest. PMID- 20715333 TI - The materiality of remembering: Freud's wolf man and the biological dimensions of memory. PMID- 20715334 TI - HIV/AIDS information by African companies: an empirical analysis. AB - This article investigates the extent of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Disclosures (HIV/AIDSD) in online annual reports by 200 listed companies from 10 African countries for the year ending 2006. Descriptive statistics reveal a very low level of overall HIV/AIDSD practices with a mean of 6 per cent disclosure, with half (100 out of 200) of the African companies making no disclosures at all. Logistic regression analysis reveals that company size and country are highly significant predictors of any disclosure of HIV/AIDS in annual reports. Profitability is also statistically significantly associated with the extent of disclosure. PMID- 20715335 TI - Hiplife, cultural agency and the youth counter-public in the Ghanaian public sphere. PMID- 20715337 TI - Ask us. Self-ligating bracket claims. PMID- 20715336 TI - Breastfeeding peer counseling: from efficacy through scale-up. AB - An increasing number of publications have evaluated various breastfeeding peer counseling models. This article describes a systematic review of (a) the randomized trials assessing the effectiveness of breastfeeding peer counseling in improving rates of breastfeeding initiation, duration, exclusivity, and maternal and child health outcomes and (b) scientific literature describing the scale-up of breastfeeding peer counseling programs. Twenty-six peer-reviewed publications were included in this review. The overwhelming majority of evidence from randomized controlled trials evaluating breastfeeding peer counseling indicates that peer counselors effectively improve rates of breastfeeding initiation, duration, and exclusivity. Peer counseling interventions were also shown to significantly decrease the incidence of infant diarrhea and significantly increase the duration of lactational amenorrhea. Breastfeeding peer counseling initiatives are effective and can be scaled up in both developed and developing countries as part of well-coordinated national breastfeeding promotion or maternal-child health programs. PMID- 20715338 TI - Resource allocation model for public health planning. A case study of tuberculosis control. PMID- 20715339 TI - The inertia of sex: Henry Adams on family and the politics of unconditional love. AB - This article offers a reassessment of the contemporary relevance of the political thought of Henry Adams through a focus on his ideas about the relationship between family and politics. Adams' ideas have been dismissed by contemporary thinkers, like Richard Rorty, who rely on similar ideas about the role family should play in politics. The article traces the role of ideas about family as a unifying theme in Adams' history, fiction, and autobiography. It shows both why Adams believed familial sentiments, especially feminine and motherly love, were crucial to political unity, and why he thought these sentiments had become increasingly difficult to rely upon. In showing how Adams wrestled with the difficulties that emerge in putting familial sentiments to use for politics, the article suggests that Adams' ideas offer useful lessons for contemporary thinkers interested in the relationship between family and politics. PMID- 20715341 TI - Body area networks could support more medical applications. PMID- 20715340 TI - Budgeting--an innovative approach. PMID- 20715342 TI - Opening doors: get noticed by the C-Suite. PMID- 20715343 TI - MediSend strives to transform healthcare in developing countries. PMID- 20715344 TI - Job swapping program takes technicians outside comfort zone. PMID- 20715345 TI - Components of a comprehensive capital equipment planning program. AB - As you may have already figured out, there is crossover and gaps between all of these capital equipment components. CE often will, and proactively should, make recommendations based on the CE, clinical, and financial components but rarely has direct knowledge of the strategic element. The clinical, finance, and administrative folks likely have visibility to most of these, but may lack full awareness of at least one component. The key is to engage key stakeholders from all these critical areas and develop a process to pull all this information together in one nice, neat package. Defining the person or persons responsible for taking the lead on this in your organization will depend greatly on the organization's type and size. For a single, standalone community hospital, it will likely be the facility administrator. For an integrated delivery network (IDN), a corporate entity, led by supply chain, finance, or both, may take the lead. Your organization may also employ consultative services or software to help facilitate this function. Regardless of who takes the lead, a weighting or scoring system that assigns certain values in all the outlined component categories, is clearly defined, and is easy to understand for all the contributors will need to be developed. If you are unaware or unclear of what the process is, find out and figure out how you can be a vital contributor to the process. This is one more way you can demonstrate the value you and your department bring to your organization. PMID- 20715346 TI - Training is key to proper video operation. PMID- 20715348 TI - Merger aims to combine the best of CE, IT worlds. PMID- 20715347 TI - Practical guide for successful performance improvement. PMID- 20715349 TI - Basic electronics: AC transformers. PMID- 20715350 TI - Audiometers--a closer look. PMID- 20715351 TI - The power of techknowledgy. AB - Knowledge can range from complex, accumulated expertise (tacit knowledge) to structured explicit content like service procedures. For most of us, knowledge management should only be one of many collaborative means to an end, not the end in itself (unless you are the corporate knowledge management director or chief knowledge officer). For that reason, KM is important only to the extent that it improves an organization's capability and capacity to deal with, and develop in, the four dimensions of capturing, codifying, storing, and using knowledge. Knowledge that is more or less explicit can be embedded in procedures or represented in documents and databases and transferred with reasonable accuracy. Tacit knowledge transfer generally requires extensive personal contact. Take for example troubleshooting circuits. While troubleshooting can be procedural to an extent, it is still somewhat of an art that pulls from experience and training. This is the kind of tacit knowledge where partnerships, mentoring, or an apprenticeship, are most effective. The most successful organizations are those where knowledge management is part of everyone's job. Tacit, complex knowledge that is developed and internalized over a long period of time is almost impossible to reproduce in a document, database, or expert system. Even before the days of "core competencies", the learning organization, expert systems, and strategy focus, good managers valued the experience and know-how of employees. Today, many are recognizing that what is needed is more than a casual approach to corporate knowledge if they are to succeed. In addition, the aging population of the baby boomers may require means to capture their experience and knowledge before they leave the workforce. There is little doubt that knowledge is one of any organization's most important resources, or that knowledge workers' roles will grow in importance in the years ahead. Why would an organization believe that knowledge and knowledge workers are important, yet not advocate active management of knowledge itself? Taking advantage of already accumulated corporate intellectual property is by far the most low-cost way to increase capability and competitive stature. These are all good reasons why it might pay to take a look at your KM usage. PMID- 20715352 TI - Dashboards: a required business management tool. PMID- 20715353 TI - Key performance parameters of a contemporary diagnostic ultrasound transducer. PMID- 20715354 TI - When a user calls: just say yes. PMID- 20715355 TI - Validation of sterilization: getting started is the most difficult part. PMID- 20715356 TI - Poster highlights sterility assurance levels. PMID- 20715357 TI - Risk management: it's not just FMEA. PMID- 20715358 TI - A guide to navigating the expanded human factors standard. PMID- 20715359 TI - FDA adverse Event Problem Codes: standardizing the classification of device and patient problems associated with medical device use. AB - The broad array of medical devices and the potential for device failures, malfunctions, and other adverse events associated with each device creates a challenge for public health device surveillance programs. Coding reported events by type of device problem provides one method for identifying a potential signal of a larger device issue. The Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) Event Problem Codes that are used to report adverse events previously lacked a structured set of controls for code development and maintenance. Over time this led to inconsistent, ambiguous, and duplicative concepts being added to the code set on an ad-hoc basis. Recognizing the limitation of its coding system the FDA set out to update the system to improve its usefulness within FDA and as a basis of a global standard to identify important patient and device outcomes throughout the medical community. METHODS: In 2004, FDA and the National Cancer Institute (NCI) signed a Memorandum of Understanding (MOU) whereby NCI agreed to provide terminology development and maintenance services to all FDA Centers. Under this MOU, CDRH's Office of Surveillance and Biometrics (OSB) convened a cross-Center workgroup and collaborated with staff at NCI Enterprise Vocabulary Service (EVS) to streamline the Patient and Device Problem Codes and integrate them into the NCI Thesaurus and Meta-Thesaurus. This initiative included many enhancements to the Event Problem Codes aimed at improving code selection as well as improving adverse event report analysis. LIMITATIONS & RECOMMENDATIONS: Staff resources, database concerns, and limited collaboration with external groups in the initial phases of the project are discussed. CONCLUSIONS: Adverse events associated with medical device use can be better understood when they are reported using a consistent and well-defined code set. This FDA initiative was an attempt to improve the structure and add control mechanisms to an existing code set, improve analysis tools that will better identify device safety trends, and improve the ability to prevent or mitigate effects of adverse events associated with medical device use. PMID- 20715360 TI - Biomechanical modeling of the rectum for the design of a novel artificial anal sphincter. AB - This paper discusses biomechanical issues that are related to the option of a novel artificial anal sphincter around the human rectum. The prosthesis consists of a compression cuff system inside and a reservoir cuff system outside, which is placed around the debilitated sphincter muscle. The micropump shifts fluid between the cuffs and thus takes over the expansion and compression function of the sphincter muscle. However, the human rectum is not a rigid pipe, and motion in it is further complicated by the fact that the bowel is susceptible to damage. With the goal of engineering a safe and reliable machine, the biomechanical properties of the in-vivo porcine rectum are studied and the tissue ischemia is analyzed. PMID- 20715361 TI - A new type of medical micropump for an endoscopic robot. AB - Researchers have developed a new type of medical micropump for an endoscopic robot, which is driven by a linear actuator based on a direct current (DC) motor. This micropump consists of two active one-way valves and a cylindrical air drum. The overall size of the pump prototype is 12.5 mm in diameter and 56 mm in length. This paper describes the structure of the micropump and linear actuator and analyzes the inflation mechanism of the micropump. The experimental results show that the driving force of the linear actuator can reach up to 2.55 N, which fulfills the need of the micropump. The rated output flow of the micropump is 16 mL/min, which can rapidly supply the gas bag with enough air with minimal noise and vibration. PMID- 20715362 TI - Why professionalism matters. PMID- 20715363 TI - Motor unit number estimations (MUNEs): past, present and future. PMID- 20715364 TI - Change in excitability of motor axons modifies statistical MUNE results. AB - Motor unit number estimation (MUNE) techniques--whether they reflect a true motor unit count or some related index--should not be confounded by changes in the neuromuscular system other than a decline in the number of functional motor units. In neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), there is evidence of changes in the excitability of motor axons. If changes in axon excitability confound a particular MUNE technique, this would influence the use of that technique in ALS patients. We hypothesized on the basis of computational models that changes in axon membrane excitability would change the outcome of a statistical MUNE test, even though the true number of motor units remained unchanged. To test the validity of the model predictions we induced changes in axon excitability of healthy control subjects by applying a polarizing current while simultaneously carrying out a statistical MUNE test. In a group of 7 subjects we found a significant difference in MUNE as a result of the change in axon excitability produced by the polarizing current (paired t test, P < 0.05). We conclude that the statistical MUNE method is confounded by changes in axon excitability. Since increasing evidence shows that axon excitability is altered as part of the pathophysiological process underlying ALS, clinical researchers should be cautious when using statistical MUNE with this patient population. PMID- 20715365 TI - Biological basis for motor unit number estimation through Bayesian statistical analysis of the stimulus-response curve. PMID- 20715366 TI - Bayesian analysis of the stimulus-response curve. PMID- 20715367 TI - Results of Bayesian statistical analysis in normal and ALS subjects. PMID- 20715368 TI - The CMAP scan. PMID- 20715369 TI - Physiological considerations, hardware and software requirements for stimulating single motor nerve fibers. PMID- 20715370 TI - Improving the accuracy of the multiple point stimulation technique. PMID- 20715371 TI - Incremental stimulation MUNE: automation with global path search and alternation pattern recognition. PMID- 20715372 TI - Motor unit number estimation with high-density surface EMG: principles and implications. PMID- 20715373 TI - Decomposition-enhanced spike triggered averaging MUNE: validity, reliability, and impact of contraction force. PMID- 20715374 TI - Motor unit number estimation in the upper trapezius muscle. PMID- 20715375 TI - Statistical motor unit number estimation and ALS trials: the effect of motor unit instability. AB - Although statistical MUNE has many positive attributes, it is inappropriate for use in multicenter ALS clinical trials. No other commonly used technique for MUNE possesses all the attributes necessary to be a valid and useful outcome measure in ALS trials. However, MUNE as a theoretical outcome measure remains extremely attractive and new techniques must be sought so that it can reach its full potential as a valid and reproducible outcome measure in ALS clinical trials. PMID- 20715376 TI - Motor neuron disorders: novel electrophysiologic approach (MUFDEC protocol). PMID- 20715377 TI - Motor unit number estimation (MUNE) in diseases of the motor neuron: utility and comparative analysis in a multimodal biomarker study. AB - We prospectively studied 64 patients with motor neuron disease (amyotrophic lateral sclerosis (ALS), familial ALS (fALS), progressive muscular atrophy (PMA) and primary lateral sclerosis (PLS)) using multiple point stimulation motor unit number estimation (MUNE), transcranial magnetic stimulation (TMS), proton magnetic resonance spectroscopic imaging (1H MRSI), diffusion tensor imaging (MRDTI), and clinical measures at baseline and every 3 months thereafter for 15 months. Substantial differences in MUNE were noted among the motor neuron disease subgroups (P = 0.0005) and mean values for each motor neuron disease subgroup were significantly lower vs. controls (ALS = 76, fALS = 80, PMA = 29, and PLS = 174) vs. the normal control average (267). MUNE correlated well with % FVC (r = 0.32; P = 0.01), manual muscle testing (r = 0.52; P < 0.0005), grip strength (r = 0.34; P = 0.007), and pinch strength (r = 0.49; P < 0.0005). Overall, MUNE showed the greatest significant change over time of any measure, clinical or otherwise, tested in this study (-2.35 linear trend % change per month, mean). MUNE clearly delineates lower motor neuron dysfunction, strongly correlates with important clinical functions (such as strength and respiration) and is a highly sensitive marker of disease progression over time. These features make MUNE an important tool for both the study of the pathophysiology of the motor neuron diseases, as well as an important measure for incorporation into future clinical trials. PMID- 20715378 TI - Motor unit number estimation in asymptomatic familial amyotrophic lateral sclerosis. PMID- 20715379 TI - Detection of pre-clinical motor unit loss in familial amyotrophic lateral sclerosis. PMID- 20715380 TI - Motor unit number estimates, quantitative motor unit analysis and clinical outcome measures in amyotrophic lateral sclerosis. PMID- 20715381 TI - Reduction in the motor unit number estimate (MUNE) after cerebral infarction. AB - We examined the relationship between the degree to which motor unit number estimates (MUNEs) decrease in association with the clinical features of patients with the infarction. Using a multiple-point stimulation technique, we obtained the MUNE of the hypothenar muscle group in 13 age-matched control subjects and 30 patients with cerebral infarction. In all patients, we obtained the Japan Stroke Scale (JSS) and head MR images. In 8 patients with acute cerebral infarction, admitted within 24 h after onset, we also obtained head MR angiograms and single photon emission CT. There was a decrease in the MUNE of the hypothenar muscle group on the affected side of 24 patients with cerebral infarction and hand weakness. The decrease in the MUNE started from 4 to 30 h after the infarction, when T1-weighted MR images of the brain involved were normal. The degree to which the MUNE decreased correlated with the part of the JSS showing the upper extremity weakness. A decrease in the MUNE of the hypothenar muscle group within 30 h after cerebral infarction may be due to transsynaptic inhibition of the spinal alpha motor neurons innervating this muscle. PMID- 20715382 TI - Prospective 15-year study of neuromuscular function in a cohort of patients with prior poliomyelitis. AB - Poliomyelitis is a monophasic illness affecting lower motor neurons and individuals may describe new problems years after the initial weakness. We have studied 38 people with the post-polio syndrome over a 15-year period assessing a number of neuromuscular measures, including motor unit number estimation (MUNE). Twenty-five individuals reported progressive weakness but there was no objective change in MUNE and other measures. There was an association with reported weakness and initial deficits. There was a slow decline in MUNE values over time in both groups. PMID- 20715383 TI - Recent MUNE studies in animal models of motor neuron disease. AB - MUNE provides valuable information when applied to animal models of motor neuron disease. It is potentially useful as a supplement to therapeutic trials on the SOD-1 transgenic mouse model and has been able to show increases in the functioning motor units in response to some stem cell transplantation. Even in models that have subtle or imperceptible phenotypes, MUNE can show reductions in motor unit compliment. Thus, it is a valuable addition to the armamentarium of investigative tools when studying models of motor unit loss. PMID- 20715384 TI - Development and use of the incremental twitch subtraction MUNE method in mice. AB - We have used a technique to estimate the number of functioning motor units (MUNE) innervating a muscle in mice based on twitch tension. The MUNE technique was verified by modeling twitch tensions from isolated ventral root stimulation. Analysis by twitch tensions allowed us to identify motor unit fiber types. The MUNE technique was used to compare normal mice with transgenic superoxide dismutase-1 mutation (G94A) mice to assess the time course of motor unit loss with respect to fiber type. Motor unit loss was found to occur well in advance of behavioral changes and the degree of reinnervation is dependent upon motor unit fiber types. PMID- 20715386 TI - Challenges in computerized MUAP analysis. PMID- 20715385 TI - Issues and expectations for EMG decomposition. PMID- 20715387 TI - Decision support for QEMG. AB - For clinicians to use quantitative electromyography (QEMG) to help determine the presence or absence of neuromuscular disease, they must manually interpret an exhaustive set of motor unit potential (MUP) or interference pattern statistics to formulate a clinically useful muscle characterization. A new method is presented for automatically categorizing a set of quantitative electromyographic (EMG) data as characteristic of data acquired from a muscle affected by a myopathic, normal or neuropathic disease process, based on discovering patterns of MUP feature values. From their numbers of occurrence in a set of training data, representative of each muscle category, discovered patterns of MUP feature values are expressed as conditional probabilities of detecting such MUPs in each category of muscle. The conditional probabilities of each MUP in a set of MUPs acquired from an examined muscle are combined using Bayes' rule to estimate conditional probabilities of the examined muscle being of each category type. Using simulated and clinical data, the ability of a "pattern discovery" based Bayesian (PD-based Bayesian) method to correctly categorize sets of test MUP data was compared to conventional methods which use data means and outliers. The simulated data were created by modeling the effects of myopathic and neuropathic diseases using a physiologically based EMG signal simulator. The clinical data was from controls and patients with known neuropathic disorders. PD-based Bayesian muscle characterization had an accuracy of 84.4% compared to 51.9% for the means and outlier based method when using all MUP features considered. PD based Bayesian methods can accurately characterize a muscle. PD-based Bayesian muscle characterization automatically maximizes both sensitivity and specificity and provides transparent rationalizations for its characterizations. This leads to the expectation that clinicians using PD-based Bayesian muscle characterization will be provided with improved decision support compared to that provided by the status quo means and outlier based methods. PMID- 20715388 TI - Optimizing and standardizing quantitative EMG. AB - Quantitative EMG (QEMG) is a useful technique to diagnose subtle neuromuscular disorders. Automated QEMG techniques rely upon computer algorithms to extract motor unit action potentials (MUAPs). A number of different algorithms are available and we have compared the performance of three of them. We have also assessed a number of variables related to the operations performed by the algorithms, including marking of MUAP metrics, data acquisitions time, and effects of raising the high-pass filter. We have also assessed whether there are differences in MUAP metrics depending upon where the needle is placed in the muscle. PMID- 20715389 TI - A comparison of three quantitative motor unit analysis algorithms. AB - This study assessed the accuracy of three automatic motor unit analysis algorithms--multi-motor unit analysis, decomposition quantitative EMG, and EMGtools--on a set of real EMG signals whose true composition was determined by manual decomposition. All three algorithms correctly identified all the MUs in signals with up to 5 active MUs, and most of the MUs in signals with up to 10 active MUs. The algorithms accurately estimated MUAP amplitudes and firing rates, but they estimated duration less accurately because of baseline noise. These findings support the validity and utility of these algorithms. PMID- 20715390 TI - Cloud interference pattern analysis (IPA) in thoracic paraspinal muscles in motor neuron disease. PMID- 20715391 TI - Anal sphincter motor unit potential (MUP) differences between sides, between rest and voluntary contraction, and between MUP analysis programs in normal subjects. AB - Trauma to the external anal sphincter resulting in incontinence is a relatively common disorder. Methods to detect damage include pudendal nerve conduction studies and needle EMG. We have applied a quantitative EMG technique using decomposition-enhanced software to isolate motor unit potentials (MUPs) and their surface representation from an anal probe electrode in healthy nulliparous women. MUPs were readily isolated and metric values compared favorably with those recorded with different software. PMID- 20715392 TI - Scalp psoriasis. AB - Psoriasis is a chronic, debilitating disease that commonly involves the scalp. Despite a wide range of therapy options, scalp psoriasis remains difficult to treat, highlighting a long-standing unmet need for the safe and effective treatment of scalp psoriasis. Many topical therapies for scalp psoriasis are also difficult or unpleasant to apply, resulting in decreased adherence and efficacy. In brief, the high level of patient dissatisfaction with currently available treatments for psoriasis supports the need for new, effective and well-tolerated treatment options for scalp psoriasis. This article aims to review the efficacy and safety of new formulations and treatment options available to control scalp psoriasis. For example, a new formulation of calcipotriene/betamethasone scalp solution has a rapid onset of action with once daily dosing that improves compliance. The CalePso study examines the safety profile of otherwise established Clobetasol propionate (CP) shampoo 0.05%, and reports that CP shampoo is safe and efficacious in the long-term management of scalp psoriasis. A new foam formulation of coal tar is shown to be cosmetically acceptable and easier to apply. PMID- 20715393 TI - How and when to use biologics in psoriasis. PMID- 20715394 TI - Enhancing the eyes: use of minimally invasive techniques for periorbital rejuvenation. AB - Facial beauty, specifically of the periorbital complex, is an important component of physical attractiveness and non-verbal communication, and is reflective of chronological age. In fact, eye contact is often the first, and some say the most important, form of interaction between individuals. These properties have made rejuvenation of the periorbital complex highly desirable. In the past, rejuvenating the eye meant the need for invasive surgical treatments. Although these may be necessary in advanced cases, minimally or noninvasive procedures have increasingly become first line treatment options since the advent of topical therapies and minimally invasive procedures, which include botulinum toxin, dermal filler injections, laser and chemical peels, laser skin resurfacing, microdermabrasion and intense pulsed light photorejuvenation. Here, the authors review the anatomy of the periorbital complex, the characteristics of an attractive eye, and a variety of techniques that may be used alone or in combination to achieve "the beautiful eye. PMID- 20715395 TI - Facial shaping: beyond lines and folds with fillers. AB - Facial attractiveness is the most important determinant of physical attractiveness, and an important factor in social and interpersonal interactions. The field of facial rejuvenation using minimally invasive procedures has expanded exponentially over the last decade. Historically, aging and the resulting changes were primarily attributed to changes in the skin and the underlying musculoskeletal system. However, more recent understanding of the changes associated with facial aging has shifted the focus to changes in the distribution of subcutaneous fat. With the introduction of seemingly endless varieties of fillers over the last decade, restoration of volume loss by subcutaneous fat, and to some extent bone, has never been easier. Here, the authors review the basic principles that govern facial beauty, facial anatomy, the aging process, and the wide variety of fillers available on the market today that enable a dermatologic surgeon to revitalize the face. PMID- 20715396 TI - [Low output syndrome; prevention and treatment]. AB - Cardiac surgery has advanced remarkably in a sense by overcoming perioperative low output syndrome (LOS). Improvement of surgical results and postoperative quality of life has expanded the range of treatment to patients with higher risk and/or advanced age. LOS is still a major concern in cardiac surgery. Of upmost importance are proper myocardial protection and precise surgery. Transesophageal echocardiography is the best perioperative monitor to prevent, and if necessary to treat, LOS. Cardiac tamponade is the most frequent cause of LOS, and should be diagnosed and resolved without delay. Spasm of the coronary artery or the bypass graft is rare complication which may bring on LOS. LOS may be caused by right heart failure, for which open-chest management is useful in case of unsuccessful inotropic support. Careful check-up of blood gas and electrolytes is also important to maintain good hemodynamics and to prevent arrhythmias. Pacing is very useful, particularly atrial or AV seguential pacing, to obtain reasonable output and to prevent arrhythmias. Mechanical circulatory support is considered when other strategies are not effective. Which support modality is to be chosen among intraaortic balloon pumping, percutaneous cardiopulmonary support and ventricular assist device is based on required strength and duration of support. PMID- 20715397 TI - [Neurological injury associated with cardiac surgery]. AB - Approximately 3% of the patients undergoing cardiac operations suffer postoperative neurological injury, which markedly worsen postoperative quality of life (QOL) of the patients. However, the causes of the complications are multifactorial. Therefore, it is essential for reduction of the incidence that a variety of attentions should be paid in pre- and post-operative management. PMID- 20715398 TI - [Perioperative management following cardiovascular surgery in patients with renal insufficiency]. AB - In recent years as the population becomes older, the number of patients undergoing cardiovascular surgery and thereafter suffering various complications has risen with increasing severity. Renal insufficiency is one of the characteristic complications. Most cardiovascular procedures require extracorporeal circulation. With extracorporeal circulation, kidney perfusion pressure and the perfusion volume decrease and this can result in potential renal tubule disorders following surgery. Therefore, it is important to prevent the postoperative aggravation of the renal function in patients with renal dysfunction before the induction of dialysis because they have a diminished renal reserve capacity and specific management is also required for patients on dialysis. The important points are as follows; (1) for the patient who is not on dialysis, it is important to maintain a sufficient blood pressure and prevent a shift to dialysis by avoiding exsiccation, (2) for the patient on dialysis, it is important to carefully evaluate the situation for each patient before resuming dialysis after surgery, (3) for both patient populations, it is important to always consider the dosage and dosage interval when any drugs are administered. PMID- 20715399 TI - [Cardiovascular surgery for patients with chronic respiratory failure and respiratory dysfunction]. AB - Chronic obstructive pulmonary disease is one of the major comorbidities in elderly patients with heart disease and thoracic aneurysm because of an overlap of risk factors. Although postoperative ventilator dependency is a major concern, recent study has suggested chronic obstructive pulmonary disease (COPD) was not a risk factor for postoperative prolonged mechanical ventilator support for off pump coronary artery bypass grafting. Cardiopulmonary bypass may induce acute lung injury, but short-term cardiopulmonary bypass alone does not give adverse effect in clinical practice. Perioperative airway management including quitting smoking, use of bronchodilator, avoiding excessive tracheal suction, and early extubation may contribute satisfactory outcome. However, a stage IV COPD patient is contraindicated for cardiac surgery. Patients with interstitial lung disease can undergo cardiac surgery safely if they have moderate performance status even when patients are under home oxygen therapy. PMID- 20715400 TI - [Ideal intraoperative management to prevent perioperative complications]. AB - Anesthesiologists can contribute considerably to prevent both intra- and post operative complications. Intraoperative transesophageal echocardiography can be utilized to visualize potential hazards at various stages in cardiac surgery; aortic and venous cannulation, left ventricular vent tube insertion and removal of residual air in cardiac chambers. Near infrared spectroscopy is employed for early detection of cerebral ischemia. A more than 20 percent of decrease from the preoperative baseline probably indicates cerebral ischemia and prompts some measures to improve cerebral oxygenation. Separate lung ventilation can be offered by using a combination of a normal endotracheal tube and a bronchial blocker instead of a double lumen tube in order to avoid a tube exchange at the end of operation which is sometimes difficult and dangerous. Intraoperative awareness should be avoided by administering additional sedatives especially at a rewarming phase of cardiopulmonary bypass. Intraoperative shivering causes excessive oxygen demands and should be prevented by giving enough amounts of muscle relaxants. Temperature and glucose controls are also important to decrease surgery-related morbidity and mortality. A premature cease of rewarming by cardiopulmonary bypass and extra heating after bypass may well be considered. High thoracic epidural anesthesia is possibly beneficial to reduce patients' stress, improve postoperative pulmonary function and hasten recovery. PMID- 20715401 TI - [Patient safety in cardiopulmonary bypass; unusual problems and managements]. AB - Since most of the facilities that conduct open heart surgery in Japan are small and do small numbers of cases each year, many modifications of circuit design in cardiopulmonary bypass (CPB) are commonly found in individual centers. In 2007, under the guidance of the Ministry of Health, Labour and Welfare, a committee consisting of members from 4 medical societies and 1 medical device manufacture association released the Japanese CPB guidelines. The aim was to standardize CPB hardware and software for patient safety and education. The guidelines include heart-lung machines, circuit designs, safety devices and monitoring equipment, perfusion practices, training and education of perfusionists, as well as emergency crisis drills and safety education. To establish safe CPB performance, education of and team work between perfusionists and cardiac surgeons are most important. For the purpose of ensuring patient's safety during CPB, common and conceivable troubles as well as major accidents in the literature should be well studied, methods of prevention should be validated, and methods of "bail-out" from the trouble should be thoroughly practiced. PMID- 20715402 TI - [Perioperative management in cardiovascular emergency surgery]. AB - Perioperative management in emergency cardiac operation is challenging because general condition of the patient is often poor and only little preoperative information is available. In order to obtain an optimal surgical outcome, careful assessment of preoperative problems and prevention and detection of complications must be done without any delay. Preoperative carotid duplex scan should be performed in every case to assess the steno-occlusive lesion or unstable plaque, which affect the surgical strategy (eg. selection of arterial cannulation site and cerebral protection). Regional cerebral oxygen saturation (rSO2) must be monitored in all the operation. If intraoperative drop in rSO2 is detected, administration of inotropic agents and increase in cardiopulmonary bypass flow is needed to maintain the mean blood pressure at higher level. Intraaortic balloon pumping (IABP) insertion should be considered when rSO2 cannot be recovered with those procedures. We have to keep in mind that many of the patients undergoing emergency surgery are at high risk for coronary artery disease. If one cannot be weaned from cardiopulmonary bypass, coronary artery bypass grafting to a major branch may be performed. Coronary angiography should be performed immediately when ST-T changes in electrocardiogram (ECG) or chest symptoms appear in the postoperative period. Hesitation in making a decision will only jeopardize the situation. PMID- 20715403 TI - [Management of mediastinitis and preventions of perioperative nosocomial infection after cardiovascular surgery]. AB - This article reviews risk factors and treatment of perioperative nosocomial infections. The primary prophylactic antibiotic is recommended to be a cefazolin or penicillin with sulbactam, because the most frequent organism cultured in cardiac surgical site infection (SSI) is Staphyloccocus. Antibiotic prophylaxis of 48 hours' duration after cardiovascular surgery is clinically effective in minimizing infectious complication. In patients considered at high risk for a staphylococcal infection, vancomycin may be recommended. In the treatment of postoperative infections, Gram-stain-based antibiotic selection is necessary and the initial empirical therapy to ensure adequate coverage of potentially infective organisms should be accompanied by de-escalation until microbiological data become available. Mediastinitis, which is one of the important infectious complications after cardiovascular surgery, requires surgical drainage and debridement, as well as antimicrobial therapy. Vacuum-assisted closure (VAC) is an effective therapy compared with the conventional technique of open packing. Continuous clinician's efforts and prolonged infection control programs are very important for prevention of perioperative nosocomial infection after cardiac surgery. PMID- 20715404 TI - [Cardiac surgery in patients with liver dysfunction; preoperative assessment, determinants, and consequences]. AB - The population of patients with liver cirrhosis and congestive liver who are referred for cardiac operation is not large and definitive indications for surgical interventions remain unknown. We reviewed the literature on its clinical features and outcomes after cardiac surgery that would help cardiac surgeons to decide cardiac modality. According to our experiences, in cirrhotic patients, cardiac surgery can be performed safely in Child-Pugh class A and selected patients with class B. In addition, liver cirrhosis causes postoperative deterioration of liver function, especially when the indocyanine green (ICG)-R15 value exceeds 40%. Technetium-99m galactosyl human serum albumin liver scintigraphy is also useful for preoperative assessment. In patients with congestive liver, preoperative serum total bilirubin and technetium-99m galactosyl human serum albumin liver scintigraphy may become the determinant of indications. Careful patient selection and intensive perioperative care are required to improve the clinical outcome in patients with liver dysfunction undergoing cardiac surgery. PMID- 20715406 TI - [Blood transfusion and its complications in cardiovascular surgery]. AB - In cardiovascular surgery, blood transfusions have been associated with infections (hepatitis B, C, and HIV) and immunologic reactions. To prevent transfusion complications, we should organize a transfusion guideline which indicate the appropriate timing of blood transfusion and the total amount of blood volume because a resourse of the blood product is limited. It is also very important to induce blood conservation techniques. Drugs that decrease bleeding and increase blood volume, devices that preserve blood, and autologous blood donation are most effective. Reduction of the transfusion requirement in cardiovascular surgery leads to a decreased morbidity and mortality. PMID- 20715405 TI - [The perioperative management of congenital heart surgery in newborn and infants]. AB - The feature of perioperative care for congenital heart surgery in newborn and infant is that the change of environment surrounding the baby should be considered. Especially the baby with anomaly of pulmonary artery, pulmonary vein, relation of the great vessels or patent ductus arteriosus (PDA) dependent heart defects is in a stable condition in the womb. Cardiopulmonary system changes immediately after birth, and symptoms of congenital heart disease will appear. In this part, we describe the pre- and post-operative care in newborn and infant with congenital heart defects. PMID- 20715407 TI - [Anticoagulant and antiplatelet therapy for cardiac surgery]. AB - Anticoagulants prevent the formation of harmful thrombi by decreasing the ability of the blood to clot. They are prescribed for a number of reasons, such as after replacement of a heart valve to prevent thrombosis or after myocardial infarction to prevent another infarct or stroke. However, there is an increased risk of severe bleeding among patients who are taking such medications. In order to optimize the therapeutic effect and avoid dangerous side effects like bleeding, careful monitoring is required during treatment, as directed by the 2006 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines and the 2002-2003 Japanese guideline on anticoagulant therapy. Heparin is used in hospitals immediately before and after cardiac surgery, while oral medications like warfarin or aspirin are being adjusted. As oral anticoagulants are long acting drugs, so these medications need to be stopped before elective surgery and the patient is switched to intravenous or subcutaneous shorter-acting heparin in hospital before the operation. However, heparin-induced thrombocytopenia (HIT) is a potentially life-threatening problem that is encountered in patients having cardiac surgery, and it is increasingly being recognized with the widespread use of heparin. The evidence suggests that heparin should not be used and that alternative anticoagulant therapy with one of the newer agents such as argatroban would be of benefit for avoiding harmful events. PMID- 20715408 TI - [Perioperative strategies for lung cancer patients with poor lung function]. AB - The most important process in the treatment for lung cancer patients with poor lung function especially due to chronic obstructive pulmonary disease (COPD) is an adequate preoperative physiologic assessment to identify patients who are at increased risk for perioperative death and severe complications. Once the patient is assessed to not have increased risk for death after curative-intent surgery, he or she should be aggressively treated to achieve best possible baseline level of function. Preoperative treatments are the same as those for patients with COPD not preparing for surgery, which consist of smoking cessation, medication including bronchodilators, and pulmonary rehabilitation. The main part of recent pulmonary rehabilitation program for patients with COPD is exercise training. A few recent manuscripts demonstrated that short-term preoperative pulmonary rehabilitation including exercise training could improve exercise capacity of lung cancer patients with COPD and might have important implications for surgical outcome. Postoperative strategies to reduce pulmonary complications include adequate pain control with epidural analgesia, oral care, and airway clearance techniques (postural drainage, coughing, huffing, flutter breathing, percussion, vibration, and squeezing). To provide optimal surgical outcome for lung cancer patients with poor lung function, there is nothing but the accumulation of the fundamental treatments. PMID- 20715409 TI - [Fluid and nutritional management after pneumoresection]. AB - For expansion of the extravascular space, secretion of antidiuretic hormone and increment of vascular permeability, a large quantity of non-functional extracellular fluid is accumulated in an extravascular space from all over the operation. Extracellular fluid returns from an extravascular space to blood vessels in refilling stage, and decrement of a pulmonary vascular bed after pneumoresection make it easy to cause pulmonary edema and tachyarrhythmia. Therefore volume of postoperative infusion is apt to be limited after pneumoresection. However, the fluid management that extremely imbalanced in dry side increases the risk of arrhythmia, myocardial infarction and cerebral infarction. It is important to perform reasonable fluid therapy without excess and deficiency postoperatively while observing amount of urine, specific gravity of urine, heart rate, blood pressure, volume of chest drainage and central venous pressure. We have few opportunity to consider about nutritional management after pneumoresection so that ingestion is started for an early postoperative period. But, the grave case that ingestion cannot start for an early postoperative period should start total parenteral nutrition or enteral feeding. In that case, the enteral feeding which is more physiological than intravenous nutrition is recommended. PMID- 20715410 TI - [Prevention and management of postresectional bronchopleural fistula]. AB - Bronchopleural fistula (BPF) is still a life-threatening complication after pulmonary resection. Several factors were identified to contribute BPF. Meticulous surgical technique and the liberal use of prophylactic, pedicled flaps are important for prevention. Although these patients often present compromised and moribund, evaluation and management should proceed in a logical, stepwise fashion. In high-risk surgical patients, bronchoscopic procedures using different glues and sealants may serve as a temporary bridge until the patient's recovery or as a permanent resolution. However persistent conservative therapy may deteriorate patient's condition. Immediate creation of open window thoracotomy has been shown to be a significant predictor of wound closure afterwards. Pedicled muscle or omental flaps are useful to close bronchial stump and to fill the residual space in the thorax after pulmonary resection. Once fistula closed, the pleural space is filled with an antibiotic solution and then the open window thoracotomy closed in layers as Clagett procedure. The transternal transpericardial approach to recalcitrant postpneumonectomy BPF can be considered when patients have failed prior closure attempt. To conclude, survival and excellent result of BPF depends on early diagnosis, and aggressive surgical intervention. PMID- 20715411 TI - [The management of intra-, and post-operative air-leakage]. AB - The intra-operative air-lekage usually is found in the operation for emphysematous patients with insufficient separation of the lobar fissure. To those, thoracic surgeons should be careful on making a reasonable line of separation between two lobes. Moreover, after the lobectomy the wide lack of visceral pleura should be repaired absolutely by the various techniques. Postoperatively if the air-leakage would be severe, re-thoracotomy will be needed for the closure of the portion of the air-leakage. PMID- 20715412 TI - [Essence of perioperative chest tube management]. AB - Physicians are required to be familiar with the basic theory of chest drainage to take care of the patients with chest diseases. This short review deals with management of the chest drainage tube including perioperative period. The indications for chest drainage are pneumothorax, pleural effusion, hemothorax, empyema, postoperative care after thoracotomy. When inserting the drainage tube, the position of the patient depends on the disease and condition. Aspiration of the pleural effusion through bronchofistura should be avoided. Injury of the intercostal vessels should also be avoided. A 3-bottle system is commonly adopted for the drainage system. Although continuous suction with negative pressure is commonly applied, several studies suggest that suction is not always required as far as the water seal is secure, and recommend the indication of suction only when air leakage persists or when sufficient expansion of the lung is not obtained. The checkpoint of bedside management of chest drainage includes flexure, torsion, disconnection and obstruction of the tube, and also the site of the side holes of the tube etc. The complications of chest drainage are infection, subcutaneous emphysema, pain, re-expansion pulmonary edema etc. Indications of removing the drainage tube are generally full-expansion of the lung, no air leakage, no hemorrhage and decrease of the pleural effusion, but the detailed criteria differ from institute to institute. Establishment of the standard management method of chest drainage is desired. PMID- 20715413 TI - [The management of post operative chylothorax]. AB - Post operative chylothorax occurs in less than a few percentages of pulmonary resection and lymph node dissection for lung cancer and is a serious complication. The management of post operative chylothorax is both conservative and surgical treatment and generally the former is used. In our hospital during 1992-2005, almost patients responded to conservative treatment. Surgical interventions with video-assisted thoracoscopic surgery (VATS) is considered that it is low invasive method and can prevent the demerits of conservative therapy such as infection of long-term drain detention and lymphocyte loss, malnutrition and so on. Early detection of surgical interventions might be one of strategies in the management of post operative chylothorax for the patients with much quantity of drainage. We consider that administration of somatostatin and lymphangiography are effective treatments and are recommended as the previous step of surgical interventions. PMID- 20715414 TI - [Prevention and management of wound infection and empyema complicating pulmonary resection]. AB - Wound infection and empyema complicating pulmonary resection is considered surgical site infection (SSI). Wound infection after pulmonary resection rarely occurs when preventative measures against SSI are taken. Empyema complicating pulmonary resection is organ/space SSI, and one of the most devastating complications after pulmonary resection. Postresectional empyema is often associated with bronchopleural fistula, which makes the management of empyema difficult and needs expertise. The initial treatment of postresectional empyema should include prompt surgical drainage by closed tube thoracostomy and institution of appropriate antibiotics. Definitive treatment of empyema includes complete obliteration of empyema space and secure closure of bronchopleural fistula if applicable. "Prevention is better than cure" does apply to SSI. PMID- 20715415 TI - [Respiratory morbidity after pulmonary resection; prevention and treatment of atelectasis and pneumonia]. AB - A respiratory morbidity such as atelectasis or pneumonia is possible to be predicted by calculated postoperative pulmonary function. The predicted postoperative 1 second forced expiratory volume (FEV1.0) is exclusively useful for predicting morbidity, but not for predicting mortality. The exercise capacity is a crucial parameter to predict survival. Thus, both parameters are helpful to make strategies for perioperative management. A prophylactic tracheostomy, a timely traheostomy and a timely bronchoscopy are applied by these parameters to treat postopeartive respiratory complications such as atelectasis or pneumonia. PMID- 20715416 TI - [How to treat arrhythmias in thoracic surgery]. AB - After major noncardiac thoracic operations, various types of arrhythmia would occur. Particularly atrial fibrillation (Af), have remained one of the most frequent complications. In the literatures, risk factors for post operative Af have identified age, male, extent of pulmonary resection and mediastinal lymph node dissection. When we would meet the patients complicated with arrhythmia, the etiology of it must be identified and treated before operations. If accidental arrhythmia occurred during or after operations, the etiology of arrhythmia as hypoxia, hypercapnea, electrolyte disorder, overhydration and cardiac ischemia would be checked and cleared at first. Then appropriate drugs should be considered to use due to the type of arrhythmia. In supraventricular tachyarrhythmia, especially Af, landiolol and verapamil would be effective for the rate control and disopyramide and procaineamide for the defibrillation. Lidocaine and propranolol would be an appropriate choice for ventricular tachyarrhythmia during operations. For ventricular tachyarrhythmia related with acute myocardial infarction, lidocaine and mexiletine would be proper. In bradyarrhythmias a temporary pacing should be the first choice for urgent therapy. A prompt assessment and an adequate therapy must be mandatory for the arrhythmias after major noncardiac thoracic operations. PMID- 20715417 TI - [Prophylaxis and management of postoperative pulmonary embolism in lung surgery]. AB - Venous thromboembolism (VTE) is the common condition of disease specified as deep vein thrombosis (DVT) or pulmonary embolism (PE), and PE is well known as one of the most important acute and chronic complications after thoracic surgery. Clinical guidelines recommend the use of low dose unfractionated heparins in the treatment and prevention of VTE, in addition to non-pharmacological interventions such as elastic stockings or intermittent sequential pneumatic compression (ISPC) aimed at reducing thrombotic risk. Even in nonsurgical patients, anticoagulation therapy carries a potential risk of exacerbating a bleeding complication, whereas administration of anticoagulation drugs in surgical patients carries an even greater risk of bleeding complications. In addition, use of inferior vena cava (IVC) filters or thrombolytic agents in patients with surgery also remains controversial. Prophylaxis in patients with VTE has received recommendations in many clinical guidelines, however, when the VTE is suspected, immediate and accurate diagnosis and appropriate treatment become important. PMID- 20715418 TI - [Postoperative nutritional management for esophageal cancer patients]. AB - High incidence of malnutrition is found in esophageal cancer patients. It is well known that to maintain good nutritional preoperative condition is very important to prevent postoperative morbidity and mortality. Hence, preoperative oral or nasogastric feeding is recommended when the patient is malnourished, at a total dose of 30 kcal/kg/day. During postoperative period, enteral nutrition should be primarily performed because of its favorable effects on immune-status and intestinal integrity to avoid septic complications. It is also important to keep circulatory volume sufficient to provide oxygen demand during catabolic phase, which leads earlier recovery from critical illness. Enteral nutrition should be immediately started afterward. An initial dose of 5-10 kcal/kg/day of the enteral nutrition is performed from the 1st or 2nd postoperative day and gradually increased to the full dose at 30 kcal/kg/ day. In cases of not administering scheduled dose of the enteral nutrition, either total or peripheral parenteral nutrition is required complementing total caloric intake. When total parenteral nutrition is used, blood glucose level should be controlled less than 150 mg/dl by pertinently administering insulin or limiting glycemic intake. Immunonutrition is promising nutritional management for critical surgical patients such as those performed esophageal cancer surgery. Continuing immune-enhancing diet at a dose of 750 to 1,000 ml/day for 5 to 7 days before surgery is necessary to bring good postoperative outcome. PMID- 20715419 TI - [Perioperative management and prevention of complication for salvage esophagectomy after definitive chemoradiotherapy]. AB - Salvage esophagectomy has been increasing as a second-line treatment after failure of definitive chemoradiotherapy (CRT) for esophageal cancer. A number of patients who have received CRT, especially those who have residual tumors and shorter waiting times until operation, have developed malnutrition and problems in their immunologic condition because of decreasing oral intake and bone marrow suppression. Because high-dose radiation causes inflammation, fibrosis and peripheral circulatory disturbance of various tissues in the treatment fields, salvage surgery can be a technically difficult operation. In our previous experience, postoperative complications of salvage esophagectomy are more frequent and more serious than that of planned esophagectomy. For example, we have experienced necrosis of the reconstructed gastric tube, esophago-tracheal fistula, mediastinal abscess, hard-to-treat acute respiratory distress syndrome (ARDS) and so on. In particular, respiratory tract necrosis or perforation is the most critical complication and frequently becomes lethal. Patients who undergo a salvage esophagectomy have a significantly higher risk of pulmonary and cardiac complication, and have high rates of repeated surgery. Rapid diagnosis and appropriate treatment of complications are necessary to reduce postoperative mortality. To improve the overall outcome, it is very important to better understand the condition of patients after CRT, so appropriate surgery can be carefully planned. Furthermore, it is absolutely essential to perform the operation with great care and to meticulously manage the perioperative care for salvage esophagectomy. PMID- 20715420 TI - The forced aggresome formation of a bovine anion exchanger 1 (AE1) mutant through association with deltaF508-cystic fibrosis transmembrane conductance regulator upon proteasome inhibition in HEK293 cells. AB - The endoplasmic reticulum (ER)-associated degradation of various polytopic proteins, involving the most common mutant of cystic fibrosis transmembrane conductance regulator (CFTR), deltaF508-CFTR, involves retrotranslocation of the polypeptide into the cytosol, leading to aggresome formation when the proteasome activity is attenuated. By contrast, an R664X nonsense mutant of the bovine anion exchanger 1 (AE1) is retained in the ER and does not form aggresomes upon proteasome inhibition in transfected HEK293 cells. Here, we report that R664X AE1 formed a large cytoplasmic aggregate when cells co-transfected with enhanced green fluorescence protein (EGFP)-deltaF508-CTR were exposed to the proteasome inhibitor lactacystin. R664X AE1 and EGFP-deltaF508-CFTR showed co-localization in the aggregates and signals of which coincided with gamma-tubulin and were caged by vimentin at the pericentriolar locus, demonstrating aggresome formation. On the other hand, EGFP-AnkN90, consisting of the N-terminal AE1 binding domain of ankyrin, a cytoplasmic protein, also exhibited co-localization with R664X AE1, but was found throughout the ER. Moreover, R664X-mutant protein was specifically immunoprecipitated with EGFP-deltaF508-CFTR from the cells co-expressing these proteins. These findings indicate that R664X AE1 is forcibly extracted from the ER to reside in aggresomes through association with deltaF508-CFTR. PMID- 20715421 TI - Serodiagnosis of ovine toxoplasmosis in Mongolia by an enzyme-linked immunosorbent assay with recombinant Toxoplasma gondii matrix antigen 1. AB - Toxoplasma gondii matrix antigen 1 (TgMAG1), known as the 65-kDa protein, which is abundantly expressed in both bradyzoites and tachyzoites, was evaluated as a candidate for the development of a diagnostic reagent for ovine toxoplasmosis. The TgMAG1 gene was expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST), and the recombinant TgMAG1 (rTgMAG1) was tested in an enzyme-linked immunosorbent assay (ELISA). The ELISA with rTgMAG1 showed a highly specific reaction with sera from mice experimentally infected with T. gondii but not with the closely related Neospora caninum. The antibodies to TgMAG1 were detectable from the acute to the chronic infectious stages in a mouse model. A total of 175 serum samples collected from sheep in 7 provinces of Mongolia were examined for the serodiagnosis of T. gondii infection by the ELISA with rTgMAG1, and the results were compared with those from the commercialized latex agglutination test (LAT). Of 175 serum samples analyzed, 42 (24.00%) and 29 (16.57%) samples were positive by the ELISA and LAT, respectively. Of 29 LAT positive samples, 27 (93.10%) were positive by the ELISA. These results suggest that rTgMAG1 could be used as a reliable antigen for the detection of T. gondii infection in sheep. PMID- 20715422 TI - Structural characteristics of goat (Capra hircus) parotid salivary glands. AB - The structural characteristics of the parotid glands in small ruminants (goat, sheep) were observed and compared to those of a major laboratory animal, the mouse. Their parotid glands consist of the purely serous type. Ultrastructurally, the serous acini of goats and sheep were characterized by the presence of well developed basolateral expansions of folds, which are characteristics of electrolyte- and water-transporting epithelium. Moreover in ruminants, unlike the mouse, the presence of numerous intercellular canaliculi as well as microvilli projecting into both the intercellular canaliculi and the lumina of the serous acini provided a large surface area for osmotic equilibrium and isotonic saliva secretion. Most of the secretory granules in goats and sheep contained peripherally located inclusions that showed dense reaction products for acid phosphatase. This indicates that most of the secretory granules undergo lysosomal degradation rather than secretion. An apocrine mode of secretion of some secretory granules was occasionally observed in some acini of goats and sheep but only exocytotic features were observed in mice. In the goat, the serous acini showed three morphologically different types, which might be an indication of different activity phases. Furthermore, alpha-smooth muscle actin-, and vimentin positive myoepithelial cells were observed only around the serous acini and the intercalated ducts. From these findings, we consider that the structural characteristics of ruminant parotid glands might reflect their physiological role in the copious isotonic saliva secretion with a low protein concentration. PMID- 20715423 TI - Treatment of hydrocephalus with high-pressure valve ventriculoperitoneal shunt in a dog. AB - A 5-month-old male Maltese with right-sided circling, deafness, and blindness was presented. A diagnosis of communicating hydrocephalus was made. A ventriculoperitoneal shunt was implanted and the cerebrospinal fluid was drained by using an adjustable valve type (Medtronic Strata). The valve was set at 2.5 (135-155 mmH2O). This was done to prevent the possibility of an overdrainage induced collapse of the brain parenchyma, which can occur rarely when canine hydrocephalus is treated by using a low-pressure valve. Computed tomography performed 6 weeks and 1 year after surgery revealed the ventricles had decreased in size. Thus, a high-pressure valve used during the treatment of hydrocephalus was able to maintain normal intracranial pressure. PMID- 20715424 TI - Future of endoscopic ultrasound in India. PMID- 20715425 TI - Endoscopic ultrasound: imaging techniques and applications in the mediastinum. AB - The esophagus passes through the superior and posterior mediastinum, and provides a window for transesophageal imaging of the mediastinum. The applications of endosonography in the mediastinum can be divided on the basis of location into: (1) periesophageal, and (2) intrinsic to the esophagus. Treatment of non-small cell lung cancer is stage dependent, and endosonography helps sample lymph nodes at levels 4L, 5, 7, 8, 9 as well as the celiac, and the left adrenal nodes. Primary lung tumours in a periesophageal location and those invading the mediastinum can also be safely biopsied. The most common causes of mediastinal lymphadenopathy are tuberculosis, sarcoidosis, metastatic and reactive. Endosonography provides for biopsy of these enlarged nodes easily, safely and with a high diagnostic yield. Endosonography is the most accurate loco-regional staging modality for esophageal cancer with a T-stage and N-stage accuracy of 75% 85%, and 65%-75%, respectively. Dilatation of stenosing esophageal tumours to allow echoendoscope passage for complete staging is controversial. Endosonography can triage patients with esophageal cancer to surgery alone, neoadjuvant therapy, and palliative therapy. Subepithelial lesions of the esophagus include leiomyomas, granular cell tumours, duplication cysts, and inflammatory fibroid polyps. These can usually be diagnosed by endosonography. Application of endosonography in portal hypertension is still experimental, and will not be described in this review. This illustrated review describes the applications of endosonography in the mediastinum, practical tips for optimal imaging, and step by-step instructions for radial and curved linear array endosonographic imaging, along with relevant applied mediastinal anatomy. PMID- 20715426 TI - [Insertion procedure of the Swan-Ganz catheter]. AB - The Swan-Ganz catheter (the pulmonary artery catheter: PAC) has been used to examine the heart diseases and to evaluate the hemodynamics by the physician in the catheter laboratory and beside the patient's bed. It is also used to monitor the hemodynamics during the cardiac surgery in the operating theater and to manage the patient in the intensive care unit (ICU) postoperatively. A very careful insertion technique is mandatory to avoid various serious complications, such as hematoma formation, arterial centesis, pneumothorax, hemothorax, perforation from cardiac chambers, rupture of the pulmonary artery, and so on. To reduce these complications, standardization of the insertion technique could be useful. When a complication unfortunately occurrs during insertion before surgery, it should be considered to abandon the following operation to avoid catastrophe. PMID- 20715427 TI - [Pericardiocentesis and drainage]. AB - Diagnosis and treatment of pericardial effusion need to be performed frequently by pericardiocentesis or surgical pericardiotomy. Large retention of the effusion is treated conventionally by percutaneous blind puncture, while possible injuries to the myocardium are avoided feasibly by ultrasonically-guided puncture even in case that the effusion remains moderately or unevenly inside the pericardial space. Along with the puncture, drainage tube introduced into the pericardial sac using coaxial method contributes to relieving coexistent pericardial or chronic exudation. The pericardium is also surgically approached traditionally via parasternal, subxiphoid, or lateral-thoracic route. Specimen of the pericardium is optionally sampled to promote analyzing the pathogenesis, and drainage tubes of larger diameter facilitate evacuating the purulent substance in the settings of infectious origins. The lateral thoracotomy is occasionally applied to the effusion around the posterior aspect of the heart, which is preferably replaced by less-invasive video-assisted procedure. Those several measures would facilitate the treatment for pericardial effusion. PMID- 20715428 TI - [Insertion and removal of the intraaortic balloon pumping]. AB - Intraaortic balloon pumping (IABP) is the most popular circulatory assist device. Although insertion and removal of IABP has proved to be a safer technique, a significant number of pitfalls have been seen. On the basis of our experience, we make several recommendations that may facilitate safer insertion and removal of IABP. Careful insertion and removal by experienced hands of cardiovascular surgeons should minimize complications. PMID- 20715429 TI - [Basic technique for the management of percutaneous cardiopulmonary support]. AB - Percutaneous cardiopulmonary support (PCPS) is one of the most important therapeutic options for emergency patients with severe heart and lung failure. Prompt establishment of the precise support enables us to improve the clinical results in those patients. The key points for the introduction of PCPS are quick and accurate techniques of the cannulation including the exact cannula selection and the decision of the cannulation sites based on the patients' conditions, ultrasonography and/or computed tomography. The use of the C-arm system and/or transesophageal echocardiography can play an important role in the insertion of the cannulae and the confirmation of the position of the cannula tips. In addition, the accurate management for possible complications during the PCPS can provide us with the stable support. Here, the techniques for the PCPS management are described. PMID- 20715430 TI - [Operative technique of median sternotomy]. AB - Median sternotomy is the most widely used incision in cardiac surgery. The skin incision should extend from just below the sternal notch to a few centimeters below the xiphoid process. Careful dissection behind sternal notch and xiphoid process should be required to prevent accidental adjacent vessels injuries. The sternotomy should be made on the midline of the sternum after detecting the lateral margin of the sternum by dipping the thumb and the index finger into the intercostal space. Off-midline sternotomy may cause the closure wires to cut through the thinner segment of the bone, which may cause wound infection. There has been an increase in the number of patients who undergo a 2nd or even a 3rd time cardiac surgery. Redo sternotomy is becoming a major technique in cardiac surgery. The sternum could be divided with an oscillating saw safely by lifting previous wires untwisted, which helps prevent possible right ventricular injury. Blunt digital manipulation or dissection can often result in tearing of the right ventricular wall which can be fatal. PMID- 20715431 TI - [Surgical techniques for thoracic and thoracoabdominal aneurysm repair]. AB - We introduce our technique for the treatment of aneurysms arising in the descending thoracic aorta and the thoracoabdominal aorta. Thoracotomy is performed at a single site. The costal arch is transected to ensure an adequate field of vision. A lifting hook is used to open the proximal side of the aorta. The diaphragm is not totally transected to preserve respiratory function after surgery. In principle, partial extracorporeal circulation is performed using a percutaneous cardiopulmonary support system. The dose of heparin for systemic treatment is limited to 50 U/kg. The abdominal branches are perfused with the use of balloon catheters. Cardiac arrest is induced for about 10 seconds by intravenous administration of adenosine triphosphate to avoid aortic injury when the proximal aorta is clamped during partial extracorporeal circulation and to prevent massive bleeding when the elephant trunk is clamped. To prevent paraplegia, the Adamkiewics artery and 2 pairs of adjacent intercostal arteries identified by preoperative computed tomography are reconstructed, and cerebrospinal drainage and motor evoked potential monitoring are performed. PMID- 20715432 TI - [Our method of exposing the femoral artery and vein and the axillary artery]. AB - A thoracic surgeon must have the skill to expose the femoral artery and vein, as well as the axillary artery, quickly without causing any complications. We briefly describe our method of exposing these vessels. We devised this method to reach the targeted blood vessel within the shortest time and distance, based on a sound knowledge of the surgical anatomy. To prevent postoperative lymphorrhoea. we ligate the lymphoducts during the operation. PMID- 20715433 TI - [Preparation for cardiopulmonary bypass]. AB - This article introduces our standard method of cannulation for extracorporeal circulation. The ascending aorta is used in most operations for arterial cannulation. Bicaval cannulation for venous return is performed through the right atrium. In order to accomplish venting the heart, we introduce a vent catheter to the left atrium through the right superior pulmonary vein. Cardioplegic solution may be administered antegradely through the aortic root or retrogradely through the coronary sinus for myocardial protection. Adequate cardiopulmonary bypass is the key to successful cardiovascular operations. PMID- 20715434 TI - [The method of atriotomy, ventriculotomy and their repairs]. AB - In this series, we describe the method of atriotomy, ventriculotomy and their repairs. Right atriotomy is needed for expose tricuspid valve, atrial and ventricular septal defect. Left atriotomy is needed for expose mitral valve disease and technique for, maze or pulmonary vein isolation. Left ventriculotomy is needed for resection of scar and/of thrombus of ventricular aneurysm, repair of ventricular septal rupture and endoaneurysmorrhphy. Recently, this method is also used to repair for ischemic mitral valve regurgitation. These techniques have already been described in many textbooks. Regarding atriotomy and ventriculotomy, the most important point is how to fully expose the tricuspid and mitral valves and others. The repair of ventriculotomy requires strips of teflon felt to strengthen the suture line and to enhance hemostasis. This method of repair is considered standard by many surgeons. PMID- 20715435 TI - [The techniques of arterial anastomosis]. AB - There are different techniques of arterial anastomosis. The selection of the most suitable technique is based on multiple evaluations, which include the position and direction of inserting point of suture, suturing procedure, anastomotic tension, suture intervals, pathogenesis and wall thickness of the artery, and satisfactory field of the anastomotic site. It is important to perform an accurate anastomosis to ensure enough blood flow without bleeding at the anastomotic site. Carrying out an accurate basic technique can prevent such complications of anastomosis as occlusion, pseudoaneurysm, and infection. PMID- 20715436 TI - [Toward the safest and most accurate graft anastomosis in coronary artery bypass grafting: basic considerations and technical tips]. AB - Surgery for revascularization of the myocardium continues to be an effective and lasting means of managing patients with multivessel coronary artery disease. Ultimately, the goal in the operating room is to provide patients with grafts that have the best long-term patency. A significant number of coronary bypass cases are now being performed without the use of cardiopulmonary bypass, while cardiopulmonary bypass is often preferred or required in a certain number of patients. In the coronary artery bypass surgery, the anastomosis of a graft either on the arrested or on the beating heart is the most important and crucial procedure. In this chapter, we discuss the basic principles of the anastomotic technique of the graft by providing some technical tips and pitfalls on the procedure. These may include the followings; the difference between on a beating heart and on an arrested heart, importance of the perpendicular placement of the needle, the way of holding a needle holder, the way to handle tweezers, keeping a steady posture, keeping eyes on the anastomosis, avoiding the intimal injury, keeping concentration and so on. PMID- 20715437 TI - [Graft harvesting in coronary artery bypass grafting]. AB - The technique of graft harvesting during coronary artery bypass grafting (CABG) consists of 2 main components: the vessel exposure at an adequate layer and the division of branches. Recently, the ultrasonic scalpel has been used for skeletonization of arterial grafts. A hook-type tip is used for the internal thoracic artery and the radial artery graft, while a shear type tip is used for the right gastroepiploic artery graft. The ultrasonic scalpel is useful both for graft vessel exposure and for the division of branches. The cavitation phenomenon is useful for the vessel exposure, while ultrasonic protein coagulation is useful for the division of branches. In endoscopic saphenous vein graft harvesting, electrocautery scissors are used for the division of branches. Avoiding thermal damage to the graft vessel is important in the use of either device. In any graft harvesting, direct contact with the main trunk should be avoided as much as possible to prevent damage. A thorough knowledge of the anatomy of the graft vessel and the surrounding organs is necessary for graft harvesting and to avoid complications. Furthermore, an understanding of characteristics of the harvesting devices is also important. PMID- 20715438 TI - [Knack and pitfall in valve replacement]. AB - We choose prosthetic or bioprosthetic valves according to AHA/ACC guidelines in valve replacement. It is important to remove only the calcification and avoid over-resection to preserve the valve annulus during aortic valve replacement. We leave posterior leaflet as well as basal chordae in mitral valve replacement in case of large mitral annulus. Sutures should be tied-down after those on both adjacent sides are pulled up and the sawing cuff and annulus are firmly attached. Intra-operative transesophageal echocardiography is useful for detecting a stack valve, perivalvular leakage and remnant air in the cardiac chambers. We performed 53 cases of valve replacement in 2009. One patient (1.9%) died because of ventricular arrhythmia during hospital stay. Re-operation was required in 2 cases (3.8%) of infective endocarditis due to prosthetic valve endocarditis. No other major complication was observed. PMID- 20715439 TI - [Tricuspid annuloplasty]. AB - Isolated tricuspid valve disease is rare. In approximately 75% of the cases, the tricuspid regurgitation (TR) is caused by dilatation of right ventricle, tricuspid annulus, and pulmonary hypertension. The presence of TR associated with left-sided valve disease, especially mitral, is very common. According to ACC/AHA 2006 Guidelines for the management of patients with valvular heart disease, severe TR should be treated during operations for multivalvular disease (class I, level of evidence : C). Tricuspid annuloplasty is indicated even for mild TR in patients undergoing mitral valve surgery when there is pulmonary hypertension or tricuspid annular dilatation (class IIa, level of evidence : C). Techniques to deal with a dilated tricuspid valve annulus with normal leaflets and chordal structures include placation of the posterior leaflet annulus (bicuspidization), semicircular purse-string reduction of the anterior and posterior leaflet annuli (DeVega technique), and rigid or flexible rings or bands placed to reduce the annular size and achieve leaflet coaptation. The procedure is easy and safe. However, further studies are mandatory in cases of mild functuional TR to achieve better long-term outcome in patients with mitral valve disease undergoing mitral valve surgery. PMID- 20715440 TI - [Thoracoplasty]. AB - Thoracoplasty was at 1st invented for the treatment of pulmonary tuberculosis during the days when no effective chemotherapeutic drugs for tuberculosis were available. Removal of some portions of the ribs by thoracoplasty deforms the chest wall and compresses tuberculous cavities. Since the introduction of potent anti-tuberculous drugs, thoracoplasty for pulmonary tuberculosis has been obsolete. Currently, thoracoplasty is mainly applied to reduction of the volume of the pleural space in the treatment of post-resectional space problems and in the treatment of thoracic empyema. Well-planned and safe resections of the affected ribs hold the keys to successful thoracoplasty. The procedure is performed alone or with muscle flaps or with omental flap, depending on the extent of space and the presence of bronchopleural fistula. Thoracic surgeons should know the current application of thoracoplasty. PMID- 20715441 TI - [Open window thoracostomy and muscle flap transposition for thoracic empyema]. AB - Open window thoracostomy for thoracic empyema: Open window thoracostomy is a simple, certain and final drainage procedure for thoracic empyema. It is most useful to drain purulent effusion from empyema space, especially for cases with broncho-pleural fistulas, and to clean up purulent necrotic debris on surface of empyema sac. For changing of packing gauzes in empyema space through a window once or twice every day after this procedure, thoracostomy will have to be made on the suitable position to empyema space. Usually skin incision will be layed along the costal bone just at the most expanded position of empyema. Following muscle splitting to thoracic wall, a costal bone just under the incision will be removed as 8-10 cm as long, and opened the empyema space through a costal bed. After the extension of empyema space will be preliminarily examined through a primary window by a finger or a long forceps, it will be decided costal bones must be removed how many (usually 2 or 3 totally) and how long (6-8 cm) to make a window up to 5 cm in diameter. Thickened empyema wall will be cut out just according to a window size, and finally skin edge and empyema wall will be sutured roughly along circular edge. Muscle flap transposition for empyema space: Pediclued muscle flap transposition is one of space-reducing operations for (chronic) empyema Usually this will be co-performed with other several procedures as curettages on empyema surface, closure of bronchopleural fistula and thoracoplasty. This is radically curable for primarily non fistulous empyema or secondarily empyema after open window thoracostomy done for fistula. Furthermore this is less invasive than other radical operations as like pleuro-pneumonectomy, decortication or air-plombage for empyema. There are 2 important points to do this technique. One is a volume of muscle flap and another is good blood flow in flap. The former suitable muscle volume is need to impact empyema space or to close fistula, and the latter over-elongation and bending of pedicles should be avoided. Actually, after removing several costal bones on the empyema space, empyema wall will be incised for about 2/3 of total empyema length along costal beds. Then muscle flap will be introduced into cleaned up space and sutured on empyema surface at several points. It is better to lay small vacuum drain tubes along flap within empyema space. PMID- 20715442 TI - [Technical pitfalls of pleural dissection in extrapleural pneumonectomy]. AB - Because extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) suffers from unsatisfiable risk/benefit ratio, very careful consideration on its indication should be required. EPP is a complicated, multi-step surgery that includes pleural dissection, division of hilum, resection of a block of pleura, lung, diaphragm and pericardium, and reconstruction of diaphragm and pericardium. Therefore establishment of surgical images of whole procedures before starting surgery is essential. Dissection of parietal pleura is a particularly important procedure of EPP, because it determinates operating time, surgical blood loss, surgical morbidity/mortality and curability. Technical difficulty of pleural dissection strikingly differs according to the degree of pleural thickening, pleural adhesion and the severity of pleural invasion of the tumor. Although good surgical view is essential for safety, excessive thoracotomy may lead to postoperative pain and respiratory disorder. Underestimation of clinical stage is rather common in MPM even after vigorous preoperative assessment. Surgeons sometimes encounter T4 (i.e., unresectable) MPM such as diffuse chest wall invasion, vascular invasion, peritoneal invasion, and positive pericardial effusion that have not been detected preoperatively. Therefore, potentially-T4 site should be 1st processed for possible discontinuance of operation. PMID- 20715443 TI - [Identification of intersegmental border in radical segmentectomy]. AB - Current evidence indicates that radical sublobar resection (segmentectomy and wedge resection) should be considered as an alternative for cT1N0 lung cancer of 2 cm or less, even in low-risk patients. Segmentectomy is an anatomic parenchyma sparing resection that is recently being performed for small-sized lung carcinoma and constitutes a useful procedure in a thoracic surgeon's armamentarium. The technique is presented that improves the identification of the intersegmental border. Under bronchofiberscopy, jet ventilation is selectively applied to the burdened bronchus to develop an anatomic plane between the inflated segment to be resected and the deflated area to be preserved. The patients with a clinical T1NOMO peripheral cancer 2 cm or smaller underwent video-assisted segmental resection called hybrid video-assisted thoracic surgery (VATS) segmentectomy in which electrocautery with no stapler was used to divide the intersegmental plane detected by selective jet ventilation. Selective segmental inflation provides an obvious intersegmental plane quickly and easily, allowing a real margin distance in the ventilated segment. Despite the minimally invasive approach, since only the segment to be resected and not the entire lobe is expanded, an appropriate surgical view is possible. PMID- 20715444 TI - [Techniques and arts of mediastinal lymph nodes dissection for lung cancer]. AB - The outcomes ofhe operations for the lung cancer depends on the quality of the hilar and mediastinal lymph nodes dissection. Especially in the mediastinal lymph nodes dissection, techniques and arts are indispensable for reliable and promising results in the lung cancer surgery. The essence of procedures of mediastinal lymph nodes dissection are as follows, ( ystematic and sharp lymph nodes dissection as a group, precise and perfect removal of lymph nodes with adjacent fatty tissues based on the anatomical structures, retrograde lymph nodes dissection from the view point of prevention of lymph node metastasis and consequent distant metastasis. Satisfactory and confidential lymph nodes dissection requires attentive assistance of the coworker-surgeons providing good fields of vision. Nowadays minimally invasive approaches by means of thoracoscopic techniques are considered to be smart and welcomed widely in the current thoracic surgery. However, essential for the lung cancer surgery is trying to choose between the operability of radical operation and the degree of minimal invasion. According to a standard rule of ND2a lymph nodes dissection, procedures of upper and middle mediastinal lymph nodes dissection under postero lateral thoracotomy are summarized. PMID- 20715445 TI - [Carinoplasty]. AB - Recently, there may be a few patients for the candidates of crinoplasty. However, general thoracic surgeon must have the skills of carinoplasty. Probably, important points of carinoplasty are 1) to make adequate and complete exposure of operative fields, 2) to avoid ischemic damage of anastomotic sites, and to reduce the tension of anastomotic sites. PMID- 20715446 TI - [Surgical treatment for tumors in the superior sulcus]. AB - Surgical challenge for tumors arising posterior-apical lung well known as Pancoast tumor and those of the apical lung involving anterior thoracic outlet structures (mainly subclavian vessels) have been continued with seeking the pathway of the proper approaches and the strategy combined modalities as radiotherapy or chemoradiotherapy followed by surgery for these 50 years, and operative outcome have been improved these decades. As complete resection of the tumors is the main factor for operative results, the preoperative evaluation on involved structures and the choice among the different approaches is important. We present our experience for Pancoast tumors with posterior approaches and for cervico-thoracic tumors resected with anterior approaches. PMID- 20715447 TI - [Completion pneumonectomy]. AB - Completion pneumonectomy (CP) is defined as the operation intended to remove the reminder of the lung after a previous operation. The indications of CP include both benign and malignant diseases and it is more demanding technical procedure with high morbidity and mortality compared to standardized pneumonectomy. In this article, we described our preferable procedures for CP, preoperative evaluation and consideration, surgical technique, management of bronchial stump, and postoperative management. CP should be performed by skilled surgeons and surgeons should know whether they have enough skills and experiences to perform CP. PMID- 20715448 TI - [Thoracoscopic surgery of mediastinal tumor]. AB - The successful key of video-assisted thoracic surgery (VATS) to mediastinal tumors (MTs) should be the correct choice of surgical approach according to anatomical positions and relationships between large vessels and tumors. The middle and posterior MTs are good indications of VATS with intercostal approach under lateral position. The superior MTs are usually not indicated to VATS because of anatomical complexity of nerves and vessels of this area Thymus is the most frequent site of MTs and is in the narrow anterior mediastinum between sternum and heart. So that VATS to the anterior MTs needs some sternal lifting devices to get working space with appropriate combinations of intercostal, infrasternal and cervical approaches under supine position. Benign neurogenic tumors and congenital cysts are good indications of VATS. Thymic cyst, benign thymic tumor. such as mature teratoma, and small thymoma [noninvasive, diameter less than 5 cm, caudal position from left brachiocephalic vein (LBCV)] are now also indicated to VATS. Vessel sealing system LigaSure V is a computer control bipolar electric scalpel and be able to seal and cut safely up to diameter 7 mm vessels. LigaSure is suitable instrument for thymic vein handling, for esophageal muscle cutting, and for inflammatory teratoma dissection. This device is an essential device for VATS of MTs. The cases of mature teratoma and esophageal cyst were presented. PMID- 20715449 TI - [Thoracoscopic extended thymectomy]. AB - Extended thymectomy is an effective treatment of myasthenia gravis. In recent years, technological development of endoscopy enables it by thoracoscopic method instead of trans-sternal approach. We perform thoracoscopic extended thymectomy via 4 trocars introduced in bilateral pleural cavity with sternum lifting method through a small incision on epigastric region. The most difficult parts in this procedure are the dissection of the left brachiocephalic vein, especially around the thymic veins and the resection of superior poles of thymus. The rate of perioperative complications by thoracoscopic approach shows no significant differences from the one by the trans-sternal operation. This technique is less invasive than trans-sternal extended thymectomy and it makes the hospital stay after the operation shorter. Since thoracoscopic extended thymectomy is a new technique, the follow-up period of the patients who underwent it for myasthenia gravis is not long enough to evaluate the effectiveness to myasthenia gravis. It is not yet shown whether the long-term results for myasthenia gravis by thoracoscopic extended thymectomy are equal to the ones by trans-sternal technique. PMID- 20715450 TI - [Lymph nodes dissection in esophageal cancer surgery]. AB - Esophageal cancer has high incidence and broad distribution of lymph node metastases. Among the sites of possible lymph node metastasis, the station along the recurrent laryngeal nerve shows the highest rate of lymph node metastasis. For complete lymph nodes clearance, dissection of lymph nodes along the nerves of both sides is essential. The procedure of lymph node dissection along the recurrent laryngeal nerve is a good indicator of the whole quality of the surgery. In order to reduce the morbidity of lymph node dissection, we preserve bronchial artery and pulmonary branches of the vagal nerve. The postoperative complication rate of esophageal cancer surgery is higher comparing other gastrointestinal cancer operations. Pulmonary complication occurs in high rate, and sometimes leads to mortality. On the 2nd and 3rd postoperative day, we have to be very careful for cardiopulmonary condition of the patient. The accuracy and quality of lymph node dissection is closely related to both curability and morbidity. PMID- 20715451 TI - [Basic technique for reconstruction after esophagectomy]. AB - The stomach as a conduit after esophagectomy is preferred to the colon because it is much simpler to prepare and involves only 1 anastomosis. The following principles should be followed in preparing the stomach as an esophageal substitute: the complete removal of lymphatics within the left gastric area, and careful preservation of the gastric intramural vascular network. The line of resection, where the vessels of the left gastric area enter the gastric wall, should be cautiously decided. Border between the left and right gastric area of the lesser curvature is identified by the courses of these arteries. The 1st GIA should be inserted slightly toward the caudal side, and the 2nd GIA should be fired along the resection-line. The final GIA should be advanced to the highest point. The space beneath the sternum in the anterior mediastinum is easily created with minimal blood loss. The space is initially created by blunt finger dissection through the abdominal and cervical incisions, and further developed by insertion of a flat malleable intestinal retractor with a hole on 1 side, which is useful for elevating the esophageal substitute without a twist. PMID- 20715452 TI - [Laparoscopic surgery for esophageal achalasia]. AB - Laparoscopic Heller myotomy and Dor fundoplication (LHD) were superior to pneumatic dilatation in terms of the treatment of esophageal achalasia according to 2 prospective randomized studies. Therefore, LHD is recommended. Some key points should be considered when performing LHD. First, the short gastric arteries and veins should be carefully divided so as not to injure the spleen. Second, during the Heller myotomy, the mucosa of the esophagus and stomach should not be injured because an inappropriate myotomy will not alleviate dysphagia, and intensive myotomy is recommended with care. When the mucosa is injured, the surgeon should repair the mucosa using absorbable sutures and the intracorporeal knot tying technique. Third, a tight fundoplication can cause dysphagia postoperatively. The endoscope should be inserted into the stomach and the fundoplication should be performed loosely. PMID- 20715453 TI - [Anti-reflux procedure]. AB - We introduced surgical indication, laparoscopic technique and procedure, management after surgery, and postoperative complication for gastroesophageal reflux diseases (GERD). Several points of laparoscopic fundoplication for GERD are shown below. 1) Exposure of abdominal esophagus: downward exposure is recommended in order to avoid postoperative dysphagia like achalasia. 2) Dissection of short gastric vessels: this procedure warrant free tension of gastric fundus at fundoplication. 3) Crural repair: create appropriate size of hiatus. 4) Fundoplication: we should do shoe shine maneuver and drop test to confirm free tension of fundus. 5) Shoulder stitch and anchor stitch: this procedure are needed to avoid dislocation of gastric fundus. PMID- 20715454 TI - [Early results of surgical repair of ventricular septal rupture]. AB - BACKGROUND AND OBJECTIVE: Ventricular septal rupture (VSR) is a lethal complication of acute myocardial infarction, and its operative results are far from good. SUBJECTS: Six patients who underwent operations for VSR in our department between 2001 and 2008. All these patients received coronary angiography, which showed 1-vessel disease in 4 patients, 2-vessel disease in 1, and 3-vessel disease in 1. The sites of myocardial infarction were the anteroseptal region in 3 patients and the inferoseptal region in 3. RESULTS: Infarct exclusion was conducted in the 3 patients with anteroseptal infarction. Of the 3 patients with inferoseptal infarction, 1 underwent infarct exclusion and 2 Daggett operation. The number of in-hospital deaths was 3 (50%). Residual shunts were observed in 3 out of the 4 patients (75%) who had received infarct exclusion. Two of these 3 patients needed reoperation. The 2 patients with inferoseptal infarction who had undergone Daggett operation presented no residual shunts, and could be easily weaned from the cardiopulmonary bypass. CONCLUSIONS: Because the infarct exclusion method frequently shows residual shunts, its technical modifications are required to improve the operative results. The Daggett method can be considered useful in patients with VSR after inferior myocardial infarction. PMID- 20715455 TI - [Effect of intra-operative low-dose infusion of landiolol hydrochloride on post operative atrial fibrillation after off-pump coronary artery bypass grafting]. AB - OBJECTIVE: The aim of this study was to evaluate the effect of intra-operative low-dose infusion of landiolol hydrochloride, a novel ultra-short acting beta-1 adrenergic receptor antagonist, on post-operative atrial fibrillation after off pump coronary artery bypass grafting (OPCAB). METHODS: Ninety-six patients who had undergone OPCAB were retrospectively analyzed. A landiolol group (L-group: n= 59) was compared with a control group (C-group : n= 37); the patients in the L group were given low-dose (4.7+/- 4.3 microg/kg/min) landiolol intravenously during OPCAB. Results : Postoperative atrial fibrillation occurred in 37.8% (14/37) of C-group and 18.6% (11/59) of L-group (p = 0.037). No side effect such as profound hypotension or bradycardia was noticed during the infusion of landiolol hydrochloride. CONCLUSION: Intra-operative low-dose infusion of landiolol hydrochloride decreases the incidence of postoperative atrial fibrillation after OPCAB. PMID- 20715456 TI - [The fluorodeoxyglucose-positron emission tomography (FDG-PET) findings and surgical strategy for pulmonary sclerosing hemangioma]. AB - The pulmonary sclerosing hemangioma is a comparatively rare lung tumor. We operated on 7 patients of the pulmonary sclerosing hemangioma during January, 2009 from December, 2001. We collected the information such as preoperative image findings, surgical methods, and the postoperative course. FDG-PET was performed in 4 patients preoperatively, and there was FDG uptake in 2 patients, and no FDG uptake in 2 patients. In 2 cases with FDG uptake, there was a tendency to increase the tumor diameter during preoperative follow-up. Among 7 patients, 1 patient underwent tumor enucleation, 2 patients underwent partial resection, and 2 patients underwent thoracoscopic lobectomy. Lung biopsy was performed in remaining 2 cases. Because a tumor was located in pulmonary hilum in 1 case, we underwent lung needle biopsy under thoracoscopy. Because another case was a multiple case, and the resection of all lesions was impossibile, we performed lung biopsy (partial resection). In all cases, the recurrence or exacerbation of the tumor was not detected postoperatively. We thought that the findings of FDG PET reflected proliferation potency of the pulmonary sclerosing hemangioma. The clinical features of the pulmonary sclerosing hemangioma are various. Therefore, the surgical treatment should be determined in each case carefully while considering the FDG-PET findings. PMID- 20715457 TI - [Rupture of mycotic arch aneurysm due to Salmonella in an elderly patient]. AB - An 80-year-old woman was admitted to the hospital for treatment of infected aortic arch aneurysm. Her C-reactive protein (CRP) was elevated to 24.2 mg/dl. We decided to operate after improvement of inflammatory reaction and physical status. However, sudden loss of consciousness occurred 9 days after admission. Chest X-ray revealed effusion and bleeding in the left pleural cavity. She was diagnosed with rupture of the aortic arch aneurysm and an emergency operation was performed. The aneurysm was treated by debridement of the infected aortic tissue, and total aortic arch replacement with a tube-graft was performed. Bacterial culture of the aneurysmal wall demonstrated Salmonella. Her postoperative course was uneventful. The patient remained well without any sign of wound infection. PMID- 20715458 TI - [Ectopic mediastinal parathyroid adenoma]. AB - We experienced 3 surgical cases with ectopic mediastinal parathyroid adenoma. All patients checked elevated serum calcium levels and parathyroid hormone levels above normal range so we diagnosed their illness as primary hyperparathyroidism. Two had treated urinary tract lithiasis for long time, and the other had no symptoms by hypercalcemia. To determine the location of abnormal parathyroid glands, 99mTc-methoxy-isobutyl-isonitrile (MIBI) scintigraphy, chest computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were done, then posterior and anterior mediastinal tumors were revealed. Especially MIBI scintigraphy was very useful as diagnostic procedure for small ectopic parathyroid adenoma. It's considered that large tumor in the posterior mediastinum like case 1 is originated from upper parathyroid gland, and small tumor in the anterior mediastinum like case 2, 3 is originated from lower parathyroid gland. Tumors were resected via small thoracotomy with thoracoscope, cervical incision and partial median sternotomy respectively. Serum calcium and parathyroid hormone levels were normalized immediately. If we can detect the accurate location of small ectopic parathyroid adenoma using some intraoperative method, the tumor is resected by less invasive procedure. PMID- 20715459 TI - [Intraoperative aortic injury caused by arterial perfusion cannula during extended aortoplasty in a patient with Williams syndrome]. AB - An 8-year-old girl with Williams syndrome underwent repair of supravalvular aortic stenosis by extended aortoplasty (Doty technique). Although she was weaned from bypass successfully, direct epiaortic ultrasound scanning disclosed the acute luminal narrowing of the ascending aorta at the level of aortic cannulation. The perfusion was restarted through the tube graft anastomosed to the left carotid artery and the ascending aorta was cross-clamped. The longitudinal incision at the site of prior aortic cannulation disclosed the intramural hematoma at the posterior wall of the ascending aorta. The stenosis was repaired with the patch enlargement of the anterior wall. As the dysplastic wall of the ascending aorta in patients with this syndrome may be injured by arterial cannula, an appropriate positioning of the cannula is mandatory to lessen the risk of intimal injury. PMID- 20715460 TI - [Endovascular repair of primary aortoenteric fistula]. AB - Aortoenteric fistulas are a rare, but often fatal cause of gastrointestinal bleeding. This report describes the use of endovascular aneurysmal repair (EVAR) for the initial treatment of gastrointestinal bleeding possibly related to an aortoenteric fistula. A 69-year-old man with an abdominal aortic aneurysm was admitted to our hospital because of melena. He initially underwent EVAR. Upper and lower endoscopic examination failed to detect a bleeding site. Twenty-five days later, a fever of 38 degrees C developed, and endograft infection was diagnosed. The patient underwent an extra-anatomic bypass and total endograft explantation. He remains well 9 months after EVAR PMID- 20715461 TI - [Sleeveresection of the left main bronchus for bronchogenic carcinoid for preserving lung parenchyma]. AB - We performed bronchoplasty for a bronchogenic tumor of low-grade malignancy without lung parenchyma resection. A 69-year-old man visited our hospital in March 2008 because of cough. Chest computed tomography (CT) revealed atelectasis of the entire left upper lobe and a 2-cm mass with strong contrast enhancement in the lumen of the left main bronchus. Bronchoscopy identified a polypoid mass in the left main bronchus, about 3 cm distal to carina, obstructing the lumen. Biopsy led to a diagnosis of typical carcinoid tumor. Surgery : Thoracotomy showed complete atelectasis of the left upper lobe. After lymph node dissection, resection of the left main bronchus including the site of tumor origin was performed. From the extent of expansion, the left upper lobe was decided to be possible to be spared, and end-to-end anastomosis of the bronchus was performed. Postoperative respiratory rehabilitation resulted in improved aeration of the left upper lobe and markedly improved respiratory function. CONCLUSION: The judgment of whether the long-standing atelectatic left upper lobe could be spared or not was a key in choosing this procedure. PMID- 20715462 TI - [Efficacy of vacuum-assisted closure therapy for various non-healing wounds after cardiovascular and thoracic surgery]. AB - Vacuum-assisted closure (VAC) therapy is an efficacious modality for treating chronic and difficult wounds. We present 3 cases that responded well to VAC therapy after cardiovascular and thoracic surgery: 1 methicillin-resistant Staphylococcus aureus (MRSA) wound infection after Stony's incision, 1 inguinal lymphorrhea, and 1 empyema after a traffic accident The duration of VAC therapy was 9, 18, and 90 days, respectively, and all 3 wounds healed completely. Familiar equipment and supplies available on the hospital ward were used, and patients were able to leave their beds. In this report, the efficacy of VAC therapy, the problems encountered, and the steps that could be taken to address them are discussed. PMID- 20715463 TI - [Norwood procedure with swing-back technique for double-inlet left ventricle, transposition of great arteries, coarctation of aorta, subaortic stenosis]. AB - Patient is 1 month old, 3.72 kg boy, he was diagnosed as {S, L, L} double-inlet left ventricle (DILV), transposition of the great arteries, coarctation of aorta, rudimentary right ventricle. Patient was undergone Norwood procedure, with "swing back technique"; end-to end anastomosis of ascending aorta with descending aorta, double-barreled style Damus-Kaye-Stansel (DKS), end-to side anastomosis of neoaorta to aortic arch. This technique has following advantages over other reported technique; discrepancy of great arteries were resolved without distortion ; reconstruction of the aorta without the use of patch materials: minimal length suture line to minimize the risk of bleeding; and more radical excision of ductal tissue without much dissection and mobilization of descending aorta. PMID- 20715464 TI - [Usefulness of photo dynamic eye system for detection of graft spasm in off-pump coronary artery bypass grafting]. AB - A 54-year-old-man on hemodialysis was admitted to the hospital because of effort angina. A coronary angiography revealed multiple stenoses including 90% stenosis in the left main trunk. Coronary artery bypass grafting (CABG) was performed with Y-composite grafts constructed by the right internal thoracic artery (RITA) and the free gastroepiploic artery (GEA) which were anastomosed to left anterior descending artery (LAD) and the diagonal branch (D1) using the off-pump technique. After completion of anastomosis, Photo Dynamic Eye (PDE) system showed fluorescence not in the free GEA but at the anastomotic site of GEA to D1. Because the graft spasm of GEA was diagnosed by PDE, papaverine solution was sprayed to the graft, which resolved the spasm and re-anastomosis was avoided. PDE system is a useful tool for the diagnosis of graft spasm, and may contribute to improvement of quality of CABG. PMID- 20715465 TI - [The liver herniation through four diaphragmatic defects, simulating lobulated diaphragmatic tumor]. AB - A 47 year-old woman, 153 cm in height and 64 kg in weight, was admitted for investigation of mass like shadow of the right lower lung field without past history of trauma and surgical treatment While magnetic resonance imaging (MRI) showed a mass 3 cm in diameter having the running vessel from the liver, computed tomography (CT) scan showed that the mass was lobulated like a tumor. We therefore performed video-assisted thoracic surgery (VATS) for diagnosis, which revealed the 4 lobulated liver tissues protruding through 4 defects of the diaphragm. The herniated parts of the liver were replaced in the abdominal cavity and diaphragmatic defects repaired by VATS. At histological features of diaphragm, thinning muscle layer was observed without any specific findings. We speculated that weakening of diaphragm was a cause of herniation. CONCLUSIONS: Liver herniation through multiple defects is sometimes difficult to be differentiated from diaphragmatic tumors. VATS is not only useful to diagnose it but also to repair the defects. PMID- 20715466 TI - [Multiple nodular pulmonary amyloidosis complicated with Sjogren syndrome]. AB - A 67-year-old woman, who had been treated for Sjogren syndrome and rheumatoid arthritis for 10 years, was consulted for examination of multiple nodular pulmonary nodules. She has been pointed out multiple pulmonary nodules on chest computed tomography (CT) for 7 years, of which the number and the size gradually increased. When visuting our hospital, approximately 20 nodules up to 10 mm in size were noted. Thoracoscopic resection of the nodule was performed and histological diagnosis was amyloid, which was negative for A- and P- component and positive for transthyretin. Neither amyloid deposition in other organs nor abnormal protein in serum and urine was detected. The diagnosis of localized nodular pulmonary amyloidosis was established. As far as our knowledge, this is the 1st report of transthyretin amyloidosis with Sjogren syndrome. PMID- 20715467 TI - [How to use Pubmed for beginners]. AB - PubMed is the world's largest biomedical journal literature database operated by the National Library of Medicine (NLM), USA. This resource is accessible via the Internet free of charge. The database covers literature in English and more than 50 other languages including Japanese. It includes the fields of medicine, health care system, and others. PubMed is a very handy, quick, and easy-to-use database, and remains an optimal tool for clinicians and researchers. PMID- 20715468 TI - [Pyothorax due to ruptured lung abscess successfully treaed by video-assisted thoracic surgery; report of a case]. AB - A 30-year-old female was admitted to our hospital for chest pain and dyspnea We diagnosed lung abscess of the left lung. On day 2, the patient required mechanical ventilation for pneumopyothorax due to ruptured lung abscess with acute respiratory distress syndrome. We managed this patient antibiotics, sivelestat sodium hydrate and steroid pulse therapy. Curettage and decortication for empyema cavity and closure of bronchopleural fistula was done under video assisted thoracic surgery with minithoracotomy on day 17. Postoperative course was uneventful. PMID- 20715469 TI - [Bronchial artery-pulmonary vein fistula undergoing right upper lobectomy; report of a case]. AB - We report a case of arteriovenous fistula of the bronchial artery. A 42-year-old woman was referred to our hospital because of an abnormal shadow noted on a chest X-ray. A chest computed tomography (CT) scan showed abnormal blood vessels in the right upper lobe. Bronchoscopic examination showed a pulsatile tortuos lesion at the orifice of the right B3 bronchus. Bronchial angiography revealed a convoluted and dilated right bronchial artery and hypervascularization in the right upper lobe. On the basis of a clinical diagnosis of bronchial artery-pulmonary vein fistula, a right upper lobectomy and ligation of the right bronchial artery were successfully performed. Bronchial arteriovenous fistula is rare, and it is risk factor for severe hemoptysis. When the surrounding lung reveals a congestive and organized changes due to the arteriovenous fistula, resection of the affected lung is considered necessary. PMID- 20715470 TI - [Neural mechanisms of substance dependence]. PMID- 20715471 TI - [Current situation of drug dependence and task against it]. AB - According to several kind of nationwide surveys and censuses, the 3rd epidemic methamphetamine abuse/dependence still continues since 1995. Methamphetamine is still most popular drug among people with drug abuse/dependence despite strict legal restriction. The majority of these are repeat offenders. This indicates the need for development of medical treatment targeting drug dependence and for its social support system. At the same time, abuse of cannabis, narcotics, MDMA has increased and non-regulatory drugs such as designer drugs emerged mainly among young people, while solvent abuse/dependence is dramatically decreased. Benzodiazepine dependence occur in patients taking therapeutic doses of benzodiazepine. The elderly patients are most vulnerable to benzodiazepine dependence. Education of benzodiazepine dependence and development of the withdrawal program are needed. PMID- 20715472 TI - [The definition of drug dependence]. AB - A number of definitions of drug dependence exist. The current idea is summarized as follows: drug dependence is a chronic, progressive disease characterized by significant impairment that is directly associated with persistent and excessive use of a psychoactive substance. Impairment may involve physiological, psychological, or social dysfunction. The most helpful one to physicians is based on the descriptions of WHO's ICD and APA's DSM. The criteria for drug dependence of ICD-10 and DSM-IV are given in this paper. To facilitate the harmonization process of the forthcoming development of DSM V and ICD-11, differences in the both definitions are also discussed. PMID- 20715473 TI - [Epidemiology of drug abuse and dependence]. AB - Drug abuse or dependence in Japan has been characterized by three epidemics of methamphetamine abuse. In addition, solvent abuse has been predominant for a long time. Since 1995, with the start of the third epidemic of methamphetamine abuse, drug abuse or dependence in Japan has obviously changed, with an obvious decrease in solvent abuse; the stabilization of methamphetamine abuse; an increase in the abuse of such drugs as cannabis or MDMA, which do not have high potential to cause drug-induced psychosis; and the emergence of designer drugs. These changes imply a shift from conduct that leads to arrest to conduct that does not lead to arrest. Therefore, Japan is urged to deal with drug abuse and dependence using both a criminal model and a medical model. PMID- 20715474 TI - [The mechanism of the development of drug dependence]. AB - Drug dependence, the physical and psychological one after chronic drug administration, is a serious clinical and social problem. The mechanism of development of drug dependence is mainly related to the modification of dopaminergic system. In addition, recent reports demonstrate that the other neuronal systems including noradorenergic, glutamatergic, serotonergic, histaminergic and orexinergic neurons could regulate the activity of dopaminergic neurons that results in the development of drug addiction after chronic drug administration. In the cellular and molecular levels, the up-regulation of some key signaling molecules such as cAMP and PKA or peptides such as NPY and dynorphin may be involved in the mechanisms. In this review, we outline the recent knowledge about the mechanism of development of drug addiction. PMID- 20715475 TI - [Overview of genetics and substance use disorders]. AB - A genetic component in etiology of substance dependence is very large, and the estimated hereditary rates by twin and family studies are 70% or more. Extensive classical linkage analyses for alcohol and substance dependence revealed numerous but weak susceptibility loci on every chromosomes. Genetic association studies including whole genome examination showed many shared genomic risks for substance dependence of diverse classes, e.g., alcohol, nicotine, opioids, cocaine, amphetamines and cannabinoids. In contrast, some specific genetic risks or protective factors for individual drug are also found. This paper reviews the current status of research into the genetics of substance dependence. PMID- 20715476 TI - [Animal models for evaluating of drug dependence liability]. AB - Assessment of psychological dependence liability of drug is essential for regulatory compliance and the drug development process. The most reliable method for evaluating the psychic dependence liability of drug is the self administration paradigm. The conditioned place preference paradigm is also useful method for evaluating the rewarding effect of drugs and is widely used. Furthermore, the drug discrimination paradigm, which analyzes the similarity with abused drugs by utilizing the effect of consciousness when taking drugs, has also been implemented. This paper summarizes the characteristics of each method and outlines the methods for evaluating drug dependence using animals. It also introduces recent findings about the studies of molecular mechanisms of drug dependence using gene-knockout and transgenic mice. PMID- 20715477 TI - [Conditioned reflex inhibition therapy for women addicted to sex under the influence of methamphetamine]. AB - If behaviour which has a physiological reward is repeated, a chain of conditioned reflexes is established in the first signal system. When exposed to a signal which is connected to a particular physiological reward, the chain reaction of conditioned reflex begins and controls that behaviour. If one's thought (the second signal system conditioned reflex) tries to stop the behaviour, friction occurs between the two systems. This is experienced as a craving for the physiological reward. In several clinical cases, women who were conditioned to the physiological reward of taking methamphetamine and then having sex were examined. They succeeded in inhibiting this craving by repeatedly simulating the act of taking methamphetamine and simulating sex positions. PMID- 20715478 TI - [Caffeine dependence]. AB - Caffeine is the most widely consumed psychoactive substance in the world and is a legal stimulant that is readily available to children. The potential for dependence on caffeine has been debated. Presently, due to a paucity of clinical evidence on caffeine dependence, no such diagnosis is included in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV TR). Although in recent studies, a subset of the general population was found to demonstrate caffeine dependence. It is valuable for psychiatrists and primary care physicians to recognize caffeine dependence as a clinical syndrome, since some people are distressed by their caffeine use and feel they can not control or stop their problematic use. PMID- 20715479 TI - [Cannabis use disorder and treatment of dependence]. AB - Cannabis, known as marijuana, has been used illicit drug by young people in the world. In our country, the number of user for cannabis is recently increased gradually. It has been suggested that regular use of cannabis might induce several adverse effects such as dependence syndrome, because delta-9 tetrahydrocannabinol(THC), a primary psychoactive component of cannabis, stimulates brain-reward areas through the activation of cannabinoid(CB1) receptor and induce drug-seeking behavior. Therefore, it is necessary to investigate and establish the medications for cannabis dependence. In fact, controlled laboratory studies and small open-label clinical studies have shown that several candidates of medications for cannabinoid dependence are identified. Further investigation in controlled clinical trials may produce the therapeutic benefit for treatment about cannabis-related problems. PMID- 20715480 TI - [Trend in the study of cocaine addiction]. AB - Psychostimulant drugs including cocaine increase extracellular levels of monoamines by blocking the neuronal plasma membrane transporters. Increased extracellular dopamine levels in mesocorticolimbic dopamine systems have been postulated to mediate the rewarding effects of cocaine. Studies in genetically modified mice models, particularly knockout mice have contributed a great deal to our understanding of the mechanisms underlying psychostimulant actions. Phenotypic analysis of genetically modified mice models has been instrumental in identifying the role of specific molecular targets of cocaine. In this article, we summarize studies that have reported the effects of cocaine using genetically modified mice especially gene knockouts of the monoamine transporters and receptors. PMID- 20715481 TI - [Hallucinogens]. AB - Hallucinogens are drugs that cause hallucinations, which is distortions in a person s perceptions of reality. Historically they were found in some plants and mushrooms and had been used mostly during religious rituals. Various hallucinogens came to be compounded chemically in the 20th century, and have spread among the young men in West European countries. Also in Japan, use of MDMA, or other hallucinogens is increasing in the young adult and minors. In recent years, Japanese medicine-related law were revised and most hallucinogens came to be treated as illegal drugs, but even now Japanese young men have got hallucinogens through the Internet and dance clubs, and medical and educational staffs and caregivers need to implement early intervention. PMID- 20715482 TI - [Inhalant-related disorder]. AB - Inhalant abuse and dependence are prevalent in adolescent population because inhalants are inexpensive, legal and accessible substance for youth. In Japan, the prevalence of inhalant abuse and dependence is gradually declining in these days, although inhalants can still become a "gateway drug" to other dependent substances such as cocaine and cannabinoids. Inhalant abuse causes show serious mental and somatic symptoms, and mortality in acute and chronic phases, while the abusers are ignorant about it. This paper reviews recent studies that investigate the symptoms and the treatments of inhalant abuse and dependence. PMID- 20715483 TI - [Current trends of nicotine dependence]. AB - This article reviews clinical features and neural mechanisms of nicotine dependence as well as medications for it. The ICD-10 and DSM-IV-TR classifications define nicotine dependence and nicotine withdrawal. The rewarding effects of nicotine have been reported to include a sense of well-being, increased vigilance, relaxation, anxiolytic effects, increased capacity to cope with stressors, and increased ability of learning and memory. These psychopharmacological effects of nicotine may be produced by the ability of nicotine to promote the release of catecholamines, acetylcholine, beta-endorphin, glucocorticoid, and other hormones. As for medications used to treat nicotine dependence, nicotine gum and nicotine patches are used to alleviate nicotine withdrawal, whereas bupropion, varenicline, and rimonabant are used to decrease rewarding effects of nicotine. PMID- 20715484 TI - [Opium (heroin * morphine)]. AB - The number of people dependent on opiate drugs, including heroin, is still high, and these abused drugs are major social issues, both in the social science and medically. The mechanisms of physical dependence and withdrawal symptoms in laboratory animals are becoming clear; however, no useful method to detoxify abusers with opioid dependence in clinical situation has been established, and alternative therapy with methadone, used in Europe and America, cannot be used in Japan. Here, I will outline the global trend of opium abuse, including heroin and morphine, and summarize the problems of heroin abuse. PMID- 20715485 TI - [Phencyclidine abuse, dependence, intoxication, and psychosis]. AB - Phencyclidine (PCP), the potent psychotomimetic drug, is an illicit street drug which is used widely among youth in the United States. The popularity of PCP abuser gradually decreased in recent years. However, the PCP abuse is still serious social problem due to its severe intoxication. In the present review, recent progress in our understanding about PCP abuse, dependence, intoxication, psychosis and the diagnosis and treatment was summarized. A long time has passed since the epidemic of PCP abuse, while there are few medical advances for PCP induced disorder. It is strongly desirable to develop medical approaches to PCP abuse, dependence, intoxication, and psychosis. PMID- 20715486 TI - [Benzodiazepine dependence]. PMID- 20715487 TI - [Biochemical investigation for clinical diagnosis of drug dependence]. AB - Specific biochemical marker is not available for clinical diagnosis of drug dependence at present. However, drug abuse is accompanied by a decrease in serotonin and the derivative in cerebrospinal fluid, suggesting central serotonergic dysfunction, that is associated with cognitive deficits, alterations in sleep architecture and neuroendocrine function, and increased impulsivity as well as an increase in the risk for aggressive behavior toward the self involving suicide. For central stimulant abusers, elevated plasma catecholamine levels are associated with psychotic episodes and cardiovascular complications involving tachycardia and arrhythmias. Biochemical investigation is useful for predicting drug-induced mental disorders, complications and the prognosis, and also for differentiation from other mental disorders, e.g., secondary to metabolic and infectious diseases, or management of acute intoxication. PMID- 20715488 TI - [Analytical methods for addictive drugs of abuse]. AB - The abuse of addictive drugs has been increasing world-wide and causing serious social problems. Recently, illegal drugs such as methamphetamine(MP) and 3,4 methylenedioxymethamphetamine (MDMA) have been frequently abused in Japan. The development and application of analytical methods of the abused drugs in biological specimens are very important for the prediction of and protection from the risk to human health. The biological specimens such as urine, blood and hair have been used for elucidation of the use of addictive drugs. Among them, hair is a powerful tool to supply historical information of drug abuse for a long period. In this section, analytical method for detection of addictive drugs of abuse was summarized. Our current study on MP and MDMA was also introduced. PMID- 20715489 TI - [Community-based prevention of drug abuse in Japan]. AB - The objective of this article is to review community-based drug abuse prevention and relapse prevention in Japan. Japan has a highly efficient system for the primary prevention of drug abuse; this system includes drug abuse education programs in schools and anti-drug abuse campaigns in communities. On the other hand, relapse prevention activities, such as counseling service at mental health welfare centers, self-help groups for drug addicts, and relapse prevention programs at outpatient clinics, are limited because of zero tolerance policies. Therefore, more relapse prevention activities are required in Japanese communities. PMID- 20715490 TI - [The recovery support system of the drug addiction]. AB - The recovery support system of the drug addiction in Japan is inadequate. It causes because of having part in the problem by the concept that each field of the medical model, justice model and welfare model is different. Each organization should wrestle with new cooperation of the recovery support. It will be necessary for there to make the support system which mainly on a social welfare model in future. It is necessary to let service provider of the welfare fill up more. I introduced the organization which participated in drug addiction and explained the present conditions and problems. PMID- 20715491 TI - [Drugs and crime]. AB - In law-related problems on drugs and crime, there are two types: (1) possession/use of drugs, (2) crimes caused by mental distress after the use of drugs. In this paper, I will focus on the former type called 'drug crimes'. Since drugs cause medically negative effects on the human body, the management/use of drugs is limited by the law which prescribes penalties. At the present, the management/use of narcotics, other mentally stimulating drugs, opium and its raw material, an opium poppy, cannabis, and antihypnotics are limited by six laws, including criminal laws. In this paper, I will introduce the contents of these laws, and the current situation of 'drug crimes'. PMID- 20715492 TI - [Treatment of social anxiety disorder (SAD)]. AB - Social anxiety disorder(SAD) is the most common anxiety disorder and it is a risk factor for subsequent substance abuse. The efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitor(SNRI) for the treatment of SAD has been reported. Cognitive behavioral therapy(CBT) was also effective for the treatment of SAD in many studies. High rate of co occurring SAD and alcohol use disorder (AUD) can be found in both clinical samples and in the general population. With regard to treatments for those suffering from SAD and AUD, little is known about the most effective treatment. Early interventions with social anxiety may thwart the development of maladaptive patterns of coping-related alcohol use from developing in the first place, and effectively prevent the developing of co-morbid SAD-AUDs. PMID- 20715493 TI - [Methylphenidate: pharmacology, indication and potential of abuse]. AB - Methylphenidate enhances dopaminergic neurotransmission in the central nervous system by same manner with cocaine and amphetamine that bind to the dopamine transporter and inhibit dopamine uptake. Methylphenidate improves social functions as well as clinical symptoms of patients suffered of narcolepsy and attention deficit hyperactivity disorder (ADHD), though it has the potential of abuse. It is reported that approximately 4% of older teens and emerging adults in the US annually misusing methylphenidate. Non-medical/illegal use of methylphenidate causes many consequences including addiction, negative reactions and medical complications. Growing number of illegal trades of methylphenidate and medical complications caused by misuse of methylphenidate urged Japanese government to introduce regulations limiting access to prescribed methylphenidate in 2008. PMID- 20715494 TI - [How to cope with patients of drug dependency in emergent department]. AB - In Japan, medical doctors are not obliged to accuse to the police, even if they diagnose a patient as intoxication of illegal drug. According to the queries to the doctors of the Tertiary Emergency Medical Center, variance of dealing existed. The promotion of the public health or interest and the duty to protect privileged information must be balanced. Each institution must prepare the manual for illegal drug patients. The limitations of qualitative analysis for drugs should be considered. PMID- 20715495 TI - [Drug dependency and drug-related sudden death]. AB - Abuse of many substances is one of the serious problems in Japan, and we often encounter an autopsy case where the individual died in association with the administration of them. Although their intoxication is mainly diagnosed on the basis of their serum concentrations, it is difficult to diagnose as their poisoning when their concentrations are less than lethal level. Moreover, the mechanism of death induced by them is still unclear. Therefore, forensic autopsy should be performed in the case where drug-related death is suspicious not only so as to make a precise diagnosis but also so as to elucidate the mechanism of the drug-related deaths, leading to the efficient therapy for drug intoxication. PMID- 20715496 TI - [Mechanisms of multi-organ failure in severe influenza]. AB - Severe influenza is characterized by cytokine storm and multi-organ failure with edema. We found that the "influenza virus-cytokine-trypsin/MMP-9 cycle" in the endothelial cells is one of the key mechanisms of vascular hyperpermeability, the major pathogen of multi-organ failure. Upregulated TNF-alpha, IL-6 and IL-beta induce ectopic pancreatic trypsin and pro-MMP-9 in the endothelial cells and in various organs. Trypsin mediates the viral hemagglutinin processing, which is crucial for viral entry and multicycles of replication. In addition, trypsin is the most potent pro-MMP-9 convertase to form active MMP-9 and both proteases synergistically destruct matrix around blood vessels. In addition upregulated trypsin triggers through its receptor, PAR-2, the modification of cellular functions, such as increase in calcium mobilization and mitochondrial membrane permeability, suppression of ATP generation and loss of tight junction constituent, zonula occludens-1. High risk patients who have impaired mitochondrial fuel utilization will easy get into energy crisis, resulting in vascular hyperpermeability in severe influenza. PMID- 20715497 TI - [Management of high-risk hypertensive patients for prevention from cardiovascular events]. AB - Hypertension is the one of the strongest predictors of cardiovascular events. Before the treatment of hypertension, the overall evaluation of cardiovascular risks in individual patients should be performed. For the evaluation, factors related to diabetes mellitus, metabolic syndrome, chronic kidney disease, cardiac complications, and hypertensive target organ damage are evaluated in addition to blood pressure to distinguish high-risk groups. Especially, diabetes mellitus, chronic kidney disease and cardiac complications including coronary heart disease, congestive heart failure, and left ventricular hypertrophy are high-risk factors. Moreover, these high-risk hypertensive patients should be strictly controlled their blood pressure by adequate anti-hypertensive agents. PMID- 20715498 TI - [Mass screening for prostate cancer at Ikeda City in Osaka Prefecture--results of screening with PSA alone between 2003 and 2007]. AB - PURPOSE: Since 2003, screening with prostate specific antigen (PSA) has been conducted to detect prostate cancer. We investigated the results between 2003 and 2007. PATIENTS AND METHODS: Screening with PSA alone was performed for males aged over 50 years who desired prostate cancer screening. We used a PSA cutoff value of 4.00 ng per milliliter. RESULTS: In 2003, there were 18,161 males aged over 50 years in Ikeda City. 3,738, 3,905, 4,129, 4,410, and 4,515 of the males underwent PSA screening in 2003, 2004, 2005, 2006, and 2007. The rate of elevated PSA levels was 7.9%-9.8% (median 9.1%). 161, 81, 70, 75 and 60 of the males visited us for secondary screening, and prostate biopsy was performed in 130 (80.7%), 57 (70.4%), 45 (64.3%), 38 (50.7%), and 42 (70.0%). Prostate cancer was detected in 91, 33, 29, 20 and 25 males, respectively. These values corresponded to 2.43%, 0.85%, 0.70%, 0.45% and 0.55% of the males who underwent primary screening. The incidence of prostate cancer was 0.96% during the 5 years. Clinical stage was B in 137 (69.2%), C in 52 (26.3%), D in 7 (3.5%), and unknown in 2. Surgery was performed in 87 (43.9%), endocrine therapy in 61 (30.8%), irradiation in 37 (18.7%), and follow up without treatment in 7 (3.5%). Treatment for 6 (3.0%) is unknown because they desired treatment at another hospital. CONCLUSIONS: 198 males were diagnosed with prostate cancer between 2003 and 2007. The clinical stage B was present in 137 (69.2%), and the early treatment was achieved. This may lead to a future decrease in the mortality rate. PMID- 20715499 TI - [Dextranomer beads in stabilized non-animal sodium hyaluronate gel (NASHA/Dx gel) for vesicoureteral reflux: multi-center study in Japanease patients]. AB - PURPOSE: To investigate the efficacy and safety of endoscopic treatment with the injectable gel of dextranomer beads in stabilized non-animal sodium hyaluronate (NASHA/Dx gel) administered submucosally close to the proximity of ureteral orifice, we performed the multi-center open study of Japanese patients with vesicoureteral reflux (VUR). We herein report the results of the study. SUBJECTS AND METHODS: Patients aged > or = 1 year with grade II-IV VUR underwent endoscopic injection with NASHA/Dx gel. Post-treatment assessment was done by voiding cystourethrography (VCUG) at 3 and 12 months. Patients with VUR grade II IV at 3 months underwent re-treatment, with VCUG assessment 3 and 12 months after retreatment. Positive response to treatment was defined as reflux grade 0 or 1. RESULTS: The initial treatment was conducted to 116 ureters in 73 patients. The per-protocol efficacy population included 97 ureters in 71 patients. On a per ureter basis, the positive response rate at 12 months after the last endoscopic treatment was 69.1%, compared with 62.0% on a per-patient basis. Improvement in reflux grade was shown to be statistically significant at both 3 months post initial treatment and 12 months post last treatment. Positive response rate decreased with increasing baseline reflux grade. There were only two mild adverse events (AEs) and one moderate laboratory fluctuation which were potentially relating to NASHA/Dx gel. CONCLUSIONS: This study has shown that endoscopic injection of NASHA/Dx gel is effective and well tolerated in Japanese patients with VUR. First-line use of this treatment for VUR could potentially be considered for Japan also. PMID- 20715500 TI - [Case report of rhabdoid tumor of the kidney occurring in own kidney following kidney transplantation from the living relative]. AB - The patient was a 30-year-old man who had undergone living-donor kidney transplantation for renal failure caused by IgA nephropathy at age 29. On post transplantation day 83, he visited our department with a chief complaint of asymptomatic hematuria. CT performed on post-transplantation day 95 revealed a tumor (size, 4 cm) in the right native kidney that had not been observed at the time of transplantation. CT performed on post-transplantation day 153 showed that the tumor had enlarged to 6 cm, while retrograde pyelogram performed on post transplantation day 171 was negative for renal pelvic tumor. On post transplantation day 193, radical right nephrectomy was performed. The tumor had directly invaded the diaphragm and the lower surface of the liver, and was histopathologically diagnosed as rhabdoid tumor of the kidney. As the pathological tissue was extremely malignant, hepatic posterior segmentectomy, right adrenalectomy, and lymph node dissection were further performed for metastases on post-transplantation day 200. On the 23rd day after radical right nephrectomy (post-transplantation day 216), the patient developed dyspnea. Chest CT showed pleural effusion, hemothorax in right lung and metastases in both lungs. The patient's general status gradually worsened thereafter, and he died on the 53rd day after radical right nephrectomy (post-transplantation day 246). Rhabdoid tumor of the kidney is a rare renal tumor that affects children, and only four adult cases have been reported to date. We report our experience with this rare case. PMID- 20715501 TI - [Spinal cord infarction following radical nephrectomy using extracorporeal circulation for renal cell carcinoma with tumor thrombus in the inferior vena cava and right atrium: a case report]. AB - A 51 year-old man admitted to our hospital for macroscopic hematuria and right abdominal mass. CT demonstrated a large hypervascular mass and tumor thrombus in the inferior vena cava and right atrium. We diagnosed right renal cancer (stage III), and he underwent radical nephrectomy and resection of tumor thrombus with extracorporeal circulation. Operative time was 9 hours. Time for extracorporeal circulation was 119 minutes, and it took 60 minutes for intraoperative balloon occlusion of descending aorta in order to arrest hemorrhage. Pathological diagnosis was clear cell carcinoma of the kidney (pT3c, N0, M0). Four days after surgery, paraplegia was evident, and a diagnosis of spinal cord infarction was made based on neurologic examination and MRI findings. In cases with such a surgery requiring extracorporeal circulation, preoperative meeting with cardiologists and anesthetists is indispensable in order to fully understand the possible complications. Especially, to keep a careful watch and prepare for spinal cord ischemia is mandatory. PMID- 20715502 TI - [Retroperitoneal fibrosis due to Schistosoma japonicum: a case report]. AB - We report a case of retroperitoneal fibrosis due to Schistosoma Japonicum in patient with urothelial carcinoma. Retroperitoneal fibrosis was observed in a-83 year-old man during examinations for postrenal renal failure. The symptoms were improved by percutaneous nephrostomy and pulse therapy using corticosteroids, however, urothelial carcinoma was detected during follow-up examinations. The biopsy of retroperitoneal tissue was performed during the surgery for urothelial carcinoma. The histopathological examination revealed scattered calcified eggs of Schistosoma Japonicum in retroperitoneal fibrosis tissue. Therefore, in this case, we assumed Schistosoma Japonicum was the cause of retroperitoneal fibrosis. In our knowledge, there is no report about retroperitoneal fibrosis due to Schistosoma Japonicum. We hypothesize the pathway that the eggs penetrate into retroperitoneal space is extravasation from intestinal wall and peritoneal cavity, although the detail of this mechanism is not obvious. It is well known about the relationship between Schistosomasis and malignant tumors. However, it seemed no evidence regarding the relationship between Schistosoma Japonicum and urothelial carcinoma, since there is no report about it and the eggs were not found in specimen of urothelial carcinoma. PMID- 20715503 TI - [Primary urothelial carcinoma with sarcomatous transformation of the prostate]. AB - A 64-year-old man visited our hospital presenting with macroscopic hematuria. Right hydronephrosis and hypertrophy of the prostate were shown by DIP and MRI respectively. A small papillary tumor at the prostatic urethra was found by cystourethroscopy. Then, we performed transurethral resection of the tumor and trans-perineal needle biopsy of the prostate, and diagnosed him as primary urothelial carcinoma of the prostate. Following neo-adjuvant chemotherapy(MVAC), the patient was treated with radical cystoprostatectomy. The histopathological examination showed urothelial carcinoma with concomitant sarcomatous transformation. Six months after the surgery, he had a recurrence of the tumor in the pelvic cavity. He was treated with the second-line chemotherapy using paclitaxel and gemcitabin combined with the radiation therapy, resulting in the disappearance of the tumor. No evidence of the recurrence has been observed for 3 years. PMID- 20715504 TI - [Follow-up of dysphagia in the elderly--clinical survey of deglutition disorder at a private ENT office]. AB - In a one-year-plus follow-up study in 17 of 26 cases involving apparent liquid aspiration during videoendoscopic screening, subjects were instructed in swallowing using video images and in choosing food, utensils, and posture. The amount of sputum decreased in 10 case (59%), and sputum sticking in the throat disappeared in 4 (18%). Body weight also increased in 4 (24%). Choking coughs noted in 11 during initial videoendoscopy disappeared in 2 (18%). We thus, concluded that detecting dysphagia symptoms early and providing follow-up could help prevent aspiration pneumonia. PMID- 20715505 TI - [Study of cerebellar infarction with isolated vertigo]. AB - Isolated vertigo is generally attributed to labyrinthine disease, but may also signal otherwise asymptomatic cerebellar infarction. Of 309 subjects admitted between April 2004 and March 2009 for the single symptom of acute vertigo initially thought to be labyrinthine, four were found to have cerebellar infarction of the posterior inferior cerebellar artery area (PICA). All were over 60 years old and had risk factors including hypertension, diabetes mellitus, arrhythmia, and/or hyperlipidemia. Two had trunk ataxia, with magnetic resonance imaging (MRI) showing infarction within a few days. The other two could walk without apparent trunk ataxia, however, it took 4 to 7 days to find the infarction, mainly through neurological, neurootological, and MRI findings. Neurologically, astasia, dysbasia or trunk ataxia were important signs. Neurootologically, nystagmus and electronystagmographic testing involving eye tracking, saccade, and optokinetic patttens were useful. PMID- 20715506 TI - [A case of thyroid crisis in acute tonsillitis treatment]. AB - We report a case of fatal thyroid crisis induced by acute tonsillitis. A 33-year old woman with untreated hyperthyroidism developed thyroid crisis during acute tonsillitis treatment. The four days passing from crisis onset to treatment initiation unduly compromised her condition, resulting in death. Such cases point up the need for prompt thyroid crisis diagnosis and treatment, the difference between a proactive life-sustaining response and a negative mortal result. PMID- 20715507 TI - [Possible mechanism for regulation of inflammatory responses with the S100A8/A9 protein]. AB - We have described a possible mechanism for the regulation of excessive inflammatory responses with S100A8/A9 protein in damaged rat livers. Recombinant human S100A8(r-S100A8) and S100A9 (r-S100A9) were expressed in E. coli cells, and their heterodimer (r-S100A8/A9) with 90% approximate purity was also prepared successfully. The effect of the r-S100A8/A9 on suppression of acute inflammatory changes in rat livers with LPS-induced damage was microscopically observed. Indeed, the liver damage diminished as the dose of the r-S100A8/A9 increased, and the minimum requirement of the protein was estimated to be 1,000 microg/rat in this study. Observation of superoxide anions was positively observed in control rats treated with LPS alone, but almost not in the livers of rats treated with the r-S 100A8/A9 1h after injection of LPS. This fact strongly suggests that the r-S100A8/A9 could indirectly suppress production of such internal oxidants according to unknown pathway (s) in acute inflammation. Expression of mRNAs of several kinds of inflammatory cytokines, such as TNF-alpha, IL-6 and IL-1beta, was also significantly suppressed, which was of much note. Therefore, the possibility that the r-S100A8/A9 partly inhibits the process of signal transduction of inflammatory responses in the immunological cells leading to down regulation of inflammatory changes in vivo was suggested in this study. Conclusively, S100A8/A9 is not necessarily an inflammatory-induced factor, and preferably effective on suppression of excessive inflammatory reaction in vivo dose-dependently, although the mechanism is still unclear. PMID- 20715508 TI - [Results of antifungal susceptibility testing of Candida species and trends of antifungal use in Niigata university medical and dental hospital]. AB - The accuracy of antifungal susceptibility testing is important for the clinical management of patients with serious infections due to fungus. Our primary objective was to analyze the results of antifungal susceptibility testing of Candida species performed at Niigata University Medical and Dental Hospital and usage of antifungal agents. Antifungal susceptibility testing was performed by the CLSI M27-A2 method. Yeast-like fungi were isolated from 6% of 6,730 samples. All isolates were Candida species, i.e., C. albicans (50%), C. parapsilosis (28%), C. guilliermondii (9%), C. krusei (5%), C. glabrata (4%), and C. tropicalis (4%). The results of the minimum inhibitory concentration that inhibits 90% of the strain tested (MIC90) were 1 microg/mL for fluconazole, 0.5 microg/mL for miconazole, 0.06 microg/mL for itoraconazole, < or = 0.03 microg/mL for micafungin, respectively. The results of non-albicans species were 32 microg/mL for fluconazole, 8 microg/mL for miconazole, 0.5 microg/mL for itoraconazole, 1 microg/mL for micafungin, respectively. All Candida species were susceptible to the available antifungal agents, except C. krusei that was resistant to fluconazole. Thus, antifungal susceptibility varies greatly according to fungal species. The accuracy of identification of the fungus and antifungal susceptibility would contribute to the proper management of patients with serious fungal infections. PMID- 20715509 TI - [Utility of microsemi LC-667CRP in point of care testing system for acute inflammatory disease]. AB - We examined the basic performance of "Microsemi LC-667CRP" (LC-667, HORIBA, Ltd.) which has been newly developed as compact laboratory instrument capable of simultaneous measuring of complete blood count (CBC) including 3-part differentials of white blood cells (WBC) and C-reactive protein (CRP) using whole blood anticoagulated with ethylenediaminetetraacetic acid (EDTA). We found that CBC and CRP were intra-assay-reproducible (n = 10, CVs < 5.0%). They also showed the good linearity and no definite carry-over. Concerning the WBC differentials, percentage of monocytes (MON%) showed less intra-assay reproducibility compared with those of granulocytes (GRA%) and lymphocytes (LYM%). We also evaluated the correlation of values obtained by LC-667 and routinely used instruments in our institute. Concerning the CBC and WBC differentials, excellent correlations were found between LC-667CRP and XE-2100 (SYSMEX CORPORATION) except MON%. In addition, whole blood CRP as well as plasma and serum CRP measured by LC-667 also showed the good correlations with serum CRP measured by 7600 (Hitachi High Technologies Corporation). From these findings, LC-667 was revealed to produce the clinically reliable data using only 18 microL of sample volume in 4 minutes. Point of care testing (POCT) has been developed as the laboratory system performed at or near the site of patient to reduce the turn around time. Therefore, LC-667 seemed useful in POCT for the patients with acute inflammatory disease especially in pediatrics. PMID- 20715510 TI - [Usefulness of semi-quantitative procalcitonin test in respiratory medical practice]. AB - PURPOSE: A lot of investigators have reported about the diagnostic and prognostic value of procalcitonin (PCT) for severe bacterial infection. We evaluated the usefulness of semi-quantitative PCT test in respiratory medical practice. METHODS: A retrospective study was performed from June to December 2008 at the Chugoku Rosai General Hospital, Hiroshima, Japan. This study analyzed consecutive adult patients, including outpatients and inpatients, who developed systemic inflammatory response syndrome (SIRS) and their PCT were measured semi quantitatively within the first 24 hours of onset or first visit. We extracted 87 patients with respiratory disease and analyzed their clinical data. RESULTS: Study patients were divided into two groups: 61 patients with bacterial infection and 26 patients without it. Semi-quantitative PCT test (cut-off value; > or = 0.5 ng/ml) showed sensitivity of 55.7% and specificity of 84.6% for diagnosis of bacterial infection. The diagnostic value of PCT was higher than that of CRP and WBC but it was thought to be not enough to accurate diagnosis. The patients with high PCT value (> or = 2.0 ng/ml) showed higher death rate than the patients without it (36.4% vs 7.7%, P = 0.016). CONCLUSION: Semi-quantitative PCT test, which anyone can use quickly and easily, has great prognostic value and limited diagnostic value for respiratory bacterial infection. PMID- 20715511 TI - [Overview of ISO15189 and accreditation with it]. AB - Because of a growing need for good quality and safety in medical care, it is necessary for clinical laboratories to improve quality and competence, and for these improvements to be disclosed to clinicians and patients. To this end, each clinical laboratory should be evaluated and accredited by an international third party organization. We, the Department of Clinical Laboratory, the University of Tokyo Hospital, achieved ISO15189 accreditation in January 2007. Thereafter, the Department of Blood Transfusion, the Department of Infection Control, and our system for specified health checkup also obtained ISO15189 accreditation in March 2008. Based on this ISO15189 accreditation, quality-certified laboratory test results are now reported and, therefore, clinicians can perform safe medical care for their patients. Furthermore, ISO15189 is useful for clinical trials and international collaboration in medical research. We hope our ISO15189 accreditation will be helpful in its dissemination in Japan, thereby playing a role in clinical laboratory standardization, benefiting both clinicians and patients. PMID- 20715512 TI - [Impact of reporting gram stain results from blood culture bottles on the selection of antimicrobial agents]. AB - We assessed the utility of reporting direct blood Gram stain results compared with the results of positive blood cultures in 482 episodes, and monitored the impact on the selection of antimicrobial treatment. We found that the groups: "Staphylococcus species (spp.)", "Pseudomonas spp. and related organisms", and "Yeasts" identified in this way perfectly matched those on later culture identification. When the report indicated "Staphylococcus spp." or "Pseudomonas spp. and related organisms", the physicians started or changed antimicrobials suitable for these bacteria more frequently than "Other streptococci" and "family Enterobacteriaceae" (p < 0.05). The incorrect recognition of Acinetobacter spp. and Pseudomonas spp. as "family Enterobacteriaceae" is still the most challenging problem in this context, but these microorganisms seemed to be cultured from patients in some special departments and clinical conditions, including malignant diseases and chemotherapy. In conclusion, Gram-stain results that definitively identify "Staphylococcus spp.", "Pseudomonas spp. and related organisms", and "Yeasts" can be reliably and rapidly provided by clinical laboratories, and this has a significant impact on the early selection of effective antimicrobials. In case of patients at a high risk of non-fermentative gram-negative rod infection, we have to consider the selection of anti-pseudomonal agents while awaiting culture identification and susceptibility tests. Further investigation is needed to assess the clinical impact of reporting Gram-stain results in the presence of bacteremia. PMID- 20715513 TI - [Appropriate use of antibiotics--practice we should employ now: appropriate use of antibiotics by pharmacists at university hospitals]. AB - Various elements, such as a quick response, effectiveness, economy, mobility (inside and outside the hospital) are needed for today's in-hospital infection control. An infection control group was established, consisting of a doctor, dentist, pharmacist, nurse, medical technologist, and an administer for the purpose of and swiftness was mobile, and being active about the establishment of investigation/a study of the prevention of in-hospital infection and measures in March, 2001. As duties to play a key role of the infection control that a pharmacist made use of professional ability in, the making of enlightenment, Therapeutic Drug Monitoring, for use situation grasp and the proper use of antimicrobial/the disinfectant and the medication guideline by the participation in planning, PK/PD characteristic to the administration plan is given. There are a lot of cases to become the fatal injury not only in-hospital infection by resistant bacteria becomes the obstruction of the treatment including MRSA, multidrug resistance Pseudomonas aeruginosa in the House. It is to support treatment by reasonable medication to be born to we pharmacist and keeps it in mind therefore to load the study of the specialty domain as a member of the team medical care. PMID- 20715514 TI - [Appropriate use of antibiotics--practices we should employ now: appropriate use of antibiotics for pharmacists in general hospitals]. AB - An authorization system regarding infection has been devised for various occupations in the field of infection control. An infection control team (ICT) consists of authorized, specialized staff, and plays an important role in clinical practice, considering the appropriate use of antibiotics. Board certified infection control pharmacy specialists also belong to this team. The appropriate use of antibiotics, which I emphasize, indicates the absence of the inappropriate selection of broad-spectrum agents and chronic administration, considering the following 3 points: the selection of antibiotics whose spectra involve causative bacteria (drug sensitivity), prescription of antibiotics using an appropriate administration method/dose based on their transfer to the infected site (pharmacokinetics), and relief of symptoms of infectious diseases (therapeutic effects). In this study, we introduce cases of pharmacists' intervention in Nakamura Memorial South Hospital with respect to the appropriate use of antibiotics by general hospital pharmacists. The contents of pharmacists' intervention included accompanying physicians on their rounds/support regarding prescription, therapeutic drug monitoring, the preparation of guidelines for the hospital use of antibiotics, culture data collection/preparation of antibiograms, ICT/Infection Control Committee (ICC) activities, hospital rounds, preparation of antibiotic injections, and gram staining of sputum. In the future, health care professionals should always consider the appropriate use of antibiotics, contributing to a medical environment in which current options can be maintained for future infectious disease treatment. PMID- 20715515 TI - [Microorganism test systems and antibiograms useful for the proper use of antibacterial agents]. AB - Antimicrobial agents are used for the accurate diagnosis of infectious diseases and effective implementation of antibacterial chemotherapy. The role of microbiological technologists is to provide data from microorganism tests useful for rapid infection treatment. Gram strain can be used to observe microorganisms and neutrophils from specimens of a patient. It is also possible to estimate the kinds of microorganism. If bacterial infectious disease is negative, there is no need for antibacterial chemotherapy. The applied dose of antibacterial agents is different in every hospital. Also, there is a difference in the percentage antibacterial agent susceptibility of isolates. Antibiograms must be created to investigate local factors. For empiric therapy, antibiograms are useful when choosing antibacterial agents showing marked efficacy against the clinical isolate. Microorganism test systems which are useful for the proper use of antibacterial agents are necessary to facilitate safe antibacterial chemotherapy and prevent the development of resistant bacteria. We report a microorganism test system employed at the Sapporo City General Hospital. PMID- 20715516 TI - [Undergraduate education of medical technologists to promote scientific and technological literacy]. AB - It is becoming increasingly important for today's medical technologists to receive proper training on the safety of medical treatment and healthcare in order to accommodate the rapid changes and advancement in medical technology. In particular, because of the increase of hospital-acquired infections, the role of medical technologists involved in infection control has become much more important. In addition, particularly in Japan, the career options available to students graduating with a degree in medical technology have become much more diverse, ranging from research laboratories to clinical services; however, undergraduate education for medical technologists is limited. It is therefore deemed necessary for undergraduate students to be provided with adequate training from their universities by offering a wider selection of classes in this subject area. In this paper, we summarize our preliminary findings on the trial lessons that are offered to medical technology students in their microbiology class. These lessons are designed to enhance students' academic potential and to engage their interest. PMID- 20715517 TI - [Comprehensive management of clinical laboratory for appropriate antimicrobial use]. AB - Accurate diagnosis of infectious diseases is essential for appropriate antimicrobial use. The following five factors should be promoted to accurately diagnose infectious diseases; everyday availability of microbiology laboratory, submitting only appropriate specimens for laboratory examination, providing accurate results to physicians with a rapid turnaround time, and reporting useful information to assist in treatment and delivering educational lectures on clinical microbiology to hospital staff. As a director of a clinical laboratory in a university hospital, I have tackled these issues. Not only laboratory performance and activity, but the information system for healthcare workers were significantly improved. As a result, appropriate antimicrobial use has been achieved in part. PMID- 20715518 TI - [Survey of skills needed to assist tracheal intubation: nurse assistants lack accurate knowledge of BURP and cricoid pressure maneuvers]. AB - BACKGROUND: The backward, upward and rightward pressure (BURP) maneuver and cricoid pressure (CP) are easily confused because of their similarities. We surveyed nurses to determine their knowledge and skills regarding these maneuvers. METHODS: Forty nurses (OR, n=20; ER, n=20) answered questionnaires regarding BURP and CP, and were then asked to apply CP to a laryngopharynx model equipped with a digital scale to measure compression force. RESULTS: As for the BURP maneuver, 26 nurses (OR 20, ER 6) noted previous experience, while only 13 (OR 3, ER 10) and 1 (OR) nurses answered correctly regarding the compression point and correct direction, respectively. As for CP, 16 nurses (OR 14, ER 2) noted previous experience, but only 3 (all ER) answered correctly. Twenty-six nurses (OR 16, ER 10) incorrectly compressed the thyroid cartilage on the laryngopharynx model, and 24 (OR 18, ER 6) incorrectly applied backward and upward pressure, which was significantly frequent among the OR nurses. The measured forces of CP were 2.11 +/- 1.3 kg (mean +/- SD) and 2.5 +/- 2.1 kg for the OR and ER nurses, respectively, which were not significantly different. CONCLUSIONS: We found that the nurses are confused with the BURP and CP maneuvers. Unless applied correctly, these maneuvers may interfere with tracheal intubation. Constant education and training are essential for effective and safe implementation of these maneuvers. PMID- 20715519 TI - [Long-term efficacy and safety of pregabalin in patients with postherpetic neuralgia: results of a 52-week, open-label, flexible-dose study]. AB - BACKGROUND: The efficacy of pregabalin was demonstrated in a randomized double blind placebo-controlled 13-week trial in 371 Japanese patients with postherpetic neuralgia (PHN). In this study, we evaluated the long-term efficacy and safety of pregabalin for relief of PHN. METHODS: 126 patients were enrolled from the preceding double-blind study into the 52-week open-label study. Patients were given pregabalin 150 to 600 mg x day(-1). Pain intensity was measured using the Short-Form McGill Pain Questionnaire (SF-MPQ: total score, visual analogue scale and present pain intensity). RESULTS: The efficacy parameter SF-MPQ showed a decrease over the treatment-term. The changes of visual analogue scale and present pain intensity at the endpoint were -28.3 mm and -1.1 score, respectively. The commonly reported adverse events were dizziness, somnolence, peripheral edema and weight gain, and most of them were mild to moderate in intensity. No new adverse events were observed due to long-term pregabalin administration. CONCLUSIONS: These results suggest that long-term treatment of pregabalin may be beneficial in patients with PHN. PMID- 20715520 TI - [A comparison of acetated Ringer's solution and bicarbanated Ringer's solution for fluid therapy during extended hystectomy]. AB - BACKGROUND: We investigated the efficacy of two types of Ringer's solutions, acetated Ringer (AR) and bicarbanated Ringer (BR), during and after high invasive abdominal surgery. METHODS: We divided 16 patients scheduled for extended hystectomy into 2 groups of AR or BR infusion group. Either AR or BR solution was administered to keep CVP at 2-8 cmH2O and Hb above 7 g x dl(-1) during the entire anesthetic period. Acid base balance, serum magnesium (Mg) and metabolic products such as lactate, pyruvic acid, citric acid, acetoacetic acid and hydroxybutyric acid were measured during and after surgery. IL-6 was determined early on the next morning. RESULTS: Metabolic products and IL-6 were not different between the two groups; however, base excess and HCO3- during surgery were kept higher in BR group than in AR group. Intraoperative serum Mg was also maintained higher in BR group. CONCLUSIONS: From the aspect of the ability to keep acid base balance and Mg level, BR seems to be a more suitable infusion fluid than AR in high invasive abdominal surgery such as extended hystectomy. PMID- 20715521 TI - [A case-control study of airway management for 68 patients with cervical spine injury: comparison of the direct laryngoscope with a Macintosh blade and the fiberoptic bronchoscope]. AB - BACKGROUND: As for cervical spine injury, special consideration for airway management is required but the optimal strategy remains controversial. Direct laryngoscopy (DL) creates some degree of cervical extension leading to secondary neurologic deterioration. Fiberoptic bronchoscopy (FOB) may facilitate tracheal intubation with little cervical motion, but has several inherent limitations. A few objective data prompted us to compare the neurologic outcome relating to the orotracheal intubation using the different types of technique, the DL with a Macintosh blade or the FOB. METHODS: To identify the effect of different methods on the intubation time, neurologic disability, and adverse effects, 68 cervical spine-injured patients with the use of DL (group L; 36 patients) or FOB (group F; 32 patients) were retrospectively reviewed using hospital records. Following the induction of general anesthesia, the trachea was intubated with no immobilizing forces in group L, while awake intubation was accomplished in group F after judicious application of local anesthesia to the larynx and trachea. RESULTS: No significant differences were observed between the groups in age, BMI, intubation time, postoperative neurologic outcome or incidence of aspiration pneumonia. Moreover, no neurologic deterioration was shown after DL and orotracheal intubation. CONCLUSIONS: We found no evidence to support the routine practice of the bronchoscope-assisted awake intubation in patients with cervical spine injury. The clinical value of this technique in offering some neurologic advantage remains limited. PMID- 20715522 TI - [Use of the airway scope for rapid sequence induction in the emergency operation]. AB - Rapid sequence intubation is a common procedure in emergency patients at risk for pulmonary gastric aspiration. However, in some of these cases may accompany a difficult airway. The Airway Scope (AWS) has been shown to be useful for difficult airway. We used AWS for rapid sequence intubation in 19 such patients. All patients were successfully intubated without any complication. We believe that AWS is a useful device for rapid sequence intubation. PMID- 20715523 TI - [Internal jugular vein cannulation guided by pulsation]. AB - BACKGROUND: We are accustomed to right internal jugular vein (IJV) cannulation guided by pulsation for 20 years or more. This study was conducted to evaluate whether this method is a safe and certain method. METHODS: After obtaining informed consent, 100 elective surgical patients requiring central venous catheterization during perioperative period were randomly assigned to either the pulsation group in which IJV pulsation was used for a landmark of puncture or the US group in which IJV was recognized with ultrasonography before puncture. RESULTS: Pulsation was observed in 98 patients. Successful rate of first attempt with a 23 G seeking needle was 85.7% in the pulsation group and 86% in the US group. IJV was successfully cannulated at 1 pass in the entire pulsation group and 92% in the US group. The frequency of puncture with cannula was significantly lower in the pulsation group than that of the US group. Arterial puncture with the seeking needle was recorded in 3 patients in the US group. Successful rate of first attempt in this study was comparable to other studies using ultrasonographic guidance. CONCLUSIONS: Internal jugular vein cannulation by pulsation method is a safe and certain method. PMID- 20715524 TI - [Remifentanil provides fast recovery and hemodynamic stability in laryngomicrosurgery anesthesia]. AB - BACKGROUND: Stressful procedures such as intratracheal intubation and direct laryngoscopy in very short operations make anesthetic management for laryngomicrosurgery difficult. This study was conducted to evaluate which anesthetic agent, remifentanil or fentanyl, is suitable in anesthesia for laryngomicrosurgery. METHODS: After obtaining informed consent prior to the study, 18 patients undergoing elective laryngomicrosurgery were randomly allocated to one of two groups to receive remifentanil (R group) or fentanyl (F group). Patients with ages above 76 years and moderate abnormalities in cardiovascular system or respiratory system were excluded. RESULTS: Average infusion rate of remifentanil was 0.24 +/- 0.02 microg x kg(-1) x min(-1) and total infused dose of fentanyl was 0.27 +/- 0.05 mg. Average bispectral index values in both groups were comparable. Cases needing sevoflurane inhalation to control blood pressure were significantly more in F group than in R group. Heart rate was significantly lower in R group than in F group. Duration from the end of operation to responses to verbal commands and extubation was significantly shorter in R group than in F group. CONCLUSIONS: Remifentanil provided faster recovery and hemodynamic stability. Therefore, remifentanil seems to be more suitable than fentanyl in anesthesia for laryngomicrosurgery. PMID- 20715525 TI - [Efficacy of remifentanil in anesthetic management for living-donor renal transplantation]. AB - BACKGROUND: We used fentanyl and remifentanil in living-donor renal transplantation patients. So, we have compared both drugs in renal function. METHODS: We used the volatile anesthetic sevoflurane as the base in 30 living donor renal transplantation patients, dividing them into a remifentanil anesthesia group of 15 patients and a fentanyl anesthesia group of 15 patients, and compared their creatinine, BUN, and serum K values before surgery, and 1 day as well as 3 days after surgery. RESULTS: The results showed improvement in their values, and there were no significant differences between the two groups. CONCLUSIONS: Since more patients in the remifentanil group had adequate diuresis beginning immediately postoperatively without taking a diuretic, remifentanil appears to be a more suitable drug to use for anesthesia for living-donor renal transplantation. PMID- 20715526 TI - [Combined spinal-epidural anesthesia for cesarean section in a parturient with myotonic dystrophy]. AB - Myotonic dystrophy (MD) is a muscle disorder characterized by progressive muscle wasting and weakness, and is the most common form of muscular dystrophy that begins in adulthood, often after pregnancy. MD might be related to occurrence of malignant hyperthermia. Therefore, the cesarean section is often performed for the parturient with MD. We had an experience of combined spinal-epidural anesthesia for cesarean section in a parturient complicated with MD. A 40-year old woman had rhabdomyolysis caused by ritodrine at 15-week gestation and was diagnosed as MD by electromyography. Her first baby died due to respiratory failure fourth day after birth. She had hatchet face, slight weakness of her lower extremities, and easy fatigability. Her manual muscle test was 5/5 at upper extremities and 4/5 at lower extremities. She underwent emergency cesarean section for premature rupture of the membrane, weak pain during labor, and obstructed labor at 33-week gestation. We placed an epidural catheter from T12/L1 and punctured arachnoid with 25 G spinal needle. We performed spinal anesthesia using 0.5% hyperbaric bupivacaine 1.5 ml and epidural anesthesia using 2% lidocaine 6 ml. Her anesthetic level reached bilaterally to T7 and operation started 18 minutes after combined spinal-epidural anesthesia. Her baby was born 23 minutes after the anesthesia. As her baby was 1/5 at Apgar score, the baby was tracheally intubated and artificially ventilated. The cesarean section was finished in 33 minutes uneventfully. She had no adverse events and was discharged on the 8th postoperative day. Later her baby was diagnosed as congenital MD by gene analysis. Combined spinal-epidural anesthesia with the amide-typed local anesthetic agents could be useful and safe for cesarean section in the parturient with MD. PMID- 20715527 TI - [A case of pulmonary edema due to excess absorption of perfusion fluid during transcervical resection using saline solution]. AB - A 39-year-old woman underwent transcervical resection (TCR) of submucosal uterus myoma. Induction and maintenance of anesthesia were managed with total intravenous anesthesia using propofol, remifentanil and rocuronium bromide. Patient had stable condition from the anesthesia induction until 75 minutes following skin incision. However, around that period, sudden tidal volume reduction, worsening oxygenation, and head and neck swelling developed. Arterial blood gas analysis indicated high-chloride metabolic acidosis. Transesophageal echocardiography showed excess right heart overload. On arriving at ICU, body weight of the patient increased about 10 kg compared to the preoperative value. Artificial ventilation and diuretics administration were done to treat excess body fluid. And the patient recovered without any subsequent complications. It should be noted that in case of TCR, unpredicted excess fluid load could develop, and careful observation and management are required by anesthesiologist in charge. PMID- 20715528 TI - [A case of Vibrio vulnificus infection presenting with invagination]. AB - A 73-year-old man with advanced lung cancer ate raw fish the day before being admitted to our hospital with severe abdominal pain, fever and vomiting. Soon afterward he fell into shock and disseminated intravenous coagulation. A CT scan revealed invagination and emergency surgery was performed. On the first day after surgery, Vibrio vulnificus was cultured from his ascites and blood. The infection was controlled by antibiotic treatment and he was discharged 23 days after the surgery. Vibrio vulnificus infection is an opportunistic infection that develops mostly in patients with liver cirrhosis within two days after eating raw seafood or having the injured skin exposed to sea water in the summer. Mortality is 70%, and more than half of these patients die within 72 hours of onset. Early diagnosis and treatment are very important. In addition, the public should be educated to protect immuno-compromised individuals from this infection. PMID- 20715529 TI - [Hypertrophic cardiomyopathy]. AB - A 68-year-old woman with severe cardiac dysfunction due to dilated phase of hypertrophic cardiomyopathy was diagnosed with sigmoid cancer and scheduled for high anterior resection. Preoperative left ventricular ejection fraction (EF) was 16% by transthoracic echocardiography. After placement of an epidural catheter at the T12-L1 interspace, and artery catheters in the left radial artery for invasive blood pressure monitoring and in the right femoral artery for stand-by IABE general anesthesia was induced by midazolam, fentanyl and sevoflurane, and maintained with sevoflurane. Analgesia was obtained by epidural administration of 1% lidocaine and 0.2% ropivacaine. A central venous catheter was placed in the right internal jugular vein through which dobutamine was infused throughout the operation. Cardiac function monitored by transesophageal echocardiography showed EF of 9% just after insertion. After arbitrary administration of phenylephrine and landiolol, the operation and anesthesia were completed without serious problems. However, congestive heart failure worsened on postoperative day 2, and was improved by increasing dobutamine and by administration of milrinone. PMID- 20715530 TI - [Anesthetic management of a patient with chronic spinal cord injury for laparoscopic cholecystectomy]. AB - Spinal cord injury (SCI) is a rare disease that offers challenges to anesthesiologists, while laparoscopic cholecystectomy (LC) has become common in recent years. We report a case of adult patient with chronic high SCI who underwent LC. A 62-year-old man, a known case of cervical SCI, was presented for LC. Anesthetic problems included circulatory and respiratory complications because of both SCI and pneumoperitoneum. Anesthesia was induced with propofol and a standard endotracheal tube was inserted with vecuronium; and thereafter anesthesia was maintained with small bolus doses of fentanyl and sevoflurane inhalation in the absence of epidural block. The intra- and post-operative course was completely uneventful without any episode of autonomic hyperreflexia. Due to a lack of sensory and motor function, SCI patients will receive little benefit from minimally invasive laparoscopic procedures. In conclusion, compared to open laparotomy, LC will minimize surgical trauma and hospital stay, but may not always minimize complications in anesthetic management. To the best of our knowlegde this is the first report in the literature which describes anesthesia for laparoscopic surgery in a SCI patient. PMID- 20715531 TI - [Anesthetic management using the arterial pressure-based cardiac output monitor and a central venous oximetry catheter for tricuspid valve replacement in a patient receiving hemodialysis]. AB - A 64-year-old man receiving hemodialysis underwent a tricuspid valve replacement. We used an arterial pressure-based cardiac output (APCO) monitor and a central venous oximetry catheter instead of pulmonary artery catheter because the enlargement of the right ventricle caused by tricuspid valve regurgitation might make it difficult to insert the pulmonary artery catheter. Aortic calcification was so severe that an arterial cannula was sewn into the right subclavian artery. Therefore, we had to insert an arterial catheter into the shunt placed on his left upper limb, and connected it to the APCO monitor FloTrac (Edwards Life sciences, U.S.A.). Anesthesia was induced with intravenous fentanyl, midazolam and rocuronium, and maintained with fentanyl and propofol. A triple lumen PreSep central venous oximetry catheter (Edwards Lifesciences, USA) was inserted via his right internal jugular vein. Under cardiopulmonary bypass beating tricuspid valve replacement was performed. Although a large amount of catecholamine was needed for weaning from cardiopulmonary bypass, it was performed referring to the cardiac index of APCO monitor. The operation was finished successfully. We concluded that cardiac function should be evaluated with the relative change of cardiac index from APCO monitor when the absolute value was uncertain from patient's pathology (e.g., valvular disease). PMID- 20715532 TI - [The perioperative management for pheochromocytoma resection in a patient with chronic renal failure requiring long-term hemodialysis]. AB - We report the perioperative management of a 55-year-old man with chronic renal failure requiring long-term hemodialysis, who underwent laparoscopic adrenalectomy for pheochromocytoma. He was pretreated with doxazosin, a calcium channel blocker and a beta-adrenoceptor antagonist to control blood pressure until surgery. His dry weight increased slowly from 57 kg to 58.5 kg for a month increasing the intravascular volume. Neither did the patient develop pulmonary edema nor congestive heart failure preoperatively. Tumor resection was successfully completed under general anesthesia. Although noraderenaline was required to keep adequate blood pressure during surgery and the first day of intensive care unit stay, there was no adverse event during perioperative period. The increasing intravascular volume before pheochromocytoma surgery in a patient on hemodialysis might make the perioperative management safer, although further study is required to determine the adequate level of increment in the preoperative dry weight. PMID- 20715533 TI - [Anesthetic management of an adult patient with Fontan circulation for laparoscopic surgery]. AB - Advances in the surgical and medical management of children with congenital heart disease have decreased the mortality of these patients. As a result, more patients are surviving into adulthood and are presenting for noncardiac surgery. We experienced a case of anesthetic management of an adult patient with Fontan circulation for laparoscopic surgery. A 29-year-old woman was scheduled for laparoscopic cholecystectomy for gallbladder stone. She had undergone single ventricle procedures for a tricuspid atresia, and at the time of the laparoscopic surgery, her cardiac physiology was Fontan circulation. To reduce the influence of the increased intraabdominal pressure on hemodynamics, the insufflation pressure was maintained at 8 cmH2O during pneumoperitoneum. To reduce systemic and pulmonary vascular resistance, milrinon was administered intravenously. Throughout the operation, including the period of pneumoperitoneum, the hemodynamic status remained stable, and adequate oxygenation and ventilation were maintained. The surgery ended uneventfully, and the trachea was extubated in the operating room. In anesthetic management of patients with Fontan circulation for laparoscopic surgery, it is important to understand the physiology of the circulation, and consider the influence of the pneumoperitoneum on the hemodynamics. PMID- 20715534 TI - [Continuous intrathecal anesthesia for total hip arthroplasty in a patient with ankylosing spondylitis]. AB - A 73-year-old man suffering from ankylosing spondylitis with limited motion of the whole spine was scheduled for right total hip arthroplasty. Ten years before, the patient had undergone left total hip arthroplasty under general anesthesia, in which epidural anesthesia impossible, intrathecal anesthesia insufficient, and tracheal intubation difficult. In the present operation, an 18 gauge epidural catheter was inserted into the epidural space at L3-4 using paramedian approach. Six ml of contrast medium was administered via the catheter, with high resistance on injection and the spread of epidural contrast medium was limited to L2 and L3. Therefore, the catheter was removed and reinserted into the intrathecal space at L3-4. Two ml of contrast medium demonstrated good spread in the intrathecal space from T12 to S2. Next injection of 0.5% isobaric bupivacaine 2.4ml produced bilateral cold sensory blockade from T10 to S5. Two hours after this injection, a single bolus of 1 ml followed by a continuous infusion at a rate of 0.5 ml x hr( 1) with 0.5% isobaric bupivacaine was commenced. There was no pain at rest and on movement, and no additional analgesics and hypertensive drugs were used until 4 hours following the discontinuation of the continuous intrathecal anesthesia in the morning after the operation. No adverse events including post-dural puncture headache were observed. Continuous intrathecal anesthesia may be effective for total hip arthroplasty in patients with ankylosing spondylitis. PMID- 20715535 TI - [A case of anaphylactic shock by multiple causes]. AB - We experienced anaphylactic shock after introduction of the general anesthesia twice in the same patient. After the first incidence of anaphylactic shock, we judged that the allergen was a latex. For the second time we planned the latex free environment, but the anaphylactic shock occurred again. As a result of the investigation, it turned out that the allergens were due to latex and sevoflurane. After the first incidence, it was necessary to retrieve the antigen from all the agents used. When we encounter the anaphylactic shock, it is necessary to examine all the medicines, and should have two or more suspectible medicines in mind. PMID- 20715536 TI - [Propofol-induced generalized tonic-clonic seizure: a case report]. AB - A 23-year-old man with no history of convulsion underwent removal of the nails in his upper arm. He received propofol infusion after axillary brachial plexus block. Ten minutes after propofol infusion (15 minutes after axillary block), generalized tonic-clonic seizure occurred. The rate of propofol infusion was increased, and midazolam was given intravenously ; however, the seizure continued. Propofol infusion was withheld, and anesthesia was maintained with sevoflurane. The seizure gradually decreased in 15 minutes after termination of propofol infusion, and it finally stopped 30 minutes after termination of propofol infusion. PMID- 20715537 TI - [Ultrasound-guided rectus sheath block for upper abdominal surgery]. AB - Upper abdominal surgery leads to severe postoperative pain. Insufficient postoperative analgesia accompanies a high incidence of complications. Therefore, postoperative analgesia is very important. The epidural analgesia has many advantages. However it has a high risk of epidural hematoma in anticoagulated patients. Rectus sheath block provided safer and more reliable analgesia in recent years, by the development of ultrasound tools. We experienced two cases of the rectus sheath block in upper abdominal surgery under ultrasound guidance. Ultrasound guided rectus sheath block can reduce the risk of peritoneal puncture, bleeding, and other complications. Rectus sheath block is very effective to reduce postoperative pain in upper abdominal surgery as an alternative method to epidural anesthesia in anticoagulated patients. PMID- 20715538 TI - [Ultrasound-guided combined femoral-obturator nerve block for the knee arthroscopic surgery of meniscal lesions: case report]. AB - We report successful management of anesthesia in two cases of knee arthroscopic surgery of meniscal lesions using ultrasound-guided combined femoral-obturator nerve block with inhalation anesthesia. The blocks were performed with 30 ml of 0.5% ropivacaine under ultrasonographic visualization. The perioperative courses were uneventful and there was no complaint about postoperative pain. Unlike spinal or epidural anesthesia, combined femoral-obturator nerve block has advantages of no muscle weakness in healthy lower limbs, no urinary retention, and no post dural puncture headache. Our technique relieved postoperative pain effectively because knee joint is innervated by the femoral and obturator nerves in great measure. Ultrasound-guided femoral and obturator nerve block is easier and more successful than sciatic nerve block. General anesthesia with combined femoral-obturator nerve block could be a useful technique with less complication for knee arthroscopic surgery. PMID- 20715539 TI - [Epidural labor analgesia for a primipara with schizophrenia]. AB - A 32-year-old primipara, who had been diagnosed as schizophrenia for a year and with good control of the disease by olanzapine administration, requested epidural labor analgesia. Olanzapine is an atypical antipsychotic, and is contraindicated to use with epinephrine, because the a receptor antagonistic action of olanzapine decreases the blood pressure in combination with epinephrine. Hypotention is one of the major complications during the labor epidural analgesia. In addition, this patient is at high risk of hypotension under antipsycotic medication. As hypotension leads to placental-fetal circulation insufficiency, extreme attention to prevent hypotension and to preserve uteroplacental blood flow should be paid. Olanzapine was discontinued before two days of the induction. Sufficient hydration with crystalloid was given beforehand to avoid hypotention. Both phenylephrine and norepinephrine were ready for an anticipated hypotention. Oxytocin infusion began after an epidural catheter was placed at L2-3 intervertebral space. She delivered a healthy baby under good pain control. Apgar score of the baby was 9 and 9 at 1 and 5 minutes after birth, respectively. Total volume of infusion was 2000 ml. No mental disturbance was observed during the labor and delivery. The patient and her baby were discharged on the 4th day postpartum. PMID- 20715540 TI - [Effect of training period on learning process in endotracheal intubation using Macintosh laryngoscope]. AB - PURPOSE: To determine the learning process in endotracheal intubation using the Macintosh laryngoscope, we investigated time needed for instrumentation and rate of erroneous esophageal intubation. METHODS: We compared the results of 456 endotracheal intubations by non-anesthesia residents with those of 81 endotracheal intubations by anesthesia residents. RESULTS: The mean (+/-SD) times for instrumentation were 77 +/- 46 seconds, 61 +/- 41 seconds, 41 +/- 21 seconds, and 41 +/- 22 seconds in non-anesthesia residents with training period for 1-2 month, 3-4 month, 5-6 month, and 7-8 month, respectively; while that by anesthesia residents was 41 +/- 21 seconds. No significant difference was found in the rate of erroneous esophageal intubation between non-anesthesia residents (34 times, 7.5%) and anesthesia residents (2 times, 2.5%). Of the 34 esophageal intubations by non-anesthesia residents, 26 (76.5%) occurred in the first- and second-month period. CONCLUSIONS: Two month training course for anesthesia management in our institution seems to be insufficient for learning skills in endotracheal intubation. It is most likely to require 6 months to acquire the sufficient skill in endotracheal intubation. PMID- 20715541 TI - [Retrospective investigation and analysis of dental injuries during endotracheal intubation]. AB - BACKGROUND: The objective of this study is to clarify the causes of dental injuries (DIs) developed during the direct laryngoscopy for the endotracheal intubation (EI) in our hospital. METHODS: Subjects are 4173 patients who had the EI from April 1, 2006 to March 31, 2007. Mallampati's classification and Miller's classification were used for the evaluation of difficult airway and the dental unsteadiness, respectively. RESULTS: There was no case between 10 and 40 years of age. Twelve cases (0.3%) had the DIs during the observation period. In 8 out of 12 cases (67%), EI was carried out by the residents with less than 3 months of the training period. Three cases (25%) were classified to the II or III grade. The dissociation of the evaluations by a dental anesthesiologist and medical anesthesiologists were found in two cases. Eight cases received temporary treatment by a dental anesthesiologist. CONCLUSIONS: Temporary treatment in the operating room was carried out by a dental anesthesiologist. Careful inquiry is needed for the proper preoperative teeth evaluation, especially in the schoolchild with milk teeth and elderly patients. A precise educational system for the residents is required for the prevention of DIs during the EI. PMID- 20715542 TI - [Assessment of the quality of the newly developed rapid oscillometric blood pressure measurement]. AB - BACKGROUND: The purpose of this study is to examine the accuracy of the Fukuda Denshi DS-7000 noninvasive blood pressure measurement device equipped with two cuff deflation mode: a normal mode and quick mode. METHODS: Twenty-one patients undergoing elective surgery were divided into two groups by using cardio-ankle vascular index (CAVI): no atherosclerotic group and atherosclerotic group. During anesthesia, two modes of blood pressure measurements were examined with the normal mode followed by the quick mode. RESULTS: All the patients completed the study, resulting in a total of 1034 paired blood pressure measurements. In both no atherosclerotic group and atherosclerotic group, there were statistically significant correlations among systolic, diastolic and mean blood pressure in two modes. This results certified the accuracy of the quick mode measurement. CONCLUSIONS: The newly developed rapid oscillometric blood pressure measurement can be useful for perioperative management especially in atherosclerotic patients. PMID- 20715543 TI - [Anesthesia for cesarean section: a retrospective analysis at the Center for Perinatal and Neonatal Medicine in Jichi Medical University Hospital]. AB - BACKGROUND: To evaluate obstetric and anesthetic problems relating to cesarean delivery, we investigated parturients who had undergone cesarean section at the Center for Perinatal and Neonatal Medicine in Jichi Medical University Hospital. METHODS: Obstetric and anesthetic data were gathered from January 2007 to December 2007 for all cesarean sections. RESULTS: In all, 607 parturients received cesarean section during the period. Of the 607 cesarean deliveries, 308 were performed in elective condition, and 299 were done in emergency situation. Of the 299 emergencies, 125 underwent cesarean section at nights and/or holidays. Population risk included maternal age (age >35 year, 33.1%), preterm birth (31.5%), and obesity (BMI >35 kg x m(-2), 3.3%). Complicated pregnancy included multifetal pregnancies (15.2%) and placenta previa (12.5%). CONCLUSIONS: At the center for perinatal and neonatal medicine, population risk is increasing because of increases in maternal age, obesity, placenta previa, and rates of multifetal pregnancies. PMID- 20715544 TI - [Discussion on evidence for principle of tuberculosis contact investigation--from the experience in Osaka City]. AB - Risk factors for tuberculosis transmission from patients to contacts were found to be younger age, presence of cavitary lesion in chest X-ray findings, shedding higher number of organisms, longer duration of respiratory symptoms, longer hours of contact, and smaller space of contact environment. It should be noted that even casual contacts identified by contact investigation developed tuberculosis later on. In the past contact investigation and subsequent latent TB infection (LTBI) treatment, preventive effects of tuberculosis was obvious, although there might be some over-diagnosis of LTBI with tuberculin skin testing (TST). Introduction of interferon-gamma release assay (IGRA) added to TST seems to increase specificity and reduce over-diagnosis of TB infection. However in case of outbreak investigation in schools, screening by TST is still effective and efficient. Only those case with 30mm or over of redness (equivalent of 15 mm of induration) of TST were tested with QFT, IGRA. If anyone shows positive QFT, test of QFT would be expanded to the contact with TST of less than 30 mm. PMID- 20715545 TI - [Interpretation of QFT results in several contact investigations]. AB - QuantiFERON TB-2G (QFT-2G) is now widely used for contact investigations, as QFT 2G is not affected by BCG vaccination, whereas the conventional tuberculin skin test (TST) is confounded by BCG vaccination. We applied the QFT-2G tests to numerous contact investigations and found that the majority of contacts who had been supposed to be infected with M. tuberculosis (Mtb) based on TST were negative in the QFT-2G tests, strongly suggesting the possibility that the unnecessary preventive chemotheraphy was indicated for many TST positive contacts due to BCG vaccination in conventional contact investigations. Although QFT-2G positive results implicate that Mtb in certain active phases presents in the body, when Mtb had been infected cannot be decided by QFT-2G. Therefore, QFT-2G results should be carefully interpreted, especially in elder persons who had been exposed to Mtb in the past in Japan. Furthermore, since there were some active TB cases in QFT-2G negative contacts, attention must be paid for QFT-2G negative contacts in highly exposed groups. In this paper, I will discuss about current usages of QFT-2G based on our experiences of contact investigations. PMID- 20715546 TI - [Tuberculosis contact examination and QFT-G testing for the prevention of hospital acquired infection]. AB - Hospital acquired infection mainly occurs at hospitals, not clinics. In Japan, QFT-G is the main tool for the diagnosis of tuberculous infection among health care workers. Contact examinations are basically done for contacts of sputum smear positive TB cases, but infection may occur at fiberbronchoscopy of sputum smear negative TB cases and at the time of irrigation of TB abscess. Therefore, contact examination requires bigger target group than usual contact examinations. Mathematical model analysis of cost effectiveness examination showed that contact examinations at the age of 20s to 40s will be cost saving if it is done for the contacts with the risk of infection of 6% and beneficial for the DALY lost due to TB infection if it is done for the contacts with the risk of infection of 3%. Addition of baseline QFT for the HCWs at the age of 20s requires 100 million yen for the recovery of 1 DALY lost due to hospital acquired TB infection. Also mathematical modeling showed that periodical QFT testing of HCWs at the age of 20s to 40s will be beneficial for the DALY lost due to TB infection if the annual risk of infection will be around 2% and will be cost saving if the annual risk of infection will be around 8%. Therefore, periodical QFT is recommended for the staff working at the environment with high risk of infection (around 2% per year). PMID- 20715547 TI - [Detection of molecular epidemiology of Mycobacterium gordonae isolates]. AB - OBJECTS: To analyze the molecular epidemiology of Mycobacterium gordonae strains from patients and environments in the hospital. SUBJECTS: A total of 46 clinical strains were obtained from patients registered at the NHO Kinki-chuo Chest Medical Center and 3 strains from hospital environments. METHODS: By using genetic data from the 16S rRNA gene and hsp65PRA, pulsed-field gel electrophoresis (PFGE) assessment of their intraspecies variability and epidemiology was carried out. RESULTS: Strains from six patients and environmental cultures exhibited the different genotypes of 16S rRNA gene sequencing and the hsp65PRA type. The PFGE analysis suggested no pseudo-outbreak and showed a polyclonal infection in one patient. CONCLUSION: These findings suggest that we should maintain effective surveillance of environments in the hospital and continuously perform molecular epidemiological investigations for infection control of M. gordonae. PMID- 20715548 TI - [Integration of tuberculosis care into general hospitals in the United States]. AB - PURPOSE: In Japan we are now urged to rethink and reform the present ward centered institutional system of clinical service for tuberculosis (TB). To provide useful information for this rethinking and reform, we performed a literature review of the process of integrating TB service into general hospitals in the US. METHOD: Literature review. RESULT: The process of integrating TB service into general hospitals in USA began around 1970, and continued until around 1980, when it was almost complete. From the experience and opinions of the authors reviewed, the following points were found to be important to successful integration: establishing an efficient outpatient department, maintaining patients' adherence to treatment, using a long-term care facility for TB patients requiring long-term in-hospital care, planning a program for integration of care fully in advance, individualizing the program according to the region, adopting a phased step-by-step program, educating hospital staff and securing financial support from governments. CONCLUSION: The reform of tuberculosis wards in Japan will occur at the same time as the reform of the country's TB control program, and will provide a good opportunity to improve our program. PMID- 20715549 TI - [Start of TB case-registration and case-management system in Japan]. AB - TB control in Japan started in 1951 through legislation of TB Control Law, consisting of three major components; mass health examination, vaccination and promotion of adequate methods of treatment for TB cases. Mass health examination was first targeted for younger generation below 30 years of age as it was believed that TB was highly prevalent among them, however, it was expanded to cover whole population based on the results of TB Prevalence Survey in 1953 revealing high prevalence of TB in all age groups except children and low awareness of TB cases. Methods of treatment for TB were developing rapidly in late 1950s and early 1960s; initially artificial pneumothorax, then surgical collapse treatment such as thoracoplasty, then pulmonary resection, and finally long term combined use of INH, SM and PAS. Up to surgical treatment era, most TB patients earnestly followed doctor's instruction, however, in chemotherapy era, as most symptoms improved rapidly after the initiation of chemotherapy, patients felt as if they were cured, and it had become difficult to maintain high adherence to treatment. Such behavior was found oftener in patients detected in early stage through mass health examinations. 1947, it was legislated for all doctors to report all diagnosed TB cases to an adjacent health center, and the cases are registered at the health center covering his (her) residence, however, standardized formula of registration was not indicated. In accordance with the progress of TB control program, the number of TB registered cases increased, and the need for standardized registration and case-management had become apparent in mid 1950s, and some preliminary trials had been done. In response to this request, the Ministry of Health and Welfare organized a research group headed by Dr. Misonou K, and the staffs of prefectural health department and enthusiastic staffs working in health centers (HCs), staffs of NIPH (National Institute of Public Health) and RIT (Research Institute of Tuberculosis) to study how to register TB cases, how to collect information and how to improve patients' adherence to treatment. Registration index cards were prepared in each HC arranged alphabetically to avoid double register. The formula of registration card was indicated in Fig. 1 and 2. Small hollows were made in the lower part of the card, and registration card container with 45 metal bars in the bottom as shown in Fig. 3 was prepared. By setting 30 cards dislocating one each hollow as shown in Fig. 3, in one card container with 30 rows, altogether 600 registration cards were stored. In most right part of the card, important information such as activity of the case, treatment status, expected time of next home visit, expiring time of public support for TB treatment, etc. are indicated by different color metal signals. This new system was applied in 216 HCs, about one fourth of all HCs in Japan in 1959, another 200 HCs were added in 1960, and finally from 1961, the new system of registration and case-management started in the whole country after making minor amendments based on experience in 1959 and 1960. Quality of TB case-management improved much after the introduction of new system, and annual statistics not only newly registered TB cases but also on prevalence of active as well as registered cases was available since then, and this was the starting point of TB surveillance system started in 1986. PMID- 20715550 TI - [Tuberculosis Annual Report 2008--Series 9. Treatment of TB (2)]. AB - The standard treatment for tuberculosis (TB) is the key to its control. Here we report on the statistics of treatment status and the duration of hospitalization/treatment. The place of initial treatment was observed among newly notified TB patients (n = 24,760) in 2008. Of those, the proportion receiving treatment in hospital among sputum smear positive pulmonary TB patients was the most (91.7%), including 2.1% hospitalized mainly due to other diseases. The proportion receiving treatment in hospital among bacteriologically negative pulmonary TB cases was the least (25.8%), including 10.3% hospitalized mainly due to other diseases. This proportion of patients receiving treatment in hospital did not differ with age, among sputum smear positive pulmonary TB cases. But, this proportion differed greatly in their age groups (e.g. 9.9% in their 20s, 25.7% in their 50s and 50.0% in their 80s), among bacteriologically negative pulmonary TB cases. The duration of hospitalization for TB treatment among newly notified cases in 2007 was observed at the end of 2008. The median hospitalization periods were 69 days, 74 days, 45 days, 38 days and 45 days, among new sputum smear positive pulmonary TB cases, retreatment sputum smear positive pulmonary TB cases, other bacillary positive pulmonary TB cases, bacilli negative pulmonary TB cases and extra-pulmonary TB cases, respectively. The duration of TB treatment among newly notified cases in 2007 was observed at the end of 2008. The median treatment duration among all forms of TB was 273 days. The longest median treatment duration was 298 days for retreatment sputum smear positive pulmonary TB cases and the shortest was 204 days for bacteriologically negative pulmonary TB cases. PMID- 20715551 TI - [Prognostic lung abscess factors]. AB - BACKGROUND: Lung abscess, although curable when caught early and treated appropriately, still may recur repeatedly or require surgery. We retrospectively assessed prognostic lung abscess factors and predictive recurrence factors. We evaluated comorbidity using the Charson comorbidity index (CCI). METHODS: Subjects numbered 44 hospitalized for lung abscesses between June 2004 and May 2009 and classified as; elderly (over 65 years) or non-elderly and cured treatment failed. RESULTS: Mean age and the CCI of failed treatment were statistically higher than in cures at 80.8 years and 3.25 vs 64.1 years and 1.25 (p < 0.05). Abscess location, smoking habits, symptoms, white blood cell count and C-reactive protein did not differ on day 1. The causative organism, fistula presence at 65.6% vs 45.5% (p = 0.30) and lesion size at 59.8 mm vs 71.6 mm (p = 0.14) did not differ between groups, but the degree of lesion size reduction in treatment failures was lower than cures at 24.9% vs 69.1% (p < 0.05). CONCLUSIONS: Lung abscess prognosis is thus adversely affected by age and comorbidity. In Japan, subjects having multiple comorbidities are expected to increase with aging. The degree of lesion size reduction appears to be a predictive factor in recurrence, underscoring the importance of follow-up in imaging, including chest computed tomography. PMID- 20715552 TI - [Rapid detection of novel influenza A virus and seasonal influenza A (H1N1, H3N2) viruses by reverse transcription-loop-mediated isothermal amplification (RT LAMP)]. AB - Reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay we developed detects novel influenza A (H1N1) of swine origin and seasonal influenza A (H1N1 and H3N2) viruses. Individual primer sets targeting the HA gene for novel H1N1, H1N1, and H3N2 were newly designed to specifically detect these subtypes. No cross-reactions occurred among novel H1N1, H1N1, and H3N2, and 7 respiratory viruses-influenza B virus, influenza C virus, adenovirus, respiratory syncytial virus, metapneumovirus, parainfluenza virus, and rhinovirus-had no reaction to 3 RT-LAMP assays. RT-LAMP is assayed at 63 degrees C for 40 min. In our RT-LAMP assay, Eriochrome Black T was added to the reaction mixture as an amplification indicator to detect virus genomes without using real-time turbidimetry. Positive reactions were indicated in blue and negative reactions remained purple. Of 139 samples from suspected novel H1N1 subjects tested by both RT-LAMP and real-time RT-PCR assay, 110 were positive in both assays. Two samples with low copy numbers were positive only in real-time RT-PCR assay. Of 27 novel negative H1N1 samples, 4 were positive for H3N2 on viral isolation and conventional RT-PCR assay. RT LAMP assay for detecting H3N2 obtained the same findings. Our RT-LAMP assay is thus potentially useful in rapidly detecting influenza A virus such as novel H1N1, H1N1, and H3N2. PMID- 20715553 TI - [Clinical usefulness of procalcitonin measurement]. AB - Procalcitonin (PCT) was initially described as a calcitonin prohormone and later shown to be a useful marker for identifying bacterial infection and sepsis. We evaluated PCT's clinical efficacy in assessing bacterial infection severity, measuring PCT and systemic inflammatory response syndrome (SIRS) markers in 180 subjects with suspected infection. PCT titer was higher with increasing infection severity. PCT was thus useful in identifying those in critical condition. PMID- 20715554 TI - [Susceptibility testing for Haemophilus influenzae isolated from pediatric cases during 2004-2008]. AB - We tested for antimicrobial susceptibility of 1,317 clinical isolates of Haemophilus influenzae at a pediatric facility during 2004-2008. The percentage distribution of beta-lactamase-non-producing ampicillin (ABPC)-sensitive strain (BLNAS) was 47.8%, that of beta-lactamase-non-producing ABPC-resistant strain (BLNAR) 32.7% that of intermediately resistant strain (BLNAI) 8.9% that of beta lactamase producing ABPC resistant strain (BLPAR) 6.8% and that of clavulanic acid/amoxicillin resistant strain (BLPACR) 3.7%. BLNAR prevalence was 30% between 2005 and 2008, increasing slowly. Though reduced susceptibility was seen in most beta-lactams, piperacillin and tazobactam/piperacillin showed good susceptibility for H. influenzae. Of 1,317 strains, 83 (6.3%) were serotype b (Hib). The frequency of Hib was high in sterilized site. PMID- 20715555 TI - [Influenza vaccination safety during pregnancy]. AB - Increased morbidity and mortality in pregnant women were reported following three major historical influenza pandemics. To prevent influenza infection during pregnancy, the Centers for Disease Control (CDC) and the American College of Obstetricians and Gynecologists (ACOG) recommend that all pregnant women and those intending to get pregnant during the influenza season be vaccinated. In 2004, they advised expanding vaccination guidelines from the second and third trimester to all three trimesters. We evaluated the safety of influenza vaccination during pregnancy in 182 subjects from 2007-2009. No adverse events were seen in pregnancy or fetal medical condition regardless of the pregnancy stage at which vaccine was administered. PMID- 20715556 TI - [A case of classical tsutsugamushi disease confirmed after an interval of 15 years in Akita Prefecture, Japan]. AB - We report the confirmation of classical tsutsugamushi disease in August 2008. A 17-year-old woman seen for fever and eschar on the back reported having been bitten by an insect nine days earlier while fishing on the Omonogawa river. The suspected culprit was Leptotrombidium akamushi. During convalescence serum IgM and IgG antibody titers rose significantly against the Kato serotype antigen in indirect immunoperoxidase staining. Epidemiology, clinical symptoms and the antibodies detected suggested classical tsutsugamushi disease infection. Such disease transmitted by L. akamushi have not been reported since 1993 in Akita Prefecture. The public should thus be informed about Orientia tsutsugamushi prevention, in case such disease re-care in this area in the future. PMID- 20715557 TI - [A Japanese patient with chikungunya fever returning from Flores Island, Indonesia]. AB - We report a case of chikungunya fever, rarely seen by Japanese physicians. A 35 year-old Japanese man admitted September 12 for a 3-day fever had traveled to Flores island, Indonesia, July 14-Sep. 10. He had bilateral wrist arthralgia, mild bilateral finger swelling, and nonitching skin eruptions on the face, trunk, and both arms. The viral chikungunya genome was identified in serum on Sep. 12. Negative serum an-tichikungunya virus IgM antibodies on Sep. 12 became positive on Sep. 14, yielding the suspected diagnosis. Given the many Japanese visiting endemic chikungunya fever areas, Japanese physicians must learn to recognize such cases among travelers returning from such areas with fever, arthralgia, and skin eruptions. PMID- 20715558 TI - [Group B streptococcal bacteremia in a 10-year-old girl undergoing corticosteroid therapy]. AB - Group B streptococcus (GBS), a major cause of neonate and pediatric sepsis and meningitis, rarely causes invasive infection beyond infancy. We report the case of a 10-year-old girl developing GBS bacteremia during corticosteroid therapy for chronic idiopathic thrombocytopenic purpura. Brought to the emergency room due to sudden high fever and abdominal pain, she was in compensated shock. White blood cell count was 19,600/mm3 and C-reactive protein 0.18 mg/dL. She was diagnosed with sepsis and admitted for evaluation. Cefotaxime (100 mg/kg/day) administration and fluid replacement were begun immediately after blood culture. Her condition improved over the next 6 hours and she was afebrile by the next day. GBS isolated from blood had a serotype of Ib. Based on routine susceptibility testing, this strain was susceptible to penicillin, cephem, carbapenem, erythromycin, clindamycin, and vancomycin, but resistant to quinolone, including levofloxacin (MIC > or = 8.0 microg/mL) and gatifloxacin (MIC > or = 4.0 microg/mL). She was discharged on hospital day 8. This is, to our knowledge, the first report of pediatric meningitis-free GBS bacteremia in Japan. Physicians should therefore be aware of the possibility of invasive GBS infection such as bacteremia in this age group, especially during immunosuppressive therapy, because epidemiological studies in the US have showed significant mortality in those aged 1 to 14 years old with invasive GBS. PMID- 20715559 TI - [Two cases of pulmonary amebiasis]. AB - CASE 1: A 74-year-old man having a week's fever and diagnosed with a liver abscess was treated with several antibiotics and percutaneous liver drainage. His respiration gradually worsened and chest computed tomography (CT) showed right pleural effusion and a left-lung mass. Percutaneous fine needle aspiration of the pulmonary mass detected Entamoeba histolytica. CASE 2: A 44-year old, zoo office worker admitted for fever and right chest pain was found in CT to have right pleural effusion and a mass with a liver abscess necessitating abscess drainage. Injected contrast medium detected a fistula connected to the right. Following surgical drainage, E. histolytica was detected from the resected lung. Both cases responded well to metronidazole. PMID- 20715560 TI - [Three cases of acute conjunctivitis caused by human adenovirus in medical workers]. AB - We report three cases of acute conjunctivitis due to different types of human adenovirus (HAdV) in medical workers. Case 1: A 37-year-old man had epidemic keratoconjunctivitis and urethritis caused by human adenovirus type 37 (HAdV-37). Case 2: A 27-year-old woman had acute conjunctivitis due to human adenovirus type 15 (HAdV-15), Case 3:A 32-year-old woman had acute follicular conjunctivitis leading to a serotype of human adenovirus-53 serotype (HAdV-53). Note that HAdV 37 infection may cause keratoconjunctrivitis and urethritis. HAdV-15, -37, and 53 are important causative agents of nosocomial outbreak, and the application of a rapid diagnostic kit or PCR to a rapid diagnosis and proper infection-control measures can significantly reduce infection spread. PMID- 20715561 TI - [Rabies pre-exposure immunization effects on rabies post-exposure prophylaxis]. PMID- 20715562 TI - [The influence of oxidized DNA on mammalian genome]. PMID- 20715563 TI - [Is whole body bone mineral density measured by the dual energy X-ray absorptiometry applied to evaluate risk of osteoporosis among Japanese adult females?]. AB - To measure whole body fat accurately, the dual energy X-ray absorptiometry (DXA) is widely utilized. Simultaneously, bone mineral density (BMD) of the whole body can also be measured. BMD is one of important information to diagnose osteoporosis. However, it is not established to use whole body BMD for this diagnosis. It is recommended that lumbar and/or hip BMD should be used for diagnosing osteoporosis by the guideline for prevention and treatment of osteoporosis. Although it is possible to measure whole body BMD and lumbar and/or hip BMD separately at the same visit, it is inevitable to expose patients to more X-ray. Therefore, an aim of this study is to elucidate the relationship between whole body BMD and lumbar BMD to find the cut off point of whole body BMD for screening of osteoporosis. Two hundred and thirty six Japanese adult females were ascertained to this study. Whole body BMD and lumbar BMD of each subject were measured with the use of Delphi W (Hologic, USA). One hundred and sixty five subjects were judged as possible osteoporosis (less than 80% of young adult mean (YAM) of lumbar BMD and/or definite fracture of lumbar vertebras). The cut off point of whole body BMD for screening possible osteoporosis was estimated by receiver operated characteristic (ROS) analysis. The cut off point of whole body BMD was 84% of YAM, equivalent to 80% of YAM of lumbar BMD, with the following sensitivity and specificity (0.84 and 0.79, respectively), indicating that whole body BMD could be used for screening osteoporosis. PMID- 20715564 TI - [High-dose-rate brachytherapy with external beam radiotherapy for localized or locally advanced prostate cancer]. AB - PURPOSE: To evaluate the therapeutic outcomes and late toxicities in patients treated by high-dose-rate brachytherapy (HDR-BT) with external beam radiotherapy (EBRT) for localized or locally advanced prostate cancer. MATERIALS AND METHODS: From May 2004 to September 2008, 86 men were treated by HDR-BT with EBRT for localized or locally advanced prostate cancer at the National Hospital Organization Kyushu Medical center. The median EBRT and HDR-BT doses were 40 Gy and 30 Gy, respectively. RESULT: With a median follow-up of 24 months, the 3-year overall, disease specific, and biochemical relapse-free survival rates in all patients were 97.3%, 100%, and 83.6% respectively. The 3-year biochemical relapse free survival rate of the patients categorized to low or intermediate risk group (91.8%) was significantly better than that of the patients categorized to the high risk group (74.3%) (p = 0.042). There was no significant difference of biochemical relapse-free survival regarding to the other clinical factors (age, T stage, Gleason score, initial prostate-specific antigen level, neoadjuvant hormone therapy, and total dose of EBRT and HDR-BT). Late Grade2 and Grade3 gastrointestinal toxicities were observed in 8 patients (9.3%) and 2 patients (2.3%), respectively. Late Grade2 genitourinary toxicities were observed in 12 patients (13.9%). There was no patient suffered from late Grade3 or greater genitourinary toxicities. CONCLUSION: HDR-BT with EBRT can be safe and effective for localized or locally advanced prostate cancer. PMID- 20715565 TI - A comparison between D2-40 and c-KIT immunohistochemistry for the human fetal testis and ovary at the second trimester of gestation. AB - Both M2A (D2-40) and c-KIT have frequently been used as markers of germ cell tumors. However, comparative studies of their immunoreactivities in human fetal gonads have been limited. Using horizontal semiserial whole-abdomen sections of 9 human abortuses at 12 weeks (2 males and 1 females; CRL 70-80 mm), 15 weeks (2 males and 3 females; 115-125 mm) and 18 weeks (1 female; 155 mm) of gestation, we identified germ cells in the testis and ovary on the basis of c-KIT immunoreactivity. M2A was also stained using near or adjacent sections. In 12 week fetuses, c-KIT immunoreactivity was weak, but M2A immunoreactivity was consistently strong. At 15 and 18 weeks of gestation, c-KIT immunoreactivity was found in most germ cells. M2A was expressed in Sertoli cells as well as in germ cells, but was not expressed in ovarian follicles undergoing meiosis. M2A appears to be a more useful marker of germ cells than c-KIT in human fetal testis and ovary at the second trimester. M2A is also reactive in fetal Sertoli cells, but its expression is consistently weaker than in germ cells. PMID- 20715566 TI - Developmental changes in the distribution of calretinin-immunoreactive cells in human fetal nasal epithelium. AB - Immunoreactivity of the calcium binging protein calretinin is often used as a marker of olfactory neurons. Although the immunoreactivity and density of olfactory neurons are known to change between developmental stages in the human fetus, previous descriptions have been limited to the olfactory epithelium and/or the nasal septum and have not included the entire nasal cavity. Using horizontal semi serial sections of heads of six mid-term fetuses (9-15 weeks of gestation), we examined the topographical anatomy of calretinin-positive olfactory neurons. By 9 weeks of gestation, the distribution of calretinin-positive cells reached levels inferior to the developing inferior meatus. By 12 weeks, concentrations in the inferior end had reached the level of the inferior meatus and the middle meatus carried abundant positive cells. However, by 15 weeks, calretinin positive cells were restricted to levels superior to the middle meatus and in the vomeronasal organ. Placode-derived cells are initially distributed antero inferiorly along the nasal epithelium, but most lose their calretinin immunoreactivity. They might differentiate into the neuroendocrine cells embedded between nasal respiratory epithelial cells. The final differentiation of calretinin-positive cells was likely to require connection to the olfactory bulb and accessory bulb. PMID- 20715567 TI - Migration and distribution of neural crest-derived cells in the human adrenal cortex at 9-16 weeks of gestation: an immunohistochemical study. AB - Neural crest-derived cells are believed to migrate into the fetal adrenal cortex from the medially-located hilus. However, there appears to be a paucity of observations of the migration and distribution of medullary cells in humans. In sagittal as well as horizontal sections of human fetuses between 9 and 16 weeks of gestation, we identified chromaffin, ganglion and Schwann-like cells in the developing adrenal gland using immunohistochemistry. Cells showing tyrosine hydroxylase (TH) immunoreactivity (i.e., candidate ganglion cells) entered the fetal cortex mainly from the medial half of the adrenal, but the path of entry also included the ventral, dorsal and caudal aspects. These cells displayed linear arrangements, forming a connection between the peripheral and central areas of the gland. S100 protein-immunoreactive cells (i.e., Schwann-like cells) accompanied most (but not all) of the TH-positive cells. The distribution of chromogranin A-immunoreactive cells (i.e., chromaffin cells) was similar to and overlapped with that of TH-positive cells. Chromogranin A-positive cells were observed around the aorta as well as in the adrenal. The entry of neural crest derived cells does not appear to be restricted to a hypothetical medial hilus, but occurs widely around the cortex, with or without the accompaniment of Schwann like cells. These cells advance in lines through the fetal cortex in a cord-like arrangement without destruction of the cortical architecture. Some of the TH positive cells very likely express chromogranin A before entry into the adrenal. PMID- 20715568 TI - Retinopetal neurons located in the diencephalon of the Japanese monkey (Macaca fuscata). AB - After a monocular injection of the cholera toxin B subunit (CTB) into the vitreous chamber of one eye, the retrogradely labeled retinopetal neurons were studied in the diencephalon of the Japanese monkey. The retrogradely transported tracer was visualized using the peroxidase antibody technique and an anti-cholera toxin antibody. The CTB-labeled nerve cell bodies were scattered in the periventricular nucleus of the hypothalamus, lateral hypothalamic area, and midline nuclei of the thalamus on both sides. In addition, a few retrogradely labeled nerve somata were observed in the most rostral portion of the lateral geniculate nucleus on the contralateral side. PMID- 20715569 TI - Study of delayed development of the upper first molars. AB - The present study was undertaken to analyze the status of formation of the upper first molar in individuals suspected as having delayed eruption of the upper first molar. The subjects of this study were 51 patients presenting to orthodontic specialists with delayed eruption of the upper first molars. The 95 teeth of these 51 patients were observed. The investigation of the tooth development status included evaluation of the tooth development stage on panoramic radiographs according to the method of Moorrees et al. The upper first molars that showed delayed development were at the stage of initial cleft formation, reflecting a delay by 2.09 years in boys and 2.84 years in girls. In most cases, the delayed eruption was bilateral, and the development stage of the subject teeth did not differ between right and left sides. The plot of the developmental stage of the subject teeth (Y-axis) against the calendar age of the subjects (X-axis) showing delayed upper first molar development was fitted to the logistic curve. The tooth development was at the stage of initial cleft formation was delayed 2.5 years or more, according to these curves. PMID- 20715571 TI - [Metabolism, functions, and related diseases of fatty acids]. PMID- 20715570 TI - [Localization, ion transport activity, and physiological function of mammalian organellar NHEs]. PMID- 20715572 TI - [Tri-split tRNA: a transfer RNA encoded on three separate genes found in hyperthermoacidophilic archaeon Caldivirga maquilingensis]. PMID- 20715573 TI - [Two faces of Janus: Recent studies on the characteristics of E. coli GroEL and its apical domain]. PMID- 20715574 TI - [Pyrrolysyl-tRNA synthetase-tRNA(Pyl) structure reveals the molecular basis of orthogonality]. PMID- 20715575 TI - [Functions and biosynthesis pathway of sulfur-modifications in tRNA]. PMID- 20715576 TI - [D-serine in the pathogenesis of amyotrophic lateral sclerosis]. PMID- 20715577 TI - [Variation and function of splicing isoforms of kinesin motor KIF1B]. PMID- 20715578 TI - [Regulation of G protein-coupled receptor endocytosis via ubiquitination]. PMID- 20715579 TI - [Prediction of protein motif activities and signal transduction research]. PMID- 20715580 TI - [Development of molecules binding to mismatched base pairs: application to the detection of gene mutation and PCR monitoring]. PMID- 20715581 TI - [Causes and differential diagnosis of AKI/acute renal failure]. PMID- 20715582 TI - [Drug induced AKI]. PMID- 20715583 TI - [Acute kidney injury (AKI) after severe cardiac damage]. PMID- 20715584 TI - [Acute kidney injury due to glomerulonephritis]. PMID- 20715585 TI - [Acute kidney injury: prevention and treatment update]. PMID- 20715586 TI - [Mechanism of renal tubular regeneration in acute kidney injury]. PMID- 20715587 TI - [Pathophysiology of sepsis induced acute kidney injury]. PMID- 20715588 TI - [Early biomarker for AKI]. PMID- 20715589 TI - [Case of MMF monotherapy for membranous nephropathy]. AB - We report the case of a 58-year-old male patient who visited our hospital for the management of edema and proteinuria. He was diagnosed as having nephrotic syndrome, with serum total protein and albumin levels of 4.6 g/dL and 2.1 g/dL, respectively, and a urinary protein excretion level of 6.0 g/day. A percutaneous renal biopsy showed features of membranous glomerulonephritis, with capillary wall granular deposits of IgG and C3 on immunofluorescence and subepithelial immune complex deposits on electron microscopy. No other secondary cause of membranous glomerulopathy was found even after extensive investigations. The patient was started on mycophenolate mofetil (MMF) monotherapy (1,500 mg/day), and 18 months after the start of this therapy, the proteinuria decreased to 0.5 g/day, with return to a normal serum albumin level. No digestive symptoms, kidney function worsening or increase in blood pressure were noted during treatment. These findings suggest that MMF monotherapy is effective and safe for the treatment of membranous nephropathy. PMID- 20715590 TI - [Case of bladder pheochromocytoma with familial clustering]. AB - We report herein a rare female case of bladder pheochromocytoma with familial clustering. Her mother had received an operation for bladder pheochromocytoma. When the present case was 20 years of age, body weight loss and fever appeared. Thereafter, nausea, vomiting and palpitation occurred especially at urination, and hypertension and tachycardia emerged. She was referred to our hospital for a further check up of hypertension at the age of 28 years. Her blood pressure was 176/130 mmHg, and pulse rate, 103/min. Hemorrhage and hard exudate were observed at the optic fundi. Twenty-four-hour ambulatory blood pressure monitoring disclosed that her hypertension was characterized by non-dipper type features and transient increases in both blood pressure and pulse rate occurring, especially at urination. Plasma noradrenalin level (14,399 pg/mL)was remarkably elevated, although the plasma adrenalin level (52 pg/mL) was within the normal limits. Computed tomography (CT) showed a mass lesion (7 cm in diameter) with central necrosis in the urinary bladder. 123I-MIBG showed strong uptake in the mass detected by CT. Venous blood sampling disclosed that the plasma noradrenalin concentration was highest at the lower level of the inferior vena cava. Therefore, a diagnosis of bladder pheochromocytoma with familial clustering was made and the pheochromocytoma was surgically removed. PMID- 20715591 TI - [Ratio of serum levels of 1,25-dihydroxyvitamin D3 and parathyroid hormone for the diagnosis and treatment of tuberculous peritonitis in a chronic kidney disease patient: a case report]. AB - An 80-year-old man was admitted to our hospital because of exacerbation of preexisting chronic kidney disease (CKD). On admission, he showed elevated levels of serum creatinine (6.37 mg/dL) and corrected calcium (13.7 mg/dL). Although the serum levels of intact parathyroid hormone (I-PTH) and parathyroid hormone related peptide(PTITH-rP)were low, the serum 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3)levels were high. Computed tomography (CT) revealed ascites, and the ascitic fluid was exudative and serous with predominance of lymphocytes. The levels of adenosine deaminase (ADA) in the ascitic fluid were also elevated, and the results of QuantiFERON-TB2G (QFT-2G)assay were positive, indicating tuberculous peritonitits. Ascites resolved rapidly after initiation of the antituberculosis therapy. The elevated levels of serum calcium and 1,25 (OH) 2D3 returned to below-normal levels; however, serum i-PTH levels increased from 8.9 pg/ mL to 432 pg/mL. Diagnosis of extrapulmonary tuberculosis is often difficult in CKD patients. CKD patients show abnormal vitamin D activation, so these patients usually have low levels of serum 1,25(OH)2D3. On the other hand, in our patient, 1,25(OH)2D3 was extrarenally produced from tuberculous granuloma and therefore, he showed high levels of serum 1,25(OH)2D3 and correspondingly, low levels of serum i-PTH. We observed that the ratio of 1,25 (OH) 2D3:i-PTH decreased due to antituberculosis therapy. This ratio facilitated the diagnosis and evaluation of treatment for this condition. PMID- 20715592 TI - [Case of AL amyloidosis associated with a remarkable histological progress in a short period]. AB - AL amyloidosis is the most common form of systemic amyloidosis. Although kidney biopsy often is the method by which the disease is identified, small amounts of amyloid in kidney biopsy specimens may be missed on routine examination unless specifically investigated. We present here a previously healthy 60-year-oldmissed on routine examination unless specifically investigated. We present here a previously healthy 60-year-old man who developed nephrotic syndrome. His first renal biopsy showed minimal change nephrotic syndromeman who developed nephrotic syndrome. His first renal biopsy showed minimal change nephrotic syndromesuggesteda subtle depost ommon formsystemicamyloidfibrilhediminationof an early lesion of renal amyloido-s (MCNS). Proteinuria remained refractory to immunosuppressive treatments. Six months later, a repeat renal biopsy clearly showed AL amyloidosis. Re-examination of the first biopsy in the light of the final diagnosis again suggested a subtle deposition of amyloid fibrils. The discrimination of an early lesion of renal amyloidosis with MCNS may often be difficult. It is necessary to maintain a high level of alertness for amyloidosis especially in aged patients with nephrotic syndrome and to consider a repeat biopsy in steroid-resistant cases. PMID- 20715593 TI - Moving ahead with maternal, infant, and young child nutrition: need to integrate actions. PMID- 20715594 TI - Maternal iron-folic acid supplementation programs: evidence of impact and implementation. AB - BACKGROUND: According to a World Health Organization (WHO) review of nationally representative surveys from 1993 to 2005, 42% of pregnant women have anemia worldwide. Almost 90% of anemic women reside in Africa or Asia. Most countries have policies and programs for prenatal iron-folic acid supplementation, but coverage remains low and little emphasis is placed on this intervention within efforts to strengthen antenatal care services. The evidence of the public health impact of iron-folic acid supplementation and documentation of the potential for scaling up have not been reviewed recently. OBJECTIVE: The purpose of this review is to examine the evidence regarding the impact on maternal mortality of iron folic acid supplementation and the evidence for the effectiveness of this intervention in supplementation trials and large-scale programs. METHODS: The impact on mortality is reviewed from observational studies that were analyzed for the Global Burden of Disease Analysis in 2004. Reviews of iron-folic acid supplementation trials were analyzed by other researchers and are summarized. Data on anemia reduction from two large-scale national programs are presented, and factors responsible for high coverage with iron-folic acid supplementation are discussed. RESULTS: Iron-deficiency anemia underlies 115,000 maternal deaths per year. In Asia, anemia is the second highest cause of maternal mortality. Even mild and moderate anemia increase the risk of death in pregnant women. Iron-folic acid supplementation of pregnant women increases hemoglobin by 1.17 g/dL in developed countries and 1.13 g/dL in developing countries. The prevalence of maternal anemia can be reduced by one-third to one-half over a decade if action is taken to launch focused, large-scale programs that are based on lessons learned from countries with successful programs, such as Thailand and Nicaragua. CONCLUSIONS: Iron-folic acid supplementation is an under-resourced, affordable intervention with substantial potential for contributing to Millennium Development Goal 5 (maternal mortality reduction) in countries where iron intakes among pregnant women are low and anemia prevalence is high. This can be achieved in the near term, as policies are already in place in most countries and iron folic acid supplements are already in lists of essential drugs. What is needed is to systematically adopt lessons about how to strengthen demand and supply systems from successful programs. PMID- 20715595 TI - Effects of docosahexaenoic acid supplementation during pregnancy on gestational age and size at birth: randomized, double-blind, placebo-controlled trial in Mexico. AB - BACKGROUND: The need for omega-3 fatty acids, especially docosahexaenoic acid (DHA), during pregnancy has received much attention, but evidence of effects on birth outcomes is limited. OBJECTIVE: To evaluate whether prenatal DHA supplementation increases gestational age and birth size. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in Cuernavaca, Mexico. We randomly assigned 1,094 pregnant women (18 to 35 years of age; median DHA dietary intake, 55 mg/day) to 400 mg/day of algal DHA or placebo from 18 to 22 weeks of gestation through delivery. Birth outcomes (968 live births and 5 stillbirths) were ascertained from hospital records within 24 hours of delivery. RESULTS: Intention-to-treat analysis showed no differences between the control and DHA group (all p > .05) in mean gestational age (39.1 + 1.7 and 39.0 +/- 1.9 weeks, respectively), weight (3.20 + 0.47 and 3.21 +/- 0.45 kg, respectively), length (50.3 +/- 2.7 and 50.3 +/- 2.3 cm, respectively) and head circumference (34.3 +/- 1.8 and 34.3 +/- 1.5 cm, respectively) at birth. Offspring of supplemented primigravidae (n = 370) were heavier (difference, 99.4 g; 95% CI, 5.5 to 193.4) and had larger head circumferences (difference, 0.5 cm; 95% CI, 0.1 to 0.9) than controls; the differences in multigravidae (n = 603) were -53.3 g (95% CI, -126.8 to 20.2) and -0.2 cm (95% CI, -0.4 to 0.1), respectively (p < .05 for heterogeneity). CONCLUSIONS: Prenatal DHA supplementation of primigravid women may result in increased birth size in a population where dietary DHA intakes are very low. Benefits of the intervention on infant health and neurodevelopment are under study. PMID- 20715596 TI - Increases in breastfeeding duration observed in Latin America and the Caribbean and the role of maternal demographic and healthcare characteristics. AB - To understand the factors contributing to changes in breastfeeding duration, we analyzed data from seven countries in Latin America and from Haiti to document changes in breastfeeding duration between 1986 and 2005. We used a novel method that permits the overall change to be separated into the portion attributable to changing population characteristics (e.g., greater urban population or increased maternal employment) and the portion resulting from changing breastfeeding behaviors within population subgroups (e.g., more breastfeeding among urban women). Our results indicate that in the low-to-middle-income countries studied, which are experiencing socioeconomic and demographic changes, improvements in breastfeeding duration occurred. These improvements are explained almost entirely by changing breastfeeding behaviors, which were particularly evident in certain subgroups of women, such as those with higher levels of education, and very little by changing population characteristics. The socioeconomic and demographic changes we studied that were previously associated with less breastfeeding no longer appear to have a large negative effect. Our findings show that individual behaviors are amenable to change and that changes in individual behaviors collectively contribute to positive national trends in breastfeeding. PMID- 20715597 TI - The role of the Codex Alimentarius process in support of new products to enhance the nutritional health of infants and young children. AB - The Codex Alimentarius is a collection of internationally recognized standards, codes of practice, guidelines, and other recommendations relating to foods, food production, and food safety. Among other functions, it is responsible for setting international standards for safety and hygiene. Codex food standards and guidelines directed at foods produced primarily for young infants and children have important implications for maintaining nutritional status and health, especially given the positioning of these products as components of established World Health Organization (WHO)/UNICEF-recommended feeding strategies. Recently, new products targeted at this age group (e.g., lipid-based nutrient supplements and micronutrient powders) have been produced and used, but these are not totally covered under existing Codex guidelines or standards. The objective of this paper is to review the role of the Codex process and specifically to suggest revisions to existing Codex guidelines on formulated complementary foods (Guidelines for Formulated Supplementary Foods for Older Infants and Young Children, CAC/GL 08 1991) to encompass this new category of fortified complementary foods and home fortificants. In reviewing the existing guidelines, potential areas for revision included the sections on the recommended nutrients in these foods and their intended use. Updating the Codex guidelines provides the opportunity to encourage production and use of new products for children and help ensure that such foods, when used as directed, do not interfere with breastfeeding. The revised guidelines would help governments develop national regulations covering all forms of formulated complementary foods. They would also lessen impediments to international trade by providing clear guidance for foods used in feeding programs and for young children, particularly in developing countries. PMID- 20715598 TI - A review of phytate, iron, zinc, and calcium concentrations in plant-based complementary foods used in low-income countries and implications for bioavailability. AB - Plant-based complementary foods often contain high levels of phytate, a potent inhibitor of iron, zinc, and calcium absorption. This review summarizes the concentrations of phytate (as hexa- and penta-inositol phosphate), iron, zinc, and calcium and the corresponding phytate:mineral molar ratios in 26 indigenous and 27 commercially processed plant-based complementary foods sold in low-income countries. Phytate concentrations were highest in complementary foods based on unrefined cereals and legumes (approximately 600 mg/100 g dry weight), followed by refined cereals (approximately 100 mg/100 g dry weight) and then starchy roots and tubers (< 20 mg/100 g dry weight); mineral concentrations followed the same trend. Sixty-two percent (16/26) of the indigenous and 37% (10/27) of the processed complementary foods had at least two phytate:mineral molar ratios (used to estimate relative mineral bioavailability) that exceeded suggested desirable levels for mineral absorption (i.e., phytate:iron < 1, phytate:zinc < 18, phytate:calcium < 0.17). Desirable molar ratios for phytate:iron, phytate:zinc, and phytate:calcium were achieved for 25%, 70%, and 57%, respectively, of the complementary foods presented, often through enrichment with animal-source foods and/or fortification with minerals. Dephytinization, either in the household or commercially, can potentially enhance mineral absorption in high-phytate complementary foods, although probably not enough to overcome the shortfalls in iron, zinc, and calcium content of plant-based complementary foods used in low income countries. Instead, to ensure the World Health Organization estimated needs for these minerals from plant-based complementary foods for breastfed infants are met, dephytinization must be combined with enrichment with animal source foods and/or fortification with appropriate levels and forms of mineral fortificants. PMID- 20715599 TI - Are peanut allergies a concern for using peanut-based formulated foods in developing countries? AB - BACKGROUND: Peanut allergy is relatively common among children in developed countries and may have severe outcomes, including anaphylaxis. However, few data about peanut allergy in developing countries are available. Meanwhile, formulated foods with peanuts as a major ingredient are being promoted to prevent and control malnutrition in developing countries. OBJECTIVE: The objectives of the paper are to review the existing epidemiologic data about peanut allergy, to determine whether the prevalence of peanut allergy is lower in developing countries, and to explore the possible reasons for onset of peanut allergy. METHODS: Publications relevant to peanut allergy were searched via Pubmed, and prevalence and etiological factors of peanut allergy were reviewed. RESULTS: Data about peanut allergy were scarce in most developing countries. The existing data support the conclusion that peanut allergy is not as common in developing countries as in developed countries and may not be a major concern for programs promoting formulated food containing peanuts for control of malnutrition. However, plans for treatment of individuals with peanut allergy could be incorporated into these formulated food supplementation programs. A few risk factors (late introduction of peanuts to children, peanut processing technology, non-oral peanut exposure, and maternal peanut exposure during pregnancy and lactation) have been hypothesized to be associated with peanut allergy. However, more conclusive data are needed to verify or disprove these hypotheses. CONCLUSIONS: Peanut allergy is not as common in developing countries as in developed countries and may not be a major concern for programs promoting formulated food containing peanuts for control of malnutrition. However, more research about prevalence of peanut allergy is warranted in developing countries. PMID- 20715600 TI - Marketing complementary foods and supplements in Burkina Faso, Madagascar, and Vietnam: lessons learned from the Nutridev program. AB - BACKGROUND: Sustainable approaches to improving infant and young child feeding are needed. The Nutridev program worked in Vietnam, Madagascar, and Burkina Faso to test different strategies to improve complementary feeding using fortified products sold to families. OBJECTIVE: To review the experiences of programs producing and marketing fortified complementary foods and to report on the feasibility of local production and marketing of fortified complementary foods to increase usage of high-quality foods among children of low-income families in a self-sustaining manner. METHODS: Project documents, surveys of mothers, and production and sales reports were reviewed. RESULTS: Nutridev experience in Vietnam, Madagascar, and Burkina Faso demonstrates that it is possible to produce affordable, high-quality complementary foods and supplements locally in developing countries. Strategies to make products readily available to the targeted population and to convince this population to consume them yielded mixed results, varying greatly based on the strategy utilized and the context in which it was implemented. CONCLUSIONS: In several contexts, the optimal approach appears to be strengthening the existing food distribution network to sell complementary foods and supplements, with the implementation of a temporary promotion and nutrition education network in partnership with local authorities (e.g., health services) to increase awareness among families about the fortified complementary food product and optimal feeding practices. In urban areas, where the density of the population is high, design and implementation of specific networks very close to consumers seems to be a good way to combine economic sustainability and good consumption levels. PMID- 20715601 TI - Monitoring the marketing, distribution, and use of Sprinkles micronutrient powders in rural western Kenya. AB - BACKGROUND: In 2007, the US Centers for Disease Control and Prevention partnered with local Kenyan institutions to implement the Nyando Integrated Child Health and Education Project, an effectiveness study that used social marketing and a community-based distribution program to promote the sale of Sprinkles and other health products. OBJECTIVE: To describe monitoring of wholesale sales, household demand, promotional strategies, and perceived factors influencing Sprinkles sales among vendors. METHODS: Ongoing quantitative and qualitative monitoring of Sprinkles sales began in May 2007 in 30 intervention villages. Data sources included baseline and follow-up cross-sectional surveys; office records of Sprinkles sales to vendors; biweekly household monitoring of Sprinkles use; and qualitative data collection, including vendor focus groups and key informant interviews. RESULTS: A total of 550 children aged 6 to 35 months were enrolled at baseline, and 451 were available at 12-month follow-up. During this period, nearly 160,000 sachets were sold wholesale to vendors, with variability in sales influenced by the social, political, and economic context. Vendors living closer to the wholesale office purchased more Sprinkles, so a second office was opened closer to remote vendors. On average, 33% of households purchased Sprinkles during household monitoring visits. Training sessions and community launches were important for community support and raising awareness about Sprinkles. Vendor incentives motivated vendors to sell Sprinkles, and consumer incentives promoted purchases. CONCLUSIONS: Sprinkles program monitoring in Kenya was critically important for understanding sales and distribution trends and vendor perceptions. Understanding these trends led to strategic changes to the intervention over time. PMID- 20715602 TI - Formative research exploring acceptability, utilization, and promotion in order to develop a micronutrient powder (Sprinkles) intervention among Luo families in western Kenya. AB - BACKGROUND: There is a lack of peer-reviewed literature describing in detail the formative research to develop Sprinkles interventions. OBJECTIVE: To describe community members' reactions to and experiences using Sprinkles, with an emphasis on acceptability, utilization, and promotion. METHODS: Fourteen initial focus group discussions on Sprinkles and a 25-family home study were conducted. For the home study, each child 6 to 59 months of age in the household received 30 sachets (1 per day). The initial 14 focus group discussions included mothers, grandmothers, vendors, women who purchased from vendors, and adults in the general population. Home study families were recruited from participants in the initial 14 focus group discussions who had at least one child 6 to 59 months of age. RESULTS: Sprinkles were highly acceptable to adults and most children; some children thought Sprinkles were sugar. Most home study families prepared and used Sprinkles correctly. All families reported positive effects, particularly increased appetite, and recommended Sprinkles; none experienced major problems. Potential barriers identified were lack of knowledge of and experience with Sprinkles, availability of Sprinkles, and cost. Promotional messages targeted to mothers, fathers, all child-care providers, and doctors focused on the positive health effects of Sprinkles. CONCLUSIONS: Issues related to Sprinkles preparation, use, and barriers required attention before implementation. Locally appropriate visual and written instructions were developed for dissemination. Intervention training sessions and promotions were tailored to answer frequently asked questions, increase knowledge of Sprinkles, and provide tangible evidence of health benefits. Information needs and perceptions changed quickly after use of Sprinkles. Existing levels of Sprinkles awareness and knowledge should be considered when designing interventions. PMID- 20715603 TI - Growing children's bodies and minds: maximizing child nutrition and development. AB - For their optimal growth, and for greater long-term human capital development, children profit not only from improved nutrition but also from improved learning opportunities in the earliest years of life. This paper describes how actions to enhance optimal infant and young child nutrition can be linked with child development interventions for children under 3 years of age. In countries with high rates of malnutrition, linking these two components will result in synergies of program activities, and will bring about a greater impact at reduced cost than either activity conducted separately. New understanding of social marketing and communication strategies can increase effectiveness of linked interventions. Public-private partnerships to improve both child development and nutrition offer promise for sustainable interventions. PMID- 20715604 TI - Validity and reliability of mothers' reports of language development in 1-year old children in a large-scale survey in Bangladesh. AB - BACKGROUND: In developing countries, it is often important to have measures of development in children under 3 years of age in large-scale surveys or evaluations of nutrition and stimulation programs. However, there is a lack of suitable instruments with established validity. OBJECTIVE: To develop a language test for children aged 12 to 18 months based on mothers' report, suitable for use in large-scale surveys, and examine its concurrent and predictive validity. To determine whether the test is sensitive to home stimulation and nutritional status and compare the test with the Bayley Scales of Infant Development (BSID). METHODS: A subsample of participants in a large, prospective cohort study in rural Bangladesh (MINIMat) was selected for a study of child development (n = 2,852). A total of 2,418 participants were interviewed concerning their children's expressive and receptive vocabulary, and children were tested using the BSID. RESULTS: The language test had reasonable short- and long-term reliability between 12 and 18 months (r = 0.50) and concurrent validity with the Bayley Mental Development Index (MDI) (r = 0.32 language comprehension to 0.41 language expression). Its predictive validity with IQ at age 5 years was similar to that of the Bayley MDI (r = 0.37 to 0.41 for language and r = 0.37 for MDI). Child language was independently associated with postnatal growth, stimulation in the home, gestational age, and socioeconomic status, and a similar set of variables predicted the Bayley MDI. CONCLUSIONS: The language test was reliable, had acceptable concurrent and predictive validity, and was sensitive to environmental and child characteristics. Mothers' reports of language could be useful in large-scale programs. PMID- 20715605 TI - Squeezed at the top: Interspecific aggression may constrain elevational ranges in tropical birds. AB - Tropical montane species are characterized by narrow elevational distributions. Recent perspectives on mechanisms maintaining these restricted distributions have emphasized abiotic processes, but biotic processes may also play a role in their establishment or maintenance. One historically popular hypothesis, especially for birds, is that interspecific competition constrains ranges of closely related species that "replace" each other along elevational gradients. Supporting evidence, however, is based on patterns of occurrence and does not reveal potential mechanisms. We experimentally tested a prediction of this hypothesis in two genera of tropical songbirds, Catharus (Turdidae) and Henicorhina (Troglodytidae), in which species have nonoverlapping elevational distributions. Using heterospecific playback trials, we found that individuals at replacement zones showed aggressive territorial behavior in response to songs of congeners. As distance from replacement zones increased, aggression toward congener song decreased, suggesting a learned component to interspecific aggression. Additionally, aggressive responses in Catharus were asymmetric, indicating interspecific dominance. These results provide experimental evidence consistent with the hypothesis that interspecific competitive interactions restrict ranges of Neotropical birds. Our results also underscore the need to consider biotic processes, such as competition, when predicting how species' ranges will shift with climate change. Asymmetric aggression could be particularly important. For example, if warming in montane landscapes allows upslope range expansion by dominant competitors, then high-elevation subordinate species could be forced into progressively smaller mountaintop habitats, jeopardizing viability of their populations. PMID- 20715606 TI - Modeling spatial variation in avian survival and residency probabilities. AB - The importance of understanding spatial variation in processes driving animal population dynamics is widely recognized. Yet little attention has been paid to spatial modeling of vital rates. Here we describe a hierarchical spatial autoregressive model to provide spatially explicit year-specific estimates of apparent survival (phi) and residency (pi) probabilities from capture-recapture data. We apply the model to data collected on a declining bird species, Wood Thrush (Hylocichla mustelina), as part of a broad-scale bird-banding network, the Monitoring Avian Productivity and Survivorship (MAPS) program. The Wood Thrush analysis showed variability in both phi and pi among years and across space. Spatial heterogeneity in residency probability was particularly striking, suggesting the importance of understanding the role of transients in local populations. We found broad-scale spatial patterning in Wood Thrush phi and pi that lend insight into population trends and can direct conservation and research. The spatial model developed here represents a significant advance over approaches to investigating spatial pattern in vital rates that aggregate data at coarse spatial scales and do not explicitly incorporate spatial information in the model. Further development and application of hierarchical capture-recapture models offers the opportunity to more fully investigate spatiotemporal variation in the processes that drive population changes. PMID- 20715607 TI - Revealing ecological networks using Bayesian network inference algorithms. AB - Understanding functional relationships within ecological networks can help reveal keys to ecosystem stability or fragility. Revealing these relationships is complicated by the difficulties of isolating variables or performing experimental manipulations within a natural ecosystem, and thus inferences are often made by matching models to observational data. Such models, however, require assumptions or detailed measurements-of parameters such as birth and death rate, encounter frequency, territorial exclusion, and predation success. Here, we evaluate the use of a Bayesian network inference algorithm, which can reveal ecological networks based upon species and habitat abundance alone. We test the algorithm's performance and applicability on observational data of avian communities and habitat in the Peak District National Park, United Kingdom. The resulting networks correctly reveal known relationships among habitat types and known interspecific relationships. In addition, the networks produced novel insights into ecosystem structure and identified key species with high connectivity. Thus, Bayesian networks show potential for becoming a valuable tool in ecosystem analysis. PMID- 20715608 TI - Parasitism in a community context: trait-mediated interactions with competition and predation. AB - Predation and competition can induce important density- and trait-mediated effects on species, with implications for community stability. However, interactions of these factors with parasitism remain understudied. Here we investigate interactions among competition, predation and parasitism by crossing tadpole density (Bufo americanus), presence of a caged predator (Notophthalmus viridescens), and Echinostoma trivolvis trematodes, experimentally partitioning their effects on tadpole exposure and susceptibility to infection. Predation did not affect E. trivolvis infection but accelerated tadpole development and growth, and decreased activity. The presence of E. trivolvis caused the opposite effects on these three responses and reduced tadpole survival. High conspecific density reduced tadpole survival, growth, and development, and increased tadpole activity. Effects of predation and parasitism on activity were only evident at low tadpole density. High-density mesocosms also had twice the number of E. trivolvis infections as low-density mesocosms, despite a lack of evidence for stress-induced immunomodulation. Instead, this effect was explained by high density delaying tadpole development, which increased both the duration of exposure to cercariae and susceptibility to infection, because tadpoles spent more time in highly susceptible early stages. These results highlight the importance of accounting for trait-mediated effects, host plasticity, and exposure vs. susceptibility in parasite ecology. PMID- 20715609 TI - Independent effects of patch size and structural complexity on diversity of benthic macroinvertebrates. AB - Despite a long history of work on relationships between area and number of species, the details of mechanisms causing patterns have eluded ecologists. The general principle that the number of species increases with the area sampled is often attributed to a sampling artifact due to larger areas containing greater numbers of individuals. We manipulated the patch size and surface area of experimental mimics of macro-algae to test several models that can explain the relationship between abundance and species richness of assemblages colonizing different habitats. Our results show that patch size and structural complexity have independent effects on assemblages of macroinvertebrates. Regardless of their structural complexity, larger habitats were colonized by more species. Patch size did not have a significant effect on numbers of individuals, so the increased number of species in larger habitats was not simply a result of random placement associated with sampling increased number of individuals. Similarly, random placement alone could not explain differences in numbers of species among habitats with different structural complexity, contrary to suggestions that the relationship between number of species and surface area might also be a sampling artifact due to more complex habitats having larger areas and therefore sampling more individuals. Future progress would benefit from manipulating properties of habitat in conjunction with experimental manipulations of area. PMID- 20715610 TI - Assessing whether mortality is additive using marked animals: a Bayesian state space modeling approach. AB - Whether different sources of mortality are additive, compensatory, or depensatory is a key question in population biology. A way to test for additivity is to calculate the correlation between cause-specific mortality rates obtained from marked animals. However, existing methods to estimate this correlation raise several methodological issues. One difficulty is the existence of an intrinsic bias in the correlation parameter. Although this bias can be formally expressed, it requires knowledge about natural survival without any competing mortality source, which is difficult to assess in most cases. Another difficulty lies in estimating the true process correlation while properly accounting for sampling variation. Using a Bayesian approach, we developed a state-space model to assess the correlation between two competing sources of mortality. By distinguishing the mortality process from its observation through dead recoveries and live recaptures, we estimated the process correlation. To correct for the intrinsic bias, we incorporated experts' opinions on natural survival. We illustrated our approach using data on a hunted population of wild boars. Mortalities were not additive and natural mortality increased with hunting mortality likely as a consequence of non-controlled mortality by crippling loss. Our method opens perspectives for wildlife management and for the conservation of endangered species. PMID- 20715611 TI - Spatiotemporal dynamics of prairie wetland networks: power-law scaling and implications for conservation planning. AB - Although habitat networks show promise for conservation planning at regional scales, their spatiotemporal dynamics have not been well studied, especially in climate-sensitive landscapes. Here I use satellite remote sensing to compile wetland habitat networks from the Prairie Pothole Region (PPR) of North America. An ensemble of networks assembled across a hydrologic gradient from deluge to drought and a range of representative dispersal distances exhibits power-law scaling of important topological parameters. Prairie wetland networks are "meso worlds" with mean topological distance increasing faster with network size than small-world networks, but slower than a regular lattice (or "large world"). This scaling implies rapid dispersal through wetland networks without some of the risks associated with "small worlds" (e.g., extremely rapid propagation of disease or disturbance). Retrospective analysis of wetland networks establishes a climatic envelope for landscape connectivity in the PPR, where I show that a changing climate might severely impact metapopulation viability and restrict long distance dispersal and range shifts. More generally, this study demonstrates an efficient approach to conservation planning at a level of abstraction addressing key drivers of the global biodiversity crisis: habitat fragmentation and climatic change. PMID- 20715612 TI - Is understory plant species diversity driven by resource quantity or resource heterogeneity? AB - What maintains plant species diversity has been the subject of much debate with no general consensus. In forest ecosystems in which understory plants account for the majority of floristic diversity, a crucial question is whether understory plant diversity is driven by resource quantity or resource heterogeneity. This study sought to reconcile the two hypotheses in relation to their effects on understory plant diversity in forest ecosystems. A database of studies that investigated the effects of resources on understory plant diversity was compiled and analyzed using log-linear models. Whether resource quantity or resource heterogeneity is the determinant of understory plant diversity in individual studies was dependent on stand successional stage(s), presence or absence of intermediate disturbance, and forest biome within which the studies were conducted. Resource quantity was found to govern species diversity in both young and mature stands, whereas resource heterogeneity dominated in old-growth stands. Resource quantity remained the important driver in both disturbed and undisturbed forests, but resource heterogeneity played an important role in disturbed forests. We argue that neither resource quantity nor heterogeneity alone structures species diversity in forest ecosystems, but rather their influences on understory plant diversity vary with stand development and disturbances in forest ecosystems. PMID- 20715613 TI - Winter climate change: a critical factor for temperate vegetation performance. AB - Winter ecological processes are important drivers of vegetation and ecosystem functioning in temperate ecosystems. There, winter conditions are subject to rapid climate change. The potential loss of a longer-lasting snow cover with implications to other plant-related climate parameters and overwintering strategies make the temperate zone particularly vulnerable to winter climate change. A formalized literature search in the ISI Web of Science shows that plant related research on the effects of winter climate change is generally underrepresented. Temperate regions in particular are rarely studied in this respect, although the few existing studies imply strong effects of winter climate change on species ranges, species compositions, phenology, or frost injury. The generally positive effect of warming on plant survival and production may be counteracted by effects such as an increased frost injury of roots and shoots, an increased insect pest risk, or a disrupted synchrony between plants and pollinators. Based on the literature study, gaps in current knowledge are discussed. Understanding the relative effects of interacting climate parameters, as well as a stronger consideration of shortterm events and variability of climatic conditions is urgent. With respect to plant response, it would be particularly worthwhile to account for hidden players such as pathogens, pollinators, herbivores, or fungal partners in mycorrhization. PMID- 20715615 TI - Partitioning diversity. PMID- 20715614 TI - Synthesizing mechanisms of density dependence in reef fishes: behavior, habitat configuration, and observational scale. AB - Coral and rocky reef fish populations are widely used as model systems for the experimental exploration of density-dependent vital rates, but patterns of density-dependent mortality in these systems are not yet fully understood. In particular, the paradigm for strong, directly density-dependent (DDD) postsettlement mortality stands in contrast to recent evidence for inversely density-dependent (IDD) mortality. We review the processes responsible for DDD and IDD per capita mortality in reef fishes, noting that the pattern observed depends on predator and prey behavior, the spatial configuration of the reef habitat, and the spatial and temporal scales of observation. Specifically, predators tend to produce DDD prey mortality at their characteristic spatial scale of foraging, but prey mortality is IDD at smaller spatial scales due to attack-abatement effects (e.g., risk dilution). As a result, DDD mortality may be more common than IDD mortality on patch reefs, which tend to constrain predator foraging to the same scale as prey aggregation, eliminating attack-abatement effects. Additionally, adjacent groups of prey on continuous reefs may share a subset of refuges, increasing per capita refuge availability and relaxing DDD mortality relative to prey on patch reefs, where the patch edge could prevent such refuge sharing. These hypotheses lead to a synthetic framework to predict expected mortality patterns for a variety of scenarios. For nonsocial, nonaggregating species and species that aggregate in order to take advantage of spatially clumped refuges, IDD mortality is possible but likely superseded by DDD refuge competition, especially on patch reefs. By contrast, for species that aggregate socially, mortality should be IDD at the scale of individual aggregations but DDD at larger scales. The results of nearly all prior reef fish studies fit within this framework, although additional work is needed to test many of the predicted outcomes. This synthesis reconciles some apparent contradictions in the recent reef fish literature and suggests the importance of accounting for the scale-sensitive details of predator and prey behavior in any study system. PMID- 20715616 TI - Diversity partitioning without statistical independence of alpha and beta. AB - Diversity partitioning has become a popular method for analyzing patterns of alpha and beta diversity. A recent evaluation of the method emphasized a distinction between additive and multiplicative partitioning and further advocated the use of multiplicative partitioning based on a presumed independence between alpha and beta. Concurrently, additive partitioning was criticized for producing dependent alpha and beta estimates. Until now, the issue of statistical independence of alpha and beta (in either type of partitioning) has not been thoroughly examined, partly due to confusion about the meaning of statistical independence. Here, we adopted a probability-based definition of statistical independence that is essentially identical to the definition found in any statistics textbook. We used a data simulation approach to show that alpha and beta diversity are not statistically independent in either additive or multiplicative partitioning. However, the extent of the dependence is not so great that it cannot be overcome by using appropriate statistical techniques to control it. Both additive and multiplicative partitioning are statistically valid and logically sound approaches to analyzing diversity patterns. PMID- 20715617 TI - Independence of alpha and beta diversities. PMID- 20715618 TI - Multiplicative partition of true diversity yields independent alpha and beta components; additive partition does not. PMID- 20715619 TI - On beta diversity decomposition: trouble shared is not trouble halved. PMID- 20715620 TI - An empirical comparison of beta diversity indices in establishing prairies. PMID- 20715621 TI - Toward a unified view of diversity partitioning. PMID- 20715622 TI - Effects of habitat patchiness on American lobster movement across a gradient of predation risk and shelter competition. AB - The influence of landscape structure on marine ecological processes is receiving increasing attention. However, few studies conducted in coastal marine habitats have evaluated whether the effects of landscape structure on species interactions and organismal behavior are consistent across the range of an organism, over which landscape context and the strength of species interactions typically vary. American lobster (Homarus americanus) juveniles seek refuge from predators within shallow rocky habitat but make short-distance movements to forage outside of shelter. We evaluated how the patchiness of cobble habitat influences juvenile lobster movement by conducting mark-recapture experiments on lobsters placed within patchy and contiguous cobble plots in three regions of New England among which risk of predation and intraspecific shelter competition vary (Rhode Island, mid-coast Maine, and eastern Maine, USA). We also evaluated whether habitat patchiness influenced lobster colonization of plots and whether lobster fidelity to individual shelters corresponds to variability in predator abundance and conspecific density among regions. Cobble patchiness reduced rates of lobster movement in all three regions in 2004 and in two of three regions in 2005, despite large differences in landscape context among regions. Region had much larger effects on lobster colonization than did patchiness, but patchy plots were colonized at higher rates than were contiguous plots where lobster densities were highest. Fidelity to shelter was higher in regions with low conspecific density (Rhode Island and eastern Maine) than in mid-coast Maine where conspecific density is high and where unmarked lobsters often occupied shelters vacated by marked lobsters. Our results indicate that cobble patchiness influences juvenile lobster movement at small scales, but that the effects of patchiness on movement were consistent across much of the range of the American lobster despite strong regional variation in predator abundance and conspecific density. PMID- 20715624 TI - Resource distribution influences positive edge effects in a seagrass fish. AB - According to conceptual models, the distribution of resources plays a critical role in determining how organisms distribute themselves near habitat edges. These models are frequently used to achieve a mechanistic understanding of edge effects, but because they are based predominantly on correlative studies, there is need for a demonstration of causality, which is best done through experimentation. Using artificial seagrass habitat as an experimental system, we determined a likely mechanism underpinning edge effects in a seagrass fish. To test for edge effects, we measured fish abundance at edges (0-0.5 m) and interiors (0.5-1 m) of two patch configurations: continuous (single, continuous 9 m2 patches) and patchy (four discrete 1-m2 patches within a 9-m2 area). In continuous configurations, pipefish (Stigmatopora argus) were three times more abundant at edges than interiors (positive edge effect), but in patchy configurations there was no difference. The lack of edge effect in patchy configurations might be because patchy seagrass consisted entirely of edge habitat. We then used two approaches to test whether observed edge effects in continuous configurations were caused by increased availability of food at edges. First, we estimated the abundance of the major prey of pipefish, small crustaceans, across continuous seagrass configurations. Crustacean abundances were highest at seagrass edges, where they were 16% greater than in patch interiors. Second, we supplemented interiors of continuous treatment patches with live crustaceans, while control patches were supplemented with seawater. After five hours of supplementation, numbers of pipefish were similar between edges and interiors of treatment patches, while the strong edge effects were maintained in controls. This indicated that fish were moving from patch edges to interiors in response to food supplementation. These approaches strongly suggest that a numerically dominant fish species is more abundant at seagrass edges due to greater food availability, and provide experimental support for the resource distribution model as an explanation for edge effects. PMID- 20715623 TI - Maternal influences on population dynamics: evidence from an exploited freshwater fish. AB - We used a field experiment, population modeling, and an analysis of 30 years of data from walleye (Sander vitreus; a freshwater fish) in Lake Erie to show that maternal influences on offspring survival can affect population dynamics. We first demonstrate experimentally that the survival of juvenile walleye increases with egg size (and, to a lesser degree, female energy reserves). Because egg size in this species tends to increase with maternal age, we then model these maternal influences on offspring survival as a function of maternal age to show that adult age structure can affect the maximum rate at which a population can produce new adults. Consistent with this hypothesis, we present empirical evidence that the maximum reproductive rate of an exploited population of walleye was approximately twice as high when older females were abundant as compared to when they were relatively scarce. Taken together, these results indicate that age- or size-based maternal influences on offspring survival can be an important mechanism driving population dynamics and that exploited populations could benefit from management strategies that protect, rather than target, reproductively valuable individuals. PMID- 20715625 TI - Dispersal decreases diversity in heterogeneous metacommunities by enhancing regional competition. AB - Experiments and models reveal that moderate dispersal rates between local communities can increase diversity by alleviating local competitive exclusion; in contrast, high dispersal rates can decrease diversity by amplifying regional competition. However, hitherto experimental tests on how dispersal affects diversity in the presence and absence of environmental heterogeneity are largely missing, although it is known that environmental heterogeneity influences diversity. For the first time we experimentally show that the interaction between dispersal rate and the presence of an environmental gradient with on-average lower resource availability than the homogeneous control treatment affects diversity. In metacommunities of nine co-occurring species of marine benthic microalgae we factorially manipulated dispersal rate and the presence and absence of a light intensity gradient across local patches to test effects on local, regional, and beta diversity and to compare results to predictions from monoculture experiments. Although species in this experiment did not show resource partitioning along the light gradient as assumed by source-sink models, dispersal limitation maintained diversity in metacommunities with light gradients but not without. Local diversity and evenness were high under low light intensities when dispersal was limited and decreased with both increasing light intensities and dispersal rates. These diversity changes can be explained by the reduction of growth of the regional superior competitor at low light intensities alleviating its competitive strength. Increasing dispersal rate in turn compensated for the superior competitor's slow growth in those local patches with rather unfavorable light conditions and thus led to decreasing diversity and evenness. In contrast, diversity in the metacommunities without a light gradient was constantly low. Here, the superior competitor contributed 90% to total community biomass in all patches. High dominance, however, likely resulted from on-average higher resource availability (i.e., higher light intensities) compared to metacommunities with light gradient and not from patch homogeneity in itself. PMID- 20715626 TI - Maternal characteristics and environment affect the costs of reproduction in female mountain goats. AB - Reproduction should reduce resources available for somatic investment and result in fundamental trade-offs among life-history traits. Using 18 years of longitudinal data from marked mountain goats (Oreamnos americanus), we assessed whether reproductive status affected female survival and future reproduction when accounting for parity, age, individual quality, population density, and environmental conditions. Reproduction reduced the probability of parturition and offspring survival in the following year. Female survival, however, was independent of previous reproduction, suggesting that females favored their own survival over that of their offspring. The lower probability of parturition in females that had a kid the previous year was only detected at high population density and among young and prime-aged females, suggesting that fitness costs of reproduction can be masked by variations in resource availability and individual characteristics. Primiparous females were less likely than multiparous females to reproduce in the subsequent year. Offspring survival was reduced at high density and after severe winters. Environmental conditions mainly influenced offspring survival, whereas female survival and fecundity were principally modulated by female characteristics. Our study highlights how different intrinsic and environmental factors can affect the probability of future reproduction and also underlines the value of long-term monitoring of known individuals. PMID- 20715627 TI - Working less to gain more: when breeding quality relates to foraging efficiency. AB - In animal populations, a minority of individuals consistently achieves the highest breeding success and therefore contributes the most recruits to future generations. On average, foraging performance is important in determining breeding success at the population level, but evidence is scarce to show that more successful breeders (better breeders) forage differently than less successful ones (poorer breeders). To test this hypothesis, we used a 10-year, three-colony, individual-based longitudinal data set on breeding success and foraging parameters of a long-lived bird, the Adelie Penguin, Pygoscelis adeliae. Better breeders foraged more efficiently than poorer breeders under harsh environmental conditions and when offspring needs were higher, therefore gaining higher net energy profit to be allocated to reproduction and survival. These results imply that adverse "extrinsic" conditions might select breeding individuals on the basis of their foraging ability. Adelie Penguins show sufficient phenotypic plasticity that at least a portion of the population is capable of surviving and successfully reproducing despite extreme variability in their physical and biological environment, variability that is likely to be associated with climate change and, ultimately, with the species' evolution. This study is the first to demonstrate the importance of "extrinsic" conditions (in terms of environmental conditions and offspring needs) on the relationship between foraging behavior and individual quality. PMID- 20715628 TI - Responding to climate change: Adelie Penguins confront astronomical and ocean boundaries. AB - Long-distance migration enables many organisms to take advantage of lucrative breeding and feeding opportunities during summer at high latitudes and then to move to lower, more temperate latitudes for the remainder of the year. The latitudinal range of the Adelie Penguin (Pygoscelis adeliae) spans approximately 22 degrees. Penguins from northern colonies may not migrate, but due to the high latitude of Ross Island colonies, these penguins almost certainly undertake the longest migrations for the species. Previous work has suggested that Adelies require both pack ice and some ambient light at all times of year. Over a three year period, which included winters of both extensive and reduced sea ice, we investigated characteristics of migratory routes and wintering locations of Adelie Penguins from two colonies of very different size on Ross Island, Ross Sea, the southernmost colonies for any penguin. We acquired data from 3-16 geolocation sensor tags (GLS) affixed to penguins each year at both Cape Royds and Cape Crozier in 2003-2005. Migrations averaged 12760 km, with the longest being 17 600 km, and were in part facilitated by pack ice movement. Trip distances varied annually, but not by colony. Penguins rarely traveled north of the main sea-ice pack, and used areas with high sea-ice concentration, ranging from 75% to 85%, about 500 km inward from the ice edge. They also used locations where there was some twilight (2-7 h with sun < 6 degrees below the horizon). We report the present Adelie Penguin migration pattern and conjecture on how it probably has changed over the past approximately 12000 years, as the West Antarctic Ice Sheet withdrew southward across the Ross Sea, a situation that no other Adelie Penguin population has had to confront. As sea ice extent in the Ross Sea sector decreases in the near future, as predicted by climate models, we can expect further changes in the migration patterns of the Ross Sea penguins. PMID- 20715629 TI - Dietary flexibility aids Asian earthworm invasion in North American forests. AB - On a local scale, invasiveness of introduced species and invasibility of habitats together determine invasion success. A key issue in invasion ecology has been how to quantify the contribution of species invasiveness and habitat invasibility separately. Conventional approaches, such as comparing the differences in traits and/or impacts of species between native and/or invaded ranges, do not determine the extent to which the performance of invaders is due to either the effects of species traits or habitat characteristics. Here we explore the interaction between two of the most widespread earthworm invaders in the world (Asian Amynthas agrestis and European Lumbricus rubellus) and study the effects of species invasiveness and habitat invasibility separately through an alternative approach of "third habitat" in Tennessee, USA. We propose that feeding behaviors of earthworms will be critical to invasion success because trophic ecology of invasive animals plays a key role in the invasion process. We found that (1) the biomass and isotopic abundances (delta13C and delta15N) of A. agrestis were not impacted by either direct effects of L. rubellus competition or indirect effects of L. rubellus-preconditioned habitat; (2) A. agrestis disrupted the relationship between L. rubellus and soil microorganisms and consequently hindered litter consumption by L. rubellus; and (3) compared to L. rubellus, A. agrestis shifted its diet more readily to consume more litter, more soil gram-positive (G+) bacteria (which may be important for litter digestion), and more non-microbial soil fauna when soil microorganisms were depleted. In conclusion, A. agrestis showed strong invasiveness through its dietary flexibility through diet shifting and superior feeding behavior and its indirectly negative effect of habitat invasibility on L. rubellus via changes in the soil microorganism community. In such context, our results expand on the resource fluctuation hypothesis and support the superior competitor hypothesis. This work presents additional approaches in invasion ecology, provides some new dimensions for further research, and contributes to a greater understanding of the importance of interactions between multiple invading species. PMID- 20715630 TI - Interspecific variation in leaf litter tannins drives decomposition in a tropical rain forest of French Guiana. AB - Tannins are believed to be particularly abundant in tropical tree foliage and are mainly associated with plant herbivore defense. Very little is known of the quantity, variation, and potential role of tannins in tropical leaf litter. Here we report on the interspecific variability of litter condensed tannin (CT) concentration among 16 co-occurring tropical rain forest tree species of French Guiana and explore the functional significance of variable litter CT concentration for litter decomposition. We compared some classical methods in the ecological literature to a method based on high-performance liquid chromatography (HPLC), coupled with CT degradation by phloroglucinolysis. The same litter was allowed to decompose in the field in the presence or absence of soil fauna. We found large interspecific differences in the average polymerization degree (2.7 to 21.3, for non-extractable CT) and concentration of litter CT (0-3.7% dry mass, for total CT) determined by HPLC, which did not correlate with Folin total phenolics but correlated reasonably well with acid butanol CT. The concentration and polymerization degree of HPLC-determined CT were the only variables of the multitude of measured initial litter quality parameters that explained a significant amount of variation in litter mass loss among species, irrespective of animal presence. However, animal presence increased mean litter mass loss by a factor of 1.5, and the fauna effect on decomposition was best explained by a negative correlation with total HPLC CT and by a positive correlation with hemicellulose. Our results suggest that the commonly used acid butanol assay yields a reliable estimate of interspecific variation in CT concentration. However, the chemical structure of CTs, such as the polymerization degree, adds important information for the understanding of the functional role of CTs in litter decomposition. We conclude that the wide variation in structure and concentration of leaf litter CTs among tropical tree species is an important driver of decomposition in this nutrient-poor Amazonian rain forest. PMID- 20715631 TI - Consumer-based limitations drive oak recruitment failure. AB - A number of North American oaks are experiencing recruitment failure, with explanatory hypotheses including a range of consumer- or resource-based limitations. Using a factorial experiment with transplanted seedlings, we demonstrate how direct and indirect consumer effects prevent recruitment by Quercus garryana, a keystone savanna species of northwestern North America. Foremost, intense herbivory by mostly exotic small mammals severely damaged or killed 100% of unprotected seedlings during winter. Many damaged seedlings survived but were 64% smaller in size and produced 75% fewer leaves. Herbivory by deer had no detectable impact despite being long hypothesized as a major contributor to oak decline. Indirectly, herbivory altered the outcome of moisture limitation and competition. Without small mammals, summer drought and a dense exotic grass cover associated with fire suppression significantly reduced growth but caused little mortality. With small mammals, both significantly increased mortality of herbivore-damaged seedlings. Herbivore damage also increased the likelihood of severe insect attack, possibly due to reduced investment in foliar defense by recovering seedlings. These results show that no single factor necessarily prevents seedling establishment by oaks, but that the combination of herbivory, undisturbed exotic grass swards, and summer drought creates an almost insurmountable barrier for recruitment. PMID- 20715632 TI - Local population extinction and vitality of an epiphytic lichen in fragmented old growth forest. AB - The population dynamics of organisms living in short-lived habitats will largely depend on the turnover of habitat patches. It has been suggested that epiphytes, whose host plants can be regarded as habitat patches, often form such patch tracking populations. However, very little is known about the long-term fate of epiphyte individuals and populations. We estimated life span and assessed environmental factors influencing changes in vitality, fertility, abundance, and distribution of the epiphytic lichen species Lobaria pulmonaria on two spatial scales, individual trees and forest patches, over a period of approximately 10 years in 66 old-growth forest fragments. The lichen had gone extinct from 7 of the 66 sites (13.0%) where it was found 10 years earlier, even though the sites remained unchanged. The risk of local population extinction increased with decreasing population size. In contrast to the decrease in the number of occupied trees and sites, the mean area of the lichen per tree increased by 43.0%. The number of trees with fertile ramets of L. pulmonaria increased from 7 (approximately 1%) to 61 (approximately 10%) trees, and the number of forest fragments with fertile ramets increased from 4 to 23 fragments. The mean annual rate of L. pulmonaria extinction at the tree level was estimated to be 2.52%, translating into an expected lifetime of 39.7 years. This disappearance rate is higher than estimated mortality rates for potential host trees. The risk of extinction at the tree level was significantly positively related to tree circumference and differed between tree species. The probability of presence of fertile ramets increased significantly with local population size. Our results show a long expected lifetime of Lobaria pulmonaria ramets on individual trees and a recent increase in vitality, probably due to decreasing air pollution. The population is, however, declining slowly even though remaining stands are left uncut, which we interpret as an extinction debt. PMID- 20715633 TI - Evidence for the spatial segregation hypothesis: a test with nine-year survivorship data in a Mediterranean shrubland. AB - A current focus of ecology is the investigation of spatial effects on population and community dynamics; however, spatiotemporal theory remains largely untested by empirical observations or experimental studies. For example, the segregation hypothesis predicts that intraspecific aggregation should increase the importance of intraspecific competition relative to interspecific competition, thereby enhancing local coexistence in plant communities. We applied recent methods of point pattern analysis to analyze a unique long-term data set on fully mapped seedling emergence and subsequent survival in a Mediterranean gorse shrubland after experimental fires and simulated torrential rainfall events. Our overall aim was to test if the observed spatial patterns were consistent with the segregation hypothesis during the entire community dynamics from early seedling emergence to the establishment of a mature community, i.e., we explored if the observed initial segregation did indeed prevent interspecific competition from becoming dominant. We used random labeling as the null model and specific test statistics to evaluate different biological effects of the spatial interactions that determine mortality. We found that mortality was clearly not random. Comparison of the probability of mortality in dependence on the distance to conspecific and to heterospecific plants showed that mortality was controlled almost entirely by intraspecific interactions, which is consistent with the segregation hypothesis. Dead plants were aggregated and segregated from surviving plants, indicating two-sided scramble competition. Spatial interactions were density dependent and changed their sign over the course of time from positive to negative when plants grew to maturity. The simulated torrential rainfall events and subsequent erosion caused nonspecific mortality of seedlings but did not reduce the prevalence of intraspecific competition. Our results provide support for the hypothesis that the spatial distribution of plants may profoundly affect competition and can be an important determinant in the coexistence of species and biodiversity. PMID- 20715634 TI - Nitrogen and phosphorus additions negatively affect tree species diversity in tropical forest regrowth trajectories. AB - Nutrient enrichment is increasingly affecting many tropical ecosystems, but there is no information on how this affects tree biodiversity. To examine dynamics in vegetation structure and tree species biomass and diversity, we annually remeasured tree species before and for six years after repeated additions of nitrogen (N) and phosphorus (P) in permanent plots of abandoned pasture in Amazonia. Nitrogen and, to a lesser extent, phosphorus addition shifted growth among woody species. Nitrogen stimulated growth of two common pioneer tree species and one common tree species adaptable to both high- and low-light environments, while P stimulated growth only of the dominant pioneer tree Rollinia exsucca (Annonaceae). Overall, N or P addition reduced tree assemblage evenness and delayed tree species accrual over time, likely due to competitive monopolization of other resources by the few tree species responding to nutrient enrichment with enhanced establishment and/or growth rates. Absolute tree growth rates were elevated for two years after nutrient addition. However, nutrient induced shifts in relative tree species growth and reduced assemblage evenness persisted for more than three years after nutrient addition, favoring two nutrient-responsive pioneers and one early-secondary tree species. Surprisingly, N + P effects on tree biomass and species diversity were consistently weaker than N-only and P-only effects, because grass biomass increased dramatically in response to N + P addition. The resulting intensified competition probably prevented an expected positive N + P synergy in the tree assemblage. Thus, N or P enrichment may favor unknown tree functional response types, reduce the diversity of coexisting species, and delay species accrual during structurally and functionally complex tropical rainforest secondary succession. PMID- 20715635 TI - Climate controls on grass culm production over a quarter century in a tallgrass prairie. AB - The flowering of grasses is a process critical to plant population dynamics and genetics, herbivore performance, and human health. To better understand the climate factors governing grass flowering, we analyzed the patterns of culm production over 25 years for three perennial tallgrass prairie species at Konza Prairie in Kansas, USA. The three species (Andropogon gerardii, Sorghastrum nutans, and Schizachyrium scoparium) all utilize the C4 photosynthetic pathway and were measured annually at the same locations for the past 25 years in an annually burned watershed. Culm production of all three species increased with higher growing-season soil moisture and precipitation but differed in their responses to water availability at different times during the growing season. Relative to Andropogon, Sorghastrum responded more to precipitation early in the growing season, and Schizachyrium responded more to precipitation late in the growing season. Flowering by each species also revealed a threshold relationship with late-season soil moisture at approximately 1 m depth, which likely is a proxy for season-long water balance. Although flowering can be influenced by conditions antecedent to the current growing season, neither soil moisture nor precipitation during the previous year influenced flowering over the 25-year period. Flowering culm production averaged 9% and 7% of total graminoid aboveground net primary production (ANPP) in the uplands and lowlands, respectively. Interannual variation in ANPP correlated only with Sorghastrum flowering, suggesting a predominant role of the species in ANPP responses to climate. PMID- 20715636 TI - Spatial niches and coexistence: testing theory with tarweeds. AB - Competitive coexistence in a spatially heterogeneous environment is traditionally attributed to niche differences, but several recent theories have proposed important additional roles for propagule limitation and chance (e.g., neutral theory, stochastic niche theory, spatial storage effect). We tested whether propagule supply and timing of disturbance affected the coexistence of three ecologically similar plants that replace one another with partial overlap along a local soil gradient. We asked what prevents the species that dominates the most common habitat (Holocarpha virgata, open hillsides) from invading the habitats where the other two species are dominant (Calycadenia pauciflora, rocky hilltops; Hemizonia congesta, clay-rich bottomlands). We added abundant Holocarpha seeds into Calycadenia and Hemizonia habitats that were experimentally disturbed at different times of year. Initial Holocarpha seedling densities in Calycadenia and Hemizonia habitats equaled or exceeded those in unmanipulated Holocarpha habitat, but Holocarpha survival, adult size, and fecundity were much lower outside its own habitat. Holocarpha persisted in Calycadenia and Hemizonia habitats for three years, and springtime disturbance promoted this expansion. However, outside its own habitat Holocarpha showed below-replacement fitness and little competitive effect on the other two species. Our results were most consistent with a deterministic view of spatial niches. Nonetheless, chance events may often cause natural communities to include some transient populations at any given time, leading them to appear "unsaturated" with species. PMID- 20715637 TI - Limited evidence for the demographic Allee effect from numerous species across taxa. AB - Extensive theoretical work on demographic Allee effects has led to the latent assumption that they are ubiquitous in natural populations, yet current empirical support for this phenomenon is sparse. We extended previous single-taxon analyses to evaluate the empirical support for demographic Allee effects in the per capita population growth rate of 1198 natural populations spanning all major taxa. For each population, we quantified the empirical support for five population growth models: no growth (random walk); exponential growth, with and without an Allee effect; and logistic growth, with and without an Allee effect. We used two metrics to quantify empirical support, information-theoretic and Bayesian strength of evidence, and observed top-rank frequency. The Ricker logistic model was both the most supported and most frequently top-ranked model, followed by random walk. Allee models had a combined relative support of 12.0% but were top ranked in only 1.1% of the time series. Accounting for local climate variation and measurement error caused the loss of top-ranked Allee models, although the latter also increased their relative support. The 13 time series exhibiting Allee models were shorter and less variable than other time series, although only three were non-trending. Time series containing observations at low abundance were not more likely and did not show higher support for Allee effect models. We conclude that there is relatively high potential for demographic Allee effects in these 1198 time series but comparatively few observed cases, perhaps due to the influences of climate and measurement error. PMID- 20715639 TI - Source and sink dynamics in meta-ecosystems. AB - We present a theory extending the source-sink concept with an ecosystem perspective. We analyze a model for meta-ecosystem dynamics in a heterogeneous environment to study how the spatial flows of materials such as inorganic nutrients and nutrients sequestered into producers, herbivores, and detritus affect the community dynamics. We show that spatial flows of an inorganic nutrient (direct nutrient flow) and organic matter (indirect nutrient flow) through detritus, producer, or herbivore compartments can reverse the source-sink dynamics of a local ecosystem. More precisely, the balance between such direct and indirect nutrient flows determines the net direction of nutrient flows between two ecosystems of contrasted productivities. It allows a sink to turn into a source and vice versa. This effect of nutrient flows on source and sink dynamics is robust to the ecosystem structure (with and without herbivores) and to specific ecosystem compartments contributing to nutrient flows (primary producers, herbivores, or detritus). Ecosystems in distinct localities thus interact together with the structure at one place influencing that of the other. In meta-ecosystems, the source-sink dynamics of an organism is not only constrained by its dispersal from the source to the sink, but also by the fertility and community composition in the neighborhood responsible for spatial flows of nutrients and energy. The meta-ecosystem perspective provides a powerful theoretical framework to address novel questions in spatial ecosystem ecology. PMID- 20715638 TI - Consumer-mediated recycling and cascading trophic interactions. AB - Cascading trophic interactions mediated by consumers are complex phenomena, which encompass many direct and indirect effects. Nonetheless, most experiments and theory on the topic focus uniquely on the indirect, positive effects of predators on producers via regulation of herbivores. Empirical research in aquatic ecosystems, however, demonstrate that the indirect, positive effects of consumer mediated recycling on primary producer stocks may be larger than the effects of herbivore regulation, particularly when predators have access to alternative prey. We derive an ecosystem model with both recipient- and donor-controlled trophic relationships to test the conditions of four hypotheses generated from recent empirical work on the role of consumer-mediated recycling in cascading trophic interactions. Our model predicts that predator regulation of herbivores will have larger, positive effects on producers than consumer-mediated recycling in most cases but that consumer-mediated recycling does generally have a positive effect on producer stocks. We demonstrate that herbivore recycling will have larger effects on producer biomass than predator recycling when turnover rates and recycling efficiencies are high and predators prefer local prey. In addition, predictions suggest that consumer-mediated recycling has the largest effects on primary producers when predators prefer allochthonous prey and predator attack rates are high. Finally, our model predicts that consumer-mediated recycling effects may not be largest when external nutrient loading is low. Our model predictions highlight predator and prey feeding relationships, turnover rates, and external nutrient loading rates as key determinants of the strength of cascading trophic interactions. We show that existing hypotheses from specific empirical systems do not occur under all conditions, which further exacerbates the need to consider a broad suite of mechanisms when investigating trophic cascades. PMID- 20715640 TI - Joseph Clover and the cobra: a tale of snake envenomation and attempted resuscitation with bellows in London, 1852. AB - The Industrial Revolution saw the creation of many new jobs, but probably none more curious than that of zookeeper. The London Zoological Gardens, established for members in 1828, was opened to the general public in 1847. In 1852 the "Head Keeper in the Serpent Room", Edward Horatio Girling, spent a night farewelling a friend departing for Australia. He arrived at work in an inebriated state and was bitten on the face by a cobra that he was handling in a less than sensible manner. He was taken by cab to University College Hospital where he was resuscitated by a number of doctors, including Joseph Clover then the resident medical officer to the hospital and later to become the leading anaesthetist in London. Clover recorded this event in his diary along with the resuscitation method used. The patient eventually died but his treatment created a flurry of correspondence in the medical and lay press. Interestingly, the attempted resuscitation was with bellows, which had been abandoned by the Royal Humane Society twenty years earlier Clover records other cases of resuscitation with bellows at University College Hospital during his time as a resident medical officer there (1848 to 1853). There is a casebook belonging to Joseph Clover in the Geoffrey Kaye Museum, in Melbourne. This story is one of the many interesting stories uncovered during a study of this book and Clover's other personal papers. PMID- 20715641 TI - The self-inflating resuscitator--evolution of an idea. AB - Based on animal experiments conducted in the sixteenth century by Vesalius, the Royal Humane Society recommended fireside bellows to resuscitate victims of drowning. In the mid-twentieth century, the bellows concept was adapted by Kreiselman and others, though none of these devices gained widespread popularity. However in 1957 the "Ambu Bag" appeared and was an immediate success. The revolutionary design was the creation of Danish anaesthetist Dr Henning Ruben. A similar product was soon developed by Asmund Laerdal of Norway, in collaboration with American anaesthesiologists Drs Elam and Safar. The self-inflating bag is such a simple device, yet it is extremely effective--it has enabled rescuers around the world to support life in virtually any environment, simply by squeezing a bag. PMID- 20715642 TI - John Urban Human and the divided airway. AB - The divided airway, a device to aid in blind orotracheal intubation, was patented in 1936 by John Urban Human. However the inventor did not describe or openly promote his airway and his identity as its inventor was not known to his contemporaries. A biography of John Urban Human and a description of the divided airway are provided. PMID- 20715643 TI - Storage, display and access--innovations at the Harry Daly Museum and the Richard Bailey Library of the Australian Society of Anaesthetists, Sydney. AB - Open storage with simple access to collection items and books is a well established form of museum display. It is particularly suited to collections in which many examples of slightly differing artefacts are acquired during the process of research and field work. In the long run, open storage saves curatorial time, relieves storage space problems and increases visitor interest and participation. Simple access procedures are essential when busy professionals require information for their ongoing research or immediate application. PMID- 20715644 TI - CNO tells nurses to carve out a role in GP-led NHS. Interview by Dave West and Clare Lomas. PMID- 20715645 TI - TV dramas must tune in to the truth to prevent misconceptions. PMID- 20715646 TI - Detecting problems after gastrostomy. PMID- 20715647 TI - The high impact actions for nursing and midwifery 2: fit and well to care. AB - Each year in the health service in England, 10.3 million working days are lost to sickness absence (Chartered Institute of Personnel and Development, 2009). This is the equivalent of 4.5% of the current workforce, or 45,000 whole time equivalent nurses. This article, the third in our series on the high impact a actions for nursing and midwifery, looks at how ward managers and team leaders can provide support and information to improve nurses' health and wellbeing. PMID- 20715648 TI - Spirituality 1: Should spiritual and religious beliefs be part of patient care? AB - Despite spirituality being an important aspect of patient care, few nurses feel they meet patients' needs in this area. This first in a two part series examines definitions of spirituality and the difference between this concept and religion. It also discusses spirituality at certain points in t hepatient pathway, such as at the end of life, and finding meaning in illness. PMID- 20715649 TI - Offering spiritual support to dying patients and their families through a chaplaincy service. AB - Despite its importance in end of life care, spiritual care is poorly addressed. This article presents the results of an innovative service in which nurses notify hospital chaplains of all patients placed on the Liverpool Care Pathway and the chaplains then visit to offer spiritual support to both patients and their carers. Nurses reported that the service was valuable not only for patients and their families but also for themselves and the whole clinical team. All nurses said they wanted the service to continue. PMID- 20715650 TI - After death 2: Exploring the procedures for laying out and preparing the body for viewing. AB - This second in a two part unit on last offices examines the procedures when preparing thebody of a deceased patient for transfer to the mortuary, and issues to consider when relatives view the body. Part 1 explored relatives' grief reactions and the importance of providing culturally sensitive care. PMID- 20715651 TI - The NHS pension scheme is hardly a tax guzzling monster. PMID- 20715652 TI - The good, the bad, and the ridiculously busy. PMID- 20715653 TI - Comparison of cytologic giemsa and real-time polymerase chain reaction technique for the diagnosis of cutaneous leishmaniasis on scraping smears. AB - OBJECTIVE: To compare the results of real-time polymerase chain reaction (RT-PCR) for detection of Leishmania DNA in Giemsa-stained skin scraping slides with direct microscopic evaluation of Giemsa-stained skin scrapings and to estimate the sensitivity and specificity of RT-PCR. STUDY DESIGN: We used 30 samples from cases diagnosed with cutaneous leishmaniasis (CL), 16 from clinically suspected individuals but negative in direct microscopic evaluation and 50 normal individuals from nonendemic dry type CL areas. RESULTS: All samples of CL positive and 8 of suspected cases were positive for RT-PCR, and all nonleishmaniasis cases were negative. The sensitivity and specificity of RT-PCR were 100% (95% CI 88-100%) and 88% (95% CI 78-95%), respectively. We also found an inverse association between the number of lympnocytes (OR = 0.90, 95% CI 0.83 0.97%), neutrophils and Leishman bodies. PMID- 20715654 TI - HPV-DNA hybrid capture test: influence of cellularity in penile samples. AB - OBJECTIVE: To evaluate if the cellularity of Hybrid Capture samples (Digene, Sao Paulo, Brazil) influences the results of HPV-DNA Hybrid Capture tests in men. STUDY DESIGN: We harvested material from penile scrapings for the Hybrid Capture HPV test. This material was then used to make cytologic smears, which we used to evaluate for the presence of nonnucleated squamous cells, nucleated squamous cells and glandular cells. The cellularity of nucleated squamous cells was classified as absent, low, moderate or high. Subsequently, we performed the Hybrid Capture test to identify the low and high risk of HPV and compared these results with the cytologic findings. We used the Fisher and odds ratio tests at CI of 95% to determine statistical significance. RESULTS: Of the 88 tests performed, 65 (74.0%) were negative for HPV-DNA and 23 (26.0%) were positive. Nucleated and nonnucleated squamous cells were absent on nine slides, all of which tested negative for HPV. When only nonnudcleated squamous cells were found, 20% of the cases were positive for HPV-DNA (p < 0.0001; OR = 26.185). The presence of nucleated squamous cells correlated with 33% HPV-DNA positivity (p < 0.0001, OR = 49.05). CONCLUSION: Assessing the presence of non-nucleated and nucleated squamous cells on cytologic smears prior to performing an HPV-DNA test is a useful tool for quality control in penile samples. PMID- 20715655 TI - Granulosa cell tumor of the ovary: cytologic findings. AB - OBJECTIVE: To describe the cytologic findings in 6 adult variants of granuloma cell tumors (AGCTs) and 1 juvenile variant (JGCT), emphasizing differences between recurrent/metastatic (REC AGCT) and nonrecurrent tumors (NED AGC7). STUDY DESIGN: Imprints and fluids were evaluated for: hypercellularity, Call-Exner bodies (CEB), sheets, single cells/naked nuclei, nuclear grooves, single cell necrosis and established histologic criteria of atypia in AGCT (>3 mitoses, pleomorphism, hyperchromasia, prominent nucleoli). RESULTS: All AGCTs and JGCT showed hypercellularity, clusters, sheets, single cells and naked nuclei. CEBs and grooves were seen only in AGCTs. Fluids had less cellularity than imprints, fewer clusters, grooves, single cells/naked nuclei and no sheets, CEBs, necrosis or vacuoles. Hyperchromasia and nucleoli were more striking in JGCT than AGCTs. All REC AGCTs had cytoplasmic vacuoles, while NED AGCTs did not. Prominent nucleoli were 3 times more common in REC AGCTs than NED AGCTs. Increased mitoses and necrosis were seen in 1 REC AGCT. CONCLUSION: CEBs and grooves are not seen in JGCT. JGCT shows more striking cellular atypia than AGCT (REC AGCTs and NED AGCTs). When evaluating pelvic washes/ascitic fluid a high index of suspicion is necessary, as tumor cells can be overlooked. AGCTs showing cytoplasmic vacuoles, prominent nucleoli, mitoses and necrosis are suggestive of aggressive behavior, and that information should be conveyed in cytology reports. PMID- 20715656 TI - Evaluation of nipple discharge cytology and diagnostic value of red blood cells in cases with negative cytology: a cytohistologic correlation. AB - OBJECTIVE: To evaluate the sensitivity and specificity of nipple discharge cytology and to determine the diagnostic value of the presence of red blood cells (RBCs) in cases with negative cytology. STUDY DESIGN: Samples were received either as air-dried or alcohol-fixed slides. All cytology cases were reported by cytopathologists in the Hammersmith Pathology Department. RESULTS: We identified 98 consecutive female patients with nipple discharge cytology in the Hammersmith and Charing Cross hospitals during the period of May 2007 to May 2009. The cytodiagnoses were as follows: 86 cases had negative cytology, 9 cases were C3 (atypia but likely benign), and 3 cases were suspicious for or consistent with malignancy. Thirty of these cases had subsequent biopsy and showed: 9 benign cases, 3 cases with atypical papilloma and 3 cases with a malignant diagnosis (in situ and/or invasive ductal carcinoma). All suspicious and malignant cases with available macroscopic description (whether positive or negative on nipple discharge cytology) were blood stained and on microscopy contained RBCs. CONCLUSION: Nipple discharge cytology is a useful method in the diagnosis of malignant and suspicious cases. Further evaluation is needed to assess the value of the presence of RBCs in cases with negative cytology and its correlation with a subsequent diagnosis of malignancy. PMID- 20715657 TI - Fine needle aspiration cytology of fetal rhabdomyomatous and teratoid Wilms tumor. AB - OBJECTIVE: To review nephrectomy specimens for pediatric renal tumors seen over a period of 9 years (1995-2003). STUDY DESIGN: Specimens categorized as fetal rhabdomyomatous Wilms tumors (WTs) or teratoid WTs were selected. Corresponding fine needle aspiration cytology slides were subjected to cytomorphologic analysis. RESULTS: Of 93 specimens of WT, 3 cases of fetal rhabdomyomatous WT and 2 cases of teratoid WT were identified. The aspirates were stromal predominant, and all of them showed rhabdomyoblasts embedded within. These stained variably green or orange on Papanicolaou stain and blue-gray on May-Grunwald-Giemsa stain. In all 5 aspirates, foci of blastema with or without tubules were identified, permitting a diagnosis of WT. A squamous morule was seen in an aspirate from teratoid WT. CONCLUSION: The outcome of fetal rhabdomyomatous and teratoid WTs is good, but the tumors do not shrink with chemotherapy. Identification of rhabdomyoblastic elements on aspirates can help in assessment of subsequent response to treatment. PMID- 20715658 TI - Fine needle aspiration cytology of the thyroid in children and adolescents: experience with 792 aspirates. AB - OBJECTIVE: To determine the distribution of thyroid lesions in pediatric and adolescent patients in Kuwait. STUDY DESIGN: During a 16-year period (January 1993-December 2008) the cytology reports of 792 thyroid aspirates (724 females and 68 males) performed on children and adolescents (ranging from 4 to 21 years) at Mubarak Al-Kabeer Hospital were reviewed. Of these 62, 150, 201 and 379 aspirates belonged to the age group 4-- <12, 12-- <16, 16-- <19 and 19-21 years, respectively. There were 745 satisfactory aspirates (678 [91%] females and 67 [9%] males). The unsatisfactory rate was 5.9%, with 51.1% of the unsatisfactory aspirates in the 19-21 age group. RESULTS: Benign cytology was reported in 578 cases (77.6%), with 522 (70.1%) aspirates from females and 56 (7.5%) from males. Chronic lymphocytic thyroiditis was observed in 121 cases (16.2%), and 7 of these were males. Papillary carcinoma was detected in 20 (2.7%), and 4 of these were males. Suspicious cytology was reported only in females and comprised 7 cases (0.9%) with a suspicion of papillary carcinoma and 19 cases (2.6%) with a follicular lesion. CONCLUSION: Fine needle aspiration cytology of children's and adolescents' thyroid nodules is feasible and reliable. The majority of the nodules in this age group are benign, and fine needle aspiration cytology helps prevent unnecessary surgery. PMID- 20715660 TI - Morphologic criteria associated with Trichomonas vaginalis in liquid-based cytology. AB - OBJECTIVE: To evaluate the morphologic criteria associated with Trichomonas vaginalis on Cytyc (Marlborough, Massachusetts, U.S.A.) liquid-based cytology and to compare results between 2 types of liquid-based cytology-Cytyc and SurePath (BD Diagnostics-TriPath, Burlington, Vermont, U.S.A). STUDY DESIGN: Forty thousand Cytyc liquid-based cytology cases were tested between January 2005 and 2008. Among these, 80 cases (0.2%) had aT vaginalis infection without intraepithelial lesions or other associated infectious organism. The 80 ThinPrep (Cytyc) slides were reexamined, and for each case, morphologic characteristics associated with the parasite were listed. Concerning the SurePath technique, only 1 paper has been found in the literature based on 60,104 cases with 88 cases of T vaginalis (0.17%). RESULTS: Among the 80 T vaginalis patients, the most frequent features associated with the infection were the presence of cannonballs (93%), perinuclear halo (90%), reactive nuclear changes (88%) and attachment of T vaginalis to squamous cells (86%). Moreover, the presence of ghost cells was significantly more frequent in SurePath than Cytyc liquid-based cytology (p = 0.00001), and the presence of neutrophils, reactive nuclear changes, dirty background and karyorrhexis and the predominance of coccobacilli were significantly more frequent in Cytyc than SurePath liquid-based cytology (p < 0.05). CONCLUSION: On the basis of these results, we conclude that SurePath and Cytyc, which are the both commonly used liquid-based cytologic techniques, are useful and have the same efficacy in the detection of T vaginalis infection (p = 0.99). PMID- 20715659 TI - Prediction of histologic type and lymph node metastasis for advanced ovarian cancer on uterine cervical and endometrial cytology. AB - OBJECTIVE: To evaluate usefulness of uterine cervical and endometrial cytology for detecting ovarian cancer and predicting histologic type. STUDY DESIGN: Retrospective analysis was performed on uterine cervical and endometrial cytology data on 163 patients with ovarian cancer. RESULTS: Cervical and endometrial abnormalities were detected in 10 and 19 of the patients evaluated. Patients whose cervical and endometrial cytology revealed abnormal cells were classified as having ovarian cancer at International Federation of Gynecology and Obstetrics (FIGO) stages III and IV Peritoneal cytology proved positive in many of the patients with abnormal findings on uterine cytologic analysis. Of the 19 patients with positive uterine cytologic findings, 12 had recurrence of ovarian cancer after radical therapies. Lymph node metastases were detected in 9 of 19 patients. Our findings indicated that it is possible to predict histologic type in ovarian cancer in 90% of cases of positive cervical smears and 79% ofabnormal endometrial smears. CONCLUSION: Our study showed that most of the ovarian cancer cases that had abnormalities in uterine cervical and endometrial cytologic tests exhibited progression of disease. As a consequence, our findings indicate that it is possible to predict development of ovarian cancer and its histologic type using cytology screening. PMID- 20715661 TI - Diagnostic value of processing cytologic aspirates of renal tumors in agar cell (tissue) blocks. AB - OBJECTIVE: To adapt a method enabling utilization of most of the harvest from a fine needle aspirate in an effort to improve diagnostic accuracy in the assessment of a renal tumor in a single histologic slide. STUDY DESIGN: In a series of 43 renal tumors, 2 fine needle aspirations were performed, 4 smears were prepared after each aspiration for conventional cytology and the remaining aspirate was processed for the improved agar microbiopsy (AM) method. Conventional cytology slides, AM slides and surgical specimens were diagnosed separately, after which the diagnoses were compared. Immunohistochemistry was performed as required on the AM sections. Surgical specimens served as the gold standard. RESULTS: In 53% of conventional cytologic smears, the cellular yield was sufficient to render a correct diagnosis. In 12% the diagnosis was incorrect, in 21% only a differential diagnosis could be formulated, and in 14% too few diagnostic cells were present in the conventional smears for a cytologic diagnosis. It was, however, possible to correctly diagnose histologic sections from 97% of AM tissue blocks. In 11 cases this was facilitated with immunohistochemistry. In only 1 case did the AM tissue block contain too few cells to formulate a diagnosis; the conventional cytologic sample in this case contained enough diagnostic cells. In all cases the AM diagnosis was confirmed in the definitive surgical specimen. CONCLUSION: Our AM technique for processing fine needle aspirates from renal tumors results in a major enhancement of diagnostic accuracy of such aspirates and should be valuable in the preoperative diagnosis of large, as well as small, renal tumors. PMID- 20715662 TI - Fine needle aspiration cytologic features of Cherubism: a case report. AB - BACKGROUND: Cherubism is characterized by hereditary and intraosseous fibrous swellings of the jaws. It presents with bilateral mandibular and maxillary involvement in young individuals. Fine needle aspiration cytologic (FNAC) features have rarely been described in the literature; they include smears showing moderate cellularity with spindle cells mixed with multinucleated giant cells of osteoclast type. Therefore, giant cell containing soft tissue and bone lesions are considered in the differential diagnosis. CASE: A 13-year-old girl presented with bilateral symmetrical mandibular enlargement and was diagnosed as having cherubism on FNAC. CONCLUSION: We describe the cytomorphologic features of cherubism along with its differential diagnosis on cytology and emphasize that with clinicoradiologic correlation, a specific diagnosis can be offered for a definitive therapeutic approach. PMID- 20715663 TI - Ascitic fluid cytology in malignant Brenner tumor: a case report. AB - BACKGROUND: Peritoneal effiusion is rare in malignant Brenner tumors and has been found in only 10% of patients. CASE: A 77-year-old woman presented with malignant Brenner tumor and ascites. The cytology of the ascitic fluid revealed many activated mesothelial cells intermingled with squamous tumoral cells. These cells were either isolated or arranged in small clusters. They were often round or oval with irregular and moderately hyperchromatic nuclei. CONCLUSION: Presence of squamous cells in ascitic fluid associated with an ovarian tumor should raise the possible diagnosis of malignant Brenner tumor in addition to malignant transformed teratoma and secondary squamous carcinoma of the ovary. PMID- 20715664 TI - Pleural liposarcoma mimicking carcinoma in pleural effusion cytology: a case report. AB - BACKGROUND: Primary pleural liposarcoma is extremely rare, and its most common subtype is the myxoid subtype. To the best of our knowledge, the number of cases reported up to now is <20. It is primarily a disease ofindividuals 50 years of age and it is more common in men. It has no specific symptoms except for cough and chest pain. CASE: A 56-year-old female presented complaining of chest pain and dyspnea for 4 months. An increase in homogeneous density on the left hemithorax, from the apex to basal area, with blurring of the borders of the heart and the diaphragm, was revealed by lung radiography. Thoracic computed tomography revealed a diffuse pleural effusion causing compressive atelectasis at the base of the left hemithorax. Cytologic examination of the pleural fluid demonstrated tumoral cells forming papillary structures with complex branching and fine fibrovascular core. The tumor cells were relatively uniform and had vacuolar cytoplasm with hyperchromatic nuclei. Upon finding CA-125 positive in the immunocytochemical examination, the case was reported as "consistent with malignancy, possibility of ovarian origin, cannot be excluded". As the gynecologic examination was normal, exploratory thoracotomy was performed to take a biopsy. The case was diagnosed as liposarcoma (myxoid type) by histopathologic examination. CONCLUSION: Cytologic diagnosis of pleural liposarcoma is difficult due to its rarity and resemblance to malignant mesothelioma. Cytologic properties of liposarcoma in pleural fluid should be well known and considered in the differential diagnosis. PMID- 20715665 TI - Epithelial-myoepithelial carcinoma with myoepithelial anaplasia: report of a case with cytologic findings of a rare variant. AB - BACKGROUND: Epithelial-myoepithelial carcinoma (EMC) is usually a low grade malignancy with rare mortality. Rare aggressive variants of EMC, dedifferentiated EMC and EMC with myoepithelial anaplasia have been reported. CASE: An 81-year-old man presented with EMC of the parotid gland showing the classical type at the time of initial presentation and a high grade type with myoepithelial anaplasia at recurrence after 10 years. We compared the histologic and cytologic findings of the initial and recurrent tumors. Aspiration cytology of the initial tumor was typical of classical EMC, represented by a biphasic pattern composed of sheetlike and tubular clusters. In contrast, cytologic specimens of the recurrent tumor, which had a focally biphasic pattern similar to that of the initial tumor, also had many isolated or discohesive piled-up clusters of spindle and polygonal cells with nuclear atypia. CONCLUSION: The cytologic findings of the recurrent tumor were consistent with a rare variant of EMC with myoepithelial anaplasia. To the best of our knowledge, this is the first report of the cytologic finding of an EMC with myoepithelial anaplasia. PMID- 20715666 TI - Unusual ovarian malignancies in ascitic fluid: a report of 2 cases. AB - BACKGROUND: Ovarian tumors of germ cell and sex-cord stromal derivation rarely exfoliate malignant cells in serous effusions. A precise tissue diagnosis in these cases may be possible on serous body fluid cytology with a combined clinical and cytopathologic approach. CASES: Ascitic fluid samples from 2 young women aged 23 and 25 years presenting with abdominal mass were cytologically analyzed, with relevant histochemical and immunohistochemical stains performed on cell block/histologic sections. Cytologically, the cases were interpreted as, or suspected to be, adenocarcinomas. However, subsequent histopathologic examination showed them to be yolk sac tumor (YST) and juvenile granulosa cell tumor (JGCT). Following histopathologic diagnosis, cytologic materials were reviewed, which revealed certain features such as hyaline globules in YST and distinct tubular structures in JGCT. These cytologic findings in view of the younger age of the patients should have prompted the correct diagnosis. CONCLUSION: This study emphasizes the importance of a combined clinical and cytologic approach when dealing with serous body fluid materials from uncommon ovarian malignancies such as YST and JGCT. This simple and systematic approach is of great practical value in identifying certain cytomorphologic features that may aid in correct diagnosis. PMID- 20715668 TI - Primary serous peritoneal carcinoma presenting first on a routine papanicolaou smear: a case report. AB - BACKGROUND: Primary peritoneal carcinoma (PPC) is a relatively uncommon malignancy, and its presentation is similar to that of advanced ovarian serous carcinoma. There have been afew case reports in which the malignant cells from PPC were discovered from routine Papanicolaou (Pap) smears. CASE: In 2006 a 49 year-old, asymptomatic female participated in the Hospital Health Fair. High grade adenocarcinoma was found by Pap smear. After negative cervical and endometrial curetting and loop electrosurgical excision procedure cone, laparoscopy revealed widespread peritoneal carcinomatosis. The subsequent surgical specimens showed primary peritoneal serous carcinoma. CONCLUSION: Although the Pap smear was originally designed to detect premalignant cervical lesions and cancer, it became apparent that malignant cells from extrauterine primaries might appear in the smears. This case illustrated the value of the Pap smear in discovering unsuspected extrauterine malignancies, including PPC. Review of 9 cases showed tumor cells in the fallopian tube lumen in 4 out of 9 cases, indicating the likely route of efflux of tumor cells to appear in the Pap smear. The new concept of serous tubal intraepithelial carcinoma as the origin of PPC suggests another source of tumor cells in Pap smears. PMID- 20715667 TI - Pulmonary langerhans cell histiocytosis diagnosed in a cervical lymph node: a case report. AB - BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is usually confined to the lungs and is therefore an unexpected finding in a cervical lymph node. CASE: A 52-year-old male with a 40-pack-year smoking history presented to our clinic with cough, fever and cervical lymphadenopathy. Chest computed tomography (CT) showed bilateral pulmonary nodules and enlarged mediastinal lymph nodes, worrisome for an infectious or malignant process. Bronchioloalveolar lavage was nondiagnostic. Fine needle aspiration cytology of the enlarged cervical lymph node revealed atypical histiocytoid cells, suspicious for malignancy. Immunohistochemistry revealed CD1a- and S-100-positive Langerhans cells. These findings, along with the patient's extensive smoking history and characteristic radiographic nodules, favored a diagnosis of PLCH with cervical lymph node involvement. The patient was advised to cease smoking, and no therapy was administered. Months later, follow-up chest CT showed spontaneous resolution of the lung nodules. CONCLUSION: The demonstration of Langerhans cells by immunohistochemical staining of CD1a and S-100 on a fine needle aspiration cell block is a useful diagnostic adjunct. In this case, definitive cytology for Langerhans cells in the appropriate clinical and radiologic setting allowed us to arrive at the correct diagnosis of PLCH in a minimally invasive manner. PMID- 20715669 TI - Fine needle aspiration cytology of adrenocortical oncocytic neoplasm: a case report. AB - BACKGROUND: Adrenocortical oncocytic neoplasms (AONs) are rare tumors that typically show marked nuclear pleomorphism and eosinophilic cytoplasm and are highly cellular on fine needle aspiration (FNA) smears. These features, worrisome in conventional adrenocortical tumors, are not necessarily signs of malignancy in AONs. CASE: A 64-year-old woman presented with 3 months of abdominal pressure. Computed tomography showed a 10-cm, solid, left adrenal mass and a 21-cm complex cystic mass in the pelvis. FNA of the adrenal mass showed hypercellular smears with dyscohesive cells having pleomorphic nuclei and abundant, granular cytoplasm. The lesion was initially interpreted as malignant. Resection of the adrenal mass demonstrated an AON without definite malignant features. The pelvic mass revealed bilateral ovarian cellular fibromas. Seventeen months of postoperative follow-up were uneventful. CONCLUSION: On FNA, cells from an AON can be hypercellular and cytologically atypical, which can be pitfalls for a malignant diagnosis. Our case is the first reported in which an AON presented with ovarian cellular fibromas. To our knowledge, there is no association between the 2 lesions. We review criteria to classify benign vs. malignant AONs and discuss the literature on this topic. PMID- 20715670 TI - Fine needle aspiration diagnosis of carotid body tumor in a case of multiple paragangliomas presenting with facial palsy: a case report. AB - BACKGROUND: Carotid body tumors (CBTs) constitute the most common extraadrenal paragangliomas. Many lesions diagnosed as CBTs by fine needle aspiration (FNA) cytology are clinically unsuspected. The main differential diagnosis is a thyroid neoplasm. The location of the mass in the lateral neck with prolonged history, hemorrhagic FNA and cytologic features resembling the endocrine neoplasm help in arriving at a suggestive diagnosis of paraganglioma. CASE: A 32-year-old male presented with left-sided facial palsy and swelling in the left side of the neck of 8 months' duration. The FNA sample was hemorrhagic and showed loosely arranged groups and acini formed by round to oval cells. A diagnosis of CBT was suggested. It was supplemented by additional noninvasive methods, such as ultrasonography of the neck region with color Doppler, computed tomography and magnetic resonance imaging of the brain, which also revealed a neoplasm suggestive of carotid body tumor in the right side of the neck and neoplastic lesion in the left cerebellopontine angle, suggestive of paraganglioma. CONCLUSION: FNA, with the other noninvasive radiologic investigations, plays an important role in the diagnosis of CBT. We present this case of multiple paragangliomas for its unusual presentation and FNA diagnosis. PMID- 20715671 TI - Pancreatic metastasis from papillary thyroid carcinoma diagnosed by endoscopic ultrasound-guided fine needle aspiration: a case report. AB - BACKGROUND: The incidence of papillary thyroid carcinoma that has metastasized to the pancreas is extremely rare. To date, only 2 cases have been reported in the literature. CASE: A case of pancreatic metastatic papillary thyroid carcinoma occurred in an 82-year-old man with a prior history of thyroid papillary carcinoma, resected 5 years earlier. Due to recurrent pancreatitis, endoscopic ultrasound (EUS) was performed and showed a pancreatic neck mass as well as diffuse changes of chronic pancreatitis. Fine needle aspiration was performed under EUS. The microscopic examination showed a highly cellular smear composed of conspicuous papillary architecture at low magnification. In addition to papillae, tumor cells were arranged in syncytial aggregates and scattered singly in the background. The tumor cell population was monotonous, with high nuclear/cytoplasmic ratios, fine powdery chromatin and small nucleoli. Nuclear changes characteristic of papillary thyroid carcinoma were identified. Nuclear folds and grooves were prominent. Occasional cells showed intranuclear cytoplasmic inclusions. The tumor cells in the cell block were positive for thyroglobulin. CONCLUSION: EUS-guided fine needle aspiration cytology can be a reliable method for the diagnosis of metastatic papillary thyroid carcinoma of the pancreas. The cytomorphology in combination with the clinical history and immunohistochemical findings can indicate a definitive diagnosis and avoid additional time-consuming diagnostic procedures for appropriate clinical management. PMID- 20715672 TI - Malignant lymphoma of the tongue with unusual cytology in a pleural effusion: a case report. AB - BACKGROUND: The diagnosis of maligan phoma (ML) in pleural effusions is often difficult. In some cases, the cytomorphology of lymphoma cells in pleural fluid differs from the histomorphology ofthe primary tumor. We report a case of ML cells in the pleural fluid with a cytomorphology and immunocytochemistry different from the morphology and immunophenotype of the original site in the tongue. CASE: A 61-year-old male was admitted with an infiltration of the tongue. The biopsy result was ofa large, B cell ML, supported by immunohistochemistry. No pleural effusion was observed at that time. Fifteen months later a small, subcutaneous tumor appeared on the abdomen, and pleural fluid was detected. Cytology revealed cells with different morphology and immunophenotype than the histomorphology and immunohistochemistry of the primary infiltrate in the tongue. CONCLUSION: The cytologic diagnosis of pleural efflsions with lymphoid cells is always difficult. One should keep in mind that in some cases the cytomorphology and even the immunopheno-type may vary from the picture of the primary tumor. PMID- 20715673 TI - Cytologic detection of urinary tract tuberculosis. PMID- 20715674 TI - Cytology education in the 21st century: living in the past or crossing the Rubicon? PMID- 20715675 TI - Ki-67 expression in breast ductal epithelium: myoepithelial cells as a potential pitfall when assessing the proliferation index. PMID- 20715676 TI - Primary vesical actinomycosis diagnosed by routine urine cytology. PMID- 20715677 TI - Role of fine needle aspiration cytology in the diagnosis of exaggerated tissue response to metal from an implant. PMID- 20715678 TI - [Anesthesia, anesthetics and anesthesia-related technology]. AB - In this review, the author summarizes the recent development in the anesthesia methods, anesthetics, and anesthesia-related technology including intraoperative monitors and anesthesia medical information systems. Modern anesthesia workstations have features called fresh gas decoupling systems to prevent excess inspiratory volume and pressures that may induce barotraumas or volutrauma to the patients' lungs. Compared to volatile inhalational anesthetics, intravenous anesthetics might have several advantages. Nowadays, intravenous anesthetic propofol is administered with recently established computer-managed syringe pumps called "target controlled infusion (TCI)". Also at present anesthesiologists can titrate dose of anesthetics with the use of excellent electroencephalography (EEG) monitor named bispectral index (BIS) as a monitor of pharmacodynamic response. In addition, newly designed anesthesia medical information system is under development. All of the advancement in anesthesia technologies facilitates advanced and complicated procedures in the thoracic surgery. It is hoped such advancement of anesthesiology will play roles in better treatment and outcome in patients undergoing respiratory and thoracic surgical procedures. PMID- 20715679 TI - [Ultrasonic scalpel]. AB - An ultrasonic scalpel is now an essential item for cardiac surgery, especially coronary artery bypass surgery. It has 2 different physiologic mechanisms called cavitation fragmentation and protein coagulation. In 1998 we developed a new technique for harvesting internal thoracic arteries (ITAs) safely and simply in a completely skeletonized fashion by applying the salient characteristic of the ultrasonic scalpel This new method, ultrasonic complete skeletonization (UCS), has enabled us to obtain longer ITAs, more ITA-flow with minimal invasiveness and better results than conventional methods of pedicle isolation. In addition, it has substantially expanded the area of possible coverage with an ITA graft. In conclusion, an ultrasonic scalpel has contributed largely to improvement in quality of coronary artery bypass grafting (CABG) enabling routine use of bilateral ITAs. PMID- 20715680 TI - [Percutaneous cardiopulmonary support]. AB - Percutaneous cardiopulmonary support (PCPS) is widely used as an emergent support device for the heart and lung failure. PCPS has a closed circuit system with a centrifugal pump and a small artificial lung, introduced by inserting a thin-wall cannula percutaneously. Its clinical results have been improved, mainly due to the development of medical technology. PMID- 20715681 TI - [Mechanical ventilator]. AB - The development of the computer technology brought reform in the field of medical equipment. Originally the mechanical ventilator was an instrument only as for running by pressure and the tool that let you breathe. However, it has a function to assist a measurement (tidal volume, peek pressure, etc.) and to wean from a ventilator. There is a case to use a mechanical ventilator for after a chest surgical operation. After the operation without the complication, it seems that there is not the special administration. However, special respiratory management is necessary in case of chronic respiratory failure and acute lung injury, acute respiratory distress syndrome. Therefore I introduce a method to use a respirator after an operation in our institution. PMID- 20715682 TI - [Video recording system of endoscopic procedures for digital forensics]. AB - Recently, endoscopic procedures including surgery, intervention, and examination have been widely performed. Medical practitioners are required to record the procedures precisely in order to check the procedures retrospectively and to get the legally reliable record. Medical Forensic System made by KS Olympus Japan offers 2 kinds of movie and patient's data, such as heart rate, blood pressure, and Spo, which are simultaneously recorded. We installed this system into the bronchoscopy room and have experienced its benefit. Under this system, we can get bronchoscopic image, bronchoscopy room view, and patient's data simultaneously. We can check the quality of the bronchoscopic procedures retrospectively, which is useful for bronchoscopy staff training. Medical Forensic System should be installed in any kind of endoscopic procedures. PMID- 20715683 TI - [Lighting and surgical exposure with head lamp and optical loupes]. AB - Exposure of the operative field and adequate illumination are essential to cardiovascular surgery. The standard fixed surgical lamp may provide acceptable lighting for most surgical procedures, but the cardiovascular surgeon often needs more intense lighting to perform a small, tedious anastomosis. We have found the fiberoptic headlamp to be a satisfactory device for lighting the surgical field in all types of cardiovascular surgery. Optical loupes can also greatly enhance the ability of the surgeon to perform more accurately. These 2 devices are now surgical requisites to obtain the better results and to prevent hemorrhage and thrombosis after operation. PMID- 20715684 TI - [Electoro-surgical device]. AB - Electro-surgical device is an essential instrument for bloodless surgery after the 1st introduction by Harvey Cushing in 1926. Basal mechanisms of electric scalpels (monopolar and bipolar), current waveforms (cut, coagulation and blend), high-frequency currents and electrical shocks were commented. After 1990s, several new electro-surgical devices such as argon beam coagulator, bipolar scissors and vessel sealing system (LigaSure) were developed and introduced in chest surgery. Argon beam coagulator is useful in sealing and hemostasis of bleeding from chest walls after extrapleural dissections. Bipolar scissors can seal small vessels less than diameter 2 mm and is useful in mediastinal lymphnode dissections. Vessel sealing system is able to seal and cut vessels up to diameter 7 mm. LigaSure V is the most suitable instrument for thymic vein handling in thoracoscopic thymectomy. Clinical applications of these new surgical devices in chest surgery are discussed. PMID- 20715685 TI - [Materials for reconstruction and reinforcement]. AB - The recent development of thoracic surgery has depended on the progressive advances of surgical materials. For the reconstruction of the pleura, the chest wall, the diaphragm, the pericardium and other cardiac structures, materials of high quality are indispensable, and their appropriate use is also important. PMID- 20715686 TI - [Intra-operative echocardiography]. AB - The usefulness of intra-operative echocardiography, especially, transesophageal echocardiography (TEE) was highlighted. Preoperative re-evaluation by TEE provides new information that is not obtainable by other preoperative examinations. In addition, real-time 3-dimensional TEE has recently become available, which may bring a lot of benefits for the mitral valve surgery. Intra operative TEE examination is useful in detecting the proper positioning of the catheter for cardiopulmonary bypass, the trapped air, residual shunt, and other abnormalities. Early postoperative TEE exam is also useful in preventing the risk of re-operation. Despite some limitations, intra-operative TEE is one of the important technology to support the thoracic and cardiovascular surgery. PMID- 20715687 TI - [Intraoperative monitoring of the brain and spinal cord ischemia during thoracic aortic surgery]. AB - Thoracic aortic surgery still involves a significant risk of neurological complications including stroke and paraplegia, associated with high morbidity and mortality. Intraoperative monitoring of the brain and the spinal cord ischemia, such as 4-channel cerebral In Vivo Optical Spectroscopy (INVOS) and myogenic transcranial motor evoked potentials (MEP), may enable us to prevent the devastating complications by prompt and proper intraoperative management. This review describes our standard methods for these procedures during thoracic aortic surgery. PMID- 20715688 TI - [Cannulae for extracorporeal circulation]. AB - Since the advent of extracorporeal circulation in 1954, its technique has developed rapidly owing to the progress of technology. Although it facilitated better outcome of cardiac surgery, lack of knowledge and malpractice of extracorporeal circulation may lead to serious complications. This article introduces different types of cannulae and their hydrodynamics during extracorporeal circulation. Characteristics of cannulae for extracorporeal circulation are described from viewpoints of material, requirements and technological background. Arterial perfusion cannulae have various flow patterns and affect shear stress on the aortic wall depending on the shape of each cannula exit. Technological background of venous drainage is also described. As a cardiovascular surgeon, it is important to understand the characteristics of each cannula in order to accomplish successful operation. Safe and effective means of providing sufficient arterial inflow in the presence of extensive aortic disease, such as atherosclerosis with aneurysm or dissections needs to be solved. PMID- 20715689 TI - [Extracorporeal circulation and cardiopulmonary bypass]. AB - Modern extracorporeal circulation is state of the art in science and technology. Development of cardiovascular surgery is based on the progress of extracorporeal circulation. If an accident occurs in extracorporeal circulation during a surgical procedure, the patient may suffer a severe injury of his vital organs. Safety management is essential in the operation of extracorporeal circulation for the repair of cardiovascular diseases. Standard manuals of safety management of cardiopulmonary bypass system has recently published by the Japan Society of Extracorporeal Circulation. Collaboration between surgeons and perfusionists is important to develop better cardiopulmonary bypass system and to keep the safety management at high level in cardiovascular surgery. PMID- 20715690 TI - [Heart positioners and proximal anastomotic devices in off-pump coronary artery bypass grafting]. AB - Owing to development of device technology, off-pump coronary artery bypass grafting (OPCAB) has become a safe, reproducible and reliable procedure. Surgeons must understand the advantages and limitations of each device and select appropriate devices in individual case to avoid device-related complication and a waste of cost. The directions and pitfalls of heart positioners, stabilizers and proximal anastomotic devices were described. With the improved heart positioners and stabilizers all coronary targets have been well visualized and accessible, maintaining hemodynamic stability. Automated proximal anastomotic devices and proximal anastomotic assist devices have reduced the occurrence of cerebral complications compared with the side-clamp of the ascending aorta. The appropriate use of devices in OPCAB would be a promising and cost-effective procedure for revascularization of ischemic heart disease. PMID- 20715691 TI - [Swan-Ganz catheter (pulmonary artery catheter)]. AB - Swan-Ganz catheter (SGC : pulmonary artery catheter) was introduced in clinical use by Swan HJ and Ganz W in 1970. Since then, the catheter has been used in many kinds of clinical fields, such as critical care medicine, cardiovascular surgery, anesthesia, and cardiology, because of its useful functions. SGC can easily advance into the pulmonary artery with its flow-directed balloon. The central venous pressure (CVP), the pulmonary artery pressure (PAP), and the pulmonary capillary wedge pressure (PCWP) can be measured, and cardiac output is obtained by thermodilution method. These days, SGC also has continuous cardiac output measurement system and mixed venous blood oxygen saturation monitoring system. Continuous cardiac output system automatically works by heating blood in the right atrium and ventricle with thermal filament periodically. Although SGC gives full diagnostic and therapeutic information of critically ill patients or cardiac surgical patients, all of the patients can not survive their tough critical clinical situation struggling with complications. Therefore, SGC has to be applied to the patients after thorough consideration whether the patients receive benefit of the catheter or not. Furthermore, the data obtained from SGC must be carefully interpreted to manage the patients. PMID- 20715692 TI - [Ablation devices in arrhythmia surgery]. AB - Creation of a conduction block is the rationale behind arrhythmia surgery. The "cut-and-sew" technique provides complete conduction block and a line of conduction block prevents propagation of abnormal activation and interrupts reentrant circuits. Alternative ablation devices have been developed to replace the "cut-and-sew" lesions in order to simplify the surgical procedure, decrease the risk of bleeding, and shorten the cardiac arrest and operative times during the surgery. However, ablation devices, such as traditional cryoablation, radiofrequency, micro wave, or ultrasound ablations, do not necessarily guarantee transmural and continuous necrosis. If the amount of surviving atrial myocardium in the incomplete ablation is a critical level, atrial activation can pass through the critical isthmus in the non-transmural or non-continuous lesion with slow conduction. Surgeons should know the precise mechanism of each surgical ablation device and have a good command of them to create complete transmural lesion. PMID- 20715693 TI - [New technology of intraaortic balloon pumping device]. AB - Intraaortic balloon pumping (IABP) is the most popular circulatory assist device in cardiac surgery. In the development of IABP several modifications have been made. First, reduction in the caliber to 6 Fr is the most important modification of the IABP catheter to relatively small Japanese patients. Second, direct pressure measurement through the tip of the catheter enabled more accurate and real-time assist. Third, a novel balloon pump automatically selects the trigger source, arranges the timing of the IABP inflation/deflation, and detects the arrhythmias. Further development of IABP will bring safer and more reliable hemodynamic management in cardiac surgery. PMID- 20715694 TI - [Technologies for cardiac valve prostheses]. AB - To show the technological development of cardiac valve prostheses, a historical review of both mechanical and biological valve prostheses and a current overview of modern cardiac valve devices are provided. Scince the 1st implantation of Starr-Edwards ball valve in 1960, both mechanical and biological valve prostheses have advanced. The valve design, the material of the leaflet and the hausing of mechanical prostheses have improved. Currently, the majority of the mechanical prostheses are bileaflet tilting disc valves made of pyrolytic carbon, which is antithromboembolic. However, anticoagulation therapy with warfarin is still required. As for the bioprostheses, although the fixation and anti-mineralization methods of the tissues improved, the durability of these valves is still limited. For the material of the current biological valves, the porcine aortic valve or bovine pericardium are used. The tissues are fixed by non-pressure or low pressure method in glutaraldehyde solution. A stented and non-stented valves are available. Epoch-making events in this field are the implantation of new bioprosthetic valves using tissue engineering methods and the development of the transcatheter valve replacement therapies. PMID- 20715695 TI - [Artificial vascular grafts for thoracic aortic surgery]. AB - Because extracorporeal circulation is used in thoracic aortic surgery, artificial vascular grafts that does not leak blood in the presence of heparin is required, and artificial vascular grafts covered with biological components are mostly used. They are prepared by soaking Dacron grafts in bovine collagen or gelatin, and they possess the following characteristics: 1) zero porosity, 2) no need for preclotting, and 3) knitted Dacron grafts can also be used. In recent years, various surgical materials have also been developed and clinically used ; grafts with a branch for revascularization of the aortic arch or the thoracoabdominal aorta, composite grafts for aortic root reconstruction, and Valsalva grafts. Recent advances in endovascular therapy have been remarkable, and various stent grafts have been developed and used worldwide. In Japan, Gore TAG (stent grafts for the thoracic aorta) was finally covered by insurance in July 2008 for the treatment of true aneurysms in the thoracic descending aorta. In Europe and USA, stent grafts with a branch are already being used clinically, while in Japan, a clinical study is being conducted on fenestrated stent grafts, and their indications for endovascular therapy may be expanded. PMID- 20715696 TI - [Ventricular assist device]. AB - There are 2 kinds of artificial heart used for clinical patients with end-stage heart failure. One is a ventricular assist device (VAD) and the other is a total artificial heart (TAH). Only paracorporeal VADs are commercially available currently in Japan, such as Toyobo VAD and BVS 5000. Paracorporeal Zeon VAD and implantable Novacor LVAD were approved by the MHLW in the past but already disappeared from the Japanese market in 2005 and 2006. A little more than 1,000 LVADs had been implanted since 1980 in Japan until last autumn, while no TAH has been implanted in patients. In the world 1st generation pulsatile implantable LVADs have been taken over by the 2nd and 3rd generation non-pulsatile implantable LVADs in the past 10 years. In Japan 4 kinds of implantable LVADs are under clinical evaluation, HeartMate XVE (1st generation, HeartMate VE was used in the Japanese clinical trial), Jarvik 2000 (2nd generation), Evaheart (2nd generation), and DuraHeart (3rd generation). All 5 patients with HeartMate VE survived more than 1 year during the clinical trial, 13 patients with Evaheart were long survivors or successfully heart-transplanted. Although follow-up interval is relatively short, all 6 patients with DuraHeart and 5 of the 6 patients with Jarvik 2000 recovered from end-stage heart failure and are keeping very good condition. Most of them returned to their home and are waiting for heart transplantation. Especially the 3rd generation of non-pulsatile LVADs is expected to have long-term durability and less frequency of thromboembolic episode. PMID- 20715697 TI - [Ultrasound, bronchoscopy]. AB - Endobronchial ultrasonography (EBUS) can be performed using either the balloon or direct contact method. We established that EBUS using 20 MHz probe shows 5 layers of the cartilaginous portion of extrapulmonary bronchus and intrapulmonary bronchus, and 3 layers of the membranous portion. EBUS for peripheral pulmonary lesions has 2 main impacts in bronchoscopic diagnosis. One impact is to analyze the internal structures of peripheral pulmonary lesions, and another impact is to detect the location of peripheral pulmonary lesions during bronchoscopy. EBUS using a guide sheath (EBUS-GS) provides the pathway to peripheral pulmonary lesions. One advantage of EBUS-GS lies in the repeatability of access to the bronchial lesion for sampling. Another advantage of EBUS-GS lies in its ability to protect against bleeding into proximal bronchus from the biopsy site. The final advantage of EBUS-GS is the ability to obtain short-axis bronchial views of peripheral pulmonary lesions. For the successful EBUS-trans-bronchial needle aspiration (TBNA), there are some knacks. One knack is not to puncture the bronchial cartilage by the needle. For getting adequate specimens, the stylet is important part of the needle. After the needle is removed from the bronchoscope, the stylet is inserted into the needle once again to push out the specimens on the filter paper. PMID- 20715698 TI - [Thoracoscopic surgery]. AB - Thoracoscopic apparatus is essential in present general thoracic surgery. Historically, the first description of diagnostic use of thoracoscopy traces back to 1910 when Jacobaeus inspected thoracic cavity with cystoscope. In Japan, Kimoto treated lung tuberculosis by thoracic ablation with thoracoscope in 1944. Thereafter thoracoscopic procedure did not spread until 1990's when laparoscopic cholecystectomy had rapidly popularized in Japan. After 1992 many reports about thoracoscopic surgery or video-assisted thoracic surgery (VATS) were published. In the early years VATS was done only for spontaneous pneumothorax, and then indication of VATS had been gradually extended for lung cancer, mediastinal tumor and other thoracic diseases. Nowadays 40% of lung cancer operations are done by VATS in Japan. A thoracoscopic surgery is minimal invasive procedure in operations of thoracic diseases, but should not be mixed with a limited operation of the thoracic diseases. It is necessary to understand that these are different meanings. In VATS the technical procedures are different from the conventional general thoracic surgical procedures and operators have to take special trainings of VATS procedure. But at present we do not have effective training systems of VATS for beginner surgeons. Various training method such as training box, animal laboratory, virtual reality system are effective respectively therefore an accurate training system should be made as soon as possible. Operators should keep in mind that the procedure of VATS or standard thoracotomy operation is not a question and that the most important is to perform a smooth operation in adequate time for patients ease. PMID- 20715699 TI - [Stapler]. AB - The use of endostaplers during thoracoscopic pulmonary resections has been a common procedure for respiratory surgeons. In Japan, we can choose 2 different types of staplers from 2 companies, namely, Tyco Healthcare Japan and Johnson & Johnson company. The staplers from each company show different characteristics. Therefore, we should choose which stapler to use by each character equipped. Each stapler has differences in compatibilities of cartridges, in sizes and in weights. Some adverse events or incidents were attributable to surgical or technical errors; many of them might be linked to the device. This manuscript aims to explain the differences and advantages in each stapler and to help to choose which stapler is suitable. However, we have to do surgery taking malfunctions of devices into consideration at all times. PMID- 20715700 TI - [Sentinel lymph node mapping in non-small cell lung cancer]. AB - The sentinel node (SN) concept is that lymphatic flux from a primary tumor initially flows into the SN. If this concept is correct, and metastasis is not found in a SN, it almost certainly that metastasis is not present in more distal lymph nodes. SN mapping and biopsy were developed as techniques for staging the lymphatic basin without the potential morbidity of lymph edema and nerve injury in cases of melanoma, or lymph edema of the arm in cases of breast cancer. Although there is also evidence of the existence of SN in non-small cell lung cancer (NSCLC), SN mapping is not widely used in the treatment of NSCLC. The potential benefit of SN mapping in NSCLC is enabling surgeons to know more precise staging of cancer. More sensitive techniques can be employed with a limited amount of tissue to detect micrometastasis. In addition, SN mapping can be applied to appropriate segmentectomy for NSCLC. PMID- 20715701 TI - [Virtual reality in video-assisted thoracoscopic lung segmentectomy]. AB - The branching patterns of pulmonary arteries and veins vary greatly in the pulmonary hilar region and are very complicated. We attempted to reconstruct anatomically correct images using a freeware program. After uploading the images to a personal computer, bronchi, pulmonary arteries and veins were traced by moving up and down in the images and the location and thickness of the bronchi and pulmonary vasculture were indicated as different-sized cylinders. Next, based on the resulting numerical data, a 3D image was reconstructed using Metasequoia shareware. The reconstructed images can be manipulated by virtual surgical procedures such as reshaping, cutting and moving. These system would be very helpful in complicated video-assisted thoracic surgery such as lung segmentectomy. PMID- 20715702 TI - [Laser therapy for endobronchial malignancies]. AB - Photodynamic therapy (PDT), neodymium yttrium aluminum garnet (Nd-YAG) laser therapy, electrocautery and microwave coagulation therapy are therapeutic options available for management of endobronchial malignancies. All of these treatment modalities have been used for both palliation of late obstructing cancers, and more recently have been used as primary treatment of early stage lung cancers. Only PDT has the curative potential for patients with early superficial squamous cell carcinoma. Nd-YAG laser therapy is used for direct thermal ablation of tissue in endobronchial malignancy. This equipment is the most widely used type of laser for bronchoscopic interventions because it has sufficient power to vaporize tissues and produces an excellent coagulation effect. But the risks of perforation and bleeding are high. Endobronchial electrocautery is the use of high-frequency electrical current that generates heat due to tissue resistance, resulting in destruction of tissue. Argon plasma coagulation (APC) is a form of noncontact electrocoagulation. The risks of perforation and igniting are much lower than with the Nd-YAG laser therapy. Microwave coagulation therapy refers to the use of all electromagnetic methods for inducing tumor destruction by using devices with frequencies of 2450 MHz. It is important to select these treatment methods appropriately according to each case. PMID- 20715703 TI - [Thoracic drainage]. AB - The thoracic drainage system is a sophisticated and useful technology, especially in thoracic surgery. therefore, lung resections are able to be performed safely in spite of air leaks which are a common problem after pulmonary resection. The thoracic drainage system is called the 3 bottles system, which are consisted of a drainage-bottle, an underwater-seal-bottle, and a continuous low-pressure-suction devise. Based on this basic structure, a lot of convenient thoracic drainage products such as a small thoracic drainage kit for pneumothorax have been developed. Some chest tubes which changed tubal form for efficient drainage are developed as well. However, each product has both advantages and disadvantages, then, we should understand characteristics of those new products and know the physiology of respiratory, when we use them. PMID- 20715704 TI - [Clinical application of sentinel node navigation surgery for esophageal cancer]. AB - In esophageal cancer, sentinel nodes (SNs) are identified as multiple nodes and widely spread from cervical to abdominal areas. In more than 80% of the cases, at least one SN is located in the 2nd or 3rd compartment of regional lymph nodes which have been considered to be "skip metastases". This characteristic distribution of SNs is attributed to the multi-directional lymphatic drainage routes from the esophagus. Clinical application of SN navigation surgery will be expected to play a key role for intraoperative diagnosis for lymph node metastasis and individualized multimodal therapy in patients with cT1N0 esophageal cancer. PMID- 20715705 TI - [Simulation of thoracoscopic esophagectomy for esophageal cancer by three dimensional computed tomography and usefulness for preservation of bronchial arteries]. AB - Thoracoscopic esophagectomy for esophageal cancer was simulated preoperatively by 3-dimensional computed tomography (3D-CT). The anatomical structures such as major vessels, bone, trachea and bronchi, esophagus, lymph nodes, and broncial arteries were extracted from multi-detector row CT scanning and integrated to build the virtual operative field by multi-volume fusion. The virtual thoracoscopy was helpful to understand the location of lymph nodes and bronchial arteries in relation to the adjacent anatomical structures. Preservation of bronchial arteries is important to avoid tracheobronchial ischemia which is a fatal complication in salvage esophagectomy after definitive chemoradiotherapy. 3D-CT revealed anatomical variations of bronchial arteries and was useful for identification and preservation of bronchial arteries in thoracoscopic esophagectomy. PMID- 20715706 TI - [New ways of education for inservice faculty]. PMID- 20715707 TI - [Possibilities of prevention of nephrotoxicity in intensive care unit]. AB - Different nephrotoxic drugs (antibiotic, antifungal, chemotherapeutic, NSAR, cyclosporine) as well as radio contrasts are mainly responsible for impairment of the renal funciton. Some patient populations, like diabetics, older patients and dehydrated patients are in additional risk for kidney failure. The challenge for protection of kidney function is complex, but it is possible in different clinical conditions to influence nephrotoxicity. The prevention of acute renal failure is very important, because this complication is according to many publications a significant risk for mortality. The administration of N acetilcystein, bicarbonate infusion, magnesium infusion, calcium channel blockers are promising strategies. It is very important to stress adequate rehydratation of every single patient, but some patient populations like diabetics, older patients and dehydrated patients are in special risk for nefrotoxicity. Because today radio contrast media are also important reason for nephrotoxicity, the use of low and iso-osmolar contrasts provides additional possibilities for prevention of potential nephrotoxicity. PMID- 20715708 TI - [Hemodynamic changes caused by cardiac arrhythmia]. PMID- 20715709 TI - Introducing Broselow colour coded system for paediatric emergency management in a non paediatric general hospital. AB - Paediatric emergency management is a very stressful clinical event especially when it occurs in a non paediatric hospital. Low self confidence, non familiarity with drug dosages and proper equipment selection are the main cause of professional insecurity. In this paper, after a short review dealing with main differences between child and adult patient, we consider the advantages offered by Broselow method approach to paediatric emergences. Finally we describe the strategy we followed to introduce Broselow method in our Institution. PMID- 20715710 TI - Hemodynamic monitoring for less invasive cardiovascular surgery. AB - Surgery does not start with the incision and end with skin suturing. Successful surgical outcome depends on close interaction between the anesthesiology, surgery and intensive care units (ICU). Adequate patient monitoring is essential part of all aforementioned departments. Using adequate hemodynamic and neurologic monitoring, less invasive anaesthesia with less invasive cardiac and vascular surgery can be performed safely, leading to better surgical results, greater patient comfort and satisfaction, and reduced hospital stay. PMID- 20715711 TI - [Lipopeptides and oxazolidinones--novel antibiotics in MRSA infection treatment]. AB - Last few years vancomycin-intermediate S. aureus and vancomycin-resistent S. aureus have emerged, giving us a task to reevaluate susceptiblity to vancomycin in treatment of methicillin-resistent S. aureus (MRSA) infections. It is also oportunity to review necessity for new generation of antibiotics in treatment of MRSA infections. Efficacy of vancomycin treatment in MRSA bacteriemia is associated with minimal inhibitory concentration (MIC) and speed of killing colonies. There is an increased probability of failure in treatment of MRSA bacteremia when there are high vancomycin MIC in vitro. That's one of the reasons why there is novel antibiotic therapy for MRSA investigated, especially daptomycin and linezolid. Daptomycin is lipopeptide and an important optional antibiotic in MRSA infections treatment: bacteremia and endocarditis, even the tricuspidal valve endocarditis. Linezolid, as novel oxazolidinon, has shown good activity against gram-positive bacteria, especially in treatment of nosocomial pneumonia and complicated skin and soft tissue infections caused by MRSA. PMID- 20715712 TI - Perioperative fluid balance in patients with heart failure. AB - Careful assessment of fluid balance is required in the perioperative period since appropriate fluid therapy is essential for successful patient outcomes. Volume status is frequently assessed by different hemodynamic variables that could be targeted as endpoints for fluid therapy and resuscitation. Goal directed fluid therapy is a method for correction of fluid status in individual patients that includes invasive hemodynamic monitoring and aggressive perioperative correction of hemodynamics. Heart failure is a syndrome of ventricular dysfunction. It is associated with a variety of patophysiological disturbances, hydro-electrolyte balance disorders and compensatory mechanisms. Heart failure indicates careful assessment of fluid balance in perioperative period. The aim of this article is to describe actual techniques of hemodynamic measurements as well as main principles of fluid therapy to maintain hydro-electrolyte balance in patients with heart failure. PMID- 20715713 TI - [Acute coronary syndrome: monitoring and invasive treatment]. AB - Acute coronary syndromes whose clinical spectrum consists of unstable angina pectoris, non-ST-elevation myocardial infarction and ST-elevation myocardial infarction carry the greatest risk of death and severe complications to patients with coronary artery disease. Patients with acute coronary syndromes may be submitted to conservative or invasive management, with differences in the timing of invasive management in patients selected for that strategy. Early diagnosis, good monitoring and appropriate global assessment of every patient improve the selection of patients for adequate modality of treatment that will prevent death, complications and other serious events. PMID- 20715714 TI - [Modern systems for hemodynamic monitoring]. PMID- 20715715 TI - [Biofilm--still a problem?]. AB - Biofilm formation is a crucial step in the pathogenesis of many subacute and chronic bacterial infections, including foreign body-related infections. Biofilms are difficult to eradicate with conventional antimicrobial agents. Bacterial biofilms have several potential antimicrobial resistance mechanisms. Persister cells play a major role in the tolerance of biofilm bacteria to antimicrobial agents. The most common microorganisms responsible for about two thirds of infections with foreign material are biofilm-forming bacteria such as staphylococci (Staphylococcus aureus, S. epidermidis, S. lungdunensis), followed by Pseudomonas aeruginosa and Enterococcus spp, as well as fungal infections such as Candida sp. Preventing early colonisation is a good strategy for reducing morbidity and furthermore, reducing biofilm-associated infection reduces the need for antibiotic use. PMID- 20715716 TI - Continous monitoring of central venous oxygen saturation in children and infants. AB - Maintenance of adequate tissue oxygenation is an important task in intensive care units. There are many variables which are measured for this purpose. Central venous oxygen saturation (ScvO2) monitoring has some advantages over the mixed venous oxygen saturation (SvO2) monitoring in children and infants as there is no need to insert a pulmonary catheter. The clinical usefulness seems promising. PMID- 20715717 TI - Preload assessment and optimization in critically ill patients. AB - Preload assessment and optimization is the basic hemodynamic intervention in critically ill. Beside clinical assessment, non-invasive or invasive assessment by measurement of various pressure or volume hemodynamic variables, are helpful for estimation of preload and fluid responsiveness. The use of dynamic variables is useful in particular subgroup of critically ill patients. In patients with inadequate preload, fluid responsiveness and inadequate flow, treatment with crystalloids or colloids is mandatory. When rapid hemodynamic response is necessary colloids are preferred. PMID- 20715718 TI - The diagnostic value of troponin in critically ill. AB - Troponin T and I are sensitive and specific markers of myocardial necrosis. They are used for the routine diagnosis of acute coronary syndrome. In critically ill patients they are basic diagnostic tool for diagnosis of myocardial necrosis due to myocardial ischemia. Moreover, the increase of troponin I and T is related with adverse outcome in many subgroups of critically ill patients. The new, high sensitivity tests which have been developed recently allow earlier and more accurate diagnosis of acute coronary syndrome. The use of the new tests has not been studied in critically ill patients, but they will probably replace the old tests and will be used on the routine basis. PMID- 20715719 TI - [News in hemodynamic monitoring, resuscitation and intensive care of patients after cardiac surgery: "Guidelines for resuscitation in cardiac arrest after cardiac surgery" of the European Association for Cardio-Thoracic Surgery]. AB - In order to simplify and to standardize procedures during cardiac arrest in patients after cardiac surgery and for professional medical staff education, working group of the European Association for Cardio-Thoracic Surgery issued in 2009 "Guideline for resuscitation in cardiac arest after cardiac surgery". There are several differences between these guidelines and guidelines for general population: in ventricular fibrillation, three sequential attempts at defibrillation should precede external cardiac massage; in asystole or extreme bradycardia, pacing should precede external cardiac massage. Where the above measures fail, and in pulseless electrical activity, early resternotomy is advocated. Adrenaline should not be routinely given. Also protocols for excluding reversible airway and breathing complications and for safe emergency resternotomy are given. These guidelines in very simple and professional way define rules for resuscitation of patients after cardiac surgery. It is a useful manual which will certainly find its place in daily work of professional medical staff involved in healthcare of these patients. PMID- 20715720 TI - [Splanchnic perfusion in anesthesia and intensive medicine]. PMID- 20715721 TI - The history of capnography. PMID- 20715722 TI - Dexamethasone for postoperative nausea and vomiting: time for a definitive phase IV trial. PMID- 20715723 TI - Equivalence and noninferiority in anaesthesia research. PMID- 20715724 TI - Systemic levels of local anaesthetic after intra-peritoneal application--a systematic review. AB - There is a lack of cohesive reports on the systemic levels of local anaesthetic after intraperitoneal application. A comprehensive systematic review with no language restriction was conducted. Eighteen suitable articles were identified. Data were compiled and presented according to local anaesthetic agent. Intraperitoneal local anaesthetic has been studied in many different procedures, including open and laparoscopic surgery. A total of 415 patients were included for analysis. There were no cases of clinical toxicity. There were 11 (2.7%) cases with a systemic level above or close to a safe threshold (as determined by the report authors) in three trials utilising intraperitoneal local anaesthetic after laparoscopic cholecystectomy. Intraperitoneal lignocaine doses varied from 100 to 1000 mg, mean Cmax ranged from 1.01 to 4.32 microg/ml and mean Tmax ranged from 15 to 40 minutes. Intraperitoneal bupivacaine doses varied from 50 to 150 mg (weight based doses also reported), mean Cmax ranged from 0.29 to 1.14 microg/ml and mean Tmax ranged from 15 to 60 minutes. Intraperitoneal ropivacaine doses varied from 100 to 300 mg, mean Cmax ranged from 0.66 to 3.76 microg/ml and mean Tmax ranged from 15 to 35 minutes. The addition of adrenaline to intraperitoneal local anaesthetic almost halves systemic levels and prolongs Tmax. Intraperitoneal local anaesthetic results in detectable systemic levels in the perioperative setting. Despite a lack of clinical toxicity, careful attention to dose is still required to prevent potential systemic toxic levels. Clinicians should also consider the addition of adrenaline to intraperitoneal local anaesthetic solutions to further add to the systemic safety profile. PMID- 20715725 TI - Formal and informal fallacies in anaesthesia. AB - Formal and informal fallacies refer to errors in reasoning or logic, which result from invalid arguments. Formal fallacies refer to arguments that have an invalid structure or 'form', while informal fallacies refer to arguments that have incorrect or irrelevant premises. There are many formal and informal fallacies that could theoretically occur in anaesthesia practice or in the appraisal of anaesthesia research. This paper describes several such potential fallacies. It is possible that a greater awareness, recognition and discussion of these logic based errors will lead to improved patient safety and more informed appraisal of clinical research. PMID- 20715726 TI - Effects of fluid preload (crystalloid or colloid) compared with crystalloid co load plus ephedrine infusion on hypotension and neonatal outcome during spinal anaesthesia for caesarean delivery. AB - Preload with crystalloid or colloid solution is widely recommended for the prevention of maternal hypotension during spinal anaesthesia. A combination of simultaneous rapid crystalloid infusion with vasopressor has also been suggested. This study tested the hypothesis that ephedrine infusion with crystalloid loading at spinal anaesthesia would reduce hypotension and alter neonatal outcome compared with fluid preloading. One hundred and twenty women undergoing elective caesarean delivery were randomly allocated to one of three groups to receive rapid infusion of lactated Ringer's solution (20 ml.kg(-1), n=40) or 4% succinylated gelatin solution (500 ml, n =40) before spinal anaesthesia or an ephedrine infusion (1.25 mg.minute(-1)) plus lactated Ringer's solution (1000 ml, n=40) after spinal anaesthesia. The incidence of hypotension (moderate and severe) and the ephedrine dose used to treat hypotension were compared. Neonatal outcome was assessed using Apgar scores and umblical venous and arterial blood gas analysis. The frequency of moderate or severe hypotension was lower in the ephedrine group than in the crystalloid or colloid preload group (10% vs. 51% and 38%; 5% vs. 21% and 23% respectively, P < 0.05). The incidence of nausea was significantly different between the crystalloid preload and ephedrine group. Umbilical blood gas analysis and Apgar scores were similar in all groups. A combination of an ephedrine infusion at 1.25 mg.minute(-1) with a crystalloid co load was more effective than fluid preloading with crystalloid or colloid in the prevention of moderate and severe hypotension. PMID- 20715727 TI - Anti-emetic dexamethasone and postoperative infection risk: a retrospective cohort study. AB - Nausea and vomiting are common complications of anaesthesia. Dexamethasone is an effective prophylaxis but is immunosuppressive and may increase postoperative infection risk. This retrospective cohort study examined the association between the administration of a single intraoperative anti-emetic dose of dexamethasone (4 to 8 mg) and postoperative infection in 439 patients undergoing single procedure, non-emergency surgery in a university trauma centre. Exclusion criteria included comorbidities, immunosuppressive medications or procedures that confer an increased infection risk. In the 10-week study period and three-month follow-up period, there were 98 documented infections (22.3% of the cohort), of which 43 were detected only on post-discharge follow-up. Anti-emetic dexamethasone was given to 108 patients (24.6%). Stepwise, multivariate logistic regression modelling identified significant associations between female gender, symptomatic reflux, respiratory disease and the risk of infection. The adjusted odds ratio for dexamethasone was 0.88 (0.5 to 1.5, P = 0.656). We did not demonstrate an association between anti-emetic doses of dexamethasone and postoperative infection. PMID- 20715728 TI - Single dose dexamethasone for postoperative nausea and vomiting--a matched case control study of postoperative infection risk. AB - Dexamethasone is an effective prophylaxis against postoperative nausea and vomiting but is immunosuppressive and may predispose patients to an increased postoperative infection risk. This matched case-control study examined the association between the administration of a single intraoperative anti-emetic dose of dexamethasone (4 to 8 mg) and postoperative infection in patients undergoing non-emergency surgery in a university trauma centre. Cases were defined as patients who developed infection between one day and one month following an operative procedure under general anaesthesia. Controls who did not develop infection were matched for procedure, age and gender Exclusion criteria included immunosuppressive medications, chronic glucocorticoid therapy, cardiac surgical and solid-organ transplantation procedures. Sixty-three cases and 172 controls were identified. Cases were more likely to have received dexamethasone intraoperatively (25.4 vs. 11%, P = 0.006), and less likely to have received perioperative antibiotic prophylaxis (60.3 vs. 84.3%, P = 0.001). Stepwise, multivariate conditional logistic regression confirmed these associations, with adjusted odds ratios of 3.03 (1.06 to 19.3, P = 0.035) and 0.12 (0.02 to 0.7, P = 0.004) respectively for the associations between dexamethasone and perioperative antibiotic prophylaxis, with postoperative infection. We conclude that intraoperative administration of dexamethasone for anti-emetic purposes may confer an increased risk of postoperative infection. PMID- 20715730 TI - The safety of recombinant factor VIIa in cardiac surgery. AB - We investigated whether there was an association between recombinant activated factor VII (rFVIIa) use in cardiac surgery and thromboembolic events by comparing cases in two medical registries. The incidence of thromboembolic events in patients undergoing cardiac surgery (except isolated coronary artery bypass grafts) who had received rFVIIa and were entered into the Australian and New Zealand Haemostasis Registry was compared with the background incidence in patients entered in the Australasian Society for Cardiac and Thoracic Surgeons database. Mortality, length of hospital stay and thromboembolic complications such as stroke, perioperative myocardial infarction and pulmonary embolism data were analysed. A total of 705 patients in the Registry were compared with 6554 patients in the Thoracic Surgeons database. The use of rFVIIa was independently associated with higher mortality (odds ratio 2.55, P < 0.001) and longer hospital stay (odds ratio 1.54, P = 0.020). However multiple regression analyses showed no independent association between rFVIIa and stroke (odds ratio 1.0, P = 0.994) or perioperative myocardial infarction (odds ratio 0.29, P = 0.053), while the use of rFVIIa was associated with fewer pulmonary emboli (odds ratio 0.02, P < 0.001). These findings indicate that patients who received rFVIIa had increased mortality and length of hospital stay, as expected, but that rFVIIa use was not associated with an increased incidence of stroke or perioperative myocardial infarction. In the absence of randomised controlled clinical trials, this analysis suggests that the off-label use of rFVIIa in cardiac surgery does not significantly increase thromboembolic events. PMID- 20715729 TI - Anti-emetic doses of dexamethasone suppress cortisol response in laparoscopic cholecystectomy. AB - The efficacy of dexamethasone alone or in combination with a serotonergic antagonist to prevent nausea and vomiting in laparoscopic cholecystectomy is well established, but few data exist regarding its effects on perioperative cortisol and glucose levels. Fourteen non-diabetic subjects having elective laparoscopic choleycystectomy and standardised general anaesthesia were randomised to receive 8 mg of intravenous dexamethasone and tropisetron or tropisetron alone. Plasma cortisol and glucose were measured preinduction, at five and 24 hours postoperatively. There was no difference in plasma cortisol at five hours postoperatively in patients who received dexamethasone, but by 24 hours there was marked suppression compared to the control group (P < 0.005) to less than 5% of the preoperative value. There was a small but statistically significant elevation in blood glucose at 24 hours (P < 0.01) in the dexamethasone-treated group. In patients undergoing laparoscopic cholecystectomy, an anti-emetic dose of dexamethasone (8 mg) markedly suppresses plasma cortisol at 24 hours and causes a minor elevation in blood glucose. PMID- 20715731 TI - A retrospective study to determine whether accessing frequency affects the incidence of microbial colonisation in peripheral arterial catheters. AB - Peripheral arterial catheters are used for the continuous monitoring of blood pressure and repeated blood sampling in critically ill patients, but can be a source of catheter-related bloodstream infection. A common assumption is that the more frequently an arterial catheter is accessed, the greater the likelihood of contamination and colonisation to occur We sought to determine whether the accessing frequency has an influence on the rate of colonisation in a peripheral arterial catheter A retrospective, unmatched, nested case control study was conducted in our intensive care unit. The intensive care unit charts of 96 arterial catheters from 83 patients were examined to measure the number of times each respective arterial catheter was accessed. Multivariate Cox proportional hazards regression was used to compare the rate of accessing of arterial catheters and account for varying arterial catheter in situ duration. Arterial catheters which had a high access rate of 8.1 or more times/day (five colonised of 32 patients: hazards ratio 1.69, 95% confidence interval 0.52 to 5.49; P = 0.77), or a medium access rate of 6.7 to 8.0 times/day (six colonised of 32 patients: hazards ratio, 1.35, 95% confidence interval, 0.37 to 4.92: P = 0.65) were not significantly more colonised when compared to arterial catheters which had a low access rate of O to 6.6 times/day (six colonised of 32 patients), adjusted for arterial catheter insertion site and place in hospital where the arterial catheter insertion was performed. We were unable to demonstrate that the accessing frequency of an arterial catheter was a major predisposing factor for the likelihood of colonisation. Other mechanisms other than hub colonisation should be investigated further. PMID- 20715732 TI - Modern blood filters do not need to be routinely changed for the majority of red blood cell transfusions in New Zealand. AB - Two experimental studies were undertaken to determine if blood flow rate changes and/or red blood cell damage occurs during red cell transfusion via a single blood filter In the first study, 12 experiments were performed in each of which four units of group specific human red blood cells, followed by 500 ml 0.9% saline were sequentially run through a blood filter/intravenous giving set system connected to a 14 gauge intravenous cannula positioned two metres below the filter The second study involved ten experiments with ten units per experiment using the same methodology. In each study, flow rates of each red cell unit/saline were measured. Average flow rates did not decrease with subsequent red cell units in either the four- or ten-unit studies. There was no significant change in blood flow rates across the ten-unit transfusion (P = 0.4). In both studies, blood was taken before and after the blood filter from the first, fourth and tenth units of red blood cells, and was measured for haemoglobin, haematocrit, lactate dehydrogenase, potassium, haemolysis levels and red cell morphology. Haemolysis and lactate dehydrogenase levels decreased after blood filtration. Red cell morphology was unchanged in the four-unit study and tended to improve in the ten-unit study. We found no evidence that red blood cell damage is increased during such transfusion. PMID- 20715733 TI - Warming the epidural injectate improves first sacral segment block: a randomised double-blind study. AB - This study investigated the effect of local anaesthetic temperature on block of the first sacral segment. Twenty-four patients undergoing lumbar epidural anaesthesia at L2-3 or L3-4 were randomly divided in double-blind fashion into two groups to receive 22 ml of lignocaine 2% with adrenaline 1:200,000, sodium bicarbonate and fentanyl, at either 21 degrees C (cold group) or 37 degrees C (warm group). The sensory block was assessed by loss of sensation to pinprick and the pain threshold after repeated electrical stimulation at L2, S1 and S3 dermatomes. Motor block was evaluated using the modified Bromage scale. Patient characteristics were comparable between the groups. Onset of block at the first sacral segment (S1) was faster in the warm group than in the cold (10 vs. 17.5 minutes, P < 0.001). The pain threshold at S1 was significantly higher in the warm group. We concluded that epidural lignocaine 2% with adrenaline 1:200,000, sodium bicarbonate and fentanyl injected at 370C hastens SI block within 10 minutes of administration. PMID- 20715734 TI - Glycaemic fluctuation predicts mortality in critically ill patients. AB - Growing evidence suggests that glycaemic variability increases diabetic complications. However, the significance of glycaemic variability in critically ill patients remains unclear. We evaluated the predictors of glycaemic fluctuation and its association with critical care outcomes. This is a nested cohort study within a clinical trial in which 523 patients at a medical surgical intensive care unit were randomised to either intensive insulin therapy (target glycaemic control: 4.4 to 6.1 mmol/l) or conventional insulin therapy (target control: 10.0 to 11.1 mmol/l). Glycaemic fluctuation was defined as the mean difference between the highest and lowest daily blood glucose. Patients were divided into wide and narrow fluctuation groups according to the median glycaemic fluctuation (6.0 mmol/l). The association between glycaemic fluctuation and different intensive care unit outcomes was studied. Predictors of glycaemic fluctuation were age (odds ratio for each year increment 1.03, 95% confidence interval 1.02 to 1.05), diabetes mellitus (odds ratio 3.00, 95% confidence interval 1.74 to 5.17), and daily insulin dose (odds ratio for each unit increment 1.04, 95% confidence interval 1.03 to 1.05). Similar levels of glucose fluctuation were observed in intensive insulin therapy and conventional insulin therapy patients. Wide glycaemic fluctuation was associated with higher mortality (22.2 vs. 8.4%, P < 0.001). Glycaemic fluctuation was identified as an independent predictor of intensive care unit mortality (odds ratio per mmol 1.08, 95% confidence interval 1.00 to 1.18) and hospital mortality (odds ratio per mmol 1.09, 95% confidence interval 1.02 to 1.17) using multivariate logistic regression analysis. In conclusion, wide glycaemic fluctuation is an independent predictor of mortality in critically ill patients. Whether reducing glycaemic fluctuation would lead to better outcomes needs further evaluation. PMID- 20715735 TI - Changes in case-mix and outcomes of critically ill patients in an Australian tertiary intensive care unit. AB - Critical care service is expensive and the demand for such service is increasing in many developed countries. This study aimed to assess the changes in characteristics of critically ill patients and their effect on long-term outcome. This cohort study utilised linked data between the intensive care unit database and state-wide morbidity and mortality databases. Logistic and Cox regression was used to examine hospital survival and five-year survival of 22,298 intensive care unit patients, respectively. There was a significant increase in age, severity of illness and Charlson Comorbidity Index of the patients over a 16-year study period. Although hospital mortality and median length of intensive care unit and hospital stay remained unchanged, one- and five-year survival had significantly improved with time, after adjusting for age, gender; severity of illness, organ failure, comorbidity, 'new' cancer and diagnostic group. Stratified analyses showed that the improvement in five-year survival was particularly strong among patients admitted after cardiac surgery (P = 0.001). In conclusion, although critical care service is increasingly being provided to patients with a higher severity of acute and chronic illnesses, long-term survival outcome has improved with time suggesting that critical care service may still be cost-effectiveness despite the changes in case-mix. PMID- 20715736 TI - Effects of age and coronary artery disease on cerebrovascular reactivity to carbon dioxide in humans. AB - Alterations in cerebrovascular reactivity to CO2, an index of cerebrovascular function, have been associated with increased risk of stroke. We hypothesised that cerebrovascular reactivity is impaired with increasing age and in patients with symptomatic coronary artery disease (CAD). Cerebrovascular and cardiovascular reactivity to CO2 was assessed at rest and during hypercapnia (5% CO2) and hypocapnia (hyperventilation) in subjects with symptomatic CAD (n=13) and age-matched old (n=9) and young (n=20) controls without CAD. Independent of CAD, reductions in middle cerebral artery blood velocity (transcranial Doppler) and cerebral oxygenation (near-infrared spectroscopy) were correlated with increasing age (r = -0.68, r = -0.51, respectively, P < 0.01). In CAD patients, at rest and during hypercapnia, cerebral oxygenation was lower (P < 0.05 vs. young). Although middle cerebral artery blood velocity reactivity was unaltered in the hypercapnic range, middle cerebral artery blood velocity reactivity to hypocapnia was elevated in the CAD and age-matched controls (P < 0.01 vs. young), and was associated with age (r = 0.62, P < 0.01). Transient drops in arterial PCO2 occur in a range of physiological and pathophysiological situations, therefore, the elevated middle cerebral artery blood velocity reactivity to hypocapnia combined with reductions in middle cerebral artery blood velocity may be important mechanisms underlying neurological risk with aging. In CAD patients, additional reductions in cerebral oxygenation may place them at additional risk of cerebral ischaemia. PMID- 20715737 TI - The effect of remifentanil on the incidence of agitation on emergence from sevoflurane anaesthesia in children undergoing adenotonsillectomy. AB - The aim of the present study was to assess the effect of remifentanil on the incidence of emergence agitation in preschool-aged children undergoing adenotonsillectomy with sevoflurane anaesthesia. Sixty children, aged three to seven years, American Society of Anesthesiologists physical status I or II, were randomised into either group S (sevoflurane alone, n=30) or group R (sevoflurane plus remifentanil, n=30). Anaesthesia was induced with an intravenous bolus injection of fentanyl 3 microg/kg and propofol 2.5 mg/kg. Endotracheal intubation was facilitated by vecuronium 0.1 mg/kg. All patients were ventilated with 50% nitrous oxide and 1.5 to 2.5% sevoflurane in oxygen. End-tidal CO2 was maintained at 35 +/- 4 mmHg. Group S received no other medication while group R received remifentanil 1 microg/kg/minute intraoperatively. Mean blood pressure, heart rate, pulse oximetry, eye-opening time and extubation time were recorded in the operating room. In recovery, emergence agitation was assessed using the Pediatric Anesthesia Emergence Delirium scale with a score > or =10 taken as indicating agitation. Emergence agitation occurred in 20 of the 30 patients in group S and seven of the 30 patients in group R (P < 0.01). In preschool-aged children undergoing adenotonsillectomy with sevoflurane general anaesthesia, after propofol and fentanyl induction, intraoperative remifentanil decreased the incidence of emergence agitation. PMID- 20715738 TI - Unplanned early readmission to the intensive care unit: a case-control study of patient, intensive care and ward-related factors. AB - The purpose of this study was to identify patient, intensive care and ward-based risk factors for early, unplanned readmission to the intensive care unit. A five year retrospective case-control study at a tertiary referral teaching hospital of 205 cases readmitted within 72 hours of intensive care unit discharge and 205 controls matched for admission diagnosis and severity of illness was conducted. The rate of unplanned readmissions was 3.1% and cases had significantly higher overall mortality than control patients (odds ratio [OR] 4.7, 95% confidence interval [CI] 2.1 to 10.7). New onset respiratory compromise and sepsis were the most common cause of readmission. Independent risk factors for readmission were chronic respiratory disease (OR 3.7, 95% CI 1.2 to 12, P = 0.029), pre-existing anxiety/depression (OR 3.3, 95% CI 1.7 to 6.6, P < 0.001), international normalised ratio >1.3 (OR 2.3, 95% CI 1.1 to 4.9, P = 0.024), immobility (OR 2.3, 95% CI 1.4 to 3.6, P = 0.001), nasogastric nutrition (OR 2.0, 95% CI 1.0 to 4.0, P = 0.041), a white cell count > 15 x 10(9)/l (OR 2.0, 95% CI 1.2 to 3.4, P = 0.012) and non-weekend intensive care unit discharge (OR 1.9, 95% CI 1.1 to 3.5, P = 0.029). Physiological derangement on the ward (OR 26, 95% CI 8.0 to 81, P < 0.001) strongly predicted readmission, although only 20% of patients meeting medical emergency team criteria had a medical emergency team call made. Risk of readmission is associated with both patient and intensive care factors. Physiological derangement on the ward predicts intensive care unit readmission, however, clinical response to this appears suboptimal. PMID- 20715739 TI - Healthcare utilisation among patients discharged from hospital after intensive care. AB - Surviving critical illness can be life-changing and presents new healthcare challenges for patients after hospital discharge. This feasibility study aimed to examine healthcare service utilisation for patients discharged from hospital after intensive care unit stay. Following Ethics Committee approval, patients aged 18 years and older were recruited over three months. Those admitted after cardiac surgery, discharged to another facility or against medical advice were excluded. Patients were informed of the study by post and followed-up by telephone at two and six months after discharge. General practitioners were also contacted (44% responded). Among 187 patients discharged from hospital, 11 died, 25 declined to participate and 39 could not be contacted. For 112 patients (60%) who completed a survey, the majority (82%) went home from hospital and were cared for by their partner (53%). More than half of the patients (58%) reported taking the same number of medications after intensive care unit stay but 30% took more (P = 0.023). While there was no change in the number of visits to the general practitioner for 64% of patients, 29% reported an increase after intensive care unit stay. At six months, 40% of responders who were not retired were unemployed. Discharge summary surveys revealed 39 general practitioners (71%) were satisfied with details of ongoing healthcare needs. Twenty-one general practitioners wrote comments: 10 reported insufficient information about ongoing needs/rehabilitation and two reported no mention of intensive care unit stay. Survivors of critical illness had increased healthcare needs and despite most returning home, had a low workforce participation rate. This requires further investigation to maximise the benefits of survival from critical illness. PMID- 20715740 TI - Anaesthetic aspects of implanting diaphragmatic pacing in patients with spinal cord injury. AB - Some patients with high cervical spinal cord injury are largely or completely dependent on mechanical ventilator support. Diaphragmatic phrenic nerve pacing is a new technique that offers some patients greater independence from mechanical ventilation. In selected patients, electrodes are placed on the abdominal side of the diaphragm via laparoscopy. An external pacing box provides the pacing stimulus. We report our experience with four patients with spinal cord injury in a pilot project, presenting for laparoscopic insertion of diaphragmatic phrenic nerve pacing leads inserted. The surgery took about two hours and diaphragmatic mapping precluded muscle relaxants. We used desflurane with remifentanil for maintenance. Apart from transferring the patients to and from their usual ventilators, other anaesthesia issues were difficult venous and arterial access for lines and long-term tracheostomies with no cuff or cuffs filled with water While hypotension was a frequent problem, one patient also developed intraoperative hypertension secondary to autonomic dysreflexia. Preoperative testing predicted pacing outcome with three of the four patients having successful pacing with tidal volumes of up to 10 ml/kg at the end of surgery. This initial Australian experience may lead to greater use of the technique. PMID- 20715741 TI - Elective caesarean section for a woman with Emery-Dreifuss muscular dystrophy. AB - Emery-Dreifuss muscular dystrophy is a rare form of muscular dystrophy involving both cardiac and skeletal muscles. Cardiac involvement frequently leads to dilated cardiomyopathy, arrhythmias and may precipitate sudden cardiac death. Skeletal involvement is characterised by early contractures and muscle weakness in the humeroperoneal distribution. We describe the anaesthetic management of a 29-year-old patient with Emery-Dreifuss muscular dystrophy presenting for elective caesarean section and discuss the disorder and its potential anaesthetic implications. PMID- 20715742 TI - Acute psychiatric syndrome leading young patients to ICU: consider anti-NMDA receptor antibodies. AB - We report on a case of anti-N-Methyl-D-Aspartate receptor antibody encephalitis, and review cases and series previously published in the literature. Anti-N-Methyl D-Aspartate receptor antibody encephalitis usually occurs in young female patients with no past medical history, in whom an ovarian teratoma is often detected. They subacutely develop predominantly psychiatric symptoms, followed by severe neurological disorders requiring transfer to the intensive care unit and prolonged ventilatory support. Complete or substantial recovery depends on early diagnosis, removal of the teratoma and immunotherapy. Our purpose is to focus intensivists' attention on this potentially lethal disorder, which should always be considered in young women admitted to the intensive care unit with characteristic neuropsychiatric disorders. PMID- 20715743 TI - The use of drotrecogin alfa in severe falciparum malaria. AB - We report the case of a 55-year-old male European who became septic after he returned from a four-week holiday to Uganda. Soon after; he was diagnosed with severe falciparum malaria and developed multi-organ failure. Due to the worsening condition of the patient, drotrecogin alfa (activated) was started, soon after which the patient's condition significantly improved. He returned home on day 36 after admission, without neurologic sequelae. Looking at those few cases of severe forms of malaria where drotrecogin alfa (activated) was successfully used, it should at least be considered for administration in patients with severe falciparum malaria with disseminated intravascular coagulation and cerebral involvement who do not respond to or deteriorate during standard treatment. PMID- 20715744 TI - Failure of tigecycline to treat severe Clostridium difficile infection. AB - Clostridium difficile infection is an emerging and often difficult-to-treat iatrogenic complication. Recent data suggest that tigecycline, a novel antibiotic with broad-spectrum antibacterial activity, can be used successfully to treat patients with severe Clostridium difficile infection. We report a 70-year-old man who developed severe Clostridium difficile infection, was admitted to the intensive care unit and eventually succumbed to complications of his illness despite receiving tigecycline for approximately three weeks in combination with vancomycin, metronidazole and intravenous immunoglobulin. Additionally, we discuss the unique challenges that emerged during tigecycline treatment, such as the development of Proteus mirabilis bacteraemia and of colonisation with Acinetobacter baumannii resistant to tigecycline. Finally, we review data on other cases reported in the medical literature. Even though tigecycline looks promising for the treatment of Clostridium difficile infection, we urge caution against its indiscriminate use for off label indications. PMID- 20715745 TI - Compression of the common carotid artery following clavicle fracture in a twelve year-old. AB - Posterior dislocation of the clavicle in the sternoclavicular joint is rare, but can result in severe complications caused by secondary damage to the adjacent structures on relocation. We present a case of a 12-year-old boy who sustained a dislocated clavicle while playing football. Against the initial request to perform immediate relocation, we opted for further computed tomography evaluation of the dislocation, which demonstrated compression of the left common carotid artery by the clavicle. Since there was no cardiothoracic standby available in our hospital on that day, the patient was transferred to the nearest centre with cardiothoracic facilities where the relocation of the clavicle was performed uneventfully. However; to avoid the potential for major complications, the risk of secondary damage to the central vessels must be kept in mind in this type of injury and adequate precautions must be in place. PMID- 20715746 TI - Bilateral brachial plexus blocks: some other issues to consider. PMID- 20715747 TI - Practice patterns for predicted difficult airway management and access to airway equipment by anaesthetists in Queensland, Australia. PMID- 20715748 TI - Supreme laryngeal mask airway as a conduit for fibrescope guided intubation. PMID- 20715749 TI - Technical terms in pre-anaesthetic consultations. PMID- 20715750 TI - Aspiration of a "speaking valve" or tracheo-oesophageal valve. PMID- 20715751 TI - Regional and rural specialists. PMID- 20715752 TI - Granuloma after short-term epidural catheterisation. PMID- 20715753 TI - Use of dexmedetomidine in sustained ventricular tachycardia. PMID- 20715754 TI - Selective left lower lobar blockade for lower oesophageal surgery. PMID- 20715755 TI - Sevoflurane, weaning and learning difficulty in the intensive care unit. PMID- 20715756 TI - Increased pressor response to noradrenaline during septic shock following clonidine? PMID- 20715757 TI - Power failure to a tertiary hospital's operating suite. PMID- 20715758 TI - Real-time in vivo simultaneous measurements of nitric oxide and oxygen using an amperometric dual microsensor. AB - This paper reports a real-time study of the codynamical changes in the release of endogenous nitric oxide (NO) and oxygen (O(2)) consumption in a rat neocortex in vivo upon electrical stimulation using an amperometric NO/O(2) dual microsensor. Electrical stimulation induced transient cerebral hypoxia due to the increased metabolic demands that were not met by the blood volume inside the stimulated cortical region. A NO/O(2) dual microsensor was successfully used to monitor the pair of real-time dynamic changes in the tissue NO and O(2) contents. At the onset of electrical stimulation, there was an immediate decrease in the cortical tissue O(2) followed by a subsequent increase in the cortical tissue NO content. The averages of the maximum normalized concentration changes induced by the stimulation were a 0.41 (+/-0.04)-fold decrease in the O(2) and a 3.6 (+/-0.9) fold increase in the NO concentrations when compared with the corresponding normalized basal levels. The peak increase in NO was always preceded by the peak decrease in O(2) in all animals (n = 11). The delay between the maximum decrease in O(2) and the maximum increase in NO varied from 3.1 to 54.8 s. This rather wide variation in the temporal associations was presumably attributed to the sparse distribution of NOS-containing neurons and the individual animal's differences in brain vasculatures, which suggests that a sensor with fine spatial resolution is needed to measure the location-specific real-time NO and O(2) contents. In summary, the developed NO/O(2) dual microsensor is effective for measuring the NO and O(2) contents in vivo. This study provides direct support for the dynamic role of NO in regulating the cerebral hemodynamics, particularly related to the tissue oxygenation. PMID- 20715759 TI - Optimization and evaluation of metabolite extraction protocols for untargeted metabolic profiling of liver samples by UPLC-MS. AB - A series of six protocols were evaluated for UPLC-MS based untargeted metabolic profiling of liver extracts in terms of reproducibility and number of metabolite features obtained. These protocols, designed to extract both polar and nonpolar metabolites, were based on (i) a two stage extraction approach or (ii) a simultaneous extraction in a biphasic mixture, employing different volumes and combinations of extraction and resuspension solvents. A multivariate statistical strategy was developed to allow comparison of the multidimensional variation between the methods. The optimal protocol for profiling both polar and nonpolar metabolites was found to be an aqueous extraction with methanol/water followed by an organic extraction with dichloromethane/methanol, with resuspension of the dried extracts in methanol/water before UPLC-MS analysis. This protocol resulted in a median CV of feature intensities among experimental replicates of <20% for aqueous extracts and <30% for organic extracts. These data demonstrate the robustness of the proposed protocol for extracting metabolites from liver samples and make it well suited for untargeted liver profiling in studies exploring xenobiotic hepatotoxicity and clinical investigations of liver disease. The generic nature of this protocol facilitates its application to other tissues, for example, brain or lung, enhancing its utility in clinical and toxicological studies. PMID- 20715761 TI - Creation and biophysical characterization of a high-affinity, monomeric EGF receptor ectodomain using fluorescent proteins. AB - X-ray structural studies revealed two conformations of the epidermal growth factor receptor (EGFR) ectodomain (ECD): a compact, tethered conformation in the absence of EGF and an untethered or extended conformation in the presence of EGF. An EGFR-ECD derivative with a monomeric red fluorescent protein (mRFP) at the N terminus and an enhanced green fluorescent protein (eGFP) at the C-terminus (dual tag-EGFR-ECD) was created and characterized. The dual-tag-EGFR-ECD construct was shown to have high affinity (nanomolar range) for both EGF and EGFR monoclonal antibody (mAb528). The dual-tag-EGFR-ECD was further characterized by fluorescence-detected analytical ultracentrifugation, lifetime FRET, and fluorescence anisotropy. We found no evidence of a tethered unliganded conformation, nor did we observe a large shape change upon ligand binding as predicted by the crystal models. Increases in steady-state anisotropy upon binding of EGF to the dual-tag-EGFR-ECD were observed and interpreted as changes in the protein flexibility and dynamics. We conclude the fluorescent protein tags perturb the EGFR-ECD structure, making it extended with a 50-fold higher affinity for EGF relative to that of the nontagged EGFR-ECD. PMID- 20715760 TI - The diheme cytochrome c(4) from Vibrio cholerae is a natural electron donor to the respiratory cbb(3) oxygen reductase. AB - The respiratory chain of Vibrio cholerae contains three bd-type quinol oxygen reductases as well as one cbb(3) oxygen reductase. The cbb(3) oxygen reductase has been previously isolated and characterized; however, the natural mobile electron donor(s) that shuttles electrons between the bc(1) complex and the cbb(3) oxygen reductase is not known. The most likely candidates are the diheme cytochrome c(4) and monoheme cytochrome c(5), which have been previously shown to be present in the periplasm of aerobically grown cultures of V. cholerae. Both cytochromes c(4) and c(5) from V. cholerae have been cloned and expressed heterologously in Escherichia coli. It is shown that reduced cytochrome c(4) is a substrate for the purified cbb(3) oxygen reductase and can support steady state oxygen reductase activity of at least 300 e(-1)/s. In contrast, reduced cytochrome c(5) is not a good substrate for the cbb(3) oxygen reductase. Surprisingly, the dependence of the oxygen reductase activity on the concentration of cytochrome c(4) does not exhibit saturation. Global spectroscopic analysis of the time course of the oxidation of cytochrome c(4) indicates that the apparent lack of saturation is due to the strong dependence of K(M) and V(max) on the concentration of oxidized cytochrome c(4). Whether this is an artifact of the in vitro assay or has physiological significance remains unknown. Cyclic voltammetry was used to determine that the midpoint potentials of the two hemes in cytochrome c(4) are 240 and 340 mV (vs standard hydrogen electrode), similar to the electrochemical properties of other c(4)-type cytochromes. Genomic analysis shows a strong correlation between the presence of a c(4)-type cytochrome and a cbb(3) oxygen reductase within the beta- and gamma proteobacterial clades, suggesting that cytochrome c(4) is the likely natural electron donor to the cbb(3) oxygen reductases within these organisms. These would include the beta-proteobacteria Neisseria meningitidis and Neisseria gonnorhoeae, in which the cbb(3) oxygen reductases are the only terminal oxidases in their respiratory chains, and the gamma-proteobacterium Pseudomonas stutzeri. PMID- 20715762 TI - PEG-based hydrogels with collagen mimetic peptide-mediated and tunable physical cross-links. AB - Mechanical properties of tissue scaffolds have major effects on the morphology and differentiation of cells. In contrast to two-dimensional substrates, local biochemical and mechanical properties of three-dimensional hydrogels are difficult to control due to the geometrical confinement. We designed synthetic 3D hydrogels featuring complexes of four-arm poly(ethylene glycol) (PEG) and collagen mimetic peptides (CMPs) that form hydrogels via physical cross-links mediated by thermally reversible triple helical assembly of CMPs. Here we present the fabrication of various PEG-CMP 3D hydrogels and their local mechanical properties determined by particle tracking microrheology. Results show that CMP mediated physical cross-links can be disrupted by altering the temperature of the gel or by adding free CMPs that compete for triple helix formation. This allowed modulation of both bulk and local stiffness as well as the creation of stiffness gradients within the PEG-CMP hydrogel, which demonstrates its potential as a novel scaffold for encoding physicochemical signals for tissue formation. PMID- 20715763 TI - Proteomics analysis of flax grown in Chernobyl area suggests limited effect of contaminated environment on seed proteome. AB - The accident at the Chernobyl Nuclear Power Plant (CNPP) on April 26, 1986 is the most serious nuclear disaster in human history. Surprisingly, while the area proximal to the CNPP remains substantially contaminated with long-lived radioisotopes including (90)Sr and (137)Cs, the local ecosystem has been able to adapt. To evaluate plant adaptation, seeds of a local flax (Linum usitatissimum) variety Kyivskyi were sown in radio-contaminated and control fields of the Chernobyl region. A total protein fraction was isolated from mature seeds, and analyzed using 2-dimensional electrophoresis combined with tandem-mass spectrometry. Interestingly, growth of the plants in the radio-contaminated environment had little effect on proteome and only 35 protein spots differed in abundance (p-value of <=0.05) out of 720 protein spots that were quantified for seeds harvested from both radio-contaminated and control fields. Of the 35 differentially abundant spots, 28 proteins were identified using state-of-the-art MS(E) method. Based on the observed changes, the proteome of seeds from plants grown in radio-contaminated soil display minor adjustments to multiple signaling pathways. PMID- 20715764 TI - Cathode potential and mass transfer determine performance of oxygen reducing biocathodes in microbial fuel cells. AB - The main limiting factor in Microbial Fuel Cell (MFC) power output is the cathode, because of the high overpotential for oxygen reduction. Oxygen reducing biocathodes can decrease this overpotential by the use of microorganisms as a catalyst. In this study, we investigated the factors limiting biocathode performance. Three biocathodes were started up at different cathode potentials, and their performance and catalytic behavior was tested by means of polarization curves and cyclic voltammetry. The biocathodes controlled at +0.05 V and +0.15 V vs Ag/AgCl produced current almost immediately after inoculation, while the biocathode controlled at +0.25 V vs Ag/AgCl produced no current until day 15. The biocathode controlled at +0.15 V vs Ag/AgCl reached the highest current density of 313 mA/m(2). Cyclic voltammetry showed clear catalysis for all three biocathodes. The biocathodes were limited by both mass transfer of oxygen and by charge transfer. Mass transfer calculations show that the transfer of oxygen poses a serious limitation for the use of dissolved oxygen as an electron acceptor in MFCs. PMID- 20715766 TI - Reductive dechlorination of alpha-, beta-, gamma-, and delta hexachlorocyclohexane isomers with hydroxocobalamin, in soil slurry systems. AB - The present study was carried out to test the viability of a method of reductive dehalogenation of alpha-, beta-, gamma-, and delta-hexachlorocyclohexane (HCH) in soil slurry systems. The soil slurries were maintained under anaerobic conditions, with titanium(III) citrate as a reducing agent and hydroxocobalamin (vitamin B(12a)) as a catalyzing agent. Experiments were carried out with two soil samples with markedly different characteristics (particularly regarding organic matter content), at a small scale and larger reactor scale. HCH concentration was monitored throughout the 24 h duration of the tests. In the low organic matter soil HCH isomers degraded rapidly, in both the small scale and reactor systems, and undetectable levels (<0.5%) were reached within 5 h. However, complete degradation of HCH isomers was not achieved in soil with high organic matter content, and there were differences between the results obtained in the small scale and reactor systems. In the small scale system, the levels of degradation reached 93, 88, 94, and 91%, for alpha-, beta-, gamma-, and delta HCH, respectively, and the nondegraded HCH was sorbed in the soil. In the reactor system, the reaction stopped after two hours (no more than 65% of any of the isomers was degraded). PMID- 20715765 TI - Evelynin, a cytotoxic benzoquinone-type Retro-dihydrochalcone from Tacca chantrieri. AB - A new benzoquinone-type retro-dihydrochalcone, named evelynin, was isolated from the roots and rhizomes of Tacca chantrieri. The structure was elucidated on the basis of the analysis of spectroscopic data and confirmed by a simple one-step total synthesis. Evelynin exhibited cytotoxicity against four human cancer cell lines, MDA-MB-435 melanoma, MDA-MB-231 breast, PC-3 prostate, and HeLa cervical carcinoma cells, with IC(50) values of 4.1, 3.9, 4.7, and 6.3 MUM, respectively. PMID- 20715767 TI - Effect of metal ions on the indigenous radicals of humic acids: high field electron paramagnetic resonance study. AB - The interaction of indigenous radicals of humic acid (HA) with metal cations has been studied using high magnetic field (10.5T-285 GHz) electron paramagnetic resonance (HFEPR) spectroscopy. Strong [HA]-[metal] interaction was observed in the case of heavy metals, Cd(2+), Pb(2+), and Sr(2+), leading to formation of covalent bonds with the radicals of HA. On the contrary, alkaline earth metal ions, such as Mg(2+), generate only electrostatic interaction. The two types of indigenous radicals that exist in all HAs are influenced by the metal cations in a unified manner. This provides evidence that the two types of indigenous radicals in HAs originate from a unique, phenolic, moiety in HA. Mg(2+) ions dramatically changed the pH profile of the two radical types of HA, downshifting their interconversion pK(a) by ca. 3 pH units. This is the first experimental observation of the effect of metals on the H-dissociation of the radical centers in HAs. PMID- 20715769 TI - Hg2+ detection by new anthracene pendant-arm derivatives of mixed N/S- and N/S/O donor macrocycles: fluorescence, matrix-assisted laser desorption/ionization time of-flight mass spectrometry and density functional theory studies. AB - The optical response of four new anthracenylmethyl pendant-arm derivatives (L1 L4) of the macrocyclic ligands [12]aneNS(3), [12]aneNS(2)O, [15]aneNS(2)O(2), and [12]aneN(2)SO toward the metal ions Zn(2+), Cd(2+), Pb(2+), Cu(2+), Hg(2+), Ag(+), Fe(2+), Co(2+), Ni(2+), Mn(2+), Ca(2+), Na(+), Mg(2+), and K(+) was investigated in 1:1 (v/v) MeCN/H(2)O solutions. A strong chelation enhancement of quenching effect was observed on the fluorescent emission intensity of L2 as a consequence of the host-guest interaction with Hg(2+) and the formation of a 1:2 metal-to-ligand complex. Density functional theory calculations confirmed the formation of a sandwich-type complex between L2 and Hg(2+) as a favorable process. A matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry study using the four ligands as active MALDI probes was also performed. L1-L4 have also been explored as fluorescence chemosensors in microsamples using NANODROP technology. PMID- 20715768 TI - Room-temperature aromatization of tetrahydro-beta-carbolines by 2-iodoxybenzoic acid: utility in a total synthesis of eudistomin U. AB - 2-Iodoxybenzoic acid is a convenient reagent for the dehydrogenation of tetrahydro-beta-carbolines to their aromatic forms under mild conditions. The utility of the method was demonstrated in a total synthesis of the marine indole alkaloid eudistomin U. PMID- 20715770 TI - Perchlorate and iodide in whole blood samples from infants, children, and adults in Nanchang, China. AB - Perchlorate, ClO(4)(-), interferes with iodide (I(-)) uptake by the sodium-iodide symporter (NIS) and thereby affects thyroid hormone production in the body. Studies have reported human exposures to perchlorate based on measurements in urine, but little is known about the levels in blood. In this study, we determined concentrations of perchlorate, iodide, and other anions (e.g., chlorate [ClO(3)(-)], bromate [BrO(3)(-)], bromide [Br(-)]) in 131 whole blood samples collected from Chinese donors aged 0.4 to 90 yr, in Nanchang, China. Perchlorate, iodide, and bromide were detected in all of the samples analyzed, whereas chlorate was found in only 27% of the samples and bromate was found in only 2%. The mean (range) concentrations of perchlorate, iodide, and bromide were 2.68 (0.51-10.5), 42.6 (1.58-812), and 2120 (1050-4850) ng/mL, respectively. Perchlorate levels in blood from Nanchang adults were 10-fold greater than levels that have been previously reported for U.S. adults. The iodide/perchlorate molar ratio ranged from 3.05 to 15.3 for all age groups, and the ratio increased with age (r = 0.732, p < 0.01). Perchlorate and bromide concentrations decreased significantly with age, whereas iodide concentrations increased with age. No significant gender-related differences in blood perchlorate, iodide, or bromide levels were found. A significant negative correlation was found between the concentrations of perchlorate and iodide in blood. Exposure doses of perchlorate were estimated for infants, toddlers, children, adolescents, and adults based on the measured concentrations in blood, using a simple pharmacokinetic model. The mean exposure doses of perchlorate for our age groups ranged from 1.12 (adults) to 2.22 MUg/kg bw/day (infants), values higher than the United States Environmental Protection Agency's (USEPA) reference dose (RfD: 0.7 MUg/kg bw/day). This is the first study on perchlorate and iodide levels in whole blood from infants, toddlers, children, adolescents, and adults from a city in China with known high perchlorate levels. PMID- 20715771 TI - Acceleration of precipitation formation in peach juice induced by high-pressure carbon dioxide. AB - Peach juice was treated by high-pressure carbon dioxide (HPCD). HPCD-induced acceleration of precipitation formation in peach juice was observed. Particle size distribution (PSD), pH, zeta-potential, protein and total phenols, pectin methylesterase (PME) activity, pectin and calcium, and viscosity in juice, contributing to the precipitation formation, were studied. HPCD resulted in a significant alteration of juice PSD pattern; the acceleration of the precipitation formation concurred with this alteration. A significant decrease of protein and a declining trend of total phenols were obtained, the contents of pectin and calcium were not changed, and the difference in PME activity in juice was not significant after HPCD. HPCD led to higher increase in juice viscosity, whereas pH and the absolute value of zeta-potential declined during HPCD. These results suggested that the pH and absolute value of zeta-potential declines induced the coagulation of protein and decrease of particle charge, responsible for the acceleration of the precipitation formation. PMID- 20715773 TI - 1,1'-Azobis-1,2,3-triazole: a high-nitrogen compound with stable N8 structure and photochromism. AB - Treatment of 1-amino-1,2,3-triazole with sodium dichloroisocyanurate led to isolation of 1,1'-azobis-1,2,3-triazole, which was well characterized. Its structure was determined by X-ray crystallographic analysis, and its thermal stability and photochromic properties were investigated. PMID- 20715772 TI - Comparative study of chemical and biochemical properties of different melon cultivars: standard, hybrid, and grafted melons. AB - Chemical and biochemical properties of standard, hybrid, and grafted melons cultivated under the same agricultural conditions in adjacent fields in the Cumra region of Turkey were investigated and compared based on pH, Brix, antioxidant activity, total phenolics, ascorbic acid, individual phenolics, sugar, and organic acid values. Seventeen different phenolic constituents were quantified by reverse phase high-performance liquid chromatography (RP-HPLC). The highest phenolic acid variability and content were detected in the standard melon. Sugar and organic acid compositions of melon cultivars were tested by capillary electrophoresis, and significant differences in types and contents of individual sugars and organic acids were determined among the cultivars. Standard Cinikiz Cumra melons had the highest ascorbic acid, total phenolics, and total sugar contents. The fructose/glucose ratio increased three times in grafted melon as compared with standard melon. While sugar alcohol mannitol existed in the standard and hybrid cultivars, this constituent disappeared in the grafted types. Citric acid found in the standard cultivar was not detected in the hybrid and grafted types. Consequently, it was concluded that the nutritional value of melons changed by the application of hybridization, grafting, or standard (open pollinated) production methods. The standard melon was found to have the highest score in terms of taste, because of its highest sweetness and sourness. It was also found preferable because of its high antioxidant activity, total phenolic and ascorbic acid contents. PMID- 20715774 TI - Bispalladacycle-catalyzed Bronsted acid/base-promoted asymmetric tandem azlactone formation-Michael addition. AB - Cooperative activation by a soft bimetallic catalyst, a hard Bronsted acid, and a hard Bronsted base has allowed the formation of highly enantioenriched, diastereomerically pure masked alpha-amino acids with adjacent quaternary and tertiary stereocenters in a single reaction starting from racemic N-benzoylated amino acids. The products can, for example, be used to prepare bicyclic dipeptides. PMID- 20715775 TI - Inhibition of pro-inflammatory responses and antioxidant capacity of Mexican blackberry (Rubus spp.) extracts. AB - Total polyphenolic and anthocyanin- and proanthocyanidin-rich fractions from wild blackberry genotypes (WB-3, WB-7, WB-10, and WB-11), a domesticated noncommercial breeding line (UM-601), and a commercial cultivar (Tupy) were evaluated for inhibition of pro-inflammatory responses [nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, cyclooxygenase-2 (COX-2) expression, and prostaglandin E2 (PGE2)] in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). At 50 microM [cyanidin-3-O-glucoside (C3G) or catechin equivalent], most fractions significantly (P<0.05) inhibited all markers. The anthocyanin-rich fraction from WB-10 and the proanthocyanidin-rich fraction from UM-601 exhibited the highest NO inhibitory activities (IC50=16.1 and 15.1 microM, respectively). Proanthocyanidin-rich fractions from the wild WB-10 showed the highest inhibition of iNOS expression (IC50=8.3 microM). Polyphenolic-rich fractions from WB-7 and UM-601 were potent inhibitors of COX-2 expression (IC50=19.1 and 19.3 microM C3G equivalent, respectively). For most of the extracts, antioxidant capacity was significantly correlated with NO inhibition. Wild genotypes of Mexican blackberries, as rich sources of polyphenolics that have both antioxidant and anti-inflammatory properties, showed particular promise for inclusion in plant improvement programs designed to develop new varieties with nutraceutical potential. PMID- 20715776 TI - The antitumoral depsipeptide IB-01212 kills Leishmania through an apoptosis-like process involving intracellular targets. AB - IB-01212, an antitumoral cyclodepsipeptide isolated from the mycelium of the marine fungus Clonostachys sp., showed leishmanicidal activity at a low micromolar range of concentrations on promastigote and amastigote forms of the parasite. Despite its cationic and amphipathic character, shared with other membrane active antibiotic peptides, IB-01212 did not cause plasma membrane lesions large enough to allow the entrance of the vital dye SYTOX green (MW = 600), even at concentrations causing full lethality of the parasite. Having ruled out massive disruption of the plasma membrane, we surmised the involvement of intracellular targets. Proof of concept for this assumption was provided by the mitochondrial dysfunction caused by IB-01212, which finally caused the death of the parasite through an apoptotic-like process. The size of the cycle, the preservation of the C2 symmetry, and the nature of the bonds linking the two tetrapeptide halves participate in the modulation of the leishmanicidal activity exerted by this compound. Here we discuss the potential of IB-01212 as a lead for new generations of surrogates to be used in chemotherapy treatments against Leishmania . PMID- 20715777 TI - Metabolomic characterization of Italian sweet pepper (Capsicum annum L.) by means of HRMAS-NMR spectroscopy and multivariate analysis. AB - HRMAS-NMR spectroscopy was used to assess the metabolic profile of sweet pepper (Capsicum Annum L.). One-dimensional and two-dimensional NMR spectra, performed directly on sample pieces of few milligrams, hence without any chemical and/or physical manipulation, allowed the assignment of several compounds. Organic acids, fatty acids, amino acids, and minor compounds such as trigonelline, C4 substituted pyridine, choline, and cinnamic derivatives were observed with a single experiment. A significant discrimination between the two sweet pepper varieties was found by using partial least-squares projections to latent structures discrimination analysis (PLS-DA). The metabolites contributing predominantly to such differentiation were sugars and organic and fatty acids. Also a partial separation according to the geographical origin was obtained always by analyzing the NMR data with PLS-DA. Some of the discriminating molecules are peculiar for pepper and contribute to define the overall commercial and organoleptic quality so that HRMAS-NMR proved to be a complementary analysis to standard tools used in food science and, in principle, can be applied to any foodstuff. PMID- 20715778 TI - A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. AB - Physiologically based pharmacokinetic (PBPK) modeling tools have become an integral part of the modern drug discovery-development process. However, accurate PK prediction of enabling formulations of poorly soluble compounds by applying PBPK modeling has been very limited. This is because current PBPK models rely only on thermodynamic drug solubility inputs (e.g., pH-solubility profile) and give little consideration to the dynamic changes in apparent drug solubility (e.g., supersaturation) that occur during gastrointestinal (GI) transit of an enabling formulation of a water insoluble drug. Moreover, biorepresentative and predictive in vitro tools to measure formulation dependent solubility changes during GI transit remain underdeveloped. In this work, we have developed an in vitro dual pH-dilution method based on rat physiology to estimate the apparent drug concentration in solution along the GI tract during release from solubility enabling formulations. This simple dual pH-dilution method was evaluated using various solubility enabling formulations (i.e., cosolvent solution, amorphous solid dispersions) made using a model early development drug candidate with poor aqueous solubility. The in vitro drug concentration-time profiles from the enabling formulations were used as solubility inputs for PBPK modeling using GastroPlus software. This resulted in excellent predictions of the in vivo oral plasma concentration-time profiles, as compared to using the traditional inputs of thermodynamic pH-solubility profiles. In summary, this work describes a novel in vitro method for facile estimation of formulation dependent GI drug concentration-time profiles and demonstrates the utility of PBPK modeling for oral PK prediction of enabling formulations of poorly soluble drugs. PMID- 20715779 TI - Deuterium isobaric amine-reactive tags for quantitative proteomics. AB - This paper demonstrates the applications of a novel isobaric reagent, named deuterium ((2)H) isobaric amine-reactive tag (DiART), for quantitative proteomics. Peptides labeled with DiART were analyzed using an electrospray ionization (ESI)-based LTQ-Orbitrap mass spectrometer. Our data showed that (2)H associated isotope effects, such as partial loss of (2)H labels during tandem mass spectrometry (MS/MS) and (2)H-related chromatographic shift, were either not observed or negligible. With the use of a hybrid collision-induced dissociation (CID)-higher energy C-trap dissociation (HCD) acquisition method, we were able to identify DiART-labeled peptides with high confidence and quantify them with high accuracy. Furthermore, we adopted a hybrid electron-transfer dissociation (ETD) HCD acquisition protocol and developed a novel data analysis approach to measure phosphorylation of peptides. Our results showed DiART had excellent performance on LTQ-Orbitrap instruments and provided a cost-effective technique for large scale quantitative proteomics measurements. PMID- 20715780 TI - Catalytic asymmetric protonation of alpha-amino acid-derived ketene disilyl acetals using P-spiro diaminodioxaphosphonium barfates as chiral proton. AB - Chiral diaminodioxaphosphonium salts have been developed and their unique abilities as a chiral proton have been revealed through the establishment of a highly enantioselective protonation of alpha-amino acid-derived ketene disilyl acetals. PMID- 20715781 TI - Highly ordered assembly of pi-stacked distyrylbenzenes by oligoadenines. AB - A well-defined nanofibrous structure with lengths of several hundred nanometers and cross-sectional width of a single size (~6 +/- 0.5 nm) was self-assembled by oligoadenines, dA(20), and thymine-appended distyrylbenzene through binary complementary A-T hydrogen bond formation and the strong pi-pi stacking interactions. This demonstrated a useful supramolecular self-assembling approach to control the packing order of pi-conjugated molecules and provided a practical means to enhance the optical properties of a material. PMID- 20715782 TI - Unraveling the Na,K-ATPase alpha(4) subunit assembling induced by large amounts of C(12)E(8) by means of small-angle X-ray scattering. AB - In the current work, we studied the effect of the nonionic detergent dodecyloctaethyleneglycol, C(12)E(8), on the structure and oligomeric form of the Na,K-ATPase membrane enzyme (sodium-potassium pump) in aqueous suspension, by means of small-angle X-ray scattering (SAXS). Samples composed of 2 mg/mL of Na,K ATPase, extracted from rabbit kidney medulla, in the presence of a small amount of C(12)E(8) (0.005 mg/mL) and in larger concentrations ranging from 2.7 to 27 mg/mL did not present catalytic activity. Under this condition, an oligomerization of the alpha subunits is expected. SAXS data were analyzed by means of a global fitting procedure supposing that the scattering is due to two independent contributions: one coming from the enzyme and the other one from C(12)E(8) micelles. In the small detergent content (0.005 mg/mL), the SAXS results evidenced that Na,K-ATPase is associated into aggregates larger than (alphabeta)(2) form. When 2.7 mg/mL of C(12)E(8) is added, the data analysis revealed the presence of alpha(4) aggregates in the solution and some free micelles. Increasing the detergent amount up to 27 mg/mL does not disturb the alpha(4) aggregate: just more micelles of the same size and shape are proportionally formed in solution. We believe that our results shed light on a better understanding of how nonionic detergents induce subunit dissociation and reassembling to minimize the exposure of hydrophobic residues to the aqueous solvent. PMID- 20715783 TI - Ethanol fermentation performance of grain sorghums (Sorghum bicolor) with modified endosperm matrices. AB - We tested 13 sorghum entries (lines and hybrids) with different endosperm matrices for ethanol production using a laboratory dry grind process. Waxy and heterowaxy samples had the highest efficiencies. Free amino nitrogen (FAN) contents in sorghum samples were positively related to the fermentation rate during fermentation (R2=0.8618). Dried distiller's grain with solubles (DDGS) from different sorghums had significantly different crude protein and crude fat contents. Residual starch content in DDGS ranged from 0.60% for the most efficient sample to 2.66% for the least efficient sample. This study showed that the HD lines (TX1, TX3, TX5, TX7, and TX9) with modified endosperm protein matrix have several attributes desirable for ethanol production: easily pasted starch granules, significantly higher FAN content in finished mashes, 30-45% faster ethanol fermentation rate during early stages, and 50-60% higher lysine content in DDGS. PMID- 20715784 TI - Sandwich-type zinc-containing polyoxometalates with a hexaprismane core [{Zn2W(O)O3}2]4+ synthesized by thermally induced isomerization of a metastable polyoxometalate. AB - Two novel sandwich-type silicotungstates, TBA(8)[{Zn(2)W(O)O(3)}(2)H(4){alpha SiW(9)O(33)}(2)].5H(2)O (alpha-Zn4; TBA = tetra-n-butylammonium) and TBA(8)[{Zn(2)W(O)O(3)}(2)H(4){beta-SiW(9)O(33)}(2)].7H(2)O (beta-Zn4), were synthesized by the solid-state thermally induced isomerization of metastable TBA(8)[{Zn(OH(2))(MU(3)-OH)}(2){Zn(OH(2))(2)}(2){gamma-HSiW(10)O(36)}(2)].9H(2)O (gamma-Zn4). Compounds alpha-Zn4 and beta-Zn4 consisted of two [SiW(9)O(33)](8-) subunits sandwiching the unprecedented distorted hexaprismane core [{Zn(2)W(O)O(3)}(2)](4+). PMID- 20715785 TI - Energy transfer dynamics in multichromophoric arrays engineered from phosphorescent Pt(II)/Ru(II)/Os(II) centers linked to a central truxene platform. AB - A rigid star-shaped tetrachromophoric trimetallic complex engineered from a 5,5',10,10',15,15'-hexabutyltruxene platform functionalized in the 2,7,12 positions with three different metal centers, namely, a terpyridine-Pt(II) ethynylene unit and Ru(II) and Os(II) bipyridine centers, was synthesized in a controlled fashion and characterized by (1)H NMR and mass spectrometry. The protocol was devised in such a way that key mono and dinuclear model complexes and two reference truxene ligands could also be prepared. Room temperature (RT) optical absorption and RT and 77 K luminescence studies were performed on the truxene ligands, the trimetallic species, the various mono- and binuclear complexes and precursors lacking the truxene fragment; RT nanosecond transient absorption measurements were also carried out in particular cases. The electronic properties of the Ru and Os subunits in the arrays were found to be unaffected by the presence of the truxene core whereas direct linking of the Pt subunit to the truxene via the sigma-alkyne bond markedly influences the spectroscopic behavior of the Pt center. Remarkably the truxene phosphorescence was clearly established in the two ligands (lifetime of 4.3 s for the mono ethynyl-bipy substituted truxene and 17.5 ms for the bis ethynyl-bipy substituted truxene) and also detected in the Pt-containing complexes PtL' (model Pt-truxene) and Pt-Os (Pt truxene-Os dyad) at low temperature. This is attributed to the closeness in energy of the Pt (3)CT level and the truxene triplet at low temperature and to the spin-orbit coupling induced by the Pt heavy atom. Transient absorbance measurements evidenced the population of the Pt-based triplet in the Pt-truxene mononuclear complex PtL' at room-temperature. For the trimetallic complex, where the various centers exhibit an energy gradient for the local excited levels, and following an approach based on the use of selected excitation of the components, an initial energy transfer was found to occur from the central truxene unit toward the peripheral Pt, Ru, and Os metal-based centers. Subsequent Pt-based and Ru-based excited state depletion contributes to the final sensitization of the low-lying Os triplet excited state; the excited state dynamics for these multicascade processes are examined in detail. PMID- 20715786 TI - A simple and efficient way to synthesize unsolvated sodium octahydrotriborate. AB - A simple and efficient way to synthesize unsolvated sodium octahydrotriborate has been developed. This method avoids the use of dangerous starting materials and significantly simplifies the reaction setup, thus enabling convenient large-scale synthesis. The structure of the unsolvated compound has been determined through powder X-ray diffraction. PMID- 20715787 TI - Correlation of skin blanching and percutaneous absorption for glucocorticoid receptor agonists by matrix-assisted laser desorption ionization mass spectrometry imaging and liquid extraction surface analysis with nanoelectrospray ionization mass spectrometry. AB - Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA) with nanoelectrospray ionization mass spectrometry (nESI-MS) have both been successfully employed to determine the degree of percutaneous absorption of three novel nonsteroid glucocorticoid receptor (GR) agonists in porcine ear sections. Historically, the ability of a glucocorticoid to elicit a skin blanching response when applied at low dose in ethanol solution to the forearms of healthy human volunteers has been a reliable predictor of their topical anti-inflammatory activity. While all three nonsteroidal GR agonists under investigation caused a skin blanching effect, the responses did not correlate with in vitro GR agonist potencies and different time courses were also observed for the skin blanching responses. MALDI MSI and LESA with nESI-MS were used to investigate and understand these different responses. The findings of the investigation was that the depth of porcine skin penetration correlates to the degree of skin blanching obtained for the same three compounds in human volunteers. PMID- 20715788 TI - Binding of dengue virus particles and dengue proteins onto solid surfaces. AB - The interaction between dengue virus particles (DENV), sedimentation hemagglutinin particles (SHA), dengue virus envelope protein (Eprot), and solid surfaces was investigated by means of ellipsometry and atomic force microscopy (AFM). The surfaces chosen are bare Si/SiO2 wafers and Si/SiO2 wafers covered with concanavalin A (ConA), jacalin (Jac), polystyrene (PS), or poly(styrene sulfonate) (PSS) films. Adsorption experiments at pH 7.2 and pH 3 onto all surfaces revealed that (i) adsorption of DENV particles took place only onto ConA under pH 7.2, because of specific recognition between glycans on DENV surface and ConA binding site; (ii) DENV particles did not attach to any of the surfaces at pH 3, suggesting the presence of positive charges on DENV surface at this pH, which repel the positively charged lectin surfaces; (iii) SHA particles are positively charged at pH 7.2 and pH 3 because they adhered to negatively charged surfaces at pH 7.2 and repelled positively charged layers at pH 3; and (iv) SHA particles carry polar groups on the surface because they attached to silanol surfaces at pH 3 and avoided hydrophobic PS films at pH 3 and pH 7.2. The adsorption behavior of Eprot at pH 7.2 revealed affinity for ConA>Jac>PSS>PS~bare Si/SiO2 layers. These findings indicate that selectivity of the Eprot adsorption is higher when it is part of virus structure than when it is free in solution. The correlation between surface energy values determined by means of contact angle measurements and DENV, SHA, or Eprot adsorption behavior was used to understand the intermolecular forces at the interfaces. A direct correlation was not found because the contributions from surface energy were probably surpassed by specific contributions. PMID- 20715789 TI - Investigation of near ohmic behavior for poly(3,4-ethylenedioxythiophene): a model consistent with systematic variations in polymerization conditions. AB - The impedance behavior of semiconducting polymer film electrodes based on poly(3,4-ethylenedioxythiophene) (PEDOT) in combination with a series of anionic dopants has been investigated using electrochemical impedance spectroscopy (EIS) over the frequency range from 0.1 Hz to 100 kHz. Films were electrodeposited on gold-coated Pt wire electrodes from a nonaqueous solution containing 3,4 ethylenedioxythiophene (EDOT). EIS results reveal that, under the optimal synthesis conditions, PEDOT electrodes consistently exhibit low, frequency independent impedance over a wide frequency range (from ~10 Hz to 100 kHz). These results suggest that the behavior originates from the two-layer homogeneous morphology of the film. A model for conduction in the films that is supported by experimental evidence is proposed, and EIS data for electrodes produced under a variety of electropolymerization conditions are presented. PMID- 20715790 TI - Nanomechanical properties of TiO2 granular thin films. AB - Post-deposition annealing effects on nanomechanical properties of granular TiO2 films on soda-lime glass substrates were studied. In particular, the effects of Na diffusion on the films' mechanical properties were examined. TiO2 photocatalyst films, 330 nm thick, were prepared by dip-coating using a TiO2 sol, and were annealed between 100 degrees C and 500 degrees C. Film's morphology, physical and nanomechanical properties were characterized by atomic force microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, differential thermo-gravimetric analysis, and nanoindentation. Contrary to expectations, the maximum film hardness was achieved for 300 degrees C annealing, with a value of 0.69+/-0.05 GPa. Higher annealing temperatures resulted in inferior mechanical properties. No pile-up or sink-in effects were observed with minimal creep for the 300 degrees C annealed sample. Considerable decrease in the amount of chemisorbed water was found with increasing annealing temperature, causing gel films densification, explaining the increasing trend of hardness with annealing temperature between 100 degrees C and 300 degrees C. DTA/TGA results also confirmed the weight loss and the endothermic reaction due to desorption of chemisorbed water. Decrease in hardness above 300 degrees C annealing is attributed to thermal diffusion of Na ions from the glass substrate, confirmed by nanoindentation tests on TiO2 films deposited on fused quartz, which did not exhibit hardness decrease after 300 degrees C annealing. PMID- 20715791 TI - Structural and functional characterization of a macrophage migration inhibitory factor homologue from the marine cyanobacterium Prochlorococcus marinus . AB - Macrophage migration inhibitory factor (MIF) is a multifunctional mammalian cytokine, which exhibits tautomerase and oxidoreductase activity. MIF homologues with pairwise sequence identities to human MIF ranging from 31% to 41% have been detected in various cyanobacteria. The gene encoding the MIF homologue from the marine cyanobacterium Prochlorococcus marinus strain MIT9313 has been cloned and the corresponding protein (PmMIF) overproduced, purified, and subjected to functional and structural characterization. Kinetic and (1)H NMR spectroscopic studies show that PmMIF tautomerizes phenylenolpyruvate and (p hydroxyphenyl)enolpyruvate at low levels. The N-terminal proline of PmMIF is critical for these reactions because the P1A mutant has strongly reduced tautomerase activities. PmMIF shows high structural homology with mammalian MIFs as revealed by a crystal structure of PmMIF at 1.63 A resolution. MIF contains a Cys-X-X-Cys motif that mediates oxidoreductase activity, which is lacking from PmMIF. Engineering of the motif into PmMIF did not result in oxidoreductase activity but increased the tautomerase activity 8-fold. The shared tautomerase activities and the conservation of the beta-alpha-beta structural fold and key functional groups suggest that eukaryotic MIFs and cyanobacterial PmMIF are related by divergent evolution from a common ancestor. While several MIF homologues have been identified in eukaryotic parasites, where they are thought to play a role in modulating the host immune response, PmMIF is the first nonparasitic, bacterial MIF-like protein characterized in detail. This work sets the stage for future studies which could address the question whether a MIF-like protein from a free-living bacterium possesses immunostimulatory features similar to those of mammalian MIFs and MIF-like proteins found in parasitic nematodes and protozoa. PMID- 20715792 TI - Structural analysis of the Smad2-MAN1 interaction that regulates transforming growth factor-beta signaling at the inner nuclear membrane. AB - MAN1, an integral protein of the inner nuclear membrane, influences transforming growth factor-beta (TGF-beta) signaling by directly interacting with R-Smads. Heterozygous loss of function mutations in the gene encoding MAN1 cause sclerosing bone dysplasias and an increased level of TGF-beta signaling in cells. As a first step in elucidating the mechanism of TGF-beta pathway regulation by MAN1, we characterized the structure of the MAN1 C-terminal region that binds Smad2. Using nuclear magnetic resonance spectroscopy, we observed that this region is comprised of a winged helix domain, a structurally heterogeneous linker, a U2AF homology motif (UHM) domain, and a disordered C-terminus. From nuclear magnetic resonance and small-angle X-ray scattering data, we calculated a family of models for this MAN1 region. Our data indicate that the linker plays the role of an intramolecular UHM ligand motif (ULM) interacting with the UHM domain. We mapped the Smad2 binding site onto the MAN1 structure by combining GST pull-down, fluorescence, and yeast two-hybrid approaches. The linker region, the UHM domain, and the C-terminus are necessary for Smad2 binding with a micromolar affinity. Moreover, the intramolecular interaction between the linker and the UHM domain is critical for Smad2 binding. On the basis of the structural heterogeneity and binding properties of the linker, we suggest that it can interact with other UHM domains, thus regulating the MAN1-Smad2 interaction. PMID- 20715793 TI - Spatial distribution of diesel transit bus emissions and urban populations: implications of coincidence and scale on exposure. AB - Macroscale emissions modeling approaches have been widely applied in impact assessments of mobile source emissions. However, these approaches poorly characterize the spatial distribution of emissions and have been shown to underestimate emissions of some pollutants. To quantify the implications of these limitations on exposure assessments, CO, NO(X), and HC emissions from diesel transit buses were estimated at 50 m intervals along a bus rapid transit route using a microscale emissions modeling approach. The impacted population around the route was estimated using census, pedestrian count and transit ridership data. Emissions exhibited significant spatial variability. In intervals near major intersections and bus stops, emissions were 1.6-3.0 times higher than average. The coincidence of these emission hot spots and peaks in pedestrian populations resulted in a 20-40% increase in exposure compared to estimates that assumed homogeneous spatial distributions of emissions and/or populations along the route. An additional 19-30% increase in exposure resulted from the underestimate of CO and NO(X) emissions by macroscale modeling approaches. The results of this study indicate that macroscale modeling approaches underestimate exposure due to poor characterization of the influence of vehicle activity on the spatial distribution of emissions and total emissions. PMID- 20715794 TI - Converting GLX2-1 into an active glyoxalase II. AB - Arabidopsis thaliana glyoxalase 2-1 (GLX2-1) exhibits extensive sequence similarity with GLX2 enzymes but is catalytically inactive with SLG, the GLX2 substrate. In an effort to identify residues essential for GLX2 activity, amino acid residues were altered at positions 219, 246, 248, 325, and 328 in GLX2-1 to be the same as those in catalytically active human GLX2. The resulting enzymes were overexpressed, purified, and characterized using metal analyses, fluorescence spectroscopy, and steady-state kinetics to evaluate how these residues affect metal binding, structure, and catalysis. The R246H/N248Y double mutant exhibited low level S-lactoylglutathione hydrolase activity, while the R246H/N248Y/Q325R/R328K mutant exhibited a 1.5-2-fold increase in k(cat) and a decrease in K(m) as compared to the values exhibited by the double mutant. In contrast, the R246H mutant of GLX2-1 did not exhibit glyoxalase 2 activity. Zn(II)-loaded R246H GLX2-1 enzyme bound 2 equiv of Zn(II), and (1)H NMR spectra of the Co(II)-substituted analogue of this enzyme strongly suggest that the introduced histidine binds to Co(II). EPR studies indicate the presence of significant amounts a dinuclear metal ion-containing center. Therefore, an active GLX2 enzyme requires both the presence of a properly positioned metal center and significant nonmetal, enzyme-substrate contacts, with tyrosine 255 being particularly important. PMID- 20715795 TI - Double duty for a conserved glutamate in pyruvate decarboxylase: evidence of the participation in stereoelectronically controlled decarboxylation and in protonation of the nascent carbanion/enamine intermediate . AB - Pyruvate decarboxylase (PDC) catalyzes the nonoxidative decarboxylation of pyruvate into acetaldehyde and carbon dioxide and requires thiamin diphosphate (ThDP) and a divalent cation as cofactors. Recent studies have permitted the assignment of functional roles of active site residues; however, the underlying reaction mechanisms of elementary steps have remained hypothetical. Here, a kinetic and thermodynamic single-step analysis in conjunction with X-ray crystallographic studies of PDC from Zymomonas mobilis implicates active site residue Glu473 (located on the re-face of the ThDP thiazolium nucleus) in facilitating both decarboxylation of 2-lactyl-ThDP and protonation of the 2 hydroxyethyl-ThDP carbanion/enamine intermediate. Variants carrying either an isofunctional (Glu473Asp) or isosteric (Glu473Gln) substitution exhibit a residual catalytic activity of less than 0.1% but accumulate different intermediates at the steady state. Whereas the predecarboxylation intermediate 2 lactyl-ThDP is accumulated in Glu473Asp because of a 3000-fold slower decarboxylation compared to that of the wild-type enzyme, Glu473Gln is not impaired in decarboxylation but generates a long-lived 2-hydroxyethyl-ThDP carbanion/enamine postdecarboxylation intermediate. CD spectroscopic analysis of the protonic and tautomeric equilibria of the cocatalytic aminopyrimidine part of ThDP indicates that an acidic residue is required at position 473 for proper substrate binding. Wild-type PDC and the Glu473Asp variant bind the substrate analogue acetylphosphinate with the same affinity, implying a similar stabilization of the predecarboxylation intermediate analogue on the enzyme, whereas Glu473Gln fails to bind the analogue. The X-ray crystallographic structure of 2-lactyl-ThDP trapped in the decarboxylation-deficient variant Glu473Asp reveals a common stereochemistry of the intermediate C2alpha stereocenter; however, the scissile C2alpha-C(carboxylate) bond deviates by ~25 30 degrees from the perpendicular "maximum overlap" orientation relative to the thiazolium ring plane as commonly observed in ThDP enzymes. Because a reactant state stabilization of the predecarboxylation intermediate can be excluded to account for the slower decarboxylation, the data suggest a strong stereoelectronic effect for the transition state of decarboxylation as supported by additional DFT studies on models. To the best of our knowledge, this is a very rare example in which the magnitude of a stereoelectronic effect could be experimentally estimated for an enzymatic system. Given that variant Glu473Gln is not decarboxylation-deficient, electrostatic stress can be excluded as a driving force for decarboxylation. The apparent dual function of Glu473 further suggests that decarboxylation and protonation of the incipient carbanion are committed and presumably proceed in the same transition state. PMID- 20715797 TI - Functional groups and sulfur K-edge XANES spectra: divalent sulfur and disulfides. AB - Sulfur K-edge XANES was measured for two divalent sulfurs (dibenzyl and benzyl phenyl) and two disulfides (dibenzyl and diphenyl). The absorption spectra could be assigned using density functional theory with the "half core hole" approximation for the core hole including relaxation of selected excited states at the absorption edge. Analysis of the molecular orbitals shows that the characteristic double peak of the dibenzyl disulfide arises as a consequence of the enhanced splitting of the LUMO (lowest unoccupied molecular orbital) and the LUMO + 1. Exchange of the ligand benzyl by phenyl introduces more transitions at the absorption edge, which enhance the broadening in the divalent sulfur and splitting of the peaks of the disulfide. It is shown that different ligand groups introduce significant differences in the absorption edge, which poses a problem for the speciation analysis when the ligand groups are not clearly defined. PMID- 20715796 TI - In vitro monitoring of dissolution of an immediate release tablet by focused beam reflectance measurement. AB - Changes in in vitro drug release profiles of oral dosage forms are commonly observed due to storage of drug product at elevated temperature and humidity. An example is presented of an immediate release drug product which underwent changes to both release profile and crystal form on storage at elevated humidity. The dissolution rate for unstressed tablets was comparable regardless of the crystal form present. Decreased release rate was only observed for stressed tablets that exhibited crystal form conversion. The cause of the dissolution change was determined by evaluating tablets manufactured with three drug substance crystal forms by fiber optic ultraviolet detection and focused beam reflectance measurement (FBRM). Tablets were also analyzed by near-infrared spectroscopy for crystal form determination. The observed change in dissolution rate correlated with detection of a greater number of larger particles by FBRM. FBRM results indicate increased aggregation of the tablet material due to crystal form conversion, resulting in the presence of slowly disintegrating and dissolving granules during the dissolution process. The improved understanding of the dissolution process allows evaluation of the potential in vivo impact of the stability changes. PMID- 20715798 TI - Investigating the anharmonicity of lattice vibrations in water-containing molecular crystals through the terahertz spectroscopy of L-serine monohydrate. AB - The influence of cocrystallized H(2)O molecules on the terahertz (THz) spectra and corresponding computational treatment of hydrated molecular crystals was investigated in the study of protonated and deuterium-substituted l-serine.H(2)O. The THz spectra of both solids have been measured in the range of 10 to 90 cm( 1), with simulations of the crystalline structure and THz vibrational modes performed using solid-state density functional theory. Significant and systematic overestimations of the predicted vibrational frequencies were observed in all calculations. Evidence provided by the comparison of the experimental and calculated vibrational frequencies for both the protonated and deuterated l serine.H(2)O solids indicates the presence of significant anharmonicity in the observed lattice vibrations. The results suggest that vibrational anharmonicity may play a much larger role in the interpretation of the THz spectra of hydrates in contrast to their corresponding anhydrous forms. PMID- 20715799 TI - Optical operation by chromophores featuring 4,5-dicyanoimidazole embedded within poly(methyl methacrylate) matrices. AB - We have studied photoinduced absorption, birefringence, and optical second harmonic generation in poly(methyl methacrylate) (PMMA) films doped by organic chromophores featuring 4,5-dicyanoimidazole in the weight content equal to 5%. The chromophores indicated as IM1-IM6 were synthesized from 2-bromo-1 methylimidazole-4,5-dicarbonitrile by either nucleophilic substitution or Suzuki Miyaura cross-coupling reaction. The samples were obtained as films of several micrometers thickness by the spin-coating method on a quartz substrate. Measurements of the optically induced birefringence were done by the Senarmont method at wavelength 1150 nm, and photoinduced absorption was studied in the spectral range 250-700 nm under optical treatment by 300 mW cw 532 nm laser. Photoinduced optical effects were studied by bicolor 1064 and 532 nm coherent laser pulses. The maximal changes were observed for the ratio between fundamental and writing beam intensities equal to about 7:1. To interpret the observed experimental measurements, theoretical simulations of photoinduced optical properties were performed by quantum chemical computational methods. PMID- 20715800 TI - Solubilities inferred from the combination of experiment and simulation. Case study of quercetin in a variety of solvents. AB - A strategy to infer solubilities from the combination of experiment and all-atom simulations is presented. From a single experimental estimate, the solubility of a substrate can be predicted in various environments from the related free energies of solvation. In the case of quercetin, the methodology was shown to reproduce the experimental solubilities in chloroform, water, acetonitrile, acetone, and tert-amyl alcohol within 0.5 log unit. The reliability of the estimates is markedly correlated to the accuracy of the experimental measure and to both the accuracy and precision of the computed free energies of solvation. PMID- 20715801 TI - Simple synthetic route for SERS-active gold nanoparticles substrate with controlled shape and organization. AB - We report a simple synthetic route based on electroless deposition (galvanic displacement) and natural lithography to simultaneously control the shape and organization of Au nanoparticles (NPs). We show for the first time the formation of organized extended domains of Au nanoflowers and nanocrowns with single crystalline tips. The dimension and morphology of the desired nanostructures (NSs) can be tuned easily by controlling the deposition conditions at room temperature using saccharin as an organic additive. The exact role of saccharin on the crystal growth process of Au NPs is also discussed. A systematic surface enhancement Raman spectroscopy (SERS) study of large, ordered areas of organized gold nanoflowers using p-mercaptoaniline (pMA) as the probe molecule shows massive and reproducible enhancements of the Raman signal. By comparing the relative enhancement of the different vibrational modes as a function of the morphology, the specific charge-transfer (chemical effect) SERS mechanism can be distinguished from the general electromagnetic field enhancement (physical effect). A wide range of applications can be envisaged for these SERS substrates. PMID- 20715802 TI - Strain-induced pseudomagnetic field for novel graphene electronics. AB - Particular strain geometry in graphene could lead to a uniform pseudomagnetic field of order 10T and might open up interesting applications in graphene nanoelectronics. Through quantum transport calculations of realistic strained graphene flakes of sizes of 100 nm, we examine possible means of exploiting this effect for practical electronics and valleytronics devices. First, we found that elastic backscattering at rough edges leads to the formation of well-defined transport gaps of order 100 meV under moderate maximum strain of 10%. Second, the application of a real magnetic field induced a separation, in space and energy, of the states arising from different valleys, leading to a way of inducing bulk valley polarization which is insensitive to short-range scattering. PMID- 20715803 TI - Carbon nanotube and CdSe nanobelt Schottky junction solar cells. AB - Developing nanostructure junctions is a general and effective way for making photovoltaics. We report Schottky junction solar cells by coating carbon nanotube films on individual CdSe nanobelts with open-circuit voltages of 0.5 to 0.6 V and modest power-conversion efficiencies (0.45-0.72%) under AM 1.5G, 100 mW/cm(2) light condition. In our planar device structure, the CdSe nanobelt serves as a flat substrate to sustain a network of nanotubes, while the nanotube film forms Shottky junction with the underlying nanobelt at their interface and also makes a transparent electrode for the device. The nanotube-on-nanobelt solar cells can work either in front (nanotube side) or back (nanobelt side) illumination with stable performance in air. Our results demonstrate a promising way to develop large-area solar cells based on thin films of carbon nanotubes and semiconducting nanostructures. PMID- 20715804 TI - Silicon nitride gate dielectrics and band gap engineering in graphene layers. AB - We show that silicon nitride can provide uniform coverage of graphene in field effect transistors while preserving the channel mobility. This insulator allowed us to study the maximum channel resistance at the Dirac (neutrality) point as a function of the strength of a perpendicular electric field in top-gated devices with different numbers of graphene layers. Using a simple model to account for surface potential variations (electron-hole puddles) near the Dirac point we estimate the field-induced band gap or band overlap in the different layers. PMID- 20715805 TI - Direct observation of Au/Ga2O3 peapodded nanowires and their plasmonic behaviors. AB - Gold-peapodded Ga(2)O(3) nanowires were fabricated successfully in a well controlled manner by thermal annealing of core-shell gold-Ga(2)O(3) nanowires. During the heating process, the core gold nanowires were broken up into chains of nanoparticles at sufficiently high temperature by the mechanism of Rayleigh instability. In addition, the size, shape, and interspacing between the particles can be manipulated by varying the annealing time and/or the forming gas. The plasmonic behaviors of these nanostructures are investigated by optical spectroscopy. A single nanowire optical device was designed, and its photonic characteristics were investigated. A remarkably high on/off photocurrent ratio in response to a 532 nm Nd:YAG laser light was found. As the size of the particle (pea) increases, the corresponding spectra are red-shifted. In addition, morphological changes of the peas lead to a distinct spectral response. The results may usher in the diverse applications in optoelectronics and biosensing devices with peapod nanostructures. PMID- 20715806 TI - The effect of antinotches on domain wall mobility in single crystal ferroelectric nanowires. AB - Changes in domain wall mobility, caused by the presence of antinotches in single crystal BaTiO(3) nanowires, have been investigated. While antinotches appeared to cause a slight broadening in the distribution of switching events, observed as a function of applied electric field (inferred from capacitance-voltage measurements), the effect was often subtle. Greater clarity of information was obtained from Rayleigh analysis of the capacitance variation with ac field amplitude. Here the magnitude of the domain wall mobility parameter (alpha) associated with irreversible wall movements was found to be reduced by the presence of antinotches--an effect which became more noticeable on heating toward the Curie temperature. The reduction in this domain wall mobility was contrasted with the noticeable enhancement found previously in ferroelectric wires with notches. Finite element modeling of the electric field, developed in the nanowires during switching, revealed regions of increased and decreased local field at the center of the notch and antinotch structures, respectively; the absolute magnitude of field enhancement in the notch centers was considerably greater than the field reduction in the center of the antinotches and this was commensurate with the manner in, and degree to, which domain wall mobility appeared to be affected. We therefore conclude that the main mechanism by which morphology alters the irreversible component of the domain wall mobility in ferroelectric wire structures is via the manner in which morphological variations alter the spatial distribution of the electric field. PMID- 20715807 TI - Optical properties of nanowire dimers with a spatially nonlocal dielectric function. AB - We study the optical spectra and electromagnetic field enhancements around cylindrical and triangular Ag nanowire dimers, allowing for a spatially nonlocal dielectric function that partially accounts for quantum mechanical effects. For the triangular structures, we pay particular attention to how these properties depend on the sharpness of the nanowire's tips. We demonstrate that significant differences exist from classical electrodynamics that employs a more common, spatially local dielectric function. These differences are shown to arise from the optical excitation of volume plasmons inside of the structures, analogous to one-particle quantum mechanical states, which lead to complex and striking patterns of material polarization. These results are important for further understanding the optical properties of structures at the nanoscale and have implications for numerous physical processes, such as surface-enhanced Raman scattering. PMID- 20715808 TI - Pitucamycin: structural merger of a phenoxazinone with an epoxyquinone antibiotic. AB - Chemical profiling of a Streptomyces griseus strain isolated from an old building with moisture damage led to the discovery of two novel phenoxazinones, chandrananimycin D and pitucamycin , along with the known grixazone B. Pitucamycin represents an unprecedented hybrid molecule composed of a phenoxazinone and an enaminomycin-like epoxyquinone moiety. PMID- 20715809 TI - New top-down approach for fabricating high-aspect-ratio complex nanostructures with 10 nm scale features. AB - We describe a new patterning technique, named "secondary sputtering lithography" that enables fabrication of ultrahigh-resolution (ca. 10 nm) and high aspect ratio (ca. 15) patterns of three-dimensional various shapes. In this methodology, target materials are etched and deposited onto the side surface of a prepatterned polymer by using low Ar ion bombarding energies, based on the angular distribution of target particles by ion-beam bombardment. After removal of the prepatterned polymer, high aspect ratios and high-resolution patterns of target materials are created. PMID- 20715810 TI - Recycling the versatile Pipecolic linker. AB - The Pipecolic linker is a new highly versatile handle which immobilizes on solid support through a carboxylic acid function a wide range of amines, alcohols, and hydrazines. The anchoring step on pipecolic resin is very easy and efficient, and compounds are released with high purities upon acidic treatment. During this treatment, an oxazolonium intermediate is hydrolyzed, yielding the cleavage of ester or amide bond and the release of free carboxylic acid of the starting linker. In this study, we report the possibility of recycling the pipecolic resin after the use of several trifluoroacetic acid (TFA) cleavage cocktails. We demonstrate that it can be reused up to five times without significant loading decrease. PMID- 20715811 TI - Scannable plasmonic trapping using a gold stripe. AB - Using counterpropagating surface plasmon polaritons (SPPs) on a gold stripe, we demonstrate a scannable integrated optical tweezer. We demonstrate the trapping of individual fluorescent beads on the stripe, which supports a single quasi transverse magnetic (TM) mode at the metal-water interface. The beads are localized to the stripe center, with a standard deviation of 51 nm transverse to the stripe, corresponding to a trap stiffness of 1.7 pN/microm. The localization along the stripe is achieved by balancing the scattering forces from the two counterpropagating SPPs excited by prism coupling. The particle position along the stripe can be controlled by varying the relative intensity of the two input beams. This work adds an important new capability to plasmonic optical tweezers, that of scanning. We anticipate that this will broaden the range of applications of plasmonic optical manipulation. PMID- 20715812 TI - Interaction of cationic nickel and manganese porphyrins with the minor groove of DNA. AB - The capacity of a series of new cationic nickel and manganese metalloporphyrins to bind in the minor groove of DNA was evaluated by binding competition experiments with manganese(III)-bis-aqua-meso-tetrakis(4-N methylpyridiniumyl)porphyrin, Mn-TMPyP, a powerful artificial nuclease when associated with KHSO(5). The four N-methylpyridiniumyl substituents on this porphyrin macrocycle are responsible for a strong binding affinity for the minor groove of AT-rich DNA. The inhibition of DNA cleavage mediated by Mn TMPyP/KHSO(5) by the various tested porphyrins correlated with their competitive occupancy of the minor groove site of Mn-TMPyP. Introduction of long and flexible cationic substituents at the periphery of the porphyrin macrocycle precluded the interaction of the porphyrin derivative in the minor groove and resulted in low affinity for DNA. On the other hand, introduction of phenylpyridiniumyl substituents on the porphyrin macrocycle surprisingly conferred the new porphyrin derivative with a tight binding in the minor groove of a six consecutive AT base pairs sequence. These data on structural requirements for minor groove DNA binding will help the rational design of porphyrin derivatives for selective targeting of quadruplex DNA versus double-stranded DNA. PMID- 20715813 TI - Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2 pyridinone donor group siderophore mimics. AB - The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pK(a)'s of N(2)(etLH)(2), N(2)(prLH)(2), and N(3)(etLH)(3), were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N(2)(etLH)(2) and N(2)(prLH)(2), and hexadentate N(3)(etLH)(3), were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N(3)(etLH)(3) forms a 1:1 complex with Fe(III) with log beta(110) = 27.34 +/- 0.04. N(2)(prLH)(2) forms a 3:2 L:Fe complex with Fe(III) where log beta(230) = 60.46 +/- 0.04 and log beta(110) = 20.39 +/- 0.02. While N(2)(etLH)(2) also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log beta(230); log beta(110) was found to be 20.45 +/- 0.04. The pFe values of 26.5 for N(3)(etLH)(3) and 24.78 for N(2)(prLH)(2) are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents. PMID- 20715814 TI - Bis(maltolato)vanadium(III)-polypyridyl complexes: synthesis, characterization, DNA cleavage, and insulin mimetic activity. AB - Four vanadium(III) complexes of the general formula [V(maltol)(2)(N-N)]ClO(4), where N-N is 2,2'-bipyridine (bpy) (1); 1,10-phenanthroline (phen) (2); dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (3), and dipyrido[3,2-a:2',3' c]phenazine (dppz) (4), have been synthesized and characterized by IR, UV visible, NMR spectroscopies, and electrospray ionization mass spectra (ESI-MS). The complexes exhibit the typical (1)H NMR spectra for paramagnetic V(III) species. The structures of complexes 1, 2, and 3 were characterized by single crystal X-ray diffraction. All complexes are monomeric and cationic containing V(III) species ligated to one neutral polypyridyl ligand and two monoanionic bidentate maltolate ligands with a distorted octahedral geometry. The complexes show an irreversible redox peak around +0.80 V versus Ag/AgCl corresponding to one-electron oxidation of V(III) to V(IV). The time-resolved UV-visible spectral changes for the complexes during the electrolysis in acetonitrile solution at +1.0 V are consistent with one-electron oxidation of the complexes to yield the stable V(IV) species. All complexes cleave plasmid pBR322 DNA without the addition of any external agents. In vitro insulin mimetic activity against insulin responsive RIN 5f cells indicates that complex 1 has similar activity to insulin while the others have moderate insulin mimetic activity. PMID- 20715815 TI - Microwave assisted synthesis of a small library of substituted N,N'-bis((8 hydroxy-7-quinolinyl)methyl)-1,10-diaza-18-crown-6 ethers. AB - N,N'-bis-((8-hydroxy-7-quinolinyl)methyl)-1,10-diaza-18-crown-6 ether 1a and its analogue 1c are known as fluorescent sensors of magnesium in living cells. With the aim to investigate the effects of the substitution pattern on the photophysical properties of ligands 1 and their metal complexes, we developed an efficient microwaves enhanced one-pot Mannich reaction to double-armed diaza crown ligands 1 carrying a variety of substituents. This new protocol is characterized by shorter reaction times, enhanced yields, and improved product purities with respect to the use of conventional conductive heating. PMID- 20715816 TI - Quantum study of laser-induced initial activation of graphite-to-diamond conversion. AB - Recently (Science 2009, 325, 181), femtosecond-resolved electron energy loss spectroscopy (FEELS) was used to map the structural changes of graphite upon laser irradiation, revealing the change from sp(2) to sp(3), i.e., diamond-like, hybridization. With a laser excitation energy of 2.39 eV and a fluence of 1.5 mJ/cm(2), the most pronounced changes were observed in approximately 180 fs, a time similar to the temporal resolution of the technique. The presence of the laser field turns the electronic wavefunction into a wavepacket whose quantum dynamics governs the onset of the structural rearrangement. Density functional theory calculations with a quantum propagator that include the laser field show that the charge density of graphite expands between the layers in an ultrafast process of the order of approximately 10 fs. Calculations as a function of the field/fluence further show different values of the maximum bond order reached at the stationary state. The experimentally used value is at the crossover between two regimes. It is tempting to associate the second regime with the electron organization necessary to achieve ablation or melting. The application of the model demonstrates its potential for examining the dynamical nature of the charge density and chemical bonding as it forms. PMID- 20715817 TI - Oriented insertion of phi29 N-hexahistidine-tagged gp10 connector protein assemblies into C20BAS bolalipid membrane vesicles. AB - Ni(2+):NTA-PEG600-grafted glass surfaces are capable of immobilizing N-his6 gp10 connector protein assemblies from the phi29 DNA packaging motor and mediating their transplantation into bolalipid vesicles whose membrane thickness is compatible with the hydrophobic domain of the gp10 assemblies. PMID- 20715818 TI - Synthesis, stereochemical separation, and biological evaluation of selective inhibitors of human MAO-B: 1-(4-arylthiazol-2-yl)-2-(3 methylcyclohexylidene)hydrazines. AB - Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC(50) ranging between 21.90 and 0.018 microM. PMID- 20715819 TI - Design, synthesis, and in vitro pharmacology of new radiolabeled gamma hydroxybutyric acid analogues including photolabile analogues with irreversible binding to the high-affinity gamma-hydroxybutyric acid binding sites. AB - Gamma-hydroxybutyric acid (GHB) is a psychotropic compound endogenous to the brain. Despite its potential physiological significance, the complete molecular mechanisms of action remain unexplained. To facilitate the isolation and identification of the high-affinity GHB binding site, we herein report the design and synthesis of the first (125)I-labeled radioligands in the field, one of which contains a photoaffinity label which enables it to bind irreversibly to the high affinity GHB binding sites. PMID- 20715820 TI - Pd(II)-catalyzed hydroxyl-directed C-H activation/C-O cyclization: expedient construction of dihydrobenzofurans. AB - A Pd(II)-catalyzed C-H activation/C-O cyclization reaction directed by a proximate hydroxyl group has been developed. This reaction provides a new method for constructing dihydrobenzofurans, including spirocyclic analogues, a process that is potentially applicable to natural product synthesis. PMID- 20715821 TI - Stereospecific decarboxylative allylation of sulfones. AB - Allyl sulfonylacetic esters undergo highly stereospecific, palladium-catalyzed decarboxylative allylation. The reaction allows the stereospecific formation of tertiary homoallylic sulfones in high yield. In contrast to related reactions that proceed at -100 degrees C and require highly basic preformed organometallics, the decarboxylative coupling described herein occurs under mild nonbasic conditions and requires no stoichiometric additives. Allylation of the intermediate alpha-sulfonyl anion is more rapid than racemization, leading to a highly enantiospecific process. Density functional theory calculations indicate that the barrier for racemization is 9.9 kcal/mol, so the barrier for allylation must be <9.9 kcal/mol. PMID- 20715822 TI - In vitro study of the release properties of soy-zein protein microspheres with a dynamic artificial digestive system. AB - The purpose of this work was to study the performance of microspheres of soy protein isolate (SPI), zein, or SPI-zein complex as vehicles of nutraceutical delivery under fasting and prandial conditions in an artificial digestive system (TIM-1). Riboflavin availability for absorption from the small intestine compartments reached 90% of the total load within 4 h, most of it (65-80%) turning up in the jejunum dialysis fluid, suggesting that this segment is the main site of absorption, regardless of the nature of the microspheres. However, the riboflavin concentrations and the availability for absorption profiles depended on microsphere formulation. Release from pure SPI and zein microspheres in the stomach compartment occurred within 15 min. The availability for absorption from both the jejunum and ileum compartment followed first-order kinetics, indicating that the limiting step in nutrient uptake with these two formulations is absorption by passive diffusion. SPI-zein complex microspheres provided sustained release of riboflavin over 4 h and a near-zero-order nutrient availability for absorption profile in both fasting and prandial states. Suspending SPI-zein complex microspheres in yogurt significantly delayed nutrient release, which would increase the likelihood of gastric-sensitive nutrients passing intact into the intestine for absorption. SPI-zein complex microspheres thus show potential for use as nutraceutical delivery vehicles in the creation of novel functional foods. PMID- 20715823 TI - Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). AB - C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8 substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats. PMID- 20715825 TI - Catalysis of transesterification by a nonfunctionalized metal-organic framework: acido-basicity at the external surface of ZIF-8 probed by FTIR and ab initio calculations. AB - The zeolite imidazolate framework ZIF-8 is shown for the first time to be able to catalyze transesterification of vegetable oil with significant activity. Rationalization of this behavior at the atomic scale is provided by combining CO adsorption monitored by FTIR and DFT calculations (clusters and periodic models). We demonstrate that the acido-basic sites are located at the external surface of the material or at defects, but not in the microporosity of ZIF-8. A great variety of sites are found the surface: OH and NH groups, hydrogenocarbonates, low-coordinated Zn atoms, and free N(-) moieties belonging to linkers. Their proportions depend on the operating conditions (temperature and pressure). The acido-basicity of the surface is then probed by adsorption of CO at low temperature. In parallel, the species present are mapped by DFT calculations combined with a thermodynamic model. An assignment of the CO region of the FTIR spectra can thus be proposed. The complex infrared spectrum is attributed to the coexistence of classical C-adducts of CO with acid sites and other modes on basic sites (O-adducts and side-on adducts). Adsorption energies and CO frequency shifts show that some strong Lewis sites exist (in particular Zn(II) species), as well as strong Bronsted acid sites (NH groups), together with basic sites (OH groups and N(-) moieties). By calculating the co-adsorption of a model ester (methyl acetate) and methanol, we show the prevailing role of Zn(II) species as acid sites, combined with N(-) moieties and OH groups as basic ones, in determining the catalytic properties of ZIF-8. This work opens new perspectives on the use of MOFs in catalysis and, more generally, on the properties of their external surface. PMID- 20715827 TI - Bicomponent hydrogels of lumichrome and melamine: photoluminescence property and its dependency on pH and temperature. AB - Lumichrome (L) and melamine (M) produce thermoreversible hydrogels in LM31 and LM11 compositions, but LM13 composition does not produce hydrogel (the numbers indicate the respective molar ratio of the components). The formation of thermoreversible gels is confirmed from morphology, DSC, and rheological experiments where LM13 system does not meet the required characteristics of thermoreversible gels. FTIR spectra suggest that H-bonding between L and M produces the supramolecular complex, and (1)H NMR spectra suggest that pi stacking of the complex produce fibrillar network structure entrapping a large amount of water producing the hydrogels. The nonplanar structure of LM13 complex probably causes difficulty in pi-stacking, prohibiting the gel formation. The UV vis spectra show a blue shift of the pi-pi* transition band (354 nm) indicating H aggregate formation but the pi-pi* band coupled with n-pi* transition (386 nm) shows a constant red shift by 7 nm, indicating independency of pi-stacking on the n-pi* transition in the different LM systems. The PL intensities of LM11 and LM31 gels become more quenched than the intensity of pure L due to formation of nonfluorescent complex (static quenching) in the gels. In the LM13 sol the degree of quenching is less than that of the gels because of absence of energy transfer through the junction points of gels. The increased lifetime values of LM gels compared to that of pure L is also indicative of H-aggregate formation. The PL intensity increases linearly with increase of temperature due to thinning of the fibers decreasing the exciton energy transfer. The emission peak shows a red shift with rise in temperature, indicating H- to J-aggregate transformation, and at the melting temperature it shows a sharp decrease. With both increase and decrease of pH from the neutral pH 7, the gels exhibit higher PL intensity because of sol formation. PMID- 20715829 TI - Preparation and periodic emission of superlattice CdS/CdS:SnS2 microwires. AB - Semiconductor superlattice micro-/nanowires could greatly increase the versatility and power of modulating electronic (or excitonic, photonic) transport, optical properties. In this communication, we report growth of a semiconductor CdS/CdS:SnS(2) superlattice microwire through a coevaporation technique with microenvironmental control. Such a novel superlattice microwire can modulate the exciton and photons to show multipeak emissions with periods in a wide spectral range, which arise in the 1-d photon crystal and confined exciton emission. This system can be widely used in producing multicolor emissions, low threshold lasing, study light-matter interaction, slow light engineering, and weak nonlinear optical devices. PMID- 20715828 TI - A carbon-supported copper complex of 3,5-diamino-1,2,4-triazole as a cathode catalyst for alkaline fuel cell applications. AB - The performance of a novel carbon-supported copper complex of 3,5-diamino-1,2,4 triazole (Cu-tri/C) is investigated as a cathode material using an alkaline microfluidic H(2)/O(2) fuel cell. The absolute Cu-tri/C cathode performance is comparable to that of a Pt/C cathode. Furthermore, at a commercially relevant potential, the measured mass activity of an unoptimized Cu-tri/C-based cathode was significantly greater than that of similar Pt/C- and Ag/C-based cathodes. Accelerated cathode durability studies suggested multiple degradation regimes at various time scales. Further enhancements in performance and durability may be realized by optimizing catalyst and electrode preparation procedures. PMID- 20715830 TI - Cu24O24Si8R8: organic soluble 56-membered copper(I) siloxane cage and its use in homogeneous catalysis. AB - Organic soluble 56-membered copper(I) siloxane cage compound Cu(24)O(24)Si(8)R(8) (1, R = (2,6-iPr(2)C(6)H(3))N(SiMe(3))) has been synthesized and structurally characterized. It consists of a copper silica-supported structure, in which the metal ions are two-coordinate and covalently anchored onto the cage surface and the weak metal...metal d(10)-d(10) interactions are widely full within the cage, that is active in catalyzing the Ullmann-Goldberg-type C-N coupling reaction involving aryl or 2-thienyl bromides with heterocyclic nitrogen nucleophiles. This work provides insight into homogeneous catalysis utilizing the heterogeneous structure. PMID- 20715831 TI - Symmetry switch of cobalt ferrocyanide framework by alkaline cation exchange. AB - We observed a reversible symmetry switch of a cobalt ferrocyanide framework by the alkaline cation exchange and resultant control of the optical properties at room temperature. PMID- 20715832 TI - An open-source java platform for automated reaction mapping. AB - This article presents software applications that have been built upon a modular, open-source, reaction mapping library that can be used in both cheminformatics and bioinformatics research. We first describe the theoretical underpinnings and modular architecture of the core software library. We then describe two applications that have been built upon that core. The first is a generic reaction viewer and mapper, and the second classifies reactions according to rules that can be modified by end users with little or no programming skills. PMID- 20715833 TI - Solvent retention, thermodynamics, rheology and small angle X-ray scattering studies on thermoreversible poly(vinylidene fluoride) gels. AB - Solvent retention power of poly(vinylidene fluoride) (PVDF) gels has been studied for various homologues of phthalate (aromatic diesters). The thermal stability has been examined for gels of varying morphology. Solvent evaporation, gelation, gel melting, and polymer degradation temperatures have increased with increasing aliphatic chain length of phthalates. The thermodynamics and polymer-solvent compound formations in the PVDF-phthalate gels have been explored. The weight fraction of polymer in compound has decreased with increasing aliphatic chain length. SAXS studies have confirmed the lamellar organization inside the fibrils, and interlamellar distance increases with aliphatic chain length of diesters. The scattering patterns follow the power law behavior (I(q) approximately q(-alpha)), and polymer gels consist of high-density mass (fibril), voids, and interlamellar region. Dynamic mechanical properties indicate the splintering and reformation of network structure in gels whose percolation frequency has reduced for higher aliphatic chain length phthalate. Morphology-dependent moduli have been observed, and greater mechanical strength has been verified for thicker fibrillar gels both for steady and dynamic measurements. PMID- 20715834 TI - Occurrence of a quadruplex motif in a unique insert within exon C of the bovine estrogen receptor alpha gene (ESR1). AB - The 5' end of exon C of the bovine estrogen receptor alpha gene (bov-ESR1) includes a unique G-rich insert, not found in other closely related mammalian genes, which lies close to both a double E-box transcription factor binding site and the site of a single nucleotide (G/A) polymorphism. Biophysical studies, using CD and UV absorbance measurements, show that this 22 base insert leads to the formation of a family of stable G-quadruplex structures which are unaffected by the G/A polymorphism. Multiplex PCR shows that the region including the G quadruplex is transcribed into RNA, and studies with a synthetic RNA transcript sequence demonstrated formation of a highly stable parallel-folded quadruplex structure. Luciferase reporter constructs demonstrate that the G-rich sequence reduces rates of translation when present in the 5'-UTR of mRNA transcripts. Mutations (GGG to AAA) that destabilize the quadruplex lead to a 15-fold enhancement of translational efficiency, suggesting that a possible biological role of the insert in exon C of the bov-ESR1 is to regulate translation of this exon. PMID- 20715835 TI - Kinetic resolution of racemic 2,3-allenoates by organocatalytic asymmetric 1,3 dipolar cycloaddition. AB - The kinetic resolution of racemic 2,3-allenoates was realized via 1,3-dipolar cycloaddition by using a bisphosphoric acid catalyst, affording the optically active 2,3-allenoates and 3-methylenepyrrolidine derivatives in high yields and enantioselectivities. PMID- 20715836 TI - Rhodium-catalyzed asymmetric arylation of azomethine imines. AB - A rhodium-catalyzed addition of sodium tetraarylborates to azomethine imines has been described. Highly efficient asymmetric catalysis has also been achieved by employing a chiral diene ligand to give 1-(diarylmethyl)pyrazolidin-3-ones with high enantioselectivity. PMID- 20715837 TI - Herbicidal activity of cineole derivatives. AB - Essential oils and their constituents have potential as ecologically acceptable pesticides that may also have novel modes of action. In this work hydroxy and ester derivatives of the naturally occurring monoterpenoids 1,8-cineole 3, the main component in most eucalyptus oils, and 1,4-cineole 4 were prepared and their pre-emergence herbicidal activity against annual ryegrass (Lolium rigidum) and radish (Raphanus sativus var. Long Scarlet) investigated in laboratory-based bioassays. 1,8-Cineole, eucalyptus oil and all derivatives showed a dose dependent herbicidal activity against annual ryegrass and radish with many of the derivatives showing improved herbicidal activity relative to 1,8-cineole and high cineole eucalyptus oil. Increased activity of cineole ester derivatives compared to their associated hydroxy-cineole and carboxylic acid was not observed. No relationship between lipophilicity of the carboxylic acid portion of cineole ester derivatives and herbicidal activity was observed. The results indicate that these cineole derivatives could be environmentally acceptable herbicides. PMID- 20715838 TI - Identity of the active site in gold nanoparticle-catalyzed Sonogashira coupling of phenylacetylene and iodobenzene. AB - XPS, TEM, and reaction studies were used to examine the catalytic behavior of gold species deposited on lanthana toward the cross-coupling of phenylacetylene and iodobenzene. Atomically dispersed Au(I) and Au(III) were catalytically inert, whereas metallic Au(0) nanoparticles were both active and very selective. Thus it is metallic gold and not ionic gold that provides the catalytically active sites. Au(0) nanoparticles supported on silica, gamma-alumina, and BaO were active but relatively unselective; however, as with lanthana, ceria-supported Au(0) nanoparticles showed high selectivity. This strong promoting effect of the lanthanide oxide supports on Sonogashira selectivity cannot be accounted for in terms of acid/base, redox, or SMSI effects; it may be tentatively ascribed to metal --> support hydrogen spillover. PMID- 20715839 TI - Histaminol: identification and HPLC analysis of a novel compound in wine. AB - Histaminol, a minor histamine metabolite originating from imidazole acetaldehyde, has been detected in a food matrix as complex as wine. The standard molecule was synthesized, and subsequently the chemical structure was confirmed by ESI-MS and NMR measurements. The development, optimization, and in-house validation of a HPLC-DAD chromatographic method for the quantitative determination of histaminol in wine are described and discussed. The expanded uncertainty (U(k=2)) of the procedure was estimated as 11.06%. Twenty commercial Italian wine samples were selected. All samples (16 red and 4 white wines) were analyzed after a C-18 SPE cartridge fractionation procedure. The content of this alcohol was in the range of 0.289-1.094 mg/L (minimum and maximum values were obtained for Nero d'Avola vintage 2007 and Barolo vintage 1969, respectively). PMID- 20715840 TI - Copper-catalyzed formal [4 + 2] annulation between alkyne and fullerene bromide. AB - A copper-catalyzed reaction of arylacetylene or enyne with C(60)Ar(5)Br effects a formal [4 + 2] annulation reaction to form a dihydronaphthalene ring fused to the fullerene core. The reaction involves a formal C-H bond activation and takes place by a copper-mediated radical mechanism. This reaction takes place in 60-75% overall yield from [60]fullerene and creates axial chirality in the product because of restricted rotation of the top aryl groups. PMID- 20715841 TI - Nickel-catalyzed C-O activation of phenol derivatives with potassium heteroaryltrifluoroborates. AB - A general method based on nickel-catalyzed C-O activation of various phenol derivatives with potassium (hetero)aryltrifluoroborates has been developed. A large number of heterobiaryls can be easily obtained with yields up to 99% using methanesulfonate cross-coupling partners. PMID- 20715842 TI - Liquid-phase chemical sensing using lateral mode resonant cantilevers. AB - Liquid-phase operation of resonant cantilevers vibrating in an out-of-plane flexural mode has to date been limited by the considerable fluid damping and the resulting low quality factors (Q factors). To reduce fluid damping in liquids and to improve the detection limit for liquid-phase sensing applications, resonant cantilever transducers vibrating in their in-plane rather than their out-of-plane flexural resonant mode have been fabricated and shown to have Q factors up to 67 in water (up to 4300 in air). In the present work, resonant cantilevers, thermally excited in an in-plane flexural mode, are investigated and applied as sensors for volatile organic compounds in water. The cantilevers are fabricated using a complementary metal oxide semiconductor (CMOS) compatible fabrication process based on bulk micromachining. The devices were coated with chemically sensitive polymers allowing for analyte sorption into the polymer. Poly(isobutylene) (PIB) and poly(ethylene-co-propylene) (EPCO) were investigated as sensitive layers with seven different analytes screened with PIB and 12 analytes tested with EPCO. Analyte concentrations in the range of 1-100 ppm have been measured in the present experiments, and detection limits in the parts per billion concentration range have been estimated for the polymer-coated cantilevers exposed to volatile organics in water. These results demonstrate significantly improved sensing properties in liquids and indicate the potential of cantilever-type mass-sensitive chemical sensors operating in their in-plane rather than out-of-plane flexural modes. PMID- 20715843 TI - Collector phase transitions during vapor-solid-solid nucleation of GaN nanowires. AB - We investigate the nucleation of Ni-induced GaN nanowires by in situ and ex situ experiments. Three nucleation stages are evidenced. In the first two stages, different crystal structures of the Ni collectors are identified. Real-time monitoring of the Ga desorption allows the amount of Ga incorporated in the collectors to be quantified. A transition of their crystal structure prior to nanowire growth is found to be in agreement with the thermodynamically stable phase sequence of the relevant phase diagrams. PMID- 20715844 TI - Nanostructured LaB6 field emitter with lowest apical work function. AB - LaB(6) nanowires are ideal for applications as an electrical field-induced ion and electron point source due to their miniature dimensions, low work function, as well as excellent electrical, thermal, and mechanical properties. We present here a reliable method to fabricate and assemble single LaB(6) nanowire-based field emitters of different crystal orientations. The atomic arrangement, emission brightness from each crystal plane, and field emission stability have been characterized using field ion microscopy (FIM) and field emission microscopy (FEM). It is found that the 001 oriented LaB(6) nanowire emitter has the highest field emission symmetry while the 012 oriented LaB(6) nanowire has the lowest apical work function. The field emission stability from the single LaB(6) nanowire emitter is significantly better than either the LaB(6) needle-type emitter or W cold field emitters. PMID- 20715846 TI - Photocleavable polyethylene glycol for the light-regulation of protein function. AB - PEGylation is commonly employed to enhance the pharmacokinetic properties of proteins, but it can interfere with natural protein function. Protein activity can thus be abrogated through PEGylation, and a controllable means to remove the polyethylene glycol (PEG) group from the protein is desirable. As such, light affords a unique control over biomolecules through the application of photosensitive groups. Herein, we report the synthesis of a photocleavable PEG reagent (PhotoPEG) and its application to the light-regulation of enzyme activity. PMID- 20715845 TI - A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells. AB - The NADPH oxidase (Nox) proteins catalyze the regulated formation of reactive oxygen species (ROS), which play key roles as signaling molecules in several physiological and pathophysiological processes. ROS generation by the Nox1 member of the Nox family is necessary for the formation of extracellular matrix (ECM) degrading, actin-rich cellular structures known as invadopodia. Selective inhibition of Nox isoforms can provide reversible, mechanistic insights into these cellular processes in contrast to scavenging or inhibition of ROS production. Currently no specific Nox inhibitors have been described. Here, by high-throughput screening, we identify a subset of phenothiazines, 2 acetylphenothiazine (here referred to as ML171) (and its related 2 (trifluoromethyl)-phenothiazine) as nanomolar, cell-active, and specific Nox1 inhibitors that potently block Nox1-dependent ROS generation, with only marginal activity on other cellular ROS-producing enzymes and receptors including the other Nox isoforms. ML171 also blocks the ROS-dependent formation of ECM degrading invadopodia in colon cancer cells. Such effects can be reversed by overexpression of Nox1 protein, which is suggestive of a selective mechanism of inhibition of Nox1 by this compound. These results elucidate the relevance of Nox1-dependent ROS generation in mechanisms of cancer invasion and define ML171 as a useful Nox1 chemical probe and potential therapeutic agent for inhibition of cancer cell invasion. PMID- 20715847 TI - A metal-free DNA nuclease based on a cyclic peptide scaffold. AB - The ability to cleave DNA with the aid of chemical nucleases has been a challenge in the scientific community, particularly in the absence of a redox active metal ion. Inspired by structural characterization of the active site found in Staphylococcal nuclease, we have designed a series of organic molecule comprising cyclic pentapeptides conjugated to a DNA intercalator (e.g., anthraquinone). The cyclic peptide is designed to cleave the phosphodiester backbone, whereas the intercalator is expected to improve binding affinity to the substrate (DNA). Our lead compound (1-AQ), composed of the cyclic peptide cyc-d-Lys-Gly-Arg-Ser-Arg conjugated to anthraquinone, degrades DNA into small fragments at physiologically relevant conditions (i.e., 37 degrees C, pH = 7.4). We find that 1-AQ is highly effective in degrading duplex DNA at micromolar concentrations as corroborated by agarose and polyacrylamide gel electrophoresis. Changing the DNA intercalator to acridine (1-Ac) renders the compound comparable in nuclease activity to 1-AQ. In comparison to control compounds (Lin-1 and 1) that lack either the cyclic scaffold or the DNA intercalator, our lead compound (1-AQ) is found to be significantly more active as a DNA chemical nuclease. We have studied the importance of the triad (Arg-Ser-Arg) as the designed module for DNA cleavage. Changing l-Ser to l-Glu (cyc-d-Lys-Gly-Arg-Glu-Arg, Glu-AQ) results in an inactive compound, whereas the cyclic peptide Gly-AQ (cyc-d-Lys-Gly-Arg-Gly-Arg, where glycine replaces l-serine) has similar DNA nuclease activity to 1-AQ. In addition, changing the stereochemistry from d-lysine to l-lysine results in a cyclic peptide (1-L-AQ) exerting weak DNA nuclease activity, highlighting the importance of the cyclic backbone conformation for efficient DNA nuclease activity. The addition of ROS scavengers does not reduce DNA nuclease activity; an observation that supports a hydrolytic cleavage mechanism. Finally, we have estimated the kinetics of DNA cleavage of a 15-mer duplex DNA substrate by compound 1-AQ. By monitoring DNA duplex degradation by following the change in absorbance (hyperchromicity) at various 1-AQ concentrations, we report a maximal k(obs) value (as an underestimation of k(max)) of 1.62 h(-1) at a 7.5-fold of 1 AQ. We have also compared the other two active peptide conjugates, namely, 1-Ac and Gly-AQ to that of 1-AQ. Both compounds exert similar nuclease activity to that of 1-AQ. To the best of our knowledge, this is the most active metal-free DNA nuclease reported to date that exerts its DNA nuclease activity at biologically relevant conditions. PMID- 20715848 TI - Thiopalmitoylated peptides from the peripheral nervous system myelin p0 protein: synthesis, characterization, and neuritogenic properties. AB - Thiopalmitoylation (i.e., the covalent attachment of palmitic acid via a thioester linkage to cysteine residues in the polypeptide backbone) is a common post-translational modification of proteins. Several proteins that have been identified as putative autoantigens in a variety of T-cell mediated autoimmune diseases are thiopalmitoylated, and thus, we have hypothesized that endogenous thiopalmitoylated peptides released during tissue breakdown may play a role in the development and chronicity of autoimmune diseases. To investigate this, we have studied the effect of thiopalmitoylation on the immunogenic and neuritogenic properties of P0, the major peripheral nervous system (PNS) myelin protein, which is thiopalmitoylated at cysteine 153, and described as a candidate autoantigen in Guillain-Barre syndrome (GBS), a human inflammatory demyelinating disease of the PNS. This paper describes the synthesis of palmitoylated peptide P0(180-199) and P0(152-171) by on-resin acylation using specific cysteine side-chain protecting groups: Mmt (labile in diluted acid) and StBu (labile in the presence of tributylphosphine). Our results show that the thiol protecting group had to be adjusted to the peptide sequence: Mmt was efficiently used for P0(180-199) thioacylation, but it was not suitable for thiopalmitoylation of P0(152-171) because of a premature deprotection of the Boc protecting group on the epsilon NH(2) Lys in the presence of 2% TFA, leading to dipalmitoylation. Palmitoylated P0(152-171) was successfully obtained by using StBu as the thiol protecting group. We could show by circular dichroism that palmitoylation has no influence on the structuration of the peptide in solution but palmitoylation increased the stability of the peptide in the presence of serum. Using EAN (experimental autoimmune neuritis), the rat model of GBS, we have compared the immunological properties of palm and non-palm P0 peptides and showed that thiopalmitoylation has indeed a great influence on their neuritogenic and immunogenic properties. This study provides further support for our hypothesis concerning the role of thiopalmitoylation in the development and chronicity of inflammatory demyelinating diseases and confirms that thiopalmitoylation of peptides may provide a simple means to increase MHC class II restricted responses. PMID- 20715849 TI - Combinatorial approach to determine functional group effects on lipidoid-mediated siRNA delivery. AB - The application of RNA interference (RNAi), either in the clinic or in the laboratory, requires safe and effective delivery methods. Here, we develop a combinatorial approach to synthesize a library of delivery vectors based on two lipid-like substrates with known siRNA delivery capabilities. Members of this library have a mixture of lipid-like tails and feature appendages containing hydroxyl, carbamate, ether, or amine functional groups as well as variations in alkyl chain length and branching. Using a luciferase reporter system in HeLa cells, we studied the relationship between lipid chemical modification and delivery performance in vitro. The impact of the functional group was shown to vary depending on the overall amine content and tail number of the delivery vector. Additionally, in vivo performance was evaluated using a Factor VII knockdown assay. Two library members, each containing ether groups, were found to knock down the target protein at levels comparable to those of the parent delivery vector. These results demonstrate that small chemical changes to the delivery vector impact knockdown efficiency and cell viability both in vitro and in vivo. The work described here identifies new materials for siRNA delivery and provides new insight into the parameters for optimized chemical makeup of lipid like siRNA delivery materials. PMID- 20715850 TI - GABAC receptor binding of quantum-dot conjugates of variable ligand valency. AB - Highly fluorescent CdSe quantum dots (qdots) can serve as a platform for tethering multiple copies of a receptor-targeted ligand, affording study of how the level of multivalency affects receptor binding. We previously showed that qdots conjugated with long PEG chains terminated by muscimol, a known GABA(C) agonist, exhibit specific binding to the surface membrane of GABA(C) receptor expressing Xenopus oocytes. The present report addresses the effect of varying the number, i.e., valency, of muscimol- (M-) terminated PEG chains attached to the qdot on binding of the resulting conjugate to GABA(C) receptors. M-PEG-qdots of differing muscimol valency were prepared by conjugating AMP-CdSe/ZnS qdots with muscimol-terminated and methylamine-terminated PEG chains in proportions designed to yield varying percentages of muscimol-terminated chains among the total approximately 150-200 chains bound to the qdot. The investigated valencies represented 0%, approximately 25%, approximately 50%, and 100% loading with muscimol (preparations termed M-PEG-qdot0, M-PEG-qdot25, M-PEG-qdot50, and M-PEG qdot100, respectively. Binding of a given conjugate to surface membranes of GABA(C) receptor-expressing oocytes was analyzed by quantitative fluorescence microscopy following defined incubation with approximately 30 nM of the conjugate. With 5-20 min incubation, the fluorescence signal resulting from incubation with M-PEG-qdot25 exceeded, by approximately 6-fold, the fluorescence level obtained with M-PEG-qdot preparations that lacked muscimol-terminated chains (M-PEG-qdot0). M-PEG-qdot50 yielded a net signal roughly similar to that of M-PEG-qdot25, and that produced by M-PEG-qdot100 exceeded, by approximately 30 50%, those for M-PEG-qdot25 and M-PEG-qdot50. The time course of changes in oocyte surface membrane fluorescence resulting from the introduction of and removal of M-PEG-qdots in the medium bathing the oocyte indicated only a modest dependence of both binding and wash-out kinetics on muscimol valency. The results demonstrate a dependence of the binding activity of the M-PEG-qdot conjugates on muscimol valency, presumably reflecting higher GABA(C) avidity and/or affinity of the muscimol at high valency, and provide insight on the interactions of membrane receptor proteins with qdot conjugates containing multiple copies of a receptor targeting ligand. PMID- 20715851 TI - Targeted cellular delivery of quantum dots loaded on and in biotinylated liposomes. AB - We describe the preparation, biophysical characterization, and receptor-mediated cellular internalization of biotinylated lipid particles (BLPs) loaded on the surface and internally with two distinct (colors) of quantum dot (QD) probes. BLPs were formulated with 1.4 and 2.7 mol % PEG-lipids containing either a fusogenic or pH-sensitive lipid to promote bilayer destabilization of endosomal membranes and favor QD cytoplasmic release. The amount of PEG was chosen to provide steric stabilization of the final construct. BLPs were loaded with a red emitting QD(655) and surface coated with a green-emitting QD(525) conjugated to the epidermal growth factor (EGF) ligand in order to target the epidermal growth factor receptor (EGFR). The targeted and QD labeled BLPs showed strong and selective binding to EGFR-expressing tumor cell line and subsequent internalization. The dual-color QD labeling strategy and colocalization analysis allow prolonged live cell imaging of BLPs and loaded cargo independently, using a single excitation wavelength and simultaneous detection of both QDs. The chemistry of bioconjugation for the EGF ligand, the QDs, and the BLPs in a single lipid particle, involves only biotin-streptavidin interaction without requiring further purification from free EGF-QDs preformed complexes. Coupled with an encapsulated drug, the targeted and QD-labeled BLPs could provide imaging and drug delivery in a single multifunctional carrier. PMID- 20715852 TI - Oligopeptide delivery carrier for osteoclast precursors. AB - Dendritic amine and guanidinium group-modified nanoparticles were investigated for the delivery of model peptide drug into primary osteoclast precursor cells (bone marrow macrophages; BMMs). The model peptide drug was encapsulated into the nanoparticle by dropping the drug/carrier dissolved in dimethylsulfoxide/methylene chloride cosolvent into water containing poly(vinyl alcohol) as a stabilizer. Flow cytometry and spectrofluorimetry analysis indicated that the model drug itself was not taken up by the BMMs; however, nanoparticle systems underwent significant cellular uptake. In particular, guanidinium group-modified nanoparticles were taken up more efficiently than amine group-modified ones. Cell viability studies showed that both amine and guanidinium group-modified nanoparticles exhibited no significant cytotoxicity up to 100 microg/mL against the cells. PMID- 20715854 TI - Bis[2-(3-carboxyphenoxy)carbonylethyl]phosphinic acid (m-BCCEP): a novel affinity cross-linking reagent for the beta-cleft modification of human hemoglobin. AB - The design and synthesis of bis[2-(3-carboxyphenoxy)carbonylethyl]phosphinic acid (m-BCCEP, 1) as a site-directed affinity reagent for cross-linking human hemoglobin have been reported as part of our long-term goal to generate artificial blood for emergency transfusions. Molecular modeling techniques were used to design the reagent, employing crystal coordinates of human hemoglobin A(0) imported from the Protein Data Bank. It was synthesized in four steps commencing from 3-hydroxybenzoic acid. The reagent 1 was converted to its trisodium salt to allow effective cross-linking in an aqueous medium. The reagent 1, as its trisodium salt, was found to specifically cross-link stroma-free human hemoglobin A(0) in the beta-cleft under oxygenated reaction conditions at neutral pH. The SDS-PAGE analyses of the modified hemoglobin pointed to the molecular mass range of 32 kDa as anticipated. The HPLC analyses of the product suggested that the cross-link had formed between the beta(1)-beta(2) subunits. Molecular dynamics simulation studies on the reagent-HbA(0) complex suggested that the predominant amino acid residues involved in the cross-linking are N-terminus Val 1 or Lys-82 on one of the beta-subunits and Lys-144 on the other. These predictions were borne out by MALDI-TOF MS analyses data of the peptide fragments obtained from tryptic digestion of the cross-linked product. The data also suggested the presence of a minor cross-link between Val-1 and Lys-82 on the opposing subunits. The oxygen equilibrium measurements of the m-BCCEP-modified hemoglobin product at 37 degrees C showed oxygen affinity (P(50) = 25.8 Torr) comparable to that of the natural whole blood (P(50) = 27.0 Torr) and significantly lower than that of stroma-free hemoglobin (P(50) = 14.19 Torr) assayed under identical conditions. The measured Hill coefficient value of 1.91 of the m-BCCEP-modified Hb product points to the reasonable retainment of oxygen binding cooperativity after the cross-link formation. PMID- 20715856 TI - Oligonucleotide carbohydrate-centered galactosyl cluster conjugates synthesized by click and phosphoramidite chemistries. AB - Oligonucleotide glycoconjugates with a mannose or galactose core bearing four galactose residues introduced by phosphoramidite chemistry and copper catalyzed azide alkyne 1,3-dipolar cycloaddition (click chemistry) have been synthesized. A first click reaction allowed the introduction on a solid support of a mannose core on which four pentynyl linkers were introduced using a phosphoramidite derivative. After the elongation of the oligonucleotide, a second click reaction performed either on solid support or in solution allowed the introduction of four galactose azide derivatives. Repeating the phosphoramidite and click chemistries afforded an oligonucleotide glycoconjugate dendrimer bearing 16 galactoses on its periphery. PMID- 20715853 TI - N-glycan targeted gene delivery to the dendritic cell SIGN receptor. AB - A novel nonviral gene delivery vector composed of a high-mannose N-glycan conjugated to a polyacridine peptide was prepared. The glycopeptide was designed to bind to plasmid DNA by a combination of polyintercalation and ionic binding, and to the DC-SIGN (dendritic cell-specific intracellular adhesion molecule-3 grabbing nonintegrin) receptor expressed on CHO cells by recognition of the high mannose N-glycan. The glycopeptide conjugate was prepared by purification of a high-mannose N-glycan from affinity fractionated soybean agglutinin (SBA). The SBA was proteolyzed to release the N-glycan which was then modified on its N terminus with Tyr and a propionate maleimide. A DNA binding polyacridine peptide, Cys-(Acr-Lys)(4), was prepared by solid-phase peptide synthesis using Fmoc Lys(Acr), then conjugated to the maleimide on the N-glycan to produce a glycopeptide. The glycopeptide bound to DNA with high affinity as determined by fluorophore displacement assay and DNA band shift on agarose gel. When bound to Cy5 labeled DNA, the glycopeptide mediated specific uptake in DC-SIGN CHO (+) cells as determined by FACS analysis. In vitro gene transfer studies established that the glycopeptide increased the specificity of gene transfer in DC-SIGN CHO (+) cells 100-fold relative to CHO (-) cells. These studies suggest that a high mannose N-glycan conjugated to a polyacridine peptide may also facilitate receptor mediated gene delivery in dendritic cells and thereby find utility in the delivery of DNA vaccines. PMID- 20715855 TI - Synthesis and evaluation of human serum albumin-modified exendin-4 conjugate via heterobifunctional polyethylene glycol linkage with protracted hypoglycemic efficacy. AB - Albumin conjugation is considered to be one of the most effective means of protracting the short in vivo lifespans of peptides and proteins. Here, we present a new long-acting antidiabetic exendin-4 conjugate linked with human serum albumin (HSA) via polyethylene glycol (PEG). As a first step toward synthesizing this conjugate, three artificial sulfhydryl groups were introduced in HSA using 2-iminothiolane at pH 8.0. This thiolated HSA was further reacted with the monomer fraction of exendin-4 (6 equiv) conjugated with maleimide PEG(5k)-N- hydroxysuccinimide (MAL-PEG(5k)-NHS) for 3 h. Because of the presence of PEG molecules, the resulting conjugate (HSA-PEG-Ex4) was found to have a greater apparent molecular weight and a larger particle size (ca. 195 kDa and 9.48 +/- 0.74 nm) than those of HSA-exendin-4 without the PEG linker (HSA-Ex4, ca. 84.3 kDa and 7.77 +/- 0.98 nm). Although the receptor binding affinity of HSA PEG-Ex4 on RIN-m5F cells was significantly lower than that of Ex4, its antihyperglycemic efficacy was slightly higher than that of Ex-4 and HSA-Ex4 in type 2 diabetic db/db mice. Furthermore, HSA-PEG-Ex4 had greater circulating t(1/2) and AUC(inf) values than HSA-Ex and native exendin-4 by 2.1- and 10.3 fold, respectively. Accordingly, its hypoglycemic duration was greatly increased to 31.0 h at a dose of 250 nmol/kg vs that of native Ex4 (7.0 h). Results show that the HSA-PEG-Ex4 conjugate produced has distinct advantages over HSA-Ex4 without PEG. We believe that this exendin-4 derivative, which has the merits of albumin conjugation and PEGylation, has considerable potential as a novel type 2 antidiabetic agent. PMID- 20715857 TI - Synthesis and evaluation of new spacers for use as dsDNA end-caps. AB - A series of aliphatic and aromatic spacer molecules designed to cap the ends of DNA duplexes have been synthesized. The spacers were converted into dimethoxytrityl-protected phosphoramidites as synthons for oligonucleotides synthesis. The effect of the spacers on the stability of short DNA duplexes was assessed by melting temperature studies. End-caps containing amide groups were found to be less stabilizing than the hexaethylene glycol spacer. End-caps containing either a terthiophene or a naphthalene tetracarboxylic acid diimide were found to be significantly more stabilizing. The former showed a preference for stacking above an A*T base pair. Spacers containing only methylene (-CH(2)-) and amide (-CONH-) groups interact weakly with DNA and consequently may be optimal for applications that require minimal influence on DNA structure but require a way to hold the ends of double-stranded DNA together. PMID- 20715859 TI - Spectral-structural effects of the keto-enol-enolate and phenol-phenolate equilibria of oxyluciferin. AB - The effects of environmental polarity on the enolization of the keto form and the deprotonation of the enol, and the role of the neutral and ionized 6'-OH group in the fluorescence of the firefly emitter, oxyluciferin, were assessed through a detailed study of the structure and absorption and fluorescence spectra of its 6' dehydroxylated analogue. It was found that the deprotonated 6'-O(-) group is a necessary, albeit insufficient, factor in accounting for the observed yellow green and red emissions of oxyluciferin. Its negative charge is essential for effective excited-state charge transfer, which lowers the emission energy and broadens the emission spectrum. Deprotonation of the 6'-OH group changes its effect on the emission energy from blue- to red-shifting. Furthermore, the combination of these opposite effects and resonance stabilization of the phenolate-keto form causes switching of the order of maximum emission wavelengths of the three species involved in the keto-enol-enolate equilibrium from enol << keto < enolate in absence of 6'-OH to keto < enol << enolate with 6'-OH, to enol < enolate < keto with 6'-O(-). If only the keto-enol-enolate equilibrium is considered, solvents of medium polarity are the most effective in decreasing the excited-state energy. Polar or very polar environments also stimulate shift of the ground-state equilibrium toward the enol form. Under such circumstances, the enol group can be partly or completely deprotonated in the ground state or from the excited state: a polar environment facilitates the ionization, while a less polar environment requires the presence of a stronger base. In the absence of bases, the ground-state keto form exists only in solvents of very weak to medium polarity, but with stronger bases, it can also exist in a nonpolar or very weakly polar environment, usually together with the enolate anion. The phenol-enolate form of oxyluciferin, a species that could not be experimentally detected prior to this study, was identified as a yellow-emitting species. PMID- 20715858 TI - Unexpected toxicity of monolayer protected gold clusters eliminated by PEG-thiol place exchange reactions. AB - Monolayer protected clusters (MPCs) are small, metal nanoparticles capped with thiolate ligands that have been widely studied for their size-dependent properties and for their ability to be functionalized for biological applications. Common water-soluble MPCs, functionalized by N-(2 Mercaptopropionyl)-glycine (tiopronin) or glutathione, have been used previously to interface with biological systems. These MPCs are ideal for biological applications not only due to their water-solubility but also their small size (<5 nm). These characteristics are expected to enable easy biodistribution and clearance. In this article, we show an unexpected toxicity is associated with the tiopronin monolayer protected cluster (TMPC), making it incompatible for potential in vivo applications. This toxicity is linked to significant histological damage to the renal tubules, causing mortality at concentrations above 20 MUM. We further show how the incorporation of poly ethylene glycol (PEG) by a simple place-exchange reaction eliminates this toxicity. We analyzed gold content within blood and urine and found an increased lifetime of the particle within the bloodstream due to the creation of the mixed monolayer. Also shown was the elimination of kidney damage with the use of the mixed-monolayer particle via Multistix analysis, MALDI-TOF MS analysis, and histological examination. Final immunological analysis showed no effect on white blood cell (WBC) count for the unmodified particle and a surprising increase in WBC count with the injection of mixed monolayer particles at concentrations higher than 30 MUM, suggesting that there may be an immune response to these mixed monolayer nanoparticles at high concentrations; therefore, special attention should be focused on selecting the best capping ligands for use in vivo. These findings make the mixed monolayer an excellent candidate for further biological applications using water-soluble nanoparticles. PMID- 20715861 TI - Evolution of clinical proteomics and its role in medicine. AB - Significant progress has been made in characterizing and sequencing genomic alterations of biospecimens from several types of cancer. Understanding the functional changes in the human proteome that arise from the genomic alterations or other factors is the next logical step in the development of high-value protein biomarkers that can be transitioned to clinical studies for biomarker qualification. Linking advances in genomic analysis to proteomic analysis will provide a pathway for qualified biomarkers which can drive the rational development of new diagnostics and therapies. The availability of these multidimensional data to the scientific community sets the stage for the development of new molecularly targeted cancer interventions. PMID- 20715862 TI - Seasonal distribution and genetic diversity of genogroups I, II, and IV noroviruses in the Tamagawa River, Japan. AB - We investigated the prevalence, seasonal dependence, and genetic diversity of noroviruses (NoVs) in the Tamagawa River, which runs through a densely populated region in Tokyo, Japan, from April 2003 to March 2004. A total of 60 water samples were collected from five sites from upstream to downstream along the river, and 500 mL of which was concentrated using the "cation-coated filter method". Of the 60 samples tested, genogroup I (GI) and GII NoVs were detected from 28 (47%) and 18 (30%) samples, respectively. GIV NoV was successfully detected from 2 (3%) samples with a newly developed seminested RT-PCR assay specific for GIV. The occurrence of NoVs in the river was significantly higher in winter/spring than in summer/autumn and also in mid- to downstream rather than upstream. A total of 176 different NoV strains were identified from river water samples based on the phylogenetic analysis of partial capsid gene sequences. GI, GII, and GIV strains were clustered into 7 (GI/1, 2, 4, 5, 8, 9, and 11), 8 (GII/2, 3, 4, 5, 6, 11, 12, and 16), and 1 (GIV/1) genotypes, respectively. The results suggest that genetically diverse NoV strains are circulating between human populations and aquatic environments. PMID- 20715863 TI - In situ production of methylmercury within a stream channel in northern California. AB - Natural stream ecosystems throughout the world are contaminated by methylmercury, a highly toxic compound that bioaccumulates and biomagnifies in aquatic food webs. Wetlands are widely recognized as hotspots for the production of methylmercury and are often assumed to be the main sources of this neurotoxin in downstream ecosystems. However, many streams lacking wetlands in their drainage basins (e.g., montane and semiarid regions in the western United States) have significant methylmercury contamination, and the sources of methylmercury in these streams remain largely unknown. In this study, we observed substantial production of methylmercury within a highly productive stream channel in northern California (South Fork Eel River) within a drainage basin lacking wetlands. We found that in situ methylmercury production is positively related to phosphorus removal and water temperature within the stream channel, supporting hypothesized biological mediation of in situ mercury transformation. Moreover, our data suggest that epiphytic microbial communities on a dominant filamentous alga (Cladophora glomerata) could play a role in in situ methylmercury production. Because peak in situ methylmercury production coincides with the period of the highest biological productivity during summer baseflow, methylmercury produced internally may be efficiently routed into local stream food webs. Our study provides strong evidence that stream channels, especially those associated with high primary productivity, can be important for regulating the bioavailability and toxicity of this global contaminant. PMID- 20715864 TI - Impact of chlorine disinfectants on dissolution of the lead corrosion product PbO2. AB - Plattnerite (beta-PbO(2)) is a corrosion product that develops on lead pipes that have been in contact with free chlorine present as a residual disinfectant. The reductive dissolution of PbO(2) can cause elevated lead concentrations in tap water when the residual disinfectant is switched from free chlorine to monochloramine. The objectives of this study were to quantify plattnerite dissolution rates in the presence of chlorine disinfectants, gain insights into dissolution mechanisms, and measure plattnerite's equilibrium solubility in the presence of free chlorine. The effects of free chlorine and monochloramine on the dissolution rates of plattnerite were quantified in completely mixed continuous flow reactors at relevant pH and dissolved inorganic carbon conditions. Plattnerite dissolution rates decreased in the following order: no disinfectant > monochloramine > chlorine, which was consistent with the trend in the redox potential. Compared with experiments without disinfectant, monochloramine inhibited plattnerite dissolution in continuous-flow experiments. Although free chlorine maintained steady-state lead concentrations below the action level of 15 MUg/L in flow-through experiments, in batch experiments lead concentrations exceeded the action level for longer residence times and approached an equilibrium value that was several orders of magnitude higher than that predicted from available thermodynamic data. PMID- 20715865 TI - Uptake of methacrolein and methyl vinyl ketone by tree saplings and implications for forest atmosphere. AB - Methacrolein (MACR) and methyl vinyl ketone (MVK) are oxygenates produced from isoprene which is abundantly emitted by trees. The uptake rate of these compounds by leaves of three different Quercus species, Q. acutissima, Q. myrsinaefolia, and Q. phillyraeoides, at typical concentrations within a forest (several part per billion by volume) were determined. The rates of uptake of croton aldehyde (CA) and methyl ethyl ketone (MEK) were also investigated for comparison. The rates of uptake of the two aldehydes MACR and CA were found to be higher than those of the two ketones. In particular, the rate of MEK uptake for Q. myrsinaefolia was exceptionally low. The ratio of intercellular to fumigated concentrations, Ci/Ca, for MACR and CA was found to be low (0-0.24), while the ratio for the two ketones was 0.22-0.90. To evaluate the contribution of tree uptake as a sink for the two isoprene-oxygenates within the forest canopy, loss rates of the compounds due to uptake by trees and by reactions with hydroxyl radicals (OH radicals) and O(3) were calculated. The loss rate by tree uptake was the highest, followed by the reaction with OH radicals, even at a high OH concentration (0.15 pptv) both for MACR and MVK, suggesting that tree uptake provides a significant sink. PMID- 20715866 TI - Adsorption of dialkyl phthalate esters on carbon nanotubes. AB - Dialkyl phthalate esters (DPEs), with endocrine disrupting functions, are widely used and categorized as priority pollutants. Carbon nanotubes (CNTs) as strong adsorbents could influence the fate, transport, and bioavailability of DPEs in the environment. Understanding adsorptive interactions between CNTs and DPEs is critical to the environmental applications of CNTs. Adsorption of DPEs by one type of single-walled CNTs (SWCNT) and three multiwalled CNTs (MWCNT) was evaluated. For a given CNT, the adsorptive affinity correlated well with hydrophobicity of DPEs with an order of dimethyl phthalate (DMP) < diethyl phthalate (DEP) < dibutyl phthalate (DBP). The normalized adsorption coefficient (K/K(HW)) of DPEs indicates that pi-pi electron-donor-acceptor (EDA) interaction was also important for adsorption of DPEs (pi-acceptor) on CNTs (pi-donor). A pi pi charge-transfer band of EDA complexes (mixture of pyrene (PYR) as pi-donor and DPEs as pi-acceptor) showed their interaction strength in the order of DMP-PYR > DEP-PYR > DBP-PYR. Calculated monolayer adsorption capacities (log Q) were bigger (for DMP and DEP) than or approximately equal to (for DBP) the estimated adsorption capacities (log Q(0)), implying that the DPEs were adsorbed on the surface area of CNTs. For a given DPE, the adsorptive capacities decreased with the increasing outer diameters of CNTs in the order of SWCNT > MWCNT10 > MWCNT20 > MWCNT40. PMID- 20715867 TI - Photo-oxidation of Cr(III)-citrate complexes forms harmful Cr(VI). AB - Photo-oxidation is a potential pathway for the transformation of Cr(III) to Cr(VI) in natural environments. In this study, the Cr(III)-citrate complex (Cr(III)-cit) was prepared and its speciation was determined by high performance liquid chromatography (HPLC). Results showed that Cr(III)-cit existed in [Cr(III) H-cit](+) and [Cr(III)-cit] species in a pH range of 3-5, in [Cr(III)-cit] only from pH 6-8, in [Cr(III)-cit] and [Cr(III)-OH-cit](-) from pH 9-11, and only in [Cr(III)-OH-cit](-) at pH 12. Additional experiments were conducted in batch systems with pHs of 5 to 12 at 25 degrees C, where aqueous Cr(III) and Cr(III) cit were fully exposed to light from medium pressure mercury lamps and a xenon lamp mimicking solar light irradiation. Results demonstrated that oxidation of Cr(III) in Cr(III)-cit was much faster than that in aqueous Cr(III). Rates of Cr(III) photo-oxidation were not sensitive to pH in the range from 7 to 9 but increased significantly with further increases in pH, which was consistent with the distribution of Cr(III) forms. It appeared that [Cr(III)-cit-OH](-) was the most photochemically active form and Cr(II), resulting from a ligand-to-metal charge-transfer (LMCT) pathway after light absorption, was a precursor of the oxidation of Cr(III) to Cr(VI). Both dissolved oxygen and the hydroxyl radical ((*)OH), an intermediate, served as oxidants and facilitated the oxidation of Cr(II) to Cr(VI) via a multiple step pathway. The photoproduction of (*)OH was detected by HPLC using benzene as a probe, supporting the proposed reaction mechanism. PMID- 20715868 TI - Oxidation reactions mediated by single-walled carbon nanotubes in aqueous solution. AB - How single-walled carbon nanotubes (SWCNT) function in redox reactions may be related to their behaviors in the induction of oxidative stress. Herein, oxidation of several biologically relevant reducing agents in the presence of SWCNT was studied in aqueous solutions. The selected reductants included a common indicator for intracellular reactive oxygen species (ROS) (2,7 dichlorodihydrofluorescein), small antioxidants (vitamin C, Trolox, and cysteine), and a high-molecular-weight ROS scavenger (bovine serum albumin). The unmodified or carboxylated SWCNT acted as both the oxidants and the catalysts in reactions. Moreover, they accelerated the oxidation reactions mediated by horseradish peroxidase, a representative member of the enzyme family actively involved in balancing oxidative stress. These diverse roles in redox reactions may serve the chemistry basis for SWCNT to induce oxidative stress in biological systems as potential environmental pollutants. PMID- 20715869 TI - Separation of C70 over C60 and selective extraction and resolution of higher fullerenes by syndiotactic helical poly(methyl methacrylate). AB - A one-handed helical polymer, syndiotactic poly(methyl methacrylate) (st-PMMA), recognizes the size and chirality of higher fullerenes through an induced-fit mechanism and can selectively extract enantiomers of the higher fullerenes, such as C(76), C(80), C(84), C(86), C(88,) C(90), C(92), C(94), and C(96). This discovery will generate a practical and valuable method for selectively extracting the elusive higher fullerenes and their enantiomers and opens the way to developing novel carbon cage materials with optical activities. PMID- 20715870 TI - Toward development of targeted nonsteroidal antiandrogen-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid-gadolinium complex for prostate cancer diagnostics. AB - Androgen receptors are present in most advanced prostate cancer specimens, having a critical role in development of this type of cancer. For correct prognosis of patient conditions and treatment monitoring, noninvasive imaging techniques have great advantages over surgical procedures. We developed synthetic methodologies for preparation of novel androgen receptor-targeting agents in an attempt to build a versatile platform for prostate cancer imaging and treatment. The structure of these compounds comprises of a lanthanoid metal ion, gadolinium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA)-based binding fragment and, connected to it by a flexible linker, bicalutamide-derived nonsteroidal antiandrogen moiety. A representative gadolinium complex 15 was evaluated as a magnetic resonance imaging (MRI) agent in C57/bl6 male mouse bearing orthotopic TRAMP C2 prostate tumor. PMID- 20715871 TI - Role of edge orientation in kinetics of electrochemical intercalation of lithium ion at graphite. AB - A relation between the amount of edge orientations and the kinetics of lithium ion intercalation at the basal plane of highly oriented pyrolytic graphite (HOPG) was studied. The fraction of edge orientations (f(edge)) exposed on the basal plane of HOPG was evaluated from the kinetics of heterogeneous electron transfer of Ru(NH(3))(6)(2+/3+). Obtained f(edge) values ranged from 0.025 to 0.067, which were in good agreement with those previously reported. The charge-transfer resistance (R(ct)) for lithium-ion intercalation at the same HOPG samples was evaluated by ac impedance spectroscopy in an electrolyte consisting of 1 mol dm( 3) LiClO(4) dissolved in a mixture of ethylene carbonate/dimethyl carbonate (1:1 by vol). A clear correlation was observed between the f(edge) and R(ct) values at the basal plane of 15 HOPG samples, and the edge-area specific resistance was evaluated to be ca. 200 Omega cm(2) at the electrode potential of 0.2 V versus Li/Li(+). These results indicate that the amount of edge orientations is one of the determining factors in the kinetics of lithium-ion intercalation at graphite. PMID- 20715872 TI - Directed self-assembly of colloidal dumbbells with an electric field. AB - We demonstrate the assembly of colloidal particles with the shape of diatomic molecules ("dumbbells") into crystals that we study with confocal microscopy. The literature on the preparation of nonspherical colloidal particles has grown steadily. Assembly of these particles into regular three-dimensional crystalline lattices, however, is rarely, if ever, achieved and has not yet been studied quantitatively in 3D real space. We find that, by application of an electric field, such particles assemble quite readily. By varying the particle aspect ratio, range of interactions, and electric field strength, we find several different crystal structures of which three have never before been observed. Moreover, the electric field can be used to switch between different structures and manipulate/switch the photonic properties. Moreover, our work sheds light on fundamental questions related to the self-assembly of nonspherical particles. PMID- 20715873 TI - Dynamic imaging of colloidal-crystal nanostructures at 200 frames per second. AB - The dynamic noninvasive imaging of colloidal nanostructures has been precluded by the diffraction-limited resolution of (confocal) light microscopy. Using Fast Stimulated Emission Depletion (STED) microscopy, we demonstrate the ability to resolve the formation of a colloidal crystal (monolayer) from particles of 200 nm size, where the voids in the crystal are as small as 30 nm. With a temporal resolution of 5 ms, we exemplify the technique by visualizing the annealing of potential point defects during the formation of the colloidal crystal. PMID- 20715874 TI - Wetting dynamics of drop spreading. New evidence for the microscopic validity of the molecular-kinetic theory. AB - We study the spontaneous wetting of liquid drops on FCC solid substrates using large-scale molecular dynamics simulations. By varying the solid lattice parameter, five different drop/solid dynamic systems are investigated. It is shown that the results are in agreement with the molecular-kinetic theory (MKT) describing the dynamics of wetting. Moreover, it is established that the microscopic parameters resulting from fits using the MKT, the so-called molecular jump frequency at equilibrium and the jump length, correspond to the values that can be estimated directly from the simulations. This agreement strongly supports the validity of the MKT at the microscopic scale. PMID- 20715875 TI - Incorporation of polyoxotungstate complexes in silica spheres and in situ formation of tungsten trioxide nanoparticles. AB - In this paper, we demonstrated a new convenient route for in situ fabrication of well separated small sized WO(3) nanoparticles in silica spheres, through a predeposition of surfactant encapsulated polyoxotungates as tungsten source, and followed by a calcination process. In a typical procedure, selected polyoxotungates with different charges were enwrapped with dioctadecyldimethylammonium cations through electrostatic interaction. Elemental analysis, thermogravimetric analysis, and spectral characterization confirmed the formation of prepared complexes with the anticipated chemical structure. The complexes were then phase-transferred into aqueous solution that predissolved surfactant cetyltrimethylammonium bromide, and finally incorporated into silica spheres through a joint sol-gel reaction with tetraethyl orthosilicate in a well dispersed state under the protection of organic layer for polyoxotungates from the alkaline reaction condition. Transmission electron microscopic images illustrated the well dispersed WO(3) nanoparticles in the size range of ca. 2.2 nm in the silica spheres after the calcination at 465 degrees C. The sizes of both the silica spheres and WO(3) nanoparticles could be adjusted independently through changing the doping content to a large extent. Meanwhile, the doped polyoxotungate complexes acted as the template for the mesoporous structure in silica spheres after the calcination. Along with the increase of doping content and surfactant, the mesopore size changed little (2.0-2.9 nm), but the specific surface areas increased quite a lot. Importantly, the WO(3)-nanoparticle-doped silica spheres displayed an interesting photovoltaic property, which is favorable for the funtionalization of these nanomaterials. PMID- 20715876 TI - Reversible fluorescence quenching by micelle selective benzophenone-induced interactions between brij micelles and polyacrylic acids: implications for chemical sensors. AB - The fluorescence response of pyrene has been studied in the presence of nonionic brij micelles and poly(acrylic acid) (PAA) with benzophenone (BP) as a neutral hydrophobic quencher. Pyrene emission is quenched ("off" state) in the presence of BP in brij 35 (polyoxyethylene-23-lauryl ether) and brij 56 (polyoxyethylene 10-cetyl ether) micelles. Quenched pyrene emission is selectively recovered ("on" state) for brij 35 micelles with the addition of PAA (starting conc 2.0 x 10(-5) M). Due to the interaction of PAA and brij 35 micelles and the relatively easier accessibility of PAA polymer chains near the bulky polyoxyethylene chain of brij 35 micelles, the chances of BP partition inside the hydrophobic polymer coil are more compared to brij 56 micelles. The PAA sensing ability of the "brij 35:pyrene:BP" system is dependent on the molecular weight (M) of the polymer. Fluorescence recovery has been observed with PAA (M approximately 150000) and complete recovery has been recorded with high M of PAA (M approximately 450000); however, no fluorescence change is observed in the presence of low M of PAA (M approximately 2000). In solution, such selective reversible fluorescence quenching has the potential for a new class of highly sensitive chemical sensor systems. PMID- 20715877 TI - Magnetic properties of nitroxide spin probes: reliable account of molecular motions and nonspecific solvent effects by time-dependent and time-independent approaches. AB - Application of a new integrated computational approach for two widely used nitroxide spin probes allows to show unequivocally that proper account of stereoelectronic, environmental, and dynamical effects leads to magnetic properties in quantitative agreement with experimental results without the need of any empirical parameter. Together with their specific interest, our results point out, in our opinion, the importance of developing and validating computational approaches able to switch on and off different effects, including environmental and dynamical ones, in order to evaluate their specific role in determining the overall experimental outcome. PMID- 20715878 TI - Cell adhesion properties on chemically micropatterned boron-doped diamond surfaces. AB - The adhesion properties of living cells were investigated on a range of chemically modified boron-doped diamond (BDD) surfaces. We studied the influence of oxidized, H-, amine- (NH(2)-), methyl- (CH(3)-), trifluoromethyl- (CF(3)-) and vinyl- (CH(2)?CH-) terminated BDD surfaces on human osteosarcoma U2OS and mouse fibroblast L929 cells behavior. Cell-surface interactions were analyzed by fluorescence microscopy in terms of cell attachment, spreading and proliferation. U2OS cells poorly adhered on hydrophobic surfaces and their growth was blocked. In contrast, L929 cells were mainly influenced by the presence of perfluoroalkyl chains in regard to their morphology. The results were subsequently applied to selectively micropattern U2OS cells on dual hydrophobic/hydrophilic surfaces prepared by a UV/ozone lithographic approach. U2OS cells colonized preferentially hydrophilic (oxide-terminated) motifs, forming confluent arrays with distinguishable edges separating the alkyl regions. PMID- 20715879 TI - pH-tunable ion selectivity in carbon nanotube pores. AB - The selectivity of ion transport in nanochannels is of primary importance for a number of physical, chemical, and biological processes ranging from fluid separation to ion-channel-regulated cellular processes. Fundamental understanding of these phenomena requires model nanochannels with well-defined and controllable structural properties. Carbon nanotubes provide an ideal choice for nanofluidic studies because of their simple chemistry and structure, the atomic scale smoothness and chemical inertness of the graphitic walls, and the tunability of their diameter and length. Here, we investigate the selectivity of single and, for the first time, binary salt mixtures transport through narrow carbon nanotubes that act as the only pores in a silicon nitride membrane. We demonstrate that negatively charged carboxylic groups are responsible for the ion rejection performance of carbon nanotube pores and that ion permeation of small salts can be tuned by varying solution pH. Investigation of the effect of solution composition and ion valences for binary electrolytes with common cation in a pressure-driven flow reveals that the addition of slower diffusing multivalent anions to a solution of faster diffusing monovalent anions favors permeation of the monovalent anion. Larger fractions and valences of the added multivalent anions lower the rejection of the monovalent anion. In some cases, we observe negative rejection at low monovalent ion content. PMID- 20715880 TI - Colloidally prepared Pt nanowires versus impregnated Pt nanoparticles: comparison of adsorption and reaction properties. AB - Ligand-capped Pt nanowires, prepared by colloidal synthesis and deposited on a high surface area gamma-Al(2)O(3) support, were subjected to surface characterization by electron microscopy and FTIR spectroscopy using CO as a probe molecule. The structural, adsorption, and catalytic reaction properties of the colloidal Pt nanowires were compared to those of conventional, impregnated Pt nanoparticles on the same Al(2)O(3) support. In situ FTIR spectroscopy indicated ligand effects on the CO resonance frequency, irreversible CO-induced surface roughening upon CO adsorption, and a higher resistance of colloidal catalysts toward oxidation (both in oxygen and during CO oxidation), suggesting that the organic ligands might protect the Pt surface. Elevated temperature induced a transformation of Pt nanowires to faceted Pt nanoparticles. The colloidal catalyst was active for hydrodechlorination of trichloroethylene (TCE), but no ligand effect on selectivity was obtained. PMID- 20715882 TI - Rate constants for the thermal decomposition of ethanol and its bimolecular reactions with OH and D: reflected shock tube and theoretical studies. AB - The thermal decomposition of ethanol and its reactions with OH and D have been studied with both shock tube experiments and ab initio transition state theory based master equation calculations. Dissociation rate constants for ethanol have been measured at high T in reflected shock waves using OH optical absorption and high-sensitivity H-atom ARAS detection. The three dissociation processes that are dominant at high T are C2H5OH--> C2H4+H2O (A) -->CH3+CH2OH (B) -->C2H5+OH (C).The rate coefficient for reaction C was measured directly with high sensitivity at 308 nm using a multipass optical White cell. Meanwhile, H-atom ARAS measurements yield the overall rate coefficient and that for the sum of reactions B and C , since H-atoms are instantaneously formed from the decompositions of CH(2)OH and C(2)H(5) into CH(2)O + H and C(2)H(4) + H, respectively. By difference, rate constants for reaction 1 could be obtained. One potential complication is the scavenging of OH by unreacted ethanol in the OH experiments, and therefore, rate constants for OH+C2H5OH-->products (D)were measured using tert-butyl hydroperoxide (tBH) as the thermal source for OH. The present experiments can be represented by the Arrhenius expression k=(2.5+/-0.43) x 10(-11) exp(-911+/-191 K/T) cm3 molecule(-1) s(-1) over the T range 857-1297 K. For completeness, we have also measured the rate coefficient for the reaction of D atoms with ethanol D+C2H5OH-->products (E) whose H analogue is another key reaction in the combustion of ethanol. Over the T range 1054-1359 K, the rate constants from the present experiments can be represented by the Arrhenius expression, k=(3.98+/ 0.76) x10(-10) exp(-4494+/-235 K/T) cm3 molecule(-1) s(-1). The high-pressure rate coefficients for reactions B and C were studied with variable reaction coordinate transition state theory employing directly determined CASPT2/cc-pvdz interaction energies. Reactions A , D , and E were studied with conventional transition state theory employing QCISD(T)/CBS energies. For the saddle point in reaction A , additional high-level corrections are evaluated. The predicted reaction exo- and endothermicities are in good agreement with the current Active Thermochemical Tables values. The transition state theory predictions for the microcanonical rate coefficients in ethanol decomposition are incorporated in master equation calculations to yield predictions for the temperature and pressure dependences of reactions A - C . With modest adjustments (<1 kcal/mol) to a few key barrier heights, the present experimental and adjusted theoretical results yield a consistent description of both the decomposition (1-3) and abstraction kinetics (4 and 5). The present results are compared with earlier experimental and theoretical work. PMID- 20715881 TI - Organically modified silicas on metal nanowires. AB - Organically modified silica coatings were prepared on metal nanowires using a variety of silicon alkoxides with different functional groups (i.e., carboxyl groups, polyethylene oxide, cyano, dihydroimidazole, and hexyl linkers). Organically modified silicas were deposited onto the surface of 6-MUm-long, ~300 nm-wide, cylindrical metal nanowires in suspension by the hydrolysis and polycondensation of silicon alkoxides. Syntheses were performed at several ratios of tetraethoxysilane to an organically modified silicon alkoxide to incorporate desired functional groups into thin organosilica shells on the nanowires. These coatings were characterized using transmission electron microscopy, X-ray photoelectron spectroscopy, and infrared spectroscopy. All of the organically modified silicas prepared here were sufficiently porous to allow the removal of the metal nanowire cores by acid etching to form organically modified silica nanotubes. Additional functionality provided to the modified silicas as compared to unmodified silica prepared using only tetraethoxysilane precursors was demonstrated by chromate adsorption on imidazole-containing silicas and resistance to protein adsorption on polyethyleneoxide-containing silicas. Organically modified silica coatings on nanowires and other nano- and microparticles have potential application in fields such as biosensing or nanoscale therapeutics due to the enhanced properties of the silica coatings, for example, the prevention of biofouling. PMID- 20715883 TI - Challenges to the student nurse on clinical placement in the rural setting: a review of the literature. AB - CONTEXT: Positive learning experiences for students on clinical placement in rural settings have the potential for supporting the recruitment of qualified nurses to these areas. Recruitment of such nurses is a global concern because current shortages have resulted in decreased healthcare quality for rural residents. By understanding the challenges faced by nursing students unfamiliar with rural settings, educational and organizational strategies can be developed to promote positive learning experiences and so enhance recruitment. ISSUE: A broad literature review was conducted to explore the question: 'What challenges do nursing students from urban communities experience while they are on clinical placements in rural areas, respecting that 'rural' is conceptualized differently by different stakeholders?' The review followed a 5 stage process: (1) identification of the problem and purpose of the review; (2) structured literature search; (3) data evaluation; (4) data analysis; and (5) presentation of findings. Thirteen studies were evaluated independently using tools from the Joanna Briggs Institute. The Ecological Model was the theoretical framework used for consideration of student challenges. LESSONS LEARNED: This literature review revealed a paucity of studies that addressed the research question, with mostly Canadian and Australian studies meeting the inclusion criteria. Findings were organized according to Ecological Model levels and suggested that students face political, environmental, community-based, nursing-related, organizational, relational, and personal challenges on rural placement. Challenges vary according to the placement setting and available student supports. Policy, educational, and nursing practice recommendations include that students should be aware of the impact of limited resources in rural settings; that comprehensive orientation should be provided to clinical and community settings; and that an exploration of financial and distance education supports prior to the placement would be beneficial. Rural practice nurse educators also require support, and it is critical that they and those at the educational institution be receptive to student questions and learning needs. PMID- 20715886 TI - An overview of attention deficits after paediatric traumatic brain injury. AB - PURPOSE: Attention could be categorized into sustained, selective, shifting, divided and attention span. The primary objective was to evaluate the type of attention deficits that occurs after paediatric traumatic brain injury. METHODS: Keywords were used such as 'attention', 'child', 'traumatic', 'brain' and 'injury' on MEDLINE articles published in 1991-2009. Articles found through MEDLINE were manually cross-referenced. MAIN OUTCOMES AND RESULTS: Out of the examined categorizes, divided and sustained attention seem to be the most vulnerably, frequently displaying deficits in the children with TBI. Attention span seemed to be the most resistant and the shifting and selective categories falling somewhere in between. Most of the recovery is expected within the first year post-injury, even if some individuals continue to improve for years, and deficits often persist into adulthood. CONCLUSIONS: The attention domains are not affected to the same extent by TBI and this should be taken into consideration when evaluating a child. The commonly used tests also seem to differ in how sensitive they are in detecting deficits. The definition of attention domains and TBI would benefit to be stricter and agreed upon, to further facilitate research and rehabilitation programmes. PMID- 20715884 TI - Uncultured marrow mononuclear cells delivered within fibrin glue hydrogels to porous scaffolds enhance bone regeneration within critical-sized rat cranial defects. AB - For bone tissue engineering, the benefits of incorporating mesenchymal stem cells (MSCs) into porous scaffolds are well established. There is, however, little consensus on the effects of or need for MSC handling ex vivo. Culture and expansion of MSCs adds length and cost, and likely increases risk associated with treatment. We evaluated the effect of using uncultured bone marrow mononuclear cells (bmMNCs) encapsulated within fibrin glue hydrogels and seeded into porous scaffolds to regenerate bone over 12 weeks in an 8-mm-diameter, critical-sized rat cranial defect. A full factorial experimental design was used to evaluate bone formation within model poly(L-lactic acid) and corraline hydroxyapatite scaffolds with or without platelet-rich plasma (PRP) and bmMNCs. Mechanical push out testing, microcomputed tomographical analyses, and histology were performed. PRP showed no benefit for bone formation. Cell-laden poly(L-lactic acid) scaffolds without PRP required significantly greater force to displace from surrounding tissues than control (cell-free) scaffolds, but no differences were observed during push-out testing of coral scaffolds. For bone volume formation as analyzed by microcomputed tomography, significant positive overall effects were observed with bmMNC incorporation. These data suggest that bmMNCs may provide therapeutic advantages in bone tissue engineering applications without the need for culture, expansion, and purification. PMID- 20715887 TI - Can teenagers with traumatic brain injury use Internet chatrooms? A systematic review of the literature and the Internet. AB - PURPOSE: To systematically review literature and electronic resources that address the topic of chatroom use of teenagers with and without traumatic brain injury (TBI). METHOD: Electronic databases and websites on the Internet were searched up to and including 25 June 2009, using terms relating to chatroom use of teenagers without and with TBI. A separate search was conducted on speechBITETM (www.speechbite.com ), using fields specific to target area, intervention and population. Literature and websites were included if they contained target search terms and were relevant to the topic of chatroom use of teenagers. RESULTS: A total of 46 sources from database searches and 66 websites from Internet searches were included in this systematic review. Most database sources were level IV evidence studies and mainly addressed chatroom and Internet use of typically-developing teenagers. Websites contained many brain injury information pages and links to chatrooms, as well as references to journal articles and books concerning chatroom use. CONCLUSIONS: Due to the lack of literature in the area of chatroom use of teenagers with TBI, there is potential to expand on existing literature and Internet resources to enable teenagers with TBI to access, participate and use this forum for social interaction and meaningful communication with peers. PMID- 20715885 TI - Management of depression in patients with coronary heart disease: association, mechanisms, and treatment implications for depressed cardiac patients. AB - IMPORTANCE OF THE FIELD: Coronary heart disease (CHD) and depression are two leading causes of death and disability in the United States and worldwide. Depression is especially common in cardiac patients, and there is growing evidence that depression is a risk factor for fatal and nonfatal events in CHD patients. AREAS COVERED IN THIS REVIEW: This paper reviews current literature of depression as a risk factor for CHD along with pharmacologic and non pharmacologic treatments for depression in cardiac patients. WHAT THE READER WILL GAIN: Readers will gain knowledge about the importance of depression as a CHD risk factor and learn the results of efforts to treat depressed CHD patients. TAKE HOME MESSAGE: Although randomized clinical trials (RCTs) of medication and non-pharmacologic therapies have not demonstrated that treating depression improves survival, there is evidence that treating depressed patients can reduce depressive symptoms and improve quality of life. Additional RCTs are needed, including evaluation of non-pharmacologic therapies such as exercise, to examine the effects of treatment of depression on medical and psychosocial outcomes. PMID- 20715888 TI - Computerized training of working memory in a group of patients suffering from acquired brain injury. AB - OBJECTIVE: Study short- and long-term transfer effects of a computerized working memory (WM) training programme for patients suffering from working memory deficits after acquired brain injury. RESEARCH DESIGN: A controlled experimental study with a cross-over design. METHODS: A consecutive sample of 21 subjects. Mean age 43.2 years, time since injury/illness onset 37 months (median). The subjects were randomly selected into two groups where one group served as controls. All subjects trained daily for 5 weeks in a computer WM task program. They were followed-up at 4 and 20 weeks after the training. RESULTS: A significant improvement in the trained WM tasks, significant improvements in neuropsychological WM-test results at 4 and 20 weeks after training compared to baseline. Improvement in the subjects' rated occupational performance and satisfaction with performance in pre-defined occupational problems. Rated quality of-life did not change. However, rated overall health increased 20 weeks after training. CONCLUSIONS: Structured and intense computerized WM training improves subjects' cognitive functioning as measured by neuropsychological WM-demanding tests, rated occupational performance, satisfaction with performance and rated overall health. The training probably has an impact on the rehabilitation outcome, returning to work, as well as on daily activities for individuals with verified WM impairments. PMID- 20715889 TI - The Infrascanner, a handheld device for screening in situ for the presence of brain haematomas. AB - PURPOSE: Early identification and treatment of intracranial haematomas in patients sustaining traumatic brain injury is fundamental to successful treatment. This pilot study evaluates the Infrascanner as a handheld medical screening tool for detection, in situ, of brain haematomas in patients with head injury. METHODS: This study included 35 TBI patients aged 17-76 (M = 47.6), admitted to the neurosurgical intensive care unit and observation unit of a University Hospital in a Level 1 trauma centre. The Infrascanner NIRS device uses near infrared light measurements to calculate optical density in brain regions. RESULTS: Results show Infrascanner sensitivity at 89.5% and specificity at 81.2%. PPV was 85% and NPV 86.7%. The device detected 90% of extra-axial, 88.9% of intra axial and 93.3% of non-surgical haematomas (less than 25 mL). PPV for this classification was 82.3%; 87.5% sensitivity was found when the Infrascanner exam was performed within 12 hours post-trauma, whereas after 12 hours post-trauma, exams had 90.1% sensitivity. CONCLUSIONS: This study demonstrates that the Infrascanner is useful in initial examinations and screenings of patients with head injury as an adjunct to a CT scan or when it is not available and may allow earlier treatment and reduce secondary injury caused by present and delayed haematomas. PMID- 20715891 TI - Patterns of agitated behaviour during acute brain injury rehabilitation. AB - OBJECTIVE: To monitor daily shift-by-shift changes in agitated behaviour during adult brain injury rehabilitation. DESIGN: A prospective, descriptive study. METHODS: Eight participants were monitored daily for up to 28 days. The Agitated Behaviour Scale (ABS) evaluated behaviour during three nursing shifts (morning, afternoon, night). Severity of agitation, peak intensity and concomitant behaviours were calculated. Shift differences and patterns of behavioural changes were analysed. RESULTS: Four hundred and seven recordings were taken with the ABS. All participants demonstrated multiple agitated behaviours (between 3-13 concomitant behaviours per person); the most common behaviours were representative of the ABS Disinhibition sub-scale. Weekly peak intensity ranged from 14-55 on the ABS. Mean ABS scores were highest during the afternoon shift and lowest at night. Improved cognition was associated with resolving agitated behaviour; while persistent agitated behaviour was associated with low levels of cognition. Minimal agitated behaviour was observed in participants who emerged from post-traumatic amnesia. CONCLUSIONS: Agitated behaviour during acute brain injury rehabilitation has a complex clinical presentation. High levels of agitation observed during the afternoon shift may be associated with low levels of structured activities available at that time, higher levels of environmental stimuli during visiting times and increased cognitive fatigue. Lower cognitive ability was related to consistently higher levels of agitated behaviour and vice versa. PMID- 20715890 TI - Effects of intensive repetition of a new facilitation technique on motor functional recovery of the hemiplegic upper limb and hand. AB - OBJECTIVE: To study the effects on the hemiplegic upper limb of repetitive facilitation exercises (RFEs) using a novel facilitation technique, in which the patient's intention to move the hemiplegic upper limb or finger was followed by realization of the movement using multiple sensory stimulations. METHODS: Twenty three stroke patients were enrolled in a cross-over study in which 2-week RFE sessions (100 repetitions each of five-to-eight types of facilitation exercise per day) were alternated with 2-week conventional rehabilitation (CR) sessions, for a total of four sessions. Treatments were begun with the 2-week RFE session in one group and the 2-week CR session in the second group. RESULTS: After the first 2-week RFE session, both groups showed improvements in the Brunnstrom stages of the upper limb and the hand, in contrast to the small improvements observed during the first CR session. The Simple Test for Evaluating Hand Function (STEF) score, which evaluates the ability of manipulating objects, in both groups improved during both sessions. After the second 2-week RFE and CR sessions, both groups showed little further improvement except in the STEF score. CONCLUSION: The novel RFEs promoted the functional recovery of the hemiplegic upper limb and hand to a greater extent than the CR sessions. PMID- 20715892 TI - A special messaging technology for two persons with acquired brain injury and multiple disabilities. AB - OBJECTIVE: To enable two persons with acquired brain injury and multiple (e.g. motor and visual) disabilities to communicate with distant partners through a special messaging technology, which served to send out text messages and read (listen to) incoming messages. METHOD: The study was carried out according to a multiple probe design across participants. Both participants (adults) started with baseline in which the technology was not available and continued with intervention in which the technology was used. The technology involved a net-book computer provided with specific software, a global system for mobile communication (GSM) modem, microswitches and pre-recorded lists of persons and messages. RESULTS: The participants' mean frequencies of messages sent out and received per 30-minute session were about three and two, respectively, during baseline and seven and four, respectively, during the intervention. All baseline messages were sent and received with guidance. Nearly all intervention messages were sent and received (listened to) independently by the participants. CONCLUSIONS: Special messaging technology may help persons with multiple disabilities acquire high levels of independent, basic communication with distant partners. PMID- 20715894 TI - Cardiac output measured by electrical velocimetry in the CT suite correlates with coronary artery enhancement: a feasibility study. AB - BACKGROUND: Cardiac output (CO) is inversely related to vascular contrast medium (CM) enhancement during computed tomography (CT). Impedance cardiography with a new technique, electrical velocimetry (EV), may create opportunities to measure CO pre-examination for adaptation of CM injection parameters. PURPOSE: To relate CO(EV) measured by radiology staff to aortic attenuation as a measure of coronary artery attenuation during CT coronary angiography (CTCA), and to formulate a tentative statistical model to adapt CM injection parameters to CO. MATERIAL AND METHODS: CO(EV) was measured immediately before 100 kVp CTCA (64-multirow detector) in 27 patients with presumed coronary artery disease. For CTCA, 260 mg I/kg (maximum dosage weight: 80/90 kg for women/men) was injected intravenously during 12 s. Simple linear regression analysis was performed to explore the correlation between aortic attenuation (Hounsfield units, HU) and body weight, the influence of CO(EV) on aortic attenuation adjusted to injected CM dose rate (HU per mg I/kg/s), and to establish a tentative formula on how to adapt CM injection parameters to CO(EV) and desired aortic attenuation. RESULTS: The correlation between aortic attenuation and body weight was weak and non significant (r=-0.14 after outlier exclusion). A significant negative correlation (r=-0.63) was found between aortic attenuation adjusted to injected CM dose rate (HU per mg I/kg/s) and CO(EV). The resulting formula, CM dose rate=CO(EV)*(aortic attenuation-240)/55, made it possible to calculate CM volumes and injection rates at various COs and, for example, the present mean aortic attenuation (438 HU), injection time (12 s), CM concentration (320 mg I/ml), and a certain body weight. CONCLUSION: EV makes it possible to measure CO in the CT suite before vascular examinations. Hence, CM doses may be decreased in low CO states to reduce the risk of CM-induced nephropathy without jeopardizing diagnostic quality and may be increased in high CO states to avoid poor enhancement. PMID- 20715895 TI - Unusual discrepancy between CT and PET/CT in the initial staging of Hodgkin's lymphoma. PMID- 20715896 TI - What doctors should not forget about transient global amnesia. PMID- 20715897 TI - The effect of brain injury terminology on university athletes' expected outcome from injury, familiarity and actual symptom report. AB - PRIMARY OBJECTIVE: To determine the influence of the terms concussion, mild traumatic brain injury and minor head injury on expected injury outcome, term related familiarity and actual symptom reporting. RESEARCH DESIGN: A questionnaire varied the terms concussion, mild traumatic brain injury and minor head injury. METHODS AND PROCEDURES: Two hundred and twenty-four university students were allocated one questionnaire version. Participants rated injury outcome statements for their truthfulness, specified term familiarity and completed measures on post-concussion symptoms, anxiety, depression, pain and affectivity. Chi-square tests compared response frequencies of statement ratings and familiarity between questionnaire versions and a rank-based multivariate method compared psychological measures between questionnaire versions. MAIN OUTCOMES AND RESULTS: Terminology significantly influenced both expected injury outcome and familiarity. Outcome expectations were reliably more negative for the term mild traumatic brain injury than concussion or minor head injury. Mild traumatic brain injury was the least familiar term. However, terminology groups did not differ in actual symptom reporting. CONCLUSIONS: The data showed that the use of terminology affected athletes' injury outcome expectations and familiarity. The impact of the data and advice for the best term for future use are discussed. While it is not easy to make a clear recommendation, the data clearly indicate a strong need for education of brain injury at university level and possibly beyond. PMID- 20715898 TI - Hyperbaric oxygen therapy improves neurogenesis and brain blood supply in piriform cortex in rats with vascular dementia. AB - BACKGROUND: Neural stem cell treatment and neurogenesis stimulation have gained attention as potential treatments for vascular dementia (VD). Currently, research mainly focuses on neurogenesis occurring in the sub-ventricular zone and dentate gyrus, while the research of the piriform cortex (Pir) is limited. Few results showed that weak neurogenesis exists in the Pir of adult rats. Since neurogenesis occurs in the Pir and is closely related to cognitive function, this study addressed the question of whether neurogenesis occurs in the Pir of an animal with the VD. PRIMARY OBJECTIVE AND HYPOTHESIS: This study investigated the effects of hyperbaric oxygen therapy on brain blood supply and neurogenesis in the piriform cortex (Pir) of rats with VD. MAIN OUTCOMES AND RESULTS: Compared to non-VD control rats (NC), rats with VD showed reduced rCBF, increased rCBV and slower MTT in the Pir. However, following hyperbaric oxygen (HBO) treatment in VD rats, rCBF increased, rCBV decreased and MTT increased. To determine whether the restoration in brain blood supply was associated with increased neurogenesis, immunohistochemical detection of nestin and doublecortin (DCX) was used. In the Pir of both normal and VD rats, nestin positive cells were localized to layer II (superficial cellular layer) and layer III (deep cellular layer). Nestin expression was increased in Pir cells in VD rats and was even more intensely expressed after the HBO treatment. DCX positive cells were mostly located in layer II from amygdaline fissure to rhinal fissure. CONCLUSION: These results suggest that HBO therapy can improve the blood supply and promote the neurogenesis in the Pir of adult rats with the VD. PMID- 20715899 TI - Work-related mild-moderate traumatic brain injuries due to falls. AB - OBJECTIVE: Workplace falls are a common cause of head injuries; however, detailed study of this is limited. The objective of the study was to examine the person, environment and occupation factors associated with work-related traumatic brain injuries (WrTBI) due to falls from elevation (FFE) and falls from the same level (FFSL). METHODS: This study is a retrospective chart review. Data was extracted from consecutive medical records of workers who sustained a head injury at work and were referred to the Toronto Rehabilitation Institute for clinical assessment. RESULTS: FFE were more likely to occur in men and result in multiple traumas, compared to FFSL. FFSL occurred more equally among men and women. Slippery conditions and placement of objects were common for WrTBI due to FFSL. Change in elevation was common for WrTBI due to FFE. WrTBI due to FFE most often occurred in trades, transport occupations and the construction industry, whereas WrTBI due to FFSL most often occurred in professional, management, skilled positions and the manufacturing industry. CONCLUSIONS: Types of falls resulting in brain injury and their mechanisms of injury vary across industries and occupations. The study provides information for more tailored workplace safety strategies and primary prevention across industries. PMID- 20715900 TI - A neurophysiological and clinical study of Brunnstrom recovery stages in the upper limb following stroke. AB - PRIMARY OBJECTIVE: To determine the extent to which the Brunnstrom recovery stages of upper limb in hemiparetic stroke patients are correlated to neurophysiological measures and the spasticity measure of Modified Modified Ashworth Scale (MMAS). RESEARCH DESIGN: A concurrent criterion-related validity study. INTERVENTIONS: Not applicable. METHODS AND PROCEDURES: Thirty patients (15 men and 15 women; mean +/- SD = 58.8 +/- 11.5 years) with upper limb spasticity after stroke were recruited. Wrist flexor spasticity was rated using the MMAS. The neurophysiological measures were Hslp/Mslp ratio, H(max)/M(max) ratio and Hslp. MAIN OUTCOMES AND RESULTS: There was a significant moderate correlation between the Brunnstrom recovery stages and the neurophysiological measures. The Brunnstrom recovery stages were highly correlated to the MMAS scores (r = -0.81, p < 0.0001). CONCLUSIONS: The Brunnstrom recovery stages are moderately correlated with neurophysiological measures and highly correlated with the MMAS regarding the evaluation of motor recovery in stroke patients. The Brunnstrom recovery stages can be used as a valid test for the assessment of patients with post-stroke hemiplegia. PMID- 20715901 TI - Glycemic index and phenolics of partially-baked frozen bread with sourdough. AB - Different lactic acid bacteria starters were used to prepare sourdough to make partially-baked frozen wholemeal wheat bread. The sourdough was prepared with a pure culture of Lactobacillus plantarum or with commercial starters containing Lactobacillus brevis combined with Saccharomyces cerevisiae var. chevalieri (LV4), Lactobacillus fermentum (PL1), or Lactobacillus fermentum with phytase (PL3). We determined the acetic and lactic acid concentrations in sourdough, bread chemical composition, total phenolics content and glycemic index (GI) in vivo. Depending on the starter, the lactic to acetic acid ratio in the sourdough was significantly different. The GI of control bread without sourdough (70) was significantly higher than that of bread containing sourdough prepared with LV4 starter (50), PL1 starter (56) or PL3 starter (56), but not from bread with L. plantarum sourdough (60). The addition of 10% sourdough with a lower molar ratio of lactic to acetic acid ( <= 4) and higher total phenolics content is preferable for generating bread with medium and low GI. PMID- 20715902 TI - Top-down modulation of human early visual cortex after stimulus offset supports successful postcued report. AB - Modulations of sensory processing in early visual areas are thought to play an important role in conscious perception. To date, most empirical studies focused on effects occurring before or during visual presentation. By contrast, several emerging theories postulate that sensory processing and conscious visual perception may also crucially depend on late top-down influences, potentially arising after a visual display. To provide a direct test of this, we performed an fMRI study using a postcued report procedure. The ability to report a target at a specific spatial location in a visual display can be enhanced behaviorally by symbolic auditory postcues presented shortly after that display. Here we showed that such auditory postcues can enhance target-specific signals in early human visual cortex (V1 and V2). For postcues presented 200 msec after stimulus termination, this target-specific enhancement in visual cortex was specifically associated with correct conscious report. The strength of this modulation predicted individual levels of performance in behavior. By contrast, although later postcues presented 1000 msec after stimulus termination had some impact on activity in early visual cortex, this modulation no longer related to conscious report. These results demonstrate that within a critical time window of a few hundred milliseconds after a visual stimulus has disappeared, successful conscious report of that stimulus still relates to the strength of top-down modulation in early visual cortex. We suggest that, within this critical time window, sensory representation of a visual stimulus is still under construction and so can still be flexibly influenced by top-down modulatory processes. PMID- 20715903 TI - Fetal stromal niches enhance human embryonic stem cell-derived hematopoietic differentiation and globin switch. AB - Hematopoiesis during mammalian embryonic development has been perceived as a migratory phenomenon, from the yolk sac blood island to the aorta-gonad mesonephros (AGM) region, fetal liver (FL), and subsequently, the fetal bone marrow. In this study, we investigated the effects of primary stromal cells from fetal hematopoietic niches and their conditioned media (CM), applied singly or in sequential orders, on induction of human embryonic stem cells, H1, H9, and H14 lines, to hematopoietic cells. Our results demonstrated that stromal support of FL, AGM + FL, and AGM + FL + fetal bone marrow significantly increased the proliferation of embryoid bodies (EB) at day 18 of hematopoietic induction in the presence of thrombopoietin, stem cell factor, and Flt-3 ligand. AGM + FL also increased hematopoietic colony-forming unit (CFU) formation. CM did not enhance EB proliferation but CM of FL and AGM + FL significantly increased the density of total CFU and early erythroid (burst-forming unit) progenitors. Increased commitment to the hematopoietic lineage was demonstrated by enhanced expressions of CD45, alpha-, beta-, and gamma-globins in CFU at day 32, compared with EB at day 18. CM of FL significantly increased these globin expressions, indicating enhanced switches from embryonic to fetal and adult erythropoiesis. Over 50% and 10% of cells derived from CFU expressed CD45 and beta-globin proteins, respectively. Expressions of hematopoietic regulatory genes (Bmi-1, beta-Catenin, Hox B4, GATA-1) were increased in EB or CFU cultures supported by FL or sequential CM. Our study has provided a strategy for derivation of hematopoietic cells from embryonic stem cells under the influence of primary hematopoietic niches and CM, particularly the FL. PMID- 20715904 TI - Ibuprofen penetration enhance by sucrose ester examined by ATR-FTIR in vivo. AB - The aim of this work was to investigate the skin penetration enhancer effect of a sucrose ester (SE) in an Ibuprofen (IBU) containing hydrogel and to examine its influence on the special lipid bilayer of the stratum corneum (SC). ATR-FTIR spectroscopic measurements were performed combined with tape stripping method on hairless mice in vivo. A SE containing gel was compared to another gel without SE. It was found that the preparations caused only minimal modifications in the lipid and the protein structure, promoting the skin hydration and therefore also the penetration of IBU. Although the degree of moisturization and penetration were more intense in the case of the SE containing gel treatment, it did not cause greater alterations in the SC structure than the gel without SE. It has been proven that SE acts as an effective and non-irritating hydration and penetration enhancer for IBU through skin. PMID- 20715905 TI - Rheological and mechanical properties of poloxamer mixtures as a mucoadhesive gel base. AB - This study described the thermosensitive formulations composed of poloxamer mixtures for use as drug delivery platform via mucosal route. It also characterized the poloxamer mixtures' rheological, mechanical and mucoadhesive properties. Poloxamer (Plx) 407 and Plx 188 were used alone and together for preparing the mucosal drug delivery platform. The mixtures of Plx 407 and Plx 188 in ratio of 15:15 (F5); 15:20 (F6); 20:10 (F7) existed liquid at room temperature, but gelled at physiological temperature. Flow rheometry studies and oscillatory analysis of each formulation were performed at 20 +/- 0.1 degrees C and 37 +/- 0.1 degrees C. F5 and F7 formulations exhibited typical gel-type mechanical spectra (G' > G") after the determined frequency value at 37 degrees C whereas F6 behaved as weakly cross-linked gel. Texture profile analysis presented that F5 and F7 showed similar mechanical properties and can be used as base for mucosal dosage form. Mucoadhesion studies indicated the difference among the formulations and the effect of the mucosal surface on mucoadhesive properties. Mucin disc, bovine vaginal and buccal mucosa were used as mucosal platform for mucoadhesion studies. It is suggested that these investigations may be usefully combined to provide a more rational basis for selecting the ratio of Plx to prepare a topical thermosensitive drug delivery system for mucosal administration. PMID- 20715906 TI - Effect of daily intake of yoghurt and bread enriched with biologically active substances on blood lipids and vitamin A in adolescents and young adults. AB - OBJECTIVE: The aim was to investigate whether the daily intake of special nutrients, enriched with supplements from natural origins, has any effect on blood parameters. DESIGN AND SUBJECTS: In this double-blind placebo-controlled clinical trial, 80 healthy subjects (mean age 26.3 years) were statistically assigned to two groups. Group I had to eat two special yoghurt and bread products a day. The other probands represented the control group (II). SETTING: Plasma concentrations of blood parameters were measured at the beginning and at the end of the study, and dietary intake was calculated. RESULTS: In group I, total cholesterol decreased. This was due to a significant drop of low-density lipoprotein-cholesterol from 106.0 to 99.0 mg/dl. A significant reduction of the apolipoprotein B and an increase of vitamin A in group I were also observed. CONCLUSION: Regular intake of specially fortified food influences parameters, especially lipids and lipoproteins. PMID- 20715908 TI - Safeguarding innovation through an economic downturn. PMID- 20715907 TI - Association of serotype with risk of death due to pneumococcal pneumonia: a meta analysis. AB - BACKGROUND: The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates. METHODS: We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors. RESULTS: Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro. CONCLUSIONS: These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property. PMID- 20715909 TI - Integrating patient-reported outcomes in healthcare policy, research and practice. PMID- 20715911 TI - Cost-effectiveness of strontium ranelate for the prevention and treatment of osteoporosis. AB - Strontium ranelate has been introduced recently for the prevention and treatment of osteoporosis in Europe and in many countries worldwide. This article reviews the published cost-effectiveness literature pertaining to strontium ranelate. Six studies were identified: two in the UK, two in Belgium and two in Sweden. The findings were consistent across the literature, suggesting that strontium ranelate is a cost-saving drug for women with osteoporosis aged over 80 years, and it is a cost-effective treatment compared with no treatment for osteoporotic women aged over 70 years and for younger women with clinical risk factors for fragility fracture. Strontium ranelate was also shown to be cost effective compared with branded risedronate in osteoporotic women aged over 75 years. Further analyses are required to assess the effectiveness and adherence to strontium ranelate in real-life settings, as well as to evaluate the cost effectiveness of strontium ranelate in other countries and in populations of men. PMID- 20715912 TI - Osteoporosis research thrives: IOF WCO-ECCEO10. AB - The recent World Congress on Osteoporosis (IOF WCO-ECCEO10), held in Florence on 5-8 May 2010, not only drew a record number of researchers and clinicians, it also attracted a far greater number of scientific abstracts than ever before (850). Needless to say, the organizing societies, the International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), were delighted to welcome a record number of attendees (5500). The record numbers suggest that research in the field is thriving and that there is strong interest in the epidemiology, diagnosis and management of osteoporosis and fragility fractures around the world. This is reflected in the attendance statistics, which showed that, as expected, the largest delegation of participants (73.89%) was from Europe, with comparatively large delegations from Asia (8.20%) and North America (6.35%). Researchers and clinicians from South America and the Middle East ( approximately 3% each) were also in attendance. Participants experienced an enriching scientific program featuring a broad range of topics covered in 12 plenary sessions, 19 primarily clinically oriented meet-the-expert topics in multiple sessions, and eight special sessions and symposia. A total of 12 satellite symposia enhanced the program by offering a wealth of information and practical new knowledge for clinicians. PMID- 20715913 TI - Cost-effectiveness of high-dose intravenous esomeprazole in patients with peptic ulcer bleeding in the USA and Europe. AB - Peptic ulcer bleeding (PUB) is life-threatening and associated with high healthcare costs. Clinical outcomes in PUB depend largely on the risk of rebleeding. Recent data indicate that intravenous proton pump inhibitors (PPIs) reduce rebleeds, the need for surgery and repeat endoscopic treatment. From a policy perspective, it is important to assess the cost-effectiveness of this treatment. Accordingly, a decision-tree model published by Barkun et al. evaluated the costs and benefits of high-dose intravenous esomeprazole in preventing rebleeds in patients with PUB based on data from a multinational, randomized clinical trial comparing this therapeutic approach to intravenous placebo. The results indicate that esomeprazole is cost effective in the USA and Sweden, and cost saving in Spain. These findings agree with most other analyses of intravenous PPIs used in PUB patients at high risk for bleeds. The therapeutic approach provides increased benefits to patients at a relatively small additional cost. PMID- 20715914 TI - Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin. AB - Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarin's narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life year gained. Owing to the inevitable assumptions that have to be made in all cost effectiveness models, great uncertainty remains regarding the cost-effectiveness of pharmacogenetic-guided warfarin dosing. PMID- 20715915 TI - General population versus disease-specific event rate and cost estimates: potential bias for economic appraisals. AB - Economic appraisals are increasingly being used for reimbursement decision making. Differences exist in the population data sources used in different studies and these differences may result in errors or biased estimates. A review of the literature suggests that very little has been written on this topic and guidelines and good practice documents are silent on the issue. Using illustrative examples, it was found that the population chosen for event/complication costing did not have a large impact on a cost-effectiveness analysis; however, the choice of population did have a large impact for cost-of illness (COI) estimation. It was found that not controlling for event/complication rates in a nondiseased population resulted in a 15% inflated COI estimate and using event costs from the general population underestimated COI by 20-32%. Our analysis suggests that using event costs from the general population instead of a diseased population may not have a significant impact on cost-effectiveness estimates; however, COI studies should only use excess event/complication rates and should also only use event costs from populations with the disease. PMID- 20715916 TI - Conceptual and methodological advances in child-reported outcomes measurement. AB - Increasingly, clinical, pharmaceutical and translational research studies use patient-reported outcomes as primary and secondary end points. Obtaining this type of information from children themselves is now possible, but effective assessment requires developmentally sensitive conceptual models of child health and an appreciation for the rapid change in children's cognitive capacities. To overcome these barriers, outcomes researchers have capitalized on innovations in modern measurement theory, qualitative methods for instrument development and new computerized technologies to create reliable and valid methods for obtaining self reported health data among 8-17-year-old children. This article provides a developmentally focused framework for selecting child-report health assessment instruments. Several generic health-related quality of life instruments and the assessment tools developed by the NIH-sponsored Patient-Reported Outcome Measurement Information System network are discussed to exemplify advances in the measurement of children's self-reported health, illness, wellbeing and quality of life. PMID- 20715917 TI - Quality of life in children and teenagers with food hypersensitivity. AB - Given that food is essential for life and that there is currently no cure for food hypersensitivity (FHS), quality of life is a key outcome measure for those affected. The quality of life of children and teenagers with FHS is particularly important given that they must learn to manage their FHS while also contending with normal developmental challenges. This article will review the current state of quality of life research in this important area, and discusses the impact of FHS on the quality-of-life of children and teenagers, the availability and suitability of disease-specific health-related quality-of-life measures for this population, and the identification of factors that may influence their health related quality of life. Two previous reviews have been conducted in this area, and this article aims to extend this work by including recent publications and qualitative studies on this topic. PMID- 20715918 TI - Patient-reported outcomes in support of oncology product labeling claims: regulatory context and challenges. AB - The US FDA has advocated the patient-reported outcome (PRO) draft guidance as the main vehicle for evaluating PRO-based labeling claims for oncology drugs. In addition, FDA-affiliated researchers have identified factors inhibiting acceptance of health-related quality of life (HRQoL)-based claims for oncology product labels. The views of the FDA on PRO claims are extensive and prescriptive. By contrast, the European Medicines Agency (EMA) has conducted authorizations without an explicitly defined approach for evaluating HRQoL data. A reflective paper released in 2005 offered only broad recommendations on HRQoL labeling claims. The different approaches between the two regulatory agencies partly stem from underlying, divergent organizational characteristics. Moreover, general issues inherent in PRO research in oncology trials including trial design, missing data, multiplicity of end points and inconsistent findings of HRQoL data are discussed. PMID- 20715919 TI - Robotic surgery in urologic oncology: gathering the evidence. AB - In less than a decade, the widespread application of robotic technology to the field of urologic oncology has permanently altered the way urologists approach malignancy. The short-term benefits of minimally invasive surgery using robotic assistance (i.e., decreased blood loss, improved convalescence and ergonomic appeal), as well as a broad marketing campaign, have helped the technology gain traction in the field of urology. Although the long-term benefits of its use in urologic surgery are less clear and the costs of robotic surgery are consistently greater than those of other approaches, the numbers of prostate, kidney and bladder cancer cases continue to rise. Identifying transferable surgical processes of care that matter most for each of the robotic cases in urologic oncology (e.g., prostatectomy, cystectomy and partial nephrectomy) is a next step toward broadly improving the quality of urologic cancer care. To this end, urologic professional societies and their surgeons should aim to identify underwriters for and participate in large clinical registries and surgical quality collaboratives. PMID- 20715921 TI - Pricing-out effect from possible user-fee policies under Taiwan's National Health Insurance. AB - This article simulates the pricing-out effect due to various user-fee policies under Taiwan's National Health Insurance. Our simulation results indicate that the lower income group is more likely to be priced out of the healthcare system than the higher income group. On average, pricing-out effects are 0.04, 0.21, 0.52 and 0.73% of total beneficiaries with respect to the new co-payment policy, the catastrophic insurance policy, the under insurance policy, and the case of no National Health Insurance, respectively. We caution that a reduction of healthcare utilization due to higher user fees could result in some patients being left behind without professional care because the pricing-out effects could be higher than the substitution effects diverting demand to other professional care alternatives. PMID- 20715920 TI - Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes. AB - Rates of antibiotic resistance in Pseudomonas aeruginosa are increasing worldwide. The multidrug-resistant (MDR) phenotype in P. aeruginosa could be mediated by several mechanisms including multidrug efflux systems, enzyme production, outer membrane protein (porin) loss and target mutations. Currently, no international consensus on the definition of multidrug resistance exists, making direct comparison of the literature difficult. Inappropriate empirical therapy has been associated with increased mortality in P. aeruginosa infections; delays in starting appropriate therapy may contribute to increased length of hospital stay and persistence of infection. In addition, worse clinical outcomes may be associated with MDR infections owing to limited effective antimicrobial options. This article aims to summarize the contemporary literature on patient outcomes following infections caused by drug-resistant P. aeruginosa. The impact of antimicrobial therapy on patient outcomes, mortality and morbidity; and the economic impact of MDR P. aeruginosa infections will be examined. PMID- 20715922 TI - Economic evaluations on cardiovascular preventive interventions in Argentina. AB - Cardiovascular diseases are the main cause of death in Argentina. This article analyzes economic evaluations on cardiovascular prevention for this country. A literature search was conducted in five electronic databases during December 2009. Inclusion criteria were complete economic evaluations addressing at least one cardiovascular health outcome for the Argentinean population. Finally, nine studies were included evaluating 14 comparisons. Interventions oriented to primary or secondary prevention in patients that had undergone coronary angioplasty, with a previous cardiovascular event or equivalents, with a hospitalization for heart failure or general population were evaluated. Bread salt reduction, antihypertensive treatment, mass educational campaigns and polypill strategies could be considered cost effective. The available economic evidence to guide resource allocation in cardiovascular disease in Argentina seems to be scarce and limited. PMID- 20715924 TI - Development of national and multiagency HIV care quality measures. AB - BACKGROUND: Human immunodeficiency virus (HIV) is now a complex, chronic disease requiring high quality care. Demonstration of quality HIV care requires uniform, aligned HIV care quality measurement. METHODS: In September 2007, the National Committee for Quality Assurance, under contract with the Health Resources and Services Administration, the Physician Consortium for Performance Improvement of the American Medical Association, and HIV Medicine Association of the Infectious Disease Society of America jointly sponsored and convened an expert panel as a HIV/AIDS Work Group to draft national HIV/AIDS performance measures for individual patient-level and system-level quality improvement. RESULTS: A total of 17 measures were developed to assess processes and outcomes of HIV/AIDS care for patients established in care, defined as having at least 2 visits in a 12 month period; thus, measures of HIV screening, testing, linkage, and access to care were not included. As a set, the measures assess a wide range of care, including patient retention, screening and prophylaxis for opportunistic infections, immunization, and initiation and monitoring of potent antiretroviral therapy. Since development, the HIV/AIDS measures' specifications have been fully determined and are being beta tested, and a majority have been endorsed by the National Quality Forum and have been adopted and implemented by the sponsoring organizations. CONCLUSIONS: HIV care quality measurement should be assessed with greater uniformity. The measures presented offer opportunities for such alignment. PMID- 20715925 TI - Quality of care for patients infected with HIV. PMID- 20715926 TI - The co phylogeny reconstruction problem is NP-complete. AB - The co phylogeny reconstruction problem is that of finding minimum cost explanations of differences between historical associations. The problem arises in parasitology, molecular systematics, and biogeography. Existing software tools for this problem either have worst-case exponential time or use heuristics that do not guarantee optimal solutions. To date, no polynomial time optimal algorithms have been found for this problem. In this article, we prove that the problem is NP-complete, suggesting that future research on algorithms for this problem should seek better polynomial-time approximation algorithms and heuristics rather than optimal solutions. PMID- 20715927 TI - Kaposi sarcoma (KS)-associated herpesvirus microRNA sequence analysis and KS risk in a European AIDS-KS case control study. AB - BACKGROUND: We recently identified polymorphisms in Kaposi sarcoma-associated herpesvirus (KSHV)-encoded microRNA (miRNA) sequences from clinical subjects. Here, we examine whether any of these may contribute to KS risk in a European AIDS-KS case-control study. METHODS: KSHV load in peripheral blood was determined by real-time quantitative polymerase chain reaction. Samples that had detectable viral loads were used to amplify the 2.8-kb miRNA encoding region plus a 646-bp fragment of the K12/T0.7 gene. Additionally, we characterized an 840-bp fragment of the K1 gene to determine KSHV subtypes. RESULTS: KSHV DNA was detected in peripheral blood mononuclear cells of 49.6% of case patients and 6.8% of controls, and viral loads tended to be higher in case patients. Sequences from the miRNA-encoding regions were conserved overall, but distinct polymorphisms were detected, some of which occurred in primary miRNAs, pre-miRNAs, or mature miRNAs. CONCLUSIONS: Patients with KS were more likely to have detectable viral loads than were controls without disease. Despite high conservation in KSHV miRNA encoded sequences, polymorphisms were observed, including some that have been reported elsewhere. Some polymorphisms could affect mature miRNA processing and appear to be associated with KS risk. PMID- 20715929 TI - Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. AB - BACKGROUND: Staphylococcus aureus is an important human pathogen of endovascular diseases, which can take a chronic course with a high relapse rate despite antimicrobial treatment. Thus far, persistent and antibiotic-refractory infections have been largely associated with a subpopulation of S. aureus, the small-colony variants (SCVs). METHODS: In this work, we used endothelial cells to investigate infection with the highly virulent wild-type isolate (6850), 2 stable isogenic SCV phenotypes (hemB mutant IIb13 and JB1), and the complemented mutant. RESULTS: All strains were highly invasive in endothelial cells but largely differed in host response induction. Microarray analysis showed that wild-type phenotypes up-regulated a large number of endothelial genes (including genes involved in innate immunity), whereas the SCVs did not cause these dramatic changes. The inflammatory response and cytotoxicity were strongest shortly after infection and largely decreased within the following days, which was accompanied by a fast elimination of intracellular wild-type bacteria. By contrast, SCVs survived within endothelial cells at high numbers. CONCLUSION: S. aureus intracellular persistence via the development of an adapted subpopulation of SCVs most likely represents an important strategy of S. aureus to hide within the host cells, which could be a reservoir for chronic infections. PMID- 20715930 TI - Multiple infections with seasonal influenza A virus induce cross-protective immunity against A(H1N1) pandemic influenza virus in a ferret model. AB - BACKGROUND: An age bias toward children and young adults has been reported for infection and hospitalizations with pandemic H1N1 influenza (A[H1N1]pdm) in the 2009 and 2010 influenza seasons in the Southern and Northern Hemispheres. Serological analysis of prepandemic samples has shown a higher incidence of cross reactive antibodies to A(H1N1)pdm virus in older populations; conserved T cell epitopes between viruses have been identified. The contribution of preexisting immunity to seasonal influenza to protection against A(H1N1)pdm infection was analyzed in a ferret model. METHODS: Ferrets were pre-infected with influenza A viruses and/or vaccinated with inactivated influenza viruses with adjuvant. Infection after challenge was assessed by measuring shedding virus, transmission to naive animals, and seroconversion. RESULTS: Homologous vaccination reduced the incidence of infection and delayed transmission. Pre-infection with virus induced sterilizing immunity to homologous challenge. One prior infection with seasonal influenza A virus improved clearance of A(H1N1)pdm virus. Prior infection with A(H1N1)pdm virus reduced shedding after seasonal influenza A challenge. Two infections with seasonal influenza A viruses reduced the incidence of infection, the amount and duration of virus shedding, and the frequency of transmission following A(H1N1)pdm challenge. CONCLUSION: These data suggest the reduced incidence and severity of infection with A(H1N1)pdm virus in the adult population during the 2009-2010 influenza season may be a result of previous exposure to seasonal influenza A viruses. PMID- 20715928 TI - Coinfection with Haemophilus influenzae promotes pneumococcal biofilm formation during experimental otitis media and impedes the progression of pneumococcal disease. AB - BACKGROUND: Otitis media is an extremely common pediatric infection and is mostly caused by bacteria that are carried within the nasopharyngeal microbiota. It is clear that most otitis media cases involve simultaneous infection with multiple agents. METHODS: Chinchillas were infected with nontypeable Haemophilus influenzae, Streptococcus pneumoniae, or a combination of both organisms, and the course of disease was compared. In vitro experiments were also performed to address how coinfection impacts biofilm formation. RESULTS: The incidence of systemic disease was reduced in coinfected animals, compared with those infected with pneumococcus alone. Pneumococci were present within surface-attached biofilms in coinfected animals, and a greater proportion of translucent colony type was observed in the coinfected animals. Because this colony type has been associated with pneumococcal biofilms, the impact of coinfection on pneumococcal biofilm formation was investigated. The results clearly show enhanced biofilm formation in vitro by pneumococci in the presence of H. influenzae. CONCLUSIONS: Based on these data, we conclude that coinfection with H. influenzae facilitates pneumococcal biofilm formation and persistence on the middle ear mucosal surface. This enhanced biofilm persistence correlates with delayed emergence of opaque colony variants within the bacterial population and a resulting decrease in systemic infection. PMID- 20715931 TI - Low postseroconversion CD4 count and rapid decrease of CD4 density identify HIV+ fast progressors. AB - CD4 expression in HIV replication is paradoxical: HIV entry requires high cell surface CD4 densities, but replication requires CD4 down-modulation. However, is CD4 density in HIV+ patients affected over time? Do changes in CD4 density correlate with disease progression? Here, we examined the role of CD4 density for HIV disease progression by longitudinally quantifying CD4 densities on CD4+ T cells and monocytes of ART-naive HIV+ patients with different disease progression rates. This was a retrospective study. We defined three groups of HIV+ patients by their rate of CD4+ T cell loss, calculated by the time between infection and reaching a CD4 level of 200 cells/microl: fast (<7.5 years), intermediate (7.5-12 years), and slow progressors (>12 years). Mathematical modeling permitted us to determine the maximum CD4+ T cell count after HIV seroconversion (defined as "postseroconversion CD4 count") and longitudinal profiles of CD4 count and density. CD4 densities were quantified on CD4+ T cells and monocytes from these patients and from healthy individuals by flow cytometry. Fast progressors had significantly lower postseroconversion CD4 counts than other progressors. CD4 density on T cells was lower in HIV+ patients than in healthy individuals and decreased more rapidly in fast than in slow progressors. Antiretroviral therapy (ART) did not normalize CD4 density. Thus, postseroconversion CD4 counts define individual HIV disease progression rates that may help to identify patients who might benefit most from early ART. Early discrimination of slow and fast progressors suggests that critical events during primary infection define long term outcome. A more rapid CD4 density decrease in fast progressors might contribute to progressive functional impairments of the immune response in advanced HIV infection. The lack of an effect of ART on CD4 density implies a persistent dysfunctional immune response by uncontrolled HIV infection. PMID- 20715932 TI - Obstructive sleep apnea is independently associated with the metabolic syndrome in obese Asian Indians in northern India. AB - INTRODUCTION: Obesity and the metabolic syndrome are rapidly increasing in developing countries. Whether the metabolic syndrome is independently associated with obstructive sleep apnea (OSA) is not clear. OBJECTIVE: This study investigated the association between OSA and the metabolic syndrome in obese Asian Indians. METHODS: We studied 240 obese subjects [body mass index (BMI) >25 kg/m2], 121 with OSA and 119 without OSA, matched for age, BMI, and percentage body fat (%BF). Full-montage digital polysomnography, fasting blood glucose (FBG), lipid levels, and blood pressure (BP) were done in all subjects. RESULTS: Subjects with OSA showed higher prevalence of the metabolic syndrome as compared to subjects without OSA [67.8% vs. 42.02%; chi2 = 16.08, P < 0.0001, odds ratio (OR) = 2.90, 95% confidence interval (CI)]. Prevalence of the metabolic syndrome was significantly higher in the severe OSA group as compared to the moderate OSA group (78.7% vs. 40.9%; chi2 = 11.57; P < 0.001; OR = 0.19, 95% CI). Fasting insulin levels were significantly higher in subjects with OSA as compared to subjects without OSA [median (range); 84.03(12.5-541.7) pmol/L vs. 64.4(10.4 520.8) pmol/L; P = 0.002)]. Regression analysis suggested that OSA was independently and positively associated with the metabolic syndrome, male gender, and fasting insulin levels. CONCLUSION: OSA is independently associated with the metabolic syndrome in Asian Indians in northern India. PMID- 20715933 TI - Apolipoprotein B and non-high-density lipoprotein cholesterol are better risk markers for coronary artery disease than low-density lipoprotein cholesterol in hypertriglyceridemic metabolic syndrome patients. AB - BACKGROUND: Metabolic syndrome is highly prevalent in the general population. Small dense low-density lipoprotein (sd-LDL) particles have been considered as a risk marker in metabolic syndrome diagnosis. Apolipoprotein B (ApoB) concentration reflects the number of LDL particles and is closely associated with atherosclerosis. The aim of this study was to compare the associations of ApoB, non-high-density lipoprotein cholesterol (NHDL-C), and low-density lipoprotein cholesterol (LDL-C) with metabolic syndrome and its relationship with significant coronary stenosis (SCS) in a Tunisian population. METHODS: We enrolled 192 patients, who underwent coronary angiography. The body mass index, blood lipids, fasting glucose, insulin concentration, and blood pressure of every patient were measured. Metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. RESULTS: The frequency of metabolic syndrome was 58.3%. The comparison of the lipidic parameters between subject with and without metabolic syndrome showed a significant increase in ApoB and NHDL-C but not in LDL-C. By considering triglyceride (TG) limits (TG <= 0.9 mmol/L and TG > 1.70 mmol/L), we noted no differences in ApoB, NHDL-C, and LDL-C between subjects with and without metabolic syndrome in triglyceridemia <=0.9 mmol/L. In triglyceridemia >1.70 mmol/L, a significant increase in ApoB and NHDL-C, but not in LDL-C, was noted. These results seem to consolidate the probability of increased sd-LDL in hypertriglyceridemic metabolic syndrome subjects. Indeed, in our study the odds ratio (OR) of SCS associated with metabolic syndrome is 3.81 (P = 0.007) in the studied population. This risk increases to 8.70 (P = 0.026) in hypertriglyceridemic subjects and seems to be associated with ApoB and NHDL-C (OR = 1.87, P = 0.038; OR = 1.26, P = 0.048). CONCLUSIONS: This study suggests that ApoB and NHDL-C seem to be more correlated to SCS in metabolic syndrome with hypertriglyceridemia than LDL-C. PMID- 20715934 TI - Comparison of foot-to-foot and hand-to-foot bioelectrical impedance methods in a population with a wide range of body mass indices. AB - BACKGROUND: Several techniques are currently used for measurement of body composition. Bioelectrical impedance assessment (BIA) is a simple, noninvasive method of assessing body composition. We aimed to compare multifrequency hand-to foot (HF-BIA) and foot-to-foot (FF-BIA) bioelectrical impedance analysis techniques to assess fat-free mass (FFM) in a population with a wide range of body mass indices (BMI). METHODS: This was a cross-sectional study of 198 adult subjects. Anthropometric and BIA measures (HF-BIA with Hydra ICF/ECF, Xitron Technologies and FF-BIA with Tanita, model TBF-300A) were recorded after a 12-h fast. RESULTS: Participants had a mean age of 42 years and BMI of 33.50.7 (range, 17.7-65.6) kg/m2. Mean FFM with HF-BIA (FFM BIA/HF) and FF-BIA (FFM BIA/FF) were 61.31.3 kg and 58.10.9 kg, respectively (P < 0.001). In subjects with BMI <25 kg/m2, FFM BIA/FF was not significantly different compared to FFMBIA/HF (-0.2 kg; P=0.8). However, FFM BIA/FF was significantly lower in subjects with BMI 25-30 kg/m2 (-2.0 kg; P=0.009), 30-34 kg/m2 (-1.8 kg; P1/40.04), 34-42 kg/m2 (-4.7 kg; P<0.001) and >42 kg/m2 (-8.0 kg; P=0.001). Pearson correlations between both methods were very high for FFM (r=0.92), fat mass (r=0.91), and % fat mass (r=0.85), all P<0.001. Correlation coefficients for FFM were high in each quintile of BMI. FFM BIA/FF was the only significant independent predictor of FFM BIA/HF (P<0.001) in linear regression analyses using clinical and FF-BIA variables, but introducing BMI in the model added precision. CONCLUSION: FFM BIA/FF correlates closely with FFM BIA/HF across all quintiles of BMI, but FF-BIA gives lower FFM in overweight and obese subjects. PMID- 20715942 TI - A biomed by any other name ... PMID- 20715943 TI - Experts urge hospitals to act on integration. PMID- 20715947 TI - Certification preparation 101: how to get ready for your exam. PMID- 20715948 TI - Technology trends. New 'phantom' tool could calibrate MRI machines. PMID- 20715949 TI - Rebirth of a profession: hybrid positions on the rise in clinical, manufacturing settings. PMID- 20715950 TI - Dean: key factors lead to thriving school. PMID- 20715951 TI - AAMI's employment survey...how does your compensation stack up? PMID- 20715952 TI - Five simple steps to project planning. PMID- 20715954 TI - Orientation program sets new employees off on the right foot. PMID- 20715955 TI - Play it safe: do your part at work. PMID- 20715956 TI - Vendors and customers: the keys to a happy working relationship. PMID- 20715957 TI - Centrifuges: take a spin. PMID- 20715958 TI - Real time location systems and asset tracking: new horizons for hospitals. PMID- 20715959 TI - Imaging innovations lead to advances in radiation therapy. PMID- 20715960 TI - Analysis: new hospital accreditation agency falls short. PMID- 20715961 TI - New to management? Here's what you need to know. PMID- 20715962 TI - National Quality Forum releases recommendations for safe practices. PMID- 20715963 TI - Study examines FDA warning letters about medical devices from 2009. PMID- 20715964 TI - IEEE 11073 standards address remote monitoring market. PMID- 20715965 TI - AAMI's benchmarking solution: analysis of cost of service ratio and other metrics. PMID- 20715966 TI - A portable, inexpensive, wireless vital signs monitoring system. AB - The University of Connecticut, Department of Biomedical Engineering has developed a device to be used by patients to collect physiological data outside of a medical facility. This device facilitates modes of data collection that would be expensive, inconvenient, or impossible to obtain by traditional means within the medical facility. Data can be collected on specific days, at specific times, during specific activities, or while traveling. The device uses biosensors to obtain information such as pulse oximetry (SpO2), heart rate, electrocardiogram (ECG), non-invasive blood pressure (NIBP), and weight which are sent via Bluetooth to an interactive monitoring device. The data can then be downloaded to an electronic storage device or transmitted to a company server, physician's office, or hospital. The data collection software is usable on any computer device with Bluetooth capability, thereby removing the need for special hardware for the monitoring device and reducing the total cost of the system. The modular biosensors can be added or removed as needed without changing the monitoring device software. The user is prompted by easy-to-follow instructions written in non-technical language. Additional features, such as screens with large buttons and large text, allow for use by those with limited vision or limited motor skills. PMID- 20715967 TI - Improved modeling of electromagnetic localization for implantable wireless capsules. AB - An electromagnetic localization method for implantable wireless capsules has been developed that employs a three-axial magnetic sensor embedded in the capsules and three energized coils attached on the abdomen. In order to further improve the localization accuracy, a novel localization model has been derived based on the Biot-Savart Law. For simplicity of the calculation without increasing the position error, the method of truncated series expansion has been used in modeling. The experiment showed that the improved model had higher precision than the original dipole model. Using the improved model, the localization error can be greatly reduced. The improved model is an elementary math function and suitable for resolving some inverse magnetic problems in engineering. PMID- 20715968 TI - Give the newbies a chance. PMID- 20715969 TI - Persistent left superior vena cava: does it have a role in the pathogenesis of hypoplastic left heart syndrome? AB - The coexistence of a persistent left superior vena cava (PLSVC) and congenital anomalies, both cardiac and noncardiac, is well documented, but whether PLSVC contributes to the development of cardiac malformations is controversial. We conducted a retrospective review of perinatal and pediatric autopsies to determine the association between PLSVC and other congenital anomalies. Of 362 patients, 91 (25%) had congenital heart disease and 19 (5.2%) had PLSVC. Eight cases (47%) were associated with specific syndromes, including heterotaxy syndrome, trisomy 18, trisomy 13, and Jacobsen syndrome. Seventeen cases of PLSVC (89%) were associated with congenital heart disease, most of which were complex. Isolated PLSVC was found in 2 cases (11%). Eight of the 19 PLSVC cases (47%) were associated with hypoplastic left heart syndrome (HLHS), a result that was statistically significant (P = 0.041). Left ventricle inflow/outflow obstruction is believed to be a critical pathogenic factor in the development of HLHS. Whereas 5 of 8 cases of HLHS had additional obstructive cardiac outflow tract lesions, 3 of 8 cases did not. PLSVC is known to be able to compromise left ventricle inflow via a dilated coronary sinus, and we speculate that PLSVC may have played a contributing role in the pathogenesis of HLHS in these three cases. As an isolated lesion, PLSVC would not be sufficient to cause HLHS, but it might contribute in combination with other obstructive lesions, or in the setting of other genetic and/or environmental factors still to be defined for HLHS. A larger series will be needed to confirm this hypothesis. PMID- 20715970 TI - Blood pressure levels constitute the most important determinant of the metabolic syndrome in a Mediterranean population: a discrimination analysis. AB - BACKGROUND: The aim of the study was to evaluate the relative importance of the determinants of the metabolic syndrome in a sample with metabolic syndrome from the Greek population. METHODS: A random sample of 824 male (56 +/- 11 years) and 1,199 female (58 +/- 10 years) subjects with metabolic syndrome [National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)], but without diabetes mellitus or established cardiovascular disease, was selected from all over Greece. Principal components analysis (PCA) was applied to evaluate the interrelationships between the inherent characteristics of the metabolic syndrome. RESULTS: Among the participants, 87.6% had elevated blood pressure levels, 79.9% had hypertriglyceridaemia, 62.6% had low high-density lipoprotein cholesterol (HDL-C) levels, 71.4% had impaired fasting glucose (FG), and 91.5% had abdominal obesity. The most common combination was elevated blood pressure levels, abdominal obesity, impaired fasting glucose (FG), and hypertriglyceridemia (14.2%). PCA revealed three main components that explained 68.4% of the total variation. The first one was heavily loaded by blood pressure (28.6% of the total variation explained), followed by a component characterized by lipid variables (21.7%) and a component characterized by FG and waist circumference measurements (18.1% explained variation). CONCLUSIONS: The most dominant characteristic of metabolic syndrome participants from a Mediterranean country (Greece) was elevated blood pressure levels, which were present in all eight of the most common combinations of metabolic syndrome components, rendering the "hypertensive aspect" of metabolic syndrome the most common one. Because a significant proportion of hypertensive subjects with metabolic syndrome receive no treatment, or are poorly controlled, targeting blood pressure levels in the general population may assist in better preventing metabolic syndrome and its complications. PMID- 20715971 TI - The triglyceride/high-density lipoprotein cholesterol ratio fails to predict insulin resistance in African-American women: an analysis of Jackson Heart Study. AB - BACKGROUND: Compared to whites, insulin-resistant African Americans have worse outcomes. Screening programs that could identify insulin resistance early enough for intervention to affect outcome often rely on triglyceride (TG) and high density lipoprotein cholesterol (HDL-C) levels. Racial differences in TG and HDL C may compromise the efficacy of these programs in African Americans. A recommendation currently exists to use the TG/HDL-C ratio >=2.0 to predict insulin resistance in African Americans. The validity of this recommendation needs examination. Therefore, our aim was to determine the ability of TG/HDL-C ratio to predict insulin resistance in African Americans. METHODS: In 1,903 African Americans [895 men, 1,008 women, age 55 +/- 12 years, mean +/- standard deviation (SD), range 35-80 years, body mass index (BMI) 31.0 +/- 6.4 kg/m(2), range 18.5-55 kg/m(2)] participating in the Jackson Heart Study, a population based study of African Americans, Jackson, Mississippi tricounty region, insulin resistance was defined by the upper quartile (>=4.43) of homeostasis model assessment of insulin resistance (HOMA-IR). An area under the receiver operating characteristic curve (AUC-ROC) of >0.70 was required for prediction of insulin resistance by TG/HDL-C. The optimal test cutoff was determined by the Youden index. RESULTS: HOMA-IR was similar in men and women (3.40 +/- 2.03 vs. 3.80 +/- 2.46, P = 0.60). Women had lower TG (94 +/- 49 vs. 109 +/- 65 mg/dL P < 0.001) and TG/HDL-C (1.9 +/- 1.4 vs. 2.7 +/- 2.1, P < 0.001). For men, AUC-ROC for prediction of insulin resistance by TG/HDL-C was: 0.77 +/- 0.01, mean +/- standard error (SE), with an optimal cutoff of >=2.5. For women, the AUC-ROC was 0.66 +/- 0.01, rendering an optimal cutoff indefinable. When women were divided in two groups according to age, 35-50 years and 51-80 years, the results did not change. CONCLUSIONS: In African-American men, the recommended TG/HDL-C threshold of 2.0 should be adjusted upward to 2.5. In African-American women, TG/HDL-C cannot identify insulin resistance. The Jackson Heart Study can help determine the efficacy of screening programs in African-Americans. PMID- 20715972 TI - Critical interplay between parasite differentiation, host immunity, and antigenic variation in trypanosome infections. AB - Increasing availability of pathogen genomic data offers new opportunities to understand the fundamental mechanisms of immune evasion and pathogen population dynamics during chronic infection. Motivated by the growing knowledge on the antigenic variation system of the sleeping sickness parasite, the African trypanosome, we introduce a mechanistic framework for modeling within-host infection dynamics. Our analysis focuses first on a single parasitemia peak and then on the dynamics of multiple peaks that rely on stochastic switching between groups of parasite variants. A major feature of trypanosome infections is the interaction between variant-specific host immunity and density-dependent parasite differentiation to transmission life stages. In this study, we investigate how the interplay between these two types of control depends on the modular structure of the parasite antigenic archive. Our model shows that the degree of synchronization in stochastic variant emergence determines the relative dominance of general over specific control within a single peak. A requirement for multiple peak dynamics is a critical switch rate between blocks of antigenic variants, which implies constraints on variant surface glycoprotein (VSG) archive genetic diversification. Our study illustrates the importance of quantifying the links between parasite genetics and within-host dynamics and provides insights into the evolution of trypanosomes. PMID- 20715973 TI - Trait- and density-mediated indirect interactions initiated by an exotic invasive plant autogenic ecosystem engineer. AB - Indirect interactions are important for structuring ecological systems. However, research on indirect effects has been heavily biased toward top-down trophic interactions, and less is known about other indirect-interaction pathways. As autogenic ecosystem engineers, plants can serve as initiators of nontrophic indirect interactions that, like top-down pathways, can involve both trait mediated indirect interactions (TMIIs) and density-mediated indirect interactions (DMIIs). Using microcosms, I examined a plant --> predator --> consumer interaction pathway involving the exotic autogenic ecosystem engineer Centaurea maculosa; native Dictyna spiders (which exhibit density and trait [web-building] responses to C. maculosa); Dictyna's insect prey, Urophora affinis; and Urophora's host plant (a secondary receiver species) to quantify DMIIs and TMIIs in an autogenic engineered pathway. Both DMIIs and TMIIs were strong enough to reduce Urophora populations, but only DMIIs, which were 4.3 times stronger than TMIIs, were strong enough to also reduce Urophora's fecundity and increase the fecundity of its host plant. Prior field studies support these results, suggesting that the differences between DMIIs and TMIIs are even stronger in nature. This study illustrates that autogenic ecosystem engineers can initiate powerful indirect interactions that generally parallel predator-initiated interactions but also differ in important functional ways. PMID- 20715974 TI - Magnesium sulfate normalizes placental interleukin-6 secretion in preeclampsia. AB - Interleukin-6 (IL-6) is one of the main proinflammatory mediators of hypertension and endothelial dysfunction in preeclampsia. In this study, we investigated the capacity of the preeclamptic placenta to secrete IL-6 and the effect of magnesium sulfate (MgSO(4)) on it. Placentas from normotensive (37-40 weeks) and preeclamptic (36-40 weeks) pregnancies were dually perfused for 6 h in the absence [normotensive (n = 3); preeclamptic (n = 4)] and presence [normotensive (n = 3); preeclamptic (n = 4)] of MgSO(4). Perfusate samples from the maternal and the fetal circulations were collected at each 30 min throughout the perfusion period and examined for IL-6 by enzyme-linked immunoassay. Statistical analysis was performed using the 2-way analysis of variance. In the absence of MgSO(4), IL 6 levels in the maternal and the fetal circulations of preeclamptic placentas (4.2 +/- 1.3 and 0.9 +/- 0.5 pg/mL/g cotyledon; respectively) were significantly higher, when compared with normotensive placentas (1.9 +/- 0.5 and 0.2 +/- 0.2 pg/mL/g cotyledon; respectively) (P < 0.05). Addition of MgSO(4) to the perfusate of normotensive placentas did not affect IL-6 secretion. However, exposure of preeclamptic placentas to MgSO(4) resulted in decreased IL-6 levels in the maternal circulations (1.7 +/- 0.3 pg/mL/g cotyledon), when compared with the control group (P < 0.05). In the fetal circulation, the addition of MgSO(4) resulted only in a nonstatistical significant tendency toward decreased IL-6 levels, when compared with the control group. Our findings indicate that the perfused preeclamptic placenta secretes increased levels of IL-6 into the fetal and the maternal circulations and that MgSO(4) may normalize these increased secreted IL-6 levels. PMID- 20715975 TI - Clinical outcomes of carbapenem-resistant Acinetobacter baumannii bloodstream infections: study of a 2-state monoclonal outbreak. AB - OBJECTIVE: To characterize the clinical outcomes of patients with bloodstream infection caused by carbapenem-resistant Acinetobacter baumannii during a 2-state monoclonal outbreak. DESIGN: Multicenter observational study. Setting. Four tertiary care hospitals and 1 long-term acute care hospital. METHODS: A retrospective medical chart review was conducted for all consecutive patients during the period January 1, 2005, through April 30, 2006, for whom 1 or more blood cultures yielded carbapenem-resistant A. baumannii. RESULTS: We identified 86 patients from the 16-month study period. Their mortality rate was 41%; of the 35 patients who died, one-third (13) had positive blood culture results for carbapenem-resistant A. baumannii at the time of death. Risk factors associated with mortality were intensive care unit stay, malignancy, and presence of fever and/or hypotension at the time blood sample for culture was obtained. Only 5 patients received adequate empirical antibiotic treatment, but the choice of treatment did not affect mortality. Fifty-seven patients (66.2%) had a single positive blood culture result for carbapenem-resistant A. baumannii; the only factor associated with a single positive blood culture result was the presence of decubitus ulcers. Interestingly, during the study period, a transition from single to multiple positive blood culture results was observed. Four patients, 3 of whom were in a burn intensive care unit, were bacteremic for more than 30 days (range, 36-86 days). CONCLUSIONS: To our knowledge, this is the first time a study has described 2 patterns of bloodstream infection with A. baumannii: single versus multiple positive blood culture results, as well as a subset of patients with prolonged bacteremia. PMID- 20715977 TI - The ACCORD LIPID trial. PMID- 20715976 TI - Integrated role of two apoliprotein E polymorphisms on apolipoprotein B levels and coronary artery disease in a biethnic population. AB - BACKGROUND: Apolipoprotein E (ApoE) plays a major role in lipoprotein metabolism and genetic variability of ApoE confers susceptibility to coronary artery disease (CAD). Beyond variability in the coding region, promoter polymorphisms in the ApoE gene impact on ApoE transcription. METHODS: We determined the ApoE - 491 A/T promoter polymorphism, ApoE isoforms, lipid and lipoprotein levels, and CAD risk factors in 313 Caucasians and 215 African Americans. RESULTS: Caucasians had a lower ApoE T allele frequency compared to African Americans (18.1% vs. 32.3%, P < 0.05). Among T/* carriers, ApoB levels were significantly lower in Caucasians, but significantly higher among African Americans, in both cases compared to A/A homozygotes (P = 0.017, and P = 0.012). For a given -491A/T genotype, levels of atherogenic lipoproteins differed across ApoE2/E3/E4 isoforms among African Americans, but not Caucasians, as T/* carriers with ApoE4 had significantly higher ApoB levels compared to T/* carriers with ApoE2 (P = 0.010). Among patients with CAD, Caucasian A/A homozygotes and African American T/* carriers had higher ApoB levels compared to the same genotype without CAD (P = 0.007, P = 0.049, respectively). CONCLUSIONS: We observed an ethnicity-specific variability in ApoB levels across the ApoE - 491 A/T polymorphism and a modulatory impact on this pattern by ApoE2/E3/E4 isoforms. PMID- 20715978 TI - Applying principles from complex systems to studying the efficacy of CAM therapies. AB - In October 2007, a National Center for Complementary and Alternative Medicine (NCCAM)-sponsored workshop, entitled "Applying Principles from Complex Systems to Studying the Efficacy of CAM Therapies," was held at Georgetown University in Washington, DC. Over a 2-day period, the workshop engaged a small group of experts from the fields of complementary and alternative medicine (CAM) research and complexity science to discuss and examine ways in which complexity science can be applied to CAM research. After didactic presentations and small-group discussions, a number of salient themes and ideas emerged. This paper article describes the workshop program and summarizes these emergent ideas, which are divided into five broad categories: (1) introduction to complexity; (2) challenges to CAM research; (3) applications of complexity science to CAM; (4) CAM as a model of complexity applied to medicine; and (5) future directions. This discusses possible benefits and challenges associated with applying complexity science to CAM research. By providing an introductory framework for this collaboration and exchange, it is hoped that this article may stimulate further inquiry into this largely unexplored area of research. PMID- 20715979 TI - Brief stress-reduction training in an academic health center. PMID- 20715980 TI - Increased poly(ADP-ribose) polymerase (PARP)-1 expression and activity are associated with inflammation but not goblet cell metaplasia in murine models of allergen-induced airway inflammation. AB - Inflammation plays a key role in lung injury and in the pathogenesis of asthma. Two murine models of allergic airway inflammation-sensitization and challenge to ovalbumin (OVA) and intratracheal exposure to interleukin-13 (IL13)-were used to evaluate the expression of poly(ADP-ribose) polymerase-1 (PARP-1) in allergic airway inflammation. Inflammation is prominent in OVA-induced allergic asthma, but this inflammation is greatly reduced by a PARP-1 inhibitor and almost eliminated when PARP-1 knockout mice are subjected to the OVA model. The present study temporally evaluated PARP-1 protein expression, localization, and activity, as well as inflammation and goblet cell metaplasia (GCM), in murine lungs following a single OVA challenge or IL13 exposure. Following OVA challenge PARP-1 protein expression and activity were greatly increased, being maximal at 3 to 5 days following OVA exposure and beginning to decrease by day 8. These changes correlated with the timing and degree of inflammation and GCM. In contrast, PARP 1 protein or activity did not change following single IL13 exposure, though GCM was manifested without inflammation. This study demonstrates that both PARP-1 protein and activity are increased by allergen-activated inflammatory mediators, excluding IL13, and that PARP-1 increase does not appear necessary for GCM, one of the characteristic markers of allergic airway inflammation in murine models. PMID- 20715981 TI - Increased synthesis of vascular endothelial growth factor in allergic airway inflammation in histidine decarboxylase knockout (HDC(-/-)) mice. AB - Histamine and vascular endothelial growth factor (VEGF) have been implicated in the pathogenesis of allergic asthma; they enhance inflammation, vascular permeability, and mucus secretion. Histamine was suggested to alter the level of VEGF via the H2 receptors. Here the authors have applied histidine decarboxylase gene-targeted (HDC(-/-)) mice, lacking histamine, to investigate the effect of histamine deficiency on VEGF expression in an animal model of asthma. HDC(-/-) and wild-type (WT) mice were sensitized and challenged with ovalbumin (OVA). VEGF mRNA expression and protein level were determined in the lung. Number of VEGF positive immune cells of bronchoalveolar lavage (BAL) and their intracellular VEGF content were measured by flow cytometry. VEGF protein level in the lung and in the BAL cells was increased in OVA treated (HDC(-/-)(ova) as well as in WT(ova)) animals compared to their controls. However, there was no difference in the VEGF levels between HDC(-/-) or WT animals, either in the lung or in the BAL cells. In conclusion, increased VEGF production of the lung or BAL immune cells can be induced by allergen provocation independently from the genetic background of the animals. These data suggest that VEGF-mediated allergic processes can persist in the absence of histamine. PMID- 20715983 TI - Differential effects of human neutrophil peptide-1 on growth factor and interleukin-8 production by human lung fibroblasts and epithelial cells. AB - alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of lung diseases, including idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and diffuse panbronchiolitis (DPB). In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in IPF and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to IPF, CF, and DPB. alpha-Defensins are known to induce interleukin (IL)-8 in airway epithelial cells, but the effects of alpha defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide (HNP)-1 (a subtype of alpha-defensin) on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of IPF, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced. PMID- 20715984 TI - Surfactant protein-A reduces translocation of mediators from the lung into the circulation. AB - The objective of this study was to characterize a mouse model of lung inflammation and determine the effect of surfactant protein A (SP-A, or sftpa) on the transfer of inflammatory mediators from these injured lungs into the systemic circulation. Lung inflammation was induced in either sftpa-deficient (-/-) or wild-type (+/+) spontaneously breathing, adult mice via intranasal lipopolysaccharide (LPS). Four hours later, lungs were isolated, perfused, and mechanically ventilated for 2 hours. Perfusate was collected for analysis over the duration of ventilation and lung lavage was obtained in groups of animals immediately before and after mechanical ventilation (MV). Lavage analysis showed an increase in interleukin-6 (IL6) and tumor necrosis factor-alpha (TNFalpha) 4 hours after LPS, with a further increase in IL6 following MV. LPS and MV also caused an increase in total cell and neutrophil numbers as well as total protein in the lavage compared to controls. Perfusate analysis revealed a significant increase in IL6 and TNFalpha after LPS and MV, with significantly greater levels of these mediators in sftpa (-/-) versus (+/+) mice. The authors conclude that LPS followed by MV resulted in lung inflammation and injury, and that SP-A significantly influenced inflammatory mediator release from these inflamed lungs into the perfusate. PMID- 20715982 TI - Evidence for in vivo nicotine-induced alveolar interstitial fibroblast-to myofibroblast transdifferentiation. AB - Nicotine exposure alters normal homeostatic pulmonary epithelial-mesenchymal paracrine signaling pathways, resulting in alveolar interstitial fibroblast (AIF) to-myofibroblast (MYF) transdifferentiation. Though this has been described under in vitro conditions, it is not known if the same phenomenon also takes place in vivo. A well-established rodent model of lung damage following perinatal nicotine exposure was used. By probing for the well-established markers of fibroblast differentiation (parathyroid hormone-related protein [PTHrP], peroxisome proliferator-activated receptor gamma [PPARgamma], adipocyte differentiation related protein, alpha-smooth muscle actin, and fibronectin) at the mRNA, protein, and tissue levels, the authors provide the first in vivo evidence for nicotine-induced AIF-to-MYF transdifferentiation. In addition, these data also provide the first evidence for nicotine-induced up-regulation of Wnt signaling, accompanying the down-regulation of PTHrP/PPARgamma signaling in vivo following nicotine exposure during pregnancy. These data provide an integrated mechanism for in utero nicotine-induced lung damage and how it could permanently alter the "developmental program" of the developing lung by disrupting critically important epithelial-mesenchymal interactions. More importantly, these data are likely to provide specific interventions to augment the pulmonary mesenchymal lipogenic pathway to ameliorate nicotine-induced in utero lung injury. PMID- 20715985 TI - Identification of a human monoclonal natural IgM antibody that recognizes early apoptotic cells and promotes phagocytosis. AB - Efficient clearance of cells undergoing apoptotic death is crucial for normal tissue homeostasis and for the prevention of autoimmunity. Engulfment of apoptotic cells is finely regulated by a highly redundant system of receptors and bridging molecules. We developed a rapid and efficient method for the identification of human natural IgM antibodies and isolated some natural human monoclonal IgM antibodies specific to the apoptotic cells. Among them, AC34 IgM bound to early apoptotic cells and promoted phagocytosis of apoptotic Jurkat cells by human monocyte-derived macrophage (HMDM). AC34 IgM recognized phosphatidylserine (PS), which means PS might be a possible molecule recognized by AC34 IgM on the surface of apoptotic cells and AC34 IgM might be a possible candidate of bridging molecules between the PS and phagocytes. The sequences of V(H) and V(L) of AC34 were almost the same with their germline counterpart. Our experiments suggest a role of natural IgM as an opsonin in the clearance of early apoptotic cells. PMID- 20715986 TI - Prokaryotic expression of Stx1B subunit of Escherichia coli O157:H7 used to generate monoclonal antibody. AB - The Shiga-like toxins (Stx) are critical virulence factors for enterohemorrhagic Escherichia coli (EHEC), causing severe human illnesses of bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). A subunit of Stx, Stx1B protein, mediates the interaction between EHEC and the specific receptor of host organs. In this article, the recombinant expression vector pGEX-Stx1B bearing a signal peptide sequence-deleted Stx1B gene was constructed and the expression of protein of interest was achieved in a prokaryotic system. The resulting Stx1B protein was used to immunize BALB/c mice followed by the preparation of corresponding monoclonal antibodies (MAbs). One MAb (1G11) was generated. Western blot analysis showed that the MAb was capable of reacting with EHEC Stx1B protein. It had high affinity binding to the Stx1B protein and it distinguished EHEC from other control bacteria. Therefore, the MAb generated in this study can be used as a specific reagent to investigate the pathogenesis mechanism and to develop a diagnostic method of EHEC infection in both humans and animals. PMID- 20715987 TI - Development of a class-specific immunochromatographic strip test for the rapid detection of organophosphorus pesticides with a thiophosphate group. AB - In recent decades, organophosphorus (OP) pesticides are widely used in agricultural and domestic fields. There is increasing demand for more rapid and economical methods of detecting pesticide residues. We have developed a gold immunochromatography assay (GICA) strip test for detecting a group of OP pesticides based on monoclonal antibodies (MAb) against a generic hapten, O,O diethyl O-(4-carboxy-3-methylphenyl) phosphorothioate. The MAb showed desirable properties for use in indirect competitive ELISA, and the minimum IC50 value (93 ng/mL) was observed in chlorpyrifos-ethyl curve. The partially purified monoclonal antibodies were conjugated with colloidal gold particles. The conjugation of the colloidal gold and antibodies was monitored by ultraviolet visible (UV-vis) spectroscopy and fluorescence spectroscopy, while the transmission electron microscopy (TEM) images were used to characterize the particle size and shape of the conjugates. Dynamic light scattering (DLC) was applied as a less expensive and faster method to substitute TEM. The colloidal gold and antibody conjugates were used for the production of a GICA strip test to detect OP pesticides. Preliminary assessment suggests that the OP pesticide, chlorpyrifos-ethyl (CE), in environmental samples could be detected by the GICA strip. This assay could potentially be used for screening large volume of samples and on-spot monitoring before the precise analysis. But the homogeneity of the detection needs to be improved further. PMID- 20715988 TI - Anti-human CD133 monoclonal antibody that could inhibit the proliferation of colorectal cancer cells. AB - CD133, a five-transmembrane molecule, has been found on many types of cancers and determined to be a cancer stem cell biomarker. In this study a functional anti human CD133 MAb 6B6 was obtained, and the specificity of this MAb was verified by flow cytometry. This MAb effectively recognized the CD133 molecule expressed on a series of malignant cell lines. Immunohistochemistry staining showed the CD133 was expressed on colorectal tumor tissue. Furthermore, we demonstrated that MAb 6B6 could inhibit the proliferation of Caco-2 cells that were derived from a human colorectal carcinoma. This functional anti-human CD133 MAb provides a valuable tool for further study of biological functions of cancer stem cell that expressed CD133. PMID- 20715989 TI - Polyclonal and monoclonal antibodies specific for USP17, a proapoptotic deubiquitinating enzyme. AB - USP17, a deubiquitinating enzyme (DUB), belongs to the ubiquitin-specific protease protein family. USP17 has highly conserved Cys, His, and Asp domains responsible for the deubiquitinating activity, and two hyaluronan binding motifs in its sequence. We reported that the presence of hyaluronan binding motifs in USP17 is responsible for the cell viability of cancerous cells. Although many if not all of the DUBs contain hyaluronan binding motifs in its sequence, the actual mechanism of hyaluronan binding motifs regulating signal transduction remains unclear. USP17 also regulates Ras activation and cell proliferation by inhibiting RCE1 activity. Thus USP17 may have a critical role in regulating tumor pathway through its deubiquitinating activity on various tumor-related proteins. This study reports the generation and characterization of polyclonal and six monoclonal antibodies against USP17 through immunoblotting, immunoprecipitation, and immunofluorescence microscopy analyses. These antibodies of USP17 will be useful as tools to investigate the mechanism of hyaluronan-mediated tumor suppression and also to screen interacting oncogenic substrates by immunoprecipitation assay. PMID- 20715990 TI - Monoclonal antibodies against the PB1-F2 protein of H1N1 influenza A virus. AB - In this report we describe the generation of a mouse monoclonal antibody (MAb) against the influenza A virus PB1-F2 protein that is derived from a +1 reading frame of the polymerase basic protein (PB1) gene segment. We further present data that the hybridoma subclone F2-6G10 produces antibodies that specifically recognize the PB1-F2 protein of H1N1 influenza virus types only. The antibody can be used for immunodetection of the PB1-F2 protein in ELISA, Western blot, immunoprecipitation, and immunofluorescence assays. PMID- 20715991 TI - Generation of monoclonal antibodies against recombinant AtSIZ1. AB - Post-translational modifications of target proteins by small ubiquitin-like modifier (SUMO) proteins modulate many cellular processes in yeast and animals. Here we present the development of monoclonal antibodies (MAb) and polyclonal antibodies (PAb) against Arabidopsis SIZ1 (AtSIZ1) protein with high specificity. Mice were immunized with recombinant AtSIZ1 protein for generating monoclonal antibodies via the classic hybridoma production technique. Anti-AtSIZ1 MAb and PAb were able to detect endogenous AtSIZ1 in Arabidopsis wild type and its complementary line formed by transforming C-siz1-2 mutant with construct containing the AtSIZ1 gene under the control of the native promoter, but not the siz1-2 deletion mutant. These results show that these anti-AtSIZ MAbs are highly sensitive to detect endogenous AtSIZ1 and can be used for immunoblotting and other experimental methods. The new anti-AtSIZ1 MAbs will be essential tools used to investigate the role of AtSIZ1 in plant developmental biology. PMID- 20715992 TI - Upregulation of PPARgamma in tissue with gastric carcinoma. AB - Here we have for the first time investigated the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in chronic gastritis, gastric mucosal dysplasia, and gastric carcinoma. Avidin-biotin peroxidase complex immunohistochemical methods were adopted to examine the expression of PPARgamma in 53 patients with gastric carcinoma, 18 with gastric mucosal dysplasia, 30 with chronic atrophic gastritis, and 31 with chronic non-atrophic gastritis. The positive rate of PPARgamma was 41.5% in gastric carcinoma, 27.8% in gastric mucosal dysplasia, 10.0% in chronic atrophic gastritis, and 6.5% in chronic non atrophic gastritis, respectively. Compared with those in chronic gastritis, expression of PPARgamma in gastric mucosal dysplasia and gastric carcinoma was significantly enhanced (p < 0.05). In gastric carcinoma, expression of PPARgamma was not associated with tumor cell differentiation and metastasis to lymph nodes (p > 0.05). Taken together, overexpression of PPARgamma was apparent in human gastric cancer, which might be an early event in carcinogenesis. PMID- 20715993 TI - Production and characterization of a monoclonal antibody against spike protein of transmissible gastroenteritis virus. AB - Transmissible gastroenteritis virus (TGEV) is a member of coronaviruses. The viral spike (S) protein mediates the interaction between TGEV and its susceptible cells. Here, we expressed a truncated gene encoding the N terminal half of TGEV S gene (designated S1 gene) in a prokaryotic system. The resulting S1 protein was used to immunize BALB/c mice followed by the generation of a monoclonal antibody (MAb). A generated MAb (7F9) was identified by ELISA and the chromosome number of the hybridoma cell was analyzed. The immunoreactivity of the MAb to TGEV S protein was confirmed by Western blot analysis. Moreover, immunofluorescence assays showed that the MAb is able to detect cell infection by TGEV. The MAb achieved in this study can be used as a specific diagnostic reagent for detecting TGEV S protein. PMID- 20715994 TI - Preparation of a novel monoclonal antibody specific to DARPP-32. AB - DARPP-32 (dopamine and cAMP-regulated phosphoprotein) is the bifunctional protein that can act as a PP1 inhibitor or a PKA inhibitor. Here we have for the first time generated a monoclonal antibody against DARPP-32. Enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting were used to screen the hybridomas. As a result, one MAb named Y8 (IgG1) was characterized, which bound to the native DARPP-32 protein. Then the MAb was used to detect the expression of DARPP-32 in gastric cancer cells and tissues. DARPP-32 was found to be downregulated in multidrug-resistant gastric cancer cells compared with drug sensitive cells. DARPP-32 was also found to be upregulated in poorly differentiated gastric cancer tissues compared with well-differentiated and moderately differentiated gastric tissues. The results showed that DARPP-32 might play an important role in carcinogenesis and multidrug resistance of gastric cancer. PMID- 20715995 TI - MAb L9E10 to blood group H2 antigen binds to colon cancer stem cells and inhibits tumor cell migration and invasion. AB - The functions of the precursor H antigen for ABO blood group antigens are still not fully understood, particularly in cancer cells. In this study, we used hybridoma technology and NSY human colon cancer cells as an immunogen to generate a monoclonal antibody designated as MAb L9E10. The binding antigen of MAb L9E10 was identified as blood group (BG) H2 antigen using carbohydrate array and erythrocyte agglutination assays. In immunofluorescence study, we found that BG H2 was expressed on the surfaces of both colon cancer stem cells and their differentiated progeny. In a functional study, we observed that MAb L9E10 inhibited tumor cell migration and invasion at a concentration of 10 microg/mL in vitro. This result suggests that MAb L9E10 could be used to study cancer biology, particularly cancer stem cell biology. In addition, it is potentially useful for studying gastric diseases caused by Helicobacter pylori bacteria, with attachment to human gastric epithelial cells mediated by blood group antigens Lewis b and H2. Finally, MAb L9E10 is an ideal biological reagent for identifying Bombay blood type in which erythrocytes have no BG-H2 antigen expression. PMID- 20715996 TI - Synthetic peptide coupled to KLH elicits antibodies against beta8 integrin. AB - The beta8 integrin, which forms alphavbeta8 heterodimers, is being widely investigated because of its specific structure and functions compared with other integrins. In this report, a 12 aa-long peptide of beta8 integrin cytoplasmic domain was synthesized according to a published sequence and covalently coupled to keyhole limpet hemocyanin (KLH). Three stable strains of hybridomas (3G6, 5C7, 5H3) that can secrete high specific monoclonal antibodies against beta8 integrin were successfully established by hybridoma technique. The isotypes of these MAbs were tested to be IgG2a. Their characterizations were shown by enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and immunocytochemistry (ICC). The affinity constants (Kaff ) of the MAbs 3G6, 5C7, and 5H3 were measured by non-competitive ELISA respectively. Western blot analyses and immunocytochemistry demonstrated that all the MAbs were directed against beta8 integrin with high specificity. PMID- 20715997 TI - Method for umbilical cord blood-derived basophils by FCM. AB - We have devised a method for the purification of human basophils from umbilical cord blood by FCM. Umbilical cord blood was collected from six healthy, full-term deliveries. After separation of red blood cells, mononuclear cells were isolated by Ficoll-Hypaque. Six samples followed by positive selection using flowcytometry (FCM) for CD203c(+)CD45(int+) cells. Purity and recovery of cells were measured. Purity and recovery of basophils by FCM with CD203c(+)CD45(int+) markers were 95.02 +/- 2.94% and 61.42 +/- 5.95%. Cell sorting for CD203c(+)CD45(int+) cells by FCM is an improved method for obtaining pure umbilical cord blood-derived basophils. We established cord blood-derived basophil purification technique as a source from which active basophils can be isolated for immunochemical characterization. PMID- 20716008 TI - Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease. AB - PURPOSE: The authors describe 2 cases of orbital xanthogranulomatous disease associated with an increase in IgG4-positive plasma cells, and also examine IgG4 in other types of orbital inflammation. METHODS: Immunohistochemistry for total IgG and IgG4 was performed in 18 cases of orbital inflammation, including chronic dacryoadenitis (n=10), necrobiotic xanthogranuloma (n=2), xanthogranuloma (n=1), idiopathic orbital inflammation/pseudotumor (n=4), and fungal infection (n=1). RESULTS: One patient presenting with necrobiotic xanthogranuloma had signs of systemic IgG4 disease. His orbital lesion showed an elevated number of IgG4 positive plasma cells (55%). An orbital xanthogranulomatous lesion in a second patient lacking systemic symptoms also contained a high percentage of IgG4 positive plasma cells (80%). Only 1 case of chronic dacryoadenitis contained prominent IgG4-positive plasma cells (mean 17/hpf). CONCLUSIONS: IgG4-positive plasma cells are relatively rare in nonsclerosing orbital inflammatory lesions. However, systemic disease IgG4 can be associated with necrobiotic xanthogranuloma of the orbit. PMID- 20716009 TI - Comparison of emulsion and vibration nozzle methods for microencapsulation of laccase and glucose oxidase by interfacial reticulation of poly(ethyleneimine). AB - Microcapsules for enzyme immobilization were successfully fabricated via interfacial cross-linking of poly(ethyleneimine) (PEI). A method based on laminar jet break-up technique using a commercial instrument developed to produce alginate beads is reported for the first time for production of PEI microcapsules. The diameter, wall thickness and pore size of membranes were obtained from confocal laser scanning microscopy by labelling PEI and proteins. The composition of membranes was analysed by elemental analysis. Larger microcapsules (ca 200 um diameter) were obtained with the encapsulation device. In comparison, the emulsion method produced smaller capsules (ca 20 um diameter) but with a wider size distribution. Encapsulation efficiency for both methods was analysed by bicinchoninic acid and fluorescence assays, yielding efficiencies of 94 +/- 2% and 83 +/- 3% for the emulsion method and encapsulation device, respectively. Glucose oxidase from Aspergillus Niger and Laccase from Trametes Versicolor were encapsulated by both microencapsulation methods and their activities were compared. PMID- 20716010 TI - Statistical methods for assessment of added usefulness of new biomarkers. AB - The discovery and development of new biomarkers continues to be an exciting and promising field. Improvement in prediction of risk of developing disease is one of the key motivations in these pursuits. Appropriate statistical measures are necessary for drawing meaningful conclusions about the clinical usefulness of these new markers. In this review, we present several novel metrics proposed to serve this purpose. We use reclassification tables constructed on the basis of clinically meaningful disease risk categories to discuss the concepts of calibration, risk separation, risk discrimination, and risk classification accuracy. We discuss the notion that the net reclassification improvement (NRI) is a simple yet informative way to summarize information contained in risk reclassification tables. In the absence of meaningful risk categories, we suggest a 'category-less' version of the NRI and integrated discrimination improvement as metrics to summarize the incremental value of new biomarkers. We also suggest that predictiveness curves be preferred to receiver operating characteristic curves as visual descriptors of a statistical model's ability to separate predicted probabilities of disease events. Reporting of standard metrics, including measures of relative risk and the c statistic, is still recommended. These concepts are illustrated with a risk prediction example using data from the Framingham Heart Study. PMID- 20716011 TI - Biomarkers for early detection of mesothelioma in asbestos-exposed subjects. PMID- 20716012 TI - The use of serial patient blood gas, electrolyte and glucose results to derive biologic variation: a new tool to assess the acceptability of intensive care unit testing. AB - BACKGROUND: Most estimates of biologic variation (s(b)) are based on periodically acquiring and storing specimens, followed by analysis within a single analytic run. We demonstrate for many intensive care unit (ICU) tests, only patient results need be statistically analyzed to provide reliable estimates of s(b). METHODS: Over 11 months, approximately 28,000 blood gas measurements (including electrolyte panels and glucose) were performed on one of two Radiometer ABL800 FLEX analyzers (Radiometer, Copenhagen, Denmark) from 1676 ICU patients. We tabulated the measurements of paired intra-patient blood samples drawn within 24 h of each other. After removal of outliers, we calculated the standard deviations of duplicates (SDD) of the intra-patient pairs grouped in 2-h intervals: 0-2 h, 2 4 h, 4-6 h, ... 20-22 h and 22-24 h. The SDDs were then regressed against the time intervals of 2-14 h; extrapolation to zero time represents the sum of s(b) and short-term analytic variation (s(a)). RESULTS: Substitution of experimentally derived analytic error permitted the calculation of coefficient of variation (biologic) (CV(b)) (100 s(b)/mean): pH, 0.3%; pCO(2), 5.7%; pO(2), 13%; Na(+), 0.6%; K(+), 4.8%; Cl(-), 0.8%; HCO(3)(-), 3.2%; iCa(++), 2.4%; and glucose, 10.3%. The CV(b) of the electrolytes very closely matches the lowest estimates obtained in the usual manner. CONCLUSIONS: Derivation of the ratio of biologic to analytic variation indicates that the ABL800 is extremely suitable for ICU testing. This analysis should be extended to other point of care instrument systems. PMID- 20716013 TI - Quantification of airborne Aspergillus allergens: redefining the approach. AB - BACKGROUND: Airborne Aspergillus species are significant environmental components involved in the pathogenesis and persistence of allergic respiratory diseases. The detection and quantification of airborne allergens is important to elucidate the clinical implications of environmental exposure of patients suffering with allergic asthma and/or allergic rhinitis. OBJECTIVE: The authors report a simple volumetric approach to measure atmospheric concentration of four common airborne species of Aspergillus-A. flavus, A. fumigatus, A. niger, and A. tamarii. METHODS: As particulate aeroallergens may also exist in amorphous form in addition to morphologically identifiable fungal spores/hyphae, a volumetric technique using membrane filters was developed for simultaneous quantification of (a) viable Aspergillus counts, i.e., colony-forming units (cfu)/m(3), and (b) actual Aspergillus allergen content (ng/m(3)) in the air. Further, immunochemically quantified airborne Aspergillus allergens were compared with their corresponding colony counts. RESULTS: The average monthly aerial counts of the four Aspergillus species recorded during the sampling year were A. flavus: 0.25-15.2 cfu/m(3); A. fumigatus: 1.25-15.6 cfu/m(3); A. niger: 0.75-16.0 cfu/m(3); and A. tamarii: 0.5-11.8 cfu/m(3) of air. Aerial Aspergillus allergen(s) concentration varied from species to species: A. flavus: 26.8-680.8 ng; A. fumigatus: 18.0-380.4 ng; A. niger: 28.2-1879.0 ng; and A. tamarii: 9.2 238.3 ng/m(3) of air. Seasonal distribution of airborne colony counts of the four species didn't correlate with their respective allergen content. CONCLUSION: Aspergillus allergens were present in the air of Delhi area throughout the year with seasonal variations. The authors feel that by using the immunochemical technique it will be possible to measure actual exposure of patients to various airborne Aspergillus allergens. PMID- 20716014 TI - A randomized controlled trial of an interactive voice response telephone system and specialist nurse support for childhood asthma management. AB - OBJECTIVES: To evaluate the effects of an automated interactive voice response system (IVR) and Specialist Nurse Support to reduce health care utilization and improve health-related quality of life in children with asthma. STUDY DESIGN: A randomized controlled trial in 121 children with doctor-diagnosed asthma and an acute presentation with asthma in the previous 12 months aged between 3 and 16 years. Children were randomized to one of three groups for a 6-month intervention receiving asthma education and management support from a Specialist Nurse by telephone or e-mail (N = 41), from IVR (N = 39), or receiving usual care (control group; N = 41). Outcomes included health care utilization and use of oral steroid rescue. Health-related quality of life (HRQOL) data using the Pediatric Asthma Quality of Life Questionnaire and Pediatric Quality of Life Inventory were collected at baseline and at the end of the study. RESULTS: There was no statistically significant benefit identified for either the IVR or the Nurse Support interventions for health care utilization, use of oral steroid rescue, or HRQOL compared with controls. Relative to controls, the incremental costs were A$225.73 (95% confidence interval [CI]: -A$840, A$391) per child for the Nurse Support intervention and -A$451.45 (-A$1075, A$173) per child for IVR. The results were most sensitive to the frequency of admissions to hospital. CONCLUSION: This study suggested that both IVR and Nurse Support interventions may be cost-saving from a health system perspective, with IVR providing the greatest benefit and this pilot study provides a strong basis for developing larger trials with longer follow-up. PMID- 20716015 TI - Exposure to indoor biomass fuel pollutants and asthma prevalence in Southeastern Kentucky: results from the Burden of Lung Disease (BOLD) study. AB - BACKGROUND: Asthma is a chronic inflammatory respiratory disease, characterized by episodic and reversible airflow obstruction and airway hyperresponsiveness and is influenced by both genetic and environmental factors. METHODS: The Burden of Obstructive Lung Disease (BOLD) survey was used to determine the prevalence of self-reported asthma in a target population of 325,000 adults aged > or =40 in Southeastern Kentucky. Postbronchodilator spirometry was used to classify subjects based on lung function. Risk factors for asthma in this population, in particular indoor usage of biomass fuels, were evaluated. RESULTS: The overall study population was comprised of 508 individuals, with 15.5% reporting current asthma and 5.8% reporting former asthma. In this population, the following risk factors for asthma were identified: female sex, smoking, less than a high school education, increasing body mass index (BMI), and a history of cooking indoors with coal and wood. Cooking indoors with wood and coal for more than 6 months of one's life was shown to significantly increase the odds of reporting current asthma (odds ratio (OR) = 2.3, confidence interval (CI) 1.1, 5.0), whereas no effect was seen from a history of heating indoors with wood and coal (OR = 0.8, CI 0.4, 1.8). CONCLUSIONS: Current or former asthma was reported by 21.3% of the adult population. A history of using biomass fuels when cooking indoors significantly increased the risk of reporting current asthma in this population. PMID- 20716016 TI - Emerging trend in nano-engineered polyelectrolyte-based surrogate carriers for delivery of bioactives. AB - IMPORTANCE OF THE FIELD: In recent decades a new colloidal drug delivery system based on layer-by-layer (LbL) technology has emerged, which offers promising means of delivering bioactive agents, specifically biological macromolecules including peptides and DNA. Nano-engineered capsules specifically fabricated from biocompatible and biodegradable polyelectrolytes (PEs) can provide a better option for encapsulation of cells thereby protecting cells from immunological molecules in the body, and their selective permeability can ensure the survival of encapsulated cells. AREAS COVERED IN THIS REVIEW: This review encompasses a strategic approach to fabricate nano-engineered microcapsules through meticulous selection of polyelectrolytes and core materials based on LbL technology. The content of the article provides evidence for its wide array of applications in medical therapeutics, as indicated by the quantity of research and patents in this area. Recent developments and approaches for tuning drug release, biocompatibility and cellular interaction are discussed thoroughly. WHAT THE READER WILL GAIN: This review aims to provide an overview on the development of LbL capsules with specific orientation towards drug and macromolecular delivery and its integration with other drug delivery systems, such as liposomes. TAKE HOME MESSAGE: Selection of PEs for the fabrication of LbL microcapsules has a profound effect on stability, drug release, biocompatibility and encapsulation efficacy. The release can be easily modulated by varying different physicochemical as well as physiological conditions. Scale-up approaches for the fabrication of LbL microcapsules by means of automation must be considered to improve the possibility of application of LbL microcapsules on a large scale. PMID- 20716017 TI - Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery. AB - IMPORTANCE OF THE FIELD: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous 'zero premature release' property. AREAS COVERED IN THIS REVIEW: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed. WHAT THE READER WILL GAIN: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices. TAKE HOME MESSAGE: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery. PMID- 20716018 TI - Interest of glycolipids in drug delivery: from physicochemical properties to drug targeting. AB - IMPORTANCE OF THE FIELD: The need for new products derived from natural sources for the replacement of the commonly used non-ionic surfactants containing ethylene oxide units with degradable carbohydrate headgroups has become an important area of research. Glycolipids offer a wide range of applications in the pharmaceutical and cosmetic fields and can compete with the most commonly used surfactants. Involved in molecular recognition mechanisms at the surface of cells, glycolipids are also used for drug targeting. AREAS COVERED IN THIS REVIEW: The structure and pharmaceutical applications of the main glycolipid categories are summarized. The review focuses on marketed glycolipids, biosurfactants and compounds developed at laboratory scale for applications such as self-assembly or drug targeting. WHAT THE READER WILL GAIN: This article aims to provide an overview of the different sugar-based surfactant classes and their potential uses. TAKE HOME MESSAGE: Beside their use as surfactants or absorption enhancers in basic formulations, glycolipids can build gels, niosomes, hexosomes and cubosomes, whose structure is directly related to lyotropic properties. These systems allow solubilization and entrapment of drugs. In innovative delivery systems, glycolipids are also used for drug targeting because their sugar moieties can be specifically recognized by carbohydrate-binding proteins exposed at the surface of cells. PMID- 20716020 TI - Update on non-viral delivery methods for cancer therapy: possibilities of a drug delivery system with anticancer activities beyond delivery as a new therapeutic tool. AB - IMPORTANCE OF THE FIELD: Cancer is the most formidable human disease. Owing to the heterogeneity of cancer, a single-treatment modality is insufficient for the complete elimination of cancer cells. Therapeutic strategies from various aspects are needed for cancer therapy. These therapeutic agents should be carefully selected to enhance multiple therapeutic pathways. Non-viral delivery methods have been utilized to enhance the tumor-selective delivery of therapeutic molecules, including proteins, synthetic oligonucleotides, small compounds and genes. AREAS COVERED IN THIS REVIEW: As non-viral delivery methods, liposomes and polymer-based delivery materials to target tumors mainly by systemic delivery, physical methods including electroporation, sonoporation, and so on, to locally inject therapeutic molecules, and virosomes to use the viral infectious machinery for the delivery of therapeutic molecules are summarized. WHAT THE READER WILL GAIN: This article aims to provide an overview of the characteristic properties of each non-viral vector. It will be beneficial to utilize appropriately the vector for cancer treatment. TAKE HOME MESSAGE: Efficient and minimally invasive vectors are generally considered to be the ideal drug delivery system (DDS). However, against cancer, DDS equipped with antitumor activities may be a therapeutic choice. By combining therapeutic molecules with DDS having antitumor activities, enhancement of the multiple therapeutic pathways may be achieved. PMID- 20716021 TI - Clinical studies assessing immunogenicity and safety of intradermally administered influenza vaccines. AB - IMPORTANCE OF THE FIELD: Human influenza A and B are major respiratory pathogens and cause high mortality and severe morbidity, especially in at-risk populations. Most of the vaccines are administered intramusculary or subcutaneously. Owing to vaccine shortage and low vaccine coverage, intradermal administration of vaccines has gained renewed interest. In addition, higher immune responses with the same quantity of antigen have been elicited with intradermal vaccine administration, offering dose-sparing capacity. AREAS COVERED IN THIS REVIEW: This review summarizes the immunogenicity and safety data accumulated from influenza vaccine trials where vaccines were administered intradermally. Clinical trials performed using reduced vaccine antigen doses in healthy volunteers or in at-risk populations and target groups are discussed as well as new devices for intradermal delivery of influenza vaccines. The studies addressed in this review were identified through a MEDLINE search. WHAT THE READER WILL GAIN: The review provides insights into the potential of intradermal vaccines to overcome hurdles such as vaccine shortage in view of mass vaccination campaigns. Moreover, evidence is provided of improved immunological responses after intradermal vaccination when new intradermal devices are being used. TAKE HOME MESSAGE: In the authors' opinion, intradermal vaccination can be considered an equally immunogenic, safe and feasible alternative to intramuscular and subcutaneous vaccination. The future looks promising because of the recent development of new intradermal vaccine delivery devices. PMID- 20716019 TI - Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. AB - IMPORTANCE OF THE FIELD: Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise. AREAS COVERED IN THIS REVIEW: This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical and clinical levels. A discussion regarding the advantages, approaches and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells. WHAT THE READER WILL GAIN: This review aims to give an overview of ZnO nanomaterials in biomedical applications. TAKE HOME MESSAGE: Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be improved further to make them attractive new anticancer agents. PMID- 20716022 TI - Recent advances in histamine H3 receptor antagonists/inverse agonists. AB - IMPORTANCE OF THE FIELD: Histamine H(3) receptor (H(3)R) antagonists/inverse agonists can be therapeutically useful in the treatment of various CNS, metabolic syndrome and allergic disorders, and constitute an attractive target in the search for new drugs. However, several drug candidates have been rejected because of unwanted effects. There is, therefore, a strong need to develop new H(3)R ligands. AREAS COVERED IN THIS REVIEW: A review was conducted of recent advances in the search for H(3)R antagonists/inverse agonists as reflected by patent applications/patents over the last 3 years. WHAT THE READER WILL GAIN: A total of around 100 patent applications/patents along with selected peer-reviewed publications are surveyed. These involve antagonists/inverse agonists of H(3)R, which the authors have divided into five groups. The above-mentioned compounds were evaluated for their potential utility in the treatment of narcolepsy, attention deficit hyperactivity disorder, epilepsy, Alzheimer's disease, schizophrenia, obesity and neuropathic pain. TAKE HOME MESSAGE: Several H(3)R antagonists/inverse agonists appear to be promising drug candidates, including at least 15 compounds undergoing evaluation in clinical development. Especially interesting is pitolisant, which is progressing through to Phase III clinical trials. PMID- 20716023 TI - 5-hydroxytryptamine subtype 6 receptor modulators: a patent survey. AB - IMPORTANCE OF THE FIELD: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT(6) receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists. AREAS COVERED IN THIS REVIEW: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers. WHAT THE READER WILL GAIN: To obtain a clear understanding of the situation and dynamics within the field of 5-HT(6) ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented. TAKE HOME MESSAGE: Several of 5-HT(6) targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease. PMID- 20716024 TI - The expanding role of H1 antihistamines: a patent survey of selective and dual activity compounds 2005-2010. AB - IMPORTANCE OF THE FIELD: Histamine plays a key role in physiological processes through its interaction with H(1-4) histamine receptors. The H(1) receptor is a key element in the pathophysiology of allergic responses. H(1) antihistamine use is a key strategy for therapy in allergy. AREAS COVERED IN THIS REVIEW: Several new chemical entities with improved efficacy in allergic disease have been pursued. Addition of multiple antagonist activities in single compounds has been the focus of current research. Involvement of the H(1) receptor in sleep has led to the evaluation of new compounds as sedative hypnotics. WHAT THE READER WILL GAIN: In all, 57 patents detail the evolution of new chemical entities. Dual H(1) CC-chemokine receptor-3 and H(1)-H(3) antagonists have entered the clinic for allergic indications. Efforts to develop H(1) antihistamines as sedative hypnotics have increased, with several compounds entering the clinic. The dual H(1)-5-HT(2A) antagonist doxepin has been approved for sleep disorders while another compound is currently in clinical trials. TAKE HOME MESSAGE: The development of multiple activity H(1) antihistamines in allergy has met with limited success due in part to a competitive commercial environment. New sedative hypnotics may show potential but will need to demonstrate significant benefits in an increasingly competitive landscape. PMID- 20716026 TI - Emerging drugs for alpha-1-antitrypsin deficiency. AB - IMPORTANCE OF THE FIELD: Alpha-1-antitrypsin (A1AT) deficiency is a common genetic condition that predisposes individuals to the development of chronic obstructive pulmonary disease (COPD) as a direct result of damage caused to the lung by proteolytic enzymes released by migrating neutrophils. The lack of A1AT fails to control these enzymes and in the most common genetic deficiency (Pi Z) is due to accumulation of A1AT in the liver as a result of polymer formation. There is no specific treatment for COPD but understanding the pathophysiology of the disease in A1AT deficiency has led to strategies being used or developed to prevent the lung and liver disease. These strategies may have benefits beyond A1AT deficiency. AREAS COVERED IN THIS REVIEW: The review covers the history of discovery of the nature and role of A1AT deficiency with particular emphasis on the pathophysiology of the lung disease. Evidence for the role of current therapies is provided together with data of preliminary or experimental strategies that are under development. WHAT THE READER WILL GAIN: The reader will gain insight into the role of proteinases in the pathophysiology of COPD with particular reference to A1AT deficiency, which is the only human model of the disease. Current evidence of the efficacy of augmentation is provided together with new ways of readdressing the balance between neutrophil proteinases and natural or synthetic inhibitors or repairing lung damage. TAKE HOME MESSAGE: A1AT deficiency is a good model to investigate the role of inflammation and proteolytic enzymes in the pathophysiology of COPD. Augmentation therapy is expensive but restores the deficiency to normal and current evidence suggests this ameliorates progression of the disease. Understanding the mechanisms involved has led to the development of newer strategies to protect the lung and liver from the development of disease but efficacy and safety concerns require careful introduction of these strategies. Although the condition is relatively common in the Northern hemisphere, the ability to deliver conventional Phase III clinical trials with lung physiology as the primary outcome will be limited by the sensitivity of the tests and number of patients required. PMID- 20716034 TI - Pharmacokinetic evaluation of lanreotide. AB - IMPORTANCE OF THE FIELD: Acromegaly is a rare and potentially life-threatening disease in adults related to excessive production of growth hormone (GH) by pituitary gland tumors and characterized by progressive somatic disfigurement that is associated with systemic manifestations related to organ overgrowth. Somatostatin analogs (SSAs) are effective in controlling GH/IGF-1 hypersecretion and in reducing tumor size. AREAS COVERED IN THIS REVIEW: We review and compare the pharmacokinetic and clinical efficacy of lanreotide, the second SSA available in the market, in its different formulations. WHAT THE READER WILL GAIN: This article concisely reviews the rationale of SSA treatment in acromegaly and the pharmacology and clinical efficacy of lanreotide and provides a detailed overview of its pharmacokinetic profiles in its slow release (SR) and autogel (ATG) formulations. TAKE HOME MESSAGE: Lanreotide is an effective and well-tolerated drug for the treatment of acromegaly. Lanreotide ATG has a more favorable pharmacokinetic profile than lanreotide SR, which permits administration once every 28 - 56 days given deep subcutaneously and by self-injection rather than intramuscular injection every 7 - 14 days. In well-designed clinical trials, subcutaneous lanreotide ATG was shown to be no less effective than intramuscular lanreotide SR or octreotide treatment. PMID- 20716035 TI - Mini-incision donor nephrectomy techniques: a systematic review. AB - OBJECTIVES: The aim of this article is to compare different mini-incision donor nephrectomy techniques in the literature. MATERIALS AND METHODS: We did a literature search using PUBMED using the search term "donor nephrectomy." We compared different surgical techniques using different parameters like length of incision, length of operation, pain medications required after the operation, site of the operation, and intraoperative and postoperative complications. RESULTS: We found 7 different surgical techniques of mini-invasive donor nephrectomy. Hakim and associates described the smallest initial incision size of 4 cm. There also are limited data on the analgesia requirements in 4 of the series, and 3 series that describe the requirements vary. CONCLUSIONS: These techniques offer advantages and disadvantages to the donor and the kidney. We hope to encourage further work. Ideally, there must be a working discussion, long term outcomes of donor kidney and recipient, as well as accurate pain records, both quantitative and qualitative, and a discussion of time to mobilization. PMID- 20716036 TI - Orthotopic liver transplant using allografts from geriatric population in the United States: is there any age limit? AB - OBJECTIVES: Observations of minimal pathophysiological changes in the liver with healthy aging represent the rationale for expanding the donor pool with older donors. However, a debate exists for their upper age limit. The aim of this study is to examine the outcomes of orthotopic liver transplants from older patients (>or= 60 years). MATERIALS AND METHODS: Using the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data, we retrospectively analyzed graft and patient survivals of orthotopic liver transplants done with octogenarian grafts (n=197) and compared them with orthotopic liver transplants done with donors aged between 60 and 79 years (n=4003) and < 60 years (n=21 290) during 2003 to 2007. RESULTS: One- and 3-year graft and patient survival rates among recipients of hepatic allografts from donors < 60 years of age were significantly superior to recipients of octogenarian grafts (graft: 84% vs 75.5% at 1 year; 74.2% vs 61.2% at 3 years; P < .001; patient: 87.8% vs 81.0% at 1-year; 79.3% vs 69.1% at 3 years; P < .001). However, there was no survival difference between recipients of allografts from donors aged > 80 years and 60-79 years (graft: 75.5% vs 77.4% at 1 year; 61.2% vs 64.2% at 3 years; P = .564; patient: 81.0% vs 83.8% at 1 year; 69.1% vs 71.8% at 3 years; P = .494). It correlates well with hepatitis C virus-seronegativity and relatively lower model for end-stage liver disease score among recipients of octogenarian grafts (P < .001). CONCLUSIONS: Careful donor evaluation, avoidance of additional donor risk factors, and their pairing with appropriate recipients offer acceptable functional recovery, even with donors > 80 years. PMID- 20716037 TI - Donor age as a predictor of risk for short-term outcomes after liver transplant. AB - OBJECTIVES: To investigate an association between short-term mortality and donor age-associated worst outcomes in liver transplant. MATERIALS AND METHODS: A total of 178 consecutive patients underwent a liver transplant between 1999 and 2007. Among these patients, there were 172 liver transplants (donor age, 32.04 +/- 16.66; range, 2-65 years) and 167 recipients. Mean recipient age was 39.16 +/- 21.61 years (range, 6 months to 71 years), and 90 were males (53.8%). RESULTS: Among 172 transplants, 32.9% recipients died during follow-up (mean, 34.37 +/- 20.50 months). A lower mean recipient and graft survival occurred in donors older than 50 years (P = .01) and 30 years (P = .02) at 7-year patient survival. At 6- month and 1-year recipient survival, cutoffs were 50 and 55 years (P < .05). Log rank test showed no statistical difference among recipients, and graft survival from donors older/younger 50 and 30 years 1.5 years after liver transplant (P < .565 and P < .259). CONCLUSIONS: Donor age is a key factor in liver transplant that carries prognostic impact in the recipients. Our data suggest that its harmful effects are exclusively elicited during the short-term, postoperative phase. We recommend careful and distinct management of recipients receiving grafts from elderly donors up to 1.5 years after liver transplant. Changes in the current early postoperative management of this selected group are encouraged. PMID- 20716038 TI - CTLA4 CT60 A/G gene polymorphism in liver transplant recipients. AB - OBJECTIVES: Cytotoxic T-lymphocyte antigen 4 (CTLA4) has a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and the single nucleotide polymorphism A/G in the CTLA-4 CT60 gene in liver transplant recipients. MATERIALS AND METHODS: Fifty one liver transplant recipients with at least 3 months' follow-up were selected and genotyped for CTLA-4 CT60 polymorphism (HpyCH4 IV). The association of each genotype with allograft acute rejection was evaluated. RESULTS: The mean age of patients was 27.9 +/- 15.17 years (minimum, 1 year, maximum, 55 years), with 39% male and 61% female. Overall, 17 recipients (33.3%) experienced acute rejection within the first 3 months after a liver transplant. In our study, 50% of the patients (n=26) have G/A , 31% (n=16) have A/A, and 17% have G/G genotypes (n=9). Distribution of alleles was not different according to underlying liver disease. There also was no difference in sex, age, and distributions of CTLA-4 CT60 alleles with acute rejection episodes. CONCLUSIONS: CT60 A/G dimorphism within the 3'-UTR of CTLA4 gene does not influence acute rejection development in liver transplant. However, organ rejection is determined by a combination of several genetic traits rather than a single gene. Therefore, more studies with larger patient numbers are necessary to investigate the effect of combinations of genetic phenotypes involved in this process. PMID- 20716039 TI - Aggressive use of ribavirin and prolonged course of peginterferon to improve the rate of viral response in liver transplant patients with recurrent hepatitis C viral infection. AB - OBJECTIVES: There are different approaches for treating recurrent hepatitis C viral infection after a liver transplant. However, sustained virologic response is achieved in < 40% of infected allografts. We examined sustained virologic response improvement using a prolonged course of peginterferon and aggressive use of ribavirin. PATIENTS AND METHODS: From October 1998 to May 2008, 24 patients (13 male, 11 female; mean age at transplant, 49.4 +/- 7.7 years) received a prolonged course of peginterferon and ribavirin (range, 48-180 weeks). The mean interval from liver transplant to hepatitis C antiviral therapy was 26.6 +/- 27.8 months. Patients began weight-based standard dosages of peginterferon and ribavirin. In case of hemolysis, patients were treated with Epogen, with and without blood transfusions. RESULTS: Fourteen patients (58.3%) had an end of treatment response, and 8 patients (33.3%) maintained sustained virologic response after the first course of therapy. Of 10 patients who did not respond to the first course, 6 received an extended course of antiviral therapy after a mean of 15 +/- 4.6 weeks from completion of first course. Five of these 6 patients achieved end of treatment response and maintained a sustained virologic response, resulting in an overall end of treatment response in 17 patients and a sustained virologic response in 13 patients. Twenty-two patients experienced hemolysis and were treated with Epogen. Fifteen patients received blood transfusions. Ribavirin dosage was reduced in 12 patients, and peginterferon dosage was reduced in 2 patients. CONCLUSIONS: Aggressive use of ribavirin and prolonged course of peginterferon provided sustained virologic response in 54.1% of liver transplant recipients with recurrent hepatitis C virus-infection. More prospective studies are warranted to evaluate the benefit of this approach fully. PMID- 20716040 TI - Determining the incidence of aspergillosis after liver transplant. AB - OBJECTIVES: Aspergillus has become an increasingly frequent cause of life threatening opportunistic infections in liver transplant recipients. This study seeks to determine the incidence of invasive aspergillosis in liver transplant recipients using routine and molecular methods in a teaching hospital in Shiraz, the unique center for liver transplant in Iran. MATERIALS AND METHODS: Four hundred eight recipients who underwent liver transplant were followed for Aspergillus infections by microscopic examination, culture, and nested polymerase chain reaction. Blood samples were cultured by bedside inoculation to BACTEC medium. RESULTS: The female-to-male ratio was 151:257 (mean age, 29.6 years; mean hospitalization, 26 days). Sensitivity and specificity of the nested polymerase chain reaction was 92.8% and 94%. Aspergillosis was detected in 19 recipients (4.6%) by routine and molecular method (4 proven, 10 probable, and 5 possible) of whom 12 recipients died (63.2%). CONCLUSIONS: This study found the incidence rate of invasive aspergillosis as an uncommon complication of liver transplant recipient cases but associated with poor outcomes. The rate is consistent with those reported in previous studies, but molecular assay that is more-sensitive and specific was used in the present study. PMID- 20716041 TI - One-suture, 1-knot technique in renal vascular transplant. AB - OBJECTIVES: We describe the results of our 1-suture, 1-knot technique for vascular anastomosis in renal transplant. This technique can be used for both of the arterial and venous anastomoses. MATERIALS AND METHODS: Between May 2006 and June 2008, a total of 386 renal transplants were done in our center, using a 1 suture, 1-knot technique. Intraoperative data including the warm and cold ischemic time, arterial and venous anastomotic time, and any early and late postoperative complications in the follow-up were recorded. RESULTS: Mean age of recipients was 37 years. Mean kidney warm and cold ischemia time was 4.8 and 26.2 minutes. Mean arterial and venous anastomotic time was 5.1 and 7.2 minutes. No vascular complications were seen in the early postoperative period. Delayed graft function was diagnosed in 36 patients, but a renal scan showed good perfusion of the allografts of these cases. In the mean follow-up of 18.5 months, we did not encounter any case of renal artery thrombosis or any suspected arterial stenosis. CONCLUSIONS: The 1-suture, 1-knot technique is a safe, rapid, and easy method for arterial and venous anastomosis of the renal allograft with low complication rates. It is especially valuable in obese patients and recipients with deep iliac fossa. PMID- 20716042 TI - Estimated glomerular filtration rate in patients with surgically acquired single kidney compared with patients with congenital single kidney: implications for kidney transplant from live donors. AB - OBJECTIVES: The pathophysiology of the single kidney is involved in the evolution toward endstage renal disease. Furthermore, most data suggest that the renal function of the donor is maintained after nephrectomy. This study sought to analyze the difference between surgically acquired single kidney and the congenital single kidney, regarding kidney function at a similar moment in time of the existence of a single kidney. MATERIALS AND METHODS: Two groups were enrolled in this study. Group A consisted of 28 patients with surgically acquired single kidney, time from nephrectomy was 30.23 +/- 10.82 years; mean age, 54.42 +/- 14.99 years. Group B consisted of 20 patients with a congenital single kidney (mean age, 30.3 +/- 10.43 years). We assessed glomerular filtration rate (Modification of Diet in Renal Disease 4 Study Equation) and the presence of classic and nonclassic risk factors for chronic kidney disease. RESULTS: The estimated glomerular filtration rate showed no statistically significant difference between the 2 groups. CONCLUSIONS: Our study did not show any influence of surgical nephrectomy on the evolution of kidney function. Kidney function in the surgically acquired single kidney was similar to the kidney function in the congenital single kidney at a comparable time interval. Our results have potential favorable implications for kidney transplant from living donors. PMID- 20716043 TI - Thrombotic microangiopathy in allogeneic stem cell transplantation in childhood. AB - OBJECTIVES: We define the incidence, risk factors, and mortality rates for the occurrence of thrombotic microangiopathy in 50 children who underwent transplants between January 2006 and June 2008 at 2 Turkish pediatric centers. MATERIALS AND METHODS: The diagnosis of thrombotic microangiopathy was done according to the reports of International Working Group in 2007. RESULTS: Fifty patients (27 male and 23 female; age range, 3 months to 18 years) were included. Patients with malignant and nonmalignant diseases were 13 (26%) and 37 (74%). Myeloablative and nonmyeloablative conditioning regimens were used in 29 (58%) and 21 patients (42%). Bone marrow was used as the source of stem cells in 32 patients (62%) and peripheral blood was used in 18 patients (36%). Thrombotic microangiopathy was seen in 3 of 50 cases (6%). Thrombotic microangiopathy developed in 3 of 18 patients in whom peripheral blood was used as the source of stem cells while none of 32 patients who had bone marrow as the source developed thrombotic microangiopathy (P < .05). CONCLUSIONS: Using peripheral blood as a source of stem cells is a risk factor for development of thrombotic microangiopathy. PMID- 20716044 TI - A comparative study on suture versus cuff anastomosis in mouse cervical cardiac transplant. AB - OBJECTIVES: To compare the cuff technique to traditional suture technique in establishing cervical heart transplant model in mice. MATERIALS AND METHODS: Eighty transplants were performed by 1 surgeon, 40 using the cuff technique, and 40 using the suture technique, under the same circumstances. RESULTS: The cuff approach was significantly superior to conventional suture anastomosis in higher surgical successful rate, less surgery, and less ischemic time (P < .05). Suture anastomosis required an intensive microsurgical training and at least a 16x surgical microscope, while the cuff anastomosis required less learning time and a 10x surgical microscope. CONCLUSIONS: The cuff technique is the preferred method in cervical heart transplant model in mice. PMID- 20716045 TI - Influence of hypothermia and cardioplegic solutions on expression of alpha-Gal epitope on porcine aortic endothelial cells. AB - OBJECTIVES: The Galalpha1-3Galbeta1-4GlcNAc-R is the major antigen on pig tissue bound by human xenoreactive natural antibodies in xenotransplant. We have investigated in vitro the influence of hypothermic storage with cardioplegic solutions on expression of Galalpha1-3Galbeta1-4GlcNAc-Rs and hyperacute xenograft rejection. MATERIALS AND METHODS: To analyze effects of hypothermia on the Galalpha1-3Galbeta1-4GlcNAc-Rs, cultured porcine aortic endothelial cells were exposed to a temperature of 4 degrees C for 1 hour, 4 hours, and 6 hours. Cell cultures of the control groups were incubated at the same time at 38 degrees C. To investigate the influence of cardioplegic solutions on the Galalpha1- 3Galbeta1-4GlcNAc-Rs, porcine aortic endothelial cells were exposed to 4 degrees C for 4 hours in the presence of University of Wisconsin solution or histidinetryptophan- ketoglutarate solution. Cells of the control groups were cooled at 4 degrees C for 4 hours without cardioplegic solution. After treatment, porcine aortic endothelial cells were submitted to fluorescence-activated cell sorter. RESULTS: Hypothermia of 4 degrees C showed no significant effect on the quantity of Galalpha1-3Galbeta1-4GlcNAc-Rs. However, the treatment of porcine aortic endothelial cells with University of Wisconsin solution resulted in a highly significant reduction of Galalpha1-3Galbeta1- 4GlcNAc-Rs by 50% (P = .006). Treatment of porcine aortic endothelial cells with histidine tryptophanketoglutarate solution decreased Alpha-Gal quantity significantly by 32% (P = .011). CONCLUSIONS: Our data offer new perspectives in the prevention of hyperacute, humoral xenograft rejection by reducing the Galalpha1-3Galbeta1 4GlcNAc-Rs after exposure to different cardioplegic solutions. PMID- 20716046 TI - Hand-assisted laparoscopic donor nephrectomy in patients with aberrant inferior vena caval anatomy. AB - OBJECTIVES: Hand-assisted laparoscopic donor nephrectomy has become an established technique for live-donor organ retrieval. In most cases, the left kidney is removed because of its more favorable anatomic relations, particularly with the major abdominal vessels. MATERIALS AND METHODS: We present 2 cases of live donation in which a hand-assisted laparoscopic approach was used to remove the right kidney as indicated by the presence of aberrant vascular anatomy, 1 being situs inversus totalis, the other a left-sided inferior vena cava. RESULTS: A 41-year-old woman and a 51-year-old man underwent assessment for live-kidney donation. During preoperative investigation, they underwent magnetic resonance imaging that demonstrated situs inversus totalis and a left-sided inferior vena cava. No contraindications to live donation were found during the investigation. In both cases, a right donor nephrectomy was performed owing to an anatomically longer right renal vein. Living donation proceeded without complication in both cases, and both patients had uneventful recoveries. CONCLUSIONS: Abnormalities in vascular anatomy should not be considered an absolute contraindication to donation, even by the hand-assisted laparoscopic donor approach. The use of magnetic resonance scanning preoperatively allows detailed planning of the approach required. PMID- 20716047 TI - Liver transplant in a patient with active pulmonary tuberculosis. AB - OBJECTIVES: Immunosuppressive treatment generally increases the severity of active infection. Therefore, liver transplant is contraindicated in the presence of active tuberculosis. Despite the importance of supportive treatment, liver transplant is the only treatment for fulminant hepatic failure. MATERIALS AND METHODS: We report a case of successful liver transplant for fulminant hepatic failure in the presence of active tuberculosis infection. RESULTS: We immediately performed a liver transplant from a live donor. The patient received low-dose immunosuppressive treatment and antituberculosis treatment. The patient was cured and discharged on the 25th day after surgery. We stopped antituberculosis treatment 10 months after discharge. The patient has been followed for 32 months after transplant with normal graft function and has been free of pulmonary tuberculosis infection. CONCLUSIONS: Liver transplant can be performed in cirrhotic patients with active infections, such as tuberculosis, as a life-saving procedure. PMID- 20716048 TI - Acute gastric variceal bleeding during orthotopic liver transplant. AB - We present a case of intraoperative gastric variceal bleeding during liver transplant. After an uneventful induction and surgical dissection, our patient developed hemodynamic instability during the anhepatic phase. We believe that an increase in portal pressures, owing to clamping of the portal system, led to spontaneous variceal rupture; however, placement of an oral gastric tube or transesophageal echocardiography probe may have contributed to this also. After intraoperative banding, the patient was stabilized and surgery proceeded uneventfully. The patient had no long-term sequelae. Anesthesiologists involved in the care of patients with end-stage liver disease should be aware of this infrequent intraoperative complication and be prepared to treat it appropriately. PMID- 20716049 TI - Switch from beta-thalassemia major to beta-thalassemia intermedia after secondary graft failure. AB - In this article, we report a switch of beta-thalassemia major to intermedia beta thalassemia after allogeneic bone marrow transplant of a 6-year-old girl from her HLA-matched brother. After stable mixed chimerism, the patient had a secondary graft rejection and returned to total recipient chimerism as assessed by real time polymerase chain reaction assay. Nonetheless, with a medium hemoglobin rate of 89 g/L, she did not need further transfusions for 60 months after rejection. We conclude that complete loss of donor cells after bone marrow transplant for beta-thalassemia major is compatible with a stable clinical state, probably due to a gamma-globin gene demethylation that enhances gamma-globin chain production and further allows constitution of a fetal hemoglobin rate compatible with free transfusion survival. PMID- 20716050 TI - Pharmacological manipulation of brain glycogenolysis as a therapeutic approach to cerebral ischemia. AB - Brain ischemia resulting from multiple disease states including cardiac arrest, stroke and traumatic brain injury, is a leading cause of death and disability. Despite significant resources dedicated to developing pharmacological interventions, few effective therapeutic options are currently available. The basic consequence of cerebral ischemia, characterized by energy failure and subsequent brain metabolic abnormalities, enables the protective effects by pharmacological manipulation of brain metabolism. We present here the important roles of brain glycogen metabolism and propose inhibition of glycogenolysis as a therapeutic approach to cerebral ischemia. PMID- 20716051 TI - Inhibition of glycogen phosphorylase in the context of type 2 diabetes, with focus on recent inhibitors bound at the active site. AB - Among the variety of approaches for pharmacological intervention in T2DM, the inhibition of GP with the aim of reducing hepatic glucose output is a validated and thoroughly investigated strategy. Both the academia and health companies participate in the search of potent inhibitors, that might be suitable for long term treatment. As several inhibitory sites have been identified for GP, interest focuses mainly on structures that can bind at either the catalytic, the allosteric, or the new allosteric sites. Glucose-based motifs and azasugars that bind at the active site constitute the most populated class of GPis. During the last two years, significant progresses have been made, since newly proposed motifs have K(i) values in the low micromolar and even sub- micromolar range. Without ignoring previously reported structures, new series based on beta-D glucopyranosyl-pyrimidine, D-glucopyranosylidene-spiro-isoxazoline and D glucopyranosylidene-spiro-oxathiazole motifs appear promising. A representative from this last series, with a 2-naphthyl residue was identified as the most potent GPi to date (K(i) = 0.16 uM). While no inhibition was found for sulfonium analogs, D-DAB remains the best inhibitor among five and six-membered iminosugars that showed inhibitory properties toward GP. A study of glucagon-induced glucose production in primary rat hepatocytes has suggested that amylo-1,6-glucosidase inhibitors in combination with GPis may lower glucose level in T2DM. Considering the limitations found for other potent GPis binding at other sites and the complexity of pharmacological development, the potential of glucose-based GPis is still not established firmly and more tests with cells, tissues, animals are required to better establish the risks and merits of these structures, as antidiabetic drugs. Further studies might also confirm other directions where glucose-based GPis could be useful. PMID- 20716052 TI - Recent advances in the allosteric inhibition of glycogen phosphorylase. AB - Glycogen phosphorylase (GP) is an important target for the development of anti hyperglycaemic drugs. GP is an enzyme which is moderated allosterically with multiple ligand binding sites where inhibitors can potentially modulate enzyme activity. The search for potent and isoform selective inhibitors of GP is ongoing with an increasing focus on allosteric inhibition. In this review, the structural diversity, and enzyme interactions of the most recent inhibitors, and in particular allosteric inhibitors, of GP at the different key binding sites are explored. A range of inhibitors of GP, with known as well as unknown binding site or mechanism is presented. PMID- 20716053 TI - Computation as a tool for glycogen phosphorylase inhibitor design. AB - Glycogen phosphorylase is an important therapeutic target for the potential treatment of type 2 diabetes. The importance of computation in the search for potent, selective and drug-like glycogen phosphorylase inhibitors which may eventually lead to antihyperglycemic drugs is now firmly established. Acting solo or more effectively in combination with experiment in a multidisciplinary approach to structure based drug design, current day modeling methods are an effective means of reducing the time and money spent on costly experimental procedures. Glycogen phosphorylase is an allosteric protein with five different ligand binding sites, hence offering multiple opportunities for modulation of enzyme activity. However, the binding sites have their own individual characteristics, so that different modeling approaches may be more effective for each. This review is focused on advances in the modelling and design of new inhibitors of the enzyme aimed towards providing the reader with some useful hints towards more successful computer-aided inhibitor (drug) design targeting glycogen phosphorylase. PMID- 20716054 TI - Synthesis of N-glucopyranosidic derivatives as potential inhibitors that bind at the catalytic site of glycogen phosphorylase. AB - Glycogen phosphorylase (GP) is a promising molecular target for the treatment of Type 2 diabetes. The design of potential inhibitors for the catalytic site of the enzyme is based on the high affinity for beta-D-glucopyranose and the presence of a beta-cavity that extends from the sugar anomeric position forming a 15 x 7.5 x 10 A available space. This review is focused on our efforts towards the design and synthesis of various families of potential inhibitors, including N-beta-D glucopyranosyl oxamic acid esters and oxamides, N-beta-D glucopyranosylaminocarbonyl L-aminoacids and peptides, as well as glucose-derived purine and pyrimidine nucleosides, spiro- and other bicyclic derivatives. Kinetic and crystallographic study of the interactions of these inhibitors with GP has increased our understanding of the importance of the various functional groups within the catalytic site and has pointed the way towards the in silico prediction and design of potent inhibitors, which are both synthetically viable and pharmacologically relevant. PMID- 20716055 TI - The prototype of glycogen phosphorylase. AB - The quest for the discovery of new antihyperglycemic agents has been more intense the last years due to the rapid increase of mortality associated with type 2 diabetes. Glycogen metabolism has been one of the major causes of the elevated blood glucose levels; hence, special attention has been drawn to the control of the enzymes implicated in the relevant pathway. To this end, the allosteric enzyme of glycogen phosphorylase, has been proposed as molecular target for the design of potential new antidiabetic agents by an interdisciplinary approach comprising organic synthesis, kinetic and X-ray crystallographic studies and physiological experiments. The results derived from the thorough investigation of the catalytic site of the enzyme with the structure-based inhibitor design approach are summarized with emphasis on the most potent inhibitors identified for different classes of compounds. PMID- 20716057 TI - Inhibition of glycogenolysis towards antidiabetic and other therapies. PMID- 20716056 TI - Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors. AB - Liver glycogen is synthesized in the postprandial state in response to elevated concentrations of glucose and insulin or by activation of neuroendocrine signals and it is degraded in the postabsorptive state in response to changes in the concentrations of insulin and counter-regulatory hormones. Dysregulation of either glycogen degradation or synthesis through changes in allosteric control or covalent modification of glycogen phosphorylase and glycogen synthase leads to disturbance of blood glucose homeostasis. Liver glycogen phosphorylase has a dual role in the control of glycogen metabolism by regulation of both glycogen degradation and synthesis. The phosphorylated form (GPa) is the active form and determines the rate of degradation of glycogen and it is also a potent allosteric inhibitor of the protein complex, involving the glycogen targeting protein G(L) and protein phosphatase-1, which catalyses dephosphorylation (activation) of glycogen synthase. Drug discovery programmes exploring the validity of glycogen phosphorylase as a therapeutic target for type 2 diabetes have generated a wide array of selective phosphorylase ligands that modulate the catalytic activity and / or the phosphorylation state (interconversion of GPa and GPb) as well as the binding of GPa to the allosteric site of G(L). Glycogen phosphorylase inhibitors that act in hepatocytes either exclusively by dephosphorylating GPa (e.g. indole carboxamides) or by allosteric inhibition of GPa (1,4-dideoxy-1,4-D-arabinitol) are very powerful experimental tools to determine the relative roles of covalent modification of glycogen phosphorylase and/or cycling between glycogen synthesis and degradation in the mechanism(s) by which insulin and neurotransmitters regulate hepatic glycogen metabolism. PMID- 20716058 TI - Marine microbes-derived anti-bacterial agents. AB - This review covers natural products isolated from marine microorganisms including bacteria, fungi and actinomycetes published in the recent years. The emphasis is mainly about new compounds, together with their anti-bacterial activities, source organisms and country of origin, biosynthetic studies as well as the mechanisms involved in their anti-bacterial activities. PMID- 20716059 TI - DNA methylation biomarkers in serum for gastric cancer screening. AB - Epigenetic alterations occur throughout the development and carcinogenesis of gastric cancer. Therefore, the detection of methylated DNA markers is predicted to be able to detect gastric cancer earlier, and improve the risk assessment, surveillance, relapse, and prognosis of patients with gastric cancer. Detection of free methylated DNA also represents a promising approach for developing serum based detection methods for the non-invasive monitoring of gastric cancer progression. PMID- 20716060 TI - Isoquinoline alkaloids and their binding with DNA: calorimetry and thermal analysis applications. AB - Alkaloids are a group of natural products with unmatched chemical diversity and biological relevance forming potential quality pools in drug screening. The molecular aspects of their interaction with many cellular macromolecules like DNA, RNA and proteins are being currently investigated in order to evolve the structure activity relationship. Isoquinolines constitute an important group of alkaloids. They have extensive utility in cancer therapy and a large volume of data is now emerging in the literature on their mode, mechanism and specificity of binding to DNA. Thermodynamic characterization of the binding of these alkaloids to DNA may offer key insights into the molecular aspects that drive complex formation and these data can provide valuable information about the balance of driving forces. Various thermal techniques have been conveniently used for this purpose and modern calorimetric instrumentation provides direct and quick estimation of thermodynamic parameters. Thermal melting studies and calorimetric techniques like isothermal titration calorimetry and differential scanning calorimetry have further advanced the field by providing authentic, reliable and sensitive data on various aspects of temperature dependent structural analysis of the interaction. In this review we present the application of various thermal techniques, viz. isothermal titration calorimetry, differential scanning calorimetry and optical melting studies in the characterization of drug-DNA interactions with particular emphasis on isoquinoline alkaloid-DNA interaction. PMID- 20716061 TI - Transcriptome atlas of glutamine family amino acid metabolism-related genes in eight regenerating liver cell types. AB - To explore glutamine family amino acid metabolism of eight liver cell types in rat liver regeneration, eight kinds of rat regenerating liver cells were isolated by using the combination of Percoll density gradient centrifugation and immunomagnetic bead methods, then Rat Genome 230 2.0 Array was used to detect the expression profiles of the genes associated with metabolism of glutamine family amino acid in rat liver regeneration and finally how these genes involved in activities of eight regenerating liver cell types were analysed by the methods of bioinformatics and systems biology. The results showed that in the priming stage of liver regeneration, hepatic stellate cells and sinusoidal endothelial cells transformed proline and glutamine into glutamate; hepatocytes, hepatic stellate cells, sinusoidal endothelial cells and dendritic cells catabolized glutamate to 2-oxoglutarate or succinate; hepatic stellate cells and sinusoidal endothelial cells catalysed glutamate into glutamyl-tRNA for protein synthesis; urea cycle, which degraded from arginine, was enhanced in biliary epithelia cells, sinusoidal endothelial cells and dendritic cells; synthesis of polyamines from arginine was enhanced in biliary epithelia cells, sinusoidal endothelial cells, Kupffer cells and dendritic cells; the content of NO was increased in sinusoidal endothelial cells and dendritic cells; degradation of proline was enhanced in hepatocytes and biliary epithelia cells. In the progress stage, biliary epithelia cells converted glutamine into GMP and glucosamine 6-phosphate; oval cells converted glutamine into glucosamine 6-phosphate; hepatic stellate cells converted glutamine into NAD; the content of NO, which degraded from arginine, was increased in biliary epithelia cells, oval cells, pit cells and dendritic cells. In the termination stage, oval cells converted proline into glutamate; glutamate degradation, which degraded from arginine, was enhanced in hepatocytes and dendritic cells; the content of NO was increased in oval cells, sinusoidal endothelial cells, pit cells and dendritic cells. The synthesis of creatine phosphate was enhanced in hepatocytes, biliary epithelia cells, pit cells and dendritic cells in both progress and termination stages. In summary, glutamine family amino acid metabolism has some differences in liver regeneration in different liver cells. PMID- 20716062 TI - Activation of RASSF2A by p300 induces late apoptosis through histone hyperacetylation. AB - Both RASSF2A (Ras-associated family 2A) and p300 are implicated in apoptosis. However, little is known about the interrelationship between these two proteins in induction of apoptosis. Here we show that p300 was able to induce late apoptosis through up-regulation of RASSF2A in human gastric cancer cells SGC-7901 (p53-mutant). Our data demonstrated that p300 stimulated RASSF2A expression in 293T cells in cooperation with the transcription factor Sp1. Results of ChIP (chromatin immunoprecipitation) assays revealed that p300 induced histones H3 and H4 hyperacetylation at RASSF2A promoter. Moreover, p300 and Sp1 reciprocally facilitated their binding to RASSF2A promoter. Overall, data arising from this study indicate that Sp1-mediated RASSF2A gene transcription is activated by p300 through histone acetylation, and this activation plays an important role in inducing late apoptosis. PMID- 20716063 TI - A variety of risk topics and risk processes within different settings. PMID- 20716065 TI - Use of gaseous 13NH3 administered to intact leaves of Nicotiana tabacum to study changes in nitrogen utilization during defence induction. AB - Nitrogen-13 (t(1/2) 9.97 m), a radioactive isotope of nitrogen, offers unique opportunities to explore plant nitrogen utilization over short time periods. Here we describe a method for administering (13)N as gaseous (13)NH(3) to intact leaves of Nicotiana tabacum L. (cv Samsun), and measuring the labelled amino acids using radio high-performance liquid chromatography (HPLC) on tissue extract. We used this method to study the effects of defence induction on plant nitrogen utilization by applying treatments of methyl jasmonate (MeJA), a potent defence elicitor. MeJA caused a significant increase relative to controls in key [(13)N]amino acids, including serine, glycine and alanine by 4 h post-treatment, yet had no effect on (13)NH(3) incorporation, a process that is primarily under the control of the glutamine synthatase/glutamate synthase pathway (GS/GOGAT) in cellular photorespiration. We suggest that the reconfiguration of nitrogen metabolism may reflect induction of non-photorespiratory sources of nitrogen to better serve the plant's defences. PMID- 20716066 TI - Phloem-derived gamma-aminobutyric acid (GABA) is involved in upregulating nodule N2 fixation efficiency in the model legume Medicago truncatula. AB - Nitrogen fixation in legumes is downregulated through a whole plant N feedback mechanism, for example, when under stress. This mechanism is probably triggered by the impact of shoot-borne, phloem-delivered compounds. However, little is known about any whole-plant mechanism that might upregulate nitrogen fixation, for example, under N deficiency. We induced emerging N-deficiency through partial excision of nodules from Medicago truncatula plants. Subsequently, the activity and composition of the remaining nodules and shifts in concentration of free amides/amino acids in the phloem were monitored. Furthermore, we mimicked these shifts through artificial feeding of gamma-aminobutyric acid (GABA) into the phloem of undisturbed plants. As a result of increased specific activity of nodules, N(2) fixation per plant recovered almost completely 4-5 d after excision. The concentration of amino acids, sugars and organic acids increased strongly in the upregulated nodules. A concomitant analysis of the phloem revealed a significant increase in GABA concentration. Comparable with the effect of nodule excision, artificial GABA feeding into the phloem resulted in an increased activity and higher concentration of amino acids and organic acids in nodules. It is concluded that GABA might be involved in upregulating nodule activity, possibly because of its constituting part of a putative amino acid cycle between bacteroids and the cytosol. PMID- 20716067 TI - Physical organization of mixed protease inhibitor gene clusters, coordinated expression and association with resistance to late blight at the StKI locus on potato chromosome III. AB - Protease inhibitors (PIs) play a role in plant defence against pests and pathogens as well as in plant development. Potato (Solanum tuberosum) contains abundant levels of diverse PIs. Most potato Kunitz-type inhibitor (KTI) genes map to the StKI locus on potato chromosome III, which is linked to a quantitative trait locus (QTL) for resistance to Phytophthora infestans. To elucidate the physical organization of PIs at the StKI locus, we screened bacterial artificial chromosome (BAC) libraries with KTI probes. Ten different clones were selected, sequenced and annotated. Of 100 putative genes, 22 corresponded to five PI classes. Expression analysis by quantitative real-time PCR (qRT-PCR) using PI class-specific primers in different tissues of the tetraploid potato cultivars 'Nikita' and 'Baltica' revealed different transcript levels, depending on PI type and genotype. During the compatible interaction with a complex race of P. infestans, four PI classes showed coordinated expression over 3 d after infection, a strong decrease in infected leaves and a transient induction in systemic leaves. Basal transcript levels in non-infected leaves differed strongly between the two genotypes examined. Two microsatellite markers located within the PI gene cluster were associated with resistance to P. infestans in a population of potato varieties and breeding clones. PMID- 20716068 TI - Water uptake and hydraulic redistribution across large woody root systems to 20 m depth. AB - Deep water uptake and hydraulic redistribution (HR) are important processes in many forests, savannas and shrublands. We investigated HR in a semi-arid woodland above a unique cave system in central Texas to understand how deep root systems facilitate HR. Sap flow was measured in 9 trunks, 47 shallow roots and 12 deep roots of Quercus, Bumelia and Prosopis trees over 12 months. HR was extensive and continuous, involving every tree and 83% of roots, with the total daily volume of HR over a 1 month period estimated to be approximately 22% of daily transpiration. During drought, deep roots at 20 m depth redistributed water to shallow roots (hydraulic lift), while after rain, shallow roots at 0-0.5 m depth redistributed water among other shallow roots (lateral HR). The main driver of HR appeared to be patchy, dry soil near the surface, although water may also have been redistributed to mid-level depths via deeper lateral roots. Deep roots contributed up to five times more water to transpiration and HR than shallow roots during drought but dramatically reduced their contribution after rain. Our results suggest that deep-rooted plants are important drivers of water cycling in dry ecosystems and that HR can significantly influence landscape hydrology. PMID- 20716069 TI - Effects of light on cyanide-resistant respiration and alternative oxidase function in Arabidopsis seedlings. AB - Mitochondrial alternative oxidase (AOX), the unique respiratory terminal oxidase in plants, catalyzes the energy wasteful cyanide (CN)-resistant respiration and plays a role in optimizing photosynthesis. Although it has been demonstrated that leaf AOX is upregulated after illumination, the in vivo mechanism of AOX upregulation by light and its physiological significance are still unknown. In this report, red light and blue light-induced AOX (especially AOX1a) expressions were characterized. Phytochromes, phototropins and cryptochromes, all these photoreceptors mediate the light-response of AOX1a gene. When aox1a mutant seedlings were grown under a high-light (HL) condition, photobleaching was more evident in the mutant than the wild-type plants. More reactive oxygen species (ROS) accumulation and inefficient dissipation of chloroplast reducing equivalents in aox1a mutant may account for its worse adaptation to HL stress. When etiolated seedlings were exposed to illumination for 4 h, chlorophyll accumulation was largely delayed in aox1a plants. We first suggest that more reduction of the photosynthetic electron transport chain and more accumulation of reducing-equivalents in the mutant during de-etiolation might be the main reasons. PMID- 20716070 TI - Intravenous vs intramuscular ketamine for pediatric procedural sedation by emergency medicine specialists: a review. AB - Ketamine is a general anesthetic agent widely used for pediatric procedural sedation outside the operating theater by nonanesthesiologists. In a setting where efficacy and safety of the agent are paramount, there are conflicting recommendations in terms of optimal mode of parenteral administration, as well as optimal dosage and need for the coadministration of adjunctive agents to decrease side effects. We investigated existing evidence to determine whether ketamine should be best administered intravenously or intramuscularly. This analysis was made difficult by limited direct comparisons of both modes of parenteral administration and a lack of consistent definitions for key outcomes such as 'effectiveness,''adverse events,''hypoxia,''ease of completion of the procedure,' and 'satisfaction' across studies that have evaluated ketamine. Based on large data sets, the safety and efficacy of both modes of administration are broadly similar. Although data on head to head comparisons of intravenous and intramuscular ketamine is limited, based on our analysis, we conclude that the trends indicate ketamine is ideally administered intravenously. PMID- 20716071 TI - Perioperative care of patients with epidermolysis bullosa: proceedings of the 5th international symposium on epidermolysis bullosa, Santiago Chile, December 4-6, 2008. AB - Epidermolysis bullosa (EB) has become recognized as a multisystem disorder that poses a number of pre-, intra-, and postoperative challenges. While anesthesiologists have long appreciated the potential difficult intubation in patients with EB, other systems can be affected by this disorder. Hematologic, cardiac, skeletal, gastrointestinal, nutritional, and metabolic deficiencies are foci of preoperative medical care, in addition to the airway concerns. Therefore, multidisciplinary planning for operative care is imperative. A multinational, interdisciplinary panel of experts assembled in Santiagio, Chile to review the best practices for perioperative care of patients with EB. This paper presents guidelines that represent a synthesis of evidence-based approaches and the expert consensus of this panel and are intended to aid physicians new to caring for patients with EB when operative management is indicated. With proper medical optimization and attention to detail in the operating room, patients with EB can have an uneventful perioperative course. PMID- 20716072 TI - The addition of ketamine to a morphine nurse- or patient-controlled analgesia infusion (PCA/NCA) increases analgesic efficacy in children with mucositis pain. AB - AIM: To assess the efficacy of adding ketamine to morphine nurse- or patient controlled analgesia (NCA/PCA) infusions in treating mucositis pain in children. BACKGROUND: Mucositis pain can be very difficult to control in some patients despite the use of parenteral opioids. In our institution, we have started adding low-dose ketamine to the morphine NCA/PCA in these children in an effort to improve analgesic efficacy. METHODS/MATERIALS: The records of all children receiving a morphine/ketamine PCA or NCA for mucositis pain in our institution from 1999 to 2007 were reviewed. At the time of treatment, details of the analgesic management and consumption, pain scores and side effects were prospectively recorded and then entered on to an electronic database. Ketamine was added at a concentration of 20 or 40 microg x kg(-1) per ml with our standard morphine NCA/PCA infusions and protocols being used. RESULTS: In 28 patients, there was no difference between average morphine consumption in the 24 h pre and post the addition of ketamine (33.1 (+/-10.7) vs 35.2 (+/-14.3) microg x kg(-1) per hour, P = 0.45) but in those with recorded pain scores (n = 16), the median percentage of pain scores > or =4 was 48% (13-100%) preketamine versus 33% (0 82%) postketamine (P = 0.01). In all patients, there was no change in the rates of nausea and vomiting and pruritus pre and post the addition of ketamine and no other significant side effects were reported. No difference was seen between those who had 20 or 40 microg x kg(-1) per ml of ketamine added. CONCLUSION: The addition of ketamine to a morphine NCA/PCA improves analgesic efficacy in children with mucositis pain with no increase in the incidence of side effects. PMID- 20716073 TI - Anesthetic management of children with in situ Berlin Heart EXCOR. AB - Modern mechanical devices can support children with severely impaired cardiac function until a donor heart is found for transplantation or native function recovers. Pediatric heart transplantation offers a good chance of survival with a high quality of life to individuals with limited life expectancy and/or severe limitation to daily activities, but many die on the transplant list or are not listed because of a shortage of donor organs. In recent cohorts, there is better outcome when ventricular assist devices (VADs) rather than extracorporeal membrane oxygenation are used as a 'bridge' to transplantation. Anesthesiologists working in centers where VADs are available may increasingly be asked to provide anesthesia to children with such devices in situ, including procedures outside the cardiac surgical operating room. The Berlin Heart EXCOR device is a VAD system with increasing popularity in pediatric practice and has system components available in sizes suitable even for neonates. Postimplantation considerations include hemodynamics, thromboembolic complications and their prevention by anticoagulation, antimicrobial therapy, and the rehabilitation and mobilization of recipients. VAD-specific emergencies must be recognized and managed appropriately by anesthesiologists looking after Berlin Heart recipients. These include malignant dysrhythmias, sudden loss of VAD output, air or clot embolism, and sudden cyanosis. Provision of anesthesia for patients with an in situ Berlin Heart requires attention to particular considerations in preoperative assessment, induction, maintenance, and postoperative care. PMID- 20716074 TI - Insufflation vs intubation during esophagogastroduodenoscopy in children. AB - OBJECTIVES: We compared adverse airway events during esophagogastroduodenoscopy (EGD) in children managed with insufflation vs intubation. BACKGROUND: Optimum airway management during EGD in children remains undecided. METHODS/MATERIALS: Following IRB approval and written informed parental consent, children between 1 and 12 years of age presenting for EGD were randomized to airway management with insufflation (Group I), intubation/awake extubation (Group A), or intubation/deep extubation (Group D). All subjects received a standardized anesthetic with sevoflurane in oxygen. Using uniform definitions, airway adverse events during and after EGD recovery were recorded. Categorical data were analysed with Chi square contingency tables or Fisher's exact test as appropriate. RESULTS: Analyzable data were available for 415 subjects (Group I: 209; Group A: 101; Group D: 105). Desaturation, laryngospasm, any airway adverse event, and multiple airway adverse events during EGD were significantly more common in subjects in Group I compared to those in Groups A and D. Complaints of sore throat, hoarseness, stridor, and/or dysphagia were more common in subjects in Groups A and D. Analysis of confounders suggested that younger age, obesity, and midazolam premedication were independent predictors of airway adverse events during EGD. CONCLUSIONS: Insufflation during EGD was associated with a higher incidence of airway adverse events, including desaturation and laryngospasm; intubation during EGD was associated with more frequent complaints related to sore throat. As our results show that insufflation during EGD offers no advantage in terms of operational efficiency and is associated with more airway adverse events, we recommend endotracheal intubation during EGD, especially in patients who are younger, obese, or have received midazolam premedication. PMID- 20716075 TI - A prospective randomized trial comparing supraglottic airways for flexible bronchoscopy in children. AB - OBJECTIVE: A prospective randomized, controlled trial was conducted comparing supraglottic airways (SGA) for flexible bronchoscopy in 100 children. BACKGROUND: Pediatric flexible bronchoscopy is commonly performed using a SGA as both a ventilation device and a conduit for flexible bronchoscopy. We observed that some disposable SGAs were associated with increased resistance to bronchoscope manipulation compared to the LMA Classic (cLMA). METHODS: We compared the cLMA to the Ambu Aura Once, Portex Soft Seal, Boss Systems disposable silicone laryngeal mask, and LMA Unique. We recorded the subjective resistance of the bronchoscope manipulation within the SGA by linear analog score and measured the time to insert the bronchoscope from the proximal end of the SGA to the right upper lobe. We also scored the view of the larynx through the bronchoscope and measured SGA cuff pressures. RESULTS: Resistance to bronchoscope manipulation during pediatric flexible bronchoscopy was higher using polyvinyl chloride (PVC) disposable SGAs (Ambu, Unique, and Portex) than the silicone re-usable cLMA (P < 0.0001). The Unique and Ambu laryngeal masks were clinically inferior to the cLMA at all levels of the airway (P < 0.0001). The Portex Soft Seal was not different above the larynx but was significantly statistically inferior at (P < 0.04) and below the larynx (P < 0.006) and inferior overall (P < 0.007). Boss Systems single-use laryngeal mask was as effective as the cLMA. CONCLUSION: In this trial, PVC single-use laryngeal masks were inferior to the silicone cLMA and Boss Systems laryngeal masks for flexible bronchoscopy in children. PMID- 20716076 TI - Incidence of sore throat in children following use of flexible laryngeal mask airways - impact of an introducer device. AB - BACKGROUND: Insertion of a flexible laryngeal mask airway (FLMA) is more difficult and therefore might result in a higher risk for trauma to the upper airway. To facilitate the insertion of FLMA, the use of an introducer device (Portex Limited, Hythe, Kent, UK) was promoted. However, the impact of the use of this device on the occurrence of postoperative sore throat is unknown. METHODS: Four hundred children (3-21 years) undergoing elective ambulatory surgery were consecutively included in this study. In 196 cases, the FLMA was inserted using an introducer device. The FLMA cuff was then inflated and the pressure adjusted to below 60 cmH(2)O (according to manufacturers guidelines) using a calibrated cuff manometer (Portex Limited). Three types of FLMA were available: FLMA classic, FLMA unique (both FLMA PacMed, Richmond, Victoria, Australia) and FLMA ProBreathe (Well Lead Medical Co Ltd., Hualong, Guangzhou, China). Prior to discharge, patients' pain was assessed using an age appropriate scale. RESULTS: Thirteen children (3.3%) developed sore throat, two (0.5%) sore neck and three (0.75%) sore jaw. Of those that developed sore throat, seven had a FLMA inserted with an introducer, six without an introducer. Using a laryngeal mask airways (LMA) with a polyvinyl chloride (PVC), surface was associated with a higher risk for sore throat compared with an LMA with a silicone surface (P = 0.0002). CONCLUSION: In this study with controlled low cuff pressures, the incidence of sore throat was low. The use of an introducer device did not affect the rate of sore throat. PMID- 20716077 TI - Incidence of self-limiting back pain in children following caudal blockade: an exploratory study. AB - BACKGROUND: Currently, in pediatric anesthesia, there is no evidence-based information available to pediatric patients and their parents regarding the incidence of back pain after neuraxial injections performed for postoperative analgesia. Back pain postepidural blockade has been reported in numerous studies with adult patients; however, it has not been investigated in children. The main objective of this study is to examine the incidence of back pain symptoms after caudal blockade (early and late onset) in children. METHODS: Patients under the age of 18 years, who received caudal blockade at the Montreal Children's Hospital between July 2006 and December 2008 were recruited in this prospective observational study. Back pain was measured prospectively by patient self-report and parental observation during the 15-day postoperative period. Patients, or their parents, were contacted by phone on postoperative day 2 (POD2) and postoperative day 15 (POD15) to answer a seven-item symptom questionnaire. RESULTS: In a sample of 135 children, the incidence of back pain symptoms was 4.7% and 1.1% on POD2 and POD15, respectively. CONCLUSIONS: The results of this study provide support that transient self-limiting back pain after caudal blockade does occur in pediatric patients. Clinically, this is useful information for physicians to provide to their patients. An exploration of factors that may be associated with back pain following caudal blockade in children is an interesting area of future research. PMID- 20716078 TI - Metabolic changes during major craniofacial surgery. AB - OBJECTIVES: The purpose of this study was to document the degree and duration of perioperative metabolic disturbance during major craniofacial surgery in children. AIM: The aim was to quantify the degree and duration of perioperative metabolic disturbance and to determine the relationship between the metabolic changes and the duration of surgery and total volume of blood and colloid given during surgery. BACKGROUND: These patients have the potential for massive blood loss and significant metabolic acidosis. Routine perioperative monitoring includes the serial measurement of base deficit (BD) as a marker of metabolic disturbance. METHODS/MATERIALS: All patients undergoing elective major craniofacial surgery were prospectively studied over a 10-month period. BD from arterial blood gas analysis was measured at standardized intervals during the perioperative period. The duration of surgery and total volume of blood and colloid given intraoperatively were used as covariates in a multiple regression analysis. RESULTS: Maximum recorded BD ranged from -3 to -20 (median -9). Median time taken to return to normal was 9.25 h (range 0-18 h). Median duration of significant BD was 3.8 h (range 0-20 h). CONCLUSIONS: Children undergoing major craniofacial surgery develop a varying degree of perioperative metabolic acidosis persisting for several hours. The maximum BD appears to be related to the amount of intraoperative blood loss and replacement rather than duration of surgery. As it is difficult to predict the extent and duration of metabolic acidosis for an individual patient, this study confirmed our current practice that all patients should be admitted to a neurosurgical high-dependency unit postoperatively for overnight monitoring. PMID- 20716080 TI - Efficacy of bupivacaine-neostigmine and bupivacaine-tramadol in caudal block in pediatric inguinal herniorrhaphy. AB - BACKGROUND: Limited duration of analgesia is among the limitations of single caudal injection with local anesthetics. Therefore, the purpose of this study was to evaluate the effectiveness and safety of bupivacaine in combination with either neostigmine or tramadol for caudal block in children undergoing inguinal herniorrhaphy. METHODS: In a double-blinded randomized trial, sixty children undergoing inguinal herniorrhaphy were enrolled to receive a caudal block with either 0.25% bupivacaine (1 ml x kg(-1)) with neostigmine (2 microg x kg(-1)) (group BN) or tramadol (1 mg x kg(-1)) (group BT). Hemodynamic variables, pain and sedation scores, additional analgesic requirements, and side effects were compared between two groups. RESULTS: Duration of analgesia was longer in group BT (17.30 +/- 8.24 h) compared with group BN (13.98 +/- 10.03 h) (P = 0.03). Total consumption of rescue analgesic was significantly lower in group BT compared with group BN (P = 0.04). There were no significant differences in heart rate, mean arterial pressure, and oxygen saturation between groups. Adverse effects excluding the vomiting were not observed in any patients. CONCLUSION: In conclusion, tramadol (1 mg x kg(-1)) compared with neostigmine (2 microg x kg( 1)) might provide both prolonged duration of analgesia and extended time to first analgesic in caudal block. PMID- 20716079 TI - Impact of chronic condition status and severity on dental treatment under general anesthesia for Medicaid-enrolled children in Iowa state. AB - OBJECTIVE: To assess the impact of chronic condition (CC) status and CC severity, respectively, on the odds of receiving dental treatment under general anesthesia (GA) for Medicaid-enrolled children by age group. METHODS: This was a retrospective analysis of Iowa Medicaid-enrolled children <15 years (n = 62 721) from 2005 to 2008. 3M Clinical Risk Grouping Software identified each child's CC status (yes/no) and assigned children with a CC into a hierarchal CC severity group (episodic/life-long/complex). Multiple variable logistic regression models were used to identify the determinants of dental treatment under GA. RESULTS: Less than 1% of children received dental treatment under GA. While there was no significant difference in dental treatment under GA by CC status for children <6, those with a life-long CC were twice as likely to receive dental treatment under GA as demographically similar children with an episodic CC (P < 0.05). Children ages 6-14 with a CC were three times as likely as those without a CC to receive treatment under GA (P = 0.001). There was also a direct relationship between CC severity and dental treatment under GA use for older children. Those living in nonmetropolitan areas were more likely to receive treatment under GA as were children who previously received dental treatment under GA. CONCLUSIONS: Chronic condition status and severity were more important determinants of dental treatment under GA for Medicaid-enrolled children ages 6-14 than for those <6. Understanding these relationships is a critical step in developing clinical strategies and interventions aimed at preventing dental disease for Medicaid enrolled children whose reasons for needing dental treatment under GA are modifiable. PMID- 20716081 TI - Emergence agitation after cataract surgery in children: a comparison of midazolam, propofol and ketamine. AB - OBJECTIVES: The aim of this study was to determine whether the concurrent use of either of a subhypnotic dose of midazolam, propofol or ketamine with fentanyl just before discontinuing the sevoflurane anesthesia would effectively sedate the children as they recovered and significantly decrease the incidence and severity of emergence agitation and would not delay patient awakening and discharge. BACKGROUND: Postoperative emergence agitation may occur in children after general anesthesia with volatile anesthetics. Children who undergo cataract surgery after sevoflurane induction and sevoflurane-remifentanil maintenance may experience this type of agitation. METHODS/MATERIALS: In 120 un-premedicated children aged 1 7 years, mask induction with sevoflurane was performed and they were then randomly assigned to one of the three antiagitation postoperative groups (n = 40). We studied the postoperative antiagitation effects of subhypnotic doses of midazolam combined with fentanyl, propofol with fentanyl or ketamine with fentanyl administered just before discontinuing the sevoflurane anesthesia. A score for the level of agitation can be assigned based on the recovery mental state (RMS) scale and the recently published pediatric anesthesia emergence delirium scale (PAED). Postoperative factors assessed included emergence behaviors, the time to eye opening, the time to discharge from the postanesthesia care unit (PACU) to the ward. RESULTS: There were significantly more agitated children in the ketamine-group when compared to the midazolam-group or to the propofol-group at all time P < 0.05), especially at 10 and 15 min. The PAED scale showed a significant advantage for midazolam-fentanyl [5 (2-15)] and propofol fentanyl [6 (3-15)] versus ketamine-fentanyl [10 (3-20)] (P < 0.05). The time to discharge from the PACU to the ward was not significantly different among the groups. CONCLUSIONS: Intravenous administration of a subhypnotic dose of midazolam or propofol in addition to a low dose of fentanyl just before discontinuing the sevoflurane anesthesia was both effective on decreasing the incidence and severity of emergence agitation in children undergoing cataract extraction without significant delaying recovery time and discharge. The effect of midazolam was clearer than that seen with propofol. PMID- 20716082 TI - Pro-con debate: cohort studies vs the randomized clinical trial methodology in pediatric anesthesia. PMID- 20716083 TI - Ultrasound-guided lung recruitment in a young infant with ARDS. PMID- 20716084 TI - Comments on attention-deficit/hyperactivity disorders and anesthesia. PMID- 20716086 TI - Incidence of complications associated with rapid sequence induction (RSI) in children - it is a matter of age and technique. PMID- 20716088 TI - A randomized trial of propofol consumption and recovery profile with BIS-guided anesthesia compared to standard practice in children. PMID- 20716089 TI - Blind intubation through the air-Q laryngeal mask in children - a word of caution. PMID- 20716090 TI - Glidescope intubation after failed fiberoptic intubation. PMID- 20716091 TI - Complications of bronchoscope removal in an infant with innominate artery. PMID- 20716092 TI - Single lung ventilation with an endotracheal tube in a small child undergoing right thoracotomy. PMID- 20716093 TI - Health care professions' education: challenges and opportunities. PMID- 20716094 TI - Balancing ethical reasoning and emotional sensibility. PMID- 20716095 TI - Education for health professionals in the emerging market economies: a literature review. AB - CONTEXT: Along with economic growth and social reforms, the emerging market economies (EMEs) are undergoing restructuring of their health care systems. There is now an increased focus on disease prevention and primary care, along with a patient-centred approach to health care delivery. However, these changes need to be complemented by alterations in the health care education system. METHODS: A review of the published literature, limited to the last 10 years, was conducted to include recent updates on medical and nursing education. This was done by systematically searching appropriate databases using keywords. This review covers only the common issues related to education and training in EMEs. RESULTS: Issues identified included: the mismatch between the health needs of the population and education curricula; outdated curricula and teaching methods; growing numbers of medical schools; the quality of education, and inadequate career guidance for students to help them make decisions about choosing a health profession as a career and, later, about choosing a field of specialisation. CONCLUSIONS: The literature provides evidence of innovative approaches adopted in several EMEs, which include: outcome-based education; community-oriented medical education; problem-based learning; initiatives to improve quality, and initiatives to resolve the shortage of skilled educators for medical and nursing schools. The health care systems in EMEs are undergoing changes imposed by economic, political and social transition. Reforms in health systems will need to be complemented by educational reforms. Education systems require to be updated through needs-based comprehensive curriculum design and innovative teaching methods. The challenges imposed by the growth in the number of public and private institutions and the need for a standardised accreditation system for quality assurance demand attention. The profiles of both family medicine and community health care will need to be raised and their status enhanced to attract high-calibre students to these specialties. PMID- 20716096 TI - A medical ethical reasoning model and its contributions to medical education. AB - OBJECTIVES: Ethical reasoning in medicine is not well understood and medical educators often find it difficult to justify what and how they teach and assess in medical ethics. To facilitate the development of moral values and professional conduct, a model of ethical reasoning was created. The purposes of this paper are to describe the ethical reasoning model and to indicate how it can be used to foster moral and ethical behaviours. METHODS: The ethical reasoning model was created from information derived from two sources: (i) an examination of different ethical models described in the literature, and (ii) think-aloud interviews with ethical experts in Taiwan and Canada. All the components and cognitive steps used by experts in ethical decision making were extracted and categorised. Interview subjects consisted of 16 voluntary ethics experts. The ethical reasoning models reported in the literature were divided into two groups according to whether they were justification-based or task-based models. Neither of the two types represented the 'whole picture' of ethical reasoning in medicine. This analysis enabled us to identify five universal cognitive steps and the gaps between 'logical decision' and 'action'. RESULTS: The think-aloud interviews verified the multi-dimensional components or steps used by experts when resolving ethical problems. The resulting model, designated the Medical Ethical Reasoning (MER) Model, reflects interactions within three domains: medical and ethical knowledge; cognitive reasoning processes, and attitude. CONCLUSIONS: The MER Model accurately reflects how doctors resolve ethical dilemmas and is seen to be helpful in identifying what and how educators should teach and assess in ethical reasoning. The model can also serve as a communication framework for curricular design. A 'humane' doctor is competent in providing quality, ethical patient care. Making an appropriate ethical decision is the foundation for subsequent ethical behaviours. By contrast with the abundant evidence cited in previous research describing how doctors solve medical problems, there is little empirical evidence indicating how doctors make appropriate ethical decisions. Thus, the cognition of ethical reasoning in medicine is not well understood. This paper represents a step towards overcoming this problem. PMID- 20716097 TI - Checking the checklist: a content analysis of expert- and evidence-based case specific checklist items. AB - OBJECTIVES: Research on objective structured clinical examinations (OSCEs) is extensive. However, relatively little has been written on the development of case specific checklists on history taking and physical examination. Background information on the development of these checklists is a key element of the assessment of their content validity. Usually, expert panels are involved in the development of checklists. The objective of this study is to compare expert-based items on OSCE checklists with evidence-based items identified in the literature. METHODS: Evidence-based items covering both history taking and physical examination for specific clinical problems and diseases were identified in the literature. Items on nine expert-based checklists for OSCE examination stations were evaluated by comparing them with items identified in the literature. The data were grouped into three categories: (i) expert-based items; (ii) evidence based items, and (iii) evidence-based items with a specific measure of their relevance. RESULTS: Out of 227 expert-based items, 58 (26%) were not found in the literature. Of 388 evidence-based items found in the literature, 219 (56%) were not included in the expert-based checklists. Of these 219 items, 82 (37%) had a specific measure of importance, such as an odds ratio for a diagnosis, making that diagnosis more or less probable. CONCLUSIONS: Expert-based, case-specific checklist items developed for OSCE stations do not coincide with evidence-based items identified in the literature. Further research is needed to ascertain what this inconsistency means for test validity. PMID- 20716098 TI - Influences of deep learning, need for cognition and preparation time on open- and closed-book test performance. AB - OBJECTIVES: The ability to master discipline-specific knowledge is one of the competencies medical students must acquire. In this context, 'mastering' means being able to recall and apply knowledge. A way to assess this competency is to use both open- and closed-book tests. Student performance on both tests can be influenced by the way the student processes information. Deep information processing is expected to influence performance positively. The personal preferences of students in relation to how they process information in general (i.e. their level of need for cognition) may also be of importance. In this study, we examined the inter-relatedness of deep learning, need for cognition and preparation time, and scores on open- and closed-book tests. METHODS: This study was conducted at the University Medical Centre Groningen. Participants were Year 2 students (n = 423). They were asked to complete a questionnaire on deep information processing, a scale for need for cognition on a questionnaire on intellectualism and, additionally, to write down the time they spent on test preparation. We related these measures to the students' scores on two tests, both consisting of open- and closed-book components and used structural equation modelling to analyse the data. RESULTS: Both questionnaires were completed by 239 students (57%). The results showed that need for cognition positively influenced both open- and closed-book test scores (beta-coefficients 0.05 and 0.11, respectively). Furthermore, study outcomes measured by open-book tests predicted closed-book test results better than the other way around (beta-coefficients 0.72 and 0.11, respectively). CONCLUSIONS: Students with a high need for cognition performed better on open- as well as closed-book tests. Deep learning did not influence their performance. Adding open-book tests to the regularly used closed book tests seems to improve the recall of knowledge that has to be known by heart. Need for cognition may provide a valuable addition to existing theories on learning. PMID- 20716099 TI - An exploration of perceptions of tutor evaluation in problem-based learning tutorials. AB - CONTEXT: Within problem-based learning (PBL) tutorials, the relationship between student and tutor is predicated on the tutor adopting the role of mentor and metacognitive coach. This rapport differs considerably from the traditional teacher-student relationship and is likely to impact on the process and outcomes of tutor evaluations. Such evaluations are a ubiquitous means of providing feedback to tutors from students about the quality of their facilitation. Although critiqued in the literature as 'popularity contests', tutor evaluations are commonly used in tertiary institutions for purposes of recruitment, re employment and promotion. METHODS: This study seeks to provide insight into students' and tutors' perceptions of evaluations of teaching within PBL tutorials. As a unique teaching and learning environment, the PBL tutorial requires sophisticated facilitation skills of tutors and considerable autonomy from students. Qualitative data were gathered from three focus group discussions and one in-depth interview with first- and second-year medical students and their PBL tutors. RESULTS: Thematic analysis identified four major themes, including: defining the 'ideal' tutor; making unthinking or deliberately false evaluations; promoting a consumer mentality, and providing support for tutors. An underlying suspicion of the purpose of the evaluation process was apparent among tutors and students. CONCLUSIONS: Findings suggest that, within the PBL tutorial environment at least, regularly evaluating tutors creates mistrust and confusion among the medical school, the tutor and the student on several levels. Suggestions for further research are proposed. PMID- 20716100 TI - Faculty development: if you build it, they will come. AB - OBJECTIVES: The goals of this study were three-fold: to explore the reasons why some clinical teachers regularly attend centralised faculty development activities; to compare their responses with those of colleagues who do not attend, and to learn how we can make faculty development programmes more pertinent to teachers' needs. METHODS: In 2008-2009, we conducted focus groups with 23 clinical teachers who had participated in faculty development activities on a regular basis in order to ascertain their perceptions of faculty development, reasons for participation, and perceived barriers against involvement. Thematic analysis and research team consensus guided the data interpretation. RESULTS: Reasons for regular participation included the perceptions that: faculty development enables personal and professional growth; learning and self-improvement are valued; workshop topics are viewed as relevant to teachers' needs; the opportunity to network with colleagues is appreciated, and initial positive experiences promote ongoing involvement. Barriers against participation mirrored those cited by non-attendees in an earlier study (e.g. volume of work, lack of time, logistical factors), but did not prevent participation. Suggestions for increasing participation included introducing a 'buddy system' for junior faculty members, an orientation workshop for new staff, and increased role-modelling and mentorship. CONCLUSIONS: The conceptualisation of faculty development as a means to achieve specific objectives and the desire for relevant programming that addresses current needs (i.e., expectancies), together with an appreciation of learning, self-improvement and networking with colleagues (i.e., values), were highlighted as reasons for participation by regular attendees. Medical educators should consider these 'lessons learned' in the design and delivery of faculty development offerings. They should also continue to explore the notion of faculty development as a social practice and the application of motivational theories that include expectancy-value constructs to personal and professional development. PMID- 20716102 TI - Supporting student-doctors from under-resourced educational backgrounds: an academic development programme. AB - OBJECTIVES: Increased student diversity in medical schools is considered necessary. However, very few medical school applicants from under-resourced educational backgrounds achieve competitive academic entrance scores. Pre admission development programmes that aim to produce competitive applicants may be inefficient in countries where under-represented communities are majority populations. This study set out to determine: (i) whether an academic development programme (ADP) integrated into an existing South African medical training programme retained ADP students and enabled them to graduate within a reasonable period of time; (ii) the academic impact of the ADP, and (iii) whether performance in high school matriculation examinations predicted performance in medical school. METHODS: This retrospective study analysed records of medical students admitted between 1991 and 2001. Non-ADP and ADP students were compared with respect to: student retention; time to graduation; matriculation scores, and performance in medical school. The association between matriculation scores and third-year examination results was determined. RESULTS: The average student retention rates for the non-ADP (1992-2001) and ADP (1991-2000) cohorts were 92% and 70%, respectively. Non-ADP and ADP students who graduated were compared with respect to four parameters: the mean additional time required to graduate by each group was 0.16 years (95% confidence interval [CI] 0.13-0.18) and 0.38 years (0.27-0.48), respectively. Mean matriculation scores were 44.5 (95% CI 44.4-44.7) and 37.4 (95% CI 37.0-37.7) points, respectively (effect size = 3.2). Mean marks for third-year courses were 65.0% (95% CI 64.6-65.4) and 58.7% (95% CI 57.7 59.6), respectively (effect size = 1.0). Mean marks for final-year courses were 68.3% (95% CI 68.1-68.5) and 64.2% (95% CI 63.6-64.7), respectively; the effect size remained constant at 1.2. Third-year marks for non-ADP and ADP students, respectively, showed moderate (11%) and low (3%) association with matriculation scores. CONCLUSIONS: Although the retention of ADP students was lower than that of non-ADP students, the ADP enabled those who graduated to overcome the effects of under-resourced schooling and to perform well in final-year examinations. PMID- 20716101 TI - Developmental challenges, stressors and coping strategies in medical residents: a qualitative analysis of support groups. AB - OBJECTIVES: Stress and burnout are endemic in postgraduate medical training, but little research is available to guide supportive interventions. The identification of the longitudinal emotional and developmental coping needs of internal medicine residents could assist in the better design and implementation of supportive interventions. METHODS: In this retrospective, exploratory study, six internal medicine resident support groups (n = 62; residents in postgraduate years [PGY] 1-3) were followed for a period of 2 years. Qualitative data were extracted from monthly support group process notes to identify common themes, stressors, emotions, coping strategies and developmental challenges faced during training. Quantitative questionnaire data were collected on burnout, group attendance and resident satisfaction. RESULTS: Using professional identity development models and classic stress and coping theory as a starting point, a derivation of grounded theory was used to identify common themes and emotions documented in support group process notes. The most common themes included understanding resident roles and responsibilities, developing an identity as a resident and doctor, building professional confidence, cognitive and behavioural responses to stress, and concerns about flaws in local and national health care training and delivery systems. Anxiety and guilt were the most commonly reported emotions, followed by positive emotions and anger. Burnout scores were highest for the second half of PGY1, but improved over subsequent training years. Support group attendance and satisfaction were both high. Residents overwhelmingly pointed to peer relationships as the most critical source of support throughout postgraduate training. CONCLUSIONS: Developmentally informed programmatic adaptations could better support the emotional growth and personal and professional development of postgraduate medical trainees. Future directions should include a controlled trial of resident support groups, assessments of 'active ingredients' (i.e. to establish which supportive interventions are most effective), and evaluations of programmatic adaptations. PMID- 20716103 TI - Exploring how students think: a new method combining think-aloud and concept mapping protocols. AB - OBJECTIVES: A key element of medical competence is problem solving. Previous work has shown that doctors use inductive reasoning to progress from facts to hypotheses and deductive reasoning to move from hypotheses to the gathering of confirmatory information. No individual assessment method has been designed to quantify the use of inductive and deductive procedures within clinical reasoning. The aim of this study was to explore the feasibility and reliability of a new method which allows for the rapid identification of the style (inductive or deductive) of clinical reasoning in medical students and experts. METHODS: The study included four groups of four participants. These comprised groups of medical students in Years 3, 4 and 5 and a group of specialists in internal medicine, all at a medical school with a 6-year curriculum in France. Participants were asked to solve four clinical problems by thinking aloud. The thinking expressed aloud was immediately transcribed into concept maps by one or two 'writers' trained to distinguish inductive and deductive links. Reliability was assessed by estimating the inter-writer correlation. The calculated rate of inductive reasoning, the richness score and the rate of exhaustiveness of reasoning were compared according to the level of expertise of the individual and the type of clinical problem. RESULTS: The total number of maps drawn amounted to 32 for students in Year 4, 32 for students in Year 5, 16 for students in Year 3 and 16 for experts. A positive correlation was found between writers (R = 0.66 0.93). Richness scores and rates of exhaustiveness of reasoning did not differ according to expertise level. The rate of inductive reasoning varied as expected according to the nature of the clinical problem and was lower in experts (41% versus 67%). CONCLUSIONS: This new method showed good reliability and may be a promising tool for the assessment of medical problem-solving skills, giving teachers a means of diagnosing how their students think when they are confronted with clinical problems. PMID- 20716104 TI - Three-dimensional visualisation improves understanding of surgical liver anatomy. AB - OBJECTIVES: Three-dimensional (3-D) representation is thought to improve understanding of complex spatial interactions and is being used more frequently in diagnostic and therapeutic procedures. It has been suggested that males benefit more than females from 3-D presentations. There have been few randomised trials to confirm these issues. We carried out a randomised trial, based on the identification of complex surgical liver anatomy, to evaluate whether 3-D presentation has a beneficial impact and if gender differences were evident. METHODS: A computer-based teaching module (TM) was developed to test whether two dimensional (2-D) computed tomography (CT) images or 3-D presentations result in better understanding of liver anatomy. Following a PowerPoint lecture, students were randomly selected to participate in computer-based testing which used either 2-D images presented as consecutive transversal slices, or one of two 3-D variations. In one of these the vessel tree of portal and hepatic veins was shown in one colour (3-D) and in the other the two vessel systems were coloured differently (3-Dc). Participants were asked to answer 11 medical questions concerning surgical anatomy and four questions on their subjective assessment of the TM. RESULTS: Of the 160 Year 4 and 5 medical students (56.8% female) who participated in this prospective randomised trial, students exposed to 3-D presentation performed significantly better than those exposed to 2-D images (p < 0.001). Comparison of the number of correct answers revealed no significant differences between the 3-D and 3-Dc modalities p > 0.1). Male students gave significantly more correct answers in the 3-D and 3-Dc modalities than female students (p < 0.03). The gender difference observed in both 3-D modalities was not evident in the 2-D group (p = 0.21). CONCLUSIONS: This study showed that 3-D imaging significantly improved the identification of complex surgical liver anatomy. Male students benefited significantly more than female students from 3-D presentations. Use of colour in 3-D presentation did not improve student performance. PMID- 20716105 TI - The UK communication curricula wheel in different contexts: providing local evidence. PMID- 20716106 TI - Qualitative research in medical education. PMID- 20716107 TI - Genotypic characterization of Brochothrix spp. isolated from meat, poultry and fish. AB - AIM: To study genotypic diversity of isolates of Brochothrix thermosphacta recovered from meat, poultry and fish. METHODS AND RESULTS: A total of 27 bacteria isolated from 19 samples of meat, poultry and fish were identified phenotypically and genotypically using PCR amplification of 16S-23S rDNA intergenic transcribed spacer (ITS-PCR), repetitive sequence-based PCR (rep-PCR) and 16S rDNA sequencing. Using ITS-PCR, all bacteria showed the same DNA profile as the reference strains of Br. thermosphacta, allowing typing of the isolates at species level. Using 16S rDNA sequencing, all isolates were identified, at genus and species level, as Br. thermosphacta. Identification as Br. campestris was observed with a lower, but very close, level of similarity. Rep-PCR was more discriminatory than ITS-PCR and allowed differentiation of four subgroups among the isolates. CONCLUSION: Minor genotypic differences among Br. thermosphacta strains from meat, poultry and fish were observed. SIGNIFICANCE AND IMPACT OF THE STUDY: A rudimentary exploration of genotypic differences of Br. thermosphacta from meat, poultry and fish resulted in preliminary confirmation of the suitability of ITS-PCR for typing Br. thermosphacta and confirmed the value of rep-PCR fingerprinting to discriminate between Br. thermosphacta strains. PMID- 20716108 TI - Oxidative protein folding in the secretory pathway and redox signaling across compartments and cells. AB - The endoplasmic reticulum (ER) is central for many essential cellular activities, such as folding, assembly and quality control of secretory and membrane proteins, disulfide bond formation, glycosylation, lipid biosynthesis, Ca(2+) storage and signaling. In addition, this multifunctional organelle integrates many adaptive and/or maladaptive signaling cues reporting on metabolism, proteostasis, Ca(2+) and redox homeostasis. We are beginning to understand how these functions and pathways are integrated with one another to regulate homeostasis at cell, tissue and organism levels. The mechanisms underlying the introduction of the proper set of disulfide bonds into secretory proteins (oxidative folding) are strictly related to redox homeostasis, ER stress sensing and signaling and provide a good example of the integration systems operative in the early secretory compartment. PMID- 20716109 TI - Rab3 proteins involved in vesicle biogenesis and priming in embryonic mouse chromaffin cells. AB - The four Rab3 paralogs A-D are involved in exocytosis, but their mechanisms of action are hard to study due to functional redundancy. Here, we used a quadruple Rab3 knockout (KO) (rab3a, rab3b, rab3c, rab3d null, here denoted as ABCD(-/-) ) mouse line to investigate Rab3 function in embryonic mouse adrenal chromaffin cells by electron microscopy and electrophysiological measurements. We show that in cells from ABCD(-/-) animals large dense-core vesicles (LDCVs) are less abundant, while the number of morphologically docked granules is normal. By capacitance measurements, we show that deletion of Rab3s reduces the size of the releasable vesicle pools but does not alter their fusion kinetics, consistent with an altered function in vesicle priming. The sustained release component has a sigmoid shape in ABCD(-/-) cells when normalized to the releasable pool size, indicating that vesicle priming follows at a higher rate after an initial delay. Rescue experiments showed that short-term (4-6 h) overexpression of Rab3A or Rab3C suffices to rescue vesicle priming and secretion, but it does not restore the number of secretory vesicles. We conclude that Rab3 proteins play two distinct stimulating roles for LDCV fusion in embryonic chromaffin cells, by facilitating vesicle biogenesis and stabilizing the primed vesicle state. PMID- 20716112 TI - Row with a team or paddle alone. Abstracts of the Australian College of Mental Health Nursing 36th International Conference. August 30-September 2, 2010. Tasmania. PMID- 20716110 TI - Sequential depletion and acquisition of proteins during Golgi stack disassembly and reformation. AB - Herein, we report the stepwise transport of multiple plant Golgi membrane markers during disassembly of the Golgi apparatus in tobacco leaf epidermal cells in response to the induced expression of the GTP-locked Sar1p or Brefeldin A (BFA), and reassembly on BFA washout. The distribution of fluorescent Golgi-resident N glycan processing enzymes and matrix proteins (golgins) with specific cis-trans Golgi sub-locations was followed by confocal microscopy during disassembly and reassembly. The first event during Golgi disassembly was the loss of trans-Golgi enzymes and golgins from Golgi membranes, followed by a sequential redistribution of medial and cis-Golgi enzymes into the endoplasmic reticulum (ER), whilst golgins were relocated to the ER or cytoplasm. This event was confirmed by fractionation and immuno-blotting. The sequential redistribution of Golgi components in a trans-cis sequence may highlight a novel retrograde trafficking pathway between the trans-Golgi and the ER in plants. Release of Golgi markers from the ER upon BFA washout occurred in the opposite sequence, with cis-matrix proteins labelling Golgi-like structures before cis/medial enzymes. Trans-enzyme location was preceded by trans-matrix proteins being recruited back to Golgi membranes. Our results show that Golgi disassembly and reassembly occur in a highly ordered fashion in plants. PMID- 20716111 TI - Trafficking and recycling of the connexin43 gap junction protein during mitosis. AB - During the cell cycle, gap junction communication, morphology and distribution of connexin43 (Cx43)-containing structures change dramatically. As cells round up in mitosis, Cx43 labeling is mostly intracellular and intercellular coupling is reduced. We investigated Cx43 distributions during mitosis both in endogenous and exogenous expressing cells using optical pulse-chase labeling, correlated light and electron microscopy, immunocytochemistry and biochemical analysis. Time-lapse imaging of green fluorescent protein (GFP)/tetracysteine tagged Cx43 (Cx43-GFP 4C) expressing cells revealed an early disappearance of gap junctions, progressive accumulation of Cx43 in cytoplasmic structures, and an unexpected subset pool of protein concentrated in the plasma membrane surrounding the midbody region in telophase followed by rapid reappearance of punctate plaques upon mitotic exit. These distributions were also observed in immuno-labeled endogenous Cx43-expressing cells. Photo-oxidation of ReAsH-labeled Cx43-GFP-4C cells in telophase confirmed that Cx43 is distributed in the plasma membrane surrounding the midbody as apparent connexons and in cytoplasmic vesicles. We performed optical pulse-chase labeling and single label time-lapse imaging of synchronized cells stably expressing Cx43 with internal tetracysteine domains through mitosis. In late telophase, older Cx43 is segregated mainly to the plasma membrane while newer Cx43 is intracellular. This older population nucleates new gap junctions permitting rapid resumption of communication upon mitotic exit. PMID- 20716113 TI - Epac as a novel effector of airway smooth muscle relaxation. AB - Dysfunctional regulation of airway smooth muscle tone is a feature of obstructive airway diseases such as asthma and chronic obstructive pulmonary disease. Airway smooth muscle contraction is directly associated with changes in the phosphorylation of myosin light chain (MLC), which is increased by Rho and decreased by Rac. Although cyclic adenosine monophosphate (cAMP)-elevating agents are believed to relieve bronchoconstriction mainly via activation of protein kinase A (PKA), here we addressed the role of the novel cAMP-mediated exchange protein Epac in the regulation of airway smooth muscle tone. Isometric tension measurements showed that specific activation of Epac led to relaxation of guinea pig tracheal preparations pre-contracted with methacholine, independently of PKA. In airway smooth muscle cells, Epac activation reduced methacholine-induced MLC phosphorylation. Moreover, when Epac was stimulated, we observed a decreased methacholine-induced RhoA activation, measured by both stress fibre formation and pull-down assay whereas the same Epac activation prevented methacholine-induced Rac1 inhibition measured by pull-down assay. Epac-driven inhibition of both methacholine-induced muscle contraction by Toxin B-1470, and MLC phosphorylation by the Rac1-inhibitor NSC23766, were significantly attenuated, confirming the importance of Rac1 in Epac-mediated relaxation. Importantly, human airway smooth muscle tissue also expresses Epac, and Epac activation both relaxed pre contracted human tracheal preparations and decreased MLC phosphorylation. Collectively, we show that activation of Epac relaxes airway smooth muscle by decreasing MLC phosphorylation by skewing the balance of RhoA/Rac1 activation towards Rac1. Therefore, activation of Epac may have therapeutical potential in the treatment of obstructive airway diseases. PMID- 20716114 TI - Survivin regulation by HER2 through NF-kappaB and c-myc in irradiated breast cancer cells. AB - Radiotherapy is an important treatment modality against cancer resulting in apoptosis and inhibition of cell growth. Survivin is an important cancer biomarker conferring to tumour cells increased survival potential by inhibiting apoptosis. In the present study, we investigated the implication of breast cancer cells features, as hormone receptors and p53 status, in the radio-resistance of breast cancer cells and in the regulation of survivin's expression by nuclear factor (NF)-kappaB and c-myc. Six breast cancer cell lines Michigan Cancer Foundation (MCF-7), MCF-7/Human Epidermal Growth Factor Receptor (HER)2, M. D. Anderson - Metastatic Breast (MDA-MB-231), SK-BR-3, BT-474 and Human Breast Lactating (HBL-100) were irradiated and cell viability as well as cell cycle distribution were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Survivin mRNA and protein levels were evaluated by real time PCR and Western blot analysis. Survivin and HER2 gene knockdown was performed with siRNA technology and investigation of transcription factors binding to survivin and c-myc gene promoters was assessed by chromatin immunoprecipitation. Student's t-test and F statistics were used for statistical evaluation. Our results demonstrated that only HER2(+) breast cancer cells up-regulated survivin upon irradiation, whereas HER2 knockdown in HER2(+) cells led to survivin's down-regulation. Survivin and especially HER2 knockdown abolished the observed G2/M cell cycle checkpoint and reduced the radio-resistance of HER2 overexpressing breast cancer cells. Additionally, HER2 was found to regulate survivin's expression through NF-kappaB and c-myc transcription factors. This study revealed the significance of HER2 in the radio-resistance of HER2(+) breast cancer cells through induction of transcription factors NF-kappaB and c-myc, leading to activation of survivin, a downstream target oncogene preventing apoptosis. PMID- 20716115 TI - miRNA profiling along tumour progression in ovarian carcinoma. AB - MicroRNAs (miRNAs) are small non-coding RNAs that exert a regulatory effect post transcriptionally by binding target mRNAs and inhibiting gene translation. miRNA expression is deregulated in cancer. The aim of this study was to characterize the differences in miRNA expression pattern and the miRNA-regulating machinery between ovarian carcinoma (OC) cells in primary tumours versus effusions. Using miRNA array platforms, we analysed a set of 21 tumours (13 effusions, 8 primary carcinomas) and identified three sets of miRNAs, one that is highly expressed in both primary carcinomas and effusions, one overexpressed in primary carcinomas and one overexpressed in effusions. Levels of selected miRNAs were analysed using quantitative PCR in an independent set of 45 additional tumours (30 effusions, 15 primary carcinomas). Reduced miR-145 and miR-214 and elevated let-7f, miR-182, miR-210, miR-200c, miR-222 and miR-23a levels were found in effusions in both sets. In silico target prediction programs identified potential target genes for some of the differentially expressed miRNAs. Expression of zinc finger E-box binding homeobox (ZEB)1 and c-Myc, targets of miR-200c, as well as of p21 protein (Cdc42/Rac)-activated kinase (PAK)1 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), predicted targets of miR-222, were analysed. Inverse correlations between expression levels of the indicated miRNAs and of the predicted target genes were found. In addition, higher expression of the miRNA processing molecules Ago1, Ago2 and Dicer was observed in effusions compared to primary carcinomas. In conclusion, our data are the first to document different miRNA expression and regulation profiles in primary and metastatic OC, suggesting a role for these molecules in tumour progression. PMID- 20716117 TI - The roles of p27(Kip1) and DNA damage signalling in the chemotherapy-induced delayed cell cycle checkpoint. AB - DNA lesions trigger the DNA damage response (DDR) machinery, which protects genomic integrity and sustains cellular survival. Increasing data underline the significance of the integrity of the DDR pathway in chemotherapy response. According to a recent work, persistent exposure of A549 lung carcinoma cells to doxorubicin induces an initial DDR-dependent checkpoint response, followed by a later DDR-independent, but p27(Kip1)-dependent one. Prompted by the above report and to better understand the involvement of the DDR signaling after chemotherapeutic stress, we examined the potential role of the canonical DDR pathway in A549 cells treated with doxorubicin. Exposure of A549 cells, prior to doxorubicin treatment, to ATM, ATR and DNA-PKcs inhibitors either alone or in various combinations, revealed that the earlier documented two-step response was DDR-dependent in both steps. Notably, inhibition of both ATM and ATR or selective inhibition of ATM or DNA-PKcs resulted in cell-cycle re-entry despite the increased levels of p27(Kip1) at all time points analyzed. We further investigated the regulation of p27(Kip1) protein levels in the particular setting. Our results showed that the protein status of p27(Kip1) is mainly determined by p38-MAPK, whereas the role of SKP2 is less significant in the doxoroubicin-treated A549 cells. Cumulatively, we provide evidence that the DNA damage signaling is responsible for the prolonged cell cycle arrest observed after persistent chemotherapy-induced genotoxic stress. In conclusion, precise identification of the molecular mechanisms that are activated during the chemotherapeutic cycles could potentially increase the sensitization to the therapy applied. PMID- 20716116 TI - Role of guanylate binding protein-1 in vascular defects associated with chronic inflammatory diseases. AB - Rheumatic autoimmune disorders are characterized by a sustained pro-inflammatory microenvironment associated with impaired function of endothelial progenitor cells (EPC) and concomitant vascular defects. Guanylate binding protein-1 (GBP-1) is a marker and intracellular regulator of the inhibition of proliferation, migration and invasion of endothelial cells induced by several pro-inflammatory cytokines. In addition, GBP-1 is actively secreted by endothelial cells. In this study, significantly increased levels of GBP-1 were detected in the sera of patients with chronic inflammatory disorders. Accordingly we investigated the function of GBP-1 in EPC. Interestingly, stable expression of GBP-1 in T17b EPC induced premature differentiation of these cells, as indicated by a robust up regulation of both Flk-1 and von Willebrand factor expression. In addition, GBP-1 inhibited the proliferation and migration of EPC in vitro. We confirmed that GBP 1 inhibited vessel-directed migration of EPC at the tissue level using the rat arterio-venous loop model as a novel quantitative in vivo migration assay. Overall, our findings indicate that GBP-1 contributes to vascular dysfunction in chronic inflammatory diseases by inhibiting EPC angiogenic activity via the induction of premature EPC differentiation. PMID- 20716118 TI - The regulatory role of c-MYC on HDAC2 and PcG expression in human multipotent stem cells. AB - Myelocytomatosis oncogene (c-MYC) is a well-known nuclear oncoprotein having multiple functions in cell proliferation, apoptosis and cellular transformation. Chromosomal modification is also important to the differentiation and growth of stem cells. Histone deacethylase (HDAC) and polycomb group (PcG) family genes are well-known chromosomal modification genes. The aim of this study was to elucidate the role of c-MYC in the expression of chromosomal modification via the HDAC family genes in human mesenchymal stem cells (hMSCs). To achieve this goal, c-MYC expression was modified by gene knockdown and overexpression via lentivirus vector. Using the modified c-MYC expression, our study was focused on cell proliferation, differentiation and cell cycle. Furthermore, the relationship of c MYC with HDAC2 and PcG genes was also examined. The cell proliferation and differentiation were checked and shown to be dramatically decreased in c-MYC knocked-down human umbilical cord blood-derived MSCs, whereas they were increased in c-MYC overexpressing cells. Similarly, RT-PCR and Western blotting results revealed that HDAC2 expression was decreased in c-MYC knocked-down and increased in c-MYC overexpressing hMSCs. Database indicates presence of c-MYC binding motif in HDAC2 promoter region, which was confirmed by chromatin immunoprecipitation assay. The influence of c-MYC and HDAC2 on PcG expression was confirmed. This might indicate the regulatory role of c-MYC over HDAC2 and PcG genes. c-MYCs' regulatory role over HDAC2 was also confirmed in human adipose tissue-derived MSCs and bone-marrow derived MSCs. From this finding, it can be concluded that c MYC plays a vital role in cell proliferation and differentiation via chromosomal modification. PMID- 20716119 TI - Cutting edge: Chk1 directs senescence and mitotic catastrophe in recovery from G2 checkpoint arrest. AB - Besides the well-understood DNA damage response via establishment of G(2) checkpoint arrest, novel studies focus on the recovery from arrest by checkpoint override to monitor cell cycle re-entry. The aim of this study was to investigate the role of Chk1 in the recovery from G(2) checkpoint arrest in HCT116 (human colorectal cancer) wt, p53(-/-) and p21(-/-) cell lines following H(2) O(2) treatment. Firstly, DNA damage caused G(2) checkpoint activation via Chk1. Secondly, overriding G(2) checkpoint led to (i) mitotic slippage, cell cycle re entry in G(1) and subsequent G(1) arrest associated with senescence or (ii) premature mitotic entry in the absence of p53/p21(WAF1) causing mitotic catastrophe. We revealed subtle differences in the initial Chk1-involved G(2) arrest with respect to p53/p21(WAF1) : absence of either protein led to late G(2) arrest instead of the classic G(2) arrest during checkpoint initiation, and this impacted the release back into the cell cycle. Thus, G(2) arrest correlated with downstream senescence, but late G(2) arrest led to mitotic catastrophe, although both cell cycle re-entries were linked to upstream Chk1 signalling. Chk1 knockdown deciphered that Chk1 defines long-term DNA damage responses causing cell cycle re-entry. We propose that recovery from oxidative DNA damage-induced G(2) arrest requires Chk1. It works as cutting edge and navigates cells to senescence or mitotic catastrophe. The decision, however, seems to depend on p53/p21(WAF1) . The general relevance of Chk1 as an important determinant of recovery from G(2) checkpoint arrest was verified in HT29 colorectal cancer cells. PMID- 20716120 TI - Reduction of reperfusion-induced ventricular fibrillation and infarct size via heme oxygenase-1 overexpression in isolated mouse hearts. AB - Heme oxygenase-1 (HO-1), also known as heat shock protein 32 (hsp-32) is a stress induced cytoprotective protein. The present investigation evaluated the capacity of HO-1 to reduce the incidence of reperfusion-induced ventricular fibrillation (VF) and infarct size. HO-1 transgenic (Tg) mice were generated using a rat HO-1 genomic transgene. Isolated mouse hearts obtained from Tg and nontransgenic (NTg) groups were exposed to 20 min of global ischemia and 120 min of reperfusion. Epicardial ECG was recorded to monitor the incidence of reperfusion-induced VF and at the end of the reperfusion period, detection of HO-1 by immunohistochemistry and measurement of infarct size using the TTC method were carried out. Results shown here provide additional support for cardioprotective effects of HO-1 as evidenced by the reduced infarct size. Moreover, overexpression of the HO-1 efficiently reduced the incidence of ischemia/reperfusion (I/R)-induced VF in HO-1 Tg mice. PMID- 20716121 TI - Postischemic cardiac recovery in heme oxygenase-1 transgenic ischemic/reperfused mouse myocardium. AB - Heme oxygenase-1 (HO-1) transgenic mice (Tg) were created using a rat HO-1 genomic transgene. Transgene expression was detected by RT-PCR and Western blots in the left ventricle (LV), right ventricle (RV) and septum (S) in mouse hearts, and its function was demonstrated by the elevated HO enzyme activity. Tg and non transgenic (NTg) mouse hearts were isolated and subjected to ischemia/reperfusion. Significant post-ischemic recovery in coronary flow (CF), aortic flow (AF), aortic pressure (AOP) and first derivative of AOP (AOPdp/dt) were detected in the HO-1 Tg group compared to the NTg values. In HO-1 Tg hearts treated with 50 MUmol/kg of tin protoporphyrin IX (SnPPIX), an HO enzyme inhibitor, abolished the post-ischemic cardiac recovery. HO-1 related carbon monoxide (CO) production was detected in NTg, HO-1 Tg and HO-1 Tg + SnPPIX treated groups, and a substantial increase in CO production was observed in the HO-1 Tg hearts subjected to ischemia/reperfusion. Moreover, in ischemia/reperfusion-induced tissue Na(+) and Ca(2+) gains were reduced in HO-1 Tg group in comparison with the NTg and HO-1 Tg + SnPPIX treated groups; furthermore K(+) loss was reduced in the HO-1 Tg group. The infarct size was markedly reduced from its NTg control value of 37 +/- 4% to 20 +/- 6% (P < 0.05) in the HO-1 Tg group, and was increased to 47 +/- 5% (P < 0.05) in the HO-1 knockout (KO) hearts. Parallel to the infarct size reduction, the incidence of total and sustained ventricular fibrillation were also reduced from their NTg control values of 92% and 83% to 25% (P < 0.05) and 8% (P < 0.05) in the HO-1 Tg group, and were increased to 100% and 100% in HO-1 KO(-/-) hearts. Immunohistochemical staining of HO-1 was intensified in HO-1 Tg compared to the NTg myocardium. Thus, the HO-1 Tg mouse model suggests a valuable therapeutic approach in the treatment of ischemic myocardium. PMID- 20716122 TI - Membrane-directed molecular assembly of the neuronal SNARE complex. AB - Since the discovery and implication of N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) proteins in membrane fusion almost two decades ago, there have been significant efforts to understand their involvement at the molecular level. In the current study, we report for the first time the molecular interaction between full-length recombinant t-SNAREs and v-SNARE present in opposing liposomes, leading to the assembly of a t-/v-SNARE ring complex. Using high-resolution electron microscopy, the electron density maps and 3D topography of the membrane-directed SNARE ring complex was determined at nanometre resolution. Similar to the t-/v-SNARE ring complex formed when 50 nm v SNARE liposomes meet a t-SNARE-reconstituted planer membrane, SNARE rings are also formed when 50 nm diameter isolated synaptic vesicles (SVs) meet a t-SNARE reconstituted planer lipid membrane. Furthermore, the mathematical prediction of the SNARE ring complex size with reasonable accuracy, and the possible mechanism of membrane-directed t-/v-SNARE ring complex assembly, was determined from the study. Therefore in the present study, using both lipososome-reconstituted recombinant t-/v-SNARE proteins, and native v-SNARE present in isolated SV membrane, the membrane-directed molecular assembly of the neuronal SNARE complex was determined for the first time and its size mathematically predicted. These results provide a new molecular understanding of the universal machinery and mechanism of membrane fusion in cells, having fundamental implications in human health and disease. PMID- 20716123 TI - Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs). AB - In this review, we focus on the adult stem/progenitor cells that were initially isolated from bone marrow and first referred to as colony forming units fibroblastic, then as marrow stromal cells and subsequently as either mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). The current interest in MSCs and similar cells from other tissues is reflected in over 10,000 citations in PubMed at the time of this writing with 5 to 10 new publications per day. It is also reflected in over 100 registered clinical trials with MSCs or related cells (http//www.clinicaltrials.gov). As a guide to the vast literature, this review will attempt to summarize many of the publications in terms of three paradigms that have directed much of the work: an initial paradigm that the primary role of the cells was to form niches for haematopoietic stem cells (paradigm I); a second paradigm that the cells repaired tissues by engraftment and differentiation to replace injured cells (paradigm II); and the more recent paradigm that MSCs engage in cross-talk with injured tissues and thereby generate microenvironments or 'quasi-niches' that enhance the repair tissues (paradigm III). PMID- 20716124 TI - Changes of anabolic processes at the cellular and molecular level in chronic wounds under topical negative pressure can be revealed by transcriptome analysis. AB - Chronic wounds--as defined by the World Union of Wound Healing Societies (WUWHS)- are a considerable worldwide health care expense and impair quality of life. In order for chronic wounds to heal, these wounds must be transformed to a more acute state to begin the healing process. Topical negative pressure (TNP) with reticulated open cell foam (ROCF) is known to promote healing in certain types of chronic wounds. However, little is known about changes at the cellular or molecular level in wounds under various treatments, especially under the physical forces induced to tissue by TNP. In the current study, chronic wound samples were obtained during routine wound debridements prior to treatment and 7-12 days after initiating TNP with a continuous setting at -125 mmHg. Whole genome transcriptome microarray analyses were performed on samples to better understand how TNP with ROCF affects these types of wounds. It was found that more genes were expressed following TNP with ROCF as compared to before therapy and to normal, non-wounded tissue. In this study, we show that TNP with ROCF transforms the chronic wound from its inflammation (non-healing) state into more of a progressive, healing phenotype from a molecular point of view with expression of genes that are commonly associated with these terms. PMID- 20716125 TI - Telocytes in endocardium: electron microscope evidence. AB - The term TELOCYTES was very recently introduced, for replacing the name Interstitial Cajal-Like Cells (ICLC). In fact, telocytes are not really Cajal like cells, they being different from all other interstitial cells by the presence of telopodes, which are cell-body prolongations, very thin (under the resolving power of light microscopy), extremely long (tens up to hundreds of micrometers), with a moniliform aspect (many dilations along), and having caveolae. The presence of telocytes in epicardium and myocardium was previously documented. We present here electron microscope images showing the existence of telocytes, with telopodes, at the level of mouse endocardium. Telocytes are located in the subendothelial layer of endocardium, and their telopodes are interposed in between the endocardial endothelium and the cardiomyocytes bundles. Some telopodes penetrate from the endocardium among the cardiomyocytes and surround them, eventually. Telopodes frequently establish close spatial relationships with myocardial blood capillaries and nerve endings. Because we may consider endocardium as a 'blood-heart barrier', or more exactly as a 'blood myocardium barrier', telocytes might have an important role in such a barrier being the dominant cell population in subendothelial layer of endocardium. PMID- 20716127 TI - Red wine antioxidant resveratrol-modified cardiac stem cells regenerate infarcted myocardium. AB - To study the efficiency of maintaining the reduced tissue environment via pre treatment with natural antioxidant resveratrol in stem cell therapy, we pre treated male Sprague-Dawley rats with resveratrol (2.5 mg/kg/day gavaged for 2 weeks). After occlusion of the left anterior descending coronary artery (LAD), adult cardiac stem cells stably expressing EGFP were injected into the border zone of the myocardium. One week after the LAD occlusion, the cardiac reduced environment was confirmed in resveratrol-treated rat hearts by the enhanced expression of nuclear factor-E2-related factor-2 (Nrf2) and redox effector factor 1 (Ref-1). In concert, cardiac functional parameters (left ventricular ejection fraction and fractional shortening) were significantly improved. The improvement of cardiac function was accompanied by the enhanced stem cell survival and proliferation as demonstrated by the expression of cell proliferation marker Ki67 and differentiation of stem cells towards the regeneration of the myocardium as demonstrated by the enhanced expression of EGFP 28 days after LAD occlusion in the resveratrol-treated hearts. Our results demonstrate that resveratrol maintained a reduced tissue environment by overexpressing Nrf2 and Ref-1 in rats resulting in an enhancement of the cardiac regeneration of the adult cardiac stem cells as demonstrated by increased cell survival and differentiation leading to cardiac function. PMID- 20716126 TI - The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. AB - Obesity, insulin resistance and the metabolic syndrome, are characterized by expansion and inflammation of adipose tissue, including the depots surrounding the heart and the blood vessels. Epicardial adipose tissue (EAT) is a visceral thoracic fat depot located along the large coronary arteries and on the surface of the ventricles and the apex of the heart, whereas perivascular adipose tissue (PVAT) surrounds the arteries. Both fat depots are not separated by a fascia from the underlying tissue. Therefore, factors secreted from epicardial and PVAT, like free fatty acids and adipokines, can directly affect the function of the heart and blood vessels. In this review, we describe the alterations found in EAT and PVAT in pathological states like obesity, type 2 diabetes, the metabolic syndrome and coronary artery disease. Furthermore, we discuss how changes in adipokine expression and secretion associated with these pathological states could contribute to the pathogenesis of cardiac contractile and vascular dysfunction. PMID- 20716129 TI - Survival and function of mesenchymal stem cells (MSCs) depend on glucose to overcome exposure to long-term, severe and continuous hypoxia. AB - Use of mesenchymal stem cells (MSCs) has emerged as a potential new treatment for various diseases but has generated marginally successful results. A consistent finding of most studies is massive death of transplanted cells. The present study examined the respective roles of glucose and continuous severe hypoxia on MSC viability and function with respect to bone tissue engineering. We hereby demonstrate for the first time that MSCs survive exposure to long-term (12 days), severe (pO(2) < 1.5 mmHg) hypoxia, provided glucose is available. To this end, an in vitro model that mimics the hypoxic environment and cell-driven metabolic changes encountered by grafted sheep cells was established. In this model, the hallmarks of hypoxia (low pO(2) , hypoxia inducible factor-1alpha expression and anaerobic metabolism) were present. When conditions switched from hypoxic (low pO(2) ) to ischemic (low pO(2) and glucose depletion), MSCs exhibited shrinking, decreased cell viability and ATP content due to complete exhaustion of glucose at day 6; these results provided evidence that ischemia led to the observed massive cell death. Moreover, MSCs exposed to severe, continuous hypoxia, but without any glucose shortage, remained viable and maintained both their in vitro proliferative ability after simulation with blood reperfusion at day 12 and their in vivo osteogenic ability. These findings challenge the traditional view according to which severe hypoxia per se is responsible for the massive MSC death observed upon transplantation of these cells and provide evidence that MSCs are able to withstand exposure to severe, continuous hypoxia provided that a glucose supply is available. PMID- 20716128 TI - Arterial calcifications. AB - Arterial calcifications as found with various imaging techniques, like plain X ray, computed tomography or ultrasound are associated with increased cardiovascular risk. The prevalence of arterial calcification increases with age and is stimulated by several common cardiovascular risk factors. In this review, the clinical importance of arterial calcification and the currently known proteins involved are discussed. Arterial calcification is the result of a complex interplay between stimulating (bone morphogenetic protein type 2 [BMP-2], RANKL) and inhibitory (matrix Gla protein, BMP-7, osteoprotegerin, fetuin-A, osteopontin) proteins. Vascular calcification is especially prevalent and related to adverse outcome in patients with renal insufficiency and diabetes mellitus. We address the special circumstances and mechanisms in these patient groups. Treatment and prevention of arterial calcification is possible by the use of specific drugs. However, it remains to be proven that reduction of vascular calcification in itself leads to a reduced cardiovascular risk. PMID- 20716130 TI - Nitric oxide and P-glycoprotein modulate the phagocytosis of colon cancer cells. AB - The anticancer drug doxorubicin induces the synthesis of nitric oxide, a small molecule that enhances the drug cytotoxicity and reduces the drug efflux through the membrane pump P-glycoprotein (Pgp). Doxorubicin also induces the translocation on the plasma membrane of the protein calreticulin (CRT), which allows tumour cells to be phagocytized by dendritic cells. We have shown that doxorubicin elicits nitric oxide synthesis and CRT exposure only in drug sensitive cells, not in drug-resistant ones, which are indeed chemo immunoresistant. In this work, we investigate the mechanisms by which nitric oxide induces the translocation of CRT and the molecular basis of this chemo immunoresistance. In the drug-sensitive colon cancer HT29 cells doxorubicin increased nitric oxide synthesis, CRT exposure and cells phagocytosis. Nitric oxide promoted the translocation of CRT in a guanosine monophosphate (cGMP) and actin cytoskeleton-dependent way. CRT translocation did not occur in drug resistant HT29-dx cells, where the doxorubicin-induced nitric oxide synthesis was absent. By increasing nitric oxide with stimuli other than doxorubicin, the CRT exposure was obtained also in HT29-dx cells. Although in sensitive cells the CRT translocation was followed by the phagocytosis, in drug-resistant cells the phagocytosis did not occur despite the CRT exposure. In HT29-dx cells CRT was bound to Pgp and only by silencing the latter the CRT-operated phagocytosis was restored, suggesting that Pgp impairs the functional activity of CRT and the tumour cells phagocytosis. Our work suggests that the levels of nitric oxide and Pgp critically modulate the recognition of the tumour cells by dendritic cells, and proposes a new potential therapeutic approach against chemo-immunoresistant tumours. PMID- 20716132 TI - Neuroprotection in acute ischemic stroke--current status. AB - With the growing understanding of the mechanism of cell death in ischemia, new approaches for treatment such as neuroprotection have emerged. The basic aim of this strategy is to interfere with the events of the ischemic cascade, blocking the pathological processes and preventing the death of nerve cells in the ischemic penumebra. This concept involves inhibition of the pathological molecular events which eventually leads to the influx of calcium, activation of free radicals and neuronal death. Despite encouraging data from experimental animal models, all clinical trials of neuroprotective therapies have to date been unsuccessful. This article reviews some of the reasons for the failure of neuroprotection in the clinical trials so far. Despite all the negative reports, we believe it would be wrong to give up at this point, since there is still reasonable hope of finding an effective neuroprotection for stroke. PMID- 20716131 TI - Vascular biology: the role of sphingosine 1-phosphate in both the resting state and inflammation. AB - The vascular and immune systems of mammals are closely intertwined: the individual components of the immune system must move between various body compartments to perform their function effectively. Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, exerts effects on the two organ systems and influences the interaction between them. In the resting state, the vascular S1P gradient contributes to control of lymphocyte recirculation through the blood, lymphoid tissue and lymphatic vasculature. The high level of S1P in blood helps maintain endothelial barrier integrity. During the inflammatory process, both the level of S1P in different immune compartments and S1P receptor expression on lymphocytes and endothelial cells are modified, resulting in functionally important changes in endothelial cell and lymphocyte behaviour. These include transient arrest of lymphocytes in secondary lymphoid tissue, crucial for generation of adaptive immunity, and subsequent promotion of lymphocyte recruitment to sites of inflammation. This review begins with an outline of the basic biochemistry of S1P. S1P receptor signalling is then discussed, followed by an exploration of the roles of S1P in the vascular and immune systems, with particular focus on the interface between them. The latter part concerns crosstalk between S1P and other signalling pathways, and concludes with a look at therapies targeting the S1P-S1P receptor axis. PMID- 20716134 TI - "Nuts, whole hazelnuts, Cadbury's take 'em and cover them with chocolate". PMID- 20716133 TI - The novel protein MANI modulates neurogenesis and neurite-cone growth. AB - Neuronal regeneration and axonal re-growth in the injured mammalian central nervous system remains an unsolved field. To date, three myelin-associated proteins [Nogo or reticulon 4 (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG)] are known to inhibit axonal regeneration via activation of the neuronal glycosylphosphatidylinositol-anchored Nogo receptor [NgR, together with p75 neurotrophin receptor (p75NTR) and Lingo 1]. In the present study we describe the novel protein MANI (myelin-associated neurite-outgrowth inhibitor) that localizes to neural membranes. Functional characterization of MANI overexpressing neural stem cells (NSCs) revealed that the protein promotes differentiation into catecholaminergic neurons. Yeast two hybrid screening and co-immunoprecipitation experiments confirmed the cell division cycle protein 27 (Cdc27) as an interacting partner of Mani. The analyses of Mani-overexpressing PC12 cells demonstrated that Mani retards neuronal axonal growth as a positive effector of Cdc27 expression and activity. We show that knockdown of Cdc27, a component of the anaphase-promoting complex (APC), leads to enhanced neurite outgrowth. Our finding describes the novel MANI-Cdc27-APC pathway as an important cascade that prevents neurons from extending axons, thus providing implications for the potential treatment of neurodegenerative diseases. PMID- 20716135 TI - Comparing apples and pears: assessment of lipid-lowering therapies differentiated by side effects. PMID- 20716136 TI - Statins and prophylaxis of venous thrombosis - a further link between arterial and venous thrombosis. PMID- 20716137 TI - Rhythm control agents and adverse events in patients with atrial fibrillation. PMID- 20716138 TI - Not yet time for a paradigm shift away from angiotensin inhibitors in chronic kidney disease, but due diligence required. PMID- 20716139 TI - Big country, small country: how the United States debated health reform while New Zealand just got on with it. PMID- 20716140 TI - Dual renin-angiotensin-aldosterone system inhibition: boon or bust? PMID- 20716141 TI - Is renoprotection with RAAS blockade a failed paradigm? Have we learnt any lessons so far? PMID- 20716142 TI - Today's Russian clinical trial environment. PMID- 20716143 TI - Assessments of complementary and alternative medicine: the clinical guidelines from NICE. PMID- 20716144 TI - Cutting through the statistical fog: understanding and evaluating non-inferiority trials. AB - Every year, results from many important randomised, controlled trials are published. Knowing the elements of trial design and having the skills to critically read and incorporate results are important to medical practitioners. The goal of this article is to help physicians determine the validity of trial conclusions to improve patient care through more informed medical decision making. This article includes a review of 162 randomised, controlled non inferiority (n = 116) and equivalence (n = 46) hypothesis studies as well as the larger Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation V study and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial. Evaluation of data from small and large trials uncovers significant flaws in design and models employed and uncertainty about calculations of statistical measures. As one example of questionable study design, discussion includes a large (n = 3922), double-blind, randomised, multicentre trial comparing the efficacy of ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and additional stroke risk factors. Investigators concluded that ximelagatran was effective compared with well-controlled warfarin for prevention of thromboembolism. However, deficiencies in design, as well as concerns about liver toxicity, resulted in the rejection of the drug by the US Food and Drug Administration. Many trials fail to follow good design principles, resulting in conclusions of questionable validity. Well-designed non-inferiority trials can provide valuable data and demonstrate efficacy for beneficial new therapies. Objectives and primary end-points must be clearly stated and rigorous standards met for sample size, establishing the margin, patient characteristics and adherence to protocol. PMID- 20716145 TI - Combination therapy with amlodipine/valsartan in essential hypertension: a 52 week, randomised, open-label, extension study. AB - BACKGROUND: A majority of hypertensive patients require > or = 2 agents to achieve target blood pressure (BP). METHODS: This 52-week, multicentre, open label, randomised extension trial to a previously reported double-blind, placebo controlled study evaluated the safety and efficacy of amlodipine/valsartan (Aml/Val) combination. Patients who successfully completed the core study without serious drug-related adverse events (AEs) and mean sitting systolic BP (MSSBP)/mean sitting diastolic BP (MSDBP) < or = 150/95 mmHg were eligible to enter the extension and be treated with Aml/Val 2.5/80 or 5/80 mg. After 4 weeks of treatment, patients underwent force-titration to receive 5/160 mg (low dose) or 10/160 mg (high dose) for 48 weeks. Addition of hydrochlorothiazide (HCTZ) 12.5 mg was permitted if BP was > or = 140/90 mmHg at Week 8 or later. Patients could be down-titrated to the prior lower combination dose with or without HCTZ if an intolerable AE occurred. Safety evaluations included monitoring of AEs. Efficacy variables were change from baseline in MSDBP (primary) and MSSBP (secondary). RESULTS: Of 1246 patients randomised, 1075 (86.3%) completed the extension study. At week 52 end-point, change in MSSBP/MSDBP from core study baseline was -22.1/-17.2 mmHg for low-dose regimen and -22.8/-18.1 mmHg for high dose regimen. For both regimens, reductions in BP were sustained over 52 weeks and mean BP maintained below approximately 135/85 mmHg at all visits. Frequent AEs in the low- and high-dose regimens were peripheral oedema (9.7% and 17.1% respectively), nasopharyngitis (8.1% and 7.2%), and dizziness (5.2% and 7.0%). Incidence of serious AEs was 3.7% with low dose and 4.1% with high dose. CONCLUSION: The combination of Aml/Val with the optional addition of HCTZ produced clinically significant and persistent reductions in BP over 52 weeks with a favourable tolerability profile. PMID- 20716146 TI - Statin use and the prevention of venous thromboembolism: a meta-analysis. AB - AIMS: Statins are thought to have antithrombotic properties and may attenuate patients' odds of developing venous thromboembolism (VTE), but clinical studies have yielded variable estimates of this effect. The aim was to conduct a meta analysis to evaluate the effect of statin use on development of VTE. METHODS: Randomised controlled trials (RCTs) and observational studies evaluating the effects of statins on the incidence of VTE were selected from MEDLINE (1996 to August 2009), Cochrane CENTRAL (second quarter, 2009), Cochrane Database of Systematic Reviews (second quarter, 2009) and a manual review of references. While no further restrictions were placed on RCTs, observational studies were only included if they reported adjusted effect sizes using appropriate methods. Development of deep vein thrombosis (DVT), pulmonary embolism (PE) and any VTE from RCTs and observational studies were pooled using traditional meta analytic techniques with a random-effects model. RESULTS: Ten studies were identified and eligible for meta-analysis. Upon meta-analysis, statin use was associated with a statistically significant reduction in the odds of developing VTE (AOR 0.68, 95% CI 0.54-0.86), DVT (AOR 0.59, 95% CI 0.43-0.82) and PE (AOR 0.70, 95% CI 0.53 0.94). DISCUSSION: Statin use is associated with significantly reduced odds of developing VTE, DVT or PE by 32%, 41% and 30% respectively. Our meta-analysis included one RCT, JUPITER, which alone provided statistically significant reduction in the odds of developing VTE and DVT (43% and 55% respectively), and a nonsignificant reduction on PE. CONCLUSION: Currently available evidence suggests that statins can reduce patients' odds of developing VTE. PMID- 20716147 TI - Evaluation of the hypothalamic-pituitary-adrenal axis in patients with antiphospholipid syndrome. AB - INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis insufficiency is the most common endocrine disorder in patients with antiphospholipid syndrome (APS). Primary adrenal failure because of venous thrombosis and/or adrenal haemorrhage is the leading diagnosis, while another possible mechanism is autoimmune adrenal failure. Prospective evaluation of the HPA axis in patients with APS has not been previously performed. AIMS: To evaluate the HPA axis in patients with APS. METHODS: Ambulatory patients (age 18 years and older) with APS were given a symptom questionnaire. Baseline aldosterone, corticotropin (ACTH) and adrenal cortex autoantibodies (ACA) were measured. Cortisol was measured at baseline and after 1-mcg ACTH stimulation. RESULTS: In all, 24 patients (18 women/6 men; mean age 44.6 +/- 16.1 years) participated in the study. Of these, 21 had primary APS with disease duration of 5.8 +/- 6.2 years. Baseline cortisol level was 12.6 +/- 4.2 mg/dl (normal 7-25). After ACTH stimulation, it was 24.7 +/- 4.1 mg/dl and 22.8 +/- 7.4 mg/dl at 30 and 60 min respectively. All patients had a stimulated cortisol level of at least 18 mg/dl, although three patients had stimulated cortisol between 18 and 20 mg/dl, one of which reported previous inhaled steroid treatment. Weakness, dizziness and nausea were reported at baseline by 50%, 38% and 25% of the patients respectively. ACA were negative in all patients examined. CONCLUSIONS: In our cohort, patients with APS did not have HPA axis insufficiency. Partial adrenal insufficiency could not be excluded in two patients. Further longitudinal studies are needed to determine the significance of periodic evaluation of the HPA axis in patients with APS. PMID- 20716148 TI - The safety and tolerability of GLP-1 receptor agonists in the treatment of type-2 diabetes. AB - Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP 1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies. PMID- 20716149 TI - A single episode of haematospermia can be safely managed in the community. AB - INTRODUCTION: This study is a ten-year single institution retrospective study of patients presenting with haematospermia, to establish standard tests for investigation, and what tests have low yield and can be omitted. MATERIALS AND METHODS: Investigations that were used were analysed to establish their diagnostic yield. The parameters examined were: digital rectal examination (DRE) findings, prostate specific antigen (PSA), abdominal and scrotal ultrasound, TRUS biopsy result (wherever applicable), flexible cystoscopy findings and final diagnosis. RESULTS: The central findings were that abdominal ultrasound never yielded an abnormality and that flexible cystoscopy never showed bladder tumours. TRUS prostate biopsies were performed in 17% of patients, and prostate cancer was confirmed in 5% of patients. Testicular malignancy was found in 2%. In 90% of patients, no specific diagnosis was made, and 85% of patients were discharged at review. CONCLUSIONS: A single episode of haematospermia is usually benign. Flexible cystoscopy and abdominal ultrasound appear valueless. Assessment should consist of clinical examination (including testicular), DRE and PSA testing. It can safely be managed in the community and only referred in the presence of, abnormal examination, elevated PSA or recurrent symptoms. PMID- 20716150 TI - The interplay between inflammation, lipids and cardiovascular risk in rheumatoid arthritis: why ratios may be better. AB - BACKGROUND: There is abundant evidence that patients with rheumatoid arthritis (RA) are at elevated cardiovascular (CV) risk. The contribution of lipids in general is well recognised, but is as yet unclear in inflammatory diseases such as RA in part because inflammation appears inversely associated with lipid levels in RA. METHODS: The CARRE study is a cohort study of 353 randomly selected RA outpatients followed since their enrollment in 2001-2002. We used data from this cohort to (i) evaluate the relationship at baseline between lipid levels [total cholesterol (TC), high-density lipoprotein (HDL)-cholesterol and the TC:HDLc ratio] and inflammation [by means of C-reactive protein (CRP)]; and (ii) determine the association of baseline TC and TC:HDLc ratio with incident (fatal and non-fatal) CV events. RESULTS: C-reactive protein correlated negatively with TC (r = -0.184, p = 0.002), more so with HDLc (r = -0.327, p = 0.001) and therefore positively with TC:HDLc ratio (r = 0.204, p = 0.001). These associations were most evident when CRP exceeded 10 mg/l. Furthermore, the TC:HDLc ratio, but not TC, was positively related to event risk, again most marked in those with elevated CRP. CONCLUSION: Our observations support use of TC:HDLc ratio rather than TC alone in assessing cardiovascular risk in RA patients, especially in those with high inflammatory activity. PMID- 20716151 TI - Current strategies for knee cartilage repair. AB - Defects in knee articular cartilage (AC) can cause pain and disability and present the clinician with an extremely challenging clinical situation. This article describes the most up-to-date surgical techniques that aim to repair and/or regenerate symptomatic focal defects in AC, which include arthroscopic debridement, microfracture bone marrow stimulation and autologous osteochondral allografting, with an emphasis on autologous chondrocyte implantation. In the future, refinement of tissue-engineering approaches promises to further improve outcome for these patients. PMID- 20716152 TI - An audit on assessment and management of pain at the time of acute hospital admission in older people. AB - BACKGROUND: Pain management is fundamental to good clinical care. All patients who are admitted into hospital with any acute condition should be assessed about the presence or absence of pain and managed appropriately at the time of admission. As the prevalence of pain is high in older people, we examined how well it is assessed and managed in the older people in a typical medical emergency setting in the UK. METHODS: We performed a retrospective audit in a district general hospital with catchment population of 250,000 in West Norfolk, UK. We included all patients admitted to care of the elderly wards during October November 2007. We evaluated management of pain within the first 24 h of acute hospital admission. RESULTS: Of the 140 patients admitted, 74 (53%) were male and their median age was 84 years (range = 56-99; = < 70, n = 8). Only 93 (66%) were asked about the presence or absence of pain on admission. Of those who complained of pain (n = 45), severity of pain was documented in 5 (11%) and the management was documented in 17 (38%). Of 17 with documented pain management, only 4 (23%) had further assessment of effectiveness of pain management. Only 70 (50%) of the patients had their mental state assessed by the abbreviated mental test score (AMTS). Among those who complained of pain and AMTS < or = 8 (n = 51), only 4 (8%) had objective documentation. CONCLUSIONS: Our findings suggest that pain management may be sub-optimal in older people in the acute medical settings. Regular monitoring and education may have potential to improve assessment and management of pain in these vulnerable older adults. PMID- 20716153 TI - Iron and sex difference in longevity. PMID- 20716155 TI - Why is influenza virus more risky for pregnant women? PMID- 20716156 TI - Highly conserved cross-reactive CD4+ T-cell HA-epitopes of seasonal and the 2009 pandemic influenza viruses. AB - BACKGROUND: The relatively mild nature of the 2009 influenza pandemic (nH1N1) highlights the overriding importance of pre-existing immune memory. The absence of cross-reactive antibodies to nH1N1 in most individuals suggests that such attenuation may be attributed to pre-existing cellular immune responses to epitopes shared between nH1N1 virus and previously circulating strains of inter pandemic influenza A viruses. RESULTS: We sought to identify potential CD4+ T cell epitopes and predict the level of cross-reactivity of responding T cells. By performing large-scale major histocompatibility complex II analyses on Hemagglutinin (HA) proteins, we investigated the degree of T-cell cross reactivity between seasonal influenza A (sH1N1, H3N2) from 1968 to 2009 and nH1N1 strains. Each epitope was examined against all the protein sequences that correspond to sH1N1, H3N2, and nH1N1. T-cell cross-reactivity was estimated to be 52%, and maximum conservancy was found between sH1N1 and nH1N1 with a significant correlation (P < 0.05). CONCLUSIONS: Given the importance of cellular responses in kinetics of influenza infection in humans, our findings underscore the role of T-cell assays for understanding the inter-pandemic variability in severity and for planning treatment methods for emerging influenza viruses. PMID- 20716157 TI - Real time reverse transcription (RRT)-polymerase chain reaction (PCR) methods for detection of pandemic (H1N1) 2009 influenza virus and European swine influenza A virus infections in pigs. AB - BACKGROUND: There is a requirement to detect and differentiate pandemic (H1N1) 2009 (H1N1v) and established swine influenza A viruses (SIVs) by real time reverse transcription (RRT) PCR methods. OBJECTIVES: First, modify an existing matrix (M) gene RRT PCR for sensitive generic detection of H1N1v and other European SIVs. Second, design an H1 RRT PCR to specifically detect H1N1v infections. METHODS: RRT PCR assays were used to test laboratory isolates of SIV (n = 51; 37 European and 14 North American), H1N1v (n = 5) and avian influenza virus (AIV; n = 43). Diagnostic sensitivity and specificity were calculated for swabs (n = 133) and tissues (n = 116) collected from field cases and pigs infected experimentally with SIVs and H1N1v. RESULTS: The "perfect match" M gene RRT PCR was the most sensitive variant of this test for detection of established European SIVs and H1N1v. H1 RRT PCR specifically detected H1N1v but not European SIVs. Validation with clinical specimens included comparison with virus isolation (VI) as a "gold standard", while field infection with H1N1v in swine was independently confirmed by sequencing H1N1v amplified by conventional RT PCR. "Perfect match" M gene RRT PCR had 100% sensitivity and 95.2% specificity for swabs, 93.6% and 98.6% for tissues. H1 RRT PCR demonstrated sensitivity and specificity of 100% and 99.1%, respectively, for the swabs, and 100% and 100% for the tissues. CONCLUSIONS: Two RRT PCRs for the purposes of (i) generic detection of SIV and H1N1v infection in European pigs, and for (ii) specific detection of H1N1v (pandemic influenza) infection were validated. PMID- 20716158 TI - A composite epidemic curve for seasonal influenza in Canada with an international comparison. AB - BACKGROUND: Empirical data on laboratory-confirmed seasonal influenza is limited by very low and possibly non-systematic case ascertainment as well as geographical variation. OBJECTIVE: To provide a visual representation of an influenza epidemic at the community and regional level using empirical data and to describe the epidemic characteristics. METHODS: Weekly influenza A confirmations were obtained from the Canadian FluWatch program and American FluView program for the 1997/1998-2006/2007 seasons; 1- year data were also available for Europe (FluNet, WHO). For seasons where at least 80% of the influenza A strains were antigenically similar, a composite epidemic curve was created by centring the local epidemics relative to their epidemic midpoint. RESULTS: The range in timing of the regional peaks varied from 5 to 13 weeks. Once the epidemic curves were centred relative to their peak, the composite epidemic curves were similar for Canada, the United States and Europe, and the epidemic growth rates were similar for most subgroups (city size; regions; H1N1 versus H3N2 seasons). During the exponential growth period, the number of cases increased by a factor of 1.5-2.0 per week, averaging 1.8. Exponential growth was evident approximately 10 weeks before the peak. Evidence of sustained transmission occurred from mid-September to early June. DISCUSSION: The shape of the composite curve created in this study clearly demonstrates a consistency in the epidemic pattern across geographically disparate locales. Laboratory confirmation will likely play an increasing role in the development of better methods for early detection and summary measures of influenza activity. PMID- 20716159 TI - Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. AB - BACKGROUND: A novel influenza A (H1N1) virus was isolated from humans in North America and has developed into the first pandemic of the 21st century. Reports of a global shortage of antiviral drugs, the evolution of drug-resistant influenza virus variants, and a 6-month delay in vaccine availability underline the need to develop new therapeutics that may be widely distributed during future pandemics. METHODS: In an effort to discover alternatives to the conventional therapeutic strategies available, we screened several classes of immunomodulatory agents possessing the potential to mitigate the effects of influenza virus-induced immunopathology. RESULTS: Here, we provide preliminary evidence that two classes of drugs, peroxisome proliferator-activated receptor-gamma agonists and AMP activated protein kinase agonists, provide protection in mice infected with highly pathogenic and pandemic strains of influenza virus. CONCLUSIONS: The extensive production in the developed world, combined with the significant degree of protection described here, establishes these drugs as a potential therapeutic option that may be broadly implemented to combat serious disease caused by future influenza epidemics or pandemics. PMID- 20716160 TI - Molecular and demographic analysis of respiratory syncytial virus infection in patients admitted to King Chulalongkorn Memorial Hospital, Thailand, 2007. AB - OBJECTIVES: To preliminary preview the molecular character and its possible clinical correlation of RSV subgroups in Thailand. DESIGN: Cross-sectional analytic design. SETTING: Admitted acute lower respiratory tract infection patients of King Chulalongkorn Memorial Hospital, Bangkok, during Jun-Dec, 2007 were recruited. SAMPLE: Nasopharyngeal aspirations were collected. MAIN OUTCOME MEASURES: All samples were analyzed for the presence of RSV glycoprotein G gene by reverse transcription PCR. Molecular character of each subgroup was determined by sequencing. Admission records were also analyzed for clinical correlations. RESULTS: Equal infectivity and severity of both RSV subgroups to the patients was shown. Mixed infection was shown to be as common as each single infection, higher than previously reported. GA2 of subgroup A and BA-IV of subgroup B were the most widespread genotypes and showed their monophyletic origins. From admission records, either type of infection did not show significantly preference in demographic record or clinical severity. Comorbidity, however, was statistically significant that more congenital heart disease was found in negative RSV cases, while more chronic pulmonary disease was in positive cases. Nevertheless, the clinical severity was insignificantly different suggesting that only patients with chronic pulmonary underlying were prone to be infected with RSV. CONCLUSIONS: This preliminary RSV study showed prevalence of subgroups, types of infection, and common genotypes in an epidemic, uncorrelated to demography or clinical severity. PMID- 20716161 TI - Centrally necrotizing carcinoma of the breast: clinicopathological analysis of 33 cases indicating its basal-like phenotype and poor prognosis. AB - AIMS: To investigate the clinicopathological features and immunophenotype of centrally necrotizing carcinoma (CNC) of the breast to ascertain its relationship to basal-like phenotype and its prognosis. METHODS AND RESULTS: The clinical and pathological characteristics of 33 CNCs were reviewed. Immunohistochemical study of oestrogen receptor, progesterone receptor, HER2, cytokeratin (CK) 8/18, high molecular-weight CK (34betaE12), CK5/6, CK14, CK17, smooth muscle antigen, p63, vimentin and epidermal growth factor receptor was performed. The striking feature of CNC was a central, necrotic or acellular zone surrounded by a ring-like area of viable tumour cells. The central zone showed three morphological types: predominance of coagulative necrosis (21 cases), predominance of fibrosis and scar tissue (nine cases) and infarction (three cases). Tumour cells displayed invasive ductal carcinoma of high grade. The expression rate of basal-like markers was higher than that of myoepithelial markers (87.9% versus 46.2%). Basal like subtype was shown by 63.6% of cases. The expression rate of CK5/6 (90.5%) was highest among basal-like markers. Follow-up data of 19 patients were available. Median progression-free survival was 15.5 months. In 12 patients (63.2%), local recurrence and/or distant metastasis developed (median time to recurrence and/or metastasis, 14.0 months). CONCLUSIONS: CNC has distinctive morphological features, which mostly exhibit a basal-like immunophenotype and poor prognosis. CNC is a typical representative of basal-like breast cancer. PMID- 20716162 TI - Profiling the expression of cytochrome P450 in breast cancer. AB - AIMS: The cytochrome P450s (P450) are key oxidative enzymes that metabolize many carcinogens and anticancer drugs. Thus, these enzymes influence tumour development, tumour response to therapy and are putative tumour biomarkers. The aim was to define the P450 expression profile in breast cancer and establish the significance of P450 expression in this tumour type. METHODS AND RESULTS: A tissue microarray containing 170 breast cancers of no special type was immunostained for a panel of 21 P450s. The highest percentage of strong immunopositivity in breast cancers was seen for CYP4X1 (50.8%), CYP2S1 (37.5%) and CYP2U1 (32.2%), while CYP2J (98.6%) and CYP3A43 (70.7%) were the P450s that most frequently displayed no immunoreactivity. CYP4V2 (P = 0.01), CYP4X1 (P = 0.01) and CYP4Z1 (P = 0.01) showed correlations with tumour grade. CYP1B1 (P = 0.001), CYP3A5 (P = 0.001) and CYP51 (P = 0.005) showed the most significant correlations with oestrogen receptor status. Correlations with survival were identified for CYP2S1 (P = 0.03), CYP3A4 (P = 0.025), CYP4V2 (P = 0.026) and CYP26A1 (P = 0.03), although none of these P450s was an independent marker of prognosis. CONCLUSIONS: This study has defined the expression profile of cytochrome P450s in breast cancer and may offer their potential application as biomarkers to aid decisions regarding optimal adjuvant hormonal therapy. PMID- 20716163 TI - Histological grading of breast cancer on needle core biopsy: the role of immunohistochemical assessment of proliferation. AB - AIMS: Histological grade assessed on needle core biopsy (NCB) moderately concurs with the grade in the surgical excision specimen (SES) (kappa-values between 0.35 and 0.65). A major cause of the discrepancy is underestimation of mitoses in the NCB specimen. The aim was to determine the best method of assessing proliferation on NCB. METHODS AND RESULTS: Proliferative activity of 101 invasive carcinomas of the breast on NCB and SES was assessed using mitotic counts on routine haematoxylin and eosin (H&E) sections and immunohistochemical markers Mib-1 and phosphorylated histone H3 (PPH3). H&E mitotic count in SES was considered as the gold standard. H&E mitotic count was found to be underestimated on NCB when compared with that in SES (P < 0.001), but no significant difference was detected between NCB and SES regarding Mib-1 (P = 0.13) or PPH3 (P = 0.073). Using receiver-operating characteristic curve, Mib-1 on NCB was found to agree with the gold standard significantly better than routine H&E on NCB. CONCLUSIONS: Immunohistochemical markers in NCB showed better concordance with H&E mitotic count in SES (gold standard) than routine H&E mitotic count in NCB. Further refinement of cut-offs and scoring methods is needed. PMID- 20716164 TI - Predictors of phyllodes tumours on core biopsy specimens of fibroepithelial neoplasms. AB - AIMS: To establish histological and biological parameters that can predict phyllodes tumours on core biopsy specimens of indeterminate fibroepithelial neoplasms. METHODS AND RESULTS: Core biopsy specimens of fibroepithelial lesions diagnosed at the Department of Pathology, Singapore General Hospital from 2002 to 2007 were reviewed. Cases in which phyllodes tumour was favoured, or could not be ruled out, were evaluated for stromal cellularity/distribution, nuclear atypia and mitoses, stromal overgrowth, epithelial fronding, epithelial hyperplasia, configuration of lesional edge, presence of pseudoangiomatous stromal hyperplasia and of adipose tissue. Antibodies to Ki67, topoisomerase IIalpha, CD34, CD117 and Bcl-2 were applied to sections subjected to immunohistochemistry using the streptavidin-biotin method. Findings were correlated with subsequent excisions. Of 261 core biopsy specimens of fibroepithelial lesions, 98 (37%) comprised cases in which phyllodes tumour could not be excluded and 57 (58%) had subsequent open surgical excisions. Marked stromal hypercellularity (5/5; 100%) and nuclear atypia (1/1; 100%), stromal overgrowth (17/17; 100%), mitoses > or =2/10 high power fields (18/18; 100%) and ill-defined lesional borders (16/16 phyllodes tumours; 100%) were features in core biopsy specimens that exclusively predicted phyllodes tumour on excision. Moderate stromal hypercellularity (20/27 phyllodes tumours; 74%), stromal overgrowth, moderate nuclear atypia (14/16 phyllodes tumours; 87%), pseudoangiomatous stromal hyperplasia (19/23 phyllodes tumours; 83%) significantly correlated with their subsequent excisions. Immunohistochemical markers Ki67 > or =5% and topoisomerase IIalpha> or =5%, and reduced or patchy CD34 on core biopsy specimens correlated significantly with a diagnosis of phyllodes. CONCLUSIONS: Stromal hypercellularity, combined with key histological features and immunohistochemical markers Ki67, topoisomerase IIalpha and CD34, reinforced by clinical findings, can predict phyllodes tumours on core biopsy specimens. PMID- 20716165 TI - Systematic assessment of protein phenotypes characterizing high-grade tumour budding in mismatch repair-proficient colorectal cancer. AB - AIMS: A tumour bud is defined as a single tumour cell or tumour cell cluster of up to five cells at the invasive tumour front. Significant differences in survival have been detected in colorectal cancer patients with low- compared to high-grade budding. The aim of this study was to identify potential multi-marker phenotypes characterizing low- and high-grade budding in mismatch repair (MMR) proficient colorectal cancer. METHODS AND RESULTS: Established and promising prognostic proteins such as epidermal growth factor receptor (EGFR), pERK, RHAMM, RKIP, beta-catenin, E-cadherin, pAKT, p16, p21, Ki67, Bcl-2, vascular endothelial growth factor (VEGF), apoptotic protease activating factor-1 (APAF-1), MUC1, EphB2, matrix metalloproteinase 7, pSMAD2, CDX2, laminin5gamma2 and MST1 were analysed on 208 MMR-proficient colorectal cancers with complete clinicopathological data. The most accurate markers for predicting high-grade budding (more than six tumour buds) were EphB2 (P < 0.001), Bcl-2 (P < 0.001), RKIP (P < 0.001), E-cadherin (P = 0.004), laminin5gamma2 (P = 0.004) and APAF-1 (P = 0.005). On multivariable analysis, only loss of Bcl-2 (P < 0.001) and EphB2 (P < 0.001) were independent predictors of high-grade budding. Bcl-2-/EphB2- tumours were more frequently poorly differentiated (P < 0.001), of advanced pT stage (P = 0.002), lymph node positive (P = 0.023), presented vascular (P = 0.053) and lymphatic invasion (P = 0.005) and had a negative impact on patient survival (P = 0.012). CONCLUSIONS: The multi-marker phenotype EphB2-/Bcl-2- is an independent predictor of high-grade budding and implies increased aggressive behaviour in MMR-proficient colorectal cancer. PMID- 20716166 TI - Smoothelin is a specific and robust marker for distinction of muscularis propria and muscularis mucosae in the gastrointestinal tract. AB - AIMS: As tumour specimens and biopsy specimens become smaller, recognition of anatomical structures relevant for staging is increasingly challenging. So far no marker is known that reliably discriminates between muscularis propria (MP) and muscularis mucosae (MM) of the gastrointestinal tract. Recently, smoothelin expression has been shown to differ in MP and MM of the urinary bladder. We aimed to analyse the expression of smoothelin in the gastrointestinal tract in MP and MM in order to define a novel diagnostic tool to identify MM bundles. METHODS AND RESULTS: The expression of smoothelin was analysed immunohistochemically in comparison with alpha-smooth muscle actin (alpha-SMA) in specimens from colon, stomach and oesophagus (n = 107). In contrast to alpha-SMA, which equally stained MM and MP, absent or significantly weaker smoothelin expression was found in MM was found, which was particularly valid in colon and gastric specimens. CONCLUSIONS: The combination of smoothelin and SMA represents a robust marker to discriminate MM from MP in the gastrointestinal tract. PMID- 20716167 TI - Specificity of DOG1 (K9 clone) and protein kinase C theta (clone 27) as immunohistochemical markers of gastrointestinal stromal tumour. AB - AIMS: DOG1 and protein kinase C (PKC) theta are both sensitive immunohistochemical markers of gastrointestinal stromal tumour (GIST). However, there are conflicting data regarding the specificity of the most commonly used PKC theta antibody (clone 27), and there are no existing data regarding the specificity of the only known commercially available DOG1 antibody (K9 clone) at the time of writing. This study's aim was to characterize the immunoreactivity patterns of both monoclonal antibodies amongst a wide range of neoplasm types including, in particular, histological mimics of GIST. METHODS AND RESULTS: Immunohistochemistry for DOG1 and PKC theta was performed on whole tissue sections from 23 different neoplasm types (total of 125 cases). Ten of these neoplasm types showed CD117 immunopositivity. Only three (Ewing's sarcoma, glomus tumour and synovial sarcoma) of the 23 neoplasm types showed DOG1 immunopositivity, and such positivity was often focal and weak in intensity. In contrast, all but four (ganglioneuromas, leiomyomas, desmoplastic small round cell tumours and PEComa/angiomyolipomas) of the 23 neoplasm types showed PKC theta immunopositivity. CONCLUSIONS: Compared with CD117, DOG1 (using the K9 antibody) is a more specific marker, whereas PKC theta (using the clone 27 antibody) is a considerably less specific immunohistochemical marker for GIST. PMID- 20716168 TI - DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. AB - AIMS: The histopathological diagnosis of gastrointestinal stromal tumours (GIST) is typically made based on a combination of clinical and morphological features supported by immunohistochemistry studies. The aim of this study was to examine the staining quality, sensitivity, specificity and utility of antibodies used commonly in GIST diagnosis. METHODS AND RESULTS: Immunohistochemistry with a panel of antibodies [CD117, DOG1, protein kinase C (PKC)-theta, nestin, CD34, smooth muscle actin (SMA), desmin, S100 and CD171] was performed on whole sections from 187 GIST and 29 gastrointestinal mesenchymal tumours, and on several microarrays including 355 GISTs and 120 soft tissue sarcomas. Results showed that DOG1 and CD117 were the most sensitive and specific antibodies used in GIST diagnosis. PKC-theta and nestin were sensitive, but less specific, also staining other spindle cell tumours commonly considered in the differential diagnosis of GIST. CD34 staining was less sensitive than many of the other antibodies and of limited aid in diagnosis. The smooth muscle markers SMA and desmin, together with the neural marker S100, were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the exclusion/diagnosis of other gastrointestinal mesenchymal tumour types. CONCLUSIONS: In the majority of histologically suspected GISTs a combination of CD117 and DOG1 immunostaining is sufficient to confirm the histological diagnosis. PMID- 20716169 TI - Down-regulation of ING4 is associated with initiation and progression of lung cancer. AB - AIMS: Tumour suppressor ING4 is one of ING family genes, which are involved in cell cycle arrest, gene transcription regulation, DNA repair and apoptosis. ING4 inhibition has been reported in various tumours, including gliomas, breast tumours, and stomach adenocarcinoma. The aim was to evaluate ING4 expression in lung cancers. METHOD AND RESULTS: By immunohistochemistry of 246 lung tumour tissues, reduced ING4 nuclear and cytoplasmic expression were both revealed in lung cancer and associated with tumour grade. Interestingly, compared with normal tissues, we found more tumours with ING4 expression in the cytoplasm higher than in the nucleus. Nuclear ING4 inhibition correlated with the tumour stage and lymph node metastasis. Consistent with these findings, semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting demonstrated decreased ING4 mRNA and expression in 100% (50/50) tumour tissues. Furthermore, ING4 expression was lower in grade III than in grades I-II tumours. Reduced ING4 mRNA correlated with lymph node metastasis. CONCLUSIONS: Our results indicate that overall inhibition of ING4 expression and ING4 expression higher in cytoplasm than in nucleus of tumour cells may be involved in the initiation and progression of lung cancers, and thus, analysis for ING4 expression may be useful as a clinical diagnostic and prognostic tool for lung cancer. PMID- 20716170 TI - Induction of the vascular endothelial growth factor pathway in the brain of adults with fatal falciparum malaria is a non-specific response to severe disease. AB - AIMS: Pathological or neuroprotective mechanisms in the brain in severe malaria may arise from microvascular obstruction with malaria-parasitized erythrocytes. This study aimed to investigate the role of hypoxia and induction of the vascular endothelial growth factor (VEGF) pathway in the neuropathophysiology of severe malaria. METHODS AND RESULTS: Immunohistochemistry was performed on post mortem brain tissue sections from 20 cases of severe malaria and examined for the expression of transcriptional regulators of VEGF [hypoxia-inducible factor-1 alpha (HIF-1alpha), HIF-2alpha], DEC-1, VEGF, VEGF receptors 1 and 2, and the activated, phosphorylated VEGF receptor 2 (pKDR). HIFs showed limited protein expression and/or translocation to cell nuclei in severe malaria, but DEC-1, which is more stable and regulated by HIF-1alpha, was observed. There was heterogeneous expression of VEGF and its receptors in severe malaria and non malarial disease controls. pKDR expression on vessels was greater in malaria cases than in controls but did not correlate with parasite sequestration. VEGF uptake by malaria parasites was observed. CONCLUSIONS: VEGF and its receptor expression levels in severe malaria reflect a non-specific response to severe systemic disease. Potential manipulation of events at the vasculature by the parasite requires further investigation. PMID- 20716171 TI - Expression of Bcl-2 family proteins and association with clinicopathological characteristics of oral squamous cell carcinoma. AB - AIMS: To characterize the expression of proteins that inhibit (Bcl-2, Bcl-x, Bcl xL, Bcl-2-related protein A1, BAG-1) or promote (Bak, Bax, Bim/Bod, Bim-Long, Bad, Bid, PUMA) apoptosis and determine possible correlations between the expression of these proteins and clinicopathological features of oral squamous cell carcinoma (OSCC). METHODS AND RESULTS: Two-hundred and twenty-nine cases of OSCC, arranged in a tissue microarray, were immunohistochemically analysed. The results demonstrated that the absence of vascular invasion was associated with increased expression of Bak, Bax, Bcl-xL, Bcl-2-related protein and PUMA. Increased expression of Bim/Bod and BAG-1 was associated with the presence of perineural infiltration. An increase in Bid and Bim-Long expression was associated with moderately to well-differentiated tumours. Increased expression of the Bcl-2-related protein and PUMA was associated with tumours occurring in the floor of mouth and increased expression of PUMA was also associated with recurrence of the tumour. Multivariate Cox analysis demonstrated that PUMA and Bim-Long were independent factors in prognosis of OSCC. CONCLUSIONS: Our results showed the involvement of the Bcl-2 family of proteins in OSCC tumorigenesis and suggest that the expression of apoptotic molecules might be used as a prognostic indicator for OSCC. PMID- 20716173 TI - Dysplastic naevi, again. PMID- 20716174 TI - Keloid type of fibromatosis-like metaplastic carcinoma of the breast with transformation into biphasic tumour in recurrences and lymph node metastases. PMID- 20716175 TI - Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders in elderly white patients. PMID- 20716176 TI - A novel method of cell embedding for tissue microarrays. PMID- 20716178 TI - Direct interaction between CD91 and C1q. AB - C1q-mediated removal of immune complexes and apoptotic cells plays an important role in tissue homeostasis and the prevention of autoimmune conditions. It has been suggested that C1q mediates phagocytosis of apoptotic cells through a receptor complex assembled from CD91 (alpha-2- macroglobulin receptor, or low density lipoprotein receptor-related protein) and calreticulin, with CD91 being the transmembrane part and calreticulin acting as the C1q-binding molecule. In the present study, we observe that C1q binds cells from a CD91 expressing monocytic cell line as well as monocytes from human blood. C1q binding to monocytes was shown to be correlated with CD91 expression and could be inhibited by the CD91 chaperone, receptor-associated protein. We also report data showing a direct interaction between CD91 and C1q. The interaction was investigated using various protein interaction assays. A direct interaction between purified C1q and CD91 was observed both by ELISA and a surface plasmon resonance assay, with either C1q or CD91 immobilized. The interaction showed characteristics of specificity because it was time-dependent, saturable and could be inhibited by known ligands of both CD91 and C1q. The results obtained show for the first time that CD91 recognizes C1q directly. On the basis of these findings, we propose that CD91 is a receptor for C1q and that this multifunctional scavenger receptor uses a subset of its ligand-binding sites for clearance of C1q and C1q bound material. PMID- 20716179 TI - Identification of a preferred substrate peptide for transglutaminase 3 and detection of in situ activity in skin and hair follicles. AB - Transglutaminases (TGases) are a family of enzymes that catalyze cross-linking reactions between proteins. During epidermal differentiation, these enzymatic reactions are essential for formation of the cornified envelope, which consists of cross-linked structural proteins. Two main transglutaminases isoforms, epidermal-type (TGase 3) and keratinocyte-type (TGase 1), are cooperatively involved in this process of differentiating keratinocytes. Information regarding their substrate preference is of great importance to determine the functional role of these isozymes and clarify their possible co-operative action. Thus far, we have identified highly reactive peptide sequences specifically recognized by TGases isozymes such as TGase 1, TGase 2 (tissue-type isozyme) and the blood coagulation isozyme, Factor XIII. In this study, several substrate peptide sequences for human TGase 3 were screened from a phage-displayed peptide library. The preferred substrate sequences for TGase 3 were selected and evaluated as fusion proteins with mutated glutathione S-transferase. From these studies, a highly reactive and isozyme-specific sequence (E51) was identified. Furthermore, this sequence was found to be a prominent substrate in the peptide form and was suitable for detection of in situ TGase 3 activity in the mouse epidermis. TGase 3 enzymatic activity was detected in the layers of differentiating keratinocytes and hair follicles with patterns distinct from those of TGase 1. Our findings provide new information on the specific distribution of TGase 3 and constitute a useful tool to clarify its functional role in the epidermis. PMID- 20716180 TI - The consensus motif for N-myristoylation of plant proteins in a wheat germ cell free translation system. AB - Protein N-myristoylation plays key roles in various cellular functions in eukaryotic organisms. To clarify the relationship between the efficiency of protein N-myristoylation and the amino acid sequence of the substrate in plants, we have applied a wheat germ cell-free translation system with high protein productivity to examine the N-myristoylation of various wild-type and mutant forms of Arabidopsis thaliana proteins. Evaluation of the relationship between removal of the initiating Met and subsequent N-myristoylation revealed that constructs containing Pro at position 3 do not undergo N-myristoylation, primarily because of an inhibitory effect of this amino acid on elimination of the initiating Met by methionyl aminopeptidase. Our analysis of the consensus sequence for N-myristoylation in plants focused on the variability of amino acids at positions 3, 6 and 7 of the motif. We found that not only Ser at position 6 but also Lys at position 7 affects the selectivity for the amino acid at position 3. The results of our analyses allowed us to identify several A. thaliana proteins as substrates for N-myristoylation that had previously been predicted not to be candidates for such modification with a prediction program. We have thus shown that a wheat germ cell-free system is a useful tool for plant N myristoylome analysis. This in vitro approach will facilitate comprehensive determination of N-myristoylated proteins in plants. PMID- 20716181 TI - Adeno-associated virus gene transfer in Morquio A disease - effect of promoters and sulfatase-modifying factor 1. AB - Mucopolysaccharidosis (MPS) IVA is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate sulfatase (GALNS), which leads to the accumulation of keratan sulfate and chondroitin 6 sulfate, mainly in bone. To explore the possibility of gene therapy for Morquio A disease, we transduced the GALNS gene into HEK293 cells, human MPS IVA fibroblasts and murine MPS IVA chondrocytes by using adeno-associated virus (AAV) based vectors, which carry human GALNS cDNA. The effects of the promoter and the cotransduction with the sulfatase-modifying factor 1 gene (SUMF1) on GALNS activity levels was evaluated. Downregulation of the cytomegalovirus (CMV) immediate early enhancer/promoter was not observed for 10 days post-transduction. The eukaryotic promoters induced equal or higher levels of GALNS activity than those induced by the CMV promoter in HEK293 cells. Transduction of human MPS IVA fibroblasts induced GALNS activity levels that were 15-54% of those of normal human fibroblasts, whereas in transduced murine MPS IVA chondrocytes, the enzyme activities increased up to 70% of normal levels. Cotransduction with SUMF1 vector yielded an additional four-fold increase in enzyme activity, although the level of elevation depended on the transduced cell type. These findings suggest the potential application of AAV vectors for the treatment of Morquio A disease, depending on the combined choice of transduced cell type, selection of promoter, and cotransduction of SUMF1. PMID- 20716183 TI - While memory holds a seat. PMID- 20716184 TI - Equine grass sickness: are we any nearer to answers on cause and prevention after a century of research? PMID- 20716185 TI - Pain relief: searching the clinical routes to this objective. PMID- 20716186 TI - Investigating the efficacy of articular medications in the horse: the science behind clinical practices. PMID- 20716187 TI - The use of sedatives, analgesic and anaesthetic drugs in the horse: an electronic survey of members of the American Association of Equine Practitioners (AAEP). AB - REASONS FOR PERFORMING STUDY: To determine the sedative, analgesic and anaesthetic drugs and techniques that are used by equine veterinarians. HYPOTHESIS OR OBJECTIVES: To provide equine veterinarians with information concerning veterinary use of anaesthetic techniques, a reflection of the collective experiences of the profession. METHODS: A survey was conducted of those members of the American Association of Equine Practitioners (AAEP) with an electronic mail address on file with the organisation using proprietary, web based software. The survey was comprised of 30 questions divided into 8 sections: nonsteroidal anti-inflammatory drugs; local anaesthesia; alternative techniques; standing chemical restraint; epidural anaesthesia; short-term anaesthesia; long term anaesthesia; and a place for the respondent to make comments. RESULTS: The response rate was 13.8% (952/6911) AAEP member veterinarians primarily use phenylbutazone and flunixin as anti-inflammatory drugs, and lidocaine and mepivacaine for local anaesthesia. Combinations of drugs are preferred for standing chemical restraint. While many veterinarians frequently utilise short term anaesthesia, longer anaesthesia is less frequently performed. CONCLUSIONS: Most AAEP member veterinarians use sedatives in combination to provide standing chemical restraint. Extra-label use of drugs is a core component of current equine sedation and anaesthetic practice. POTENTIAL RELEVANCE: Equine veterinarians can compare their choices of anaesthetic drugs with others practising equine medicine and surgery and may be stimulated to investigate alternative methods of providing comfort to horses. PMID- 20716188 TI - Prevalence of Clostridium perfringens in faeces and ileal contents from grass sickness affected horses: comparisons with 3 control populations. AB - REASONS FOR PERFORMING STUDY: While previous studies have demonstrated an association between equine grass sickness (EGS) and the presence of Clostridium botulinum within ileal contents and faeces, no such associations with other intestinal-derived anaerobic bacteria have been extensively investigated. HYPOTHESIS: The prevalence of C. perfringens in the ileal contents and faeces of EGS horses is greater than control horses; the detection of C. perfringens in faeces by ELISA could be diagnostically beneficial in a clinical setting. METHODS: The prevalence of C. perfringens in faeces from EGS horses and healthy grazing control horses was determined by both selective culture and ELISA to permit both validation of the ELISA and inter-group comparisons. Additionally, the prevalence of C. perfringens (ELISA) in ileal contents from EGS horses was compared with that for control horses with nongastrointestinal disease. Finally, the prevalence of C. perfringens (ELISA) in faeces from EGS cases was compared with that from both horses with which they shared pasture at the time of disease onset and non-EGS colic horses. RESULTS: When compared with culture, the ELISA had a sensitivity and specificity of 86 and 98%, respectively. The prevalence of C. perfringens in faeces as determined by both culture and ELISA was significantly higher (P<0.001) for EGS horses (7/9 and 15/37, respectively) than for healthy grazing controls (0/60 and 1/74, respectively). The prevalence of C. perfringens in ileal contents from EGS horses (5/10) was greater than that for horses with nongastrointestinal disease (1/12) at a level that approached significance (P = 0.056). EGS cases had a significantly greater prevalence of C. perfringens in faeces (15/37) than co-grazing horses (1/18) and colic (1/16) horses. The specificity (93%) and PPV (94%) of the detection of C. perfringens by ELISA on faecal samples in relation to disease status (EGS compared with colic horses) was good. Sensitivity (41%) and NPV (39%) were poor. CONCLUSIONS AND POTENTIAL RELEVANCE: The use of a commercial ELISA to detect faecal C. perfringens may be diagnostically beneficial when differentiating EGS cases from colic cases, although further work is required to fully evaluate its potential. PMID- 20716189 TI - Distances between thoracic spinous processes in Warmblood foals: a radiographic study. AB - REASON FOR PERFORMING STUDY: The aetiological factors behind impinged or overriding of dorsal spinous processes ('kissing spine syndrome', KSS) are not clearly understood. Back conformation, breed, age, training and gender may play important roles in this condition. Radiographic changes vary and abnormalities are seen in many clinically normal horses, but the conclusion of previous studies in mature horses is that interspinous spaces <4 mm are considered too narrow and potentially indicative of KSS. OBJECTIVES: To evaluate whether narrowing of the interspinous space was present in a population of normal Warmblood foals. MATERIALS AND METHODS: The mean interspinous space width in the area of T10-L1 was measured on radiographs from 25 Warmblood foals aged 9-88 days. RESULTS: Mean +/- s.d. interspinous space width was found to be between 5.9 +/- 1.2 and 8.9 +/- 2.6 mm with the narrowest space in the area T16-T17 and the widest space in T10 T12. No interspinous spaces were <4 mm wide. Gender and location of the interspinous space significantly affected the width of the distance between the spinous processes. CONCLUSIONS AND POTENTIAL RELEVANCE: In this study none of the interspinous spaces were <4 mm and therefore none of the foals showed signs of impinged or overriding of dorsal spinous processes known as KSS based on the current definitions. Consequently, in this population, there did not appear to be a congenital narrowing of the interspinous space. However, long-term follow-up studies, including detailed information on imposed factors such as training, are needed in order to further elucidate a possible congenital component in the aetiology of KSS. PMID- 20716190 TI - Is there an association between ossification of the cartilages of the foot and collateral desmopathy of the distal interphalangeal joint or distal phalanx injury? AB - REASONS FOR PERFORMING STUDY: Associations between degree of ossification of the cartilages of the foot and injuries to other structures of the foot have been suggested, but have not been investigated by large scale studies. OBJECTIVES: To describe the frequency of grade >3 ossification of the cartilages of the foot (possibly significant ossification, PSO), mediolateral symmetry of ossification and left-right symmetry between feet; and to investigate associations between PSO and injury of either the collateral ligaments (CLs) of the distal interphalangeal (DIP) joint or the distal phalanx. HYPOTHESES: Possibly significant ossification of the cartilages of the foot is associated with CL and distal phalanx injury. Distal phalanx injury is associated with a mediolateral difference in ossification grade of > or =2. METHODS: Horses were examined for lameness localised to the foot by perineural analgesia, and underwent radiographic and magnetic resonance imaging examinations. Age, breed, occupation, duration of lameness, lame(st) limb, primary cause of lameness, and presence or absence of CL injury were recorded. Dorsopalmar (dorsoplantar) radiographs were examined and ossification of the cartilages of the foot graded using a modification of a previously published scale. RESULTS: One foot from each of 462 horses was included for analysis. There was left-right symmetry of ossification between feet, and significant association between grades of each foot, with lateral > or =medial cartilages. Possibly significant ossification occurred in the maximally ossified cartilage in 59 (12.8%) feet. There were significant associations between PSO of the maximally ossified cartilage of the foot and injuries of both the CLs of the DIP joint and the distal phalanx. There was no association between distal phalanx injury and marked asymmetry of the ossified cartilages of the foot. CONCLUSIONS AND CLINICAL RELEVANCE: Extensively ossified cartilages of the foot are significantly associated with CL or distal phalanx injury. Markedly asymmetric ossification did not increase the likelihood of distal phalanx injury and should be considered at a prepurchase examination. PMID- 20716191 TI - Distribution of radiodense contrast medium after perineural injection of the palmar and palmar metacarpal nerves (low 4-point nerve block): an in vivo and ex vivo study in horses. AB - REASONS FOR PERFORMING STUDY: Evidence-based information is limited on distribution of local anaesthetic solution following perineural analgesia of the palmar (Pa) and palmar metacarpal (PaM) nerves in the distal aspect of the metacarpal (Mc) region ('low 4-point nerve block'). OBJECTIVES: To demonstrate the potential distribution of local anaesthetic solution after a low 4-point nerve block using a radiographic contrast model. METHODS: A radiodense contrast medium was injected subcutaneously over the medial or the lateral Pa nerve at the junction of the proximal three-quarters and distal quarter of the Mc region (Pa injection) and over the ipsilateral PaM nerve immediately distal to the distal aspect of the second or fourth Mc bones (PaM injection) in both forelimbs of 10 mature horses free from lameness. Radiographs were obtained 0, 10 and 20 min after injection and analysed subjectively and objectively. Methylene blue and a radiodense contrast medium were injected in 20 cadaver limbs using the same techniques. Radiographs were obtained and the limbs dissected. RESULTS: After 31/40 (77.5%) Pa injections, the pattern of the contrast medium suggested distribution in the neurovascular bundle. There was significant proximal diffusion with time, but the main contrast medium patch never progressed proximal to the mid-Mc region. The radiological appearance of 2 limbs suggested that contrast medium was present in the digital flexor tendon sheath (DFTS). After PaM injections, the contrast medium was distributed diffusely around the injection site in the majority of the limbs. In cadaver limbs, after Pa injections, the contrast medium and the dye were distributed in the neurovascular bundle in 8/20 (40%) limbs and in the DFTS in 6/20 (30%) of limbs. After PaM injections, the contrast and dye were distributed diffusely around the injection site in 9/20 (45%) limbs and showed diffuse and tubular distribution in 11/20 (55%) limbs. CONCLUSIONS AND POTENTIAL RELEVANCE: Proximal diffusion of local anaesthetic solution after a low 4-point nerve block is unlikely to be responsible for decreasing lameness caused by pain in the proximal Mc region. The DFTS may be penetrated inadvertently when performing a low 4-point nerve block. PMID- 20716192 TI - Isolation of equine bone marrow-derived mesenchymal stem cells: a comparison between three protocols. AB - REASON FOR PERFORMING THE STUDY: There is a need to assess and standardise equine bone marrow (BM) mesenchymal stem cell (MSC) isolation protocols in order to permit valid comparisons between therapeutic trials at different sites. OBJECTIVE: To compare 3 protocols of equine BM MSC isolation: adherence to a plastic culture dish (Classic) and 2 gradient density separation protocols (Percoll and Ficoll). MATERIALS AND METHODS: BM aspirates were harvested from the sternum of 6 mares and MSCs isolated by all 3 protocols. The cell viability after isolation, MSC yield, number of MSCs attained after 14 days of culture and the functional characteristics (self-renewal (CFU) and multilineage differentiation capacity) were determined for all 3 protocols. RESULTS: The mean +/- s.d. MSC yield from the Percoll protocol was significantly higher (6.8 +/- 3.8%) than the Classic protocol (1.3 +/- 0.7%). The numbers of MSCs recovered after 14 days culture per 10 ml BM sample were 24.0 +/- 12.1, 14.6 +/- 9.5 and 4.1 +/- 2.5 x 10(6) for the Percoll, Ficoll and Classic protocols, respectively, significantly higher for the Percoll compared with the Classic protocol. Importantly, no significant difference in cell viability or in osteogenic or chondrogenic differentiation was identified between the protocols. At Passage 0, cells retrieved with the Ficoll protocol had lower self-renewal capacity when compared with the Classic protocol but there was no significant difference between protocols at Passage 1. There were no significant differences between the 3 protocols for the global frequencies of CFUs at Passage 0 or 1. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that the Percoll gradient density separation protocol was the best in terms of MSC yield and self-renewal potential of the MSCs retrieved and that MSCs retrieved with the Ficoll protocol had the lowest self-renewal but only at passage 0. Then, the 3 protocols were equivalent. However, the Percoll protocol should be considered for equine MSC isolation to minimise culture time. PMID- 20716193 TI - Pathology of lethal peripartum broad ligament haematoma in 31 Thoroughbred mares. AB - REASONS FOR PERFORMING STUDY: Broad ligament haemorrhage in peripartum mares is a life-threatening disease and there are few reports on the aetiology and pathogenesis of broad ligament haematoma. OBJECTIVES: To obtain information regarding the sites for the early diagnosis and pathogenesis of broad ligament haematoma of mares. METHODS: Thirty-one mares that died of broad ligament haematoma peripartum were examined pathologically for bleeding sites. The arterial distribution of 5 young mares with several parities served as negative controls. RESULTS: Age and/or multiparity were the predisposing factors for the disease. Arterial injuries were most commonly observed in the uterine artery (24 of 31 mares). Among these, the proximal uterine artery that lies within 15 cm of the bifurcation of the iliac artery was the most frequent site for rupture (18 mares). The lesions occurred preferentially at the bifurcations, lateral part of curvatures and abrupt flexures of the artery. The morphology of the injuries was classified into 3 types: ruptures with and without longitudinal fissures, and transections. Histologically, the arterial wall adjacent to the rupture showed atrophy of smooth muscle cells with fibrosis of the tunica media and disruption and/or calcification of the internal elastic lamina. CONCLUSIONS: Arterial injuries that led to broad ligament haematoma in peripartum mares occurred most frequently in the proximal uterine artery, and atrophy of smooth muscle cells with fibrosis of the arterial wall was as one of the predisposing factors in aged and multiparous mares. POTENTIAL RELEVANCE: Monitoring small aneurysms, mural tearing, medial fibrosis at the proximal uterine artery by transrectal echography could provide useful information for the early diagnosis and possible prevention of broad ligament haematoma of peripartum mares. PMID- 20716194 TI - Considerations for pacing of the cricoarytenoid dorsalis muscle by neuroprosthesis in horses. AB - REASONS FOR PERFORMING STUDY: The success rate of prosthetic laryngoplasty is limited and may be associated with significant sequelae. Nerve muscle pedicle transplantation has been attempted but requires a year before function is restored. OBJECTIVE: To determine the optimal parameters for functional electrical stimulation of the recurrent laryngeal nerve in horses. METHODS: An experimental in vivo study was performed on 7 mature horses (2-21 years). A nerve cuff was placed on the distal end of the common trunk of the recurrent laryngeal nerve (RLN). In 6 horses the ipsilateral adductor branch of RLN was also transected. The electrodes were connected to programmable internal stimulator. Stimulation was performed using cathodic phase and then biphasic pulses at 24 Hz with a 0.427 ms pulse duration. Stimulation-response experiments were performed at monthly intervals, from one week following implantation. The study continued until unit failure or the end of project (12 months). Two of the horses were stimulated continuously for 60 min to assess onset of fatigue. RESULTS: Excellent arytenoid cartilage abduction (mean arytenoid angle of 52.7 degrees, range 48.5 56.2 degrees) was obtained in 6 horses (laryngeal grades I or II (n = 3) and III (n = 2). Poor abduction was obtained in grade IV horses (n = 2). Arytenoid abduction was maintained for up to a year in one horse. Technical implant failure resulted in loss of abduction in 6 horses at one week to 11 months post operatively. Mean tissue impedance was 1.06 kOhm (range 0.64-1.67 kOhm) at one week, twice this value at 2 months (mean 2.32, range 1.11-3.75 kOhm) and was stable thereafter. Maximal abduction was achieved at a stimulation range of 0.65 7.2 mA. No electrical leakage was observed. Constant stimulation of the recurrent laryngeal nerve for 60 min led to full abduction without evidence of muscle fatigue. CONCLUSIONS: Functional electrical stimulation of the recurrent laryngeal nerve leading to full arytenoid abduction can be achieved. The minimal stimulation amplitude for maximal abduction angle is slightly higher than those for man and dogs. CLINICAL RELEVANCE: This treatment modality could eventually be applicable to horses with recurrent laryngeal neuropathy. PMID- 20716195 TI - Use of blood culture medium enrichment for synovial fluid culture in horses: a comparison of different culture methods. AB - REASONS FOR PERFORMING STUDY: Standard methods for culturing equine synovial fluid (SF) are often unrewarding. Evidence-based information on the relative efficiency of different systems used for optimisation of isolation of microorganisms from equine SF is lacking. OBJECTIVES: To compare the results of different culture systems performed in parallel on SF samples from horses clinically diagnosed with synovial sepsis. METHODS: Synovial fluid specimens were collected between February 2007 and October 2008 from all horses admitted to a referral hospital that were clinically diagnosed with synovial sepsis and from control horses. Synovial fluid samples were cultured in parallel by: 1) direct agar culture (DA); agar culture after: 2) lysis-centrifugation pretreatment (LC); 3) conventional enrichment (CE); 4) combined LC/CE; or 5) blood culture medium enrichment using an automated system (BACTEC 9050). RESULTS: Ninety SF samples from 82 horses were included, together with 40 control samples. Seventy-one of 90 samples (79%) were culture-positive by using blood culture medium enrichment (BACTEC), which was significantly higher compared to all other methods. BACTEC enrichment was never negative while any of the other methods was positive. Although agar culture following LC and/or CE resulted in a slightly higher number of positive samples compared to DA, this difference was not significant. All control samples were culture negative by the 5 different techniques. Although the majority of samples containing isolates recovered without enrichment, culture results after BACTEC enrichment were available on the same day as for agar culture with or without LC (19/23 samples), while CE postponed recovery by at least one day in 20/23 samples. CONCLUSION: Blood culture medium enrichment is superior to other techniques for isolation of bacteria from SF of horses. The use of an automated system allows enrichment without substantially postponing recovery of microorganisms. POTENTIAL RELEVANCE: The efficient and fast isolation of microorganisms from infected SF by the BACTEC system allows for rapid susceptibility testing and a more appropriate antibiotic treatment. PMID- 20716196 TI - Which anatomical region determines a positive flexion test of the distal aspect of a forelimb in a nonlame horse? AB - REASONS FOR PERFORMING STUDY: The flexion test is used routinely as part of lameness and prepurchase examinations. However, little is known about the mechanisms that cause a positive response to a flexion test. OBJECTIVE: To determine which anatomical regions play a role in a positive outcome of a flexion test of the distal aspect of a forelimb in a nonlame horse. METHODS: Eight clinically sound Dutch Warmblood horses were subjected to a standardised flexion test (force 250 N, time 60 s) inducing a consistent lameness. To discriminate between different areas of the distal aspect of a forelimb, effects of various nerve blocks on the outcome of the flexion test were investigated. Low palmar digital, palmar at the abaxial aspects of the base of the proximal sesamoids, high palmar, ulnar and low 4-point nerve blocks were performed. Flexion test induced lameness was scored before and after each nerve block in separate sessions. RESULTS: The low palmar digital nerve blocks and nerve blocks of the palmar nerves at the abaxial aspect of the base of the proximal sesamoid bones had no significant effect on the flexion test induced lameness score. The ulnar, high palmar and, most dramatically, the low 4-point nerve blocks all caused a significant (P<0.05) reduction in the flexion test induced lameness score. CONCLUSIONS: Anatomical structures (soft tissue nor synovial structures) located distal to the metacarpophalangeal joint appear to contribute only minimally to the outcome of a positive flexion test of the distal aspect of a forelimb in a clinically nonlame horse. The structures in the region of, and including, the metacarpophalangeal joint appear to contribute most to a positive flexion test of the distal aspect of a forelimb in a nonlame horse. POTENTIAL RELEVANCE: The flexion test of the distal aspect of a forelimb may be sensitive for investigating the metacarpophalangeal joint region in horses free from lameness, but may be less relevant for structures distal to this region. PMID- 20716197 TI - Quantitative evaluation of subchondral bone injury of the plantaro-lateral condyles of the third metatarsal bone in Thoroughbred horses identified using nuclear scintigraphy: 48 cases. AB - REASONS FOR PERFORMING STUDY: Increased radio-isotope uptake (IRU) in the subchondral bone of the plantaro-lateral condyle of the third metatarsus (MTIII) is a commonly reported scintigraphic finding and potential cause of lameness in UK Thoroughbred racehorses in training and has not been fully documented. OBJECTIVES: To characterise lameness attributable to IRU of the subchondral bone of MTIII, compare the scintigraphic findings of these horses with a normal population and evaluate the use of scintigraphy as an indicator of prognosis. HYPOTHESIS: IRU will be in significantly higher in horses with subchondral bone injury and will be related to prognosis and future racing performance. METHODS: Data were analysed from 48 horses in which subchondral bone injury of the plantaro-lateral condyle of MTIII had been diagnosed using nuclear scintigraphy and that met the inclusion criteria. Data recorded included age, sex, trainer, racing discipline, lameness assessment, treatment regimes, radiographic and scintigraphic findings, response to diagnostic analgesia where performed and racing performance pre- and post diagnosis. Region of interest (ROI) counts were obtained for the plantar condyle and the mid diaphysis from the latero-medial view, the ratio calculated and then compared with a control group of clinically unaffected horses. RESULTS: The mean condyle mid-diaphysis ROI ratio was significantly (P<0.001) higher in the affected population and with positively correlation (P = 0.024) with the level of lameness. The presence of radiographic findings had no significant effect on the ROI ratio. CONCLUSION: Subchondral bone injury of the plantar lateral condyles of MTIII is a significant cause of lameness in UK Thoroughbred racehorses. Nuclear scintigraphy is a useful diagnostic imaging modality in the detection of affected horses but is a poor indicator of prognosis for the condition. POTENTIAL RELEVANCE: Better understanding of the clinical manifestations, diagnosis of and prognosis for subchondral bone injury will benefit the Thoroughbred industry in the UK. PMID- 20716198 TI - Arthroscopic removal of fractures of the lateral malleolus of the tibia in the tarsocrural joint: a retrospective study of 13 cases. AB - There is limited information on the treatment of lateral malleolus (LM) fractures in the horse, with no previously published case series for the outcome following arthroscopic removal of such fractures. This report reviews and evaluates findings of a retrospective study of 13 horses admitted to a private equine referral hospital over a 10 year period (1999-2009) that underwent arthroscopic removal of fractures of the LM. Hospital records were reviewed and details including patient history, aetiology of the fracture and limb affected, results of all diagnostic tests and surgical reports were documented. Performance information concerning Thoroughbred horses that went onto race post operatively was collected using an online database. Owners and trainers were contacted regarding the return to performance for non-Thoroughbred cases or those that did not go onto race post operatively. Of the 13 horses presented, 12 were Thoroughbreds, 9 of which were National Hunt racehorses and 3 were Flat racehorses. The other horse in the study was used for general purpose riding. All cases presented with an acute unilateral fracture. Eleven of the 13 had >6 months post operative follow-up and all were nonlame. Of the 12 Thoroughbreds, 10 have raced again, a total of 104 times (median 5 times). The median time from surgery to return to racing was 241 days (180-366 days). It is concluded that horses with fractures of the LM have an excellent prognosis for return to full athletic performance following arthroscopic debridement; and that arthroscopic fragment removal is an appropriate treatment method for fractures of the LM. PMID- 20716199 TI - The use of intra-articular corticosteroids in the horse: what is known on a scientific basis? AB - Intra-articular use of corticosteroids has become a recent focus (or re-focus) of attention in the Thoroughbred racing industry. This manuscript reviews the clinical use and scientific basis of intra-articular corticosteroid administration including catastrophic injury, articular cartilage degradation and the development of osteoarthritis (OA), as well as the timing of injection relative to racing. PMID- 20716200 TI - Report of the Second Havemeyer EHV-1 Workshop, Steamboat Springs, Colorado, USA, September 2008. AB - This report summarises the findings of the Second Havemeyer EHV-1 Workshop, which was held in Steamboat Springs, Colorado, USA in September 2008. A total of 38 delegates, consisting of veterinary clinicians and scientists from academia and industry participated in a series of sessions that focused on equine herpesvirus myeloencephalopathy (EHM). Each session consisted of a review, followed by short presentations on current research topics. The sessions included EHM epidemiology, in vivo and in vitro models for studying EHM, EHV-1 virulence determinants, real time PCR diagnostics, antiviral medications and new vaccination technologies. The report summarises the key advances identified during and since the meeting. Citations are restricted to selected reviews and papers published since the workshop. PMID- 20716202 TI - Trends in weights, heights, BMI and comparison of their differences in urban and rural areas for Iranian children and adolescents 2-18-year-old between 1990-1991 and 1999. AB - BACKGROUND: Secular trends in height and weight are interesting because in middle and low-income countries they are a marker for changes in population health. The present study aims to evaluate the secular trend in height and weight and body mass index (BMI) of Iranian children and adolescents aged 2-18 years old between 1990-1991 and 1999 and compare the magnitude of urban-rural differences during this period for the first time in an Asian country. METHODS: Data from two national health surveys in 1990-1991 and 1999, of 22,349 and 25,196 weight and height measures of Iranian children and adolescents were used to study the trend and compare its difference in urban and rural children. Logarithmic transformation of weight, height and BMI was modelled as a polynomial in age for urban and rural boys and girls in each survey separately. The trend in urban and rural growth indexes (weight, height and BMI) and also the comparisons of urban rural differences between two national surveys were tested in logarithmic scale using a weighted form of Z statistic for comparison of two means adjusted for age groups. RESULTS: Urban and rural boys and girls became taller and heavier (P<= 0.02) with no change of BMI (P > 0.05) during the period. There was not any significant difference between the magnitudes of urban-rural difference between two surveys (P>= 0.61). CONCLUSION: Although generally positive weight and height trend was observed among urban and rural residents, the magnitude of their differences was not changed. PMID- 20716203 TI - Children's understanding of cancer and views on health-related behaviour: a 'draw and write' study. AB - BACKGROUND: Few studies have explored young children's understanding of cancer and health-related behaviours yet this is essential to develop health promotion initiatives that build on young children's current knowledge levels and awareness. METHOD: An exploratory descriptive design using the 'draw and write' technique was used to investigate children's views of cancer and health behaviours. The sample included 195 children aged eight to 11 years from five schools in deprived, affluent and rural locations in Scotland. RESULTS: When asked about cancer children demonstrated a good level of awareness by responding with text and drawings about the what they understood cancer to be; types of cancer; causes of cancer; what happens to people who have cancer; their personal experience of cancer and the emotions they associated with cancer. Older children, and children attending affluent schools, have more defined ideas about the causes of cancer and awareness of broader issues such as the risk of passive smoking or the potential impact on the family. Factors such as alcohol and illegal drugs were only reported by children attending schools in deprived locations. Children demonstrated considerable knowledge about healthy and unhealthy lifestyle behaviours; however, it is not clear whether this knowledge translates into their behaviours or the choices offered within their home environment. CONCLUSIONS: Children view cancer in a negative way from an early age, even without personal experience. There is a need to demystify cancer in terms of its causes, how to recognize it, how it is treated and to publicize improved survival rates. There is a need for targeted and developmentally appropriate approaches to be taken to health education in schools, with an awareness of the influence of the media on children's information. Strategies should take into consideration the socio-economic and cultural contexts of children's lives which influence their choices and behaviours. PMID- 20716204 TI - Normative data collection of the Marburg Concentration Test for Pre-school Children (German: MKVK). AB - OBJECTIVE: The objective of this study was the standardization of the Marburg Concentration Test for Pre-school Children (German: MKVK) for 3- to 6-year-old children as an instrument for the early diagnosis of lack of concentration in connection with language development disorders. PATIENTS AND METHODS: We conducted the MKVK on 309 children in 15 day-care centres. The MKVK is a matter of a simple sorting task of 80 cards according to pictures. The ascertainment of the concentration performance is conducted using the criteria processing time and error count. The results are analysed in seven age groups. RESULTS: An age dependence is seen in the execution time and a tendency in the amount of errors. Three-year-olds require more time and make more errors than 4.5- and 5-year-olds. Two groups become apparent in the 3-year-olds: children with whom the test is easy to take and children who are still overwhelmed with the instructions and processing. CONCLUSION: The MKVK is easy to conduct and shows children's ability to concentrate at pre-school ages. It proves to be of particular value for the 4- and 5-year-olds. The study gives hints on different work methods of the children. Indications for a differentiated facilitation could be deduced from that. PMID- 20716205 TI - LEEways: tales of EPEC, ATEC and EHEC. AB - Intestinal pathogenic Escherichia coli are a major cause of worldwide morbidity and mortality. Currently seven intestinal pathovars are recognized causing a wide range of intestinal disorders that are sometimes associated with severe and even lethal complications. The arsenal of virulence factors is used to subvert cellular functions of the host thereby enhancing adaptation, virulence and pathogenicity. Virulence factor profiles are largely the result of the acquisition of mobile genetic elements such as prophages and pathogenicity islands. A group of highly adapted intestinal pathogenic E. coli that are characterized by the induction of 'attaching-and-effacing (A/E) lesions' have acquired a decisive pathogenicity island, the 'locus of enterocyte effacement - LEE' by horizontal gene transfer. This review focuses on recent advances in our understanding of A/E E. coli. It highlights novel functions of effector proteins, addresses the LEE flanking regions where additional genetic elements such as the LifA/Efa1 region have been identified, and points to implications for diagnostics and therapy due to the putative interconversion of A/E E. coli during infection. PMID- 20716206 TI - Aspergillus fumigatus: contours of an opportunistic human pathogen. AB - Aspergillus fumigatus is currently the major air-borne fungal pathogen. It is able to cause several forms of disease in humans of which invasive aspergillosis is the most severe. The high mortality rate of this disease prompts increased efforts to disclose the basic principles of A. fumigatus pathogenicity. According to our current knowledge, A. fumigatus lacks sophisticated virulence traits; it is nevertheless able to establish infection due to its robustness and ability to adapt to a wide range of environmental conditions. This review focuses on two crucial aspects of invasive aspergillosis: (i) properties of A. fumigatus that are relevant during infection and may distinguish it from non-pathogenic Aspergillus species and (ii) interactions of the pathogen with the innate and adaptive immune systems. PMID- 20716208 TI - Topical 5-fluorouracil treatment of anal intraepithelial neoplasia in human immunodeficiency virus-positive men. AB - BACKGROUND: Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV) induced potential precursor lesion of anal cancer, is frequent among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). So far, only a few prospective studies have been performed on the topical treatment of AIN, especially at the intra-anal location. OBJECTIVES: To evaluate the efficacy and safety of self-administered topical 5-fluorouracil (5-FU) treatment of AIN in HIV-positive MSM. METHODS: High-resolution anoscopy (HRA) was performed and patients with AIN (grade 1-3) were treated with 5-FU twice weekly for a total of 16 weeks. HRA-guided lesional biopsies were repeated after 5-FU treatment for histopathological evaluation. Lesional swabs were obtained before and after treatment for HPV typing and HPV-DNA load determination of the high-risk types HPV16, 18, 31 and 33. Responding patients returned 6 months after treatment for follow-up. RESULTS: A total of 46 patients with AIN were included in this open prospective pilot study; 76% had multifocal disease and 74% had high-grade lesions (AIN 2 or 3). In an intention-to-treat analysis, 26 of 46 patients (57%) responded to 5-FU treatment. Eighteen patients (39%) had a complete clearance of AIN and eight patients (17%) had a partial response. Seventeen patients (37%) did not respond (unchanged grade of AIN in 16 patients and progression from low- to high-grade AIN in one patient). 5-FU treatment led to a significant decrease of HPV16-DNA load and cumulative high-risk HPV-DNA load in both responding and nonresponding patients. Thirty-nine patients (85%) experienced side-effects during therapy, but only two discontinued 5-FU treatment. One patient was lost to follow-up. Six months later, 50% of the complete responders had a recurrence. CONCLUSIONS: A substantial proportion of HIV-positive MSM with AIN completely cleared their lesions with topical 5-FU treatment. In those with partial response, pretreatment with topical 5-FU might facilitate subsequent ablative therapy. PMID- 20716207 TI - Anaplasma phagocytophilum AptA modulates Erk1/2 signalling. AB - Anaplasma phagocytophilum causes human granulocytic anaplasmosis, one of the most common tick-borne diseases in North America. This unusual obligate intracellular pathogen selectively persists within polymorphonuclear leucocytes. In this study, using the yeast surrogate model we identified an A. phagocytophilum virulence protein, AptA (A. phagocytophilum toxin A), that activates mammalian Erk1/2 mitogen-activated protein kinase. This activation is important for A. phagocytophilum survival within human neutrophils. AptA interacts with the intermediate filament protein vimentin, which is essential for A. phagocytophilum induced Erk1/2 activation and infection. A. phagocytophilum infection reorganizes vimentin around the bacterial inclusion, thereby contributing to intracellular survival. These observations reveal a major role for the bacterial protein, AptA, and the host protein, vimentin, in the activation of Erk1/2 during A. phagocytophilum infection. PMID- 20716209 TI - Stem cell therapies for recessive dystrophic epidermolysis bullosa. AB - Human epidermis is composed of a stratified squamous epithelium that provides a mechanical barrier against the external environment and which is renewed every 3 4 weeks by resident stem cells in the epidermis. However, in the inherited skin fragility disorder, recessive dystrophic epidermolysis bullosa (RDEB), there is recurrent trauma-induced subepidermal blistering that disrupts epidermal homeostasis and is likely to deplete the epidermal stem cell pool. This review article discusses the nature of epidermal stem cells and other stem cell populations in the skin, as well as other possible extracutaneous sources of stem cells, that might have physiological or therapeutic relevance to cell therapy approaches for RDEB. Strategies to identify, create and use cells with multipotent or pluripotent properties are explored and current clinical experience of stem cell therapy in RDEB is reviewed. There is currently no single optimal therapy for patients with RDEB, but cell therapy technologies are evolving and hold great potential for modifying disease severity and improving quality of life for people living with RDEB. PMID- 20716210 TI - Nuclear magnetic resonance spectroscopy of urine in male genital lichen sclerosus. PMID- 20716211 TI - Hair casts are a dermoscopic clue for the diagnosis of traction alopecia. PMID- 20716212 TI - Interleukin-17 expression in the urticarial rash of familial cold autoinflammatory syndrome: a case report. PMID- 20716213 TI - Trends in reported sun bed use, sunburn, and sun care knowledge and attitudes in a U.K. region: results of a survey of the Northern Ireland population. AB - BACKGROUND: Sunburn and sun bed use increase risk of malignant melanoma, the incidence of which continues to rise. OBJECTIVES: To document trends in reported sun bed use, sunburn, and sun care knowledge and attitudes in a U.K. region where there have been 20 years of sun-related health promotion campaigns. METHODS: In 2000, 2004 and 2008, a 'care in the sun' module was included in the Northern Ireland (NI) Omnibus survey. Each year 2200 subjects aged 16 years and over were randomly selected and invited to complete a sun-related questionnaire. Proportions of respondents were analysed by demographic and socioeconomic factors, with differences tested using z-tests and the chi(2) -squared test. RESULTS: In total, 3623 persons responded (response rate 50-59%). Skin cancer knowledge in 2008 was high at 97%. Skin type reporting was inaccurate and since 2000 has become weighted towards the darker Fitzpatrick skin types IV and V (chi(2) = 21.5, P = 0.006). Reported sunburn rose over the 8-year period to 60% in 2008, with 39% of those aged 16-24 years reporting sunburn at least once in the previous year. Twenty per cent reported sun bed use in 2008, a fall from 28% in 2004 (P = 0.01), with greater reported use among those aged 16-24 years (24%) and among women (31% vs. 9% men, P < 0.001). Tanning was reported to make respondents feel healthier (42%) and more attractive (47%), with these attitudes more likely among young women. CONCLUSIONS: Skin cancer and sun care knowledge is good among the NI population but reported behaviours of sun bed use and sunburn pose risks for further rises in skin cancer. Barriers for future sun care campaigns to address include poorer sun care knowledge among men, poor skin type awareness, and women's attitudes regarding the health and attractiveness of tanning. Sun bed use, although high, has fallen, possibly in response to recent campaigns. PMID- 20716214 TI - Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review. AB - Most of the publications on isotretinoin, pregnancy and compliance with the pregnancy prevention programme (PPP) originate from North America. Information specific for the European situation is very limited. The aim of this study was to identify publications describing the use of isotretinoin in humans and the compliance with the PPP in Europe, a systematic search in Medline and Embase was conducted using the terms 'isotretinoin, pregnancy (and Europe)'. Furthermore, a manual search in publications was performed. A total of 17 publications were identified. Publications consisted of case reports of exposed pregnancies, surveys among dermatologists or pharmacists and database studies evaluating compliance with the PPP. The studies and surveys dealt with groups of patients exposed to isotretinoin before or during pregnancy and/or compliance with the isotretinoin PPP. Where the information was provided, in 6-26% of cases isotretinoin was prescribed in full accordance with the PPP. Pregnancy incidence was seen in 0.2-1.0 per 1000 women of childbearing age using isotretinoin. Between 65% and 87% of these pregnancies were terminated. This review of studies in Europe performed to date shows failures in the implementation of the PPP. Therefore, the isotretinoin PPP must be scrutinized to identify whether new measures should be taken or whether the failures in the implementation need to be corrected. New measures should take into account the definition of the ultimate goal of a PPP and the acceptable burden. In the meantime, stakeholders could make a start with adjustments in the implementation of the PPP by taking responsibility and enhancing the performance by explicit instructions, monitoring the performance and adjusting, if necessary. PMID- 20716215 TI - The role of sunlight exposure in determining the vitamin D status of the U.K. white adult population. AB - BACKGROUND: Vitamin D is necessary for bone health and is potentially protective against a range of malignancies. Opinions are divided on whether the proposed optimal circulating 25-hydroxyvitamin D [25(OH)D] level (>= 32 ng mL-1) is an appropriate and feasible target at population level. OBJECTIVES: We examined whether personal sunlight exposure levels can provide vitamin D sufficient (>= 20 ng mL-1) and optimal status in the U.K. public. METHODS: This prospective cohort study measured circulating 25(OH)D monthly for 12 months in 125 white adults aged 20-60 years in Greater Manchester. Dietary vitamin D and personal ultraviolet radiation (UVR) exposure were assessed over 1-2 weeks in each season. The primary analysis determined the post-summer peak 25(OH)D required to maintain sufficiency in wintertime. RESULTS: Dietary vitamin D remained low in all seasons (median 3.27 MUg daily, range 2.76-4.15) while personal UVR exposure levels were high in spring and summer, low in autumn and negligible in winter. Mean 25(OH)D levels were highest in September [28.4 ng mL-1; 28% optimal, zero deficient (<5 ng mL 1)], and lowest in February (18.3 ng mL-1; 7% optimal, 5% deficient). A February 25(OH)D level of 20 ng mL-1 was achieved following a mean (95% confidence interval) late summer level of 30.4 (25.6-35.2) and 34.9 (27.9-41.9) ng mL-1 in women and men, respectively, with 62% of variance explained by gender and September levels. CONCLUSIONS: Late summer 25(OH)D levels approximating the optimal range are required to retain sufficiency throughout the U.K. winter. Currently the majority of the population fails to reach this post-summer level and becomes vitamin D insufficient during the winter. PMID- 20716216 TI - Ustekinumab: effective in a patient with severe recalcitrant generalized pustular psoriasis. PMID- 20716217 TI - Eyebrow regrowth in patients with frontal fibrosing alopecia treated with intralesional triamcinolone acetonide. PMID- 20716218 TI - A cross-sectional study using the Children's Dermatology Life Quality Index (CDLQI) in childhood psoriasis: negative effect on quality of life and moderate correlation of CDLQI with severity scores. AB - BACKGROUND: Juvenile psoriasis is a chronic and incurable skin disease that affects approximately 0.7% of children. OBJECTIVES: To achieve more insight into the quality of life (QoL) in childhood psoriasis and to investigate whether disease severity scores correlate with QoL scores. METHODS: All consecutive patients with juvenile plaque psoriasis (<= 18 years old) who visited our outpatient department were included. At baseline, the Children's Dermatology Life Quality Index (CDLQI) questionnaire was completed and disease severity was assessed by the Psoriasis Area and Severity Index (PASI) and the Physician Global Assessment (PGA). RESULTS: Thirty-nine patients were included in the study. A median CDLQI of 6 [interquartile range (IQR) 5-9] was reported. Median PASI was 6.3 (IQR 3.3-8.2) and median PGA was 2 (IQR 1-3). The correlation coefficient between PASI and CDLQI was 0.47 (P = 0.003), whereas the correlation coefficient between PGA and CDLQI was 0.51 (P = 0.001). CONCLUSIONS: The negative effect on QoL in juvenile psoriasis was confirmed in the largest cohort presented up to now. The correlation between disease severity scores and disease-related QoL in children with psoriasis is only moderate. Therefore, both clinical outcome parameters (PASI, PGA) and measures of QoL (CDLQI) should be included in adequate, patient-oriented clinical decision making. PMID- 20716219 TI - Interleukin (IL)-22, IL-17, IL-23, IL-8, vascular endothelial growth factor and tumour necrosis factor-alpha levels in patients with psoriasis before, during and after psoralen-ultraviolet A and narrowband ultraviolet B therapy. AB - BACKGROUND: Several cross-sectional studies have shown that different cytokines and growth factors are enhanced in psoriasis. OBJECTIVES: We aimed to understand the role/relation of interleukin (IL)-22, IL-17, IL-23, IL-8, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF)-alpha in psoriasis vulgaris, addressing their levels and changes before, during and after psoralen-ultraviolet A (PUVA) and narrowband ultraviolet B (NB-UVB) treatment. METHODS: A cross-sectional and a longitudinal study (n = 34) - before (T0) and at 3 (T3), 6 (T6) and 12 (T12) weeks of NB-UVB and PUVA therapy - were performed; 17 patients started NB-UVB and 17 PUVA, and IL-22, IL-17, IL-23, IL-8, TNF-alpha and VEGF levels were evaluated. RESULTS: At T0, compared with controls (n = 20), all the parameters were significantly higher in patients, except for TNF-alpha. Both NB-UVB and PUVA treatment gave, at T3, a significant decrease in TNF-alpha and IL 23; IL-22 and IL-17 decreased significantly at T6; all parameters and Psoriasis Area and Severity Index decreased significantly at T12. However, in both groups, at T12, VEGF was still significantly higher than control. CONCLUSIONS: Psoriasis seems to be a complex disease in which the cytokine network is disturbed, namely in levels of IL-22, IL-17, IL-23, IL-8, TNF-alpha and VEGF. NB-UVB and PUVA follow-up studies suggested that the reduction in the IL-23/Th17 axis might be important in the pathogenic mechanisms of psoriasis. Further follow-up studies of patients with psoriasis treated with these and other therapies could be very helpful for the understanding of the disturbance in the cytokine network in psoriasis and indirectly in its pathogenesis. PMID- 20716220 TI - Tobacco smoking and hand eczema: a population-based study. AB - BACKGROUND: Tobacco smoking has been proposed to promote hand eczema. OBJECTIVES: To examine the association between tobacco smoking and hand eczema and to investigate a possible dose-response relation. METHODS: A national environmental health survey was performed in 2007. A questionnaire was mailed to 43,905 individuals and responses were obtained from 25,851 (59%). Questions on 1-year prevalence of hand eczema and on previous and current smoking were included. Respondents were asked to report number of cigarettes per day and to provide information on history of atopy and frequency of hand exposure to water. RESULTS: In total, answers regarding smoking and hand eczema were obtained from 25,428 individuals. Of regular daily smokers, 10.0% reported hand eczema vs. 9.1% of nonsmokers (P = 0.0951). A history of atopy showed the strongest influence on the occurrence of hand eczema: prevalence proportion ratio (PPR) 3.46. The PPR for hand eczema among individuals smoking > 15 cigarettes per day was 1.25 and 1.40 in uni- and multivariate analysis, respectively. Age, history of atopy, sex and water exposure were found to be confounders but not effect modifiers. A dose response relation between level of smoking and 1-year prevalence of hand eczema was revealed with a PPR of 1.05 (P < 0.001) for the continuous variable of smoking habits, indicating a significantly increased prevalence of hand eczema among individuals with higher consumption of tobacco. CONCLUSIONS: An association between heavy smoking and hand eczema was confirmed. It is important to consider the level of exposure, as a dose-response relation was revealed, and to be aware of confounding factors. PMID- 20716221 TI - Elevation of serum epidermal growth factor and interleukin 1 receptor antagonist in active psoriasis vulgaris. AB - BACKGROUND: Psoriatic plaques present a complex expression profile, including high levels of cytokines, chemokines and growth factors. Circulating cytokines have been suggested to reflect the activation status of the inflammatory process. OBJECTIVES: To analyse 20 cytokines, chemokines and growth factors in 14 patients with psoriasis vulgaris at the start and during the course of ultraviolet B treatment. METHODS: A multiplex cytokine assay was used. RESULTS: We identified increased serum levels of epidermal growth factor (EGF) (mean 323 vs. 36.6 pg mL 1, P = 0.0001), interleukin (IL)-1 receptor antagonist (mean 39.1 vs. 14.6 pg mL 1, P = 0.02) and tumour necrosis factor-alpha (mean 7.5 vs. 4.5 pg mL-1, P = 0.04) at baseline in patients with psoriasis compared with matched controls. None of these cytokines was correlated to the severity of the disease (Psoriasis Area and Severity Index) or decreased with phototherapy, suggesting that sources other than lesional skin contribute to the production of these cytokines. Using cluster analysis, we observed coordinate upregulation of EGF, IL-6, macrophage inflammatory protein-1beta and vascular endothelial growth factor. CONCLUSIONS: The sustained high expression of inflammatory circulating cytokines is a potential mechanism linking psoriasis with its extracutaneous comorbidities. PMID- 20716222 TI - Activating BRAF mutations in eruptive melanocytic naevi. AB - BACKGROUND: Eruptive melanocytic naevi (EMN) are melanocytic proliferations developing rapidly on previously unaffected skin in association with various clinical scenarios, most commonly systemic immunosuppression. However, the exact mechanism leading to development of EMN is not understood. In particular, it is not known whether EMN harbour the BRAF mutations which occur frequently in melanoma and most common naevi. OBJECTIVES: To evaluate whether activating BRAF mutations may play a role in genesis of EMN. METHODS: Genomic DNA was isolated from 20 EMN from a patient treated with 6-mercaptopurine (6-MP). Primary BRAF genotyping was performed by allelespecific polymerase chain reaction, followed by validation using direct sequencing. RESULTS: The BRAF V600E mutation was identified in 85% of EMN examined. CONCLUSIONS: Our results implicate mutational activation of the BRAF-MAPK pathway as a factor in development of EMN in the setting of 6-MP treatment. The mechanism leading to development of EMN in this, and potentially other patients, may relate to synergistic mutagenic effects of thioguanines and ultraviolet (UV) A. Together with the documented importance of BRAF mutations in melanoma development and maintenance, these findings highlight the importance of UVA protection, especially in patients treated with thiopurines such as 6-MP. PMID- 20716223 TI - Repeated exposure to hair dye induces regulatory T cells in mice. AB - BACKGROUND: We have recently shown that commercial p-phenylenediamine (PPD) containing hair dyes are potent immune activators that lead to severe contact hypersensitivity in an animal model. However, only a minority of people exposed to permanent hair dyes develops symptomatic contact hypersensitivity. This suggests that the majority of people exposed to hair dyes does not become sensitized or develop immunological tolerance. OBJECTIVES: To study the immune response in mice repeatedly exposed to PPD-containing hair dye in a consumer-like manner. METHODS: A commercial hair dye containing PPD was tested in C57BL/6 mice. The local immune response was measured by ear swelling and by histological examinations. The immune response in the draining lymph nodes was analysed by flow cytometry. RESULTS: The hair dye induced local inflammation as seen by swelling and cell infiltration of the treated ears. In addition, exposure to hair dye caused T-cell activation as seen by T-cell proliferation and production of interferon-gamma and interleukin (IL)-17 within the draining lymph nodes. The inflammatory response peaked at the fourth exposure to hair dye. From this point on, an upregulation of regulatory T cells and IL-10-producing cells was seen. CONCLUSIONS: This study shows that PPD-containing hair dyes strongly affect the immune system. In addition to being potent skin sensitizers that activate inflammatory T cells, hair dyes also induce anti-inflammatory mechanisms. This might explain why many consumers can use hair dyes repeatedly without developing noticeable allergies, but it also raises the question whether the immune modulatory effects of hair dyes might influence the development of autoimmune diseases and cancers. PMID- 20716224 TI - Long-term follow-up study of occupational hand eczema. AB - BACKGROUND: Long-term follow-up studies on the prognosis and consequences of occupational hand eczema (OHE) and the prognostic risk factors for persistent OHE are sparse. OBJECTIVES: To determine the medical and occupational outcome after a follow-up of 7-14 years in 605 patients diagnosed with OHE and to identify the prognostic risk factors for the continuation of hand eczema. METHODS: Patients examined at the Finnish Institute of Occupational Health in 1994-2001 completed a follow-up questionnaire 7-14 years after diagnosis. RESULTS: The hand eczema had healed (no eczema during the last year) in 40% of patients with OHE. The duration of hand eczema before diagnosis was strongly associated with the continuation of eczema. Age, sex and diagnosis (allergic or irritant contact dermatitis) were not associated with the prognosis, but skin atopy, and especially respiratory atopy, were correlated with the continuation of hand eczema. Contact allergies in general were not risk factors for persistent OHE, but the presence of a work related chromate allergy was associated with poor healing. A total of 34% of patients had changed their occupation due to OHE, and their long-term prognosis was better than those who had not. The hand eczema of patients originally in food related occupations continued on an unfavourable course. CONCLUSIONS: In the logistic model, risk factors for the continuation of OHE were a long duration of hand eczema before diagnosis, respiratory atopy, skin atopy, and continuation in the same occupation. Those who ended up changing occupation due to their OHE had a better medical and economic prognosis. PMID- 20716225 TI - Adalimumab for psoriasis: practical experience in a U.K. tertiary referral centre. AB - BACKGROUND: There are few reports of the practical use of adalimumab outside of a clinical trial setting and, to our knowledge, none from the U.K. OBJECTIVES: We assessed the efficacy and safety of adalimumab in a cohort of patients with severe psoriasis attending a tertiary dermatology referral centre in the U.K. METHODS: A retrospective case-note review was used to identify all patients initiated on adalimumab for psoriasis. RESI;TS: Baseline Psoriasis Area and Severity Index (PASI) was 24+/-11 (range 9-54; n=46). After 4 months' treatment with adalimumab 64% (29/45), of patients had achieved PASI 75 (75% decrease from baseline) whilst 80% (36/45) of patients met NICE criteria for continuation of treatment. Therapy was well-tolerated. Importantly, 68% (21/31) of patients who had previously received another tumour necrosis factor alpha inhibitor met NICE criteria for continuation of treatment at 16 weeks. CONCLUSIONS: In a cohort of U.K. patients with severe psoriasis, adalimumab has proved to be a significant addition to the expanding armamentarium of biologics for psoriasis. Pharmacovigilance, in the form of registries, is essential to assess the long term safety of such drugs. PMID- 20716226 TI - Clinical and genetic predictors of response to narrowband ultraviolet B for the treatment of chronic plaque psoriasis. AB - BACKGROUND: There is considerable variability in the number of exposures of narrowband ultraviolet B (NB-UVB) needed to clear psoriasis and in the duration of remission. OBJECTIVES: We assessed clinical parameters as predictors of the number of exposures needed to clear psoriasis and of the duration of remission. The influence of genetic polymorphisms of the vitamin D receptor (VDR) on treatment response was also evaluated. METHODS: This was a prospective study of 119 patients with chronic plaque psoriasis treated with NB-UVB until clearance was achieved. They were then followed for up to 1 year or until relapse occurred. The frequency of the Fok1, Apa1, Bsm1, Taq1 and rs4516035 polymorphisms of the VDR gene was assessed in 93 of the 119 patients. RESULTS: Of the 119 patients, 105 completed the course of phototherapy. Using an intention to treat analysis, 83% of the initial cohort (99 of 119 patients) achieved clearance, in a median of 26 exposures (interquartile range 19-35) with a median remission duration of 16 weeks (interquartile range 9-22). Factors significantly associated with a lower number of exposures to clearance included a lower baseline Psoriasis Area and Severity Index (P = 0.004), lower baseline Dermatology Life Quality Index (P = 0.047), female sex (P = 0.043), lower body weight (P = 0.008), and a higher number of previous courses of TL-01 (P = 0.005). The only clinical factor influencing remission duration was number of exposures (P = 0.0009), with a decreased remission duration in those who required a greater number of exposures to clear. The Taq1 VDR polymorphism (rs731236) also significantly predicted remission duration (P = 0.038). Patients homozygous for the C allele, which is associated with decreased activity of the VDR, had a shorter remission duration than those heterozygous for the allele (P = 0.026) and those homozygous for the T allele (P = 0.013). CONCLUSIONS: This study highlights the fact that both genetic and clinical parameters are important in determining treatment outcomes in psoriasis. PMID- 20716227 TI - How stress gets under the skin: cortisol and stress reactivity in psoriasis. AB - BACKGROUND: Psychological stressors might contribute to the severity of chronic inflammatory diseases such as psoriasis by dysregulating hypothalamic-pituitary adrenal (HPA) axis activity. OBJECTIVES: To evaluate the role of cortisol, a key component of the HPA axis, in reaction to psychological stress in patients with psoriasis. METHODS: Serum cortisol, clinical indicators of disease severity (Psoriasis Area and Severity Index) and self-report measures of daily stressors were measured monthly for 6 months in 62 patients with psoriasis. RESULTS: In addition to the previous findings in this sample showing that peak levels of daily stressors predicted an increase in disease severity a month later, the peak levels of daily stressors were also significantly associated with a lower cortisol level. Moreover, patients who persistently experienced higher levels of daily stressors had lower mean cortisol levels than patients who experienced lower levels of daily stressors. CONCLUSIONS: Results suggest that daily stressors influence disease outcome in patients with psoriasis by affecting cortisol levels at moments of high stress. Furthermore, patients with persistently high levels of stressors seem to have a specific psychophysiological profile of lowered cortisol levels and may be particularly vulnerable to the influence of stressors on their psoriasis. PMID- 20716228 TI - Functional variability of the adenosine A3 receptor (ADORA3) gene polymorphism in aspirin-induced urticaria. AB - BACKGROUND: To improve understanding of aspirin hypersensitivity, this study focused on adenosine as a noncyclooxygenase target molecule of aspirin. Adenosine may affect the release of histamine from cutaneous mast cells through a mechanism mediated by the adenosine A3 receptor. OBJECTIVES: To investigate the genetic contribution of adenosine A3 receptor gene (ADORA3) polymorphisms in the pathogenesis of aspirin-induced urticaria (AIU) in a case-control association study in a Korean population. METHODS: A case-control association study was performed in 385 patients with AIU and 213 normal controls from a Korean population. The functional variability of genetic polymorphisms in the ADORA3 gene was analysed in in vitro studies that included a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA), and ex vivo studies that included real-time polymerase chain reaction for mRNA expression in peripheral blood mononuclear cells and a histamine release assay. RESULTS: A significant association of ADORA3 promoter polymorphism at -1050G/T was found with the phenotype of AIU. Patients with AIU showed higher frequency of the haplotype, ht1 (T(-1050) C(-564) ), compared with normal healthy controls. Moreover, ht1 (TC) was found to be a high-transcript haplotype by the luciferase activity assay, and a -564C allele-specific DNA binding protein was found by EMSA. Increased basophil histamine release was noted in subjects who had the high-transcript haplotype, ht1 (TC). CONCLUSION: These results suggest that the high-transcript haplotype, ht1 (TC), of the ADORA3 gene may contribute to the development of cutaneous hyper reactivity to aspirin, leading to the clinical presentation of AIU. PMID- 20716229 TI - From NCE to NICE: the role of pharmacoeconomics. PMID- 20716231 TI - Generic and therapeutic substitutions in the UK: are they a good thing? AB - There is considerable interest and debate concerning the place of generic substitution (switching from a brand to generic product); and on therapeutic substitution, that is, switching to a cheaper, but apparently equivalent, product, usually within the drug class. Generic substitution by pharmacists is standard practice in UK hospital settings, and is being proposed for implementation in primary care. Although most prescriptions are already written generically (83% in the community in England in 2008), there are still cost savings that could be made if generic medicines are substituted against prescriptions written by branded name or by getting prescribers to adhere to advice to prescribe generically. Therapeutic substitution is more contentious, as direct evidence to support equivalence is normally lacking. However, the price differential between established drugs whose patents have expired and for which generics are available and newer, branded medicines within the same therapeutic class, makes therapeutic substitution an attractive application of cost minimization analysis for the more efficient use of healthcare resources. Here we explore the tension that exists between the clinical appropriateness and safety of switching from an individual patient perspective and the consideration of value for money which is required to maximize population health from a health service perspective. Although substitution may affect individual patients (such as, for instance, reduced adherence, increased potential for medication error), it might be a price worth paying given the opportunity cost associated with the use of medicines that are clinically no better than cheaper alternatives. PMID- 20716232 TI - Drugs, money and society (Part II). AB - Pharmacoeconomics started as marketing but has developed into a valuable tool in the fuller assessment of drug therapies. Its principles are now widely accepted, and many countries have government-funded agencies with responsibility for its application, most notably the National Institute for Health and Clinical Excellence in England. Many clinical pharmacologists are active in this area, and the discipline itself is part of the clinical pharmacology trainees' curriculum. Further developments will include value-based pricing and its use in cost sharing arrangements between health service and manufacturers. PMID- 20716233 TI - Pharmacoeconomics: NICE's approach to decision-making. PMID- 20716230 TI - Effectiveness, safety and cost of drug substitution in hypertension. AB - Cost-containment measures in healthcare provision include the implementation of therapeutic and generic drug substitution strategies in patients whose condition is already well controlled with pharmacotherapy. Treatment for hypertension is frequently targeted for such measures. However, drug acquisition costs are only part of the cost-effectiveness equation, and a variety of other factors need to be taken into account when assessing the impact of switching antihypertensives. From the clinical perspective, considerations include maintenance of an appropriate medication dose during the switching process; drug equivalence in terms of clinical effectiveness; and safety issues, including the diverse adverse event profiles of available alternative drugs, differences in the 'inactive' components of drug formulations and the quality of generic formulations. Patients' adherence to and persistence with therapy may be negatively influenced by switching, which will also impact on treatment effectiveness. From the economic perspective, the costs that are likely to be incurred by switching antihypertensives include those for additional clinic visits and laboratory tests, and for hospitalization if required to address problems arising from adverse events or poorly controlled hypertension. Indirect costs and the impact on patients' quality of life also require assessment. Substitution strategies for antihypertensives have not been tested in large outcome trials and there is little available clinical or economic evidence on which to base decisions to switch drugs. Although the cost of treatment should always be considered, careful assessment of the human and economic costs and benefits of antihypertensive drug substitution is required before this practice is recommended. PMID- 20716234 TI - Cost-effectiveness analysis and efficient use of the pharmaceutical budget: the key role of clinical pharmacologists. AB - The purpose of this paper is to provide information about cost-effectiveness analysis and the roles of clinical pharmacologists generally in providing efficient health care. The paper highlights the potential consequences of 'off label prescribing' and 'indication creep' behaviour given slower growth (or potential cuts) in the NHS budget. This paper highlights the key roles of clinical pharmacologists in delivering an efficient health care system when resources are allocated using cost-effectiveness analyses. It describes what cost effectiveness analysis (CEA) is and how incremental cost-effectiveness ratios (ICERs) are used to identify efficient options. After outlining the theoretical framework within which using CEA can promote the efficient allocation of the health care budget, it considers the place of disinvestment within achieving efficient resource allocation. Clinical pharmacologists are argued to be critical to providing improved population health under CEA-based resource allocation processes because of their roles in implementation and disinvestment. Given that the challenges facing the United Kingdom National Health Service (NHS) are likely to increase, this paper sets out the stark choices facing clinical pharmacologists. PMID- 20716235 TI - General practitioners' views and experiences of over-the-counter simvastatin in Scotland. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Statins are widely used for the primary and secondary prevention of coronary events in high risk populations. In 2004 simvastatin was reclassified in the UK from prescription only to being available over-the-counter (OTC). WHAT THIS STUDY ADDS: The majority of GPs do not support the supply of OTC simvastatin by the community pharmacist. GPs were particularly concerned by the lack of cholesterol and blood pressure data in the CHD risk assessment prior to sale. AIMS: The aims of this study were to determine the views and experiences of Scottish GPs towards CVD risk assessment by community pharmacists and the supply and sale of simvastatin. METHODS: A cross sectional postal questionnaire survey of all primary care general practices in Scotland was carried out. The main outcome measure was GPs' awareness of and opinions regarding OTC simvastatin use, experience of OTC simvastatin and opinions regarding community pharmacist involvement in CHD risk assessment. RESULTS: A response rate of 45.7% was obtained. The majority (92.6%, 428) were aware that community pharmacists could sell simvastatin to reduce the risk of a first coronary event in individuals at moderate risk of CHD. However, over half (55.6%, 257) believed that the OTC sale of simvastatin was inappropriate. Just over half were unaware that the pharmacist's CHD risk assessment for the sale of simvastatin did not include lipid (54.8%, n=253) or blood pressure measurement (53.7%, n=248) and 56.7% (262) and 57.8% (267) of respondents, respectively, thought these omissions inappropriate. Almost half of the respondents (48.1%, 222) supported community pharmacists supplying simvastatin as supplementary prescribers while fewer (26.6%, 132) were in favour of supply via an independent prescribing arrangement. CONCLUSION: This study confirms that the majority of GPs do not support the supply of OTC simvastatin by the community pharmacist, being particularly concerned by the lack of cholesterol and blood pressure data in the CHD risk assessment prior to sale. Other methods of pharmacy based simvastatin supply including supplementary prescribing merit further evaluation. PMID- 20716236 TI - Value based pricing, research and development, and patient access schemes. Will the United Kingdom get it right or wrong? AB - The National Health Service (NHS) should reward innovation it values. This will enable the NHS and the United Kingdom (UK) economy to benefit and impact positively on the Research and Development (R&D) decision making of companies. The National Institute for Health and Clinical Excellence (NICE) currently seeks to do this on behalf of the NHS. Yet the Office of Fair Trading proposals for Value Based Pricing add price setting powers--initially for the Department of Health (DH) and then for NICE. This introduces an additional substantial uncertainty that will impact on R&D and, conditional on R&D proceeding, on launch (or not) in the UK. Instead of adding to uncertainty the institutional arrangements for assessing value should seek to be predictable and science based, building on NICE's current arrangements. The real challenge is to increase understanding of the underlying cost-effectiveness of the technology itself by collecting evidence alongside use. The 2009 Pharmaceutical Price Regulation Scheme sought to help do this with Flexible Pricing (FP) and Patient Access Schemes (PASs). The PASs to date have increased access to medicines, but no schemes proposed to date have yet helped to tackle outcomes uncertainty. The 2010 Innovation Pass can also be seen as a form of 'coverage with evidence development.' The NHS is understandably concerned about the costs of running such evidence collection schemes. Enabling the NHS to deliver on such schemes will impact favourably on R&D decisions. Increasing the uncertainty in the UK NHS market through government price setting will reduce incentives for R&D and for early UK launch. PMID- 20716237 TI - Influence of methotrexate exposure on outcome in patients treated with MBVP chemotherapy for primary central nervous system lymphoma. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Although treated using the same high dose methotrexate (HD-MTX)-based multiagent chemotherapy, patients with primary central nervous system lymphoma (PCNSL) have significant differences in outcome. However, little information has been published about factors influencing outcome in PCNSL. As it is known that the pharmacokinetics of MTX vary considerably between subjects leading to different exposure in patients receiving the same dose, it is important to evaluate its role in response to chemotherapy. WHAT THIS STUDY ADDS: This study is the first to evaluate the exposure-response relationship in patients treated with MBVP chemotherapy. We found that patients who were early non-responders to MBVP chemotherapy had poor survival, whatever the salvage regimen. Tumour response at early evaluation was not associated with MTX pharmacokinetics and increasing the dose would probably not improve results. AIMS: Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles. METHODS: We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients. RESULTS: Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n=12) than in those who received three cycles (8.04 years) (group 2, n=25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles. CONCLUSIONS: We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome. PMID- 20716238 TI - Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for cysteamine. Regular cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS: This is the only study that provides pharmacokinetic data for cysteamine delivered in an enteric-release preparation in normal subjects. EC-cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. EC-cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS: Cysteamine bitartrate (Cystagon) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following cysteamine bitartrate non enteric-coated and cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS: Enteric-coated cysteamine was prepared. Following single doses of cysteamine bitartrate non-enteric-coated 450 mg and cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma cysteamine and gastrin concentrations were measured. Two subjects also received cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS: Six healthy adults (mean age 20.7 years, range 18-24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml(-1)). The tmax following cysteamine bitartrate non-enteric-coated (mean and SD is 75+/-19 min) was shorter than cysteamine bitartrate enteric coated (220+/-74 min) (P=0.001), but only the Cmax and AUC estimates following 900 mg cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P<0.05). One patient had GI symptoms following both 900 mg cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated. CONCLUSION: Although patient numbers were low, single high doses of cysteamine bitartrate enteric-coated were better tolerated than similar doses of cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following cysteamine bitartrate enteric-coated suggested that the cysteamine was released enterically. PMID- 20716239 TI - Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Active metabolism of clopidogrel is mainly mediated by CYP2C19. There are genetic differences in the activity of CYP2C19. Therefore, active metabolism of clopidogrel is affected by CYP2C19 genotypes. The main metabolizing enzyme of proton pump inhibitors (PPIs) is CYP2C19. Therefore, the anti-platelet function of clopidogrel is attenuated by concomitant use of PPIs. There are differences in the metabolic disposition among different PPIs. Affinity to CYP2C19 differs among different PPIs. WHAT THIS STUDY ADDS: Whether a PPI attenuates the efficacy of clopidogrel depends on CYP2C19. Individuals who are decreased metabolizers, i.e. carriers the allele of CYP2C19*2 and/or *3, are more likely to convert from 'responder' to 'non-responder' to clopidogrel when placed on a concomitant PPI. We found that rabeprazole, whose affinity to CYP2C19 has been considered lower, attenuated the efficacy of clopidogrel. * We tested whether the separate dosing of a PPI and clopidogrel decreased the risk of attenuation of clopidogrel efficacy. We unfortunately found that separate dosing did not avoid the problematic interaction between clopidogrel and a PPI in subject's with CYP2C19*2 and/or CYP2C19*3. AIMS: The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status. METHODS: Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a 'low responder'. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning. RESULTS: In rapid metabolizers (RMs, *1/*1, n=15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n=24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became 'low-responders' when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs. CONCLUSIONS: The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs. PMID- 20716240 TI - New genetic variant that might improve warfarin dose prediction in African Americans. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles. WHAT THIS STUDY ADDS: In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log transformed warfarin maintenance dose, independent of the influence of VKORC1 1173C>T and CYP2C9*2 and *3. However, replication of our finding is needed to confirm the association of rs1786199 SNP in African Americans, since Limdi et al.[3] did not examine the effect of this SNP because the prevalence of the rs1786199 A-allele was too low. AIMS: To raise hypotheses with regards to whether genetic variants in the VKORC1, CYP2C9, EPHX1, GGCX and ALB genes might influence warfarin dose in African Americans and Caucasians, independent of the effects of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. METHODS: From a prospective cohort study, we obtained additional DNA on 36 Caucasian and 22 African American warfarin users who reached maintenance dose and genotyped them for tagSNPs (r2<0.8) in VKORC1, EPHX1, GGCX and ALB genes, and one exonic CYP2C9 SNP. Linear regression models were fitted to estimate the relationship (P value) between log transformed maintenance dose and each SNP and the amount of the warfarin dose variability accounted for by each SNP (partial R2). RESULTS: In African Americans, the VKORC1 rs17886199 A-allele was associated with a lower dose (GG=46.3 mg and GA=25.6 mg; P=0.002), independent of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. Even after applying Bonferroni correction, the P value would still be considered statistically significant. The VKORC1 rs17886199 variant was not found in Caucasians. In Caucasians, the EPHX1 rs1051741 T-allele was associated with a lower dose (CC=41.3 mg and CT=30.0 mg; P=0.04). The latter was no longer statistically significant after applying Bonferroni correction. CONCLUSIONS: Our pilot study suggests that the VKORC1 rs17886199 variant could influence warfarin maintenance dose among African Americans, even after accounting for the influence of the VKORC1 1173C>T variant. Future studies with a larger sample size will be needed to confirm our findings. PMID- 20716242 TI - Perceived adverse drug reactions among non-institutionalized children and adolescents in Germany. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Drug safety in paediatric medication is a public health concern. According to previous studies, the incidence of adverse drug reactions (ADRs) varies greatly from 0.7% to 2.7% among paediatric outpatients and from 2.6% to 18.1% among paediatric inpatients. Little has been reported on the risks of drug use in the general child population. WHAT THIS STUDY ADDS: Our study showed that the prevalence of perceived ADRs in Germany was 0.9% among non-institutionalized children in general and 1.7% among children who had used at least one medicine within the 7 days before the medical interview. Perceived ADRs in the general child population were clustered with gastrointestinal disorders and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range reported in other studies. Health surveys covering the use of a diverse range of drugs might be suitable for computing ADR prevalence and for identifying risk factors among non institutionalized children. They should be taken into account together with other pharmacovigilance systems. AIMS: Little has been reported on the risks of drug use in the general child population. This study investigated perceived adverse drug reactions (ADRs) among non-institutionalized children in Germany. METHODS: All medicines used in the last 7 days before the medical interview were recorded among the 17 450 children aged 0-17 years who participated in the 2003-06 German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Perceived ADRs were reported by the children's parents and confirmed by trained medical professionals during the medical interview. RESULTS: One hundred and fifty-seven medicines were involved in the occurrence of 198 perceived ADRs in 153 patients. This corresponded to 1.1% of total used drugs, 0.9% (95% confidence intervals 0.7, 1.1%) of all children, and 1.7% (1.4, 2.1%) of children treated with medications. About 40% of all perceived ADRs involved gastrointestinal disorders and 16% involved skin tissue disorders. Perceived ADRs were most frequently reported in relation to drugs acting on the nervous system (25.8%), followed by systemic anti-infectives (18.7%) and drugs acting on the respiratory system (16.2%). Risk factors for perceived ADRs included older age groups, polypharmacy (>or=2) and a poor health status. CONCLUSION: Perceived ADRs in the general child population were clustered with gastrointestinal disorders and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range reported in other studies. Health surveys covering the use of a diverse range of drugs might be suitable for computing ADR prevalence and identifying risk factors among non-institutionalized children. They should be taken into account together with other pharmacovigilance systems. PMID- 20716241 TI - Impaired irinotecan biotransformation in hepatic microsomal fractions from patients with chronic liver disease. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The anticancer agent irinotecan is a prodrug that is hydrolyzed by hepatic carboxylesterase to its active and toxic metabolite SN-38 and oxidized by CYP3A4 to its inactive metabolite APC. Irinotecan therapy is complicated by co-administered drugs that inhibit CYP3A4 and decrease APC formation and that indirectly increase SN-38 formation. Dose adjustment in cancer patients with liver disease has been recommended. WHAT THIS STUDY ADDS: In microsomal fractions from patients with severe hepatic dysfunction both APC and SN-38 formation were decreased due to down-regulation of CYP3A4 and carboxylesterase enzymes. Thus relative SN-38 : APC formation was preserved. In some fractions the SN-38:APC ratio was increased, thus providing a possible explanation for clinical reports of increased SN-38 exposure in some patients with liver dysfunction. Close monitoring of SN-38 formation in patients with severe liver disease is warranted. AIMS: Dose modification with the anticancer agent irinotecan is recommended in patients with severe liver dysfunction. This study evaluated the impact of liver disease on the relative formation of phase I products of irinotecan biotransformation in human microsomes in vitro. METHODS: Microsomes from subjects with normal liver function and liver dysfunction (n=20) were assessed for irinotecan biotransformation and the expression of cytochrome P450 (CYP) 3A4 and carboxylesterase (CES) enzymes. RESULTS: Liver disease down regulated CYP3A4 expression (median 33% of control, range 0-126%, P<0.05) and impaired CYP3A4-dependent oxidation of irinotecan to the inactive 7-ethyl-10-[4-N (5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) (median 0.2, range 0-1.21 pmol mg protein(-1) min(-1) compared with median 0.66, range 0-2.35 in control, P<0.01). CES-mediated hydrolysis of irinotecan to 7-ethyl-10 hydroxycamptothecin (SN-38) was also impaired in liver disease (median 8.38, range 0-20.7 pmol mg protein(-1) min(-1) compared with median 13.3, range 0-28.9 in control, P<0.05). In seven of 20 liver disease microsomes neither metabolite was detected but in three the SN-38:APC ratio was high (41-68) compared with the remaining 10 samples (ratio 11-36). CONCLUSIONS: Down-regulation of CYP3A4 in liver disease decreased APC formation from irinotecan. SN-38 production was decreased and CES1 and 2 were down-regulated in most samples. However, in a subset of disease samples SN-38 production was relatively high because CYP3A4 activity was markedly impaired. This may account for clinical reports of increased SN-38 exposure in some patients with liver disease. Dose adjustments in cancer patients with liver disease who receive irinotecan are important and circulating SN-38 concentrations should be monitored closely. PMID- 20716243 TI - Effectiveness of antibiotics for acute sinusitis in real-life medical practice. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Determining bacterial aetiology of acute sinusitis is difficult without employing invasive procedures. Most episodes of acute sinusitis resolve spontaneously. Antibiotics have demonstrated efficacy for the treatment of acute bacterial sinusitis in clinical trials yet little is known of their effectiveness in real-life treatment settings. WHAT THIS STUDY ADDS: Most cases of untreated acute sinusitis resolved spontaneously. Antibiotics were more effective when given within the first 10 days of treatment. This had no effect on later recurrence. Patients with poor oro-dental condition or recent antibiotic use may derive the most benefit from an antibiotic prescription and this should be considered by prescribers. The antibiotics used were found to be equally effective. Existing recommendations to identify acute sinusitis with high probability of bacterial origin, such as the French recommendations, fever or duration of symptoms fail to identify patients in whom antibiotics are more effective. AIMS: To assess the effectiveness of antibiotics in acute bacterial sinusitis. METHODS: This was a prospective cohort study with 2 months follow-up of 5640 patients with acute sinusitis included by a random sample from 1174 GPs and 120 ENT specialists. Main outcomes were short-term initial success, defined as the absence of prescription of (another) antibiotic or sinus lavage within 10 days, and lack of recurrence between the 11th and 60th day, after initial success. RESULTS: Initial success was found in 88.7% (95% CI 85.1, 91.4%) of patients without antibiotic prescription at inclusion and 96.2% (95% CI 95.7, 96.7%) of patients prescribed antibiotics. The 10 day adjusted hazard ratio (HR) for treatment failure (new antibiotic prescription or sinus drainage) with initial antibiotics compared with no antibiotics was 0.30 (95% CI 0.21, 0.42) with no difference between antibiotics. Antibiotics were more effective in patients with poor oro-dental condition (HR 0.04, 95% CI 0.01, 0.20) and in patients who had already used antibiotics during the previous 2 months (HR 0.09, 95% CI 0.03, 0.28). For patients without failure at 10 days, recurrence between the 11th and 60th day was similar whether or not they had initially been prescribed an antibiotic, 94.1% (95% CI 93.4, 94.7%) and 93.4% (95%CI 90.3, 95.5%), respectively. CONCLUSION: Most acute sinusitis cases not prescribed antibiotics resolve spontaneously. Antibiotics reduced by 3.3-fold the risk of failure within 10 days, without impact on later recurrence. The greatest benefit of antibiotics was found for patients with poor oro-dental condition or with antibiotic use within the previous 2 months. PMID- 20716244 TI - Concomitant use of ibuprofen and paracetamol and the risk of major clinical safety outcomes. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are widely used analgesics in the prescription and non prescription settings. Although both classes of drug are generally well tolerated, they can lead to well-characterized adverse effects. Both drugs are widely co-prescribed and it is of interest to understand better safety outcomes when the two drugs are taken concomitantly. WHAT THIS STUDY ADDS?: Relative rates and hazard ratio patterns of safety outcomes were broadly similar for patients prescribed ibuprofen alone, paracetamol alone and concomitant ibuprofen and paracetamol. The risks of the various safety outcomes examined do not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone. AIMS: To evaluate and compare the risk of specific safety outcomes in patients prescribed ibuprofen and paracetamol concomitantly with those in patients prescribed ibuprofen or paracetamol alone. The outcomes were evaluated according to dose, duration and exposure. METHODS: The study used a retrospective longitudinal cohort design with data from the UK General Practice Research Database (GPRD). The study population included patients aged 18 years or over who were prescribed ibuprofen alone, paracetamol alone or concomitant ibuprofen and paracetamol (tablets or capsules only). The safety outcomes evaluated were upper gastrointestinal events, myocardial infarction, stroke, renal failure (excluding chronic), congestive heart failure, intentional or accidental overdose, suicidal behaviour and mortality. Time-dependent Cox regression was used to estimate relative rates for the safety outcomes, by treatment group. A further analysis evaluated whether the hazard rates (i.e. absolute risks) varied over time with changes in drug exposure. RESULTS: The study population included 1.2 million patients. There was considerable heterogeneity in both patient and exposure characteristics. When comparing with past users, for most safety outcomes, current users of concomitant paracetamol and ibuprofen had relative rates between those for current users of ibuprofen alone and paracetamol alone. The hazard rates were generally proportional over time, from current to past exposure, following a prescription for concomitant paracetamol and ibuprofen compared with ibuprofen alone or paracetamol alone. CONCLUSIONS: The known risk of the safety outcomes examined does not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone. PMID- 20716245 TI - A life in new drug research. PMID- 20716246 TI - The failure to show bioequivalence is not evidence against generics. PMID- 20716247 TI - Neonatal seizures on EEG after in utero exposure to venlafaxine. PMID- 20716250 TI - Antiretroviral therapy and preterm delivery-a pooled analysis of data from the United States and Europe. AB - OBJECTIVE: To investigate reported differences in the association between highly active antiretroviral therapy (HAART) in pregnancy and the risk of preterm delivery among HIV-infected women. DESIGN: Combined analysis of data from three observational studies. SETTING: USA and Europe. POPULATION: A total of 19, 585 singleton infants born to HIV-infected women, 1990-2006. METHODS: Data from the Pediatric Spectrum of HIV Disease project (PSD), a US monitoring study, the European Collaborative Study (ECS), a consented cohort study, and the National Study of HIV in Pregnancy and Childhood (NSHPC), the United Kingdom and Ireland surveillance study. MAIN OUTCOME MEASURE: Preterm delivery rate (<37 weeks of gestation). RESULTS: Compared with monotherapy, HAART was associated with increased preterm delivery risk in the ECS (adjusted odds ratio [AOR] 2.40, 95% CI 1.49-3.86) and NSHPC (AOR 1.43, 95% CI 1.10-1.86), but not in the PSD (AOR 0.92, 95% CI 0.67-1.26), after adjusting for relevant covariates. Because of heterogeneity, data were not pooled for this comparison, but heterogeneity disappeared when HAART was compared with dual therapy (P = 0.26). In a pooled analysis, HAART was associated with 1.5-fold increased odds of preterm delivery compared with dual therapy (95% CI 1.19-1.87, P=0.001), after adjusting for covariates. CONCLUSIONS: Heterogeneity in the association between HAART and preterm delivery was not explained by study design, adjustment for confounders or a standard analytical approach, but may have been the result of substantial differences in populations and data collected. The pooled analysis comparing HAART with dual therapy showed an increased risk of preterm delivery associated with HAART. PMID- 20716251 TI - Risk of uterine rupture in Australian women attempting vaginal birth after one prior caesarean section: a retrospective population-based cohort study. AB - OBJECTIVE: Higher risks of uterine rupture have been reported among women attempting vaginal birth after caesarean (VBAC) particularly following induction with prostaglandins, compared with women who do not labour. This study aimed to estimate these risks as well as that associated with oxytocin use. DESIGN: Population-based retrospective cohort study involving all women who had their first births by caesarean. In their second birth, risks of uterine rupture among women without labour and women who had labour augmented or induced were compared with women who gave birth after spontaneous labour. SETTING: Four Australian states in 1998-2000. POPULATION: Women on pregnancy outcome databases with a second birth after a prior caesarean for their first birth. METHODS: From 29, 008 women identified from the databases, those with uterine rupture were identified and validated using hospital case records. MAIN OUTCOME MEASURE: Uterine rupture. RESULTS: The risk of complete uterine rupture among women without labour was 0.01%. The risk in spontaneous labour without augmentation was 0.15%, considerably higher when there was augmentation with oxytocin (1.91%). The risk with induction of labour was 0.54% for oxytocin alone, 0.68% for prostaglandin alone, 0.63% without either and 0.88% when they were combined. Compared with spontaneous labour, risks were increased three- to five-fold for any induction, six-fold for prostaglandin combined with oxytocin and 14-fold for augmentation with oxytocin. CONCLUSIONS: Careful consideration should be given to the use of oxytocin for augmentation of labour or induction by any method for women with a previous caesarean in view of increased risks of uterine rupture. PMID- 20716252 TI - Implementing the national invasive cervical cancer audit: a local perspective. AB - OBJECTIVE: To monitor the effectiveness of the cervical screening programme and identify suboptimal management in order to improve patient care. DESIGN: Retrospective study. SETTING: A university hospital serving a population of 1 million people. POPULATION: All women diagnosed with a cervical cancer between 2003 and 2006. METHODS: Analysis of data from invasive cervical cancer reviews. MAIN OUTCOME MEASURE: Categorisation of cervical cancer cases according to the Invasive Cervical Cancer Audit classification. RESULTS: Eighty-seven women were diagnosed with cervical cancer during the 3-year study period. The 'lapsed attender' group accounted for the greatest number of cases (30%), followed by screen detected (26%), interval cancers (13%), never attended (12%), lost to follow-up (10%) and never invited (9%). Women who had never attended for cytology presented with higher stage disease, stage-II or above, compared with the screen detected cases: 60% were stage II or above, compared with 13.0%, Chi-square P = 0.018. The most frequently identified screening programme problem was patient compliance, which was determined to be the principle contributing factor in 39 cases (45%) and a secondary factor in a further ten cases. CONCLUSIONS: The categorisation of cervical cancer cases has the potential of yielding invaluable information for improving programme effectiveness. Patient compliance is the greatest challenge to the screening programme, and the need for regular screening and adherence to follow-up regimens needs to be reinforced in order to maximise the efficacy of the national screening programme. PMID- 20716254 TI - Delivery outcome of women with epilepsy: a population-based cohort study. AB - OBJECTIVE: To investigate whether women with epilepsy have increased risks of complications during labour, and to explore the impact of antiepileptic drug use. DESIGN: Population-based cohort study. SETTING: Data from the Medical Birth Registry of Norway 1999-2005. POPULATION: All births (n=372,128) delivered in Norway, ensured through linkage with the National Population Registry run by Statistics Norway. All singleton births and the first child in multiple pregnancies were included, leaving 365,107 pregnancies for analysis. METHODS: Data from the Medical Birth Registry of Norway 1999-2005 were analysed. MAIN OUTCOME MEASURES: Induction, caesarean section, use of forceps and vacuum, abnormal presentation, placental abruption, mechanical disproportion, postpartum haemorrhage, atony and Apgar score <7 after 5 minutes. RESULTS: We compared 2805 pregnancies in women with a current or past history of epilepsy (0.8%) and 362,302 pregnancies in women without a history of epilepsy. Antiepileptic drugs were used in 33.6% (n=942) of pregnant women with epilepsy. Women with epilepsy had an increased risk of induction [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.1-1.4], caesarean section (OR, 1.4; 95% CI, 1.3-1.6) and postpartum haemorrhage (OR, 1.2; 95% CI, 1.1-1.4) compared with women without epilepsy. These rates were even higher for women with epilepsy and antiepileptic drug use, with ORs (95% CIs) of 1.6 (1.4-1.9), 1.6 (1.4-1.9) and 1.5 (1.3-1.9), respectively. In addition, the risk of an Apgar score <7 was higher (OR, 1.6; 95% CI, 1.1-2.4). For women with epilepsy without antiepileptic drug use, only a slightly increased risk of caesarean delivery was observed and no increased risk for any other complications studied. CONCLUSIONS: Pregnant women with epilepsy have a low complication rate; however, they have a slightly increased risk of induction, caesarean section and postpartum haemorrhage. It is not possible to ascertain on the basis of this study whether this is a result of more severe epilepsy or antiepileptic drug use. PMID- 20716255 TI - Efficacy and safety of moxifloxacin in uncomplicated pelvic inflammatory disease: the MONALISA study. AB - OBJECTIVE: To evaluate the efficacy and safety of moxifloxacin versus levofloxacin plus metronidazole in uncomplicated pelvic inflammatory disease (uPID) in Asia. DESIGN: Prospective, randomised, double-blind, double-dummy, parallel-group study. SETTING: Multicentre, multinational study in the inpatient and/or outpatient setting. POPULATION: Women (aged >=18 years) with uPID (defined as PID with no pelvic or tubo-ovarian abscess on pelvic ultrasonography and at laparoscopic examination) and not requiring intravenous treatment. METHODS: Women received a 14-day course of either oral moxifloxacin, 400 mg once daily, or oral levofloxacin, 500 mg once daily, plus oral metronidazole, 500 mg twice daily. Additionally, a single dose of ceftriaxone, 250 mg intramuscularly, was administered to women who had a positive screening test for Neisseria gonorrhoeae. MAIN OUTCOME MEASURES: The primary measure of efficacy was clinical response at test-of-cure (TOC) (7-14 days after the last dose of study drug) in the per-protocol population. Non-inferiority of moxifloxacin to the comparator regimen was demonstrated if lower limit of 95% CI was >-15%. Other measures were clinical response during therapy and at 4-week follow up, microbiological response at TOC, and safety. RESULTS: A total of 460 women were randomised to the study. For the primary measure of efficacy (clinical cure at TOC), moxifloxacin was noninferior to levofloxacin plus metronidazole (moxifloxacin: 152/194, 78.4%; comparator 155/190, 81.6%; 95% CI -10.7 to +4.9). The most commonly isolated pathogens at baseline included Neisseria gonorrhoeae, Chlamydia trachomatis, Escherichia coli, Staphylococcus aureus, Peptostreptococcus spp., Proteus mirabilis, Streptococcus agalactiae and Klebsiella pneumoniae. Bacteriological success rates were high and comparable between treatment arms (microbiologically valid populations, moxifloxacin 27/30, 90.0%; comparator 22/26, 84.6%; 95% CI 12.7 to +20.3). Both treatments were well tolerated. CONCLUSIONS: Moxifloxacin monotherapy, 400 mg once daily for 14 days, is an effective and well-tolerated oral treatment for women with uPID. PMID- 20716256 TI - Rickettsial evolution in the light of comparative genomics. AB - Rickettsia are best known as strictly intracellular vector-borne bacteria that cause mild to severe diseases in humans and other animals. Recent advances in molecular tools and biological experiments have unveiled a wide diversity of Rickettsia spp. that include species with a broad host range and some species that act as endosymbiotic associates. Molecular phylogenies of Rickettsia spp. contain some ambiguities, such as the position of R. canadensis and relationships within the spotted fever group. In the modern era of genomics, with an ever increasing number of sequenced genomes, there is enhanced interest in the use of whole-genome sequences to understand pathogenesis and assess evolutionary relationships among rickettsial species. Rickettsia have small genomes (1.1-1.5 Mb) as a result of reductive evolution. These genomes contain split genes, gene remnants and pseudogenes that, owing to the colinearity of some rickettsial genomes, may represent different steps of the genome degradation process. Genomics reveal extreme genome reduction and massive gene loss in highly vertebrate-pathogenic Rickettsia compared to less virulent or endosymbiotic species. Information gleaned from rickettsial genomics challenges traditional concepts of pathogenesis that focused primarily on the acquisition of virulence factors. Another intriguing phenomenon about the reduced rickettsial genomes concerns the large fraction of non-coding DNA and possible functionality of these "non-coding" sequences, because of the high conservation of these regions. Despite genome streamlining, Rickettsia spp. contain gene families, selfish DNA, repeat palindromic elements and genes encoding eukaryotic-like motifs. These features participate in sequence and functional diversity and may play a crucial role in adaptation to the host cell and pathogenesis. Genome analyses have identified a large fraction of mobile genetic elements, including plasmids, suggesting the possibility of lateral gene transfer in these intracellular bacteria. Phylogenetic analyses have identified several candidates for horizontal gene acquisition among Rickettsia spp. including tra, pat2, and genes encoding for the type IV secretion system and ATP/ADP translocase that may have been acquired from bacteria living in amoebae. Gene loss, gene duplication, DNA repeats and lateral gene transfer all have shaped rickettsial genome evolution. A comprehensive analysis of the entire genome, including genes and non-coding DNA, will help to unlock the mysteries of rickettsial evolution and pathogenesis. PMID- 20716257 TI - Is this the last word on 'an unfortunate experiment'? Urinary oestriol assay for monitoring fetoplacental function. 1991. PMID- 20716258 TI - Benefits of introducing universal umbilical cord blood gas and lactate analysis into an obstetric unit. AB - BACKGROUND: Current evidence suggests that umbilical arterial pH analysis provides the most sensitive reflection of birth asphyxia. However, there's debate whether umbilical cord blood gas analysis (UC-BGA) should be conducted on some or all deliveries. AIM: The aim of this study was to evaluate the impact of introducing universal UC-BGA at delivery on perinatal outcome. METHODS: An observational study of all deliveries > or =20 weeks' gestation at a tertiary obstetric unit between January 2003 and December 2006. Paired UC-BGA was performed on 97% of deliveries (n = 19,646). Univariate and adjusted analysis assessed inter-year UC-BGA differences and the likelihood of metabolic acidosis and nursery admission. RESULTS: There was a progressive improvement in umbilical artery pH, pO(2), pCO(2), base excess and lactate values in univariate and adjusted analyses (P < 0.001). There was a significant reduction in the newborns with an arterial pH <7.10 (OR = 0.71; 95%CI 0.53-0.95) and lactate >6.1 mmol/L (OR = 0.37; 95%CI 0.30-0.46). Utilising population specific 5th and 95th percentiles, there was a reduction in newborns with arterial pH less than 5th percentile (pH 7.12; OR = 0.75; 95%CI 0.59-0.96) and lactate levels greater than 95th percentile (6.7 mmol/L; OR = 0.37; 95%CI 0.29-0.49). There was a reduction in term (OR = 0.65; 95%CI 0.54-0.78), and overall (OR = 0.75; 95%CI 0.64-0.87) nursery admissions. These improved perinatal outcomes were independent of intervention rates. CONCLUSIONS: These data suggest that introduction of universal UC-BGA may result in improved perinatal outcomes, which were observed to be independent of obstetric intervention. We suggest that these improvements might be attributed to provision of biochemical data relating to fetal acid-base status at delivery influencing intrapartum care in subsequent cases. PMID- 20716259 TI - Predicting the outcome of induction of labour. AB - OBJECTIVE: To test whether prediction of delivery outcome is feasible in post term nulliparous pregnant women, using a published model and a locally produced model combining clinical and ultrasound assessment. METHODS: This is a prospective pilot study of 53 nulliparous women seen in a postdates clinic between 40 weeks four days and 41 weeks three days of gestation. They underwent a routine assessment including transabdominal ultrasound to determine amniotic fluid index, a Bishop score, and translabial ultrasound to determine the station of the fetal head at rest and bladder neck descent at rest and on valsalva. Additional information such as body weight at booking and current weight, height and a family history of caesarean section was obtained. Delivery outcome and labour details were obtained from the local obstetric database. Two models for prediction of delivery outcome were tested. RESULTS: Forty-nine complete datasets were analysed. Fourteen women had a normal vaginal delivery, 17 instrumental deliveries and 18 caesarean sections. A published model predicted the induction outcome in 62%. A local model using maternal age, body mass index, family history of caesarean section, station of the fetal head and bladder neck descent predicted vaginal delivery in 70% in our study. CONCLUSION: Prediction of delivery outcome is of limited feasibility in post-term nulliparous pregnant women. Our locally produced model was successful in predicting vaginal delivery in 70% of women. Prediction of delivery outcome may not be sufficiently powerful to allow modification of current obstetric practice. PMID- 20716260 TI - The development and initiation of the NSW Department of Health interprofessional Fetal welfare Obstetric emergency Neonatal resuscitation Training project. AB - BACKGROUND: The Fetal Welfare Obstetric emergency Neonatal resuscitation Training (FONT) project was initiated on a background of rising notifications of adverse events in NSW maternity units, the significant proportion of which were related to fetal welfare assessment. AIMS: The aim of the study is to describe the development and introduction of the NSW state-wide interprofessional FONT project. METHODS: Following development and risk assessment, FONT was launched in February 2008. The project consists of an online component and two face-to-face training days to be completed each 3 years; the first day for fetal welfare assessment and the second for obstetric and newborn emergencies. Eight, 2-day training sessions were conducted throughout NSW for FONT trainers. Each trainer underwent pre- and post-testing for changes in knowledge of fetal welfare assessment. The 2005-2008 NSW adverse event report numbers were assessed. RESULTS: From 20 February to 17 April 2008, 240 trainers had been trained in fetal welfare assessment, and by the end of 2008 these trainers had trained 954 clinicians. There were significant improvements in the interpretation and management planning of electronic fetal heart rate patterns following training. Analysis of Severity Assessment Codes 1 and 2 showed no significant trend in the number of notifications for adverse events related to fetal welfare assessment. CONCLUSIONS: In the first 11 months, 25% of the state's maternity practitioners had received training in the first stage of the FONT project. The FONT project has shown short-term improvements in learning and communication skills and in the participants of the project. PMID- 20716261 TI - Prenatal family support, postnatal family support and postpartum depression. AB - BACKGROUND: Inadequate social support is an important determinant of postpartum depression (PPD). Social support for pregnant women consists of supports from various sources and can be measured at different gestation periods. Differentiating the effects of social support from different sources and measured at different gestation periods may have important implications in the prevention of PPD. In the family centred Chinese culture, family support is likely to be one of the most important components in social support. AIMS: The aim of this study was to assess the association of prenatal family support and postnatal family support with PPD. METHODS: A prospective cohort study was conducted between February and September 2007 in Hunan, China. Family support was measured with social support rating scale at 30-32 weeks of gestation (prenatal support) and again at 2 weeks of postpartum visit (postnatal support). PPD was defined as Edinburgh Postnatal Depression Scale (EPDS) score > or =13. RESULTS: A total of 534 pregnant women were included, and among them, 103 (19.3%) scored 13 or more on the EPDS. PPD was 19.4% in the lowest tertile versus 18.4% in the highest quartile (adjusted odds ratio: 1.04, 95% confidence interval 0.60, 1.80) for prenatal support from all family members, and PPD was 39.8% in the lowest tertile versus 9.6% in the highest tertile (adjusted odds ratio: 4.4, 95% confidence interval 2.3, 8.4) for postnatal support from all family members. Among family members, support from husband had the largest impact on the risk of developing PPD. CONCLUSIONS: Lack of postnatal family support, especially the support from husband, is an important risk factor of PPD. PMID- 20716262 TI - Audit of severe acute maternal morbidity describing reasons for transfer and potential preventability of admissions to ICU. AB - BACKGROUND: Maternal mortality is a rare event in the developed world. Assessment of severe acute maternal morbidity (SAMM) is therefore an appropriate measure of the quality of maternity care. AIMS: The aim of the study was to conduct a retrospective audit of SAMM cases (pregnant women admitted to a New Zealand Intensive Care Unit) to describe clinical, socio-demographic characteristics, pregnancy outcomes and preventability. METHODS: Severe acute maternal morbidity cases were reviewed by a multidisciplinary panel to determine reasons for admission to ICU, to classify organ-system dysfunction and to determine whether the SAMM case was preventable or not. Inclusion criteria were: admission to ICU between 2005 and 2007 during pregnancy or within 42 days of delivery. RESULTS: Twenty-nine SAMM cases were reviewed, of which 10 (35%) were deemed preventable. The most common reasons for transfer to ICU were: the need for invasive vascular monitoring, hypotension and disseminated intravascular coagulation. The most frequent types of preventable events were: inadequate diagnosis/recognition of high-risk status, inappropriate treatment, communication problems and inadequate documentation. All five SAMM cases of septicaemia were deemed preventable. Of the ten preventable cases, three were Maori (50% of the Maori in total audit), four were Pacific (67% of the Pacific in total audit) and three were women of 'other' ethnicities (17.6%, 3 of 17 in the audit). CONCLUSIONS: An audit of SAMM cases describing reasons for transfer to ICU and preventability is feasible. We recommend that a prospective national SAMM audit process be introduced in New Zealand as a quality of care measure. PMID- 20716263 TI - Maternal sleep deprivation, sedentary lifestyle and cooking smoke: Risk factors for miscarriage: A case control study. AB - AIMS: To determine risk factors for miscarriage. METHODS: A case control study was carried out at the gynaecological wards and antenatal clinics of the De Soysa Maternity Hospital in Sri Lanka. A case was defined as that of mothers with a confirmed diagnosis of partial or full expulsion of the fetus during the first 28 weeks of gestation. Controls comprised ante-natal clinic attendees whose period of gestation was <28 weeks and carrying a viable fetus. Two hundred and thirty cases and 504 controls were selected. A pre-tested interviewer-administered questionnaire and modified life events inventory were used to gather data. Multivariate logistic regression was applied separately for first and second trimester miscarriages and the results were expressed as odds ratios (OR) and as 95% confidence intervals (95% CI). RESULTS: Sleeping < or =8 h/day (OR:3.80, 95% CI:1.01-14.3) was found to be a risk factor for first trimester miscarriage controlling for the effect of period of gestation. Sleeping < or =8 h/day (OR:2.04, 95% CI:1.24-3.37), standing < or =3 h/day (OR:1.83, 95% CI:1.08-3.10), exposure to cooking smoke (OR:3.83, 95% CI:1.50-9.90) and physical trauma during the pregnancy (OR:43.2, 95% CI:4.55-411.4) were found to be risk factors for second trimester miscarriage controlling for the effect of period of gestation. CONCLUSIONS: Sleep deprivation, a sedentary lifestyle, exposure to cooking smoke and physical trauma during pregnancy were risk factors for miscarriage. Most of the risk factors are therefore modifiable. PMID- 20716264 TI - Amniotic fluid lamellar body concentration as a marker of fetal lung maturity at term elective caesarean delivery. AB - BACKGROUND: Caesarean birth, without prior labour, is associated with an increased risk of neonatal respiratory morbidity among term infants. The concentration of lamellar bodies in amniotic fluid reflects pulmonary surfactant production and release, and is thus used in preterm populations as a marker of fetal lung maturity. Whether amniotic fluid lamellar body concentration (AFLBC) may correlate with risk factors for term respiratory distress has not previously been evaluated. AIMS: To determine the relationship between AFLBC and risk factors for respiratory distress following term caesarean birth. METHODS: The AFLBC of 249 women at the time of term caesarean birth was examined for an association with gestational age, gender, presentation and neonatal respiratory distress requiring special care nursery (SCN) admission. RESULTS: There was a significant increase in AFLBC with gestation. When compared with caesarean deliveries performed during the 37th week of gestation, there was a 50%, 54% and 56% increase in lamellar body concentrations (LBCs) taken during the 38th, 39th and 40th week of gestation respectively (P < 0.05 for all). Female fetuses had a 16% higher LBC than males (P < 0.05). An LBC <100 x 10(9) mL(-1) was associated with increased risk of admission to the SCN with respiratory distress (RR = 5.6; 1.2-26.5, P < 0.05). CONCLUSION: Known risk factors for term respiratory distress are reflected in the AFLBC. A significant relationship exists between AFLBC and respiratory morbidity following term caesarean birth. However, the low prevalence of this condition limits the clinical role of AFLBC as a predictive test for term respiratory morbidity. PMID- 20716266 TI - Relationship between the serum CA-125 level and bone mineral density in healthy pre- and post-menopausal women. AB - BACKGROUND: Osteoporosis and tumour-associated antigen (TAA) levels are associated with inflammatory processes, but little remains known about TAA levels and bone mineral density (BMD). AIMS: We determined whether or not high-normal TAA levels are associated with a lower BMD in healthy women. METHODS: A total of 3769 healthy women were enrolled from the health screening programme over 5 years. Each participant had undergone a basic health examination. Serum carbohydrate antigen (CA)-125, CA-19-9, carcinoembryonic antigen (CEA) and alpha fetoprotein levels were evaluated as tumour markers. The correlations between serum TAA levels and BMD were analysed. RESULTS: Carbohydrate antigen 125 and CEA levels were positively associated with a higher BMD in the pre-menopause. In the post-menopause, the CA-125 level was positively associated with BMD. In the pre menopause, CA-125 (r = 0.102; P < 0.001) and CEA levels (r = 0.134; P < 0.001) had a significant correlation with BMD. In the post-menopause, CA-125 was negatively associated with alkaline phosphatase (r = -0.298; P < 0.001). CONCLUSIONS: There was a significant positive association between CA-125 and BMD in healthy women. Additional basic and clinical studies on the relationship between CA-125 and bone are needed. PMID- 20716265 TI - Consequences in women of participating in a study of the natural history of cervical intraepithelial neoplasia 3. AB - BACKGROUND: A retrospective cohort study was performed in 1063 women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3) (previously termed carcinoma in situ- CIS) in the National Women's Hospital, Auckland, New Zealand. The study describes the clinical management and outcomes for women with CIN3 diagnosed in the decade of 1965-1974, when treatment with curative intent was withheld in an unethical clinical study of the natural history of CIS. A comparison is made with women who were diagnosed earlier (1955-1964) and later (1975-1976). AIMS: The aim of the study is to record the medical encounters, frequency and management of cytological abnormalities and the occurrence of invasive cancers. The medical records, cytology and histopathology were reviewed and data linked with cancer and death registers. RESULTS: Women diagnosed with CIN3 in 1965-1974 (n = 422), compared with those diagnosed earlier (n = 385) or later (n = 256): (i) were less likely to have initial treatment with curative intent (51% vs 95 and 85%, respectively); (ii) had more follow-up biopsies (P < 0.0005); (iii) were more likely to have positive cytology during follow-up (P < 0.005) and positive smears that were not followed within six months by a treatment with curative intent (P < 0.005); and (iv) experienced a higher risk of cancer of the cervix or vaginal vault (RR = 3.3 compared with the first period, 95% CI: 1.7-5.3). Among women diagnosed in 1965-1974, those initially managed by punch or wedge biopsy alone had a cancer risk ten times (95% CI: 3.9-25.7) higher than women initially treated with curative intent. CONCLUSIONS: During the 'clinical study' (1965-1974), women underwent numerous interventions that were aimed to observe rather than treat their condition, and their risk of cancer was substantially increased. PMID- 20716267 TI - Rate of X chromosome aneuploidy in young fertile women: Comparison of cultured and uncultured cell preparations using fluorescence in situ hybridisation. AB - BACKGROUND: X chromosome aneuploidy <10% in female patients is a routinely used reporting limit in diagnostic cytogenetics. X aneuploidy (<10%) is commonly detected in women investigated for infertility or recurrent miscarriages. It is unclear if this aneuploidy is causally relevant or related to the culture process. Information about the background rate of X aneuploidy in young fertile women would be helpful in resolving this issue. AIM: This study aimed to investigate the rate of X aneuploidy in young fertile women in cultured and uncultured samples to determine if the commonly used <10% limit is relevant. METHOD: Volunteers (aged 22-40 years) with proven fertility (n = 78) participated. The number of X chromosome signals in 500 cultured and 500 uncultured preparations were enumerated using FISH. RESULTS: Significantly, all participants had <5% X aneuploidy in both preparations, X chromosome loss occurred (2.4%) more frequently than gain (0.7%). Cultured preparations had a mean of 2.1% cells with X chromosome aneuploidy (95% CI 1.9-2.3%) compared with a mean rate of 0.9% aneuploidy in uncultured preparations (95% CI 0.7-1.1%). The relative risk for cultured preparations having X aneuploidy compared with uncultured cells was 2.33 (P < 0.001) (95% CI 2.1-2.6). CONCLUSION: Young fertile women had <5% X aneuploidy. The rate of X aneuploidy was higher in cultured (2.1%) compared with uncultured (0.9%) preparations (P < 0.001). This data may provide useful background information when considering low level X aneuploidy in other groups of women with clinical indications for karyotype. PMID- 20716268 TI - Lignocaine gel in minimally invasive surgery - A pilot cohort study. AB - BACKGROUND: The administration of local anaesthetic at the conclusion of minimally invasive procedures has been shown to reduce postoperative pain. However, it is often not feasible to reach target surgical sites using a needle, making it difficult to administer injectable local anaesthetic. Formulations currently available for topical use are also not sterile, adhere poorly, and are not adjusted to neutral pH at the time of use. To address these limitations, a new sterile, aqueous 4.8% lignocaine gel was formulated for topical application on surgical wounds. AIMS: To determine the clinical feasibility, safety and tolerability of the topical lignocaine gel. METHODS: A total of 125 female patients underwent minimally invasive gynaecological procedures. The lignocaine gel was applied to any intra-abdominal, intra-uterine or intra-vaginal surgical wounds. The incidence of any intra- or postoperative complications was determined via retrospective review of surgical reports, hospital files and outpatient clinic files. RESULTS: In all cases, the surgeon was able to apply the gel successfully to the desired site. There were no intra-operative complications. There were no adverse events encountered during recovery or hospitalisation which are likely to be associated with the lignocaine gel. Eight patients experienced adverse events during the postoperative period which could be linked to the use of the gel. However, the incidence of these was within the known range of adverse events for these procedures. CONCLUSIONS: A sterile lignocaine gel can be safely used in minimally invasive surgery. PMID- 20716269 TI - Complications of laparoscopic myomectomy: A single surgeon's series of 1001 cases. AB - OBJECTIVE: The objective of this retrospective study was to evaluate the safety, intra-operative and post-operative morbidity of laparoscopic approach for myomectomy. METHODS: The total 1001 subjects who underwent endoscopic surgery over a 16-year period were studied retrospectively. All the data were collected regarding clinical presentation, intra-operative findings, intra-operative and post-operative complications, and hospital stay, and statistically analysed. RESULTS: The average age of subjects was 32.62 years and the most common indication for surgery was infertility (48.5%). A total of 2167 myomas were removed; 43.98% of subjects required removal of multiple myomas. The average blood loss was 248 mL, and the average hospital stay was 1.5 days. The overall major and minor complication rate is very low except one subject who required laparotomy for post-operative bleeding, and there was one unexplained post operative death. CONCLUSIONS: Laparoscopic myomectomy is comparable to laparotomy myomectomy in terms of duration of surgery, blood loss and complication rates. This large single surgeon series on laparoscopic myomectomy also shows a low complication rate suggesting that laparoscopic myomectomy is a safe and reliable procedure, even in the presence of multiple or large myomas. PMID- 20716270 TI - Randomised prospective study of abdominal wall closure in patients with gynaecological cancer. AB - BACKGROUND: Median laparotomy is the most common approach to the abdominopelvic cavity in patients with gynaecological tumours. AIMS: The primary endpoint of the study was to evaluate the onset of incisional hernia. The secondary endpoint was to evaluate the onset of infection, wound dehiscence, wound infection, and scar pain during the post-operative period. METHODS: A total of 191 patients were eligible for the study. They were divided into three groups. Group A underwent en bloc closure of the peritoneum and fascia with Premilene suture, Group B en bloc closure of the peritoneum and fascia with Polydioxanone suture, and Group C separate closure of the peritoneum and fascia with single stitches of Ethibond suture. Statistical analysis was performed using the Statistical Software Package for Social Sciences 12.0. RESULTS: Group A and Group B comprised 63 patients, and Group C included 65 patients. The three groups proved homogeneous on statistical analysis (P > 0.05). The statistical analysis did not reveal significant differences between the different suture types and techniques with respect to the incidence of incisional hernia (P > 0.05). CONCLUSION: In our study, the incidence of incisional hernia was 8%. Randomised patients were homogeneous for sample size and risk factors. No significant differences were found between suture types or techniques. Currently, there is no suture material or technique that can be considered superior to others. When possible, we believe that the best way to prevent incisional hernia is to preserve the integrity of the abdominal wall using minimally invasive techniques. PMID- 20716271 TI - Hysteroscopic removal of intrauterine contraceptive device embedded within submucous myoma. AB - We report that an intrauterine contraceptive device (IUCD) embedded within intrauterine tumour (submucous myoma) in a postmenopausal woman was misdiagnosed, definitively diagnosed and successfully removed with hysteroscopic resection. Hysteroscopy and hysteroscopic resection of the submucous myoma with IUCD should be reserved as a minimally invasive, safe and reliable treatment method, and can avoid a laparotomy and hysterotomy. This is believed to be the first reported case of such an occurrence. PMID- 20716272 TI - Pseudomyxoma Peritonei arising from a mucinous borderline ovarian tumour: Case report and literature review. PMID- 20716273 TI - Successful pregnancy outcome with the use of antenatal high-dose intravenous immunoglobulin following previous neonatal death associated with neonatal haemochromatosis. PMID- 20716274 TI - Re: IVIG - Is it the answer? Maternal administration of immunoglobulin for severe red cell alloimmunisation during pregnancy: a case series. Connan K, Kornman L, Savoia H et al. 2009; 49: 612-618. PMID- 20716275 TI - Comment on: an anonymous survey of registrar training in the use of Kjelland's forceps in Australia. Aust N Z J Obstet Gynaecol 2009; 49: 515-516. PMID- 20716276 TI - Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation. AB - Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway. The oncogenic potential of Bcl-2 is well established, with its overexpression reported in various cancers. The antiapoptotic function of Bcl-2 is closely associated with its expression levels. Reactive oxygen and nitrogen species (ROS/RNS) are important intracellular signaling molecules that play a key role in various physiological processes including apoptosis. We have recently reported that ROS and RNS can regulate Bcl-2 expression levels, thereby impacting its function. Superoxide anion (*O(2)(-)) plays a proapoptotic role by causing downregulation and degradation of Bcl-2 protein through the ubiquitin-proteasomal pathway. In contrast, nitric oxide (NO)-mediated S-nitrosylation of Bcl-2 prevents its ubiquitination and subsequent proteasomal degradation, leading to inhibition of apoptosis. Interestingly, NO-mediated S-nitrosylation and stabilization of Bcl-2 protein was the primary mechanism involved in the malignant transformation of nontumorigenic lung epithelial cells in response to long-term carcinogen exposure. We describe a novel mechanism of Bcl-2 regulation by *O(2)(-) and NO, providing a new dimension to reactive species-mediated Bcl-2 stability, apoptotic cell death, and cancer development. PMID- 20716278 TI - The role of iNOS-mediated DNA damage in infection- and asbestos-induced carcinogenesis. AB - Chronic inflammation contributes to a substantial part of environmental carcinogenesis. Various infectious diseases and physical, chemical, and immunological factors participate in inflammation-related carcinogenesis. Under inflammatory conditions, reactive oxygen and nitrogen species are generated from inflammatory and epithelial cells, and resulting DNA damage may participate in carcinogenesis. 8-Nitroguanine is a mutagenic DNA lesion formed during chronic inflammation. We performed immunohistochemical analysis, and demonstrated that 8 nitroguanine was formed at the sites of carcinogenesis in animal models and patients with various cancer-prone infectious and inflammatory diseases, caused by parasites, viruses, and asbestos exposure. In asbestos-exposed mice, 8 nitroguanine was formed in bronchial epithelial cells, and it is noteworthy that crocidolite induced significantly more intense 8-nitroguanine formation than chrysotile, inconsistent with their carcinogenic potentials. On the basis of these findings, we have proposed that 8-nitroguanine could be a potential biomarker to evaluate the risk of inflammation-related carcinogenesis. PMID- 20716277 TI - Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model. AB - Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived IL-6, IL-8, bFGF, and VEGF were observed in mice at 7 days postinjection of either MM line, and a striking neutrophilia was observed at all time points. Free-floating tumor spheroids developed in mice at 14 days, and both spheroids and adherent MM tumor masses occurred in all mice at 30 days. Results suggest that inflammation and cytokine production precede and may be critical to the development of MMs. PMID- 20716279 TI - Regulation of apoptosis through cysteine oxidation: implications for fibrotic lung disease. AB - Tissue fibrosis is believed to be a manifestation of dysregulated repair following injury, in association with impaired reepithelialization, and aberrant myofibroblast activation and proliferation. Numerous pathways have been linked to the pathogenesis of fibrotic lung disease, including the death receptor Fas, which contributes to apoptosis of lung epithelial cells. A redox imbalance also has been implicated in disease pathogenesis, although mechanistic details whereby oxidative changes intersect with profibrotic signaling pathways remain elusive. Oxidation of cysteines in proteins, such as S-glutathionylation (PSSG), is known to act as a regulatory event that affects protein function. This manuscript will discuss evidence that S-glutathionylation regulates death receptor induced apoptosis, and the potential implications for cysteine oxidations in the pathogenesis of in fibrotic lung disease. PMID- 20716280 TI - Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols. AB - Tocopherols, which exist in alpha, beta, gamma, and delta forms, are antioxidative nutrients also known as vitamin E. Although alpha-tocopherol (alpha T) is the major form of vitamin E found in the blood and tissues, gamma- and delta-T have been suggested to have stronger anti-inflammatory activities. In the present study, using a tocopherol mixture that is rich in gamma-T (gamma-TmT, which contains 57%gamma-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, gamma-TmT inhibited chemically induced lung tumorigenesis in the A/J mice as well as the growth of human lung cancer cell H1299 xenograft tumors. gamma-TmT also decreased the levels of 8 hydroxydeoxyguanosine, gamma-H2AX, and nitrotyrosine in tumors. More evident anti inflammatory and cancer preventive activities of dietary gamma-TmT were demonstrated in mice treated with azoxymethane and dextran sulfate sodium. These results demonstrate the antioxidative, anti-inflammatory, and anticarcinogenic activities of tocopherols. PMID- 20716281 TI - Reactive oxygen species and alpha,beta-unsaturated aldehydes as second messengers in signal transduction. AB - Signaling by H(2)O(2), alpha,beta-unsaturated aldehydes, such as 4-hydroxy-2 nonenal (HNE) and related chemical species, is thought to differ from signaling by other second messengers because the oxidants and other electrophiles can readily undergo nonenzymatic reactions and are therefore classified as "reactive." This brief review will describe how and when the chemistry of signaling is similar or differs from classic second messengers, such as cyclic AMP, or posttranslational signaling, such as farnesylation or ubiquitination. The chemistry of cysteine provides a common factor that underlies signaling by H(2)O(2) and HNE. Nonetheless, as H(2)O(2) and HNE are rapidly metabolized in vivo, spatial considerations are extremely important in their actions. Therefore, the locations of sources of H(2)O(2) and alpha,beta-unsaturated aldehydes, the NADPH oxidases, mitochondria, membrane lipids, and redox cycling toxicants, as well as their targets, are key factors. The activation of the JNK pathway by HNE and endogenously generated H(2)O(2) illustrates these principles. PMID- 20716283 TI - Oxidative stress: acute and progressive lung injury. AB - Oxidative stress in lung often occurs in humans during acute lung injury (ALI) and in the acute respiratory distress syndrome. The lung inflammatory response may proceed to the development of pulmonary fibrosis, a devastating complication that occurs in premature infants after prolonged exposure to high oxygen concentrations. Oxidant-related ALI can be induced by airway deposition of lipopolysaccharide or IgG immune complexes, resulting in activation of recruited neutrophils and residential macrophages, whose oxidants and proteases produce reversible ALI. In the presence of a powerful trigger of leukocytes (phorbol myristate acetate), or following intrapulmonary deposition of enzymes that generate oxidants, extensive endothelial and epithelial damage and destruction occurs, overwhelming repair mechanisms of lung and resulting in pulmonary fibrosis. How residential or circulating stem cells participate in regeneration of damaged/destroyed cells may provide clues regarding therapy in humans who are experiencing lung inflammatory damage. PMID- 20716282 TI - Redox signaling in inflammation: interactions of endogenous electrophiles and mitochondria in cardiovascular disease. AB - Reactive species derived from oxygen and nitric oxide are produced during inflammation and promote oxidation and nitration of biomolecules, including unsaturated fatty acids. Among the products of these reactions are alpha,beta unsaturated carbonyl and nitro derivatives of fatty acids, electrophilic species whose reactivity with nucleophilic amino acids provides a means of posttranslational protein modification and signaling. These electrophilic fatty acids activate cytosolic and nuclear stress-response pathways (through Nrf2/Keap1 and PPARgamma, for example). There is also growing evidence that mitochondria generate electrophilic species. This appreciation, when combined with the role of mitochondrial dysfunction in conditions where exogenously delivered electrophiles exhibit therapeutic benefit, suggests that mitochondrial electrophile targets are also important in the resolution and prevention of inflammatory injury. Cardioprotective signaling pathways in particular appear to converge on mitochondria, with nitro-fatty acids recently shown to protect against cardiac ischemia/reperfusion injury in a murine model. Although numerous mitochondrial proteins are subject to modification by electrophiles, defining the targets most relevant to cytoprotection during inflammatory stress remains a clinically relevant goal. PMID- 20716285 TI - Cigarette smoke-mediated oxidative stress, shear stress, and endothelial dysfunction: role of VEGFR2. AB - Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), a tyrosine kinase receptor, is activated by VEGF and fluid shear stress (FSS), and its downstream signaling is important in regulation of endothelial functions, such as cell migration, endothelium-dependent relaxation, and angiogenesis. Inhibition of VEGFR2 augments cigarette smoke (CS)-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. CS-derived reactive oxygen/nitrogen species interact with VEGFR2, causing posttranslational modifications that render VEGFR2 inactive for downstream signaling, resulting in endothelial dysfunction. CS-mediated oxidants/carbonyl stress decreases SIRT1 levels and causes eNOS acetylation, which has ramifications in endothelial dysfunction. CS also affects endothelial cell survival pathway by disrupting VEGF- and FSS-mediated VEGFR2/PI3 kinase signaling, leading to decreased Akt phosphorylation and eNOS acetylation. We describe here the mechanisms whereby CS alters VEGF- and FSS-mediated VEGFR2 eNOS signaling, which may have implications for understanding the pathogenesis of pulmonary and cardiovascular diseases. PMID- 20716284 TI - Macrophages, reactive nitrogen species, and lung injury. AB - Evidence has accumulated over the past several years demonstrating that lung injury following inhalation of irritants like ozone is due, not only to direct effects of the chemical, but also indirectly to the actions of inflammatory mediators released by infiltrating macrophages. Among the mediators involved in the cytotoxic process, reactive nitrogen species (RNS) are of particular interest because of their well-documented cytotoxic potential. Findings that macrophage suppression blocks RNS production and ozone-induced toxicity provide strong support for a role of these cells and inflammatory mediators in lung injury. Recent investigations have focused on understanding pathways by which macrophages become activated to release RNS. One protein that has attracted considerable attention is caveolin-1, a membrane scaffolding molecule that functions to negatively regulate cell signaling. The fact that expression of caveolin-1 is down-regulated in macrophages after ozone inhalation suggests a mechanism controlling the release of cytotoxic mediators by these inflammatory cells. PMID- 20716286 TI - Nitric oxide and zinc homeostasis in pulmonary endothelium. AB - We have shown that zinc-thiolate moieties of the metal binding protein metallothionein (MT) are critical targets for nitric oxide (NO) with resultant increases in intracellular labile zinc. Such an NO-MT-Zn signaling pathway appears to participate in important cardiovascular functions associated with biosynthesis of NO including hypoxic vasoconstriction in the lung. Although downstream effector signaling molecules and critical contractile targets remain unclear, current investigations reveal a contributory role for zinc dependent protein kinases and cytoskeletal proteins in mediating hypoxic induced constriction of pulmonary endothelial cells. PMID- 20716287 TI - Inhibition of epithelial sodium channels by respiratory syncytial virus in vitro and in vivo. AB - Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and children worldwide. Infection of mice with RSV decreased sodium (Na(+)) dependent alveolar fluid clearance (AFC), resulting in increased lung water content and hypoxemia. RSV infection resulted in higher levels of pyrimidines and purines in the alveolar space. Intratracheal administration of UTP or UDP also decreased AFC. The effects of RSV on AFC and oxygen saturation of Balb/c mice were reversed by intraalveolar administration of antagonists of P2Y nucleotide receptors, enzymes that enhance the breakdown of pyrimidines and systemic or intranasal administration of inhibitors of the de novo pathway of pyrimidine synthesis. RSV infection of H441 or mouse tracheal epithelial cells decreased the amiloride-sensitive Na(+) currents and pretreatment of H441 cells with A77 prevented this effect. These findings indicate that the harmful effects of RSV on lung epithelia are mediated at least in part via the production of UTP and its paracrine action on ENaC. PMID- 20716288 TI - Molecular mechanisms of oxidative stress in airways and lungs with reference to asthma and chronic obstructive pulmonary disease. AB - Oxidative stress is an important pathophysiological component of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), which cause significant morbidity and mortality. Oxidative stress leads to the activation of transcription factors and signaling pathways, partly through the activation of the innate immune response through toll-like receptors 2 and 4. Such activation leads to the release of cytokines and chemokines. In addition, adaptive immune responses are initiated through activation of dendritic cells and antigen presentation to T-helper cells, with direct activation of NKT cells. Corticosteroid insensitivity is a feature of severe asthma and COPD, and oxidative stress is an important factor in its development by inhibition of HDAC 2 activity and expression through serine hyperphosphorylation. Activation of kinases such as p38 mitogen-activated protein kinase or phospho-inositol 3-kinase delta may also be involved through phosphorylation of the glucocorticoid receptor. Antioxidants may prove to be beneficial in inhibiting inflammatory responses and restoring corticosteroid function. PMID- 20716290 TI - Potential mechanisms for reduced delivery of nitric oxide to peripheral tissues in diabetes mellitus. AB - Nitric oxide (NO) bioavailability is crucial for normal vascular endothelial function and health. Recent studies have demonstrated an endocrine role for NO equivalents that may be transported in the blood to peripheral tissue beds, where under hypoxic conditions they can liberate NO and cause vasodilation. Exercise training improves endothelial function but its effect on NO bioavailability in peripheral tissues during acute exercise stress in CVD is unclear. This paper will present evidence and discuss possible mechanisms by which NO delivery to peripheral tissues may be dysfunctional in diabetic subjects. PMID- 20716289 TI - Oxidants and antioxidants in sulfur mustard-induced injury. AB - Sulfur mustard (SM) is a chemical weapon that targets the skin, eyes, and lung. It was first employed during World War I and it remains a significant military and civilian threat. As a bifunctional alkylating agent, SM reacts with a variety of macromolecules in target tissues including nucleic acids, proteins and lipids, as well as small molecular weight metabolites such as glutathione. By alkylating subcellular components, SM disrupts metabolism, a process that can lead to oxidative stress. Evidence for oxidative stress in tissues exposed to SM or its analogs include increased formation of reactive oxygen species, the presence of lipid peroxidation products and oxidized proteins, and increases in antioxidant enzymes such as superoxide dismutase, catalase, and glutathione-S-transferase. Inhibition of antioxidant enzymes including thioredoxin reductase by SM can also disrupt cellular redox homeostasis. Consistent with these findings, SM-induced toxicity has been shown to be reduced by antioxidants in both in vitro and in vivo models. These data indicate that drugs that target oxidative stress pathways may represent important candidates for reducing SM-induced tissue injury. PMID- 20716291 TI - Acute effects of motor vehicle traffic-related air pollution exposures on measures of oxidative stress in human airways. AB - Epidemiological studies have linked exposure to traffic-related air pollutants to increased respiratory and cardiovascular morbidity and mortality. Evidence from human, animal, and in vitro studies supports an important role for oxidative stress in the pathophysiological pathways underlying the adverse health effects of air pollutants. In controlled-exposure studies of animals and humans, emissions from diesel engines, a major source of traffic-related air pollutants, cause pulmonary and systemic inflammation that is mediated by redox-sensitive signaling pathways. Assessment of human responses to traffic-related air pollution under realistic conditions is challenging due to the complex, dynamic nature of near-roadway exposure. Noninvasive measurement of biomarkers in breath and breath condensate may be particularly useful for evaluating the role of oxidative stress in acute responses to exposures that occur in vehicles or during near-roadway activities. Promising biomarkers include nitric oxide in exhaled breath, and nitrite/nitrate, malondialdehyde, and F2-isoprostanes in exhaled breath condensate. PMID- 20716292 TI - Genetic mechanisms of susceptibility to ozone-induced lung disease. AB - Environmental oxidants remain a major public health concern in industrialized cities throughout the world. Population and epidemiological studies have associated oxidant air pollutants with morbidity and mortality outcomes, and underscore the important detrimental effects of these pollutants on the lung. Interindividual variation in pulmonary responses to air pollutants suggests that some subpopulations are at increased risk to detrimental effects of pollutant exposure, and it has become clear that genetic background is an important susceptibility factor. A number of genetics and genomics tools have recently emerged to enable identification of genes that contribute to differential responsiveness to oxidants, including ozone (O(3)). Integrative omics approaches have been applied in inbred mice to identify genes that determine differential responsiveness to O(3)-induced injury and inflammation, including Tnf, Tlr4, and MHC Class II genes. Combined investigations across cell models, inbred mice, and humans have provided, and will continue to provide, important insight to understanding genetic factors that contribute to differential susceptibility to oxidants. PMID- 20716293 TI - Mechanisms of oxidant generation by catalase. AB - The enzyme catalase converts solar radiation into reactive oxidant species (ROS). In this study, we report that several bacterial catalases (hydroperoxidases, HP), including Escherichia coli HP-I and HP-II also generate reactive oxidants in response to ultraviolet B light (UVB). HP-I and HP-II are identical except for the presence of NADPH. We found that only one of the catalases, HPI, produces oxidants in response to UVB light, indicating a potential role for the nucleotide in ROS production. This prompts us to speculate that NADPH may act as a cofactor regulating ROS generation by mammalian catalases. Structural analysis of the NADPH domains of several mammalian catalases revealed that the nucleotide is bound in a constrained conformation and that UVB irradiation induces NADPH oxidation and positional changes. Biochemical and kinetic analysis indicate that ROS formation by the enzyme is enhanced by oxidation of the cofactor. Conformational changes following absorption of UVB light by catalase NADPH have the potential to facilitate ROS production by the enzyme. PMID- 20716294 TI - Redox regulation of responses to hypoxia and NO-cGMP signaling in pulmonary vascular pathophysiology. AB - Pulmonary vascular responses elicited by hypoxia and NO-cGMP signaling are potentially influenced by ROS and redox mechanisms that change during the progression of disease processes. Our studies in endothelium-rubbed bovine pulmonary arteries suggest increased glucose-6-phosphate dehydrogenase levels (compared to coronary arteries) seem to maintain a tonic peroxide-mediated relaxation removed by hypoxia through NADPH fueling superoxide generation from Nox oxidase. The activities of glucose-6-phosphate dehydrogenase, oxidases (i.e., Nox4), and systems metabolizing superoxide and peroxide markedly influence hypoxic pulmonary vasoconstriction (HPV). Activation of soluble guanylate cyclase and cGMP protein kinase seems to participate in peroxide-elicited relaxation. Endogenous NO helps maintain low pulmonary arterial pressure and suppresses HPV. Multiple redox processes potentially occurring during the progression of pulmonary hypertension may also attenuate NO-mediated relaxation beyond its scavenging by superoxide, including oxidation of guanylate cyclase heme and thiols normally maintained by cytosolic NADPH redox control. PMID- 20716295 TI - The role of oxidative stress in the pathogenesis and treatment of asthma. AB - The role of oxidative stress in asthma is gaining increasing scientific attention. The hallmark of asthma is airway inflammation. Oxidative stress may initiate and augment inflammation, and may also result from inflammation. Exposure to tobacco smoke, ozone, diesel exhaust, and a variety of other pollutants generates reactive oxygen species and other oxidative stressors. Some studies suggest that asthmatics have a decreased ability to respond to oxidative stress, while others find upregulated antioxidative function. Oxidative stress may alter the Th(1)/Th(2) immune response and result in activation of NF-kbeta, a powerful inducer of pro-inflammatory genes. Genetic polymorphisms may play an important role in determining susceptibility to oxidative stress. Many therapeutic strategies to decrease oxidative stress in asthma have been suggested. Dietary changes, antioxidant vitamins, other antioxidant drugs, Ayurvedic supplements, and even radon exposure in a hot bathroom have been studied. Minimizing exposure of young children to environmental tobacco smoke remains paramount. PMID- 20716296 TI - Oxidative/nitrosative stresses trigger type I diabetes: preventable in streptozotocin rats and detectable in human disease. AB - Recently we demonstrated that streptozotocin (STZ) diabetes (type I) in rats is preventable using a simultaneous equimolar injection of carboxy-PTIO (c-PTIO). Both changes in blood sugar and cataracts are prevented. This apparently occurs because the nitric oxide (NO) (from STZ) generated in the beta cells is oxidized to nitrite by c-PTIO preventing diabetes. STZ generates NO producing a NO-based toxin. The toxin damages DNA by nicking and activates poly-ADP-ribose causing necrosis and triggering inflammation. Is there evidence that O/N stress occurs in early human type I diabetes? We studied 40 children with or without early type I diabetes and observed that urate is decreased 25% in all these diabetic children each over the age of 3 years. Urate is a major portion of blood-antioxidant load. Surely this decrease in urate indicates ongoing O/N stress. Does O/N stress initiate disease? STZ studies in rats indicates that this is correct. PMID- 20716297 TI - Detection of hydrogen sulfide in plasma and knee-joint synovial fluid from rheumatoid arthritis patients: relation to clinical and laboratory measures of inflammation. AB - Blood concentrations of hydrogen sulfide (H(2)S) are markedly elevated in several animal models of inflammation. Pharmacological inhibition of H(2)S synthesis reduces inflammation and swelling, suggesting that H(2)S is a potential inflammatory mediator. However, it is currently unknown whether H(2)S synthesis is perturbed in human inflammatory conditions or whether H(2)S is present in synovial fluid. We analyzed paired plasma and synovial fluid (SF) aspirates from rheumatoid arthritis (RA; n= 20) and osteoarthritis (OA; n= 4) patients and plasma from age matched healthy volunteers (n= 20). Median plasma H(2)S concentrations from healthy volunteers and RA and OA patients were 37.6, 36.6, and 37.6 microM, respectively. In RA patients, median synovial fluid H(2)S levels (62.4 microM) were significantly higher than paired plasma (P= 0.002) and significantly higher than in synovial fluid from OA patients (25.1 microM; P= 0.009). SF H(2)S levels correlated with clinical indices of disease activity (tender joint count, r= 0.651; P < 0.05) and markers of chronic inflammation; Europhile count (r=-0.566; P < 0.01) and total white cell count (r=-0.703; P < 0.01). Our study shows for the first time that H(2)S is present in synovial fluid and levels correlated with inflammatory and clinical indices in RA patients. PMID- 20716298 TI - Vascular oxidative stress and inflammation increase with age: ameliorating effects of alpha-lipoic acid supplementation. AB - Increased oxidative stress and inflammation causally contribute to cardiovascular diseases, for which advanced age is a major risk factor. We found that indicators of oxidative stress, including NADPH oxidase activity and superoxide levels, were significantly increased in aortas of old (22-24 months) versus young (3-4 months) male F344 rats, whereas superoxide dismutase (SOD) activity was decreased. Aortic mRNA and protein levels of NOX4, the principal catalytic subunit of NADPH oxidase in vascular cells, also were increased with age, but not NOX2 and p22(phox). Indicators of inflammation, including activation of NFkappaB and upregulation of vascular cell adhesion molecule-1 (VCAM-1) in aorta, and monocyte chemotactic protein-1 (MCP-1) in plasma, also were significantly increased in old rats. Supplementation with 0.2% (wt/wt) (R)-alpha-lipoic acid (LA) for 2 weeks caused a nonsignificant decrease in NADPH oxidase activity in aged aorta and a significant decrease in mRNA--but not protein--levels of NOX4 and VCAM-1. Furthermore, LA reversed the age-dependent changes in aortic SOD activity and plasma MCP-1 levels. Hence, vascular oxidative stress and inflammation increase with age and are ameliorated by LA supplementation. PMID- 20716299 TI - Measurement of inflammation and oxidative stress following drastic changes in air pollution during the Beijing Olympics: a panel study approach. AB - Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure. PMID- 20716300 TI - Anxiety disorders among methamphetamine dependent adults: association with post treatment functioning. AB - Although anxiety is one of the most prominent psychiatric complaints of methamphetamine (MA) users, little is known about the association between anxiety disorders and treatment outcomes in this population. Using data from 526 adults in the largest psychosocial clinical trial of MA users conducted to date, this study examined psychiatric, substance use, and functional outcomes of MA users with concomitant anxiety disorders 3 years after treatment. Anxiety disorders were associated with poorer alcohol and drug use outcomes, increased health service utilization, and higher levels of psychiatric symptomatology, including suicidality. Addressing anxiety symptoms and syndromes in MA users may be helpful as a means of optimizing treatment outcomes. PMID- 20716301 TI - Obesity, smoking, and frontal brain dysfunction. AB - Obesity, smoking, and conduct problems have all been associated with decrements in brain function. However, their additive and interactive effects have rarely been examined. To address the deficiency, we studied P300a and P300b electroencephalographic potentials in 218 women grouped by the presence versus absence of: (1) a BMI > or = 30 kg/m(2); (2) recent smoking; and (3) > or = 2 childhood conduct problems. Analyses revealed smaller P300a and P300b amplitudes over the posterior scalp among recent smokers versus nonsmokers. No corresponding group differences were found in P300 latencies or frontal scalp amplitudes. The most interesting analysis result was an interaction between conduct problems and obesity limited to the frontally generated P300a component: its latency was significantly greater in women with both attributes than in those with either or neither attribute. An exploratory ANOVA, substituting the genotype of a GABRA2 SNP for conduct problems, also demonstrated an interaction with obesity affecting P300a latency. It is hypothesized that conduct problems, and a conduct-problem associated GABRA2 genotype, decrease the age-of-onset and/or increase the lifetime duration of obesity. As a result, they may potentiate the adverse effects of obesity on frontal white matter and thereby increase P300a latency. Smoking may affect brain function by a different mechanism to reduce posterior scalp P300a and P300b amplitudes while preserving frontal scalp P300a latency and amplitude. PMID- 20716303 TI - The timing of onset of pain and substance use disorders. AB - Using data from the National Comorbidity Survey--Replication, this study examined the timing of onset of self-report comorbid chronic nonarthritis pain and substance use disorders (SUDs) and characteristics associated with different onset patterns. Most individuals (58.2%; N = 351/632) report that the SUD preceded the onset of pain. Relative to those with SUDs prior to the onset of chronic pain, those experiencing pain first were less likely to have a drug use disorder, more likely to have head pain, to be younger at the onset of the first condition, and to have a shorter duration between condition onsets. PMID- 20716302 TI - The safety and efficacy of varenicline in cocaine using smokers maintained on methadone: a pilot study. AB - In this double-blind, placebo-controlled trial, we compared varenicline (2 mg) to placebo for treatment for cocaine and tobacco dependence in 31 methadone maintained subjects. Subjects received weekly counseling during the 12-week study participation. Our results indicate that varenicline is safe to give to this subject population, as there were no adverse events related to medication during this study. Varenicline was no more effective than placebo for abstinence from cocaine. Treatment with varenicline was associated with a reduced number of cigarettes smoked per day, even though subjects received only a brief education for smoking cessation. The self-report reduction in smoking was corroborated by CO levels and the Fagerstrom Test of Nicotine Dependence. However, self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group, although this appears to be due to randomization differences related to lifetime depression diagnosis. These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone. PMID- 20716304 TI - Co-occurring psychiatric symptoms are associated with increased psychological, social, and medical impairment in opioid dependent pregnant women. AB - The interaction of psychiatric symptoms with drug dependence during pregnancy is not well understood. This study examines the relationship of psychiatric symptoms to severity of drug use and drug-related problems among participants in a clinical trial of pharmacologic treatment of opioid dependence during pregnancy (N = 174). A total of 64.6% reported additional psychiatric symptoms (48.6% mood symptoms, 40.0% anxiety symptoms, and 12.6% suicidal thinking). Women who endorsed co-occurring psychiatric symptoms showed more severe impairment on the Addiction Severity Index. Further investigation is warranted to understand the effect of psychiatric symptoms on long-term maternal and neonatal outcomes. PMID- 20716305 TI - A randomized trial of oral naltrexone for treating opioid-dependent offenders. AB - Offenders with a history of opioid dependence are a particularly difficult group to treat. A large proportion of offenders typically relapse shortly after release from prison, commit drug-related crimes, and then are arrested and eventually re incarcerated. Previous research demonstrated that oral naltrexone was effective in reducing opioid use and preventing recidivism among offenders under federal supervision. The 111 opioid-dependent offenders in this study were under various levels of supervision that included county and federal probation/parole, a treatment court, an alternative disposition program, and an intermediate punishment program. Subjects were randomly assigned to receive 6 months of either 300 mg per week of oral naltrexone plus standard psychosocial treatment as usual (n = 56) or standard psychosocial treatment as usual (TAU) without naltrexone (n = 55). While the TAU subjects who remained in treatment used more opioids than the naltrexone subjects who remained, the high dropout rate for both groups made it difficult to assess the effectiveness of naltrexone. The study provides limited support for the use of oral naltrexone for offenders who are not closely monitored by the criminal justice system. PMID- 20716306 TI - Applying the transtheoretical model to the readiness to change blood-borne virus transmission behaviors among drug-dependent inmates. AB - Our study set out to assess readiness to change blood-borne virus transmission behaviors using the Transtheoretical Model among inmates in a court-ordered detention center. A cross-sectional descriptive study was conducted in southern Taiwan. All men convicted of illicit drug use and sentenced to undergo the 6 month detoxification program were invited to participate. Half of the 172 participating inmates described themselves as being in the contemplation stage of change. The length of residency in the detoxification program was not associated with self-reported readiness to change, chi(2)= 6.53, p = .16. Inmates in the precontemplation stage had increased rates for high-risk behaviors than those in the contemplation and action stages (p < .001). The efficacy of forced-abstinence detention programs on readiness to change risky behaviors needs to be reevaluated. PMID- 20716307 TI - Independent predictors for lifetime and recent substance use disorders in patients with rapid-cycling bipolar disorder: focus on anxiety disorders. AB - We set out to study independent predictor(s) for lifetime and recent substance use disorders (SUDs) in patients with rapid-cycling bipolar disorder (RCBD). Extensive Clinical Interview and Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV Axis I diagnoses of RCBD, anxiety disorders, and SUDs. Data from patients enrolling into four similar clinical trials were used. Where appropriate, univariate analyses with t-test or chi-square were applied. Stepwise logistic regression was used to examine the relationship among predictor variables and lifetime and recent SUDs. Univariate analysis showed that patients with co-occurring anxiety disorders (n = 261) had significantly increased rates of lifetime (odds ratio [OR]= 2.1) and recent (OR = 1.9) alcohol dependence as well as lifetime (OR = 3.4) and recent (OR = 2.5) marijuana dependence compared to those without co-occurring anxiety disorder (n = 303). In logistic regression analyses, generalized anxiety disorder (GAD) was associated with increased risk for lifetime SUDs (OR = 2.34), alcohol dependence (OR = 1.73), and marijuana dependence (OR = 3.36) and recent marijuana dependence (OR = 3.28). A history of physical abuse was associated with increased risk for lifetime SUDs (OR = 1.71) and recent marijuana dependence (OR = 3.47). Earlier onset of first mania/hypomania was associated with increased risk for lifetime SUDs (5% per year), and recent marijuana dependence (12% per year) and later treatment with a mood stabilizer were also associated with increased risk for recent SUDs (8% per year). Positive associations between GAD, later treatment with a mood stabilizer, and early childhood trauma and history of SUDs suggest that adequate treatment of comorbid anxiety, early treatment with a mood stabilizer, and prevention of childhood trauma may reduce the risk for the development of SUDs in patients with bipolar disorder. PMID- 20716308 TI - Covariates of craving in actively drinking alcoholics. AB - The goal of this cross-sectional study was to assess the relationship of alcohol craving with biopsychosocial and addiction factors that are clinically pertinent to alcoholism treatment. Alcohol craving was assessed in 315 treatment-seeking, alcohol dependent subjects using the Penn Alcohol Craving Scale questionnaire. Standard validated questionnaires were used to evaluate a variety of biological, addiction, psychological, psychiatric, and social factors. Individual covariates of craving included age, race, problematic consequences of drinking, heavy drinking, motivation for change, mood disturbance, sleep problems, and social supports. In a multivariate analysis (R(2)= .34), alcohol craving was positively associated with mood disturbance, heavy drinking, readiness for change, and negatively associated with age. The results from this study suggest that alcohol craving is a complex phenomenon influenced by multiple factors. PMID- 20716309 TI - A case report of transient but clinically relevant interaction between methadone and duloxetine: a reply to McCance-Katz et al. PMID- 20716310 TI - Medical marijuana and adolescent treatment. PMID- 20716311 TI - Retrospective review of acute acamprosate exposures to a poison control system. PMID- 20716314 TI - General considerations on rapid desensitization for drug hypersensitivity - a consensus statement. AB - Drug hypersensitivity reactions can occur with most drugs, are unpredictable, may affect any organ or system, and range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. However, for certain patients, the particular drug may be essential for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance of a compound responsible for a hypersensitivity reaction. It is performed by administering increasing doses of the medication concerned over a short period of time (from several hours to a few days) until the total cumulative therapeutic dose is achieved and tolerated. It is a high-risk procedure used only in patients in whom alternatives are less effective or not available after a positive risk/benefit analysis. Desensitization protocols have been developed and are used in patients with allergic reactions to antibiotics (mainly penicillin), insulins, sulfonamides, chemotherapeutic and biologic agents, and many other drugs. Desensitization is mainly performed in IgE-mediated reactions, but also in reactions where drug-specific IgE have not been demonstrated. Desensitization induces a temporary tolerant state, which can only be maintained by continuous administration of the medication. Thus, for treatments like chemotherapy, which have an average interval of 4 weeks between cycles, the procedure must be repeated for every new course. In this paper, some background information on rapid desensitization procedures is provided. We define the drugs and drug reactions indicated for such procedures, describe the possible mechanism of action, and discuss the indications and contraindications. The data should serve as background information for a database (accessible via the EAACI homepage) with standardized protocols for rapid desensitization for antibiotics, chemotherapeutic agents, monoclonal antibodies/fusion proteins, and other drugs. PMID- 20716315 TI - What are the 'ideal' features of an adrenaline (epinephrine) auto-injector in the treatment of anaphylaxis? AB - Anaphylaxis is a systemic allergic reaction that often involves respiratory symptoms and cardiovascular collapse, which are potentially life-threatening if not treated promptly with intramuscular adrenaline. Owing to the unpredictable nature of anaphylaxis and accidental exposure to allergens (such as peanuts and shellfish), patients should be prescribed intramuscular adrenaline auto-injectors and carry these with them at all times. Patients also need to be able to use their auto-injectors correctly while under high stress, when an anaphylactic attack occurs. Despite this, an alarming number of patients fail to carry their auto-injectors and many patients, carers of children with known anaphylaxis and healthcare professionals do not know how to use the device correctly, despite having had training. Currently available auto-injector devices have various limitations that may impede their use in the management of anaphylaxis. There is also a lack of validated assessment criteria and regulatory requirements for new devices. This review describes the different delivery systems used in currently available auto-injectors and discusses the key barriers to the use of adrenaline auto-injectors, with the goal of identifying the 'ideal' features/characteristics of such devices in the emergency treatment of anaphylaxis that will ensure ease of use, portability and accurate delivery of a life-saving drug. PMID- 20716316 TI - Vaccination of adults with asthma and COPD. AB - Vaccines play a major role in preventing potentially life-threatening diseases. More attention is now focused on the adult population, particularly as they age, as a reservoir for vaccine-preventable diseases. Adults with comorbid conditions such as asthma and chronic obstructive pulmonary disease (COPD) are considered to be at higher risk for invasive diseases, many of which are preventable through routine vaccination. This article reviews the pertinent literature for the use of vaccines in the management of adult patients with asthma and COPD. PMID- 20716317 TI - The 2009-2010 H1N1 vaccination campaign for patients with egg allergy in a region of France. AB - We describe our experience of the influenza H1N1 vaccination in patients with egg allergy. All patients tolerated the vaccination in a simple or double dose protocol without any significant allergic reaction in this series. PMID- 20716318 TI - No association between FADS polymorphisms and atopic diseases in children from the GINI and LISA birth cohorts. PMID- 20716319 TI - Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics. AB - BACKGROUND: Previous studies suggest that pre/probiotics can be used in the prevention and treatment of early allergic disease in newborns and young children. OBJECTIVE: To determine the effect of treatment with synbiotics (90% short-chain galacto-oligosaccharides, 10% long-chain fructo-oligosaccharides: Immunofortis((r)) and Bifidobacterium breve M-16V) on allergic responses in adults with established allergic asthma. Primary outcome was allergen-induced bronchial inflammation as represented by eosinophil counts. METHODS: Twenty-nine patients with asthma and house dust mite (HDM) allergy were randomized in a double-blind, parallel design to receive placebo or synbiotics for 4 weeks. At study entry and after treatment, a bronchial allergen challenge with HDM was performed, followed by lung function tests, collection of blood (in/ex vivo IL-5) and induced sputum (inflammatory parameters). During treatment, a diary was kept with peak expiratory flow (PEF) and asthma scores. RESULTS: Treatment did not affect the allergen-induced increase in sputum eosinophils at 6 and 24 h after challenge. Likewise, other parameters for bronchial inflammation and early and late changes in lung function did not differ upon treatment. Both the morning and evening PEF, however, significantly increased during synbiotics treatment (morning P = 0.003, evening P = 0.011). Also, the increase in serum IL-5 after allergen challenge was significantly inhibited by synbiotics (P = 0.034), as was ex vivo allergen-induced Th2-cytokine (IL-5 and IL-4+ IL-13) production by PBMCs (P = 0.046). In vivo (24 h) and ex vivo IL-5 production were associated. CONCLUSION: Four-week treatment with synbiotics had no effect on bronchial inflammation and LAR, but did significantly reduce systemic production of Th2 cytokines after allergen challenge and improved PEF. PMID- 20716320 TI - Is atopic disease a risk factor for attention-deficit/hyperactivity disorder? A systematic review. AB - The increase in prevalence and burden of atopic diseases, i.e. eczema, rhinitis, and asthma over the past decades was paralleled by a worldwide increase in attention-deficit/hyperactivity disorder (ADHD) diagnoses. We systematically reviewed epidemiologic studies investigating the relationship between atopic diseases and ADHD. Electronic literature search in PubMed and PsycINFO (until 02/2010) supplemented by handsearch yielded 20 relevant studies totaling 170,175 individuals. Relevant data were abstracted independently by two reviewers. Six studies consistently reported a positive association between eczema and ADHD with one study suggesting effect modification by sleeping problems. Twelve studies consistently found a positive association between asthma and ADHD, which, however, appeared to be at least partly explained (confounded) by concurrent or previous eczema. Rhinitis and serum-IgE level were not related to ADHD symptomatology. We conclude that not atopic disease in general, but rather that eczema appears to be independently related to ADHD. Conclusions about temporality and whether the observed association constitutes a causal relationship are impossible, as most studies were cross-sectional (n = 14; 70%) or case-control studies without incident exposure measurement (n = 5; 25%). Another methodological concern is that the criteria to define atopic disease and ADHD were inadequate in most studies. A failure to adjust for confounders in the majority of studies was an additional limitation so that meta-analysis was not indicated. Future interdisciplinary high-quality prospective research is needed to better understand the mechanisms underlying the relationship between eczema and ADHD and to eventually establish targeted preventive and treatment strategies. PMID- 20716321 TI - Association between attendance of day care centres and increased prevalence of eczema in the German birth cohort study LISAplus. AB - BACKGROUND: Day care centre attendance is much more common in East than in West Germany. Although there is evidence that early day care might be protective against atopic diseases, several studies have shown a higher prevalence of childhood eczema in East Germany compared to West Germany. OBJECTIVES: To compare prevalence and cumulative incidence of eczema in a birth cohort study in East and West Germany and to identify risk factors that are associated with eczema, which might explain regional differences. METHODS: We used data from the ongoing population-based birth cohort study Influence of Life-style factors on the development of the Immune System and Allergies in East and West Germany Plus the influence of traffic emissions and genetics. In 1997, 3097 children from study areas in East and West Germany were recruited. Cumulative incidence and 1-year prevalences of eczema up to the age of 6 years were determined from yearly questionnaires. Cox regression and generalized estimating equations/logistic regression were used to quantify regional differences and to identify risk factors that might explain them. RESULTS: Prevalence and incidence of eczema were higher in children living in East Germany than those living in West Germany. We identified 11 risk factors that showed significant regional differences. From these factors, only 'day care attendance during the first 2 years of life' was significantly associated with eczema (odds ratio 1.56, 95% confidence interval CI 1.31-1.86). The regional differences in eczema could be explained by differences in early day care utilization. CONCLUSION: Day care centre attendance is associated with an increased prevalence and incidence of eczema. Regional differences in eczema prevalence could be explained by regional differences in utilization of early day care. PMID- 20716322 TI - Natural killer-dendritic cell interaction in lymphocyte responses in hypersensitivity reactions to betalactams. AB - BACKGROUND: Betalactams are the commonest cause of allergic reactions mediated by either IgE or T lymphocytes in which innate and adaptive immune systems mediate the earlier stages of immunological responses. One of the links between these systems is related to the interaction between natural killer (NK) and dendritic cells (DC). We have evaluated the role of NK cells and NK-DC interaction in the immunopathological mechanisms of nonimmediate reactions to betalactams. METHODS: Patients allergic to amoxicillin (AX) (N = 17) and tolerant controls (N = 13) were included. Changes in phenotype (CD69, IFNgamma, perforin, and granzyme B) in AX-stimulated NK cells, the cytotoxic activity on mature or immature DC (imDC), and the proliferation and phenotype of NK lymphocytes after culture with AX and DC were determined by flow cytometry. RESULTS: Amoxicillin induced activation and increases of perforin and granzyme B (P = 0.007 and P = 0.041 respectively) but not IFNgamma production in NK cells from patients. In NK subpopulations, AX induced a significant enhancement of perforin and granzyme B in CD56(dim) (P = 0.005 and P = 0.002 respectively) and of IFNgamma in CD56(bright) (P = 0.001). The cytotoxic phenotype was demonstrated by an increase of annexin V only in imDC (P < 0.001). Amoxicillin also induced an increased NK proliferation with different patterns, cytotoxic or proinflammatory, depending on the presence of imDC or mature DC, respectively. No differences were observed in NK cells from tolerant controls. CONCLUSION: These data could demonstrate the involvement of NK cells in the immunopathological mechanisms of nonimmediate allergic reactions to AX, showing that both the innate and adaptive immune systems are involved and crosstalk, producing amplification of the harmful effects observed in these drug reactions. PMID- 20716323 TI - Interobserver variability for retreatment indications after Ranibizumab loading doses in neovascular age-related macular degeneration. AB - PURPOSE: To assess the interobserver variability (IOV) in indicating retreatment for neovascular Age-related macular degeneration 4 weeks after three Ranibizumab loading doses using spectral domain OCT (SD-OCT) as the primary objective diagnostic tool. MATERIAL AND METHODS: Four observers decided for or against 4th Ranibizumab injection in 108 patients by six different rating rounds (RR) based on the SD-OCT findings after the loading doses. Postoperative OCT images were supplemented consecutively with information from a chart review as the 'patients subjective estimation of vision (SE)', the course of best-corrected visual acuity (BCVA) and the preoperative OCT as well as all information collectively. Agreement rates (AR) and Kappa statistics were calculated. RESULTS: Based on post treatment OCT findings only (RR1), mean reinjection rate of all observers was 37.5%. Adding supplementary information, mean reinjection rate decreased to 20% when all information was available reflecting the 'real' situation (RR 6). Interobserver agreement rates varied from 66.7% to 90.7% depending on rating rounds and interobserver pairs. Mean AR and Kappa values (KV) were as following: AR 81.6%, KV 0.61 (RR1: 'only post-OP OCT'); AR 76.7%, KV 0.33 (RR2: post-OP OCT + SE); AR 80.3%, KV 0.45 (RR3: post-OP OCT + BCVA); AR 80.7%, KV 0.46 (RR4: pre- and post-OP OCT); AR 82.2%, KV 0.49 (RR5: post-OP OCT + SE + BCVA); and finally AR 83.6%, KV 0.47 (RR6: pre- and post-OP OCT + SE + BCVA). The overall mean agreement rate was 80.9% with a Kappa of 0.47. CONCLUSION: IOV for indicating retreatment after three Ranibizumab loading doses reveals only moderate agreement in Kappa statistics, which seems to be too low considering the high costs for retreatments. More concise guidelines based on the post-treatment OCT scans as the presumably most sensitive and noninvasive objective tool to follow choroidal neovascularization activity by judging the course of sub- and intraretinal fluid are necessary. PMID- 20716324 TI - Comparison of visual performance of silicone and acrylic multifocal IOLs utilizing the same diffractive design. AB - PURPOSE: To compare the visual outcomes in patients implanted with a diffractive silicone multifocal in one eye and a diffractive acrylic multifocal IOL in their fellow eye. SETTING: Augenklinik, Bad Hersfeld, Germany. METHODS: Forty-two eyes of 21 cataract surgery patients were randomized to undergo implantation with either a silicone diffractive multifocal IOL (Tecnis ZM900, Abbott Medical Optics, Santa Ana, CA, USA) or an acrylic diffractive multifocal IOL (Tecnis ZMA00, AMO). The two IOLs share the same design platform. Outcome measurements included uncorrected and best-corrected distance and near visual acuity, spherical equivalent, reading speed and reading acuity, as well as photic phenomena. Patients were followed for 6 months following surgery. RESULTS: The mean spherical equivalent was 0.161 D (acrylic) and 0.065 D (silicone). The mean uncorrected visual acuity was 0.17 logMAR for the acrylic eyes and 0.17 logMAR for the silicone eyes, a difference of 0.01 (p=0.861). The mean best-corrected visual acuity (BCVA) was 0.08 for the acrylic eyes and 0.10 for the silicone lens, a difference of 0.03 (p=0.321). CONCLUSIONS: Given that the designs of the lenses are identical and that this was a contralateral eye study, it is reasonable to expect that the results between the two eyes and two types of lenses were similar. Both versions of this lens provide excellent visual function. PMID- 20716325 TI - Spontaneous branch artery occlusion in idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis syndrome despite panretinal laser photocoagulation of widespread retina nonperfusion. PMID- 20716326 TI - Betel nut chewing and incidence of newly diagnosed type 2 diabetes mellitus in Taiwan. AB - BACKGROUND: Betel nut chewing is associated with type 2 diabetes mellitus (T2DM) in a recent prevalence study in Taiwan. The present study further investigated its link with the incidence of newly diagnosed T2DM during the years 1992-1996. METHODS: Population-based datasets of a sample of 93,484 out of 256,036 diabetic patients from 66 medical settings using the National Health Insurance scheme covering > 96% of the population, published population prevalence of betel nut chewing and the governmental census of national population were used for calculation of odds ratios, incidence rates and incidence rate ratios between chewers and never-chewers in the male population for the year 1992 to 1996. RESULTS: Ever chewers among the diabetic patients were younger, more obese and had higher prevalence of parental diabetes than never-chewers (all p values < 0.001). Odds ratios for T2DM for ever chewers vs. never-chewers in the age of < 40, 40-49, 50-59, 60-69 and >=70 years were 1.06 (0.92-1.23), 1.60 (1.45-1.76), 2.12 (1.88-2.39), 3.58 (3.10-4.13) and 7.14 (5.47-9.31), respectively. In 1996, incidence rates (per 100,000 population) in the respective age groups were 19.1, 251.5, 567.3, 721.7 and 971.4 for never-chewers; and were 30.2, 520.9, 2566.9, 11672.8 and 630.3 for ever chewers. The respective incidence rate ratios were 1.58, 2.07, 4.52, 16.17 and 0.65. The age-specific incidence rates and rate ratios were relatively consistent from 1992 to 1996. The differences in obesity and parental diabetes between ever chewers and never-chewers were mostly not statistically significant after age stratification, suggesting the link could not be attributed to these two factors. CONCLUSIONS: Chewing betel nut is associated with newly diagnosed T2DM, supporting the suggestion that the habit is diabetogenic. PMID- 20716327 TI - Hippocampal CA1/subiculum-prefrontal cortical pathways induce plastic changes of nociceptive responses in cingulate and prelimbic areas. AB - BACKGROUND: Projections from hippocampal CA1-subiculum (CA1/SB) areas to the prefrontal cortex (PFC), which are involved in memory and learning processes, produce long term synaptic plasticity in PFC neurons. We examined modifying effects of these projections on nociceptive responses recorded in the prelimbic and cingulate areas of the PFC. RESULTS: Extracellular unit discharges evoked by mechanical noxious stimulation delivered to the rat-tail and field potentials evoked by a single stimulus pulse delivered to CA1/SB were recorded in the PFC. High frequency stimulation (HFS, 100 Hz) delivered to CA1/SB, which produced long term potentiation (LTP) of field potentials, induced long-term enhancement (LTE) of nociceptive responses in 78% of cases, while, conversely, in 22% responses decreased (long-term depression, LTD). These neurons were scattered throughout the cingulate and prelimbic areas. The results obtained for field potentials and nociceptive discharges suggest that CA1/SB-PFC pathways can produce heterosynaptic potentiation in PFC neurons. HFS had no effects on Fos expression in the cingulated cortex. Low frequency stimulation (LFS, 1 Hz, 600 bursts) delivered to the CA1/SB induced LTD of nociceptive discharges in all cases. After recovery from LTD, HFS delivered to CA1/SB had the opposite effect, inducing LTE of nociceptive responses in the same neuron. The bidirectional type of plasticity was evident in these nociceptive responses, as in the homosynaptic plasticity reported previously. Neurons inducing LTD are found mainly in the prelimbic area, in which Fos expression was also shown to be inhibited by LFS. The electrophysiological results closely paralleled those of immunostaining. Our results indicate that CA1/SB-PFC pathways inhibit excitatory pyramidal cell activities in prelimbic areas. CONCLUSION: Pressure stimulation (300 g) applied to the rat-tail induced nociceptive responses in the cingulate and prelimbic areas of the PFC, which receives direct pathways from CA1/SB. HFS and LFS delivered to the CA1/SB induced long-term plasticity of nociceptive responses. Thus, CA1/SB-PFC projections modulate the nociceptive responses of PFC neurons. PMID- 20716328 TI - Psychometric validation of the Dutch translation of the quality of life in reflux and dyspepsia (QOLRAD) questionnaire in patients with gastroesophageal reflux disease. AB - BACKGROUND: The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire is one of the best-characterized disease-specific instruments that captures health related problems and symptom-patterns in patients with gastroesophageal reflux disease (GERD). This paper reports the psychometric validation of a Dutch translation of the QOLRAD questionnaire in gastroenterology outpatients with GERD. METHODS: Patients completed the QOLRAD questionnaire at visit 1 (baseline), visit 2 (after 2, 4 or 8 weeks of acute treatment with esomeprazole 40 mg once daily), and visit 4 (after 6 months with on-demand esomeprazole 40 mg once daily or continuous esomeprazole 20 mg once daily). Symptoms were assessed at each visit, and patient satisfaction was assessed at visits 2 and 4. RESULTS: Of the 1166 patients entered in the study, 97.3% had moderate or severe heartburn and 55.5% had moderate or severe regurgitation at baseline. At visit 2, symptoms of heartburn and regurgitation were mild or absent in 96.7% and 97.7%, respectively, and 95.3% of patients reported being satisfied with the treatment. The internal consistency and reliability of the QOLRAD questionnaire (range: 0.83-0.92) supported construct validity. Convergent validity was moderate to low. Known groups validity was confirmed by a negative correlation between the QOLRAD score and clinician-assessed severity of GERD symptoms. Effect sizes (1.15-1.93) and standardized response means (1.17-1.86) showed good responsiveness to change. GERD symptoms had a negative impact on patients' lives. CONCLUSIONS: The psychometric characteristics of the Dutch translation of the QOLRAD questionnaire were found to be satisfactory, with good reliability and responsiveness to change, although convergent validity was at best moderate. PMID- 20716329 TI - Transcriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases. AB - BACKGROUND: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response in acute phase of the infectious disease is poorly understood. RESULTS: Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease (day 2-4 after hospitalization) or in convalescence phase (day 7-10). This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged. For instance, transcripts associated with inflammatory and anti-inflammatory reactions (TNFRSF1A, IL1R1, IL1R2, IL10RB) and with oxidative stress (HMOX1, GPX1, SOD2, PRDX6) were more abundant while those associated with T-cell functions (CD28, CD69, LCK) were less abundant in acute phase. The abundance of seven of these transcripts (CD28, CD69, LCK, CTSD, HMOX1, TNFRSF1A and PRDX6) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase, compromising an efficient response. CONCLUSION: This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons. PMID- 20716330 TI - "Mi voglio bene": a pediatrician-based randomized controlled trial for the prevention of obesity in Italian preschool children. AB - BACKGROUND: The first years of life are crucial to start preventive interventions that can have an impact on lifestyle and later overweight and obesity. Under the Italian National Health System (INHS), children are cared for by family pediatricians who perform health balances at regular intervals. The Italian Society of Preventive and Social Pediatrics (SIPPS) has designed a randomized controlled trial (RCT) to evaluate the effectiveness of family pediatricians for the prevention of childhood obesity in preschool children. We report the rationale and protocol of such trial, named the "Mi voglio bene" ("I love myself") study. METHODS: "Mi voglio bene" is a parallel-arm RCT. Family pediatricians willing to participate to the trial will be randomly assigned to a control group and to an experimental group. The control group will provide the usual standard of care while the experimental group will implement 10 preventive actions (promotion of breastfeeding, avoidance of solid foods, control of protein intake, avoidance of sugar-sweetened beverages, avoidance of bottle, active means of transportation, identification of early adiposity rebound, limitation of television viewing, promotion of movement, and teaching portion size) at 10 time points during a 6-yr follow-up. The main outcome measures is the prevalence of overweight and obesity at 6 years of age. The experimental intervention is expected to reduce the prevalence of overweight and obesity from 25% to 20% and the study requires a total of 3610 children. Each pediatrician will enroll 30 consecutive newborns into the study so that a total of 120 pediatricians will participate to the study. DISCUSSION: "Mi voglio bene" is expected to provide important information for the INHS and possibly other institutional child care settings about the effectiveness of a pediatrician-based approach to the prevention of childhood obesity. We published this study protocol with the aim of opening a discussion with all people interested in fighting childhood obesity and to receive useful criticisms. PMID- 20716331 TI - Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells. AB - OBJECTIVE: To investigate the effect of all-trans retinoic acid(ATRA) on the proliferation and differentiation of brain tumor stem cells(BTSCs) in vitro. METHODS: Limiting dilution and clonogenic assay were used to isolate and screen BTSCs from the fresh specimen of human brain glioblastoma. The obtained BTSCs, which were cultured in serum-free medium, were classified into four groups in accordance with the composition of the different treatments. The proliferation of the BTSCs was evaluated by MTT assay. The BTSCs were induced to differentiate in serum-containing medium, and classified into the ATRA group and control group. On the 10th day of induction, the expressions of CD133 and glial fibrillary acidic protein (GFAP) in the differentiated BTSCs were detected by immunofluorescence. The differentiated BTSCs were cultured in serum-free medium, the percentage and the time required for formation of brain tumor spheres (BTS) were observed. RESULTS: BTSCs obtained by limiting dilution were all identified as CD133 positive by immunofluorescence. In serum-free medium, the proliferation of BTSCs in the ATRA group was observed significantly faster than that in the control group, but slower than that in the growth factor group and ATRA/growth factor group, and the size of the BTS in the ATRA group was smaller than that in the latter two groups(P < 0.01). In serum-containing medium, the expression percentages of CD133 and GFAP in the differentiated BTSCs were (2.29% +/- 0.27%) and (75.60% +/- 4.03%) respectively in the ATRA group, and (7.05% +/- 0.49%) and (12.51% +/- 0.77%) respectively in the control group. The differentiation rate of BTSCs in the ATRA group was significantly higher than that in the control group (P < 0.05), but there was still CD133 expressed in the ATRA group. The differentiated BTSCs could re-form BTSs in serum-free medium. The percentage of BTS formation in the ATRA group was(4.84% +/- 0.32%), significantly lower than that in the control group (17.71% +/- 0.78%) (P < 0.05), and the time required for BTS formation in the ATRA group was (10.07 +/- 1.03)d, significantly longer than that in the control group (4.08 +/- 0.35)d (P < 0.05). CONCLUSION: ATRA can promote the proliferation and induce the differentiation of BTSCs, but the differentiation is incomplete, terminal differentiation cannot be achieved and BTSs can be formed again. PMID- 20716332 TI - Time trends in cardiovascular disease mortality in Russia and Germany from 1980 to 2007 - are there migration effects? AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Large variations in CVD mortality between countries and also between population subgroups within countries have been observed. Previous studies showed significantly lower risks in German repatriates and Jews emigrating from Russia than in the general Russian population. We examined to what degree the migration of large subgroups influenced national CVD mortality rates. METHODS: We used WHO data to map the CVD mortality distribution in Europe in 2005. Supplemented by data of the Statistisches Bundesamt, the mortality trends in three major CVD groups between 1980 and 2007 in Russia and Germany are displayed, as well as demographic information. The effects of migration on demography were estimated and percentage changes in CVD mortality trends were calculated under the assumption that migration had not occurred. RESULTS: Cardiovascular disease mortality patterns within Europe showed a strong west-east gradient with ratios up to sixfold. In Germany, the CVD mortality levels were low and steadily decreasing, whereas in Russia they fluctuated at high levels with substantial differences between the sexes and strong correlations with political changes and health campaigns. The trends in both Russia and Germany were affected by the migration that occurred in both countries over recent decades. However, our restricted focus in only adjusting for the migration of German repatriates and Jews had moderate effects on the national CVD mortality statistics in Germany (+1.0%) and Russia (-0.6%). CONCLUSIONS: The effects on CVD mortality rates due to migration in Germany and Russia were smaller than those due to secular economical changes. However, migration should still be considered as a factor influencing national mortality trends. PMID- 20716333 TI - Rapid T1 quantification based on 3D phase sensitive inversion recovery. AB - BACKGROUND: In Contrast Enhanced Magnetic Resonance Imaging fibrotic myocardium can be distinguished from healthy tissue using the difference in the longitudinal T1 relaxation after administration of Gadolinium, the so-called Late Gd Enhancement. The purpose of this work was to measure the myocardial absolute T1 post-Gd from a single breath-hold 3D Phase Sensitivity Inversion Recovery sequence (PSIR). Equations were derived to take the acquisition and saturation effects on the magnetization into account. METHODS: The accuracy of the method was investigated on phantoms and using simulations. The method was applied to a group of patients with suspected myocardial infarction where the absolute difference in relaxation of healthy and fibrotic myocardium was measured at about 15 minutes post-contrast. The evolution of the absolute R1 relaxation rate (1/T1) over time after contrast injection was followed for one patient and compared to T1 mapping using Look-Locker. Based on the T1 maps synthetic LGE images were reconstructed and compared to the conventional LGE images. RESULTS: The fitting algorithm is robust against variation in acquisition flip angle, the inversion delay time and cardiac arrhythmia. The observed relaxation rate of the myocardium is 1.2 s-1, increasing to 6 - 7 s-1 after contrast injection and decreasing to 2 2.5 s-1 for healthy myocardium and to 3.5 - 4 s-1 for fibrotic myocardium. Synthesized images based on the T1 maps correspond very well to actual LGE images. CONCLUSIONS: The method provides a robust quantification of post-Gd T1 relaxation for a complete cardiac volume within a single breath-hold. PMID- 20716335 TI - Validation of a constraint-based model of Pichia pastoris metabolism under data scarcity. AB - BACKGROUND: Constraint-based models enable structured cellular representations in which intracellular kinetics are circumvented. These models, combined with experimental data, are useful analytical tools to estimate the state exhibited (the phenotype) by the cells at given pseudo-steady conditions. RESULTS: In this contribution, a simplified constraint-based stoichiometric model of the metabolism of the yeast Pichia pastoris, a workhorse for heterologous protein expression, is validated against several experimental available datasets. Firstly, maximum theoretical growth yields are calculated and compared to the experimental ones. Secondly, possibility theory is applied to quantify the consistency between model and measurements. Finally, the biomass growth rate is excluded from the datasets and its prediction used to exemplify the capability of the model to calculate non-measured fluxes. CONCLUSIONS: This contribution shows how a small-sized network can be assessed following a rational, quantitative procedure even when measurements are scarce and imprecise. This approach is particularly useful in lacking data scenarios. PMID- 20716334 TI - Multi-level, cross-sectional study of workplace social capital and smoking among Japanese employees. AB - BACKGROUND: Social capital is hypothesized to be relevant to health promotion, and the association between community social capital and cigarette smoking has been examined. Individual-level social capital has been found to be associated with smoking cessation, but evidence remains sparse on the contextual effect of social capital and smoking. Further, evidence remains sparse on the association between smoking and social capital in the workplace, where people are spending an increasing portion of their daily lives. We examined the association between workplace social capital and smoking status among Japanese private sector employees. METHODS: We employed a two-stage stratified random sampling procedure. Of the total of 1,800 subjects in 60 companies, 1,171 (men/women; 834/337) employees (65.1%) were identified from 46 companies in Okayama in 2007. Workplace social capital was assessed in two dimensions; trust and reciprocity. Company level social capital was based on inquiring about employee perceptions of trust and reciprocity among co-workers, and then aggregating their responses in order to calculate the proportion of workers reporting mistrust and lack of reciprocity. Multilevel logistic regression analysis was conducted using Markov Chain Monte Carlo methods to explore whether individual- and company-level social capital was associated with smoking. Odds ratios (ORs) and 95% credible intervals (CIs) for current smoking were obtained. RESULTS: Overall, 33.3% of the subjects smoked currently. There was no relationship between individual-level mistrust of others and smoking status. By contrast, one-standard deviation change in company level mistrust was associated with higher odds of smoking (OR: 1.25, 95% CI: 1.06 1.46) even after controlling for individual-level mistrust, sex, age, occupation, educational attainment, alcohol use, physical activity, body mass index, and chronic diseases. No clear associations were found between lack of reciprocity and smoking both at the individual- and company-level. CONCLUSIONS: Company-level mistrust is associated with higher likelihood of smoking among Japanese employees, while individual perceptions of mistrust were not associated. The link between lack of reciprocity and smoking was not supported either at the individual- or company-level. Further studies are warranted to examine the possible link between company-level trust and smoking cessation in the Japanese workplace. PMID- 20716336 TI - Distinct choline metabolic profiles are associated with differences in gene expression for basal-like and luminal-like breast cancer xenograft models. AB - BACKGROUND: Increased concentrations of choline-containing compounds are frequently observed in breast carcinomas, and may serve as biomarkers for both diagnostic and treatment monitoring purposes. However, underlying mechanisms for the abnormal choline metabolism are poorly understood. METHODS: The concentrations of choline-derived metabolites were determined in xenografted primary human breast carcinomas, representing basal-like and luminal-like subtypes. Quantification of metabolites in fresh frozen tissue was performed using high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). The expression of genes involved in phosphatidylcholine (PtdCho) metabolism was retrieved from whole genome expression microarray analyses. The metabolite profiles from xenografts were compared with profiles from human breast cancer, sampled from patients with estrogen/progesterone receptor positive (ER+/PgR+) or triple negative (ER-/PgR-/HER2-) breast cancer. RESULTS: In basal like xenografts, glycerophosphocholine (GPC) concentrations were higher than phosphocholine (PCho) concentrations, whereas this pattern was reversed in luminal-like xenografts. These differences may be explained by lower choline kinase (CHKA, CHKB) expression as well as higher PtdCho degradation mediated by higher expression of phospholipase A2 group 4A (PLA2G4A) and phospholipase B1 (PLB1) in the basal-like model. The glycine concentration was higher in the basal like model. Although glycine could be derived from energy metabolism pathways, the gene expression data suggested a metabolic shift from PtdCho synthesis to glycine formation in basal-like xenografts. In agreement with results from the xenograft models, tissue samples from triple negative breast carcinomas had higher GPC/PCho ratio than samples from ER+/PgR+ carcinomas, suggesting that the choline metabolism in the experimental models is representative for luminal-like and basal-like human breast cancer. CONCLUSIONS: The differences in choline metabolite concentrations corresponded well with differences in gene expression, demonstrating distinct metabolic profiles in the xenograft models representing basal-like and luminal-like breast cancer. The same characteristics of choline metabolite profiles were also observed in patient material from ER+/PgR+ and triple-negative breast cancer, suggesting that the xenografts are relevant model systems for studies of choline metabolism in luminal-like and basal-like breast cancer. PMID- 20716337 TI - The European paediatric legislation: benefits and perspectives. AB - BACKGROUND: The lack of availability of appropriate medicines for children is an extensive and well known problem. Paediatricians and Physicians who take care of the paediatric population are primarily exposed to cope with this negative situation very often as more than half of the children are prescribed off-label or unlicensed medicines. DISCUSSION: Medicinal products used to treat this population should be subjected to ethical research of high quality and be explicitly authorized for use in children as it happens in adults. For that reason, and following the US experience, the European Paediatric Regulation has been amended in January 2007 by the European Commission. The objective of the Paediatric Regulation is to improve the development of high quality and ethically researched medicines for children aged 0 to 17 years, to facilitate the availability of information on the use of medicines for children, without subjecting children to unnecessary trials, or delaying the authorization of medicines for use in adults. SUMMARY: The Paediatric Regulation is dramatically changing the regulatory environment for paediatric medicines in Europe and is fuelling an increased number of clinical trials in the paediatric population. Nevertheless, there are some risks and pitfalls that need to be anticipated and controlled in order to ensure that children will ultimately benefit from this European initiative. PMID- 20716338 TI - Violence against women: the perspective of academic women. AB - BACKGROUND: Opinion surveys about potential causes of violence against women (VAW) are uncommon. This study explores academic women's opinions about VAW and the ways of reducing violence. METHODS: Quantitative and qualitative methods were used in this descriptive study. One hundred-and-fifteen academicians participated in the study from two universities. A questionnaire was used regarding the definition and the causes of VAW, the risk groups and opinions about the solutions. Additionally, two authors interviewed 8 academicians from universities other than that of the interviewing author. RESULTS: Academicians discussed the problem from the perspective of "gender-based violence" rather than "family violence". The majority of the participants stated that nonworking women of low socioeconomic status are most at risk for VAW. They indicated that psychological violence is more prevalent against educated women, whilst physical violence is more likely to occur against uneducated and nonworking women. Perpetrator related factors were the most frequently stated causes of VAW. Thirty-five percent of the academicians defined themselves as at risk of some act of VAW. Recommendations for actions against violence were empowerment of women, increasing the educational levels in the society, and legal measures. CONCLUSIONS: Academic women introduced an ecological approach for the explanation of VAW by stressing the importance of taking into account the global context of the occurrence of VAW. Similar studies with various community members -including men- will help to define targeted interventions. PMID- 20716339 TI - Triggers of self-conscious emotions in the sexually transmitted infection testing process. AB - BACKGROUND: Self-conscious emotions (shame, guilt and embarrassment) are part of many individuals' experiences of seeking STI testing. These emotions can have negative impacts on individuals' interpretations of the STI testing process, their willingness to seek treatment and their willingness to inform sexual partners in light of positive STI diagnoses. Because of these impacts, researchers have called for more work to be completed on the connections between shame, guilt, embarrassment and STI testing. We examine the specific events in the STI testing process that trigger self-conscious emotions in young adults who seek STI testing; and to understand what it is about these events that triggers these emotions.Semi-structured interviews with 30 adults (21 women, 9 men) in the Republic of Ireland. FINDINGS: Seven specific triggers of self-conscious emotions were identified. These were: having unprotected sex, associated with the initial reason for seeking STI testing; talking to partners and peers about the intention to seek STI testing; the experience of accessing STI testing facilities and sitting in clinic waiting rooms; negative interactions with healthcare professionals; receiving a positive diagnosis of an STI; having to notify sexual partners in light of a positive STI diagnosis; and accessing healthcare settings for treatment for an STI. Self-conscious emotions were triggered in each case by a perceived threat to respondents' social identities. CONCLUSION: There are multiple triggers of self-conscious emotions in the STI testing process, ranging from the initial decision to seek testing, right through to the experience of accessing treatment. The role of self-conscious emotions needs to be considered in each component of service design from health promotion approaches, through facility layout to the training of all professionals involved in the STI testing process. PMID- 20716340 TI - Deregulated expression of hnRNP A/B proteins in human non-small cell lung cancer: parallel assessment of protein and mRNA levels in paired tumour/non-tumour tissues. AB - BACKGROUND: Heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A/B type (hnRNP A1, A2/B1, A3) are highly related multifunctional proteins participating in alternative splicing by antagonising other splicing factors, notably ASF/SF2. The altered expression pattern of hnRNP A2/B1 and/or splicing variant B1 alone in human lung cancer and their potential to serve as molecular markers for early diagnosis remain issues of intense investigation. The main objective of the present study was to use paired tumour/non-tumour biopsies from patients with non small cell lung cancer (NSCLC) to investigate the expression profiles of hnRNP A1, A2/B1 and A3 in conjunction with ASF/SF2. METHODS: We combined western blotting of tissue homogenates with immunohistochemical examination of fixed tissue sections and quantification of mRNA expression levels in tumour versus adjacent normal-looking areas of the lung in the same patient. RESULTS: Our study, in addition to clear evidence of mostly uncoupled deregulation of hnRNPs A/B, has revealed hnRNP A1 to be the most deregulated protein with a high frequency of over-expression (76%), followed by A3 (52%) and A2/B1 (43%). Moreover, direct comparison of protein/mRNA levels showed a lack of correlation in the case of hnRNP A1 (as well as of ASF/SF2), but not of A2/B1, suggesting that different mechanisms underlie their deregulation. CONCLUSION: Our results provide strong evidence for the up-regulation of hnRNP A/B in NSCLC, and they support the existence of distinct mechanisms responsible for their deregulated expression. PMID- 20716341 TI - Patterns in deer-related traffic injuries over a decade: the Mayo Clinic experience. AB - BACKGROUND: Our American College of Surgeons Level 1 Trauma Center serves a rural population. As a result, there is a unique set of accidents that are not present in an urban environment such as deer related motor vehicle crashes (dMVC). We characterized injury patterns between motorcycle/all-terrain vehicles (MCC) and automobile (MVC) crashes related to dMVC (deer motor vehicle crash) with the hypotheses that MCC will present with higher Injury Severity Score (ISS) and that it would be related to whether the driver struck the deer or swerved. METHODS: The records of 157 consecutive patients evaluated at our institution for injury related to dMVC from January 1st, 1997 to December 31st, 2006 were reviewed from our prospectively collected trauma database. Demographic, clinical, and crash specific parameters were abstracted. Injury severity was analyzed by the Abbreviated Injury Scale score for each body region as well as the overall Injury Severity Score (ISS). RESULTS: Motorcycle crashes presented with a higher median ISS than MVCs (14 vs 5, p < 0.001). Median Abbreviated Injury Score (AIS) of the spine for MCC riders was higher (3 vs 0, p < 0.001) if they swerved rather than collided. Seventy-seven percent of riders were not wearing a helmet which did not result in a statistically significant increase in median ISS (16 vs 10), head AIS (2 vs 0) or spine AIS (0 vs 0).Within the MVC group, there was no difference between swerving and hitting the deer in any AIS group. Forty-seven percent of drivers were not wearing seat belts which resulted in similar median ISS (6 vs 5) and AIS of all body regions. CONCLUSIONS: Motorcycle operators suffered higher ISS. There were no significant differences in median ISS if a driver involved in a deer-related motor vehicle crash swerved rather than collided, was helmeted, or restrained. PMID- 20716342 TI - Novel strong tissue specific promoter for gene expression in human germ cells. AB - BACKGROUND: Tissue specific promoters may be utilized for a variety of applications, including programmed gene expression in cell types, tissues and organs of interest, for developing different cell culture models or for use in gene therapy. We report a novel, tissue-specific promoter that was identified and engineered from the native upstream regulatory region of the human gene NDUFV1 containing an endogenous retroviral sequence. RESULTS: Among seven established human cell lines and five primary cultures, this modified NDUFV1 upstream sequence (mNUS) was active only in human undifferentiated germ-derived cells (lines Tera-1 and EP2102), where it demonstrated high promoter activity (approximately twice greater than that of the SV40 early promoter, and comparable to the routinely used cytomegaloviral promoter). To investigate the potential applicability of the mNUS promoter for biotechnological needs, a construct carrying a recombinant cytosine deaminase (RCD) suicide gene under the control of mNUS was tested in cell lines of different tissue origin. High cytotoxic effect of RCD with a cell-death rate approximately 60% was observed only in germ-derived cells (Tera-1), whereas no effect was seen in a somatic, kidney-derived control cell line (HEK293). In further experiments, we tested mNUS-driven expression of a hyperactive Sleeping Beauty transposase (SB100X). The mNUS-SB100X construct mediated stable transgene insertions exclusively in germ-derived cells, thereby providing further evidence of tissue-specificity of the mNUS promoter. CONCLUSIONS: We conclude that mNUS may be used as an efficient promoter for tissue-specific gene expression in human germ-derived cells in many applications. Our data also suggest that the 91 bp-long sequence located exactly upstream NDUFV1 transcriptional start site plays a crucial role in the activity of this gene promoter in vitro in the majority of tested cell types (10/12), and an important role--in the rest two cell lines. PMID- 20716343 TI - Assessing the relationship between HIV infection and cervical cancer in Cote d'Ivoire: a case-control study. AB - BACKGROUND: The association between HIV infection and invasive cervical cancer that has been reported may reflect differential prevalence of human papillomavirus (HPV) infection or uncontrolled confounding. We conducted a case control study in a West African population to assess the relationship between HIV infection and invasive cervical cancer, taking into account HPV infection and other potential risk factors for cervical cancer. METHODS: Women with invasive cervical cancer (cases) or normal cervical cytology (controls) were recruited in a hospital-based case-control study in Abidjan, Cote d'Ivoire. Odds ratios and 95% confidence intervals (CI) were estimated in logistic regression analyses controlling for important cofactors. RESULTS: HIV infection was noted in 22/132 (16.7%) cases and 10/120 (8.3%) controls (p = 0.048). High-risk HPV infection was detected in cervical tumor samples from 89.4% of case-participants and in cervical cytology samples in 31.1% of control-participants. In logistic regression analysis, HIV infection was associated with cervical cancer in women with HPV (OR 3.4; 95% CI 1.1-10.8). Among women aged 2 (OR 7.0; 95% CI 1.9-25.7) and HIV infection (OR 4.5; 95% CI 1.5-13.6). Among women aged > 40 years, high-risk HPV infection (OR 23.5; 95% CI 9.1-60.6) and parity > 2 (OR 5.5; 95% CI 2.3-13.4), but association with HIV infection was not statistically significant. CONCLUSIONS: These data support the hypothesis that HIV infection is a cofactor for cervical cancer in women with HPV infection, and, as in all populations, the need for promoting cervical screening in populations with high prevalence of HIV infection. PMID- 20716344 TI - Mechanism of endothelial progenitor cell recruitment into neo-vessels in adjacent non-tumor tissues in hepatocellular carcinoma. AB - BACKGROUND: We investigated the distribution and clinical significance of mobilized endothelial progenitor cells (EPCs) in hepatocellular carcinoma (HCC). We found that many more EPCs were recruited to nonmalignant liver tissue (especially into adjacent non-tumor tissues (AT)) than to tumor vessels. These results suggest that the mechanism underlying the recruitment of EPCs into microvessels in AT merits further investigation METHODS: Angiogenic factors were detected in three tissue microarrays comprising normal liver, paired tumor tissue (TT) and AT from 105 patients (who had undergone hepatectomy for HCC) using immunohistochemistry. Also, the number of EPCs (positive for Sca-1, Flk-1 and c Kit) in the blood and liver of cirrhotic mice were determined by flow cytometry and immunohistochemistry. The distribution of these labeled EPCs in tumor and non tumor tissues was then studied. RESULTS: The results from the tissue microarrays showed that the expression levels of VEGF-A, bFGF, TGF-beta, MCP-1, TSP-1, MMP-9, TIMP-2, and endostatin were significantly higher in AT than in either normal liver or TT (p < 0.05), but no significant difference was found in the expression levels of COX-2 and NOS-2 between AT and TT. The expression of VEGF-A, bFGF, TGF beta, MCP-1, TSP-1, MMP-9, TIMP-2, endostatin, COX-2, and NOS-2 in normal liver tissue was weaker than that in AT or TT. In cirrhotic mice, the number of circulating endothelial progenitor cells gradually increased, before decreasing again. In this mouse model, increased numbers of EPCs were recruited and homed specifically to the cirrhotic liver. CONCLUSIONS: Both liver cirrhosis and HCC led to increased expression of pro-angiogenic factors, which resulted in the recruitment of EPCs into AT. Also, EPCs were mobilized, recruited and homed to cirrhotic liver. The unique pathology of HCC coupled with liver cirrhosis may, therefore, be associated with the distribution and function of EPCs. PMID- 20716345 TI - Parkinson's disease candidate gene prioritization based on expression profile of midbrain dopaminergic neurons. AB - BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Genetic association studies have linked 13 human chromosomal loci to Parkinson's disease. Identification of gene(s), as part of the etiology of Parkinson's disease, within the large number of genes residing in these loci can be achieved through several approaches, including screening methods, and considering appropriate criteria. Since several of the identified Parkinson's disease genes are expressed in substantia nigra pars compact of the midbrain, expression within the neurons of this area could be a suitable criterion to limit the number of candidates and identify PD genes. METHODS: In this work we have used the combination of findings from six rodent transcriptome analysis studies on the gene expression profile of midbrain dopaminergic neurons and the PARK loci in OMIM (Online Mendelian Inheritance in Man) database, to identify new candidate genes for Parkinson's disease. RESULTS: Merging the two datasets, we identified 20 genes within PARK loci, 7 of which are located in an orphan Parkinson's disease locus and one, which had been identified as a disease gene. In addition to identifying a set of candidates for further genetic association studies, these results show that the criteria of expression in midbrain dopaminergic neurons may be used to narrow down the number of genes in PARK loci for such studies. PMID- 20716346 TI - Major effect genes or loose confederations? The development of insecticide resistance in the malaria vector Anopheles gambiae. AB - Insecticide use in public health and agriculture presents a dramatic adaptive challenge to target and non-target insect populations. The rapid development of genetically modulated resistance to insecticides is postulated to develop in two distinct ways: By selection for single major effect genes or by selection for loose confederations in which several factors, not normally associated with each other, inadvertently combine their effects to produce resistance phenotypes. Insecticide resistance is a common occurrence and has been intensively studied in the major malaria vector Anopheles gambiae, providing a useful model for examining how insecticide resistance develops and what pleiotropic effects are likely to emerge as a consequence of resistance. As malaria vector control becomes increasingly reliant on successfully managing insecticide resistance, the characterisation of resistance mechanisms and their pleiotropic effects becomes increasingly important. PMID- 20716347 TI - Interactions of the apolipoprotein C-III 3238C>G polymorphism and alcohol consumption on serum triglyceride levels. AB - BACKGROUND: Both apolipoprotein (Apo) C-III gene polymorphism and alcohol consumption have been associated with increased serum triglyceride (TG) levels, but their interactions on serum TG levels are not well known. The present study was undertaken to detect the interactions of the ApoC-III 3238C>G (rs5128) polymorphism and alcohol consumption on serum TG levels. METHODS: A total of 516 unrelated nondrinkers and 514 drinkers aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoC-III 3238C>G was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Interactions of the ApoC-III 3238C>G genotype and alcohol consumption was assessed by using a cross-product term between genotypes and the aforementioned factor. RESULTS: Serum total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C), ApoA-I and ApoB levels were higher in drinkers than in nondrinkers (P < 0.05-0.001). There was no significant difference in the genotypic and allelic frequencies between the two groups. Serum TG levels in nondrinkers were higher in CG genotype than in CC genotype (P < 0.01). Serum TC, TG, low-density lipoprotein cholesterol (LDL-C) and ApoB levels in drinkers were higher in GG genotype than in CC or CG genotype (P < 0.01 for all). Serum HDL-C levels in drinkers were higher in CG genotype than in CC genotype (P < 0.01). Serum TC, TG, HDL-C and ApoA-I levels in CC genotype, TC, HDL-C, ApoA-I levels and the ratio of ApoA-I to ApoB in CG genotype, and TC, TG, LDL-C, ApoA-I and ApoB levels in GG genotype were higher in drinkers than in nondrinkers (P < 0.05 0.01). But the ratio of ApoA-I to ApoB in GG genotype was lower in drinkers than in nondrinkers (P < 0.01). Multivariate logistic regression analysis showed that the levels of TC, TG and ApoB were correlated with genotype in nondrinkers (P < 0.05 for all). The levels of TC, LDL-C and ApoB were associated with genotype in drinkers (P < 0.01 for all). Serum lipid parameters were also correlated with age, sex, alcohol consumption, cigarette smoking, blood pressure, body weight, and body mass index in both groups. CONCLUSIONS: This study suggests that the ApoC-III 3238CG heterozygotes benefited more from alcohol consumption than CC and GG homozygotes in increasing serum levels of HDL-C, ApoA-I, and the ratio of ApoA I to ApoB, and lowering serum levels of TC and TG. PMID- 20716348 TI - Warwick Hip Trauma Study: a randomised clinical trial comparing interventions to improve outcomes in internally fixed intracapsular fractures of the proximal femur. Protocol for the WHiT Study. AB - BACKGROUND: Controversy exists regarding the optimal treatment for patients with displaced intracapsular fractures of the proximal femur. The recognised treatment alternatives are arthroplasty and internal fixation. The principal criticism of internal fixation is the high rate of non-union; up to 30% of patients will have a failure of the fixation leading to revision surgery. We believe that improved fracture healing may lead to a decreased rate of failure of fixation. We therefore propose to investigate strategies to both accelerate fracture healing and improve fixation that may significantly improve outcomes after internal fixation of intracapsular femoral fractures. We aim to test the clinical effectiveness of the osteoinductive agent platelet rich plasma and conduct a pilot study of a novel fixed-angle fixation system. DESIGN: We have planned a three arm, single centre, standard-of-care controlled, double blinded, pragmatic, randomised clinical trial. The trial will include a standard two-way comparison between platelet-rich plasma and standard-of-care fixation versus standard-of care fixation alone. In addition there will be a subsidiary pilot arm testing a fixed-angle screw and plate fixation system. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49197425. PMID- 20716349 TI - Ultrastructural localization of extracellular matrix proteins of the lymph node cortex: evidence supporting the reticular network as a pathway for lymphocyte migration. AB - BACKGROUND: The lymph node (LN) is a crossroads of blood and lymphatic vessels allowing circulating lymphocytes to efficiently recognize foreign molecules displayed on antigen presenting cells. Increasing evidence indicates that after crossing high endothelial venules, lymphocytes migrate within the node along the reticular network (RN), a scaffold of fibers enwrapped by fibroblastic reticular cells (FRC). Light microscopy has shown that the RN contains specific extracellular matrix (ECM) proteins, which are putative molecular "footholds" for migration, and are known ligands for lymphocyte integrin adhesion receptors. RESULTS: To investigate whether ECM proteins of the RN are present on the outer surface of the FRC and are thus accessible to migrating lymphocytes, ultrastructural immunohistochemical staining of cynomolgus monkey LN was performed using antibodies to human ECM proteins that were successfully employed at the light microscopic level. The fibrillar collagens I and III were observed primarily within the reticular network fibers themselves. In contrast, the matrix proteins laminin, fibronectin, collagen IV, and tenascin were observed within the reticular fibers and also on the outer membrane surface of the FRC. CONCLUSIONS: These findings suggest a molecular basis for how the RN functions as a pathway for lymphocyte migration within the lymph node. PMID- 20716350 TI - Gill transcriptome response to changes in environmental calcium in the green spotted puffer fish. AB - BACKGROUND: Calcium ion is tightly regulated in body fluids and for euryhaline fish, which are exposed to rapid changes in environmental [Ca2+], homeostasis is especially challenging. The gill is the main organ of active calcium uptake and therefore plays a crucial role in the maintenance of calcium ion homeostasis. To study the molecular basis of the short-term responses to changing calcium availability, the whole gill transcriptome obtained by Super Serial Analysis of Gene Expression (SuperSAGE) of the euryhaline teleost green spotted puffer fish, Tetraodon nigroviridis, exposed to water with altered [Ca2+] was analysed. RESULTS: Transfer of T. nigroviridis from 10 ppt water salinity containing 2.9 mM Ca2+ to high (10 mM Ca2+ ) and low (0.01 mM Ca2+) calcium water of similar salinity for 2-12 h resulted in 1,339 differentially expressed SuperSAGE tags (26 bp transcript identifiers) in gills. Of these 869 tags (65%) were mapped to T. nigroviridis cDNAs or genomic DNA and 497 (57%) were assigned to known proteins. Thirteen percent of the genes matched multiple tags indicating alternative RNA transcripts. The main enriched gene ontology groups belong to Ca2+ signaling/homeostasis but also muscle contraction, cytoskeleton, energy production/homeostasis and tissue remodeling. K-means clustering identified co expressed transcripts with distinct patterns in response to water [Ca2+] and exposure time. CONCLUSIONS: The generated transcript expression patterns provide a framework of novel water calcium-responsive genes in the gill during the initial response after transfer to different [Ca2+]. This molecular response entails initial perception of alterations, activation of signaling networks and effectors and suggests active remodeling of cytoskeletal proteins during the initial acclimation process. Genes related to energy production and energy homeostasis are also up-regulated, probably reflecting the increased energetic needs of the acclimation response. This study is the first genome-wide transcriptome analysis of fish gills and is an important resource for future research on the short-term mechanisms involved in the gill acclimation responses to environmental Ca2+ changes and osmoregulation. PMID- 20716352 TI - Perinatal mortality in rural Burkina Faso: a prospective community-based cohort study. AB - BACKGROUND: There is a scarcity of reliable data on perinatal mortality (PNM) in Sub-Saharan Africa. The PROMISE-EBF trial, during which we promoted exclusive breastfeeding, gave us the opportunity to describe the epidemiology of PNM in Banfora Health District, South-West in Burkina Faso. STUDY OBJECTIVES: To measure the perinatal mortality rate (PNMR) in the PROMISE-EBF cohort in Banfora Health District and to identify potential risk factors for perinatal death. METHODS: We used data collected prospectively during the PROMISE-EBF-trial to estimate the stillbirth rate (SBR) and early neonatal mortality rate (ENMR). We used binomial regression with generalized estimating equations to identify potential risk factors for perinatal death. RESULTS: 895 pregnant women were enrolled for data collection in the EBF trial and followed-up to 7 days after birth. The PNMR, the SBR and the ENMR, were 79 per 1000 (95% CI: 59-99), 54 per 1000 (95% CI: 38-69) and 27 per 1000 (95% CI: 9-44), respectively. In a multivariable analysis, nulliparous women (RR = 2.90, 95% CI: 1.6-5.0), primiparae mothers (RR = 2.20, 95% CI: 1.2-3.9), twins (RR = 4.0, 95% CI: 2.3-6.9) and giving birth during the dry season (RR = 2.1 95% CI: 1.3-3.3) were factors associated with increased risk of perinatal death. There was no evidence that risk of perinatal death differed between deliveries at home and at a health centre CONCLUSION: Our study observed the highest PNMR ever reported in Burkina. There is an urgent need for sustainable interventions to improve maternal and newborn health in the country. PMID- 20716351 TI - Indicators of "healthy aging" in older women (65-69 years of age). A data-mining approach based on prediction of long-term survival. AB - BACKGROUND: Prediction of long-term survival in healthy adults requires recognition of features that serve as early indicators of successful aging. The aims of this study were to identify predictors of long-term survival in older women and to develop a multivariable model based upon longitudinal data from the Study of Osteoporotic Fractures (SOF). METHODS: We considered only the youngest subjects (n = 4,097) enrolled in the SOF cohort (65 to 69 years of age) and excluded older SOF subjects more likely to exhibit a "frail" phenotype. A total of 377 phenotypic measures were screened to determine which were of most value for prediction of long-term (19-year) survival. Prognostic capacity of individual predictors, and combinations of predictors, was evaluated using a cross validation criterion with prediction accuracy assessed according to time-specific AUC statistics. RESULTS: Visual contrast sensitivity score was among the top 5 individual predictors relative to all 377 variables evaluated (mean AUC = 0.570). A 13-variable model with strong predictive performance was generated using a forward search strategy (mean AUC = 0.673). Variables within this model included a measure of physical function, smoking and diabetes status, self-reported health, contrast sensitivity, and functional status indices reflecting cumulative number of daily living impairments (HR >or= 0.879 or RH or =2 was considered normal CFR. RESULTS: Coronary arteriography revealed patency of both branches of Y-G after six months. Accuracy of TTE was 100% for LAD and 85% for LCx. Feasibility was 100% for LAD and 85% for LCx. CFR improved from baseline in LAD (2.21 +/- 0.5 to 2.6 +/- 0.5, p = 0.03) and in LCx (1.7 +/- 1 to 2.12 +/- 1, p = 0.05). CFR was under normal at baseline in 30% of patients vs 8% after six months in LAD (p = 0.027), and in 69% of patients vs 30% after six months in LCx (p = 0.066). CONCLUSION: CFR in Y-G is sometimes reduced in both left territories postoperatively but it improves at six months follow-up. A follow-up can be done non-invasively by TTE and CFR evaluation. PMID- 20716358 TI - Weighted bootstrapping: a correction method for assessing the robustness of phylogenetic trees. AB - BACKGROUND: Non-parametric bootstrapping is a widely-used statistical procedure for assessing confidence of model parameters based on the empirical distribution of the observed data 1 and, as such, it has become a common method for assessing tree confidence in phylogenetics 2. Traditional non-parametric bootstrapping does not weigh each tree inferred from resampled (i.e., pseudo-replicated) sequences. Hence, the quality of these trees is not taken into account when computing bootstrap scores associated with the clades of the original phylogeny. As a consequence, traditionally, the trees with different bootstrap support or those providing a different fit to the corresponding pseudo-replicated sequences (the fit quality can be expressed through the LS, ML or parsimony score) contribute in the same way to the computation of the bootstrap support of the original phylogeny. RESULTS: In this article, we discuss the idea of applying weighted bootstrapping to phylogenetic reconstruction by weighting each phylogeny inferred from resampled sequences. Tree weights can be based either on the least-squares (LS) tree estimate or on the average secondary bootstrap score (SBS) associated with each resampled tree. Secondary bootstrapping consists of the estimation of bootstrap scores of the trees inferred from resampled data. The LS and SBS-based bootstrapping procedures were designed to take into account the quality of each "pseudo-replicated" phylogeny in the final tree estimation. A simulation study was carried out to evaluate the performances of the five weighting strategies which are as follows: LS and SBS-based bootstrapping, LS and SBS-based bootstrapping with data normalization and the traditional unweighted bootstrapping. CONCLUSIONS: The simulations conducted with two real data sets and the five weighting strategies suggest that the SBS-based bootstrapping with the data normalization usually exhibits larger bootstrap scores and a higher robustness compared to the four other competing strategies, including the traditional bootstrapping. The high robustness of the normalized SBS could be particularly useful in situations where observed sequences have been affected by noise or have undergone massive insertion or deletion events. The results provided by the four other strategies were very similar regardless the noise level, thus also demonstrating the stability of the traditional bootstrapping method. PMID- 20716359 TI - Characterization of antibodies elicited by XMRV infection and development of immunoassays useful for epidemiologic studies. AB - BACKGROUND: Xenotropic Murine Leukemia Virus-related Virus (XMRV) is a human gammaretrovirus recently identified in prostate cancer tissue and in lymphocytes of patients with chronic fatigue syndrome. To establish the etiologic role of XMRV infection in human disease requires large scale epidemiologic studies. Development of assays to detect XMRV-specific antibodies would greatly facilitate such studies. However, the nature and kinetics of the antibody response to XMRV infection have yet to be determined. RESULTS: Three rhesus macaques were infected with XMRV to determine the dynamics of the antibody responses elicited by infection with XMRV. All macaques developed antibodies to XMRV during the second week of infection, and the predominant responses were to the envelope protein gp70, transmembrane protein p15E, and capsid protein p30. In general, antibody responses to gp70 and p15E appeared early with higher titers than to p30, especially in the early period of seroconversion. Antibodies to gp70, p15E and p30 persisted to 158 days and were substantially boosted by re-infection, thus, were identified as useful serologic markers. Three high-throughput prototype assays were developed using recombinant proteins to detect antibodies to these viral proteins. Both gp70 and p15E prototype assays demonstrated 100% sensitivity by detecting all Western blot (WB) positive serial bleeds from the XMRV-infected macaques and good specificity (99.5-99.9%) with blood donors. Seroconversion sensitivity and specificity of the p30 prototype assay were 92% and 99.4% respectively. CONCLUSIONS: This study provides the first demonstration of seroconversion patterns elicited by XMRV infection. The nature and kinetics of antibody responses to XMRV in primates were fully characterized. Moreover, key serologic markers useful for detection of XMRV infection were identified. Three prototype immunoassays were developed to detect XMRV-specific antibodies. These assays demonstrated good sensitivity and specificity; thus, they will facilitate large scale epidemiologic studies of XMRV infection in humans. PMID- 20716360 TI - A novel approach to modelling water transport and drug diffusion through the stratum corneum. AB - BACKGROUND: The potential of using skin as an alternative path for systemically administering active drugs has attracted considerable interest, since the creation of novel drugs capable of diffusing through the skin would provide a great step towards easily applicable -and more humane- therapeutic solutions. However, for drugs to be able to diffuse, they necessarily have to cross a permeability barrier: the stratum corneum (SC), the uppermost set of skin layers. The precise mechanism by which drugs penetrate the skin is generally thought to be diffusion of molecules through this set of layers following a "tortuous pathway" around corneocytes, i.e. impermeable dead cells. RESULTS: In this work, we simulate water transport and drug diffusion using a three-dimensional porous media model. Our numerical simulations show that diffusion takes place through the SC regardless of the direction and magnitude of the fluid pressure gradient, while the magnitude of the concentrations calculated are consistent with experimental studies. CONCLUSIONS: Our results support the possibility for designing arbitrary drugs capable of diffusing through the skin, the time delivery of which is solely restricted by their diffusion and solubility properties. PMID- 20716361 TI - Systematic Review of topotecan (Hycamtin) in relapsed small cell lung cancer. AB - BACKGROUND: To undertake a systematic review of the available data for oral and intravenous topotecan in adults with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first line regimen is not considered appropriate. METHODS: We searched six databases from 1980 up to March 2009 for relevant trials regardless of language or publication status. Relevant studies included any randomised trial of any chemotherapeutic treatment against any comparator in this licensed indication. Where possible we used opposite quantitative methods. Where meta-analysis was considered unsuitable for some or all of the data, we employed a narrative synthesis method. For indirect comparisons we used the method of Bucher et al., where available data allowed it, otherwise we used narrative descriptions. RESULTS: Seven unique studies met the inclusion criteria, four of which could be used in our analyses. These included one study comparing oral topotecan plus best supportive care (BSC) to BSC alone, one study comparing intravenous topotecan to cyclophosphamide, adriamycin and vincristine (CAV), and two studies comparing oral topotecan with intravenous topotecan. All four studies appear to be well conducted and with low risk of bias. Oral topotecan plus BSC has advantages over BSC alone in terms of survival (hazard ratio = 0.61; 95% CI, 0.43 to 0.87) and quality of life (EQ-5 D difference: 0.15; 95% CI, 0.05 to 0.25). Intravenous topotecan was at least as effective as CAV in the treatment of patients with recurrent small-cell lung cancer and resulted in improved quality of-life with respect to several symptoms. CAV was associated with significantly less grade 4 thrombocytopenia compared with IV topotecan (risk ratio = 5.83; 95% CI, 2.35 to 14.42). Survival (hazard ratio = 0.98; 95% CI, 0.77 to 1.25) and response (pooled risk ratio = 1.04; 95% CI, 0.58 to 1.85) data were similar for the oral and IV topotecan groups. Symptom control was also very similar between the trials and between the oral and IV groups. Toxicity data showed a significant difference in favour of oral topotecan for neutropenia (pooled risk ratio = 0.65; 95% CI, 0.47 to 0.89). Indirect evidence showed that oral topotecan was at least as good as or better than CAV on all outcomes (survival, response rates, toxicities, and symptoms) that allowed indirect comparisons, with the only exception being grade four thrombocytopenia which occurred less often on CAV treatment. CONCLUSIONS: Concerning topotecan both the oral and intravenous options have similar efficacy, and patient preference may be a decisive factor if the choice would be between the two formulations. The best trial evidence for decision making, because it was tested versus best supportive care, exists for oral topotecan. Indirectly, because we have two head-to-head comparisons of oral versus intravenous topotecan, and one comparison of intravenous topotecan versus CAV in similar patients as in the trial against best supportive care, one might infer that IV topotecan and CAV could also be superior to best supportive care, and that oral topotecan has similar effects to CAV with possibly better symptom control. From the evidence discussed above, it is evident that oral topotecan has similar efficacy to IV topotecan (direct comparison) and CAV (indirect comparison). There is no further evidence base of direct or possible indirect comparisons for other comparators than CAV of either oral or IV topotecan. PMID- 20716362 TI - Effect of different intravenous iron preparations on lymphocyte intracellular reactive oxygen species generation and subpopulation survival. AB - BACKGROUND: Infections in hemodialysis (HD) patients lead to high morbidity and mortality rates and are associated with early cardiovascular mortality, possibly related to chronic inflammation. Intravenous (IV) iron is widely administered to HD patients and has been associated with increased oxidative stress and dysfunctional cellular immunity. The purpose of this study was to examine the effect of three commercially available IV iron preparations on intracellular reactive oxygen species generation and lymphocyte subpopulation survival. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from healthy donor buffy coat. PBMC were cultured and incubated with 100 microg/mL of sodium ferric gluconate (SFG), iron sucrose (IS) or iron dextran (ID) for 24 hours. Cells were then probed for reactive oxygen species (ROS) with dichlorofluorescein diacetate. In separate studies, isolated PBMCs were incubated with the 25, 50 or 100 microg/mL iron concentrations for 72 hours and then stained with fluorescein conjugated monoclonal antibodies for lymphocyte subpopulation identification. Untreated PBMCs at 24 hours and 72 hours served as controls for each experiment. RESULTS: All three IV iron preparations induced time dependent increases in intracellular ROS with SFG and IS having a greater maximal effect than ID. The CD4+ lymphocytes were most affected by IV iron exposure, with statistically significant reduction in survival after incubation with all three doses (10, 25 and 100 microg/mL) of SFG, IS and ID. CONCLUSION: These data indicate IV iron products induce differential deleterious effects on CD4+ and CD16+ human lymphocytes cell populations that may be mediated by intracellular reactive oxygen species generation. Further studies are warranted to determine the potential clinical relevance of these findings. PMID- 20716363 TI - Correlation of NF-kappaB signal pathway with tumor metastasis of human head and neck squamous cell carcinoma. AB - BACKGROUND: Nuclear factor-kappa B (NF-kappaB) signaling constitutes a key event in the multistep process of carcinogenesis, progression and treatment in many cancer types. However, the significance of NF-kappaB pathway for complex and tissue-specific aspects of head and neck cancer progression, such as invasion and metastasis, is less understood. METHODS: The expression of NF-kappaB p65 in squamous cell carcinoma of the head and neck (SCCHN) clinical specimens by immunohistochemistry. The role of NF-kappaB activity in head and neck squamous cell carcinoma was determined by western blot, reporter assay and EMSA analysis in vitro and metastasis assays in vivo in different metastatic potential tumor cells. Furthermore, the apoptosis rate and expression of metastasis-related protein such as MMP9 and VEGF were examined by Annexin V/PI staining and Western blot, respectively. RESULTS: A higher level of active nuclear-localized NF-kappaB was observed in the metastatic SCCHN specimens group (p < 0.01). The NF-kappaB activities of SCCHN cell lines with different metastatic potentials were then determined and in excellent agreement with results found in SCCHN specimens, highly metastatic SCCHN cell lines expressed high level of NF-kappaB activity. The treatment of highly metastatic SCCHN cells with NF-kappaB inhibitors reduced the in vitro cell invasion capacity of the cells without affecting the apoptotic rate. Additionally, the NF-kappaB inhibitors significantly inhibited the experimental lung metastasis of Tb cells and lymph node metastasis of TL cells in nude mice. Furthermore, the expression of metastasis-related proteins, such as matrix metalloproteinase 9 and vascular endothelial growth factor, was inhibited by pyrrolidine dithiocarbonate. CONCLUSIONS: This study suggests that NF-kappaB activity significantly contributes to tumor hematologic and lymphatic metastases and may aid in the development of early detection methods or therapies targeting non-conventional molecular targets. PMID- 20716364 TI - EF1alpha and RPL13a represent normalization genes suitable for RT-qPCR analysis of bone marrow derived mesenchymal stem cells. AB - BACKGROUND: RT-qPCR analysis is a widely used method for the analysis of mRNA expression throughout the field of mesenchymal stromal cell (MSC) research. Comparison between MSC studies, both in vitro and in vivo, are challenging due to the varied methods of RT-qPCR data normalization and analysis. Therefore, this study focuses on putative housekeeping genes for the normalization of RT-qPCR data between heterogeneous commercially available human MSC, compared with more homogeneous populations of MSC such as MIAMI and RS-1 cells. RESULTS: Eight genes including; ACTB, B2M, EF1alpha, GAPDH, RPL13a, YWHAZ, UBC and HPRT1 were tested as possible housekeeping genes based on their expression level and variability. EF1alpha and RPL13a were validated for RT-qPCR analysis of MIAMI cells during expansion in varied oxygen tensions, endothelial differentiation, neural precursor enrichment, and during the comparison with RS-1 cells and commercially available MSC. RPL13a and YWHAZ were validated as normalization genes for the cross-species analysis of MIAMI cells in an animal model of focal ischemia. GAPDH, which is one of the most common housekeeping genes used for the normalization of RT-qPCR data in the field of MSC research, was found to have the highest variability and deemed not suitable for normalization of RT-qPCR data. CONCLUSIONS: In order to make comparisons between heterogeneous MSC populations, as well as adult stem cell like MSC which are used in different laboratories throughout the world, it is important to have a standardized, reproducible set of housekeeping genes for RT-qPCR analysis. In this study we demonstrate that EF1alpha, RPL13a and YWHAZ are suitable genes for the RT-qPCR analysis and comparison of several sources of human MSC during in vitro characterization and differentiation as well as in an ex vivo animal model of global cerebral ischemia. This will allow for the comparative RT-qPCR analysis of multiple MSC populations with the goal of future use in animal models of disease as well as tissue repair. PMID- 20716365 TI - Combination of genomic approaches with functional genetic experiments reveals two modes of repression of yeast middle-phase meiosis genes. AB - BACKGROUND: Regulation of meiosis and sporulation in Saccharomyces cerevisiae is a model for a highly regulated developmental process. Meiosis middle phase transcriptional regulation is governed by two transcription factors: the activator Ndt80 and the repressor Sum1. It has been suggested that the competition between Ndt80 and Sum1 determines the temporal expression of their targets during middle meiosis. RESULTS: Using a combination of ChIP-on-chip and expression profiling, we characterized a middle phase transcriptional network and studied the relationship between Ndt80 and Sum1 during middle and late meiosis. While finding a group of genes regulated by both factors in a feed forward loop regulatory motif, our data also revealed a large group of genes regulated solely by Ndt80. Measuring the expression of all Ndt80 target genes in various genetic backgrounds (WT, sum1Delta and MK-ER-Ndt80 strains), allowed us to dissect the exact transcriptional network regulating each gene, which was frequently different than the one inferred from the binding data alone. CONCLUSION: These results highlight the need to perform detailed genetic experiments to determine the relative contribution of interactions in transcriptional regulatory networks. PMID- 20716366 TI - TOPSAN: a collaborative annotation environment for structural genomics. AB - BACKGROUND: Many protein structures determined in high-throughput structural genomics centers, despite their significant novelty and importance, are available only as PDB depositions and are not accompanied by a peer-reviewed manuscript. Because of this they are not accessible by the standard tools of literature searches, remaining underutilized by the broad biological community. RESULTS: To address this issue we have developed TOPSAN, The Open Protein Structure Annotation Network, a web-based platform that combines the openness of the wiki model with the quality control of scientific communication. TOPSAN enables research collaborations and scientific dialogue among globally distributed participants, the results of which are reviewed by experts and eventually validated by peer review. The immediate goal of TOPSAN is to harness the combined experience, knowledge, and data from such collaborations in order to enhance the impact of the astonishing number and diversity of structures being determined by structural genomics centers and high-throughput structural biology. CONCLUSIONS: TOPSAN combines features of automated annotation databases and formal, peer reviewed scientific research literature, providing an ideal vehicle to bridge a gap between rapidly accumulating data from high-throughput technologies and a much slower pace for its analysis and integration with other, relevant research. PMID- 20716367 TI - Intrapleural instillation of autologous blood for persistent air leak in spontaneous pneumothorax- is it as effective as it is safe? AB - OBJECTIVE: The aim of the present study was to evaluate the efficacy of autologous blood pleurodesis in the management of persistent air leak in spontaneous pneumothorax. PATIENTS AND METHODS: A number of 15 patients (10 male and 5 female) were included in this prospective study between March 2005 and December 2009. The duration of the air leak exceeded 7 days in all patients. The application of blood pleurodesis was used as the last preoperative conservative method of treatment in 12 patients. One patient refused surgery and two were ineligible for operation due to their comorbidities. A blood sample of 50 ml was obtained from the patient's femoral vein and immediately introduced into the chest tube. RESULTS: A success rate of 27% was observed having the air leak sealed in 4 patients in less than 24 hours. CONCLUSION: Despite our disappointingly poor outcome, the authors believe that the procedure's safety, convenience and low cost establish it as a worth trying method of conservative treatment for patients with the aforementioned pathology for whom no other alternative than surgery would be a choice. PMID- 20716368 TI - Postresectional lung injury in thoracic surgery pre and intraoperative risk factors: a retrospective clinical study of a hundred forty-three cases. AB - INTRODUCTION: Acute respiratory dysfunction syndrome (ARDS), defined as acute hypoxemia accompanied by radiographic pulmonary infiltrates without a clearly identifiable cause, is a major cause of morbidity and mortality after pulmonary resection. The aim of the study was to determine the pre and intraoperative factors associated with ARDS after pulmonary resection retrospectively. METHODS: Patients undergoing elective pulmonary resection at Adnan Menderes University Medical Faculty Thoracic Surgery Department from January 2005 to February 2010 were included in this retrospective study. The authors collected data on demographics, relevant co-morbidities, the American Society of Anesthesiologists (ASA) Physical Status classification score, pulmonary function tests, type of operation, duration of surgery and intraoperative fluid administration (fluid therapy and blood products). The primary outcome measure was postoperative ARDS, defined as the need for continuation of mechanical ventilation for greater than 48-hours postoperatively or the need for reinstitution of mechanical ventilation after extubation. Statistical analysis was performed with Fisher exact test for categorical variables and logistic regression analysis for continuous variables. RESULTS: Of one hundred forty-three pulmonary resection patients, 11 (7.5%) developed postoperative ARDS. Alcohol abuse (p = 0.01, OR = 39.6), ASA score (p = 0.001, OR: 1257.3), resection type (p = 0.032, OR = 28.6) and fresh frozen plasma (FFP)(p = 0.027, OR = 1.4) were the factors found to be statistically significant. CONCLUSION: In the light of the current study, lung injury after lung resection has a high mortality. Preoperative and postoperative risk factor were significant predictors of postoperative lung injury. PMID- 20716369 TI - Longitudinally and circumferentially directed movements of the left ventricle studied by cardiovascular magnetic resonance phase contrast velocity mapping. AB - OBJECTIVE: Using high resolution cardiovascular magnetic resonance (CMR), we aimed to detect new details of left ventricular (LV) systolic and diastolic function, to explain the twisting and longitudinal movements of the left ventricle. METHODS: Using CMR phase contrast velocity mapping (also called Tissue Phase Mapping) regional wall motion patterns and longitudinally and circumferentially directed movements of the left ventricle were studied using a high temporal resolution technique in healthy male subjects (n = 14, age 23 +/- 3 years). RESULTS: Previously undescribed systolic and diastolic motion patterns were obtained for left ventricular segments (based on the AHA segmental) and for basal, mid and apical segments. The summation of segmental motion results in a complex pattern of ventricular twisting and longitudinal motion in the normal human heart which underlies systolic and diastolic function. As viewed from the apex, the entire LV initially rotates in a counter-clockwise direction at the beginning of ventricular systole, followed by opposing clockwise rotation of the base and counter-clockwise rotation at the apex, resulting in ventricular torsion. Simultaneously, as the entire LV moves in an apical direction during systole, the base and apex move towards each other, with little net apical displacement. The reverse of these motion patterns occur in diastole. CONCLUSION: Left ventricular function may be a consequence of the relative orientations and moments of torque of the sub-epicardial relative to the sub-endocardial myocyte layers, with influence from tethering of the heart to adjacent structures and the directional forces associated with blood flow. Understanding the complex mechanics of the left ventricle is vital to enable these techniques to be used for the evaluation of cardiac pathology. PMID- 20716370 TI - Aphid reproductive investment in response to mortality risks. AB - BACKGROUND: Aphids are striking in their prodigious reproductive capacity and reliance on microbial endosymbionts, which provision their hosts with necessary amino acids and provide protection against parasites and heat stress. Perhaps as a result of this bacterial dependence, aphids have limited immune function that may leave them vulnerable to bacterial pathogens. An alternative, non immunological response that may be available to infected aphids is to increase reproduction, thereby ameliorating fitness loss from infection. Such a response would reduce the need to mount a potentially energetically costly immune response, and would parallel that of other hosts that alter life-history traits when there is a risk of infection. Here we examined whether pea aphids (Acyrthosiphon pisum) respond to immunological challenges by increasing reproduction. As a comparison to the response to the internal cue of risk elicited by immunological challenge, we also exposed pea aphids to an external cue of risk--the aphid alarm pheromone (E)-beta-farnesene (EBF), which is released in the presence of predators. For each challenge, we also examined whether the presence of symbionts modified the host response, as maintaining host fitness in the face of challenge would benefit both the host and its dependent bacteria. RESULTS: We found that aphids stabbed abdominally with a sterile needle had reduced fecundity relative to control aphids but that aphids stabbed with a needle bearing heat-killed bacteria had reproduction intermediate, and statistically indistinguishable, to the aphids stabbed with a sterile needle and the controls. Aphids with different species of facultative symbiotic bacteria had different reproductive patterns overall, but symbionts in general did not alter aphid reproduction in response to bacterial exposure. However, in response to exposure to alarm pheromone, aphids with Hamiltonella defensa or Serratia symbiotica symbiotic infections increased reproduction but those without a facultative symbiont or with Regiella insecticola did not. CONCLUSIONS: Overall, our results suggest that pea aphids are able to increase their reproduction in response to specific cues and that symbiont presence sometimes moderates this response. Such increased reproduction in response to risk of death increases the fitness of both aphids and their vertically transmitted symbionts, and since these organisms have high reproductive capacity, slight increases in reproduction could lead to a very large numerical advantage later in the season. Thus both symbiotic partners can benefit by increasing host fecundity under dangerous conditions. PMID- 20716371 TI - Administration of the GABAA receptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures. Supramammillary picrotoxin and c-Fos expression. AB - BACKGROUND: Picrotoxin blocks GABAA receptors, whose activation typically inhibits neuronal firing activity. We recently found that rats learn to selectively self-administer picrotoxin or bicuculline, another GABAA receptor antagonist, into the supramammillary nucleus (SuM), a posterior hypothalamic structure localized anterior to the ventral tegmental area. Other drugs such as nicotine or the excitatory amino acid AMPA are also self-administered into the SuM. The SuM appears to be functionally linked with the mesolimbic dopamine system and is closely connected with other brain structures that are implicated in motivational processes, including the prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Here, we hypothesized that these brain structures are activated by picrotoxin injections into the SuM. RESULTS: Picrotoxin administration into the SuM markedly facilitated locomotion and rearing. Further, it increased c-Fos expression in this region, suggesting blockade of tonic inhibition and thus the disinhibition of local neurons. This manipulation also increased c-Fos expression in structures including the ventral tegmental area, medial shell of the nucleus accumbens, medial prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. CONCLUSIONS: Picrotoxin administration into the SuM appears to disinhibit local neurons and recruits activation of brain structures associated with motivational processes, including the mesolimbic dopamine system, prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. These regions may be involved in mediating positive motivational effects triggered by intra-SuM picrotoxin. PMID- 20716372 TI - Quality of life in childhood epilepsy with lateralized epileptogenic foci. AB - BACKGROUND: Measuring quality of life (QOL) helps to delineate mechanisms underlying the interaction of disease and psychosocial factors. In adults, epileptic foci in the left temporal lobe led to lower QOL and higher depression and anxiety as compared to the right-sided foci. No study addressed the development of QOL disturbances depending on the lateralization of epileptogenic focus. The objective of our study was to examine QOL in children with lateralized epileptiform discharges. METHODS: Thirty-one parents of children with epilepsy filled the Health-Related Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). Fifteen children had foci in the left hemisphere and sixteen in the right, as verified with Electroencephalography (EEG) examinations. RESULTS: We found a significant correlation between foci lateralization and reduced QOL (Spearman's rho = 0.361, p < 0.046). Children with right hemispheric foci exhibited lower overall QOL, particularly in five areas: anxiety, social activities, stigma, general-health, and quality-of-life. CONCLUSIONS: We demonstrated for the first time that in children left- and right-hemispheric foci were associated with discordant QOL scores. Unlike in adults, foci in the right hemisphere led to worse emotional and social functioning demonstrating that seizures impact the brain differentially during development. PMID- 20716373 TI - Consequences of lower extremity and trunk muscle fatigue on balance and functional tasks in older people: a systematic literature review. AB - BACKGROUND: Muscle fatigue reduces muscle strength and balance control in young people. It is not clear whether fatigue resistance seen in older persons leads to different effects. In order to understand whether muscle fatigue may increase fall risk in older persons, a systematic literature review aimed to summarize knowledge on the effects of lower extremity and trunk muscle fatigue on balance and functional tasks in older people was performed. METHODS: Studies were identified with searches of the PUBMED and SCOPUS data bases.Papers describing effects of lower extremity or trunk muscle fatigue protocols on balance or functional tasks in older people were included. Studies were compared with regards to study population characteristics, fatigue protocol, and balance and functional task outcomes. RESULTS: Seven out of 266 studies met the inclusion criteria. Primary findings were: fatigue via resistance exercises to lower limb and trunk muscles induces postural instability during quiet standing; induced hip, knee and ankle muscle fatigue impairs functional reach, reduces the speed and power of sit-to-stand repetitions, and produces less stable and more variable walking patterns; effects of age on degree of fatigue and rate of recovery from fatigue are inconsistent across studies, with these disparities likely due to differences in the fatigue protocols, study populations and outcome measures. CONCLUSION: Taken together, the findings suggest that balance and functional task performance are impaired with fatigue. Future studies should assess whether fatigue is related to increased risk of falling and whether exercise interventions may decrease fatigue effects. PMID- 20716374 TI - Effect of the carbohydrate counting method on glycemic control in patients with type 1 diabetes. AB - BACKGROUND: The importance of achieving and maintaining an appropriate metabolic control in patients with type 1 diabetes mellitus (DM1) has been established in many studies aiming to prevent the development of chronic complications. The carbohydrate counting method can be recommended as an additional tool in the nutritional treatment of diabetes, allowing patients with DM1 to have more flexible food choices. This study aimed to evaluate the influence of nutrition intervention and the use of multiple short-acting insulin according to the carbohydrate counting method on clinical and metabolic control in patients with DM1. METHODS: Our sample consisted of 51 patients with DM1, 32 females, aged 25.3 +/- 1.55 years. A protocol of nutritional status evaluation was applied and laboratory analysis was performed at baseline and after a three-month intervention. After the analysis of the food records, a balanced diet was prescribed using the carbohydrate counting method, and short-acting insulin was prescribed based on the total amount of carbohydrate per meal (1 unit per 15 g of carbohydrate). RESULTS: A significant decrease in A1c levels was observed from baseline to the three-month evaluation after the intervention (10.40 +/- 0.33% and 9.52 +/- 0.32%, respectively, p = 0.000). It was observed an increase in daily insulin dose after the intervention (0.99 +/- 0.65 IU/Kg and 1.05 +/- 0.05 IU/Kg, respectively, p = 0.003). No significant differences were found regarding anthropometric evaluation (BMI, waist, hip or abdominal circumferences and waist to hip ratio) after the intervention period. CONCLUSIONS: The use of short-acting insulin based on the carbohydrate counting method after a short period of time resulted in a significant improvement of the glycemic control in patients with DM1 with no changes in body weight despite increases in the total daily insulin doses. PMID- 20716375 TI - Characterization and functional analysis of seven flagellin genes in Rhizobium leguminosarum bv. viciae. Characterization of R. leguminosarum flagellins. AB - BACKGROUND: Rhizobium leguminosarum bv. viciae establishes symbiotic nitrogen fixing partnerships with plant species belonging to the Tribe Vicieae, which includes the genera Vicia, Lathyrus, Pisum and Lens. Motility and chemotaxis are important in the ecology of R. leguminosarum to provide a competitive advantage during the early steps of nodulation, but the mechanisms of motility and flagellar assembly remain poorly studied. This paper addresses the role of the seven flagellin genes in producing a functional flagellum. RESULTS: R. leguminosarum strains 3841 and VF39SM have seven flagellin genes (flaA, flaB, flaC, flaD, flaE, flaH, and flaG), which are transcribed separately. The predicted flagellins of 3841 are highly similar or identical to the corresponding flagellins in VF39SM. flaA, flaB, flaC, and flaD are in tandem array and are located in the main flagellar gene cluster. flaH and flaG are located outside of the flagellar/motility region while flaE is plasmid-borne. Five flagellin subunits (FlaA, FlaB, FlaC, FlaE, and FlaG) are highly similar to each other, whereas FlaD and FlaH are more distantly related. All flagellins exhibit conserved amino acid residues at the N- and C-terminal ends and are variable in the central regions. Strain 3841 has 1-3 plain subpolar flagella while strain VF39SM exhibits 4-7 plain peritrichous flagella. Three flagellins (FlaA/B/C) and five flagellins (FlaA/B/C/E/G) were detected by mass spectrometry in the flagellar filaments of strains 3841 and VF39SM, respectively. Mutation of flaA resulted in non-motile VF39SM and extremely reduced motility in 3841. Individual mutations of flaB and flaC resulted in shorter flagellar filaments and consequently reduced swimming and swarming motility for both strains. Mutant VF39SM strains carrying individual mutations in flaD, flaE, flaH, and flaG were not significantly affected in motility and filament morphology. The flagellar filament and the motility of 3841 strains with mutations in flaD and flaG were not significantly affected while flaE and flaH mutants exhibited shortened filaments and reduced swimming motility. CONCLUSION: The results obtained from this study demonstrate that FlaA, FlaB, and FlaC are major components of the flagellar filament while FlaD and FlaG are minor components for R. leguminosarum strains 3841 and VF39SM. We also observed differences between the two strains, wherein FlaE and FlaH appear to be minor components of the flagellar filaments in VF39SM but these flagellin subunits may play more important roles in 3841. This paper also demonstrates that the flagellins of 3841 and VF39SM are possibly glycosylated. PMID- 20716376 TI - Abnormal fetal movements, micrognathia and pulmonary hypoplasia: a case report. Abnormal fetal movements. AB - BACKGROUND: Micrognathia is a facial malformation characterized by mandibular hypoplasia and a small, receding chin that fails to maintain the tongue in a forward position. We previously reported a system of prenatal screening that we developed to identify fetuses with compromised central nervous system function by observing fetal behavior. In this paper we report the case of a preterm infant with micrognathia and pulmonary hypoplasia who presented abnormal fetal movements. CASE PRESENTATION: A 27-year-old Japanese primigravida at 33 weeks of gestation was referred to our hospital. Ultrasonographic examination revealed clinical polyhydramnios. Micrognathia was evident on midsagittal and 3 D scan. The lung area was less than the mean -2.0 standard deviations for the gestational age. The infant had mandibular hypoplasia and glossoptosis. After emergency cesarean delivery for non-reasuring fetal status, required immediate tracheostomy and cardiopulmonary resuscitation with mechanical ventilatory support. However, the infant's cardiopulmonary condition did not improve and she died 21 hours after birth. CONCLUSIONS: The findings of our ultrasound exam are suggestive of brain dysfunction. The observation of fetal behavior appears to be effective for the prediction of prognosis of cases with micrognathia. PMID- 20716377 TI - Prevalence and correlates of physical disability and functional limitation among community dwelling older people in rural Malaysia, a middle income country. AB - BACKGROUND: The prevalence and correlates of physical disability and functional limitation among older people have been studied in many developed countries but not in a middle income country such as Malaysia. The present study investigated the epidemiology of physical disability and functional limitation among older people in Malaysia and compares findings to other countries. METHODS: A population-based cross sectional study was conducted in Alor Gajah, Malacca. Seven hundred and sixty five older people aged 60 years and above underwent tests of functional limitation (Tinetti Performance Oriented Mobility Assessment Tool). Data were also collected for self reported activities of daily living (ADL) using the Barthel Index (ten items). To compare prevalence with other studies, ADL disability was also defined using six basic ADL's (eating, bathing, dressing, transferring, toileting and walking) and five basic ADL's (eating, bathing, dressing, transferring and toileting). RESULTS: Ten, six and five basic ADL disability was reported by 24.7% (95% CI 21.6-27.9), 14.4% (95% CI 11.9-17.2) and 10.6% (95% CI 8.5-13.1), respectively. Functional limitation was found in 19.5% (95% CI 16.8-22.5) of participants. Variables independently associated with 10 item ADL disability physical disability, were advanced age (> or = 75 years: prevalence ratio (PR) 7.9; 95% CI 4.8-12.9), presence of diabetes (PR 1.8; 95% CI 1.4-2.3), stroke (PR 1.5; 95% CI 1.1-2.2), depressive symptomology (PR 1.3; 95% CI 1.1-1.8) and visual impairment (blind: PR 2.0; 95% CI 1.1-3.6). Advancing age (> or = 75 years: PR 3.0; 95% CI 1.7-5.2) being female (PR 2.7; 95% CI 1.2-6.1), presence of arthritis (PR 1.6; 95% CI 1.2-2.1) and depressive symptomology (PR 2.0; 95% CI 1.5-2.7) were significantly associated with functional limitation. CONCLUSIONS: The prevalence of physical disability and functional limitation among older Malaysians appears to be much higher than in developed countries but is comparable to developing countries. Associations with socio-demographic and other health related variables were consistent with other studies. PMID- 20716378 TI - Assessing the association of the HNF1A G319S variant with C-reactive protein in Aboriginal Canadians: a population-based epidemiological study. AB - BACKGROUND: C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased risk of developing cardiovascular disease. Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1alpha have been associated with plasma CRP in predominantly European Caucasian samples. HNF1A might therefore have an impact on vascular disease and diabetes risk that is mediated by CRP. In an Aboriginal Canadian population, a private polymorphism, HNF1A G319S, was associated with increased prevalence of type 2 diabetes. However, it has not been investigated whether this association is mediated by CRP. We aimed to investigate whether CRP was mediating the association between HNF1A G319S and type 2 diabetes in an Aboriginal Canadian population with a high prevalence of diabetes. METHODS: A total of 718 individuals who participated in a diabetes prevalence and risk factor survey were included in the current analysis. Participants were genotyped for HNF1A G319S. Fasting plasma samples were analyzed for CRP. Fasting plasma glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes. RESULTS: The prevalence rate of type 2 diabetes was 17.4% (125/718) using the 1999 World Health Organization definition and was higher among S319 allele carriers compared to G/G homozygotes (p < 0.0001). Among participants without type 2 diabetes, CRP levels were higher among G/G homozygotes (1.64 [95% confidence interval 1.35-2.00] mg/l) than in S319 carriers (1.26 [1.04-1.54] mg/l) (p = 0.009) after adjustment for age, sex, 2-h post-load glucose, waist circumference, and serum amyloid A. CRP levels were elevated among those with diabetes after similar adjustment (4.39 [95% confidence interval 3.09-6.23] and 4.44 [3.13-6.30] mg/L, respectively), and no significant difference in CRP was observed between S319 carriers and non-carriers (p = 0.95). CONCLUSIONS: CRP levels were lower in S319 allele carriers of the HNF1A gene compared to non-carriers among individuals without diabetes, but this difference was not present among those with diabetes, who uniformly had elevated CRP levels. Therefore, while HNF1A appears to influence CRP concentrations in the non diabetic state, chronic elevation of CRP is unlikely mediating the association between the HNF1A polymorphism and the high prevalence of type 2 diabetes in this Aboriginal population. PMID- 20716379 TI - Relationship of body mass index to percent body fat and waist circumference among schoolchildren in Japan--the influence of gender and obesity: a population-based cross-sectional study. AB - BACKGROUND: Although the correlation coefficient between body mass index (BMI) and percent body fat (%BF) or waist circumference (WC) has been reported, studies conducted among population-based schoolchildren to date have been limited in Japan, where %BF and WC are not usually measured in annual health examinations at elementary schools or junior high schools. The aim of the present study was to investigate the relationship of BMI to %BF and WC and to examine the influence of gender and obesity on these relationships among Japanese schoolchildren. METHODS: Subjects included 3,750 schoolchildren from the fourth and seventh grade in Ina town, Saitama Prefecture, Japan between 2004 and 2008. Information about subject's age, sex, height, weight, %BF, and WC was collected from annual physical examinations. %BF was measured with a bipedal biometrical impedance analysis device. Obesity was defined by the following two criteria: the obese definition of the Centers for Disease Control and Prevention, and the definition of obesity for Japanese children. Pearson's correlation coefficients between BMI and %BF or WC were calculated separately for sex. RESULTS: Among fourth graders, the correlation coefficients between BMI and %BF were 0.74 for boys and 0.97 for girls, whereas those between BMI and WC were 0.94 for boys and 0.90 for girls. Similar results were observed in the analysis of seventh graders. The correlation coefficient between BMI and %BF varied by physique (obese or non-obese), with weaker correlations among the obese regardless of the definition of obesity; most correlation coefficients among obese boys were less than 0.5, whereas most correlations among obese girls were more than 0.7. On the other hand, the correlation coefficients between BMI and WC were more than 0.8 among boys and almost all coefficients were more than 0.7 among girls, regardless of physique. CONCLUSIONS: BMI was positively correlated with %BF and WC among Japanese schoolchildren. The correlations could be influenced by obesity as well as by gender. Accordingly, it is essential to consider gender and obesity when using BMI as a surrogate for %BF and WC for epidemiological use. PMID- 20716380 TI - Prevalence and barriers to HIV testing among mothers at a tertiary care hospital in Phnom Penh, Cambodia. Barriers to HIV testing in Phnom Penh, Cambodia. AB - BACKGROUND: One-third of all new HIV infections in Cambodia are estimated to be due to mother-to-child transmission. Although the Ministry of Health adopted a policy of provider-initiated HIV testing and counseling (PITC), nearly a quarter of pregnant mothers were not tested in 2007. Greater acceptance of HIV testing is a challenge despite Cambodia's adoption of the PITC policy. METHODS: A hospital based quantitative and cross-sectional survey was conducted to assess the prevalence of and barriers to HIV testing among mothers after delivery at the National Maternal and Child Health Center in Phnom Penh. The Center is one of the largest maternal and child care hospitals in the country to offer PITC services. All 600 eligible mothers who were admitted to the hospital after delivery from October to December 2007 were approached and recruited. Data were collected via a semi-structured questionnaire. RESULTS: The prevalence of HIV testing among women who delivered at the hospital was 76%. In multivariate logistic regression, factors such as the perceived need to obtain a partner's permission to be tested (OR=0.27, 95% CI=0.14-0.51, p<0.01), the lack of knowledge about HIV prevention and treatment (OR=0.38, CI=0.22-0.66, p<0.01), and the lack of access to ANC services (OR=0.35, 95% CI=0.21-0.58, p<0.01) were found to be the main barriers to HIV testing. CONCLUSION: To achieve greater acceptance of HIV testing, counseling on HIV prevention and treatment must be provided not only to mothers but also to their partners. In addition, utilization of non-laboratory staff such as midwives to provide HIV testing services in rural health facilities could lead to the greater acceptance of HIV testing. PMID- 20716381 TI - An adaptive optimal ensemble classifier via bagging and rank aggregation with applications to high dimensional data. AB - BACKGROUND: Generally speaking, different classifiers tend to work well for certain types of data and conversely, it is usually not known a priori which algorithm will be optimal in any given classification application. In addition, for most classification problems, selecting the best performing classification algorithm amongst a number of competing algorithms is a difficult task for various reasons. As for example, the order of performance may depend on the performance measure employed for such a comparison. In this work, we present a novel adaptive ensemble classifier constructed by combining bagging and rank aggregation that is capable of adaptively changing its performance depending on the type of data that is being classified. The attractive feature of the proposed classifier is its multi-objective nature where the classification results can be simultaneously optimized with respect to several performance measures, for example, accuracy, sensitivity and specificity. We also show that our somewhat complex strategy has better predictive performance as judged on test samples than a more naive approach that attempts to directly identify the optimal classifier based on the training data performances of the individual classifiers. RESULTS: We illustrate the proposed method with two simulated and two real-data examples. In all cases, the ensemble classifier performs at the level of the best individual classifier comprising the ensemble or better. CONCLUSIONS: For complex high-dimensional datasets resulting from present day high-throughput experiments, it may be wise to consider a number of classification algorithms combined with dimension reduction techniques rather than a fixed standard algorithm set a priori. PMID- 20716382 TI - Mutational analysis of an archaeal minichromosome maintenance protein exterior hairpin reveals critical residues for helicase activity and DNA binding. AB - BACKGROUND: The mini-chromosome maintenance protein (MCM) complex is an essential replicative helicase for DNA replication in Archaea and Eukaryotes. While the eukaryotic complex consists of six homologous proteins (MCM2-7), the archaeon Sulfolobus solfataricus has only one MCM protein (ssoMCM), six subunits of which form a homohexamer. We have recently reported a 4.35A crystal structure of the near full-length ssoMCM. The structure reveals a total of four beta-hairpins per subunit, three of which are located within the main channel or side channels of the ssoMCM hexamer model generated based on the symmetry of the N-terminal Methanothermobacter thermautotrophicus (mtMCM) structure. The fourth beta hairpin, however, is located on the exterior of the hexamer, near the exit of the putative side channels and next to the ATP binding pocket. RESULTS: In order to better understand this hairpin's role in DNA binding and helicase activity, we performed a detailed mutational and biochemical analysis of nine residues on this exterior beta-hairpin (EXT-hp). We examined the activities of the mutants related to their helicase function, including hexamerization, ATPase, DNA binding and helicase activities. The assays showed that some of the residues on this EXT-hp play a role for DNA binding as well as for helicase activity. CONCLUSIONS: These results implicate several current theories regarding helicase activity by this critical hexameric enzyme. As the data suggest that EXT-hp is involved in DNA binding, the results reported here imply that the EXT-hp located near the exterior exit of the side channels may play a role in contacting DNA substrate in a manner that affects DNA unwinding. PMID- 20716383 TI - Universal prevention of depression in women postnatally: cluster randomized trial evidence in primary care. AB - BACKGROUND: To test whether receiving care from a health visitor (HV) trained in identification and psychological intervention methods prevents depression 6-18 months postnatally in women who are not depressed 6 weeks postnatally. METHOD: The study was a prospective cluster trial, randomized by GP practice, with follow up for 18 months in 101 primary care teams in the Trent area of England. The participants were women scoring <12 on the postal Edinburgh Postnatal Depression Scale (EPDS) at 6 weeks postnatally (1474 intervention and 767 control women). Intervention HVs (n=89, 63 clusters) were trained in identifying depressive symptoms using the EPDS and face-to-face clinical assessment and in providing psychologically orientated sessions based on cognitive behavioral or person centered principles. The control group comprised HVs (n=49, 37 clusters) providing care as usual (CAU). The primary outcome measure was the proportion of women scoring >= 12 on the EPDS at 6 months postnatally. Secondary outcomes were mean EPDS score, Clinical Outcomes in Routine Evaluation - Outcome Measure (CORE OM) score, State-Trait Anxiety Inventory (STAI), 12-item Short Form Health Survey (SF-12) and Parenting Stress Index Short Form (PSI-SF) scores at 6, 12 and 18 months. RESULTS: After adjusting for individual-level covariates, living alone, previous postnatal depression (PND), the presence of one or more adverse life events and the 6-week EPDS score, the odds ratio (OR) for EPDS >= 12 at 6 months was 0.71 [95% confidence interval (CI) 0.53-0.97, p=0.031] for the intervention group (IG) women compared with the control (CAU) group women. Two subgroups were formed by baseline severity: a 'subthreshold' subgroup with a 6-week EPDS score of 6-11 (n=999) and a 'lowest severity' subgroup with a 6-week EPDS score of 0-5 (n=1242). There was no difference in psychological effectiveness by subgroup (interaction term: z=-0.28, p=0.782). CONCLUSIONS: This study provides new evidence of a universal, enduring preventive effect for depression in women who screen negative for depression postnatally. PMID- 20716384 TI - Potential use of RNA interference in cancer therapy. AB - RNA interference (RNAi) is an evolutionary conserved mechanism for specific gene silencing. This mechanism has great potential for use in targeted cancer therapy. Understanding the RNAi mechanism has led to the development of several novel RNAi based therapeutic approaches currently in the early phases of clinical trials. It remains difficult to effectively deliver the nucleic acids required in vivo to initiate RNAi, and intense effort is under way in developing effective and targeted systemic delivery systems for RNAi. Description of in vivo delivery systems is not the focus of this review. In this review, we cover the rationale for pursuing personalised cancer therapy with RNAi, briefly review the mechanism of each major RNAi therapeutic technique, summarise and sample recent results with animal models applying RNAi for cancer, and provide an update on current clinical trials with RNAi-based therapeutic agents for cancer therapy. RNAi-based cancer therapy is still in its infancy, and there are numerous obstacles and issues that need to be resolved before its application in personalised therapy focusing on patient-cancer-specific targets can become standard cancer treatment, either alone or in combination with other treatments. PMID- 20716385 TI - Haemocytes play a commensal role in the synthesis of the dihydroxybenzoate required as a precursor for sclerotization of the egg case (ootheca) in the cockroach Periplaneta americana (L). AB - The secretions of the two colleterial glands give rise to the walls of the ootheca which, when hardened, serve to protect fertilised eggs in the cockroach P. americana. The larger left gland (LCG) secretes a beta-D-glucoside of 3,4 dihydroxybenzoate, several proteins (oothecins), calcium oxalate crystals and a latent phenoloxidase enzyme. The smaller right gland (RCG) secretes a beta glucosidase. When the two secretions mix in the genital vestibulum, the glucoside is hydrolyzed to glucose and free dihydroxybenzoate, which is then oxidized by the phenoloxidase to the o-benzoquinone, which cross-links the oothecins Scanning and thin section electron microscopy (EM) showed haemocytes adhering to the LCG. The haemocytes were obtained by washing the gland with insect saline; and, when they were incubated with labelled tyrosine, they showed an enhanced ability to decarboxylate L-p-tyrosine to tyramine and then deaminate and oxidize tyramine to give p-hydroxyphenylacetate. After removal of adhering haemocytes, the LCG was no longer able to decarboxylate tyrosine. Injection of alpha-ecdysone into the abdomens of recently emerged adult females inhibited synthesis of a phenolic glucoside in the developing LCG but not of beta-glucosidase produced by RCG. Furthermore, injecting inhibitors of the decarboxylase and monoamineoxidase enzymes partly closed down synthesis in vivo of the phenolic glucoside by LCG. Therefore, in the adult female cockroach, tyramine was converted to p hydroxyphenylacetate in the haemocytes and then transferred to the gland where it was hydroxylated to 3,4-dihydroxyphenylacetate, which gave rise to a dihydroxybenzoate. Evidence suggested that biosynthesis of the oothecal sclerotizing agent could be controlled by juvenile hormone (JH) acting on the LCG or on haemocytes adhering to the gland. PMID- 20716386 TI - A longitudinal study examining the independence of apathy and depression after stroke: the Sydney Stroke Study. AB - BACKGROUND: There is growing recognition that apathy is not only a symptom of depression but may be an independent syndrome. This is the first study to investigate the relationship of apathy and depression longitudinally following stroke and to examine the association with dementia. METHOD: 106 consecutive eligible participants following stroke received extensive medical, psychiatric and neuropsychological assessments at three to six months (index assessment) and 15 months (follow-up assessment) after their stroke. A subset of participants received magnetic resonance imaging (MRI) scans at index assessment. Ratings were made for DSM-IV major or minor depression and for apathy using the Apathy Evaluation Scale (AES). RESULTS: While there was no significant overlap between apathy and depression at index assessment (OR = 1.79, 95% CI 0.48, 6.66), the overlap was significant a year later (OR = 7.75, 95% CI 2.60, 23.13). Dementia at index assessment was a common risk factor for both apathy and depression at follow-up (OR = 12.45, 95% CI 2.98, 52.02 and OR = 10.35, 95% CI 2.84, 37.72, respectively). CONCLUSIONS: Apathy and depression after stroke have a common predictor and overlap longitudinally. The overlap might be due to cumulative vascular pathology and because of the relationship of each of these syndromes to dementia, which was an important, possibly causal, predictor for both. PMID- 20716387 TI - Prevalence of dementia and dementia subtypes among community-dwelling elderly people in northern Nigeria. AB - BACKGROUND: Dementia has important public health implications. The magnitude of the problem remains largely unknown in the developing countries. METHODS: Three hundred and twenty-two community dwelling elderly persons and their caregivers in Zaria, Northern-Nigeria were enrolled in this study. They were interviewed using Community Screening Interview for Dementia (CSI-D), Consortium to Establish Registry for Alzheimer's disease (CERAD), Stick Design Test (SDT), Blessed Dementia Scale and a sociodemographic questionnaire. The data obtained were analyzed using the Statistical Package for Social Sciences version 15 for Windows. Diagnosis was based on fulfilling criteria for dementia in both the International Classification of Disease, 10th edition and the Diagnostic and Statistical Manual, 4th edition. RESULTS: The mean age of the subjects was 75.5 +/- 9.4 years. The prevalence of dementia was 2.79% (CI 1-4.58%). Alzheimer's disease constituted 66.67% of all the cases of dementia in this community. Age was the only demographic factor associated with dementia. CONCLUSION: The prevalence rates of dementia and dementia subtypes in the developing countries are similar using standard diagnostic criteria and methods. PMID- 20716388 TI - Age-related patterns in mental health-related complementary and alternative medicine utilization in Canada. AB - BACKGROUND: The aim of this study was to examine whether age-related differences in rates of use of complementary and alternative medicine (CAM) specifically for mental health problems parallel well-known age-related differences in use of conventional mental health services and medications. METHODS: A sample of middle aged (45-64 years; n = 10,762), younger-old (65-74; n = 4,113) and older-old adults (75 years and older; n = 3,623) was drawn from the 2001-2002 Canadian Community Health Survey (CCHS), Cycle 1.2, Mental Health and Wellbeing. Age related utilization rates of conventional and complementary mental health services and medications/products were calculated. Logistic regression analyses were used to examine the strength of association between age group and utilization of services and medications or products in the context of other important sociodemographic and clinical characteristics. RESULTS: When considered in the context of other sociodemographic and clinical characteristics, older age was positively associated with mental health-related utilization of alternative health products. Older age was not significantly associated with mental health related consultations with CAM providers. CONCLUSIONS: Overall, age-related patterns in mental health-related use of CAM did not directly correspond to age related patterns in conventional mental health care utilization, suggesting different sets of predictors involved in seeking each type of care. PMID- 20716389 TI - Improvement of quality of life in hospitalized depressed elderly. AB - BACKGROUND: Quality of life is important for all individuals, but is frequently overlooked in psychiatric populations. Our purpose was to assess the quality of life (QOL) of depressed psychiatrically hospitalized elderly patients, examine the association of QOL and depression, and explore any QOL differences related to electroconvulsive therapy (ECT). METHODS: This Institutional Review Board (IRB) approved prospective study recruited geropsychiatric inpatients aged 65 years and older who were depressed, had Mini-mental State Examination (MMSE) scores >18/30, and adequate communication skills. Surveys were completed upon admission and discharge to measure depression (Hamilton Depression Rating Scale (HDRS)), quality of life (Linear Analogue Scales of Assessment (LASA); Medical Outcomes Short Form-36 Health Survey (SF-36)), cognitive function (MMSE; Executive Interview (EXIT 25)), and coping (Brief COPE Inventory (COPE)). Spearman correlations and Wilcoxon signed rank tests were used to assess changes in measures during hospitalization and relationships among variables. RESULTS: The 45 study participants who completed the study had a mean age of 74 years. The majority were female (67%), married (58%), Protestant (60%), with at least high school education (78%). Admission scores demonstrated severe depression (HDRS 24.88 +/- 10.14) and poor QOL (LASA overall QOL 4.4 +/- 2.79, and SF-36 mental [27.68 +/- 9.63] and physical [46.93 +/- 10.41] component scores). At discharge, there was a significant improvement of depression (HDRS 24.88v12.04, p < 0.0001) and QOL (LASA overall QOL 4.4v6.66, p < 0.0001; and SF-36 mental [27.68v39.10, p < 0.0001] and physical [46.93v50.98, p = 0.003] component scores). Not surprisingly, depression was negatively correlated with overall QOL, mental well being, physical well-being, and emotional well-being at both admission and discharge. For the group who received ECT, there was a greater magnitude of improvement in SF-36 vitality (p = 0.002) and general health perception (p = 0.04), but also a reduction in EXIT 25 scores at discharge (p = 0.008). CONCLUSIONS: There was improvement of both QOL and depression during the course of hospitalization. Additionally, improvement of QOL was associated with improvement of depression. Perhaps future studies could develop interventions to improve both mood and QOL in elderly depressed inpatients. PMID- 20716390 TI - Suicide and deliberate self harm in older Irish adults. AB - BACKGROUND: Hospital-treated deliberate self harm and suicide among older adults have rarely been examined at a national level. METHODS: The Irish Central Statistics Office provided suicide and undetermined death data for 1980-2006. The National Registry of Deliberate Self Harm collected data relating to deliberate self harm presentations made in 2006-2008 to all 40 Irish hospital emergency departments. RESULTS: Rates of female suicide among older adults (over 55 years) were relatively stable in Ireland during 1980-2006 whereas male rates increased in the 1980s and decreased in more recent decades. Respectively, the annual male and female suicide and undetermined death rate was 22.1 and 7.6 per 100,000 in 1997-2006. Male and female deliberate self harm was 3.0 and 11.0 times higher at 67.4 and 83.4 per 100,000, respectively. Deliberate self harm and suicide decreased in incidence with increasing age. Deliberate self harm generally involved drug overdose (male: 72%; female 85%) or self-cutting (male: 15%; female 9%). The most common methods of suicide were hanging (41%) and drowning (29%) for men and drowning (39%) and drug overdose (24%) for women. City and urban district populations had the highest rates of hospital-treated self harm. The highest suicide rates were in urban districts. CONCLUSIONS: Older Irish adults have high rates of hospital-treated deliberate self harm but below average rates of suicide. Drowning was relatively common as a method of suicide. Restricting availability of specific medications may reduce both forms of suicidal behavior. PMID- 20716391 TI - Urinary tract infection in very old women is associated with delirium. AB - BACKGROUND: The aim of the study was to investigate whether urinary tract infection (UTI) in a representative sample of 85-, 90- and >=95-year-old women is associated with delirium. METHODS: In 504 out of 643 women (78.4%) it was possible to evaluate UTI and delirium. Assessments such as the Organic Brain Syndrome (OBS) Scale, the Geriatric Depression Scale-15 (GDS-15) and the Mini mental State Examination (MMSE) were performed during home visits. Delirium, dementia and depression were diagnosed according to the DSM-IV criteria. A diagnosed, symptomatic UTI with or without ongoing treatment, documented in medical records or detected in association with the assessments, was registered. RESULTS: Eighty-seven of 504 women (17.2%), were diagnosed as having a UTI with or without ongoing treatment when they were assessed, and almost half of them (44.8%) were diagnosed to be delirious or having had episodes of delirium during the past month. One hundred and thirty-seven of the 504 women (27.2%) were delirious or had had episodes of delirium during the past month and 39 (28.5%) of them were diagnosed to have a UTI. In a multivariate logistic regression model, delirium was significantly associated with Alzheimer's disease (OR = 5.8), multi infarct dementia (OR = 5.4), depression (OR = 3.1), heart failure (OR = 2.3) and urinary tract infection (OR = 1.9). CONCLUSIONS: A large proportion of very old women with UTI suffered from delirium which might indicate that UTI is a common cause of delirium. There should be more focus on detecting, preventing and treating UTI to avoid unnecessary suffering among old women. PMID- 20716392 TI - The utility of questionnaires in cognitive and functional assessment in Alzheimer's disease. PMID- 20716393 TI - A systematic review of the prevalence, associations and outcomes of dementia in older general hospital inpatients. AB - BACKGROUND: Older people are commonly admitted to the acute hospital and increasing numbers will have dementia. In this study we systematically reviewed the prevalence, associations and outcomes of dementia in older people in the general hospital, to examine the range of diagnostic tools used and highlight gaps in the literature. METHODS: We searched the English language literature using Embase, PsychInfo and Medline. Studies were included if they used validated criteria for diagnosing dementia, involved subjects over the age of 55 years and were set in the general hospital. RESULTS: Fourteen papers were identified. Prevalence estimates for dementia in studies with robust methodology were 12.9 63.0%. Less than a third of studies screened for delirium or depression and therefore some subjects may have been misclassified as having dementia. The data were highly heterogeneous and prevalence estimates varied widely, influenced by study setting and demographic features of the cohorts. Patients with dementia in the acute hospital are older, require more hours of nursing care, have longer hospital stays, and are more at risk of delayed discharge and functional decline during admission. CONCLUSIONS: When planning liaison services, the setting and demographic features of the population need to be taken into account. Most study cohorts were recruited from medical wards. More work is required on the prevalence of dementia in surgical and other specialties. A wider range of associations (particularly medical and psychiatric comorbidity) and outcomes should be studied so that care can be improved. PMID- 20716394 TI - Maternal socioeconomic and demographic factors associated with the sex ratio at birth in Vietnam. AB - In recent years Vietnam has experienced a high sex ratio at birth (SRB) amidst rapid socioeconomic and demographic changes. However, little is known about the differentials in SRB between maternal socioeconomic and demographic groups. The paper uses data from the annual Population Change Survey (PCS) in 2006 to examine the relationship of the sex ratio of the most recent birth with maternal socioeconomic and demographic characteristics and the number of previous female births. The SRB of Vietnam was significantly high at 111.4 (95% CI 109.7-113.1) for the period 1st April 2000 to 31st March 2006. Multivariate analysis reveals that sex of the most recent birth is strongly related with the number of previous female births. This association is consistent across different socioeconomic and demographic groups of women. Given the high SRB in Vietnam, further research into the reasons for high SRB in these groups is required, as are intervention programmes such as those raising the public awareness of its negative consequences. PMID- 20716395 TI - Gill ectoparasite assemblages of two non-native Cichla populations (Perciformes, Cichlidae) in Brazilian reservoirs. AB - The gills of 41 Cichla piquiti and 39 C. kelberi from Itaipu and Lajes reservoirs, respectively, Brazil, were examined to describe the ectoparasite assemblages of these two non-native peacock-bass populations. All ectoparasite species of the two studied hosts (C. piquiti and C. kelberi) were dominant, but Ascocotyle sp. (metacercariae) was the prevalent (58.53%) and most abundant helminth species in C. piquiti hosts, while Sciadicleithrum ergensi was the dominant species in C. kelberi hosts. Gill ectoparasites of C. piquiti and C. kelberi showed a typical pattern of overdispersion or aggregation, which is commonly reported for many other freshwater fishes. Ectoparasite prevalence and abundance did not vary between host sexes of the two Cichla populations. The prevalence and abundance of Ascocotyle sp. were positively correlated with C. piquiti standard length (SL), but only the abundance of S. ergensi showed a positive correlation with C. kelberi SL. Although environmental differences between reservoirs might also have influenced the results, we anticipated that the presence of a close congener in Itaipu reservoir and the lack of other Cichla species in Lajes reservoir were the key factors to explain the contrasts between C. piquiti and C. kelberi gill ectoparasites. Overall, our results suggest that the trend of parasite species loss through the invasion process may have contributed to the establishment of non-native C. piquiti and C. kelberi populations in Brazilian reservoirs. PMID- 20716396 TI - Attenuated responses to emotional expressions in women with generalized anxiety disorder. AB - BACKGROUND: Generalized anxiety disorder (GAD) is under-researched despite its high prevalence and large impact on the healthcare system. There is a paucity of functional magnetic resonance imaging (fMRI) studies that explore the neural correlates of emotional processing in GAD. The present study investigated the blood oxygen level dependent (BOLD) response to processing positive and negative facial emotions in patients with GAD. METHOD: A total of 15 female GAD patients and 16 female controls undertook an implicit face emotion task during fMRI scanning. They also performed a face emotion recognition task outside the scanner. RESULTS: The only behavioural difference observed in GAD patients was less accurate detection of sad facial expressions compared with control participants. However, GAD patients showed an attenuated BOLD signal in the prefrontal cortex to fearful, sad, angry and happy facial expressions and an attenuated signal in the anterior cingulate cortex to happy and fearful facial expressions. No differences were found in amygdala response. CONCLUSIONS: In contrast with previous research, this study found BOLD signal attenuation in the ventrolateral and medial prefrontal cortex and the anterior cingulate cortex during face emotion processing, consistent with a hypothesis of hypo-responsivity to external emotional stimuli in GAD. These decreases were in areas that have been implicated in emotion and cognition and may reflect an altered balance between internally and externally directed attentional processes. PMID- 20716397 TI - Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters' perspective. AB - Innovation is essential for the identification of novel pharmacological therapies to meet the treatment needs of patients with psychiatric disorders. However, over the last 20 yr, in spite of major investments targets falling outside the classical aminergic mechanisms have shown diminished returns. The disappointments are traced to failures in the target identification and target validation effort, as reflected by the poor ability of current bioassays and animal models to predict efficacy and side-effects. Mismatch between disease biology and how psychiatric diseases are categorized has resulted in clinical trials of highly specific agents in heterogeneous patients, leading to variable treatment effects and failed studies. As drug hunters, one sees the opportunity to overhaul the pharmaceutical research and development (R&D) process. Improvements in both preclinical and clinical translational research need to be considered. Linking pharmacodynamic markers with disease biology should provide more predictive and innovative early clinical trials which in turn will increase the success rate of discovering new medicines. However, to exploit these exciting scientific discoveries, pharmaceutical companies need to question the conventional drug research and development model which is silo-driven, non-integrative across the confines of a company, non-disclosing across the pharmaceutical industry, and often independent from academia. This leads to huge redundancy in effort and lack of contextual learning in real time. Nevertheless, there are signs that drug discovery in the 21st century will see more intentional government, academic and industrial collaborations to overcome the above challenges that could eventually link mechanistic disease biology to segments of patients, affording them the benefits of rational and targeted therapy. PMID- 20716399 TI - [Promotion of MAG-1 on Metastasis of Lung Cancer Cells in vitro and Its Expression in Lung Cancer Tissue of 24 Cases.]. AB - BACKGROUND: Tumor metastasis is a multistep process with many genes involved in. A novel gene MAG-1, identified by suppression subtractive hybridization from lung cancer cells was found to be associated with tumor metastasis. The aims of this work are to investigate the metastasis related effects of MAG-1 on human lunggiant-cell line PLA801, and to compare the expression rate of MAG-1 in cancer tissue from lung cancer patients with different metastatic status. METHODS: Sense and anti-sense expressing vectors of MAG-1 were constructed and transfected into PLA801C and PLA801D respectively. Colony forming, adherence assay, MTT assay and Transwell experiments were used to evaluate the alterations of clone forming, cell-matrix adherence, proliferating and invasion of the stable transfected cell strains. Western blot was employed to detect the proteins levels of CD44, and MMP 2 in cell strains and mRNA state of MAG-1 in lung cancer tissue from patients with or without pathological metastasis were also analyzed by RTPCR. RESULTS: MAG 1 could increase cell-ECM (Extracellular Matrix) adhesive capacity, promote invasion, enhance cell proliferation and had no effects on clone forming ability of PLA801 cells in soft agar. MAG-1 was also found have positive effects on the protein level of CD44 and MMP-2 in PLA801 cells, and the detection rate of MAG-1 mRNA was much higher in cancer tissue from metastatic patients (7/12) than that in non-metastatic patients (2/12). CONCLUSIONS: MAG-1 could promote lung cancer metastasis and might be a metastasis associated gene of lung cancer. PMID- 20716398 TI - Changes in body weight during pharmacological treatment of depression. AB - The risk of weight gain is an important determinant of the acceptability and tolerability of antidepressant medication. To compare changes in body weight during treatment with different antidepressants, body weight and height were measured at baseline and after 6, 8, 12 and 26 wk treatment with escitalopram or nortriptyline in 630 adults with moderate-to-severe unipolar depression participating in GENDEP, a part-randomized open-label study. Weight increased significantly more during treatment with nortriptyline compared to escitalopram. The weight gain commenced during the first 6 wk of nortriptyline treatment, reached on average 1.2 kg at 12 wk (0.44-point BMI increase), and continued throughout the 6-month follow-up period. Participants who were underweight at baseline gained most weight. Participants who were obese at baseline did not gain more weight during treatment. Weight gain occurred irrespective of whether weight loss was a symptom of current depressive episode and was identified as an undesired effect of the antidepressant by most participants who gained weight. There was little weight change during treatment with escitalopram, with an average increase of 0.14 kg (0.05-point BMI increase) over 12 wk of treatment. In conclusion, treatment with the tricyclic antidepressant nortriptyline was associated with moderate weight gain, which cannot be explained as a reversal of symptomatic weight loss and is usually perceived as an undesired adverse effect. While treatment with nortriptyline may be recommended in underweight subjects with typical neurovegetative symptoms, escitalopram is a suitable alternative for subjects at risk of weight gain. PMID- 20716400 TI - [The Effects of Interfering COX-2 Gene Expression on Malignant Proliferation of Human Lung Adenocarcinoma A2 Cell in vitro.]. AB - BACKGROUND: COX-2 was highly expressed in many tumor tissues and was involved in the initiation and development of tumors. The RNAi technique is a method to inhibit gene expression economically, quickly, efficiently and specifically. This study used RNAi technique to explore the interfering effect of COX-2 gene expression and the influence on the malignant proliferation of A2 cells after quenching COX-2 in vitro . METHODS: Three COX-2 siRNA expression vectors with human U6 promoter were constructed. The COX-2 siRNA vectors and the vacant vector (pEGFP) were transfected into A2 cells with lipofectamine respectively. The cell strains transfected were selected. The change of COX-2 expression levels was examined by Western blot and RT-PCR. The effects on the proliferation of A2 cells after silencing COX-2 were detected by cell growth curve and clonogenic assay in vitro . RESULTS: The three siRNA and U6 promoter cloned into pEGFP plasmid were validated by PCR, restriction endonucleases identification, DNA sequencing and BLAST alignment. The cell strains transfected were coded as A2-3, A2-7, A2-10 and A2-p respectively. Green fluorescence was seen in A2-p cells and not in A2-3, A2 7 and A2-10 cells in 24 h, 48 h and 72 h after transfected. The results of RT-PCR and Western blot showed the three siRNA expression vectors acted effectively and the expression of COX-2 was inhibited in different extent. In contrast to A2 cells, COX-2 mRNA levels of A2-3, A2-7 and A2-10 cells were reduced 15.6%, 20.4% and 64.2% respectively, and COX-2 protein expressions of them were reduced 23.7%, 36.7% and 60.2% respectively. The results of cell growth curve and clonogenic assay showed the growth of A2-10 cell slowed and the clonal formation rate was reduced. However the growth of A2-3 and A2-7 cells had no obvious changes vs controls (A2 and A2-p). CONCLUSIONS: Silencing COX-2 gene in vitro by RNAi technique can significantly inhibit the malignant proliferation of A2 cells. PMID- 20716401 TI - [The recovery process of murine tracheal epithelium injured by 5-fu and its microarray analysis.]. AB - BACKGROUND: CAlthough there are increasing reports on localization of tracheal stem cells, the mechanism of proliferation and differentiation of tracheal stem cells remains unclear. METHODS: In this study, we developed an ex vivo model of murine tracheal epithelial injury and regeneration induced by 5-FU. The regeneration process of murine tracheal epithelium was observed and analyzed by morphological, immunofluorescence and microarray methods. RESULTS: After treatment with 5-FU, the differentiated mature cells were dead and desquamated. Only a few cells remained in G0 phase and located on the basement membrane. After being put back in normal culture media, the cells became flat, cubic and restored as pseudostratified epithelium at last. These G0 phase cells were ABCG2 positive. We detected the differences of stem cell genes between normal tracheal epithelial cells and regenerated epithelial cells at 24 h and 48 h after injured by 5-FU using stem cell differentiation gene microarray. At 24 h, 8 genes were up regulated and 31 genes were down-regulated. At 48 h, 5 genes were up-regulated and 42 genes were down-regulated. CONCLUSIONS: The differently expressed genes were mainly associated with cell cycle regulation, intercellular junction, FGF, BMP, Notch and Wnt signaling pathways, which suggested these alterations might be closely associated with the proliferation and differentiation of tracheal stem cells. PMID- 20716402 TI - [The Relationship between TSG101 Protein and Notch3 Receptor in Lung Cancer.]. AB - BACKGROUND: TSG101 protein is one of the key factors in Endosomal sorting pathway. The abnormality of this pathway could decrease degradation of Notch receptor which leads to disorder of cell differentiation and development in drosophila. In mammal, the Notch3 receptors correlate with lung tissue development and lung carcinogenesis. The purpose of this study is to explore the relationship between TSG101 protein and Notch3 receptor in human lung cancer. METHODS: Immunohistochemical method (S-P method) and Western blot were applied to detect the expressions of TSG101 protein and Notch3 receptor in lung cancer tissues and cell lines, in comparison with the corresponding normal tissues and cell lines. Besides, the expression of Notch3 receptor was observed when TSG101 protein was blocked by its specific antibody. RESULTS: The TSG101 protein expressions in tumor tissues were significantly lower than those in the neighboring noncancerous tissue, with higher expressions of Notch3 receptor in tumor tissues, which were correlated with the cellular differentiation and lymph node metastases. The expression of Notch3 receptor increased after blockage of TSG101 protein by its specific antibody. CONCLUSIONS: Down-regulation of TSG101 protein was correlated with the up- regulation of Notch 3 receptor in lung cancer. PMID- 20716403 TI - [Expression of DLL4 and VEGF in Lung Adenocarcinoma and their Relationship with Angiogenesis in Tumor.]. AB - BACKGROUND: Angiogenesis depends on the interaction of a variety of promoting factors and inhibiting factors. Vascular endothelial growth factor (VEGF) and Notch signaling pathway take part in this process. This experiment investigates the expression of Notch ligand DLL4 and VEGF in lung adenocarcinoma and their relationship with angiogenesis in tumor. METHODS: Immunohistochemical method was used to detect DLL4, VEGF and CD34 protein expression in 80 cases of lung adenocarcinoma (including bronchioloalveolar carcinoma and common lung adenocarcinoma) paraffin section tissues. RESULTS: The expression of DLL4 and VEGF was closely related to tumor diameter, clinical stage, histological grade and lymph node metastasis, the VEGF expression rate in DLL4 positive expression cases was significantly more than the DLL4 negative cases, the correlation between microvascular density and DLL4, VEGF co-expression was more significant, the expression of DLL4 in common lung adenocarcinoma was significantly higher than that in bronchioloalveolar carcinoma. CONCLUSIONS: The prognosis of lung adenocarcinoma is significant correlated with the angiogenesis, high expression of DLL4 is closely related to the metastasis and the prognosis. PMID- 20716404 TI - [The retrospective analysis of different therapies on 150 elderly patients with advanced non-small cell lung cancer.]. AB - BACKGROUND: There is still no standard regiment for the treatment of advanced elderly patients with non-small cell lung cancer (NSCLC). The aim of this study is to explore the best method for the advanced elderly NSCLC patients by analyzing the efficacy and toxicity of cisplatin combined chemotherapy, docetaxel chemotherapy and the best support care (BSC). METHODS: One hundred and fifty elderly NSCLC patients (>=65 years) with different treatments from March 2003 to March 2007 in our hospital were retrospectively analyzed. RESULTS: The objective response rate (ORR) was 41.2% in cisplatin combined chemotherapy, which was significantly higher than 20.0% in docetaxel chemotherapy (P <0.05). Median survival time (MST) was 10.7 months, 9.2 months and 6.3 months, and one year survival rate was 39.7%, 36.7% and 17.3%, respectively in cisplatin combined chemotherapy, docetaxel chemotherapy and the best support care. MST was significantly longer (P <0.05) and one year survival rate was significantly higher (P <0.05) in the patients with chemotherapy than that with best support care. There was no significant difference of MST and one year survival between cisplatin combined chemotherapy and docetaxel chemotherapy (P >0.05). Grade 3-4 toxicity was more serious in cisplatin combined group than that in docetaxel group (P <0.05). CONCLUSIONS: Chemotherapy can prolong the survival time in elderly NSCLC patients. Even though the ORR is higher in cisplatin combined chemotherapy than that in docetaxel chemotherapy, there was no significant difference of MST and one year survival between cisplatin combined chemotherapy and docetaxel chemotherapy (P >0.05), which may due to the more serious toxicity. Docetaxel chemotherapy should be one of the standard regiment for the elderly NSCLC patients. PMID- 20716405 TI - [The role of thyroid transcription factor-1 DNA binding activity in lung cancer.]. AB - BACKGROUND: TTF-1 is a homeodomain transcriptional regulator of both structural organization of the lung and differentiation of highly specialized epithelial cell types such as alveolar typeII cells. This study is to investigate the Thyroid transcription factor-1 (TTF-1) DNA binding activity in lung cancer tissue and its significance with lung cancer pathologic type and differentiation level. METHODS: The TTF-1 DNA binding activity was detected in lung cancer tissue by Electrophoretic mobility shift assay (EMSA), autoradiography and photo densitometry. RESULTS: The optical density of TTF-1 DNA binding activity in adenocarcinoma tissue was 172+/-23.2 and it was remarkably higher than that in other pathological types, including 141+/-16.3 of small cell carcinomas and 122+/ 13.6 of squamous carcinoma (P <0.05). The optical density of TTF-1 DNA binding activity in highly differentiated lung cancer tissues was significantly higher than that in poor-differentiated lung cancer (P <0.05). Overall survival and disease-free survival rates were better among patients with low TTF-1 DNA binding activity levels than those in patients with high levels. CONCLUSIONS: TTF-1 DNA binding activity is a potential predictor of lung cancer metastasis and survival. PMID- 20716406 TI - [Expression of FHIT Protein in Lung Cancer by Cell Array.]. AB - BACKGROUND: Fragile histidine triad (FHIT) is a candidate tumor suppressor gene. Aberrance of FHIT has been observed in multiple carcinomas induced by environmental carcinogens, especially in lung cancer. In this study, the expression of FHIT protein in cell array was detected to further development of cell array and for a rapid, simple, and economical method. METHODS: The lung cancer samples were collected from the Tianjin Medical University General Hospital, the First Central Hospital and the Tianjin Chest Hospital from May to August in 2005. A total of 112 dots cell array were constructed in this study including the pleural fluid of 50 cases of lung cancer and 6 cases of normal, the cell array was done with the home-made cell array survey setting. Immunohistochemical stains were performed. RESULTS: All points rank in a good order without distortion in cell array. After IHC stains of FHIT, the number of cells did not decrease. The positive expression was totally the same to that from the tissue microarry. CONCLUSIONS: Cell array is a rapid and high-throughput technique with high specificity, which could be broadly used in the clinical diagnosis and the screen of epidemilology. PMID- 20716407 TI - [Sequential Changes of Serum Tumor Markers Before and After the Radioactive (125)I-seed Implantation in the Treatment of Lung Cancer.]. AB - BACKGROUND: The brachytherapy with iodine seeds is characterized by radioactive (125)I very close to or in contact with the target organ. This study is to evaluate the clinical value of implanted radioactive (125)I-seed in the treatment of lung cancer patients. METHODS: Sixty-three cases of lung cancer were enrolled in this study, and in every case, (125)I-seeds were planted into tumor mass guided by CT. Serum CEA, CA125, NSE and CYFRA21-1 were detected by radioimmunoassay in lung cancer patients before and after planting. The therapeutic effect was evaluated by WHO standards. The relation between the therapeutic effect and the tumor markers levels was observed. RESULTS: Just one month after planting, the levels of serum CEA, CA125, NSE and CYFRA21-1 were induced significantly in all cases. There was no significant difference among 1 month, 3 month and 6 month in the levels of tumor markers after therapy. CONCLUSIONS: (125)I-seed could effectively decrease the level of tumor markers in the treatment of lung cancer patients. PMID- 20716408 TI - [Rigid bronchoscope combined with soft electronic bronchoscope for treatment of main airway neoplasma.]. AB - BACKGROUND: Main airway severe obstruction is a problem facing difficulty flexible bronchoscope because the patient is not able to breath smoothly under prostration, and death from suffocation is a frequent outcome. Managing the airway of patients with critical tracheal stenosis remains a formidable challenge to bronchoscopists. This study is to evaluate the application and efficacy of argon plasma coagulation (APC) and cryoextraction for the treatment of endobronchial neoplasma under rigid bronchoscope combined with flexible bronchoscope. METHODS: Two groups of airway pathologically proved neoplasma were retrospectively reviewed for the different endobronchial intervation modalities. Group A: Argon plasma coagulation (APC) and cryoextraction were used for the treatment of endobronchial neoplasma under rigid bronchoscope combined with electronic bronchoscope in 19 cases with tracheobronchial carcinoma. Rigid bronchoscope was inserted into trachea with general anesthesia. Then the endobronchial tumor was removed by the combination APC and cryoextraction. Group B: APC and grasp or cryoextraction were used for the debulking of endobronchial tumor under flexible bronchoscope in 20 cases with airway tumor. RESULTS: Both tracheal and bronchial obstruction were more severe in Group A than those in Group B, but the tumor debulking was higher for the first time in Group A than in Group B. There were no difference on debulking volume between trachea and bronchus in the same group. The procedures were less complex in Group A than in Group B. The clinical improvement was better in Group A than in Group B. There were no severe complications directly related to the procedures. CONCLUSIONS: The combination of APC and cryoextraction is a rapid and effective method for the treatment of endoluminal airway tumor under rigid bronchoscope combined with electronic bronchoscope. Cryoextraction could rapidly debulk airway tumor and APC could effectively ablate tumor and stop bleeding. Electronic bronchoscope is used for the maintenance after rigid bronchoscope and for the treatment of slightly airway obstruction. PMID- 20716409 TI - [Human FLJ20420 and Its Bio-Functions.]. PMID- 20716410 TI - [Advances of HIF-1alpha and Its Role in Lung Cancer.]. PMID- 20716411 TI - [The application of decellularized matrices in the tissue engineering of vascular graft.]. PMID- 20716412 TI - [The biologic characteristics and treatment of non-small cell lung cancer in non smokers.]. PMID- 20716414 TI - [Advances in bevacizumab therapy of primary lung cancer.]. PMID- 20716413 TI - [(18)F-FDG PET/CT in Staging of Lung Cancer.]. PMID- 20716415 TI - [The Correlation between FDG PET/CT Imaging and Molecule Makers in Non-Small Cell Lung Cancer.]. AB - BACKGROUND: PET is a sensitive and special method of determining malignant degree of the lung cancer. This study investigates the correlation between (18)F deoxyglucose (FDG) uptake and various biological markers in clinical stage I non small cell lung cancer (NSCLC). METHODS: The non-small cell lung cancer specimens of 23 patients were examined by flow cytometry and immunohistochemistry, the relationship between the max standard uptake value (SUV) of FDG and the expression of the biological markers p53, Ki-67, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT-1), S-phase fraction (SPF) were studied. RESULTS: The max SUV was correlated with the expression of p53 (P <0.05), Ki-67 (P <0.05), PCNA (P <0.05), VEGF (P <0.05) and SPF (P <0.05) in stage I NSCLC. Glut-1 expression showed significant correlation with FDG uptake (P =0.001), however the max SUV showed no correlation with tumor pathology. CONCLUSIONS: Our study indicates that (18)F-FDG uptake in NSCLC correlates well with the expression of p53, Ki-67, PCNA, VEGF, GLUT-1, SPF. PMID- 20716416 TI - [Comparison of Oral Topotecan/Intravenous Cisplatin (TC) with Intravenous Etoposide/Cisplatin (EP) as First Line Chemotherapy in Untreated Small Cell Lung Cancer Patient.]. AB - BACKGROUND: Topotecon is a specific inhibitor of topoisomerase I. It is an effective drug of small cell lung cancer. An oral formulation of topotecan is available and has just rectified to treat extensivedisease small cell lung cancer by FDA this year. The aim of this trial is to compare oral topotecan/intravenous cisplatin (TC) with intravenous etoposide/cisplatin (EP) in patients untreated small cell lung cancer. METHODS: Sixty-six patients were enrolled. Thirty patients were assigned to oral topotecan 1.4 mg*m(-2)*d(-1), from d1 to d5, with cisplatin 75 mg/m(2) on d1. Thirty-six patients were assigned to etoposide 100 mg*m(-2)*d(-1), from d1 to d3, with cisplatin 75 mg/m(2) on d1 every 21 days. RESULTS: Response rate was similar between groups TC, 53.3% vs EP, 60.0%. Overall survival was little different TC, 14.58 month vs EP, 12.19 months. The regimens were similarly tolerable. Grade 3/4 neutropenia and thrombocytopenia occurred more frequently with EP (42.8% vs 10.0% and 11.4% vs 3.3%, respectively), whereas grade 3/4 anaemia occurred more frequently with TC (10% vs 2.8%). CONCLUSIONS: Oral topotecan/cisplatin provide similar efficacy and tolerability to the standard etoposide/cisplatin in patient untreated small cell lung cancer. It may provide more convenience method to intravenous treatment. PMID- 20716417 TI - [Surgical treatment of synchronous lung cancer and hepatic metastasis.]. PMID- 20716418 TI - Pro-Gastrin-Releasing Peptide (ProGRP)-A Diagnostic Biomarker for Small-Cell Lung Cancer. PMID- 20716419 TI - [Establishment of a Multidrug Resistance Cell Line A549/cDDP of Human Lung Adenocarcinoma and Expression Analysis of Multidrug Resistance-Associated Genes.]. AB - BACKGROUND: It has been proven that chemotherapy failure caused by multidrug resistance in lung tumor cells is the main cause for the patient's survival rate. The aim of this study is to establish a multidrug resistance cell line of human lung adenocarcinoma and study the mechanism of multidrug resistance. METHODS: Human lung adenocarcinoma cell line A549 was induced to multidrug resistance cell line A549/cDDP by intermittent administration of high dose of cisplatin (cDDP). The multidrug resistance was detected by using MTT assay. The levels of expression of MDR-1 gene-coded P-glycoportein (P-gp), multidrug resistance associated protein (MRP), and GSH/GST were examined by flow cytometric assay. The levels of expression of MDR and MRP gene were also detected by RTPCR in both A549/cDDP and A549 cell lines. RESULTS: A549/cDDP was resistant to many anti tumor agents. The IC50 of A549/cDDP was 16.87 times higher than that of A549. The expressions of P-gp and MRP in A549/cDDP were increased significantly to (70.5+/ 4.9)% and (29.4+/-2.9)%, respectively, vs (42.4+/-5.6)% and (21.4+/-3.5)% in A549. There was no difference of the GSH/GST expression between A549/cDDPand A549 cells CONCLUSIONS: A549/cDDP is a model with multidrug resistance and the levels of MDR and MRP mRNA expressions are remarkably higher in A549/cDDP than those in A549. PMID- 20716420 TI - [The Study on the Phosphorylation Activity of Mutant nm23-H1.]. AB - BACKGROUND: The Phosphorylation is the key activity of nm23-H1. The aim of this study is to explore the effect of different amino acid mutation on the phosphorylation status of nm23-H1. METHODS: The wild type nm23-H1 was as the control of this study. Autoradiography was used for detecting the serine and histidine autophosphorylation of wild type (WT) and mutant nm23-H1 (P96S, H118F, S120G and S44A); RP-HPLC was used for detecting the NDPK activity of above proteins. RESULTS: The autophosphorylation activities of serine and histidine from high to low were P96S, WT, S44A, S120G and H118F, respectively, while the NDPK activities from high to low were WT, S120G, P96S, S44A, H118F. A highly positive correlation was found between serine and histidine autophosphorylation activity of above proteins (r =0.985, P <0.01), but no significant correlation was found between NDPK and serine or histidine autophosphorylation activity (r=0.458, P >0.05, and r =0.482, P >0.05, respectively). CONCLUSIONS: Site mutation of nm23-H1 can affect the phosphorylation activity. H118 site was the key amino acid of kinase activity, P96 site maybe related to phosphotransferring, S120 was the site of histidine autophosphorylation and serine autophosphorylation, while the S44 site may be another amino acid which possessed NDPK activity. PMID- 20716421 TI - [Inhibition of Zoledronic Acid on Cell Proliferation and Invasion of Lung Cancer Cell Line 95D.]. AB - BACKGROUND: Abnormal proliferation and metastasis is the basic characteristic of malignant tumors. The aim of this work is to explore the effects of zoledronic acid on cell proliferation and invasion in lung cancer cell line 95D. METHODS: The effect of zoledrnic acid (ZOL) on proliferation of lung cancer cell line 95D was detected by MTT. The expression of proliferation and invasion-relation genes and proteins were detected by Western blot, RT-PCR and immunofluorescence. Changes of invasion of lung cancer cell numbers were measured by polycarbonates coated with Matrigel. RESULTS: ZOL could inhibit the proliferation of lung cancer cell line 95D in vitro in a time-dependant and a dose-dependant manner. With time extending after ZOL treated, the mRNA expresion of VEGF, MMP9, MMP2 and protein expression of VEGF, MMP9, ERK1/ERK2 were decreased. The results of Tanswell invasion showed the numbers of invasive cells were significantly reduced in 95D cells treated with ZOL 4 d and 6 d later. CONCLUSIONS: ZOL could inhibit cell proliferation and invasion of lung cancer cell line 95D. PMID- 20716422 TI - [Distribution and mRNA Expression of BAMBI in Non-small-cell Lung Cancer.]. AB - BACKGROUND: BAMBI structure is similar with that of the receptor I of TGF-beta, it broadly participates in the control of TGF-beta signaling. The aim of this study is to investigate the expression and its significance of BAMBI in non-small cell lung cancer (NSCLC) and explore the relation between BAMBI and clinical and pathological factors of NSCLC. METHODS: Sixty-three cases with NSCLC and adjacent normal tissue specimens were used for immunohistochemical assay. Thirty-one fresh lung cancer tissue specimens and surrounding normal lung tissue specimens was preserved for RT-PCR in -70 (o)C after quick-frozen in liquid nitrogen immediately. RESULTS: The level of BAMBI mRNA in cancer tissues was higher than that in the corresponding adjacent tissues (0.358+/-0.135 vs 0.249+/-0.129), with the difference being statistically significant (P =0.003). BAMBI protein expressed mainly in the membrane and the cytoplasm close to the membrane, its expression in the cancer tissue was higher than that in the adjacent tissues, the difference was significant (P <0.01). Expression of BAMBI in the cancer tissue was higher than that in the adjacent tissues, and the expression of BAMBI in adenocarcinoma of lung is higher than that in squamous carcinoma. CONCLUSIONS: The expressions of BAMBI significantly increase in NSCLC. It might be a common affair in carcinogenesis of NSCLC. PMID- 20716423 TI - [Kanglaite for Treating Advanced Non-small-cell Lung Cancer: A Systematic Review.]. AB - BACKGROUND: In the past years, many reports on Kanglaite were publicated in China, researchers across the country. The aim of this study is to review the effectiveness and safety of Kanglaite for treating advanced non-small-cell lung cancer. METHODS: Authors searched the Cochrane Library, Pubmed, Embase, Cancerlit, CBM, CNKI and VIP. Mannual and additional search were also conducted. All randomized controlled trials/quasi-RCT comparing Kanglaite with other lung cancer treatment were included. Two reviewers independently performed data extraction and appraised the publications using the Juni instrument, disagreements were resolved by consensus. Double data were entered and analyzed by RevMan 4.2 software are by Cochrane Collaboration. RESULTS: Sixteen reports were included in the meta-analysis. The quality of 16 studies was low. Pooling data of 5 studies indicated that the effect of Kanglaite+NP (Vinorelbine+Cisplatin) was better than NP with RR 1.46, 95% Confidence Interval 1.13 to 1.91. Pooling data of 3 studies of MVP (Mitomycin+Vindsine+ Cisplatin) plus Kanglaite indicated that the effect was better with RR 1.84, 95%CI 1.22 to 2.76. Pooling data of 2 studies showed that the effect of GP (Gemcitabine+Cisplatin) plus Kanglaite was better than GP with RR 1.63, 95%CI 1.09 to 2.43. Fourteen studies revealed that Kanglaite may reduce the side-effect induced by regular treatment. Ten studies showed regular treatment plus Kanglaite can stabilite/improve quality of life. CONCLUSIONS: Kanglaite can enhance clinical effect of regular treatment, reduce side-effect and stabilite/improve quality of life, but the effect of Kanglaite being used in clinical settings needs to be confirmed by further large and multicenter. PMID- 20716424 TI - [The Expression of COX-2 in Human Lung Cancer and its Relationship with Expression of K-ras and Mcl-1.]. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) is a subtype of rate-limiting enzyme in arachidonic acid metabolism, and it is related with tumorignesis, development and metastasis. In this study, we investigated the expression and clinical significance of COX-2 and its relationship with expression of K-ras and Mcl-1 proteins. METHODS: The expression of COX-2, K-ras and Mcl-1 were detected in 101 lung cancer tissues and 7 normal lung tissues by immunohistochemical method and image analysis system. RESULTS: The overexpression of COX-2 protein was detected in non-small cell lung cancer (P <0.05), especially in adenocarcinoma; There was overexpression of COX-2 in the peripheral type and late stage lung cancer (P <0.05); There was positive correlation among the COX-2, K-ras and Mcl-1(P <0.05). CONCLUSIONS: The expression of COX-2 was closely related with K-ras gene mutation and Mcl-2 upregulation, it played an important role during differentiation and progression of lung cancer. PMID- 20716425 TI - [A systematic review of talc compared with bleomycin for patients with malignant pleural effusion.]. AB - BACKGROUND: Malignant pleural effusions are a common complication in advanced malignancy. Talc, bleomycin and the tetracyclines are the three most frequently used sclerosants. The aim of this study is to evaluate the efficacy and adverse effects of patients with malignant pleural effusions treated with talc and bleomycin. METHODS: We searched PubMed, Embase, the Cochrane Library, Chinese biomedicine literature database (CBM), CNKI, VIP, references of included studies for randomized controlled trials comparing talc with bleomycin for patients with malignant pleural effusions. The quality of included studies was assessed independently by two reviewers, discrepancies were resolved by discussion with the third person. We analyzed the data using Review Manager (version 5.0) software. RESULTS: Six studies totaling 224 patients were included. Meta analysis results were as follows: there was significant difference in treatment success (RR=1.22, 95%CI: 1.05-1.42), recurrence rate (RR=0.31, 95%CI: 0.11-0.87) between talc group and bleomycin group, there was no significant difference between the two groups in case fatality rate (RR=1.39, 95%CI: 0.84-2.30), fever (RR=0.68, 95%CI: 0.24-1.94), pain (RR=0.22, 95%CI: 0.01-4.32). CONCLUSIONS: Current evidence indicate that talc is super to bleomycin for patients with malignant pleural effusions in terms of improving treatment success and reducing recurrence rate, there is no significant difference between the two group with regard to case fatality rate, fever, pain, the results mentioned above still need to be confirmed by high quality, large sample, multicenter randomized controlled trial. PMID- 20716426 TI - [Long-term Effect of Chemotherapy of Lung Cancer by Isolated Lung Perfusion and Planted Drug Pump on Pulmonary Artery.]. AB - BACKGROUND: How to treat non-surgical lung cancer effectively is always a great subject in the research and therapy of lung cancer. The aim of this study is to study chemotherapy of lung cancer through isolated lung perfusion (ILP), and to observe the protective efficacy. METHODS: After high dose of chemotherapy through circular perfusion, plant a duct into the inflicted pulmonary artery and lead the duct to a subcutaneous drug pump implanted. Study group of 51 cases was dripped through the pump with ADM, meanwhile dripped drag of GP schedule. Chemo group of 50 cases was applied intravenous GP schedule. RESULTS: Disease control rate (CR+PR+SD) is 78.4% in study group and 56.0% in control group (P =0.016); Survival rate of one year is 81.2% and 23.3% (P <0.001), survival rate of three year is 27.5% and 8.0% (P =0.012), and survival rate of five year is 6.0% and 0 (P =0.240) respectively; Toxin side-effect: ILP had a lesser degree of toxin side effect, and the side-effect sustained shorter and the recovery was faster; Quality of existence: quality of life in study group was improved obviously. CONCLUSIONS: ILP is a safe and feasible novelty of treating late lung cancer. The advantage is its high concentration, precise local administration and lesser side effect; subcutaneous drug pump facilitates the intermittent local administration of drag and could clearly improve the survival rate and life quality. PMID- 20716427 TI - [Acceptable safety of bevacizumab therapy in combination with chemotherapy in patients with advanced lung cancer.]. AB - BACKGROUND: Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) in October 2006 for use in combination with carboplatin and paclitaxel for the initial treatment of patients with unresectable, locally advanced, recurrent, or metastatic, nonsquamous, non-small cell lung cancer (NSCLC). The aim of this study is to observe the safety of bevacizumab therapy in combination with chemotherapy in Chinese patients with NSCLC. METHODS: Patients with advanced non-squamous NSCLC were treated with Bevacizumab 15 mg/kg, d1, repeated every 21 days until PD; Plus paclitaxel 175 mg/m(2), on dl and carboplatin AUC=6 on dl. The cycle was repeated every 21 days. RESULTS: One grade 3 epistaxis was observed in one patient. One grade 4 thrombosis was observed in one patient. 3/4-grade epistaxis and thrombosis was the most significant adverse events. Other adverse effects, such as hemoptysis, hypertension and proteinuria, were not severe and could be well tolerated. CONCLUSIONS: Most chemotherapy-naive patients with advanced non-squamous NSCLC treated with bevacizumab in combination with paclitaxel and carboplatin have little adverse effects that can be well tolerated. PMID- 20716428 TI - [Diagnostic value of transbronchial lung biopsy in peripheral lung cancer.]. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Because the locations of peripheral lung cancer are special, diagnosis of peripheral lung cancer is difficult. The aim of this study was to evaluate diagnostic value of transbronchial lung biopsy (TBLB) in peripheral lung cancer. METHODS: Transbronchial lung biopsy (TBLB) were performed in 78 cases of peripheral lung cancer which could not be observed by bronchoscope, 42 cases among whom were diagnosed by pathology and cytologic examination. Thirty-six cases of peripheral lung cancer were not able to be diagnosed by TBLB, 22 cases among them were diagnosed by percutaneous lung biopsy (PNLB), and 14 cases being left were diagnosed by surgical operation, lymphadenopathy biopsy, pleura biopsy and sputum cytologic examination successively. RESULTS: The positive rate produced by transbronchial lung biopsy, brush biopsy were 53.8% and 8.9% respectively. The total positive rate was 57.7%. The positive rate produced by TBLB was higher than that of brush biopsy (P <0.01). Along with tumor's diameter enlarge, the positive rate of diagnosis was higher. The positive rate of right lung was higher than that of left lung. The positive rate of inferior lung was higher than that of upper lung. The lesions near the inner belt and hilus pulmonis, had the higher positive rate. Complicatin frequency in PNLB was much higher than that in TBLB. CONCLUSIONS: Transbronchial lung biopsy is an important method in diagnosing of peripheral lung cancer. Combination of TBLB can increase the diagnostic positive rate of peripheral lung cancer. PMID- 20716429 TI - [Recent Advances on in vivo Imaging with Fluorescent Proteins for the Research of Lung Cancer.]. PMID- 20716430 TI - [Chemotherapy of Advanced Non-small Cell Lung Cancer in Elderly Patients.]. PMID- 20716431 TI - [Advance of Early Lung Cancer Screening by Low-Dose Spiral CT.]. PMID- 20716432 TI - [Research Advance of TRAIL Molecular Target in the Therapy of Lung Cancer.]. PMID- 20716433 TI - [Non-surgical Minimal Interventions of Early Central Non-small Cell Lung Carcinoma.]. PMID- 20716434 TI - [A case report of sudden death due to acute myocardial infarction and gemcitabine plus Cisplatin scheme.]. PMID- 20716435 TI - Structural characterization and stability of dimethylaminoethanol and dimethylaminoethanol bitartrate for possible use in cosmetic firming. AB - 2-Dimethylaminoethanol (DMAE) (also known as deanol) has been used as an ingredient in skin care, and in cognitive function- and mood-enhancing products. It is marketed as a free base or salt, and in theory, the two forms should be equally effective and able to substitute for each other in pharmaceutical formulations. Detecting possible alterations in the active principle is a basic part of preformulation studies. Accordingly, this study compared DMAE and DMAE bitartrate to identify potential alterations or differences between the free base and the salt that might compromise the long-term stability of cosmetic preparations at different temperatures, and also compared the behavior of the base substance and derivative alone and in solution. Samples were analyzed with different physicochemical methods such as differential scanning calorimetry, ultraviolet and infrared spectroscopy, and nuclear magnetic resonance spectroscopy. PMID- 20716436 TI - Wild Plum: novel particles of improved optical brightness and fluorescence. AB - A novel compound named Wild Plum fluoresces blue, and has been synthesized to camouflage skin imperfections, addressing the market demand for an anti-aging product. Wild Plum imparts optical brightness and fluorescence and can be used as an ingredient in cosmetic formulations. Skin appearance before and after application of Wild Plum compounds demonstrated an improved appearance of skin including a decreased number of wrinkles. When added to makeup, lotions, creams, and powders, Wild Plum conveys the glow of healthy youthful skin, replacing other costly or invasive alternatives such as cosmetic surgery. PMID- 20716437 TI - Morphological study of cationic polymer-anionic surfactant complex precipitated in solution during the dilution process. AB - We investigated the phase diagrams and the morphology of the complexes that were formed by cationic polymers, cationic cellulose (CC) and cationic dextran (CD), and by anionic surfactant-based sodium poly(oxyethylene) lauryl ether sulfate (LES). The anionic charge of the LES-based surfactants was changed by adding an amphoteric surfactant, lauryl amidopropyl betaine acetate (LPB), or a nonionic surfactant, polyoxyethylene stearyl ether (C18EO25). We discuss the relationship between the complex aggregation process and the morphology of the precipitated complexes. The morphologies of CC complex aggregates, which precipitated during the dilution process in a model shampoo solution, changed from membranous forms to mesh-like forms by decreasing the charges of both the CC and the surfactant. Their touch on hair in the rinsing process changed from sticky to smooth and velvety, corresponding to their rheological properties. In contrast, CD complex aggregates had a membranous form and a smooth touch independently of the charges on the polymer and surfactant. These results suggested that the control of the charges of both the polymer and surfactant and the choice of polymer structure are important for excellent conditioning effects upon rinsing with shampoo. PMID- 20716438 TI - Regional variation in the free amino acids in the stratum corneum. AB - Regional differences in water-binding free amino acids (FAAs) in the stratum corneum (SC) may be expected, since differences in skin biophysical properties are well known. The objective was to determine whether differences in skin hydration as a function of body site may arise from differences in the chemical makeup of the skin, specifically the FAAs. Levels were quantified from serial SC samples collected from the forearm, calf, back, torso, and jaw in two studies using HPLC methods. FAA levels were higher from the calf versus the forearm and lower from the jaw compared to torso and back skin. Body site variations in skin hydration could not be attributed to differences in FAA levels. PMID- 20716439 TI - Evaluation of the effect of Thai breadfruit's heartwood extract on the biological functions of fibroblasts from wrinkles. AB - In previous studies, extract from Artocarpus incisus's heartwood (breadfruit tree) had antioxidant and antimelanogenic activities. Here, we investigated the extract's action on facial skin fibroblasts from wrinkled skin and nonwrinkled skin biopsies, particularly in the production of type I procollagen and metalloproteinase- 1 (MMP-1) and in the reorganization of collagen fibers. We found that the extract at a concentration of 50 microg/ml significantly enhanced percent viability and proliferation of wrinkled-skin fibroblasts. Flow cytometry showed that a 3.6-fold increased proportion of the wrinkled-skin fibroblasts were in their cell cycle S-phase, indicating increased proliferation. Type I procollagen synthesis by wrinkled-skin fibroblasts was augmented by the extract. Nonwrinkled-skin fibroblasts had higher synthesis and were unaffected by the extract. MMP-1 secretion was greater for wrinkled-skin fibroblasts, but the extract decreased its secretion for both fi broblasts samples. Fibroblasts were incorporated in collagen lattice disks. Lattices with nonwrinkled-skin fibroblasts contracted uniformly by 56% after a three-day culture and the extract had little effect. However, wrinkled-skin fi broblast lattices failed to show appreciable contractions (to 12% after three days). But remarkably, the extract conferred an ability of the wrinkled-skin fibroblast lattices to fully contract (to 53%). This shows that wrinkled-skin fi broblasts have the ability to reorganize collagen but that the extract can reactivate this latent potential. Our findings for the first time reveal that A. incisus's heartwood extract reversed the fibroblast deficiencies in the metabolism and reorganization of collagen and may underlie a wrinkle treatment. PMID- 20716442 TI - How well does urinary lyso-Gb3 function as a biomarker in Fabry disease? AB - BACKGROUND: Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb(3)), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb(3)), is increased in patients with the disease. Until now, lyso-Gb(3) was not detectable in urine, possibly because of the presence of interfering compounds. METHODS: We undertook to: 1) characterize lyso-Gb(3) in urine; 2) develop a method to quantitate urinary lyso Gb(3) by mass spectrometry; 3) evaluate urinary lyso-Gb(3) as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb(3) is an inhibitor of alpha-galactosidase A activity. We analyzed urinary lyso-Gb(3) from 83 Fabry patients and 77 healthy age-matched controls. RESULTS: The intraday and interday bias and precision of the method were <15%. Increases in lyso-Gb(3)/creatinine correlated with the concentrations of Gb(3) (r(2)=0.43), type of mutations (p=0.0006), gender (p<0.0001) and enzyme replacement therapy status (p=0.0012). Urine from healthy controls contained no detectable lyso-Gb(3). Lyso-Gb(3) did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb(3) of Fabry patients correlated well with a number of indicators of disease severity. CONCLUSION: Lyso-Gb(3) is a reliable independent biomarker for clinically important characteristics of Fabry disease. PMID- 20716444 TI - Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK. AB - Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ET(B)) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-kappaB specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ET(B) receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ET(B) receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ET(B) receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ET(B) receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ET(B) receptors. Thus, the MAPK-mediated upregulation of contractile ET(B) receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke. PMID- 20716443 TI - Paragonimus westermani possesses aerobic and anaerobic mitochondria in different tissues, adapting to fluctuating oxygen tension in microaerobic habitats. AB - We previously showed that adult Paragonimus westermani, the causative agent of paragonimiasis and whose habitat is the host lung, possesses both aerobic and anaerobic respiratory chains, i.e., cyanide-sensitive succinate oxidase and NADH fumarate reductase systems, in isolated mitochondria (Takamiya et al., 1994). This finding raises the intriguing question as to whether adult Paragonimus worms possess two different populations of mitochondria, one having an aerobic succinate oxidase system and the other an anaerobic fumarate reductase system, or whether the worms possess a single population of mitochondria possessing both respiratory chains (i.e., mixed-functional mitochondria). Staining of trematode tissues for cytochrome c oxidase activity showed three types of mitochondrial populations: small, strongly stained mitochondria with many cristae, localised in the tegument and tegumental cells; and two larger parenchymal cell mitochondria, one with developed cristae and the other with few cristae. The tegumental and parenchymal mitochondria could be separated by isopycnic density-gradient centrifugation and showed different morphological characteristics and respiratory activities, with low-density tegumental mitochondria having cytochrome c oxidase activity and high-density parenchymal mitochondria having fumarate reductase activity. These results indicate that Paragonimus worms possess three different populations of mitochondria, which are distributed throughout trematode tissues and function facultatively, rather than having mixed-functional mitochondria. PMID- 20716445 TI - Production and purification of human papillomavirus type 33 L1 virus-like particles from Spodoptera frugiperda 9 cells using two-step column chromatography. AB - The major capsid protein L1 of human papillomavirus (HPV) is essential in construction of recombinant antigen vaccines against cervical cancer. HPV type 33 accounts for about 10% of all HPV infections in Asia. The gene encoding the major capsid protein L1 of the high-risk HPV type 33 was isolated from a Korean patient and expressed in Sf-9 insect cells using a baculovirus expression system. HPV33 L1 protein was isolated by two-step chromatographic purification using strong cation exchange and ceramic hydroxyapatite chromatography. Strong-cation-exchange chromatography was performed to achieve initial purification of HPV33 L1 and to remove most contaminating proteins, and secondary ceramic hydroxyapatite chromatography yielded pure HPV33 L1 virus-like particles (VLPs). Ceramic hydroxyapatite columns are particularly useful in the purification of antibodies, antigens, human viruses, and VLPs, and we thus used this system. The expression of HPV L1 protein in Sf-9 cells was examined by SDS-PAGE, Western-blotting, and ELISA analyses, and the data showed that HPV33 L1 VLPs were determined to > 98% purity and 58.7% recovery by a quantitative immuno-ELISA assay. Transmission electron microscopy analysis revealed that the HPV VLPs were approximately 50-60 nm in diameter and created by self-assembly of HPV L1 protein. The efficient and simple purification process described here should be useful in production of a cervical cancer vaccine. PMID- 20716446 TI - Expression and purification of an adenylation domain from a eukaryotic nonribosomal peptide synthetase: using structural genomics tools for a challenging target. AB - Nonribosomal peptide synthetases (NRPSs) are large multimodular and multidomain enzymes that are involved in synthesising an array of molecules that are important in human and animal health. NRPSs are found in both bacteria and fungi but most of the research to date has focused on the bacterial enzymes. This is largely due to the technical challenges in producing active fungal NRPSs, which stem from their large size and multidomain nature. In order to target fungal NRPS domains for biochemical and structural characterisation, we tackled this challenge by using the cloning and expression tools of structural genomics to screen the many variables that can influence the expression and purification of proteins. Using these tools we have screened 32 constructs containing 16 different fungal NRPS domains or domain combinations for expression and solubility. Two of these yielded soluble protein with one, the third adenylation domain of the SidN NRPS (SidNA3) from the grass endophyte Neotyphodium lolii, being tractable for purification using Ni-affinity resin. The initial purified protein exhibited poor solution behaviour but optimisation of the expression construct and the buffer conditions used for purification, resulted in stable recombinant protein suitable for biochemical characterisation, crystallisation and structure determination. PMID- 20716447 TI - Autoimmunity in 2009. AB - The number of 2009 publications in indexed journals dealing with 'autoimmunity' has maintained its increasing trend compared to the previous five years. Numerous developments have been proposed in our understanding of systemic and organ specific autoimmune diseases (particularly multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis) and of basic autoimmunity mechanisms (particularly Th17, T regulatory cells, and autoantibodies). Both these lines of evidence share a significant potential to be translated into new therapeutic options to impact clinical practice. This article will discuss selected publications from prominent scientific journals dedicated to immunology and autoimmunity and ultimately include some expectations in branches of autoimmunity that appear promising for future developments. PMID- 20716449 TI - Regulatory effect of vasoactive intestinal peptide on the balance of Treg and Th17 in collagen-induced arthritis. AB - Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide. The capacity of VIP can be exhibited through inhibiting inflammatory responses, shifting the Th1/Th2 balance in favor of anti inflammatory Th2 immunity and inducing regulatory T cells (Tregs) with suppressive activity. In addition to pro-inflammatory Th1 response, Th17 are also believed to play important roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we used collagen-induced arthritis (CIA) model in Wistar rats to investigate the role of VIP in the balance of CD4(+) CD25(+) Tregs and Th17 on RA. Data presented here showed that administration of VIP decreased incidence and severity of CIA. Disease suppression was associated with the upregulation of CD4(+) CD25(+) Tregs, downregulation of Th17- and Th1-type response and influence on the RANK/RANKL/OPG system. The results provide novel evidence that the therapeutic effects of VIP on CIA rats were associated with the balance of CD4(+) CD25(+) Tregs and Th17. PMID- 20716448 TI - In silico CD4+ T-cell epitope prediction and HLA distribution analysis for the potential proteins of Neisseria meningitidis Serogroup B--a clue for vaccine development. AB - Neisseria meningitidis, an exclusive human pathogen, is a major cause of mortality due to meningococcal meningitis and sepsis in many developing countries. Three meningococcal serogroup B proteins, i.e. T-cell stimulating protein A (TspA), autotransporter A (AutA), and IgA-specific serine endopeptidase (IGA1) elicits CD4+ T-cell response and may enhance the effectiveness of meningococcal vaccines by acting as protective immunogens. A very limited data on T-helper cell epitopes in MenB proteins is available. Hence, in silico prediction of peptide sequences which may act as helper T lymphocyte epitopes in MenB proteins was carried out by NetMHCIIpan web server. HLA distribution analysis was done by using the population coverage tool of Immune Epitope Database to determine the fraction of individuals in various populations expected to respond to a given set of predicted T-cell epitopes based on HLA genotype frequencies. Six epitopic core sequences, two from each MenB proteins, i.e. AutA, TspA and IgA1 protease were predicted to associate with a large number of HLA-DR alleles. These six peptides may act as T-cell epitope in more than 95% of populations in 8 out of 12 populations considered. The T-cell stimulation potential of these predicted peptides containing the core epitopic sequences is to be validated by using laboratory experiments for their efficient use as peptide vaccine candidates against N. meningitidis serogroup B. PMID- 20716450 TI - Discrimination between receptor- and store-operated Ca(2+) influx in human neutrophils. AB - Ca(2+) and Sr(2+) entry pathways activated by pro-inflammatory agonists FMLP, LTB(4) and PAF have been compared to thapsigargin in human neutrophils. 2-APB (10microM) increased Ca(2+) influx and to a greater extent in agonist than in thapsigargin stimulated neutrophils. This action of 2-APB was specific to Ca(2+) because 2-APB did not augment Sr(2+) entry in agonist and thapsigargin stimulated neutrophils. This suggests that Ca(2+) and Sr(2+) entry can be used to discriminate between receptor and non-receptor (store)-operated Ca(2+) influx. Our data show for the first time that Pyr3 whilst partially inhibiting agonist induced Ca(2+) influx almost completely abolished Ca(2+) influx after thapsigargin stimulation. PMID- 20716451 TI - The influence of polarity of additive molecules on micelle structures of polystyrene-block-poly(4-vinylpyridine) in the fabrication of nano-porous templates. AB - Block copolymers are useful for in situ synthesis of nanoparticles as well as producing nanoporous templates. As such, the effects of precursors on the block copolymer micelle structure is important. In this study, we investigate the effects of polarity of molecules introduced into block copolymer micelle cores on the micelle structure. The molecular dipole moment of the additive molecules has been evaluated and their effects on the block copolymer micelles investigated using light scattering spectroscopy, small-angle X-ray scattering, transmission electron microscopy and atomic force microscopy. The molecule with the largest dipole moment resulted in spherical structures with a polydispersity of less than 0.06 in a fully translational diffusion system. Surprisingly, the less polar additive molecules produced elongated micelles and the aspect ratio increases with decreasing polarity. The change in structure from spherical to elongated structure was attributed to P4VP chain extension, where compounds with polarity most similar to P4VP induce the most chain extension. The second virial coefficients of the solutions with elongated micelles are lower than that for spherical micelle systems by up to one order in magnitude, indicating a strong tendency for micelles to coalesce. On rinsing the spin-cast films, pores were obtained from spherical micelles and ridges from elongated micelles, suggesting a viable alternative for morphology modification using mild conditions where external annealing treatments to the film are not preferred. The knowledge of polarity effects of additive molecules on micelle structure has wider implications for supramolecular block copolymer systems where, depending on the application requirements, changes to the shape of the micelle structure can be induced or avoided. PMID- 20716452 TI - Wettability designing by ZnO periodical surface textures. AB - A facile and effective aqueous chemical synthesis approach towards well control of periodical ZnO textures in large-scale areas is reported, by which considerable adjusting of surface wettability can be realized. With the assistance of polystyrene spheres monolayer template and morphology control agent, we succeeded in preparing a series of ordered ZnO microbowls with different sag height. It was found that the contact angle could be well adjusted by changing geometry of microbowl. Such novel, ordered arrays are expected to exploit the great potentiality in waterproof or self-cleaning micro/nanodevices, and even microfluidic devices. PMID- 20716453 TI - Amphiphilic invertible polymers for adsolubilization on hydrophilic and hydrophobized silica nanoparticles. AB - Adsolubilization of poorly water-soluble 2-naphthol into amphiphilic invertible polymers (AIPs) has been successfully performed on hydrophilic and hydrophobized silica nanoparticles. The polymers adsolubilize molecules of sparingly water soluble 2-naphthol into the adsorbed layer on both substrates. AIP macromolecules show different surface activity depending on length of the hydrophobic fragment in macromolecules. Different AIP fragments are responsible for polymer adsorption on hydrophilic and hydrophobized silica. It is expected that mainly AIP hydrophobic fragments interact with 2-naphthol molecules and facilitate adsolubilization. The amount of adsolubilized 2-naphthol does not depend on substrate nature and length of the hydrophobic fragment in polymer. It is primarily regulated by the total length of the adsorbed macromolecules. PMID- 20716454 TI - Fabrication and electrocatalytic activities of porphyrin and 12-molybdophosphoric acid hybrid films. AB - Hybrid films composed of oppositely charged Keggin-type 12-molybdophosphoric acid H(3)PMo(12)O(40).nH(2)O (PMo(12)) and water-soluble cationic meso-tetra (N-methyl 4-pyridyl) porphinetetratosylate (TMPyP) were fabricated onto silicon and ITO substrates by a layer-by-layer (LbL) self-assembly technique. The LbL films were characterized by UV-vis spectroscopy, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and cyclic voltammetry (CV). The electrochemical properties of the prepared multilayer films were controlled by adjusting the solution pH. Moreover, with increase in the layer number of TMPyP/PMo(12), the electrocatalytic current toward the reduction of IO(3)(-) was enhanced. The LbL films also displayed good electrocatalytic activities toward the reduction of BrO(3)(-), IO(3)(-) , and S(2)O(8)(2-). PMID- 20716455 TI - Effects of C358A missense polymorphism of the endocannabinoid degrading enzyme fatty acid amide hydrolase on weight loss after a hypocaloric diet. AB - The Pro129THr, C385A, polymorphism of FAAH gene (rs324420C>A) has been associated with overweight and obesity. We investigate the role of this polymorphism on anthropometric and metabolic responses to a weight loss program. Obese individuals (n = 122) were assessed at baseline and after 3 months of a hypocaloric diet. There were 76.2% (n = 93) homozygotes for the C allele, 23.8% (n = 27) AC heterozygotes, and 1.6% (n = 2) homozygotes for the A allele. After the dietary intervention, all individuals decreased their body weight (in kilograms), body mass index (in kilograms per square meter), fat mass (in kilograms), waist circumference (in centimeters), and systolic blood pressure (in millimeters of mercury). In mutant-type group, the decrease in weight was 3.5 +/- 3.6 kg (decrease in wild-type group, 2.4 +/- 3.8 kg); and the decrease in waist circumference was 5.4 +/- 6.4 cm (decrease in wild-type group, 2.6 +/- 4.8 cm). Individuals with the A/C or AA genotype had a significant reduction (P < .05) in glucose (96.5 +/- 12.5 vs 92.3 +/- 10.5 mg/dL; difference, 2.68 +/- 1.81 mg/dL), total cholesterol (215.3 +/- 49 vs 193.3 +/- 27.6 mg/dL; difference, 14.31 +/- 7.21 mg/dL), and low-density lipoprotein cholesterol (133.6 +/- 53 vs 106.7 +/- 39.2 mg/dL; difference, 15.87 +/- 9.61 mg/dL) levels. The A allele at rs324420 in the FAAH gene was associated with larger improvements in glucose, total cholesterol, low-density lipoprotein cholesterol, body mass, and waist circumference after a dietary intervention. PMID- 20716456 TI - Effectiveness of a puppet show on iodine knowledge, attitudes and behaviour of elementary students and the indirect effects on their parents and households in Ho Chi Minh City: a pilot study. PMID- 20716457 TI - Does attendance at preschool affect adult health? A systematic review. AB - BACKGROUND: Early child development interventions can set children on positive social and educational trajectories. The aim of this review was to examine the evidence for the adult health impacts of centre-based preschool interventions for preschoolers. METHODS: Medline, Embase, ERIC, Psych Info, Sociological Abstracts, the Cochrane Library, C2-SPECTR and the Head Start database were searched (1980 2008), and reference lists were searched for articles missed by the electronic search. RESULTS: The 12 eligible articles reviewed reported multi-faceted interventions and involved disadvantaged populations in all but one study. Limitations included a restricted range of health outcomes, reliance on self report measures (11 studies), small sample sizes (nine studies with <100 in each arm) and a relatively young adult age at follow-up. There were positive intervention effects across the majority of behavioural outcomes, and a suggestion of a reduction in symptoms of depression. Non-communicable disease outcomes (e.g. diabetes mellitus) tended to have adverse or near-zero effect estimates. CONCLUSIONS: The reviewed articles provide some support for the role of early childhood interventions to improve health behaviours but not chronic disease outcomes. Population health researchers should become more involved in the evaluation of preschool interventions as there is great potential for broad population health benefit. PMID- 20716458 TI - A ferricyanide-mediated activated sludge bioassay for fast determination of the biochemical oxygen demand of wastewaters. AB - Activated sludge was successfully incorporated as the biocatalyst in the fast, ferricyanide-mediated biochemical oxygen demand (FM-BOD) bioassay. Sludge preparation procedures were optimized for three potential biocatalysts; aeration basin mixed liquor, aerobic digester sludge and return activated sludge. Following a 24h starving period, the return activated sludge and mixed liquor sludges reported the highest oxidative degradation of a standard glucose/glutamic acid (GGA) mixture and the return activated sludge also recorded the lowest endogenous FM-respiration rate. Dynamic working ranges up to 170 mg BOD(5)L(-1) for OECD standard solutions and 300mg BOD(5)L(-1) for GGA were obtained. This is a considerable improvement upon the BOD(5) standard assay and most other rapid BOD techniques. Time-series ferricyanide-mediated oxidation of the OECD(170) standard approached that of the GGA(198) standard after 3-6h. This is noteworthy given the OECD standard is formulated as a synthetic sewage analogue. A highly significant correlation with the BOD(5) standard method (n=35, p<0.001, R=0.952) was observed for a wide diversity of real wastewater samples. The mean degradation efficiency was indistinguishable from that observed for the BOD(5) assay. These results demonstrate that the activated sludge FM-BOD assay may be used for simple, same-day BOD analysis of wastewaters. PMID- 20716459 TI - Carbon nanotube blended polyethersulfone membranes for fouling control in water treatment. AB - Multi-walled carbon nanotube/polyethersulfone (C/P) blend membranes were synthesized via the phase inversion method. The resultant membranes were then characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and contact angle. The C/P blend membranes appeared to be more hydrophilic, with a higher pure water flux than the polyethersulfone (PES) membranes. It was also found that the amount of multi-walled carbon nanotubes (MWCNTs) in the blend membranes was an important factor affecting the morphology and permeation properties of the membranes. After 24 h of surface water filtration with 7 mgC/L TOC content, the C/P blend membranes displayed a higher flux and slower fouling rate than the PES membranes. Subsequent analyses of the desorbed foulants showed that the amount of foulant on bare PES membranes was 63% higher than the C/P blend membrane for 2% MWCNTs content. Thus, the carbon nanotube content of the C/P membranes was shown to alleviate the membrane fouling caused by natural water. PMID- 20716460 TI - Tracing sediment loss from eroding farm tracks using a geochemical fingerprinting procedure combining local and genetic algorithm optimisation. AB - Eroding farm tracks represent important spatially distributed features in many agricultural landscapes and there is concern over their role in catchment sediment problems. It is, however, important to place eroding farm tracks in the context of catchment sediment sources more generally, especially since the former afford potential for targeted sediment mitigation. A sediment source tracing procedure was therefore used to assess the importance of eroding farm track surfaces as a contemporary primary suspended sediment source relative to inputs from pasture or cultivated topsoils and channel banks/subsurface sources, in the upper River Piddle catchment (~100km(2)), in southern England. The study provided a timely opportunity to assess the performance of both local and global (genetic algorithm; GA) optimisation techniques in the sediment geochemistry mass balance modelling used to apportion sources. Over the duration of the study, average median source contributions for individual time-integrated suspended sediment samples collected from three sub-catchments ranged between 1+/-1 and 19+/-3% for farm track surfaces, 31+/-3 and 55+/-2% for pasture topsoils, 1+/-1 and 19+/-1% for cultivated topsoils and 23+/-2 and 49+/-1% for channel banks/subsurface sources. Comparison of the local and GA optimisation techniques demonstrated that GA with random initial values improved the minimisation of the objective functions compared to local searching by 0.01-0.04% of 5000 repeat Monte Carlo iterations. GA informed by the outputs of the local optimisation as initial values improved corresponding performance by 0.05-0.20%. These findings increased confidence in the outputs from the local optimisation mass balance modelling, but fingerprint property datasets should be treated on an individual basis. Future sediment source tracing studies should always endeavour to combine local and global search tools to avoid the risk of using localised solutions for source apportionment estimates. PMID- 20716461 TI - Arbuscular mycorrhiza alters metal uptake and the physiological response of Coffea arabica seedlings to increasing Zn and Cu concentrations in soil. AB - Studies on mycorrhizal symbiosis effects on metal accumulation and plant tolerance are not common in perennial crops under metal stress. The objective of this study was to evaluate the influence of mycorrhization on coffee seedlings under Cu and Zn stress. Copper (Cu) and zinc (Zn) uptake and some biochemical and physiological traits were studied in thirty-week old Coffea arabica seedlings, in response to the inoculation with arbuscular mycorrhizal fungi (AMF) and to increasing concentrations of Cu or Zn in soil. The experiments were conducted under greenhouse conditions in a 2*4 factorial design (inoculation or not with AMF and 0, 50, 150 and 450mgkg(-1) Cu or 0, 100, 300 and 900mgkg(-1) Zn). Non mycorrhizal plants maintained a hampered and slow growth even in a soil with appropriate phosphorus (P) levels for this crop. As metal levels increased in soil, a greater proportion of the total absorbed metals were retained by roots. Foliar Cu concentrations increased only in non-mycorrhizal plants, reaching a maximum concentration of 30mgkg(-1) at the highest Cu in soil. Mycorrhization prevented the accumulation of Cu in leaves, and mycorrhizal plants showed higher Cu contents in stems, which indicated a differential Cu distribution in AMF associated or non-associated plants. Zn distribution and concentrations in different plant organs followed a similar pattern independently of mycorrhization. In mycorrhizal plants, only the highest metal concentrations caused a reduction in biomass, leading to significant changes in some biochemical indicators, such as malondialdehyde, proline and amino acid contents in leaves and also in foliar free amino acid composition. Marked differences in these physiological traits were also found due to mycorrhization. In conclusion, AMF protected coffee seedlings against metal toxicity. PMID- 20716462 TI - The promotion of neurological recovery in the rat spinal cord crushed injury model by collagen-binding BDNF. AB - Spinal cord crushed injury is clinically common. Promoting targeted neural regeneration at the crushed site of spinal cord could be important for the repair. It has been demonstrated in our previous work that native human BDNF fused with a collagen-binding domain (CBD-BDNF) can bind to collagen specifically to exert the neurotrophic effect on promoting axonal regeneration. After injury, collagen is highly accumulated at the injury site. We thus speculate that CBD BDNF will bind to the extracellular matrix collagen and concentrate at the injury site to improve the therapy. Using the rat spinal cord crushed injury model, we have found that CBD-BDNF by one-time intrathecally injection could be retained and concentrated at the injury site for a longer time than native BDNF without collagen-binding domain. CBD-BDNF could promote better neural regeneration and locomotion recovery. PMID- 20716464 TI - Mass spectrometric analysis of activity-dependent changes of neuropeptide profile in the snail, Helix pomatia. AB - Terrestrial snails are able to transform themselves into inactivity ceasing their behavioral activity under unfavorable environmental conditions. In the present study, we report on the activity-dependent changes of the peptide and/or polypeptide profile in the brain and hemolymph of the snail, Helix pomatia, using MALDI TOF and quadrupole mass spectrometry. The present data indicate that the snails respond to low temperature by increasing or decreasing the output of selected peptides. Average mass spectra of the brain and hemolymph revealed numerous peaks predominantly present during the active state (19 and 10 peptides/polypeptides, respectively), while others were observed only during hibernation (11 and 13). However, there were peptides and/or polypeptides or their fragments present irrespective of the activity states (49 and 18). The intensity of fourteen peaks that correspond to previously identified neuropeptides varied in the brain of active snails compared to those of hibernating animals. Among those the intensity of eight peptides increased significantly in active animals while in hibernated animals the intensity of another six peptides increased significantly. A new peptide or peptide fragment at m/z 1110.7 was identified in a brain of the snail with the following suggested amino acid sequence: GSGASGSMPATTS. This peptide was found to be more abundant in active animals because the intensity of the peptide was significantly higher compared to hibernating animals. In summary, our results revealed substantial differences in the peptide/polypeptide profile of the brain and hemolymph of active and hibernating snails suggesting a possible contribution of peptides in the process of hibernation. PMID- 20716465 TI - Attentional bias in untreated panic disorder. AB - The role of attentional biases in panic disorder has been well characterised. However, recent studies suggest an important effect of antidepressant and anxiolytic drugs on cognitive bias and most studies have included medicated patients in their sample. This study therefore examined cognitive bias in an untreated sample of participants with panic disorder (PD). A sample of 23 untreated participants with panic disorder with or without agoraphobia (PPD) and 22 healthy controls (HC) were tested with a Facial Expression Recognition task featuring different emotional intensities, a Faces Dot Probe task, a Self Beliefs task and an Emotional Stroop task. PPD showed exaggerated attentional biases to negative face and word stimuli in two different paradigms and endorsed more panic related and negative self-attributions. They also showed enhanced perception of facial expressions of sadness. These tasks are sensitive to cognitive bias in a community-based sample of untreated PD participants. Attentional biases in panic disorder cannot be explained by the use of medication in this group and may therefore play a critical role in the underlying pathogenesis of the disorder. PMID- 20716463 TI - Wnt signalling in implantation, decidualisation and placental differentiation- review. AB - The family of secreted Wingless ligands plays major roles in embryonic development, stem cell maintenance, differentiation and tissue homeostasis. Accumulating evidence suggests that the canonical Wnt pathway involving nuclear recruitment of beta-catenin and activation of Wnt-dependent transcription factors is also critically involved in development and differentiation of the diverse reproductive tissues. Here, we summarise our present knowledge about expression, regulation and function of Wnt ligands and their frizzled receptors in murine and human endometrial and placental cell types. In mice, Wnt signalling promotes early trophoblast lineage development, blastocyst activation, implantation and chorion-allantois fusion. Moreover, different Wnt ligands play essential roles in the development of the murine uterine tract, in cycling endometrial cells and during decidualisation. In humans, estrogen-dependent endometrial cell proliferation, decidualisation, trophoblast attachment and invasion were shown to be controlled by the particular signalling pathway. Failures in Wnt signalling are associated with infertility, endometriosis, endometrial cancer and gestational diseases such as complete mole placentae and choriocarcinomas. However, our present knowledge is still scarce due to the complexity of the Wnt network involving numerous ligands, receptors and non-canonical pathways. Hence, much remains to be learned about the role of different Wnt signalling cascades in reproductive cell types and their changes under pathological conditions. PMID- 20716466 TI - On-line groundwater velocity probe: laboratory testing and field evaluation. AB - An automated on-line instrument has been developed to rapidly measure groundwater velocity within a screened well. The instrument consists of a carbon dioxide gas tracer that is periodically delivered to a permeable chamber located within a screened well. The rate of diffusion of the tracer through the wall of the permeable chamber was rapid and the effective diffusion into the groundwater was controlled by the mass transfer limitations at the groundwater/chamber interface with gas entrainment proportional to the groundwater velocity past the chamber. By periodically delivering the gas tracer and monitoring the reduction in concentration of the tracer from the permeable chamber, the groundwater velocity was determined multiple times daily. Laboratory experiments undertaken within a calibrated flow chamber have demonstrated that the instrument can be used to accurately and reliably determine groundwater flow velocities at 3h intervals for flow rates between 25 and 300 m y(-1). Field testing of the velocity probe at multiple well locations in a sandy aquifer gave velocities consistent with another monitoring technique (passive flux meter) and site modelling. PMID- 20716467 TI - Synthesis, characterization and anti-microbial studies of some novel 2,4 disubstituted thiazoles. AB - In the present study a series of novel 2,4-disubstituted thiazole derivatives containing substituted pyrazole moiety was synthesized by the reaction of 3-Aryl 1H-pyrazole-4-carbaldehyde thiosemicarbazone with 6-Bromo/H-3-(bromoacetyl)-2H chromen-2-one/phenacyl chloride. Structures of newly synthesized compounds were characterized by spectral studies. New compounds were screened for their antibacterial studies against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. The results revealed that compounds 7c, 8e, and 8f having 2,5-dichlorothiophene substituent and 8c, 8d having 2,4 dichlorophenyl substituent showed significant antibacterial activity against all tested microorganisms. PMID- 20716468 TI - Synthesis, cytotoxic activities and DNA binding properties of beta-carboline derivatives. AB - In a continuing effort to develop novel beta-carbolines endowed with better pharmacological profile, a series of water-soluble beta-carbolines bearing a flexible amino side chain was designed and synthesized, and the cytotoxic activities in vitro of these compounds were evaluated. The N(9)-arylated alkyl substituted beta-carbolines represented the most interesting cytotoxic agents, and compounds 4c and 4d were found to be the most potent compounds with IC(50) values lower than 10 MUM against ten human tumor cell lines. The results confirmed that the N(9)-arylated alkyl substituents of beta-carboline played a very important role in the modulation of the cytotoxic potencies. In addition, the interaction with DNA of these compounds was also investigated, these compounds were found to exhibit significant DNA binding affinity. PMID- 20716469 TI - Estimating mercury emissions from a zinc smelter in relation to China's mercury control policies. AB - Mercury concentrations of flue gas at inlet/outlet of the flue gas cleaning, electrostatic demister, reclaiming tower, acid plant, and mercury contents in zinc concentrate and by-products were measured in a hydrometallurgical zinc smelter. The removal efficiency of flue gas cleaning, electrostatic demister, mercury reclaiming and acid plant was about 17.4%, 30.3%, 87.9% and 97.4% respectively. Flue gas cleaning and electrostatic demister captured 11.7% and 25.3% of the mercury in the zinc concentrate, respectively. The mercury reclaiming tower captured 58.3% of the mercury in the zinc concentrate. About 4.2% of the mercury in the zinc concentrate was captured by the acid plant. Consequently, only 0.8% of the mercury in the zinc concentrate was emitted to the atmosphere. The atmospheric mercury emission factor was 0.5 g t(-1) of zinc produced for the tested smelter, indicating that this process offers the potential to effectively reduce mercury emissions from zinc smelting. PMID- 20716470 TI - Back-calculation of the strength and location of hazardous materials releases using the pattern search method. AB - Predicting quickly and accurately the strength and location of hazardous materials releases becomes a critical problem in emergency rescue. A technique that coupled the concentrations observed in the downwind direction of the source with a dispersion model was presented to back-calculate the strength and location of the release source by using the pattern search method. The technique was described as an optimization problem with an objective function constructed from a sum of squared errors between the observed concentrations and the calculated concentrations. The utility of the pattern search method was illustrated by testing the simulation data with practical data. The advantages of the method were demonstrated by a comparison with a gradient-based algorithm and an intelligent optimization algorithm. The computations indicate that this method can achieve optimal solutions in a relatively shorter time, hence more efficiently meeting the needs of emergency rescue. PMID- 20716471 TI - Fludrocortisone therapy in a newborn with cerebral salt wasting due to hypernatremia and severe hyperbilirubinemia. PMID- 20716472 TI - Risk profiles for overweight/obesity among preschoolers. AB - BACKGROUND: The epidemic of overweight/obesity among U.S. children has led to an alarming increase in health-related consequences, including early-onset diabetes and cardiovascular disease. Recent research has identified the independent contribution of several maternal and child factors to the development of childhood overweight/obesity. Few studies, however, have examined risk profiles of childhood obesity. AIM: This study used classification and regression tree (CART) analysis to examine the combined effect of maternal and child factors in generating risk profiles for overweight/obesity among preschoolers. STUDY DESIGN: Data from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B) study were used. The sample was comprised of preschool children. CART and logistic regression models were built and compared. RESULTS: Children who were overweight/obese at two years of age had an increased risk of being overweight/obese at four years of age. Children born to overweight/obese mothers were more likely to be overweight/obese by age four, even if their BMI at two years of age was normal. Children with high birth weight (> or = 4000 g.) were also more likely to be overweight/obese at age four years if they were born to mothers with a normal pregravid BMI, but were of a lower socioeconomic status. Among preschoolers whose mothers were black or white and who had a high pregravid BMI, breastfeeding duration and parity played an important role in determining their risk of being overweight/obese. CONCLUSIONS: Classification tree analysis confirms and extends current knowledge of preschool overweight/obesity by providing preliminary risk profiles that are structured within the context of prenatal and postnatal maternal and child characteristics. PMID- 20716473 TI - Evaluation of iodine, iron, and selenium in biological samples of thyroid mother and their newly born babies. AB - BACKGROUND: There is accumulating facts that the metabolism of essential trace elements is altered in thyroid patients. AIM: The aim of present study was to compare the status of essential trace elements, iodine, iron (Fe), and selenium (Se) in biological samples (serum and urine) of goitrous mothers (age ranged 30 40) and their newly born infants (n=76). An age matched 68 non-goitrous mothers and their infants, residing in the same locality, were selected as referents. For a comparative study, the biological samples of non-goitrous and goitrous pregnant and non pregnant female subjects of the same age group and socio-economic status were also analyzed. METHODS: The Fe and Se concentrations in biological samples were determined by a flame and hydride generation atomic absorption spectrometry respectively, while iodine was measured by iodide-ion selective electrode, prior to microwave assisted acid digestion. The validity and accuracy of the methodology was checked by certified reference materials. RESULTS: The mean values of iodine, Fe and Se in serum and urine samples of thyroid mothers and their infants were significantly lower as compared to the referent mothers infants pairs (p<0.01). CONCLUSIONS: The deficiencies of essential trace elements may adversely affect the health of women and their neonates. PMID- 20716474 TI - Acute onset quadriparesis with sine wave: a rare presentation. PMID- 20716475 TI - A randomized controlled trial comparing minichest tube and needle aspiration in outpatient management of primary spontaneous pneumothorax. AB - OBJECTIVES: The aim of this study was to compare outcomes and complications associated with needle aspiration (NA) and minichest tube (MCT) insertion with Heimlich valve attachment in the treatment of primary spontaneous pneumothorax at an emergency department (ED). METHODS: Patients presenting with primary spontaneous pneumothorax were randomized to NA or MCT. They had repeat chest x rays immediately after the procedure and 6 hours later. Patients who underwent NA were discharged if repeat x-rays showed less than 10% pneumothorax. Those who had MCT were discharged if repeat x-rays did not show worsening of pneumothorax. They were reviewed at the outpatient clinic within 3 days. The primary outcomes of interest were failure rate and admission rate. The secondary outcomes were complication rate, pain and satisfaction scores, length of hospital stay, and rate of full recovery during outpatient follow-up. RESULTS: There were 48 patients whose mean age was 25 years. We found no difference in failure rate between the groups, except that there were more MCT (24%) than NA patients (4%) with complete expansion at first review (difference, -0.20; 95% confidence interval, -0.38 to -0.01). Thirty-five percent of NA group and 20% of MCT group needed another procedure at the ED. Fifty-two percent of NA patients and 28% of MCT patients were admitted from the ED to the inpatient ward. Nine percent and 12%, respectively, of patients who had NA and MCT were admitted from the review clinic. Both groups of patients had equivalent pain scores, satisfaction scores, and complication rates. CONCLUSION: Both MCT and NA allowed safe management of primary spontaneous pneumothorax in the outpatient setting. PMID- 20716476 TI - Renal injury study in critical ill patients in accordance with the new definition given by the Acute Kidney Injury Network. AB - OBJECTIVE: This research aims to apply the definition proposed by the Acute Kidney Injury Network (AKIN) research group to assess the incidence, risk factors, and outcomes in acute kidney injury (AKI) patients admitted at the intensive care unit (ICU). DESIGN: This is a retrospective cohort study. Patients who were admitted to the ICU from January 1, 2003 to December 31, 2004 were studied. INTERVENTIONS: Medical records of all patients were reviewed. Demographic information, diagnoses, risk factors for AKI, laboratory data, urinary output, frequency and days of exposure to mechanical ventilation, ICU and hospital stay, and outcomes were recorded. MEASUREMENTS AND MAIN RESULTS: A total of 794 patients were studied. There were 39.8% of patients who presented AKI (stage 1: 13.9%, stage 2: 12%, stage 3: 13.9%). The variables that were associated with the presence of AKI in the multivariable analysis were as follows: sepsis (odds ratio [OR], 5.29; 95% confidence interval [CI], 3.36-8.33), heart failure (OR, 3.01; 95% CI, 1.59-5.67), vasopressor use (OR, 1.89; 95% CI, 1.26-2.83), and age (beta = 1.02; 95% CI, 1.01-1.03). The mean hospital stay increased with renal commitment: patients without AKI, 10.9 days; AKIN stage 1, 17.8; AKIN stage 2, 21.1; and AKIN stage 3, 22.1 days (P < .0001). Mortality rate increased as more advanced the AKI stage was (no AKI, 7.3%; AKI 1, 16.4%; AKI 2, 34.7%; and AKIN 3, 45.5%; P < .0001). CONCLUSIONS: All of the result indicators- stay days in ICU, hospital stay days, frequency and days of mechanical ventilation, and mortality--considerably increased with more acute AKI stage. The most important risk factor of AKI was the sepsis. PMID- 20716477 TI - Predictors of early postdischarge mortality in critically ill patients: a retrospective cohort study from the California Intensive Care Outcomes project. AB - PURPOSE: Existing intensive care unit (ICU) mortality measurement systems address in-hospital mortality only. However, early postdischarge mortality contributes significantly to overall 30-day mortality. Factors associated with early postdischarge mortality are unknown. METHODS: We performed a retrospective study of 8484 ICU patients. Our primary outcome was early postdischarge mortality: death after hospital discharge and 30 days or less from ICU admission. Cox regression models assessed the association between patient, hospital, and utilization factors and the primary outcome. RESULTS: In multivariate analyses, the hazard for early postdischarge mortality increased with rising severity of illness and decreased with full-code status (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.21-0.49). Compared with discharges home, early postdischarge mortality was highest for acute care transfers (HR, 3.18; 95% CI, 2.45-4.12). Finally, patients with very short ICU length of stay (<1 day) had greater early postdischarge mortality (HR, 1.86; 95% CI; 1.32-2.61) than those with longest stays (>=7 days). CONCLUSIONS: Early postdischarge mortality is associated with patient preferences (full-code status) and decisions regarding timing and location of discharge. These findings have important implications for anyone attempting to measure or improve ICU performance and who rely on in hospital mortality measures to do so. PMID- 20716478 TI - Off-label medication use in adult critical care patients. AB - PURPOSE: This study evaluated the use of off-label medications in the intensive care unit (ICU) setting and their varying levels of evidence. MATERIALS AND METHODS: Thirty-seven ICUs from 24 US sites participated in this prospective, multicenter, observational study during a single 24-hour period. All medication orders were evaluated for Food and Drug Administration-labeled indications, strength of evidence, and strength of recommendation. Off-label medication orders were evaluated for indication, dose, route of administration, duration of therapy, and whether they were supported by institutional guidelines. RESULTS: A total of 414 patients were enrolled, yielding 5237 medication orders for analysis. Of these, 1897 orders (36.2%) were off-label. The 3 drug classes that accounted for the most off-label orders were bronchorespiratory, gastrointestinal, and immunology. The majority of off-label medication orders (89.1%) were initiated after patient admission to the ICU. Nine hundred twenty eight (48.3%) of the off-label medication orders had grade C or no evidence. CONCLUSIONS: The use of off-label medication therapies in the US adult critical care units is common, a majority of which are initiated after admission to the ICU and a significant portion of which are supported with inferior levels of evidence. PMID- 20716479 TI - Comparing clinical and neurocognitive features of the schizophrenia prodrome to the bipolar prodrome. AB - BACKGROUND: There is an increased interest in early intervention strategies for severe mental disorders with hopes of mitigating the emergence and impact of the illness. Individuals at clinical high-risk (CHR) for schizophrenia have been primarily identified by the presence of attenuated positive symptoms. Although bipolar disorder and schizophrenia may have overlapping etiologies, few studies have investigated the potential prodrome in bipolar disorder. We sought to determine if there is a prodrome to bipolar disorder and if clinical or neurocognitive measures could distinguish between the bipolar and schizophrenia prodromes. METHODS: We examined subjects who were initially identified as CHR for schizophrenia during the prodromal phase of the illness and followed them prospectively. Unexpectedly, eight subjects developed bipolar disorder. Baseline data from subjects who eventually developed bipolar disorder (pre-BP; N=8), schizophrenia or a psychotic disorder (pre-SZ; N=24) and a non-converter comparison group (NCC; N=115) were compared. RESULTS: The pre-BP and pre-SZ groups did not differ on attenuated positive symptom severity, global measures of functioning or on the global neurocognitive score. Compared to NCC individuals, both pre-BP and pre-SZ patients reported more severe attenuated positive symptoms and were more likely to be on antipsychotic medication at baseline. The pre-SZ group had a significantly lower current IQ and was significantly more impaired than the NCC group on the overall neurocognitive score. CONCLUSIONS: This study provides preliminary support for a bipolar prodrome, which may be indistinguishable from the schizophrenia prodrome based on clinical and neurocognitive measures currently used in high-risk schizophrenia programs. PMID- 20716481 TI - Palliative radiotherapy for non-melanoma skin cancer. AB - AIMS: The primary objective of this study was to assess the rate of tumour response to the palliative radiotherapy regimen used at our centre (8 Gy/fraction on days 0, 7, 21) for non-melanoma skin cancer. The secondary objective was to evaluate symptom palliation. MATERIALS AND METHODS: A retrospective chart review identified patients treated with this palliative radiotherapy regimen from August 2003 to December 2008. Patient age, gender, tumour histology, location, size, presenting symptoms and radiation treatment factors were recorded at baseline. The tumour size and tumour-related symptoms were recorded at each fraction and follow-up visit. The results were analysed on an intent to treat basis. RESULTS: Twenty-eight patients received 31 courses of palliative radiation for basal cell (five) or squamous cell (26) carcinoma of the skin. Twenty-one patients with 23 tumours attended at least one follow-up visit, and seven patients had incomplete follow-up data. At the time of last follow-up (median 17 weeks), the response rate was 58.1% (complete response 15/31; partial response 3/31). A complete response to treatment was correlated with a smaller tumour size at day 21 (P=0.0143). Presenting symptoms were alleviated in 61.3% (19/31) of symptomatic sites. No severe late toxicities were seen. CONCLUSIONS: This palliative regimen offers impressive response rates and effective symptom palliation for patients with non-melanoma skin cancer. PMID- 20716480 TI - Reduced intra-amygdala activity to positively valenced faces in adolescent schizophrenia offspring. AB - Studies suggest that the affective response is impaired in both schizophrenia and adolescent offspring of schizophrenia patients. Adolescent offspring of patients are developmentally vulnerable to impairments in several domains, including affective responding, yet the bases of these impairments and their relation to neuronal responses within the limbic system are poorly understood. The amygdala is the central region devoted to the processing of emotional valence and its sub nuclei including the baso-lateral and centro-medial are organized in a relative hierarchy of affective processing. Outputs from the centro-medial nucleus converge on regions involved in the autonomous regulation of behavior, and outputs from the baso-lateral nucleus modulate the response of reward processing regions. Here using fMRI we assessed the intra-amygdala response to positive, negative, and neutral valenced faces in a group of controls (with no family history of psychosis) and offspring of schizophrenia parents (n=44 subjects in total). Subjects performed an affective continuous performance task during which they continually appraised whether the affect signaled by a face on a given trial was the same or different from the previous trial (regardless of facial identity). Relative to controls, offspring showed reduced activity in the left centro-medial nucleus to positively (but not negatively or neutral) valenced faces. These results were independent of behavioral/cognitive performance (equal across groups) suggesting that an impaired affective substrate in the intra amygdala response may lie at the core of deficits of social behavior that have been documented in this population. PMID- 20716482 TI - Chronic respiratory disease and multimorbidity: prevalence and impact in a general practice setting. AB - BACKGROUND: Multimorbidity is defined as two or more co-existing chronic conditions in an individual and is common in general practice. It is associated with poorer outcomes for patients. This study aimed to establish the prevalence of multimorbidity in patients with chronic respiratory disease in general practice and to describe its impact on health service use. METHODS: Cross sectional study based in general practice in Dublin. Drug and disease code searches were performed to identify adult patients with a diagnosis of chronic respiratory disease. Medical records were reviewed for chronic respiratory diagnosis, other chronic conditions, demographic characteristics, General Practitioner (GP) and practice nurse utilisation rates, and numbers of medications. RESULTS: In a general practice population of 16,946 patients 3.9% had chronic respiratory disease and 60% of these had one or more co-existing chronic condition(s). GP and practice nurse utilisation rates, and number of medications were significantly higher among those with multimorbidity compared with those with respiratory disease alone. Multivariate analysis showed that increasing age and low socio-economic status were significantly associated with multimorbidity. CONCLUSION: The majority of patients with chronic respiratory disease have multimorbidity. Clinical guidelines based on single disease entities and outcomes are not as easy to implement and may not be as effective in this group. PMID- 20716483 TI - Enhancement effect of ethyl-2-methyl acetoacetate on triacylglycerols production by a freshwater microalga, Scenedesmus sp. LX1. AB - Microalgae are very promising in biodiesel production. To reduce the production cost, approaches to enhance lipid and triacylglycerols (TAGs) production by microalgae have gained much attention. Effect of ethyl-2-methyl acetoacetate (EMA) on the lipid and TAGs production by a freshwater microalga, Scenedesmus sp. LX1, was studied in this paper. EMA below a concentration of 2 mg L(-1) had no significant effect on microalgal biomass or lipid production. The biomass and lipid productivity were about 0.47 g L(-1) and 139 mg L(-1), respectively, and the lipid content per biomass was about 30% (w/w). Promisingly, comparing with the one without EMA treatment, under EMA concentrations of 1.0-2.0 mg L(-1) the TAGs content per lipid (about 20% (w/w)) and TAGs productivity (about 23 mg L( 1)) were increased by 79% and 40%, respectively. Therefore, exposing algal cells with trace amount of EMA offers a viable method to enhance the TAGs production in Scenedesmus sp. LX1. PMID- 20716484 TI - Two-liquid-phase mesophilic and thermophilic biotrickling filters for the biodegradation of alpha-pinene. AB - alpha-Pinene biodegradation was evaluated in mesophilic and thermophilic biotrickling filters. The potential of silicone oil for enhancing the removal was evaluated too, at both temperatures. Performance was studied at empty bed residence times between 60 and 14s, and concentrations of 0.06-38.84 gm(-3), with or without silicone oil. Efficiency decreased as the pollutant concentration was increased, showing higher elimination capacities at higher EBRTs. In the absence of silicone oil, better results were obtained in the thermophilic than in the mesophilic bioreactor. At similar loads (360 gm(-3)h(-1)), in the thermophilic bioreactor the elimination capacity was 293 gm(-3)h(-1), with a removal efficiency of 81%, while in the mesophilic BTF the elimination capacity only reached 195 gm(-3)h(-1), for that same load. The presence of a second liquid phase improved performance of both bioreactors. With 5% silicone oil, elimination capacities as high as 2,000 gm(-3)h(-1) were achieved, under either mesophilic or thermophilic conditions. PMID- 20716485 TI - Purification and characterization of an extracellular laccase from the anthracene degrading fungus Fusarium solani MAS2. AB - An extracellular laccase was purified from the culture medium of the non-white rot, anthracene-degrading fungal strain Fusarium solani MAS2. Both native PAGE and SDS-PAGE revealed one single band corresponding to a molecular weight of about 72 kDa. Treatment with endoglycosidase H reduced the molecular weight by 12%. The purified laccase maintained stable at pH 3-11 and up to 50 degrees C. The highest activity was detected at pH 3.0 and at 70 degrees C. The enzyme retained 46.2-97.2% of it activity in the presence of 20mM Pb(2+), Ni(2+), Cr(3+), and its activity was enhanced in the presence of 20mM Hg(2+). The laccase retained more than 50% of its activity in the presence of 5% acetone, acetonitrile, dimethyl sulphoxide (DMSO), ethanol and methanol. The kinetic constants (K(m) and k(cat)) showed that 2,6-dimethoxyphenol (DMOP) and 2,2'-azino bis-(3-ethylbenzthiazoline-6-sulphonic acid) diammonium salt (ABTS) were the more effective substrates rather than catechol and guaiacol. The novel properties of this laccase suggest its potential for biotechnological and environmental applications. PMID- 20716486 TI - Analysis of a reactive extraction process for biodiesel production using a lipase immobilized on magnetic nanostructures. AB - Magnetic nanoparticles were prepared by coprecipitating Fe(2+) and Fe(3+) ions in a sodium hydroxide solution and used as support for lipase. The lipase-coated particles were applied in a reactive extraction process that allowed separation of the products formed during transesterification. Kinetics data for triolein and ethanol consumption during biodiesel (ethyl oleate) synthesis together with a thermodynamic phase equilibrium model (liquid-liquid) were used for simulation of batch and continuous processes. The analysis demonstrated the possibility of applying this biocatalytic system in the reactive zone using external magnetic fields. This approach implies new advantages in efficient location and use of lipases in column reactors for producing biodiesel. PMID- 20716487 TI - A new series of macrolide derivatives with 4''-O-saccharide substituents. AB - A series of novel derivatives of macrolide with 4''-O-mono- or disaccharides were synthesized. The corresponding glycosyl trichloroacetimidates were used as the donors in the glycosylations. The in vitro antibacterial activities of 7a-f and 13-16 against a panel of susceptible and resistant pathogens were tested. The modification of 4''-O-mono- or disaccharides may lead to the understanding of interaction of the macrolide and the bacterial ribosome. PMID- 20716488 TI - Identification of small molecule compounds with higher binding affinity to guanine deaminase (cypin) than guanine. AB - Guanine deaminase (GDA; cypin) is an important metalloenzyme that processes the first step in purine catabolism, converting guanine to xanthine by hydrolytic deamination. In higher eukaryotes, GDA also plays an important role in the development of neuronal morphology by regulating dendritic arborization. In addition to its role in the maturing brain, GDA is thought to be involved in proper liver function since increased levels of GDA activity have been correlated with liver disease and transplant rejection. Although mammalian GDA is an attractive and potential drug target for treatment of both liver diseases and cognitive disorders, prospective novel inhibitors and/or activators of this enzyme have not been actively pursued. In this study, we employed the combination of protein structure analysis and experimental kinetic studies to seek novel potential ligands for human guanine deaminase. Using virtual screening and biochemical analysis, we identified common small molecule compounds that demonstrate a higher binding affinity to GDA than does guanine. In vitro analysis demonstrates that these compounds inhibit guanine deamination, and more surprisingly, affect GDA (cypin)-mediated microtubule assembly. The results in this study provide evidence that an in silico drug discovery strategy coupled with in vitro validation assays can be successfully implemented to discover compounds that may possess therapeutic value for the treatment of diseases and disorders where GDA activity is abnormal. PMID- 20716489 TI - FRET-based sensors for the human M1-, M3-, and M5-acetylcholine receptors. AB - Based on the recently developed approach to generate fluorescence resonance energy transfer (FRET)-based sensors to measure GPCR activation, we generated sensor constructs for the human M(1)-, M(3)-, and M(5)-acetylcholine receptor. The receptors were labeled with cyan fluorescent protein (CFP) at their C terminus, and with fluorescein arsenical hairpin binder (FlAsH) via tetra cysteine tags inserted in the third intracellular loop. We then measured FRET between the donor CFP and the acceptor FlAsH in living cells and real time. Agonists like acetylcholine, carbachol, or muscarine activate each receptor construct with half-maximal activation times between 60 and 70ms. Removal of the agonist caused the reversal of the signal. Compared with all other agonists, oxotremorine M differed in two major aspects: it caused significantly slower signals at M(1)- and M(5)-acetylcholine receptors and the amplitude of these signals was larger at the M(1)-acetylcholine receptor. Concentration-response curves for the agonists reveal that all agonists tested, with the mentioned exception of oxotremorine M, caused similar maximal FRET-changes as acetylcholine for the M(1)-, M(3)- and M(5)-acetylcholine receptor constructs. Taken together our data support the notion that orthosteric agonists behave similar at different muscarinic receptor subtypes but that kinetic differences can be observed for receptor activation. PMID- 20716490 TI - Feline models of viral pathogenesis: opportunity knocks. PMID- 20716491 TI - 15N-15N spin-spin coupling constants through intermolecular hydrogen bonds in the solid state. AB - A 2hJNN intermolecular spin-spin coupling constant (SSCC) of 10.2+/-0.4 Hz has been measured for the powdered tetrachlorogallate salt of pyridinium solvated by pyridine (pyridine-H+?pyridine cation 3). Density Functional Theory (DFT) calculations at the B3LYP/6-311++G(d,p) level reproduced this value and two others reported in the literature for 2hJ intermolecular SSCCs, which were measured for complexes in solution. PMID- 20716493 TI - Pediatric acquired brain injury. AB - BACKGROUND: Although pediatric patients are sometimes included in studies about visual problems in patients with acquired brain injury (ABI), few studies deal solely with children. Unlike studies dealing with adult patients, in which mechanisms of brain injury are divided into cerebral vascular accident (CVA) and traumatic brain injury (TBI), studies on pediatric patients deal almost exclusively with traumatic brain injury, specifically caused by accidents. CASE REPORT: Here we report on the vision problems of 4 pediatric patients, ages 3 to 18 years, who were examined in the ophthalmology/optometry clinic at a children's hospital. All patients had an internally caused brain injury and after the initial insult manifested problems in at least one of the following areas: acuity, binocularity, motility (tracking or saccades), accommodation, visual fields, and visual perceptual skills. CONCLUSION: Pediatric patients can suffer from a variety of oculo-visual problems after the onset of head injury. These patients may or may not be symptomatic and can benefit from optometric intervention. PMID- 20716492 TI - Performance assessment for EEG-based neonatal seizure detectors. AB - OBJECTIVE: This study discusses an appropriate framework to measure system performance for the task of neonatal seizure detection using EEG. The framework is used to present an extended overview of a multi-channel patient-independent neonatal seizure detection system based on the Support Vector Machine (SVM) classifier. METHODS: The appropriate framework for performance assessment of neonatal seizure detectors is discussed in terms of metrics, experimental setups, and testing protocols. The neonatal seizure detection system is evaluated in this framework. Several epoch-based and event-based metrics are calculated and curves of performance are reported. A new metric to measure the average duration of a false detection is proposed to accompany the event-based metrics. A machine learning algorithm (SVM) is used as a classifier to discriminate between seizure and non-seizure EEG epochs. Two post-processing steps proposed to increase temporal precision and robustness of the system are investigated and their influence on various metrics is shown. The resulting system is validated on a large clinical dataset of 267h. RESULTS: In this paper, it is shown how a complete set of metrics and a specific testing protocol are necessary to extensively describe neonatal seizure detection systems, objectively assess their performance and enable comparison with existing alternatives. The developed system currently represents the best published performance to date with an ROC area of 96.3%. The sensitivity and specificity were ~90% at the equal error rate point. The system was able to achieve an average good detection rate of ~89% at a cost of 1 false detection per hour with an average false detection duration of 2.7 min. CONCLUSIONS: It is shown that to accurately assess the performance of EEG-based neonatal seizure detectors and to facilitate comparison with existing alternatives, several metrics should be reported and a specific testing protocol should be followed. It is also shown that reporting only event-based metrics can be misleading as they do not always reflect the true performance of the system. SIGNIFICANCE: This is the first study to present a thorough method for performance assessment of EEG-based seizure detection systems. The evaluated SVM based seizure detection system can greatly assist clinical staff, in a neonatal intensive care unit, to interpret the EEG. PMID- 20716494 TI - Lateral supragenicular pedicle perforator flap: clinical results and vascular anatomy. AB - BACKGROUND: The lateral supragenicular artery flap has been previously described for soft-tissue reconstruction around the knee. It provides an excellent alternative to muscle and musculocutaneous flaps with less morbidity. The evolution of the understanding of perforator flap anatomy has increased their clinical use and improved flap design. METHODS: The authors present a series of cadaveric anatomic studies to further delineate the anatomy of the lateral supragenicular pedicled perforator (LSGAP) flap. The lateral genicular perforator was injected with barium sulphate to locate and map the perforator vascular territories, zones of perfusion and location in relation to standard bony landmarks. Two case presentations exemplify the clinical application of the anatomic findings. RESULTS: Anatomic dissections and selective injection of the genicular perforator found consistent anatomic attributes of pedicle location, axis of flow, linking vessels and vascular territory. LSGAP flaps were used in the case presentations with excellent flap viability and coverage. CONCLUSIONS: The LSGAP is another option for soft-tissue coverage around the knee and poplitaeal fossa. The morbidity is minimal as the donor site may frequently be closed primarily without incurring functional impairment. The anatomy of the lateral supragenicular perforator perforasome is reliable and consistent resulting in an additional dependable flap option in our reconstructive armamentarium for coverage of knee and poplitaeal defects. PMID- 20716495 TI - Regularization of phase retrieval with phase-attenuation duality prior for 3-D holotomography. AB - We consider the phase retrieval problem in 3-D holotomography for strongly absorbing objects. Holotomography combines phase retrieval from Fresnel diffraction patterns with tomographic reconstruction to reconstruct the 3-D refractive index distribution. The main interest is the increase in sensitivity of up to three orders of magnitude compared to standard, absorption based tomography. Most existing algorithms are based upon linearization of the forward problem. This is motivated by the large problem size, since it yields computationally efficient solutions. Here, the mixed approach is used, which allows for both strong absorption and long propagation distances. Previous implementations have shown promising results, but in practice often suffer from strong low frequency artifacts. To address this problem, we introduce a homogeneous object assumption through a regularizing term based upon the absorption image. This allows the homogeneous object assumption to be introduced only in the low frequency range. The proportionality constant between absorption and refractive index is assumed to be known. The regularizing parameter is found using the standard L-curve technique. The benefits of our approach are illustrated using data measured at the European Synchrotron Radiation Facility. Low frequency noise in the reconstruction is alleviated, but the result is only quantitative in the areas of the sample where the homogeneous object assumption is fulfilled. PMID- 20716496 TI - Prostate cancer localization with multispectral MRI using cost-sensitive support vector machines and conditional random fields. AB - Prostate cancer is a leading cause of cancer death for men in the United States. Fortunately, the survival rate for early diagnosed patients is relatively high. Therefore, in vivo imaging plays an important role for the detection and treatment of the disease. Accurate prostate cancer localization with noninvasive imaging can be used to guide biopsy, radiotherapy, and surgery as well as to monitor disease progression. Magnetic resonance imaging (MRI) performed with an endorectal coil provides higher prostate cancer localization accuracy, when compared to transrectal ultrasound (TRUS). However, in general, a single type of MRI is not sufficient for reliable tumor localization. As an alternative, multispectral MRI, i.e., the use of multiple MRI-derived datasets, has emerged as a promising noninvasive imaging technique for the localization of prostate cancer; however almost all studies are with human readers. There is a significant inter and intraobserver variability for human readers, and it is substantially difficult for humans to analyze the large dataset of multispectral MRI. To solve these problems, this study presents an automated localization method using cost sensitive support vector machines (SVMs) and shows that this method results in improved localization accuracy than classical SVM. Additionally, we develop a new segmentation method by combining conditional random fields (CRF) with a cost sensitive framework and show that our method further improves cost-sensitive SVM results by incorporating spatial information. We test SVM, cost-sensitive SVM, and the proposed cost-sensitive CRF on multispectral MRI datasets acquired from 21 biopsy-confirmed cancer patients. Our results show that multispectral MRI helps to increase the accuracy of prostate cancer localization when compared to single MR images; and that using advanced methods such as cost-sensitive SVM as well as the proposed cost-sensitive CRF can boost the performance significantly when compared to SVM. PMID- 20716497 TI - User-friendly interactive image segmentation through unified combinatorial user inputs. AB - One weakness in the existing interactive image segmentation algorithms is the lack of more intelligent ways to understand the intention of user inputs. In this paper, we advocate the use of multiple intuitive user inputs to better reflect a user's intention. In particular, we propose a constrained random walks algorithm that facilitates the use of three types of user inputs: 1) foreground and background seed input, 2) soft constraint input, and 3) hard constraint input, as well as their combinations. The foreground and background seed input allows a user to draw strokes to specify foreground and background seeds. The soft constraint input allows a user to draw strokes to indicate the region that the boundary should pass through. The hard constraint input allows a user to specify the pixels that the boundary must align with. Our proposed method supports all three types of user inputs in one coherent computational framework consisting of a constrained random walks and a local editing algorithm, which allows more precise contour refinement. Experimental results on two benchmark data sets show that the proposed framework is highly effective and can quickly and accurately segment a wide variety of natural images with ease. PMID- 20716498 TI - Noninvasive estimation of global activation sequence using the extended Kalman filter. AB - A new algorithm for 3-D imaging of the activation sequence from noninvasive body surface potentials is proposed. After formulating the nonlinear relationship between the 3-D activation sequence and the body surface recordings during activation, the extended Kalman filter (EKF) is utilized to estimate the activation sequence in a recursive way. The state vector containing the activation sequence is optimized during iteration by updating the error variance/covariance matrix. A new regularization scheme is incorporated into the "predict" procedure of EKF to tackle the ill-posedness of the inverse problem. The EKF-based algorithm shows good performance in simulation under single-site pacing. Between the estimated activation sequences and true values, the average correlation coefficient (CC) is 0.95, and the relative error (RE) is 0.13. The average localization error (LE) when localizing the pacing site is 3.0 mm. Good results are also obtained under dual-site pacing (CC = 0.93, RE = 0.16, and LE = 4.3 mm). Furthermore, the algorithm shows robustness to noise. The present promising results demonstrate that the proposed EKF-based inverse approach can noninvasively estimate the 3-D activation sequence with good accuracy and the new algorithm shows good features due to the application of EKF. PMID- 20716499 TI - A supervised framework for the registration and segmentation of white matter fiber tracts. AB - A supervised framework is presented for the automatic registration and segmentation of white matter (WM) tractographies extracted from brain DT-MRI. The framework relies on the direct registration between the fibers, without requiring any intensity-based registration as preprocessing. An affine transform is recovered together with a set of segmented fibers. A recently introduced probabilistic boosting tree classifier is used in a segmentation refinement step to improve the precision of the target tract segmentation. The proposed method compares favorably with a state-of-the-art intensity-based algorithm for affine registration of DTI tractographies. Segmentation results for 12 major WM tracts are demonstrated. Quantitative results are also provided for the segmentation of a particularly difficult case, the optic radiation tract. An average precision of 80% and recall of 55% were obtained for the optimal configuration of the presented method. PMID- 20716500 TI - Online sparse Gaussian process regression and its applications. AB - We present a new Gaussian process (GP) inference algorithm, called online sparse matrix Gaussian processes (OSMGP), and demonstrate its merits by applying it to the problems of head pose estimation and visual tracking. The OSMGP is based upon the observation that for kernels with local support, the Gram matrix is typically sparse. Maintaining and updating the sparse Cholesky factor of the Gram matrix can be done efficiently using Givens rotations. This leads to an exact, online algorithm whose update time scales linearly with the size of the Gram matrix. Further, we provide a method for constant time operation of the OSMGP using matrix downdates. The downdates maintain the Cholesky factor at a constant size by removing certain rows and columns corresponding to discarded training examples. We demonstrate that, using these matrix downdates, online hyperparameter estimation can be included at cost linear in the number of total training examples. We describe a robust appearance-based head pose estimation system based upon the OSMGP. Numerous experiments and comparisons with existing methods using a large dataset system demonstrate the efficiency and accuracy of our system. Further, to showcase the applicability of OSMGP to a wide variety of problems, we also describe a regression-based visual tracking method. Experiments show that our OSMGP algorithm generalizes well using online learning. PMID- 20716501 TI - Dealing with parallax in shape-from-focus. AB - We propose a new method that extends the capability of shape-from-focus (SFF) to estimate the depth profile of 3-D objects in the presence of structure-dependent pixel motion. Existing SFF techniques work under the constraint that there is no parallax in the captured stack of frames. However, in off-the-shelf cameras, there can be appreciable pixel motion among the observations when there is relative motion between the object and the camera. In such a scenario, the depth estimates will be erroneous if the parallax effect is not factored in. Our degradation model accounts for pixel migration effects in the observations due to parallax resulting in a generalization of the SFF technique. We show that pixel motion and defocus blur therein are tightly coupled to the underlying shape of the 3-D object. Simultaneous reconstruction of the underlying 3-D structure and the all-in-focus image is carried out within an optimization framework using local image operations. The proposed method when tested on many examples, both synthetic and real, is very effective and delivers state-of-the-art performance. PMID- 20716502 TI - Multiregion image segmentation by parametric kernel graph cuts. AB - The purpose of this study is to investigate multiregion graph cut image partitioning via kernel mapping of the image data. The image data is transformed implicitly by a kernel function so that the piecewise constant model of the graph cut formulation becomes applicable. The objective function contains an original data term to evaluate the deviation of the transformed data, within each segmentation region, from the piecewise constant model, and a smoothness, boundary preserving regularization term. The method affords an effective alternative to complex modeling of the original image data while taking advantage of the computational benefits of graph cuts. Using a common kernel function, energy minimization typically consists of iterating image partitioning by graph cut iterations and evaluations of region parameters via fixed point computation. A quantitative and comparative performance assessment is carried out over a large number of experiments using synthetic grey level data as well as natural images from the Berkeley database. The effectiveness of the method is also demonstrated through a set of experiments with real images of a variety of types such as medical, synthetic aperture radar, and motion maps. PMID- 20716503 TI - Reference sharing mechanism for watermark self-embedding. AB - This paper proposes two novel self-embedding watermarking schemes based upon a reference sharing mechanism, in which the watermark to be embedded is a reference derived from the original principal content in different regions and shared by these regions for content restoration. After identifying tampered blocks, both the reference data and the original content in the reserved area are used to recover the principal content in the tampered area. By using the first scheme, the original data in five most significant bit layers of a cover image can be recovered and the original watermarked image can also be retrieved when the content replacement is not too extensive. In the second scheme, the host content is decomposed into three levels, and the reference sharing methods with different restoration capabilities are employed to protect the data at different levels. Therefore, the lower the tampering rate, the more levels of content data are recovered, and the better the quality of restored results. PMID- 20716504 TI - Adaptive fuzzy decentralized control for large-scale nonlinear systems with time varying delays and unknown high-frequency gain sign. AB - In this paper, an adaptive fuzzy decentralized robust output feedback control approach is proposed for a class of large-scale strict-feedback nonlinear systems without the measurements of the states. The nonlinear systems in this paper are assumed to possess unstructured uncertainties, time-varying delays, and unknown high-frequency gain sign. Fuzzy logic systems are used to approximate the unstructured uncertainties, K-filters are designed to estimate the unmeasured states, and a special Nussbaum gain function is introduced to solve the problem of unknown high-frequency gain sign. Combining the backstepping technique with adaptive fuzzy control theory, an adaptive fuzzy decentralized robust output feedback control scheme is developed. In order to obtain the stability of the closed-loop system, a new lemma is given and proved. Based on this lemma and Lyapunov-Krasovskii functions, it is proved that all the signals in the closed loop system are uniformly ultimately bounded and that the tracking errors can converge to a small neighborhood of the origin. The effectiveness of the proposed approach is illustrated from simulation results. PMID- 20716505 TI - Novel exponential stability criteria of high-order neural networks with time varying delays. AB - The global exponential stability is analyzed for a class of high-order Hopfield type neural networks with time-varying delays. Based on the Lyapunov stability theory, together with the linear matrix inequality approach and free-weighting matrix method, some less conservative delay-independent and delay-dependent sufficient conditions are presented for the global exponential stability of the equilibrium point of the considered neural networks. Two numerical examples are provided to demonstrate the effectiveness of the proposed stability criteria. PMID- 20716506 TI - Tracking by third-order tensor representation. AB - This paper proposes a robust tracking algorithm by third-order tensor representation and adaptive appearance modeling. In this method, the target in each video frame is represented by a third-order tensor. This representation preserves the spatial correlation inside the target region and can integrate multiple appearance cues for target description. Based on this representation, a multilinear subspace is learned online to model the target appearance variations during tracking. Compared to other methods, our approach can detect local spatial structure in the target tensor space and fuse information from different feature spaces. Therefore, the learned appearance model is more discriminative when there are significant appearance variations of the target or when the background gets cluttered. Applying the multilinear algebra, our appearance model can efficiently be learned and updated online, without causing high-dimensional data-learning problems. Then, tracking is implemented in the Bayesian inference framework, where a likelihood model is defined to measure the similarity between a test sample and the learned appearance model, and a particle filter is used to recursively estimate the target state over time. Theoretic analysis and experiments compared with other state-of-the-art methods demonstrate the effectiveness of the proposed approach. PMID- 20716507 TI - Sleep-states-transition model by body movement and estimation of sleep-stage appearance probabilities by Kalman filter. AB - The judgment standards of R-K method include ambiguities and are thus compensated by subjective interpretations of sleep-stage scorers. This paper presents a novel method to compensate uncertainties in judgments by the subjective interpretations by the sleep-model estimation approach and by describing the judgments in probabilistic terms. Kalman filter based on the two sleep models with no body movement and with body movement was designed. Sleep stages judged by three different scorers were rejudged by the filter. The two sleep models were stochastically estimated from biosignals from 15 nights' data and the rejudged scores by the filter were evaluated by the data from 5 nights. The average values of kappa statistics, which show the degree of agreement, were 0.85, 0.89, and 0.81, respectively, for the original sleep stages. Because the new method provides probabilities on how surely the sleep belongs to each sleep stage, we were able to determine the most, second most, and third most probable sleep stage. The kappa statistics between the most probable sleep stages were improved to 0.90, 0.93, and 0.84, respectively. Those of sleep stages determined from the most and second most probable were 0.92, 0.94, and 0.89 and those from the most, second most, and third most probable were 0.95, 0.97, and 0.92. The sleep stages estimated by the filter are expressed by probabilistic manner, which are more reasonable in expression than those given by deterministic manner. The expression could compensate the uncertainties in each judgments and thus were more accurate than the direct judgments. PMID- 20716508 TI - Blood and urine cadmium, blood pressure, and hypertension: a systematic review and meta-analysis. AB - BACKGROUND: Cadmium exposure has been inconsistently related to blood pressure. OBJECTIVES: We updated and reevaluated the evidence regarding the relationships of blood cadmium (BCd) and urine cadmium (UCd) with blood pressure (BP) and hypertension (HTN) in nonoccupationally exposed populations. DATA SOURCES AND EXTRACTION: We searched PubMed and Web of Science for articles on BCd or UCd and BP or HTN in nonoccupationally exposed populations and extracted information from studies that provided sufficient data on population, smoking status, exposure, outcomes, and design. DATA SYNTHESIS: Twelve articles met inclusion criteria: eight provided data adequate for comparison, and five reported enough data for meta-analysis. Individual studies reported significant positive associations between BCd and systolic BP (SBP) among nonsmoking women [beta = 3.14 mmHg per 1 MUg/L untransformed BCd; 95% confidence interval (CI), 0.14-6.14] and among premenopausal women (beta = 4.83 mmHg per 1 nmol/L log-transformed BCd; 95% CI, 0.17-9.49), and between BCd and diastolic BP (DBP) among women (beta = 1.78 mmHg comparing BCd in the 90th and 10th percentiles; 95% CI, 0.64-2.92) and among premenopausal women (beta = 3.84 mmHg per 1 nmol/L log-transformed BCd; 95% CI, 0.86-6.82). Three meta-analyses, each of three studies, showed positive associations between BCd and SBP (p = 0.006) and DBP (p < 0.001) among women, with minimal heterogeneity (I2 = 3%), and a significant inverse association between UCd and HTN among men and women, with substantial heterogeneity (I2 = 80%). CONCLUSION: Our results suggest a positive association between BCd and BP among women; the results, however, are inconclusive because of the limited number of representative population-based studies of never-smokers. Associations between UCd and HTN suggest inverse relationships, but inconsistent outcome definitions limit interpretation. We believe a longitudinal study is merited. PMID- 20716509 TI - Selenium and mercury in the Brazilian Amazon: opposing influences on age-related cataracts. AB - BACKGROUND: Age-related cataracts (ARCs) are an important cause of blindness in developing countries. Although antioxidants may be part of the body's defense to prevent ARC, environmental contaminants may contribute to cataractogenesis. In fish-eating populations of the lower Tapajos region, elevated exposure to mercury (Hg) has been reported, and blood levels of selenium (Se) range from normal to very high (> 1,000 microg/L). OBJECTIVES: We examined ARCs in relation to these elements among adults (> or = 40 years of age) from 12 riverside communities. METHODS: Participants (n = 211) provided blood samples and underwent an extensive ocular examination. Inductively coupled plasma mass spectrometry was used to assess Hg and Se in blood and plasma. RESULTS: One-third (n = 69; 32.7%) of the participants had ARC. Lower plasma Se (P-Se; < 25th percentile, 110 microg/L) and higher blood Hg (B-Hg; > or = 25th percentile, 25 microg/L) were associated with a higher prevalence odds ratio (POR) of ARC [adjusted POR (95% confidence interval), 2.69 (1.11-6.56) and 4.45 (1.43-13.83), respectively]. Among participants with high P-Se, we observed a positive but nonsignificant association with high B-Hg exposure, whereas among those with low B-Hg, we observed no association for P-Se. However, compared with the optimum situation (high P-Se, low B-Hg), the POR for those with low P-Se and high B-Hg was 16.4 (3.0-87.9). This finding suggests a synergistic effect. CONCLUSION: Our results suggest that persons in this population with elevated Hg, the cataractogenic effects of Hg may be offset by Se. Because of the relatively small sample size and possible confounding by other dietary nutrients, additional studies with sufficient power to assess multiple nutrient and toxic interactions are required to confirm these findings. PMID- 20716510 TI - Novel familial cases of ICCA (infantile convulsions with paroxysmal choreoathetosis) syndrome. AB - Epilepsy and paroxysmal dyskinesia are two episodic cerebral disorders that can share a common genetic basis. Rare families with infantile seizures and paroxysmal dyskinesia [predominantly paroxysmal kinesigenic dyskinesia (PKD)], co inherited as a single autosomal dominant trait, have been described (infantile convulsions with paroxysmal choreoathetosis; ICCA syndrome) and a disease gene has been mapped at chromosome 16p12-q12 (ICCA region). We report the clinical picture of seven previously unreported families with ICCA syndrome. The identification of novel ICCA families should contribute to better knowledge regarding the clinical manifestations of ICCA syndrome as well as the search for the underlying genetic defect(s). PMID- 20716511 TI - Commentary to the letter to the editor re: role of magnesium in metabolic syndrome. PMID- 20716512 TI - X-ray cross correlation analysis uncovers hidden local symmetries in disordered matter. AB - We explore the different local symmetries in colloidal glasses beyond the standard pair correlation analysis. Using our newly developed X-ray cross correlation analysis (XCCA) concept together with brilliant coherent X-ray sources, we have been able to access and classify the otherwise hidden local order within disorder. The emerging local symmetries are coupled to distinct momentum transfer (Q) values, which do not coincide with the maxima of the amorphous structure factor. Four-, 6-, 10- and, most prevalently, 5-fold symmetries are observed. The observation of dynamical evolution of these symmetries forms a connection to dynamical heterogeneities in glasses, which is far beyond conventional diffraction analysis. The XCCA concept opens up a fascinating view into the world of disorder and will definitely allow, with the advent of free electron X-ray lasers, an accurate and systematic experimental characterization of the structure of the liquid and glass states. PMID- 20716513 TI - Crystal structures of glycinamide ribonucleotide synthetase, PurD, from thermophilic eubacteria. AB - Glycinamide ribonucleotide synthetase (GAR-syn, PurD) catalyses the second reaction of the purine biosynthetic pathway; the conversion of phosphoribosylamine, glycine and ATP to glycinamide ribonucleotide (GAR), ADP and Pi. In the present study, crystal structures of GAR-syn's from Thermus thermophilus, Geobacillus kaustophilus and Aquifex aeolicus were determined in apo forms. Crystal structures in ligand-bound forms were also determined for G. kaustophilus and A. aeolicus proteins. In general, overall structures of GAR syn's are similar to each other. However, the orientations of the B domains are varied among GAR-syn's and the MD simulation suggested the mobility of the B domain. Furthermore, it was demonstrated that the B loop in the B domain fixes the position of the beta- and gamma- phosphate groups of the bound ATP. The structures of GAR-syn's and the bound ligands were compared with each other in detail, and structures of GAR-syn's with full ligands, as well as the possible reaction mechanism, were proposed. PMID- 20716514 TI - Time-saving multiplex detection of single nucleotide polymorphisms by ultrasensitive DNA microarray. AB - Rapid and multiplex detection system using an ultrasensitive DNA microarray was developed and utilized for the analysis of six pharmacokinetically relevant single nucleotide polymorphisms (SNPs) (MDR1-C1236T, MDR1-G2677TA, MDR1-C3435T, CYP3A5-A6986G, CYP2C19-G681A, CYP2C19-G636A) from blood samples derived from liver transplant patients. The SNP detection system is comprised of three processes: multiplex PCR, single base extension with fluorescently labelled di deoxy-nucleotides and detection by DNA microarray. The entire workflow of this system completes within 5 h. The final genotype call was obtained statistically by Mahalanobis distance which was calculated from the bi-coloured fluorescent signals detected by the microarray. In order to detect the six SNPs, this system required only 50 copies of genomic DNA, and the obtained detection calls completely matched with the results by the sequencing-based genotyping method. With the high sensitivity and rapid processing, our SNP detection system utilizing ultrasensitive microarray is a promising device applicable for diagnostic utility. PMID- 20716515 TI - MicroRNA-target pairs in human renal epithelial cells treated with transforming growth factor beta 1: a novel role of miR-382. AB - We reported previously an approach for identifying microRNA (miRNA)-target pairs by combining miRNA and proteomic analyses. The approach was applied in the present study to examine human renal epithelial cells treated with transforming growth factor beta1 (TGFbeta1), a model of epithelial-mesenchymal transition important for the development of renal interstitial fibrosis. Treatment of human renal epithelial cells with TGFbeta1 resulted in upregulation of 16 miRNAs and 18 proteins and downregulation of 17 miRNAs and 16 proteins. Of the miRNAs and proteins that exhibited reciprocal changes in expression, 77 pairs met the sequence criteria for miRNA-target interactions. Knockdown of miR-382, which was up-regulated by TGFbeta1, attenuated TGFbeta1-induced loss of the epithelial marker E-cadherin. miR-382 was confirmed by 3'-untranslated region reporter assay to target five genes that were downregulated at the protein level by TGFbeta1, including superoxide dismutase 2 (SOD2). Knockdown of miR-382 attenuated TGFbeta1 induced downregulation of SOD2. Overexpression of SOD2 ameliorated TGFbeta1 induced loss of the epithelial marker. The study provided experimental evidence in the form of reciprocal expression at the protein level for a large number of predicted miRNA-target pairs and discovered a novel role of miR-382 and SOD2 in the loss of epithelial characteristics induced by TGFbeta1. PMID- 20716517 TI - Autonomous zinc-finger nuclease pairs for targeted chromosomal deletion. AB - Zinc-finger nucleases (ZFNs) have been successfully used for rational genome engineering in a variety of cell types and organisms. ZFNs consist of a non specific FokI endonuclease domain and a specific zinc-finger DNA-binding domain. Because the catalytic domain must dimerize to become active, two ZFN subunits are typically assembled at the cleavage site. The generation of obligate heterodimeric ZFNs was shown to significantly reduce ZFN-associated cytotoxicity in single-site genome editing strategies. To further expand the application range of ZFNs, we employed a combination of in silico protein modeling, in vitro cleavage assays, and in vivo recombination assays to identify autonomous ZFN pairs that lack cross-reactivity between each other. In the context of ZFNs designed to recognize two adjacent sites in the human HOXB13 locus, we demonstrate that two autonomous ZFN pairs can be directed simultaneously to two different sites to induce a chromosomal deletion in ~ 10% of alleles. Notably, the autonomous ZFN pair induced a targeted chromosomal deletion with the same efficacy as previously published obligate heterodimeric ZFNs but with significantly less toxicity. These results demonstrate that autonomous ZFNs will prove useful in targeted genome engineering approaches wherever an application requires the expression of two distinct ZFN pairs. PMID- 20716516 TI - Archaeal/eukaryal RNase P: subunits, functions and RNA diversification. AB - RNase P, a catalytic ribonucleoprotein (RNP), is best known for its role in precursor tRNA processing. Recent discoveries have revealed that eukaryal RNase P is also required for transcription and processing of select non-coding RNAs, thus enmeshing RNase P in an intricate network of machineries required for gene expression. Moreover, the RNase P RNA seems to have been subject to gene duplication, selection and divergence to generate two new catalytic RNPs, RNase MRP and MRP-TERT, which perform novel functions encompassing cell cycle control and stem cell biology. We present new evidence and perspectives on the functional diversification of the RNase P RNA to highlight it as a paradigm for the evolutionary plasticity that underlies the extant broad repertoire of catalytic and unexpected regulatory roles played by RNA-driven RNPs. PMID- 20716518 TI - Diversity and strength of internal outward-oriented promoters in group IIC-attC introns. AB - Integrons are genetic elements that incorporate mobile gene cassettes by site specific recombination and express them as an operon from a promoter (Pc) located upstream of the cassette insertion site. Most gene cassettes found in integrons contain only one gene followed by an attC recombination site. We have recently shown that a specific lineage of group IIC introns, named group IIC-attC introns, inserts into the bottom strand sequence of attC sites. Here, we show that S.ma.I2, a group IIC-attC intron inserted in an integron cassette array of Serratia marcescens, impedes transcription from Pc while allowing expression of the following antibiotic resistance cassette using an internal outward-oriented promoter (P(out)). Bioinformatic analyses indicate that one or two putative P(out), which have sequence similarities with the Escherichia coli consensus promoters, are conserved in most group IIC-attC intron sequences. We show that P(out) with different versions of the -35 and -10 sequences are functionally active in expressing a promoterless chloramphenicol acetyltransferase (cat) reporter gene in E. coli. P(out) in group IIC-attC introns may therefore play a role in the expression of one or more gene cassettes whose transcription from Pc would otherwise be impeded by insertion of the intron. PMID- 20716519 TI - AUF1 p42 isoform selectively controls both steady-state and PGE2-induced FGF9 mRNA decay. AB - Fibroblast growth factor 9 (FGF9) is an autocrine/paracrine growth factor that plays vital roles in many physiologic processes including embryonic development. Aberrant expression of FGF9 causes human diseases and thus it highlights the importance of controlling FGF9 expression; however, the mechanism responsible for regulation of FGF9 expression is largely unknown. Here, we show the crucial role of an AU-rich element (ARE) in FGF9 3'-untranslated region (UTR) on controlling FGF9 expression. Our data demonstrated that AUF1 binds to this ARE to regulate FGF9 mRNA stability. Overexpression of each isoform of AUF1 (p37, p40, p42 and p45) showed that only the p42 isoform reduced the steady-state FGF9 mRNA. Also, knockdown of p42(AUF1) prolonged the half-life of FGF9 mRNA. The induction of FGF9 mRNA in prostaglandin (PG) E(2)-treated human endometrial stromal cells was accompanied with declined cytoplasmic AUF1. Nevertheless, ablation of AUF1 led to sustained elevation of FGF9 expression in these cells. Our study demonstrated that p42(AUF1) regulates both steady-state and PGE(2)-induced FGF9 mRNA stability through ARE-mediated mRNA degradation. Since almost half of the FGF family members are ARE-containing genes, our findings also suggest that ARE-mediated mRNA decay is a common pathway to control FGFs expression, and it represents a novel RNA regulon to coordinate FGFs homeostasis in various physiological conditions. PMID- 20716520 TI - Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. AB - Proprotein convertase, subtilisin/kexin type 9 (PCSK9), a key regulator of plasma LDL-cholesterol (LDL-c) and cardiovascular risk, is produced in liver and secreted into plasma where it binds hepatic LDL receptors (LDLR), leading to their degradation. PCSK9 is transcriptionally activated by sterol response element-binding protein (SREBP)-2, a transcription factor that also activates all genes for cholesterol synthesis as well as the LDLR. Here we investigated the relationship between plasma PCSK9 levels and the lathosterol-to-cholesterol ratio, a marker of cholesterol biosynthesis, in 18 healthy subjects during a 48 h fast. In all individuals, plasma PCSK9 levels declined steadily during the fasting period, reaching a nadir at 36 h that was ~58% lower than levels measured in the fed state (P < 0.001). Similarly, the lathosterol-to-cholesterol ratio declined in parallel with plasma PCSK9 concentrations during the fast, reaching a nadir at 36 h that was ~28% lower than that measured in the fed state (P = 0.024). In summary, fasting has a marked effect on plasma PCSK9 concentrations, which is mirrored by measures of cholesterol synthesis in humans. Inasmuch as cholesterol synthesis and PCSK9 are both regulated by SREBP-2, these results suggest that plasma PCSK9 levels may serve as a surrogate marker of hepatic SREBP 2 activity in humans. PMID- 20716521 TI - A major fraction of glycosphingolipids in model and cellular cholesterol containing membranes is undetectable by their binding proteins. AB - Glycosphingolipids (GSLs) accumulate in cholesterol-enriched cell membrane domains and provide receptors for protein ligands. Lipid-based "aglycone" interactions can influence GSL carbohydrate epitope presentation. To evaluate this relationship, Verotoxin binding its receptor GSL, globotriaosyl ceramide (Gb(3)), was analyzed in simple GSL/cholesterol, detergent-resistant membrane vesicles by equilibrium density gradient centrifugation. Vesicles separated into two Gb(3/)cholesterol-containing populations. The lighter, minor fraction (<5% total GSL), bound VT1, VT2, IgG/IgM mAb anti-Gb(3), HIVgp120 or Bandeiraea simplicifolia lectin. Only IgM anti-Gb(3), more tolerant of carbohydrate modification, bound both vesicle fractions. Post-embedding cryo-immuno-EM confirmed these results. This appears to be a general GSL-cholesterol property, because similar receptor-inactive vesicles were separated for other GSL-protein ligand systems; cholera toxin (CTx)-GM1, HIVgp120-galactosyl ceramide/sulfatide. Inclusion of galactosyl or glucosyl ceramide (GalCer and GlcCer) rendered VT1 unreactive Gb(3)/cholesterol vesicles, VT1-reactive. We found GalCer and GlcCer bind Gb(3), suggesting GSL-GSL interaction can counter cholesterol masking of Gb(3). The similar separation of Vero cell membrane-derived vesicles into minor "binding," and major "non-binding" fractions when probed with VT1, CTx, or anti SSEA4 (a human GSL stem cell marker), demonstrates potential physiological relevance. Cell membrane GSL masking was cholesterol- and actin-dependent. Cholesterol depletion of Vero and HeLa cells enabled differential VT1B subunit labeling of "available" and "cholesterol-masked" plasma membrane Gb(3) pools by fluorescence microscopy. Thus, the model GSL/cholesterol vesicle studies predicted two distinct membrane GSL formats, which were demonstrated within the plasma membrane of cultured cells. Cholesterol masking of most cell membrane GSLs may impinge many GSL receptor functions. PMID- 20716522 TI - Metabolic depression and increased reactive oxygen species production by isolated mitochondria at moderately lower temperatures. AB - Temperature (T) reduction increases lifespan, but the mechanisms are not understood. Because reactive oxygen species (ROS) contribute to aging, we hypothesized that lowering T might decrease mitochondrial ROS production. We measured respiratory response and ROS production in isolated mitochondria at 32, 35, and 37 degrees C. Lowering T decreased the rates of resting (state 4) and phosphorylating (state 3) respiration phases. Surprisingly, this respiratory slowdown was associated with an increase of ROS production and hydrogen peroxide release and with elevation of the mitochondrial membrane potential, DeltaPsi(m). We also found that at lower T mitochondria produced more carbon-centered lipid radicals, a species known to activate uncoupling proteins. These data indicate that reduced mitochondrial ROS production is not one of the mechanisms mediating lifespan extension at lower T. They suggest instead that increased ROS leakage may mediate mitochondrial responses to hypothermia. PMID- 20716523 TI - Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. AB - Certain primary transcripts of miRNA (pri-microRNAs) undergo RNA editing that converts adenosine to inosine. The Epstein-Barr virus (EBV) genome encodes multiple microRNA genes of its own. Here we report that primary transcripts of ebv-miR-BART6 (pri-miR-BART6) are edited in latently EBV-infected cells. Editing of wild-type pri-miR-BART6 RNAs dramatically reduced loading of miR-BART6-5p RNAs onto the microRNA-induced silencing complex. Editing of a mutation-containing pri miR-BART6 found in Daudi Burkitt lymphoma and nasopharyngeal carcinoma C666-1 cell lines suppressed processing of miR-BART6 RNAs. Most importantly, miR-BART6 5p RNAs silence Dicer through multiple target sites located in the 3'-UTR of Dicer mRNA. The significance of miR-BART6 was further investigated in cells in various stages of latency. We found that miR-BART6-5p RNAs suppress the EBNA2 viral oncogene required for transition from immunologically less responsive type I and type II latency to the more immunoreactive type III latency as well as Zta and Rta viral proteins essential for lytic replication, revealing the regulatory function of miR-BART6 in EBV infection and latency. Mutation and A-to-I editing appear to be adaptive mechanisms that antagonize miR-BART6 activities. PMID- 20716524 TI - Regulation of the AGS3.G{alpha}i signaling complex by a seven-transmembrane span receptor. AB - G-protein signaling modulators (GPSM) play diverse functional roles through their interaction with G-protein subunits. AGS3 (GPSM1) contains four G-protein regulatory motifs (GPR) that directly bind Galpha(i) free of Gbetagamma providing an unusual scaffold for the "G-switch" and signaling complexes, but the mechanism by which signals track into this scaffold are not well understood. We report the regulation of the AGS3.Galpha(i) signaling module by a cell surface, seven transmembrane receptor. AGS3 and Galpha(i1) tagged with Renilla luciferase or yellow fluorescent protein expressed in mammalian cells exhibited saturable, specific bioluminescence resonance energy transfer indicating complex formation in the cell. Activation of alpha(2)-adrenergic receptors or MU-opioid receptors reduced AGS3-RLuc.Galpha(i1)-YFP energy transfer by over 30%. The agonist mediated effects were inhibited by pertussis toxin and co-expression of RGS4, but were not altered by Gbetagamma sequestration with the carboxyl terminus of GRK2. Galpha(i)-dependent and agonist-sensitive bioluminescence resonance energy transfer was also observed between AGS3 and cell-surface receptors typically coupled to Galpha(i) and/or Galpha(o) indicating that AGS3 is part of a larger signaling complex. Upon receptor activation, AGS3 reversibly dissociates from this complex at the cell cortex. Receptor coupling to both Galphabetagamma and GPR-Galpha(i) offer additional flexibility for systems to respond and adapt to challenges and orchestrate complex behaviors. PMID- 20716525 TI - Characterization of a novel WDR5-binding site that recruits RbBP5 through a conserved motif to enhance methylation of histone H3 lysine 4 by mixed lineage leukemia protein-1. AB - Histone modification is well established as a fundamental mechanism driving the regulation of transcription, replication, and DNA repair through the control of chromatin structure. Likewise, it is apparent that incorrect targeting of histone modifications contributes to misregulated gene expression and hence to developmental disorders and diseases of genomic instability such as cancer. The KMT2 family of SET domain methyltransferases, typified by mixed lineage leukemia protein-1 (MLL1), is responsible for histone H3 lysine 4 methylation, a marker of active genes. To ensure that this modification is correctly targeted, a multiprotein complex associates with the methyltransferase and directs activity. We have identified a novel interaction site on the core complex protein WD repeat protein-5 (WDR5), and we mapped the complementary site on its partner retinoblastoma-binding protein-5 (RbBP5). We have characterized this interaction by x-ray crystallography and show how it is fundamental to the assembly of the complex and to the regulation of methyltransferase activity. We show which region of RbBP5 contributes directly to mixed lineage leukemia activation, and we combine our structural and biochemical data to produce a model to show how WDR5 and RbBP5 act cooperatively to stimulate activity. PMID- 20716526 TI - Transmembrane and trans-subunit regulation of ectodomain shedding of platelet glycoprotein Ibalpha. AB - Ectodomain shedding of transmembrane proteins may be regulated by their cytoplasmic domains. To date, the effecting cytoplasmic domain and the shed extracellular domain have been in the same polypeptide. In this study, shedding of GPIbalpha, the ligand-binding subunit of the platelet GPIb-IX complex and a marker for platelet senescence and storage lesion, was assessed in Chinese hamster ovary cells with/without functional GPIbalpha sheddase ADAM17. Mutagenesis of the GPIb-IX complex, which contains GPIbalpha, GPIbbeta, and GPIX subunits, revealed that the intracellular membrane-proximal calmodulin-binding region of GPIbbeta is critical for ADAM17-dependent shedding of GPIbalpha induced by the calmodulin inhibitor, W7. Perturbing the interaction between GPIbalpha and GPIbbeta subunits further lessened the restraint of GPIbbeta on GPIbalpha shedding. However, contrary to the widely accepted model of calmodulin regulation of ectodomain shedding, the R152E/L153E mutation in the GPIbbeta cytoplasmic domain disrupted calmodulin binding to GPIbbeta but had little effect on GPIbalpha shedding. Analysis of induction of GPIbalpha shedding by membrane permeable GPIbbeta-derived peptides implicated the association of GPIbbeta with an unidentified intracellular protein in mediating regulation of GPIbalpha shedding. Overall, these results provide evidence for a novel trans-subunit mechanism for regulating ectodomain shedding. PMID- 20716527 TI - Tissue-specific functions in the fatty acid-binding protein family. AB - The intracellular fatty acid-binding proteins (FABPs) are abundantly expressed in almost all tissues. They exhibit high affinity binding of a single long-chain fatty acid, with the exception of liver FABP, which binds two fatty acids or other hydrophobic molecules. FABPs have highly similar tertiary structures consisting of a 10-stranded antiparallel beta-barrel and an N-terminal helix-turn helix motif. Research emerging in the last decade has suggested that FABPs have tissue-specific functions that reflect tissue-specific aspects of lipid and fatty acid metabolism. Proposed roles for FABPs include assimilation of dietary lipids in the intestine, targeting of liver lipids to catabolic and anabolic pathways, regulation of lipid storage and lipid-mediated gene expression in adipose tissue and macrophages, fatty acid targeting to beta-oxidation pathways in muscle, and maintenance of phospholipid membranes in neural tissues. The regulation of these diverse processes is accompanied by the expression of different and sometimes multiple FABPs in these tissues and may be driven by protein-protein and protein membrane interactions. PMID- 20716528 TI - The ATP synthase a-subunit of extreme alkaliphiles is a distinct variant: mutations in the critical alkaliphile-specific residue Lys-180 and other residues that support alkaliphile oxidative phosphorylation. AB - A lysine residue in the putative proton uptake pathway of the ATP synthase a subunit is found only in alkaliphilic Bacillus species and is proposed to play roles in proton capture, retention and passage to the synthase rotor. Here, Lys 180 was replaced with alanine (Ala), glycine (Gly), cysteine (Cys), arginine (Arg), or histidine (His) in the chromosome of alkaliphilic Bacillus pseudofirmus OF4. All mutants exhibited octylglucoside-stimulated ATPase activity and beta subunit levels at least as high as wild-type. Purified mutant F(1)F(0)-ATP synthases all contained substantial a-subunit levels. The mutants exhibited diverse patterns of native (no octylglucoside) ATPase activity and a range of defects in malate growth and in vitro ATP synthesis at pH 10.5. ATP synthesis by the Ala, Gly, and His mutants was also impaired at pH 7.5 in the presence of a protonophoric uncoupler. Thus Lys-180 plays a role when the protonmotive force is reduced at near neutral, not just at high pH. The Arg mutant exhibited no ATP synthesis activity in the alkaliphile setting although activity was reported for a K180R mutant of a thermoalkaliphile synthase (McMillan, D. G., Keis, S., Dimroth, P., and Cook, G. M. (2007) J. Biol. Chem. 282, 17395-17404). The hypothesis that a-subunits from extreme alkaliphiles and the thermoalkaliphile represent distinct variants was supported by demonstration of the importance of additional alkaliphile-specific a-subunit residues, not found in the thermoalkaliphile, for malate growth of B. pseudofirmus OF4. Finally, a mutant B. pseudofirmus OF4 synthase with switched positions of Lys-180 (helix 4) and Gly 212 (helix 5) retained significant coupled synthase activity accompanied by proton leakiness. PMID- 20716529 TI - Adipose tissue-specific inhibition of hypoxia-inducible factor 1{alpha} induces obesity and glucose intolerance by impeding energy expenditure in mice. AB - Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1alpha (hypoxia-inducible factor 1alpha), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1alpha in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1alpha developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1alpha in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue. PMID- 20716530 TI - Effect of vitamin K-dependent protein precursor propeptide, vitamin K hydroquinone, and glutamate substrate binding on the structure and function of {gamma}-glutamyl carboxylase. AB - The gamma-glutamyl carboxylase utilizes four substrates to catalyze carboxylation of certain glutamic acid residues in vitamin K-dependent proteins. How the enzyme brings the substrates together to promote catalysis is an important question in understanding the structure and function of this enzyme. The propeptide is the primary binding site of the vitamin K-dependent proteins to carboxylase. It is also an effector of carboxylase activity. We tested the hypothesis that binding of substrates causes changes to the carboxylase and in turn to the substrate enzyme interactions. In addition we investigated how the sequences of the propeptides affected the substrate-enzyme interaction. To study these questions we employed fluorescently labeled propeptides to measure affinity for the carboxylase. We also measured the ability of several propeptides to increase carboxylase catalytic activity. Finally we determined the effect of substrates: vitamin K hydroquinone, the pentapeptide FLEEL, and NaHCO(3), on the stability of the propeptide-carboxylase complexes. We found a wide variation in the propeptide affinities for carboxylase. In contrast, the propeptides tested had similar effects on carboxylase catalytic activity. FLEEL and vitamin K hydroquinone both stabilized the propeptide-carboxylase complex. The two together had a greater effect than either alone. We conclude that the effect of propeptide and substrates on carboxylase controls the order of substrate binding in such a way as to ensure efficient, specific carboxylation. PMID- 20716532 TI - Feature selection in finite mixture of sparse normal linear models in high dimensional feature space. AB - Rapid advancement in modern technology has allowed scientists to collect data of unprecedented size and complexity. This is particularly the case in genomics applications. One type of statistical problem in such applications is concerned with modeling an output variable as a function of a small subset of a large number of features based on relatively small sample sizes, which may even be coming from multiple subpopulations. As such, selecting the correct predictive features (variables) for each subpopulation is the key. To address this issue, we consider the problem of feature selection in finite mixture of sparse normal linear (FMSL) models in large feature spaces. We propose a 2-stage procedure to overcome computational difficulties and large false discovery rates caused by the large model space. First, to deal with the curse of dimensionality, a likelihood based boosting is designed to effectively reduce the number of candidate features. This is the key thrust of our new method. The greatly reduced set of features is then subjected to a sparsity inducing procedure via a penalized likelihood method. A novel scheme is also proposed for the difficult problem of finding good starting points for the expectation-maximization estimation of mixture parameters. We use an extended Bayesian information criterion to determine the final FMSL model. Simulation results indicate that the procedure is successful in selecting the significant features without including a large number of insignificant ones. A real data example on gene transcription regulation is also presented. PMID- 20716531 TI - Peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC 1{alpha}) promotes skeletal muscle lipid refueling in vivo by activating de novo lipogenesis and the pentose phosphate pathway. AB - Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC 1alpha). PGC-1alpha enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1alpha levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1alpha-mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC 1alpha and human muscle biopsies pre- and post-exercise. We demonstrate that PGC 1alpha enhances lipogenesis in skeletal muscle through liver X receptor alpha dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1alpha and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post exercise. Our findings suggest that PGC-1alpha coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo. PMID- 20716533 TI - Recent expansion of a new Ingi-related clade of Vingi non-LTR retrotransposons in hedgehogs. AB - Autonomous non-long terminal repeat (non-LTR) retrotransposons and their repetitive remnants are ubiquitous components of mammalian genomes. Recently, we identified non-LTR retrotransposon families, Ingi-1_AAl and Ingi-1_EE, in two hedgehog genomes. Here we rename them to Vingi-1_AAl and Vingi-1_EE and report a new clade "Vingi," which is a sister clade of Ingi that lacks the ribonuclease H domain. In the European hedgehog genome, there are 11 non-autonomous families of elements derived from Vingi-1_EE by internal deletions. No retrotransposons related to Vingi elements were found in any of the remaining 33 mammalian genomes nearly completely sequenced to date, but we identified several new families of Vingi and Ingi retrotransposons outside mammals. Our data suggest the horizontal transfer of Vingi elements to hedgehog, although the vertical transfer cannot be ruled out. The compact structure and trans-mobilization of nonautonomous derivatives of Vingi can make them useful for in vivo retrotransposition assay system. PMID- 20716544 TI - Independent association of prospective memory with retrospective memory and intelligence in schizophrenia: a controlled study. AB - Prospective memory (PM) refers to the ability to remember to do something in the future. This study examined the relationship between three PM subtypes, and intelligence and retrospective memory (RM) in schizophrenia patients and healthy controls. The study sample comprised 110 schizophrenia patients and 110 healthy controls matched according to age, sex, and level of education. The patients' clinical condition was evaluated with the Brief Psychiatric Rating Scale. Time-, event-, and activity-based PM and RM (immediate and delayed Logical Memory subtests of the Wechsler Memory Scales-Revised), executive functioning (Design Fluency Test, Tower of London-4 disk, and Wisconsin Card Sorting Test), and intelligence (Raven's Progressive Matrices) tests were administered to all participants. Correlation analyses showed time- and event-based PM to be significantly associated with RM in both the patients and controls, but with intelligence only in the patients. After controlling for covariates, only time based PM was associated with RM in the controls and only event-based PM with intelligence in the patients. In schizophrenia, PM deficit may arise from the impairments of the retrospective components of memory. PMID- 20716546 TI - Scholarly discourse. PMID- 20716545 TI - Prospective memory deficits in patients with bipolar disorder: a preliminary study. AB - Prospective memory (PM) is the ability to remember to do something in the future without explicit prompts. To date, little has been known about PM deficits in bipolar disorder (BD). This study examined the nature and correlates of PM in patients with BD. Forty clinically stable BD patients and 40 matched healthy controls formed the study sample. Socio-demographic characteristics, PM, psychosocial functioning, retrospective memory (RM), and IQ were measured in all participants, whereas clinical condition was measured in patients with standardized assessment instruments. Patients performed significantly more poorly on the time-based PM task than controls (10.6 +/- 5.0 vs. 14.6 +/- 3.0, p < .001). In correlation analyses, older age, lower education, more severe depressive and manic symptoms, poor psychosocial functioning, poor RM, and lower scores in IQ were significantly associated with poor performance in the time based PM task, whereas poor RM and lower scores in IQ associated with poorer performance in the event-based PM task in patients. In multivariate analyses, severity of depression and older age significantly contributed to poor performance in the time-based PM task, whereas poor RM contributed to poor performance in the event-based PM task in patients. The time-based PM is impaired in BD patients. Depressive symptoms, age, and RM were determinants of certain aspects of impaired PM performance in BD patients. PMID- 20716547 TI - Whether Black men have a poorer prognosis compared with White men following a diagnosis of prostate cancer. Letter to the editor. PMID- 20716548 TI - Impact of routine transoesophageal echocardiography on safety, outcomes, and cost of pulmonary vein ablation: inferences drawn from a decision analysis model. AB - AIMS: The practice of routine vs. selective transoesophageal echocardiography (TEE) surveillance for left atrial appendage or intracavitary thrombus prior to pulmonary vein isolation (PVI) varies widely as evidence to guide this decision in terms of important clinical outcomes is lacking. METHODS AND RESULTS: We constructed a decision analysis model to compare the cost-effectiveness of routine TEE for detection of left atrial thrombus vs. no TEE. The model incorporated health outcomes and costs. Markov methodology was used to follow patients as they transition through varying health states. We examined a hypothetical cohort of patients with symptomatic atrial fibrillation suitable for PVI, and expected outcomes were modelled over a period of 2 years. Simulated patients (SPs) undergoing a strategy of a routine TEE experienced significantly fewer transient ischemic attacks (TIAs) [OR 0.28 (0.22-0.37)], and debilitating strokes [OR 0.23 (0.15-0.33)]. Routine TEE led to an absolute risk reduction for stroke of 1.2% [number needed to treat (NNT) 84 (79-100)] and 1.9% for TIA [NNT 53 (48-59)]. The incremental cost-effectiveness ratio (ICER) for TEE was $226,608 per quality-adjusted life year (QALY). The ICER for TEE among high-risk SPs, with pre-existing clot in the left atrium, was $2232 per QALY. CONCLUSION: Decision analysis and microsimulation suggest that routine use of TEE in an unselected population prior to PVI lowers the incidence of cerebral thrombo-embolic events but with considerable cost per QALY. PMID- 20716549 TI - Frontiers in clinical immunology and immunoregulation 2010: the highlight. PMID- 20716550 TI - Molecular mechanisms of ligand-mediated attenuation of DNA binding by MarR family transcriptional regulators. AB - Bacteria and archaea encode members of the large multiple antibiotic resistance regulator (MarR) family of transcriptional regulators. Generally, MarR homologs regulate activity of genes involved in antibiotic resistance, stress responses, virulence or catabolism of aromatic compounds. They constitute a diverse group of transcriptional regulators that includes both repressors and activators, and the conventional mode of regulation entails a genetic locus in which the MarR homolog and a gene under its regulation are encoded divergently; binding of the MarR homolog to the intergenic region typically represses transcription of both genes, while binding of a specific ligand to the transcription factor results in attenuated DNA binding and hence activated gene expression. For many homologs, the natural ligand is unknown. Crystal structures reveal a common architecture with a characteristic winged helix domain for DNA binding, and recent structural information of homologs solved both in the absence and presence of their respective ligands, as well as biochemical data, is finally converging to illuminate the mechanisms by which ligand-binding causes attenuated DNA binding. As MarR homologs regulate pathways that are critical to bacterial physiology, including virulence, a molecular understanding of mechanisms by which ligands affect a regulation of gene activity is essential. Specifying the position of ligand-binding pockets further has the potential to aid in identifying the ligands for MarR homologs for which the ligand remains unknown. PMID- 20716551 TI - Factors influencing long-term adherence to two previously implemented hospital guidelines. AB - OBJECTIVE AND SETTING: After successful implementation, adherence to hospital guidelines should be sustained. Long-term adherence to two hospital guidelines was audited. The overall aim was to explore factors accounting for their long term adherence or non-adherence. DESIGN AND PARTICIPANTS: A fluid balance guideline (FBG) and body temperature guideline (BTG) were developed and implemented in our hospital in 2000. Long-term adherence was determined retrospectively based on data from patient files. Focus groups were launched to explore nurses' perceptions of barriers and facilitators regarding long-term adherence. The predominant themes from the nurses' focus groups were posed to clinicians in questionnaires. RESULTS: Nurses involved in the FBG (overall adherence 100%) stated that adherence has immediate advantages in terms of safety and a gain in time. Nurses and oncologists acted unanimously which was thought to enhance adherence. On the other hand, opinions differed on the BTG within the nursing teams and medical staff (overall adherence 50%). Although the guideline discourages routine postoperative body temperature measurements, temperature should be measured according to the guideline in a considerable number of cases due to changes in patient characteristics since the year 2000. Therefore, adherence was judged to be rather complex. CONCLUSIONS: To secure adherence to hospital guidelines after their successful implementation, guidelines should preferably be comprehensive in terms of being applicable to the majority of the patients in that particular setting and to the most common clinical situations. All healthcare professionals involved should be aware of its immediate benefits for themselves or to their patients. PMID- 20716552 TI - Impact of a nationwide outreach program on the diffusion of evidence-based practice in Taiwan. AB - RATIONALE: To disseminate evidence-based practice (EBP) among hospital-based health professionals, since 2007 the National Health Research Institutes (NHRI) of Taiwan has run a complex outreach program that includes information resource support and promotional campaigns. OBJECTIVE: The aim is to evaluate the impact of this outreach program on the diffusion of EBP. SETTING: Sixty-one regional hospitals in Taiwan. DESIGN: A cross-sectional, pre- and post-survey of a nationally representative sample of physicians and nurses was carried out in 2007 and 2009 to examine views related to EBP including changes in beliefs, attitudes, knowledge, skills, perceived barriers and behaviors. RESULTS: Physicians and nurses in the 2009 survey tended to have more knowledge and skill of EBP than their counterparts in the 2007 survey. They were less likely, however, to believe that EBP can improve patient care quality and to support the implementation of EBP. The prevalence of perceived barriers to EBP declined during the 2-year study period. In addition, physicians and nurses were more likely to access the online evidence retrieval databases according to the 2009 survey when compared with responses to the 2007 survey. CONCLUSIONS: The knowledge of, skill in, and behavior regarding EBP have improved among physicians and nurses of regional hospitals in Taiwan after a promotion period of 2 years and they perceive fewer barriers to EBP. These data suggest that the multifaceted nationwide promotion program of the type conducted by NHRI succeeded in diffusion and implementation of EBP among professionals. PMID- 20716553 TI - Evaluation of the in vivo efficacy of intramuscularly administered ceftaroline fosamil, a novel cephalosporin, against a methicillin-resistant Staphylococcus aureus strain in a rabbit endocarditis model. PMID- 20716554 TI - Oral antibiotic prescribing during pregnancy in primary care: UK population-based study. AB - OBJECTIVES: To examine patterns of prescribing of oral antibiotics during pregnancy and to determine whether women were more or less likely to receive specific types of antibiotics in pregnancy than in the years before and after pregnancy. Finally, to identify socio-demographic factors associated with antibiotic prescribing in pregnancy. PATIENTS AND METHODS: We identified 114 999 women who gave live birth between 1992 and 2007 in The Health Improvement Network (THIN) UK primary care database. Antibiotic prescribing during pregnancy was estimated for each calendar year between 1992 and 2007. Self-controlled case series (SCCS) methodology was used to compare antibiotic prescribing during pregnancy with the years before and after pregnancy, and Poisson regression to examine association between demographic factors and antibiotic prescribing. RESULTS: A third of pregnant women received at least one antibiotic prescription during pregnancy. In each trimester, 14% of women received at least one antibiotic. Prescribing of antibiotics was lower in pregnancy than during a comparable period 1 year earlier [incidence rate ratio (IRR) 0.91 (95% CI 0.90 0.93)], but some antibiotics were prescribed more frequently in pregnancy: broad spectrum penicillins [IRR 1.46 (1.42-1.49)]; cephalosporins [IRR 2.22 (2.13 2.31)]; and antibiotics for urinary tract infections [IRR 2.29 (2.01-2.61)]. Respiratory, urinary, skin and ear infections were the commonest indications. Urinary indications increased and respiratory, skin and ear infection indications declined during pregnancy, although a large proportion were prescribed without indication. Young age and social deprivation were associated with increased antibiotic prescribing during pregnancy. CONCLUSIONS: Antibiotic prescribing is widespread in pregnancy although marginally reduced compared with the year before pregnancy. There were substantial changes in types of antibiotics as well as in their indications during pregnancy. This may be explained by changes in threshold for treatment, diseases, detection and recording. Younger women and women from deprived areas were most likely to receive antibiotics in pregnancy. PMID- 20716555 TI - Isolated ventricular septal rupture secondary to blunt trauma. AB - A ventricular septal rupture (VSR) is a rare complication of blunt chest trauma. We describe the case of a 25-year-old man who developed a VSR as a result of a high-speed road accident. The rupture was closed by left ventricular remodeling and replacement of the diseased myocardium with a Dacron patch. The patch sutures were reinforced with glue. Redo surgery was necessary at nine months due to patch detachment and embolization of the glue in the right lower lobe. The patient is asymptomatic, at 13-month follow-up. PMID- 20716556 TI - Gastric and diaphragmatic rupture in early pregnancy. AB - Simultaneous gastric and diaphragmatic rupture is an exceptional situation during pregnancy and it implies a high-risk of maternal and fetal mortality. They are usually associated with previous diaphragmatic abnormalities such as diaphragmatic hernia or diaphragmatic eventration. Both gastric and diaphragmatic rupture can be triggered by situations involving high intra-abdominal pressure. We present the case of a 35-year-old pregnant woman presenting an unspecific clinical picture of intense chest pain and hypoventilation at 15 weeks of pregnancy. She was diagnosed with diaphragmatic rupture complicated by a gastric rupture. PMID- 20716557 TI - The stented elephant trunk procedure combined total arch replacement for Debakey I aortic dissection: operative result and follow-up. AB - The stented elephant trunk technique in aortic arch replacement combined with transaortic stented graft implantation into the descending aorta has been introduced as a means of eliminating the residual false lumen in the descending thoracic aorta and improving long-term outcomes of surgical intervention for Debakey I aortic dissection. This report summarizes the operative and follow-up data with this new procedure. Between August 2004 and May 2009, 28 stented elephant trunk operations were performed for Debakey I aortic dissection at Nanjing First Hospital. A 10 cm long woven Dacron graft was implanted through the aortic arch during hypothermic circulatory arrest. Patent false lumina were evaluated using computed tomography three months after the operation. Mean cardiopulmonary bypass time was 213.2+/-47.2 min, and selected cerebral perfusion time was 38.8+/-9.7 min. Hospital mortality was 14.3% (4/28). Thrombus obliteration of the residual false lumen in the descending aorta was observed in 91.7% of the aortic dissections three months postoperatively. The survival rate was 87.5% at five years and the freedom from reoperation rate was 91.7%. Total aortic arch replacement combined with transaortic stented graft implantation into the descending aorta is an effective treatment for Debakey type I aortic dissection. PMID- 20716559 TI - Analysis of the relationships between oxidative stress, DNA damage and sperm vitality in a patient population: development of diagnostic criteria. AB - BACKGROUND: DNA damage in human spermatozoa is known to be associated with a variety of adverse clinical outcomes affecting both reproductive efficiency and the health and wellbeing of the offspring. However, the origin of this damage, its biochemical nature and strategies for its amelioration, still await resolution. METHODS: Using novel methods to simultaneously assess DNA fragmentation (modified TUNEL assay), DNA-base adduct formation (8-hydroxy-2' deoxyguanosine [8OHdG]) and cell vitality, spermatozoa from a cohort of 50 assisted conception patients were examined and compared with a group of donors. Receiver operating characteristic (ROC) curve analysis was then used to examine the frequency distribution of the data and to determine optimized thresholds for identifying patients exhibiting abnormally high levels of DNA damage. RESULTS: 8OHdG formation and DNA fragmentation were highly correlated with each other and frequently associated with cell death. Percoll centrifugation improved sperm quality but, unexpectedly, increased 8OHdG formation in live cells, as did sperm fractionation using Puresperm gradients. ROC analysis indicated that the frequency distribution of 8OHdG and DNA fragmentation data were significantly different between patients and donors (P < 0.001), permitting the development of thresholds that would allow the accurate diagnosis of DNA damage in the male germ line. CONCLUSION: The aetiology of DNA damage in spermatozoa involves a cascade of changes that progress from the induction of oxidative stress and oxidized DNA base adduct formation to DNA fragmentation and cell death. Preparation of spermatozoa on discontinuous density gradients aggravates the problem by stimulating the formation of 8OHdG in live cells. However, the development of novel methods and optimized thresholds for diagnosing oxidative DNA damage in human spermatozoa should assist in the clinical management of this pathology. PMID- 20716558 TI - Decision trees for identifying predictors of treatment effectiveness in clinical trials and its application to ovulation in a study of women with polycystic ovary syndrome. AB - BACKGROUND: Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables. METHODS: The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses. RESULTS: Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (>= 19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin. CONCLUSIONS: Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation. PMID- 20716560 TI - Genetic variation within the hypothalamus-pituitary-ovarian axis in women with recurrent miscarriage. AB - BACKGROUND: Recurrent miscarriage affects 1-2% of couples trying to conceive, and is idiopathic in nearly half. Female fertility is controlled by the hypothalamus pituitary-ovarian (HPO) axis and we hypothesize that genetic polymorphisms affecting the function of genes involved in regulating the HPO axis will be associated with recurrent miscarriage. METHODS: Whole peripheral blood DNA from 227 women with recurrent miscarriage and 130 control women was obtained for this study. Using the Sequenom iPlex assay for fragment analysis, 31 single-nucleotide polymorphisms (SNPs) and 4 short tandem repeat (STR) polymorphisms in 20 candidate genes were evaluated for genetic association with recurrent miscarriage. RESULTS: Several candidate associations were identified with an uncorrected P-value of 0.05. Genotype distribution at an SNP (rs37389) in the prolactin receptor gene (P = 0.03), and allele distributions at an SNP (rs41423247) in the glucocorticoid receptor gene (P = 0.04) and an STR polymorphism in the estrogen receptor beta gene (P = 0.03) were associated with recurrent miscarriage. The T allele of an SNP (rs2033962) within the activin receptor type 1 gene (ACVR1) was associated with increased number of miscarriages in an additive manner (P = 0.02). These candidate associations were not statistically significant after correcting for multiple analyses. CONCLUSIONS: Candidate associations were identified between recurrent miscarriage and genetic variation within ESR2, PRLR, GCCR and ACVR1 genes. Independent confirmation of these results is needed, as limitations of this study include the heterogeneous etiology of recurrent miscarriage, limited sample size, partial availability of reproductive history of the control group and investigation of only a subset of the genetic variation within each gene. PMID- 20716561 TI - Achievement test performance in children conceived by IVF. AB - BACKGROUND: Long-term follow-up studies of children conceived by IVF are limited. We examine academic performance on standardized tests [Iowa Tests of Basic Skills/Educational Development (ITBS/ITED)] of children conceived by IVF. METHODS: Parents of children 8-17 years of age at the onset of the study (March 2008) who were conceived by IVF at the University of Iowa Hospitals and Clinics and living in the state of Iowa were contacted by mail. Parents completed questionnaires on their child's health and education and parental education. ITBS/ITED scores from school grades 3-12 were obtained on IVF children and a group of anonymous children matched by grade, year, gender and school district. Scores were analyzed using linear mixed models. RESULTS: Four hundred and ninety seven couples were contacted. Two hundred and ninety-five couples (463 children) agreed to participate (59.4% of parents), with ITBS/ITED scores available on 423 children (91.4% of participants). IVF children scored higher than the national mean (P < 0.0001) across all grades and subtests and higher than their matched peers for grades 3-11. A trend toward lower test scores in multiple gestations was present (but not significant). Factors found to affect test scores included parental level of education, maternal age, divorce and child's BMI. Cryopreservation, length of embryo culture and method of insemination did not affect scores. CONCLUSIONS: IVF children scored higher on standardized tests than their matched peers, suggesting that IVF does not have a negative effect on cognitive development. However, long-term follow-up of IVF children is still limited. Further research should be performed on the effect of multiple gestation on academic performance. PMID- 20716562 TI - Does a prediction model for pregnancy of unknown location developed in the UK validate on a US population? AB - BACKGROUND: A logistic regression model (M4) was developed in the UK to predict the outcome for women with a pregnancy of unknown location (PUL) based on the initial two human chorionic gonadotrophin (hCG) values, 48 h apart. The purpose of this paper was to assess the utility of this model to predict the outcome for a woman (PUL) in a US population. METHODS: Diagnostic variables included log transformed serum hCG average of two measurements, and linear and quadratic hCG ratios. Outcomes modeled were failing PUL, intrauterine pregnancy (IUP) and ectopic pregnancy (EP). This model was applied to a US cohort of 604 women presenting with symptomatic first-trimester pregnancies, who were followed until a definitive diagnosis was made. The model was applied before and after correcting for differences in terminology and diagnostic criteria. RESULTS: When retrospectively applied to the adjusted US population, the M4 model demonstrated lower areas under the curve compared with the UK population, 0.898 versus 0.988 for failing PUL/spontaneous miscarriage, 0.915 versus 0.981 for IUP and 0.831 versus 0.904 for EP. Whereas the model had 80% sensitivity for EP using UK data, this decreased to 49% for the US data, with similar specificities. Performance only improved slightly (55% sensitivity) when the US population was adjusted to better match the UK diagnostic criteria. CONCLUSIONS: A logistic regression model based on two hCG values performed with modest decreases in predictive ability in a US cohort for women at risk for EP compared with the original UK population. However, the sensitivity for EP was too low for the model to be used in clinical practice in its present form. Our data illustrate the difficulties of applying algorithms from one center to another, where the definitions of pathology may differ. PMID- 20716563 TI - Complete deletion of the AZFb interval from the Y chromosome in an oligozoospermic man. AB - BACKGROUND: Deletion of the entire AZFb interval from the Y chromosome is strictly associated with azoospermia arising from maturation arrest during meiosis. Here, we describe the exceptional case of an oligozoospermic man, 13 1217, with an AZFb + c (P5/distal-P1) deletion. Through the characterization of this patient, and two AZFb (P5/proximal-P1) patients with maturation arrest, we have explored three possible explanations for his exceptionally progressive spermatogenesis. METHODS AND RESULTS: We have determined the precise breakpoints of the deletion in 13-1217, and shown that 13-1217 is deleted for more AZFb material than one of the AZFb-deleted men (13-5349). Immunocytochemical analysis of spermatocytes with an antibody against a synaptonemal complex component indicates synapsis to be largely unaffected in 13-1217, in contrast to 13-5349 where extended asynapsis is frequent. Using PCR-based analyses of RNA and DNA from the same testicular biopsy, we show that 13-1217 expresses post-meiotic germ cell markers in the absence of genomic DNA and transcripts from the AZFb and AZFc intervals. We have determined the Y chromosome haplogroup of 13-1217 to be HgL M185. CONCLUSIONS: Our results indicate that the post-meiotic spermatogenesis in 13-1217 is not a consequence of mosaicism or retention of a key AZFb gene. On the contrary, since the Hg-L Y chromosome carried by 13-1217 is uncommon in Western Europe, a Y-linked modifier locus remains a possible explanation for the oligozoospermia observed in patient 13-1217. Further cases must now be studied to understand how germ cells complete spermatogenesis in the absence of the AZFb interval. PMID- 20716564 TI - Can an understanding of the past influence research funding of the future? PMID- 20716565 TI - Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model. AB - BACKGROUND: Extracorporeal circuit priming and intravascular volume expansion during cardiopulmonary bypass (CPB) may lead to dilutional coagulopathy and excessive diffuse postoperative bleeding. Prothrombin complex concentrate (PCC) containing clotting factors II (FII), VII (FVII), IX (FIX), and X (FX) could be of potential value in correcting dilutional coagulopathy and reducing blood loss. METHODS: Anaesthetized pigs underwent CPB with hypothermia for 2 h at 25 degrees C followed by 1 h of normothermia. Approximately 1 h after CPB, animals randomly received either isotonic saline 1 ml kg-1 or PCC 30 IU kg-1 in a volume of 1 ml kg-1. Diffuse coagulopathic bleeding was assessed as suture hole blood loss from a Gore-Tex patch placed over a full-thickness incision in the left carotid artery. RESULTS: After CPB, levels of FII, FVII, FIX, and FX declined from baseline by 32% to 48%, and PCC fully or partially reversed those deficits. Median suture hole blood loss after administration of saline placebo was 74 ml. PCC reduced suture hole bleeding by a median of 54 ml with a 95% confidence interval of 6-112 ml (P=0.026) compared with saline. PCC, but not saline, normalized skin bleeding time. Peak thrombin generation markedly decreased after CPB, but then returned in PCC-treated animals to a level higher than baseline by 28.7 nM (14.5-41.1 nM; P=0.031). CONCLUSIONS: PCC was effective in correcting dilutional coagulopathy and reducing diffuse bleeding in an in vivo large-animal CPB model. Further research is warranted on PCC as a haemostatic agent in CPB. PMID- 20716567 TI - Prognostic studies of perioperative risk: robust methodology is needed. PMID- 20716568 TI - Minimum volume of local anaesthetic required for an axillary brachial plexus block. PMID- 20716569 TI - Comparison between single-step and balloon dilatational tracheostomy. PMID- 20716570 TI - Desaturation during Onyx embolization. PMID- 20716571 TI - Self-citation in anaesthesia and critical care journals: introducing a flat tax. PMID- 20716572 TI - Usefulness of spirometry in air leak evaluation during laparoscopic surgery in an obese patient with laryngeal mask airway SupremeTM. PMID- 20716573 TI - Anaesthesia for a paediatric patient with Rosai-Dorfman disease. PMID- 20716575 TI - Differences in pollen viability in relation to different deceptive pollination strategies in Mediterranean orchids. AB - BACKGROUND AND AIMS: To date, current research involving pollen viability has been evaluated in a relatively low number of orchid species. In the present study, we focused on five related Mediterranean orchid genera (Anacamptis, Orchis, Dactylorhiza, Ophrys and Serapias) that are characterized by different types of deceptive pollination. METHODS: The in vitro germination ability of increasingly aged pollinaria of eight food-, seven sexually and two shelter deceptive species was evaluated. Pollination experiments on two food-, one sexually and one shelter-deceptive species were also performed and the percentage of embryonate seeds derived from the increasingly aged pollinaria was checked. KEY RESULTS: All of the examined species showed long-term viabilities (=50 % pollen tube growth) that ranged from 8 to 35 d. Species with the same deceptive pollination strategies exhibited the same pollen viability trends. Interestingly, pollen viabilities of species groups with different deception types have shown significant differences, with sexually and shelter- deceptive species exhibiting a shorter life span than food-deceptive species. CONCLUSIONS: This study confirms the prolonged germination and fertilization capacities of orchid pollinaria, and to our knowledge is the first report demonstrating a clear relationship between pollen viability and pollination system. It is proposed that this relationship is attributed to the different types of reproductive barriers, pre- or post-zygotic, that characterize Ophrys and Serapias and the food-deceptive species, respectively. PMID- 20716576 TI - Transbronchial needle aspiration in the diagnosis of mediastinal amyloidosis. PMID- 20716577 TI - Oxidative stress by monoamine oxidases is causally involved in myofiber damage in muscular dystrophy. AB - Several studies documented the key role of oxidative stress and abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs). The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mitochondria by monoamine oxidase (MAO) contributes to MD pathogenesis. Pargyline, an MAO inhibitor, reduced ROS accumulation along with a beneficial effect on the dystrophic phenotype of Col6a1(-/-) mice, a model of Bethlem myopathy and Ullrich congenital MD, and mdx mice, a model of Duchenne MD. Based on our previous observations on oxidative damage of myofibrillar proteins in heart failure, we hypothesized that MAO-dependent ROS might impair contractile function in dystrophic muscles. Indeed, oxidation of myofibrillar proteins, as probed by formation of disulphide cross-bridges in tropomyosin, was detected in both Col6a1(-/-) and mdx muscles. Notably, pargyline significantly reduced myofiber apoptosis and ameliorated muscle strength in Col6a1(-/-) mice. This study demonstrates a novel and determinant role of MAO in MDs, adding evidence of the pivotal role of mitochondria and suggesting a therapeutic potential for MAO inhibition. PMID- 20716578 TI - Kismet/CHD7 regulates axon morphology, memory and locomotion in a Drosophila model of CHARGE syndrome. AB - CHARGE syndrome (CS, OMIM #214800) is a rare, autosomal dominant disorder, two thirds of which are caused by haplo-insufficiency in the Chd7 gene. Here, we show that the Drosophila homolog of Chd7, kismet, is required for proper axonal pruning, guidance and extension in the developing fly's central nervous system. In addition to defects in neuroanatomy, flies with reduced kismet expression show defects in memory and motor function, phenotypes consistent with symptoms observed in CS patients. We suggest that the analysis of this disease model can complement and expand upon the existing studies for this disease, allowing a better understanding of the role of kismet in neural developmental, and Chd7 in CS pathogenesis. PMID- 20716579 TI - A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. AB - Genome-wide association studies (GWAS) identified multiple susceptible loci for prostate cancer (PC), and recent GWAS implicated that a common variant rs1512268 on chromosome 8p21 is associated with PC susceptibility, which is located at 14 kb downstream of a prostate tumor suppressor gene NKX3.1. To clarify a susceptibility gene and functional variants in this locus, we performed re sequencing and fine mapping of this region and identified 12 candidates of functional single nucleotide polymorphisms that were absolutely linked with each other. Screening of these variants by RNA stability assay, electrophoretic mobility shift assay (EMSA) and reporter assay indicated that rs11781886 in the 5'-UTR of NKX3.1 displayed different binding affinity to nuclear proteins between the alleles, and that the transcriptional activity of the NKX3.1 promoter was significantly lower in the susceptible allele of this variant. Sp1 was determined to be the transcription factor that binds to the susceptible G allele, but not to the non-susceptible A allele. Allele-specific transcript quantification (ASTQ) and quantitative PCR analyses showed that the expression of NKX3.1 in the prostate was significantly lower in the subjects with the haplotype carrying the susceptible allele. These results suggest that the functional variant rs11781886 in the 5'-UTR of NKX3.1 can affect its transcription by altering the binding affinity of a transcriptional factor Sp1, and might result in PC susceptibility by lowering expression of NKX3.1 in the prostate. PMID- 20716580 TI - Implicit and explicit selective attention to smoking cues in smokers indexed by brain potentials. AB - Substance use disorders are characterized by cognitive processing biases, such as automatically detecting and orienting attention towards drug-related stimuli. However, it is unclear how, when and what kind of attention (i.e. implicit, explicit) interacts with the processing of these stimuli. In addition, it is unclear whether smokers are hypersensitive to emotionally significant cues in general or to smoking-related cues in particular. The present event-related potential study aimed to enhance insight in drug-related processing biases by manipulating attention for smoking and other motivationally relevant (emotional) cues in smokers and non-smokers using a visual oddball task. Each of the stimulus categories served as a target (explicit attention; counting) or as a non-target (implicit attention; oddball) category. Compared with non-smokers, smokers' P300 (350-600 ms) was enhanced to smoking pictures under both attentional conditions. P300 amplitude did not differ between groups in response to positive, negative, and neutral cues. It can be concluded from this study that attention manipulation affects the P300 differently in smokers and non-smokers. Smokers display a specific bias to smoking-related cues, and this bias is present during both explicit and implicit attentional processing. Overall, it can be concluded that both explicit and implicit attentional processes appear to play an important role in drug-related processing bias. PMID- 20716581 TI - Should the concomitant use of erlotinib and acid-reducing agents be avoided? The drug interaction between erlotinib and acid-reducing agents. AB - CONTEXT: Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, exhibits a drug interaction with proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). The manufacturer recommends avoidance of the combination however, the extent of the drug interaction is not clearly understood. Evidence acquisition. A literature search was performed and the pharmacokinetics and pharmacology of acid-reducing agents were reviewed. RESULTS: Acid-reducing agents reduce the solubility, and subsequent absorption, of erlotinib by raising gastric pH. Our literature search was unable to identify any published studies or case reports that address this issue. Until more information is available, the clinical relevance of this interaction, and whether it actually leads to failure of therapy, is unknown. PPIs would all be expected to exhibit a similar effect on erlotinib. Of the H2RAs, co-administration appears to have a greater impact than administering them separately. Ranitidine, famotidine, and nizatidine should likely have similar effects on erlotinib absorption. Cimetidine has a shorter duration of action, but should be used with caution because of its effects on cytochrome P450 3A4, a pathway also utilized by erlotinib. Antacids are not expected to have a significant effect. CONCLUSIONS: The clinical relevance of this drug interaction is unknown. Until more information is available, decision making regarding this interaction should be on a patient-by patient basis. The indication for acid-reducing therapy should be reevaluated and stopping therapy or changing therapy can be considered. However, there may be occasions where any benefit of such actions will be exceeded by its risks. PMID- 20716584 TI - Methods to evaluate renal function in elderly patients: a systematic literature review. AB - CONTEXT: multiple studies of elderly patients show that the prevalence of chronic renal failure in people aged 65 years and older is dependent on the method used to calculate the glomerular filtration rate. We performed a systematic literature search with research question: What is the best method that could be applicable in clinical practice for evaluating renal function in the elderly? Studies using inulin, Cr-51-EDTA, Tc-DTPA or iohexol assays as the gold standard were included. METHODS: we searched the PubMed and EMBASE databases. Articles found were screened first by title and abstract and then by five criteria. Retained articles were scored using an adapted version of QUADAS. RESULTS: twelve articles had an identified population or subpopulation aged 65 years and older. The studies were heterogeneous with regard to the population investigated and the statistical procedures used to compare the methods and equations with the gold standard. The Cockcroft-Gault (CG) and MDRD equations and the serum cystatin C concentration produced the highest correlations with the gold standard. CONCLUSIONS: no accurate method to evaluate renal function in the elderly was found. Serum cystatin C concentration and the CG and MDRD formula might be valuable parameters, although there is insufficient evidence. PMID- 20716585 TI - Cryoablation of a left coronary cusp ventricular tachycardia. PMID- 20716586 TI - Evaluating the Mexican Federal District's integrated solid waste management programme. AB - Generation of solid waste is a problem of great environmental significance in the Mexican Federal District. With an estimated daily generation of 12 500 tons, waste management is a priority for the district government. Integrated waste management programmes have been implemented in the Mexican Federal District in the past. They have failed. This research has examined the most recent initiative in an effort to discover the causes of failure, using a case study approach. In addition to identifying barriers to and opportunities for implementation of an effective integrated waste management system in the Federal District, this research recommends options for a newly proposed waste management system with the aim of achieving the objectives desired by the government, while aiding in the pursuit of sustainable development. PMID- 20716587 TI - Antidiabetic effects of dendropanoxide from leaves of Dendropanax morbifera Leveille in normal and streptozotocin-induced diabetic rats. AB - The present study evaluated the antidiabetic effect of Dendropanoxide (DP) from Dendropanax morbifera Leveille in normal and streptozotocin-induced diabetic rats. DP in the streptozotocin-induced diabetic rats showed significant hypoglycemic activity for 14 days significantly decreased the serum glucose, total cholesterol, triglycerides, urea, uric acid, creatinine, aspartate amino transferase (AST) and alanine amino transferase (ALT) while it increased the serum insulin in diabetic rats but not in normal rats (p < 0.05; at doses of 30, 60 and 100 mg/kg for 14 days). A comparison was made between the action of DP and glibenclamide (600 MUg/kg), a known antidiabetic drug. The antidiabetic effect of the DP was more effective than that observed with glibenclamide. PMID- 20716588 TI - Recent advances in imaging epilepsy. AB - Around 30 000 people are diagnosed with epilepsy every year in the UK. While many of these respond well to antiepileptic drugs, 20-30% have seizures that are resistant to best medical treatment. For these patients it is important to identify any structural abnormalities responsible for generating seizure activity that may be amenable to surgical resection. There are many imaging modalities available to investigate epilepsy including computed tomography (CT), nuclear medicine and magnetic resonance imaging (MRI). Additional techniques are available in specific circumstances including single positron emission CT, diffusion imaging, MR spectroscopy, perfusion imaging and functional MRI. Clearly with so many options, a targeted approach is required to reach a diagnosis efficiently. In this article, each modality is discussed along with the imaging options for the common causes of focal seizure activity. PMID- 20716589 TI - Meta-analysis of binary outcomes from two-by-two tables when the length of follow up varies and hazards are proportional. AB - Odds ratios (ORs) and relative risks (RRs) are sensitive to the length of follow up. In meta-analyses, pooling such results from studies with different lengths of follow-up may lead to an artificial heterogeneity and discrepancy caused by the choice of the summary index. In this article, we explore the utility of a meta analysis method that uses the ratio of logarithms of survival probability as the measure of association, and that avoids the problems mentioned above when hazards are proportional. Meta-analyses of ORs, RRs and ratios of logarithms of survival probability are compared through a simulation study, in which data are simulated from a proportional hazard model and the length of follow-up varies across studies using realistic patterns of variability. Results show that the heterogeneity increases with the variability of length of follow-up for OR and RR, but not for the ratio of the logarithms of survival probability. A published meta-analysis is used to illustrate the method. PMID- 20716590 TI - Everything all right in method comparison studies? AB - Researchers and clinicians often need to know whether a new method of measurement is equivalent to an established one that is already in use. For this problem, the estimation of limits of agreement advocated by Bland and Altman is a widely used solution. However, this approach ignores two vital issues in method comparisons. First, does the appropriate re-scaling of the test method bring the methods into agreement? Second, independent of lying 'adequately' between the limits of agreement or not, it is important to know whether one method is equal to or better than another. This article proposes an approach and a model, where both these questions will be addressed simultaneously. In this model, the error variation of the standard method stands for 'acceptable' precision in measurements. Accordingly, the between-subject component of the measurements by the standard method will be used as a 'gold standard' against which the properties of the test method will be evaluated. Application of the model is demonstrated using the peak expiratory flow rate data of Bland and Altman. PMID- 20716591 TI - Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. AB - Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens. PMID- 20716592 TI - Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells. AB - High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking gamma-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13 cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neuronal differentiation, and significantly reduced cell motility. The combination of GSIs and 13-cis RA resulted in the enhanced growth inhibition, differentiation, and migration of neuroblastoma cells. In summary, our data suggest that a combination of GSIs with 13-cis RA offers a therapeutic advantage over a single agent, indicating a potential novel therapy for neuroblastoma. PMID- 20716593 TI - Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. AB - Childhood cancer survivors exposed to CNS irradiation are at increased risk for neurocognitive deficits; however, limited data exist linking outcomes with region specific exposure to CNS irradiation. We report associations between region specific radiation dose and self-reported neurocognitive and health-related quality of life (HRQOL) outcomes in 818 adult survivors of childhood central nervous system (CNS) malignancies from the Childhood Cancer Survivor Study. Survivors were compared with a sibling group and national normative samples to calculate standardized scores. Cumulative radiation dose was calculated for 4 specific brain regions. Logistic regression was used to estimate the association between radiation dose to specific brain regions and outcome measures of functional impairment adjusted for clinical and demographic factors, including sex and age at diagnosis. High radiation dose levels to temporal regions were associated with a higher risk for memory impairment (radiation doses >=30 to <50 Gy: OR, 1.95; 95% CI, 1.01-3.78; dose >=50 Gy: OR, 2.34; 95% CI, 1.25-4.39) compared with those with no radiation exposure. No such association was seen with radiation exposure to other regions. Exposure to temporal regions was associated with more social and general health problems, whereas exposure to frontal regions was associated with general health problems and physical performance limitations. Adult survivors of childhood CNS malignancies report higher rates of neuropsychological and HRQOL outcomes, which vary as a function of dose to specific neuroanatomical regions. Survivors with a history of radiation exposure to temporal brain regions are at increased risk for impairment in memory and social functioning. PMID- 20716596 TI - Access to welfare benefits in primary care. PMID- 20716594 TI - Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. AB - Over the last two decades, chemotherapy has been introduced in protocols for patients with intracranial germinoma with the objective of reducing the volume and the dose of irradiation without compromising survival rates. The aim of this work is to critically analyze the pattern of relapse in a cohort of patients with nonmetastatic germinoma prospectively treated with chemotherapy followed by focal field radiation. Data of all germinoma patients registered in the French protocol for intracranial germ cell tumors between 1990 and 1999 were reviewed. The pattern of relapse, management, and outcome were analyzed in 10 of 60 patients who developed a recurrence after initial treatment. In 9 patients, the site of recurrence was local or loco-regional, notably in the periventricular area for 8. One patient only had isolated distant leptomeningeal relapse. The review of the sites of relapse suggests that most recurrences could have been avoided with a larger ventricular field of radiation. Treatment at first relapse included chemotherapy (10 patients), high-dose chemotherapy and stem cell transplant (8 patients), and/or radiation therapy (4 patients). Five patients experienced a second relapse. At a median follow-up of 72 months since the first relapse, 8 patients are alive in second or third remission. This review identified an excess of periventricular relapses when the focal field of radiation is used in the combined management of germinoma. These relapses are predominantly marginal or outside radiation fields. Ventricular field radiation appears a logical alternative to decrease the incidence of such relapses. Future trials should aim at better identifying patients who may benefit from local and ventricular radiation, respectively. PMID- 20716597 TI - Predicting which people with psychosocial distress are at risk of becoming dependent on state benefits: analysis of routinely available data. AB - OBJECTIVES: To examine whether there was significant variation in levels of claiming incapacity benefit across general practices. To establish whether it is possible to identify people with mental health problems who are more at risk of becoming dependent on state benefits for long term health problems based on their general practice consulting behaviour. DESIGN: Interrogation of routinely available data in the Scottish Health Surveys and the British Household Panel Survey. SETTING: Scotland and the United Kingdom. PARTICIPANTS: Respondents to the Scottish Health Surveys in 1995, 1998, and 2003 (7932, 12,39 and 11,72 respondents, respectively). Respondents to the British Household Panel Survey, 1991-2007 (more than 5000 households). MAIN OUTCOME MEASURES: Intracluster correlation coefficient for probability of work incapacity by general practice. Caseness according to the general health questionnaire (GHQ-12) and frequency of consultation with general practitioner in years before and after starting to claim incapacity benefit. RESULTS: There was a small and non-significant amount of variation across general practices in Scotland in rate of claims for incapacity benefit after adjustment for other explanatory variables (intracluster correlation coefficient 0.01, P=0.135). There was a significant increase in rates of GHQ-12 caseness from two years before the start of claiming incapacity benefit (odds ratio 1.6, 95% confidence interval 1.3 to 1.9) and an increase in frequent consultation with a general practitioner from three years before the start of claiming incapacity benefit (1.8, 1.3 to 2.4). People with GHQ-12 caseness showed a significant increase in frequent consultations with a general practitioner from two years before the start of claiming incapacity benefit (2.1, 1.4 to 3.2). CONCLUSIONS: There was no variation in levels of claiming incapacity benefit across general practices in Scotland after adjustment for differences in population characteristics and so initiatives targeted at practices with high levels are unlikely to be effective. People with mental health problems who are likely to have problems remaining in work can be identified up to three years before they transit on to long term benefits related to ill health. PMID- 20716598 TI - Should NHS funding be ring fenced? Yes. PMID- 20716599 TI - Should the NHS budget be ring fenced? No. PMID- 20716600 TI - Treatment of heavy menstrual bleeding. PMID- 20716601 TI - Circumcision: Divided we fall. PMID- 20716602 TI - What does the white paper mean for hospital consultants? PMID- 20716607 TI - Income needed to achieve a minimum standard of living. PMID- 20716609 TI - Poorest people are more likely to die in hospital. PMID- 20716610 TI - Computational analysis of microRNA function in heart development. AB - Emerging evidence suggests that specific spatio-temporal microRNA (miRNA) expression is required for heart development. In recent years, hundreds of miRNAs have been discovered. In contrast, functional annotations are available only for a very small fraction of these regulatory molecules. In order to provide a global perspective for the biologists who study the relationship between differentially expressed miRNAs and heart development, we employed computational analysis to uncover the specific cellular processes and biological pathways targeted by miRNAs in mouse heart development. Here, we utilized Gene Ontology (GO) categories, KEGG Pathway, and GeneGo Pathway Maps as a gene functional annotation system for miRNA target enrichment analysis. The target genes of miRNAs were found to be enriched in functional categories and pathway maps in which miRNAs could play important roles during heart development. Meanwhile, we developed miRHrt (http://sysbio.suda.edu.cn/mirhrt/), a database aiming to provide a comprehensive resource of miRNA function in regulating heart development. These computational analysis results effectively illustrated the correlation of differentially expressed miRNAs with cellular functions and heart development. We hope that the identified novel heart development-associated pathways and the database presented here would facilitate further understanding of the roles and mechanisms of miRNAs in heart development. PMID- 20716611 TI - Calpain modulates capacitation and acrosome reaction through cleavage of the spectrin cytoskeleton. AB - Research on fertilization in mammalian species has revealed that Ca(2+) is an important player in biochemical and physiological events enabling the sperm to penetrate the oocyte. Ca(2+) is a signal transducer that particularly mediates capacitation and acrosome reaction (AR). Before becoming fertilization competent, sperm must experience several molecular, biochemical, and physiological changes where Ca(2+) plays a pivotal role. Calpain-1 and calpain-2 are Ca(2+)-dependent proteases widely studied in mammalian sperm; they have been involved in capacitation and AR but little is known about their mechanism. In this work, we establish the association of calpastatin with calpain-1 and the changes undergone by this complex during capacitation in guinea pig sperm. We found that calpain-1 is relocated and translocated from cytoplasm to plasma membrane (PM) during capacitation, where it could cleave spectrin, one of the proteins of the PM associated cytoskeleton, and facilitates AR. The aforementioned results were dependent on the calpastatin phosphorylation and the presence of extracellular Ca(2+). Our findings underline the contribution of the sperm cytoskeleton in the regulation of both capacitation and AR. In addition, our findings also reveal one of the mechanisms by which calpain and calcium exert its function in sperm. PMID- 20716612 TI - The effect of systemic and ovarian infusion of glucose, galactose and fructose on ovarian function in sheep. AB - Glucose is a critical metabolic fuel in most mammals although many foodstuffs also contain high levels of the monosaccharides, galactose and fructose. The aims of this work were to determine the insulin response to challenges of these sugars (experiment 1) and to examine the effect of systemic (experiment 2) and direct ovarian (experiment 3) infusion of these monosaccharides on ovarian function in ewes with autotransplanted ovaries. In experiment 1, both fructose (fourfold increase peaking in 2 h) and galactose (twofold increase; 30 min) elicited markedly different (P<0.001) insulin responses than glucose (sevenfold increase; 20 min) although the total amount released following fructose and glucose challenge was similar. In experiment 2, low-dose systemic fructose infusion had no acute effect on insulin but did depress FSH (P<0.05), and following the end of fructose infusion, a transient increase in FSH and insulin was observed (P<0.05), which was associated with an increase (P<0.05) in ovarian oestradiol and androstenedione secretion. Systemic infusion of neither glucose nor galactose had a significant effect on ovarian steroidogenesis although glucose acutely suppressed insulin levels. In contrast, ovarian arterial infusion of fructose and glucose had no effect on ovarian function whereas galactose suppressed ovarian follicle number and steroid secretion (P<0.05). In conclusion, this work indicates that fructose and galactose can influence ovarian function in vivo in sheep and that different mechanisms are involved. Thus, fructose exerts stimulatory effects through indirect modulation of peripheral insulin and/or gonadotrophin levels whereas galactose exerts primarily suppressive effects by direct actions on the ovary. PMID- 20716613 TI - Premature ovarian failure. AB - Premature ovarian failure (POF) is a common cause of infertility in women, and is characterised by amenorrhoea, hypo-oestrogenism and elevated gonadotrophin levels in women under the age of 40. Known causes include iatrogenic agents that cause permanent damage to the ovaries, such as chemotherapy, radiation therapy and surgery, autoimmune conditions, X-chromosome abnormalities and autosomal genetic conditions. However, few genes have been identified that can explain a substantial proportion of cases of POF. Most women with POF are deeply upset by the diagnosis, partly due to the unexpected menopausal symptoms, but also due to infertility. Therefore, early detection would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help to direct potential targets for future treatment. PMID- 20716615 TI - Exchangeable random variables. PMID- 20716614 TI - Dynamic changes in gene expression during human early embryo development: from fundamental aspects to clinical applications. AB - BACKGROUND: The first week of human embryonic development comprises a series of events that change highly specialized germ cells into undifferentiated human embryonic stem cells (hESCs) that display an extraordinarily broad developmental potential. The understanding of these events is crucial to the improvement of the success rate of in vitro fertilization. With the emergence of new technologies such as Omics, the gene expression profiling of human oocytes, embryos and hESCs has been performed and generated a flood of data related to the molecular signature of early embryo development. METHODS: In order to understand the complex genetic network that controls the first week of embryo development, we performed a systematic review and study of this issue. We performed a literature search using PubMed and EMBASE to identify all relevant studies published as original articles in English up to March 2010 (n = 165). We also analyzed the transcriptome of human oocytes, embryos and hESCs. RESULTS: Distinct sets of genes were revealed by comparing the expression profiles of oocytes, embryos on Day 3 and hESCs, which are associated with totipotency, pluripotency and reprogramming properties, respectively. Known components of two signaling pathways (WNT and transforming growth factor-beta) were linked to oocyte maturation and early embryonic development. CONCLUSIONS: Omics analysis provides tools for understanding the molecular mechanisms and signaling pathways controlling early embryonic development. Furthermore, we discuss the clinical relevance of using a non-invasive molecular approach to embryo selection for the single-embryo transfer program. PMID- 20716617 TI - Postdiagnosis diet quality is inversely related to a biomarker of inflammation among breast cancer survivors. AB - BACKGROUND: Inflammation and immune response have potential prognostic implications for breast cancer survivors. We examined how postdiagnosis diet quality is cross-sectionally related to biomarkers of inflammation and adipose derived hormones among breast cancer survivors and determined whether physical activity or body size modified any observed associations. METHODS: Participants included 746 women diagnosed with stage 0 to IIIA breast cancer. Thirty months after diagnosis, the women completed food frequency questionnaires. We scored diet quality with the Healthy Eating Index (HEI)-2005. Serum concentrations of C reactive protein (CRP), serum amyloid A, leptin, and adiponectin were measured in fasting 30 mL blood samples. Log biomarker values were regressed on quartiles of HEI-2005 scores in multivariate models, and beta scores were exponentiated and expressed as geometric means within quartiles of HEI-2005 scores. RESULTS: Women with better versus poor quality postdiagnosis diets, as defined by higher HEI 2005 scores (Q4 versus Q1), had lower concentrations of CRP (1.6 mg/L versus 2.5 mg/L), but no significant difference in concentrations of serum amyloid A, leptin, or adiponectin. Among women not engaging in recreational physical activity after diagnosis, better diet quality was associated with lower CRP concentrations (2.5 mg/L versus 5.0 mg/L), but no association was observed among women engaging in any recreational physical activity (1.4 mg/L versus 1.6 mg/L; P heterogeneity = 0.03). CONCLUSIONS: Among breast cancer survivors, a better quality diet seems to be associated with lower levels of chronic inflammation. IMPACT: Lower levels of chronic inflammation have been associated with improved survival after breast cancer. PMID- 20716618 TI - ST14 gene variant and decreased matriptase protein expression predict poor breast cancer survival. AB - BACKGROUND: Matriptase plays a role in carcinogenesis, but the role of its genetic variation or that of the hepatocyte growth factor activator inhibitor-1 (HAI-1) has not been evaluated. This study aimed to examine the genetic variation of matriptase (ST14 gene) and HAI-1 (SPINT1 gene) in breast cancer risk and prognosis, to assess matriptase and HAI-1 gene and protein expression in breast tumors, and to identify their clinicopathologic correlations and prognostic significance. METHODS: Five single nucleotide polymorphisms in ST14 and three in SPINT1 were genotyped in 470 invasive breast cancer cases and 446 healthy controls. Gene expression analysis was done for 40 breast cancer samples. Protein expression was assessed by immunohistochemical analyses in 377 invasive breast tumors. The statistical significance of the associations among genotypes, clinicopathologic variables, and prognosis was assessed. RESULTS: The ST14 single nucleotide polymorphism rs704624 independently predicted breast cancer survival, a poor outcome associated with the minor allele (P = 0.001; risk ratio, 2.221; 95% confidence interval, 1.382-3.568). Moreover, ST14 gene expression levels were lower among the minor allele carriers (P = 0.009), and negative/low matriptase protein expression was independently predictive of poorer survival (P = 0.046; risk ratio, 1.554; 95% confidence interval, 1.008-2.396). CONCLUSIONS: The ST14 variant rs704624 and protein expression of matriptase have prognostic significance in breast cancer. This study adds to the evidence for the role of matriptase in breast cancer and has found new evidence for the genotypes having an impact in breast cancer. IMPACT: This is the first study showing that genetic variation in matriptase has clinical importance. The results encourage further study on the genetic variation affecting protein levels and function in type II transmembrane serine proteases. PMID- 20716619 TI - A randomized trial of a computer-tailored decision aid to improve prostate cancer screening decisions: results from the Take the Wheel trial. AB - OBJECTIVE: To evaluate a decision aid (DA) designed to promote informed decision making for prostate cancer screening. METHODS: Twelve work sites were randomly assigned to an intervention or nonintervention comparison condition. Intervention sites received access to a computer-tailored DA at the workplace. Male employees age 45 years and above (n = 625) completed surveys at baseline and at 3-month follow-up, documenting aspects of informed decision making. RESULTS: Using an intention-to-treat analysis, men in the intervention group were significantly more likely to have made a screening decision and to have improved knowledge without increased decisional conflict, relative to men in the comparison group. These changes were observed despite the fact that only 30% of men in intervention sites used the DA. Among DA users, similar improvements were observed, although the magnitudes of changes were substantially greater, and significant improvements in decision self-efficacy were observed. CONCLUSIONS: A DA offered in the workplace promoted decision making, improved knowledge, and increased decision self-efficacy among users, without increasing decisional conflict. However, participation was suboptimal, suggesting that better methods for engaging men in workplace interventions are needed. IMPACT STATEMENT: This trial shows the efficacy of a computer-tailored DA in promoting informed decisions about prostate cancer screening. The DA was delivered through work sites, thereby providing access to resources required to participate in informed decision making without requiring a medical appointment. However, participation rates were suboptimal, and additional strategies for engaging men are needed. PMID- 20716620 TI - Adherence to a breast cancer screening program and its predictors in underserved women in southern Brazil. AB - BACKGROUND: Adherence to breast cancer screening is a key element to ensure effectiveness of programs aiming at downstaging of breast cancer. In this study, we evaluated adherence to a screening program and its predictors in underserved women in southern Brazil. METHODS: Attendance to the program, which is based on yearly mammogram and clinical examination, was evaluated prospectively. Mean time frames between visits were calculated. Possible predictors of adherence (defined as mean intervals <=18 mo), such as socioeconomic indicators and health/lifestyle behaviors, were investigated. RESULTS: A total of 3,749 women (age 51 +/- 8 y, illiteracy rate of 6.8%, 57.4% with parity >=3) were analyzed. Median time between screening rounds was 16.5 months (interquartile range, 13.1-25.7), and median number of rounds attended was 3 (interquartile range, 2-4); 57.6% had mean intervals <=18, and 71% <=24 months. The most important independent predictors of adherence were high genetic risk [relative risk (RR), 1.25; 95% confidence interval (95% CI), 1.11-1.40], illiteracy (RR, 0.77; 95% CI, 0.67-0.90), parity >=5 (RR, 0.89; 95% CI, 0.83-0.96), and smoking (RR, 0.82; 95% CI, 0.77-0.88). CONCLUSIONS: Although the proposed screening interval was 1 year, compliance to biannual screening (accepted in several international programs) was high, especially when considering the low socioeconomic level of the sample. IMPACT: This project aims to test a breast cancer screening model for underserved populations in limited-resource countries where adherence is an issue. The identification of worst adherence predictors can point to interventions to improve outcomes of similar public health screening strategies. PMID- 20716621 TI - Genetic polymorphisms in adaptive immunity genes and childhood acute lymphoblastic leukemia. AB - BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) has been hypothesized to have an infection- and immune-related etiology. The lack of immune priming in early childhood may result in abnormal immune responses to infections later in life and increase ALL risk. METHODS: The current analyses examined the association between childhood ALL and 208 single-nucleotide polymorphisms (SNP) of 29 adaptive immune function genes among 377 ALL cases and 448 healthy controls. Single SNPs were analyzed with a log-additive approach using logistic regression models adjusted for sex, age, Hispanic ethnicity, and race. Sliding window haplotype analyses were done with haplotypes consisting of 2 to 6 SNPs. RESULTS: Of the 208 SNPs, only rs583911 of IL12A, which encodes a critical modulator of T-cell development, remained significant after accounting for multiple testing (odds ratio for each copy of the variant G allele, 1.52; 95% confidence interval, 1.25-1.85; P = 2.9 x 10(-5)). This increased risk was stronger among firstborn children of all ethnicities and among non-Hispanic children with less day care attendance, consistent with the hypothesis about the role of early immune modulation in the development of childhood ALL. Haplotype analyses identified additional regions of CD28, FCGR2, GATA3, IL2RA, STAT4, and STAT6 associated with childhood ALL. CONCLUSION: Polymorphisms of genes on the adaptive immunity pathway are associated with childhood ALL risk. IMPACT: Results of this study support an immune-related etiology of childhood ALL. Further confirmation is required to detect functional variants in the significant genomic regions identified in this study, in particular for IL12A. PMID- 20716622 TI - Estrogen receptor expression is required for low-dose resveratrol-mediated repression of aryl hydrocarbon receptor activity. AB - The putative cardioprotective and chemopreventive properties of the red wine phenolic resveratrol (RES) have made it the subject of a growing body of clinical and basic research. We have begun investigations focusing on the effects of RES on the activity of the aryl hydrocarbon receptor (AHR) complex. Our evidence suggests that RES is a potent repressor of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible gene transcription in estrogen receptor (ER)-positive human breast, lung, and colon cancer cell lines. RES activates the transcription of the ER target genes to the same degree as estradiol (E(2)) in human MCF-7 breast cancer cells. Unlike E(2), which can only diminish TCDD-inducible CYP1A1 gene transcription by approximately 50%, RES can completely abrogate this response. Furthermore, 50% repression of TCDD-inducible transcription can be achieved with 100 nM RES, approximately 2.5 orders of magnitude lower than concentrations required for maximal inhibition, suggesting that multiple mechanisms are responsible for this effect. RES (100 nM) does not prevent ligand binding of a TCDD analog, nor does it prevent AHR from binding to its response element in the 5'-regulatory region of the CYP1A1 gene. Small inhibitory RNAs directed to ERalpha have demonstrated that RES-mediated repression of CYP1A1 depends on ERalpha. Whereas CYP1A1 protein levels in MCF-7 cells are refractory to the low dose transcriptional effects of RES, a concomitant decrease in CYP1A1 protein levels is observed in Caco-2 cells. These results highlight a low-dose RES effect that could occur at nutritionally relevant exposures and are distinct from the high-dose effects often characterized. PMID- 20716623 TI - Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20 tetranorisocarbacyclin methyl ester for the evaluation of hepatobiliary transport. AB - A quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic analysis of hepatobiliary transport. Serial abdominal PET scans were performed on normal and multidrug resistance-associated protein 2 (Mrp2) deficient rats after intravenous injection of (15R)-16-m-[(11)C]tolyl-17,18,19,20 tetranorisocarbacyclin methyl ester (15R-[(11)C] TIC-Me) as a radiotracer. 15R [(11)C]TIC-Me was rapidly converted to its acid form in blood within 10 s. PET scans revealed that 15R-[(11)C]TIC was localized mainly in the liver within 5 min of injection. By 90 min, total radioactivity in bile of Mrp2-deficient rats was significantly reduced compared with controls. Metabolite analysis by thin-layer chromatography autoradiography showed that 15R-[(11)C]TIC is converted to at least three metabolites (M1, M2, and M3), and M2 and M3 are the major metabolites in plasma and bile, respectively. Hepatic uptake clearance of total radioactivity in normal rats was close to the hepatic blood flow rate and slightly higher than that in Mrp2-deficient rats. The intrinsic canalicular efflux clearance of M3 (CL(int,bile,M3)) in Mrp2-deficient rats was decreased to 12% of controls, whereas clearance of M2 was moderately decreased (54%). An in vitro transport assay detected ATP-dependent uptake of both M2 and M3 by rat Mrp2-expressing membrane vesicles. These results demonstrated that M3 is excreted primarily into the bile by Mrp2 in normal rats. We conclude that PET studies using 15R [(11)C]TIC-Me could be useful for in vivo analyses of Mrp2-mediated hepatobiliary transport. PMID- 20716624 TI - Morphine regulates dopaminergic neuron differentiation via miR-133b. AB - Morphine is one of the analgesics used most to treat chronic pain, although its long-term administration produces tolerance and dependence through neuronal plasticity. The ability of morphine to regulate neuron differentiation in vivo has been reported. However, the detailed mechanisms have not yet been elucidated because of the inability to separate maternal influences from embryonic events. Using zebrafish embryos as the model, we demonstrate that morphine decreases miR 133b expression, hence increasing the expression of its target, Pitx3, a transcription factor that activates tyrosine hydroxylase and dopamine transporter. Using a specific morpholino to knock down the zebrafish MU-opioid receptor (zfMOR) in the embryos and selective mitogen-activated protein kinase inhibitors, we demonstrate that the morphine-induced miR-133b decrease in zebrafish embryos is mediated by zfMOR activation of extracellular signal regulated kinase 1/2. A parallel morphine-induced down-regulation of miR-133b was observed in the immature but not in mature rat hippocampal neurons. Our results indicate for the first time that zebrafish embryos express a functional MU-opioid receptor and that zebrafish serves as an excellent model to investigate the roles of microRNA in neuronal development affected by long-term morphine exposure. PMID- 20716625 TI - Evaluation of the SCA instrument for measuring patient satisfaction with cancer care administered via paper or via the Internet. AB - BACKGROUND: Patients' perspectives provide valuable information on quality of care. This study evaluates the feasibility and validity of Internet administration of Service Satisfaction Scale for Cancer Care (SCA) to assess patient satisfaction with outcome, practitioner manner/skill, information, and waiting/access. PATIENTS AND METHODS: Primary data collected from November 2007 to April 2008. Patients receiving cancer care within 1 year were recruited from oncology, surgery, and radiation clinics at a tertiary care hospital. An Internet based version of the 16-item SCA was developed. Participants were randomised to Internet SCA followed by paper SCA 2 weeks later or vice versa. Seven-point Likert scale responses were converted to a 0-100 scale (minimum-maximum satisfaction). Response distribution, Cronbach's alpha, and test-retest correlations were calculated. RESULTS: Among 122 consenting participants, 78 responded to initial SCA. Mean satisfaction scores for paper/Internet were 91/90 (outcome), 95/94 (practitioner manner/skill), 89/90 (information), and 86/86 (waiting/access). Response rate and item missingness were similar for Internet and paper. Except for practitioner manner/skill, test-retest correlations were robust r = 0.77 (outcome), 0.74 (information), and 0.75 (waiting/access) (all P < 0.001). CONCLUSIONS: Internet SCA administration is a feasible and a valid measurement of cancer care satisfaction for a wide range of cancer diagnoses, treatment modalities, and clinic settings. PMID- 20716626 TI - The prognostic significance of p16 overexpression in oropharyngeal squamous cell carcinoma: implications for treatment strategies and future clinical studies. PMID- 20716627 TI - Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors. AB - BACKGROUND: Synovial sarcoma (SS) is a malignant soft tissue sarcoma with a poor prognosis because of late local recurrence and distant metastases. To our knowledge, no studies have minimum follow-up of 10 years that evaluate long-term outcomes for survivors. PATIENTS AND METHODS: Data on 62 patients who had been treated for SS from 1968 to 1999 were studied retrospectively in a multicenter study. Mean follow-up of living patients was 17.2 years and of dead patients 7.7 years. RESULTS: Mean age at diagnosis was 35.4 years (range 6-82 years). Overall survival was 38.7%. The 5-year survival was 74.2%; 10-year survival was 61.2%; and 15-year survival was 46.5%. Fifteen patients (24%) died of disease after 10 years of follow-up. Local recurrence occurred after a mean of 3.6 years (range 0.5-14.9 years) and metastases at a mean of 5.7 years (range 0.5-16.3 years). Only four patients were treated technically correctly with a planned biopsy followed by a wide resection or amputation. Factors associated with significantly worse prognosis included larger tumor size, metastases at the time of diagnosis, high-grade histology, trunk-related disease, and lack of wide resection as primary surgical treatment. CONCLUSIONS: In SS, metastases develop late with high mortality. Patients with SS should be followed for >10 years. PMID- 20716628 TI - Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate the efficacy and toxicity of single-agent docetaxel (Taxotere) as therapy in patients with disseminated nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with histologically confirmed metastatic or recurrent NPC who have failed at least one line of palliative chemotherapy regimen but no prior docetaxel were eligible. Patients received weekly docetaxel every 28 days (docetaxel 30 mg/m(2) on days 1, 8 and 15) and were evaluated every two cycles of treatment of response assessment. Quality-of-life (QoL) assessments during the treatment period were done using the European Organization for Research and Treatment of Cancer QoL questionnaire QLQ-C30; version 3.0. RESULTS: Thirty patients were assessable for toxicity and response. The median age of the patients was 47 years (range 25-68 years) and the majority of patients had good performance status (Eastern Cooperative Oncology Group 0-1). Grade 3 or 4 toxicity included fatigue (13%), anemia (10%) and diarrhea (3%) of patients. Eleven (37%) and four (13.3%) patients achieved partial response and stable disease, respectively. The median progression-free survival was 5.3 months and median overall survival of 12.8 months. The partial responders had a mean duration of response of 4.1 months. Docetaxel caused a significant decline in QoL scores during treatment of patients responding or progressing with the treatment. CONCLUSIONS: Our findings suggest that weekly docetaxel is well tolerated and is an active agent in patients with disseminated NPC who were previously exposed and largely refractory to platinum-based chemotherapy but can cause a significant decline in QoL during treatment. PMID- 20716629 TI - Prognostic significance of Ki-67 labeling index after short-term presurgical tamoxifen in women with ER-positive breast cancer. AB - BACKGROUND: Studies have shown that Ki-67 response after short-term neoadjuvant aromatase inhibitors may predict recurrence in postmenopausal breast cancer, whereas its prognostic effect in premenopausal women is unknown. PATIENTS AND METHODS: We compared the prognostic and predictive value of baseline and post treatment Ki-67 in 120 pre- and postmenopausal women with early-stage estrogen receptor-positive breast cancer who participated in a 4-week presurgical trial of tamoxifen. RESULTS: After 7.2 years of follow-up, women with post-treatment Ki-67 in the second (14%-19%), third (20%-29%) and top (>=30%) quartiles had a recurrence hazard ratio of 2.92 [95% confidence interval (CI) 0.95-8.96], 4.37 (1.56-12.25) and 6.05 (2.07-17.65), respectively, as compared with those in the bottom quartile (<14%) (P-trend = 0.001). The risk of invasive disease recurrence was 2.2% (95% CI 0.9-5.0) per point increase in baseline Ki-67 (P-trend = 0.076) and 5.0% (95% CI 2.3-7.7) per point increase in post-tamoxifen Ki-67 (P-trend < 0.001). The risk of death was 5.5 (95% CI 1.26-23.16) times higher in patients with post-drug Ki-67 >=20% than in those with Ki-67 <20% (P-trend = 0.006). CONCLUSIONS: Ki-67 response after short-term neoadjuvant tamoxifen is a good predictor of recurrence-free survival and overall survival, further supporting its use as surrogate biomarker to personalize adjuvant treatment and to screen novel drugs cost-effectively. PMID- 20716630 TI - A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice. AB - Lung cancer is the leading cause of cancer mortality in the United States and worldwide. The identification of key regulatory and molecular mechanisms involved in lung tumorigenesis is therefore critical to increase our understanding of this disease and could ultimately lead to targeted therapies to improve prevention and treatment. Induction of members of the activator protein-1 (AP-1) transcription factor family has been described in human non-small cell lung carcinoma. Activation of AP-1 can either stimulate or repress transcription of multiple gene targets, ultimately leading to increased cell proliferation and inhibition of apoptosis. In the present study, we show induction of AP-1 in carcinogen-induced mouse lung tumors compared with surrounding normal lung tissue. We then used a transgenic mouse model directing conditional expression of the dominant-negative c-jun mutant TAM67 in lung epithelial cells to determine the effect of AP-1 inhibition on mouse lung tumorigenesis. Consistent with low AP-1 activity in normal lung tissue, TAM67 expression had no observed effects in adult mouse lung. TAM67 decreased tumor number and overall lung tumor burden in chemically induced mouse lung tumor models. The most significant inhibitory effect was observed on carcinoma burden compared with lower-grade lesions. Our results support the concept that AP-1 is a key regulator of mouse lung tumorigenesis, and identify AP 1-dependent transcription as a potential target to prevent lung tumor progression. PMID- 20716631 TI - Low-carbohydrate diets and prostate cancer: how low is "low enough"? AB - Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD. A total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC 4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm(3). Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein 3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03). LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal). PMID- 20716632 TI - Molecular alterations associated with sulindac-resistant colon tumors in ApcMin/+ mice. AB - Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc(Min/+) mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc(Min/+) mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, beta catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-gamma. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear beta-catenin accumulation. Importantly, p21(WAF1/cip1) and peroxisome proliferator-activated receptor-gamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance. PMID- 20716633 TI - Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. AB - Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-pi level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess phase II enzymes. After the baseline evaluation, study participants took 1 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-pi level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions. PMID- 20716634 TI - Enhanced induction of mucin-depleted foci in estrogen receptor {beta} knockout mice. AB - The role of the estrogen receptor beta (ERbeta) in the colon has received considerable interest, yet in vivo models are needed to better define its protective actions. In the present study, wild-type (WT), ERalpha, and ERbeta knockout (alphaERKO and betaERKO) mice were injected with azoxymethane, a colon chemical carcinogen. Fourteen weeks after azoxymethane exposure, the incidence of aberrant crypt foci (ACF) was assessed by methylene blue staining. betaERKO mice showed significantly higher incidence (P < 0.001) of ACF (15.0 +/- 2.5) compared with alphaERKO (3.4 +/- 1.0) and WT (4.6 +/- 1.0) mice. The colons in several betaERKO mice had increased thickness and loss of normal morphology. It has been reported that ERbeta plays a role in the maintenance of the colonic crypt architecture; this may explain the loss of crypt organization in the colonic epithelium of betaERKO mice. The presence of mucin-depleted foci (MDF) has been shown, both in humans and in rodents, as an early event in colon cancer. Therefore, to surpass the limitations with ACF scoring, we performed Alcian blue neutral red staining to assess the presence of MDF. This assay allowed the assessment of precancerous lesions on all the betaERKO mice colons (38.3 +/- 4.0; P < 0.001), comparing to WT and alphaERKO mice (6.6 +/- 1.5 and 10.0 +/- 1.9, respectively), and served to confirm the ACF results. Together, these data support the use of MDF staining as a biomarker for precancerous lesions and the protective role of ERbeta in colon carcinogenesis. PMID- 20716635 TI - A dietary tomato supplement prevents prostate cancer in TRAMP mice. AB - Transgenic adenocarcinoma of the mouse prostate (TRAMP) is a model for progressive prostate cancer that mirrors the stages of the human form. In this study, the effects of a diet enriched with processed whole tomatoes on survival, tumorigenesis, and progression of prostate cancer, and the antioxidant and inflammatory status of TRAMP mice were investigated. Tomato diet significantly increased overall survival (P < 0.01), delayed progression from prostatic intraepithelial neoplasia to adenocarcinoma, and decreased the incidence of poorly differentiated carcinoma. Biochemical data disclosed an increase in serum antioxidant activity and a reduction of serum inflammation/angiogenesis biomarkers of particular importance in prostate carcinogenesis. PMID- 20716636 TI - The influence of mood on attribution. AB - Four studies show that mood systematically affects attributions of observed behavior by altering relative attention to actor and context. When the actor is more salient, sad people are more inclined to perceive an actor in stable trait terms and favor dispositional over situational explanations, whereas the opposite is true for happy people (Studies 1-3). However, when the context is made more salient, this pattern reverses, such that those in a negative mood make more situational attributions than those in a positive mood (Study 4). Taken together, these findings provide strong support for our hypothesis that mood and salience interact to affect attributions. PMID- 20716637 TI - Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response. AB - The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer. PMID- 20716638 TI - More than markers: biological significance of cancer stem cell-defining molecules. AB - Small populations within an increasing array of solid tumors, labeled cancer stem cells (CSC) or tumor-initiating cells (TIC), have the ability to differentiate, self-renew, and replicate the original tumor in vivo. To date, these cells have been distinguished from the bulk-tumor population by the expression pattern of cell-surface proteins (e.g., CD24, CD44, CD133) and cellular activities, such as the efflux of Hoechst dye or aldehyde dehydrogenase activity. Recent data have shown that these markers are inducible by exposure to anticancer agents; this finding highlights not only the potential fluidity of the CSC compartment, but also the functionality of these markers. The involvement of CD44 in invasion, adhesion, and metastasis, or the role of CD24 in modulation of src, FAK, and GLI1 are examples of these relevant roles. Instead of looking solely at the marker expression in these populations, we hope to clarify the biologically significant roles these markers and activities play in tumor progression, metastases, and as possible targets for therapy. PMID- 20716640 TI - From NPC therapeutic target identification to potential treatment strategy. AB - Nasopharyngeal carcinoma (NPC) is relatively rare in Western countries but is a common cancer in southern Asia. Many differentially expressed genes have been linked to NPC; however, how to prioritize therapeutic targets and potential drugs from unsorted gene lists remains largely unknown. We first collected 558 upregulated and 993 downregulated NPC genes from published microarray data and the primary literatures. We then postulated that conversion of gene signatures into the protein-protein interaction network and analyzing the network topologically could provide insight into key regulators involved in tumorigenesis of NPC. Of particular interest was the presence of cliques, called fully connected subgraphs, in the inferred NPC networks. These clique-based hubs, connecting with more than three queries and ranked higher than other nodes in the NPC protein-protein interaction network, were further narrowed down by pathway analysis to retrieve 24 upregulated and 6 downregulated bottleneck genes for predicting NPC carcinogenesis. Moreover, additional oncogenes, tumor suppressor genes, genes involved in protein complexes, and genes obtained after functional profiling were merged with the bottleneck genes to form the final gene signature of 38 upregulated and 10 downregulated genes. We used the initial and final NPC gene signatures to query the Connectivity Map, respectively, and found that target reduction through our pipeline could efficiently uncover potential drugs with cytotoxicity to NPC cancer cells. An integrative Web site (http://140.109.23.188:8080/NPC) was established to facilitate future NPC research. This in silico approach, from target prioritization to potential drugs identification, might be an effective method for various cancer researches. PMID- 20716639 TI - Urokinase plasminogen activator receptor and/or matrix metalloproteinase-9 inhibition induces apoptosis signaling through lipid rafts in glioblastoma xenograft cells. AB - Small interfering RNA (siRNA)-mediated transcriptional knockdown of urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9), alone or in combination, inhibits uPAR and/or MMP-9 expression and induces apoptosis in the human glioblastoma xenograft cell lines 4910 and 5310. siRNA against uPAR (pU-Si), MMP-9 (pM-Si), or both (pUM-Si) induced apoptosis and was associated with the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase. Furthermore, protein levels of the Fas receptor (APO-1/CD-95) were increased following transcriptional inactivation of uPAR and/or MMP-9. In addition, Fas siRNA against the Fas death receptor blocked apoptosis induced by pU-Si, pM-Si, or pUM-Si, thereby indicating the role for Fas signaling in pU-Si-, pM-Si-, or pUM-Si-mediated apoptotic cell death of human glioma xenograft cells. Thus, transcriptional inactivation of uPAR and/or MMP-9 enhanced localization of Fas death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts. Additionally, disruption of lipid rafts with methyl beta cyclodextrin prevented Fas clustering and pU-Si-, pM-Si-, or pUM-Si induced apoptosis, which is indicative of coclustering of Fas death receptor into lipid rafts in the glioblastoma xenograft cell lines 4910 and 5310. These data indicate the crucial role of the clusters of apoptotic signaling molecule enriched rafts in programmed cell death, acting as concentrators of death receptors and downstream signaling molecules, and as the linchpin from which a potent death signal is launched in uPAR- and/or MMP-9-downregulated cells. PMID- 20716641 TI - TAK-701, a humanized monoclonal antibody to hepatocyte growth factor, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. AB - Most non-small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKI) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827 HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827 HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, extracellular signal-regulated kinase, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK 701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation. PMID- 20716642 TI - Aesthetic evaluation of profile incisor inclination. AB - The objectives of this study were to evaluate (1) the impact of maxillary incisor inclination on the aesthetics of the profile view of a smile, (2) to determine the most aesthetic inclination in the profile view of a smile and correlate it with facial features, and (3) to determine if dentists, orthodontists, and laypeople appreciate differently incisor inclination in smile aesthetics. A smiling profile photograph of a female subject (22 years of age) who fulfilled the criteria of soft tissue normative values and a balanced smile was obtained. The photograph was manipulated to simulate six lingual and labial inclinations at 5 degree increments to a maximum of 15 degrees. The seven photographs were randomly distributed in a binder to three groups of raters (30 dentists, 30 orthodontists, and 30 laypeople) who scored the attractiveness of the photographic variations using a visual analogue scale. Comparison of the mean scores was carried out by repeated analysis of variance, univariate tests, and multiple Bonferroni comparisons. The results showed a statistically significant interaction between the rater's profession and the aesthetic preference of incisor inclination (P = 0.013). The profile smile corresponding to an increase of 5 degrees in a labial direction had the highest score among all professions and among male and female raters. Orthodontists preferred labial crown torque; dentists and laypeople did not appreciate excessive incisor inclination in either the lingual or the labial directions. The most preferred smile matched with a maxillary incisor inclined 93 degrees to the horizontal line and +7 degrees to the lower facial third. PMID- 20716643 TI - The what, how, why, and where of self-construal. AB - Since the publication of Markus and Kitayama's pivotal article on culture and the self, the concepts of independent, relational, and interdependent self-construal have become important constructs in cultural psychology and research on the self. The authors review the history of these constructs, their measurement and manipulation, and their roles in cognition, emotion, motivation, and social behavior. They make suggestions for future research and point to problems still to be sorted out. Researchers interested in these constructs have many opportunities to make important contributions to the literature in a variety of fields, including health psychology, education, counseling, and international relations. PMID- 20716644 TI - A meta-analysis of interventions to reduce loneliness. AB - Social and demographic trends are placing an increasing number of adults at risk for loneliness, an established risk factor for physical and mental illness. The growing costs of loneliness have led to a number of loneliness reduction interventions. Qualitative reviews have identified four primary intervention strategies: (a) improving social skills, (b) enhancing social support, (c) increasing opportunities for social contact, and (d) addressing maladaptive social cognition. An integrative meta-analysis of loneliness reduction interventions was conducted to quantify the effects of each strategy and to examine the potential role of moderator variables. Results revealed that single group pre-post and nonrandomized comparison studies yielded larger mean effect sizes relative to randomized comparison studies. Among studies that used the latter design, the most successful interventions addressed maladaptive social cognition. This is consistent with current theories regarding loneliness and its etiology. Theoretical and methodological issues associated with designing new loneliness reduction interventions are discussed. PMID- 20716646 TI - Defining a rat blood pressure quantitative trait locus to a <81.8 kb congenic segment: comprehensive sequencing and renal transcriptome analysis. AB - Evidence from multiple linkage and genome-wide association studies suggest that human chromosome 2 (HSA2) contains alleles that influence blood pressure (BP). Homologous to a large segment of HSA2 is rat chromosome 9 (RNO9), to which a BP quantitative trait locus (QTL) was previously mapped. The objective of the current study was to further resolve this BP QTL. Eleven congenic strains with introgressed segments spanning <81.8 kb to <1.33 Mb were developed by introgressing genomic segments of RNO9 from the Dahl salt-resistant (R) rat onto the genome of the Dahl salt-sensitive (S) rat and tested for BP. The congenic strain with the shortest introgressed segment spanning <81.8 kb significantly lowered BP of the hypertensive S rat by 25 mmHg and significantly increased its mean survival by 45 days. In contrast, two other congenic strains had increased BP compared with the S. We focused on the <81.8 kb congenic strain, which represents the shortest genomic segment to which a BP QTL has been mapped to date in any species. Sequencing of this entire region in both S and R rats detected 563 variants. The region did not contain any known or predicted rat protein coding genes. Furthermore, a whole genome renal transcriptome analysis between S and the <81.8 kb S.R congenic strain revealed alterations in several critical genes implicated in renal homeostasis. Taken together, our results provide the basis for future studies to examine the relationship between the candidate variants within the QTL region and the renal differentially expressed genes as potential causal mechanisms for BP regulation. PMID- 20716647 TI - H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle. AB - Citrate synthase (CS) is an enzyme of the Krebs cycle that plays a key role in mitochondrial metabolism. The aim of this study was to investigate the mechanisms underlying low activity of citrate synthase (CS) in A/J mice compared with other inbred strains of mice. Enzyme activity, protein content, and mRNA levels of CS were studied in the quadriceps muscles of A/J, BALB/cByJ, C57BL/6J, C3H/HeJ, DBA/2J, and PWD/PhJ strains of mice. Cytochrome c protein content was also measured. The results of the study indicate that A/J mice have a 50-65% reduction in CS activity compared with other strains despite similar levels of Cs mRNA and lack of differences in CS and cytochrome c protein content. CS from A/J mice also showed lower Michaelis constant (K(m)) for both acetyl CoA and oxaloacetate compared with the other strains of mice. In silico analysis of the genomic sequence identified a nonsynonymous single nucleotide polymorphism (SNP) (rs29358506, H55N) in Cs gene occurring near the site of the protein interacting with acetyl CoA. Allelic variants of the polymorphism segregated with the catalytic properties of CS enzyme among the strains. In summary, H55N polymorphism in Cs could be the underlying cause of low CS activity and its high affinity for substrates in A/J mice compared with other strains. This SNP might also play a role in resistance to obesity of A/J mice. PMID- 20716648 TI - Decisional involvement: staff nurse and nurse manager perceptions. AB - Enhancing involvement in organizational decisions is one strategy to improve the work environment of registered nurses and to increase their recruitment and retention. Little is known about the type of decision making and the level of involvement nurses desire. This was a descriptive study exploring staff nurse and nurse manager ratings of actual and preferred decisional involvement and differences between staff nurses and nurse managers. A sample of 320 RNs from a Midwestern health care network was surveyed using the Decisional Involvement Scale. Nurse managers and staff nurses had statistically significant differences in their perceptions of who was involved in actual decision making in the areas of unit governance and leadership and collaboration or liaison activities. There were statistically significant differences in preferred decisional involvement between staff nurses and nurse managers in the overall DIS scale and the subscales of unit governance and leadership and quality of support staff practice. PMID- 20716645 TI - Negative energy balance and hepatic gene expression patterns in high-yielding dairy cows during the early postpartum period: a global approach. AB - In high-yielding dairy cows the liver undergoes extensive physiological and biochemical changes during the early postpartum period in an effort to re establish metabolic homeostasis and to counteract the adverse effects of negative energy balance (NEB). These adaptations are likely to be mediated by significant alterations in hepatic gene expression. To gain new insights into these events an energy balance model was created using differential feeding and milking regimes to produce two groups of cows with either a mild (MNEB) or severe NEB (SNEB) status. Cows were slaughtered and liver tissues collected on days 6-7 of the first follicular wave postpartum. Using an Affymetrix 23k oligonucleotide bovine array to determine global gene expression in hepatic tissue of these cows, we found a total of 416 genes (189 up- and 227 downregulated) to be altered by SNEB. Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with widespread changes in gene expression classified into 36 gene networks including those associated with lipid metabolism, connective tissue development and function, cell signaling, cell cycle, and metabolic diseases, the three most significant of which are discussed in detail. SNEB cows displayed reduced expression of transcription activators and signal transducers that regulate the expression of genes and gene networks associated with cell signaling and tissue repair. These alterations are linked with increased expression of abnormal cell cycle and cellular proliferation associated pathways. This study provides new information and insights on the effect of SNEB on gene expression in high-yielding Holstein Friesian dairy cows in the early postpartum period. PMID- 20716649 TI - Psychometric evaluation of the index of self-regulation. AB - Index of Self-Regulation (ISR) is a nine-item scale designed primarily to measure individuals' level of self-regulation for physical activity. The aim of this study is to report psychometric characteristics of the ISR. The ISR scale was administered in a sample of 183 adult patients at 2 weeks following graduation from cardiac rehabilitation, 3 months following graduation, and 6 months following graduation. The internal consistency of the ISR was high at all three time points, with Cronbach's alphas of .81 to .96 across time points. The test retest reliability was fairly high, with an overall coefficient of .73. There was evidence of concurrent validity of the ISR based on its moderately significant correlations with other theoretically relevant variables, including self knowledge and motivational appraisal for physical activity. In conclusion, the ISR is a reliable and valid measure to assess the level of self-regulation in the maintenance of physical activity. PMID- 20716651 TI - Cerebral sparganosis. PMID- 20716650 TI - The future of imaging: developing the tools for monitoring response to therapy in oncology: the 2009 Sir James MacKenzie Davidson Memorial lecture. AB - Since the days of Sir James MacKenzie Davidson, radiology discoveries have been shaping the way patients are managed. The lecture on which this review is based focused not on anatomical imaging, which already has a great impact on patient management, but on the molecular imaging of cancer targets and pathways. In this post-genomic era, we have several tools at our disposal to enable the discovery of new probes for stratifying patients for therapy and for monitoring response to therapy sooner than is possible using conventional cross-sectional imaging methods. I describe a chemical library approach to discovering new imaging agents, as well as novel methods for improving the metabolic stability of existing probes. Finally, I describe the evaluation of these probes for clinical use in both pre-clinical and clinical validation. The chemical library approach is exemplified by the discovery of isatin sulfonamide probes for imaging apoptosis in tumours. This approach allowed important desirable features of radiopharmaceuticals to be incorporated into the design strategy. A lead compound, [(18)F]ICMT11, is selectively taken up in vitro in cancer cells and in vivo in tumours undergoing apoptosis. Improvement of the metabolic stability of a probe is exemplified by work on [(18)F]fluoro-[1,2-(2)H(2)]choline ("[(18)F]-D4 choline"), a novel probe for imaging choline metabolism. Deuterium substitution significantly reduced the systemic metabolism of this compound relative to that of non-deuteriated analogues, supporting its future clinical use. In order for probes to be useful for monitoring response a number of validation and/or qualification studies need to be performed, including assessments of whether the probe measures the target or pathway of interest in a specific and reproducible manner, whether the probe is stable to metabolism in vivo, what is the best time to assess response with these probes and finally whether changes in radiotracer uptake are associated with clinical outcome. [(18)F]Fluorothymidine, a probe for proliferation imaging has been validated and qualified for use in breast cancer. In summary, the ability to create new molecules that can report on specific targets and pathways provides a strategy for studying response to treatment in cancer earlier than it is currently possible. This could fundamentally change the way medicine is practised in the next 5-10 years. PMID- 20716652 TI - Hepatic artery-targeting guidewire technique during transjugular intrahepatic portosystemic shunt. AB - OBJECTIVE: This study evaluated the feasibility and safety of the transjugular intrahepatic portosystemic shunt (TIPS) procedure using the hepatic artery targeting guidewire technique for the puncture step. METHODS: We retrospectively reviewed 11 consecutive patients (5 men and 6 women, aged 46-76 years (mean 64 years)) with portal hypertension in whom the TIPS procedure was performed. As the first step in the TIPS procedure in all cases, a micro-guidewire was inserted into the hepatic arterial branch accompanying the portal venous branch through a microcatheter coaxially advanced from a 5-French catheter positioned in the coeliac or common hepatic artery. At the puncture step, the tip of the metallic cannula was aimed 1 cm posterior to the distal part of this micro-guidewire, after which the TIPS procedure was performed. Success rate, number of punctures and complications were evaluated. RESULTS: The TIPS procedure was successfully performed in all 11 patients. The mean number of punctures until success in entering the targeted portal venous branch was 5 (range 1-14). In 3 patients (27%), the right portal venous branch was entered at the first puncture attempt. The hepatic artery was punctured once in one patient and the bile duct was punctured once in another patient. No serious procedure-induced complications occurred. CONCLUSION: The TIPS procedure can be accomplished safely, precisely and relatively easily using the hepatic artery-targeting guidewire technique. PMID- 20716653 TI - The role of multidetector CT arthrography in the investigation of suspected intra articular hip pathology. AB - The aim of this study was to evaluate the role of multidetector CT (MDCT) arthrography in the diagnosis of intra-articular hip pathology. A retrospective review of 96 patients who had undergone CT hip arthrography was performed. Data regarding the presence of a labral tear, paralabral cyst, chondral loss, acetabular version, femoral morphology and fibrocystic change were collected. We detected 28 labral tears (24 anterior, 2 anterolateral, 1 lateral and 1 posterolateral). An abnormal labral-chondral transitional zone was seen in 9 patients and 4 patients had surface labral fraying. We identified three paralabral cysts. Acetabular cartilage loss was detected in 45 and femoral cartilage loss in 9 patients. An abnormal anterior femoral head and neck junction was present in 18 hips and fibrocystic change in 8. Acetabular retroversion was present in 11 hips. 63 sets of patient notes were reviewed, of which 49 were in patients with abnormal MDCT arthrogram findings. Surgical correlation was available in 27 patients. There was a discrepancy between the findings of a labral tear in one patient (false negative, 90% sensitivity and 100% specificity) and the presence of acetabular cartilage loss (88% sensitivity and 100% specificity) and femoral cartilage loss (94% sensitivity and 100% specificity) in three patients. MDCT arthrography affords accurate detection of intra-articular hip pathology. PMID- 20716654 TI - Psychiatric morbidity in paediatric primary care clinic in Ilorin, Nigeria. AB - BACKGROUND: We observed poor attendance at the recently established child and adolescent psychiatric clinic in our hospital, despite our sensitization efforts prior and after the establishment of the unit. The study was conducted at the paediatric clinics of the Family medicine/General out-patient department (GOPD) of university of Ilorin teaching hospital (UITH), Ilorin. OBJECTIVE: The study was aimed at finding out the prevalence, types and associated factors of psychiatric disorders among children attending the primary care unit of University of Ilorin Teaching Hospital (UITH). METHOD: A cross-sectional two stage study in which 350 children aged 7-14 years were screened with the parents' version of Child Behaviour Questionnaire or Rutter Scale A2. Of these, a stratified sub-sample of 157 (consisting of all high scorers and ~30% of low scorers, randomly selected) were interviewed jointly with their mothers using the children's version of the schedule for affective disorders and schizophrenia (Kiddie-SADS-PL or K-SADS-PL). RESULTS: An overall prevalence of 11.4% (40 of 350) for the presence of one or more DSM IV disorders was obtained. Enuresis with significant distress was present in 6.0%, behavioural disorders of Conduct and ADHD in 3.1%, emotional disorders of depression and anxiety in 1.7% and mental retardation in 0.6%. The presence of chronic medical illness and frequent hospital visits were factors associated with risk of having psychiatric disorders. CONCLUSION: The study supports earlier ones in Nigeria that child psychiatric disorders are common in hospital patients, although differences may exist in pattern and types. It emphasizes the need to screen hospital patients for morbidity to ensure early detection and treatment of psychiatric disorders in childhood. This is to limit the period of illness and avoid its adverse effects on growth and development of the children and to reduce the risk of carrying over remediable problems in childhood into adulthood. PMID- 20716655 TI - Biological therapy for psoriatic arthritis in clinical practice: outcomes up to 2 years. AB - OBJECTIVE: To evaluate the performance of biological drugs in psoriatic arthritis (PsA) in a routine care setting, using the Finnish national register of biological treatment (ROB-FIN). METHODS: Patients with PsA who started therapy with infliximab or etanercept between June 2000 and February 2006 (n = 127) were followed for up to 24 months. Response was evaluated using American College of Rheumatology response criteria including individual measures. RESULTS: Significantly diminished values for swollen and tender joints, patient's global and pain assessments, doctor's global assessment of disease activity, erythrocyte sedimentation rate, C-reactive protein, and Health Assessment Questionnaire score were observed within 3 months after commencement of both infliximab and etanercept. Values remained significantly lower throughout the 24 months of followup. ACR20 response at 3 months was 79% (n = 22/28) for infliximab and 76% (n = 34/45) for etanercept. The first biological drug was discontinued in 16% due to lack of effectiveness and in 6% due to adverse events. CONCLUSION: Anti-tumor necrosis factor-alpha therapy, often combined with conventional disease-modifying antirheumatic drugs, appeared to have limited toxicity and persistent effectiveness for up to 2 years in a cohort of Finnish patients with severe peripheral PsA. PMID- 20716656 TI - Use of highly sensitive C-reactive protein for followup of Wegener's granulomatosis. AB - OBJECTIVE: Since Wegener's granulomatosis (WG) represents a relapsing disease, efforts have been made to reliably predict relapses using blood tests. Followup measures such as conventionally determined C-reactive protein (CRP), antineutrophil cytoplasmic antibody (C-ANCA) titer, and proteinase-3 (PR3) ELISA are applied. We evaluated whether during remission elevated highly sensitive CRP (hsCRP) precedes relapse as a marker of subclinical inflammation and thus might improve clinical assessment. METHODS: We investigated 227 sera of 57 patients with WG: 74 sera collected from patients in remission who subsequently relapsed (before relapse), 30 sera collected during relapse, and 123 sera from patients in remission without relapse. We also distinguished between major and minor relapse. hsCRP, conventionally determined CRP (CRP), C-ANCA, PR3-ELISA, and erythrocyte sedimentation rate (ESR) were measured using commercial kits, and levels were correlated to clinical status. RESULTS: Only hsCRP and ANCA titer, but not CRP levels, were higher in sera from patients who subsequently relapsed versus those who did not, indicating patients at risk. Levels of hsCRP, CRP, and ESR were higher in sera collected during relapse than in the sera before relapse. hsCRP, conventional CRP, and ESR were also higher in samples collected during major relapse than before major relapse. Looking at the levels just before relapse compared to previous levels during remission, none of these measures rose directly before the clinical manifestation of the relapse. CONCLUSION: Our study provides evidence for an additional value of hsCRP in the clinical assessment of patients with WG. PMID- 20716657 TI - Cost of illness from the public payers' perspective in patients with ankylosing spondylitis in rheumatological care. AB - OBJECTIVE: To estimate the incremental costs to public payers for patients with ankylosing spondylitis (AS) of working age compared with reference subjects from the general population. METHODS: We investigated total costs for 3 years (2005 2007) in 116 outpatients under 66 years of age with AS attending rheumatological care in Malmo, Sweden. Mean (SD) age was 46 (11) years and mean (SD) disease duration was 24 (11) years. Two subjects per AS patient matched for age, sex, and residential area were selected from the Population Register to serve as a reference group. We retrieved data concerning sick leave, prescription drugs, and healthcare consumption from Swedish health-cost registers by the unique personal identification numbers. RESULTS: The mean total cost for the 3-year period 2005 2007 was US $37,095 (SD $30,091) for patients with AS, and $11,071 (SD $22,340) for the reference group. The mean indirect cost was $19,618 and $5905, respectively. Mean cost for healthcare was $8998 for the AS patients and $4187 for the reference subjects, and mean cost for drugs was $8479 and $979, respectively. The patients with AS treated with biological therapy constituted 80% of the total drug cost, but just 40% of the cost for disability pension. CONCLUSION: Patients with AS had 3-fold increase in costs compared to reference subjects from the general population, and the drug costs were almost 10 times as high. Production losses (indirect cost) represented more than half of total cost (53%). PMID- 20716658 TI - Care gap in patients with early inflammatory arthritis with a high fracture risk identified using FRAX((r)). AB - OBJECTIVE: To determine the proportion of patients with early inflammatory arthritis in a Canadian cohort who are at high risk for a major osteoporotic fracture using the Fracture Risk Assessment Tool (FRAX((r))), and to determine if a care gap exists in high-risk patients. METHODS: FRAX was applied to 238 patients enrolled in the Canadian Early Arthritis Cohort (CATCH) study based on norms from the United States and the United Kingdom, without the use of bone mineral density measurements. RESULTS: FRAX identified 5%-13% of patients at high risk for fracture, using a conservative analysis. Based on US norms, there was a significant correlation between increasing fracture risk groups and oral glucocorticoid use (p = 0.012) and baseline erosions (p = 0.040). Calcium or vitamin D use did not vary among the different fracture risk groups (p = NS), nor did bisphosphonate use (p = NS). The Disease Activity Score with 28 joint count in the high-risk group was significantly higher compared to the low-risk group (p = 0.048). CONCLUSION: Patients at increased risk had higher disease activity, more frequent glucocorticoid use, and more baseline erosions compared to patients at low risk. A care gap exists, in that a very low proportion of patients at high risk are being treated with calcium, vitamin D, and/or bisphosphonates. A higher fracture risk was calculated in our cohort using the US FRAX calculation tool compared to the UK calculation tool. These data highlight the need to identify and modify fracture risk in patients with early inflammatory arthritis. PMID- 20716659 TI - LupusQoL-US benchmarks for US patients with systemic lupus erythematosus. AB - OBJECTIVE: The LupusQoL-US instrument was recently validated in the US. We studied the benchmarks for a US patient cohort with systemic lupus erythematosus (SLE) and relevant demographic and disease correlates. METHODS: LupusQoL-US was administered to 185 patients with SLE. Demographic data (age, sex, ethnicity, marital status) and disease features (duration, disease activity and damage) were assessed simultaneously. Descriptive statistics were obtained. LupusQoL-US domain scores were calculated, and compared by sex, ethnicity, and marital status using nonparametric tests. Correlation between LupusQoL-US domains and age, disease duration, disease activity, and disease damage were obtained. RESULTS: Mean age of patients was 42.2 +/- 14.5 years; 94% of subjects were women. African American patients comprised 60% of the study cohort. The most affected domains were Fatigue and Physical Health. The least affected was Intimate Relationships. Age correlated with Physical Health, Pain, and Body Image (r = 0.15-0.18). Differences were observed based on sex and marital status, but not by ethnicity; there the LupusQoL-US correlated inversely with disease activity (r = -0.001 to 0.36) and damage (r = -0.003 to -0.40). CONCLUSION: All domains of the LupusQoL US based health related quality of life (HRQOL) were affected adversely. HRQOL varied by age, sex, and marital status in our SLE cohort. PMID- 20716660 TI - Antiendothelial cell antibodies induce apoptosis of bone marrow endothelial progenitors in systemic sclerosis. AB - OBJECTIVE: Patients with systemic sclerosis (SSc) have significantly fewer and functionally impaired endothelial progenitor cells (EPC) in peripheral blood and bone marrow; further, endothelial apoptosis seems to play a primary role in the pathogenesis of vascular damage. We investigated whether the failure of bone marrow EPC is related to their apoptotic phenotype and analyzed the possible mechanisms inducing apoptosis. METHODS: The presence of apoptotic cells was investigated in bone marrow aspirates taken from patients with SSc; microvessel density (MVD) and the immunohistochemical expression of vascular endothelial growth factor (VEGF) were also measured in bone marrow biopsies. A correlation between EPC apoptosis and the presence of antiendothelial cell antibodies (AECA) was also investigated. RESULTS: We confirmed the presence of bone marrow EPC dysfunction in SSc, while hematopoiesis was not impaired. Bone marrow studies showed a high percentage of apoptotic progenitors, no signs of fibrosis or an altered MVD, and an increased VEGF index. The patients' bone marrow plasma showed significant titers of AECA, and their presence correlated with that of apoptotic progenitors. These findings were further confirmed by an in vitro assay in which the apoptosis of normal progenitors was induced by the addition of AECA+ purified IgG. CONCLUSION: Our results showed that apoptosis in patients with SSc involves the source compartment of endothelial progenitors and correlates with AECA activity. These findings support the hypothesis that AECA may play a pathogenetic role by affecting the bone marrow EPC machinery that should repair the peripheral vascular lesions. PMID- 20716661 TI - Utility of serum S100B protein for identification of central nervous system involvement in systemic lupus erythematosus. AB - OBJECTIVE: To evaluate utility of S100B protein in serum as a marker of central nervous system involvement in systemic lupus erythematosus (SLE). METHODS: Forty patients with SLE, hospitalized because of central neuropsychiatric (cNP) manifestations (n = 36) and peripheral NP manifestations (pNP, n = 4) were studied. Patients were evaluated at hospitalization and 6 months later, including a serum and cerebrospinal fluid (CSF) sample. As controls, 4 SLE patients with septic meningitis (SLEsm), 13 surgical SLE patients (SLE surgical), 14 patients with nonautoimmune diseases, and 4 patients with primary NP syndromes were included. Serum and CSF S100B protein levels were determined by ELISA. RESULTS: At baseline, serum levels of S100B protein did not differ across SLE groups. Using an arbitrary cutoff value, positive S100B levels in serum were observed in 7 (19%), 6 (46%), and 1 patient from the cNPSLE, SLE surgical, and SLEsm groups, respectively. S100B protein levels in cNPSLE and SLE surgical patients were similar. In CSF, S100B protein levels did not differ among SLE groups, except in patients with SLEsm. Paired serum/CSF samples were obtained in 23 patients with cNPSLE at 6 months after the acute event. Overall, levels of S100B protein in serum did not change despite the decrease observed in CSF (p = 0.004). The correlation coefficient of serum and CSF S100B protein levels among all the SLE patients at baseline was poor (r = 0.23). CONCLUSION: Serum levels of S100B protein do not differentiate SLE patients with and those without central neurological manifestations. PMID- 20716662 TI - Assessment of ankylosing spondylitis criteria in patients with chronic low back pain and vertebral endplate Modic I signal changes. AB - OBJECTIVE: Patients with chronic low back pain (cLBP) and vertebral endplate Modic I signal changes on lumbar magnetic resonance imaging (MRI) have clinical features that could mimic inflammatory back pain related to spondyloarthritis (SpA) and/or ankylosing spondylitis (AS). We aimed to assess whether such patients fulfilled criteria for SpA and/or AS. METHODS: For 5 months in 2008, all patients (n = 314) referred to a tertiary care physical medicine and rehabilitation facility in France were consecutively screened. A total of 185 hospitalized for non-specific cLBP were prospectively assessed. Forty patients fulfilling inclusion criteria were consecutively enrolled and included in 2 groups according to MRI findings: Modic I (n = 15) and non-Modic I (n = 25). MRI findings were assessed independently by 2 spine specialists and a radiologist. HLA-B27 status was determined. Data were collected on clinical measurements and fulfillment of Amor criteria (AC) and modified New York criteria (mNYC). All assessors were blinded to HLA-B27 status. RESULTS: Whatever the Modic group, no patient fulfilled AC or mNYC, and mean total scores were comparable [3 +/- 2 (range 0-22; p = 0.977), 1 +/- 1 (range 0-3; p = 1.000), and 0 +/- 0 (range 0-1; p = 1.000) for AC and clinical and radiological mNYC, respectively]. HLA-B27 status was similar in both groups [n = 2 (13%) vs n = 0 (0%); p = 0.135]. CONCLUSION: Patients with cLBP and Modic I vertebral endplate signal changes on lumbar MRI do not fulfill widely used and validated criteria for SpA and/or AS. Such cases are clinically distinct from SpA and AS. PMID- 20716663 TI - B cell abnormalities in Wegener's granulomatosis and microscopic polyangiitis: role of CD25+-expressing B cells. AB - OBJECTIVE: The use of rituximab in vasculitis has increased interest in B cell biology. A subpopulation of B cells expressing CD25 shows antigen-presenting properties and may have regulatory functions. We assessed subpopulations of B cell maturation (Bm) and markers related to activity and antigen presentation, and related the findings to disease activity. METHODS: Multiparameter flow cytometry was used to assess numbers and proportions of circulating lymphocytes from 34 patients with vasculitis (16 remission, 18 active) and 20 controls. RESULTS: Active vasculitis samples showed decreased proportions of Bm1 (7.8% vs 11%; p = 0.041), Bm2' (0.2% vs 0.7%; p = 0.002), and Bm3/Bm4 (0.1% vs 0.3%; p = 0.006), compared with controls; Bm2 cells were the most frequently occurring B cells but they were not significantly different in active vasculitis (74% vs 62%; p = 0.083). In patients with remission the proportion of CD25+ B cells was increased compared to controls (48% vs 29%, respectively; p = 0.006) and also compared to active vasculitis (23%; p = 0.006). The proportion of CD86+ B cells was also increased (31%) compared to active vasculitis (8%; p = 0.001), and to controls (6%; p = 0.0003). In multivariate analysis, Bm2' cells and CD25+27- B cells were independently influencing the patient group. CONCLUSION: In active vasculitis, a lower proportion of Bm1 cells may indicate activated B cells. Patients in remission had higher proportions of CD25+ (alpha-chain of interleukin 2 receptor) and CD86+ (costimulatory molecule) B cells. We suggest that these B cells may have a regulatory role, or alternatively may result from previous treatment. PMID- 20716664 TI - Factors associated with a longer time to access pediatric rheumatologists in Canadian children with juvenile idiopathic arthritis. AB - OBJECTIVE: The Research on Arthritis in Canadian Children Emphasizing Outcomes (ReACCh Out) cohort is a prospective inception cohort of patients with newly diagnosed juvenile idiopathic arthritis (JIA) seen in 16 Canadian pediatric rheumatology (PR) centers. We used data from this cohort to explore factors associated with longer time from symptom onset to the first visit to (PR), and with longer time from first visit to a diagnosis of JIA. METHODS: We included children enrolled in ReACCh Out within 6 months of JIA diagnosis, for whom the dates of symptom onset and first PR visit were recorded. We used Cox proportional hazard modeling to investigate the effects of history, physical examination, and laboratory evaluation on the interval from JIA symptom onset to first PR assessment. RESULTS: In total, 319 children from the cohort were included. Having a fever (hazard ratio 1.80, 95% CI 1.10, 2.93), any part South Asian ethnicity (HR 1.75, 95% CI 1.04, 2.95), highly educated parents (HR 1.69, 95% CI 1.18, 2.44), and limp (HR 1.55, 95% 1.16, 2.06) were significantly associated with shorter time from symptom onset to first PR assessment, while a history of heel pain or enthesitis (HR 0.61, 95% 0.38, 0.97) was significantly associated with a longer time to first PR visit. CONCLUSION: Children with a history of a fever, limp, any part South Asian ethnicity, or highly educated parents were more likely to see PR sooner than patients without these features, while children with a history of enthesitis received PR care later than those without enthesitis. PMID- 20716665 TI - Probiotic therapy for the treatment of spondyloarthritis: a randomized controlled trial. AB - OBJECTIVE: To investigate the effect of an orally administered probiotic on disease activity, fatigue, quality of life, and intestinal symptoms in patients with active spondyloarthritis. METHODS: Patients with active spondyloarthritis [defined as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >= 3, Bath Ankylosing Spondylitis Functional Index (BASFI) >= 3, Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) >= 2, or peripheral joint count >= 2] were randomized to oral probiotic or placebo for 12 weeks. Patients and assessors were blinded to treatment allocation. The primary outcome measure was 10% improvement in the BASFI. Additional outcome measures were improvements in the ASsessments in Ankylosing Spondylitis (ASAS)-endorsed core domains: pain, spinal mobility, patient global, peripheral joint and entheseal scores, stiffness, C-reactive protein, and fatigue. The ASAS20 criteria, a composite measure of response, were also applied. Quality of life and bowel symptoms were quantified using the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) and Dudley Inflammatory Bowel Symptom Questionnaire (DISQ). RESULTS: Sixty-three patients were randomized to oral probiotic (n = 32) or placebo (n = 31). All patients completed the trial. No significant difference was noted between groups in any of the core domains. The mean BASFI fell from 3.5 +/- 2.0 to 2.9 +/- 1.9 in the probiotic group and from 3.6 +/- 1.9 to 3.1 +/- 2.2 in the placebo group (p = 0.839). The mean BASDAI fell from 4.2 +/- 2.2 to 3.2 +/- 2.1 in the probiotic group and 4.5 +/- 2.0 to 3.9 +/- 2.2 in the placebo group (p = 0.182). No significant adverse events were recorded in the probiotic-treated group. CONCLUSION: In this randomized controlled trial, the probiotic combination administered did not demonstrate significant benefit over placebo, despite a theoretical rationale for this therapy. PMID- 20716666 TI - p53 binds preferentially to genomic regions with high DNA-encoded nucleosome occupancy. AB - The human transcription factor TP53 is a pivotal roadblock against cancer. A key unresolved question is how the p53 protein selects its genomic binding sites in vivo out of a large pool of potential consensus sites. We hypothesized that chromatin may play a significant role in this site-selection process. To test this, we used a custom DNA microarray to measure p53 binding at approximately 2000 sites predicted to possess high-sequence specificity, and identified both strongly bound and weakly bound sites. When placed within a plasmid, weakly bound sites become p53 responsive and regain p53 binding when stably integrated into random genomic locations. Notably, strongly bound sites reside preferentially within genomic regions whose DNA sequence is predicted to encode relatively high intrinsic nucleosome occupancy. Using in vivo nucleosome occupancy measurements under conditions where p53 is inactive, we experimentally confirmed this prediction. Furthermore, upon p53 activation, nucleosomes are partially displaced from a relatively broad region surrounding the bound p53 sites, and this displacement is rapidly reversed upon inactivation of p53. Thus, in contrast to the general assumption that transcription-factor binding is preferred in sites that have low nucleosome occupancy prior to factor activation, we find that p53 binding occurs preferentially within a chromatin context of high intrinsic nucleosome occupancy. PMID- 20716667 TI - Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. AB - Epigenetic silencing plays an important role in cancer development. An attractive hypothesis is that local DNA features may participate in differential predisposition to gene hypermethylation. We found that, compared with methylation resistant genes, methylation-prone genes have a lower frequency of SINE and LINE retrotransposons near their transcription start site. In several large testing sets, this distribution was highly predictive of promoter methylation. Genome wide analysis showed that 22% of human genes were predicted to be methylation prone in cancer; these tended to be genes that are down-regulated in cancer and that function in developmental processes. Moreover, retrotransposon distribution marks a larger fraction of methylation-prone genes compared to Polycomb group protein (PcG) marking in embryonic stem cells; indeed, PcG marking and our predictive model based on retrotransposon frequency appear to be correlated but also complementary. In summary, our data indicate that retrotransposon elements, which are widespread in our genome, are strongly associated with gene promoter DNA methylation in cancer and may in fact play a role in influencing epigenetic regulation in normal and abnormal physiological states. PMID- 20716668 TI - International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. AB - Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca(2+) and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels. PMID- 20716673 TI - Antibodies to the endoplasmic reticulum-resident chaperones calnexin, BiP and Grp94 in patients with rheumatoid arthritis and systemic lupus erythematosus. AB - OBJECTIVES: To investigate the presence of autoantibodies against mammalian chaperones of the endoplasmic reticulum (ER) in patients with RA and other immune mediated diseases. METHODS: Sera from healthy donors, from early RA patients with two follow-up samples, patients with SLE, SSc and IBD were collected and analysed for anti-ER chaperone antibodies. Detection of serum IgG antibodies against immunoglobulin heavy chain binding protein (BiP), glucose-regulated protein 94 (Grp94) and calnexin was carried out using ELISA. The specificity of sera positive for individual ER chaperones was confirmed by immunoblotting. Statistical analysis was performed using Welch's t-test, Mann-Whitney U-test, partial correlation and Pearson's correlation. RESULTS: In patients with RA and SLE, autoantibody titres against BiP, Grp94 and calnexin were significantly higher than those in healthy controls. These autoantibodies were detectable in patients with early RA and titres remained stable for at least 6-12 months. Also several SSc and IBD patients exhibited autoantibodies against these ER chaperones; however, titres and frequencies were lower than in RA or SLE patients. Furthermore, anti-calnexin antibodies correlated significantly with the presence of BiP and Grp94 autoantibodies in patients with RA and SLE. CONCLUSION: Calnexin and Grp94 were identified as novel autoantigens in RA and calnexin in SLE. Since calnexin, Grp94 and BiP are ER-resident proteins of eukaryotic cells, our data suggest that autoantibody generation against ER chaperones is independent of initial exposure to the corresponding bacterial chaperones; rather, ER chaperones may represent genuine autoantigens. PMID- 20716674 TI - Do new biologics meet the unmet medical need in rheumatoid arthritis? Safety and efficacy of abatacept following B-cell depletion. PMID- 20716675 TI - The non-specific effects of vaccines. PMID- 20716677 TI - Question 1 Does caffeine treatment for apnoea of prematurity improve neurodevelopmental outcome in later life? PMID- 20716670 TI - Frequent deregulations in the hedgehog signaling network and cross-talks with the epidermal growth factor receptor pathway involved in cancer progression and targeted therapies. AB - The hedgehog (Hh)/glioma-associated oncogene (GLI) signaling network is among the most important and fascinating signal transduction systems that provide critical functions in the regulation of many developmental and physiological processes. The coordinated spatiotemporal interplay of the Hh ligands and other growth factors is necessary for the stringent control of the behavior of diverse types of tissue-resident stem/progenitor cells and their progenies. The activation of the Hh cascade might promote the tissue regeneration and repair after severe injury in numerous organs, insulin production in pancreatic beta-cells, and neovascularization. Consequently, the stimulation of the Hh pathway constitutes a potential therapeutic strategy to treat diverse human disorders, including severe tissue injuries; diabetes mellitus; and brain, skin, and cardiovascular disorders. In counterbalance, a deregulation of the Hh signaling network might lead to major tissular disorders and the development of a wide variety of aggressive and metastatic cancers. The target gene products induced through the persistent Hh activation can contribute to the self-renewal, survival, migration, and metastasis of cancer stem/progenitor cells and their progenies. Moreover, the pivotal role mediated through the Hh/GLI cascade during cancer progression also implicates the cooperation with other oncogenic products, such as mutated K-RAS and complex cross-talk with different growth factor pathways, including tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), Wnt/beta catenin, and transforming growth factor-beta (TGF-beta)/TGF-beta receptors. Therefore, the molecular targeting of distinct deregulated gene products, including Hh and EGFR signaling components and other signaling elements that are frequently deregulated in highly tumorigenic cancer-initiating cells and their progenies, might constitute a potential therapeutic strategy to eradicate the total cancer cell mass. Of clinical interest is that these multitargeted approaches offer great promise as adjuvant treatments for improving the current antihormonal therapies, radiotherapies, and/or chemotherapies against locally advanced and metastatic cancers, thereby preventing disease relapse and the death of patients with cancer. PMID- 20716679 TI - Question 2 Should a child with ADHD and epilepsy be given ritalin? PMID- 20716680 TI - Question 3 What is the effect of cardiopulmonary resuscitation at birth on survival and neurodevelopmental outcome of extremely preterm infants? PMID- 20716682 TI - Medial patellofemoral ligament repair for recurrent patellar dislocation. AB - BACKGROUND: The medial patellofemoral ligament (MPFL) is the primary restraint to extreme lateral displacement and is typically disrupted with an acute lateral patellar dislocation. Patients who fail a comprehensive nonoperative program and experience recurrent lateral patellar instability episodes are candidates for surgical treatment. Current surgical procedures include a variety of proximal realignment techniques, including repair or reconstruction of the MPFL along with distal realignment of the tibial tubercle when indicated. PURPOSE: The objective of this study was to review the clinical, functional, and radiographic outcomes of isolated MPFL repair for recurrent lateral patellar dislocation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The records of all patients undergoing MPFL repair for recurrent patellar dislocation at the Mayo Clinic from 2001 to 2006 were retrospectively reviewed. Twenty-seven patients (29 knees) with an average age of 19 years (range, 11-32 years) were included in this study. Clinical, functional, and radiographic outcomes were assessed at an average of 4 years after surgery (range, 2-7 years), using recurrent instability as the primary end point. RESULTS: The success rate of MPFL repair for preventing recurrent dislocations was 72% (21 of 29 knees). Eight patients (28%) experienced a recurrent lateral patellar dislocation. Five of these patients required a reoperation, including two MPFL reconstructions, 1 tibial tubercle osteotomy with MPFL reconstruction, 1 tibial tubercle osteotomy with revision MPFL repair, and 1 revision MPFL repair. At final follow-up, the mean Lysholm and Kujala scores were 86 (range, 42-100) and 92 (range, 57-105), respectively. Postoperative radiographs revealed a mean patellofemoral congruence angle improvement of 27 degrees (range, 5 degrees -44 degrees ). The only statistically significant risk factor for failure was nonanatomical MPFL repair at the medial femoral condyle (P = .004). CONCLUSION: Isolated repair of the MPFL for recurrent patellar instability is associated with a relatively high failure rate, but remains a viable surgical option if surgical technique principles are followed. The clinical success of this operation depends on restoration of the anatomical origin of the MPFL and careful patient selection. PMID- 20716683 TI - High school concussions in the 2008-2009 academic year: mechanism, symptoms, and management. AB - BACKGROUND: An estimated 136 000 concussions occur per academic year in high schools alone. The effects of repetitive concussions and the potential for catastrophic injury have made concussion an injury of significant concern for young athletes. PURPOSE: The objective of this study was to describe the mechanism of injury, symptoms, and management of sport-related concussions using the High School Reporting Information Online (HS RIO) surveillance system. STUDY DESIGN: Descriptive epidemiology study. METHODS: All concussions recorded by HS RIO during the 2008-2009 academic year were included. Analyses were performed using SPSS software. Chi-square analysis was performed for all categorical variables. Statistical significance was considered for P < .05. RESULTS: A total of 544 concussions were recorded. The most common mechanism (76.2%) was contact with another player, usually a head-to-head collision (52.7%). Headache was experienced in 93.4%; 4.6% lost consciousness. Most (83.4%) had resolution of their symptoms within 1 week. Symptoms lasted longer than 1 month in 1.5%. Computerized neuropsychological testing was used in 25.7% of concussions. When neuropsychological testing was used, athletes were less likely to return to play within 1 week than those for whom it was not used (13.6% vs 32.9%; P < .01). Athletes who had neuropsychological testing appeared less likely to return to play on the same day (0.8% vs 4.2%; P = .056). A greater proportion of injured, nonfootball athletes had computerized neuropsychological testing than injured football players (23% vs 32%; P = .02) CONCLUSION: When computerized neuropsychological testing is used, high school athletes are less likely to be returned to play within 1 week of their injury. Concussed football players are less likely to have computerized neuropsychological testing than those participating in other sports. Loss of consciousness is relatively uncommon among high school athletes who sustain a sport-related concussion. The most common mechanism is contact with another player. Some athletes (1.5%) report symptoms lasting longer than 1 month. PMID- 20716684 TI - All-inside meniscal repair with bioabsorbable meniscal screws or with bioabsorbable meniscus arrows: a prospective, randomized clinical study with 2 year results. AB - BACKGROUND: All-inside meniscal repairs have gained popularity in the past few years. However, only a few prospective, randomized clinical studies have been done to compare different all-inside meniscal repair techniques. HYPOTHESIS: Meniscal repair with bioabsorbable meniscal screws and arrows results in similar clinical outcome on short-term follow-up. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Forty-two patients were prospectively randomized to have all-inside meniscal repair either by using bioabsorbable meniscal screws or bioabsorbable meniscus arrows (21 patients, 23 meniscal repairs in each group) for the fixation. The evaluation methods were clinical examination, Lysholm score, the International Knee Documentation Committee (IKDC) knee score, and magnetic resonance arthrography (MRA) evaluation. The average follow-up time was 27 months (standard deviation, 8). RESULTS: There were no differences between the study groups preoperatively. All 42 patients (100%) were available for the follow-up. However, during the follow-up, 11 patients had clinical failure, confirmed at second-look arthroscopy, of the repair leading to partial meniscal resection. Four failures (all on the medial meniscus) were observed with the use of meniscal screw fixation (17%), and 7 (4 on the medial meniscus, and 3 on the lateral meniscus) with the use of meniscus arrow fixation (30%) (P = .242). Six patients with meniscus arrows (29%) had chondral damage on the femoral condyles evaluated by MRA or at second-look arthroscopy, while none of the patients with the meniscal screws had the same (P = .018). However, the Lysholm and the IKDC scores were similar in both groups at follow-up. CONCLUSION: All-inside meniscal repair with bioabsorbable meniscal screws and arrows resulted in similar clinical outcome, although significantly more chondral damage was observed when using bioabsorbable meniscus arrows for fixation. PMID- 20716685 TI - CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors. AB - CpG dinucleotides contribute to epigenetic mechanisms by being the only site for DNA methylation in mammalian somatic cells. They are also mutation hotspots and approximately 5-fold depleted genome-wide. We report here a study focused on CpG sites in the coding regions of Hox and other transcription factor genes, comparing methylated genomes of Homo sapiens, Mus musculus, and Danio rerio with nonmethylated genomes of Drosophila melanogaster and Caenorhabditis elegans. We analyzed 4-fold degenerate, synonymous codons with the potential for CpG. That is, we studied "silent" changes that do not affect protein products but could damage epigenetic marking. We find that DNA-binding transcription factors and other developmentally relevant genes show, only in methylated genomes, a bimodal distribution of CpG usage. Several genetic code-based tests indicate, again for methylated genomes only, that the frequency of silent CpGs in Hox genes is much greater than expectation. Also informative are NCG-GNN and NCC-GNN codon doublets, for which an unusually high rate of G to C and C to G transversions was observed at the third (silent) position of the first codon. Together these results are interpreted as evidence for strong "pro-epigenetic" selection acting to preserve CpG sites in coding regions of many genes controlling development. We also report that DNA-binding transcription factors and developmentally important genes are dramatically overrepresented in or near clusters of three or more CpG islands, suggesting a possible relationship between evolutionary preservation of CpG dinucleotides in both coding regions and CpG islands. PMID- 20716686 TI - PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy. AB - Dynamic nucleocytoplasmic shuttling of class IIa histone deacetylases (HDACs) is a fundamental mechanism regulating gene transcription. Recent studies have identified several protein kinases that phosphorylate HDAC5, leading to its exportation from the nucleus. However, the negative regulatory mechanisms for HDAC5 nuclear exclusion remain largely unknown. Here we show that cAMP-activated protein kinase A (PKA) specifically phosphorylates HDAC5 and prevents its export from the nucleus, leading to suppression of gene transcription. PKA interacts directly with HDAC5 and phosphorylates HDAC5 at serine 280, an evolutionarily conserved site. Phosphorylation of HDAC5 by PKA interrupts the association of HDAC5 with protein chaperone 14-3-3 and hence inhibits stress signal-induced nuclear export of HDAC5. An HDAC5 mutant that mimics PKA-dependent phosphorylation localizes in the nucleus and acts as a dominant inhibitor for myocyte enhancer factor 2 transcriptional activity. Molecular manipulations of HDAC5 show that PKA-phosphorylated HDAC5 inhibits cardiac fetal gene expression and cardiomyocyte hypertrophy. Our findings identify HDAC5 as a substrate of PKA and reveal a cAMP/PKA-dependent pathway that controls HDAC5 nucleocytoplasmic shuttling and represses gene transcription. This pathway may represent a mechanism by which cAMP/PKA signaling modulates a wide range of biological functions and human diseases such as cardiomyopathy. PMID- 20716671 TI - cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. AB - To date, studies suggest that biological signaling by nitric oxide (NO) is primarily mediated by cGMP, which is synthesized by NO-activated guanylyl cyclases and broken down by cyclic nucleotide phosphodiesterases (PDEs). Effects of cGMP occur through three main groups of cellular targets: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and PDEs. cGMP binding activates PKG, which phosphorylates serines and threonines on many cellular proteins, frequently resulting in changes in activity or function, subcellular localization, or regulatory features. The proteins that are so modified by PKG commonly regulate calcium homeostasis, calcium sensitivity of cellular proteins, platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes. Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators (nitroglycerin), PDE5 inhibitors [sildenafil (Viagra and Revatio), vardenafil (Levitra), and tadalafil (Cialis and Adcirca)] for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension; the PDE3 inhibitors [cilostazol (Pletal) and milrinone (Primacor)] are used for treatment of intermittent claudication and acute heart failure, respectively. Potential for use of these medications in the treatment of other maladies continues to emerge. PMID- 20716687 TI - Structural basis for the regulation of NtcA-dependent transcription by proteins PipX and PII. AB - PII, an ancient and widespread signaling protein, transduces nitrogen/carbon/energy abundance signals through interactions with target proteins. We clarify structurally how PII regulates gene expression mediated by the transcription factor NtcA, the global nitrogen regulator of cyanobacteria, shedding light on NtcA structure and function and on how NtcA is activated by 2 oxoglutarate (2OG) and coactivated by the nonenzymatic PII target, protein PipX. We determine for the cyanobacteria Synechococcus elongatus the crystal structures of the PII-PipX and PipX-NtcA complexes and of NtcA in active and inactive conformations (respective resolutions, 3.2, 2.25, 2.3, and 3.05 A). The structures and the conclusions derived from them are consistent with the results of present and prior site-directed mutagenesis and functional studies. A tudor like domain (TLD) makes up most of the PipX structure and mediates virtually all the contacts of PipX with PII and NtcA. In the PII-PipX complex, one PII trimer sequesters the TLDs of three PipX molecules between its body and its extended T loops, preventing PipX activation of NtcA. Changes in T loop conformation triggered by 2OG explain PII-PipX dissociation when 2OG is bound. The structure of active dimeric NtcA closely resembles that of the active cAMP receptor protein (CRP). This strongly suggests that with these proteins DNA binding, transcription activation, and allosteric regulation occur by common mechanisms, although the effectors are different. The PipX-NtcA complex consists of one active NtcA dimer and two PipX monomers. PipX coactivates NtcA by stabilizing its active conformation and by possibly helping recruit RNA polymerase but not by providing extra DNA contacts. PMID- 20716688 TI - Single-molecule derivation of salt dependent base-pair free energies in DNA. AB - Accurate knowledge of the thermodynamic properties of nucleic acids is crucial to predicting their structure and stability. To date most measurements of base-pair free energies in DNA are obtained in thermal denaturation experiments, which depend on several assumptions. Here we report measurements of the DNA base-pair free energies based on a simplified system, the mechanical unzipping of single DNA molecules. By combining experimental data with a physical model and an optimization algorithm for analysis, we measure the 10 unique nearest-neighbor base-pair free energies with 0.1 kcal mol(-1) precision over two orders of magnitude of monovalent salt concentration. We find an improved set of standard energy values compared with Unified Oligonucleotide energies and a unique set of 10 base-pair-specific salt-correction values. The latter are found to be strongest for AA/TT and weakest for CC/GG. Our unique energy values and salt corrections improve predictions of DNA unzipping forces and are fully compatible with melting temperatures for oligos. The method should make it possible to obtain free energies, enthalpies, and entropies in conditions not accessible by bulk methodologies. PMID- 20716690 TI - A national study examining emergency medicine specialty training and quality measures in the emergency department. AB - The objective of this study was to measure the relationship between emergency medicine (EM) specialty training and quality measures in the emergency department (ED). Data were gathered from the 2003-2004 National Hospital Ambulatory Medical Care Survey. The outcome was proportion of patients with acute myocardial infarction (AMI), pneumonia (PNA), and long-bone fracture (LBF) who received recommended therapy. These measures were analyzed with respect to EM residency completion. Compared with EDs with more than 80% EM-trained physicians, EDs with fewer than 80% EM-trained physicians had similar rates of aspirin (43% vs 42%) and beta-blocker (26% vs 19%) use for AMI, appropriate antibiotics (78% vs 83%) and pulse oximetry (51% vs 55%) for PNA, and analgesia (85% vs 79%) for LBF. Additionally, a composite end point and an adjusted model showed no statistical difference across these measures. The proportion of residency-trained EM physicians did not affect the use of recommended treatment for AMI, PNA, and LBF. PMID- 20716691 TI - The therapeutic test: an ancient malady in the 21st century. AB - The response to treatment was the diagnostic mainstay in ancient times when diseases were poorly understood. Now that the bases of most diseases are known, appropriate diagnostic means are available. However, many physicians still rely on therapeutic tests to establish diagnoses. Since most illnesses are self limited and because of the placebo effect, many physicians and patients attribute the improvement to the medication and believe that the correct diagnosis was made. However, inappropriate therapeutic tests often lead to diagnostic delays, rapid emergence of antibiotic-resistant bacterial pathogens, increased risks of adverse drug reactions, and unnecessary expenses. To reduce the frequency of unwarranted therapeutic tests, health-care professionals and educators must take steps to rectify the problem. PMID- 20716692 TI - Milnacipran for treatment of fibromyalgia. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of milnacipran and evaluate relevant clinical trial data. DATA SOURCES: MEDLINE, International Pharmaceutical Abstracts, and Google Scholar searches (1966-June 2010) were conducted using the key words fibromyalgia, milnacipran, and serotonin norepinephrine reuptake inhibitor. Searches were limited to articles published in English. STUDY SELECTION AND DATA EXTRACTION: All available English-language articles of human studies were evaluated. One pharmacokinetic study reviewed included animal data. References cited in identified articles were used for additional evaluation. DATA SYNTHESIS: Milnacipran is a serotonin-norepinephrine reuptake inhibitor with a 3-fold increased selectivity for norepinephrine compared to serotonin. It is well absorbed with 85-90% bioavailability. Maximum concentrations are achieved 2-4 hours after administration. Milnacipran does not undergo cytochrome P450 metabolism and has a half-life of 6-8 hours. Fifty-five percent of each dose is excreted unchanged in the urine. Dose adjustment is needed in patients with an estimated creatinine clearance of <30 mL/min. Clinical trials indicated that twice-daily dosing at 100 mg/day or 200 mg/day was superior to single-daily dosing. Studies further established the effectiveness of both doses in the treatment of fibromyalgia pain utilizing patient self-reported pain scores, as well as on a visual analog scale, Patient Global Impression of Change scale, and the Short-Form 36 Physical Component Summary. A 6-month extension trial, which evaluated patients continued on milnacipran for up to 1 year, demonstrated continued pain relief. The most common adverse drug reaction associated with milnacipran was nausea, which was reduced with slow-dose titration and administration with food. CONCLUSIONS: Milnacipran is an effective treatment option for patients with fibromyalgia. More head-to-head clinical trials are necessary to assess its ultimate place in therapy. PMID- 20716693 TI - Escitalopram and ischemic stroke: cause or chance association? PMID- 20716694 TI - Improvement in beta-cell function in patients with normal and hyperglycemia following Roux-en-Y gastric bypass surgery. AB - Glycemic disorders resolve following Roux-en-Y gastric bypass (RYGB) surgery, but early and longer-term mechanisms regarding effects on beta-cell dysfunction as well as relationships with decreasing adiposity are not well understood. We evaluated longitudinal changes in peripheral insulin sensitivity (Si), the acute insulin response to glucose (AIRg), and the composite estimate of beta-cell function, the disposition index (DI), over 24 mo via frequently sampled intravenous glucose tolerance testing in severely obese women who had fasting normoglycemia (n = 16) and hyperglycemia (n = 11) before RYGB surgery; homeostatic model assessment (HOMA-IR) estimated insulin resistance; air displacement plethysmography determined adipose tissue mass. At baseline, subjects with normoglycemia had adequate DI associated with elevated AIRg, but DI was markedly reduced in subjects with hyperglycemia. Within 1-6 mo post-RYGB, glycemic control was normalized in subjects with hyperglycemia related to reduced HOMA-IR (-54% at 1 mo, P < 0.005) and increased DI (23-fold at 6 mo vs. baseline, P < 0.05). Over 24 mo, DI improved in subjects with hyperglycemia (15-fold vs. baseline, P < 0.005) and also modestly in subjects with normoglycemia (58%, P < 0.05), due largely to increased Si. Decreasing adiposity correlated with longer term HOMA-IR and Si values at 6 and 24 mo, respectively. In patients exhibiting fasting hyperglycemia before surgery, beta-cell function improved early following RYGB, due largely to increases in insulin secretion. For both normoglycemic and hyperglycemic subjects, further improvement or stabilization of beta-cell function over the 2 yr is due largely to improved Si associated with reduced adiposity. PMID- 20716695 TI - Vagal control of pancreatic beta-cell proliferation. AB - The physiological mechanisms that preserve pancreatic beta-cell mass (BCM) are not fully understood. Although the regulation of islet function by the autonomic nervous system (ANS) is well established, its potential roles in BCM homeostasis and compensatory growth have not been adequately explored. The parasympathetic vagal branch of the ANS serves to facilitate gastrointestinal function, metabolism, and pancreatic islet regulation of glucose homeostasis, including insulin secretion. Given the functional importance of the vagus nerve and its branches to the liver, gut, and pancreas in control of digestion, motility, feeding behavior, and glucose metabolism, it may also play a role in BCM regulation. We have begun to examine the potential roles of the parasympathetic nervous system in short-term BCM maintenance by performing a selective bilateral celiac branch-vagus nerve transection (CVX) in normal Sprague-Dawley rats. CVX resulted in no detectable effects on basic metabolic parameters or food intake through 1 wk postsurgery. Although there were no differences in BCM or apoptosis in this 1-wk time frame, beta-cell proliferation was reduced 50% in the CVX rats, correlating with a marked reduction in activated protein kinase B/Akt. Unexpectedly, acinar proliferation was increased 50% in these rats. These data suggest that the ANS, via the vagus nerve, contributes to the regulation of BCM maintenance at the level of cell proliferation and may also mediate the drive for enhanced growth under physiological conditions when insulin requirements have increased. Furthermore, the disparate effects of CVX on beta-cell and acinar cells suggest that the endocrine and exocrine pancreas respond to different neural signals in regard to mass homeostasis. PMID- 20716696 TI - An acylic polyisoprenoid derivative, geranylgeranylacetone protects against visceral adiposity and insulin resistance in high-fat-fed mice. AB - Induction of heat shock protein (HSP)72 improves insulin resistance and obesity in diabetic animal models. Geranylgeranylacetone (GGA), known as an antiulcer drug, induces HSP72 and protects organs against several cellular stresses. This study investigated whether GGA administration would induce HSP72 in liver and render physiological protection against high-fat feeding in mice. A single and 4 wk oral administration of 200 mg/kg GGA was performed in high-fat diet (HFD)-fed mice. Metabolic parameters, cytokines, and gene expressions related to insulin signaling were evaluated. A single administration of GGA induced HSP72 in liver of normal chow-fed and HFD-fed mice. Insulin resistance after HFD was slightly ameliorated. Four weeks of GGA administration also increased HSP72 in liver and significantly improved insulin resistance and glucose homeostasis upon glucose challenge. Activation of c-jun NH2-terminal kinase (JNK) was attenuated, and insulin signaling was improved in the liver of HFD mice. Visceral adiposity was decreased in GGA-treated mice, accompanied by reduced leptin and increased adiponectin levels. GGA can be a novel therapeutic approach to treat metabolic syndrome as well as type 2 diabetes by improving insulin signaling and reducing adiposity. These beneficial effects of GGA could be mediated through HSP72 induction and JNK inactivation in the liver. PMID- 20716697 TI - mzML--a community standard for mass spectrometry data. AB - Mass spectrometry is a fundamental tool for discovery and analysis in the life sciences. With the rapid advances in mass spectrometry technology and methods, it has become imperative to provide a standard output format for mass spectrometry data that will facilitate data sharing and analysis. Initially, the efforts to develop a standard format for mass spectrometry data resulted in multiple formats, each designed with a different underlying philosophy. To resolve the issues associated with having multiple formats, vendors, researchers, and software developers convened under the banner of the HUPO PSI to develop a single standard. The new data format incorporated many of the desirable technical attributes from the previous data formats, while adding a number of improvements, including features such as a controlled vocabulary with validation tools to ensure consistent usage of the format, improved support for selected reaction monitoring data, and immediately available implementations to facilitate rapid adoption by the community. The resulting standard data format, mzML, is a well tested open-source format for mass spectrometer output files that can be readily utilized by the community and easily adapted for incremental advances in mass spectrometry technology. PMID- 20716698 TI - Redox regulation of the NPR1-TGA1 system of Arabidopsis thaliana by nitric oxide. AB - The role of reactive oxygen and nitrogen species in local and systemic defense reactions is well documented. NPR1 and TGA1 are key redox-controlled regulators of systemic acquired resistance in plants. NPR1 monomers interact with the reduced form of TGA1, which targets the activation sequence-1 (as-1) element of the promoter region of defense proteins. Here, we report the effect of the physiological nitric oxide donor S-nitrosoglutathione on the NPR1/TGA1 regulation system in Arabidopsis thaliana. Using the biotin switch method, we demonstrate that both NPR1 and TGA1 are S-nitrosylated after treatment with S nitrosoglutathione. Mass spectrometry analyses revealed that the Cys residues 260 and 266 of TGA1 are S-nitrosylated and S-glutathionylated even at GSNO concentrations in the low micromolar range. Furthermore, we showed that S nitrosoglutathione protects TGA1 from oxygen-mediated modifications and enhances the DNA binding activity of TGA1 to the as-1 element in the presence of NPR1. In addition, we observed that the translocation of NPR1 into the nucleus is promoted by nitric oxide. Taken together, our results suggest that nitric oxide is a redox regulator of the NPR1/TGA1 system and that they underline the importance of nitric oxide in the plant defense response. PMID- 20716699 TI - Characterization of the molecular mechanism underlying gibberellin perception complex formation in rice. AB - The DELLA protein SLENDER RICE1 (SLR1) is a repressor of gibberellin (GA) signaling in rice (Oryza sativa), and most of the GA-associated responses are induced upon SLR1 degradation. It is assumed that interaction between GIBBERELLIN INSENSITIVE DWARF1 (GID1) and the N-terminal DELLA/TVHYNP motif of SLR1 triggers F-box protein GID2-mediated SLR1 degradation. We identified a semidominant dwarf mutant, Slr1-d4, which contains a mutation in the region encoding the C-terminal GRAS domain of SLR1 (SLR1(G576V)). The GA-dependent degradation of SLR1(G576V) was reduced in Slr1-d4, and compared with SLR1, SLR1(G576V) showed reduced interaction with GID1 and almost none with GID2 when tested in yeast cells. Surface plasmon resonance of GID1-SLR1 and GID1-SLR1(G576V) interactions revealed that the GRAS domain of SLR1 functions to stabilize the GID1-SLR1 interaction by reducing its dissociation rate and that the G576V substitution in SLR1 diminishes this stability. These results suggest that the stable interaction of GID1-SLR1 through the GRAS domain is essential for the recognition of SLR1 by GID2. We propose that when the DELLA/TVHYNP motif of SLR1 binds with GID1, it enables the GRAS domain of SLR1 to interact with GID1 and that the stable GID1-SLR1 complex is efficiently recognized by GID2. PMID- 20716700 TI - Context and sequelae of food insecurity in children's development. AB - The authors examined the role of food insecurity in the etiology of children's cognitive and mental health problems. Data from a prospective longitudinal study of 1,116 United Kingdom families with twins (sample constructed in 1999-2000) were used to test associations among household food insecurity; income; maternal personality; household sensitivity to children's needs; and children's cognitive, behavioral, and emotional development. Food-insecure children had lower IQs and higher levels of behavioral and emotional problems relative to their peers. After differences in household income, the personalities of children's mothers, and the sensitivity of household organization to children's needs were accounted for, food-insecure children had moderately higher levels of emotional problems relative to food-secure children (beta = 0.22, P = 0.02). Differences in children's cognitive development were accounted for by household income, and differences in their behavioral development were accounted for by their mothers' personalities and their households' sensitivity to children's needs. Results suggest that food insecurity was associated with school-aged children's emotional problems but not with their cognitive or behavioral problems after accounting for differences in the home environments in which children were reared. Mothers' personality and household sensitivity to children's needs may present challenges to improving outcomes of children with food insecurity. PMID- 20716701 TI - Case-control study of body size and breast cancer risk in Nigerian women. AB - Previous studies have shown that weight is inversely associated with premenopausal breast cancer and positively associated with postmenopausal disease. Height has been shown to be positively correlated with breast cancer risk, but the association was not conclusive for premenopausal women. These previous studies were conducted primarily in Western countries, where height is not limited by nutritional status during childhood. The authors assessed the association between breast cancer and anthropometric measures in the Nigerian Breast Cancer Study (Ibadan, Nigeria). Between 1998 and 2009, 1,233 invasive breast cancer cases and 1,101 controls were recruited. The multivariate-adjusted odds ratio for the highest quartile group of height relative to the lowest was 2.03 (95% confidence interval (CI): 1.51, 2.72; P-trend < 0.001), with an odds ratio of 1.22 (95% CI: 1.14, 1.32) for each 5-cm increase, with no difference by menopausal status. Comparing women with a body mass index in the lowest quartile group, the adjusted odds ratio for women in the highest quartile category was 0.72 (95% CI: 0.54, 0.94; P-trend = 0.009) for premenopausal and postmenopausal women. Influence of height on breast cancer risk was quite strong in this cohort of indigenous Africans, which suggests that energy intake during childhood may be important in breast cancer development. PMID- 20716702 TI - Trends in asthma prevalence and incidence in Ontario, Canada, 1996-2005: a population study. AB - In the 1980s and early 1990s, asthma prevalence increased significantly in most Westernized countries. In more recent years, asthma trends have been less clear, with some studies suggesting that they are still rising and others suggesting that they have stabilized or decreased. A population-based cohort study was conducted to estimate asthma prevalence and incidence trends in one large Canadian province, Ontario. All individuals with asthma living in Ontario, a province of Canada with a multicultural population of approximately 12 million, were identified in universal, population health administrative databases by using a validated health administrative case definition of asthma. Annual asthma prevalence, incidence, and all-cause mortality rates were estimated from 1996 to 2005. During this time, the prevalence of asthma increased by 70.5%. The age- and sex-standardized asthma prevalence increased from 8.5% in 1996 to 13.3% in 2005, a relative increase of 55.1% (P < 0.0001). Asthma incidence rates increased in children by 30.0% and were relatively stable in adults. Overall all-cause mortality decreased. Asthma prevalence in Ontario, Canada, has increased significantly. This is attributable, in part, to an increase in the incidence of asthma in children. Effective clinical and public health strategies are needed to prevent and manage asthma in the population. PMID- 20716704 TI - Treatment effects in the presence of unmeasured confounding: dealing with observations in the tails of the propensity score distribution--a simulation study. AB - Frailty, a poorly measured confounder in older patients, can promote treatment in some situations and discourage it in others. This can create unmeasured confounding and lead to nonuniform treatment effects over the propensity score (PS). The authors compared bias and mean squared error for various PS implementations under PS trimming, thereby excluding persons treated contrary to prediction. Cohort studies were simulated with a binary treatment T as a function of 8 covariates X. Two of the covariates were assumed to be unmeasured strong risk factors for the outcome and present in persons treated contrary to prediction. The outcome Y was simulated as a Poisson function of T and all X's. In analyses based on measured covariates only, the range of PS's was trimmed asymmetrically according to the percentile of PS in treated patients at the lower end and in untreated patients at the upper end. PS trimming reduced bias due to unmeasured confounders and mean squared error in most scenarios assessed. Treatment effect estimates based on PS range restrictions do not correspond to a causal parameter but may be less biased by such unmeasured confounding. Increasing validity based on PS trimming may be a unique advantage of PS's over conventional outcome models. PMID- 20716703 TI - The potentially modifiable burden of incident heart failure due to obesity: the atherosclerosis risk in communities study. AB - The authors estimated the generalized impact fraction (GIF) for heart failure (HF) related to obesity, representing the proportion of incident HF events that could be prevented from reductions in obesity and/or overweight. The Atherosclerosis Risk in Communities Study is a biracial population-based cohort study of persons aged 45-64 years from 4 US communities with a median 14 years of follow-up (1987-2003) for incident, hospitalized, or fatal HF. Body mass index (BMI; weight (kg)/height (m)(2)) was measured at baseline (1987-1989) and categorized as normal weight (BMI <25), overweight (BMI 25-29.9), or obese (BMI >=30). After exclusion of prevalent HF, missing BMI, and poorly represented racial groups, the sample size was 14,642. The GIF and attributable fraction were calculated using a case-load weighted-sum method. A 95% distribution of the GIF was estimated from bootstrapped data sets. A 30% hypothetical reduction in obesity/overweight would potentially prevent 8.5% (95% simulation interval: 6.1, 10.7) of incident HF events. The attributable fraction, which assumes complete elimination of obesity/overweight, was 28% (95% simulation interval: 20, 36) approximately 3 times larger than the most optimistic GIF calculated here. Investigators studying exposures that are unlikely to be eradicated given current prevention efforts, such as obesity, should consider estimating the GIF to avoid overestimates of population impact. PMID- 20716705 TI - Gains in statistical power from using a dietary biomarker in combination with self-reported intake to strengthen the analysis of a diet-disease association: an example from CAREDS. AB - A major problem in detecting diet-disease associations in nutritional cohort studies is measurement error in self-reported intakes, which causes loss of statistical power. The authors propose using biomarkers correlated with dietary intake to strengthen analyses of diet-disease hypotheses and to increase statistical power. They consider combining self-reported intakes and biomarker levels using principal components or a sum of ranks and relating the combined measure to disease in conventional regression analyses. They illustrate their method in a study of the inverse association of dietary lutein plus zeaxanthin with nuclear cataracts, using serum lutein plus zeaxanthin as the biomarker, with data from the Carotenoids in Age-Related Eye Disease Study (United States, 2001 2004). This example demonstrates that the combined measure provides higher statistical significance than the dietary measure or the serum measure alone, and it potentially provides sample savings of 8%-53% over analysis with dietary intake alone and of 6%-48% over analysis with serum level alone, depending on the definition of the outcome variable and the choice of confounders entered into the regression model. The authors conclude that combining appropriate biomarkers with dietary data in a cohort can strengthen the investigation of diet-disease associations by increasing the statistical power to detect them. PMID- 20716706 TI - Frequency of epileptiform discharges in the sleep-deprived electroencephalogram in children evaluated for attention-deficit disorders. AB - The authors determined the frequency of epileptiform discharges in the electroencephalogram (EEG) of a cohort of children and adolescents referred to a neurology specialty clinic for evaluation of attention-deficit disorders. Of 624 records, 461 (73.9%) were normal and 163 (26.1%) abnormal. Of abnormal EEGs, 70 (42.9%) had focal epileptiform discharges only, 68 (41.7%) had generalized epileptiform discharges only, and 19 (11.6%) had both independent focal and generalized spikes. Focal spikes were localized chiefly in central, frontal, and temporal regions. Of 163 records with abnormalities, 154 (94.5%) were sleep deprived and 159 (97.5%) were sleep records. One-quarter of the nonepileptic children evaluated for attention-deficit disorder have epileptiform discharges in the EEG, and just more than half are focal. Sleep-deprived sleep is essential to exclude epileptiform abnormalities. The utility of the EEG in the management of attention-deficit disorders and selection of stimulant or nonstimulant medication deserves further study. PMID- 20716707 TI - Association between peptic ulcer and personality disorders in a nationally representative US sample. AB - OBJECTIVE: To assess the association between peptic ulcer and a wide range of personality disorders in a large sample representative of the general population in the United States. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions, on the basis of a face-to-face interview of more than 43,000 adults. Univariate and multivariate logistic regression were used to examine the relationship between self-reported "stomach ulcer" and personality disorders. RESULTS: All seven personality disorders assessed in the National Epidemiologic Survey on Alcohol and Related Conditions (i.e., avoidant, dependent, obsessive-compulsive, paranoid, schizoid, histrionic, and antisocial personality disorders) were associated with stomach ulcer, with odds ratio ranging from 2.26 (obsessive compulsive personality disorder) to 5.54 (dependent personality disorder). Participants with ulcer were five times more likely to have more than three personality disorders than participants without ulcer. The relationship between ulcer and personality disorders was only slightly attenuated after adjusting for sociodemographic conditions, physical and psychiatric disorders, and addictions. CONCLUSIONS: Self-reported peptic ulcer is associated with increased rates of personality disorders, beyond the influence of psychiatric disorders or addictions. PMID- 20716708 TI - Influence of psychological stress on upper respiratory infection--a meta-analysis of prospective studies. AB - OBJECTIVE: To quantify the available evidence for the hypothesis that reduced resistance caused by psychological stress may influence the development of clinical disease in those exposed to an infectious agent. METHODS: We conducted a systematic review and meta-analysis of 27 prospective studies examining the association between psychological stress and subsequent upper respiratory infection (URI). RESULTS: The results revealed a significant overall main effect of psychological stress on the risk of developing URI (effect size correlation coefficient, 0.21; 95% confidence interval, 0.15-0.27). Further analyses showed that effect sizes for the association did not vary according to type of stress, how URI was assessed, or whether the studies had controlled for preexposure. CONCLUSIONS: The meta-analytical findings confirmed the hypothesis that psychological stress is associated with increased susceptibility to URI, lending support to an emerging appreciation of the potential importance of psychological factors in infectious disease. PMID- 20716709 TI - Relationship between loneliness and proangiogenic cytokines in newly diagnosed tumors of colon and rectum. AB - OBJECTIVE: To investigate the association of serum levels of proangiogenic cytokines with different indices of social support and loneliness by measuring the levels of expression of two important proangiogenic cytokines, vascular endothelial growth factor (VEGF), and interleukin-6 in tumors of colon and rectum. Lack of social support has been prospectively associated with cancer progression. METHODS: Fifty-one newly diagnosed patients with colorectal tumors (mean age, 68.3 years) completed two measures of loneliness 1 to 2 days before their surgical treatment. The first was an explicit self-report questionnaire, which tapped into negative feelings as a result of low social support. The second was a standardized computer-based task, which measured loneliness implicitly. Immunohistochemical analyses were performed on tumor tissues post surgery to determine the expression of cytokines. RESULTS: Logistic regression showed that higher levels of implicit loneliness independently predicted stronger expression of VEGF, controlling for Dukes stage and explicit loneliness, both of which were nonsignificant predictors. No significant relationships were found between the loneliness measures and interleukin-6. CONCLUSIONS: The results of this study suggest VEGF to be an angiogenic mechanism through which loneliness may lead to worse cancer-related outcomes. Implications are discussed in terms of devising targeted psychosocial and immunotherapeutic interventions for cancer patients with low social support. PMID- 20716710 TI - Dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in early adolescence: the Ryukyus Child Health Study. AB - OBJECTIVE: To examine the association between dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in a group of adolescents. METHODS: This cross-sectional study, conducted in all public junior high schools in Naha City and Nago City, Okinawa, Japan, included 3,067 boys and 3,450 girls aged 12 years to 15 years (52.3% of eligible sample). Dietary intake was assessed using a validated, self-administered diet history questionnaire. Depressive symptoms were defined as present when participants had a Center for Epidemiologic Studies Depression Scale score of >=16. RESULTS: The prevalence of depressive symptoms was 22.5% for boys and 31.2% for girls. Folate intake was inversely associated with depressive symptoms in both boys (adjusted odds ratio (OR) [95% confidence interval (CI)] in the highest (compared with the lowest) quintile, 0.60 [0.45, 0.79]; p for trend = .002) and girls (OR [95% CI], 0.61 [0.48, 0.77]; p for trend = <.001). Vitamin B-6 intake was inversely associated with depressive symptoms in both boys (OR [95% CI], 0.73 [0.54, 0.98]; p for trend = .02) and girls (OR [95% CI], 0.72 [0.56, 0.92]; p for trend = .002). Riboflavin intake was inversely associated with depressive symptoms in girls (OR [95% CI], 0.85 [0.67, 1.08]; p for trend = .03), but not in boys. No clear association was seen between vitamin B-12 intake and depressive symptoms in either sex. CONCLUSIONS: This study suggests that higher intake of dietary B vitamins, particularly folate and vitamin B-6, is independently associated with a lower prevalence of depressive symptoms in early adolescence. PMID- 20716711 TI - Stress and poverty predictors of treatment adherence among people with low literacy living with HIV/AIDS. AB - OBJECTIVE: To examine the association of social, health, and poverty-related stressors in relation to antiretroviral therapy adherence in a sample of people with low-literacy living with HIV/AIDS in the southeastern United States. Emotional distress is among the more common factors associated with HIV treatment adherence. Typical barriers to adherence may be overshadowed by poverty experiences in the most disadvantaged populations of people living with HIV/AIDS, such as people with lower-literacy skills. METHODS: One hundred eighty-eight men and women living with HIV/AIDS who demonstrated poor health literacy completed measures of social and health-related stress, indicators of extreme poverty, as well as other factors associated with nonadherence. HIV treatment adherence was monitored prospectively, using unannounced pill counts. RESULTS: Two-thirds of the sample demonstrated adherence <85% of pills taken. Multivariable analyses showed that food insufficiency and hunger predicted antiretroviral therapy nonadherence over and above depression, internalized stigma, substance use, and HIV-related social stressors. CONCLUSIONS: Interventions for HIV treatment nonadherence with the most socially disadvantaged persons in developed countries should be reconceptualized to directly address poverty, especially food insufficiency and hunger, as both a moral and public health imperative. PMID- 20716669 TI - Glutamate receptor ion channels: structure, regulation, and function. AB - The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors. PMID- 20716713 TI - Feeling vigorous and the risks of all-cause mortality, ischemic heart disease, and diabetes: a 20-year follow-up of healthy employees. AB - OBJECTIVE: To investigate prospectively the effects of vigor at work on the end points of mortality and the prevalence of ischemic heart disease (IHD) and diabetes. METHODS: We tested the hypothesized beneficial effects of feeling vigorous at work at baseline on the risks of all-cause mortality, IHD, and diabetes during a 20-year follow-up. Participants were healthy employees (n = 968) who underwent a routine health check at baseline. We calculated the risk of all-cause mortality, IHD, and diabetes, with days as the time scale, using the Cox proportional hazard model. In our analyses, we predicted the above end points by baseline vigor, age, gender, and educational level, adjusting for the physiological risk factors of total cholesterol, glucose, and body mass index, the behavioral risk factors of smoking, alcohol intake, and physical activity, and the psychological risk factors of depressive and anxiety symptoms. RESULTS: As hypothesized, we found that, after the above adjustments, baseline vigor decreased the risk of follow-up mortality by 26% (hazard ratio, 0.74; 95% confidence interval, 0.58-0.95) and the risk of diabetes by 17% (hazard ratio, 0.83; 95% confidence interval, 0.68-0.98). However, vigor did not have a significant effect on the risk of IHD. CONCLUSIONS: Independently of physiological, behavioral, and psychological risk factors, feeling vigorous at work protected the participants from diabetes and reduced their risk of mortality. PMID- 20716712 TI - Effect of omega-3 fatty acids on heart rate variability in depressed patients with coronary heart disease. AB - OBJECTIVE: To determine whether omega-3 fatty acid (FA) increases the natural log of very low frequency (lnVLF) power, an index of heart rate variability (HRV), and reduces 24-hour heart rate (HR) in depressed patients with coronary heart disease (CHD). Low intake of omega-3 FAs is associated with depression and with low HRV, and all three are associated with an increased risk of death in patients with CHD. METHODS: Thirty-six depressed patients with CHD randomized to receive 50 mg of sertraline and 2 g of omega-3/day, and 36 randomized to sertraline and a placebo, had 24-hour HRV measured at baseline and after 10 weeks of treatment. RESULTS: There was a significant treatment * time interaction for covariate adjusted lnVLF (p = .009), for mean 24-hour HR (p = .03), and for 1-minute resting HR (p = .02). The interaction was not significant for three other measures of HRV. LnVLF did not change over time in the omega-3 arm but decreased in the placebo arm (p = .002), suggesting that omega-3 may have prevented or slowed deterioration in cardiac autonomic function. CONCLUSIONS: The effects of omega-3 FAs on lnVLF and HR, although modest, were detected after only 10 weeks of treatment with 2 g per day of omega-3. Whether a longer course of treatment or a higher dose of omega-3 would further decrease HR, improve other indices of HRV, or reduce mortality in depressed CHD patients should be investigated. PMID- 20716714 TI - Comparative effectiveness of angiotensin-converting enzyme inhibitors versus beta blockers as second-line therapy for hypertension. AB - BACKGROUND: Trials comparing hypertension monotherapies have found either no difference or modest differences in blood pressure (BP) and cardiovascular events. However, no trial has assessed the comparative effectiveness of 2nd-line therapy in patients whose BP was not controlled with a thiazide diuretic. METHODS AND RESULTS: This was an observational study conducted with a hypertension registry of adults enrolled in 3 large integrated health care delivery systems from 2002 to 2007. Patients newly started on thiazide monotherapy whose BP remained uncontrolled were observed after addition of either an angiotensin converting enzyme (ACE) inhibitor or beta-blocker for subsequent BP control and cardiovascular events. Patients for whom either add-on drug was indicated or contraindicated were excluded. After adjustment for patient characteristics and study year, BP control during the subsequent 6 to 18 months was comparable for the 2 agents (70.5% ACE, 69.0% beta-blockers; P=0.09). Rates of incident myocardial infarction (hazard ratio, 1.05; 95% confidence interval, 0.69 to 1.58) and stroke (hazard ratio, 1.01; 95% confidence interval, 0.68 to 1.52) were also similar for the ACE inhibitor and beta-blocker groups during an average of 2.3 years of follow-up. There were also no differences in heart failure or renal function. CONCLUSIONS: ACE inhibitors and beta-blockers are equally effective in lowering BP and preventing cardiovascular events for patients whose BP is not controlled with a thiazide diuretic alone and who have no compelling indication for a specific 2nd-line agent. PMID- 20716715 TI - Optimal medical therapy for non-ST-segment-elevation acute coronary syndromes: exploring why physicians do not prescribe evidence-based treatment and why patients discontinue medications after discharge. AB - BACKGROUND: Acute coronary syndrome (ACS) patients in the highest risk categories are least likely to receive evidence-based treatments (EBTs). We sought to determine why physicians do not prescribe EBTs for patients with non-ST-segment elevation ACSs and the factors determining use of these treatments after 1 year. METHODS AND RESULTS: One thousand nine hundred fifty-six non-ST-segment-elevation ACS patients were enrolled in the prospective, multicenter Canadian ACS registry II between October 2002 and December 2003. Each patient's physician gave reasons why guideline-indicated medication(s) was not prescribed during hospitalization. Medication use and reason(s) for discontinuation after 1 year were obtained by telephone interview of the patients. The commonest reason for not prescribing EBTs was "not high-enough risk" or "no evidence/guidelines to support use." However, Global Registry of Acute Coronary Events scores of patients not treated for this reason were often similar to or higher than those of patients prescribed such treatment. After 1 year, 77% of patients not on optimal ACS treatment at discharge remained without optimal treatment, and overall antiplatelet, beta blocker, and angiotensin-converting enzyme inhibitor use declined. Approximately one third of patients not taking EBTs had stopped their medication without instruction from their doctor. CONCLUSIONS: Nonprovision of EBTs may be due to subjective underestimation of patient risk and hence, likely treatment benefit. Oversights in care delivery were also apparent. Objective risk stratification, combined with efforts to ensure provision and adherence to EBTs, should be encouraged. PMID- 20716716 TI - Prediction of 1-year mortality with different measures of ST-segment recovery in all-comers after primary percutaneous coronary intervention for acute myocardial infarction. AB - BACKGROUND: Post hoc analyses from several randomized, controlled trials have established the prognostic importance of different measures of ST-segment recovery in highly selected patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction (STEMI). In this single-center registry, we investigated whether various measures of ST segment recovery can be applied to unselected STEMI patients undergoing primary PCI. METHODS AND RESULTS: We analyzed 12-lead ECGs from 2124 consecutive STEMI patients who underwent primary PCI at our institution between November 1, 2000, and January 1, 2007. ECGs were recorded at the catheterization laboratory immediately before arterial puncture and at the end of PCI. We examined measures assessing ST-segment recovery on the postprocedural ECG and measures comparing both ECGs and related these to 1-year, all-cause mortality. Cumulative ST-segment recovery (?ST-D resolution) at a 50% cutoff had the highest unadjusted accuracy (C statistic, 0.646; 95% confidence interval, 0.602 to 0.689; P<0.001) as compared with the other 8 measures evaluated. Furthermore, ?ST-D resolution was the strongest contributor to both the net reclassification and integrated discrimination improvement. CONCLUSIONS: Although each measure of ST-segment recovery provided univariable prognostic information, the ?ST-D resolution measure comparing summed ST-segment deviations on the preprocedural and postprocedural ECG was the best independent predictor of 1-year mortality in all comer STEMI patients after primary PCI. PMID- 20716717 TI - Automatic remote monitoring of implantable cardioverter-defibrillator lead and generator performance: the Lumos-T Safely RedUceS RouTine Office Device Follow-Up (TRUST) trial. AB - BACKGROUND: Monitoring performance of implantable cardioverter-defibrillator (ICD) generators and leads is important. Methods available are with in-person evaluations or by automatic remote home monitoring (HM). These were prospectively evaluated and compared in the TRUST trial. The HM technology tested performed daily self-checks and databasing with rapid event notifications for out-of-range (including asymptomatic) conditions. METHODS AND RESULTS: Patients (n=1339) were randomly assigned after ICD implant 2:1 to HM or to conventional groups. Both groups underwent scheduled checks every 3 months and were followed for 15 months. In HM, in-person office visits were scheduled at 3 and 15 months. At 6, 9, and 12 months, HM only was used with subsequent office visits if necessary. Between these time points, ICDs triggered event notifications for system integrity problems. Patients randomly assigned to conventional follow-up were evaluated with office visits only. HM and conventional patients were similar (age, 63.3+/ 12.8 versus 64.0+/-12.1 years; 72.0% versus 73.1% male; New York Heart Association II class, 55.9% versus 60.4%; left ventricular ejection fraction, 29.0+/-10.7% versus 28.5+/-9.8%; coronary artery disease, 64.8% versus 71.7%; primary prevention, 72.2% versus 73.8%; DDD devices, 57.8% versus 56.6%). Four patients crossed over from conventional to HM because of advisories. Scheduled checks were more successfully accomplished in HM (92.7% versus 89.2% in conventional, P<0.001). Sixty-two device-related events (53 in HM versus 9 in conventional) were observed in 46 patients (40 [4.4%] in HM versus 6 [1.39%] in conventional, P=0.004). Forty-seven percent were asymptomatic. HM detected generator and lead problems earlier (HM versus conventional: median, 1 versus 5 days; P=0.05). A total of 20 device problems (eg, lead fracture, elective replacement indicators) requiring surgical revision (0.012 per patient-year) were found, 15 in HM and 5 in the conventional groups. Other events were managed nonsurgically (eg, reprogramming, initiation of antiarrhythmics). CONCLUSIONS: ICD lead and generator malfunction was infrequent and often asymptomatic. Only a minority of detected events required surgical intervention. Automatic HM enhanced discovery, permitted prompt detection, and facilitated management decisions. Longitudinal parameter trending, with component function evaluated daily by remote monitoring, may enable long-term performance assessment. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00336284. PMID- 20716720 TI - The fourth dimension: endocavitary ventricular tachycardia. PMID- 20716718 TI - Cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction: a pooled analysis from the international BEACON consortium. AB - BACKGROUND: Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose-response, and duration of cigarette smoking cessation. METHODS: We used primary data from 10 population-based case-control studies and two cohort studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided. RESULTS: The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose-response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and > or =10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar. CONCLUSIONS: Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks. PMID- 20716721 TI - Short QT syndrome: from bench to bedside. PMID- 20716722 TI - Think before you pull--not every lead has to come out. PMID- 20716723 TI - Lead extraction is preferred for lead revisions and system upgrades: when less is more. PMID- 20716728 TI - The cover. Eve of Saint John. PMID- 20716729 TI - A piece of my mind. Journalist feels palpitations, enrolls in medical school. PMID- 20716730 TI - Successes, challenges emerge from efforts to shift away from industry-funded CME. PMID- 20716731 TI - Report clarifies scientists' understanding of association between diabetes and cancer. PMID- 20716732 TI - Coronary artery calcium score and cardiovascular event prediction. PMID- 20716733 TI - Coronary artery calcium score and cardiovascular event prediction. PMID- 20716734 TI - Pneumococcal vaccination and cardiovascular events in men. PMID- 20716735 TI - Early physician follow-up and 30-day readmission among older patients with heart failure. PMID- 20716736 TI - Cognitively impaired older drivers, risk assessment, and physician responsibility. PMID- 20716737 TI - Prediction of critical illness during out-of-hospital emergency care. AB - CONTEXT: Early identification of nontrauma patients in need of critical care services in the emergency setting may improve triage decisions and facilitate regionalization of critical care. OBJECTIVES: To determine the out-of-hospital clinical predictors of critical illness and to characterize the performance of a simple score for out-of-hospital prediction of development of critical illness during hospitalization. DESIGN AND SETTING: Population-based cohort study of an emergency medical services (EMS) system in greater King County, Washington (excluding metropolitan Seattle), that transports to 16 receiving facilities. PATIENTS: Nontrauma, non-cardiac arrest adult patients transported to a hospital by King County EMS from 2002 through 2006. Eligible records with complete data (N = 144,913) were linked to hospital discharge data and randomly split into development (n = 87,266 [60%]) and validation (n = 57,647 [40%]) cohorts. MAIN OUTCOME MEASURE: Development of critical illness, defined as severe sepsis, delivery of mechanical ventilation, or death during hospitalization. RESULTS: Critical illness occurred during hospitalization in 5% of the development (n = 4835) and validation (n = 3121) cohorts. Multivariable predictors of critical illness included older age, lower systolic blood pressure, abnormal respiratory rate, lower Glasgow Coma Scale score, lower pulse oximetry, and nursing home residence during out-of-hospital care (P < .01 for all). When applying a summary critical illness prediction score to the validation cohort (range, 0-8), the area under the receiver operating characteristic curve was 0.77 (95% confidence interval [CI], 0.76-0.78), with satisfactory calibration slope (1.0). Using a score threshold of 4 or higher, sensitivity was 0.22 (95% CI, 0.20-0.23), specificity was 0.98 (95% CI, 0.98-0.98), positive likelihood ratio was 9.8 (95% CI, 8.9-10.6), and negative likelihood ratio was 0.80 (95% CI, 0.79- 0.82). A threshold of 1 or greater for critical illness improved sensitivity (0.98; 95% CI, 0.97-0.98) but reduced specificity (0.17; 95% CI, 0.17-0.17). CONCLUSIONS: In a population-based cohort, the score on a prediction rule using out-of-hospital factors was significantly associated with the development of critical illness during hospitalization. This score requires external validation in an independent population. PMID- 20716739 TI - System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. AB - CONTEXT: Timely reperfusion therapy is recommended for patients with ST-segment elevation myocardial infarction (STEMI), and door-to-balloon delay has been proposed as a performance measure in triaging patients for primary percutaneous coronary intervention (PCI). However, focusing on the time from first contact with the health care system to the initiation of reperfusion therapy (system delay) may be more relevant, because it constitutes the total time to reperfusion modifiable by the health care system. No previous studies have focused on the association between system delay and outcome in patients with STEMI treated with primary PCI. OBJECTIVE: To evaluate the associations between system, treatment, patient, and door-to-balloon delays and mortality in patients with STEMI. DESIGN, SETTING, AND PATIENTS: Historical follow-up study based on population-based Danish medical registries of patients with STEMI transported by the emergency medical service and treated with primary PCI from January 1, 2002, to December 31, 2008, at 3 high-volume PCI centers in Western Denmark. Patients (N = 6209) underwent primary PCI within 12 hours of symptom onset. The median follow-up time was 3.4 (interquartile range, 1.8-5.2) years. MAIN OUTCOME MEASURES: Crude and adjusted hazard ratios of mortality obtained by Cox proportional regression analysis. RESULTS: A system delay of 0 through 60 minutes (n = 347) corresponded to a long-term mortality rate of 15.4% (n = 43); a delay of 61 through 120 minutes (n = 2643) to a rate of 23.3% (n = 380); a delay of 121 through 180 minutes (n = 2092) to a rate of 28.1% (n = 378); and a delay of 181 through 360 minutes (n = 1127) to a rate of 30.8% (n = 275) (P < .001). In multivariable analysis adjusted for other predictors of mortality, system delay was independently associated with mortality (adjusted hazard ratio, 1.10 [95% confidence interval, 1.04-1.16] per 1-hour delay), as was its components, prehospital system delay and door-to-balloon delay. CONCLUSION: System delay was associated with mortality in patients with STEMI treated with primary PCI. PMID- 20716738 TI - Effect of an implantable gentamicin-collagen sponge on sternal wound infections following cardiac surgery: a randomized trial. AB - CONTEXT: Despite the routine use of prophylactic systemic antibiotics, sternal wound infection still occurs in 5% or more of cardiac surgical patients and is associated with significant excess morbidity, mortality, and cost. The gentamicin collagen sponge, a surgically implantable topical antibiotic, is currently approved in 54 countries. A large, 2-center, randomized trial in Sweden reported in 2005 that the sponge reduced surgical site infection by 50% in cardiac patients. OBJECTIVE: To test the hypothesis that the sponge prevents infection in cardiac surgical patients at increased risk for sternal wound infection. DESIGN, SETTING, AND PARTICIPANTS: Phase 3 single-blind, prospective randomized controlled trial, 1502 cardiac surgical patients at high risk for sternal wound infection (diabetes, body mass index >30, or both) were enrolled at 48 US sites between December 21, 2007, and March 11, 2009. INTERVENTION: Single-blind randomization to insertion of 2 gentamicin-collagen sponges (total gentamicin of 260 mg) between the sternal halves at surgical closure (n = 753) vs no intervention (control group: n = 749). All patients received standardized care including prophylactic systemic antibiotics and rigid sternal fixation. MAIN OUTCOME MEASURES: The primary end point was sternal wound infection occurring through 90 days postoperatively as adjudicated by a clinical events classification committee blinded to study treatment group. The primary study comparison was done in the intent-to-treat population. Secondary outcomes included (1) superficial wound infection (involving subcutaneous tissue but not extending down to sternal fixation wires), (2) deep wound infection (involving the sternal wires, sternal bone, and/or mediastinum), and (3) score for additional treatment, presence of serous discharge, erythema, purulent exudate, separation of the deep tissues, isolation of bacteria, and duration of inpatient stay (ASEPSIS; minimum score of 0 with no theoretical maximum). RESULTS: Of 1502 patients, 1006 had diabetes (67%) and 1137 were obese (body mass index >30) (76%). In the primary analysis, there was no significant difference in sternal wound infection in 63 of 753 patients randomized to the gentamicin-collagen sponge group (8.4%) compared with 65 of 749 patients randomized to the control group (8.7%) (P = .83). No significant differences were observed between the gentamicin-collagen sponge group and the control group, respectively, in superficial sternal wound infection (49/753 [6.5%] vs 46/749 [6.1%]; P = .77), deep sternal wound infection (14/753 [1.9%] vs 19/749 [2.5%]; P = .37), ASEPSIS score (mean [SD], 1.9 [6.4] vs 2.0 [7.2]; P = .67), or rehospitalization for sternal wound infection (23/753 [3.1%] vs 24/749 [3.2%]; P = .87). CONCLUSION: Among US patients with diabetes, high body mass index, or both undergoing cardiac surgery, the use of 2 gentamicin-collagen sponges compared with no intervention did not reduce the 90-day sternal wound infection rate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00600483. PMID- 20716740 TI - Change in prevalence of hearing loss in US adolescents. AB - CONTEXT: Hearing loss is common and, in young persons, can compromise social development, communication skills, and educational achievement. OBJECTIVE: To examine the current prevalence of hearing loss in US adolescents and determine whether it has changed over time. DESIGN: Cross-sectional analyses of US representative demographic and audiometric data from the 1988 through 1994 and 2005 through 2006 time periods. SETTING: The Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994, and NHANES 2005-2006. PARTICIPANTS: NHANES III examined 2928 participants and NHANES 2005-2006 examined 1771 participants, aged 12 to 19 years. MAIN OUTCOME MEASURES: We calculated the prevalence of hearing loss in participants aged 12 to 19 years after accounting for the complex survey design. Audiometrically determined hearing loss was categorized as either unilateral or bilateral for low frequency (0.5, 1, and 2 kHz) or high frequency (3, 4, 6, and 8 kHz), and as slight loss (> 15 to < 25 dB) or mild or greater loss (> or = 25 dB) according to hearing sensitivity in the worse ear. The prevalence of hearing loss from NHANES 2005-2006 was compared with the prevalence from NHANES III (1988-1994). We also examined the cross-sectional relations between several potential risk factors and hearing loss. Logistic regression was used to calculate multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of any hearing loss increased significantly from 14.9% (95% CI, 13.0%-16.9%) in 1988-1994 to 19.5% (95% CI, 15.2%-23.8%) in 2005-2006 (P = .02). In 2005-2006, hearing loss was more commonly unilateral (prevalence, 14.0%; 95% CI, 10.4%-17.6%, vs 11.1%; 95% CI, 9.5%-12.8% in 1988-1994; P = .005) and involved the high frequencies (prevalence, 16.4%; 95% CI, 13.2%-19.7%, vs 12.8%; 95% CI, 11.1%-14.5% in 1988-1994; P = .02). Individuals from families below the federal poverty threshold (prevalence, 23.6%; 95% CI, 18.5%-28.7%) had significantly higher odds of hearing loss (multivariate adjusted OR, 1.60; 95% CI, 1.10-2.32) than those above the threshold (prevalence, 18.4%; 95% CI, 13.6%-23.2%). CONCLUSION: The prevalence of hearing loss among a sample of US adolescents aged 12 to 19 years was greater in 2005-2006 compared with 1988-1994. PMID- 20716741 TI - Does this patient have delirium?: value of bedside instruments. AB - CONTEXT: Delirium occurs in many hospitalized older patients and has serious consequences including increased risk for death and admission to long-term care. Despite its importance, health care clinicians often fail to recognize delirium. Simple bedside instruments may lead to improved identification. OBJECTIVE: To systematically review the evidence on the accuracy of bedside instruments in diagnosing the presence of delirium in adults. DATA SOURCES: Search of MEDLINE (from 1950 to May 2010), EMBASE (from 1980 to May 2010), and references of retrieved articles to identify studies of delirium among inpatients. STUDY SELECTION: Prospective studies of diagnostic accuracy that compared at least 1 delirium bedside instrument to the Diagnostic and Statistical Manual of Mental Disorders-based diagnosis made by a geriatrician, psychiatrist, or neurologist. DATA SYNTHESIS: There were 6570 unique citations identified with 25 prospectively conducted studies (N = 3027 patients) meeting inclusion criteria and describing use of 11 instruments. Positive results that suggested delirium with likelihood ratios (LRs) greater than 5.0 were present for the Global Attentiveness Rating (GAR), Memorial Delirium Assessment Scale (MDAS), Confusion Assessment Method (CAM), Delirium Rating Scale Revised-98 (DRS-R-98), Clinical Assessment of Confusion (CAC), and Delirium Observation Screening Scale (DOSS). Normal results that decreased the likelihood of delirium with LRs less than 0.2 were calculated for the GAR, MDAS, CAM, DRS-R-98, Delirium Rating Scale (DRS), DOSS, Nursing Delirium Screening Scale (Nu-DESC), and Mini-Mental State Examination (MMSE). The Digit Span test and Vigilance "A" test in isolation have limited utility in diagnosing delirium. Considering the instrument's ease of use, test performance, and clinical importance of the heterogeneity in the confidence intervals (CIs) of the LRs, the CAM has the best available supportive data as a bedside delirium instrument (summary-positive LR, 9.6; 95% CI, 5.8-16.0; summary-negative LR, 0.16; 95% CI, 0.09-0.29). Of all scales, the MMSE (score <24) was the least useful for identifying a patient with delirium (LR, 1.6; 95% CI, 1.2-2.0). CONCLUSION: The choice of instrument may be dictated by the amount of time available and the discipline of the examiner; however, the best evidence supports use of the CAM, which takes 5 minutes to administer. PMID- 20716742 TI - The President's Global Health Initiative. PMID- 20716743 TI - The US Global Health Initiative: informing policy with evidence. PMID- 20716744 TI - Minimizing bias in randomized trials: the importance of blinding. PMID- 20716745 TI - Physician compensation, cost, and quality. PMID- 20716746 TI - Assessing critical illness during emergency medical services care. PMID- 20716747 TI - JAMA patient page. Delirium. PMID- 20716749 TI - Association of bilirubin with cardiovascular outcomes: more hype than substance? PMID- 20716750 TI - TRPM4-linked isolated cardiac conduction defects: bad trafficking causes electrical gridlock. PMID- 20716751 TI - Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. AB - BACKGROUND: Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, but the genetic basis in the majority of cases remains unknown. Genes encoding desmosomal proteins, currently regarded as synonymous with another disorder, arrhythmogenic right ventricular cardiomyopathy, are known to cause left ventricular dysfunction, but their importance in unselected patients with unequivocal dilated cardiomyopathy is unknown. The objective of this study was to determine the prevalence of mutations in 5 desmosomal protein genes in patients with dilated cardiomyopathy. METHODS AND RESULTS: We studied 100 unrelated patients with idiopathic dilated cardiomyopathy consecutively referred to a dedicated cardiomyopathy unit. Patients underwent clinical evaluation, ECG, echocardiography, exercise testing, 24-hour ambulatory ECG monitoring, and mutation screening of 5 genes implicated in arrhythmogenic right ventricular cardiomyopathy: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Of the 100 patients (mean age at evaluation, 46.8+/-13.8 years; range, 17.0 to 72.8 years; male sex, 63%), 5 were found to carry pathogenic desmosomal protein gene mutations. An additional 13 patients had sequence variants of uncertain pathogenic significance and were excluded from further comparative analysis. Patients harboring desmosomal gene mutations had a phenotype indistinguishable from the 82 noncarriers, with the exception of exercise-induced ventricular ectopy, which was more frequent in the desmosomal mutation carriers (P=0.033). None of the 5 carriers of desmosomal mutations fulfilled current diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy, but 1 had fibrofatty change in the left ventricle at autopsy. CONCLUSIONS: Heart failure caused by a dilated, poorly contracting left ventricle and arrhythmogenic right ventricular cardiomyopathy have been considered distinct clinicopathologic entities. This study suggests that both clinical presentations can be caused by mutations in desmosomal protein genes. PMID- 20716752 TI - Percutaneous tricuspid valve replacement for a stenosed bioprosthesis. PMID- 20716753 TI - Letter by Lozano et al regarding article "previous coronary stent implantation and cardiac events in patients undergoing noncardiac surgery". PMID- 20716756 TI - Pharmacoinvasive strategy for ST-segment elevation myocardial infarction: wading through the treatment options. PMID- 20716757 TI - Role of the paclitaxel-eluting stent and tirofiban in patients with ST-elevation myocardial infarction undergoing postfibrinolysis angioplasty: the GRACIA-3 randomized clinical trial. AB - BACKGROUND: A catheter-based approach after fibrinolysis is recommended if fibrinolysis is likely to be successful in patients with acute ST-elevation myocardial infarction. We designed a 2x2 randomized, open-label, multicenter trial to evaluate the efficacy and safety of the paclitaxel-eluting stent and tirofiban administered after fibrinolysis but before catheterization to optimize the results of this reperfusion strategy. METHODS AND RESULTS: We randomly assigned 436 patients with acute ST-elevation myocardial infarction to (1) bare metal stent without tirofiban, (2) bare-metal stent with tirofiban, (3) paclitaxel-eluting stent without tirofiban, and (4) paclitaxel-eluting stent with tirofiban. All patients were initially treated with tenecteplase and enoxaparin. Tirofiban was started 120 minutes after tenecteplase in those patients randomly assigned to tirofiban. Cardiac catheterization was performed within the first 3 to 12 hours after inclusion, and stenting (randomized paclitaxel or bare stent) was applied to the culprit artery. The primary objectives were the rate of in segment binary restenosis of paclitaxel-eluting stent compared with that of bare metal stent and the effect of tirofiban on epicardial and myocardial flow before and after mechanical revascularization. At 12 months, in-segment binary restenosis was similar between paclitaxel-eluting stent and bare-metal stent (10.1% versus 11.3%; relative risk, 1.06; 95% confidence interval, 0.74 to 1.52; P=0.89). However, late lumen loss (0.04+/-0.055 mm versus 0.27+/-0.057 mm, P=0.003) was reduced in the paclitaxel-eluting stent group. No evidence was found of any association between the use of tirofiban and any improvement in the epicardial and myocardial perfusion. Major bleeding was observed in 6.1% of patients receiving tirofiban and in 2.7% of patients not receiving it (relative risk, 2.22; 95% confidence interval, 0.86 to 5.73; P=0.14). CONCLUSIONS: This trial does not provide evidence to support the use of tirofiban after fibrinolysis to improve epicardial and myocardial perfusion. Compared with bare metal stent, paclitaxel-eluting stent significantly reduced late loss but appeared not to reduce in-segment binary restenosis. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00306228. PMID- 20716758 TI - New drug-eluting stents: an overview on biodegradable and polymer-free next generation stent systems. PMID- 20716759 TI - Use of real-time 3D transesophageal echocardiography in percutaneous intervention of a flush-occluded pulmonary vein. PMID- 20716760 TI - Commentary: further comments on Mycoplasma pulmonis and lymphoma in bioassays of rats. AB - The authors recently assessed the likelihood that lifetime cancer bioassays of aspartame, methanol, and methyl tertiary butyl ether conducted with conventional (not specific pathogen free) Sprague-Dawley rats were compromised by Mycoplasma pulmonis disease. From the tumor data and other information, the authors concluded that the rats used in these bioassays likely had M pulmonis disease and that lesions of the disease were plausibly interpreted as lymphoma. Subsequently, they analyzed the nonneoplastic lesion data from these bioassays for occurrence of inflammatory lesions and found that 2,267 of 2,960 rats (76.6%) were reported to have bronchitis, the signature lesion of M pulmonis disease, and that 633 rats (21.4%) were reported to have otitis, another common lesion of the disease. Also, documentation is now available containing serologic evidence of mycoplasma infection in the rats. In contrast, the reports of 6 National Toxicology Program bioassays based on specific pathogen-free Sprague-Dawley rats listed no instances of bronchitis or otitis. These findings provide substantial additional evidence that the bioassays in question were compromised by M pulmonis disease. Therefore, the reported induction of lymphoma in these studies should not be considered in cancer risk assessments. The authors also found that inflammatory lesions were prevalent in lymph nodes, thymus, pleura, and brain. Finally, they found that of all 328 cases of lymphoimmunoblastic lymphoma affecting the lung (the primary form of lymphoma reported), 218 (66.5%) occurred within the first 104 weeks of the studies, showing that occurrence of such lesions was not due to appearance in rats surviving beyond that interval. PMID- 20716761 TI - Cutaneous schwannomas in 22 horses. AB - Schwannomas are uncommonly recognized in horses. This study describes cutaneous schwannomas in 22 horses aged 8 to 25 years: 12 male, 7 female, and 3 of unknown sex. The horses had solitary cutaneous masses: 9 on the head, 3 on the neck, and the others on the shoulder, hip, thorax, abdomen, rump, extremities, or tail. The location of 1 tumor was unknown. The dermal tumors were well demarcated and expansile. Twelve had a multinodular pattern, whereas 10 formed a single nodule. Antoni A areas were observed in all tumors, and 10 tumors contained Antoni B areas. In Antoni A areas, the densely packed spindle-shaped neoplastic cells were arranged in short fascicles with nuclear palisading. In the hypocellular Antoni B areas, neoplastic cells were separated by abundant myxomatous stroma. Tumors commonly had hyalinization of stroma and vessel walls and ancient change. Cellular vacuolation was observed in 18 tumors. In all 22 cases, neoplastic cells were immunopositive for S100 protein. Expression of laminin and glial fibrillary acidic protein was observed in all 6 tumors evaluated by immunohistochemistry for these markers. One tumor was examined ultrastructurally: Neoplastic cells had branched cytoplasmic processes and were surrounded by an external lamina. Follow up information was available 8 months to 10 years postexcision for 9 horses, for which surgical excision of the tumor was curative. The equine cutaneous schwannomas in this study had microscopic features like those of human schwannoma and had benign clinical behavior. Correct classification of equine cutaneous schwannoma will facilitate accurate prognosis and appropriate treatment. PMID- 20716762 TI - Arginine: master and commander in innate immune responses. AB - The activation of macrophages through Toll-like receptor (TLR) signaling pathways is a major component of innate immune responses to infection. Because the production of nitric oxide (NO) from arginine by the inducible isoform of NO synthase (iNOS) in activated macrophages is essential for host defense against many pathogens, arginine availability is a critical determinant of resistance to infection. Thus, induction of the arginine catabolic enzyme arginase is exploited by some pathogens as a means of immune evasion. Details of this mechanism are revealed by studies that demonstrate that mycobacteria use a component of the TLR pathway to induce the type I isoform of arginase in macrophages through an autocrine-paracrine mechanism that involves macrophage-produced cytokines. Separate studies show that, in addition to inhibiting NO synthesis by substrate limitation, reducing the availability of arginine simply by nutrient deprivation can blunt the innate immune response by impairing a specific mitogen-activated protein kinase (MAPK) pathway downstream of TLR4. These findings illustrate the growing complexity of the roles of arginine as an enzyme substrate and also as a regulatory molecule in signal transduction pathways in immune cells. PMID- 20716763 TI - TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. AB - The innate immune response is influenced by the nutrient status of the host. Mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase 1 (ERK1) and ERK2, are activated after the stimulation of macrophages with bacterial lipopolysaccharide (LPS) and are necessary for the optimal production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). We uncovered a role for the extracellular nutrient arginine in the activation of ERK1/2 in LPS-stimulated macrophages. Arginine facilitated the activation of MAPKs by preventing the dephosphorylation and inactivation of the MAPK kinase kinase tumor-promoting locus 2 (TPL-2). Starvation of mice decreased the concentration of arginine in the plasma and impaired the activation of ERK1/2 by LPS. Supplementation of starved mice with arginine promoted the subsequent activation of ERK1/2 and the production of TNF-alpha in response to LPS. Thus, arginine is critical for two aspects of the innate immune response in macrophages: It is the precursor used in the generation of the antimicrobial mediator nitric oxide, and it facilitates MAPK activation and consequently cytokine production. PMID- 20716765 TI - Phosphatidylinositol 3-kinase signaling in thymocytes: the need for stringent control. AB - The thymus serves as the primary site for the lifelong formation of new T lymphocytes; hence, it is essential for the maintenance of an effective immune system. Although thymocyte development has been widely studied, the mechanisms involved are incompletely defined. A comprehensive understanding of the molecular events that control regular thymocyte development will not only shed light on the physiological control of T cell differentiation but also probably provide insight into the pathophysiology of T cell immunodeficiencies, the molecular basis that underpins autoimmunity, and the mechanisms that instigate the formation of T cell lymphomas. Phosphatidylinositol 3-kinases (PI3Ks) play a critical role in thymocyte development, although not all of their downstream mediators have yet been identified. Here, we discuss experimental evidence that argues for a critical role of the PI3K-phosphoinositide-dependent protein kinase (PDK1) protein kinase B (PKB) signaling pathway in the development of both normal and malignant thymocytes, and we highlight molecules that can potentially be targeted therapeutically. PMID- 20716766 TI - von Willebrand factor promotes leukocyte extravasation. AB - von Willebrand factor (VWF) is an important player in hemostasis but has also been suggested to promote inflammatory processes. Gene ablation of VWF causes a simultaneous defect in P-selectin expression making it difficult to identify VWF specific functions. Therefore, we analyzed whether blocking antibodies against VWF would be able to interfere with neutrophil extravasation. We found that these antibodies inhibited neutrophil recruitment into thioglycollate-inflamed peritoneum and KC-stimulated cremaster by approximately 50%. Whereas platelet-VWF was not involved, the contribution of VWF to granulocyte recruitment was strictly dependent on the presence of platelets and the accessibility of their VWF receptor glycoprotein Ib. Surprisingly, platelet P-selectin was largely dispensable for leukocyte extravasation, in agreement with our observation that anti-VWF antibodies did not affect leukocyte rolling and adhesion. Searching for possible effects downstream of leukocyte capture, we found that anti-VWF antibodies significantly inhibited thioglycollate-induced vascular permeability. The increase of permeability was independent of circulating granulocytes, showing that it was not a side effect of neutrophil diapedesis. Collectively, our results demonstrate that VWF-associated platelets strongly support neutrophil extravasation at a step downstream of leukocyte docking to the vessel wall. This step could be related to leukocyte diapedesis facilitated by destabilization of the endothelial barrier. PMID- 20716764 TI - Arginine usage in mycobacteria-infected macrophages depends on autocrine paracrine cytokine signaling. AB - Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens, and its regulation is essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) competes with NO synthases for arginine, a substrate common to both types of enzymes, to inhibit NO production. Two signal transduction pathways control the production of Arg1 in macrophages: One pathway dependent on the Toll-like receptor adaptor protein myeloid differentiation marker 88 (MyD88) induces the expression of Arg1 during intracellular infections, whereas another pathway, which depends on signal transducer and activator of transcription 6 (STAT6), is required for Arg1 expression in alternatively activated macrophages. We found that mycobacteria-infected macrophages produced soluble factors, including interleukin-6 (IL-6), IL-10, and granulocyte colony stimulating factor (G-CSF), that induced expression of Arg1 in an autocrine paracrine manner. Arg1 expression was controlled by the MyD88-dependent production of these cytokines rather than by cell-intrinsic MyD88 signaling to Arg1. Our study revealed that the MyD88-dependent pathway that induced the expression of Arg1 after infection by mycobacteria required STAT3 activation and that this pathway may cause the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages. PMID- 20716767 TI - The JAK3-selective inhibitor PF-956980 reverses the resistance to cytotoxic agents induced by interleukin-4 treatment of chronic lymphocytic leukemia cells: potential for reversal of cytoprotection by the microenvironment. AB - Extensive evidence suggests that the malignant cells of chronic lymphocytic leukemia (CLL) patients are in close contact with activated T lymphocytes, which secrete a range of cytoprotective cytokines including interleukin-4 (IL-4). IL-4 induced the rapid phosphorylation and activation of the signal transducer and activator of transcription 6 transcription factor in CLL cells in vitro. Longer incubation with IL-4 resulted in up-regulation of the antiapoptotic proteins, Mcl 1 and Bcl-X(L). All of these events were blocked by the JAK3-selective inhibitor, PF-956980. A dye reduction cytotoxicity assay showed that IL-4 induced resistance to the cytotoxic drugs fludarabine and chlorambucil and to the novel p53 elevating agent nutlin 3. IL-4-induced drug resistance was reversed by PF-956980. These conclusions were confirmed by independent assays for apoptosis induction (annexin V binding, cleavage of poly[ADP-ribose] polymerase, and morphologic analysis). Coculture with bone marrow stromal cells in the presence of supernatants derived from activated T-lymphocyte cultures also protected CLL cells from apoptosis induction by chlorambucil. Protection by these combined signals was reversed by PF-956980. The data here provide a preclinical rationale for the possible therapeutic use of PF-956980 in conjunction with conventional cytotoxic drugs to achieve more extensive killing of CLL cells by overcoming antiapoptotic signaling by the microenvironment. PMID- 20716768 TI - Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques. AB - Infants infected with HIV have a more severe course of disease and persistently higher viral loads than HIV-infected adults. However, the underlying pathogenesis of this exacerbation remains obscure. Here we compared the rate of CD4(+) and CD8(+) T-cell proliferation in intestinal and systemic lymphoid tissues of neonatal and adult rhesus macaques, and of normal and age-matched simian immunodeficiency virus (SIV)-infected neonates. The results demonstrate infant primates have much greater rates of CD4(+) T-cell proliferation than adult macaques, and that these proliferating, recently "activated" CD4(+) T cells are infected in intestinal and other lymphoid tissues of neonates, resulting in selective depletion of proliferating CD4(+) T cells in acute infection. This depletion is accompanied by a marked increase in CD8(+) T-cell activation and production, particularly in the intestinal tract. The data indicate intestinal CD4(+) T cells of infant primates have a markedly accelerated rate of proliferation and maturation resulting in more rapid and sustained production of optimal target cells (activated memory CD4(+) T cells), which may explain the sustained "peak" viremia characteristic of pediatric HIV infection. Eventual failure of CD4(+) T-cell turnover in intestinal tissues may indicate a poorer prognosis for HIV-infected infants. PMID- 20716769 TI - Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia. AB - Patients with thymic malignancy have high rates of autoimmunity leading to a variety of autoimmune diseases, most commonly myasthenia gravis caused by anti acetylcholine receptor autoantibodies. High rates of autoantibodies to cytokines have also been described, although prevalence, spectrum, and functionality of these anti-cytokine autoantibodies are poorly defined. To better understand the presence and function of anti-cytokine autoantibodies, we created a luciferase immunoprecipitation system panel to search for autoantibodies against 39 different cytokines and examined plasma from controls (n = 30) and patients with thymic neoplasia (n = 17). In this screen, our patients showed statistically elevated, but highly heterogeneous immunoreactivity against 16 of the 39 cytokines. Some patients showed autoantibodies to multiple cytokines. Functional testing proved that autoantibodies directed against interferon-alpha, interferon beta, interleukin-1alpha (IL-1alpha), IL-12p35, IL-12p40, and IL-17A had biologic blocking activity in vitro. All patients with opportunistic infection showed multiple anti-cytokine autoantibodies (range 3-11), suggesting that anti-cytokine autoantibodies may be important in the pathogenesis of opportunistic infections in patients with thymic malignancy. This study was registered at http://clinicaltrials.gov as NCT00001355. PMID- 20716771 TI - Polycomb proteins in hematologic malignancies. AB - The Polycomb group (PcG) of proteins is a major mechanism of epigenetic regulation that has been broadly linked to cancer. This system can repress gene expression by chromatin modification and is essential for establishing cell identity. PcG proteins are important for stem cell function and differentiation and have a profound impact during hematopoiesis. In recent years, several published studies have deepened our knowledge of the biology of the PcG in health and disease. In this article, we review the current understanding of the mechanisms of PcG-mediated repression and their relation to DNA methylation, and we discuss the role of the PcG system in hematopoiesis and hematologic malignancies. We suggest that alteration of different PcG members is a frequent event in leukemia and lymphomas that confers the stem cell properties on tumor cells. Thus, drugs targeting Polycomb complexes could be useful for treating patients with these diseases. PMID- 20716770 TI - Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo controlled trial of the Eastern Cooperative Oncology Group 3999. AB - Zosuquidar, which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp-mediated resistance in acute myeloid leukemia without increased toxicity. A total of 449 adults older than 60 years with acute myeloid leukemia or high-risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (Eastern Cooperative Oncology Group 3999). Overall survival was compared between patients receiving conventional-dose cytarabine and daunorubicin and either zosuquidar (550 mg; 212 patients) or placebo (221 patients). Median and 2-year overall survival values were 7.2 months and 20% on zosuquidar and 9.4 months and 23% on placebo, respectively (P = .281). Remission rate was 51.9% on zosuquidar and 48.9% on placebo. All cause mortality to day 42 was not different (zosuquidar 22.2% vs placebo 16.3%; P = .158). In vitro modulation of P-gp activity by zosuquidar and expression of P-gp, multidrug resistance-related protein 1, lung resistance protein, and breast cancer resistance protein, were comparable in the 2 arms. Poor-risk cytogenetics were more common in P-gp(+) patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is registered at www.clinicaltrials.gov as #NCT00046930. PMID- 20716772 TI - The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the EMU- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. AB - Inhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a promising therapeutic approach in chronic lymphocytic leukemia (CLL), but experimental in vivo evidence to support this view is still lacking. We have now investigated whether inhibition of BCR signaling with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop in the EMU-TCL1 transgenic mouse model of CLL. Similarly to human CLL, these leukemias express stereotyped BCRs that react with autoantigens exposed on the surface of senescent or apoptotic cells, suggesting that they are antigen driven. We show that R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs despite the relatively modest cytotoxic effect in vitro and is independent of basal Syk activity, suggesting that R788 functions primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect of R788 was found to be selective for the malignant clones, as no disturbance in the production of normal B lymphocytes was observed. Collectively, these data provide further rationale for clinical trials with R788 in CLL and establish the BCR-signaling pathway as an important therapeutic target in this disease. PMID- 20716774 TI - Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. AB - This retrospective study assessed the outcome of 576 adult acute lymphoblastic leukemia patients aged >= 45 years, and who received a reduced-intensity conditioning (RIC; n = 127) or myeloablative conditioning (MAC; n = 449) allogeneic stem cell transplantation (allo-SCT) from a human leukocyte antigen identical sibling while in complete remission. With a median follow-up of 16 months, at 2 years, the cumulative incidences of nonrelapse mortality and relapse incidence were 29% +/- 2% (MAC) versus 21% +/- 5% (RIC; P = .03), and 31% +/- 2% (MAC) versus 47% +/- 5% (RIC; P < .001), respectively. In a multivariate analysis, nonrelapse mortality was decreased in RIC recipients (P = .0001, hazard ratio [HR] = 1.98) whereas it was associated with higher relapse rate (P = .03, HR = 0.59). At 2 years, LFS was 38% +/- 3% (MAC) versus 32% +/- 6% (RIC; P = .07). In multivariate analysis, the type of conditioning regimen (RIC vs. MAC) was not significantly associated with leukemia-free survival (P = .23, HR = 0.84). Despite the need for randomized trials, we conclude that RIC allo-SCT from a human leukocyte antigen-identical donor is a potential therapeutic option for acute lymphoblastic leukemia patients aged >= 45 years in complete remission and not eligible for MAC allo-SCT. PMID- 20716773 TI - Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin. AB - Podoplanin is a small transmembrane protein required for development and function of the lymphatic vascular system. To investigate the effects of interfering with its function, we produced an Fc fusion protein of its ectodomain. We found that podoplanin-Fc inhibited several functions of cultured lymphatic endothelial cells and also specifically suppressed lymphatic vessel growth, but not blood vessel growth, in mouse embryoid bodies in vitro and in mouse corneas in vivo. Using a keratin 14 expression cassette, we created transgenic mice that overexpressed podoplanin-Fc in the skin. No obvious outward phenotype was identified in these mice, but surprisingly, podoplanin-Fc-although produced specifically in the skin entered the blood circulation and induced disseminated intravascular coagulation, characterized by microthrombi in most organs and by thrombocytopenia, occasionally leading to fatal hemorrhage. These findings reveal an important role of podoplanin in lymphatic vessel formation and indicate the potential of podoplanin-Fc as an inhibitor of lymphangiogenesis. These results also demonstrate the ability of podoplanin to induce platelet aggregation in vivo, which likely represents a major function of lymphatic endothelium. Finally, keratin 14 podoplanin-Fc mice represent a novel genetic animal model of disseminated intravascular coagulation. PMID- 20716775 TI - FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells. AB - Little is known about whether autophagic mechanisms are active in hematopoietic stem cells (HSCs) or how they are regulated. FIP200 (200-kDa FAK-family interacting protein) plays important roles in mammalian autophagy and other cellular functions, but its role in hematopoietic cells has not been examined. Here we show that conditional deletion of FIP200 in hematopoietic cells leads to perinatal lethality and severe anemia. FIP200 was cell-autonomously required for the maintenance and function of fetal HSCs. FIP200-deficient HSC were unable to reconstitute lethally irradiated recipients. FIP200 ablation did not result in increased HSC apoptosis, but it did increase the rate of HSC proliferation. Consistent with an essential role for FIP200 in autophagy, FIP200-null fetal HSCs exhibited both increased mitochondrial mass and reactive oxygen species. These data identify FIP200 as a key intrinsic regulator of fetal HSCs and implicate a potential role for autophagy in the maintenance of fetal hematopoiesis and HSCs. PMID- 20716781 TI - New antimicrobial agents approved by the U.S. Food and Drug Administration from 2007 to 2009 and new indications for previously approved agents. PMID- 20716776 TI - Krox20/EGR2 deficiency accelerates cell growth and differentiation in the monocytic lineage and decreases bone mass. AB - Krox20/EGR2, one of the 4 early growth response genes, is a highly conserved transcription factor implicated in hindbrain development, peripheral nerve myelination, tumor suppression, and monocyte/macrophage cell fate determination. Here, we established a novel role for Krox20 in postnatal skeletal metabolism. Microcomputed tomographic analysis of 4- and 8-week-old mice revealed a low bone mass phenotype (LBM) in both the distal femur and the vertebra of Krox20(+/-) mice. This was attributable to accelerated bone resorption as demonstrated in vivo by increased osteoclast number and serum C-terminal telopeptides, a marker for collagen degradation. Krox20 haploinsufficiency did not reduce bone formation in vivo, nor did it compromise osteoblast differentiation in vitro. In contrast, growth and differentiation were significantly stimulated in preosteoclast cultures derived from Krox20(+/-) splenocytes, suggesting that the LBM is attributable to Krox20 haploinsufficiency in the monocytic lineage. Furthermore, Krox20 silencing in preosteoclasts increased cFms expression and response to macrophage colony-stimulating factor, leading to a cell-autonomous stimulation of cell-cycle progression. Our data indicate that the antimitogenic role of Krox20 in preosteoclasts is the predominant mechanism underlying the LBM phenotype of Krox20-deficient mice. Stimulation of Krox20 expression in preosteoclasts may present a viable therapeutic strategy for high-turnover osteoporosis. PMID- 20716782 TI - Dosing ethambutol in obese patients. PMID- 20716783 TI - Estimating the length of hospitalization attributable to multidrug antibiotic resistance. PMID- 20716784 TI - International recommendations for training future toxicologic pathologists participating in regulatory-type, nonclinical toxicity studies. AB - The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type, nonclinical toxicology studies. Optimally, trainees should undertake a scientific curriculum of at least five years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain four or more years of intensive pathology practice during a residency and/or on-the-job "apprenticeship," at least two years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A nonclinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one's understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID- 20716785 TI - Evaluation of novel biomarkers of nephrotoxicity in two strains of rat treated with Cisplatin. AB - Cisplatin is an anticancer agent that induces renal proximal tubule lesions in many species. Studies were conducted in Sprague-Dawley and Han-Wistar rats to evaluate the utility of novel preclinical biomarkers of nephrotoxicity for renal lesions caused by this compound. Groups of 10 males of each strain were given a single intraperitoneal injection of 0.3, 1, or 3 mg/kg cisplatin and were sacrificed on days 2, 3, and 5. The novel biomarkers alpha-glutathione-S transferase (alpha-GST) (for proximal tubular injury), MU-glutathione-S transferase (MU-GST) (for distal tubular injury), clusterin (for general kidney injury), and renal papillary antigen-1 (RPA-1) (for collecting duct injury) were measured in urine by enzyme immunoassay. Histologically, degeneration and necrosis of the S3 segment of the renal proximal tubule were observed on day 2 (Han-Wistar) and days 3 and 5 (both strains) at 1 and 3 mg/kg. Results showed that in both strains of rats, urinary alpha-GST and clusterin can be detected in urine soon after injury, are more sensitive than BUN and serum creatinine, and therefore are usable as noninvasive biomarkers of proximal tubule injury. Changes in both MU-GST or RPA-1 were considered to represent secondary minor effects of proximal tubular injury on distal segments of the nephron. PMID- 20716786 TI - Drug-induced valvulopathy: an update. AB - Drug-induced valvulopathy is a serious liability for certain compound classes in development and for some marketed drugs intended for human use. Reports of valvulopathy led to the withdrawal of fenfluramines (anorexigens) and pergolide (antiparkinson drug) from the United States market in 1997 and 2007, respectively. The mechanism responsible for the pathogenesis of valvulopathy by these drugs is likely a result of an "off-target" effect via activation of 5 hydroxytryptamine (5-HT) 2B receptor (5-HT2BR) expressed on heart valve leaflets. Microscopically, the affected valve leaflets showed plaques of proliferative myofibroblasts in an abundant extracellular matrix, composed primarily of glycosaminoglycans. However, the valvular effects caused by fenfluramines and pergolide were not initially predicted from routine preclinical toxicity studies, and to date there are no specific validated animal models or preclinical/toxicologic screens to accurately predict drug-induced valvulopathy. This review covers the structure and function of heart valves and highlights major advances toward understanding the 5-HT2BR-mediated pathogenesis of the lesion and subsequently, development of appropriate animal models using novel techniques/experiments, use of functional screens against 5-HT2BR, and more consistent sampling and pathologic evaluation of valves in preclinical studies that will aid in avoidance of future drug-induced valvulopathy in humans. PMID- 20716787 TI - Industry survey of approaches to examination and terminology of spontaneous changes in the heart of young rats. PMID- 20716788 TI - Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury. AB - Drug-induced vascular injury (DIVI) is a nonclinical finding that often confounds the toxicological evaluation of investigational drugs, but there is an absence of qualified biomarkers that can be used to detect and monitor its appearance in animals and patients during drug development and clinical use. It is well known that endothelial cell (EC) activation plays a key role in the expression and evolution of DIVI, and the various immunological and inflammatory factors involved in its expression may serve as potential biomarker candidates. Activated ECs change their morphology and gene expression, generating endothelial adhesion molecules, pro-coagulant molecules, cytokines, chemokines, vasodilators, nitric oxide, and acute-phase reactants. This review provides a brief historical background of EC activation and the search for biomarkers of early EC activation for monitoring DIVI. At present, no biomarkers of EC activation have been qualified to predict DIVI in the nonclinical or clinical context, and a robust pathologic foundation for their use is still lacking. We propose three categories of EC activation biomarkers: recommended surrogate markers, potentially useful markers, and emerging candidate markers. This review alerts pharmaceutical companies, research institutions, and regulatory agencies to the continuing need for reliable biomarkers of EC activation in drug development. PMID- 20716789 TI - A shifting paradigm in strengthening laboratory health systems for global health: acting now, acting collectively, but acting differently. PMID- 20716790 TI - Leaders wanted: a call to change the status quo in approaching health care quality, once again. PMID- 20716791 TI - Laboratory systems and services are critical in global health: time to end the neglect? AB - The $63 billion comprehensive global health initiative (GHI) emphasizes health systems strengthening (HSS) to tackle challenges, including child and maternal health, HIV/AIDS, family planning, and neglected tropical diseases. GHI and other initiatives are critical to fighting emerging and reemerging diseases in resource poor countries. HSS is also an increasing focus of the $49 billion program of the US President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis and Malaria. Laboratory systems and services are often neglected in resource-poor settings, but the funding offers an opportunity to end the neglect. To sustainably strengthen national laboratory systems in resource-poor countries, the following approaches are needed: (1) developing integrative national laboratory strategic plans and policies and building systems to address multiple diseases; (2) establishing public-private partnerships; (3) ensuring effective leadership, commitment, and coordination by host governments of efforts of donors and partners; (4) establishing and/or strengthening centers of excellence and field epidemiology and laboratory training programs to meet short- and medium term training and retention goals; and (5) establishing affordable, scalable, and effective laboratory accreditation schemes to ensure quality of laboratory tests and bridge the gap between clinicians and laboratory experts on the use of test results. PMID- 20716792 TI - Strengthening laboratory systems in resource-limited settings. AB - Considerable resources have been invested in recent years to improve laboratory systems in resource-limited settings. We reviewed published reports, interviewed major donor organizations, and conducted case studies of laboratory systems in 3 countries to assess how countries and donors have worked together to improve laboratory services. While infrastructure and the provision of services have seen improvement, important opportunities remain for further advancement. Implementation of national laboratory plans is inconsistent, human resources are limited, and quality laboratory services rarely extend to lower tier laboratories (eg, health clinics, district hospitals). Coordination within, between, and among governments and donor organizations is also frequently problematic. Laboratory standardization and quality control are improving but remain challenging, making accreditation a difficult goal. Host country governments and their external funding partners should coordinate their efforts effectively around a host country's own national laboratory plan to advance sustainable capacity development throughout a country's laboratory system. PMID- 20716793 TI - Country leadership and policy are critical factors for implementing laboratory accreditation in developing countries: a study on Uganda. AB - Accreditation of laboratories is one means to promote quality laboratory services, underscoring the need to document factors that facilitate laboratory accreditation. A desk review and key informant's interviews were conducted to determine the roles of country leadership and policies in laboratory accreditation. Overall, the review revealed that Uganda has enabling factors for laboratory accreditation, putting the country in a state of accreditation readiness and including strong leadership that provides stewardship and availability of a national health laboratory policy with an explicit statement on laboratory accreditation. A National Laboratory Technical and Policy Committee coordinated the development of the policy. Laboratory training schools provide leadership in training laboratory professionals, while the Association of Medical Laboratory Technologists provides professional leadership. Although there is no national accreditation system, some laboratories are participating in international laboratory accreditation. Key informants expressed strong support for and observed that laboratory accreditation is beneficial and can be implemented in Uganda. Lessons from this study can benefit countries planning to implement laboratory accreditation. Countries that have not developed national laboratory policies and strategic plans should do so to guide the strengthening of laboratory systems and services as a part of health systems strengthening, which would be a springboard for laboratory accreditation. PMID- 20716794 TI - The role of standards and training in preparing for accreditation. AB - Laboratory test results are the cornerstone for patient diagnosis and treatment, and the principles of high-quality laboratory testing are the same anywhere in the world. It is one area of health care that can and should be standardized. Resource-limited countries' laboratories lack equipment, proper funding, adequate training for laboratory workers, and systematic management of work, making it difficult to deliver accurate and reliable results. Quality management tools are being used to improve practices, with accreditation being a means to demonstrate that standards are being met. The World Health Organization (WHO), the US Centers for Disease Control and Prevention, and the Clinical and Laboratory Standards Institute have assumed responsibility for leading a harmonized approach to the provision of education and training in laboratories by publishing a training tool kit. The WHO Regional Office for Africa is leading a new stepwise approach to accreditation. PMID- 20716795 TI - The World Health Organization African region laboratory accreditation process: improving the quality of laboratory systems in the African region. AB - Few developing countries have established laboratory quality standards that are affordable and easy to implement and monitor. To address this challenge, the World Health Organization Regional Office for Africa (WHO AFRO) established a stepwise approach, using a 0- to 5-star scale, to the recognition of evolving fulfillment of the ISO 15189 standard rather than pass-fail grading. Laboratories that fail to achieve an assessment score of at least 55% will not be awarded a star ranking. Laboratories that achieve 95% or more will receive a 5-star rating. This stepwise approach acknowledges to laboratories where they stand, supports them with a series of evaluations to use to demonstrate improvement, and recognizes and rewards their progress. WHO AFRO's accreditation process is not intended to replace established ISO 15189 accreditation schemes, but rather to provide an interim pathway to the realization of international laboratory standards. Laboratories that demonstrate outstanding performance in the WHO-AFRO process will be strongly encouraged to enroll in an established ISO 15189 accreditation scheme. We believe that the WHO-AFRO approach for laboratory accreditation is affordable, sustainable, effective, and scalable. PMID- 20716796 TI - Improving quality management systems of laboratories in developing countries: an innovative training approach to accelerate laboratory accreditation. AB - The Strengthening Laboratory Management Toward Accreditation (SLMTA) program was developed to promote immediate, measurable improvement in laboratories of developing countries. The laboratory management framework, a tool that prescribes managerial job tasks, forms the basis of the hands-on, activity-based curriculum. SLMTA is implemented through multiple workshops with intervening site visits to support improvement projects. To evaluate the effectiveness of SLMTA, the laboratory accreditation checklist was developed and subsequently adopted by the World Health Organization Regional Office for Africa (WHO AFRO). The SLMTA program and the implementation model were validated through a pilot in Uganda. SLMTA yielded observable, measurable results in the laboratories and improved patient flow and turnaround time in a laboratory simulation. The laboratory staff members were empowered to improve their own laboratories by using existing resources, communicate with clinicians and hospital administrators, and advocate for system strengthening. The SLMTA program supports laboratories by improving management and building preparedness for accreditation. PMID- 20716797 TI - Field experience in implementing ISO 15189 in Kisumu, Kenya. AB - Quality medical laboratory services are an integral part of routine health care, medical research, and public health systems. Despite this vital role, quality laboratory services in Africa are scarce. The crucial need for expanding quality laboratory services throughout sub-Saharan Africa is especially critical because of the region's burden of disease. Fortunately, several plans from supporting international partners are underway to help strengthen laboratory infrastructure in this region. A key component of these initiatives is the enforcement of quality assurance services through accreditation by international standards such as the International Organization for Standardization (ISO) 15189. However, acquisition and maintenance of these standards are a significant challenge, especially in resource-limited settings. The most common limiting factors can include funding, government support, equipment, training opportunities, and poor procurement infrastructure. In this article, we discuss the challenges and benefits accrued in pursuing and sustaining ISO 15189 accreditation for the Kenya Medical Research Institute/Centre for Disease Control HIV-Research Laboratory in Kisumu, Kenya. PMID- 20716798 TI - Validation of lamellar body counts using three hematology analyzers. AB - The lamellar body count (LBC) represents an alternative method to the TDx-FLM II (Abbott Laboratories, Abbott Park, IL), which is planned to be discontinued, for assessing fetal lung maturity. Our objective was to validate the LBC on 3 hematology analyzers (Coulter LH 750 and Coulter Ac.T diff2, Beckman Coulter, Brea, CA; and Sysmex XE-2100, Sysmex, Mundelein, IL) to serve as a template for other laboratories attempting to perform in-house validation. Intra-assay and interassay coefficients of variation ranged from 1.7% to 21.8% and 1.9% to 7.1%, respectively, and all analyzers demonstrated excellent linearity. Whole blood and meconium were shown to interfere with LBCs, and specimens with these contaminants should be tested using phosphatidyl glycerol. With a TDx-FLM II cutoff of 55 mg/g or more and an LBC cutoff of 50,000/microL or more for maturity, concordance between the TDx-FLM II and the LBC on all instruments was poor (<80% in all cases). Concordance between hematology analyzers was excellent (>or=94%). When laboratories are performing in-house validations, they should not correlate LBC with TDx-FLM II results without outcome data. Correlation with another validated LBC method is preferred. PMID- 20716799 TI - CD71 (transferrin receptor): an effective marker for erythroid precursors in bone marrow biopsy specimens. AB - Accurate analysis of the erythroid lineage is essential in evaluating bone marrow biopsy specimens and can be particularly challenging in the setting of dyserythropoiesis. Transferrin receptor (CD71) mediates the uptake of transferrin iron complexes and is highly expressed on the surface of cells of the erythroid lineage. Although CD71 has been used for flow cytometric analysis, its usefulness in paraffin-embedded bone marrow biopsy specimens has not been examined. This study defined the immunohistochemical profile of CD71, as compared with glycophorin A (CD235a) and hemoglobin, in 65 bone marrow biopsy specimens, including normal marrow specimens and cases of myelodysplastic syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, plasma cell neoplasm, and metastatic carcinoma. Immunoreactivity for CD71 was restricted to erythroid precursors in normal and dyspoietic marrow samples and exhibited a membranous and cytoplasmic staining pattern. The vast majority of mature erythrocytes lack expression of CD71, greatly facilitating interpretation. CD71 is a highly effective marker for the detection of cells of erythroid lineage in bone marrow biopsy specimens. PMID- 20716800 TI - Prevalence of RhD variants, confirmed by molecular genotyping, in a multiethnic prenatal population. AB - RhD determination in pregnant women is critical to facilitate Rh immune globulin prophylaxis for RhD-negative women. A single amino acid change in the RhD antigen can cause epitope loss, giving rise to "partial D" variants. Women with some partial D variants may develop anti-D against the missing epitope after pregnancy. RBCs with partial D may type as D-positive or D-negative depending on the reagent used. We screened routine blood bank samples from 501 prenatal patients for RhD variants by 3 commercially available serologic methods. Discordant serologic results were found in 11 cases. Weak D (n = 5) and partial D (n = 5) variants were confirmed by molecular genotyping in all but 1 case. RhD variants, confirmed molecularly, occur in 2.2% of our multiethnic population. Consideration of patients' ethnic background and close cooperation between pathologists and obstetric providers facilitate optimal prenatal care in these cases. PMID- 20716801 TI - Receipt of older RBCs does not predispose D-negative recipients to anti-D alloimmunization. AB - The effect of the age of RBCs on anti-RBC alloimmunization has not been investigated in previous studies of the RBC storage lesion. D-negative recipients of at least 1 D-positive RBC unit were identified. Responders produced an anti-D, while nonresponders had not made anti-D when the database was searched. The 2 groups were matched for age, sex, length of serologic follow-up, and hospital location. There were 29 responders and 58 nonresponders. The median number of all RBCs transfused to the responders was 6, vs 10 for the nonresponders (P < .01); the median age of the RBCs was 15 vs 14 days, respectively (P = .70). Responders received a median of 3 D-positive RBC units vs 4 D-positive RBCs for nonresponders (P = .02); median ages of the D-positive RBCs were 16 vs 14 days, respectively (P = .21). There was no association between the age of transfused RBCs and the likelihood of anti-D alloimmunization. PMID- 20716802 TI - Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System for Reporting Thyroid Cytopathology. AB - Fine-needle aspiration (FNA) is an important test for triaging patients with thyroid nodules. The 2007 National Cancer Institute Thyroid Fine-Needle Aspiration State-of-the-Science Conference helped instigate the recent publication of The Bethesda System for Reporting Thyroid Cytopathology. We reviewed 3,080 thyroid FNA samples and recorded interpretations according to the proposed standardized 6-tier nomenclature, and pursued follow-up cytology and histology. Of the 3,080 FNAs, 18.6% were nondiagnostic, 59.0% were benign, 3.4% were atypical follicular lesion of undetermined significance (AFLUS), 9.7% were "suspicious" for follicular neoplasm (SFN), 2.3% were suspicious for malignancy (SM), and 7.0% were malignant. Of 574 cases originally interpreted as nondiagnostic, 47.9% remained nondiagnostic. In 892 cases, there was follow-up histology. Rates of malignancy were as follows: nondiagnostic, 8.9%; benign, 1.1%; AFLUS, 17% (9/53); SFN, 25.4%; SM, 70% (39/56), and malignant, 98.1%. Thus, classification of thyroid FNA samples at the University of Virginia Health System, Charlottesville, according to The Bethesda System yields similar results for risk of malignancy as reported by others. Universal application of the new standardized nomenclature may improve interlaboratory agreement and lead to more consistent management approaches. PMID- 20716803 TI - p62+ Hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease. AB - Mallory bodies (MBs) and hyaline globules (HGs) are recognized as hepatocellular cytoplasmic inclusions in liver diseases. We reviewed 123 intrahepatic cholangiocarcinomas (ICCs) and encountered 16 cases (13.0%) in which cancer cells had MB-type inclusions and/or HG-type inclusions, both of which are positive for p62 and ubiquitin. The HG type was present in all 16 cases, and 5 cases contained the MB type. Of 16 patients, 12 had chronic liver disease that was related to alcoholic abuse in 4, hepatitis B surface antigen-positive in 3, and hepatitis C virus antibody-positive in 8. Viral infection and liver cirrhosis were more common in ICCs with p62+ inclusions (P = .0004 and P = .0199, respectively). Of 16 ICCs, 15 with hyaline inclusions had a peripheral tumor location (P = .0052). On ultrastructural examination, the MB type had an electron-dense fibrillar appearance, while the HG type appeared as rounded masses of granular materials. Our results suggest that intracytoplasmic hyaline bodies occasionally can be found in cholangiocarcinoma with chronic liver disease related to viral hepatitis or alcoholic intake. PMID- 20716804 TI - Specimen labeling errors in surgical pathology: an 18-month experience. AB - Elimination of medical errors is important for pathologists. Errors occurring in surgical pathology involve specimen defects, specimen labeling, processing, diagnosis, and reporting defects. Errors occur during prelaboratory, laboratory, and postlaboratory phases. We reviewed our experience with mislabeled specimens in the laboratory for an 18-month period. The percentage of error was calculated on a per case, block, and slide basis. Errors were characterized by site and as incorrect patient or site. The study involved 75 labeling errors (0.25% of cases) that were detected. Of the 75 errors, 55 (73%) involved patient name, and 18 (24%) involved site. The majority of mislabelings (52 [69%]) occurred in the gross room. Although infrequent, labeling errors involved misidentification of patient or specimen source. Of the errors, 73% (55/75) of errors resulted in slides assigned to an incorrect patient. Most errors occurred in the gross room. Newer technologies such as bar coding and radio frequency chip methods may reduce the frequency of specimen labeling errors. PMID- 20716805 TI - High serum thymidine kinase 1 level predicts poorer survival in patients with chronic lymphocytic leukemia. AB - Serum thymidine kinase 1 (TK1) levels have been reported to have prognostic significance in patients with chronic lymphocytic leukemia (CLL). Until recently, serum TK1 levels were assessed using inconvenient radioenzyme assays. In this study, we used a novel chemiluminescence assay to assess serum TK1 levels in patients with CLL at the time of first examination. We show that high serum TK1 levels predict poorer overall survival and correlate with unmutated immunoglobulin variable region genes, CD38 and ZAP-70 expression, and subsequent risk of developing large B-cell lymphoma (Richter syndrome). Similar findings were observed in a subset of patients treated with current fludarabine-based chemotherapy regimens. We suggest that serum TK1 levels analyzed using this convenient chemiluminescence assay may be useful in the risk assessment of patients with CLL. PMID- 20716806 TI - Biomarker-based prediction of response to therapy for colorectal cancer: current perspective. AB - The diagnosis and management of colorectal cancer (CRC) has been impacted by the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. Recently, CRC has been reclassified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. At the same time, a number of new prognostic and predictive single genes and proteins have been discovered that are designed to reflect sensitivity and/or resistance to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical extirpation. More recently, a number of biomarkers tested by a variety of methods have been proposed as specific predictors of chemotherapy and radiotherapy response. Other markers have been successfully used to predict toxic effects of standard therapies. In this review, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome. PMID- 20716809 TI - Renal dysfunction, hemodialysis, and the NT-proBNP/BNP ratio. PMID- 20716810 TI - Biomedical Journals in India: some critical concerns. PMID- 20716811 TI - Importance of accurate information on causes of maternal deaths for informing health care programmes. PMID- 20716812 TI - Chandipura virus - what we know & do not know. PMID- 20716813 TI - Cancer biomarkers - current perspectives. AB - In the recent years, knowledge about cancer biomarkers has increased tremendously providing great opportunities for improving the management of cancer patients by enhancing the efficiency of detection and efficacy of treatment. Recent technological advancement has enabled the examination of many potential biomarkers and renewed interest in developing new biomarkers. Biomarkers of cancer could include a broad range of biochemical entities, such as nucleic acids, proteins, sugars, lipids, and small metabolites, cytogenetic and cytokinetic parameters as well as whole tumour cells found in the body fluid. A comprehensive understanding of the relevance of each biomarker will be very important not only for diagnosing the disease reliably, but also help in the choice of multiple therapeutic alternatives currently available that is likely to benefit the patients. This review provides a brief account on various biomarkers for diagnosis, prognosis and therapeutic purposes, which include markers already in clinical practice as well as various upcoming biomarkers. PMID- 20716814 TI - Cause of death among reproductive age group women in Maharashtra, India. AB - BACKGROUND & OBJECTIVES: Reliable data on mortality and morbidity among women of reproductive age group are scarce in India. The present study is the Maharashtra component of a large multicentric task force study on the cause of death by verbal autopsy conducted in five States of India. The data pertaining to deaths among reproductive age group women are presented along with the factors contributing to these deaths. METHODS: House-to-house surveys of a representative population from rural and urban areas in six districts of Maharashtra were undertaken by probability of proportion to size (PPS) sampling. Information on death was obtained from the relatives of the deceased and cause of death was assigned using the standardized algorithm prepared. International Classification of Diseases - ICD- 10 was used to code the assigned cause of death. RESULTS: A total of 103 deaths in reproductive age group women were investigated, of which 7 (5.6%) were maternal while 96 (93.2%) were due to non maternal causes. Six out of seven maternal deaths were in rural area. Among the non maternal deaths, 46.8 per cent women had symptoms suggestive of anaemia and the leading cause of death was infectious and parasitic diseases (25%), tuberculosis being the top killer in this group. This was followed by injury and poisoning (20.8%), suicides being the leading cause in this category. Among non-communicable diseases, cancers contributed to 10.6 per cent deaths among which cancer esophagus and cancer cervix took a major toll. INTERPRETATION & CONCLUSION: Communicable diseases, injury and poisoning and cancers are the major killers among reproductive age group women. Several factors responsible for accidents and suicides also contributed substantially to the mortality load among these women. Majority of the maternal deaths were seen in rural areas indicating the need to strengthen the maternal health care. PMID- 20716815 TI - Chandipura virus growth kinetics in vertebrate cell lines, insect cell lines & embryonated eggs. AB - BACKGROUND & OBJECTIVES: Since not much information on Chandipura virus is available, an attempt was made to study the growth kinetics of the virus in certain vertebrate, invertebrate cell lines and embryonated chicken eggs. METHODS: Comparative study of Chandipura virus (CHPV) growth kinetics in three vertebrate cell lines [Vero E6, Rhabdo myosarcoma (RD), Porcine stable kidney (PS) cell lines], two insect cell lines [Aedes aegypti (AA) and Phlebotomus papatasi (PP-9) cell lines] and embryonated pathogen free chicken eggs was conducted, by tissue culture infective dose 50 per cent (TCID(50)) and indirect immunofluorescence assay (IFA). RESULTS: All the cell lines and embryonated egg supported the growth of CHPV and yielded high virus titre. The vertebrate cell lines showed distinct cytopathic effect (CPE) within 4-6 h post infection (PI), while no CPE was observed in insect cell lines. PP-9 cell line was the most sensitive system to CHPV as viral antigen could be detected at 1 h PI by IFA. INTERPRETATION & CONCLUSIONS: Our results demonstrated that all the systems were susceptible to CHPV and achieved high yield of virus. However, the PP-9 cell line had an edge over the others due to its high sensitivity to the virus which might be useful for detection and isolation of the virus during epidemics. PMID- 20716816 TI - Influenza A H1N1 virus in Indian pigs & its genetic relatedness with pandemic human influenza A 2009 H1N1. AB - BACKGROUND & OBJECTIVES: With the emergence of a new reassortant influenza A H1N1 virus that caused the 2009 pandemic it was felt necessary that pigs should be closely monitored for early detection of any influenza virus infection. Therefore, we investigated disease outbreaks with clinical history suggestive for swine influenza reported to our laboratory by owners of affected pig farms in Uttar Pradesh. METHODS: Detection of swine influenza A virus (SIV) was attempted by isolation in embryonated chicken eggs. Presence of virus was detected by haemagglutination (HA) test and RT-PCR for amplification of different gene segments, cloning and sequencing. BLAST analysis of sequence data, phylogenetic analysis and mutation analysis based on HA, NA and matrix genes was done. RESULTS: SIV could be isolated from one farm and all eight gene segments amplified by RT-PCR. BLAST analysis of partial nucleotide sequences and phylogenetic analysis using nucleotide sequence of HA (601 nt), NA (671 nt) and M (1031 nt) genes indicated close genetic relationship of the Indian swine isolate (A/Sw/UP-India-IVRI01/2009) with human pandemic 2009 (H1N1). The HA gene showed close relationship with the viruses of "North American Swine" lineage, whereas the NA and M genes clustered with the viruses of "Eurasian Swine" lineage, indicating a novel HA-NA reassortant. The remaining of 5 genes (NP, PA, PB1, PB2 and NS) belonged to "North American Swine" lineage. INTERPRETATION & CONCLUSIONS: This is perhaps the first report describing swine influenza among Indian pigs caused by an influenza A H1N1 virus sharing close homology with the human pandemic (H1N1) 2009 virus. Further reassortment with circulating influenza viruses must be closely monitored. PMID- 20716817 TI - Safety & immunogenicity of tgAAC09, a recombinant adeno-associated virus type 2 HIV-1 subtype C vaccine in India. AB - BACKGROUND & OBJECTIVES: A phase 1 trial of adeno-associated virus based HIV-1 subtype C vaccine (tgAAC09) was conducted at two sites in Germany and Belgium and one site in India. This paper reports the safety and immunogenicity of tgAAC09 in healthy adult Indian volunteers. METHODS: Between January 2005 and December 2006, 30 consenting volunteers were enrolled in the placebo controlled double-blind dose-escalation trial [3x10(9), 3x10(10) and 3x10(11) DNase resistant particles (DRPs)/ml]. Single injection of the candidate vaccine was administered to ten volunteers randomized in 8:2 ratio in vaccine and placebo arms at each dosage level. RESULTS: The mean age of study volunteers (16 men and 14 women) was 34 yr. Six local reactogenicity events and 14 systemic reactogenicity events like malaise, fever, headache and myalgia were reported, both were dose-dependent. The difference between the adverse events reported by vaccine and placebo recipients (79 and 67%) was not significant. A modest IFN-gamma ELISPOT response [248 spot forming units (SFU)/million cells] was detected in one volunteer from high dose group and low response (56 and 75 SFU/million cells) in two volunteers in low and mid-dose groups. A post-vaccination dose-dependent increase was observed in anti AAV2 neutralizing titres. None of the volunteers showed a positive antibody response to HIV-1. INTERPRETATION & CONCLUSIONS: The trial was a benchmark in phase I clinical evaluation of HIV candidate vaccines in India. The vaccine was generally well tolerated and raised no safety concerns. The vaccine was found to be weakly immunogenic. It is essential to understand the role of pre-existing immunity against vectors and significance of evaluation in a prime-boost strategy. PMID- 20716818 TI - jefA (Rv2459), a drug efflux gene in Mycobacterium tuberculosis confers resistance to isoniazid & ethambutol. AB - BACKGROUND & OBJECTIVES: Drug efflux pumps have been contributing factor(s) in the development of multidrug resistance in various clinically relevant bacteria. During efflux pump gene expression studies on mycobacteria, we have found a previously uncharacterized open reading frame (ORF) Rv2459 to be overexpressed in drug stressed conditions. The objective of the present study was to investigate the role of this ORF as a drug efflux pump, which might add new information in our understanding about the alternative mechanisms of drug resistance in mycobacteria. METHODS: The open reading frame Rv2459 of Mycobacterium tuberculosis encoding a probable drug efflux protein has been cloned using pSD5 E.coli-Mycobacterium shuttle vector and overexpressed in M. tuberculosis H(37)Rv. This ORF was named as jefA. Overexpression of this gene in clones has been verified by real-time reverse transcription PCR. Minimum inhibitory concentrations (MICs) of recombinant as well as non-recombinant clones were determined by resazurin microtitre assay plate method (REMA) with and without efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and verapamil. RESULTS: In recombinant strains of M. tuberculosis, the overexpression of this gene led to an increase in MIC of anti-tubercular drugs isoniazid and ethambutol when tested by REMA. In the presence of CCCP and verapamil, the recombinant strains showed decrease in MIC for these drugs. Bioinformatic analysis has shown a close relation of JefA protein with drug efflux pumps of other clinically relevant bacteria. In homology derived structure prepared from nearest available model, it was observed that amino acids forming TMH 1, 8 and 11 participated in ethambutol specificity and those forming TMH 2, 7 and 10 participated in isoniazid specificity in JefA. INTERPRETATION & CONCLUSION: The increased transcription of jefA leads to increased resistance to ethambutol and isoniazid in M. tuberculosis via efflux pump like mechanism and contributes in the development of resistance to these drugs. JefA amino acid sequence is well conserved among clinically important bacterial genera, which further provides evidence of being a potent drug efflux pump. The involvement in drug resistance and very little homology with any of the human proteins makes JefA important to be included in the list of potential drug targets. PMID- 20716819 TI - A new approach on stress-related depression and anxiety: Neuro-Psycho- Physical Optimization with Radio Electric Asymmetric-Conveyer. AB - BACKGROUND & OBJECTIVES: Chronic social stress is an important factor responsible for the worsening of depressive disorders in humans. In this study we present the relational Neuro-Psycho-Physical Optimization (NPPO) with Radio Electric Asymmetric Conveyer (REAC-CRM) as the treatment to tackle the unconscious dysfunction adjustments carried out by the central nervous system as a response to environmental stresses. METHODS: Psychological stress was measured in a group of 888 patients using the Psychological Stress Measure (PSM) test, a self administered questionnaire. Data were collected immediately before and after the 4-wk therapy cycle. The detection of anxiety and depression clusters by PSM test has been based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR, APA, 2000) criteria. Six hundred and eighty eight patients (212 males, 476 females, average PSM test total scores 107.9 +/- 23.13) were treated with REAC CRM therapy; 200 (64 males, 136 females, average PSM test total scores 107.86 +/- 25.80) were treated with "placebo REAC-CRM therapy"and used as control. RESULTS: This study showed a significant reduction in scores measuring subjective perceptions of stress in the patients treated with a cycle of REAC-CRM therapy. At the end-point the number of patients reporting symptoms of stress-related anxiety and depression on the PSM test was significantly reduced (P<0.001); in the placebo group no significant difference was highlighted. INTERPRETATION & CONCLUSIONS: NPPO therapy with a cycle of REAC-CRM was shown to reduce subjective perceptions of stress measured by the PSM test and in particular, symptoms of stress-related anxiety and depression. PMID- 20716820 TI - Prevalence and determinants of depression in type 2 diabetes patients in a tertiary care centre. AB - BACKGROUND & OBJECTIVES: Depression is common among people with diabetes and it is associated with poor outcomes. This study was carried out to investigate the prevalence and determinants of depression in patients with established type 2 diabetes (T2DM) attending a tertiary care hospital in north India. METHODS: Patients with established T2DM were evaluated for depression by administering the nine-item PHQ-9 (Hindi version). Binary logistic regression model was used to examine association between predictor variables and risk of depression. Results were expressed as odds ratio and 95 per cent confidence interval. Cronbach alpha was calculated to assess internal consistency of PHQ-9. RESULTS: Patients with T2DM (n=300) were evaluated [147(49%) male and 153(51%) female]. The median duration of diabetes (IQ) was 8(4-13) yrs. Of the study patients, 68 (23%) met the criteria for major depression, 54 (18%) for moderate depression and the remaining 178 (59%) had no clinically significant depression. Depression was strongly associated with age >54 yr (OR 1.26, 95% CI 1.02-1.67; P<0.05), central obesity (OR 1.34, 95% CI 1.04-1.64; P<0.001), neuropathy (OR 1.94, 95% CI 1.03 3.66; P=0.002), nephropathy (OR 1.81, 95% CI 1.02-3.21; P=0.041), peripheral vascular disease (OR 6.08, 95% CI 1.07-34.6; P=0.042), diabetic foot disease (OR 2.32, 95% CI 1.06-5.86; P<0.001) and pill burden (>4) (OR 1.27, 95%CI 1.01-1.44; P=0.035 ). However, the likelihood of depression was not significant with duration of diabetes and insulin use. INTERPRETATION & CONCLUSION: This study showed high prevalence of depression in patients with T2DM. The risk factors for depression were age, central obesity, diabetic complications particularly neuropathy and diabetic foot disease and increased pill burden. PMID- 20716821 TI - Qualitative high performance thin layer chromatography (HPTLC) analysis of cannabinoids in urine samples of Cannabis abusers. AB - BACKGROUND & OBJECTIVES: Cannabis is one of the most commonly abused drugs worldwide. There is a distinct clinical correlation between cannabis abuse and mental disorders. However, it is essential to establish cannabis intake in the abusers in order to establish causality between cannabis and psychiatric illness. The limitations of current detection methods using commercial cassettes prompted us to standardize the method of extraction and detection of cannabinoids in the urine samples of cannabis abusers attending a de-addiction centre in south India. METHODS: In this study, diagnostic tests on 102 male patients suspected with cannabis abuse were done. Liquid-liquid extraction of cannabinoids from urine was done and screened by Duquenois-Levine, fast blue B salt and p dimethylaminobenzaldehyde (p-DMAB) tests. All the results were confirmed by high performance thin layer chromatography (HPTLC). Samples were considered positive for cannabis based on the positive indication in colour test and by detection of 11-nor-delta(9) tetrahydrocannabinol-9-carboxylic acid (THC-COOH) on HPTLC. RESULTS: Based on the colour tests and HPTLC, cannabis abuse was detected in 64 of 102 patients tested. HPTLC method was found to be sensitive for detection and possible quantitation of THC-COOH. INTERPRETATION & CONCLUSION: We report the standardization and utility of cannabinoid extraction, screening and detection by HPTLC in the urine samples of cannabis abusers. The HPTLC method was found to be high throughput, sensitive, reproducible and cost-effective compared to commercial kits. PMID- 20716822 TI - Effect of hydrostatic pressure of various magnitudes on osteoarthritic chondrocytes exposed to IL-1beta. AB - BACKGROUND & OBJECTIVES: Several in vitro studies have shown the importance of mechanical compression or hydrostatic pressure (HP) as a modulator of cartilage metabolism. The present study was undertaken to evaluate the in vitro effects of cyclical low HP (1-5 MPa) and continuous high HP (24 MPa) applied in the presence or absence of interleukin (IL)-1beta on human osteoarthritis (OA) chondrocytes. METHODS: Chondrocytes obtained from OA cartilage were cultivated for 48 h and then exposed to pressurization in the presence or absence of IL-1beta. After pressurization, the culture medium was collected to detect the amount of proteoglycans (PG) and nitric oxide (NO) and the chondrocytes were immediately fixed for transmission electron microscopy (TEM) and processed for immunocytochemistry to localize the inducible nitric oxide synthase (iNOS). RESULTS: A significant increase in the level of PG and a small, non-significant, decrease in NO production were observed upon exposure to cyclical low HP. On the other hand, exposure to continuous high HP resulted in a significant decrease in the PG levels and a significant increase in NO production. The presence of IL 1beta led to a significant decrease in PG levels as well as a significant increase in NO production. The cyclical low HP did not increase the PG levels significantly but caused a statistically significant decrease in NO production in cultures damaged with IL-1beta. The continuous high HP in chondrocyte cultures stimulated with IL-1beta did not significantly decrease PG production, but significantly increased NO production. The results concerning metabolic production were further confirmed by morphological findings obtained by TEM and immunocytochemical studies. INTERPRETATION & CONCLUSION: The findings of this study confirmed that the response of chondrocytes varies with magnitude and frequency of HP. These findings are important to understand aetiopathogenetic mechanisms of OA and to find out which type of physical activity may be best suited for the prevention and therapy of OA. PMID- 20716823 TI - Evaluation of the anti-ulcer activity of NR-ANX-C (a polyherbal formulation) in aspirin & pyloric ligature induced gastric ulcers in albino rats. AB - BACKGROUND & OBJECTIVES: The aetiology of gastric ulcers is not completely understood and continuous use of anti-ulcer agents leads to many side effects. In this study we evaluated the anti-ulcer efficacy of a polyherbal formulation with potent antioxidant activity in aspirin and pyloric ligature induced gastric ulcers in rats. METHODS: The efficacy of the polyherbal formulation NR-ANX-C (composed of the extracts from Withania somnifera, Camellia sinensis, Ocimum sanctum, shilajith and triphala) was evaluated in terms of antioxidant potential as assessed in terms of protection from lipid peroxidation and the antiulcer activity as seen by the area of gastric lesions, gastric juice volume, gastric pH, total acidity and total adherent gastric mucus content. RESULTS: In our study, NR-ANX-C (25 and 50 mg/kg) was more efficacious than ranitidine in reducing ulcer index in both the models. At the highest dose tested (50 mg/kg), NR-ANX-C was comparable to omeprazole in preventing ulcer formation in the pyloric ligature model. NR-ANX-C showed a dose- dependent decrease in gastric juice volume and total acidity in both the models. A dose-dependent increase in gastric pH and total adherent gastric mucus was also seen in NR-ANX-C treated groups. The extent of lipid peroxidation was also reduced in the test drug treated groups. INTERPRETATION & CONCLUSION: Based on our findings, we presume that the cytoprotective, anti-secretary and antioxidant properties of NR-ANX-C were responsible for its anti-ulcer activity. These findings suggest the potential for use of NR-ANX-C as an adjuvant in the treatment of gastric ulcer. PMID- 20716824 TI - Research funding in India: need to increase the allocation for public health. PMID- 20716825 TI - Ethical considerations in developing a national vaccine policy. PMID- 20716826 TI - Policy document: evidence-based national vaccine policy. PMID- 20716827 TI - Issue raised about incomplete reporting of research in press releases. PMID- 20716828 TI - Revisiting the free radical theory using next-generation sequencing technology. PMID- 20716829 TI - Prevalence of abnormal cervical cytology among subfertile Saudi women. AB - BACKGROUND AND OBJECTIVES: Since cervical cancer is reportedly the seventh most frequent cancer in women in Saudi Arabia and the eighth most frequent cancer among women aged between 15 and 44 years, we wanted to determine the prevalence of abnormal cervical cytology among subfertile women attending the reproductive medicine unit of a tertiary care center in Saudi Arabia. METHODS: This was a retrospective, cross-sectional, hospital-based study. A Pap smear was done for 241 of 493 (48.9%) subfertile women from January 2008 through February 2009. RESULTS: The Pap smear was normal in 166 of 241 patients (67.9%), abnormal in 71 (29.5%), and unsatisfactory for evaluation in 4 (1.7%). According to the revised Bethesda system, epithelial cell abnormality was found in 7 (2.9%), inflammation in 55 (22.8%), and infection in 9 (3.7%) patients. Epithelial cell abnormalities were further classified as atypical squamous cells of undetermined significance (ASC-US) (n=3, 42.8%), atypical squamous cells of high grade (ASC-H) (n=1, 14.3%), low-grade squamous intraepithelial lesion (LSIL) (n=2, 28.5%), and glandular cell abnormalities (AGS) (n=1, 14.3%). CONCLUSION: The high prevalence of abnormal cervical cytology in our subfertile women accentuates the need for screening in patients eligible for in vitro fertilization. In addition, a well organized screening program for cervical cell abnormalities at the national level should be implemented to allow identification of subfertile women at risk so that potentially life-saving measures can be undertaken early. PMID- 20716831 TI - Cardioprotection by hormetic responses to aldehyde. AB - Everyone encounters various stressors (causes of stress), such as psychological pressure, mental fluctuations, and physical burdens, in their everyday life. It is well accepted that the highest levels of perceived stress correlate with early onset of cardiovascular disease. Conversely, appropriate (mild to moderate) stressors, such as physical activity, have been shown to promote health. This bidirectional dose - response relationship of treatments that are beneficial at low levels but noxious at higher levels is referred to as "hormesis". In the fields of toxicology, pharmacology, radiation biology, and medicine, the significance of the biological effects of low-level exposure to various agents has attracted considerable attention. It is very important to understand how biological systems respond to low levels of stress and their implications within society. Aldehydes, the major endproducts of lipid peroxidation, have been implicated in the pathogenesis of oxidative stress-associated diseases. In addition to the pathogenic effect associated with oxidative stress, sublethal levels of aldehydes interact with signaling systems to upregulate the expression of genes to counteract the stressor challenge and to re-establish homeostasis. The present review article discusses current discoveries regarding the hormetic response to aldehyde and its clinical significance in cardioprotection. PMID- 20716832 TI - Catheter ablation is established as a treatment option for atrial fibrillation- is catheter ablation established as a treatment option of atrial fibrillation? (Pro). AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and it has a significant impact on morbidity and mortality. Large randomized trials have failed to demonstrate a benefit for mortality of the pharmacological rhythm control strategy as compared with the rate control strategy, indicating that rate control may be an adequate treatment for AF. However, further study determined that the presence of AF at the time of study termination was a more potent predictor of mortality than the treatment strategy, suggesting the importance of sinus rhythm. On the other hand, catheter ablation recently has emerged as an alternative treatment option to pharmacological therapy for AF. Although AF ablation is an invasive strategy, over the past decade its efficacy has increased and the complication rate has decreased with the growing experience of operators and evolving technology. Moreover, the ablation methodology, such as pulmonary vein isolation based ablation, is consistent worldwide and the success rate of AF ablation, especially in paroxysmal AF, is similar. Therefore, catheter ablation is established as a treatment option for AF. PMID- 20716830 TI - A guideline for the inpatient care of children with pyelonephritis. AB - BACKGROUND AND OBJECTIVES: Febrile urinary tract infections and pyelonephritis are common in children and frequently lead to hospitalization for management, especially in the child who appears toxic. The American Academy of Pediatrics (AAP) practice parameter on the diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children provides experience and evidence-based guidelines for the practitioner caring for children between the ages of 2 months to 2 years. No established guideline exists for older children and the AAP guideline does not specifically focus on inpatient care. METHODS: We conducted a comprehensive review of recently published literature and practice guidelines to develop a consensus on the inpatient diagnosis and management of children with pyelonephritis. RESULTS: Eight recommendations are proposed for the diagnosis and management, including revised guidelines for the imaging studies postpyelonephritis on the basis of current best evidence. CONCLUSION: Proper diagnosis of pyelonephritis, timely initiation of appropriate therapy and identification of children at risk for renal injury will help to reduce immediate as well as long-term complications due to chronic kidney disease. PMID- 20716833 TI - Is catheter ablation a mature fruit for treatment of atrial fibrillation?--is catheter ablation established as a treatment optionof atrial fibrillation? (Con). AB - In recent years, catheter ablation for atrial fibrillation (AF) has evolved in tandem with the results from many large-scale randomized clinical studies with antiarrhythmic drugs. The current situations seem to be a concerted move from pharmacological to non-pharmacological treatment. However, the clinical studies with medications have revealed an important viewpoint for the management of AF: the importance of the core aim of AF treatment and the position of electrographic findings as a surrogate marker. Catheter ablation is under challenge as the answers to these issues are awaited. Moreover, many problems with this invasive therapy are to be solved, most of them deriving from the vague definition of success of ablation and no standardization of the technique. For these reasons, catheter ablation is still on the way to maturation and multicenter studies in Japan are required to set a fair benchmark for Japanese patients, drawing a lesson from randomized clinical studies with medications. PMID- 20716834 TI - Cardiovascular side-effects of modern cancer therapy. AB - Recent advances in chemotherapy have substantially improved the prognosis of cancer patients. However, many anticancer drugs, especially newly developed ;molecular-target drugs', such as the anti-HER2 blocking antibody and the anti vascular endothelial growth factor antibody, have serious cardiovascular side effects such as heart failure, thromboembolism, severe hypertension and lethal arrhythmia, which interrupt cancer treatment and decrease the patient's quality of life. Despite the increasing clinical significance, cardiologists have not been focusing enough of their attention on this issue. The major cardiovascular complications associated with anticancer drugs, and current diagnosis, treatment and prevention strategies are reviewed. Close collaborations between oncologists and cardiologists is necessary to tackle cardiovascular complications and advance cancer treatment. PMID- 20716835 TI - Study on cutoff value setting for differential diagnosis between Graves' disease and painless thyroiditis using the TRAb (Elecsys TRAb) measurement via the fully automated electrochemiluminescence immunoassay system. AB - The purposes of this study are to set the Elecsys TRAb cutoff value by which GD and PT can be accurately diagnosed simply; and to investigate the usefulness of the vascularity index (VI) obtained from power Doppler sonography (PDS). Using 109 normal controls, 186 GD patients, and 109 PT patients who were diagnosed through Tc-99m uptake, we set the cutoff value by conducting ROC analysis on the Elecsys TRAb values. The cutoff value as a result of the ROC analysis on the Elecsys TRAb values of the normal controls and GD patients was 0.8 IU/L with 100% of sensitivity and specificity. Because all 89 cases (81.6% of the entire PT cases) with Elecsys TRAb =<0.8 IU/L are PT, the cutoff =<0.8IU/L can thus be diagnosed as PT. In contrast, because all 166 cases (88.7% of the entire GD) with Elecsys TRAb >=3.0 IU/L except for one case of PT are GD, the cutoff >=3.0 IU/L can be diagnosed as GD. So Elecsys TRAb between 0.8-3.0 IU/L was dubbed gray zone (GZ). Finally, the cutoff value of 1.5 IU/L from the ROC on the PT and GD cases was chosen as the cutoff with 96.2% of sensitivity and 94.6 of specificity. All PDS VI >=80% were GD including 4 of 6 cases with GZ and all PDS VI <50% plus Elecsys TRAb-negative cases were PT including 4 of 5 cases with GZ. In conclusion, Elecsys TRAb cutoff and VI value for differential diagnosis between GD and PT has been set successfully. PMID- 20716836 TI - Low serum albumin levels and in-hospital adverse outcomes in acute coronary syndrome. AB - Epidemiological studies have demonstrated an association between low serum albumin levels and coronary heart disease and mortality. Nevertheless, the impact of a low serum albumin level during acute coronary syndrome has not yet been established. The aim of the present study was to investigate whether low serum albumin levels are associated with adverse outcomes in acute coronary syndrome. We enrolled 82 consecutive patients with acute coronary syndrome from whom venous blood for serum albumin measurement was drawn immediately upon hospital admission. Thirty-five patients had a low albumin level (hypoalbuminemia) and 47 had a normal albumin level (normoalbuminemia). In-hospital adverse outcomes (death, acute heart failure, cardiogenic shock, and reinfarction) were recorded during hospitalization in the intensive coronary care unit. The results of our study showed that the incidence of in-hospital adverse outcomes was 43%, with death occurring in 8 patients (10%). In-hospital adverse outcomes occurred more frequently in patients presenting with hypoalbuminemia, whereas mortality did not differ significantly. Univariate analysis showed that hypoalbuminemia was associated with a 2.8-fold greater risk of developing adverse outcomes. This risk was greater in the subgroup of NSTEACS (5.4-fold increased risk), but not in those with STEMI. Adjustment with other covariates revealed that hypoalbuminemia did not predict independently in-hospital adverse outcomes. It interacted with other predictors, especially Killip class II-IV, which was consistently an independent predictor of in-hospital adverse outcomes. PMID- 20716837 TI - Bare metal stent restenosis is benign clinical entity in Japanese patients. AB - Recently, several studies have showed that bare metal stent (BMS) restenosis is not a benign clinical entity. However, clinical presentation of BMS restenosis in Japanese patients has not been fully evaluated. Follow-up coronary angiography after BMS implantation was performed in 473 patients with 523 lesions. Of these, BMS restenosis was observed in 167 lesions (31.9%). Clinical presentation of BMS restenosis was classified into 4 categories: 1) acute myocardial in-farction, 2) unstable angina, 3) stable angina, and 4) no symptom. Acute myocardial infarction (0%) and unstable angina (3.8%) were infrequent clinical presentations in patients with BMS restenosis compared to stable angina (26.9%) and no symptom (69.2%). BMS restenosis may be a benign clinical entity in Japanese patients. PMID- 20716838 TI - Cobalt chromium coronary stents and drug-eluting stents in real practice. AB - Cobalt chromium stents (CCS) are seldom compared to drug-eluting stents (DES) for coronary intervention in published clinical trials. We evaluated the daily usage patterns of CCS in comparison to DES unconstrained by eligibility criteria. We compared consecutive patients (n = 303) with de novo lesions treated exclusively with a CCS to 432 patients treated exclusively with a DES. Patients in the CCS group were older, frequently had heart failure, renal failure, prior coronary balloon angioplasty, prior stroke, more comorbidities, and more multivessel disease than the DES group. The DES group had longer and more type C and left anterior descending (LAD) coronary artery lesions. The in-hospital major adverse cardiac events (MACE; death, myocardial infarction, stroke and target lesion revascularization (TLR)) were similar. At 6 months, the cumulative rate of MACE was 12.9% in the CCS group and 5.6% in the DES group (P < 0.001), and this was driven by TLR. The rates of stent thrombosis were similar in CCS (0.9%) and DES (1.0%) patients. In conclusion, the CCS were used in clinically higher risk patients, while DES were used in more severely diseased coronary arteries. Drug eluting stent use resulted in lower rates of clinically driven repeat revascularization with similar rates of death, MI, stroke, and stent thrombosis. PMID- 20716839 TI - Effect of Tai Chi training on baroreflex sensitivity and heart rate variability in patients with coronary heart disease. AB - Tai Chi is a traditional Chinese conditioning exercise that has been used to integrate slow movements, controlled breathing, and mental concentration. The aim of the study was to determine whether Tai Chi training in addition to cardiac rehabilitation would result in a shift toward increased vagal activity of autonomic markers, such as baroreflex sensitivity (BRS) and heart rate variability (HRV). Twenty patients with coronary heart disease (CHD) (male/female: 13/7, mean age: 67.8 +/- 4.2 years, mean interval time after a coronary event: 19.8 months) completed this study. The Tai Chi group (n = 10) practiced supervised Tai Chi training once a week and home-based Tai Chi training three times a week together with conventional cardiac rehabilitation for one year. The control group (n = 10) conducted the conventional cardiac rehabilitation only. BRS and HRV were evaluated at the baseline and after one year of Tai Chi training. Compared with the controls, patients in the Tai Chi group showed statistically significant improvement in BRS (P = 0.036). These associations persisted after adjustment for age and other covariates. On the other hand, there were no significant trends seen in HRV. Additional Tai Chi training during cardiac rehabilitation may augment reflex vagal regulation, which adds importantly to knowledge of cardiac rehabilitation on autonomic regulation and clinical management of CHD. PMID- 20716840 TI - Symptoms of atrial fibrillation in patients with and without subsequent permanent atrial fibrillation based on a retrospective questionnaire survey. AB - The aim of the present study was to determine whether symptoms of atrial fibrillation (AF) differ between patients with and without subsequent permanent AF. Sixty-four patients (68 +/- 10 years old, 45 males) were recruited. AF follow up was started at the age of 61 +/- 10 years and accomplished in a median period of 4.9 years (396 person-years). Permanent AF, defined as lasting > 180 days, developed in 17 patients (14 males) (43 per 1000 person-years). The AF follow-up period was longer in the permanent AF group than in the non-permanent AF group (median, 9.8 versus 4.2 years, P < 0.001). For baseline characteristics, hypertension was less frequent in the permanent AF group than in the nonpermanent AF group (18% versus 45%, P < 0.05). A retrospective questionnaire survey regarding initial AF symptoms was conducted. The severity of AF symptoms by a 4 grade scale was significantly milder in the permanent AF group than in the nonpermanent AF group (P < 0.05). Cox proportional hazards model analysis revealed that the severity of initial AF symptoms was related to the subsequent development of permanent AF (hazard ratio 0.46 per grade, 95% confidence interval 0.23 - 0.93, P < 0.05), but age, gender, hypertension, diabetes mellitus, organic heart disease, and left atrial dimension were not. The permanent AF-free rate was significantly lower in 33 patients with mild symptoms than in 31 patients with severe symptoms (log-rank test, P < 0.05). These results point to an inconspicuous feature in the development of permanent AF. PMID- 20716841 TI - Efficacy and safety of continuous hemodiafiltration for acute decompensated heart failure. AB - The mortality of heart failure patients with renal insufficiency is high, and these patients tend to develop diuretic resistance. Under these conditions, continuous hemodiafiltration (CHDF) is a possible alternative volume reduction therapy to diuretics. However, its efficacy and safety are not clear. Between April 2005 and March 2008, 248 patients with acute decompensated heart failure were admitted to the CCU of Kyoto City Hospital. Of those patients, 31 (20 volume overloaded heart failure, 11 cardiogenic shock) received CHDF therapy, and their weight loss, acute hemodynamic changes, and clinical outcome were assessed to evaluate the efficacy and safety of CHDF therapy. CHDF was performed for 6.5 +/- 6.5 days. There was no significant change in acute hemodynamics after CHDF initiation. In the volume overloaded heart failure (VH) group, significant weight loss was observed at 24 hours and 48 hours after CHDF initiation (P < 0.001). In hospital mortality of the VH group and cardiogenic shock (CS) group were 10.0% and 54.5%, respectively. CHDF for acute decompensated heart failure (ADHF) is a safe, effective, and reliable volume reduction therapy for volume overloaded heart failure. Further investigation is required to assess the effectiveness of CHDF for cardiogenic shock. PMID- 20716842 TI - Fixed-dose telmisartan/hydrochlorothiazide in comparison with losartan/hydrochlorothiazide in decreasing serum hepatocyte growth factor and improving endothelial dysfunction in hypertensive patients. AB - Combined treatment with an angiotensin II receptor blocker and hydrochlorothiazide (HCT) is advocated to control hypertension (HT). Hepatocyte growth factor (HGF) may be a new marker to evaluate endothelial dysfunction (ED), which is a potential target in treating HT. The aim of the present study was to compare the effects of Telmisartan/HCT with Losartan/HCT on serum HGF and ED in hypertensive patients. Hypertensive patients were randomly divided into a Telmisartan/HCT (group T) or Losartan/HCT group (group L) and received one tablet of either drug per day for 8 weeks. Serum HGF, nitric oxide (NO), plasma von Willebrand factor (vWF), and endothelin (ET) were measured before treatment and after 8 weeks of treatment. Twenty healthy subjects were selected as controls (control group). HGF, vWF, ET, and the ET/NO ratio were higher, and NO was lower in hypertensive patients than those in the control group (all P < 0.01). After treatment for 8 weeks, HGF, vWF and ET decreased, and NO increased significantly in both groups (all P < 0.01). The reductions in BP and HGF and increase in NO (DeltaNO) were not significantly different between the two groups (all P > 0.05), but the reductions in vWF and ET (DeltaET) and DeltaET/DeltaNO ratio were more obvious in group T than in group L (all P < 0.01). There was no significant correlation between the changes in most of the measured parameters and the extent of BP reduction in either group. Both Telmisartan/HCT and Losartan/HCT could decrease serum HGF and improve ED, which was independent of the antihypertensive effects. However, the improvement in ED may be superior with Telmisartan/HCT than Losartan/HCT when the BP-lowering effects are the same. PMID- 20716843 TI - Cumulative episodes of rejection altered myocardial sarcoplasmic reticulum Ca(2+) ATPase and ryanodine receptor-2 mRNA expression in heart transplant recipients. AB - The aim of the present study was to investigate the relationship between rejections and gene expression of Ca(2+)-handling proteins in heart transplant recipients. Thirty-seven heart transplant recipients underwent routine endomyocardial biopsy. Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) and ryanodine receptor-2 mRNAs in endomyocardial tissue were quantified by a real time quantitative reverse transcription polymerase chain reaction (RT-PCR) method. Rejections were diagnosed according to the conventional International Society for Heart and Lung Transplantation criteria. Patients were classified as follows; group AR(+) (n = 9) with rejection grade of 2 or higher versus group AR( ) (n = 28) with rejection grade of 0, 1a or 1b at the time of biopsy, and group Rec-AR(+) (n = 6) with a history of more than 4 episodes of treatment required rejection versus group Rec-AR(-) (n = 31) without history of recurrent rejection. The mRNA levels of the SERCA2/GAPDH ratio and ryanodine receptor-2/GAPDH ratio were not different between group AR(+) and group AR(-); however, they were reduced in group Rec-AR(+) more than in group Rec-AR(-) (0.83 +/- 0.07 versus 0.90 +/- 0.07, P = 0.034, 0.74 +/- 0.06 versus 0.84 +/- 0.10, P = 0.027, respectively). A single episode of on-going rejection would not affect myocardial Ca(2+)-handling proteins; however, cumulative rejection episodes might alter the gene expression of myocardial Ca(2+)-handling proteins in heart transplant recipients. PMID- 20716844 TI - Clinical course and outcome of heart transplant recipients: single center experience at the National Cardiovascular Center in Japan. AB - The number of heart transplant (HTx) surgeries in Japan is expected to increase under the Revised Organ Transplant Law. To date, among 69 HTx surgeries performed in Japan, 27 operations (39.1%) were performed at our institution, the National Cardiovascular Center (NCVC), located in Osaka. We have reviewed the outcomes of HTx conducted at NCVC during a 10 year period (May 1999 to January 2009). Among 27 heart transplant recipients at NCVC, the clinical charts of 26 recipients whose post-HTx period exceeded 1 year were retrospectively reviewed and compared to data from the International Society for Heart and Lung Transplantation (ISHLT) Registry. The survival rate of our recipients was 96.2% at 10.8 years, which was excellent even compared to the ISHLT Registry. The immunosuppressive regimen at NCVC was equivalent to that of the ISHLT Registry, except for more frequent use of Muromonab-CD3 (26.9% versus 3.3%, P < 0.0001) and an initial CSA-based regimen (65.3% versus 34.4%, P < 0.001). The drug we use for induction therapy has been recently changed from Muromonab-CD3 to Basiliximab. The incidences of post-HTx hypertension, diabetes, hyperlipidemia, and renal insufficiency were significantly less in patients at NCVC compared to those in the ISHLT Registry, however, the incidence of transplant coronary artery disease (TxCAD) was almost identical. Clinical review of post-HTx outcome at NCVC can provide useful information for Japanese transplant cardiologists who will engage in HTx management. PMID- 20716845 TI - Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. AB - Recently, platelet-derived growth factor (PDGF) has been implicated in the abnormal proliferation and migration of pulmonary artery vascular smooth muscle cells. Imatinib meslylate, a PDGF receptor antagonist, has been reported to dramatically improve pulmonary arterial hypertension (PAH) in some human cases as well as animal models. Five patients with PAH (3 scleroderma-associated PAH and 2 idiopathic/familial PAH) taking no less than 2 PAH agents were treated with low dose imatinib (100 mg/day) for 24 weeks. Imatinib was titrated up to 200 mg/day unless major complications were observed. Before and after the treatment, right heart catheterization, cardiopulmonary exercise test, respiratory function test, and plasma concentration measurements of PDGF-BB and vascular endothelial growth factor (VEGF) were performed. Plasma PDGF-BB levels were significantly decreased after 12 weeks of treatment (P = 0.04), while VEGF did not change. Although 24 week administration of imatinib did not show a significant effect on hemodynamics and exercise capacity, 2 patients with high plasma PDGF-BB levels showed a good initial response of more than a 15% decrease in pulmonary vascular resistance. Diffusion capacity of the lung for carbon monoxide significantly improved after 12 weeks of treatment (P < 0.01) and this improvement tended to be sustained for 24 weeks (P = 0.05). Renal dysfunction was observed in 3 patients during imatinib therapy. The upregulated PDGF-BB in patients with PAH could be suppressed by imatinib treatment, and also seemed to be one of the determinant factors for its efficacy. PMID- 20716846 TI - The role of MEKK1 in hypertrophic cardiomyopathy. AB - MEKK1 is a ubiquitously expressed mitogen activated protein kinase that is involved in tissue remodeling in a variety of settings including carotid artery blood flow cessation, wound healing, and breast adenocarcinoma intravasation. Here, we have tested the function of MEKK1 in genetic hypertrophic cardiomyopathy (HCM). MEKK1 was genetically deleted in C57Bl6/J mice expressing a mutant alpha myosin heavy chain (HCM-MEKK1(-/-)). The absence of MEKK1 in HCM resulted in a more pronounced hypertrophy when compared to HCM mice with the MEKK1 gene intact without further increases in atrial natriuretic factor and beta-myosin heavy chain (MyHC) expression and fibrosis. Since MEKK1 is required for the induction of several tissue proteases, we tested the hypothesis that cardiac enlargement of HCM- MEKK1(-/-) mice was due to altered expression of urokinase-type plasminogen activator (uPA), JunB, matrix-metalloproteinase (MMP), and tissue inhibitors of MMPs (TIMPs). Because of its role in preventing apoptosis, we also tested the loss of MEKK1 on apoptotic mediators Bcl-2, cytochrome C, caspase-9, and caspase 3. uPA expression was decreased while JunB, MMP-9, caspase-9, and caspase-3 activities were elevated in HCM- MEKK1(-/-) hearts when compared to MEKK1(-/-), wild-type (WT), and HCM mice. Bcl-2 and Cyt C expression was elevated only in HCM mice. We conclude that the absence of MEKK1 induces a more pronounced cardiac hypertrophy to HCM through altered expression of proteases implicated in cardiac remodeling and increased apoptosis. PMID- 20716848 TI - Optical coherence tomography findings in a case of acute coronary syndrome caused by coronary vasospasm. AB - Culprit lesions of acute coronary syndrome (ACS) were observed by intravascular optical coherence tomography (OCT). OCT images revealed diffuse intimal thickening, reduced lumen area with vascular contraction, and thrombus formation. No OCT images of atherosclerotic plaque disruption were found. Vascular contraction disappeared and the lumen was dilated after intracoronary injection of nitroglycerin. The main mechanism of ACS in this case was therefore considered to be coronary vasospasm. OCT may be useful for evaluating the mechanism of ACS. PMID- 20716847 TI - Effects of sarcolemmal Ca(2+) entry, ryanodine function, and kinase inhibitors on a rabbit model of heart failure. AB - QT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca(2+) cycling is the proximate cause of EADs, and Ca(2+) cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP. In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 +/- 1.3 minutes and 10.3 +/- 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01). KB-R7943, W-7, and KN-93 accelerated onset of TdP. Blockades of L type Ca(2+) channel, ryanodine channel, and protein kinase A prevent dofetilide induced TdP, suggesting roles for intracellular Ca(2+) overload and Ca(2+) signaling pathways in drug-induced TdP. PMID- 20716849 TI - Primary aldosteronism with right-dominant heart failure. AB - A 48 year-old obese male with hypertension was admitted to our department because of severe right-dominant heart failure. His heart rhythm was 2:1 atrial flutter and the left ventricle was diffusely hypertrophic and hypokinetic. Primary aldosteronism was diagnosed based on severe hypokalemia (2.6 mEq/L) and a low renin-high aldosterone state with hypertension despite the use of an angiotensin II receptor blocker, but its etiology could not be clarified with computed tomography, adrenal scintigraphy, and adrenal vein sampling. Ascites and edema rapidly worsened. Ascites aspiration was performed daily, until serum potassium was normalized by a full dose of an aldosterone receptor blocker (spironolactone 100 mg/day). A diuretic (furosemide) was then added. Rate control of atrial flutter was obtained with a beta-adrenergic blocker, and anticoagulation therapy was started. His heart failure was successfully controlled. Coronary arteries were normal on coronary arteriograms, and an endomyocardial biopsy sample obtained from the left ventricle did not show any specific pathological findings. Blood pressure was well controlled with the full dose of the aldosterone receptor blocker, but he died one year later due to intracerebral hemorrhage. As his heart failure was right dominant, we believe that its etiology may have been hyperaldosteronism-induced cardiomyopathy, and not advanced hypertensive heart disease. PMID- 20716850 TI - [Role of cytokine secretion of human keratinocytes in dermatophytosis]. AB - The clinical presentation of dermatophytosis depends on species of the infecting fungus. The infections caused by the anthropophilic species tend to be chronic and intractable, and the resultant inflammation is minimal. On the other hand, the infections caused by the geophilic and zoophilic species tend to be self healing, and the resultant inflammation is more severe. We investigated the role of cytokine secretion of human keratinocyte during dermatophyte infections: Arthroderma benhamiae, a zoophilic dermatophyte, and Trichophyton tonsurans, an anthropophilic dermatophyte. The results demonstrate that keratinocytes secrete a broad spectrum of cytokines including proinflammatory cytokines, chemokines, and immunomodulatory cytokines in response to A. benhamiae infection, whereas T.tonsurans infection stimulates the production of only a limited number of cytokines. Such differential cytokine secretion of the keratinocytes in response to infection by dermatophyte species may reflect the distinct inflammatory responses in the skin. PMID- 20716851 TI - Cell surface hydrophobicity and adhesion: a study on fifty clinical isolates of Candida albicans. AB - Cell surface hydrophobicity (CSH) of 50 clinical isolates of Candida albicans was studied, and values varied broadly in the range 2% to 41%. Purpose of the present work was to investigate correlation of CSH with the C. albicans adherence to solid surfaces, if any. To elucidate this, adhesion to the polystyrene model surface was studied for all the clinical isolates. Adherence varied in the range of 79 to 478 cells per microscopic field. Results indicated no correlation between CSH of the clinical isolates and their adhesion to polystyrene. PMID- 20716852 TI - [Therapeutic effect of oligonol, a low-molecular polyphenol formulation derived from lychee fruits on murine oral candidiasis]. AB - We assessed the potential of oligonol, a low molecular polyphenol formulation prepared from lychee fruits, for treatment of oral candidiasis using a murine model. Oligonol at concentration of more than 313 microg/ml inhibited the mycelial growth of Candida albicans in vitro. When 50 microl of oligonol (20 mg/ml ) was administered three times into the oral cavity of orally Candida infected mice, the number of viable Candida cells in the oral cavity was reduced significantly and the score of lesions on the tongue recovered on day 2. These findings suggest that oligonol could have potential as a food component supporting anti- Candida treatment. PMID- 20716853 TI - Matings among three teleomorphs of Trichophyton mentagrophytes. AB - Three genetically hybrid F1 progenies produced between a clinical isolate of Arthroderma simii (KMU4810) and a tester strain of A. vanbreuseghemii (RV27961) were crossed with two tester strains of A. vanbreuseghemii (RV27961 and RV27960) and a tester strain of A. benhamiae (RV30001), respectively. Three crossings yielded hybrid second progenies. Another interspecies crossing between A. simii (KMU4810) and a tester strain of A. benhamiae (RV26680) yielded one hybrid F1 progeny (Asb57). The second crossings of F1 progeny (Asb57) with A. vanbreuseghemii (RV27961) and A. benhamiae (RV30001) yielded many hybrid second progenies. Some hybrid second progenies produced between F1 progeny and A. vanbreuseghemii were confirmed to have genes from three species. The gene exchangeability among three Arthroderma species was shown and the meaning of these events discussed. PMID- 20716854 TI - [A study for testing the antifungal susceptibility of yeast by the Japanese Society for Medical Mycology (JSMM) method. The proposal of the modified JSMM method 2009]. AB - The Japanese Society for Medical Mycology (JSMM) method used for testing the antifungal susceptibility of yeast, the MIC end point for azole antifungal agents, is currently set at IC(80). It was recently shown, however that there is an inconsistency in the MIC value between the JSMM method and the CLSI M27-A2 (CLSI) method, in which the end- point was to read as IC(50). To resolve this discrepancy and reassess the JSMM method, the MIC for three azoles, fluconazole, itraconazole and voriconazole were compared to 5 strains of each of the following Candida species: C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei, for a total of 25 comparisons, using the JSMM method, a modified JSMM method, and the CLSI method. The results showed that when the MIC end- point criterion of the JSMM method was changed from IC(80) to IC(50) (the modified JSMM method) , the MIC value was consistent and compatible with the CLSI method. Finally, it should be emphasized that the JSMM method, using a spectrophotometer for MIC measurement, was superior in both stability and reproducibility, as compared to the CLSI method in which growth was assessed by visual observation. PMID- 20716855 TI - Genotyping of fluconazole-resistant Candida albicans isolated from Uighurian people in Xinjing (China) using ALTS/RFLP and micro-TGGE method. AB - Antifungal susceptibility tests were performed for 38 Candida albicans strains isolated from oral cavities of 43 Uighurian AIDS patients. Results showed that six isolates were resistant to fluconazole; one showed low susceptibility. We attempted to examine these strains molecular-epidemiologically, but 25S rDNA genotyping was insufficient for their discrimination. To estimate whether the origins of resistant strains were identical, we developed a new combination method of C. albicans tandem repeating units (ALTS)/RFLP and micro-temperature gradient gel electrophoresis (micro-TGGE). This new method was able to distinguish all seven strains. A suspected nosocomial infection was ruled out. PMID- 20716856 TI - Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: proteins interacting with the third cytoplasmic loop of dopamine D2 and D3 receptors. AB - Among the various dopamine receptors, D(2)-like receptors (D2R, D3R, and D4R) are characterized by a large third cytoplasmic loop, a short carboxyl-terminal tail, and the ability to activate inhibitory G proteins. The diverse activities of D(2) like receptors are partly mediated by proteins that interact with the third cytoplasmic loop, which regulate receptor signaling, receptor trafficking, and stability. Furthermore, in the case of D2R and D3R genes, mRNA splicing generates isoforms in the region of the third cytoplasmic loop. The gene encoding D2R gives rise to two isoforms, termed the dopamine D(2) receptor long isoform (D2LR) and the dopamine D(2) receptor short isoform (D2SR), which lacks 29 amino acids of the D2LR within the third cytoplasmic loop. The D3R gene also produces at least seven distinct alternative splicing variants including D3nf, in which 98 base pairs in the carboxyl-terminal region of the third intracellular loop are deleted. In this review, we focus on proteins interacting with the dopamine D(2)/D(3) receptors in the third cytoplasmic loop. We also define a novel binding protein, heart-type fatty acid-binding protein (H-FABP), which specifically interacts with the 29 D2LR amino acids deleted in D2SR and document its function in D2LR signaling. PMID- 20716857 TI - Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: Ser311Cys polymorphisms of the dopamine D2-receptor gene and schizophrenia. AB - Schizophrenia is a debilitating and complex mental disorder with a prevalence of approximately 1% worldwide. The etiology remains unclear, despite massive research efforts. Hyperactive dopaminergic signal transduction in the central nervous system is suggested to be involved in the pathophysiology of schizophrenia (the dopamine hypothesis). The dopamine D(2)-receptor (DRD2) gene is thus a promising candidate for associations with risk of schizophrenia. We investigated DRD2 and found a novel missense nucleotide change causing an amino acid substitution of serine with cysteine at codon 311 (Ser311Cys). We performed an association study using 156 schizophrenia patients and 300 controls. Cys311 in DRD2 was significantly associated with schizophrenia. Patients with the Cys311 allele displayed shorter duration of hospitalization and less severe negative symptoms and were more frequently married compared to patients without this allele, suggesting good response to treatment. We expanded samples to 291 patients with schizophrenia (including 11 postmortem brain samples), 579 controls, and 78 patients with affective disorders in a further case-control study. Cys311 was associated with schizophrenia, particularly in patients without negative symptoms, and bipolar disorder with mood-incongruent psychotic symptoms. Three meta-analyses using over 20 published studies confirmed the association. In vitro studies showed that Cys311-type D(2) receptor impairs dopamine-induced sequestration, which appears to be consistent with the dopamine hypothesis. PMID- 20716858 TI - Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: biochemical and behavioral profiles of phosphodiesterase inhibition in dopaminergic neurotransmission. AB - Dopamine plays a central role in the regulation of psychomotor functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade and therefore controlled by phosphodiesterases (PDEs). Multiple PDEs with different substrate specificities and subcellular localization are expressed in the striatum, and the functional roles of PDE10A, PDE4, and PDE1B are extensively studied. Biochemical and behavioral profiles of PDE inhibition by selective inhibitors and/or genetic deletion related to dopaminergic neurotransmission are compared among those PDEs. The inhibition of PDE up-regulates cAMP/PKA signaling in three neuronal subtypes, resulting in the stimulation of dopamine synthesis at dopaminergic terminals, the inhibition of dopamine D(2)-receptor signaling in striatopallidal neurons, and the stimulation of dopamine D(1)-receptor signaling in striatonigral neurons. Predominant roles of PDE families or isoforms are implicated in each neuronal subtype: PDE4 at dopaminergic terminals, PDE10A and PDE4 in striatopallidal neurons, and PDE1B in striatonigral neurons. PDE10A and PDE4 inhibition may exhibit D(2) antagonist-like, antipsychotic effects, whereas PDE1B inhibition may exhibit D(1) agonist-like effects in the striatum. Development of PDE isoform-specific inhibitors is essential for better understanding of the function of each PDE isoform and treatment of neuropsychiatric disorders. PMID- 20716859 TI - Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: regulation of dopaminergic neural transmission by tyrosine hydroxylase protein at nerve terminals. AB - 5R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) is an essential cofactor for tyrosine hydroxylase (TH). Recently, a type of dopa-responsive dystonia (DRD) (DYT5, Segawa's disease) was revealed to be caused by dominant mutations of the gene encoding GTP cyclohydrolase I (GCHI), which is the rate-limiting enzyme of BH(4) biosynthesis. In order to probe the role of BH(4) in vivo, we established BH(4)-depleted mice by disrupting the 6-pyruvoyltetrahydropterin synthase (PTS) gene (Pts(-/-)) and rescued them by introducing human PTS cDNA under the control of the human dopamine beta-hydroxylase (DBH) promoter (Pts(-/-)-DPS). The Pts(-/ )-DPS mice developed hyperphenylalaninemia. Interestingly, tyrosine hydroxylase protein was dramatically reduced in the dopaminergic nerve terminals of these mice, and they developed abnormal posture and motor disturbance. We propose that the biochemical and pathologic changes of Pts(-/-)-DPS mice are caused by mechanisms common to human DRD, and understanding these mechanisms could give us insight into other movement disorders. PMID- 20716860 TI - Spatiotemporal distribution of chondroitin sulfate proteoglycans in the developing mouse retina and optic nerve. AB - The aim of the present study was to determine the distribution of chondroitin sulfate proteoglycans in the mouse retina and optic nerve of the prenatal and postnatal mouse by immunohistochemistry. At embryonic day (E) 18, chondroitin-4 sulfate (C4S), chondroitin-6-sulfate (C6S) and biglycan were detected in the retina and optic nerve. However, aggrecan was seen in the retina but not in the optic nerve. At postnatal day (P) 7, aggrecan and biglycan were clearly observed in the optic nerve, inner nuclear layer and ganglion cell layer and diffuse in the outer retina. C4S diffusely distributed in the retina and optic nerve, but C6S was mainly confined to the photoreceptor layer and optic nerve sheath. At P42, biglycan showed diffuse distribution in the retina and optic nerve with intense staining in nerve-fiber rich layers. Aggrecan showed weak staining at the inner plexiform layer with higher density in the outer and inner nuclear layers, outer plexiform layer and ganglion cell layer. Both C4S and C6S were detected in the optic nerve and retina, but C6S showed strong immunostaining in the photoreceptor layer. The distributions of these proteoglycans with respect of time course during development of the retina and optic nerve suggest that they may have unique or overlapping roles in development and maintenance of the retina and optic nerve. PMID- 20716861 TI - Characterization of Edwardsiella tarda isolated from farm-cultured eels, Anguilla japonica, in the Republic of Korea. AB - We surveyed the occurrence of edwardsiellosis on eel farms and investigated the characteristics of Edwardsiella tarda isolated from farm-cultured eels in the Republic of Korea. The occurrence rate of edwardsiellosis was 72% in the investigated samples. Among the edwardsiellosis cases, 46% were found to be mixed infections, with parasites and other kinds of bacteria. Some of the biochemical characteristics of the E. tarda isolates were different from those of the previously reported E. tarda isolated from several kinds of fish from different countries, especially in terms of hydrogen sulfide and indole production. The E. tarda isolated from the eels in the Republic of Korea had the characteristics of two biogroups, the wild-type biogroup and biogroup 1. The enzymatic activity of the E. tarda showed similar patterns to previously reported E. tarda strains and ATCC strains. This is the first it has been reported that E. tarda isolated from farm-cultured eels had some different biochemical characteristics from those of previously reported E. tarda isolated from several kinds of fish. PMID- 20716862 TI - Effect of NEFA and glucose levels on CPT-I mRNA expression and translation in cultured bovine hepatocytes. AB - The objective of this study was to determine the effects of NEFA and glucose on carnitine palmitoyltransferase-I (CPT-I) mRNA expression in cultured bovine hepatocytes using real-time reverse transcription polymerase chain reaction and ELISA methods. The results indicated that CPT-I transcription increased gradually, but that CPT-I translation was not significantly changed, with glucose concentrations ranging from 0 to 3.0 mmol/L (P<0.01). Furthermore CPT-I transcription and translation were enhanced significantly when the NEFA concentrations increased from 0 to 1.2 mmol/L and decreased significantly when the NEFA concentrations increased from 1.2 to 4.8 mmol/L (P<0.01). A high concentration NEFA was found to reduce fatty acid oxidation, potentially explaining the development from NEB to ketosis in dairy cows. PMID- 20716863 TI - A retrospective study in 21 Shiba dogs with chronic enteropathy. AB - We retrospectively studied the clinical and laboratory features and outcomes of chronic enteropathy in Shiba dogs. Among 99 dogs with chronic enteropathy, 21 Shiba dogs (21%) were included in the study (odds ratio, 7.14). No significant differences were seen in signalment, clinical signs, symptoms or laboratory profiles between the Shiba and non-Shiba groups. Severe histopathological lesions in the duodenum were a common finding in the Shiba group. The median overall duration of survival in the Shiba group was 74 days, while that of the dogs in the non-Shiba group could not be determined because more than half of the cases remained alive at the end of this study. The difference between the groups was statistically significant (P<0.0001). The 6-month and 1-year survival rates for the Shiba group were 46% and 31%, respectively. Conversely, the 6-month, 1-year and 3-year survival rates for the non-Shiba group were 83%, 74% and 67%. The results obtained here demonstrated that the Shiba dog is predisposed to chronic enteropathy and shows severe duodenum lesions and poor outcomes, indicating a breed-specific disease. PMID- 20716864 TI - [What is ghrelin for gastric cancer?]. AB - Ghrelin is a novel and 28-amino-acid peptide hormone. It was identified in the stomach as the endogenous ligand for the growth hormone secretagogue receptor by a Japanese researcher in 1999. Besides the stimulation, ghrelin has been known to have a wide spectrum of biological functions such as regulation of appetite and food intake, gastrointestinal motility, gastric acid secretion, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologic processes. Therefore, studies of ghrelin have been rapidly increasing. However, the reports on the relationship between ghrelin and gastric cancer are few, though ghrelin is secreted mainly from the stomach. The purpose of this review is to consider what ghrelin is from a gastric cancer perspective. The studies and clinical applications of ghrelin in near future are also discussed. PMID- 20716865 TI - [Clinicopathological features of small intestinal tumors]. AB - Small intestinal neoplasms are rare, accounting for only 1-2% of all gastrointestinal neoplasms. Variable neoplasms are recognized in the small intestine. Comparatively frequent malignant lesions are carcinoma, carcinoid tumor, malignant lymphoma, and GIST (gastrointestinal stromal tumor). The prognosis of small intestinal cancer is poor, because preoperative diagnosis is difficult and it is usually discovered at the advanced stage. In addition, it is thought that there are few small intestinal cancers of an adenoma origin, but dysplasia is considered to be associated with that complicated by Crohn's disease. The incidence of carcinoid tumor is lower in Japan than in Western countries. Although it is often discovered at the advanced stage, its prognosis is relatively good in spite of the high incidence of metastasis because of its low-grade malignancy. Among malignant lymphomas of the small intestine, the incidence of MALT lymphoma is lower, and those of T cell and follicular ones are higher than in the stomach. Lymphomas with minimal cellular atypia are often encountered, and in such cases biopsy diagnosis is difficult. The prognosis of small intestinal lymphoma is better than for small intestinal cancer. It must be recalled that multiple GIST occurs in specific disorders such as von Recklinghausen's disease and familial disease among small intestinal GIST, although very rarely. The prognosis of malignant small intestinal disease will improve through early diagnosis with the recent progress in the procedures for detecting small intestinal disease. PMID- 20716866 TI - [Diagnosis of small bowel carcinoma by capsule endoscopy]. AB - Now in Japan, the use of capsule endoscopy for small bowel is approved only for the diagnosis of obscure gastrointestinal bleeding. Since the small bowel is anatomically difficult to approach, and small bowel carcinomas are often asymptomatic at early stages, they were usually diagnosed only after symptoms such as intestinal stenosis have developed. The advent of capsule endoscopy, however, enabled us to diagnose small bowel carcinoma at an early stage. However, we must be careful of the risk of capsule retention. The combination of capsule endoscopy, double balloon endoscopy, and traditional examination modalities including radiography or computed tomography will make it possible to diagnose and treat small bowel carcinoma at an early stage, and further progress is expected in this field. PMID- 20716867 TI - [Carcinoma of the small intestine diagnosed by double balloon endoscopy]. AB - There are no specific symptoms of patients with carcinoma of the small intestine. Therefore, it is difficult to diagnose in the early stage by imaging modalities such as radiological enteroclysis, computed tomography, and classical endoscopy. However, double balloon endoscopy makes it possible to diagnose the carcinoma of the entire small bowel by taking tissue samples for pathological assessment. The characteristic of endoscopic findings is irregular ulcerated tumor with malignant stricture. It is still difficult to find carcinoma of small intestine in patients without symptoms and most cases are advanced when diagnosis is achieved. We should try to diagnose in early stage by combining images modalities, capsule endoscopy and double balloon endoscopy safely and efficiently, resulting in improving the patients' prognosis. PMID- 20716868 TI - [Radiological imaging of small-bowel tumors]. AB - While diagnosis of small-bowel tumors is clinically difficult, imaging examinations have a great role in it. Small-bowel enteroclysis allows viewing of the entire small-bowel for evaluating tumor location, size, and shape. CT gives information on both the intra- and extraluminal features of small-bowel tumors, mesenteric abnormalities, and distant organ spread. Multidetector- row computed tomography (MDCT) has improved image quality and reduced scan times. Furthermore, CT enteroclysis using MDCT with adequate visceral distension allows good visualization of small-bowel tumors. It is very important for clinicians to know the characteristic imaging findings of small-bowel tumors, although they are rare. PMID- 20716869 TI - [Treatment and outcome in small bowel cancer]. AB - In adenocarcinoma of the small intestine, delays in diagnosis are frequent, and the majority of patients present with advanced- stage disease and either lymph node involvement or distant metastatic disease. Surgical resection is a mainstay in treatment of this disease, but the role of adjuvant therapy is unclear. Recent retrospective and prospective studies have helped to clarify the optimal chemotherapy approach for advanced small bowel adenocarcinoma. The combination of capecitabine and oxaliplatin is reportedly highly effective. Further clinical studies on this rare type of tumor are needed. This article reviews the focuses on recent advances in management. The 72nd Japanese Society for Cancer of the Colon and Rectum have conducted a retrospective review of Japanese patients with adenocarcinoma of the jejunum or ileum. The data indicated that although not statistically significant, there was a trend in median overall survival favoring the chemotherapy for advanced jejunal or ileal adenocarcinoma (17 months vs. 8 months, p=0.114). PMID- 20716870 TI - [A comparative study of concurrent chemoradiotherapy with S-1 or CDDP for pharyngeal or laryngeal cancer]. AB - Adverse events and therapeutic effects were analyzed in patients with pharyngeal or advanced laryngeal squamous cell carcinomas(SCCs)receiving concurrent chemoradiotherapy (CCRT) with S-1 or weekly CDDP between 2004 and 2007. Low-dose CDDP (25 mg/m2) was administered once a week and S-1 (65 mg/m2) was administered for 3 weeks with one-week rest during conventional radiation with 2 Gy/fraction. Both of the two CCRT regimens showed little toxicity with grade 4 toxicities in less than 5%of the patients. However, CCRT with S-1 more frequently induced grade 3 and 4 oral mucositis than CCRT with CDDP. As a result, the completion rate of CCRT with S-1 was lower than that of CCRT with CDDP. The two regimens achieved a similar complete response rate of the primary sites, local control rate(LCR)and larynx preservation rate; the LCR for T1 and 2 disease was more than 70%. However, the LCR for T3 or 4 disease by the two regimens was less than 50%. CCRT with S-1 showed significantly higher LCR in patients with poorly or undifferentiated SCCs than those with well or moderately-differentiated SCCs. It is suggested that the two CCRT regimens are useful treatment modalities for patients with locally(primary site)non-advanced pharyngeal or laryngeal SCCs, and that CCRT with S-1 is highly sensitive to poorly or undifferentiated SCCs. In order to achieve local control and larynx preservation, more intensive CCRT might be necessary for patients with locally(primary site)advanced pharyngeal or laryngeal SCCs. PMID- 20716871 TI - [Evaluation of liaison-clinical pathway for patients with breast cancer undergoing adjuvant therapy after curative operation--data from questionnaire survey of 56 clinics and 105 patients]. AB - To evaluate the liaison-clinical pathway for patients with breast cancer introduced since May 2008, the data from a questionnaires survey of 56 clinics and 105 patients were reviewed. Half of the clinics specialized in internal medicine. 93% of physicians recognized the utility of the pathway while 24% made the most of the pathway. About 40% of the clinics wished to enlarge both the patient number and treatment materials. Half of the patients were employed. 55% of patients valued the pathway as helpful. And 29% of patients used the patient booklet at all times. 8% of patients replied they had complaints went to clinics. There has been no serious problem in using the pathway. Countermeasures to electronic health records in clinics, and responses to requests from each patient will be needed. PMID- 20716872 TI - [Feasibility of FEC 100 followed by DOC 100 as adjuvant chemotherapy for breast cancer]. AB - As adjuvant chemotherapy for breast cancer, the addition of taxane to regimens containing anthracycline has been shown to be effective. However, in Japan, it is not probability yet as for safety. We examined the feasibility of FEC 100 followed by DOC 100 as adjuvant chemotherapy for breast cancer. METHODS: Node positive breast cancer patients or node-negative high-risk patients were eligible. The treatment completion rate and toxicity were evaluated in 3 courses of FEC 100 mg/m2 followed by 3 courses of DOC 100 mg/m2. RESULTS: Twenty-one patients were registered and completion rate was 100%. The relative dose intensity (RDI) was 94.2% for FEC 100 and 97.8% for DOC 100. Grade 3 or higher neutropenia observed in 38% and febrile neutropenia developed in 14%. Non hematological toxicities were slight. CONCLUSION: The regimen of FEC 100 followed by DOC 100 was safe in adjuvant chemotherapy for breast cancer in our country. PMID- 20716873 TI - [Impact of HER2, EGFR, IGF-1R, and VEGFR expressions on the outcome of chemotherapy for advanced gastric cancer]. AB - We aimed to elucidate the clinical significance of the expressions of HER2, epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGF 1R), and vascular endothelial growth factor receptor 1, 2, 3 (VEGF-R1, VEGF-R2, and VEGF-R3) in gastric cancer. The study group comprised 57 patients who had undergone gastrectomy at the National Cancer Center Hospital and subsequently received first-line chemotherapy (S-1 monotherapy [n=29] or irinotecan+cisplatin [n=28]) for recurrent or residual tumors. We performed immunohistochemical analysis of formalin-fixed paraffinembedded specimens of surgically removed primary tumors to determine the expressions of HER2, EGFR, IGF-1R, and VEGFR1 in tumor cells and the expressions of VEGF-R1, VEGF-R2, and VEGF-R3 in tumor stromal vessels. The expressions of HER2 (p=0.017) and IGF-1R (p=0.025) were significantly more common in intestinal type tumors than in diffuse type. The protein expressions did not correlate with tumor response in either chemotherapy regimen group. Among the patients who underwent S-1 monotherapy, those with cytoplasmic VEGF-R1-positive tumors had significantly shorter progression-free survival (logrank, p=0.017). In the survival analysis of all the patients, coexpression of membranous IGF-1R and VEGF-R3 in stromal vessels was the most significant predictor of poor survival (hazard ratio, 1.82; 95% CI, 1.31-2.63; p<0.001). The results of our study will facilitate more efficient use of molecular targeted agents in patients with gastric cancer. PMID- 20716874 TI - [Delayed hepatic resection for synchronous liver metastases from colorectal cancer]. AB - BACKGROUND: This study aimed to compare the surgical outcome and long-term survival between simultaneous and delayed resection of liver metastases from colorectal cancer (LM). METHODS: Seventy-four patients with LM were divided into two groups, i. e., 32 patients who underwent hepatectomy at the time of colorectal surgery (simultaneous group) and 35 patients who underwent delayed liver resection (delayed group). RESULTS: In 12 of the 35 (34%) patients from the delayed group, new metastatic lesions were found in the same and/or different segments after re-evaluation during the interval between operations. These patients had a shorter interval between procedures, and larger tumors than patients without tumor progression. There were significant differences (p=0.0454 and 0.0077) of hepatic disease-free survival between the metachronous or delayed groups and the simultaneous group. Multivariate analysis showed that simultaneous resection was one of three independent prognostic indicators with an influence on hepatic disease-free survival. CONCLUSIONS: Tumor progression could be recognized and occult metastases were detected during the interval between operations. Delayed resection of synchronous LM may be useful to reduce the risk of rapid recurrence in the remnant liver. PMID- 20716875 TI - [Effect of pylorus-preserving pancreaticoduodenectomy on serum levels of 5 fluorouracil during S-1 treatment for pancreaticobiliary malignancy]. AB - AIMS: The aim of this study was to evaluate the effect of surgical procedures on the serum levels of 5-fluorouracil (5-FU) in patients undergoing S-1 treatment for pancreaticobiliary malignancy. METHODOLOGY: From January 2003 through December 2008, 27 chemotherapy-naive patients who underwent a surgical procedure for pancreaticobiliary malignancy received S-1 chemotherapy for unresectable or recurrent disease. The primary site of disease was: the extra hepatic bile duct (n=10); gallbladder (n=8); pancreas (n=6); or ampulla of Vater (n=3). The surgical procedure was: pylorus-preserving pancreaticoduodenectomy (PPPD) (n=6); combined major hepatic and bile duct resection (n=6); bilioenteric anastomosis (n=4); or exploratory laparotomy (n=11). S-1 (80-120 mg/day) was administered orally twice daily for 28 days, followed by 14 days without therapy. Subsequently, the serum levels of 5-FU were measured using the HPLC-UV method. RESULTS: The median number of cycles administered per patient was 6 (range, 2 13). Although grade 3 watery eye developed in one patient, neither grade 4 toxicities nor treatment-related deaths were observed. The overall response rate was 19%, the median overall survival time was 9 months, and the 1-year cumulative survival rate was 11%. The maximum levels of 5-FU in the sera of individual patients differed significantly according to the surgical procedure (Kruskal Wallis test; p=0. 0049); the patients who underwent PPPD had the highest 5-FU levels, as compared with the other patients (Mann-Whitney test; p= 0.003). CONCLUSIONS: The type of operative procedure appears to influence the serum levels of 5-FU in S-1-treated surgical patients with pancreaticobiliary malignancy. Given the possibility of elevated levels of 5-FU in the sera of patients who are treated with S-1 after PPPD, adverse events must be monitored carefully in this cohort. PMID- 20716876 TI - [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Japanese patients with bone metastases--The Japanese version of the EORTC QLQ-BM22]. AB - Bone metastasis is a frequent complication of malignant cancer. Previous clinical trials of bone metastasis have largely focused on skeletal related events (SREs) as objective end-points. However, a subjective health-related outcome such as quality of life (QOL) is also a first-priority principle for all patients with malignant cancer. In response to the need for a comprehensive module to evaluate bone metastasis-specific QOL, the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group has developed a Quality of Life Questionnaire for patients with Bone Metastases (EORTC QLQ-BM22). In this study, we introduce the official Japanese version of the EORTC QLQ-BM22 as a module to evaluate QOL in patients with bone metastasis. This module has been developed to be used together with the EORTC QLQ-C30, a QOL scale for patients with cancer, or with its shortened version, EORTC QLQ-C-15-PAL. PMID- 20716877 TI - [Performance of a portable continuous infusion pump (SUREFUSER A) in continuous infusion of 5-FU]. AB - Therapy with mFOLFOX6/FOLFIRI used in treating colorectal cancer is typical of the regimens performed in outpatient settings. In this therapy, 46-h continuous infusion of 5-fluorouracil (5-FU) with concomitant oxaliplatin and irinotecan hydrochloride is conducted. The portable continuous infusion pump that makes continuous infusion possible has a non-electric structure, so variation in the infusion rate is seen. There are known effects of 5-FU concentration and temperature, and many studies have reported on the precision. In our hospital, we have experienced many cases of incomplete infusion and delays for the above reasons. We changed the specifications of the infusion pump to correspond to the kinematic viscosity of 5-FU and made all drug solution amounts uniform. We measured the time required to administer the drug solution from the time the infusion was started (recorded by a nurse) and the time it was completed (recorded by the patient), and confirmed the precision of the pump after the changes were made. It was found that while there was a decrease in the infusion rate at which the effect of the kinematic viscosity of 5-FU is seen, the mean infusion time was kept to within 46+/-10% hours in more than 90% of patients. There were no effects from concentration differences in 5-FU, and the completion time was reduced. The management and lifestyles of individual patients are potential factors in precision errors, and it is important to explain in advance to patients the necessity of secure fixation and infusion pump problems that might occur. PMID- 20716878 TI - [Clinical analysis of 12 cases of pneumothorax during intensive chemotherapy for malignant neoplasms]. AB - Twelve cases of pneumothorax during intensive chemotherapy for malignant neoplasms were found in a retrospective study of patients being treated at our hospital in the period 2001-2009. All of the patients were men, and their diseases were lung cancer (9 cases), gastric cancer (2 cases) and esophageal cancer (one case). Operation for pneumothorax was performed 9 times in 7 patients(twice in two patients). Thoracoscopic surgery was done in 6 patients, and one patient with severe pulmonary emphysema was performed by open thoracotomy. Pleurodesis was performed 5 times using OK-432 only or OK-432 and minocyclin. Five patients died during the treatment for pneumothorax. The causes of death were interstitial pneumonia after pleurodesis (one case), and progression of cancer during interruption of chemotherapy (4 cases). Development of pneumothorax during intensive chemotherapy should be recognized and treated as soon as possible because it may hinder the treatment for malignant tumors and lead to severe pulmonary dysfunction. PMID- 20716879 TI - [Microarray analysis of tumor xenograft model]. AB - We carried out gene expression profiling of forty human tumor cells for research choice method of the most fitting anticancer drug, using unsupervised hierarchal clustering analysis. This clustering analysis is based on a tumor growth inhibition panel of nine antitumor drugs (MMC, CDDP, ACNU, CPT-11, CPA, FT-207, UFT, 5'-DFUR and ADM) for forty human cancers. These cancers(eleven stomach, seven colon, six breast, three pancreas, five lung, two esophageal carcinomas, one liver, one renal cell carcinoma, one uterus, two ovarian, and one melanoma) have been maintained by serial s. c. passages in nude mice of the same sex of donor patients. Nine antitumor drugs were divided into two groups, a 5-FU-related drug group (5'-DFUR, FT-207 and UFT) and another group. On the other hands, forty cells were clustered into four groups. By using GeneChip (Hu95Av2, Affymetrix), we investigated gene expression profiling of the matched tumor cells and selected specific genes in each group. Interestingly, a pathway analysis revealed that expressions of p53-related genes were up-regulated in the 5-FU-sensitive groups. This result suggested that chemosensitivity was predicted by gene expression profiling of tumor cells. We considered that microarray analysis would be a good tool for further tailor-made medications. PMID- 20716880 TI - [Usefulness of instruction by pamphlets in cancer chemotherapy]. PMID- 20716881 TI - [Effectiveness of simultaneous combination therapy using S-1, nedaplatin and radiotherapy for 7 cases of oropharynx cancer]. AB - Various treatments for oropharynx cancer included radiotherapy, arterial injection chemotherapy (as well as combined chemoradiotherapy), combined concurrent chemoradiotherapy, and surgical resection and reconstruction. There are also treatment differences among facilities. Our department has been providing a treatment modality for head and neck malignancies with the aims of functional and morphological preservation with a high cure rate. We herein report the treatment efficacy in 7 cases of oropharynx cancer (6 cases on lateral wall and 1 case on superior wall)treated with S-1, nedaplatin and radiotherapy (SN therapy) at our department between April 2006 and December 2006. The total of 7 cases included 1 case of T1N1M0, 1 of T2N0M0, 2 of T2N2bM0, 1 of T2N2cM0, 1 of T3N2cM0, and 1 case of T4N2cM0. The patients were all male and their ages ranged from 57 to 76 years old, with the average age of 68.4 years. Six of the 7 cases are surviving without cancer through treatment and their functions and morphologies have been preserved. In the 1 case of T4N2cM0, the tumor did not disappear and the patient expired due to the original lesion. Although SN therapy supposedly enables functional and morphological preservation, it is necessary to increase the number of cases and examine the efficacy of SN therapy for oropharynx cancer for functional and morphological preservation and the survival rate. PMID- 20716882 TI - [Primary malignant melanoma of the esophagus--detection of circulating tumor cells]. AB - Primary malignant melanoma of esophagus (PMME) is a rare tumor; therefore, the prognostic factors, predictive factors, and difference in biological behaviors of cutaneous melanoma and primary esophageal squamous cell carcinoma remain uncertain. Although we did not adopt a standard therapeutic strategy, we performed surgical resection, chemotherapy, immunotherapy, and radiotherapy either alone or in combination; all procedures resulted in poor outcomes. A 67 year-old woman presented with a swallowing disorder. An esophagogastroduodenoscopy was performed, leading to diagnosis of PMME. According to the Japanese Classification of Esophageal Cancer, the pathological stage was T1b, ly0, v0, N0, M0, stage I . KIT immunostaining was focally positive. After subtotal esophagectomy, adjuvant chemotherapy was performed, but the malignant melanoma relapsed in the mediastinum and the patient died 10 months after diagnosis. We serially monitored the patient using several new modalities, including PET/CT, metabolites of melanin: 5-S-CD, and circulating tumor cells (CTCs) by reverse transcription-polymerase chain reaction to identify the melanoma-specific gene. To our knowledge, this is the first report of a case in which CTCs in PMME were detected. PMID- 20716883 TI - [Combined chemotherapy with cisplatin plus vinorelbine showed efficacy in a case of metastatic primary cutaneous adenoid cystic carcinoma]. AB - We report a case of a 65-year-old man with metastatic primary cutaneous adenoid cystic carcinoma that was effectively treated by combination chemotherapy with cisplatin (CDDP) plus vinorelbine(VNR). He detected a tumor mass on the anterior surface of his left patella in 2003 and underwent a tumorectomy in October 2008. He was given a diagnosis of primary cutaneous adenoid cystic carcinoma with metastatic lesions to multiple lungs and left tibial bone and then given chemotherapy combining CDDP plus VNR as the first treatment in December 2008. By this treatment for six cycles, the lung metastatic tumors gradually reduced on chest CT. We reported the efficacy of combined treatment with CDDP plus VNR for primary cutaneous adenoid cystic carcinoma, because this clinical condition was very rare and the standard treatment has still not been established. PMID- 20716884 TI - [A case of metachronous double primary adenocarcinoma in both lungs]. AB - A 78-year-old man underwent a right lower lobectomy for adenocarcinoma in January 2004. The follow-up CT scanning showed a nodule in the left upper lobe in March 2006, and we suspected pneumonia. After clarithromycin (CAM) was administered for three months, CT scanning demonstrated in July 2008 that the nodule was enlarged more than the CT scanning of 2006. We had performed bronchoscopy on April 2009, and obtained a specimen for the nodule. We diagnosed adenocarcinoma from the specimen. We planned adjuvant surgery of left S4S5 partial resection after chemotherapy of carboplatin 450 mg/body (day 1)+paclitaxel 80 mg/body (day 1, 8, 15). We demonstrated the standard thoracotomy and S4S5 partial resection in June of 2009. We experienced two adenocarcinomas as metachronous double primary lung cancer. For both lung cancers one must consider the range of the surgical resection and the respiratory function of the residual lungs. If we find an abnormal shadow in the lung of postoperative lung cancer, it is necessary to consider the possibility of metachronous lung cancer. PMID- 20716886 TI - [An elderly advanced breast cancer with a good response to anastrozole]. AB - The patient was an 86-year-old woman. In December 2005, she became aware of a tumor in her right breast at the nipple, gradually increasing in size and bleeding, and visited our department in April 2006. Roughly 3.5 cm in size, the tumor had a prominent large skin surface, bled profusely, and a dark red-colored was found at the E area of the right breast. Ultrasonography and mammography revealed that the tumor had invaded the skin and pectoralis major muscle (T4b). Core needle biopsy examination indicated invasive breast cancer (pap-tub), ER(+), PgR(+), HER2(3+). Chest CT scan and bone scintigraphy revealed swollen changes at the right axillary lymph nodes and osteoblastic changes in the 7th thoracic vertebra. We started anastrozole 1mg/day treatment. Tumor blood loss after one month was confirmed. After six months, the primary tumor size was reduced to 2 cm and the axillary lymph nodes disappeared. Administration continued about three years, and the tumor showed only the scar-like changes, and was unclear from ultrasonography (cPR). We report the long-term effect of aromatase inhibitor for elderly breast cancer patients without operation. PMID- 20716885 TI - [A dialysis patient with advanced lung adenocarcinoma who was safely given biweekly gemcitabine therapy]. AB - BACKGROUND: Although the number of advanced lung cancer patients on hemodialysis is expected to increase in the future, there has been no established treatment regimen yet. We report our experience with gemcitabine safely administered to an elderly patient requiring hemodialysis who had advanced lung adenocarcinoma. CASE: A 87-year-old man had been on dialysis for chronic renal failure. Left pleural effusions were detected in November 2007 and he was admitted to our hospital in January 2008. A diagnosis of Stage IIIB lung adenocarcinoma was made based on the findings of cytology from the pleural effusions and radiological examinations. After intrapleural cisplatin administration, he was given outpatient chemotherapy. Gemcitabine was administered every 14 days for 20 months. Adverse reactions observed included grade 1 neutropenia and grade 1 appetite loss. CONCLUSION: We described a dialysis patient with advanced non small cell lung cancer who was given biweekly gemcitabine for 20 months. This regimen in a dialysis patient can be safely conducted on an outpatient basis. PMID- 20716887 TI - [Weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide were very effective for a case of advanced accessory breast cancer]. AB - Reported is a case of advanced accessory breast cancer to which weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide proved very effective. The patient was a 49-year-old woman who noticed a tumor in the right axilla around October 2007 but then left it alone. In October 2008, the patient visited a nearby physician who made a diagnosis of locally advanced accessory breast cancer. Because the tumor enlarged despite endocrinotherapy, the patient was referred to our hospital in July 2009. CT scan showed a tumor with a size of infant's head, multiple lymph node metastases and metastases to the skin, liver and bones. Following weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide for 4 months, the tumor in the right axilla and metastases to the lymph nodes, skin and liver disappeared. Adverse events were alopecia and grade 1 peripheral neuropathy. The treatment continues at present. Weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide has few adverse reactions and can be performed at an outpatient clinic, suggesting that it is a useful treatment. PMID- 20716888 TI - [A case of anastomotic recurrence of gastric cancer who underwent esophagojejunostomy, treated with S-1 monotherapy leading to complete response (CR)]. AB - A 67-year-old male with an anastomotic recurrence of gastric cancer who underwent esophagojejunostomy, was treated with S-1 monotherapy leading to a complete response (CR). The patient was diagnosed with gastric cardia cancer and underwent a total gastrectomy with lymph node dissection. Two years and 2 months after surgery, the patient was administered S-1 100 mg/day (4-week administration and 2 week rest) because anastomotic recurrence was confirmed. The patient was unable to take anything by mouth, but this chemotherapy could be orally administered after one course. After six courses, tumor tissue completely disappeared and he had a CR. Administration of S-1 was continued for eight courses and then discontinued. There was no relapse for two years after discontinuation. PMID- 20716889 TI - [A very elderly case of recurrent gastric cancer with peritoneal dissemination effectively treated by combination chemotherapy of docetaxel (DOC) and S-1]. AB - We report a case of a 77-year-old man with gastric cancer of Borrmann type 3, pyloric stenosis and liver invasion. Distal gastrectomy with liver film resection was performed. Pathological staging was IV(sig, pT4, pN2, H0, P0, CY0, M0, ly3, v3). We recommended adjuvant chemotherapy but the patient refused. He was diagnosed with a recurrence of peritoneal dissemination 4 months after the operation. He received docetaxel(DOC)at a starting dose of 40 mg/m2 by iv infusion on day 1 and S- 1 at a full dose of 100 mg/body daily for two weeks every three weeks. After 5 cycles of this combination therapy, the gastric cancer with peritoneal dissemination completely disappeared. He was recognized to have grade 2 hematologic toxicity, hand foot syndrome and stomatitis, and all treatment-related toxicities were resolved. No re-growth of gastric cancer has been seen for 9 months with this chemotherapy. PMID- 20716890 TI - [A case of scirrhous gastric carcinoma with peritoneal dissemination which was treated by curative gastrectomy after S-1/CDDP chemotherapy]. AB - The present patient was a 53-year-old female diagnosed as gastric cancer with peritoneal dissemination by staging laparoscopy. She was treated with chemotherapy using S-1 (80 mg/body/day) and CDDP (80 mg/body/day, day 8) administered for 3 weeks followed by a drug-free 2 weeks, in five-week courses. Stable disease (SD) was obtained after six courses, and then she underwent second staging laparoscopy. Because of disappearing peritoneal disseminated nodules both macroscopically and histologically, she underwent curative total gastrectomy with D2 lymph node dissection and reconstruction by the Roux-en Y method. The postoperative pathological findings showed T2 (se) N1M0, stage IIIa and chemotherapy effective evaluation demonstrated Grade 1b. Postoperatively, S 1/CDDP therapy was carried out, after two cycles she suffered from anorexia, and then S-1 only was given. Fourteen months later, peritoneal dissemination developed. Despite changes in the regimen such as docetaxel or CPT-11, she died 23 months after the initial gastrectomy. PMID- 20716891 TI - [A case of gastric adenosquamous carcinoma successfully treated with second-line chemotherapy (CPT-11 and CDDP)]. AB - Gastric adenosquamous carcinoma is known as an infrequent histological cancer with a poor prognosis. A 69-year-old man was revealed to have gastric squamous carcinoma on the gastric body remote from esophagus (cT4 cN3, cStage IV). A curative operation was impossible so he was treated with systemic chemotherapy using S-1+docetaxel. After 1 course, we changed to second-line chemotherapy combining CPT-11+CDDP because of heterochronic multiple hepatic metastases. PET CT and CT findings after 5 courses of second-line therapy showed reduced primary tumor and metastatic lesions. The curative operation was performed based on the effective response with downstaging. The final histological diagnosis showed gastric adenosquamous carcinoma. The adjuvant chemotherapy of CPT-11 was continued without relapse for almost 2 years. PMID- 20716892 TI - [A case of metastatic colorectal cancer suffering from hyperammonemic encephalopathy induced by 5-FU, continuously treated with FOLFOX therapy]. AB - We report a rare case of metastatic colorectal cancer who suffered from hyperammonemic encephalopathy induced by 5- FU and was continuously treated with FOLFOX therapy. A 50-year-old man with ileus was diagnosed with ascending colon cancer Stage IV, and a right hemicolectomy was performed. Postoperative chemotherapy with modified FOLFOX6 was performed. Complications of nausea and vomiting were seen on day 2 , with confusion and cognitive disturbances on day 3 . None of the other radiographic examinations provided an explanation for his symptoms. Laboratory examination revealed hyperammonemia, so branched-chain amino acid solutions and high-volume drip infusion were started for its treatment. His symptoms entirely disappeared on day 4. We changed to chemotherapy for FOLFOX4 using branched-chain amino acid solutions and drip infusion. The tumor marker level normalized following two courses, and CT following ten courses showed that the size of the lung metastasis and abdominal lymph node had reduced significantly. The patient is currently receiving FOLFOX4. PMID- 20716893 TI - [A case of rectal cancer combined with intraperitoneal abscess responding completely to uracil/tegafur (UFT) plus oral leucovorin (LV) therapy]. AB - The patient was a 55-year-old man who complained of lower abdominal pain and fever, and was admitted to an emergency clinic. His diagnosis was rectal perforation combined with intraperitoneal abscess. Because his condition was in the preseptic state, an emergency operation was performed for colostomy and abscess drainage. After operation, he was diagnosed with rectal cancer colonoscopically. He refused reoperation and selected an oral chemotherapy regimen (UFT+LV therapy). 18 months later, he underwent Hartmann's operation. Histologically, cancer cells were absent. Complete response to chemotherapy was confirmed. He is free from any sign of recurrence until now. PMID- 20716894 TI - [Response in a case of inoperable bile duct cancer treated by combined chemotherapy of S-1 and gemcitabine]. AB - A 60-year-old male patient was diagnosed as bile duct cancer with left neck and abdominal para-aortic lymph node metastasis. He was treated by combined chemotherapy of S-1 and gemcitabine(GEM). S-1 (120 mg/day) was administered 14 days followed by 14 days rest as one course. GEM (1,000 mg/m2) was administered at 8 and 15 days after the start of S-1. Combined therapy could be continued, though S-1 and GEM were reduced for neutropemia. After 5 courses of treatment, CT and MRCP revealed a partial response. S-1/GEM combined therapy was effective for inoperable biliary tract carcinoma. PMID- 20716895 TI - [An effective case of gemcitabine therapy with post-operative peritoneal recurrence of intrahepatic cholangiocarcinoma]. AB - The patient was a 53-year-old man who had undergone left hepatectomy due to intrahepatic cholangiocarcinoma in August 2007. Pathologically, the tumor was diagnosed as a cholangiocellular carcinoma (T2, N0, M0, Stage II). Ascites appeared about one year after surgery and control was difficult using diuretics. Since abdominal CT revealed peritoneal recurrence with massive ascites, we conducted chemotherapy using gemcitabine (GEM) in September 2008. In the outpatient setting, GEM at a dose of 1, 000 mg/body was administered once a week with a 1-week rest as 1 course. The response was assessed as a complete response (CR) because abdominal CT after 7 courses of chemotherapy showed the disappearance of both ascites and the peritoneal nodules. An adverse effect for GEM was grade 3 anemia, but we could continue the chemotherapy until September 2009. At present, CR has been observed, and one year and three months have passed since the peritoneal reccurrence. PMID- 20716896 TI - [A case of recurrent gallbladder cancer with a remarkable tumor response to S-1]. AB - We herein report a case of recurrent gallbladder cancer with a remarkable tumor response to S-1 after a failure of gemcitabine (GEM) treatment. A 70-year-old man underwent cholecystectomy and abdominal drainage because of acute cholecystitis and biliary peritonitis. Postoperative pathological diagnosis revealed gallbladder cancer with subserous layer invasion. Subsequently, he had additional radical surgery. After eight months, abdominal CT showed a local tumor recurrence at the hepatic hylum, for which 4 courses of GEM were administered. The therapy was considered ineffective because of the increase in tumor size, and a new lesion in the segment 6 of liver. This led us to change the chemotherapeutic regimen from GEM to S-1. After two courses of S-1, the local recurrent tumor showed a marked decrease in size and liver metastases almost disappeared. The response duration was approximately 8 months, and median survival time from the start of GEM treatment was 17. 5 months. S-1, as a second-line chemotherapeutic drug, produced remarkable local tumor control and most likely survival time with good quality of life in this patient. PMID- 20716897 TI - [A case of interstitial pneumonitis induced by S-1]. AB - S-1, an oral fluoropyrimidine derivative, has been identified as an effective agent for the treatment of breast cancer. We present here a case of interstitial pneumonitis that occurred after S-1 treatment. A n 80-year-old woman was diagnosed with stage III infiltrating ductal carcinoma of the left breast and underwent a modified radical mastectomy in November 2001, followed by six courses of paclitaxel. In October 2008, metastatic disease was detected in her skeletal system. Therefore, S-1 chemotherapy was initiated (100 mg/body). Five days after starting S-1, she developed severe eruptions along with dyspnea. X-rays and CT scan showed diffuse ground glass shadow. Both her symptoms and the radiographic findings resolved dramatically after the start of high-dose corticosteroid therapy. Clinicians should be aware that S-1 has the potential to cause lung injury when it is included in chemotherapy. PMID- 20716898 TI - [A case of breast meningeal carcinomatosis caused by trastuzumab treatment as adjuvant chemotherapy]. AB - A 52-year-old woman underwent modified radical mastectomy and axillary lymph node resection for right breast cancer (stage IIB). Afterwards FEC therapy (5-FU 500 mg/m/2, epirubicin 75 mg/m2, cyclophosphamide 500 mg/m2) x 4, docetaxel therapy (60 mg/m2) x 4 and radiation of the illness side collarbone, upper and lower lymph nodes were enforced for adjuvant therapy after the operation. Furthermore, administration of aromatase inhibitor (anastrozole) and trastuzumab was started due to the postoperative pathological diagnosis of hormone receptor-positive and HER2 (score 3+). This became an urgent hospital admission because of the sudden escape power from impaired consciousness due to the articulation disorders and limb weakness when trastuzumab was administered nine times. It was diagnosed by MRI examination and the cerebrospinal fluid cytology as meningeal carcinomatosis of breast cancer, and she died on the 31st recurrence of disease. A serious relapse may be caused in a case of fast-progressing breast cancer like this while being administered trastuzumab as an adjuvant treatment. PMID- 20716899 TI - [A case of irinotecan-induced interstitial pneumonia during treatment of recurrent colon cancer]. AB - A 75-year-old man undergoing operations for rectal cancer was given adjuvant chemotherapy for 6 months. Fourteen months after surgery, peritoneal dissemination was found, so mFOLFOX6 therapy was started. After 34 courses of mFOLFOX6 therapy, peritoneal dissemination progressed. As a second-line treatment, we administered FOLFIRI therapy. The patient visited our emergency unit with the chief complaint of a fever thirteen days after the second course was completed. A chest imaging study showed diffuse infiltrative shadow and ground glass shadow bilaterally. Chemical interstitial pneumonia was suspected from his clinical findings. In the ICU, respiratory care by BiPAP and steroid pulse therapy(mPSL 1 g/day for three days)were performed. Steroid therapy improved his respiratory status and chest image findings, and he was able to leave the ICU on the seventh day. We continued steroid internal use treatment and he was discharged on the 70th day. The agent causing interstitial pneumonia was thought to be CPT-11 from the administration history. The incidence of interstitial pneumonia as an adverse event of CPT-11 is low, but it can be fatal without adequate attention. Steroid pulse therapy was validated for treatment, and it served to prolong life. PMID- 20716900 TI - [A case of rupture of the right femoral artery pseudo aneurysm occurring in the site of a port for hepatic arterial infusion]. AB - A 77-year-old man diagnosed with rectal cancer and multiple liver metastases underwent transverse colostomy in June 2008, and subsequently underwent radiotherapy of the whole pelvis; chemotherapy was started with 5-FU+l-LV and then switched to mFOLFOX6+bevacizumab. In February 2009, hepatic arterial infusion chemotherapy was carried out because of the exacerbation of appetite loss with chemotherapy and importance of the control of liver metastases. In March 2009, he had redness and swelling of the site of a port and was admitted to our hospital. The port was removed, but a CT scan showed a pseudo aneurysm with impending rupture in the right femoral artery necessitating emergency surgery. The right femoral artery was closed and a bypass between right external iliac artery and popliteal artery through the obturator foramen was constructed. This case is a rare complication, but rapid diagnosis and treatment are required when a pseudo aneurysm is suspected. PMID- 20716901 TI - [The new communication system about each patient's treatment from the ward to the chemotherapy center in our hospital]. AB - Because the expert nurse of the chemotherapy center collected his profile from his chart and the hospital summary of nursing and we orientated about the induced chemotherapy regimen to the patient who got it after discharge from the ward former, we could not grasp neither his general condition nor mental status adequately. The merit of the outpatient chemotherapy is the improvement of the quality of life, but the patient feels the solitude and anxiety because of the lack of the medical and nursing staff around him. Then we changed that we have visited the patients to collect their profile and orientate about new regimen on his bedside for the smooth conversion to the outpatient chemotherapy. We visited a-total of 45 patients in 2007. Thirty-eight patients visited before their discharge answered, The orientation of the new chemotherapy before my discharge let me get with a security. The visit also enabled both staffs of the chemotherapy center and the ward to possess the common information of each patient and to do the common nursing. We thought that the visit before discharge was effective for the smooth conversion to the outpatient chemotherapy. We would like to reduce the anxiety of the patients who had chemotherapy and to support their struggle against diseases, cooperating to other department and standardizing our care program. PMID- 20716902 TI - Change in serum proteome during allogeneic hematopoietic stem cell transplantation and clinical significance of serum C-reactive protein and haptoglobin. AB - Successful hematopoietic stem cell transplantation (HSCT) involves the restoration of hematopoietic function after engraftment, arising from the differentiation and proliferation of hematopoietic stem cells. Several factors could influence the course of allogeneic-HSCT (allo-HSCT). Therefore, knowledge of serum proteome changes during the allo-HSCT period might increase the efficacy of diagnosis and disease prevention efforts. This study conducted proteomic analyses to find proteins that were significantly altered in response to allo HSCT. Sera from five representative patients who underwent allo-HSCT were analyzed by 2-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry, and were measured on a weekly basis before and after allo-HSCT in additional 78 patients. Fourteen protein spots showing changes in expression were further examined, and most proteins were identified as acute phase proteins (APPs). Studies of 78 additional patients confirmed that C-reactive protein (CRP) and haptoglobin undergo expression changes during allo-HSCT and thus may have the potential to serve as representative markers of clinical events after allo-HSCT. Maximal CRP level affected the development of major transplant-related complications (MTCs) and other problems such as fever of unknown origin. Particularly, an increase in CRP level 21 days after allo-HSCT was found to be an independent risk factor for MTC. Maximal haptoglobin and haptoglobin level 14 days after allo-HSCT were predictive of relapses in underlying hematologic disease. Our results indicated that CRP and haptoglobin were significantly expressed during allo-HSCT, and suggest that their level can be monitored after allo-HSCT to assess the risks of early transplant-related complications and relapse. PMID- 20716903 TI - Environmental stimulus package: potential for a rising oxidative deficit. PMID- 20716904 TI - Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships. AB - A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines, and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting. There is a discussion of receptor binding, electrical effects, cell signaling and other modes of action. Mescaline is a nonselective, seretonin receptor agonist. 5 HTP receptors are involved in the stimulus properties. Research addresses the aspect of stereochemical requirements. Receptor binding may involve the proposed quinone metabolite and/or the amino sidechain via protonation. Electroencephalographic studies were performed on the effects of mescaline on men. Spikes are elicited by stimulation of a cortical area. The potentials likely originate in nonsynaptic dendritic membranes. Receptor-mediated signaling pathways were examined which affect mescaline behavior. The hallucinogen belongs to the class of 2AR agonists which regulate pathways in cortical neurons. The research identifies neural and signaling mechanisms responsible for the biological effects. Recently, another hallucinogen, psilocybin, has been included within the unifying mechanistic framework. This mushroom constituent is hydrolyzed to the phenol psilocin, also active, which is subsequently oxidized to an ET o-quinone or iminoquinone. PMID- 20716906 TI - Acacia Senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity. AB - Cylophosphamide (CYCL) is a strong anticancer and immunosuppressive agent but its urotoxicity presents one of the major toxic effects that limit its wide usage particularly in high dose regimens. Therefore, this study aimed to investigate Acacia Senegal gum exudate ,Gum Arabic (GA), for its possible role as a natural, nontoxic agent against CYCL-induced urotoxicity. Male Swiss albino rats were exposed to CYCL (150 mg/kg BW, once i.p) with or without GA oral supplementation (7.5 g/kg/day for 6 days) through drinking water. Glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO) bladder contents were assessed. Responsiveness of the bladder rings to acetylcholine (ACh) in vitro, microscopic and macroscopic features are also investigated. CYCL produced pronounced harmful effects on bladder urothelial lining with significant increases in (MDA) and NO levels in the tissue homogenates. Bladder-GSH content is dropped by over 60% following CYCL injection. Bladder contractility, as measured by its responsiveness to ACh, recorded a marked reduction. The isolated bladders exhibited such macroscopic changes as severe edema, inflammation and extravasation. The bladder weight increased as well. Histological changes were evident in the form of severe congestion, petechial hemorrhage and chronic inflammatory reaction in the lamina propria accompanied with desquamated epithelia. GA, a potential protective agent, produced an almost complete reversal of NO induction, lipid peroxidation or cellular GSH bladder contents in the GA+CYCL-treated group. Likewise, bladder inflammation and edema were reduced. Bladder rings showed a remarkable recovery in their responsiveness to ACh. Bladder histological examination showed a near normal configuration and structural integrity, with a significant reduction in inflammation and disappearance of focal erosions. These remarkable effects of GA may be attributed to its ability to neutralize acrolein, the reactive metabolite of CYCL and/or the resultant reactive oxygen metabolites, through a scavenging action. GA may limit the cascading events of CYCL -induced damage, initiating a cytoprotective effect leading to structural and functional recovery of the bladder tissues. PMID- 20716905 TI - Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. AB - Oxidative stress contributes to the pathophysiology of exposure to heavy metals/metalloid. Beneficial renal effects of some medications, such as chelation therapy depend at least partially on the ability to alleviate oxidative stress. The administration of various natural or synthetic antioxidants has been shown to be of benefit in the prevention and attenuation of metal induced biochemical alterations. These include vitamins, N-acetylcysteine, alpha-lipoic acid, melatonin, dietary flavonoids and many others. Human studies are limited in this regard. Under certain conditions, surprisingly, the antioxidant supplements may exhibit pro-oxidant properties and even worsen metal induced toxic damage. To date, the evidence is insufficient to recommend antioxidant supplements in subject with exposure to metals. Prospective, controlled clinical trials on safety and effectiveness of different therapeutic antioxidant strategies either individually or in combination with chelating agent are indispensable. The present review focuses on structural, chemical and biological aspects of antioxidants particularly related to their chelating properties. PMID- 20716907 TI - Oxidative stress in the hippocampus during experimental seizures can be ameliorated with the antioxidant ascorbic acid. AB - Ascorbic acid has many nonenzymatic actions and is a powerful water-soluble antioxidant. It protects low density lipoproteins from oxidation and reduces harmful oxidants in the central nervous system. Pilocarpine-induced seizures have been suggested to be mediated by increases in oxidative stress. Current studies have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures. The objective of the present study was to evaluate the neuroprotective effects of ascorbic acid (AA) in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), ascorbic acid (500 mg/kg, i.p., AA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of ascorbic acid (500 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of ascorbic acid (AA plus pilocarpine group). After the treatments all groups were observed for 6h. The enzyme activities as well as the lipid peroxidation and nitrite concentrations were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of ascorbic acid were also evaluated on the same parameters. In pilocarpine group there was a significant increase in lipid peroxidation and nitrite level. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the lipid peroxidation level and nitrite content as well as increased the superoxide dismutase and catalase activities in hippocampus of adult rats after seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, proving that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences, and also imply that a strong protective effect could be achieved using ascorbic acid. PMID- 20716908 TI - Methanol extract of Ocimum gratissimum protects murine peritoneal macrophages from nicotine toxicity by decreasing free radical generation, lipid and protein damage and enhances antioxidant protection. AB - In the present study, methanol extract of Ocimum gratissimum Linn (ME-Og) was tested against nicotine-induced murine peritoneal macrophage in vitro. Phytochemical analysis of ME-Og shown high amount of flavonoid and phenolic compound present in it. The cytotoxic effect of ME-Og was studied in murine peritoneal macrophages at different concentrations (0.1 to 100 microg/ml) using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) method. To establish the protective role of ME-Og against nicotine toxicity, peritoneal macrophages from mice were treated with nicotine (10 mM), nicotine+ME-Og (1 to 25 microg/ml) for 12h in culture media. The significantly (P< 0.05) increased super oxide anion generation, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, myeloperoxidase (MPO) activity, lipid peroxidation, protein carbonyls, oxidized glutathione levels were observed in nicotine-treated group as compared to control group; those were significantly (p < 0.05) reduced in ME-Og supplemented groups in concentration dependent manner. More over, significantly (p < 0.05) reduced antioxidant status due to nicotine exposure was effectively ameliorated by ME-Og supplementation in murine peritoneal macrophages. Among the different concentration of ME-Og, maximum protective effect was observed by 25 microg/ml, which does not produce significant cell cytotoxicity in murine peritoneal macrophages. These findings suggest the potential use and beneficial role of O. gratissimum as a modulator of nicotine induced free radical generation, lipid-protein damage and antioxidant status in important immune cell, peritoneal macrophages. PMID- 20716909 TI - Oral administration of L-arginine in patients with angina or following myocardial infarction may be protective by increasing plasma superoxide dismutase and total thiols with reduction in serum cholesterol and xanthine oxidase. AB - Administration of L-arginine has been shown to control ischemic injury by producing nitric oxide which dilates the vessels and thus maintains proper blood flow to the myocardium. In the present study attempt has been made to determine whether oral administration of L-arginine has any effect on oxidant/ antioxidant homeostasis in ischemic myocardial patients [represented by the patients of acute angina (AA) and acute myocardial infarction (MI)]. L-arginine has antioxidant and antiapoptotic properties, decreases endothelin-1 expression and improves endothelial function, thereby controlling oxidative injury caused during myocardial ischemic syndrome. Effect of L-arginine administration on the status of free radical scavenging enzymes, pro-oxidant enzyme and antioxidants viz. total thiols, carbonyl content and plasma ascorbic acid levels in the patients has been evaluated. We have observed that L-arginine administration (three grams per day for 15 days) resulted in increased activity of free radical scavenging enzyme superoxide dismutase (SOD) and increase in the levels of total thiols (T SH) and ascorbic acid with concomitant decrease in lipid per-oxidation, carbonyl content, serum cholesterol and the activity of proxidant enzyme, xanthine oxidase (XO). These findings suggest that the supplementation of L-arginine along with regular therapy may be beneficial to the patients of ischemic myocardial syndromes. PMID- 20716910 TI - Role of tyrosine phosphorylation in the antioxidant effects of the p75 neurotrophin receptor. AB - The p75 neurotrophin receptor (p75NTR) is an alpha- and gamma-secretase substrate expressed preferentially in the cholinergic neurons of the nucleus basalis of Meynert, the hippocampus, and the cerebellum of the adult brain. Mutations of the gamma-secretase, presenilin, have been implicated in familial Alzheimer's disease. Furthermore, oxidative and inflammatory injury to the cholinergic neurons of the nucleus basalis of Meynert and hippocampus plays a critical role in the pathology of Alzheimer's disease. The intracellular domain of p75NTR (p75ICD) is the alpha- and gamma-secretase cleavage fragment of the holoreceptor that functions as an antioxidant in PC12 rat pheochromocytoma cells. Phosphorylation of the receptor is thought to be necessary for many of its functions, and two tyrosines in p75ICD have been among the functionally important phosphorylation sites. Site-directed mutagenesis was used to generate three p75ICD mutants that cannot be phosphorylated at either or both tyrosines, respectively. Each of these mutants was expressed in p75NTR-deficient PC12 cells to determine the effects of blocking phosphorylation at specific sites on the antioxidant activity of p75ICD. Interfering with phosphorylation at tyrosine-337 impairs antioxidant function, while interfering with phosphorylation at tyrosine 366 does not, and may in fact impart protection from oxidant stress. Neither MAPK (i.e., p38, ERK1, ERK2) content nor NF-kappaB activation accounts for the differential sensitivity to oxidant stress among the differentially phosphorylated p75NTR cell lines. However, differences in the time course of ERK1,2 phosphorylation among the lines account in large measure for their differential oxidant sensitivity. The phosphorylation state of specific sites on p75ICD may modulate the resistance of neurons in Alzheimer's disease-relevant brain regions to oxidant stress. PMID- 20716911 TI - Role of creatine supplementation on exercise-induced cardiovascular function and oxidative stress. AB - Many degenerative diseases are associated with increased oxidative stress. Creatine has the potential to act as an indirect and direct antioxidant; however, limited data exist to evaluate the antioxidant capabilities of creatine supplementation within in-vivo human systems. This study aimed to investigate the effects of oral creatine supplementation on markers of oxidative stress and antioxidant defenses following exhaustive cycling exercise. Following preliminary testing and two additional familiarization sessions, 18 active males repeated two exhaustive incremental cycling trials (T1 and T2) separated by exactly 7 days. The subjects were assigned, in a double-blind manner, to receive either 20 g of creatine (Cr) or a placebo (P) for the 5 days preceding T2. Breath-by-breath respiratory data and heart rate were continually recorded throughout the exercise protocol and blood samples were obtained at rest (preexercise), at the end of exercise (postexercise), and the day following exercise (post24 h). Serum hypdroperoxide concentrations were elevated at postexercise by 17 +/- 5% above pre-exercise values (P = 0.030). However, supplementation did not influence lipid peroxidation (serum hypdroperoxide concentrations), resistance of low density lipoprotein to oxidative stress (t1/2max LDL oxidation) and plasma concentrations of non-enzymatic antioxidants (retinol, alpha-carotene, beta-carotene, alpha tocopherol, gamma-tocopherol, lycopene, and vitamin C). Heart rate and oxygen uptake responses to exercise were not affected by supplementation. These findings suggest that short-term creatine supplementation does not enhance non-enzymatic antioxidant defence or protect against lipid peroxidation induced by exhaustive cycling in healthy males. PMID- 20716912 TI - Competing forces of nature: improving the odds with full disclosure. PMID- 20716913 TI - Oxidative stress as a mediator of cardiovascular disease. AB - During physiological processes molecules undergo chemical changes involving reducing and oxidizing reactions. A molecule with an unpaired electron can combine with a molecule capable of donating an electron. The donation of an electron is termed as oxidation whereas the gaining of an electron is called reduction. Reduction and oxidation can render the reduced molecule unstable and make it free to react with other molecules to cause damage to cellular and sub cellular components such as membranes, proteins and DNA. In this paper, we have discussed the formation of reactive oxidant species originating from a variety of sources such as nitric oxide (NO) synthase (NOS), xanthine oxidases (XO), the cyclooxygenases, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase isoforms and metal-catalysed reactions. In addition, we present a treatise on the physiological defences such as specialized enzymes and antioxidants that maintain reduction-oxidation (redox) balance. We have also given an account of how enzymes and antioxidants can be exhausted by the excessive production of reactive oxidant species (ROS) resulting in oxidative stress/nitrosative stress, a process that is an important mediator of cell damage. Important aspects of redox imbalance that triggers the activity of a number of signalling pathways including transcription factors activity, a process that is ubiquitous in cardiovascular disease related to ischemia/reperfusion injury have also been presented. PMID- 20716914 TI - Plant polyphenols as dietary antioxidants in human health and disease. AB - Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases. Here we present knowledge about the biological effects of plant polyphenols in the context of relevance to human health. PMID- 20716916 TI - The plant extracts of Momordica charantia and Trigonella foenum-graecum have anti oxidant and anti-hyperglycemic properties for cardiac tissue during diabetes mellitus. AB - Oxidative stress is currently suggested to play a major role in the development of diabetes mellitus. There is an increasing demand of natural anti-diabetic agents, as continuous administration of existing drugs and insulin are associated with many side effects and toxicity. The present study was aimed to investigate the effect of Momordica charantia (MC) and Trigonella foenum graecum (TFG) extracts (aqueous) on antioxidant status and lipid peroxidation in heart tissue of normal and alloxan induced diabetic rats. In a 30 days treatment, rats were divided into six groups (I-VI) of five animals in each,experiments were repeated thrice. Administration of MC (13.33 g pulp/kg body weight/day) and TFG (9 g seeds powder/kg body weight/day) extracts in diabetic rats has remarkably improved the elevated levels of fasting blood glucose. A significant decrease in lipid peroxidation (p<0.001) and significant increase in the activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and reduced glutathione (GSH ) contents in heart tissue of diabetic rats were observed (group V and VI) upon MC and TFG treatment. Our studies demonstrate the anti-hyperglycemic and anti-oxidative potential of Momordica charantia and Trigonella foenum graecum, which could exert beneficial effects against the diabetes and associated free radicals complications in heart tissue. PMID- 20716919 TI - cAMP activates the generation of reactive oxygen species and inhibits the secretion of IL-6 in peripheral blood mononuclear cells from type 2 diabetic patients. AB - Peripheral blood mononuclear cells (PBMNC) from patients with type 2 diabetes (DM2) have generated higher levels of reactive oxygen species (ROS) that were higher than those in cells from healthy individuals. In the presence of a cAMP elevating agent, ROS production was significantly activated in PBMNC from DM2 patients but it was inhibited in cells from healthy subjects. Higher levels of IL 6 has been detected in the supernatant of PBMNC cultures from DM2 patients in comparison with healthy controls. When cells were cultured in the presence of a cAMP-elevating agent, the level of IL-6 decreased has by 46% in the supernatant of PBMNC from DM2 patients but it remained unaltered in controls. No correlations between ROS and IL-6 levels in PBMNC from DM2 patients or controls have been observed. Secretions of IL-4 or IFNgamma by PBMNC from patients or controls have not been affected by the elevation of cAMP. cAMP elevating agents have activated the production of harmful reactive oxidant down modulated IL-6 secretion by these cells from DM2 patients, suggesting an alteration in the metabolic response possibly due to hyperglicemia. The results suggest that cAMP may play an important role in the pathogenesis of diabetes. PMID- 20716918 TI - The fat-1 transgene in mice increases antioxidant potential, reduces pro inflammatory cytokine levels, and enhances PPAR-gamma and SIRT-1 expression on a calorie restricted diet. AB - Both n-3 fatty acids (FA) and calorie-restriction (CR) are known to exert anti inflammatory and anti-oxidative effects in animals and humans. In this study, we investigated the synergistic anti-inflammatory and anti-oxidative capacity of n-3 FA and CR using Fat-1 transgenic mice (Fat-1) that are capable of converting n-6 FA to n-3 FA endogenously. Wild type (WT) and Fat-1 mice were maintained on ad libitum (AL) or CR (40% less than AL) AIN-93 diet supplemented with 10% corn oil (rich in n-6 FA) for 5 months. Significantly lower levels of n-6/n-3 FA ratio were observed in serum, muscle and liver of Fat-1 mice fed AL or CR as compared to that of WT mice fed AL or CR. Muscle catalase (CAT), super oxide dismutase (SOD), glutathione peroxidase (GPX) activities, and liver CAT and SOD activities were found higher in Fat-1 mice as compared to that of WT mice. These activities were more pronounced in Fat-1/CR group as compared to other groups. Serum pro inflammatory markers, such as tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, and IL-6 were found lower in Fat-1 mice, as compared to that of WT mice. This anti-inflammatory effect was also more pronounced in Fat-1/CR group as compared to that of other groups. Furthermore, significantly higher levels of peroxisome proliferator-activated receptor (PPAR)-gamma and life prolonging gene, sirtuin (SIRT)-1 expression were found in liver of Fat-1/CR mice, as compared to that of WT/CR mice. These data suggest that n-3 FA along with moderate CR may prolong lifespan by attenuating inflammation and oxidative stress. PMID- 20716915 TI - New strategies for Alzheimer's disease and cognitive impairment. AB - Approximately five million people suffer with Alzheimer's disease (AD) and more than twenty-four million people are diagnosed with AD, pre-senile dementia, and other disorders of cognitive loss worldwide. Furthermore, the annual cost per patient with AD can approach $200,000 with an annual population aggregate cost of $100 billion. Yet, complete therapeutic prevention or reversal of neurovascular injury during AD and cognitive loss is not achievable despite the current understanding of the cellular pathways that modulate nervous system injury during these disorders. As a result, identification of novel therapeutic targets for the treatment of neurovascular injury would be extremely beneficial to reduce or eliminate disability from diseases that lead to cognitive loss or impairment. Here we describe the capacity of intrinsic cellular mechanisms for the novel pathways of erythropoietin and forkhead transcription factors that may offer not only new strategies for disorders such as AD and cognitive loss, but also function as biomarkers for disease onset and progression. PMID- 20716917 TI - Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. AB - BACKGROUND: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)-alpha is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNF alpha/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. RESULTS: We found (a) abundant tissue TNF alpha and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNF-alpha/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNF-alpha-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNF-alpha-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-rho) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNF-alpha/ROS-induced intestinal epithelial cell injury; (e) TNF-alpha induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNF-alpha/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a late phenomenon. METHODS: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNF-alpha and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-rho) intestinal epithelial cells were used to determine the effects of TNF-alpha on mitochondrial function. CONCLUSIONS: Our findings suggest that TNF-alpha induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC. Therapies directed against mitochondria/ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NEC. PMID- 20716920 TI - Intestinal oxidative state can alter nutrient and drug bioavailability. AB - Organic cations (OCs) are substances of endogenous (e.g. dopamine, choline) or exogenous (e.g. drugs like cimetidine) origin that are positively charged at physiological pH. Since many of these compounds can not pass the cell membrane freely, their transport in our out of cells must be mediated by specific transport systems. Transport by organic cation transporters (OCTs) can be regulated rapidly by altering their trafficking and/or affinities in response to a stimuli. However, for example, a specific disease could lead to modifications in the expression of OCTs. Chronic exposure to oxidative stress has been suggested to alter regulation and functional activity of proteins through several pathways. According to results from a previous work, oxidation-reduction pathways were thought to be involved in intestinal organic cation uptake modulation. The present work was performed in order to evaluate the influence of oxidative stressors, especially glutathione, on the intestinal organic cation absorption. For this purpose, the effect of compounds with different redox potential (glutathione, an endogenous antioxidant, and procyanidins, diet antioxidants) was assessed on MPP+ (1-methyl-4-phenylpyridinium iodide) uptake in an enterocyte cell line (Caco-2). Caco-2 cells were subcultured with two different media conditions (physiological: 5 mM glucose, referred as control cells; and high glucose: 25 mM glucose, referred as HG cells). In HG cells, the uptake was significantly lower than in control cells. Redox changing interventions affected MPP+ uptake, both in control and in high-glucose Caco-2 cells. Cellular glutathione levels could have an important impact on membrane transporters activity. The results indicate that modifications in the cellular oxidative state modulate MPP+ uptake by Caco-2 cells. Such modifications may reflect in changes of nutrient and drug bioavailability. PMID- 20716921 TI - Cardiac and renal function are progressively impaired with aging in Zucker diabetic fatty type II diabetic rats. AB - This study investigated the temporal relationship between cardiomyopathy and renal pathology in the type II diabetic Zucker diabetic fatty (ZDF) rat. We hypothesized that changes in renal function will precede the development of cardiac dysfunction in the ZDF rat. Animals (10 weeks old) were divided into four experimental groups: Lean Control (fa/?) LC(n = 7), untreated ZDF rats (n = 7) sacrificed at 16 weeks of age, and LC (n = 7) untreated ZDF rats (n = 9) sacrificed at 36 weeks of age. LV structural/functional parameters were assessed via Millar conductance catheter. Renal function was evaluated via markers of proteinuria and evidence of hydronephrosis. LV mass was significantly less in the ZDF groups at both time points compared to age-matched LC. End diastolic volume was increased by 16% at 16 weeks and by 37% at 36 weeks of age (p < 0.05 vs. LC). End diastolic pressure and end systolic volume were significantly increased (42% and 27%respectively) at 36 weeks of age in the ZDF compared to LC. Kidney weights were significantly increased at both 16 and 36 week in ZDF animals (p < 0.05 vs. LC). Increased urinary albumin and decreased urinary creatinine were paralleled by a marked progression in the severity of hydronephrosis from 16 to 36 weeks of age in the ZDF group. In summary, there is evidence of progressive structural and functional changes in both the heart and kidney, starting as early as 16 weeks,without evidence that one pathology precedes or causes the other in the ZDF model of type II diabetes. PMID- 20716922 TI - Ringing in the New Year: new prospects for development, aging and longevity. PMID- 20716923 TI - Markers of oxidative stress in erythrocytes and plasma during aging in humans. AB - Aging is an inevitable universal biological process, which can be characterized by a general decline in physiological function with the accumulation of diverse adverse changes and increased probability of death. Among several theories, oxidative stress/free radical theory offers the best mechanistic elucidation of the aging process and other age -related phenomenon. In the present paper , we discuss the aging process and have focused on the importance of some reliable markers of oxidative stress which may be used as biomarkers of the aging process. PMID- 20716924 TI - Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity. AB - Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3'-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and ant-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties. PMID- 20716926 TI - gamma-Tocotrienol prevents oxidative stress-induced telomere shortening in human fibroblasts derived from different aged individuals. AB - The effects of palm gamma-tocotrienol (GGT) on oxidative stress-induced cellular ageing was investigated in normal human skin fibroblast cell lines derived from different age groups; young (21-year-old, YF), middle (40-year-old, MF) and old (68-year-old, OF). Fibroblast cells were treated with gamma-tocotrienol for 24 hours before or after incubation with IC50 dose of H2O2 for 2 hours. Changes in cell viability, telomere length and telomerase activity were assessed using the MTS assay (Promega, USA), Southern blot analysis and telomere repeat amplification protocol respectively. Results showed that treatment with different concentrations of gamma-tocotrienol increased fibroblasts viability with optimum dose of 80 microM for YF and 40 microM for both MF and OF. At higher concentrations, gamma-tocotrienol treatment caused marked decrease in cell viability with IC50 value of 200 microM (YF), 300 microM (MF) and 100 microM (OF). Exposure to H2O2 decreased cell viability in dose dependent manner, shortened telomere length and reduced telomerase activity in all age groups. The IC50 of H2O2 was found to be; YF (700 microM), MF (400 microM) and OF (100 microM). Results showed that viability increased significantly (p < 0.05) when cells were treated with 80 microM and 40 microM gamma-tocotrienol prior or after H2O2-induced oxidative stress in all age groups. In YF and OF, pretreatment with gamma-tocotrienol prevented shortening of telomere length and reduction in telomerase activity. In MF, telomerase activity increased while no changes in telomere length was observed. However, post-treatment of gamma-tocotrienol did not exert any significant effects on telomere length and telomerase activity. Thus, these data suggest that gamma-tocotrienol protects against oxidative stress induced cellular ageing by modulating the telomere length possibly via telomerase. PMID- 20716927 TI - Modulation of ionizing radiation induced oxidative imbalance by semi-fractionated extract of Piper betle: an in vitro and in vivo assessment. AB - The study was planned to evaluate modulatory effect of aqueous extract of Piper betle leaf (PBL) on ionizing radiation mediated oxidative stress leading to normal tissues damage during radiotherapy and other radiation exposures. The total polyphenols and flavonoids known as free radical scavenger (chelators) were measured in the extract. To ascertain antioxidant potential of PBL extract we studied free radical scavenging, metal chelation, reducing power, lipid peroxidation inhibition and ferric reducing antioxidant properties (FRAP) using in vitro assays. Mice were exposed to varied radiation doses administered with the same extract prior to irradiation to confirm its oxidative stress minimizing efficacy by evaluating ferric reducing ability of plasma, reduced glutathione, lipid peroxidation and micro-nuclei frequency. PBL extract was effective in scavenging DPPH (up to 92% at 100 microg/ml) and superoxide radicals (up to 95% at 80 microg/ml), chelated metal ions (up to 83% at 50 microg/ml) and inhibited lipid peroxidation (up to 55.65% at 500 microg/ml) in a dose dependant manner using in vitro model. Oral administration of PBL extract (225 mg/kg body weight) 1 hr before irradiation in mice significantly enhanced (p < 0.01) radiation abated antioxidant potential of plasma and GSH level in all the observed organs. The treatment with extract effectively lowered the radiation induced lipid peroxidation at 24 hrs in all the selected organs with maximum inhibition in thymus (p < 0.01). After 48 hrs, lipid peroxidation was maximally inhibited in the group treated with the extract. Frequency of radiation induced micronucleated cells declined significantly (34.78%, p < 0.01) at 24 hrs post-irradiation interval by PBL extract administration. The results suggest that PBL extract has high antioxidant potential and relatively non-toxic and thus could be assertively used to mitigate radiotherapy inflicted normal tissues damage and also injuries caused by moderate doses of radiation during unplanned exposures. PMID- 20716925 TI - Redox regulation in cancer: a double-edged sword with therapeutic potential. AB - Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and cell's own antioxidant defenses. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Ultraviolet (UV) exposures, gamma-radiation and other environmental carcinogens generate ROS in the cells, which can exert apoptosis in the tumors, thereby killing the malignant cells or induce the progression of the cancer growth by blocking cellular defense system. Cancer stem cells take the advantage of the aberrant redox system and spontaneously proliferate. Oxidative stress and gene environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Prolonged lifetime exposure to estrogen is associated with several kinds of DNA damage. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. BRCA1, a tumor suppressor against hormone responsive cancers such as breast and prostate cancer, plays a significant role in inhibiting ROS and estrogen mediated DNA damage; thereby regulate the redox homeostasis of the cells. Several transcription factors and tumor suppressors are involved during stress response such as Nrf2, NF-kappaB and BRCA1. A promising strategy for targeting redox status of the cells is to use readily available natural substances from vegetables, fruits, herbs and spices. Many of the phytochemicals have already been identified to have chemopreventive potential, capable of intervening in carcinogenesis. PMID- 20716928 TI - Transient glutathione depletion determines terminal differentiation in HL-60 cells. AB - To better define the role of glutathione (GSH) in cell differentiation, the present study measured GSH concentrations during terminal HL-60 cell differentiation, in the presence and absence of differentiation-inducing agents, and in the presence and absence of GSH altering agents. Interestingly, there was a small transient increase in intracellular GSH levels during dimethyl sulfoxide (DMSO) or 1alpha,25-dihydroxyvitamin D3 (VD3) induced differentiation. This increase coincided with an increase in nitroblue tetrazolium (NBT) reduction capacity, a measure of superoxide anion production, but there was no apparent change in the GSH/glutathione disulfide (GSSG) ratio. Surprisingly, treatment of cells with low doses of 1-chloro-2,4-dinitrobenzene (CDNB; 5 microM) or diethylmaleate (DEM; 0.5 mM), which transiently deplete GSH levels to about 40% of control levels, resulted in enhanced differentiation of HL-60 cells exposed to VD3 or all-trans-retinoic acid (ATRA), as well as under un-induced conditions (i.e., spontaneous differentiation). Enhanced differentiation occurred when cells were treated with the GSH-depleting agents 4 hours after treatment with differentiation inducers. These findings indicate that intracellular GSH levels are regulated in a complex fashion during HL-60 cell differentiation, and that transient GSH depletion using low doses of CDNB and DEM enhances the differentiation process. PMID- 20716929 TI - Antineoplastic activities of MT81 and its structural analogue in Ehrlich ascites carcinoma-bearing Swiss Albino mice. AB - Many fungal toxins exhibit in vitro and in vivo antineoplastic effects on various cancer cell types. Luteoskyrin,a hydroxyanthraquinone has been proved to be a potent inhibitor against Ehrlich ascites tumor cells. The comparative antitumor activity and antioxidant status of MT81 and its structural analogue [Acetic acid MT81 (Aa-MT81)] having polyhydroxyanthraquinone structure were assessed against Ehrlich ascites carcinoma (EAC) tumor in mice. The in vitro cytotoxicity was measured by the viability of EAC cells after direct treatment of the said compounds. In in vivo study, MT81 and its structural analogue were administered (i.p.) at the two different doses (5, 7 mg MT81; 8.93, 11.48 mg Aa-MT81/kg body weight) for 7 days after 24 hrs. of tumor inoculation. The activities were assessed using mean survival time (MST), increased life span (ILS), tumor volume, viable tumor cell count, peritoneal cell count, protein percentage and hematological parameters. Antioxidant status was determined by malondialdehyde (MDA) and reduced glutathione (GSH) content, and by the activity of superoxide dismutase (SOD) and catalase (CAT). MT81 and its structural analogues increased the mean survival time, normal peritoneal cell count. They decreased the tumor volume, viable tumor cell count, hemoglobin percentage and packed cell volume. Differential counts of WBC, total counts of RBC & WBC that altered by EAC inoculation, were restored in a dose-dependent manner. Increased MDA and decreased GSH content and reduced activity of SOD, and catalase in EAC bearing mice were returned towards normal after the treatment of MT81 and its structural analogue. Being less toxic than parent toxin MT81, the structural analogue showed more prominent antineoplastic activities against EAC cells compared to MT81. At the same time, both compounds exhibit to some extent antioxidant potential for the EAC-bearing mice. PMID- 20716930 TI - Role of peroxiredoxin III in the pathogenesis of pre-eclampsia as evidenced in mice. AB - As a member of peroxiredoxin (Prx) family, PrxIII has been demonstrated to play an important role in scavenging intracellular reactive oxygen species (ROS). Since PrxIII knockout mice exhibited oxidative stress in placentas resembling pathophysiologic changes in placentas of human pre-eclampsia, we measured blood pressure through the carotid artery and detected oxidative status by Western blotting in pregnant mice. We did not notice hypertension in pregnant PrxIII knockout mice as compared with wild-type littermates, although endothelin-1 was over-expressed in PrxIII-deficient placentas. Our results indicate that PrxIII is not involved in pre-eclamptic development. Instead, PrxIII is an indispensable antioxidant in placentas where oxidative stress exists. PMID- 20716931 TI - Heal thyself: Endogenous pathways of protection for oxidative stress. PMID- 20716932 TI - Reactive oxygen species and age-related genes p66shc, Sirtuin, FOX03 and Klotho in senescence. AB - Reactive oxygen species (ROS) superoxide and hydrogen peroxide perform important signaling functions in many physiological and pathophysiological processes. Cell senescence and organismal age are not exemptions.Aging-regulating genes p66shc, Sirtuin, FOXO3a and Klotho are new important factors which are stimulated by ROS signaling. It has been shown that ROS participate in initiation and prolongation of gene-dependent aging development.ROS also participate in the activation of protein kinases Akt/PKB and extracellular signal-regulated kinase ERK, which by themselves or through gene activation stimulates or retards cell senescence.Different retarding/stimulating effects of ROS might depend on the nature of signaling species-superoxide or hydrogen peroxide. Importance of radical anion superoxide as a signaling molecule with"super-nucleophilic" properties points to the possibility of the use of superoxide scavengers (SOD mimetics, ubiquinones and flavonoids) for retarding the development of aging. PMID- 20716934 TI - Advanced glycation end products, oxidative stress and diabetic nephropathy. AB - About 246 million people worldwide have diabetes in 2007. The global figure of people with diabetes is projected to increase to 370 million in 2030. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. In this paper, we review the pathophysiological role of AGEs and their receptor (RAGE)-oxidative stress system in diabetic nephropathy. PMID- 20716935 TI - Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. AB - Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and reported on a global scale. The uremic milieu predisposes to multiple metabolic toxicities including increased levels of reactive oxygen species and inflammation. Increased oxidative stress and inflammation promote this arteriolopathy by adversely affecting endothelial function resulting in a prothrombotic milieu and significant remodeling effects on vascular smooth muscle cells. These arteriolar pathological effects include intimal hyperplasia, inflammation, endovascular fibrosis and vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Systemic factors promoting this vascular condition include elevated calcium, parathyroid hormone, and hyperphosphatemia with consequent increases in the calcium x phosphate product. The uremic milieu contributes to a marked increased in upstream reactive oxygen species - oxidative stress and subsequent downstream increased inflammation, in part, via activation of the nuclear transcription factor NFkappaB and associated downstream cytokine pathways. Consitutive anti-calcification proteins such as Fetuin-A and matrix GLA proteins and their signaling pathways may be decreased, which further contributes to medial vascular calcification. The resulting clinical entity is painful, debilitating and contributes to the excess morbidity and mortality associated with chronic kidney disease and end stage renal disease. These same histopathologic conditions also occur in patients without uremia and therefore, the term calcific obliterative arteriolopathy could be utilized in these conditions. PMID- 20716933 TI - Multifaceted approach to resveratrol bioactivity: Focus on antioxidant action, cell signaling and safety. AB - Resveratrol (RVT) is a naturally occurring trihydroxy stilbene that displays a wide spectrum of physiological activity. Its ability to behave therapeutically as a component of red wine has attracted wide attention. The phenol acts as a protective agent involving various body constituents. Most attention has been given to beneficial effects in insults involving cancer, aging, cardiovascular system, inflammation and the central nervous system. One of the principal modes of action appears to be as antioxidant. Other mechanistic pathways entail cell signaling, apoptosis and gene expression. There is an intriguing dichotomy in relation to pro-oxidant property. Also discussed are metabolism, receptor binding, rationale for safety and suggestions for future work. This is the first comprehensive review of RVT based on a broad, unifying mechanism. PMID- 20716936 TI - Release of B cell-activating factor of the TNF family in bronchoalveolar lavage from Behcet's disease with pulmonary involvement. AB - Pulmonary artery aneurysms, arterial and venous thrombosis, pulmonary infarction, recurrent pneumonia, bronchiolitis obliterans organized pneumonia, and pleurisy are the main features of pulmonary involvement in Behcet's disease. The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B-cell survival and immunoglobulin class-switch recombination, in bronchoalveolar lavage (BAL) fluid from BD patients having pulmonary manifestation. Bronchoalveolar lavage (BAL) was performed in 15 BD patients with pulmonary manifestation and 18 BAL from healthy controls. Concentrations of B cell-active cytokines, including BAFF, IL-6, and IL 13, were measured by using specific ELISA and cytometric bead array assays. Levels of BAFF protein were significantly increased in BAL fluid from active BD [109 +/- 21.78 pg/mL] compared with those oh healthy controls [4.83 +/- 1.75 pg/mL; P<0.0001]. In the BAL fluid, BAFF levels were significantly correlated with absolute numbers of total cells [r = 0.823; P<0.0001], lymphocytes [r = 0.709; P<0.0001], neutrophils [r = 0.809; P<0.0001] and macrophages [r = 0.742; P<0.0001]. Normalization to albumin indicated that BAFF production occurred locally in the airways. BAFF levels were also significantly correlated with the other B cell-activating cytokines IL-6 [r = 0.882, P<0.001] and IL-13 [r = 0.659, P<0.001].The antigen-induced production of BAFF in the lung of active BD with pulmonary manifestations might contribute to immunoglobulin synthesis by B cells. The cells residing in the lung might affect each other through BAFF. PMID- 20716937 TI - A novel dietary supplement containing multiple phytochemicals and vitamins elevates hepatorenal and cardiac antioxidant enzymes in the absence of significant serum chemistry and genomic changes. AB - A novel dietary supplement composed of three well-known phytochemicals, namely, Salvia officinalis (sage) extract, Camellia sinensis (oolong tea) extract, and Paullinia cupana (guarana) extract, and two prominent vitamins (thiamine and niacin) was designed to provide nutritional support by enhancing metabolism and maintaining healthy weight and energy. The present study evaluated the safety of this dietary supplement (STG; S=sage; T=tea; G=guarana) and assessed changes in target organ antioxidant enzymes (liver, kidneys and heart), serum chemistry profiles and organ histopathology in Fisher 344 rats. Adult male and female Fisher 344 rats were fed control (no STG) or STG containing (1X and 7X, 1X=daily human dose) diets and sacrificed after 2 and 4 months. Serum chemistry analysis and histopathological examination of three vital target organs disclosed no adverse influence on protein, lipid and carbohydrate profiles, genomic integrity of the liver and/or the tissue architecture. However, analysis of the most important antioxidant components in the liver, kidney and heart homogenates revealed a dramatic increase in total glutathione concentrations, glutathione peroxidase and superoxide dismutase enzyme activities. Concomitantly, oxidative stress levels (malondialdehyde accumulation) in these three organs were less than control. Organ specific serum markers (ALT/AST for the liver; CPK/AST for the heart; BUN/creatinine for kidneys) and the genomic integrity disclosed no STG induced alteration. Some of the serum components (lipid and protein) showed insignificant changes. Overall, STG-exposed rats were more active, and the results suggest that STG exposure produces normal serum chemistry coupled with elevated antioxidant capacity in rats fed up to seven times the normal human dose and does not adversely influence any of the vital target organs. Additionally, this study reiterates the potential benefits of exposure to a pharmacologically relevant combination of phytochemicals compared to a single phytochemical entity. PMID- 20716938 TI - Sustained delivery of nicotinamide limits cortical injury and improves functional recovery following traumatic brain injury. AB - Previously, we have demonstrated that nicotinamide (NAM), a neuroprotective soluble B-group vitamin, improves recovery of function following traumatic brain injury (TBI). However, no prior studies have examined whether NAM is beneficial following continuous infusions over 7 days post-TBI. The purpose of this study was to investigate the preclinical efficacy of NAM treatment as it might be delivered clinically; over several days by slow infusion. Rats were prepared with either unilateral controlled cortical impact (CCI) injuries or sham procedures and divided into three groups: CCI-NAM, CCI-vehicle, and sham. Thirty minutes following CCI, Alzet osmotic mini-pumps were implanted subcutaneously. NAM was delivered at a rate of 50 mg/kg/day for 7 days immediately post-CCI. On day 7 following injury, the pumps were removed and blood draws were collected for serum NAM and nicotinamide adenine dinucleotide (NAD+) analyses. Starting on day 2 post CCI, animals were tested on a battery of sensorimotor tests (bilateral tactile adhesive removal, locomotor placing, and limb-use asymmetry). Continuous infusion of NAM resulted in a significant serum elevation in NAM, but not NAD+. Statistical analyses of the tactile removal and locomotor placing data revealed that continuous administration of NAM significantly reduced the initial magnitude of the injury deficit and improved overall recovery compared to the vehicle treated animals. NAM treatment also significantly decreased limb-use asymmetries compared to vehicle-treated animals. The overall extent of the cortical damage was also reduced by NAM treatment. No detrimental effects were seen following continuous infusion. The present results suggest that NAM delivered via a clinically relevant therapeutic regimen may truncate behavioral damage following TBI. Thus our results offer strong support for translation into the clinical population. PMID- 20716940 TI - Tolerance: a virtue during times of stress. PMID- 20716939 TI - Wnt1 neuroprotection translates into improved neurological function during oxidant stress and cerebral ischemia through AKT1 and mitochondrial apoptotic pathways. AB - Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression of Wnt1 or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress. PMID- 20716941 TI - Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer. AB - Autophagy is a catalytic process of the bulk degradation of long-lived cellular components, ultimately resulting in lysosomal digestion within mature cytoplasmic compartments known as autophagolysosomes. Autophagy serves many functions in the cell, including maintaining cellular homeostasis, a means of cell survival during stress (e.g., nutrient deprivation or starvation) or conversely as a mechanism for cell death. Increased reactive oxygen species (ROS) production and the resulting oxidative cell stress that occurs in many disease states has been shown to induce autophagy. The following review focuses on the roles that autophagy plays in response to the ROS generated in several diseases. PMID- 20716942 TI - Acetaldehyde adducts in alcoholic liver disease. AB - Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD), with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC). Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2-15%) versus cirrhosis (15 20%) is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular system and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC. PMID- 20716944 TI - Role of gender, smoking profile, hypertension, and diabetes on saphenous vein and internal mammary artery endothelial relaxation in patients with coronary artery bypass grafting. AB - The aim of this study was to investigate if there was a link between the relaxant responses in saphenous vein (SV) and internal mammary artery (IMA) segments obtained from patients undergoing coronary artery bypass grafting and the patients' cardiovascular risk factors. Endothelium-(in)dependent relaxations were assessed by isometric tension studies. Endothelium-dependent relaxant responses were greater in IMA than SV and gender, smoking profile and history of hypertension but not diabetes appeared to have an influence on these responses. Endothelium-dependent relaxant responses in both IMA and SV were greater in males than females and relaxant responses in IMA segments were attenuated in smokers, whereas the opposite effect was noted in SV segments. Endothelium-dependent relaxant responses in SV were lower in patients with hypertension. Endothelium independent relaxant responses were greater in IMA than SV. Endothelium independent responses were greater in male patients' SV segments, but gender played no role in IMA segments. Diabetes had no effect on endothelium-independent responses in IMA, but SV segments from diabetic patients had greater responses. Neither conduit's endothelium-independent response was affected by hypertensive status. The relationship between risk factor status and endothelial responses is multifactorial, with gender, hypertension, diabetes and smoking status all contributing. PMID- 20716945 TI - Redox homeostasis of albumin in relation to alpha-lipoic acid and dihydrolipoic acid. AB - Albumin represents the predominant circulating antioxidant agent in plasma exposed to continuous oxidative stress and a change in serum albumin structure accounts for its antioxidant properties. Alterations in the redox status of albumin may result in impairments of its biological properties. Alpha-lipoic acid (LA), a naturally occurring thiol compound found in virtually all species, is a potent antioxidant with high efficacy which is also involved in the chelation of metal ions, regeneration of antioxidants, and repair of oxidatively damaged proteins. In human body LA is rapidly reduced to dihydrolipoic acid (DHLA) after intake into the cell. Both, LA and DHLA are amphipathic molecules which act as antioxidants both in hydrophilic and lipophilic environments. The present study aimed to investigate the antioxidant/pro-oxidant effects of LA and DHLA due to their concentrations in metal-catalyzed protein oxidation (MCO) of human serum albumin (HSA). Progressive oxidative modification of albumin was found in MCO system by an increased content of protein hydroperoxides (POOH), protein carbonyl groups (PCO) which is the former's major breakdown product, and other protein oxidation markers such as advanced oxidized protein products (AOPP) and protein thiol groups (P-SH). The possible antioxidant protective effects of LA and DHLA were observed with 25 microM and 50 microM; DHLA being more influential. Protein oxidation parameters were found to be lower and P-SH levels seemed higher. However, prooxidant effects of both LA and DHLA came on the scene with increased concentrations of 75 microM and 100 microM where the latter seemed the most hazardous with contradicted results. It is clear that the loss of biological activity of human serum albumin by MCO system appears of medical relevance and if LA exerts similar effects seen in the present study, it is possible that cellular prooxidant activity can also result consuming this unique antioxidant in certain doses. PMID- 20716943 TI - Forever young: mechanisms of natural anoxia tolerance and potential links to longevity. AB - While mammals cannot survive oxygen deprivation for more than a few minutes without sustaining severe organ damage, some animals have mastered anaerobic life. Freshwater turtles belonging to the Trachemys and Chrysemys genera are the champion facultative anaerobes of the vertebrate world, often surviving without oxygen for many weeks at a time. The physiological and biochemical mechanisms that underlie anoxia tolerance in turtles include profound metabolic rate depression, post-translational modification of proteins, strong antioxidant defenses, activation of specific stress-responsive transcription factors, and enhanced expression of cytoprotective proteins. Turtles are also known for their incredible longevity and display characteristics of "negligible senescence". We propose that the robust stress-tolerance mechanisms that permit long term anaerobiosis by turtles may also support the longevity of these animals. Many of the mechanisms involved in natural anoxia tolerance, such as hypometabolism or the induction of various protective proteins/pathways, have been shown to play important roles in mammalian oxygen-related diseases and improved understanding of how cells survive without oxygen could aid in the understanding and treatment of various pathological conditions that involve hypoxia or oxidative stress. In the present review we discuss the recent advances made in understanding the molecular nature of anoxia tolerance in turtles and the potential links between this tolerance and longevity. PMID- 20716946 TI - Oxidative stress in fetal distress: potential prospects for diagnosis. AB - Our aim was to investigate the relation between fetal distress and oxidative stress. Fetal distress was associated with increased concentration of superoxide in the fetal blood and with significant increase of the level of H2O2 in both maternal and fetal blood. The activity of superoxide dismutase was increased roughly sixfold (p<0.01) in the maternal (7330 +/- 2240 U/g of hemoglobin in controls (C) and 36811 +/- 16862 U/g in fetal distress (FD)) and fetal blood (C: 5930 +/- 2641 U/g; FD: 41912 +/- 17133 U/g). In contrast, fetal distress was related to a considerable decrease of catalase activity in both maternal (C: 26011 +/- 8811 U/g; FD: 7212 +/- 1270 U/g) and fetal blood (C: 37194 +/- 9191 U/g; FD: 6173 +/- 1965 U/g). From this we concluded that in fetal distress, the maternal and fetal bloods are exposed to superoxide- and H2O2-mediated oxidative stress, which could be initiated by hypoxic conditions in the fetal blood and placenta. A tremendous increase/decrease of the activities of superoxide dismutase/catalase in the blood of women bearing a distressed fetus in comparison to healthy subjects implies that the assessment of superoxide dismutase/catalase activity could be of use for establishing a timely and accurate ante- or intrapartum diagnosis of fetal distress. PMID- 20716947 TI - Potential redox-sensitive Akt activation by dopamine activates Bad and promotes cell death in melanocytes. AB - Dopamine (DA) is a well known oxidative neurotoxin. In addition, Akt has been reported to deliver a survival signal that inhibits apoptosis. However, it has also been reported that chronic Akt activation leads to apoptosis in response to oxidative stress. The objective of the present study was to investigate the possible role of the Akt pathway in vitiligo and its possible relationship with DA-induced cell death using Mel-Ab cells. Cultured Mel-Ab cells were treated with DA with and without N-Acetyl-L-cysteine (NAC), which is known to have antioxidative properties. Cell viability was then assessed by a crystal violet assay and Annexin staining was performed. The changes in the expression of Akt were analyzed by western blot analysis. The cell viability was reduced by approximately 60% in response to treatment with 500 microM DA, and NAC effectively prevented this cytotoxic effect. Likewise, treatment with DA produced numerous Annexin positive cells, while treatment with NAC prevented this apoptotic cell death. Akt was slowly phosphorylated after treatment with DA, while NAC clearly inhibited the DA-induced Akt activation. Western blot analysis also showed that treatment with DA induced the activation of Bad. Finally, LY294002 exerted a protective effect against DA-induced apoptotic cell death. DA may induce redox-sensitive Akt activation and increase the level of Bad, which can promote cell death by heterodimerization with survival proteins. Moreover, NAC effectively protects against DA-induced melanocyte death via inhibition of DA induced Akt activation. PMID- 20716949 TI - Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. AB - The methylation and demethylation of CpG dinucleotides that are embedded in promoters play an important role in controlling gene transcription. In the mammalian brain, CpG promoter methylation is a postreplicative process mediated by a group of DNA methyltransferases (DNMT), such as DNMT1 and DNMT3a, DNMT3b. Several studies demonstrate that in addition to DNMTs, promoter methylation in the brain can be regulated by a putative DNA demethylation process that specifically removes the methyl group from the carbon-5 of cytosines. To test the existence of a possible active DNA demethylation activity in postmitotic neuronal or glial cells, we incubated an SssI methylated mouse reelin (Reln) promoter fragment (-720 to +140) with nuclear extracts from the mouse frontal cortex (FC). We observed the presence of DNA demethylation activity, which was increased in FC nuclear extracts from mice treated with valproate (VPA, 2.2 mmol/kg, twice a day for 3 days). VPA not only reduces anxiety, and cognitive deficits, and other symptoms in bipolar disorder (BP) disorder and schizophrenia (SZ) patients but also upregulates Reln and glutamic acid decarboxylase 67 (Gad67) mRNA/protein expression by reducing the methylation of their promoters. We believe that the identification of an enzyme in brain that facilitates DNA-demethylation and an understanding of how drugs induce DNA demethylation are crucial to progress in a new line of pharmacological interventions to treat neurodevelopment, neuropsychiatric, and neurodegenerative diseases. PMID- 20716950 TI - BCL2 interaction with actin in vitro may inhibit cell motility by enhancing actin polymerization. AB - In addition to its well-defined role as an antagonist in apoptosis, we propose that BCL2 may act as an intracellular suppressor of cell motility and adhesion under certain conditions. Our evidence shows that, when over-expressed in both cancer and non-cancer cells, BCL2 can form a complex with actin and gelsolin that functions to decrease gelsolin-severing activity to increase actin polymerization, and, thus, suppress cell adhesive processes. The linkage between increased BCL2 and increased actin polymerization on the one hand, and suppression of cell adhesion, spreading, and motility on the other hand, is a novel observation that may provide a plausible explanation for why BCL2 over expression in some tumors is correlated with improved patient survival. In addition, we have identified conditions in vitro in which F-actin polymerization can be increased while cell motility is reduced. These findings underscore the possibility that BCL2 may be involved in modulating cytoskeleton reorganization, and may provide an opportunity to explore signal transduction pathways important for cell adhesion and migration and to develop small molecule therapies for suppression of cancer metastasis. PMID- 20716948 TI - Regulating a master regulator: establishing tissue-specific gene expression in skeletal muscle. AB - MyoD is a master regulator of the skeletal muscle gene expression program. ChIP Seq analysis has recently revealed that MyoD binds to a large number of genomic loci in differentiating myoblasts, yet only activates transcription at a subset of these genes. Here we discuss recent data suggesting that the ability of MyoD to mediate gene expression is regulated through the function of Polycomb and Trithorax Group proteins. Based on studies of the muscle-specific myog gene, we propose a model where the transcriptional activators Mef2d and Six4 mediate recruitment of Trithorax Group proteins Ash2L/MLL2 and UTX to MyoD-bound promoters to overcome the Polycomb-mediated repression of muscle genes. Modulation of the interaction between Ash2L/MLL2 and Mef2d by the p38alpha MAPK signaling pathway in turns provides fine-tuning of the muscle-specific gene expression program. Thus Mef2d, Six4, and p38alpha MAPK function coordinately as regulators of a master regulator to mediate expression of MyoD target genes. PMID- 20716951 TI - Differential epithelial cell response upon stimulation with the Aggregatibacter actinomycetemcomitans strains VT 1169, VT 1560 DAM- and ATCC 4318. AB - Aggregatibacter actinomycetemcomitans is known to play a role in human inflammatory oral diseases. The present study aimed to test whether GECs from different individuals show an altered immune response when exposed to wild-type A. actinomycetemcomitans biofilms (VT 1169 and ATCC43718) versus VT 1560 lacking a DNA-adenine-methyltransferase (DAM-). GECs were cultured from biopsies derived from three healthy subjects (A, B, and C). To obtain A. actinomycetemcomitans biofilms, each strain (VT 1169, ATCC 43718, and VT 1560 DAM-) was separately cultured on polymer disks. The mRNA expression of hBD-2, Rnase7, IL-8, and glycerylaldehyd-3-phosphodehydrogenase was analyzed using semi-quantitative RT PCR. In GECs, the DAM- strain VT 1560 led to a reduced gene expression of hBD-2 and IL-8 compared to VT 1169, but not ATCC 43718. In GECs from subject C, the mRNA expression of hBD-2 and IL-8 was significantly up regulated in response to A. actinomycetemcomitans VT 1169 compared to VT 1560 DAM- and ATCC 43718 (p<=0,05), whereas GECs from subject A and B did not show significant changes for hBD-2 or IL-8 gene expression upon stimulation with either of the strains tested. The present study indicates strain-dependent and subject-specific immune responses in GECs after exposure to DAM(+) or DAM- A. actinomycetemcomitans. PMID- 20716952 TI - Driver mutations: a roadmap for getting close and personal in pancreatic cancer. PMID- 20716953 TI - Preferential association of irreversibly silenced E2F-target genes with pericentromeric heterochromatin in differentiated muscle cells. AB - The heterochromatin-associated H3K9 tri-methylase Suv39h1 is involved in the permanent silencing of E2F target genes in differentiating but not in quiescent cells. Here, we tested the hypothesis that permanent silencing of E2F target genes is associated with their subnuclear positioning close to the pericentromeric heterochromatin compartment, enriched in Suv39h1. Using fluorescence in situ hybridization, we analyzed the subnuclear localization of three E2F target genes relative to the pericentromeric heterochromatin, in cycling fibroblasts or differentiating myoblasts. We observed that all three E2F target genes have a tendency to relocate closer to the pericentromeric heterochromatin, only when cells differentiate and undergo an irreversible cell cycle withdrawal. These data suggest that repression of E2F target genes in cycling or in differentiating cells is achieved through distinct mechanisms. In differentiating cells, permanent silencing is driven by a Suv39h1-dependent H3K9 tri-methylation and positioning close to the heterochromatin compartment, whereas repression in cycling cells seems independent from subnuclear positioning and requires distinct H3K9 methylation levels. PMID- 20716954 TI - SOX17 antagonizes WNT/beta-catenin signaling pathway in hepatocellular carcinoma. AB - SRY-box containing gene 17 (SOX17) was reported to be indispensable for embryonic development and a candidate tumor suppressor gene which antagonizes the canonical WNT/beta-catenin signaling pathway in colorectal cancer. In this study, we investigated the function and epigenetic regulation of SOX17 in human hepatocellular carcinoma (HCC). DNA methylation of SOX17 was analyzed in 62 human HCC tissues and HCC cell lines by MSP. A role as a tumor suppressor gene was evaluated by colony formation assay and regulation of WNT/beta-catenin signal pathway by SOX17 was determined by IHC and luciferase reporter assay. DNA methylation of the SOX17 promoter region occurs in 82% of HCC tissues and is associated with nuclear accumulation of beta-catenin. Restoration of SOX17 inhibits HepG2 colony formation and beta-catenin/TCF-dependent transcription with the presence of HMG box in SOX17. In conclusion, SOX17 negatively regulates canonical WNT/beta-catenin signaling pathway and inhibits human HCC cells growth, providing an explanation for the loss of expression by epigenetic mechanisms in these tumors. PMID- 20716955 TI - Allele-specific methylation in the human genome: implications for genetic studies of complex disease. AB - Across the genome, outside of a small number of known imprinted genes and regions subject to X-inactivation in females, DNA methylation at CpG dinucleotides is often assumed to be complementary across both alleles in a diploid cell. However, recent findings suggest the reality is more complex, with the discovery that allele-specific methylation (ASM) is a common feature across the genome. A key observation is that the majority of ASM is associated with genetic variation in cis, although a noticeable proportion is also non-cis in nature and mediated, for example, by parental origin. ASM appears to be both quantitative, characterized by subtle skewing of DNA methylation between alleles, and heterogeneous, varying across tissues and between individuals. These findings have important implications for complex disease genetics; whilst cis-mediated ASM provides a functional consequence for non-coding genetic variation, heterogeneous and quantitative ASM complicates the identification of disease-associated loci. We propose that non-cis ASM could contribute toward the 'missing heritability' of complex diseases, rendering certain loci hemizygous and masking the direct association between genotype and phenotype. We suggest that the interpretation of results from genomewide association studies can be improved by the incorporation of epi-allelic information, and that in order to fully understand the extent and consequence of ASM in the human genome, a comprehensive sequencing-based analysis of allelic methylation patterns across tissues and individuals is required. PMID- 20716956 TI - Biotech outsourcing strategies cmc--biologics stream. June 17, 2010, Copenhagen, Denmark. AB - Now in its third year, the Biotech Outsourcing Strategies (BOS) meeting organized by Bio2Business took place at the Sohuset Conference Centre in Horsholm, Copenhagen. The focus of this year's event was the demanding and challenging area of chemistry, manufacturing and controls (CMC), and the meeting provided ample opportunity for lively discussion of the key issues surrounding this area. New for the 2010 conference, a biologics-focused lecture stream ran in parallel to the established small molecule stream. Both streams boasted a distinguished panel of keynote speakers who discussed all aspects of CMC from early stage scale-up through late stage clinical development. In addition to the keynote speakers, selected contract research organizations (CROs) gave short presentations on the solutions that they could provide to some of the challenges facing CMC. The meeting attracted more than 150 delegates from leading drug development companies and CRO service providers, and greatly facilitated the forging of new working relationships through pre-arranged one-to-one meetings. Moreover, exhibitions from event sponsors and considerable scheduled networking time over lunch and evening reception further enhanced the highly productive and interactive nature of the meeting. PMID- 20716958 TI - Regulation of yeast forkhead transcription factors and FoxM1 by cyclin-dependent and polo-like kinases. AB - Members of the forkhead-box (Fox) family of transcription factors are present in many eukaryotes. More than 100 such proteins that share homology in the winged helix DNA-binding domain have been identified in higher eukaryotes. This family of transcription factors is implicated in the regulation of a variety of cellular processes, including the cell cycle, apoptosis, DNA repair, stress resistance and metabolism. A subfamily of Fox proteins are required to activate expression of the genes encoding B-type cyclins, Cdc25 and Polo-like kinase (Plk) during the mitotic cell cycle and meiosis in organisms from yeast to mammals. These proteins are activators of cyclin-dependent kinase 1 (Cdk1). Cdk1 and Plk phosphorylate Fox and its associated proteins at different sites, resulting in activation or repression of Fox transcriptional activity, depending on the target genes. In addition to their documented transcriptional functions, Fox proteins are involved in the regulation of pre-mRNA processing, at least in yeast. In this review, we will focus on the role of Fox proteins in the fission yeast Schizosaccharomyces pombe and budding yeast Saccharomyces cerevisiae, in addition to the role of FoxM1 in mammals in the cell cycle and in pre-mRNA processing, as revealed in recent studies. PMID- 20716957 TI - Targeting HER2: a report on the in vitro and in vivo pre-clinical data supporting trastuzumab as a radioimmunoconjugate for clinical trials. AB - The potential of the HER2-targeting antibody trastuzumab as a radioimmunoconjugate useful for both imaging and therapy was investigated. Conjugation of trastuzumab with the acyclic bifunctional chelator CHX-A"-DTPA yielded a chelate:protein ratio of 3.4 +/- 0.3; the immunoreactivity of the antibody unaffected. Radiolabeling was efficient, routinely yielding a product with high specific activity. Tumor targeting was evaluated in mice bearing subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian, and prostate carcinomas. High uptake of the radioimmunoconjugate, injected intravenously (i.v.), was observed in each of the models, and the highest tumor %ID/g (51.18 +/ 13.58) was obtained with the ovarian (SKOV-3) tumor xenograft. Specificity was demonstrated by the absence of uptake of 111In-trastuzumab by melanoma (A375) s.c. xenografts and 111In-HuIgG by s.c. LS-174T xenografts. Minimal uptake of i.v. injected 111In-trastuzumab in normal organs was confirmed in non-tumor bearing mice. The in vivo behavior of 111In-trastuzumab in mice bearing intraperitoneal (i.p.) LS-174T tumors resulted in a tumor %ID/g of 130.85 +/- 273.34 at 24 h. Visualization of tumor, s.c. and i.p. xenografts, was achieved by gamma-scintigraphy and PET imaging. Blood pool was evident as expected, but cleared over time. The blood pharmacokinetics of i.v. and i.p. injected 111In trastuzumab was determined in mice with and without tumors. The data from these in vitro and in vivo studies supported advancement of radiolabeled trastuzumab into two clinical studies, a Phase 0 imaging study in the Molecular Imaging Program of the National Cancer Institute and a Phase 1 radioimmunotherapy study at the University of Alabama. PMID- 20716959 TI - Engineering host cell lines to reduce terminal sialylation of secreted antibodies. AB - Covalently-linked glycans on proteins have many functional roles, some of which are still not completely understood. Antibodies have a very specific glycan modification in the Fc region that is required for mediating immune effector functions. These Fc glycans are typically highly heterogeneous in structure, and this heterogeneity is influenced by many factors, such as type of cellular host and rate of Ab secretion. Glycan heterogeneity can affect the Fc-dependent activities of antibodies. It has been shown recently that increased Fc sialylation can result in decreased binding to immobilized antigens and some Fcgamma receptors, as well as decreased antibody-dependent cell-mediated cytotoxicity (ADCC) activity. In contrast, increased Fc sialylation enhances the anti-inflammatory activity of antibodies. To produce antibodies with increased effector functions, we developed host cell lines that would limit the degree of sialylation of recombinantly-expressed antibodies. Towards this end, the catalytic domain of the Arthrobacter ureafaciens sialidase (sialidase A) was engineered for secreted expression in mammalian cell lines. Expression of this sialidase A gene in mammalian cells resulted in secreted expression of soluble enzyme that was capable of removing sialic acid from antibodies secreted into the medium. Purified antibodies secreted from these cells were found to possess very low levels of sialylation compared with the same antibodies purified from unmodified host cells. The low sialylated antibodies exhibited similar binding affinity to soluble antigens, improved ADCC activity, and they possessed pharmacokinetic properties comparable to their more sialylated counterparts. Further, it was observed that the amount of sialidase A expressed was sufficient to thoroughly remove sialic acid from Abs made in high-producing cell lines. Thus, engineering host cells to express sialidase A enzyme can be used to produce recombinant antibodies with very low levels of sialylation. PMID- 20716960 TI - Deciphering the anticancer mechanisms of sunitinib. PMID- 20716962 TI - The MUC1-C oncoprotein as a target in hematologic malignancies. PMID- 20716961 TI - Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health. AB - The INK4b-ARF-INK4a locus encodes for two cyclin-dependent kinase inhibitors, p15(INK4b) and p16(INK4a) and a regulator of the p53 pathway, ARF. In addition ANRIL, a non-coding RNA, is also transcribed from the locus. ARF, p15(INK4b) and p16(INK4a) are well-established tumor suppressors which function is frequently disabled in human cancers. Recent studies showed that single nucleotide polymorphisms mapping in the vicinity of ANRIL are linked to a wide spectrum of conditions, including cardiovascular disease, ischemic stroke, type 2 diabetes, frailty and Alzheimer's disease. The INK4b-ARF-INK4a locus is regulated by Polycomb repressive complexes (PRCs), and its expression can be invoked by activating signals. Other epigenetic modifiers such as the histone demethylases JMJD3 and JHDM1B, the SWI/SNF chromatin remodeling complex and DNA methyltransferases regulate the locus interplaying with PRCs. In view of the intimate involvement of the INK4b-ARF-INK4a locus on disease, to understand its regulation is the first step for manipulate it to therapeutic benefit. PMID- 20716963 TI - Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome. AB - MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate post transcriptional gene expression. They influence a wide range of physiological functions, including neuronal processes, and are regulated by various mechanisms, such as DNA methylation. This epigenetic mark is recognized by transcriptional regulators such as the methyl CpG binding protein Mecp2. Rett syndrome is a complex neurological disorder that has been associated with mutations in the gene coding for Mecp2. Thus, we examined the possible miRNA misregulation caused by Mecp2 absence in a mouse model of Rett syndrome. Using miRNA expression microarrays, we observed that the brain of Rett syndrome mice undergoes a disruption of the expression profiles of miRNAs. Among the significantly altered miRNAs (26%, 65 of 245), overall downregulation of these transcripts was the most common feature (71%), whilst the remaining 30% were upregulated. Further validation by quantitative RT-PCR demonstrated that the most commonly disrupted miRNAs were miR-146a, miR-146b, miR-130, miR-122a, miR-342 and miR-409 (downregulated), and miR-29b, miR329, miR-199b, miR-382, miR-296, miR-221 and miR 92 (upregulated). Most importantly, transfection of miR-146a in a neuroblastoma cell line caused the downregulation of IL-1 receptor-associated kinase 1 (Irak1) levels, suggesting that the identified defect of miR-146a in Rett syndrome mice brains might be responsible for the observed upregulation of Irak1 in this model of the human disease. Overall, we provide another level of molecular deregulation occurring in Rett syndrome that might be useful for understanding the disease and for designing targeted therapies. PMID- 20716964 TI - Differential methylation of STOX1 in human placenta. AB - The 10q22 chromosomal region with genomic linkage to pre-eclampsia in Dutch females shows a parent-of-origin effect with maternal transmission of the Y153H susceptibility allele of the STOX1 gene. Although the CpG island within the STOX1 promoter region shows no differential methylation, this study describes the identification of a differentially methylated region (DMR) in intron 1 of the STOX1 gene. Methylation coincides with STOX1 expression, where high methylation leads to reduced expression. In the SGHPL-5 extravillous trophoblast cell line allele-specific expression was observed in a subset of cells. Although no allele specific expression could be detected in early placenta samples, these samples did show an increase in methylation when they were homozygous for the Y153H susceptibility allele. Allele-specific methylation was observed in column extravillous trophoblast samples with the methylated allele being paternal in origin. We conclude that STOX1 is paternally imprinted, maternally expressed, with the DMR identified in this study showing parental-specific methylation in specific cell-types, hypothesized to occur in villous cytotrophoblasts, and proven in column extravillous trophoblasts originating from the anchoring villus. In other (placental) cells methylation is independent of parental origin, but regulates STOX1 expression with the Y153H genotype directing the level of methylation. PMID- 20716965 TI - Quantitative analysis of promoter methylation in exfoliated epithelial cells isolated from breast milk of healthy women. AB - Promoter methylation analysis of genes frequently silenced in breast cancer is a promising indicator of breast cancer risk, as these methylation events are thought to occur long before presentation of disease. The numerous exfoliated epithelial cells present in breast milk may provide the breast epithelial DNA needed for detailed methylation analysis and assessment of breast cancer risk. Fresh breast milk samples and health, lifestyle, and reproductive history questionnaires were collected from 111 women. Pyrosequencing analysis was conducted on DNA isolated from the exfoliated epithelial cells immunomagnetically separated from the total cell population in the breast milk of 102 women. A total of 65 CpG sites were examined in six tumor suppressor genes: PYCARD (also known as ASC or TMS1), CDH1, GSTP1, RBP1 (also known as CRBP1), SFRP1, and RASSF1. A sufficient quantity of DNA was obtained for meaningful analysis of promoter methylation; women donated an average of 86 ml of milk with a mean yield of 32,700 epithelial cells per ml. Methylation scores were in general low as expected of benign tissue, but analysis of outlier methylation scores revealed a significant relationship between breast cancer risk, as indicated by previous biopsy, and methylation score for several CpG sites in CDH1, GSTP1, SFRP1, and RBP1. Methylation of RASSF1 was positively correlated with women's age irrespective of her reproductive history. Promoter methylation patterns in DNA from breast milk epithelial cells can likely be used to assess breast cancer risk. Additional studies of women at high breast cancer risk are warranted. PMID- 20716966 TI - Deregulated Ras signaling compromises DNA damage checkpoint recovery in S. cerevisiae. AB - The DNA damage checkpoint maintains genome stability by arresting the cell cycle and promoting DNA repair under genotoxic stress. Cells must downregulate the checkpoint signaling pathways in order to resume cell division after completing DNA repair. While the mechanisms of checkpoint activation have been well characterized, the process of checkpoint recovery, and the signals regulating it, has only recently been investigated. We have identified a new role for the Ras signaling pathway as a regulator of DNA damage checkpoint recovery. Here we report that in budding yeast, deletion of the IRA1 and IRA2 genes encoding negative regulators of Ras prevents cellular recovery from a DNA damage induced arrest. The checkpoint kinase Rad53 is dephosphorylated in an IRA-deficient strain, indicating that recovery failure is not caused by constitutive checkpoint pathway activation. The ira1Delta ira2Delta recovery defect requires the checkpoint kinase Chk1 and the cAMP-dependent protein kinase (PKA) catalytic subunit Tpk2. Furthermore, PKA phosphorylation sites on the anaphase promoting complex specificity factor Cdc20 are required for the recovery defect, indicating a link between the recovery defect and PKA regulation of mitosis. This work identifies a new signaling pathway that can regulate DNA damage checkpoint recovery and implicates the Ras signaling pathway as an important regulator of mitotic events. PMID- 20716967 TI - Nutlin's two roads toward apoptosis. PMID- 20716968 TI - Development of a novel mammalian cell surface antibody display platform. AB - Antibody display systems have been successfully applied to screen, select and characterize antibody fragments. These systems typically use prokaryotic organisms such as phage and bacteria or lower eukaryotic organisms, such as yeast. These organisms possess either no or different post-translational modification functions from mammalian cells and prefer to display small antibody fragments instead of full-length IgGs. We report here a novel mammalian cell based antibody display platform that displays full-length functional antibodies on the surface of mammalian cells. Through recombinase-mediated DNA integration, each host cell contains one copy of the gene of interest in the genome. Utilizing a hot-spot integration site, the expression levels of the gene of interest are high and comparable between clones, ensuring a high signal to noise ratio. Coupled with fluorescence-activated cell sorting (FACS) technology, our platform is high throughput and can distinguish antibodies with very high antigen binding affinities directly on the cell surface. Single-round FACS can enrich high affinity antibodies by more than 500 fold. Antibodies with significantly improved neutralizing activity have been identified from a randomly mutagenized library, demonstrating the power of this platform in screening and selecting antibody therapeutics. PMID- 20716969 TI - Non-traditional drug targets in behavioural pharmacology. PMID- 20716971 TI - Comment on Edlund et al "trends in use of opioids for chronic noncancer pain among individuals with mental health and substance abuse disorders: the TROUP study". PMID- 20716973 TI - Technology: friend or foe? PMID- 20716974 TI - Using mobile health technology to enhance patient-centered care. PMID- 20716975 TI - Vasopressors in septic shock: a possible deadly intervention. PMID- 20716970 TI - In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis. AB - The pathophysiological role of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20 one (allopregnanolone) in neuropsychiatric disorders has been highlighted in several recent investigations. For instance, allopregnanolone levels are decreased in the CSF of patients with post-traumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants, including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. PTSD-like behavioral dysfunctions, including heightened aggression, exaggerated fear, and anxiety-like behavior associated with a decrease in corticolimbic allopregnanolone content are modeled in mice by protracted social isolation stress. Allopregnanolone is not only synthesized by principal glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons, but also locally, potently, positively, and allosterically modulates GABA action at postsynaptic and extrasynaptic GABAA receptors. Hence, this paper will review preclinical studies, which show that in socially isolated mice, rather than selective serotonin reuptake inhibitor mechanisms, allopregnanolone biosynthesis in glutamatergic corticolimbic neurons offers a nontraditional target for fluoxetine to decrease signs of aggression, normalize fear responses, and decrease anxiety-like behavior. At low selective serotonin reuptake inhibitor inactive doses, fluoxetine and related congeners potently increase allopregnanolone levels by acting as potent selective brain steroidogenic stimulants (SBSS), thereby facilitating GABAA receptor neurotransmission and improving behavioral dysfunctions. Although the precise molecular mechanisms that underlie the action of these drugs are not fully understood, findings from socially isolated mice may ultimately generate insights into novel drug targets for the treatment of psychiatric disorders, such as anxiety and panic disorders, depression, and PTSD. PMID- 20716976 TI - Clinical nurse specialist-led evaluation of temporal artery thermometers in acute care. AB - PURPOSE: A systematic review of literature and intensive evaluation were conducted using a quality process to assess temporal artery thermometer (TAT) accuracy in an acute-care setting. BACKGROUND: Inaccurate temperature measurements were reported following adoption of the TAT. Concern for patient safety and outcomes generated a need to reevaluate use of the TAT. DESCRIPTION OF THE PROJECT: Using components of evidence-based practice and intensive evaluation processes, a clinical nurse specialist (CNS)-led team evaluated existing research, assessed current practice, and obtained additional clinical data. OUTCOMES: Existing research provides inadequate evidence to support use of the TAT for acutely ill hospitalized patients. Findings from an intensive evaluation indicated low interrater reliability in controlled testing, inaccurate technique by staff despite retraining, lack of nurse confidence in the accuracy of the device, and a need for continuous costly retraining. These findings are consistent with findings in a University HealthSystem Consortium report. SUMMARY AND CONCLUSIONS: A multifaceted evaluation process was needed for the team to compile data, identify issues, and make decisions. A recommendation was made to discontinue use of the TAT. IMPLICATIONS: : Clinical nurse specialists have the knowledge and ability to provide clinical leadership at a system level. When usual processes result in safety concerns, the CNS provides leadership to identify patterns, provide direction, creatively integrate evaluation processes, synthesize findings, and uses his/her influence within the system to change practice. PMID- 20716978 TI - Sustaining excellence: clinical nurse specialist practice and magnet designation. AB - Clinical nurse specialist practice is essential in providing the clinical expertise, leadership, and organizational influence necessary for attaining the excellence in care reflected by the American Nurses Credentialing Center's Magnet designation. Clinical nurse specialists, prepared as advanced practice nurses, bring clinical expertise, knowledge of advanced physiology, and pathology and a system-wide vision for process improvements. This unique curriculum specifically prepares clinical nurse specialists (CNSs) to immediately practice as leaders of interdisciplinary groups to improve outcomes. Clinical nurse specialist graduates possess an understanding of complex adaptive systems theory, advanced physical assessment, and pathophysiology and knowledge of optimal learning modalities, all applicable to improving the health care environment. Their practice specifically links complex clinical data with multidisciplinary partnering and understanding of organizational systems. The basis for optimal clinical practice change and sustained process improvement, foundational to Magnet designation, is grounded in the combined educational preparation and systems impact of CNS practice. This article describes the role of the CNS in achieving and sustaining Magnet designation in an urban, academic quaternary care center. Using the National Association of Clinical Nurse Specialists model of spheres of influence, focus is on the CNS's contribution to improving clinical outcomes, nurse satisfaction, and patient satisfaction. Exemplars demonstrating use of a champion model to implement practice improvement and rapid adoption of optimal practice guidelines are provided. These exemplars reflect improved and sustained patient care outcomes, and implementation strategies used to achieve these improvements are discussed. PMID- 20716977 TI - Advanced practice nursing: meeting the caregiving challenges for families of persons with frontotemporal dementia. AB - Frontotemporal dementia (FTD), once thought to be a rare cause for dementia, is now acknowledged to be the most common presenile (before age 65 years) cause of dementia. Frontotemporal dementia is associated with profound changes in behavior, personality, emotions, and cognition. The purpose of this article is to describe 2 cases of patients with FTD to illustrate salient aspects of the caregiving experience. Issues faced by caregivers are organized into 6 categories: diagnosis, behavioral symptoms, function, communication, long-term management and care, and maintenance of the caregiver's emotional and physical health. Examples of interventions directed by advanced practice nurses are described. We suggest that management of FTD requires expertise as scientific advances and discoveries about FTD continually change the landscape of care. PMID- 20716979 TI - Nursing identification of delirium. AB - PURPOSE: Describe nurses' ability to recognize delirium on both intensive care unit and medical-surgical units. DESIGN: This is a descriptive cross-sectional study using a convenience sample. SAMPLE AND SETTING: Sixty-one registered nurses (RNs) were recruited from both medical-surgical and intensive care units from 2 midsized hospitals in the Midwest. METHODS: : For this study, a survey was developed using true/false and Likert-type scale questions to assess (1) nurse knowledge of symptoms associated with delirium, (2) negative sequelae associated with delirium, and (3) confidence levels regarding assessing for delirium. CONCLUSION: Tremendous opportunity exists in nursing education for learning about negative outcomes associated with delirium and the importance of routine assessment. Clarification of negative sequelae related to delirium will lead nurses to value and understand the importance of early detection. Appropriate use of a standard cognitive assessment and an instrument designed to detect delirium is vital in a successful delirium prevention program. Providing nurses with educational resources and opportunities to apply knowledge will increase confidence in identification and management of delirium. PMID- 20716980 TI - Clinical nurse specialist profile. Elissa Brown, MSN, RN. PMID- 20716982 TI - Clinical nurse specialists-practitioner contributing to primary care: a briefing paper. PMID- 20716981 TI - Victoria Rhinehart's Portrait of healing: curing in the woods. PMID- 20716983 TI - Probiotics and European Food Safety Authority health claims. PMID- 20716984 TI - 2010--the year of inflammatory bowel disease: a special interview with WDHD campaign leader, Dr Charles Bernstein. PMID- 20716985 TI - Durable alteration of the colonic microbiota by the administration of donor fecal flora. AB - GOALS: To determine whether fecal bacteriotherapy results in a durable beneficial change in the colonic microbiota of patients with flora-related disorders. BACKGROUND: Earlier studies have implicated the colonic microbiota in a number of conditions. Administration of a fecal suspension from a healthy individual to an ill individual (fecal bacteriotherapy) can cure Clostridium difficile infection and potentially other diseases. Oral probiotics do not work in this condition, yet there has been no study to determine whether fecal bacteriotherapy results in prolonged implantation. STUDY: Fecal samples were collected from 10 patients undergoing fecal bacteriotherapy. Patients completed an antibiotic schedule and bowel lavage before the infusion of healthy donor feces. Using a molecular approach, the bacterial populations in patient fecal samples were followed from pretreatment to 24 weeks post-initial infusion and compared with the initial infused donor fecal suspension. RESULTS: At intervals of 4, 8, and 24 weeks after the procedure, the bacterial populations in the patients' fecal samples consisted predominantly of bacteria derived from the healthy donor samples. Comparisons of similarity at 4, 8, and 24 week samples to the donor-infused sample were made and each recipient's baseline sample was statistically significant with Friedman test. CONCLUSIONS: This study demonstrates a durable beneficial change in the patients' bacterial populations of the colon to represent those of the healthy donor's microbiota. Manipulation of the colonic microbiota to improve its protective and beneficial role represents a promising field of new therapeutic strategies for the treatment of gastrointestinal conditions. PMID- 20716986 TI - Neurologic physical therapy at the nexus of recovery, restoration, and regeneration. PMID- 20716987 TI - The effect of balance training on balance performance in individuals poststroke: a systematic review. AB - BACKGROUND AND PURPOSE: Stroke is a leading cause of long-term disability, and impaired balance after stroke is strongly associated with future function and recovery. Until recently there has been limited evidence to support the use of balance training to improve balance performance in this population. Information about the optimum exercise dosage has also been lacking. This review evaluated recent evidence related to the effect of balance training on balance performance among individuals poststroke across the continuum of recovery. On the basis of this evidence, we also provide recommendations for exercise prescription in such programs. METHODS: A systematic search was performed on literature published between January 2006 and February 2010, using multiple combinations of intervention (eg, "exercise"), population (eg, "stroke"), and outcome (eg, "balance"). Criteria for inclusion of a study was having at least 1 standing balance exercise in the intervention and 1 study outcome to evaluate balance. RESULTS: Twenty-two published studies met the inclusion criteria. We found moderate evidence that balance performance can be improved following individual, "one-on-one" balance training for participants in the acute stage of stroke, and either one-on-one balance training or group therapy for participants with subacute or chronic stroke. Moderate evidence also suggests that in the acute stage, intensive balance training for 2 to 3 times per week may be sufficient, whereas exercising for 90 minutes or more per day, 5 times per week may be excessive. DISCUSSION AND CONCLUSIONS: This review supports the use of balance training exercises to improve balance performance for individuals with moderately severe stroke. Future high-quality, controlled studies should investigate the effects of balance training for individuals poststroke who have severe impairment, additional complications/comorbidities, or specific balance lesions (eg, cerebellar or vestibular). Optimal training dosage should also be further explored. Studies with long-term follow-up are needed to assess outcomes related to participation in the community and reduction of fall risk. PMID- 20716988 TI - Rehabilitation of reaching poststroke: a randomized pilot investigation of tactile versus auditory feedback for trunk control. AB - BACKGROUND AND PURPOSE: For individuals poststroke, reaching with the paretic limb is often associated with compensatory trunk movement due to limited active arm movement. We conducted a pilot feasibility study to compare the effects of task-related training on reaching with the paretic limb using each of 2 different techniques for providing feedback about trunk position. We hypothesized that the use of an auditory feedback signal in response to pressure (Sensor group) would be more effective than feedback arising from an external device used to restrain the trunk (Stabilizer group). METHODS: Sixteen individuals with chronic stroke were enrolled. Participants had scores of 20 to 44 on the Upper-Arm subsection of the Fugl-Meyer Scale and demonstrated some trunk movement during the pretest assessment of the Reaching Performance Scale (RPS). Participants were randomly assigned to either the Sensor or the Stabilizer group. Both groups participated in 12 structured rehabilitation sessions with equal time duration, number of repetitions, and task-related training activities. Feedback was systematically and equally faded for all training. Clinical outcome measures were assessed prior to and following training. RESULTS: Both forms of feedback were associated with changes in active shoulder motion, Wolf Motor Function Test (WMFT), Fugl-Meyer Scale and RPS (near and far) as determined by a 2 x 2 (Group x Time) analysis of variance. An interaction of RPS-near revealed that the Sensor group improved more than the Stabilizer group for this measure. However, sample size may not have been sufficient to identify differences in other measures. DISCUSSION: Although both forms of feedback led to improvements in the majority of outcome measures, the auditory feedback signal was associated with greater improvement in RPS-near scores. CONCLUSION: In the rehabilitation of reaching function in individuals with stroke, the use of an auditory signaling device appears to be a feasible alternative to imposed trunk stabilization. Additional studies with larger sample sizes are needed to determine whether one approach is superior to the other. PMID- 20716989 TI - Development and validation of the Function In Sitting Test in adults with acute stroke. AB - BACKGROUND AND PURPOSE: Research studies indicate that sitting balance ability is a substantial predictor of functional recovery after stroke. There are no gold standards for sitting balance assessment, and commonly used balance measures do not isolate sitting balance abilities. This study was designed to develop, pilot test, and analyze reliability and validity of a short test of functional sitting balance in patients following acute stroke. METHODS: The Function In Sitting Test (FIST) was constructed after reviewing balance measures and interviewing 15 physical therapists. A written survey regarding the FIST items and scoring scales was designed, pilot tested, and sent to 12 additional physical therapists with expertise in measurement construction, balance assessment, and/or research. Thirty-one adults who were within 3 months following stroke participated in this study. RESULTS: The expert panel survey was returned by 83.3% of the participants. Survey feedback and weighted rank analysis reduced the number of FIST items from 26 to 17. After subject testing, Item Response Theory analysis eliminated 3 additional items. The person separation index was 0.978 and the coefficient alpha was 0.98, indicating high internal consistency of the FIST. The Item Response Theory analysis confirmed content and construct validity. Concurrent validity was supported by high correlations to the modified Rankin Scale, static balance indices, and dynamic balance grades. DISCUSSION AND CONCLUSIONS: The 14-item FIST is reliable and valid in adults following acute stroke. Studies of intra- or intertester reliability and evaluative validity studies including applications to other patient populations with sitting balance dysfunction are now necessary. PMID- 20716990 TI - Use of an elliptical machine for improving functional walking capacity in individuals with chronic stroke: a case series. AB - BACKGROUND AND PURPOSE: Decreased functional walking capacity is a common consequence of stroke. Identifying practical and cost-effective methods to improve walking in individuals with stroke is an important goal of rehabilitation professionals. PARTICIPANTS: Participants were 3 men with chronic (>6 month) stroke, who could walk on level surfaces either without an assistive device or with a single-point cane. INTERVENTION: Participants trained 2 to 3 times per week for 8 weeks, using an elliptical machine. The training target was 20 minutes of uninterrupted training, while maintaining predetermined parameters of heart rate and perceived exertion. OUTCOMES: Outcome measures assessed before and after training included habitual and fast gait speed, 6-minute walk test (6MWT), Timed "Up & Go" test, and Berg Balance Scale. Following training there was no change in walking speed. There was no change in 6MWT performance for participants 1 and 2. While participant 3 showed a 25% improvement in 6MWT, this change did not meet the minimal detectable change for walking speed in individuals with stroke. All participants demonstrated improved Berg Balance Scale performance (9%-28%), with participant 1 exceeding the minimal detectable change in this measure. Timed Up & Go test performance improved by 5% to 15% in all participants. DISCUSSION: Elliptical training appears to be a safe and feasible training alternative for ambulatory individuals with chronic stroke. Training 2 to 3 days per week resulted in no improvements in walking speed; however, participants did demonstrate variable improvements in endurance, balance, and functional mobility. It is possible that a higher training frequency and/or training speed are required to influence walking performance in individuals who are ambulatory. Equipment design, principles of exercise prescription, and participant characteristics should be considered when selecting elliptical training as an intervention. PMID- 20716991 TI - Perspective from the practice committee: is autonomous practice in neurologic physical therapy defined differently based on the type of practice setting? AB - The answer to the question, "Is autonomous practice in neurologic physical therapy defined differently based on the type of practice setting?" is no. Autonomous practice is a characteristic of the physical therapist, embodying excellence, communication and collaboration, and advocacy and caring. It is our belief that many physical therapists already practice autonomously, even though they may not recognize their practice as being autonomous; and it is our hope that physical therapists who are functioning as autonomous practitioners will provide peer mentoring to help bring their colleagues to the same level of practice and the same recognition. The full position statement on autonomous practice is available on the Neurology Section Web site at http://www.neuropt.org/go/healthcareprofessionals/autonomous-practice. PMID- 20716995 TI - Keep the single payer vision. PMID- 20716996 TI - Baseline infection with a sexually transmitted disease is highly predictive of reinfection during follow-up in Malagasy sex workers. AB - Female sex workers who had prevalent chlamydial, gonococcal, or trichomonal infection at enrollment into a randomized trial in Madagascar were 2 to 4 times as likely to become infected during follow-up, compared to women without STIs at baseline, despite provision of condoms, safer sex counseling, and repeat STI testing and treatment. PMID- 20716997 TI - Why we should save our STD clinics. PMID- 20716998 TI - Intradermal nodular fasciitis: a rare lesion analyzed in a series of 24 cases. AB - Nodular fasciitis, a benign myofibroblastic proliferation that usually occurs in the subcutaneous tissues of the upper extremities, trunk, as well as head and neck of young adults, is not widely recognized to arise primarily within the dermis. Here, we examined the clinicopathologic and immunohistochemical features of a series of 24 cases of intradermal nodular fasciitis retrieved from consult files. Clinical follow-up was obtained from medical records and referring physicians. Fourteen patients were females and 10 were males, with age ranging from 8 to 77 years (mean 27.5 y and median 22.5 y). Most patients presented with a rapidly growing painless solitary mass. Grossly, the lesions were solid, nodular, rubbery, or firm (mean size 1.96 cm and median 1.3 cm). Nine cases (37.5%) arose on limbs, 9 cases (37.5%) on the trunk, and 6 (25%) on the head and neck. All tumors were situated primarily in the dermis and were well circumscribed but unencapsulated. One case showed ill-defined margins. The epidermis was ulcerated in 11 cases. All tumors were composed of cytologically bland, uniform plump spindle cells with elongated, tapering nuclei, vesicular chromatin, small nucleoli, and palely eosinophilic cytoplasm, with no significant cytologic atypia or pleomorphism. These cells were arranged in short-intersecting bundles within a focally microcystic myxoid stroma, containing extravasated red blood cells and scattered lymphocytes. Mitoses ranged from 1 to 6 per 10 high power fields (mean 2.5). All cases examined were diffusely positive for smooth muscle actin. Only one tumor "recurred" locally. No lesion metastasized. In summary, intradermal nodular fasciitis occurs most commonly on the limbs and trunk of young adults, shows morphologic features similar to nodular fasciitis at conventional sites and should not be confused with sarcoma. PMID- 20717000 TI - Dedifferentiated classic adamantinoma of the tibia: a report of a case with eventual complete revertant mesenchymal phenotype. AB - Adamantinomas of the long bones are low-grade malignant tumours. They seem to be related to osteofibrous dysplasia with a mesenchymal-to-epithelial transformation. We report a case of an adamantinoma with a revertant sarcomatoid transformation that showed a complete loss of epithelial differentiation. It corresponded to a 41-year-old male presented with an 8-cm multilobated lesion in the centre of the distal tibia. On the en bloc resection specimen, areas of classic adamantinoma were found but most of the tumor corresponded to a high grade neoplasm with 2 histologic patterns: one made up by epithelial nests with a basaloid arrangement and positive for pankeratins and so-called glandular keratins, and a second sarcomatoid component, negative for these epithelial markers. Five months after surgery the patient had a massive relapse that consisted solely of the second sarcomatous component also negative for epithelial antibodies.Three cases of adamantinomas with sarcomatoid transformation of the epithelial component have been described but the tumours still preserved an epithelial immunophenotype. However, our case represents the extreme end of the sarcomatoid dedifferentiation of a classic adamantinoma with complete sarcomatoid transformation and total loss of epithelial markers. To our knowledge this has not been described previously. PMID- 20716999 TI - Peritoneal elastic laminal invasion of colorectal cancer: the diagnostic utility and clinicopathologic relationship. AB - To determine whether the peritoneal elastic lamina can be a useful pathologic hallmark to classify the level of tumor spreading in colorectal cancer, we performed elastica staining in 564 pT3 and pT4a colorectal cancer cases. Associations between peritoneal elastic laminal invasion of the tumor and clinicopathologic features were evaluated. Next, morphology of tumor was compared between cases with and those without peritoneal elastic laminal invasion to estimate the morphologic alteration that occurs when tumor invades beyond the peritoneal elastic lamina. Morphometric analysis of tumor area beyond the peritoneal elastic lamina was performed and compared with other tumor area to elucidate morphologic characteristics of the tumor area beyond the peritoneal elastic lamina. Clinicopathologic analysis revealed that peritoneal elastic laminal invasion was associated with higher tumor stage, palliative resection, deeper tumor invasion, deeper ulceration, over 5 mm of muscular layer elevation and peritoneal surface retraction with fibro-inflammation, higher budding grade, and high grade of lymphovascular invasion (P<0.01). Peritoneal elastic laminal invasion was associated with recurrence and prognosis in colon cancer and was an independent risk factor for the recurrence of stage II colon cancer. Furthermore, morphometric analysis revealed that tumor area in subserosal invasive front beyond peritoneal elastic lamina exhibited significantly more prominent fibrosis and tumor budding than other tumor area (P<0.01). Peritoneal elastic lamina was useful hallmark to determine the level of tumor invasion, and was powerful indicator to predict prognosis in colon cancer. Tumor area beyond the elastic lamina is characterized by extensive tumor budding and fibrosis. PMID- 20717001 TI - Heterotopic breast epithelial inclusion of the heart: report of a case. AB - We report a case of heterotopic breast epithelial inclusion of the heart incidentally found on a native heart in a 73-year-old man who received orthotopic heart transplantation for ischemic cardiomyopathy. The lesion could not be recognized on gross inspection. Histologic sections from the left anterior atrium to interatrial septum showed focally microcystic ductal/tubular structures lined by a biphasic pattern of cuboidal to columnar apical epithelial cells with an outer layer of flattened basal cells. These glandular structures were arranged in vaguely lobular and focally infiltrative patterns in the epicardium and interstitium. No architectural or cytologic atypia or mitotic or apoptotic figures were seen. The apical epithelial cells were immunoreactive for pankeratin, cytokeratin (CK) 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein-15, and negative for CK20, calretinin, Wilms' tumor suppressor gene (WT1), CD31, suggestive of mammary epithelial differentiation. The basal cells were immunoreactive for pankeratin, CK7, CK5/6, D2-40, smooth muscle actin and focally S100, suggestive of myoepithelial differentiation. Although the heterotopic breast tissue on the skin along the milk line is well recognized, it has not been described to involve internal organs including the heart. PMID- 20717002 TI - Interobserver reproducibility in the diagnosis of invasive micropapillary carcinoma of the urinary tract among urologic pathologists. AB - Invasive micropapillary carcinoma (IMPC) of the urinary tract is a well-described variant of the urothelial carcinoma with aggressive clinical behavior. Recent studies have proposed that patients with IMPC on transurethral resection should be treated with radical cystectomy regardless of the pathologic stage. Despite the potentially important therapeutic implications of this diagnosis, interobserver variation in the diagnosis of IMPC has not been studied. Sixty digital images, each from hematoxylin and eosin-stained slides, representing 30 invasive urothelial carcinomas (2 images per case), were distributed to 14 genitourinary subspecialists and each pathologist was requested to classify cases as IMPC or not. These cases included "classic" IMPC (n=10) and urothelial carcinoma with retraction and variably sized nests that might potentially be regarded as IMPC (n=20). The following 13 morphologic features were recorded as positive/negative for all cases independent of the reviewers' diagnoses: columnar cells, elongate nests or processes, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial ring forms, intracytoplasmic vacuolization, multiple nests within the same lacunar space, back-to-back lacunar spaces, epithelial nest anastomosis/confluence, marked nuclear pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, and tumor nest size. In addition, a mean tumor nest size was calculated for each image based on the number of nuclei spanning the width of the nests. Interobserver reproducibility was assessed and the morphologic features were correlated with the classic IMPC and nonclassic/potential IMPC groups. In addition, the relationships between morphologic features, pathologists' interpretations, and case type (classic IMPC vs. nonclassic/potential IMPC) were evaluated using unsupervised hierarchical clustering analysis. Interobserver reproducibility for a diagnosis of IMPC in the 30 study cases was moderate (kappa: 0.54). Although classification as IMPC among the 10 "classic" IMPC cases was relatively uniform (93% agreement), the classification in the subset of 20 invasive urothelial carcinomas with extensive retraction and varying sized tumor nests was more variable. Multiple nests within the same lacunar space had the highest association with a diagnosis of classic IMPC. These findings suggest that more study of IMPC is needed to identify the individual pathologic features that might potentially correlate with an aggressive outcome and response to intravesical therapy. PMID- 20717003 TI - Glycolytic flux occurs in Drosophila melanogaster recovering from camptothecin treatment. AB - Camptothecin (CPT) and CPT-derived drugs are widely used against gynaecological and colorectal cancers. On account of their mechanism of action these drugs target rapidly dividing cells and may have an adverse effect on normal tissues. We sought to investigate their impact on normal cells by using Drosophila as a model. We investigated the possible involvement of Drosophila homologue of p53 (Dmp53) and a member of the retinoblastoma binding protein 6 family, known as Snama. On account of its molecular features and experimental evidence gleaned from mammalian studies we propose Snama as a candidate in Dmp53 regulation. We have used proteomics and core molecular biology techniques on embryos and on adult flies. We found that flies that recover from CPT treatment display a metabolic programme characterized by glycolytic flux, depletion of Dmp53 and increase of Snama transcripts. When we introduced methyl pyruvate in the diet to bypass the glycolytic pathway, we noticed differential expression of Dmp53 and Snama and improvement in reproduction and embryonic development. The development of embryos into the pupal stage was significantly improved to 40% (P=0.02) when CPT was given to mothers in combination with methyl pyruvate. This investigation highlights the importance of energy production mechanisms in cells that recover from chemotherapy and differences between the metabolic programmes used by recovering cells and those adopted by cancer cells. PMID- 20717004 TI - Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells. AB - Arginine deprivation achieved by means of recombinant arginine-degrading enzymes is currently being developed as a novel anticancer enzymotherapy. In this study, we showed that arginine deprivation in vitro profoundly and selectively sensitized human cancer cells of different organ origin to low doses of canavanine, an arginine analogue of plant origin. In sensitive cancer cells arginine starvation led to the activation of caspase-9, caspase-3 and caspase-7, cleavage of reparation enzyme, polyADP ribosyl polymerase, and DNA fragmentation, which are the typical hallmarks of intrinsic apoptosis realized by the mitochondrial pathway. Co-administration of canavanine significantly accelerated and enhanced apoptotic manifestations induced by arginine deprivation. The augmentation of canavanine toxicity for cancer cells was observed when either a formulated arginine-free medium or complete medium supplemented with bovine arginase preparation was used. Cycloheximide efficiently rescued malignant cells from canavanine-induced cytotoxicity under arginine deprivation, suggesting that it results mainly from canavanine incorporation into newly synthesized proteins. Cancer cells sensitive or resistant to arginine deprivation alone were not capable of restoring their proliferation after 24 h of combined treatment, whereas pseudonormal cells retained such ability. Our data suggest that the incorporation of canavanine into anticancer treatment schemes based on artificially created arginine starvation could be a novel strategy in tumor enzymochemotherapy. PMID- 20717005 TI - Celecoxib inhibits cell proliferation through the activation of ERK and p38 MAPK in head and neck squamous cell carcinoma cell lines. AB - It has been observed that several cyclooxygenase-2 (COX-2) inhibitory chemicals might inhibit proliferation of various cancer cells through COX-2-independent action. We also identified that celecoxib more selectively kills cell lines derived from head and neck squamous cell carcinoma (HNSCC) than its non-cancerous counterparts, irrespective of COX-2 expression. Herein, we investigated whether the regulation of mitogen-activated protein kinases activity might be one of the main mechanisms related to a conspicuous COX-2-independent tumor-killing effect of celecoxib in HNSCC cell lines. We assessed the effect of celecoxib on extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase activity by a transcription factor activation assay then evaluated, if these factors might be involved in the COX-2-independent tumor-killing effect of celecoxib by blocking their activity. We found that the blocking activation of ERK and/or p38 could reverse the celecoxib-induced cell growth inhibition by 50 80% in HNSCC cell lines, but it was not tested in cancer cells of other types. In conclusion, our study suggests that most COX-2-independent tumor-killing action of celecoxib is mediated by the upregulation of ERK and/or p38 activity in HNSCC cells. These results encourage investigation on the underlying mechanisms and detailed outcomes of mitogen-activated protein kinases activation by celecoxib more concisely, for using its excellent tumor-killing effect more safely in the clinical field of cancer treatment. PMID- 20717006 TI - Management of myocardial infarction in children with Kawasaki disease. AB - Kawasaki disease is an acute, systemic vasculitis of unknown cause affecting mainly neonates (infants) and young children. Despite treatment during the acute phase with intravenous immunoglobulin and aspirin, up to 5% of those affected will develop coronary aneurysms, predisposing them to thrombotic complications that could result in myocardial infarction and/or death. There are treatment protocols in place for the management of myocardial infarction in adults, but the practical nature of medication is unclear in children. To date, there are no clinical trials or specific recommendations on the dosing of thrombolytic therapy for the treatment of myocardial infarction in Kawasaki pediatric patients. However, there are reports of the use of thrombolytic agents, including streptokinase, urokinase and tissue plasminogen activator, as well as the monoclonal platelet glycoprotein (GP)IIb/IIIa receptor inhibitor, abciximab, that have been used to treat myocardial infarction in children with Kawasaki disease. The outcomes in these reports are varied. This review provides a summary of the available data on the management of children with Kawasaki disease suffering from myocardial infarction or thrombotic complications that can potentially lead to myocardial infarction. PMID- 20717007 TI - A case of probable Bohring-Opitz syndrome with medulloblastoma. PMID- 20717008 TI - Pentalogy of Cantrell associated with bilateral anophthalmos. PMID- 20717009 TI - Fetal alcohol syndrome: a phenocopy of spondylocarpotarsal synostosis syndrome? PMID- 20717010 TI - The premature infant pain profile: evaluation 13 years after development. AB - OBJECTIVE: To review the (1) reliability, validation, feasibility, and clinical utility and (2) the use of the Premature Infant Pain Profile (PIPP) from 1996 to 2009 to determine the effectiveness of pain management strategies. METHODS: Data sources included MEDLINE, CINAHL, EMBASE, PsycINFO, and the Web of Science. Published studies evaluating the measurement properties of the PIPP and intervention studies using the PIPP as an outcome measure of acute pain were included. One reviewer screened studies for relevance and inclusion. Four reviewers rated intervention studies for methodological quality and extracted data for the evidence tables. RESULTS: Of the 62 studies included, 14 focused on the measurement properties of the PIPP. Reliability of the PIPP was supported in 5 studies and construct validation was supported in 13 studies. The feasibility of the PIPP was addressed in 4 studies, whereas clinical utility was discussed in 2 studies. Twenty-seven of the 48 studies that were considered to have high methodological quality used the PIPP as the major outcome to evaluate the effectiveness of pain management interventions in infants. DISCUSSION: The PIPP continues to be a reliable and valid measure of acute pain in infants with numerous positive validation studies. There is substantial support for the use of the PIPP as an effective outcome measure in pain intervention studies in infants. Further research with health professionals is required to better support the feasibility and clinical utility of this measure. PMID- 20717011 TI - Acute and chronic pain following craniotomy. AB - PURPOSE OF REVIEW: The purpose of the review is to describe what is currently known about the mechanisms, incidence and risk factors for acute and chronic postcraniotomy pain. The review will also summarize the evidence supporting the prevention and management of acute and chronic postcraniotomy pain. RECENT FINDINGS: Current studies suggest acute and chronic pain is common in patients after craniotomy. Surgical and patient factors may influence the incidence and severity of pain and a multimodal approach to acute postcraniotomy pain is recommended. Although codeine and tramadol are frequently used in the postoperative period, research suggests morphine provides superior efficacy with a good safety profile. Local anesthesia with nerve blocks has not been shown to consistently reduce acute postoperative pain, though it has recently been demonstrated to dramatically reduce the incidence of chronic pain. Despite this, little is known about the mechanisms, prevention and treatment of chronic postcraniotomy pain. SUMMARY: Acute and chronic pain following craniotomy is frequent and underrecognized. Several surgical and patient risk factors predispose patients to pain following neurosurgery. Further research is needed to determine the mechanisms, predictors, prevention and optimal treatment of acute and chronic pain following craniotomy. PMID- 20717012 TI - Anaesthesia for endoscopic neurosurgical procedures. AB - PURPOSE OF REVIEW: Endoscopic neurosurgical procedures are becoming more frequent and popular in the treatment of intracranial disease. When endoscopy involves the intraventricular structures, irrigating solutions are required and may contribute to sudden and sharp increases in intracranial pressure. More recently, nasal endoscopic approach has been used to perform skull base surgery for aneurysms and tumours. We have analysed published articles in order to detect anaesthesia management and perioperative complications. RECENT FINDINGS: Sudden and dangerously low decreases in cerebral perfusion pressures do not provoke the 'traditional Cushing's response' usually associated with significantly high intracranial pressure. It is important to note that tachycardia (not bradycardia) and/or hypertension are the most frequent haemodynamic complications during neuroendoscopic procedures. With the transnasal approach severe intraoperative haemorrhage is the most important complication to consider followed by direct injury to surrounding neural structures. SUMMARY: Invasive arterial blood pressure and intracranial pressure should be measured continuously during neuroendoscopies to detect early intraoperative cerebral ischaemia instead of waiting for the appearance of bradycardia which may be a late sign. General anaesthesia remains the technique of choice. Intracranial haemorrhage increases the likelihood of perioperative complications. Close postoperative monitoring is required to diagnose and treat complications such as convulsions, persistent hydrocephalus, haemorrhage or electrolytic imbalance. PMID- 20717013 TI - Thromboprophylactic management in the neurosurgical patient with high risk for both thrombosis and intracranial bleeding. AB - PURPOSE OF REVIEW: Pharmacologic thromboprophylaxis is indicated in neurosurgery patients having high risk for venous or arterial thrombosis. The pharmacologic thromboprophylaxis, as well as temporary interruption of antithrombotic drugs because of surgery, and possible use of substitutive medication ('bridging therapy') are reviewed. RECENT FINDINGS: Pharmacologic thromboprophylaxis is used for most neurosurgical patients, but clinical practices vary a lot. There are only few reports of the management of neurosurgery patients having mechanical prosthetic heart valves, atrial fibrillation with comorbidities, history of deep venous thrombosis, thrombophilia, or coronary artery stent. These patients present a high risk for both thrombosis and bleeding as temporary interruption of antithrombotic medication as well as a substitutive medication would be indicated. Generally, the bridging therapy with low-molecular-weight heparin (LMWH) is a feasible approach in patients needing interruption of vitamin K antagonists. Experiences in neurosurgery patients emphasize carefully secured hemostasis and tailored dose as well as timing of LMWH. In patients with a recent coronary artery stent scheduled for neurosurgery, an individualized plan is needed. Bridging therapy for antiplatelet agents or novel oral anticoagulants is not yet settled. SUMMARY: Pharmacologic thromboprophylaxis, or bridging therapy, should be tailored according to the individual risks and the type of neurosurgery. The bleeding risk is likely minimized by allowing coagulation capacity to normalize preoperatively and by using reduced doses of LMWH starting relatively late after neurosurgery. PMID- 20717015 TI - Acute and long-term effects of exercise on appetite control: is there any benefit for weight control? AB - PURPOSE OF REVIEW: To examine the relationship between energy intake, appetite control and exercise, with particular reference to longer term exercise studies. This approach is necessary when exploring the benefits of exercise for weight control, as changes in body weight and energy intake are variable and reflect diversity in weight loss. RECENT FINDINGS: Recent evidence indicates that longer term exercise is characterized by a highly variable response in eating behaviour. Individuals display susceptibility or resistance to exercise-induced weight loss, with changes in energy intake playing a key role in determining the degree of weight loss achieved. Marked differences in hunger and energy intake exist between those who are capable of tolerating periods of exercise-induced energy deficit, and those who are not. Exercise-induced weight loss can increase the orexigenic drive in the fasted state, but for some this is offset by improved postprandial satiety signalling. SUMMARY: The biological and behavioural responses to acute and long-term exercise are highly variable, and these responses interact to determine the propensity for weight change. For some people, long-term exercise stimulates compensatory increases in energy intake that attenuate weight loss. However, favourable changes in body composition and health markers still exist in the absence of weight loss. The physiological mechanisms that confer susceptibility to compensatory overconsumption still need to be determined. PMID- 20717014 TI - Biomarker-assisted diagnosis of acute aortic dissection: how far we have come and what to expect. AB - PURPOSE OF REVIEW: Acute aortic dissection is a disease that is often a challenge to diagnose. Early and immediate diagnosis is important for initiation of treatment and improved survival. Despite recent advances in imaging methods to diagnose the disease, biochemical methods are not available. RECENT FINDINGS: Biomarkers that might be useful for the biochemical detection of acute aortic dissection have been recently described, such as assays for the circulating proteins, smooth muscle myosin heavy chain, creatine kinase BB-isozyme, calponin (smooth muscle troponin) and elastin. C-reactive protein and D-dimer have also been shown to be useful. SUMMARY: Biomarker-assisted diagnosis of acute aortic dissection would be helpful in detecting this acute catastrophic aortic disease, which still remains a challenge to diagnose. Although recent progress in development of biomarkers has been made, there is no widely accepted strategy. Available biomarkers such as D-dimer may play an assistive role in the meantime. PMID- 20717016 TI - Vitamin B12: the forgotten micronutrient for critical care. AB - PURPOSE OF REVIEW: To analyse the anti-inflammatory and antioxidant properties of vitamin B12 and evaluate current evidence on vitamin B12 status in the critically ill with systemic inflammation. RECENT FINDINGS: Data on vitamin B12 status of intensive care unit patients are scarce. Cobalamins could potentially be useful agents for inhibiting nitric oxide synthase and nitric oxide production, controlling nuclear factor-kappa B activation, and restoring optimal bacteriostasis and phagocytosis in which transcobalamins play a proven role. The antioxidant properties of vitamin B12, with a glutathione-sparing effect, are secondary to stimulation of methionine synthase activity and reaction with free oxygen or nitrogen radicals. Large parenteral doses are routinely administered for cyanide poisoning, with only mild, reversible side-effects. Current evidence suggests that high-dose parenteral vitamin B12 may prove an innovative approach to treat critically ill systemic inflammatory response syndrome patients, especially those with severe sepsis/septic shock. In this setting, vitamin B12 and transcobalamins could modulate systemic inflammation contributing to the anti inflammatory cascade and potentially improve outcome. SUMMARY: Despite evidence from animal studies, so far there are no clinical intervention trials that have studied vitamin B12 as a pharmaconutrient strategy for critical care. Well designed animal and clinical studies are required to clarify several outstanding questions on the optimal posology, safety, and efficacy of high-dose vitamin B12 in the critically ill. PMID- 20717017 TI - Acid diet (high-meat protein) effects on calcium metabolism and bone health. AB - PURPOSE OF REVIEW: Update recent advancements regarding the effect of high-animal protein intakes on calcium utilization and bone health. RECENT FINDINGS: Increased potential renal acid load resulting from a high protein (intake above the current Recommended Dietary Allowance of 0.8 g protein/kg body weight) intake has been closely associated with increased urinary calcium excretion. However, recent findings do not support the assumption that bone is lost to provide the extra calcium found in urine. Neither whole body calcium balance is, nor are bone status indicators, negatively affected by the increased acid load. Contrary to the supposed detrimental effect of protein, the majority of epidemiological studies have shown that long-term high-protein intake increases bone mineral density and reduces bone fracture incidence. The beneficial effects of protein such as increasing intestinal calcium absorption and circulating IGF-I whereas lowering serum parathyroid hormone sufficiently offset any negative effects of the acid load of protein on bone health. SUMMARY: On the basis of recent findings, consuming protein (including that from meat) higher than current Recommended Dietary Allowance for protein is beneficial to calcium utilization and bone health, especially in the elderly. A high-protein diet with adequate calcium and fruits and vegetables is important for bone health and osteoporosis prevention. PMID- 20717018 TI - New insights into thyroid hormone actions and lipid metabolism. PMID- 20717019 TI - Interrelationships between the pancreas and the thyroid. AB - PURPOSE OF REVIEW: To review advances in understanding of the relationships between the thyroid gland and endocrine function of the pancreas. RECENT FINDINGS: Recent advances reviewed here are the association of certain thyroid diseases with diabetes mellitus, the possible contribution of insulin resistance to thyroid pathology, insulin and glucose metabolism in states of thyroid dysfunction and insulin requirements in diabetic patients with thyroid disease. SUMMARY: Appreciation of associations between the functions of the thyroid gland and endocrine pancreas provides certain insights into clinical management of these conditions. PMID- 20717020 TI - Metabolic syndrome with the atypical antipsychotics. AB - PURPOSE OF REVIEW: Metabolic syndrome and cardiovascular diseases are important causes of morbidity and mortality among patients with severe mental illnesses. Atypical or second-generation antipsychotics (SGAs) are associated with obesity and other components of metabolic syndrome, particularly abnormal glucose and lipid metabolism. This review aims to provide a summary of recent evidence on metabolic risks associated with SGAs, current recommendations for metabolic monitoring, and efficacy of treatment options currently available. RECENT FINDINGS: Studies have identified younger, antipsychotic-naive patients with first-episode psychosis as a population vulnerable to adverse metabolic effects from SGAs. These patients gained more weight and developed evident lipid and glucose abnormalities as soon as 8-12 weeks after treatment initiation. Findings are more striking among children and adolescents. The differential effects of various SGAs are well described, with clozapine and olanzapine associated with the highest metabolic risk. In addition to behavioral therapy, emerging data suggest that pharmacological therapy, most notably metformin, is efficacious in the treatment and possibly prevention of SGA-associated metabolic derangements. SUMMARY: More data have become available on the burden from metabolic complications associated with SGAs. New and effective treatment options are required in the near future to improve cardiovascular health in this susceptible population. PMID- 20717022 TI - The role of the macrophage in sentinel responses in intestinal immunity. AB - PURPOSE OF REVIEW: The purpose of this review is to highlight macrophages as central mediators of intestinal immune homeostasis and inflammation. RECENT FINDINGS: We review recent developments elucidating distinct phenotypic adaptations in intestinal macrophages that determine their functional role in a microbe-rich environment. The involvement of intestinal macrophages in the pathogenesis of inflammatory bowel disease is also discussed. SUMMARY: Intestinal macrophages represent the largest pool of tissue macrophages in the human body and a critical interface with the enteric microbiota. In normal physiology, luminal microbes breach the intestinal epithelial barrier and gain access to the lamina propria. Bacteria are efficiently phagocytosed by macrophages strategically located underneath the epithelium. The importance of functional adaptations of macrophages to perform their role in this unique environment is best illustrated by failure of these mechanisms during the development of chronic inflammatory bowel diseases. Compared with monocytes or macrophages from any other organ, intestinal macrophages express different phenotypic markers, efficiently eradicate intracellular bacteria, but do not mount potent inflammatory responses. Converging human genetic and functional findings suggest that dysregulation of macrophage-specific immune responses against an otherwise harmless enteric microbiota are key factors in the pathogenesis of inflammatory bowel disease. PMID- 20717023 TI - Epidemiological considerations for the use of databases in transfusion research: a Scandinavian perspective. AB - PURPOSE OF REVIEW: At current safety levels, with adverse events from transfusions being relatively rare, further progress in risk reductions will require large-scale investigations. Thus, truly prospective studies may prove unfeasible and other alternatives deserve consideration. In this review, we will try to give an overview of recent and historical developments in the use of blood donation and transfusion databases in research. In addition, we will go over important methodological issues. RECENT FINDINGS: There are at least three nationwide or near-nationwide donation/transfusion databases with the possibility for long-term follow-up of donors and recipients. During the past few years, a large number of reports have been published utilizing such data sources to investigate transfusion-associated risks. In addition, numerous clinics systematically collect and use such data on a smaller scale. SUMMARY: Combining systematically recorded donation and transfusion data with long-term health follow-up opens up exciting opportunities for transfusion medicine research. However, the correct analysis of such data requires close attention to methodological issues, especially including the indication for transfusion and reverse causality. PMID- 20717021 TI - HIV protease inhibitors and obesity. AB - PURPOSE OF REVIEW: To review the current scientific literature and recent clinical trials on HIV protease inhibitors and their potential role in the pathogenesis of lipodystrophy and metabolic disorders. RECENT FINDINGS: HIV protease inhibitor treatment may affect the normal stimulatory effect of insulin on glucose and fat storage. Further, chronic inflammation from HIV infection and protease inhibitor treatment trigger cellular homeostatic stress responses with adverse effects on intermediary metabolism. The physiologic outcome is such that total adipocyte storage capacity is decreased, and the remaining adipocytes resist further fat storage. This process leads to a pathologic cycle of lipodystrophy and lipotoxicity, a proatherogenic lipid profile, and a clinical phenotype of increased central body fat distribution similar to the metabolic syndrome. SUMMARY: Protease inhibitors are a key component of antiretroviral therapy and have dramatically improved the life expectancy of HIV-infected individuals. However, they are also associated with abnormalities in glucose/lipid metabolism and body fat distribution. Further studies are needed to better define the pathogenesis of protease inhibitor-associated metabolic and body fat changes and their potential treatment. PMID- 20717024 TI - Allogeneic transplantation for lymphoma: long-term outcome. AB - PURPOSE OF REVIEW: In the last 20 years, allogeneic stem cell transplantation (alloSCT) has been increasingly applied in lymphoma patients, due to the shift towards reduced intensity and nonmyeloablative conditioning. This review reports on the most significant long-term results of allografted lymphoma patients coming from both prospective studies and retrospective analyses. RECENT FINDINGS: AlloSCT can cure 40-60% of aggressive B-cell lymphomas, but an unfavourable outcome has been observed in case of chemorefractory and active disease at the time of allografting. Indolent lymphoma displays the best outcome, and reduced intensity alloSCT should be always considered in patients relapsing after an autologous SCT and in cases of chemorefractory disease. Most recent findings in Hodgkin's and T-cell lymphoma are also encouraging. SUMMARY: Although the nonrelapse mortality has been reduced and survival curves show a plateau, the analysis of the long-term outcome reveals that a significant proportion of patients still experiences disease relapse and delayed morbidity and mortality. At the best of our knowledge, the process of decision-making should be based on lymphoma subtype, chemosensitivity, disease status and patient comorbidities at the time of allografting. To answer some of the still open questions, physicians should try to improve the enrolment of patients in multicentre prospective clinical trials. PMID- 20717025 TI - Sirolimus immunosuppression for graft-versus-host disease prophylaxis and therapy: an update. AB - PURPOSE OF REVIEW: Sirolimus is being used increasingly as an immunosuppressant in allogeneic hematopoietic stem cell transplantation. This article reviews recent results in sirolimus-based graft-versus-host disease (GVHD) prophylaxis, as well as outcomes using sirolimus for established acute and chronic GVHD. RECENT FINDINGS: In uncontrolled experiments, sirolimus provides good control of steroid-resistant acute or chronic GVHD. Similarly, the addition of sirolimus to GVHD prophylaxis regimens appears to reduce the rate of acute GVHD in the myeloablative and reduced-intensity settings, when used in matched, related, and unrelated donor transplantation. The use of sirolimus in haploidentical transplantation is now being explored as well. SUMMARY: Sirolimus should be considered for use in steroid-resistant acute and chronic GVHD. Sirolimus appears promising as primary prophylaxis for GVHD prevention. Randomized trials are currently being performed to determine whether sirolimus-based immunosuppression is superior to traditional GVHD prophylaxis. PMID- 20717026 TI - Minority donation in the United States: challenges and needs. AB - PURPOSE OF REVIEW: In the United States, blood donation rates of African Americans are 25-50% of that of white individuals. As African-Americans make up an ever increasing and now substantial minority, and African-American recipients of blood transfusion, both specialized, such as sickle cell disease patients, and general hospitalized patients, have a better chance of receiving phenotype matched or appropriate red blood cell units when there is a significant percentage of products in the inventory from African-American donors, it is important to understand the reason for the observed difference. RECENT FINDINGS: Possible reasons for this discrepancy in donation rates include increased rates of donor deferral and ineligibility; increased barriers to donation, such as fear and distrust; and different marketing and education strategies. Thus, to increase the blood availability to African-American recipients, the reasons for these donation rate differences must be better understood and subsequently addressed through improved blood donor recruitment programs. The majority of African American donor recruitment programs have focused on donating for sickle cell disease patients, particularly children, which have been of limited success. SUMMARY: Significant improvements in African-American donor recruitment are needed to adequately meet the demand of African-American patients as well as the entire population. PMID- 20717027 TI - Are we any closer to beating the biofilm: novel methods of biofilm control. AB - PURPOSE OF REVIEW: A multidisciplinary approach to the treatment and management of biofilms has resulted from the growing appreciation of the role that biofilms play in modern medicine. Conventional antimicrobial agents are generally ineffective against biofilms, and as a result novel laboratory-based and clinical strategies have emerged. The purpose of this review is to analyse the recent literature relating to novel treatment strategies targeting the growing spectrum of clinically relevant biofilms. RECENT FINDINGS: Microscopy and molecular techniques have provided greater insights into identifying the key bacterial and fungal biofilm pathogens. Knowledge of these microorganisms has provided a foundation for the development of specific molecules, often microbial derived, with antimicrobial and/or biofilm disruptive properties, augmenting conventional antibiotics treatments. The validity of some such rationally designed therapeutics has been explored in clinical trials. SUMMARY: Biofilms are inherently difficult to treat, and mechanical disruption is the mainstay of clinical management. With scientific progress in molecular microbiology, there is an abundance of newly discovered molecules and pathways, providing novel therapeutic and prophylactic targets. PMID- 20717029 TI - Influenza in travellers. AB - PURPOSE OF REVIEW: The importance of travelling as an important factor for spread of influenza has become even more evident during the recent pandemic year. All the same, the mechanism for seasonal spreading of influenza is not yet fully understood. RECENT FINDINGS: The incidence of influenza in returning febrile travellers from subtropical and tropical regions is between 5 and 15% with no significant differences between those vaccinated and not vaccinated in the reviewed studies. The power of the studies to detect differences are, however, low. In these studies, 12-85% of the travellers or pilgrims were vaccinated against influenza. Air transportation, and especially long-haul flight, is a key factor for the spread of influenza even though travel restrictions seem to be of no use for preventing a pandemic spread. SUMMARY: Influenza should always be considered in a febrile traveller with or without respiratory symptoms. Future studies on incidence of travel-related influenza should consider the short incubation period for a better estimate. Vaccine from the opposite hemisphere should be made available for travellers, and influenza vaccine studies should focus on optimizing the effect of the vaccine in the elderly and immunocompromised. PMID- 20717028 TI - An inside job: subversion of the host secretory pathway by intestinal pathogens. AB - PURPOSE OF REVIEW: The cellular secretory pathway, composed of the endoplasmic reticulum, Golgi apparatus, and cellular vesicles, mediates the intracellular trafficking of proteins and lipids. Gastrointestinal pathogens frequently affect the functions of enterocytes, the differentiated cells involved in secretion and absorption of extracellular molecules. Microbial pathogenesis can be enhanced by altering the trafficking of key molecules such as brush border enzymes, soluble immune mediators such as cytokines and chemokines, and MHC Class I molecules, all of which rely on the secretory pathway for their appropriate cellular localization. This review focuses on our current understanding of the distinct mechanisms employed by enteric pathogens to antagonize the secretory pathway. RECENT FINDINGS: Many pathogens encode individual or multiple proteins to antagonize the secretory pathway, including disrupting the trafficking of vesicles between the endoplasmic reticulum, Golgi, and plasma membrane. This antagonism allows for increased pathogenesis and can assist, directly or indirectly, in microbial replication. Virtually all arms of the secretory pathway are targeted by intestinal pathogens, supporting the pathogenic significance of shutting this pathway down. SUMMARY: This review summarizes the mechanisms utilized by gut pathogens to disrupt the cellular secretory pathway and addresses potential therapeutic targets to combat these highly prevalent and burdensome microbes. PMID- 20717030 TI - MicroRNAs in hair cell development and deafness. AB - PURPOSE OF REVIEW: The identification of transcriptional activators and repressors of hair cell fates has recently been augmented by the discovery of microRNAs (miRNAs) that can function as post-transcriptional repressors in sensory hair cells. RECENT FINDINGS: miRNAs are approximately 21-nucleotide single-stranded ribonucleic acids that can each repress protein synthesis of many target genes by interacting with messenger RNA transcripts. A triplet of these miRNAs, the miR-183 family, is highly expressed in vertebrate hair cells, as well as a variety of other peripheral neurosensory cells. Point mutations in one member of this family, miR-96, underlie DFNA50 autosomal deafness in humans and lead to abnormal hair cell development and survival in mice. In zebrafish, overexpression of the miR-183 family induces extra and ectopic hair cells, whereas knockdown reduces hair cell numbers. Genetically engineered mice with a block in miRNA biosynthesis during early ear development, or during hair cell differentiation, reveal the necessity of miRNAs at these crucial time points. SUMMARY: Because miRNAs can simultaneously down-regulate dozens to perhaps hundreds of transcripts, they will soon be explored as potential therapeutic agents to repair or regenerate hair cells in animal models. PMID- 20717031 TI - Cellular mechanisms of aminoglycoside ototoxicity. AB - PURPOSE OF REVIEW: To summarize advances in the study of the interaction between sensory hair cells and aminoglycoside antibiotics. RECENT FINDINGS: Aminoglycosides enter hair cells through mechanotransduction channels and initiate an active signaling pathway that leads to cell death. Early expression of heat shock proteins can protect hair cells from aminoglycosides, although signaling from surrounding supporting cells appears to promote hair cell death. Studies of certain human deafness mutations have revealed new insights into the role of mitochondria in aminoglycoside ototoxicity. SUMMARY: The cellular mechanisms of aminoglycoside ototoxicity continue to be an active topic of research and newly developed animal models offer great promise for future advances. Nevertheless, proven clinical methods for the prevention of ototoxic injury are not yet available. PMID- 20717033 TI - Laboratory testing of the vestibular system. AB - PURPOSE OF REVIEW: Recent reports on vestibular testing, relevant to clinical diagnosis, are reviewed.Besides the case history and bedside examination, objective measurement of the vestibuloocular reflex in all of its facets remains the cornerstone in the diagnostic process. RECENT FINDINGS: In recent years, this has been enhanced considerably by reliable unilateral tests for the otolith organs, most notably by vestibular-evoked myogenic potential recording and estimation of subjective visual vertical. In addition, progress has been made in the investigation of multisensory interaction, involving visual acuity and posturography.Technological developments include improved eye movement measurement techniques, electrotactile and vibrotactile sensory enhancement or substitution, the use of virtual reality devices and motion stimulators such as hexapods and the rediscovery of galvanic vestibular stimulation as a research and diagnostic tool. SUMMARY: The recent introduction of new tests, together with the development of novel technologies, is gradually increasing the scope of the physical and bedside examination of the dizzy patient (see chapter 'Medical management of peripheral disorders' in this issue). The use of more complex equipment, such as rotating chairs, linear sleds, hexapods and posturography platforms, is likely to become limited to specialized laboratories and rehabilitation centers in future years. Further, high resolution magnetic resonance tomography (MRT) and computed tomography have allowed insight into the morphology and determination of malformations of the human labyrinth. PMID- 20717032 TI - Cochlear efferent innervation and function. AB - PURPOSE OF REVIEW: This review covers topics relevant to olivocochlear-efferent anatomy and function for which there are new findings in papers from 2009 to early 2010. RECENT FINDINGS: Work within the review period has increased our understanding of medial olivocochlear (MOC) mechanisms in outer hair cells, MOC reflex tuning, MOC effects on distortion product otoacoustic emissions, the time course of MOC effects, MOC effects in psychophysical tests and on understanding speech, MOC effects in attention and learning, and lateral efferent function in binaural hearing. In addition, there are new insights into efferent molecular mechanisms and their effect on cochlear development. SUMMARY: Techniques for measuring efferent effects using otoacoustic emissions are now well developed and have promise in clinical applications ranging from predicting which patients are susceptible to acoustic trauma to characterizing relationships between efferent activation and learning disabilities. To realize this promise, studies are needed in which these techniques are applied with high standards. PMID- 20717034 TI - Ear canal cholesteatoma: meta-analysis of clinical characteristics with update on classification, staging and treatment. AB - PURPOSE OF REVIEW: We present an update on clinical evaluation, staging, classification and treatment of canal cholesteatoma, including a meta-analysis of clinical data of the last 30 years. RECENT FINDINGS: Ear canal cholesteatoma is frequently associated secondarily to other canal pathologies. The cause for the rare idiopathic form of the disease remains enigmatic. Epidemiologic and experimental studies of its pathogenesis have increased; however, the main explanatory theory of a deficient migratory capacity of the canal epithelium affected has been falsified only recently. Therefore, the debate on the pathogenesis has gained additional impetus and more data is needed. SUMMARY: Canal cholesteatoma is a rarity in otologic pathology, often leading to misdiagnosis as external otitis or otomycosis by physicians unfamiliar with the disease. It presents typically with otorrhea, focal erosion and keratin accumulation in the osseous ear canal and has to be distinguished from keratosis obturans, which leads to otalgia and bilateral conductive hearing loss by ceruminal plugs, with circumferential distention of the ear canal. Treatment by canaloplasty is curative and highly successful. Alternative conservative treatment is feasible, however, requiring long-term follow up, with often painful cleaning of the lesion. PMID- 20717035 TI - Healthcare provision for adults with congenital heart disease in Europe: a review. AB - PURPOSE OF REVIEW: To draw attention to the substantial growth of number of centres that provide specialized care for adult congenital heart disease, to what is needed in such a specialized centre and--most importantly--to the big proportion of patients who are lost to follow-up. RECENT FINDINGS: For a long time it was assumed that loss of follow-up or lapse of care started at the time of transfer of care from paediatric cardiology to an adult setting. In recent years it became clear, from studies from all over the world, that the loss of follow-up was much larger than assumed and that it started to become substantial after childhood, in the adolescent and teenage years. SUMMARY: The implication of these findings is that--to avoid the very substantial loss to follow-up--a timely transition programme must start, that is before the big loss to follow-up starts, at the beginning of the adolescent years. The current workforce is inadequate to care for the vast number of adult congenital heart disease patients in the community; it will be necessary to establish more adult congenital heart disease programmes, to train more adult congenital heart disease cardiologists, to implement transition programmes and to take nurse specialists on staff. PMID- 20717036 TI - Long-term prognosis of Kawasaki disease: increased cardiovascular risk? AB - PURPOSE OF REVIEW: Whereas the cause of Kawasaki disease is still unknown, progress in treatment during its acute phase has decreased the incidence of coronary artery lesions from 25-30% to 3-5%. In addition to acute-phase coronary disturbances, sclerotic vascular changes are often observed in post-Kawasaki disease patients, including those without coronary lesions during the acute phase. Survivors of Kawasaki disease are now reaching the age of atherosclerosis and it is unknown if these individuals carry a higher risk of coronary disease. This review aims to report the current state of knowledge concerning the long term prognosis of patients with Kawasaki disease. RECENT FINDINGS: Histopathological studies prove the changes of Kawasaki disease to be distinctive from those of atherosclerosis. However, endothelial dysfunction and risk factors for the development of atherosclerosis, such as dyslipidemia, decreased vascular elasticity, increased C-reactive protein, oxidative stress, inflammatory cytokines, and reactive oxygen species, are known to be present in the late phase of Kawasaki disease. In addition, postarteritis coronary arteries in animal models are more prone to the development of atherosclerotic changes. SUMMARY: Potential cardiovascular risks are present in survivors of Kawasaki disease. Epidemiological studies enrolling a large cohort of Kawasaki disease patients surviving to middle age are awaited. PMID- 20717037 TI - Managing traumatized children: a trauma systems perspective. AB - PURPOSE OF REVIEW: To review the current research on trauma-informed child serving systems. Research on this topic, although sparse, is critically important because most children who come into contact with systems, including the child welfare and juvenile justice systems, have experienced at least one traumatic event. RECENT FINDINGS: Very little research has actually been done on this topic area. Although it makes intuitive sense to integrate a trauma-informed approach into child-serving systems, much more research needs to be conducted in order to determine the efficacy of trauma-informed thinking in child-serving systems. SUMMARY: A number of research studies have been conducted that focus on adults with co-occurring disorders who have received trauma-informed treatment. These results suggest that a 'trauma-informed' approach is a helpful and effective way to implement services. These same principles may be applied to work with children in order to create a 'trauma-informed child-serving system'. Twelve literature supported and research-supported components of such a system are introduced in this review, ranging from the importance of specialized knowledge about trauma to trauma assessment and the value of trauma-informed policy. PMID- 20717038 TI - The intelligibility of delusion. AB - PURPOSE OF REVIEW: The question of the intelligibility of delusion has recently been addressed from within empirical psychology, analytical philosophy, and existential phenomenology. The different presuppositions, aims and paradigms for understanding deployed by these several approaches have not always been clearly distinguished. RECENT FINDINGS: Psychological theories of delusion approach the delusional subject as a sense-maker labouring under various intelligible strains in their social world and in their emotional and cognitive constitution. Philosophically minded psychopathologists continue to urge that delusion reflects a deeper disturbance of mindedness that renders questionable the application of approaches which seek everyday forms of intelligibility. SUMMARY: Analytical philosophers have most clearly articulated the ways in which delusions cannot, whereas phenomenologists have best articulated the ways in which delusions can, be understood. As we become clearer about the diverse forms our understanding can take, and the different conditions in which such diverse forms may - and may not each be deployed, a more nuanced answer to the question of the intelligibility of delusion becomes possible. PMID- 20717039 TI - What can low and high technologies do for late-life mental disorders? AB - PURPOSE OF REVIEW: To identify and review the latest research in the use of low and high technology in the areas of mood disorders, psychosis, normal ageing, mild cognitive impairment and dementia. RECENT FINDINGS: Technology use varied in type and extent of use across the different areas that have been reviewed. Telepsychiatry, internet-delivered therapy programs and bright-light therapy were used in managing symptoms associated with depression. In psychosis, multisensory therapy, reminiscence and virtual cognitive stimulation showed some benefits. Navigation aids and computerized diaries assisted in maintaining independence in the normally ageing and mildly cognitively impaired, although the benefits of cognitive stimulation are yet to be consistently established. By far, dementia technology received the most research attention. Benefits in this population included reductions in behavioural and psychological symptoms and carer burden and increased independence, task engagement and safety. SUMMARY: Research in the use of low and high technology in late-life mental disorders continues to evolve in its scope and innovation. To progress the accessibility and acceptability of technology, involvement of stakeholders and users in the design and application, as well as examination of cost-effectiveness and robust methodologically designed studies are necessary. PMID- 20717040 TI - Trends and determinant factors for population blood pressure with 25 years of follow-up: results from the Copenhagen City Heart Study. AB - OBJECTIVE: This study aimed to evaluate within-population trends in population blood pressure (BP) over 25 years and to identify important determinants for a changing population BP. DESIGN: Copenhagen City Heart Study is a prospective longitudinal epidemiological study. The study population (15 508) did not receive antihypertensive therapy. METHODS: The BP measurement was fully standardized and measurement method was unchanged throughout the observation period. A questionnaire concerning drinking habits, smoking, medical therapy and physical exercise was completed by the participants and double checked by the technicians. RESULTS: After an initial increase, population systolic BP (SBP) decreased. All risk factors were tested in the longitudinal model by means of a residual likelihood ratio test. The final model included sex, age and body mass index as significant factors and covariates. Two interactions were included. The first interaction 'age*sex' showed that the sex differences diminished with age. The second interaction 'age*survey' showed that the value of SBP in the young generations decreased survey by survey. SBP in the elderly also decreased survey by survey, but to a lesser degree. Diastolic BP (DBP) increased to a peak value in survey 3 and hereafter decreased. CONCLUSION: SBP decreased. body mass index, sex and age have an effect on population BP. A decreasing trend in SBP among new entrants is responsible for (part of) the observed decrease in population SBP. The decreasing SBP among the elderly was affected by the fact that an increasing number of the elderly population started antihypertensive medication. DBP decreased, but none of the investigated factors affected DBP. PMID- 20717041 TI - Consumer perceptions of direct-to-consumer personalized genomic risk assessments. AB - PURPOSE: To evaluate consumer perceptions of direct-to-consumer personalized genomic risk assessments and assess the extent to which consumer characteristics may be associated with attitudes toward testing. METHODS: Adult participants aged 18-85 years of age purchased a personalized genomic risk test at a subsidized rate and were administered a web-based health assessment that included questions regarding perceptions and attitudes toward undergoing testing. RESULTS: Assessments were obtained for 3640 individual study participants, and 49.7% expressed overall concerns about undergoing testing. Logistic regression analysis revealed that women were more likely to express concerns (odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.04 -1.39), as were individuals employed by a health care organization (OR = 1.23, 95% CI: 1.04 -1.46). Further, younger age (OR = 0.97, 95% CI: 0.96-0.98), higher education (OR = 1.09, 95% CI: 1.04 -1.14), and higher trait anxiety (OR = 1.28, 95% CI: 1.20-1.37) were also significantly associated with expressing concerns related to testing. Attitudes regarding disclosure of genetic risk for a nonpreventable disease were also assessed. None of the individuals in our sample indicated that they would definitely not want to know their risk, and a total of 82.4% indicated that they would want to know. CONCLUSION: Among individuals who undergo direct-to-consumer genetic testing, approximately half still express concerns about the process/experience. Further, given that concerns vary among different subgroups of consumers, if the clinical validity and utility of these tests are demonstrated, tailored genetic education and counseling services may be of benefit. PMID- 20717042 TI - The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. AB - BACKGROUND: Leptin is an adipocyte-derived hormone that plays a crucial role in energy homeostasis and lipid metabolism. Most of the biological effects of leptin are exerted through activation of the Janus kinase-2/signal transducer and activator of transcription-3 pathway. Signal transducer and activator of transcription-3 activation ultimately leads to an increased transcription and expression of suppressors of cytokine signaling-3, which acts as a feedback inhibitor by attenuating leptin signaling. Apart from inhibiting leptin signaling, suppressor of cytokine signaling-3 inhibits insulin signaling. Leptin increases with increasing fatty mass as a compensatory mechanism to preserve insulin sensitivity, but persistent hyperleptinemia is implicated in liver fibrinogenesis and carcinogenesis. HYPOTHESIS: Considering this dual role of leptin in the liver pathophysiology, we hypothesized that leptin resistance may vary according to the different types of liver cells and nonalcoholic fatty liver disease progression. CLINICAL CONSEQUENCES: It is speculated that recombinant leptin, proposed to be used in common forms of obesity or nonalcoholic fatty liver disease, might have serious unfavorable therapeutical drawbacks, through promotion of insulin resistance, fibrosis, and hepatocellular carcinoma. PMID- 20717043 TI - Genetic predisposition to thrombophilia in inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is linked to a definite risk of thromboembolic events (TE), but data on the role of prothrombotic genetic mutations are conflicting. STUDY: Fourteen genetic factors involved in TE pathogenesis were investigated in a homogeneous cohort of Sicilian patients with IBD with and without history of TE and in healthy controls. Forty IBD patients (21 CD, 19 UC) and 20 healthy individuals were enrolled. Genetic testing was based on the reverse hybridization principle by a commercial assay that analyzes 14 polymorphisms involved in thrombophilia and cholesterol metabolism. The rate of genetic polymorphisms and mutations was compared between IBD patients and healthy controls. RESULTS: No significant difference in allelic frequency was found between IBD patients and controls except AGT T/T, though a trend toward significance was found also for ACE D/D. Eight out of 9 patients with earlier history of TE had more than 1 polymorphism, compared with 12 out of 31 without TE. In patients with IBD the mutation AGT T/T was related to male sex (P<0.0259) and, marginally, to arterial hypertension (P<0.06) and diabetes (P<0.09). CONCLUSIONS: Our data confirm a definite risk of TE in IBD (22.5% of our series). An increased frequency of the genotypes ACE D/D and AGT T/T, never reported so far, was found. In IBD patients TE has a multifactorial genesis with involvement of several genes as well and acquired factors. Genetic screening for prothrombotic factors could help segregate IBD patients at higher risk of TE. PMID- 20717044 TI - A randomized controlled trial of valdecoxib and glyceryl trinitrate for the prevention of post-ERCP pancreatitis. AB - BACKGROUND: Efforts to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis have been largely unsuccessful. Cyclo-oxygenase-2 enzyme-mediated inflammatory pathway has been suggested in the pathophysiology of acute pancreatitis. Glyceryl trinitrate (GTN) might prevent post-ERCP pancreatitis by relaxing the sphincter of Oddi. OBJECTIVE: To evaluate the efficacy of valdecoxib, a cyclo-oxygenase-2 inhibitor, and GTN transdermal patch for the prevention of post-ERCP pancreatitis. METHODS: Patients undergoing first ERCP procedure from October 2003 to August 2005 were randomized to receive either 20 mg intravenous valdecoxib or GTN patch (10 mg/h) at the start of ERCP, or assigned to control group. The study followed CONSORT guidelines. Primary outcome measure was frequency of post-ERCP pancreatitis in the 3 groups. RESULTS: A total of 380 patients were randomized; 121 patients in valdecoxib (group 1), 124 in GTN (group 2), and 126 in the control arm (group 3) were analyzed. There was no difference in the frequency of post-ERCP pancreatitis between the groups (12 each in groups 1 and 2, and 13 in group 3; P=0.986). None of the patients had severe pancreatitis. The frequency of post-ERCP pain and amylase levels were also similar in the 3 groups (P=0.769 and P=0.947, respectively). Pancreatic duct cannulation, cholecystectomy, difficult cannulation, and pre-cut were risk factors for pancreatitis on univariate analysis. On multivariate analysis, pancreatic duct cannulation was the only independent risk factor for pancreatitis (P<=0.001; odds ratio 5.67; 95% confidence interval: 2.76-11.63). CONCLUSIONS: Valdecoxib and GTN were not effective for the prevention of post-ERCP pancreatitis. PMID- 20717045 TI - Is gastroduodenal biopsy safe in patients receiving aspirin and clopidogrel?: a prospective, randomized study involving 630 biopsies. AB - GOALS: To assess prospectively the bleeding risk attributable to gastroduodenal biopsy in subjects taking antiplatelet medications. BACKGROUND: No prospective data exist regarding the bleeding risk attributable to endoscopic biopsy in patients taking antiplatelet agents. A majority of Western endoscopists withdraw antiplatelet agents before upper endoscopy, despite expert guidelines to the contrary. STUDY: We performed a prospective, single-blind, randomized study in healthy volunteers participating in a larger study regarding the effect of antiplatelet agents on gastroduodenal mucosal healing. Multiple gastroduodenal biopsies were performed during 2 esophagogastroduodenoscopy in subjects dosed with aspirin enteric-coated 81 mg once daily or clopidogrel 75 mg once daily. Data for endoscopic bleeding, clinical bleeding, blood vessel size, and depth of biopsy in histology specimens were collected. RESULTS: Four hundred and five antral biopsies and 225 duodenal biopsies were performed during 90 esophagogastroduodenoscopy in 45 subjects receiving aspirin or clopidogrel. Median maximum blood vessel diameter per biopsy was 31.9 MU (range: 9.2 to 133.8). About 50.8% of biopsy specimens breached the muscularis mucosa. In the clopidogrel group, no bleeding events were noted after 350 biopsies [upper confidence limit (UCL) for probability of bleeding=0.0085]. In the aspirin group, there were no clinical events (UCL=0.0106) and one minor endoscopic bleeding event (UCL=0.0169). CONCLUSIONS: Consistent with expert guidelines, the absolute risk attributable to gastroduodenal biopsy in adults taking antiplatelet agents seems to be low. Half of routine biopsies enter submucosa. The largest blood vessels avulsed during biopsy correspond to midsized and large arterioles and venules. PMID- 20717046 TI - The hunter and the pianist: two hepatic encephalopathy tales. AB - Details of 2 patients with cirrhosis and hepatic encephalopathy whose hobby or job were possibly responsible for a selectively enhanced performance in 1 neuropsychiatric test are reported. Clinicians should be alert to the fact that personal inclinations and habits may impinge on both neuropsychological and psychophysic performance, thus producing a mismatch between the results of different mental status tests. A prospective study with accurate history taking, use of comprehensive assessment protocols, and modeling/critical interpretation of the test results is required to confirm this hypothesis. PMID- 20717047 TI - Marathon pancreatitis. PMID- 20717048 TI - Anterior lens capsule versus mitomycin-C as an adjunct to trabeculectomy in combined phacotrabeculectomy. AB - AIM: Efficacy of using the anterior lens capsule removed during combined phacotrabeculectomy as an adjunct to trabeculectomy and comparing it to Mitomycin C. METHODS: Prospective randomized study. Two site phacotrabeculectomy and at the end of the surgery, the removed anterior lens was placed under the scleral flap in group I and Mitomycin C in group II. RESULTS: No significant difference between the intraocular pressure, antiglaucoma medications, or visual acuity. No complications were related to anterior lens capsule. CONCLUSIONS: Anterior lens capsule is effective in phacotrabeculectomies. PMID- 20717049 TI - Adjunctive use of bevacizumab versus mitomycin C with Ahmed valve implantation in treatment of pediatric glaucoma. AB - PURPOSE: Evaluate the use of bevacizumab (avastin) injected around valve body intraoperatively versus the use of mitomycin C as a single intraoperative application at the site of Ahmed valve implantation to enhance the survival of Ahmed valve in cases of pediatric glaucoma's as regarding the efficacy and complications. METHOD: Twenty eyes of 16 patients with pediatric glaucoma underwent Ahmed valve implantation with bevacizumab (avastin) (1.25 mg in 0.05 mL) injected around the valve body after completing the surgery compared with 20 eyes of 14 patients with pediatric glaucoma who underwent Ahmed valve implantation with application of mitomycin C (0.4 mg/mL for 3 min) before valve implantation and 20 eyes of 18 patients managed by Ahmed valve only (control group). The follow-up period was 12 months. RESULTS: The results revealed that 80% total success (70% complete success and 10% qualified success) in first group in which avastin augmented Ahmed valve was performed compared with group II in which mitomycin C was used during Ahmed valve implantation 90% total success (80% complete success and 10% qualified success) and this difference between the 2 groups was nonsignificant (P>0.05), but in group III complete success occurred in (60%) only with no cases of qualified success (P>0.05). CONCLUSIONS: The adjunctive use of bevacizumab or mitomycin C during Ahmed valve implantation significantly enhances the valve survival and the first drug seems to be much safer with no visually devastating complications. PMID- 20717050 TI - Comparison of retinal nerve fiber layer thickness measurements using time domain and spectral domain optical coherence tomography, and visual field sensitivity. AB - PURPOSE: To investigate the relationship between the peripapillary retinal nerve fiber layer (RNFL) thickness, as measured by Stratus time domain optical coherence tomography (OCT) (Stratus OCT) and Cirrus spectral domain OCT (Cirrus HD-OCT), and the severity indices of the visual field (VF) defects in glaucoma patients. METHODS: This was a prospective, cross-sectional study. Correlations between the individual VF sensitivity at 52 test points and the Stratus OCT and Cirrus HD-OCT, which determined peripapillary RNFL thicknesses from 6 sectors, were calculated in 54 eyes with open-angle glaucoma and 22 normal control eyes. The association between the RNFL thickness and VF sensitivity was evaluated using a second-order regression model. RESULTS: A significant correlation was found for the RNFL thicknesses determined by the 2 OCT devices (r=0.51 to 0.95; P<0.001). VF sensitivities at each test point were also significantly correlated with the sectoral RNFL thicknesses. The inferotemporal RNFL sector exhibited the highest coefficient of determination, whereas the superotemporal test point had the highest VF sensitivity (Stratus, 0.70; Cirrus, 0.62). CONCLUSIONS: The structure function relationship was comparable between Cirrus HD-OCT and Stratus OCT RNFL measurements. PMID- 20717051 TI - Multifocal pupillographic perimetry with white and colored stimuli. AB - PURPOSE: We investigated issues that could impair the capacity of multifocal pupilliographic perimetry to detect visual field damage. Differential blue light absorbance causes between-subject variance so we compared stimuli with differing blue content. We also quantified declining response gain at higher stimulus intensities (saturation), which can reduce sensitivity to changes in the visual field. METHODS: Independent stimuli were delivered to 44 regions of both eyes whereas pupil responses were recorded under infrared illumination. Luminance response functions were measured at 88 locations for white, yellow, and red stimuli at luminances ranging from 36 to 288 cd/m2. Response saturation was quantified by fitting power functions: Response =alpha Luminance, z<1 indicating declining response gain. Experiments were conducted on 2 groups containing 16 and 18 different normal subjects. The second experiment was designed to confirm the results of the first and to include red stimuli. RESULTS: Response saturation occurred in all visual field regions: the mean exponents ranged from 0.57 +/- 0.01 to 0.74 +/- 0.02 (mean +/- SE), that is up to 30 SE away from an exponent of 1 (no saturation). The stimulus-response functions appeared to be determined by luminance rather than color. Signal to noise ratios and regional visual field sensitivities were similar for all stimulus colors. CONCLUSIONS: Response saturation was a feature of all visual field locations. Stimuli with reduced blue light content produced the same signal to noise ratios as white stimuli. Given that these stimuli would not be affected by variable lens brunescence, they might be preferable for perimetry. PMID- 20717052 TI - Optic disc size and other parameters from optical coherence tomography in Vietnamese-Americans. AB - PURPOSE: To investigate the optic disc parameters by optical coherence tomography (OCT) in Vietnamese with various types of glaucoma. PATIENTS AND METHODS: Medical charts of Vietnamese and White patients within a single practice were reviewed. Disc and rim areas by OCT were compared among nonglaucoma controls, different types of glaucoma, and glaucoma suspect. The association of these parameters with demographic and ocular features was evaluated. RESULTS: Data from 1416 Vietnamese and 57 White patients were included. A larger mean disc area was observed in eyes with primary angle-closure glaucoma than in eyes with primary angle-closure and primary angle-closure suspect (both P<0.001). There was no association between disc size with central corneal thickness (P=0.051) and sex (P=0.155). Vietnamese patients with glaucoma and glaucoma suspicion had larger discs than diagnosis matched Whites (P=0.043 and 0.021, respectively). CONCLUSIONS: Vietnamese patients with glaucoma seem to have larger optic discs than White patients. Central corneal thickness had no association with disc area in this study population. PMID- 20717053 TI - The "ISN'T rule" in healthy participant optic nerve head by confocal scanning laser ophthalmoscopy. AB - PURPOSE: In normal patients the rim had a characteristic configuration with the rim width being broadest in the inferior disc region, followed by the superior, the nasal, and the temporal sector. The aim of this study was to assess whether the rim shape as measured by the Heidelberg Retina Tomograph 3 (HRT3) followed the ISN'T rule or any other specific distribution pattern. METHODS: This is a prospectively planned cross-sectional study. Two hundred and twenty-six healthy eyes were recruited into this study. All the patients who were included had normal ocular examination, an intraocular pressure less than 21 mm Hg and a normal visual field by the Humphrey Field Analyzer (program 24-2, Swedish Interactive Threshold Analysis standard). For each patient, the optic nerve head was morphometrically evaluated by using the HRT3. All data were analyzed by the analysis of variance test and Tukey's Multiple Comparison Test. RESULTS: When the rim area and rim volume were considered, a statistically significant difference (P<0.001) was found between the temporal rim area and superior, nasal, and inferior rim area. No significant difference was found among the superior, nasal, and inferior rim area. A similar result was found for the cup area. The temporal cup shape measure was significantly (P<0.001) different from the other disc sectors. CONCLUSIONS: In healthy participants the rim shape as measured by the HRT did not follow the ISN'T rule, except that the smallest rim part was located in the temporal disc region. The thickness of the rim was similar in the superior and the inferior sectors by HRT. PMID- 20717054 TI - Posterior revision for failed blebs: long-term outcomes. AB - AIM: To report the long-term efficacy and safety of same site revision trabeculectomy with mitomycin application via a posterior approach. METHODS: A noncomparative retrospective case series of consecutive revision trabeculectomies performed for inadequate bleb function between March 2003 and March 2007 by a single surgeon. Surgery involved a posterior/fornix incision with opening of the scleral flap posteriorly at the same site as previous surgery and application of 0.2 to 0.4 mg/mL mitomycin. RESULTS: Fifty-seven eyes were followed for an average of 33 +/- 15 months. Mean baseline intraocular pressure (IOP) reduced from 21.5 +/- 6.5 to 11.2 +/- 4.4 and 8 +/- 3.6 mm Hg at 1 and 5 years, respectively (P<0.001). On Kaplan-Meier survival analysis the probability of maintaining IOP <= 15 mm Hg without medication at the end of 1 year was 95% (n=57) and at 3 (n=36) and 5 years (n=7) was 84%. Eighty-five percent of patients were on no antiglaucoma drops at last follow-up. Four cases required a second procedure (7%), transient choroidal effusions occurred in 4 eyes (7%), corneal decompensation in 1 eye (1.7%), and ptosis in 1 (1.7%). CONCLUSIONS: Posterior approach to surgical revision of failed filtration surgery is an effective procedure with good long-term control of IOP. PMID- 20717055 TI - A population-based study of care-seeking behavior in rural Tanzanians with glaucoma blindness. AB - PURPOSE: To describe the care-seeking behavior of a representative sample of rural Africans blind from glaucoma. PATIENTS AND METHODS: Patients blind from posterior segment diseases (including diseases affecting the retina or optic nerve) were identified though a population-based survey in Kilimanjaro Region, Tanzania in 2007. A year later they were traced to their homes to detail the diagnoses with more thorough examination. In-depth interviews were conducted to determine healthcare sought and received and symptoms which prompted this. Data were analyzed by framework analysis. RESULTS: Of 30 patients previously identified, 20 were found and interviewed, 4 had died, 2 had moved, 2 lived too far to trace, and 2 could not be located. The average age was 77 years. Few patients could give a clear temporal history of how their vision failed or a sequential description of visits made to healthcare facilities over the years. However, every patient had sought eye care and most made numerous visits. Understanding of the disease and treatment was uniformly limited. Most received topical medicines and the histories of nonglaucoma and glaucoma blind were similar except that 5 glaucoma patients had received surgery. Patients described obstacles to care including poverty and other lack of support. CONCLUSIONS: These findings contrast to previous which showed that most rural Africans blind from glaucoma have not sought or received treatment. It is likely that this is partly the result of widely accessible services offered in Kilimanjaro Region. However, the challenges in treating this chronic disease are highlighted. PMID- 20717056 TI - Correlation of frequency-doubling perimetry with retinal nerve fiber layer thickness and optic disc size in ocular hypertensives and glaucoma suspects. AB - PURPOSE: To determine the structure-function correlation using frequency-doubling technology (FDT) perimetry and optical coherence tomography (OCT) in glaucoma suspects, and analyze their relationship to optic disc size. METHODS: Sixty eyes of 60 ocular hypertensive patients (OHT) and 54 eyes of 54 subjects with optic disc features suspicious of glaucoma (disc suspects) with normal visual fields on Standard Achromatic Perimetry were recruited. All subjects underwent FDT perimetry using the N-30 program, and the mean deviation (FDT-MD) and FDT-pattern SD were computed. Average and inferior retinal nerve fiber layer (RNFL) thickness and disc area were measured on Stratus OCT. Pearson correlation coefficient was calculated among all the measurements. RESULTS: In disc suspects, FDT-MD correlated significantly with RNFL thickness measurements (P<0.001; P=0.003) and disc area (P<0.001). There was no correlation with the vertical cup-disc area ratio (VCDR) and FDT indices. In OHT, FDT-MD correlated significantly with average RNFL thickness (P=0.038), and there was a significant negative correlation between FDT-MD and the VCDR (0.042). The FDT-pattern SD negatively correlated with RNFL thickness measurements (P=0.008; P=0.03). The disc area correlated significantly with the average and inferior average RNFL thickness measurements in both groups of patients (P=0.029 and P=0.007; P=0.013 and P=0.013, respectively). CONCLUSIONS: In OHT, optic discs with larger VCDR and thinner RNFL had lower FDT-MD values. In disc suspects, smaller-sized discs had thinner RNFL and lower values of FDT-MD. FDT perimetry and OCT seem to be useful adjuncts to detect these eyes, which might warrant close follow-up to eventually detect glaucoma by Standard Achromatic Perimetry. PMID- 20717057 TI - Corneal edema and haze after selective laser trabeculoplasty. AB - PURPOSE: To report 2 cases of corneal edema, haze, and thinning in patients after undergoing selective laser trabeculopasty. METHODS: Selective laser trabeculoplasty was performed for the treatment of primary open-angle glaucoma on 2 patients who subsequently developed corneal stromal haze within 24 to 48 hours of the procedure. RESULTS: The patients were treated with topical steroids for several weeks. Although their corneal edema resolved, both patients were left with residual corneal scarring and thinning. One patient had a significant hyperopic shift. CONCLUSIONS: Corneal edema, haze, and thinning after selective laser trabeculoplasty is an extremely rare event, with only 2 other cases reported in the literature. Although certain causes are postulated to play a role in this complication, it is not yet understood what may predispose a patient to corneal changes as a result of this laser procedure. PMID- 20717058 TI - Treatment of congenital pseudarthrosis of the fibula by periosteal flap. AB - Pseudarthroses of the fibula are frequently associated with a pseudarthrosis of the tibia, but they can be isolated. To treat them it is usually necessary to have ankle alignment at skeletal maturity. We report six cases of fibular pseudarthrosis treated with periosteal flap, all having Recklinghausen's neurofibromatosis type 1. The mean age at the time of treatment was 4 years. Four children were diagnosed with isolated congenital pseudarthrosis of the fibula, with a simple curvature of the tibia, and two children had an associated pseudarthrosis of the tibia that was treated earlier. Treatment of the pseudarthrosis of the fibula was indicated to prevent a fracture of a curved tibia or to prevent ankle valgus. The technique of periosteal flap was different: in one case, the periosteum was taken from the fibular diaphysis as a free pedicled flap; in two cases, the flap was taken with its proximal pedicle; and in three cases, the flap was taken from the fibular diaphysis with its distal pedicle and returned to the pseudarthrosis. We analyzed the different operative techniques used for each patient, the complications and the functional result to follow-up. We did not use any osteosynthesis in two cases; a centro-medullary wire and a screwed plate were used in two cases. The pseudarthrosis healed in four cases in a mean period of 10 months. Healing was faster in the cases treated with distal pedicled returned periosteal flaps, a relatively simple technique not requiring vascular sutures. The distal pedicled returned periosteal flap permits good mobility of the periosteum and gives the best healing times. This treatment is indicated for young children to prevent a fracture and a pseudarthrosis of a dysplastic or congenital curvature of the tibia, or after treatment of congenital pseudarthrosis of the leg after healing of the tibia to prevent ankle instability and severe ankle valgus formation. PMID- 20717059 TI - In search of a middle ground: hormone therapy and its role in modern menopause management. PMID- 20717060 TI - Ameliorating hot flashes/awakenings in the context of breast cancer treatments. PMID- 20717061 TI - Brain plasticity, memory and neurological disorders: an epigenetic perspective. AB - Epigenomic settings control gene regulation in both developing and postmitotic tissue, whereas abnormal regulation of epigenomic settings has been implicated in many developmental and neurological disorders. Evidence is emerging for the roles of epigenetic mechanisms in the mature nervous system, in the dynamic processes of learning and memory. The discovery of the involvement of DNA methylation and histone acetylation and methylation in neuronal processing provides a possible answer to the long-standing riddle of how memories persist in a biological system whose cellular composition is in a constant state of flux and renewal. This mini review focuses on present research in DNA methylation and histone posttranslational modifications in learning and memory, age-related cognitive decline, and related pathological disorders. PMID- 20717062 TI - What is heavier, a kilo of feathers or a kilo of lead? What you know determines what you understand. AB - We study how world knowledge is processed in the context of sentence reading. Participants read sentences presented word by word in the middle of the screen while event-related brain potentials were recorded. There were sentences whose interpretation could be influenced by the people's world knowledge about quantities. After reading each sentence, the participants verified whether the sentences were true or false. The results indicated an enhanced N400 in false sentences compared with true sentences. This effect was only observed in sentences that were influenced by the participants' world knowledge. These results indicate that N400 is sensitive to the processing of prior knowledge about quantities during online sentence comprehension. PMID- 20717063 TI - Diagnostic value of SPECT versus SPECT/CT in femoral avascular necrosis: preliminary results. AB - OBJECTIVE: With the advent of single-photon emission computer tomography/computed tomography (SPECT/CT), its applications and indications have to be evaluated clinically for a more efficient and cost-effective use in patient management. This retrospective study investigated the clinical value of conventional Tc MDP SPECT against SPECT/CT in diagnosing hip avascular necrosis (AVN). METHODS: This retrospective study evaluated all patients who underwent SPECT/CT during the period from 1 March 2008 to 31 July 2009 for possible femoral AVN for which MRI was contraindicated. The SPECT and SPECT/CT images were reviewed separately by two radiologists with different levels of experience in a double-blinded manner. The likelihood of AVN for each symptomatic hip was graded according to the level of confidence. Clinical outcome was considered as the gold standard. The sensitivity, specificity, and accuracy for SPECT and SPECT/CT by each radiologist was obtained and compared with the gold standard. The corresponding receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic power of SPECT against SPECT/CT. RESULTS: A total of 22 patients and 24 symptomatic hips were analyzed. Seven hips (29%) were confirmed to have AVN. The AUCs obtained from ROC for trainee radiologist for SPECT vs. SPECT/CT were 0.828 and 0.916, respectively. The AUC for specialist radiologist increased from 0.916 to 0.941 with CT. CONCLUSION: We concluded that SPECT/CT is beneficial for the improvement of AUC in ROC on the diagnostic of hip AVN compared with SPECT alone. PMID- 20717064 TI - Preliminary studies of differential impairments of the dopaminergic system in subtypes of progressive supranuclear palsy. AB - BACKGROUND: Richardson's syndrome (RS) and progressive supranuclear palsy parkinsonism (PSP-P) are the most common subtypes of PSP syndrome. The clinical features, responses to levodopa, and progression are relatively different but overlap. Determining whether combined molecular imaging studies of dopamine transporter and D2 receptor are helpful for further differentiation of these two subtypes is important. METHODS: Ten patients with PSP (six suffering from RS and four from PSP-P) were studied. We also enrolled 10 patients with Parkinson's disease (PD) as disease control and seven healthy individuals as normal controls. Each individual underwent two sets of single photon emission computer tomography imaging, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2 yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-) N2,N2',S2,S2']oxo[1R-(exo-exo)])-[Tc] Technetium (Tc-TRODAT-1) dopamine transporter (DAT) and I-iodobenzamide D2 receptor. The specific uptake ratio was calculated as (basal ganglia counts-occipital cortex counts)/occipital cortex counts. RESULTS: In DAT scan, the mean striatal uptake was reduced in the RS group compared with that in the PSP-P group, although it did not reach statistical significance. The putamen-to-caudate nucleus ratios were significantly different between PD and all PSP patients (P<0.001), but no difference in putamen-to-caudate ratios was found between the RS and PSP-P groups. In the I iodobenzamide scan, striatal uptake was significantly reduced in the RS group (-22.62%, P=0.022); on the contrary, it was mildly increased in the PSP-P group. CONCLUSION: The studies showed different alterations of DAT and D2 receptor function between the RS and PSP-P groups. Different DAT imaging might be helpful to distinguish PSP-P from PD in the early stage. PMID- 20717065 TI - F-18 FDG PET imaging of chronic traumatic brain injury in boxers: a statistical parametric analysis. AB - PURPOSE: The participation in concussive susceptible sports such as boxing may cause chronic traumatic brain injury. The objective of this study was to determine whether there are unique patterns of reduced brain glucose metabolism in professional and amateur boxers. METHOD: We compared the fluorine-18 fluorodeoxyglucose (F-18 FDG) PET brain scans of boxers (group) (N=19) with those of controls (group) (N=7) using both statistical parametric mapping and region of interest analysis. RESULTS: Boxers showed decreased F-18 FDG uptake by 8-15% in the following brain areas: posterior cingulate cortex, parieto-occipito, frontal lobes (Broca's area) bilaterally, and the cerebellum (P<0.005) as compared with controls. CONCLUSION: Our results suggest that F-18 FDG PET scans of boxers suspected of chronic traumatic brain injury show unique patterns of hypometabolism, and that these patterns may reflect the mechanisms of repeated traumatic brain injury unique to boxers. PMID- 20717066 TI - Stenting versus non-stenting in pancreaticojejunostomy: a prospective study limited to a normal pancreas without fibrosis sorted by using dynamic MRI. AB - OBJECTIVES: We prospectively investigated the efficacy of an external pancreatic duct stent to prevent pancreatic fistula in the nonfibrotic pancreas after pancreaticojejunostomy, in which the degree of pancreatic fibrosis was assessed objectively by using dynamic magnetic resonance imaging (MRI). METHODS: Among the 67 consecutive patients who underwent pancreatic head resection, 45 patients were judged to have a normal pancreas without fibrosis based on the preoperative assessment of pancreatic fibrosis based on MRI. The patients were randomly allocated to 1 of 2 groups with (n=23) or without (n=22) use of an external pancreatic duct stent in performing a pancreaticojejunostomy. RESULTS: Pancreatic fistula developed in 8 (34.5%) patients in the stented group: 3 grade A and 5 grade B; whereas in the nonstented group, 9 (40.9%) patients developed pancreatic fistula: 3 grade A and 6 grade B. There were no significant differences in the incidence or severity of pancreatic fistula between the 2 groups. CONCLUSIONS: The utility of the external pancreatic duct stent after pancreaticojejunostomy was not found in the nonfibrotic pancreases, which were sorted according to the degree of pancreatic fibrosis using the pancreatic time-signal intensity curve analysis from MRI. PMID- 20717067 TI - Profiling of somatostatin receptor subtype expression by quantitative PCR and correlation with clinicopathological features in pancreatic endocrine tumors. AB - OBJECTIVES: Pancreatic endocrine tumor (PET) presents variable clinical features. Five subtypes of somatostatin receptor (SSTR) are involved in hormone secretion and cell proliferation. In this paper, we explore the correlation between the SSTR subtype messenger RNA (mRNA) expression and clinicopathological features of PET. METHODS: Twenty-one cases of PET and 5 cases of pancreatic adenocarcinomas (AC) were studied. Using total RNA extracted from paraffin sections and fresh tissues, SSTR subtype mRNA was quantified by real-time polymerase chain reaction. The hormones and MIB1 index were examined using immunohistochemical techniques. RESULTS: The mRNA levels of SSTR1, SSTR2, SSTR3, and SSTR5 were high in PET compared with AC, whereas the expression of SSTR4 was low in PET and AC. Levels of each subtype did not vary with histological grades. Somatostatin receptor 2 levels in functioning tumors were slightly low compared with nonfunctioning tumors. Four distinct groups of PET were identified by hierarchical cluster analysis, and two of these groups showed reduced SSTR5 with elevation of MIB1 index. CONCLUSIONS: The study showed a heterogeneous expression profile of SSTR subtype mRNA and the association of reduction in SSTR5 with high proliferative activity. Such profiling of SSTR subtypes may provide useful information on tumor biology and treatment of PET. PMID- 20717069 TI - Cystic neoplasms of the pancreas: results of 114 cases. AB - OBJECTIVES: To identify clinical, radiographic, and histopathologic characteristics associated with cancer in cystic pancreatic neoplasms and to evaluate our preoperative diagnostic accuracy to predict cancer in such cysts. METHODS: Retrospective case series of 114 patients with cystic lesions of the pancreas who underwent resection between 1992 and 2006. RESULTS: Eighty-nine patients (78%) had benign or premalignant cysts; 25 patients (22%) had malignant cysts (carcinoma in situ and/or an invasive cancer). The factors most predictive of malignancy were age (P = 0.03), presence of symptoms (P = 0.02), and a dilated pancreatic duct (P = 0.01). Of the symptoms recorded, weight loss (P = 0.01) and jaundice (P = 0.02) had the strongest correlation with malignancy. We correctly predicted the pathological diagnosis (benign vs malignant) for only 39 (67%) of the 58 patients where a preoperative diagnosis was clearly evident. Endoscopic ultrasound did not seem to improve our ability to preoperatively differentiate benign from malignant cysts (P > 0.05). CONCLUSIONS: This series confirms that age, the presence of symptoms, and a dilated pancreatic duct on imaging are significantly associated with cancer in pancreatic cysts, and it highlights our inability to consistently make the preoperative diagnosis of cancer. Until more accurate markers of malignancy are available, an aggressive approach to management seems justified. PMID- 20717068 TI - Are genetic variants in the platelet-derived growth factor [beta] gene associated with chronic pancreatitis? AB - OBJECTIVES: Platelet-derived growth factor [beta] (PDGF-[beta]) is a major signal in proliferation and matrix synthesis through activated pancreatic stellate cells, leading to fibrosis of the pancreas. Recurrent acute pancreatitis (RAP) seems to predispose to chronic pancreatitis (CP) in some patients but not others. We tested the hypothesis that 2 known PDGF-[beta] polymorphisms are associated with progression from RAP to CP. We also tested the hypothesis that PDGF-[beta] polymorphisms in combination with environmental risk factors such as alcohol and smoking are associated with CP. METHODS: Three hundred eighty-two patients with CP (n = 176) and RAP (n = 206) and 251 controls were evaluated. Platelet-derived growth factor [beta] polymorphisms +286 A/G (rs#1800818) seen in 5'-UTR and +1135 A/C (rs#1800817) in first intron were genotyped using single-nucleotide polymorphism polymerase chain reaction approach and confirmed by DNA sequencing. RESULTS: The genotypic frequencies for PDGF-[beta] polymorphisms in positions +286 and +1135 were found to be similar in controls and patients with RAP and CP. There was no difference in genotypic frequencies among RAP, CP, and controls in subjects in the alcohol and smoking subgroups. CONCLUSIONS: Known variations in the PDGF-[beta] gene do not have a significant effect on promoting or preventing fibrogenesis in pancreatitis. Further evaluation of this important pathway is warranted. PMID- 20717070 TI - Alpha-lactalbumin in human milk alters the proteolytic degradation of soluble CD14 by forming a complex. AB - Mother's milk represents a foundational step in the proper development of newborn immunity. This is achieved, in part, through the action of numerous regulatory proteins such as soluble cluster of differentiation 14 (sCD14) found in significant quantities in human milk (~25-50 MUg/mL). In adults, CD14 stimulates cytokine production in response to lipopolysaccharide (LPS), the major lipid component found in the outer membrane of Gram-negative bacteria. However, the fate and function of sCD14 in the neonatal gastrointestinal (GI) tract are unknown and may function differently from adults. Therefore, we administered human sCD14 to experimental animals and observed that it persisted in the upper GI tract after feeding. In our search for potential proteolytic protectants, immunoprecipitation of sCD14 from human milk revealed a 15-kD novel protein that copurified with sCD14. Mass spectrometry analysis of the protein identified alpha lactalbumin. CD14 was also identified by immunoblot after immunoprecipitation of alpha-lactalbumin from milk. In vitro digestion assays revealed that purified alpha-lactalbumin decreases the proteolytic degradation of human milk derived sCD14 in vitro, suggesting a mechanism by which this key LPS receptor may remain functional in the neonate gut. PMID- 20717071 TI - Altered immunomodulation by glucocorticoids in neonatal pigs exposed to a psychosocial stressor. AB - Stressful early life experiences can have short- and long-term effects on neuroendocrine and immune mechanisms of adaptation, which are primarily modulated by glucocorticoids. This study aimed to examine how the stress and immune systems interact to cope with psychosocial stress induced by a single social isolation (4 h) in neonatal pigs at 7, 21, or 35 d of age. This social isolation provoked increased plasma ACTH and cortisol concentrations and reduced TNF-alpha levels but had no significant effect on IL-6 levels. Socially isolated piglets had a higher lipopolysaccharide (LPS)-stimulated proliferative response of peripheral blood mononuclear cells (PBMCs) than controls, whereas concanavalin A (ConA) induced proliferation was not affected by isolation. A single social isolation also induced a dose-dependent cortisol resistance in ConA- and LPS-stimulated PBMCs compared with controls, which may be an adaptive response in the short term. Moreover, LPS-stimulated cultures from control piglets showed a reduction in cortisol sensitivity with increasing age. Conclusively, these findings provide stress-related measures for the psychophysiological assessment of livestock handling practices but might also have implications for stress and health studies in young animals and humans. PMID- 20717072 TI - Chorioamnionitis induced hepatic inflammation and disturbed lipid metabolism in fetal sheep. AB - Chorioamnionitis frequently induces a fetal inflammatory response syndrome (FIRS), characterized by an elevation of proinflammatory mediators and systemic inflammation. Although there is increasing evidence that inflammation and lipid metabolism influence each other, the effects of chorioamnionitis-induced FIRS on fetal lipid homeostasis are currently not known. Accordingly, we hypothesize that chorioamnionitis induces an inflammatory response in the fetal liver, consequently leading to metabolic disturbances. Chorioamnionitis was induced by intra-amniotic injection of 10 mg endotoxin (control) for 2 d or 2 wk before delivery. Saline injections were given to controls. The effect of chorioamnionitis on hepatic inflammation and metabolic parameters was analyzed in ovine fetuses at the GA of 125 d (normal GA = 150 d). We found that 2 d after the endotoxin injections, inflammatory markers were significantly higher compared with controls. In addition, lipid and glucose metabolism were disturbed in response to endotoxin. Moreover, the antioxidant state capacity was reduced, and hepatic damage was apparent. Two weeks after the endotoxin injections, the fetal livers were still inflamed and had higher glucose concentrations in the blood. In addition, the levels of markers for hepatic damage (alanine aminotransferase and aspartate aminotransferase) were increased. In conclusion, chorioamnionitis induces liver inflammation leading to metabolic disturbances in the fetus. PMID- 20717073 TI - Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. AB - BACKGROUND: The lack of an accepted definition of transplantation-associated thrombotic microangiopathy (TMA) has led the Blood and Marrow Transplants Clinical Trials Network (CTN) and International Working Group (IWG) to propose a definition for TMA with some differences. However, there have been few studies validating and comparing both newly proposed criteria for TMA. METHODS: To validate recently proposed criteria for TMA by CTN and IWG, we analyzed 672 patients who underwent allogeneic stem-cell transplantation between January 2002 and December 2006. RESULTS: The cumulative incidences of TMA by CTN and IWG were 6.1% and 2.5%, respectively. The cumulative incidence of overall TMA (O-TMA) including probable-TMA defined as meeting CTN criteria without renal or neurologic dysfunction, as well as TMA by CTN (definite-TMA), was 12.7%. Sixty six percent of TMA by CTN did not have any degree of schistocytosis by IWG criteria (>=4%), and 18% of TMA by IWG criteria did not have renal or neurologic dysfunction. On multivariate analyses, probable-TMA as well as definite-TMA adversely affected the survival of a cohort including all patients. In patients with O-TMA, the degree of schistocytosis (>=4% or not) failed to show prognostic significance, whereas renal involvement was a significant prognostic factor associated with poor survival. CONCLUSIONS: Both proposed consensus criteria have major pitfalls in their use as uniformly accepted diagnostic criteria for TMA. The use of O-TMA as a broad definition for TMA and the grading system by the presence of renal involvement may be a counterproposal for future trials. PMID- 20717074 TI - A facile synthesis of 3-substituted 9H-pyrido[3,4-b]indol-1(2H)-one derivatives from 3-substituted beta-carbolines. AB - A mild and efficient two-step synthesis of 3-substituted beta-carbolinone derivatives from 3-substituted beta-carboline in good yields is described. A possible reaction mechanism for the formation of the skeleton of beta-carbolin-1 one is proposed. The structures of these compounds were established by IR, 1H NMR, 13C-NMR, mass spectrometry and elemental analysis, as well as X-ray crystallographic analysis of 4-2 and 6-2. PMID- 20717075 TI - Management of an affiliated Physics Residency Program using a commercial software tool. AB - A review of commercially available allied health educational management software tools was performed to evaluate their capacity to manage program data associated with a CAMPEP-accredited Therapy Physics Residency Program. Features of these software tools include: a) didactic course reporting and organization, b) competency reporting by topic, category and didactic course, c) student time management and accounting, and d) student patient case reporting by topic, category and course. The software package includes features for recording school administrative information; setting up lists of courses, faculty, clinical sites, categories, competencies, and time logs; and the inclusion of standardized external documents. There are provisions for developing evaluation and survey instruments. The mentors and program may be evaluated by residents, and residents may be evaluated by faculty members using this feature. Competency documentation includes the time spent on the problem or with the patient, time spent with the mentor, date of the competency, and approval by the mentor and program director. Course documentation includes course and lecture title, lecturer, topic information, date of lecture and approval by the Program Director. These software tools have the facility to include multiple clinical sites, with local subadministrators having the ability to approve competencies and attendance at clinical conferences. In total, these software tools have the capability of managing all components of a CAMPEP-accredited residency program. The application database lends the software to the support of multiple affiliated clinical sites within a single residency program. Such tools are a critical and necessary component if the medical physics profession is to meet the projected needs for qualified medical physicists in future years. PMID- 20717076 TI - Radiation skyshine from a 6 MeV medical accelerator. AB - This study assesses the dose level from skyshine produced by a 6 MeV medical accelerator. The analysis of data collected on skyshine yields professional guidance for future investigators as they attempt to quantify and qualify radiation protection concerns in shielding therapy vaults. Survey measurements using various field sizes and at varying distances from a primary barrier have enabled us to identify unique skyshine behavior in comparison to other energies already seen in literature. In order to correctly quantify such measurements outside a shielded barrier, one must take into consideration the fact that a skyshine maximum may not be observed at the same distance for all field sizes. A physical attribute of the skyshine scatter component was shown to increase to a maximum value at 4.6 m from the barrier for the largest field size used. We recommend that the largest field sizes be used in the field for the determination of skyshine effect and that the peak value be further analyzed specifically when considering shielding designs. PMID- 20717077 TI - Dosimetric performance of the new high-definition multileaf collimator for intracranial stereotactic radiosurgery. AB - The objective was to evaluate the performance of a high-definition multileaf collimator (MLC) of 2.5 mm leaf width (MLC2.5) and compare to standard 5 mm leaf width MLC (MLC5) for the treatment of intracranial lesions using dynamic conformal arcs (DCA) technique with a dedicated radiosurgery linear accelerator. Simulated cases of spherical targets were created to study solely the effect of target volume size on the performance of the two MLC systems independent of target shape complexity. In addition, 43 patients previously treated for intracranial lesions in our institution were retrospectively planned using DCA technique with MLC2.5 and MLC5 systems. The gross tumor volume ranged from 0.07 to 40.57 cm3 with an average volume of 5.9 cm3. All treatment parameters were kept the same for both MLC-based plans. The plan evaluation was performed using figures of merits (FOM) for a rapid and objective assessment on the quality of the two treatment plans for MLC2.5 and MLC5. The prescription isodose surface was selected as the greatest isodose surface covering >or= 95% of the target volume and delivering 95% of the prescription dose to 99% of target volume. A Conformity Index (CI) and conformity distance index (CDI) were used to quantifying the dose conformity to a target volume. To assess normal tissue sparing, a normal tissue difference (NTD) was defined as the difference between the volume of normal tissue receiving a certain dose utilizing MLC5 and the volume receiving the same dose using MLC2.5. The CI and normal tissue sparing for the simulated spherical targets were better with the MLC2.5 as compared to MLC5. For the clinical patients, the CI and CDI results indicated that the MLC2.5 provides better treatment conformity than MLC5 even at large target volumes. The CI's range was 1.15 to 2.44 with a median of 1.59 for MLC2.5 compared to 1.60-2.85 with a median of 1.71 for MLC5. Improved normal tissue sparing was also observed for MLC2.5 over MLC5, with the NTD always positive, indicating improvement, and ranging from 0.1 to 8.3 for normal tissue receiving 50% (NTV50), 70% (NTV70) and 90% (NTV90) of the prescription dose. The MLC2.5 has a dosimetric advantage over the MLC5 in Linac-based radiosurgery using DCA method for intracranial lesions, both in treatment conformity and normal tissue sparing when target shape complexity increases. PMID- 20717078 TI - Inverse planning optimization for hybrid prostate permanent-seed implant brachytherapy plans using two source strengths. AB - The purpose is to demonstrate the ability to generate clinically acceptable prostate permanent seed implant plans using two seed types which are identical except for their activity. The IPSA inverse planning algorithms were modified to include multiple dose matrices for the calculation of dose from different sources, and a selection algorithm was implemented to allow for the swapping of source type at any given source position. Five previously treated patients with a range of prostate volumes from 20-48 cm3 were re-optimized under two hybrid scenarios: (1) using 0.32 and 0.51 mGy m2 / h 125I, and (2) using 0.64 and 0.76 mGy m2 / h 125I. Isodose lines were generated and dosimetric indices , V150Prostate, D90Prostate, V150Urethra, V125Urethra, V120Urethra,V100Urethra, and D10Urethra were calculated. The algorithm allows for the generation of single isotope, multi-activity hybrid brachytherapy plans. By dealing with only one radionuclide, but of different activity, the biology is unchanged from a standard plan. All V100Prostate were within 2.3 percentage points for every plan and always above the clinically desirable 95%. All V150Urethra were identically zero, and V120Urethra is always below the clinically acceptable value of 1.0 cm3. Clinical optimization times for the hybrid plans are still under one minute, for most cases. It is possible to generate clinically advantageous brachytherapy plans (i.e. obtain the same quality dose distribution as a standard single activity plan) while incorporating leftover seeds from a previous patient treatment. This method will allow a clinic to continue to provide excellent patient care, but at a reduced cost. Multi-activity hybrid plans were equal in quality (as measured by the standard dosimetric indices) to plans with seeds of a single activity. Despite the expanded search space, optimization times for these studies were still under two minutes on a modern day laptop and can be reduced to below one minute in a clinical setting. With the typical cost of a set of PPI seeds on the order of thousands of dollars, it is possible to reduce the cost of brachytherapy treatments by allowing for easier use of seeds left over from a previous patient or unused due to a cancelled treatment. PMID- 20717079 TI - Suggesting a new design for multileaf collimator leaves based on Monte Carlo simulation of two commercial systems. AB - Due to intensive use of multileaf collimators (MLCs) in clinics, finding an optimum design for the leaves becomes essential. There are several studies which deal with comparison of MLC systems, but there is no article with a focus on offering an optimum design using accurate methods like Monte Carlo. In this study, we describe some characteristics of MLC systems including the leaf tip transmission, beam hardening, leakage radiation and penumbra width for Varian and Elekta 80-leaf MLCs using MCNP4C code. The complex geometry of leaves in these two common MLC systems was simulated. It was assumed that all of the MLC systems were mounted on a Varian accelerator and with a similar thickness as Varian's and the same distance from the source. Considering the obtained results from Varian and Elekta leaf designs, an optimum design was suggested combining the advantages of three common MLC systems and the simulation results of this proposed one were compared with the Varian and the Elekta. The leakage from suggested design is 29.7% and 31.5% of the Varian and Elekta MLCs. In addition, other calculated parameters of the proposed MLC leaf design were better than those two commercial ones. Although it shows a wider penumbra in comparison with Varian and Elekta MLCs, taking into account the curved motion path of the leaves, providing a double focusing design will solve the problem. The suggested leaf design is a combination of advantages from three common vendors (Varian, Elekta and Siemens) which can show better results than each one. Using the results of this theoretical study may bring about superior practical outcomes. PMID- 20717080 TI - Quantification and reduction of peripheral dose from leakage radiation on Siemens Primus accelerators in electron therapy mode. AB - In this work, leakage radiation from EA200 series electron applicators on Siemens Primus accelerators is quantified, and its penetration ability in water and/or the shielding material Xenolite-NL established. Initially, measurement of leakage from 10 x 10 - 25 x 25 cm2 applicators was performed as a function of height along applicator and of lateral distance from applicator body. Relative to central-axis ionization maximum in solid water, the maximum leakage in air observed with a cylindrical ion chamber with 1 cm solid water buildup cap at a lateral distance of 2 cm from the front and right sidewalls of applicators were 17% and 14%, respectively; these maxima were recorded for 18 MeV electron beams and applicator sizes of >or=20 x 20 cm2. In the patient plane, the applicator leakage gave rise to a broad peripheral dose off-axis distance peak that shifted closer to the field edge as the electron energy increases. The maximum peripheral dose from normally incident primary electron beams at a depth of 1 cm in a water phantom was observed to be equal to 5% of the central-axis dose maximum and as high as 9% for obliquely incident beams with angles of obliquity 0.05. Using one method of calculation, probability of a secondary malignancy was 5.88% for the linear accelerator and 4.08% for helical TomoTherapy. Helical TomoTherapy delivers more dose than a linac immediately above and below the treatment field, contributing to the higher peripheral doses adjacent to the field. At distances beyond one field width (where leakage is dominant), helical TomoTherapy doses are lower than linear accelerator doses. PMID- 20717082 TI - Evaluation of a commercially-available block for spatially fractionated radiation therapy. AB - In this paper, we present the dosimetric characteristics of a commercially produced universal GRID block for spatially fractioned radiation therapy. The dosimetric properties of the GRID block were evaluated. Ionization chamber and film measurements using both Kodak EDR2 and Gafchromic EBT film were performed in a solid water phantom to determine the relative output of the GRID block as well as its spatial dosimetric characteristics. The surface dose under the block and at the openings was measured using ultra thin TLDs. After introducing the GRID block into the treatment planning system, a treatment plan was created using the GRID block and also by creating a GRID pattern using the multi-leaf collimator. The percent depth doses measured with film showed that there is a shift of the dmax towards shallower depths for both energies (6 MV and 18 MV) under investigation. It was observed that the skin dose at the GRID openings was higher than the corresponding open field by a factor as high as 50% for both photon energies. The profiles showed the transmission under the block was in the order of 15-20% for 6 MV and 30% for 18 MV. The MUs calculated for a real patient using the block were about 80% less than the corresponding MUs for the same plan using the multileaf collimator to define the GRID. Based on this investigation, this brass GRID compensator is a viable alternative to other solid compensators or MLC based fields currently in use. Its ease of creation and use give it decided advantages. Its ability to be created once and used for multiple patients (by varying the collimation of the linear accelerator jaws) makes it attractive from a cost perspective. We believe this compensator can be put to clinical use, and will allow more centers to offer GRID therapy to their patients. PMID- 20717083 TI - Assessment of a commercially available automatic deformable registration system. AB - In recent years, a number of approaches have been applied to the problem of deformable registration validation. However, the challenge of assessing a commercial deformable registration system - in particular, an automatic registration system in which the deformable transformation is not readily accessible - has not been addressed. Using a collection of novel and established methods, we have developed a comprehensive, four-component protocol for the validation of automatic deformable image registration systems over a range of IGRT applications. The protocol, which was applied to the Reveal-MVS system, initially consists of a phantom study for determination of the system's general tendencies, while relative comparison of different registration settings is achieved through postregistration similarity measure evaluation. Synthetic transformations and contour-based metrics are used for absolute verification of the system's intra-modality and inter-modality capabilities, respectively. Results suggest that the commercial system is more apt to account for global deformations than local variations when performing deform-able image registration. Although the protocol was used to assess the capabilities of the Reveal-MVS system, it can readily be applied to other commercial systems. The protocol is by no means static or definitive, and can be further expanded to investigate other potential deformable registration applications. PMID- 20717084 TI - Evaluation of tumor motion effects on dose distribution for hypofractionated intensity-modulated radiotherapy of non-small-cell lung cancer. AB - Respiration-induced tumor motion during intensity-modulated radiotherapy (IMRT) of non-small-cell lung cancer (NSCLC) could cause substantial differences between planned and delivered doses. While it has been shown that, for conventionally fractionated IMRT, motion effects average out over the course of many treatments, this might not be true for hypofractionated IMRT (IMHFRT). Numerical simulations were performed for nine NSCLC patients (11 tumors) to evaluate this problem. Dose distributions to the Clinical Target Volume (CTV) and Internal Target Volume (ITV) were retrospectively calculated using the previously-calculated leaf motion files but with the addition of typical periodic motion (i.e. amplitude 0.36 1.26cm, 3-8sec period). A typical IMHFRT prescription of 20Gy x 3 fractions was assumed. For the largest amplitude (1.26 cm), the average +/- standard deviation of the ratio of simulated to planned mean dose, minimum dose, D95 and V95 were 0.98+/-0.01, 0.88 +/- 0.09, 0.94 +/- 0.05 and 0.94 +/- 0.07 for the CTV, and 0.99 +/-0.01, 0.99 +/- 0.03, 0.98 +/- 0.02 and 1.00 +/- 0.01 for the ITV, respectively. There was minimal dependence on period or initial phase. For typical tumor geometries and respiratory amplitudes, changes in target coverage are minimal but can be significant for larger amplitudes, faster beam delivery, more highly-modulated fields, and smaller field margins. PMID- 20717085 TI - Dosimetric assessment of rigid setup error by CBCT for HN-IMRT. AB - Dose distributions in HN-IMRT are complex and may be sensitive to the treatment uncertainties. The goals of this study were to evaluate: 1) dose differences between plan and actual delivery and implications on margin requirement for HN IMRT with rigid setup errors; 2) dose distribution complexity on setup error sensitivity; and 3) agreement between average dose and cumulative dose in fractionated radiotherapy. Rigid setup errors for HN-IMRT patients were measured using cone-beam CT (CBCT) for 30 patients and 896 fractions. These were applied to plans for 12HN patients who underwent simultaneous integrated boost (SIB) IMRT treatment. Dose distributions were recalculated at each fraction and summed into cumulative dose. Measured setup errors were scaled by factors of 2-4 to investigate margin adequacy. Two plans, direct machine parameter optimization (DMPO) and fluence only (FO), were available for each patient to represent plans of different complexity. Normalized dosimetric indices, conformity index (CI) and conformation number (CN) were used in the evaluation. It was found that current 5 mm margins are more than adequate to compensate for rigid setup errors, and that standard margin recipes overestimate margins for rigid setup error in SIB HN-IMRT because of differences in acceptance criteria used in margin evaluation. The CTV to-PTV margins can be effectively reduced to 1.9 mm and 1.5 mm for CTV1 and CTV2. Plans of higher complexity and sharper dose gradients are more sensitive to setup error and require larger margins. The CI and CN are not recommended for cumulative dose evaluation because of inconsistent definition of target volumes used. For fractionated radiotherapy in HN-IMRT, the average fractional dose does not represent the true cumulative dose received by the patient through voxel-by voxel summation, primarily due to the setup error characteristics, where the random component is larger than systematic and different target regions get underdosed at each fraction. PMID- 20717086 TI - Evaluation of the setup accuracy of a stereotactic radiotherapy head immobilization mask system using kV on-board imaging. AB - The purpose of this study was to evaluate setup accuracy and quantify random and systematic errors of the BrainLAB stereotactic immobilization mask and localization system using kV on-board imaging. Nine patients were simulated and set up with the BrainLAB stereotactic head immobilization mask and localizer to be treated for brain lesions using single and hypofractions. Orthogonal pairs of projections were acquired using a kV on-board imager mounted on a Varian Trilogy machine. The kV projections were then registered with digitally-reconstructed radiographs (DRR) obtained from treatment planning. Shifts between the kV images and reference DRRs were calculated in the different directions: anterior posterior (A-P), medial-lateral (R-L) and superior-inferior (S-I). If the shifts were larger than 2mm in any direction, the patient was reset within the immobilization mask until satisfying setup accuracy based on image guidance has been achieved. Shifts as large as 4.5 mm, 5.0 mm, 8.0 mm in the A-P, R-L and S-I directions, respectively, were measured from image registration of kV projections and DRRs. These shifts represent offsets between the treatment and simulation setup using immobilization mask. The mean offsets of 0.1 mm, 0.7 mm, and -1.6 mm represent systematic errors of the BrainLAB localizer in the A-P, R-L and S-I directions, respectively. The mean of the radial shifts is about 1.7 mm. The standard deviations of the shifts were 2.2 mm, 2.0 mm, and 2.6 mm in A-P, R-L and S-I directions, respectively, which represent random patient setup errors with the BrainLAB mask. The Brain-LAB mask provides a noninvasive, practical and flexible immobilization system that keeps the patients in place during treatment. Relying on this system for patient setup might be associated with significant setup errors. Image guidance with the kV on-board imager provides an independent verification technique to ensure accuracy of patient setup. Since the patient may relax or move during treatment, uncontrolled and undetected setup errors may be produced with patients that are not well-immobilized. Therefore, the combination of stereotactic immobilization and image guidance achieves more controlled and accurate patient setup within 2mm in A-P, R-L and S-I directions. PMID- 20717087 TI - Design and clinical implementation of a TG-106 compliant linear accelerator data management system and MU calculator. AB - In an attempt to minimize errors and improve patient outcome in radiation therapy, a linear accelerator data management system was developed to provide radiation oncology physicists with a set of computerized tools to manage linear accelerator physics data. The entire program is written in Microsoft Visual Basic and has a user-friendly, front-end window with the following features and modules: (1) Generate, edit and approve commissioning and QA reports and other regulatory documents, (2) Configure commissioning tasks, (3) Acquire output factors, (4) Import scanned data, (5) Import PDD, TMRs and OAR tables directly from the scanning software, (6) Query physics data such as TMR, PDDs, OFs, and WFs, (7) Compare physics data to a different machine or a standard, (8) Compare physics data from the same machine (e.g. during annual calibrations), (9) Perform MU calculations on plans exported from the planning system via DICOM RT, (10) Perform TG-51 calibration, (11) Perform monthly calibration, (12) FTP physics data for purposes of remote peer review and/or inspections. PMID- 20717088 TI - Validation of the Eclipse AAA algorithm at extended SSD. AB - The accuracy of dose calculations at extended SSD is of significant importance in the dosimetric planning of total body irradiation (TBI). In a first step toward the implementation of electronic, multi-leaf collimator compensation for dose inhomogeneities and surface contour in TBI, we have evaluated the ability of the Eclipse AAA to accurately predict dose distributions in water at extended SSD. For this purpose, we use the Eclipse AAA algorithm, commissioned with machine specific beam data for a 6 MV photon beam, at standard SSD (100 cm). The model was then used for dose distribution calculations at extended SSD (179.5 cm). Two sets of measurements were acquired for a 6 MV beam (from a Varian linear accelerator) in a water tank at extended SSD: i) open beam for 5 x 5, 10 x 10, 20 x 20 and 40 x 40 cm2 field sizes (defined at 179.5 cm SSD), and ii) identical field sizes but with a 1.3 cm thick acrylic spoiler placed 10 cm above the water surface. Dose profiles were acquired at 5 cm, 10 cm and 20 cm depths. Dose distributions for the two setups were calculated using the AAA algorithm in Eclipse. Confidence limits for comparisons between measured and calculated absolute depth dose curves and normalized dose profiles were determined as suggested by Venselaar et al. The confidence limits were within 2% and 2 mm for both setups. Extended SSD calculations were also performed using Eclipse AAA, commissioned with Varian Golden beam data at standard SSD. No significant difference between the custom commissioned and Golden Eclipse AAA was observed. In conclusion, Eclipse AAA commissioned at standard SSD can be used to accurately predict dose distributions in water at extended SSD for 6 MV open beams. PMID- 20717089 TI - Angular dependence of the output of a kilovoltage X-ray therapy unit. AB - During the recommissioning of a Philips RT-250 kilovoltage X-ray unit, unexpected output variations with tube head rotation (cross-plane) and tube head tilt (in plane) were observed. The measured output showed an increase of up to 7.3% relative to the neutral position (0? in-plane and 0? cross-plane) over the possible range of angles of in-plane rotation for 75 kVp (half-value layer, HVL = 1.84 mm Al). A less pronounced but noticeable output change (with respect to the neutral position) was observed for cross-plane rotation reaching 2% for the 225 kVp beam (HVL = 0.90 mm Cu). This output variation was observed while manually adjusting the current to maintain constancy according to the current meter gauge. In order to address the observed output dependence with head orientation, the dose rate monitor chamber of the kilovoltage unit was calibrated to monitor the beam output in real time. The dose rate was manually adjusted to maintain a constant dose rate (in r/min) as displayed on the r/min gauge. This approach resulted in maintaining beam output for the 75 kVp and the 225 kVp beams within +/- 2% for the in-plane angle variation and +/- 0.5% for the cross-plane angle variation. A daily output check that includes ion chamber-based measurements at the neutral position and an in-plane angle of 45? has been implemented using the constant dose rate approach to monitor the stability of the X-ray beams. As a result of the output variations with in/cross-plane rotation, the quality control (QC) procedures that are typically used for clinical setup have been modified to test the stability of the beams under the non-neutral positioning of the X-ray tube. PMID- 20717090 TI - A dosimetric comparison of stereotactic body radiation therapy techniques for lung cancer: robotic versus conventional linac-based systems. AB - The aim of this study is to compare the dosimetric characteristics of robotic and conventional linac-based SBRT techniques for lung cancer, and to provide planning guidance for each modality. Eight patients who received linac-based SBRT were retrospectively included in this study. A dose of 60 Gy given in three fractions was prescribed to each target. The Synchrony Respiratory Tracking System and a 4D dose calculation methodology were used for CyberKnife and linac-based SBRT, respectively, to minimize respiratory impact on dose calculation. Identical image and contour sets were used for both modalities. While both modalities can provide satisfactory target dose coverage, the dose to GTV was more heterogeneous for CyberKnife than for linac planning/delivery in all cases. The dose to 1000 cc lung was well below institutional constraints for both modalities. In the high dose region, the lung dose depended on tumor size, and was similar between both modalities. In the low dose region, however, the quality of CyberKnife plans was dependent on tumor location. With anteriorly-located tumors, the CyberKnife may deliver less dose to normal lung than linac techniques. Conversely, for posteriorly-located tumors, CyberKnife delivery may result in higher doses to normal lung. In all cases studied, more monitor units were required for CyberKnife delivery for given prescription. Both conventional linacs and CyberKnife provide acceptable target dose coverage while sparing normal tissues. The results of this study provide a general guideline for patient and treatment modality selection based on dosimetric, tumor and normal tissue sparing considerations. PMID- 20717091 TI - Dosimetric comparison of various optimization techniques for high dose rate brachytherapy of interstitial cervix implants. AB - HDR brachytherapy treatment planning often involves optimization methods to calculate the dwell times and dwell positions of the radioactive source along specified afterloading catheters. The purpose of this study is to compare the dose distribution obtained with geometric optimization (GO) and volume optimization (VO) combined with isodose reshaping. This is a retrospective study of 10 cervix HDR interstitial brachytherapy implants planned using geometric optimization and treated with a dose of 6 Gy per fraction. Four treatment optimization plans were compared: geometric optimization (GO), volume optimization (VO), geometric optimization followed by isodose reshape (GO_IsoR), and volume optimization followed by isodose reshape (VO_IsoR). Dose volume histogram (DVH) was analyzed and the four plans were evaluated based on the dosimetric parameters: target coverage (V100), conformal index (COIN), homogeneity index (HI), dose nonuniformity ratio (DNR) and natural dose ratio (NDR). Good target coverage by the prescription dose was achieved with GO_ IsoR (mean V100 of 88.11%), with 150% and 200% of the target volume receiving 32.0% and 10.4% of prescription dose, respectively. Slightly lower target coverage was achieved with VO_IsoR plans (mean V100 of 86.11%) with a significant reduction in the tumor volume receiving high dose (mean V150 of 28.29% and mean V200 of 7.3%). Conformity and homogeneity were good with VO_ IsoR (mean COIN = 0.75 and mean HI = 0.58) as compared to the other optimization techniques. VO_IsoR plans are superior in sparing the normal structures while also providing better conformity and homogeneity to the target. Clinically acceptable plans can be obtained by isodose reshaping provided the isodose lines are dragged carefully. PMID- 20717092 TI - Evaluation of the interfractional biological effective dose (BED) variation in MammoSite high dose rate brachytherapy. AB - The objective of this work is to evaluate the interfractional biological effective dose (BED) variation in MammoSite high dose rate (HDR) brachytherapy. Dose distributions of 19 patients who received 34 Gy in 10 fractions were evaluated. A method was employed to account for nonuniform dose distribution in the BED calculation. Furthermore, a range of alpha/beta values was utilized for specific clinical end points: fibrosis, telangiectasia, erythema, desquamation and breast carcinoma. Two scenarios were simulated to calculate the BED value using: i) the same dose distribution of fraction 1 over fractions 2-10 (constant case, CC), and ii) the actual delivered dose distribution for each fraction 1-10 (interfractiondose variation case, IVC). Although the average BED difference (IVC - CC) was < 0.7 Gy for all clinical endpoints, the range of difference for fibrosis and telangiectasia reached -11% to +3% and -9% to +9% for one of the patients, respectively. By disregarding high inhomogeneity in HDR brachytherapy, the conventional BED calculation tends to overestimate the BED for fibrosis by 16% on average, while it underestimates the BED for erythema (7.6%) and desquamation (10.2%). In conclusion, the BED calculation accounting for the nonuniform dose distribution provides a more clinically relevant description of the clinical delivered dose. Though the average BED difference was clinically insignificant, the maximum difference of BED for late effects can differ by a single fractional dose (10%) for a specific patient due to the interfraction dose variation in MammoSite treatment. PMID- 20717093 TI - Comparison of single and multiple dwell position methods in MammoSite high dose rate (HDR) brachytherapy planning. AB - The purpose of this study is to dosimetrically compare two plans generated using single dwell position method (SDPM) and multiple dwell position methods (MDPM) in MammoSite high dose rate (HDR) brachytherapy planning for 19 breast cancer patients. In computed tomography (CT) image-based HDR planning, a surface optimization technique was used in both methods. Following dosimetric parameters were compared for fraction 1 plans: %PTV_EVAL (planning target volume for plan evaluation) coverage, dose homogeneity index (DHI), dose con-formal index (COIN), maximum dose to skin and ipsilateral lung, and breast tissue volume receiving 150% (V150[cc]) and 200% (V200[cc]) of the prescribed dose. In addition, a plan was retrospectively generated for each fraction 2-10 to simulate the clinical situation where the fraction 1 plan was used for fractions 2-10 without modification. In order to create nine derived plans for each method and for each of the 19 patients, the catheter location and contours of target and critical structures were defined on the CT images acquired prior to each fraction 2-10, while using the same dwell-time distribution as used for fraction 1 (original plan). Interfraction dose variations were evaluated for 19 patients by comparing the derived nine plans (each for fractions 2-10) with the original plan (fraction 1) using the same dosimetric parameters used for fraction 1 plan comparison. For the fraction 1 plan comparison, the MDPM resulted in slightly increased %PTV_EVAL coverage, COIN, V150[cc] and V200[cc] values by an average of 1.2%, 0.025, 0.5 cc and 0.7cc, respectively, while slightly decreased DHI, maximum skin and ipsilateral lung dose by an average of 0.003, 3.2 cGy and 5.8 cGy, respectively. For the inter-fraction dose variation comparison, the SDPM resulted in slightly smaller variations in %PTV_EVAL coverage, DHI, maximum skin dose and V150[cc] values by an average of 0.4%, 0.0005, 0.5 cGy and 0.2 cc, respectively, while slightly higher average variations in COIN, maximum ipsilateral lung dose and V200[cc] values by 0.0028, 0.2 cGy and 0.2 cc, respectively. All differences were too small to be clinically significant. Compared to the MDPM, the SDPM combined with a surface optimization technique can generate a clinically comparable fraction 1 treatment plan with a similar interfraction dose variation if a single source is carefully positioned at the center of the balloon catheter. PMID- 20717094 TI - Validation of Pinnacle treatment planning system for use with Novalis delivery unit. AB - For an institution that already owns the licenses, it is economically advantageous and technically feasible to use Pinnacle TPS (Philips Radiation Oncology Systems, Fitchburg, WI) with the BrainLab Novalis delivery system (BrainLAB A.G., Heimstetten, Germany). This takes advantage of the improved accuracy of the convolution algorithm in the presence of heterogeneities compared with the pencil beam calculation, which is particularly significant for lung SBRT treatments. The reference patient positioning DRRs still have to be generated by the BrainLab software from the CT images and isocenter coordinates transferred from Pinnacle. We validated this process with the end-to-end hidden target test, which showed an isocenter positioning error within one standard deviation from the previously established mean value. The Novalis treatment table attenuation is substantial (up to 6.2% for a beam directed straight up and up to 8.4% for oblique incidence) and has to be accounted for in calculations. A simple single contour treatment table model was developed, resulting in mean differences between the measured and calculated attenuation factors of 0.0%-0.2%, depending on the field size. The maximum difference for a single incidence angle is 1.1%. The BrainLab micro-MLC (mMLC) leaf tip, although not geometrically round, can be represented in Pinnacle by an arch with satisfactory dosimetric accuracy. Subsequently, step-and-shoot (direct machine parameter optimization) IMRT dosimetric agreement is excellent. VMAT (called "SmartArc" in Pinnacle) treatments with constant gantry speed and dose rate are feasible without any modifications to the accelerator. Due to the 3 mm-wide mMLC leaves, the use of a 2 mm calculation grid is recommended. When dual arcs are used for the more complex cases, the overall dosimetric agreement for the SmartArc plans compares favorably with the previously reported results for other implementations of VMAT: gamma(3%,3mm) for absolute dose obtained with the biplanar diode array passing rates above 97% with the mean of 98.6%. However, a larger than expected dose error with the single-arc plans, confined predominantly to the isocenter region, requires further investigation. PMID- 20717095 TI - Improved image quality of low-dose thoracic CT examinations with a new postprocessing software. AB - In 2008 a phantom study indicated that there is a potential for reducing the CT doses when using a new postprocessing filter. The purpose of this study was to test this new postprocessing filter clinically for low-dose chest CT examinations, to assess whether the diagnostic performance is the same or improved. A standardized clinical chest CT protocol was used on patients with colorectal cancer. Only mA settings changed between patients according to patient size. One standard and one low-dose chest protocol were performed for all patients. The low-dose images were postprocessed with a new software filter, which provides context-controlled restoration of digital images by using adaptive filters. Three radiologists assessed randomly all the images independently. A total of 24 scan series were evaluated with respect to image quality according to quality criteria from the European guidelines for chest CT using a five-point scale; 576 details were assessed. Overall mean score is the average score for all details rated for all three readers for all full-dose series, low-dose series and low-dose enhanced series, respectively. The statistical methods used for comparison were paired sampled t-test and intraclass correlation coefficient. The postprocessing filter improved the diagnostic performance compared to the unenhanced low-dose images. Mean score for full-dose, low-dose and low-dose enhanced series were 3.8, 3.0 and 3.3, respectively. For all patients the full dose series gave higher scores than the low-dose series. Intraclass correlation coefficients were 0.2, 0.1 and 0.3 for the full-dose, low-dose and low-dose enhanced series, respectively. There is a potential for improving diagnostic performance of low-dose CT chest examinations using this new postprocessing filter. PMID- 20717096 TI - A comprehensive study on decreasing the kilovoltage cone-beam CT dose by reducing the projection number. AB - The objective of this study was to evaluate the effect of kilovoltage cone-beam computed tomography (CBCT) on registration accuracy and image qualities with a reduced number of planar projections used in volumetric imaging reconstruction. The ultimate goal is to evaluate the possibility of reducing the patient dose while maintaining registration accuracy under different projection-number schemes for various clinical sites. An Elekta Synergy Linear accelerator with an onboard CBCT system was used in this study. The quality of the Elekta XVI cone-beam three dimensional volumetric images reconstructed with a decreasing number of projections was quantitatively evaluated by a Catphan phantom. Subsequently, we tested the registration accuracy of imaging data sets on three rigid anthropomorphic phantoms and three real patient sites under the reduced projection-number (as low as 1/6th) reconstruction of CBCT data with different rectilinear shifts and rota-tions. CBCT scan results of the Catphan phantom indicated the CBCT images got noisier when the number of projections was reduced, but their spatial resolution and uniformity were hardly affected. The maximum registration errors under the small amount transformation of the reference CT images were found to be within 0.7 mm translation and 0.3 masculine rotation. However, when the projection number was lower than one-fourth of the full set with a large amount of transformation of reference CT images, the registration could easily be trapped into local minima solutions for a nonrigid anatomy. We concluded, by using projection-number reduction strategy under conscientious care, imaging-guided localization procedure could achieve a lower patient dose without losing the registration accuracy for various clinical sites and situations. A faster scanning time is the main advantage compared to the mA decrease-based, dose-reduction method. PMID- 20717098 TI - A 'biomarker signature' for tolerance in transplantation. AB - In the past decade, an explosion in the number of high-throughput tools for the measurement of different cellular products has occurred. These tools have the potential to further our understanding of human disease and this development has facilitated the identification of new biomarkers in all areas of medicine. In the field of solid organ transplantation, two different areas have developed: the use of biomarkers to predict allograft tolerance for the identification of patients who can be weaned from immunosuppressive therapy, and biomarkers for the prediction of allograft rejection, so that parenchymal damage can be prevented before it becomes irreversible. In this Review, we discuss the development of biomarkers that are indicative of transplant tolerance. Identifying patients in whom donor-specific tolerance has developed would constitute a major advance in the care of organ transplant recipients. This ability would allow the minimization or even the withdrawal of immunosuppressive therapy in selected patients, thus reducing the number of adverse effects and costs, and optimizing long-term graft outcomes. The routine clinical use of these biomarkers, once validated, would bring to the fore the possibility of personalized medicine. PMID- 20717099 TI - Tolerance: an overview and perspectives. AB - Self tolerance is dependent on mechanisms that operate on T cells and B cells from the earliest stages, that is, from when they first express anti-self receptors in the primary lymphoid organs of the thymus and bone marrow, all the way through to when they engage with self antigens in the peripheral immune system and within tissues themselves. This continuum of checkpoints and fail safes ensures that the risk of developing harmful autoimmune diseases remains very small. Certain tissues have a degree of privilege that allows them to mute the immune response against them by mechanisms that are also well represented in cancers. An understanding of the underlying mechanisms of self tolerance is hoped to spawn a new range of therapeutics designed to both reprogram the immune system to avoid long-term intense immunosuppression, and to override the immune system to achieve more effective immunity against cancers and persistent viral infections. PMID- 20717100 TI - Obesity punches above its weight in osteoarthritis. AB - Arthritis Research UK published a report in 2009 entitled "Osteoarthritis and obesity" in which they highlight the severe consequences of obesity for musculoskeletal health. Throughout the report, however, the mechanical effect of excess body weight is assumed to be the direct cause of osteoarthritis (OA). Although this assumption is common, is it supported by the evidence? A survey of the studies associating OA with obesity is inconclusive on whether body weight is the causative factor. The increase in direct-loading on joints due to weight-gain is not as great as is often believed, and compensatory gait patterns ameliorate much of the kinematic effects. One manifestation of obesity, however, is increased adipose tissue--a rich source of proinflammatory endocrine factors. I propose that body weight might not be the main problem in OA pathogenesis, but that increased adipose tissue itself might be both an indicator and a driver of widespread disease. PMID- 20717101 TI - The nuclear receptor PPARgamma individually responds to serotonin- and fatty acid metabolites. AB - The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), recognizes various synthetic and endogenous ligands by the ligand binding domain. Fatty-acid metabolites reportedly activate PPARgamma through conformational changes of the Omega loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARgamma to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub pockets, and the PPARgamma antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARgamma-target gene. Collectively, these results suggest a novel agonism, in which PPARgamma functions as a multiple sensor in response to distinct metabolites. PMID- 20717102 TI - Crystal structure of a transfer-ribonucleoprotein particle that promotes asparagine formation. AB - Four out of the 22 aminoacyl-tRNAs (aa-tRNAs) are systematically or alternatively synthesized by an indirect, two-step route requiring an initial mischarging of the tRNA followed by tRNA-dependent conversion of the non-cognate amino acid. During tRNA-dependent asparagine formation, tRNA(Asn) promotes assembly of a ribonucleoprotein particle called transamidosome that allows channelling of the aa-tRNA from non-discriminating aspartyl-tRNA synthetase active site to the GatCAB amidotransferase site. The crystal structure of the Thermus thermophilus transamidosome determined at 3 A resolution reveals a particle formed by two GatCABs, two dimeric ND-AspRSs and four tRNAs(Asn) molecules. In the complex, only two tRNAs are bound in a functional state, whereas the two other ones act as an RNA scaffold enabling release of the asparaginyl-tRNA(Asn) without dissociation of the complex. We propose that the crystal structure represents a transient state of the transamidation reaction. The transamidosome constitutes a transfer-ribonucleoprotein particle in which tRNAs serve the function of both substrate and structural foundation for a large molecular machine. PMID- 20717103 TI - Hyperactive sleeping beauty transposase enables persistent phenotypic correction in mice and a canine model for hemophilia B. AB - Sleeping Beauty (SB) transposase enables somatic integration of exogenous DNA in mammalian cells, but potency as a gene transfer vector especially in large mammals has been lacking. Herein, we show that hyperactive transposase system delivered by high-capacity adenoviral vectors (HC-AdVs) can result in somatic integration of a canine factor IX (cFIX) expression-cassette in canine liver, facilitating stabilized transgene expression and persistent haemostatic correction of canine hemophilia B with negligible toxicity. We observed stabilized cFIX expression levels during rapid cell cycling in mice and phenotypic correction of the bleeding diathesis in hemophilia B dogs for up to 960 days. In contrast, systemic administration of an inactive transposase system resulted in rapid loss of transgene expression and transient phenotypic correction. Notably, in dogs a higher viral dose of the active SB transposase system resulted into transient phenotypic correction accompanied by transient increase of liver enzymes. Molecular analysis of liver samples revealed SB mediated integration and provide evidence that transgene expression was derived mainly from integrated vector forms. Demonstrating that a viral vector system can deliver clinically relevant levels of a therapeutic protein in a large animal model of human disease paves a new path toward the possible cure of genetic diseases. PMID- 20717104 TI - Cognitive intervention in Alzheimer disease. AB - Alzheimer disease (AD) is one of the most prevalent chronic medical conditions affecting the elderly population. The effectiveness of approved antidementia drugs, however, is limited-licensed AD medications provide only moderate relief of clinical symptoms. Cognitive intervention is a noninvasive therapy that could aid prevention and treatment of AD. Data suggest that specifically designed cognitive interventions could impart therapeutic benefits to patients with AD that are associated with substantial biological changes within the brain. Moreover, evidence indicates that a combination of pharmacological and non pharmacological interventions could provide greater relief of clinical symptoms than either intervention given alone. Functional and structural MRI studies have increased our understanding of the underlying neurobiological mechanisms of aging and neurodegeneration, but the use of neuroimaging to investigate the effect of cognitive intervention on the brain remains largely unexplored. This Review provides an overview of the use of cognitive intervention in the healthy elderly population and patients with AD, and summarizes emerging findings that provide evidence for the effectiveness of this approach. Finally, we present recommendations for future research on the use of cognitive interventions in AD and discuss potential effects of this therapy on disease modification. PMID- 20717106 TI - 5-aminosalicylates prevent relapse of Crohn's disease after surgically induced remission: systematic review and meta-analysis. AB - OBJECTIVES: Evidence from randomized controlled trials (RCTs) for the use of 5 aminosalicylic acid (5-ASA) drugs in Crohn's disease (CD) in remission after a surgical resection is conflicting. We conducted a systematic review and meta analysis of RCTs to examine this issue. METHODS: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through April 2010). Eligible trials recruited adults with luminal CD in remission after a surgical resection and compared 5-ASAs with placebo, or no treatment. Dichotomous data were pooled to obtain relative risk (RR) of relapse of disease activity, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. RESULTS: The search strategy identified 3,061 citations. Eleven RCTs were eligible for inclusion containing 1,282 patients. The RR of relapse of CD in remission after surgery with 5-ASA vs. placebo or no therapy was 0.86 (95% CI=0.74-0.99) (NNT=13). Sulfasalazine was of no benefit in preventing relapse in 448 patients (RR=0.97; 95% CI=0.72-1.31), but mesalamine was more effective than placebo or no therapy (RR=0.80; 95% CI=0.70-0.92) in 834 patients, with an NNT of 10. CONCLUSIONS: Mesalamine is of modest benefit in preventing relapse of CD in remission after surgery. Its use should be considered in those in whom immunosuppressive therapy is either not warranted or contraindicated. PMID- 20717105 TI - Targeting dendritic cells to treat multiple sclerosis. AB - Multiple sclerosis (MS) is considered to be a predominantly T-cell-mediated disease, and emerging evidence indicates that dendritic cells have a critical role in the initiation and progression of this debilitating condition. Dendritic cells are specialized antigen-presenting cells that can prime naive T cells and modulate adaptive immune responses. Their powerful biological functions indicate that these cells can be exploited by immunotherapeutic approaches. Therapies that inhibit the immunogenic actions of dendritic cells through the blockade of proinflammatory cytokine production and T cell co-stimulatory pathways are currently being pursued. Furthermore, novel strategies that can regulate dendritic cell development and differentiation and harness the tolerogenic capacity of these cells are also being developed. Here, we evaluate the prospects of these future therapeutic strategies, which focus on dendritic cells and dendritic cell-related targets to treat MS. PMID- 20717107 TI - Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort. AB - OBJECTIVES: Serrated polyps are precursors in an alternative pathway to colon cancer. These polyps are frequently sessile or flat, located in the proximal colon, and may be overlooked during colonoscopy. Histological criteria to classify these polyps have only recently been described. This study assessed the variation of serrated polyp detection among endoscopists and pathologists in an average risk-screening cohort and trends in detection over time. METHODS: Endoscopy and pathology reports were reviewed from all average risk-screening colonoscopies at an urban academic medical center from 2006 through 2008. Polyps were classified as adenoma (tubular, tubulovillous, or villous), serrated polyp (hyperplastic polyp (HP), sessile serrated adenoma (SSA), or dysplastic serrated polyp (DSP)), adenocarcinoma, or other. Differences in polyp detection among endoscopists and pathologists were tested with chi(2)-tests. Potential predictors of polyp detection were modeled with Poisson regression. RESULTS: Included in the study were 4,335 polyps from 7,192 colonoscopies. Detection prevalence (patients with at least one polyp per 100 colonoscopies) was 22.2 for adenomas, 11.7 for HP, 0.6 for SSA, and 0.2 for DSP. Detection prevalence of proximal SSAs increased from 0.2 in 2006 to 4.4 in 2008 (P<0.001). Detection prevalences among endoscopists differed significantly for adenomas, HP, and SSA. Classification rates among pathologists differed significantly for HP and SSA, but not for adenoma or DSP. On multivariate analysis, endoscopist was a significant predictor of adenoma, HP, and SSA. Pathologist was a significant predictor of HP, SSA, and DSP, but not adenoma. CONCLUSIONS: This study describes the detection of colorectal polyps in an average risk-screening cohort at an urban academic medical center. Detection of proximal SSAs increased during the study period. Detection of adenoma, HP, and SSA differed significantly by endoscopist. Classification of HP and SSA differed significantly by pathologist. Endoscopy and pathology practices should consider educational interventions to improve serrated polyp detection and standardize classification. PMID- 20717108 TI - A randomized, double-blind trial of succinylated gelatin submucosal injection for endoscopic resection of large sessile polyps of the colon. AB - OBJECTIVES: Succinylated gelatin (SG) is an inexpensive, safe, colloidal solution. It was superior to normal saline (NS) in a porcine colon endoscopic resection (ER) model. Our aim was to compare the efficacy, efficiency, and safety of ER with SG vs. NS. METHODS: A randomized double-blind trial of submucosal injection with SG vs. NS was conducted for patients undergoing colonoscopy and ER for sessile lesions >=20 mm in size at an Australian academic hospital endoscopy unit. The primary end point was the "Sydney Resection Quotient" (SRQ), defined as "lesion size in mm divided by the number of pieces to resect." This allows a comparison of technical outcomes for lesions of various sizes. A large lesion removed in fewer pieces gives a greater value. RESULTS: Eighty patients (45 men, mean age 69) with lesions sized 20-100 mm were randomized. A total of 41 SG subjects were well matched to 39 NS subjects, with median (interquartile range) lesion size 40 mm (25-45) vs. 35 mm (30-50), respectively (P=0.382). Complete single-session lesion excision was 90% in both groups. There were no adverse events attributable to SG. The SRQ (median (interquartile range)) was SG 10.0 (7.5-20.0) vs. NS 5.9 (4.4-11.7), P=0.004. Other end points (median (interquartile range)) included fewer resections per lesion in the SG group: 3.0 (1.0-6.0) vs. NS 5.5 (3.0-10.0), P=0.028; fewer injections per lesion with SG: 2.0 (1.0-3.0) vs. NS 3.0 (2.0-11.0), P=0.002; lower injection volume: 14.5 ml (8.5-23.0) vs. NS 20.0 ml (16.0-46.0), P=0.009; and shorter procedure duration with SG: 12.0 min (8.0-28.0) vs. NS 24.5 min (15.0-36.0), P=0.006. CONCLUSIONS: SG significantly improves SRQ by almost halving the number of resections for piecemeal ER. SG also safely halves procedure duration. PMID- 20717109 TI - Insulin-like growth factors and liver cancer risk in male smokers. AB - BACKGROUND: The liver is the primary source of circulating insulin-like growth factor (IGF)-I, yet the relation between IGFs and liver cancer is uncertain. METHODS: In a case-cohort study within a cohort of 29,133 male smokers we examined associations of serum IGF-I and IGF binding protein (IGFBP)-3 with liver cancer (50 cases). RESULTS: Nonlinear associations between liver cancer and IGF-I and IGFBP-3 were observed (P=0.04 and P<0.01, respectively), strongest association at lowest levels (odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1-0.7 for 80 vs 30 ng ml(-1) of IGF-I; OR=0.2, 95% CI=0.1-0.6 for 1400 vs 700 ng ml(-1) of IGFBP-3). CONCLUSIONS: Low IGF-I and IGFBP-3 levels in male smokers are associated with increased risk of liver cancer. PMID- 20717110 TI - The relationship between the presence and site of cancer, an inflammation-based prognostic score and biochemical parameters. Initial results of the Glasgow Inflammation Outcome Study. AB - BACKGROUND: Cancer incidence is increasing in the United Kingdom, as well as on a global basis. Biochemical parameters, such as C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score, mGPS), alkaline phosphatase (Alk phos), gamma-glutamyl transferase (GGT) and serum calcium have been reported to be associated with cancer and non-cancer mortality. Therefore, to definitively examine the interrelationships between the above biochemical parameters, the mGPS and the presence of cancer, the Glasgow Inflammation Outcome Study was undertaken. The aim of this initial study was to examine the effect of cancer on markers of systemic inflammation induced by the liver (mGPS) and on levels of routine biochemical parameters. METHODS: Patients (n=223 303) who had a single incidental sample taken for C-reactive protein, albumin, calcium and serum liver function tests where available, between 2000 and 2008 were studied. Those with a pathological diagnosis of cancer (n=22 715) were identified. The mGPS was constructed and liver function tests classified in accordance with the local reference ranges. RESULTS: Patients with cancer had higher C-reactive protein and lower albumin levels (and thus a higher mGPS), higher adjusted calcium, Alk phos and GGT levels, but lower aspartate transaminase (AST) and alanine transaminase (ALT) levels (all P<0.001). The strongest associations (Spearman's correlation > or =0.3) in both the non-cancer and cancer groups were found between albumin, C reactive protein and Alk phos, AST and ALT, AST and GGT and ALT and GGT (all P<0.001). On multivariate analysis, the associations with the presence of cancer remained with age, deprivation, C-reactive protein, albumin, adjusted calcium, Alk phos and GGT (all P<0.01). Patients following a diagnosis of cancer had lower albumin levels and thus higher mGPS (all P<0.001). Also, post-diagnosis patients were more likely to have lower adjusted calcium, bilirubin, Alk Phos, AST, ALT and GGT levels (all P<0.05). When the cancer diagnoses were ranked from those with the lowest proportion of mGPS 1 or 2 to those with the highest, the percentage of cases with a mGPS of 1 or 2 ranged from 21% in breast cancer to 46% in prostate cancer and to 68% in pulmonary cancer. Compared with breast cancer the mGPS was significantly higher in those diagnosed with dermatological, bladder, endocrinological, gynaecological, prostate, musculoskeletal, gastroesophageal, haematological, renal, colorectal, head and neck, pancreaticobiliary and pulmonary cancers (all P<0.001). CONCLUSION: The results of the present study indicate that the systemic inflammatory response is common in a large patient cohort, increased by the presence of cancer and associated with the perturbation of a number of biochemical parameters previously reported to be associated with mortality. There is a striking parallel between the proportions of cases with a mGPS of 1 or 2 and reported survival rates in these tumours. PMID- 20717111 TI - A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours. AB - BACKGROUND: Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours. METHODS: Sunitinib was initially administered once daily at 37.5 mg per day on days 1-14 of a 21-day cycle, in which irinotecan 250 mg m(-2) was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies. RESULTS: In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug-drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1-14) with irinotecan 250 mg m(-2) (day 1), but no activity was observed at this dose. CONCLUSION: Although a higher sunitinib dose of 37.5 mg per day (days 1-14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies. PMID- 20717112 TI - Education, survival and avoidable deaths in cancer patients in Finland. AB - BACKGROUND: Relative survival after cancer in Finland is at the highest level observed in Europe and has, in general, been on a steady increase. The aim of this study is to assess whether the high survival is equally shared by different population subgroups and to estimate the possible gains that might be achieved if equity prevailed. MATERIALS AND METHOD: The educational level and occupation before the cancer diagnosis of patients diagnosed in Finland in 1971-2005 was derived from an antecedent population census. The cancers were divided into 27 site categories. Cancer (cause)-specific 5-year survival proportions were calculated for three patient categories based on the educational level and for an occupational group of potentially health-conscious patients (physicians, nurses, teachers etc.). Proportions of avoidable deaths were derived by assuming that the patients from the two lower education categories would have the same mortality owing to cancer, as those from the highest educational category. Estimates were also made by additionally assuming that even the mortalities owing to other causes of death were all equal to those in the highest category. RESULTS: For almost all the sites considered, survival was consistently highest for patients with the highest education and lowest for those with only basic education. The potentially health-conscious patients had an even higher survival. The differences were, in part, attributable to less favourable distributions of tumour stages in the lower education categories. In 1996-2005, 4-7% of the deaths in Finnish cancer patients could have potentially been avoided during the first 5 year period after diagnosis, if all the patients had the same cancer mortality as the patients with the highest educational background. The proportion would have also been much higher, 8-11%, if, in addition, the mortality from other causes had been the same as that in the highest educational category. INTERPRETATION: Even in a potentially equitable society with high health care standards, marked inequalities persist in cancer survival. Earlier cancer diagnosis and the ability to cope within the health care system may be a partly relevant explanation, but personal habits and lifestyles also have a role, particularly for the cancer patients' mortality from other causes of death than cancer. PMID- 20717113 TI - SV40 associated miRNAs are not detectable in mesotheliomas. AB - BACKGROUND: Simian virus-40 (SV40) is a DNA tumour virus that was introduced into the human population with contaminated poliovirus vaccine, and its role in mesothelioma is widely debated. PCR based testing has been called into question, as false positives can be because of cross-reactivity with related viruses, or to laboratory contamination. The Institute of Medicine has recommended the development of more sensitive and specific tests to resolve this controversy. METHODS: We have characterized highly sensitive RT-PCR based assays that are specific for SV40-encoded microRNAs (miRNAs), as an alternative to current testing methods. RESULTS: Using this sensitive and specific detection method, we were unable to identify SV40 miRNA expression in human malignant pleural mesothelioma (MM) samples. CONCLUSION: Our work indicates that SV40 miRNAs are not likely to contribute to mesothelioma tumourogenesis, but highlights the value of this approach when compared with the relatively unspecific current testing methods. PMID- 20717114 TI - Selective cyclooxygenase-2 silencing mediated by engineered E. coli and RNA interference induces anti-tumour effects in human colon cancer cells. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression is strongly associated with colorectal tumourigenesis. It has been demonstrated that the chronic use of non steroidal anti-inflammatory drugs (COX inhibitors) partially protects patients from colorectal cancer (CRC) development and progression but induces severe cardiovascular side effects. New strategies for selective COX-2 blockade are required. METHODS: We developed an improved technique, based on RNA interference (RNAi), to gain a selective COX-2 silencing in CRC cells by a tumour-dependent expression of anti-COX-2 short-hairpin RNA (shCOX-2). Anti-COX-2 shRNA-expressing vectors were delivered in CRC cells (in vitro) and in colon tissues (ex vivo) using engineered Escherichia coli strains, capable of invading tumour cells (InvColi). RESULTS: A highly tumour-dependent shCOX-2 expression and a significant COX-2 silencing were observed in CRC cells following InvColi strain infection. Cyclooxygenase-2 silencing was associated with a strong reduction in both proliferative and invasive behaviour of tumour cells. We also demonstrated a pivotal role of COX-2 overexpression for the survival of CRC cells after bacterial infection. Moreover, COX-2 silencing was achieved ex vivo by infecting colon tissue samples with InvColi strains, leading to anti-inflammatory and anti tumour effects. CONCLUSION: Our RNAi/InvColi-mediated approach offers a promising tool for a highly selective COX-2 blockade in vitro and in vivo. PMID- 20717115 TI - Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularised and poor prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. METHODS: Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 microg m(-2) once every 3 weeks. The primary aim of the study was progression-free survival (PFS). RESULTS: No grade 3-4 treatment related toxicities were noted. Common toxicity included mild-to-moderate, short lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months. CONCLUSION: NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest. PMID- 20717116 TI - Breast cancer patients' clinical outcome measures are associated with Src kinase family member expression. AB - BACKGROUND: This study determined mRNA expression levels for Src kinase family (SFK) members in breast tissue specimens and assessed protein expression levels of prominent SFK members in invasive breast cancer to establish associations with clinical outcome. Ki67 was investigated to determine association between SFK members and proliferation. METHODS: The mRNA expression levels were assessed for eight SFK members by quantitative real-time PCR. Immunohistochemistry was performed for c-Src, Lyn, Lck and Ki67. RESULTS: mRNA expression was quantified in all tissue samples. SRC and LYN were the most highly expressed in malignant tissue. LCK was more highly expressed in oestrogen receptor (ER)-negative, compared with ER-positive tumours. High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival. Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival. Ki67 expression correlated with tumour grade and nuclear c-Src, but was not associated with survival. CONCLUSIONS: All eight SFK members were expressed in different breast tissues. Src kinase was highest expressed in breast cancer and had a negative impact on disease-specific survival. Membrane expression of Lck was associated with improved clinical outcome. High expression of Src kinase correlated with high proliferation. PMID- 20717117 TI - Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases. AB - BACKGROUND: The WASF3 protein is involved in cell movement and invasion, and to investigate its role in prostate cancer progression we studied the phenotypic effects of knockdown in primary tumors and cell lines. METHODS: ShRNA was used to knockdown WASF3 function in prostate cell lines. Cell motility (scratch wound assay), anchorage independent growth and in vivo tumorigenicity and metastasis were then compared between knockdown and wild-type cells. RESULTS: Increased levels of expression were seen in high-grade human prostate cancer and in the PC3 and DU145 cell lines. Inactivation of WASF3 using shRNAs reduced cell motility and invasion in these cells and reduced anchorage independent growth in vitro. The loss of motility was accompanied by an associated increase in stress fiber formation and focal adhesions. When injected subcutaneously into severe combined immunodeficiency (SCID) mice, tumor formation was significantly reduced for PC3 and DU145 cells with WASF3 knockdown and in vivo metastasis assays using tail vain injection showed a significant reduction for PC3 and DU145 cells. The loss of the invasion phenotype was accompanied by down-regulation of matrix metalloproteinase 9. CONCLUSIONS: Overall, these observations demonstrate a critical role for WASF3 in the progression of prostate cancer and identify a potential target to control tumorigenicity and metastasis. PMID- 20717118 TI - NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration. AB - BACKGROUND: The influence of the stromal microenvironment on the progression of epithelial cancers has been demonstrated. Unravelling the mechanisms by which stromal cells affect epithelial behaviour will contribute in understanding cellular malignancy. It has been proposed that redox environment has a role in the acquisition of malignancy. In this work, we studied the influence of epithelial cells on the stromal redox status and the consequence of this phenomenon on MCF-7 cell motility. METHODS: We analysed in a co-culture system, the effect of RMF-EG mammary stromal cells on the migratory capacity of MCF-7 cell line. To test whether the NOX-dependent stromal redox environment influences the epithelial migratory behaviour, we knocked down the expression of NOX4 using siRNA strategy. The effect of TGF-beta1 on NOX4 expression and activity was analysed by qPCR, and intracellular ROS production was measured by a fluorescent method. RESULTS: Migration of MCF-7 breast epithelial cells was stimulated when co-cultured with RMF-EG cells. This effect depends on stromal NOX4 expression that, in turn, is enhanced by epithelial soluble factors. Pre-treatment of stromal cells with TGF-beta1 enhanced this migratory stimulus by elevating NOX4 expression and intracellular ROS production. TGF-beta1 seems to be a major component of the epithelial soluble factors that stimulate NOX4 expression. CONCLUSIONS: Our results have identified that an increased stromal oxidative status, mainly provided by an elevated NOX4 expression, is a permissive element in the acquisition of epithelial migratory properties. The capacity of stromal cells to modify their intracellular ROS production, and accordingly, to increase epithelial motility, seems to depend on epithelial soluble factors among which TGF-beta1 have a decisive role. PMID- 20717119 TI - In vitro antitrypanosomal activity of 12 low-molecular-weight antibiotics and observations of structure/activity relationships. PMID- 20717120 TI - Antimicrobial activity of doripenem against bacterial isolates from humans and animals. PMID- 20717121 TI - The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. AB - After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate driven neuroplasticity. PMID- 20717122 TI - The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. AB - The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1alpha, soluble CD40 ligand, GRO, IL1beta, platelet derived growth factor (PDGF)-AA, MIP1beta, RANTES; day 2: IL1 receptor antagonist (ra). IL6, granulocyte-colony stimulating factor (G-CSF), chemokine CXC motif ligand 10 (IP10); days 4 to 5: IL12p70, IL10. Brain extracellular fluid concentrations were significantly higher than plasma concentrations for 19 cytokines: basic fibroblast growth factor (FGF2), G-CSF, IL1alpha, IL1beta, IL1ra, IL3, IL6, IL8, IL10, IL12p40, IL12p70, IP10, monocyte chemotactic protein (MCP)1, MCP3, MIP1alpha, MIP1beta, PDGF-AA, transforming growth factor (TGF)alpha and vascular endothelial growth factor. No clear arterio-jugular venous gradients were apparent. These data provide evidence for the cerebral production of these cytokines and show a stereotyped temporal pattern after TBI. PMID- 20717123 TI - Predictive value of platelet activation for the rate of cognitive decline in Alzheimer's disease patients. AB - Vascular risk factors contribute to the progression of dementia in Alzheimer's disease (AD) and influence platelet activation. However, the degree of platelet activation as a possible underlying mechanism of this progression has not been studied till now. Significantly higher baseline expression of both platelet activation biomarkers, activated glycoprotein IIb-IIIa complex and P-selectin, was observed in patients with AD with fast cognitive decline compared with AD patients with slow cognitive decline during a 1-year follow-up period. These results suggest that platelet activation could be a putative prognostic biomarker for the rate of cognitive decline and a potential new treatment target in AD patients. PMID- 20717125 TI - Analysis of the health economic impact of medical nutrition in the Netherlands. AB - OBJECTIVE: A health economic analysis was performed to assess the cost effectiveness of oral nutritional supplements (ONS), being a medical nutrition product, in the Netherlands. METHODS: This analysis is based on a comparison of the use of ONS versus 'no use' of ONS in patients undergoing abdominal surgery. The costs and benefits of the two treatment strategies were assessed using a linear decision analytical model reflecting treatment patterns and outcomes in abdominal surgery. The incremental cost difference was based on costs associated with ONS and hospitalization. Clinical probabilities and resource utilization were based on clinical trials and published literature; cost data were derived from official price tariffs. RESULTS: The use of ONS reduces the costs with a ?[euro] 252 (7.6%) cost saving per patient. The hospitalization costs reduce from ?[euro] 3,318 to ?[euro] 3,044 per patient, which is a 8.3% cost saving and corresponds with 0.72 days reduction in length of stay. The use of ONS would lead to an annual cost saving of a minimum of ?[euro] 40.4 million per year. Sensitivity analyses showed that the use of ONS remains cost saving compared with 'no use' of ONS. A threshold analysis on the length of stay shows that at 0.64 days, the use of ONS is still cost-effective, which is an unrealistic value. CONCLUSIONS: This analysis shows that the use of medical nutrition, ONS in this case, is a cost-effective treatment in the Netherlands and is dominant over standard care without medical nutrition: it leads to cost savings and a higher effectiveness. PMID- 20717124 TI - Outcome-related metabolomic patterns from 1H/31P NMR after mild hypothermia treatments of oxygen-glucose deprivation in a neonatal brain slice model of asphyxia. AB - Human clinical trials using 72 hours of mild hypothermia (32 degrees C-34 degrees C) after neonatal asphyxia have found substantially improved neurologic outcomes. As temperature changes differently modulate numerous metabolite fluxes and concentrations, we hypothesized that (1)H/(31)P nuclear magnetic resonance (NMR) spectroscopy of intracellular metabolites can distinguish different insults, treatments, and recovery stages. Three groups of superfused neonatal rat brain slices underwent 45 minutes oxygen-glucose deprivation (OGD) and then were: treated for 3 hours with mild hypothermia (32 degrees C) that began with OGD, or similarly treated with hypothermia after a 15-minute delay, or not treated (normothermic control group, 37 degrees C). Hypothermia was followed by 3 hours of normothermic recovery. Slices collected at different predetermined times were processed, respectively, for 14.1 Tesla NMR analysis, enzyme-linked immunosorbent assay (ELISA) cell-death quantification, and superoxide production. Forty-nine NMR-observable metabolites underwent a multivariate analysis. Separated clustering in scores plots was found for treatment and outcome groups. Final ATP (adenosine triphosphate) levels, severely decreased at normothermia, were restored equally by immediate and delayed hypothermia. Cell death was decreased by immediate hypothermia, but was equally substantially greater with normothermia and delayed hypothermia. Potentially important biomarkers in the (1)H spectra included PCr-(1)H (phosphocreatine in the (1)H spectrum), ATP-(1)H (adenosine triphosphate in the (1)H spectrum), and ADP-(1)H (adenosine diphosphate in the (1)H spectrum). The findings suggest a potential role for metabolomic monitoring during therapeutic hypothermia. PMID- 20717126 TI - The effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise. AB - OBJECTIVES: L-Ornithine has an important role in ammonia metabolism via the urea cycle. This study aimed to examine the effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise. SUBJECTS/METHODS: In all, 14 healthy young adults (age: 22.2+/-1.0 years, height: 173.5+/-4.6 cm, body mass: 72.5+/-12.5 kg) who trained regularly conducted incremental exhaustive ergometer bicycle exercises after -ornithine hydrochloride supplementation (0.1 g/kg, body mass) and placebo conditions with a cross-over design. The exercise time (sec) of the incremental ergometer exercise, exercise intensity at exhaustion (watt), maximal oxygen uptake (ml per kg per min), maximal heart rate (beats per min) and the following serum parameters were measured before ingestion, 1 h after ingestion, just after exhaustion and 15 min after exhaustion: ornithine, ammonia, urea, lactic acid and glutamate. All indices on maximal aerobic capacity showed insignificant differences between both the conditions. RESULTS: Plasma ammonia concentrations just after exhaustion and at 15 min after exhaustion were significantly more with ornithine ingestion than with placebo. Plasma glutamate concentrations were significantly higher after exhaustion with ornithine ingestion than with placebo. CONCLUSIONS: It was suggested that, although the ingestion of L-ornithine hydrochloride before the exercise cannot be expected to improve performance, it does increase the ability to buffer ammonia, both during and after exercise. PMID- 20717127 TI - Predictors of physical activity energy expenditure in Afro-Caribbean children. AB - BACKGROUND/OBJECTIVES: We hypothesized that maternal size during pregnancy and birth size are determinants of childhood physical activity energy expenditure (PAEE). Also, childhood PAEE is inversely related to adiposity and levels of cardiovascular risk factors. SUBJECTS/METHODS: The Vulnerable Windows Cohort Study is a longitudinal observational study of 569 Afro-Jamaican mothers recruited from the first trimester and their offspring. Anthropometry, bioelectrical impedance, PAEE (using the Actical monitor) and cardiovascular risk factors (blood pressure, fasting glucose, insulin and lipids) were measured in 124 boys and 160 girls at a mean age of 13.2 years. RESULTS: Boys had more fat free mass (FFM) and expended more energy than girls (12.3+/-3.3 vs 9.6+/-2.8 kcal/kg/day; P<0.001). Maternal weight was associated with child's PAEE (r=0.29; P<0.001). PAEE was not significantly associated with birth weight. Maternal weight, after adjusting for child's age and sex, was positively associated with the child's FFM, fat mass and %fat (P-values ?0.01). Age- and sex-adjusted PAEE was positively associated with FFM, fat mass and % fat (P-values <0.001), but not after adjusting for current weight. Age- and sex-adjusted PAEE was positively associated with triglycerides, insulin and systolic blood pressure (P-values <0.05), but not after adjusting for weight and height. PAEE was associated with fasting glucose after controlling for age, sex, weight and height (r=-0.12; P=0.02). CONCLUSIONS: Maternal size, but not birth weight, is a determinant of childhood PAEE. PAEE is not strongly associated with childhood body composition, but is inversely related to fasting glucose concentration. PMID- 20717128 TI - Eating patterns and overweight in 9- to 10-year-old children in Telemark County, Norway: a cross-sectional study. AB - BACKGROUND/OBJECTIVES: Increasing prevalence of overweight in children is a growing health problem. The aim of this study was to describe the eating patterns of 9- to 10-year-old schoolchildren, and to investigate the relationship between overweight and eating patterns. SUBJECTS/METHODS: We recruited 1045 children for a cross-sectional study in Telemark County, Norway. The children's food, snacking and meal frequencies were reported by their parents using a retrospective food frequency questionnaire. Height and weight were measured by health professionals, and body mass index categories were calculated using international standard cutoff points (International Obesity Task Force values). Complete data were obtained for 924 children. Four distinct eating patterns were identified using principal component analysis. We used multiple logistic regression and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for being overweight, and adjusted for parental characteristics and physical activity levels of the children (aORs). RESULTS: Parental characteristics and physical activity were associated with both obesity and eating patterns. Children adhering to a 'junk/convenient' eating pattern had a significantly lower likelihood of being overweight (aOR: 0.6; 95% CI: 0.4, 0.9), whereas children adhering to a 'varied Norwegian' or a 'dieting' eating pattern had a significantly higher likelihood of being overweight (respective values: aOR: 2.1; 95% CI: 1.3, 3.2; aOR: 2.2; 95% CI: 1.4, 3.4). No association with overweight was seen for a 'snacking pattern'. CONCLUSIONS: The main finding was that, although family characteristics influenced both the prevalence of overweight and overall dietary behaviour, independent associations were evident between eating patterns and overweight, indicating parental modification of the diets of overweight children. PMID- 20717129 TI - Urinary fructose: a potential biomarker for dietary fructose intake in children. AB - BACKGROUND/OBJECTIVES: Recently, urinary fructose and sucrose excretion in 24-h urine have been established experimentally as new biomarkers for dietary sugar intake in adults. Our objective was to investigate 1) whether the fructose biomarker is also applicable in free-living children and 2) for what kind of sugar it is standing for. SUBJECTS/METHODS: Intakes of added and total sugar (including additional sugar from fruit and fruit juices) were assessed by 3-day weighed dietary records in 114 healthy prepubertal children; corresponding 24-h urinary fructose excretion was measured photometrically. The associations between dietary sugar intakes and urinary fructose excretion were examined using linear regression models. To determine whether one of the two sugar variables may be better associated with the urinary biomarker, the statistical Pitman's test was used. RESULTS: Added and total sugar correlated significantly with urinary fructose, but the linear regression indicated a weak association between intake of added sugar and urinary log-fructose excretion (beta=0.0026, R(2)=0.055, P=0.01). The association between total sugar intake and log-urinary fructose (beta=0.0040, R(2)=0.181, P<0.001) showed a significantly better fit (P<0.05). CONCLUSIONS: Urinary fructose excretion seems to be rather applicable for the estimation of total sugar intake than for the estimation of added dietary sugar intake in children. However, as excreted fructose stems almost exclusively from the diet (both from food-intrinsic and added intakes), it can be assumed that urinary fructose represents a potential biomarker for total dietary fructose intake, irrespective of its source. PMID- 20717130 TI - Celiac disease and obesity: need for nutritional follow-up after diagnosis. AB - More than 20 years of serological approach to diagnosis of celiac disease (CD) has deeply changed the classical clinical presentation of the disease, and some reports indicate that CD and obesity can coexist in both childhood and adolescence. We reviewed clinical records of 149 children with CD followed in our institution between 1991 and 2007, considering weight, height and body mass index (BMI), both at diagnosis and after at least 12 months of gluten-free diet (GFD). In all, 11% of patients had BMI z-score >+1 and 3% were obese (z-score >+2) at presentation. In our population, there was a significant (P=0.008) increase in BMI z-score after GFD and the percentage of overweight (z-score >+1) subjects almost doubled (11 vs 21%, P=0.03). Our data suggest the need for a careful follow-up of nutritional status after diagnosis of CD, especially addressing those who are already overweight at presentation. PMID- 20717131 TI - Maternal perception of the causes and consequences of sibling differences in eating behaviour. AB - BACKGROUND/OBJECTIVES: The aim of this study is to explore mothers' perceptions of differences between their children in the eating behaviour domain. SUBJECTS/METHODS: Twelve semistructured interviews were carried out with mothers who had at least two children aged between 6 and 15 years, to discuss feeding experiences, particularly around healthy eating. Interviews were recorded and transcribed verbatim and analysed using Framework Analysis. RESULTS: Mothers frequently identified differences in appetite and food preferences between their children, which they attributed largely to genetic factors. These sibling differences meant that although feeding goals might be common, the pathways to the goals varied depending on each child's appetitive characteristics. The overall pattern was one of flexible responsiveness to each child. In contrast to perceptions of their own children's eating behaviours, feeding difficulties in other families were usually attributed to lack of parental control. CONCLUSIONS: The feeding relationship is complex and interactive, resulting in parents modulating their feeding strategies to match each child's eating behaviour. Guidance to parents on healthy feeding needs to acknowledge the nuanced and interactive nature of feeding practices. PMID- 20717132 TI - Estimate of total salt intake in two regions of Belgium through analysis of sodium in 24-h urine samples. AB - OBJECTIVES: To evaluate total salt intake in the adult population through an analysis of sodium in 24-h urine samples in two regions of Belgium. METHODS: Urine samples were collected over 24 h from participants and they had to complete a specific questionnaire about salt intake afterwards. Sodium and creatinine concentrations were analysed in these samples. SUBJECTS: The target population comprised adults aged 45-65 years in the region of Ghent and Liege. A total of 123 and 157 volunteers from Ghent and Liege, respectively, were included in the study. RESULTS: The mean creatinine level in Flanders (n=114) amounted to 0.173+/ 0.035 mmol/kg/day, whereas in the Walloon region (n=135) it amounted to 0.161+/ 0.036 mmol/kg/day, after the exclusion of subjects with incomplete urine collection. Intake of sodium in Flanders (n=114) was 4.29+/-1.29 g/day, whereas in the Walloon region (n=135) it was 3.94+/-1.44 g/day. In both regions, sodium intake in men was higher than in women. CONCLUSION: Salt intake was more or less twice as high as the recommended intake. Salt intake as estimated from 24-h urine collections is substantially higher than that previously calculated on the basis of food consumption data. A salt reduction programme for Belgium is primordial. PMID- 20717133 TI - Trends in adherence to the Mediterranean diet in an Italian population between 1991 and 2006. AB - BACKGROUND/OBJECTIVES: The aim of this study is to investigate whether adherence to the Mediterranean diet changed during the period 1991-2006 in an Italian population. SUBJECTS/METHODS: We derived data from the comparison groups of a network of case-control studies on cancer and acute myocardial infarction conducted in the greater Milan area between 1991 and 2006. Subjects were 3247 adults (1969 women, 1278 men; median age 59 years) admitted to major teaching and general hospitals for a wide spectrum of acute conditions unrelated to long-term modifications of diet. Trained interviewers collected data on selected socioeconomic and demographic characteristics, lifestyle habits and other personal and familial factors. Information on diet was collected through an interviewer-administered, reproducible and validated food-frequency questionnaire. We computed a Mediterranean diet score (MDS) on the basis of nine a priori defined peculiar characteristics of the Mediterranean dietary pattern. RESULTS: In multiple linear regression models, adjusted for age, education, place of birth and residence, and total energy intake, there was no significant association between the period of interview and MDS in both sexes. Subjects aged 55-64 years, those with high education, and those born in central and southern Italy showed the highest adherence to the Mediterranean diet in both sexes. CONCLUSIONS: In this population, adherence to the Mediterranean diet showed no significant change over the last 15 years. PMID- 20717134 TI - An inverse association between serum leptin concentration and reported alcohol intake in patients with manifest vascular disease. AB - BACKGROUND/OBJECTIVES: It has been reported that alcohol stimulates appetite. We aimed to establish the association between leptin, as a major food intake regulating factor, and alcohol intake in patients with chronic manifest coronary artery or cerebrovascular disease. SUBJECTS/METHODS: A cross-sectional study of 820 subjects after acute coronary syndrome, coronary revascularization or after first ischemic stroke (the Czech part of EUROASPIRE III surveys). Leptin concentrations were evaluated among predefined categories of reported weekly alcohol intake: abstainers, light drinkers (up to 2 drinks weekly, 1-44 g of pure alcohol), mild regular drinkers (3-14 drinks weekly, 45-308 g) and moderate or heavy drinkers (more than 15 drinks, >= 309 g of alcohol). RESULTS: Leptin showed a clear negative trend among the alcohol intake categories. Mild regular drinkers showed significantly lower leptin levels (9.3(8.2) ng/ml) compared with abstainers (18.7(18.7) ng/ml, P<0.0001) and light occasional drinkers (14.2(17.8) ng/ml, P=0.00064). The negative association between leptin and alcohol intake as a dependent variable remained significant even after adjustment for potential confounders in multiple linear regression analysis (P=0.00032). CONCLUSIONS: Drinking of small amounts of alcohol was, in our setting, associated with decreased serum leptin concentration, with a possible benefit in terms of cardiovascular risk. PMID- 20717135 TI - Variation in umami taste perception in the German and Norwegian population. AB - In this study, we investigated inter-individual differences in sensitivity to mono-sodium glutamate (MSG) and elucidated the familiarity to umami taste in two European populations. The study consisted of two parts: (1) a survey based on questionnaire and (2) psychophysical screening for inter-individual variation of MSG sensitivity. The psychophysical tests revealed that 3.2% of the German participants and 4.6% of the Norwegian participants were potential non-tasters of MSG. In conclusion, our study confirms inter-individual differences in sensitivity to MSG in humans. PMID- 20717136 TI - Adherence to recommendations of the German food pyramid and risk of chronic diseases: results from the EPIC-Potsdam study. AB - BACKGROUND: The German food pyramid was set up to foster and communicate healthy food choices. METHODS: The adherence to recommendations of the food pyramid was translated into an index (German Food Pyramid Index (GFPI)) by scoring the ratio of consumed and recommended daily servings of eight food groups, wherein higher scores indicated greater adherence. The GFPI was calculated for 23 531 subjects who participated in the European Prospective Investigation into Cancer and Nutrition-Potsdam study and were recruited between 1994 and 1998. Associations between quintiles of GFPI scores and risk of incident cardiovascular diseases (CVD), type-2 diabetes (T2D) and cancer were evaluated using Cox proportional hazard regression models. During 183 740 person-years of follow-up, 363 incident cases of CVD (myocardial infarction or stroke), 837 incident cases of T2D and 844 incident cases of cancer occurred. RESULTS: The GFPI was inversely related to CVD risk in men (multivariable-adjusted hazard ratio (HR) for highest versus lowest quintiles=0.56; 95% confidence interval (CI): 0.34-0.94) but not in women (HR=1.39; 95% CI: 0.76-2.55). No association between GFPI and cancer was observed. An inverse relation between GFPI and T2D (men: HR= 0.71 (0.52-0.97); women: HR= 0.69 (0.50-0.96)) in age-adjusted models was substantially attenuated after multivariable adjustments, particularly by body mass index (BMI) (men: HR=0.94 (0.69-1.30); women: HR=1.09 (0.77-1.54)). The same was observed for overall major chronic disease risk (CVD, T2D and total cancer). CONCLUSION: Adherence to the German food pyramid recommendations is not associated with a decreased risk of chronic diseases when considering BMI as confounder, except of CVD in men. PMID- 20717137 TI - Focus on the spatial organization of signalling. PMID- 20717138 TI - Spatial organization of transmembrane receptor signalling. AB - The spatial organization of transmembrane receptors is a critical step in signal transduction and receptor trafficking in cells. Transmembrane receptors engage in lateral homotypic and heterotypic cis-interactions as well as intercellular trans interactions that result in the formation of signalling foci for the initiation of different signalling networks. Several aspects of ligand-induced receptor clustering and association with signalling proteins are also influenced by the lipid composition of membranes. Thus, lipid microdomains have a function in tuning the activity of many transmembrane receptors by positively or negatively affecting receptor clustering and signal transduction. We review the current knowledge about the functions of clustering of transmembrane receptors and lipid protein interactions important for the spatial organization of signalling at the membrane. PMID- 20717139 TI - Spatial cycles in G-protein crowd control. AB - The nature of living systems and their apparent resilience to the second law of thermodynamics has been the subject of extensive investigation and imaginative speculation. The segregation and compartmentalization of proteins is one manifestation of this departure from equilibrium conditions; the effect of which is now beginning to be elucidated. This should not come as a surprise, as even a cursory inspection of cellular processes reveals the large amount of energetic cost borne to maintain cell-scale patterns, separations and gradients of molecules. The G-proteins, kinases, calcium-responsive proteins have all been shown to contain reaction cycles that are inherently coupled to their signalling activities. G-proteins represent an important and diverse toolset used by cells to generate cellular asymmetries. Many small G-proteins in particular, are dynamically acylated to modify their membrane affinities, or localized in an activity-dependent manner, thus manipulating the mobility modes of these proteins beyond pure diffusion and leading to finely tuned steady state partitioning into cellular membranes. The rates of exchange of small G-proteins over various compartments, as well as their steady state distributions enrich and diversify the landscape of possibilities that GTPase-dependent signalling networks can display over cellular dimensions. The chemical manipulation of spatial cycles represents a new approach for the modulation of cellular signalling with potential therapeutic benefits. PMID- 20717140 TI - The march of the PINs: developmental plasticity by dynamic polar targeting in plant cells. AB - Development of plants and their adaptive capacity towards ever-changing environmental conditions largely depend on the spatial distribution of the plant hormone auxin. At the cellular level, various internal and external signals are translated into specific changes in the polar, subcellular localization of auxin transporters from the PIN family thereby directing and redirecting the intercellular fluxes of auxin. The current model of polar targeting of PIN proteins towards different plasma membrane domains encompasses apolar secretion of newly synthesized PINs followed by endocytosis and recycling back to the plasma membrane in a polarized manner. In this review, we follow the subcellular march of the PINs and highlight the cellular and molecular mechanisms behind polar foraging and subcellular trafficking pathways. Also, the entry points for different signals and regulations including by auxin itself will be discussed within the context of morphological and developmental consequences of polar targeting and subcellular trafficking. PMID- 20717141 TI - An intimate liaison: spatial organization of the endoplasmic reticulum mitochondria relationship. AB - Organelle localization is often crucial to properly modulate cellular functions and signalling cascades. For example, the distribution of organelles in axons is crucial for their function and is dysregulated in several diseases. Similarly, relative positioning of two or more organelles is also important to perform certain specialized processes. Perhaps, the best-known form of interorganellar organization is that between endoplasmic reticulum (ER) and mitochondria. Close communication between these two compartments has been observed for a long time. Recent evidence suggests that this is the basis for a bidirectional communication regulating a number of physiological processes ranging from mitochondrial energy and lipid metabolism to Ca(2+) signalling and cell death. The recent discovery of some of the molecular mediators of the tethering already allowed to extend the function of this paradigmatic spatial organization to previously unexpected functions, and will foster future research to explore it in cellular signalling cascades as well as in disease. PMID- 20717142 TI - Spatial organization in bacterial chemotaxis. AB - Spatial organization of signalling is not an exclusive property of eukaryotic cells. Despite the fact that bacterial signalling pathways are generally simpler than those in eukaryotes, there are several well-documented examples of higher order intracellular signalling structures in bacteria. One of the most prominent and best-characterized structures is formed by proteins that control bacterial chemotaxis. Signals in chemotaxis are processed by ordered arrays, or clusters, of receptors and associated proteins, which amplify and integrate chemotactic stimuli in a highly cooperative manner. Receptor clusters further serve to scaffold protein interactions, enhancing the efficiency and specificity of the pathway reactions and preventing the formation of signalling gradients through the cell body. Moreover, clustering can also ensure spatial separation of multiple chemotaxis systems in one bacterium. Assembly of receptor clusters appears to be a stochastic process, but bacteria evolved mechanisms to ensure optimal cluster distribution along the cell body for partitioning to daughter cells at division. PMID- 20717143 TI - Cellular responses to extracellular guidance cues. AB - Extracellular guidance cues have a key role in orchestrating cell behaviour. They can take many forms, including soluble and cell-bound ligands (proteins, lipids, peptides or small molecules) and insoluble matrix substrates, but to act as guidance cues, they must be presented to the cell in a spatially restricted manner. Cells that recognize such cues respond by activating intracellular signal transduction pathways in a spatially restricted manner and convert the extracellular information into intracellular polarity. Although extracellular cues influence a broad range of cell polarity decisions, such as mitotic spindle orientation during asymmetric cell division, or the establishment of apical-basal polarity in epithelia, this review will focus specifically on guidance cues that promote cell migration (chemotaxis), or localized cell shape changes (chemotropism). PMID- 20717144 TI - Protein homeostasis and synaptic plasticity. AB - It is clear that de novo protein synthesis has an important function in synaptic transmission and plasticity. A substantial amount of work has shown that mRNA translation in the hippocampus is spatially controlled and that dendritic protein synthesis is required for different forms of long-term synaptic plasticity. More recently, several studies have highlighted a function for protein degradation by the ubiquitin proteasome system in synaptic plasticity. These observations suggest that changes in synaptic transmission involve extensive regulation of the synaptic proteome. Here, we review experimental data supporting the idea that protein homeostasis is a regulatory motif for synaptic plasticity. PMID- 20717146 TI - Neurons don't appreciate FUSsing in the cytoplasm. PMID- 20717148 TI - Stem cells: holding on to the memories. PMID- 20717145 TI - Spatial organization of adhesion: force-dependent regulation and function in tissue morphogenesis. AB - Integrin- and cadherin-mediated adhesion is central for cell and tissue morphogenesis, allowing cells and tissues to change shape without loosing integrity. Studies predominantly in cell culture showed that mechanosensation through adhesion structures is achieved by force-mediated modulation of their molecular composition. The specific molecular composition of adhesion sites in turn determines their signalling activity and dynamic reorganization. Here, we will review how adhesion sites respond to mecanical stimuli, and how spatially and temporally regulated signalling from different adhesion sites controls cell migration and tissue morphogenesis. PMID- 20717149 TI - Post-translational modification: NRMT organizes methyl transfer. PMID- 20717147 TI - Molecular mechanisms of organelle inheritance: lessons from peroxisomes in yeast. AB - Preserving a functional set of cytoplasmic organelles in a eukaryotic cell requires a process of accurate organelle inheritance at cell division. Studies of peroxisome inheritance in yeast have revealed that polarized transport of a subset of peroxisomes to the emergent daughter cell is balanced by retention mechanisms operating in both mother cell and bud to achieve an equitable distribution of peroxisomes between them. It is becoming apparent that some common mechanistic principles apply to the inheritance of all organelles, but at the same time, inheritance factors specific for each organelle type allow the cell to differentially and specifically control the inheritance of its different organelle populations. PMID- 20717150 TI - Cell migration: ESCRTing integrin degradation. PMID- 20717151 TI - Stem cells: Holding onto the memories. PMID- 20717152 TI - Evolution: Gene duplicate holds back its sister. PMID- 20717153 TI - Small RNAs: A novel class. PMID- 20717154 TI - Genome editing with engineered zinc finger nucleases. AB - Reverse genetics in model organisms such as Drosophila melanogaster, Arabidopsis thaliana, zebrafish and rats, efficient genome engineering in human embryonic stem and induced pluripotent stem cells, targeted integration in crop plants, and HIV resistance in immune cells - this broad range of outcomes has resulted from the application of the same core technology: targeted genome cleavage by engineered, sequence-specific zinc finger nucleases followed by gene modification during subsequent repair. Such 'genome editing' is now established in human cells and a number of model organisms, thus opening the door to a range of new experimental and therapeutic possibilities. PMID- 20717155 TI - Computational solutions to large-scale data management and analysis. AB - Today we can generate hundreds of gigabases of DNA and RNA sequencing data in a week for less than US$5,000. The astonishing rate of data generation by these low cost, high-throughput technologies in genomics is being matched by that of other technologies, such as real-time imaging and mass spectrometry-based flow cytometry. Success in the life sciences will depend on our ability to properly interpret the large-scale, high-dimensional data sets that are generated by these technologies, which in turn requires us to adopt advances in informatics. Here we discuss how we can master the different types of computational environments that exist - such as cloud and heterogeneous computing - to successfully tackle our big data problems. PMID- 20717156 TI - The ethics of using transgenic non-human primates to study what makes us human. AB - A flood of comparative genomic data is resulting in the identification of human lineage-specific (HLS) sequences. As apes are our closest evolutionary relatives, transgenic introduction of HLS sequences into these species has the greatest potential to produce 'humanized' phenotypes and also to illuminate the functions of these sequences. We argue that such transgenic apes would also be more likely than other species to experience harm from such research, which renders such studies ethically unacceptable in apes and justifies regulatory barriers between these species and other non-human primates for HLS transgenic research. PMID- 20717158 TI - Density-regulated population dynamics and conditional dispersal alter the fate of mutations occurring at the front of an expanding population. AB - There is an increasing recognition that the interplay between ecological and evolutionary processes shapes the genetic footprint of populations during and after range expansions. However, more complex ecological processes regularly considered within spatial ecology remain unexplored in models describing the population genetics of range expansion. In this study we integrate flexible descriptions of population growth and competition as well as conditional dispersal into a model that simulates the fate of mutations occurring at the wave front of an expanding population. Our results show that the survival and distribution of a mutation is not only affected by its bias (that is, whether it is deleterious, neutral or beneficial) but also by the mode of local density regulation and conditional dispersal of the simulated populations. It is in particular the chance of a mutation to establish at the front of advance and 'surf' to high frequencies that critically depends on the investigated ecological processes. This is because of the influence of these processes on demographic stochasticity in the system and the differential responses of deleterious, neutral and beneficial mutations to this stochasticity. Generally, deleterious mutations rely more on chance and thus profit the most from ecological processes that enhance demographic stochasticity during the period of establishment. Our study emphasizes the importance of incorporating more ecological realism into evolutionary models to better understand the consequences of shifting geographic ranges for the genetic structure of populations and to find efficient adaptation strategies to mitigate these effects. PMID- 20717157 TI - Genetic panmixia and demographic dependence across the North Atlantic in the deep sea fish, blue hake (Antimora rostrata). AB - The efficient investment of resources and effort into conservation strategies depends on the accurate identification of management units. At the same time, understanding the processes by which population structure evolves requires an understanding of the conditions under which panmixia may exist. Here, we study a species with an unusual, apparently sex-biased pattern of distribution, and test the hypothesis that distribution processes associated with this pattern (for example, congregating at a single dominant spawning site or periodic mixing during reproduction) could lead to panmixia over a large geographic range. Using 13 microsatellite markers, we compared 393 blue hake (Antimora rostrata) from 11 sample sites across a geographic range of over 3000 km, and found no evidence of population structure. We estimated current effective population size and found it to be large (~15,000) across the sampled area. In addition, we used simulation models to test expectations about demographic correlation among populations and our ability to detect relevant levels of gene flow. All data were consistent with the interpretation of long-range panmixia. PMID- 20717159 TI - Stripes, sex and sparrows: what processes underlie heteromorphic chromosome evolution? PMID- 20717160 TI - Variability and loss of functionless traits in cave animals. Reply to Jeffery (2010). PMID- 20717161 TI - Cohort-structured tree populations. PMID- 20717162 TI - The narrow endemic Norwegian peat moss Sphagnum troendelagicum originated before the last glacial maximum. AB - It is commonly found that individual hybrid, polyploid species originate recurrently and that many polyploid species originated relatively recently. It has been previously hypothesized that the extremely rare allopolyploid peat moss Sphagnum troendelagicum has originated multiple times, possibly after the last glacial maximum in Scandinavia. This conclusion was based on low linkage disequilibrium in anonymous genetic markers within natural populations, in which sexual reproduction has never been observed. Here we employ microsatellite markers and chloroplast DNA (cpDNA)-encoded trnG sequence data to test hypotheses concerning the origin and evolution of this species. We find that S. tenellum is the maternal progenitor and S. balticum is the paternal progenitor of S. troendelagicum. Using various Bayesian approaches, we estimate that S. troendelagicum originated before the Holocene but not before c. 80,000 years ago (median expected time since speciation 40 000 years before present). The observed lack of complete linkage disequilibrium in the genome of this species suggests cryptic sexual reproduction and recombination. Several lines of evidence suggest multiple origins for S. troendelagicum, but a single origin is supported by approximate Bayesian computation analyses. We hypothesize that S. troendelagicum originated in a peat-dominated refugium before last glacial maximum, and subsequently immigrated to central Norway by means of spore flow during the last thousands of years. PMID- 20717163 TI - Alternative splice variants of the USH3A gene Clarin 1 (CLRN1). AB - Clarin 1 (CLRN1) is a four-transmembrane protein expressed in cochlear hair cells and neural retina, and when mutated it causes Usher syndrome type 3 (USH3). The main human splice variant of CLRN1 is composed of three exons that code for a 232 aa protein. In this study, we aimed to refine the structure of CLRN1 by an examination of transcript splice variants and promoter regions. Analysis of human retinal cDNA revealed 11 CLRN1 splice variants, of which 5 have not been previously reported. We studied the regulation of gene expression by several promoter domains using a luciferase assay, and identified 1000 nt upstream of the translation start site of the primary CLRN1 splice variant as the principal promoter region. Our results suggest that the CLRN1 gene is significantly more complex than previously described. The complexity of the CLRN1 gene and the identification of multiple splice variants may partially explain why mutations in CLRN1 result in substantial variation in clinical phenotype. PMID- 20717164 TI - Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database. AB - The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n=18) or to cause erroneous splicing (n=7), with the exception of a pathogenic de novo 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database. PMID- 20717165 TI - Type II familial synpolydactyly: report on two families with an emphasis on variations of expression. AB - Type II familial synpolydactyly is rare and is known to have variable expression. However, no previous papers have attempted to review these variations. The aim of this paper was to review these variations and show several of these variable expressions in two families. The classic features of type II familial synpolydactyly are bilateral synpolydactyly of the third web spaces of the hands and bilateral synpolydactyly of the fourth web spaces of the feet. Several members of the two families reported in this paper showed the following variations: the third web spaces of the hands showing syndactyly without the polydactyly, normal feet, concurrent polydactyly of the little finger, concurrent clinodactyly of the little finger and the 'homozygous' phenotype. It was concluded that variable expressions of type II familial synpolydactyly are common and awareness of such variations is important to clinicians. PMID- 20717166 TI - Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein Taybi syndrome detected by aCGH. AB - We demonstrate the utility of an exon coverage microarray platform in detecting intragenic deletions: one in exons 24-27 of the EP300 gene and another in exons 27 and 28 of the CREBBP gene in two patients with Rubinstein-Taybi syndrome (RSTS). RSTS is a heterogeneous disorder in which approximately 45-55% of cases result from deletion or mutations in the CREBBP gene and an unknown portion of cases result from gene changes in EP300. The first case is a 3-year-old female with an exonic deletion of the EP300 gene who has classic facial features of RSTS without the thumb and great toe anomalies, consistent with the milder skeletal phenotype that has been described in other RSTS cases with EP300 mutations. In addition, the mother of this patient also had preeclampsia during pregnancy, which has been infrequently reported. The second case is a newborn male who has the classical features of RSTS. Our results illustrate that exon-targeted array comparative genomic hybridization (aCGH) is a powerful tool for detecting clinically significant intragenic rearrangements that would be otherwise missed by aCGH platforms lacking sufficient exonic coverage or sequencing of the gene of interest. PMID- 20717167 TI - FGF21 signalling pathway and metabolic traits - genetic association analysis. AB - Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB) facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry. PMID- 20717168 TI - Cervix smear abnormalities: linking pathology data in female twins, their mothers and sisters. AB - Mass screening for cervical cancer precursors has decreased the incidence of cervical cancer in several countries, including the Netherlands. Persistent infections of certain types of human papillomavirus are strongly associated with the development of cervical cancer. A number of factors may affect the liability to infection and subsequent progression to cervical intraepithelial neoplasia and cancer. This paper examines whether genetic factors are involved in explaining individual differences in liability. Data of 3178 women registered with the Netherlands Twin Register were successfully linked to the nationwide Dutch Pathology database that contains all results of mass screening for cervical cancer. The data from mono- and dizygotic twins and their female relatives were used to disentangle the influence of heritable and environmental factors on cervix smear abnormalities. Results showed that differences in cervix smear results clustered within families and resemblance was stronger in monozygotic twins (correlation 0.37, 95% confidence interval: 0.12-0.58) compared with other first-degree relatives (correlation 0.14, 95% confidence interval: -0.01-0.29). The familial clustering for an abnormal cervix smear is due to shared genetic factors that explain 37% of the variance in liability. The largest proportion of the variation in cervical smear abnormalities is due to unique environmental factors. PMID- 20717169 TI - FTO genotype and adiposity in children: physical activity levels influence the effect of the risk genotype in adolescent males. AB - Studies of the fat mass and obesity-associated (FTO) gene provide compelling evidence of genetic variation in the general population that influences fat levels and obesity risk. Studies of the interaction between genetic and environmental factors such as physical activity (PA) will promote the understanding of how lifestyle can modulate genetic contributions to obesity. In this study, we investigated the effect of FTO genotype, and interactions with PA or energy intake, in young children and adolescents. In all, 1-5-year-old children from the Growth, Exercise and Nutrition Epidemiological Study in preSchoolers (GENESIS) study (N=1980) and 11-18-year-old Greek adolescents (N=949) were measured for adiposity-related phenotypes and genotyped at the FTO single-nucleotide polymorphism (SNP) marker, rs17817449. Adolescents were classified as physically active or inactive based on self-reported levels of PA. In adolescents, FTO genotype influenced weight (P=0.001) and BMI (P=0.007). There was also a significant SNP(*)PA(*)gender interaction (P=0.028) on BMI, which reflected the association between FTO genotype and BMI in males (P=0.016), but not females (P=0.15), and significant SNP(*)PA interaction in males (P=0.007), but not females (P=0.74). The FTO genotype effect was more pronounced in inactive than active males. Inactive males homozygous for the G allele had a mean BMI 3 kg/m(2) higher than T carriers (P=0.008). In the GENESIS study, no significant association between FTO genotype and adiposity was found. The present findings highlight PA as an important factor modifying the effect of FTO genotype. PMID- 20717170 TI - p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. AB - Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, 26 patients (5 having CF, 10 CBAVD (congenital bilateral absence of the vas deferens) and 11 with CF-like symptoms) and 14 healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from >2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution, give several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD. PMID- 20717171 TI - Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3. AB - Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease. PMID- 20717172 TI - The Cartwright legacy: shifting the focus of attention from the doctor to the patient. PMID- 20717173 TI - The missing manuscript. PMID- 20717174 TI - A response to criticisms of The History of the 'Unfortunate Experiment' at National Women's Hospital. PMID- 20717175 TI - Acute coronary syndromes in New Zealand hospitals. PMID- 20717179 TI - Audit of cervical screening in women with HIV infection in the Auckland and Northland regions of New Zealand. AB - AIM: We aimed to review our current cohort of women with HIV infection to document the number of women who had received a yearly cervical smear since their diagnosis of HIV infection and the number of women who were likely to have had undiagnosed HIV infection at the time of their first abnormal cervical smear. METHOD: This audit was a retrospective review of the cervical smear history of all adult women (> or =16 years) with HIV infection who were under active follow up by the Infectious Diseases and Sexual Health Services at Auckland City Hospital on 31 December 2007. RESULTS: Sixty-nine of the 123 (56%) women in this audit met the definition for yearly cervical smears. The factor associated with not receiving yearly cervical smears was women who had received cervical smears from their general practitioner (GP). Taking into account the women's CD4 count at the time of the diagnosis of their HIV infection, it is very likely that seven women had undiagnosed HIV infection at the time of their first abnormal cervical smear. CONCLUSION: The proportion of women with HIV infection in the Auckland and Northland regions who received a yearly cervical smear during the audit period was low. We have put a number of interventions in place that we expect will improve this rate. These interventions include informing GPs of the need for yearly cervical smears for women with HIV infection, informing the National Cervical Screening Unit that these women are immunocompromised which will result in a yearly recall comment and informing these women of options for obtaining a cervical smear at little or no cost. Cervical smear takers should consider offering an HIV test to all women with an abnormal cervical smear who have resided in areas with high rates of HIV infection. PMID- 20717178 TI - A programme of Enhanced Recovery After Surgery (ERAS) is a cost-effective intervention in elective colonic surgery. AB - AIM: There are few published ERAS cost-analyses in colorectal surgery. The aim of this paper is to evaluate whether costs saved by reduced postoperative resource utilisation would offset the financial burden of setting up and maintaining such an ERAS programme. METHODS: A cost-effectiveness analysis from a healthcare provider perspective using a case-control model. The study group consisted of patients enrolled in the ERAS program for elective colonic surgery at Manukau Surgical Centre between December 2005 and March 2007. The control group consisted of consecutive patients from September 2004 to September 2005 (before the start of ERAS). Groups were matched with respect to operation, BMI, ASA, and Cr-POSSUM score. RESULTS: Data were available for 50 patients in each group. There was a significant reduction in total hospital stay, intravenous fluid use, and duration of epidural use in the ERAS group. There were significantly fewer complications in the ERAS group. Implementation of ERAS cost approximately $NZ102,000, but this has been more than offset by costs saved in reduced postoperative resource utilisation, with an overall cost-saving of approximately NZ$6900 per patient. CONCLUSION: Implementing an ERAS program is cost-effective in the medium term, with costs offset by those recovered by reduced resource utilisation in the postoperative period. PMID- 20717176 TI - Patients admitted with an acute coronary syndrome (ACS) in New Zealand in 2007: results of a second comprehensive nationwide audit and a comparison with the first audit from 2002. AB - AIMS: To audit all patients admitted to a New Zealand (NZ) Hospital with an acute coronary syndrome (ACS) over a 14-day period, to assess their number, presentation type and patient management during the hospital admission and at discharge. To compare patient management in 2007 with the 1st NZ Cardiac Society ACS Audit from 2002. METHODS: We updated the established NZ ACS Audit group of 36 hospitals to 39 hospitals now admitting ACS patients across New Zealand. A comprehensive data form was used to record individual patient information for all patients admitted between 00.00 hours on 14 May 2007 to 24.00 hours on 27 May 2007. RESULTS: 1003 patients, 9% more than in 2002 (n=930), were admitted with a suspected or definite ACS: 8% with a ST-segment-elevation myocardial infarction (STEMI), 41% with a non-STEMI (NSTEMI), 33% with unstable angina pectoris (UAP), and 17% with another cardiac or medical condition. In 2007 non-invasive risk stratification following presentation remained similar to 2002 and was suboptimal: exercise treadmill tests (21% vs 20%, p=0.62), echocardiograms (19% vs 20%, p=0.85). An increase in utilisation of coronary angiography was noted (32% vs 21%, p<0.0001). In hospital revascularisation rates remained low in patients with diagnosed ACS (n=828): STEMI (45%), NSTEMI (23%) and UAP (7.3%). In comparison to 2002, changes were noted in revascularisation techniques with percutaneous coronary intervention (PCI) performed in 19% vs 7% (p<0.0001). The use of coronary artery bypass grafting (CABG) remained extremely low: 2.8% vs 3.5% (p=0.20). The use of hospital and discharge medication of proven benefit was also limited. CONCLUSIONS: A collaborative group of clinicians and nurses has performed a second nationwide audit of ACS patients. Despite a small increase in access to cardiac angiography, guideline recommended risk stratification following the index suspected ACS admission with a treadmill test or cardiac angiogram occurred in only 1 in 2 (48%) patients. Furthermore, in patients with a definite ACS, levels of revascularisation are low. (PCI 19%, CABG 2.8%). These aspects of care remain of significant concern and have not substantially changed in 5 years. There remains an urgent need to develop a comprehensive national strategy to improve all aspects of ACS patient management. PMID- 20717180 TI - Homozygous familial hypercholesterolaemia and treatment by LDL apheresis. PMID- 20717177 TI - ACS patients in New Zealand experience significant delays to access cardiac investigations and revascularisation treatment especially when admitted to non interventional centres: results of the second comprehensive national audit of ACS patients. AB - AIM: To compare the management of acute coronary syndrome (ACS) patients presenting to interventional versus non-interventional New Zealand hospitals, with emphasis, on access delays for invasive assessment and revascularisation treatments. METHODS: Using data collected by the New Zealand Cardiac Society ACS Audit Group over 14 days from each hospital in New Zealand (n=39) that admits ACS patients, patient management at intervention centres (6 public, 3 private) was compared with non-intervention centres (30 public). Investigations and revascularisation procedures performed on transferred patients were attributed to the referring centre. RESULTS: From 00.00 hours on 14 May 2007 to 24.00 hours on 27 May 2007, 1003 patients were admitted to a New Zealand hospital with a suspected or definite ACS: ST-segment-elevation myocardial infarction [STEMI] (8%), non-STEMI [NSTEMI] (41%), unstable angina pectoris [UAP] 33%, or another cardiac or medical diagnosis (17%). Patients admitted to a non-intervention centre (n=556) were older (median age 70 vs 66 years, p=0.0097), with similar risk factors, and were more likely to be of Maori (12% vs 5.8%, p<0.0001), and less likely to be of Indian (1.3% vs 4.5%, p=0.0026) or Pacific Island (2.0% vs 4.9%, p=0.012) ethnicity. Patients admitted to a non-intervention centre were less likely to have a chest X-ray performed (84% vs 93 %, p<0.0001), but, as likely to have an echocardiogram, exercise test, or cardiac angiogram for cardiac risk assessment as patients admitted to an intervention centre (n=447). However, only 1 in 2 patients overall underwent either treadmill testing or angiography, and only 1 in 3 underwent angiography. Time delays to access cardiac angiography were evident with only 23% of all patients receiving this test within 48 hours of hospital admission. Patients at non-intervention centres had a significantly longer median wait for cardiac angiography than those admitted to an intervention centre (5.1 vs 2.5 days, p<0.0001). CONCLUSIONS: Patients admitted to a New Zealand hospital with an acute coronary syndrome experience delays in accessing investigations and subsequent revascularisation. Furthermore, inequity exists with delays being significantly longer for patients admitted to a non intervention centre. A comprehensive national strategy is needed to improve access to optimal cardiac care. PMID- 20717181 TI - Angiomatosis: a case report. PMID- 20717183 TI - Medical image. Refractory ascites due to ascites praecox. PMID- 20717182 TI - A case of intestinal-type gastric adenocarcinoma metastatic to a caecal tubulovillous polyp. PMID- 20717184 TI - Equipment of Yore: a contribution from the Cotter Medical History Trust. PMID- 20717185 TI - The 1987 National Women's Hospital (NWH) 'Unfortunate Experiment'. Accusations of unethical experiments and undertreatment, resulting in excess deaths from cervical cancer. Facts and fables. PMID- 20717186 TI - Why did so many women develop cancer? Part 2. PMID- 20717187 TI - Why won't defenders of the Cartwright Inquiry provide evidence to justify their use of the term 'conventional treatment' for carcinoma in situ? PMID- 20717189 TI - A particular relationship. PMID- 20717188 TI - A response to Ron Jones' letter of 30 April 2010. PMID- 20717190 TI - Discussion of Morris and Jewell's editorial 'Array of hope for high-resolution genetic screening services in New Zealand'. PMID- 20717192 TI - Patents. AB - 4,938,556; 4,674,830; 4,941,147; 4,991,917; 4,993,039; 4,993,040; 4,995,699; 4,995,720; 4,996,692; 4,997,282; 5,002,349; 5,002,352; 5,002,353. PMID- 20717191 TI - Managing your student loan. PMID- 20717193 TI - Nasa patter. PMID- 20717194 TI - Measurement of the coherence length of a laser using a holographically generated phase-conjugated wave front. AB - A simple and quick method is reported for measurement of the coherence length of a laser by using a holographically generated phase-conjugated wave front employing realtime recording material. PMID- 20717195 TI - Encircled energy of laser-diode beams. AB - The included energy of circular pupils illuminated by single-spatial-mode, laser diode beams is evaluated. Numerical results are presented and compared with measurements. PMID- 20717196 TI - Binary arithmetic using optical symbolic substitution and integrated phototransistor surface-emitting laser logic. AB - We outline an architecture for performing binary addition by using optical symbolic substitution and optical logic gates based on heterojunctionphototransistors and verticalcavity surface-emitting lasers. PMID- 20717197 TI - Irradiance invariance for scattering according to a Rayleigh phase function compared to a Rayleigh phase matrix for a plane-parallel medium: erratum. AB - The author would like to draw attention to an error in the conclusion in a 1990 paper. PMID- 20717198 TI - Group-delay diagnostic for measuring vapor column density. AB - We describe a technique for determining Nfl by measuring the group-velocity delay of a probe laser beam propagating through a vapor. This diagnostic has wide dynamic range, is simple to implement, and can be used as a high-bandwidth vapor rate monitor. In addition, it can be used to measure column density, Nl, number density, N, oscillator strengths, f, or absorption cross sections, collisional line broadening, and vapor group-velocity delay. PMID- 20717199 TI - Two-mirror wave-front-dividing interferometer for infrared synchrotron radiation. AB - We describe what is to our knowledge the first instrument specifically designed for use with infrared synchrotron radiation that takes advantage of the spatial coherence of this radiation. Beam splitting is achieved by wave-front division. We show data taken with the instrument over the wavelength region from 10 to 1000 microm (1-mm wavelengths) and discuss the advantages of this instrument over a conventional one. PMID- 20717200 TI - Unstable resonator alignment study using off-axis injection. AB - A brief qualitative experiment and subsequent theoretical study provide new insight concerning off-axis injection of unstable resonators. Theoretical results for aligned resonators show that the regurgitated beam intensity distribution and direction of travel are sensitive to the size, tilt, and other parameters of the injected beam, to the coherence length and number of longitudinal modes of the injecting laser, to clipping and diffraction from apertures, and to resonator length tuning. It is concluded that visual observations of output asymmetries can be used to align the resonator to some degree, but precise alignment using measurement of output asymmetries by a detector array is questionable. PMID- 20717201 TI - Determination of the optical functions of transparent glasses by using spectroscopic ellipsometry. AB - Two-channel spectroscopic polarization-modulation ellipsometry measurements have been made on four different glasses (fused SiO(2), finely annealed BK-7, a lead indium-phosphate glass, and a germanium-arsenic-selenium glass). We show that this technique is sensitive to thin surface layers and that these surface layers can be modeled by using the Bruggeman effective-medium theory with 50% glass and 50% voids. By correcting the experimental spectra for this surface layer, we determined the refractive index of the sample within an error of +/-0.002 in the transparent region. For wavelength regions where the material is normally opaque, the ellipsometric data can be corrected for this overlayer, thereby increasing the accuracy of the determination of both the refractive index and the extinction coefficient. PMID- 20717202 TI - Novel dichroic beam separator for frequency-doubled lasers. AB - A novel glass rhomb has been demonstrated for separating the residual fundamental beam from the harmonic beam in a frequency-doubled or frequency-tripled laser. This device features simple fabrication, damage resistance of uncoated glass, essentially loss-free transmittance for the harmonic beam, high (> 95%) rejection of the fundamental, mechanical and thermal stability, and high optical quality. PMID- 20717203 TI - Two- and three-grating resonators for high-power pulsed CO(2) lasers. AB - Development of broadly tunable narrow-linewidth CO(2) lasers is critical to the continued development of tunable far-infrared Raman lasers and could also improve many other optical pumping experiments. Here we extend the use of multiple intracavity gratings, a widely used dye laser technique, to multiatmosphere continuously tunable CO(2) lasers. We analyze the angular dispersion, wavelength tuning performance, and grating size requirements for several different grating configurations. Experimentally, by double passing each of two gratings worked near grazing incidence in a three-mirror 10-atm laser resonator, we have produced approximately 200-mJ pulses with < 600-MHz linewidth, and our analysis shows that operation in a single longitudinal mode (SLM) should be possible at somewhat reduced output levels. The simpler experimental task of producing SLM operation in a two-grating CO(2) transversely excited atmospheric laser has also been accomplished. PMID- 20717204 TI - Measurement of stimulated emission cross section and fluorescence branching ratio for Nd(3+) in sodium-beta'' alumina. AB - Room-temperature measurements of laser emission cross sections of Nd(3+) ion in sodium-beta" alumina at 1.06 and 1.35 microm as well as the fluorescence branching ratios of (4)F(3/2) to (4)I(j) manifolds are reported. A theoretical calculation based on absolute absorption measurements when a modified Judd-Ofelt phenomenological intensity analysis was used is reported. The cross sections thus determined are sigma(1.06) = 3.1 +/- 0.3 x 10(-20) cm(2) and sigma(1.35) = 0.6 +/ 0.1 x 10(-20) cm(2), respectively. The emission cross section at 1.06 microm was also determined by small-signal-gain measurements and was found to be in good agreement with the above value. PMID- 20717205 TI - Alignment system for solid-surface extreme-ultraviolet laser targets. AB - A simple and new target-alignment scheme for short-wavelength lasers is presented in the context of the alignment requirements a nickel-like molybdenum extreme ultraviolet laser. The current optical design for the system is presented, along with data indicating alignment capabilities of at least 16 microm. PMID- 20717206 TI - Optical limiting in solutions of diphenyl polyenes. AB - The optical-limiting behavior of a series of trans-alpha, omega-diphenyl polyene compounds was observed in solutions of chloroform. The influence of planarity, the substitution of donor and acceptor groups, and the extent of pi-electron delocalization on the nonlinear thresholds of the diphenyl polyenes in an optical limiting geometry were examined. A saturation effect of optical-limiting nonlinear thresholds, consistent with the theoretical work, was observed at 10-11 pi-electron bonds. The temporal profiles of the transmitted laser pulses and the power dependence of the nonlinear thresholds as a function of spot size and wavelength were examined. These examinations led to the conclusion that the predominant nonlinear mechanism was quasi-steady-state self-focusing. Nonlinear thresholds an order of magnitude lower, and thus effective n(2) and X(3) values an order of magnitude higher, than the well-known self-focusing medium CS(2) were observed. Our studies demonstrate that this series of polyenes consists of efficient broadband nonresonant optical-limiting materials. PMID- 20717207 TI - Multiple Stokes wavelength generation in H(2), D(2), and CH(4) for lidar aerosol measurements. AB - We report experimental results of multiple Stokes generation of a frequency doubled Nd:YAG laser in H(2), D(2), and CH(4) in a focusing geometry. The energies at four Stokes orders were measured as functions of pump energy and gas pressure. The characteristics of the Stokes radiation generated in these gases are compared for optical production of multiple wavelengths. The competition between Raman components is analyzed in terms of cascade Raman scattering and four-wave mixing. The results indicate the possibility of using these generation processes for atmospheric aerosol measurements by means of multiwavelength lidar systems. Also this study distinguishes between the gases, as regards the tendency to produce several wavelengths (H(2), D(2)) versus the preference to produce mainly first Stokes radiation (CH(4)). PMID- 20717208 TI - Laser-induced plasma formation in Xe, Ar, N(2), and O(2) at the first four Nd:YAG harmonics. AB - Irradiance values have been measured for the onset of laser-induced plasma formation in Xe, Ar, N(2), and O(2) at pressures from 760 to 25 Torr at wavelengths of 1.064, 0.532, 0.355, and 0.266 microm. These values have been compared with the results of other workers who used similar experimental setups. There is agreement within a factor of 4 when irradiance values are compared and within a factor of 2 when ratios of irradiance values for different gasses are compared. Comparisons among workers who used widely different pulse lengths indicate that the onset of plasma formation is measured better by energy fluence than by irradiance. PMID- 20717209 TI - Transversely pumped 11-pass amplifier for femtosecond optical pulses. AB - An off-axis near-concentric interferometer is used for multiple passages through a small (2-mm-diameter) cylindrical volume of amplifying dye. The gain volume is pumped transversely by a copper-vapor laser, in a geometry designed for uniform pump. Pulse-to-pulse reproducibility better than 1% is obtained by operating with full saturation and using a solvent with a vanishing temperature-induced change in index of refraction (dn/dT = 0). PMID- 20717210 TI - Optical analog-to-digital conversion using acousto-optic theta modulation and table lookup. AB - As an extension of an existing electron-beam deflector, an optical analog-to digital conversion scheme is presented. As a fast theta modulator, we used a wide band acousto-optic deflector that performs a voltage-to-optical beam-deflection angle mapping. Using a GaP acousto-optic deflector, we experimentally demonstrate a proof-of-principle 6-bit analog-to-digital converter. PMID- 20717211 TI - Picosecond streak camera display of an intermodal coupling matrix at a multimode fiber splice. AB - We have developed a technique that permits direct visualization of the coupling matrix for all guided modes of a moderately multimode fiber optic at a splice or mode coupler. The matrix is formed by an array of spots at the output of a picosecond streak camera. The technique also permits unambiguous determination of the phase velocity and group velocity of the modes. PMID- 20717212 TI - Optimum placement of a fiber-optical amplifier in high-bit-rate direct-detection systems. AB - Six system configurations of an erbium-doped fiber amplifier are analyzed accurately. Amplifier placement in the middle of the transmission link is shown to be optimum. PMID- 20717213 TI - Selective mode injection and observation for few-mode fiber optics. AB - By etching the cladding along several millimeters of circular- or elliptical-core few-mode fiber optics, we gain access to the core and can inject extremely pure modes. The same etching technique allows one to measure the modal purity at the far end of the fiber. Modal purities of -26 dB have been obtained. We also demonstrate a holographic technique that allows all the light of each mode to be focused to an independent spot. PMID- 20717214 TI - Nondestructive two-dimensional refractive-index profiling of integrated-optical waveguides by an interferometric method. AB - We describe an interferometric method that uses an interference microscope that permits the determination of the complete two-dimensional refractive-index profile of integrated optical waveguides, provided that the form of the one dimensional depth profile is known. Results are reported for potassium-sodium ion exchanged channel waveguides and are shown to be in good agreement with theory. PMID- 20717215 TI - Corrugation gratings for fast integrated complementary metal-oxide semiconductor photodetectors: implementation and diffraction analyses. AB - We present simulation experiments to show the feasibility of using a corrugation grating structure at the silicon-silicon dioxide interface to reduce photon absorption depth and therefore to improve response times for shallow p-n junction photodiodes for use in the optical interconnection of very-large-scale-integrated circuits. A fabrication method that uses standard complementary metal-oxide semiconductor fabrication steps is presented for generating the grating structure. Simulations show reduction in 1/e photon-penetration depth to one half the value that is expected with no grating. PMID- 20717216 TI - Studies on the relation between the diffusion process and optical properties in Ti-diffused planar optical waveguides. AB - The kinetics of Ti diffusion into Y-cut LiNbO(3) was investigated. Scanning electron microscopy and Auger electron spectroscopy techniques were used to study the diffusion process, while end-fire and prism coupling of light at different wavelengths was used for optical characterization. A Gaussian profile was chosen as a solution to the diffusion equation, and the diffusion constant and the activation energy for this profile were found. By comparison of the result of optical measurements with numerical theoretical calculations, we obtained an empirical relation between the initial Ti thickness and the extraordinary refractive-index change. PMID- 20717217 TI - Effect of beam defocus on the efficiency of planar waveguide grating couplers. AB - Results of theoretical calculations and experimental measurements of variation of grating coupling efficiency with beam-defocus position are presented. Our results indicate that (1) coupling efficiency is not necessarily maximum at the beam waist, (2) coupling efficiency as a function of defocus position shows oscillatory behavior particularly for a tightly focused beam. The effect of beam size alone cannot account for the observed behavior of variation of coupling efficiency with defocus position. The results of measured angular dependence of coupling efficiency for various defocus conditions are also presented. PMID- 20717218 TI - Real-time determination of molecular orientation in Langmuir-Blodgett monolayers on integrated-optical structures. AB - Waveguide linear-dichroism measurements were used in determining the molecular orientation of N-(sulfopropyl)-4-(p-dioctylaminostyryl) pyridinium in Langmuir Blodgett monolayers upon 150-microm-thick glass (Ti:Zn) substrates in real time. Acquisition of complete spatial-decay curves in t - 1 s with P(laser) = 100 microW was made possible by combining propagation in integrated-optical structures with direct imaging of monolayer or glass fluorescence onto the active area of a charge-coupled device camera. Multichannel detection permitted measurement of optical waveguide loss coefficients and ultimately of molecular orientations in approximately 10(-3) of the amount of time required by previous methodology. The effects of sample preparation and materials processing on the accuracy and precision of dichroic ratios are discussed. Observed dichroic ratios for a hemicyanine dye revealed no measurable change in the orientation of the electronic transition-dipole moment when Langmuir-Blodgett films were deposited at different surface pressures. These results are in good agreement with the results from singly resonant second-harmonic generation experiments. PMID- 20717219 TI - Error bounds of a fast atmospheric correction algorithm for the Landsat thematic mapper and multispectral scanner bands. AB - Error bounds of ground reflectance were calculated for the Landsat thematic mapper and multispectral scanner bands by using a fast atmospheric correction algorithm now based on LOWTRAN 7. The algorithm neglects the scan angle dependence of the radiance received at the sensor and employs a linear relationship between planetary (Earth/atmosphere) reflectance and ground reflectance. The errors caused by these two approximations are small enough (<2%) that the algorithm can have many applications in remote sensing, so in these cases the fast algorithm can be used instead of more complex methods. Note that the errors are in addition to the errors in the LOWTRAN code resulting from the two-stream approximation of multiple scattering. Although the method itself is independent of the LOWTRAN code, the overall accuracy depends on the code. The proposed fast correction method is particularly suited for airborne and spaceborne imaging spectrometers with a small swath angle. PMID- 20717220 TI - Derivation of total ozone abundance and cloud effects from spectral irradiance measurements. AB - We describe a method to infer total ozone abundance and effective cloud transmission from global (diffuse plus direct) spectral irradiance measurements taken at the Earth's surface. The derivation of total ozone abundance relies on the comparison of measured irradiance ratios at two wavelengths in the UV part of the spectrum with a synthetic chart of this ratio computed for a variety of ozone abundances. One of these wavelengths should be appreciably absorbed by ozone (e.g., 305 nm) compared with the other one (e.g., 340 nm). This synthetic ratio (and therefore also the inferred total ozone abundance) is insensitive to the value of the surface albedo used in the model computations. Comparison with independent in situ and remote (from ground and space) determinations of total ozone abundance shows that measurements of global irradiances provide a reliable means of inferring the total column ozone amount for clear as well as cloudy sky conditions. Computer simulations are used to demonstrate that the ozone abunance inferred from global irradiance measurements is quite insensitive to cloud effects, whereas the use of the scattered irradiance only or the zenith sky intensity (measured routinely in the Dobson network on overcast days) requires substantial corrections for cloud effects. Effective cloud transmission is estimated from the data by comparing the measured irradiance at a wavelength where ozone absorption is minimal (e.g., 350 nm) to the clear-sky value. Irradiances generated by a plane-parallel radiation model as a function of cloud optical thickness are used to estimate an equivalent stratified cloud optical depth. These estimates of cloud transmission and optical depth are sensitive to ground reflection, implying that the accurate determination of cloud attenuation requires precise knowledge of the surface albedo. PMID- 20717221 TI - Diffuse reflectance of oceanic waters: its dependence on Sun angle as influenced by the molecular scattering contribution. AB - A spectral model of the inherent optical properties (absorption and scattering coefficients a and b, respectively) of oceanic case 1 waters with varying chlorophyll concentrations C is operated. It provides the initial conditions for Monte Carlo simulations aimed at examining the diffuse reflectance directly beneath the surface R and its variations with the solar zenith angle zeta. In most oceanic waters, molecular scattering is not negligible, and molecular backscattering may largely exceed backscattering. The variable contributions (depending on C and wavelength) of water molecules and particles in the scattering process result in considerable variations in the shape of the volume scattering function. R(zeta) is sensitive to this shape. From the simulations, R (which increases as zeta increases) appears to be linearly related to cos zeta, with a slope that is strongly dependent on eta(b), the ratio of molecular backscattering to particle backscattering. The value of the single-scattering albedo (?= b/a + b) has a negligible influence on the R(zeta) function provided that ? < 0.8, a condition that is always fulfilled when dealing with oceanic case 1 waters. Practical formulas for R(zeta) are proposed. They include the influence of the diffuse sky radiation. The history of each photon and the number of collisions it experiences before exiting have been recorded. These histories and also a probabilistic approach allow the variations of R with cos zeta, eta(b), and ? to be understood. PMID- 20717222 TI - Light scattering from glossy coatings on paper. AB - The application of angle-resolved light scattering (ARLS) to the measurement of the surface roughness of glossy coatings on paper was investigated. To this end, ARLS patterns were measured for laser light scattered from several glossy paper samples, and these patterns were compared with those calculated using a theoretical model based on plane-wave scattering from an isotropic rough surface. Mechanical stylus profilometry data for the rms roughnesses and the autocorrelation functions of the coatings were used as input to calculate the patterns. For all the paper samples measured, as well as for all the incidence angles used, there was good agreement between the experimental and the calculated patterns when all the rms roughnesses measured by profilometry were reduced by 30%. The indication from these experiments is that ARLS may be used to determine the roughness parameters of the coatings. As a check on these results, measurements were also performed with a commercial optical surface probe; these data agreed well with both the ARLS and the stylus profilometry results. PMID- 20717223 TI - Patents. AB - 4,743,117; 4,861,160; 4,861,161; 4,865,436; 4,904,082; 4,919,519; 4,921,328; 4,928,294; 4,931,630; 4,941,163; 4,968,110; 4,991,924. PMID- 20717224 TI - Improvement in polishing of fused-silica parts. PMID- 20717226 TI - Applied optics of optics and optics. PMID- 20717227 TI - Sensing with fiber specklegrams. AB - The fiber specklegram is highly sensitive to the relative modal phases and is of multiplexing capability. Its properties are analyzed and experimentally demonstrated. PMID- 20717228 TI - Angular scanning mechanism for ellipsometers. AB - We describe the implementation of an elliptical mirror for variable angle, fixed position beam alignment in ellipsometers. The proposed configuration reduces mechanical complexity and allows for the determination of differential angular measurements of ellipsometric parameters. PMID- 20717229 TI - Simple method for checking the beam path in reflective Fourier-transform infrared optics. AB - A simple method is described that yields, in reflective optics as well as in Fourier-transformin frared spectrometers,a beam of bright visible light coincident with the invisible infrared beam so that foci and beam locations can be checked easily. PMID- 20717230 TI - Frequency-domain reflectance for the determination of the scattering and absorption properties of tissue. AB - Measurements of the phase and modulation of amplitudemodulated light diffusely reflected by turbid media can be used to deduce absorption and scattering coefficients. PMID- 20717231 TI - Interferometric calibration of gauge blocks by using one stabilized laser and a white-light source. AB - An automated interferometer for primary calibration of gauge blocks is described that requires no prior knowledge of the gauge length. For short gauge blocks, the results agree with previous calibrations to within 10 nm. PMID- 20717232 TI - Measurement of the focal length of a collimating lens using the Talbot effect and the moire technique. AB - A method using the magnification of the Talbot image and the moire technique to measure the focal length of a collimating lens is described. PMID- 20717233 TI - Near-field optical disk recording for very high data density. AB - The use of subwavelength near-field apertures opens the possibility of optical dish data density increases in excess of 4 orders of magnitude. PMID- 20717234 TI - Technique for simultaneous alignment and collimation of a laser diode in an optical data storage head. AB - An autocollimatoris used to align and detect collimation of a laser diode in an optical data storage head. High wavefront quality is achieved without interferometric equipment. PMID- 20717235 TI - How to increase the sensitivity in a polarization interferometer. AB - Two methods to measure the difference between the phase shifts in a dielectric reflection and a metal one are compared. Both methods consist of using a Smith type interferometer, and they differ in the analyzer used. PMID- 20717236 TI - Blackbody source in the -50 to +200 degrees C range for the calibration of radiometers and radiation thermometers. AB - A high-accuracy, large-aperture calibration source for radiometers and infrared radiation pyrometers operating in the range from -50 to +200 degrees C is described. It is shown that by means of reflecting surfaces inside the blackbody the requirements for temperature uniformity can be substantially relaxed while high accuracy in the characterization of the effectivet emperaturei s maintained. PMID- 20717237 TI - Achromatic thin-film polarization-preserving beam displacers stable for thickness variations. AB - A pair of two-layer-coated totally reflecting thin-film systems that mutually compensate for the polarization changes and have a good stability for the thickness errors is investigated. PMID- 20717238 TI - Cryogenic far-infrared Fabry-Perot etalon. AB - A small cryogenic Fabry-Perot etalon was fabricated for the far-infrared region. This design used freestanding metal meshes for the reflecting elements. Using a combination of gold-coated copper mesh on stainless steel, we reproduced the spacing to 1 part in 10(6) with repeated cooling. The properties and methods used for alignment and calibration are presented. PMID- 20717239 TI - Modified J(1) ... J(4) method for linear readout of dynamic phase changes in a fiber-optic homodyne interferometer. AB - Fiber-optic interferometers have been studied extensively for sensing applications. Recently a technique described as the J(1) ... J(4) technique was reported for the linear measurement of dynamic phase changes in a fiber interferometer that requires no phase bias and for which the measurement is independent of random phase fluctuations. However, the implementation of the J(1) ... J(4) technique is limited because only the magnitude of the J(1) ... J(4) Bessel components can be measured on a spectrum analyzer without information available on the sign of the Bessel function. Here a modified signal-processing technique that overcomes the limitations mentioned above is described. PMID- 20717240 TI - Errors in phase-measurement interferometry with high numerical apertures. AB - If phase-measurement interferometry (PMI) is applied for a high numerical aperture (NA), specific errors can occur. The resulting phase no longer varies linearly with the height difference in the test surface. Thus, for height measurements, a constant correction factor or NA scaling factor, which depends only on the NA and the illumination of its stop, does not exist here. This is shown for several pupil illuminations (intensity approximately cos(2) alpha, intensity approximately cos alpha, intensity constant; alpha is the incident angle). For example (NA = 0.9, pupil illumination intensity is constant, wedge angle approximately 0, PMI phase increments = pi/2 for normal incidence), the correction factor can vary from 1.20 (height difference approximately 0) to 1.37 (height difference approximately lambda;/4), i.e., by 17%. PMID- 20717241 TI - Light scattering in Intralipid-10% in the wavelength range of 400-1100 nm. AB - The absorption, scattering, and anisotropy coefficients of the fat emulsion Intralipid-10% have been measured at 457.9, 514.5, 632.8, and 1064 nm. The size and shape distributions of the scattering particles in Intralipid-10% were determined by transmission electron microscopy. Mie theory calculations performed by using the particle size distribution yielded values for the scattering and anisotropy coefficients from 400 to 1100 nm. The agreement with experimental values is better than 6%. PMID- 20717242 TI - Monte Carlo simulation of light transmission through living tissues. AB - To analyze the fundamental characteristics of light transmitted through living tissues, we used the Monte Carlo method to trace the paths of the rays incident upon slabs of particles. The slabs contained either (i) two types of scattering particles in a solution or (ii) one type of particle with pigment added to the solution. Temporal analyses of the transmittance have illustrated that the differences in the optical density among the slabs having different absorption coefficients with the same scattering coefficient vary linearly with time. Also, their gradients have been shown to be proportional to the differences in the absorption coefficients, thus verifying the microscopic Beer-Lambert law in highly scattering media when temporally resolved measurement is used. PMID- 20717243 TI - Ray-tracing calculations for uniaxial optical components with curved surfaces. AB - A method of ray-tracing calculations for uniaxial optical components with curved surfaces is presented. A set of simple ray-tracing formulas is derived. With the spatial ray-tracing method in geometrical optics, by using a computer we plot spot diagrams of extraordinary-ray images formed by some crystal systems. PMID- 20717244 TI - Cryogenic gallium phosphide acousto-optic deflectors. AB - We present measurements of the acoustic intensity in a gallium phosphide acousto optic deflector for the 0.6-1.3-GHz frequency range and the 8-295-K temperature range. The data show a significant increase in the available time aperture of this deflector as a result of cryogenic cooling. PMID- 20717246 TI - Electromagnetic study of transmission gratings. AB - The performances of triangular groove photoresist gratings used in transmission are studied in the visible and near-infrared regions with the electromagnetic theory. The mounting considered here associates triangular groove gratings on the hypotenuse face of a right-angle prism in a configuration, usually called a grism, in such a way that for a chosen wavelength the deviations of the prism and the grating compensate. To assist designers of spectrometric systems, we have covered a complete range of blaze wavelengths and, consequently, of blaze angles. We studied the influence on grating efficiencies when the line density is increased, and the optimal choice angle of incidence is discussed. PMID- 20717245 TI - Extended Rayleigh-Fano theory and its application to grating polarization. AB - A simple method of calculating the degree of polarization of light diffracted by a grating having shallow grooves and finite conductivity has been developed by extending the Rayleigh-Fano theory. Its validity is examined by comparing the computed degree of polarization with the experimental data obtained in the visible and vacuum ultraviolet for the +/- 1st and -2nd orders of Al- and Au coated blazed gratings and holographic gratings used in the specific mountings. The calculations are in good agreement with the observed polarization behavior of the gratings, verifying the usefulness of the present method. PMID- 20717247 TI - Surface classification by an optoelectronic implementation of the Karhunen-Loeve expansion. AB - An optical-digital approach to the classification of rough surfaces that uses a Fourier-transform feature space is described. The sampling of the two-dimensional Fourier spectrum is achieved with a charge-coupled device detector array, which has a polar-sampling geometry and reduces an infinitely dimensioned spectrum image into a set of 72 measurements. To discriminate among three plastic samples in this reduced subspace, we use the Karhunen-Loeve transformation. Then the classification procedure automatically selects the best subspace from the Karhunen-Loeve vectors. PMID- 20717248 TI - Experimental and theoretical studies on monitored signals from semiconductor diodes undergoing antireflection coatings. AB - Rate equations have been used to analyze the variations of the outputs from the facets of the diodes being coated during the antireflection-coating process. Good agreement between the experimental recordings and theoretical predictions has been achieved. As a result, an auxiliary criterion for on-time assessment of the antireflection coating has been established. PMID- 20717249 TI - Plasma-enhanced chemical vapor deposition of low-loss SiON optical waveguides at 15-microm wavelength. AB - Good optical-quality SiON layers deposited upon a SiO(2) buffer layer placed upon silicon wafers have been obtained by using plasma-enhanced chemical vapor deposition from SiH(4), NH(3), and N(2)O. Optical planar waveguides with a thickness of 5 microm and a refractive index of 1.470 have been deposited and investigated in the wavelength region of 1.3-1.6 microm. Three absorption bands at 1.40, 1.48, and 1.54 microm have been detected and interpreted as Si-OH, N-H, and Si-H vibrational modes, respectively. Absorption losses of 3.8 dB/cm at 1.4 microm and 3.2 dB/cm at 1.51 microm have been measured. A mild annealing at approximately 800 degrees C completely removes the band at 1.40 microm, whereas strong reduction of absorption at 1.51 microm requires 3 h of annealing at 1100 degrees C. As a result, propagation losses of 0.36 to 0.54 dB/cm have been measured at 1.54-microm wavelength. PMID- 20717250 TI - Infrared minus-filter coatings: design and production. AB - Infrared minus-filter coatings on zinc selenide substrates have been developed with a new design concept. This concept gives either a narrow or a wide rejection band by adjusting the varying shift factors. Most of the optimized designs are characterized by low-ripple optical performance in all high-transmittance regions. PMID- 20717251 TI - Patents. AB - 4,859,852; 5,004,309; 5,004,341; 5,005,954; 5,007,690; 5,016,976. PMID- 20717252 TI - Applied optics of optics & opticists. PMID- 20717253 TI - Transmit/receive time-delay beam-forming optical architecture for phased-array antennas. AB - A robust, compact, and efficient time-delay beam-forming optical architecture is introduced that operates in both the antenna transmit and receive modes. PMID- 20717254 TI - Electro-optic SLM-based architecture for ternary phase/amplitude filtering. AB - A new architecture for ternary phase/amplitude spatial light modulation is presented. Based on a polarizationmodulating spatial light modulator, the new architecture may be realized by using available spatial light modulators and additional optics. PMID- 20717255 TI - Feature enhancement of images using maximal contrast pixel to pixel. AB - A digital processing method is proposed to enhance image contrast with significant visibility of details. The technique is based on the local contrast associated with each pixel with a given surrounding point. PMID- 20717256 TI - Two-dimensional patterns for optical alignment. AB - Two-dimensional patterns that have properties suited for optical alignment have been constructed from one-dimensional binary Barker codes. Applications include automated alignment of masks with patterns in photolithography. PMID- 20717257 TI - Speckle photography fringe analysis: effect of imaging geometry on displacement errors. AB - Random errors in the measured displacement components from double-exposure speckle photographs recorded through a rectangular aperture are considered both by numerical simulations and by simple dimensional analysis. PMID- 20717258 TI - Programmable liquid-crystal TV spatial light modulator: modified drive electronics to improve device performance for spatial-light-modulation operation. AB - Liquid crystal television (LCTV) continues to play a useful role as a spatial light modulator in the development and evaluation of systems for optical image processing. We outline new addressing electronics developed for a commercially available LCTV that permit writing to individual pixels at an improved display up date rate and allow the input video signal to cover a much greater transmittance range of the TV display for black and white pixels. We illustrate this by measuring the diffraction efficiency for gratings written onto the display. For vertical gratings written along the display columns the diffraction efficiency is increased significantly, but there is no improvement for horizontal gratings. Some merits of the modified LCTV modulator for optical processing applications are considered briefly. PMID- 20717259 TI - Spatial image differentiation using programmable binary optical elements. AB - Spatial differentiation can be performed by imaging an input pattern with a binary optical element consisting of Fresnel lenses having identical focal lengths but different center locations. Each of these lenses forms an image of the object at a different transverse location in the image plane. If the two lenses have a phase shift of pi rad, the two images will be subtracted, resulting in an image that is differentiated in the direction of the shifted lens positions. We show experimental results in which the optical element is written onto a programmable magneto-optic spatial light modulator. PMID- 20717260 TI - Holographic writing and erasure in unipolar photorefractive materials with multiple active centers: theoretical analysis. AB - A general formalism based on the Kukhtarev equations is developed to describe the kinetics of holographic recording and erasure in unipolar photorefractive materials containing multiple active centers. One primary relevant result is that the exchange of charge among the various centers and the holographic grating dynamics, involving charge transport, are uncoupled after appropriate linearization of the equations. The formalism is then applied to the simple but physically meaningful case of two active centers, an optical donor and a thermally active trap. Detailed computer simulations have been carried out to investigate the influence of trap energy depth, trap concentration, temperature, and light intensity on the holographic behavior. The results qualitatively account for a number of unexpected features in the kinetics of grating recording and erasure observed in several photorefractive materials. PMID- 20717261 TI - Kinoform using an electrically controlled birefringent liquid-crystal spatial light modulator. AB - A programmable kinoform using an electrically controlled birefringent liquid crystal spatial modulator (ECB-LCSLM) is discussed. The LCSLM is capable of continuous phase modulation from 0 to 2piFor the kinoform generation, the phase distribution is calculated by iterative methods and recorded on the LCSLM with 16 quantizing levels. We discuss the characteristics and the structure of the LCSLM for the implementation of the programmable kinoform while comparing the computed results and optical reconstructions. PMID- 20717262 TI - Iterative techniques to integrate different optical functions in a diffractive phase element. AB - Diffractive optics allows the incorporation of several optical functions, e.g., wave shaping and focusing, in one element. A method suitable to calculate a diffractive phase element with this feature is described. Coding and quantization effects are analyzed. As an example an array generator with integrated focal power is designed. PMID- 20717263 TI - Image sensor operating in a persistence-integration mode. AB - We propose a novel solid-state image sensor based on a new charge integration concept. This sensor is suitable for imaging low-speed or static objects at low light levels. A model of the sensor as well as the experimental results of a single pixel device is presented. The dynamic range is approximately 110 dB. The linearity is gamma ? 0.71 at low-light levels. The signal gain of the device can automatically increase with a decrease of incident light power. PMID- 20717265 TI - Digital phase-encoded inverse filter for optical pattern recognition. AB - Optical pattern recognition can profit from the progress in coding theory and technology that has been made in digital holography. The calculation of a phase encoded inverse filter is described. This filter allows compromises between discrimination capability and diffraction efficiency. Phase quantization facilitates the materialization of the filter. PMID- 20717264 TI - Optical binary phase-only filters for circular harmonic correlations. AB - In our previous paper we proposed using successively binary cosine and sine filters and combining the correlation intensities for rotation-invariant phase only circular harmonic correlation. This paper presents an alternative method that uses a single filter. We present theory and optical and computer experimental results to show that, with a spatial frequency carrier, the binary phase-only filter [1, -1] and the binary filter [1, 0] yield the impulse response of a continuous phase-only filter. Compared with conventional computer-generated holographic filters, the binary phase-only filter and the binary filter have no representation-related error, require a minimum space-bandwidth product, and may be implemented in a spatial light modulator. PMID- 20717266 TI - Vibration fringes by phase stepping on an electronic speckle pattern interferometer: an analysis. AB - A detailed analysis of the vibration fringes obtained by phase stepping on a time averaged electronic speckle pattern interferometer is presented. It is shown that the contrast of the fringes remains relatively high for any phase step between 30 degrees and 180 degrees for low electronic noise and fringe density. Also, for the four-phase-stepped method, the vibration fringes have the same contrast as that of the pi-phase-shift method except that the high-frequency speckles are smoothed. The contrast of the fringes obtained with extra phase steps along with incoherent superimposition is shown to be higher than the single- or four-phase step method. Both theory and experimental results are presented. PMID- 20717267 TI - Imaging colorimetry: a new approach. AB - A new technique is described for the in-process measuring of the color content of images with pixel resolution, using commercially available devices. Color measurement is extremely important in the printing industry for assessing the quality of printed graphic images. Commercially available instruments designed to measure color, in process, have outputs that represent the average color content over specific areas of the printed surface. The color content of an image feature on the printed surface that may be important to consumers is then difficult to assess from these general readings. Instead of an average reading, the technique that we describe provides a color measurement of each pixel within the area of interest on the printing surface so that the color content of specific features can be evaluated. PMID- 20717269 TI - Optical particle sizing: an introduction by the feature editors. AB - This issue of Applied Optics features 36 papers on topics related to particle sizing by optical methods. The contributions to this special issue derive primarily, though not exclusively, from papers presented at the Second International Congress on Optical Particle Sizing held in Tempe, Arizona, on 5-9 March 1990. The congress was the second in what we hope will be a continuing series of international meetings, held at 3-year intervals, on topics related to particle-size measurements by optical techniques. The 1990 Congress built on the successful First International Congress held in Rouen, France, in 1987. A third Congress is planned for 1993 in Yokohama, Japan. PMID- 20717268 TI - Optical activities in industry. PMID- 20717270 TI - Ludvig Lorenz and nineteenth century optical theory: the work of a great Danish scientist. AB - The career of the Danish physicist Ludvig V. Lorenz (1829-1891) is outlined and his contributions to optical theory between 1860 and 1891 are discussed: the elastic theory of light (1860-1861), the phenomenological wave equation (1862 1864), the electrodynamic theory of light (1867), the Lorenz-Lorentz refraction theory (1869), and the theory of scattering of plane waves by spherical particles (1890). The differences between the Lorenz and the Maxwell theories of light are pointed out, and it is argued that Lorenz's phenomenological attitude and indifference to Maxwellian theory were the main reasons why his mature works in optics exerted little influence. PMID- 20717271 TI - Gustav Mie: the person. AB - About 25 years ago, when I became acquainted with the name Gustav Mie, I was unable to find an entry for him in such major encyclopedias as the Britannica or even in several listings of famous scientists [T. I. Williams, A Biographical Sketch of Scientists (Wiley, New York, 1967); J. Turkevich and L. Turkevich, Prominent Scientists of Continental Europe (Elsevier, New York, 1968)]. This puzzled me indeed when I considered that Mie's 1908 paper and the terms Mie scattering and Mie effect were and continue to be copiously cited in the literature on particle light scattering. One can find few issues of Applied Optics, the Journal of Aerosol Science, Aerosol Science and Technology, and many related publications that do not mention Mie. Yet he is a shadowy figure, almost a disembodied three-letter name without much real existence. Within this biographical note, I try to put some flesh and bones on that apparently ghostly scientist. PMID- 20717272 TI - Founding fathers of light scattering and surface-enhanced Raman scattering. AB - One can view our comprehension of surface-enhanced Raman scattering, particularly that by colloidal dispersions of metal sols, as the merging of two traditions in light-scattering theory and practice. One of these originated with Michael Faraday's work on brilliantly colored metal sols, which was taken up by Richard Zsigmondy and then by Gustav Mie, who accounted for the colors by electromagnetic scattering theory. The other tradition starts with John Tyndall's work with aerosols, which stimulated Lord Rayleigh's entry into the field. Lord Rayleigh was perplexed by observations made with sulfur hydrosols, which in turn were explored by C. V. Raman. Raman's extensive work in light scattering led to his subsequent discovery of the Raman effect. These two traditions were then intertwined when it was shown that the same physical effect that caused Faraday's sols to exhibit their brilliant colors was also the origin of the enhancement of Raman signals from molecules adsorbed on the metal particles that compose these sols. PMID- 20717273 TI - Electromagnetic field for a beam incident on two adjacent spherical particles. AB - Through an application of our previously derived single spherical particle arbitrary beam interaction theory, an iterative procedure has been developed for the determination of the electromagnetic field for a beam incident on two adjacent spherical particles. The two particles can differ in size and composition and can have any positioning relative to each other and relative to the focal point and propagation direction of the incident beam. Example calculations of internal and near-field normalized source function ( approximately |E|(2)) distributions are presented. Also presented are calculations demonstrating the effect of the relative positioning of the second adjacent particle on far-field scattering patterns. PMID- 20717274 TI - Optical resonances and two-sphere systems. AB - After a historical review of previous research into cooperative scattering, a theoretical investigation of the effects of interparticle coupling on morphology dependent resonances of spheres is conducted. Bispheres composed of identical, slightly dissimilar, and very different monomers are considered. Calculations are presented of resonance spectra for selected orientations of the bispheres relative to the incident wave vector along with spectra that should prove useful in describing the scattering properties of a monodisperse ensemble of randomly oriented bispheres. (The bispheres in this dispersion may be constituted from dissimilar monomers.) Normalized source functions for regions inside and near the scatterers are also provided. Finally a numerical simulation of an interesting experiment is carried out in which a resonating aerosol passes through the focal volume of a relatively large, spherical microlens. PMID- 20717275 TI - Modeling of light scattering by irregularly shaped particles using a ray-tracing method. AB - A method of calculating the light scattering of irregularly shaped particles by a ray-tracing program is presented together with a new procedure for the three dimensional reconstruction of the particle shapes. The simulation is based on geometrical optics. The paths of rays are calculated until they encounter specific end conditions (e.g., detection by a transducer). The result of the calculation is the scattering function of the particle in any arbitrary orientation. The results of the program have been successfully compared with those of the Mie theory with microwave-scattering experiments and light scattering measurements involving individual, electrodynamically suspended particles. PMID- 20717276 TI - Calculation of far-field scattering from nonspherical particles using a geometrical optics approach. AB - A numerical method was developed using geometrical optics to predict far-field optical scattering from particles that are symmetric about the optic axis. The diffractive component of scattering is calculated and combined with the reflective and refractive components to give the total scattering pattern. The phase terms of the scattered light are calculated as well. Verification of the method was achieved by assuming a spherical particle and comparing the results to Mie scattering theory. Agreement with the Mie theory was excellent in the forward scattering direction. However, small-amplitude oscillations near the rainbow regions were not observed using the numerical method. Numerical data from spheroidal particles and hemispherical particles are also presented. The use of hemispherical particles as a calibration standard for intensity-type optical particle-sizing instruments is discussed. PMID- 20717277 TI - Absorption and scattering of light by polydisperse aggregates. AB - The absorption, scattering, and differential scattering cross sections are presented for polydisperse aggregates of prescribed fractal dimension and uniform primary particle size. These optical properties are formulated for polydisperse aggregates in terms of the primary particle diameter, the appropriate moments of the discrete size distribution function, and the mean-square radius of gyration. The absorption and scattering cross sections are compared with Rayleigh theory in the small size limit and with the results of the computational simulations of Mountain and Mulholland [Langmuir 4, 1321 (1988)] for intermediate and large aggregates. The differential scattering cross sections are well correlated by the law of Guinier together with a power-law expression for the larger sizes. The cross sections that are described herein apply in particular to polydisperse fractallike aggregates that are formed by cluster-cluster aggregation and possess a size scale that is pertinent to laboratory experiments and industrial processes. PMID- 20717278 TI - Glare points. AB - Glare points are the intensity maxima seen when a water drop illuminated by a wide beam is viewed from a certain direction and imaged. We show that good resolution in both the scattering angle and the glare point position can be achieved only if the size parameter x = 2pia/lambda is >>1 and that the positions of the glare points can be computed by a Fourier transform from the familiar Lorenz-Mie scattering function. Sample computations made with x = 10,000 and x = 20,000 are presented. Glare points corresponding to rays that have suffered as many as 15 internal reflections can be identified, in agreement with experimental findings. PMID- 20717279 TI - Critical angle light scattering from bubbles: an asymptotic series approximation. AB - The critical scattering angle at 82.8 degrees from an air bubble in water locates the transition from partial to total re-flection from elementary geometrical optics. The irradiance scattered into a narrow angular region near the critical scattering is a monotonically increasing function of bubble radius a provided a >> lambda, and the weak contributions from rays reflected internally from the far side of the bubble are neglected. The asymptotic series for critical angle scattering derived here leads to a simple approximation for the irradiance. It also describes the breakdown of elementary geometrical optics for reflection at the critical angle from a curved surface. The leading correction to the scattering amplitude relative to the perfect reflection amplitude is found to be O(beta(-(1/4))), where beta = 2pia/lambda is the size parameter and lambda is the wavelength of light in water. The series is confirmed by comparison (as a function of beta) with smoothed Mie computations. The leading correction is significant for beta as large as 20,000, and it is larger when the light is polarized with the E field parallel to the scattering plane rather than perpendicular to it. The dependence on beta(-(1/4)) is also shown from an average of the reflection coefficient over a Fresnel zone. Applications to optical bubble sizing are noted, and the nature of approximations in previous physical-optics models of critical angle scattering is clarified. PMID- 20717280 TI - Theoretical model of the laser imaging of small aerosols: applications to aerosol sizing. AB - A theoretical model is presented for the formation of small-particle shadow images in a single-lens laser-imaging system. The model uses a modification of classical Lorenz-Mie theory, presented by the authors in an earlier paper, to calculate the external electromagnetic fields resulting from the interaction of a Gaussian laser beam with a finite absorbing spherical particle. Propagation of the electric field through the imaging system components is developed from a scalar viewpoint using the thin-lens transformation and the Fresnel approximation to the Huygens-Fresnel propagation equation. The theoretical model is valid for either transparent or absorbing spheres and has no restrictions on the allowable degree or direction of aerosol defocus. Direct comparisons between theoretical calculations and experimental observations are reported for 53-microm-diameter transparent water droplets and 66-microm-diameter absorbing nickel spheres for defocus ranging from -2 mm (toward the lens) to +2 mm (away from the lens). Theory and experiment showed good agreement in the boundary edge gradient and the location of the external peaks, while observable differences existed in the magnitude of the central spots. Theoretical results, comparing water and nickel aerosols, showed observable differences in the calculated average internal intensity (AII). In contrast, the boundary edge gradient showed less dependence on changes in the optical properties of the particle. These results indicate that criteria, such as the AII, used in focus determination must be reevaluated when applying in-focus sizing algorithms to aerosols with significantly different optical properties. PMID- 20717281 TI - Particle sizing by inversion of the optical transform pattern. AB - An inversion method is presented for recovering size information from the optical transform pattern for spherical particles. Comparisons are made with the Shifrin inversion method for two different types of particle-size distribution. For a monodispersed size distribution optical transform experiments reveal that the new method shows better capabilities in recovering information about the size and number of scatterers. Using a noise-free continuous distribution in a computer simulation, we found that the two methods are equally capable of recovering the form of the original distribution function. Then shot noise is simulated in the transform pattern, and it is shown that the new inversion method is less susceptible to error. PMID- 20717282 TI - Analytical inversion for laser diffraction spectrometry giving improved resolution and accuracy in size distribution. AB - We formulate the Chin-Shifrin integral transform inversion for calculating the particle-size distribution from an observed forward-scattering pattern in a way that does not require knowledge of the derivative of the data. The resulting equations are suitable for use with a photodiode array of the type commonly used to record forward-scattering signatures. By attention to the range of integration in the inversion, and by suitable apodization of the input signal, we are able to reduce noise in the inversion to an acceptable level. Some sample analyses are presented. PMID- 20717283 TI - Sampling and inversion of data in diffraction particle sizing. AB - In optical diffraction particle sizing a numerical transform is sought so that a particle size distribution can be determined from angular measurements of near forward scattering. We consider the nonuniqueness and instability of this transform for discrete data. Our arguments are based on the approximation of the kernel by a function to which it is asymptotic. The results, which include an angular sampling criterion and a rescaling of the forward transform, are applied to choosing and developing algorithms for inverting experimental measurements of scattering. Measurements of scattering from distributions of polystyrene spheres are successfully inverted. PMID- 20717284 TI - Deconvolution of light-scattering patterns by observing intensity fluctuations. AB - Results are presented on the statistical fluctuations occurring in a forward light-scattering experiment to determine the particle size distribution. A sample of glass beads was measured using a Malvern 2600D instrument and analyzed with a proposed deconvolution procedure that incorporates the observed intensity fluctuations. This procedure yields a qualitative improvement of the solution, provides error intervals, and offers a better means for model discrimination. PMID- 20717285 TI - Direct measurement of suspended particulate volume concentration and far-infrared extinction coefficient with a laser-diffraction instrument. AB - A laser-diffraction instrument is described for measuring directly and in situ the absolute particulate volume concentration or the infrared optical extinction coefficient of a polydisperse aerosol. Diffraction and Mie theory are used to write integrals that describe the interaction of light scattered by the particles and the optics of the instrument. These integrals are inverted to yield variable transmission filters that interact with the scattered light to give the desired instrument response. The particle-size dependency of the instrument's performance is established, and the effect of the refractive index of the particles is evaluated. The design, major components, and absolute and field calibrations of the instrument are described. Examples of measurements in the field and laboratory are given. PMID- 20717286 TI - General solution to the inverse near-forward-scattering particle-sizing problem in multiple-scattering environments: theory. AB - A general solution to the problem of measuring the size distribution of large particles in optically thick media by using small-angle light scattering is presented. The approach is general in the sense that no assumption of the form of the particle-size distribution function is required, although the particles must be distributed uniformly throughout the medium. The method is based on a successive order, discrete ordinates approach for modeling multiple-scattering phenomena and requires that the particle field be interrogated by using an array of near-forward input light angles. The scattering redistribution matrix is thereby determined, which permits a numerical inversion of the problem to obtain the single-scattering signature. Finally, conventional inverse scattering methods are used to reconstruct the particle-size distribution from the near-forward (single-scattering) light-scattering pattern. PMID- 20717287 TI - Particle sizing by laser diffraction spectrometry in the anomalous regime. AB - The application of laser diffraction spectrometry to determine the size distributions of particles in the anomalous diffraction regime, i.e., particles with a refractive-index ratio close to one, has been examined. From a computer simulation, using the Mie theory and the geometrical optics approximation, it could be concluded that for suspensions with a refractive-index ratio near 1, the corresponding scattering matrix is required for calculation of the correct particle size distribution, even in the case of particles that are much larger than the wavelength of the incident light. In a system with the refractive-index ratio almost at unity, a suspension of ice crystals in a sucrose solution, the ice particles were sized by means of optical microscopy and laser diffraction spectrometry, and the results were compared. PMID- 20717288 TI - Spherical particle sizing based on the VanderLugt correlator. AB - We present a flexible architecture for particle sizing based on the VanderLugt correlator with a multiplexed matched spatial filter. Theoretical and experimenal data obtained using opaque spherical particle projections demonstrate the potential uses and simplicity of the architecture. The system is capable of handling spherical and nonspherical particles and shows potential for handling high particle concentrations. PMID- 20717289 TI - Method for measuring mean particle size of the bulk powder using speckle patterns. AB - We report a method for measuring the mean size of fine particles in a bulk state using the correlation properties of two speckle patterns. With this method, the correlation between the two speckle patterns produced from the same region of the upper surface of the powder bed under two coherent illuminations is measured using double-exposure speckle photography and a cross-correlated method. It is found to be directly related to the surface-area mean diameter of particles over the bed surface and the incidence angle difference between two illuminations. This technique has the advantage of simplicity in the measuring procedure, including the pretreatment of the sample powder. PMID- 20717290 TI - Optical structure factor measurements of soot particles in a prmixed flame. AB - We have measured the scattered-light intensity as a function of the scattering angle for light scattered from soot particles in a premixed methane/oxygen flame. This yields the optical structure factor for the soot particles. We find that the structure factor shows the soot particles to have a morphology consistent with a fractal interpretation with a fractal dimension in the 1.6 /= 2 W(G) >/= W(L), and the equal sign applies when and only when mode-field distribution is Gaussian. In addition, the application of this relation to fiber design is discussed. PMID- 20717313 TI - Infrared optical characteristics of type 2A diamonds. AB - The absorption coefficient of two samples of type 2A diamond was measured by laser calorimetry at 10.6 microm and found to be 0.033 and 0.0415 cm(-1). Transmission properties from 2.5 to 20 microm are also presented. PMID- 20717315 TI - Performance of a wideband soft x-ray polarizer. AB - Performance of a Ru/Si multilayer polarizer of the doublecrystal monochromator type is evaluated in the soft x-ray region. Its polarization was found to be higher than 99.5% at 89 and 97 eV. PMID- 20717316 TI - Imaging performance analysis of adaptive optical telescopes using laser guide stars. AB - The use of laser guide stars in conjunction with adaptive optical telescopes offers the possibility of nearly diffraction-limited imaging performance from large, ground-based telescopes. We investigate the expected imaging performance of an adaptive telescope, using laser guide stars created in the mesospheric sodium (Na) layer. A 2-3-m class telescope is analyzed for the case of a single, on-axis guide star at an altitude of 92 km (the nominal height of the mesospheric Na layer). We analyze an annular telescope pupil with approximately 15 wave-front sensor subapertures and mirror actuators spanning the pupil diameter. The imaging performance is quantified in terms of the pupil-averaged rms wave-front error, the optical transfer function, the point spread function, the Strehl ratio, and finally the angular resolution. The performance analysis takes into account the degradation caused by the limitation of the wave-front sensor as well as the deformable mirror. These limitations include the finite spacing and size of the wave-front sensor subapertures and the spacing and influence function of the mirror actuators. The effects of anisoplanatism and shot noise are also included in the analysis. The results of the investigation indicate that a 3-m adaptive telescope using a single Na guide star is capable of achieving a Strehl ratio of 0.57 and an angular resolution nearly matching that of diffraction-limited performance (0.05 arcsec). This performance is achieved assuming that r(0) = 20 cm and a 5-W laser is used to create the guide star. The effect of variations in seeing conditions and guide star brightness is also investigated. PMID- 20717317 TI - Properties of fiber optics for application in astronomical interferometry. AB - We tested such properties of single-mode and multimode fiber optics that are relevant for use in a long-baseline astronomical interferometer, and we give quantitative values for modulation, transmission, and stability of the fiber optics as measured in a Mach-Zehnder interferometer configuration. Only polarization-maintaining single-mode fibers gave satisfying results. Good preservation of modulation and ease of beam combining are strong features of these fibers, whereas the light losses that are due to imperfect coupling may present a serious problem. PMID- 20717318 TI - Design and evaluation of laser sources with high-quality wave fronts. AB - The design and evaluation of laser sources that have high-quality wave fronts with minimal residual aberrations and irregularities are described. Two such sources have been developed-a collimated reference source and a point reference source. The collimated reference source provides a collimated wave front with a wave-front irregularity of <0.01 wave rms over a 6-mm clear aperture. Collimation is better than 0.067 wave peak to valley, with an angular ray departure of <1.75 x 10(-5) rad. The point reference source provides a diverging wave front with a wave-front irregularity of <0.01 wave rms over a 0.60 numerical aperture and 0.005 wave rms over a 0.35 numerical aperture. Source wavelengths are 670, 780, and 820 nm. These laser sources may be characterized in terms of their fourth order wave-front polynomial coefficients by using the testing methods developed in this paper. Once characterized, the sources are used as a known input for testing the optical response of unknown systems. This enables complete characterization of an unknown system in terms of aberration polynomials or other criteria of interest when used in conjunction with a wave-front sensing interferometer. These sources are used to evaluate an equal-path, phase-modulated Mach-Zehnder interferometer. Applications include general-purpose laboratory sources as well as tools for evaluating the accuracy of optical systems. PMID- 20717319 TI - Electro-optic variable focal-length lens using PLZT ceramic. AB - Proposed is an electro-optic (E-O) variable focal-length lens by combining EO material with numerous transparent fine electrodes on its surface. Coating indium tin oxide transparent electrodes on a lanthanum-modified lead zirconate titanate (9/65/35) ceramic plate and introducing a parabolic index profile with dc voltage, we successfully demonstrate a positive EO variable focal-length lens, obtaining its focal length from infinity to 1 m with applied voltage up to 300 V to an electrode gap of 50 microm. Theoretical analysis is also given, together with a discussion for improving aberration and resolving power. PMID- 20717320 TI - Spatial resolution of images reconstructed from a bulk-detection scanning-laser microscope. AB - We present theory and experimental data on the minimum detectable feature size and spatial resolution for a scanning-laser microscope system that uses bulk photodetection. In the analysis, interactions of laser photons with an object are given a probability function that varies with the position within an object. Typical interactions that can be measured with such a scanning device include photon absorption (densitometry), scattering, and photofluorescence. Because bulk photodetection is used, image resolution is a function of laser-probe spot size and recording precision. We present data from simulations that predict a minimum separation between feature centers of approximately 1.56 times the half-width of the laser spot. Experimental verification by scans of U.S. Air Force test targets confirms this theory. PMID- 20717321 TI - Miniaturized fiber-optic Michelson-type interferometric sensors. AB - We present a novel, miniaturized Michelson-type fiber-optic interferometric sensor that is relatively insensitive to temperature drifts. A fused-biconical tapered coupler is cleaved immediately after the coupled length and polished down to the region of the fused cladding, but short of the interaction region. The end of one core is selectively coated with a reflective surface and is used as the reference arm; the other core serves as the sensing arm. We report the detection of surface acoustic waves, microdisplacements, and magnetic fields. The sensor is shown to be highly stable in comparison to a classic homodyne, uncompensated Michelson interferometer, and signal-to-noise ratios of 65 dB have been obtained. PMID- 20717322 TI - Coherence sensing of time-addressed optical-fiber sensors illuminated by a multimode laser diode. AB - A reflective array of optical-fiber sensors multiplexed in time and with their status read using coherence sensing associated with directly modulated multimode laser-diode illumination is investigated. Sensor sensitivity as determined by primary noise sources is evaluated and numerical results are presented. The concept is demonstrated with two all-fiber Michelson interferometers and applied to the measurement of periodic and quasi-static parameters. It is shown that the effect of feedback light into the laser cavity on the level of the system noise floor is negligible, making unnecessary the use of source optical isolation. PMID- 20717323 TI - Transmission and damage-threshold measurements in AgGaSe(2) at 2.1 microm. AB - Measurements of transmission loss coefficients in AgGaSe(2) at 2.1 microm ranged from 0.012 to 0.072 cm(-1). Energy density, not peak-power density, proved to be the determining factor in AgGaSe(2) damage threshold. Coated-surface damage thresholds originally were found to be in the 1.1-2.5-J/cm(2) region by using 180 nsec laser pulses, but damage thresholds as high as 3.5 J/cm(2), with a 3 J/cm(2) average, were measured in coated samples with improved surface quality. PMID- 20717324 TI - Jones and Mueller matrices for specular reflection from a chiral medium: determination of the basic chiral parameters using the elements of the Mueller matrix and experimental configurations to measure the basic chiral parameters. AB - Using Fresnel reflection amplitudes, the Jones and Mueller matrices for reflection from a nonabsorbing gyrotropic medium are presented. Some basic chiral parameters are defined by using the elements of the Mueller matrix; experimental configurations are described. PMID- 20717325 TI - Simple radiometric method for measuring the thermal broadband emissivity of material samples. AB - Whereas thermal emissivities, together with surface temperatures, are decisive factors with regard to object signatures observed in infrared imagery, it is unfortunate that emissivity measurements are not easily made. Known methods may require specially built or expensive equipment or may be selective with respect to the types of material that can be investigated. No internationally agreed-on method is available. From basic physical principles, I outline a radiometric outdoor technique by which essentially all types of material can be measured by utilizing the difference between ground and sky temperatures. The accuracy of this simple method appears to compare favorably with that of other methods that cover the 8-14-microm wave band. PMID- 20717326 TI - Phase-conjugate interferometric analysis of thin films. AB - We used phase-conjugate interferometry to determine the optical parameters of absorbing thin films: the refractive index, the extinction coefficient, and the thickness. The use of self-pumped phase-conjugate reflectors in place of mirrors causes optical distortions in the substrate to cancel and makes the interferometer self-aligning. The results of measurement of single-layer absorbing thin films are presented. PMID- 20717327 TI - Patents. AB - 4,981,332; 4,983,003; 4,998,786; 4,998,787; 4,998,788; 5,000,542; 5,000,571. PMID- 20717328 TI - Information processing technology in Japan: 2. AB - An international symposium on New Information Processing Technologies held in Japan in March 1991 is described, based on a report by D. K. Kahaner of the U. S. Office of Naval Research Asian Office. PMID- 20717329 TI - Complex reference discriminant functions implemented iteratively on a joint transform correlator. AB - Iterative learning procedures on hybrid electro-optics ystems were employed to generate complex reference discriminant functions. The procedure was implemented using a joint transform correlator equipped with a single inexpensive spatial light modulator. Experimental results demonstrate efficient two-class discrimination. PMID- 20717331 TI - Organization of k x k switches (k >/= 4) interconnected by d-dimensional (d >/= 2) regular optical patterns. AB - The concept for the generation of arbitrary permutations of d-dimensional data cubes in a multistage manner is presented. In particular, d-dimensional switching cubes are proposed, and the geometry of the ports of the switches and their locations within the switching cubes (d = 3,4) are discussed. A new addressing scheme for the ports of these switches is presented, which is called the horizontal coding of addresses because the ports of the switches are distributed to the subsequently arranged arrays of the cube(s) in a horizontal manner. This addressing scheme permits any desired organization of the switches and the ports by reordering the absolute d-tuple addresses. This reordering is described by permutation matrices and explained by means of several examples. Within this addressing scheme relative addresses of the ports of the switches (which are a subset of the common absolute addresses) are introduced. Relative addresses offer an additional saving of hardware if applied within the concept of rearrangeability. PMID- 20717330 TI - Improved arithmetic Fourier transform algorithm. AB - A new, improved version of the arithmetic Fourier transform algorithm is presented. This algorithm computes the Fourierc oefficientso f continuous-times ignals by using the number-theoretic technique of Mobius inversion. The improved algorithm can calculate all the Fourier coefficients including the dc component. It also requires a smaller number of delays and arithmetic operations than the standard arithmetic Fourier transform algorithm. PMID- 20717332 TI - Optical triode operation characteristics of nonlinear etalons. AB - Optical triode operation characteristics of nonlinear etalons such as on-off ratio, fan-out, thresholding power, and switching time are strongly dependent on material, cavity parameters, operating conditions (detuning and operating power), and operating method. We studied these dependences and trade offs with regard to various factors, especially operating conditions. Applying the results, optical gate operations of both transmission-and reflection-type devices were demonstrated. PMID- 20717333 TI - Slitless rainbow holography. AB - In this paper we suggest that a one-dimensional grating may be employed in place of the random diffuse screen and slit used in one-step, two-dimensional rainbow holography. A demonstration of this slitless rainbow holography is given by means of Fourier optics. Holograms fabricated in this manner in a 4f-like processing system prove to be satisfactory. This slitless rainbow holographic system is energy saving and hence remarkably reduces exposure time. One-dimensional diffuse screens can also be used in the same way as the grating. PMID- 20717334 TI - Noise reduction and amplified reconstruction of a low-intensity static optical field by holography. AB - A method for amplified reconstruction and noise reduction of a static low intensity optical field by holography is suggested. The technique consists of a reduction of the reference beam intensity to that of the object field during the holographic exposure. The noise-reduced hologram obtained can then produce the amplified image with an increased reference beam. The technique is demonstrated by the detection of surface scratches on glass. PMID- 20717335 TI - Photoresist resolution measurement during the exposure process. AB - The index-modulation evolution of a positive photoresist material was measured during the holographic exposure of sinusoidal patterns. The exposures were performed in a stabilized holographic setup that permits easy changes in the period. The results show the lowering of the recorded index modulation when the period decreases. PMID- 20717336 TI - Hologram interferometry: carrier fringes. AB - The sensitivity of the interferometric techniques to longitudinal variations of the optical path can be increased by introducing carrier fringes. A new method for introducing such fringes is presented. PMID- 20717337 TI - Image superresolution by using a source-encoding technique. AB - A source-encoding technique is utilized to achieve image superresolution. The method overcomes several drawbacks of previous methods and shows a new approach for further study of practical applications of the superresolution technology. PMID- 20717338 TI - Deconvolution of two-dimensional images with zeros in the transfer function. AB - Although it is generally believed that the information at the zeros of the transfer function is lost and cannot be recovered, this is not true: the information can be recovered, even in the presence of noise, because the lost information is coded into intermediate points where the transfer function is not zero. We extend our previous one-dimensional treatment [Can. J. Phys. 49: 1865 (1971)] to two dimensions and apply the results to the restoration of images degraded by noise and by linear filtering, such as movement blurring. The filter used is an honest filter in the sense that in the absence of noise, it yields a perfect restoration, including frequencies at the zeros of the transfer function. It is shown that the method considerably improves the restoration of linearly degraded real images. PMID- 20717339 TI - Circular-harmonic function, minimum average correlation energy filters. AB - New distortion-invariant correlation filters for in-plane rotation invariance are considered. These use circular-harmonic functions combined with minimum-average correlation-plane filter techniques. Various circular-harmonic function shortcomings are quantified. PMID- 20717340 TI - Gaussian-minimum average correlation energy filters. AB - Correlation filters with sharp delta-function correlation peaks [such as phase only filters and minimum average correlation energy (MACE) filters] do not recognize images on which they are not trained. We show that the MACE filter cannot always recognize intermediate images of true class objects (e.g., aspect views or rotations midway between two training images). New Gaussian-MACE filters offer a solution to this problem. PMID- 20717341 TI - Redundant-interconnection interpattern-association neural network. AB - We have shown that introducing interconnection redundancy can make a neural network more robust. We describe performances under noisy input and partial input that show that the optimum-redundant interconnection improves both the noise tolerance and the pattern discriminability. Simulated and experimental demonstrations are also provided. PMID- 20717342 TI - Bacteriorhodopsin oriented in polyvinyl alcohol films as an erasable optical storage medium. AB - Films of oriented bacteriorhodopsin have been formed in polyvinyl alcohol with excellent optical quality. Images with high contrast have been impressed and erased on these films. Second-harmonic microscopy has been used to read the image on a bacteriorhodopsin-polyvinyl alcohol film without erasure. The potential of these films for molecular information storage and computation is discussed. PMID- 20717344 TI - Nasa patter. PMID- 20717343 TI - Patents. AB - 4,836,675; 4,836,679; 4,840,489; 4,848,910; 4,863,271; 4,863,271; 4,863,272; 4,863,273; 4,865,452; 4,881,817; 4,886,364; 4,889,404; 4,881,817; 4,886,364; 4,889,404. PMID- 20717346 TI - Fractal fiber optics. AB - Analysis of the geometry of recursive tilings has led to the development of a new class of highly ordered optical composites that exhibit fractal surface character. These objects are, we believe, the first engineered fractal objects. The mathematics of tiling and examples of fractal fiber array devices are reviewed. PMID- 20717347 TI - Double-grating transversely excited atmosphere CO(2) laser as a narrow-band pumping source for far-infrared lasers. AB - The practical application of the narrow-band transversely excited atmosphere CO(2) laser, which uses a double-grating cavity, is demonstrated by pumping spectrally pure farinfrared lines in a CH(2)OH laser. PMID- 20717348 TI - Dispersion measurements of single-mode fibers in the blue-green spectral region by an interferometric method. AB - The chromatic dispersion of a single-mode, polarizationpreserving fiber in the blue-green spectral region was measured by using an interferometric method. PMID- 20717349 TI - Inclination distributions and size measurements of hemlock and red spruce needles. PMID- 20717350 TI - Frequency calibration in the ArF excimer laser-tuning range using laser-induced fluorescence of NO. AB - A frequency calibration in the tuning range of the ArF excimer laser near 193 nm was performed. Different electronic spectra of NO were measured by laser-induced fluorescence in a cell and in an oxyacetylene flame. Spectra were measured with a frequency-doubled and Raman-shifted dye laser system and with a tunable ArF excimer laser with a modified configuration. A list of absolute frequencies of the B(2)II(upsilon' = 7) ? X(2)II(upsilon'' = 0) and D(2)Sigma(+)(upsilon' = 0) ? X(2)II(upsilon'' = 1) transitions in this spectral region is given, including a more comprehensive assignment of the latter excitation spectrum. PMID- 20717351 TI - Application of ray tracing to the design of a monolithic nonplanar ring laser. AB - This paper presents some simple and useful-ray tracing techniques for the design of a monolithic nonplanar solid-state ring laser. With appropriate constraints the approach gives a complete cavity stability map and the angular and dimensional tolerances required for fabrication. PMID- 20717352 TI - Predicting multipulse laser-induced failure for molybdenum metal mirrors. AB - In combination with known thermomechanical-fatigue data for Mo, we have conducted transient photothermal deflection (TPD) measurements to develop a model for the multipulse laser damage of Mo mirrors to predict their lifetimes. In laser-damage experiments to verify the model, Mo mirrors were irradiated with 10-ns Nd:YAG laser pulses at 1064 nm at a 10-Hz repetition rate. Digitized TPD waveforms indicated peak surface angular deflection that could then be converted into surface displacement. Numerical modeling of the vertical heat distribution enabled the peak surface-deflection signal to be converted into peak surface temperature. The thermomechanical model was verified by both the experimental and the numerical results. Conventional mechanical-fatigue data for Mo were used to derive a predictive equation for the laser-accumulation lifetime of Mo mirrors. Experiments were performed with 1-10(4) pulses per site, yielding laser-damage thresholds and accumulation curves. The accumulation behavior predicted from measurements of mechanical fatigue was in excellent agreement with the measured behavior. Thus a single-pulse TPD measurement of peak deformation at a subthreshold laser fluence, in conjunction with mechanical-fatigue data, may be used to estimate the safe operating fluence for a component in a multipulse laser environment. PMID- 20717353 TI - High-repetition-rate infrared-pump, infrared-probe spectrometer. AB - A method for generating two independently tunable 25-ps infrared pulses at 500 Hz was demonstrated. The apparatus is based on two dye lasers, a regenerative amplifier, and two lithium iodate optical-parametric amplifiers. Using the pump probe technique, we measured the lifetime of the excited vibrational-state absorption of tungsten hexacarbonyl in solution. PMID- 20717354 TI - Use of a vacuum-planar photodiode to drive an electro-optic Q switch directly. AB - A vacuum photodiode was used to drive a Pockels cell directly in an optical feedback arrangement. This technique was used to achieve Q switching and a single longitudinal-mode operation in a flash-lamp-pumped Nd:YAG laser. Synchronization within 2 ns with an external short-pulse laser source was demonstrated. PMID- 20717355 TI - Low-cost wavemeter with a solid Fizeau interferometer and fiber-optic input. AB - A wavemeter suitable for measuring the wavelength of pulsed and continuous laser light has been constructed on the basis of a solid Fizeau interferometer (SFI). An accuracy of 1 part in 10(6) has been demonstrated in a range extending from 563 to 613 nm. The use of the SFI and of a combination of a single-mode optical fiber and an achromatic lens as a beam collimating system substantially simplifies the optical layout and reduces cost. The difficulties connected with the dispersion of the SFI have been overcome by an analytical description of the characteristics of the interferometer and accurate temperature stabilization. PMID- 20717356 TI - Connection mechanism of physical-contact optical fiber connectors with spherical convex polished ends. AB - We present an experimental and analytical investigation of the connection mechanism of physical-contact optical-fiber connectors with spherical convex polished ends and confirm that reducing the curvature radius of the spherical convex ferrule end face is effective for establishing a stable connection with slight axial compressive force on the ferrules. PMID- 20717357 TI - Aberration-limited coupling efficiency from a plano-convex lens into an optical fiber. AB - Ray-tracing calculations of the coupling efficiency from a plano-convex lens of relatively low f/number ( approximately 2.35) into highly multimode step-index optical fibers have been performed for both orientations of the lens. The results of the calculations yield surprising discontinuities and asymmetries in the slope of the coupling efficiency versus longitudinal displacement. These features are explained in terms of the multiplicity of roots in the mapping of incident-ray heights onto the fiber core radius. In addition, it is found that the paraxial coupling efficiency result is in marked qualitative and quantitative disagreement with exact theoretical results, except at coupling efficiencies of less than a few percent. The relationship of these features to longitudinal spherical aberration, paraxial coupling, and the ray caustic is discussed. PMID- 20717358 TI - Ground state saturated population distribution of OH in an acetylene-air flame measured by two optical double resonance pump-probe approaches. AB - Two optical double-resonance pump-probe techniques were used to determine the ground-state rotational population distributions of OH in an acetylene-air flame when a saturating laser beam is tuned to the Q(1)4 transition of the (0, 0) Sigma II band. The saturated absorption technique is based on the detection of absorption by a probe laser under conditions of saturation with a pump laser and no saturation. In the fluorescence technique, a probe laser is scanned through the (1, 0) band, while a saturating pump laser, tuned to the (0, 0) band, is on or off. We found that approximately 15% of the total population of the ground state was transferred to the excited state. Perturbation of the rotational population distribution was greater for rotational levels close to the directly excited laser-coupled level. The rotational energy transfer rate in the ground state was somewhat greater than in the excited state. The assumption of the balanced cross-rate model was verified as a means of determining the absoslute OH number density with adequate accuracy. PMID- 20717359 TI - Investigation of continental aerosols with high-spectral-resolution solar extinction measurements. AB - A modified implementation of the Langley method has been used to measure the atmospheric optical-depth spectrum at 5-nm intervals from 0.36 to 1.10 microm. Extensive measurements of the aerosol optical depth at 550 nm and the Junge exponent showed that there was a distinct separation of atmospheric conditions into clear and hazy conditions. A study of the sensitivity of the retrieval of the 550-nm surface reflectance factor from spaceborne observations was carried out, using the above characterization of typical atmospheric conditions in terms of mean and standard-deviation values for the aerosol optical depth and Junge exponent. PMID- 20717360 TI - Line-frequency measurements and analysis of N(2)O between 900 and 4700 cm(-1). AB - The N(2)O infrared spectrum from 900 to 4700 cm(-1) has been studied with a high resolution Fourier-transform spectrometer. Measurements were made of line frequencies of several N(2)O isotopes for several ground-state and hot bands. A few of these bands are being reported for the first time, to my knowledge: the 1530-0330, 2330-0330, 0441-0440, 0441-0330, 0531-0330, and 1331-0330 bands of (14)N(2)(16)O. Also for the first time to my knowledge, perturbation-enhanced transitions in the 0710-0110 and 0730-0110 bands were assigned and measured. The frequencies have been analyzed to obtain a unique set of effective vibration rotation parameters for each vibrational state. The results obtained from this research are of high accuracy for the ground-state and the first-excited-state bands of (14)N(2)(16)O, in which the computed frequencies derived from the least squares fits are known to an absolute uncertainty of only +/-4 x 10(-5) for nonperturbed transitions. PMID- 20717361 TI - Optical properties of aggregate particles whose outer diameter is comparable to the wavelength. AB - I describe results of numerical calculations of the optical properties (extinction efficiency, single-scattering albedo, phase function, and linear polarization) of aggregate particles whose outer diameter is comparable with the wavelength. Results are presented for two types of particle, one composed of monomers whose radius is small compared with the wavelength and a second containing monomers with larger radii. The shape of the forward-scattered lobe of the phase function is diagnostic of the mean projected area (but differs from that for an equal-area sphere), while the linear polarization, phase function at large scattering angles, and single-scattering albedo depend on the monomer diameter. The wavelength dependence of the extinction efficiency differs markedly from that for equal-area spheres. These results can be used to infer particle properties from remotely sensed data. PMID- 20717362 TI - Coherent laser radar performance for general atmospheric refractive turbulence. AB - The signal-to-noise ratio (SNR) and heterodyne efficiency are investigated for coherent (heterodyne detection) laser radar under the Fresnel approximation and general conditions. This generality includes spatially random fields, refractive turbulence, monostatic and bistatic configurations, detector geometry, and targets. For the first time to our knowledge, the effects of atmospheric refractive turbulence are included by using the path-integral formulation. For general conditions the SNR can be expressed in terms of the direct detection power and a heterodyne efficiency that can be estimated from the laser radar signal. For weak refractive turbulence (small irradiance fluctuations at the target) and under the Markov approximation, it is shown that the assumption of statistically independent paths is valid, even for the monostatic configuration. In the limit of large path-integrated refractive turbulence the SNR can become twice the statistically independent-path result. The effects of the main components of a coherent laser radar are demonstrated by assuming untruncated Gaussians for the transmitter, receiver, and local oscillator. The physical mechanisms that reduce heterodyne efficiency are identified by performing the calculations in the receiver plane. The physical interpretations of these results are compared with those obtained from calculations performed in the target plane. PMID- 20717363 TI - Patents. AB - 4,991,925; 4,991,938; 4,993,796; 4,993,818; 4,996,412; 4,997,241; 4,997,261; 5,000,527; 5,000,546; 5,002,380; 5,004,312; 5,004,319. PMID- 20717364 TI - Measurement of Mueller matrices. AB - A technique that allows Mueller matrix components to be measured and involves the use of two phase modulators instead of the usual method that uses four modulators is discussed. It allows true matrix components to be measured instead of the ratio of sums of matrix components, which are measured using a single modulator. PMID- 20717365 TI - On-axis irradiance for obscured rectangular apertures. AB - A method of computing the diffraction integral has been developed for application to the on-axis irradiance of rectangular focused light beams with central and noncentral rectangular obscurations. Numerical methods for the generation of quantitative results are presented. PMID- 20717366 TI - Holographic optical generation of prism anamorphs. AB - Analyses of prism anamorphic optical systems with single and multiple prisms in plane and spherical wave illumination geometries are presented. A theoretical evaluation and experimental demonstration of a new technique for recording holographic anamorphic elements by using prism anamorphic optical systems is discussed. It is seen that this technique offers the advantage of generating elements with low f/number. Another advantage of this recording is the easy generation of elements with different anamorphic factors by using a single configuration. PMID- 20717367 TI - Upper bound on the diffraction efficiency of phase-only fanout elements. AB - For one-dimensional binary-phase [(0, pi) and (0, non-pi)] fanout elements and for one-dimensional continuous or multilevel quantized phase fanout elements, an upper bound on diffraction efficiency is presented for fanouts ranging from 2 to 25. The upper bound is determined by optimizing with respect to the array phase the upper bound on diffraction efficiency for a coherent array. To determine the upper bound for binary-phase gratings, restrictions on the array phase are imposed. For fanouts that are >5, the upper bound on the diffraction efficiency for continuous phase fanouts ranges between 97 and 98%; for (0, pi)-binary-phase fanouts the upper bound ranges between 83 and 84%; and for (0, non-pi)-binary phase, between 87 and 88%. PMID- 20717368 TI - Design of two- and three-element diffractive Keplerian telescopes. AB - Design procedures for simple two- and three-element diffractive telescopes, suitable for monochromatic applications, are described. We obtained the basic configuration for the two-element design analytically by solving design equations to set the Seidel aberrations to target values. Computer optimization is used to complete the design of the doublet and triplet telescopes. The two- and three element designs exhibit similar optical performance and diffraction efficiency. We show that diffraction-limited performance can be obtained from these all diffractive systems. PMID- 20717369 TI - Silica glass fiber photorefractometer. AB - We report a fiber-optic refractive-index sensor that is applicable to a long distance measurement. The sensor consists of a silica glass fiber bent into a U shape with a bending radius of typically several hundred micrometers. The cladding at the tip of the sensor is stripped off. The sensing mechanism is based on the variation of the output intensity that is induced by radiation loss at the bend, which enables us to measure the refractive index of the outer medium. A fabrication method of fusing the sensor with a CO(2) laser and etching with HF is described. Multipoint measurements of optical-time-domain reflectometry are also described. PMID- 20717370 TI - Liquid-level sensor with optical fibers. AB - A liquid-level sensor, consisting of three optical fibers, is described. A light is projected onto an oil surface through a transmitting fiber. A receiving fiber picks up the light reflected from the oil surface. A reference fiber transmits the light from a light-emitting diode back and forth along the same path as that of the transmitting fiber and the receiving fiber. Division is accomplished by using the reflected signal and the reference signal, so it becomes possible to eliminate apparent distance variations that are due to the variations in light intensity, which may be caused by external forces and temperature changes. The distance range is 100 mm. PMID- 20717371 TI - Theory of noncontact point thermal sensing by fiber-optic radiometry. AB - This paper formulates a theory of noncontact point thermal sensing by fiber-optic radiometry. This theory covers the field of mid- and far-infrared fibers that are suitable for low-temperature radiometry. However, new problems arise in the infrared range, the emission of thermal radiation from the fiber itself due to infrared absorption introduces perturbations into the radiometry, and this must be taken into consideration. The model presented is based on three-dimensional optical geometry of bounded and tunneling skew rays and yields an analytical expression for the inclination and the skewness angle distribution of the guided power collected by the fiber from various layers of a thermal body. The effective field of view, the surface resolution, and the temperature resolution of fiber optic radiometry are discussed. Thermal sensing by direct coupling is shown to have an advantage over the coupling of a focusing lens located behind the fiber tip. A formulation of fiber emissivity is presented that quantifies the suppression of radiometric perturbations in fiber-optic thermal sensing. Bulk and surface absorption in the fiber core and cladding absorption are all taken into consideration deriving emissivity. Combining the transmissivity and emissivity of the fiber, we propose a measurable criterion, a figure of merit, for fiber-optic radiometry. PMID- 20717372 TI - Line-shape distortions in misaligned cube corner interferometers. AB - Line-shape distortions caused by the misalignment of the moving cube mirror in Fourier transform spectrometers have been described. A method of studying and correcting these distortions is presented. By using this method we can estimate the accuracy of the line position, which is especially important in high resolution Fourier transform spectroscopy. The method is verified in simulations, and in practice it has been used to align the Oulu Fourier transform spectrometer. PMID- 20717373 TI - Talbot interferometry in noncollimated illumination for curvature and focal length measurements. AB - We describe a simple method for measuring the radius of curvature by using Talbot interferometry in a noncollimated light beam. This scheme can also be used to determine the focal length of the collimating lens employed in the setup. Results of the measurements are presented. A discussion of achievable accuracies and the proper choice of parameters is included. PMID- 20717374 TI - Talbot effect reinterpreted. AB - Pattern generation in Talbot planes has generally been interpreted in terms of image formation, the repetitive slits are said to make repetitive images of themselves. In this context, Fourier optics developments have correctly predicted the positions of some but not all of the Talbot planes. Now, wave-optics methods are used to obtain general expressions for the positions of all known Talbot planes and the lateral positions of the diffraction fringes within them. These equations predict the key features of the Talbot effect, and they better relate multiple-slit diffraction in the Fresnel and Fraunhofer domains. PMID- 20717375 TI - Infrared refractive index of germanium-silicon alloy crystals. AB - The relationship between infrared refractive index and near-infrared, visible, and ultraviolet absorption spectra is examined. The long-wavelength limit and dispersion are determined as simple functions of composition. The computed results are compared with infrared ellipsometric measurements. PMID- 20717376 TI - Resonant cryogenic chopper. AB - We describe the design, construction, and performance of a resonant cryogenic chopper that operates at 4.2 K. The chopper is mechanically and thermally robust; it can occult a 2.54-cm aperture at 4.5 Hz while dissipating ~1 mW. Both the stator and rotor magnetic fields are controllable to allow for performance optimization and to help in measuring any possible interference effects. Data on long-term amplitude stability are presented. PMID- 20717377 TI - Some infrared materials for the Cooke triplet design for the 3-5-microm spectral region: a comparison. AB - The suitability of zinc sulfide versus germanium for the middle negative lens of the Cooke triplet is studied. For this purpose two designs based on the Cooke triplet configuration are developed with a focal length of 100 mm and a relative aperture of f/2 to cover a total field of 14 deg for use in the 3-5-microm region of the spectrum. For the outer positive lenses both designs use silicon. For the middle negative lens one design uses zinc sulfide and the other uses germanium. The performances of the two designs are compared. It is found that the design with the zinc sulfide negative lens performs better in monochromatic applications, and the design with a germanium negative lens performs better in polychromatic applications. PMID- 20717378 TI - Reflection and transmission coefficients in plane-parallel layers with refractive index mismatch. AB - A ray-tracing calculation that uses reflection and transmission coefficients for layers with refractive-index matched boundaries leads to the corresponding coefficients for refractive-index mismatch. The model is compared with Monte Carlo calculations for a range of layer parameters. The absorption by a mismatched layer is higher than the corresponding layer with matched boundaries and relatively insensitive to the extent of scattering anisotropy. The model should be useful for practical calculations on biological tissues where refractive-index mismatch is usually present. PMID- 20717379 TI - Variability in the vacuum-ultraviolet transmittance of magnesium fluoride windows. AB - In the course of the development of a domed magnesium fluoride detector window for the Space Telescope Imaging Spectrograph, slated to be a second-generation instrument aboard the Hubble Space Telescope, sample window materials from various commercial sources displayed a wide variability in vacuum ultraviolet transmittance. As a result a test program was undertaken in cooperation with the supplier of a prototype domed window to maximize transmittance. Results of the program have provided clues to the causes of the variations experienced, and they point to careful selection of raw materials and strict process control to achieve optimization. PMID- 20717380 TI - Delayed elastic effects in Zerodur at room temperature. AB - Continuous testing at room temperature of large optics made of Zerodur has revealed a delayed elastic effect under low stress levels during both load and recovery after removal. Using a high-performance mechanical profilometer, a delayed strain of the order of 1% is realized over a period of a few weeks. The time-dependent phenomenon is elastic and reversible, but must be accounted for in various applications of optical design. PMID- 20717381 TI - Image speckle contrast reduction resulting from integrative synthetic aperture imaging. AB - Reduction of image speckle noise with the use of an integrative synthetic aperture imaging technique is studied. It is found that the Fourier inversion of the mutual intensity estimate [Appl. Opt. 30, 206-213 (1991)] yields an image intensity that corresponds exactly to the illumination of the object with partially coherent light from source optics imaging a delta-function incoherent source. An expression for the signal-to-noise ratio at an image point is derived for a large rough object with delta-function correlated amplitude reflection. A synthetic aperture system receiver of sufficiently small diameter yields image speckle with a signal-to-noise ratio (SNR) equal to 1. When the receiver and the transmitter diameters are equal, the SNR is 2 for linearly polarized speckle. The SNR continues to increase with receiver size and is linear in the diameter for large receiver-to-transmitter diameter ratios. PMID- 20717382 TI - Distribution temperature calculations by fitting the Planck radiation curve to a measured spectrum. AB - A method of calculating distribution temperatures by numerically fitting Planck radiation curves to measured spectra is discussed. Numerically generated spectra were used to test the method and to determine the sensitivity to noise and the effects of linear emissivity changes. A comparison with the multiple-pair method of calculating color temperature as described in a previous paper [Appl. Opt. 27, 4073 (1988)] is presented. It was found that the method described here is ~ 2 times less sensitive to noise than the previously described method. Nonconstant emissivity (the linear model) produces the same effect on calculated distribution temperatures regardless of the calculating method. PMID- 20717383 TI - Analytic solutions for the optical properties of V-trough concentrators. AB - Closed-form analytic solutions that describe the optical behavior of V-trough concentrators are derived. The procedure analyzes the angular and spatial distribution of all the rays that undergo a given number of reflections (0, 1, 2), referred to as reflection modes. Then we obtain (1) the optical efficiency for beam and diffuse radiation, and (2) spatial and angular flux distribution on the absorber, with proper account being taken of reflective losses (in addition to the geometric losses of rejected rays). These are often essential -data for evaluation of V-trough solar energy collectors, in particular for photovoltaic applications where homogeneous flux distributions are desirable. PMID- 20717384 TI - Optical diagnostics of slightly rough surfaces. AB - The relationship between the statistical structure parameters of a rough surface and the associated correlation parameters of a scattered field is used to develop a method for rough-surface diagnostics. The treatment is based on the model of a random phase object with an inhomogeneity phase dispersion sigma(phi0)(2) < 1. The proposed diagnostic methods are applicable to surfaces with a roughness period comparable to the radiation wavelength employed and the surfaces of a thin plane-parallel plate. The sensitivity limit of the methods in measuring the standard deviation of surface-roughness element heights is ~0.003 microm. PMID- 20717386 TI - Dichromated gelatin reflection holographic optical element derived from Kodak 649F plates. AB - The characteristics of diffraction efficiency and spectral bandwidth of dichromated gelatin reflection holograms formed by a modified processing method are presented. PMID- 20717385 TI - Modulation-transfer function measurement of SPRITE detectors: sine-wave response. AB - A method is presented for measuring the modulation transfer function of signal processing in the element (SPRITE) detectors with a HgCdTe composition optimized for the 3-5-microm band. This method incorporates a 3.39-microm He-Ne laser to generate Young's fringes of varying spatial frequency, which are scanned across the detector elements. The results are consistent with theoretical models for these devices and indicate a limited resolution capability for SPRITE detectors used for the 3-5-microm band. PMID- 20717387 TI - Full complex modulation using liquid-crystal televisions. AB - An optical architecture is proposed that uses two modified liquid-crystal televisions (LCTV's) to control amplitude and phase modulation independently. Two applications in pattern recognition are discussed. PMID- 20717388 TI - Metrics for assessing pattern-recognition performance. AB - Various metrics used to measure correlation filter performance are discussed. Their similarities and deficiencies are noted, and modifications are suggested. A computer simulation is included to highlight these differences. PMID- 20717389 TI - Fault avoidance for fixed-interconnect optical computers. AB - Optical computers can be assembled by using fixed-interconnect structures to connect two-dimensional optical arrays. A four-phase model of the optical computer assembly is described, and the roles of design density (i.e., the number of available gates used in a design) and fault density and the assembly technique are empirically investigated. Low-cost array assignment techniques that make use of optical logic arrays with faulted gates and multiple-array orientations are introduced and shown to increase an effective yield by between 50 and 100%. These techniques provide near-optimal solutions to the general optimal array assignment problem, which is shown to belong to the complexity class NP-hard. PMID- 20717390 TI - Cascade-connective optical parallel logic processor using electrophotonic devices. AB - To perform image or arithmetic processing optically, it is necessary that a large number of required optical processors be connected in a series. For such cascade connections, however, coding and decoding processes are undesirable because of the necessity for the complicated hardware that often results. We propose here a new logic algorithm for application to cascade connections, which utilizes, in place of coding and decoding processes, true logic signals and their complements. Its optical implementation is also discussed. A processing module is constructed from electro-photonic devices referred to as vertical to surface transmission electro-photonic devices, a ferroelectrical liquid-crystal spatial light modulator, and a planar microlens array. Its logic operations are successfully demonstrated. PMID- 20717391 TI - Coherent optical processing using noncoherent light after source masking. AB - Coherent optical processing starting with spatially noncoherent illumination is described. Good spatial coherence is introduced in the far field by modulating a noncoherent source when masks with sharp autocorrelation are used. The far-field mutual coherence function of light is measured and it is seen that, for the masks and the source size used here, we get a fairly large area over which the mutual coherence function is high and flat. We demonstrate traditional coherent processing operations such as Fourier transformation and image deblurring when coherent light that is produced in the above fashion is used. A coherence redundancy merit function is defined for this type of processing system. It is experimentally demonstrated that the processing system introduced here has superior blemish tolerance compared with a traditional processor that uses coherent illumination. PMID- 20717392 TI - Zone plates with black focal spots. AB - Computer-designed linear and circular zone plates are considered that utilize a pi ;-phase jump in order to create destructive interference in the focus. Intensity distributions in the focal plane as well as along the optical axis are calculated for a few examples. A significant decrease of the black spot diameter in comparison with the dimensions of the ordinary focal spot is obtained. Further reduction is achieved when the central region of the zone plate is obstructed. Some applications to alignment and the schlieren technique are suggested. Experimental results that confirm the calculated distributions are presented. PMID- 20717393 TI - Holographic associative memory based on adaptive learning including outer-product learning. AB - We have developed a new holographic associative memory based on adaptive learning, which uses a learning pattern method (LPM). This LPM utilizes the simple optical implementation of outer-product learning. However, we have obtained a better performance from adaptive learning. Results from the optical experiment and computer simulation are represented. PMID- 20717394 TI - Rainbow holography using a large aperture lens for a full object beam. AB - A method of making rainbow holograms by using a full object beam is described. In this technique we simultaneously use a moving object and a moving imaging lens, instead of using a slit during the exposure process. The position of the synthetic slit is independent of the position of the imaging lens and its focal length. Using this method, a one-step rainbow holographic image with a large visual field and high resolution can be obtained. A theoretical analysis and some experimental results are presented. PMID- 20717395 TI - Double-pulse characteristics of a single-oscillator Nd:YAG laser affecting its performance in TV holography. AB - The relevance of several double-pulse laser parameters for the fringe quality in TV holography is emphasized theoretically. It is demonstrated that single oscillator Nd:YAG lasers can show significantly reduced characteristics in double pulse operation, limiting the performance of these lasers in double-pulse TV holography. PMID- 20717396 TI - Holographic three-dimensional printer: new method. AB - We propose a holographic three-dimensional (3-D) printer that produces 3-D hard copies of computer data. A new technique for synthesizing a holographic stereogram (HS) has been invented for the purpose of making accurate hard copies of 3-D objects. The flat-format, Lippmann-type HS is printed by one optical step and is ideally suitable for 3-D printer application. This type of HS has both horizontal and vertical parallaxes so that the reconstructed image is free from distortion. The principle and the image quality of this type of HS are described, and a reconstructed image from this type of HS with 160 x 128 elements is experimentally demonstrated. The systematic constitution of a holographic 3-D printer is also discussed. PMID- 20717397 TI - Computer-generated three-dimensional image holograms. AB - A synthetic generation of three-dimensional image holograms is suggested. The complex amplitude in the hologram is calculated by using the spectrum of plane waves. Specifically, three-dimensional images are composed of planar and inclined two-dimensional distributions. In display applications, large hologram apertures can be achieved by introducing a remote exit pupil. A synthetic three-dimensional image is optically reconstructed. PMID- 20717398 TI - Target location measurement by optical correlators: a performance criterion. AB - When optical correlators are used for target location measurement or tracking, errors in the position estimation may be induced by the presence of noise and additional objects in the field of view. The variance of the positioning error is evaluated with its dependence on the capabilities of the spatial filter to discriminate among the patterns in the observation field, the shape of the correlation functions, and the noise. PMID- 20717399 TI - Large fanout optical interconnects using thick holographic gratings and substrate wave propagation. AB - Substrate wave propagation and Bragg diffraction by multiplexed holographic gratings have been used to demonstrate a new 1-to-30 fanout optical interconnect having an overall diffraction efficiency of 87.8% at 514.5 nm and an individual channel efficiency of approximately 3.0 +/- 0.8%. The device configuration utilizes the large multiplexing capability of dichromated gelatin polymer films and substrate total internal reflection to realize large channel fanouts within the plane of a soda-lime glass substrate. A simplified theoretical formulation is presented to treat the corresponding three-dimensional holographic diffraction problem in the Bragg regime for slanted phase gratings. Results are compared with experimentally measured quantities for singly exposed phase gratings in different polarization conditions and incident angle orientations. The limitations of using multiplexed holograms in multiplanar substrate interconnection applications are also discussed. PMID- 20717400 TI - Quasi-symmetric electrochromic device for light modulation. AB - A new quasi-symmetric electrochromic device is described for transmission modulation of a switchable window. The calculation technique to design such an electrochromic window for transmission (or reflection) modulation is applied to the (electrode/WO(3)/electrolyte/WO(x)/electrode) system. Advantages and limits of such a quasi-symmetrical system are also discussed. PMID- 20717401 TI - Three-dimensional lensless imaging using laser frequency diversity. AB - A laser radar system for three-dimensional (3-D) lensless imaging is analyzed in theory and experiment. 3-D imaging is accomplished by making use of the relationship between the angular and wavelength dependence of the scattered light and an object's 3-D Fourier transform. The concept is demonstrated by obtaining a 3-D image of an extended object by using a charge-coupled device detector array and an argon-ion laser with a tunable intracavity etalon. PMID- 20717402 TI - Noise analysis of polarization-based optoelectronic connectionist machines. AB - Adaptive optical systems such as the bipolar, polarization-based optical connectionist machine are capable of operating in the presence of substantial noise generated by optoelectronic devices such as spatial light modulators, sources, and detectors. We present results on two optoelectronic connectionist machines that implement the single-layer delta rule and backward error propagation neural network algorithms and analyze the influence of noise on their performance. Results show that an optoelectronic neural network with 200 input units can easily classify 30 random patterns with a spatial light modulator contrast ratio of 10:1 and output cross talk of 10%. PMID- 20717403 TI - Patents. AB - 4,930,887; 4,969,717; 4,890,893; 4,942,581; 4,968,107; 4,921,354; 4,972,429. PMID- 20717404 TI - Nasa patter. PMID- 20717406 TI - Women swell ranks of science but remain invisible at the top. PMID- 20717407 TI - Diffraction-limited collimation optics for a channel waveguide Cerenkov frequency doubler for diode lasers. AB - Optical path analysis applying diffraction theory and geometrical ray tracing, and with collimation experiments shows that a hemiconic lens can convert the arc of blue radiation formed by Cerenkov second-harmonic generation to a parallel plane wave. To obtain an aberration-free plane wave, we modified the apex angle of the cone according to the birefringence of the waveguide. To correct chromatic aberration, we needed to have diode laser wavelength tuning with the aid of an achromatic cone lens doublet. PMID- 20717408 TI - Aerosol-induced laser breakdown thresholds: effect of resonant particles. AB - Laser intensity thresholds for the onset of stimulated Raman scattering and the breakdown in resonant micro-meter-sized droplets are reduced to below those for nonresonant droplets by a factor of ~ 3. This reduction is most likely caused by the enhancement of electromagnetic energy (photon) densities within the droplets over and above that in nonresonant droplets. The magnitude of the threshold reduction for breakdown is consistent with the assertion that (1) input (pump) wavelength resonances that initiate plasma have cavity Q's of ~ 10(4) and (2) finite regions of high-electromagnetic-energy density within the droplet, with dimensions of the order of the Debye length, are required to initiate plasma. PMID- 20717409 TI - Mode-medium instability and its correction with a Gaussian-reflectivity mirror. AB - A high-power CO(2) laser beam is known to deteriorate after a few microseconds because of a mode-medium instability (MMI) that results from an intensity dependent heating rate that is related to the vibrationalto-translational decay of the upper and lower CO(2) lasing levels. An iterative numerical technique has been developed to model the time evolution of the beam as it is affected by the MMI. The technique is used to study the MMI in an unstable CO(2) resonator with a hard-edge output mirror for different parameters, e.g., the Fresnel number and the gas density. The results show that the mode of the hard-edge unstable resonator deteriorates because of the diffraction ripples in the mode. We use a Gaussian-reflectivity mirror to correct the MMI. This mirror produces a smoother intensity profile, which significantly reduces the effects of the MMI. Quantitative results on the peak density variation and beam quality are presented. PMID- 20717410 TI - High-speed switching of far-infrared radiation by photoionization in a semiconductor. AB - An investigation of subnanosecond switching of 119-microm radiation achieved by irradiating high-resistivity silicon wafers with 1.7-ns, 337-nm pulses from a nitrogen laser is presented. The experimental results are compared with a one dimensional numerical multilayer model, which accounts for the generation, recombination, and diffusion of the free carriers and the resulting change of the far-infrared optical properties of the Si wafer. PMID- 20717411 TI - Low power response of all-optical crossbar networks in quantum well heterostructures. AB - A new device configuration has been examined for its potential as a compact, all optical modulator, operating at low input powers (~ 3 mW). This device utilizes the large optical nonlinearities of Al(x)Ga(1-x)As/GaAs multiple quantum well heterostructures to modulate a low power-guided wave test beam with an orthogonally propagating control beam. This configuration has the advantage of maximizing the packing density of nonlinear modulators having interaction lengths of only ~ 5 microm. Several modes of device operation are possible, including thermal modulation, optical limiting, bistable switching, and multiple-input logic. We present experimental results for the throughput of single and multiple waveguide beams, as well as for the operation of this device as a waveguide modulator array. A theoretical model is compared with the experimental results for input pulse lengths ranging from ~ 300 ns to 1 s and input powers up to ~ 3 mW. Several optical nonlinearities are experimentally observed, including an electronic nonlinearity and two thermal effects, which are classified as either local or global in origin, with time constants of ~ 30 ns, ~ 4 micros, and ~ 40 ms, respectively. For an optimized waveguide geometry, the intrinsic optical device described herein should be suitable for use in systems requiring fast, high-density waveguide arrays for optical computing and serial/parallel data processing applications. PMID- 20717412 TI - Application of time-resolved infrared spectral photography to chemical kinetics. AB - We discuss the application of time-resolved infrared spectral photography to the determination of the time-dependent reactant and product concentrations in the simple chain reaction of chlorine atoms, generated by pulsed photolysis, with ethane-Cl(2) mixtures. The technique and experimental results are discussed in terms of the limitations and advantages of the method for general kinetic studies in the microsecond and submicrosecond time domain. PMID- 20717413 TI - Lidar receivers without overlap of the photomultiplier's single pulses. AB - Lidar receivers of linear performance without overlap of the single pulses are analyzed. The statistics of output signals are investigated by using a model of the photoreceiving system that is based on the conversion of secondary electron trains into single-frequency decayed oscillations. I show that the lidar profile can be separated into nonuniform and uniform parts and a background and sampled by low-speed analog-to-digital converters (12-16 bits/0.01-100 kHz) to provide high amplitude and temporal resolution. The nonstationary background is reduced without chopping to the square root of its intensity. The use of the lidar receivers is discussed. PMID- 20717414 TI - Third-order anisotropies in cubic crystals. AB - Third-order difference-frequency generation of the type omega = 2omega(1) - omega(3) has been used to determine accurately the cubic nonlinearities of various crystals of the space group Fm3m. The samples were rotated under well defined polarization conditions of the incoming fields of frequencies omega(1) and omega(3). Ratios of anisotropic to isotropic contributions have been derived, and an attempt has been made to obtain absolute nonlinear susceptibility data by comparison with BK7 glass. PMID- 20717415 TI - Approximate methods for modeling the scattering properties of nonspherical particles: evaluation of the Wentzel-Kramers-Brillouin method. AB - Several approximate methods for modeling the electromagnetic (em) scattering properties of nonspherical particles are examined and evaluated. Although some of the approaches are applicable to arbitrary shapes we confine our attention here mainly to spheres and cylinders, for which exact solutions are available for comparisons. Evaluations include comparisons of the computed angular phase function, total extinction efficiency, and backscatter efficiency. Approximate methods investigated include the Rayleigh-Gans (RG) approximation, the Wentzel Kramers-Brillouin or WKB approximation [and the closely related eikonal approximation (EA)], diffraction theory, and the second-order Shifrin iterative technique. Examples using spheres indicate that for weakly absorbing particles of moderate- to large-size parameters with a real refractive index near unity (i.e., the optically soft case), all models work well in representing the phase function over all scattering angles, with the Shifrin approximation showing the best agreement with the exact solutions. For larger refractive indices, however, the Shifrin approximation breaks down, whereas the WKB method continues to perform relatively well for all scattering angles over a wide range of particle sizes, including those appropriate in both the RG (small particle) and the diffraction (large particle) limits. The relationship between the WKB, eikonal, and anomalous diffraction descriptions of particle extinction is discussed briefly. Backscatter is also discussed in the context of the WKB model, and two modifications to improve the description are included: one to add an internal-reflected internal wave and the other to add a multiplicative scaling factor to preserve the correct backscatter result for strong absorption in the geometric optics limit. A major conclusion of the paper is that the WKB method offers a viable alternative to the more widely used RG and diffraction approximations and is a method that offers significant improvement in accuracy with only a slight increase in mathematical complexity. PMID- 20717416 TI - Spatial coherence of KrF excimer lasers. AB - The spatial coherence and the beam divergence at 248 nm of a KrF excimer laser were obtained experimentally. These results are in good agreement with the theoretical calculations based on a simple pulse-laser model and the van Cittert Zernike theorem. The relation between the spatial coherence and the beam divergence was obtained theoretically and supported by experimental results. This expression is given as a function of the wavelength of the laser but includes no parameters related to the laser structure. It is shown that these theoretical results are applicable to various kinds of pulse laser. PMID- 20717417 TI - Diffraction effects in a resonant cavity with two nonequivalent apertures. AB - Diffraction patterns and divergence of the fundamental mode of a laser are studied in the case of a plano-concave cavity with two-apertured mirrors. The effects of both apertures are shown to be nonequivalent. The sizes of their diameters control the geometry of the beam and, in particular, control the increase or the decrease of the divergence with respect to that of the nondiaphragmed cavity. PMID- 20717418 TI - Mode locking of a Cr:YAG laser with carbon nanotubes. AB - We report on mode locking of a bulk Cr:YAG laser by using a transmission-type single-walled carbon nanotube saturable absorber. Stable and self-starting laser operation in the picosecond and femtosecond regimes is obtained at wavelengths around 1.5 microm. Tunable transform-limited sub-100 fs pulses are generated at a repetition rate of 85 MHz with an output power up to 110 mW. PMID- 20717419 TI - All optical wavelength broadcast based on simultaneous Type I QPM broadband SFG and SHG in MgO:PPLN. AB - We experimentally demonstrate wavelength broadcast based on simultaneous Type I quasi-phase-matched (QPM) broadband sum-frequency generation (SFG) and second harmonic generation (SHG) in 5 mol.% MgO-doped periodically poled lithium niobate (MgO:PPLN). One signal has been synchronously converted into seven different wavelengths using two pumps at a 1.5 microm band via quadratic cascaded nonlinear wavelength conversion. By selecting different pump regions, i.e., selecting different cascaded chi((2)):chi((2)) interactions, the flexible wavelength conversions with shifting from one signal to single, double, and triple channels were also demonstrated. PMID- 20717420 TI - Passive mode locking in a Ti:sapphire laser using a single-walled carbon nanotube saturable absorber at a wavelength of 810 nm. AB - We report mode locking in a Ti:sapphire (Ti:Sa) laser at the wavelength of 810 nm using a polymer film with single-walled carbon nanotubes (SWNTs) applied as a saturable absorber. Pulses with 600 fs duration and 0.4 nJ energy were generated from the Ti:Sa laser with polymer-SWNT composite film for cw passive mode locking. PMID- 20717421 TI - Efficient second-harmonic generation and modal dispersion effects in orientation patterned GaAs waveguides. AB - Efficient second-harmonic conversion of 4 microm radiation was demonstrated in orientation-patterned GaAs (OPGaAs) waveguides (WGs). An experimentally corrected phase-matching curve for second harmonic generation (SHG) in OPGaAs WGs is presented. Influence of WG modes on the SHG process was studied. Two distinct types of SHG in the waveguides were identified and related to the TE and TM modes. Each type has its own dependence on pump polarization. The 21% W(-1) normalized conversion efficiency is within a factor of 0.75 from the predicted value for an ideal WG. PMID- 20717422 TI - Cylindrical cloaking at oblique incidence with optimized finite multilayer parameters. AB - We propose multilayer cylindrical invisibility cloaks that are optimized for oblique incidences through a combination of analytic formalism of scattering and genetic optimization. We show that by using only four layers of homogeneous and anisotropic metamaterials without large values of constitutive parameters, the scattering for oblique incidences can be reduced by 2 orders. Although the optimization is done at a single incident angle, the cloak provides reduced scattering over a large range of incident angles. PMID- 20717423 TI - On the theory of the modulation instability in optical fiber amplifiers. AB - The modulation instability (MI) in optical fiber amplifiers and lasers with anomalous dispersion leads to cw radiation breakup. This can be both a detrimental effect limiting the performance of amplifiers and an underlying physical mechanism in the operation of MI-based devices. Here we revisit the analytical theory of MI in fiber optical amplifiers. The results of the exact theory are compared with the previously used adiabatic approximation model, and the range of applicability of the latter is determined. PMID- 20717424 TI - Pulsed orange generation optimized in a diode-pumped Nd:YVO4 laser using monolithic dual PPLN electro-optic Q switches. AB - We report a pulsed intracavity sum-frequency generator in a diode-pumped, dual wavelength Nd:YVO(4) laser whose operation was optimized with two electro-optic Q switches built in a monolithic periodically poled lithium niobate (PPLN) crystal. The dual PPLN Q switches, though integrated, are able to work separately at their respective working wavelengths of 1064 and 1342 nm. At 4.8 W diode pump power and 5 kHz Q-switching rate, a maximum orange (593 nm) output peak power of >480 W was achieved in this laser system using the Q-switch opening-time offset technique. This power is approximately 1.7 times higher than that obtained with the system operated in a conventional single-Q-switch mode. PMID- 20717425 TI - Continuous-wave spontaneous lasing in mercury pumped by resonant two-photon absorption. AB - We demonstrate the first cw two-photon absorption laser-induced stimulated emission. The 7(1)S(0)-6(1)P(1) transition in mercury at a 1014 nm wavelength is used, and selective lasing of different isotopes is observed. PMID- 20717426 TI - Plasmonic modes of extreme subwavelength nanocavities. AB - We study the physics of a new type of subwavelength nanocavities. They are based on U-shaped metal-insulator-metal waveguides supporting the excitation of surface plasmon polaritons. The nanocavity arrays are excited by plane waves at either a normal or oblique incidence. Because of their finite length, discrete modes emerge within the nanocavity. We show that the excitation symmetry with respect to the cavity ends permits the observation of even and odd modes. Our investigations include near- and far-field simulations and predict a strong spectral far-field response of the comparably small nanoresonators. The strong near-field enhancement observed in the cavity at resonance might be suitable to increase the efficiency of nonlinear optical effects and quantum analogies and might facilitate the development of optical elements, such as active plasmonic devices. PMID- 20717427 TI - On the generation of octave-spanning optical frequency combs using monolithic whispering-gallery-mode microresonators. AB - Octave-spanning optical frequency combs are especially interesting in optical metrology owing to the ability of self-referencing. We report a theoretical study on the generation of octave-spanning combs in the whispering gallery modes of a microresonator. Through a modal expansion model simulation in a calcium fluoride microcavity, we show that a combination of suitable pump power, Kerr nonlinearity, and dispersion profile can lead to stable and robust octave spanning optical frequency combs. PMID- 20717428 TI - Signal-to-noise performance of a short-wave infrared nanoinjection imager. AB - We report on the signal-to-noise performance of a nanoinjection imager, which is based on a short-wave IR InGaAs/GaAsSb/InP detector with an internal avalanche free amplification mechanism. Test pixels in the imager show responsivity values reaching 250 A/W at 1550 nm, -75 degrees C, and 1.5V due to an internal charge amplification mechanism in the detector. In the imager, the measured imager noise was 28 electrons (e(-)) rms at a frame rate of 1950 frames/s. Additionally, compared to a high-end short-wave IR imager, the nanoinjection camera shows 2 orders of magnitude improved signal-to-noise ratio at thermoelectric cooling temperatures primarily due to the small excess noise at high amplification. PMID- 20717429 TI - Fracture-induced subbandgap absorption as a precursor to optical damage on fused silica surfaces. AB - The optical damage threshold of indentation-induced flaws on fused silica surfaces was explored. Mechanical flaws were characterized by laser damage testing, as well as by optical, secondary electron, and photoluminescence microscopy. Localized polishing, chemical leaching, and the control of indentation morphology were used to isolate the structural features that limit optical damage. A thin defect layer on fracture surfaces, including those smaller than the wavelength of visible light, was found to be the dominant source of laser damage initiation during illumination with 355 nm, 3 ns laser pulses. Little evidence was found that either displaced or densified material or fluence intensification plays a significant role in optical damage at fluences >35 J/cm(2). Elimination of the defect layer was shown to increase the overall damage performance of fused silica optics. PMID- 20717430 TI - Geometric superresolution of a CCD pixel. AB - In digital imaging, resolution is mostly limited by the nonzero pixel size of the CCD detector. The pixel averages out all the spatial variations falling over it and reduces the overall resolution of the digital image. This Letter introduces a geometric superresolution technique for resolving a pixel into N number of subpixels in one dimension by scanning a mask over it while keeping the imager and scene relatively fixed. PMID- 20717431 TI - Group-index engineering in silicon corrugated waveguides. AB - We demonstrate group-index engineering in a one-dimensional periodic silicon structure consisting of a deep-etched laterally corrugated waveguide with circular holes patterned onto its wide section. Our theoretical analysis, supported by experimental results, shows that the first-order optical mode can propagate inside the Brillouin zone with a relatively high group index over a wide frequency range. Nearly constant group index as high as 13.5 over a wavelength range of approximately 14 nm is experimentally demonstrated in a 50 microm-long waveguide. PMID- 20717432 TI - All-optical fabrication of ellipsoidal caps on azobenzene functional polymers. AB - We have fabricated an azobenzene (azo) polymer microellipsoidal cap array of hexagonal symmetry with high-power laser ablation and subsequent single-beam induced mass migration. High-power interference with polarization-controlled triple beams is utilized to inscribe a circular bump array directly on the surface of the azo polymer film. The produced circular cap array is exposed to the linearly polarized beam, and the caps are stretched along the polarization direction of the irradiating beam. A model of gradient force emerged by the interaction of the polarized beam and azo polymer is constructed to explain the mechanism of such polarization-induced microscale shape deformation. PMID- 20717433 TI - High-repetition-rate, high-peak-power, linear-polarized 473 nm Nd:YAG/BiBO blue laser by extracavity frequency doubling. AB - We report on a high-repetition-rate, high-peak-power, linear-polarized 473 nm blue laser. A high-power 946 nm fundamental laser was obtained based on a diode pumped acousto-optically (AO) Q-switched Nd:YAG laser using a thermal compensating resonator and a microchannel heat sink for thermal dissipation. A pulsed 473 nm laser was generated using a BiB(3)O(6) (BiBO) crystal as an extracavity frequency doubler. The highest peak power of a 16.7 kW blue laser was obtained at a pulse repetition rate of 10 kHz with a pulse width of 9 ns. Stable operation of the pulsed blue laser can even reach 50 kHz. PMID- 20717434 TI - Broadband emission spectrum dynamics of large water droplets exposed to intense ultrashort laser radiation. AB - We report on experiments on the interaction of a gigawatt femtosecond laser pulse train with hanging isolated millimeter-sized water droplets. A transparent droplet experienced explosive boiling-up and emitted light in the visible spectrum as a result of laser-induced plasma formed inside the droplet volume. The droplet emission spectra showed remarkable broadening, depending on the laser power. The role of pulse self-phase modulation in measured spectral broadening when the pulse propagates through the droplet is discussed. PMID- 20717435 TI - Circularly polarized guided modes in dielectrically chiral photonic crystal fiber. AB - The effect of dielectric chirality on the polarization states and mode indices of guided modes in photonic crystal fiber (PCF) is investigated by a modified plane wave expansion (PWE) method. Using a solid-core chiral PCF as a numerical example, we show that circular polarization is the eigenstate of the fundamental mode. Mode index divergence between right-handed circularly polarized (RCP) and left-handed circularly polarized (LCP) states is demonstrated. Chirality's effect on mode index and circular birefringence (CB) in such a PCF is found to be similar to that in bulk chiral media. PMID- 20717436 TI - Extracting photon periodic orbits from spontaneous emission spectra in laterally confined vertically emitted cavities. AB - We report our observation of the signature of photon periodic orbits in the spontaneous emission spectra of large-aperture vertical-cavity surface-emitting lasers (VCSELs). The high-resolution measurement clearly demonstrates that over a thousand cavity modes with a narrow linewidth can be perfectly exhibited in the spontaneous emission spectrum just below the lasing threshold. The Fourier transformed spectrum is analyzed to confirm that the spontaneous emission spectra of large-aperture VCSELs can be exploited to analogously investigate the energy spectra of the 2D quantum billiards. PMID- 20717437 TI - Wavelength-division-multiplexing fiber coupler based on bending-insensitive holey optical fiber. AB - A wavelength-division-multiplexing (WDM) coupler has been made with a bending insensitive holey optical fiber (HOF) by using the fused biconical tapered (FBT) method. The transmission band of the proposed HOF WDM coupler could be easily tuned by adjusting the pulling length during the FBT process. Interestingly, it was observed that the air-hole structure of the HOF should be maintained to have the property of a WDM coupler. As the air holes collapse, the HOF WDM exhibits high-pass-filter-like properties. The cross-sectional scanning electron microscope images of the implemented HOF WDM coupler are presented along with the light intensity distribution measured at the coupling region of the coupler. The proposed HOF couplers may also find applications in optical coarse WDM systems and optical fiber sensors. PMID- 20717438 TI - Plasmonic resonance scattering from silver nanowire illuminated by tightly focused singular beam. AB - We investigate scattering features of tightly focused singular beams by placing a cylindrical nanowire in the vicinity of a line phase singularity. Applying an illumination wavelength corresponding to silver cylinder plasmonic resonance, we compare the scattering response with that of a perfect conductor. The rigorous modeling employs a 2D version of the Richards-Wolf focusing method and the source model technique. It is found that a cylinder with a plasmonic resonance produces a strong scattering response by deflecting the power flow toward the optical singularity region, where otherwise the power approaches zero. PMID- 20717439 TI - Time-gated optical projection tomography. AB - We present an imaging technique that combines optical projection tomography with ballistic imaging using ultrafast time gating. The method provides high resolution reconstruction of scattering samples and is suitable for three dimensional (3D) imaging of biological models. PMID- 20717441 TI - Observation of localized modes at phase slips in two-dimensional photonic lattices. AB - We experimentally study light localization at phase-slip waveguides and at the intersection of phase slips in a two-dimensional (2D) square photonic lattice. Such systems allow for the observation of a variety of effects, including the existence of spatially localized modes for low powers, the generation of strongly localized states in the form of discrete bulk and surface solitons, as well as a crossover between one-dimensional and 2D localization. PMID- 20717440 TI - Endoscope lens with dual fields of view and resolutions for multiphoton imaging. AB - We report the development of a miniaturized dual-optical-zone endoscope objective lens. The lens has two foci, with 0.18 and 0.50 NAs. We demonstrate multiphoton imaging with dual fields of view and resolutions using the new lens. A combination of multiphoton and single-photon microscopic imaging is also demonstrated. PMID- 20717442 TI - Integrated approach to laser delivery and confocal signal detection. AB - We present an on-chip arrayed waveguide grating (AWG) sensor based on the confocal arrangement of two AWGs, one acting as focusing illuminator and one as signal collector. The chip can be close to, or in direct contact with, a sample, e.g., biological tissue, without the need of external optics. The collection efficiency of our device can be more than 1 order of magnitude higher than that of a standard AWG, in which light is collected by one input channel. Experimental results on the collection efficiency and volume are presented, together with a demonstration of multiwavelength imaging. PMID- 20717443 TI - Coherent and ultrafast manipulation of entanglement sudden death and recurrence. AB - We investigate the entanglement dynamics of the bipartite system, consisting of two interacting two-level atoms in QED, which are driven additionally by coherent double ultrashort laser pulses characterized by various phase differences. Results show that the relative phase difference can exert significant influence on the entanglement evolution, such as delaying or accelerating entanglement sudden death and recurrence (ESD and ESR). Furthermore, with the increase of detuning, ESD and ESR disappear, irrespective of various phase differences. Our analysis is helpful in manipulating entanglement. PMID- 20717444 TI - Full-scale phase demodulation approach for photonic instantaneous frequency measurement. AB - A full-scale phase demodulation approach based on two quadrature power ratios is proposed to perform photonic instantaneous frequency measurement (P-IFM). In the proposed approach, a delay-line interferometer (DLI) and two laser sources are used. The wavelengths of two lasers are located at the peak point of and at the 3 dB point of the comb filtering response of the DLI. Therefore, at the two wavelengths, a cosine-shape and a sine-shape filtering response are formed to process the +1st or -1st order sidebands, which are generated by externally modulating the light waves of the two lasers with a microwave signal. After being filtered, two quadrature power ratios, cosine-shaped and sine-shaped responses, are obtained at the two wavelengths via power detection and power comparison. The phase term induced by the frequency is then demodulated from the two power ratios without ambiguity within the full-scale range of 0-2pi, the so-called full-scale phase demodulation, which has been verified in a proof-of-concept experiment. Unlike a half-scale range of 0-pi, such a full-scale range of the proposed approach makes it a potential solution to design parallel or cascaded configurations to P-IFM to enhance the measurement range and the resolution. PMID- 20717445 TI - Rapid passage signals induced by chirped quantum cascade laser radiation: K state dependent-delay effects in the nu2 band of NH3. AB - In this Letter, a 10 microm quantum cascade laser operating in the intrapulse mode is used observe rapid passage (RP) effects within a 40 cm single-pass gas cell containing low pressures of NH(3). The laser tuning range allows the rotational states J=2 with K=0, 1, and 2 to be probed. We show that the RP structures change as a function of optical density and that the magnitude of the delay in the switch from absorption to emission as a function of increased gas pressure is dependent upon the initial value of K. These measurements are qualitatively well modeled using the Maxwell-Bloch equations. PMID- 20717446 TI - 40 GHz electro-optic modulation in hybrid silicon-organic slotted photonic crystal waveguides. AB - In this Letter we demonstrate broadband electro-optic modulation with frequencies of up to 40 GHz in slotted photonic crystal waveguides based on silicon-on insulator substrates covered and infiltrated with a nonlinear optical polymer. Two-dimensional photonic crystal waveguides in silicon enable integrated optical devices with an extremely small geometric footprint on the scale of micrometers. The slotted waveguide design optimizes the overlap of the optical and electric fields in the second-order nonlinear optical medium and, hence, the interaction of the optical and electric waves. PMID- 20717447 TI - Dissipative soliton generation in Yb-fiber laser with an invisible intracavity bandpass filter. AB - We report on dissipative soliton (DS) generation in an Yb-doped (YDF) fiber laser passively mode locked with the nonlinear polarization rotation (NPR) technique. We found that even without the insertion of a physical bandpass filter in the cavity, not only could DSs be automatically formed in the laser but also the formed DSs have a spectral bandwidth that is far narrower than the Yb-fiber gain bandwidth. Numerical simulations well reproduced the experimental observations. Our results suggest that a physical intracavity bandpass filter is not a crucial component for the generation of DSs in all-normal-dispersion YDF lasers mode locked with the NPR technique. PMID- 20717448 TI - Dual-mode control of light by two-dimensional periodic structures realized in liquid-crystalline composite materials. AB - We report on the realization of a 2D refractive structure consisting of a polymer liquid-crystal polymer slice grid. Nematic liquid crystal microdomains are confined inside well-sculptured elliptical cavities; experimental investigation shows that the liquid crystal director lies in the plane of the structure and its orientation follows a preferred direction. The sample exhibits both an electro optical and an all-optical response owing to a small percentage of photosensitive azo dye included in the structure. A double external control of the two dimensional grating efficiency can indeed be operated either by an optical pump beam or by the standard technique of applying a suitable external voltage to the sample. PMID- 20717449 TI - Intermodulation distortion in microwave phase shifters based on slow and fast light propagation in semiconductor optical amplifiers. AB - We show theoretically and validate experimentally the effect of filtering on the nonlinear behavior of slow and fast light links based on coherent population oscillations in semiconductor optical amplifiers. The existence of a dip in the power-versus-current characteristics for the fundamental frequency, as well as for the third-order intermodulation product, is clearly evidenced. These two dips occur at different bias currents. Their depths increase as the filtering strength of the red sideband is increased, and they completely vanish in the unfiltered case. Influence on the microwave photonics link is discussed. PMID- 20717450 TI - Anisotropic Raman scattering in collagen bundles. AB - Collagen is the main connective tissue protein of vertebrates and shows exceptional mechanical and optical properties. The alignment of collagen fibrils correlates to the function of a specific tissue and leads to optical anisotropy. The effect of the molecular alignment on Raman scattering, however, has barely been investigated. We found that the peak intensities of the C-C, C=O, and N-H vibrational modes, which are typical for the Raman bands of the protein backbone, change with the orientation of the collagen fibrils. These observations demonstrate that Raman spectra contain specific information regarding molecular and fiber alignment. PMID- 20717451 TI - Highly anisotropic decay rates of single quantum dots in photonic crystal membranes. AB - We have measured the variation of the spontaneous emission rate with polarization for self-assembled single quantum dots in two-dimensional photonic crystal membranes. We observe a maximum anisotropy factor of 6 between the decay rates of the two bright exciton states. This large anisotropy is attributed to the substantially different projected local density of optical states for differently oriented dipoles in the photonic crystal. PMID- 20717452 TI - Label-free biosensor array based on silicon-on-insulator ring resonators addressed using a WDM approach. AB - We report a silicon-on-insulator ring resonator biosensor array with one output port, using wavelength division multiplexing as the addressing scheme. With the use of on-chip referencing for environmental drift cancellation, simultaneous monitoring of multiplexed molecular bindings is demonstrated, with a resolution of 0.3 pg/mm(2) (40 ag of total mass) for protein concentrations over 4 orders of magnitude down to 20 pM. Reactions are measured over time periods as long as 3 h with high stability. PMID- 20717453 TI - Highly efficient three-level blazed grating in the resonance domain. AB - We designed, fabricated, and characterized three-level transmission gratings in the resonance domain with reduced shadowing losses based on a three-wave interference mechanism. A new technological approach allows for fabrication of homogeneous and large area multilevel gratings without spurious artifacts. To our knowledge, the measured efficiency of 86% exhibits the largest value yet reported for a multilevel transmission grating in the resonance domain close to normal incidence. PMID- 20717454 TI - Temperature- and strain-independent torsion sensor using a fiber loop mirror based on suspended twin-core fiber. AB - In this Letter, we present a fiber loop mirror configuration based on a suspended twin-core fiber for sensing applications. Using the suspended twin-core fiber, the fringe pattern is due to the differential optical patch of the light in the two cores associated with a refractive index difference of approximately 10(-3), which indicates an advantage of this approach compared with those based on high birefringent fibers, namely, the possibility of using a small length of fiber. The sensing configuration was characterized for torsion, temperature, and strain. Using the fast Fourier transform technique, it is possible to obtain measurand induced amplitude variations of the fringe pattern. The results obtained indicate the viability of a temperature- and strain-independent torsion sensor. PMID- 20717455 TI - Acousto-optic modulation by pulsed optical excitation: implications to imaging in turbid media. AB - We show that the transient response of acoustically modulated optical flux in a turbid medium irradiated by a pulsed point source of light is delayed in time relative to the light-alone flux obtained in the absence of acoustic modulation. The time delay is shown to result from an initial phase of flux reversal, as determined by the time point of the input pulse onset with reference to the ultrasound cycle. Both the time delay and amplitude of modulation are shown to be dependent on the effective attenuation coefficient of the medium. Application of a periodic train of excitation pulses spaced at equal intervals at, or in multiples of, the ultrasound period enables a time-locked detection of the modulated light, without the deleterious effects caused by speckle artifacts. PMID- 20717456 TI - Quantum-cascade laser integrated with a metal-dielectric-metal-based plasmonic antenna. AB - Optical nanoantennas are capable of enhancing the near-field intensity and confining optical energy within a small spot size. We report a novel metal dielectric-metal coupled-nanorods antenna integrated on the facet of a quantum cascade laser. Finite-difference time-domain simulations showed that, for dielectric thicknesses in the range from 10 to 30 nm, peak optical intensity at the top of the antenna gap is 4000 times greater than the incident field intensity. This is 4 times higher enhancement compared to a coupled metal antenna. The antenna is fabricated using focused ion-beam milling and measured using modified scanning probe microscopy. Such a device has potential applications in building mid-IR biosensors. PMID- 20717457 TI - Optimum output coupling in optical oscillators using an antiresonant ring interferometer. AB - We describe a simple and universal method for absolute optimization of output power from optical oscillators using interferometry. By incorporating an antiresonant ring interferometer in one arm of the oscillator cavity, simple adjustments to the interferometer provide continuously variable output coupling over a broad spectral range and under any operating conditions. We demonstrate the technique using a femtosecond optical parametric oscillator (OPO), where we show continuously adjustable output coupling from 1% to 60%. By operating the OPO under an optimized output coupling of approximately 30%, we obtain approximately 200 mW of extracted power, more than twice that with an approximately 4% conventional output coupler, across the full tuning range. We also show that the technique has no detrimental effect on the spatiotemporal characteristics of the output, with the extracted signal exhibiting a Gaussian beam profile and near transform-limited pulse durations. PMID- 20717458 TI - Use of nonlinear upconverting nanoparticles provides increased spatial resolution in fluorescence diffuse imaging. AB - Fluorescence diffuse imaging (FDI) suffers from limited spatial resolution. In this Letter, we report a scanning imaging approach to increase the resolution of FDI using nonlinear fluorophores. The resolution of a linear fluorophore was compared with nonlinear upconverting nanoparticles (NaYF(4):Yb(3+)/Tm(3+)) in a tissue phantom. A resolution improvement of a factor of 1.3 was found experimentally. Simulations suggested a maximum resolution improvement of a factor of 1.45. Usage of nonlinear fluorophores is a promising method for increasing the spatial resolution in FDI. PMID- 20717459 TI - Subnanoscale resolution for microscopy via coherent population trapping. AB - We present a coherent-population-trapping-based scheme to attain subnanoscale resolution for microscopy. We use three-level atoms coupled to an amplitude modulated probe field and a spatially dependent (standing-wave or Laguerre Gaussian) coupling field. The probe field modulation allows us to tap into the steep dispersion normally associated with electromagnetically induced transparency and offers subnanometer resolution using optical fields. PMID- 20717460 TI - Arbitrary-order nonlinear contribution to self-steepening. AB - On the basis of the recently published generalized Miller formulas, we derive the spectral dependence of the contribution of arbitrary-order nonlinear indices to the group-velocity index. We show that in the context of laser filamentation in gases, all experimentally accessible orders (up to the ninth-order nonlinear susceptibility chi((9)) in air and chi((11)) in argon) have contributions of alternative signs and similar magnitudes. Moreover, we show both analytically and numerically that the dispersion term of the nonlinear indices must be considered when computing the intensity-dependent group velocity. PMID- 20717461 TI - Interplay between group-delay-dispersion-induced polarization gating and ionization to generate isolated attosecond pulses from multicycle lasers. AB - We implemented a new experimental scheme for the generation of single-shot extreme-UV continua that exploits a combination of transform-limited 15 fs, 800 nm pulses and chirped 35 fs, 800 nm pulses with orthogonal polarizations. Continua are interpreted as the formation of a single attosecond pulse and attributed to the interplay between polarization, ionization gating, and trajectory selection operated by suitable phase-matching conditions. PMID- 20717462 TI - Spatially mapping random lasing cavities. AB - A mapping technique is developed to spatially resolve random laser-emission spectra from disordered solid media with an optical gain above the threshold excitation intensity for lasing; the technique is applied to pi-conjugated polymer 1 ms. By mapping the spatial extent of emission peaks in the random laser spectrum, bright areas that correspond to naturally formed lasing microcavities are unraveled. The size of the obtained microcavities matches the size extracted from the Fourier transform analysis of the laser-emission spectrum. Mapping at increased excitation intensities shows multiple resonant microcavities that lase at increasing threshold intensities. PMID- 20717463 TI - Influence of domain disorder on parametric noise in quasi-phase-matched quantum frequency converters. AB - Ideal quantum frequency conversion (QFC) devices enable wavelength translation of a quantum state of light while preserving its essential quantum characteristics, namely photon statistics and coherence. However, the generation of noise photons due to spontaneous scattering of the strong classical pump used in the three-wave mixing process can limit QFC fidelity. We experimentally and theoretically characterize the noise properties of a difference-frequency generation device for QFC and find that fabrication errors in the quasi-phase-matching grating enhance generation of noise photons by parametric fluorescence. PMID- 20717464 TI - High-power dissipative solitons from an all-normal dispersion erbium fiber oscillator. AB - We demonstrate output pulse energies of 20 nJ from an erbium-doped fiber oscillator that contains only positive dispersion fibers and is mode locked by use of nonlinear polarization evolution and stabilized with a birefringent filter. The fiber oscillator operates at a repetition rate of 3.5 MHz with a central wavelength of 1550 nm. The positively chirped output pulses have a duration of 53 ps and are compressed to 750 fs. The large positive chirp of the output pulses and the steep side edges of the pulse spectrum indicate dissipative soliton operation. PMID- 20717465 TI - High-temperature multiparameter sensor based on sapphire fiber Bragg gratings. AB - We present, for the first time to our knowledge, a dual strain/temperature sapphire fiber Bragg grating sensor. Temperature and strain coefficients of the grating are evaluated. By recording the blackbody radiation level above 650 degrees C, wavelength shifts due to temperature can be decoupled from those due to strain. PMID- 20717466 TI - Nonlinear spectral broadening of femtosecond pulses in solid-core photonic bandgap fibers. AB - We study nonlinear spectral broadening and supercontinuum generation mechanisms in two-dimensional solid-core photonic bandgap fibers. Using rigorous frequency domain numerical simulations, we determine how the spectral characteristics are influenced by the strong frequency dependence of the effective area, dispersion, and confinement losses. We also investigate soliton stabilization and the conditions under which efficient nonlinear spectral energy transfer is possible across high attenuation between adjacent bandgaps. Our results provide insight into recent experiments. PMID- 20717467 TI - Spatiotemporal evolution of femtosecond laser pulses guided in air-clad fused silica nanoweb. AB - We investigate nonlinear propagation and self-focusing of femtosecond Ti:sapphire laser pulses in an 800-nm-thick silica nanoweb fiber. Different dispersion regimes are accessible by launching TE- or TM-polarized light. Excitation in the anomalous dispersion regime (TM) results in pulse splitting and spectral broadening, which lead to supercontinuum generation, whereas, for normal dispersion (TE, excited close to a zero dispersion wavelength), self-phase modulation causes spectral broadening, which leads at higher power to beam collapse and the creation of a damage track. PMID- 20717468 TI - Diffraction from an edge in a self-focusing medium. AB - We experimentally demonstrate diffraction from a straight edge in a medium with self-focusing nonlinearity. Diffraction into the shadow region is suppressed with increasing nonlinearity, but mode coupling leads to excitations and traveling waves on the high-intensity side. Theoretically, we interpret these modulations as spatially dispersive shock waves with negative pressure. PMID- 20717469 TI - Whispering-gallery-mode-resonator-based ultranarrow linewidth external-cavity semiconductor laser. AB - We demonstrate a miniature self-injection locked distributed-feedback laser using resonant optical feedback from a high-Q crystalline whispering-gallery-mode resonator. The linewidth reduction factor is greater than 10,000, with resultant instantaneous linewidth of less than 200 Hz. The minimal value of the Allan deviation for the laser-frequency stability is 3 x 10(-12) at the integration time of 20 micros. The laser possesses excellent spectral purity and good long term stability. PMID- 20717470 TI - Polarization structuring of focused field through polarization-only modulation of incident beam. AB - We proposed a method of polarization shaping in the focal region with the polarization modulation of incident light. By using an iterative optimization based on a vectorial diffraction calculation with the help of the fast Fourier transform, we can tailor the polarization structure in the focal plane. This provides a novel way to control the vectorial feature of the focal volume with the help of polarization tailoring, which is different from the method using wavefront shaping. The capability of polarization-only modulation on the incident light is demonstrated by optical experiments. PMID- 20717471 TI - Characterization of a refractive logarithmic axicon. AB - We show that it is feasible to design and manufacture a refractive logarithmic axicon that generates a quasi-diffraction-free/Bessel beam with nearly constant beam size and intensity over a predetermined range. The novel optical element was characterized with both coherent and incoherent light, and good correspondence with the predicted behavior of the intensity distribution and spot size was found. The energy flow was also found to be nearly constant over most of the designed range. Logarithmic axicons may find applications in situations where large depth of field and uniform axial intensity/energy distributions are important. PMID- 20717474 TI - A Diels-Alder Route to Angularly Functionalized Bicyclic Structures. AB - A Diels-Alder based route to trans-fused angularly functionalized bicyclic structures has been developed. This transformation features the use of a tetrasubstituted dienophile in the cycloaddition step. PMID- 20717475 TI - Reply to: Should physicians aggressively treat pre-hypertension? PMID- 20717473 TI - Characterization of the Brain 26S Proteasome and its Interacting Proteins. AB - Proteasome-mediated proteolysis is important for synaptic plasticity, neuronal development, protein quality control, and many other processes in neurons. To define proteasome composition in brain, we affinity purified 26S proteasomes from cytosolic and synaptic compartments of the rat cortex. Using tandem mass spectrometry, we identified the standard 26S subunits and a set of 28 proteasome interacting proteins that associated substoichiometrically and may serve as regulators or cofactors. This set differed from those in other tissues and we also found several proteins that associated only with either the cytosolic or the synaptic proteasome. The latter included the ubiquitin-binding factor TAX1BP1 and synaptic vesicle protein SNAP-25. Native gel electrophoresis revealed a higher proportion of doubly-capped 26S proteasome (19S-20S-19S) in the cortex than in the liver or kidney. To investigate the interplay between proteasome regulation and synaptic plasticity, we exposed cultured neurons to glutamate receptor agonist NMDA. Within 4 h, this agent caused a prolonged decrease in the activity of the ubiquitin-proteasome system as shown by disassembly of 26S proteasomes, decrease in ubiquitin-protein conjugates, and dissociation of the ubiquitin ligases UBE3A (E6-AP) and HUWE1 from the proteasome. Surprisingly, the regulatory 19S particles were rapidly degraded by proteasomal, not lysosomal degradation, and the dissociated E3 enzymes also degraded. Thus the content of proteasomes and their set of associated proteins can be altered by neuronal activity, in a manner likely to influence synaptic plasticity and learning. PMID- 20717476 TI - Optimization of Landmark Selection for Cortical Surface Registration. AB - Manually labeled landmark sets are often required as inputs for landmark-based image registration. Identifying an optimal subset of landmarks from a training dataset may be useful in reducing the labor intensive task of manual labeling. In this paper, we present a new problem and a method to solve it: given a set of N landmarks, find the k(< N) best landmarks such that aligning these k landmarks that produce the best overall alignment of all N landmarks. The resulting procedure allows us to select a reduced number of landmarks to be labeled as a part of the registration procedure. We apply this methodology to the problem of registering cerebral cortical surfaces extracted from MRI data. We use manually traced sulcal curves as landmarks in performing inter-subject registration of these surfaces. To minimize the error metric, we analyze the correlation structure of the sulcal errors in the landmark points by modeling them as a multivariate Gaussian process. Selection of the optimal subset of sulcal curves is performed by computing the error variance for the subset of unconstrained landmarks conditioned on the constrained set. We show that the registration error predicted by our method closely matches the actual registration error. The method determines optimal curve subsets of any given size with minimal registration error. PMID- 20717477 TI - Non-Rigid Multi-Modal Image Registration Using Cross-Cumulative Residual Entropy. AB - In this paper we present a new approach for the non-rigid registration of multi modality images. Our approach is based on an information theoretic measure called the cumulative residual entropy (CRE), which is a measure of entropy defined using cumulative distributions. Cross-CRE between two images to be registered is defined and maximized over the space of smooth and unknown non-rigid transformations. For efficient and robust computation of the non-rigid deformations, a tri-cubic B-spline based representation of the deformation function is used. The key strengths of combining CCRE with the tri-cubic B-spline representation in addressing the non-rigid registration problem are that, not only do we achieve the robustness due to the nature of the CCRE measure, we also achieve computational efficiency in estimating the non-rigid registration. The salient features of our algorithm are: (i) it accommodates images to be registered of varying contrast+brightness, (ii) faster convergence speed compared to other information theory-based measures used for non-rigid registration in literature, (iii) analytic computation of the gradient of CCRE with respect to the non-rigid registration parameters to achieve efficient and accurate registration, (iv) it is well suited for situations where the source and the target images have field of views with large non-overlapping regions. We demonstrate these strengths via experiments on synthesized and real image data. PMID- 20717478 TI - Shape L'Ane Rouge: Sliding Wavelets for Indexing and Retrieval. AB - Shape representation and retrieval of stored shape models are becoming increasingly more prominent in fields such as medical imaging, molecular biology and remote sensing. We present a novel framework that directly addresses the necessity for a rich and compressible shape representation, while simultaneously providing an accurate method to index stored shapes. The core idea is to represent point-set shapes as the square root of probability densities expanded in a wavelet basis. We then use this representation to develop a natural similarity metric that respects the geometry of these probability distributions, i.e. under the wavelet expansion, densities are points on a unit hypersphere and the distance between densities is given by the separating arc length. The process uses a linear assignment solver for non-rigid alignment between densities prior to matching; this has the connotation of "sliding" wavelet coefficients akin to the sliding block puzzle L'Ane Rouge. We illustrate the utility of this framework by matching shapes from the MPEG-7 data set and provide comparisons to other similarity measures, such as Euclidean distance shape distributions. PMID- 20717479 TI - A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition. AB - Here we report the discovery of ON044580, an alpha-benzoyl styryl benzyl sulfide that possesses potent inhibitory activity against two unrelated kinases, JAK2 and BCR-ABL, and exhibits cytotoxicity to human tumor cells derived from chronic myelogenous leukemia (CML) and myelodysplasia (MDS) patients or cells harboring a mutant JAK2 kinase. This novel spectrum of activity is explained by the non-ATP competitive inhibition of JAK2 and BCR-ABL kinases. ON044580 inhibits mutant JAK2 kinase and the proliferation of JAK2(V617F)-positive leukemic cells and blocks the IL-3-mediated phosphorylation of JAK2 and STAT5. Interestingly, this compound also directly inhibits the kinase activity of both wild-type and imatinib resistant (T315I) forms of the BCR-ABL kinase. Finally, ON044580 effectively induces apoptosis of imatinib-resistant CML patient cells. The apparently unrelated JAK2 and BCR-ABL kinases share a common substrate, STAT5, and such substrate competitive inhibitors represent an alternative therapeutic strategy for development of new inhibitors. The novel mechanism of kinase inhibition exhibited by ON044580 renders it effective against mutant forms of kinases such as the BCR-ABL(T315I) and JAK2(V617F). Importantly, ON044580 selectively reduces the number of aneuploid cells in primary bone marrow samples from monosomy 7 MDS patients, suggesting another regulatory cascade amenable to this agent in these aberrant cells. Data presented suggest that this compound could have multiple therapeutic applications including monosomy 7 MDS, imatinib-resistant CML, and myeloproliferative neoplasms that develop resistance to ATP-competitive agents. PMID- 20717481 TI - Geostatistical modeling of the spatial variability and risk areas of southern root-knot nematodes in relation to soil properties. AB - Identifying the spatial variability and risk areas for southern root-knot nematode [Meloidogyne incognita (Kofoid & White) Chitwood] (RKN) is key for site specific management (SSM) of cotton (Gossypium hirsutum L.) fields. The objectives of this study were to: (i) determine the soil properties that influence RKN occurrence at different scales; and (ii) delineate risk areas of RKN by indicator kriging. The study site was a cotton field located in the southeastern coastal plain region of the USA. Nested semivariograms indicated that RKN samples, collected from a 50*50 m grid, exhibited a local and regional scale of variation describing small and large clusters of RKN population density. Factorial kriging decomposed RKN and soil properties variability into different spatial components. Scale dependent correlations between RKN data showed that the areas with high RKN population remained stable though the growing season. RKN data were strongly correlated with slope (SL) at local scale and with apparent soil electrical conductivity deep (EC(a-d)) at both local and regional scales, which illustrate the potential of these soil physical properties as surrogate data for RKN population. The correlation between RKN data and soil chemical properties was soil texture mediated. Indicator kriging (IK) maps developed using either RKN, the relation between RKN and soil electrical conductivity or a combination of both, depicted the probability for RKN population to exceed the threshold of 100 second stage juveniles/100 cm(3) of soil. Incorporating EC(a-d) as soft data improved predictions favoring the reduction of the number of RKN observations required to map areas at risk for high RKN population. PMID- 20717480 TI - Silent corticogonadotroph adenomas: clinical and cellular characteristics and long-term outcomes. AB - Silent corticotrophins adenomas (SCAs) are clinically silent and non-secreting but immunostain positively for ACTH. We hypothesize that SCAs comprise both corticotroph and gonadotroph characteristics. Cohort analysis from 1994-2008 with follow-up time ranging from 1-15 years in a tertiary referral center. We compared preoperative and postoperative clinical results and tumor cytogenesis in 25 SCAs and 84 nonfunctioning adenomas in 109 consecutive patients diagnosed pre operatively with nonfunctioning pituitary adenomas. Clinical outcomes were radiologic and hormonal measures. Pathologic outcomes were expression of relevant pituitary hormones, tissue-specific transcription factors, and electron microscopy features. Preoperative SCA presentation was similar to that observed for nonfunctioning adenomas. However, SCAs recurred postoperatively at a median of 3 years vs. 8 years for nonfunctioning adenomas (p<0.0001). Fifty-four percent of patients with SCAs had new onset postoperative hypopituitarism vs. 17% of nonfunctioning adenomas (p<0.025). SCAs (n=18) were immunopositive for ACTH, cytoplasmic and nuclear SF-1, NeuroD1, DAX-1, and alpha-gonadotropin subunit, but Tpit negative, and co-expression of tumor ACTH with either SF-1 or LH was detected. In contrast, functional corticotroph adenomas (n=11) were immunopositive for ACTH, nuclear SF-1, NeuroD1, and Tpit, but negative for DAX-1, a gonadotroph cell transcription factor. Gonadotroph adenomas (n=23) were immunonegative for ACTH and Tpit but positive for nuclear SF-1, NeuroD1, and DAX 1. SCA electron microscopy demonstrated ultrastructural features consistent with corticotroph and gonadotroph cells. As SCAs exhibit features consistent with both corticotroph and gonadotroph cytologic origin, we propose a pathologic and clinically distinct classification of SCAs as silent corticogonadotroph adenomas. PMID- 20717482 TI - A New Method of Probability Density Estimation with Application to Mutual Information Based Image Registration. AB - We present a new, robust and computationally efficient method for estimating the probability density of the intensity values in an image. Our approach makes use of a continuous representation of the image and develops a relation between probability density at a particular intensity value and image gradients along the level sets at that value. Unlike traditional sample-based methods such as histograms, minimum spanning trees (MSTs), Parzen windows or mixture models, our technique expressly accounts for the relative ordering of the intensity values at different image locations and exploits the geometry of the image surface. Moreover, our method avoids the histogram binning problem and requires no critical parameter tuning. We extend the method to compute the joint density between two or more images. We apply our density estimation technique to the task of affine registration of 2D images using mutual information and show good results under high noise. PMID- 20717483 TI - Decreased risk of bladder cancer in men treated with quinazoline-based alpha1 adrenoceptor antagonists. AB - Previous studies documented that human bladder cancer cells are sensitive to the apoptotic effects of quinazoline-derived alpha1-adrenoreceptor antagonists and bladder tumors exhibit reduced tissue vascularity in response to terazosin. More recent evidence suggests that exposure to quinazoline alpha1-adrenorecptor antagonists leads to a significant reduction in prostate cancer incidence. This retrospective observational cohort study was conducted to determine whether male patients treated with quinazoline alpha1-adrenoceptor antagonists for either benign prostate hyperplasia (BPH) or hypertension have a decreased risk of developing bladder cancer. Review of the medical records of all male patients enrolled at the Lexington Veterans Administration (VA) Medical Center identified men exposed to quinazoline-based alpha1-adrenoceptor antagonists (Jan 1, 1998-Dec 31, 2002) for either hypertension and/or benign prostate obstructive symptoms. The whole group of 27,138 male patients was linked to the Markey Cancer Center's Kentucky Cancer Registry (KCR), part of the NCI's Surveillance, Epidemiology, and End Results (SEER) Program, to identify all incident bladder cancer cases diagnosed in this population. Measures of disease incidence, relative risk, and attributable risk were calculated to compare the risk of developing bladder cancer for alpha1-blocker-exposed versus unexposed men. A two-by-two contingency table of alpha1-antagonist exposure versus bladder cancer diagnoses was constructed and the relative risk was calculated. Our analysis revealed a cumulative bladder cancer incidence of 0.24% among the alpha1-blocker-exposed men compared to 0.42% in the unexposed group. Thus, there was a risk difference of 0.0018, which indicates that 1.8 fewer bladder cancer cases developed per 1000 exposed men. Alternatively stated, 556 men would need to be treated with quinazoline alpha1-blockers to prevent one case of bladder cancer. Exposure to quinazoline alpha1-blockers thus may have prevented 7 to 8 bladder cancer cases among the 4173 treated men during the study period. The data yield an unadjusted risk ratio of 0.57 (95% CI: 0.30, 1.08) and therefore, men treated with alpha1 adrenoreceptor antagonists have a 43% lower relative risk of developing bladder cancer than unexposed men (p=0.083). Our inability to determine person-years at risk of developing bladder cancer for each unexposed control patient, was a limitation for calculating an incidence ratio and rate difference. These results offer an initial indication that exposure to doxazosin and terazosin decreases the incidence of bladder cancer. This is the first epidemiological evidence that the anti-tumor action of quinazoline-based alpha1-antagonists may potentially translate into a protective effect from bladder cancer development. PMID- 20717484 TI - Intent-to-Treat vs. Non-Intent-to-Treat Analyses under Treatment Non-Adherence in Mental Health Randomized Trials. PMID- 20717485 TI - Comparison of Two Brief Parent-Training Interventions for Child Distress During Parent-Administered Needle Procedures. AB - This randomized clinical trial employed a 2-group (general child behavior management training vs. distraction for pain management training) design across repeated parent-administered needle procedures. Forty-seven children with a chronic illness requiring recurrent injections were observed at baseline and 2 intervention sessions. Videotaped observations of parent-child interactions were coded for child behavioral distress and parents' use of behavior management strategies. Across groups, many children displayed minimal to no distress at baseline. Among participants with significant distress, neither intervention group displayed consistently decreased procedural distress or increased use of child behavior management strategies. PMID- 20717486 TI - Two-Part Factor Mixture Modeling: Application to an Aggressive Behavior Measurement Instrument. AB - This study introduces a two-part factor mixture model as an alternative analysis approach to modeling data where strong floor effects and unobserved population heterogeneity exist in the measured items. As the names suggests, a two-part factor mixture model combines a two-part model, which addresses the problem of strong floor effects by decomposing the data into dichotomous and continuous response components, with a factor mixture model, which explores unobserved heterogeneity in a population by establishing latent classes. Two-part factor mixture modeling can be an important tool for situations in which ordinary factor analysis produces distorted results and can allow researchers to better understand population heterogeneity within groups. Building a two-part factor mixture model involves a consecutive model building strategy that explores latent classes in the data for each part as well as a combination of the two-part. This model building strategy was applied to data from a randomized preventive intervention trial in Baltimore public schools administered by the Johns Hopkins Center for Early Intervention. The proposed model revealed otherwise unobserved subpopulations among the children in the study in terms of both their tendency toward and their level of aggression. Furthermore, the modeling approach was examined using a Monte Carlo simulation. PMID- 20717487 TI - Geographic Information Systems. AB - This chapter presents an overview of the development, capabilities, and utilization of geographic information systems (GIS). There are nearly an unlimited number of applications that are relevant to GIS because virtually all human interactions, natural and man-made features, resources, and populations have a geographic component. Everything happens somewhere and the location often has a role that affects what occurs. This role is often called spatial dependence or spatial autocorrelation, which exists when a phenomenon is not randomly geographically distributed. GIS has a number of key capabilities that are needed to conduct a spatial analysis to assess this spatial dependence. This chapter presents these capabilities (e.g., georeferencing, adjacency/distance measures, overlays) and provides a case study to illustrate how GIS can be used for both research and planning. Although GIS has developed into a relatively mature application for basic functions, development is needed to more seamlessly integrate spatial statistics and models.The issue of location, especially the geography of human activities, interactions between humanity and nature, and the distribution and location of natural resources and features, is one of the most basic elements of scientific inquiry. Conceptualizations and physical maps of geographic space have existed since the beginning of time because all human activity takes place in a geographic context. Representing objects in space, basically where things are located, is a critical aspect of the natural, social, and applied sciences. Throughout history there have been many methods of characterizing geographic space, especially maps created by artists, mariners, and others eventually leading to the development of the field of cartography. It is no surprise that the digital age has launched a major effort to utilize geographic data, but not just as maps. A geographic information system (GIS) facilitates the collection, analysis, and reporting of spatial data and related phenomena. The capabilities of GIS are much more than just mapping, although map production is one of the most utilized features. GIS applications are relevant in a tremendous number of areas ranging from basic geographic inventories to simulation models.This chapter presents a general overview of geographic information system topics. The purpose is to provide the reader with a basic understanding of a GIS, the types of data that are needed, the basic functionality of these systems, the role of spatial analysis, and an example in the form of a case study. The chapter is designed to provide advanced students and experts outside of the field of GIS sufficient information to begin to utilize GIS and spatial analytic concepts, but it is not designed to be the sole basis for becoming a GIS expert. There is a tremendous level of sophistication related to the digital cartographic databases and manipulation of those databases underlying the display and use of GIS that is more appropriately a part of geographic information science (i.e., basic research issues associated with geographic data including technical as well as theoretical aspects such as the impact on society [1]) rather than being relevant to this chapter. The utilization of GIS for conducting spatial analysis is the guiding theme for the chapter. PMID- 20717489 TI - Anxiety Disorders with Comorbid Substance Use Disorders: Diagnostic and Treatment Considerations. PMID- 20717488 TI - Prodrug and conjugate drug delivery strategies for improving HIV/AIDS therapy. AB - Despite the wide variety of highly potent anti-HIV drugs that have been developed and made available in clinical practice over the years, eradication of HIV infection has not been achieved. Currently, HIV infection and AIDS are thought to be chronically treatable. HIV attacks host immune cells namely macrophages and CD4(+)T-cells and sequesters itself into sanctuary and reservoir sites such as the lymphoid tissues, testes, and brain. Initial drug delivery efforts with prodrugs and drug conjugates focused on improving the physicochemical (i.e. solubility), biopharmaceutic (i.e. absorption, metabolism), and pharmacokinetic (i.e. blood concentrations) properties of the parent drugs. Eradicating HIV, however, will require advanced drug delivery approaches in order to access and maintain effective drug concentrations for prolonged periods of time in sanctuary sites. The current review discusses prodrug/conjugate efforts, clinical successes and describes drug delivery challenges and approaches for eradicating HIV infection. PMID- 20717490 TI - Conversational Self-Focus in Adolescent Friendships: Observational Assessment of an Interpersonal Process and Relations with Internalizing Symptoms and Friendship Quality. AB - Although youth with internalizing symptoms experience friendship difficulties, surprisingly little is known about their problematic interpersonal behaviors. The current observational study identifies a new construct, conversational self focus, defined as the tendency to direct the focus of conversations to the self and away from others. Results indicated that youth with internalizing symptoms were especially likely to engage in self-focus when discussing problems with friends and that doing so was related to their friends perceiving the relationship as lower in quality, particularly helping. Content analyses further indicated that self-focused youth talked about themselves in ways that were distracting from their friends' problems and that they changed the subject abruptly. Last, conversational self-focus was not redundant with related constructs of rumination and self-disclosure. This research highlights the importance of intervention efforts aimed at teaching self-focused youth ways to cope with distress that are more effective and will not damage their friendships. PMID- 20717492 TI - Quality of Research Design Moderates Effects of Grade Retention on Achievement: A Meta-analytic, Multi-level Analysis. AB - The present meta-analysis examined the effect of grade retention on academic outcomes and investigated systemic sources of variability in effect sizes. Using multi-level modeling, we investigated characteristics of 207 effect sizes across 22 studies published between 1990 and 2007 at two levels: the study (between) and individual (within) levels. Design quality was a study-level variable. Individual level variables were median grade retained and median number of years post retention. Quality of design was associated with less negative effects. Studies employing middle to high methodological designs yielded effect sizes not statistically significantly different from zero and 0.34 higher (more positive) than studies with low design quality. Years post retention was negatively associated with retention effects, and this effect was stronger for studies using grade comparisons versus age comparisons. Results challenge the widely held view that retention has a negative impact on achievement. Suggestions for future research are discussed. PMID- 20717491 TI - Contingency Learning and Reactivity in Preterm and Full-Term Infants at 3 Months. AB - Learning difficulties in preterm infants are thought to reflect impairment in arousal regulation. We examined relationships among gestational age, learning speed, and behavioral and physiological reactivity in 55 preterm and 49 full-term infants during baseline, contingency, and nonreinforcement phases of a conjugate mobile paradigm at 3 months corrected age. For all infants, negative affect, looking duration, and heart rate levels increased during contingency and nonreinforcement phases, whereas respiratory sinus arrhythmia (RSA, an index of parasympathetic activity) decreased and cortisol did not change. Learners showed greater RSA suppression and less negative affect than nonlearners. This pattern was particularly evident in the preterm group. Overall, preterm infants showed less learning, spent less time looking at the mobile, and had lower cortisol levels than full-term infants. Preterm infants also showed greater heart rate responses to contingency and dampened heart rate responses to nonreinforcement compared to full-term infants. Findings underscore differences in basal and reactivity measures in preterm compared to full-term infants and suggest that the capacity to regulate parasympathetic activity during a challenge enhances learning in preterm infants. PMID- 20717493 TI - Two-phase Filtering Strategy for Efficient Peptide Identification from Mass Spectrometry. AB - Peptide identification by tandem mass spectrometry (MS/MS) is one of the most important problems in proteomics. Recent advances in high throughput MS/MS experiments result in huge amount of spectra, and the peptide identification process should keep pace. In this paper, we strive to achieve high accuracy and efficiency for peptide identification with the presence of noise by a two-phase filtering strategy. Our algorithm transforms spectra to high dimensional vectors, and then uses self-organizing map (SOM) and multi-point range query (MPRQ) as very efficient coarse filters to select a number of candidate peptides from database. These candidate peptides are subsequently scored and ranked by an accurate tag-based scoring function S(lambda). Experiments showed that our approach is both fast and accurate for peptide identification. PMID- 20717494 TI - EFFECTS OF EXPOSURE ON PREVALENCE AND CUMULATIVE RELATIVE RISK: DIRECT AND INDIRECT EFFECTS IN A RECURSIVE HAZARD MODEL. AB - This paper outlines decomposition methods for assessing how exposure affects prevalence and cumulative relative risk. Let x denote a vector of exogenous covariates and suppose that a single dimension of time t governs two event processes T(1) and T(2). If the occurrence of the event T(1) determines entry into the risk of the event T(2), then subgroup variation in T(1) will affect the prevalence T(2), even if subgroups in the population are otherwise identical. Although researchers often acknowledge this phenomenon, the literature has not provided procedures to assess the magnitude of an exposure effect of T(1) on the prevalence of T(2). We derive decompositions that assess how variation in exposure generated by direct and indirect effects of the covariates x affect measures of absolute and relative prevalence of T(2). We employ a parametric but highly flexible specification for baseline hazard for the T(1) and T(2) processes and use the resulting parametric proportional hazard model to illustrate the direct and indirect effects of family structure when T(1) is age at first sexual intercourse and T(2) is age at a premarital first birth for data on a cohort of nonhispanic white U.S. women. PMID- 20717496 TI - Development of the Smoking Knowledge, Attitudes, and Practices (S-KAP) Instrument. AB - This report describes the development and measurement characteristics of a new measure of smoking knowledge, attitudes, and practices (S-KAP) among treatment providers. Data are based on survey responses from 336 paid staff working in one of three drug abuse treatment or HIV care settings. Exploratory factor analysis, used to examine the factor structure, pointed towards five underlying factors: a single "knowledge" factor, three "attitude" factors ('treatment barriers,' 'counselor self-factor. The Knowledge scale had a standardized Cronbach's alpha coefficient of .85. The coefficients for Barriers, Self-Efficacy, and Attitudes were .81, .72, and .74, respectively. The Practice scale had a standardized Cronbach's alpha coefficient of .91. These results indicate that the proposed scales have reasonably good psychometric characteristics and will allow researchers to quantify staff knowledge, attitudes, and practices regarding smoking cessation treatments and issues. PMID- 20717497 TI - NONPARAMETRIC ESTIMATION OF CONDITIONAL CUMULATIVE HAZARDS FOR MISSING POPULATION MARKS. AB - A new function for the competing risks model, the conditional cumulative hazard function, is introduced, from which the conditional distribution of failure times of individuals failing due to cause j can be studied. The standard Nelson-Aalen estimator is not appropriate in this setting, as population membership (mark) information may be missing for some individuals owing to random right-censoring. We propose the use of imputed population marks for the censored individuals through fractional risk sets. Some asymptotic properties, including uniform strong consistency, are established. We study the practical performance of this estimator through simulation studies and apply it to a real data set for illustration. PMID- 20717498 TI - Reply to Letter to Editor E08-5108A. PMID- 20717495 TI - Actin and Actin-Binding Proteins: Masters of Dendritic Spine Formation, Morphology, and Function. AB - Dendritic spines are actin-rich protrusions that comprise the postsynaptic sites of synapses and receive the majority of excitatory synaptic inputs in the central nervous system. These structures are central to cognitive processes, and alterations in their number, size, and morphology are associated with many neurological disorders. Although the actin cytoskeleton is thought to govern spine formation, morphology, and synaptic functions, we are only beginning to understand how modulation of actin reorganization by actin-binding proteins (ABPs) contributes to the function of dendritic spines and synapses. In this review, we discuss what is currently known about the role of ABPs in regulating the formation, morphology, motility, and plasticity of dendritic spines and synapses. PMID- 20717499 TI - FACILE PREPARATION OF NANOPARTICLES BY INTRAMOLECULAR CROSSLINKING OF ISOCYANATE FUNCTIONALIZED COPOLYMERS. AB - A new synthetic approach to the preparation of intramolecularly collapsed nanoparticles under mild, room temperature conditions has been developed from commercially available vinyl monomers. Reaction of isocyanate functionalized linear copolymers with a diamine in dilute solution leads to the efficient formation of nanoparticles where the diameter of the nanoparticle can be varied by controlling both the molecular weight and mole percentage of isocyanate repeat units. Physical properties for the intramolecularly collapsed nanoparticles were fully consistent with a three-dimensional structure and analysis of the collapse reaction revealed that approximately 75% of the isocyanate groups along the backbone underwent crosslinking with 25% being available for further reaction with mono-functional amines. This stepwise consumption of the isocyanates allows the chemical and physical properties of the nanoparticles to be further tuned and significantly opens up the range of nanoparticles that can be prepared using this mild and highly efficient chemistry. PMID- 20717500 TI - Dependence of accuracy of ESPRIT estimates on signal eigenvalues: the case of a noisy sum of two real exponentials. AB - This paper is devoted to estimation of parameters for a noisy sum of two real exponential functions. Singular Spectrum Analysis is used to extract the signal subspace and then the ESPRIT method exploiting signal subspace features is applied to obtain estimates of the desired exponential rates. Dependence of estimation quality on signal eigenvalues is investigated. The special design to test this relation is elaborated. PMID- 20717501 TI - Tandem Time-of-Flight (TOF/TOF) Mass Spectrometry and Proteomics. AB - A dual reflectron tandem time-of-flight (TOF/TOF) mass spectrometer reported in 1993 gave rise to the invention and development of the curved-field reflectron (CFR) for focusing product ions. The CFR is used in this case as the second mass analyzer in a tandem instrument (based on the Kratos AXIMA CFR) in which the first mass analyzer is a linear TOF that focuses ions by pulsed extraction. Because ions can be focused over a broad range of kinetic energies, deceleration of precursor ions and/or reacceleration of product ions is not required. Thus, product ions produced by post-source processes (laser induced dissociation or LID, metastable decomposition and opportunistic collisions) are recorded in the product ion mass spectra at the same times as their isomass ions produced by collision induced dissociation (CID). In general both LID and CID product ion mass spectra are very similar, producing primarily b-series and y-series ions, though there is some preference for fragmentation at weaker bonds such as those at proline or aspartic acid residues. The tandem mass spectrometer has been used to determine the acetylation sites for a histone acetyl transferase (HAT) protein. A novel and improved method for derivatizing tryptic fragments by N terminal sulfonation produces almost exclusively y-series ions, and has been used to determine protein ubiquitination. The tandem mass spectrometer has also been used to identify potential biomarkers associated with heart failure, in particular that fraction containing albumin that is generally removed from serum samples to permit protein biomarker analysis. Analysis of the unfractionated serum, the albuminome, and the depleted serum is also carried out using surface enhanced laser desorption/ionization (SELDI) and the high molecular weight proteins are monitored by using a Comet macromizer TOF mass spectrometer with a very high mass cryocooled detector. PMID- 20717502 TI - Simulation studies for a multistage dynamic process of immune memory response to influenza: experiment in silico. AB - This communication provides an illustration for the use of computer simulations in human immunology. When traditional experiments are impossible, unethical, or unfeasible, in silico modeling procedures may help to fill the gaps in our knowledge of an immune system response to a pathogen. In our study, we define terms and properties of modeled entities: "a clonotype", its distribution, and rank-frequency summaries, and describe properties associated with each of these three clonotype-related entities. We simulate a multistage dynamic process of an immune memory response to influenza. We believe that illustrated properties of fractality and self-similarity might arise due to the following process. The memory T cells operate in a complex environment of shifting pathogen concentrations, increasing and then decreasing inflammatory signals, and multiple interactions with other immune cells and their infected targets. Therefore, a fractal structure to such a population would represent an optimization in terms of percolation into immune/inflammatory space. PMID- 20717503 TI - Cognitive Dimensions in Alzheimer's Disease, Mild Cognitive Impairment, and Normal Elderly: Developing a Common Metric. AB - The aim of this research was to assess similarity in cognitive factor structures underlying neuropsychological test performance of elders belonging to three clinical groups: Alzheimer's disease (AD), Mild Cognitive Impairment (MCI), and normal elderly. We administered a battery of neuropsychological tests to 214 elderly participants in the groups. First, the underlying cognitive structure of a Combined-Set of AD, MCI, and Control subjects was determined by Principal Components Analysis (PCA), including quantitative relationships (loadings) between the test measures and the factors. The PCA resolved 17 neuropsychological test measures into 6 interpretable factors, accounting for 78% of the variance. This cognitive structure was compared with separate cognitive structures from an AD-Set, an MCI-Set, and a Control-Set (different individuals in each set) in additional PCA using Procrustes factor rotation. Analysis of congruence coefficients between each set and the Combined-Set by a bootstrapping statistical procedure supported the factor invariance hypothesis. These close similarities across groups in their underlying neuropsychological dimensions support the use of a common metric system (the factor structure of a Combined-Set) for measuring neuropsychological factors in all these elderly individuals. PMID- 20717504 TI - Enantioselective alpha-Chlorination of Aldehydes with Recyclable Fluorous (S) Pyrrolidine-Thiourea Bifunctional Organocatalyst. AB - A novel fluorous (S)-pyrrolidine-thiourea bifunctional organocatalyst is prepared. The catalyst shows good activity and enantioselectivity for direct alpha-chlorination of aldehydes using N-chlorosuccinimide (NCS) as the chlorine source. It can be recovered from the reaction mixture by fluorous solid-phase extraction with excellent purity for direct reuse. PMID- 20717505 TI - Notochordal cells influence gene expression of inflammatory mediators of annulus fibrosus cells in proinflammatory cytokines stimulation. AB - OBJECTIVE: Notochordal cells in the intervertebral disc interact with nucleus pulposus (NP) cells and support the maintenance of disc homeostasis by regulation of matrix production. However, the influence of notochordal cells has not been evaluated in the annulus fibrosus (AF), which is the primary pain generator in the disc. We hypothesized that the notochordal cell has the capacity to modulate inflammatory mediators secreted by AF cells secondary to stimulation. METHODS: Notochordal and AF cells were isolated from adult New Zealand white rabbits. AF pellets were cultured with notochordal cell clusters or in notochordal cell conditioned media (NCCM) for 24 or 48 hours with proinflammatory cytokines at varying concentrations. Gene expression in AF pellets were assayed for nitric oxide synthase (iNOS), cyclo-oxygenase (COX)-2, and interleukin (IL)-6 by real time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: AF pellet in NCCM significantly decreased the iNOS and COX-2 messenger ribonucleic acid (mRNA) levels compared to AF pellets alone and AF pellets with notochordal cells (p < 0.05). AF pellet resulted in dose-dependent iNOS and COX-2 expression in response to IL-1beta, stimulation, demonstrating that 1 ng/ml for 24 hours yielded a maximal response. AF pellet in NCCM significantly decreased the expression of iNOS and COX-2 in response to 1ng/ml IL-1beta, stimulation at 24 hours (p < 0.05). There was no difference in IL-6 expression compared to AF pellets alone or AF pellets with notochordal cell clusters. CONCLUSION: We conclude that soluble factors from notochordal cells mitigate the gene expression of inflammatory mediators in stimulated AF, as expected after annular injury, suggesting that notochordal cells could serve as a novel therapeutic approach in symptomatic disc development. PMID- 20717506 TI - Comparative analysis of serum proteomes of moyamoya disease and normal controls. AB - OBJECTIVE: The etiology and pathogenesis of moyamoya disease remain unclear. Furthermore, the definitive diagnostic protein-biomarkers for moyamoya disease are still unknown. The present study analyzed serum proteomes from normal controls and moyamoya patients to identify novel serological biomarkers for diagnosing moyamoya disease. METHODS: We compared the two-dimensional electrophoresis patterns of sera from moyamoya disease patients and normal controls and identified the differentially-expressed spots by matrix-assisted laser desorption/ionization-time-of flight mass spectrometry and electrospray ionization quadruple time-of-flight mass spectrometry. RESULTS: We found and analyzed 22 differently-expressed proteomes. Two proteins were up-regulated. Twenty proteins were down-regulated. Complement C1 inhibitor protein and apolipoprotein C-III showed predominantly changed expressions (complement C1 inhibitor protein averaged a 7.23-fold expression in moyamoya patients as compared to controls, while apolipoprotein C-III averaged a 0.066-fold expression). CONCLUSION: Although our study had a small sample size, our proteomic data provide serologic clue proteins for understanding moyamoya disease. PMID- 20717507 TI - Loss of heterozygosity at 1p, 7q, 17p, and 22q in meningiomas. AB - OBJECTIVE: Allelic losses or loss of heterozygosity (LOH) at many chromosomal loci have been found in the cells of meningiomas. The objective of this study was to evaluate LOH at several loci of different chromosomes (1p32, 17p13, 7q21, 7q31, and 22q13) in different grades of meningiomas. METHODS: Forty surgical specimens were obtained and classified as benign, atypical, and anaplastic meningiomas. After DNA extraction, ten polymorphic microsatellite markers were used to detect LOH. Medical and surgical records, as well as pathologic findings, were reviewed retrospectively. RESULTS: LOH at 1p32 was detected in 24%, 60%, and 60% in benign, atypical, and anaplastic meningiomas, respectively. Whereas LOH at 7q21 was found in only one atypical meningioma. LOH at 7q31 was found in one benign meningioma and one atypical meningioma. LOH at 17p13 was detected in 4%, 40%, and 80% in benign, atypical, and anaplastic meningiomas, respectively. LOH at 22q13 was seen in 48%, 60%, and 60% in benign, atypical, and anaplastic meningiomas, respectively. LOH results at 1p32 and 17p13 showed statistically significant differences between benign and non-benign meningiomas. CONCLUSION: LOH at 1p32 and 17p13 showed a strong correlation with tumor progression. On the other hand, LOH at 7q21 and 7q31 may not contribute to the development of the meningiomas. PMID- 20717508 TI - GRIM-19 Expression and Function in Human Gliomas. AB - OBJECTIVE: We determined whether the expression of GRIM-19 is correlated with pathologic types and malignant grades in gliomas, and determined the function of GRIM-19 in human gliomas. METHODS: Tumor tissues were isolated and frozen at -80 just after surgery. The tissues consisted of normal brain tissue (4), astrocytomas (2), anaplastic astrocytomas (2), oligodendrogliomas (13), anaplastic oligodendrogliomas (11), and glioblastomas (16). To profile tumor related genes, we applied RNA differential display using a Genefishing DEG kit, and validated the tumor-related genes by reverse transcription polymerase chain reaction (RT-PCR). A human glioblastoma cell line (U343MG-A) was used for the GRIM-19 functional studies. The morphologic and cytoskeletal changes were examined via light and confocal microscopy. The migratory and invasive abilities were investigated by the simple scratch technique and Matrigel assay. The antiproliferative activity was determined by thiazolyl blue Tetrazolium bromide (MTT) assay and FACS analysis. RESULTS: Based on RT-PCR analysis, the expression of GRIM-19 was higher in astrocytic tumors than oligodendroglial tumors. The expression of GRIM-19 was higher in high-grade tumors than low-grade tumors or normal brain tissue; glioblastomas showed the highest expression. After transfection of GRIM-19 into U343MG-A, the morphology of the sense-transfection cells became larger and more spindly. The antisense-transfection cells became smaller and rounder compared with wild type U343MG-A. The MTT assay showed that the sense-transfection cells were more sensitive to the combination of interferon beta and retinoic acid than U343MG-A cells or antisense-transfection cells; the anti-proliferative activity was related to apoptosis. CONCLUSION: GRIM-19 may be one of the gene profiles which regulate cell death via apoptosis in human gliomas. PMID- 20717509 TI - Mobile computed tomography : early experience in Korea. AB - OBJECTIVE: With improved technology, the values of intraoperative computed tomography (iCT) have been reevaluated. We describe our early clinical experience with a mobile CT (mCT) system for iCT and discuss its clinical applications, advantages and limitations. METHODS: Compared with intraoperative magnetic resonance imaging, this mCT system has no need for major reconstruction of a preexisting operating room for shielding, or for specialized instruments or equipment. Patients are placed on a radiolucent head clamp that fits within the gantry. Because it consists simply of a scanner and a workstation, it can be moved between locations such as an operating room, an intensive care unit (ICU) or an emergency room without difficulty. Furthermore, it can achieve nearly all types of CT scanning procedures such as enhancement, temporal bone imaging, angiography and three-dimensional reconstruction. RESULTS: For intracranial surgery, mCT can be used for intraoperative real-time neuronavigation by interacting with preoperative images. It can also be used for intraoperative confirmation of the extent of resection of intracranial lesions and for immediate checks for preventing intraoperative unexpected accidents. Therefore, the goals of maximal resection or optimal treatment can be achieved without any guesswork. Furthermore, mCT can achieve improved patient care with safety and faster diagnosis for patients in an ICU who might be subjected to a ventilator and/or various monitoring devices. CONCLUSION: Our initial experience demonstrates that mCT with high-quality imaging offers very useful information in various clinical situations. PMID- 20717510 TI - Surgical treatment of craniovertebral junction instability : clinical outcomes and effectiveness in personal experience. AB - OBJECTIVE: Craniovertebral junction (CVJ) consists of the occipital bone that surrounds the foramen magnum, the atlas and the axis vertebrae. The mortality and morbidity is high for irreducible CVJ lesion with cervico-medullary compression. In a clinical retrospective study, the authors reviewed clinical and radiographic results of occipitocervical fusion using a various methods in 32 patients with CVJ instability. METHODS: Thirty-two CVJ lesions (18 male and 14 female) were treated in our department for 12 years. Instability resulted from trauma (14 cases), rheumatoid arthritis (8 cases), assimilation of atlas (4 cases), tumor (2 cases), basilar invagination (2 cases) and miscellaneous (2 cases). Thirty-two patients were internally fixed with 7 anterior and posterior decompression with occipitocervical fusion, 15 posterior decompression and occipitocervical fusion with wire-rod, 5 C1-2 transarticular screw fixation, and 5 C1 lateral mass-C2 transpedicular screw. Outcome (mean follow-up period, 38 months) was based on clinical and radiographic review. The clinical outcome was assessed by Japanese Orthopedic Association (JOA) score. RESULTS: Nine neurologically intact patients remained same after surgery. Among 23 patients with cervical myelopathy, clinical improvement was noted in 18 cases (78.3%). One patient died 2 months after the surgery because of pneumonia and sepsis. Fusion was achieved in 27 patients (93%) at last follow-up. No patient developed evidence of new, recurrent, or progressive instability. CONCLUSION: The authors conclude that early occipitocervical fusion to be recommended in case of reducible CVJ lesion and the appropriate decompression and occipitocervical fusion are recommended in case of irreducible craniovertebral junction lesion. PMID- 20717511 TI - The use of pedicle screw-rod system for the posterior fixation in cervico thoracic junction. AB - OBJECTIVE: In cervico-thoracic junction (CTJ), the use of strong fixation device such as pedicle screw-rod system is often required. Purpose of this study is to analyze the anatomical features of C7 and T1 pedicles related to screw insertion and to evaluate the safety of pedicle screw insertion at these levels. METHODS: Nineteen patients underwent posterior CTJ fixation with C7 and/or T1 included in fixation levels. Seventeen patients had tumorous conditions and two with post laminectomy kyphosis. The anatomical features were analyzed for C7 and T1 pedicles in 19 patients using computerized tomography (CT). Pedicle screw and rod fixation system was used in 16 patients. Pedicle violation by screws was evaluated with postoperative CT scan. RESULTS: The mean values of the width, height, stable depth, safety angle, transverse angle, and sagittal angle of C7 pedicles were 6.9 +/- 1.34 mm, 8.23 +/- 1.18 mm, 30.93 +/- 4.65 mm, 26.42 +/- 7.91 degrees, 25.9 +/- 4.83 degrees, and 10.6 +/- 3.39 degrees. At T1 pedicles, anatomic parameters were similar to those of C7. The pedicle violation revealed that 64.1% showed grade I violation and 35.9% showed grade II violation, overall. As for C7 pedicle screw insertion, grade I was 61.5% and grade II 38.5%. At T1 level, grade I was 65.0% and grade II 35.0%. There was no significant difference in violation rate between the whole group, C7, and T1 group. CONCLUSION: C7 pedicles can withstand pedicle screw insertion. C7 pedicle and T1 pedicle are anatomically very similar. With the use of adequate fluoroscopic oblique view, pedicle screw can be safely inserted at C7 and T1 levels. PMID- 20717512 TI - Experiences of neuroform stent applications for ruptured anterior communicating artery aneurysms with small parent vessel. AB - OBJECTIVE: The purpose of this study was to review the safety and durability of aneurysms treated with stent-assisted coiling of ruptured anterior communicating artery aneurysms with small parent vessels (< 2.0 mm). METHODS: Retrospective review of all ruptured aneurysm treated with stent assisted endovascular coiling between March 2005 and March 2009 at our institution was conducted. We report 11 cases of the Neuroform stent placement into cerebral vessels measuring less than 2.0 mm in diameter (range, 1.3-1.9 mm) in anterior cerebral artery. Clinical follow-up ranged from 3 to 12 months and imaging follow-up was performed with cerebral angiography at 6 months and 12 months after discharge. RESULTS: Complete occlusion was achieved in 10 patients, and a remnant neck was evident in one. No stent displacement or no dislodgement occurred during stent placement. There was no evidence of thromboembolic complication, arterial dissection and spasm during procedure. We performed follow-up angiography in all patients at 6 months and/or 12 months from the first procedure. The follow-up angiographic data showed successfully results except one in-stent stenosis case. All patients improved clinical performances except one patient with severe vasospasm who showed poor clinical condition initially. CONCLUSION: We have safely and successfully treated 11 vessels smaller than 2.0 mm in diameter with self-expanding stents with good short and intermediate term results. More clinical data with longer follow-ups are needed to establish the role of stent-assisted coiling in ruptured aneurysms with small parent vessels. PMID- 20717513 TI - Racemose cysticercosis in the cerebellar hemisphere. AB - Neurocysticercosis is the most common parasitic disease of the central nervous system in humans, caused by infection of the larval stage of the pork tapeworm, Taenia solium. However, cerebellar involvement is rarely reported. We report of a case of racemose cysticercosis in the cerebellar hemisphere. A 44-year-old man presented with headache and dizziness. Magnetic resonance imaging showed hydrocephalus and an ill-defined, multicystic cerebellar mass with hypersignal on T2-weighted images, hyposignal on T1-weighted images and rim enhancement after gadolinium injection. The patient underwent endoscopic third ventriculostomy and the cyst resection was done through a craniotomy. In surgical field, cysts were conglomerated in a dense collagen capsule that were severely adherent to surrounding cerebellar tissue, and transparent cysts contained white, milky fluid. Histological findings confirmed the diagnosis of cysticercosis. He received antiparasitic therapy with praziquantel after surgery. Racemose cysticercosis is rare in the cerebellar hemisphere but neurocysticercosis should be taken into consideration as a differential diagnosis of multiple cystic lesions in the cerebellum. PMID- 20717514 TI - Chordoid glioma : a case report of unusual location and neuroradiological characteristics. AB - Since the World Health Organization (WHO) classification for central nervous system neoplasms was declared in 2000, chordoid glioma of the third ventricle has been noted as a newly recognized tumor for central nervous system neoplasms. Although there is not enough universal experience to know the nature of this tumor due to its rarity, the origin of chordoid glioma was guardedly proposed to be the ependymal cells of the third ventricle. Such an idea has been primarily based on the specific location of the tumor, that is, third ventricle, suprasellae, and hypothalamus. However, we report a rare case of histologically confirmed chordoid glioma located in the left thalamus, not attached to any of the midline structures having unusual neuroradiological characteristics. PMID- 20717515 TI - Surgical experience of neglected lower cervical spine fracture in patient with ankylosing spondylitis. AB - The management of lower cervical fractures in patients with ankylosing spondylitis (AS) differs from normal cervical fractures. Patients with AS are highly susceptible to extensive neurologic injuries and spinal deformities after cervical fractures from even minor traumatic forces. These injuries are uniquely complex, require careful imaging assessment, and aggressive surgical management to optimize spinal stability and functional outcomes. PMID- 20717516 TI - Bilateral pedicle stress fracture accompanying spondylolysis in a patient with ankylosing spondylitis. AB - Bilateral pedicle stress fracture is a rare entity and few cases have been reported in the literature. Furthermore, the majority of these reports concern previous spine surgery or stress-related activities. Here, the authors report ankylosing spondylitis as a new cause of bilateral pedicle stress fractures accompanying spondylolysis. The reported case adds to the literature on bilateral pedicle stress fracture and spondylolysis by documenting that ankylosing spondylitis is another cause of this condition. PMID- 20717517 TI - Rapid Development of Brain Abscess Caused by Streptococcus Pyogenes Following Penetrating Skull Injury via the Ethmoidal Sinus and Lamina Cribrosa. AB - OBJECTIVE: Streptococcus pyogenes is a beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as group A streptococci (GAS). There have been five reported case in terms of PubMed-based search but no reported case of brain abscess caused by Streptococcus pyogenes as a result of penetrating skull injury. We present a patient who suffered from penetrating skull injury that resulted in a brain abscess caused by Streptococcus pyogenes. METHODS: The patient was a 12 year-old boy who fell down from his bicycle while cycling and ran into a tree. A wooden stick penetrated his skin below the right lower eyelid and advanced to the cranium. He lost consciousness on the fifth day of the incident and his body temperature was measured as 40. While being admitted to our hospital, a cranial computed tomography revealed a frontal cystic mass with a perilesional hypodense zone of edema. There was no capsule formation around the lesion after intravenous contrast injection. Paranasal CT showed a bone defect located between the ethmoidal sinus and lamina cribrosa. RESULTS: Bifrontal craniotomy was performed. The abscess located at the left frontal lobe was drained and the bone defect was repaired. CONCLUSION: Any penetrating lesion showing a connection between the lamina cribrosa and ethmoidal sinus may result in brain abscess caused by Streptococcus pyogenes. These patients should be treated urgently to repair the defect and drain the abscess with appropriate antibiotic therapy started due to the fulminant course of the brain abscess caused by this microorganism. PMID- 20717518 TI - Hydrocephalus as a presenting manifestation of neurosarcoidosis : easy to misdiagnose as tuberculosis. AB - We present a case of hydrocephalus as the primary manifestation of neurosarcoidosis. Sarcoidosis is a rare disease in Korea and its incidence is much lower than that of tuberculosis. Diagnosis is made by pathologic findings and by exclusion of other granulomatous disorders. Neurosarcoidosis is observed in approximately 5% of sarcoidosis. Its common manifestations are facial palsy (50% of patients with neurosarcoidosis) and optic neuritis. Hydrocephalus is a very uncommon reported finding. Although the typical presentation of sarcoidosis such as facial palsy is not a diagnostic dilemma, more atypical presentations such as hydrocephalus with altered mentality in a tuberculosis patient can lead to a misdiagnosis. PMID- 20717519 TI - Two cases with persistent falcine sinus as congenital variation. AB - The falcine sinus is an abnormal anatomic structure located in the falx cerebri that is closed after birth and is rarely observed. We describe two cases of persistent falcine sinus. A 60-year-old woman presented with headache. An 11-year old girl presented with intermittent headache and a palpable scalp mass in the middle of the high parietal area. The straight sinuses were absent in both patients. In both patients, drainage of the galenic system took place through a sinus within the falx, also known as a falcine sinus. Suspicious dysplastic tentorium cerebelli was observed in one patient. It can be concluded that a mesenchymal disorder can be the primary cause for a persistent falcine sinus. PMID- 20717520 TI - A solitary skull lesion of syphilitic osteomyelitis. AB - We experienced a rare case of solitary syphilitic osteomyelitis of the skull without any other clinical signs or symptoms of syphilis. A 20-year-old man was referred due to intermittent headache and mild tenderness at the right parietal area of the skull with a palpable coin-sized lesion of softened cortical bone. On radiological studies, the lesion was a radiolucent well enhanced mass (17 mm in diameter). The erythrocyte sedimentation rate (52 mm/h) and C-reactive protein (2.24 mg/dL) were elevated on admission. Serum venereal disease research laboratory (VDRL) and Treponema pallidum haemagglutination assay (TPHA) tests were positive. There were no clinical signs or symptoms of syphilis. After treatment with benzathine penicillin, we removed the lesion and performed cranioplasty. The pathologic finding of the skull lesion was fibrous proliferation with lymphoplasmocytic infiltration forming an osteolytic lesion. In addition, a spirochete was identified using the Warthin-starry stain. The polymerase chain reaction study showed a positive band for Treponema pallidum. Solitary osteomyelitis of the skull can be the initial presenting pathological lesion of syphilis. PMID- 20717521 TI - Retroperitoneal hematoma as a serious complication of endovascular aneurysmal coiling. AB - Retroperitoneal hematoma (RH) due to radiologic intervention for an intracranial lesion is relatively rare, difficult to diagnose, and can be life-threatening. We report a case of RH that developed in a patient on anticoagulant therapy following endovascular coiling of a ruptured anterior communicating artery (AcoA) aneurysm. An 82-year-old man presented with a 12-day history of headache. Computed tomography (CT) on admission demonstrated slight subarachnoid hemorrhage, and left carotid angiography revealed an AcoA aneurysm. The next day, the aneurysm was occluded with coils via the femoral approach under general anesthesia. The patient received a bolus of 5,000 units of heparin immediately following the procedure, and an infusion rate of 10,000 units/day was initiated. The patient gradually became hypotensive 25 hours after coiling. Abdominal CT showed a huge, high-density soft-tissue mass filling the right side of the retroperitoneum space. The patient eventually died of multiple organ failure five days after coiling. RH after interventional radiology for neurological disease is relatively rare and can be difficult to diagnose if consciousness is disturbed. This case demonstrates the importance of performing routine physical examinations, sequentially measuring the hematocrit and closely monitoring systemic blood pressures following interventional radiologic procedures in patients with abnormal mental status. PMID- 20717522 TI - Neurocysticercosis involving the pituitary stalk : case report and literature review. AB - Neurocysticercosis (NCC) is the most common parasitic infestation of the central nervous system. Most cases of NCC are to related and/or associated with inflammation within the cerebral parenchyma. A 71-year-old woman presented with a 4-year history of visual disturbance. This symptom had become aggravated 4 weeks earlier. Her visual acuity gradually decreased and superior hemianopsia was noted. Magnetic resonance imaging (MRI) revealed an enhanced and thickened pituitary stalk accompanying a suspicious mass. The provisional diagnoses were lymphoma, glioma, or other inflammatory conditions. Laboratory studies, including blood and hormonal studies, showed normal findings. Surgical resection was performed. In the pathological examination, degenerated parasitic wall structure was seen and its contents were composed of completely degenerated focal globular structures suggesting the scolex of cysticercus. We report an unusual case of NCC involving the pituitary stalk which was presented with a juxtasellar tumor. The possible underlying mechanisms are discussed with a review of pertinent literature. PMID- 20717523 TI - Sequential events in the irreversible thermal denaturation of human brain-type creatine kinase by spectroscopic methods. AB - The non-cooperative or sequential events which occur during protein thermal denaturation are closely correlated with protein folding, stability, and physiological functions. In this research, the sequential events of human brain type creatine kinase (hBBCK) thermal denaturation were studied by differential scanning calorimetry (DSC), CD, and intrinsic fluorescence spectroscopy. DSC experiments revealed that the thermal denaturation of hBBCK was calorimetrically irreversible. The existence of several endothermic peaks suggested that the denaturation involved stepwise conformational changes, which were further verified by the discrepancy in the transition curves obtained from various spectroscopic probes. During heating, the disruption of the active site structure occurred prior to the secondary and tertiary structural changes. The thermal unfolding and aggregation of hBBCK was found to occur through sequential events. This is quite different from that of muscle-type CK (MMCK). The results herein suggest that BBCK and MMCK undergo quite dissimilar thermal unfolding pathways, although they are highly conserved in the primary and tertiary structures. A minor difference in structure might endow the isoenzymes dissimilar local stabilities in structure, which further contribute to isoenzyme-specific thermal stabilities. PMID- 20717524 TI - Analysis of the nucleophilic solvation effects in isopropyl chlorothioformate solvolysis. AB - Correlation of the solvent effects through application of the extended Grunwald Winstein equation to the solvolysis of isopropyl chlorothioformate results in a sensitivity value of 0.38 towards changes in solvent nucleophilicity (l) and a sensitivity value of 0.72 towards changes in solvent ionizing power (m). This tangible l value coupled with the negative entropies of activation observed indicates a favorable predisposition towards a modest rear-side nucleophilic solvation of a developing carbocation. Only in 100% ethanol was the bimolecular pathway dominant. These observations are very different from those obtained for the solvolysis of isopropyl chloroformate, where dual reaction channels were proposed, with the addition-elimination reaction favored in the more nucleophilic solvents and a unimolecular fragmentation-ionization mechanism favored in the highly ionizing solvents. PMID- 20717525 TI - Antibiotic producing potentials of three freshwater actinomycetes isolated from the Eastern Cape Province of South Africa. AB - Crude extracts of three actinomycetes species belonging to Saccharopolyspora (TR 046 and TR 039) and Actinosynnema (TR 024) genera were screened for antibacterial activities against a panel of several bacterial strains. The extracts showed antibacterial activities against both gram-negative and gram-positive test bacteria with inhibition zones ranging from 8 to 28 mm (TR 046); 8 to15 mm (TR 039); and 10 to 13 mm (TR 024). The minimum inhibitory concentrations ranged from 0.078 to 10 mg/mL (TR 046); 5 to >10 mg/mL (TR 039); and 1.25 to 5 mg/mL (TR 024). Time-kill studies revealed that crude extract of TR 046 showed strong bactericidal activity against Bacillus pumilus (ATCC14884), reducing the bacterial load by 10(4) cfu/mL and 10(2) cfu/mL at 4x MIC and 2x MIC, respectively, after 6 h of exposure. Similarly, against Proteus vulgaris (CSIR 0030), crude extract of TR 046 achieved a 0.9log(10) and 0.13log(10) cfu/mL reduction at 5 mg/mL (4x MIC) and 1.25 mg/mL (2x MIC) after 12 h of exposure. The extract was however weakly bactericidal against two environmental bacterial strains (Klebsiella pneumoniae and Staphylococcus epidermidis); and against Pseudomonas aeruginosa (ATCC 19582): the extract showed bacteriostatic activities at all concentrations tested. These freshwater actinomycetes appear to have immense potential as a source of new antibacterial compound(s). PMID- 20717526 TI - Decreased erythrocyte CCS content is a biomarker of copper overload in rats. AB - Copper (Cu) is an essential trace metal that is toxic in excess. It is therefore important to be able to accurately assess Cu deficiency or overload. Cu chaperone for Cu/Zn superoxide dismutase (CCS) protein expression is elevated in tissues of Cu-deficient animals. Increased CCS content in erythrocytes is particularly sensitive to decreased Cu status. Given the lack of a non-invasive, sensitive and specific biomarker for the assessment of Cu excess, we investigated whether CCS expression in erythrocytes reflects Cu overload. Rats were fed diets containing normal or high levels of Cu for 13 weeks. Diets contained 6.3 +/- 0.6 (Cu-N), 985 +/- 14 (Cu-1000) or 1944 +/- 19 (Cu-2000) mg Cu/kg diet. Rats showed a variable response to the high Cu diets. Some rats showed severe Cu toxicity, while other rats showed no visible signs of toxicity and grew normally. Also, some rats had high levels of Cu in liver, whereas others had liver Cu concentrations within the normal range. Erythrocyte CCS protein expression was 30% lower in Cu-2000 rats compared to Cu-N rats (P < 0.05). Notably, only rats that accumulated high levels of Cu in liver had lower erythrocyte CCS (47% reduction, P < 0.05) compared to rats fed normal levels of Cu. Together, these data indicate that decreased erythrocyte CCS content is associated with Cu overload in rats and should be evaluated further as a potential biomarker for assessing Cu excess in humans. PMID- 20717527 TI - Conducting polymer nanostructures: template synthesis and applications in energy storage. AB - Conducting polymer nanostructures have received increasing attention in both fundamental research and various application fields in recent decades. Compared with bulk conducting polymers, conducting polymer nanostructures are expected to display improved performance in energy storage because of the unique properties arising from their nanoscaled size: high electrical conductivity, large surface area, short path lengths for the transport of ions, and high electrochemical activity. Template methods are emerging for a sort of facile, efficient, and highly controllable synthesis of conducting polymer nanostructures. This paper reviews template synthesis routes for conducting polymer nanostructures, including soft and hard template methods, as well as its mechanisms. The application of conducting polymer mesostructures in energy storage devices, such as supercapacitors and rechargeable batteries, are discussed. PMID- 20717528 TI - The effect of treadmill training pre-exercise on glutamate receptor expression in rats after cerebral ischemia. AB - Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat model undergoing middle cerebral artery occlusion (MCAO). Thirty-six rats were divided into three groups: a sham control group, a non-exercise with operation group and an exercise with operation group. After treadmill training, ischemia was induced by occluding the MCA for 2 h, followed by reperfusion. Half of the rats in each group were sacrificed for mRNA detection of mGluR5 and NR2B 80 min after occlusion. The remaining animals were evaluated for neurological deficits by behavioral scoring and then decapitated to assess the infarct volume. The mRNA expression of mGluR5 and NR2B was detected by real-time PCR. The results suggest that pre-ischemic treadmill training may induce brain ischemic tolerance by reducing the mRNA levels of mGluR5 and NR2B, and thus, the results indicate that physical exercise might be an effective method to establish ischemic preconditioning. PMID- 20717529 TI - Molecular epidemiological study of pyrazinamide-resistance in clinical isolates of mycobacterium tuberculosis from South India. AB - Pyrazinamide (PZA) has been in use for almost 50 years as a first-line drug for short-course chemotherapy against Mycobacterium tuberculosis. In this study, PCR mediated automated DNA sequencing is used to check the prevalence of PZA resistance among treatment failure cases of pulmonary tuberculosis. Out of 50 clinical isolates examined, 39 had mutations in the pncA gene that encodes Pyrazinamidase, an enzyme required to activate PZA. Of these, 31 (79.5%) were localized to three regions of pncA. We found two isolates with hitherto unreported mutation at amino acid 26 (Ala-->Gly) of pncA. PMID- 20717530 TI - Principal component analysis of HPLC retention data and molecular modeling structural parameters of cardiovascular system drugs in view of their pharmacological activity. AB - Evaluation of relationships between molecular modeling structural parameters and high-performance liquid chromatography (HPLC) retention data of 11 cardiovascular system drugs by principal component analysis (PCA) in relation to their pharmacological activity was performed. The six retention data parameters were determined on three different HPLC columns (Nucleosil C18 AB with octadecylsilica stationary phase, IAM PC C10/C3 with chemically bounded phosphatidylcholine, and Nucleosil 100-5 OH with chemically bounded propanodiole), and using isocratically acetonitrile: Britton-Robinson buffer as the mobile phase. Additionally, molecular modeling studies were performed with the use of HyperChem software and MM+ molecular mechanics with the semi-empirical AM1 method deriving 20 structural descriptors. Factor analysis obtained with the use of various sets of parameters: structural parameters, HPLC retention data, and all 26 considered parameters, led to the extraction of two main factors. The first principal component (factor 1) accounted for 44-57% of the variance in the data. The second principal component (factor 2) explained 29-33% of data variance. Moreover, the total data variance explained by the first two factors was at the level of 73-90%. More importantly, the PCA analysis of the HPLC retention data and structural parameters allows the segregation of circulatory system drugs according to their pharmacological (cardiovascular) properties as shown by the distribution of the individual drugs on the plane determined by the two principal components (factors 1 and 2). PMID- 20717532 TI - Biomass thermogravimetric analysis: uncertainty determination methodology and sampling maps generation. AB - The objective of this study was to develop a methodology for the determination of the maximum sampling error and confidence intervals of thermal properties obtained from thermogravimetric analysis (TG), including moisture, volatile matter, fixed carbon and ash content. The sampling procedure of the TG analysis was of particular interest and was conducted with care. The results of the present study were compared to those of a prompt analysis, and a correlation between the mean values and maximum sampling errors of the methods were not observed. In general, low and acceptable levels of uncertainty and error were obtained, demonstrating that the properties evaluated by TG analysis were representative of the overall fuel composition. The accurate determination of the thermal properties of biomass with precise confidence intervals is of particular interest in energetic biomass applications. PMID- 20717534 TI - Anti-allergic activity of a platycodon root ethanol extract. AB - Platycodon grandiflorum (Campanulaceae) is used as traditional medicine in Asian countries. In Korean traditional medicine, Platycodon root has been widely used since ancient times as a traditional drug to treat cold, cough and asthma. However, its effects on bone marrow-derived mast cell (BMMC)-mediated allergy and inflammation mechanisms remain unknown. In this study, the biological effect of Platycodon root ethanol extract (PE) was evaluated in BMMC after induction of allergic mediators by phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (A23187) stimulation. The effect of PE on the production of several allergic mediators, such as interleukin-6 (IL-6), prostaglandin D(2) (PGD(2)), leukotriene C(4) (LTC(4)), beta-Hexosaminidase (beta-Hex) and cyclooxygenase-2 (COX-2) protein, was investigated. The results demonstrate that PE inhibits PMA + A23187 induced production of IL-6, PGD(2), LTC(4), beta Hexosaminidase and COX-2 protein. Taken together, these results indicate that PE has the potential for use in the treatment of allergy. PMID- 20717535 TI - Crystallisation of wild-type and variant forms of a recombinant plant enzyme beta D-glucan glucohydrolase from barley (Hordeum vulgare L.) and preliminary X-ray analysis. AB - Wild-type and variant crystals of a recombinant enzyme beta-d-glucan glucohydrolase from barley (Hordeum vulgare L.) were obtained by macroseeding and cross-seeding with microcrystals obtained from native plant protein. Crystals grew to dimensions of up to 500 x 250 x 375 mum at 277 K in the hanging-drops by vapour-diffusion. Further, the conditions are described that yielded the wild type crystals with dimensions of 80 x 40 x 60 mum by self-nucleation vapour diffusion in sitting-drops at 281 K. The wild-type and recombinant crystals prepared by seeding techniques achived full size within 5-14 days, while the wild type crystals grown by self-nucleation appeared after 30 days and reached their maximum size after another two months. Both the wild-type and recombinant variant crystals, the latter altered in the key catalytic and substrate-binding residues Glu220, Trp434 and Arg158/Glu161 belonged to the P4(3)2(1)2 tetragonal space group, i.e., the space group of the native microcrystals was retained in the newly grown recombinant crystals. The crystals diffracted beyond 1.57-1.95 A and the cell dimensions were between a = b = 99.2-100.8 A and c = 183.2-183.6 A. With one molecule in the asymmetric unit, the calculated Matthews coefficients were between 3.4-3.5 A(3).Da(-1) and the solvent contents varied between 63.4% and 64.5%. The macroseeding and cross-seeding techniques are advantageous, where a limited amount of variant proteins precludes screening of crystallisation conditions, or where variant proteins could not be crystallized. PMID- 20717533 TI - Nitric oxide: perspectives and emerging studies of a well known cytotoxin. AB - The free radical nitric oxide (NO(*)) is known to play a dual role in human physiology and pathophysiology. At low levels, NO(*) can protect cells; however, at higher levels, NO(*) is a known cytotoxin, having been implicated in tumor angiogenesis and progression. While the majority of research devoted to understanding the role of NO(*) in cancer has to date been tissue-specific, we herein review underlying commonalities of NO(*) which may well exist among tumors arising from a variety of different sites. We also discuss the role of NO(*) in human physiology and pathophysiology, including the very important relationship between NO(*) and the glutathione-transferases, a class of protective enzymes involved in cellular protection. The emerging role of NO(*) in three main areas of epigenetics-DNA methylation, microRNAs, and histone modifications-is then discussed. Finally, we describe the recent development of a model cell line system in which human tumor cell lines were adapted to high NO(*) (HNO) levels. We anticipate that these HNO cell lines will serve as a useful tool in the ongoing efforts to better understand the role of NO(*) in cancer. PMID- 20717536 TI - Reactivity of heteropolytungstate and heteropolymolybdate metal transition salts in the synthesis of dimethyl carbonate from methanol and CO2. AB - A series of Keggin-type heteropoly compounds (HPC) having different countercations (Co, Fe) and different addenda atoms (W, Mo) were synthesized and characterized by means of Fourier-Transform Infrared Spectrometer (FT-IR) and X ray powder diffraction (XRD). The catalytic properties of the prepared catalysts for the dimethyl carbonate (DMC) synthesis from CO(2) and CH(3)OH were investigated. The experimental results showed that the catalytic activity is significantly influenced by the type of the countercation and addenda atoms transition metal. Among the catalysts examined, Co(1.5)PW(12)O(40) is the most active for the DMC synthesis, owing to the synergetic effect between Co and W. Investigating the effect of the support showed that the least acidic one (Al(2)O(3)) enhanced the conversion but decreased the DMC selectivity in favor of that of methyl formate (MF), while that of dimethoxy methane remained stable. PMID- 20717538 TI - Successful smoking cessation and duration of abstinence--an analysis of socioeconomic determinants. AB - Smoking does not affect every socioeconomic subgroup of the population equally, resulting in major inequalities in terms of smoking-related morbidity and mortality. While previous studies mainly focused on inequalities in smoking prevalence, we have analysed the socioeconomic dimensions that might be associated with two other smoking-related outcomes: the odds of successfully quitting and the duration of abstinence. Using nationally representative Swiss data, we found evidence of a socioeconomic gradient in successful cessation and abstinence duration with respect to education level and income for both men and women. PMID- 20717539 TI - Parenthood--a contributing factor to childhood obesity. AB - Prevalence of childhood obesity and its complications have increased world-wide. Parental status may be associated with children's health outcomes including their eating habits, body weight and blood cholesterol. The National Health and Nutrition Examination Survey (NHANES) for the years 1988-1994, provided a unique opportunity for matching parents to children enabling analyses of joint demographics, racial differences and health indicators. Specifically, the NHANES III data, 1988-1994, of 219 households with single-parents and 780 dual-parent households were analyzed as predictors for primary outcome variables of children's Body Mass Index (BMI), dietary nutrient intakes and blood cholesterol. Children of single-parent households were significantly (p < 0.01) more overweight than children of dual-parent households. Total calorie and saturated fatty acid intakes were higher among children of single-parent households than dual-parent households (p < 0.05). On average, Black children were more overweight (p < 0.04) than children of other races. The study results implied a strong relationship between single-parent status and excess weight in children. Further studies are needed to explore the dynamics of single-parent households and its influence on childhood diet and obesity. Parental involvement in the development of school- and community-based obesity prevention programs are suggested for effective health initiatives. Economic constraints and cultural preferences may be communicated directly by family involvement in these much needed public health programs. PMID- 20717537 TI - Chelation in metal intoxication. AB - Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications. PMID- 20717540 TI - Association between chronic arsenic exposure and nutritional status among the women of child bearing age: a case-control study in Bangladesh. AB - The role of nutritional factors in arsenic metabolism and toxicity is yet to be fully elucidated. A low protein diet results in decreased excretion of DMA and increased tissue retention of arsenic in experimental studies. Malnourished women carry a higher risk of adverse pregnancy outcomes. Chronic exposure to high arsenic (>50 microg/L) through drinking water also increases the risk of adverse pregnancy outcomes. The synergistic effects (if any) of malnutrition and chronic arsenic exposure may worsen the adverse pregnancy outcomes. This population based case control study reports the association between chronic arsenic exposure and nutritional status among the rural women in Bangladesh. 348 cases (BMI < 18.5) and 360 controls (BMI 18.5-24.99) were recruited from a baseline survey conducted among 2,341 women. An excess risk for malnutrition was observed among the participants chronically exposed to higher concentrations of arsenic in drinking water after adjusting for potential confounders such as participant's age, religion, education, monthly household income and history of oral contraceptive pills. Women exposed to arsenic >50 microg/L were at 1.9 times (Odds Ratio = 1.9, 95% CI = 1.1-3.6) increased risk of malnutrition compared to unexposed. The findings of this study suggest that chronic arsenic exposure is likely to contribute to poor nutritional status among women of 20-45 years. PMID- 20717541 TI - The incidence of norovirus-associated gastroenteritis outbreaks in Victoria, Australia (2002-2007) and their relationship with rainfall. AB - The relationship between the incidence of norovirus-associated gastroenteritis outbreaks (NAGOs) in Victoria, Australia for the period 2002-2007 and rainfall was examined. Statistical analysis involving the correlation between time series indicated that there was a statistically significant (p < 0.05) correlation between monthly NAGO incidence and average monthly rainfall. There was a lag of an average of about three months between peak average rainfall and a NAGO epidemic. The findings thus indicate rainfall can influence NAGO incidence. In an era where there is concern about the potential effects of global warming on weather patterns, it should be borne in mind that future changes in NAGO incidence may reflect altered world weather patterns. PMID- 20717542 TI - Cancer, infant mortality and birth sex-ratio in Fallujah, Iraq 2005-2009. AB - There have been anecdotal reports of increases in birth defects and cancer in Fallujah, Iraq blamed on the use of novel weapons (possibly including depleted uranium) in heavy fighting which occurred in that town between US led forces and local elements in 2004. In Jan/Feb 2010 the authors organised a team of researchers who visited 711 houses in Fallujah, Iraq and obtained responses to a questionnaire in Arabic on cancer, birth defects and infant mortality. The total population in the resulting sample was 4,843 persons with and overall response rate was better than 60%. Relative Risks for cancer were age-standardised and compared to rates in the Middle East Cancer Registry (MECC, Garbiah Egypt) for 1999 and rates in Jordan 1996-2001. Between Jan 2005 and the survey end date there were 62 cases of cancer malignancy reported (RR = 4.22; CI: 2.8, 6.6; p < 0.00000001) including 16 cases of childhood cancer 0-14 (RR = 12.6; CI: 4.9, 32; p < 0.00000001). Highest risks were found in all-leukaemia in the age groups 0-34 (20 cases RR = 38.5; CI: 19.2, 77; p < 0.00000001), all lymphoma 0-34 (8 cases, RR = 9.24;CI: 4.12, 20.8; p < 0.00000001), female breast cancer 0-44 (12 cases RR = 9.7;CI: 3.6, 25.6; p < 0.00000001) and brain tumours all ages (4 cases, RR = 7.4;CI: 2.4, 23.1; P < 0.004). Infant mortality was based on the mean birth rate over the 4 year period 2006-2009 with 1/6th added for cases reported in January and February 2010. There were 34 deaths in the age group 0-1 in this period giving a rate of 80 deaths per 1,000 births. This may be compared with a rate of 19.8 in Egypt (RR = 4.2 p < 0.00001) 17 in Jordan in 2008 and 9.7 in Kuwait in 2008. The mean birth sex-ratio in the recent 5-year cohort was anomalous. Normally the sex ratio in human populations is a constant with 1,050 boys born to 1,000 girls. This is disturbed if there is a genetic damage stress. The ratio of boys to 1,000 girls in the 0-4, 5-9, 10-14 and 15-19 age cohorts in the Fallujah sample were 860, 1,182, 1,108 and 1,010 respectively suggesting genetic damage to the 0-4 group (p < 0.01). Whilst the results seem to qualitatively support the existence of serious mutation-related health effects in Fallujah, owing to the structural problems associated with surveys of this kind, care should be exercised in interpreting the findings quantitatively. PMID- 20717543 TI - Access to healthcare interpreter services: where are we and where do we need to go? AB - Due to international migration, health care professionals in Switzerland increasingly encounter language barriers in communication with their patients. In order to examine health professionals' attitudes and practices related to healthcare interpreting, we sent a self-administered questionnaire to heads of medical and nursing departments in public healthcare services in the canton of Basel-Stadt (N = 205, response rate 56%). Strategies used to communicate with foreign-language speaking patients differed, depending on the patient's language. While nearly half of respondents relied on patients' relatives to translate for Albanian, Tamil, Bosnian, Croatian, Serbian, Portuguese and Turkish, a third did so for Spanish, and a fourth did so for Arabic. Eleven percent relied on professional interpreters for Spanish and 31% did so for Tamil and Arabic. Variations in strategies used appear to mainly reflect the availability of bilingual staff members for the different languages. Future efforts should focus on sensitizing health professionals to the problems associated with use of ad hoc interpreters, as well as facilitating access to professional interpreters. PMID- 20717544 TI - Perinatal bisphenol A exposure in C57B6/129svj male mice: potential altered cytokine/chemokine production in adulthood. AB - Pregnant mice (n = 3) were exposed to BPA by intraperitoneal injection, from gestation day 9.5 until end of lactation. Male offspring were evaluated for cytokine production at 20 wk-of-age. One pregnant control mouse produced no males, precluding statistical analysis. However, recurring shifts in cytokines were suggested in the adult BPA offspring. Serum showed a numeric increase in 16 of 21 basal cytokine levels. ConA-stimulated splenocytes showed a numeric increase in 17 of 21 cytokines, and LPS-stimulated splenocytes an increase in 18 of 21 cytokines. The cytokine profile was one of T(H)1 up-regulation more than T(H)2, and with skewing toward T(H)17 responses. PMID- 20717545 TI - Is participation in after-school physical activity associated with increased total physical activity? A study of high school pupils in the Czech Republic. AB - This study assessed the physical activity (PA) levels and its variability across days, months and seasons of two groups of high school pupils: those who did and those who did not participate in regular organized after-school physical activity (ASPA). Thirteen pupils wore pedometers continuously for one school-year, logged their step counts into record sheets and were then interviewed for information as regards their participation in any ASPA. Repeated measures analysis of variance showed that regardless of the day, month and season, ASPA pupils achieved significantly more mean step counts/day than the non-ASPA pupils. There were no significant fluctuations across months and seasons in PA levels of ASPA pupils when compared to non-ASPA pupils. We conclude that regular organised ASPA might increase the pupils' total PA levels; and could help to maintain a relatively constant PA level for adolescents across the whole school-year regardless of the influences of a range of weather and meteorological indicators that are related to months/seasons. PMID- 20717546 TI - Impact of climate change on ambient ozone level and mortality in southeastern United States. AB - There is a growing interest in quantifying the health impacts of climate change. This paper examines the risks of future ozone levels on non-accidental mortality across 19 urban communities in Southeastern United States. We present a modeling framework that integrates data from climate model outputs, historical meteorology and ozone observations, and a health surveillance database. We first modeled present-day relationships between observed maximum daily 8-hour average ozone concentrations and meteorology measured during the year 2000. Future ozone concentrations for the period 2041 to 2050 were then projected using calibrated climate model output data from the North American Regional Climate Change Assessment Program. Daily community-level mortality counts for the period 1987 to 2000 were obtained from the National Mortality, Morbidity and Air Pollution Study. Controlling for temperature, dew-point temperature, and seasonality, relative risks associated with short-term exposure to ambient ozone during the summer months were estimated using a multi-site time series design. We estimated an increase of 0.43 ppb (95% PI: 0.14-0.75) in average ozone concentration during the 2040's compared to 2000 due to climate change alone. This corresponds to a 0.01% increase in mortality rate and 45.2 (95% PI: 3.26-87.1) premature deaths in the study communities attributable to the increase in future ozone level. PMID- 20717547 TI - On measurement of avoidable and unavoidable cost of alcohol: an application of method for estimating costs due to prior consumption. AB - This study estimates the avoidable and unavoidable costs of alcohol-related, liver cirrhosis inpatient care, controlling for the lag structure and period of decline in disease risk. Lag structures with different lengths are applied to the exposure to risk from alcohol consumption, which allows for differentiation between avoidable and unavoidable cases due to prior consumption. A lag length of 20 (men) and 23 (women) years (expected remaining life years) gives a total cost of 592 million SEK. Given alcohol consumption is reduced to zero, 72% of cost could potentially be avoided. It is important to account for the length and structure of the risk decline following a consumption change as this substantially affects the estimates. PMID- 20717548 TI - Future intentions regarding quitting and reducing cigarette use in a representative sample of Canadian daily smokers: implications for public health initiatives. AB - Pre-cessation reduction is associated with quitting smoking. However, many smokers reduce the amount consumed but may not quit altogether. Using a representative sample of adult current daily smokers, this project explored future intentions of smokers regarding cigarette consumption. This information is important because it can provide a framework within which to plan tobacco cessation initiatives. A random digit dialing telephone survey was conducted of 889 Canadian current daily smokers, 18 years and older. The response rate was 65% (of households with a smoker in residence, 65% agreed to participate). Analyses focused on the 825 respondents who smoked at least 10 cigarettes per day at some point in their lives. As part of this survey, respondents were asked their future plans about their smoking (maintain, increase, reduce, quit). Of these 825 respondents, the majority of respondents had plans to change their cigarette use, with 55% planning to quit, 18.8% to reduce and 22.5% to maintain the amount they smoked (3.4% did not know and 2 respondents planned to increase). Most smokers who planned to reduce their smoking saw it as a step towards quitting smoking completely. These results present a picture of smokers, the majority of whom appear to be in some form of transition. Many smokers planned to reduce, of which the overwhelming majority saw their reduction as a step towards quitting. Opportunities exist to capitalize on these intentions to change in efforts to promote tobacco cessation. PMID- 20717550 TI - Situational analysis of household energy and biomass use and associated health burden of indoor air pollution and mitigation efforts in Pakistan. AB - Biomass fuel burning leads to high levels of suspended particulate matter and hazardous chemicals in the indoor environment in countries where it is in common use, contributing significantly to indoor air pollution (IAP). A situational analysis of household energy and biomass use and associated health effects of IAP was conducted by reviewing published and un-published literature about the situation in Pakistan. In addition to attempt to quantify the burden of ill health due to IAP, this paper also appraises the mitigation measures undertaken to avert the problem in Pakistan. Unfortunately, IAP is still not a recognized environmental hazard in Pakistan and there are no policies and standards to control it at the household level. Only a few original studies related to health effects of IAP have been conducted, mainly on women's health and birth outcome, and only a few governmental, non-governmental and academic institutions are working to improve the IAP situation by introducing improved stoves and renewable energy technology at a small scale. Control of IAP health hazards in Pakistan requires an initial meeting of the stakeholders to define a policy and an action agenda. Simultaneously, studies gathering evidence of impact of intervention through available technologies such as improved stoves would have favorable impact on the health, especially of women and children in Pakistan. PMID- 20717549 TI - A critical review of naphthalene sources and exposures relevant to indoor and outdoor air. AB - Both the recent classification of naphthalene as a possible human carcinogen and its ubiquitous presence motivate this critical review of naphthalene's sources and exposures. We evaluate the environmental literature on naphthalene published since 1990, drawing on nearly 150 studies that report emissions and concentrations in indoor, outdoor and personal air. While naphthalene is both a volatile organic compound and a polycyclic aromatic hydrocarbon, concentrations and exposures are poorly characterized relative to many other pollutants. Most airborne emissions result from combustion, and key sources include industry, open burning, tailpipe emissions, and cigarettes. The second largest source is off gassing, specifically from naphthalene's use as a deodorizer, repellent and fumigant. In the U.S., naphthalene's use as a moth repellant has been reduced in favor of para-dichlorobenzene, but extensive use continues in mothballs, which appears responsible for some of the highest indoor exposures, along with off label uses. Among the studies judged to be representative, average concentrations ranged from 0.18 to 1.7 microg m(-3) in non-smoker's homes, and from 0.02 to 0.31 microg m(-3) outdoors in urban areas. Personal exposures have been reported in only three European studies. Indoor sources are the major contributor to (non occupational) exposure. While its central tendencies fall well below guideline levels relevant to acute health impacts, several studies have reported maximum concentrations exceeding 100 microg m(-3), far above guideline levels. Using current but draft estimates of cancer risks, naphthalene is a major environmental risk driver, with typical individual risk levels in the 10(-4) range, which is high and notable given that millions of individuals are exposed. Several factors influence indoor and outdoor concentrations, but the literature is inconsistent on their effects. Further investigation is needed to better characterize naphthalene's sources and exposures, especially for indoor and personal measurements. PMID- 20717551 TI - Biomonitoring of urinary cotinine concentrations associated with plasma levels of nicotine metabolites after daily cigarette smoking in a male Japanese population. AB - Human biomonitoring of plasma and urinary levels of nicotine, cotinine, and 3' hydroxycotinine was conducted after daily cigarette smoking in a population of 92 male Japanese smokers with a mean age of 37 years who had smoked an average of 23 cigarettes per day for 16 years. Members of the population were genotyped for the nicotine-metabolizing enzyme cytochrome P450 2A6 (CYP2A6). The mean levels of nicotine, the levels of its metabolites cotinine and 3'-hydroxycotinine, and the sum of these three levels in subjects one hour after smoking the first cigarette on the sampling day were 20.1, 158, 27.7, and 198 ng/mL in plasma and 846, 1,020, 1,010, and 2,870 ng/mL in urine under daily smoking conditions. Plasma levels of 3'-hydroxycotinine and urinary levels of nicotine and 3'-hydroxycotinine were dependent on the CYP2A6 phenotype group, which was estimated from the CYP2A6 genotypes of the subjects, including those with whole gene deletion. Plasma cotinine levels were significantly correlated with the number of cigarettes smoked on the day before sampling (r = 0.71), the average number of cigarettes smoked daily (r = 0.58), and the Brinkman index (daily cigarettes x years, r = 0.48) under the present conditions. The sum of nicotine, cotinine, and 3' hydroxycotinine concentrations in plasma showed a similar relationship to that of the plasma cotinine levels. Urinary concentrations of cotinine and the sum of nicotine metabolite concentrations also showed significant correlations with the plasma levels and the previous day's and average cigarette consumption. The numbers of cigarettes smoked per day by two subjects with self-reported light smoking habits were predicted by measuring the urinary cotinine concentrations and using linear regression equations derived from above-mentioned data. These results indicate that biomonitoring of the urinary cotinine concentration is a good, easy-to-use marker for plasma levels of cotinine and the sum of nicotine metabolites in smokers independent of genetic polymorphism of CYP2A6. PMID- 20717552 TI - Climate change and mortality in Vienna--a human biometeorological analysis based on regional climate modeling. AB - The potential development of heat-related mortality in the 21th century for Vienna (Austria) was assessed by the use of two regional climate models based on the IPCC emissions scenarios A1B and B1. Heat stress was described with the human biometeorological index PET (Physiologically Equivalent Temperature). Based on the relation between heat stress and mortality in 1970-2007, we developed two approaches to estimate the increases with and without long-term adaptation. Until 2011-2040 no significant changes will take place compared to 1970-2000, but in the following decades heat-related mortality could increase up to 129% until the end of the century, if no adaptation takes place. The strongest increase occurred due to extreme heat stress (PET >or= 41 degrees C). With long-term adaptation the increase is less pronounced, but still notable. This encourages the requirement for additional adaptation measurements. PMID- 20717553 TI - Total fume and metal concentrations during welding in selected factories in Jeddah, Saudi Arabia. AB - Welding is a major industrial process used for joining metals. Occupational exposure to welding fumes is a serious occupational health problem all over the world. The degree of risk to welder's health from fumes depends on composition, concentration, and the length of exposure. The aim of this study was to investigate workers' welding fume exposure levels in some industries in Jeddah, Saudi Arabia. In each factory, the air in the breathing zone within 0.5 m from welders was sampled during 8-hour shifts. Total particulates, manganese, copper, and molybdenum concentrations of welding fumes were determined. Mean values of eight-hour average particulate concentrations measured during welding at the welders breathing zone were 6.3 mg/m(3) (Factory 1), 5.3 mg/m(3) (Factory 2), 11.3 mg/m(3) (Factory 3), 6.8 mg/m(3) (Factory 4), 4.7 mg/m(3) (Factory 5), and 3.0 mg/m(3) (Factory 6). Mean values of airborne manganese, copper, and molybdenum levels measured during welding were in the range of 0.010 mg/m(3) 0.477 mg/m(3), 0.001 mg/m(3)-0.080 mg/m(3) and 0.001 mg/m(3)-0.058 mg/m(3) respectively. Mean values of calculated equivalent exposure values were: 1.50 (Factory 1), 1.56 (Factory 2), 5.14 (Factory 3), 2.21 (Factory 4), 2.89 (Factory 5), and 1.20 (Factory 6). The welders in factories 1, 2, 3, and 4 were exposed to welding fume concentration above the SASO limit value, which may increase the risk of respiratory health problems. PMID- 20717555 TI - Synthesis of chiral beta-aminoalcohol palladium complexes exhibiting cytotoxic properties. AB - Original palladium complexes involving (-)-ephedrine, (-)-norephedrine, L prolinol, L-valinol and L-isoleucinol have been rapidly prepared in neutral or basic medium and simply purified. They have been fully characterized by classical analytical methods and four of them were characterized by X-Ray analysis. In parallel with the experimental work, HF-DFT(B3LYP/PCM) computations were performed to obtain additional structural information. Their antiproliferative properties have been evaluated and some complexes showed small activities especially towards HT29 human cancer cells. PMID- 20717554 TI - Endocrine disruptors and obesity: an examination of selected persistent organic pollutants in the NHANES 1999-2002 data. AB - Recent evidence suggests that endocrine disrupting chemicals (EDCs) may cause perturbations in endogenous hormonal regulation that predispose to weight gain. Using data from NHANES (1999-2002), we investigated the association between body mass index (BMI), waist circumference (WC) and selected persistent organic pollutants (POPs) via multiple linear regressions. Consistent interaction was found between gender, ln oxychlordane and ln p,p' DDT. Also, we found an association between WC and ln oxychlordane and ln hpcdd in subjects with detectable levels of POPs, whereas an association between WC and ln p,p' DDT was observed in all subjects. Furthermore, ln Ocdd showed an increase with higher WC and BMI, whereas, ln trans-nonachlor decreased with higher BMI. Hence, BMI and WC are associated with POPs levels, making the chemicals plausible contributors to the obesity epidemic. PMID- 20717556 TI - Cyclometalated red iridium(III) complexes containing carbazolyl-acetylacetonate ligands: efficiency enhancement in polymer LED devices. AB - The design, synthesis, photophysical and significantly improved electrooptical properties of a series of red emitting cyclometalated iridium(iii) complexes containing carbazolyl-acetylacetonate ligands are described. PMID- 20717557 TI - Cation recognition and pseudorotaxane formation of tris-dipyrrin BF2 macrocycles. AB - Macrocyclic planar tris-dipyrrin BF(2) complexes exhibit strong alkali-metal recognition and pseudorotaxane formation ability with a secondary ammonium salt through BF(2)-cation interactions. PMID- 20717558 TI - Urinary metabonomics study in a rat model in response to protein-energy malnutrition by using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. AB - Systematic studies were performed on the biological perturbations in metabolic phenotype responding to protein-energy malnutrition through global metabolic profiling analysis, in combination with pattern recognition. The malnutrition rat model was established through five weeks of strict diet restriction, and the metabonome data obtained from gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were integrated to approximate the comprehensive metabolic signature. Principal component analysis and orthogonal projection to latent structure analysis were used for the classification of metabolic phenotypes and discovery of differentiating metabolites. The perturbations in the urine profiles of malnourished rats were marked by higher levels of creatine, threitol, pyroglutamic acid, gluconic acid and kynurenic acid, as well as decreased levels of succinic acid, cis-aconitic acid, citric acid, isocitric acid, threonic acid, trimethylglycine, N methylnicotinic acid and uric acid. The alterations in these metabolites were associated with perturbations in energy metabolism, carbohydrate, amino acid, and fatty acid metabolism, purine metabolism, cofactor and vitamin metabolism, in response to protein and energy malnutrition. Our findings show the integration of GC-MS and LC-MS techniques for untargeted metabolic profiling analysis was promising for nutriology. PMID- 20717559 TI - Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. AB - The study of biological systems in a holistic manner (systems biology) is increasingly being viewed as a necessity to provide qualitative and quantitative descriptions of the emergent properties of the complete system. Systems biology performs studies focussed on the complex interactions of system components; emphasising the whole system rather than the individual parts. Many perturbations to mammalian systems (diet, disease, drugs) are multi-factorial and the study of small parts of the system is insufficient to understand the complete phenotypic changes induced. Metabolomics is one functional level tool being employed to investigate the complex interactions of metabolites with other metabolites (metabolism) but also the regulatory role metabolites provide through interaction with genes, transcripts and proteins (e.g. allosteric regulation). Technological developments are the driving force behind advances in scientific knowledge. Recent advances in the two analytical platforms of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy have driven forward the discipline of metabolomics. In this critical review, an introduction to metabolites, metabolomes, metabolomics and the role of MS and NMR spectroscopy will be provided. The applications of metabolomics in mammalian systems biology for the study of the health-disease continuum, drug efficacy and toxicity and dietary effects on mammalian health will be reviewed. The current limitations and future goals of metabolomics in systems biology will also be discussed (374 references). PMID- 20717560 TI - Redox-active radical scavenging nanomaterials. AB - Reactive oxygen and nitrogen species play a critical role in many degenerative diseases and in aging. Nanomaterials, especially modified fullerenes and cerium oxide nanoparticles, have been shown to effectively protect mammalian cells against damage caused by increased reactive oxygen or nitrogen species, likely through their direct reaction with superoxide radical, since each of these materials has been shown to act as effective superoxide dismutase mimetics in vitro. This critical review discusses the chemistry of these nanomaterials and the context in which their radical scavenging activities have been studied in biological model systems. Current studies are focused on determining the uptake, metabolism, distribution, toxicity and fate of these nanomaterials in cell and animal model systems. Ultimately if shown to be safe, these nanomaterials have the potential to be used to reduce the damaging effects of radicals in biological systems (101 references). PMID- 20717561 TI - RNA interference: a chemist's perspective. AB - Since the first unequivocal description of RNA interference (RNAi) in 1998, it has remained one of the hottest topics under investigation, culminating in the award of a Nobel Prize to its discoverers in 2006. Excitement over this technique derives from the ease with which it can be used to switch-off a specific gene in almost any organism, thereby allowing the role of that gene to be identified. More importantly, it offers the potential to treat certain diseases by switching off the causative genes. Key to the RNAi pathway are the small-interfering RNAs (siRNAs), which at 21-23 nucleotides in length are very amenable to analogue development by chemists. However in comparison to the use of oligonucleotides as antisense agents, an area where many chemists first developed an interest in nucleic acids, the RNAi pathway is exceedingly complex. The literature is also complicated by the fact that the phenomenon has been studied in a wide range of organisms. In this tutorial review we have presented the subject from a more chemical perspective, incorporating a glossary to give a clear explanation of the specialist terms. However, the coverage of the biology remains sufficiently detailed to give the reader the necessary insight that we believe will be essential for the successful design of chemically modified siRNA. PMID- 20717562 TI - Dispersion of multi-walled carbon nanotubes in an aqueous medium by water dispersible conjugated polymer nanoparticles. AB - Vertically aligned multi-walled carbon nanotubes (MWCNTs) synthesized by the alcohol catalytic CVD (ACCVD) technique are dispersed in water with the aid of water-dispersible conjugated polymer nanoparticles (CPNs). The interactions between CPNs and CNTs are studied with spectroscopy (UV-Vis, fluorescence and Raman) and electron microscopy techniques are used to confirm attachment of CPNs to the CNT sidewalls. PMID- 20717563 TI - Molecular trafficking based on latch circuit. AB - A new fluorescent chemosensor 3 based on calix[4]arene of partial cone conformation possessing dansyl moieties has been synthesized. The chemosensor demonstrates selective optical recognition of Hg(2+) ions in mixed aqueous media and mimics the operation of a traffic signal based on the R-S Latch Logic circuit with pH, Hg(2+) and Cl(-)/Br(-)/I(-) as chemical inputs. PMID- 20717564 TI - Strong location dependent surface enhanced Raman scattering on individual gold semishell and nanobowl particles. AB - We demonstrate strong spatial localization of SERS on single symmetry-reduced gold semishell and nanobowl particles. A ~30 nm carbon nanoparticle acts as a Raman reporter and is placed on different locations on a single semishell or nanobowl by e-beam induced deposition method, and remarkably different SERS intensities are observed. PMID- 20717565 TI - Complex function by design using spatially pre-structured synthetic microbial communities: degradation of pentachlorophenol in the presence of Hg(ii). AB - Naturally occurring microbes perform a variety of useful functions, with more complex processes requiring multiple functions performed by communities of multiple microbes. Synthetic biology via genetic engineering may be used to achieve desired multiple functions, e.g. multistep chemical and biological transformations, by adding genes to a single organism, but this is sometimes not possible due to incompatible metabolic requirements or not desirable in certain applications, especially in medical or environmental applications. Achieving multiple functions by mixing microbes that have not evolved to function together may not work due to competition of microbes, or lack of interactions among microbes. In nature, microbial communities are commonly spatially structured. Here, we tested whether spatial structure can be used to create a community of microbes that can perform a function they do not perform individually or when simply mixed. We constructed a core-shell fiber with Sphingobium chlorophenolicum, a pentachlorophenol (PCP) degrader, in the core layer and Ralstonia metallidurans, a mercuric ion (Hg(ii)) reducer, in the shell layer as a structured community using microfluidic laminar flow techniques. We applied a mixture of PCP and Hg(ii) to either a simple well-mixed culture broth (i.e. the unstructured community) or the spatially structured core-shell fibers. We found that without spatial structure, the community was unable to degrade PCP in the presence of Hg(ii) because S. chlorophenolicum is sensitive to Hg(ii). In contrast, with spatial structure in a core-shell fiber system, S. chlorophenolicum in a core layer was protected by R. metallidurans deposited in a shell layer, and the community was able to completely remove both PCP and Hg(ii) from a mixture. The appropriate size of the core-shell fiber was determined by the Damkohler number-the timescale of removal of Hg(ii) was on the same order of the timescale of diffusion of Hg(ii) through the outer layer when the shell layer was on the order of ~200 MUm. Ultimately, with the ease of a child putting together 'Legos' to build a complex structure, using this approach one may be able to put together microorganisms to build communities that perform functions in vitro or even in vivo, e.g. as in a "microbiome on a pill". PMID- 20717571 TI - Structure and dynamics of the UO2+ ion in aqueous solution: an ab initio QMCF-MD study. AB - The quantum mechanical charge field molecular dynamics (QMCF-MD) framework was applied in a simulation of the uranyl(v) ion in aqueous solution. The structure was evaluated on the basis of overall and sectorial radial distribution functions, angular distribution functions, tilt- and Theta-angle distribution functions and coordination number distributions. The cation is strongly coordinated by 4 water ligands at an average distance of 2.51 A, while the oxygen atoms are on average bound to 1.2 water molecules at a distance of 2.9 A. A mean residence time of 2.83 ps was evaluated for the oxygen sites of the uranyl(v) ion. The results are in good agreement with previous experimental and theoretical data on the hydration of similar ions. PMID- 20717570 TI - Endogenous patterns of mechanical stress are required for branching morphogenesis. AB - Spatial patterning of cell behaviors establishes the regional differences within tissues that collectively develop branched organs into their characteristic treelike shapes. Here we show that the pattern of branching morphogenesis of three-dimensional (3D) engineered epithelial tissues is controlled in part by gradients of endogenous mechanical stress. We used microfabrication to build model mammary epithelial tissues of defined geometry that branched in a stereotyped pattern when induced with growth factors. Branches initiated from sites of high mechanical stress within the tissues, as predicted numerically and measured directly using 3D traction force microscopy. Branch sites were defined by activation of focal adhesion kinase (FAK), inhibition of which disrupted morphogenesis. Stress, FAK activation, and branching were all altered by manipulating cellular contractility, matrix stiffness, intercellular cohesion and tissue geometry. These data suggest that the pattern and magnitude of mechanical stress across epithelial tissues cooperate with biochemical signals to specify branching pattern. PMID- 20717572 TI - Intermolecular vibrations of (CH2)2O-HF and -DF hydrogen bonded complexes investigated by Fourier transform infrared spectroscopy and ab initio calculations. AB - A series of Fourier transform infrared spectra (FTIR) of the hydrogen bonded complexes (CH(2))(2)O-HF and -DF have been recorded in the 50-750 cm(-1) range up to 0.1 cm(-1) resolution in a static cell maintained at near room temperature. The direct observation of three intermolecular transitions enabled us to perform band contour analysis of congested cell spectra and to determine reliable rovibrational parameters such as intermolecular frequencies, rovibrational and anharmonic coupling constants involving two l(1) and l(2) librations and one sigma stretching intermolecular motion. Inter-inter anharmonic couplings could be identified between nu(l(1)), nu(l(2)), nu(sigma) and the two lowest frequency bending modes. The positive sign of coupling constants (opposite with respect to acid stretching intra-inter ones) reveals a weakening of the hydrogen bond upon intermolecular excitation. The four rovibrational parameters nu(sigma) and x(sigmaj) (j = sigma, delta(1), delta(2)) derived in the present far-infrared study and also in a previous mid-infrared one [Phys. Chem. Chem. Phys. 2005, 1, 592] make deviations appear smaller than 1% for frequencies and 12% for coupling constants which gives confidence to the reliability of the data obtained. Anharmonic frequencies obtained at the MP2 level with Aug-cc-pvTZ basis set agree well with experimental values over a large set of frequencies and coupling constants. An estimated anharmonic corrected value of the dissociation energy D for both oxirane-HF (2424 cm(-1)) and -DF (2566 cm(-1)) has been derived using a level of theory as high as CCSD(T)/Aug-cc-pvQZ, refining the harmonic value previously calculated for oxirane-HF with the MP2 method and a smaller basis set. Finally, contrary to short predissociation lifetimes evidenced for acid stretching excited states, any homogeneous broadening related to vibrational dynamics of (CH(2))(2)O-HF and -DF has been observed within the three highest frequency intermolecular states, as expected with low excitation energies largely below the dissociation limit as well as a negligible IVR contribution. PMID- 20717573 TI - Passive self-synchronized two-droplet generation. AB - We describe the use of two passive components to achieve controllable and alternating droplet generation in a microfluidic device. The approach overcomes the problems associated with irregularities in channel dimensions and fluid flow rates, and allows precise pairing of alternating droplets in a high-throughput manner. We study droplet generation and self-synchronization in a quantitative fashion by using high-speed image analysis. PMID- 20717575 TI - Creating chirality in the inner walls of silica nanotubes through a hydrogel template: chiral transcription and chiroptical switch. AB - An L- or D-glutamic acid based bolaamphiphile was found to form uniform helical nanotubes in water, which were used as the template to generate silica nanotubes. The formed silica nanotubes have supramolecular chirality in the inner walls, and were further used to load photoactive azobenzene moieties to realize a chiroptical switch. PMID- 20717574 TI - Core-shell TiC/C quasi-aligned nanofiber arrays on biomedical Ti6Al4V for sensitive electrochemical biosensing. AB - Core-shell TiC/C-QANFAs are produced directly on a Ti6Al4V substrate by a simple thermochemical process that does not require a metal catalyst or template. The nanostructured arrays show Nernstian behavior and fast electron-transfer kinetics in the electrochemical reactions of Fe(CN)(6)(3-/4-) and demonstrate high selectivity and sensitivity in the simultaneous detection of AA, DA, and UA. PMID- 20717576 TI - Thermo- and light responsive micellation of azobenzene containing block copolymers. AB - In this communication, the synthesis and characterization of thermo- and light responsive block copolymers is reported. PEO-b-PNIPAM polymers with azobenzene moieties were prepared and analyzed by turbidimetry, fluorescence, NMR and DLS measurements. A temperature controlled reversible formation as well as a light induced disruption and reformation of micellar structures in water was found. PMID- 20717578 TI - Enhanced photoinduced surface reactivity of mesoporous titania modified with benzene siloxane. AB - Mesoporous TiO(2) modified with benzene siloxane displays a capability to generate more hydroxyl radicals upon photo-illumination, which substantially enhances its surface reactivity for the degradation of organic dyes. PMID- 20717577 TI - To boost c-type cytochrome wire efficiency of electrogenic bacteria with Fe3O4/Au nanocomposites. AB - A significant increase (ca. 22-fold) in the electricity generation due to a Shewanella oneidensis MR-1 biofilm was observed in the presence of Fe(3)O(4)/Au nanocomposites. PMID- 20717579 TI - Potential photoactivated metallopharmaceuticals: from active molecules to supported drugs. AB - Apart from cisplatin and some derivatives successful metallopharmaceuticals are still scarce in antitumour therapy. Although novel metal complexes have been investigated in preclinical settings several promising compounds failed in different phases. With the rise of new anticancer compounds new activation strategies have also evolved. Photochemical activation is one of the most important concepts as it uses pro-drugs whose activity can be triggered by light. This strategy offers the possibility to control the location, timing, and dosage of the therapeutic metal complex. Recent developments in the photoactivation of potential metallopharmaceuticals are summarized. Immobilisation of those drugs on solid matrices, such as films, particles, gels, and fibers, is an emerging field and recent findings are also discussed. PMID- 20717580 TI - A three-dimensional network of two-electron-transferred [Ru2]2TCNQ exhibiting anomalous conductance due to charge fluctuations. AB - A new D(2)A-type charge-transfer three-dimensional network with a charge distribution of [{Ru(2)}(delta+)-(BTDA-TCNQ(2delta-))-{Ru(2)}(delta+)] where delta ~ 1, which exhibits a sudden decrease in electronic resistance, formed from the assembly of a paddlewheel diruthenium(II, II) complex ([Ru(2)]) as a donor (D) and bis(1,2,5-thiadiazolo)tetracyanoquinodimethane (BTDA-TCNQ) as an acceptor (A). PMID- 20717582 TI - Sn[Si(SiMe3)3]3- and Sn3[Si(SiMe3)3]4: first insight into the mechanism of the disproportionation of a tin monohalide gives access to the shortest double bond of tin. AB - In the course of the disproportionation reaction of a monohalide beside metalloid clusters like Sn(10)[Si(SiMe(3))(3)](6) also molecular compounds with an average oxidation state of the tin atoms larger than one must be present. First results of such oxidized species are presented where the bonding is strongly influenced by the steric bulk of the ligands leading to the shortest tin-tin double bond. PMID- 20717581 TI - Bronsted acid differentiated metal catalysis by kinetic discrimination. AB - A Bronsted acid differentiated metal catalyzed hydrogenation has been developed. A combinatorial variation of chiral triflylamides with achiral metal complexes results in a highly active catalyst for the asymmetric reduction. PMID- 20717583 TI - DNA photocleavage by an osmium(II) complex in the PDT window. AB - The extended pi-delocalization of dppn (benzo[i]dipyrido[3,2-a:2,3-c]phenazine) results in a (3)pipi* state as the lowest triplet excited state in [Os(bpy)(2)(dppn)](2+) (bpy = 2,2'-bipyridine), which generates a (1)O(2) quantum yield of 0.42. Together with its (3)MLCT absorption, this new osmium complex shows efficient DNA cleavage under irradiation of lambda(irr) > or = 645 nm. PMID- 20717584 TI - Specific reactivity of step sites towards CO adsorption and oxidation on platinum single crystals vicinal to Pt(111). AB - In this work, surface modification at an atomic level, coupled with CO as molecular probe, was applied to study the step-site reactivity of platinum single crystals. Stepped platinum single crystal electrodes with (111) terraces and step sites of different symmetry were modified by irreversible adsorption of Bi and Te adatoms selectively deposited on steps, and characterized in 0.1 M HClO(4) solution. CO charge-displacement and oxidative stripping were employed to investigate the reactivity changes before and after modification of the electrode surfaces. The values of potential of zero total charge (pztc) determined from CO displacement experiments were found to shift positively on all decorated electrodes. The CO oxidation peaks also shifted to higher potential once the step sites were blocked by the adatoms, indicating a catalytic effect of the step sites for this reaction. The CO coverage values on the step sites were determined by comparing the stripping charges and the change in the hydrogen de/adsorption charge, using the pztc's for double layer correction. The CO coverage was determined to be ca. 0.7 for (110) step sites while only 0.4 for (100) step sites, which suggests a different bond of CO adsorbed on the different step sites. This was confirmed by in situ infrared reflection-absorption spectroscopy (IRAS) studies, showing that the (110) step sites are dominated by atop CO while bridged bonded CO are prevalent on (100) step sites. The comparison of CO stripping and hydrogen adsorption charges before and after adatom modification allows the separation of step and terrace contributions to the overall CO coverage. PMID- 20717585 TI - Rules for selectivity in oxidation processes on RuO2(110). AB - Selectivity is a must for new high performance catalysts which are required to fit strict environmental regulations. RuO(2) has been proposed as a mild oxidant capable of performing selective oxidations of alcohols to aldehydes and ketones. However, it fails in another appealing partial oxidation, that of ethylene to its epoxide, where complete oxidation occurs. In contrast, both reactions are selective on Ag, a catalyst that shows similar binding energies for the active oxidation species, oxygen. By means of density functional theory applied to slabs we have been able to unravel the origin of the, in principle erratic, selectivity of RuO(2) in partial oxidations. The behavior can be understood as being due to a combination of the basicity of O atoms, the relative binding energies of reactants and products to the surface (thermodynamic factor), and the structure sensitivity of some steps in the oxidation process due to difficult O mobility on RuO(2). PMID- 20717586 TI - The mechanism and energetics of insertion reactions of silylenes. AB - 56 insertion reactions between seven silylenes and eight reactants were investigated using B3LYP/cc-pVTZ method. The reaction energies and the stability of the silylenes are in good correlation. Silaimidazole-2-ylidene gives the highest reaction energies while Kira's stable five membered ring dialkylsilylene shows the smallest reaction energies. All the reaction energies and activation energies of the six-membered ring diazasilylene ({HC[CMeN(R)](2)}Si, R = 2,6 diisopropylphenyl) were found equal to that of the saturated five-membered diazasilole. The sum of the reaction free energies (DeltaG) and activation free energies (DeltaG(?)) of a reaction depend on the reactant but are independent of the silylene. PMID- 20717587 TI - Rare earth metal bis(trimethylsilyl)amido complexes bearing pyrrolyl-methylamide ligand. Synthesis, structure, and catalytic activity towards guanylation of amines. AB - The N-arylaminomethyl substituted pyrrolyl ligand 2-[(2,4,6 Me(3)C(6)H(2))NHCH(2)](C(4)H(3)NH) (1) was synthesized by reduction of 2-[(2,4,6 Me(3)C(6)H(2))N=CH](C(4)H(3)NH) using NaBH(4). Treatment of [(Me(3)Si)(2)N](3)Ln(MU-Cl)Li(THF)(3) with 1 equiv. of 1 in reflux toluene for 24 h, afforded the corresponding trivalent rare earth metal amides with formula {(MU eta(5):eta(1)):eta(1)-2-[(2,4,6 Me(3)C(6)H(2))NCH(2)]C(4)H(3)N]LnN(SiMe(3))(2)}(2) (Ln = Y(2), Nd(3), Sm(4), Dy(5), Er(6)). All compounds were fully characterised by spectroscopic methods and elemental analyses. The structures of complexes 2, 4 and 6 were determined by single-crystal X-ray analyses. X-Ray analyses discovered that two rare-earth metal ions were bridged by dianion ligand with the pyrrolyl ring which coordinated to one rare earth metal in an eta(5) mode, the tethered nitrogen anion and nitrogen atom of the pyrrolyl ring coordinated to another rare earth metal in eta(1) modes forming the centrosymmetric dinuclear structures. The rare earth metal complexes as catalysts for the guanylation of aromatic amines were studied. Results showed all rare earth metal complexes exhibited a high catalytic activity on the guanylation of aromatic amines. PMID- 20717590 TI - An iridium(III)-caged complex with low oxygen quenching. AB - We here report the synthesis and structural characterization of the first iridium(III) complex with a caged ligand structure, which shows a 80% decrease of oxygen quenching compared to the archetypical Ir(ppy)(3). PMID- 20717588 TI - Luminescent cyclometallated iridium(III) bis(quinolylbenzaldehyde) diimine complexes--synthesis, photophysics, electrochemistry, protein cross-linking properties, cytotoxicity and cellular uptake. AB - Four new luminescent cyclometallated iridium(III) bis(quinolylbenzaldehyde) diimine complexes [Ir(qba)(2)(N?N)](PF(6)) (Hqba = 4-(2-quinolyl)benzaldehyde, N?N = 2,2'-bipyridine, bpy (1); 1,10-phenanthroline, phen (2); 3,4,7,8 tetramethyl-1,10-phenanthroline, Me(4)-phen (3); 4,7-diphenyl-1,10 phenanthroline, Ph(2)-phen (4)) have been synthesised and characterised, and their electronic absorption, emission and electrochemical properties investigated. The X-ray crystal structures of complexes 1 and 2 have been determined. Upon irradiation, complexes 1-4 exhibited intense and long-lived orange-yellow emission in fluid solutions at 298 K and in alcohol glass at 77 K. The emission has been assigned to a triplet intra-ligand ((3)IL) excited state associated with the qba ligand, probably with mixing of some triplet metal-to ligand charge-transfer ((3)MLCT) (dpi(Ir) ->pi*(qba)) character. Reductive amination reactions of complexes 1-4 with the protein bovine serum albumin (BSA) afforded the bioconjugates 1-BSA-4-BSA, respectively. Upon photoexcitation, these bioconjugates displayed intense and long-lived (3)MLCT (dpi(Ir) ->pi*(N?C)) emission in aqueous buffer at 298 K. The cross-linked nature of the Ir-BSA bioconjugates has been verified by SDS-PAGE. Additionally, the cytotoxicity of the complexes towards human cervix epithelioid carcinoma (HeLa) cells has been examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cellular uptake of complex 4 has been investigated by laser scanning confocal microscopy and flow cytometry. PMID- 20717591 TI - Motif-programmed artificial proteins mediated nucleation of octacalcium phosphate on titanium substrates. AB - We report the creation of motif-based artificial proteins that bind to titanium surfaces and mediate the deposition of crystalline calcium phosphate. These proteins enabled in aqua surface modification of titanium materials having an intricate structure used in medical applications. PMID- 20717592 TI - "Nindigo": synthesis, coordination chemistry, and properties of indigo diimines as a new class of functional bridging ligands. AB - Reactions of indigo with anilines provide a simple route to indigo N,N' diaryldiimines ("Nindigo"), a new binucleating ligand with two beta-diketiminate type metal binding sites. Bis-palladium complexes have interesting ligand-centred properties such as redox activity and intense near infrared absorption. PMID- 20717593 TI - Low molecular weight gelator-dextran composites. AB - Incorporation of dextran into a hydrogel formed using a low molecular weight dipeptide-conjugate gelator results in controlled modification of the material properties. PMID- 20717594 TI - In situ reaction monitoring of microwave-mediated reactions using IR spectroscopy. AB - An IR probe has been interfaced with a scientific microwave unit, this allowing for real-time in situ monitoring of microwave-assisted reactions using IR spectroscopy. A number of organic transformations have been probed and the apparatus shown to work effectively as a tool for qualitative studies. PMID- 20717595 TI - Effects of annealing on the microstructures and photoactivity of fluorinated N doped TiO2. AB - We investigated the effects of annealing in air on fluorinated N-doped TiO(2) (F/N-TiO(2)) photocatalysts prepared by hydrothermal process. The textural properties (specific surface areas) and surface properties (surface defect density, surface [triple bond]Ti-F density) were significantly modified upon annealing. In contrast, due to the shielding effect of surface fluorination, the phase transformation from anatase to rutile as well as removal of N-dopants during annealing was greatly inhibited. The evolution of the chemical nature of doped nitrogen species upon annealing in air was investigated and correlated with the generation and annihilation of oxygen deficiency. The defect density dominated the visible-light absorption and production of active OH. The textural properties and the surface characteristics were crucial for UV-light photocatalytic performance, while the visible-light photocatalytic activity was mainly associated with the defect density. The 300 degrees C-annealed F/N-TiO(2) sample showed considerable photocatalytic activity under both UV and visible light irradiation. PMID- 20717596 TI - Computation of nodal surfaces in fixed-node diffusion Monte Carlo calculations using a genetic algorithm. AB - The fixed-node diffusion Monte Carlo (DMC) algorithm is a powerful way of computing excited state energies in a remarkably diverse number of contexts in quantum chemistry and physics. The main difficulty in implementing the procedure lies in obtaining a good estimate of the nodal surface of the excited state in question. Although the nodal surface can sometimes be obtained from symmetry or by making approximations this is not always the case. In any event, nodal surfaces are usually obtained in an ad hoc way. In fact, the search for nodal surfaces can be formulated as an optimization problem within the DMC procedure itself. Here we investigate the use of a genetic algorithm to systematically and automatically compute nodal surfaces. Application is made to the computation of excited states of the HCN-(4)He complex and to the computation of tunneling splittings in the hydrogen bonded HCl-HCl complex. PMID- 20717597 TI - Predicted compounds of radon with acetylene and water. AB - It is found that HRnCCH and HRnOH are metastable, chemically bound compounds of radon. These molecules are studied by multi-reference ab initio methods. Equilibrium geometry, NBO partial charges and bond orders, harmonic frequencies, are calculated. Intrinsic life-times are obtained by calculating the dissociation barriers and related partition functions, and by applying transition state theory. HRnCCH and HRnOH are found to be protected by an energy barrier of 2.1 and 0.79 eV, respectively. Using transition state theory, HRnOH is predicted to have a half-life of 1 h at about 230 K. HRnCCH is found to be kinetically stable at room temperature with its lifetime limited by the lifetime of the radioactive Rn atom. The significance of compound formation of radon with acetylene and water is discussed. PMID- 20717598 TI - Quantification of copper phases, their reducibility and dispersion in doped CuCl2/Al2O3 catalysts for ethylene oxychlorination. AB - The comprehensive understanding of the composition, behaviour and reactivity of a catalyst used inside industrial plants is an extremely hard task that is rarely achieved. It requires the use of different spectroscopic techniques, applied under in situ or in operando conditions, and combined with the investigation of the catalyst activity. Often the operating experimental conditions are different from technique to technique and the different results must be compared with care. In the present contribution, we combined in situ XANES/EXAFS, IR spectroscopy of adsorbed CO, CO chemisorption and catalytic tests performed using a pulse reactor in depletive mode. This multitechnical approach resulted in the understanding of the role that dopants (LiCl, KCl, CsCl, MgCl(2) LaCl(3)) have in the nature, relative fraction, reducibility and dispersion of Cu-phases on CuCl(2)/gamma Al(2)O(3) catalysts for oxychlorination reaction, a key step of the PVC chemistry. In the undoped catalyst two Cu phases coexist: Cu-aluminate and supported CuCl(2), being the latter the only active one [J. Catal., 2000, 189, 91]. EXAFS and XANES highlighted that all dopants contribute more or less efficiently in increasing the fraction of the active copper species, that reaches a value of almost 100% in the case of MgCl(2) or LaCl(3). EXAFS directly, and IR indirectly, proved that the addition of KCl or CsCl (and less efficiently of LiCl) results in the formation of mixed CuK(x)Cl(2+x) or CuCs(x)Cl(2+x) phases, so altering the chemical nature of the active phase. XANES spectroscopy indicates that addition of MgCl(2) or LaCl(3) does not affect the reducibility by ethylene (under static conditions) of the active CuCl(2) phase and that the reducibilility of the new copper-dopant mixed chloride are in the order CuCl(2) > CuLi(x)Cl(2+x) > CuK(x)Cl(2+x) > CuCs(x)Cl(2+x). However, when reduction is done inside a pulse reactor, a more informative picture comes out. The last technique is able to differentiate all samples, and their ability to be reduced by ethylene resulted in the order: La- > Mg- > Li-doped > undoped > K- > Cs-doped catalyst. To understand this apparent discrepancy the dispersion of the active phase, measured by CO chemisorption, was needed: it has been found that addition of LiCl increases enormously the dispersion of the active phase, LaCl(3) significantly and MgCl(2) barely, while addition of both KCl and CsCl results in a decrease of the surface area of the active phase. The mechanism of the enhancing effect of La and Mg on catalytic activity is still not clear, but it could be associated to the modification that they induce to the support surface: the Cu is so highly dispersed that almost all is in direct contact with support surface. It is finally worth noticing that the previous EXAFS and XANES study allowed us to refer the chemisorption data to the active phase only, while the IR study allowed us to fix the Cu(+)/CO surface stoichiometry. Summarizing the use of a multidisciplinary approach has been the conditio sine qua non (mandatory condition) to understand the complex role that the different additives have on the active phase of the CuCl(2)/gamma-Al(2)O(3) catalysts for ethylene oxychlorination. PMID- 20717599 TI - High purity graphenes prepared by a chemical intercalation method. AB - A simple method of fabricating pristine few-layer and single-layer graphene which could be used for production on a gram scale is described. PMID- 20717600 TI - Synthesis and characterization of the titanium complexes bearing two beta enaminoketonato ligands with electron withdrawing groups/modified phenyls and their behaviors for ethylene (co-)polymerization. AB - A series of new titanium complexes with two asymmetric bidentate beta enaminoketonato [N,O] ligands (2b-t), [PhN=C(CF(3))CHC(Ar)O](2)TiCl(2) (2b, Ar = C(6)H(4)F(o); 2c, Ar = -C(6)H(4)F(m); 2d, Ar = -C(6)H(4)F(p); 2e, Ar = C(6)H(4)Cl(p); 2f, Ar = -C(6)H(4)OMe(p); 2g, Ar = -C(6)H(4)CF(3)(p); 2h, Ar = C(6)H(4)CF(3)(m); 2i, Ar = -C(6)H(4)CF(3)(o); 2j, Ar = -C(6)H(4)Cl(o); 2k, Ar = C(6)H(4)Br(o); 2l, Ar = -C(6)H(4)I(o); 2m, Ar = -C(6)H(3)F(2)(2,4); 2n, Ar = C(6)H(3)F(2)(2,6); 2o, Ar = -C(6)H(3)F(2)(3,4); 2p, Ar = -C(6)H(3)F(2)(3,5); 2q, Ar = -C(6)F(5); 2r, Ar = C(6)F(4)OMe; 2s, Ar = -C(6)H(3)Cl(2)(2,6); 2t, Ar = C(6)H(3)Cl(2)(2,5)), have been synthesized based on substituted acetophenones. X Ray analyses reveal that complexes 2h, 2k, 2m, and 2n adopt distorted octahedral geometry around the titanium center, in which the two chloride ligands are situated in the cis-orientation. 2s also adopts distorted octahedral geometry, but the two chloride ligands in it are situated in the trans-orientation due to the increase of the steric effect of the phenyl derived from the acetophenone. The influence of the substituent effects on catalyst performance, including catalytic activities and the molecular weight distribution of the polymers obtained, was investigated in detail. With modified methylaluminoxane (MMAO) as a cocatalyst, complexes 2b-r and 2t are active catalysts for ethylene polymerization at room temperature, and produce high molecular weight polymers. It is observed that the catalytic activities are significantly enhanced by introducing some electron-withdrawing groups, such as -F, -Cl and -CF(3), into the suitable positions of the phenyl ring close to the oxygen donor. It should be noted that complexes 2c-i, 2p, 2n and 2t are also capable of promoting the living copolymerization of ethylene with norbornene at room temperature, yielding high molecular weight copolymers with narrow molecular weight distributions (PDI = 1.05-1.30). PMID- 20717602 TI - Directing semiconductor nanorod assembly into 1D or 2D supercrystals by altering the surface charge. AB - Coulomb repulsion due to the surface charge on semi-conductor nanorods works against the dipole-dipole attraction that tends to direct the nanorods to self assemble; the nature of this self-assembly for CdSe nanorods can be thus altered by pyridine washing, which charges the rods surface--thereby allowing the Coulomb repulsion to tailor the alignment. PMID- 20717601 TI - Fluorescence detection of alkaline phosphatase activity with beta-cyclodextrin modified quantum dots. AB - An alkaline phosphatase activity detection system was constructed based on the different quenching effect of the enzyme substrate and product on the beta-CD functionalized CdTe QDs. PMID- 20717603 TI - Mesoporous metal organic framework-boehmite and silica composites. AB - Mesoporous composites of metal organic frameworks (MOFs) with boehmite and silica were prepared by one-pot microwave hydrothermal synthesis in the presence of Pluronic-type triblock-copolymer. PMID- 20717604 TI - Unsymmetrical one-electron oxidized Ni(II)-bis(salicylidene) complexes: a protonation-induced shift of the oxidation site. AB - The spin density in the nickel(II) radical salen complex (2*)(+) could be localized on a specific ring by controlling the acidity of the medium. PMID- 20717605 TI - Fullerene attached all-semiconducting diblock copolymers for stable single component polymer solar cells. AB - A fullerene attached all-semiconducting polymer was synthesized and applied to single component polymer photovoltaic cells. The current approach gives a method of obtaining a reliable donor acceptor mixing morphology by molecular design and achieving efficient photovoltaic devices with long thermal stability. PMID- 20717607 TI - Remote amide-directed palladium-catalyzed benzylic C-H amination with N fluorobenzenesulfonimide. AB - An unprecedented remote amide-directed palladium-catalyzed intermolecular highly selective benzylic C-H amination with N-fluorobenzenesulfonimide is developed, which represents the first direct benzylic C-H amination with a non-nitrene nitrogen source. This methodology provides a novel approach to circumvent the common ortho aromatic C-H selectivity in directed palladium catalyzed C-H functionalization. PMID- 20717606 TI - Responsive and mitochondria-specific ruthenium(II) complex for dual in vitro applications: two-photon (near-infrared) induced imaging and regioselective cell killing. AB - A mitochondria-permeable ruthenium(II) complex has been designed as a responsive probe which may be used to sensitize the formation of singlet oxygen (Phi(Delta) = 0.93) and cause local damage in cellulo when exposed to UV and near-infrared laser excitation. PMID- 20717608 TI - Rhodium-catalyzed asymmetric conjugate alkynylation of nitroalkenes. AB - Asymmetric addition of (triisopropylsilyl)acetylene to nitroalkenes took place in the presence of a rhodium/chiral bisphosphine catalyst to give beta-alkynylated nitroalkanes in high yields with high enantioselectivity. PMID- 20717609 TI - Photochromic inorganic-organic hybrid: a new approach for switchable photoluminescence in the solid state and partial photochromic phenomenon. AB - A photochromic inorganic-organic hybrid based on in situ generated MV(2+) cation (MV(2+) = methyl viologen = N,N'-dimethyl-4,4'-bipyridinium) has been obtained, in which a vagarious partial photochromic phenomenon together with its photoluminescence modulation properties are reported for the first time in the inorganic-organic hybrids. PMID- 20717610 TI - Alkali metal-sulfur dioxide complexes stabilized by halogenated closo dodecaborate anions. AB - The alkali metal salts (M = Li, Na, K, Rb, Cs) of the perchlorinated closo dodecaborate [B(12)Cl(12)](2-) were prepared by reaction of [NEt(3)H](2)[B(12)Cl(12)] with the corresponding alkali metal hydroxide. Crystallization of M(2)[B(12)Cl(12)] from liquid sulfur dioxide gave the sulfur dioxide complexes [Li(2)(SO(2))(8)][B(12)Cl(12)], Na(2)[B(12)Cl(12)].4SO(2), K(2)[B(12)Cl(12)].8SO(2), Rb(2)[B(12)Cl(12)].4SO(2), and Cs(2)[B(12)Cl(12)].SO(2), which were characterized by single crystal X-ray diffraction. In this work structurally characterized SO(2) complexes of the alkali metal cations K(+) and Rb(+) are reported for the first time. The structure of [Li(2)(SO(2))(8)][B(12)Cl(12)] contains discrete [Li(2)(SO(2))(8)](2+) dications and [B(12)Cl(12)](2-) dianions. Born-Haber cycles based on quantum chemical calculations and estimations of lattice enthalpies for the solid state explain the stability of the discrete dication [Li(2)(SO(2))(8)](2+) in the solid state. Heavier alkali metals form three dimensional networks containing metal-anion and metal-sulfur dioxide contacts. The crystal structures of Na(2)[B(12)Br(12)].8SO(2) and Na(2)[B(12)I(12)].8SO(2) were determined to investigate the influence of the halogen substituent on the anion. They contain similar three-dimensional network structures. Na(2)[B(12)Br(12)].8SO(2) is isostructural to K(2)[B(12)Cl(12)].8SO(2). In addition the crystal structures of the complexes Na(2)[B(12)I(12)].8SO(2).H(2)O and Na(2)[B(12)H(12)].6SO(2).2H(2)O, which contain water ligands, are reported as well. A comparison of halogenated dodecaborates [B(12)X(12)](2-) (X = F, Cl, Br, I) based on [small nu, Greek, tilde](N-H) stretching frequencies of the corresponding [Oct(3)NH](2)[B(12)X(12)] (X = F - I) salts shows that the fluorinated anion [B(12)F(12)](2-) is the least basic and the iodinated anion [B(12)I(12)](2-) is the most basic anion in this series. These findings are in agreement with those for the corresponding series of perhalogenated carboranes and are explained by the polarizability of the halogen substituent. PMID- 20717611 TI - Concise and very efficient synthesis of the N-methylwelwistatin tetracyclic core based on an anionic domino process. AB - An efficient synthesis of the N-methylwelwistatin tetracyclic core in only two steps from Kornfeld's ketone is described, whose key transformation involves the generation of a fused bicyclo[4.3.1]decane ring system through a one-pot sequence comprising a Michael-intramolecular aldolization anionic domino process and a DBU promoted hydrolysis of the N-pivaloyl protecting group. Besides providing the most efficient synthesis of the welwistatin core to date, this method has the advantage of installing an oxygenated function at the welwistatin D ring. PMID- 20717616 TI - Isolation and characterization of a new type of mu-hydroxo-bis-Zn(salphen) assembly. AB - A series of assemblies comprising hydroxo-bridged dinuclear Zn(salphen) structures have been isolated and fully characterized in solution and by X-ray crystallography. The solution stability of these assembled species was evaluated in polar media, in the presence of excess of building blocks and competing ligands. The catalytic potential of this type of complex was investigated in phosphoester cleavage reactions. PMID- 20717617 TI - A modular approach for the generation, storage, mixing, and detection of droplet libraries for high throughput screening. AB - The desire to make microfluidic technology more accessible to the biological research community has led to the notion of "modular microfluidics", where users can build a fluidic system using a toolkit of building blocks. This paper applies a modular approach for performing droplet-based screening, including the four integral steps of library generation, storage, mixing, and optical interrogation. Commercially available cross-junctions are used for drop generation, flexible capillary tubing for storage, and tee-junctions for serial mixing. Optical interrogation of the drops is achieved using fiber-optic detection modules which can be incorporated inline at one or more points in the system. Modularity enables the user to hand-assemble systems for functional assays or applications. Three examples are shown: (1) a "mix and read" assay commonly used in high throughput screening (HTS); (2) generation of chemically distinct droplets using microfractionation in droplets (microFD); and (3) in situ encapsulation and culture of eukaryotes. Using components with IDs ranging from 150 microm to 1.5 mm, this approach can accommodate drop assays with volumes ranging from 2 nL to 2 microL, and storage densities ranging from 300 to 3000 drops per metre tubing. Generation rates are up to 200 drops per second and merging rates are up to 10 drops per second. The impact of length scale, carrier fluid viscosity, and flow rates on system performance is considered theoretically and illustratively using 2D CFD simulations. Due to its flexibility, the widespread availability of components, and some favorable material properties compared to PDMS, this approach can be a useful part of a researcher's toolkit for prototyping droplet based assays. PMID- 20717619 TI - Solving problems. PMID- 20717618 TI - Measurement of the volume growth rate of single budding yeast with the MOSFET based microfluidic Coulter counter. AB - We report on measurements of the volume growth rate of ten individual budding yeast cells using a recently developed MOSFET-based microfluidic Coulter counter. The MOSFET-based microfluidic Coulter counter is very sensitive, provides signals that are immune from the baseline drift, and can work with cell culture media of complex composition. These desirable features allow us to directly measure the volume growth rate of single cells of Saccharomyces cerevisiae LYH3865 strain budding yeast in YNB culture media over a whole cell cycle. Results indicate that all budding yeast follow a sigmoid volume growth profile with reduced growth rates at the initial stage before the bud emerges and the final stage after the daughter gets mature. Analysis of the data indicates that even though all piecewise linear, Gomperitz, and Hill's function models can fit the global growth profile equally well, the data strongly support local exponential growth phenomenon. Accurate volume growth measurements are important for applications in systems biology where quantitative parameters are required for modeling and simulation. PMID- 20717620 TI - Investigating dynamics of inhibitory and feedback loops in ERK signalling using power-law models. AB - The investigation of the structure and dynamics of signal transduction systems through data-based mathematical models in ordinary differential equations or other paradigms has proven to be a successful approach in recent times. Extending this concept, we here analysed the use of kinetic models based on power-law terms with non-integer kinetic orders in the validation of hypotheses concerning regulatory structures in signalling systems. We integrated pre-existent biological knowledge, hypotheses and experimental quantitative data into a power law model to validate the existence of certain regulatory loops in the Ras/Raf 1/MEK/ERK pathway, a MAPK pathway involved in the transduction of mitogenic and differentiation signals. Towards this end, samples of a human mammary epithelial cell line (MCF-10A) were used to obtain time-series data, characterising the behaviour of the system after epidermal growth factor stimulation in different scenarios of expression for the critical players of the system regarding the investigated loops (e.g., the inhibitory protein RKIP). The mathematical model was calibrated using a computational procedure that included: analysis of structural identifiability, global ranking of parameters to detect the most sensitivity ones towards the experimental setup, model calibration using global optimization methods to find the parameter values that better fit the data, and practical identifiability analysis to estimate the confidence in the estimated values for the parameters. The obtained model was used to perform computational simulations concerning the role of the investigated regulatory loops in the time response of the signalling pathway. Our findings suggest that the special regularity in the structure of the power-law terms make them suitable for a data based validation of regulatory loops in signalling pathways. The model-based analysis performed identified RKIP as an actual inhibitor of the activation of the ERK pathway, but also suggested the existence of an intense feedback-loop control of the pathway by the activated ERK that maybe responsible for the damped oscillations we saw in the fraction of activated MEK both in the experiments and simulations. In addition, the model analysis suggested that phosphorylation/deactivation of RKIP during the transient stimulation may have a significant effect on the signalling peaks of both MEK and ERK. This later result suggests that dynamic modulation of signal inhibitors during stimulation may be a regulatory mechanism in ERK signalling and other pathways. PMID- 20717621 TI - Influence of chirality using Mn(III) salen complexes on DNA binding and antioxidant activity. AB - Chiral Mn(iii) salen complexes S-1, R-1, S-2, R-2, S-3 and R-3 derived from the respective chiral salen ligands, viz., (1S,2S)-N,N'-bis-[3-tert-butyl-5 chloromethyl-salicylidine]-1,2-cyclohexanediamine S-1'/(1R,2R)-N,N'-bis-[3-tert butyl-5-chloromethyl-salicylidine]-1,2-cyclohexanediamine R-1'/(1S,2S)-N,N'-bis [3-tert-butyl-5-N,N'N'triethylaminomethyl-salicylidine]-1,2-cyclohexanediamine dichloride S-2'/(1R,2R)-N,N'-bis-[3-tert-butyl-5-N,N'N'triethylaminomethyl salicylidine]-1,2-cyclohexanediamine dichloride R-2'/(1S,2S)-N,N'-bis-[3,5-di tert-butylsalicylidene]-1,2-cyclohexanediamine S-3' and (1R,2R)-N,N'-bis-[3,5-di tert-butyl-salicylidene]-1,2-cyclohexanediamine R-3', were synthesized. Characterization of the complexes was done by microanalysis, IR, LC-MS, UV-vis. and circular dichroism (CD) spectroscopy. Binding of these complexes with calf thymus DNA (CT-DNA) was studied by absorption spectroscopy, competitive binding study, viscosity measurements, circular dichroism measurements, thermal denaturation study and observation of their different antioxidant activities. Among all the complexes used, the best result in terms of binding constant (intercalative) (130.4 x 10(4)) was achieved with the complex S-1 by spectroscopic titration. The complex S-1 showed strong antioxidant activity as well. PMID- 20717626 TI - Facile central-element exchange in neutral hexacoordinate germanium and silicon complexes; synthesis and characterization of germanium complexes. AB - Neutral hexacoordinate germanium complexes with hydrazido chelating ligands have been synthesized and characterized. Facile exchange of central element between silicon and germanium in these complexes is demonstrated, following given selectivity constraints. PMID- 20717627 TI - Contributors to the emerging investigators issue. PMID- 20717629 TI - ADAMTS-7, a novel proteolytic culprit in vascular remodeling. AB - Vascular remodeling is being recognized as a fundamental process during atherosclerosis and restenosis. Cumulative studies have demonstrated that extracellular matrix (ECM) degrading enzymes play a critical role during vascular remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is a recently identified metalloproteinase family which also has capacity to degrade ECM. ADAMTS family consists of 19 members and has been linked to a variety of physiological processes including development, angiogenesis, coagulation etc. Aberrant expression or function of ADAMTS members have been implicated to many disease states such as arthritis, cancer, thrombocytopenic purpura, but barely described with regard to cardiovascular disease. This review summarizes the recent advance with respect to the role of ADAMTS-7 in vascular remodeling. We review the structure, tissue distribution, substrate, expression and regulation of ADAMTS-7, especially highlight the fine tune by ADAMTS-7 of its substrate cartilage oligomeric matrix protein (COMP) in maintaining vascular homeostasis. By use of rat carotid artery balloon injury model to mimic vascular injury in vivo, we found that ADAMTS-7 protein was accumulated preferentially in neointima and mainly localized in vascular smooth muscle cells (VSMCs). Adenovirus-elicited ADAMTS-7 overexpression greatly accelerated VSMCs migration and proliferation both in vivo and in vitro, and subsequently aggravated neointima thickening post-injury. Conversely, siRNA-mediated ADAMTS-7 knock down bona fide inhibited VSMCs migration and proliferation in cultured VSMCs and injured arteries, and ultimately ameliorated neointima area. Further studies demonstrated that ADAMTS-7 facilitated VSMCs migration through degradation of its substrate COMP. Moreover, we elucidated that COMP has the capacity to maintain the contractile phenotype of VSMCs through interacting with integrin alpha7beta1. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis. PMID- 20717630 TI - [Roles of cyclin-dependent kinase 5 in central nervous system development and neurodegenerative diseases]. AB - Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, and plays multiple roles in neuron development and synaptic plasticity. The active form of Cdk5 is found primarily in the central nervous system (CNS) due to its activator proteins p35 or p39 ubiquitously expressed in neuronal cells. Normally, the transcription and activity of Cdk5 are strictly regulated by several ways. In the physiological condition, Cdk5 plays a key role in the CNS development by phosphorylating the specific serine or threonine site of numerous substrate proteins that are closely associated with the neuronal migration, synaptogenesis, synaptic transmission as well as synaptic plasticity. Under pathological conditions, p35 can be truncated into p25, which can strongly and consistently activate Cdk5, change the cellular localization of Cdk5 and lead to neuronal death ultimately. The increasing evidence has showed that Cdk5 is involved in the pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis etc., indicating that Cdk5 may be a potential target in the treatment of the neurodegenerative diseases. In this article, we reviewed the recent progress regarding the roles of Cdk5 in CNS development and neurodegenerative diseases. PMID- 20717628 TI - A general glycomimetic strategy yields non-carbohydrate inhibitors of DC-SIGN. AB - Shikimic acid can be transformed into monovalent and multivalent glycomimetics that target different members of the C-type lectin class, including DC-SIGN, a dendritic cell lectin that facilitates HIV transmission. PMID- 20717631 TI - [Perception and selectivity of sound duration in the central auditory midbrain]. AB - Sound duration plays important role in acoustic communication. Information of acoustic signal is mainly encoded in the amplitude and frequency spectrum of different durations. Duration selective neurons exist in the central auditory system including inferior colliculus (IC) of frog, bat, mouse and chinchilla, etc., and they are important in signal recognition and feature detection. Two generally accepted models, which are "coincidence detector model" and "anti coincidence detector model", have been raised to explain the mechanism of neural selective responses to sound durations based on the study of IC neurons in bats. Although they are different in details, they both emphasize the importance of synaptic integration of excitatory and inhibitory inputs, and are able to explain the responses of most duration-selective neurons. However, both of the hypotheses need to be improved since other sound parameters, such as spectral pattern, amplitude and repetition rate, could affect the duration selectivity of the neurons. The dynamic changes of sound parameters are believed to enable the animal to effectively perform recognition of behavior related acoustic signals. Under free field sound stimulation, we analyzed the neural responses in the IC and auditory cortex of mouse and bat to sounds with different duration, frequency and amplitude, using intracellular or extracellular recording techniques. Based on our work and previous studies, this article reviews the properties of duration selectivity in central auditory system and discusses the mechanisms of duration selectivity and the effect of other sound parameters on the duration coding of auditory neurons. PMID- 20717632 TI - [Alterations in aortic vasomotor function in rats with chronic heart failure and its mechanism]. AB - The aim of the present study was to investigate the alterations in thoracic aortic vasomotor function in rats with chronic heart failure (CHF) post myocardial infarction (MI), and then explored the possible mechanism of pathological changes. Male Sprague-Dawley rats were divided into sham and CHF groups randomly. The CHF model group of rats was generated by ligating the left anterior descending artery. In sham-operated rats the ligation was placed but not tightened. A total of 20 rats underwent either sham-operated (n=8) or surgery for MI (n=12). All sham-operated rats survived the surgical procedure and the post surgical period, whereas total mortality among MI-rats was 25% (3 out of 12). Only MI-rats with infarct-size >30% of the left ventricle (LV) were included for analysis (8 out of 9). Ten weeks after surgery, rats were anaesthetized for hemodynamic measurements, which contains systolic pressure, diastolic pressure, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LV+dp/dt(max) and LV-dp/dt(max). After that hearts were rapidly excised and weighed. Myocardial infarct size was determined by triphenyltetrazolium chloride (TTC) staining method. Isolated thoracic artery ring preparations were studied in a wire-myograph. The arterial constrictive responses to KCl, CaCl2, phenylephrine (PE), and caffeine and the arterial diastolic responses to acetylcholine (ACh) were recorded by the Multi Myograph System. To explore the possible mechanism, nitric oxide synthase (NOS) inhibitor N-nitrl-L-arginine methylester (L-NAME) and non-selective cyclooxygenase (COX) inhibitor indomethacin (Indo) were used. The results obtained were as follows: (1) CHF group showed an increased contraction response to KCl (5-100 mmol/L) and PE (1x10(-8)-3x10(-4) mol/L), and a reduced endothelium-dependent relaxation response to ACh (1x10(-12)-1x10(-4) mol/L) compared with those observed in sham group (P<0.01, P<0.05); (2) In the presence of L-NAME (1 mmol/L), the endothelium dependent cumulative contractions to ACh (1x10(-7)-1x 10(-4) mol/L) was significantly enhanced in CHF group (P<0.05), and this effect was reversed by pretreatment with Indo (10 mumol/L); (3) In CHF group, the vessels incubated with Indo (10 mumol/L) showed an increased vasodilation induced by ACh (1x10(-12) 1x10(-4) mol/L) (P<0.05); (4) In the Ca(2+)-free K-H solution, calcium-dependent contraction curves induced by CaCl2 (1x10(-4)-3x10(-2) mol/L) in CHF group significantly shifted to the left compared with sham group (P<0.05); while the vascular contraction induced by caffeine (30 mmol/L) had no significant changes. These findings suggest that thoracic arteries of rats with CHF have endothelial dysfunction, and the contribution of endothelial dilation and contraction was significantly altered in CHF rats. The mechanism could be partly associated with the increased endothelium-dependent contracting factors by COX pathway, or the increased extracellular Ca(2+) influx through voltage-operated channels, thus leading to elevated vasoconstriction. PMID- 20717633 TI - [Alterations of cardiac hemodynamics, sodium current and L-type calcium current in rats with L-thyroxine-induced cardiomyopathy]. AB - The aim of the present study is to investigate the alterations of cardiac hemodynamics, sodium current (I(Na)) and L-type calcium current (I(Ca-L)) in the cardiomyopathic model of rats. The model of cardiomyopathy was established by intraperitoneal injection of L-thyroxine (0.5 mg/kg) for 10 d. The hemodynamics was measured with biological experimental system, and then I(Na) and I(Ca-L) were recorded by using whole cell patch clamp technique. The results showed that left ventricular systolic pressure (LVSP), left ventricular developed pressure (LVDP), +/-dp/dt(max) in cardiomyopathic group were significantly lower than those in the control group, while left ventricular end-diastolic pressure (LVEDP) in cardiomyopathic group was higher than that in the control group. Intraperitoneal injection of L-thyroxine significantly increased the current density of I(Na) [( 26.2+/-3.2) pA/pF vs (-21.1+/-6.3) pA/pF, P<0.01], shifted steady-state activation and inactivation curves negatively, and markedly prolonged the time constant of recovery from inactivation. On the other hand, the injection of L thyroxine significantly increased the current density of I(Ca-L) [(-7.9+/-0.8) pA/pF vs (-5.4+/-0.6) pA/pF, P<0.01)], shifted steady-state activation and inactivation curves negatively, and obviously shortened the time constant of recovery from inactivation. In conclusion, the cardiac performance of cardiomyopathic rats is similar to that of rats with heart failure, in which the current density of I(Na) and especially the I(Ca-L) are enhanced, suggesting that calcium channel blockade and a decrease in Na(+) permeability of membrane may play an important role in the treatment of cardiomyopathy. PMID- 20717634 TI - [Sphingomyelin synthase 2 deficiency decreases atherosclerosis and inhibits inflammation in mice]. AB - Plasma sphingomyelin (SM) has been shown to be an independent risk factor for coronary heart disease, and sphingomyelin synthase 2 (SMS2) contributes to de novo SM biosynthesis and plasma membrane SM levels. The aim of the present study is to evaluate the in vivo role of SMS2 deficiency in serum SM metabolism and atherosclerosis (AS) development. We used male SMS2 knockout (SMS2(-/-)) and C57BL/6J (wild-type, WT) mice as experimental and control groups, respectively. Each group was fed high-fat diet (1% cholesterol, 20% leaf fat), as well as bile salt for accelerating the atherosclerotic formation. After three months of feeding, the mice were killed to observe aortic arches and oil red-stained longitudinal sections of thoracoabdominal aortae. Fasting blood samples were taken from the tail vein before and after high-fat diet, and the serum lipid and SM levels were measured by using kits and enzymatic method respectively. Western blot was used to analyze the contents of nuclear factor-kappaB (NFkappaB) p65 subunit in peritoneal macrophages stimulated with lipopolysaccharide (LPS) after high-fat diet. The results showed that after high-fat diet, SMS2(-/-) mice presented decreased atherosclerotic lesions in aortic arch and thoracoabdominal aorta compared with WT mice. Regardless of whether high-fat diet were given or not, SMS2(-/-) mice showed a significant decrease in serum SM level (P<0.05), but no significant changes in serum lipid levels, compared with WT mice. The expressions of NFkappaB p65 were attenuated in macrophages from SMS2(-/-) mice in response to LPS stimulation compared with those of the WT mice. These results suggest that SMS2 deficiency decreases AS and inhibits inflammation in mice. Thus, SMS2 deficiency may be a potential therapeutic strategy. PMID- 20717635 TI - [Changes of dystrophin and desmin in rat gastrocnemius under micro-damage induced by hypoxia]. AB - To explore the changes and regulation mechanism of dystropin and desmin under muscle injury without mechanic stress, 40 male Sprague-Dawley rats were randomly divided into 5 groups, which included normoxia control and hypoxia groups for 1, 2, 4 and 7 d with 10% O2. Two rats from each group were examined for sarcolemma integrity using Evans blue dye (EBD) and EBD-positive fiber typing by metachromatic dye-ATPase method. The rest six rats from each group were analyzed for the changes of protein content and gene expression using Western blot, RT-PCR and fluorescence assays. The results showed that the EBD-positive muscle fibers, mainly type IIA and type IIB, appeared at 1 d after hypoxia exposure. Both the ratio of EBD-positive cell and the mean fluorescence density were significantly higher in hypoxia groups than those in control group (P<0.05). The contents of dystrophin and desmin fluctuated after hypoxia exposure, increased at 1 d, decreased at 2 d, increased dramatically again at 4 d, and returned to a normal level at 7 d. Consistently, the gene expression began to increase significantly after 2 d. The total activity of calpain was significantly higher in hypoxia groups at 1, 4 and 7 d. Significantly higher levels of HSP70 and HSP90 were also observed at 4 and 7 d, respectively (P<0.05). These results suggest that the mechanical stress is not the only cause of damage of sarcolemma membrane integrity. In contrast to eccentric contraction, hypoxia-induced muscle damage is not accompanied by the loss of dystrophin and desmin. The types of muscle fibers recruited by motor units and the activities of calpain may be important in hypoxia-induced damage of sarcolemma membrane integrity. PMID- 20717636 TI - Transient receptor potential A1 is involved in cold-induced contraction in the isolated rat colon smooth muscle. AB - Transient receptor potential (TRP) A1, a member of TRP channel family, is activated by noxious cold. The aims of this study were to determine if TRPA1 contributed to cold-induced contractions in the isolated rat colon preparations and explore the potential mechanisms. The colon smooth muscle layers were surgically isolated from the male Wistar rats and changes in isotonic tension of longitudinal muscle under various treatments were recorded as colonic motilities. Cold stimuli were obtained by the reperfusion with Krebs-Henseleit solution at given temperature using Constant Flow Pump. The mRNA expressions of TRPA1, TRPV1 and TRPM8 in rat colon smooth muscle layer were examined by using reverse transcription-polymerase chain reaction (RT-PCR) techniques. The results showed that the contractions induced by cold stimuli (from 37 degrees C to 12 degrees C stepwise) were inversely proportional to the temperature with a maximum contraction at 17 degrees C in both proximal and distal colons (P<0.01). RT-PCR analysis revealed the expression of TRPA1, but not TRPM8 and TRPV1, in the rat proximal and distal colon smooth muscle layers. Cold-induced colonic contractions were specially inhibited by TRPA1 blocker, ruthenium red (30 MUmol/L), in the proximal and distal colon (P<0.05). The cold-induced contractions of proximal (P<0.01, P<0.05) and distal colons (both P<0.001) were almost abolished or inhibited by the pretreatments of TRPA1 agonists, Allyl isothiocyanate (AITC, 300 MUmol/L) and cinnamaldehyde (CA, 1 mmol/L). Extracellular calcium removal (EGTA, 1 mmol/L), PLC blocker (U73122, 10 MUmol/L) and IP(3) receptor blocker (2 aminoethoxydiphenyl borate, 2-APB, 30 MUmol/L) all decreased the contractions evoked by the cooling at 17 degrees C in the proximal and distal colon (P<0.001, P<0.05, P<0.001). Atropine (1 MUmol/L) had no effects on these contractions. L type Ca(2+) channels blocker nifedipine (1 MUmol/L) and neurotoxin tetrodotoxin (TTX, 2 MUmol/L) decreased the contractile response in the distal colon (P<0.01, P<0.05), but not in the proximal colon. In conclusion, TRPA1 contributes to cold induced contractions of the rat colon smooth muscle, and the mechanism of TRPA1 activation involves PLC/IP(3)/Ca(2+) pathway. L-type Ca(2+) channel and neurogenic mechanism other than muscarinic receptor might be partially involved in cold-induced contraction of the distal colon, which probably resulted in higher contraction of distal colon compared with that of proximal colon. PMID- 20717637 TI - Ghrelin acts on rat dorsal vagal complex to stimulate feeding via arcuate neuropeptide Y/agouti-related peptide neurons activation. AB - Ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, stimulates feeding and increases body weight. The primary action site of ghrelin has been reported to be the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus (ARC). In addition to the hypothalamus, the caudal brainstem also appears to be an important mediator for the orexigenic activity of ghrelin. However, it is not clear whether ghrelin applied directly to the caudal brainstem activates forebrain structures. The aim of this study was to determine whether recruitment of forebrain structures was required for hyperphagic responses stimulated by ghrelin delivery within the caudal brainstem. In our experiment, all rats were surgically implanted with indwelling cannulas in the dorsal vagal complex (DVC), and ghrelin (20 pmol in 0.5 MUL) was delivered to the DVC. After the injection, the orexigenic response to ghrelin was recorded by Feeding and Activity Analyser, and NPY/AgRP mRNA expressions in rat hypothalamus were detected by real-time PCR. In addition, the NPY immunoreactive neurons in the ARC were assayed by immunohistochemistry. The results showed that ghrelin significantly increased cumulative food intake at 1, 2 and 3 h after ghrelin injection, maximal response occurring at 2 h after injection. NPY/AgRP mRNA levels in ARC treated with ghrelin increased significantly compared with those in control group (injected with saline). The highest levels of NPY and AgRP mRNA were detected at 2 h after injection. The total number and mean optical density of NPY-positive neurons increased in ghrelin treated rats compared with those in control group. Consistently, ghrelin's effect was most pronounced at 2 h after injection. Taken together, we conclude that the activation of NPY/AgRP neurons in the ARC is involved in the mediation of the hyperphagic response to brainstem ghrelin administration in neurologically intact rats. PMID- 20717638 TI - [Dynamic ion mechanism of bursting in the stomatogastric ganglion neurons of crayfish]. AB - The purpose of this study is to identify the electrical activity of neuron, the existence of the transition from bursting pattern to spiking pattern and the ion mechanism of the bursting pattern. The intracellular electrical activity patterns of single neurons in the stomatogastric ganglion (STG) of crayfish were recorded when the extracellular calcium concentration ([Ca(2+)](o)) or calcium-dependent potassium channel blocker tetraethylammonium concentration ([TEA](o)) were changed, using intracellular recording method. These single neurons were also functionally isolated from the ganglion by application of atropine and picrotoxin which could block the inhibitory acetylcholine synapses and glutamatergic synapses respectively. When [Ca(2+)](o) was decreased by increasing EGTA, the membrane potential of the neuron was increased, and the electrical activity patterns were changed from the resting state with lower potential value (resting state of polarization) to the bursting pattern firstly, and then to the spiking pattern, at last to the resting state with higher potential value (resting state of depolarization). When [TEA](o) was increased, the membrane potential of the neuron was increased, and the electrical activity pattern was changed from the resting state with lower potential value (resting state of polarization) to the bursting pattern firstly, and then to the spiking pattern. The duration of the burst of the bursting pattern was increased. When [Ca(2+)](o) was increased or [TEA](o) was decreased, an inverse procedure of the electrical activity pattern was exhibited. On one hand, the results indicate that a single neuron can generate various electrical activity patterns corresponding to different physiological conditions, and the regularity of the transitions between different electrical activity patterns. On the other hand, the results identify that the initiation and termination of the burst in bursting pattern are determined by calcium-activated potassium conductance, which is adjusted by intracellular calcium concentration influenced by inward calcium current. It may be the ionic mechanism of generation of the bursting pattern in a single neuron. PMID- 20717639 TI - [Enhancing effect of porcine coagulation factor VIII A1 and A3 domains on secretion of post-translationally spliced human/porcine hybrid coagulation factor VIII]. AB - Low levels of coagulation factor VIII (fVIII) protein expression caused by its inefficient secretion and the over-sized fVIII gene affect the transgene-based gene therapy for hemophilia A adversely. Our previous study demonstrated that intein-mediated protein trans-splicing for delivery of the fVIII gene with a dual vector system could improve secretion of post-translationally spliced fVIII by light chain in cis. In this study, a human/porcine hybrid fVIII (HP-fVIII) containing replaced A1 and A3 domains of porcine fVIII was investigated for secretion and activity of the spliced HP-fVIII after intein-based dual-vector delivery of the HP-fVIII gene. A pair of expression plasmids comprising intein fused HP-fVIII heavy and light chains were constructed and transiently co transfected into COS-7 cells. The spliced HP-fVIII and bio-activity in culture media were quantitatively analyzed by ELISA and Coatest method respectively. The intracellular splicing of HP-fVIII was detected by Western blotting. The results showed that in the culture supernatant of cells co-transfected with HP-fVIII, the amount and activity of spliced HP-fVIII were significantly higher than those of spliced hfVIII secreted from the cells co-transfected with human fVIII [(184+/-34 ng/mL) vs (48+/-12) ng/mL, P<0.01; (1.18+/-0.22) IU/mL vs (0.31+/-0.10) IU/mL, P<0.01], demonstrating the dramatically enhancing effect of porcine A1 and A3 domains on the secretion of intein-spliced HP-fVIII. The spliced HP-fVIII protein and its activity were also detected in the supernatant from combined cells separately transfected with intein-fused HP-fVIII heavy and light chain genes, indicating that the intein-mediated HP-fVIII splicing was independent of cellular mechanism and could occur outside the cell after the secretion of precursor proteins. Additionally, an intracellularly spliced HP-fVIII band was found with a molecular weight similar to human fVIII protein, confirming the HP-fVIII splicing. These results provided experimental basis for ongoing study using intein-based dual adeno-associated virus (AAV) vector to transfer HP-fVIII gene in animal models. PMID- 20717640 TI - [Difference in the expression of Kv channel in lymphocytes between spontaneously hypertensive rats and Wistar rats]. AB - The present study aimed to investigate the difference in the voltage dependent potassium channel (Kv) expression in lymphocytes between the spontaneously hypertensive rats (SHRs) and Wistar rats. Peripheral blood lymphocytes were collected from 10 male SHRs and 10 normotensive Wistar rats aged 16 weeks. First, by using the patch-clamp technique, Kv channel current was recorded in freshly isolated lymphocytes from SHRs and normotensive Wistar rats. Total RNAs were extracted from lymphocytes by using TRIzol reagent. Real-time PCR was used to determine the expression of Kv1.3 mRNA and Western blot technique was used to measure the expression of Kv1.3 protein in lymphocytes from SHRs and normotensive Wistar rats. The results showed that: (1) The current density of Kv channel in the step voltage of +60 mV was higher in lymphocytes from SHRs than that from the normotensive Wistar rats [(119+/-10) pA/pF vs (56+/-9) pA/pF, P<0.05]; (2) The level of Kv1.3 mRNA expression in lymphocytes from SHRs was significantly increased compared with that of the normotensive Wistar rats (0.0313+/-0.017 vs 0.0023+/-0.005, P<0.05); (3) The expression of Kv1.3 protein was significantly elevated in lymphocytes (1.02+/-0.04 vs 0.41+/-0.03, P<0.05) from SHRs compared with that of the normotensive Wistar rats. The results obtained demonstrate that the lymphocytes Kv channels are increased in SHR, and the Kv channel may be involved in activation of lymphocytes from SHR. PMID- 20717642 TI - [Diagnostics and therapy of vasculitis]. PMID- 20717643 TI - [Therapy of peripheral vessel stenosis and occlusion in patients with thromboangiitis obliterans]. AB - Vasculitis consists of a group of diseases characterized by an inflammatory process of the vessel wall. There is a wide variation in symptoms and almost any organ or tissue can be affected. Thromboangiitis obliterans (TAO; also known as Buerger's disease) is a special form of vasculitis with recurring inflammation and thrombosis of small and medium size arteries and veins of the hands and feet. To date the etiology still remains unclear but there is a strong association with the use of tobacco products. Ulcerations and gangrene of the extremities are common complications often resulting in the need for amputation of the extremity involved. Treatment of TAO includes both surgical and non-surgical methods but there is still no agreement concerning the optimal treatment strategy. In this contribution the advantages and disadvantages of different treatment options will be addressed and representative cases will be discussed. PMID- 20717644 TI - [Vasculitis in the trunk: Imaging patterns of typical organ manifestations due to primary vasculitis of small and medium sized vessels]. AB - Vasculitis of small and medium sized vessels mostly affects several organ systems and causes unspecific symptoms. The trunk, lungs, heart and the gastrointestinal and urogenital tracts are most frequently involved. Due to an unclear clinical picture imaging is part and parcel of diagnostics. The knowledge of typical and rare imaging patterns as well as knowledge of the correct imaging method is crucial for classification. Projection radiography is still the gold standard for imaging of the lungs. Using computed tomography discrete ground-glass pattern opacities, nodules and consolidations can be depicted. In the abdomen computed tomography and magnetic resonance imaging can depict swelling of the intestinal wall. Digital subtraction angiography may contribute to further differentiation and reveal microaneurysms in cases of polyarteriitis nodosa. PMID- 20717645 TI - [Imaging diagnostics of large vessel vasculitis]. AB - At present non-invasive imaging is of paramount importance in the diagnostic evaluation of large vessel vasculitis. For evaluation of the cranial and extracranial aortic branches color coded sonography is the method of choice, whereas CT and MRI are useful in assessing the thoracic aorta. Positron emission tomography (PET) imaging allows direct visualization of the extent of vascular inflammation. To date the diagnostic benefit of combined PET and morphological imaging (PET-CT) as well as the value of imaging procedures in order to assess disease activity and therapy control remain unclear. PMID- 20717646 TI - [Classification and therapy of vasculitis according to recommendations of the European League Against Rheumatism (EULAR)]. AB - Vasculitis is still being classified according the criteria of the American College of Rheumatology and the Chapel Hill Consensus Conference Definitions. Diagnostic criteria are currently being established. The classification criteria are based on the size of the inflamed blood vessel (e.g. large vessel vasculitis with inflammation of the aorta and its branches), clinical symptoms and findings (such as cephalalgia in giant cell arteritis) and histological findings. In recent years a definition of disease stages and activity has been established and a number of controlled trials have been carried out in order to provide evidence based stage and activity adapted therapy regimens. Recommendations for the management of vasculitis have been published in 2009 by EULAR (European League Against Rheumatism). This article gives a review of the classification of vasculitis and summarizes the current European guidelines on management. PMID- 20717647 TI - [Optimizing treatment of advanced testicular germ cell tumors]. AB - Testicular germ cell cancer represents the most frequent solid neoplasm in young men aged 20-40 years. Depending on the prognosis according to the IGCCCG classification, the treatment of choice for advanced germ cell tumors consists in three to four cycles of bleomycin, etoposide, and cisplatin (BEP) in accordance with the current European Consensus Guidelines. Although residual tumor resection (RTR) adheres to guidelines as the treatment for residual metastatic lesions, numerous questions remain unresolved, which we intend to systematically answer within the scope of our research group by conducting prospective/retrospective and clinical/molecular investigations in cooperation with national and international project groups. PMID- 20717648 TI - [Association between residual urinary volume and urinary tract infection: prospective trial in 225 male patients]. AB - PURPOSE: Urinary tract infections can result from bladder outlet obstruction and consecutive post-void residual urine. In a recent publication, a cutoff for post void residual urine of 180 ml was calculated, revealing sensitivity and specificity of 87 and 98.5%, respectively, regarding occurrence of significant bacteriuria in asymptomatic men. In the present study the association between post-void residual urine volume and urinary tract infection was evaluated, and different cutoff values were validated. MATERIALS AND METHODS: A total of 225 asymptomatic patients (median age 66 years) were prospectively evaluated regarding the following criteria: prostate-specific antigen, prostate volume, International Prostate Symptom Score, peak urinary flow rate, urine culture results, urinary test strip, and post-void residual urine volume. By ROC analysis a cutoff predicting significant bacteriuria was calculated, and different cutoff values were validated. The independent influence of several parameters on the incidence of urinary tract infection was measured using multivariate regression analyses. RESULTS: Of the patients, 60% were able to completely empty the bladder (post-void residual urine volume Cu(2+) > Zn(2+) > Cd(2+). Compared with the pseudo first-order model, the pseudo second-order model described the adsorption kinetics much better, indicating a two-step biosorption process. The present study confirmed that fruiting bodies of the jelly fungi should be useful for the treatment of wastewater containing Cd(2+), Cu(2+), Pb(2+), and Zn(2+). PMID- 20717664 TI - Cloning and characterization of thermotolerant xylitol dehydrogenases from yeast Pichia angusta. AB - Pichia angusta (syn. Hansenula polymorpha) represents one of the rare yeast that can grow and ferment both xylose and glucose at higher temperature (50 degrees C). However, little is known about the enzymes involved in xylose utilization from this species. Previous studies indicated the presence of one xylose reductase and two xylitol dehydrogenase genes in P. angusta. In this study, we have expressed both xylitol dehydrogenases (PaXdh1p and PaXdh2p) in Escherichia coli and purified them as 6X-Histidine-tagged proteins. Biochemical characterization of the recombinant proteins reveals that both PaXdh1p and PaXdh2p are thermotolerant enzymes. PaXdh2p contains a catalytic and a structural Zn atom. However, the structural Zn atom is not present in PaXdh1p. Both enzymes also differ in their affinity for the substrate as well as in the catalytic efficiency. Through mutagenesis and modeling approaches, we have also identified residues important for catalysis and substrate binding. PMID- 20717665 TI - Engineering of ethanolic E. coli with the Vitreoscilla hemoglobin gene enhances ethanol production from both glucose and xylose. AB - Escherichia coli strain FBR5, which has been engineered to direct fermentation of sugars to ethanol, was further engineered, using three different constructs, to contain and express the Vitreoscilla hemoglobin gene (vgb). The three resulting strains expressed Vitreoscilla hemoglobin (VHb) at various levels, and the production of ethanol was inversely proportional to the VHb level. High levels of VHb were correlated with an inhibition of ethanol production; however, the strain (TS3) with the lowest VHb expression (approximately the normal induced level in Vitreoscilla) produced, under microaerobic conditions in shake flasks, more ethanol than the parental strain (FBR5) with glucose, xylose, or corn stover hydrolysate as the predominant carbon source. Ethanol production was dependent on growth conditions, but increases were as high as 30%, 119%, and 59% for glucose, xylose, and corn stover hydrolysate, respectively. Only in the case of glucose, however, was the theoretical yield of ethanol by TS3 greater than that achieved by others with FBR5 grown under more closely controlled conditions. TS3 had no advantage over FBR5 regarding ethanol production from arabinose. In 2 L fermentors, TS3 produced about 10% and 15% more ethanol than FBR5 for growth on glucose and xylose, respectively. The results suggest that engineering of microorganisms with vgb/VHb could be of significant use in enhancing biological production of ethanol. PMID- 20717666 TI - Serratia odorifera: analysis of volatile emission and biological impact of volatile compounds on Arabidopsis thaliana. AB - Bacteria emit a wealth of volatiles. The combination of coupled gas chromatography/mass spectrometry (GC/MS) and proton-transfer-reaction mass spectrometry (PTR-MS) analyses provided a most comprehensive profile of volatiles of the rhizobacterium Serratia odorifera 4Rx13. An array of compounds, highly dominated by sodorifen (approximately 50%), a bicyclic oligomethyl octadiene, could be detected. Other volatiles included components of the biogeochemical sulfur cycle such as dimethyl disulfide (DMDS), dimethyl trisulfide and methanethiol, terpenoids, 2-phenylethanol, and other aromatic compounds. The composition of the bouquet of S. odorifera did not change significantly during the different growth intervals. At the beginning of the stationary phase, 60 MUg of volatiles per 24 h and 60 easily detectable components were released. Ammonia was also released by S. odorifera, while ethylene, nitric oxide (NO) and hydrogen cyanide (HCN) could not be detected. Dual culture assays proved that 20 MUmol DMDS and 2.5 MUmol ammonia, individually applied, represent the IC(50) concentrations that cause negative effects on Arabidopsis thaliana. PMID- 20717667 TI - Apoptosis of human lung adenocarcinoma A549 cells induced by prodigiosin analogue obtained from an entomopathogenic bacterium Serratia marcescens. AB - An entomopathogenic bacterial strain SCQ1 was isolated from silkworm (Bombyx mori) and identified as Serratia marcescens via 16S rRNA gene analysis. This strain produces a red pigment that causes acute septicemia of silkworm. The red pigment of strain SCQ1 was identified as prodigiosin analogue (PGA) with various reported biological activities. In this study, we found that low concentration of PGA showed significant anticancer activity in human lung adenocarcinoma A549 cells, but has little effect in human bone marrow stem cells, in vitro. By exposure to different concentrations of PGA for 24 h, morphological changes and the MTT assay showed that A549 cell line was very sensitive to PGA, with IC(50) value about 2.2 mg/L. Early stage of apoptosis was detected by flow cytometry while A549 cells were treated with PGA for 4 and 12 h, respectively. The proportion of dead cells was increased with treatment time or the concentrations of PGA, but it was inversely proportional to that of apoptotic cells. These results indicate that PGA obtained from strain SCQ1 induces apoptosis in A549 cells, but the molecular mechanisms of cell death are complicated, and the S. marcescens strain SCQ1 may serve as a source of the anticancer compound, PGA. PMID- 20717668 TI - Asymmetric reduction of activated alkenes using an enoate reductase from Gluconobacter oxydans. AB - A recombinant enoate reductase from Gluconobacter oxydans was heterologously expressed, purified, characterised and applied in the asymmetric reduction of activated alkenes. In addition to the determination of the kinetic properties, the major focus of this work was to utilise the enzyme in the biotransformation of different interesting compounds such as 3,5,5-trimethyl-2-cyclohexen-1,4-dione (ketoisophorone) and (E/Z)-3,7-dimethyl-2,6-octadienal (citral). The reaction proceeded with excellent stereoselectivities (>99% ee) as well as absolute chemo- and regioselectivity, only the activated C=C bond of citral was reduced by the enoate reductase, while non-activated C=C bond and carbonyl moiety remained untouched. The described strategy can be used for the production of enantiomerically pure building blocks, which are difficult to prepare by chemical means. In general, the results show that the investigated enoate reductase is a promising catalyst for the use in asymmetric C=C bond reductions. PMID- 20717669 TI - Urinary neopterin does not reflect the local antitumor immune milieu in ovarian cancer. AB - The main objective of the present investigation was to study the urinary neopterin excretion in the context of the activation of the adaptive cellular immune system at the tumor site. For this purpose, we compared pre-treatment urinary neopterin levels measured in 92 ovarian cancer patients, with intratumoral levels of mRNA transcripts from factors either involved in the adaptive antitumor immune defense (CD3, IFN-gamma, IRF-1, IRF-2, SOCS1 and iNOS) or immune tolerance (FoxP3). This study did not reveal an association between urinary neopterin and one of these investigated "on tumor site transcripts". From all the factors reflecting the magnitude of the local adaptive antitumor response, intratumoral IRF-1 expression above the edge of the 25th percentile was found to predict most reliably favorable progression-free (median 34 months vs. 10 months; p < 0.001) and overall (median 52 months vs. 16 months; p < 0.001) survival. In contrast, pre-treatment urinary neopterin excretion above 275 MUmol/mol creatinine, which indicates an unspecific activation of the innate immune system, was associated with a very poor overall survival with a median of only 11 months when compared with a median overall survival of 40 months in patients with lower urinary neopterin excretion (p = 0.021). Interestingly, the considerable survival benefit in patients with high IRF-1-expressing cancers was completely abrogated as well for progression-free as for overall survival when urinary neopterin concentrations were found to be concomitantly elevated. These findings demonstrate that in ovarian carcinomas the unspecific "cancer-related inflammation" contributes to a significant subversion of the adaptive antitumor immune defense mounted at the tumor site. PMID- 20717670 TI - Coil migration through skin after posterior tibial artery pseudoaneurysm trapping. PMID- 20717671 TI - Severe complication after a doxorubicin-eluting-bead embolization: surgical management and pathological findings. AB - Doxorubicin-eluting-bead embolization (DEB) is considered a safe and efficient treatment of hepatocellular carcinoma (HCC) with a low complication rate and an increased tumor response compared with conventional transarterial chemoembolization. We describe a case of a 69-year-old patient who underwent DEB for HCC and who developed a liver abscess requiring urgent left liver lobectomy. Despite this severe complication, efficacy of DEB embolization was histologically proved as a large ischemic zone with complete tumor necrosis. PMID- 20717672 TI - Photorhabdus luminescens subsp. kleinii subsp. nov. (Enterobacteriales: Enterobacteriaceae). AB - Association between bacteria Photorhabdus and their nematode hosts Heterorhabditis represents one of the emerging models in symbiosis studies. In this study, we isolated the bacterial symbionts of the nematode Heterorhabditis georgiana. Using gyrB sequences for phylogenetic analysis, these strains were shown to be part of the species of Photorhbdus luminescens but with clear separation from currently recognized subspecies. Physiological properties and DNA DNA hybridization profiles also supported the phylogenetic relationship of these strains. Therefore, a new subspecies, Photorhabdus luminescens subsp. kleinii subsp. nov., is proposed with the type strain KMD37(T) (=DSM 23513 =ATCC =NRRL B 59419). PMID- 20717673 TI - Effect of 1-(1-Naphtylmethyl)-piperazine, an efflux pump inhibitor, on antimicrobial drug susceptibilities of clinical Acinetobacter baumannii isolates. AB - In this study, the effects of 1-(1-naphtylmethyl)-piperazine (NMP), an efflux pump inhibitor, on antimicrobial drug susceptibilities of 42 clinical Acinetobacter baumannii isolates were investigated by the disc diffusion method. The inhibition zone diameters of antibiotic discs were tested in the presence and absence of NMP and then these zone diameters were compared. Presence of NMP restored ciprofloxacin susceptibility in 15 intermediate and 2 resistant isolates. One ciprofloxacin resistant isolate became intermediate in the presence of NMP. One isolate resistant to gentamicin became intermediate with NMP. Interestingly, one isolate susceptible to meropenem became resistant in the presence of NMP. Although NMP increased the inhibition zone diameters of some of the tested antibiotics against the resistant isolates, the increase was not enough to restore susceptibility. In conclusion, the presence of NMP increases the zone diameters of ciprofloxacin and levofloxacin. Intermediate strains become susceptible but the resistant isolates do not. PMID- 20717674 TI - Promotion of Monacolin K production by Agrobacterium tumefaciens-mediated transformation in Monascus albidus 9901. AB - The binary vector pCAMBIA3300-gpdA-hph-trpC with hygromycin B phosphotransferase (hph) was constructed and transformed into Monascus albidus 9901 by Agrobacterium tumefaciens-mediated transformation, with gene hph as the selective marker. In order to improve the efficiency of A. tumefaciens-mediated transformation in M. albidus 9901, we optimized various factors including concentration of M. albidus 9901 spores, cell density of A. tumefaciens, co-cultivation time, temperature, and acetosyringone concentration. Most transformants of M. albidus 9901 could grow stably on media containing 50 MUg ml-1 hygromycin B up to five generations. The presence of hph was identified by PCR. Two transformants H1 and H2 which produced more Monacolin K than M. albidus 9901 were screened, and the concentration of Monacolin K in the fermented millet by H1 and H2 increased by 42.15% and 40.34% respectively compared with that produced by M. albidus 9901. PMID- 20717675 TI - RpoE may promote flagellar gene expression in Salmonella enterica serovar typhi under hyperosmotic stress. AB - Salmonella enterica serovar Typhi z66 positive strain contains a fljBA-like operon on a linear plasmid. The operon contains the gene fljB:z66 which encodes the z66 antigen. RpoE is a sigma factor sigma(E) that initiates transcription of a series of genes in Escherichia and Salmonella under environmental stresses. To investigate whether the gene fljB:z66 is regulated by RpoE (sigma(E)), a rpoE deletion mutant of S. enterica serovar Typhi (DeltarpoE) was prepared in this study. The defective motility of the DeltarpoE was confirmed firstly. Transcriptional expression of flagellar genes was screened using a genomic DNA microarray. Some class-2 and most class-3 flagellar genes were downregulated in the DeltarpoE after 30 min of hyperosmotic stress. The expression of fliA and fljB:z66, a class-2 flagellar gene and a class-3 flagellar gene, obviously decreased; however, expression of the class-1 flagellar genes flhDC did not change obviously in the DeltarpoE compared to the wild-type strain in the same conditions. Results of quantitative real-time PCR (qRT-PCR) showed that the expression levels of fliA and fljB:z66 in the DeltarpoE after 30 min of hyperosmotic stress decreased about five and eightfold, respectively, compared to the wild-type strain. Similar results were observed at 120 min of hyperosmotic stress. Western blotting and qRT-PCR analysis showed that expression of fliA and fljB:z66 was significantly increased after supplemental expression of rpoE with a recombinant plasmid pBADrpoE in the DeltarpoE strain. These results demonstrated that RpoE promoted the expression of class-3 flagellar genes and it might be performed by initiating the expression of fliA in S. enterica serovar Typhi under hyperosmotic stress. PMID- 20717676 TI - Isolation and purification of two bacteriocins 3D produced by Enterococcus faecium with inhibitory activity against Listeria monocytogenes. AB - Strain 3D, isolated from fermented traditional Moroccan dairy product, and identified as Enterococcus faecium, was studied for its capability to produce two bacteriocins acting against Listeria monocytogenes. Bacteriocins 3 Da and 3Db were heat stable inactivated by proteinase K, pepsin, and trypsin but not when treated with catalase. The evidenced bacteriocins were stable in a wide pH range from 2 to 11 and bactericidal activity was kept during storage at 4 degrees C. However, the combination of temperature and pH exhibited a stability of the bacteriocins. RP-HPLC purification of the anti-microbial compounds shows two active fractions eluted at 16 and 30.5 min, respectively. Mass spectrometry analysis showed that E. faecium 3D produce two bacteriocins Enterocin 3 Da (3893.080 Da) and Enterocin 3Db (4203.350 Da). This strain is food-grade organism and its bacteriocins were heat-stable peptides at basic, neutral, and acid pH: such bacteriocins may be of interest as food preservatives. PMID- 20717677 TI - Variabilities of two Drechslerella dactyloides isolates in Korea and high predacity against Bursaphelenchus xylophilus. AB - Drechslerella dactyloides generates elongate ellipsoid conidia and three-celled rings. Recently, Drechslerella dactyloides CNU 091025 and CNU 091026 were isolated in Korea, which generated elongate ellipsoid, Y-shaped and reaphook shaped conidia, three-celled rings and fishhook-shaped traps. Therefore, molecular phylogenetic analysis, morphological variability, and nematode capturing ability were tested in this study. CNU 091025 generated two-celled or three-celled Y-shaped conidia, reaphook-shaped conidia, and elongate ellipsoid conidia, 17.2, 40.9, and 41.9%, respectively. Some fishhook-shaped rings connecting together formed two-dimensional web. Both fungi showed high trap forming and nematode-capturing ability; especially CNU 091026 captured 100% Bursaphelenchus xylophilus within 24 h after inoculation. PMID- 20717678 TI - Global dynamics of hematopoietic stem cells and differentiated cells in a chronic myeloid leukemia model. AB - We consider a mathematical model describing evolution of normal and leukemic hematopoietic stem cells (HSC) and differentiated cells in bone marrow. We focus on chronic myeloid leukemia (CML), a cancer of blood cells resulting from a malignant transformation of hematopoietic stem cells. The dynamics are given by a system of ordinary differential equations for normal and leukemic cells. Homeostasis regulates the proliferation of normal HSC and leads the dynamics to an equilibrium. This mechanism is partially efficient for leukemic cells. We define homeostasis by a functional of either hematopoietic stem cells, differentiated cells or both cell lines. We determine the number of hematopoietic stem cells and differentiated cells at equilibrium. Conditions for regeneration of hematopoiesis and persistence of CML are obtained from the global asymptotic stability of equilibrium states. We prove that normal and leukemic cells can not coexist for a long time. Numerical simulations illustrate our analytical results. The study may be helpful in understanding the dynamics of normal and leukemic hematopoietic cells. PMID- 20717680 TI - [Molecular biological evaluation of prognostic parameters in GIST. Development of an integrative model of tumor progression]. AB - Prognosis evaluation in gastrointestinal stromal tumors (GIST) is currently based on tumor diameter, mitotic counts and anatomic localisation. There are two risk classifications as well as the first ever TNM classification for GISTs, whereby the risk classification according to the Armed Forces Institute of Pathology (AFIP) has the best correlation with clinical follow-up according to own experiences. "Very low/low risk" GISTs are almost benign, while the majority of "high risk" GISTs metastasize and benefit from adjuvant therapy. Careful evaluation of mitotic counts in 50 high-power fields is of particular relevance for correct risk classification. Apart from these classical prognostic factors, many molecular genetic parameters with correlation to follow-up have been evaluated and may help to improve prognosis evaluation of GISTs in the future. Since most of the molecular genetic parameters are associated or even determined by the clinico-pathological parameters, an integrated model for tumor progression of GISTs is helpful to interpret the different factors in correlation to one another. In particular for "intermediate risk" GISTs, additional parameters are needed for improved prognosis evaluation. PMID- 20717682 TI - [Volker Becker 20 November 1922 - 11 December 2008]. PMID- 20717681 TI - [Molecular pathology of thyroid tumors]. AB - Molecular genetic analysis is gaining in significance for the differential diagnosis of thyroid tumours. Identifying specific mutations and/or rearrangements offers not only the possibility to distinguish benign from malignant tumours, but also to classify thyroid malignancies more precisely, which can have a substantial influence on the clinical management of patients. In recent years expression analysis of micro-RNA (miRNA) has become an additional tool to improve diagnostic accuracy in thyroid tumours. In addition to its diagnostic contribution, molecular genetic evaluation of thyroid tumours has significantly deepened our understanding of the development, progression and therapy of these tumours. PMID- 20717683 TI - Extreme individual flexibility of heterothermy in free-ranging Malagasy mouse lemurs (Microcebus griseorufus). AB - Flexibility in physiological processes is essential to adequately respond to changes in environmental conditions. Madagascar is a particularly challenging environment because climatic conditions seem less predictable than in comparative ecosystems in other parts of the world. We used the reddish-gray mouse lemur (Microcebus griseorufus) from the most unpredictable environment in Madagascar as a model to investigate the flexibility of energy saving strategies to cope with the unpredictability of their habitat. For this we measured T (sk) of free ranging mouse lemurs throughout the year using temperature data loggers. M. griseorufus showed a very strong seasonal as well as an individual flexibility in thermoregulation. During the rainy season all M. griseorufus remained normothermic. At the beginning of the dry season individuals started to exhibit different energy saving strategies: irregular short torpor bouts, regular daily torpor, prolonged torpor of a few days, and hibernation over several weeks. The accumulation of sufficient seasonal body fat was the crucial factor determining the thermal behavior of individuals. The observed intraspecific and sex independent variation in thermoregulatory patterns within one population inhabiting the same small geographical area is exceptional and gives M. griseorufus the ability to respond to current environmental as well as individual conditions. This thermal plasticity might be seen as a key to success and survival for M. griseorufus in an extremely unpredictable environment. PMID- 20717684 TI - Primary Rathke's cleft cyst in the cerebellopontine angle associated with apoplexy. AB - Rathke's cleft cyst (RCC) is a congenital, benign, epithelial tumor and mainly occurs in sellar region and occasionally in suprasellar region; ectopic RCC is exceedingly rare. We report an uncommon RCC in cerebellopontine angle (CPA) associated with RCC apoplexy and investigated the possible hypothesis of its origin. A 12-year-old female student was admitted to hospital for 3-month history of vertigo, headache, nausea, and vomiting and aggravated for 1 week. Magnetic resonance imaging (MRI) revealed a space-occupying lesion with short T1 and long T2 signals in the left CPA and an intracystic floating nodule with hypointensity on T1- and T2-weighted imaging. The patient underwent the total tumor removal via the retrosigmoid approach with a good recovery. Primary RCC was confirmed by pathology. Follow-up MRI showed no recurrence 3.5 years after craniotomy. Primary RCC can occur in CPA and present special neuroimaging features associated with RCC apoplexy. We presumed that a mimicking mechanism of ectopic craniopharyngioma in CPA leads to the formation in the present case. Microsurgical resection is the optimal strategy for management. Further research and longer follow-up are helpful to better understanding the pathogenesis and development history of RCC in CPA. PMID- 20717686 TI - B cell acute lymphocytic leukemia in pregnancy. AB - Acute lymphocytic leukemia (ALL) is a rare occurrence in pregnancy and can be rapidly fatal if left untreated. The need for immediate treatment of ALL, coupled with the maternal-fetal risks from the chemotherapy regimen render a therapeutic dilemma in pregnant women with ALL. We report a case of ALL diagnosed in the 24th week of pregnancy to outline our management strategy, to demonstrate the feasibility of treatment with multi-agent chemotherapy, and to provide a review of the literature. PMID- 20717687 TI - HIV testing in pregnancy: are we testing enough? AB - OBJECTIVE: The crucial first step in the prevention of mother-to-child transmission of HIV is awareness of pregnant women of their HIV status. The aim of this study was to define the percentage of patients who received HIV tests between 2001 and 2007 in a German city hospital. MATERIALS AND METHODS: In this retrospective cohort analysis at a University hospital in a German urban area, 12,873 deliveries were retrospectively analysed to determine whether an HIV test had been performed during prenatal counselling. RESULTS: The number of HIV tests performed increased significantly between 2001 and 2007 from 59.6 to 76.7%. On average, 69.9% of the analysed deliveries were tested for HIV. CONCLUSIONS: Although awareness of the importance of HIV screening in newborns has increased in recent years, the numbers are still unsatisfactory. Therefore, further education is necessary to prevent HIV infection in early pregnancy and avoid HIV mother-to-child transmission. PMID- 20717685 TI - Polycomb genes expression as a predictor of poor clinical outcome in children with medulloblastoma. AB - INTRODUCTION: Medulloblastoma is the most frequent type of embryonal tumor in the pediatric population, accounting for 20-25% of all brain tumors in children. Recently, the suspected contribution of the Polycomb group (PcG) genes in medulloblastoma development was described. PcG genes play an important role in developmental processes; they are also involved in the self-renewal of hematopoietic and neural stem cells as well as in malignant transformation. PURPOSE: In this study, we evaluated the expression of BMI1and PCGF2, members of family of PcG genes, and their potential target, MYC oncogene, and analyzed their association with demographic and clinical data. MATERIALS AND METHODS: Thirty-one children (18 males and 13 females, aged from 0.4 to 17 years) with medulloblastoma were included in this study. The gene's expression level was measured by quantitative real-time PCR, obtained using the two-color multiplexing technique. RESULTS: We found that the higher expression levels of BMI1 and PCGF2 genes were associated with significantly decreased patient survival (p = 0.02 and p = 0.012, respectively). Significant differences between gender were found, with a higher expression level of the PCGF2 gene observed among females (p = 0.02). CONCLUSION: Our analysis showed correlation between BMI1 and PCGF2 gene's expression and survival in children with medulloblastoma. PMID- 20717688 TI - Recent advances in spinal cord neurology. AB - This short review summarizes developments and achievements made during the last few years in spinal neurology and includes all relevant papers published in the Journal of Neurology during this time. A focus of the review concerns the debate about the significance of translational medicine in spinal cord injury with the introduction of new drugs directed to achieve some spinal cord repairs. PMID- 20717689 TI - Patients' psychological well-being and resilient coping protect from secondary somatoform vertigo and dizziness (SVD) 1 year after vestibular disease. AB - Secondary somatoform dizziness and vertigo (SVD) is an underdiagnosed and handicapping psychosomatic disorder, leading to extensive utilization of health care and maladaptive coping. Few long-term follow-up studies have focused on the assessment of risk factors and little is known about protective factors. The aim of this 1-year follow-up study was to identify neurootological patients at risk for the development of secondary SVD with respect to individual psychopathological disposition, subjective well-being and resilient coping. In a prospective interdisciplinary study, we assessed mental disorders in n=59 patients with peripheral and central vestibular disorders (n=15 benign paroxysmal positional vertigo, n=15 vestibular neuritis, n=8 Meniere's disease, n=24 vestibular migraine) at baseline (T0) and 1 year after admission (T1). Psychosomatic examinations included the structured clinical interview for DSM-IV, the Vertigo Symptom Scale (VSS), and a psychometric test battery measuring resilience (RS), sense of coherence (SOC), and satisfaction with life (SWLS). Subjective well-being significantly predicted the development of secondary SVD: Patients with higher scores of RS, SOC, and SWLS at T0 were less likely to acquire secondary SVD at T1. Lifetime mental disorders correlated with a reduced subjective well-being at T0. Patients with mental comorbidity at T0 were generally more at risk for developing secondary SVD at T1. Patients' dispositional psychopathology and subjective well-being play a major predictive role for the long-term prognosis of dizziness and vertigo. To prevent secondary SVD, patients should be screened for risk and preventive factors, and offered psychotherapeutic treatment in case of insufficient coping capacity. PMID- 20717690 TI - Conversion disorder as initial diagnosis in pantothenate kinase associated neurodegeneration. PMID- 20717691 TI - Occupational asthma caused by triglycidyl isocyanurate. AB - BACKGROUND: Several cases of allergic contact dermatitis, two cases of occupational asthma from over one decade ago and one case of hypersensitivity pneumonitis have been documented in painters who use polyester powder paint containing triglycidyl isocyanurate (TGIC). METHODS: We report a 28-year-old female who, 4 months after beginning work in a powder-coating factory, developed asthma-like symptoms. In her workplace, aluminium frames were treated with an electrostatic powder paint containing 2.5-10% TGIC. RESULTS: Serial peak-flow measurements performed during both working and non-working periods demonstrated peak-flow variability of up to 46% on work days. Bronchial methacholine test results also varied between times at work and away from work. PC(20) methacholine was 0.32 mg/ml and fraction of exhaled nitric oxide (FENO) was 18 ppb. A controlled exposure challenge was performed with a placebo yielding no changes in FEV(1) over a 24-hour period. On visit 2, the patient was placed in the chamber and exposed to TGIC (4% in lactose) at a mean concentration of 3.61 mg/m(3) for a total of 15 min. A 20% fall in FEV(1) from baseline was elicited at 10 min, together with cough and wheezing. No late response was demonstrated. Twenty-four hours after the challenge, neither methacholine PC(20) nor FENO levels varied from baseline values. No IgE was detected by ELISA testing and no IgE-binding bands were found by immunoblot analysis of patient and control serum. CONCLUSIONS: The aforementioned results demonstrate that TGIC inhalation induced immunologic occupational asthma, although no IgE mechanism was evidenced. PMID- 20717692 TI - Renal impairment caused by chronic occupational chromate exposure. AB - PURPOSE: To determine the nephritic toxicity of chromate after chronic occupational exposure. METHODS: The environmental contamination was assessed by measuring the chromium (Cr) in 8-h airborne sampler. The integrated level of Cr was determined by Cr concentrations in the whole blood (WB-Cr) and the urine (U Cr). The renal glomerular and tubule impairment was evaluated by determination of cystatin C (Cys-C) in the serum and microalbumin (mALB), urinary beta(2) microglobulin (beta(2)M), N-acetyl-beta-D-glucosaminidase (NAG) activity in the urine. RESULTS: The mean occupational exposure time to Cr was 12.86 years with average daily air level of 27.13 MUg/m(3) comparing to 0.11 MUg/m(3) of the background level. The WB-Cr and U-Cr were 23.49 MUg/L and 17.41 MUg/g creatinine (Cre), respectively in the chromate-exposed workers comparing to 3.32 MUg/L and 1.52 MUg/g Cre in the controls. The serum Cys-C and urinary mALB were significantly increased in the chromate-exposed workers. Exposure to Cr seems to induce an enhanced level of urinary NAG activity and beta(2)M concentration. The increased serum Cys-C concentration was positively correlated with the level of serum Cre. The U-Cr was positively correlated to the concentrations of urinary mALB, beta(2)M, and the activity of NAG. CONCLUSIONS: Chronic occupational exposure to chromate causes comprehensive renal impairment though more severity could occur in the tubule than in the glomerular. PMID- 20717693 TI - Effect of lower limb muscle fatigue on anticipatory postural adjustments associated with bilateral-forward reach in the unipedal dominant and non-dominant stance. AB - Voluntary arm movements are preceded by dynamical and electromyographical (EMG) phenomena in "postural segments" (i.e. body segments not directly involved in the voluntary movement) called "anticipatory postural adjustments" (APA). The present study examined how the central nervous system organizes APA under fatigued state of postural musculature elicited by series of high-level isometric contractions (HIC), i.e. corresponding to 60% of maximal voluntary contraction. Subjects (N = 14) purposely performed series of bilateral-forward reach task (BFR) under unipodal stance (dominant and non-dominant) before ("no fatigue" condition, NF) and after ("fatigue" condition, F) a procedure designed to obtain major fatigue in hamstrings. Centre-of-gravity acceleration, centre-of-pressure displacement, and electrical activity of trunk and leg muscles were recorded and quantified within a time-window typical of APA. Results showed that there was no significant effect of fatigue on the level of muscle excitation and APA onset in any of the postural muscles recorded. Similarly, no change in APA onset could be detected from the biomechanical traces. In contrast, results showed that the amplitude of anticipatory centre-of-pressure displacement and centre-of-gravity acceleration reached lower value in F than in NF. Similar results were obtained whether dominant or non-dominant leg was considered. The changes in biomechanical APA features could not be ascribed to a different focal movement performance (maximal BFR velocity and acceleration) between F and NF. These results suggest that, when fatigue is induced by HIC, the capacity of the central nervous system to adapt APA programming to the fatigued state of the postural muscle system might be altered. PMID- 20717694 TI - 25-hydroxy vitamin D deficiency causes parathyroid incidentalomas. AB - PURPOSE: 25-OH D3 (D3) deficiency causes secondary hyperparathyroidism. Asymmetric gland hypertrophy may also lead to unnecessary parathyroid gland resection by mistaking these glands for parathyroid incidentalomas. We tested the hypothesis that D3 deficiency causes parathyroid gland hypertrophy. METHOD: This is a prospective study of 100 consecutive patients undergoing total thyroidectomy. Pre-operative D3 measurement was made at first presentation and on the day after surgery. During thyroidectomy, the parathyroid glands were searched for and measured. Using an ellipsoid volume calculator, the gland volume was calculated. This was correlated with D3 and other possible confounding factors. RESULTS: Normal parathyroid volume is 25.1 mm(3). Parathyroid gland size correlated with D3 levels, p < 0.001. There is a greater asymmetry in gland volume in those patients with the lowest levels of D3 (Spearman's rank correlation coefficient r = -0.51). There was a significant difference in individual gland volume between D3 levels >30 ng/ml and those <30 ng/ml. However, there was no difference in mean gland volume between these groups. There was no difference in correlation according to pathology or thyroid specimen weight. CONCLUSION: There is a significant difference in both individual gland volume and variation in parathyroid gland volume according to D3 levels. Patients with a D3 level <30 ng/ml have a more asymmetrical hyperplasia corresponding with parathyroid incidentalomas. D3 levels should be measured pre-operatively in all patients undergoing total thyroidectomy to avoid unnecessary parathyroid resection. PMID- 20717695 TI - Turn-over of the small non-coding RNA RprA in E. coli is influenced by osmolarity. AB - The sRNA RprA is known to activate rpoS translation in E. coli in an osmolarity dependent manner. We asked whether RprA stability contributes to osmolarity dependent regulation and how the RNA binding protein Hfq and the major E. coli endonucleases contribute to this turn-over. The study reveals that osmolarity dependent turn-over of RprA indeed contributes to its osmolarity-dependent abundance. RprA is stabilized by the RNA chaperone Hfq and in absence of Hfq its turn-over is no longer osmolarity-dependent. The stability of the RprA target mRNA rpoS shows a lower extent of osmolarity dependence, which differs from the profile observed for RprA. Thus, the effect of sucrose is specific for individual RNAs. We can attribute a role of the endoribonuclease RNase E in turn-over of RprA and an indirect effect of the endoribonuclease III in vivo. In addition, RprA is stabilized by the presence of rpoS suggesting that hybrid formation with its target may protect it against ribonucleases. In vitro RprA is cleaved by the RNase E containing degradosome and by RNase III and rpoS interferes with RNase III cleavage. We also show that temperature affects the stabilities of the sRNAs binding to rpoS and of rpoS mRNA itself differentially and that higher stability of DsrA with decreasing temperature may contribute to its high abundance at lower temperatures. This study demonstrates that environmental parameters can affect the stability of sRNAs and consequently their abundance. PMID- 20717696 TI - Outcomes after laparoscopic adrenalectomy. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) has become the standard of care for many conditions requiring removal of the adrenal gland. Previous studies on outcomes after LA have had limitations. This report describes the 30-day morbidity and mortality rates after LA and analyzes factors affecting operative time, hospital length of stay (LOS), and postoperative morbidity. METHODS: Patients undergoing LA in 2007 and 2008 were identified from the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP). Using multivariate analysis of variance (ANOVA) and logistic regression, 52 demographic/comorbidity variables were analyzed to ascertain factors affecting operative time, LOS, and morbidity. RESULTS: The mean age of the 988 patients was 53.5 +/- 13.7 years, and 60% of the patients were women. The mean body mass index (BMI) of the patients was 31.8 +/- 7.9 kg/m(2). The 30-day morbidity and mortality rates were 6.8% and 0.5%, respectively. The mean and median operative times were 146.7 +/- 66.8 min and 134 min, respectively. The mean and median hospital stays were 2.6 +/- 3.1 days and 2 days, respectively. Compared with independent status, totally dependent functional status was associated with a 9.5 day increase in LOS (P = 0.0006) and an increased risk for postoperative morbidity (odds ratio [OR], 14.7; 95% confidence interval [CI], 2.4-91.9; P < 0.0001). Peripheral vascular disease (OR, 7.3; 95% CI, 1.7-31.7; P = 0.008) also was associated with increased 30-day morbidity. Neurologic and respiratory comorbidities were associated with increased LOS (P < 0.05). American Society of Anesthesiology (ASA) class 4 patients had a longer operative time than ASA class 1 patients (P = 0.002). CONCLUSIONS: The morbidity and mortality rates after LA are low. Dependent functional status and peripheral vascular disease predispose to postoperative morbidity. Dependent status, higher ASA class, and respiratory and neurologic comorbidities are associated with longer operative time and LOS. PMID- 20717697 TI - The promoting effect of retinoic acid on proliferation of chicken primordial germ cells by increased expression of cadherin and catenins. AB - Proliferation and cellular aggregation are both crucial features for survival and self-renewal of primordial germ cells (PGCs). Adhesive proteins play pivotal roles in cell-cell adhesion and signal exchanges under the influence of cytokines, growth factors and bioactive metabolites such as retinoic acid (RA). In this study, proliferation-promoting effect of RA on chicken PGCs was investigated by revealing changes in adhesive proteins E-cadherin and alpha/beta catenins. PGCs were isolated from the genital ridge of 4-day-old chicken embryos and cultured on embryonic fibroblast feeder. RA (10(-7)-10(-5) M) increased PGCs aggregation and mRNA expression of E-cadherin and alpha/beta-catenins. Furthermore, E-cadherin and beta-catenin protein expression levels were increased by RA treatment. However, RA-elicited effect was significantly attenuated by a PKC inhibitor H(7). In addition, the number and area of PGC colonies were increased by RA treatment at 10(-7)-10(-5) M. Again, this increase was reduced by combined treatment of H(7). The proliferating effect of RA on PGCs was further confirmed by increased mRNA expression of cyclins, CCND1 and CCNE1, and cyclin dependent kinases 6 and 2, which are critical for G1-S progression in cell cycle. Moreover, flow cytometry analysis confirmed that RA-treated PGC populations displayed a significant increase in the proportion of S and G2 phase cells. Likewise, this stimulating action was hindered by combined H(7) treatment. These results indicate that RA, as a bioactive metabolite of vitamin A, may promote PGC proliferation and increase intercellular aggregation of PGCs via E-cadherin and alpha/beta-catenins expression through the PKC signaling pathway. PMID- 20717698 TI - Periodontal treatment decreases plasma oxidized LDL level and oxidative stress. AB - Periodontitis induces excessive production of reactive oxygen species in periodontal lesions. This may impair circulating pro-oxidant/anti-oxidant balance and induce the oxidation of low-density lipoprotein (LDL) in blood. The purpose of this study was to monitor circulating oxidized LDL and oxidative stress in subjects with chronic periodontitis following non-surgical periodontal treatment. Plasma levels of oxidized LDL and oxidative stress in 22 otherwise healthy non smokers with chronic periodontitis (mean age 44.0 years) were measured at baseline and at 1 and 2 months after non-surgical periodontal treatment. At baseline, chronic periodontitis patients had higher plasma levels of oxidized LDL and oxidative stress than healthy subjects (p < 0.001). Periodontal treatment was associated with a significant reduction in plasma levels of oxidized LDL (oxLDL)(p < 0.001) and oxidative stress (p < 0.001). At 2 months after periodontal treatment, the degree of change in the oxLDL was positively correlated with that in the oxidative stress (r = 0.593, p = 0.004). These observations indicate that periodontitis patients showed higher levels of circulating oxLDL and oxidative stress than healthy subjects. In addition, improved oral hygiene and non-surgical periodontal treatment were effective in decreasing oxLDL, which was positively associated with a reduction in circulating oxidative stress. PMID- 20717699 TI - Quantitative analysis of pathological nails using laser-induced breakdown spectroscopy (LIBS) technique. AB - Laser-induced breakdown spectroscopy (LIBS) has been used as a potential method for simultaneous measurement of the elements Ca, Na, and K, for normal and pathological nails. We compared the measured LIBS spectra of these elements for normal and pathological nails. The B2?+ --> X2?+ violet band emission spectrum of CN was used for the estimation of the transient temperature of the plasma plume and consequently of the sample surface considering thermodynamic equilibrium. PMID- 20717700 TI - How removing prescription drugs from reimbursement lists increases the pharmaceutical expenditures for alternatives. AB - Changing the status of drugs from prescription-only to over-the-counter and removing them from reimbursement list has been used as a cost reduction measure by several third-party payers. In June 2006, the Turkish government, in an effort to curtail costs, removed many prescription drugs from the reimbursement list. This paper examines the effect of this policy on the expenditures for drugs that were removed from the reimbursement list and for their reimbursable alternatives that can be prescribed by physicians on patient request. To accomplish these goals, actual expenditures in four anatomical therapeutic chemical (ATC) groups were compared with expected expenditures in the absence of policy change for both removed and alternative drugs. The findings indicated that the expenditures on alternative drugs beyond expectations. In two of the four ATC groups involved in the study, the increase was large enough to wipe out the reduction in expenditures on the drugs removed from the reimbursement list. PMID- 20717701 TI - Early experience using an online reporting system for interventional radiology procedure-related complications integrated with a digital dictation system. AB - The absence of user-friendly systems for reporting complications is a major barrier to improving quality assurance (QA) programs in interventional radiology (IR) services. We describe the implementation of a QA application that is completely integrated with the radiology dictation system. We implemented an IR QA process as a module within the electronic medical record and radiologist dictation system applications used at our institution. After a radiologist completes a dictation, he or she must select from a drop-down list of complications before proceeding to the next case. Delayed QA events can be entered using the same applications. All complication entries are sent to a database, which is queried to run reports. During the study period, all the 20,034 interventional procedures were entered in the QA database, 1,144 complications were reported, 110 (9.6%) of which were classified as major. Although majority of the complications (996) were entered at the time of dictation, 148 complications (12.9%) were entered afterwards. All major complications were referred to the IR peer review committee, and 30 of these were discussed in the morbidity and mortality meetings. We studied post-lung-biopsy pneumothorax and chest tube rates and initiated a quality improvement process based on the results.The integration of the IR QA reporting system into the workflow process and the mandatory requirements for completion has the potential to minimize the work effort required to enter complication data, and improve participation in the QA process. PMID- 20717702 TI - Methods for the genetic manipulation of Nonomuraea sp. ATCC 39727. AB - Nonomuraea sp. ATCC 39727 belongs to the Streptosporangiaceae family of filamentous actinomycetes. This microorganism produces the teicoplanin-like glycopeptide A40926, which is the starting material for the synthesis of the second-generation glycopeptide dalbavancin. Notwithstanding the strain's pharmaceutical relevance, the lack or poor efficiency of genetic tools to manipulate Nonomuraea sp. ATCC 39727 has hampered strain and product improvement. Here we report the development of gene transfer systems based on protoplast transformation and intergeneric conjugation from Escherichia coli. Efficiency of transformation and conjugation, followed by site specific or homologous recombination with the Nonomuraea sp. genome, were determined using the integrative plasmid pSET152 (5.7 kb), and the Supercos1 derivative cosmid A40DeltaY (30 kb). To our knowledge, this is the first report of the transformation of protoplasts of Nonomuraea sp. ATCC 39727, even though the improved procedure for intergeneric conjugation makes it the method of choice for introducing large segments of DNA into Nonomuraea sp. ATCC 39727. PMID- 20717703 TI - In vivo and in vitro inhibition of mice thioredoxin reductase by methylmercury. AB - The thioredoxin (Trx) system, involving redox active Trxs and thioredoxin reductases (TrxRs), sustain a number of important Trx-dependent pathways. These redox active proteins support several processes crucial for cell function, cell proliferation, antioxidant defense, and redox-regulated signaling cascades. Methylmercury (MeHg) is an important environmental toxicant that has a high affinity for thiol groups and can cause oxidative stress. The Trx system is the major system responsible for maintaining the redox state of cells and this function involves thiol reduction mediated by selenol groups in TrxRs. MeHg has a great affinity to thiols and selenols, thus the potential toxic effects of MeHg on TrxR inhibition were determined in the current study. A single administration of MeHg (1, 5, and 10 mg/Kg) caused a marked inhibition of kidney TrxR activity, while significant inhibition was observed in the liver after exposure to 5 and 10 mg/Kg of MeHg. TrxR activity was determined 24 h after MeHg. In the brain, MeHg did not inhibit TrxR activity. In vitro exposure to MeHg indicated that MeHg inhibits cerebral (IC(50), 0.158 MUM), hepatic (IC(50), 0.071 MUM), and renal TrxR activity (IC(50), 0.078 MUM). The results presented herein demonstrated for the first time that renal and hepatic TrxRs can serve as an in vivo target for MeHg. This study suggests that MeHg can bind to selenocysteine residues present in the catalytic site of TrxR, in turn causing enzyme inhibition that can compromise the redox state of cells. PMID- 20717704 TI - Lipid replacement therapy: a nutraceutical approach for reducing cancer associated fatigue and the adverse effects of cancer therapy while restoring mitochondrial function. AB - Cancer-associated fatigue is one of the most common symptoms in all forms and stages of cancer, yet scant attention is usually given to patients who have symptomatic complaints of fatigue. Cancer-associated fatigue is also associated with cellular oxidative stress, and during cancer therapy, excess drug-induced oxidative stress can limit therapeutic effectiveness and cause a number of side effects, including fatigue, nausea, vomiting, and more serious adverse effects. Cancer-associated fatigue and the chronic adverse effects of cancer therapy can be reduced by lipid replacement therapy using membrane lipids along with antioxidants and enzymatic cofactors, such as coenzyme Q(10), given as food supplements. Administering these nutraceutical supplements can reduce oxidative membrane damage and restore mitochondrial and other cellular functions. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefits of lipid replacement therapy in reducing fatigue and restoring mitochondrial electron transport function. PMID- 20717705 TI - Micronutrient synergy--a new tool in effective control of metastasis and other key mechanisms of cancer. AB - Consumption of a plant-based diet has been associated with prevention of the development and progression of cancer. We have developed strategies to inhibit cancer development and its spread by targeting common mechanisms used by all types of cancer cells that decrease stability and integrity of connective tissue. Strengthening of collagen and connective tissue can be achieved naturally through the synergistic effects of selected nutrients, such as lysine, proline, ascorbic acid and green tea extract (NM). This micronutrient mixture has exhibited a potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines. Its anti-cancer effects include inhibition of metastasis, tumor growth, matrix metalloproteinase (MMP) secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. Many cancers are often diagnosed at later stages, when metastasis has occurred, which standard treatment has been unable to control. Our studies on NM effects on hepatic and pulmonary metastasis demonstrated profound, significant suppression of metastasis in a murine model. Evaluation of effects of NM on xenografts in murine models demonstrated significant reduction in tumor size and tumor burden in all human cancer cell lines tested. In vitro studies demonstrated that NM was very effective in inhibition of cell proliferation (by MTT assay), MMP secretion (by gelatinase zymography), cell invasion (through Matrigel), cell migration (by scratch test), induction of apoptosis (by live green caspase) and induction of pro-apoptotic genes in many diverse cancer cell lines. Furthermore, in vivo and in vitro studies of effects of individual micronutrients compared to their specific combination demonstrated synergistic effects resulting in improved anticancer potency. PMID- 20717706 TI - Do nutraceutics play a role in the prevention and treatment of colorectal cancer? AB - Colorectal cancer is the third most common cancer worldwide with a 5-year survival of 50%. Current chemotherapeutic regimens used for advanced colorectal cancer provide an average survival of approximately 20 months. Non-toxic agents such as nutraceutics and supplements have been shown to aid in the prevention and adjuvant treatment of colorectal cancer. This article will discuss the epidemiology, progression, prevention, treatment, and recurrence of colorectal cancer and the role of nutraceutics and supplements in the treatment process. PMID- 20717707 TI - Naringenin promote apoptosis in cerebrally implanted C6 glioma cells. AB - Naringenin (NGEN), a naturally occurring citrus flavonone, has shown cytotoxicity in various human cancer cell lines as well as inhibitory effects on tumor growth. It has been also shown to access the brain and there is an increasing interest in its therapeutic applications. The up-regulated expression of Cx43 leads to the suppression of tumorigenicity with promoted apoptotic events. In this study, we investigated the in vivo effect of NGEN in fostering apoptosis in cerebrally implanted C6 glioma cells rat model. We analysed the expression of Cx43, caspase 3, caspase-9, Cyt C, Bcl-2 and Bax in vivo by immunoblot analysis and the ultra structure of brain cells by transmission electron microscopy. Supplementation of NGEN to experimental animals modulated Bcl-2/Bax ratio and up-regulation of caspase-3 and 9. NGEN was also found to up-regulate the expression of Cx43. These findings provide evidence that NGEN's apoptotic effect, modulation of Bcl-2/Bax ratio leads to release of Cyt C from mitochondria, thereby activation of caspase 3 and caspase-9 is mediated by enhanced expression of Cx43. These observations were well supported by the transmission electron microscopic results which showed the characteristic apoptotic features. In conclusion, our findings demonstrate that NGEN promotes apoptosis in rat C6 glioma model. PMID- 20717708 TI - Analysis of the protein expression changes during taxol-induced apoptosis under translation inhibition conditions. AB - Taxol is currently used in chemotherapeutic treatments of different types of cancers. In this article, we demonstrate that taxol induces apoptosis and translation down-regulation in human embryonic kidney (HEK293T) cells. Antibody arrays are a promising new tool for the analysis of protein levels changes in cells responding to different stimuli. Using this approach, we have identified changes in the expression of 38 proteins (20 down-regulated and 18 up-regulated), implicated in several cellular processes mainly in apoptosis, cell cycle and signal transduction pathways, and also cytoskeleton proteins. Among them, we have confirmed a considerable decrease in the expression of p14(ARF) and a significant increase in the levels of dystrophin and c-Myc. It is known that c-Myc mRNA has an internal ribosome entry segment (IRES) element in its 5'UTR that could regulate its expression under global protein synthesis inhibition conditions. We demonstrate that after taxol treatment, the c-Myc IRES activity is maintained meanwhile cap-dependent activity is inhibited. In addition, an increase in c-Myc mRNA was also observed after taxol treatment. We conclude that taxol-induced c Myc expression is regulated at both transcriptional and translational levels, the last of them by a mechanism mediated by IRES. PMID- 20717709 TI - The effect of ultrasound on the setting reaction of zinc polycarboxylate cements. AB - The set of glass ionomer cement (GIC) is accelerated by application of ultrasound. Although GIC has somewhat displaced zinc polycarboxylate cement (ZPC) in dental applications the latter is still extensively used. Like GIC, it provides direct adhesion to tooth and can provide F release, but is more radiopaque and biocompatible than GIC. The aim of this study is to examine the effect of ultrasound on the setting of ZPC using Fourier transform infra red spectroscopy and any interaction with SnF(2) addition. ZPC with and without SnF(2) addition (+/-S) at luting (L) 2:1 P/L ratio and restorative (R) 4:1 P/L ratio consistencies. Ultrasound is applied to the cement using Piezon-Master 400, EMS, Switzerland at 60 s from start of mixing for 15 s. The ratios of absorbance peak height at 1,400 cm(-1) -COO(-) to that at 1,630 cm(-1) -COOH were measured and compared those obtained for the cement not treated with US. These values were taken at the elapsed time at which no further change in spectrum [ratio] was observed at room temperature [10-20 min]. The US results are taken at 2 or 3 min. No US: R/+S (1.09), R/-S (1.2), L/+S (1.07), L/-S (1.04); US: R/+S (1.50), R/-S (1.64), L/+S (1.38), L/-S (1.05). The results show all four ZPC formulations are very sensitive to ultrasound whether with or without SnF(2). Reducing US to 10 s produces lower initial ratios but these increase up to 10 min when very high ratios (>2) are obtained. Previous studies with restorative GICs found that 40-55 s US was needed to produce the effect found with 15 s on ZPCs. ZPC powder is more basic than GIC glass; this may account for ZPC's greater sensitivity to US. Ultrasound may provide a useful adjunct to the clinical use of ZPC both as luting agent and temporary restorative. PMID- 20717710 TI - Evaluation of alginate hydrogels under in vivo-like bioreactor conditions for cartilage tissue engineering. AB - Alginate hydrogels in forms of discs and packed beds of microbeads (~800 MUm) were tested in a novel bioreactor at 10% strain using two regimes: at a loading rate of 337.5 MUm/s and at sequential increments of 50 MUm displacement every 30 min. Compressive strength increased with the increase in alginate concentration (1.5 vs. 2% w/w) and the content of guluronic residues (38.5 vs. 67%). Packed beds of microbeads exhibited significantly higher (~1.5-3.4 fold) compression moduli than the respective discs indicating the effects of gel form and entrapped water. Short-term cultivation of microbeads with immobilized bovine calf chondrocytes (1.5% w/w, 33 * 10(6) cells/ml) under biomimetic conditions (dynamic compression: 1 h on/1 h off, 0.42 Hz, 10% strain) resulted in cell proliferation and bed compaction, so that the compression modulus slightly increased. Thus, the novel bioreactor demonstrated advantages in evaluation of biomaterial properties and cell-biomaterial interactions under in vivo-like settings. PMID- 20717711 TI - Nitric oxide regulates stretch-induced proliferation in C2C12 myoblasts. AB - Mechanical stretch of skeletal muscle activates nitric oxide (NO) production and is an important stimulator of satellite cell proliferation. Further, cyclooxygenase (COX) activity has been shown to promote satellite cell proliferation in response to stretch. Since COX-2 expression in skeletal muscle can be regulated by NO we sought to determine if NO is required for stretch induced myoblast proliferation and whether supplemental NO can counter the effects of COX-2 and NF-kappaB inhibitors. C2C12 myoblasts were cultured for 24 h, then switched to medium containing either the NOS inhibitor, L-NAME (200 microM), the COX-2 specific inhibitor NS-398 (100 microM), the NF-kappaB inhibiting antioxidant, PDTC (5 mM), the nitric oxide donor, DETA-NONOate (10-100 microM) or no supplement (control) for 24 h. Subgroups of each treatment were exposed to 1 h of 15% cyclic stretch (1 Hz), and were then allowed to proliferate for 24 h before fixing. Proliferation was measured by BrdU incorporation during the last hour before fixing, and DAPI stain. Stretch induced a twofold increase in nuclear number compared to control, and this effect was completely inhibited by L-NAME, NS-398 or PDTC (P < 0.05). Although DETA-NONOate (10 microM) did not affect basal proliferation, the NO-donor augmented the stretch-induced increase in proliferation and rescued stretch-induced proliferation in NS-398-treated cells, but not in PDTC-treated cells. In conclusion, NO, COX-2, and NF-kappaB are necessary for stretch-induced proliferation of myoblasts. Although COX-2 and NF kappaB are both involved in basal proliferation, NO does not affect basal growth. Thus, NO requires the synergistic effect of stretch in order to induce muscle cell proliferation. PMID- 20717713 TI - CCSV-MPase, a novel procoagulant metalloproteinase from Cerastes cerastes venom: purification, biochemical characterization and protein identification. AB - A procoagulant metalloproteinase called CCSV-MPase was purified from C. cerastes venom by successive chromatographic methods starting with gel-filtration through Sephadex G-75; ion-exchange DEAE-Cellulose A-50; affinity chromatography on Benzamidine Sepharose 6B and RP-HPLC on a C8 column. CCSV-MPase has been isolated to an extent of about tenfolds and its molecular mass was evaluated at 70 kDa by SDS-PAGE. CCSV-MPase hydrolyzes casein and fibrinogene as natural substrates. Its proteolytic activity was inhibited by EDTA and 1.10-phenanthroline, a chelators of bivalent cation metals and Zn(2+) respectively. CCSV-MPase is therefore a Zn(2+)-metalloproteinase with fibrinogenolytic but not hemorrhagic activity. It greatly decreased levels of plasmatic fibrinogen when administered to rats for 24 h. This fibrinogenase hydrolyzes the Bbeta chain of human fibrinogen in vitro releasing fibrinopeptide B only. LC MS/MS analysis of tryptic fragments of CCSV MPase demonstrated that it showed some sequence similarities with four other venom metalloproteinases. CCSV-MPase could be considered as a potential therapeutic agent as it is a non-hemorrhagic enzyme and could be useful in thrombotic diseases because of its defibrinogenation of blood. PMID- 20717712 TI - Diverse and active roles for adipocytes during mammary gland growth and function. AB - The mammary gland is unique in its requirement to develop in close association with a depot of adipose tissue that is commonly referred to as the mammary fat pad. As discussed throughout this issue, the mammary fat pad represents a complex stromal microenvironment that includes a variety of cell types. In this article we focus on adipocytes as local regulators of epithelial cell growth and their function during lactation. Several important considerations arise from such a discussion. There is a clear and close interrelationship between different stromal tissue types within the mammary fat pad and its adipocytes. Furthermore, these relationships are both stage- and species-dependent, although many questions remain unanswered regarding their roles in these different states. Several lines of evidence also suggest that adipocytes within the mammary fat pad may function differently from those in other fat depots. Finally, past and future technologies present a variety of opportunities to model these complexities in order to more precisely delineate the many potential functions of adipocytes within the mammary glands. A thorough understanding of the role for this cell type in the mammary glands could present numerous opportunities to modify both breast cancer risk and lactation performance. PMID- 20717714 TI - Bridging the research-to-practice gap in autism intervention: an application of diffusion of innovation theory. AB - There is growing evidence that efficacious interventions for autism are rarely adopted or successfully implemented in public mental health and education systems. We propose applying diffusion of innovation theory to further our understanding of why this is the case. We pose a practical set of questions that administrators face as they decide about the use of interventions. Using literature from autism intervention and dissemination science, we describe reasons why efficacious interventions for autism are rarely adopted, implemented, and maintained in community settings, all revolving around the perceived fit between the intervention and the needs and capacities of the setting. Finally, we suggest strategies for intervention development that may increase the probability that these interventions will be used in real-world settings. PMID- 20717715 TI - Selective suppression of cervical cancer Hela cells by 2-O-beta-D-glucopyranosyl L-ascorbic acid isolated from the fruit of Lycium barbarum L. AB - Lycium barbarum fruit has been used as a Chinese traditional medicine and dietary supplement for centuries. 2-O-beta-D-Glucopyranosyl-L-ascorbic acid (AA-2betaG), a novel stable vitamin C analog, is one of the main biologically active components of the fruit. In this report, we investigated the cytotoxic and antiproliferative effect of AA-2betaG against cancer cells in vitro and identified the proteins with significantly differential expression in the cervical cancer cells (Hela) cultured in the presence of AA-2betaG proteomic analysis. Our results demonstrated that the cytotoxic and antiproliferative activity of AA-2betaG on cancer cell lines were in a cell type-, time-, and dose dependent manner. Similar to vitamin C, the AA-2betaG selectively induced cell death repressed the proliferation of Hela cells by the mechanism of cell apoptosis and cell cycle arrest induced by AA-2betaG through a mechanism of stabilizing p53 protein. However, the biological activity of inhibition of cell proliferation in other malignant cancer cell lines or primary cells were varied, as demonstrated by either moderate inhibition or slight promotion following treatment with AA-2betaG. Comparative analysis of the proteomic profiles and immunoblot analysis identified 15 proteins associated with repressing cell apoptosis and/or stimulating cell proliferation in Hela cells that were downregulated in the presence of AA-2betaG or vitamin C. These data indicate that a mechanism of the AA-2betaG and vitamin C mediated antitumor activity by downregulating the expression of proteins involved in cell apoptosis and proliferation and consequently inducing Hela cell apoptosis and cell cycle arrest, suggesting that AA-2betaG and vitamin C may share a similar mechanism of inducing Hela cell apoptosis. These results also suggest that the L. barbarum fruit may be a potential dietary supplement and anticancer agent aimed at the prevention and treatment of cervical cancer. PMID- 20717716 TI - Fat element-a new marker for chromosome and genome analysis in the Triticeae. AB - Chromosomal distribution of the Fat element that was isolated from bacterial artificial chromosome (BAC) end sequences of wheat chromosome 3B was studied in 45 species representing eight genera of Poaceae (Aegilops, Triticum, Agropyron, Elymus, Secale, Hordeum, Avena and Triticale) using fluorescence in situ hybridisation (FISH). The Fat sequence was not present in oats and in two barley species, Hordeum vulgare and Hordeum spontaneum, that we investigated. Only very low amounts of the Fat element were detected on the chromosomes of two other barley species, Hordeum geniculatum and Hordeum chilense, with different genome compositions. The chromosomes of other cereal species exhibited distinct hybridisation patterns with the Fat probe, and labelling intensity varied significantly depending on the species or genome. The highest amount of hybridisation was detected on chromosomes of the D genome of Aegilops and Triticum and on chromosomes of the S genome of Agropyron. Despite the bioinformatics analysis of several BAC clones that revealed the tandem organisation of the Fat element, hybridisation with the Fat probe produces uneven, diffuse signals in the proximal regions of chromosomes. In some of the genomes we investigated, however, it also forms distinct, sharp clusters in chromosome-specific positions, and the brightest fluorescence was always observed on group 4 chromosomes. Thus, the Fat element represents a new family of Triticeae-specific, highly repeated DNA elements with a clustered-dispersed distribution pattern. These elements may have first emerged in cereal genomes at the time of divergence of the genus Hordeum from the last common ancestor. During subsequent evolution, the amount and chromosomal distribution of the Fat element changed due to amplification, elimination and re-distribution of this sequence. Because the labelling patterns that we detected were highly specific, the Fat element can be used as an accessory probe in FISH analysis for chromosome identification and investigation of evolutionary processes at the chromosomal level. PMID- 20717718 TI - Mesozooplankton distribution near an active volcanic island in the Andaman Sea (Barren Island). AB - The study addresses the distribution and diversity of mesozooplankton near the active volcano-Barren Island (Andaman Sea) in the context of persistent volcanic signature and warm air pool existing for the last few months. Sampling was done from the stations along the west and east side of the volcano up to a depth of 1,000 m during the inter monsoon (April) of 2006. Existence of feeble warm air pool was noticed around the Island (Atm. Temp. 29 degrees C). Sea surface temperature recorded as 29.9 degrees C on the west and 29.6 degrees C on the east side stations. High mesozooplankton biomass was observed in the study area than the earlier reports. High density and biomass observed in the surface layer decreased significantly to the deeper depths. Lack of correlation was observed between mesozooplankton biomass and density with chl. a. Twenty-three mesozooplankton taxa were observed with copepoda as the dominant taxa followed by chaetognatha. The relative abundance of chaetognatha considerably affected the copepod population density in the surface layer. A noticeable feature was the presence of cumaceans, a hyperbenthic fauna in the surface, mixed layer and thermocline layer on the western side station where the volcano discharges in to the sea. The dominant order of copepoda, the calanoida was represented by 52 species belonging to 17 families. The order poecilostomatoida also had a significant contribution. Copepods exhibited a clear difference in their distribution pattern in different depth layers. The families Calanidae and Pontellidae showed a clear dominance in the surface whereas small-sized copepods belonging to the families Clausocalanidae and Paracalanidae were observed as the predominant community in the mixed layer and thermocline layer depth. Families Metridinidae, Augaptilidae and Aetideidae were observed as dominant in deeper layers. PMID- 20717717 TI - Hemocitical responses to environmental stress in invertebrates: a review. AB - Although invertebrates are recognized by the great facility to accumulate pollutants present in their environment and many of them are used as sentinel species in biomonitoring studies, little is known about the impact of toxicants on the immune system of these animals. In this regard, hemocytes play a fundamental role: these cells circulate freely through the hemolymph of invertebrates and act on the recognition of foreign material to the organism, mediating and effecting the cellular defense, such as phagocytosis, nodulation, and encapsulation. Different morphological types can be recognized but still there is controversy among the researchers about the exact classification of the hemocytes due to the diversity of techniques for the preservation and observation of these cells. In the present study, a review on the main hemocyte responses to environmental stress in different invertebrate organisms is presented, emphasizing the contamination by heavy metals. It is discussed parameters such as: alteration in the number of cells involved in the defense reaction, phagocytic activity, lysosomal responses, and production of reactive oxygen species. PMID- 20717719 TI - RGD-xyloside conjugates prime glycosaminoglycans. AB - Glycosaminoglycans (GAG) play decisive roles in various cardio-vascular & cancer associated processes. Changes in the expression of GAG fine structures, attributed to deregulation of their biosynthetic and catabolic enzymes, are hallmarks of vascular dysfunction and tumor progression. The wide spread role of GAG chains in blood clotting, wound healing and tumor biology has led to the development of modified GAG chains, GAG binding peptides and GAG based enzyme inhibitors as therapeutic agents. Xylosides, carrying hydrophobic aglycone, are known to induce GAG biosynthesis in various systems. Given the important roles of GAG chains in vascular and tumor biology, we envision that RGD-conjugated xylosides could be targeted to activated endothelial and cancer cells, which are known to express alpha(v)beta(3) integrin, and thereby modulate the pathological processes. To accomplish this vision, xylose residue was conjugated to linear and cyclic RGD containing peptides using click chemistry. Our results demonstrate that RGD-conjugated xylosides are able to prime GAG chains in various cell types, and future studies are aimed toward evaluating potential utility of such xylosides in treating myocardial infarction as well as cancer-associated thrombotic complications. PMID- 20717720 TI - Evaluation of the potential of the common cockle (Cerastoderma edule L.) for the ecological risk assessment of estuarine sediments: bioaccumulation and biomarkers. AB - Common cockles (Cerastoderma edule, L. 1758, Bivalvia: Cardiidae) were subjected to a laboratory assay with sediments collected from distinct sites of the Sado Estuary (Portugal). Cockles were obtained from a mariculture site of the Sado Estuary and exposed through 28-day, semi-static, assays to sediments collected from three sites of the estuary. Sediments from these sites revealed different physico-chemical properties and levels of metals and organic contaminants, ranging from unimpacted (the reference site) to moderately impacted, when compared to available sediment quality guidelines. Cockles were surveyed for bioaccumulation of trace elements (Ni, Cu, Zn, As, Cd and Pb) and organic contaminants (PAHs, PCBs and DDTs). Two sets of potential biomarkers were employed to assess toxicity: whole-body metallothionein (MT) induction and digestive gland histopathology. The bioaccumulation factor and the biota-to-soil accumulation factor were estimated as ecological indices of exposure to metals and organic compounds. From the results it is inferred that C. edule responds to sediment-bound contamination and might, therefore, be suitable for biomonitoring. The species was found capable to regulate and eliminate both types of contaminants. Still, the sediment contamination levels do not account for all the variation in bioaccumulation and MT levels, which may result from the moderate metal concentrations found in sediments, the species' intrinsic resistance to pollution and from yet unexplained xenobiotic interaction effects. PMID- 20717721 TI - Na+, K+ ATPase activity is reduced in amygdala of rats with chronic stress induced anxiety-like behavior. AB - In this study, we examined the effects of two chronic stress regimens upon anxiety-like behavior, Na(+), K(+)-ATPase activity and immunocontent, and oxidative stress parameters (antioxidant enzymes and reactive oxygen species production) in the amygdala. Male rats were subjected to chronic unpredictable and to chronic restraint stress for 40 days. Subsequently, anxiety-like behavior was examined. Both stressed groups presented increased anxiety-like behavior. Reduced amygdalal Na(+), K(+)-ATPase activity in the synaptic plasma membranes was also observed, without alterations in the amygdala immunocontent. In addition, when analyzing oxidative stress parameters, only superoxide dismutase activity was decreased in the amygdala of animals subjected to unpredictable stress. We conclude that both models of chronic stress lead to anxiety-like behavior and decreased amygdalal Na(+), K(+)-ATPase activity, which appears not to be related to oxidative imbalance. The relationship between this decreased activity and anxiety-like behavior remains to be studied. PMID- 20717722 TI - Synergetic analgesia of propentofylline and electroacupuncture by interrupting spinal glial function in rats. AB - Previous studies indicated that disruption of glial function in the spinal cord enhanced electroacupuncture (EA) analgesia in arthritic rats, suggesting glia is involved in processing EA analgesia. To probe into the potential value for clinical practice, the present study was to investigate the effect of propentofylline, a glia inhibitor, on EA analgesia in rats. Mechanical allodynia induced by tetanic stimulation of sciatic nerve (TSS) was used as a pain model. On day 7 after TSS, EA treatment induced a significant increase in paw withdrawal threshold to mechanical stimulation. Intrathecal or intraperitoneal injection of propentofylline relieved TSS-induced mechanical allodynia. The combination of low dosage of propentofylline and EA produced more potent anti-allodynia than propentofylline or EA alone. Immunohistochemistry exhibited that TSS-induced activation of microglia and astrocytes was inhibited significantly by propentofylline. These results indicate that propentofylline and EA induce synergetic analgesia by interrupting spinal glial function. PMID- 20717723 TI - Anticoccidial activity of the methanolic extract of Musa paradisiaca root in chickens. AB - The study was designed to evaluate the anticoccidial activity of the methanolic extract of Musa paradisiaca root in chickens. The chickens were divided into six groups of 12 chickens each. Each chicken in five groups was infected with 8,000 infective coccidia (Eimeria tenella) oocysts at day 28 of age while one group served as uninfected control. At day 7 post-infection, two chickens remaining in each group were sacrificed for postmortem examination to confirm coccidiosis. Also at day 7 post-infection, each chicken in four infected groups was given graded doses (250, 500 and 1,000 mg/kg b.w.) of the extract or amprolium (conventional drug). Two groups (an infected and uninfected group) did not receive treatment. Parameters used to assess progress of infection and response to treatment included clinical signs typical of coccidiosis, oocyst count per gramme of faeces (OPG) and packed cell volume (PCV). Treatment of previously infected chickens with M. paradisiaca root extract resulted in a progressive decrease in severity of observed clinical signs, marked reductions in OPG and a gradual increase in PCV. In each case, the changes were dose dependent. There was no significant difference in mean OPG and mean PCV of the extract (at 1,000 mg/kg b.w.) and amprolium-treated groups at termination of the study (at day 50 of age). In the acute toxicity study, the extract was found to be non-toxic to the chickens even at the highest dose of 4,000 mg/kg b.w. The results of this study demonstrated that the extract has anticoccidial activity in a dose-dependent manner and at a dosage of 1,000 mg/kg b.w. had similar efficacy with amprolium in the treatment of chicken coccidiosis. PMID- 20717724 TI - Outbreak investigations and genetic characterization of foot-and-mouth disease virus in Ethiopia in 2008/2009. AB - The study was conducted in three regional states of Ethiopia: Amhara, Oromia, and Addis Ababa from August 2008 to April 2009 with the objectives of identifying the genetic diversity of serotypes and topotypes in Ethiopia, and determining the attack rate and associations of potential risk factors with foot-and-mouth disease (FMD) seropositivity. A total of 496 cattle were clinically and serologically examined for presence of specific lesions and nonstructural protein for FMD, respectively. Of which, 140 (28.2%) manifested clinical signs and lesions suggestive of FMD, and 219 (44.2%) were seropositive. From a total of 7,781 animals observed and recorded on a designed format in six districts, 1,409 (19.6%) were infected, and 15 (0.12%) died during outbreaks of FMD. Epidemiological investigations revealed that the morbidity rate of the disease was 21.1% in Akaki-kality sub-city, but the mortality rate was <2% in all districts. Furthermore, the mortality and case fatality rates were relatively higher, 1.6% and 8.9% in calves than the other age groups, respectively. From a total of 33 bovine epithelial tissue-cultured samples, 19 (57.6%) showed CPE for FMD virus, in which 16 samples had serotype O and EA-3 topotype, while three samples had found serotype A, Africa topotype, and G-VII strain. Various strains of FMD viruses were isolated in Ethiopia in this study, and therefore, further detailed studies on the evaluation of available vaccines and the development of a vaccine which contains cocktails of antigens of FMD virus strains in the country should be encouraged. PMID- 20717725 TI - Frailty, ageing and inflammation: reality and perspectives. PMID- 20717726 TI - The mechanical properties of endovascular stents: an in vitro assessment. AB - Endovascular stents are commonly used to manage arterial diseases such as Aortic Abdominal Aneurysm (AAA), aortic dissection and coarctation. The radial force the stent applies to the vessel must be large enough to resist stent migration, but not so large that the mechanical stimulus initiates adverse vessel remodeling. We employed two approaches to characterize the radial force of Gianturco stents: first, by applying an external pressure to the stent and, second, by measuring the force exerted by the stent when deployed. From the second approach, we determined the force exerted at various area reductions that correspond to clinically relevant diameter oversizings. In this study, stent stiffness was determined from the force-area reduction curves. Comparing similar stents of various diameters revealed that smaller diameter stent had greater radial force and stiffness than larger diameter stents. Comparing similar stents of various lengths revealed that stents with longer lengths (and greater number of wires) has greater force and stiffness. Overlapping two stents increased the force and stiffness to values greater than the sum of those parameters for the individual stents. These data may have important clinical implications for understanding the effect of oversized and overlapped stents on vessel mechanics. PMID- 20717727 TI - Survivin is released from cancer cells via exosomes. AB - Inhibitor of apoptosis (IAP) and Heat shock proteins (HSPs) provide assistance in protecting cells from stresses of hypoxia, imbalanced pH, and altered metabolic and redox states commonly found in the microenvironmental mixture of tumor and nontumor cells. HSPs are upregulated, cell-surface displayed and released extracellularly in some types of tumors, a finding that until now was not shared by members of the IAP family. The IAP Survivin has been implicated in apoptosis inhibition and the regulation of mitosis in cancer cells. Survivin exists in a number of subcellular locations such as the mitochondria, cytoplasm, nucleus, and most recently, the extracellular space. Our previous work showing that extracellular survivin was able to enhance cellular proliferation, survival and tumor cell invasion provides evidence that Survivin might be secreted via an unidentified exocytotic pathway. In the present study, we describe for the first time the exosome-release of Survivin to the extracellular space both basally and after proton irradiation-induced stress. To examine whether exosomes contributed to Survivin release from cancer cells, exosomes were purified from HeLa cervical carcinoma cells and exosome quantity and Survivin content were determined. We demonstrate that although proton irradiation does not influence the exosomal secretory rate, the Survivin content of exosomes isolated from HeLa cells treated with a sublethal dose of proton irradiation (3 Gy) is significantly higher than control. These data identify a novel secretory pathway by which Survivin can be actively released from cells in both the basal and stress-induced state. PMID- 20717728 TI - Screening of dried plant seed extracts for adiponectin production activity and tumor necrosis factor-alpha inhibitory activity on 3T3-L1 adipocytes. AB - To search for dried plant seeds with potent anti-diabetes activity, we conducted a large scale screening for inhibitory activity on tumor necrosis factor-alpha and facilitating activity on adiponectin production in vitro. These activities in 3T3-L1 adipocytes were screened from ethanol extracts of 20 kinds of dried plant seed marketed in Japan. komatsuna (Brassica rapa var. perviridis), common bean (Phaseolus vulgaris L.), qing geng cai (Brassica rapa var. chinensis), green soybean (Glycine max), spinach (Spinacia oleracea L.) and sugar snap pea (Pisum sativum L.) markedly enhanced adiponectin production (11.3 ~ 12.7 ng/ml) but Japanese radish (Raphanus sativus), edible burdock (Arctium lappa L.), bitter melon (Momordica charantia) and broccoli (Brassica oleracea var. italica) did not (0.9 ~ 2.7 ng/ml). All adiponectin-production-enhancing seeds except spinach (2.7 pg/ml) and okra (Abelmoschus esculentus) (6.6 pg/ml) effectively decreased tumor necrosis factor-alpha levels (0.0 pg/ml). We further examined the effects on free radical scavenging activities in the dried seed extracts. Although scavenging activity correlated well with total phenolic content of samples, no correlation was observed with adiponectin production. These results point to the potential of dried seed extracts as a means to modify the activity of tumor necrosis factor alpha for the adiponectin production. PMID- 20717729 TI - Anemia in a cohort of men with macroprolactinomas: increase in hemoglobin levels follows prolactin suppression. AB - Men with hypogonadism tend to have low hemoglobin (HGB) levels. We have investigated a cohort of 36 consecutive male patients with macroprolactinomas to evaluate HGB during presentation and following treatment with cabergoline to suppress prolactin (PRL). Patients' mean age at diagnosis was 48 years, the mean adenoma size measured 31 mm. The median PRL at baseline was 1,969 ng/ml; the mean testosterone level was low, 1.5 ng/ml. PRL had been successfully normalized in all but six men by using cabergoline. Mean baseline HGB at diagnosis was 13.1 gr%. Sixteen patients had HGB <= 13 gr%, including 4 men with HGB <= 11.5 gr%. In the subgroup of 15 men with very low testosterone (<= 1 ng/ml), baseline HGB was 12.6 gr% compared with 13.5 gr% in patients with higher testosterone (P < 0.005). In 30 men in whom follow-up CBC data were available, mean baseline HGB increased from 13.2 to 13.9 gr% following PRL suppression by cabergoline. Baseline HGB levels inversely correlated with tumor size, reaching levels of 13.7 gr% in 10 men with macroprolactinomas of 10-20 mm in size, 13.0 gr% in 18 subjects with macroadenomas of 21-40 mm, and 12.4 gr% in 7 patients with giant prolactinomas (>40 mm). In 22 men with normal follow-up testosterone, current HGB levels measured 14.5 gr%, but only 12.8 gr% in 9 men with current low testosterone (P < 0.0005). In men with macroprolactinomas, anemia is common. It is associated with hypogonadism and tumor size, and improves following treatment that normalizes PRL and increases testosterone. PMID- 20717730 TI - Cumulative imaging radiation exposure following breast-conservation therapy. AB - INTRODUCTION: Radiation from medical imaging may induce cellular damage and increase the risk of cancer. While health care workers are restricted to an annual dose of 50 milliSieverts (mSv), the exposure to patients is not typically recorded. After breast-conservation therapy (BCT), patients are subjected to screening mammography, diagnostic breast imaging, and systemic surveillance imaging (SSI). Our objectives are to determine the cumulative radiation exposure of breast cancer survivors after completion of BCT, and to compare exposure levels in two historical cohorts. We also evaluated the indications of SSI. METHODS: We performed a retrospective study of 68 patients with stage I or II breast cancer who received BCT in 1997 or 2002. Cumulative radiation exposure during follow-up from all imaging attributable to the breast cancer diagnosis was recorded, including both breast and non-breast imaging. The indications for SSI were recorded. RESULTS: In the first 5 years after BCT, patients received a median annual dose of 0.92 mSv with no difference between the 1997 and 2002 cohorts. A median of 90% of radiation exposure was due to mammography. From 1997 to 2002, the percentage of patients receiving computed tomography (CT) scans increased. Additional SSI occurred in 65% of patients, with the majority of tests ordered in the asymptomatic patient. Patients with nodal positivity were more likely to receive SSI (p = 0.03). CONCLUSIONS: In the first 5 years after BCT, annual radiation exposure due to imaging was low. However, it seems prudent to consider the risks of radiation exposure when ordering potentially low-yield screening studies in asymptomatic patients. PMID- 20717732 TI - Sentinel lymph node biospy. PMID- 20717733 TI - Predicting individual prognosis for patients undergoing resection of colorectal liver metastases. PMID- 20717734 TI - Pancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal papillary mucinous neoplasms of the pancreas. AB - INTRODUCTION: There are no reliable markers of dysplasia in patients with incidentally discovered intraductal papillary mucinous neoplasms of the pancreas (IPMN). IPMN dysplasia may be associated with mucin protein (MUC) expression and histopathologic subtype. We hypothesize that MUC expression in cyst fluid and serum can identify lesions with high risk of malignancy. METHODS: Cyst fluid and serum were collected from 40 patients during pancreatectomy for IPMN between 2005 and 2009. Samples were grouped into low-risk (low-grade or moderate dysplasia, n = 21) and high-risk groups (high-grade dysplasia or carcinoma, n = 19). Mucin expression (MUC1, MUC2, MUC4, and MUC5AC) was assessed utilizing enzyme-linked immunosorbent assays. RESULTS: MUC2 and MUC4 cyst fluid concentrations were elevated in high-risk versus low-risk groups (10 +/- 3.0 ng/ml vs. 4.4 +/- 1.2 ng/ml, p = 0.03; 20.6 +/- 10.6 ng/ml vs. 4.5 +/- 1.4 ng/ml, p = 0.03, respectively). Corresponding serum samples revealed higher levels of MUC5AC in high-risk compared with low-risk patients (19.9 +/- 9.3 ng/ml vs. 2.2 +/- 1.1 ng/ml, p = 0.04). Histopathologic subtype was significantly associated with grade of dysplasia, and the intestinal subtype displayed increased MUC2 cyst fluid concentrations (13.8 +/- 6.5 ng/ml vs. 4.1 +/- 0.9 ng/ml, p = 0.02). CONCLUSIONS: In this study, high-risk IPMN showed elevated cyst fluid concentrations of MUC2 and MUC4, and increased serum levels of MUC5AC. High-risk IPMN also displayed a distinct mucin expression profile in specific histologic subtypes. These data, if validated, may allow surgeons to more appropriately select patients for operative resection. PMID- 20717735 TI - In vivo MRI tracking of cell invasion and migration in a rat glioma model. AB - PURPOSE: Malignant brain tumors are characterized by extensive infiltration into the normal brain tissue. Tumor migration is a complicated process which results from the interplay of a number of mechanisms, and the extent to which anatomic structure determined the migration pattern has not been extensively addressed. In the present study, we labeled C6 glioma cells with iron oxide nanoparticles and monitored the fate of the cells in vivo with magnetic resonance imaging (MRI). PROCEDURES: C6 glioma cells were labeled with ferumoxide-poly-L-lysine complexes and their migration in the brains of rats tracked by T2-weighted MRI. The same amount of iron-laden cells were implanted into the caudate nucleus (CN) and at the vicinity of anterior commissure (AC), respectively, and MRI was performed during the course of 20-day monitoring period to track tumor growth and migration. RESULTS: A clear tendency of tumor migration along the white matter fiber tracts was observed in the AC group, which is consistent with the previous reports; by contrast, tumor expanded to but remained confined within the boundary of right hemisphere in the CN group. CONCLUSION: We successfully demonstrated the ability of MRI to investigate the impact of anatomical structure on the glioma migration pathway in vivo. PMID- 20717736 TI - Effects of skin wrinkles, age and wetness on mechanical loads in the stratum corneum as related to skin lesions. AB - Finite element models of skin were developed to determine the effects of wetness, age, and wrinkles on mechanical strains and stresses in the stratum corneum (SC) as related to skin lesions. We modeled two geometries, young (0.12-mm-deep wrinkles) and aged (0.18-mm-deep wrinkles), and for each geometry, three loading conditions were applied (compression in a dry environment, compression and shear in dryness, and compression with shear in wetness). Effects of skin wrinkling were studied independently or while coupled with age-related mechanical property changes. For each simulation, we calculated the peak maximal shear strain and stress in the SC, peak shear stress on the skin surface, and volumetric exposure of the SC to potentially injurious shear stresses (<70 kPa). Compression and shear with wetness produced the highest skin surface loads. Volumetric exposure of aged skin to potentially injurious shear stresses was six times greater than in the young skin for these conditions. Deeper wrinkles caused elevated loads in the SC consistently for all outcome measures and independently of the age factor. Thinning and/or stiffening the SC increased both the surface and internal SC stresses. Our findings indicate that theoretically, wetness, skin aging, and/or skin wrinkling are all risk factors for skin lesions such as superficial pressure ulcers. PMID- 20717737 TI - Neuroimmune pharmacology from a neuroscience perspective. AB - The focus of this commentary is to describe how neuroscience, immunology, and pharmacology intersect and how interdisciplinary research involving these areas has expanded knowledge in the area of neuroscience, in particular. Examples are presented to illustrate that the brain can react to the peripheral immune system and possesses immune function and that resident immune molecules play a role in normal brain physiology. In addition, evidence is presented that the brain immune system plays an important role in mediating neurodegenerative diseases, the aging process, and neurodevelopment and synaptic plasticity. The identification of these mechanisms has been facilitated by pharmacological studies and has opened new possibilities for pharmacotherapeutic approaches to the treatment of brain disorders. The emerging field of neuroimmune pharmacology exemplifies this interdisciplinary approach and has facilitated the study of basic cellular and molecular events and disease states and opens avenues for novel therapies. PMID- 20717738 TI - Postprandial proximal gastric acid pocket in patients after Roux-en-Y gastric bypass. AB - INTRODUCTION: An unbuffered postprandial proximal gastric acid pocket (PPGAP) has been noticed in normal individuals and patients with gastroesophageal reflux disease (GERD). The role of gastric anatomy in the physiology of the PPGAP remains unclear. It is also unclear whether operations that control GERD, such as Roux-en-Y gastric bypass (RYGB) and Nissen fundoplication, change the PPGAP. AIMS: This study aims to analyze the presence of PPGAP in patients submitted to RYGB. METHODS: Fifteen patients who had a RYGB for morbid obesity (mean age 53 years, 14 females, mean time from operation 3 years) were studied. All patients were free of foregut symptoms. Patients underwent a high-resolution manometry to identify the location of the lower border of the lower esophageal sphincter (LBLES). A station pull-through pH monitoring was performed from 5 cm below the LBLES to the LBLES in increments of 1 cm in a fasting state and 10 min after a standardized fatty meal (40 g of chocolate, 50% fat). RESULTS: Acidity was not detected in the stomach of four patients before meal. After meal, PPGAP was not found in eight patients. In three patients, a PPGAP was noted with an extension of 1 to 3 cm. CONCLUSION: PPGAP is present in a minority of patients after RYGB; this finding may explain part of the GERD control after RYGB and that the gastric fundus may play a role in the genesis of the PPGAP. PMID- 20717739 TI - Single-incision laparoscopic endorectal pull-through (SILEP) for hirschsprung disease. AB - BACKGROUND: Over the last 15 years, the laparoscopic-assisted endorectal pull through procedure first described by Georgeson has become the standard treatment for Hirschsprung disease in many centers around the world. We report the first six patients who were operated using a single-incision endosurgical approach. METHODS: Six infants (one female) diagnosed with Hirschsprung disease underwent laparoscopic endorectal pull-through via a single 1 cm horizontal skin incision in the umbilicus. Firstly, laparoscopic seromuscular leveling biopsies of the rectum and sigmoid were obtained. The affected rectosigmoid colon and rectum was then mobilized distally beyond the peritoneal reflection, facilitating the subsequent perineal dissection, pull-through, and coloanal anastomosis. Operative variables were compared between single-incision and conventional laparoscopic endorectal pull-through. RESULTS: The patients' average age and weight was 28 days and 3.8 kg, respectively. Operative time ranged from 90 to 220 min, with a mean estimated blood loss of 3.7 ml. There were no intraoperative complications. Postoperatively, all six patients recovered uneventfully and were discharged home on full feeds after a median of 7 days. On follow-up, the patients had virtually no appreciable scar, were feeding well, stooling, and gaining weight appropriately. The results were similar to those of conventional laparoscopic endorectal pull-through. CONCLUSION: Although technically challenging, laparoscopic-assisted endorectal pull-through in infants with Hirschsprung disease can be performed safely through a single umbilical incision with good postoperative results and excellent cosmesis. PMID- 20717740 TI - Tumors arising at previous anastomotic site may have poor prognosis in patients with gastric stump cancer following gastrectomy. AB - INTRODUCTION: We analyzed the clinicopathological characteristics and outcomes of patients with gastric stump cancer (GSC) to identify important prognostic factors. PATIENTS AND METHODS: We retrospectively reviewed clinical reports of 34 patients with GSC treated at Kochi Medical School from 1982 to 2008 to analyze the clinical and pathological factors that influenced patient survival. RESULTS: The median interval between initial and second operation was 15.8 years; this interval was significantly longer in patients diagnosed originally with benign disease than in those with previous malignant disease. Histologically, the incidence of diffuse-type cancer was significantly prominent in patients with previous benign gastric disease than in those with previous malignant gastric disease. The overall 5-year survival rate was 53.3%, with presence of lymph node metastasis and pathological serosal invasion of the tumor associated with poor survival. The final analysis revealed tumor located at anastomosis, tumor size greater than 5 cm, serosal invasion, the presence of lymph node metastasis, and stage III or higher to be significantly associated with poor survival. CONCLUSIONS: Follow-up programs after gastrectomy should account for long latency periods of disease. Early detection, attentive observation of anastomotic site, and sufficient surgical resection were important influences on outcome for patients with GSC after Billroth I or Billroth II reconstruction. PMID- 20717742 TI - HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma. AB - HIV infection is associated with a much higher risk for the development of non Hodgkin lymphoma (AIDS-NHL). The principal causes of lymphomagenesis in HIV infected individuals are thought to be the loss of immune function seen in HIV infection, which results in the loss of immunoregulation of Epstein-Barr virus infected B cells, as well as HIV infection-associated immune dysregulation, including chronic B-cell activation. In this review, we discuss recent reports that further support the importance of these factors, and we highlight emerging evidence of different mechanisms that potentially drive lymphomagenesis in HIV infected individuals. PMID- 20717743 TI - Biology and pathophysiology of the new human retrovirus XMRV and its association with human disease. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a new human retrovirus originally identified in prostate cancer patients with a deficiency in the antiviral enzyme RNase L. XMRV has been detected with varying frequencies in cases of prostate cancer and chronic fatigue syndrome (CFS), as well as in a small proportion of healthy individuals. An etiologic link between XMRV infection and human disease, however, has yet to be established. Here, we summarize existing knowledge regarding the characteristics of XMRV replication, association of XMRV with prostate cancer and CFS, and potential mechanisms of XMRV pathophysiology. We also highlight several areas, such as the establishment of standardized assays and the development of animal models, as future directions to advance our current understanding of XMRV and its relevance to human disease. PMID- 20717744 TI - Mechanism of activation of PKB/Akt by the protein phosphatase inhibitor Calyculin A. AB - The protein phosphatase inhibitor calyculin A activates PKB/Akt to ~50% of the activity induced by insulin-like growth factor 1 (IGF1) in HeLa cells promoting an evident increased phosphorylation of Ser473 despite the apparent lack of Thr308 phosphorylation of PKB. Nevertheless, calyculin A-induced activation of PKB seems to be dependent on basal levels of Thr308 phosphorylation, since a PDK1 dependent mechanism is required for calyculin A-dependent PKB activation by using embryonic stem cells derived from PDK1 wild-type and knockout mice. Data shown suggest that calyculin A-induced phosphorylation of Ser473 was largely blocked by LY294002 and SB-203580 inhibitors, indicating that both PI3-kinase/TORC2 dependent and SAPK2/p38-dependent protein kinases contributed to phosphorylation of Ser473 in calyculin A-treated cells. Additionally, our results suggest that calyculin A blocks the IGF1-dependent Thr308 phosphorylation and activation of PKB, likely due to an enhanced Ser612 phosphorylation of insulin receptor substrate 1 (IRS1), which can be inhibitory to its activation of PI3-kinase, a requirement for PDK1-induced Thr308 phosphorylation and IGF1-dependent activation of PKB. Our data suggest that PKB activity is most dependent on the level of Ser473 phosphorylation rather than Thr308, but basal levels of Thr308 phosphorylation are a requirement. Additionally, we suggest here that calyculin A regulates the IGF1-dependent PKB activation by controlling the PI3-kinase associated IRS1 Ser/Thr phosphorylation levels. PMID- 20717745 TI - Diabetes-related alteration of occludin expression in rat blood-spinal cord barrier. AB - Occludin is an essential component of tight junctions, which are involved in controlling the integrity of the blood-brain barrier and blood-spinal cord barrier (BSCB). Diabetes-induced alteration of occludin in rat BSCB and the relationship between occludin level and disease course was examined. Diabetes was induced using streptozotocin. Occludin rat spinal cord mRNA levels were assessed by real-time quantitative RT-PCR. Protein levels were examined by western blot. Occludin expression in 1-month diabetic rats was significantly reduced compared to the controls (0.20 +/- 0.01 vs 1.00 +/- 0.01, respectively; P < 0.05). Expression was also significantly lower in the 3-month diabetic group (0.06 +/- 0.02; P < 0.01). Occludin protein levels of 1-month (0.53 +/- 0.01) and 3-month (0.31 +/- 0.01) diabetic rats were also significantly reduced compared to controls (0.91 +/- 0.06; P < 0.01 for both). Diabetes decreased BSCB occludin expression at the mRNA and protein level. This down-regulation appears to correlate with the course of the disease, and may be a causal factor of diabetes induced increase of BSCB permeability. PMID- 20717741 TI - Prospects of a novel vaccination strategy for human gamma-herpesviruses. AB - Due to the oncogenic potential associated with persistent infection of human gamma-herpesviruses, including Epstein-Barr virus (EBV or HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), vaccine development has focused on subunit vaccines. However, the results using an animal model of mouse infection with a related rodent virus, murine gamma-herpesvirus 68 (MHV-68, gammaHV-68, or MuHV-4), have shown that the only effective vaccination strategy is based on live attenuated viruses, including viruses engineered to be incapable of establishing persistence. Vaccination with a virus lacking persistence would eliminate many potential complications. Progress in understanding persistent infections of EBV and KSHV raises the possibility of engineering a live attenuated virus without persistence. Therefore, we should keep the option open for developing a live EBV or KSHV vaccine. PMID- 20717746 TI - The mechanism and characterization of learning and memory impairment in sleep deprived mice. AB - Objectives are to examine the effects of sleep deprivation (SD) on spatial learning and memory in mice, to determine how SD effects the expression of phosphorylated cyclic AMP responsive element binding protein (pCREB) in mouse hippocampus, and to explore the mechanism of influence of sleep deprivation on cognitive function. Twenty, 3-month-old female C57BL/6J mice were randomly assigned into two groups, the sleep deprivation group (SD, n = 10) and control group with normal sleep (CC, n = 10). The mice in SD group were deprived sleep by "gentle touch" for 20 days and then all the mice were subjected for Morris Water Maze test to determine the mean latency of escape (LE). Percentage of time spent in the target quadrant was calculated. Mouse hippocampus pCREB levels were quantified by western blot. Compared with CC group, SD mice had a significantly longer mean LE time (P < 0.05) and spent less time in the target quadrant (P < 0.05). Western blot revealed that hippocampus pCREB levels in the SD group were significantly lower than that in control group (0.71 +/- 0.03 vs 0.82 +/- 0.06, P < 0.01). The impairment in spatial learning and memory in sleep-deprived animals may be associated with the reduction of pCREB in the hippocampus. PMID- 20717747 TI - Treatment of trigeminal neuralgia with percutaneous glycerol injection into Meckel's cavity: experience in 4012 patients. AB - Percutaneous glycerol injection into Meckel's cavity is widely used to treat trigeminal neuralgia. Reports published to date summarized clinical experiences in small or intermediately sized groups of patients. The efficacy of this procedure in a large group of patients has not been evaluated so far. From December 1983 to November 2008, patients with primary trigeminal neuralgia were treated in our clinic using percutaneous glycerol injection into Meckel's cavity which was conducted according to the Hakanson's anterior puncture method with some modifications. In total, 4012 patients (2205 female) with a mean age of 56.5 (23-87) years were treated. The majority of patients (99.23%) experienced unilateral pain, while a small cohort of patients (31; 0.77%) had bilateral pain. The immediate success rate of the procedure was 97.1%. There was a significant (P < 0.01) positive correlation between the presence of cerebrospinal fluid (CSF) outflow and the curative effect. Follow-up was done in 3157 patients for the period of 1-25 years. The long-term success rate was 81.18%. No serious adverse effects were observed. The procedure is very effective and applicable to a wide variety of patients with trigeminal neuralgia. The presence of CSF outflow during puncture predicts better immediate and long-term outcomes. PMID- 20717749 TI - Desmopressin for the treatment of aspirin-induced platelet dysfunction. PMID- 20717748 TI - A comparison of EMG and muscle biopsy in ICU weakness. AB - BACKGROUND: Patients can become weak in ICU from various etiologies and mechanisms. Establishing the diagnosis is invaluable for prognostic determination and specific management. We evaluated the relative contributions of clinical, laboratory, electomyographic studies (EMG), and percutaneous muscle biopsy (MB) in determining the cause of muscular weakness that developed in a series of patients while in ICU. The principal objective is to determine the concordance between results of the EMG and MB studies in patients with ICU-acquired weakness. METHODS: We retrospectively reviewed hospital charts for clinical features, and results of laboratory investigations, EMG studies, and MB results in 11 consecutive patients who underwent both EMG and MB while in ICU. We excluded patients with previously diagnosed muscular weakness or neurological conditions prior to ICU admission. RESULTS: Electomyographic studies suggested axonal neuropathy in three cases; MB confirmed this in one case, but showed myopathic features in two. EMG showed myopathic features in two cases; MB confirmed this in both cases. EMG suggested neuromyopathy in four cases, confirmed by MB in one case only. One patient, subsequently diagnosed with myasthenia gravis with decrement on repetitive nerve stimulation and positive anti-acetylcholine receptor antibodies, had non-specific findings on MB. CONCLUSIONS: EMG and MB are complementary investigations. They agreed completely in four cases but in the rest of the cases there was uncertainty as to the primary process based on the results of electrophysiological studies. In only one case was there a clear discordance between electrophysiological studies and muscle biopsy. We suggest that muscle biopsy should be performed more frequently as it establishes the diagnosis and thus the prognosis with more certainty than EMG in some patients. EMG is much more difficult in the ICU and more susceptible to confounding technical factors, but remains indispensable for the diagnosis of neuromuscular transmission defects. PMID- 20717750 TI - Prospective, randomized trial of higher goal hemoglobin after subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: In patients with subarachnoid hemorrhage (SAH), higher hemoglobin (HGB) has been associated with better outcomes, but packed red blood cell (PRBC) transfusions with worse outcomes. We performed a prospective pilot trial of goal HGB after SAH. METHODS: Forty-four patients with SAH and high risk for vasospasm were randomized to goal HGB concentration of at least 10 or 11.5 g/dl. We obtained blinded clinical outcomes at 14 days (NIH Stroke Scale and modified Rankin Scale, mRS), 28 days (mRS), and 3 months (mRS), and blinded interpretation of brain MRI for cerebral infarction at 14 days. This trial is registered at www.stroketrials.org. RESULTS: Forty-four patients were randomized. Patients with goal HGB 11.5 g/dl received more PRBC units per transfusion [1 (1 2) vs. 1 (1-1), P < 0.001] and more total PRBC units [3 (2-4) vs. 2 (1-3), P = 0.045]. Prospectively defined safety endpoints were not different between groups. HGB concentration was different between study groups from day 4 onwards. The number of cerebral infarctions on MRI (6 of 20 vs. 9 of 22), NIH Stroke Scale scores at 14 days [1 (0-9.75) vs. 2 (0-16)], and rates of independence on the mRS at 14 days (65% vs. 44%) and 28 days (80% vs. 67%) were similar, but favored higher goal HGB (P > 0.1 for all). CONCLUSIONS: Higher goal hemoglobin in patients with SAH seems to be safe and feasible. A phase III trial of goal HGB after SAH is warranted. PMID- 20717751 TI - Acute intrathecal baclofen withdrawal: a brief review of treatment options. AB - BACKGROUND: Acute baclofen toxicity and withdrawal can present with a constellation of symptoms making differentiation between these two entities and other potential diagnoses challenging. Baclofen withdrawal is associated with numerous complications which may require neurocritical care expertise such as respiratory failure, refractory seizures, delirium, and blood pressure lability. METHODS: Case report and literature review. RESULTS: This case report discusses a case of intrathecal baclofen (ITB) withdrawal, focusing on the differential diagnosis for acute baclofen withdrawal and reviews the various options that exist to treat the symptoms of acute baclofen withdrawal such as benzodiazepines, propofol, skeletal muscle relaxants, and tizanidine. CONCLUSIONS: Critical care practitioners should be prepared to treat this potentially devastating and often refractory complication of ITB therapy. PMID- 20717752 TI - Trend in outcome and financial impact of subdural hemorrhage. AB - BACKGROUND: Little current data exists regarding outcome, cost, and length of stay (LOS) after subdural hemorrhage (SDH). We sought to examine predictors of discharge disposition, ICU and hospital LOS and direct, indirect, ICU, surgical, and diagnostic costs for SDH. METHODS: A retrospective review was conducted of 216 SDH patients, aged >18 years admitted to our hospital between 1/2001 and 12/2008. Discharge disposition was characterized as dead, poor or good. Multivariable logistic regression analysis was performed to identify predictors of disposition, LOS, and cost. RESULTS: Of 216 SDH patients, the median age was 74 (19-95), and the median admission Glasgow Coma Scale (GCS) was 14 (3-15). The SDH was characterized as acute in 14%, subacute in 44%, chronic in 12%, and mixed in 30%. Surgical evacuation was performed in 139 (64%) patients. Death occurred in 29 (13%) patients and poor disposition in 43 (20%). Significant predictors of death included age, admission GCS, and hospital LOS (P < 0.05). Longer hospital LOS was associated with poor disposition, while shorter ICU LOS was associated with good disposition (P < 0.01). Median hospital LOS was 8 (1-99) days. Median total direct costs for hospitalization were $10,670 ($907-238,856). ICU and hospital LOS were significant predictors of all measures of cost (P < 0.05). SDH size, chronicity, and surgical intervention were not predictors of any outcome. There was no significant change in any outcome variable between 2001 and 2008. CONCLUSIONS: Despite good admission neurological status, death or poor discharge disposition is common after SDH. LOS and costs remain high and have not improved in the last decade. PMID- 20717753 TI - Multiple drug resistance mechanisms in cancer. AB - Multiple drug resistance (multidrug resistance; MDR), a phenomenon whereby human tumours that acquire resistance to one type of therapy are found to be resistant to several other drugs that are often quite different in both structure and mode of action, has been recognised clinically for several decades. An important advance in our understanding of MDR came with the identification of P glycoprotein and other related transporters that were expressed in some cancer cells and could recognise and catalyse the efflux of diverse anticancer drugs from cells. A second advance came from an understanding of the mechanism of programmed cell death or apoptosis, leading to MDR mediated by increased to resistance to anticancer drug-induced apoptosis. A third advance came with the finding that the proliferation of human tumours was driven by a small population of self-renewing tumour cells, focussing attention on the MDR properties of these so-called tumour stem cells rather than on the cells that comprised the majority of the tumour population. A fourth advance was the delineation of features of the tumour microenvironment, including immunosuppression, which essentially provided tumour stem cells with an MDR phenotype. Most published work on the overcoming of MDR has concentrated on inhibition of drug transporters but the complexity of mechanisms contributing demands a broad strategy for the development of methods to overcome MDR in a clinical setting. PMID- 20717754 TI - Induction of lung epithelial cell transformation and fibroblast activation by Yunnan tin mine dust and their interaction. AB - Tumor-stroma interactions play a significant role in tumor development and progression. Our study employed an in vitro co-culture model of epithelial cells and fibroblasts to investigate the mechanism of and interaction between lung epithelial cell transformation and fibroblast activation induced by Yunnan tin mine dust. Epithelial cell transformation was evaluated using concanavalin A agglutination and anchorage-independent growth assays, and fibroblast activation was assessed via immunohistochemistry. The TGF-beta1/Smad pathway was monitored by Western blot analysis and ELISA. We found concanavalin A agglutination and anchorage-independent growth assays of dust-exposed epithelial cells were positive, dust-exposed fibroblasts expressed alpha-SMA, and during the mine dust induced tumorigenesis, TGF-beta1/Smad signaling pathway changed. In conclusion, Yunnan tin mine dust is able to induce the malignant transformation of bronchial epithelial cells and fibroblast activation. Epithelial cells are the main target of mine dust. Bronchial epithelial cell transformation and fibroblast activation are correlated and synergistic. Their interdependence is related to the TGF beta1/Smad signaling pathway. PMID- 20717755 TI - Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy. AB - Sarcomatoid renal cell cancer is associated with a very poor prognosis, characterized by rapid progression of advanced disease. We previously reported the outcome of 18 patients with advanced sarcomatoid renal cell cancer treated with a regimen consisting of doxorubicin, 50 mg/m2 and gemcitabine, 1,500-2,000 mg/m2, administered every two weeks with growth factor support (A/G). Among the 18 patients, there were two complete and 5 partial responses and two patients with stable disease of more than 6 months of duration. We now report long-term survival of 4 patients with stage IV sarcomatoid renal cell carcinoma treated with this regimen at the 1,500 mg/m2 dose of gemcitabine, and achieving complete response (2 patients), or rendered complete responders following surgery after maximum response (2 patients). The two complete responders are alive, disease free at 6+ and 8+ years after starting A/G, and the 2 patients rendered CR by surgery survived 31/2 and 6 years, respectively. Both died of progressive disease, one with clear cell recurrence, one with sarcomatoid recurrence. In summary, this regimen is associated with a high response rate, overall improvement in progression free survival and occasional meaningful long-term survival in a disease expected to be fatal within one year. PMID- 20717756 TI - The combination of stem cell markers CD133 and ABCG2 predicts relapse in stage I non-small cell lung carcinomas. AB - The aim of the study was to investigate the expression of two cancer stem cell markers CD133 and ATP-binding cassette superfamily G member 2 (ABCG2) in non small cell lung carcinomas (NSCLC) and evaluate their prognostic values for postoperative relapse. The expression levels of CD133 and ABCG2 in 145 stage I NSCLC tumors were detected by immunohistochemistry. Positive CD133 and ABCG2 expression was defined in 31.7 and 37.9% of the NSCLC tumors, respectively. Both stem markers alone did not correlate with any of the clinicopathological characteristics and were insufficient to predict recurrence after surgery. However, our results showed that the dual expression of CD133 and ABCG2 (CD133+/ABCG2+) status was an independent predictor of postoperative recurrence for patients with stage I NSCLC. Furthermore, CD133+/ABCG2+ NSCLC tumors (33 cases, 22.8%) had a significantly higher microvessel density and higher expression levels of angiogenic factors than the other subgroups. In conclusion, this study suggests that NSCLC patients with the dual expression of CD133 and ABCG2 have a high risk of early relapse and might benefit from anti-angiogenesis therapy. PMID- 20717757 TI - Isolated extramedullary relapse in childhood acute lymphocytic leukemia. AB - Although the vast majority of children with acute lymphocytic leukemia attain remission with modern therapies, an unacceptably high number will suffer a disease relapse. Both the duration of remission and the site of relapse are important prognostic factors. This review focuses on leukemic relapse isolated to sites outside the bone marrow (extramedullary sites). Data from cooperative study groups as well as large single institutions are reviewed with respect to the incidence of isolated extramedullary relapse as well as the outcome following relapse. The unique anatomic and physiologic properties of the testes and the central nervous system-the two most common sites of isolated extramedullary relapse-are discussed. Finally, the evolution of leukemia therapy is reviewed, bringing into focus the goals and challenges of future therapeutic endeavors. PMID- 20717758 TI - The effect of chitosan as internal or external coating on the 5-ASA release from calcium alginate microparticles. AB - The effect of chitosan as internal or external coating on the mesalamine (5-ASA) release from calcium alginate microparticles (CaAl) was studied, and a delayed release of 5-ASA system intended for colonic drug delivery was developed. The external chitosan coating was developed by immersion of wetted CaAl in chitosan solution and the internal coating by mixing 5-ASA with chitosan solution and drying before the preparation of CaAl. Both systems were coated with Acryl-EZE(r) using combined fluid bed coating and immersion procedure. The results showed that in phosphate medium (pH 7.5), chitosan as 5-ASA coating promotes a quick erosion process accelerating drug release, but chitosan as external coating (CaAlCS) does not increase the T (50) value compared with the microparticles without chitosan (CaAl). Chitosan as internal or external coating was not effective to avoid the quick 5-ASA release in acidic medium (pH 1.2). The presence of beta-glucosidase enzymes increases significantly the 5-ASA release for CaAl, while no effect was observed with chitosan as internal or external coating. Fourier transform infrared spectroscopy, thermogravimetric analysis, and X-ray data revealed that 5 ASA did not form a solid solution but was dispersed in the microparticles. The Acryl-EZE(r) coating of microparticles was effective because all the formulations showed a low release, less than 15%, of 5-ASA in acid medium at pH 1.2. Significant differences in the percentage of 5-ASA released between formulations were observed in phosphate buffer at pH 6.0. In phosphate buffer at pH 7.2, all the formulations released 100% of 5-ASA. PMID- 20717759 TI - Influences of sodium carbonate on physicochemical properties of lansoprazole in designed multiple coating pellets. AB - Lansoprazole (LSP), a proton-pump inhibitor, belongs to class II drug. It is especially instable to heat, light, and acidic media, indicating that fabrication of a formulation stabilizing the drug is difficult. The addition of alkaline stabilizer is the most powerful method to protect the drug in solid formulations under detrimental environment. The purpose of the study was to characterize the designed multiple coating pellets of LSP containing an alkaline stabilizer (sodium carbonate) and assess the effect of the stabilizer on the physicochemical properties of the drug. The coated pellets were prepared by layer-layer film coating with a fluid-bed coater. In vitro release and acid-resistance studies were carried out in simulated gastric fluid and simulated intestinal fluid, respectively. Furthermore, the moisture-uptake test was performed to evaluate the influence of sodium carbonate on the drug stability. The results indicate that the drug exists in the amorphous state or small (nanometer size) particles without crystallization even after storage at 40 degrees C/75% for 5 months. The addition of sodium carbonate to the pellet protects the drug from degradation in simulated gastric fluid in a dose-dependent manner. The moisture absorbed into the pellets has a detrimental effect on the drug stability. The extent of drug degradation is directly correlated with the content of moisture absorption. In conclusion, these results suggest that the presence of sodium carbonate influence the physicochemical properties of LSP, and the designed multiple coating pellets enhance the drug stability. PMID- 20717761 TI - The technetium shortage. PMID- 20717760 TI - A cell-based screen for inhibitors of protein folding and degradation. AB - Cancer cells are exposed to external and internal stresses by virtue of their unrestrained growth, hostile microenvironment, and increased mutation rate. These stresses impose a burden on protein folding and degradation pathways and suggest a route for therapeutic intervention in cancer. Proteasome and Hsp90 inhibitors are in clinical trials and a 20S proteasome inhibitor, Velcade, is an approved drug. Other points of intervention in the folding and degradation pathway may therefore be of interest. We describe a simple screen for inhibitors of protein synthesis, folding, and proteasomal degradation pathways in this paper. The molecular chaperone-dependent client v-Src was fused to firefly luciferase and expressed in HCT-116 colorectal tumor cells. Both luciferase and protein tyrosine kinase activity were preserved in cells expressing this fusion construct. Exposing these cells to the Hsp90 inhibitor geldanamycin caused a rapid reduction of luciferase and kinase activities and depletion of detergent-soluble v Src::luciferase fusion protein. Hsp70 knockdown reduced v-Src::luciferase activity and, when combined with geldanamycin, caused a buildup of v Src::luciferase and ubiquitinated proteins in a detergent-insoluble fraction. Proteasome inhibitors also decreased luciferase activity and caused a buildup of phosphotyrosine-containing proteins in a detergent-insoluble fraction. Protein synthesis inhibitors also reduced luciferase activity, but had less of an effect on phosphotyrosine levels. In contrast, certain histone deacetylase inhibitors increased luciferase and phosphotyrosine activity. A mass screen led to the identification of Hsp90 inhibitors, ubiquitin pathway inhibitors, inhibitors of Hsp70/Hsp40-mediated refolding, and protein synthesis inhibitors. The largest group of compounds identified in the screen increased luciferase activity, and some of these increase v-Src levels and activity. When used in conjunction with appropriate secondary assays, this screen is a powerful cell-based tool for studying compounds that affect protein synthesis, folding, and degradation. PMID- 20717762 TI - Measuring myocardium at risk in acute myocardial infarction--a continuing challenge. PMID- 20717763 TI - Neuroprotection of interleukin-6 against NMDA-induced apoptosis and its signal transduction mechanisms. AB - We have previously shown that interleukin-6 (IL-6)-protected neurons against the suppression of neuronal vitality and overload of intracellular Ca(2+) induced by glutamate or N-methyl-D: -aspartate (NMDA). Herein we provide further evidence for IL-6 neuroprotection against NMDA-induced apoptosis and explore the signal transduction mechanisms underlying the anti-apoptotic action of IL-6. Cerebellar granule neurons (CGNs) from postnatal 8-day infant rats were chronically exposed to IL-6 (40 or 120 ng/ml) for 8 days, and stimulated with NMDA (100 MUM) for 30 min. To observe the signaling pathways, we employed AG490 (5 or 10 MUM), an inhibitor of Janus kinases (JAKs), or LY294002 (5 or 10 MUM), an inhibitor of phosphatidylinositol 3-kinase (PI3K), to pretreat the CGNS together with IL-6. The levels of phosphorylation for the downstream effectors of JAKs and PI3K, i.e., phosphorylated STAT3 and Akt, were quantified by Western blot assay. In the cultured CGNs with various drug exposures, the expressions of Bcl-2, Bax, and caspase-3 were measured by real-time PCR and Western blot, and the percentage of apoptotic nuclei was tested by Hoechst 33342 staining. After the CGNs were chronically exposed to IL-6, NMDA stimulation led to an increase in the expression of Bcl-2 mRNA and a decrease in the expression of Bax and caspase-3 mRNAs and proteins when compared with those neurons lacking IL-6 exposure. IL-6 pretreatment of the neurons without NMDA stimulation concentration-dependently enhanced the expressions of Bcl-2 mRNA and protein while attenuating the expressions of Bax and caspase-3 mRNAs and proteins in comparison with control lacking any treatment. Furthermore, IL-6 prevented the increase in the percentage of apoptotic neurons induced by NMDA. The combined pretreatment of the CGNs with AG490 and IL-6 or with LY294002 and IL-6 reduced these anti-apoptotic effects of IL-6. Neither AG490 nor LY294002 exposure alone altered the expressions of Bcl-2, Bax, and cleaved caspase-3 proteins. IL-6 up-regulated the levels of phosphorylated STAT3 and Akt, and this was blocked by AG490 and LY294002, respectively. These results suggest that IL-6 protects neurons against NMDA induced apoptosis, and that the IL-6 neuroprotection is jointly mediated by JAK STAT3 and PI3K-Akt signaling pathways. PMID- 20717764 TI - Organophosphate ester flame retardant-induced acute intoxications in dogs. AB - INTRODUCTION: Flame retardants have wide industrial applications and are incorporated into articles found in automobiles and home environments, including seat cushions. These compounds differ widely chemically and in their toxic potential. We report here two cases involving dogs following ingestion of car seat cushions impregnated with organophosphate ester fire retardants. CASE REPORTS: Two case reports are presented. Two adult American Pit Bull dogs were presented at an emergency clinic with acute signs of central nervous system excitation including seizures. The most severely affected dog died 15 min after presentation, while the less affected dog fully recovered following treatment. In the second case, both a German Shepherd and a Rottweiler were found dead in the morning after they were left in a car overnight. A comprehensive toxicological analysis of samples from both cases revealed the presence of significant amounts (>2 ppm) of tris(2-chloroethyl)phosphate (TCEP) in stomach contents. This compound is a known inducer of epileptic seizures. Some other structurally related organophosphate ester compounds were found, and their role in the acute intoxications reported here is not known and remains to be determined. CONCLUSION: This is the first report linking acute deaths in dogs to the ingestion of car seat cushions found to contain large amounts of TCEP, an organophosphate ester compound. It is highly likely that this compound caused death through its known seizure-inducing activity. PMID- 20717765 TI - Analysis of beta-catenin alterations in colon tumors: a novel exon 3 mutation. AB - The great majority of colorectal cancers have defects in the Wnt signaling pathway indicating that this pathway has an important role in carcinogenesis. Alterations in the beta-catenin gene are observed in 10-50% of the patients with colorectal cancer. Mutations of the beta-catenin gene frequently occur in a region coding the protein phosphorylation domain harboring the Ser33/37/Thr41 and Ser45 sites and the inhibition of phosphorylation. Disruption of the beta-catenin regulation plays a critical role in tumor development. In this study, we analyzed expression and mutations of beta-catenin and phosphorylation of the Ser45 and Ser33/37/Thr41 residues in the tumors and matched normal tissue samples of patients with colorectal cancer. We did not observe significant differences in the phosphorylation rates between the patients and the control group. Samples displaying different levels of phosphorylation in the tumor and normal tissue were analyzed for exon 3 mutations of the beta-catenin gene. In three of 57 patients, a novel G to A substitution was found at codon 15. This nucleotide change has not been reported previously in the literature. beta-catenin protein levels and the degree of Ser45 or Ser33/37/Thr41 phosphorylation in tumor and normal tissue were not associated with the clinical parameters. Our results indicate that differences in the expression and phosphorylation of beta-catenin are not very frequent in colon cancer, but mutations in exon 3 of the beta catenin gene may be responsible for a significant proportion of the tumors. PMID- 20717770 TI - [George Soulie de Morant : the first French expert in acupuncture]. AB - George Soulie de Morant was consul in China, an expert of China, and later an acupuncturist. He was indeed the first in Europe to build a theoretical discourse, to make reference to Chinese medical texts, but also, to practice acupuncture. The life and work of George Soulie de Morant, eclectic and nonconformist, show how formal and institutional recognition do not always correspond to the social recognition of the value of expertise. PMID- 20717769 TI - [Wu Youxing and pestilential epidemics : a medical expert in late Ming China]. AB - FACED WITH THE TERRIBLE MORTALITY OF THE EPIDEMICS DURING THE LAST YEARS OF THE MING DYNASTY: (1368-1644) AND THE INEFFICACY OF THE TREATMENTS APPLIED, WU YOUXING: (ca 1580-1660), the author of the Wenyilun (Treatise on warm factor epidemics), completed in 1642, proposed a new etiological explanation of these diseases, with a highly critical attitude towards his predecessors. Reception to the book was mixed; it sometimes encountered opposition due to the audacity of some of Wu Youxing's conceptions, but also, most likely, to the discrepancy between the author's assertions and the failures in actual application. PMID- 20717774 TI - Gene therapy of salivary diseases. AB - For many years, our laboratory has been developing gene transfer approaches for salivary gland disorders that currently lack effective therapy. The purpose of this chapter is to describe key methods used in this developmental process. Specifically, we focus on one clinical condition, irradiation-induced salivary hypofunction, and address the choice of transgene and vector to be used, the construction of recombinant viral vectors, how vector delivery is accomplished, and methods for assessing vector function in vitro and in an appropriate animal model. PMID- 20717775 TI - Collection, storage, and processing of saliva samples for downstream molecular applications. AB - Saliva is an ideal translational research tool and diagnostic medium and is being used in novel ways to provide molecular biomarkers for a variety of oral and systemic diseases and conditions. The ability to analyze saliva to monitor health and disease is a highly desirable goal for oral health promotion and research. Saliva has been used to detect caries risk, periodontitis, oral cancer, breast cancer, salivary gland diseases, and systemic disorders such as hepatitis, HIV and HCV. Technology advancement has allowed high-throughput studies to be performed at a scale unrealized previously and is serving to advance the discovery and validation of salivary disease biomarkers. Of course, successful measurement of salivary analytes requires optimal collection, processing, and storage procedures and conditions. This chapter describes protocols for saliva collection, processing, and storage for the molecular analysis of salivary diagnostic constituents. PMID- 20717776 TI - Proteomic analysis of saliva: 2D gel electrophoresis, LC-MS/MS, and Western blotting. AB - Saliva harbors a wide spectrum of proteins that may reflect the health/disease status in the human body. Profiling of the proteins in saliva from a disease population can potentially yield valuable clinical parameters to be used for diagnosis and prognosis of the disease. Advances in proteomic technologies have enabled comprehensive profiling of protein expression in cells, tissue, and body fluids. When applied to readily accessible saliva samples from disease patients for biomarker study, such a global approach allows attaining the most discriminatory protein biomarkers that can best predict the disease status. In this chapter, we describe the protocols for proteomic analysis of saliva using 2D gel electrophoresis, Western blotting, and LC-MS/MS. PMID- 20717777 TI - Transcriptomic analyses of saliva. AB - Salivary biomarkers for diagnostic and prognostic assessments have become increasingly well established in recent years. Salivary mRNA transcriptomic analyses create a new paradigm in the emerging field for noninvasive molecular diagnosis. In this chapter, we will overview the development of sensitive and robust microarray and multiplex quantitative reverse transcriptase-PCR assays for the discovery and validation of mRNA biomarkers in human saliva. Total RNA isolated from human saliva is used for microarray profiling through Human Genome U133 Plus 2.0 and Exon 1.0 ST array platforms. A universal RNA linear amplification strategy was used to amplify RNA from nanogram scale followed by reverse transcription-PCR reaction, cleaned up enzymatically, and validated by quantitative PCR. Further, the integrity of RNA can be analyzed by the Agilent Bioanalyzer and quantified using a Nanodrop microvolume spectrophotometer. Using these invaluable technical tools, one can identify thousands of mRNA species in saliva. These methods indicate that salivary mRNA provides an efficient medium for biomarker discovery in oral and systemic diseases detection. PMID- 20717778 TI - The oral microbiota: general overview, taxonomy, and nucleic acid techniques. AB - Application of nucleic acid technology to the analysis of the bacterial diversity in the oral cavity in conditions of health and disease has not only confirmed the findings from early culture studies but also significantly expanded the list of oral inhabitants and candidate pathogens associated with the major oral diseases. Over 800 bacterial distinct species-level taxa have been detected in the oral cavity and recent studies using high-throughput technology suggest that the breadth of bacterial diversity can be much larger. This chapter provides an overview of the diversity and taxonomy of oral bacteria. Emphasis is also given on nucleic acid technologies that have been widely used for the study of the oral microbiota. PMID- 20717779 TI - Microbial community profiling using terminal restriction fragment length polymorphism (T-RFLP) and denaturing gradient gel electrophoresis (DGGE). AB - In their natural environments, microorganisms usually live in organized communities. Profiling analysis of microbial communities has recently assumed special relevance as it allows a thorough understanding of the diversity of the microbiota, its behavior over time, and the establishment of patterns associated with health and disease. The application of molecular biology approaches holds the advantage of including culture-difficult and as-yet-uncultivated phylotypes in the profiles, providing a more comprehensive picture of the microbial community. This chapter focuses on two particular techniques: the terminal restriction fragment length polymorphism (T-RFLP) and denaturing gradient gel electrophoresis (DGGE), both of which have been widely used in environmental studies and have been recently successfully used by the authors in the study of the oral microbial communities associated with conditions of health and disease. PMID- 20717780 TI - Protocols to study the physiology of oral biofilms. AB - The oral cavity harbors several hundred different bacterial species that colonize both hard (teeth) and soft tissues, forming complex populations known as microbial biofilms. It is widely accepted that the phenotypic characteristics of bacteria grown in biofilms are substantially different from those grown in suspensions. Because biofilms are the natural habitat for the great majority of oral bacteria, including those contributing to oral diseases, a better understanding of the physiology of adherent populations is clearly needed to control oral microbes in health and disease. In this chapter, we use oral streptococci as examples for studying the physiology of oral biofilms. PMID- 20717781 TI - Adhesion of yeast and bacteria to oral surfaces. AB - Colonization of surfaces in the human body by microorganisms is an early, essential, step in the initiation of infectious disease. We have developed in vitro assays to investigate interactions between yeast or bacterial cells and human tissues, fluids, or prostheses. Such assays can be used to identify the adhesins, ligands, and receptors involved in these interactions, for example by determining which components of the microbe or human tissue/fluid interfere with adherence in the assay. The assays can also be applied to finding ways of preventing adhesion, and subsequent disease, by investigating the effects of different conditions and added compounds on adherence in the in vitro assays. We describe six assays for measuring adhesion of the oral yeast Candida albicans, a common commensal and opportunistic pathogen, or the bacterium Staphylococcus epidermidis, which is not normally pathogenic but is known to form biofilms on medical prostheses. The assays described represent two approaches to investigating adhesion; retention at a fixed time point following liquid washes; and retention against a continuous flow of medium. PMID- 20717782 TI - Quantitative analysis of periodontal pathogens by ELISA and real-time polymerase chain reaction. AB - The development of analytical methods enabling the accurate identification and enumeration of bacterial species colonizing the oral cavity has led to the identification of a small number of bacterial pathogens that are major factors in the etiology of periodontal disease. Further, these methods also underpin more recent epidemiological analyses of the impact of periodontal disease on general health. Given the complex milieu of over 700 species of microorganisms known to exist within the complex biofilms found in the oral cavity, the identification and enumeration of oral periodontopathogens has not been an easy task. In recent years however, some of the intrinsic limitations of the more traditional microbiological analyses previously used have been overcome with the advent of immunological and molecular analytical methods. Of the plethora of methodologies reported in the literature, the enzyme-linked immunosorbent assay (ELISA), which combines the specificity of antibody with the sensitivity of simple enzyme assays and the polymerase chain reaction (PCR), has been widely utilized in both laboratory and clinical applications. Although conventional PCR does not allow quantitation of the target organism, real-time PCR (rtPCR) has the ability to detect amplicons as they accumulate in "real time" allowing subsequent quantitation. These methods enable the accurate quantitation of as few as 10(2) (using rtPCR) to 10(4) (using ELISA) periodontopathogens in dental plaque samples. PMID- 20717783 TI - Bacterial viability determination in a dentinal tubule infection model by confocal laser scanning microscopy. AB - Dentinal tubule invasion protects bacteria from chemo-mechanical disinfection and frequently results in root canal treatment failures. Enterococcus faecalis is a primary causative agent, particularly in persistent, asymptomatic, and chronic apical periodontitis. In order to assess and compare the efficacies of endodontic antimicrobial agents and application strategies, we have developed a convenient and robust method to measure bacterial viability and assess distribution in an ex vivo tubule infection model. Following infection and antimicrobial treatment of prepared ex vivo roots, the tubule bacteria are exposed to nucleic acid-binding fluorescent stains (LIVE/DEAD BacLight stain), sectioned, and examined by confocal laser scanning microscopy. The proportion of red-fluorescing (dead) and green-fluorescing (live) bacteria is then visualized in situ and quantified with image analysis software. PMID- 20717784 TI - Characterization of anti-competitor activities produced by oral bacteria. AB - Most bacteria in nature exist in multispecies communities known as biofilms. In the natural habitat where resources (nutrient, space, etc.) are usually limited, individual species must compete or collaborate with other neighboring species in order to perpetuate in the multispecies community. The human oral cavity is colonized by >700 microbial species known as the indigenous microflora. This indigenous flora normally maintains an ecological balance through antagonistic as well as mutualistic interspecies interactions. However, environmental perturbation may disrupt this balance, leading to overgrowth of pathogenic species, which could in turn initiate diseases such as dental caries (tooth decay) and periodontitis (gum disease). Understanding the mechanisms of diversity maintenance may help development of novel approaches to manage these "polymicrobial diseases." In this chapter, we will focus on a well-characterized form of biochemical warfare: bacteriocins produced by Streptococcus mutans, a primary dental caries pathogen, and H(2)O(2) produced by Streptococcus sanguinis, an oral commensal. We will describe detailed methodologies on the competition assay, isolation, purification, and characterization of bacteriocins. PMID- 20717785 TI - Natural transformation of oral streptococci. AB - Natural transformation is found in most groups of oral streptococci, including the mitis, the anginosus, and the mutans groups. This ability has been applied as a powerful tool to explore streptococcal gene functions and regulatory pathways, particularly in Streptococcus mutans and Streptococcus gordonii. The range of strains and species amenable to transformation has expanded in recent years with the identification of several competence-stimulating peptide signals (CSPs). In this chapter we present protocols for natural transformation in strains found in the three groups of transformable oral streptococci, with focus on methods using synthetic CSPs. We also include suggestions on how to optimize competence conditions for individual species or strains. PMID- 20717786 TI - Use of in vivo-induced antigen technology (IVIAT) to identify virulence factors of Porphyromonas gingivalis. AB - Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with the initiation and progression of adult periodontal disease. The pathogenicity of P. gingivalis is multifaceted and the infection process is influenced by both microbial and host factors. It is generally accepted that genes of a pathogen that are specifically expressed during infection are likely to be important for pathogenicity. Numerous technologies have been developed to identify these genes. A novel strategy known as in vivo-induced antigen technology (IVIAT) avoids the use of animal models and utilizes serum from patients who have experienced disease caused by the pathogen of interest. While a number of putative virulence factors have been described for P. gingivalis, the identity, relevance, and mechanisms of action of virulence factors that actually provide a selective advantage to the organism in the oral cavity of diseased patients is still unclear. Here we describe the IVIAT protocol for identification of in vivo induced genes of P. gingivalis, which can be adapted with few modifications to any microbial pathogen. PMID- 20717787 TI - Oral bacterial genome sequencing using the high-throughput Roche Genome Sequencer FLX System. AB - For over 30 years, the chain termination method of DNA sequencing (commonly known as Sanger sequencing) has been the mainstay of any DNA sequencing project. In the past, whole-genome sequencing employing exclusively Sanger chemistry has been a labor-intensive and costly exercise and an option unfeasible for the average research group. However, within the last 4 years, the introduction of three high throughput sequencing technologies (454, SOLiD, and Illumina) has revolutionized genomics by facilitating unprecedented levels (up to gigabasepairs) of reliable DNA sequence output in a relatively short time frame and at a much lower cost per sequenced basepair. Here, we provide laboratory and bioinformatic protocols that will allow the average research group to undertake high-throughput sequencing of oral bacterial genomes using the Roche Genome Sequencer FLX System which employs 454 pyrosequencing technology. PMID- 20717788 TI - Use of a yeast-based membrane protein expression technology to overexpress drug resistance efflux pumps. AB - Azole antifungal drugs are used widely to treat people with oral fungal infections. Unfortunately, fungi can develop resistance to these drugs. This resistance can be due to the overexpression or mutation of cytochrome P450 14alpha-lanosterol demethylase, also known as ERG11 or CYP51, and/or the overexpression of membrane-located multidrug efflux pumps. We have developed a heterologous membrane protein expression system that can be used to study the structure and function of these proteins in the non-pathogenic, genetically stable, and versatile eukaryotic model organism, Saccharomyces cerevisiae. In this chapter we describe the techniques used to express the Candida albicans efflux pump Cdr1p in S. cerevisiae. PMID- 20717789 TI - Explant culture of embryonic craniofacial tissues: analyzing effects of signaling molecules on gene expression. AB - The in vitro culture of embryonic tissue explants allows the continuous monitoring of growth and morphogenesis at specific embryonic stages. The functions of soluble regulatory molecules can be examined by adding them into culture medium or by introducing them with beads to specific locations in the tissue. Gene expression analysis using in situ hybridization, quantitative PCR, and reporter constructs can be combined with organ culture to examine the functions of the regulatory molecules. PMID- 20717790 TI - A method to isolate, purify, and characterize human periodontal ligament stem cells. AB - Human periodontal ligament stem cells (PDLSCs) are a unique population of mesenchymal stem cells (MSCs) which demonstrate the capacity to generate cementum and periodontal ligament-like structures in vivo. As such, PDLSCs represent a promising cell-based therapy in reconstructive dentistry for the treatment of periodontal disease. The present chapter describes two methods for isolating PDLSCs from human PDL tissue including traditional plastic adherence and immunomagnetic selection based on the expression of MSC-associated surface markers STRO-1 antigen, CD146 (MUC-18), CD29 (integrin beta-1), CD44, and CD106 (VCAM-1). Although no single antibody demonstrates specificity for MSCs, isolation based on the expression of individual markers results in homogeneous preparations of PDLSCs. Methods to further characterize the immunophenotype and multipotent capacity of PDLSCs to differentiate into adipocytes, osteoblast- and cementoblast-like cells in vitro, and cementum- and periodontal ligament-like tissues in vivo are also described. PMID- 20717791 TI - Preclinical methods for the evaluation of periodontal regeneration in vivo. AB - For the determination of key factors or devices that promote periodontal regeneration, preclinical investigations using in vivo animal models are critical for evaluating the biological responses before human clinical trial testing. In this chapter, we provide an overview on the commonly used preclinical animals for the study of reconstructive procedures to promote bone and soft tissue repair of tooth-supporting periodontal defects. Steps are provided on the animal management for evaluation of outcome measures using descriptive histology, histomorphometry, three-dimensional imaging, and safety assessments. The use of these key measures of periodontal regeneration should aid investigators in the selection of appropriate surrogate endpoints to be utilized in the clinical arena, which are not practical or ethical in humans. These methods will prepare investigators and assist them in identifying endpoints that can then be adapted to human clinical trial planning. PMID- 20717792 TI - Proteomic analysis of dental tissue microsamples. AB - Improved understanding of dental enamel development will benefit not only dentistry but also biomedicine more generally. Rat and mouse models of enamel development are relatively well characterized and experimentally powerful. However, the diminutive size of murine teeth makes them difficult to study using standard proteomic approaches. Here we describe gel-based proteomic methods that enable parallel quantification, identification, and functional characterization of proteins from developing rat and mouse teeth. These refined methods are also likely to be applicable to other scarce samples. PMID- 20717793 TI - Immunological techniques: ELISA, flow cytometry, and immunohistochemistry. AB - Techniques to analyze the host immune response elicited by the presence of oral microorganisms and their products are central to our understanding of the local and systemic effects of oral diseases. This immune response has been extensively investigated for periodontal disease. The local response may result in lesions involving the gingival tissues and depending upon host susceptibility and microbial virulence may lead to local tissue destruction. More recently, however, the importance of the systemic inflammatory and immune response to oral organisms has been recognized. These systemic responses have been associated with an increased risk for cardiovascular disease, diabetes, and preterm low birth weight. A number of techniques are used extensively by researchers investigating humoral and cellular immune responses to oral organisms both in local oral tissues and fluids and systemically in peripheral blood. These are enzyme-linked immunosorbent assay (ELISA) to quantify specific antibody and cytokines in serum, gingival crevicular fluid (GCF), and saliva; characterization of T cells from peripheral blood and gingival tissues using flow cytometry; and immunohistological analysis of the inflammatory cell infiltrate in gingival tissues. PMID- 20717794 TI - Analysis of immune responses to purified recombinant antigens of periodontal pathogens. AB - The accumulating knowledge about host-pathogen interactions in infectious diseases shows how the immune system interfaces with pathogens, and thus, helps us in understanding the pathogenesis of diseases and improving their treatment. Purified antigens are indispensable while investigating the immune response in both innate and acquired immunities. It is ideal to use native antigens purified from the host organisms in native conditions that sustain their biological activity completely. However, purification of native antigens, especially on a large scale, is technically difficult and generally time consuming. Purifying protein as a peptide-tagged fusion protein is an effective approach. Purification of a recombinant protein engineered to incorporate a polyhistidine tag at either the carboxyl or amino terminus is an established method, and it can be easily modified to obtain optimal results under different conditions. Heat-shock proteins were highly conserved during evolution and are highly homologous between prokaryotic and eukaryotic cells. Their molecular mimicry might have roles in the pathogenesis of chronic inflammatory diseases. We successfully generated histidine-tagged recombinant heat-shock proteins from the periodontopathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. The recombinant proteins allowed us to evaluate the immune response to these antigens in periodontitis patients. PMID- 20717795 TI - Single-strand conformation polymorphism analysis for the diagnosis of T-cell clonality in periodontal disease. AB - T cells recognize antigens via the T-cell receptor (TCR). Diversity in antigen recognition by T cells is generated in part by the recombination of V, (D), J, and C segments of the TCR. It is further enhanced by the N region, in addition to non-germline-encoded nucleotides at the V-(D)-J junction. It is generally believed that each T cell bears a distinct clonotype of TCR and that each clonotype is responsible for an antigen-specific T-cell response. T-cell clonal expansion has been detected in the peripheral blood or the disease-affected sites in patients with infections, autoimmune diseases, malignancy, and post transplantation complications. Since antigen stimulation of T cells induces the proliferation of specific T cells, clonal T-cell expansion is considered to be a result of an antigen-specific immune response. For the analysis of such antigen specific T cells, it is common to use their specific antigens if they are known. However, there are many diseases, such as periodontal diseases, in which there are a number of putative pathogenic antigens involved. In these circumstances, the detection of clonally expanded T cells is an effective method to evaluate whether antigen-specific immune responses are involved, since only a few clonally expanded T cells are detected in healthy individuals. In addition, the characterization of any clonally expanded T cells that are detected would further promote the understanding of the disease mechanisms. By using single-strand conformation polymorphism (SSCP) analysis, we demonstrated that oligoclonal T cell accumulation was present in periodontitis lesions, in contrast to a heterogeneous T-cell population in the peripheral blood. SSCP is a powerful tool for analyzing specific T-cell responses both in vitro and in vivo. PMID- 20717796 TI - Real-time PCR focused-gene array profiling of gingival and periodontal ligament fibroblasts. AB - The techniques for the establishment of primary gingival and periodontal ligament fibroblast cultures have been well established for over 30 years. It is only more recently, with the commercial availability of real-time PCR (RT-PCR) gene arrays that the expression profiles of up to 84 genes can be carried out simultaneously. Each focused panel of genes can identify the up- or down-regulation of genes associated with any one of over 100 biological pathways or specific disease states. Fibroblasts for RNA extraction and subsequent gene expression analysis can be collected under various experimental conditions and stored in RNA preserving solution (e.g., RNAlater) for processing at a later date or extracted immediately. The "gold standard" method for the extraction of RNA from fibroblasts for RT-PCR purposes is the TRIzol reagent method. With the addition of a spin-column clean-up step, any phenol carried over from the TRIzol step is removed, thus ensuring a high yield of quality RNA. The RNA is then reverse transcribed to cDNA and analyzed using the RT-PCR focused-gene arrays. Data analysis is made easy using on-line array analysis software packages. PMID- 20717797 TI - The use of gene arrays in deciphering the pathobiology of periodontal diseases. AB - Gene expression profiling, i.e., the systematic cataloging of messenger RNA sequences in a cell population, organ, or tissue sample, is a powerful means of generating comprehensive genome-level data sets on complex diseases. We have recently applied a systematic transcriptome-based approach in the study of healthy and diseased gingival tissues, as well in the response of peripheral blood mononuclear cells after periodontal therapy. Our data indicate that both the gingival and the circulating transcriptomes correlate with discernible phenotypic characteristics and may further our understanding of the pathobiology of periodontitis. In this chapter, we outline the laboratory steps required for the processing of gingival tissue and blood samples in view of hybridization with whole-genome microarrays. PMID- 20717798 TI - Bioinformatics techniques in microarray research: applied microarray data analysis using R and SAS software. AB - Exploration of the underlying biological mechanisms of disease is useful for many purposes such as the development of novel treatment modalities in addition to informing on-going risk factor research. DNA-microarray technology is a relatively recent and novel approach to conducting genome-wide gene expression studies to identify previously unknown biological pathways associated with disease. The copious data arising from microarray experiments is not conducive to traditional analytical approaches. Beyond the analytical challenges, there are equally important issues related to the interpretation and presentation of results. This chapter outlines appropriate techniques for analyzing microarray data in a fashion that also yields a list of top genes with differential expression in a given experiment. Derivatives of the top genes list can be used as a starting point for the presentation of study results. The list also serves as the basis for additional techniques related to enhanced interpretation and presentation of results. All analyses described in this chapter can be performed using relatively limited computational resources such as a lap top PC with at least 2.0 GB of memory and 2.0 GHz of processing speed. PMID- 20717799 TI - A core collection and mini core collection of Oryza sativa L. in China. AB - The extent of and accessibility to genetic variation in a large germplasm collection are of interest to biologists and breeders. Construction of core collections (CC) is a favored approach to efficient exploration and conservation of novel variation in genetic resources. Using 4,310 Chinese accessions of Oryza sativa L. and 36 SSR markers, we investigated the genetic variation in different sized sub-populations, the factors that affect CC size and different sampling strategies in establishing CC. Our results indicated that a mathematical model could reliably simulate the relationship between genetic variation and population size and thus predict the variation in large germplasm collections using randomly sampled populations of 700-1,500 accessions. We recommend two principles in determining the CC size: (1) compromising between genetic variation and genetic redundancy and (2) retaining the main types of alleles. Based on the most effective scheme selected from 229 sampling schemes, we finally developed a hierarchical CC system, in which different population scales and genetic diversities allow a flexible use of genetic resources. The CC, comprising 1.7% (932) of the accessions in the basic collection, retained more than 85% of both the SSR and phenotypic variations. A mini core collection, comprising 0.3% (189) of the accessions in the basic collection, retained 70.65% of the SSR variation and 76.97% of the phenotypic variation, thus providing a rational framework for intensive surveys of natural variation in complex traits in rice genetic resources and hence utilization of variation in rice breeding. PMID- 20717800 TI - Visuomotor adaptation and proprioceptive recalibration in older adults. AB - Previous studies have shown that both young and older subjects adapt their reaches in response to a visuomotor distortion. It has been suggested that one's continued ability to adapt to a visuomotor distortion with advancing age is due to the preservation of implicit learning mechanisms, where implicit learning mechanisms include processes that realign sensory inputs (i.e. shift one's felt hand position to match the visual representation). The present study examined this proposal by determining if changes in sense of felt hand position (i.e. proprioceptive recalibration) follow visuomotor adaptation in older subjects. As well, we examined the influence of age on proprioceptive recalibration by comparing young and older subjects' estimates of the position at which they felt their hand was aligned with a visual reference marker before and after aiming with a misaligned cursor that was gradually rotated 30 degrees clockwise of the actual hand location. On estimation trials, subjects moved their hand along a robot-generated constrained pathway. At the end of the movement, a reference marker appeared and subjects indicated if their hand was left or right of the marker. Results indicated that all subjects adapted their reaches at a similar rate and to the same extent across the reaching trials. More importantly, we found that both young and older subjects recalibrated proprioception, such that they felt their hand was aligned with a reference marker when it was approximately 6 degrees more left (or counterclockwise) of the marker following reaches with a rotated cursor. The leftward shift in both young and older subjects' estimates was in the same direction and a third of the extent of adapted movement. Given that the changes in the estimate of felt hand position were only a fraction of the changes observed in the reaching movements, it is unlikely that sensory recalibration was the only source driving changes in reaches. Thus, we propose that proprioceptive recalibration combines with adapted sensorimotor mappings to produce changes in reaching movements. From the results of the present study, it is clear that changes in both sensory and motor systems are possible in older adults and could contribute to the preserved visuomotor adaptation. PMID- 20717820 TI - Nasal polyps with metaplastic ossification: CT and MR imaging findings. AB - INTRODUCTION: Metaplastic ossification is a rare event in nasal polyps. The purpose of this study was to review the computed tomography (CT) and magnetic resonance (MR) imaging findings of nasal polyps with metaplastic ossification. METHODS: CT (n=5) and MR (n=3) images of five patients (four men and one woman; mean age, 59 years) with surgically proven nasal polyp with metaplastic ossification were retrospectively reviewed. The location and morphologic characteristics of metaplastic ossification were documented as well. RESULTS: All lesions were seen as lobulated (n=3), ovoid (n=1), or dumbbell-shaped (n=1) benign-looking masses with a mean size of 3.7 cm (range, 2.4-6.5 cm), located unilaterally in the posterior nasal cavity and nasopharynx (n=2), posterior nasoethmoidal tract (n=2), and maxillary sinus and nasal cavity (n=1). Compared with the brain stem, the soft tissue components of all lesions demonstrated isoattenuation on precontrast CT scans, slight hypointensity on T1-weighted MR images, and hyperintensity on T2-weighted MR images. On contrast-enhanced MR images, heterogeneous enhancement with marked peripheral enhancement was seen in two and homogeneous moderate enhancement in one. All lesions contained centrally located radiodense materials on CT scans, the shape of which was multiple clustered in three, single nodular in one, and single large lobulated in one. CONCLUSION: Although rare, metaplastic ossification can occur within nasal polyps. The possibility of its diagnosis may be raised when one sees a benign looking sinonasal mass with centrally located radiodense materials on CT scans. MR imaging may be useful when mycetoma or inverted papilloma cannot be ruled out on CT scans. PMID- 20717821 TI - Reversible bilateral hypacusis after aneurysmal subarachnoid hemorrhage. PMID- 20717822 TI - Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr positive tumours. AB - PURPOSE: Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His Sta-Leu-NH(2) via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as (111)In and (68)Ga. METHODS: RM2 was synthesized on a solid support and evaluated in vitro in PC-3 cells. IC(50) and K(d) values were determined. The antagonist potency was evaluated by immunofluorescence-based internalization and Ca(2+) mobilization assays. Biodistribution studies were performed in PC-3 and LNCaP tumour-bearing mice with (111)In-RM2 and (68)Ga-RM2, respectively. PET/CT studies were performed on PC-3 and LNCaP tumour-bearing nude mice with (68)Ga-RM2. RESULTS: RM2 and (111)In-RM2 are high-affinity and selective ligands for the GRP receptor (7.7 +/- 3.3 nmol/l for RM2; 9.3 +/- 3.3 nmol/l for (nat)In-RM2). The potent antagonistic properties were confirmed by an immunofluorescence-based internalization and Ca(2+) mobilization assays. (68)Ga- and (111)In-RM2 showed high and specific uptake in both the tumour and the pancreas. Uptake in the tumour remained high (15.2 +/- 4.8%IA/g at 1 h; 11.7 +/- 2.4%IA/g at 4 h), whereas a relatively fast washout from the pancreas and the other abdominal organs was observed. Uptake in the pancreas decreased rapidly from 22.6 +/- 4.7%IA/g at 1 h to 1.5 +/- 0.5%IA/g at 4 h. CONCLUSION: RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that (111)In-RM2 and (68)Ga-RM2 are ideal candidates for clinical SPECT and PET studies. PMID- 20717823 TI - Functional oestrogen receptor alpha imaging in endometrial carcinoma using 16alpha-[18F]fluoro-17beta-oestradiol PET. AB - PURPOSE: To investigate the correlation between uptake of 16alpha-[(18)F]fluoro 17beta-oestradiol (FES) and expression of oestrogen receptors as well as other related immunohistochemistry markers, positron emission tomography (PET) was performed in patients with endometrial carcinoma before surgery. METHODS: Nineteen patients with endometrioid adenocarcinoma underwent preoperative PET studies with FES and 2-[(18)F]fluoro-2-deoxy-D: -glucose (FDG). Standardized uptake values (SUVs) for each tracer and the regional FDG to FES SUV ratio were calculated using images after coregistration. PET values were compared with postoperative stage, differentiation grade and immunohistochemical scores including oestrogen receptor subtypes (ERalpha, ERbeta), progesterone receptor B (PR-B), Ki-67 and glucose transporter 1 (GLUT1). RESULTS: FES uptake showed a significantly positive correlation with expression of ERalpha. The FDG to FES ratio showed a significantly negative correlation with expression of ERalpha and PR-B. The FES uptake and FDG to FES ratio did not correlate with expression of ERbeta, Ki-67 or GLUT1. FDG uptake was not correlated with any of the immunohistochemical scores. The PR-B score was strongly correlated with the ERalpha score. Well-differentiated carcinoma (grade 1) showed a significantly higher FES uptake and significantly lower FDG to FES ratio than moderately or poorly differentiated carcinoma (grade 2-3). None of the PET parameters were significantly different between advanced-stage carcinoma (>= stage IB) and early stage carcinoma (IA) based on the Federation International de Gynecologie et d'Obstetrique (FIGO) staging classification. Differentiation grade was the most closely correlated parameter to FES uptake and FDG to FES ratio by multivariate analyses. CONCLUSION: FES PET combined with FDG would be useful for non-invasive evaluation of ERalpha distribution, as well as ERalpha function, which reflects differentiation grade in endometrial carcinoma. PMID- 20717824 TI - Hybrid cardiac imaging: SPECT/CT and PET/CT. A joint position statement by the European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC). AB - Improvements in software and hardware have enabled the integration of dual imaging modalities into hybrid systems, which allow combined acquisition of the different data sets. Integration of positron emission tomography (PET) and computed tomography (CT) scanners into PET/CT systems has shown improvement in the management of patients with cancer over stand-alone acquired CT and PET images. Hybrid cardiac imaging either with single photon emission computed tomography (SPECT) or PET combined with CT depicts cardiac and vascular anatomical abnormalities and their physiologic consequences in a single setting and appears to offer superior information compared with either stand-alone or side-by-side interpretation of the data sets in patients with known or suspected coronary artery disease (CAD). Hybrid systems are also advantageous for the patient because of the single short dual data acquisition. However, hybrid cardiac imaging has also generated controversy with regard to which patients should undergo such integrated examination for clinical effectiveness and minimization of costs and radiation dose, and if software-based fusion of images obtained separately would be a useful alternative. The European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC) in this paper want to present a position statement of the institutions on the current roles of SPECT/CT and PET/CT hybrid cardiac imaging in patients with known or suspected CAD. PMID- 20717825 TI - Differentiation of hepatocellular adenoma and focal nodular hyperplasia using 18F fluorocholine PET/CT. AB - The aim of this pilot study was to evaluate the use of PET/CT with (18)F fluorocholine in the differentiation of hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH). Patients with liver lesions larger than 2 cm suspicious for HCA or FNH were prospectively included. All patients underwent PET/CT with (18)F-fluorocholine and histopathological diagnosis was obtained by either liver biopsy or surgery. The ratios between the maximum standardized uptake value (SUV) of the lesion and the mean SUV of normal liver parenchyma were calculated and a receiver operating characteristic (ROC) curve analysis was performed. Ten patients with FNH and 11 with HCA were included. The mean SUV ratio was 1.68+/-0.29 (+/-SD) for FNH and 0.88+/-0.18 for HCA (p<0.001). An SUV ratio cut-off value between 1.12 and 1.22 differentiated patients with FNH from those with HCA with 100% sensitivity and 100% specificity. This pilot study showed that PET/CT with (18)F-fluorocholine can differentiate HCA from FNH. PMID- 20717826 TI - Diagnostic and prognostic impact of 18F-FDG PET/CT in follicular lymphoma. AB - PURPOSE: The aim of this study was to assess the usefulness of positron emission tomography/computed tomography in staging, prognosis evaluation and restaging of patients with follicular lymphoma. METHODS: A retrospective study was performed on 45 patients with untreated biopsy-proven follicular lymphoma who underwent 18F fluorodeoxyglucose PET/CT (FDG PET/CT) and CT before and after chemoimmunotherapy induction treatment (rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone). RESULTS: PET/CT detected more nodal (+51%) and extranodal (+89%) lesions than CT. PET/CT modified Ann Arbor staging in eight patients (18%). Five patients (11%) initially considered as being early stage (I/II) were eventually treated as advanced stage (III/IV). In this study, an initial PET/CT prognostic score was significantly more accurate than the Follicular Lymphoma International Prognostic Index score in identifying patients with poor prognosis (i.e. patients with incomplete therapeutic response or early relapse). The accuracy of PET/CT for therapeutic response assessment was higher than that of CT (0.97 vs 0.64), especially due to its ability to identify inactive residual masses. In addition, post-treatment PET/CT was able to predict patients' outcomes. The median progression-free survival was 48 months in the PET/CT-negative group as compared with 17.2 months for the group with residual uptake (p<10(-4)). CONCLUSION: FDG PET/CT is useful for staging and assessing the prognosis and therapeutic response of patients with follicular lymphoma. PMID- 20717827 TI - A case of non-cardiogenic acute pulmonary edema in a patient with POEMS syndrome associated pulmonary arterial hypertension. PMID- 20717828 TI - Diagnostic accuracy of whole-body MRI/DWI image fusion for detection of malignant tumours: a comparison with PET/CT. AB - OBJECTIVE: To prospectively evaluate the diagnostic accuracy of whole-body T2 weighted (wbT2), whole-body diffusion-weighted imaging (wbDWI) and wbT2/wbDWI image fusion for malignant tumour detection compared with PET/CT. METHODS: Sixty eight patients (44 men; 60 +/- 14 years) underwent PET/CT for staging of malignancy and were consecutively examined by 1.5-Tesla MRI including wbT2 and wbDWI. Two radiologists independently assessed wbDWI, wbT2, wbT2 + wbDWI (side-by side) and wbT2 + wbDWI + wbT2/wbDWI image fusion for the presence of malignancy. PET/CT served as a reference standard. RESULTS: PET/CT revealed 374 malignant lesions in 48/64 (75%) patients. Detection rates and positive predictive value (PPV) of wbT2 and wbDWI alone were 64% and 84%, and 57% and 93%, respectively. Detection rates and PPV of wbT2 and wbDWI for side-by-side analysis without and with fused images were 72% and 89%, and 74% and 91%, respectively. The detection rate was significantly higher with side-by-side analysis and fused image analysis compared with wbT2 and wbDWI alone (p = .0159; p < .0001). There was no significant difference between fused image interpretation and side-by-side analysis. CONCLUSIONS: WbDWI allows detection of malignant lesions with a similar detection rate to wbT2. Side-by-side analysis of wbT2 and wbDWI significantly improves the overall detection rate and fused image data provides no added value. PMID- 20717830 TI - Suppression of TGF-beta1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: its potential therapeutic use in the chemoprevention of keloid. AB - Keloid is a fibrotic disease characterized by abnormal accumulation of extracellular matrix (ECM) in the dermis. It is a late spreading skin overgrowth and may be considered a plastic surgeon's nightmare. In nature, curcuminoid is composed of curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (bDMC). Curcuminoids have been found to inhibit fibrosis. However, their role in the synthesis of ECM in the keloid fibroblasts (KFs) has remained unclear. In this series of studies, a total of seven primary KFs cultures were used as the KFs model for investigating the inhibitory effect of curcuminoids on the expression of ECM and TGF-beta1. A sensitive and reproducible HPLC method was developed to provide a quantitative analysis on the cellular uptake of curcuminoids onto the KF cells. The level of ECM in the primary KFs was elevated. The elevation of ECM and TGF-beta1/p-SMAD-2 level was substantially blocked by the cellular uptake of curcumin in a dose-dependent manner in all the seven primary KFs. The results have led to the conclusion that the excessive production of ECM in the KF cells could be blocked and/or rapidly decreased by curcumin. PMID- 20717829 TI - Differentiation of oncocytoma and renal cell carcinoma in small renal masses (<4 cm): the role of 4-phase computerized tomography. AB - PURPOSE: We investigate the use of 4-phase computerized tomography with intravenous contrast to help distinguish oncocytoma from renal cell carcinoma (RCC) in tumors <4 cm. METHODS: We retrospectively identified patients who underwent surgical management for renal tumors <4 cm from 2005 to 2008. Patients who had pre-operative CT evaluation as per our institution's renal mass protocol and had confirmed pathological diagnosis of either oncocytoma or RCC were included in the study. Enhancement readings were obtained for the tumor and the renal cortex using the same slice simultaneously. RESULTS: Our cohort involved 69 patients (46 men, 23 women; mean age 66) who presented with 79 renal masses. Histopathologically 40 were clear cell, 22 papillary, 5 chromophobe RCC and 12 oncocytoma. On the arterial, venous and delayed phase images, oncocytoma showed the highest mean enhancement change, i.e.,546, 396 and 239% followed by clear cell RCC 261, 261 and 174%, chromophobe RCC 147, 127 and 66% and papillary RCC 137, 184 and 118%, respectively. The enhancement pattern differed significantly on comparing oncocytoma with RCC (P < 0.007). The mean percentage contrast excreted at the end of the delayed phase was 33.3, 13.8, 32 and 53% for clear cell, papillary, chromophobe and oncocytoma, respectively. CONCLUSION: The enhancement and washout values in Hounsfield units obtained by multiphasic CT scan aid in distinguishing oncocytoma from the commonly seen subtypes of RCC in renal masses <4 cm. This preliminary study demonstrates that arterial phase enhancement greater than 500% and washout values of greater than 50% are exclusively seen in renal oncocytomas. PMID- 20717831 TI - Genome duplication effects on pollen development and the interrelated physiological substances in tetraploid rice with polyploid meiosis stability. AB - The breeding of polyploid rice made no breakthrough for a long time because of low seed set. The discovery and application of polyploid meiosis stability (PMeS) material played a pivotal role in solving this problem. Our results indicated that genome duplication led to different outcomes in different rice cultivars in terms of pollen fertility, viability, and the accumulation of important physiological substances such as free proline and endogenous hormones. Pollen from the PMeS HN2026-4X lines showed a high fertility and viability similar to those of HN2026-2X (4X indicates tetraploid while 2X indicates the diploid), whereas both rates decreased dramatically in Balilla-4X. The results of pollen microstructure and ultrastructure investigations suggested that the pollen development pattern in HN2026-4X appeared normal at all stages, but a lot of changes were discovered in Balilla-4X. Stable meiosis, timely tapetum degradation, and normal mitochondria development were critical factors insuring the high frequency pollen fertility of PMeS rice. The free proline content increased markedly in HN2026-4X as compared to HN2026-2X, but it was decreased for Balilla-4X. Genome duplication effects on regulating endogenous hormones accumulation in pollen were evident, resulting in the clear difference between PMeS HN2026-4X and Balilla-4X. The accumulation of IAA, ZR, and GA in mature pollen distinguished HN2026-4X from Balilla-4X, which was linked to normal pollen development. In particular, the excessive accumulation of ABA at the meiosis stage may be correlated to disorganized meiosis in Balilla-4X. All the results provided unequivocal evidence that genome duplication played specific roles in the normal pollen development of PMeS HN2026-4X. PMID- 20717832 TI - RNAi-mediated silencing of a novel Ascaris suum gene expression in infective larvae. AB - In the present study, the potential of RNA interference (RNAi) as a gene silencing tool and the resultant effects on Ascaris suum larval development was examined by targeting a gene (represented by the EST 06G09) specifically expressed in the infective larvae of A. suum. BALB/c mice were infected with RNAi treated larvae. The results showed that the target gene was silenced after soaking for 72 h, and the survival rate of the RNAi-treated larvae was reduced by 17.25% (P<0.01). A significant difference (P<0.05) was detected in the numbers of larvae collected from the livers and lungs of infected mice 4 days after infection with untreated larvae (164.29 +/- 21.51) and RNAi-treated larvae (71.43 +/- 14.35). Significant differences (P<0.01) were also found in the body length and width between untreated larvae (480 +/- 105.77 MUm for length and 23.93 +/- 3.72 MUm for width) and RNAi-treated larvae (400.57 +/- 71.31 MUm for length and 20.20 +/- 2.43 MUm for width). These results show that the gene represented by EST 06G09 may play a role in the development of A. suum larvae. PMID- 20717833 TI - Closing-opening wedge osteotomy for severe, rigid, thoracolumbar post-tubercular kyphosis. AB - Childhood spinal tuberculosis, especially when associated with severe vertebral destruction of more than two vertebral bodies can end up in severe deformity. These children show progressive deformity throughout the period of growth and can develop severe kyphosis of >100 degrees . Such kyphosis is severely disabling with significant risk of neurological deficit and respiratory compromise. Surgical correction of these deformities by both anterior and posterior approaches has been described but each have serious limitations of approach, correctability and safety. We describe here a technique of posterior closing anterior opening osteotomy, which allowed us to correct a rigid post-tubercular deformity of 118 degrees in a 13-year-old boy with neglected spinal tuberculosis. The patient was a 13-year-old boy, who had contracted spinal tuberculosis at the age of 6 years. Although the disease was cured by anti tubercular chemotherapy, he continued to deteriorate in deformity and presented to us with severe thoracolumbar kyphosis (118 degrees ). He was neurologically intact but was beginning to show shortness of breath on exertion. Patient also had fore shortening of the trunk with impingement of the rib cage on the iliac crest. Radiographs revealed complete destruction of T12, L1 and L2 vertebral bodies with the T11 vertebra fusing with L3 anteriorly. CT scans and MRI revealed severe collapse of the vertebral column and the spinal cord being stretched over the 'internal gibbus', which was formed by the remnants of the destroyed vertebrae. A single stage closing-opening osteotomy was done by a midline posterior approach with continuous intraoperative spinal cord monitoring. The procedure involved extensive laminectomy of T11-L2, pedicle screw fixation of three levels above and three levels below the apex, a wedge osteotomy at the apex of the deformity from both sides, anterior column reconstruction by appropriate sized titanium cage and gradual correction of deformity by closing the posterior column using the cage as a fulcrum. This allowed us to achieve a correction to 38 degrees (68% correction). There was no intraoperative or perioperative adverse event and patient had good functional and radiological outcome at 1-year follow up. In this Grand Rounds case presentation, we have also discussed the aetiology and evolution of severe post-tubercular kyphosis, which is the most common cause of spinal deformity in the developing world. Early identification of children at risk for severe deformity, the time and ideal methods of prevention of such deformities are discussed. The pros and cons of the available options of surgical correction of established deformity and the merits of our surgical technique are discussed. PMID- 20717834 TI - Effects of pulse phase duration and location of stimulation within the inferior colliculus on auditory cortical evoked potentials in a guinea pig model. AB - The auditory midbrain implant (AMI), which consists of a single shank array designed for stimulation within the central nucleus of the inferior colliculus (ICC), has been developed for deaf patients who cannot benefit from a cochlear implant. Currently, performance levels in clinical trials for the AMI are far from those achieved by the cochlear implant and vary dramatically across patients, in part due to stimulation location effects. As an initial step towards improving the AMI, we investigated how stimulation of different regions along the isofrequency domain of the ICC as well as varying pulse phase durations and levels affected auditory cortical activity in anesthetized guinea pigs. This study was motivated by the need to determine in which region to implant the single shank array within a three-dimensional ICC structure and what stimulus parameters to use in patients. Our findings indicate that complex and unfavorable cortical activation properties are elicited by stimulation of caudal-dorsal ICC regions with the AMI array. Our results also confirm the existence of different functional regions along the isofrequency domain of the ICC (i.e., a caudal dorsal and a rostral-ventral region), which has been traditionally unclassified. Based on our study as well as previous animal and human AMI findings, we may need to deliver more complex stimuli than currently used in the AMI patients to effectively activate the caudal ICC or ensure that the single shank AMI is only implanted into a rostral-ventral ICC region in future patients. PMID- 20717835 TI - T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays. AB - Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades. PMID- 20717838 TI - Treatment of food processing wastewater in a full-scale jet biogas internal loop anaerobic fluidized bed reactor. AB - A full-scale jet biogas internal loop anaerobic fluidized bed (JBILAFB) reactor, which requires low energy input and allows enhanced mass transfer, was constructed for the treatment of food processing wastewater. This reactor has an active volume of 798 m(3) and can treat 33.3 m(3) wastewater per hour. After pre treating the raw wastewater by settling, oil separating and coagulation-air floating processes, the reactor was operated with a relatively shorter start-up time (55 days). Samples for the influent and effluent of the JBILAFB reactor were taken and analyzed daily for the whole process including both the start-up and stable running periods. When the volumetric COD loading fluctuated in the range of 1.6-5.6 kg COD m(-3) day(-1), the COD removal efficiency, the volatile fatty acid(VFA)/alkalinity ratio, the maximum biogas production and the content of CH(4) in total biogas of the reactor were found to be 80.1 +/- 5%, 0.2-0.5, 348.5 m(3 )day(-1) and 94.5 +/- 2.5%, respectively. Furthermore, the scanning electron microscope (SEM) results showed that anaerobic granular sludge and microorganism particles with biofilm coexisted in the reactor, and that the bacteria mainly in bacilli and cocci were observed as predominant species. All the data demonstrated that the enhanced mass transfer for gas, liquid and solid phases was achieved, and that the formation of microorganism granules and the removal of inhibitors increased the stability of the system. PMID- 20717837 TI - Enhanced susceptibility of T lymphocytes to oxidative stress in the absence of the cellular prion protein. AB - The cellular prion glycoprotein (PrP(C)) is ubiquitously expressed but its physiologic functions remain enigmatic, particularly in the immune system. Here, we demonstrate in vitro and in vivo that PrP(C) is involved in T lymphocytes response to oxidative stress. By monitoring the intracellular level of reduced glutathione, we show that PrP(-/-) thymocytes display a higher susceptibility to H(2)O(2) exposure than PrP(+/+) cells. Furthermore, we find that in mice fed with a restricted diet, a regimen known to increase the intracellular level of ROS, PrP(-/-) thymocytes are more sensitive to oxidative stress. PrP(C) function appears to be specific for oxidative stress, since no significant differences are observed between PrP(-/-) and PrP(+/+) mice exposed to other kinds of stress. We also show a marked evolution of the redox status of T cells throughout differentiation in the thymus. Taken together, our results clearly ascribe to PrP(C) a protective function in thymocytes against oxidative stress. PMID- 20717836 TI - Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy. AB - O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O (6)-benzylguanine and O (6)-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy. PMID- 20717839 TI - Predicting intestinal precipitation--a case example for a basic BCS class II drug. AB - PURPOSE: To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans. METHODS: Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses. RESULTS: All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations. CONCLUSIONS: This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods. PMID- 20717840 TI - Encoding the fine-structured mechanism of action potential dynamics with qualitative motifs. AB - This work presents a neuroinformatic method for deriving mechanistic descriptions of fine-structured neural activity. This is a new development in the computer assisted analysis of dynamics in conductance-based models, which is illustrated using single compartment models of an action potential. A sequence of abstract, qualitative motifs is inferred from this analysis, forming a template that is independent of the specific equations from which they were abstracted. The template encodes the assumptions behind the model reduction steps used to derive the motifs, and so specifies quantitative information about their domains of validity. The template representation of a mechanism is converted to a hybrid dynamical system, which is simulated as a sequence of low-dimensional reduced models (in this example, phase plane models) with appropriate switching conditions taken from the motifs. We demonstrate the validity of the template on a detailed single neuron model of spiking taken from the literature, and show that the corresponding hybrid system simulation closely mimics the spiking dynamics of the full model. PMID- 20717841 TI - Local contextual processing effects with increasing stimulus presentation rate. AB - We investigated the effects of stimulus presentation rates on local contextual processing. Local context was defined as the occurrence of a short predictive series of stimuli occurring before delivery of a target event. EEG was recorded in 12 subjects during two sessions: a slower (150 ms stimulus presentation, 1,000 ms interstimulus interval (ISI)) and a faster session (50 ms stimulus presentation, 800 ms ISI). Stimuli were presented to either the left or right visual field and consisted of 15% targets (downward facing triangle) and 85% of equal numbers of three types of standards (triangles facing left, upwards and right). Recording blocks consisted of targets preceded by randomized sequences of standards and by sequences including a predictive sequence signaling the occurrence of a subsequent target event. Subjects pressed a button in response to targets. Reaction times were faster for predicted compared to random targets in both sessions. Faster presentation rates of stimuli induced a greater P3b latency shift between predicted and random targets compared to slower presentation rates, such that P3b latency for predicted targets was shorter in the faster task compared to the slower task. These findings suggest that as stimulus presentation rates increase, predictive local context is utilized to a greater extent, increasing decision confidence in the detection of targets. PMID- 20717842 TI - Early error detection predicted by reduced pre-response control process: an ERP topographic mapping study. AB - Advanced ERP topographic mapping techniques were used to study error monitoring functions in human adult participants, and test whether proactive attentional effects during the pre-response time period could later influence early error detection mechanisms (as measured by the ERN component) or not. Participants performed a speeded go/nogo task, and made a substantial number of false alarms that did not differ from correct hits as a function of behavioral speed or actual motor response. While errors clearly elicited an ERN component generated within the dACC following the onset of these incorrect responses, I also found that correct hits were associated with a different sequence of topographic events during the pre-response baseline time-period, relative to errors. A main topographic transition from occipital to posterior parietal regions (including primarily the precuneus) was evidenced for correct hits ~170-150 ms before the response, whereas this topographic change was markedly reduced for errors. The same topographic transition was found for correct hits that were eventually performed slower than either errors or fast (correct) hits, confirming the involvement of this distinctive posterior parietal activity in top-down attentional control rather than motor preparation. Control analyses further ensured that this pre-response topographic effect was not related to differences in stimulus processing. Furthermore, I found a reliable association between the magnitude of the ERN following errors and the duration of this differential precuneus activity during the pre-response baseline, suggesting a functional link between an anticipatory attentional control component subserved by the precuneus and early error detection mechanisms within the dACC. These results suggest reciprocal links between proactive attention control and decision making processes during error monitoring. PMID- 20717844 TI - Abstracts of the European Society of Clinical Pharmacy International Workshop on Patient Safety and Pharmacy. May 10-11, 2010. Uppsala, Sweden. PMID- 20717843 TI - Development of a novel LAMP diagnostic method for visible detection of swine Pasteurella multocida. AB - A set of four specific primers for six regions of kmt1 gene from a species specific region was designed for developing the loop-mediated isothermal amplification diagnostic method of swine Pasteurella multocida (Pm-LAMP). After the Pm-LAMP was carried out at 63 degrees C for 1 h, the LAMP products could be visually confirmed using fluorescent dyes as detection reagent under UV illumination. In sensitivity, the detection limit of the Pm-LAMP was 10 cfu/mL, and was 1 log less than that of the PCR method. In specificity, the Pm-LAMP did not amplify genomic DNA of swine common respiratory pathogens. Furthermore, based on results for clinical swab samples (n = 31) using PCR detection as golden standard, relative sensitivity of the Pm-LAMP was 100%, relative specificity of the Pm-LAMP was 90.9%, and percentage of observation agreement was 93.5% (Kappa = 0.85). The Pm-LAMP method should be a useful diagnostic tool for rapid and visible detection of swine Pasteurella multocida. PMID- 20717847 TI - An intronic mutation in MLH1 associated with familial colon and breast cancer. AB - Single base substitutions can lead to missense mutations, silent mutations or intronic mutations, whose significance is uncertain. Aberrant splicing can occur due to mutations that disrupt or create canonical splice sites or splicing regulatory sequences. The assessment of their pathogenic role may be difficult, and is further complicated by the phenomenon of alternative splicing. We describe an HNPCC patient, with early-onset colorectal cancer and a strong family history of colorectal and breast tumors, who harbours a germ line MLH1 intronic variant (IVS9 c.790 +4A>T). The proband, together with 2 relatives affected by colorectal cancer and 1 by breast cancer, have been investigated for microsatellite instability, immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification. The effect of the intronic variant was analyzed both by splicing prediction software and by hybrid minigene splicing assay. In this family, we found a novel MLH1 germline intronic variant (IVS9 c.790 +4A>T) in intron 9, consisting of an A to T transversion, in position +4 of the splice donor site of MLH1. The mutation is associated with the lack of expression of the MLH1 protein and MSI in tumour tissues. Furthermore, our results suggest that this substitution leads to a complete skip of both exon 9 and 10 of the mutant allele. Our findings suggest that this intronic variant plays a pathogenic role. PMID- 20717848 TI - The effect of nasal continuous positive airway pressure on the symptoms of Gulf War illness. AB - PURPOSE: We performed a pilot study to determine whether nasal continuous positive airway pressure (CPAP) alleviates the symptoms of veterans with Gulf War illness (GWI) and sleep disordered breathing (SDB). METHODS: Eighteen male veterans with GWI and SDB recruited by advertisement, participated in a randomized, single-masked, sham-controlled treatment trial. Participants received 3 weeks of treatment during sleep with either therapeutic nasal CPAP or sham nasal CPAP. Using validated questionnaires, pain, fatigue, cognitive function, sleep disturbance, and general health were assessed by self-report before and after treatment. One of the participants assigned to therapeutic CPAP was excluded from the trial before starting treatment, leaving 17 participants. RESULTS: Compared to the nine sham nasal CPAP recipients, the eight participants receiving therapeutic nasal CPAP experienced improvements in pain (34%; p = 0.0008), fatigue (38%; p = 0.0002), cognitive function (33%; p = 0.004), sleep quality (41%; p = 0.0003), physical health (34%; p = 0.0003), and mental health (16%; p = 0.03). CONCLUSIONS: Our findings in this pilot study suggest that nasal CPAP may greatly improve symptoms in veterans with GWI and SDB. PMID- 20717849 TI - Determination of zinc, copper, iron, and manganese in different regions of lamb brain. AB - The levels of zinc, copper, iron, and manganese were measured in the hippocampus, thalamus, gyrus cinguli, hypothalamus, and in the prefrontal, parietal, temporal, and occipital cortexes of lamb brain by flame atomic absorption spectrometry. Standard addition method was also applied to samples and it was observed that there was no matrix interference affecting the determination of elements interested. In the determination of Cu, a slotted tube atom trap was used to improve sensitivity. One-way analysis of variance was used for the statistical evaluation of the results for each element. Limit of detection results for Zn, Cu, Fe, and Mn were found to be 24, 4.5, 60, and 25 ng/mL, respectively. Region specific differences were found for all elements interested. Mn concentration ranging from 0.29 +/- 0.04 to 0.61 +/- 0.04 mg/kg was found to be the lowest in all brain regions among the all elements interested. PMID- 20717850 TI - Effect of different selenium sources on productive performance, serum and milk Se concentrations, and antioxidant status of sows. AB - The experiment was conducted to study the effects of different selenium (Se) sources on productive performance, serum and milk Se concentrations, and antioxidant status of sows. A total of 12 sows (Landrace*Yorkshire) with same pregnancy were randomly divided into two groups; each group was replicated six times. These two groups received the same basal gestation and lactation diets containing 0.042 mg Se/kg, supplemented with 0.3 mg Se/kg sodium selenite or selenomethionine (i.e., seneno-DL: -methylseleno), respectively. The feeding trial lasted for 60 days, with 32 and 28 days for gestation and lactation period, respectively. Compared with sodium selenite, maternal selenomethionine intake significantly increased (P < 0.05) the weaning litter weight and average weight of piglet. The Se concentration in the serum, colostrum, and milk of sows were significantly higher (p < 0.05) in the selenomethionine-treated group. The antioxidant status was greatly improved in sows of selenomethionine-treated group and was illuminated by the increased total antioxidant capability (T-AOC; P < 0.05) and decreased malondialdehyde (MDA; P < 0.01) level in the serum of sows, increased T-AOC (P < 0.05), glutathione (GSH) peroxidase (P < 0.05), superoxide dismutase (P < 0.05) and GSH (P < 0.05), and MDA (P < 0.05) level in the colostrum and milk of sows. These results suggested that maternal selenomethionine intake improved Se concentration and antioxidant status of sows, thus maintain maternal health and increase productive performance after Se was transferred to its offspring. PMID- 20717851 TI - Single-base extension and ELISA-based approach for single-nucleotide polymorphisms genotyping. AB - Single-nucleotide polymorphisms (SNPs) emerge as a fundamental tool in personalized medicine due to their association with drug responses or disease predisposition. Single-base extension (SBE) is a common method for characterizing known SNPs, but involves complicated procedures or requires costly analytical instruments. Here, we describe a novel SNP genotyping based on SBE and enzyme linked immunosorbent assay (ELISA). During the SBE, the 5' end fluorescein isothiocyanate-labeled allele-specific primer will extend with biotinylated dideoxynucleotides which are complementary to the SNP sites. The extension product will then be captured by streptavidin-coated nanoparticle and develop blue color in the ELISA assay. We validated this method by detecting SNPs for TP53 gene codon 273 from 68 individuals and the data were 100% in concordant with DNA sequencing. Thus, SBE and ELISA-based SNPs assay is a simple and accurate method for SNP genotyping. PMID- 20717852 TI - Novel activity of UDP-galactose-4-epimerase for free monosaccharide and activity improvement by active site-saturation mutagenesis. AB - Uridine diphosphogalactose-4-epimerase (UDP-galactose-4-epimerase, GalE, EC 5.1.3.2) mediates the 4-epimerization of nucleic acid-activated galactose into UDP-glucose. To date, no enzyme is known to mediate 4-epimerization of free monosaccharide substrates. To determine the potential activity of GalE for free monosaccharide, Escherichia coli GalE was expressed and purified using Ni affinity chromatography, and its ability to mediate 4-epimerization of a variety of free keto- and aldohexoses was assessed. Purified GalE was found to possess 4 epimerization activity for free galactose, glucose, fructose, tagatose, psicose, and sorbose at 0.47, 0.31, 2.82, 9.67, 15.44, and 2.08 nmol/mg protein per minute, respectively. No 4-epimerization activity was found for allose, gulose, altrose, idose, mannose, and talose. The kinetic parameters of 4-epimerization reactions were K (m) = 26.4 mM and k (cat) = 0.0155 min(-1) for D-galactose and K (m) = 237 mM and k (cat) = 0.327 min(-1) for D-tagatose. The 4-epimerization of tagatose, a reaction of commercial interest, was enhanced twofold (19.79 nmol/mg protein per minute) when asparagine was exchanged with serine at position 179. The novel activity of GalE for free monosaccharide may be beneficial for the production of rare sugars using cheap natural resources. Potential strategies for developing enhanced GalE with increased 4-epimerization activity are discussed in the context of the above findings and an analysis of a 3D structural model. PMID- 20717854 TI - Treatment regimens for HIV neurocognitive dysfunctions in the highly active antiretroviral therapy (HAART) era. PMID- 20717853 TI - Frontotemporal dementia and primary progressive aphasia: an update. AB - Frontotemporal dementias are syndromes of progressive dysfunction of the frontal and/or temporal lobes, either unilaterally or bilaterally. These syndromes were described clinically under the terms "primary progressive aphasia" in the United States and "frontotemporal dementia" in Europe and the United Kingdom. They are diagnosed by the clinical features of a frontal lobe neurobehavioral syndrome, or a language and cognitive deterioration. In recent years, molecular genetic findings in these syndromes, especially the tau and progranulin mutations on chromosome 17, have provided a molecular and genetic foundation for the understanding of frontotemporal dementia. These disorders are distinct from Alzheimer's disease but have some overlap with the syndrome of corticobasal degeneration, and with motor neuron disease. Treatments remain very limited, mainly involving therapy for the mood and behavioral symptoms, but advances in the molecular and genetic understanding of these conditions will hopefully lead to more specific therapies in the future. PMID- 20717855 TI - Orthopaedic case of the month: A 30-year-old woman with a painful forearm mass. PMID- 20717856 TI - The Frank Stinchfield Award: the impact of socioeconomic factors on outcome after THA: a prospective, randomized study. AB - BACKGROUND: Most studies of total hip arthroplasty (THA) focus on the effect of the type of implant on the clinical result. Relatively little data are available on the impact of the patient's preoperative status and socioeconomic factors on the clinical results following THA. QUESTIONS/PURPOSES: We determined the relative importance of patient preoperative and socioeconomic status compared to implant and technique factors in predicting patient outcome as reflected by scores on commonly utilized rating scales (eg, Harris Hip Score, WOMAC, SF-12, degree of patient satisfaction, or presence or severity of thigh pain) following cementless THA. METHODS: All patients during the study period were offered enrollment in a prospective, randomized study to receive either a titanium, tapered, proximally coated stem; or a Co-Cr, cylindrical, extensively coated stem; 102 patients were enrolled. We collected detailed patient data preoperatively including diagnosis, age, gender, insurance status, medical comorbidities, tobacco and alcohol use, household income, educational level, and history of treatment for lumbar spine pathology. Clinical evaluation included Harris Hip Score, SF-12, WOMAC, pain drawing, and UCLA activity rating and satisfaction questionnaire. Implant factors included stem type, stem size, fit in the canal, and stem-bone stiffness ratios. Minimum 2 year followup was obtained in 95% of the enrolled patients (102 patients). RESULTS: Patient demographics and preoperative status were more important than implant factors in predicting the presence of thigh pain, dissatisfaction, and a low hip score. The most predictive factors were ethnicity, educational level, poverty level, income, and a low preoperative WOMAC score or preoperative SF-12 mental component score. No implant parameter correlated with outcome or satisfaction. CONCLUSION: Socioeconomic factors and preoperative status have more impact on the clinical outcome of cementless THA than implant related factors. LEVEL OF EVIDENCE: Level I, prospective, randomized clinical trial. See the guidelines online for a complete description of level of evidence. PMID- 20717857 TI - Letter to the editor: The functional outcome of hip resurfacing and large-head THA is the same: a randomized, double-blind study. PMID- 20717858 TI - The John Charnley Award: risk factors for cup malpositioning: quality improvement through a joint registry at a tertiary hospital. AB - BACKGROUND: Few studies have examined factors that affect acetabular cup positioning. Since cup positioning has been linked to dislocation and increased bearing surface wear, these factors affecting cup position are important considerations. QUESTION/PURPOSES: We determined the percent of optimally positioned acetabular cups and whether patient and surgical factors affected acetabular component position. METHODS: We obtained postoperative AP pelvis and cross-table lateral radiographs on 2061 consecutive patients who received a THA or hip resurfacing from 2004 to 2008. One thousand nine hundred and fifty-two hips had AP pelvic radiographs with correct position of the hip center, and 1823 had both version and abduction angles measured. The AP radiograph was measured using Hip Analysis SuiteTM to calculate the cup inclination and version angles, using the lateral film to determine version direction. Acceptable ranges were defined for abduction (30 degrees -45 degrees ) and version (5 degrees -25 degrees ). RESULTS: From the 1823 hips, 1144 (63%) acetabular cups were within the abduction range, 1441 (79%) were within the version range, and 917 (50%) were within the range for both. Surgical approach, surgeon volume, and obesity (body mass index > 30) independently predicted malpositioned cups. Comparison of low versus high volume surgeons, minimally invasive surgical versus posterolateral approach, and obesity versus all other body mass index groups showed a twofold (1.5-2.8), sixfold (3.5-10.7), and 1.3-fold (1.1-1.7) increased risk for malpositioned cups, respectively. CONCLUSIONS: Factors correlated to malpositioned cups included surgical approach, surgeon volume, and body mass index with increased risk of malpositioning for minimally invasive surgical approach, low volume surgeons, and obese patients. Further analyses on patient and surgical factors' influence on cup position at a lower volume medical center would provide a valuable comparison. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20717859 TI - Diagnostic approach to Clostridium difficile infection. PMID- 20717860 TI - Extracorporeal shock wave lithotripsy and endotherapy for pancreatic calculi-a large single center experience. AB - AIM: Large pancreatic ductal calculi and pain are a feature of chronic calcific pancreatitis (CCP) in the tropics. This large single center study evaluates the role of extracorporeal shock wave lithotripsy (ESWL) in fragmentation of large pancreatic stones and relief of pain in patients with CCP. METHODS: Patients with CCP presenting with pain and large pancreatic duct (PD) calculi (>5 mm diameter) not amenable to extraction at routine endoscopic retrograde cholangio pancreatography (ERCP) were taken up for ESWL using a 3rd generation lithotripter. Stones in the head and body of pancreas were targeted at ESWL; 5,000 shocks were given per session. The calculi were fragmented to <3 mm size and then cleared by endotherapy. Pancreatic duct stents were deployed when indicated. A total of 1,006 patients underwent ESWL. Complete clearance was achieved in 762 (76%), partial clearance in 173 (17%) and unsuccessful in the rest. More than 962 (90%) of patients needed less than three sessions of ESWL. At 6 months, 711 (84%) of 846 patients who returned for follow up had significant relief of pain with a decrease in analgesic use. Complications were mild and minimal. CONCLUSION: ESWL is an effective and safe modality for fragmentation of large PD calculi in patients with CCP. PMID- 20717862 TI - [Transcatheter aortic valve implantation (TAVI)TAVI): A new therapeutic option for patients with severe symptomatic aortic stenosis who are not suitable or at high risk for surgical valve replacement]. AB - BACKGROUND: Percutaneous transcatheter aortic valve implantation (TAVI) is a new therapeutic method for patients with severe symptomatic aortic stenosis who are at very high surgical risk or in whom there are contraindications to surgical valve replacement. PATIENTS AND METHODS: Between August 2008 and December 2009, sixty such patients underwent TAVI at our hospital. RESULTS: The mean age of the patients was 82 +/- 6.1 years, 25 of them were men. The mean "European system for cardiac operative risk" (EuroSCORE) was 25.8 +/- 17.0%. A very high surgical risk was the indication for TAVI in 51 patients. The mean aortic valve orifice area was 0.6 +/- 0.1cm(2) and the mean transvalvular gradient 48.2 +/- 14.4 mm Hg before the intervention. The mean duration of the intervention was 62.6 +/- 19.9 minutes and the screening time 11.8 +/- 5.1 minutes. The procedure was technically successful in all but one patient. The post-interventional mean transvalvular gradient was 2.87.0 mm Hg. Significant residual aortic regurgitation (more than grade 3) was present in six patients but was reduced by the catheter-based "snare" technique in most cases. Mean hospital stay was 15.4 +/- 18.9 days. A permanent pacemaker was implanted in 22 of the patients. Eight patients died during the hospital stay, most of them for reasons not directly related to the intervention. CONCLUSIONS: TAVI is becoming a new therapeutic method for elderly patients with severe co-morbidities and severe symptomatic aortic stenosis. Complications of TAVI are not trivial and their management by catheter techniques is challenging. In consequence the selection of patients and of suitably experienced hospitals is crucial for the further development of this promising new technique. PMID- 20717863 TI - [Pulmonary embolism as a cause of a reduced performance capacity of endurance trained men - report of 2 cases]. AB - HISTORY AND ADMISSION FINDINGS: Two trained long-distance runners, aged 53 and 58 years, respectively, presented (independently) at our outpatient department because of an acute reduction in physical performance after considerable exertion. Neither had specific clinical symptoms, particularly no dyspnea. INVESTIGATIONS: Neither patient had abnormal findings on physical examination, such as signs for deep venous thrombosis. The electrocardiogram and echocardiography were normal. Exercise tests revealed a significant limitation in physical performance and, in one patient, a reduction in arterial blood oxygen and elevated d-dimers as the only abnormal laboratory test result. DIAGNOSIS, TREATMENT AND COURSE: The diagnosis of pulmonary embolism was made by computed tomography, which showed the typical changes. In both patients venous phlebography revealed deep vein thrombosis and signs of post-thrombotic changes. Laboratory tests were unremarkable, with normal blood coagulation and no factor II mutations. Anticoagulants were administered to each patient and they slowly resumed their training program. At a subsequent examination physical performance had improved, but there was still a reduction in arterial oxygen during exercise. CONCLUSION: Even endurance-trained sportspersons without thrombophilic risk factors may develop deep vein thrombosis. Even when there are no symptoms, pulmonary embolism should always be included in the differential diagnosis of a sudden and significant reduction in physical performance. PMID- 20717864 TI - [66-year-old patient with necrolytic migratory erythema, weight loss, anemia and diabetes mellitus]. PMID- 20717865 TI - [Muscle wasting (sarcopenia/cachexia) and malnutrition: new insights into development and therapy]. PMID- 20717866 TI - [Biological weapons]. AB - Biological weapons are weapons of mass destruction that use pathogens (bacteria, viruses) or the toxins produced by them to target living organisms or to contaminate non-living substances. In the past, biological warfare has been repeatedly used. Anthrax, plague and smallpox are regarded as the most dangerous biological weapons by various institutions. Nowadays it seems quite unlikely that biological warfare will be employed in any military campaigns. However, the possibility remains that biological weapons may be used in acts of bioterrorism. In addition all diseases caused by biological weapons may also occur naturally or as a result of a laboratory accident. Risk assessment with regard to biological danger often proves to be difficult. In this context, an early identification of a potentially dangerous situation through experts is essential to limit the degree of damage. PMID- 20717867 TI - [Patient-centered medicine: a physician's challenge]. AB - The success of the biological and technical driven medicine is eminent. This disease-centered medicine however requires as a supplement and balance patient centered medicine, which embraces the perspectives, values and preferences of the patient. Patient-centered care is as well important for a better patient physician communication as for the diagnostic-therapeutic work of the physician. PMID- 20717868 TI - Molecular targets of natural drug substances: idiosyncrasies and preferences. AB - All creatures - bacteria, plants, animals, humans - have many building blocks in common, down to biochemical structures and information processing languages. That is why natural substances seem to be better able to bind, and bind specifically, to drug targets in man, and to interact specifically with human biochemical networks. Property analyses of a large number of combinatorial and natural products and drugs have revealed the greater chemical similarity of the latter two. How about target preferences of natural products in comparison to synthetic drugs? On the basis of a comprehensive compilation and analysis of molecular targets of drug substances irrespective of their origin, the review categorises targets chemically and analyses the nature of drug targets. The dynamics of drug action are highlighted because an effective drug target comprises a biochemical system rather than a single molecule. The review is restricted to targets of natural compounds that are in use as therapeutic agents, comparing them with targets of marketed drugs in general. Differences are traced to historical, chemical, pharmacological, and social reasons. To give an example, the prevalence of natural products among antibacterial agents seems to be derived from, first, the necessity to have several hydrophilic binding sites for strong and lasting attachment to vital targets of bacteria, and synthetic drug candidates tend to be more hydrophobic than natural compounds. Second, other microorganisms are well equipped with - natural, of course - compounds with defensive or symbiotic functions that interfere with bacterial metabolism. PMID- 20717869 TI - Procyanidins from apples (Malus pumila Mill.) extend the lifespan of Caenorhabditis elegans. AB - Apple polyphenols (AP) mainly consist of procyanidins (PC), which are composed of (-)-epicatechins and (+)-catechins. In order to investigate the antiageing effects of PC, we measured the lifespan of CAENORHABDITIS ELEGANS worms treated with PC. Treatment with 65 ug/mL PC extended the mean lifespan of wild-type N2 and FEM-1 worms by 12.1 % and 8.4 %, respectively, i.e., to a similar extent as resveratrol. In addition, treatment with 100 ug/mL AP also significantly prolonged the mean lifespan of the same worms by 12.0 % and 5.3 %, respectively, i.e., to a similar extent as PC. In contrast, treatment with (-)-epicatechin did not extend the lifespan of the worms. PC did not modify the growth, food intake, or fecundity of C. elegans. Treatment with PC did not extend the lifespan of MEV 1 worms, which show excessive oxidative stress, indicating that PC had no antioxidant ability in the MEV-1 mutant. Moreover, treatment with PC had no effect on the longevity of SIR-2.1 worms, which lack the activity of SIR-2, a member of the sirtuin family of NAD (+)-dependent protein deacetylases. These results indicated that PC has SIR-2.1-dependent antiageing effects on C. elegans. PMID- 20717870 TI - Arctigenin suppresses unfolded protein response and sensitizes glucose deprivation-mediated cytotoxicity of cancer cells. AB - The involvement of unfolded protein response (UPR) activation in tumor survival and resistance to chemotherapies suggests a new anticancer strategy targeting UPR pathway. Arctigenin, a natural product, has been recently identified for its antitumor activity with selective toxicity against cancer cells under glucose starvation with unknown mechanism. Here we found that arctigenin specifically blocks the transcriptional induction of two potential anticancer targets, namely glucose-regulated protein-78 (GRP78) and its analog GRP94, under glucose deprivation, but not by tunicamycin. The activation of other UPR pathways, e.g., XBP-1 and ATF4, by glucose deprivation was also suppressed by arctigenin. A further transgene experiment showed that ectopic expression of GRP78 at least partially rescued arctigenin/glucose starvation-mediated cell growth inhibition, suggesting the causal role of UPR suppression in arctigenin-mediated cytotoxicity under glucose starvation. These observations bring a new insight into the mechanism of action of arctigenin and may lead to the design of new anticancer therapeutics. PMID- 20717871 TI - Glycyrol induces apoptosis in human Jurkat T cell lymphocytes via the Fas FasL/caspase-8 pathway. AB - Glycyrrhiza uralensis (Leguminosae) has long been used to treat inflammatory ailments, such as gastric ulcers, arthritis, and rheumatism. From this traditional herbal plant, glycyrol, a coumestan with anti-bacterial and anti inflammatory activities, was first isolated and synthesized to test its apoptosis inducing properties in human Jurkat cells. Flow cytometry analysis indicated that glycyrol can arrest the cell cycle in S phase and subsequently induce apoptosis in both time- and dose-dependent manners. Consequently, it was shown that caspase 8 and -9 were involved in the activation of apoptosis after glycyrol treatment. Despite its known NF- kappaB inhibitory activity, glycyrol did not influence the prosurvival Bcl-2 and the proapoptotic Bax. Interestingly, glycyrol was revealed to enhance the Fas level independently from p53, which even slightly decreased. Thus, glycyrol acts in a similar manner as known cytostatic drugs and may have a potential as lead for the development of drugs for cancer treatment. PMID- 20717872 TI - Oxymatrine, the main alkaloid component of Sophora roots, protects heart against arrhythmias in rats. AB - Oxymatrine is one of the main alkaloid components extracted from SOPHORA roots and has been shown to play various protective roles in the cardiovascular system. The present study was designed to study the protective effect of oxymatrine on arrhythmias and their ionic channel mechanism. Rat arrhythmic models were established by aconitine injection and coronary artery ligation. Rat cardiomyocytes were acutely isolated, and the whole-cell patch clamp technique was employed to investigate the effects of oxymatrine on sodium channels. Pretreatment with oxymatrine markedly increased the dose of aconitine required to induce arrhythmias in rats. Additionally, oxymatrine significantly delayed the initial time and shortened the duration time of rat arrhythmias induced by coronary artery ligation. Cardiac mortality rate in coronary artery ligation induced arrhythmias was also effectively decreased by oxymatrine in rats. The electrophysiological study showed that oxymatrine could significantly inhibit sodium and calcium currents in isolated rat cardiomyocytes in a concentration dependent manner. In summary, oxymatrine plays a remarkably preventive role in rat arrhythmias through the inhibition of sodium and calcium currents. PMID- 20717873 TI - Osthole ameliorates insulin resistance by increment of adiponectin release in high-fat and high-sucrose-induced fatty liver rats. AB - The objectives of this study were to determine the effect of osthole on the insulin resistance (IR) in high-fat and high-sucrose-induced fatty liver rats and to investigate its potential mechanisms. The rat model was established by orally feeding high-fat and high-sucrose emulsion by gavage for 9 weeks. The experimental rats were treated with osthole 5 and 10 mg/kg, lipanthyl 30 mg/kg, and rosiglitazone 4 mg/kg after oral high-fat and high-sucrose emulsion for 6 weeks and were sacrificed 4 weeks after administration. The total cholesterol (TC), triglycerides (TG), and free fatty acids (FFA) in serum and hepatic tissue, fasting blood glucose (FBG), fasting serum insulin (FINS), serum adiponectin, and liver weight were measured. The homeostasis model assessment of insulin resistance (HOMA-IR) and coefficient of hepatic weight were calculated. The results showed that after treatment with osthole, the serum levels of TC, TG, and FFA, the contents of TG and FFA in hepatic tissue, and body weight gain were lowered, especially in the osthole 10 mg/kg group (p < 0.05 or p < 0.01). Moreover, the histological evaluation of liver specimens demonstrated that the steatosis and inflammation in liver in osthole-treated groups were improved, especially in the 10 mg/kg group (p < 0.05). Importantly, the levels of FBG, FINS, and HOMA-IR in the osthole 10 mg/kg group were decreased (p < 0.01), while the level of serum adiponectin in the osthole-treated groups, like PPAR alpha agonist lipanthyl and PPAR gamma agonist rosiglitazone, was increased (p < 0.05). These results revealed that osthole could improve the IR induced by high-fat and high-sucrose emulsion in fatty liver rats, and its mechanism might be associated with increment of adiponectin release via activation of PPAR alpha/ gamma pathway. PMID- 20717874 TI - Inhibitory effects of Dendrobium alkaloids on memory impairment induced by lipopolysaccharide in rats. AB - Dendrobium alkaloids (DNLA), extracted from Dendrobium nobile Lindl. whose botanical name is Dendrobium moniliforme, Orchidaceae family, were studied for their effect on lipopolysaccharide (LPS)-induced memory impairment in rats. SD rats were pretreated with DNLA (40, 80, 160 mg/kg/d for 7 d), followed by LPS (50 ug) injection into the right lateral ventricle to produce memory impairment. DNLA treatment continued for another 13 days. The spatial behavior was tested by the Morris water maze; the level of tumor necrosis factor receptor 1 (TNFR1) mRNA was detected by real time RT-PCR, and the protein level of TNFR1, nuclear factor kappa-B (NF- kappaB) and phosphorylated p38 mitogen-activated protein kinases (p p38 MAPK) by Western blotting. The results showed that DNLA significantly improved the neurobehavioral performance and prevented LPS-induced elevation in TNFR1 mRNA and protein levels. LPS-induced activation of p38 MAPK and NF- kappaB pathway was also suppressed. In conclusion, DNLA is effective in protecting against LPS-induced brain impairment, and this effect is due, at least in part, to prevent overexpression of TNFR1 via inhibition of p-p38 MAPK and the downstream NF- kappaB signal pathway. PMID- 20717875 TI - Clinical evaluation of efficacy and tolerability of HMC05 in healthy subjects with normal and high-normal blood pressure: a pilot study. AB - HMC05, a formulation containing eight different herbal extracts, has been used widely for several thousand years in China, Japan, and Korea as a remedy for hypertension and headache. Although its anti-inflammatory effects in mouse monocytic cell lines and anti-atherosclerotic effects in apoE-knockout mice have been reported, the pharmacodynamic effects of HMC05 in human subjects have not yet been investigated. We evaluated the efficacy and tolerability of this drug in 14 healthy male Korean subjects with normal or high-normal blood pressure (BP) in a randomized, single-blind, crossover study with a 2-week washout period. Four 500-mg tablets of HMC05 or placebo were orally administered three times daily to nine subjects with normal BP and five subjects with high-normal BP for 4 weeks. To assess the pharmacodynamic effects of HMC05, levels of high-sensitivity C reactive protein and homocysteine, BP, and flow-mediated vasodilation were measured before and after the 4-week medication period with evaluation of tolerability. All 14 subjects completed the study, and HMC05 was well tolerated with no significant adverse events. HMC05 did not exhibit a significant BP lowering effect in either BP group, and there were no significant differences in other pharmacodynamic values after HMC05 or placebo administration in the two groups. Further study is needed to evaluate the efficacy and tolerability of HMC05 in an adequate number of patients with hypertension. PMID- 20717876 TI - Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes. AB - Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 uM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 uM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study. PMID- 20717877 TI - Inhibition of advanced glycation end product formation by medicinal plant extracts correlates with phenolic metabolites and antioxidant activity. AB - Nonenzymatic formation of advanced glycation end products (AGEs) is accelerated under hyperglycemic conditions characteristic of type 2 diabetes mellitus and contributes to the development of vascular complications. As such, inhibition of AGE formation represents a potential therapeutic target for the prevention and treatment of diabetic complications. In the present study, ethanolic extracts of 17 medicinal plants were assessed for inhibitory effects on in vitro AGE formation through fluorometric and immunochemical detection of fluorescent AGEs and N(epsilon)-(carboxymethyl)lysine adducts of albumin (CML-BSA), respectively. Most extracts inhibited fluorescent AGE formation with IC (50) values ranging from 0.4 to 38.6 ug/mL and all extracts reduced CML-BSA formation but to differing degrees. Results obtained through both methods were highly correlated. Antiglycation activities were positively correlated with total phenolic content, free radical scavenging activity and reduction in malonyldiadehyde levels following oxidation of low-density lipoprotein, but negatively correlated with lag time to formation of conjugated dienes. Together, these results provide evidence that antioxidant phenolic metabolites mediate the antiglycation activity of our medicinal plant collection, a relationship that likely extends to other medicinal and food plants. PMID- 20717878 TI - Inhibitory effect of human breast cancer cell proliferation via p21-mediated G1 cell cycle arrest by araliadiol isolated from Aralia cordata Thunb. AB - A new polyacetylenic compound, araliadiol, was isolated from the leaves of Aralia cordata Thunb. (Araliaceae). The structure of araliadiol was determined to be 3( S),8( R)-pentadeca-1,9( Z)-diene-4,6-diyne-3,8-diol by MS, NMR, IR, and UV spectroscopic analysis as well as Mosher ester reaction. Araliadiol displayed a significant inhibitory effect on the growth of a human breast adenocarcinoma cell line (MCF-7), with an IC (50) value for cytotoxicity of 6.41 ug/mL. Cell cycle analysis revealed that the proportion of cells in the G (1) phase of the cell cycle increased in a dose-dependent manner (from 54.7 % to 72.0 %) after 48 h exposure to araliadiol at dosages ranging from 0 to 80 uM. The results suggest that araliadiol inhibits cell cycle progression of MCF-7 at the G (1)-S transition. After treatment with araliadiol, phosphorylation of retinoblastoma protein (Rb) in MCF-7 cells was inhibited, accompanied by a decrease in the levels of cyclin D (3) and cyclin-dependent kinase 4 (cdk4) and an increase in the expression of p21 (WAF-1/Cip1). However, the expression of phosphorylated p53 (Ser15) and Chk2 was not altered in MCF-7 cells. These findings indicate that araliadiol exhibits its growth-inhibitory effects on MCF-7 cells through downregulation of cdk4 and cyclin D (3), and upregulation of p21 (WAF-1/Cip1) by a p53-independent mechanism. PMID- 20717879 TI - Monoterpenoid indole alkaloids mediating DNA strand scission from Turpinia arguta. AB - Two new monoterpenoid indole alkaloid derivatives, turpiniside (1) and 11 methoxyjavaniside (2), along with the known alkaloids, vincosamide (3), (3 R) pumiloside (4), and paratunamide C (5), were isolated from the leaves of Turpinia arguta (Lindl.) Seem. Their structures were determined on the basis of spectroscopic data. Compounds 1 and 3-5 were found to effect relaxation of the supercoiled pBR322 plasmid DNA in the presence of Cu2+. PMID- 20717880 TI - [Quality of health care--also physicians' offices included]. PMID- 20717881 TI - [Autologous chondrocyte transplantation--more evidence for cartilage substitution]. PMID- 20717882 TI - [Hip head cap implantation--osteonecrosis is associated with fracture of the neck of the femur]. PMID- 20717883 TI - [Proximal humerus fracture--total shoulder endoprosthesis no longer number 1?]. PMID- 20717884 TI - [Distal tibia fracture--plates or nails?]. PMID- 20717885 TI - [Joint replacement--biomarkers for the proof of infection]. PMID- 20717886 TI - [Overseas experience--2 research years and life in New York]. PMID- 20717887 TI - Seizure-induced lumbar burst fracture associated with conus medullaris-cauda equina compression. AB - A 36-year-old male developed a burst fracture of the L1 vertebra following a seizure. The patient experienced conus-cauda equina compression resulting in urinary retention and patchy sensory loss. An MRI of the spine revealed short tau inversion recovery (STIR) hyperintensity at L1 with 70% loss of vertebral body height, 8-mm posterior bony retropulsion into the spinal canal and T2-weighted hyperintensity in the cord, which is consistent with cord edema. A thorough physical exam and imaging is critical for immediate diagnosis of spine injuries to prevent grave neurological complications. PMID- 20717888 TI - Defining conditions for covalent immobilization of angiogenic growth factors onto scaffolds for tissue engineering. AB - Rapid vascularization of engineered tissues in vitro and in vivo remains one of the key limitations in tissue engineering. We propose that angiogenic growth factors covalently immobilized on scaffolds for tissue engineering can be used to accomplish this goal. The main objectives of this work were: (a) to derive desirable experimental conditions for the covalent immobilization of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) on porous collagen scaffolds; and (b) to determine whether primary endothelial cells respond to these scaffolds with covalently immobilized angiogenic factors. VEGF and Ang1 were covalently immobilized onto porous collagen scaffolds, using 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (EDC) chemistry. To improve covalent immobilization conditions: (a) different reaction buffers [phosphate buffered saline (PBS), distilled water, or 2-(N-morpholino)ethanesulphonic acid (MES)] were used; and (b) step immobilization was compared to bulk immobilization. In step immobilization, growth factors are applied after EDC activation of the scaffold, while in bulk immobilization, reagents are simultaneously applied to the scaffold. PBS as the reaction buffer resulted in higher amounts of VEGF and Ang1 immobilized (ELISA), higher cell proliferation rates (XTT) and increased lactate metabolism compared to water and MES as the reaction buffers. Step immobilization in PBS buffer was also more effective than bulk immobilization. Immobilized growth factors resulted in higher cell proliferation and lactate metabolism compared to soluble growth factors used at comparable concentrations. Tube formation by CD31-positive cells was also observed in collagen scaffolds with immobilized VEGF or Ang1 using H5V and primary rat aortic endothelial cells but not on control scaffolds. PMID- 20717889 TI - Impact of co-culture on pancreatic differentiation of embryonic stem cells. AB - Promise of cellular therapy for type 1 diabetes has inspired the search for transplantable cell sources, and embryonic stem cells (ESCs) have emerged as strong candidates. We have developed a directed differentiation protocol to obtain insulin-producing cells from ESCs. The ESCs are first induced towards a homogeneous monolayer of definitive endoderm-like cells by co-culture with primary hepatocytes. Pancreatic commitment is induced by plating the ESC-derived endoderms on Matrigel, along with Sonic hedgehog inhibition and retinoid induction. More than 70% of differentiated cells positively upregulated Pdx-1, along with pro-endocrine transcription factors Ngn3, beta2/neroD1, Nkx2.2 and Nkx6.1. Final maturation to islet-specific cells is achieved by co-culturing the ESC-derived pancreatic endocrine cells with endothelial cells, which resulted in Insulin 1 upregulation in 60% of the cell population, along with high levels of IAPP and Glut2. The differentiated cell population also secreted high levels of insulin. Our findings illustrate the significant effect of co-culture in different stages of differentiation and maturation of ESCs in vitro. Such a high yield of pancreatic islet cells has not yet been reported. Our findings establish a robust protocol for islet differentiation. PMID- 20717890 TI - Cognitive error as the most frequent contributory factor in cases of medical injury: a study on verdict's judgment among closed claims in Japan. AB - BACKGROUND: Cognitive errors in the course of clinical decision-making are prevalent in many cases of medical injury. We used information on verdict's judgment from closed claims files to determine the important cognitive factors associated with cases of medical injury. METHODS: Data were collected from claims closed between 2001 to 2005 at district courts in Tokyo and Osaka, Japan. In each case, we recorded all the contributory cognitive, systemic, and patient-related factors judged in the verdicts to be causally related to the medical injury. We also analyzed the association between cognitive factors and cases involving paid compensation using a multivariable logistic regression model. RESULTS: Among 274 cases (mean age 49 years old; 45% women), there were 122 (45%) deaths and 67 (24%) major injuries (incomplete recovery within a year). In 103 cases (38%), the verdicts ordered hospitals to pay compensation (median; 8,000,000 Japanese Yen). An error in judgment (199/274, 73%) and failure of vigilance (177/274, 65%) were the most prevalent causative cognitive factors, and error in judgment was also significantly associated with paid compensation (odds ratio, 1.9; 95% confidence interval [CI], 1.0-3.4). Systemic causative factors including poor teamwork (11/274, 4%) and technology failure (5/274, 2%) were less common. CONCLUSIONS: The closed claims analysis based on verdict's judgment showed that cognitive errors were common in cases of medical injury, with an error in judgment being most prevalent and closely associated with compensation payment. Reduction of this type of error is required to produce safer healthcare. PMID- 20717892 TI - Quality and financial outcomes from gainsharing for inpatient admissions: a three year experience. AB - BACKGROUND: Gainsharing is a way to provide incentives to physicians to decrease hospital costs without compromising quality. METHODS: A pay-for-performance program was instituted over a three-year period from July 2006 to June 2009. Baseline length of stay (LOS) and case costs were developed during the year prior to the inception of the program. Best practice norms (BPNs) were established at the top 25th percentile of physicians for each all patient refined (APR) diagnosis related group (DRG). Hospital costs were analyzed in several areas, including operating room charge (OR), supplies and implants, nursing and per-diem room costs. Payments were based upon case level performance compared to BPN's and the physician's historic performance. Eligible cases included commercial insurance only for the first 2 years but Medicare cases were included after October 2008 resulting from a Centers for Medicare and Medicaid Services (CMS) approved demonstration project. Payments to physicians required meeting quality thresholds, including chart completion, and compliance with core measures. RESULTS: A total of 184 (54%) physicians enrolled into the program. There was a $25.1 million reduction in hospital costs during the 3 years ($16 million from participating and $9.1 million from non-participating physicians, P < 0.01). Most cost reductions were attributed to reduced LOS and reductions in medical supply costs. Total physician payouts were over $2 million (average $1,866 per quarter). Delinquent medical records decreased from an average of 43% in the second quarter 2006 to 30% (P < 0.0001) in the second quarter 2009. Quality measures improved during the study period but not by a statistical significance. CONCLUSIONS: Gainsharing provided an incentive for physicians to reduce hospital costs while maintaining hospital quality. PMID- 20717891 TI - Advancing geriatrics education: an efficient faculty development program for academic hospitalists increases geriatric teaching. AB - BACKGROUND: Hospitalists care for an increasing number of older patients. As teachers, they are uniquely positioned to teach geriatric skills to residents. Faculty development programs focused on geriatrics teaching skills are often expensive and time-intensive, and may not enhance trainee learning. OBJECTIVES: To evaluate a train-the-trainer (TTT) model designed to equip hospitalists with knowledge and skills to teach geriatric topics to residents in a time constrained, resource-limited environment. DESIGN: Cross-sectional survey. SETTING: Academic tertiary hospital. INTERVENTION: A 10-hour geriatric curriculum, the Reynolds Program for Advancing Geriatrics Education (PAGE), cotaught by geriatricians and hospitalists at preexisting noon conferences over 1 year that consisted of exportable teaching modules. MEASUREMENTS: Session leaders' and faculty participants' satisfaction, hospitalist geriatrics teaching self-efficacy, residents' self-report of frequency of geriatric teaching received, and frequency of geriatric skill use. RESULTS: The curriculum was highly rated by session leaders and hospitalist faculty. Hospitalists perceived improvement in geriatric teaching skills, indicating (1: "unlikely" to 5: "highly likely") that they are likely to use these teaching tools in the future (M = 4.61, standard deviation [SD] = 0.53). Residents reported both significantly more geriatrics teaching by hospitalists (P < 0.05) and a borderline significant increase in their practice of geriatric clinical skills (P = 0.05). CONCLUSIONS: A time-efficient geriatric faculty development program for hospitalists suggests improvement in the amount and quality of geriatrics teaching and skill practice among faculty and residents at an academic medical center. Concise faculty development programs within preexisting faculty meetings may be a feasible, successful method to increase geriatric skill development in the hospital setting. PMID- 20717893 TI - Implementation of a hospitalist-run observation unit and impact on length of stay (LOS): a brief report. AB - BACKGROUND: While the impact of hospitalists on length of stay (LOS) for inpatient medicine services has been studied, there has been little work on the impact of hospitalist involvement in short-stay or observation units. OBJECTIVE: The primary objective was to examine the impact of a hospitalist-run observation unit on LOS. The secondary objective was to assess utilization of the unit through examining case-weight and LOS. DESIGN: Retrospective cohort study with a preimplementation/postimplementation analysis. SETTING: University Hospital, the 604-bed teaching hospital for Bexar County, San Antonio, Texas. PATIENTS: All patients discharged from the inpatient medicine and observation units with diagnoses of chest pain, asthma, syncope, cellulitis, and pyelonephritis. INTERVENTION: Creation of a hospitalist-run, nonteaching, 10-bed "Clinical Decision Unit" (CDU). MEASUREMENTS: The overall LOS of the "top 5" most common diagnoses was compared for the 12 months preimplementation and postimplementation of the unit. RESULTS: The overall LOS for all patients decreased from 2.4 to 2.2 days (P = 0.05) between the 12 months preimplementation and postimplementation. The greatest decreases were seen for cellulitis (2.4-1.9 days; P < 0.001) and asthma (2.2-1.2 days; P < 0.001). CONCLUSIONS: Implementation of a hospitalist run observation unit was associated with a significantly decreased LOS for all patients regardless of location, suggesting that the unit has led to more efficient care. PMID- 20717894 TI - Gaining efficiency and satisfaction in the handoff process. AB - BACKGROUND: Handoffs, or transfers of patient care responsibility, occur frequently on hospitalist teams. The reliability and efficiency of the handoff process is a national and local concern. Most studies in the literature regard physicians-in-training. We studied the morning handoff process of hospitalist teams comprised of staff physicians and nurse practitioner and/or physician assistants. METHODS: An improvement team observed morning handoffs. Four problems were identified: unpredictable start and finish times, inefficiency, poor environment (hallway noise and distracting in-room conversations), and poor communication. The team restructured the process and observed post-intervention behavior at 15 and 90 days. A participant-provider survey was conducted before and after the intervention regarding wasted time, total time-in-report, and satisfaction with the process. RESULTS: Pre-intervention 60.5% of providers (23/38) believed morning handoff was performed in a timely fashion compared to 100% (15/15) post-intervention (P = 0.005). Average time spent in morning report was 11 minutes, compared to 5 minutes after the intervention (P < 0.0028). Pre intervention 6.5 minutes were believed wasteful, compared to 0.5 minutes post intervention (P < 0.0001). CONCLUSIONS: This study identifies deficiencies in the handoff process that were addressed by enhancing the physical environment (smaller room, noise reduction, closed door), assigned seating (visual cues by table tent cards), non-clinicians providing printed materials, standardization of written updates, team times (consistent & precise daily time for each team report), culture change including deference of attention to team receiving report with opportunity for questions, and minimization of side conversations. This intervention package resulted in an improvement in satisfaction and timeliness of clinicians involved. PMID- 20717895 TI - Effectiveness of an inpatient smoking cessation program. AB - BACKGROUND: Inpatient smoking cessation may increase the success of quitting smoking post-hospital discharge. METHODS: Using a quasiexperimental study design, use of cessation methods, mortality, self-reported abstinence, and quit status 6 months post-hospital discharge were measured to assess the effectiveness of an inpatient smoking cessation program. Subjects were interviewed by telephone 6 months post-hospital discharge. Outcomes for patients who were seen by the inpatient smoking cessation counselor were compared to consecutive patients who were not seen by the counselor. Electronic medical records (EMRs) and administrative data were used to construct baseline measures, comorbidity covariates, pharmaceutical use rates during hospitalization, readmission, and mortality outcomes. Multivariate methods included logistic regression and survival analysis. RESULTS: At baseline, the study groups varied by mean age, length of stay (LOS), comorbidity index, cardiovascular diagnosis, and acuity. At 6 months post-hospital discharge, the intent to treat estimate for point prevalence abstinence was 16% in the intervention group compared to 10% in the comparison group (P = 0.02) while self-reported quit status in the intervention group was 44% vs. 30% in the comparison group (P = 0.00). The intervention group used more nicotine replacement therapy (NRT) than the comparison group both in hospital and following discharge. Crude post-hospital discharge mortality was significantly less in the intervention group (0.02) than in the comparison group (0.04). A multivariate survival model, controlling for baseline imbalances, showed a significantly reduced mortality in the intervention group (hazard ratio [HR] = 0.37; P = 0.04). CONCLUSIONS: Inpatient smoking cessation programs effectively improve quit outcomes, NRT use, and mortality post-hospital discharge. PMID- 20717898 TI - Consistency of captive giraffe behavior under two different management regimes. AB - Long-term animal behavior studies are sometimes conducted at a single site, leading to questions about whether effects are limited to animals in the same environment. Our ability to make general conclusions about behavior is improved when we can identify behaviors that are consistent across a range of environments. To extend Veasey and colleagues' ([1996b] Anim Welf 5:139-153) study, I compared not only activity budgets but also social behavior of an all female group of giraffe at The Maryland Zoo in Baltimore (MZiB) to those previously observed in breeding groups at The San Diego Zoo's Wild Animal Park (SDZWAP; Bashaw et al. [2007] J Comp Psychol 121:46-53). Morning activity budgets and the maintenance of social relationships were consistent across groups. MZiB female giraffe interacted more frequently and the identity of animals that formed the strongest relationships was less predictable than at SDZWAP. Results support earlier findings that captive giraffe maintain social relationships and suggest that studies of giraffe social relationships and activity are generalizable across a range of captive conditions. PMID- 20717899 TI - Hand-raising a spectral tarsier (Tarsius tarsier) at the Ueno Zoological Gardens. AB - On February 10, 2008, a newborn male spectral tarsier (Tarsius tarsier) was found on the floor of the indoor exhibit room in the Small Mammal House of the Ueno Zoological Gardens. The dam showed no signs of providing maternal care and therefore we decided to hand-raise the infant. Its birth weight was 18.7 g. We placed the dam and infant in an incubator and gave 12.5-25% formula (for kittens), until the 145th day after birth. We limited the volume of formula intake to avoid excessive intake and to prevent diarrhea. For nutrition enrichment, we added a chicken liver homogenate to the formula 1-3 times per day. The infant was given a sunbath for 10 min on the 28th day. He showed no serious decline in health, except for diarrhea that occurred during the first few days after birth. He ate a small cricket for the first time on the 50th day and easily caught mealworms on his own on the 105th day. Gradual changes in feeding times, formula concentration, and the nutritionally enriched formula were essential for successfully hand-raising the tarsier. PMID- 20717897 TI - Myeloid-specific GPCR kinase-2 negatively regulates NF-kappaB1p105-ERK pathway and limits endotoxemic shock in mice. AB - G-protein-coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G-protein-coupled receptors. It is expressed in high levels in myeloid cells and its levels are altered in many inflammatory disorders including sepsis. To address the physiological role of myeloid cell-specific GRK2 in inflammation, we generated mice bearing GRK2 deletion in myeloid cells (GRK2?mye). GRK2?mye mice exhibited exaggerated inflammatory cytokine/chemokine production, and organ injury in response to lipopolysaccharide (LPS, a TLR4 ligand) when compared to wild-type littermates (GRK2fl/fl). Consistent with this, peritoneal macrophages from GRK2?mye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NF-kappaB1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-kappaB1p105-MEK ERK pathway is significantly enhanced in the GRK2?mye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2?mye macrophages, limits the enhanced production of LPS-induced cytokines/chemokines. Taken together, our studies reveal previously undescribed negative regulatory role for GRK2 in TLR4-induced p105-ERK pathway as well as in the consequent inflammatory cytokine/chemokine production and endotoxemia in mice. PMID- 20717900 TI - Type-1 polarized dendritic cells loaded with apoptotic prostate cancer cells are potent inducers of CD8(+) T cells against prostate cancer cells and defined prostate cancer-specific epitopes. AB - BACKGROUND: In order to develop improved vaccines for patients with recurrent prostate cancer (PCa), we tested the feasibility of using type-1 polarized dendritic cells (alphaDC1s) to cross-present antigens from allogeneic PCa cells and to induce functional CD8(+) T cell responses against PCa cells and against defined MHC class I-restricted PCa-relevant epitopes. METHODS: Monocyte-derived DCs from PCa patients were matured using the "standard" cytokine cocktail (IL 1beta/TNFalpha/IL-6/PGE2) or using the alphaDC1-polarizing cocktail (IL 1beta/TNFalpha/IFNalpha/IFNgamma/poly-I:C), loaded with UV-irradiated LNCaP cells, and used to sensitize autologous CD8(+) T cells. RESULTS: alphaDC1s from PCa patients secreted 10-30 times higher levels of IL-12p70 than sDCs. Importantly this elevated capacity for IL-12p70 secretion was not inhibited by loading with apoptotic tumor cells. Compared to standard DCs, alphaDC1s induced higher numbers of CD8(+) T cells capable of recognizing both the original PCa cells as well as another PCa cell line, DU145, in MHC class I-restricted fashion. Furthermore, alphaDC1s induced higher numbers of CD8(+) T cells recognizing defined PCa-specific class I-restricted peptide epitopes of prostate-specific antigen and prostatic acid phosphatase: PAP(135-143) (average 49-fold higher), PAP(112-120) (average 24-fold), PSA(141-150) (average 5.5-fold), and PSA(146-154) (average 11-fold). CONCLUSION: Type-1 polarization of GM-CSF/IL-4-generated DCs enhances their ability to present allogeneic tumor cells and to induce CD8(+) T cells recognizing different PCa cells and multiple defined PCa-specific epitopes. These observations help to develop improved immunotherapies of PCa for patients with different HLA types and lacking autologous tumor material. PMID- 20717901 TI - Prominin-1 (CD133) is not restricted to stem cells located in the basal compartment of murine and human prostate. AB - BACKGROUND: Rodent and human prominin-1 are expressed in numerous adult epithelia and somatic stem cells. A report has shown that human PROMININ-1 carrying the AC133 epitope can be used to identify rare prostate basal stem cells (Richardson et al., J Cell Sci 2004; 117:3539-3545). Here we re-investigated its general expression in male reproductive tract including mouse and human prostate and in prostate cancer samples using various anti-prominin-1 antibodies. METHODS: The expression was monitored by immunohistochemistry and blotting. Murine tissues were stained with 13A4 monoclonal antibody (mAb) whereas human samples were examined either with the AC133 mAb recognizing the AC133 glycosylation-dependent epitope or 80B258 mAb directed against the PROMININ-1 polypeptide. RESULTS: Mouse prominin-1 was detected at the apical domain of epithelial cells of ductus deferens, seminal vesicles, ampullary glands, and all prostatic lobes. In human prostate, immunoreactivity for 80B258, but not AC133 was revealed at the apical side of some epithelial (luminal) cells, in addition to the minute population of AC133/80B258-positive cells found in basal compartment. Examination of prostate adenocarcinoma revealed the absence of 80B258 immunoreactivity in the tumor regions. However, it was found to be up-regulated in luminal cells in the vicinity of the cancer areas. CONCLUSIONS: Mouse prominin-1 is widely expressed in prostate whereas in human only some luminal cells express it, demonstrating nevertheless that its expression is not solely associated with basal stem cells. In pathological samples, our pilot evaluation shows that PROMININ-1 is down regulated in the cancer tissues and up-regulated in inflammatory regions. PMID- 20717902 TI - Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells. AB - BACKGROUND: Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) are cholesterol-lowering drugs that are widely used to prevent and treat atherosclerotic cardiovascular disease. Recent epidemiological studies suggest that statins reduce serum prostate-specific antigen (PSA) levels and decrease the risk of prostate cancer. In the present study, we determined the molecular mechanisms related to the regulation of PSA, androgen receptor (AR) and cell proliferation in prostate cancer cell lines by statins. METHODS: Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis and a cell proliferation assay were used to resolve the regulatory role of statins (mevastatin and simvastatin) in three prostate cancer cell lines, RWPE-1, 22Rv1, and LNCaP. RESULTS: Western blotting revealed that both mevastatin and simvastatin downregulated AR and PSA protein. However, these statins did not downregulate AR mRNA expression, while they decreased PSA mRNA. The protease inhibitor MG132 inhibited the downregulation of AR protein which suggested that statins decreased AR protein levels by increasing AR proteolysis. Furthermore, statins reduced cell proliferation in AR positive cells but not in AR negative cells, suggesting that statins regulate cell proliferation via AR expression. In addition, cell proliferation assay at various concentrations of dihydrotestosterone (DHT) showed that statins decreased androgen sensitivity in LNCaP cells. CONCLUSIONS: Statins decreased AR protein by proteolysis but not mRNA transcription. The drop in AR levels resulted in a reduction in androgen sensitivity and a decrease in cell proliferation in AR positive prostate cancer cells. PMID- 20717903 TI - Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in African American men: the Flint Men's Health Study. AB - BACKGROUND: Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States and the second leading cause of cancer-related mortality. African American men have substantially increased risk of both being diagnosed and dying from the disease. Recent genome-wide genetic association studies have identified a number of common single nucleotide genetic polymorphisms (SNPs) that are associated with prostate cancer in men of European descent. Only a small number of studies have evaluated the association between these genetic variants and prostate cancer in African Americans. METHODS: We used logistic regression models to assess the association between prostate cancer in African American men and 24 SNPs from regions previously reported to be associated with prostate cancer in men of European descent. RESULTS: We found nominal evidence (P < 0.05) for association between prostate cancer and three chromosome 8q24 (rs6983561, rs16901979, and rs7000448) and two 10q11 (rs7904463 and rs10740051) SNPs. CONCLUSIONS: We confirm recent reports that 8q24 variants identified to be associated with prostate cancer in men of European descent are also associated with prostate cancer in African Americans. Our report is the first to find evidence of association between SNPs near MSMB and prostate cancer in African Americans. Of note, rs7000448 is in strong linkage disequilibrium with rs10761581 in NCOA4, a SNP that has been implicated to be independently associated, with respect to the widely reported SNP rs10993994 in the nearby gene MSMB, with prostate cancer in men of European descent. PMID- 20717904 TI - Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1). AB - BACKGROUND: Metastasis-associated protein 1 (MTA1) is overexpressed in many forms of cancer types but its role in prostate cancer (PCa) progression and metastasis has not been explored. In this study, we addressed the functional and biological role of MTA1 in PCa. METHODS: Gene expression profiling was used to determine MTA1 overexpression during PCa cell-bone interaction. Immunohistochemistry was used to detect MTA1 on tissue microarrays (TMA) and vascular endothelial growth factor (VEGF), CD31, and Ki67 in xenografts. We used retroviral or lentiviral RNAi transduction of PCa cells to establish MTA1 knockdowns. RT-PCR, Western blot, invasion, and endothelial cell migration assays were used to characterize the cells in vitro. The role of MTA1 in PCa tumorigenesis was evaluated in mouse xenografts. RESULTS: We identified MTA1 as a component of bone metastasis signature in PCa, which suggested a possible role for MTA1 in PCa progression and metastasis. MTA1 was expressed at higher levels in PCa cell lines than in normal prostate epithelial cells. Silencing MTA1 significantly suppressed the invasion and angiogenic activity of the cells in vitro and delayed tumor formation and development in mouse xenografts. Tumors that express MTA1 had higher proliferative indices, secreted higher levels of VEGF and were more vascularized. Analysis of the human TMA showed positive correlation between MTA1 nuclear localization/staining intensity and PCa aggressiveness. CONCLUSIONS: MTA1 pro angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa. PMID- 20717905 TI - Nucleic acid sequence design via efficient ensemble defect optimization. AB - We describe an algorithm for designing the sequence of one or more interacting nucleic acid strands intended to adopt a target secondary structure at equilibrium. Sequence design is formulated as an optimization problem with the goal of reducing the ensemble defect below a user-specified stop condition. For a candidate sequence and a given target secondary structure, the ensemble defect is the average number of incorrectly paired nucleotides at equilibrium evaluated over the ensemble of unpseudoknotted secondary structures. To reduce the computational cost of accepting or rejecting mutations to a random initial sequence, candidate mutations are evaluated on the leaf nodes of a tree decomposition of the target structure. During leaf optimization, defect-weighted mutation sampling is used to select each candidate mutation position with probability proportional to its contribution to the ensemble defect of the leaf. As subsequences are merged moving up the tree, emergent structural defects resulting from crosstalk between sibling sequences are eliminated via reoptimization within the defective subtree starting from new random subsequences. Using a Theta(N(3) ) dynamic program to evaluate the ensemble defect of a target structure with N nucleotides, this hierarchical approach implies an asymptotic optimality bound on design time: for sufficiently large N, the cost of sequence design is bounded below by 4/3 the cost of a single evaluation of the ensemble defect for the full sequence. Hence, the design algorithm has time complexity Omega(N(3) ). For target structures containing N ?{100,200,400,800,1600,3200} nucleotides and duplex stems ranging from 1 to 30 base pairs, RNA sequence designs at 37 degrees C typically succeed in satisfying a stop condition with ensemble defect less than N/100. Empirically, the sequence design algorithm exhibits asymptotic optimality and the exponent in the time complexity bound is sharp. PMID- 20717906 TI - Use of post-exercise laryngoscopy to evaluate exercise induced dyspnea. AB - We present the case of a child with asthma who continued to have marked exercise induced dyspnea despite appropriate treatment, and in the face of adequate control of all other asthma symptoms. Spirometry showed a marked truncation of inspiratory flow, and laryngoscopy performed immediately after exercise showed laryngomalacia with dynamic, partial inspiratory obstruction. Exercise induced laryngomalacia (EIL) is a rare cause of exercise induced dyspnea which is diagnosed by post exercise flexible laryngoscopy and may require supraglottoplasty. PMID- 20717907 TI - The feasibility and validity of forced spirometry in ataxia telangiectasia. AB - OBJECTIVES: To explore the feasibility and validity of forced spirometry in patients with ataxia telangiectasia (A-T). STUDY DESIGN: Twenty-eight patients (aged 3.7-19.3 years) performed spirometry on 47 occasions. Parameters studied were technical quality and relation to: predicted values, pulmonary illness. RESULTS: Start of test criteria for correct expiratory effort was significantly prolonged (183 +/- 115 ms; P < 0.001). The rise-time to peak flow in children free of respiratory symptoms (Group-FRS; n = 8) increased by 16.2 +/- 12.5 ms/year above recommended and in children having recurrent infections (n = 8) 30.4 +/- 16.1 ms/year, P < 0.01. Expiration-time was significantly shorter than requested (1.21 +/- 0.47 sec) and was ended abruptly in 57% of the patients. FEV(1) could not be established by 8/20 patients. The intra-subject reproducibility met criteria (4.4 +/- 2.7%, 5.2 +/- 2.8%, 2.9 +/- 3.2%, 6.3 +/- 5.3%, for FVC, FEV(0.5), PEF, FEF(25-75), respectively). Group-FRS showed yearly deterioration in FVC of 2.2%, while patients with hyper-reactive airways (Group HRA; n =12) had a deterioration rate of 3.6%/year. FEV(0.5) deterioration rate was similar in both groups (2.2 and 2.0, respectively), but baseline values in Group-HRA were significantly lower than those of Group-FRS (P = 0.029) in similar young ages, indicating airway obstruction at early ages in Group-HRA. FEV(0.5) values deterioration also correlated with body mass index (P < 0.017). CONCLUSION: Forced spirometry in A-T patients is reproducible and has a distinct pattern, although curves do not meet other recommendations for acceptable criteria. The study insinuates that a rapid deterioration in lung function occurs in A-T patients with recurrent respiratory infection, suggesting that early intervention may prevent further deterioration or improve their lung function. Further studies are needed to confirm our results. PMID- 20717908 TI - An exciting but challenging road ahead for computational enzyme design. PMID- 20717909 TI - Milk protein and Oil-Red-O staining of alveolar macrophages in chronic respiratory disease of infancy. AB - Aspiration is a suspected cause of chronic respiratory disease in infants. We assessed the probability of aspiration by immunocytochemical staining of alveolar macrophages for milk proteins (alpha-lactalbumin and beta-lactoglobulin) and compared these findings with the Oil-Red-O staining score. Broncho-alveolar lavage (BAL), 24-hr esophageal pH-measurement and/or gastro-esophageal scintigraphy were performed in 111 children. Seventy-nine patients were enrolled. Ten exclusively soya milk formula fed children served as a control group. Individual scores, expressed as the mean percentage of positive staining macrophages counted by three blinded authors were made. Relying on the control group, a positive score was defined as a value higher than 1%. A positive score was found in 26% (18/69). Forty-four percent (8/18) of them had positive gastro esophageal reflux (GER) tests. In 61% (11/18) a concomitant diagnosis of laryngo /tracheomalacia was made. A positive score was found in 48% (11/23) of patients with laryngo-/tracheomalacia, compared to 15% (7/46) in infants with normal laryngeal and tracheal anatomy. No correlation was found between the immunocytochemical staining score for milk proteins and the Oil-Red-O staining score. We conclude that assuming the 1% criterion, persistent respiratory symptoms were associated with a positive immunostaining score, suggestive for aspiration, in 26% of infants, in 48% in case of concomitant laryngo- and/or tracheomalacia and in 15% of infants with normal laryngeal and tracheal anatomy. No correlation was found between the immunocytochemical staining score for cow milk proteins and the Oil-Red-O staining score. PMID- 20717911 TI - The diagnostic value and safety of transbronchial needle aspiration biopsy in children with mediastinal lymphadenopathy. AB - INTRODUCTION: Anterior mediastinal masses in children can have different causes which includes, Mycobacterium tuberculosis (MTB) or malignant lymphadenopathy. Transbronchial needle aspiration (TBNA) has been described as a safe and effective diagnostic procedure in adult patients with lung cancer. AIM: To describe the use of TBNA as a diagnostic test in children with large subcarinal lymphadenopathy and to determine the safety of the procedure in children. PATIENTS AND METHODS: Prospective descriptive study of children with subcarinal mediastinal lymph nodes who underwent TBNA. The majority of the children were referred due to treatment failure. Children were enrolled if the diagnosis remained unclear after computer tomography of the chest. RESULTS: Thirty patients were enrolled in this study; TBNA was done in 28 patients. A definitive diagnosis was made by TBNA in 54% (n = 15) of patients; MTB lymphadenopathy (n = 13), metastatic nephroblastoma (n = 1), and fibrosing mediastinitis (n = 1). In seven (25%) cases the TBNA was the sole source of the specimens from which the definitive diagnosis was made. No serious complications were encountered during or after the procedure. CONCLUSION: TBNA is a safe procedure in children with mediastinal lymphadenopathy of unknown cause resulting in a definitive diagnosis in 57% of cases. TBNA adds additional value to flexible bronchoscopy in the diagnosis of mediastinal lymphadenopathy in children. PMID- 20717910 TI - Do New Zealand children with non-cystic fibrosis bronchiectasis show disease progression? AB - BACKGROUND: There is minimal literature available on the long-term outcome of pediatric non-cystic fibrosis (CF) bronchiectasis. AIM: To document 5-year outcomes of children with chest computerized tomography (CT) scan diagnosed bronchiectasis from a tertiary New Zealand (NZ) respiratory clinic. METHODS: Review of a clinical database identified 91 children. Demographics, clinical data, lung function, chest X-ray (CXR), sputum, presumed etiology, admission data, and the NZ deprivation index (NZDep) were collected. Univariate and multivariate regression were used to correlate clinical findings with lung function data and CXR scores using the Brasfield Scoring System. RESULTS: Of the 91 children, 53 (59%) were Pacific Island, 22 (24%) Maori, 14 (15%) European, and 2 (2%) Other. The median follow-up period was 6.7 years (range 5.0-15.3 years) and median age at diagnosis was 7.3 years (range 11 months-16 years). Lung function data (n = 64) showed a mean decline of -1.6% predicted/year. In 30 children lung function declined (mean FEV(1) -4.4% predicted/year, range 1-17%), remained stable in 13 and improved in 21 children (mean FEV(1) of +3% predicted/year, range 1-15%). Reduced lung function was associated with male gender, chronic Haemophilus influenzae infection, longevity of disease, and Maori and Pacific Island ethnicity. There was a significant correlation with FEV(1) and CXR score at beginning (n = 47, r = 0.45, P = 0.001) and end (n = 26, r = 0.59, P = 0.002) of the follow-up period. The only variable consistently related to CXR score was chronic Haemophilus influenzae infection occurring in 27 (30%) (r(2) = 0.52, P = <0.0001). Only four children were chronically infected with Pseudomonas species. Six children died. CONCLUSION: In our experience despite management in a tertiary multidisciplinary bronchiectasis clinic, progression of lung disease continues in a group of children and young adults. PMID- 20717912 TI - Postinfectious bronchiolitis obliterans in children: clinical and pulmonary function findings. AB - AIM: Postinfectious bronchiolitis obliterans (PIBO) is an infrequent yet potentially severe disorder following acute lower pulmonary infection (ALRI) in children. In infants and young children PIBO have been strongly associated with Adenovirus (Ad). The purpose of this study was to analyze the clinical features and pulmonary function findings in children with PIBO. Cases caused by Ad were compared with cases in which no viral agent was identified. METHODS: Fifty-eight children with PIBO were prospectively studied. Clinical data and pulmonary function tests (spirometry and plethysmography) were evaluated. Patients were divided in two groups according to the identification of the causal agent. Group 1 (G1): Adenovirus (+) Group 2: No etiologic agent identified. RESULTS: Fifty eight patients (male/female ratio 3.4:1); median age 8 years; mean age at initial injury 11 months; median time of hospitalization at acute stage of disease 60 days. Spirometry: FVC 68 +/- 13%, FEV1 40.5 +/- 11%, FMMF(25-75%) 16.7 +/- 7.5%. Pletysmography: TLC 136 +/- 22%, FRC 208 +/- 50%, RV 343 +/- 102%, RV/TLC 59 +/- 10, SGaw 0.05 +/- 0.02. When clinical, spirometric and plethysmographic data were compared, no statistically significant difference was found between the two groups. CONCLUSIONS: PIBO is an extremely crippling lung disease with significant obstructive pattern in PFT. Both analyzed groups shared similar characteristics in the acute phase of the disease and in the severity of the sequelar pulmonary disease. PMID- 20717913 TI - Clara cell protein in full-term pregnancies: the influence of intrauterine growth restriction. AB - BACKGROUND: Clara cell protein (CC16) is an immunomodulatory/anti-inflammatory broncho-alveolar-derived molecule and a biomarker of pulmonary epithelial cells maturity and alveolo-capillary membrane injury. Intrauterine growth-restricted (IUGR) neonates may present with structural lung immaturity, impaired immunocompetence and increased risk for respiratory infections and chronic obstructive lung disease in later life. OBJECTIVES: To investigate circulating CC16 concentrations in maternal, fetal, and neonatal samples from IUGR and appropriate for gestational age (AGA) pregnancies. METHODS: Serum CC16 concentrations were determined by EIA in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses-neonates on postnatal days 1 (N1) and 4 (N4). RESULTS: No significant differences in CC16 concentrations were observed between IUGR and AGA groups. In both groups, maternal CC16 concentrations were lower compared to N1 and N4 ones (P < 0.001 in each case). Fetal CC16 concentrations were significantly lower compared to N1 and N4 ones (P < 0.001 in each case). In the AGA group, N1 CC16 concentrations were significantly higher than N4 ones (P < 0.001). Combining groups, N1 CC16 concentrations positively correlated with gestational age (r = 0.364, P = 0.021). Finally, the effect of gender, parity, and maternal age on CC16 concentrations was not significant. CONCLUSIONS: The lack of differences in CC16 concentrations between IUGR and AGA groups possibly suggests that the lung immaturity and later respiratory diseases, associated with the former, may not be related to early CC16 deficiency. CC16 concentrations increase with advancing gestational age and peak on the first day of life, possibly indicating a vital role of the protein in fetal lung maturation and extrauterine pulmonary adaptation. PMID- 20717914 TI - Polysomnographic characteristics in patients with mucopolysaccharidoses. AB - To evaluate the prevalence of obstructive sleep apnea (OSA) and to clarify sleep characteristics in patients with mucopolysaccharidoses (MPS), we performed overnight polysomnographic studies in 24 patients (22 males and 2 females; 3 with MPS I, 15 with MPS II, 1 with MPS III, 1 with MPS IV, and 4 with MPS VI; mean age, 10.8 +/- 6.0 years; age range, 2.0-23.7 years; 2 patients >=18 years of age). The nadir arterial oxygen saturation (SaO(2) ) was 74.5 +/- 12.3%, and the average percentage of sleep time with an SaO(2) of <95% was 39.4%. The percentages of total sleep time spent in sleep stages N1, N2, N3, and R were 18.6 +/- 10.8%, 50.3 +/- 7.6%, 14.8 +/- 8.1%, and 15.3 +/- 4.6%, respectively. The respiratory disturbance index (RDI) was 21.8 +/- 20.4/hr, and obstructive apnea hypopnea index (OAHI) and central apnea index were 21.4 +/- 19.9/hr and 0.4 +/- 0.6/hr, respectively. The desaturation index was 17.6 +/- 17.8/hr. All patients had some degree of OSA. For 22 children, the disorder was mild (OAHI 1.5-5) in 2, moderate (OAHI 5-10) in 7, and severe (OAHI > 10) in 13. Two patients with MPS II who received enzyme replacement therapy had reductions in RDI after treatment (38.9-10.8 and 3.5-2.0, respectively). The prevalence of moderate to severe OSA was 88% (21/24) in patients with MPS. The overnight polysomnography will help to determine the abnormalities of breathing during sleep more precisely and urge the clinicians to take necessary action for patients with severe manifestations. PMID- 20717916 TI - RTN3 and RTN4: Candidate modulators in vascular cell apoptosis and atherosclerosis. AB - The vascular cell apoptosis may play an important role in the development of atherosclerosis. Reticulons, the only molecular so far to participate in all three apoptosis signaling pathways, may be a novel player in the progress of AS. We presumes that reticulons may belong to the principle node of apoptosis pathway and be the candidate factor linking apoptosis and AS. PMID- 20717915 TI - Pulmonary outcome prediction (POP) tools for cystic fibrosis patients. AB - RATIONALE: Loss of lung function in patients with cystic fibrosis (CF) is associated with increased mortality and varies between individuals and over time. Predicting this decline could improve patient management. OBJECTIVES: To develop simple pulmonary outcome prediction (POP) tools to estimate lung function at age 6 in patients aged 2-5 years (POP(2-5)) and lung function change over a 4-year period in patients aged 6-17 years (POP(6-17)). METHODS: Analyses were conducted using patients from the Epidemiologic Study of CF (ESCF). To be included in any analysis, patients had to have 1 year of clinical history recorded in ESCF prior to a clinically stable routine Index Clinic Visit (ICV). In addition to this criterion, for the POP(2-5) tool patients had to be between 2 and 5 years old at ICV and have a second clinically stable visit with spirometric measures at age 6. For the POP(6-17) tool, patients had to be between the ages of 6 and 17 years old at an ICV that included spirometric measures and had to have a second clinically stable visit with spirometric measures from 3 to 5 years after ICV. All patients enrolled in ESCF who met these inclusion criteria were studied. POP(2-5) and POP(6-17) populations were further divided into development groups (with ICV before January 1, 1998) and validation groups (with ICV after that date). Development groups were used to model forced expiratory volume in 1 sec (FEV(1)) percent predicted at age 6 years (for POP(2-5)) and annualized FEV(1) % predicted change from ICV to the second visit (for POP(6-17)) by multivariable linear regression using age, sex, weight-for-age percentile, cough, sputum production, clubbing, crackles, wheeze, sinusitis, number of exacerbations requiring intravenous antibiotics in the past year, elevated liver enzymes, pancreatic enzyme use, and respiratory tract culture status, plus height-for-age percentile (POP(2-5)) and index FEV(1) (POP(6-17)). Integer-based POP(2-5) and POP(6-17) tools created from selected variables were evaluated by Pearson correlation and then prospectively validated with separate data collected later from ESCF patients with ICV after January 1, 1998. MAIN RESULTS: POP(2-5) and POP(6-17) development groups included 2,709 and 6,113 patients and validation groups included 3,458 and 7,086 patients, respectively. Variables retained were weight for-age percentile, clubbing, crackles, wheeze, number of exacerbations, and Pseudomonas aeruginosa culture status (both tools), daily cough (POP(2-5)), and age, sex, and index FEV(1) % predicted (POP(6-17)). Correlation coefficients for POP(2-5) and POP(6-17) tools prospectively applied to validation groups were +0.32 and +0.37, respectively. CONCLUSIONS: These simple integer-based POP algorithms employ variables available at clinic visits and can be used to predict the probability of different future pulmonary outcomes for individual patients and patient populations. PMID- 20717917 TI - c-Cbl regulates glioma invasion through matrix metalloproteinase 2. AB - c-Cbl, a multifunctional adaptor and an E3 ubiquitin ligase, plays a role in such cytoskeleton-mediated events as cell adhesion and migration. Invasiveness of human glioma is dependent on cell adhesion, migration, and degradation of extracellular matrix (ECM). However, the function of c-Cbl in glioma invasion has never been investigated. We report here, for the first time, that c-Cbl plays a positive role in the invasion of ECM by SNB19 glioma cells. RNAi-mediated depletion of c-Cbl decreases SNB19 cell invasion and expression of matrix metalloproteinase 2 (MMP2). Consistent with these findings, SNB19 cells expressing wild-type, but not mutant c-Cbl show increased invasion and MMP2 expression. We demonstrate that the observed role of c-Cbl in invasion of SNB19 cells is not mediated by the previously shown effects of c-Cbl on cell adhesion and migration or on EGFR signaling. Together, our results suggest that c-Cbl promotes glioma invasion through up-regulation of MMP2. PMID- 20717918 TI - Microarray profile of gene expression during osteoclast differentiation in modelled microgravity. AB - Microgravity (uXg) leads to a 10-15% loss of bone mass in astronauts during space flight. Osteoclast (OCL) is the multinucleated bone-resorbing cell. In this study, we used the NASA developed ground-based rotating wall vessel bioreactor (RWV), rotary cell culture system (RCCS) to simulate uXg conditions and demonstrated a significant increase (2-fold) in osteoclastogenesis compared to normal gravity control (Xg). Gene expression profiling of RAW 264.7 OCL progenitor cells in modelled uXg by Agilent microarray analysis revealed significantly increased expression of critical molecules such as cytokines/growth factors, proteases and signalling proteins, which play an important role in enhanced OCL differentiation/function. Transcription factors such as c-Jun, MITF and CREB implicated in OCL differentiation are upregulated; however no significant change in the levels of NFATc1 expression in preosteoclast cells subjected to modelled uXg. We also identified high-level expression of calcium binding protein, S100A8 (calcium-binding protein molecule A8/calgranulin A) in preosteoclast cells under uXg. Furthermore, modelled uXg stimulated RAW 264.7 cells showed elevated cytosolic calcium (Ca(2+)) levels/oscillations compared to Xg cells. siRNA knock-down of S100A8 expression in RAW 264.7 cells resulted in a significant decrease in modelled uXg stimulated OCL differentiation. We also identified elevated levels of phospho-CREB in preosteoclast cells subjected to modelled uXg compared to Xg. Thus, modelled uXg regulated gene expression profiling in preosteoclast cells provide new insights into molecular mechanisms and therapeutic targets of enhanced OCL differentiation/activation to prevent bone loss and fracture risk in astronauts during space flight missions. PMID- 20717919 TI - Fyn promotes proliferation, differentiation, survival and function of osteoclast lineage cells. AB - c-Src and Lyn are the only Src family kinases (SFKs) with established activity in osteoclasts (OCs). c-Src promotes function via cytoskeletal organization of the mature resorptive cell while Lyn is a negative regulator of osteoclastogenesis. We establish that Fyn, another SFK, also impacts the OC, but in a manner distinctly different than c-Src and Lyn. Fyn deficiency principally alters cells throughout the osteoclastogenic process, resulting in diminished numbers of resorptive polykaryons. Arrested OC formation in the face of insufficient Fyn reflects reduced proliferation of precursors, in response to M-CSF and retarded RANK ligand (RANKL)-induced differentiation, attended by suppressed activation of the osteoclastogenic signaling molecules, c-Jun, and NF-kappaB. The anti apoptotic properties of RANKL are also compromised in cells deleted of Fyn, an event mediated by increased Bim expression and failed activation of Akt. The defective osteoclastogenesis of Fyn-/- OCs dampens bone resorption, in vitro. Finally, while Fyn deficiency does not regulate basal osteoclastogenesis, in vivo, it reduces that stimulated by RANKL by ~2/3. Thus, Fyn is a pro-resorptive SFK, which exerts its effects by prompting proliferation and differentiation while attenuating apoptosis of OC lineage cells. PMID- 20717920 TI - Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. AB - Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and exerts its function in the target organs by binding the FGF receptor (FGFR) and Klotho. Since recent studies suggested that extracellular inorganic phosphate (Pi) itself triggers signal transduction and regulates gene expression in some cell types, we tested the notion that extracellular Pi induces signal transduction in the target cells of FGF23 also and influences its signaling, utilizing a human embryonic kidney cell line HEK293. HEK293 cells expressed low levels of klotho, and treatment with a recombinant FGF23[R179Q], a proteolysis resistant mutant of FGF23, resulted in phosphorylation of ERK1/2 and induction of early growth response-1 (EGR1) expression. Interestingly, increased extracellular Pi resulted in activation of the Raf/MEK/ERK pathway and expression of EGR1, which involved type III sodium/phosphate (Na(+)/Pi) cotransporter PiT-1. Since the effects of an inhibitor of Na(+)/Pi cotransporter on FGF23 signaling suggested that the signaling triggered by increased extracellular Pi shares the same downstream cascade as FGF23 signaling, we further investigated their convergence point. Increasing the extracellular Pi concentration resulted in the phosphorylation of FGF receptor substrate 2alpha (FRS2alpha), as did treatment with FGF23. Knockdown of FGFR1 expression diminished the phosphorylation of both FRS2alpha and ERK1/2 induced by the Pi. Moreover, overexpression of FGFR1 rescued the decrease in Pi-induced phosphorylation of ERK1/2 in the cells where the expression of PiT-1 was knocked down. These results suggest that increased extracellular Pi triggers signal transduction via PiT-1 and FGFR and influences FGF23 signaling in HEK293 cells. PMID- 20717921 TI - Thapsigargin-induced Ca2+ increase inhibits TGFbeta1-mediated Smad2 transcriptional responses via Ca2+/calmodulin-dependent protein kinase II. AB - Transforming growth factor beta (TGFbeta) signalling plays important roles in a variety of tissues and cell types. Impaired TGFbeta signalling contributes to several pathologies, including cancer, fibrosis as well as neurodegenerative diseases. TGFbeta receptor type I-mediated phosphorylation of Smad2, the formation of the Smad2-Smad4 complex and translocation to the nucleus are critical steps of the TGFbeta signalling pathway. Here, we demonstrate that thapsigargin-mediated increase of intracellular Ca(2+) concentrations inhibited TGFbeta1-induced Smad2 transcriptional activity in the oligodendroglial cell line OLI-neu. We provide evidence that thapsigargin treatment dramatically reduced the nuclear translocation of Smad2 after TGFbeta1 treatment but had no effect on its phosphorylation at Ser465/467. Moreover, using Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitors and a constitutively active CaMKII mutant, we provide evidence that the observed inhibition of TGFbeta signalling in OLI-neu cells was strongly dependent on Ca(2+)-mediated CaMKII activation. In summary, this study clearly shows that the TGFbeta1-induced Smad2 nuclear translocation is negatively regulated by intracellular Ca(2+) in OLI-neu cells and that increased intracellular Ca(2+) concentrations block Smad2-mediated transcription of TGFbeta target genes. These results underline the importance of intracellular Ca(2+) for the regulation of TGFbeta signalling. PMID- 20717922 TI - Capacitation suppression by mouse seminal vesicle autoantigen involves a decrease in plasma membrane Ca2+-ATPase (PMCA)-mediated intracellular calcium. AB - Successful fertilization is tightly regulated by capacitation and decapacitation processes. Without appropriate decapacitation regulation, sperm would undergo a spontaneous acrosome reaction which leads to loss of fertilization ability. Seminal plasma is known to negatively regulate sperm capacitation. However, the suppressive mechanisms still remain unclear. In this study, we demonstrate the decapacitation mechanism of mouse seminal vesicle autoantigen (SVA) might target membrane sphingomyelin (SPM) and regulate plasma membrane Ca(2+)-ATPase (PMCA) activity. The SVA was shown to suppress sperm capacitation induced by a broad panel of capacitation factors (bovine serum albumin (BSA), PAF, and cyclodextrin (CD)). Furthermore, SVA significantly decreased [Ca(2+)](i) and NaHCO(3)-induced [cAMP](i). Cyclic AMP agonists bypassed the SVA's suppressive ability. Importantly, the SVA may regulate PMCA activity which was evidenced by the fact that the SVA decreased the [Ca(2+)](i) and intracellular pH (pH(i)) of sperm; meanwhile, a PMCA inhibitor (carboxyeosin) could reverse SVA's suppression of [Ca(2+)](i). The potential target of the SVA on membrane SPM/lipid rafts was highlighted by the high binding affinity of SPM-SVA (with a K(d) of ~3 uM) which was close to the IC(50) of SVA's suppressive activity. Additionally, treatment of mink lung epithelial cells with the SVA enhanced plasminogen activator inhibitor (PAI)-1 expression stimulated by tumor growth factor (TGF)-beta and CD. These observations supported the membrane lipid-raft targeting of SVA. In summary, in this paper, we demonstrate that the decapacitation mechanism of the SVA might target membrane sphingolipid SPM and regulate PMCA activity to lower [Ca(2+)](i), thereby decreasing the [cAMP](i) level and preventing sperm pre-capacitation. PMID- 20717923 TI - Role of lysyl oxidase propeptide in secretion and enzyme activity. AB - Lysyl oxidase (LOX) is secreted as a proenzyme (proLOX) that is proteolytically processed in the extracellular milieu to release the propeptide and mature, active LOX. LOX oxidizes lysyl residues of a number of protein substrates in the extracellular matrix and on the cell surface, which impacts several physiological and disease states. Although the LOX propeptide (LOX-PP) is glycosylated, little is known about the role of this modification in LOX secretion and activity. To gain insight into this issue, cells were transfected with native, full-length LOX cDNA (pre-pro-LOX), the N-glycosylation null pre-[N/Q]pro-LOX cDNA and the deletion mutant pre-LOX cDNA, referred to as secretory LOX, in which mature LOX is targeted to the secretory pathway without its N-terminal propeptide sequence. The results show that glycosylation of the LOX-PP is not required for secretion and extracellular processing of pro-LOX but it is required for optimal enzyme activity of the resulting mature LOX. Complete deletion of the propeptide sequence prevents mature LOX from exiting the endoplasmic reticulum (ER). Taken together, our study points out the requirement of the LOX-PP for pro-LOX exit from the ER and is the first to highlight the influence of LOX-PP glycosylation on LOX enzyme activity. PMID- 20717924 TI - Hedgehog signaling and osteogenic differentiation in multipotent bone marrow stromal cells are inhibited by oxidative stress. AB - Oxidative stress may play a major role in age-related osteoporosis in part by inhibiting osteoblast generation from osteoprogenitors cells. In the present study, we hypothesized that oxidative stress may inhibit the osteogenic differentiation of bone marrow stromal cells (MSC) in part by inhibiting the Hedgehog (Hh) signaling pathway, which is essential for bone development and maintenance and induces osteogenic differentiation of osteoprogenitor cells. To test this hypothesis, we examined the effects of oxidative stress on Sonic Hh (Shh)-induced osteogenic differentiation and signaling in M2-10B4 (M2) MSC, C3H10T1/2 embryonic fibroblasts, and mouse primary MSC. Treatment of cells with H(2)O(2) inhibited Shh-induced osteogenic differentiation determined by the inhibition of Shh-induced expression of osteogenic differentiation markers alkaline phosphatase (ALP), osterix (OSX), and bone sialoprotein (BSP). Similar effects were found when oxidative stress was induced by xanthine/xanthine oxidase (XXO) or minimally oxidized LDL (MM-LDL). H(2)O(2) , XXO, and MM-LDL treatment inhibited Shh-induced expression of the Hh target genes Gli1 and Patched1 as well as Gli-dependent transcriptional activity in M2 cells. H(2)O(2) treatment also inhibited Hh signaling induced by the direct activation of Smoothened by purmorphamine (PM), but not by Gli1 overexpression. This suggests that oxidative stress may inhibit Hh signaling upstream of Gli activation and Gli-induced gene expression. These findings demonstrate for the first time that oxidative stress inhibits Hh signaling associated with osteogenic differentiation. Inhibition of Hh signaling-mediated osteogenic differentiation of osteoprogenitor cells may in part explain the inhibitory effects of oxidative stress on osteoblast development, differentiation, and maintenance in aging. PMID- 20717925 TI - VEGF stimulation enhances Livin protein synthesis through mTOR signaling. AB - Livin is a member of inhibitors of apoptosis proteins (IAPs) and overexpressed in transformed cells and several cancers. Although strategies to decrease Livin levels have been conducted for rational cancer therapy, the molecular mechanism controlling Livin expression in tumors has not been completely elucidated. Here, we show that vascular endothelial growth factor (VEGF) stimulation can increase Livin expression in HeLa cells or SK-MEL-28 cells. This response is independent of de novo gene transcription or changes in mRNA expression but occurs at protein expression levels. VEGF stimulation results in mTOR signaling activation which changes the phosphorylation status of 4E-BP1, the downstream of mTOR signaling, and ultimately contributes to the translation initiation of Livin protein. Livin silencing, Rapamycin alone or in combination with cytotoxic agent can reduce Livin protein levels, and decrease cells viability. Thus, ablation of Livin translation contributes to remove an anti-apoptotic mechanism potentially contributing to aggressive tumor behavior. Pharmacologic inhibition of VEGF/mTOR/Livin signaling may provide a novel strategy for cancer treatment. PMID- 20717926 TI - Glutamate preferentially suppresses osteoblastogenesis than adipogenesis through the cystine/glutamate antiporter in mesenchymal stem cells. AB - We have shown that glutamate (Glu) signaling machineries, such as receptors (GluR) and transporters, are functionally expressed by mesenchymal stem cells, in addition to by their progeny cells such as osteoblasts and chondrocytes. Sustained exposure to Glu induced significant decreases in alkaline phosphatase (ALP) staining and osteoblastic marker gene expression in the mesenchymal C3H10T1/2 stem cells infected with runt-related transcription factor-2 (Runx2) adenovirus, without markedly affecting Oil Red O staining for adipocytes in cells cultured with adipogenic inducers. In cells with Runx2 adenovirus, the cystine/Glu antiporter substrate cystine significantly prevented the decreases by Glu in both ALP staining and osteoblastic marker gene expression, with GluR agonists being ineffective. In cells with Runx2 adenovirus, Glu significantly decreased [14C]cystine uptake, intracellular glutathione (GSH) level, Runx2 recruitment to osteocalcin promoter and nuclear Runx2 protein level, respectively. Cystine again significantly prevented the decreases by Glu in both GSH levels and Runx2 recruitment. In mouse bone marrow stromal cells, Glu and a GSH depleter significantly decreased ALP staining without affecting Oil Red O staining. Knockdown of the cystine/Glu antiporter led to markedly decreased ALP staining and GSH levels, with concomitant prevention of the decrease by Glu, in cells with Runx2 adenovirus. These results suggest that Glu may play a role as a negative regulator at an early differentiation stage into osteoblasts than adipocytes through a mechanism relevant to nuclear translocation of Runx2 after regulation of intracellular GSH levels by the cystine/Glu antiporter expressed in mesenchymal stem cells. PMID- 20717927 TI - Lysyl oxidase propeptide sensitizes pancreatic and breast cancer cells to doxorubicin-induced apoptosis. AB - RAS mutations or its activation by upstream receptor tyrosine kinases are frequently associated with poor response of carcinomas to chemotherapy. The 18 kDa propeptide domain of lysyl oxidase (LOX-PP) released from the secreted precursor protein (Pro-LOX) has been shown to inhibit RAS signaling and the transformed phenotype of breast, pancreatic, lung, and prostate cancer cells in culture, and formation of tumors by Her-2/neu-driven breast cancer cells in a mouse xenograft model. Here, we tested the effects of LOX-PP on MIA PaCa-2 pancreatic cancer cells, driven by mutant RAS. In MIA PaCa-2 cells in culture, LOX-PP attenuated the ERK and AKT activities and decreased the levels of the NF kappaB p65 and RelB subunits and cyclin D1, which are activated by RAS signaling. In mouse xenograft growth, LOX-PP reduced growth of tumors by these pancreatic cancer cells, and the nuclear levels of the p65 NF-kappaB subunit and cyclin D1 proteins. While biological agents attenuate tumor growth when used alone, often they have additive or synergistic effects when used in combination with chemotherapeutic agents. Thus, we next tested the hypotheses that LOX-PP sensitizes pancreatic and breast cancer cells to the chemotherapeutic agent doxorubicin. Purified LOX-PP enhanced the cytotoxic effects of doxorubicin in pancreatic and breast cancer cells, as judged by ATP production, Cell Death ELISA assays, caspase 3 activation, PARP cleavage, and Annexin V staining. Thus, LOX-PP potentiates the cytotoxicity of doxorubicin on breast and pancreatic cancer cells, warranting additional studies with a broader spectrum of current cancer treatment modalities. PMID- 20717928 TI - Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells. AB - Osteoblasts and adipocytes originate from common mesenchymal progenitor cells and although a number of compounds can induce osteoblastic and adipogenic differentiation from progenitor cells, the underlying mechanisms have not been elucidated. The present study examined the synergistic effects of dexamethasone (Dex) and bone morphogenetic protein (BMP)-2 on the differentiation of clonal mesenchymal progenitor cells isolated from rat calvaria into osteoblasts and adipocytes, as well as the effects of the timing of treatment. Cells were cultured for various periods of time in the presence of Dex and/or BMP-2. When cells were treated with Dex+BMP-2 during the early phase of differentiation, they differentiated into adipocytes. However, when cells were treated with Dex+BMP-2 during the late phase of differentiation, a synergistic effect on in vitro matrix mineralization was observed. To examine differences between the early and late phases of differentiation, ALP activity was measured in the presence of BMP-2. ALP activity increased markedly on Day 9, corresponding to the onset of the synergistic effect of Dex. Dex treatment inhibited osterix (OSX) expression in cells committed to adipogenic differentiation, but not in cells committed to osteogenic differentiation following BMP-2 treatment. The isoform2 OSX promoter region was found to be involved in the effects of Dex on cells during the early phase of differentiation. Furthermore, cells stably expressing OSX (isoform2) formed mineralized nodules even though they had been treated with Dex+BMP-2 during the early phase of differentiation. It appears that Dex modulates osteogenesis and adipogenesis in mesenchymal stem cells by regulating OSX expression. PMID- 20717929 TI - Regulation of UDP-glucose dehydrogenase is sufficient to modulate hyaluronan production and release, control sulfated GAG synthesis, and promote chondrogenesis. AB - Glycosaminoglycans (GAGs) are critical for extracellular matrix (ECM) integrity in cartilage but mechanisms regulating their synthesis are not defined. UDP glucose dehydrogenase (UGDH) catalyses UDP-glucose oxidation to UDP-glucuronic acid, an essential monosaccharide in many GAGs. Our previous studies in articular surface (AS) cells from embryonic joints have established pivotal roles for mitogen-activated protein kinases (MAPK) in synthesis of the unsulfated GAG, hyaluronan (HA). We investigated the functional significance of UGDH in GAG production and chondrogenesis, and determined roles for MEK-ERK and p38MAPK pathways in regulating UGDH expression and function. Inhibitors of MEK and p38MAPK reduced UGDH protein in AS cells. Treatment with TGF-beta (archetypal growth factor) increased UGDH expression, sulfated (s)-GAG/HA release and pericellular matrix formation in a p38MAPK-dependent manner. Retroviral overexpression of UGDH augmented HA/sGAG release and pericellular matrix elaboration, which were blocked by inhibiting MEK but not p38MAPK. UGDH overexpression increased cartilage nodule size in bone marrow culture, promoted chondrogenesis in limb bud micromass culture and selectively suppressed medium HA levels and modified GAG sulfation, as assessed by FACE analysis. Our data provide evidence that: (i) TGF-beta regulates UGDH expression via p38MAPK to modulate sGAG/HA secretion, (ii) MEK-ERK, but not p38MAPK facilitates UGDH-induced HA and sGAG release, and (iii) increased UGDH expression promotes chondrogenesis directly and differential modifies GAG levels and sulfation. These results indicate a more diverse role for UGDH in the support of selective GAG production than previously described. Factors regulating UGDH may provide novel candidates for restoring ECM integrity in degenerative cartilage diseases, such as osteoarthritis.Arthritis Research Campaign. PMID- 20717930 TI - Induction of small G protein RhoB by non-genotoxic stress inhibits apoptosis and activates NF-kappaB. AB - It has been reported by us and other groups that the expression of small GTP binding protein RhoB can be induced by genotoxic stressors and glucocorticoid (GC), a stress hormone that plays a key role in stress response. Until now stress induced genes that confer cytoprotection under stressed conditions are largely unknown. In this study, we investigated the effects and mechanism of non genotoxic stressors, including scalding in vivo and heat stress in vitro on the expression of RhoB. We found for the first time that both scalding, which could induce typical neuroendocrine responses of acute stress and cellular heat stress significantly increased the expression of RhoB at mRNA and protein levels. Moreover, in vitro experiments in human lung epithelial cells (A549) showed that induction of RhoB by heat stress was in a glucocorticoid receptor (GR) independent manner and through multiple pathways including stabilization of RhoB mRNA and activation of p38 MAPK. Further experiments demonstrated that up regulation of RhoB significantly inhibited heat stress-induced apoptosis and elevated transcriptional activity of NF-kappaB, but did not affect the expression of Hsp70 in A549 cells. In conclusion, we showed for the first time that RhoB was up-regulated by scalding in vivo and heat stress in vitro and played an important cytoprotective role during heat stress-induced apoptotic cell death. PMID- 20717931 TI - Hyperosmolarity-mediated mitochondrial dysfunction requires Transglutaminase-2 in human corneal epithelial cells. AB - Hyperosmolar-induced ocular surface cell death is a key mitochondria-mediated event in inflammatory eye diseases. Transglutaminase (TGM)-2, a cross-linking enzyme, is purported to mediate cell death, but its link to mitochondria is unclear. In the cornea, the integrity of the epithelial cells is important for maintaining transparency of the cornea and therefore functional vision. We evaluated the role of TGM-2 and its involvement in hyperosmolarity-stimulated mitochondrial cell death in human corneal epithelial (HCE-T) cells. HCE-T cell lines stably expressing either shRNA targeting TGM-2 (shTG) or scrambled shRNA (shRNA) were constructed. Hyperosmolar conditions reduced viability and increased mitochondrial depolarization in shRNA cells. However, hyperosmolarity failed to induce mitochondrial depolarization to the same extent in shTG cells. Transient overexpression of TGM-2 resulted in very high levels of TGM-2 expression in shTG and shRNA cells. In the case of shTG cells after overexpression of TGM-2, hyperosmolarity induced the same extent of mitochondrial depolarization as similarly treated shRNA cells. Overexpression of TGM-2 also elevated transamidase activity and reduced viability. It also induced mitochondrial depolarization, increased caspase-3/7 and -9 activity, and these increases were partially suppressed by pan-caspase inhibitor Z-VAD-FMK. Corneal epithelial apoptosis via mitochondrial dysfunction after hyperosmolar stimulation is partially dependent on TGM-2. This TGM-2-dependent mechanism occurs in part via caspase-3/7 and -9. Protection against mitochondrial stress in the ocular surface targeting TGM-2 may have important implications in the survival of cells in hyperosmolar stress. PMID- 20717933 TI - Exceptional structural and mechanical flexibility of the nuclear pore complex. AB - Nuclear pore complexes (NPCs) mediate all transport between the cytosol and the nucleus and therefore take centre stage in physiology. While transport through NPCs has been extensively investigated little is known about their structural and barley anything about their mechanical flexibility. Structural and mechanical flexibility of NPCs, however, are presumably of key importance. Like the cell and the cell nucleus, NPCs themselves are regularly exposed to physiological mechanical forces. Besides, NPCs reveal striking transport properties which are likely to require fairly high structural flexibility. The NPC transports up to 1,000 molecules per second through a physically 9 nm wide channel which repeatedly opens to accommodate macromolecules significantly larger than its physical diameter. We hypothesised that NPCs possess remarkable structural and mechanical stability. Here, we tested this hypothesis at the single NPC level using the nano-imaging and probing approach atomic force microscopy (AFM). AFM presents the NPC as a highly flexible structure. The NPC channel dilates by striking 35% on exposure to trans-cyclohexane-1,2-diol (TCHD), which is known to transiently collapse the hydrophobic phase in the NPC channel like receptor-cargo complexes do in transit. It constricts again to its initial size after TCHD removal. AFM-based nano-indentation measurements show that the 50 nm long NPC basket can astonishingly be squeezed completely into the NPC channel on exposure to incremental mechanical loads but recovers its original vertical position within the nuclear envelope plane when relieved. We conclude that the NPC possesses exceptional structural and mechanical flexibility which is important to fulfilling its functions. PMID- 20717932 TI - Decrease in claudin-2 expression enhances cell migration in renal epithelial Madin-Darby canine kidney cells. AB - Migration of renal epithelial cells increases after renal tubular damage, but its mechanism has not been clarified in detail. Hyperosmotic stress increased a cellular injury concomitant with a decrease in mRNA and protein expression of claudin-2 in renal tubular epithelial Madin-Darby canine kidney cells. We hypothesized that claudin-2 is involved in the regulation of cell migration. To knockdown claudin-2 expression, we made the cells expressing doxycycline inducible claudin-2 shRNA vector. Claudin-2 knockdown affected neither the endogenous expression levels of claudin-1, -3, -4, and -7 nor the Triton X-100 solubility of these claudins. Transepithelial electrical resistance was increased by claudin-2 knockdown without affecting permeability to FITC-dextran (4,000 Da). BrdU incorporation assay and cell counting revealed that cell proliferation and viability are unaffected by claudin-2 knockdown. In the wound-healing assay, the recovery rate of wound area was increased by claudin-2 knockdown. The mRNA expression and activity of matrix metalloproteinase-9 (MMP-9) were increased by claudin-2 knockdown. A selective MMP-9 inhibitor suppressed cell migration in the claudin-2 knockdown cells. Hyperosmotic stress increased the expression and activity of MMP-9, which were inhibited by claudin-2 overexpression. These results suggest that the decrease in claudin-2 expression enhances cell migration mediated by the increase in the expression and activity of MMP-9. PMID- 20717934 TI - Changes to exhaled nitric oxide in asthmatic children after drinking a caffeine containing cola drink. AB - INTRODUCTION: Exhaled nitric oxide (FE(NO)) may be a biomarker for airway eosinophilia and of use in the management of childhood asthma. Caffeine ingestion has been associated with changes in FE(NO) concentration in adults. The present study tested the hypothesis that ingestion of a caffeine-containing cola drink will increase FE(NO) in asthmatic children. METHODS: Exhaled NO was measured in children with asthma before, 30 and 60 min after taking a cola drink containing 0.7 mg/kg caffeine. Intrasubject changes in FE(NO) and flow independent NO parameters were determined including bronchial wall NO flux (J'awNO). RESULTS: Eleven children with asthma were recruited, 10 were prescribed inhaled corticosteroids and 9 were skin prick positive. The median [interquartile range, IQR] FE(NO) at baseline was 47 parts per billion [9,64] and this rose to 56 ppb [11, 66] after 30 min and returned to 46 ppb [9, 62] after 60 min, Friedman's test P = 0.003. J'awNO rose from a median [IQR] 2,843 nl/sec [356, 4,247] at baseline to 3,304 nl/sec [479, 4,387] after 30 min and returned to 2,937 nl/sec [356, 4,153] after 60 min, Freidman's test P = 0.003. There was no significant change in other flow independent NO parameters. CONCLUSIONS: Ingestion of a caffeine-containing cola drink was associated with a modest and transient rise in FE(NO) which is mostly explained by increased NO production in the proximal airways. Ingestion of a caffeine-containing cola drink may result in clinically relevant acute changes in FE(NO) for children with asthma. PMID- 20717936 TI - Exhaled air temperature in children with bronchopulmonary dysplasia. AB - BACKGROUND: Because they have similar functional and clinical profiles, bronchopulmonary dysplasia (BPD) survivors are often treated as asthmatic patients. In truth, very little is known about the possible biochemical and inflammatory mechanisms playing a part in BPD survivors' lungs. The aim of this study was to measure exhaled breath temperature in BPD survivors by comparison with asthmatic cases and healthy controls. METHODS: Three groups of age-matched adolescents (n = 17 each), that is, BPD survivors (gestational ages <31 weeks, birth weights <1,500 g), asthmatic subjects and healthy controls, underwent exhaled breath temperature and exhaled nitric oxide measurements, and spirometry. RESULTS: Exhaled breath temperature was significantly lower in the BPD survivors (26.72 degrees C [25.11-27.57]) than in the asthmatic patients (29.60 degrees C [29.20-30.02], P < 0.001), while no significant difference emerged by comparison with healthy controls (26.97 degrees C [26.58-27.38]). Considering the whole study population, a significant correlation was found between exhaled breath temperatures and exhaled nitric oxide concentrations (R = 0.42, P = 0.004). Spirometry revealed an obstructive lung function pattern in both the asthmatic cases and the BPD survivors, with lower parameters in the latter. CONCLUSIONS: Exhaled breath temperatures and exhaled nitric oxide concentrations are significantly lower in BPD survivors than in asthmatic cases, suggesting that different pathogenetic mechanisms characterize these two chronic obstructive lung diseases. PMID- 20717935 TI - Trends in the use of routine therapies in cystic fibrosis: 1995-2005. AB - Many therapies are used to treat manifestations of cystic fibrosis (CF). Trends in routine therapy use in Epidemiologic Study of Cystic Fibrosis patients were studied from 1995 to 2005. Patients (15,087) were assessed in 1995; 12,778 in 2005. Observed differences in therapy use of >=2% were statistically significant at P < 0.001. Comparing the 1995 and 2005 populations, mean age was 13.9 versus 15.5 years; weight-for-age percentile was 30.3 versus 36.9; and mean forced expiratory volume in 1 sec (FEV(1)) was 73.7% (n = 7065) versus 78.7% (n = 7867) predicted. Use of several therapies increased, including airway clearance (69.9 89.6%), inhaled bronchodilators (72.0-84.0%), dornase alfa (44.8-67.2%), inhaled corticosteroids (16.0-49.3%), inhaled antibiotics (6.5-43.1%), oral nutritional supplements (18.3-24.5%), and insulin/oral hypoglycemic agents (4.9-10.2%). Use of mast cell stabilizers (from 22.0% to 5.3%) and oral bronchodilators (from 10.4% to 1.5%) decreased. Less dramatic changes occurred for pancreatic enzymes (92.6-91.0%), oral nonquinolone antibiotics (44.7-39.8%), oral corticosteroids (7.8-5.2%), mucolytics (4.4-2.5%), NSAIDs/high-dose ibuprofen (3.6-3.3%), enteral nutrition (5.2% vs. 8.2%), and oxygen (4.7-4.5%). Therapies not tracked in 1995 were evident in 2005, including oral macrolide antibiotics (33.8%), leukotriene inhibitors/antagonists (10.8%), and inhaled hypertonic saline (2.6%). Routine therapies were generally used more often by older patients and those with lower FEV(1). Notable increases in use of therapies, particularly of inhaled therapies, suggest that overall patient treatment burden must have risen correspondingly. PMID- 20717937 TI - Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho-kinase inhibitor fasudil. AB - Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho-kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho-kinase inhibitors could ameliorate PVR, little is known about the role of Rho-kinase in left ventricular dysfunction-induced PH. We utilized the ascending aortic-banded rat and assessed the effect of Rho-kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho-kinase II, Rho kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho-kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho-kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings. PMID- 20717938 TI - Monocytes from children with clinically stable cystic fibrosis show enhanced expression of Toll-like receptor 4. AB - SUMMARY: Lung disease in patients with cystic fibrosis (CF) is characterized by recurrent bacterial respiratory infections and intense airway inflammation. Pattern recognition receptors such as Toll-like receptor 2 (TLR2) and TLR4 identify bacterial pathogens and activate the innate immune response. We therefore hypothesized that increased expression of these receptors would be found on circulating immune cells from children with CF. A cohort of 66 young children (median age 3 years) with CF was studied and compared to both healthy controls (n = 14) and children without CF who were being investigated for recurrent respiratory infections (non-CF disease controls; n = 17) of a similar age. Surface expression of TLR2 and TLR4 on peripheral blood monocytes was analyzed using flow cytometry. TLR4 expression was significantly higher in patients with CF compared to healthy controls (P = 0.017) and non-CF disease controls (P = 0.025) but did not vary according to the presence or absence of pulmonary infection with Gram-negative or Gram-positive bacteria (P = 0.387) in the CF group. In contrast, TLR2 expression was similar across all three study groups (P = 0.930). The increased surface expression of TLR4 seen in young children with CF appears to be related to having CF per se and not related to current pulmonary infection. PMID- 20717939 TI - PHF11 is not a major candidate gene for asthma or eczema in Chinese children. AB - SUMMARY: Positional cloning and candidate gene studies in different Caucasian populations identified the gene encoding plant homeodomain zinc finger protein 11 (PHF11) to be associated with asthma and eczema. Microarray analysis also confirmed increased PHF11 expression in type 1 T-helper lymphocytes. However, such disease associations are unclear in Asian subjects. This case-control genetic association study investigated the relationship between asthma and eczema phenotypes and tagging single-nucleotide polymorphisms (SNPs) of PHF11 in Hong Kong Chinese children. Three hundred and nineteen asthmatic children and 236 children with eczema were recruited from hospital clinics and 445 children without any history of allergic disease were recruited as controls from local schools and hospitals. Atopy was defined by the presence of allergen-specific IgE in plasma or positive skin prick tests with wheal >or=3 mm larger than negative control. Lung function of asthmatics was evaluated by pre-bronchodilator spirometry. Ten PHF11 SNPs were genotyped by multiplex SNaPshot assay. Genotyping call rates were 100% for all SNPs, which also followed Hardy-Weinberg equilibrium. These SNPs were tightly linked in one haplotype block (D' >or= 0.95 for nearly all SNP pairs). Physician-diagnosed asthma was weakly associated with PHF11 +20860 and +22818 (P = 0.032 for both). Atopy was also associated with PHF11 +22398 (P = 0.029). However, none of the PHF11 SNPs was associated with eczema diagnosis and plasma total IgE and spirometric parameters in our patients. Our findings do not support PHF11 to be a major candidate gene for asthma, eczema and aeroallergen sensitization in Chinese children. PMID- 20717940 TI - The floor-of-nose flap for reconstruction of endoscopic maxillectomy defects. PMID- 20717941 TI - Evaluation of guinea pig model for ocular and cervical vestibular-evoked myogenic potentials for vestibular function test. AB - OBJECTIVES/HYPOTHESIS: This study used air-conducted sound (ACS) and bone conducted vibration (BCV) stimuli in eliciting ocular vestibular-evoked myogenic potential (oVEMP) and cervical VEMP (cVEMP) in guinea pigs. STUDY DESIGN: Prospective study. METHODS: Ten guinea pigs were treated with gentamicin (4 mg) on the left ear, whereas the right ear served as a control. One week after treatment, each animal underwent oVEMP and cVEMP tests using ACS and BCV modes in a randomized order, and was sacrificed for morphological study. RESULTS: Using ACS mode, oVEMPs were absent in all 10 (100%) animals despite the stimulus intensity increased up to 120 dB pe SPL. Conversely, using BCV mode, oVEMPs were present on the left (lesion) eye, and absent on the right (control) eye in all (100%) animals. For the cVEMPs via ACS mode, all right (control) necks had clear cVEMPs, and all (100%) left (lesion) necks revealed absent cVEMPs. However, via BCV mode, all right (control) necks and six (60%) left (lesion) necks showed clear cVEMPs. Morphological study demonstrated substantial loss of hair cells in the utricular and saccular macula. CONCLUSIONS: The cVEMP test via ACS mode is specific for investigating the saccular disorder, whereas the oVEMP test via BCV mode is preferable for investigating the utricular disorders in humans. The guinea pig model is consistent with the findings of humans. Restated, appropriate animal models for cVEMP and oVEMP in guinea pigs are via ACS and BCV modes, respectively. PMID- 20717942 TI - New techniques to detect unknown primaries in cervical lymph node metastasis. AB - OBJECTIVE: Various methods have been reported for the detection of unknown primaries in cervical lymph node metastasis. Recently, we applied new optical devices and modifications of endoscopic techniques for the detection of primary lesions, and obtained excellent results. The detection rate of the new method was compared with that of previous methods. STUDY DESIGN: Retrospective. METHODS: A total of 51 patients with cervical lymph node metastasis from an unknown primary site (CUP) were referred to our hospital between January 2000 and May 2009, and were retrospectively analyzed. Between 2000 and 2005, the observation by normal video-endoscope in straight head position was performed to detect the primary lesions in the outpatient setting. Since 2006, a new method for detection of primary lesions has been employed. The method includes the use of new optical devices (hooded video-endoscope and narrow-band imaging endoscope) and different head positions (head torsion technique, Valsalva maneuver, and the Killian position). RESULTS: The detection rate of primary lesions using the new method was 71% (15 of 21), which was better than the 30% (10 of 30) obtained with the conventional method. All primary lesions identified using the new method were located in the hypopharynx. CONCLUSIONS: The new method was able to detect primary lesions in 71% of cases with CUP. The higher rate achieved with the new method was probably due to the clear visualization of the hypopharynx. Thus, the new method was shown to be useful for the detection of primary lesions in cases of CUP. PMID- 20717943 TI - Simultaneous involvement of larynx and middle ear in pulmonary tuberculosis. AB - We present a rare case of simultaneous involvement of larynx and ear in a patient with pulmonary tuberculosis. The aim of this article is to create an awareness of Ear Nose Throat tuberculosis, and to consider tuberculosis in the differential diagnosis of ear and laryngeal diseases. PMID- 20717944 TI - Selective neck dissection and deintensified postoperative radiation and chemotherapy for oropharyngeal cancer: a subset analysis of the University of Pennsylvania transoral robotic surgery trial. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to determine the regional recurrence rate of node-positive oropharyngeal squamous cell carcinoma (OPSCC) in patients undergoing transoral robotic surgery (TORS) and selective neck dissection (SND) followed by observation, radiation, or concurrent chemoradiation. STUDY DESIGN: A prospective, phase I, single-arm study was conducted. All OPSCC patients who voluntarily participated in a surgical trial with TORS and SND at an academic tertiary referral center from May 2005 to July 2007 were included. METHODS: Thirty-one patients with previously untreated OPSCC undergoing TORS and SND (29 unilateral and two bilateral) were included. There were 29 males and two females, with ages ranging from 36 to 76 years (median = 55 years) with one palate, one lateral wall, 17 tonsil, 11 base of tongue, and one vallecula primary tumor classified as follows: T1 (n = 9, 29%), T2 (n = 15, 48.4%), T3 (n = 7, 22.6%), N0 (n = 6, 19.4%), N1 (n = 15, 48.4%), N2b (n = 10, 32.3%), and N2c (n = 1, 3.2%). There were three stage I (9.7%), two stage II (6.5%), 15 stage III (48.4%) and 11 stage IVa (35.5%) patients. Twenty-two patients were treated postoperatively with adjuvant therapy (12 radiation alone and 12 combined radiation and chemotherapy). Primary outcome measured was regional recurrence rate. RESULTS: There was one regional recurrence on the contralateral, non-operated neck and one distant recurrence among the 31 patients who underwent SND. CONCLUSIONS: SND after TORS resection of primary OPSCC enables the use of selective and deintensified adjuvant therapy to reduce regional recurrence rates. PMID- 20717946 TI - The relationship between depressive symptoms and Voice Handicap Index scores in laryngopharyngeal reflux. AB - OBJECTIVES/HYPOTHESIS: To determine if a relationship exists between depression and Voice Handicap Index (VHI) scores in patients with laryngopharyngeal reflux (LPR) disease. STUDY DESIGN: Retrospective analysis of prospectively collected data. METHODS: One hundred nineteen patients were prospectively evaluated with the VHI questionnaire and the Beck Depression Inventory Fast Screen (BDI-FS) survey. Patients with a pre-existing diagnosis of depression were excluded. RESULTS: Complete data was available for 36 patients with LPR and 53 controls. No significant differences existed between groups with respect to age, race, or gender. Mild depressive symptoms were identified in 9% of controls and 3% of LPR patients by BDI-FS screening (P = .4); no patients had moderate or severe depression symptoms. Compared to controls, patients with LPR had significantly higher mean scores for total VHI (16.2 vs. 6.6, P = .002), functional VHI (5.8 vs. 2.4, P = .02), and physical VHI (6.9 vs. 2.5, P = .008) domains. Mean scores for the VHI emotional domain (3.5 vs. 1.7, P = .2) and BDI-FS (0.2 vs. 0.8, P = .3) did not differ between patients with LPR and controls. For all participants, a positive correlation was found between BDI-FS score and VHI emotional domain score (r = 0.3, P = .008). CONCLUSIONS: Patients with LPR report poorer VHI functional and physical scores compared to controls; however, LPR symptoms do not result in significantly worse VHI emotional domain scores or depressive symptoms. There is a correlation between VHI emotional domain scores and BDI-FS scores. These data suggest that LPR patients with poor VHI emotional domain scores might benefit from screening for depressive symptoms. PMID- 20717945 TI - Cyclooxygenase-2 signaling in vocal fold fibroblasts. AB - OBJECTIVES/HYPOTHESIS: Inflammation and its role in a coordinated fibroplastic response, which disrupts the structure of the vocal folds following injury, is critical. Cyclooxygenase-2 (COX-2) is an important enzyme involved in both inflammation and fibrosis; in addition, it is a prime target for therapeutic intervention. We sought to study this pathway in vocal fold fibroblasts to provide a foundation for future interventional studies. STUDY DESIGN: In vitro. METHODS: Human vocal fold fibroblasts were incubated with IL-1 beta to determine the effects on COX-2 signaling, along with upstream regulatory mechanisms and downstream mediators of wound healing. In vitro methods to assess mRNA expression, as well as intracellular and secreted protein (sodium dodecyl sulfate polyacrylamide gel electrophoresis and enzyme-linked immunosorbent assay) were employed. RESULTS: IL-1 beta regulation of COX-2 mRNA and protein levels was dose and time dependent and IL-1 beta altered PGE(2) metabolism, via regulation of both synthetic and degradative enzymes. IL-1 beta increased nuclear factor (NF) kappaB activation and nuclear translocation. Inhibition of the p50 and p65 subunits of NF-kappaB decreased IL-1 beta-induced COX-2 transcription. IL-1 beta also altered mRNA expression of four cell-surface prostaglandin receptors. CONCLUSIONS: Inflammation and fibrosis are important in the vocal fold pathophysiologic response to injury. Our data suggest that COX-2 and PGE(2) are inducible in human vocal fold fibroblasts, and this response appears to be NF kappaB-dependent. We purport this fundamental investigation will lead to increased insight regarding injury and repair in the vocal folds, with the ultimate goal of developing novel clinical care paradigms. PMID- 20717947 TI - Prototypical category learning in high-functioning autism. AB - An ongoing debate in developmental cognitive neuroscience is whether individuals with autism are able to learn prototypical category representations from multiple exemplars. Prototype learning and memory were examined in a group of high functioning autistic boys and young men, using a classic paradigm in which participants learned to classify novel dot patterns into one of two categories. Participants were trained on distorted versions of category prototypes until they reached a criterion level of performance. During transfer testing, participants were shown the training items together with three novel stimulus sets manifesting variable levels of physical distortion (low, medium, or high distortion) relative to the unseen prototypes. Two experiments were conducted, differing only in the manner in which the physical distortions were defined. In the first experiment, a subset of autistic individuals learned categories more slowly than controls, accompanied by an overall diminution in transfer-testing performance. The autism group did, however, manifest a typical pattern of performance across the testing conditions, relative to controls. In the second experiment, group means did not differ statistically in either the training or testing phases. Taken together, these data indicate that high-functioning autistic individuals do not manifest gross deficits in prototypical category learning. A theoretical discussion is given in terms of how perceptual grouping may interact with category learning. PMID- 20717948 TI - Systemic steroid reduces long-term hearing loss in experimental pneumococcal meningitis. AB - OBJECTIVES/HYPOTHESIS: Sensorineural hearing loss is a common complication of pneumococcal meningitis. Treatment with corticosteroids reduces inflammatory response and may thereby reduce hearing loss. However, both experimental studies and clinical trials investigating the effect of corticosteroids on hearing loss have generated conflicting results. The objective of the present study was to determine whether systemic steroid treatment had an effect on hearing loss and cochlear damage in a rat model of pneumococcal meningitis. STUDY DESIGN: Controlled animal study of acute bacterial meningitis. METHODS: Adult rats were randomly assigned to two experimental treatment groups: a group treated with systemic steroid (n = 13) and a control group treated with saline (n = 13). Treatment was initiated 21 hours after infection and repeated once a day for three days. Hearing loss and cochlear damage were assessed by distortion product otoacoustic emissions (DPOAE), auditory brainstem response (ABR) at 16 kHz, and spiral ganglion neuron density. RESULTS: Fifty-six days after infection, steroid treatment significantly reduced hearing loss assessed by DPOAE (P < .05; Mann Whitney) and showed a trend toward reducing loss of viable neurons in the spiral ganglion (P = .0513; Mann-Whitney). After pooling data from day 22 with data from day 56, we found that systemic steroid treatment significantly reduced loss of spiral ganglion neurons (P = .0098; Mann-Whitney test). CONCLUSIONS: Systemic steroid treatment reduces long-term hearing loss and loss of spiral ganglion neurons in experimental pneumococcal meningitis in adult rats. The findings support a beneficial role of anti-inflammatory agents in reducing hearing loss and cochlear damage in meningitis. PMID- 20717949 TI - Spontaneous cerebrospinal fluid rhinorrhea: a clinical and anatomical study. AB - OBJECTIVES/HYPOTHESIS: Spontaneous nasal cerebrospinal fluid (CSF) fistula represents a rare clinical entity. The possible etiology and the localization of the rhinorrhea remain an ongoing clinical challenge. The purpose of this study was to evaluate the localization of spontaneous CSF fistula and to correlate it with anatomical studies. STUDY DESIGN: Retrospective clinical study, prospective anatomical study. METHODS: Twenty-nine patients with spontaneous CSF rhinorrhea were retrospectively studied, 10 males and 19 females. Ages ranged from 10 to 92 years (mean, 50 years). In addition, 48 human skulls from newborns to adults were examined for the postnatal development of the anterior and middle cranial fossa. RESULTS: In our study isolated cribriform plate defects were found in four patients. The lateral lamina of the ethmoid bone showed defects in three patients. In nine patients the bony defect could be found in the region of the fovea ethmoidalis. The bony defect between the extra- and intracranial space was found in the lateral recess of the sphenoid sinus in eight patients. Five patients had special sites (e.g., supraorbital recess and frontal recess). CONCLUSIONS: This study supports the theory that bony dehiscence in the lateral lamina of the ethmoid bone can be congenital and can also be spontaneously acquired later. The bony dehiscence in the lateral wall of the sphenoid sinus can only develop during pneumatization. PMID- 20717950 TI - Anatomical considerations for endoscopic endonasal skull base surgery in pediatric patients. AB - OBJECTIVES/HYPOTHESIS: Pediatric skull base surgery is limited by several boney sinonasal landmarks that must be overcome prior to tumor dissection. When approaching a sellar or parasellar tumor, the piriform aperture, sphenoid sinus pneumatization, and intercarotid distances are areas of potential limitation. Quantitative pediatric anatomical measurements relevant to skull base approaches are lacking. Our goal was to use radio-anatomic analysis of computed tomography scans to determine anatomical limitations for trans-sphenoidal approaches in pediatric skull base surgery. STUDY DESIGN: A radio-anatomic cross-sectional survey. METHODS: Measurements included the diameter of the piriform aperture, posterior extent of sphenoid sinus pneumatization, and intercarotid distances on fine-cut, age-stratified maxillofacial scans. Fifty pediatric (<18 years of age) and 10 adult patients were equally subdivided into seven age groups and compared to determine age-related differences in sphenoid sinus pneumatization, skull base thicknesses, and intercarotid distances. RESULTS: Piriform aperture width was significantly greater in adults than in patients under age 7 years (P 12 h. Moreover, DEX (10(-6) M) increased the level of glucocorticoid receptor (GR)-alpha mRNA and protein expression, but not GR-beta mRNA. The increases in DEX-induced migration were inhibited by the GR antagonist mifepristone (10(-7) M). In addition, DEX increased integrin-linked kinase (ILK) and alpha-parvin expression but did not change PINCH-1/2 expression in lysate. DEX also increased formations of complex with ILK and alpha-parvin, and ILK and PINCH-1/2 as shown by immunoprecipitation, which were all inhibited by mifepristone. DEX-induced migration was blocked by ILK and alpha-parvin small interfering(si)RNAs. In addition, DEX increased focal adhesion kinase (FAK) and paxillin expression, which were attenuated by ILK and alpha-parvin siRNAs. DEX-induced cell migration was inhibited by FAK/paxillin siRNAs. DEX also increased beta1-integrin expression, which was blocked by FAK/paxillin siRNAs. In addition, DEX-induced cell migration was inhibited by beta1-integrin siRNA. Downregulation of ILK, alpha-parvin, FAK/paxillin and beta1 integrin expression by siRNAs decreased DEX-induced filamentous(F)-actin organization and migration of hMSCs. In conclusion, DEX partially stimulates hMSC migration by the expression of beta1-integrin through formation of a PINCH 1/2/ILK/alpha-parvin complex (PIP complex), and FAK and paxillin expression. PMID- 20717961 TI - Forced activation of Stat5 subjects mammary epithelial cells to DNA damage and preferential induction of the cellular response mechanism during proliferation. AB - Parity-dependent adenocarcinoma tumors developed in postestropausal transgenic mice expressing a constitutively active Stat5 variant (STAT5ca) in their mammary gland. These tumors maintained elevated expression levels of genes regulating the cellular DNA damage response (DDR) mechanism, compared to the intact gland. No correlation with STAT5ca expression was observed for these genes in the established tumors. However, activated Stat5a in individual cells of the rarely and earlier developed hyperplasia was associated with induced Chk2 activity. Deregulated Stat5 may already cause DNA damage during the fertile period. This hypothesis and the specific vulnerable stage were further studied in mammary epithelial cells that were stably transfected with beta-lactoglobulin (BLG)/STAT5ca and exposed to a reproduced reproductive cycle. During the pregnancy-like proliferative state, STAT5ca expression was induced by the added lactogenic hormones. Production of reactive oxygen species, rather than proliferation, served as the primary mediator of DNA damage and cellular DDR. Differentiated cells expressed higher levels of STAT5ca and retained the DNA nicks. However, the elevated expression of the genes involved in DDR was downregulated. Higher levels of DNA damage were also detected in the mammary gland of transgenic mice expressing the BLG/STAT5ca during pregnancy and lactation. However, the relative number of damaged cells was much lower than that in the reproduced in vitro stages and the insults were generally associated with apoptosis and DDR. This study implicates pregnancy as the vulnerable stage for deregulated Stat5 activity, and demonstrates that DNA insults in viable differentiated mammary epithelial cells are ignored by the DDR mechanism. PMID- 20717962 TI - Flow cytometric sorting of neuronal and glial nuclei from central nervous system tissue. AB - Due to the complex cellular heterogeneity of the central nervous system (CNS), it is relatively difficult to reliably obtain molecular descriptions with cell-type specificity. In particular, comparative analysis of epigenetic regulation or molecular profiles is hampered by the lack of adequate methodology for selective purification of defined cell populations from CNS tissue. Here, we developed a direct purification strategy of neural nuclei from CNS tissue based on fluorescence-activated cell sorting (FACS). We successfully fractionated nuclei from complex tissues such as brain, spinal cord, liver, kidney, and skeletal muscle extruded mechanically or chemically, and fractionated nuclei were structurally maintained and contained nucleoproteins and nuclear DNA/RNA. We collected sufficient numbers of nuclei from neurons and oligodendrocytes using FACS with immunolabeling for nucleoproteins or from genetically labeled transgenic mice. In addition, the use of Fab fragments isolated from papain antibody digests, which effectively enriched the specialized cell populations, significantly enhanced the immunolabeling efficacy. This methodology can be applied to a wide variety of heterogeneous tissues and is crucial for understanding the cell-specific information about chromatin dynamics, nucleoproteins, protein-DNA/RNA interactions, and transcriptomes retained in the nucleus, such as non-coding RNAs. PMID- 20717963 TI - Bcr-Abl-induced tyrosine phosphorylation of Emi1 to stabilize Skp2 protein via inhibition of ubiquitination in chronic myeloid leukemia cells. AB - Our previous study demonstrates that Bcr-Abl fusion oncogene frequently found in chronic myeloid leukemia (CML) cells can up-regulate Skp2 expression via transcriptional activation. However, Bcr-Abl also modulates Skp2 protein stability in these cells. Treatment of Bcr-Abl kinase inhibitor imatinib led to G1 growth arrest accompanied with reduced Skp2 expression. Interestingly, reduction of Skp2 protein occurred prior to down-regulation of Skp2 mRNA suggesting a post-translational control. The half-life of Skp2 protein was significantly attenuated in imatinib-treated cells. These effects are not cell line specific because similar results were also found in CML cells obtained from patients. Knockdown of Bcr-Abl similarly caused Skp2 protein instability. The decrease of Skp2 was induced by increased protein degradation through the ubiquitin/proteasome pathway. Imatinib treatment or Bcr-Abl knockdown reduced Emi1, an endogenous inhibitor of the E3 ligase APC/Cdh1 which mediated Skp2 degradation. We found that Emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested Bcr-Abl induced Emi1 phosphorylation might be mediated by Src kinase. Firstly, Src inhibitor SU6656 inhibited Emi1 tyrosine phosphorylation in K562 cells. Secondly, transfection of v-Src rescued the reduction of Emi1 by imatinib. Thirdly, mutation of tyrosine 142 to phenylalanine (Y142F) abolished the phosphorylation of Emi1 by recombinant Src kinase. In addition, ectopic expression of wild type but not Y142F mutant Emi1 counteracted imatinib-caused growth arrest. Collectively, our results suggest that Bcr-Abl increases Emi1 phosphorylation and stability to prevent Skp2 protein degradation via APC/Cdh1-induced ubiquitination and to enhance proliferation of CML cells. PMID- 20717964 TI - Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N-terminal peptide (NT-S100A8). AB - After isolating NT-S100A8 from pancreatic cancer (PC) tissue of diabetic patients, we verified whether this peptide alters PC cell growth and invasion and/or insulin release and [Ca(2+)](i) oscillations of insulin secreting cells and/or insulin signaling. BxPC3, Capan1, MiaPaCa2, Panc1 (PC cell lines) cell growth, and invasion were assessed in the absence or presence of 50, 200, and 500 nM NT-S100A8. In NT-S100A8 stimulated beta-TC6 (insulinoma cell line) culture medium, insulin and [Ca(2+)] were measured at 2, 3, 5, 10, 15, 30, and 60 min, and [Ca(2+)](i) oscillations were monitored (epifluorescence) for 3 min. Five hundred nanomolars NT-S100A8 stimulated BxPC3 cell growth only and dose dependently reduced MiaPaCa2 and Panc1 invasion. Five hundred nanomolars NT S100A8 induced a rapid insulin release and enhanced beta-TC6 [Ca(2+)](i) oscillations after both one (F = 6.05, P < 0.01) and 2 min (F = 7.42, P < 0.01). In the presence of NT-S100A8, [Ca(2+)] in beta-TC6 culture medium significantly decreased with respect to control cells (F = 6.3, P < 0.01). NT-S100A8 did not counteract insulin induced phosphorylation of the insulin receptor, Akt and IkappaB-alpha, but it independently activated Akt and NF-kappaB signaling in PC cells. In conclusion, NT-S100A8 exerts a mild effect on PC cell growth, while it reduces PC cell invasion, possibly by Akt and NF-kappaB signaling, NT-S100A8 enhances [Ca(2+)](i) oscillations and insulin release, probably by inducing Ca(2+) influx from the extracellular space, but it does not interfere with insulin signaling. PMID- 20717965 TI - Protein kinases and ovarian functions. AB - The present focus survey represents a short review of current knowledge concerning involvement of protein kinases in control of basic ovarian functions. Ovarian cells produce a number of protein kinases, whose expression depends on type of cells, their state and action of hormones and other protein kinases. A number of protein kinases are involved in control of ovarian cell proliferation, apoptosis, oocyte maturation, hormone release, reception and response to hormones, as well as in mediating action of hormones on these ovarian functions. Complexity of interrelationships between different protein kinase-dependent signaling pathways occurs. Protein kinases and their regulators could be used for characterization, prediction and control of ovarian folliculogenesis and atresia, Corpus luteum functions, oocyte maturation, fertility, release of hormones, response of ovarian structures to hormonal regulators, as well as for treatment of some reproductive disorders. The present data demonstrate importance of protein kinases in control of basic ovarian function and potential usage of protein kinases for characterization, prediction and control of these functions. PMID- 20717966 TI - Expression of micro-RNA-145 is regulated by a highly conserved genomic sequence 3' to the pre-miR. AB - Micro-RNA-145 (miR145), a tumor suppressor miR, dramatically inhibits growth of cancer cells in culture and plays a significant role in human stem cells differentiation. We have isolated a human genomic sequence of 864 bp comprising the pre-miR and its flanking sequences. The cloned miR145 genomic sequence expresses a mature miR145 in transfected cells. We show here that flanking sequences on either side of the pre-miR sequence can modulate its expression levels. Surprisingly, a highly conserved sequence 3' to the pre-miR plays a crucial role in miR145 expression. PMID- 20717967 TI - Characterization of GFP-tagged GnRH-containing terminalis neurons in transgenic zebrafish. AB - The terminalis nerve (TN) has been described in all vertebrate species, in which it plays important roles in animal behavior and physiology. In teleost fish, the TN is located in the olfactory bulb and in its nerve tract. Here, we report a study on the characterization of the TN cell development, axon projection and physiology in zebrafish (Danio rerio). We have generated several lines of transgenic zebrafish [Tg (GnRH-3::GFP)] that express GFP in the TN cells. The transgenes are expressed under the transcriptional control of the zebrafish GnRH 3 promoter. During development, the first GFP-positive TN cell was identified at approximately 34 h post-fertilization (hpf). By 38 hpf, several clusters of TN cells were identified in the olfactory bulb and olfactory nerve tract. In the olfactory bulb, the TN cells projected axons caudally. In the forebrain, some of the TN axons extended caudally, but most crossed the midline of the brain at the commissural anterior. In the midbrain, some of the TN axons extended dorsally towards the tectum, whereas other axons extended caudally, or extended ventrally to the optic nerve where they entered the neural retina. We also examined the cell membrane property of the TN cells. Using patch-clamp techniques, we recorded spontaneous and evoked action potentials from isolated TN cells. We examined the expression of glutamate receptors in the TN cells. The data shed light on the mechanisms of TN function in the nervous system and in the regulation of animal physiology. PMID- 20717968 TI - Interaction of profilin-1 and F-actin via a beta-arrestin-1/JNK signaling pathway involved in prostaglandin E(2)-induced human mesenchymal stem cells migration and proliferation. AB - Although many previous reports have examined the function of prostaglandin E(2) (PGE(2)) in the migration and proliferation of various cell types, the role of the actin cytoskeleton in human mesenchymal stem cells (hMSCs) migration and proliferation has not been reported. The present study examined the involvement of profilin-1 (Pfn-1) and filamentous-actin (F-actin) in PGE(2)-induced hMSC migration and proliferation and its related signal pathways. PGE(2) (10(-6) M) increased both cell migration and proliferation, and also increased E-type prostaglandin receptor 2 (EP2) mRNA expression, beta-arrestin-1 phosphorylation, and c-Jun N-terminal kinase (JNK) phosphorylation. Small interfering RNA (siRNA) mediated knockdown of beta-arrestin-1 and JNK (-1, -2, -3) inhibited PGE(2) induced growth of hMSCs. PGE(2) also activated Pfn-1, which was blocked by JNK siRNA, and induced F-actin level and organization. Downregulation of Pfn-1 by siRNA decreased the level and organization of F-actin. In addition, specific siRNA for TRIO and F-actin-binding protein (TRIOBP) reduced the PGE(2)-induced increase in hMSC migration and proliferation. Together, these experimental data demonstrate that PGE(2) partially stimulates hMSCs migration and proliferation by interaction of Pfn-1 and F-actin via EP2 receptor-dependent beta-arrestin-1/JNK signaling pathways. PMID- 20717969 TI - Application of an aqueous two-phase systems high-throughput screening method to evaluate mAb HCP separation. AB - Aqueous two-phase systems (ATPSs) as separation technique have regained substantial interest from the biotech industry. Biopharmaceutical companies faced with increasing product titers and stiffening economic competition reconsider ATPS as an alternative to chromatography. As the implementation of an ATPS is material, time, and labor intensive, a miniaturized and automated screening process would be beneficial. In this article such a method, its statistical evaluation, and its application to a biopharmaceutical separation task are shown. To speed up early stage ATPS profiling an automated application of the cloud point method for binodal determination was developed. PEG4000-PO(4) binodals were measured automatically and manually and were found to be identical within the experimental error. The ATPS screening procedure was applied to a model system and an industrial separation task. PEG4000-PO(4) systems at a protein concentration of 0.75 mg/mL were used. The influence of pH, NaCl addition, and tie line length was investigated. Lysozyme as model protein, two monoclonal antibodies, and a host cell protein pool were used. The method was found to yield partition coefficients identical to manually determined values for lysozyme. The monoclonal antibodies were shifted from the bottom into the upper phase by addition of NaCl. This shift occurred at lower NaCl concentration when the pH of the system was closer to the pI of the distributed protein. Addition of NaCl, increase in PEG4000 concentration and pH led to significant loss of the mAb due to precipitation. Capacity limitations of these systems were thus demonstrated. The chosen model systems allowed a reduction of up to 50% HCP with a recovery of greater than 95% of the target proteins. As these values might not be industrially relevant when compared to current chromatographic procedures, the developed screening procedure allows a fast evaluation of more suitable and optimized ATPS system for a given task. PMID- 20717970 TI - Detection and reduction of microaggregates in insulin preparations. AB - Insulin is an important biotherapeutic protein, and it is also a model protein used to study amyloid diseases, such as Alzheimer's and Parkinson's. The preparation of the protein can lead to small amounts of aggregate in the solution, which in turn may lead to irreproducible in vitro results. Using several pre-treatment methods, we have determined that pH cycling and diafiltration of the insulin removes microaggregates that may be present in the solution. These microaggregates were not detectable with traditional biochemical methods, but using small-angle neutron scattering, we were able to show that pH cycling reduces the radius of gyration of the insulin. Diafiltration removes the aggregates by size and pH cycling dissolves the aggregates by adjusting the pH through the pI of the protein. Pre-treating the insulin with either pH cycling or diafiltration allowed reproducible kinetics of fibrillation for the insulin protein. Microaggregates are a common problem in protein production, formulation, and preparation; here we show that they are the main cause for inconsistent behavior and how pH cycling and diafiltration can mitigate this problem. PMID- 20717971 TI - Functional characterization of propane-enhanced N-nitrosodimethylamine degradation by two actinomycetales. AB - Propane-induced cometabolic degradation of n-nitrosodimethylamine (NDMA) by two propanotrophs is characterized through kinetic, gene presence, and expression studies. After growth on propane, resting cells of Rhodococcus sp. RR1 possessed a maximum transformation rate (v(max,n)) of 44 +/- 5 ug NDMA (mg protein)(-1) h( 1); the rate for Mycobacterium vaccae (austroafricanum) JOB-5 was modestly lower with v(max,n) of 28 +/- 3 ug NDMA (mg protein)(-1) h(-1). Both strains were capable of degrading environmentally relevant, trace quantities of NDMA to below the experimental limit of detection, calculated as 20 ng NDMA L(-1). However, a comparison of half saturation constants (K(s,n)) and NDMA degradation in the presence of propane revealed pronounced differences between the strains. The K(s,n) for strain RR1 was 36 +/- 10 ug NDMA L(-1) while the propane concentration needed to inhibit NDMA rates by 50% (K(inh)) occurred at 7,700 ug propane L(-1) (R(2) = 0.9669). In contrast, strain JOB-5 had a markedly lower affinity for NDMA verses propane with a calculated K(s,n) of 2,200 +/- 1,000 ug NDMA L(-1) and K(inh) of 120 ug propane L(-1) (R(2) = 0.9895). Genomic and transcriptional investigations indicated that the functional enzymes involved in NDMA degradation and propane metabolism are different for each strain. For Rhodococcus sp. RR1, a putative propane monooxygenase (PrMO) was identified and implicated in NDMA oxidation. In contrast, JOB-5 was not found to possess a PrMO homologue and two functionally analogous alkane monoxygenases (AlkMOs) were not induced by growth on propane. Differences between the PrMO in this Rhodococcus and the unidentified enzyme(s) in the Mycobacterium may explain differences in NDMA degradation and inhibition kinetics between these strains. PMID- 20717972 TI - E. coli K5 fermentation and the preparation of heparosan, a bioengineered heparin precursor. AB - Heparosan is an acidic polysaccharide natural product, which serves as the critical precursor in heparin biosynthesis and in the chemoenzymatic synthesis of bioengineered heparin. Heparosan is also the capsular polysaccharide of Escherichia coli K5 strain. The current study was focused on the examination of the fermentation of E. coli K5 with the goal of producing heparosan in high yield and volumetric productivity. The structure and molecular weight properties of this bacterial heparosan were determined using polyacrylamide gel electrophoresis (PAGE) and Fourier transform mass spectrometry. Fermentation of E. coli K5 in a defined medium using exponential fed-batch glucose addition with oxygen enrichment afforded heparosan at 15 g/L having a number average molecular weight of 58,000 Da and a weight average molecular weight of 84,000 Da. PMID- 20717973 TI - A GFP complementation system for monitoring and directing nanomaterial mediated protein delivery to human cellular organelles. AB - Protein-based therapeutics are gaining importance for their biocompatibility and activity toward specific targets. When these targets are intracellular, it is critical to deliver biomolecules to sites in the cell cytoplasm while retaining biomolecule activity in the complex cellular milieu. However, intracellular protein delivery is not viable unless accompanied by an active uptake mechanism or carrier mediated delivery. Moreover, once entry into the cell is achieved, detection of the biomolecule requires laborious techniques that lack real-time measurement. We have developed a fluorescence-based complementary protein delivery sensing system using split green fluorescence protein (GFP(1-10) and GFP(11)) fragments, which can be used as an indicator for protein delivery and retention of activity, and as a means to pinpoint subcellular localization. We demonstrate in vitro localized delivery by expressing the GFP(11) fragment onto the mitochondrial outer membrane of human cells, and using a model carrier (15 nm silica nanoparticles) to deliver GFP(1-10) and image trafficking and mitochondrial localization of protein delivery. Our results indicate that nanoscale materials can be used as protein carriers for targeting cell constituents including functional molecules, signaling pathways, and organelles. We envision that this GFP complementation system is ideally suited for directing nanoparticle-based delivery of drugs and other bioactive molecules into subcellular locations within cells, which can impact protein-protein interactions, signal transduction pathways, and organelle function in vitro within the context of high-throughput screening protocols. PMID- 20717974 TI - Enhanced gene expression in insect cells and silkworm larva by modified polyhedrin promoter using repeated Burst sequence and very late transcriptional factor-1. AB - The Burst of expression from polyhedrin (polh) promoter during very late phase of baculovirus infection requires a sequence located between TAAG and the translation initiation site, typically referred to as burst sequence (BS). The expression of polh promoter is stimulated by specifically binding of very late transcriptional factor 1 (VLF-1) to BS. In order to enhance the production of recombinant proteins the polh promoter was modified via a multiple BS bacmid system in which the number of BSs was increased. Compared to an expression from a normal polh promoter, beta-glucuronidase (GUS) activity in High Five insect cells was three times higher with a modified polh promoter containing two BSs. Using a modified polh promoter that contains nine BSs in silkworm expression system, beta1-3-N-acetylglucosaminyltransferase 2 (beta3GnT2) activity per larva was 6.8 fold higher than control. Furthermore, the co-expression of modified promoters along with VLF-1-enhanced beta3GnT activity. Thus, an increased optimal number of BS and its co-expression with VLF-1 leads to the production of higher level of gene expression in insect cells and silkworm larvae. This new modified promoter engineered in the current study is the strongest promoter for overexpressing foreign proteins in an eukaryotic cell and system, thus leading a progress in baculovirus-insect cell and silkworm biotechnology. PMID- 20717975 TI - Imputation aware meta-analysis of genome-wide association studies. AB - Genome-wide association studies have recently identified many new loci associated with human complex diseases. These newly discovered variants typically have weak effects requiring studies with large numbers of individuals to achieve the statistical power necessary to identify them. Likely, there exist even more associated variants, which remain to be found if even larger association studies can be assembled. Meta-analysis provides a straightforward means of increasing study sample sizes without collecting new samples by combining existing data sets. One obstacle to combining studies is that they are often performed on platforms with different marker sets. Current studies overcome this issue by imputing genotypes missing from each of the studies and then performing standard meta-analysis techniques. We show that this approach may result in a loss of power since errors in imputation are not accounted for. We present a new method for performing meta-analysis over imputed single nucleotide polymorphisms, show that it is optimal with respect to power, and discuss practical implementation issues. Through simulation experiments, we show that our imputation aware meta analysis approach outperforms or matches standard meta-analysis approaches. PMID- 20717976 TI - African and non-African admixture components in African Americans and an African Caribbean population. AB - Admixture is a potential source of confounding in genetic association studies, so it becomes important to detect and estimate admixture in a sample of unrelated individuals. Populations of African descent in the US and the Caribbean share similar historical backgrounds but the distributions of African admixture may differ. We selected 416 ancestry informative markers (AIMs) to estimate and compare admixture proportions using STRUCTURE in 906 unrelated African Americans (AAs) and 294 Barbadians (ACs) from a study of asthma. This analysis showed AAs on average were 72.5% African, 19.6% European and 8% Asian, while ACs were 77.4% African, 15.9% European, and 6.7% Asian which were significantly different. A principal components analysis based on these AIMs yielded one primary eigenvector that explained 54.04% of the variation and captured a gradient from West African to European admixture. This principal component was highly correlated with African vs. European ancestry as estimated by STRUCTURE (r(2)=0.992, r(2)=0.912, respectively). To investigate other African contributions to African American and Barbadian admixture, we performed PCA on approximately 14,000 (14k) genome-wide SNPs in AAs, ACs, Yorubans, Luhya and Maasai African groups, and estimated genetic distances (F(ST)). We found AAs and ACs were closest genetically (F(ST)=0.008), and both were closer to the Yorubans than the other East African populations. In our sample of individuals of African descent, approximately 400 well-defined AIMs were just as good for detecting substructure as approximately 14,000 random SNPs drawn from a genome-wide panel of markers. PMID- 20717977 TI - Investigation of the mesoscale structure and volumetric features of biofilms using optical coherence tomography. AB - Optical coherence tomography (OCT) was successfully applied to visualize the mesoscale structure of three different heterotrophic biofilms. For this purpose, biofilm volumes of 4 * 4 * 1.6 mm(3) were scanned with spatial resolutions lower than 20 um within an acquisition time of 2 min. A heterogeneous structure was detected for biofilms cultivated in laminar as well as transient flow conditions. The structure was found to be more homogeneous for the biofilm grown in turbulent flow. This biofilm structure was characterized by a volumetric porosity of 0.36, whereas the porosity calculated for biofilms grown in laminar and transient conditions was 0.65. These results were directly generated from the distribution of porosity calculated from the OCT images acquired and can be linked to structural properties. Up to now, the mesoscale biofilm structure was only observable with time-consuming and expensive studies, for example, magnetic resonance microscopy. OCT will most certainly be helpful for improved understanding and prediction of biofilm physics with respect to macroscale processes, for example, mass transfer and detachment as the information about mesoscale is easily accessible using this method. In the context of this study, we show that CLSM images do not necessarily provide an accurate representation of the biofilm structure at the mesoscale. Additionally, the typical characteristic parameters obtained from CLSM image stacks differ largely from those calculated from OCT images. Nevertheless, to determine the local distribution of biofilm constituents, microscopic methods such as confocal laser scanning microscopy are required. PMID- 20717978 TI - Brief communication: Population data support the adaptive nature of HACNS1 sapiens/neandertal-chimpanzee differences in a limb expression domain. AB - The 546-base pair enhancer of limb expression HACNS1, which is highly constrained in all terrestrial vertebrates, has accumulated 16 human-specific changes after the human-chimpanzee split. There has been discussion whether this process was driven by positive selection or biased gene conversion, without considering population data. We studied 83 South Amerindian, 11 Eskimo, 35 Europeans, 37 Bantu, and non-Bantu Sub-Saharan speakers, and 28 Brazilian mestizo samples and found no variation in this DNA region. Similar lack of variability in this region was found in four Africans, five Europeans or Euro-derived, two Asians, one Paleo Eskimo, and one Neandertal sequence, whose whole genomes are publicly available. No difference was found. This result favors the interpretation of past positive and present conservative selection, as would expected in a region which influences Homo-specific traits as important as opposable thumbs, manual dexterity, and bipedal walking. Am J Phys Anthropol, 2010. (c) 2010 Wiley-Liss, Inc. PMID- 20717979 TI - Solution structures of the trihelix DNA-binding domains of the wild-type and a phosphomimetic mutant of Arabidopsis GT-1: mechanism for an increase in DNA binding affinity through phosphorylation. AB - GT-1 is a plant transcription factor that binds to one of the cis-acting elements, BoxII, which resides within the upstream promoter region of light responsive genes. GT-1 was assumed to act as a molecular switch modulated through Ca(2+)-dependent phosphorylation/dephosphorylation in response to light signals. It was shown previously that the phosphorylation of threonine 133 in the DNA binding domain (DBD) of GT-1 results in enhancement of the BoxII-binding activity. Interestingly, point mutation of Thr133 to Asp also enhances the BoxII binding activity. Here, we report the solution structures of hypothetical trihelix DBDs of the wild-type (WT) and a phosphomimetic mutant (T133D) of GT-1. First, we demonstrated that the isolated DBD of GT-1 alone has the ability to bind to DNA, and that the T133D mutation of the isolated DBD can enhance the DNA binding affinity. The structures of these DBDs turned out to be almost identical. The structural topology resembles that of Myb DBDs, but all alpha-helices are longer in GT-1. Our NMR titration experiments suggested that these longer alpha helices yield an enlarged DNA-binding surface. The phosphorylation site is located at the N-terminus of the third alpha-helix. We built a structural model of the T133D DBD:BoxII complex with the program HADDOCK. The model resembles the structure of the TRF1 DBD:telomeric DNA complex. Interestingly, the model implies that the phosphorylated side chain may directly interact with the bases of DNA. On the basis of our findings, we propose a mechanism by which the DNA-binding activity toward BoxII of the phosphorylated GT-1 could be enhanced. PMID- 20717980 TI - Viewing FOP through rosi-colored glasses. PMID- 20717981 TI - Localization of artesunate and its derivatives in the pregnant rat and fetus following oral administration and relationship to developmental toxicity. AB - BACKGROUND: The antimalarial drug artesunate affects erythroid cells leading to developmental toxicity and adult reticulocytopenia. We report on a kinetic study in rats and the tissue distribution of radioactivity following oral administration of [(3)H]-artesunate to pregnant rats using quantitative whole body autoradiography (QWBA). METHODS: Rats were dosed orally with chlorproguanil/dapsone/artesunate (including 11.8 mg/kg artesunate) and plasma concentrations of artesunate and the active metabolite dihydroartemisinin (DHA) were determined. In the QWBA study, 6 rats received 13 mg/kg [(3)H]-artesunate on day 18 of gestation. Groups of 2 rats were euthanized at 1, 6, and 24 hours after dosing, rapidly frozen, and sectioned in a cryostat. Sagittal sections were freeze-dried and placed in contact with imaging plates. Tissue concentrations of radioactivity were quantified. RESULTS: Systemic exposure to DHA was up to 22 fold higher than the parent compound and was higher in non-pregnant females than males. In the QWBA study, high concentrations of radioactivity were seen in maternal tissues involved in absorption and excretion, the bone marrow and spleen. Fetal blood and liver levels were 3.8- to 8.8-fold higher than maternal blood levels at all timepoints. CONCLUSIONS: Excluding tissues involved in absorption and excretion, the highest concentrations of radioactivity were observed in tissues involved in hemoglobin synthesis and/or destruction in both the mother and the fetus and likely account for the maternal reticulocytopenia and embryotoxicity. Radioactivity concentrations in the fetal blood were 2.1- to 2.8-fold higher than maternal bone marrow at all timepoints and this difference could contribute to the lower dose threshold for embryotoxicity. PMID- 20717982 TI - Polymer-fullerene bulk-heterojunction solar cells. AB - Solution-processed bulk heterojunction organic photovoltaic (OPV) devices have gained serious attention during the last few years and are established as one of the leading next generation photovoltaic technologies for low cost power production. This article reviews the OPV development highlights of the last two decades, and summarizes the key milestones that have brought the technology to today's efficiency performance of over 7%. An outlook is presented on what will be required to drive this young photovoltaic technology towards the next major milestone, a 10% power conversion efficiency, considered by many to represent the efficiency at which OPV can be adopted in wide-spread applications. With first products already entering the market, sufficient lifetime for the intended application becomes more and more critical, and the status of OPV stability as well as the current understanding of degradation mechanisms will be reviewed in the second part of this article. PMID- 20717983 TI - High-density stretchable electronics: toward an integrated multilayer composite. PMID- 20717984 TI - Device physics of dye solar cells. AB - Design of new materials for nanostructured dye solar cells (DSC) requires understanding the link between the material properties and cell efficiency. This paper gives an overview of the fundamental and practical aspects of the modeling and characterization of DSCs, and integrates the knowledge into a user-friendly DSC device model. Starting from basic physical and electrochemical concepts, mathematical expressions for the IV curve and differential resistance of all resistive cell components are derived and their relation to electrochemical impedance spectroscopy (EIS) is explained. The current understanding of the associated physics is discussed in detail and clarified. It is shown how the model parameters can be determined from complete DSCs by current dependent EIS and incident-photon-to-collected-electron (IPCE) measurements, supplemented by optical characterization, and used to quantify performance losses in DSCs. The paper aims to give a necessary theoretical background and practical guidelines for establishing an effective feedback-loop for DSC testing and development. PMID- 20717985 TI - Determination of the local chemical structure of graphene oxide and reduced graphene oxide. PMID- 20717986 TI - Carbon nanotubes in the biological interphase: the relevance of noncovalence. AB - With the increasing interest in the biological applications of carbon nanotubes, their interactions in the biological interphase and their general cytotoxicity have become major issues. In spite of their salient properties, major hurdles still exist for their use in biological applications, due to their main characteristics, including their hydrophobic surfaces and tendency to aggregate, as well as their unknown interactions in the cellular interphase. In this Research News, these characteristics of carbon nanotubes, a model nanomaterial, are investigated. Thus, the cytotoxicity of carbon nanotubes, the influence of functionalization, as well as their interactions with different mammalian cell lines are studied. Moreover, suggestions for the improvement of their biocompatibility and the design of biocompatible carbon nanotube-based systems are provided. PMID- 20717987 TI - Layer-by-layer assembly of beta-estradiol loaded mesoporous silica nanoparticles on titanium substrates and its implication for bone homeostasis. AB - Drug-loadingmesoporous silica nanoparticles that serve as a nanoreservoir-type drug-delivery system are successfully attached to titanium substrates via the layer-by-layer assembly technique (see scheme). The obtained structure demonstrates great potential for regulating the biological behaviors of osteoblasts/ steoclasts in order to maintain bone homeostasis. The approach we present here may have wide applications in implant technology, tissue engineering, and regenerative medicine. PMID- 20717988 TI - Strong efficiency improvements in ultra-low-cost inorganic nanowire solar cells. PMID- 20717989 TI - Tensile tests on individual single-walled carbon nanotubes: linking nanotube strength with its defects. PMID- 20717990 TI - News from the west: ancient DNA from a French megalithic burial chamber. AB - Recent paleogenetic studies have confirmed that the spread of the Neolithic across Europe was neither genetically nor geographically uniform. To extend existing knowledge of the mitochondrial European Neolithic gene pool, we examined six samples of human skeletal material from a French megalithic long mound (c.4200 cal BC). We retrieved HVR-I sequences from three individuals and demonstrated that in the Neolithic period the mtDNA haplogroup N1a, previously only known in central Europe, was as widely distributed as western France. Alternative scenarios are discussed in seeking to explain this result, including Mesolithic ancestry, Neolithic demic diffusion, and long-distance matrimonial exchanges. In light of the limited Neolithic ancient DNA (aDNA) data currently available, we observe that all three scenarios appear equally consistent with paleogenetic and archaeological data. In consequence, we advocate caution in interpreting aDNA in the context of the Neolithic transition in Europe. Nevertheless, our results strengthen conclusions demonstrating genetic discontinuity between modern and ancient Europeans whether through migration, demographic or selection processes, or social practices. PMID- 20717991 TI - Proteomic profiling of human colon cancer cells treated with the histone deacetylase inhibitor belinostat. AB - The anticancer drug belinostat is a hydroxamate histone deacetylase inhibitor that has shown significant antitumour activity in various tumour models and also in clinical trials. In this study, we utilized a proteomic approach in order to evaluate the effect of this drug on protein expression in the human colon cancer cell line HCT116. Protein extracts from untreated HCT116 cells, and cells grown for 24 h in the presence of 1 and 10 muM belinostat were analysed by 2-D gel electrophoresis. Proteins were visualized by colloidal Coomassie blue staining and quantitative analysis of gel images revealed 45 unique differentially expressed proteins that were identified by LC-MSMS analysis. Among these proteins, of particular interest are the downregulated proteins nucleophosmin and stratifin, and the upregulated proteins nucleolin, gelsolin, heterogeneous nuclear ribonucleoprotein K, annexin 1, and HSP90B that all were related to the proto-oncogene proteins p53, Myc, activator protein 1, and c-fos protein. The modulation of these proteins is consistent with the observations that belinostat is able to inhibit clonogenic cell growth of HCT116 cells and the biological role of these proteins will be discussed. PMID- 20717992 TI - Thermodynamic underpinnings of cell alignment on controlled topographies. PMID- 20717993 TI - An electro-optical device from a biofilm structure created by bacterial activity. PMID- 20717994 TI - Long-term corticosterone treatment induced lobe-specific pathology in mouse prostate. AB - BACKGROUND: Glucocorticoids influence prostate development and pathology, yet the underlying mechanisms including possible direct glucocorticoid effect on the prostate are not well characterized. METHODS: We evaluated the expression of the glucocorticoid receptor (GR) together with the effects of supraphysiological glucocorticoid (corticosterone) on mouse prostate morphology and epithelial proliferation. Mature male mice were treated by weekly subdermal implantation of depot pellets containing either 1.5 mg corticosterone or placebo providing steady state release for 4 weeks. RESULTS: Corticosterone treatment significantly increased dorsolateral and anterior prostate weights as well as prostate epithelial cell proliferation while epithelial apoptosis remained low upon corticosterone treatment. Histological analysis of the anterior lobe demonstrated abnormal, highly disorganized luminal epithelium with frequent formation of bridge-like structures lined by continuous layer of basal cells not observed following placebo treatment. Molecular analysis revealed corticosterone-induced increase in expression of stromal growth factor Fgf10 which, together with prominent stromal GR expression, suggest that glucocorticoid modify stromal-to epithelial signaling in the mouse prostate. The mitogenic effects were prostate specific and not mediated by systemic effects on testosterone production suggesting that corticosterone effects were primarily mediated via prostate GR expression. CONCLUSION: These data demonstrate that murine prostate is significantly and directly influenced by corticosterone treatment via aberrant stromal-to-epithelial growth factor signaling. PMID- 20717995 TI - Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior. AB - BACKGROUND: Chronic inflammation and subsequent tissutal alterations may play a key role in prostate carcinogenesis. In this way, molecular alterations of the suppressor of cytokine signaling 3 (SOCS3), one of the most important inhibitory molecule of inflammatory signal transduction circuitries, could contribute to explain the pleiotropic role of interleukin-6 (IL-6) in this type of cancer. METHODS: We analyzed the methylation status and mRNA expression of SOCS3 in 20 benign prostate hyperplasias (BPH) and in 51 prostate cancer specimens. We analyzed the SOCS3 methylation status using methylation-specific PCR. Hypermethylation was confirmed by sequencing after subcloning. Epigenetic silencing of this gene was also demonstrated by real-time PCR and by immunohistochemistry. Results and correlation with clinical data were statistically analyzed. RESULTS: We found that the promoter of SOCS3 was methylated in 39.2% of prostate cancer. On the contrary, all BPH and normal controls had an unmethylated pattern. Real-time analysis showed that in methylated cases SOCS3 mRNA expression was reduced by three and four folds as compared to BPH and unmethylated cases, respectively. Interestingly, SOCS3 mRNA level was higher in unmethylated prostate cancer than in BPH. The immunohistochemical staining analysis for SOCS 3 confirmed mRNA results. Moreover, methylation of SOCS3 promoter significantly associated with intermediate-high grade Gleason score (P = 0.0007) and with an unfavorable clinical outcome (P = 0.0019). CONCLUSIONS: Our data suggest that SOCS3 hypermethylation may be involved in the pathogenesis of prostate cancer and could identify a tumor subset with an aggressive behavior. PMID- 20717996 TI - Piscine aquaporins: an overview of recent advances. AB - Aquaporins are a superfamily of integral membrane proteins that facilitate the rapid and yet highly selective flux of water and other small solutes across biological membranes. Since their discovery, they have been documented throughout the living biota, with the majority of research focusing on mammals and plants. Here, we review available data for piscine aquaporins, including Agnatha (jawless fish), Chondrichthyes (chimaeras, sharks, and rays), Dipnoi (lungfishes), and Teleostei (ray-finned bony fishes). Recent evidence suggests that the aquaporin superfamily has specifically expanded in the chordate lineage consequent to serial rounds of whole genome duplication, with teleost genomes harboring the largest number of paralogs. The selective retention and dichotomous clustering of most duplicated paralogs in Teleostei, with differential tissue expression profiles, implies that novel or specialized physiological functions may have evolved in this clade. The recently proposed new nomenclature of the piscine aquaporin superfamily is discussed in relation to the phylogenetic signal and genomic synteny, with the teleost aquaporin-8 paralogs used as a case study to illustrate disparities between the underlying codons, molecular phylogeny, and physical locus. Structural data indicate that piscine aquaporins display similar channel restriction residues found in the tetrapod counterparts, and hence their functional properties seem to be conserved. However, emerging evidence suggests that regulation of aquaporin function in teleosts may have diverged in some cases. Cell localization and experimental studies imply that the physiological roles of piscine aquaporins extend at least to osmoregulation, reproduction, and early development, although in most cases their specific functions remain to be elucidated. PMID- 20717997 TI - Differences in Brachypelma albopilosa (Theraphosidae) hemolymph proteome between subadult and adult females. AB - The changes in the hemolymph proteome of mygalomorph Brachypelma albopilosa females were examined for the first time in relation to their developmental stage (subadult and adult period). Seven distinct subunits of hemocyanin (a, b, c, d, e, f, and g chains), as well as actin were clearly identified and their sequence partly characterized using a combination of one- and two-dimensional gel electrophoresis and mass spectrometry. The different structures determined along with possible post-translational modifications may reflect a role of hemocyanin in molting, immunity, and reproduction. In addition, despite no precise identification, additional peptide sequences from eight protein bands (four bands >200 kDa and four bands in the 95-200 kDa mass range) were determined. As reported in other spider species, the putative corresponding structures are the coagulogen protein and/or lipoproteins (HDL-1, HDL-2, VHDL) for which quantitative differences between adult and subadult individuals could be related to the molting process and/or cuticle lipid and protein composition according to the developmental stage. PMID- 20717998 TI - Male dominance and reproductive success in wild white-faced capuchins (Cebus capucinus) at Lomas Barbudal, Costa Rica. AB - Theory and a growing body of empirical evidence suggest that higher ranking males experience reproductive advantages in group-living mammals. White-faced capuchins (Cebus capucinus) exhibit an interesting social system for investigating the relationship between dominance and reproductive success (RS) because they live in multimale multifemale social groups, in which the alpha males can have extraordinarily long tenures (i.e. they coreside with daughters of reproductive age). Genetic paternity was determined from fecal samples for 120 infants born into three social groups of wild C. capucinus at Lomas Barbudal Biological Reserve, Costa Rica. Alpha males produced far more offspring than expected by chance, and significantly high Nonac's B indices (a measure of deviation from a random distribution of RS among potentially breeding individuals) were a feature of six out of eight male tenures. The likelihood of the alpha male siring a particular offspring was predicted by the kin relationship between the mother and the alpha male, as well as the total number of males and females in the group. The almost complete lack of father-daughter inbreeding [Muniz et al., 2006] constitutes an impediment to alpha male reproductive monopolization in this population, particularly toward the end of long alpha male tenures. PMID- 20717999 TI - Individual differences in emotionality: social temperament and health. AB - Individual differences, the importance of which was identified by Darwin more than 150 years ago, are evident in multiple domains. This review discusses the role of temperament in health-related outcomes in rhesus monkeys. Temperament is proposed as affecting health outcomes via behavioral means, and also via physical means either through its direct association with variation in physiological systems (a "main effects" model), or through its impact on functioning when organisms are in stressful circumstances (an "interaction effects" model). The specific temperament factor described is Sociability, which reflects a tendency to affiliate, and which is associated with positive affect, and with differences in sensitivity of brain dopamine systems. Data are reviewed showing that individual differences in Sociability in rhesus monkeys are related to variation in sympathetic innervation of lymphoid tissue (a main effect), as well as to patterns of coping in socially stressful circumstances (an interaction effect). Results such as these have implications for studies in behavioral ecology, medicine, and even for management practices in captive colonies of nonhuman primates. PMID- 20718000 TI - Externalizing problems and problematic sexual behaviors: same etiology? AB - The study sought to determine whether maltreatment subtypes, family sexuality, and personal characteristics predicted and distinguished child problematic sexual behaviors (PSB) and externalizing problems (EP). Participants were families of 188 children, 6-11 years old, referred by child welfare services in four Quebec districts. Caregivers completed interviews and questionnaires. Results suggested that family environment and maltreatment subtypes had partially different impacts on PSB and EP. When EP and gender were controlled, younger children in a sexualized family environment and those verbally victimized were more likely to exhibit PSB. When PSB and gender were controlled, verbal abuse and neglect emerged as predictors of EP. Potential implications for child PSB research and interventions are discussed. PMID- 20718001 TI - Estimating the effect of gang membership on nonviolent and violent delinquency: a counterfactual analysis. AB - This study reconsiders the well-known link between gang membership and criminal involvement. Recently developed analytical techniques enabled the approximation of an experimental design to determine whether gang members, after being matched with similarly situated nongang members, exhibited greater involvement in nonviolent and violent delinquency. Findings indicated that while gang membership is a function of self-selection, selection effects alone do not account for the greater involvement in delinquency exhibited by gang members. After propensity score matching was employed, gang members maintained a greater involvement in both nonviolent and violent delinquency when measured cross-sectionally, but only violent delinquency when measured longitudinally. Additional analyses using inverse probability of treatment weights reaffirmed these conclusions. PMID- 20718002 TI - Gang involvement: psychological and behavioral characteristics of gang members, peripheral youth, and nongang youth. AB - Research has noted the existence of a loose and dynamic gang structure. However, the psychological processes that underpin gang membership have only begun to be addressed. This study examined gang members, peripheral youth, and nongang youth across measures of criminal activity, the importance they attach to status, their levels of moral disengagement, their perceptions of out-group threat, and their attitudes toward authority. Of the 798 high school students who participated in this study, 59 were identified as gang members, 75 as peripheral youth, and 664 as nongang youth. Gang members and peripheral youth were more delinquent than nongang youth overall; however, gang members committed more minor offenses than nongang youth and peripheral youth committed more violent offenses than nongang youth. Gang members were more anti-authority than nongang youth, and both gang and peripheral youth valued social status more than nongang youth. Gang members were also more likely to blame their victims for their actions and use euphemisms to sanitize their behavior than nongang youth, whereas peripheral youth were more likely than nongang youth to displace responsibility onto their superiors. These findings are discussed as they highlight the importance of examining individual differences in the cognitive processes that relate to gang involvement. PMID- 20718003 TI - Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females. AB - The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers >=35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations. PMID- 20718004 TI - Stress-induced nanostructures through laser-assisted scanning probe nanolithography. AB - We demonstrate a methodology using a laser-assisted scanning probe nanolithography (LASPN) technique to generate organized nanostructures. Experimental approach combined with finite element analysis was utilized to study the interfacial interactions between a gold-coated probe of an atomic force microscope and a single crystal silicon substrate. Research results proved that the tip temperature had been raised via LASPN to 900 K at a laser power of 12 mW. Nanolines were formed during sliding while the silicon substrate was heated at a laser power of 5 mW. We propose an energy model to explain the phenomenon. PMID- 20718005 TI - Skin wound healing in axolotls: a scarless process. AB - Urodele amphibians, such as the axolotl (Ambystoma mexicanum), have the unique faculty among vertebrates to regenerate lost appendages (limbs and tail) and other body parts (apex of the heart, forebrain and jaw) after amputation. Interestingly, axolotls never seem to form scar tissue at the site of amputation once regeneration is completed. Before now, very few studies were directly focused on the description of the events happening during wound healing after a skin injury in salamanders. In this paper, we directly investigated skin wound healing after excisional wounding which removed the epidermis, dermis and basement membrane in the axolotl. Axolotls were wounded with a 1.5-mm skin biopsy punch. Results show rapid re-epithelialization of the wound within 8 hrs after wounding. Histological analysis of wound healing confirmed the absence of tissue fibrosis throughout the process and shows that skin integrity is re-established by 90 days after wounding. Results also reveal the absence of neutrophils in the wound area, suggestive of a lack of or low inflammatory response. The expression of proteins central to wound healing seemed different than in mammals as alpha smooth muscle actin was absent and transforming growth factor beta-1 was only transiently expressed during wound healing in the axolotl. Finally, subcutaneous injections of bleomycin were performed to verify whether the induction of scar tissue was possible in axolotls. Surprisingly, results show that axolotls are not resistant to bleomycin-induced tissue fibrosis, but the resulting scar tissue does not seem to contain significant amounts of collagen. PMID- 20718006 TI - A gel-free quantitative proteomics approach to investigate temperature adaptation of the food-borne pathogen Cronobacter turicensis 3032. AB - The opportunistic food-borne pathogen Cronobacter sp. causes rare but significant illness in neonates and is capable to grow at a remarkably wide range of temperatures from 5.5 to 47 degrees C. A gel-free quantitative proteomics approach was employed to investigate the molecular basis of the Cronobacter sp. adaptation to heat and cold-stress. To this end the model strain Cronobacter turicensis 3032 was grown at 25, 37, 44, and 47 degrees C, and whole-cell and secreted proteins were iTRAQ-labelled and identified/quantified by 2-D-LC-MALDI TOF/TOF-MS. While 44 degrees C caused only minor changes in C. turicensis growth rate and protein profile, 47 degrees C affected the expression of about 20% of all 891 identified proteins and resulted in a reduced growth rate and rendered the strain non-motile and filamentous. Among the heat-induced proteins were heat shock factors, transcriptional and translational proteins, whereas proteins affecting cellular morphology, proteins involved in motility, central metabolism and energy production were down-regulated. Notably, numerous potential virulence factors were found to be up-regulated at higher temperatures, suggesting an elevated pathogenic potential of Cronobacter sp. under these growth conditions. Significant alterations in the protein expression profile and growth rate of C. turicensis exposed to 25 degrees C indicate that at this temperature the organism is cold-stressed. Up-regulated gene products comprised cold-shock, DNA-binding and ribosomal proteins, factors that support protein folding and proteins opposing cold-induced decrease in membrane fluidity, whereas down-regulated proteins were mainly involved in central metabolism. PMID- 20718007 TI - Proteomic analysis of synaptosomal protein expression reveals that cerebral ischemia alters lysosomal Psap processing. AB - Cerebral ischemia (CI) induces dramatic changes in synaptic structure and function that precedes delayed post-ischemic neuronal death. Here, a proteomic analysis was used to identify the effects of focal CI on synaptosomal protein levels. Contralateral and ipsilateral synaptosomes, prepared from adult mice subjected to 60 min middle cerebral artery occlusion, were isolated following 3, 6 and 20 h of reperfusion. Synaptosomal protein samples (n=3) were labeled using the cleavable ICAT system prior to analysis with nanoLC-MS/MS. Each sample was analyzed by LC-MS to identify differential expressions using InDEPT software and differentially expressed peptides were identified by targeted LC-MS/MS. A total of 62 differentially expressed proteins were identified and Gene Ontology classification (cellular component) indicated that the majority of the proteins were located in the mitochondria and other components consistent with synaptic localization. The observed alterations in synaptic protein levels poorly correlated with gene expression, indicating the involvement of post transcriptional regulatory mechanisms in determining post-ischemic synaptic protein content. Additionally, immunohistochemistry analysis of prosaposin (Psap) and saposin C (SapC) indicates that CI disrupts Psap processing and glycosphingolipid metabolism. These results demonstrate that the synapse is adversely affected by CI and may play a role in mediating post-ischemic neuronal viability. PMID- 20718008 TI - Madin-Darby canine kidney cells are increased in aerobic glycolysis when cultured on flat and stiff collagen-coated surfaces rather than in physiological 3-D cultures. AB - We investigate the influence of the dimensionality and the biochemistry of the culture system on the cellular functionality by analyzing the protein expression levels in Madin-Darby canine kidney (MDCK) cells grown in 3-D and 2-D substrates. We cultured MDCK cells on a hard and flat 2-D uncoated plastic surface, on a 2-D collagen-coated plastic surface and in 3-D collagen gel and employed 2-D gel electrophoresis, MALDI-TOF-MS, and LC-MS/MS analysis to identify the differentially regulated proteins. We found significant differences in the expression of antioxidant proteins, actin-binding proteins, glycolytic enzymes, and heat-shock proteins/chaperons among the three types of cultures. While MDCK cells cultured in 3-D collagen up-regulate antioxidant proteins and proteins involved in the dynamic remodeling of the actin cytoskeleton, 2-D collagen-coated plastic surfaces induce the up-regulation of glycolytic enzymes. Our data shows that the culture conditions have profound effects on the physiology of the cell. Culture in 3-D collagen induces a differentiated polarized phenotype. In contrast, collagen-coated 2-D substrates favor a tumor-like phenotype with increased glycolysis. Thus, the suitability of 2-D cultures to study the physiological behavior of cells, especially in drug discovery, bioprocessing, and toxicology, should be carefully reconsidered. PMID- 20718009 TI - Catanionic tubules with tunable charge. PMID- 20718010 TI - Probing the kinetics of short-distance drug release from nanocarriers to nanoacceptors. PMID- 20718011 TI - Photocatalytic aerobic oxidation of alcohols on TiO2: the acceleration effect of a Bronsted acid. PMID- 20718012 TI - Mechanical properties of thin polymer films on stiff substrates. AB - Force-displacement curves have been acquired with a commercial atomic force microscope on thin films of poly(n-butyl methacrylate) on glass substrates in order to examine the so-called "mechanical double layer" topic, i.e. the influence of the substrate on the mechanical properties of the film in dependence of the film thickness. The hyperbolic fit, a novel semi-empirical equation introduced in previous articles, has been further corroborated. The interpretation of this equation has been deepened, yielding a quantitative and demonstrative characterization of the mechanical properties of double layers. Provided that the Young's moduli of bulk polymer and substrate are measured from the deformation curves, this mathematical model permits to fit the deformation force curves on the double layers and to determine the thickness of the polymer films in wide range (0-200 nm). PMID- 20718013 TI - Multiphoton microscopic imaging of normal human rectum tissue. AB - In this paper, multiphoton microscopy (MPM), based on two-photon excited fluorescence and second harmonic generation signals, was used to image microstructures of human rectal mucosa and submucosa. The morphology and distribution of the main components in mucosa layer, goblet cells, intestinal glands, and a little collagen fibers have been clearly monitored, and the content and distribution of collagen, elastic fibers, and blood vessels in submucosa layer have also been distinctly obtained. The variation of these components is very relevant to the pathology in gastrointestinal system, especially early rectal cancer. Our results indicate that the MPM technique has the potential application in vivo in the clinical diagnosis and monitoring of early rectal cancer. PMID- 20718014 TI - Scanning electron microscope (SEM) disclosure of the effects of snake venom on living tissue integrity and cell surfaces. AB - The tissue destruction produced by the bite of the viper is well known and the venom enzyme[s] that produce it have been thoroughly studied. Not so well examined is the view of the damage available to the electron microscope, especially the scanning electron microscope. Here we have used the SEM to view the effects of viper venom on living tissue in situ. PMID- 20718015 TI - Do predators cause frog deformities? The need for an eco-epidemiological approach. AB - Renewed controversy has emerged over the likely causes and consequences of deformed amphibians, particularly those with missing limbs. The results of a series of experiments by Ballengee and Sessions (2009) implicate aquatic predators (i.e. dragonfly larvae) in causing such abnormalities. Skelly and Benard (2010), however, argued that the small scale of these experiments and the absence of a correlation between predator abundance and deformity frequencies in natural amphibian populations undermine such a conclusion. Drawing upon our experiences with frog malformations, we suggest that the study of amphibian deformities has been hindered by two, interrelated problems. First, empirical studies often fail to critically define the expected baseline level of abnormalities and differentiate between "epidemic" and "endemic" frequencies of malformations. Second, recognizing the likelihood of multiple causes in driving amphibian malformations, continued research needs to embrace a "multiple lines of evidence" approach that allows for complex etiologies by integrating field surveys, diagnostic pathology, comparative modeling, and experiments across a range of ecological scales. We conclude by highlighting the results of a recent study that uses this approach to identify the role of aquatic predators (i.e., fishes and dragonflies) in causing high frequencies of deformed frogs in Oregon. By combining long-term data, comparative data and mechanistic experiments, this study provides compelling evidence that certain predators do cause deformities under ecologically relevant conditions. In light of continuing concerns about amphibian deformities and population declines, we emphasize the need to integrate ecological, epidemiological, and developmental tools in addressing such environmental enigmas. PMID- 20718016 TI - Ross Granville Harrison (1870-1959) and perspectives on regeneration. AB - Historical case studies can serve as cautionary tales, reminding us to reflect on underlying assumptions and on limitations of any particular approach. Ross Harrison's work recorded at the beginning and end of his career in the Journal of Experimental Zoology reveal his own morphological and experimental convictions, as they played out in his studies of regeneration. A closer look at this particular example of Harrison's contributions offers a perspective from which to view current studies of regenerative phenomena and assumptions about appropriate research approaches and the driving questions involved. PMID- 20718017 TI - Skull modularity in neotropical marsupials and monkeys: size variation and evolutionary constraint and flexibility. AB - An organism is built through a series of contingent factors, yet it is determined by historical, physical, and developmental constraints. A constraint should not be understood as an absolute obstacle to evolution, as it may also generate new possibilities for evolutionary change. Modularity is, in this context, an important way of organizing biological information and has been recognized as a central concept in evolutionary biology bridging on developmental, genetics, morphological, biochemical, and physiological studies. In this article, we explore how modularity affects the evolution of a complex system in two mammalian lineages by analyzing correlation, variance/covariance, and residual matrices (without size variation). We use the multivariate response to selection equation to simulate the behavior of Eutheria and Metharia skulls in terms of their evolutionary flexibility and constraints. We relate these results to classical approaches based on morphological integration tests based on functional/developmental hypotheses. Eutherians (Neotropical primates) showed smaller magnitudes of integration compared with Metatheria (didelphids) and also skull modules more clearly delimited. Didelphids showed higher magnitudes of integration and their modularity is strongly influenced by within-groups size variation to a degree that evolutionary responses are basically aligned with size variation. Primates still have a good portion of the total variation based on size; however, their enhanced modularization allows a broader spectrum of responses, more similar to the selection gradients applied (enhanced flexibility). Without size variation, both groups become much more similar in terms of modularity patterns and magnitudes and, consequently, in their evolutionary flexibility. PMID- 20718018 TI - An unusual galactofuranose lipopolysaccharide that ensures the intracellular survival of toxin-producing bacteria in their fungal host. PMID- 20718020 TI - The potential reuse of biodegradable municipal solid wastes (MSW) as feedstocks in vermicomposting. AB - There is an urgent need globally to find alternative sustainable steps to treat municipal solid wastes (MSW) originated from mismanagement of urban wastes with increasing disposal cost. Furthermore, a conglomeration of ever-increasing population and consumerist lifestyle is contributing towards the generation of more MSW. In this context, vermicomposting offers excellent potential to promote safe, hygienic and sustainable management of biodegradable MSW. It has been demonstrated that, through vermicomposting, MSW such as city garbage, household and kitchen wastes, vegetable wastes, paper wastes, human faeces and others could be sustainably transformed into organic fertiliser or vermicompost that provides great benefits to agricultural soil and plants. Generally, earthworms are sensitive to their environment and require temperature, moisture content, pH and sometimes ventilation at proper levels for the optimum vermicomposting process. Apart from setting the optimum operational conditions for the vermicomposting process, other approaches such as pre-composting, inoculating micro-organisms into MSW and redesigning the conventional vermireactor could be introduced to further enhance the vermicomposting of MSW. Thus the present mini-review discusses the potential of introducing vermicomposting in MSW management, the benefits of vermicomposted MSW to plants, suggestions on how to enhance the vermicomposting of MSW as well as risk management in the vermicomposting of MSW. PMID- 20718021 TI - Residue content of carbaryl applied on greenhouse cucumbers and its reduction by duration of a pre-harvest interval and post-harvest household processing. AB - BACKGROUND: Carbaryl is widely used to control various insect pests on greenhouse cucumbers in Iran. Therefore the control of residual levels of this insecticide is highly necessary. The effects of the household processing such as washing, peeling and refrigeration storage, at 4 degrees C for 2 days on the reduction of residue levels in the plant tissues were investigated in the different groups. Samples were collected at 1 h to 14 days after application and analysed to determine the content and dissipation rate of carbaryl. Analysis was carried out by the QuEChERS method using HPLC-UV. RESULTS: Carbaryl residue in samples, which were collected post-application in different times showed a gradual and significant (P < 0.05) decrease. The half-life (t(1/2)) of carbaryl applied on cucumbers was 3.2 days. Carbaryl residues were detected in concentration ranges of 0.22-4.91 mg kg(-1). Also, the results indicated that the consumable safety time of carbaryl was found to be more than 14 days on cucumber. CONCLUSION: Household processing, such as washing and peeling and refrigeration storage, was effective in reducing the residue levels. Also, peeling was the most effective way to reduce the carbaryl residues of the cucumber samples. Washing and refrigerated storage also decreased carbaryl residues. PMID- 20718022 TI - Fruit dry matter concentration: a new quality metric for apples. AB - BACKGROUND: In the fresh apple market fruit must be crisp and juicy to attract buyers to purchase again. However, recent studies have shown that consumer acceptability could be further enhanced by improving taste. This study evaluates the use of fruit dry matter concentration (DMC) as a new fruit quality metric for apple. RESULTS: Fruit samples collected at harvest, in the two main fruit growing regions of New Zealand, showed a variation in mean fruit DMC from 130 to 156 g kg(-1) with 'Royal Gala' and with 'Scifresh' from 152 to 176 g kg(-1). Individual fruit DMC showed a larger range, from 108 to 189 g kg(-1) with 'Royal Gala' and from 125 to 201 g kg(-1) with 'Scifresh'. Fruit DMC proved a more reliable predictor of total soluble solids after 12 weeks of air storage at 0.5 degrees C than TSS at harvest for both 'Royal Gala' and 'Scifresh'. Fruit DMC was also positively related to flesh firmness, although this relationship was not as strong as that seen with soluble solids and was more dependent on cultivar. Consumer studies showed that consumer preference was positively related to fruit DMC of 'Royal Gala' apples. CONCLUSION: Fruit DMC can therefore be measured before or at harvest, and be used to predict the sensory potential for the fruit after storage. PMID- 20718023 TI - Freshness characterisation of whiting (Merlangius merlangus) using an SPME/GC/MS method and a statistical multivariate approach. AB - BACKGROUND: The freshness of whiting was studied at five stages of ice storage by comparing the analysis of volatile compounds obtained through solid phase microextraction/gas chromatography/mass spectrometry (SPME/GC/MS) with two sensory methods. RESULTS: Of the volatile compounds identified, 38 were analysed using a statistical multivariate approach and classified according to their role in the estimation of freshness during storage as markers of freshness or spoilage. Regarding the evolution of the presence or absence of individual compounds, three categories were defined. For example, the volatile compounds propanal, hexanal, 1-penten-3-ol, pentanal, 2,3-pentanedione, 1-penten-3-one, heptanal, (E)-2-pentenal, 2,3-octanedione, (Z)-2-penten-1-ol, 1-pentanol, butanal, octanal, 3,5,5-trimethyl-2-hexene, 1-hexanol and 4,4-dimethyl-1,3 dioxane appeared highly relevant, because they are found throughout storage and can be divided into several categories that are directly related to the quality of fish. CONCLUSION: SPME/GC/MS combined with a statistical multivariate approach may be a useful method to identify volatile compounds and characterise fish freshness during storage. PMID- 20718024 TI - Characterization and discrimination of premium-quality, waxy, and black-pigmented rice based on odor-active compounds. AB - BACKGROUND: Odor-active compounds have been studied in cooked aromatic rice, but not in specialty rice types that have distinctly different flavors. We analyzed the odor-active compounds emanating from three different types of specialty rice (premium-quality, waxy and black-pigmented) and identified the differences in odor-active compounds among them. RESULTS: Twenty-one, 21 and 23 odorants were detected using GC-O for cooked samples of premium-quality, waxy and black pigmented rice cultivars, respectively. Hexanal was the main odorant in premium quality and waxy cultivars; however, waxy cultivars had 16 times higher hexanal odor activity values (OAVs) than premium-quality cultivars, indicating premium quality rice had a less pronounced overall aroma. 2-Acetyl-1-pyrroline was the main contributor to overall aroma in black-pigmented rice, followed by guaiacol. The three types of specialty rice were clearly discriminated based on the OAVs of their odor-active compounds using multivariate analyses. Six odor-active compounds [2-acetyl-1-pyrroline, guaiacol, hexanal, (E)-2-nonenal, octanal and heptanal] contributed the most in discriminating the three types of specialty rice. Six very similar superior cultivars of premium rice could likewise be readily separated using aroma chemistry. CONCLUSION: The ability to discriminate the aroma among rice types using the OAVs of the principal odor-active compounds facilitates our understanding of the aroma chemistry of specialty rice. PMID- 20718025 TI - Influence of the cultivar on the organic acid and sugar composition of potatoes. AB - BACKGROUND: Citric, malic, tartaric, oxalic, ascorbic, aconitic and fumaric acids, and sucrose, fructose and glucose, were determined in ten potato cultivars (Azucena negra, Bonita, Bonita negra, Borralla, Colorada de baga, Mora, Negra, Palmera lagarteada, Peluca blanca and Terrenta) from the Canary Islands in order to differentiate them. The influence of the production zone was also considered. RESULTS: Citric acid and sucrose were the most abundant organic acid and sugar, respectively. There were significant differences in all the analysed sugars and organic acids between the potato cultivars, except for oxalic and malic acids. Differences associated with the production zone were found in the contents of organic acids for some cultivars. Linear discriminant analysis is a useful tool to differentiate the potato samples according to the cultivar and the zone of production. CONCLUSIONS: Seven organic acids (citric, oxalic, malic, tartaric, aconitic, fumaric, and ascorbic acids) were identified and quantified in potatoes. The main sugars (sucrose, glucose and fructose) were also determined. The genetic information of the cultivars determines marked differences in sugars and organic acid contents among the analysed potato cultivars. The soil and climatic conditions affect the organic acid and sugar contents of some potato cultivars. PMID- 20718026 TI - Complementary effect of Phloxine B on the insecticidal efficacy of Isaria fumosorosea SFP-198 wettable powder against greenhouse whitefly, Trialeurodes vaporariorum West. AB - BACKGROUND: Insecticidal activities of five photoactive dyes against greenhouse whitefly (GWF), Trialeurodes vaporariorum West., in tomatoes were investigated to improve the control efficacy of an entomopathogenic fungal product, Isaria fumosorosea SFP-198 wettable powder (WP). Azorubine, Eosin B, Erythrosine, Brilliant Green and Phloxine B were used in this work, accompanying pyriproxyfen emulsifiable concentrate (EC) as a commercial standard for comparison. RESULTS: Phloxine B had the highest control efficacy in glasshouse conditions. The most suitable dose of Phloxine B was determined as 0.005 g L(-1) , given the dosage dependent control efficacy and phytotoxicity of the dye, and its influence on the germination of SFP-198 conidia. In field conditions, SFP-198 WP + Phloxine B (2 + 0.005 g L(-1) ; tank mix) showed 89.1 and 95.3% control efficacy 7 and 14 days post-application, which was significantly higher than the efficacy of SFP-198 WP alone (43.5 and 64.0%), Phloxine B (47.5 and 30.7%) or pyriproxyfen EC (67.7 and 80.2%). CONCLUSION: Phloxine B cooperates with SFP-198 WP complementarily, possibly in the order of killing action (early: Phloxine B; late: SFP-198 WP). The dye can be incorporated into SFP-198 WP to improve its efficacy and applied to other Hypocrelean entomopathogenic fungal products. PMID- 20718027 TI - Cultivar choice provides options for local production of organic and conventionally produced tomatoes with higher quality and antioxidant content. AB - BACKGROUND: Tomatoes (Solanum lycopersicum L.) are widely consumed and well known for their health benefits, many of which have been associated with the high levels of antioxidants present in tomatoes. With a growing interest in local and organic foods, it would be helpful to determine whether farmers could naturally improve the quality and antioxidant content of tomatoes for sale in local markets. This study evaluated antioxidant properties, quality attributes, and yield for 10 tomato cultivars grown for 2 years using certified organic and conventional practices. RESULTS: Cultivar and year effects impacted (P < 0.05) all tests conducted, while growing method influenced (P < 0.05) yield, soluble solids content, ascorbic acid, and antioxidant radical scavenging capacity. Even when accounting for year-to-year variability, cultivars in the highest groups had 1.35- to 1.67-fold higher antioxidant levels than cultivars in the lowest groups. 'New Girl', 'Jet Star', 'Fantastic', and 'First Lady' were always in the highest groups, while 'Roma' and 'Early Girl' consistently had the lowest antioxidant content. CONCLUSION: Compared to production practices and environmental effects of years that are generally beyond the control of small-scale producers, choice of cultivar provides the simplest and most effective means of increasing antioxidant properties. Knowledge of tomato cultivars with naturally higher antioxidant levels could assist smaller-scale producers to grow fruit that may provide a competitive advantage and the opportunity to capitalize on the increasing popularity of locally grown, high-quality fresh produce. PMID- 20718028 TI - Nutritional composition and condensed tannin concentration changes as browse leaves become litter. AB - BACKGROUND: The role of condensed tannins (CT) in ruminant nutrition and health makes changes in leaf litter (LL) after abscission of interest. This study compared the effect of different drying methods of green leaves (GL) with that of natural drying of LL on CT, fibre, crude protein (CP) and phosphorus (P) concentrations in nine Texas browse species. Leaves harvested before autumn shedding were oven-dried (OD) or freeze-dried (FD). RESULTS: Where different (P < 0.05), extractable CT concentrations were higher while protein- and fibre-bound CT concentrations were lower in GL-FD than in LL. Drying method changed total CT concentration in three species. Where different, fibre fraction concentrations were greater in LL than in GL, regardless of drying method. In some species, CP and P concentrations were lower in LL than in GL, but in five species they did not change (P > 0.05) from GL to LL, with CP concentrations ranging from 63 to 151 g kg(-1) in the latter. CONCLUSION: Browse LL had high nutritive value and CT concentrations, explaining why browsing ruminants utilise this feed resource. However, changes in nutrient and CT concentrations as leaves become litter in some species mean that information on one is not necessarily applicable to the other. PMID- 20718029 TI - Chemical composition and nutritional quality of sea cucumbers. AB - BACKGROUND: The dried form of sea cucumbers has been a seafood and medicinal cure for Asians over many centuries. In this study the chemical composition and nutritional quality of eight common sea cucumbers (Stichopus herrmanni, Thelenota ananas, Thelenota anax, Holothuria fuscogilva, Holothuria fuscopunctata, Actinopyga mauritiana, Actinopyga caerulea and Bohadschia argus) were determined. RESULTS: All species except T. anax and A. caerulea had higher protein and lower fat levels. A. mauritiana and B. argus had less ash content. Glycine was the dominant amino acid found in all species, and content ranged from 126 to 216 mg g(-1) of crude protein. All species exhibited low lysine:arginine ratio and higher essential amino acid scores were obtained by threonine and phenylalanine + tyrosine. A. mauritiana had proportionally less saturated fatty acids (31.23%), and more monounsaturated fatty acids (45.64%) and polyunsaturated fatty acids (PUFA, 23.13%) than other species. Arachidonic acid (C20:4n-6) was the major PUFA in all species. T. ananas, A. mauritiana and A. caerulea contained more n-3 PUFA. The n-3/n-6 ratios of eight sea cucumbers species ranged from 0.25 to 0.61. CONCLUSION: Sea cucumbers are a seafood with high protein and low fat levels. The amino acid contents were similar but fatty acid profiles were different among species. The comparison showed that T. ananas, A. mauritiana and B. argus possessed higher nutritional values than other sea cucumber species. PMID- 20718030 TI - Effects of tannic acid on gluten protein structure, dough properties and bread quality of Chinese wheat. AB - BACKGROUND: The effects of tannic acid, which is present in many plants, on the structure of gluten proteins and the properties of dough and bread were studied. Tannic acid was added at levels of 0.01, 0.02 and 0.03 g kg(-1) during the dough making process. RESULTS: The added tannic acid acted negatively on disulfide bond formation but interacted with gluten proteins via other covalent bonds, as detected by UV spectroscopy and dynamic rheometry. Rheological properties and texture of the bread were measured by farinograph, extensograph and texture profile analyser. Texture analysis indicated little change in adhesiveness and resilience of the bread at all three levels of tannic acid compared with the control, but changes in hardness and chewiness of the bread made with added tannic acid indicated that tannic acid could delay bread staling. CONCLUSION: The effect of tannic acid on flour and dough is different from that of other flour redox agents. It breaks down disulfide bonds but also has positive effects on dough properties and bread quality. Disulfide bonds are commonly considered to be the most important factor affecting changes in the quality of bread. However, this study presents the new concept that other covalent bonds can also improve the quality of flour and bread and uses this property to investigate new, safe and efficient flour additives. PMID- 20718031 TI - Modulation of salt (NaCl)-induced effects on oil composition and fatty acid profile of sunflower (Helianthus annuus L.) by exogenous application of salicylic acid. AB - BACKGROUND: Salicylic acid (SA) is a potential endogenous plant hormone that plays an important role in plant growth and development. Since sunflower yield and its seed oil yield are adversely affected by salinity, in this study the role of SA in modulating salt (NaCl)-induced effects on various yield and oil characteristics of sunflower was investigated. For this purpose a greenhouse experiment comprising two sunflower hybrid lines (Hysun-33 and SF-187), two NaCl levels (0 and 120 mmol L(-1)) and four SA levels (0, 100, 200 and 300 mg L(-1)) was conducted. RESULTS: Salt stress markedly reduced yield, oil content, linoleic acid and delta-tocopherol in both sunflower lines, while it increased linolenic acid, palmitic acid, stearic acid and alpha- and gamma-tocopherols. However, increasing levels of foliar-applied SA resulted in improved achene yield and hundred-achene weight in both lines. Foliar-applied SA caused a significant decrease in oil stearic acid and alpha- and gamma-tocopherols in both lines under non-saline and saline conditions. CONCLUSION: Salt-induced harmful effects on achene yield and oil characteristics of sunflower could be alleviated by exogenous application of SA. High doses of SA caused a marked increase in sunflower achene oil content as well as some key fatty acids. PMID- 20718032 TI - Temperature effects on type I pepsin-solubilised collagen extraction from silver line grunt skin and its in vitro fibril self-assembly. AB - BACKGROUND: Fish skin is a potential source of collagen. Increasing the extraction temperature increases the yield of collagen. However, it may also result in degradation of the peptide chains, thus damaging the 3D structure of collagen that is vital for its application as a biomaterial. This work investigated the effects of extraction temperature on the yield and characteristics, including fibril self-assembly, of type I pepsin-solubilised fish skin collagen. RESULTS: Pepsin-solubilised collagens were extracted from fresh skin of silver-line grunt at 4, 10, 20 and 28 degrees C for 6 h. Extraction at 10 degrees C gave the highest yield of collagens (439.32 +/- 96.43 mg g(-1) fresh skin, dry basis), which were identified as type I and comprised beta, alpha1 and alpha2 subunits. Extraction at higher temperatures (20 and 28 degrees C) resulted in the formation of low-molecular-weight peptide fragments, thus reducing the yield of the resultant type I collagen. The denaturation temperatures of collagens extracted at 4 and 10 degrees C, as determined by thermal analysis using differential scanning calorimetry, were 39.5 and 37.5 degrees C respectively. In vitro fibril self-assembly of 1 mg mL(-1) collagen solution (pH 6) incubated at 25 degrees C was only observed with collagens extracted at 4 and 10 degrees C. The 10 degrees C collagen not only showed a higher rate of self-assembly, but its matrix also had a larger fibril diameter of 0.50 +/- 0.07 um (compared with 0.41 +/- 0.07 um for the 4 degrees C collagen) after 4 h of incubation. CONCLUSION: The results indicated strong effects of extraction temperature on the yield and characteristics of the collagen obtained. Extraction of pepsin-solubilised collagen from silver-line grunt skin at 4-10 degrees C gave a high yield of type I collagen with molecular integrity suitable for tissue-engineering applications. PMID- 20718033 TI - Use of microfungi in the treatment of oak chips: possible effects on wine. AB - BACKGROUND: Oak barrels are commonly used in the aging of wines and spirits because of their positive effects on the product. In recent years the addition of oak chips has been used to introduce desirable wood aromas and flavours into wines. In this study, oak chips in saline solution or laboratory medium were inoculated with Penicillium purpurogenum, Aureobasidium pullulans, Phialemonium obovatum, Phanerochaete chrysosporium and a combination of Ph. chrysosporium and A. pullulans. After 12 weeks of incubation, oak chips (2 g L(-1)) were macerated in a red wine for 17 days. Gas chromatography/mass spectrometry and high performance liquid chromatography were used to evaluate 14 compounds, namely furfural, furfuryl alcohol, guaiacol, syringol, cis-beta-methyl-gamma octalactone, 2-phenylethanol, 4-vinylguaiacol, benzyl alcohol, 2,3-butanediol, gamma-butyrolactone, benzaldehyde, 4-ethylguaiacol, gallic acid and ellagic acid. RESULTS: The microfungal treatments increased the concentration of some components. In particular, P. purpurogenum resulted in a significant improvement in the levels of guaiacol, furfural, syringol, furfuryl alcohol and 2 phenylethanol. CONCLUSION: Penicillium purpurogenum and Ph. chrysosporium showed a constant trend (enrichment of furfural and benzaldehyde) independent to some extent of the medium used for chip treatment. PMID- 20718034 TI - Factors affecting usefulness of triticale grain for bioethanol production. AB - BACKGROUND: Triticale grain could be a useful material for bioethanol production. The aim of this study was to examine how grain cultivar, nitrogen fertilisation level, location and year affect the starch content in triticale grain and which method of starch determination, polarimetric, enzymatic or near-infrared transmission (NIT), gives the best prediction of real bioethanol productivity from triticale grain. RESULTS: It was found that the starch content in triticale grain was correlated positively with test weight and 1000-kernel weight but negatively with falling number and protein content. All factors, i.e. cultivar, nitrogen fertilisation level, location and year, as well as the intrinsic interaction between these factors, had a significant effect on the starch level in triticale grain. The NIT procedure of starch determination gave the best results in predicting the real yield of ethanol obtained on the basis of classic fermentation (95% match), while the enzymatic and polarimetric methods corresponded with the real results at levels of 89-90 and 78-82% respectively. CONCLUSION: Grain growth conditions related to location and nitrogen fertilisation level had the most noticeable effect on grain starch content, while grain yield per hectare had the most significant effect on ethanol productivity. PMID- 20718035 TI - Differential bone-forming capacity of osteogenic cells from either embryonic stem cells or bone marrow-derived mesenchymal stem cells. AB - For more than a decade, human mesenchymal stem cells (hMSCs) have been used in bone tissue-engineering research. More recently some of the focus in this field has shifted towards the use of embryonic stem cells. While it is well known that hMSCs are able to form bone when implanted subcutaneously in immune-deficient mice, the osteogenic potential of embryonic stem cells has been mainly assessed in vitro. Therefore, we performed a series of studies to compare the in vitro and in vivo osteogenic capacities of human and mouse embryonic stem cells to those of hMSCs. Embryonic and mesenchymal stem cells showed all characteristic signs of osteogenic differentiation in vitro when cultured in osteogenic medium, including the deposition of a mineralized matrix and expression of genes involved in osteogenic differentiation. As such, based on the in vitro results, osteogenic ES cells could not be discriminated from osteogenic hMSCs. Nevertheless, although osteogenic hMSCs formed bone upon implantation, osteogenic cells derived from both human and mouse embryonic stem cells did not form functional bone, indicated by absence of osteocytes, bone marrow and lamellar bone. Although embryonic stem cells show all signs of osteogenic differentiation in vitro, it appears that, in contrast to mesenchymal stem cells, they do not possess the ability to form bone in vivo when a similar culture method and osteogenic differentiation protocol was applied. PMID- 20718036 TI - The intermembrane space domain of Tim23 is intrinsically disordered with a distinct binding region for presequences. AB - Proteins targeted to the mitochondrial matrix are translocated through the outer and the inner mitochondrial membranes by two protein complexes, the translocase of the outer membrane (TOM) and one of the translocases of the inner membrane (TIM23). The protein Tim23, the core component of TIM23, consists of an N terminal, soluble domain in the intermembrane space (IMS) and a C-terminal domain that forms the import pore across the inner membrane. Before translocation proceeds, precursor proteins are recognized by the N-terminal domain of Tim23, Tim23N (residues 1-96). By using NMR spectroscopy, we show that Tim23N is a monomeric protein belonging to the family of intrinsically disordered proteins. Titrations of Tim23N with two presequences revealed a distinct binding region of Tim23N formed by residues 71-84. In a charge-hydropathy plot containing all soluble domains of TOM and TIM23, Tim23N was found to be the only domain with more than 40 residues in the IMS that is predicted to be intrinsically disordered, suggesting that Tim23N might function as hub in the mitochondrial import machinery protein network. PMID- 20718037 TI - A strategic approach for the design and operation of two-phase partitioning bioscrubbers for the treatment of volatile organic compounds. AB - A strategic approach for the design of two-phase partitioning bioscrubbers (TPPBs) has been formulated using, as a basis, a re-evaluation of extensive literature data available for the degradation of benzene by Achromobacter xylosoxidans Y234 in TPPBs with n-hexadecane as the partitioning phase. Using a previously determined maintenance coefficient for benzene, we determined that an inlet benzene loading rate of 100 mg/h requires 5,928 mg cell mass at biological steady state and 243.0 mg O(2) /h. The total oxygen-transfer rates (TOTRs) into the TPPB increased by 83.5% with 33.3% of organic phase compared with a single aqueous phase and were significantly influenced by gas flow rate, whereas agitation has a minor affect. The fraction of organic phase used was suggested to be the primary parameter with which the TOTR into the TPPB may be altered. Although the presence of an organic solvent in the TPPB remarkably increased the TOTR, the total benzene transfer rate into the TPPB remained largely insensitive due to the intrinsic low Henry's law constant (or relatively high solubility) of benzene in water. Finally, we have integrated the elements of this analysis into a set of heuristic criteria that can serve as a guideline for the design of TPPB systems for future volatile organic compound treatment applications. PMID- 20718038 TI - A mutant form of PTEN linked to autism. AB - The tumor suppressor, phosphatase, and tensin homologue deleted on chromosome 10 (PTEN), is a phosphoinositide (PI) phosphatase specific for the 3-position of the inositol ring. PTEN has been implicated in autism for a subset of patients with macrocephaly. Various studies identified patients in this subclass with one normal and one mutated PTEN gene. We characterize the binding, structural properties, activity, and subcellular localization of one of these autism-related mutants, H93R PTEN. Even though this mutation is located at the phosphatase active site, we find that it affects the functions of neighboring domains. H93R PTEN binding to phosphatidylserine-bearing model membranes is 5.6-fold enhanced in comparison to wild-type PTEN. In contrast, we find that binding to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)) model membranes is 2.5-fold decreased for the mutant PTEN in comparison to wild-type PTEN. The structural change previously found for wild-type PTEN upon interaction with PI(4,5)P(2), is absent for H93R PTEN. Consistent with the increased binding to phosphatidylserine, we find enhanced plasma membrane association of PTEN-GFP in U87MG cells. However, this enhanced plasma membrane association does not translate into increased PI(3,4,5)P(3) turnover, since in vivo studies show a reduced activity of the H93R PTEN-GFP mutant. Because the interaction of PI(4,5)P(2) with PTEN's N-terminal domain is diminished by this mutation, we hypothesize that the interaction of PTEN's N-terminal domain with the phosphatase domain is impacted by the H93R mutation, preventing PI(4,5)P(2) from inducing the conformational change that activates phosphatase activity. PMID- 20718039 TI - Generation of high-affinity fully human anti-interleukin-8 antibodies from its cDNA by two-hybrid screening and affinity maturation in yeast. AB - We have developed a technology for rapidly generating novel and fully human antibodies by simply using the antigen DNA. A human single-chain variable fragment (scFv) antibody library was constructed in a yeast two-hybrid vector with high complexity. After cloning cDNA encoding the mature sequence of human interleukin-8 (hIL8) into the yeast two-hybrid system vector, we have screened the human scFv antibody library and obtained three distinct scFv clones that could specifically bind to hIL8. One clone was chosen for further improvement by a novel affinity maturation process using the error-prone PCR of the scFv sequence followed by additional rounds of yeast two-hybrid screening. The scFv antibodies of both primary and affinity-matured scFv clones were expressed in E. coli. All purified scFvs showed specific binding to hIL8 in reciprocal coimmunoprecipitation and ELISA assays. All scFvs, as well as a fully human IgG antibody converted from one of the scFv clones and expressed in the mammalian cells, were able to effectively inhibit hIL8 in neutrophil chemotaxis assays. The technology described can generate fully human antibodies with high efficiency and low cost. PMID- 20718040 TI - Changes in skeletal robusticity in an iron age agropastoral group: the Samnites from the Alfedena necropolis (Abruzzo, Central Italy). AB - Cross-sectional geometrical (CSG) properties of an Iron Age Samnite group from the Alfedena necropolis (Abruzzo, Italy, 2600-2400 B.P.) are compared with a Ligurian Neolithic sample (6000-5500 B.P.). In the period under examination, Samnites were organized in a tribal confederation led by patrilinear aristocracies, indicating incipient social stratification. In comparison, Neolithic society lacked clear signs of social hierarchy. The subsistence of both groups was mainly based on pastoralism and agriculture, but changes in habitual behavior are expected due to the socio-economic transformations that characterized the Iron Age. The Samnites' warlike ideology suggests that unimanual weapon-use and training would have become frequent for males. The intensification of agriculture and the adoption of transhumant pastoralism, performed by a smaller subset of the population, likely led to a lower average level of logistic mobility. The strongly genderized ideology of the period suggests a strict sexual division of labor, with women primarily performing sedentary tasks. CSG properties based on periosteal contours were calculated for humeri, femora, and tibiae (N = 61). Results corroborated the expectations: Alfedena males show substantial humeral bilateral asymmetry, indicating prevalent use of one arm, likely due to weapon training. In both sexes lower limb results indicate reduced mobility with respect to the Neolithic group. Sexual dimorphism is significant in both humeral asymmetry and lower limb indicators of mobility. Although both groups could be broadly defined as agropastoral based on archeological and historical evidence, CSG analysis confirmed important differences in habitual behavior. PMID- 20718041 TI - On the genome-wide analysis of copy number variants in family-based designs: methods for combining family-based and population-based information for testing dichotomous or quantitative traits, or completely ascertained samples. AB - We propose a new approach for the analysis of copy number variants (CNVs)for genome-wide association studies in family-based designs. Our new overall association test combines the between-family component and the within-family component of the family-based data so that the new test statistic is fully efficient and, at the same time, maintains robustness against population admixture and stratification, like classical family-based association tests that are based only on the within-family component. Although all data are incorporated into the test statistic, an adjustment for genetic confounding is not needed, even for the between-family component. The new test statistic is valid for testing either quantitative or dichotomous phenotypes. If external CNV data are available, the approach can also be applied to completely ascertained samples. Similar to the approach by Ionita-Laza et al. ([2008]. Genet Epidemiol 32:273 284), the proposed test statistic does not require a CNV-calling algorithm and is based directly on the CNV probe intensities. We show, via simulation studies, that our methodology increases the power of the FBAT statistic to levels comparable to those of population-based designs. The advantages of the approach in practice are demonstrated by an application to a genome-wide association study for body mass index. PMID- 20718042 TI - Pooled versus individual genotyping in a breast cancer genome-wide association study. AB - We examine the measurement properties of pooled DNA odds ratio estimates for 7,357 single nucleotide polymorphisms (SNPs) genotyped in a genome-wide association study of postmenopausal breast cancer. This study involved DNA pools formed from 125 cases or 125 matched controls. Individual genotyping for these SNPs subsequently came available for a substantial majority of women included in seven pool pairs, providing the opportunity for a comparison of pooled DNA and individual odds ratio estimates and their variances. We find that the "per minor allele" odds ratio estimates from the pooled DNA comparisons agree fairly well with those from individual genotyping. Furthermore, the log-odds ratio variance estimates support a pooled DNA measurement model that we previously described, although with somewhat greater extra-binomial variation than was hypothesized in project design. Implications for the role of pooled DNA comparisons in the future genetic epidemiology research agenda are discussed. PMID- 20718044 TI - A variance components factor model for genetic association studies: a Bayesian analysis. AB - Studies of gene-trait associations for complex diseases often involve multiple traits that may vary by genotype groups or patterns. Such traits are usually manifestations of lower-dimensional latent factors or disease syndromes. We illustrate the use of a variance components factor (VCF) model to model the association between multiple traits and genotype groups as well as any other existing patient-level covariates. This model characterizes the correlations between traits as underlying latent factors that can be used in clinical decision making. We apply it within the Bayesian framework and provide a straightforward implementation using the WinBUGS software. The VCF model is illustrated with simulated data and an example that comprises changes in plasma lipid measurements of patients who were treated with statins to lower low-density lipoprotein cholesterol, and polymorphisms from the apolipoprotein-E gene. The simulation shows that this model clearly characterizes existing multiple trait manifestations across genotype groups where individuals' group assignments are fully observed or can be deduced from the observed data. It also allows one to investigate covariate by genotype group interactions that may explain the variability in the traits. The flexibility to characterize such multiple trait manifestations makes the VCF model more desirable than the univariate variance components model, which is applied to each trait separately. The Bayesian framework offers a flexible approach that allows one to incorporate prior information. PMID- 20718043 TI - Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome. AB - Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r(2)> or = 0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over transmitted to cases with AVSD (P=0.05) and under-transmitted to controls (P=0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS. PMID- 20718046 TI - Genome-wide association studies using haplotype clustering with a new haplotype similarity. AB - Association analysis, with the aim of investigating genetic variations, is designed to detect genetic associations with observable traits, which has played an increasing part in understanding the genetic basis of diseases. Among these methods, haplotype-based association studies are believed to possess prominent advantages, especially for the rare diseases in case-control studies. However, when modeling these haplotypes, they are subjected to statistical problems caused by rare haplotypes. Fortunately, haplotype clustering offers an appealing solution. In this research, we have developed a new befitting haplotype similarity for "affinity propagation" clustering algorithm, which can account for the rare haplotypes primely, so as to control for the issue on degrees of freedom. The new similarity can incorporate haplotype structure information, which is believed to enhance the power and provide high resolution for identifying associations between genetic variants and disease. Our simulation studies show that the proposed approach offers merits in detecting disease-marker associations in comparison with the cladistic haplotype clustering method CLADHC. We also illustrate an application of our method to cystic fibrosis, which shows quite accurate estimates during fine mapping. PMID- 20718045 TI - Quality control and quality assurance in genotypic data for genome-wide association studies. AB - Genome-wide scans of nucleotide variation in human subjects are providing an increasing number of replicated associations with complex disease traits. Most of the variants detected have small effects and, collectively, they account for a small fraction of the total genetic variance. Very large sample sizes are required to identify and validate findings. In this situation, even small sources of systematic or random error can cause spurious results or obscure real effects. The need for careful attention to data quality has been appreciated for some time in this field, and a number of strategies for quality control and quality assurance (QC/QA) have been developed. Here we extend these methods and describe a system of QC/QA for genotypic data in genome-wide association studies (GWAS). This system includes some new approaches that (1) combine analysis of allelic probe intensities and called genotypes to distinguish gender misidentification from sex chromosome aberrations, (2) detect autosomal chromosome aberrations that may affect genotype calling accuracy, (3) infer DNA sample quality from relatedness and allelic intensities, (4) use duplicate concordance to infer SNP quality, (5) detect genotyping artifacts from dependence of Hardy-Weinberg equilibrium test P-values on allelic frequency, and (6) demonstrate sensitivity of principal components analysis to SNP selection. The methods are illustrated with examples from the "Gene Environment Association Studies" (GENEVA) program. The results suggest several recommendations for QC/QA in the design and execution of GWAS. PMID- 20718048 TI - Strengths and weaknesses of data-driven docking in critical assessment of prediction of interactions. AB - The recent CAPRI rounds have introduced new docking challenges in the form of protein-RNA complexes, multiple alternative interfaces, and an unprecedented number of targets for which homology modeling was required. We present here the performance of HADDOCK and its web server in the CAPRI experiment and discuss the strengths and weaknesses of data-driven docking. HADDOCK was successful for 6 out of 9 complexes (6 out of 11 targets) and accurately predicted the individual interfaces for two more complexes. The HADDOCK server, which is the first allowing the simultaneous docking of generic multi-body complexes, was successful in 4 out of 7 complexes for which it participated. In the scoring experiment, we predicted the highest number of targets of any group. The main weakness of data driven docking revealed from these last CAPRI results is its vulnerability for incorrect experimental data related to the interface or the stoichiometry of the complex. At the same time, the use of experimental and/or predicted information is also the strength of our approach as evidenced for those targets for which accurate experimental information was available (e.g., the 10 three-stars predictions for T40!). Even when the models show a wrong orientation, the individual interfaces are generally well predicted with an average coverage of 60% +/- 26% over all targets. This makes data-driven docking particularly valuable in a biological context to guide experimental studies like, for example, targeted mutagenesis. PMID- 20718047 TI - Fluctuation dynamics analysis of gp120 envelope protein reveals a topologically based communication network. AB - Human Immunodeficiency Virus (HIV) infection is initiated by binding of the viral glycoprotein gp120, to the cellular receptor CD4. On CD4 binding, gp120 undergoes conformational change, permitting binding to the chemokine receptor. Crystal structures of gp120 ternary complex reveal the CD4 bound conformation of gp120. We report here the application of the Gaussian network model (GNM) to the crystal structures of gp120 bound to CD4 or CD4 mimic and 17b, to study the collective motions of the gp120 core and determine the communication propensities of the residue network. The GNM fluctuation profiles identify residues in the inner domain and outer domain that may facilitate conformational change or stability, respectively. Communication propensities delineate a residue network that is topologically suited for signal propagation from the Phe43 cavity throughout the gp120 outer domain. These results provide a new context for interpreting gp120 core envelope structure-function relationships. PMID- 20718049 TI - New insights into induction of early-stage neovascularization in an improved tissue-engineered model of psoriasis. AB - We have previously shown that putrescine induces a psoriatic phenotype in tissue engineered skin. The initial aim of this study was to further develop this in vitro model by introducing endothelial cells to mimic the increased vascularization found in psoriasis. Human keratinocytes and fibroblasts, which did not express CD34 or CD31 in 2D culture, were added to de-epidermised acellular human dermis and cultured for 4 weeks. For induction of a psoriatic phenotype, putrescine was added during this period. We report that after 4 weeks of culture, and particularly when exposed to putrescine, this model showed expression of vertically organised clusters of CD31 positive cells in the dermis in the absence of any exogenous endothelial cells. Further investigation in 2D cell cultures showed an indirect effect of putrescine on normal keratinocytes causing them to produce soluble factors that increased expression of CD133, CD34 and CD31 in cultured human dermal fibroblasts, previously negative for these antigens. This study reports a new and improved model of psoriasis for in vitro studies and offers a new insight into early stage neovascularization, which is of relevance not only to psoriasis, but to tissue engineering and wound healing in general. PMID- 20718051 TI - Molecular property-affinity relationship of flavanoids and flavonoids for HSA in vitro. AB - The relationship between the structural properties of selected dietary flavanoids and flavonoids and their affinities for HSA were investigated by fluorescence analysis. The binding process with HSA was strongly influenced by the structural differences of the compounds under study. Methylation of hydroxyl groups improved the affinities for HSA by 2-16-fold. Hydroxylation on rings A, B, and C also affected the affinity for HSA significantly. Glycosylation decreased the affinities for HSA by 1-3 orders of magnitude depending on the conjugation site and the class of sugar moiety. Hydrogenation of the C2=C3 double bond also decreased the binding affinity. Galloylated catechins and pyrogallol-type catechins exhibited higher binding affinities for HSA than non-galloylated and catechol-type catechins, respectively. The affinities for HSA increased with increasing partition coefficients and decreased with increasing hydrogen bond donor and acceptor numbers of flava(o)noids, which suggested that the binding interaction was mainly caused by hydrophobic forces. PMID- 20718050 TI - Three-dimensional 10% cyclic strain reduces bovine aortic endothelial cell angiogenic sprout length and augments tubulogenesis in tubular fibrin hydrogels. AB - The development of a functional microvasculature is critical to the long-term survival of implanted tissue-engineered constructs. Dynamic culture conditions have been shown to significantly modulate phenotypic characteristics and stimulate proliferation of cells within hydrogel-based tissue engineered blood vessels. Although prior work has described the effects uniaxial or equibiaxial mechanical stimulation has on endothelial cells, no work has outlined effects of three-dimensional mechanical stimulation on endothelial cells within tubular vessel analogues. We demonstrate here that 7 days of 10% cyclic volumetric distension has a deleterious effect on the average length and density of angiogenic sprouts derived from pellets of bovine aortic endothelial cells. Although both groups demonstrated lumen formation, the sprouts grown under dynamic culture conditions typically had wider, less-branching sprout patterns. These results suggest that prolonged mechanical stimulation could represent a cue for angiogenic sprouts to preferentially develop larger lumens over cellular migration and subsequent sprout length. PMID- 20718052 TI - Chemoprevention of colonic tumorigenesis by dietary hydroxylated polymethoxyflavones in azoxymethane-treated mice. AB - SCOPE: Hydroxylated polymethoxyflavones (PMFs), existing exclusively in citrus genus, have been reported to exhibit a broad spectrum of biological activity. Here we investigated the chemopreventive effects and underlying molecular mechanisms of dietary administration of hydroxylated PMFs in an azoxymethane (AOM)-induced colonic tumorigenesis model. METHODS AND RESULTS: Male, Institute of Cancer Research (ICR), mice at age of 6 wk were injected with AOM twice weekly at a dose of 5 mg/kg for 2 wk and continuously fed control diet or diets containing 0.01 and 0.05% hydroxylated PMFs, respectively. Mice were then sacrificed at 6 and 20 wk, and colonic tissues were collected and examined. Hydroxylated PMFs feeding dose-dependently decreased the number of aberrant crypt foci in colonic tissues of mice. More importantly, we found that hydroxylated PMFs caused a strong reduction in numbers of large aberrant crypt foci and tumors in colonic tissue. Molecular analysis exhibited the anti-proliferative, anti inflammatory, anti-angiogenic and pro-apoptotic activities of hydroxylated PMFs by significantly decreasing the levels of inducible nitric oxide synthase, cyclooxygenase, cyclin D1 and vascular endothelial growth factor through interfering with Wnt/beta-catenin and epidermal growth factor receptor/Ras/mitogen-activated protein kinase signaling pathways as well as the activation of transcription factors NF-kappaB and STAT3 in colonic tissue, thus resulting in suppression of colonic tumorigenesis. CONCLUSION: Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary hydroxylated PMFs against AOM induced colonic tumorigenesis. PMID- 20718053 TI - Calcium phosphate mineralization beneath a polycationic monolayer at the air water interface. AB - The self-assembly of the amphiphilic block copolymer poly(n-butyl methacrylate) block-poly[2-(dimethylamino)ethyl methacrylate] at the air-water interface has been investigated at different pH values. Similar to Rehfeldt et al. (J. Phys. Chem. B 2006, 110, 9171), the subphase pH strongly affects the monolayer properties. The formation of calcium phosphate beneath the monolayer can be tuned by the subphase pH and hence the monolayer charge. After 12 h of mineralization at pH 5, the polymer monolayers are still transparent, but transmission electron microscopy (TEM) shows that very thin calcium phosphate fibers form, which aggregate into cotton ball-like features with diameters of 20 to 50 nm. In contrast, after 12 h of mineralization at pH 8, the polymer film is very slightly turbid and TEM shows dense aggregates with sizes between 200 and 700 nm. The formation of calcium phosphate is further confirmed by Raman and energy dispersive X-ray spectroscopy. The calcium phosphate architectures can be assigned to the monolayer charge, which is high at low pH and low at high pH. The study demonstrates that the effects of polycations should not be ignored if attempting to understand the colloid chemistry of biomimetic mineralization. It also shows that basic block copolymers are useful complementary systems to the much more commonly studied acidic block copolymer templates. PMID- 20718055 TI - Semiconductor gas sensors: dry synthesis and application. AB - Since the development of the first chemoresistive metal oxide based gas sensors, transducers with innovative properties have been prepared by a variety of wet- and dry-deposition methods. Among these, direct assembly of nanostructured films from the gas phase promises simple fabrication and control and with the appropriate synthesis and deposition methods nm to MUm thick films, can be prepared. Dense structures are achieved by tuning chemical or vapor deposition methods whereas particulate films are obtained by deposition of airborne, mono- or polydisperse, aggregated or agglomerated nanoparticles. Innovative materials in non-equilibrium or sub-stoichiometric states are captured by rapid cooling during their synthesis. This Review presents some of the most common chemical and vapor-deposition methods for the synthesis of semiconductor metal oxide based detectors for chemical gas sensors. In addition, the synthesis of highly porous films by novel aerosol methods is discussed. A direct comparison of structural and chemical properties with sensing performance is given. PMID- 20718054 TI - Combined technologies for microfabricating elastomeric cardiac tissue engineering scaffolds. AB - Polymer scaffolds that direct elongation and orientation of cultured cells can enable tissue engineered muscle to act as a mechanically functional unit. We combined micromolding and microablation technologies to create muscle tissue engineering scaffolds from the biodegradable elastomer poly(glycerol sebacate). These scaffolds exhibited well defined surface patterns and pores and robust elastomeric tensile mechanical properties. Cultured C2C12 muscle cells penetrated the pores to form spatially controlled engineered tissues. Scanning electron and confocal microscopy revealed muscle cell orientation in a preferential direction, parallel to micromolded gratings and long axes of microablated anisotropic pores, with significant individual and interactive effects of gratings and pore design. PMID- 20718056 TI - The beginnings of N-heterocyclic carbenes. PMID- 20718057 TI - Monooxygenase-like reactivity of an unprecedented heterobimetallic {FeO2Ni} moiety. PMID- 20718058 TI - Complete regio- and stereoselective construction of highly substituted silyl enol ethers by three-component coupling. PMID- 20718059 TI - Morphosynthesis of nanostructured gold crystals by utilizing interstices in periodically arranged silica nanoparticles as a flexible reaction field. PMID- 20718060 TI - Efficient silver-catalyzed regio- and stereospecific aziridination of dienes. PMID- 20718061 TI - Elementary steps in gold catalysis: the significance of gem-diauration. PMID- 20718062 TI - Enantiodifferentiating endo-selective oxylactonization of ortho-alk-1 enylbenzoate with a lactate-derived aryl-lambda3-iodane. PMID- 20718063 TI - A polymer-supported chiral dirhodium(II) complex: highly durable and recyclable catalyst for asymmetric intramolecular C-H insertion reactions. PMID- 20718064 TI - The electrode/ionic liquid interface: electric double layer and metal electrodeposition. AB - The last decade has witnessed remarkable advances in interfacial electrochemistry in room-temperature ionic liquids. Although the wide electrochemical window of ionic liquids is of primary concern in this new type of solvent for electrochemistry, the unusual bulk and interfacial properties brought about by the intrinsic strong interactions in the ionic liquid system also substantially influence the structure and processes at electrode/ionic liquid interfaces. Theoretical modeling and experimental characterizations have been indispensable in reaching a microscopic understanding of electrode/ionic liquid interfaces and in elucidating the physics behind new phenomena in ionic liquids. This Minireview describes the status of some aspects of interfacial electrochemistry in ionic liquids. Emphasis is placed on high-resolution and molecular-level characterization by scanning tunneling microscopy and vibrational spectroscopies of interfacial structures, and the initial stage of metal electrodeposition with application in surface nanostructuring. PMID- 20718065 TI - Segregation into layers: a general problem for structural instability under pressure, exemplified by SnH4. AB - When a molecular compound is thermodynamically unstable (but kinetically persistent) with respect to the elements, structures that contain segregated layers of the elements may be favored at moderate pressures, as a compromise between the potential stability of novel electronic configurations and decomposition into the elements (or other stable compounds). We use stannane, SnH(4), to approach this quite general problem theoretically, since the heat of formation of SnH(4) is so positive. Our ground-state DFT searches for optimal structures begin with slabs formed from 1-4 layers of tin atoms in the beta-Sn and bcc configurations, and also slabs of molecular hydrogen or hydrogen atoms, preserving the overall SnH(4) stoichiometry. As argued, segregated layers are an important structural feature in the lower- and moderate-pressure regime (0 and 50 GPa). By 140 GPa (V/V(0)=0.21) the coordination of tin and hydrogen increases and the slabs disappear, as judged from the optimized structures. PMID- 20718066 TI - Synthesis of 5-substituted 1H-tetrazoles from nitriles and hydrazoic acid by using a safe and scalable high-temperature microreactor approach. PMID- 20718067 TI - Rate coefficients for reactions of OH and Cl with esters. AB - Rate coefficients for the gas-phase reactions of OH radicals with n-propyl butyrate (k(1)), n-butyl propionate (k(2)) and n-butyl butyrate (k(3)) are measured by both absolute and relative methods. The kinetics data obtained over the temperature range 273-372 K are used to derive the Arrhenius expressions (in units of cm(3) molecule(-1) s(-1)): k(1)=(1.92+/-0.50)*10(-12) exp[(400+/-80)/T], k(2)=(2.98+/-1.32)*10(-12) exp[(209+/-139)/T] and k(3)=(5.35+/-3.34)*10(-12) exp[(180+/-194)/T]. In addition, the rate coefficients for reactions of the three esters with Cl atoms are determined by the relative-rate method at room temperature and atmospheric pressure. The rate coefficients measured are (in units of 10(-10) cm(3) molecule(-1) s(-1)) as follows: n-propyl butyrate (1.4+/ 0.1), n-butyl propionate (1.6+/-0.1), and n-butyl butyrate (1.7+/-0.1). The values obtained are presented, compared with previous determinations and discussed. Reactivity trends and atmospheric implications resulting from this work are also presented. PMID- 20718068 TI - Fundamental aspects of electrodeposition for the realization of plasmonic nanostructures. AB - Electrodeposition is used for the preparation of nanoparticles and nanostructures that allow, in principle, surface plasmon excitation. The (photo)electrodeposition process of Rh and Au nanoparticles as well as of heterodimeric enzymes onto silicon surfaces is investigated and the resulting structures are discussed with regard to applications in photoelectroctalysis and biosensing. Electrodeposition of Rh onto H-terminated p-Si surfaces generates nanostructures of the metal nanoparticles with simultaneous oxidation of the substrate thus forming nano-dimensioned metal-oxide-semiconductor (MOS)-type contacts. The excess minority carrier harvesting in these nanoemitter structures, where semispherical space charge layers underneath the metal exist are discussed based on spectral sensitivity and capacitance measurements The deposition of Au nanoparticles by a combined chemical-electrochemical method on Si is presented as an example for sensing actuators where the resonance frequency is changed by adsorption. Similarly, site-selective deposition of the enzyme reverse transcriptase onto nanostructured (step-bunched) silicon serves as precursor experiment for biosensing in a Kretschmann-type ATR configuration. Future applications based on plasmonically active structures are outlined. PMID- 20718069 TI - External heavy-atom effect on the prompt and delayed fluorescence of [70]fullerenes. AB - The influence of the external heavy-atom effect (HAE) on the fluorescence properties of C(70) and a C(70) methano monoadduct is determined. For this purpose the photophysics of these [70]fullerenes is studied in polystyrene (PS) and in a related heavy-atom polymer, poly(4-bromostyrene) (PBS). In the absence of HAE (PS matrix) both fullerenes display a strong thermally activated delayed fluorescence (DF) that is more pronounced in the case of C(70). In the presence of HAE (PBS matrix) both prompt (PF) and DF intensities decrease significantly, the same happening to the delayed fluorescence lifetimes. The relative fluorescence intensities (DF intensity/PF intensity) for each fullerene are on the other hand surprisingly similar to the respective ones in PS for the full experimental temperature range. The HAE is responsible for a significant increase of the S(1)->T(1) and S(1)<-T(1) intersystem crossing (ISC) rates, and of the T(1)->S(0) radiative rate. In particular, the HAE on a S(1)<-T(1) ISC rate is reported here for the first time. The overall substantial insensitivity of relative fluorescence intensities to HAE is explained by a compensation effect: As the S(1)->T(1) and S(1)<-T(1) ISC rates on the one hand, and the T(1)->S(0) radiative rate on the other hand work in opposition with respect to DF, a near cancellation of effects occurs. PMID- 20718070 TI - Luminescence enhancement of organic nanoparticles induced by photocrosslinking. PMID- 20718071 TI - Symmetric stretching vibration of CH4 in clathrate hydrate structures. PMID- 20718072 TI - NOC chemistry for tuberculosis-further investigations on the structure-activity relationships of antitubercular isoxazole-3-carboxylic acid ester derivatives. PMID- 20718073 TI - Synthesis and antiplasmodial activity of highly active reverse analogues of the antimalarial drug candidate fosmidomycin. PMID- 20718074 TI - Synthesis of fatty acid amides of catechol metabolites that exhibit antiobesity properties. AB - A series of fatty acid amides of 3,4-methylenedioxymethamphetamine (MDMA) catechol metabolites were synthesized in order to evaluate their biological activities. Upon administration, all synthesized compounds resulted in negative modulation of food intake in rats. The most active compounds have affinity for the CB(1) receptor and/or PPAR-alpha; part of their biological activity may be caused by these double interactions. PMID- 20718075 TI - Surface structural transformation and the phase transition kinetics of brookite TiO2. PMID- 20718076 TI - Identifying HAM-A cutoffs for mild, moderate, and severe generalized anxiety disorder. AB - The aim of the current study was to identify and evaluate cutoffs for mild, moderate, and severe ranges of Hamilton Anxiety Rating Scale (HAM-A) scores. Data were from a four-week randomized trial of treatment for generalized anxiety disorder. Measures included the HAM-A, SF-36, Hospital Anxiety and Depression Scale (HADS), and Clinical Global Impressions of Severity (CGI-S) scale. HAM-A cutoffs were identified based on literature review, expert panel input, and MANOVA models. The optimal cutoff set was evaluated based on association with clinician CGI-S ratings. The sample included 144 patients (56.3% female; 73.6% white; mean age = 35.7 years; mean baseline HAM-A score = 23.7). The optimal HAM A score ranges were: mild anxiety = 8-14; moderate = 15-23; severe >= 24 (scores <= 7 were considered to represent no/minimal anxiety). Analysis of variance (ANOVA) models found statistically significant differences among these groups in the SF-36 and HADS. The HAM-A severity ranges closely corresponded to clinicians' CGI-S ratings. The study represents the first step towards developing severity ranges for the HAM-A. These cutoffs should be used with caution and validated in larger samples. If the proposed cutoffs are accepted for general use, they could make results more meaningful and interpretable for researchers, clinicians, and patients. PMID- 20718077 TI - The role of glucagon- and somatostatin-secreting cells in the regulation of insulin release and beta-cell function in heterotypic pseudoislets. AB - BACKGROUND: Pseudoislet studies have concentrated on single beta-cell lines or a combination of insulin and glucagon-secreting cells, overlooking the potential role of somatostatin in insulin release. This study sought to evaluate a heterotypic pseudoislet model containing insulin- (MIN6), glucagon- (alphaTC1.9) and somatostatin (TGP52)-secreting cells of mouse origin and to compare these pseudoislets with traditional monolayer preparations. METHODS: Cellular viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays), proliferation (5-bromo-2-deoxyuridine ELISA), hormone content and functional insulin release in response to a variety of stimuli were measured. Differential expression of E-cadherin, connexin 36 and connexin 43 was assessed by reverse transcriptase-polymerase chain reaction and Western blot to determine a possible role for adherens in insulin release from these pseudoislets. RESULTS: All pseudoislet cells displayed reduced proliferation coupled with an increase in cell death which may contribute to their static size in culture. While MIN6 and TGP52 cells expressed E-cadherin and showed sustained or improved hormone content when configured as pseudoislets, alphaTC1.9 lacked E cadherin and contained less glucagon following pseudoislet formation. MIN6 and alphaTC1.9 cells expressed connexin 36, but not connexin 43 and TGP52 cells expressed connexin 43 only. In the presence of Alanine, Arginine and glucagon like peptide-1, heterotypic pseudoislet cultures secreted levels of insulin that were comparable to that of MIN6 pseudoislets. In addition, pseudoislets comprising all three cell lines released more insulin into the surrounding culture medium than MIN6 pseudoislets when studied over a 1-week period. CONCLUSIONS: The current model may prove useful in studying the role of islet cell interactions in the release of insulin from pancreatic islets. PMID- 20718078 TI - Brucellosis as priority public health challenge in South Eastern European countries. PMID- 20718079 TI - Uniform ICMJE Conflict of Interest Declaration Form: Report of Test Use in Croatian Medical Journal in 2009-2010. PMID- 20718080 TI - Toward more uniform conflict disclosures: the Updated ICMJE conflict of interest reporting form. PMID- 20718081 TI - Brucellosis - regionally emerging zoonotic disease? AB - AIM: To gain deeper insight into the seroprevalence of brucellosis, which remains a zoonotic disease of worldwide public health concern, by reviewing studies from countries including North Africa, the Middle East, and India. METHODS: Studies on brucellosis performed in countries that are neighbors or important trading partners of the European Union and on trade animals and their products were analyzed. We reviewed 37 seroprevalence studies on brucellosis published from 1948 to 2009 retrieved from Pubmed, Google, and ScienceDirect. RESULTS: The set of studies was heterogeneous in the number of samples and laboratory tests used. We included studies from Algeria (n=1), Egypt (n=7), India (n=3), Iran (n=3), Iraq (n=1), Jordan (n=5), Libya (n=3), Saudi Arabia (n=3), Syria (n=1), Turkey (n=5), and Yemen (n=2). The total number of animals in these studies was 116317 (cattle 75375; buffalo 9644; sheep 10550; goats 14447; camels 6301). The prevalence of brucellosis in different animal species varied widely. Representative surveillance data have not recently been published in any of the countries. CONCLUSIONS: Wars in the Middle East, insufficient preventive measures, the lack of adequate control programs in some countries, as well as uncontrolled animal transportation through "open" borders increased the risk that brucellosis will spread in some regions. New seroprevalence data are needed urgently to evaluate the current situation and for continuous monitoring of necessary control programs. PMID- 20718082 TI - Diagnosis of brucellosis in livestock and wildlife. AB - AIM: To describe and discuss the merits of various direct and indirect methods applied in vitro (mainly on blood or milk) or in vivo (allergic test) for the diagnosis of brucellosis in animals. METHODS: The recent literature on brucellosis diagnostic tests was reviewed. These diagnostic tests are applied with different goals, such as national screening, confirmatory diagnosis, certification, and international trade. The validation of such diagnostic tests is still an issue, particularly in wildlife. The choice of the testing strategy depends on the prevailing brucellosis epidemiological situation and the goal of testing. RESULTS: Measuring the kinetics of antibody production after Brucella spp. infection is essential for analyzing serological results correctly and may help to predict abortion. Indirect ELISAs help to discriminate 1) between false positive serological reactions and true brucellosis and 2) between vaccination and infection. Biotyping of Brucella spp. provides valuable epidemiological information that allows tracing an infection back to the sources in instances where several biotypes of a given Brucella species are circulating. Polymerase chain reaction and new molecular methods are likely to be used as routine typing and fingerprinting methods in the coming years. CONCLUSION: The diagnosis of brucellosis in livestock and wildlife is complex and serological results need to be carefully analyzed. The B. abortus S19 and B. melitensis Rev. 1 vaccines are the cornerstones of control programs in cattle and small ruminants, respectively. There is no vaccine available for pigs or for wildlife. In the absence of a human brucellosis vaccine, prevention of human brucellosis depends on the control of the disease in animals. PMID- 20718083 TI - Review of detection of Brucella spp. by polymerase chain reaction. AB - Here we present a review of most of the currently used polymerase chain reaction (PCR)-based methods for identification of Brucella bacteria in biological samples. We focused in particular on methods using single-pair primers, multiplex primers, real-time PCRs, PCRs for marine Brucella, and PCRs for molecular biotyping. These methods are becoming very important tools for the identification of Brucella, at the species level and recently also at the biovar level. These techniques require minimum biological containment and can provide results in a very short time. In addition, genetic fingerprinting of isolates aid in epidemiological studies of the disease and its control. PCR-based methods are more useful and practical than conventional methods used to identify Brucella spp., and new methods for Brucella spp. identification and typing are still being developed. However, the sensitivity, specificity, and issues of quality control and quality assurance using these methods must be fully validated on clinical samples before PCR can be used in routine laboratory testing for brucellosis. PMID- 20718084 TI - Evaluation of competitive ELISA for detection of antibodies to Brucella infection in domestic animals. AB - AIM: To evaluate competitive enzyme-linked immunosorbent assay (cELISA) for its suitability as an additional serological test for the diagnosis of animal brucellosis. METHODS: cELISA, which was developed at the Veterinary Laboratories Agency, has been evaluated for its accuracy and suitability as an additional serological test for the diagnosis of animal brucellosis. Samples from naturally and experimentally infected animals and those from Brucella-free flocks and herds were tested. RESULTS: Data obtained since 1991 were analyzed from routine surveillance, animals experimentally infected with Brucella, and stored sera to validate cELISA for the detection of antibodies to Brucella in cows, small ruminants, and pigs. The sensitivity of the test ranged from 92.31% to 100%, in comparison with 77.14% to 100% for the complement fixation test (CFT). Specificities for cELISA, indirect enzyme-linked immunosorbent assay, and CFT were greater than 90%. CONCLUSION: cELISA can be used on a variety of animal species, and an added advantage is its suitability for use on poor-quality samples such as those affected by hemolysis. PMID- 20718085 TI - Serological, bacteriological, and molecular diagnosis of brucellosis in domestic animals in Croatia. AB - AIM: To present the surveillance data on Brucella melitensis, B. suis, and B. ovis infection in cattle, sheep, goats, and swine in Croatia obtained in 2008 by serological, bacteriological, and molecular methods for diagnostics of brucellosis in domestic animals. METHODS: We serologically tested 42,785 cattle serums, 22,686 sheep and goat serums, and 28520 swine serums using the Rose Bengal test, complement fixation test, and various immunosorbent assays. We also tested 10,173 ram blood samples for B. ovis infection using the complement fixation test. Bacteriological examination was conducted on 214 samples collected from 34 serologically positive animals. Different molecular methods were employed in the identification and typing of 20 isolates from the samples. RESULTS: B. melitensis biovar (bv.) 3 was confirmed with different identification methods in 2 flocks in 2 Croatian counties and B. suis bv. 2 in 3 flocks in 3 counties. B. melitensis in cows was confirmed for the first time in Croatia. Infection with B. ovis was serologically confirmed in 202 rams in 12 counties. CONCLUSIONS: In 2008, the size of the brucellosis-affected area in Croatia and the efficiency of detection and prevention of brucellosis in sheep, goats, and swine were satisfactory. Infection with B. melitensis in cattle was confirmed for the first time and possible links for infection in humans were detected. More efficient measures for suppression and control of ovine epididymitis are required and a new strategy may be necessary for complete eradication of this disease. PMID- 20718087 TI - Epidemiological characteristics of brucellosis in Serbia, 1980-2008. AB - AIM: To analyze the epidemiological characteristics of human brucellosis in Serbia from 1980 to 2008 and the most important factors affecting its emergence and spread. METHODS: Public sources of data on brucellosis were used, including official reports of infectious diseases and epidemics, as well as monthly and annual reports of the Serbia and Vojvodina Institutes of Public Health. RESULTS: From 1980 through 2008, there were 1521 human brucellosis cases in Serbia. The annual number ranged from 2 in 2000 to 324 in 1991. Infections occurred more often in men (67% of cases) than in women (odds ratio, 2.17; 95% confidence interval, 1.57-3.00; chi2=24.52, P<0.001). The largest number of patients over the entire study period (1184) was recorded in Kosovo and Metohija, which accounted for 78% of the total number of patients. The maximum incidence rate in Kosovo and Metohija was 12 per 100,000 in 1991. In Vojvodina, the first autochthonous human cases of brucellosis were recorded in 1999, and 101 affected persons were registered by the end of 2008. During the period 1994-2008, the largest number of patients in Serbia was recorded from June to September (310 of 623 cases, 50%). The disease was most prevalent among people aged 30-49 years, accounting for 81 of 177 (46%) of the cases in Serbia from 1999 to 2008. CONCLUSION: Brucellosis has been a significant public health concern in Serbia. This problem may be solved by joint efforts of all relevant factors, first of all human and veterinary medical services. PMID- 20718086 TI - Human brucellosis in Macedonia - 10 years of clinical experience in endemic region. AB - AIM: To present our 10-year clinical experience with brucellosis patients at the University Clinic for Infectious Diseases and Febrile Conditions in Skopje, Republic of Macedonia. METHODS: A total of 550 patients with brucellosis treated between 1998 and 2007 were retrospectively assessed for their demographic, epidemiological, and clinical characteristics and outcomes. RESULTS: Of the 550 patients, 395 (72%) were male. The median age was 34.5 years (range, 1-82). Direct contact with infected animals was recorded in 333 (61%) patients and positive family history in 310 (56%). The most frequently seen symptoms were arthralgia (438, 80%), fever (419, 76%), and sweating (394, 72%). The most common signs were fever and hepatomegaly, which were verified in 357 (65%) and 273 (50%) patients, respectively. Focal brucellosis was found in 362 patients (66%) and osteoarticular in 299 (54%). Therapeutic failures were registered in 37 (6.7%) patients. Of the 453 (82%) patients who completed a follow-up period of at least 6 months, relapses occurred in 60 (13%). CONCLUSION: Due to non-specific clinical manifestation and laboratory parameters, brucellosis should be considered one of the differential diagnoses of any patient suffering from obscure involvement of various organs in a brucellosis-endemic region. High percentage of relapses and therapeutic failures in spite of the use of currently recommended therapeutic regimens indicates the seriousness of this zoonosis and the need to control it. PMID- 20718088 TI - Epidemiological characteristics of brucellosis in Federation of Bosnia and Herzegovina. AB - AIM: To analyze the frequency and distribution of human brucellosis in the Federation of Bosnia and Herzegovina in the period 2001-2008, and measures and activities undertaken for prevention and control of the disease. METHOD: In this descriptive, retrospective study, we used official reports on infectious diseases from public health institutes at the federal and cantonal level, as well as epidemiological surveys. For comparison with animal brucellosis cases, we used the distribution data from veterinary surveillance. RESULTS: Since 2001, the number of infected people has rapidly increased and brucellosis has become a very important public health problem. In the period 2001-2008, there were 1639 human brucellosis cases and the number of cases increased every year. The morbidity rate over the study period ranged from 3.8 to 33.4 per 100,000 inhabitants. According to epidemiological surveys, in villages human brucellosis was transmitted mostly by contact with infected animals and their products, and in cities by consumption of dairy products made from contaminated, unpasteurized milk. When test-and-slaughter control approach was used, the prevalence of seropositive livestock was 4.6% and approximately 70,000 animals were slaughtered after testing between 2001 and 2008. From 1 June 2009, this approach was replaced with mass vaccination of sheep and goats. CONCLUSION: The large number of human brucellosis cases and seropositive livestock poses a very serious problem for Bosnia and Herzegovina. The solution may be the introduction of mass vaccination. PMID- 20718089 TI - Gaps in brucellosis eradication campaign in sheep and goats in Republic of Macedonia: lessons learned. AB - AIM: To identify why "test and slaughter policy" for eradication of brucellosis did not significantly reduce the prevalence in sheep and goats in Macedonia. METHOD: Coverage of sampled vs expected number of sheep and goats, absolute number of positive animals, prevalence, frequency distribution, and classes of disease prevalence were retrospectively analyzed at the village level for 2004 2006. A comparative analysis of the disease prevalence in the investigated villages was also performed. The percentage of slaughtered animals was analyzed for 2000-2006. RESULTS: We found differences between the expected and actual number of sampled animals, which were related to the type of livestock breeding. Traditionally maintained flocks and migratory flocks were considered to be responsible for the transmission of the disease. The absolute number of positive animals and the number of infected vs non-infected holdings did not decrease over the study period. Most of the villages had between 1 and 10 positive animals. Between 2000 and 2006, 55% of the positive animals were slaughtered, 41% in 2001 and up to 79% in 2002. Moreover, in 2005 and 2006, 34% and 53% of sheep and goats were found to be positive at the slaughter line, respectively, demonstrating that only 21%-23% of the infected animals were correctly removed from the herds. CONCLUSION: Based on the findings of this study, Macedonia changed its control strategy from "test and slaughter" to a vaccination policy for sheep and goats in 2008. PMID- 20718090 TI - Judge the article, not the author. PMID- 20718091 TI - Goodbye collaboration, welcome partnerships in international research? PMID- 20718092 TI - If the stars were mine... PMID- 20718093 TI - Vanishing act. PMID- 20718094 TI - Obesity--who is responsible? PMID- 20718095 TI - Commentary on "SILS and NOTES cholecystectomy: a tailored approach". PMID- 20718096 TI - 12th World Congress on Gastrointestinal Cancer. PMID- 20718098 TI - Proceedings and abstracts of the International Symposium on Declining Fertility in Dairy Cows in the World; Its Causes and Possible Solutions, January 30-31, 2010, Miyazaki, Japan. PMID- 20718097 TI - How accurate is online information? PMID- 20718099 TI - Australian Cough Guidelines summary statement. PMID- 20718100 TI - Pain: new familial pain syndrome caused by TRPA1 mutation. PMID- 20718101 TI - Alzheimer disease: fibrinogen links amyloid with vascular dysfunction. PMID- 20718102 TI - Neuro-oncology: a molecular staging system for ependymoma. PMID- 20718103 TI - Patient information page from the Hormone Foundation: Adrenal Insufficiency. PMID- 20718104 TI - Patient information page from the Hormone Foundation: insuficiencia suprarrenal. PMID- 20718105 TI - [No change in continuing education]. PMID- 20718106 TI - [Professional education based on competences]. PMID- 20718107 TI - [Professional education, from a disciplinary base to a competence base]. PMID- 20718108 TI - [Development of a staffing program for students, implications for the teams]. PMID- 20718109 TI - [Voluven--third generation plasma expander]. AB - Crystalloid solutions are considered a good choice for lower scale blood loss (up to 20%). The usage of colloids facilitates faster and more durable blood volume substitution. Besides, some colloids (HES 130/04) are considered to have a beneficial effect on microcirculation, capillary membrane integrity, inflammatory response and endothelium integrity. Colloid solutions characteristics as well as the possible side effects within their group vary. It is therefore important to know that HES 130/04, a new generation colloid solution, is linked to a lower frequency of side effects. Nonetheless, it seems that the individual approach and procedure-specific choices are more important than other factors. PMID- 20718110 TI - Residual neuromuscular block--twenty years on. PMID- 20718111 TI - An unholey nasogastric tube. PMID- 20718112 TI - Cerebrovascular disease: novel mechanism of cerebral microvascularrecanalization demonstrated in mice. PMID- 20718113 TI - Stroke: embolus detection could predict risk of stroke. PMID- 20718114 TI - Stroke: retinal abnormalities predict brain infarcts. PMID- 20718115 TI - Pain: do cytokines cause pain in small-fiber neuropathy? PMID- 20718116 TI - A Decade Later: assessing successes and challenges in Manitoba's Provincial Immigrant Nominee Program. AB - During the past decade, Manitoba's Provincial Nominee Program (MPNP) has increased immigration to the province and dispersed immigrants more widely within Manitoba. At the same time, the rapid growth of the program and the decentralized way in which it has been implemented have contributed to some challenges. This ten-year analysis of the MPNP finds that many places in Manitoba are experiencing settlement service gaps, and that immigrants and communities are taking on much of the burden for MPNP application and settlement. In addition, the analysis demonstrates that the fragmented way in which the MPNP has been marketed and implemented (i.e., by relying on particular employers, consultants, and ethnocultural organizations) has resulted in a sort of ethnocultural inequality where certain groups are ushered into the province-often to perform particular occupations-while others are bypassed. PMID- 20718118 TI - Child rearing in the "risk" society: on the discourse of rights and the "best interests of a child". AB - Due to a number of radical changes in society, the role of parents in the upbringing of their children has been redefined. In this essay, Paul Smeyers argues that "risk" thinking, and the technologization that goes with it in the context of child rearing, naturally leads to the rights discourse, but that thinking about the relation between parents and children in terms of rights confronts one with a number of insurmountable problems. The concept of the "best interests of a child" that is often invoked is, to say the least, not at all clear. Smeyers contends that while the discourse of rights is clearly important and relevant insofar as the relation between parents and the state are discussed, it impoverishes our understanding of relations of family members when used as an all-inclusive framework in that context. Therefore, he concludes that we must surpass the totalizing tendency of the transformation of the social realm into a system, of defining the relation between parents and children in technical terms, and of holding parents liable for their children's upbringing. PMID- 20718117 TI - The next pandemic. PMID- 20718119 TI - Space-time variations of human capital assets across U.S. metropolitan areas, 1980 to 2000. AB - This article examines the changing structure of human capital in U.S. metropolitan regions from 1980 to 2000. Data are drawn from the Dictionary of Occupational Titles and from the Integrated Public Use Microdata Series. Intensive empirical investigation leads to three main conclusions. First, forms of human capital in the United States are becoming more oriented to labor tasks that call for cognitive-cultural skills. Second, cognitive-cultural skills are accumulating most intensively in large metropolitan areas. Third, physical or practical forms of human capital are increasingly being relegated to smaller metropolitan areas. That said, important residues of human capital, focused on physical or practical tasks, remain a durable element of the economies of large metropolitan areas. I offer a brief theoretical explanation of these results. PMID- 20718120 TI - Graduate program in Collective Health in the context of developing science and technology in Brazil. PMID- 20718121 TI - [Tuberculosis epidemiology and failures of the antituberculosis campaign for children]. PMID- 20718122 TI - Dependence liability of "non-narcotic" drugs. PMID- 20718123 TI - Treponema pallidum. A bibliographical review of the morphology, culture and survival of T. pallidum and associated organisms. PMID- 20718124 TI - TRICARE: non-physician referrals for physical therapy, occupational therapy, and speech therapy. Final rule. AB - The Department of Defense is publishing this final rule to provide TRICARE approval for authorizing certified physician assistants and certified nurse practitioners (non-physicians) to engage in referrals of beneficiaries to the Military Health System for physical therapy, occupational therapy, and speech therapy. Upon implementation of this provision, certified physician assistants, or certified nurse practitioners will be allowed to issue referrals to patients for physical therapy, occupational therapy, and speech therapy without having the patient see a physician. This rule will align TRICARE with Medicare's allowance of "non-physician providers" to provide, certify, or supervise therapy services. PMID- 20718125 TI - TRICARE: Transitional Assistance Management Program (TAMP). Final rule. AB - The Department of Defense is publishing this final rule to implement section 4 of the Hubbard Actand section 734 of the Duncan Hunter National Defense Authorization Act for Fiscal Year 2009. These Acts provide two new categories of beneficiaries for the Transitional Assistance Management Program (TAMP). Specifically, a member who receives a sole survivorship discharge and a member who is separated from Active Duty who agrees to become a member of the Selected Reserve of the Ready Reserve of a reserve component are eligible for TAMP. PMID- 20718126 TI - TRICARE; TRICARE delivery of health care in Alaska. Final rule. AB - TRICARE has recognized the unique circumstances existing in Alaska which make the provision of medical care to TRICARE beneficiaries through the TRICARE program operated in the other 49 states unrealistic. Recognizing these unique conditions and circumstances, the Department of Defense has conducted a demonstration project in the state of Alaska since implementation of the TRICARE program under which certain exceptions have been made for administration of the program in Alaska. This rule incorporates the waiver of the requirement for financial underwriting by a TRICARE contractor as a permanent change to the administration of the TRICARE program in Alaska. This rule proposes no change to the TRICARE benefit or to those who are eligible for it. However, the rule does eliminate the financial underwriting of health care costs in the state of Alaska by a TRICARE contractor. PMID- 20718127 TI - Vector control. PMID- 20718128 TI - Major illness and financial disaster: how close is the connection? PMID- 20718129 TI - Foreword: this issue of the Seton Hall Law Review presents contributions to Preparing for Pharmaceutical Response to Pandemic Influenza, a two-day Symposium held at Seton hall University School of Law in the fall of 2008. PMID- 20718131 TI - Action on alcohol misuse. PMID- 20718130 TI - Allocating vaccines and antiviral medications during an influenza pandemic. PMID- 20718132 TI - Nil: the value of patents in a major crisis such as an influenza pandemic. PMID- 20718133 TI - Achieving clinical equality in an influenza pandemic: patent realities. AB - A twenty-first century novel influenza A (H1N1) pandemic is currently unfolding, and the eventual scope of this public health crisis is not clear. In addition, ongoing surveillance of the avian influenza A (H5N1) virus reveals outbreaks of human-to-human transmission of the virus, with significant mortality. Effective pandemic management depends on pharmaceutical intervention with two different clinical objectives: the generation of an immune response to specific viral strains (vaccination) and the reduction of viral replication in an infected individual (antiviral administration). The ability to offer pharmaceutical interventions for a public health crisis depends on three factors: development, capacity, and access. Pharmaceutical measures must be developed, capacity must be established, and access must be ensured. The article discusses the three nodes of patenting that influence the availability of pharmaceutical countermeasures in an influenza pandemic. Identification of the causative influenza virus is the first step in pandemic management and precedes vaccine design, and the virus and its RNA sequence are both knowledge assets and inputs for vaccine design. Vaccine development, therefore, will be influenced by any patents on the genetic sequences or proteins of the pandemic virus, as well as on novel methods for vaccine production, the actual vaccine or adjuvant technology, all of which are relevant to the assembly of a working vaccine on short notice. Pharmaceutical treatment of influenza infection during a pandemic could also rely on use of patented antiviral drugs, whose efficacy may be revealed as the pandemic unfolds. Unlike vaccines, these are not generally developed de novo for a pandemic, but their availability could be dependent on the exercise of patent rights by market incumbents. Patent rights could control capacity, which may determine access. Pandemic planning must consider how patenting can influence development, capacity and access to pharmaceutical interventions. The national and international public health authorities are slowly integrating intellectual property considerations into pandemic planning. Further integration will anticipate the emergence of patent claims, identify any relevant patents, encourage access norms, and consider the use of legal mechanisms that could alleviate patent-mediated obstacles to the availability of critical products and methods that may be patented. Pandemic management must also co-exist with existing efforts to control seasonal influenza outbreaks. The article analyzes the intersection of patent nodes relevant to vaccine development and to antiviral distribution during a global influenza pandemic, identifying where such patents may facilitate or inhibit the availability of pharmaceutical countermeasures, and offers preliminary observations on the emerging novel H1N1 pandemic. The goal of international clinical equality is essential for the eradication of an influenza pandemic, and strategies for its achievement can also be applied to other diseases. PMID- 20718134 TI - Clinical research in a public health crisis: the integrative approach to managing uncertainty and mitigating conflict. AB - In order to advance science while preserving social solidarity and institutional trust, clinical research must carefully manage ethical tensions created by the two overlapping dynamics of conflict and uncertainty. One of these dynamics is inherent in the research enterprise itself and the other arises in the particular context of a public health emergency. One test for both the moral soundness and practical utility of a framework for research ethics is its ability to help stakeholders understand and manage these ethical tensions as much as possible. After clarifying the dynamics that give rise to these tensions, this paper argues that two common approaches to evaluating clinical research have significant shortcomings in this regard. This paper then sketches and defends the integrative approach to managing these tensions. PMID- 20718136 TI - [Teaching human science in medical schools in the Czech Republic. 9th Symposium of medical schools in the Czech Republic, Prague, 18 February 2009]. PMID- 20718135 TI - Backdoor eugenics: the troubling implications of certain damages awards in wrongful birth and wrongful life claims. PMID- 20718137 TI - [8th Congress of Pediatric Allergologists and Clinical Immunologists. Krahulci u Telce, 19-21 June 2009]. PMID- 20718138 TI - Acclimatization to heat. PMID- 20718139 TI - Sir Frederic Bartlett Lectureship. PMID- 20718140 TI - Hyperbaric oxygenation. PMID- 20718141 TI - Treatment of Cushing's syndrome and acromegaly. PMID- 20718142 TI - Amenorrhoea. PMID- 20718143 TI - Mycoplasmas and leukaemia. PMID- 20718144 TI - [Atherosclerosis 2009. Prague, 9-11 September 2009]. PMID- 20718145 TI - [5th International Conference on Analytical Cytometry. Olomouc, 5-8 September 2009]. PMID- 20718146 TI - [Surveillance and the future of epidemiology. Prague, 11 October 2009. 100th anniversary of the birth of Professor Karl Raska]. PMID- 20718148 TI - [Surgery of ruptured left ventricular free wall]. PMID- 20718147 TI - [George von Bekesy. (1899-1972)]. PMID- 20718149 TI - Kicking the (Medicare) can down the road. PMID- 20718150 TI - National health care reform--Canadian deja vu? PMID- 20718151 TI - Cell phones and driving ... like apples and oranges. PMID- 20718152 TI - Uncharted waters. PMID- 20718153 TI - National health care reform: look in rear-view mirror important as MAG, physician driven coalition grip wheel for future. PMID- 20718154 TI - Health care law will exacerbate physician shortage. PMID- 20718155 TI - Managing end-of-life care. PMID- 20718156 TI - Tort reform in the Georgia Supreme Court. PMID- 20718157 TI - Health care reform: what every physician should know. PMID- 20718158 TI - A Muslim woman and childbirth. PMID- 20718159 TI - Standard of care deviation results in patient's death. Copy & paste documentation not helpful to the defense. PMID- 20718160 TI - 'I covered my eyes and plugged it in'. PMID- 20718161 TI - A study of knowledge and attitude improvement on epilepsy among Thai physicians and nurses. AB - OBJECTIVE: To study improvement ofknowledge and attitudes on epilepsy care among two groups ofphysicians and nurses. MATERIAL AND METHOD: Knowledge and attitudes of 164 physicians and 403 nurses before and after attending educational courses on epilepsy care was assessed using questionnaires. RESULTS: After the courses, knowledge and attitudes of physicians and nurses was improved with statistical significance (pair-t-test: t (163) = 10.19, p < 0.001; t (402) = 18.41, p < 0.001). The most misunderstanding were incorrectfirst aid of seizure, misinterpretation of blood changes after antiepileptic drug therapy inadequate awareness of epilepsy surgery, and prohibition of swimming in people with epilepsy No differences between baseline and post training scores among physicians in neurology internal medicine, emergency medicine, and general practice were observed. CONCLUSION: The present study is the first to objectively measure improvement of knowledge and attitudes among Thai physicians and nurses after courses about epilepsy care, reflecting importance of additional epilepsy education. Items showing misapprehension can be used to provide the educational contents. PMID- 20718162 TI - Effect of high dose ergocalciferol in chronic kidney disease patients with 25 hydroxyvitamin D deficiency. AB - OBJECTIVE: To evaluate 25 hydroxyvitamin D (25-OH-D) deficiency in a cohort ofpredialysis CKD patients and the treatment effect and safety of high dose ergocalciferol supplement in predialysis CKD. MATERIAL AND METHOD: Fifty-six predialysis CKD patients who came for a regular visit at a single hospital with calculated glomerular filtration rate < or =60 mL/min/1.73 m2 were screened for 25-OH-D levels. Forty-four patients with 25-OH-D deficiency were recruited into this prospective observational study that examined the effect of high dose oral ergocalciferol supplementation. After eight weeks, 37 patients completed the follow-up and biochemical parameters were reevaluated and analyzed. RESULTS: The mean 25-OH-D level of 56 patients was 25.6 +/- 8 ng/mL. Forty-four (78.5%) patients had 25-OH-D levels less than 30 ng/mL and four (7.1%) had severe deficiency with the level less than 15 ng/mL. High dose ergocalciferol supplement successively increased 25-OH-D levels in 35 (95%) patients. 25-OH-D levels increased significantly from 22 +/- 4.8 to 34.5 +/- 10.8 ng/mL after eight weeks (p < 0.001). During the study period, there were no changes in serum calcium, phosphate, and PTH. There was no other side effect associated with the treatment. CONCLUSION: 25-OH-D deficiency were found in this cohort of predialysis CKD patients. Ergocalciferol was a safe and effective supplement for the 25-OH-D in predialysis CKD. PMID- 20718163 TI - The role of liquid simethicone in enhancing endoscopic visibility prior to esophagogastroduodenoscopy (EGD): A prospective, randomized, double-blinded, placebo-controlled trial. AB - BACKGROUND: Simethicone improves endoscopic visibility and diagnostic accuracy during colonoscopy and capsule endoscopy. Nevertheless, there have been limited data on its usefulness in esophagogastroduodenoscopy (EGD). OBJECTIVE: To evaluate the effectiveness of simethicone on enhancing endoscopic visibility in patients undergoing EGD. MATERIAL AND METHOD: 121 patients were randomized to take 2 ml ofeither liquid simethicone or placebo in 60 ml of water at 15-30 minutes before EGD. The severity scores of foam and bubbles at the esophagus, stomach and duodenum were compared. RESULTS: Simethicone improved endoscopic visibility by diminishing mean cumulative (6.83 +/- 2.4 vs. 11.05 +/- 2.6, p < 0.001) and local scores offoam and bubbles at all areas, and decreased the number and timing ofadjunctive simethicone washing (17.5% vs. 74.1%, p < 0.001 and 0 vs. 19 seconds, p < 0.001). Simethicone increased endoscopist and patient satisfaction significantly without having adverse effects. CONCLUSION: Using simethicone before EGD enhances endoscopic visibility, reduces adjunctive simethicone washing and increases endoscopist and patient satisfaction. PMID- 20718164 TI - Balloon pulmonary valvuloplasty in tetralogy of Fallot: effects on growth of pulmonary annulus and transannular patch. AB - BACKGROUND: Balloon pulmonary valvuloplasty and its benefit on the growth of pulmonary annulus and pulmonary artery in tetralogy of Fallot (TOF) patients remains controversial. The purpose ofthe present study was to determine the growth of pulmonary valve annulus and pulmonary artery and to evaluate the need of transannular patch during total surgical correction in patients with tetralogy of Fallot (TOF) after balloon pulmonary valvuloplasty. MATERIAL AND METHOD: Fifty one severely hypoxic TOF patients, who underwent balloon dilatation ofpulmonary valve, were included in the present study. The clinical outcomes, oxygen saturation, and echocardiographic parameters before and after balloon dilatation were analyzed. RESULTS: There were 33 males and 18females. The mean age was 3 years 5 months old (range, I month-15 years 8 months old). The mean oxygen saturation increasedfrom 73.9 +/- 9.1 to 84.8 +/- 6.7% immediately after the procedure (p-value < 0.05). There was no serious procedural-related complication. At the mean follow-up period of 2 years and 4 months, the mean Z-score of pulmonary annulus size increased from -2.56 SD to -1.87 SD (p-value < 0.05) and the right pulmonary artery size from -0.29 SD to + 0.46 SD (p-value < 0.05). Thirty-seven patients (66.1%) underwent corrective surgery. Pulmonary transannular patch was performed in 11 of37 patients (29.7%). CONCLUSION: Pulmonary valve dilatation in patients with TOF is safe. It promotes the growth ofthe pulmonary valve annulus and pulmonary artery and may decrease the need of transannular patch at the time of surgical correction. PMID- 20718165 TI - Duration of symptoms in brain tumors: influencing factors and its value in predicting malignant tumors. AB - BACKGROUND: Although brain tumor is a common neurosurgical condition, diagnosis is generally made after long duration of symptoms. This may have negative impact on treatment outcome. OBJECTIVE: Study the duration of symptoms of brain tumor, how it is influenced by various factors, and find their value in predicting malignant tumors. MATERIAL AND METHOD: The authors retrospectively reviewed 185 patients with pathologically proven brain tumors. Pertinent data including age, types of tumors, locations of tumors, symptoms, and duration of symptoms were analyzed by univariate and multivariate analysis. RESULTS: There were 70 males and 115 females. The mean age at diagnosis was 47.3 years. The average duration of symptoms was 471 days with median of 120 days. On univariate analysis, hormone symptoms (p = 0.001), age more than 45 years old (p = 0.005), malignant tumor (p < 0.001), auditory symptoms (p = 0.004), and motor symptoms (p < 0.001) had significant influence on duration of symptom. In multivariate analyses, malignant types of tumor, age, and hormonal symptoms were significant. In addition, there was higher risk of malignant brain tumor in patients with duration of symptoms 1 month or less (p < 0.001). CONCLUSION: Certain factors were associated with longer duration of symptoms in brain tumors. This information may lead to early diagnosis of brain tumors. Furthermore, duration ofsymptoms of 1 month or less was suggestive of malignant brain tumors. PMID- 20718166 TI - Internal sphincter myectomy for adult Hirschsprung's disease: a single institute experience. AB - OBJECTIVE: Adult Hirschsprungs disease is a rare disease and frequently misdiagnosed as the long-standing refractory constipation. Almost all cases have short or ultra-short aganglionic segment of distal rectum. The clinical features are different from those in childhood when the diseased segment is long. Amongst the few successful operations that have been used to treat this condition, internal sphincter myectomy has been proposed as a simple and low morbidity procedure, but only a few literatures reported the results. The present study aimed to evaluate the outcomes of anorectal myectomy in adult Hirschsprung's disease. MATERIAL AND METHOD: All medical records of adult Hirschsprung's disease between January 1, 1997 and April 30, 2008 were retrospectively reviewed The histological criteria for diagnosis were increase in the number of cholinergic nerve fibers in the lamina propria, muscularis mucosae, and submucosa, and the absence of ganglia in the submucosa. All cases underwent internal sphincter myectomy as the first operation. Post-operative complications, number of defecation per week, and the need for a second operation were studied. RESULTS: Seven patients met the criteria. All patients had the long history of constipation. Anorectal myectomy was performed as the first operation in all cases. Four patients (57%) had good results, without complication and no further operation was needed up to the last follow-up (26-86 months). Two cases underwent subtotal and total colectomy after myectomy to achieve good results eventually. Only one patient had a poor result after Left colectomy and Total proctocolectomy with ileal pouch anal anastomosis. CONCLUSION: Internal sphincter myectomy, the simple and complication-free procedure, provides the satisfactory outcomes for adult Hirschsprung's disease. This technique should be the first operation for this condition. PMID- 20718167 TI - Tuberculosis of the urinary tract in southern Thailand. AB - BACKGROUND: The urinary system is one of the common sites of involvement of extrapulmonary tuberculosis (TB). The accurate diagnosis and treatment of extrapulmonary TB is complex and difficult. OBJECTIVE: To address the epidemiology and drug susceptibility of urinary tract TB in southern Thailand. MATERIAL AND METHOD: A retrospective analysis of data collected at the time of diagnosis of urinary tract TB cases, during a 10-year period from 1998 to 2007. Data collection included demography, presenting symptoms, laboratory investigations, and imaging studies of the urinary system. RESULTS: During a 10 year period of the present study, 35 new cases of urinary tract TB were diagnosed, with a male/female ratio of 1.3:1 and a common age group of 31-40 years. 34.3% of the patients were farmers. The most presenting symptoms were polyuria, dysuria and acidic urinary pH with pyuria. 80% ofthe patients had abnormal imaging studies ofthe urinary system, with hydronephrosis being the most frequently found condition. Fifty seven point one percent had positive urine cultures for Mycobacterium and 0.05% of them had streptomycin resistance, while none ofthem had an HIV coinfection. CONCLUSION: The urinary tract TB was more common in male with a common age group of 31-40 years. The common presenting symptoms were long-standing urinary symptoms as frequency in urination, dysuria, hematuria and acidic urinary pH associated with pyuria. In the present study, there was only 0.05% of streptomycin resistance, however, no patients with HIV infection. PMID- 20718168 TI - Correction with instrumented fusion versus non-corrective surgery for degenerative lumbar scoliosis: a systematic review. AB - OBJECTIVE: To evaluate the effect of surgical treatment between correction and non-correction surgery for degenerative lumbar scoliosis by systematic review method. MATERIAL AND METHOD: The database inclusions were PubMed (January 1, 1960 to March 31, 2009), EMBASE (January 1, 1985 to March 31, 2009), The Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and various articles. Grey literature was searched from Scirus. The quality of the studies was graded by MINORS. Studies that were classified level I to IV were included in analysis of surgical treatment outcome in degenerative lumbar scoliosis. Patient centered outcomes, surgical outcomes, and complication were collected. Two reviewers independently assessed trial quality and extracted data. RESULTS: Seventeen studies were included in analysis comprising 598 patients with degenerative lumbar scoliosis and treated by operative treatment. Overall, 451 patients received correction procedure. All trials were non-randomized and noncomparative studies. Almost all level evidence of the study was level III to IV Overall results were comparable between correction and non-corrective operation. CONCLUSION: There were insufficient good-quality comparative studies for surgical treatment outcome comparing between corrective deformity and non-corrective procedures. The correction of deformity in degenerative lumbar scoliosis was classified Level 2C (very weak recommendations). PMID- 20718169 TI - Protocol-directed vs. physician-directed weaning from ventilator in intra abdominal surgical patients. AB - BACKGROUND: Previous studies have demonstrated that protocol-directed weaning is better than physician-directed weaning in terms of shorter duration of mechanical ventilation in general critically ill patients. In this prospective, randomized controlled trial, the authors compared duration of mechanical ventilation between protocol based nurse-directed weaning and physician-directed weaning in patients following intra-abdominal surgery. MATERIAL AND METHOD: One hundred intra abdominal surgical patients requiring mechanical ventilation for more than 24 hours were randomly assigned to receive either protocol-directed (n=51) or physician-directed (n=49) weaning from mechanical ventilation. Patients assigned to the protocol-directed weaning group underwent daily screening and a spontaneous breathing trial by nursing staff OUTCOMES: The primary outcome was the duration of mechanical ventilation. RESULTS: The median duration of mechanical ventilation was 40 and 72 hrs in protocol-directed and physician directed groups, respectively (p < 0.001). Two patients in the protocol-directed group and three patients in the physician directed group were re-intubated within the first 72 hours after extubation (p = 0.61). CONCLUSION: Daily screening of respiratory function in intra-abdominal surgical patients followed by trials ofspontaneous breathing performed by nurses resulted in a shorter duration of mechanical ventilation when compared to traditional physician-directed weaning. PMID- 20718171 TI - Central corneal thickness in the central retinal vein occlusion fellow eyes. AB - OBJECTIVE: To investigate the central corneal thickness (CCT) in the central retinal vein occlusion fellow eye (CRVO-fellow eye) patients. MATERIAL AND METHOD: A cross-sectional study with 97 CRVO-fellow eye patients and 112 healthy subjects. Three measurements of CCT were obtained with ultrasonic pachymetry. RESULTS: Mean age of CRVO-fellow eye was higher than controls, 59.7 +/- 10.3 vs. 46.4 +/- 5.8 years, (p < 0.001). Males were more prevalent in CRVO-fellow eye than in the controls, 47.4% vs. 25%, (p = 0.001). In CRVO-fellow eye group, systemic diseases were more prevalent. Glaucoma and ocular hypertension were detected in 23 eyes (23.7%) of CRVO-fellow eye. Mean CCT of CRVO-fellow eye was thinner than controls, 529.2 +/- 30.3 vs. 543.3 +/- 31.8 on, (p = 0.001). Multiple linear regression models adjusted for age, sex, diabetes, hypertension, cup-to-disc ratio, IOP, and axial length revealed that mean CCT of CRVO-fellow eye was 16.9 microm thinner than controls. CONCLUSION: CRVO-fellow eye patients have thinner CCT than controls. The pathophysiology of this association is unclear It may be related to less lamina cribosa rigidity in the thin corneal eye. Lamina cribosa displacement may compress central retinal vein, leading to CR VO. PMID- 20718170 TI - The post-operative analgesic efficacy of celecoxib compared with placebo and parecoxib after total hip or knee arthroplasty. AB - BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) in combination with opioids is a model of multimodal analgesia. NSAIDs have the oral and parenteral forms. OBJECTIVE: The aim of the present study was to evaluate the efficacy of celecoxib compared with placebo and parecoxib after total hip or knee arthroplasty. MATERIAL AND METHOD: A total of 120, ASA 1-2, aged 18-75 years, patients were randomly assigned to receive one of the three groups: Group I (control) received placebo (n=40), group II received 400 mg celecoxib orally (n=40) and group III received 40 mg parecoxib intravenously (n=40). The present study medication was administered I hour before surgery. All patients had access to patient-controlled analgesia (PCA) with intravenous morphine. Patients were studied at 0, 1, 6, 12 and 24 hours postoperatively for verbal numerical rating scale (VNRS), morphine consumption, satisfaction score and side effects. RESULTS: The intraoperatively fentayl requirement were similar among the three groups (p < 0.00). Celecoxib and parecoxib significantly decreased the amount of morphine requirement after total hip or knee arthroplasty compared to placebo at 1, 6, 12 and 24 hours (p < 0.00). The celecoxib group required more morphine than the parecoxib group at 1, 6, 12 and 24 hours (p < 0.00). The VNRS score in parecoxib group was significantly lower than the celecoxib and control groups at 1, 6, 12 but not at 24 hours. The VNRS score was lower in the celecoxib group compared to the control group at I and 6 hours postoperatively (p = 0.01, p < 0. 01 respectively). The placebo group had a higher sedation score (p = 0.008) but not for nausea vomiting (p = 0.36) and pruritus (p = 0.12) compared to the treatment groups. CONCLUSION: Within 12 hours after total hip and knee arthroplasty, pre operative administration of parenteral parecoxib 40 mg was more effective than oral celecoxib 400 mg and placebo in terms of morphine consumption and VNRS score. PMID- 20718172 TI - Quality of life in patients with chronic rhinitis after radiofrequency inferior turbinate reduction. AB - OBJECTIVE: This prospective, before-and-after study was aimed to demonstrate the effectiveness of radiofrequency (RF) inferior turbinate reduction in patients with chronic rhinitis refractory to medication on quality of life. MATERIAL AND METHOD: From April 2007 to April 2008, there were 28 patients enrolled in the present study. The temperature-controlled radiofrequency (RF) was applied at inferior turbinate on both sides. To compare before and at the 8th weeks after RF treatment, the patients were given Rhinoconjuctivitis Quality of Life questionnaires (Rcq-36) and questionnaires using visual analog scales (0-10) to assess subjective symptoms such as the frequency and severity of nasal obstruction, nasal discharge, hyposmia, and sneezing. The acoustic rhinometry and active rhinomanometry were also done to evaluate objective outcomes. RESULTS: At the 8th week after RF treatment, the patients quality of life in every dimension of Rcq-36 and all symptoms revealed a significant improvement (p < 0.05). Particularly, the severity and frequency of nasal congestion were reduced from 6.8 +/- 2.5 and 6.3 +/- 2.5 to 2.6 +/- 2.2 and 2.5 +/- 2.1 respectively (p < 0.001). However, there was no statistically significant change in objective findings. All patients reported only minimal pain and no complication. CONCLUSION: This is the first study to show that radiofrequency inferior turbinate reduction can improve quality ofhlife ofthe patients with chronic rhinitis in all dimensions. It is a simple and minimal invasive procedure, and thus will be a good alternative treatment. PMID- 20718173 TI - Identification of the external laryngeal nerve: its anatomical relations to inferior constrictor muscle, superior thyroid artery, and superior pole of the thyroid gland in Thais. AB - BACKGROUND: The external laryngeal nerve (ELN) is not routinely identified during thyroid surgery despite clear benefits from doing so. One reason is its anatomical variations, which differ from papers to papers. There were also very few studies of ELN in Thais, especially its relation to inferior constrictor muscle and tip of superior pole of the thyroid gland, which serve as important landmarks when identifying the ELN intraoperatively. OBJECTIVE: To describe the course of ELN and its relations to the inferior constrictor muscle, superior thyroid artery (STA), and tip of superior pole of the thyroid gland in Thais in order to serve as a guide for identification and preservation of the nerve. MATERIAL AND METHOD: One hundred thirty four ELNs from 68 cadavers with normal sized thyroid glands and no signs of neck abnormality were studied Three areas were studied, (1) its relation to inferior constrictor muscle, (2) the nearest distance from the nerve to tip of the superior pole of the thyroid gland, and (3) the crossing point of the ELN and STA in relation to the tip of the superior pole of the thyroid gland. All distances were measured in mm using a vernier caliper. RESULTS: The three areas of the study were reported separately using established classifications and compared to the previous published papers. All ELNs run superficially, at the least on the upper portion of the inferior constrict muscle, rendering it more vulnerable to injury in Thais. CONCLUSION: The course of the ELN and its relations to nearby structures can vary considerably and are influenced by many factors. Nevertheless, these findings should encourage the surgeons to identify the ELN intraoperatively with meticulous dissection to minimize the risk of ELN injury. PMID- 20718174 TI - Comparative evaluation of two different dosage calculation protocols of iodine 131 in the treatment of hyperthyroidism. AB - OBJECTIVE: To compare the effectiveness of radioiodine therapy with estimated dose and calculated dose in hyperthyroid patients. MATERIAL AND METHOD: A prospective randomized study in 144 hyperthyroid patients referred for 131I treatment was performed between June and December 2007. The patients were divided into two groups according to the 131I dose administered, estimated group using dose based on gland size and calculated group using dose based on both gland size and 24-hour 131I uptake. Outcome assessment was done at 12 months post-treatment. RESULTS: Eleven of 144 patients were excluded due to loss to follow-up and five became euthyroid before 131I treatment. Fifty-six of 128 patients (45.3%) experienced persistent/recurrent hyperthyroidism, 26 (20.3%) developed hypothyroidism, and 44 (34.4%) were euthyroid. Outcome was unrelated to the methods of I-131 dosing. Only gender and goiter size were found to be correlated with the clinical outcomes. CONCLUSION: An estimated I-131 dosing method using gland size determined by palpation is as effective as calculated method using 131I uptake. This method is more cost effective and brings greater patient convenience. PMID- 20718175 TI - Sebaceous neoplasms in Siriraj Hospital, Mahidol University: a 9-year retrospective study. AB - BACKGROUND: Sebaceous neoplasms are adnexal neoplasms that contain a varying number ofsebocytes, i.e. large cells with lipid-laden vacuolated cytoplasm, soap bubble in appearance, and crenate nuclei. They are uncommon compared to other adnexal neoplasms. Various sebaceous neoplasms with complex histopathologic features and varying degree ofsebaceous cells differentiation have been described in the literature. OBJECTIVES: To study the prevalence of sebaceous neoplasms, i.e., nevus sebaceus, sebaceous hyperplasia, sebaceous adenoma, sebaceoma, sebaceous epithelioma, superficial epithelioma with sebaceous differentiation, and sebaceous carcinoma diagnosed in the Department of Pathology, Siriraj Hospital, Mahidol University during the 9-year-period between 1997 and 2005. To study the prevalence of tumor transformation that occurs in nevus sebaceus. MATERIAL AND METHOD: A retrospective study of all sebaceous neoplasms including Nevus sebaceous, sebaceous hyperplasia, sebaceous adenoma, sebaceoma, sebaceous epithelioma, superficial epithelioma with sebaceous differentiation, sebaceous carcinoma, and all neoplasms containing the term "sebaceous" was performed. All slides were re-analyzed and re-diagnosed, without knowledge of the previous diagnosis or any clinical data, according to the criteria described in the standard textbooks of dermatopathology by Elder, McKee. Comparison between the previous diagnoses and the reviewed diagnoses was performed to assess the initial accuracy of all sebaceous neoplasms diagnosed. Small-sized biopsies or biopsies that possess incomplete sebaceous differentiation, in which the sebocytes were few and subtle, sometimes are difFicult to diagnose. In these instances, the clinical correlation was needed for positive diagnosis. Afterwards, these reviewed diagnoses were recorded and classified according to the patient's age, gender, and localization. RESULTS: Two hundred seven sebaceous neoplasms (2.34%) from the 8819 skin biopsies that were taken in the Department of Pathology, Siriraj Hospital during the 9-year-period, were included After exclusion of some authentically non-sebaceous neoplasms, 182 sebaceous neoplasms were found Nevus sebaceus (n=85, 46.7%) and sebaceous hyperplasia (n=64, 35.1%) were the two most common benign lesions. The others were sebaceoma (n=3, 1.6%), sebaceous adenoma (n=2, 1.1%), sebaceous epithelioma (n=1, 0.5%), sebaceous carcinoma (n=26, 14.3%), and one unclassified sebaceous lesion that could not be considered a neoplasm. Tumor degeneration was found in 14 nevus sebaceus in which 21 neoplasms existed, namely, trichilemmoma (wart)-like lesion (n=4), primitive follicular induction (n=7), syringocystadenoma papilliferum (n=3), trichoblastoma (n=3), and one of each of trichoepithelioma, sebaceous adenoma, tumor of follicular infundiculum, and mucoepidermoid carcinoma. CONCLUSION: Twenty-six sebaceous carcinomas out of 182 sebaceous neoplasms, occurring mostly on the patients'eyelids, were found The most common sebaceous neoplasm was nevus sebaceus (n=85); the prophylactic excision of this lesion was recommended as tumor degeneration was frequent (14 out of 85 cases). Epithelial membrane antigen (EMA) usually decorated both normal and abnormal sebocytes. It was very helpful in the detection of sebocytes in basaloid cells in sebaceous neoplasms and among lymphoid cells within metastasized lymph nodes and a discriminant between sebaceous and nonsebaceous neoplasms. PMID- 20718176 TI - Effect of "tailored goal oriented community brief intervention model" on AUDIT reduction in Thai communities. AB - OBJECTIVE: The present study aimed to test the result of Tailored Goal oriented Community Brief Intervention Model (TGCBI) the change of Alcohol Use Disorder Identification Test (AUDIT) scores. MATERIAL AND METHOD: A quasi-experimental research comparing between two high drinking prevalence communities in Lop Buri Province, Thailand, an intervention group with TGCBI Model, and a control group without TGCBI. The TGCBI is a treatment that lies on three components. Firstly the TGCBI based on FRAMES consisting of Feedback, Responsibility, Advice, Menu of Option, Empathy, and Self-Efficacy Secondly, drinkers must voluntarily set-up their goal and drinking reduction design suitable for them and their community. Lastly, key informants such as monks, health personnel, family, and friends can be a source to complete the FRAMES. MEASUREMENT: Measurements are done using AUDIT scores. RESULTS: Fifty subjects in control and forty-seven in intervention drinkers completing 1, 3, and 6 monthly intervals were followed-up. The follow-up of the change of AUDIT score after 1, 3, and 6 months of TGCBI in the two communities showed that intervention community, with TGCBI had a decrease in AUDIT score when compared within its community and with a controlled community. CONCLUSION: The results proved TGCBI model is effective in AUDIT reduction. PMID- 20718177 TI - Left sided inferior vena cava: a case report. AB - OBJECTIVE: To report a case of left sided inferior vena cava (IVC). MATERIAL AND METHOD: The authors carried out the standard dissection survey of939 embalmed cadavers between 1974 and 2008. RESULTS: The authors encountered a case of left sided IVC in a male donated cadaver aged 65 years at decease. The IVC formed behind the left common iliac artery at the L5 vertebra and coursed proximally on the left of the aorta until it reached the left renal vein and then crossed anterior to the abdominal aorta to assume the normal right side. At the point of crossing, it received the left renal vein. The right renal vein emptied into the IVC on the right side. CONCLUSION: In the era of laparoscopic urological surgery, preoperative diagnosis of this uncommon but important entity is essential to prevent unwarranted surgical mishaps. PMID- 20718178 TI - Extranodal NK/T cell lymphoma, nasal type, presenting with primary cutaneous lesion mimicking granulomatous panniculitis: a case report and review of literature. AB - BACKGROUND: Cutaneous extranodal NK/T-cell lymphoma, nasal type (NK/T) is relatively rare, associated with aggressive behavior and poor prognosis. Histopathological findings, immunohistochemical study and EBV-encoded RNA (EBER) in situ hybridization are essential for the diagnosis. CASE REPORT: A 54-year-old Thai man with NK/T of the nasal cavity initially presented with cutaneous NK/T mimicking granulomatous panniculitis. The skin biopsies were performed twice due to the marked necrosis in the first one. The second biopsy revealed small, medium, and large atypical lymphoid cells infiltrating fat lobules with necrotic foci and granulomatous reaction. Within the granulomatous inflammation, the atypical lymphoid cells showing involvement of the blood vessel (angiocentricity) were noted. Immunostaining demonstrated that the atypical lymphoid cells marked with CD3, CD56, and TIA-1, but they did not mark with CD5, CD20, CD15, or CD30. EBER in situ hybridization was positive. CONCLUSION: Cutaneous NK/T can produce granulomatous panniculitis. The recognition of atypical lymphoid cells showing angiocentricity together with immunohistochemistry and EBER in situ hybridization are crucial for the correct diagnosis. PMID- 20718179 TI - Ibuprofen and acute kidney injury in the newborn. AB - The pharmacological treatment of patent ductus arteriosus (PDA) in preterm infants remains a controversial issue, particularly with regard to the type of drug to be prescribed (ibuprofen or indomethacin) and the timing of the treatment, given their comparable effectiveness. For many years, indomethacin has been the drug of choice in the treatment of PDA. In April 2006, the United States Food and Drug Administration approved the use of ibuprofen lysine for closure of clinically significant PDA in premature infants < 32 weeks' gestation and weighing 500-1500 g. The available knowledge on the effects of ibuprofen on renal function in the neonate is discussed herein, since the good renal tolerability of this drug is a major argument in favor of its use in the routine treatment of PDA. PMID- 20718180 TI - The presentation of celiac disease in 220 Turkish children. AB - The aim of this study was to investigate the presentation pattern of newly diagnosed celiac disease (CD) in Turkish children in the last eight years. Two hundred twenty patients with newly diagnosed CD were included. The medical records of all the patients between January 2000 and October 2008 were reviewed. The clinical spectrum was divided into three categories according to the main symptoms that led to the diagnosis: gastrointestinal presentation, non gastrointestinal presentation, and silent cases. The mean age of the patients was 7.2 +/- 4.3 years at diagnosis. According to the presenting signs, the patients were defined as gastrointestinal presentation (129 patients, 58.6%), non gastrointestinal presentation (76 patients, 34.6%) and silent cases (15 patients, 6.8%). This study showed that the number/percentage of CD cases who presented with non-gastrointestinal symptoms/conditions, so-called "non-gastrointestinal presentation", have been increasing in the last eight years. PMID- 20718181 TI - Infectious mononucleosis in Turkish children. AB - The aim of this study was to analyze the demographic, clinical and laboratory characteristics and prognoses of children diagnosed with infectious mononucleosis (IM). The demographic features, referral complaints, clinical and laboratory findings, follow-up, and prognoses of 44 patients diagnosed with IM between January 2000 and June 2006 at the Infectious Diseases Department of Hacettepe University Ihsan Dogramaci Children's Hospital were analyzed retrospectively. The children suspected of IM based on clinical findings and whose diagnoses were proven by serological tests were enrolled in the study. In addition, the patients were divided into four groups -namely, age 0-4, age 5-8, age 9-12 and age 13-16, and the differences among groups were investigated in terms of their clinical and laboratory findings. The patients were aged between 3 months and 16 years. The median age was 4, and 56.8% of patients were below age 5. The male/female ratio was 1.6. No statistically significant variation was observed in the seasonal distribution of patients (p = 0.131). The most common referral complaints were swollen cervical lymph nodes or swollen neck (68.1%), followed by fever (43.1%) and sore throat (25%). Lymphadenopathy (79.5%), tonsillopharyngitis (72.7%), splenomegaly (34%), and hepatomegaly (25%) were the most common physical examination findings. Leukocyte count was normal in 68.3% of the cases. Leukocytosis was detected in 29.5% of the patients, and leukopenia in 2.2%. Lymphocytosis was detected in 44.7% of patients. Downey cell was detected in the peripheral blood smear of 23.6% of patients, and thrombocytopenia in 11.3%. Elevated alanine aminotransferase and aspartate aminotransferase levels were detected in 61.9% and 90.4% of patients who were investigated for these parameters, respectively. The clinical, hematological and biochemical findings of patients did not vary significantly among age groups (p > 0.05). Only one complication (hemophagocytic syndrome) was observed in one patient. PMID- 20718183 TI - Effect of glutamine supplementation on lymphocyte subsets in children with acute diarrhea. AB - To study the effect of glutamine supplementation on lymphocyte subpopulation counts in children with acute diarrhea, children aged 6-24 months were enrolled in a double-blind randomized study. Cases had received either 0.3 g/kg/day of glutamine or placebo orally for seven days. The counts of blood leukocytes, lymphocytes and lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD16+CD56+) were determined both on admission and seven days later using a flow cytometry. When adjusting for sex, current breastfeeding status, dehydration, and nutritional status of children, lymphocyte subpopulations did not differ significantly between the glutamine- and placebo-supplemented groups on the 7th day of intervention. PMID- 20718182 TI - Clinical course of primary focal segmental glomerulosclerosis (FSGS) in Turkish children: a report from the Turkish Pediatric Nephrology FSGS Study Group. AB - The clinical course of focal segmental glomerulosclerosis (FSGS) is heterogeneous in children. To evaluate the clinical course and the predictors of outcome in Turkish children with primary FSGS, a retrospective study was conducted by the Turkish Pediatric Nephrology Study Group in 14 pediatric nephrology centers. Two hundred twenty-two patients (92 boys, 130 girls, aged 1-16 years) with biopsy proven primary FSGS were included. One hundred forty-eight patients were followed up for a median of 51 months (range: 0.26-270). The clinical course was characterized by complete remission in 50 (33.8%), persistent proteinuria in 50 (33.8%) and progression to renal failure in 48 (32.4%) patients. Progression to end-stage renal disease (ESRD) was significantly higher in patients who did not attain remission. Complete remission, partial remission and progress to renal failure were recorded in 37%, 32% and 28%, respectively, of the patients (n = 73) treated with prednisone combined cyclophosphamide/cyclosporine A. However, in patients (n = 33) treated with pulse methyl prednisolone plus oral prednisone (up to 20 months) combined with cyclophosphamide, complete remission in 51.5% and partial remission in 27.3% of the patients were noted. Progression to renal failure was observed in 9.1% of this group of patients. Multivariate analysis showed that only plasma creatinine at presentation was an independent predictive value for outcome. Patients with serum creatinine level higher than 1.5 mg/dl had 6.6 times increased rate of progression to renal failure. Failure to achieve remission is a predictor of renal failure in children with primary FSGS. The use of immunosuppressive treatment in conjunction with prolonged steroid seems beneficial in primary FSGS in children. PMID- 20718184 TI - Home mechanical ventilation: outcomes according to remoteness from health center and different family education levels. AB - Throughout the world, home mechanical ventilation (HMV) is being increasingly employed to treat patients suffering from chronic respiratory failure. This present study aimed to examine the characteristics and outcomes of 27 children seen in our department over a four-year period who were treated with HMV. The causes of chronic respiratory failure were as follows: 16 (59.3%) neuromuscular disease, 6 (22.2%) primary respiratory diseases, 3 (11.1%) congenital heart disease, and 2 (7.4%) storage disease. The mean age was 59.4 months (1 day-15 years); mean follow-up for invasive ventilation was 356 (0-1200) days and for non invasive HMV was 517 (30-1440) days. With respect to maternal educational level, 13 had graduated from elementary school and 14 from high school or university. Nine of our patients resided in Ankara, while 18 lived in rural areas of Turkey. Eleven of the 27 patients died during the HMV period (1-36 months) at home. Five patients were weaned from HMV between 1-19 months. Our experience showed that HMV can be applied successfully in chronic respiratory failure patients in Turkey. Length of the follow-up period and mortality rate were not affected by the patient's place of residence (city center or rural) or maternal level of education. PMID- 20718185 TI - Once-daily intrapleural urokinase treatment of complicated parapneumonic effusion in pediatric patients. AB - In this paper, we describe our experience in the treatment of childhood empyema using urokinase. Patients' ages ranged from 2 to 12 years. Urokinase (dosage: 3,100 IU/kg/day) was diluted in normal saline to produce 1000 IU/ml (maximum dosage 100,000 IU in 100 ml of normal saline). After 2 hours, the clamped catheters were released and connected to water-seal suction at a negative pressure of 10 cm H2O. Pleural irrigations were continued once a day until thoracostomy tube output decreased to less than 10 ml/day (urokinase treatment mean duration: 11.5 days). The complete resolution of the chest effusion was assessed on chest ultrasound scan and radiographs. None of the patients experienced any side effects due to urokinase. It would now seem reasonable to advocate small chest tube thoracostomy and intrapleural urokinase as first-line treatment of pleural empyema in children, with surgery indicated as a secondary intervention. PMID- 20718186 TI - The role of magnetic resonance imaging in early prediction of cerebral palsy. AB - This work was undertaken to assess the usefulness of magnetic resonance imaging (MRI) of the brain for early prognosis of cerebral palsy. The study group included 47 neonates (24 term and 23 preterm) with symptoms of perinatal asphyxia. MRI examinations in term neonates were performed during the first month of life but not before the second week of life, while in preterm neonates MRI data were acquired between 38 and 40 weeks from conception. MRI of the brain demonstrated hypoxic-ischemic findings in all neonates born with perinatal asphyxia who later progressed to cerebral palsy. These results support the hypothesis that MRI performed in the neonatal period plays an essential role in predicting cerebral palsy in both term and preterm neonates, regardless of their gestational age. PMID- 20718187 TI - A household survey: unintentional injury frequency and related factors among children under five years in Malatya. AB - Accidents constitute a major public health problem around the world. They are one of the leading causes of death among children under five, with residential accidents accounting for the majority. Since there is no recording system that provides routine and reliable data about accidents, the data about the frequency of accidents and related factors are available only through researches. The aim of this study was to determine the frequency of injury-producing accidents and related factors among children aged under five who live in Malatya city center. In this cross-sectional epidemiological study, we covered first each regional health center in Malatya city center, a total of 30 clusters out of the population using a proportional systematic sampling method, and in turn, a sample size of 704 children under five. The frequency of injury-producing accidents was determined as 12.6%. The majority of the accidents occurred in the house, and 65.3% of them were due to falls; in 65.1%, accidents occurred in the presence of the mother. The frequency of the accidents was highest for the 4-5 age group (14.1%) and lowest among those < or = 1 year. It was found that maternal age < or = 30 (odds ratio [OR] = 1.9) and patient age of 4-5 years (OR = 5.4) primarily affected the chances of having an accident. A drawing of a kitchen setting, representing a total of 13 accident-producing risks, was given to the mothers, who were able to define an average of only 5.1 +/- 0.2 risks. The average number of risks defined by the mothers was found to be associated with the age of the child, educational background of the mother, her occupation, type of family, and monthly family income. No relation was determined between the accident risk awareness and accident frequency. In conclusion, the injury-producing accident frequency among children aged under five in central Malatya was found to be high. Given the finding that children have accidents in the presence of their mothers, it seems reasonable to provide mothers with parenting applications and training programs to reduce the home-based risks. PMID- 20718188 TI - The urinary cotinine levels of infants and the determinants. AB - The aim of this study was to determine the effect of the route of tobacco smoke exposure on urinary cotinine levels of infants. A cross-sectional analysis was done on 254 six-month-old infants. The infants were grouped according to the route of tobacco smoke exposure. The urinary cotinine/creatinine ratios were determined. Forty-nine percent (124/254) of mothers were smokers. Urinary cotinine levels in infants of smoking mothers were statistically significantly higher than levels in infants of non-smoking mothers. The highest mean cotinine/creatinine level was found in the breast-milk-exposed group. Linear regression analysis showed that maternal smoking increased urinary cotinine level by 541 times and breastfeeding increased it by 171 times, whereas early start of formula feeding decreased it by 63 times. Tobacco exposure by breastfeeding may be more harmful than other routes of exposure. Mothers should be encouraged to stop smoking during the breastfeeding period even if they avoid exposing their infants to passive tobacco smoke. PMID- 20718189 TI - Convulsion following gastroenteritis in children without severe electrolyte imbalance. AB - Three to five million children from among one billion with gastroenteritis die annually worldwide. The etiologic agent in developed countries is viral in 15-60% of cases, while in developing countries, bacteria and parasites are frequently reported as the etiologic factors. Neurologic signs including convulsion are seen in some cases of diarrhea. This study aimed to investigate the etiology, risk factors and short-term prognosis of gastroenteritis with convulsion. During a case-control study, 100 patients with gastroenteritis were enrolled into the case and control groups on the basis of convulsion or no convulsion development, respectively. This study was conducted in Tabriz Children's Hospital from March 2004 to March 2007. The age of patients ranged from 2 months to 7 years, and the groups were age- and sex-matched. Body temperature (BT), severity and type of dehydration, stool exam and culture, past history of convulsion in the patient and first-degree relatives, electrolyte imbalance, and short-term prognosis were studied and compared. The mean weight of groups was not different, while the frequency of fever at the time of admission, past history of febrile convulsion in first-degree relatives and severity of dehydration were significantly higher in the case group (p < 0.001). The BT of the case group on admission was higher than in the control group (39.01+/- 0.80 vs. 37.52 +/- 0.67 degrees C; p < 0.001). Past history of febrile convulsion in the patient, shigellosis and antibiotic usage were also significantly higher in the case group (p = 0.025, p = 0.014 and p = 0.001). Convulsion mostly occurred in mild gastroenteritis accompanied with fever and positive history of febrile convulsion in first-degree relatives. History of febrile convulsion in the patient and shigellosis were associated with development of convulsion in patients with gastroenteritis. No significant electrolyte imbalance was observed in patients with gastroenteritis experiencing febrile convulsion. PMID- 20718190 TI - Mollaret meningitis: a case report. AB - Mollaret meningitis is characterized by three or more episodes of benign recurrent aseptic meningitis in which symptoms and signs resolve spontaneously within two to five days. Severe headache with an acute onset, fever and meningismus are the main clinical features. We report a case of Mollaret meningitis in a seven-year-old girl who presented with four aseptic meningitis episodes in one year. PMID- 20718191 TI - Tympanic membrane cholesteatoma: a rare finding. AB - We report a rare finding of tympanic membrane cholesteatoma in a two-year-old girl. Tympanic membrane cholesteatoma without trauma or surgery to the ear is a rare entity, with few cases documented in the literature. The exact etiology of this lesion is still unclear. The presentation, clinical course and management are discussed. A whitish spot on the tympanic membrane should raise suspicion for cholesteatoma. Early diagnosis and treatment are imperative to allow an easy removal and avoid middle ear involvement. PMID- 20718192 TI - Growth hormone deficiency due to traumatic brain injury in a patient with X linked congenital adrenal hypoplasia. AB - X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HH). The production of other pituitary hormones (adrenocorticotropic hormone [ACTH], growth hormone [GH], thyroid-stimulating hormone [TSH], and prolactin [PRL]) is usually normal. Mutations of the DAX-1 gene have been reported in patients with AHC and HH. We present a 13-year-old male patient with AHC caused by a nonsense mutation in the DAX-1 gene who developed GH deficiency following head trauma. He showed signs of adrenal insufficiency at the age of 23 months, and glucocorticoid and mineralocorticoid treatment was started. His parents reported head trauma due to a traffic accident at the age of 21 months. Adrenal computed tomography revealed hypoplasia of the left and agenesis of the right adrenal gland. Decreased growth rate was noted at the age of 12.5 years while receiving hydrocortisone 15 mg/m2/day. His height was 139.9 cm (-1.46 SD), body weight was 54.9 kg, pubic hair was Tanner stage 1, and testis size was 3 ml. His bone age was 7 years. His gonadotropin (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and testosterone levels were prepubertal. The evaluation of GH/insulin-like growth factor-1 (IGF-1) secretion at the age of 13 years revealed GH deficiency. Pituitary magnetic resonance imaging demonstrated a hypoplastic hypophysis (< 2.5 mm) and a normal infundibulum. GH treatment (0.73 IU/kg/week) was started. This paper reports a patient with genetically confirmed AHC demonstrating GH deficiency possibly due to a previous head trauma. Complete pituitary evaluation should be performed in any child who has survived severe traumatic brain injury. PMID- 20718193 TI - Anti-GQ1b-negative Miller Fisher syndrome presented with one-sided horizontal gaze palsy. AB - Miller Fisher syndrome classically presents with ophthalmoplegia, ataxia and areflexia. The syndrome may present rarely with atypical clinical features. Whether the central or peripheral nervous system is primarily involved remains controversial. Miller Fisher syndrome usually follows an infection, the most likely being Campylobacter jejuni. Mycoplasma pneumoniae has been reported rarely as the antecedent infectious agent in some patients. Herein, we report a 13-year old girl with positive mycoplasma immunoglobulin (Ig)M and IgG serology who presented with one-sided horizontal gaze palsy, ataxia, areflexia, and bulbar palsy. Her cranial magnetic resonance imaging was normal and blood serum was negative for anti-GQ1b IgG antibodies. PMID- 20718194 TI - A mother and son with Noonan syndrome resulting from a PTPN11 mutation: first report of molecularly proven cases from Turkey. AB - Noonan syndrome is an autosomal dominant disorder characterized by short stature, typical craniofacial features, and congenital heart defects. The underlying genetic defects were not clear until 2001. This report is the first to describe a molecular analysis and associated clinical features of a Turkish mother and son, who were clinically diagnosed as Noonan syndrome when the boy was referred to our department due to short stature. The analysis revealed an A --> G transition at position 923 in exon 8 of the PTPN11 gene, indicating an Asn308Ser substitution. PMID- 20718195 TI - Congenital pulmonary fibrosarcoma in a newborn with hypoglycemia and respiratory distress: case report. AB - Although primary bronchopulmonary fibrosarcoma is a rare tumor, it may be characterized by the symptoms of acute respiratory distress occurring during the first moments of life in a newborn. It is one of the leading congenital malignant neoplasms of the lung, but is considered a borderline tumor since its biological behavior is much more favorable than that of adult fibrosarcomas. In the absence of metastases, complete resection is curative. Histopathological diagnosis is not simple, as the microscopic characteristics may be confused with benign fibromatosis or malignant mesenchymal neoplasms. In this case report, we present a case of congenital pulmonary spindle cell tumor showing the features of fibrosarcoma, and we discuss the differential diagnosis of spindle cell lesions localized within the thorax. PMID- 20718196 TI - Cowden syndrome with bronchial asthma. AB - Cowden's syndrome (CS) is a rare autosomal dominant disorder characterized by multiple hamartomas and an increased risk of breast, thyroid and endometrial carcinomas. Mutations of tumor suppressor gene PTEN (phosphatase and tensin homolog) on chromosome 10p23.2, which encodes a lipid phosphatase mediating cell cycle arrest and apoptosis, were first described in CS. Some studies have also implicated PTEN in the pathogenesis of bronchial asthma. Herein, we describe a boy with CS referred to the pediatric allergy unit with bronchial asthma symptoms. This patient is one of the very few reported cases with CS with lung disease and possibly the first with bronchial asthma. PMID- 20718197 TI - Menkes disease with gastroesophageal reflux disease and successful surgical treatment: a case report and literature review. AB - The complication of Menkes disease (MD) and gastroesophageal reflux disease (GERD) is extremely rare. This report describes the very rare case of a one-year old boy with MD complicated with GERD, and the successful surgical treatment of GERD. We review the literature on this relationship between MD and GERD, and discuss the clinical features of this association. Furthermore, the possible cause of the onset of GERD complicated with MD is explored in this report. PMID- 20718198 TI - Double heterotopic pancreas and Meckel's diverticulum in a child: do they have a common origin? AB - Heterotopic pancreatic tissue consists of normally differentiated pancreatic tissue without a real anatomic and vascular connection to the pancreas, whereas Meckel's diverticulum is one of the most important cause of lower gastrointestinal bleeding in children. Although heterotopic pancreatic tissue is related to various gastrointestinal diseases/malformations in both humans and animals, it is rarely associated with Meckel's diverticulum. Herein, we report a five-year old boy who presented with melena and hematochezia, which were discovered to be the result of Meckel's diverticulum. He also had multiple heterotopic pancreatic tissues in various parts of the gastrointestinal tract. The reason for this association is not known, but might involve some abnormalities of signaling molecules expressed in the development of the gastrointestinal tract and associated organs. In clinical practice, it is important to remember that Meckel's diverticulum and heterotopic pancreatic tissue might occur together or accompany various other gastrointestinal anomalies. PMID- 20718199 TI - Quadricuspid aortic valve diagnosed by transthoracic echocardiography in childhood. AB - Quadricuspid aortic valve is a rare congenital malformation of the heart leading to significant aortic regurgitation or stenosis. Its diagnosis by transthoracic echocardiography is difficult. Most of the cases are diagnosed during surgery or autopsy. Associated abnormalities of the coronary arteries should also be searched, since surgical injury may have devastating results. We herein present an eight-year-old girl found to have a quadricuspid aortic valve during evaluation of chronic renal disease and systemic hypertension. PMID- 20718200 TI - [Educational effects of a single distribution of a leaflet on alcohol and pregnancy among female university students]. AB - OBJECTIVE: To evaluate the educational effects of a single leaflet distributed once without explanation of its content. METHODS: All the 58 seniors on a dietitian course and all the 81 students who took "health and nutrition" as their elective in a women's university in F Prefecture were recruited. They were assigned to intervention or control groups. Both groups were asked the following choice questions in a baseline survey: "What do you think about alcohol drinking during pregnancy?" "What do you suppose you yourself will do in the future?" and "Do you know about the fetal alcohol syndrome (FAS)?" One month later, a leaflet was distributed to the intervention group only. One week after the distribution, a second questionnaire was administered to both groups. The leaflet and the two questionnaires were distributed and collected during class with the help of teaching staff. The leaflet was made by a NPO and it recommended stopping drinking when planning to become pregnant. RESULTS: The participation rate was 83%. There were no significant associations between groups and grades, current drinking habit, and learning experience on this topic. Almost 80% of the intervention group read the leaflet. Change in their thinking about drinking during pregnancy before and after the intervention did not significantly differ between the two groups. Compared to 57 controls, 66 students who received the leaflet showed significant improved changes in their attitudes toward drinking during pregnancy and the knowledge about FAS. CONCLUSIONS: No significant change in their thinking about drinking during pregnancy could be due to the fact that, even before the intervention, nearly 80% of the students thought pregnant women must abstain from alcohol entirely. This might be related to the sample characteristics, since 75% of them were majoring in nutrition. The improvement in attitudes was considered to reflect the content of the leaflet. In the intervention group, the percentage of the students who chose the alternative of "I plan to stop drinking when I wish to get pregnant" increased as the leaflet recommended and more than half of them said they learned about FAS by this leaflet. To sum up, even a single distribution of a leaflet in a school setting had educational effects which improved attitude and knowledge. Since the current sample seemed to have particular knowledge and interest in health, it is now necessary to examine effects of the same approach in the general population. PMID- 20718201 TI - [Development of a self-efficacy scale for going out among community-dwelling elderly]. AB - OBJECTIVES: Prevention and support for Tojikomori has been a focus of recent regional preventive efforts in reducing the need for nursing care in the elderly, requiring indicators for evaluating effects including psychological influences on the elderly. Behavior change theory suggests potential benefits of self-efficacy in outing to reduce Tojikomori elderly. However, evaluation scales for such psychological effects have hitherto been lacking. The purpose of this study was to develop a self-efficacy scale regarding going out among community-dwelling elderly (hereinafter referred to as the SEGE) and to assess its reliability and validity. METHODS: We collected survey items from 18 community-dwelling older people in A Ward, Tokyo. Based on these items, we developed a 13-item prototype scale through a preliminary survey among 258 community-dwelling elderly in O City, located in Japan. The main survey was conducted through the mail by randomly selecting 8,000 community-dwelling elderly in A Ward. The survey included the prototype scale' items and basic attributes, such as age and gender, and items from evaluation scales to be used to examine the validity of the prototype scale. RESULTS: A total of 2,627 elderly people (1,145 men and 1,482 women, average age 73.8 +/- 6.6 years) were analyzed. Of these people, 86.1% left home at least once a week. Principal component analysis revealed that the prototype scale created through the preliminary survey had a one-factor structure. Through a stepwise variable selection procedure in exploratory factor analysis, a six-item scale was developed. The alpha coefficient of internal consistency was 0.96 for these six items, confirming high reliability. Lower outing frequencies tended to be associated with lower scores of the SEGE, which correlated significantly with self-efficacy of ADL, self-rated health, and health related quality of life (QOL), confirming criterion-related and construct validity. In addition, a confirmatory factor analysis showed that SEGE and self efficacy of ADL, although highly correlated with each other, measured different concepts. CONCLUSIONS: A six-item and one-factor SEGE was developed with high reliability and validity confirmed. With this new indicator, we can measure the psychological effects of prevention and support approaches for Tojikomori. This scale is now expected to widely used in Japan. PMID- 20718202 TI - [Modifications in health and welfare jobs transferred to thirty-five participating "core cities"]. AB - PURPOSE: The aim of this study was to determine modifications in health and welfare jobs transferred to thirty-five participating "core cities. METHODS: We focused on health and welfare jobs in the following sectors: (1) local welfare; (2) health care; (3) city planning; (4) environmental protection; (5) education; and (6) urban revitalization. We developed a self-report questionnaire regarding implementation of administrative jobs transferred from prefectures to the core cities with attention to affects of changes in the jobs on the city administrative efficiency and the health of both the citizens and the city officials. The questionnaire, consisting of 27 multiple-choice and 12 open-ended questions, was forwarded via e-mail to lead city officials of the thirty-five core cities in mid-February 2008. RESULTS: Twenty-seven cities responded to the questionnaire in mid-March 2008 (collection rate: 77%). The core cities incorporated almost all the jobs transferred from the prefectures, in spite of some limitations regarding time taken for delivering assistive equipment to disabled children, implementing wider administrative plans and establishing educational centers. Almost all core cities answered that they implemented their jobs independently, autonomously and systematically. Seventeen out of 27 core cities established new health care centers during the transition period and increased their number of staff. The majority of these 17 answered that establishment of organizations directly providing services to citizens contributed to improvement in the efficiency of the administrative jobs. CONCLUSIONS: The core cities incorporated almost all the jobs transferred from the prefectures in spite of some limitations. The core cities which established their new health care centers during this transition period increased their number of staff to address modifications to the work load. PMID- 20718203 TI - [Indirect effects of school volunteering by senior citizens on parents through the "REPRINTS" intergenerational health promotion program]. AB - BACKGROUND AND PURPOSE: We have launched a new intervention study, called "REPRINTS" (Research of productivity by intergenerational sympathy), in which senior volunteers aged 60 years and over are engaged in reading picture books to school children, regularly visiting public elementary schools since 2004. METHODS: So far, no repeated cross-sectional studies to demonstrate indirect effects on parents have been reported, although reciprocal effects on senior volunteers and children have been demonstrated. The purpose of this study was to examine the changes of evaluation of "REPRINTS" program by parents of school children during the 2 years. SUBJECTS & SETTING: Four to six volunteers as a group visited an elementary school in a suburb of Kawasaki city twice a week to read picture books. A baseline survey was conducted one month after launching the volunteer activity. First to fourth follow-up surveys were conducted every 6 months after baseline surver. Of 368 parents, 230 whose children were in 1st-4th grade were analyzed. MEASUREMENTS: School grade of children, gender, emotional image scale of older adults by the SD (Semantic Differential) method (13 items), parents' evaluation of activity of "REPRINTS" volunteers such as promotion of reading for children, or children's respect for older adults, appreciation, familiarity with older adults, indirect effects on promotion of safety in the community, and reducing parent's physical and psychological burdens of volunteer service for school. Repeated cross-sectional analyses by ANCOVA, adjusted for confounding factors, were conducted in order to compare changes in responses between parents of 1st-2nd grade children (lower-grade children) with those of 3rd-4th grade-children (middle-grade children). We examined experiences of being read with picture books, greeting and having conversations with volunteers among all of 330 students of 1st-4th grade. These three items were examined using Chi squared test to compare longitudinal change between parents of lower-grade and middle-grade children. RESULTS: Evaluation of children's familiarity with older adults significantly declined among parents of middle-grade children, but was maintained among those of lower-grade children during the 2 years. Physical burdens of volunteer service for school were lower among parents' of lower-grade children at baseline, and were significantly reduced among parents' of all grades. Promotion of reading for children, indirect effects on promotion of safety in the community, and frequency of hearing episodes of "REPRINTS" volunteers from children were higher among parents' of lower-grade children at baseline. Psychological burdens were reduced and level of knowledge of "REPRINTS" volunteers was increased among parents' of all grades. In terms of parents' emotional image scale of older adults in general, no significant difference was found among the grades of school children and number of surveys for all the subscales of 'socialization', 'activity', and 'cheerfulness'. CONCLUSION: The level of knowledge and a number of items of evaluation of "REPRINTS" volunteers were significantly increased among parents of both lower-grade and middle-grade children during the 2-year intervention. This study indicates that the "REPRINTS" program can contribute to establishing trust and reliance between generations of older adults and parents of school children with the children as mediators. PMID- 20718204 TI - [Content analysis of television commercials for snacks and of snack packaging targeted at children]. AB - OBJECTIVE: To describe the marketing of snacks and beverages to children in television (TV) commercials and on food packages. METHODS: Study 1: For 5 weeks from April 1 to May 7, 2007, TV commercials were recorded from one of five channels each week (Nihon, TBS, Fuji, Asahi, and Tokyo). Study 2: The energy values of the products advertised in the TV commercials analyzed in Study 1 were determined, along with whether marketing information (e.g., presents, campaigns, and URLs) was included on the packages. The data were shown in frequency tables, and a chi2 test was conducted to examine the relationship between the energy values of the products (under or over 200 kcal) and descriptions concerning consumption of the products presented in the TV commercials (none, eating alone and eating with others). RESULTS: Five hours and 18 minutes of food commercials and 2 hours and 57 minutes of snack commercials were obtained from the 105 hours of recordings. Of the food commercials, 55.7% were for snacks. Commercials that were repeated or that targeted adults were excluded, leaving 197 commercials for analysis. There were many beverage commercials, most often associating products with mood, such as having fun and good times. No relationship between the energy value of the products (under or over 200 kcal), and the description of consuming the product in the TV commercials (none, eating alone and eating with others) was found (chi2 (2) = 2.2, P = 0.33). A scene showing someone eating alone was the most common depiction for products with energy levels both under and over 200 kcal. The analysis of 164 snack packages showed that most gave URLs. DISCUSSION: Although the present study had several limitations, such as the relatively short research period, as the first to describe TV commercials for snacks and beverages in Japan it provides new insights. It is now necessary to understand the current state of commercials in other media, and to consider the content of nutrition education for the future, including media literacy education. PMID- 20718205 TI - [Validity and reproducibility of a food frequency questionnaire with 82-food items (FFQW82) for nutrition education]. AB - OBJECTIVE: To assess the validity and reproducibility of a food frequency questionnaire with 82-food items (FFQW82) for nutrition education to modify eating habits. METHODS: The validity of nutrient intake assessed by FFQW82 was evaluated with seven-day diet records (7d-DR) as the gold standard, with questionnaire being administered twice with a one month interval to assess reproducibility. Twenty nine men (ages 42-63) and sixty women (ages 35-53) completed both surveys. Daily consumption of energy for 12 food groups and 9 nutrients was calculated from the FFQW82 and the 7d-DR with respect to breakfast, lunch, dinner, and whole-day meals. A Pearson correlation coefficient was obtained for each using log-transformed data. RESULTS: The estimated energy intakes from FFQW82 were higher than those from 7d-DR for men and women (relative differences of the median were 7% and 15%, respectively). As for validity, Pearson correlation coefficients of total energy intakes were 0.61 for men and 0.47 for women. Those for breakfast and lunch ranged from 0.66 to 0.89, while those for dinner were 0.19 and 0.26 for men and women. The daily intakes of nine nutrients ranged from 0.28 (potassium) to 0.65 (carbohydrate) in men and from 0.39 (fat) to 0.59 (calcium) in women. Regarding reproducibility, Pearson correlation coefficients for whole-day total energy intake were 0.65 for men and 0.69 for women. Those for the other nutrients ranged from 0.46 (salt) to 0.70 (carbohydrate) in men and from 0.59 (fat) to 0.70 (salt) in women. CONCLUSION: The results suggest that FFQW82 could be used as a tool to obtain information concerning unbalance energy intake with reference to individual meals and to understand appropriate intake of the various food groups for nutrition education of middle-aged men and women. PMID- 20718206 TI - Accuracy of the Doppler-derived pressure gradient in pediatric patients with aortic valvular stenosis: is the correction for pressure recovery necessary? AB - The Doppler echocardiography derived peak instantaneous systolic pressure gradient (peak instantaneous Doppler PG), the mean PG (mean Doppler PG) and the aortic valvular area are the accepted standard for determining the prognosis and optimal timing of intervention because of good agreement between Doppler-derived and catheter-measured PGs in adult patients with aortic valvular stenosis. However, several investigators reported that pressure recovery can cause discrepancies between Doppler-derived and catheter-measured PGs, so that the correction for pressure recovery has been proposed. In pediatric patients with aortic valvular stenosis, the discrepancy between Doppler-derived and catheter measured PGs and the correction for pressure recovery have not been studied well. Therefore, the purpose of current study was to clarify the role of echocardiography for estimating the prognosis and optimal timing of intervention and to assess the influence of pressure recovery on the Doppler-derived PG in pediatric patients with aortic valvular stenosis. Thirteen pediatric patients with aortic valvular stenosis were studied with echocardiography and cardiac catheterization. PG determined by the catheterization was compared with PG determined by the echocardiography with linear regression and Bland and Altman analysis. As result, Doppler-derived PGs corrected for pressure recovery did not correlated well with catheter-measured PGs. By contrast, Doppler-derived PGs correlated well with catheter-measured PGs. In particular, the mean Doppler PG correlated excellently with the mean catheter PG. In conclusion, the mean Doppler PG demonstrated an excellent correlation with the mean catheter PG without the correction for pressure recovery. Thus, the mean Doppler PG is useful in order to determine the prognosis and optimal timing of intervention in pediatric patients with aortic valvular stenosis. PMID- 20718207 TI - Effect of chlorhexidine on bond strength of two-step etch-and-rinse adhesive systems to dentin of primary and permanent teeth. AB - PURPOSE: To evaluate the influence of chlorhexidine digluconate (CHX) application on the immediate microtensile bond strength (microTBS) of two-step etch-and-rinse adhesive systems to the dentin of primary and permanent teeth. METHODS: Noncarious human teeth (24 primary molars and 24 premolars) were used. The primary and permanent teeth were randomly assigned to three groups (n = 8) according to the adhesive system: Adper Single Bond, Prime & Bond NT and Excite DSC. Each group was further divided in two subgroups (n = 4) in which the phosphoric acid-etched dentin was treated with 20 microL of either 2% CHX or deionized water for 60 seconds prior to adhesive system application. The adhesive systems were applied according to the manufacturers' instructions and resin composite blocks were built up on the treated surfaces. The teeth were vertically sectioned perpendicular to adhesive interface and beam-shaped specimens with a 0.81 mm2 cross-sectional area were obtained and subjected to microTBS testing at a crosshead speed of 0.05 mm/minute. MicroTBS data were analyzed statistically by ANOVA and Tukey's test (alpha = 0.05). The failure modes were verified with a stereomicroscope. RESULTS: CHX application increased significantly (P < 0.05) the microTBS of Prime & Bond NT and Single Bond to the acid-etched primary and permanent dentin, while no positive or negative effect was observed for Excite DSC. There was a predominance of adhesive failures in all control and CHX-treated groups. No fracture distribution pattern was observed. PMID- 20718208 TI - Resin composite polyethylene fiber reinforcement: effect on fracture resistance of weakened marginal ridges. AB - PURPOSE: To investigate the in vitro effect of polyethylene woven fiber reinforcement of resin composite on the fracture resistance of weakened marginal ridges in molar teeth. METHODS: 50 sound extracted human mandibular molars were used. Specimens were divided into five groups (n = 10). Group 1: served as a control for comparison; Group 2: Class I cavity preparation with resin composite (Prodigy); Group 3: Class I cavity preparation with polyethylene ribbon fiber (Ribbond) and resin composite. Group 4: Class II cavity preparation with resin composite restoration; Group 5: Class II cavity preparation with polyethylene woven fiber and resin composite. Specimens were stored in 100% humidity at 37 degrees C for 7 days. Compressive loading of the teeth was performed with a universal testing machine at a cross-head speed of 0.5 mm/minute until failure. The data were analyzed with 1-way ANOVA followed by the Ryan-Einot-Gabriel-Welsch Multiple Range Test (alpha = 0.05). RESULTS: Reinforcement with polyethylene fiber resulted in significant differences for fracture resistance (P < 0.001). Mean fracture resistance (SD) was [1737.4 (84.8) N] for control group. Among the experimental groups, the highest mean fracture resistance (SD) [1543.8 (71.1) N] was associated with Class I cavity preparation with polyethylene fiber and resin composite. The lowest mean fracture resistance (SD) [869.2 (91.7) N] was recorded for Class II cavity preparation with conventional resin composite. PMID- 20718209 TI - Effect of oxalate desensitizers and dentin moisture during total-etch bonding. AB - PURPOSE: To evaluate the effect of oxalate during total-etch bonding, under different dentin moisture conditions, over time. The null hypothesis tested was that microtensile bond strength (microTBS) was not affected by oxalate treatment and dentin moisture during two evaluation periods. METHODS: Extracted human third molars had their mid-coronal dentin exposed flat and polished with 600-grit SiC paper. The surfaces were etched with 35% phosphoric acid for 15 seconds, washed and blot dried. After etching, a 3% potassium oxalate gel was applied for 120 seconds, except for the control group (no desensitizer). The surface was then washed and left moist (Wet bonding) or air-dried for 30 seconds (Dry bonding). The surfaces were bonded with: (1) two 2-step etch-and-rinse adhesives: Single Bond (SB); Prime & Bond NT (PBNT) and (2) one 3-step etch-and-rinse adhesive: Scotchbond Multi Purpose (SBMP). Composite buildups were constructed incrementally with Tetric Ceram resin composite. Each increment was cured for 40 seconds. After storage in water for 24 hours or 1 year at 37 degrees C, the specimens were prepared for microTBS testing with a cross-sectional area of approximately 1 mm2. They were then tested in tension in an Instron machine at 0.5 mm/minute. Data were analyzed by ANOVA and Student-Newman-Keuls at alpha = 0.05. RESULTS: Application of potassium oxalate had no significant effect on the bond strengths of SBMP and PBNT, regardless of the surface moisture condition (P > 0.05). Conversely, reduced bond strengths were observed after oxalate treatment for SB in both moisture conditions, that being significantly lower when using a dry-bonding procedure (P < 0.05). Lower bond strength was obtained for PBNT when a dry-bonding technique was used, regardless of the oxalate treatment (P < 0.05). After aging the specimens for 1 year, bond strengths decreased. Smaller reductions were observed for SBMP, regardless of moisture conditions. For the WB technique, smaller reductions after 1 year were observed without oxalate treatment for SB and after oxalate treatment for PBNT. PMID- 20718210 TI - The effect of aging on the fracture toughness of esthetic restorative materials. AB - PURPOSE: To compare the fracture toughness (KIc) of tooth-colored restorative materials based on a four-point bending; to assess the effect of distilled water and a resin surface sealant (G-Coat Plus) on the resistance of the materials to fracture. METHODS: Specimens were prepared from six materials: Quix Fil; Dyract (Dentsply), Freedom (SDI), Fuji VII (GC), Fuji IX (GC); Fuji II LC (GC). Fuji II LC and Fuji IX were tested both with and without applying G-Coat Plus (GC). The specimens were divided into the three groups which were conditioned in distilled water at 37 degrees C for 48 hours, 4 and 8 weeks. The specimens were loaded in a four-point bending test using a universal testing machine. The maximum load to specimen failure was recorded and the fracture toughness calculated. RESULTS: There were significant differences among most of the materials (P < 0.001). Quix Fil had the highest mean KIc value and Fuji VII the lowest. Immersion in distilled water for the resin composite and polyacid-modified resin composites caused a significant decrease in KIc as the time interval increased. For glass ionomer cements, KIc decreased significantly after 4 weeks, and after 8 weeks immersion slightly increased. G-Coat Plus affected Fuji II LC positively while it had no effect on the Fuji IX. PMID- 20718211 TI - Effect of gingival ceramic veneer thickness on the fracture strength of zirconia based fixed dental prostheses. AB - PURPOSE: To assess the effect of different thicknesses of porcelain at the gingival of pontics, on the fracture load of zirconia-based, all-ceramic fixed dental prostheses (FDPs), anchored by inlays. METHODS: Box inlay cavities were prepared on mandibular molars and premolars. 40 FDPs with yttrium-stabilized zirconia frameworks of identical dimensions were manufactured using a CAD/CAM system and veneered with a press ceramic. The FDPs, replacing a premolar and a molar, were divided into four groups. In Group FR, the framework was all around unveneered. The next three groups received a 1 mm ceramic veneer on the buccal, occlusal and lingual side, but differed in the thickness of the ceramic veneer in the gingival, tensile zone of the pontics. In Group B-0, the gingival veneering was 0 mm, in Group B 1 mm and in Group B-2, 2 mm of gingival porcelain. A group of inlay-retained metal-ceramic FDPs (mc) served as control. All FDPs were subjected to thermal cycling and 600,000 cycles of mechanical load of 50 N. The load to fracture (N) was measured and fracture sites were evaluated macroscopically. A single-factor Analysis of Variance was used to analyze the data. RESULTS: None of the FDPs debonded after thermal cycling or mechanical loading and no signs of fractures or other defects were observed. The mean fracture loads and standard deviations in parentheses were: 647 N (123) for Group B-0, 716 N (102) for Group FR, 812 N (48) for Group B-1, 934 N (129) for Group B 2 and 1005 N (SD 81) for Group MC. Means for Groups B-0 and FR were not shown to differ, and the same for mean fracture strength of Groups B-2 and MC. PMID- 20718212 TI - Microtensile bond strength of two-step etch-and-rinse adhesive systems on sound and artificial caries-affected dentin. AB - PURPOSE: To evaluate the microtensile bond strength of two-step etch-and-rinse adhesive systems on sound and artificial caries-affected dentin (CAD) produced by in vitro monoculture of Streptococcus mutans. METHODS: 10 recently extracted non carious human third molars were ground to expose a flat dentin surface. Each tooth was sectioned through the long axis with a diamond saw to create two similar halves. One half was used as control (sound dentin - SD) while the other was submitted to caries lesion induction in vitro, using 40 mL of Brain Heart Infusion broth containing 1% sucrose and 40 microL of Streptococcus mutans UA159 inoculum (final bacterial concentration: 1-2 x 105 CFU/mL). The specimens were incubated at 37 degrees C for 4 weeks, and the culture medium was changed every 3 days for 4 weeks. Sound or CAD were alternatively restored as follow (n = 5): Single Bond 2/sound dentin (SB-SD); Single Bond 2/artificial caries-affected dentin (SB-CAD); Prime&Bond NT/sound dentin (PB-SD); and Prime&Bond NT/CAD (PB CAD).The adhesives were applied to dentin according to manufacturers' instructions, and build-ups of resin composite (Filtek Z250) were prepared and polymerized with a LED light-curing unit (Radii). The restored teeth were stored in distilled water at 37 degrees C for 24 hours and thereafter sectioned perpendicular to the bonded interface with a refrigerated low-speed diamond saw, obtaining three slices per half-tooth (n = 15). The microtensile bond strength (microTBS) test was performed in a universal test machine with a crosshead speed of 1 mm/minute. Bond strengths were calculated in MPa and analyzed by Kruskal Wallis and Student-Newman-Keuls at a 0.05 level of significance. Failure patterns were examined with an optical microscope. RESULTS: SD produced significantly higher microTBS values than CAD for both adhesive systems. Furthermore, independently of the dentin condition, Single Bond 2 had higher values than Prime Bond NT (P < 0.05). Single Bond 2 showed higher microTBS than Prime Bond NT, in both substrates, and application to CAD reduced the adhesion. PMID- 20718213 TI - Bond strength of a total-etch and two self-etch adhesives to dentin with and without intermediate flowable liner. AB - PURPOSE: To evaluate the effect of flowable resin composite application on the microtensile bond strength of a total-etch and two self-etch adhesive systems to dentin. METHODS: Occlusal surfaces of 30 human third molars were ground to obtain flat dentin surfaces. One of the following adhesive systems was applied to the dentin surface following manufacturers' instructions: Admira Bond, Futurabond DC and Clearfil SE Bond. For each adhesive, half of the specimens received a layer of flowable composite (Amaris Flow) applied into dentin and light-cured (experimental groups). The other teeth received no liner and served as control group. For all teeth, resin composite (Amaris) was applied in 2 mm thickness to form a crown segment 5-6 mm height and each increment was light-cured. The restored teeth were stored in water at 37 degrees C for 24 hours. Each tooth was serially sectioned in a longitudinal direction in order to obtain several bonded slabs (1.0 mm2 in cross-section). Each slab was attached to the set-up by their lateral sides and placed in a universal testing machine. Tensile load was applied at cross-head speed of 0.5 mm/minute until failure. Data were analyzed by two-way ANOVA and Tukey's test at 5% significance level. RESULTS: Placement of a low viscosity resin after adhesive application increased the microtensile bond strength for all tested adhesive systems. However, such increase was not significant (P > 0.05). The percentage of cohesive failure was increased in specimens with flowable resin liner. PMID- 20718214 TI - Controlled, prospective clinical split-mouth study of cast gold vs. ceramic partial crowns: 5.5 year results. AB - PURPOSE: To investigate the long-term clinical performance of cast gold partial crowns (CGPCs) as compared to partial ceramic crowns (PCCs). The null hypothesis tested was that CGPCs and PCCs would show similar clinical outcomes. In the present evaluation, the 5.5 year results are reported. METHODS: This was a controlled, prospective, clinical split-mouth study. In each patient, one CGPC (Degulor C) and one PCC (Vita Mark II ceramic/Cerec 3) had been inserted at baseline. After 5.5 years, 22 CGPC and 22 PCC restorations in 22 subjects attending the recall visit were clinically assessed using modified United States Public Health Service (USPHS) criteria. Kaplan-Meier survival rates were calculated for CGPCs and PCCs of the 29 subjects who had been originally enrolled in the study. RESULTS: 22 subjects (8 male, 14 female) participated in the 5.5 year recall with a total of 44 restorations. 22 CGPCs and 11 PCCs were placed in molars; 11 PCCs were placed in premolars. The median patient age was 37 years (32 44 years). All subjects revealed a papilla bleeding index (PBI) of < 20% (median: 7%). After 5.5 years, PCCs revealed a statistically significant, time dependant decrease of Alfa ratings for criteria anatomic form, marginal adaptation and marginal discoloration. Furthermore, PCCs as compared to CGPCs showed a statistically significant material-related decrease of Alfa ratings for criteria anatomic form and marginal discoloration. Kaplan-Meier survival analysis revealed a 93.3% cumulative survival rate for CGPCs and an 88.8% cumulative survival rate for PCCs after 5.5 years. Survival functions did not differ significantly across groups. At 5.5 years, CGPCs and PCCs exhibited satisfactory clinical outcomes. For PCCs, Bravo ratings increased significantly over time, however this did not compromise clinical survival of the restorations as compared to CGPCs. PMID- 20718215 TI - Influence of acid etching on hydrogen peroxide diffusion through human dentin. AB - PURPOSE: To evaluate the influence of dentin etching with phosphoric acid on hydrogen peroxide diffusion through human dentin in internal bleaching. METHODS: 46 human premolars were extracted for orthodontic reasons from adolescents. The teeth were endodontically treated and a flat defect was created at the enamel cementum junction. The teeth were divided into two groups: the access cavity was etched for 30 seconds with 35% H3PO4 in the first group and left intact in the second group. The teeth were filled with 20 microL of 35% hydrogen peroxide gel. The receiving medium on the other side was renewed at Day 1, Day 2 and Day 7 to quantify the diffusing hydrogen peroxide. An analysis of variance was performed to compare the diffusion between the two groups. RESULTS: This work demonstrated a higher hydrogen peroxide diffusion when the access cavity was etched (P < 0.01). PMID- 20718217 TI - A randomized cross-over clinical trial to evaluate the effect of a 0.454% stannous fluoride dentifrice on the reduction of oral malodor. AB - PURPOSES: To compare the oral malodor protection efficacy of a 0.454% stannous fluoride dentifrice versus a negative control (0.243% sodium fluoride) using a sulfide monitor (halimeter) as the measurement. A secondary objective was to assess the effects of tongue brushing. METHODS: This was a four-treatment, five period, examiner-blinded, crossover, randomized study. Healthy subjects who met the entrance criteria were enrolled into the study. A 5-day acclimation period, in which subjects brushed twice daily in their customary manner with a standard sodium fluoride dentifrice, occurred prior to baseline. After baseline halimeter measurements, subjects were randomly assigned to one of four treatments (SnF2 dentifrice groups, with or without tongue brushing; negative control dentifrice groups, with or without tongue brushing) based on baseline halimeter scores, age, and gender. Test products were used three times a day. Breath measurements were taken 24 hours after baseline (after three product uses). Subjects then brushed again with the product treatment. Final breath measurements were taken 4 hours later, 28 hours after baseline. A 5-day washout separated each treatment period. RESULTS: 33 subjects were enrolled and completed the study. The adjusted mean volatile sulfur compound (VSC) levels were significantly lower in the SnF2 groups than the NaF groups, at both 24 (P < 0.01) and 28 (P < 0.001) hours post baseline time points. Tongue brushing did not provide additional statistically significant breath benefits when compared to toothbrushing alone. Both dentifrices were well tolerated. PMID- 20718216 TI - Peroxide penetration from the pulp chamber to the external root surface after internal bleaching. AB - PURPOSE: To quantify the amount of peroxide penetration from the pulp chamber to the external surface of teeth during the walking bleaching technique. METHODS: Seventy-two bovine lateral incisors were randomly divided over five experimental groups and one control (n = 12 per group): (1) 35% hydrogen peroxide (HP); (2) 35% carbamide peroxide (CP); (3) sodium perborate (SP); (4) (HP+SP); (5) (CP+SP) and (6) Control (CG), deionized water. All groups were treated according to the walking bleach technique. After 7 days at 37 degrees C in an acetate buffer solution, 100 microl violet leukocrystal coloring and 50 microl peroxidase was added, producing a blue stain that could be measured in a spectrophotometer and then converted into peroxide microg/ml. RESULTS: G5 exhibited the greatest penetration, while G2 and G3 produced the lowest values. All bleaching agents penetrated from the pulp chamber to the external root surface. There was a direct correlation between the presence of oxidative agents and penetration potential. Sodium perborate in distilled water was less oxidative and appeared to be the least aggressive bleaching agent. PMID- 20718218 TI - Fluoride-releasing orthodontic adhesives and topical fluoride effect on enamel caries formation: an in vitro study. AB - PURPOSE: To examine in vitro orthodontic bonding sealants combined with daily fluoride (NaF) rinse on caries-like lesion depths. METHODS: Permanent molar teeth (n = 40) were randomly divided into four treatment groups: 1: Pro-Seal, 2: Light Bond, 3: Pro-Seal with NaF rinsing, and 4: Light Bond with NaF rinsing. Orthodontic sealant material was placed on buccal surfaces of each group and surrounded by acid-resistant varnish on the buccal and a control window on the lingual. Each group underwent synthetic saliva rinsing and lesion initiation. Groups 3 and 4 were subjected to 0.05% NaF for 1 minute per day. Artificial caries were created in vitro. The specimens in each treatment group were sectioned and mean lesion depth was assessed with polarized light microscopy (water imbibition). Lesion depth was compared among the treament groups using ANOVA and Duncan's Multiple Range Test. RESULTS: The ProSeal and Light Bond treatment groups exhibited significant reductions in mean lesion depths as compared to the controls (P < 0.05). ProSeal with NaF rinsing and Light Bond with NaF rinsing treatment groups exhibited significant reductions in mean lesion depth when compared to Pro Seal and Light Bond treatment without fluoride rinsing and controls (P < 0.05). The enamel-resin interfaces of all treatment groups were intact and exhibited no caries-like lesion formation. PMID- 20718219 TI - Social support at work and affective commitment to the organization: the moderating effect of job resource adequacy and ambient conditions. AB - This study investigated whether both supervisor and coworker support may be positively related to affective commitment to the organization on one hand; and on the other hand, it examined the moderating effect of job resource adequacy and ambient conditions on these relationships. The sample included 215 participants working within a health care organization. Results of regression analysis showed that supervisor and coworker support have an additive effect on affective commitment. Hierarchical regression analyses indicated that supervisor and coworker support are more strongly related to affective commitment when job resource adequacy is high. Furthermore, ambient conditions moderate the relationship between supervisor support and affective commitment in such a way that favorable ambient conditions strengthen this relationship. Overall, these findings reinforce the importance of taking into account contingent factors in the study of antecedents of affective commitment to the organization. PMID- 20718220 TI - Sex, sexual orientation, and sexism: what influence do these factors have on verdicts in a crime-of-passion case? AB - This study investigated the influence of defendant sex, sexual orientation, and participant sex on perceptions of a crime-of-passion. An online sample of 458 individuals read a scenario describing a homicide and provided judgments of verdict, sentence length, legal elements, and sexism. We hypothesized heterosexual female defendants would most likely receive a verdict of manslaughter, be found less guilty, and receive shorter sentences. We were also interested in whether benevolent sexism would contribute to defendant culpability decisions. Lastly, perceptions of legal elements for manslaughter (e.g., great provocation) and murder (e.g., intentionality of actions) were explored. Results demonstrated heterosexual female defendants were less guilty and received the shortest sentences. Also, heterosexual defendants were most likely to meet the manslaughter legal elements. Benevolent sexism contributed significantly to guilt perceptions. PMID- 20718221 TI - On coffee talk and break-room chatter: perceptions of women who gossip in the workplace. AB - The present study examined perceptions of female gossipers in the workplace. Male and female participants (N=129) were asked to think of a woman who either frequently or rarely contributed negative information about other people during conversation. Participants then completed ratings on the target using the six dimensions of the FIRO-B. As predicted, high gossipers were perceived as having a greater need to exert control of others, but less need for others to control them, than low gossipers. Higher gossipers were also perceived as less emotionally warm than low gossipers. The implications of these findings for gossip research are presented. PMID- 20718222 TI - How do I see you relative to myself? Relationship quality as a predictor of self- and partner-enhancement within cross-sex friendships, dating relationships, and marriages. AB - Individuals tend to rate themselves more positively than strangers or acquaintances--a self-enhancement effect. But such self-enhancement is potentially detrimental to one's intimate relationships. We hypothesized that higher relationship quality would predict (1) partner-enhancement (i.e., rating the partner more positively than the self) and (2) higher feelings of being understood and validated (FUV). In addition, (3) partner-enhancement would add to relationship quality's prediction of FUV. These hypotheses were tested among cross-sex friendships (N=92) and dating relationships (N=90) in University students and in a married, non-University sample (N=94). All hypotheses were supported in romantic relationships. For cross-sex friendships, regardless of relationship quality, individuals partner-enhanced on the negative traits but neither self- nor partner-enhanced on the positive traits. Finally, relationship quality predicted partner-perceptions more strongly than selfperceptions. PMID- 20718223 TI - Lay beliefs about developing countries in relation to helping behaviors. AB - We study the beliefs in a developed country about the attribution of responsibility for the situation in developing countries, in relation to helping behaviors and level of commitment. Two samples were used: one for the synthesis of knowledge (N=527) and a second for the synthesis of beliefs (N=287). From the results, we analyze the synthesis of beliefs and obtain the structure of beliefs. The synthesis of beliefs sample was made up of 137 individuals who help developing countries and 150 who do not. ANOVAs show that developed countries activate three implicit theories as beliefs to explain poverty in developing countries. Attribution external to the actor is more significant at higher levels of commitment to help. The implications for social communication campaigns in the developed world are discussed. PMID- 20718224 TI - Assessment of body image in younger and older women. AB - Body image was compared in younger versus older women using questionnaires and women's responses to fatter and thinner images of their own bodies versus responses to line drawings of bodies in the Figure Ratings Scale. We found that younger and older women have similar body dissatisfaction but that younger women have a higher drive for thinness and experience more societal influence on their body image. Using images of one's own body versus line drawings did not result in different body dissatisfaction in younger versus older women. These data suggest that age affects some facets of body image but not others and that ratings of body image do not differ in normal, healthy younger and older women when personalized measures are used. PMID- 20718225 TI - Retention of a time pressure heuristic in a target identification task. AB - S. Rice and D. Keller (2009) previously reported that participants who were put under time pressure tended to comply more with a diagnostic aid than participants who were not put under time pressure. The present study investigates whether or not learning the benefits of this time pressure heuristic carries over to a second session. Seventy-two New Mexico State University students performed a simulated target-detection task, assisted by a 95% reliable diagnostic aid. Participants were exposed to the following conditions, which were composed of two sessions: speeded-speeded, unspeeded-speeded, speeded-unspeeded, or unspeeded unspeeded. Results showed that participants who completed the speeded condition for Session 1 performed just as well in the 2nd session regardless of whether or not they were put under time pressure. Participants found that complying with the aid was beneficial to overall performance and continued to comply in a 2nd session even when allowed more time to overrule the aid. PMID- 20718226 TI - The impact of size of cooperative group on achievement, social support, and self esteem. AB - The effect of cooperative learning in pairs and groups of 4 and in individualistic learning were compared on achievement, social support, and self esteem. Sixty-two Italian 7th-grade students with no previous experience with cooperative learning were assigned to conditions on a stratified random basis controlling for ability, gender, and self-esteem. Students participated in 1 instructional unit for 90 min for 6 instructional days during a period of about 6 weeks. The results indicate that cooperative learning in pairs and 4s promoted higher achievement and greater academic support from peers than did individualistic learning. Students working in pairs developed a higher level of social self-esteem than did students learning in the other conditions. PMID- 20718227 TI - Delay discounting of different commodities. AB - When outcomes are delayed, their value is decreased. Delay discounting is a much studied topic because it is correlated with certain disorders (e.g., pathological gambling). The present study attempts to determine how people would delay discount a number of different commodities, ranging from money to dating partners to federal education legislation. Participants completed delay discounting tasks pertaining to 5 different commodities, with a different set of 5 commodities for 2 groups. Results showed that different commodities were often discounted differently. Both data sets were also subjected to factor analysis. A 2-factor solution was found for both, suggesting that there are multiple "domains" of commodities. This finding is of interest because it suggests that measuring delay discounting for one commodity within a particular domain of commodities will be predictive of how people discount other commodities within that domain but will not be predictive of how they discount commodities within another domain. PMID- 20718228 TI - How do people form behavioral intentions when others have the power to determine social consequences? AB - Much literature has suggested that people who are discriminated against or are in collectivist cultures are particularly susceptible to the social consequences of society. In the present study, the authors conducted 3 experiments to test how this factor influences attitudinal versus normative control over behaviors. First, they measured males' and females' attitudes, subjective norms, and behavioral intentions with respect to a large number of behaviors. Although between-participants analyses were mostly uninformative, within-participants analyses uncovered strong evidence that behaviors are more under attitudinal control for females than for males. Similar analyses in a crosscultural experiment involving participants from the United States, the United Kingdom, China, and Mexico support the hypothesis that behaviors are more under attitudinal control for collectivists than for individualists. Finally, experimental data collected in the United States and Saudi Arabia further support this conclusion. Taken together, the findings suggest that although social consequences are both "social" and "consequences", the latter is more important than the former. PMID- 20718229 TI - Using PPT to analyze suboptimal human-automation performance. AB - Diagnostic automation aids are designed to improve human performance by increasing accuracy in event detection tasks. However, human-automation performance has frequently fallen short of expectations, particularly when the aid is highly reliable. In those cases, human-automation performance is often suboptimal, in that a human being augmented with a diagnostic aid does more poorly than the automation itself. Previously, there have been only ambiguous explanations for why this occurs, with few suggestions on how to effectively eliminate suboptimal performance. Fortunately, with the advent of a new general theory of task performance, termed Potential Performance Theory (PPT) by D. Trafimow and S. Rice (2008; 2009), one can now determine exactly why suboptimal performance occurs. Results from the present study reveal that inconsistency is the culprit, rather than just poor strategy selection. Furthermore, PPT allows one to determine exactly how much of the performance decrement is because of inconsistency. PMID- 20718230 TI - Views of the self and others at different ages: utility of repertory grid technique in detecting the positivity effect in aging. AB - Socioemotional selectivity theory (Carstensen, 1995) posits a "positivity effect" in older adults, describing an increasing tendency to attend to, process, interpret, and remember events and others in life in a positive fashion as one ages. Drawing on personal construct theory, Viney (1993) observes increasing integration of constructions of self with others across the lifespan. The current study extends assessment of the positivity effect, integrating it with personal construct theory, by use of Repertory Grid (RepGrid) analysis. Consistent with the positivity effect, older adults (ages 54-86) described others more positively on RepGrid measures in comparison to younger adults (ages 18-25). Older adults also described the self as more similar to others and tended to describe the self more positively. The age groups did not differ in measures of psychological distress or well being with the exception of older adults describing more autonomy. PMID- 20718231 TI - Using the Montessori approach for a clientele with cognitive impairments: a quasi experimental study design. AB - BACKGROUND: The choice of activities responding to the needs of people with moderate to severe dementia is a growing concern for care providers trying to target the need for a feeling of self-accomplishment by adapting activities to the abilities of elderly patients. The activities created by Maria Montessori seem to be adaptable to this clientele. This study evaluates the short-term effects, as compared to regular activities offered in the milieu. METHODS: This is a quasi-experimental study where each of the 14 participants was observed and filmed in two conditions: during Montessori activities, during regular activities, and one control condition (no activity). RESULTS: The results show that Montessori activities have a significant effect on affect and on participation in the activity. They support the hypothesis that when activities correspond to the needs and abilities of a person with dementia, these positive effects are also observed on behaviours. CONCLUSIONS: This study enabled its authors to corroborate the findings presented in the literature and to contribute additional elements on the positive effects of the use of Montessori activities and philosophy. Used with people with moderate to severe dementia these allow the satisfaction of their basic psychological needs, their well being, and hence, on their quality of life. PMID- 20718232 TI - Optimism and well-being in older adults: the mediating role of social support and perceived control. AB - To investigate how psychosocial resources may improve well-being for older adults, this study explored the relationship among questionnaire measures of optimism, social support and perceptions of control in predicting subjective well being (measured with the positive affect subscale of the Affect Balance Scale) (Bradburn, 1969) and psychological well-being (measured with the purpose in life scale of the Ryff Psychological Well-being scales) (Ryff, Lee, Essex, & Schmutte, 1994) among older adults. The potential mediating roles of perceived social support and perception of control were also explored. Participants were 225 adults aged from 65 to 94 years. Optimism was found to be a predictor of both subjective and psychological well-being, and perceived social support was found to mediate the relationship between optimism and subjective well-being, but not psychological well-being. In contrast, perception of control was found to mediate the relationship between optimism and psychological well-being, but not subjective wellbeing. Longitudinal research is needed to confirm these pathways. PMID- 20718233 TI - Relationships among social support, perceived control, and psychological distress in late life. AB - Social support has been shown to buffer the relationship between life stress and psychological distress in late life. However, little attention has been paid to personality variables that are associated with the capacity to effectively utilize social support. Although the buffering effects of social support were replicated in our sample of 134 community-dwelling individuals over the age of 65, perceived control was found to significantly moderate the relationship between stress, social support, and psychological distress. Specifically, older adults who were highly satisfied with social support consistently reported less psychological distress than those who were less satisfied with social support, regardless of perceived control. However, under conditions of both low and high satisfaction with social support, external controllers were found to be less reactive to stress than internal controllers. Implications for developing more complex models of the relationship between stress, social support and psychological distress are discussed. PMID- 20718234 TI - Getting involved in research: whose initiative is this? PMID- 20718235 TI - Spouses' experiences of impact on daily life regarding physical limitations in the loved one with heart failure: a phenomenographic analysis. AB - BACKGROUND: Physical limitation is a great burden for patients with heart failure, but little is known about how that affects spouses. Beneficial effects of support on the prognosis for the patient with chronic heart failure may come at a psychological and physical cost to the person providing the support. PURPOSE: The aim of this study was to explore and describe how spouses conceive the physical limitations in patients with heart failure and the impact these limitations have on the daily life of the spouse. DESIGN: A qualitative design with a phenomenographic approach was chosen for the study. FINDINGS: The informants were 15 spouses of heart failure patients. The spouses perceived a variety of aspects pertaining to how they conceive the physical limitations in the loved one with heart failure and the implication this had on their daily life. The referential aspects were: Losing self-containment, Missing communality, Accommodating to the situation and Finding satisfaction in life. IMPLICATIONS AND CONCLUSIONS: Awareness must be raised among health care professionals about the profound impact heart failure in loved ones has on the spouses and explore how the spouses' needs can be appropriately met. Since spouses have an important role to play in the management of heart failure, it is of great importance that nurses identify and support spouses to manage daily life activities. Taking care of the good days in order to have a rich life and to help spouses see possibilities is necessary since it is difficult to predict the future. PMID- 20718237 TI - Qualitative interviewing: preparation for practice. AB - Oualitative research approaches are diverse and provide the opportunity to explore the experiences, behaviours,. contexts and lifestyle choices of individuals with cardiovascular disease. Understanding these complex health and social factors is essential to the delivery of responsive health care services that improve patient satisfaction and health outcomes. In-depth interviewing is a popular and versatile data collection method used in qualitative inquiry. Qualitative research interviews are not as simple as they may first seem and involve complex interactions that employ a range of communication and interpretation skills. Preparation for interview practice can promote rigour and help avoid pitfalls, such as premature interpretation of research data, inadequate depth of questioning, and the identification of researcher presuppositions that may influence data collection and analysis. In this research column, an overview of qualitative interviewing is presented followed by a brief outline of practice techniques to improve the execution and outcomes of this valuable data collection method. PMID- 20718236 TI - Perceived control: a construct to guide patient education. AB - BACKGROUND: Educational needs for patients who are hospitalized with cardiovascular health issues are often underestimated by those caring for them. Perceived control is a construct that has been employed to guide understanding these needs. PURPOSE: The purpose of this exploratory study was to expose cardiac nurses to the construct of perceived control during an annual cardiac education day in February 2009, and evaluated whether the nurses find perceived control constructive in their current practice. The exploratory study also evaluated whether the nurses planned to alter their approach to patient teaching to incorporate perceived control based on the information contained in the presentation. METHOD: Data were collected from registered nurses (n=16) employed in a tertiary cardiac intervention unit, who attended an annual cardiac education day in February 2009. The nurses completed a one-time cross-sectional survey, created de novo, which explored their beliefs around perceived control and patient education. FINDINGS: The survey revealed that the nurses generally agreed that perceived control had the potential to positively impact patient teaching. This was despite the nurses' lack of previous knowledge about perceived control. Younger nurses tended to find that perceived control had an impact on patient adherence more than older nurses, although this result was not statistically significant. Younger and less experienced nurses were also more open to theory and research underpinning patient education. CONCLUSION: Further study is required with a larger sample size and validated measurement tool. PMID- 20718238 TI - A historical context for understanding "An eye roll test for hypnotizability" by Herbert Spiegel, M.D. AB - Herb Spiegel was known for many professional and scientific achievements. He is may be best remembered for his discovery of the Eye Roll Sign (ERS) and its relation to innate trance capacity and the parallel creation and development of the Hypnotic Induction Profile (HIP). The present paper provides a historical context for understanding Herb's 1972 publication of "An Eye Roll Test for Hypnotizability" which originally appeared in the American Journal of Clinical Hypnosis 38 years ago and is reprinted in this journal issue. PMID- 20718239 TI - An eye-roll test for hypnotizability. 1972. PMID- 20718240 TI - Hypnotically facilitated exposure response prevention therapy for an OIF veteran with OCD. AB - The highly stressful conditions of a war zone may exacerbate or trigger a wide variety of symptoms including Obsessive Compulsive Disorder (OCD) once a service member returns home. Service members and new veterans of the Iraq and Afghanistan wars present to treatment with multiple psychosocial concerns and co-morbid psychiatric conditions. Evidence-based treatments including exposure based therapies are commonly recommended for use with returning veterans. Although studies support the efficacy of Exposure Response Prevention (ERP) therapy for treating OCD, eligibility for these studies limits participation to subjects who self-report a well-defined, circumscribed complaint. This approach is not typical of clinic clients who, more often than not, report multiple psychological issues. The following individual case study demonstrates how integrating hypnosis facilitated the cognitive-behavioral ERP therapy and treatment for a patient suffering from OCD. PMID- 20718241 TI - A new bioinformatics paradigm for the theory, research, and practice of therapeutic hypnosis. AB - In a 2008 pilot study we used DNA microarrays to explore the historical ideo plastic faculty of therapeutic hypnosis. We documented how to measure changes in activity or experience-dependent gene expression over relatively brief time periods (1 hour and 24 hours) following a single intervention of therapeutic hypnosis (about 1 hour). In the present paper we utilize bioinformatic software to explore the possible meaning and significance of this ideo-plastic faculty of therapeutic hypnosis. Indications suggest that the ideo-plastic process of therapeutic hypnosis may be associated with (1) the heightening of a molecular genomic signature for the up-regulation (heightened activity) of genes characteristic of stem cell growth, (2) a reduction in cellular oxidative stress, and (3) a reduction in chronic inflammation. We identify these three empirical associations as an initial beta version of the molecular-genomic signature of the ideo-plastic process of therapeutic hypnosis, which can serve as a theoretical and practical guide for clinical excellence by beginners as well as senior professionals. We propose this molecular-genomic level of discourse as a supplement to the traditional cognitive-behavioral description of therapeutic suggestion, hypnosis, and psychotherapy that is consistent with "translational research" currently funded by the National Institute of Mental Health (NIMH). PMID- 20718242 TI - Hypnosis and the relationship between trance, suggestion, expectancy and depth: some semantic and conceptual issues. AB - In the first of two recent papers, Pekala, Kumar, Maurer, Elliot-Carter, Moon and Mullen (2010a) review what they consider to be the relationships between trance or altered state effects, suggestibility, and expectancy, and how they relate to the concepts of hypnosis and hypnotism. They also suggest that these concepts can be assessed with an instrument they term the PCI-HAP (Phenomenology of Consciousness: Inventory-Hypnotic Assessment Procedure). In the second paper (Pekala, Kumar, Elliot-Carter, Moon, & Mullen, 2010b), they set out to determine empirically whether these concepts can predict hypnotic depth scores using the PCI-HAP. They conclude that their results support the view that all of these component processes may be involved in 'hypnotism' and experiences of hypnotic depth. However, according to their conceptualization, 'hypnosis' itself involves, or consists of, only altered state or trance effects. These papers raise a number of fundamental methodological, semantic and conceptual issues that are discussed in this commentary. Topics discussed include distinctions between concepts such as 'hypnosis', and 'hypnotism,' the role of inductions and suggestion in producing hypnotic phenomena, and the measurement and conceptualization of 'hypnotic depth.' It is concluded that many of the problems relating to the definition and conceptualization of terms associated with hypnosis may be clarified by placing the terms in their historical context, and that difficulties in identifying the origins of the experiences and behaviours associated with hypnosis may stem from insufficient attention to the role of suggestion and expectancies in producing hypnotic phenomena, and an over-reliance on the role of the procedures and mechanics of the induction process. PMID- 20718243 TI - Quantitative ultrasound assessment of cervical microstructure. AB - The objective of this preliminary study was to determine whether quantitative ultrasound (QUS) can provide insight into, and characterization of, uterine cervical microstructure. Throughout pregnancy, cervical collagen reorganizes (from aligned and anisotropic to disorganized and isotropic) as the cervix changes in preparation for delivery. Premature changes in collagen are associated with premature birth in mammals. Because QUS is able to detect structural anisotropy/isotropy, we hypothesized that it may provide a means of noninvasively assessing cervical microstructure. Thorough study of cervical microstructure has been limited by lack of technology to detect small changes in collagen organization, which has in turn limited our ability to detect abnormal and/or premature changes in collagen that may lead to preterm birth. In order to determine whether QUS may be useful for detection of cervical microstructure, radiofrequency (rf) echo data were acquired from the cervices of human hysterectomy specimens (n = 10). The angle between the acoustic beam and tissue was used to assess anisotropic acoustic propagation by control of transmit/receive angles from -20 degrees to +20 degrees. The power spectrum of the echo signals from within a region of interest was computed in order to investigate the microstructure of the tissue. An identical analysis was performed on a homogeneous phantom with spherical scatterers for system calibration. Power spectra of backscattered rf from the cervix were 6 dB higher for normal (0 degree) than steered (+/- 20 degrees) beams. The spectral power for steered beams decreased monotonically (0.4 dB at +5 degrees to 3.6 dB at +20 degrees). The excess difference (compared to similar analysis for the phantom) in normally incident (0 degree) versus steered beams is consistent with scattering from an aligned component of the cervical microstructure. Therefore, QUS appears to reliably identify an aligned component of cervical microstructure; because collagen is ubiquitously and abundantly present in the cervix, this is the most likely candidate. Detection of changes in cervical collagen and microstructure may provide information about normal versus abnormal cervical change and thus guide development of earlier, more specific interventions for preterm birth. PMID- 20718244 TI - Interactive vs. automatic ultrasound image segmentation methods for staging hepatic lipidosis. AB - The aim of this study was to test the hypothesis that automatic segmentation of vessels in ultrasound (US) images can produce similar or better results in grading fatty livers than interactive segmentation. A study was performed in postpartum dairy cows (N=151), as an animal model of human fatty liver disease, to test this hypothesis. Five transcutaneous and five intraoperative US liver images were acquired in each animal and a liverbiopsy was taken. In liver tissue samples, triacylglycerol (TAG) was measured by biochemical analysis and hepatic diseases other than hepatic lipidosis were excluded by histopathologic examination. Ultrasonic tissue characterization (UTC) parameters--Mean echo level, standard deviation (SD) of echo level, signal-to-noise ratio (SNR), residual attenuation coefficient (ResAtt) and axial and lateral speckle size- were derived using a computer-aided US (CAUS) protocol and software package. First, the liver tissue was interactively segmented by two observers. With increasing fat content, fewer hepatic vessels were visible in the ultrasound images and, therefore, a smaller proportion of the liver needed to be excluded from these images. Automatic-segmentation algorithms were implemented and it was investigated whether better results could be achieved than with the subjective and time-consuming interactive-segmentation procedure. The automatic-segmentation algorithms were based on both fixed and adaptive thresholding techniques in combination with a 'speckle'-shaped moving-window exclusion technique. All data were analyzed with and without postprocessing as contained in CAUS and with different automated-segmentation techniques. This enabled us to study the effect of the applied postprocessing steps on single and multiple linear regressions ofthe various UTC parameters with TAG. Improved correlations for all US parameters were found by using automatic-segmentation techniques. Stepwise multiple linear-regression formulas where derived and used to predict TAG level in the liver. Receiver-operating-characteristics (ROC) analysis was applied to assess the performance and area under the curve (AUC) of predicting TAG and to compare the sensitivity and specificity of the methods. Best speckle-size estimates and overall performance (R2 = 0.71, AUC = 0.94) were achieved by using an SNR-based adaptive automatic-segmentation method (used TAG threshold: 50 mg/g liver wet weight). Automatic segmentation is thus feasible and profitable. PMID- 20718245 TI - Simulation study of amplitude-modulated (AM) harmonic motion imaging (HMI) for stiffness contrast quantification with experimental validation. AB - The objective of this study is to show that Harmonic Motion Imaging (HMI) can be used as a reliable tumor-mapping technique based on the tumor's distinct stiffness at the early onset of disease. HMI is a radiation-force-based imaging method that generates a localized vibration deep inside the tissue to estimate the relative tissue stiffness based on the resulting displacement amplitude. In this paper, a finite-element model (FEM) study is presented, followed by an experimental validation in tissue-mimicking polyacrylamide gels and excised human breast tumors ex vivo. This study compares the resulting tissue motion in simulations and experiments at four different gel stiffnesses and three distinct spherical inclusion diameters. The elastic moduli of the gels were separately measured using mechanical testing. Identical transducer parameters were used in both the FEM and experimental studies, i.e., a 4.5-MHz single-element focused ultrasound (FUS) and a 7.5-MHz diagnostic (pulse-echo) transducer. In the simulation, an acoustic pressure field was used as the input stimulus to generate a localized vibration inside the target. Radiofrequency (rf) signals were then simulated using a 2D convolution model. A one-dimensional cross-correlation technique was performed on the simulated and experimental rf signals to estimate the axial displacement resulting from the harmonic radiation force. In order to measure the reliability of the displacement profiles in estimating the tissue stiffness distribution, the contrast-transfer efficiency (CTE) was calculated. For tumor mapping ex vivo, a harmonic radiation force was applied using a 2D raster-scan technique. The 2D HMI images of the breast tumor ex vivo could detect a malignant tumor (20 x 10 mm2) surrounded by glandular and fat tissues. The FEM and experimental results from both gels and breast tumors ex vivo demonstrated that HMI was capable of detecting and mapping the tumor or stiff inclusion with various diameters or stiffnesses. HMI may thus constitute a promising technique in tumor detection (>3 mm in diameter) and mapping based on its distinct stiffness. PMID- 20718246 TI - Crawling waves from radiation force excitation. AB - Crawling waves are generated by an interference of two oscillating waves traveling in opposite directions, with a progressive movement resulting from a frequency difference or a phase difference between the sources. While the idea has been applied to numerous applications, all the previous reports used mechanical sources to vibrate the medium. It is shown, through experiments and simulation, that crawling waves can be generated from focused beams that produce radiation force excitation within the tissue. Some examples are also shown. PMID- 20718247 TI - Importance of axial compression verification to correct interpretation of axial shear strain elastograms in breast lesions. AB - We have recently shown that the appearance of Axial-Shear Strain Elastograms (ASSEs) for the case of loosely-bonded, elliptical inclusions (like fibroadenomas in the breast) is unique and therefore has the potential to distinguish benign fibroadenomas from malignant tumors in the breast. The ASSEs were obtained using quasi-static axial compressions, in a like manner as in normal axial-strain elastography. However, strict axial compression is achieved most often only by computer-controlled acquisitions and not by more practical freehand acquisitions. In a freehand acquisition, the frame sequence may contain several frames that do not experience strict axial compression but may also experience rotation or shear deformations. In this paper, we demonstrate the importance of accounting for the type of deformation applied to a target tissue for the correct interpretation of the resulting ASSEs. Using freehand acquired in vivo examples, we show that such a frame experiencing rotation or shear deformations results in ASSEs that may potentially be misinterpreted. This may be far more detrimental compared to the corresponding axial elastogram frames that may only suffer from inferior image quality in terms of contrast-to-noise ratio (CNR). Further, we show that we may be able to eliminate these frames from a sequence of freehand acquired in vivo breast lesion data by implementing a special filtering scheme, thus significantly improving the reliability of the remaining ASSE frames. This work further suggests that under freehand conditions, frames have to be checked for the presence of undesirable deformations. PMID- 20718248 TI - Salvage external beam radiotherapy for prostate cancer after radical prostatectomy: current status and controversy. AB - Prostate cancer is the second most common cause of cancer death in American men. What to do when prostate cancer recurs months or years after a patient undergoes radical prostatectomy is an area of active research. Patients who underwent radical prostatectomy without immediate adjuvant radiation therapy (ART) but subsequently have evidence of recurrent disease are candidates for Salvage Radiation Therapy (SRT). Though there are three prospective randomized trials illustrating the efficacy of post-operative ART for selected patients, similarly strong evidence is lacking for SRT. In this article, we define the biochemical recurrence of prostate cancer, distinguish SRT from ART, outline the evidence for SRT, and make recommendations with regard to radiotherapy volume and dose. We discuss the known side effects from SRT, weigh the cost and benefit of SRT, and discuss possible tools that may improve the cost/benefit ratio for SRT by helping to select patients whom SRT may be more likely to benefit. PMID- 20718249 TI - Who, when, where, and how: salvage prostate cancer with radiotherapy. PMID- 20718250 TI - Deciding which patients to treat with salvage radiotherapy after prostatectomy. PMID- 20718251 TI - New advances in ovarian cancer. AB - Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with approximately 15,000 deaths per year. Platinum/taxane doublets have long been considered the standard treatment regimen for advanced-stage disease; however, recent studies have sought to improve on the outcome from this therapy. Intraperitoneal (IP) chemotherapy has been shown to yield superior progression-free survival (PFS) and overall survival (OS); however, logistical problems and toxicities have limited more widespread adoption. Recent studies have also suggested that a "dose-dense" schedule of paclitaxel in combination with carboplatin may result in improved outcomes, and the impact of biological therapies in the first-line setting is under active investigation. In the setting of recurrent disease, preliminary results suggest that novel doublet regimens such as carboplatin and pegylated liposomal doxorubicin may have similar activity to standard platinum/taxane doublets while carrying a reduced risk of allergic reactions. Additionally, targeted therapy remains an active area of investigation, with evidence of activity from agents such as PARP inhibitors, anti-angiogenics, and PI3 kinase inhibitors. Here, we review recent advances in our understanding of ovarian cancer and its treatment in both the newly diagnosed and recurrent settings. PMID- 20718252 TI - Ovarian cancer care: it's time for "personalized" approaches. PMID- 20718253 TI - Challenges to the paclitaxel/carboplatin algorithm in ovarian cancer treatment. PMID- 20718254 TI - Bone complications of cancer treatment in the elderly. AB - Osteopenia and osteoporosis are increasingly common in cancer patients, owing to the aging of the population and to new forms of cancer treatment. Androgen and estrogen deprivation, as well as some forms of cytotoxic chemotherapy, may lead to osteopenia and osteoporosis. Patients at risk for osteoporosis include those treated with aromatase inhibitors and with androgen deprivation for more than 1 year. In addition, all patients 65 years of age and older are at risk of osteoporosis when treated with cytotoxic agents, and so should be screened for bone loss. Several treatments have been effective in the prevention and management of osteoporosis. In patients at risk for this complication, it is recommended to obtain a bone density evaluation and to start appropriate treatment. This may include calcium and vitamin D supplementation for mild forms of osteopenia, and bisphosphonate therapy or denosumab (Prolia) for more advanced osteopenia and osteoporosis. PMID- 20718255 TI - Osteoporosis, fractures, and risk of falls. PMID- 20718256 TI - Quantitation of individual risk for osteoporotic fracture. PMID- 20718257 TI - Simultaneously detected bilateral testicular cancer of different histopathological origin--a challenging situation for the urologist. AB - BACKGROUND: A 36-year-old male with a history of cryptorchidism of the right side, treated with orchidopexy at the age of 4, presented with bilateral testicular swelling. INVESTIGATIONS: Investigations included laboratory workup, ultrasound of both testes, as well as CT-scan of the chest, abdomen, and pelvis. Initial treatment was bilateral orchiectomy. RESULTS: Scrotal examination revealed a mass on the left side and a small right testis with a hard mass at the lower pole. One markedly enlarged right inguinal lymph node was palpable. LDH, betaHCG, and AFP were significantly elevated. Scrotal ultrasound revealed a homogeneous hypoechoic right testis without a mass and a heterogeneous mass containing multiple inhomogeneous cystic areas on the left side. A hypoechoic mass was visualized in the right groin. CT evaluation revealed an enlarged retroperitoneal lymph node on the left side. DIAGNOSIS: Histopathological evaluation revealed seminoma of the right testis, nonseminomatous germ cell tumor of the left testis, and metastatic seminoma in the right groin postoperatively. CONCLUSIONS: Due to improved diagnostic tools as well as the establishment of various adjuvant treatment options, the mortality of testicular cancer generally decreased in the last decades. However, metastatic bilateral testicular cancer of different histology is a challenging situation for the urologist, which warrants further discussion. Adjuvant treatment as well as postoperative follow-up should be chosen carefully. PMID- 20718258 TI - The approach to the patient with synchronous bilateral germ cell tumors: a lesson in oncologic prioritization. PMID- 20718259 TI - Integrative oncology. Saw palmetto. PMID- 20718260 TI - [Long-term course of treatment strategies in panic disorder: an update narrative review 1999-2010]. AB - Panic disorder (PD) represents an insidious, often chronic, recurrent and relapsing illness. Although studying PD is a topical subject because it affects both treatment costs and patients' quality of life, the literature demonstrates that long-term studies are rare and not very systematic. Even if many short-term studies (within 6 months) show that the present treatment strategies have very good results, the outcome data in the long- term suggest that a significant rate of patients with PD, in remission at the end of a treatment, relapses during the follow-up, so that there is the need to find treatment strategies to maintain the remission achieved in the short-term as long as possible. This study offers an overview of 35 studies on the long-term outcomes of PD, reviewing the recent follow-up studies with at least 6 months of follow-up and that investigate the role of comorbidity in the follow-up of PD, the outcome predictors and the present treatment strategies. PMID- 20718261 TI - Terrorists: analogies and differences with mental diseases. A phenomenological metaphysical perspective. AB - Are islamic terrorists insane? International scholars generally concede that Al Qaeda members are not mentally ill. But, until now, there has not been a shared consensus and a strong argument that can prove it. This paper intends to throw light on the specific dehumanization of terrorists and to show that they are always responsible for their acts, unlike those who are affected by mental diseases. The members of Al Qaeda deny the world of life and take the distance from its sense and value: in their perspective only subversive action makes sense. However they always maintain a transcendent relation with the world (I you; I-it). Persons with serious mental diseases have generally lost the sense of their self and the transcendence with the world. Terrorists and people with mental illness share a common separation from the world of life: one is voluntary, the other is the consequence of a number of factors (biological, social, etc.). Terrorists and psychotics have nevertheless something in common: the deprivation of the self. A loss of being that--I argue--is at the origin of the ordinariness of terrorists and the experience of void in psychotics. Two symptoms that reveal the condition of an intimate dryness, from a phenomenological and a metaphysical point of view as a consequence of a distorted relation with the world of life. I shall discuss how ordinariness is strictly related with the blurring definition of terrorism. PMID- 20718262 TI - Hospitalization for anorexia nervosa in Italy. AB - OBJECTIVE: This study provides: a) rates of hospitalization for anorexia nervosa (AN) in Italy in 2004-2005 period; b) an estimate of the incidence of moderate to severe hospitalized AN in the same period among persons aged 10-19 years. METHOD: 9863 hospital discharges of patients aged 10-59 years with a diagnosis of AN (ICD9CM code 307.1) were extrapolated from the Italian Hospital Discharges Database. Patients aged 10-19 years, first admitted in 2004-2005, never hospitalized for AN in 2001-2003, were assumed to be a reasonable proxy of incident cases. RESULTS: Crude rate of AN associated hospitalization was 24.2 per 100,000 person-years among women and 1.6 per 100,000 person-years among men. Estimated incidence rate of AN was 22.8 per 100,000 among women compared with 2.0 per 100,000 among men in the 10-19 years age group. DISCUSSION: This study provides, for the first time, nationwide incidence estimates of AN in Italy. PMID- 20718263 TI - [Assessment of simulation and dissimulation in the MMPI-2 test profiles]. AB - The aim of this study is to identify the criteria which would allow a differentiation between the Minnesota Multiphasic Personality Inventory-2 (MMPI 2) profiles, obtained from patients who present with problems of minimization of attitude (dissembling) who have shown a minimization of their problems; from patients who answered in a spontaneous and genuine fashion. METHODS: Six hundred and fifty five MMPI profiles of outpatients of the Clinical Psychology Unit, University Hospital, Sapienza University of Rome. Patients were subdivided into two groups, based on the reason for attending: those who submitted voluntarily to a psychodiagnostic assessment and those who were assessed by request of an outside authority, e.g., in the case of those whose driving license was suspended. It has hypothesized that the latter group would not present with problems which would preclude obtaining the benefits required. The variables analyzed were the clinical scale and the validity scale MMPI-2, index F-K and the Ds scale of Gough. On the basis of the values of the F-K index and Ds scale, the patients were reclassified into three simulation categories: spontaneous registration; defended and doubtful's. RESULTS: All indexes, validity scales and clinical scales of the standard profile were found to have significant differences between the "dissimulation" and "normal" groups. Sensibility and specificity of profile classification was according to both indexes 76%. CONCLUSIONS: Current evidence indicates that simulation of pathology is identifiable in MMPI-2 profiles. Our data demonstrate that it is possible to identify case of defensive minimization. These results confirm the hypothesis that simulation is a dimensional characteristic of MMPI which can reach extreme values in both ways: worsening of slight problems or suppression of existing problems. PMID- 20718264 TI - [Evaluations for informed consent for various long-term psychiatric treatments]. AB - OBJECTIVES: The study was created with two distinct objectives: the first, an investigation into the quality of informed consent in patients assited by the mental health department for the Region of Puglia. The second, to look at the possibility of implementing a systematic use of tested monitoring of the daily practices of the psychiatric services. METHODS: The use of the structured MacCAT T (modified) interview was implemented. The interview was carried out on 708 patients across all areas of the mental health deparment for the Region of Puglia: 77 SPDC patients, 336 outpatients and 295 patients residing in rehabilitation centres. RESULTS: 31.2% of patients voluntarily hospitalised in SPDC did not know the motivations for their hospitalisation. 46.1% of patients in rehabilitation centres were also unaware of the reasons for their stay. Further problems arose in data regarding the prognosis of the disorders: 62.3% of SPDC patients, 65% of patients in rehabilitation centres and 39% of outpatients coud not describe the prognosis of their disorder. DISCUSSION: As a result of the study, the authors therefore propose: consensus monitoring through a standardised method providing targets for service improvement. The monitoring however, must be made integral in the daily activities of clinical observation. Applying the practice of consent evaluation would provide adequate support in requiring then suitable methods of legal protection, such as administrative support, which could then aid in creating correct legal continuity in treatment. PMID- 20718265 TI - [Psychosomatic approach to patients with headache: alternative or integrated diagnoses?]. AB - Each person has an inseparable body-mind unity, with psychic factors that can also manifest themselves through changes in the functions of the body, and with changing somatic states that contribute to mental experience. This explains why somatic symptoms fall within psychiatry. When a patient complains about physical symptoms, it is essentially an integrated, multidisciplinary diagnosis which is used to identify the various factors (biological and psychological) which worsen the disorder, and a psychiatric dimensional approach is used to integrate the descriptive symptomatic diagnosis with the psychostructural diagnosis. The same symptoms, in fact, may underlie different psychological dynamics that direct the treatment and determine the prognosis, as explained in three clinical cases that we described. The literature on headaches reports a high rate of co-morbidity between migraines and psychiatric disorders, but doesn't take into account the fact that often the symptom of headache is part of the disorder, even when it presents on its own. In conclusion, a holistic approach is needed for the patient to be diagnosed as having a "psychiatric" form of headache. A medical examination of the illness leading to a diagnoses is essential, according to the criteria of the International Classification of Headache Disease (ICHD-II). In clinical practice, we have integrated the descriptive diagnosis (ICHD-II mini-Plus) with the psychological (Diagnostic Criteria of Psychosomatic Research - DCPR) and psycho-structural (Kenberg's interview, Minnesota Multiphasic Personality Inventory - MMPI) diagnoses. The clarification of the dynamics underlying the definition of symptoms and the role played by psychological factors has influenced the identification of therapeutic objectives and in the identification of the most appropriate strategies. PMID- 20718266 TI - The role of registration in accurate surgical guidance. AB - Registration is presented as the central issue of surgical guidance. The focus is on the accuracy of approaches employed today, all of which use pre-operative images to guide surgery on rigid anatomy. The three most well-established approaches to guidance, namely the stereotactic frame, point fiducials, and surface matching, are examined in detail, together with two new approaches based on microstereotactic frames. It is shown that each method relies on the registration of points in the image to corresponding points in the operating room, and therefore that the error patterns associated with point registration are similar for all of them. Three types of registration error, namely fiducial localization error (FLE), fiducial registration error (FRE), and target registration error (TRE), are highlighted, as well as two additional guidance errors, namely target localization error and total targeting error, the latter of which is the overall error of the guidance system. Statistical relationships between TRE and FLE, between FRE and FLE, and between TRE, TLE, and TTE are given. Finally some myths concerning fiducial registration are highlighted. PMID- 20718267 TI - Active constraint control for image-guided robotic surgery. AB - The concept of active constraint control for image-guided robotic surgery is introduced, together with its benefits and a short outline of its history. The clinical use of active constraint control in orthopaedic surgery is discussed, together with the outcomes of a clinical trial for unicondylar knee replacement surgery. The evolution of the robotic design from large costly structures towards simpler, more cost-effective systems is also presented, leading to the design of the Acrobot 'Sculptor' system. A new approach to the achievement of robotic total knee replacement is also presented, in which a high-speed rotary cutter is used to slice through the bone to achieve a speedy resection. The control concept is presented, together with the results of trials on animal bones and a cadaver, showing that it is possible to remove large quantities of bone both quickly and accurately. PMID- 20718268 TI - Percutaneous inner-ear access via an image-guided industrial robot system. AB - Image-guided robots have been widely used for bone shaping and percutaneous access to interventional sites. However, due to high-accuracy requirements and proximity to sensitive nerves and brain tissues, the adoption of robots in inner ear surgery has been slower. In this paper the authors present their recent work towards developing two image-guided industrial robot systems for accessing challenging inner-ear targets. Features of the systems include optical tracking of the robot base and tool relative to the patient and Kalman filter-based data fusion of redundant sensory information (from encoders and optical tracking systems) for enhanced patient safety. The approach enables control of differential robot positions rather than absolute positions, permitting simplified calibration procedures and reducing the reliance of the system on robot calibration in order to ensure overall accuracy. Lastly, the authors present the results of two phantom validation experiments simulating the use of image-guided robots in inner-ear surgeries such as cochlear implantation and petrous apex access. PMID- 20718269 TI - A review of medical robotics for minimally invasive soft tissue surgery. AB - This paper provides an overview of recent trends and developments in medical robotics for minimally invasive soft tissue surgery, with a view to highlight some of the issues posed and solutions proposed in the literature. The paper includes a thorough review of the literature, which focuses on soft tissue surgical robots developed and published in the last five years (between 2004 and 2008) in indexed journals and conference proceedings. Only surgical systems were considered; imaging and diagnostic devices were excluded from the review. The systems included in this paper are classified according to the following surgical specialties: neurosurgery; eye surgery and ear, nose, and throat (ENT); general, thoracic, and cardiac surgery; gastrointestinal and colorectal surgery; and urologic surgery. The systems are also cross-classified according to their engineering design and robotics technology, which is included in tabular form at the end of the paper. The review concludes with an overview of the field, along with some statistical considerations about the size, geographical spread, and impact of medical robotics for soft tissue surgery today. PMID- 20718270 TI - Trackerless ultrasound-integrated bone cement detection using a modular minirobot in revision total hip replacement. AB - Medical robots are superior to freehand manipulation if an accurate, precise, and time-efficient implementation of a preplanned intervention is required. In the first part of this contribution a new modular minirobot for automatic ultrasound based bone cement detection followed by subsequent cement milling in revision total hip replacement is presented. A minirobot integrated ultrasound module eliminates the need for external position tracking (e.g. by an optical system) as well as patient registration since the scanned contours can be directly provided within the robot's coordinate system. Further, the modular minirobot concept allows kinematics, workspace, and mechanical parameters to be easily adapted to the requirements of related or even new surgical applications. In the experimental part, the impact of ultrasound module integration on the implementation of optimized scanning strategies is investigated and evaluated in a laboratory set-up. As wave mode conversion and refraction artefacts due to angular sound incidence influence the detection accuracy, the transducer alignment can be optimized with respect to the number of degrees of freedom (DOFs) provided by the minirobot. A model-based scanning approach using two degrees of freedom (2DOFs), three degrees of freedom (3DOFs), and four degrees of freedom (4DOFs) respectively is presented. For automated scanning path calculation, a 2DOF distal-proximal prescan has been performed to estimate the principal components of the cement cavity's geometry using either a model-based or a statistical approach. In a cadaver study, the model-based approach consistently outperformed the statistical approach. The 3DOFs and 4DOFs scanning strategies yielded a significantly higher scanning accuracy if compared with the 2DOFs approach whereas the 3DOFs approach represents a trade-off between system complexity and detection accuracy. PMID- 20718271 TI - The Pathfinder image-guided surgical robot. AB - This paper first describes the workflow of the Pathfinder image-guided surgical robot that has been designed to replace the stereotactic frame in neurosurgery, and then details the calibration stages employed in order to achieve submillimetre positioning accuracy of a tool tip. The process uses non-linear parameter identification techniques in conjunction with some procedures for camera calibration, which exploit the fact that the camera is mounted to a calibrated robot arm that executes precise motions. PMID- 20718272 TI - Robotic and artificial intelligence for keyhole neurosurgery: the ROBOCAST project, a multi-modal autonomous path planner. AB - The robot and sensors integration for computer-assisted surgery and therapy (ROBOCAST) project (FP7-ICT-2007-215190) is co-funded by the European Union within the Seventh Framework Programme in the field of information and communication technologies. The ROBOCAST project focuses on robot- and artificial intelligence-assisted keyhole neurosurgery (tumour biopsy and local drug delivery along straight or turning paths). The goal of this project is to assist surgeons with a robotic system controlled by an intelligent high-level controller (HLC) able to gather and integrate information from the surgeon, from diagnostic images, and from an array of on-field sensors. The HLC integrates pre-operative and intra-operative diagnostics data and measurements, intelligence augmentation, multiple-robot dexterity, and multiple sensory inputs in a closed-loop cooperating scheme including a smart interface for improved haptic immersion and integration. This paper, after the overall architecture description, focuses on the intelligent trajectory planner based on risk estimation and human criticism. The current status of development is reported, and first tests on the planner are shown by using a real image stack and risk descriptor phantom. The advantages of using a fuzzy risk description are given by the possibility of upgrading the knowledge on-field without the intervention of a knowledge engineer. PMID- 20718273 TI - Pure science with a practical aim: the meanings of fundamental research in Britain, circa 1916-1950. AB - Historians tell us that the term "fundamental research" entered the discourse of science in the interwar period as a synonym for "pure science" and that both terms referred to work concerned with the search for knowledge, without thought of application. The aim of this paper is to show that when the expression "fundamental research" was used in Britain during and after World War I, it had a particular status that was not equivalent to pure science. In the annual reports of the Department of Scientific and Industrial Research (DSIR) "fundamental research" was endowed with multiple meanings, including work that was orientated towards some practical goal. The fluidity of the meaning of "fundamental research" in the reports of the DSIR can be understood as a strategy; "fundamental research" was a rhetorical term that served to persuade more than one audience of the legitimacy of the DSIR and its policies. PMID- 20718274 TI - An alarming solution: Bedwetting, medicine, and behavioral conditioning in mid twentieth-century America. AB - This article explores the history of the bedwetting alarm, invented in 1938 by two psychologists to cure enuresis, or bedwetting, using the principles of classical conditioning. Infused with the optimism of behaviorism, the bedwetting alarm unexpectedly proved difficult to implement in practice, bearing a multitude of unanticipated complications that hindered its widespread acceptance. Introduced as a medical and psychological technology, in practice the alarm was also a child-rearing device, encouraging the kind of behavioristic attitudes that had prompted its initial development, while simultaneously promoting the child centered approach that would become dominant in the early 1950s. The life story of the bedwetting alarm muddies the traditional account of how childrearing theories progressed in tidy succession, suggesting both that behavioristic approaches did not die out in the 1930s and that elements of permissive child rearing were being considered earlier than we traditionally assume. PMID- 20718275 TI - Fabricating authenticity: modeling a whale at the American Museum of Natural History, 1906-1974. AB - Historians of science have in recent years become increasingly attentive to the ways in which issues of process, matter, meaning, and value combine in the fabrication of scientific objects. This essay examines the techniques that went into the construction--and authentication--of one such scientific object: a model of a blue, or "sulfur-bottom," whale manufactured at the American Museum of Natural History in 1907. In producing their model, exhibitors at the American Museum employed a patchwork of overlapping discursive, procedural, and material techniques to argue that their fabrication was as authentic--as truthful, accurate, authoritative, and morally and aesthetically worthy of display--as an exhibit containing a real, preserved cetacean. Through an examination of the archival and published traces left by these exhibitors as they built their whale, I argue that the scientific meanings of authenticity at the American Museum were neither static nor timeless, but rather were subject to constant negotiation, examination, re-evaluation, and upkeep. PMID- 20718276 TI - Focus: new perspectives on science and the Cold War. Introduction. AB - Twenty years after the fall of the Berlin Wall, the Cold War looks ever more like a slice of history rather than a contemporary reality. During those same twenty years, scholarship on science, technology, and the state during the Cold War era has expanded dramatically. Building on major studies of physics in the American context--often couched in terms of "big science"--recent work has broached scientific efforts in other domains as well, scrutinizing Cold War scholarship in increasingly international and comparative frameworks. The essays in this Focus section take stock of current thinking about science and the Cold War, revisiting the question of how best to understand tangled (and sometimes surprising) relationships between government patronage and the world of ideas. PMID- 20718277 TI - Transnational science during the Cold War: the case of Chinese/American scientists. AB - This essay examines the experiences of about five thousand Chinese students/scientists in the United States after the Communist takeover of mainland China in 1949. These experiences illustrate the often hidden transnational movements of people, instruments, and ideas in science and technology across the Iron Curtain during the Cold War. I argue that those hundreds who returned to China represented a partial "Americanization" of Chinese science and technology, while the rest of the group staying in the United States contributed to a transnationalization of the American scientific community. PMID- 20718278 TI - Technophilic hubris and espionage styles during the Cold War. AB - During the Cold War the United States developed an espionage style that reflected its love affair with technology (technophilia) whereas the Soviet Union and the East Bloc continued a tradition of using humans to collect intelligence. This essay places the origins and development of these espionage styles during the Cold War in historical and social context, and assesses their strengths and weaknesses by drawing on examples from particular cases. While the United States won the Cold War, the East Bloc won the spy wars because of a more effective espionage style. I conclude with some reflections on the uses of history for future policy, and suggest areas for further study. PMID- 20718279 TI - Mathematical models, rational choice, and the search for Cold War culture. AB - A key feature of the social, behavioral, and biological sciences after World War II has been the widespread adoption of new mathematical techniques drawn from cybernetics, information theory, and theories of rational choice. Historians of science have typically sought to explain this adoption either by reference to military patronage, or to a characteristic Cold War culture or discursive framework strongly shaped by the concerns of national security. This essay explores several episodes in the history of game theory--a mathematical theory of rational choice--that demonstrate the limits of such explanations. Military funding was indeed critical to game theory's early development in the 1940s. However, the theory's subsequent spread across disciplines ranging from political science to evolutionary biology was the result of a diverse collection of debates about the nature of "rationality" and "choice" that marked the Cold War era. These debates are not easily reduced to the national security imperatives that have been the focus of much historiography to date. PMID- 20718280 TI - Social science in the Cold War. AB - This essay examines ways in which American social science in the late twentieth century was--and was not--a creature of the Cold War. It identifies important work by historians that calls into question the assumption that all social science during the Cold War amounts to "Cold War social science." These historians attribute significant agency to social scientists, showing how they were enmeshed in both long-running disciplinary discussions and new institutional environments. Key trends in this scholarship include a broadening historical perspective to see social scientists in the Cold War as responding to the ideas of their scholarly predecessors; identifying the institutional legacies of World War II; and examining in close detail the products of extramural--especially governmental--funding. The result is a view of social science in the Cold War in which national security concerns are relevant, but with varied and often unexpected impacts on intellectual life. PMID- 20718281 TI - "Hypothetical machines": the science fiction dreams of Cold War social science. AB - The introspectometer was a "hypothetical machine" Robert K. Merton introduced in the course of a 1956 how-to manual describing an actual research technique, the focused interview. This technique, in turn, formed the basis of wartime morale research and consumer behavior studies as well as perhaps the most ubiquitous social science tool, the focus group. This essay explores a new perspective on Cold War social science made possible by comparing two kinds of apparatuses: one real, the other imaginary. Even as Merton explored the nightmare potential of such machines, he suggested that the clear aim of social science was to build them or their functional equivalent: recording machines to access a person's experiential stream of reality, with the ability to turn this stream into real time data. In this way, the introspectometer marks and symbolizes a broader entry during the Cold War of science-fiction-style aspirations into methodological prescriptions and procedural manuals. This essay considers the growth of the genre of methodological visions and revisions, painstakingly argued and absorbed, but punctuated by sci-fi aims to transform "the human" and build newly penetrating machines. It also considers the place of the nearly real-, and the artificial "near-substitute" as part of an experimental urge that animated these sciences. PMID- 20718282 TI - Health, peace and conflict: roles for health professionals. PMID- 20718283 TI - Cluster munitions: a threat to health and human rights. AB - Over the course of 2009, dozens of nations signed a new convention on cluster munitions, and several nations ratified the convention. To determine how public health professionals can participate in preventing death and injury from cluster munitions, we review the history of these weapons, their effects on individuals and communities, the history of efforts to limit their use, the Convention on Cluster Munitions, and ways that health professionals can support efforts to ban their use. Cluster munitions are a threat to civilians in conflict and post conflict settings. They render homes, farms and businesses dangerous and inaccessible, and delay resettlement after the end of a conflict. Health professionals have led efforts to limit the use and proliferation of other weapons, and global collaboration to support the Convention on Cluster Munitions would be a step towards protecting the public's health. PMID- 20718284 TI - Demystifying the Maoist barefoot doctors of Nepal. AB - Though not purposefully targeted, Nepal's decade-long violent conflict waged by the United Communist Party Nepal-Maoist (UCPN-M) has had considerable impact on the health of the population. Fairly early on the UCPN-M established its own primary health care services in the rural areas under its control. This questionnaire study included 197 Maoist health workers recruited from a wide range of backgrounds in terms of age, experience, gender, caste and ethnicity, and schooling. Many appear to be young paramedics with few skills, who received a short training during the decade long conflict. For two-thirds of them political ideology was a key motivating factor for joining, and for unemployed youths this proportion was significantly higher. Nine out of 10 considered themselves as 'qualified' to work as support level health workers in the future. Regression analysis shows that a significantly higher proportion of women and those with previous academic and basic type of training were willing to integrate/rehabilitate into the mainstream health sector since the conflict ended in 2006. It is important to capitalize upon this opportunity to redevelop the health services, especially in rural areas in Nepal, and to contribute to the peace process. PMID- 20718285 TI - From Goya to Afghanistan--an essay on the ratio and ethics of medical war pictures. AB - For centuries pictures of the dead and wounded have been part and parcel of war communications. Often the intentions were clear, ranging from medical instructions to anti-war protests. The public's response could coincide with or diverge from the publisher's intention. Following the invention of photography in the nineteenth century, and the subsequent claim of realism, the veracity of medical war images became more complex. Analysing and understanding such photographs have become an ethical obligation with democratic implications. We performed a multidisciplinary analysis of War Surgery (2008), a book containing harsh, full-colour photographs of mutilated soldiers from the Iraq and Afghanistan wars. Our analysis shows that, within the medical context, this book is a major step forward in medical war communication and documentation. In the military context the book can be conceived as an attempt to put matters right given the enormous sacrifice some individuals have suffered. For the public, the relationship between the 'reality' and 'truth' of such photographs is ambiguous, because only looking at the photographs without reading the medical context is limiting. If the observer is not familiar with medical practice, it is difficult for him to fully assess, signify and acknowledge the value and relevance of this book. We therefore assert the importance of the role of professionals and those in the humanities in particular in educating the public and initiating debate. PMID- 20718286 TI - Healing Africa? Reflections on the peace-building role of a health-based non governmental organization operating in eastern Democratic Republic of Congo. AB - Whilst there are convincing theoretical arguments about the peace-building potential of the health sector, case studies documenting its interventions remain limited. This article contributes to the existing 'Peace through Health' literature by considering the model of HEAL Africa, a health-based non governmental organization operating in Eastern Congo. Several of HEAL Africa's projects seek to prevent and reduce key risk factors; for conflict, and to contribute to longer term rehabilitation. Many of these interventions are born out of HEAL's emphasis on providing emergency health care--and the neutrality, legitimacy, access and longevity which this generates. However, this focus also tends to act as a limiting factor on the application and resourcing of its conflict prevention and reconstruction efforts. Whilst this case study warns against overstating the potential role of the health sector in promoting peace, HEAL's activities provide evidence of the types of positive contributions that can be made in practice. The role of the health sector, equipped as it is with useful tools for conflict transformation, should therefore be considered more proactively by the peace-building community. PMID- 20718287 TI - Feelings of betrayal by the United Nations High Commissioner for Refugees and emotionally distressed Sudanese refugees in Cairo. AB - Thousands of Sudanese refugees have fled to Cairo, Egypt in the wake of Sudanese civil conflicts. Sudanese refugees were evaluated with respect to symptoms of depression, post-traumatic stress disorder (PTSD) and social stress. Four respondents (22%) indicated that their interactions with the United Nations High Commissioner for Refugees (UNHCR) in Cairo, Egypt were the worst experiences since war-related atrocities. Fourteen participants (63.6%) felt 'extremely' betrayed by the UNHCR on a four point scale. Greater feelings of betrayal by the UNHCR were associated with greater avoidance and arousal symptoms of PTSD, symptoms of depression and trait anger. This is the first study of which we are aware that examines the relationship between sense of betrayal by the UNHCR and symptoms of PTSD, depression and anger among asylum seekers. PMID- 20718288 TI - Purification and characterization of a solvent-stable protease from Geomicrobium sp. EMB2. AB - A moderately haloalkaliphilic bacterium, Geomicrobium sp. EMB2, was isolated from the Sambhar Salt Lake located in the western part of India. It secreted an alkaline protease, which was stable and active in the presence of a wide range of organic solvents. The protease was purified by hydrophobic interaction chromatography on Phenyl Sepharose 6 Fast Flow matrix, and a 22.6-fold purification with 51.2% recovery was attained. The apparent molecular mass was estimated to be 38 kDa. The enzyme was stable in the pH range 6.0-12.0, the optimum being 10.0. The Km and Vmax towards casein were found to be 0.10 mM and 526 U/min, respectively. The protease was most active at 50 degrees C. It appeared to be serine type, owing to its sensitivity to phenylmethylsulphonyl fluoride (PMSF). It withstood a range of detergents and surfactants, and exhibited remarkable stability in the presence of solvents having a log P >2. The presence of NaCl or osmolytes exerted a protective effect and further enhanced the stability of the enzyme. These properties make this novel protease potentially useful for catalysis in non-aqueous medium. PMID- 20718289 TI - Purification and characterization of a novel extracellular protease from a halo alkaliphilic Bacillus sp. 17N-1, active in polar organic solvents. AB - A novel enzyme of molecular mass about 29 kDa was purified from the strain halo alkaliphilic Bacillus sp. 17N-1 and designated protease-B-17N-1. This enzyme is likely to be a cysteine protease; it was found active in media containing EDTAK2 and dithiothreitol, it maintained considerable activity at temperatures 14 degrees C to 33 degrees C and pH 6.50 to 8.50 with optimum k(cat)/Km and/or k(cat) values at pH 7.00 and 25 degrees C. The activity of protease-B-17N-1 was strongly affected by the specific irreversible inhibitor of cysteine proteases E 64, while it remained unaffected by the 3,4-dichloro-isocoumarine, an irreversible inhibitor specific for serine proteases. Protease-B-17N-1 retained full activity at 25 degrees C after 30 min incubation at 8 degrees C or at 33 degrees C; moreover, it was found to be stable and active in the polar organic solvents DMSO and acetonitrile. The enzyme hydrolyzed the substrate Cbz-FR-pNA via Michaelis-Menten kinetics, while it showed insignificant activity for the substrate Suc-AAA-pNA. Valuable pK(a)s, rate constants, activation energies and other important features were estimated from the profiles of parameters k(cat)/Km, k(cat) and Km, versus pH, temperature, and [NaCl]. In addition, interesting results were obtained from the effect of different metallic ions and polar organic solvents on the Michaelis-Menten parameters of protease-B-17N-1, showing that it performs catalysis via a (Cys)-S(-)/(His)-Im(+)H ion-pair, as well as its industrial and biotechnological potential, respectively. PMID- 20718290 TI - Molecular characterization of the glucose isomerase from the thermophilic bacterium Fervidobacterium gondwanense. AB - The gene coding for xylose isomerase from the thermophilic bacterium Fervidobacterium gondwanense was cloned and overexpressed in Escherichia coli. The produced xylose isomerase (XylA), which closely resembles counterparts from Thermotoga maritima and T. neapolitana, was purified and characterized. It is optimally active at 70 degrees C, pH 7.3, with a specific activity of 15.0 U/mg for the interconversion of glucose to fructose. When compared with T. maritima XylA at 85 degrees C, a higher catalytic efficiency was observed. Divalent metal ions Co2+ and Mg2+ were found to enhance the thermostability. PMID- 20718291 TI - A lipase with broad temperature range from an alkaliphilic gamma-proteobacterium isolated in Greenland. AB - A gamma-proteobacterium related to the genera Alteromonadales and Pseudomonadales, isolated from a cold and alkaline environment in Greenland, has been shown to produce a lipase active between 5 degrees C and 80 degrees C, with optimal activity at 55 degrees C and pH 8. PCR-based screening of genomic DNA from the isolated bacterium, followed by genome walking, resulted in two complete open reading frames, which were predicted to encode a lipase and its helper protein, a lipase foldase. The amino acid sequence derived for the lipase showed resemblance to lipases from Pseudomonas, Rhodoferax, Aeromonas and Vibrio. The two genes were cloned into different expression systems in E. coli with or without a putative secretion sequence, but despite the fact that both recombinant lipase and lipase foldase were observed on SDS-PAGE, no recombinant lipase activity was detected. Attempts to refold the recombinant lipase in vitro using a purified lipase foldase remained unsuccessful. PMID- 20718292 TI - Enzymatic reactions and synthesis of n-butyl caproate: esterification, transesterification and aminolysis using a recombinant lipase from Geobacillus thermoleovorans CCR11. AB - The recombinant lipase LipMatCCR11 from the thermophilic strain Geobacillus thermoleovorans CCR11 was applied in the synthesis of n-butyl caproate via transesterification in hexane and xylene. The short chain flavour ester was obtained by alcoholysis from ethyl caproate and n-butyl alcohol and acidolysis from n-butyl butyrate and caproic acid. This enzyme was also used in the condensation reaction from caproic acid and n-butanol. The conversion percentages at equilibrium (Xe) were similar to those obtained with Candida antarctica lipase fraction B (CAL-B) in the same reaction conditions, while lower conversion velocities (k) were attained. LipMatCCR11 reached high conversion percentages in either hexane or xylene as organic media (> 63%); the enzyme was also able to catalyze the aminolysis reaction of ethyl caproate with benzyl amine in hexane obtaining a conversion percentage > 62%. PMID- 20718293 TI - Identification, cloning and expression of a cold-active beta-galactosidase from a novel Arctic bacterium, Alkalilactibacillus ikkense. AB - A novel, cold-active beta-galactosidase was isolated from an Arctic Gram-positive bacterium, Alkalilactibacillus ikkense. The corresponding gene was cloned and expressed as an active enzyme in Escherichia coli. Denaturing gel electrophoresis of both the native and the recombinant beta-galactosidase showed a monomeric molecular weight of 115-120 kDa. Analysis of the DNA sequence showed sequence similarity to known Glycosyl Hydrolase Family 2 beta-galactosidases from the genera Bacillus, Paenibacillus, Geobacillus, and Lactobacillus. The beta galactosidase from this study was purified and shown to be highly active at low temperatures with more than 60% of its maximal activity maintained at 0 degrees C. The apparent optimal activity was observed at temperatures between 20 degrees C and 30 degrees C and at pH 8. The purified recombinant enzyme was stable without stabilizing agents for more than 100 hours at temperatures at and below 10 degrees C. At temperatures 40 degrees C and above, the beta-galactosidase was irreversibly inactivated within 10 minutes. When lactose was present in substantial amounts, the enzyme displayed transgalactosylation activity. Comparison of the beta-galactosidase with a commercially available enzyme showed that the conversion rate of the A. ikkense enzyme was approximately two-fold higher at temperatures between 0 degrees C and 20 degrees C. PMID- 20718294 TI - Hyperthermophilic phosphotriesterases/lactonases for the environment and human health. AB - In the last decades the idea to use enzymes for environmental bioremediation has been more and more proposed and, in the light of this, new solutions have been suggested and detailed studies on some classes of enzymes have been performed. In particular, our attention in the last few years has been focused on the enzymes belonging to the amidohydrolase superfamily. Several members of this superfamily are endowed with promiscuous activities. The term 'catalytic promiscuity' describes the capability of an enzyme to catalyse different chemical reactions, called secondary activities, at the active site responsible for the main activity. Recently, a new family of microbial lactonases with promiscuous phosphotriesterase activity, dubbed PTE-Like Lactonase (PLL), has been ascribed to the amidohydrolase superfamily. Among members of this family are enzymes found in the archaea Sulfolobus solfataricus and Sulfolobus acidocaldarius, which show high thermophilicity and thermal resistance. Enzymes showing phosphotriesterase activity are attractive from a biotechnological point of view because they are capable of hydrolysing the organophosphate phosphotriesters (OPs), a class of synthetic compounds employed worldwide both as insecticides and chemical warfare agents. Furthermore, from a basic point of view, studies of catalytic promiscuity offer clues to understand natural evolution of enzymes and to translate this into in vitro adaptation of enzymes to specific human needs. Thermostable enzymes able to hydrolyse OPs are considered good candidates for the set-up of efficient detoxification tools. PMID- 20718295 TI - Extremolyte-like applicability of an archaeal exopolymer, poly-gamma-L-glutamate. AB - An extremely halophilic archaeon Natrialba aegyptiaca produces extracellular poly gamma-glutamate (PGA), in which only L-glutamate is polymerized via gamma-amide linkages. We examined the extremolyte-like applicability of archaeal PGA and found the ameliorating effects of L-PGA on the resistibility to freeze-thawing and proteolysis, thermostability, and alkalotolerance of a model enzyme, labile DNA ligase. For example, the coexistence of low (e.g. 0.01 mg mL(-1)) and high (e.g. 0.1 mg mL(-1)) concentrations of L-PGA with an average molecular mass of 1000 kDa increased the midpoint of thermal inactivation of DNA ligase by about 15 degrees C and 18 degrees C, respectively, and the model enzyme further remained active even under extremely alkaline conditions of pH 11.4 in the presence of the high concentration of L-PGA. This is the first characterization of the stereo regular PGA molecules as atypical extremolytes. L-PGA from extremophiles has great potential as a bio-based protectant (or stabilizer) with industrial versatility. PMID- 20718296 TI - Metagenomics and recovery of enzyme genes from alkaline saline environments. AB - Enzymes functioning at alkaline pH are widely used in the detergent industry as additives to improve the stain removal properties of domestic and industrial cleaning products. This industry provides by far the major mass market for enzymes. With constantly changing formulations in detergents and concerns over energy demands, new and improved enzymes are constantly in demand. Soda lakes host dense populations of alkali-loving microbes and, as such, provide vast reservoirs of potentially useful enzymes for such an industry. Traditional recovery methods for new enzymes have involved the isolation of microbes, preferably from a compatible chemical environment such as a soda lake, followed by screening of the isolates for useful enzymic activity. At least two commercially significant enzymes originating from soda lake microbes have been marketed following this route. However, the failure to cultivate more than a small percentage of microbes from most environments necessarily markedly reduces the recovery of new enzymes. In recent years, interest has focussed on more comprehensive recovery methods based around detecting appropriate enzyme genes in nucleic acids extracted from potentially useful sites, thus maximizing coverage of the whole genetic resource in a particular biotope. Here we review progress to date in soda lake biotopes and discuss ways the field may develop in the future. PMID- 20718297 TI - Exopolysaccharides from extremophiles: from fundamentals to biotechnology. AB - Exopolysaccharides (EPSs) make up a substantial component of the extracellular polymers surrounding most microbial cells in extreme environments like Antarctic ecosystems, saline lakes, geothermal springs or deep sea hydrothermal vents. The extremophiles have developed various adaptations, enabling them to compensate for the deleterious effects of extreme conditions, e.g. high temperatures, salt, low pH or temperature, high radiation. Among these adaptation strategies, EPS biosynthesis is one of the most common protective mechanisms. The unusual metabolic pathways revealed in some extremophiles raised interest in extremophilic microorganisms as potential producers of EPSs with novel and unusual characteristics and functional activities under extreme conditions. Even though the accumulated knowledge on the structural and theological properties of EPSs from extremophiles is still very limited, it reveals a variety in properties, which may not be found in more traditional polymers. Both extremophilic microorganisms and their EPSs suggest several biotechnological advantages, like short fermentation processes for thermophiles and easily formed and stable emulsions of EPSs from psychrophiles. Unlike mesophilic producers of EPSs, many of them being pathogenic, extremophilic microorganisms provide non pathogenic products, appropriate for applications in the food, pharmaceutical and cosmetics industries as emulsifiers, stabilizers, gel agents, coagulants, thickeners and suspending agents. The commercial value of EPSs synthesized by microorganisms from extreme habitats has been established recently. PMID- 20718298 TI - Thermophilic enzymes and their applications in biocatalysis: a robust aldo-keto reductase. AB - Extremophiles are providing a good source of novel robust enzymes for use in biocatalysis for the synthesis of new drugs. This is particularly true for the enzymes from thermophilic organisms which are more robust than their mesophilic counterparts to the conditions required for industrial bio-processes. This paper describes a new aldo-keto reductase enzyme from a thermophilic eubacteria, Thermotoga maritima which can be used for the production of primary alcohols. The enzyme has been cloned and over-expressed in Escherichia coli and has been purified and subjected to full biochemical characterization. The aldo-keto reductase can be used for production of primary alcohols using substrates including benzaldehyde, 1,2,3,6-tetrahydrobenzaldehyde and para-anisaldehyde. It is stable up to 80 degrees C, retaining over 60% activity for 5 hours at this temperature. The enzyme at pH 6.5 showed a preference for the forward, carbonyl reduction. The enzyme showed moderate stability with organic solvents, and retained 70% activity in 20% (v/v) isopropanol or DMSO. These properties are favourable for its potential industrial applications. PMID- 20718300 TI - Mental health services within a comprehensive community care program help the frail elderly. PMID- 20718301 TI - Hope and humanity amongst devastation and chaos. PMID- 20718299 TI - The genus Thermotoga: recent developments. AB - The genus Thermotoga comprises extremely thermophilic (Topt > or = 70 degrees C) and hyperthermophilic (Topt > or = 80 degrees C) bacteria, which have been extensively studied for insights into the basis for life at elevated temperatures and for biotechnological opportunities (e.g. biohydrogen production, biocatalysis). Over the past decade, genome sequences have become available for a number of Thermotoga species, leading to functional genomics efforts to understand growth physiology as well as genomics-based identification and characterization of novel high-temperature biocatalysts. Discussed here are recent developments along these lines for this group of microorganisms. PMID- 20718302 TI - Shakespeare was on target--don't be a borrower or lender. PMID- 20718303 TI - Endorsement of Advanced Practice Nurses as independent practitioners. PMID- 20718304 TI - Pathway to nursing for urban core youth. AB - The issue of diversity in the workforce as one component of a nursing workforce shortage is a growing problem. Underrepresentation of minority nurses in clinical settings is also suspected to play a role in low patient satisfaction with health care. After holding a focus group of local high school students and their parents, a school of nursing located in an urban core developed an outreach program to help increase the enrollment of students from the urban core, and to help assure that they are prepared in every way to persist to graduation. This intervention program is described in this article. PMID- 20718305 TI - An introduction to oral health inequalities among Indigenous and non-Indigenous populations. AB - This overview revealed that substantial oral health inequalities exist between Indigenous and non-Indigenous child and adult populations in the United States, Canada, Brazil, Australia and New Zealand, with evidence suggesting that these inequalities are increasing. Despite the marked differences in geography, culture, language and history experienced by these groups, it is notable how similar the oral health inequalities were. A number of reasons are discussed in the paper. PMID- 20718306 TI - Promising directions for caries prevention with American Indian and Alaska Native children. AB - Profound and consequential disparities in oral health persist for American Indians and Alaska Natives. Decades of epidemiological studies have documented rates of early childhood caries (ECC) among American Indian children that are more than six times higher than those for white children, and three times higher than the rates for the general US population. While there is alarming need among this population, and there is clear evidence that dental caries can be prevented, successful programmes for prevention are rare. This report will review caries trends among American Indian children and describe promising approaches that take into account culturally defined responses of AI/AN tribes and communities. The work of the Center for Oral Health Disparities will be described, with its emphasis on community and behavioral strategies that have proven successful for working with AI/AN populations in areas of other health needs. PMID- 20718307 TI - An oral health intervention for the Maori indigenous population of New Zealand: oranga niho Maori (Maori oral health) as a component of the undergraduate dental curriculum in New Zealand. AB - Maori are the Indigenous people of New Zealand having migrated across the Pacific from Hawaiki over a 500 year period from 800AD to 1300AD establishing a society based on whanau (family), hapu (subtribe) and iwi (tribe). Today, like other Indigenous populations throughout the world, New Zealand Maori do not enjoy the same oral health status as non-Maori across all age groups. An intervention strategy to improve Maori oral health and to reduce disparities is to develop a dental health workforce that has an understanding of contemporary Maori society and Maori oral health. The Faculty of Dentistry (Te Kaupeka Puniho) of the University of Otago has a well developed undergraduate programme in Maori culture and Maori oral health. This programme has been reinforced by the adoption of a new Maori Strategic Framework (MSF) which has been designed to be "a vibrant contributor to Maori development and the realisation of Maori aspirations." Goal 5 of the MSF, Nga Whakahaerenga Pai (Quality Programmes) has the objective to develop and integrate Maori content in the undergraduate course. This paper will discuss the oranga niho Maori (Maori oral health) component of the undergraduate dental curriculum. PMID- 20718308 TI - Oral health interventions among Indigenous populations in Canada. AB - There has been a great deal of research describing the risk factors and determinants that impact on the health and well being of Aboriginal Canadians that has revealed tremendous oral health inequalities between these groups and their non-Aboriginal counterparts. Building on this research, culturally-based preventive interventions are now needed to address the significantly higher rates of oral disease among Aboriginals across Canada. Included in this article is an overview of oral health interventions targeted at First Nations, Inuit and Metis peoples in Canada, offering a glimpse of some of the innovative research initiatives originating from within Aboriginal communities that are being used to develop new health programmes and policies to improve the health and well being of this population. Particular emphasis is placed upon community-based and national initiatives to prevent dental caries in young Indigenous children that begin by improving the oral and general health of young women and mothers through pre-conception interventions. In addition, recently developed and implemented national First Nations- and Inuit-led oral health surveys are set to provide new evidence to inform future programmes and policy initiatives that will help to reduce dental disease burden and inequalities affecting Indigenous Canadians. PMID- 20718309 TI - Oral health in transition: the case of Indigenous peoples from Brazil. AB - The objective of this paper is to summarise epidemiological information about the distribution of dental caries among Indigenous peoples in Brazil. The authors also present a case study of a specific group of Xavante Indians, one of the most numerous of Brazil's Indigenous peoples, describing how their oral health has deteriorated over recent decades, and showing how an oral health programme is attempting to reverse the present trend of increase in caries. The programme at Etenheritipa Xavante village incorporated three principal components: educational, preventive, and clinical. From the beginning, the programme included epidemiological record keeping for monitoring the level of caries in the population. Transversal studies of the condition of oral health among the Xavante of Etenheritipa were undertaken in 1999, 2004, and 2007. In the period from 2004 to 2007 the DMFS values in the 11-15 age cohort had a significant reduction in caries experience. The mean DMFS score fell from 4.95 in 2004 to 2.39 in 2007 (p < 0.01). An increase in the percent of individuals who were free from caries was also noted: in 1999, 20% of adolescents 11-15 had no caries; in 2007, the proportion had risen to 47%. The Xavante case is a prime example of the transition in oral health that is taking place among the Indigenous peoples of the Americas, and it highlights the importance of oral health promotion through preventive measures such as access to fluoridation and basic care in reducing the inequality between Indians and non-Indians. PMID- 20718310 TI - A dental intervention with an Alaskan Native population: lessons learned. AB - This paper briefly describes a dental intervention within the Alaska Native population to reduce early childhood dental disease, the challenges faced in conducting the research, and the lessons learned. The American Indian/Alaska Native populations share a disproportionate burden of childhood dental disease compared to their majority counterparts. Despite the gains in oral health for the general population not all groups have equally benefited. Even recently, severe dental disease was found within > 60% of young Alaska Native children. There have been few intervention studies to reduce dental disease in Alaska Natives or their children. One study aimed at reducing dental disease in very young children via an intervention directed at the pregnant woman. Several challenges, anticipated and unanticipated, were faced in the development and conduct of the intervention. These challenges and the resulting lessons learned are presented here. PMID- 20718312 TI - The Strong Teeth Study; background, rationale and feasibility of fluoridating remote Indigenous communities. AB - The caries experience of Australian Indigenous children has deteriorated at the same time as that of non-Indigenous children has greatly improved. Fluoridating the water supplies of Indigenous communities emerged as a policy direction at the beginning of the 2000s. However, remote Indigenous communities are small, highly dispersed and isolated. This paper describes the Strong Teeth Study, a series of projects for the fluoridation of remote Indigenous communities in the Northern Territory. The background and rationale for two demonstration fluoridation projects are presented and the feasibility of operating small-scale fluoridation plant and measuring the impact on caries experience described. The demonstration fluoridation projects were commenced, but not sustained. The lessons learnt about environmental enablers and essential service requirements are highlighted. Fluoridation has the potential to improve oral health so as to contribute positively to child development as part of the broader mission of closing the gap in health between Indigenous and non-Indigenous Australians. PMID- 20718311 TI - A comprehensive approach to health promotion for the reduction of dental caries in remote Indigenous Australian children: a clustered randomised controlled trial. AB - AIM: To evaluate the effect of a community-oriented primary health care (CPHC) intervention on oral health behaviours of Indigenous preschool children living in remote communities of Australia's Northern Territory. METHODS: The study was a community-clustered randomised controlled trial over two years, set in 30 remote Indigenous communities in the Northern Territory of Australia. Children aged 18 47 months at baseline were enrolled in the study. The intervention included fluoride varnish applications, training of primary care workers, and health promotion for oral health at an individual, family and community level. Intervention communities received six-monthly visits over two years and control communities were visited at baseline and two years later with no contact in the intervening period. The outcome measures reported in this paper are the impact of the intervention on two secondary endpoints: oral health promotion activities in the community and personal oral health practice of children. RESULTS: The intervention did not produce any significant change in oral health behaviours, clinical measures of oral hygiene, or community programmes promoting oral health. Dental caries can be reduced but will continue to be a problem among young remote Indigenous children while they experience major social disadvantage. PMID- 20718313 TI - Choledocholithiasis: endotherapy versus surgery. AB - When multiple treatment options are available, debate invariably persists regarding the optimal option. Confusion and controversy must then be resolved based on scientific evidence, but one needs to be practical because options depend on the available expertise. We aimed to evaluate the efficacy of endotherapy vis-a-vis surgery in patients with choledocholithiasis. The records of 349 patients with stone disease from February 2005 to January 2010 were analyzed. A total of 349 patients were analyzed: 279 patients with gallstones alone, 56 with choledocholithiasis, 3 with stones with stricture, 5 with common bile duct (CBD) and pancreatic duct (PD) stones, and 6 with combined choledocholithiasis and hepatolithiasis. In the 56 patients with choledocholithiasis alone, preoperative endoscopic retrograde cholangio pancreatography (ERCP) and endotherapy were followed by cholecystectomy within 48 hours. Endotherapy was successful in 15 patients, whereas surgery was required in the remaining 41 patients. Surgery is an efficacious option and can be carried out safely with acceptable morbidity and no mortality, even in difficult situations. PMID- 20718314 TI - A study on the weights and ratios of hepatic segments in 438 adult Japanese autopsies. AB - This study presents relationships of the actual weights and their weight ratios of each hepatic segment. A total of 438 adult Japanese autopsies performed at the Tokyo Metropolitan Medical Examiner's Office were used. Examined cases consisted of 258 normal livers and 182 pathological livers. Weights of the whole liver, the right and left surgical hepatic lobes, and each hepatic segment, and the results of their statistical analyses, are reported by age and sex. The normal 256 liver weights were significantly different according to age (P < 0.001) and sex (P = 0.001). An approximate liver weight per kilogram of body weight is roughly about 25 g in all ages and both sexes. The weight ratios of the lateral, medial, anterior, and posterior segments were approximated to be 20:20:35:25, respectively, not only in normal and pathological livers in which the liver retained an ordinary shape but also in adult age groups and both sexes. PMID- 20718315 TI - Classification and comparison of niche services for developing strategy of medical tourism in Asian countries. AB - Medical tourism is a new trend in medical service. It is booming not only in Asian countries but also in European and South American countries. Worldwide competition of medical service is expected in the future, and niche service will be a "trademark" for the promotion of global medicine. Niche service also functions for market segmentation. Niche services are usually surgical procedures. A study was carried out to compare different strategies for developing medical tourism in Asian countries. The role of a niche service is evaluated in the initiation and further development of medical tourism for individual countries. From this study, a general classification was proposed in terms of treatment procedures. It can be used as a useful guideline for additional studies in medical tourism. Niche service plays the following roles in the development of medical tourism: (1) It attracts attention in the mass media and helps in subsequent promotion of business, (2) it exerts pressure on the hospital, which must improve the quality of health care provided in treating foreign patients, especially the niche services, and (3) it is a tool for setting up the business model. E-Da Hospital is an example for developing medical tourism in Taiwan. A side effect is that niche service brings additional foreign patients, which will contribute to the benefit of the hospital, but this leaves less room for treating domestic patients. A niche service is a means of introduction for entry into the market of medical tourism. How to create a successful story is important for the development of a niche service. When a good reputation has been established, the information provided on the Internet can last for a long time and can spread internationally to form a distinguished mark for further development. Niche services can be classified into 3 categories: (1) Low-risk procedures with large price differences and long stay after retirement; (2) high-risk procedures with less of a price difference, and (3) banned procedures that are not allowed legally in home countries of foreign patients, such as stem cell therapy. In establishing a niche service, a high-quality, nonmedical segment should be integrated as well. PMID- 20718316 TI - Unusual groin resistance--a case study. AB - Extraskeletal osteochondroma is a benign, cartilaginous, slow-growing tumor with typical location near the joints of hands, feet, and knees. The authors present the case of a 44-year-old patient who experienced increasing pain in the right groin. Two isolated calcium deposits formed an encapsulated mass in the iliopsoas muscle, and the extraskeletal osteochondroma was diagnosed. An unusual location required that the operation be performed by a vascular surgeon. The authors present a wide range of groin-resistance differential diagnoses. PMID- 20718317 TI - Malignant melanoma of the vagina: report of two cases and review of the literature. AB - Vaginal melanoma (VM) is a rare disease comprising <1% of all melanomas among women, and about 3% of all vaginal malignancies. Patients experience a poor prognosis, showing <15% 5-year survival. The report concerns two premenopausal patients with VM treated by surgery with radical intent. The first patient presented with a large lesion also infiltrating the proximal paracolpium and the bladder. The second patient had a persistent lesion of the lower third of the vagina. However, in the absence of any evidence-based guidelines or even clear suggestions from the literature, it is reasonable to believe that an appropriate management of primary malignant VM should address the radical tumor resection with wide tumor-free surgical margins and symptom relief. PMID- 20718318 TI - Clinicopathologic characteristics of mucinous carcinoma of the breast. AB - The mucinous carcinoma of breast cancer is a relatively rare malignant tumor. This study investigated the clinical and pathologic features of mucinous carcinoma. The medical records of 237 patients with invasive breast cancer who underwent surgery between 1995 and 2006 were reviewed. These cases included 10 patients (4.2%) with mucinous carcinoma. The age of the patients ranged from 43 to 71 years (mean, 55.5 years). The tumor size was T1 in 5 patients and T2 in 5 patients. Lymph node metastasis was diagnosed as being negative in 9 patients and positive in 1 patient. Six patients (60%) were positive both for estrogen and progesterone receptor. The 10-year survival rates of mucinous carcinoma and other types of invasive breast cancer were 87.5% and 80.7%, respectively. Mucinous carcinoma showed a lower incidence of lymph node metastasis than other types of invasive breast cancer. Mucinous carcinoma tended to have a better prognosis in comparison with other types of invasive breast carcinoma. PMID- 20718319 TI - Surgical treatment of symptomatic sacral cysts: report of 5 cases. AB - Sacral cysts are collections of cerebrospinal fluid (CSF) between the endoneurium and the perineurium of the sacral nerve root sheath. Surgery is recommended for large cysts with symptoms attributable to them. We report 5 patients with symptomatic sacral cysts treated at our institution, including 1 male and 4 females with an average age of 51.8 years (range, 36-66 years). Surgical intervention included posterior laminectomy, direct excision of the cysts and repair, and replication or cover of the dura defect by sutures or biomaterials. Pathologic examination disclosed cystic lesions with a fibrous wall without an inner arachnoid lining. All patients recovered and remained symptom-free for 39.6 months (range, 30-51 months). Treatment methods for symptomatic sacral cysts vary. Direct decompression and cyst excision are effective methods with highly successful rates and expectations. PMID- 20718321 TI - Lymph node surgery in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma is the most common type of thyroid cancer, and cervical lymph node metastasis of the disease is high. Lymph node surgery of the papillary thyroid carcinoma is controversial because of the good prognosis of the disease. Although controversy continues on prophylactic lymph node dissection, therapeutic lymph node dissection is recommended in all guidelines for patients who have known lymph node metastases. PMID- 20718320 TI - CD40-CD40L costimulation blockade induced the tolerogenic dendritic cells in mouse cardiac transplant. AB - We aimed to investigate whether tolerogenic dendritic cells (DCs) were induced in the tolerant recipients with the blockade of CD40-CD40L costimulation. Mouse heterotopic heart transplantation was performed. DCs were sorted from rejected and tolerant recipients using magnetic-activated cell sorting. Their expression of CD40, CD80, and CD86 was examined using fluorescence-activated cell sorting. DCs were stimulated with lipopolysaccharide in vitro, and interleukin 10 (IL-10) and IL-12 levels in the supernatants were evaluated using enzyme-linked immunosorbent assay. By using mixed leukocyte reaction, we investigated the stimulatory capacities and tolerogenic capability of DCs. DCs from tolerant recipients expressed lower level of costimulatory molecules, including CD40, CD80, and CD86 and released higher levels of IL-10 and lower levels of IL-12. In addition, DCs from tolerant recipients were weak stimulators of the mixed leukocyte reaction and inhibited the proliferation of splenocytes. IL-10(high)IL 12(low) DCs with immature phenotype were induced in the tolerant recipients with the blockade of CD40-CD40L costimulation, and they obtained the tolerogenic function. PMID- 20718322 TI - Clinicopathologic features of gastric carcinoma patients who undergo a total gastrectomy. AB - Epidemiologic studies show a continued increase in the number of total gastrectomies (TGs) performed. We compared the clinicopathologic features and outcomes of patients who underwent a TG to those who received a distal gastrectomy (DG). Cases of 696 patients treated with TG were reviewed retrospectively. Multivariate analysis showed that age, tumor size, presence of serosal invasion, lymph node metastasis, and curability were significant prognostic factors for survival of patients who had a TG. The 5-year survival rate of patients who underwent a TG (39.5%) was lower than that of those receiving a DG (56.1%; P < 0.001). Patients who underwent a TG had a poor prognosis, which was mainly due to its more-advanced stage compared to that of patients who received a DG. Early detection is important for improving the prognosis. PMID- 20718323 TI - Outcome of colorectal cancer surgery in the early fast-track era with special regard to elderly patients. AB - Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in the Western world. Differentiated surgical therapy in the last years have made a curative resection possible in more than 80% of the cases. Two hundred ninety consecutive patients with colorectal cancer over 6 years were enrolled in a retrospective follow-up study based on the electronic patient record, with special regard to patients more than 70 years old. The outcome was evaluated using the following endpoints: resectability, 30-days morbidity (local and general complications), mortality, re-operation rate, and survival. The mean age of the 290 patients was 71.5 years; 176 patients were more than 70 years old and the male to female ratio was 148:142. Three hundred eight tumors had been diagnosed in the 290 patients. Tumor staging was as follows: stage I, 18.5%; stage II, 30%; stage III, 32%; and stage IV, 19.5%. A local R0 resection was made possible in 97% of the tumors. The 30-days morbidity incidence for patients younger/older than 70 years was 33%/57% (P < 0.05), the mortality incidence was 2.6%/3.4% (P value not significant), and the reoperation rate was 7.0%/9.1% (P value not significant). Anastomotic leaks occurred in 3.5% of the patients. The 1 , 2-, and 5-year survival rates were 81.4%, 66.3%, and 61.5%, respectively. Our findings show that colorectal carcinomas may be operated with mostly curative intent with a low mortality rate, a high R0 resection rate, and similar complications, mortality, and re-operation rates, even in patients more than 70 years old. PMID- 20718324 TI - Optimal timing for removal of abdominal drainage after liver resection for hepatocellular carcinoma. AB - The aim of this study was to retrospectively assess the optimal timing for removal of abdominal drainage after liver resection for hepatocellular carcinoma (HCC). A total of 148 patients were divided into 2 groups. In Group I, drains were removed according to the judgment of the surgeon. In Group II, drains were removed on postoperative day (POD) 2, except in cases of bile leakage, purulent ascites, or hemorrhage. Postoperative complications were compared between the 2 groups. Postoperative hospital stay was shorter in Group II than in Group I. Six patients required drain reinsertion for abdominal abscess and massive ascites. The risk factor for drain reinsertion was volume of drain discharge greater than 450 mL on POD 2. Early removal of the drain is desirable after surgical treatment of HCC. Moreover, it seems preferable to determine the necessity of drain removal based on assessment of the volume and nature of drain discharge on POD 2. PMID- 20718325 TI - Postoperative surgical complications after radical axillary lymph node dissection in melanoma disease result in increased pain. AB - Postoperative pain is one of the major problems caused by the operative trauma. We recorded the postoperative pain of patients who underwent a radical axillary lymph node dissection (RALND) to evaluate the quality of our standardized perioperative pain management program and the influence of surgical complications. Between August 2003 and December 2007, we registered the postoperative level of pain of 111 patients who underwent a therapeutic RALND, using a visual analog scale (VAS). Patients received standardized perioperative pain therapy according to level I of the World Health Organization (WHO) ladder of pain. We registered a VAS score of 10 in patients at rest during the first 3 postoperative days, but after mobilization of the arm, patients had significantly more pain (P < 0.0001). Patients with a postoperative surgical complication needed significantly more central analgesia to reach the same level of pain (P = 0.04) as patients without complication. Level I of the WHO ladder of pain is not enough for patients after an RALND. Patients with a postoperative complication do have increased pain, and use of only peripheral analgesia is insufficient. PMID- 20718326 TI - The prognosis of the traumatic subarachnoid hemorrhage: a prospective report of 121 patients. AB - Recent investigations have shown the significance of subarachnoid bleeding on computed tomography scans first taken after admission for head injuries. In our study, we describe a prospective follow-up of 121 patients with traumatic subarachnoid hemorrhage (tSAH). From January 2004 to January 2007 we collected data prospectively from 121 patients admitted with diagnosis of tSAH to our trauma intensive care unit, on the basis of admission with a computed tomography scan. The classification of tSAH was performed using the Fisher scale with modification, and the follow-up was performed using the Glasgow Outcome Scale (GOS). The minimum period for a follow-up was established 6 months after the injury. Traffic accident was the main cause of head injuries (72% in total; 48% involving cars and 24% involving motorcycles), followed by falls (23%) and aggression (5%). Twenty-eight percent of patients sustained major multiple injuries, with spinal injury as the main associated trauma. The outcome was favorable (GOS score 4 or 5) in 54 patients (45%) and unfavorable (GOS score 1, 2, or 3) in 67 patients (55%). The mortality rate was proportionally greater in patients who had cisternal clots >1 mm (P < 0.001), assessed by the Fisher scale with modification. When functional recovery was evaluated using the GOS, the recovery rate and the daily life activities were lower in patients with intraventricular bleeding (P = 0.001). Our results showed that patients with severe tSAH had the worst prognosis. PMID- 20718327 TI - Retrograde jejunojejunal intussusception status following Roux-en-Y gastrojejunostomy. AB - Reported herein is an experience with retrograde intussusception. The index case was a 25-year-old African American woman who was status post-multiple previous intraperitoneal procedures, including a truncal vagotomy, distal gastrectomy, and Roux-en-Y gastrojejunostomy for the treatment of gastric outlet obstruction secondary to type 2 peptic ulcer disease. The patient presented most recently with symptoms and signs of a high-grade mechanical intestinal obstruction. Preoperatively, computerized axial tomography revealed retrograde intussusception. Urgent exploratory celiotomy confirmed retrograde intussusception of a segment of the common channel just distal to the jejunojejunostomy. The jejunojejunostomy, including the nonreducible intussusceptum and intussuscipiens, was resected. The alimentary tract was reconstituted in conventional fashion. Light microscopic histopathologic analysis revealed acute greater than chronic inflammation, transmural edema, ischemia/necrosis of the intussusceptum, and hypertrophy of the intussuscipiens. Mechanistically, intussusception has been characterized as an internal prolapse. It usually is aboral/antegrade/isoperistaltic in direction with circumferential intraluminal invagination/prolapse/propagation/telescoping of the proximal/cephalad intussusceptum into the distal/caudad intussuscipiens. Retrograde intussusception is the reverse. More specifically, retrograde intussusception is adoral/retrograde/antiperistaltic in direction with circumferential extraluminal exvagination/propagation/telescoping of the proximal/cephalad intussuscipiens over and around the distal/caudad intussusceptum. We speculate that suture lines, staple lines, adhesive disease, and incomplete closure of mesenteric defects are proximate and determinant causes of retrograde intussusception. PMID- 20718328 TI - Intrapancreatic accessory spleen. AB - Intrapancreatic accessory spleen is a rare cause of pancreatic pseudotumors and is located in the pancreatic tail in approximately 1% to 2%. Accessory spleen itself is found in approximately 7% to 15% of the population. Our findings show a case of an intrapancreatic accessory spleen suspected for a malignancy in the pancreatic tail. A 63-year-old man admitted for cholecystitis was incidentally diagnosed with a tumor at the pancreatic tail. On hyperintense magnetic resonance imaging, a solid mass of 1.5 cm in diameter in the pancreatic tail was seen, which contrasted as hyperdense in T2-weighted imaging. Because of inhomogeneous enhancement on the early vascular phase, the diagnosis of a endocrine pancreatic tail carcinoma was suspected. Intraoperatively, an accessory spleen was found in the pancreatic tail. An oncologic left pancreatectomy was performed because of a malignant tumor. Histology showed an intrapancreatic accessory spleen in the pancreatic tail that excluded the presence of cancer. In conclusion, intrapancreatic accessory spleen is a rare cause of unnecessary laparotomy, but the absence of reliable diagnostics for this entity make histologic ascertainment of a benign tumor indispensable. Therefore, we still needed an oncologic tumor resection. PMID- 20718329 TI - Lateral inclination of the trunk and falling frequency in Parkinson's disease patients. AB - OBJECTIVE: To investigate clinical features of postural instability and the relationship between severity of instability and falls during daily living in patients with Parkinson's disease (PD). METHODS AND SUBJECTS: We recorded trunk movements of subjects maintaining a seated position for 2 minutes using both a force plate and a position sensor system. We compared 13 patients with falls (fallers), 7 without falls (non-fallers), and 8 age-matched normal controls. RESULTS: The tendency for the values of both lateral COP displacement and trunk displacement was to increase in 1) patients compared with controls, and 2) fallers compared to non-fallers. Among patients who showed a large value of lateral COP displacement, greater than the value of the mean plus one standard deviation of controls, 90% had lumbar scoliosis and 60% of these patients fell down more than 5 times during the one-year follow-up period. CONCLUSION: We demonstrated that PD patients who had fallen frequently tended to have a 1) lumbar scoliosis, and 2) large value of lateral COP displacement. These results suggest that the measurement of both lateral COP displacement during sitting and spinal curvature would be useful in predicting the risk of falling in PD patients. PMID- 20718330 TI - Electromyographic validation of the muscles deltoid (anterior portion) and pectoralis major (clavicular portion) in military press exercises with open grip. AB - It was analized the deltoid muscle anterior portion and the pectoralis major clavicular portion in 24 male volunteers using a two-channel electromyograph TECA TE 4, and Hewllet Packard surface electrodes, in 4 modalities of military press exercises with open grip. The results showed high inactivity for PMC in almost all the modalities while DA developed very high levels of action potentials in all the modalities assessed. PMID- 20718331 TI - Electromyographic and haemodynamic activities in lumbar muscles during bicycle ergometer exercise and walking. AB - Although bicycle ergometer exercise and walking are recommended as aerobic exercise for patients with lumbago, little research has been done to examine the muscular activities and circulatory dynamics during these exercises. In this study, we aimed at obtaining basic information on aerobic exercises effective for patients with lumbago by investigating the activities and circulatory dynamics of their lumbar muscles during bicycle ergometer exercise and walking. As subjects, we selected 10 healthy adults (23.7 +/- 3.4 years old) with no anamnestic history of lumbago. The measurement conditions were 4 types of exercise: walking (4.0 km/h); 25W, 50W and 75W bicycle ergometer exercises. The activities of the lumbar muscles during the exercises were measured by a surface electromyograph, and percent of MVC was calculated from the maximal voluntary contraction (MVC). With regard to the circulatory dynamics of the lumbar muscles, we measured oxygenated hemoglobin (Oxy-Hb) and deoxygenated hemoglobin (Deoxy-Hb) before and after the exercises with near infrared spectroscopy (NIRS). The change rates during the exercises were calculated based on the values before the exercises. Paired t test was employed to analyse the comparison of the circulatory dynamics of the lumbar muscles between, before and during the exercises. With respect to the comparison of the change rates of the muscular activities and circulatory dynamics among each of the exercises, we employed the one-way analysis of variance (ANOVA) (p < .05). The lumbar muscular activities during the walking were significantly higher than those during the bicycle ergometer exercise were at each load level. The Oxy Hb increased significantly during the 25W and 50W bicycle ergometer exercises, as opposed to before the exercises. It showed a tendency to decrease during the 75W bicycle ergometer exercise and walking, but not significant. The change rate of the Oxy-Hb during the 25W bicycle ergometer exercise indicated a higher value than that of the other exercises. The Deoxy-Hb, on the other hand, declined significantly in every exercise compared with those before the exercises, with no significant differences in the change rates between each of the exercises. Bicycle ergometer exercise has been suggested as an aerobic exercise permitting as much oxygen uptake as walking does, with fewer loads on lumbar muscles and less likelihood of inducing a hypoxic state on lumbar muscles. PMID- 20718332 TI - The effect of epoch length on the electromyographic mean power frequency and amplitude versus time relationships. AB - The electromyographic (EMG) mean power frequency (MPF) and amplitude versus time relationships are commonly used to characterize localized muscle fatigue. PURPOSE: The purpose of this study was to compare the effect of epoch length on the individual and mean slope coefficients and y-intercepts resulting from the EMG MPF and amplitude versus time relationships of the vastus medialis (VM) muscle during fatiguing isometric muscle actions at 30 and 75% of maximum voluntary isometric contraction (MVC). METHODS: Eight adults performed two continuous, isometric muscle actions of the leg extensors at 30 and 75% MVC to exhaustion. Six, 5.0 s epochs of the surface EMG signals were recorded from the VM during each minute. Epoch lengths of 0.5, 1.0, and 2.0 s were selected from the middle of each 5.0 s epoch. Linear regression was used to estimate the slope coefficient and y-intercept values for the EMG MPF and amplitude versus time relationships for each epoch length (0.5, 1.0, 2.0, and 5.0 s) and subject. RESULTS: There were no significant differences between epoch lengths for the individual or mean slope coefficients or y-intercepts (EMG MPF and amplitude versus time relationships). CONCLUSION: This study indicated that epochs of 0.5 - 5.0 s resulted in the same characterization of EMG (MPF and amplitude) versus time relationships during isometric muscle actions. PMID- 20718333 TI - Influence of fingertip contact with a wall on postural sway and electromyographyic activity of the soleus muscle. AB - Standing and walking balance decreases in many kinds of neuromuscular, musculoskeletal and sensory disorders, and in elderly people because of age related physiologic diminution. Recent studies have shown that contact cues from a cane or a fingertip provide information that leads to reduced postural sway in subjects. The first purpose of this study was to investigate the influence of light and forceful fingertip contacts with a wall on the postural sway while standing upright. The second purpose was to investigate the influence of fingertip contact on the EMG activity of the soleus muscle. Twelve healthy male volunteers (20.8 +/- 0.7 years old) participated in this study. Standing balance or postural sway was measured by sway of the center of pressure (COP) under three conditions: (1) standing without touching a wall, (2) standing with the right index fingertip lightly touching (< 1N) to a wall (3), and standing with the right index fingertip forcefully touching (5 approximately 10N) to a wall. Bipolar surface electrodes were placed over the right soleus muscle to measure EMG activity associated with anterior-posterior sway. More significant length, and rectangular and environmental areas of the COP were observed while standing without touching a wall than while standing while lightly or forcefully touching a wall, but there was no significant difference between the two touching conditions. No significant difference in the EMG activity of the soleus muscle was observed among the three conditions. The results of this study suggested that the fingertip touch contact with a wall decreased sway during static standing but did not influence the EMG activity of the soleus muscle. PMID- 20718334 TI - Which parameter is more reliable in a cold hand, NCV or latency. AB - Temperature affects distal sensory & motor latencies & nerve conduction velocity but not necessarily at the same degree. Purpose of this study is to see which one is affected less and thus could be more reliable in cold conditions. A total of 32 healthy individuals with age range of 18-28 years (mean 22.25 +/- 2.2) participated in this study. Skin Temperature was recorded at wrist. Distal median motor & sensory latencies and transcarpal median NCV were recorded before and after immersion in cold water. Statistical analysis was performed using paired t test with SPSS. All parameters were affected by cold but the effect was less dramatic in transcarpal NCV. Transcarpal median NCV is least affected parameter by cold, so it may be more reliable than sensory & motor latencies at wrist. PMID- 20718335 TI - Analysis of postural oscillation in children with cerebral palsy. AB - It is believed that static balance undergoes changes in children with cerebral palsy (CP). Thus, we analyzed postural oscillation in 19 children with the aim of comparing balance between healthy children and those with CP. The sample was divided into two groups--one with 10 children diagnosed with diparetic CP (CPG) and a control group (CG) with nine healthy children, all capable of remaining in an orthostatic position without support and obeying spoken commands. The assessment of postural oscillation was performed with the children barefoot, arms alongside the body and looking toward a fixed point while standing on an unrestricted base for the feet. Data collection was performed using a TEKScan force platform with 30-second duration for each condition. The children had an average age of 7.9 years (+/- 2.07) in the CPG and 7.5 years (+/- 1.58) for the CG. Postural oscillation data in the anterior-posterior and medial-lateral directions were analyzed using the Data Analysis and Technical Graphics Origin 6.0 program. Statistical analysis of the mean oscillation value in the conditions of eyes open and eyes closed did not differ significantly between groups. However, there was a significant difference in mean anterior-posterior oscillation between groups (p = 0.00). The groups behaved similarly with regard to the visual deprivation. We conclude that children with CP exhibit less postural oscillation in comparison to healthy children under the same conditions. PMID- 20718336 TI - Cross-talk among monopolar surface electromyographic signals from the superficial quadriceps femoris muscles. AB - This study used a within-subjects design. The purpose of this study was to examine cross-talk among monopolar surface electromyographic (EMG) signals from the superficial quadriceps femoris muscles. The "efficiency of electrical activity" technique for assessing muscle function uses monopolar EMG. Thus, knowledge of the potential for cross-talk among the superficial quadriceps femoris muscles when using monopolar recording will be valuable in rehabilitative settings. Fourteen healthy men (mean +/- SD age = 22.0 +/- 3.9 years) volunteered to perform submaximal to maximal isometric muscle actions of the dominant leg extensors in 10% increments from 10% to 100% of the maximum voluntary contraction (MVC). During each muscle action, monopolar surface EMG signals were detected from the superficial quadriceps femoris muscles. Three separate cross correlations were performed to examine cross-talk among the vastus lateralis and rectus femoris, vastus medialis and rectus femoris, and vastus lateralis and vastus medialis. The peak cross-correlation coefficients ranged from R(x,y) = 0.182-0.944, with the greatest cross-talk occurring between the vastus lateralis and vastus medialis. In addition, the cross-correlation coefficients generally increased with force. These findings showed moderate to large degrees of crosstalk among monopolar surface EMG signals from the superficial quadriceps femoris muscles. Thus, the monopolar EMG signals from these muscles should be interpreted carefully and with the understanding that at least a portion of the signal from each muscle is due to cross-talk. PMID- 20718337 TI - Modulation of the ipsilateral and contralateral H reflexes following ipsilateral mechanical pressure of the foot in normal subjects. AB - OBJECTIVE: Mechanoreceptors from the foot sole likely contribute in the reflex regulations. Therefore, it was hypothesized that repetitive low threshold afferents stimulation would have an inhibitory effect on the soleus H-reflexes. METHODS: Sixteen normal subjects voluntarily, participated in the study and were randomly allocated. Subjects were remained in prone position. The Cutaneous Mechanical Pressure (CMP equal to 50% of leg and foot weight) was applied to the ipsilateral lateral and Medial plantar surface by a designed instrument through a square plate (30 x 30 mm). H reflex as an indicator for excitability of motoneurones was bilaterally elicited before and after the application of the CMP. The H-reflex parameters were estimated. RESULTS: Mechanical pressure significantly depressed soleus H-reflex excitability in ipsilateral and contralateral feet in all subjects. CONCLUSION: The demonstration of a decrease in H-reflex excitability as a result of applied pressure to the foot sole suggests that the change in reflex excitability is the result of a common spinal mechanism. The results highlight the modulatory effects that natural stimulation of afferents can have on reflex excitability. SIGNIFICANCE: The placement of a small flat plate, in order to apply pressure to the plantar eminence, may be useful for modulation of muscle tone. In addition, these findings might be useful for reducing spasticity; because spasticity is at least partially caused by hyperexcitability of the motorneuron pool. PMID- 20718338 TI - [Characterization of pseudotyped viruses coated with hemagglutinin of H5N1 avian influenza]. AB - OBJECTIVE: To construct pseudovirus bearing H5N1 HA based on a lentivirus vector system. Then we study the biological feature of the pseudovirus. With the newly established viral particles, we performed the serological tests. METHODS: H5N1 avian influenza virus that isolated from human case was cloned to construct pLP HA, then pLP-HA co-transfected with lentivirus vector plasmids pLP1, pLP2 and pEmGFP into 293T cells. The supernatant was harvested 48h post-transfection. Concentrated by super centrifuge, the pseudotyped viruses were analyzed by infection test, HA test and micro-neutralization test. At the same time, optimized HA gene and a Vietnam H5N1 HA gene were used to construct pseudotyped virus for comparison. RESULTS: Pseudotyped virus particles can be observed with electronic microscope. Western-blot revealed that HA glycoprotein can be expressed in the virions. Our neutralization assay by using the pseudoviruses was comparable with the conventional microneutralization assay with wild-type viruses. A high degree of correlation was detected. CONCLUSION: Pseudotyped Viruses coated with HA of H5N1 High Pathogenic Avian Influenza were successfully constructed; it can be used to for the microneutralization assay. The HA gene from different sources affect the efficiency of the packaging of the pseudovirus. But the optimized HA gene can not obviously improve packaging efficiency of the pseudovirus. PMID- 20718339 TI - [Study on the antigenicity and HA1 gene characteristics of influenza A viruses during 2004-2008 year in China]. AB - OBJECTIVE: To under stand influenza A viruses epidemic, antigenicity and genetic characteristics variation between the vaccine and Circulation strains during 2004 2008 year in China. METHODS: The influenza A viruses (H1N1, H3N2) isolated from 2004-2008 year were under took antigenic and sequence analysis. Influenza A virus antigenicity and genetic characteristics were analyzed thought amino acid variation compassion of HA1 protein of influenza A virus isolates. RESULTS: The antigenicity of influenza H1N1 subtype viruses isolated from 2004 to 2007 is very similar with vaccine strain A/New Caledonia/20/1999 (HIN1)-like virus. The influenza H1N1 viruses circulated in 2008 year had similar antigenic characteristics with A/Brisben/59/2007 (H1N1) which is component of influenza vaccines for northern hemisphere 2008-2009 year. The influenza H3N2 subtype viruses of 2004-2005 year had antigenic variation comparatively with vaccine strain A/Fujian/411/12002 (H3N2), The antigenicity of 2006-2007 H3N2 viruses and 2008 year's is A/Wiscansin/67/2006(H3N2) and A/ Brisben/10/2006(H3N2) respectively. CONCLUSION: There is change of influenza A viruses (H1N1, H3N2) antigenic and genetic characteristics during 2004-2008 in China. PMID- 20718340 TI - [The virus isolation analysis of the H5N1 subtype human avain influenza cases in mainland China from 2005 to 2009]. AB - OBJECTIVE: To analyse the correlation between the virus isolation and the specimen collection of the H5N1 human high pathogenic avain influenza cases in Mainland China. METHODS: The specimens were collected in Mainland China from 2005.10 to 2009.3 and the H5N1 viruses were isolated by passage in embryonated chicken eggs. RESULTS: Most specimens were obtained within 14 days after disease onset. For the specimens collected within 7 days, the isolation rate was relatively high and the difference of the positive rate between different years was lower than those specimens collected after 7 days. Most of the samples in our study were collected from the upper or lower respiratory tract with few from blood, feces, et al. The isolation rate of lower respiratory specimens was higher and the difference of the positive rate between different years was relatively lower than those from upper respiratory specimens. CONCLUSION: We suggest that the samples should be collected from lower respiratory tract during the acute phase to get the higher isolation rate. PMID- 20718341 TI - [Study on preparation and identification of monoclonal antibodies immunized with H5N1 influenza virus M1 protein]. AB - OBJECTIVE: To prepare monoclonal antibodies specific for M1 protein of H5N1 subtype human influenza virus, this work may provide new tool in rapid diagnosis and study of type A influenza virus. METHODS: BALB/c mice were immunized with purified recombinant H5N1 (A/Anhui/1/2005)/M1 protein expressed in E. coli. Spleen cells of the immunized mice were fused with sp2/0 cells to produce hybridoma cell lines. ELISA was performed to identify the monoclonal antibody against M1 protein of H5N1. Immunofluorescence assay (IFA) were applied to identify the specificity of these antibodies. RESULTS: Three hybridoma cell lines steadily secreting anti-H5N1/M1 McAb were obtained, and their cross reactivity was confirmed by cross-reaction test and IFA. CONCLUSION: Monoclonal antibodies immunized with H5N1 subtype influenza virus M1 protein are cross-reactive, which can be used to detect different subtype of influenze virus type A. PMID- 20718342 TI - [Secreted expression of dengue virus type I envelope glycoprotein in 293T cells]. AB - OBJECTIVE: To expression prM/E gene of dengue virus type I in mammalia cells. METHODS: The full-length prM/E gene of dengue virus type I strain GZ01/95 was amplified by RT-PCR, the signal peptide preceding the prM gene was added or the carboxyl-terminal 20% of DEN-1 E was replaced with the corresponding JE sequence in the meanwhile, and three of the constructions were cloned into the pcDNA5/FRT.Then they were transfected into 293T cells by lipofectamine respectively. The expression of recombinant proteins were identified by indirect immuno-fluorescence assay(IFA) as well as Western blot. RESULTS: In the cytoplasm of 293T cells transfected with all the recombinant plasmids DNA, the expressed products for gene of dengue virus type I were confirmed by IFA. The secreted expression products for gene of dengue virus type I specific protein bands were confirmed by Western blot only existing in the cell supernatants transfected with the modified recombinant plasmids DNA. CONCLUSION: The prM/E protein of dengue virus type 1 were expressed in 293T cells transfected with all the three recombinant plasmids DNA. The prM/E protein was obtained secretion after transfecting the modified recombinant plasmids adding a signal peptide preceding the prM gene or replacing the carboxyl-terminal 20% of E with the corresponding JE sequence. PMID- 20718343 TI - [Identification and construction of replicon vectors of Japanese encephalitis virus (strain SA14-14-2)]. AB - OBJECTIVE: In order to lay the groundwork for studying the novel vaccine Identified. METHODS: (1) Two replicons were constructed. One's prM/E gene was deleted completely (Full AprM/E Replicon), the other's prM/E gene was deleted partially (213 bp of C terminal of E gene was reserved; Partial delta prM/E Replicon), and the deleted parts was replaced as the MCS. (2) Replicons RNA were which will use the JEV as the vector, replicon vectors of JEV was constructed and transfected into BHK-21 cell. After 24, 48, 72, 96 h, method of real-time PCR was used to identify Replicons' replication ability. (3) YFP gene was inserted into the MCS of those two replicons. Their RNA was transfected into BHK-21 cell. Expression of YFP was tested by the fluorescence microscopy and flow cytometer. RESULTS: (1) After the two replicons RNA were transfected into BHK-21 cell, as time went by, the quantity of RNA increased. (2) After RNA of the replicons with YFP were transfected into BHK-21 cell, increasing trend of fluorescent signal and rate of YFP positive cell was observed and tested. CONCLUSION: Full delta prM/E Replicon and Partial delta prM/E Replicon have the ability to duplicate itself and express the foreign protein. PMID- 20718344 TI - [Comparison of the immnunogenicity of rAAV2/1 and rAd5 rad5 expressing HIV-1 gag]. AB - OBJECTIVE: To compare the immunogenicity of rAAV2/1 and rAd5 expressing HIV-1 gag in BALB/c mice. METHODS: BALB/c mice were immunized with rAAV2/1-gag or rAd5-gag once or twice. HIV-1 specific cellular immune responses were analyzed by in vivo CTL and intracellular cytokine staining assays. HIV-1 Gag specific antibodies were tested by ELISA. RESULTS: Mice immunized with rAd5-gag once induced stronger Gag specific cellular immune responses and similar level of Gag specific antibody compared with rAAV2/1-gag. Mice immunized with rAd5-gag reached the peak immune responses more rapidly than rAAV2/1-gag. However, mice immunized with rAAV2/1-gag twice elicited better Gag specific IgG. CONCLUSION: rAd5-gag induced strong HIV-1 specific cellular and antibody responses, and rAAV2/1-gag induced high level of HIV-1 specific IgG and moderate cellular immune responses. PMID- 20718345 TI - [Analyze the bioactivity of PD-1 and PD-L1 recombination protein which expressed by prokaryotic system]. AB - OBJECTIVE: To analyze the interaction of PD-1 and PD-L1 recombination protein and to know their bioactivity and affinity. METHODS: Stick the PD-1 protein on the surface of CM5 sensor chip by the method of Ammine coupling after being preconsentrated. Dilute the PD-L1 protein step by step and reject it to the passage on CM5 sensor chip which had been stick by PD-1. The time of combination is 3 minutes and of separation is 15 minutes, respectively. Observe the procession and analyze data by BIA Evaluation software 4. RESULTS: On the consistency of 40 microg/ml, pH 4.5, the PD-1 protein could couple steady on the surface of CM5sensor chip, RU is 3300. On the density of 200 mmol/ml PD-L1 could combine with PD-1 specifically, RU = 150, K(D) = 3.5 x 10(-6). CONCLUSION: The PD 1 and PD-L1 recombination protein which we expressed by prokaryotic system have good affinity and bioactivity. The results could provide basic condition for later study. PMID- 20718346 TI - [Expression of recombinant VP2 gene in insect sf9 cells and screening of clinical specimens]. AB - OBJECTIVE: To clone and express VP, gene from HBoV, and the expressed VP, protein was as the antigen in order to detect serum from children in Wenling area with lower respiratory tract infections. METHODS: The VP, gene was recombined with the genome of Baculovirus, which infected the insect cell. The fusion protein with HA tag was applied to confirm the specificity of expressed protein. Furthermore, the recombinant protein was observed using electron microscopy. The 176 serum from children in Wenling area with lower respiratory tract infections was screened using Western blot. RESULTS: The expressed VP2 protein was more than 60% in total proteins from insect cell, and MWt about 60 x 10(3). The virus-like particle (VLP) was observed using electron microscopy, and size about 20 nm. The 176 serum from children in wenling area with lower respiratory tract infections was screened using Western blot. The HBoV positive rate was 2.28% (4/176). CONCLUSION: The VP2 protein from human bocavirus was expressed in insect cell successfully. Through HA tag the VP2 protein was specific, and then the assay using SDS-PAGE with Western blot could detect and screen the antibody in serum from children with lower respiratory tract infections rapidly and accurately. PMID- 20718347 TI - [Association between HLA-DQA1 gene polymorphism and the outcomes of hepatitis B virus infection]. AB - OBJECTIVE: To investigate the association between HLA-DQA1 gene polymorphism and the outcomes of hepatitis B virus infection in Chinese Han population. METHODS: A total of 180 consecutive patients with biopsy-proven hepatitis B virus infection (120 patients with chronic hepatitis B and 60 patients with asymptomatic HBV carrier) and 60 subjects who resolved from HBV infection spontaneously were studied. Genotype of human leukocyte antigen(HLA)-DQA1 was detected by polymerase chain reaction sequence specific primer(PCR-SSP). RESULTS: (1) The frequency of HLA-DQA1 * 0201 allele in chronic hepatitis B group was significant higher than the frequency in resolved from HBV infection spontaneously group (38.3% vs. 5.8%, P < 0.001, A = 10.04, 95% CI: 4.48-22.48). The frequency of HLA-DQA1 * 0102 allele in chronic hepatitis B group was significant lower than the frequency in resolved from HBV infection spontaneously group (9.6% vs. 36.7%, P < 0.001, A = 0.183, 95% CI: 0.10-0.32). (2) The frequency of HLA-DQA1 * 0201 allele in chronic hepatitis B group was significant higher than the frequency in asymptomatic HBV carrier group (38.3% vs. 7.5%, P < 0.01, A = 7.667, 95% CI:3.7-15.87). The frequency of HLA-DQA1 * 0102 allele in chronic hepatitis B group was significant lower than the frequency in asymptomatic HBV carrier group (20% vs. 9.6%, P < 0.01, A = 0.424, 95% CI: 0.23-0.79). CONCLUSION: HLA-DQA1 gene polymorphism may play an important role in the outcomes of hepatitis B virus infection in-Chinese Han population. The HLA-DQA1 * 0102 allele could keep individuals away from HBV infection, and HLA-DQA1 * 0201 allele could aggravate persistant infection of HBV and hepatic inflammatory. PMID- 20718348 TI - [Expression of partial S gene of Hantavirus Z10 in Pichia pastoris]. AB - OBJECTIVE: The purpose of this study is to express partial S gene of Hantavirus Z10. METHODS: The 300 bp S gene of Z10 strain was synthesized by using a successive PCR method for the optimal expression in Pichia pastoris and subcloned into pMD19-T. The SP300 gene was constructed into pPICZaA and sequenced. The recombinant pPICZaA-SP300 and pPICZaA-S300 was transformed into Pichia with LiCI. RESULTS: The recombination Pichia were cultivate, and expressed the SP300 or S300 gene induced in Pichia by methanol. CONCLUSION: The nucleocapsid secreted from the Pichia can be detected by ELISA and WesternBlot. PMID- 20718349 TI - [Isolation and cell culture of human bocavirus (HBoV) by human bronchial epithelial cell lines]. AB - OBJECTIVE: To investigate pave a way for studying pathogenicty of HBoV. METHODS: Isolation and cell culture of HBoV by human bronchial epithelial cell line, which was founded in our laboratory. The morphology of the virus were primarily studied with a transmission electron microscope. In addition, transcript mRNA was detected in human bronchial epithelial cells, which was passaged and infected within HBoV, using the reverse-transcription polymerase chain reaction (RT-PCR). The amplified products nucleotide sequence of HBoV were sequencing and sequence analysis. RESULTS: Cytopathic effect (CPE) was observed after the aseptic residue of filtration of 2 case sputum specimens with HBoV, which was inoculated to the human bronchial epithelial cell line. The virus particles were observed in the cytoplasm, which were hexagonal or spherical in shape and 18-26 nm in diameter,bulk was 20 nm. cDNA amplicon obtained 295 bp fragment results of electrophoresis bands as same as NS1 region of the conserved matrix gene of publish sequence of HboV. PCR products nucleotide sequence of HboV were compared with corresponding HboV GeneBank sequences. The comparison/alignment and construction of phylogenetic trees also point to an affiliation of the parvovirus to the species HBoV. CONCLUSION: Isolation and identification of HBoV could be done in the human bronchial epithelial cell, and we found some characterizing CPE in the human bronchial epithelial cell after HBoV infection. The above studies pave a way for studying pathogenicty of human bocavirus. PMID- 20718350 TI - [Following surveillance on HIV infection after blood transfusion]. AB - OBJECTIVE: To study epidemiological features of HIV infection after blood transfusion and the situation of transmission among members of family. METHODS: The persons infected with HIV through blood transfusion and their intrafamilial transmission in some city were analyzed and testing methods of ELISA, Western blot, RT-PCR and subtype analyzing were used. The whole surveillance data came from residents investigation around problem medical centres and HIV monitoring network around Hebei province. RESULTS: 173 people infected with HIV after blood transfusion in some city, including 89 cases found in hospital and 84 cases in CDC, accounted for 68.7% (173/252) of all of infected persons by blood transfusion in Hebei province. The rate of intrafamilial transmission, spousal transmission and mother-to-child transmission((MTCT) were 32.0% (49/153),17.0% (26/153) and 32.7% (32/98), respectively. Most of persons infected with HIV were youth among who the female were more than the male. Childbearing and women's ailments were the main cause of blood transfusion from 1990 to 1999, and traumatism surgery took second place. Infected persons by HIV blood, whose time to diagnostic were the year from 1999 to 2009, spread over Kangtai hospital and other hospital which accounted for 45.1% (78/173) and 42.2% (73/173), respectively. The genetype of all patients were B' subtype. CONCLUSION: The medical centers at the grass-roots level in some city resulted in outbreak of infected persons by HIV blood because of having no screening test antibody of HIV for liid blood donors. PMID- 20718351 TI - [Expression of peroxiredoxin III in cervical lesions]. AB - OBJECTIVE: To investigate the expression feature of peroxiredoxin III in cervical lesions and to further understand the mechanism for cervical cancer development/progression. METHODS: Expression of peroxiredoxin III was immunohistochemically detected in cervical cancer. In addition, cervical epithelia were transfected with recombinant adeno-associated virus vector containing human papillomavirus 16 E6/E7 and peroxiredoxin III expression was detected by quantitative real time PCR and Western blotting. RESULTS: Peroxiredoxin III was significantly up-regulated in cervical cancer tissues. Nevertheless, expression of peroxiredoxin III remained unchanged in cervical epithelial cells after transfection. CONCLUSION: It seems that Prx III is not related to cervical cancer initiation. Up-regulation of peroxiredoxin III in cervical cancer might be an active response to oxidative stress in malignant cells, which protects against oxidatiton-induced apoptosis. PMID- 20718352 TI - [Sequence polymorphisms of mitochondrial DNA hypervariable 1 of peripheral blood cells from 47 HIV/AIDS patients of Han nationality]. AB - OBJECTIVE: To investigate alterations of hyper variable region 1 (HR 1) of mitochondrial DNA Blood cells were (mtDNA) in white blood cells of Chinese Han nationality HIV/AIDS patients. METHODS: obtained from 47 cases of therapy-naive HIV/AIDS patients without opportunity infection and DNA were extracted using blood DNA extracted kit. About 600 bp fragments which contain HR 1 were amplified by PCR. Alterations were determined by directed DNA sequencing. RESULTS: There were 124 polymorphism sites in mtDNA HR 1 (nb16024-16383) in 47 HIV/AIDS patients. The alteration rate was 0 to 20.47% (median 5.33%). 36 cases experienced C to T nucleotide change at nt 16 223, and the alteration rate was 70.97%. At nt 16 362, 26 individuals showed T to C nucleotide change and 3 individuals showed T to G alteration, alteration rate was 55.32% (26/47) and 6.38% (3/47) individually. CONCLUSION: HIV infection may cause more alterations in HR 1 regions. PMID- 20718353 TI - [Study on immunogenicity of a recombinant adenovirus vaccine containing neuraminidase gene of H5N1 influenza virus (A/Anhui/1/2005) in mice]. AB - OBJECTIVE: To investigate immunity of a recombinant adenovirus vaccine (rAdV) containing codon-modified neuraminidase (Mod. NA) gene of H5N1 influenza virus in BALB/c mice and to screen for appropriate dose. METHODS: BALB/c mice were immunized with the rAdV-Mod.NA vaccine intramuscularly twice (double injection at 0 and 4th week) in three groups, low dosage (10(5) TCID50 per dose), medium dosage (10(7) TCID50 per dose) and high dosage (10(9) TCID50 per dose). The effect of humoral and cell-mediated immunity were analysed at 5th week. RESULTS: (1) The rAdV-Mod.NA vaccine could elicit both humoral and cell-mediated robust NA specific immunity in mice by neuraminidase inhibitor assay and IFN-gamma ELISpot assay; (2) 10(7) TCID50 per dose was the appropriate dose; (3) Peptide NA(109 124): CRTFFLTQGALLNDKH and peptide NA(182-199): AVAVLKYNGIITDTIKSW were the dominant epitopes for neuraminidase-immunized BALB/c mice, which was screened out from the whole length of neuraminidase of an H5N1 virus, A/Anhui/1l/2005. CONCLUSION: The recombinant adenovirus NA could induce specific humoral and cellular immune responses in BALB/c after immunization, which suggest rAdV-Mod.NA vaccine was a potential vaccine candidate against H5N1 influenza and worthy of further investigation. PMID- 20718354 TI - [Human papillomavirus type 16 E5 sequence evolution analysis]. AB - OBJECTIVE: To investigate the distribution of HPV 16 variants in Han women patients without Cervical intraepithelial neoplasia in the diagnosis and treatment center for cervical disease, department of Obstetrics and Gynecology in China-Japan friendship hospital with HPV 16 E5 sequence phylogenetic analysis. METHODS: PCR amplification of HPV 16 E5 sequences and sequenced. The association between variations types and different cervical lesions was analyzed. RESULTS: In this research, We first found that variant classification based on HPV 16 E5 DNA sequence (236 bp) alone had high rate of accuracy. In addition, for the first time, our research revealed that single-4075T can distinguished the As variant from all other variants. CONCLUSION: If E5 sequence was used for phylogenetic analysis, it will greatly reduce the experimental costs and improve efficiency and cost-effectiveness. For the first time, our research revealed that single 4075T can distinguished the As variant from all other variants. PMID- 20718355 TI - [Molecular characterization of coxsackievirus B3 isolated from an outbreak of aseptic meningitis in Shandong Province, China]. AB - OBJECTIVE: To identify the pathogen caused an outbreak of aseptic meningitis in Tancheng county of Shandong province in 2008, and to analyze the molecular characterization of VP1 gene of the Coxsackievirus B3(CVB3) isolates. METHODS: Stool and cerebrospinal fluid(CSF) specimens were collected from this outbreak for virus isolation with RD and Hep-2 cell. After typing by neutralization test, the VP1 gene of the isolates were amplified by RT-PCR and sequenced. Homologous comparison and phylogenetic analysis were performed. RESULTS: 35 strains of enteviruse were isolated from 22 stools and 120 CSFs(7 from stools and 28 from CSFs), 34 strains identified as CVB3 and 1 as Echovirus 30(ECHO30) by neutralization test. The nucleotide homologies were 90.5%-100.0% in the partial VP1 gene (381 bp) among 34 CVB3 isolates. Homology comparisons indicated that Shandong strains have the identity of 79.5%-81.6% with the CVB3 prototype strain Nancy. 012/2008TC/SD/CHN and 177/2008TC/SD/CHN showed the highest nucleotides homologies (98.2% and 91.0% respectively) with Fuyang19 strain of Anhui province in 2008 in complete VP1 gene. The phylogenetic tree based on complete VP1 genes showed that all the CVB3 correlated with aseptic meningitis in China recently came from the same evolution linkage and formed a monophyletic cluster. CONCLUSION: The causative agent of this outbreak of aseptic meningitis was CVB3. CVB3 circulated in China was genetically different from other countries. PMID- 20718356 TI - [Study on the phenomenon of splashes and sprays from virology]. AB - OBJECTIVE: To investigate the phenomenon of accidental splashes and sprays from manipulation of recombinant virus material and to measure the approximate spilled distance when recombinant virus material inadvertently dropped in the biosafety laboratory. METHODS: first, two groups owning different experience simulated the course of accidental spills and splashes by recombinant adenovirus (rADV) which expressed green fluorescence protein (GFP), the GFP signal were observed in 96 well cell plate after spills appeared; Second, the routine two heights (75 cm and 110 cm) and capacity (1 ml, 1.5 ml, 4 ml and 8 ml) of virus were chose to simulate the experiment of unexpected dropping. RESULTS: First, the positive quantity of the first group owning 5 years' experience is much less than the second group owning 2 years' work experience, the former was 7 positive wells, the latter was 81 positive when they used the pipette to operation. Second, when the unclosed test tubes (1 ml, 1.5 ml, 4 ml and 8 ml recombinant virus) inadvertently dropped, the largest spill distance was 0.92 m, 1.57 m, 2.63 m and2.68 m respectively. CONCLUSION: The better experience is important to make sure safety when we make infectious material; the contaminated distance increased with the amount of recombinant virus material. PMID- 20718357 TI - [Bioinformatics analysis of mosquito densovirus nostructure protein NS1]. AB - OBJECTIVE: To analyze and predict the structure and function of mosquito densovirus (MDV) nostructual protein1 (NS1). METHODS: Using different bioinformatics software, the EXPASY pmtparam tool, ClustalX1.83, Bioedit, MEGA3.1, ScanProsite, and Motifscan, respectively to comparatively analyze and predict the physic-chemical parameters, homology, evolutionary relation, secondary structure and main functional motifs of NS1. RESULTS: MDV NS1 protein was a unstable hydrophilic protein and the amino acid sequence was highly conserved which had a relatively closer evolutionary distance with infectious hypodermal and hematopoietic necrosis virus (IHHNV). MDV NS1 has a specific domain of superfamily 3 helicase of small DNA viruses. This domain contains the NTP-binding region with a metal ion-dependent ATPase activity. A virus replication roller rolling-circle replication(RCR) initiation domain was found near the N terminal of this protein. This protien has the biological function of single stranded incision enzyme. CONCLUSION: The bioinformatics prediction results suggest that MDV NS1 protein plays a key role in viral replication, packaging, and the other stages of viral life. PMID- 20718358 TI - [Epidemiological study and clinical analysis of 113 laboratory-confirmed cases with hand, foot and mouth disease]. AB - OBJECTIVE: To analyse the epidemiological and clinical characteristics of different pathogenesis type cases, severe and common cases of hand, foot and mouth disease. METHODS: Descriptive epidemic method was used to analyse the epidemiological and clinical characteristics of laboratory-confirmed cases with hand,foot and mouth disease. RESULTS: The epidemiological characteristics 113 cases were the same as epidemic situation at the same time in Anji county. Clinical characteristics were difference in different pathogenesis type cases, severe and common cases of hand, foot and mouth disease. CONCLUSION: Prevention and control work taken should according to the characteristics of the disease, such as early identification of severe cases, handling and controlling over the outbreaks in order to reduce the severe cases and the death. PMID- 20718359 TI - [The short-term efficacy of antiviral treatment in patients with acute-on-chronic hepatitis B liver failure]. AB - OBJECTIVE: To investigate the short-term efficacy of antiviral therapy in acute on-chronic liver failure associated with hepatitis B. METHODS: A total of 348 patients with acute-on-chronic liver failure associated with hepatitis B, of which 173 cases of low viral load (HBV DNA <105 copies/ml) and 175 cases of high viral load (HBV DNA > or =105 copies/ml), were divided into two groups. One was treated with antiviral therapy (LAM or ETV or Ltd) and routine supportive therapy, and the other received supportive therapy only. The clinical features, survival rate and the short-term efficacy of antiviral therapy were compared between the two. RESULTS: It was indicated in Cox regression analysis of multiple factors that antiviral therapy is the favorable factor of affecting prognosis. The survival rate of the group receiving antiviral therapy was higer than that of the one in control group in a 24-week observation. In patients with 4 weeks treatment there were statistical significant differences (P < or = 0.05) in both the level of TBil in serum and the decreasing amplitude of HBV DNA between the two groups. Also after 24-week therapy the survival rates of the patients with both low and high viral load was higer in the group with antiviral therapy,and that made statistically significant (P < or = 0.05). CONCLUSION: Antiviral therapy can improve the survival rate of the acute-on-chronic liver failure associated with hepatitis B. And it is also needed in patients with low viral load. PMID- 20718360 TI - [Clinical study on cross-infection of mycoplasma pneumoniae and other viruses in children]. AB - OBJECTIVE: To investigate the clinical cross infections of mycoplasma pneumoniae (MP) and other viruses in children, providing a reference for the diagnosis and treatment of respiratory disease. METHODS: Serum specimens of the children hospitalized with fever, respiratory symptom besides positive results of MP-Ab IgM detection were collected. And several common viruses popular in children were investigated within the specimens collected by ELISA kits or indirect immunofluorescence. RESULTS: (1) The PCT levels of 385 cases (81.7%) appear to be under 0.5 ng/ml. (2) In the 514 cases detected for Cox-IgG and Cox-IgM, the positive rates are respectively 40.3% and 35.6%. (3) 2 cases (0.8%) appear to be influenza B virus positive. And the positive rates of parainfluenza virus 1, 2 and 3 are 0.8%, 0, and 9%. 4, 84 cases (11.8%) are positive for EB-IgM and 451 cases (63.6%) positive for EB-IgG. CONCLUSION: Cross infections rarely occur between MP and common respiratory viruses in Children. The cross-infection rate between Cox-virus and MP is up to 35.6%. PMID- 20718361 TI - [Efficacy and durability of generic adefovir dipivoxil in patients with HBeAg positive chronic hepatitis]. AB - OBJECTIVE: To study the efficacy and durability of generic adefovir dipivoxil (ADV) in patients with HBeAg positive chronic hepatitis. METHODS: 54 nucleosides naive patients with HBeAg positive chronic hepatitis were enrolled in this randomized, double-blinded, placebo-controlled, prospective study. 38 patients received ADV (10 mg once daily) and the others received placebo. Then all the patients were treated with ADV for 96 weeks and were followed up for 12 weeks. RESULTS: (1) At week 12, the level of ALT declined significantly in ADV group(135.84 +/- 10.63 U/L to 58.92 +/- 4.95 U/L, P < 0.001) compared with placebo group (145.56 +/- 17.19 U/L to 159.50 +/- 37.05 U/L) (P < 0.001). The HBV DNA level also declined significantly in adefovir group compared with placebo group (2.51 vs. 1.04 log10 copies/ml, P < 0.001). (2) The rates of normal ALT, normal of AST and undetectable HBV-DNA at 48 and 96 weeks of therapy with ADV were 63.30%, 70.50%, 87.80%, 88.60%, 53.06%, 54.55%, respectively. (3) There were 17 patients discontinuated ADV after 96 weeks. The follow-up results showed that HBV-DNA became positive again in all these 17 patients and abnormal liver function developed in 88.24% (15/17) patients. CONCLUSIONS: Treatment of chronic hepatitis B with generic ADV was effective and well tolerated, but relapse may develop when treatment was discontinued. PMID- 20718362 TI - [Evaluation of genotyping of human papilomavirus by a new DNA liquid chip based on Luminex XMAP]. AB - OBJECTIVE: To evaluate the diagnostic value of Luminex XMAP liquid chip for HPV detection. METHODS: Detect HPV DNA with the liquid chip and HC II in 264 cases, including 231 of cervical cancer and 33 of cervical scrapes. The accordance of two methods were compared and DNA sequencing was performed in conflicting samples and single (infection samples. RESULTS: There is an excellent agreement between the methods. The overall incidence of HPV was 82.95%, the most common genotypes were HPV 16, 52, 58, 18, 11, 31, 6, 39, 33, 56, 70. Among all the positive types, 117 were single type and 102 were multiple types, and 87.43% were high-risk HPV genotypes and 12.57% were low-risk genotypes. Based on the criteria of histology and pathology, the sensitivity, specificity, positive and negative-predictive value of HPV liquid chip and HC II for detecting all cases of CIN II, III and carcinomas were respectively 93.07%, 87.88%, 98.17%, 64.44% and 94.81%, 87.88%, 98.21%, 70.73%. CONCLUSION: The common types of HPV infection are 16, 52, 58, 18, 11, 6, 56 and 31. Multiplex HPV genotyping by Luminex XMAP liquid chip appears to be highly suitable for diagnostic screening and large-scale epidemiological studies. PMID- 20718363 TI - [Evaluation of the accuracy of domestic commercial HBV DNA real-time polymerase chain reaction kits using COBAS TaqMan HBV Test as reference]. AB - OBJECTIVE: To evaluate of the accuracy of domestic commercial HBV DNA real-time polymerase chain reaction kits. METHODS: Using COBAS TaqMan HBV Test as reference, we evaluate the accuracy of a domestic commercial HBV DNA real-time polymerase chain reaction kit (PG). RESULTS: Among the samples with viral load at the range of 10(1), 10(2), 10(3), 10(4), 10(5), 10(6), 10(7) (IU/mL), the Coefficient of Correlation(r) between the result determined by domestic kit (PG) and those of Roche COBAS TaqMan HBV Test were: -0.08011, -0.05056, 0.105642, 0.312181, 0.908046, 0.866175, -0.23295, respectively; the percentage of false negative results were 60%, 30%, 33.3%, 8.3%, 0, 0, 0, respectively. Among the samples with viral load over than 10(7) (IU/ml), the result determined by PG is significantly lower. CONCLUSION: The accuracy of PG is not satisfied, especially in those samples with viral load less than 10(4) (IU/ml). A implication from these observation is that samples from patients received antiviral treatment should be tested by Roche COBAS TaqMan HBV Test. PMID- 20718364 TI - [A nested multiplex PCR assay for rapid subtyping the prevailing HIV-1 strains in Guangxi]. AB - OBJECTIVE: To establish a rapid nested multiplex PCR assay for subtyping HIV-1 CRF01_AE, CRF07_BC, CRF08_BC, B, and C strains prevailing in Guangxi. METHOD: Subtype-specific primers were designed for these subtypes based on their gag sequences. The subtypes of HIV-1 samples from Guangxi were determined by nested multiplex PCR and DNA sequencing and phylogenetic analysis, respectively, and then the sensitivity and the specificity of nested multiplex PCR were calculated. RESULTS: Nested multiplex PCR could correctly classify the 5 known-subtype samples, and were not reactive to all HIV-negative samples. Of the 72 HIV positive samples, 66 were correctly identified as CRF01_AE, CRF07_BC, CRF08_BC, and B by this assay, giving a sensitivity of 91.7% (66/72), and a specificity of 100%. CONCLUSION: This assay is a simple, fast, and cost-effective subtyping method for HIV-1 CRF01-AE, CRF07_BC, CRF08_BC, and B strains prevailing in Guangxi. PMID- 20718365 TI - [Improvement of quantitative method on anti-HBs]. AB - OBJECTIVE: Through detecting the standard preparation with series of concentration to indirectly calculate the anti-HBs concentration of the serum samples, a suitable anti-HBs quantitative method for our laboratory was found after comparing the two kinds of methods. METHODS: Detecting the anti-HBs standard preparation with series of concentration by RIA method, standard curvilinear equations were obtained by the means of fitting the detected result and the corresponding concentration by log-log model and exponential curve model respectively. Then the fitting efficiency of two curves was compared. By calculating the concentrations of the reference using two standard curvilinear equations, we can compare the accuracy of two quantitative methods. RESULT: The error mean square of the exponential curve model is low as 1.2971 and the determinate coefficient is close to 1 with the value of 0.9904. The average concentrations (n=6) of the detected reference calculated by two curvilinear equation with the actual concentration of 30.0 mIU/mL are (32.28 +/- 1.06) and (31.91 +/- 1.06) mIU/ mL respectively. The concentration calculated by exponential curve model is only 6.37% higher than the actual concentration. CONCLUSION: Fitting by exponential curve model is more practical to estimate the actual concentration of the serum samples those will be detected. It can be used as an optimal quantitative method to detect anti-HBs concentration. PMID- 20718366 TI - [Detection and analysis of the enterovirus infection within 159 cases of hand foot-mouth disease by a real-time reverse transcription-PCR assay]. AB - OBJECTIVE: To reveal the enterovirus infection within children suffering hand foot-mouth disease (HFMD) in the Capital Institute of Pediatrics from Aprial to August, 2009, for the sake of clinical diagnosis and treatment. METHODS: Both throat swab and vesicle fluid were taken respectively from 159 children with HFMD. And RNA were extracted from each sample followed with real-time fluorescence quantitative RT-PCR kits with three reagents: universal enterovirus primer, Coxsackievirus A16 (CA16) primer and enterovirus 71 (EV71) primer. Parts of postivive samples were sequenced and analyzed. RESULTS: (1) EV genes were detected from 152 cases, of which, 102 cases were positive for CA16 and 43 were positive for EV71. (2) CV16:EV71 was 2.37:1. The positive rates of throat swabs and vesicle fluid samples were not statistically significant. (3) The PCR results were same with that of sequence analysis. CONCLUSION: The hand-foot-mouth disease recently appeared in our hospital was mainly related to the EV71 or CA16 infection. And the percentage of EV71 infections obviously increased compared to that of 2007. PMID- 20718367 TI - [The analysis of the test results in HIV screening laboratory of Beijing Friendship Hospital in 2008]. AB - OBJECTIVE: According to test results of the Hospital of AIDS screening laboratory in 2008, after counting analysis to assess the prevalence of AIDS, we can early detect positive cases in the future and effectively control the spread of AIDS. METHODS: All serum samples were screened by ELISA method and we reexaminated the samples by PA. As long as one result is positive by the two methods, then we sent the positive samples to Beijing Center for Disease Control and Prevention by Western Blot method to confirm the result. RESULTS: A total of 21 467 samples were detected and 29 (13.5% 0) were positive screening results. We confirm there were 7 (24.1%) positive samples and 12 (41.4%) suspected samples. We researched the epidemiology of the specimens by its source and age and sex. CONCLUSION: Application of ELISA method for HIV screening test has a practical significance, it is accurate and fit to record the results of the screening test for AIDS. PMID- 20718368 TI - One in four nurses would strike as job fears increase. PMID- 20718369 TI - It's a triumph that degree nurses are no longer viewed as alien stock. PMID- 20718370 TI - The high impact actions for nursing and midwifery. 3: Staying safe, preventing falls. AB - The National Patient Safety Agency reported 152,000 falls in England and Wales in acute hospitals in 2009, 26,000 in mental health trusts and 28,000 in community hospitals. The number of falls is due to rise in line with increasing numbers of older and frail people who have more complex health needs. Many of these falls are preventable; the challenge for the NHS is to improve patient safety while protecting independence patients' rights to make informed choices. PMID- 20718371 TI - How to ensure acute pain in older people is appropriately assessed and managed. AB - The increasing ageing population and the common occurrence of acute and chronic pain in this group means that nurses are likely to come into contact with many older patients who need pain management. This article examines the assessment of acute pain in older people, as well as different approaches to and challenges in pain management. PMID- 20718372 TI - Implementing a health promotion model in a young offender institution. AB - Young people in young offender institutions experience more physical and mental health problems than the general population. This article explores how the primary nursing service at HM Young Offenders Institution Huntercombe used national policy as a framework for managing change. In outlining the challenges and opportunities that influence practice development, we hope to demystify nursing in a prison setting, which is a hidden and often misunderstood aspect of healthcare. PMID- 20718373 TI - Spirituality. 2: Exploring how to address patients' spiritual needs in practice. AB - Although meeting patients' spiritual needs is important, many nurses are uncertain about what spiritual care involves and lack confidence in this area. This second article in a two part series on spirituality considers ways of addressing spiritual needs and provides an overview of the principles of assessment and implementation. Part 1 explored definitions of spirituality, the difference between religion and spirituality, and finding meaning in illness. PMID- 20718374 TI - You can help us stop dangerous frontline cuts. PMID- 20718376 TI - Another reprieve. PMID- 20718377 TI - Epiploic appendagitis: a clinically valuable imaging diagnosis. AB - Epiploic appendagitis occurs more commonly than previously thought and the clinical presentation can mimic other serious acute abdominal processes such as diverticulitis and appendicitis. Epiploic appendagitis can be confidently diagnosed via CT scan in nearly all cases. As a result of the accurate diagnosis unnecessary antibiotics, laboratory testing, dietary restrictions, surgical consultation, hospitalization, overtreatment, and unnecessary costs to the patient and health care system can be avoided. Patients with epiploic appendagitis can be conservatively managed as outpatients. PMID- 20718378 TI - Obesity and school lunch programs. Interview by Dace Blaskovitz. PMID- 20718379 TI - Culling the herd. PMID- 20718380 TI - Comment on Increased caesarean section rate over time (1994-2006) is not associated with improved outcomes in very low birth weight infants. PMID- 20718381 TI - The Coumadin dilemma. PMID- 20718382 TI - Honoring those we serve. PMID- 20718383 TI - Adaptability to perturbation as a predictor of future falls: a preliminary prospective study. AB - BACKGROUND: Falls often result from failed responses to unexpected, externally applied perturbations. Whether performance-based, reaction-based, and/or adaptation-based assessment tools can predict future fails among community dwelling older adults is unknown. PURPOSE: This preliminary prospective study examined the relationship between older adults' future fall risk and their reactive responses and adaptations to repeated slips, and their functional status. METHODS: Thirteen community-dwelling adults (>64 years) were exposed initially to a session of repeated slips. About 30 months later, self-reported falls experience data were collected for the preceding year from these participants. Slip outcome (fall, loss of balance, or recovery), slip score (weighted sum of slip outcomes), Timed Up and Go scores, and future fall incidence were recorded. RESULTS: Four participants who reported at least 1 fall had significantly higher slip scores than the rest. In contrast, neither failed recovery on the first slip nor a higher TUG score predicted greater odds of future falls. CONCLUSION: Community-dwelling older adults' adaptability to externally imposed perturbations may reveal their future fall risk. PMID- 20718384 TI - Defining community ambulation from the perspective of the older adult. AB - BACKGROUND: Little is known regarding destinations and distances necessary for independent community ambulation after enactment of the Americans with Disability Act. OBJECTIVE: To qualitatively describe community locations visited by older adults and to determine ambulation distance required to visit these locations. DESIGN: Descriptive study. METHODS: Nineteen subjects, 65 years or older and who were independent with transportation, ambulation, and basic activities of daily living, were recruited from 4 senior centers in urban areas of central Alabama. The study was divided into 2 phases. In part 1, using qualitative methodology, older adults were interviewed to determine locations they visited in the community. In part 2, we visited the types of locations identified in part 1 and measured distances required to conduct business at each location. Obstacles, if any, to reaching these locations were identified. RESULTS: Subjects had a mean age of 76.6 (5.8) years; 80% were women, and 50% lived alone in the community. Locations visited by subjects were identified and measured. Researchers categorized locations as essential, essential to some people, and nonessential. Essential locations included bank, doctor's office, and either a grocery store, pharmacy, and department store or a "superstore". A minimum of approximately 200 m was required for community ambulation to most locations, although this distance varied significantly among locations. LIMITATIONS: Geographic location and urban setting may not reflect distances necessary for rural residents. CONCLUSIONS: Physical therapists can use the 200-m distance as a starting point for goal setting for older adults desiring a return to community independence. PMID- 20718385 TI - The impact of assistive device prescription on gait following total knee replacement. AB - PURPOSE: To determine whether patients using a wheeled walker post-total knee replacement (TKR) surgery walk differently prior to hospital discharge and 6 weeks after surgery when compared with patients using a standard walker. METHODS: Fifty-one patients, mean age 67.2 (8.3), seen for TKR were assigned to either a standard walker group (n=23) or front-wheeled walker group (n=28). Most participants were assigned to a walker group on the basis of the type of walker procured in anticipation of the surgery; however, those without a walker were randomly assigned to a group. All participants received postoperative physical therapy consisting of a standardized protocol of exercises and gait training twice a day with the assigned walker. Step length, cadence, gait velocity, step length differential, and walking endurance were measured at discharge from the acute care setting and at 6 weeks following surgery. RESULTS: At discharge from the acute care setting, the gait of the 2 groups was similar, with the exception of faster velocity and a longer step length on the noninvolved lower extremity for the wheeled walker group. Six weeks after surgery, both groups walked with faster velocity, longer step lengths, and faster cadence, with no differences between groups for walking endurance, perceived exertion, fall occurrence after surgery, functional scores, or days necessary to graduate from walker use. CONCLUSION: The use of a front wheeled walker can facilitate greater velocity and longer step lengths in the immediate days following TKR than the use of a standard walker. However, this study provides no evidence that participants using wheeled walkers require fewer inpatient therapy sessions or have greater long term gains in ambulation speed or quality. This study suggests that both types of walkers can safely be used for ambulation after TKR surgery. PMID- 20718386 TI - Impact of participation in a wellness program on functional status and falls among aging adults in an assisted living setting. AB - PROBLEM: Aging adults residing in assisted living facilities are vulnerable to the effects of cumulative chronic illness and increasingly sedentary lifestyle, both contributing to risk of functional decline over time. Participation in regular exercise appears to preserve functional status and may minimize the rate of functional decline. PURPOSE: This quasi-experimental study evaluated the longitudinal impact of regular participation in a wellness exercise program on functional status of residents in assisted living. METHODS: Thirty-six aging adults participating in a multimodal wellness program were evaluated on enrollment and after 12 months of participation. Cognitive status (Mini-Mental State Examination score), postural control/fall risk (Berg Balance Scale score), and cardiovascular endurance/mobility (6-Minute Walk Test distance) were examined on enrollment and at annual reassessment. Falls over 12 months were determined by tracking annual reported incidence of falls. Subjects were classified as "regular" or "nonregular" exercisers on the basis of participation frequency and adherence. Chi-square analysis and analysis of variance were used to screen for initial differences between groups. Repeated-measures analysis of variance evaluated differences in cognitive status, falls, and functional measures between groups at annual reassessment. RESULTS: Mean age (SD) of participants was 85.5 (6.3) years (range = 72-96 years). There were no differences between groups at the time of enrollment. At annual reassessment, regular exercisers demonstrated better preservation of functional status and a lower rate of falling than nonregular exercisers. CONCLUSION: Regular participation in an individualized wellness program as little as twice weekly for 9 of 12 months provides protection against functional decline and risk of falls in older adults in assisted living settings. PMID- 20718387 TI - The effects of a home-based exercise program on physical function in frail older adults. AB - BACKGROUND AND PURPOSE: Exercise has been shown to improve physical function in frail older adults; however, the effects of exercise may vary with degree of frailty, the format and intensity of the exercise intervention, and level of supervision. This cohort study describes the effects of participation in a 6-week home-based exercise program on measures of physical function as well as exercise related beliefs, including exercise self-efficacy and outcomes expectation, in frail older adults. METHODS: Participants were 72 frail older adults who participated in a 6-week home-based exercise program supervised by graduate physical therapy students. Individualized home-based exercises targeted strength, flexibility, balance, gait, and cardiovascular fitness. Physical function was measured at baseline and after completion of the 6-week exercise program using the Functional Fitness Test (Biceps Curl, Chair Stand, 8-Foot Up and Go) and velocity on a 4-m walk. Measures of exercise-related beliefs included the Self Rated Abilities for Health Practices Scale and Exercise Outcome Expectations. OUTCOMES: Participation in the 6-week home-based exercise program was associated with improvements in measures of physical function, including an average increase of 3 repetitions (35%) on the biceps curl, 2.4 repetitions (59%) on the chair stand, and an average increase of 0.17 m/s (33%) in gait velocity. Average decrease in Timed Up and Go test scores was 5.7 seconds (26%). Scores for exercise-related beliefs also improved (self-efficacy average increase was 7 points [40%], and average increase in outcome expectations was 3 [47%]). DISCUSSION: A supervised 6-week, multidimensional home-based exercise program was safe and associated with improvements in physical and exercise-related belief outcome measures in this cohort study of frail older adults. PMID- 20718388 TI - The effects of a home-based exercise program on balance confidence, balance performance, and gait in debilitated, ambulatory community-dwelling older adults: a pilot study. AB - PURPOSE: The purpose of this pilot study was to evaluate the effects of a home based standing exercise and balance training program on balance confidence, balance performance, and gait in debilitated, ambulatory community-dwelling older adults. METHODS: A quasi-experimental single group pre- to posttest design was utilized in 14 subjects, 9 male and 5 female, aged 71 to 85 years receiving home care. Measurements included the Falls Efficacy Scale (FES), Performance Oriented Mobility Assessment (POMA), and the One-Leg Stance Test (OLST) administered prior to and following 4 weeks of exercise and balance training. Participants trained twice per day, 5 days per week for 4 weeks, and maintained exercise logs. RESULTS: Pre- to posttest differences on the FES, POMA, and OLST were analyzed with the Wilcoxon signed rank test and the 2-tailed paired t test, respectively, with statistical significance set at .05. Analysis demonstrated significant improvements on the FES, POMA, and OLST following 4-weeks of standing exercise and balance training. Based on entrance and exit interviews, 6 of the 14 participants had a history of falls in the 6 months prior to the study, while only 2 participants reported having a single, minor fall by discharge. CONCLUSIONS: The results of the present pilot study demonstrated significant improvement in balance confidence, balance performance, and gait in debilitated, ambulatory community-dwelling older adults following participation in a home based exercise and balance training program. However, definitive conclusions need to await validation from more rigorously designed studies before the present training program can be confidently recommended to physical therapists engaged in home care practice. PMID- 20718389 TI - Responsiveness of the physical mobility scale in long-term care facility residents. AB - PURPOSE: The Physical Mobility Scale (PMS) is used to evaluate the functional ability of aged adults. It has been shown to be reliable and has evidence to support its validity; however, there has been only 1 study performed to date that has addressed its responsiveness. The purpose of this study was to evaluate the responsiveness of the PMS using residents of a long-term care facility. METHODS: Seventy participants who were permanent residents of a long-term care facility were recruited for this study. To determine minimal detectable changes at the 95% confidence level (MDC95), each participant was assessed using the PMS on 2 occasions. To determine the clinically important difference, participants were also tested on 2 separate occasions 3 months apart. The treating physical therapist then used a 7-point Likert scale to rate the participants' change in function. RESULTS: Intrarater reliability for the pre- and post-PMS scores for all 70 participants was excellent (intraclass correlational coefficients = 0.982). At the individual level, the MDC95 was 3.98 points. At the group level, the MDC95 for the 70 participants was 0.476 points. Minimal clinically important difference results suggest that a positive change of 5 points is "improved" clinically whereas a 4-point decrease in score is considered "worsened" clinically. CONCLUSIONS: The psychometric properties of the PMS in an aging adult population of long-term residents are excellent, demonstrating good reliability and responsiveness. These results also offer some support to the validity of the PMS in this patient population. The utility of the PMS in the long-term care setting for assessing patient status and positive and/or negative functional outcomes is of value to both researcher and clinician. PMID- 20718390 TI - Transcendence in care of the dying? PMID- 20718391 TI - Whole-person care research: a team approach. PMID- 20718392 TI - Family caregivers of palliative cancer patients at home: the puzzle of pain management. AB - The purpose of this grounded theory study was to understand the processes used by family caregivers to manage the pain of cancer patients at home. A total of 24 family caregivers participated. They were recruited using purposeful then theoretical sampling. The data sources were taped, transcribed (semi-structured) interviews and field notes. Data analysis was based on Strauss and Corbin's (1998) requirements for open, axial, and selective coding. The result was an explanatory model titled "the puzzle of pain management," which includes four main processes: "drawing on past experiences"; "strategizing a game plan"; "striving to respond to pain"; and "gauging the best fit," a decision-making process that joins the puzzle pieces. Understanding how family caregivers assemble their puzzle pieces can help health care professionals make decisions related to the care plans they create for pain control and help them to recognize the importance of providing information as part of resolving the puzzle of pain management. PMID- 20718393 TI - Quality of life in terminally ill cancer patients: contributors and content validity of instruments. AB - Over the last few decades, improvement in the quality of life (QOL) of cancer patients has received a lot of attention in oncology. This study aims to further explore what factors terminally ill cancer patients report as influencing their QOL. Content analysis of 110 terminally ill cancer patients' answers to the McGill Quality of Life Questionnaire open-ended question was performed. Negative and positive factors reported by patients as having an impact on their QOL were identified then categorized into eight domains: "physical condition and symptoms," "psychological status," "existential," "relationships and support," "quality of care," "physical environment and living facilities," "hobbies and daily activities," and "finances." The "physical condition and symptoms" and "relationships and support" domains were the two most often described by participants as important to their QOL. The results support previous work identifying domains important to the QOL of terminally ill patients with cancer, but they also identify "finances" as a new domain. Based on these findings, we suggest including "finances" in QOL instruments for the terminally ill as an experimental domain. PMID- 20718394 TI - Quality of life and symptom burden in cancer patients admitted to an acute palliative care unit. AB - This paper describes the quality of life and symptom burden of 211 cancer patients admitted to an acute palliative care unit (PCU) in a comprehensive cancer centre. Participants completed the McGill Quality of Life Questionnaire (MQOL), Edmonton Symptom Assessment Scale (ESAS), Short Orientation-Memory Concentration Test, and Palliative Performance Scale within 24 hours of admission to the PCU. The mean MQOL total was 6.1 +/- 1.4, and the mean single-item scale score was 4.9 +/- 2.4. The mean total ESAS score was 36.3 +/- 15.8, with a median of six reported symptoms. Women and younger patients reported a lower quality of life (QoL) and a higher symptom burden. Regression and correlational analyses highlighted the importance of the existential and psychological domains to overall QoL. These findings emphasize the need for interdisciplinary, collaborative approaches to managing the complex physical, psychosocial, and existential needs of cancer patients admitted to acute PCUs. PMID- 20718395 TI - It takes a whole community: the contribution of rural hospice volunteers to whole person palliative care. AB - Although volunteers are widely acknowledged as important members of the palliative care team, their unique contribution to whole-person care has not been well documented or theorized, especially in rural communities. We conducted a focused ethnography in a small rural community, asking key community informants about their understanding of the role of hospice volunteers with dying people and their families. Our results show that these volunteers inhabit a unique third culture of care that fuses elements of formal care with the informal visiting of friends and neighbours. Their role is shaped to a community context where dying is not a private medical event, but rather a whole-person-in-community event, and where care is offered as a natural expression of the interdependence and reciprocity that characterizes rural community life. Our results are a reminder that it takes an entire community to care for the dying, and that hospice volunteers are a crucial link in the network of care that allows people to die with dignity and quality of life. PMID- 20718396 TI - Skills training to support patients considering place of end-of-life care: a randomized control trial. AB - The effect of a program to train clinicians to support patients making decisions about place of end-of-life care was evaluated. In all, 88 oncology and/or palliative care nursing and allied health providers from three Ontario health networks were randomly assigned to an education or control condition. Quality of decision support provided to standardized patients was measured before and after training, as were participants' perceptions about the acceptability of the training program and their intentions to engage in patient decision support. Compared to controls, intervention group members improved the quality of decision support provided and were more likely to address a wider range of decision-making needs. Intervention group members scored higher on a knowledge test of decision support than controls and rated the components as acceptable. Improvements in the quality of decision support can be made by providing training and practical tools such as a patient decision aid. PMID- 20718397 TI - Care provider perspectives on end-of-life care in long-term-care homes: implications for whole-person and palliative care. AB - This study holistically explores the experience of dying and end-of-life care for older persons with dementia in long-term care (LTC) from the perspective of care providers. Using a focused ethnography methodology, seven researchers interviewed LTC staff, residents' families, volunteers, management staff, and spiritual advisers/clergy over a five-day period. Research was guided by two key questions: What is the dying experience of people living in LTC from the perspective of different care providers? and, What are the salient issues in providing palliative care for elderly people dying in LTC? Based on a thematic analysis of verbatim data, three common themes were identified: tension between completing job tasks on time and "being there" for residents; the importance of family-like bonds between front-line staff and residents; and the importance of communication among staff and between staff and residents and their families at the end of life. Findings are discussed in relation to their implications for policies and practices that can support whole-person care and ultimately a good death for residents of LTC facilities. PMID- 20718398 TI - Preliminary outcomes of "the Dementia Difference" workshop at the Lodge at Broadmead, Victoria, BC. PMID- 20718399 TI - Re: A New Zealand perspective on palliative care for Maori. PMID- 20718400 TI - Indirect nanoplasmonic sensing: ultrasensitive experimental platform for nanomaterials science and optical nanocalorimetry. AB - Indirect nanoplasmonic sensing is a novel experimental platform for measurements of thermodynamics and kinetics in/on nanomaterials and thin films. It features simple experimental setup, high sensitivity, small sample amounts, high temporal resolution (<10(-3) s), operating conditions from UHV to high pressure, wide temperature range, and applicability to any nano- or thin film material. The method utilizes two-dimensional arrangements of nanoplasmonic Au sensor nanoparticles coated with a thin dielectric spacer layer onto which the sample material is deposited. The measured signal is spectral shifts of the Au-sensor localized plasmons, induced by processes in/on the sample material. Here, the method is applied to three systems exhibiting nanosize effects, (i) the glass transition of confined polymers, (ii) catalytic light-off on Pd nanocatalysts, and (iii) thermodynamics and kinetics of hydrogen uptake/release in Pd nanoparticles <5 nm. In (i) and (iii), dielectric changes in the sample are detected, while (ii) demonstrates a novel optical nanocalorimetry method. PMID- 20718401 TI - Surface energies control the self-organization of oriented In2O3 nanostructures on cubic zirconia. AB - Highly aligned one-dimensional (1D) nanorods of the transparent conducting oxide In(2)O(3) have been grown on (110)-oriented Y-stabilized ZrO(2) substrates, whereas growth on (100) and (111) substrates leads respectively to blocklike 3D islands and continuous films. It is shown that the striking influence of substrate orientation on the growth morphology is controlled by differences in energies between the low index surfaces of In(2)O(3) and that spontaneous self organization is driven by minimization of surface energies. PMID- 20718402 TI - Edges bring new dimension to graphene nanoribbons. AB - Chemistry at the edges of saturated graphene nanoribbons can cause ribbons to leave the plane and form three-dimensional helical structures. Calculations, based on density functional theory and enabled by adopting helical symmetry, show that F-terminated armchair ribbons are intrinsically twisted in helices, unlike flat H-terminated strips. Twisting ribbons of either termination couple the conduction and valence bands, resulting in band gap modulation. This electromechanical response could be exploited in switches and sensor applications. PMID- 20718403 TI - Charge transport and rectification in arrays of SAM-based tunneling junctions. AB - This paper describes a method of fabrication that generates small arrays of tunneling junctions based on self-assembled monolayers (SAMs); these junctions have liquid-metal top-electrodes stabilized in microchannels and ultraflat (template-stripped) bottom-electrodes. The yield of junctions generated using this method is high (70-90%). The junctions examined incorporated SAMs of alkanethiolates having ferrocene termini (11-(ferrocenyl)-1-undecanethiol, SC(11)Fc); these junctions rectify currents with large rectification ratios (R), the majority of which fall within the range of 90-180. These values are larger than expected (theory predicts R 100 MUM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP. PMID- 20718419 TI - Transition state of ADP-ribosylation of acetyllysine catalyzed by Archaeoglobus fulgidus Sir2 determined by kinetic isotope effects and computational approaches. AB - Sirtuins are protein-modifying enzymes distributed throughout all forms of life. These enzymes bind NAD(+), a universal metabolite, and react it with acetyllysine residues to effect deacetylation of protein side chains. This NAD(+)-dependent deacetylation reaction has been observed for sirtuin enzymes derived from archaeal, eubacterial, yeast, metazoan, and mammalian species, suggesting conserved chemical mechanisms for these enzymes. The first chemical step of deacetylation is the reaction of NAD(+) with an acetyllysine residue which forms an enzyme-bound ADPR-peptidylimidate intermediate and nicotinamide. In this manuscript, the transition state for the ADP-ribosylation of acetyllysine is solved for an Archaeoglobus fulgidus sirtuin (Af2Sir2). Kinetic isotope effects (KIEs) were obtained by the competitive substrate method and were [1(N)-(15)N] = 1.024(2), [1'(N)-(14)C] = 1.014(4), [1'(N)-(3)H] = 1.300(3), [2'(N)-(3)H] = 1.099(5), [4'(N)-(3)H] = 0.997(2), [5'(N)-(3)H] = 1.020(5), [4'(N)-(18)O] = 0.984(5). KIEs were calculated for candidate transition state structures using computational methods (Gaussian 03 and ISOEFF 98) in order to match computed and experimentally determined KIEs to solve the transition state. The results indicate that the enzyme stabilizes a highly dissociated oxocarbenium ionlike transition state with very low bond orders to the leaving group nicotinamide and the nucleophile acetyllysine. A concerted yet highly asynchronous substitution mechanism forms the ADPR-peptidylimidate intermediate of the sirtuin deacetylation reaction. PMID- 20718421 TI - (R,S)-anti-1-amino-2-[18F]fluorocyclopentyl-1-carboxylic acid: synthesis from racemic 2-benzyloxycyclopentanone and biological evaluation for brain tumor imaging with positron emission tomography. AB - (R,S)-anti-1-amino-2-fluorocyclopentyl-1-carboxylic acid (2-FACPC, 4b) was radiolabeled in 39% yield starting from cyclic sulfamidate 12. The 9L gliosarcoma cells assays showed that 4b is mainly a substrate for the L-type amino acid transport with some affinity to the A-type. In rats bearing 9L gliosarcoma tumors, 4b displayed high tumor to brain ratio (10:1) at 120 min after injection. FACPC is an attractive candidate for imaging brain tumors with PET, and its isolated enantiomers are under investigation. PMID- 20718422 TI - Structural consequences of beta-amino acid preorganization in a self-assembling alpha/beta-peptide: fundamental studies of foldameric helix bundles. AB - We report high-resolution crystal structures of six new alpha/beta-peptide foldamers that have a regular alpha-residue/alpha-residue/beta-residue (alphaalphabeta) backbone repeat pattern. All of these foldamers were crystallized from aqueous solution, and all display four-helix bundle quaternary structure in the crystalline state. These oligomers are based on the well-studied 33-residue alpha-peptide GCN4-pLI, which is an engineered derivative of the dimerization domain of GCN4, a yeast transcription factor. GCN4-pLI forms a stable tetramer in solution and crystallizes as a four-helix bundle (Harbury et al. Science 1993, 262, 1401-1407). Previously we described a foldamer (designated 1 here) that was generated from GCN4-pLI by replacing every third alpha-amino acid residue with the homologous beta(3)-amino acid residue; this alphaalphabeta oligomer retains the side chain sequence of the original alpha-peptide, but the backbone contains 11 additional CH(2) units, which are evenly distributed (Horne et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9151-9156). Despite the expanded backbone, 1 was found to retain the ability to form a tetrameric quaternary structure in which the individual molecules adopt an alpha-helix-like conformation. Here we compare nine analogues of 1 that have the same alphaalphabeta backbone but in which one or more of the flexible beta(3)-amino acid residues is/are replaced with an analogous cyclic beta-residue. The motivation for beta(3)-->cyclic replacements is to enhance conformational stability; however, a crystal structure of the one previously reported example (designated 2 here) revealed a "stammer" distortion of the helix-bundle architecture relative to 1. The results reported here suggest that the stammer is a peculiarity of 2, because all six of the new alpha/beta-peptides display undistorted four-helix bundle quaternary structures. More broadly, our results indicate that beta(3)-->cyclic replacements are generally well-accommodated in helix-bundle quaternary structure, but that such replacements can be destabilizing in certain instances. PMID- 20718423 TI - Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5'-methylthioadenosine nucleosidase and 5'-methylthioadenosine phosphorylase. AB - 5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5'-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5' position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano- to picomolar dissociation constants and are potentially novel bacterial anti infective and anticancer drug candidates. PMID- 20718424 TI - Photomediated synthesis of silver triangular bipyramids and prisms: the effect of pH and BSPP. AB - The photomediated synthesis of silver right triangular bipyramids and prisms has been studied, and we have determined that pH and [BSPP]/[Ag(+)] ratio (bis(p sulfonatophenyl)phenylphosphine, BSPP) finely control the reaction rate and, consequently, the crystal growth pathway and morphology of final products. A fast reaction rate, realized at a high pH such as 10 or 11 and a [BSPP]/[Ag(+)] ratio close to 1.0, is necessary to synthesize (100)-faceted right triangular bipyramids in high yield by preferential deposition on (111) facets of planar twinned seeds. A slower reaction rate, which occurs at lower pH or higher [BSPP]/[Ag(+)] ratios, results in preferential deposition on (100) facets of planar-twinned seeds and the formation of nanoparticles possessing a larger surface area defined by (111) facets, such as truncated triangular bipyramids or prisms. BSPP further influences the reaction rate by ensuring a relatively constant concentration of aqueous Ag(+). In the absence of BSPP, the aqueous [Ag(+)] steadily decreases as it is consumed and results in a continuously decreasing reaction rate, which changes the preferred facet for silver deposition. At the beginning of the reaction, growth on (111) facets almost exclusively occurs and results in the formation of right triangular bipyramids, which only have (100) facets. When the reaction rate is decreased due to the consumption of Ag(+) through the course of the reaction, the facet deposition preference changes from (111) to (100) and results in the formation of truncated bitetrahedra, with (111) facets, as the predominant product. PMID- 20718425 TI - In situ characterization of cloud condensation nuclei, interstitial, and background particles using the single particle mass spectrometer, SPLAT II. AB - The aerosol indirect effect remains the most uncertain aspect of climate change modeling, calling for characterization of individual particles sizes and compositions with high spatial and temporal resolution. We present the first deployment of our single particle mass spectrometer (SPLAT II) operated in dual data acquisition mode to simultaneously measure particle number concentrations, density, asphericity, and individual particle size and quantitative composition, with temporal resolution better than 60 s, thus yielding all the required properties to definitively characterize the aerosol-cloud interaction in this exemplary case. We find that particles are composed of oxygenated organics, many mixed with sulfates, biomass burning particles, some with sulfates, and processed sea-salt. Cloud residuals are found to contain more sulfates than background particles, explaining their higher efficiency to serve as cloud condensation nuclei (CCN). Additionally, CCN sulfate content increased with time due to in cloud droplet processing. A comparison between the size distributions of background, CCN, and interstitial particles shows that while nearly all CCN particles are larger than 100 nm, over 80% of interstitial particles are smaller than 100 nm. We conclude that for this cloud, particle size is the controlling factor on aerosol activation into cloud-droplets, with higher sulfate content playing a secondary role. PMID- 20718426 TI - Analytical possibilities of total reflection X-ray spectrometry (TXRF) for trace selenium determination in soils. AB - Selenium content of soils is an important issue due to the narrow range between the nutritious requirement and toxic effects upon Se exposure. However, its determination is challenging due to low concentrations within complex matrices that hamper the analysis in most spectroscopic techniques. In this study, we explored the possibilities of several analytical approaches combined with total reflection X-ray (TXRF) spectrometry for soil Se determinations. The direct analysis of a solid suspension using 20 mg of fine ground material (<50 MUm) has a relatively high Se limit of detection (LOD) of 1 mg/kg (worldwide Se average in soils = 0.4 mg/kg) and is therefore only suitable for seleniferous soils. Several fast and simple analytical strategies were developed to decrease matrix effects and improve the LOD for Se determination in soil digests. On one hand, the application of a liquid-liquid extraction procedure using ethyl ether and the introduction of a Cr absorbent in the instrument configuration were carried out to avoid the associated problems on TXRF analysis of soil extracts due to the high Fe concentrations (~700 mg/L). On the other hand, a dispersive liquid-liquid microextraction procedure (DLLME) before the TXRF analysis of the soil digest was also developed. The effects of various experimental parameters such as sample volume, effect of major elements present in the soil matrix (Fe), and Se concentration in the sample were investigated. The LOD using this analytical methodology (0.05 mg/kg of Se) was comparable to or lower than those obtained in previous works using other popular spectrometric techniques such as GFAAS, ICPMS, and AFS. The calculated Se concentration for JSAC-0411 ([Se] = 1.32 +/- 0.27 mg/kg) using the combination of DLLME and TXRF ([Se] = 1.40 +/- 0.23 mg/kg) was in agreement with the certified value. PMID- 20718427 TI - Quasi-confocal, multichannel parallel scan hyperspectral fluorescence imaging method optimized for analysis of multicolor microarrays. AB - The microarray technique, which can provide parallel detection with high throughput in biomedical research, has generated considerable interest since the end of the 20th century. A number of instruments have been reported for microarray detection. In this paper, we have developed a quasi-confocal, multichannel parallel scan hyperspectral fluorescence imaging system for multicolor microarray research. Hyperspectral imaging records the entire emission spectrum for every voxel within the imaged area in contrast to recording only fluorescence intensities of filter-based scanners. When coupled with data analysis, the recorded spectral information allows for quantitative identification of the contributions of multiple, spectrally overlapping fluorescent dyes and elimination of unwanted artifacts. This system is improved with a specifically designed, high performance spectrometer which can offer a spectral resolution of 0.2 nm and operates with spatial resolutions ranging from 2 to 30 MUm. We demonstrate the application of the system by reading out arrays for identification of bacteria. PMID- 20718428 TI - Trypsin coatings on electrospun and alcohol-dispersed polymer nanofibers for a trypsin digestion column. AB - The construction of a trypsin column for rapid and efficient protein digestion in proteomics is described. Electrospun and alcohol-dispersed polymer nanofibers were used for the fabrication of highly stable trypsin coatings, which were prepared by a two-step process of covalent attachment and enzyme cross-linking. In a comparative study with the trypsin coatings on as-spun and nondispersed nanofibers, it has been observed that a simple step of alcohol dispersion improved not only the enzyme loading but also the performance of protein digestion. In-column digestion of enolase was successfully performed in less than 20 min. By applying the alcohol dispersion of polymer nanofibers, the bypass of samples was reduced by filling up the column with well-dispersed nanofibers, and subsequently, interactions between the protein and the trypsin coatings were improved, yielding more complete and reproducible digestions. Regardless of alcohol dispersion or not, trypsin coatings showed better digestion performance and improved performance stability under recycled uses than covalently attached trypsin, in-solution digestion, and commercial trypsin beads. The combination of highly stable trypsin coatings and alcohol dispersion of polymer nanofibers has opened up a new potential to develop a trypsin column for online and automated protein digestion. PMID- 20718429 TI - AlN passivation layer-mediated improvement in tensile failure of flexible ZnO:Al thin films. AB - AlN passivation layer-mediated improvement in tensile failure of ZnO:Al thin films on polyethersulfone substrates is investigated. ZnO:Al films without any passivation layer were brittle with a crack-initiating bending strain epsilonc of only about 1.13% with a saturated crack density rhos of 0.10 MUm(-1) and a fracture energy Gamma of 49.6 J m(-2). On passivation by an AlN overlayer, the fracture energy of the system increased considerably and a corresponding improvement in epsilonc was observed. AlN layers deposited at higher discharge powers yielded higher fracture energy and exhibited better performance in terms of epsilonc and rhos. PMID- 20718430 TI - Ag-TiO2 nanoparticle codoped SiO2 films on ZrO2 barrier-coated glass substrates with antibacterial activity in ambient condition. AB - Anatase TiO2 and Ag nanoparticles (NPs) codoped SiO2 films were prepared by the sol-gel method. Proportionate amounts of 3-(glycidoxypropyl)trimethoxysilane (GLYMO), tetraethylorthosilicate (TEOS) and 3 (methacryloxypropyl)trimethoxysilane (MEMO) derived inorganic-organic silica sol, commercially available dispersed anatase TiO2 NPs, and AgNO3 were used to prepare the sols. The films were prepared on ZrO2 (cubic) precoated soda-lime glass substrates by a single-dipping technique and heat-treated at 450 degrees C in air and H2/Ar atmosphere to obtain hard, relatively porous, and transparent coatings of thickness>600 nm. The ZrO2 barrier layer was previously applied on soda-lime glass to restrict the diffusion of Ag into the substrate. The Ag-TiO2 NPs incorporated SiO2 films were intense yellow in color and found to be fairly stable at ambient condition for several days under fluorescent light. These films show a considerable growth inhibition on contact with the gram negative bacteria E. coli. PMID- 20718431 TI - Ionothermal synthesis of layered zirconium phosphates and their tribological properties in mineral oil. AB - In an attempt to synthesize novel zirconium phosphate materials, a series of syntheses have been performed in a deep eutectic solvent (DES), composed of tetrapropylammonium bromide (TPABr) and oxalic acid. As a result, this DES does not act as a template provider in reaction probably owing to the steric effects of the longer chains of the TPA cation, and only the alpha-Zr(HPO(4))(2).H(2)O (alpha-ZrP) phase has been achieved. However, after organic amine was added to the initial reaction mixture in a normal way, the additives did act as a template to induce the zirconium phosphate framework. For example, with 1,4 dimethylpiperazine as an additive, a novel layered compound, [C(6)H(16)N(2)](0.5)Zr(H(0.5)PO(4))(2).H(2)O (denoted as ZrPO(4)-DES8) was obtained. Its structure was determined from single-crystal X-ray diffraction (XRD) data and consists of zirconium phosphate layers with the protonated 1,4 dimethylpiperazine and water molecules in between. Interestingly, the two layered materials as additives in a liquid lubricant exhibit excellent friction behavior with higher load-carrying and antiwear capacities in comparison to typical lubricant additives such as MoS(2) and graphite, increase the P(B) value of the base oil by 27.2% and 8.5%, and decrease the wear scar diameter of the base oil by 43% and 36%, respectively. Scanning electron microscopy, XRD, and energy dispersive X-ray spectrometry are used to investigate the lubricant behavior of those materials. PMID- 20718432 TI - Comparison on characterization of longan (Dimocarpus longan Lour.) polyphenoloxidase using endogenous and exogenous substrates. AB - Longan polyphenoloxidase (PPO) was extracted and partially purified using ammonium sulfate precipitation and dialysis. The PPO characterizations were compared using endogenous substrate (-)-epicatechin and exogenous substrate catechol. The optimal pH and optimal temperature for the PPO activity were different when reacting with both substrates. The addition of ethylenediaminetetraacetic acid disodium salt into both substrate-enzyme systems exhibited the same lowest inhibition of the PPO activity. L-ascorbic acid and L cysteine were the best inhibitors to endogenous substrate-enzyme system, while L ascorbic acid and glutathione were most effective inhibitors to exogenous substrate-enzyme system. Cupric (Cu2+), ferric (Fe3+), and ferrous (Fe2+) ions accelerated the enzymatic-catalyzed reactions of both substrates. Kinetic analysis indicated that longan PPO strongly bound endogenous substrate but possessed a higher catalytic efficiency to exogenous substrate, and moreover, (-) epicatechin was determined as the optimal substrate for longan PPO. This study is useful to exactly illuminate the enzymatic-catalyzed browning mechanism of postharvest longan fruit. PMID- 20718434 TI - Mechanistic elucidation of the formation of the inverse Ca(I) sandwich complex [(thf)3Ca(mu-C6H3-1,3,5-Ph3)Ca(thf)3] and stability of aryl-substituted phenylcalcium complexes. AB - The formation of the stable inverse Ca(I) sandwich complex [(thf)(3)Ca(mu C(6)H(3)-1,3,5-Ph(3))Ca(thf)(3)] (1) has been investigated mechanistically by the reaction of bromo-2,4,6-triphenylbenzene with calcium in varying stoichiometric ratios. The key intermediate consists of a solvent-separated ion pair consisting of a dinuclear calcium cation with a bridging doubly deprotonated triphenylbenzene and a triphenylbenzene radical counteranion [(thf)(3)Ca(mu C(6)H(2)-C(6)H(4)Ph(2))(mu-O-CH=CH(2))Ca(thf)(3)][C(6)H(3)Ph(3)] (4). A precondition of the formation of 1 is the lability of the heavy Grignard reagent [{2,4,6-Ph(3)C(6)H(2)}Ca(thf)(3)Br] (2), which has been studied along with the role of ether degradation reactions. The strong reducing reagent 1 is stable in THF solution, and ether cleavage does not occur. However, toluene is metalated in good yields, and the dibenzylcalcium complex [(tmta)(2)Ca(CH(2)C(6)H(5))(2)] (5) is generated after addition of 1,3,5-trimethyl-1,3,5-triazinane (tmta). The substitution pattern of arylcalcium halides was modified, and it was found that phenyl substituents at the para position induce lability, leading to an enhanced tendency to cleave ethers. Kinetic stabilization of the Ca-C(ipso) bond can be achieved by ortho substitution using m-terphenyl-based ligands. Direct reaction of iodo-2,6-di(4-tolyl)benzene (6) with activated calcium in THF at low temperatures yielded the first example of a stable m-terphenylcalcium halide, namely, [{2,6-(4-tol)(2)C(6)H(3)}Ca(thf)(3)I] (8). The latter reacts via insertion of carbon dioxide to form the dimeric benzoate [{2,6-(4 tol)(2)C(6)H(3)CO(2)}Ca(thf)(3)I](2) (9). PMID- 20718433 TI - Development of a competitive indirect ELISA for the determination of lincomycin in milk, eggs, and honey. AB - Polyclonal antibodies to lincomycin (LIN) were developed in rabbit as a result of immunization with BSA-LIN conjugate. Periodate oxidizing of hapten was the common step of both immunogen synthesis and preparation of conjugated antigens for coating plates (homologous and heterologous). Several ELISA variants on a base of the different antigens immobilized on polystyrene were compared. Heterology of solid-phase antigens was provided with relative hapten clindamycin (CLIN) and ethylene- or hexanediamine as spacer arm between hapten and carrier. The spacer insertion yielded no desirable effect, whereas gelatin-CLIN assay variant showed better test characteristics in comparison with the homologous one, although insignificant (IC(50) was 9.15 vs 18.3 ng mL(-1)). The detection limits of the developed test, being estimated as 0.43 ng mL(-1) (milk) and 0.65 ng mL(-1) (eggs), were sufficient to measure maximum residue levels for LIN in examined matrices. This value for honey was 1.9 ng mL(-1) (1.3 MUg kg(-1)). The assay sensitivity was enough to dilute milk, egg, and honey samples by 10-100 times to minimize matrix effect. The examination of matrix effect and simple ways of its overcoming are detailed in the paper. The developed assay showed 111% cross reactivity with CLIN; therefore, it is suitable for the determination of both lincosamides. PMID- 20718435 TI - Discovery of imidacloprid and further developments from strategic molecular designs. AB - The invention of imidacloprid, the most important neonicotinoid insecticide, was initiated by replacement of the framework of nithiazine with an imidazolidine ring. Through the finding of 1-(6-chloro-3-pyridylmethyl)-2 nitromethyleneimidazolidine, imidacloprid was invented. At the same time cyanoiminothiazolidinyl neonicotinoid thiacloprid was discovered. These products possess pronounced systemic properties and improved photostability in addition to supreme insecticidal ability. Crystal structure analysis led to the drug-receptor interaction model consisting of the guanidine (amidine) part conjugated to a powerful electron-withdrawing group bearing an H-bond accepting tip such as NO(2) or CN, and the chloronicotinyl group enhances the binding to the receptor. The QSAR study not only supports the key pharmacophore but also clarifies the crucial involvement of the phamacokinetic factors in the insecticidal activity. A concept for strategic and rational design led to the discovery of alkylene-tethered bis imidacloprid derivatives with unexpected systemic insecticidal property and the unique binding mechanism revealing the second cavity in the neonicotinoid receptor. PMID- 20718436 TI - Responsive polymers end-tethered in solid-state nanochannels: when nanoconfinement really matters. AB - Solid state nanochannels modified with supramolecular architectures are a new and interesting class of stimuli-responsive nanofluidic element. Their fundamental understanding requires describing the behavior of soft-materials in confined geometries and its responses to changes in solution conditions. Here, a nanochannel modified with a polyelectrolyte brush is studied with a molecular theory that incorporates the conformational behavior of the polymers, electrostatic, van der Waals, and repulsive interactions coupled with the ability of the polymer segments to regulate their charge through acid-base equilibrium. The theory predicts pH-dependent ionic conductivity in excellent agreement with experimental observations. The polymer chains undergo large conformational changes triggered by variations in the outer solution environment and the conductivity of the device is shown to be controlled by the charge state of the polymer. The degree of polymer charge is largely affected by charge regulation and nanoconfinement effects. The molecular calculations show that the apparent pK(a) inside the pore departs from that in solution when increasing the curvature of the nanochannel. PMID- 20718437 TI - Mott and Efros-Shklovskii variable range hopping in CdSe quantum dots films. AB - The model of variable range hopping conductivity predicts a crossover between Mott and Efros-Shklovskii as a function of temperature and density of states. This is observed using monodispersed CdSe colloidal quantum dot 3D solids where the density of states at the Fermi level is varied by electrochemistry. At low density of states, both below the lowest state (<0.4e(-)/dot) and in the conductivity gap between the first and second state (2e(-)/dot), the temperature dependence of the conductivity shows the 1/4 exponent of Mott hopping. At other fillings up to 6e(-)/dot, the conductivity shows the 1/2 exponent of Efros Shklovskii hopping. The non-Ohmic conductivity is also found to be explained quantitatively by the variable range hopping model. PMID- 20718438 TI - Expeditious construction of the DEF ring system of thiersinine B. AB - Construction of a DEF ring model of thiersinine B has been achieved from a Wieland-Miescher ketone derivative by a five-step sequence featuring a one-pot regioselective alpha-allylation of the starting alpha,beta-unsaturated ketone via the Claisen rearrangement and a double dihydroxylation of a dienone intermediate. PMID- 20718439 TI - Continuous shape- and spectroscopy-tuning of hematite nanocrystals. AB - Uniform hexagonal hematite (alpha-Fe(2)O(3)) nanoplates have been synthesized by a facile alcohol-thermal reaction, and a new nanostructure of alpha-Fe(2)O(3) has been proposed. Each nanoplate is enclosed by (0001) basal planes and {1012} side surfaces. The phase, size, shape, and growth orientation of these nanocrystals were characterized by powder X-ray diffraction and electron microscopy. The thickness and diameter of these nanocrystals could be finely tuned by the selective use of alcohol solvent with increasing carbon atom number in the linear alkyl chain. A variety of nanocrystals with systemically changeable shapes from nanoplates to nanograins have been obtained. Specific adsorption of alcohol molecules on polar (0001) facets is proposed to be the main issue to modify the growth behavior of hematite nanocrystals. The presence of distilled water and the addition of sodium acetate have also been investigated. Either of them has a great influence on the growth of hematite nanocrystals, and shape-controlled growth can be rationally achieved. In addition, the post-aging of as-grown hematite nanocrystals in alcohol and distilled water has also been described. Both vibration spectroscopy (i.e., FTIR and Raman) and electronic spectra (diffused reflectance spectra) of these nanocrystals with a continuing shape change show a highly shape-dependent nature. PMID- 20718440 TI - Novel benzimidazole inhibitors bind to a unique site in the kinesin spindle protein motor domain. AB - Affinity selection-mass spectrometry (AS-MS) screening of kinesin spindle protein (KSP) followed by enzyme inhibition studies and temperature-dependent circular dichroism (TdCD) characterization was utilized to identify a series of benzimidazole compounds. This series also binds in the presence of Ispinesib, a known anticancer KSP inhibitor in phase I/II clinical trials for breast cancer. TdCD and AS-MS analyses support simultaneous binding implying existence of a novel non-Ispinesib binding pocket within KSP. Additional TdCD analyses demonstrate direct binding of these compounds to Ispinesib-resistant mutants (D130V, A133D, and A133D + D130V double mutant), further strengthening the hypothesis that the compounds bind to a distinct binding pocket. Also importantly, binding to this pocket causes uncompetitive inhibition of KSP ATPase activity. The uncompetitive inhibition with respect to ATP is also confirmed by the requirement of nucleotide for binding of the compounds. After preliminary affinity optimization, the benzimidazole series exhibited distinctive antimitotic activity as evidenced by blockade of bipolar spindle formation and appearance of monoasters. Cancer cell growth inhibition was also demonstrated either as a single agent or in combination with Ispinesib. The combination was additive as predicted by the binding studies using TdCD and AS-MS analyses. The available data support the existence of a KSP inhibitory site hitherto unknown in the literature. The data also suggest that targeting this novel site could be a productive strategy for eluding Ispinesib-resistant tumors. Finally, AS-MS and TdCD techniques are general in scope and may enable screening other targets in the presence of known drugs, clinical candidates, or tool compounds that bind to the protein of interest in an effort to identify potency-enhancing small molecules that increase efficacy and impede resistance in combination therapy. PMID- 20718441 TI - Super-resolution optical imaging of single-molecule SERS hot spots. AB - We present the first super-resolution optical images of single-molecule surface enhanced Raman scattering (SM-SERS) hot spots, using super-resolution imaging as a powerful new tool for understanding the interaction between single molecules and nanoparticle hot spots. Using point spread function fitting, we map the centroid position of SM-SERS with +/-10 nm resolution, revealing a spatial relationship between the SM-SERS centroid position and the highest SERS intensity. We are also able to measure the unique position of the SM-SERS centroid relative to the centroid associated with nanoparticle photoluminescence, which allows us to speculate on the presence of multiple hot spots within a single diffraction-limited spot. These measurements allow us to follow dynamic movement of the SM-SERS centroid position over time as it samples different locations in space and explores regions larger than the expected size of a SM SERS hot spot. We have proposed that the movement of the SERS centroid is due to diffusion of a single molecule on the surface of the nanoparticle, which leads to changes in coupling between the scattering dipole and the optical near field of the nanoparticle. PMID- 20718442 TI - Highly efficient restoration of graphitic structure in graphene oxide using alcohol vapors. AB - Solution-based processes involving the chemical oxidation of graphite and reduction of the obtained graphene oxide (GO) sheets have attracted much attention for preparing graphene films for printed electronics and biosensors. However, the low electrical conductivity of reduced GO is still hindering the development of electronic applications. This article presents that GO sheets reduced by high-temperature alcohol vapors exhibit highly graphitic structures and excellent electrical conductivity. The sheet resistance of thin transparent films is lowered to ~15 kOmega/? (>96% transparency). Field-effect transistors produced from these reduced GO sheets exhibit high effective field-effect hole mobility up to 210 cm(2)/V x s. Raman spectroscopic studies reveal that the conductivity enhancement in the low mobility regime is attributed to the removal of chemical functional groups and the formation of six-fold rings. In the high mobility regime, the growth of the graphitic domain size becomes dominant for enhancing its electrical conductivity. The excellent electrical conductivity of the reduced GO sheets promises potential electronic applications. PMID- 20718443 TI - Functional electrospun polystyrene nanofibers incorporating alpha-, beta-, and gamma-cyclodextrins: comparison of molecular filter performance. AB - Electrospinning has been used to successfully create polystyrene (PS) nanofibers containing either of three different types of cyclodextrin (CD); alpha-CD, beta CD, and gamma-CD. These three CDs are chosen because they have different sized cavities that potentially allow for selective inclusion complex (IC) formation with molecules of different size or differences in affinity of IC formation with one type of molecule. The CD containing electrospun PS nanofibers (PS/CD) were initially characterized by scanning electron microscopy (SEM) to determine the uniformity of the fibers and their fiber diameter distributions. X-ray photoelectron spectroscopy (XPS) was used to quantitatively determine the concentration of each CD on the different fiber surfaces. Static time-of-flight secondary ion mass spectrometry (static-ToF-SIMS) showed the presence of each type of CD on the PS nanofibers by the detection of both the CD sodium adduct molecular ions (M + Na+) and lower molecular weight oxygen containing fragment ions. The comparative efficiency of the PS/CD nanofibers/nanoweb for removing phenolphthalein, a model organic compound, from solution was determined by UV-vis spectrometry, and the kinetics of phenolphthalein capture was shown to follow the trend PS/alpha-CD > PS/beta-CD > PS/gamma-CD. Direct pyrolysis mass spectrometry (DP-MS) was also performed to ascertain the relative binding strengths of the phenolphthalein for the CD cavities, and the results showed the trend in the interaction strength was beta-CD > gamma-CD > alpha-CD. Our results demonstrate that nanofibers produced by electrospinning that incorporate cyclodextrins with different sized cavities can indeed filter organic molecules and can potentially be used for filtration, purification, and/or separation processes. PMID- 20718444 TI - Conformational polymorphism in sulfonylurea drugs: electronic structure analysis. AB - Quantum chemical calculations have been performed using HF, B3LYP, and MP2 methods on the model sulfonylurea PhSO(2)NHC(=O)NHMe to understand the conformational and tautomeric preferences. The results indicate that a conformer with intramolecular hydrogen bond SLU-1 (hitherto not considered) is more stable than the conformer SLU-2 (which is generally considered) for sulfonylureas. The energy difference between these two conformers is about 4 kcal/mol in the gas phase; however, the energy differences between the two rotamers become negligible in the solvent phase. Iminol tautomeric forms of sulfonylurea (which were also not studied until now) are only about 5-6 kcal/mol higher in energy as per both gas-phase and solvent-phase analyses, indicating easy accessibility of tautomeric states in sulfonylureas. Quantum chemical analysis has also been carried out on the possible dimeric structures of these three important isomers of sulfonylurea, and correlations have been made to the known crystal structures of polymorphic states of sulfonylurea drugs. PMID- 20718445 TI - Cholic acid-modified dendritic multimolecular micelles and enhancement of anticancer drug therapeutic efficacy. AB - To improve the efficacy and bioacceptability of polyamidoamine (PAMAM) in potential biomedical applications, the PAMAM dendrimers (first generation) were partially modified with cholic acid. (1)H NMR studies and acid-base titration show that two cholic acid molecules are linked to one PAMAM. The modified PAMAM dendrimers self-assemble to form dendritic multimolecular micelles in aqueous solutions, with a diameter of 120 nm measured by dynamic light scattering. These micelles can encapsulate hydrophobic drug molecules in aqueous media and exhibit pH sensitivity. The in vitro results demonstrate that the anticancer activity of camptothecin is significantly enhanced at low drug dose after being encapsulated by these micelles in the presence of serum. Therefore, the dendritic multimolecular micelles based on low generation dendrimers may have potential applications in the delivery of drugs. PMID- 20718446 TI - Revealing the magnetostructural dynamics of [2Fe-2S] ferredoxins from reduced dimensionality analysis of antiferromagnetic exchange coupling fluctuations. AB - Metalloproteins are biomolecular hybrids composed of an "inorganic core" embedded in a "bioorganic matrix". Cofactors typically contain transition metal clusters with complex electronic structure whereas the protein host undergoes dynamics on many length and time scales. This renders computational studies of spectroscopic properties challenging, in particular, when magnetic interactions are involved. In the present study we introduce a simplified description of the antiferromagnetic exchange coupling J in reduced dimensionality which allows one to study magnetostructural dynamics of [2Fe-2S] type iron-sulfur proteins in their oxidized form by molecular dynamics. It is demonstrated that parametrization in terms of a 2D J-surface faithfully reproduces the rigorous results both in vacuo and in Anabaena ferredoxin. In particular, we present a parametrization which relies on a spin-projected density functional approach based on two Kohn-Sham determinants corrected for self-interaction via a self consistent linear-response Hubbard-U technique. This yields an average J for Anabaena Fd in close agreement with experimental in vitro results without any specific adjustment or fitting. The analytical J-surface can be used for [2Fe-2S] proteins in their oxidized form in general and the idea can be extended to other metalloproteins as well as to other spectroscopic properties. PMID- 20718447 TI - Dual-color luciferase mouse directly demonstrates coupled expression of two clock genes. AB - We have established a dual-color transgenic mouse that simultaneously reports the expression of two clock genes, Bmal1 and Per2, in a single tissue. The expression of the two genes is monitored with green- and red-emitting beetle luciferases with a single luminescent substrate. Antiphasic oscillations of Bmal1 and Per2, consistent with their endogenous mRNA profiles, were clearly monitored in the suprachiasmatic nucleus (SCN), the master circadian pacemaker, and in the peripheral tissues, demonstrating that the system allows the long-term, quantitative, and simultaneous monitoring of the expression of the two genes. We also showed that although the expression patterns of Bmal1 and Per2 in each organ are strictly antiphasic, the recorded circadian phases and periods of both genes varied between organs. The phase shifts in the expression of both genes in the SCN, induced by a change of medium, also occurred in a similar manner. Therefore, this dual-color luciferase mouse allows noninvasive and continuous monitoring of the coupled expression of two clock genes. This system provides a simple technique with which to unravel the complex interactions of two genes in the body. PMID- 20718448 TI - Synthesis of highly substituted pyrroles via nucleophilic catalysis. AB - A nucleophilic catalysis method providing a concise synthesis of di-, tri-, and tetrasubstituted pyrroles is described. This regioselective one-pot method relies on nucleophilic catalysis of the intermolecular addition of oximes to activated alkynes and thermal rearrangement of the in situ generated O-vinyl oximes to form pyrroles that contain a functional group handle at the C3/C4 position. PMID- 20718449 TI - Cytotoxic isomalabaricane derivatives and a monocyclic triterpene glycoside from the sponge Rhabdastrella globostellata. AB - Seven new isomalabaricane derivatives, rhabdastins A-G (1-7), and a new monocyclic triterpene glycoside, rhabdastoside A (8), have been isolated from the methanol extract of the sponge Rhabdastrella globostellata, collected at Amami oshima, Japan. Three of them were isolated as their corresponding methyl esters, rhabdastins A-D (1-3). Their structures were determined on the basis of spectroscopic and X-ray diffraction analyses. The isolated compounds were evaluated for their cytotoxicity against the proliferation of promyelocytic leukemia HL-60 cells. Compounds 4, 5, 7, and 11, possessing a cyclopentane side chain, exhibited weak activity, with IC(50) values of 21, 29, 44, and 11 MUM, respectively, while compounds 1, 2, and 3, with a 2-substituted-propanoate side chain, were inactive at 100 MUM. In addition, the mechanism of cytotoxicity of compounds 4 and 5 was investigated. PMID- 20718450 TI - Steroidal saponins from fresh stems of Dracaena angustifolia. AB - Six new steroidal saponins (1-6), angudracanosides A-F, were isolated from fresh stems of Dracaena angustifolia, together with eight known compounds. The structures of compounds 1-6 were determined by detailed spectroscopic analyses and chemical methods. Antifungal testing of all compounds showed that 6 and 7 were active against Cryptococcus neoformans with IC(50)s of 9.5 and 20.0 MUg/mL, respectively. PMID- 20718451 TI - Chiral conducting surfaces via electrochemical oxidation of L-leucine oligothiophenes. AB - Polythiophenes bearing a specific chiral center such as L-leucine have been prepared via the electrochemical oxidation of a series of L-leucine functionalized oligothiophenes (monothiophenes and terthiophenes). These oligothiophenes have been prepared through the condensation of L-leucine methyl ester and the corresponding thiophene monomers in the presence of hydroxybenzotriazole (HOBt) and N,N'-dicyclohexylcarbodiimide (DCC) followed by hydrolysis of the esters. The electroactive polymers are electrochemically stable and exhibit excellent adhesive properties on electrode surfaces (platinum, gold, and glassy carbon) as well as interesting optical properties in both doped and undoped states. Hydrogen bonds between a free amino acid (L-leucine, D-leucine, L alanine, D-alanine, and D/L-alanine) and the L-leucine based polythiophenes (chiral conducting surface) were probed using cyclic voltammetry. Preliminary results show that the capacitive current of a modified L-leucine-polythiophene electrode decreases as a result of the formation of a hydrogen bond barrier on the surface of the chiral conducting surface accompanied with a shift of the oxidation potential. Cyclic voltammetry responses resulting from the interaction of the chiral conducting surface with L and Dfree amino acid isomers are similar. The formation of hydrogen bonds between the chiral conducting surfaces and the free amino acids was characterized by (1)H NMR. A chemical shift was observed for the N-H group in monomer 6 as a result of the hydrogen bond formation between the L-leucine methyl ester (D-leucine methyl ester, D/L-leucine methyl ester) and monomer 6. PMID- 20718452 TI - Lewis acid catalyzed inverse electron-demand Diels-Alder reaction of 1,2 diazines. AB - A systematic approach toward Lewis acid catalyzed inverse electron-demand Diels Alder (IEDDA) reactions of 1,2-diazines is described. The general concept is first investigated by DFT calculations, supported by spectroscopic data, and finally proven in the experiment. PMID- 20718453 TI - Stereospecific consecutive epoxide ring expansion with dimethylsulfoxonium methylide. AB - Consecutive ring-expansion reactions of oxiranes with dimethylsulfxonium methylide were studied experimentally and modeled computationally at the density functional theory (DFT) and second-order Moller-Plesset (MP2) levels of theory utilizing a polarizable continuum model (PCM) to account for solvent effects. While the epoxide to oxetane ring expansion requires 13-17 kcal mol(-1) activation and occurs at elevated temperatures, the barriers for the ring expansions to oxolanes are higher (ca. 25 kcal mol(-1)) and require heating to 125 degrees C. Further expansions of these oxolanes to the six-membered oxanes are hampered by high barriers (ca. 40 kcal mol(-1)). We observe the complete conservation of the enantiomeric purities for the nucleophilic ring expansions of enantiomeric 2-mono- and 2,2-disubstituted epoxides and oxetanes with dimethylsulfoxonium methylide. This is a convenient general approach for the high yielding preparation of optically active four- and five-membered cyclic ethers from oxiranes. PMID- 20718454 TI - Undulations enhance the effect of helical structure on DNA interactions. AB - During the past decade, theory and experiments have provided clear evidence that specific helical patterns of charged groups and adsorbed (condensed) counterions on the DNA surface are responsible for many important features of DNA-DNA interactions in hydrated aggregates. The effects of helical structure on DNA-DNA interactions result from a preferential juxtaposition of the negatively charged sugar phosphate backbone with counterions bound within the grooves of the opposing molecule. Analysis of X-ray diffraction experiments confirmed the mutual alignment of parallel molecules in hydrated aggregates required for such juxtaposition. However, it remained unclear how this alignment and molecular interactions might be affected by intrinsic and thermal fluctuations, which cause structural deviations away from an ideal double helical conformation. We previously argued that the torsional flexibility of DNA allows the molecules to adapt their structure to accommodate a more electrostatically favorable alignment between molecules, partially compensating disruptive fluctuation effects. In the present work, we develop a more comprehensive theory, incorporating also stretching and bending fluctuations of DNA. We found the effects of stretching to be qualitatively and quantitatively similar to those of twisting fluctuations. However, this theory predicts more dramatic and surprising effects of bending. Undulations of DNA in hydrated aggregates strongly amplify rather than weaken the helical structure effects. They enhance the structural adaptation, leading to better alignment of neighboring molecules and pushing the geometry of the DNA backbone closer to that of an ideal helix. These predictions are supported by a quantitative comparison of the calculated and measured osmotic pressures in DNA. PMID- 20718455 TI - Bergman cyclization of acyclic amino acid derived enediynes leads to the formation of 2,3-dihydrobenzo[f]isoindoles. AB - Enediyne-peptide conjugates are recently recognized as useful tools in targeting various proteins, while the mechanism underlying the observed activity remains somewhat unclear. Addressing these issues, we have prepared acyclic amino acid derived enediynes and disclosed a novel thermally induced cyclization-elimination pathway. Initial formation of 1,4-benzene diradical and H-atom abstraction from an external donor is followed by S(N)2 substitution leading to 2,3 dihydrobenzo[f]isoindoles. The proposed mechanism is supported by experimental and computational data. Additionally, we showed that amino acid side chains, although placed three bonds away from acetylene terminuses, have an appreciable influence on the reactivity of studied enediynes. These results demonstrate that amino acid or peptide parts of enediyne-peptide conjugates cannot be considered as recognition elements exclusively but may also participate in various reactions through amine functionality. PMID- 20718456 TI - Anion ZEKE-spectroscopy of the weakly bound iodine water complex. AB - Zero kinetic electron energy photodetachment spectroscopy of I(-).H(2)O and I( ).D(2)O has been performed from 27 660 to 28 500 cm(-1) and from 27 660 to 35 900 cm(-1), respectively. The I(-).D(2)O spectral data and theoretical studies resulted in a reassignment of earlier anion-ZEKE spectra of iodide water ( Bassmann , C. ; et al. Int. J. Mass Spectrom. Ion Processes 1996 , 159 , 153 ). In opposite to the I(-).H(2)O, the I(-).D(2)O spectrum reveals a regular progression of the iodine-water van der Waals stretching mode and a short progression of even quanta of the van der Waals rocking mode. A rough estimation delivers dissociation thresholds of the anionic and of the lower and the upper spin-orbit component of the neutral van der Waals complex. A high resolution ZEKE spectrum of the van der Waals stretching mode (v = 1) reveals significant fine structure, which is found again in a former photodissociation spectrum of the anionic complex ( Ayotte , P. ; et al. J. Phys. Chem. A 1998 , 102 , 3067 ). Our assignments are supported by theoretical calculations of molecular structures and vibrational motions. Vibrational frequencies and isotope effects are reproduced very satisfyingly by these calculations. PMID- 20718457 TI - Shorter still: compressing C-C single bonds. AB - How short can a C-C single bond get? The bonding in a set of molecules that are related structurally to previously synthesized or theoretically examined systems with short C-C bonds is investigated. According to calculations, a single C-C bond could be compressed to 1.313 A! To the best of our knowledge, this is the shortest single C-C bond reported to date. This shortening is a consequence of a change in the C-C-C bond angle, theta, to minimize strain in the cages and an effort to offset the tension in the surrounding bridges. PMID- 20718458 TI - A calorimetric and computational study of aminomethoxybenzoic acids. AB - The standard (p(0) = 0.1 MPa) molar enthalpies of formation, in the crystalline phase, of five aminomethoxybenzoic acids, at T = 298.15 K, were derived from the standard molar energies of combustion in oxygen, measured by static-bomb combustion calorimetry. Combining these results with literature results of the standard molar enthalpies of sublimation, at T = 298.15 K, the standard molar enthalpies of formation, in the gaseous phase, were derived. Additionally, the enthalpies of formation of the ten possible isomers of aminomethoxybenzoic acid were estimated using accurate Double Hybrid Density Functional Theory (DHDFT) computational methods. The good agreement between the experimental and estimated values of the enthalpies of formation of the five isomers studied experimentally allows us to be confident on the estimated values for the other five isomers. A quantitative evaluation and analysis of the aromatic character of all the studied isomers based on the calculation of Nucleus Independent Chemical Shifts (NICS) was also conducted. PMID- 20718459 TI - Backbone amide dynamics studies of Apo-L75F-TrpR, a temperature-sensitive mutant of the tryptophan repressor protein (TrpR): comparison with the (15)N NMR relaxation profiles of wild-type and A77V mutant Apo-TrpR repressors. AB - Backbone amide dynamics studies were conducted on a temperature-sensitive mutant (L75F-TrpR) of the tryptophan repressor protein (TrpR) of Escherichia coli in its apo (i.e., no l-tryptophan corepressor-bound) form. The (15)N NMR relaxation profiles of apo-L75F-TrpR were analyzed and compared to those of wild-type (WT) and super-repressor mutant (A77V) TrpR proteins, also in their apo forms. The (15)N NMR relaxation data ((15)N-T(1), (15)N-T(2), and heteronuclear (15)N-{(1)H} nOe) recorded on all three aporepressors at a magnetic field strength of 600 MHz ((1)H Larmor frequency) were analyzed to extract dynamics parameters, including diffusion tensor ratios (D(?)/D(?)), correlation times (tau(m)) for overall reorientations of the proteins in solution, reduced spectral density terms [J(eff)(0), J(0.87omega(H)), J(omega(N))], and generalized order parameters (S(2)), which report on protein internal motions on the picosecond to nanosecond and slower microsecond to millisecond chemical exchange time scales. Our results indicate that all three aporepressors exhibit comparable D(?)/D(?) ratios and characteristic time constants, tau(m), for overall global reorientation, indicating that in solution, all three apoproteins display very similar overall shape, structure, and rotational diffusion properties. Comparison of (15)N NMR relaxation data, reduced spectral density profiles, and generalized S(2) order parameters indicated that these parameters are quite uniform for backbone amides positioned within the four (A-C and F) core alpha-helices of all three aporepressors. In contrast, small but noticeable differences in internal dynamics were observed for backbone amides located within the helix D-turn-helix E DNA binding domain of the apo-TrpR proteins. The significance of these dynamics differences in terms of the biophysical characteristics and ligand binding properties of the three apo-TrpR proteins is discussed. PMID- 20718460 TI - Toward well-defined metal-polymer interfaces: temperature-controlled suppression of subsurface diffusion and reaction at the calcium/poly(3-hexylthiophene) interface. AB - The thickness of the reaction zone at the interface between calcium and regioregular poly(3-hexylthiophene), which is one of the best performing metal/polymer combinations in photovoltaic devices, depends critically on the temperature of the polymer during the initial phase of metal deposition. It is shown that deposition at 130 K reduces the thickness of the reaction zone, an effect that also persists after warming to room temperature. PMID- 20718462 TI - Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. AB - Mesoporous silica nanoparticles (MSNP) have proven to be an extremely effective solid support for controlled drug delivery on account of the fact that their surfaces can be easily functionalized in order to control the nanopore openings. We have described recently a series of mechanized silica nanoparticles, which, under abiotic conditions, are capable of delivering cargo molecules employing a series of nanovalves. The key question for these systems has now become whether they can be adapted for biological use through controlled nanovalve opening in cells. Herein, we report a novel MSNP delivery system capable of drug delivery based on the function of beta-cyclodextrin (beta-CD) nanovalves that are responsive to the endosomal acidification conditions in human differentiated myeloid (THP-1) and squamous carcinoma (KB-31) cell lines. Furthermore, we demonstrate how to optimize the surface functionalization of the MSNP so as to provide a platform for the effective and rapid doxorubicin release to the nuclei of KB-31 cells. PMID- 20718464 TI - Formation process of self-assembled monolayer on gold nanosphere probed by second harmonic generation. AB - The formation process of a hemicyanine-terminated alkanethiolate self-assembled monolayer (SAM) on gold nanospheres immobilized on a glass substrate was studied by absorption spectroscopy, optical second harmonic generation, and Monte Carlo simulation. It was found that hemicyanine thiolate SAMs mainly form in the upper hemisphere region of the gold nanospheres in the early stage, followed by the additional SAM formation in the lower region of gold nanospheres. The hemicyanine SAM does not homogeneously form over the nanosphere surface and does not fully cover the nanospheres even after long exposure to the hemicyanine solution. This is because of the narrow space under the nanosphere, where the binding of the alkane disulfide to the gold surface is considered to be a diffusion-controlled reaction. The orientation of the hemicyanine molecules on gold nanospheres is similar to that of hemicyanine on a flat gold substrate. These results are important to understand the surface chemistry at nanostructure surfaces as well as the localized surface plasmon biosensing using metallic nanostructures. PMID- 20718463 TI - Characterization of isolated nitrogenase FeVco. AB - The cofactors of the Mo- and V-nitrogenases (i.e., FeMoco and FeVco) are homologous metal centers with distinct catalytic properties. So far, there has been only one report on the isolation of FeVco from Azotobacter chroococcum. However, this isolated FeVco species did not carry the full substrate-reducing capacity, as it is unable to restore the N(2)-reducing ability of the cofactor deficient MoFe protein. Here, we report the isolation and characterization of a fully active species of FeVco from A. vinelandii. Our metal and activity analyses show that FeVco has been extracted intact, carrying with it the characteristic capacity to reduce C(2)H(2) to C(2)H(6) and, perhaps even more importantly, the ability to reduce N(2) to NH(3). Moreover, our EPR and XAS/EXAFS investigations indicate that FeVco is similar to, yet distinct from FeMoco in electronic properties and structural topology, which could account for the differences in the reactivity of the two cofactors. The outcome of this study not only permits the proposal of the first EXAFS-based structural model of the isolated FeVco but also lays a foundation for future catalytic and structural investigations of this unique metallocluster. PMID- 20718465 TI - One-pot synthesis of five and six membered N, O, S-heterocycles using a ditribromide reagent. AB - In a one-pot procedure, bromine less brominating reagent 1,1'-(ethane-1,2 diyl)dipyridinium bistribromide (EDPBT) has been utilized as an efficient desulfurizing agent for the construction of a library of heterocycles containing N, O, and S starting from aryl/alkyl isothiocyanates. In this approach, aryl/alkyl isothiocyanate reacts with o-phenylenediamine (o-PD), o-aminophenol, and o-aminothiophenol to form their monothiourea which on desulfurization with EDPBT led to the formation of corresponding 2-aminobenzimidazoles, 2 aminobenzoxazoles, and 2-aminobenzothiazoles, respectively. An interesting regioselectivity was observed for unsymmetrical thiourea having a naphthyl moiety on the one side and an ortho amino or an ortho hydroxy phenyl group on the other side giving a completely different product which is mainly dependent on the nature of the nucleophiles (-OH or -NH(2)). Further, the bis-thioureas resulted from the aliphatic 1,2-diamine with 2 equiv of aryl isothiocyanates on treatment with EDPBT gave imidazolidenecarbothioamides, whereas bis-thioureas resulted from aromatic 1,2-diamine yielded benzimidazoles with concurrent expulsion of an isothiocyanate unit. This method is simple and applied to various substrates which are amenable to bromination that reveals the desulfurizing ability of EDPBT predominating over its brominating ability. Finally, the spent reagent EDPDB can be recovered, regenerated, and reused without any loss of activity. PMID- 20718466 TI - Generation of diverse 2H-isoindol-1-ylphosphonates via three-component reaction of 2-alkynylbenzaldehyde, aniline, and phosphite. AB - Diverse 2H-isoindol-1-ylphosphonates as potential HCT-116 inhibitors are easily generated via a FeCl(3) and PdCl(2) cocatalyzed three-component reaction of 2 alkynylbenzaldehyde, aniline, and phosphite. The focused small library is constructed based on parallel diversity-oriented synthesis. PMID- 20718467 TI - Physiologically based pharmacokinetic (PBPK) models for lifetime exposure to PCB 153 in male and female harbor porpoises (Phocoena phocoena): model development and evaluation. AB - Physiologically based pharmacokinetic (PBPK) models were developed for the most persistent polychlorinated biphenyl (PCB 153) in male and female harbor porpoises (Phocoena phocoena) to elucidate processes such as uptake, distribution, and elimination. Due to its limited metabolic capacities, long life span, and top position in marine food chains, this species is highly sensitive to pollution. The models consist of 5 compartments, liver, blubber, kidney, brain, and a compartment which accounts for the rest of the body, all connected through blood. All physiological and biochemical parameters were extracted from the literature, except for the brain/blood partition coefficient and rate of excretion, which were both fitted to data sets used for validation of the models. These data sets were compiled from our own analyses performed with GC-MS on tissue samples of harbor porpoises. The intake of PCB 153 was from milk from birth to 4 months, and after weaning fish was the main food source. Overall, these models reveal that concentrations of PCB 153 in males increase with age but suggest that, as the animals grow older, metabolic transformation can be a possible pathway for elimination as well. In contrast, the model for females confirms that gestation and lactation are key processes for eliminating PCB 153 as body burdens decrease with age. These PBPK models are capable of simulating the bioaccumulation of PCB 153 during the entire life span of approximately 20 years of the harbor porpoises. PMID- 20718468 TI - Enediyne antitumor antibiotic maduropeptin biosynthesis featuring a C methyltransferase that acts on a CoA-tethered aromatic substrate. AB - The enediyne antitumor antibiotic maduropeptin (MDP) is produced by Actinomadura madurae ATCC 39144. The biosynthetic pathway for the 3,6-dimethylsalicylic acid moiety of the MDP chromophore is proposed to be comprised of four enzymes: MdpB, MdpB1, MdpB2, and MdpB3. Based on the previously characterized biosynthesis of the naphthoic acid moiety of neocarzinostatin (NCS), we expected a biosynthetic pathway featuring carboxylic acid activation by the MdpB2 CoA ligase immediately before its coupling to an enediyne core intermediate. Surprisingly, the MDP aromatic acid biosynthetic pathway employs an unusual logic in which MdpB2 catalyzed CoA activation occurs before MdpB1-catalyzed C-methylation, demonstrating that MdpB1 is apparently unique in its ability to C-methylate a CoA tethered aromatic acid. MdpB2 is a promiscuous CoA ligase capable of activating a variety of salicylic acid analogues, a property that could be potentially exploited to engineer MDP analogues. PMID- 20718470 TI - Polymersome stomatocytes: controlled shape transformation in polymer vesicles. AB - We report here a controllable shape transformation of polymer vesicles (polymersomes) constructed from block copolymers of which the hydrophobic part is a high-molecular-weight glassy segment. Control over the shape transformation is obtained by kinetic manipulation of the phase behavior of this glassy hydrophobic segment. Kinetic manipulation of the phase behavior of polymer membranes allows for different shapes of polymersomes to be captured at specific times, which directly translates into physically robust nanostructures that are otherwise unobtainable. Combining the morphological diversity of giant liposomes and the physical robustness of polymersomes, our finding can be a general way to realize unusual nanostructures in a predictable manner. PMID- 20718469 TI - Anticancer and anti-inflammatory effects of cysteine metabolites of the green tea polyphenol, (-)-epigallocatechin-3-gallate. AB - (-)-Epigallocatechin-3-gallate (EGCG) has been shown to have cancer preventive activity in vitro and in vivo. We have previously shown that EGCG can undergo conjugation to cysteine to form 2'-cysteinyl-EGCG and 2''-cysteinyl-EGCG. Studies of thiol-conjugated metabolites of methamphetamine indicate that such metabolites are not detoxified but retain biological activity. Here, we examined the growth inhibitory, pro-oxidant, and anti-inflammatory activities of the cysteine metabolites of EGCG. Both compounds dose-dependently inhibited the growth of colon cancer and intestinal cell lines. Both metabolites prevented aberrant arachidonic acid release and nitric oxide production by lipopolysaccharide stimulated RAW264.7 cells. Under cell culture conditions, 2''-cysteinyl-EGCG produced H2O2 at a faster rate than EGCG. The results of the present study show that cysteine conjugates of EGCG retain the growth inhibitory, anti-inflammatory, and pro-oxidant activities of EGCG in vitro and may play a role in disease prevention in vivo. These results remain to be confirmed in vivo. PMID- 20718471 TI - Matrix photochemistry at low temperatures and spectroscopic properties of gamma butyrothiolactone. AB - The five-membered heterocyclic gamma-butyrothiolactone was isolated in a low temperature, inert Ar matrix, and the UV-visible (200 [Ln(2)(Lk)(2)(NO(3))(6)] can be evidenced across the complete ligand series. Detailed thermodynamic studies show that the dimeric complexes result from the formation of primary intermetallic nitrate bridges whose strength depends on the metallic size. For each complex, secondary nonspecific interstrand van der Waals interactions produce nonartifactual enthalpy/entropy compensation. In the absence of solvent, only the complexes with the most extended ligands L5 and L6 produce thermotropic mesophases. Layered organizations are dominant (smectic A) with the induction of nematogenic behavior at high temperature when interstrand interactions are modulated by methyl substitutions. Correlations between the trend of dimerization and the sequences of thermotropic mesophases are attempted. PMID- 20718489 TI - Proteomic characterization of human plasma high density lipoprotein fractionated by gel filtration chromatography. AB - Plasma levels of high density lipoprotein cholesterol (HDL-C) are inversely proportional to the incidence of cardiovascular disease. Recent applications of modern proteomic technologies have identified upward of 50 distinct proteins associated with HDL particles with many of these newly discovered proteins implicating HDL in nonlipid transport processes including complement activation, acute phase response and innate immunity. However, almost all MS-based proteomic studies on HDL to date have utilized density gradient ultracentrifugation techniques for HDL isolation prior to analysis. These involve high shear forces and salt concentrations that can disrupt HDL protein interactions and alter particle function. Here, we used high-resolution size exclusion chromatography to fractionate normal human plasma to 17 phospholipid-containing subfractions. Then, using a phospholipid binding resin, we identified proteins that associate with lipoproteins of various sizes by electrospray ionization mass spectrometry. We identified 14 new phospholipid-associated proteins that migrate with traditionally defined HDL, several of which further support roles for HDL in complement regulation and protease inhibition. The increased fractionation inherent to this method allowed us to visualize HDL protein distribution across particle size with unprecedented resolution. The observed heterogeneity across subfractions suggests the presence of HDL particle subpopulations each with distinct protein components that may prove to impart distinct physiological functions. PMID- 20718490 TI - A novel negative regulation mechanism of bacterial outer membrane proteins in response to antibiotic resistance. AB - Although some outer membrane (OM) proteins involved in antibiotic resistance have been previously reported, the OM proteins regulating chlortetracycline (CTC) resistance are largely unknown. In this study, we employed a subproteomics approach to identify altered OM proteins of Escherichia coli in response to CTC exposure. Upregulation of TolC and downregulation of LamB, FadL, OmpC, OmpT, and OmpW were found in E. coli strains exposed to CTC at a high concentration that was increased suddenly and at a half-minimum inhibitory concentration (MIC) that was kept constant in the culture medium. These changes in the level of protein expression were validated using Western blotting. In addition, the possible roles of these altered proteins and their regulation mechanisms in response to CTC exposure were investigated using genetically modified strains with gene deletion of these altered proteins. It was found that deletion of tolC, fadL, ompC, ompT, or ompW resulted in a decrease in the MICs and survival capabilities of the gene deleted strains, whereas the absence of lamB led to an improvement of the two abilities. The downregulation of LamB expression in the CTC-resistant E. coli strain and the increased antibiotic resistance in its gene-deleted strain suggested a negative regulation mechanism in E. coli in response to CTC exposure. Meanwhile, the direction of the regulation pattern in response to CTC exposure was different from that in E. coli in response to exposure to other antibiotics. These findings uncover a novel antibiotic-resistant mechanism in which bacteria respond to exposure to antibiotics through alteration of the direction of regulation of OM proteins. PMID- 20718491 TI - Preservation of field samples for enzymatic and proteomic characterization: analysis of proteins from the trophallactic fluid of hornets and yellowjackets. AB - Proteomics is fast becoming one of the most interdisciplinary fields, bridging many chemical and biological disciplines. Major challenges, however, can limit the reach of proteomics to studies of model organisms. Challenges include the adequate preservation of field samples and the reliance of in-depth proteomics on sequenced genomes. Seeking to better establish the evolutionary relationships of hornets and yellowjackets comprising the subfamily Vespinae, we are combining classical morphological and genomic information with a functional genomics trait using proteomics. Vespine species form highly social colonies and exhibit division of labor in almost all aspects of colony life. An extreme digestive division of labor has been reported in Vespa orientalis, in which larvae but not adult workers exhibit the capacity to digest proteins fully. This makes the colony dependent upon the amino acid-rich trophallactic fluid released to adults by larvae and implies that the V. orientalis superorganism possesses larval specific proteases. Identifying the proteases and the species exhibiting such extreme partitioning of digestive labor will allow for tracing the phylogenetic origins and elaboration of that digestive partitioning in the Vespinae. Herein we describe methods, generally applicable to field samples, showing the preservation of proteins and proteolytic activity from adult and larval vespine trophallactic fluid. PMID- 20718492 TI - Investigations on the 4-quinolone-3-carboxylic acid motif. 3. Synthesis, structure-affinity relationships, and pharmacological characterization of 6 substituted 4-quinolone-3-carboxamides as highly selective cannabinoid-2 receptor ligands. AB - A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting Ki>100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors. PMID- 20718493 TI - Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency. AB - Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer. PMID- 20718494 TI - Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8 (trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury. AB - Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis. PMID- 20718495 TI - Improved syntheses of 5'-S-(2-aminoethyl)-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAENTA), analogues, and fluorescent probe conjugates: analysis of cell-surface human equilibrative nucleoside transporter 1 (hENT1) levels for prediction of the antitumor efficacy of gemcitabine. AB - 5'-S-(2-aminoethyl)-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAENTA), 5'-S-(2 acetamidoethyl)-6-N-[(4-substituted)benzyl]-5'-thioadenosine analogues, 5'-S-[2 (6-aminohexanamido)]ethyl-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAHENTA), and related compounds were synthesized by S(N)Ar displacement of fluoride from 6 fluoropurine intermediates with 4-(substituted)benzylamines. Conjugation of the pendant amino groups of SAENTA and SAHENTA with fluorescein-5-yl isothiocyanate (FITC) gave fluorescent probes that bound at nanomolar concentrations specifically to human equilibrative nucleoside transporter 1 (hENT1) produced in recombinant form in model expression systems and in native form in cancer cell lines. Transporter binding effects were studied and the ability of the probes to predict the potential antitumor efficacy of 2'-deoxy-2',2'-difluorocytidine (gemcitabine) was demonstrated. PMID- 20718496 TI - Effect of synthetic peptides belonging to E2 envelope protein of GB virus C on human immunodeficiency virus type 1 infection. AB - The use of synthetic peptides as HIV-1 inhibitors has been subject to research over recent years. Although the initial therapeutic attempts focused on HIV-coded enzymes, structural HIV proteins and, more specifically, the mechanisms that the virus uses to infect and replicate are now also considered therapeutic targets. The interest for viral fusion and entry inhibitors is growing significantly, given that they are applicable in combined therapies or when resistance to other antiretroviral drugs is seen and that they act before the virus enters the cell. The 124 synthetic sequences of the GBV-C E2 envelope protein have been obtained by SPPS. The interaction of certain GBV-C peptide sequences with the HIV-1 fusion peptide has been proven through the use of biophysical techniques. We also show how GBV-C E2 domains notably decrease cellular membrane fusion and interfere with the HIV-1 infectivity in a dose-dependent manner, highlighting their potential utility in future anti-HIV-1 therapies. PMID- 20718497 TI - Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models. AB - Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2 pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2' deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds. PMID- 20718499 TI - Tribute to Klaus Ruedenberg. PMID- 20718505 TI - NMR studies of translocation of the Zif268 protein between its target DNA Sites. AB - Zif268 is a zinc-finger protein containing three Cys(2)-His(2)-type zinc-finger domains that bind the target DNA sequence GCGTGGGCG in a cooperative manner. In this work, we characterized translocation of the Zif268 protein between its target DNA sites using NMR spectroscopy. The residual dipolar coupling data and NMR chemical shift data suggested that the structure of the sequence-specific complex between Zif268 and its target DNA in solution is the same as the crystal structure. Using two-dimensional heteronuclear (1)H-(15)N correlation spectra recorded with the fast acquisition method, we analyzed the kinetics of the process in which the Zif268 protein transfers from a target site to another on a different DNA molecule on a minute to hour time scale. By globally fitting the time-course data collected at some different DNA concentrations, we determined the dissociation rate constant for the specific complex and the second-order rate constant for direct transfer of Zif268 from one target site to another. Interestingly, direct transfer of the Zif268 protein between its target sites is >30000-fold slower than corresponding direct transfers of the HoxD9 and the Oct-1 proteins, although the affinities of the three proteins to their target DNA sites are comparable. We also analyzed translocation of the Zif268 protein between two target sites on the same DNA molecules. The populations of the proteins bound to the target sites were found to depend on locations and orientations of the target sites. PMID- 20718504 TI - Role of the highly conserved middle region of prion protein (PrP) in PrP-lipid interaction. AB - Converting normal prion protein (PrP(C)) to the pathogenic PrP(Sc) isoform is central to prion disease. We previously showed that, in the presence of lipids, recombinant mouse PrP (rPrP) can be converted into the highly infectious conformation, suggesting a crucial role of lipid-rPrP interaction in PrP conversion. To understand the mechanism of lipid-rPrP interaction, we analyzed the ability of various rPrP mutants to bind anionic lipids and to gain lipid induced proteinase K (PK) resistance. We found that the N-terminal positively charged region contributes to electrostatic rPrP-lipid binding but does not affect lipid-induced PK resistance. In contrast, the highly conserved middle region of PrP, consisting of a positively charged region and a hydrophobic domain, is essential for lipid-induced rPrP conversion. The hydrophobic domain deletion mutant significantly weakened the hydrophobic rPrP-lipid interaction and abolished the lipid-induced C-terminal PK resistance. The rPrP mutant without positive charges in the middle region reduced the amount of the lipid-induced PK resistant rPrP form. Consistent with a critical role of the middle region in lipid-induced rPrP conversion, both disease-associated P105L and P102L mutations, localized between lysine residues in the positively charged region, significantly affected lipid-induced rPrP conversion. The hydrophobic domain-localized 129 polymorphism altered the strength of hydrophobic rPrP-lipid interaction. Collectively, our results suggest that the interaction between the middle region of PrP and lipids is essential for the formation of the PK-resistant conformation. Moreover, the influence of disease-associated PrP mutations and the 129 polymorphism on PrP-lipid interaction supports the relevance of PrP-lipid interaction to the pathogenesis of prion disease. PMID- 20718506 TI - Urinary proteomics and drug discovery in chronic kidney disease: a new perspective. AB - Chronic kidney disease (CKD) is becoming a worldwide public health problem. The identification of a specific set of early biomarkers for CKD is extremely relevant to progress in disease knowledge, improving diagnosis, treatment, or development, and monitoring efficacy of new drugs. As kidney fibrosis can be considered the common pathological way to end stage renal failure, independent of the initial renal insult, these biomarkers are therefore biomarkers of early tubulo-interstitial fibrosis. The availability of a specific set of biomarkers for CKD is the mandatory condition to create new dedicated drugs and validate them in clinics without waiting years for a functional response in patients. We suggest here specific cohorts of patients where this early signature of fibrosis may be simpler to be identified. PMID- 20718507 TI - Proteomics in nutrition: status quo and outlook for biomarkers and bioactives. AB - Food and beverages are the only physical matter we take into our body, if we disregard the air we inhale and the drugs we may have to apply. While traditional nutrition research has aimed at providing nutrients to nourish populations and preventing specific nutrient deficiencies, it more recently explores health related aspects of individual bioactive components as well as entire diets and this at group rather than population level. The new era of nutrition research translates empirical knowledge to evidence-based molecular science. Modern nutrition research focuses on promoting health, preventing or delaying the onset of disease, optimizing performance, and assessing risk. Personalized nutrition is a conceptual analogue to personalized medicine and means adapting food to individual needs. Nutrigenomics and nutrigenetics build the science foundation for understanding human variability in preferences, requirements, and responses to diet and may become the future tools for consumer assessment motivated by personalized nutritional counseling for health maintenance and disease prevention. The scope of this paper is to review the current and future aspects of nutritional proteomics, focusing on the two main outputs: identification of health biomarkers and analysis of food bioactives. PMID- 20718508 TI - The ubiquitin-proteasome pathway is important for dengue virus infection in primary human endothelial cells. AB - Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are the most severe forms of dengue virus infection with hemorrhage and plasma leakage. However, pathogenic mechanisms of DHF and DSS remain poorly understood. We therefore investigated host responses as determined by changes in the cellular proteome of primary human endothelial cells upon infection with dengue virus serotype 2 (DEN-2) at a multiplicity of infection (MOI) of 10 for 24 h. Two dimensional PAGE and quantitative intensity analysis revealed 38 significantly altered protein spots (16 upregulated and 22 downregulated) in DEN-2-infected cells compared to mock controls. These altered proteins were successfully identified by mass spectrometry, including those involved in oxidative stress response, transcription and translation, cytoskeleton assembly, protein degradation, cell growth regulation, apoptosis, cellular metabolism, and antiviral response. The proteomic data were validated by Western blot analyses [upregulated ubiquitin-activating enzyme E1 (UBE1) and downregulated annexin A2] and an immunofluorescence study (upregulated MxA). Interestingly, we found that MxA was colocalized with DEN-2 viral capsid protein, strengthening its role as an antiviral protein. Moreover, we also identified upregulation of a proteasome subunit. Our functional study revealed the significant role of ubiquitination in dengue infection and UBE1 inhibition by its specific inhibitor (UBEI-41) caused a significant reduction in the level of viral protein synthesis and its infectivity. Our findings suggest that various biological processes were triggered in response to dengue infection, particularly antiviral IFN and ubiquitin-proteasome pathways. PMID- 20718509 TI - Get smarty pants: cognitive ability, personality, and victimization. AB - Drawing on the victim precipitation model, this study provides an empirical investigation of the relationship between cognitive ability and victimization at work. We propose that people high in cognitive ability are more prone to victimization. In this study, we also examine the direct and moderating effects of victims' personality traits, specifically the 2 interpersonally oriented personality dimensions of agency and communion. Results support the direct positive relationship of cognitive ability and victimization. The positive relationship between high cognitive ability and victimization is moderated by the victims' personality traits; agency personality traits strengthen the relationship of cognitive ability and victimization, whereas communion personality traits weaken this relationship. PMID- 20718510 TI - Retesting after initial failure, coaching rumors, and warnings against faking in online personality measures for selection. AB - A large sample (N = 32,311) of applicants for managerial positions at a nationwide retailer completed a personality test online over the course of several years. A new type of faking was observed in their responses: the use of only extreme responses (all 1s and 5s), which is labeled blatant extreme responding (BER). An increase in BER over time was observed for internal but not for external applicants, suggesting the presence of a coaching rumor. A subsample of internal applicants chose to retake the test after initial failure. These individuals showed substantial increases in both test scores and rate of BER, with higher prevalence of faking at retest than the main sample. To reduce faking, an interactive warning was implemented one year after the initial administration. Differing patterns of faking were observed before and after warnings, allowing for an examination of warning effectiveness in the presence of a coaching rumor. Results suggest that faking increases over time as the coaching rumor spreads but that warnings deter this spread. Evidence suggests that faking is indeed a problem in real-world selection settings. PMID- 20718511 TI - Self-gain or self-regulation impairment? Tests of competing explanations of the supervisor abuse and employee deviance relationship through perceptions of distributive justice. AB - Two competing explanations for deviant employee responses to supervisor abuse are tested. A self-gain view is compared with a self-regulation impairment view. The self-gain view suggests that distributive justice (DJ) will weaken the abusive supervision-employee deviance relationship, as perceptions of fair rewards offset costs of abuse. Conversely, the self-regulation impairment view suggests that DJ will strengthen the relationship, as experiencing abuse drains self-resources needed to maintain appropriate behavior, and this effect intensifies when employees receive inconsistent information about their organizational membership (fair outcomes). Three field studies using different samples, measures, and designs support the self-regulation impairment view. Two studies found that the Abusive Supervision * DJ interaction was mediated by self-regulation impairment variables (ego depletion and intrusive thoughts). Implications for theory and research are discussed. PMID- 20718512 TI - The influence of creative process engagement on employee creative performance and overall job performance: a curvilinear assessment. AB - Integrating theories addressing attention and activation with creativity literature, we found an inverted U-shaped relationship between creative process engagement and overall job performance among professionals in complex jobs in an information technology firm. Work experience moderated the curvilinear relationship, with low-experience employees generally exhibiting higher levels of overall job performance at low to moderate levels of creative process engagement and high-experience employees demonstrating higher overall performance at moderate to high levels of creative process engagement. Creative performance partially mediated the relationship between creative process engagement and job performance. These relationships were tested within a moderated mediation framework. PMID- 20718513 TI - Where do I stand? Examining the effects of leader-member exchange social comparison on employee work behaviors. AB - Taking an approach integrating principles of leader-member exchange (LMX) differentiation with social comparison theory, we contend that subjective ratings by individuals of their LMX compared to the LMXs of coworkers (labeled LMX social comparison, or LMXSC) explain unique and meaningful variance in outcomes beyond LMX and the actual standing of those individuals in the LMX distribution, referred to as relative LMX, or RLMX. Our findings demonstrate that employees' perceptions of LMXSC are positively related beyond the effects of LMX and RLMX to job performance and citizenship behaviors. Further, we argue that LMXSC mediates the RLMX->outcomes relationships. Analyses showed that, in a sample of 254 employees nested in 50 work groups, a significant part of the effects of RLMX on job performance and citizenship behaviors was mediated through LMXSC after controlling for LMX. PMID- 20718514 TI - When goal orientations collide: effects of learning and performance orientation on team adaptability in response to workload imbalance. AB - The authors draw on resource allocation theory (Kanfer & Ackerman, 1989) to develop hypotheses regarding the conditions under which collective learning and performance orientation have interactive effects and the nature of those effects on teams' ability to adapt to a sudden and dramatic change in workload. Consistent with the theory, results of a laboratory study in which teams worked on a computerized, decision-making task over 3 performance trials revealed that learning and performance orientation had independent effects on team adaptability when teams had slack resources available for managing their changed task. Time helped explain the independent effects of performance orientation. Results also revealed that learning and performance orientation had interactive effects when teams did not have slack resources. Finally, the results of this study indicate that teams lacking slack resources were better able to balance high levels of learning and performance orientation over time with practice on the changed task. PMID- 20718515 TI - Task conflict and team creativity: a question of how much and when. AB - Bridging the task conflict, team creativity, and project team development literatures, we present a contingency model in which the relationship between task conflict and team creativity depends on the level of conflict and when it occurs in the life cycle of a project team. In a study of 71 information technology project teams in the greater China region, we found that task conflict had a curvilinear effect on team creativity, such that creativity was highest at moderate levels of task conflict. Additionally, we found this relationship to be moderated by team phase, such that the curvilinear effect was strongest at an early phase. In contrast, at later phases of the team life cycle, task conflict was found to be unrelated to team creativity. PMID- 20718516 TI - Leader-member exchange and affective organizational commitment: the contribution of supervisor's organizational embodiment. AB - In order to account for wide variation in the relationship between leader-member exchange and employees' affective organizational commitment, we propose a concept termed supervisor's organizational embodiment (SOE), which involves the extent to which employees identify their supervisor with the organization. With samples of 251 social service employees in the United States (Study 1) and 346 employees in multiple Portuguese organizations (Study 2), we found that as SOE increased, the association between leader-member exchange and affective organizational commitment became greater. This interaction carried through to in-role and extra role performance. With regard to antecedents, we found in Study 1 that supervisor's self-reported identification with the organization increased supervisor's expression of positive statements about the organization, which in turn increased subordinates' SOE. PMID- 20718517 TI - Speaking up in groups: a cross-level study of group voice climate and voice. AB - Despite a growing body of research on employee voice-defined as the discretionary communication of ideas, suggestions, or opinions intended to improve organizational or unit functioning-the effects of shared or collective-level cognitions have received scant attention. There has also been relatively little research on voice within work groups. Our goal in this study was to address these important gaps by focusing on the effects of group-level beliefs about voice (i.e., group voice climate) on individual voice behavior within work groups. We conducted a cross-level investigation of voice behavior within 42 groups of engineers from a large chemical company. Consistent with our hypotheses, group voice climate was highly predictive of voice and explained variance beyond the effects of individual-level identification and satisfaction, and procedural justice climate. Also consistent with predictions, the effect of identification on voice was stronger in groups with favorable voice climates. These findings provide evidence that voice is shaped not just by individual attitudes and perceptions of the work context, as past research has shown, but also by group level beliefs. The results also highlight the importance of broadening our conceptual models of voice to include shared cognitions and of conducting additional cross-level research on voice. PMID- 20718518 TI - Decomposing model fit: measurement vs. theory in organizational research using latent variables. AB - Goodness-of-fit indices have an important role in structural equation model evaluation. However, some studies (e.g., McDonald & Ho, 2002; Mulaik et al., 1989) have raised concerns that overall fit values primarily reflect the fit of the measurement model, and this allows significant misspecification among the latent variables to be masked. Using an approach analogous to Anderson and Gerbing's (1988) 2-step approach that isolates the measurement component of a composite model, we present the rationale and evidence for the root mean square error of approximation of the path component (RMSEA-P), a relatively new fit index that isolates the path component. We reviewed 5 of the top organizational behavior/human resources journals from 2001 to 2008 and identified 43 studies using structural equation modeling in which the overall composite model could be decomposed into its measurement and path components. The RMSEA-P for these studies generally showed unfavorable results, with many values failing to meet commonly accepted standards. Incorporating the RMSEA-P and its confidence interval into James, Mulaik, and Brett's (1982) framework for model testing, we provide evidence that many of the conclusions based upon the goodness of fit of the overall model may be inaccurate. We conclude with recommendations for how researchers can focus more attention on path models and latent variable relations and improve their model evaluation process. PMID- 20718519 TI - Well-connected leaders: the impact of leaders' social network ties on LMX and members' work attitudes. AB - We examined the proposition that leaders' social network ties in the larger organization influence the quality of their leader-member exchange (LMX) with their employees, which, in turn, impacts these employees' job satisfaction and turnover intentions. Using multilevel, multisource data from a field study of 184 bank employees nested within 42 branch managers, we found that leaders who had higher quality relationships with their bosses and who were more central in their peer networks were perceived by their subordinates as having greater status in the organization and, therefore, were able to form higher quality relationships with them. Further, the effects of the leaders' perceived status on LMX were stronger when subordinates were less central in their own peer network. Finally, LMX mediated the impact of leaders' perceived status in the organization on subordinates' job satisfaction and turnover intentions. Implications for theory and practice are discussed. PMID- 20718520 TI - A conceptual and empirical analysis of the cognitive ability-voluntary turnover relationship. AB - Despite much research into cognitive ability as a selection tool and a separate large literature on the causes of voluntary turnover, little theoretical or empirical work connects the two. We propose that voluntary turnover is also a potentially key outcome of cognitive ability. Incorporating ideas from the person environment fit literature and those regarding push and pull influences on turnover, we posit a theoretical connection between cognitive ability and voluntary turnover that addresses both why and how voluntary turnover is related to cognitive ability. Integrating data from 3 different sources, our empirical analyses support the theoretical perspective that the relationship between cognitive ability and voluntary turnover depends on the cognitive demands of the job. When the cognitive demands of a job are high, our findings support the hypothesized curvilinear relationship between cognitive ability and voluntary turnover, such that employees of higher and lower cognitive ability are more likely than medium cognitive ability employees to leave voluntarily. With regard to jobs with low cognitive demands, our data are more consistent with a negative linear relationship between cognitive ability and voluntary turnover, such that higher cognitive ability employees are less likely to leave voluntarily. We also examine the role of job satisfaction, finding that job satisfaction is more strongly linked to voluntary turnover in jobs with high cognitive demands. PMID- 20718521 TI - Task-contingent conscientiousness as a unit of personality at work. AB - The present study examined the viability of incorporating task-contingent units into the study of personality at work, using conscientiousness as an illustrative example. We used experience-sampling data from 123 managers to show that (a) momentary conscientiousness at work is contingent on the difficulty and urgency demands of the tasks people are engaged in, (b) there are significant and stable differences between people in the extent to which their conscientiousness behaviors are contingent on task demands, and (c) individual differences in task contingent conscientiousness are related to, though distinct from, individual differences in trait conscientiousness. We also provide evidence in relation to (a) need for cognition as a possible antecedent of task-contingent conscientiousness and (b) adaptive performance on a cognitive task as a possible consequence of it. We discuss the theoretical implications of our findings for the cognitive nature of personality and the way in which conscientiousness is expressed at work. Practical implications in relation to the predictive function of personality and applications that focus on behavioral change are also discussed. PMID- 20718522 TI - Beyond status: relating status inequality to performance and health in teams. AB - Status structures in organizations are ubiquitous yet largely ignored in organizational research. We offer a conceptualization of team status inequality, or the extent to which status positions on a team are dispersed. Status inequality is hypothesized to be negatively related to individual performance and physical health for low-status individuals when uncooperative behavior is high. Trajectories of the outcomes across time are also explored. Analyses using multilevel modeling largely support our hypotheses in a sample of National Basketball Association players across six time points from 2000 to 2005. PMID- 20718523 TI - Leadership perceptions as a function of race-occupation fit: the case of Asian Americans. AB - On the basis of the connectionist model of leadership, we examined perceptions of leadership as a function of the contextual factors of race (Asian American, Caucasian American) and occupation (engineering, sales) in 3 experiments (1 student sample and 2 industry samples). Race and occupation exhibited differential effects for within- and between-race comparisons. With regard to within-race comparisons, leadership perceptions of Asian Americans were higher when race-occupation was a good fit (engineer position) than when race-occupation was a poor fit (sales position) for the two industry samples. With regard to between-race comparisons, leadership perceptions of Asian Americans were low relative to those of Caucasian Americans. Additionally, when race-occupation was a good fit for Asian Americans, such individuals were evaluated higher on perceptions of technical competence than were Caucasian Americans, whereas they were evaluated lower when race-occupation was a poor fit. Furthermore, our results demonstrated that race affects leadership perceptions through the activation of prototypic leadership attributes (i.e., implicit leadership theories). Implications for the findings are discussed in terms of the connectionist model of leadership and leadership opportunities for Asian Americans. PMID- 20718524 TI - The downside of goal-focused leadership: the role of personality in subordinate exhaustion. AB - Exhaustion has a significant impact on employees and organizations, and leader behavior may affect it. We applied conservation of resources theory to test propositions regarding the joint effects of goal-focused leadership (GFL) and personality on employee exhaustion. We proposed that the relationship between GFL and exhaustion depends on employees' standing on both conscientiousness and emotional stability. Specifically, we expected that high-conscientiousness subordinates experience greater compatibility with a goal-focused leader because of their predisposition to direct resources toward achievement and goal setting, resulting in lower exhaustion under such a leader than among low conscientiousness employees. Furthermore, high emotional stability may compensate for GFL incompatibility among low-conscientiousness employees by providing additional resources to manage GFL. In contrast, employees low on both traits likely experience greater exhaustion under a goal-focused leader compared with other employees. Results revealed a 3-way interaction in 2 independent samples and were generally supportive of our predictions. GFL was associated with heightened exhaustion among individuals in the low-emotional-stability, low conscientiousness group but not among workers having any other trait combination. PMID- 20718525 TI - Genetics, the Big Five, and the tendency to be self-employed. AB - We applied multivariate genetics techniques to a sample of 3,412 monozygotic and dizygotic twins from the United Kingdom and 1,300 monozygotic and dizygotic twins from the United States to examine whether genetic factors account for part of the covariance between the Big Five personality characteristics and the tendency to be an entrepreneur. We found that common genes influenced the phenotypic correlations between only Extraversion and Openness to Experience and the tendency to be an entrepreneur. Although the phenotypic correlations between the personality characteristics and the tendency to be an entrepreneur were small in size, genetic factors accounted for most of them. PMID- 20718526 TI - Sabbatical leave: who gains and how much? AB - A rigorous quasi-experiment tested the ameliorative effects of a sabbatical leave, a special case of respite from routine work. We hypothesized that (a) respite increases resource level and well-being and (b) individual differences and respite features moderate respite effects. A sample of 129 faculty members on sabbatical and 129 matched controls completed measures of resource gain, resource loss, and well-being before, during, and after the sabbatical. Among the sabbatees, resource loss declined and resource gain and well-being rose during the sabbatical. The comparison group showed no change. Moderation analysis revealed that those who reported higher respite self-efficacy and greater control, were more detached, had a more positive sabbatical experience, and spent their sabbatical outside their home country enjoyed more enhanced well-being than others. PMID- 20718527 TI - A multilevel model of minority opinion expression and team decision-making effectiveness. AB - The consideration of minority opinions when making team decisions is an important factor that contributes to team effectiveness. A multilevel model of minority opinion influence in decision-making teams is developed to address the conditions that relate to adequate consideration of minority opinions. Using a sample of 57 teams working on a simulated airport security-screening task, we demonstrate that team learning goal orientation influences the confidence of minority opinion holders and team discussion. Team discussion, in turn, relates to minority influence, greater decision quality, and team satisfaction. Implications for managing decision-making teams in organizations are discussed. PMID- 20718528 TI - Staying well and engaged when demands are high: the role of psychological detachment. AB - The authors of this study examined the relation between job demands and psychological detachment from work during off-job time (i.e., mentally switching off) with psychological well-being and work engagement. They hypothesized that high job demands and low levels of psychological detachment predict poor well being and low work engagement. They proposed that psychological detachment buffers the negative impact of high job demands on well-being and work engagement. A longitudinal study (12-month time lag) with 309 human service employees showed that high job demands predicted emotional exhaustion, psychosomatic complaints, and low work engagement over time. Psychological detachment from work during off-job time predicted emotional exhaustion and buffered the relation between job demands and an increase in psychosomatic complaints and between job demands and a decrease in work engagement. The findings of this study suggest that psychological detachment from work during off job time is an important factor that helps to protect employee well-being and work engagement. PMID- 20718529 TI - Exploring the dual-level effects of transformational leadership on followers. AB - We developed a dual-level transformational leadership scale to measure individual focused behavior at the individual level and group-focused behavior at the group level, and we validated the scale using a sample of 203 members from 60 work groups in a Canadian company. Results show that individual-focused leadership behavior, at the individual level, was positively related to task performance and personal initiative; group-focused leadership behavior, at the group level, was positively associated with team performance and helping behavior. Implications for leadership theory and practice are offered. PMID- 20718530 TI - Differentiated leader-member exchanges: the buffering role of justice climate. AB - The leader-member exchange (LMX) literature has established that leaders differentiate among their followers. Yet little is known about the effects of LMX differentiation (within-group variation in LMX quality). In this study, we contend that the effects of LMX differentiation on the employee outcomes of work attitudes, coworker relations, and employee withdrawal behaviors will be contingent upon the level of procedural and distributive justice climate. Data from 276 employees working in 25 stores of a retail chain in Turkey supported our hypotheses such that LMX differentiation was related to more negative work attitudes and coworker relations, and higher levels of withdrawal behaviors only when justice climate was low. PMID- 20718531 TI - Attachment at (not to) work: applying attachment theory to explain individual behavior in organizations. AB - In this article, we report the results of 2 studies that were conducted to investigate whether adult attachment theory explains employee behavior at work. In the first study, we examined the structure of a measure of adult attachment and its relations with measures of trait affectivity and the Big Five. In the second study, we examined the relations between dimensions of attachment and emotion regulation behaviors, turnover intentions, and supervisory reports of counterproductive work behavior and organizational citizenship behavior. Results showed that anxiety and avoidance represent 2 higher order dimensions of attachment that predicted these criteria (except for counterproductive work behavior) after controlling for individual difference variables and organizational commitment. The implications of these results for the study of attachment at work are discussed. PMID- 20718532 TI - Comparing victim attributions and outcomes for workplace aggression and sexual harassment. AB - In 2 studies, we investigated victim attributions (Study 1) and outcomes (Study 2) for workplace aggression and sexual harassment. Drawing on social categorization theory, we argue that victims of workplace aggression and sexual harassment may make different attributions about their mistreatment. In Study 1, we investigated victim attributions in an experimental study. We hypothesized that victims of sexual harassment are more likely than victims of workplace aggression to depersonalize their mistreatment and attribute blame to the perpetrator or the perpetrator's attitudes toward their gender. In contrast, victims of workplace aggression are more likely than victims of sexual harassment to personalize the mistreatment and make internal attributions. Results supported our hypotheses. On the basis of differential attributions for these 2 types of mistreatment, we argue that victims of workplace aggression may experience stronger adverse outcomes than victims of sexual harassment. In Study 2, we compared meta-analytically the attitudinal, behavioral, and health outcomes of workplace aggression and sexual harassment. Negative outcomes of workplace aggression were stronger in magnitude than those of sexual harassment for 6 of the 8 outcome variables. Implications and future directions are discussed. PMID- 20718533 TI - Initial evaluations in the interview: relationships with subsequent interviewer evaluations and employment offers. AB - The authors of this study examine how evaluations made during an early stage of the structured interview (rapport building) influence end of interview scores, subsequent follow-up employment interviews, and actual internship job offers. Candidates making better initial impressions received more internship offers (r = .22) and higher interviewer ratings (r = .42). As predicted, initial evaluations of candidate competence extend beyond liking and similarity to influence subsequent interview outcomes from the same interviewer (DeltaR2 = .05), from a separate interviewer (DeltaR2 = .05), and from another interviewer who skipped rapport building (DeltaR2 = .05). In contrast, assessments of candidate liking and similarity were not significantly related to other judgments when ratings were provided by different interviewers. The findings of this study thus indicate that initial impressions of candidates influence employment outcomes, and that they may be based on useful judgments of candidate competence that occur in the opening minutes of the structured interview. PMID- 20718534 TI - Coping with perceived peer stress: gender-specific and common pathways to symptoms of psychopathology. AB - This study investigated gender differences in the moderating and mediating effects of responses to stress on the association between perceived peer stress and symptoms of psychopathology. A sample of 295 middle school students (63.7% female; M(age) = 12.39 years, SD = 0.99) completed self-report surveys on stress, coping, and behavioral problems. Involuntary responses to stress (e.g., physiological arousal, intrusive thoughts, impulsive action) mediated the association between perceived stress and anxiety/depression and aggression for girls and for boys. Disengagement coping (e.g., denial, avoidance) partially mediated the association between peer stress and anxiety/depression for boys and for girls. In contrast, disengagement coping mediated the association between peer stress and overt aggression for boys only. Finally, engagement coping (e.g., problem solving, emotion regulation, cognitive restructuring) buffered the indirect effect of peer stress on symptoms of psychopathology for girls only. Implications for prevention and intervention efforts are discussed. PMID- 20718535 TI - Children's spatial analysis of hierarchical patterns: construction and perception. AB - Two experiments were reported that aimed at investigating the development of spatial analysis of hierarchical patterns in children between 3 and 9 years of age. A total of 108 children participated in the drawing experiment, and 224 children were tested in a force-choice similarity judgment task. In both tasks, participants were exposed to consistent and inconsistent targets for short (300 ms) and long (3-s) durations. The drawing task showed that 3-year-old children either preferred to draw the local level or reproduced both levels in a nonintegrated manner. Coordination between the 2 processes started to emerge at 4 years of age, and 6-year-old children produced essentially correct integrated responses. The similarity judgment task confirmed that local processing dominated at 3 years of age. Preference for global processing appeared at 5 years of age, and it gained in strength later. Significant effects of stimulus consistency and stimulus duration were also found. In particular, the use of inconsistent patterns in the similarity judgment task revealed a phenomenon of local-to-global interference in the 3-year-olds. PMID- 20718536 TI - Age-related differences in transfer costs: evidence from go/nogo tasks. AB - To assess whether age-related differences in suppressing nontarget material impact subsequent performance, the authors initially asked younger and older adults to perform a go/nogo task with colored letters used as conflicting go/nogo stimuli and 2 colored numbers as low-conflict nogo stimuli. Next, participants performed another go/nogo task. A previous number was reused as a nogo stimulus and the other as a go stimulus, with new numbers serving as a baseline. In a 1st block of trials, younger adults showed slower responses to previous nogo/now-go numbers than to new go numbers, an effect not shown by older adults. Alternative accounts of these differential transfer costs are discussed. PMID- 20718537 TI - Destination memory impairment in older people. AB - Older adults are assumed to have poor destination memory-knowing to whom they tell particular information-and anecdotes about them repeating stories to the same people are cited as informal evidence for this claim. Experiment 1 assessed young and older adults' destination memory by having participants tell facts (e.g., "A dime has 118 ridges around its edge") to pictures of famous people (e.g., Oprah Winfrey). Surprise recognition memory tests, which also assessed confidence, revealed that older adults, compared to young adults, were disproportionately impaired on destination memory relative to spared memory for the individual components (i.e., facts, faces) of the episode. Older adults also were more confident that they had not told a fact to a particular person when they actually had (i.e., a miss); this presumably causes them to repeat information more often than young adults. When the direction of information transfer was reversed in Experiment 2, such that the famous people shared information with the participants (i.e., a source memory experiment), age-related memory differences disappeared. In contrast to the destination memory experiment, older adults in the source memory experiment were more confident than young adults that someone had shared a fact with them when a different person actually had shared the fact (i.e., a false alarm). Overall, accuracy and confidence jointly influence age-related changes to destination memory, a fundamental component of successful communication. PMID- 20718538 TI - Recognition of posed and spontaneous dynamic smiles in young and older adults. AB - In 2 studies, we investigated age effects in the ability to recognize dynamic posed and spontaneous smiles. Study 1 showed that both young and older adult participants were above chance in their ability to distinguish between posed and spontaneous smiles in young adults. In Study 2, we found that young adult participant performance declined when judging a combination of both young and older adult target smiles, while older adult participants outperformed young adult participants in distinguishing between posed and spontaneous smiles. A synthesis of results across the 2 studies showed a small-to-medium age effect (d = -0.40), suggesting that older adults have an advantage in discriminating between smile types. Mixed stimuli (i.e., a mixture of young and older adult faces) may impact accurate smile discrimination. In future research, both the sources (cues) and behavioral effects of age-related differences in the discrimination of positive expressions should be investigated. PMID- 20718539 TI - Impact of sensory acuity on auditory working memory span in young and older adults. AB - The impact of sensory acuity, processing speed, and working memory capacity on auditory working memory span (L-span) performance at 5 presentation levels was examined in 80 young adults (18-30 years of age) and 26 older adults (60-82 years of age). Lowering the presentation level of the L-span task had a greater detrimental effect on the older adults than on the younger ones. Furthermore, the relationship between sensory acuity and L-span performance varied as a function of age and presentation level. These results suggest that declining acuity plays an important explanatory role in age-related declines in cognitive abilities. PMID- 20718540 TI - Staying on and getting back on the wagon: age-related improvement in self regulation during a low-calorie diet. AB - In the present study, we investigated whether self-regulation improves across adulthood, especially regarding the mastery of setbacks and failure in an important health-related behavior, namely, staying on a low-calorie diet when overweight. Overweight women (N = 126; 19-77 years of age, M = 47.2) filled out weekly questionnaires on the outcomes of behavioral, emotional, and cognitive self-regulation during a dieting program; outcomes included deviations from the diet, weight loss, affect, and rumination. Confirming hypotheses, multilevel analyses revealed that-even after controlling for prior dieting attempts-age was associated with better self-reported self-regulation (i.e., fewer deviations from the diet, lower disinhibition and rumination after failure, and higher affective well-being) but not with more weight loss. Results suggest that self-regulation improves with age and shows positive effects on subjective indicators of successfully coping with setbacks but does not directly influence the target outcome weight loss. PMID- 20718542 TI - A silent emergence of culture: the social tuning effect. AB - Scholars have long been concerned with understanding the psychological mechanisms by which cultural (i.e., shared) knowledge emerges. This article proposes a novel psychological mechanism that allows for the formation of cultural memories, even when intragroup communication is absent. Specifically, the research examines whether a stimulus is more psychologically and behaviorally prominent when it is assumed to be experienced by more similar versus less similar others. Findings across 3 studies suggest that stimuli such as time pressure (Study 1), words (Study 2), and paintings (Study 3) are more psychologically and behaviorally prominent when they are thought to be experienced by more (vs. less) similar others. Critically, the effect is absent when similar others are thought to be experiencing distinct stimuli from the participant (Study 3). Taken as a whole, these results are consistent with the hypothesis that stimuli which are assumed to be experienced by one's social group are more prominent in both cognition and behavior. Theoretical implications for the emergence of culture are discussed. PMID- 20718541 TI - The benefits and costs of repeated testing on the learning of face-name pairs in healthy older adults. AB - We compared the benefits of repeated testing and repeated study on cued recall of unfamiliar face-name pairs in healthy middle-aged and older adults. We extended Karpicke and Roediger's (2008) paradigm to compare the effects of repeated study versus repeated testing after each face-name pair was correctly recalled once. The results from Experiment 1, which provided no feedback during the acquisition phase, yielded a crossover interaction: Middle-aged adults showed the expected benefit of repeated testing, whereas older adults produced a benefit of repeated study. When participants were given feedback in Experiment 2, both middle-aged and older adults benefited from repeated testing. We suggest that for face-name pairs, feedback may be particularly important for individuals who have relatively poor memory to produce benefits from repeated testing. PMID- 20718543 TI - The psychology of voice and performance capabilities in masculine and feminine cultures and contexts. AB - In this article, we examine the hypothesis that in masculine cultures or in other contexts that emphasize competitive achievement, those with higher performance capabilities will feel empowered to have input in decisions and, hence, will desire opportunities to voice their opinions about decisions to be made. In contrast, in more feminine cultures or in other contexts that value the importance of nurturing people with lower capability, those with lower capabilities will feel valued as important group members, will feel worthy of receiving voice and, hence, will appreciate voice opportunities. We provide evidence for these predictions in 2 studies, 1 conducted in the United States (a more masculine culture) and 1 in the Netherlands (a more feminine culture). Evidence also comes from experimental conditions in both studies, in which we made salient to participants countercultural norms and values, that is, nurturing the less capable in the United States and competitive achievement in the Netherlands. Implications for the psychology of voice and cross-cultural research are discussed. PMID- 20718544 TI - Predicting relationship and life satisfaction from personality in nationally representative samples from three countries: the relative importance of actor, partner, and similarity effects. AB - Three very large, nationally representative samples of married couples were used to examine the relative importance of 3 types of personality effects on relationship and life satisfaction: actor effects, partner effects, and similarity effects. Using data sets from Australia (N = 5,278), the United Kingdom (N = 6,554), and Germany (N = 11,418) provided an opportunity to test whether effects replicated across samples. Actor effects accounted for approximately 6% of the variance in relationship satisfaction and between 10% and 15% of the variance in life satisfaction. Partner effects (which were largest for Agreeableness, Conscientiousness, and Emotional Stability) accounted for between 1% and 3% of the variance in relationship satisfaction and between 1% and 2% of the variance in life satisfaction. Couple similarity consistently explained less than .5% of the variance in life and relationship satisfaction after controlling for actor and partner effects. PMID- 20718545 TI - Faith and unfaithfulness: can praying for your partner reduce infidelity? AB - Because religion and/or spirituality is integral to the lives of a majority of the world population, we conducted 3 studies on the role of prayer in romantic relationships. Study 1 (N = 375) showed that prayer for the partner predicted lower levels of extradyadic romantic behavior over a 6-week period, over and beyond relationship satisfaction, and initial levels of extradyadic romantic behavior. In Study 2 (N = 83), we used an experimental design to show that participants assigned to pray for each day for 4 weeks engaged in lower levels of extradyadic romantic behavior during that time, compared with those who engaged in daily positive thoughts about the partner or a neutral activity. Perception of the relationship as sacred mediated the relation between experimentally manipulated prayer and later infidelity. Study 3 (N = 23) showed that objective observers rated participants who had been praying for their partner for 4 weeks as more committed to their romantic relationship than control participants. The implications of these results are then discussed. Because religion and/or spirituality is integral to the lives of a majority of the world population, we conducted 3 studies on the role of prayer in romantic relationships. Study 1 (N = 375) showed that prayer for the partner predicted lower levels of extradyadic romantic behavior over a 6-week period, over and beyond relationship satisfaction, and initial levels of extradyadic romantic behavior. In Study 2 (N = 83), we used an experimental design to show that participants assigned to pray for each day for 4 weeks engaged in lower levels of extradyadic romantic behavior during that time, compared with those who engaged in daily positive thoughts about the partner or a neutral activity. Perception of the relationship as sacred mediated the relation between experimentally manipulated prayer and later infidelity. Study 3 (N = 23) showed that objective observers rated participants who had been praying for their partner for 4 weeks as more committed to their romantic relationship than control participants. The implications of these results are then discussed. PMID- 20718547 TI - The influence of blocking on overt attention and associability in human learning. AB - Previous studies have demonstrated a retardation in the rate of novel learning about previously blocked cues as compared to appropriate control cues. We report an experiment investigating whether this retardation in novel learning about a blocked cue is accompanied by a reduction in attention to this cue, as anticipated by attentional theories of associative learning. Consistent with these theories, eye gaze measures revealed a reduction in overt attention to the blocked cue both during the compound training phase of the blocking procedure, and also during novel learning with respect to new outcomes. Moreover, the extent of the bias in overt attention away from blocked cues was positively correlated with the subsequent reduction in rate of novel learning about these cues. PMID- 20718546 TI - Stimulus compounding in interval timing: the modality-duration relationship of the anchor durations results in qualitatively different response patterns to the compound cue. AB - We have previously demonstrated that rats trained on a two-duration peak procedure in which two modal signals (i.e., tone and houselight) predicted probabilistic reinforcement availability at two times (10 s and 20 s) would respond in a scalar manner at a time between the trained durations in response to the simultaneous compound cue (tone + houselight). In these experiments, we evaluated whether this scalar response pattern would remain with greater relative separation between the anchor durations. Results revealed an effect of the modality-duration relationship, such that scalar responding was seen on compound trials in rats trained that the auditory stimulus signaled the shorter duration, whereas the visual stimulus signaled the longer duration, but not in the reverse condition. In rats showing scalar responding on compound trials, post hoc analyses demonstrated that the peak time of compound responding was most accurately predicted by the reinforcement probability weighted average of anchor peak times. In contrast, rats trained that the visual stimulus signaled the shorter duration, whereas the auditory stimulus signaled the longer duration, responded in a highly rightward skewed manner. In these rats, initiation of responding to the compound stimulus appeared to be controlled by the visual stimulus only, whereas response terminations reflected control by both modal stimuli. These latter data provide evidence of separate determinants of response initiation and termination. PMID- 20718548 TI - Black-capped chickadees (Poecile atricapillus) anticipate future outcomes of foraging choices. AB - In 2 experiments we investigated the cognitive abilities of wild-caught black capped chickadees (Poecile atricapillus) in future anticipation tasks. Chickadees were sensitive to anticipatory contrast effects over time horizons of 5, 10, and 30 min (Experiment 1). Chickadees also learned the order of events and anticipated that the quality of future foraging outcomes was contingent on current foraging choices. This behavior was demonstrated while foraging in a naturalistic aviary environment with a 30-min delay between the initial choice and the future outcome (Experiment 2). These results support the hypothesis that black-capped chickadees can cognitively travel in time both retrospectively and prospectively using episodic memory. This result shows the occurrence of anticipatory cognition in a noncorvid species of food-storing bird and supports the idea that cognitive time travel may have evolved in nonhuman animals in response to specific ecological selection pressures. PMID- 20718549 TI - Differential outcome effects in pavlovian biconditional and ambiguous occasion setting tasks. AB - Three experiments with rats explored the differential outcome effect (DOE) using a pavlovian magazine approach conditioning preparation. Experiment 1 compared groups trained on a biconditional discrimination (AX+, AY-, BX-, BY+) with differential or nondifferential outcomes, and Experiment 2 examined this using an ambiguous occasion setting task (e.g., AX+, X-, Y+, AY-). In both experiments, subjects trained with differential outcomes learned the tasks better than subjects trained with nondifferential outcomes. Furthermore, subjects given differential outcome training learned the positive occasion setting component of the ambiguous task more efficiently than the negative occasion setting component, although both were enhanced by differential outcome training. Experiment 3 demonstrated that the ambiguous occasion setting task was reversed more readily when the target-outcome relations (as opposed to the modulator-outcome relations) were maintained during the reversal phase. These data suggest that an acquired distinctiveness effect may be responsible for the DOE in pavlovian learning. PMID- 20718550 TI - The pattern of responding in the peak-interval procedure with gaps: an individual trials analysis. AB - Humans and lower animals time as if using a stopwatch that can be "stopped" or "reset" on command. This view is challenged by data from the peak-interval procedure with gaps: Unexpected retention intervals (gaps) delay the response function in a seemingly continuous fashion, from stop to reset. We evaluated whether these results are an artifact of averaging over trials, or whether subjects use discrete alternatives or a continuum of alternatives in individual trials: A Probability-of-Reset hypothesis proposes that in individual gap trials subjects stochastically use discrete alternatives (stop/reset), such that when averaged over trials, the response distribution in gap trials falls in between "stop" and "reset." Alternatively, a Resource Allocation hypothesis proposes that during individual gap trials working memory for the pregap duration decays, such that the response function in individual gap trials is shifted rightward in a continuous fashion. Both hypotheses provided very good fits with the observed individual-trial distributions, although the Resource Allocation hypothesis generated reliably better fits. Results provide support for the usefulness of individual-trial analyses in dissociating theoretical alternatives in interval timing tasks. PMID- 20718551 TI - Slope-driven goal location behavior in pigeons. AB - A basic tenet of principles of associative learning applicable to models of spatial learning is that a cue should be assigned greater weight if it is a better predictor of the goal location. Pigeons were trained to locate a goal in an acute corner of an isosceles trapezoid arena, presented on a slanted floor with 3 (Experiment 1) or 2 (Experiment 2) orientations. The goal could be consistently determined by the geometric shape of the arena; however, its position with respect to the slope gradient varied, such that slope position was not a good predictor of the goal. Pigeons learned to solve the task, and testing on a flat surface revealed successful encoding of the goal relative to the geometric shape of the arena. However, when tested in the arena placed in a novel orientation on the slope, pigeons surprisingly made systematic errors to the other acute-but geometrically incorrect-mirror image corner. The results indicate that, for each arena orientation, pigeons encoded the goal location with respect to the slope. Then, in the novel orientation, they chose the corner that matched the goal's position on the slope plus local cue (corner angle). Although geometry was 2 times (Experiment 2) or even 3 times (Experiment 1) as predictive as slope, it failed to control behavior during novel test trials. Instead, searching was driven by the less predictive slope cues. The reliance on slope and the unresponsiveness to geometry are explained by the greater salience of slope despite its lower predictive value. PMID- 20718552 TI - Two kinds of attention in Pavlovian conditioning: evidence for a hybrid model of learning. AB - Four appetitive Pavlovian conditioning experiments with rats examined the rate at which the discrimination between compounds AY and AX was solved relative to the discrimination between compounds AY and BY. In Experiments 1 and 2, these discriminations were preceded by training in which A and B were continuously reinforced and X and Y were partially reinforced. Consistent with the Pearce and Hall (1980) model, the results showed that the AY/AX discrimination was solved more readily than the AY/BY discrimination. In Experiments 3 and 4, the discriminations were preceded by feature-positive training in which trials with AX and BY signaled food but trials with X and Y did not. Consistent with the Mackintosh (1975) model, the results showed that the AY/BY discrimination was solved more readily than the AY/AX discrimination. These results are discussed with respect to a hybrid model of conditioning and attention. PMID- 20718553 TI - Learning and generalization of tool use by tufted capuchin monkeys (Cebus apella) in tasks involving three factors: reward, tool, and hindrance. AB - We tested 4 captive tufted capuchin monkeys (Cebus apella) for their understanding of physical causality in variations of a 2-choice tool use task, 1 alternative of which allowed the monkeys easier access to food. Our monkeys, who had been adept at this task involving 2 items, that is, tool and food, quickly learned 3-term problems involving food, tool, and 1 type of hindrance (an obstacle or a trap, which could prevent success). All of the monkeys generalized their performance to new problems with the other type of hindrance and those with another familiar tool. These results suggest flexibility of their abilities to process complex physical information comprising 3 items in the environment, that is food-tool-hindrance spatial relationships. Such flexibility also implies that capuchin monkeys may possess rudimentary understanding of causal relationships involved in tool use. PMID- 20718554 TI - Pigeons prefer conditional stimuli over their absence: a comment on Roberts et al. (2009). AB - Recently, Roberts et al. (2009) have suggested that pigeons performing delayed matching-to-sample appear unwilling to request to see the sample again (or even for the first time) prior to choice, even if that choice would result in an increase in matching accuracy. In each of their four experiments, however, presentation (Experiments 3 & 4) or representation of the sample (Experiments 1 & 2) resulted in an added delay to reinforcement. Thus, the pigeons had to choose between an immediate reinforcer on about 50% of the trials and a delayed reinforcer on a significantly higher percentage of the trials. In the present research, when we equated the two alternatives for delay to reinforcement, we found that pigeons generally showed a significant preference for trials with a relevant sample over trials with an irrelevant sample. When the contingencies were reversed, most of the pigeons reversed their preference. Although these results do not present evidence for metacognition, they do show that pigeons are sensitive to the potential for a higher probability of reinforcement when delay to reinforcement is controlled. PMID- 20718555 TI - An experimental analysis of steady-state response rate components on variable ratio and variable interval schedules of reinforcement. AB - Three experiments explored a novel approach to analyzing the different components of response rate that are produced by exposure to free-operant schedules of reinforcement. It has been suggested that overall response rate comprises a tendency to initiate responding, and to continue to respond once the bout is initiated. Previous post hoc analyses of interresponse times (IRT) data have suggested several features of these different aspects of responding that the current experimental procedure broadly confirmed. Increasing the size of a variable interval (VI) schedule decreases the number of "burst-initiation" responses, but has less effect on responding once the burst has been initiated (Experiment 1); that the major difference between a variable ratio (VR) schedule and a VI schedule, is not in the number of "burst-initiation" responses, but in the number of "within-burst" responses, with shorter interresponse times that are emitted, with greater numbers of such "within-burst" responses being emitted on a VR schedule (Experiments 2 and 3). PMID- 20718557 TI - Ambiguity and context processing in human predictive learning. AB - Two experiments explored the role of ambiguity on context processing by using relative stimulus validity designs in human predictive learning. Two groups of participants were trained with 2 stimulus compounds (XY and XZ). In Group TD (true discrimination), compound XY was always followed by the outcome, whereas compound XZ was never followed by it. In Group PD (pseudodiscrimination) the presentation of each compound was followed by the outcome in half of the trials. Experiment 1 found that pseudodiscrimination facilitated context dependency of reliable predictors regardless of whether they were trained in the same context in which pseudodiscrimination took place or in an alternative context in which true discrimination was conducted. Experiment 2 found context dependency of reliable predictors trained and tested in PD contexts, suggesting that the ambiguity in the meaning of the cues produced by pseudodiscrimination training is at least partially responsible for the context switch effects found in ambiguous situations in human predictive learning. PMID- 20718556 TI - The learning of exclusive-or categories by monkeys (Macaca mulatta) and humans (Homo sapiens). AB - A central question in categorization research concerns the categories that animals and humans learn naturally and well. Here, the authors examined monkeys' (Macaca mulatta) and humans' (Homo sapiens) learning of the important class of exclusive-or (XOR) categories. Both species exhibited--through a sustained level of ongoing errors--substantial difficulty learning XOR category tasks at 3 stimulus dimensionalities. Clearly, both species brought a linear-separability constraint to XOR category learning. This constraint illuminates the primate category-learning system from which that of humans arose, and it has theoretical implications concerning the evolution of cognitive systems for categorization. The present data also clarify the role of exemplar-specific processes in fully explaining XOR category learning, and suggest that humans sometimes overcome their linear-separability constraint through the use of language and verbalization. PMID- 20718558 TI - Great apes select tools on the basis of their rigidity. AB - Wild chimpanzees select tools according to their rigidity. However, little is known about whether choices are solely based on familiarity with the materials or knowledge about tool properties. Furthermore, it is unclear whether tool manipulation is required prior to selection or whether observation alone can suffice. We investigated whether chimpanzees (Pan troglodytes) (n = 9), bonobos (Pan paniscus) (n = 4), orangutans (Pongo pygmaeus) (n = 6), and gorillas (Gorilla gorilla) (n = 2) selected new tools on the basis of their rigidity. Subjects faced an out-of-reach reward and a choice of three tools differing in color, diameter, material, and rigidity. We used 10 different 3-tool sets (1 rigid, 2 flexible). Subjects were unfamiliar with the tools and needed to select and use the rigid tool to retrieve the reward. Experiment 1 showed that subjects chose the rigid tool from the first trial with a 90% success rate. Experiments 2a and 2b addressed the role of manipulation and observation in tool selection. Subjects performed equally well in conditions in which they could manipulate the tools themselves or saw the experimenter manipulate the tools but decreased their performance if they could only visually inspect the tools. Experiment 3 showed that subjects could select flexible tools (as opposed to rigid ones) to meet new task demands. We conclude that great apes spontaneously selected unfamiliar rigid or flexible tools even after gathering minimal observational information. PMID- 20718559 TI - Bi-stability of movement coordination as a function of skill level and task difficulty. AB - This study investigated whether the level of practice interacts with the initial conditions (here manipulated as preparatory movements) and task difficulty (ball angular velocity and friction) in determining the stability of movement coordination for a roller ball motor task. Practice level and task difficulty were manipulated as two control parameters that theoretically were hypothesized to change the threshold for the transition between task success and failure. The findings showed bi-stability and hysteresis in the coordination mode as a manifestation of dependence on the initial conditions. The transition from failure to success in the roller ball task as a function of practice time can be modeled as a saddle-node bifurcation corresponding to a first order phase transition. It is proposed that task difficulty acts as a control parameter that is a dual to skill level and that also effectively compensates for practice time. PMID- 20718560 TI - Priming from distractors in rapid serial visual presentation is modulated by image properties and attention. AB - We investigated distractor processing in a dual-target rapid serial visual presentation (RSVP) task containing familiar objects, by measuring repetition priming from a priming distractor (PD) to Target 2 (T2). Priming from a visually identical PD was contrasted with priming from a PD in a different orientation from T2. We also tested the effect of attention on distractor processing, by placing the PD either within or outside the attentional blink (AB). PDs outside the AB induced positive priming when they were in a different orientation to T2 and no priming, or negative priming, when they were perceptually identical to T2. PDs within the AB induced positive priming regardless of orientation. These findings demonstrate (1) that distractors are processed at multiple levels of representation; (2) that the view-specific representations of distractors are actively suppressed during RSVP; and (3) that this suppression fails in the absence of attention. PMID- 20718561 TI - Revisiting the relationship between the processing of gaze direction and the processing of facial expression. AB - There is mixed evidence on the nature of the relationship between the perception of gaze direction and the perception of facial expressions. Major support for shared processing of gaze and expression comes from behavioral studies that showed that observers cannot process expression or gaze and ignore irrelevant variations in the other dimension. However, these studies have not considered the role of head orientation, which is known to play a key role in the processing of gaze direction. In a series of experiments, the relationship between the processing of expression and gaze was tested both with head orientation held constant and with head orientation varied between trials, making it a relevant source of information for computing gaze direction. Results show that when head orientation varied between trials, the processing of facial expression was not interfered with gaze direction, and conversely, the processing of gaze could be made without being interfered from irrelevant variations in expression. These findings suggest that the processing of gaze and the processing of expression are not functionally interconnected as was previously assumed. PMID- 20718563 TI - On the speed of pop-out in feature search. AB - When something unique is present in a scene, this element may become immediately visible and one has the impression that it pops out from the scene. This phenomenon, known as pop-out in the visual search literature, is thought to produce the fastest search possible, and response times for the detection of the pop-out target do not vary as a function of the number of nontargets. In this study, we challenge this notion and show that the detection of a given visual feature is faster for multiple targets than for a single pop-out target. However, when the task requires a detailed target analysis, the pop-out condition can be faster than the multiple-target condition. Current models of visual search are discussed in light of the findings. PMID- 20718562 TI - An fMRI study of parietal cortex involvement in the visual guidance of locomotion. AB - Locomoting through the environment typically involves anticipating impending changes in heading trajectory in addition to maintaining the current direction of travel. We explored the neural systems involved in the "far road" and "near road" mechanisms proposed by Land and Horwood (1995) using simulated forward or backward travel where participants were required to gauge their current direction of travel (rather than directly control it). During forward egomotion, the distant road edges provided future path information, which participants used to improve their heading judgments. During backward egomotion, the road edges did not enhance performance because they no longer provided prospective information. This behavioral dissociation was reflected at the neural level, where only simulated forward travel increased activation in a region of the superior parietal lobe and the medial intraparietal sulcus. Providing only near road information during a forward heading judgment task resulted in activation in the motion complex. We propose a complementary role for the posterior parietal cortex and motion complex in detecting future path information and maintaining current lane positioning, respectively. PMID- 20718565 TI - How object-specific are object files? Evidence for integration by location. AB - Given the distributed representation of visual features in the human brain, binding mechanisms are necessary to integrate visual information about the same perceptual event. It has been assumed that feature codes are bound into object files--pointers to the neural codes of the features of a given event. The present study investigated the perceptual criteria underlying integration into an object file. Previous studies confounded the sharing of spatial location with belongingness to the same perceptual object, 2 factors we tried to disentangle. Our findings suggest that orientation and color features appearing in a task irrelevant preview display were integrated irrespective of whether they appeared as part of the same object or of different objects (e.g., 1 stationary and the other moving continuously, or a banana in a particular orientation overlaying an apple of a particular color). In contrast, integration was markedly reduced when the 2 objects were separated in space. Taken together, these findings suggest that spatial overlap of visual features is a sufficient criterion for integrating them into the same object file. PMID- 20718564 TI - Statistical learning induces discrete shifts in the allocation of working memory resources. AB - Observers can voluntarily select which items are encoded into working memory, and the efficiency of this process strongly predicts memory capacity. Nevertheless, the present work suggests that voluntary intentions do not exclusively determine what is encoded into this online workspace. Observers indicated whether any items from a briefly stored sample display had changed. Unbeknown to observers, these changes were most likely to occur in a specific quadrant of the display (the dominant quadrant). Across 84 subjects and 5 groups of observers, change detection accuracy was significantly higher for items in the dominant quadrant, suggesting that memory encoding was biased towards the dominant quadrant. Only 9 of the 84 subjects were able to correctly specify the dominant quadrant when asked whether any location was more likely to contain the changed item, but more sensitive forced-choice procedures did reveal above-chance discrimination of the dominant quadrant. Nevertheless, because forced choice performance was unrelated to the size of the bias and no observer reported a biased encoding strategy, the bias was unlikely to depend on voluntary encoding strategies. The encoding bias was not due to a reduction in the response threshold for indicating changes in the dominant quadrant (Experiment 2). Finally, separate measures of the number and resolution of the representations in memory suggested that encoding was biased in a discrete slot-based fashion (Experiment 3). That is, although items in the dominant quadrant were more likely to be encoded into memory, mnemonic resolution for the favored items was not affected. PMID- 20718566 TI - The role of fractality in perceptual learning: exploration in dynamic touch. AB - Perceptual systems must learn to explore and to use the resulting information to hone performance. Optimal performance depends on using information available at many time scales, from the near instantaneous values of variables underlying perception (i.e., detection), to longer term information about appropriate scaling (i.e., calibration), to yet longer term information guiding variable use (i.e., attunement). Fractal fluctuations in explorations would entail fluctuation at all time scales, allowing perceptual systems a flexible way to detect information at all time scales. We tested whether perceptual learning in dynamic touch is related to the fractality of wielding behaviors. A reanalysis of wielding behaviors from Arzamarski, Isenhower, Kay, Turvey, and Michaels (2010) revealed that exploratory movements were fractal and that a fractal-scaling exponent predicts individual differences in haptic judgments. PMID- 20718567 TI - The relationship between Stroop interference and facilitation effects: statistical artifacts, baselines, and a reassessment. AB - The relationship between interference and facilitation effects in the Stroop task is poorly understood yet central to its implications. At question is the modal view that they arise from a single mechanism-the congruency of color and word. Two developments have challenged that view: (a) the belief that facilitation effects are fractionally small compared with interference effects, or nonexistent altogether; and (b) the finding that interference and facilitation effects are inversely correlated. Statistical simulations, reanalysis of past data, and two new experiments indicate that facilitation is robust and substantial when congruency is deconfounded from lexicality, and that the inverse correlations are mostly spurious. Instead, interference and facilitation are uncorrelated, or at most weakly but inversely related. Resolution of response conflict and lexical convergence can explain either finding. Modeling and interpretation of the Stroop task must distinguish between nonspecific lexicality-based effects and specific color-word congruency effects. PMID- 20718568 TI - Featural guidance in conjunction search: the contrast between orientation and color. AB - Four experiments examined the effects of precues on visual search for targets defined by a color-orientation conjunction. Experiment 1 showed that cueing the identity of targets enhanced the efficiency of search. Cueing effects were stronger with color than with orientation cues, but this advantage was additive across array size. Experiment 2 demonstrated that cueing effects interacted with bottom-up segmentation processes, whereas Experiment 3 showed the stronger effects of color cues remained in a compound task. Experiment 4 confirmed the enhanced effect of color cueing even when verbal rather than visual cues were used. The targets used were balanced for search efficiency within both orientation and color dimensions. We suggest search benefits from the top-down cueing of color compared with orientation because color cueing enhances the segmentation of displays into color groups more efficiently. This enables search to an appropriate color group to be initiated earlier. We discuss how top-down segmentation processes interact with differences in bottom-up segmentation to further improve target detection. PMID- 20718569 TI - Why it is too early to lose control in accounts of item-specific proportion congruency effects. AB - The item-specific proportion congruency (ISPC) effect is the finding of attenuated interference for mostly incongruent as compared to mostly congruent items. A debate in the Stroop literature concerns the mechanisms underlying this effect. Noting a confound between proportion congruency and contingency, Schmidt and Besner (2008) suggested that ISPC effects are entirely contingency based. We introduce a broader theoretical analysis that points to the contribution of both contingency and item-specific control mechanisms. Our analysis highlights that proportion congruency is not confounded with contingency when the relevant dimension functions as the ISPC signal, and predicts that evidence of item specific control should be obtained by shifting the signal from the irrelevant to the relevant dimension. We examine this prediction in a picture-word Stroop paradigm. When the relevant dimension functions as the ISPC signal (Experiments 1 and 2), evidence of control is obtained. When the irrelevant dimension functions as the ISPC signal (Experiment 3), contingencies can account for the ISPC effect. These patterns support our theoretical analysis, challenge a pure contingency account, and favor the inclusion of control in accounts of ISPC effects. PMID- 20718570 TI - Temporal frequency modulates reaction time responses to first-order and second order motion. AB - This study investigated the effect of temporal frequency and modulation depth on reaction times for discriminating the direction of first-order (luminance defined) and second-order (contrast-defined) motion, equated for visibility using equal multiples of direction-discrimination threshold. Results showed that reaction times were heavily influenced by temporal frequency, especially in the case of second-order motion. At 1 Hz, reaction times were faster for first-order compared with second-order motion. As temporal frequency increased, reaction times for first-order motion decreased slightly, but those for second-order motion decreased more rapidly. At 8 Hz, reaction times for second-order motion were, in many cases, faster than those for first-order motion. Reaction times decreased as stimulus modulation depth increased at approximately the same rate for both motion types. The findings demonstrate that behavioral response latencies to first-order and second-order motion are dependent on specific stimulus parameters and may, in some cases, be shorter in response to second order compared with first-order motion. PMID- 20718571 TI - Rhythms that speed you up. AB - This study investigates whether a rhythm can orient attention to specific moments enhancing people's reaction times (RT). We used a modified version of the temporal orienting paradigm in which an auditory isochronous rhythm was presented prior to an auditory single target. The rhythm could have a fast pace (450 ms Inter-Onset-Interval or IOI) or a slow pace (950 ms IOI). The target was presented after a variable foreperiod of either 200, 400, 900, 1400, or 1600 ms following the offset of the rhythm. In Experiment 1, the rhythmic pace validly predicted the moment of target appearance; i.e., the target appeared after a foreperiod that matched the rhythmic pace on 60% of the trials. The results showed an effect on RT performance of the fast rhythmic pace compared to the slow rhythmic pace at the 200 and 400 ms foreperiods, while no effects were found at the long foreperiods, probably due to a foreperiod effect. In Experiment 2, non predictive rhythmic paces did not modulate the foreperiod effect. The addition of temporal uncertainty by including catch trials in Experiment 3 clearly unveiled the effect of non-predictive rhythmic pace at short and long foreperiods. Taken together, the results of the experiments reported here highlight the ability of rhythms to orient temporal attention enhancing participants' response speed not only at short intervals but also at long time intervals, suggesting the involvement of a flexible mechanism. PMID- 20718572 TI - The speed of feature-based attention: attentional advantage is slow, but selection is fast. AB - When paying attention to a feature (e.g., red), no attentional advantage is gained in perceiving items with this feature in very brief displays. Therefore, feature-based attention seems to be slow. In previous feature-based attention studies, attention has often been measured as the difference in performance in a secondary task. In our recent work on Boolean map theory (Huang & Pashler, 2007), we distinguished between 2 concepts that are often conflated with the term attention, namely the selection of information from stimulus and the following processing optimization (i.e., attentional advantage) of the selected stimulus. Attention, as examined in previous feature-based attention studies, only fits the definition of processing optimization, but does not fit the definition of selection of information. Therefore, it is open to question whether feature-based attention, when defined as selection, is fast or slow. In this study, I systematically measured the speed of feature-based attention in relation to both definitions. Attention was found to be slow (~100 ms) in terms of processing optimization (i.e., attentional advantage) but fast in terms of the selection of information (<50 ms). These results support the view that feature-based attention works by creating a spatial representation (i.e., a Boolean map; Huang & Pashler, 2007) for the stimulus of a feature and a processing optimization of the visual information residing in the region of this spatial representation. PMID- 20718573 TI - Objects and events as determinants of parallel processing in dual tasks: evidence from the backward compatibility effect. AB - The backward-compatibility effect (BCE) is a major index of parallel processing in dual tasks and is related to the dependency of Task 1 performance on Task 2 response codes (Hommel, 1998). The results of four dual-task experiments showed that a BCE occurs when the stimuli of both tasks are included in the same visual object (Experiments 1 and 2) or belong to the same perceptual event (Experiments 3 and 4). Thus, the BCE may be modulated by factors that influence whether both task stimuli are included in the same perceptual event (objects, as studied in cognitive experiments, being special cases of events). As with objects, drawing attention to a (selected) event results in the processing of its irrelevant features and may interfere with task execution. PMID- 20718574 TI - Trial-to-trial modulations of the Simon effect in conditions of attentional limitations: Evidence from dual tasks. AB - Interference effects are reduced after trials including response conflict. This sequential modulation has often been attributed to a top-down mediated adaptive control mechanism and/or to feature repetition mechanisms. In the present study we tested whether mechanisms responsible for such sequential modulations are subject to attentional limitations under dual-task situations. Participants performed a Simon task in mixed single- and dual-task contexts (Experiment 1), in blocked contexts with dual-task load either, in trialN (Experiment 2a), in trialN 1 (Experiment 2b), or in both trials (Experiment 3). Results showed that the occurrence of a sequential modulation did not depend on dual-task load per se as it occurred predominantly in conditions of lowest and highest task load. Instead, task factors such as the repetition of task episodes and stimulus-response repetitions determined whether a sequential modulation occurred. PMID- 20718575 TI - Dual-task processing when task 1 is hard and task 2 is easy: reversed central processing order? AB - Five psychological refractory period (PRP) experiments were conducted with an especially time-consuming first task (Experiments 1, 3, and 5: mental rotation; Experiments 2 and 4: memory scanning) and with equal emphasis on the first task and on the second (left-right tone judgment). The standard design with varying stimulus onset asynchronies (SOAs) was extended by a condition with blocked SOAs in Experiments 3 and 4. Based on the optimization account (Miller, Ulrich, & Rolke, 2009) it was expected that participants would-at short, but not long SOAs tend to process the relatively fast central stage of Task 2 before the time consuming central stage of Task 1 and consequently emit the response to Task 2 before the response to Task 1. Such an optimization tendency was found, more so for the mental rotation task and for the blocked SOA condition. The results indicate that preparation, Task 1 characteristics, and TRT (total reaction time) optimization are-among others-factors influencing central processing order in PRP tasks. PMID- 20718576 TI - Attention to hierarchical level influences attentional selection of spatial scale. AB - Ample evidence suggests that global perception may involve low spatial frequency (LSF) processing and that local perception may involve high spatial frequency (HSF) processing (Shulman, Sullivan, Gish, & Sakoda, 1986; Shulman & Wilson, 1987; Robertson, 1996). It is debated whether SF selection is a low-level mechanism associating global and local information with absolute LSF and HSF content, or whether it is a higher level mechanism involving a selective process that defines the SF range in which global and local can then be relatively defined. The present study provides support for the latter claim by demonstrating that allocating attention to global or local levels of hierarchical displays biased selection of LSFs or HSFs, respectively, in subsequently presented compound gratings. This bias occurred despite a change in the response dimension (from letter identification in the hierarchical stimulus to orientation discrimination in the grating) and despite a difference in retinal location of the hierarchical stimuli and the grating stimulus. Moreover, the bias was determined by the relationship between the 2 SFs in the compound grating (i.e., their relative frequency) rather than the absolute SF values. PMID- 20718578 TI - The human Ku autoantigen shares amino acid sequence homology with fungal, but not bacterial and viral, proteins. AB - CONTEXT: Molecular mimicry between autoantigens and microbial antigens is a possible triggering mechanism of autoimmunity. Human Ku is a DNA-associated autoantigen targeted by autoantibodies in patients with systemic lupus erythematosus and related disorders; available data are consistent with a role of molecular mimicry in the pathogenesis of Anti-Ku autoimmunity, but no research exist on this topic. OBJECTIVE: We aimed to define the most probable microbial triggers of anti-Ku autoimmunity via molecular mimicry. Materials and methods. We performed a computer-assisted search for amino acid sequence homologies between the two subunits of human Ku and proteins of known human pathogens. RESULTS: Some fungal, but no bacterial or viral, proteins have statistically significant amino acid sequence homology with the p70 or p80 subunit of Ku. Twenty-six fungal proteins contain long segments highly homologous to p70 (14 proteins) or p80 (12 proteins) and belong to human pathogens (Aspergillus clavatus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Chaetomium globosum, Cryptococcus neoformans, Coccidioides immitis, Malassezia globosa, Neosartorya fischeri, Penicillium chrysogenum Wisconsin, Penicillium marneffei, and Yarrowia lipolytica). Twelve p70-homologous and eleven p80 homologous segments span at least one T cell epitope-containing part of the respective human Ku subunit (in the other cases, overlap is almost complete). DISCUSSION AND CONCLUSION: We postulate that, in genetically predisposed persons, infection by the above fungi can be a trigger in the onset of anti-Ku autoimmunity via molecular mimicry between fungal proteins and the Ku autoantigen. Due to the low frequency of anti-Ku autoimmunity, multicentric collaboration is necessary to verify our hypothesis. PMID- 20718577 TI - Immunosuppressive activity of tilmicosin on the immune responses in mice. AB - Tilmicosin, a semi-synthetic macrolide antibiotic that is only used in the veterinary clinic, was evaluated for its immunosuppressive activity on the immune responses to ovalbumin (OVA) in mice. Tilmicosin suppressed concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated splenocyte proliferation in vitro. BALB/c mice were immunized subcutaneously with OVA on day 1 and 4. Beginning on the day of boosting immunization, the mice were administered intraperitoneally with tilmicosin at a single dose of 10, 30, and 90 mg/kg for 10 consecutive days. On day 14, blood samples were collected for measuring specific total immunoglobulin G (total-IgG), IgG1, IgG2b, and splenocytes were harvested for determining lymphocyte proliferation and interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4 production. The results demonstrated that tilmicosin could significantly suppress Con A-induced splenocyte proliferation in a dose-dependent manner, decrease LPS-and OVA-induced splenocyte proliferation only at high concentration, produced less IL-2, IL-4, and IFN-gamma as compared to the control in the OVA-immunized mice. Moreover, the OVA-specific IgG, IgG1, and IgG2b levels in the OVA-immunized mice were reduced by tilmicosin. These results suggest that tilmicosin could suppress the cellular and humoral immune response in mice. PMID- 20718579 TI - Rapid aneuploidy testing versus traditional karyotyping in amniocentesis for certain referral indications. AB - OBJECTIVE: (1) To determine the suitability of replacing full karyotype analysis with quantitative fluorescent polymerase chain reaction (QF-PCR) for prenatal diagnosis in amniotic fluid samples obtained by amniocentesis. (2) To evaluate an indication-based classification of cases at risk of missing clinically relevant chromosomal disorders by QF-PCR. METHODS: We reviewed all fetal karyotypes obtained by amniocentesis between January 2004 and December 2008. We compared the cytogenetic findings obtained through conventional karyotype with those that would have been theoretically obtained using QF-PCR. RESULTS: Of the 4007 karyotypes obtained, 110 abnormal karyotypes were found (2.8%). Out of these, 30 (27%) were chromosomal abnormalities (CA) which would not have been detected by PCR alone. These included 16 cases (53%) predicted to confer no increased risk, 9 (30%) predicted to have a low risk, and 5 (17%) with an uncertain or high risk of fetal abnormality. A policy of QF-PCR alone would have identified 80 of 85 (94%) clinically significant CA. When QF-PCR shows a normal result, the overall residual risk is 0.75% for any CA and 0.12% for a clinical significant CA. CONCLUSION: In our population, a policy of QF-PCR alone would miss 0.12% clinically relevant CA. QF-PCR directed to common aneuploidies can be considered as an economically and clinically acceptable prenatal diagnosis policy, offering full karyotype only for specific indications. PMID- 20718580 TI - Reducing nosocomial infections in neonatal intensive care. AB - BACKGROUND: Nosocomial infection is a common problem in neonatal intensive care. A pilot quality improvement initiative focussing on hand hygiene and aimed at reducing nosocomial infection in very low birth weight (VLBW) infants was introduced in five Neonatal Intensive Care Units. METHODS: Line associated laboratory confirmed bloodstream infection (LCBSI) and ventilator associated pneumonia (VAP) were chosen as main outcome measures. RESULTS: In VLBW infants, the rate of line associated LCBSI per 1000 central venous catheter days fell by 24%. The rate of VAP per 1000 ventilator days in VLBW infants fell by 38%. Pre- and post-intervention questionnaires showed a statistically significant increase in use of alcohol-based gels and increased knowledge of hand hygiene. PMID- 20718581 TI - Three cases of acute fatty liver of pregnancy: postpartum clinical course depends on interval between onset of symptoms and termination of pregnancy. AB - We report our experience with three cases of acute fatty liver of pregnancy. Case 1 complained of hydrodipsia 4 days before delivery. Case 2 presented with nausea, vomiting and dizziness 6 days before delivery. Case 3 developed loss of appetite and general fatigue with jaundice 10 days before delivery. They underwent termination of pregnancy after diagnosis was made. Case 3 still developed hepatic encephalopathy, and finally she required liver transplantation. We hypothesise that the interval between the onset of symptoms and termination of pregnancy is an important factor for acuity of the disorder and patient morbidity or mortality. PMID- 20718582 TI - Fetal retroperitoneal lipoblastoma: ultrasonographic appearance of a rare embryonal soft tissue tumor. PMID- 20718583 TI - The virtual ISPOG Academy: how E-learning can enrich (our) society. PMID- 20718584 TI - Chronic psychosocial stressors are detrimental to ovarian reserve: a study of infertile women. AB - OBJECTIVE: In a cross sectional study of 89 infertile women, we explore a relationship between aspects of psycho-social stress and ovarian reserve parameters. METHODS: Questionnaires assessed general health and mood (profile of mood state) were administered. Serum (cycle days 1-3) was collected for biomarkers of ovarian reserve (follicle stimulating hormone (FSH), Mullerian Inhibitory Substance, Inhibin B) and stress (Cortisol). Multivariable regression analyses evaluated associations between parameters of interest (dysphoric mood, morning serum cortisol levels reflecting current stress; personal history of abuse, family and/or personal history of substance abuse reflecting chronic stress), with ovarian reserve biomarkers and with the likelihood of being diagnosed with diminished ovarian reserve (DOR). RESULTS: Women with DOR were almost four times more likely to acknowledge personal history of recreational substance use (0.023) and family history of early menopause (p = 0.018). Adjusted analyses demonstrated advancing age, family history of early menopause, body mass index and chronic psycho-social stressors as independent correlates to serum FSH levels; age, family history of early menopause and chronic stress were predictive of likelihood for DOR. No demonstrable relationship was observed between ovarian reserve and current stress. CONCLUSIONS: Our findings identify aspects reflecting 'chronic' lifetime psycho-social stressors (i.e., personal history of abuse and of recreational drug use and/or family history of drug use) rather than 'current' stress (as reflected by dysphoric mood score and morning serum cortisol level) as detriments to ovarian reserve (i.e., were predictive of higher FSH levels and of an enhanced likelihood for DOR). PMID- 20718585 TI - 'They all supported me but I felt like I suddenly didn't belong anymore': an exploration of perceived disadvantages to online support seeking. AB - In recent years, there has been a significant rise in the number of online support communities dedicated to issues surrounding infertility. The aim of this study was to focus on investigating the perceived disadvantages of online infertility support communities from the perspective of those who access and participate in them. A total of 295 participants completed an online questionnaire about their use of online support communities. Responses were analysed using inductive content analysis. Since the majority of respondents were women, the results of the study largely reflect the experiences of the female population. Over half of the sample (57.9%) reported experiencing disadvantages to online support. Content analysis revealed that the most commonly cited disadvantages were reading about negative experiences (10.9%), reading about other peoples pregnancies (8.8%), inaccurate information (7.8%) and its addictive (5.8%). These results suggest that there are many perceived disadvantages to online infertility support communities. While some of these disadvantages reflect fears commonly cited in the literature, there are also unique disadvantages associated with the experience of infertility and its treatment. The study highlights a number of important areas in which health professionals and community moderators could intervene to better support and improve the online experiences of patients experiencing infertility. PMID- 20718586 TI - Correlates of fertility issues in an internet survey of cancer survivors. AB - PURPOSE: The objectives of this study were (1) to determine what young cancer survivors know about the effect of their cancer on fertility, how fertility difficulties affected their lives and whether they would opt for fertility preservation (FP) and (2) to assess the sources of information and the helpfulness of them. METHODS: Women of at least 18 years with cancer affecting reproductive function were recruited from eight cancer websites for this online survey. The Cancer and Fertility Survey (CFS) contained items from validated inventories and items to assess fertility issues in cancer patients. Quantitative analyses (t-tests, chi(2), analysis of variance) and thematic analysis of free text data were performed. RESULTS: Of the 80 participating women, 68.1% rated the risk of infertility as high. The mean number of professionals consulted was 3.56 (SD = 2.7), but 20% of women had not discussed fertility with any professional. The weighted mean helpfulness index was the highest for spouses and oncologists. Strength of positive attitudes towards FP was significantly greater than that of negative attitudes. CONCLUSION: The need to discuss fertility is high among women searching for information on cancer websites. Options to preserve fertility were positively viewed but the actual use may be limited by concerns about safety. PMID- 20718587 TI - Association of size-resolved number concentrations of particulate matter with cardiovascular and respiratory hospital admissions and mortality in Prague, Czech Republic. AB - We analyzed the association of particle number and PM(2.5) concentrations with mortality and cardiorespiratory hospital admissions in Prague. Number concentrations of submicron particles in the range of 15-487 nm were measured continuously at a central site in 2006. The particle number concentrations were integrated into four groups with count median diameters of 31 (NC(31)), 128 (NC(128)), and 346 nm (NC(346)). The total number concentration of submicron particles 15-487 nm (NC(tot)) was also constructed. The studied health outcomes were the daily hospital admissions due to cardiovascular and respiratory diseases and daily cardiovascular and respiratory mortality and the total mortality. The Poisson regression was used for data analysis. The strongest association was found for the accumulation mode particles (NC(346)) (RR 1.164, 95% CI: 1.052 1.287 for cardiovascular and 1.334, 95% CI: 1.126-1.579 for respiratory admissions for a 7-day moving average for 1000 particles per 1 cm(3) increase). Reasonable association between both the cardiovascular and respiratory admissions and NC(346) was also found for lag 0, lag 1, lag 2 (not for respiratory admissions), and the 4-day moving average. For NC(128) and NC(tot), the association was also significant for both cardiovascular and respiratory admissions at lag 0, lag 1, and lag 2 (not for respiratory admissions) for the 4 day and 7-day moving average. The association between the PM(2.5) and daily cardiovascular hospital admissions was significant at 2-day lag and for a 4-day average. Positive association with respiratory admissions was significant only for a 7-day average. No association was found between the studied air pollution variables and daily mortality. PMID- 20718588 TI - Hypertensive nephropathy: prevention and treatment recommendations. AB - IMPORTANCE OF THE FIELD: A worldwide epidemic of chronic kidney disease (CKD) exists; hypertensive nephropathy is second only to diabetes as a leading cause of progressive CKD. Due to the increasing morbidity and mortality and escalating costs associated with end-stage renal disease (ESRD), novel therapeutic strategies are needed urgently to maximally reduce albuminuria, control blood pressure, and delay progression of hypertensive nephropathy to ESRD. In particular, rational use of renin-angiotensin-aldosterone (RAAS) blockers and achieving blood pressure targets are crucial to reduce cardiovascular and renal outcomes. AREAS COVERED IN THIS REVIEW: We discuss the pathophysiology of hypertensive nephropathy and review current research evidence in support of i) albuminuria reduction as a key factor to maximally slow CKD progression, ii) the blood pressure (BP) goal of < 130 mmHg, and iii) strategies for prevention and optimal treatment of hypertensive nephropathy. WHAT WILL THE READER GAIN: Insight into the complexity of treating patients with hypertensive nephropathy and the effective strategies required for reducing albuminuria, achieving BP goals and delaying progression of hypertensive nephropathy. TAKE HOME MESSAGE: Patients with hypertensive proteinuric nephropathy need aggressive BP-lowering with multiple agents that should include RAAS blockers, calcium antagonists and diuretics to maximally slow progression to ESRD. PMID- 20718589 TI - Stroke prevention in atrial fibrillation patients. AB - IMPORTANCE OF THE FIELD: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of stroke, mortality and significant morbidity. Given the rapidly increasing incidence and prevalence of AF, and the resulting public health burden of the consequences associated with this arrhythmia, stroke prevention is an extremely important topic. AREAS COVERED IN THIS REVIEW: This review covers the epidemiology of AF, the pathophysiology of ischemic stroke in AF and current antithrombotic therapy choices for stroke prevention in this condition. In addition, this article discusses important topics such as the assessment of stroke risk stratification and bleeding risk assessment, which are key issues in deciding upon thromboprophylaxis for AF patients. Finally, the review highlights the advent of new anticoagulant therapies and discusses the future challenges for researchers in this area. WHAT THE READER WILL GAIN: This review summarizes all of the major antithrombotic trials conducted in AF patients over the last twenty years and highlights the importance of anticoagulation therapy for the prevention of stroke, after appropriate individual stroke and bleeding risk assessment. TAKE HOME MESSAGE: Assessment of individual stroke risk and bleeding risk is key in determining appropriate thromboprophylaxis for AF patients, given the associated thromboembolic and hemorrhagic complications. The availability of newer, safer and more convenient drugs will mean that oral anticoagulation is available for a larger proportion of AF patients who may benefit from it. PMID- 20718590 TI - Clinical development of onercept, a tumor necrosis factor binding protein, in psoriasis. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha plays a critical role in psoriasis pathogenesis, and several anti-TNF agents have been developed as therapeutic drugs in this indication. SCOPE: To present the preclinical rationale and clinical data for onercept, a novel anti-TNF agent developed for the treatment of moderate-to-severe psoriasis, and to critically evaluate the onercept clinical development program. FINDINGS: Onercept was shown in preclinical studies to inhibit TNF-alpha and suppress clinical signs in several inflammatory conditions. In phase II studies onercept demonstrated a therapeutic benefit in psoriasis and psoriatic arthritis and no safety issues were identified. Based on these results, a phase III program comprising three multicenter, randomized, double-blind, placebo-controlled studies examining onercept in moderate-to-severe plaque psoriasis was initiated. Following the occurrence of two cases of systemic inflammatory response syndrome (SIRS) and lower than expected efficacy results, an independent Data Safety Monitoring Board (DSMB) determined that the risk benefit ratio was not sufficiently favorable to justify continued development, and all clinical studies were promptly terminated. Although not initially diagnosed as such by the investigators, two further SIRS events were reported, one after study discontinuation. Although an increased incidence of infection and sepsis-like events has been associated with other anti-TNF therapies, an increased risk of infection was not observed with onercept treatment. Moreover, no infectious etiology was determined in the SIRS cases. The data suggest that the SIRS reactions were due to a systemic inflammatory response. CONCLUSIONS: Despite promising early clinical results, onercept showed many of the expected risks associated with other anti-TNF agents and proved not to have an exceptional efficacy and safety profile. The clinical development of onercept highlights the critical importance of DSMBs and closely monitoring patient safety and evaluating risk-benefit profiles in large clinical programs. PMID- 20718591 TI - Novel agents to inhibit microbial virulence and pathogenicity. AB - IMPORTANCE OF THE FIELD: The rising levels of antibiotic resistance in pathogenic microorganisms create an urgent need for new antimicrobial agents that are not affected by resistance mechanisms already present in the bacterial population. Targeting virulence is one of the alternative approaches to find new molecules to treat infections due to resistant bacteria. Novel strategies to identify these new antimicrobial agents have been reported. AREAS COVERED IN THIS REVIEW: A variety of virulence factors are now the target for inhibition mainly in the antibacterial field. This review focuses exclusively on the new virulence inhibitors published in patents (worldwide collection of patents filed) or in the literature since 2006. WHAT THE READER WILL GAIN: New efficacy in vitro assays have been developed allowing screening of large numbers of molecules. These inhibitors are mainly antibacterial molecules, a few natural products, peptides and antibodies. A growing number of these published studies provide results showing a proof of concept with antivirulence compounds that were able to prevent or treat an infection in vivo. Moreover, some new antivirulence agents could inhibit virulence mechanisms that are common to different related pathogenic species, extending the potential spectrum of antivirulence compounds. TAKE HOME MESSAGE: The progress reported recently for antivirulence molecules at the preclinical stages should allow new classes of molecules to enter into development as new antimicrobial agents with new mechanisms of action. PMID- 20718592 TI - The global emergence of IPE and collaborative care. PMID- 20718593 TI - The WHO Framework for Action. PMID- 20718594 TI - Where in the world is interprofessional education? A global environmental scan. AB - Despite increasing recognition for the importance of interprofessional education (IPE), little is known about where in the world it occurs, how it is conducted and why it is offered. This international environmental scan was commissioned by the World Health Organization (WHO) to answer these questions and inform efforts to support IPE on a global scale. An internet-based survey targeting educators and researchers in WHO's 193 Member States was conducted between February and April 2008. Participants were recruited by WHO staff through a range of country focal points, collaborating centres, regional networks and partner organizations. The scan garnered 396 responses representing 41 countries from WHO's six regions, various income-economies and many health professions. IPE was often (i) voluntary (22%); (ii) not based on explicit learning outcomes (34%); (iii) not assessed for what was learned (63%); (iv) not offered by trained facilitators (69%); and (v) not formally evaluated (30%). Participants reported many benefits of IPE for education, practice and policy. Results are limited primarily by reliance on self reports and an English-only, internet-based questionnaire. Significant efforts are required to ensure that IPE is designed, delivered and evaluated in keeping with internationally recognized best practice. PMID- 20718595 TI - Collaborative practice in a global health context: Common themes from developed and developing countries. AB - This paper reports on a study commissioned by the World Health Organization (WHO) to explore common themes of collaborative practice. The WHO requested global clarification of (1) the nature of collaborative practice, (2) its perceived importance, and (3) strategies for systematizing collaborative practice throughout national health systems. While there are many interpretations of collaborative practice around the world, there was a need to ascertain common underlying themes that illustrate good practice in both developed and developing countries to inform an international Framework for Action. A multiple case study design was used to examine collaborative practice in primary health care and commonalities across countries. Staff at each of WHO's six regional offices invited key informants in one or two primary health care organizations where collaborative practice was the model of care to complete case studies. Ten case studies were received from ten different countries, representing all six WHO regions. The results are described according to the study's three areas of focus: describing collaborative practice globally, the shared importance of collaborative practice, and systematizing collaborative practice. Collaborative practice requires a strong political framework that encourages interprofessional education and teamworking. Shared governance models and enabling legislation are required. At a practical level, interprofessional health care teams function most efficiently with shared clinical pathways and a common patient record. PMID- 20718596 TI - Learning outcomes for interprofessional education (IPE): Literature review and synthesis. AB - As part of a World Health Organization (WHO) initiative we searched the literature to explore defined learning outcomes for interprofessional education between 1988, when the last WHO technical report on interprofessional education was published, and 2009. We describe and synthesize findings from 88 citations over this 21 year period. There is a variety in the way learning outcomes are presented but there are many similarities between specific outcomes and/or objectives. Papers describing educational interventions do not always include specific outcomes or objectives. Our findings have been integrated into a list of learning outcomes with six categories for further debate and discussion. This project is part of a wider initiative initiated by the WHO in 2007 to review the current position of interprofessional education worldwide. It is also a sub project of a learning and teaching grant funded by the Carrick Institute for Learning and Teaching within Australia. In this paper we use the CAIPE definition of interprofessional education: "Occasions when two or more professions learn with, from and about each other to improve collaboration and the quality of care" (Barr, 2002 ). PMID- 20718597 TI - Interprofessional education at Laval University: Building an integrated curriculum for patient-centred practice. AB - The Laval University Faculty of Medicine, Faculty of Nursing, and School of Social Work, in partnership with the Vieille-Capitale Health and Social Services Centre in Quebec City, obtained funding from Health Canada to design, implement, and evaluate an integrated interprofessional education (IPE) program for family medicine, nursing, and social work students and for professionals from those professions working in primary care. The program was developed around four components and produced the following outcomes: a 45-hour undergraduate curriculum; IPE practical training for professionals, supervisors, residents and trainees in primary care teaching settings; a continuing education model for professionals based on a coaching approach, and; information and communication technology resources. After briefly describing the implementation process, educational content, and evaluation highlights of each component, the integrated program is discussed with respect to the inter-area complementarities and coherence with the conceptual dimensions that have guided the development of the program: IPE, collaboration, and collaborative patient-centered practice. The positive evaluation outcomes, the sustainability of the educational activities, and the enthusiasm of the different partners led to the creation of the Collaborative Network on Interprofessional Practices at Laval University and its affiliated health and social services clinical network. PMID- 20718598 TI - Exploring an IPE faculty development program using the 3-P model. PMID- 20718599 TI - Angiogenesis-related gene expression profiling in ventilated preterm human lungs. AB - Preterm infants exposed to oxygen and mechanical ventilation are at risk for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disorder characterized by arrested alveolar development and nonsprouting, dysmorphic microvascular angiogenesis. The molecular regulation of this BPD-associated pathological angiogenesis remains incompletely understood. In this study, the authors used focused microarray technology to characterize the angiogenic gene expression profile in postmortem lung samples from short-term ventilated preterm infants (born at 24 to 27 weeks' gestation) and age-matched control infants. Microarray analysis identified differential expression of 13 of 112 angiogenesis related genes. Genes significantly up-regulated in ventilated lungs included the antiangiogenic genes thrombospondin-1, collagen XVIII alpha-1, and tissue inhibitor of metalloproteinase-1 (TIMP1), as well as endoglin, transforming growth factor-alpha, and monocyte chemoattractant protein-1 (CCL2). Increased expression of thrombospondin-1 in ventilated lungs was verified by real-time polymerase chain reaction (PCR) and immunolocalized primarily to intravascular platelets and fibrin aggregates. Down-regulated genes included proangiogenic angiogenin and midkine, as well as vascular endothelial growth factor (VEGF)-B, VEGF receptor-2, and the angiopoietin receptor TEK/Tie-2. In conclusion, short term ventilated lungs show a shift from traditional angiogenic growth factors to alternative, often antisprouting regulators. This angiogenic shift may be implicated in the regulation of dysmorphic angiogenesis and, consequently, deficient alveolarization characteristic of infants with BPD. PMID- 20718601 TI - Glycerogelatin-based ocular inserts of aceclofenac: physicochemical, drug release studies and efficacy against prostaglandin E2-induced ocular inflammation. AB - An attempt has been made in the present study to formulate soluble ocular inserts of aceclofenac to facilitate the bioavailability of the drug into the eye, as no eye drop solution could be formulated. Glycero-gelatin ocular inserts/films were prepared and physicochemical parameters and drug release profiles of glycerol gelatin films of aceclofenac were compared with surface cross-linked films of similar compositions. Ocular irritation of the developed formulation was also checked by HET-CAM test and efficacy of the developed formulation against prostaglandin-induced ocular inflammation in rabbit eye was determined. The non cross-linked films showed poor mechanical, physicochemical properties, and very little potential of sustaining drug release, however cross-linking the films enhanced tensile strength by 70%, but elasticity decreased by 95%. The cross linked ocular inserts showed less swelling than non-cross-linked. Formulation AF8 (20% gelatin and 70% glycerin, treated by cross-linker for 1 h) demonstrated the longest drug release for 24 h. As per the kinetic models all films showed a constant drug release with Higuchi diffusion mechanism. Formulation was found to be practically non-irritant. The optimized formulation was tested and compared with eye drops of aceclofenac for anti-inflammatory activity in rabbits against PGE2-induced inflammation. In vivo studies with developed formulation indicated a significant inhibition of PGE2-induced PMN migration as compared to eye drops. In conclusion, ocular inserts of aceclofenac was found promising as it achieved sustained drug release and better pharmacodynamic activity. PMID- 20718602 TI - gamma-H2AX and phosphorylated ATM focus formation in cancer cells after laser plasma X irradiation. AB - The usefulness of laser plasma X-ray pulses for medical and radiation biological studies was investigated, and the effects of laser plasma X rays were compared with those of conventional sources such as a linear accelerator. A cell irradiation system was developed that used copper-Kalpha (8 keV) lines from an ultrashort high-intensity laser to produce plasma. The absorbed dose of the 8 keV laser plasma X-ray pulse was estimated accurately with Gafchromic(r) EBT film. When the cells were irradiated with approximately 2 Gy of laser plasma X rays, the circular regions on gamma-H2AX-positive cells could be clearly identified. Moreover, the numbers of gamma-H2AX and phosphorylated ataxia telangiectasia mutated (ATM) foci induced by 8 keV laser plasma X rays were comparable to those induced by 4 MV X rays. These results indicate that the laser plasma X ray source may be useful for radiation biology studies. PMID- 20718603 TI - Pifithrin-alpha as a potential cytoprotective agent in radiotherapy: protection of normal tissue without decreasing therapeutic efficacy in glioma cells. AB - Activation of p53 has been causally linked to normal tissue damage after irradiation. Pifithrin-alpha (PFT-alpha), a specific inhibitor of p53, has been suggested as a combinatory agent in the treatment of p53-deficient tumors in which inhibition of p53 would not compromise therapeutic efficacy but would decrease p53-mediated side effects in normal tissue. We tested this concept for radiotherapy of p53-deficient and -proficient glioma. We observed significant interaction of PFT-alpha with radiation-induced G(1) checkpoint activation and plating efficiency only in glioma cells expressing at least one wild-type allele of p53. This interaction was correlated with PFT-alpha-mediated inhibition of radiation-induced expression of the p53 target gene p21(Waf1). Despite inhibition of p53 function we did not observe significant changes in radiosensitivity after treatment with PFT-alpha in either p53-deficient or p53-proficient tumor cells. We confirmed these results in p53-proficient lung cancer cells. In contrast, PFT alpha significantly increased the fraction of normal astrocytes and fibroblasts surviving irradiation; this was accompanied by improved DNA damage repair, speaking against an accumulation of cells with genetic lesions after PFT-alpha treatment. In conclusion, PFT-alpha might prove useful in protecting normal tissue from the side effects of radiotherapy without reducing the efficacy of treatment for both p53-proficient and -deficient tumors. PMID- 20718604 TI - Evaluation of nucleic acid sequence based amplification using fluorescence resonance energy transfer (FRET-NASBA) in quantitative detection of Aspergillus 18S rRNA. AB - We attempted to apply fluorescence resonance energy transfer technology to nucleic acid sequence-based amplification (FRET-NASBA) on the platform of the LightCycler system to detect Aspergillus species. Primers and probes for the Aspergillus 18S rRNA were newly designed to avoid overlapping with homologous sequences of human 18s rRNA. NASBA using molecular beacon (MB) showed non specific results which have been frequently observed from controls, although it showed higher sensitivity (10(-2) amol) than the FRET. FRET-NASBA showed a sensitivity of 10(-1) amol and a high fidelity of reproducibility from controls. As FRET technology was successfully applied to the NASBA assay, it could contribute to diverse development of the NASBA assay. These results suggest that FRET-NASBA could replace previous NASBA techniques in the detection of Aspergillus. PMID- 20718605 TI - Genetic susceptibility to aspergillosis in allogeneic stem-cell transplantation. AB - Invasive aspergillosis (IA) is a major threat to positive outcomes for allogeneic stem-cell transplantation (allo-SCT) patients. Despite presenting similar degrees of immunosuppression, not all individuals at-risk ultimately develop infection. Therefore, the traditional view of neutropenia as a key risk factor for aspergillosis needs to be accommodated within new conceptual advances on host immunity and its relationship to infection. Polymorphisms in innate immune genes, such as those encoding TLRs, cytokines and cytokine receptors, have recently been associated with susceptibility to IA in allo-SCT recipients. This suggests that understanding host-pathogen interactions at the level of host genetic susceptibility will allow the formulation of new targeted and patient-tailored antifungal therapeutics, including improved donor screening. PMID- 20718606 TI - Clinical risk factors for invasive aspergillosis. AB - Despite improvements in the antifungal armamentarium and diagnostic modalities, invasive aspergillosis (IA) remains an important cause of morbidity and mortality in immunocompromised patients. There is an emergence of non-traditional groups at risk for IA, including intensive care unit (ICU) patients, post-operative patients, those with chronic pulmonary diseases, patients with AIDS and patients on immunomodulating drugs (TNF-alpha inhibitors). Identification of clinical risk factors for IA may help in determining which patients require risk modification and other prevention measures. PMID- 20718607 TI - ICU-acquired immunosuppression and the risk for secondary fungal infections. AB - Sepsis and related infectious syndromes, including nosocomial infections, represent a major but largely under recognized healthcare problem worldwide, accounting for thousands of deaths every year. After a short pro-inflammatory phase, severely injured ICU patients enter a stage of protracted immunosuppression illustrated by reactivation of dormant viruses or infections due to microorganisms, including fungi, which are normally pathogenic solely in immunocompromised hosts. This brief review will focus on immune dysfunctions described so far in ICU patients regarding monocytes and T lymphocytes (as examples for innate and adaptive immune cells) and on their potential use as biomarkers for identification of patients at risk of secondary nosocomial infections and for guidance of immunotherapy. Finally, we will more specifically focus on the risk for fungal infections in ICU patients, and on the potential beneficial effects of adjunctive therapy not only to prevent these infections, but also to reinforce immune responses once they are already diagnosed. PMID- 20718608 TI - Pneumocystis jirovecii dihydropteroate synthase (DHPS) genotypes in non-HIV immunocompromised patients: a tertiary care reference health centre study. AB - Studies on Pneumocystis jirovecii dihydropteroate synthase (DHPS) genotypes among non-HIV immunocompromised patients from developing countries are rare. In the present prospective investigation, 24 (11.8%) cases were found to be positive for Pneumocystis jirovecii out of 203 non-HIV patients with a clinical suspicion of Pneumocystis pneumonia (PCP). Dihydropteroate synthase (DHPS) genotype 1 (Thr55+Pro57) was noted in 95.8% P. jirovecii isolates in the present study in contrast to only 4.1% of patients with DHPS genotype 4 (Thr55Ala + Pro57Ser). PMID- 20718609 TI - Species distribution and in vitro antifungal susceptibility of clinical Candida isolates from a university hospital in Turkey over a 5-year period. AB - We retrospectively evaluated the distribution of clinical Candida spp. isolated over a 5-year period in our hospital relative to year, specimen types, hospital departments and their antifungal susceptibility patterns. Overall 3,756 Candida spp. were recovered from 10,857 specimens. In vitro antifungal susceptibility tests were conducted with 2,068 isolates against amphotericin B, fluconazole and itraconazole using the Etest method. C. albicans was isolated frequently from non sterile body specimens while non-C. albicans Candida spp. were commonly recovered from sterile body specimens. Isolation rates of C. albicans were 83%, 61.2% and 49% in non-sterile body specimens, sterile body specimens and blood-sterile body fluids, respectively. C. krusei was an important isolate from specimens of patients in the Haematology and Bone Marrow Transplantation units and its rate of recovery increased in these departments. Amphotericin B resistance was detected in only seven C. krusei isolates, whereas 80% (n = 1,653), 76% (n = 1,572) and 99% (n = 2,061) of all isolates were susceptible to fluconazole, itraconazole and amphotericin B, respectively. In conclusion, the distribution of Candida species was variable among hospital departments and among body sites. These results may be useful in predicting potential fungal pathogens and the choice of antifungal treatment. PMID- 20718610 TI - Naming Aspergillus species: progress towards one name for each species. AB - The nomenclature of fungi is governed by the International Code of Botanical Nomenclature. That Code is revised at each International Botanical Congress. This Code has permitted most fungi expressing both sexual and asexual states (i.e., pleomorphic fungi) to be accorded separate name(s) for the asexual states. Prior to 1981, the rules on naming pleomorphic fungi had become complicated and were not being applied consistently by mycologists. The changes made in 1981 simplified procedures but resulted in numerous name changes in Aspergillus. Molecular data in particular can now resolve the phylogenetic position of a fungus regardless of whether it expresses sexual or asexual structures. A growing consensus now wishes to either remove entirely or drastically amend the provision to permit separate names to be used for different states of the same species. Some initial changes towards that eventual goal were made at the 2005 International Botanical Congress, and a Special Committee then appointed is debating the most appropriate action to take. In the interim, in order to minimize confusion, mycologists working with Aspergillus and other affected genera are urged to refrain from both introducing new scientific names for further states of already known species, and also from using any such names proposed. PMID- 20718611 TI - Developing a safe antifungal treatment protocol to eliminate Batrachochytrium dendrobatidis from amphibians. AB - Batrachochytrium dendrobatidis is one of the most pathogenic microorganisms affecting amphibians in both captivity and in nature. The establishment of B. dendrobatidis free, stable, amphibian captive breeding colonies is one of the emergency measures that is being taken to save threatened amphibian species from extinction. For this purpose, in vitro antifungal susceptibility testing and the development of efficient and safe treatment protocols are required. In this study, we evaluated the use of amphotericin B and voriconazole to treat chytridiomycosis in amphibians. The concentration at which the growth of five tested B. dendrobatidis strains was inhibited was 0.8 MUg/ml for amphotericin B and 0.0125 MUg/ml for voriconazole. To completely eliminate a mixture of sporangia and zoospores of strain IA042 required 48 h of exposure to 8 MUg/ml of amphotericin B or 10 days to 1.25 MUg/ml of voriconazole. Zoospores were killed within 0.5 h by 0.8 MUg/ml of amphotericin B, but even after 24 h exposure to 1.25 MUg/ml of voriconazole they remained viable. Amphotericin B was acutely toxic for Alytes muletensis tadpoles at 8 MUg/ml, whereas toxic side effects were not noticed during a seven-day exposure to voriconazole at concentrations as high as 12.5 MUg/ml. The voriconazole concentrations remained stable in water during this exposure period. On the basis of this data, experimentally inoculated postmetamorphic Alytes cisternasii were sprayed once daily for 7 days with a 1.25 MUg/ml solution of voriconazole in water which eliminated the B. dendrobatidis infection from all treated animals. Finally, treatment of a naturally infected colony of poison dart frogs (Dendrobatidae) using this protocol, combined with environmental disinfection, cleared the infection from the colony. PMID- 20718612 TI - Primary diagnostic approaches of invasive aspergillosis--molecular testing. AB - The PCR methods published for the diagnosis of invasive aspergillosis (IA) are diverse in terms of amplification protocols and methods, equipment, fluorescent detection dyes, PCR chemistries, and clinical specimens used. This explains why PCR is still not included in the revised EORTC/MSG definitions of IA despite encouraging results. Therefore, achieving consensual PCR procedures at the international level is mandatory. When using PCR as a diagnostic tool, emphasis must be put on limiting false positive results due to contamination either with previously amplified products or with environmental commensals. Internal amplification controls are compulsory to evidence false negative results. For most of these aspects, quantitative PCR (qPCR) should improve both the results' reliability and the clinicians' confidence. A checklist of items (Minimum information for publication of quantitative real-time PCR experiments) has been proposed to help scientists and reviewers. Currently, the main limitation relies in the DNA extraction procedure the choice of which dramatically depends on the still unknown origin of the Aspergillus DNA to amplify. There is an urgent need for basic studies to elucidate the origin and kinetics of Aspergillus DNA in blood. Once a technical consensus is achieved, clinical studies should be initiated to integrate qPCR in the diagnostic armentarium of IA. PMID- 20718613 TI - Invasive aspergillosis in developing countries. AB - To review invasive aspergillosis (IA) in developing countries, we included those countries, which are mentioned in the document of the International Monetary Fund (IMF), called the Emerging and Developing Economies List, 2009. A PubMed/Medline literature search was performed for studies concerning IA reported during 1970 through March 2010 from these countries. IA is an important cause of morbidity and mortality of hospitalized patients of developing countries, though the exact frequency of the disease is not known due to inadequate reporting and facilities to diagnose. Only a handful of centers from India, China, Thailand, Pakistan, Bangladesh, Sri Lanka, Malaysia, Iran, Iraq, Saudi Arabia, Egypt, Sudan, South Africa, Turkey, Hungary, Brazil, Chile, Colombia, and Argentina had reported case series of IA. As sub-optimum hospital care practice, hospital renovation work in the vicinity of immunocompromised patients, overuse or misuse of steroids and broad-spectrum antibiotics, use of contaminated infusion sets/fluid, and increase in intravenous drug abusers have been reported from those countries, it is expected to find a high rate of IA among patients with high risk, though hard data is missing in most situations. Besides classical risk factors for IA, liver failure, chronic obstructive pulmonary disease, diabetes, and tuberculosis are the newly recognized underlying diseases associated with IA. In Asia, Africa and Middle East sino-orbital or cerebral aspergillosis, and Aspergillus endophthalmitis are emerging diseases and Aspergillus flavus is the predominant species isolated from these infections. The high frequency of A. flavus isolation from these patients may be due to higher prevalence of the fungus in the environment. Cerebral aspergillosis cases are largely due to an extension of the lesion from invasive Aspergillus sinusitis. The majority of the centers rely on conventional techniques including direct microscopy, histopathology, and culture to diagnose IA. Galactomannan, beta-D glucan test, and DNA detection in IA are available only in a few centers. Mortality of the patients with IA is very high due to delays in diagnosis and therapy. Antifungal use is largely restricted to amphotericin B deoxycholate and itraconazole, though other anti-Aspergillus antifungal agents are available in those countries. Clinicians are aware of good outcome after use of voriconazole/liposomal amphotericin B/caspofungin, but they are forced to use amphotericin B deoxycholate or itraconazole in public-sector hospitals due to economic reasons. PMID- 20718614 TI - The galactocele of male infants: an intriguing entity. Study and reflection about a case, with review of the literature. AB - In this report, the authors investigate and discuss a galactocele that developed in the breast of a 5-month-old male. Based on the histological and immunohistochemical findings, they suggest that the rare and intriguing process that is exclusively observed in males in the absence of any detectable hormonal stimulation at time of investigation could represent a developmental anomaly possibly promoted by an obstructive phenomenon involving a defect of hollowing of some primary epidermal buds, the precursors of the mammary ducts. PMID- 20718615 TI - Critical aspects of detection of sperm DNA fragmentation by TUNEL/flow cytometry. AB - Despite the many studies documenting an increase of sperm DNA damage in subfertile and infertile subjects, determining whether this parameter is relevant for the clinic is still an open question. Indeed, results of clinical investigations on sperm DNA damage and outcome of ART procedures are often conflicting as many factors affect the predictive power of these tests. The techniques used to reveal such damage is one of these factors. Techniques detecting sperm DNA damage are indeed numerous and heterogeneous. In addition, it is not obvious that they reveal the same type of DNA damage and that their results are equivalent. One of the available methods to detect sperm DNA damage is the TUNEL assay. Since it was developed in the 1990s the TUNEL assay has been widely employed, becoming one of the most popular strategies to investigate the origin, the mechanism, and the clinical meaning of sperm DNA damage. Our group has used TUNEL coupled to flow cytometry to investigate sperm DNA fragmentation for about 10 years. According to our experience, this technique presents some pitfalls and limitations in the accuracy and reproducibility of the measures of sperm DNA fragmentation. In this review, we discuss several technical features of TUNEL and report the solutions adopted by our group to overcome some of its limitations. PMID- 20718616 TI - Roxatidine, an H(2) receptor blocker, is an estrogenic compound--experimental evidence. AB - Roxatidine is an H(2) receptor blocker frequently used in the treatment of peptic ulcers. H(2) receptor blockers are reported to show antifertility activity. To examine the mechanism of antifertility, estrogenic and antiestrogenic activity was studied using an in vitro rat and rabbit uterine receptor binding assay and in vivo using the uterotrophic assay in immature Wistar rats. The results revealed that roxatidine showed mild receptor binding affinity to both rat and rabbit uterine receptors when compared to estradiol. Interstingly, in vivo roxatidine increases the wet uterine weight of immature Wistar rats significantly (P<0.001) when compared to a control group. The increase in uterine weight within the roxatidine treated group was somewhat similar to that of the estradiol treated group. Histopathological results and the structure of the roxatidine support that H(2) receptor blocker roxatidine is an estrogenic compound. PMID- 20718617 TI - Venom of the Chilean Latrodectus mactans alters bovine spermatozoa calcium and function by blocking the TEA-sensitive K(+) current. AB - The morphology and size of spermatozoa make it difficult to study the functional properties of the plasma membrane, however, some studies have revealed the presence of a number of ion channels in this cell. We measured the calcium (Ca(++)) influx induced by depolarization of the plasma membrane and by venom isolated from the Chilean black widow spider (Latrodectus mactans), and functional changes in the presence of either high potassium or total venom. Our results indicate that the venom increased the Ca(++) influx, with an EC50 of 6.1 microg/mL and triggering the acrosome reaction in 43.26% of the cells. The application of potassium (10 mM K(+)) or total venom (10 microg/mL) did not affect the morphology or DNA stability of the sperm. The effects induced by high K(+) and venom suggest that direct blocking of K(+) currents alters the passive properties of the plasma membrane, leading to the entry of Ca(++). These results show the importance of functional changes induced by depolarizing the spermatozoa and by venom. This venom possesses one or more molecules that may be used as pharmacological tools for studies on spermatozoa and have potential applications in reproductive biotechnology. PMID- 20718618 TI - Follicular dynamics and apoptosis following unilateral oophorectomy. AB - Ovarian physiology has been based on the assumption that the mammalian ovary has a constant germ cell pool. According to this accepted doctrine primordial follicles, which are limited in number, are depleted through ovulation or atresia. Therefore, the primary goal of this study was to examine the follicle dynamics and morphologic apoptotic changes following unilateral oophorectomy. In order to evaluate the short-, mid-, and long term effects of unilateral oophorectomy, three groups of rats were included in the study. One ovary was removed from each rat on day 0 and used as a control. In group A (n=7), the remaining ovaries were removed via relaparatomy on the 7th day, group B (n=8), the remaining ovaries were removed via relaparatomy on the 14th day, and group C (n=8), the remaining ovaries were removed via relaparatomy on the 42nd day. The changes in the number of primordial, primary, and growing follicles and the difference in apoptotic index were assessed. Even after 10-12 oestrus cycles (in group C) following unilateral oophorectomy, follicle reserve did not show a decrease in the remaining ovary. However, within the growing follicle the ovulatory rate increased. Atretic follicles were elevated contrary to the belief that reproductive functions are compensated as a result of the reduction in atresia. The observations suggest that the number of primordial follicles remains relatively constant. PMID- 20718620 TI - HIV type 1 pol gene diversity and genotypic antiretroviral drug resistance mutations in Malabo, Equatorial Guinea. AB - In this study, HIV strains circulating among military personnel were characterized, in Malabo, the capital city of Equatorial Guinea. One sample was found to be HIV-2 group A while a high degree of genetic diversity was recorded in the pol region of 41 HIV-1-positive samples. CRF02_AG accounted for 53.7% of the strains, and 11 different variants were obtained in the remaining 19 samples: subtype G (n = 3), A3 (n = 2), C (n = 2), CRF26_A5U (n = 2), F2 (n = 1), CRF06 (n = 1), CRF09 (n = 1), CRF11 (n = 1), CRF22 (n = 1), and divergent subtype A (n = 1) and F (n = 1). One strain could not be classified and three were unique recombinants. Analysis of antiretroviral drug resistance mutations revealed two patients each harboring one major mutation, M46I in protease and D67N in reverse transcriptase sequences, respectively. The high genetic diversity and emerging ARV resistance mutations call for frequent surveys and appropriate monitoring of ARV considering the increasing access to ARV in the country. PMID- 20718621 TI - Retention of functional DC-NK cross-talk following up to 18 weeks therapy interruptions in chronically suppressed HIV type 1+ subjects. PMID- 20718622 TI - Boosting in athletes with high-level spinal cord injury: knowledge, incidence and attitudes of athletes in paralympic sport. AB - Autonomic dysreflexia (AD) is unique to individuals with spinal injuries (SCI) at T6 or above and can be voluntarily induced. Although AD improves wheelchair racing performance in some athletes, it also elicits exaggerated blood pressure, which could be dangerous. The International Paralympic Committee considers AD doping and banned its use. PURPOSE: The purpose of this study is to evaluate AD knowledge, incidence and attitudes (KIA) of Paralympians with SCI. METHODS: An existing questionnaire was modified to include questions of AD KIA, validated by three experts and piloted with a small sample. It was administered on-line, mailed to members of a scientific network and distributed during the Beijing Paralympic Games. Fisher Exact test was used to evaluate differences across gender, injury and education. RESULTS: Of 99 participants, 54.5% had previously heard of AD while 39.4% were unaware; 16.7%, all males, had used AD to enhance performance. Participants reported that AD was (1) useful for middle (78.6%) and long distance (71.4%), marathon (64.3%) and wheelchair rugby (64.3%); (2) somewhat dangerous (48.9%), dangerous (21.3%) or very dangerous (25.5%) to health. Results were not influenced by age, injury level or injury duration. CONCLUSIONS: Findings indicate the need for educational programmes directed towards enhancing the AD knowledge of rehabilitation professionals, coaches and trainers working with SCI individuals. PMID- 20718623 TI - State anxiety, psychological stress and positive well-being responses to yoga and aerobic exercise in people with schizophrenia: a pilot study. AB - PURPOSE: Worsening of schizophrenia symptoms is related to stress and anxiety. People with schizophrenia often experience difficulties in coping with stress and possess a limited repertoire of coping strategies. A randomised comparative trial was undertaken in patients with schizophrenia to evaluate changes in state anxiety, psychological stress and subjective well-being after single sessions of yoga and aerobic exercise compared with a control condition. METHOD: Forty participants performed a single 30-min yoga session, 20-min of aerobic exercise on a bicycle ergometre at self-selected intensity and a 20-min no exercise control condition in random order. RESULTS: After single sessions of yoga and aerobic exercise individuals with schizophrenia or schizoaffective disorder showed significantly decreased state anxiety (p < 0.0001), decreased psychological stress (p < 0.0001) and increased subjective well-being (p < 0.0001) compared to a no exercise control condition. Effect sizes ranged from 0.82 for psychological stress after aerobic exercise to 1.01 for state anxiety after yoga. The magnitude of the changes did not differ significantly between yoga and aerobic exercise. CONCLUSION: People with schizophrenia and physiotherapists can choose either yoga or aerobic exercise in reducing acute stress and anxiety taking into account the personal preference of each individual. PMID- 20718624 TI - A model for maternal depression. AB - With the awareness of maternal depression as a prevalent public health issue and its important link to child physical and mental health, attention has turned to how healthcare providers can respond effectively. Intimate partner violence (IPV) and the use of alcohol, tobacco, and other drugs are strongly related to depression, particularly for low-income women. The American College of Obstetricians and Gynecologists (ACOG) recommends psychosocial screening of pregnant women at least once per trimester, yet screening is uncommonly done. Research suggests that a collaborative care approach improves identification, outcomes, and cost-effectiveness of care. This article presents The Perinatal Mental Health Model, a community-based model that developed screening and referral partnerships for use in community obstetric settings in order to specifically address the psychosocial needs of culturally diverse, low-income mothers. PMID- 20718625 TI - Effects of smoking cessation on body composition in postmenopausal women. AB - BACKGROUND: Smoking cessation is associated with weight gain, but the effects of smoking cessation on measures of body composition (BC) have not been adequately evaluated. The purpose of this study is to examine the effects of 16 months of cigarette abstinence on areas of BC measured by dual-energy x-ray absorptiometry (DXA). METHODS: One hundred fifty-two postmenopausal women participated in a smoking cessation study using the nicotine patch. Secondary analyses were conducted on data from 119 subjects (age 56 +/- 7 years, range 41-78 years) who had had DXA scans at baseline and 16 months later. Participants were classified either as quitters (self-reported cigarette abstinence confirmed with exhaled carbon monoxide [co] 30 years and 5.1% (95% CI: 3.5-7.2) of positive women with CD4 <200 cells/microl tested "recent" by BED. Thus, the proportions of BED-positive women in either of these subgroups (data that would be available in surveys measuring HIV and BED status) provided a reasonably tight upper bound fo epsilon, which can be used to provide a lower bound for HIV incidence. PMID- 20718628 TI - Ankle brachial index screening for occult vascular disease is not useful in HIV positive patients. AB - Metabolic complications common to the HIV-positive population may increase the risk for cardiovascular disease. Asymptomatic peripheral arterial disease (PAD) is associated with increased cardiovascular risk. The ankle-brachial pressure index (ABI) is a screening tool commonly used for the detection of asymptomatic PAD. The prevalence of asymptomatic PAD based on ABI in HIV-positive patients is unknown. This study was cross-sectional in design and assessed PAD by measuring the systolic ABI as determined by a handheld 8-MHz Doppler probe with the patient at rest in a supine position. A brief medical history including pertinent risk factors was obtained. One hundred and sixty-seven HIV-positive patients were evaluated (97.6% male; mean age 52.0 years; 31.2% current smokers, 29.4% former smokers, 26.3% diabetes mellitus). Asymptomatic PAD (ABI < or = 0.9) was found in four patients (2.4%, 95% CI: 0.3-4.5%). Smoking was a significant predictor of PAD. Patients with a positive test for PAD had at least two major risk factors for the disease including smoking, a history of disease in another vascular bed, dyslipidemia, diabetes, and hypertension. All patients with a positive test for PAD had a high risk (>20%) for cardiovascular disease according to the Framingham risk score. Three of the four patients with positive tests had previously diagnosed vascular disease (CAD, stroke). Three patients presenting with PAD were evaluated and all had a positive ABI. The prevalence of PAD compared to previous studies on PAD in HIV was low and identified only those patients with high cardiovascular risk based on other features. ABI was not useful in detecting occult vascular disease in HIV-positive patients and offers no additional information to that derived from cardiovascular risk stratification. PMID- 20718629 TI - Genotypic and phenotypic cross-drug resistance of harboring drug-resistant HIV type 1 subtype B' strains from former blood donors in central Chinese provinces. AB - The objective of this study was to assess the patterns of genotypic and phenotypic resistance in a population of blood donor patients infected with HIV-1 subtype B' (Thai B', a clade of HIV-1 B) from central China, previously treated and harboring NRTI and NNRTI resistance mutations, with the purpose of designing effective therapeutic regimens. The HIV-1 pol genes from 65 patients were sequenced and estimated for drug resistance while the viruses isolated from the patients were used to analyze the phenotype based on the TZM-bl cell line. All the HIV-1 strains harboring one or more drug resistance mutations to HIV-1 RTIs possessed high cross-resistance to EFV (100%) and DLV (92%), as well as to ABC (84%) and TDF (77%), which are much higher than both FTC and 3TC (42%). There were more thymidine analog mutation (TAM)-associated mutations in the AZT/ddI/NVP group (62.5%) than in the d4T/ddI/NVP group (32.65%). A phenotypic assay showed high concordance between genotypic and phenotypic cross-resistance. This study showed there was a high level of cross-drug resistance to HIV-1 RTIs among Chinese AIDS patients harboring resistant strains, and there is also a high prevalence of primary resistance to 3TC, suggesting that one important recommendation should be the realization of genotypes in all naive patients due to the high prevalence of NRTI and NNRTI mutations. PMID- 20718630 TI - Evidence of impact of maternal HIV infection on immunoglobulin levels in HIV exposed uninfected children. AB - HIV infection affects B cell function and is associated with increased immunoglobulin levels, including in HIV-infected pregnant women. It is unknown if maternal HIV infection affects immunoglobulins in their uninfected children. We investigated this using prospective longitudinal data from children born to HIV infected women enrolled in the European Collaborative Study (ECS). Data from children enrolled in the European Paediatric Hepatitis C Virus Network (EPHN) were used as a comparison group. Associations between infant and maternal factors and child log(10) total IgG, IgM, and IgA levels were quantified in linear regression analyses. A total of 1751 HIV-uninfected (ECS) and 167 HCV-uninfected children (EPHN) were included. HIV-uninfected children had significantly higher IgG, IgM, and IgA levels than HCV-uninfected children up to at least 24 months. Among HIV-exposed uninfected children, IgG levels from birth until 5 years of age were correlated with increased maternal IgG levels. ART exposure in fetal and early neonatal life was associated with lower IgG. These findings indicate alterations in immunoglobulin levels in uninfected children born to HIV-infected women, suggesting that fetal exposure to a chronically activated maternal immune system is associated with an altered humoral response. PMID- 20718631 TI - How important is placental examination in cases of perinatal deaths? AB - Research on stillbirths and placental pathology has traditionally been given low priority, causing a lack of understanding of the mechanisms leading to death. The purpose of this study was to gain knowledge on how many perinatal deaths relate to morphologic changes in the placenta, and what role the placenta plays in the pathogenesis of intrauterine, intrapartum, and neonatal deaths. The autopsy reports from 104 consecutive perinatal deaths in a 5-year period (2004-2008) were reviewed. Intrauterine, intrapartum, and neonatal deaths ranging from gestational age of 22 weeks up to 7 days postpartum were included. The following three questions were considered: Could placental examination (with autopsy) explain fetal/infant death; could the cause of death be explained by placental examination alone; and could the cause of death be explained with autopsy alone? The distribution of pathologic findings in the placenta was registered. The placenta had changes that could explain fetal/infant death in 69.2% of the cases. The cause of death could be explained by placental examination alone, without autopsy, in 48.1% of the cases. Only 16.3% of the deaths could be explained by autopsy alone. The most frequently observed diagnoses were infection (22.1%), degenerative changes (13.5%), and abruptio placentae (12.5%). To conclude, our study shows that placental examination in addition to autopsy is necessary in investigating the causes of perinatal deaths. Further research, including maternal and environmental factors, is needed to clarify the underlying causes of placental malfunction. PMID- 20718633 TI - Usefulness of exhaled nitric oxide for diagnosing asthma. AB - RATIONALE: A standard asthma diagnosis is made based on clinical history, reversibility of airway obstruction, and bronchial hyperresponsiveness. Fractional exhaled nitric oxide (FeNO) is a noninvasive airway inflammatory marker that has been suggested as a diagnostic tool for asthma. The aim of this study was to establish a FeNO cut-off value for asthma diagnosis. METHODS: One hundred and fourteen consecutive adult patients (mean age 34 +/- 13 years) reporting symptoms consistent with asthma, with normal spirometric parameters and a negative bronchodilator test, were included in the study. All underwent a methacholine challenge test following the five-breath dosimeter protocol. FeNO was measured with a portable device (NioxMino, Aerocrine AB, Sweden) just before the methacholine challenge. The sensitivity, specificity, and diagnostic performance of FeNO measurement were calculated. RESULTS: Thirty-five out of the 114 patients (30.7%) were diagnosed with asthma. A positive methacholine challenge was associated with higher FeNO levels and with lower forced expiratory volume in one second (FEV(1)) at baseline. No correlation was found between methacholine provocative concentration causing a decrease of 20% in FEV(1) (PC(20)) and FeNO levels. A receiver-operating characteristic curve was constructed for FeNO levels (area under the curve [AUC]: 0.762; 95% confidence interval [CI]: 0.667-0.857; p < .001). The FeNO cut-off point with maximal specificity and sensitivity for asthma diagnosis was 40 ppb. CONCLUSIONS: Patients with confirmed asthma showed higher FeNO levels. A cut-off value of 40 ppb was calculated as the most efficient for asthma diagnosis in our population. The use of FeNO measurement may be a helpful tool to rule out a diagnosis of asthma, especially in patients in whom a methacholine challenge is not feasible or available. PMID- 20718632 TI - Cardiac oxidative stress and dysfunction by fine concentrated ambient particles (CAPs) are mediated by angiotensin-II. AB - Inhalation exposure to fine concentrated ambient particles (CAPs) increases cardiac oxidants by mechanisms involving modulation of the sympathovagal tone on the heart. Angiotensin-II is a potent vasoconstrictor and a sympatho-excitatory peptide involved in the regulation of blood pressure. We hypothesized that increases in angiotensin-II after fine particulate matter (PM) exposure could be involved in the development of cardiac oxidative stress. Adult rats were treated with an angiotensin-converting enzyme (ACE) inhibitor (benazepril), or an angiotensin receptor blocker (ARB; valsartan) before exposure to fine PM aerosols or filtered air. Exposures were carried out for 5 hours in the chamber of the Harvard fine particle concentrator (fine PM mass concentration: 440 +/- 80 microg/m(3)). At the end of the exposure the animals were tested for in situ chemiluminescence (CL) of the heart, thiobarbituric acid reactive substances (TBARS) and for plasma levels of angiotensin-II. Also, continuous electrocardiogram (ECG) measurements were collected on a subgroup of exposed animals. PM exposure was associated with statistically significant increases in plasma angiotensin concentrations. Pre-treatment with the ACE inhibitor effectively lowered angiotensin concentration, whereas ARB treatment led to increases in angiotensin above the PM-only level. PM exposure also led to significant increases in heart oxidative stress (CL, TBARS), and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin angiotensin system in the development of particle-related acute cardiac events. PMID- 20718634 TI - G protein-coupled receptor oligomerization for what? AB - Although the G protein-coupled receptor (GPCR) oligomerization has been questioned during the last decade, under some premises the existence of a supramolecular organization of these receptors begins now to be widely accepted by the scientific community. Indeed, GPCR oligomers may enhance the diversity and performance by which extracellular signals are transferred to the G proteins in the process of receptor transduction, although the mechanism that underlie this phenomenon remains still unexplained. Recently, a trans-conformational switching model has been proposed as a mechanism allowing direct inhibition of receptor activation. Thus, heterotropic receptor-receptor allosteric regulations are behind the GPCR oligomeric function. Accordingly, we revise here how GPCR oligomerization impinge in several important receptor functions like biosynthesis, plasma membrane diffusion or velocity, pharmacology and signaling. Overall, the rationale of receptor oligomerization might lie in the cellular need of sensing complex extracellular signals and to translate into a simple computational mode. PMID- 20718636 TI - Asymptomatic herpes simplex virus type 2 shedding-potential pitfalls of broader testing and aggressive suppression. PMID- 20718637 TI - High aspect ratio materials: role of surface chemistry vs. length in the historical "long and short amosite asbestos fibers". AB - In nanotoxicology the question arises whether high aspect ratio materials should be regarded as potentially pathogenic like asbestos, merely on the base of their biopersistence and length to diameter ratio. A higher pathogenicity of long asbestos fibers is associated to their slower clearance and frustrated phagocytosis. In the past decades, two amosite fibers were prepared and studied to confirm the role of fiber length in asbestos toxicity. Long fiber amosite (LFA) and short fiber amosite (SFA) have here been revisited, to check differences in their surface properties, known to modulate the biological responses elicited. We report: (i) micromorphology (abundance of exposed cylindrical vs. truncated surfaces; (ii) surface reactivity (oxidation and coordination state of surface iron, free radical generation and oxidizing potential); (iii) activation of nitric oxide (NO) synthase in lung epithelial cells, as representative of an inflammatory cell response. LFA shows a higher free radical yield, stimulates, more than SFA, NO production by cells and reacts with ascorbic acid, thus depriving the lung lining layer of its antioxidant defenses. The higher activity of LFA than SFA is ascribed to the presence of Fe2+ ions poorly coordinated to the surface. SFA shows only a large number of loosely bound Fe3+ ions, pristine Fe2+ ions having been oxidized during the grinding process converting LFA into SFA. Several factors determine a higher toxicity of LFA than SFA, beside length. The lesson from asbestos indicates that other features besides aspect ratio contribute to the pathogenic potential of a fiber type. All these aspects should be considered when predicting the possible hazard associated to any new fibrous material proposed to the market, let alone nanofibers. PMID- 20718639 TI - Risks and benefits of opioid availability. PMID- 20718640 TI - Efficacy of the sustained-release hydromorphone in neuropathic pain management: pooled analysis of three open-label studies. AB - This pooled analysis was designed to determine whether the analgesic response to treatment with OROS hydromorphone, as measured by the "pain on average" scale of the Brief Pain Inventory (BPI), was different in patients with neuropathic pain compared to those with nociceptive pain, after adjusting for differences in baseline characteristics. Three open-label studies on patients with neuropathic and nociceptive malignant and nonmalignant chronic pain were analyzed. A mixed model for repeated measures linear regression analysis was used to compare the effect of OROS hydromorphone on patients with neuropathic and nociceptive pain, adjusting for potentially confounding factors. Data from patients with pure neuropathic pain and mixed pain were also compared. Safety and tolerability was assessed by recording the number of adverse events. The primary outcome was "pain on average" (BPI item 5) over time. Secondary outcomes were the effect of OROS hydromorphone on other BPI items including "pain relief" and "interference with sleep." Patients with neuropathic pain showed a similar response to treatment with OROS hydromorphone to those patients with nociceptive pain. There was no statistically significant difference between the pain groups (difference between groups -0.552 at visit 7; P = .060 for overall difference between groups). For some outcome variables, treatment was more effective for patients with neuropathic pain. The treatment was generally well tolerated. This pooled analysis shows that treatment with OROS hydromorphone had similar efficacy for neuropathic and nociceptive pain. PMID- 20718641 TI - Patient controlled analgesia: redefining its role in an Indian cancer hospital. AB - This report describes a noninterventional audit of current patient-controlled analgesia (PCA) use in an Indian cancer hospital over a 1-year period. Because there appeared to be an underutilization of PCA in the authors' hospital, they performed this audit. A major reason to start PCA was inadequate analgesia despite ongoing epidural or standard PRN analgesic regimes, especially in thoracic, major abdominal, and pelvic bone surgeries. PCA was used for an average 52.13 hours. The reason to stop the PCA in 72 patients was minimal usage due to decreased need after the second postoperative day. Multiple triggers at the same time were a common problem encountered in 21 patients. A blocked intravenous (IV) line was encountered in 12 patients. Thirty-one patients ranked their pain relief with PCA as excellent and 39 patients stated it as good. Their protocols shall be suitably amended to ensure that PCA shall be used in immediate postoperative period as a principal modality of pain relief, especially in the above-mentioned group in absence of epidural analgesia. PMID- 20718642 TI - Utah clinical guidelines on prescribing opioids for treatment of pain. AB - Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain were produced and made available to medical providers in March 2009. These guidelines were developed by a multidisciplinary consensus panel after a review of existing evidence-based guidelines. Common recommendations were compiled and presented to the panel for review. The guidelines consist of a set of recommendations for both acute and chronic pain. A second panel reviewed existing tools for providers and determined the need for any new tools. The final guidelines include 20 tools for providers to use in their practice. The complete version of the guidelines and the accompanying tools are available at: www.useonlyasdirected.org or www.health.utah.gov/prescription. PMID- 20718643 TI - Gabapentin withdrawal syndrome in a post-liver transplant patient. AB - A 41-year-old male with a previous orthotopic liver transplant began experiencing insomnia, anxiety, diaphoresis, headaches, and palpitations that progressed over a 2-day period. As part of his home medication regimen, the patient was taking gabapentin for peripheral neuropathy. His acute onset of increasing symptoms coincided with an inadvertent discontinuation of gabapentin. After reinitiation of gabapentin therapy, the symptoms slowly improved over the next 24 hours and the episode of gabapentin withdrawal syndrome resolved. PMID- 20718644 TI - Opioid inaccessibility and its human consequences: reports from the field. AB - Strong opioids such as morphine are rarely accessible in low- and middle-income countries, even for patients with the most severe pain. The three cases reported here from three diverse countries provide examples of the terrible and unnecessary suffering that occurs everyday when this essential, inexpensive, and safe medication is not adequately accessible by patients in pain. The reasons for this lack of accessibility are explored, and ways to resolve the problem are proposed. PMID- 20718645 TI - Research in end-of-life settings: an ethical inquiry. AB - A fundamental tension surrounds the ethics of conducting research in vulnerable populations, and specifically, research involving patients at or near the end-of life. In Palliative Medicine, these patients' care has historically been based on compassion, clinical judgment and experience, and anecdote rather than on data generated through high-quality clinical trials. A robust evidence base to support clinical practice in the end-of-life setting is lacking. Multiple ethical objections to the conduct of research at the end of life have impeded efforts to build such an evidence base. Arguments can be categorized into claims that the goals of research conflict with the goals of care; research unduly burdens vulnerable patients and families/caregivers; genuine equipoise does not exist; and research in the palliative care setting is too difficult. The authors explore and respond to these objections, noting the vital importance of research at this stage of the illness trajectory. The authors conclude that barriers to palliative care research are surmountable, and, indeed, that the "research imperative" and principles laid out in the Belmont Report of 1979 require us to rigorously study clinical interventions used for palliative care patients-so as to provide optimal safety and outcomes for present and future patients. PMID- 20718646 TI - Cost and comorbidities associated with opioid abuse in managed care and Medicaid patients in the United Stated: a comparison of two recently published studies. AB - Opioid abuse places a large burden on the U.S. society. Two similarly designed studies recently identified the economic and health impact of opioid abuse in patients with private or Medicaid insurance. The prevalence of opioid abuse was estimated to be over 10 times higher in Medicaid beneficiaries than private insurance populations, 87 versus 8 per 10,000, respectively. Opioid abusers incurred annual medical costs that were $14,054 to $6650 higher than nonabusers in patients with private insurance or Medicaid beneficiaries, respectively (P < .01 for both). Annual costs were similar for abusers with private insurance ($15,884) or Medicaid beneficiaries ($13,658). Costs for nonabuser Medicaid beneficiaries were $7008 versus $1830 for those with private insurance, which likely reflects the lower health status of the overall Medicaid population. In both studies, the prevalence of comorbidities associated with substance abuse or chronic pain were significantly higher in abusers than nonabusers. These studies confirm that opioid abuse is associated with comorbidities that increase direct medical costs for patients with private insurance and for Medicaid beneficiaries, increasing the societal burden of opioid abuse. PMID- 20718647 TI - Evidence-based pain management and palliative care in the April issue 2010 of the Cochrane Library. AB - The Cochrane Library of Systematic Reviews is published monthly online and in a DVD format four times a year. The April 2010 issue contains 6049 complete reviews, 1924 protocols for reviews in production, and 11887 one-page summaries of systematic reviews published in the general medical literature. In addition, there are citations of over 608,000 randomized controlled trials, and 12,700 cited papers in the Cochrane methodology register. The health technology assessment database contains over 7700 citations. This edition of the Library contains 91 new reviews, of which 9 have potential relevance for practitioners in pain and palliative medicine. PMID- 20718648 TI - Baxter v. Montana, libertarianism, and end-of-life: the ripe time for a paradigm shift. AB - Baxter v. Montana (2009 WL 5155363 [Mont. 2009]) is a recent decision from the Montana Supreme Court that provides new legal insight into the societal issue of aid in dying. This case involves interests of persons with terminal illness, medical practitioners, law enforcement, legislative and judicial bodies, as well as the citizens of Montana. A summary judgment ruling at the Montana district court level was based almost entirely on a constitutional fundamental rights analysis. In contrast, the Montana Supreme Court affirming decision was based almost entirely on a statutory rights analysis. Both rulings from the Montana courts support the position that licensed prescribers in Montana who provide aid in dying assistance to terminally ill patients have some immunity from criminal prosecution. Each side in the case argued what they believed to be the intents and purposes of the people of Montana. Baxter v. Montana illustrates different methods to determine the will of the people concerning aid in dying and public policy. This case very subtly suggests a paradigm shift may be occurring in aid in dying policy. PMID- 20718649 TI - Irritable bowel syndrome. AB - Questions from patients about analgesic pharmacotherapy and responses from the authors are presented to help educate patient sand make them more effective self advocates. The topics addressed in this issue are the signs, symptoms, and treatment of irritable bowel syndrome (IBS). A discussion of pain management and complementary therapies is included. PMID- 20718652 TI - Emergency department visits involving nonmedical use of selected prescription drugs in the United States, 2004-2008. AB - This report, adapted from the lead article in the June 10, 2010, issue of Morbidity and Mortality Weekly Reports, describes the alarming increase in overdose deaths involving prescription drugs. Oxycodone, hydrocodone, and methadone were the drugs most highly implicated. Data were derived from the federal Drug Abuse Warning Network (Dawn). Other drugs commonly used in managing pain patients, including benzodiazepines and muscle relaxants, also were implicated. PMID- 20718653 TI - Consumer medication guides. AB - The United States Food and Drug Administration (FDA) publishes consumer guides to encourage safe and appropriate use of both nonprescription and prescription drugs by patients. Clinicians should know what information their patients receive, especially from credible sources such as the FDA. These consumer guides are available on the FDA consumer Web site: http://www.fda.gov/ForConsumers . The current consumer guides on Safe Use of Pain Medicine and on Nonsteroidal Antiinflammatory Drugs are presented. PMID- 20718654 TI - Medicare Payment Advisory Commission report to the Congress, March 2010. AB - The Medicare Payment Advisory Commission is required to report to Congress each March. A summary of the 2010 report is presented including payment policy recommendations for 10 payment systems and the Commission response to the Medicare Improvements for Patients and Providers Act. The status of Medicare Advantage and prescription drug plans also are addressed. PMID- 20718659 TI - Tai Chi Chuan increases circulating myeloid dendritic cells. AB - Dendritic cells, the most potent antigen-presenting cells linking innate and adoptive immunity, are thought to be important targets of immune modulators such as exercise. We examined the effect of Tai Chi Chuan (TCC) on dendritic cells. TCC practitioners were further divided to high-level practitioners (TCC-H) and low-level practitioners (TCC-L). The quantities of myeloid and plasmacytoid dendritic cells were estimated by flow cytometry. We examined parameters including age, body weight, body length, body fat, and serum albumin level, in the controls, TCC-H and TCC-L, which did not differ significantly. The mean peak VO(2) (volume of O(2) utilization) of the TCC-H group was greater than that of the sedentary control group. White blood cell (WBC) count in the entire TCC group was greater than that of the controls. The quantity of myeloid dendritic cells was significantly greater in the TCC group, whereas the quantity of plasmacytoid dendritic cells was similar for both groups. Among the TCC subgroups, the quantity of myeloid dendritic cells, but not plasmacytoid dendritic cells, in the TCC-H group was greater than that of TCC-L practitioners. TCC could increase the number of circulating myeloid dendritic cells, but not plasmacytoid dendritic cells, in a performance level-dependent manner. PMID- 20718658 TI - Changes in composition of IgM polymers in patients suffering from recurrent urinary bacterial infections after bacterial immunization treatment. AB - IgM is the first antibody produced during the immune response to infection or immunization, and it can be secreted as pentamer (containing a small polypeptide, termed as J chain) or hexamer (lacking J chain). In this paper we have analyzed structural characteristics (by electrophoresis and immunoblot) and anti-bacterial specificity (by enzyme-linked immunosorbent assay) of IgM antibodies purified from female patients suffering from recurrent bacterial infections of lower urinary tract and therapeutically immunized with the mixture of heat-inactivated uropathogenic bacteria. We report on changes in the composition of IgM polymers in tested patients. The immunization induced the raise of the levels of hexamers in patients that did not respond to immunization (non-responders), while the IgM polymers remained on the pentameric level in immunization dependent responders. We propose that the composition of IgM polymers could influence the immunization outcome and should be taken in count regarding the treatment of recurrent bacterial infections. PMID- 20718660 TI - The hemodynamics of human septic shock relate to circulating innate immunity factors. AB - The role of innate immunity, e.g., complement activation and cytokine release in the hemodynamic alterations in the course of human septic shock is largely unknown. We prospectively studied 14 consecutive septic shock patients with a pulmonary artery catheter in place. For 3 days after admission, hemodynamic variables and plasma levels of C3a, a product of complement activation, and interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha) were measured 6 hourly. Doses of vasoactive drugs were recorded. Of the 14 patients, 8 died in the ICU. Patients had a hyperdynamic circulation with tachycardia, mild hypotension, increased cardiac index, peripheral vasodilation and myocardial depression. C3a, IL-6 and TNF-alpha plasma levels were supranormal in 123 of 138 (89%), 132 of 138 (96%) and 83 of 111 (75%) measurements, respectively. Independently of blood culture results, treatment with vasoactive drugs and outcome, mean arterial blood pressure and systemic vascular resistance index were lower when IL-6 levels were higher and left ventricular function was less depressed when C3a levels were higher in the course of septic shock. The TNF alpha levels did not invariably relate to peripheral vascular and myocardial function parameters. Our serial observations suggest that, in human septic shock, peripheral vasodilation is most strongly and independently, of all inflammatory factors, associated with IL-6 release, whereas complement activation partly offsets the myocardial depression of the syndrome. Innate immunity factors may thus differ in their contribution to the course of hemodynamic abnormalities of septic shock. PMID- 20718661 TI - In vitro inhibition of human MMP-2 collagenolytic and gelatinolytic activity by neutralizing monoclonal antibodies. AB - Matrix metalloproteinases (MMPs) have been implicated in the degradation of the extracellular matrix in normal and pathological tissue remodelling. Among the MMPs, MMP-2 is the most commonly studied protease that has been involved in cancer, inflammation, infective diseases, degenerative diseases of the brain and vascular diseases. In this study, monoclonal antibodies (MAbs) were generated against human MMP-2, purified, characterized and tested for their ability to inhibit the enzymatic activity of MMP-2. Out of 12 positive clones generated against MMP-2, 2 clones (F2-1-11 and G8-25-5) were selected for further characterization. The selected clones react specifically with human pro and active form of MMP-2 in enzyme linked immunosorbant assay (ELISA), dot immunobinding assay (DIA) and Western blot and do not cross react with other human metalloproteinases or MMP-2 from other species. Additionally, these MAbs (F2-1-11 and G8-25-5) selectively inhibit collagenolytic and gelatinolytic activity of APMA ((p-aminophenylmercuric acetate)-activated-pro-MMP-2 and MMP-2, respectively. PMID- 20718662 TI - The clinical significance of OPG/sRANKL ratio in thalassemia patients suffering from osteopenia or osteoporosis in Egyptian patients. AB - Osteopenia and osteoporosis are considered major health problems in patients suffering from thalassemia due to increased life expectancy of those patients. Osteoprotegerin (OPG) and receptor activator of NF-kappa-B ligand (RANKL) have been recently implicated in the pathogenesis of various types of osteoporosis. The aim of this study is to evaluate the role of serum OPG/RANKL ratio in patients suffering from thalassemia complicated with osteoporosis. Serum OPG and RANKL were measured in thalassemia patients and 20 healthy control subjects, using ELISA methods. Stastistically, the results demonstrate lower OPG and OPG/RANKL ratio in patients suffering from thalassemia with documented osteopenia or osteoporosis in comparison with control group and patients suffering from thalassemia without osteopenia or osteoporosis. OPG/RANKL ratio could become a promising rapid and cheap screening marker for osteopenia or osteoporosis in patients suffering from thalassemia. Furthermore, OPG may become a therapeutic option in treatment of osteoporosis of various etiologies including thalassemia. PMID- 20718663 TI - Analysis of epitope regions for autoantibodies in catalase. AB - Catalase is reported to be one of the target antigens for autoantibodies in various pathologies. To understand the mechanism of autoantibody production, we compared the several properties of autoantigenic epitopes (AE)-1 and -2 of mouse catalase, which reported to react with antibodies from sera of Helicobacter hepaticus-infected mice; AE-3 and -4 of rat catalase, which we found to be susceptible to autoimmunity; and antigenic epitope (E)-1 of H. pylori catalase, which is recognized by monoclonal antibodies produced by immunized mice. Amino acid sequences of AE-1 and -2 were similar among both mammalian and pathogenic microorganism catalases, whereas that of E-1 differed. Amino acid sequences of AE 3 and -4 were similar among mammalian catalases but differed from pathogenic microorganism catalases. Based on local relative rates of evolution, these vertebrate catalases were divided into 5 segments. E-1 included a faster evolving region, whereas AE-1 and -2 included a slowly evolving region; AE-3 and -4 comprised a slowly evolving patch within a faster evolving region. In conclusion, although AE-1 and -2 of catalase have been reported to contribute to autoimmune responses in animals infected with catalase-producing pathogens, AE-3 and -4 appear to have a different mechanism for autoantibody production. PMID- 20718664 TI - Anti-CD44 monoclonal antibody inhibits heart transplant rejection mediated by alloantigen-primed CD4(+) memory T cells in nude mice. AB - Donor-reactive CD4(+)memory T cells threaten the survival of transplanted organs. In this study, we used anti-CD44 monoclonal antibody (mAb) to inhibit adoptively transferred B6-reactive CD4(+)memory T cells (BALB/c origin) and to induce tolerance of B6 hearts in nude mice. The median survival time (MST) of the grafts was 6 days in the isotype group, and more than 100 days in the group treated with 8 doses of anti-CD44 at four-day intervals. Histological analysis revealed that the mean rejection level was Grade 3 in the isotype group, and Grade 0 or 1 in the multi-dose anti-CD44 treatment group. Compared with the isotype group, the multiply treated anti-CD44 group had significantly decreased IL-2 and IFN-gamma expressions, while IL-10 and TGF-beta were increased in the serum and the graft. Foxp3 in the graft was also increased. These data demonstrate that alloreactive CD4(+) memory T cells mediate the destruction of allografts, and the adhesion molecule CD44 plays an important role in this course. Anti-CD44 mAb may promote the reduction of CD4(+)memory T cells and the production of regulatory T cells (Tregs). Furthermore, Tregs are maintained at a certain level while suppressing cellular immunity and inducing the grafts long-term survival in transplant recipients. PMID- 20718665 TI - The dengue threat to the United States. AB - Over the past 3 decades, dengue has spread rapidly and has emerged as one of the world's most common mosquitoborne viral diseases. Although often found in tropical and semitropical areas, dengue is capable of being transmitted in temperate climates as well. Dengue is currently endemic to Mexico, most other Latin American countries, and parts of the Caribbean, and it has the potential to become reestablished as an endemic disease in the United States. In fact, sustained transmission of dengue has occurred in Florida within the past year. Conditions exist in the U.S. that could facilitate sustained dengue transmission, including environmental factors, competent mosquito vectors, limited vector and dengue surveillance, increased domestic outdoor daytime activities in warmer months, and low public awareness of the disease. If dengue were to be reestablished in the U.S., it could have significant medical, public health, and economic consequences for the country. The impact of dengue as a public health threat could be lessened through enhanced awareness and reporting of cases, increased support for vector surveillance and control programs, and a greater focus on vaccine development. PMID- 20718666 TI - Immunological aspects of allogeneic mesenchymal stem cell therapies. AB - Allogeneic mesenchymal stem or stromal cells (MSCs) are proposed as cell therapies for degenerative, inflammatory, and autoimmune diseases. The feasibility of allogeneic MSC therapies rests heavily on the concept that these cells avoid or actively suppress the immunological responses that cause rejection of most allogeneic cells and tissues. In this article the validity of the immune privileged status of allogeneic MSCs is explored in the context of recent literature. Current data that provide the mechanistic basis for immune modulation by MSCs are reviewed with particular attention to how MSCs modify the triggering and effector functions of innate and adaptive immunity. The ability of MSCs to induce regulatory dendritic and T-cell populations is discussed with regard to cell therapy for autoimmune disease. Finally, we examine the evidence for and against the immune privileged status of allogeneic MSCs in vivo. Allogeneic MSCs emerge as cells that are responsive to local signals and exert wide-ranging, predominantly suppressive, effects on innate and adaptive immunity. Nonetheless, these cells also retain a degree of immunogenicity in some circumstances that may limit MSC longevity and attenuate their beneficial effects. Ultimately successful allogeneic cell therapies will rely on an improved understanding of the parameters of MSC-immune system interactions in vivo. PMID- 20718667 TI - Transstadial transmission of Pythium in Bradysia impatiens and lack of adult vectoring capacity. AB - Fungus gnats have been shown to transmit a variety of plant-pathogenic fungi that produce aerial dispersal stages. However, few studies have examined potential interactions between fungus gnats and oomycetes, including Pythium spp. A series of laboratory experiments were conducted to determine whether fungus gnat adults are vectors of several common greenhouse Pythium spp., including Pythium aphanidermatum, P. irregulare, and P. ultimum. An additional objective was to determine whether P. aphanidermatum can be maintained transstadially in the gut of a fungus gnat larva through the pupal stadium to be transmitted by the subsequent adult. Adult fungus gnats did not pick up infectious Pythium propagules from diseased plants and transmit them to healthy plants in any experiment. Species-specific primers and a probe for real-time polymerase chain reaction were developed to detect the presence of P. aphanidermatum DNA in fungus gnat tissue samples. P. aphanidermatum DNA was detectable in the larval and pupal stages; however, none was detected in adult fungus gnats. These results are in agreement with previous studies that have suggested that adult fungus gnats are unlikely vectors of Pythium spp. PMID- 20718668 TI - A combined 1H nuclear magnetic resonance and electrospray ionization-mass spectrometry analysis to understand the basal metabolism of plant-pathogenic Fusarium spp. AB - Many ascomycete Fusarium spp. are plant pathogens that cause disease on both cereal and noncereal hosts. Infection of wheat ears by Fusarium graminearum and F. culmorum typically results in bleaching and a subsequent reduction in grain yield. Also, a large proportion of the harvested grain can be spoiled when the colonizing Fusarium mycelia produce trichothecene mycotoxins, such as deoxynivalenol (DON). In this study, we have explored the intracellular polar metabolome of Fusarium spp. in both toxin-producing and nonproducing conditions in vitro. Four Fusarium spp., including nine well-characterized wild-type field isolates now used routinely in laboratory experimentation, were explored. A metabolic "triple-fingerprint" was recorded using (1)H nuclear magnetic resonance and direct-injection electrospray ionization-mass spectroscopy in both positive- and negative-ionization modes. These combined metabolomic analyses revealed that this technique is sufficient to resolve different wild-type isolates and different growth conditions. Principal components analysis was able to resolve the four species explored-F. graminearum, F. culmorum, F. pseudograminearum, and F. venenatum-as well as individual isolate differences from the same species. The external nutritional environment was found to have a far greater influence on the metabolome than the genotype of the organism. Conserved responses to DON-inducing medium were evident and included increased abundance of key compatible solutes, such as glycerol and mannitol. In addition, the concentration of gamma aminobutyric acid was elevated, indicating that the cellular nitrogen status may be affected by growth on DON-inducing medium. PMID- 20718670 TI - Effect of valsartan on the incidence of diabetes. PMID- 20718671 TI - Dutasteride and prostate cancer. PMID- 20718672 TI - Ultrasound-guided internal jugular vein cannulation. PMID- 20718676 TI - The physiological basis of geographic variation in rates of embryonic development within a widespread lizard species. AB - The duration of embryonic development (e.g., egg incubation period) is a critical life-history variable because it affects both the amount of time that an embryo is exposed to conditions within the nest and the seasonal timing of hatching. Variation in incubation periods among oviparous reptiles might result from variation in either the amount of embryogenesis completed before laying or the subsequent developmental rates of embryos. Selection on incubation duration could change either of those traits. We examined embryonic development of fence lizards (Sceloporus undulatus) from three populations (Indiana, Mississippi, and Florida) that occur at different latitudes and therefore experience different temperatures and season lengths. These data reveal countergradient variation: at identical temperatures in the laboratory, incubation periods were shorter for lizards from cooler areas. This variation was not related to stage at oviposition; eggs of all populations were laid at similar developmental stages. Instead, embryonic development proceeded more rapidly in cooler-climate populations, compensating for the delayed development caused by lower incubation temperatures in the field. The accelerated development appears to occur via an increase in heart mass (and, thus, stroke volume) in one population and an increase in heart rate in the other. Hence, superficially similar adaptations of embryonic developmental rate to local conditions may be generated by dissimilar proximate mechanisms. PMID- 20718677 TI - General anxiety disorder symptoms, tension reduction, and marijuana use among young adult females. AB - BACKGROUND: The current study tested the hypothesis that tension reduction expectancies mediate the relationship between anxiety symptoms and marijuana use. METHODS: Interview data for 332 young adult females from Southern New England were collected from 2004 to 2009. RESULTS: In structural equation modeling, anxiety symptoms had a significant direct effect (b(yx) = 0.227, 95% confidence interval [CI] 0.086-0.369, p < 0.05) on tension reduction expectancies and a significant indirect effect (b(yx) = 0.026, 95% CI 0.010-0.046, p < 0.05) on marijuana use. CONCLUSIONS: The effect of anxiety symptoms on marijuana use was fully mediated by tension reduction expectancies. Implications for tension reduction as a possible component of treatment interventions are discussed. PMID- 20718678 TI - Obstetrician practice patterns and recommendations for physical activity during pregnancy. AB - BACKGROUND AND METHODS: Many women do not attain minimum American College of Obstetricians and Gynecologists (ACOG) recommendations for physical activity during pregnancy. This study assessed the self-reported practice patterns and recommendations of 384 obstetricians working in Texas through a mailed survey on physical activity during pregnancy. RESULTS: The most common exercise elements routinely collected from pregnant women included types of exercise (81%), history of exercise before pregnancy (79%), and frequency of exercise (76%). Fewer obstetricians collected duration (68%) or intensity (69%) of exercise. The percentage of obstetricians recommending avoidance of nine household activities and exercises (including lifting groceries, starting a new exercise program, or participating in walking, jogging, or bicycling) was significantly higher with each successive trimester. Most obstetricians agreed that pregnant women would gain some benefit from mild exercise (99.5%), but fewer agreed that moderate (74%) or vigorous exercise (6%) would be beneficial. Sixty-two percent of obstetricians reported that women who have never exercised could begin an exercise program during pregnancy. Almost all participants agreed that physical activity might make a woman feel more energetic (98%) and improve her labor and delivery (89%), but fewer agreed that exercise during pregnancy causes lower weight babies (23%) or could trigger labor (18%). CONCLUSIONS: Dissemination of current recommendations and discussion about the benefits and risks of physical activity during pregnancy, such as through continuing education, appear warranted. Future research could address the causes of disparities between self reported practice patterns and current ACOG guidelines. PMID- 20718679 TI - The prevalence of thyrotoxicosis-related seizures. AB - BACKGROUND: Central nervous system dysfunction, such as hyperexcitation, irritability, and disturbance of consciousness, may occur in patients with thyrotoxicosis. There are also a few case reports of seizures attributed to thyrotoxicosis. The objective of the present study was to determine the prevalence of seizures that appeared to be related to the thyrotoxic state in patients with thyrotoxicosis. METHODS: We retrospectively determined the prevalence and clinical features of seizures in 3382 patients with hyperthyroidism. Among patients with seizures, we excluded those with other causes of seizures or a history of epilepsy. We did not exclude two patients in whom later work-up showed an abnormal magnetic resonance imaging, as their seizures resolved after they became euthyroid. RESULTS: Among the 3382 patients with hyperthyroidism, there were seven patients (0.2%) with seizures who met our criteria. Primary generalized tonic-clonic seizures occurred in four patients (57%), complex partial seizures with secondary generalized tonic-clonic seizures occurred in two patients (29%), and one patient had a focal seizure (14%). The initial electroencephalography (EEG) was normal in two patients (29%), had generalized slow activity in four patients (57%), and had diffuse generalized beta activity in one patient (14%). On magnetic resonance imaging, one patient had diffuse brain atrophy, and one had an old basal ganglia infarct. After the patients became euthyroid, the EEG was repeated and was normal in all patients. During follow-up periods ranging from 18 to 24 months, none of the patients had seizures. CONCLUSIONS: Hyperthyroidism is the precipitating cause of seizures in a small percentage of these patients. In these patients, the prognosis is good if they become euthyroid. The prevalence of thyrotoxicosis-related seizures reported here can be used in conjunction with the prevalence of thyrotoxicosis in the population to estimate the prevalence of thyrotoxicosis-related seizures in populations. PMID- 20718680 TI - Graves' disease and thymic hyperplasia: the relationship of thymic volume to thyroid function. AB - BACKGROUND: Thymic hyperplasia is associated with Graves' disease, particularly in young patients. The degree of thymic transformation is minimal in most but not all patients. In the latter group radiological measurements of thyroid size and their change with treatment have rarely been reported. We present two patients with Graves' disease and relatively rapid resolution of thymic enlargement after successful treatment of their hyperthyroidism. SUMMARY: Three patients with thyrotoxicosis secondary to Graves' disease and marked thymic enlargement were seen at our institution during a 2-year period. On computed tomography (CT) studies their volumes were 67, 81, and 54 cm(3). Thymic hyperplasia in the setting of Graves' disease was the diagnosis of exclusion. Two of the patients returned for follow-up after successful treatment of thyrotoxicosis as requested. On repeat CT their thymic volumes had decreased by 72% and 78%, respectively. Two types of histological modifications of the thymus have been described in association with Graves' disease, namely, thymic parenchyma hyperplasia and medullary lymphoid hyperplasia. The mechanisms underlying thymic transformation in patients with Graves' hyperthyroidism are not completely elucidated, but autoimmune processes underlying Graves' disease are presumed to play a role. The clinical course of our patients is consistent with earlier literature, indicating that thymic enlargement may occur in conjunction with Graves' hyperthyroidism, and that it usually resolves as hyperthyroidism is treated, but there is little quantitative pre- and posttreatment of hyperthyroidism data. CONCLUSION: Although every patient must be individually considered, it appears that thymic hyperplasia can be diagnosed in most Graves' hyperthyroid patients by considering the clinical context and appropriate radiologic studies such as CT. Raising awareness of the association of thymic hyperplasia in patients with Graves' hyperthyroidism and its resolution with the reversibility of the hyperthyroid state should prevent unnecessary thymic evaluation and surgery with its attendant risks. PMID- 20718681 TI - Simultaneous metastatic papillary thyroid carcinoma and carcinoid of the small intestine in the cervical lymph node group. AB - BACKGROUND: Malignancies, primary or metastatic, and infections are the main causative factors that should be included in the differential diagnosis of cervical adenopathy. SUMMARY: We present a 56-year-old woman who was admitted to our department because of a supraclavicular mass. A neck dissection was performed and two different masses were excised. The histopathological examination showed that the larger mass (measuring 5 cm) was a block of lymph nodes with metastatic papillary carcinoma of the thyroid. In the adjacent fibroadipose tissue, two lymph nodes with metastatic carcinoid tumor were found. The smaller mass (measuring 2 cm) was a lymph node with metastatic carcinoid tumor. The patient underwent total thyroidectomy with ipsilateral radical neck dissection. Histopatological examination of the thyroid gland showed a lesion of papillary carcinoma, measuring 0.6 cm. No further lesions of carcinoid were found. CONCLUSIONS: To our knowledge, this is the first report of a coexistence of metastatic papillary thyroid carcinoma and intestinal carcinoid tumor in cervical lymph nodes. PMID- 20718682 TI - Expression of benign and malignant thyroid tissue in ovarian teratomas and the importance of multimodal management as illustrated by a BRAF-positive follicular variant of papillary thyroid cancer. AB - BACKGROUND: The most common type of ovarian germ cell tumor is the teratoma. Thyroid tissue, both benign and malignant, may be a component of an ovarian teratoma. Here we review this topic and illustrate major features by presenting multimodal management of a patient with BRAF-positive disseminated follicular thyroid cancer arising in an ovarian teratoma. SUMMARY: Malignant thyroid tissue is often difficult to distinguish from benign thyroid tissue arising in ovarian teratomas. Preoperatively, an elevated thyroglobulin (Tg) level, laboratory or clinical evidence of hyperthyroidism, or ultrasonography appearance of "struma pearl" should prompt referral to oncologist for surgical management of a possibly malignant ovarian teratoma. Postoperatively, tumor tissue should be referred to pathologists experienced with differentiating benign from malignant struma ovarii. Once diagnosed, treatment of this rare condition should be handled by a team of specialists with combined treatment modalities. We cared for woman with disseminated thyroid cancer arising in an ovarian teratoma whose history illustrates the complexity of managing ovarian teratomas with malignant thyroid tissue. At age 33 she had an intraoperative rupture of an ovarian cyst, thought to be struma ovarii. During her next pregnancy, pelvic masses were noted; biopsies revealed well-differentiated papillary thyroid carcinoma, follicular variant. She was euthyroid, but had elevated serum Tg levels. Surgical staging demonstrated widely metastatic intraabdominal dissemination. A thyroidectomy revealed no malignancy. A post-(131)I treatment scan revealed diffuse uptake throughout the abdomen. She then developed abdominal pain and, on computed tomography, was found to have multiple intraabdominal foci of disease. Serum Tg was 264 ng/mL while on L-thyroxine for hypothyroidism and to obtain thyrotropin suppression. A 18 fluorodeoxyglucose positron emission tomography scan showed no pathological uptake. The tumor was found to be BRAF mutation positive (K601E). She underwent extensive secondary debulking and a second course of (131)I with lithium pretreatment. Posttreatment scan revealed diffuse abdominal uptake. Six months posttherapy, the patient is asymptomatic with a serum Tg of 18.1 ng/mL. CONCLUSIONS: Aggressive multimodal management appears to be the most promising approach for malignant thyroid tissue arising in ovarian teratomas. PMID- 20718683 TI - A phase II study of imatinib in patients with advanced anaplastic thyroid cancer. AB - BACKGROUND: Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. METHODS: Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. RESULTS: From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. CONCLUSIONS: Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting. PMID- 20718684 TI - Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death. AB - BACKGROUND: Studies have shown that overt hypothyroidism is associated with a substantial risk of miscarriage. There is controversy as to whether subclinical hypothyroidism has the same effect and whether such effect is mediated by the presence of antithyroid antibodies. Our hypothesis is that maternal thyroid function in the first trimester is altered in pregnancies ending in miscarriage or fetal death. METHODS: Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine, anti-thyroperoxidase antibody, and anti-thyroglobulin antibody at 11-13 weeks of gestation were measured in 202 singleton pregnancies that subsequently resulted in miscarriage or fetal death, and the values were compared with the results of 4318 normal pregnancies. RESULTS: In the fetal loss group, compared to the unaffected group, there was an increase in median TSH multiple of the normal median (1.133 vs. 1.007 MoM), decrease in median FT4 MoM (0.958 vs. 0.992 MoM), and increase in the incidence of TSH above the 97.5th centile (5.9% vs. 2.5%) and FT4 below the 2.5th centile (5.0% vs. 2.5%). Logistic regression analysis demonstrated that in the prediction of fetal loss there were significant contributions from FT4 MoM, maternal black ethnic origin, history of chronic hypertension, and use of ovulation drugs. The prevalence of antithyroid antibody positivity was not significantly different in the fetal loss group compared to that of normal pregnancies (15.3% vs. 16.8%). CONCLUSIONS: Impaired thyroid function may predispose to miscarriage and fetal death. PMID- 20718685 TI - A rare case of chronic lymphocytic leukemia/small lymphocytic lymphoma presenting in the thyroid gland. AB - BACKGROUND: Lymphoma involving the thyroid gland is rare. Diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma are the two most common histologic subtypes of primary thyroid lymphoma. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presenting initially as a thyroid abnormality is extremely rare, with very few reported cases in the literature. SUMMARY: We report a case of a patient with a long history of Hashimoto's thyroiditis and goiter who presented with a recent enlargement of her thyroid gland. The sonographic finding of a distinct thyroid nodule in the heterogeneous background of chronic lymphocytic thyroiditis led to the performance of a fine needle aspiration biopsy and flow cytometry, with a high index of suspicion for thyroid lymphoma. Subsequent surgical removal of the thyroid gland, prompted by the patient's history of head and neck radiation, confirmed the diagnosis of CLL/SLL. The patient's systemic illness was recognized only after the management of her thyroid disease. Although thyroiditis has long been associated with lymphoma arising in the thyroid gland, CLL/SLL involving the thyroid has not been linked to chronic lymphocytic thyroiditis. Therefore, the patient also had coexisting thyroiditis. CONCLUSIONS: Due to the rarity of thyroid lymphomas, our experience in the detection and management of this disease is limited. Primary thyroid lymphoma should be suspected in a patient with a history of chronic lymphocytic thyroiditis presenting with a rapidly enlarging neck mass. The initial diagnostic method for thyroid lymphoma should consist of a fine-needle aspiration biopsy with the use of ancillary techniques such as flow cytometry and immunohistochemistry for improved diagnostic accuracy. Although controversial, the treatment of thyroid lymphoma is typically guided by the histologic subtype and extent of disease. CLL/SLL is one of the rarest subtypes of lymphoma that can involve the thyroid gland. Diagnosis of this entity is difficult, particularly before the recognition of systemic involvement, requiring the expertise of a multidisciplinary team for early detection and optimal management. PMID- 20718686 TI - Papillary thyroid carcinoma in an autonomous hyperfunctioning thyroid nodule: case report and review of the literature. AB - BACKGROUND: Whereas thyroid nodules are less common among children than among adults, the anxiety generated by the finding of a thyroid nodule is high because 20% of nodules found in children contain thyroid cancer. Discovery of a nodule in the context of hyperthyroidism is usually comforting due to the presumption that the nodule represents a benign toxic adenoma. SUMMARY: An 11-year-old girl presented with heavy menses, fatigue, and a right thyroid mass. Laboratory evaluation revealed elevated triiodothyronine and undetectable thyroid stimulating hormone. Thyroid ultrasonography revealed a 3.5 cm nonhomogenous nodule, and scintigraphy was consistent with an autonomous hyper-functioning nodule. Fine-needle aspiration biopsy could not rule out malignancy, and patient underwent right hemithyroidectomy and isthmusectomy. Pathology was consistent with papillary thyroid carcinoma. CONCLUSIONS: We report the discovery of papillary thyroid carcinoma in an autonomously hyperfunctioning nodule in an 11 year-old girl. Detection of an autonomously functioning thyroid nodule in children and adolescents does not exclude the possibility of thyroid carcinoma and warrants careful evaluation and appropriate therapy. PMID- 20718688 TI - Risk behavior disclosure during HIV test counseling. AB - Individualized risk assessments during HIV testing are an integral component of prevention counseling, a currently recommended behavioral intervention for patients in high-risk settings. Additionally, aggregate risk assessment data are the source of aggregate behavioral statistics that inform prevention programs and allocation of resources. Consequently, inaccurate or incomplete risk behavior disclosure during test counseling may impact the efficacy of the counseling intervention, as well as bias aggregate behavioral statistics. To quantify client reported accuracy during the risk assessment and identify barriers and facilitators to risk behavior disclosure, we interviewed young men accessing HIV testing services in a southeastern United States city using mixed methodology. Data were collected from August 2007 to April 2008. Based on data collected via an audio and computer-assisted self-interview (n = 203), over 30% of men reported that they were not accurate during the risk assessment. Participants reported numerous interpersonal facilitators to complete disclosure. During qualitative interviews (n = 25), participants revealed that many did not understand the purpose of the risk assessment. Findings suggest that risk assessments completed during HIV test counseling may be incomplete. Modifications to the risk assessment process, including better explaining the role of the risk assessment in prevention counseling, may increase the validity of the data. PMID- 20718687 TI - The impact of shame on health-related quality of life among HIV-positive adults with a history of childhood sexual abuse. AB - Childhood sexual abuse is prevalent among people living with HIV, and the experience of shame is a common consequence of childhood sexual abuse and HIV infection. This study examined the role of shame in health-related quality of life among HIV-positive adults who have experienced childhood sexual abuse. Data from 247 HIV-infected adults with a history of childhood sexual abuse were analyzed. Hierarchical linear regression was conducted to assess the impact of shame regarding both sexual abuse and HIV infection, while controlling for demographic, clinical, and psychosocial factors. In bivariate analyses, shame regarding sexual abuse and HIV infection were each negatively associated with health-related quality of life and its components (physical well-being, function and global well-being, emotional and social well-being, and cognitive functioning). After controlling for demographic, clinical, and psychosocial factors, HIV-related, but not sexual abuse-related, shame remained a significant predictor of reduced health-related quality of life, explaining up to 10% of the variance in multivariable models for overall health-related quality of life, emotional, function and global, and social well-being and cognitive functioning over and above that of other variables entered into the model. Additionally, HIV symptoms, perceived stress, and perceived availability of social support were associated with health-related quality of life in multivariable models. Shame is an important and modifiable predictor of health-related quality of life in HIV positive populations, and medical and mental health providers serving HIV infected populations should be aware of the importance of shame and its impact on the well-being of their patients. PMID- 20718689 TI - Dexmedetomidine: pediatric pharmacology, clinical uses and safety. AB - IMPORTANCE OF THE FIELD: Dexmedetomidine is an alpha(2)-adrenoceptor agonist with sedative, anxiolytic and analgesic properties. It is used off-label in pediatric patients due to its efficacy and lack of adverse respiratory effects. Dexmedetomidine may cause severe circulatory complications in adults. Despite its popularity, the safety of dexmedetomidine in the pediatric population has not been extensively studied. AREAS COVERED IN THIS REVIEW: This article reviews the current literature (up to 2010) focusing on applications and safety of dexmedetomidine administered to pediatric patients. WHAT THE READER WILL GAIN: Dexmedetomidine is a useful sedative and anxiolytic drug in the pediatric intensive care unit as well as during diagnostic and therapeutic procedures. Deleterious effects of dexmedetomidine include hypotension and bradycardia. Additionally, hypertension may occur during the "loading dose" or with high infusion rates. Few studies have been performed to evaluate the safety of dexmedetomidine in pediatrics. The development of tolerance and withdrawal has not been studied in children. TAKE HOME MESSAGE: Despite its favorable respiratory profile, dexmedetomidine may cause deleterious cardiovascular effects. Close monitoring of circulatory dynamics and judicious titration is recommended. Further studies are needed to better define adverse effects following long-term infusions as well as in special populations such as pre-term infants. PMID- 20718690 TI - Tendon healing and platelet-rich plasma therapies. AB - IMPORTANCE OF THE FIELD: The therapeutic use of platelet-rich plasma (PRP) is an autologous biotechnology that relies on the local delivery of a wide range of growth factors and cytokines with the aim of enhancing tissue healing. Understanding both tendon healing and PRP therapies is an area of research that is critically important in developing optimal formulations and protocols to achieve the intended therapeutic effects. AREAS COVERED IN THIS REVIEW: We summarise recent information on the mechanisms inherent to the earliest response to tendon injury. We then describe the positive effect of PRP therapies on tendon healing. Research on tendinopathy has produced several biological hypotheses based on histopathological, biochemical and clinical findings showing that cell apoptosis, angiofibroblastic features or abnormal biochemical adaptations underlie the condition. WHAT THE READER WILL GAIN: The article provides insights into early healing mechanisms and the influence of PRP therapies on inflammation, cell migration, angiogenesis and the proliferation and synthesis of extracellular matrix. The knowledge gained helps to better understand and optimize tendon therapies. TAKE HOME MESSAGE: The use of endogenous therapies has a positive effect on experimental tendon healing. However, several obstacles need to be addressed to optimise medical practice in this field. PMID- 20718691 TI - Formulation of a stable and high-loaded quercetin injectable emulsion. AB - The purpose of this paper was to prepare a stable and high-loaded quercetin emulsion with the quercetin-phospholipid complex. The complex was analyzed by FT IR and SEM. Quercetin and soybean lecithin were reacted in dichloromethane at a ratio of 1:2.5 for 2 h at 40 degrees C to prepare the complex. The optimum quercetin emulsion formulation consisted of (according to quality percentage), the complex (quercetin 0.06% in the emulsion), miglyol 812 10%, soybean oil 2%, solutol HS 15 1.2%, cremophor ELP 0.4%, vitamin E 0.2%, oleic acid 0.5%, glycerol 2.5%. The quercetin emulsion was sterilized at 121 degrees C for 15 min. The drug content and particle size distribution of the emulsion before and after sterilization were almost unchanged. The results of accelerate stability (stored at 40 degrees C over one month) and short-time stability (stored at room temperature over six months) tests showed that the quercetin emulsion had enough physicochemical stability to undergo storage. The histopathological examination for rabbit ear vein irritation test indicated that the quercetin emulsion produced no more irritation than normal saline. PMID- 20718692 TI - Tolosa-Hunt syndrome in a patient with autoimmune hemolytic anemia. AB - Tolosa-Hunt syndrome is a steroid responsive painful opthalmoplegia due to a nonspecific inflammation of the cavernous sinus. Autoimmune hemolytic anemia is caused by antibodies directed against unmodified autologous red cells. They are both rare conditions. Here we describe the simultaneous occurrence of Tolosa-Hunt syndrome and severe hemolytic crisis in the same patient. PMID- 20718693 TI - Hippocampal stem cell grafting-mediated recovery of injured hippocampus in the rat model of temporal lobe epilepsy. AB - Hippocampal stem cells (HSCs) are considered promising donor cells to promote reorganization of degenerated regions of the injured hippocampus in the epileptic brain. However, the efficacy of HSC grafting for repairing injured hippocampus remains unclear. To address this issue, we transplanted neonatal rat HSCs into the right hippocampus in rats with kainite acid (KA)-induced epilepsy. The activity of the hippocampus and amygdala nucleus was monitored with electroencephalogram (EEG) throughout 24 weeks posttransplantation. Rats with grafted HSCs exhibited reduced frequency of epileptic wave discharge and a 50% decrease in the amplitude of discharge. At 1, 4, 8, and 24 weeks posttransplantation, the aberrant mossy fiber sprouting (MFS) was evaluated with Timm's stain and the number of CA3 pyramidal neurons was analyzed with Nissl staining. Aberrant MFS induced by KA-lesion was notably suppressed by HSC grafts beginning 4 weeks posttransplantation, and was most effective by 8 weeks. In addition, the loss of CA3 pyramidal neurons was partially restored and reached the most recovery at 8 weeks. Taken together, these results suggest that HSCs derived from the postnatal hippocampus offer a promising reparative effect on KA induced epileptic brain. PMID- 20718695 TI - Fluid pressure and flow as a cause of bone resorption. AB - BACKGROUND: Unstable implants in bone become surrounded by an osteolytic zone. This is seen around loose screws, for example, but may also contribute to prosthetic loosening. Previous animal studies have shown that such zones can be induced by fluctuations in fluid pressure or flow, caused by implant instability. METHOD: To understand the roles of pressure and flow, we describe the 3 dimensional distribution of osteolytic lesions in response to fluid pressure and flow in a previously reported rat model of aseptic loosening. 50 rats had a piston inserted in the proximal tibia, designed to produce 20 local spikes in fluid pressure of a clinically relevant magnitude (700 mmHg) twice a day. The spikes lasted for about 0.3 seconds. After 2 weeks, the pressure was measured in vivo, and the osteolytic lesions induced were studied using micro-CT scans. RESULTS: Most bone resorption occurred at pre-existing cavities within the bone in the periphery around the pressurized region, and not under the piston. This region is likely to have a higher fluid flow and less pressure than the area just beneath the piston. The velocity of fluid flow was estimated to be very high (roughly 20 mm/s). INTERPRETATION: The localization of the resorptive lesions suggests that high-velocity fluid flow is important for bone resorption induced by instability. PMID- 20718696 TI - Lipoprotein-specific transport of circulating lipid peroxides. AB - BACKGROUND: Serum lipoproteins, the carriers of cholesterol and other lipophilic substances in blood, are known to contain variable amounts of lipid peroxides. We investigated the transport of food-derived and endogenously formed lipid peroxides by serum lipoproteins under physiological conditions. METHODS: Five independent trials were conducted in which different groups of healthy volunteers either consumed a test meal (a standard hamburger meal rich in lipid peroxides) or underwent strenuous physical exercise. The transport function was characterized by analyzing the kinetics of lipid peroxides in lipoprotein fractions. For evaluation of their potential involvement, indicators of oxidative stress (8-isoprostanes, malondialdehyde, 8-oxo-deoxyguanosine), antioxidant functions (total antioxidant potential, paraoxonase activity), and serum lipids were also analyzed. RESULTS: We found that food lipid peroxides are incorporated into serum triglyceride-rich lipoproteins and low-density lipoprotein, directing the flow of lipid peroxides towards peripheral tissues. High-density lipoprotein appears to have an opposite and protective function, and is able to respond to oxidative stress by substantially increasing the reverse transport of lipid peroxides. CONCLUSIONS: We propose that the specific atherosclerosis-related effects of serum lipoproteins are not explained by cholesterol transport alone and may rather result from the transport of the more directly atherogenic lipid peroxides. PMID- 20718697 TI - Preclinical studies on specific gene therapy for recessive retinal degenerative diseases. AB - Inherited retinal diseases are non-lethal and have a wide level of genetic heterogeneity. Many of the genes involved have now been identified and their function elucidated, providing a major step towards the development of gene-based treatments. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV) because they mediate long-term transgene expression in a variety of retinal cell types and elicit minimal immune responses. Extensive preclinical evaluation of gene transfer strategies in small and large animal models is key to the development of successful gene-based therapies for the retina. These preclinical studies have already allowed the field to reach the point where gene therapy to treat inherited blindness has been brought to clinical trial. In this manuscript, we focus on recombinant AAV-mediated specific gene therapy for recessive retinal degenerative diseases we describe the preclinical studies for the treatment of retinal degeneration caused by retinal pigmented epithelium (RPE) cells or photoreceptor defects and the immune response induced by retinal rAAV gene transfer. PMID- 20718698 TI - Gene transfer by electrical fields. PMID- 20718699 TI - Implication of heat shock protein 90 (HSP90) in tumor angiogenesis: a molecular target for anti-angiogenic therapy? AB - The inhibition of oncogenic signaling pathways has gained great interest for cancer therapy. In this context, the molecular chaperone heat shock protein 90 (HSP90) has emerged as a promising molecular target, since it is critically involved in maintaining stability, integrity and functions of key oncogenic proteins. A variety of HSP90 inhibitors have been developed in the past decade and have shown convincing anti-neoplastic activity in pre-clinical tumor models. Importantly, HSP90 inhibitors are predominantly being recognized as "tumor cell targeting" agents since cancer cells a) overexpress HSP90 protein, b) highly rely on HSP90 function for maintaining oncogenic signaling, and c) HSP90 inhibitors bind with high affinity to HSP90 in tumor cells. Nevertheless, results from recent studies also suggest that HSP90 inhibitors elicit anti-angiogenic properties by affecting the PI-3K/Akt/eNOS signal transduction pathway in endothelial cells, as well as through down-regulation of VEGFR-2 expression, a crucial component of the angiogenic process. In addition, blocking HSP90 may also diminish the secretion and expression of tumor cell-derived pro-angiogenic growth factors and cytokines, thus leading to "indirect" anti-angiogenic effects. This review article focuses on the role of HSP90 in angiogenesis and on delineating the effects of HSP90 inhibitors on angiogenic signaling pathways involved in tumor vascularization. PMID- 20718700 TI - Endothelial progenitor cells: hope beyond controversy. AB - The capacity to induce new blood vessel formation or to repair damaged vessels is an attractive idea that has, for a long time, captured the attention and imagination of researchers. Beside the identification of the pro-angiogenic growth factors and their counterpart inhibitors, the discovery of endothelial progenitor cells (EPC) in adults and their putative vascular-promoting and/or vascular-healing properties, has generated some of the biggest fascination and debate in the broad field of vascular biology. The simple concept of a population of undifferentiated cells being able to generate new endothelial cells and the corresponding blood vessels in adults is both intriguing and, as seen in the last 10 years, controversial. Academic rivalry or pure scientific dispute has accompanied the research on EPC for some time. The major issues put forward by opposing groups of scientists regarding the identity and the role of EPCs as well as the optimal isolation and detection techniques are discussed in this review. The clinical relevance of EPCs and their potential applications in cancer treatments are also highlighted. PMID- 20718701 TI - Histone deacetylases: anti-angiogenic targets in cancer therapy. AB - Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost 40 years, this concept has inspired generations of researchers to identify anti-angiogenic molecules that could be used therapeutically to stop blood vessels formation and starve tumors of nutrients and oxygen. Tumor angiogenesis requires complex cellular and molecular interactions between endothelial and cancer cells. In response to external stimuli such as hypoxia, cancer cells secrete pro-angiogenic factors into the extracellular matrix that activate the surrounding endothelial cells to proliferate, migrate and form new blood vessels. So, vascularization of malignant lesions depends on the expression of specific genes in both endothelial and tumor cells and accumulating evidences shows that several members of the histone deacetylase (HDAC) family play key roles in the regulation of these genes. Indeed, numerous in vitro and in vivo studies demonstrated that inhibitors of HDAC modulate angiogenic gene expression in both endothelial and cancer cells and disturb the delicate and complex balance between the collective action of pro angiogenic factors and angiogenesis inhibitors. Thus, HDAC are currently recognized as promising targets for the development of anti-cancer drugs. This review is an effort to present and discuss the role, functions and mechanisms of action of HDAC during tumor-driven angiogenesis as well as a brief summary of the clinical status of the main HDAC inhibitors (HDACi) currently under development in cancer therapy. PMID- 20718702 TI - Anti-angiogenic therapies for children with cancer. AB - Tumor angiogenesis, i.e. the development of neovascularisation in and around solid tumors, plays a key role in the local and distant growth of cancer and anti angiogenic treatments are now established strategies to treat cancer patients. Specific inhibitors of angiogenesis such as bevacizumab or receptor tyrosine kinase inhibitors targeting VEGFR or PDGFR are now in clinical trials and are being increasingly validated for the treatment of poor prognostic cancers. Other anti-angiogenic strategies such as cilengitide or metronomic chemotherapy (low dose anti-angiogenic chemotherapy) have been developed to treat certain types of adult cancer. In children, the clinical potential of anti-angiogenic approach is still in an early stage of investigation. This review will focus on the role of angiogenesis in pediatric solid tumors and will describe the pre-clinical and clinical experience with several anti-angiogenic compounds as a potential treatment for children with cancer. PMID- 20718703 TI - RAS pathways in prostate cancer - mediators of hormone resistance? AB - Although not frequently mutated in prostate cancer Ras isoforms play a pivotal role in multiple pathways that have been implicated in prostate cancer progression to androgen independence. These have included growth factor and cytokine induced activation of the androgen receptor and its coregulators by post translational modification. Current evidence suggests that Ras is also required for androgen receptor activation in hormone sensitive cells. More recently Ras has been shown to work synergistically with other pathways to promote prostate tumorigenesis. We review the multiple lines of evidence implicating Ras as therapeutic target in androgen dependent and independent prostate cancer. PMID- 20718704 TI - Strategies for overcoming inherent and acquired resistance to EGFR inhibitors by targeting downstream effectors in the RAS/PI3K pathway. AB - Mutations in K-Ras are observed in approximately 40% of colon tumours. This has significant implications for predicting likelihood of response to the antibody based EGFR inhibitors, cetuximab and panitumumab, with K-Ras mutant patients now clearly shown to be inherently resistant to these agents. Alternative treatment strategies for K-Ras mutant patients are therefore urgently needed. Farnesyltransferase inhibitors, developed to inhibit K-Ras, have to-date been largely unsuccessful. However, a number of agents which target signaling components in the MAPK and PI3K pathways downstream of mutant K-Ras are currently being evaluated in clinical trials and will be discussed. A further clinical concern is that K-Ras wild type patients who initially respond to EGFR inhibitors eventually develop acquired resistance to these agents and experience tumour progression. Studies from the use of related agents in other disease settings as well as pre-clinical studies provide important insights into mechanisms by which this may occur. While no evidence presently exists for somatic mutations as a basis for acquired resistance to EGFR inhibitors in colon cancer, several studies implicate upregulation and signaling via other Her family members, c-Met, IGFR and Src. Upregulation of the pro-angiogenic factor, VEGF, is also a possible mechanism of acquired resistance. This review discusses drugs currently in clinical trials that may potentially achieve more efficient and prolonged targeting of the EGFR pathway by overcoming these mechanisms of resistance. PMID- 20718705 TI - KRAS mutation testing of colorectal cancer for anti-EGFR therapy: dogmas versus evidence. AB - KRAS mutation testing opened up a new era in routine pathological diagnostics of colorectal cancer similar to the introduction of HER-2 testing in breast cancer with the significant difference that mutational analysis exclusively relies on molecular methodologies. In order to critically analyze the current rational of KRAS mutation testing in colorectal carcinoma we have performed evaluation of related articles available in PubMed/Medline, Society recommendations, anti-EGFR antibody registration documents and NCCN guidelines. KRAS mutation is frequent in colorectal cancer and data suggest a negative prognostic, but neutral predictive significance, with the exception of its strong negative predictive value in case of anti-EGFR antibody therapies. However, there is only scattered information on the significance of rare mutations and copy number changes of KRAS. Furthermore, other mutations in EGFR signaling pathway may also have predictive value such as BRAF, PIK3CA or PTEN. It also seems to be a critical issue whether the K-RAS testing must be done on primary, regional or distant metastatic tissues: data already suggest a small but significant chance of alteration during tumor progression. Technically KRAS mutation testing can be performed by various methods characterized by different sensitivities and specificities, although the clinical significance of these parameters are unknown at the present. The consensus strongly suggests the need for an effective quality control program for these methods. KRAS mutation testing in colorectal cancer raised fundamental biological, clinical and molecular pathological questions as it has become a standard application for predicting sensitivity for anti-EGFR antibody therapies. However, these questions can only be answered by rigorous, dogma-free preclinical and clinical studies. PMID- 20718707 TI - Biomarkers downstream of RAS: a search for robust transcriptional targets. AB - The small GTP-binding proteins HRAS, KRAS and NRAS belong to a family of oncoproteins associated with many types of human cancer. Signal transduction processes initiated at receptor tyrosine kinases converge on RAS proteins which serve as molecular switches linking upstream signals with the transcriptional machinery. RAS proteins interact with a number of effector proteins that in turn activate the Raf/MEK/ERK pathway, the PI3K/PKB/Akt pathway, the RalGDS/Ral pathway and other downstream pathways. Mutations in RAS lock the protein in its active form. Chronic activation of the KRAS isoform is the basis for resistance toward antibody therapies targeting receptor tyrosine kinases, as an upstream stimulus through growth factor receptor-mediated activation is no longer required. However, the complexity of the RAS signaling system necessitates the search for additional activating mechanisms as well as biomarkers associated with pathway activation. During recent years, several RAS pathway-related gene signatures were identified, mostly by microarray-based gene expression profiling of normal versus RAS-transformed cells. The signatures can serve as a source of common biomarkers indicating functionally relevant downstream effects of the RAS signaling system. In searching for new markers, we compared the gene expression signatures compiled in 24 independent studies. We analyzed differentially regulated genes recovered in microarray studies on human specimens to discriminate paired normal and tumor tissues. Although the overlap between individual studies was low, this meta-analysis revealed Kruppel-like factor 5 (KLF5), the CD44 antigen and members of the epidermal growth factor (EGR)-family as common downstream effectors of RAS. PMID- 20718706 TI - Targeting Ras-RAF-ERK and its interactive pathways as a novel therapy for malignant gliomas. AB - Malignant gliomas are the most common and the deadliest brain malignancies in adults. Despite the lack of a complete understanding of the biology of these tumors, significant advances have been made in the past decades. One of the key discoveries made in the area of malignant gliomas is that these tumors can be induced and maintained by aberrant signaling networks. In this context, the Ras pathway has been extensively exploited, from both basic and translational perspectives. Although somatic oncogenic mutations of Ras genes are frequent in several cancer types, early investigations on gliomas revealed disappointing facts that the Ras mutations are nearly absent in malignant gliomas and that the BRAF mutations are present in a very small percentage of gliomas. Therefore, the observed deregulation of the Ras-RAF-ERK signaling pathway in gliomas is attributed to its upstream positive regulators, including, EGFR and PDGFR known to be highly active in the majority of malignant gliomas. In contrast to the initial negative results on the somatic mutations of H-Ras, K-Ras and BRAF, recent breakthrough studies on pediatric low-grade astrocytomas uncovered genetic alterations of the BRAF gene involving copy number gains and rearrangements. The 7q34 rearrangements result in a novel in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E). In light of the earlier findings and recent breakthroughs, this review summarizes our current understanding of the Ras-RAF-ERK signaling pathway in gliomas and the outcome of preclinical and clinical studies that evaluated the efficacy of Ras targeted therapy in malignant gliomas. PMID- 20718708 TI - The crosstalk of RAS with the TGF-beta family during carcinoma progression and its implications for targeted cancer therapy. AB - Both RAS and transforming growth factor (TGF)-beta signaling cascades are central in tumorigenesis and show synergisms depending on tumor stage and tissue context. In this review we focus on the interaction of RAS subeffector proteins with signaling components of the TGF-beta family including those of TGF-betas, activins and bone morphogenic proteins. Compelling evidence indicates that RAS signaling is essentially involved in the switch from tumor-suppressive to tumor promoting functions of the TGF-beta family leading to enhanced cancer growth and metastatic dissemination of primary tumors. Thus, the interface of these signaling cascades is considered as a promising target for the development of novel cancer therapeutics. The current pharmacological anti-cancer concepts combating the molecular cooperation between RAS and TGF-beta family signaling during carcinoma progression are critically discussed. PMID- 20718710 TI - Predictive molecular markers of response to epidermal growth factor receptor(EGFR) family-targeted therapies. AB - Constitutive activation of the EGFR/RAS/PI3K cell-signaling pathway that may occur through molecular aberrations in core pathway components occurs in many solid tumours, including colorectal cancer(CRC), non-small-cell lung cancer(NSCLC) and breast cancer. Predictive biomarkers of response to therapeutics targeting this pathway are necessary to select patients more likely to respond, and importantly, to avoid treating patients likely to suffer a worse outcome with therapy compared to standard of care. Determination of EGFR by immunohistochemistry(IHC) is not strongly predictive of response to EGFR-targeted therapy in CRC and NSCLC. EGFR gene mutations in the tyrosine kinase(TK) binding domain are predictive of response to EGFR tyrosine kinase inhibitors(TKIs) in NSCLC, and the acquisition of a point mutation in a gene encoding an amino acid in an adjacent area, T790M, is predictive of resistance. However, novel irreversible EGFR inhibitors such as BIBW-2992 and HKI-272 may retain activity in tumours with T790M mutations. It is well established in CRC that mutations in KRAS are predictive of resistance to EGFR pathway inhibition, and may predict for a poorer outcome with therapy. Other potentially useful biomarkers of resistance to EGFR-targeted therapy in the process of clinical validation include mutations in BRAF, PTEN loss and PI3KCA mutations, nuclear factor-kappa beta(NF-Kappabeta) pathway activity, and expression of alternative EGFR ligands. Functional genomics elucidation of drug resistance pathways using RNA interference (RNAi) techniques may provide novel therapeutic approaches in disease resistant to EGFR pathway targeting and accelerate predictive biomarker development. PMID- 20718709 TI - Ras-induced senescence and its physiological relevance in cancer. AB - Activated oncogenes like Ras have traditionally been thought as promoting unrestrained proliferation; therefore, the concept of oncogene-induced senescence has been, and still is, controversial. The counter-intuitive notion that activation of oncogenes leads to the prevention of cellular proliferation has initially been fueled by in vitro studies using ectopic expression of activated Ras in primary fibroblasts. While these initial studies demonstrated unambiguously the existence of a new type of cellular senescence, induced by oncogenes in an ex-vivo system, questions were raised about the physiological relevance of this process. Indeed, recent technical advances in mouse modeling for cancer have suggested that the occurrence of Ras-induced senescence is highly dependent on the cellular context, as well as the level of expression of activated Ras, and may not be pertinent to the study of human cancer initiation and/or progression. However, our increased knowledge of the molecular basis for cellular senescence has led to a better understanding of the molecular events modulating cancer progression in vivo. Recent studies have not only clearly established the incidence of cellular senescence in pre-neoplasic lesions, but also its role as a potential tumor-suppressor mechanism in vivo. Here, we review the recent and exciting new findings regarding the physiological relevance of Ras induced senescence, and discuss their implications in terms of cancer therapy. PMID- 20718711 TI - Preparation and characterization of RGD tumour-homing-peptide-modified plasminogen K5. AB - Plasminogen K5 (kringle 5) has strong inhibitory effects on endothelial-cell proliferation and migration. It was reported that K5 can reduce tumour neovascularization, resulting in clinically relevant antitumour effects. To determine whether addition of a tumour-targeting peptide could improve the tumour homing and antitumour activities of K5, we genetically modified K5 with an RGD (Arg-Gly-Asp) motif, which is a ligand with high affinity for alphavbeta3 and alphavbeta5 integrins. The fusion protein RGD-K5 was expressed in the Pichia pastoris system and the biological activity of RGD-K5 was assessed in vitro and in vivo. The results showed that the RGD-K5 exhibited a more potent effect of inhibiting endothelial cell proliferation and migration compared with that of traditional K5. RGD-K5 also displayed stronger anti-angiogenic activity in a CAM (chick chorioallantoic membrane) assay. Furthermore, RGD-K5 also showed stronger anti-angiogenic and antitumour effects in B16F10 melanoma-bearing mice compared with traditional K5. In conclusion, the biological activity of K5 can be further improved by the addition of a tumour-homing peptide, and the RGD-K5 may prove to be a promising novel candidate for cancer therapy. PMID- 20718712 TI - Sodium butyrate induces differentiation of gastric cancer cells to intestinal cells via the PTEN/phosphoinositide 3-kinase pathway. AB - NaB (sodium butyrate) inhibits cell proliferation and induces differentiation in a variety of tumour cells. In this study, we aimed to determine whether NaB induced differentiation and regulated the expression of the mucosal factor MUC2 through the PTEN/PI3K (phosphoinositide 3-kinase) pathway. BGC823 cells treated with NaB for 24-72 h showed marked inhibition of cell proliferation and alteration in cellular morphology. NaB treatment markedly increased the expression of PTEN and MUC2, but it decreased the expression of PI3K. These effects were enhanced by intervention with PI3K inhibitors and were reduced by intervention with PTEN siRNA. Hence, we conclude that NaB increased PTEN expression, promoted the expression of MUC2 and induced the differentiation of gastric cancer cells through the PTEN/PI3K signalling pathway. PMID- 20718713 TI - Down-regulation of CREB-binding protein expression inhibits thrombin-induced proliferation of endothelial cells: possible relevance to PDGF-B. AB - Thrombin acts as a potent mitogenic factor for ECs (endothelial cells) by the release of several growth factors, including PDGF-B (platelet-derived growth factor-B). CBP (CREB-binding protein), which functions as a transcriptional coactivator, links the changes in the extracellular stimuli with alterations in gene expression. Therefore, we hypothesized that CBP could mediate thrombin induced proliferation of ECs via PDGF-B-dependent way. Short hairpin RNA was used to down-regulate the expression of CBP in ECs. CBP and PDGF-B levels were analysed by real-time RT-PCR and Western blot. To evaluate ECs proliferation, cell cycle and DNA synthesis were analysed by flow cytometry and BrdU (bromodeoxyuridine) incorporation assay, respectively. PDGF-B was involved in the mitogenic effect of thrombin on ECs. Down-regulation of CBP attenuated ECs proliferation and inhibited cell cycle progression induced by thrombin. Silencing CBP expression also suppressed thrombin-induced PDGF-B expression in ECs. Mitogenic activity of thrombin was impaired by silencing CBP expression in ECs. This inhibitory effect was, in part, related to the inability to up-regulate PDGF B expression in ECs. CBP could be regarded as a potential therapeutic target for vascular injury. PMID- 20718714 TI - Antimicrobial resistance 1979-2009 at Karolinska hospital, Sweden: normalized resistance interpretation during a 30-year follow-up on Staphylococcus aureus and Escherichia coli resistance development. AB - To utilize a material of inhibition zone diameter measurements from disc diffusion susceptibility tests between 1979 and 2009, an objective setting of epidemiological breakpoints was necessary because of methodological changes. Normalized resistance interpretation (NRI) met this need and was applied to zone diameter histograms for Staphylococcus aureus and Escherichia coli isolates. The results confirmed a slow resistance development as seen in Northern countries. The S. aureus resistance levels for erythromycin, clindamycin and fusidic acid in 2009 were 3.2%, 1.8% and 1.4% with denominator correction. A rise in resistance to four antimicrobials in 1983 was probably because of a spread of resistant Methicillin Susceptible Staphylococcus Aureus (MSSA). For E. coli, the denominator-corrected resistance levels in 2009 were 27% for ampicillin, around 3% for third-generation cephalosporins, 0.1% for imipenem, 2.5% for gentamicin, 19% for trimethoprim, 4.5% for co-trimoxazole, 1.2% for nitrofurantoin and 9% for ciprofloxacin. The temporal trends showed a rise in fluoroquinolone resistance from 1993, a parallel increase in gentamicin resistance, a substantial increase in trimethoprim and sulphonamide resistance in spite of decreased consumption, and a steady rise in ampicillin resistance from a constant level before 1989. A short review of global resistance surveillance studies is included. PMID- 20718715 TI - Twist is inversely associated with claudins in germ cell tumors of the testis. AB - We investigated the expression of claudins 1, 3-7 and transcriptional factor twist in a set of testicular germ cell tumors. The material consisted of 17 seminomas, 13 teratomas, 9 teratocarcinomas, 20 embryonal carcinomas and 9 mixed germ cell tumors. They were immunostained with antibodies to claudins 1, 3-7 and twist. As expected, all claudins were variably present in germ cell tumors with epithelial elements or differentiation, but the intensity of expression varied depending on the claudin type. Mesenchymal elements in teratomatous tumors remained negative for claudins. Expression of different claudins was less intense and inconsistent in other types of germ cell tumors. Choriocarcinomatous elements in germ cell tumors expressed relatively strongly claudin 4 and weaker positivity for claudins 5-7, while claudins 1 and 3 were negative. Seminomas showed expression only for claudins 5 and 7. The transcriptional factor twist was most strongly expressed in seminoma followed by embryonal carcinoma. Twist expression was inversely associated with several claudins (claudins 1, 3, 4 and 6). Germ cell tumors vary in their expression of claudins 1-7. Twist expression was inversely associated with several claudins, suggesting that it takes part in the downregulation of claudins in testicular tumors. PMID- 20718716 TI - Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It is characterized by activating mutations in the tyrosine kinase genes c-kit or PDGFRA. This study examined the mutation rate and type in a population-based material. All gastrointestinal mesenchymal tumors over the years 1990-2004 were evaluated and GIST tumors identified using immunohistochemistry (c-kit) and conventional pathologic parameters. Paraffin sections from all tumors were subjected to mutation analysis on exons 9, 11, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. To screen for mutations, we used a highly sensitive conformation-sensitive gel electrophoresis (CSGE) and to define the mutated alleles, we employed direct automated DNA sequencing. All c-kit-positive gastrointestinal mesenchymal tumors were entered into the study. Fifty-six tumors from 55 patients were analyzed. Mutations were found in 52 tumors representing a 92.9% mutational rate. Most of the mutations were found in c-kit exon 11 (76.8%), followed by c-kit exon 9 (10.7%). PDGFRA mutations were only found in three tumors. No correlation of mutation type with biologic behavior was found. This population-based study, using a sensitive CSGE method, identifies mutations in the great majority of patients with GIST. PMID- 20718717 TI - The association of genomic variation of Epstein-Barr virus BamHI F fragment with the proliferation of nasopharyngeal carcinoma. AB - To investigate the f variant of Epstein-Barr virus (EBV) in nasopharyngeal carcinogenesis, we detected the f variant in primary nasopharyngeal carcinoma (NPC), metastatic carcinoma of the lymph node (LN), and chronic inflammation of the nasopharynx from the Guangdong region. Meanwhile, we analyzed the relationship between the f variant of EBV and LMP1, Fascin, pStat3, p53, Bcl-2, and Ki-67 expression in NPC. The results showed that the f variant of EBV was found in 11 cases of primary NPCs with LN metastasis, 12 LN metastases, and 18 primary NPCs without LN metastasis. However, only one demonstrated the F/f variant in 50 cases of chronic inflammation of the nasopharynx. The expression rate of LMP1, Fascin, pStat3, p53, Bcl-2, and Ki-67 in NPC with the f or F/f variant was higher than that with the F prototype. Furthermore, there was a significantly positive correlation between the f variant of EBV and Ki-67 expression (p < 0.05). Our study suggests that the f variant of EBV may be closely related to nasopharyngeal carcinogenesis. PMID- 20718718 TI - Persistence of borrelial DNA in the joints of Borrelia burgdorferi-infected mice after ceftriaxone treatment. AB - We have earlier shown that Borrelia burgdorferi-infected and ceftriaxone-treated mice have viable spirochetes in their body, since immunosuppressive treatment allows B. burgdorferi to be detected by culture. However, the niche of the persisting spirochetes remained unknown. In the present study, we analyzed the tissues of B. burgdorferi-infected and ceftriaxone-treated mice by culture and PCR to reveal the foci of persisting spirochetes. C3H/HeN mice were infected via intradermal needle injection with B. burgdorferi s.s. N40. The mice were treated as follows: (i) short (5 days) and (ii) long (18 days) course of ceftriaxone at 2 weeks of infection and killed after either 10 or 30 weeks, or (iii) the mice received ceftriaxone for 5 days at 18 weeks of infection and were killed 21 weeks after the treatment. All samples of ceftriaxone-treated mice were culture negative, whereas all untreated controls were culture positive. Importantly, B. burgdorferi DNA was detected in the joints of 30-100% of the treated mice. In conclusion, these results combined with earlier results suggest that the joint or a tissue adjacent to the joint is the niche of persisting B. burgdorferi in ceftriaxone-treated mice. PMID- 20718719 TI - In vitro activity of dermaseptin S1 derivatives against genital pathogens. AB - The aim of this study was to evaluate the biological activity of nine dermaseptin S1 (DRS-S1) derivatives (synthesized by solid-phase methods and purified) against different pathogens causing genital infections (Trichomonas vaginalis, Herpes simplex virus, Papillomavirus). The in vitro activity on T. vaginalis was determined by counting the protozoon in a hemocytometer after vital staining with trypan blue; antiviral activity of the compounds was tested on monolayers of Vero cells for Herpes simplex virus-1 (GFP) and on 293TT cells for human papillomavirus (HPV-16) pseudovirions (GFP). The cytotoxicity of the derivatives was assessed by evaluating both the hemolytic activity and the effect on Vero and 293TT cells. The DRS-S1 longer peptides demonstrated a superior activity on T. vaginalis but also a certain cytopathic effect. The compounds with 29 amino acids exhibited activity against the two viruses tested at concentrations not toxic to cells. The results obtained show that some of the synthetic peptides assessed have inhibitory activity against the pathogens tested, indicating a potential for the development of new molecules for use as topical microbicides to prevent the sexual transmission of microorganisms. PMID- 20718720 TI - Use of Cervista HPV HR assay for detection of human papillomavirus in samples with hybrid capture borderline negative results. AB - We have evaluated Cervista HPV HR for papillomavirus detection in 65 samples previously borderline negative by the hybrid capture method (Digene), using InnoLipa and sequencing as confirmatory techniques. Nine samples were found to be positive by Cervista HPV HR, of which five (7.6%) were confirmed by InnoLipa. Four samples (6.1%) were false positive, of which three samples were reactive for A9 probes. The Cervista HPV HR assay can detect HPV-positive samples from those with hybrid capture borderline results but can produce false-positive results when tested for reactivity with A9 probes. PMID- 20718721 TI - Triplex real-time PCR assay for detection and differentiation of Bordetella pertussis and Bordetella parapertussis. AB - A triplex real-time PCR assay for detection and differentiation of Bordetella pertussis and Bordetella parapertussis was developed. Three targets were used for amplification in a single tube: the insertion sequence IS481 and the pertussis toxin promoter region (ptxP) for B. pertussis, and the insertion sequence IS1001 for B. parapertussis. The performance of this PCR assay was evaluated in parallel in three single-target real-time PCR assays using DNA extracted from B. pertussis and B. parapertussis reference strains and nasopharyngeal swabs taken from 105 patients who had been coughing for more than 7 days. The minimum detection limit of the triplex PCR was one to five colony-forming units (CFU) of B. pertussis and 1 CFU of B. parapertussis per reaction, and the coefficients of both intra- and inter-assay variation were less than 7%. Results were available within 4 h. Of the 105 nasopharyngeal samples, seven were culture positive and 23 were PCR positive for B. pertussis. All culture-positive samples were also PCR positive. Our single-tube triplex real-time PCR assay proved to be sensitive, specific and suitable for simultaneous detection and discrimination of B. pertussis and B. parapertussis. PMID- 20718722 TI - Praziquantel efficacy in mice infected with PZQ non-susceptible S. mansoni isolate treated with artemether: parasitological, biochemical and immunohistochemical assessment. AB - Based on the fact that artemether (ART) affects immature schistosomes and that the effect of praziquantel (PZQ) mainly targets mature schistosomes, this work investigates the possible enhanced efficacy of PZQ in combination with ART in mice harboring a PZQ non-susceptible Schistosoma mansoni isolate. Associated schistosomal, inflammatory, hepatic histopathological changes have been investigated by examining the tissue markers expressing apoptosis using FAS (CD95), anti-apoptosis (Bcl2) and angiogenesis [vascular endothelial growth factor (VEGF)]. A batch of Swiss albino mice infected with a PZQ non-susceptible (EE10) S. mansoni isolate was divided into 12 groups. Animals of the first group were left without treatment as infected controls, while groups 2-6 received PZQ in increasing doses. The animals of group 7 received ART in double doses. Those comprising groups 8-12 received combined therapy of PZQ and ART in the same doses and at the same timings postinfection (PI) as those belonging to groups 2-6. Parasitological parameters, liver function, and histopathological and immunohistochemical studies of FAS, Bcl2 and VEGF antibodies were assessed. Combined administration of ART and PZQ reduced the ED(50) (the dose at which the worm burden was decreased by 50%) of PZQ. Typical granulomas were not seen in animals treated with ART alone and combined with PZQ, with least expression of FAS and VEGF and increased expression of Bcl2. The minimal histopathological changes recorded in mice treated with both ART and PZQ could be related to a synergistic/additive effect of ART, markedly reducing the intensity of infection. Improved liver function tests support the less severe histopathological changes under the influence of this treatment protocol. This study encourages human trials especially in areas where malaria is not endemic, and differing combination doses should be investigated in view of the antagonistic effect noticed with some dose regimens. PMID- 20718723 TI - Cell-specific elevation of NRF2 and sulfiredoxin-1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. AB - Human idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) have been proposed to be attributable to oxidative stress. The nuclear factor, erythroid derived 2, like protein (NRF2)-sulfiredoxin-1 (SRX1) pathway was hypothesized to be associated with the pathogenesis of human pulmonary fibrosis. Several methods including digital morphometry were used in the assessment of the cell-specific localization and expression of NRF2 and SRX1 and selected proteins linked to their activation/stability in human IPF/usual interstitial pneumonia (UIP) and NSIP lung. The proteins of the NRF2 pathway were localized in the hyperplastic alveolar epithelium and inflammatory cells in IPF and NSIP, but were absent in the fibroblastic foci characteristic of IPF. Morphometric evaluation revealed NRF2 and KEAP1 to be significantly elevated in the hyperplastic alveolar epithelium compared with the normal alveolar epithelium, and NRF2 was remarkably expressed in the nuclear compartment of the hyperplastic cells. SRX1 was expressed mainly in alveolar macrophages, and the number of SRX1-positive macrophages/surface area was elevated in NSIP, a disease which contains more marked inflammatory reaction compared with the IPF/UIP lung. The expression of the NRF2 pathway in human IPF and NSIP is further evidence that the pathogenesis of human fibrotic lung diseases is oxidant-mediated and originates from the alveolar epithelium. PMID- 20718724 TI - Outbreak of CTX-M-15-producing Klebsiella pneumoniae of sequence type 199 in a Latvian teaching hospital. AB - Previous studies on the epidemiology of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in Latvia are lacking. ESBL-producing Klebsiella pneumoniae (n = 32) were subjected to pulsed-field gel electrophoresis (PFGE) and selected isolates to multi-locus sequence typing (MLST). Species identification and susceptibility testing were performed using VITEK2, and sequencing of bla(CTX M) was performed in selected isolates. PFGE revealed one major clone (n = 23), with most of the isolates derived from the ICU. The clone harboured bla(CTX-M 15), was sequence type 199 and comprised two ertapenem non-susceptible isolates. This is the first report of an ESBL outbreak in Latvia, and calls for increased epidemiological typing of ESBL-producing Enterobacteriaceae, as well as improved infection control routines. PMID- 20718726 TI - Improving the definition of the structure of the isochromosome i(7)(q10) in Shwachman-Diamond Syndrome. PMID- 20718729 TI - Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics. AB - BACKGROUND AND PURPOSE: Inosine monophosphate dehydrogenases, encoded by IMPDH1 and IMPDH2, are targets for the important immunosuppressive drug, mycophenolic acid (MPA). Variation in MPA response may result, in part, from genetic variation in IMPDH1 and IMPDH2. EXPERIMENTAL APPROACH: We resequenced IMPDH1 and IMPDH2 using DNA from 288 individuals from three ethnic groups and performed functional genomic studies of the sequence variants observed. KEY RESULTS: We identified 73 single nucleotide polymorphisms (SNPs) in IMPDH1, 59 novel, and 25 SNPs, 24 novel, in IMPDH2. One novel IMPDH1 allozyme (Leu275) had 10.2% of the wild-type activity as a result of accelerated protein degradation. Decreased activity of the previously reported IMPDH2 Phe263 allozyme was primarily due to decreased protein quantity, also with accelerated degradation. These observations with regard to the functional implications of variant allozymes were supported by the IMPDH1 and IMPDH2 X-ray crystal structures. A novel IMPDH2 intron 1 SNP, G > C IVS1(93), was associated with decreased mRNA quantity, possibly because of altered transcription. CONCLUSIONS AND IMPLICATIONS: These results provide insight into the nature and extent of sequence variation in the IMPDH1 and IMPDH2 genes. They also describe the influence of gene sequence variation that alters the encoded amino acids on IMPDH function and provide a foundation for future translational studies designed to correlate sequence variation in these genes with outcomes in patients treated with MPA. PMID- 20718728 TI - Imaging calcium signals in vivo: a powerful tool in physiology and pharmacology. AB - The design and engineering of organic fluorescent Ca(2+) indicators approximately 30 years ago opened the door for imaging cellular Ca(2+) signals with a high degree of temporal and spatial resolution. Over this time, Ca(2+) imaging has revolutionized our approaches for tissue-level spatiotemporal analysis of functional organization and has matured into a powerful tool for in situ imaging of cellular activity in the living animal. In vivo Ca(2+) imaging with temporal resolution at the millisecond range and spatial resolution at micrometer range has been achieved through novel designs of Ca(2+) sensors, development of modern microscopes and powerful imaging techniques such as two-photon microscopy. Imaging Ca(2+) signals in ensembles of cells within tissue in 3D allows for analysis of integrated cellular function, which, in the case of the brain, enables recording activity patterns in local circuits. The recent development of miniaturized compact, fibre-optic-based, mechanically flexible microendoscopes capable of two-photon microscopy opens the door for imaging activity in awake, behaving animals. This development is poised to open a new chapter in physiological experiments and for pharmacological approaches in the development of novel therapies. PMID- 20718730 TI - Ca2+ paradox injury mediated through TRPC channels in mouse ventricular myocytes. AB - BACKGROUND AND PURPOSE The Ca(2+) paradox is an important phenomenon associated with Ca(2+) overload-mediated cellular injury in myocardium. The present study was undertaken to elucidate molecular and cellular mechanisms for the development of the Ca(2+) paradox. EXPERIMENTAL APPROACH Fluorescence imaging was performed on fluo-3 loaded quiescent mouse ventricular myocytes using confocal laser scanning microscope. KEY RESULTS The Ca(2+) paradox was readily evoked by restoration of the extracellular Ca(2+) following 10-20 min of nominally Ca(2+) free superfusion. The Ca(2+) paradox was significantly reduced by blockers of transient receptor potential canonical (TRPC) channels (2-aminoethoxydiphenyl borate, Gd(3+), La(3+)) and anti-TRPC1 antibody. The sarcoplasmic reticulum (SR) Ca(2+) content, assessed by caffeine application, gradually declined during Ca(2+)-free superfusion, which was further accelerated by metabolic inhibition. Block of SR Ca(2+) leak by tetracaine prevented Ca(2+) paradox. The Na(+) /Ca(2+) exchange (NCX) blocker KB-R7943 significantly inhibited Ca(2+) paradox when applied throughout superfusion period, but had little effect when added for a period of 3 min before and during Ca(2+) restoration. The SR Ca(2+) content was better preserved during Ca(2+) depletion by KB-R7943. Immunocytochemistry confirmed the expression of TRPC1, in addition to TRPC3 and TRPC4, in mouse ventricular myocytes. CONCLUSIONS AND IMPLICATIONS These results provide evidence that (i) the Ca(2+) paradox is primarily mediated by Ca(2+) entry through TRPC (probably TRPC1) channels that are presumably activated by SR Ca(2+) depletion; and (ii) reverse mode NCX contributes little to the Ca(2+) paradox, whereas inhibition of NCX during Ca(2+) depletion improves SR Ca(2+) loading, and is associated with reduced incidence of Ca(2+) paradox in mouse ventricular myocytes. PMID- 20718731 TI - Amplification of EDHF-type vasodilatations in TRPC1-deficient mice. AB - BACKGROUND AND PURPOSE: TRPC1 channels are expressed in the vasculature and are putative candidates for intracellular Ca(2+) handling. However, little is known about their role in endothelium-dependent vasodilatations including endothelium derived hyperpolarizing factor (EDHF) vasodilatations, which require activation of Ca(2+) -activated K(+) channels (K(Ca)). To provide molecular information on the role of TRPC1 for K(Ca) function and the EDHF signalling complex, we examined endothelium-dependent and independent vasodilatations, K(Ca) currents and smooth muscle contractility in TRPC1-deficient mice (TRPC1-/-). EXPERIMENTAL APPROACH: Vascular responses were studied using pressure/wire myography and intravital microscopy. We performed electrophysiological measurements, and confocal Ca(2+) imaging for studying K(Ca) channel functions and Ca(2+) sparks. KEY RESULTS: TRPC1 deficiency in carotid arteries produced a twofold augmentation of TRAM-34- and UCL1684-sensitive EDHF-type vasodilatations and of endothelial hyperpolarization to acetylcholine. NO-mediated vasodilatations were unchanged. TRPC1-/- exhibited enhanced EDHF-type vasodilatations in resistance-sized arterioles in vivo associated with reduced spontaneous tone. Endothelial IK(Ca) /SK(Ca)-type K(Ca) currents, smooth muscle cell Ca(2+) sparks and associated BK(Ca)-mediated spontaneous transient outward currents were unchanged in TRPC1-/ . Smooth muscle contractility induced by receptor-operated Ca(2+) influx or Ca(2+) release and endothelium-independent vasodilatations were unaltered in TRPC1-/-. TRPC1-/- exhibited lower systolic blood pressure as determined by tail cuff blood pressure measurements. CONCLUSIONS AND IMPLICATIONS: Our data demonstrate that TRPC1 acts as a negative regulator of endothelial K(Ca) channel dependent EDHF-type vasodilatations and thereby contributes to blood pressure regulation. Thus, we propose a specific role of TRPC1 in the EDHF-K(Ca) signalling complex and suggest that pharmacological inhibition of TRPC1, by enhancing EDHF vasodilatations, may be a novel strategy for lowering blood pressure. PMID- 20718733 TI - 6-Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase-9 expression via blockade of nuclear factor kappaB activation. AB - BACKGROUND AND PURPOSE: Shogaols are reported to possess anti-inflammatory and anticancer activities. However, the antimetastatic potential of shogaols remains unexplored. This study was performed to assess the effects of shogaols against breast cancer cell invasion and to investigate the underlying mechanisms. EXPERIMENTAL APPROACH: The anti-invasive effect of a series of shogaols was initially evaluated on MDA-MB-231 breast cancer cells using the matrigel invasion assay. The suppressive effects of 6-shogaol on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) gelatinolytic activity and nuclear factor-kappaB (NF-kappaB) activation were further determined. KEY RESULTS: Shogaols (6-, 8- and 10-shogaol) inhibited PMA-stimulated MDA-MB-231 cell invasion with an accompanying decrease in MMP-9 secretion. 6-Shogaol was identified to display the greatest anti-invasive effect in association with a dose-dependent reduction in MMP-9 gene activation, protein expression and secretion. The NF-kappaB transcriptional activity was decreased by 6-shogaol; an effect mediated by inhibition of IkappaB phosphorylation and degradation that subsequently led to suppression of NF-kappaB p65 phosphorylation and nuclear translocation. In addition, 6-shogaol was found to inhibit JNK activation with no resulting reduction in activator protein-1 transcriptional activity. By using specific inhibitors, it was demonstrated that ERK and NF-kappaB signalling, but not JNK and p38 signalling, were involved in PMA-stimulated MMP-9 activation. CONCLUSIONS AND IMPLICATIONS: 6-Shogaol is a potent inhibitor of MDA-MB-231 cell invasion, and the molecular mechanism involves at least in part the down regulation of MMP-9 transcription by targeting the NF-kappaB activation cascade. This class of naturally occurring small molecules thus have potential for clinical use as antimetastatic treatments. PMID- 20718734 TI - Haem arginate infusion stimulates haem oxygenase-1 expression in healthy subjects. AB - BACKGROUND AND PURPOSE: Haem oxygenase 1 (HO-1) is an inducible protein that plays a major protective role in conditions such as ischaemia-reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO-1 expression and its correlation with the GT length polymorphism (GT(n)) in the promoter of the HO-1 gene. EXPERIMENTAL APPROACH: In a dose-escalation, randomized, placebo-controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GT(n) genotype received intravenous HA. HO-1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period. KEY RESULTS: We found that the baseline mRNA levels of HO-1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose-dependent increase in the baseline corrected area under the curve values of HO-1 mRNA and protein over 48 h. The response of HO-1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups. CONCLUSIONS AND IMPLICATION: HA is an effective inducer of HO-1 in humans irrespective of the GT(n) genotype. The potential therapeutic application of HA needs to be evaluated in clinical trials. PMID- 20718735 TI - Activation of a nuclear factor of activated T-lymphocyte-3 (NFAT3) by oxidative stress in carboplatin-mediated renal apoptosis. AB - BACKGROUND AND PURPOSE: Although carboplatin is currently used as a therapeutic drug for ovarian, breast, and non-small cell lung cancers, it has serious side effects including renal and cardiac toxicity. Herein, we examined the effect of carboplatin on murine renal tubular cell (RTC) apoptosis both in vivo and in vitro and the underlying molecular mechanisms associated with its activation of the nuclear factor of activated T-lymphocytes-3 (NFAT3). EXPERIMENTAL APPROACH: Mechanisms of carboplatin-mediated renal apoptosis were examined using NFAT reporter transgenic mice and RTCs with NFAT3 overexpression or knockdown. KEY RESULTS: We demonstrated that carboplatin initiated an intrinsic apoptotic pathway of activating caspase-3 and -9, accompanied by a decrease in the ratio of Bcl-XL/Bax and a significant increase in Bcl-XS. Carboplatin increased NFAT activation in NFAT-luciferase reporter transgenic mice, RTCs and cells exogenously overexpressing NFAT3 that exacerbated cell death. Furthermore, the addition of either N-acetylcysteine (NAC, an antioxidant) or NFAT inhibitors, including FK-506 (tacrolimus), cyclosporin A (CsA, a calcineurin inhibitor), and BAPTA-AM (a calcium chelator) successfully reversed carboplatin-mediated cell apoptosis, which was further confirmed using siNFAT3. Additionally, NAC blocked NFAT3 activation by inhibition of NADPH oxidase activation, and ERK/JNK and PKC pathways, resulting in a decrease in cell apoptosis; the therapeutic effect of NAC was verified in vivo. CONCLUSION AND IMPLICATIONS: The results presented herein show that carboplatin-mediated reactive oxygen species might signal calcineurin and NFAT3 activation in RTCs, whereas NAC and NFAT inhibitors reversed carboplatin-mediated RTC apoptosis, suggesting that oxidative stress mediated NFAT3 activation is essential for carboplatin-mediated RTC apoptosis. PMID- 20718736 TI - The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis. AB - Diuretics are drugs that increase the rate of urine flow and sodium excretion to adjust the volume and composition of body fluids. There are several major categories of this drug class and the compounds vary greatly in structure, physicochemical properties, effects on urinary composition and renal haemodynamics, and site and mechanism of action. Diuretics are often abused by athletes to excrete water for rapid weight loss and to mask the presence of other banned substances. Because of their abuse by athletes, diuretics have been included on The World Anti-Doping Agency's (WADA) list of prohibited substances; the use of diuretics is banned both in competition and out of competition and diuretics are routinely screened for by anti-doping laboratories. This review provides an overview of the pharmacology and toxicology of diuretics and discusses their application in sports. The most common analytical strategies currently followed by the anti-doping laboratories accredited by the WADA are discussed along with the challenges laboratories face for the analysis of this diverse class of drugs. PMID- 20718737 TI - Methylenedioxymethamphetamine ('Ecstasy')-induced immunosuppression: a cause for concern? AB - Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a ring-substituted amphetamine and a popular drug of abuse. In addition to ability to induce euphoria, MDMA abuse is associated with a range of acute and long-term hazardous effects. This paper is focused on once such adverse effect: its ability to negatively impact on functioning of the immune system. Research demonstrates that MDMA has immunosuppressive properties, with both innate and adaptive arms of the immune system being affected. The ability of MDMA to suppress innate immunity is indicated by impaired neutrophil phagocytosis and reduced production of dendritic cell/macrophage-derived pro-inflammatory cytokines including tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-12 and IL-15. MDMA also suppresses innate IFN-gamma production, and considering the role of IFN-gamma in priming antigen-presenting cells, it is not surprising that MDMA reduces MHC class II expression on dendritic cells and macrophages, and inhibits co-stimulatory molecule expression. Paradoxically, studies demonstrate that MDMA elicits pro inflammatory actions in the CNS by activating microglia, the resident innate immune cells in the brain. In terms of adaptive immunity, MDMA reduces circulating lymphocyte numbers, particularly CD4(+) T-cells; suppresses T-cell proliferation; and skews cytokine production in a Th(2) direction. For the most part, the immunosuppressive effects of MDMA cannot be attributed to a direct action of the drug on immune cells, but rather due to the release of endogenous immunomodulatory substances. In this regard, peripheral beta-adrenoceptors and cholinergic receptors have been shown to mediate some immunosuppressive effects of MDMA. Finally, we discuss emerging evidence indicating that MDMA-induced immunosuppression can translate into significant health risks for abusers. PMID- 20718738 TI - Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen-glucose depletion. AB - BACKGROUND AND PURPOSE: Several clinical trials and in vivo animal experiments have suggested that blockade of angiotensin receptor type 1 (AT(1)) improves ischaemic outcomes. However, the mechanism(s) underlying these effects has not been elucidated. Here, we have investigated the protective effects of pretreatment with AT(1) receptor antagonists, losartan or telmisartan, against ischaemic insult to neurons in vitro. EXPERIMENTAL APPROACH: Primary rat neuron astrocyte co-cultures and astrocyte-defined medium (ADM)-cultured pure astrocyte cultures were prepared. Ischaemic injury was modelled by oxygen-glucose depletion (OGD) and lactate dehydrogenase release after OGD was measured with or without AT(1) receptor antagonists or agonists (L162313), AT(2) receptor antagonist (PD123319) or agonist (CGP-42112A) pretreatment, for 48 h. Activity of glutamate transporter 1 (GLT-1) was evaluated by [(3)H]-glutamate uptake assays, after AT(1) receptor agonists or antagonists. Immunoblot and real-time PCR were used for analysis of protein and mRNA levels of GLT-1. KEY RESULTS: AT(1) receptor agonists augmented OGD-induced cellular damage, which was attenuated by AT(1) receptor antagonists. AT(1) receptor antagonists also suppressed OGD-induced extracellular glutamate release, reactive oxygen species production and nitric oxide generation. GLT-1 expression and glutamate uptake activity were significantly enhanced by AT(1) receptor antagonists and impaired by AT(1) receptor agonists. AT(1) receptor stimulation suppressed both ADM-induced GLT-1 protein expression and mRNA levels. AT(1)b receptor knock-down with siRNA enhanced GLT-1 expression. In postnatal (P1-P21) rat brains, protein levels of GLT-1 and AT(1) receptors were inversely correlated. CONCLUSIONS AND IMPLICATIONS: Suppression of AT(1) receptor stimulation induced GLT-1 up regulation, which ameliorated effects of ischaemic injury. PMID- 20718739 TI - Sustained morphine-mediated pain sensitization and antinociceptive tolerance are blocked by intrathecal treatment with Raf-1-selective siRNA. AB - BACKGROUND AND PURPOSE: Long-term morphine treatment enhances pain neurotransmitter [such as calcitonin gene-related peptide (CGRP)] levels in the spinal cord. It has been suggested previously that increased spinal CGRP may contribute to sustained morphine-mediated paradoxical pain sensitization and antinociceptive tolerance. Previous in vitro studies from our group indicated that Raf-1 kinase-mediated adenylyl cyclase superactivation played a crucial role in sustained morphine-mediated augmentation of basal and evoked CGRP release from cultured primary sensory neurons. The present study was aimed to evaluate the physiological significance of this molecular mechanism in vivo, in rats. EXPERIMENTAL APPROACH: Rats were intrathecally (i.th) injected with a Raf-1 selective small interfering RNA (siRNA) mixture for 3 days and were subsequently infused with saline or morphine, s.c. for 7 days. Thermal and mechanical sensory thresholds of the animals were assessed by daily behavioural tests. After final behavioural testing (day 6), spinal cords were isolated from each animal group and spinal CGRP and Raf-1 protein levels were measured using elisa and immunohistochemistry. KEY RESULTS: Selective knockdown of spinal Raf-1 protein levels by i.th Raf-1-selective siRNA pretreatment significantly attenuated sustained morphine-mediated up-regulation of CGRP immunoreactivity in the spinal cord of rats and prevented the development of thermal hyperalgesia, mechanical allodynia and antinociceptive tolerance. CONCLUSIONS AND IMPLICATIONS: Raf-1 played a significant role in sustained morphine-mediated paradoxical pain sensitization and antinociceptive tolerance in vivo. These findings suggest novel pharmacological approaches to improve the long-term utility of opioids in the treatment of chronic pain. PMID- 20718740 TI - Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands - in vitro and in vivo characterization. AB - BACKGROUND AND PURPOSE: Subunit-specific modulators of gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a beta(2/3) subunit-specific modulator of GABA(A) receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABA(A) receptor modulators and to gain insight into the structure-activity relation of this molecule. EXPERIMENTAL APPROACH: The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABA(A) receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (I(GABA)) through GABA(A) receptors (EC(50)) and efficacies (maximal stimulation of I(GABA)) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS: Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater I(GABA) enhancement than VA) and highest potency (EC(50)= 13.7 +/- 2.3 microM) on alpha(1)beta(3) receptors. Higher efficacy and potency of VA-A were also observed on alpha(1)beta(2)gamma(2s) and alpha(3)beta(3)gamma(2s) receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS: Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting beta(3) subunit containing GABA(A) receptors for development of anxiolytics. PMID- 20718741 TI - Selective inhibition of persistent sodium current by F 15845 prevents ischaemia induced arrhythmias. AB - BACKGROUND AND PURPOSE: Myocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (I(Nap)) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on I(Nap) and in integrative models of I(Nap)-induced arrhythmias. EXPERIMENTAL APPROACH: Sodium current was investigated using patch clamp technique on wild-type and DeltaKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia- and aconitine-induced arrhythmias in the rat. KEY RESULTS: We demonstrated that F 15845 is a potent blocker of I(Nap) acting from the extracellular side of the channel. Blockade of I(Nap) was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the I(Nap) activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where I(Nap) is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias. CONCLUSIONS AND IMPLICATIONS: F 15845, a novel anti-anginal drug targeting I(Nap), demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias. PMID- 20718742 TI - Possible involvement of GLP-1(9-36) in the regional haemodynamic effects of GLP 1(7-36) in conscious rats. AB - BACKGROUND AND PURPOSE: The incretin hormone, glucagon-like peptide (GLP)-1(7 36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9-36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7-36), and determine the extent to which the cardiovascular effects of GLP-1(7-36) were influenced by DPP 4 inhibition and reproduced by GLP-1(9-36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7 36). EXPERIMENTAL APPROACH: Regional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7-36) amide and GLP-1(9-36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7-36) were also assessed. KEY RESULTS: Glucagon like peptide-1(7-36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9-36) was devoid of any cardiovascular actions. The effects of GLP-1(7-36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were beta-adrenoceptor-mediated. CONCLUSIONS AND IMPLICATIONS: In conscious rats, the cardiovascular effects of GLP-1(7-36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9-36). PMID- 20718743 TI - Regional enhancement of cannabinoid CB₁ receptor desensitization in female adolescent rats following repeated Delta-tetrahydrocannabinol exposure. AB - BACKGROUND AND PURPOSE: Disruption of the substantial re-organization of the brain during adolescence may be induced by persistent abuse of marijuana. The aim of this study was to determine whether adolescent and adult rats exhibit differential adaptation of brain cannabinoid (CB(1)) receptors after repeated exposure to Delta(9)-tetrahydrocannabinol (THC). EXPERIMENTAL APPROACH: Rats of both ages and sexes were dosed with 10 mg kg(-1) THC or vehicle twice daily for 9.5 days. Subsequently, CB(1) receptor function and density were assessed. KEY RESULTS: In all brain regions, THC treatment produced desensitization and down regulation of CB(1) receptors. While the magnitude of down-regulation did not differ across groups, greater desensitization was evident in the brains of THC treated female adolescent rats for most regions. Adolescent females showed greater desensitization than adult females in the prefrontal cortex, hippocampus, periaqueductal gray (PAG) and ventral midbrain. In contrast, adolescent males exhibited less desensitization in the prefrontal cortex, hippocampus and PAG, an effect opposite to that seen in females. With the exception of the PAG, sex differences were seen only in adolescents, with greater desensitization in the prefrontal cortex, striatum, hippocampus, PAG, and ventral midbrain of females. CONCLUSIONS AND IMPLICATIONS: These results suggest that the brains of adolescent females may be particularly vulnerable to disruption of CB(1) receptor signalling by marijuana abuse. Alternatively, increased desensitization may reflect protective adaptation. Given the extensive re-organization of the brain during adolescence, this disruption has potential long-term consequences for maturation of the endocannabinoid system. PMID- 20718744 TI - Emodin, a natural product, selectively inhibits 11beta-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice. AB - BACKGROUND AND PURPOSE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11beta-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. EXPERIMENTAL APPROACH: Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11beta-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. KEY RESULTS: Emodin is a potent and selective 11beta-HSD1 inhibitor with the IC(50) of 186 and 86 nM for human and mouse 11beta-HSD1, respectively. Single oral administration of emodin inhibited 11beta-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11beta-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. CONCLUSIONS AND IMPLICATIONS: This study demonstrated a new role for emodin as a potent and selective inhibitor of 11beta-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes. PMID- 20718745 TI - Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. AB - BACKGROUND AND PURPOSE: Glutamate excitotoxicity may be involved in ischaemic injury to the CNS and some neurodegenerative diseases, such as Alzheimer's disease. Donepezil, an acetylcholinesterase (AChE) inhibitor, exerts neuroprotective effects. Here we demonstrated a novel mechanism underlying the neuroprotection induced by donepezil. EXPERIMENTAL APPROACH: Cell damage in primary rat neuron cultures was quantified by lactate dehydrogenase release. Morphological changes associated with neuroprotective effects of nicotine and AChE inhibitors were assessed by immunostaining. Cell surface levels of the glutamate receptor sub-units, NR1 and NR2A, were analyzed using biotinylation. Immunoblot was used to measure protein levels of cleaved caspase-3, total NR1, total NR2A and phosphorylated NR1. Immunoprecipitation was used to measure association of NR1 with the post-synaptic protein, PSD-95. Intracellular Ca(2+) concentrations were measured with fura 2-acetoxymethylester. Caspase 3-like activity was measured using enzyme substrate, 7-amino-4-methylcoumarin (AMC) DEVD. KEY RESULTS: Levels of NR1, a core subunit of the NMDA receptor, on the cell surface were significantly reduced by donepezil. In addition, glutamate mediated Ca(2+) entry was significantly attenuated by donepezil. Methyllycaconitine, an inhibitor of alpha7 nicotinic acetylcholine receptors (nAChR), inhibited the donepezil-induced attenuation of glutamate-mediated Ca(2+) entry. LY294002, a phosphatidyl inositol 3-kinase (PI3K) inhibitor, had no effect on attenuation of glutamate-mediated Ca(2+) entry induced by donepezil. CONCLUSIONS AND IMPLICATIONS: Decreased glutamate toxicity through down regulation of NMDA receptors, following stimulation of alpha7 nAChRs, could be another mechanism underlying neuroprotection by donepezil, in addition to up regulating the PI3K-Akt cascade or defensive system. PMID- 20718746 TI - Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists. AB - BACKGROUND AND PURPOSE: Bone morphogenetic proteins (BMPs) were first identified through their role in inducing bone and cartilage formation, but many other important functions have since been ascribed to BMPs, including dorsoventral patterning, angiogenesis and tissue homeostasis. Using dorsomorphin and LDN193189, selective small molecule inhibitors of BMP signalling, we investigated the role of BMP signalling in early vascular patterning in zebrafish. EXPERIMENTAL APPROACH: The effects of dorsomorphin and LDN193189 on vascular endothelial growth factor-a (VEGF) and BMP signalling in developing zebrafish and in human pulmonary artery endothelial cells were determined using confocal microscopy, Western blotting and quantitative PCR. KEY RESULTS: We showed that dorsomorphin, similar to the VEGF inhibitor SU5416, strongly inhibits intersegmental vessel formation in zebrafish and that this is due to inhibition of VEGF activation of VEGF receptor 2 (VEGFR2), leading to reduced VEGF-induced phospho-ERK (extracellular regulated kinase) 1/2 and VEGF target gene transcription. These effects occurred at concentrations of dorsomorphin that block BMP signalling. We also showed that LDN193189, an analogue of dorsomorphin, more potently blocks BMP signalling but has no effect on VEGF signalling in zebrafish and does not disrupt early vascular patterning. CONCLUSIONS AND IMPLICATIONS: Dorsomorphin inhibits both BMP and VEGF signalling, whereas LDN193189 is a more selective BMP antagonist. Results obtained in cardiovascular studies using dorsomorphin need to be interpreted with caution, and use of LDN193189 would be preferable due to its selectivity. Our data also suggest that BMP signalling is dispensable for early patterning of intersegmental vessels in zebrafish. PMID- 20718747 TI - beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations. AB - BACKGROUND AND PURPOSE: The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often induces higher binding affinity for agonists. Here, we examined interactions between AT(1A) receptors and beta-arrestins to look for differences between the AT(1A) receptor interaction with beta-arrestin1 and beta-arrestin2. EXPERIMENTAL APPROACH: Ligand-induced interaction between AT(1A) receptors and beta-arrestins was measured by Bioluminescence Resonance Energy Transfer 2. AT(1A)-beta arrestin1 and AT(1A)-beta-arrestin2 fusion proteins were cloned and tested for differences using immunocytochemistry, inositol phosphate hydrolysis and competition radioligand binding. KEY RESULTS: Bioluminescence Resonance Energy Transfer 2 analysis showed that beta-arrestin1 and 2 were recruited to AT(1A) receptors with similar ligand potencies and efficacies. The AT(1A)-beta-arrestin fusion proteins showed attenuated G protein signalling and increased agonist binding affinity, while antagonist affinity was unchanged. Importantly, larger agonist affinity shifts were observed for AT(1A)-beta-arrestin2 than for AT(1A) beta-arrestin1. CONCLUSION AND IMPLICATIONS: beta-Arrestin1 and 2 are recruited to AT(1A) receptors with similar ligand pharmacology and stabilize AT(1A) receptors in distinct high-affinity conformations. However, beta-arrestin2 induces a receptor conformation with a higher agonist-binding affinity than beta arrestin1. Thus, this study demonstrates that beta-arrestins interact with AT(1A) receptors in different ways and suggest that AT(1) receptor biased agonists with the ability to recruit either of the beta-arrestins selectively, would be possible to design. PMID- 20718748 TI - Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide induced TdP arrhythmias is based upon a shared and a different mode of action. AB - BACKGROUND AND PURPOSE: The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca(2+) channel antagonists, flunarizine and verapamil against TdP were investigated. EXPERIMENTAL APPROACH: Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca(2+) sparks in RyR2(R4496+/+) mouse myocytes; and (iii) peak and late I(Na) in SCN5A-HEK 293 cells. KEY RESULTS: Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I(Na). Ca(2+) sparks were reduced with verapamil. CONCLUSIONS AND IMPLICATIONS: Robust anti arrhythmic efficacy was seen with both Ca(2+) channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs. PMID- 20718749 TI - Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery. AB - BACKGROUND AND PURPOSE: Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems. EXPERIMENTAL APPROACH: Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)(2) receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over express recombinant CB(2) receptor. KEY RESULTS: Anandamide and S1P induced relaxation of the rat CA. CB(2) receptor antagonists attenuated anandamide induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P(3). Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P(3), specifically within the vascular endothelium, was required for anandamide mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB(2) receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB(2) receptor was also observed in HEK293 cells over-expressing the CB(2) receptor. CONCLUSIONS AND IMPLICATIONS: In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P(3). In addition, we report that S1P may exert some of its effects via a CB(2) receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P(3) to induce vascular relaxation. PMID- 20718750 TI - alpha-Adrenoceptor-mediated depletion of phosphatidylinositol 4, 5-bisphosphate inhibits activation of volume-regulated anion channels in mouse ventricular myocytes. AB - BACKGROUND AND PURPOSE: Volume-regulated anion channels (VRACs) play an important role in cell-volume regulation. alpha(1)-Adrenoceptor stimulation by phenylephrine (PE) suppressed the hypotonic activation of VRAC current in mouse ventricular cells and regulatory volume decrease (RVD) was also absent in PE treated cells. We examined whether the effects of alpha(1)-adrenoceptor stimuli on VRAC current were modulated by phosphatidylinositol signalling. EXPERIMENTAL APPROACH: Whole-cell patch-clamp method was used to record the hypotonicity induced VRAC current in mouse ventricular cells. RVD was analyzed by videomicroscopic measurement of cell images. KEY RESULTS: The attenuation of VRAC current by PE was suppressed by alpha(1A)-adrenoceptor antagonists (prazosin and WB-4101), anti-G(q) protein antibody and a specific phosphoinositide-specific phospholipase C (PLC) inhibitor (U-73122), but not by antagonists for alpha(1B)-, alpha(1D)- or beta-adrenoceptor, or protein kinase C inhibitors. The inhibition of VRAC by PE was antagonized by intracellular excess phosphatidylinositol 4,5 bisphosphate (PIP(2)), while intracellular anti-PIP(2) antibody (PIP(2) Ab) inhibited the activation of VRAC currents. When cells were loaded with phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) with or without PIP(2) Ab, PE little affected the VRAC current. Extracellular m-3M3FBS (an activator of PLC) suppressed VRAC in the absence of PE, and this effect was reversed by intracellular excess PIP(2). CONCLUSIONS AND IMPLICATIONS: Our results indicate that the stimulation of alpha(1A)-adrenoceptors by PE inhibited the activation of cardiac VRAC current via PIP(3) depletion brought about by PLC-dependent reduction of membrane PIP(2) level. PMID- 20718751 TI - GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo. AB - BACKGROUND AND PURPOSE: Recently identified antagonists of the urotensin-II (U II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity. EXPERIMENTAL APPROACH: The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays. KEY RESULTS: GSK1440115 (pK(i)= 7.34-8.64 across species) and GSK1562590 (pK(i)= 9.14-9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA(2)= 5.59-7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pK(b)= 8.93-10.12 across species), but a competitive antagonist in monkey arteries (pK(b)= 8.87 8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT. CONCLUSIONS AND IMPLICATIONS: Whereas both GSK1440115 and GSK1562590 represent high affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo. PMID- 20718752 TI - Ciprofloxacin inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes. AB - BACKGROUND AND PURPOSE Advanced glycation end products (AGEs) subtypes, proteins or lipids that become glycated after exposure to sugars, can induce complications in diabetes. Among the various AGE subtypes, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) are involved in inflammation in diabetic patients; monocytes are activated by these AGEs. Ciprofloxacin (CIP), a fluorinated 4-quinolone, is often used clinically to treat infections associated with diabetis due to its antibacterial properties. It also modulates immune responses in human peripheral blood mononuclear cells (PBMC) therefore we investigated the involvement of AGEs in these effects. EXPERIMENTAL APPROACH Expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 was examined by flow cytometry. The production of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, prostaglandin E(2) (PGE(2)) and cAMP were determined by enzyme-linked immunosorbent assay. Cyclooxygenase (COX)-2 expression was determined by Western blot analysis. Lymphocyte proliferation was determined by [(3)H]-thymidine uptake. KEY RESULTS CIP induced PGE(2) production in monocytes, irrespective of the presence of AGE-2 and AGE-3, by enhancing COX-2 expression; this led to an elevation of intracellular cAMP in monocytes. Non-selective and selective COX-2 inhibitors, indomethacin and NS398, inhibited CIP-induced PGE(2) and cAMP production. In addition, CIP inhibited AGE-2- and AGE-3-induced expressions of ICAM-1, B7.1, B7.2 and CD40 in monocytes, the production of TNF alpha and IFN-gamma and lymphocyte proliferation in PBMC. Indomethacin, NS398 and a protein kinase A inhibitor, H89, inhibited the actions of CIP. CONCLUSIONS AND IMPLICATIONS CIP exerts immunomodulatory activity via PGE(2), implying therapeutic potential of CIP for the treatment of AGE-2- and AGE-3-induced inflammatory responses. PMID- 20718753 TI - Huaier aqueous extract inhibits proliferation of breast cancer cells by inducing apoptosis. AB - Aqueous extract of Trametes robiniophila murr (Huaier) has been commonly used in China for cancer complementary therapy in recent years; however, the mechanisms of its anticancer effects are largely unknown. In the present study, we aim to investigate its inhibitory effect on both MCF-7 and MDA-MB-231 cells, and explore the possible mechanisms of its anticancer effect. Cell viability and motility were measured by MTT and invasive assays, migration and scratch assays in vitro, respectively. The distribution of cell cycle, PI-Annexin-V staining and Rhodamine 123 assay were analyzed by flow cytometry, and western blot were used to test the apoptotic pathways. We found that Huaier extract could strongly inhibit cell viability of MCF-7 and MDA-MB-231 cells in a time- and dose-dependent manner; however, MDA-MB-231 cells showed more susceptibility to the treatment. Furthermore, cell invasiveness and migration were also suppressed with exposure to Huaier extract. We also indicated that Huaier could induce G0/G1 cell-cycle arrest, p53 accumulation and activation selectively in MCF-7 cells. Inspiringly, the PI-Annexin-V staining assay and western blot analysis confirmed cell apoptosis executed by caspase-3. Decreased mitochondrial membrane potential by Rhodamine 123 assay and down-regulation of Bcl-2 and up-regulation of BCL2 associated X protein (BAX) indicated that Huaier induced apoptosis through the mitochondrial pathway. Caspase activation during Huaier-induced apoptosis was confirmed by pan-caspase inhibitor, Z-VAD-fmk. As expected, the inhibitor decreased Huaier-induced apoptosis in both cell lines. Based on our findings, Huaier can induce cell apoptosis in both ER-positive and ER-negative breast cancer cell lines and is an effective complementary agent for breast cancer treatment. PMID- 20718754 TI - Multicenter, phase II, placebo-controlled, double-blind, randomized study of aprepitant in Japanese patients receiving high-dose cisplatin. AB - Aprepitant is a new neurokinin-1 (NK(1) ) receptor antagonist developed as a treatment for chemotherapy-induced nausea and vomiting (CINV). To evaluate the efficacy and safety of aprepitant used in combination with standard therapy (granisetron and dexamethasone), we conducted a multicenter, phase II, placebo controlled, double-blind, randomized study in Japanese cancer patients who received cancer chemotherapy including cisplatin (>=70mg/m(2) ). Aprepitant was administered for 5days. A total of 453 patients were enrolled. In the three study groups, (i) standard therapy, (ii) aprepitant 40/25mg (40mg on day 1 and 25mg on days 2-5) and (iii) aprepitant 125/80mg (125mg on day 1 and 80mg on days 2-5), the percentage of patients with complete response (no emesis and no rescue therapy) was 50.3% (75/149 subjects), 66.4% (95/143 subjects) and 70.5% (103/146 subjects), respectively. This shows that efficacy was significantly higher in the aprepitant 40/25mg and 125/80mg groups than in the standard therapy group (chi(2) test [closed testing procedure]: P=0.0053 and P=0.0004, respectively) and highest in the aprepitant 125/80mg group. The delayed phase efficacy (days 2-5) was similar to the overall phase efficacy (days 1-5), indicating that aprepitant is effective in the delayed phase when standard therapy is not very effective. In terms of safety, aprepitant was generally well tolerated in Japanese cancer patients. (ClinicalTrials.gov number, NCT00212602.) PMID- 20718755 TI - Tumor antigen analysis in neuroblastoma by serological interrogation of bioinformatic data. AB - The identification of tumor antigens remains a major objective in tumor immunology, especially in pediatric malignancies where solid tumors often do not express a single dominant antigen. Methods such as the Serological Screening of Recombinant cDNA Expression Libraries (SEREX) have been used in the discovery of tumor-expressed proteins by virtue of their ability to induce an antibody response. To focus and accelerate this approach, we first identified candidate antigens by gene expression profiling data from clinical neuroblastoma specimens and then used an animal model to generate an antibody response to an engineered cell-based vaccine. Candidate tumor antigens were expressed as recombinant proteins in a mammalian system and screened for antibody recognition using serum from mice vaccinated with a neuroblastoma cell-based vaccine engineered to express CD80 and CD86, with or without Treg depletion. Through this procedure, the never in mitosis A (NIMA)-related kinase NEK2 was identified as a tumor associated antigen. Direct testing of serum from patients newly diagnosed with neuroblastoma showed specific serological responses in two of 20 patients. Although NEK2 was not universally recognized, it may serve as a tumor antigen for some patients. PMID- 20718756 TI - ABCC11/MRP8 confers pemetrexed resistance in lung cancer. AB - We have previously shown that overexpression of thymidylate synthetase (TS) resulted in pemetrexed (MTA) resistance. To investigate another mechanism of MTA resistance, we investigated the expression of ATP-binding cassette (ABC) transporters in MTA-resistant lung cancer cell lines and found that the gene and protein expression of ABCC11/MRP8 (ABCC11) was higher in MTA-resistant cells than in the parental cells. The MTA resistant cells showed cross-resistance to methotrexate (MTX), which is a substrate for ABCC11, and intracellular MTX accumulation in MTA-resistant cells was lower than in the parental cells. We then tested the effect of decreasing the expression of ABCC11 by siRNA and found that decreased expression of ABCC11 enhanced MTA cytotoxicity and increased intracellular MTX accumulation in MTA-resistant cells. These findings suggested that ABCC11 directly confers resistance to MTA by enhancing efflux of the intracellular anti-cancer drug. Next, we analyzed the relationship between ABCC11 gene expression and MTA sensitivity of 13 adenocarcinoma cells, but there was no correlation. The ABCC11 gene has been shown to have a functional single nucleotide polymorphism (SNP), 538G>A. We then classified 13 lung adenocarcinoma cell lines into three groups based on the genotype of this ABCC11 SNP: G/G, G/A and A/A. The A/A group showed a significant reduction in the IC(50) of MTA compared with the combined G/G and G/A groups, indicating that the SNP (538G>A) in the ABCC11 gene is an important determinant of MTA sensitivity. These results showed that ABCC11 may be one of the biomarkers for MTA treatment in adenocarcinomas. PMID- 20718757 TI - Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-beta-disrupted diffuse-type gastric carcinoma. AB - Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-beta and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-beta signaling via introduction of a dominant negative form of the TGF-beta type II receptor (dnTbetaRII) into diffuse type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-beta induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnTbetaRII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnTbetaRII expression, which was completely abolished when TIMP2 was coexpressed with dnTbetaRII. Although the blood vessel density of TIMP2 expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2. PMID- 20718758 TI - Prognosis of percutaneous coronary intervention and coronary artery bypass grafts for ostial right coronary lesions in propensity-matched individuals. AB - OBJECTIVE: Our aim was to evaluate the relative safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass grafts (CABG) for the treatment of ostial right coronary stenosis (ORCS) lesions. METHODS: Three hundred fifty-nine cases of ORCS lesion were treated via CABG (n = 232) or PCI (n = 127) procedures. Propensity scores for undergoing the CABG procedure were estimated and used to match 105 pairs of patients between the two groups. Kaplan-Meier major adverse cardiac and cerebrovascular events (MACCE)-free curves were constructed to compare long-term MACCE-free survival between the two groups. RESULTS: For the 105 propensity matched pairs, patients were more likely to undergo repeat revascularization with CABG in the PCI group than in the CABG group during the first 30 days (4 cases vs. 0 case, P= 0.043, chi(2) = 4.08) and the 1-year follow-up (5 cases vs. 0 case, P= 0.02, chi(2) = 5.17). With a mean follow-up of 12.04 +/- 6.47 months and a total of 210.67 patient-years, the freedom from MACCE in the CABG group was significantly higher than that in the PCI group (Log rank test, chi(2) = 4.48, P= 0.03). There were no significant differences in the rates of death, myocardial infarction, nonfatal stroke, death/myocardium infarction/stroke, or repeated PCI between the two groups during the first 30 days and during the 1-year follow-up period. CONCLUSION: For OCRS lesions, CABG provided greater protection than PCI procedure in terms of freedom from MACCE, mainly due to the reduced number of repeated revascularization procedures. CABG should be considered as first-choice revascularization strategy for ORCS lesions. PMID- 20718759 TI - Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. AB - The prevalence of diabetes has dramatically increased worldwide due to the vast increase in the obesity rate. Diabetic nephropathy is one of the major complications of type 1 and type 2 diabetes and it is currently the leading cause of end-stage renal disease. Hyperglycemia is the driving force for the development of diabetic nephropathy. It is well known that hyperglycemia increases the production of free radicals resulting in oxidative stress. While increases in oxidative stress have been shown to contribute to the development and progression of diabetic nephropathy, the mechanisms by which this occurs are still being investigated. Historically, diabetes was not thought to be an immune disease; however, there is increasing evidence supporting a role for inflammation in type 1 and type 2 diabetes. Inflammatory cells, cytokines, and profibrotic growth factors including transforming growth factor-beta (TGF-beta), monocyte chemoattractant protein-1 (MCP-1), connective tissue growth factor (CTGF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-18 (IL-18), and cell adhesion molecules (CAMs) have all been implicated in the pathogenesis of diabetic nephropathy via increased vascular inflammation and fibrosis. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species are a primary candidate. Thus, targeting oxidative stress-inflammatory cytokine signaling could improve therapeutic options for diabetic nephropathy. The current review will focus on understanding the relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy to help elucidate the question of which comes first in the progression of diabetic nephropathy, oxidative stress, or inflammation. PMID- 20718760 TI - Atrial fibrillation and dabigatran: has the time come to use new anticoagulants? AB - Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance found in clinical practice, increasing in prevalence with age. AF is often associated with structural heart disease, although a significant proportion has no detectable heart disease. In the last 2 decades, there has been an increase of 66% in hospitalizations for AF, and it is an extremely costly public health problem. AF is associated with an increased long-term risk of stroke, heart failure, and all-cause mortality. In fact, the mortality rate in patients with AF is about double that of patients in normal sinus rhythm. Antithrombotic therapy is recommended for all patients with AF to prevent thromboembolism, except those with lone AF or contraindications. Selection of the antithrombotic agent should be based upon the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient. However, despite oral anticoagulation with vitamin K antagonists (warfarin or acenocoumarol) some patients still have thromboembolic events. Furthermore, for the majority of patients, international normalized ratio (INR) monitoring may be an inconvenience. This is why new anticoagulants, such as the direct thrombin inhibitors, are being investigated. The results of the RE-LY trial have recently been published. In this study, in a population of patients with AF, dabigatran at 110 mg b.i.d was associated with stroke and systemic embolism rates similar to those associated with warfarin, and with lower rates of major hemorrhage. However, when dabigatran was administered at a dose of 150 mg, lower rates of stroke and systemic embolism and similar rates of major hemorrhage were found compared with warfarin. The aim of this review is to update information on the prevention of thromboembolic events in patients with AF and how dabigatran may change daily clinical practice. PMID- 20718761 TI - Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. AB - Anyone who has been in an endocrine clinic will appreciate that associations exist between autoimmune thyroid disease (AITD) and other autoimmune disorders. However, the full extent of these associations is still not fully appreciated, and new associations are being uncovered which may shed new light on the pathogenic basis for these connections, and the underlying reasons for them are only now becoming understood. This review is based on the British Thyroid Association Pitt-Rivers Lecture 2010. The first section provides an update on studies which have detailed the strength of various autoimmune disease associations, the second section discusses the environmental and genetic factors which underlie these associations and the final section describes some recently identified, unexpected AITD associations. Unravelling these associations further will illuminate the pathogenesis of autoimmune diseases and offers the prospect of new therapeutic approaches. PMID- 20718762 TI - Morbidity and mortality in mild primary hyperparathyroidism. PMID- 20718763 TI - Adrenal function and mortality in children and adolescents with Prader-Willi syndrome attending a single centre from 1991-2009. PMID- 20718764 TI - Sex steroids and mortality in men referred for coronary angiography. AB - OBJECTIVE: Accumulating evidence suggests that sex steroids are associated with various chronic diseases. We aimed at evaluating whether total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG) are associated with all-cause mortality and specific fatal events. DESIGN, SETTING AND PARTICIPANTS: We measured TT and SHBG levels in 2078 men who were routinely referred for coronary angiography (1997-2000). FT was calculated according to Vermeulen. MEASUREMENTS: The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non cardiovascular causes and from cancer according to SHBG, FT and TT. RESULTS: Multivariable-adjusted HRs (with 95% confidence intervals) in the fourth compared to the first SHBG quartile for all-cause, non-cardiovascular and cancer mortality were 1.61 (1.16-2.23), 2.44 (1.39-4.28), and 2.86 (1.03-7.32), respectively. There was no significant association of SHBG levels with cardiovascular mortality. All-cause mortality was significantly reduced per 1 SD increase in FT in the multivariate-adjusted analyses [0.49 (0.30-0.81)]. We observed no significant associations of FT with cardiovascular and cancer mortality, and TT levels were not independently related to any fatal events. CONCLUSION: High levels of SHBG are associated with adverse health outcomes in a large cohort of older men referred for coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms for our findings. PMID- 20718765 TI - Characterization of a novel loss-of-function mutation of PAX8 associated with congenital hypothyroidism. AB - BACKGROUND: Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80-85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30-45%), absent (agenesis, 35-40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD. OBJECTIVE: Our aim was to identify and functionally characterize novel PAX8 mutations with autosomal dominant transmission responsible for TD. DESIGN: The PAX8 gene was sequenced in a mother and child both suffering from congenital hypothyroidism (CH) because of thyroid hypoplasia. Subsequently, expression vectors encoding the mutated PAX8 were generated, and the effects of the mutation on both the DNA-binding capability and the transcriptional activity were evaluated. RESULTS: PAX8 gene sequencing revealed a heterozygous mutation that consists of the substitution of a histidine residue with a glutamine at position 55 of the PAX8 protein (H55Q). When tested in cotransfection experiments with a thyroglobulin promoter reporter construct, the mutant protein turned out to be still able to bind DNA in Electrophoretic Mobility Shift Assay assays but transcriptionally inactive. CONCLUSIONS: Our findings confirm the important role of PAX8 in normal thyroid development and support the evidence that in humans haploinsufficiency of PAX8 is associated with TD. PMID- 20718766 TI - Recombinant human prolactin for the treatment of lactation insufficiency. AB - CONTEXT: Lactation insufficiency has many aetiologies including complete or relative prolactin deficiency. Exogenous prolactin may increase breast milk volume in this subset. We hypothesized that recombinant human prolactin (r-hPRL) would increase milk volume in mothers with prolactin deficiency and mothers of preterm infants with lactation insufficiency. DESIGN: Study 1: R-hPRL was administered in an open-label trial to mothers with prolactin deficiency. Study 2: R-hPRL was administered in a randomized, double-blind, placebo-controlled trial to mothers with lactation insufficiency that developed while pumping breast milk for their preterm infants. PATIENTS: Study 1: Mothers with prolactin deficiency (n = 5). Study 2: Mothers of premature infants exclusively pumping breast milk (n = 11). DESIGN: Study 1: R-hPRL (60 MUg/kg) was administered subcutaneously every 12 h for 28 days. Study 2: Mothers of preterm infants were randomized to receive r-hPRL (60 MUg/kg), placebo or r-hPRL alternating with placebo every 12 h for 7 days. MEASUREMENTS: Change in milk volume. RESULTS: Study 1: Peak prolactin (27.9 +/- 17.3 to 194.6 +/- 19.5 MUg/l; P < 0.003) and milk volume (3.4 +/- 1.6 to 66.1 +/- 8.3 ml/day; P < 0.001) increased with r-hPRL administration. Study 2: Peak prolactin increased in mothers treated with r-hPRL every 12 h (n = 3; 79.3 +/- 55.4 to 271.3 +/- 36.7 MUg/l; P < 0.05) and daily (101.4 +/- 61.5 vs 178.9 +/- 45.9 MUg/l; P < 0.04), but milk volume increased only in the group treated with r-hPRL every 12 h (53.5 +/- 48.5 to 235.0 +/- 135.7 ml/day; P < 0.02). CONCLUSION: Twice daily r-hPRL increases milk volume in mothers with prolactin deficiency and in preterm mothers with lactation insufficiency. PMID- 20718767 TI - Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. AB - OBJECTIVE: Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG. DESIGN: Because consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families. PATIENTS: Hundred and thirty-nine children with CHNG phenotype born to consanguineous families. MEASUREMENTS: First, we investigated cases for evidence of linkage to the four known CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition, in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation specific disease phenotype. RESULTS: Homozygous germline TSHR mutations were detected in six families (5%), but no mutations were detected in PAX8, TSHB and NKX2-5. Four of TSHR mutations had not previously been described. Genotype phenotype correlations were established and found to be related to the predicted structural effects of the mutations. CONCLUSIONS: Known causative genes account for the development of CHNG only in a minority of cases, and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG. PMID- 20718768 TI - The pituitary-thyroid axis set point in women is uninfluenced by X chromosome inactivation pattern? A twin study. AB - OBJECTIVE: The pituitary-thyroid axis (PTA) set point is determined by a combination of genetic and environmental factors. However, despite considerable efforts to characterize the background, the causative genes as well as environmental factors are not well established. Theoretically, as shown for autoimmune thyroid disease, the pattern of X chromosome inactivation (XCI) could offer a novel explanation for the observed variability of the PTA set point in women. DESIGN AND PATIENTS: To examine the impact of XCI pattern on the PTA set point, we studied whether within-cohort (n = 318 subjects) and within-twin pair (n = 159 pairs) differences in XCI are correlated with serum concentrations of thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). METHODS: X chromosome inactivation was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid variables were measured using a solid-phase time-resolved fluoroimmunometric assay. Zygosity was established by DNA fingerprinting. RESULTS: In the overall study population (within cohort), no significant correlations were found between TSH [regression coefficient (beta) = -0.28 (95% confidence intervals, -0.66 to 0.11), P = 0.158], FT3 [beta = -0.25 (-0.85 to 0.34), P = 0.403], FT4 [beta = 0.08 (-0.91 to 1.07), P = 0.876] and XCI pattern. Essentially similar results were found in the within pair analysis. Controlling for confounders such as age, body mass index, smoking and zygosity did not change the findings. CONCLUSIONS: In a sample of female twins, we found no evidence of a relationship between XCI pattern and PTA set point. PMID- 20718769 TI - Vitamin D status and PTH in young men: a cross-sectional study on associations with bone mineral density, body composition and glucose metabolism. AB - OBJECTIVE: Although vitamin D and bone metabolism are closely related, few studies have addressed the effects of vitamin D status on bone in men at time of peak bone mass. The objectives of this study were to evaluate the prevalence of vitamin D inadequacy in a cross-sectional study in young men and the effects of vitamin D and parathyroid hormone (PTH) on bone mass, bone markers and metabolic function. DESIGN AND PARTICIPANTS: The study population consisted of 783 men aged 20-29 years. MEASUREMENTS: Bone mineral density (BMD) of the total hip, femoral neck and lumbar spine was measured. dual-energy X-ray absorptiometry was used to evaluate total body fat mass (BFAT). Visceral fat mass and abdominal subcutaneous fat mass (ViFM and ScFM) were assessed using magnetic resonance imaging. A radioimmunoassay was used to measure the level of 25-hydroxy vitamin D (25OHD). RESULTS: The prevalence of vitamin deficiency (serum 25OHD < 50 nm) was 6.3% during summer and 43.6% during winter. Serum 25OHD was associated with BMD at all sites and inversely associated with bone-specific alkaline phosphatase and directly with carboxyterminal telopeptide of type-1-collagen. 25OHD and PTH were inversely associated with BFAT, whereas 25OHD also was inversely associated with body mass index, waist-hip ratio, ViFM and ScFM after adjustment for confounders. The associations were found only to be present in participants with insufficient levels of 25OHD. 25-Hydroxy vitamin D and PTH were inversely related to insulin resistance in vitamin-insufficient participants only. No associations between PTH or 25OHD and blood pressure were noted. CONCLUSION: The study showed a high prevalence of 25OHD deficiency in young, northern European men, which was significantly associated with decreased BMD. PTH and 25OHD were found to be inversely related to the markers of insulin resistance. PMID- 20718770 TI - High thyrotrophin levels at end term increase the risk of breech presentation. AB - OBJECTIVE: To study the relationship between maternal thyrotrophin (TSH) and breech presentation at term. DESIGN: Combined data sets of two prospective studies to obtain adequate epidemiological power. PATIENTS: One thousand and fifty-eight healthy pregnant women (58 breech, 1000 cephalic) and 131 women who presented in breech at an obstetrical outpatient clinic. MEASUREMENTS: Maternal thyroid parameters [TSH, free thyroid hormone (FT4), thyroid peroxidase antibody (TPO-Ab)] and foetal presentation were assessed in both groups between 35 and 38 weeks gestation. Power calculations suggested that at least 148 breech cases were required. RESULTS: The characteristics of the women in breech in both samples were similar. Women in breech (n = 58 + 131) had significantly higher TSH (but not FT4) than those (n = 1000) with cephalic presentation (Mann-Whitney U-test, P = 0.003). Different cut-offs were used to define high TSH in the 916 TPO-Ab negative women with cephalic presentation: the 90th, 95th and 97.5th percentiles were 2.4 mIU/l (n = 149), 2.7 mIU/l (n = 77) and 3.2 mIU/l (n = 37). The prevalence rates of breech presentation in these women were all higher compared to the prevalence of breech in women below these cut-offs (df = 1, P < 0.01). The relative risk of the 149 women with a TSH >90th percentile (>2.4 mIU/l) to present in breech was 1.82 (95% CI: 1.30-2.56). CONCLUSIONS: Women with high TSH at end term are at risk for breech presentation. Substantial evidence for a relation between breech presentation and neurodevelopmental delay exists. As high TSH during gestation has also been linked to poor neurodevelopment, the relation between breech presentation and poor neurodevelopment might be thyroid-related. PMID- 20718771 TI - Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. AB - OBJECTIVE: Men with the metabolic syndrome (MetS) have low plasma testosterone (T) levels. The aim of this study was to establish whether the normalization of plasma T improves the features of the MetS. DESIGN: A randomized, placebo controlled, double-blinded, phase III trial of 184 men suffering from both the MetS and hypogonadism. PATIENTS: One hundred and eighty-four men, aged 35-70, with the MetS and hypogonadism (baseline total T level <12.0 nm or calculated free T level <225 pm.), recruited in the outpatient andrology and urology clinic, Research Center for Endocrinology in Moscow, Russia. INTERVENTION: Treatment for 30 weeks with either parenteral T undecanoate (n = 113; TU; 1000 mg IM) or placebo (n = 71), administered at baseline, and after 6 and 18 weeks. One hundred and five (92.9%) men receiving TU and 65 (91.5%) receiving placebo completed the trial. MEASUREMENTS: Body weight, body mass index (BMI), waist circumference (WC), hip circumference, waist-to-hip ratio, insulin, leptin, glucose, cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein (CRP), interleukin-1-beta (IL-1beta), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-alpha). RESULTS: There were significant decreases in weight, BMI and WC in the TU vs placebo group. Levels of leptin and insulin also decreased, but there were no changes in serum glucose or lipid profile. Of the inflammatory markers, IL-1beta, TNF-alpha and CRP decreased, while IL-6 and IL-10 did not change significantly. CONCLUSIONS: Thirty weeks of T administration normalizing plasma T in hypogonadal men with the MetS improved some components of the MetS and a number of inflammatory markers. PMID- 20718772 TI - A case of Takotsubo's cardiomyopathy and multiple endocrine neoplasia 2A syndrome. PMID- 20718773 TI - Multiple doses of pegylated long-acting growth hormone are well tolerated in healthy male volunteers and possess a potential once-weekly treatment profile. AB - OBJECTIVES: Recombinant human growth hormone (rhGH) replacement therapy in children and adults currently requires daily subcutaneous injections for several years or lifelong. The current study examined safety, tolerability, pharmacokinetic and pharmacodynamic response parameters after single and multiple doses of a long-acting rhGH preparation (NNC126-0083). DESIGN: Randomized, double blinded, placebo-controlled, multiple-dose, dose-escalating (0.02, 0.04, 0.08 and 0.16 mg protein/kg), sequential dose group trial. SUBJECTS: Forty adult Japanese healthy male volunteers (aged 20-45; body mass index: 18.0-27.0 kg/m(2)). Five groups (n = 8) were randomized to receive multiple doses of NNC126-0083 (n = 6) or placebo (n = 2). METHODS: Primary outcome was safety, and tolerability of multiple doses of NNC126-0083 compared with placebo. Blood samples for the assessment of pharmacokinetics (PK) and pharmacodynamics response [insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3)] were taken after multiple ascending doses. RESULTS: NNC126-0083 was well tolerated and not associated with any local injection-site reactions or lipoatrophy. Following administration, NNC126-0083 levels increased rapidly and remained elevated for several days, returning to baseline before each weekly injection. Steady-state PK was achieved after the third dosing. A more than dose-proportional exposure was observed at the highest NNC126-0083 dose (0.16 mg protein/kg). A strong dose dependent pharmacodynamic response in circulating concentrations of both IGF-I and IGFBP-3 compared with placebo (P < 0.0001) was observed during the administration of all doses. CONCLUSIONS: Multiple administration of NNC126-0083 in healthy male volunteers indicates that NNC126-0083 has the potential for an efficacious, well-tolerated, once-weekly rhGH compound in the treatment of GH deficiency. PMID- 20718774 TI - AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED. AB - OBJECTIVE: To assess autoimmune regulator (AIRE) gene mutations, class II HLA haplotypes, and organ- or non-organ-specific autoantibodies in patients with chronic hypoparathyroidism (CH) without associated Addison's disease (AD) or chronic candidiasis (CC). DESIGN, PATIENTS AND MEASUREMENTS: Twenty-four patients who had CH without AD or CC were included in the study. AIRE gene mutations in all 14 exons were studied using PCR in 24 patients, 105 healthy controls and 15 first-degree relatives of CH patients with AIRE mutations. Human leucocyte antigens (HLA) were determined for all 24 patients and 105 healthy controls. Autoantibodies to a range of antigens including NACHT leucine-rich-repeat protein 5 (NALP5) and interferon omega (IFNomega) were tested in all 24 patients. RESULTS: AIRE gene mutations were found in 6 of 24 (25%) patients, all females, and this was significantly higher (P < 0.001) compared with AIRE mutations found in healthy controls (2/105). Three patients (12.5%) had homozygous AIRE mutations characteristic of Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal-Dystrophy and all three were also positive for IFNomega-autoantibodies. Three patients (12.5%) had heterozygous AIRE mutations; two of these were novel mutations. One of the patients with heterozygous AIRE mutations was positive for both NACHT leucine-rich-repeat protein 5 and IFNomega autoantibodies. Heterozygous AIRE mutations were found in 10 of 15 first-degree relatives of CH patients with AIRE mutations, although none was affected by CH. Class II HLA haplotypes were not statistically different in patients with CH compared to healthy controls. CONCLUSIONS: Analysis of AIRE gene mutations together with serum autoantibody profile should be helpful in the assessment of patients with CH, in particular young women with associated autoimmune diseases. PMID- 20718775 TI - How do you monitor the patient with Turner's syndrome in adulthood? AB - Within endocrinology, the long-term management of Turner syndrome (TS) in adults is fast becoming a specialist subject in its own right. The complications of TS can affect every system in the body, and the main reason why it falls to endocrinologists to coordinate health care is that many features are clearly within the endocrine remit: hypothyroidism, diabetes, hypertension, osteoporosis, hypogonadism. Endocrinologists as general physicians can often cover surveillance of problems in other areas such as congenital heart disease, inflammatory bowel disease and deafness, calling upon specialist input only if the need arises. In this way, a simple 'one stop shop' can offer a well-woman service for women with TS in a cost-effective manner. Such a service requires a multidisciplinary approach. PMID- 20718777 TI - Diclofenac enhances allergic responses in a mouse peanut allergy model. AB - BACKGROUND: Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) interfere with cyclo-oxygenase-mediated synthesis of prostaglandins, resulting in the inhibition of inflammatory immune responses. In contrast, it is known that NSAIDs are able to induce gastrointestinal damage. OBJECTIVE: Our aim was to investigate whether NSAIDs are able to enhance sensitization or abrogate tolerance to food antigens. METHODS: Mice were exposed to diclofenac and sensitized to peanut using cholera toxin as a mucosal adjuvant. In a tolerance model, oral tolerance was induced via feeding of peanut 3 weeks before sensitization with peanut. Diclofenac was administered before peanut feeding. After 4 weeks, peanut-specific antibodies in the serum and cytokine production in the spleen were measured. Induction of intestinal damage after oral exposure with diclofenac and peanut + cholera toxin was examined microscopically. RESULTS: Diclofenac-exposed animals showed increased levels of peanut-specific IgG1, IgG2a and IgE in the serum compared with vehicle-treated animals. Furthermore, peanut induced cytokine production in the spleen was elevated upon diclofenac treatment. Importantly, diclofenac did not induce peanut-allergic responses in the absence of the cholera toxin, although exposure to diclofenac and peanut + cholera toxin resulted in intestinal epithelial damage. Reduced peanut-specific antibody production in the case of oral tolerance was not reversed after diclofenac exposure. However, oral tolerance, as measured by inhibition of peanut-specific cytokine responses, was reverted by diclofenac. CONCLUSIONS: These data point towards an increased risk for induction of food-allergic responses by diclofenac, when other circumstances are also in favour of induction of allergy. PMID- 20718778 TI - Environmental epigenetics and allergic diseases: recent advances. AB - Significant strides in the understanding of the role of epigenetic regulation in asthma and allergy using both epidemiological approaches as well as experimental ones have been made. This review focuses on new research within the last 2 years. These include advances in determining how environmental agents implicated in airway disease can induce epigenetic changes, how epigenetic regulation can influence T helper cell differentiation and T regulatory cell production, and new discoveries of epigenetic regulation associated with clinical outcomes. PMID- 20718779 TI - Body mass index in young children and allergic disease: gender differences in a longitudinal study. AB - BACKGROUND: The increase in allergic diseases has occurred in parallel with the obesity epidemic, suggesting a possible association. OBJECTIVE: We investigated the relationship of body mass index (BMI) up to age 8 years with allergic disease within a birth cohort. METHODS: Children were followed from birth and were reviewed at age 3, 5 and 8 years (n=731; male 406). Parents completed questionnaires; children were weighed, measured, skin prick tested and examined. RESULTS: Increasing BMI at 3, 5 and 8 years increased the risk of current wheezing at the corresponding age (odds ratio [95% confidence interval] per standardized deviation score: age 3, 1.26 [1.04-1.53], P=0.02; age 5, 1.33 [1.06 1.67], P=0.02; age 8, 1.27 [1.0-1.62], P=0.05). The effect of BMI on wheeze at age 8 years differed between boys and girls, with a significant positive association in girls, but not in boys (P=0.04 for interaction). The effect of BMI at earlier ages on current or subsequent wheezing did not differ significantly between genders. Increasing BMI significantly increased the risk of physician diagnosed eczema at age 5 (1.23 [1.04-1.47], P=0.02) and 8 (1.23 [1.03-1.45], P=0.02), with a significant interaction between gender and BMI at age 5 (P=0.04). There was no association between BMI and sensitization. Being overweight at age 3 years was significantly associated with late-onset wheeze (3.83 [1.51-9.75], P=0.005), persistent wheeze (4.15 [2.07-8.32], P<0.001) and persistent eczema (1.79 [1.03-3.13], P=0.04) in both boys and girls. CONCLUSIONS: Being overweight is associated with an increased risk of allergic disease in childhood. However, the strength of the association varies with the gender, age and atopic phenotype. PMID- 20718780 TI - Unique populations of lung mast cells are required for antigen-mediated bronchoconstriction. AB - BACKGROUND: Studies in both human and mouse indicate that mediators released by mast cells can lead to bronchoconstriction, and thus these are important effector cells in lifethreatening anaphylaxis. Much of our understanding of the various functions of mast cells emanates from the study of mice lacking these cells, particularly mice carrying mutations in the tyrosine kinase gene Kit. Definitive evidence for the role of mast cells in the altered immune response requires the demonstration that this response can be normalized by reconstitution of the mice with cultured bone marrow-derived mast cells (BMMCs). While many mast cell niches can be restored with BMMCs, this has not been demonstrated for mast cells present in the airways of the lung, cells poised to mediate bronchoconstriction during allergic responses. OBJECTIVE: To determine if mast cell-deficient Kit(Wsh/Wsh) reconstituted lines are an appropriate model for the study of the role of these cells in bronchoconstriction associated with allergic responses. METHODS: Kit(Wsh/Wsh) mice were reconstituted with either whole bone marrow (WBM) or BMMCs and responses to IgE-mediated mast cell activation were determined; including systemic hypothermia, mediator release, and bronchoconstriction in anaesthetized, mechanically ventilated animals. RESULTS: Engraftment of Kit(Wsh/Wsh) mice with WBM and BMMCs results in reconstitution of the central airways with mast cells. While the treatment of the two groups of animals resulted in systemic changes when challenged with IgE/Ag in a model of passive anaphylaxis, bronchoconstriction was observed only in kit(Wsh/Wsh) animals, which had received a bone marrow transplant. CONCLUSIONS: While BMMCs can populate the lung, they cannot restore IgE/Ag-mediated bronchoconstriction to mast cell-deficient animals. This suggests that the mast cell population, which mediates this function, may be unique, and to fill this niche in the lung cells must undergo a specific developmental programme, one that is no longer available to cultured mast cells. PMID- 20718781 TI - Serum total tryptase levels are increased in patients with active chronic urticaria. AB - BACKGROUND: We have demonstrated previously mast cell histamine release upon incubation with chronic urticaria (CU) sera, presumably by degranulation. OBJECTIVE: To explore total and mature tryptase in order to assess whether any increase in total tryptase levels is due in part to mast cell degranulation or to mast cell burden. We also wanted to explore differences between the autoimmune groups called idiopathic (serum unable to activate basophils), and to correlate total and mature tryptase levels with different urticaria features. METHODS: We measured total and mature tryptase serum levels in 81 CU patients, 16 atopic donors and 21 healthy control sera. We assessed autoimmunity by measuring the CD63 expression in normal basophil donors upon incubation with CU sera. RESULTS: We found significantly higher levels of total tryptase in the sera of CU patients (6.6 +/-4.1 MUg/L) than in sera from healthy non-atopic subjects (4.4 +/-2.8 MUg/L) and from atopic subjects (4.5 +/-1.7 MUg/L). Mature tryptase levels were undetectable (<1 ng/mL). Total tryptase levels in the autoimmune urticaria group were significantly higher (9.8 +/-5.4 MUg/L) than the idiopathic urticaria group (4.4 +/-2.2 MUg/L). A significant difference in total tryptase was found between symptomatic patients (7.3 +/-4.1 MUg/L) compared with asymptomatic ones (5.7 +/ 4.1 MUg/L) at the time of venesection. No difference was found in mature tryptase levels either. CONCLUSION: Total elevated tryptase levels are not accompanied by an elevated mature tryptase levels, as might be expected if the serum levels reflected mast cell degranulation. PMID- 20718782 TI - Vigilance in industry: cosmetics and household cleaning products. Balance sheet of case report from 2005 to 2007. AB - BACKGROUND: Unlike medicinal products, cosmetics are not subject to marketing authorization in France. Nevertheless, the Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS; French Agency for the Safety of Healthcare Products) has been working on the development of a cosmetovigilance system for several years, with the aim of establishing standard procedures for collecting adverse reactions to cosmetics from the manufacturers. AIM: To assess the incidence of skin reactions to cosmetics or household products. Unilever established its own 'vigilance' standard system in France in late 2003. This report describes the experience acquired from 2005 to 2007. METHODS: Case reports were collected in compliance with a standard procedure. The cases were then analysed by the consultant dermatologist in accordance with a pharmacovigilance based method (chronological criteria, clinical criteria, possible rechallenge test, patch tests). RESULTS: During the period 2005 to 2007, a total of 102,689 consumers contacted the consumer department, including 842 (0.82%) who reported skin reactions. After analysis of the collected data, 0.144 skin reaction cases per million units sold were found to be attributable to cosmetic or household products. CONCLUSIONS: The implementation of a structured vigilance system in the cosmetics and household products industry is an efficient tool for manufacturers, both for information purposes and for product improvement, as well as meeting the transparency requirements of health authorities and consumers. PMID- 20718783 TI - The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease. AB - The study is designed to investigate the changes and roles of T helper type 17/regulatory T cells (Th17/T(reg) ) in the immunological pathogenesis of Kawasaki disease (KD). In addition, we explore the alteration and significance of Th17 cells in patients with intravenous immune globulin-resistant KD. Real-time polymerase chain reaction (PCR) was used to evaluate the mRNA levels of interleukin (IL)-17A/F, retinoic acid-related orphan receptor (ROR)-gammat and forkhead box P3 (FoxP3) in CD4-positive cells. The proportions of Th17 cells and CD4(+) CD25(+) FoxP3(high) T(regs) were analysed by flow cytometry. Plasma cytokine [IL-17A, IL-6, IL-23 and transforming growth factor (TGF)-beta] concentrations were measured by sandwich enzyme-linked immunosorbent assay. Our data demonstrate that Th17 proportions and expression levels of cytokines (IL-17, IL-6 and IL-23) and transcription factors (IL-17A/F, ROR-gammat) were up regulated significantly, while T(reg) proportions and expression levels of T(reg ) transcription factor (FoxP3) were down-regulated significantly in children with acute KD (P<0.01). Compared with the sensitive group, the Th17 proportions were up-regulated significantly during the acute phase in immune globulin-resistant KD (P < 0.01). The plasma IL-17A, IL-6 and IL-23 concentrations in patients with KD were significantly higher compared with the concentrations in normal controls (NC) and infectious disease (ID). Plasma TGF-beta concentrations were markedly lower in the KD group than the NC and ID groups (P < 0.05). These results suggest that Th17/T(reg) cells imbalance exists in the patients with KD. Th17/T cells imbalance may be important factors causing disturbed immunological function and resulting in immunoglobulin-resistant KD. PMID- 20718784 TI - Use of bioluminescence imaging to track neutrophil migration and its inhibition in experimental colitis. AB - Inflammatory bowel disease (IBD) is associated with neutrophil infiltration into the mucosa and crypt abscesses. The chemokine interleukin (IL)-8 [murine homologues (KC) and macrophage inflammatory protein (MIP)-2] and its receptor CXCR2 are required for neutrophil recruitment; thus, blocking this engagement is a potential therapeutic strategy. In the present study, we developed a preclinical model of neutrophil migration suitable for investigating the biology of and testing new drugs that target neutrophil trafficking. Peritoneal exudate neutrophils from transgenic beta-actin-luciferase mice were isolated 12h after intraperitoneal injection with thioglycollate, and were assessed phenotypically and functionally. Exudate cells were injected intravenously into recipients with dextran sodium sulphate (DSS)-induced colitis followed by bioluminescence imaging of whole-body and ex vivo organs at 2, 4 and 16-22h post-transfer. Anti-KC antibody or an isotype control were administered at 20 ug/mouse 1h before transfer, followed by whole-body and organ imaging 4h post-transfer. The peritoneal exudate consisted of 80% neutrophils, 39% of which were CXCR2(+) . In vitro migration towards KC was inhibited by anti-KC. Ex vivo bioluminescent imaging showed that neutrophil trafficking into the colon of DSS recipients was inhibited by anti-KC 4h post-cell transfer. In conclusion, this study describes a new approach for investigating neutrophil trafficking that can be used in preclinical studies to evaluate potential inhibitors of neutrophil recruitment. PMID- 20718785 TI - Bifocal lens control of myopic progression in children. AB - Bifocal spectacle lenses have been used as a strategy to slow myopic progression in children since the 1950s and perhaps earlier. The reported success of this strategy varies greatly, as does the design of studies reporting the outcomes of their use-from earlier retrospective analysis of records to later prospective clinical trials. Collectively, published data support the suggestion that bifocal lenses inhibit myopic development in children but only by a small amount and only in a subset of children. Possible reasons for the greatly varying outcomes include a lack of individualism of the treatment and failure to take the vergence system into account. This review summarises the results of bifocal and multifocal studies, describes how accommodation, convergence and their interaction are linked to myopic development and details how a bifocal treatment that takes this into account may be devised. Also discussed is whether alterations to peripheral retinal blur contribute to bifocal lens effects. PMID- 20718786 TI - Corneal imaging with slit-scanning and Scheimpflug imaging techniques. AB - Modern anterior segment imaging techniques, such as slit-scanning and Scheimpflug imaging, greatly improved the field of corneal imaging. Devices such as the Orbscan (Bausch & Lomb Surgical, Inc) and, more recently, the Pentacam (Oculus, Inc) and the Galilei (Ziemer Ophthalmic Systems AG) have brought a whole new range of clinical possibilities and sparked interest in the academic community. These new tomographers create three-dimensional models of the cornea and enable the direct measurement of both the anterior and posterior surface elevations. In this paper, we present a review of some available literature on those systems, regarding their optical principles and their performance in current clinical applications. PMID- 20718787 TI - Sarcoidosis presenting as acute bulbar follicular conjunctivitis. PMID- 20718788 TI - Multiple evanescent white dot syndrome: a review and case report. AB - BACKGROUND: Multiple evanescent white dot syndrome (MEWDS) is a rare chorioretinal syndrome that usually presents with a unilateral, multifocal retinitis affecting mostly young women. The typical presentation includes multiple white spots extending from the posterior pole out to the mid-peripheral retina, possible vitritis and a granular appearance to the fovea. Symptoms can include a prodromal flu-like episode, photopsia, scotoma and decreased vision. Ophthalmoscopy is the most common method of diagnosing MEWDS but fluorescein angiography, electrodiagnostic testing, visual fields and optical coherence tomography can help confirm the diagnosis. MEWDS is usually a self-limiting condition with complete visual recovery, although subsequent retinal sequellae may be possible. CASE REPORT: A healthy 21-year-old myopic female presented with unilateral, sudden onset of photopsia, blurred vision and a 'grey area' in the temporal visual field. Initial examination found a vitritis, maculopathy and the presence of white dots in all four quadrants of the mid-peripheral retina. A retinal ophthalmologist confirmed the diagnosis of MEWDS. Although the patient was less than compliant with the retinal specialist's recommendations, a subsequent examination found complete resolution of signs and symptoms. CONCLUSIONS: In the primary optometric setting, the uncommon syndrome known as MEWDS must be considered when the common symptoms of photopsia and blurred vision, combined with the atypical clinical presentation of white spots in the fundus appear in an otherwise healthy patient. PMID- 20718789 TI - The Australian optometric workforce 2009. AB - BACKGROUND: This paper presents the findings of the Optometrists Association Australia 2009 optometric workforce study. METHODS: Data from the Association's database, the Australian Bureau of Statistics, Medicare Australia and the Department of Veterans Affairs were applied to create a profile of the optometric workforce in Australia, including the number of optometrists in clinical practice, the number of equivalent full-time optometrists (EFTOs), population to optometrist ratios and workloads in the states and territories and Australia overall. RESULTS: In July 2009, 3,719 (87.4 per cent) of the 4,255 optometrists registered to practise in Australia were in clinical practice. Adjusting for the number of hours worked, there were 3,664 EFTOs. The ratio of population to EFTO was 5,944:1 overall. Ratios were higher in the states without schools of optometry (South Australia 8,631:1, Western Australia 7,687:1, Tasmania 7,615:1, Australian Capital Territory 7,635:1) and highest in the remote and lightly populated Northern Territory (9,367). The ratios were fewer than 6,200 people per EFTO in states with optometry schools: New South Wales (5,247), Queensland (5,723) and Victoria (6,126). Women comprised 45.3 per cent of the profession, while 45 per cent of the profession was aged under 40 years. The majority of the female (80.7 per cent) and male (60.7 per cent) optometrists were aged under 50 years. On average male and female optometrists worked 40.3 and 32.9 hours per week, respectively. The average time per week spent on Medicare and Veterans Affairs consultations was estimated to be 22.2 hours, varying from 20.1 hours in NSW to 30.6 hours in SA. CONCLUSIONS: Population to optometrist ratios indicate that the number of optometrists in 2009 was more than adequate to meet the needs of the community. Further analysis is needed to determine whether the supply of optometrists meets community needs at more local levels. PMID- 20718790 TI - Molecular analysis of 30 Niemann-Pick type C patients from Spain. AB - Mutations in the NPC1 or NPC2 gene are responsible for Niemann-Pick type C (NPC) disease (OMIM #257220), an autosomal recessive neurodegenerative lysosomal storage disorder caused by an incorrect regulation of intracellular lipid trafficking. A molecular analysis carried out in 30 unrelated patients identified 43 distinct mutations in the NPC1 gene, 12 of which had not been previously described. The novel NPC1 alleles were four amino acid substitutions (p.F995L, p.F1079S, p.L1106P and p.G1209E), a nonsense mutation (p.E1089X), a 1-bp insertion (p.L1117PfsX4), an in-frame deletion (p.N916del), four intronic changes (c.58-3280C>G, c.882-28A>T, c.2604+5G>A and c.3591+5G>A) that affect the splicing mechanism, and the first deletion including the whole gene described in NPC disease. In all the splice site mutations, the formation of abnormal spliced transcripts was confirmed by cDNA analysis, and mRNA degradation by the nonsense mediated mRNA decay process was also assessed. As it has been previously reported in this disease, genotype-phenotype correlations are limited due to the large number of private mutations. We describe for the first time one homozygous patient for p.I1061T mutation, who presented the severe infantile clinical onset, and another patient with the variant biochemical phenotype, whose clinical presentation was the neonatal form of the disease. PMID- 20718792 TI - Desmin-related myopathy. AB - Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype-phenotype correlations. Meta-analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype. PMID- 20718793 TI - Mendelian susceptibility to mycobacterial disease. AB - The host response to mycobacterial infection is mediated by the type I cytokine pathway (cell-mediated immunity). Deficiencies in this response result in susceptibility to poorly pathogenic mycobacterial species such as bacille Calmette-Guerin and environmental mycobacteria. In recent years a number of mutations in the genes encoding major components in the type I cytokine axis have been described which predispose to disseminated infection with these weakly virulent mycobacterial species. Affected individuals are also prone to extra intestinal disease caused by non-typhoidal Salmonella. The genes involved display a high level of allelic heterogeneity, accounting for a number of distinct genetic disorders which vary in their mode of inheritance and clinical presentation. These disorders have been termed Mendelian susceptibility to mycobacterial disease and are discussed in this review article. PMID- 20718791 TI - Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. AB - Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. Over 40 chromosomal loci have been identified for autosomal dominant, recessive, and X-linked HSP. Mutations in the genes atlastin, spastin and REEP1 are estimated to account for up to 50% of autosomal-dominant HSP and currently guide the molecular diagnosis of HSP. Here, we report the mutation screening results of 120 HSP patients from North America for spastin, atlastin, and REEP1, with the latter one partially reported previously. We identified mutations in 36.7% of all tested HSP patients and describe 20 novel changes in spastin and atlastin. Our results add to a growing number of HSP disease associated variants and confirm the high prevalence of atlastin, spastin, and REEP1 mutations in the HSP patient population. PMID- 20718794 TI - Association of polymorphisms in 9p21 region with CAD in North Indian population: replication of SNPs identified through GWAS. AB - Coronary artery disease (CAD) is one of the leading causes of death worldwide that is influenced by both environmental as well as genetic factors. Several recent genome-wide association studies (GWAS) have reported the association of multiple single nucleotide polymorphisms (SNPs) mainly in the 9p21 region with CAD. However, the association of these SNPs with CAD has not been rigorously tested in Indian population, which accounts for the largest incidences of CAD in the world. Herein, we genotyped six such SNPs (rs10116277, rs10757274, rs1333040, rs2383206, rs2383207 and rs1994016) identified through GWAS, in 754 individuals (311 angiography-confirmed CAD patients and 443 treadmill test controls) recruited mainly from North India to evaluate if these SNPs were associated with CAD. The minor allele frequency of these six SNPs was comparable to that reported in the respective GWAS. We found that three of these SNPs (rs10116277, rs1333040 and rs2383206) present at the locus 9p21 were significantly associated with CAD even after controlling for the confounding factors such as age, sex, body mass index, homocysteine, hypertension, diabetes, smoking, diet, etc. In conclusion, the locus 9p21 found to be significantly associated with cardiovascular diseases in the Caucasian populations seems to be also important in North Indian population. PMID- 20718795 TI - SLITRK5, a protein that links striatal deficits to OCD-like behaviours in mice. PMID- 20718796 TI - A novel link between Tourette's syndrome and histaminergic signalling. PMID- 20718797 TI - SET(BP1)-ing the stage for a better understanding of Schinzel-Giedion syndrome. PMID- 20718798 TI - Validation of a four-primer real-time PCR as a diagnostic tool for single and mixed Plasmodium infections. AB - Although microscopy remains the reference standard for malaria diagnosis, molecular tools are attracting increasing interest. To improve the detection of mixed infections, we developed a four-primer real-time PCR with four Plasmodium species-specific forward primers, based on the pan-primer design with universal Plasmodium primers as described previously. After validation for analytical sensitivity, specificity and reproducibility, the four-primer PCR was evaluated on 351 blood samples from patients presenting at the outpatient clinic of the Institute of Tropical Medicine (Belgium). With the four-primer PCR, we identified 188 Plasmodium falciparum (Pf), 54 Plasmodium vivax (Pv), 52 Plasmodium ovale (Po) and 13 Plasmodium malariae (Pm) single infections, 27 mixed infections (14 Pf + Pm; 12 Pf + Po; one Pv + Pm) and 17 negative specimens. We found lower cycle threshold values than with the pan-primer PCR, with a mean difference of 2.23, a higher analytical sensitivity (in asexual parasites/MUL: Pf/Pv, 0.02; Po, 0.004; Pm, 0.006) and 15 extra mixed infections. As compared with microscopy, 17 extra mixed infections were detected and Plasmodium species were identified in four microscopy-positive samples in which species identification was not possible. Additionally, the PCR corrected 13 species mismatches between Po and Pv, and in 11 cases detected Pf as a second species that was not identified by microscopy and in five of them was not detected by rapid diagnostic tests (RDTs). PCR confirmed the presence of Pf in 30/46 histidine-rich protein-2-positive samples that were microscopy-negative. We conclude that the presently developed four primer real-time PCR is complementary to standard malaria diagnostic tests in clinical laboratories, with an added value for simultaneous identification of the four Plasmodium species and the detection of mixed infections. PMID- 20718799 TI - Nationwide pseudo-outbreak of Salmonella enterica ssp. diarizonae, France. AB - To investigate an increased incidence of human cultures growing Salmonella enterica ssp. diarizonae serotype 61:k:1,5,7 in France in 2008, we reviewed medical records of case patients and identified the material used during invasive procedures and for bacterial culture. Trace-back investigations incriminated culture media containing contaminated sheep blood agar. PMID- 20718800 TI - Gastroenteritis outbreak caused by norovirus associated with the children's club of a hotel located in Majorca, Spain. AB - A possible gastroenteritis outbreak in a hotel located in northern Majorca was reported on June 2009. The subsequent investigation revealed a total of 14 cases with onset of symptoms from 18 June to 26 June. Symptoms affected mainly the children, their parents and the staff related to the children's club; a vomiting episode was described at the beginning of the outbreak. Genotype 2 norovirus was detected in stool samples, demonstrating its role as the aetiological agent. The special hygienic measures implemented allowed the outbreak to be controlled. PMID- 20718801 TI - Surveillance of autopsy cases for D222G substitutions in haemagglutinin of the pandemic (H1N1) 2009 virus in Alberta, Canada. AB - Pandemic (H1N1) 2009 virus-positive specimens were collected from autopsy patients and matched to pandemic (H1N1) 2009 virus-positive nasopharyngeal specimens from community control patients and pandemic (H1N1) 2009 virus-positive specimens from intensive-care unit (ICU) patients. Specimens were analysed for polymorphisms at amino acid 222 of the haemagglutinin (HA) glycoprotein. Whereas some specimens from autopsy patients were positive for D222N, none was positive for D222G. All control patient specimens were wild-type D222. D222G polymorphisms were also identified in a subset of ICU patients with admixtures of D222G and D222 and of D222N, D222G and D222 present. The relevance of D222N and D222G to influenza pathogenesis and transmissibility currently remains unclear. PMID- 20718802 TI - Faecal carriage of extended-spectrum beta-lactamase-producing and AmpC beta lactamase-producing bacteria among Danish army recruits. AB - During May and June 2008, 84 Danish army recruits were tested for faecal carriage of extended-spectrum beta-lactamase (ESBL)-producing and AmpC beta-lactamase producing bacteria. Three ESBL-producing (CTX-M-14a) Escherichia coli isolates, two AmpC-producing (CMY-2) E. coli isolates and one AmpC-producing (CMY-34) Citrobacter freundii isolate were detected. Two of the CTX-M-14a E. coli isolates had similar pulsed-field gel electrophoresis and multilocus sequence typing profiles, indicating the same origin or transmission between the two army recruits. The bla(CTX-M-14a) genes were transferable to an E. coli recipient. These commensal bacteria therefore constitute a reservoir of resistance genes that can be transferred to other pathogenic bacteria in the intestine. PMID- 20718803 TI - Rapid method for direct identification of bacteria in urine and blood culture samples by matrix-assisted laser desorption ionization time-of-flight mass spectrometry: intact cell vs. extraction method. AB - Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a fast and reliable technology for the identification of microorganisms with proteomics approaches. Here, we compare an intact cell method and a protein extraction method before application on the MALDI plate for the direct identification of microorganisms in both urine and blood culture samples from clinical microbiology laboratories. The results show that the intact cell method provides excellent results for urine and is a good initial method for blood cultures. The extraction method complements the intact cell method, improving microorganism identification from blood culture. Thus, we consider that MALDI-TOF MS performed directly on urine and blood culture samples, with the protocols that we propose, is a suitable technique for microorganism identification, as compared with the routine methods used in the clinical microbiology laboratory. PMID- 20718804 TI - Candida tropicalis fungaemia: incidence, risk factors and mortality in a general hospital. AB - The risk factors and clinical features of patients with Candida tropicalis fungaemia have not been fully defined. We performed a case-control study comparing 59 cases of C. tropicalis fungaemia with 177 episodes of fungaemia caused by other species of Candida in our hospital over a 24-year period (January 1985 to December 2008). Patients with C. tropicalis fungaemia were more likely to be older (median age, 67 vs. 56 years; p 0.01), to have cancer (45.5% vs. 31.6%, p 0.04), and to have the abdomen as the portal of entry (32.2% vs. 11.9%, p 0.001), and had a higher in-hospital mortality rate (61% vs. 44%, p 0.03). Multivariate analysis showed that the independent risk factors for C. tropicalis fungaemia were cancer (OR 4.5; 95% CI 1.05-3.83; p 0.03) and the abdomen as the portal of entry (OR 13.6; 95% CI 1.9-8.2; p <0.001). When survivors were compared with non-survivors, the risk factors associated with a poor outcome were neutropenia (19.4% vs. 0; p 0.03), corticosteroid treatment (36% vs. 13%; p 0.07), and septic shock (50% vs. 17.4%; p 0.01). The independent risk factors for mortality in the multivariate analysis were corticosteroid treatment (OR 8.2; 95% CI 0.9-27.7; p 0.04) and septic shock (OR 14.6; 95% CI 2.4-90.2; p 0.004), whereas urinary tract infection (OR 0.07; 95% CI 0.01-0.8; p 0.03) and catheter removal (OR 0.06; 95% CI 0.01-0.4; p 0.002) were protective factors. C. tropicalis is the fourth most common cause of fungaemia in our hospital. It is associated with underlying malignancy, the abdomen as the portal of entry, and poor outcome. PMID- 20718806 TI - Peak cardiac power output in healthy, trained men. AB - Previous investigations into peak cardiac power output (CPO peak) have been limited to clinical populations and healthy, but non-athletic adults, and normative data on trained individuals would allow a greater understanding of this parameter. Therefore, we recruited eight healthy, well-trained male cyclists. Peak oxygen consumption ((.)VO2 peak) was assessed using an incremental ergometer test, and following a 40-min recovery period, peak cardiac output ((.)QT peak) was measured during a constant load test that elicited (.)VO2 peak (+/-5%) using the Defares CO2 rebreathing technique. CPO peak was calculated as described by Cooke et al. (1998). Mean (+/-SD) values during the constant load test were: (.)VO2 peak, 4.94 +/- 0.41 l min-1; (.)QT peak, 36.5 +/- 3.7 l min-1; mean arterial pressure, 123 +/- 8 mmHg and CPO peak, 9.9 +/- 1.0 W. These results demonstrate CPO peak in a well-trained population to be approximately twice those observed in healthy, but non-athletic adults. The current data provide useful information regarding the upper limits and possible 'trainability' of cardiac pumping capacity for sedentary and clinically compromised individuals. PMID- 20718805 TI - Successive deep dives impair endothelial function and enhance oxidative stress in man. AB - The aim of this study was to assess the effects of successive deep dives on endothelial function of large conduit arteries and plasma pro-oxidant and antioxidant activity. Seven experienced divers performed six dives in six consecutive days using a compressed mixture of oxygen, helium and nitrogen (trimix) with diving depths ranging from 55 to 80 m. Before and after first, third and sixth dive, venous gas emboli formation and brachial artery function (flow-mediated dilation, FMD) was assessed by ultrasound. In addition, plasma antioxidant capacity (AOC) was measured by ferric reducing antioxidant power, and the level of oxidative stress was assessed by thiobarbituric acid-reactive substances (TBARS) method. Although the FMD was reduced to a similar extent after each dive, the comparison of predive FMD showed a reduction from 8.6% recorded before the first dive to 6.3% before the third (P = 0.03) and 5.7% before the sixth dive (P = 0.003). A gradual shift in baseline was also detected with TBARS assay, with malondialdehyde values increasing from 0.10 +/- 0.02 MUmol l-1 before the first dive to 0.16 +/- 0.03 before the sixth (P = 0.005). Predive plasma AOC values also showed a decreasing trend from 0.67 +/- 0.20 mmol l-1 trolox equivalents (first day) to 0.56 +/- 0.12 (sixth day), although statistical significance was not reached (P = 0.08). This is the first documentation of acute endothelial dysfunction in the large conduit arteries occurring after successive deep trimix dives. Both endothelial function and plasma pro-oxidant and antioxidant activity did not return to baseline during the course of repetitive dives, indicating possible cumulative and longer lasting detrimental effects. PMID- 20718807 TI - The influence of a fast ramp rate on peak cardiopulmonary parameters during arm crank ergometry. AB - The influence of a very fast ramp rate on cardiopulmonary variables at ventilatory threshold and peak exercise during a maximal arm crank exercise test has not been extensively studied. Considering that short arm crank tests could be sufficient to achieve maximal oxygen consumption (VO2), it would be of practical interest to explore this possibility. Thus, this study aimed to analyse the influence of a fast ramp rate (20 W min-1) on the cardiopulmonary responses of healthy individuals during a maximal arm crank ergometry test. Seventeen healthy individuals performed maximal cardiopulmonary exercise tests (Ultima CardiO2; Medical Graphics Corporation, St Louis, USA) in arm ergometer (Angio, LODE, Groningen, The Netherlands) following two protocols in random order: fast protocol (increment: 2 w/6 s) and slow protocol (increment: 1 w/6 s). The fast protocol was repeated 60-90 days after the 1st test to evaluate protocol reproducibility. Both protocols elicited the same peak VO2 (fast: 23.51 +/- 6.00 versus slow: 23.28 +/- 7.77 ml kg-1 min-1; P = 0.12) but peak power load in the fast ramp protocol was higher than the one in the slow ramp protocol (119 +/- 43 versus. 102 +/- 39 W, P < 0.001). There was no other difference in ventilatory threshold and peak exercise variables when 1st and 2nd fast protocols were compared. Fast protocol seems to be useful when healthy young individuals perform arm cardiopulmonary exercise test. The usefulness of this protocol in other populations remains to be evaluated. PMID- 20718808 TI - Endothelial function and hemodynamics in systemic sclerosis. AB - INTRODUCTION: Systemic sclerosis (SSc) is characterized by the development of fibrosis of skin and internal organs that is associated with vascular damage. However, its related parameters have not been fully explored. The aim of this study was to investigate endothelial function in SSc and its relationship with systolic pulmonary artery pressure and systemic arterial compliance (SAC). METHODS: We studied 14 SSc females (4 with diffuse and 10 with limited cutaneous form of the disease) and 14 healthy controls matched for age and for cardiovascular risk factors. Endothelium-dependent dilation (i.e. flow-mediated) and endothelium-independent (i.e. nitroglycerin-induced) dilation of the brachial artery were measured as the percentage of change from baseline (FMD and NMD, respectively). In patients with SSc, SAC, cardiac output (CO), systemic arterial resistance and pulmonary artery pressure were estimated using echocardiography Doppler. RESULTS: Heart rate, brachial artery pressure and body mass index did not differ between patients with SSc and controls. Flow-mediated vasodilation (FMD) and NMD were significantly decreased in patients with SSc (10.3 +/- 8.6 versus 26.6 +/- 7.4%, P<0.001; 24.2 +/- 8.4 versus 33.3 +/- 10.1%, P<0.001, respectively). Postischaemia reactive hyperaemia was lower in patients with SSc (275 +/- 185 versus 618 +/- 366%, P<0.001). FMD and nitrate-mediated dilation (NMD) were associated with CO, but not with SAC; moreover, FMD correlated with pulmonary artery pressure and peripheral arterial resistance conversely to NMD. CONCLUSIONS: Endothelium function in SSc is impaired independently to SAC. Furthermore, the severity of both small artery and pulmonary artery involvement may impact on endothelium-dependent function. PMID- 20718809 TI - Lymphoedema of the lower extremities--background, pathophysiology and diagnostic considerations. AB - Lymphoedema of the lower extremities is a chronic debilitating disease that is often underdiagnosed. Early diagnosis and treatment is paramount in reducing the risk of progression and complications. Lymphoedema has traditionally been defined as interstitial oedema and protein accumulation because of a defect in the lymphatic drainage; however, some findings suggest that the interstitial protein concentration may be low in some types of lymphoedema. Primary lymphoedema is caused by an inherent defect in the lymphatic vessels or lymph nodes. Secondary lymphoedema is caused by damages to the lymphatic system most often caused by cancer or its treatment. Many of the underlying pathophysiological mechanisms have yet to be elucidated. Many methods have been developed for examination of the lymphatic system. Lymphoscintigraphy is presently the preferred diagnostic modality. Lack of consensus regarding protocol and qualitative interpretation criteria results in a too observer dependent outcome. Methods for objectifying the scintigraphy through quantification have been criticized. Depot clearance rates are an alternative method of quantification of lymphatic drainage capacity. This method however has mostly been applied on upper extremity lymphoedema. The aim of this review is to provide a literature-based overview of the aetiology and pathophysiology of lower extremity lymphoedema and to summarize the current knowledge about lymphoscintigraphy and depot clearance techniques. The abundance of factors influencing the outcome of the examination stresses the need for consensus regarding examination protocols and interpretation. Further studies are needed to improve diagnostic performance and understanding of pathophysiological mechanisms. PMID- 20718810 TI - Medical education in the United States: are we building a multitiered system? PMID- 20718811 TI - Why clinical research centers? PMID- 20718812 TI - Clinical research and the public: if not them, who? PMID- 20718813 TI - Association of an intronic, but not any exonic, FRMD4B sequence variant and heart failure. AB - Common forms of heart failure (HF) exhibit familial clustering, but specific genetic risk factors have been challenging to identify. A recent single nucleotide polymorphism (SNP) microarray study implicated a locus within an intron of FRMD4B in Caucasian HF. Here, we used next-generation resequencing of pooled DNA and individual Sequenom genotyping to test for associations between FRMD4B SNPs and ischemic and/or nonischemic cardiomyopathy in two independent populations. Exonic resequencing of Caucasians and African-Americans identified 32 FRMD4B SNPs, 13 of which had allele frequencies greater than 1%. None of these common FRMD4B SNPs were significantly associated with ischemic, nonischemic, or all-cause HF in either of the study populations. We individually genotyped the seminal intronic rs6787362 FRMD4B SNP in the primary study population and compared genotypes between HF cases and controls. The rs6787362 variant allele was more frequent in Caucasians with ischemic cardiomyopathy, and carriers (heterozygous or homozygous) of the variant allele had increased risk of HF (OR 1.437, CI 1.085-1.904; p= 0.0118). No such association was seen for African American HF. These results confirm an association between the intronic rs6787362 FRMD4B SNP and ischemic cardiomyopathy in a European-derived population, but do not support the proposition that coding FRMD4B variants are susceptibility factors in common HF. PMID- 20718814 TI - Short-term treatment with high-dose atorvastatin reduces LDL cholesterol but shows no anti-inflammatory effects in normolipidemic subjects with normal CRP levels. AB - The benefit in reducing cardiovascular risk with statins has been attributed both to cholesterol lowering and pleiotropic effects. These pleiotropic effects are thought to include attenuation of the inflammatory response due to reduced prenylation of proteins in the inflammatory cascade. We conducted studies in normolipidemic subjects to determine if treatment with high-dose (80 mg) atorvastatin could reduce circulating levels of inflammatory markers. We also determined whether high-dose atorvastatin affected the inflammatory response of monocytes stimulated with lipopolysaccharide (LPS) ex vivo. We found that treatment with atorvastatin rapidly and significantly reduced plasma low-density lipoprotein (LDL) cholesterol levels in subjects treated for 2 weeks. However, statin treatment had no discernible effect on plasma levels of the inflammatory markers high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF) alpha, or interleukin (IL-6) and no effect on the cytokine response of monocytes following ex vivo stimulation with LPS. High-dose atorvastatin treatment of normolipidemic subjects with normal C-reactive protein levels has no effect on the inflammatory response assessed by monocyte stimulation with LPS ex vivo despite significant reductions in LDL cholesterol levels. PMID- 20718816 TI - A new class of human mast cell and peripheral blood basophil stabilizers that differentially control allergic mediator release. AB - Treatments for allergic disease block the effects of mediators released from activated mast cells and blood basophils. A panel of fullerene derivatives was synthesized and tested for their ability to preempt the release of allergic mediators in vitro and in vivo. The fullerene C(70)-tetraglycolic acid significantly inhibited degranulation and cytokine production from mast cells and basophils, while C(70)-tetrainositol blocked only cytokine production in mast cells and degranulation and cytokine production in basophils. The early phase of FcepsilonRI inhibition was dependent on the blunted release of intracellular calcium stores, elevations in reactive oxygen species, and several signaling molecules. Gene microarray studies further showed the two fullerene derivatives inhibited late phase responses in very different ways. C(70)-tetraglycolic acid was able to block mast cell-driven anaphylaxis in vivo, while C(70)-tetrainositol did not. No toxicity was observed with either compound. These findings demonstrate the biological effects of fullerenes critically depends on the moieties added to the carbon cage and suggest they act on different FcepsilonRI specific molecules in mast cells and basophils. These next generation fullerene derivatives represent a new class of compounds that interfere with FcepsilonRI signaling pathways to stabilize mast cells and basophils. Thus, fullerene-based therapies may be a new approach for treating allergic diseases. PMID- 20718815 TI - Predicting intermediate phenotypes in asthma using bronchoalveolar lavage-derived cytokines. AB - An important problem in realizing personalized medicine is the development of methods for identifying disease subtypes using quantitative proteomics. Recently we found that bronchoalveolar lavage (BAL) cytokine patterns contain information about dynamic lung responsiveness. In this study, we examined physiological data from 1,048 subjects enrolled in the US Severe Asthma Research Program (SARP) to identify four largely separable, quantitative intermediate phenotypes. Upper extremes in the study population were identified for eosinophil- or neutrophil predominant inflammation, bronchodilation in response to albuterol treatment, or methacholine sensitivity. We evaluated four different statistical ("machine") learning methods to predict each intermediate phenotype using BAL A-cytokine measurements on a 76 subject subset. Comparison of these models using area under the ROC curve and overall classification accuracy indicated that logistic regression and multivariate adaptive regression splines produced the most accurate methods to predict intermediate asthma phenotypes. These robust classification methods will aid future translational studies in asthma targeted at specific intermediate phenotypes. PMID- 20718818 TI - Identifying interdisciplinary research priorities to prevent and treat pediatric obesity in New York City. AB - It is well recognized that an interdisciplinary approach is essential in the development and implementation of solutions to address the current pediatric obesity epidemic. In two half-day meetings that included workshops and focus groups, faculty from diverse fields identified critically important research challenges, and gaps to childhood obesity prevention. The purpose of this white paper is to describe the iterative, interdisciplinary process that unfolded in an academic health center setting with a specific focus on underrepresented minority groups of Black and Hispanic communities, and to summarize the research challenges and gaps related to pediatric obesity that were identified in the process. Although the research challenges and gaps were developed in the context of an urban setting including high-risk populations (the northern Manhattan communities of Washington Heights, Inwood, and Harlem), many of the issues raised are broadly applicable. The processes by which the group identified research gaps and methodological challenges that impede a better understanding of how to prevent and treat obesity in children has resulted in an increase in research and community outreach collaborations and interdisciplinary pursuit of funding opportunities across units within the academic health center and overall university. PMID- 20718817 TI - Molecular therapy drives patient-centric health care paradigms. PMID- 20718819 TI - Advancing the research mission in an academic department: the creation of a center for translational medicine. AB - Multidisciplinary research centers have multiplied in academic medical centers over the past decade and several recent reports have described their structure, strengths and limitations, and the difficulties that they may face. However, little attention has been paid to the role of a multidisciplinary center in the context of a single academic department. In 2003, the Department of Medicine at Jefferson Medical College launched the Center for Translational Medicine in order to facilitate multidisciplinary research, optimally utilize space and resources, enhance the educational experience for trainees, link basic investigation with clinical research programs, and develop a program of research excellence. Herein, we describe the structure of the Center and provide evidence of its success. The development of the Center has resulted in increased total funding, an increased number of students and residents pursuing translational research, a more effective utilization of space, the development of multidisciplinary research projects, and a significant increase in the number of individual and programmatic federally funded grants. Though the creation of the Center was not without challenges, the overall benefits for the department and the university have been substantial. The concept of a translational medicine center may be useful for many departments of academic medical centers. PMID- 20718820 TI - Lessons from the Salk polio vaccine: methods for and risks of rapid translation. AB - The Salk inactivated poliovirus vaccine is one of the most rapid examples of bench-to-bedside translation in medicine. In the span of 6 years, the key basic lab discoveries facilitating the development of the vaccine were made, optimization and safety testing was completed in both animals and human volunteers, the largest clinical trial in history of 1.8 million children was conducted, and the results were released to an eagerly awaiting public. Such examples of rapid translation cannot only offer clues to what factors can successfully drive and accelerate the translational process but also what mistakes can occur (and thus should be avoided) during such a swift process. In this commentary, we explore the translational path of the Salk polio vaccine from the key basic science discoveries to the 1954 Field Trials and delve into the scientific and sociopolitical factors that aided in its rapid development. Moreover, we look at the Cutter and Wyeth incidents after the vaccine's approval and the errors that led to them. PMID- 20718821 TI - Burnout among early career clinical investigators. AB - Burnout is a pervasive problem among clinicians. However, little is known about burnout among early career clinical investigators, who must balance clinical responsibilities with challenges related to research. We aimed to determine the prevalence of and demographic associations with burnout in a cohort of early career clinical investigators. A cross-sectional questionnaire was administered to 179 trainees at the University of Pittsburgh Institute for Clinical Research Education in 2007-2008. We used chi-square analyses and Fisher's exact test to determine whether associations between demographic characteristics and burnout were significant. Of the participants, 29 (16%) reported feeling burned out. Burnout was more prevalent among those over 35 years of age relative to their younger counterparts (29% vs. 13%, p= 0.01) and among females relative to males (22% vs. 10%, p= 0.03). With regard to race and ethnicity, burnout was most common among underrepresented minorities (30%) followed by Caucasians (18%) and Asians (3%); these differences were significant (p= 0.02). Considering the early career status of these research trainees, rates of burnout were concerning. Certain demographic subgroups-including older trainees, females, and underrepresented minorities-had particularly high rates of burnout and may benefit from interventions that provide them with skills needed to sustain successful clinical research careers. Clin Trans Sci 2010; Volume 3: 186-188. PMID- 20718823 TI - Difficulty in sustaining hepatic outflow in left lobe but not right lobe living donor liver transplantation. AB - BACKGROUND: Hepatic outflow block is one of the major complications leading to severe graft dysfunction after left lobe living donor liver transplantation (LDLT). METHODS: Medical records of 46 recipients of a left lobe LDLT were reviewed. The method of outflow reconstruction and post-transplant morphological changes of hepatic veins were investigated. The subjects were followed up until September 2008, with a median follow-up period of 2.0 yr (range: 0.5-5.9 yr). RESULTS: There were no multiple outflow tracts to be reconstructed, and the median caliber of the single orifices with or without venoplasty was 32.0 mm. The difference between the angle of hepatic veins to the sagittal plane measured on computed tomography was calculated for pre-operative donors and post-operative recipients a month after LDLT. Both left and middle hepatic veins showed a significantly greater change in angle than the right hepatic vein. Both left and middle hepatic veins more frequently showed a nearly flat wave form on Doppler study one month after LDLT. In the 46 recipients of left lobe grafts, three developed outflow block (6.5%). CONCLUSIONS: The middle and left hepatic veins tend to distort and stretch during graft regeneration. These characteristics seem to be associated with outflow disturbances. PMID- 20718822 TI - Phospholemman: a novel cardiac stress protein. AB - Phospholemman (PLM), a member of the FXYD family of regulators of ion transport, is a major sarcolemmal substrate for protein kinases A and C in cardiac and skeletal muscle. In the heart, PLM co-localizes and co-immunoprecipitates with Na(+)-K(+)-ATPase, Na(+)/Ca(2+) exchanger, and L-type Ca(2+) channel. Functionally, when phosphorylated at serine(68), PLM stimulates Na(+)-K(+)-ATPase but inhibits Na(+)/Ca(2+) exchanger in cardiac myocytes. In heterologous expression systems, PLM modulates the gating of cardiac L-type Ca(2+) channel. Therefore, PLM occupies a key modulatory role in intracellular Na(+) and Ca(2+) homeostasis and is intimately involved in regulation of excitation-contraction (EC) coupling. Genetic ablation of PLM results in a slight increase in baseline cardiac contractility and prolongation of action potential duration. When hearts are subjected to catecholamine stress, PLM minimizes the risks of arrhythmogenesis by reducing Na(+) overload and simultaneously preserves inotropy by inhibiting Na(+)/Ca(2+) exchanger. In heart failure, both expression and phosphorylation state of PLM are altered and may partly account for abnormalities in EC coupling. The unique role of PLM in regulation of Na(+)-K(+)-ATPase, Na(+)/Ca(2+) exchanger, and potentially L-type Ca(2+) channel in the heart, together with the changes in its expression and phosphorylation in heart failure, make PLM a rational and novel target for development of drugs in our armamentarium against heart failure. Clin Trans Sci 2010; Volume 3: 189-196. PMID- 20718824 TI - Long-term follow-up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin. AB - BACKGROUND: Early withdrawal of steroids after liver transplantation has benefits, but rarely is total avoidance of steroids used. We evaluated long-term results of patients with ab initio monotherapy with cyclosporin (CYA) vs. tacrolimus (TAC), in randomized and cohort studies. METHODS: We evaluated long term outcomes in 66 adults randomized to TAC or CYA and 94 subsequent patients who received TAC. Protocol liver biopsies were performed. Rejection was treated with three 1 g/d methylprednisolone. Further rejection after two courses of methylprednisolone was defined as monotherapy failure. RESULTS: Actuarial five-yr survival was 68% in TAC and 70% CYA. Monotherapy failed in 8% TAC and 13% CYA patients; no rejection in 24% TAC and 19% CYA patients; 42% TAC and 33% CYA patients were not exposed to any steroids. Rejection episodes were less with TAC, compared to CYA: mean 1.8 vs. 2.5, p = 0.042. Chronic rejection occurred in only 4 (11%) CYA patients. During follow-up of median 97 months (range: 0.06-145), there were 16 (44%) deaths in CYA and 48 (39%) in TAC patients (p > 0.05). CONCLUSIONS: TAC monotherapy ab initio is a viable immunosuppressive strategy in liver transplantation and was associated with lower rejection rates and renal complications, compared to CYA. PMID- 20718825 TI - Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients. AB - Little is known about the proportion of renal transplant candidates who are considered ineligible by the transplant center, the reasons of their ineligibility and their survival during dialysis. In this retrospective, single center study of 445 adult patients referred between 2001 and 2006, 36 (8%) were deemed ineligible for medical contraindications. The leading reason was cardiovascular (CV) (75%), specifically aorto-iliac, and/or limb vessels atheromatosis or calcifications; ischemic heart disease; or a combination thereof. Nine patients had other contraindications that were absolute for three of them; six patients displayed a combination of relative contraindications. When compared to eligible patients (N = 409), those ineligible were significantly older (60 yr vs. 48), more often diabetics (50% vs. 15%), obese (39% vs. 17%) suffering from coronary artery disease (53% vs. 11%) and peripheral arterial disease (86% vs. 11%). Their primary nephropathy was more often diabetic and/or hypertensive/nephroangiosclerosis (61% vs. 23%), and their median dialysis vintage prior to evaluation was longer (29 months vs. 10, p < 0.0001). The actuarial survival of ineligible patients was significantly lower than that of eligible patients (at five yr: 53% vs. 88%). Adequate control of CV risk factors before dialysis and early referral for transplantation might help to improve eligibility of renal transplant candidates. PMID- 20718826 TI - Pre-operative dietary restriction is feasible in live-kidney donors. AB - Dietary restriction (DR), defined as reduced energy intake without malnutrition, confers protection against renal ischemia and reperfusion injury in animal models. This pilot study investigates for the first time the feasibility of pre operative DR in the clinical setting. Live-kidney donors were randomized between pre-operative DR or ad libitum intake. Seventeen participants were instructed to follow a 30% calorie-restricted diet, followed by one day of water-only fasting prior to surgery. Thirteen participants were allowed to eat ad libitum pre operatively. Ninety-four percent of the donors adhered to the diet, 31.4% reduction in caloric intake was achieved. Post-operative well-being, appetite and ability to perform daily tasks were not different between both groups. There was no difference in post-transplant graft function of kidneys obtained from DR donors or control donors as determined by serum creatinine levels during the first post-operative month and renograms at post-operative day one. This study shows that mild dietary restriction is feasible in the setting of live-kidney donation. No effect was observed regarding post-operative graft function. Additional studies are warranted to investigate the appropriate regimen of dietary restriction to protecting against ischemia and reperfusion injury, such as increasing the magnitude and/or duration of the reduction in daily caloric intake. PMID- 20718828 TI - Genomics and pharmacogenomics of dementia. AB - Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1*N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4 *1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3 *1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics. PMID- 20718827 TI - Knowledge, attitudes, practices and behaviors regarding deceased organ donation and transplantation in Malaysia's multi-ethnic society: a baseline study. AB - BACKGROUND: Malaysia's organ and tissue donation rates are among the lowest in the world. The study aims to explore the knowledge, attitudes, practices and behaviors regarding deceased organ donation and transplantation in the diverse ethnic communities in the state of Selangor, Malaysia. METHODS: A cross sectional, population-based, computer-assisted telephone interview exploring multi-ethnic participants' knowledge, attitudes, practices and behavioral on deceased organ donation and transplantation was conducted from February to April 2009. RESULTS: Although only 5.5% of the total participants (N = 1174) reported that they have registered to be organ donor, a further 35.2% of those who have not register for organ donation indicated willingness to donate their own. Significant socio-demographic disparities with respect to knowledge and attitudes scores were observed. In particular, Malays (20.7%) indicated lower willingness to donate organs compared to the Chinese (36.6%) and Indians (51.4%) (p < 0.001). In multivariate logistic regression analysis, willingness to donate one's own organ was associated with knowledge score (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.13-1.22), attitude score (OR = 1.17, 95% CI = 1.05-1.31), secondary school education (OR = 1.46, 95% CI = 1.05-2.02), and Malay ethnicity (OR = 0.18, 95% CI = 0.03-0.94). CONCLUSION: Findings assist organ donation and transplantation organizations to reach out the diverse socio-demographic and ethnic communities with cultural-specific information about organ donation. PMID- 20718829 TI - Genomics and pharmacogenomics of schizophrenia. AB - Schizophrenia (SCZ) is among the most disabling of mental disorders. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environment-genome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, gamma-aminobutiric acid (GABAergic), neuropeptidergic and glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection, neuroimmune dysfunction, and epigenetic dysregulation. SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes. Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system (CNS) disorders. PMID- 20718830 TI - Right lateral position for laparoscopic splenic flexure mobilization. AB - AIM: Standard laparoscopic splenic flexure mobilization is often hampered by redundant small bowel and usually necessitates additional ports. The retraction required runs the risk of inadvertent injury to the surrounding structures including the spleen. METHOD: We present a new technique that permits a safe, rapid and complete mobilization of the splenic flexure even for the more difficult patients. RESULTS: We have used it in 15 consecutive patients without mortality, re-operation or conversion to open surgery. CONCLUSION: The right lateral position for splenic flexure mobilization gives better exposure of the left upper quadrant allowing complete dissection of the splenic flexure from the tail of the pancreas facilitating mobilization even in more difficult cases. PMID- 20718831 TI - Technical aspects and outcome of a standardized full laparoscopic approach to the reversal of Hartmann's procedure in a teaching centre. AB - AIM: Laparoscopic reversal of Hartmann's procedure is technically demanding. We evaluated the technical aspects and outcome of a standardized approach in a single centre and examined the feasibility of including this into training curricula. METHOD: The procedure entails a laparoscopy for adhesiolysis and identification and mobilization of the rectal stump. Mobilization of the splenic flexure is performed if necessary, and a colorectal anastomosis is fashioned after introduction of the stapler anvil via the colostomy with intra-abdominal positioning and delivery into the proximal colonic segment to be anastomosed. The stoma is excised as the last step in the operation. RESULTS: Forty-two patients underwent the procedure over an 8-year period with either an expert (n=21) or trainee under expert mentorship (n=21) as first operator. Intra-operative data and postoperative outcomes were evaluated by retrospective review of clinical charts and theatre records. There was a 9.5% conversion rate and 0% mortality. One patient suffered a ureteric injury, while postoperative surgical complications occurred in 7 patients (including one clinical anastomotic leakage). The mean operative time was 117 min. There was no significant difference in intra operative technical parameters or postoperative clinical consequences between procedures performed by a trained surgeon or by a trainee under mentorship. CONCLUSION: Adherence to a standardized operative protocol and expert mentorship allows this technically demanding operation to be associated with low conversion and complication rates. The absence of any difference between procedures performed by a trainee or trained surgeon suggests that the operation can be included in training programmes for laparoscopic surgery. PMID- 20718832 TI - Panniculectomy: an alternative approach to the revision of a difficult stoma. AB - AIM: We describe a modified abdominoplasty technique as an alternative approach to the revision of a difficult stoma. METHOD: A patient with a retracted colostomy secondary to change in abdominal wall contour following significant weight loss was treated with this technique. The patient had previous colostomy revision with marlex mesh insertion for combined parastomal and massive ventral hernia repair. A preoperatively marked crescent shaped left upper quadrant segment of skin and subcutaneous fat was excised and the defect was approximated in multiple layers. This shifted the stoma opening cephalad and eliminated the cutaneous crease that originally made it difficult to obtain a proper stoma seal. RESULTS: At one year follow up the patient was extremely satisfied with the results and was able to properly pouch the stoma. CONCLUSION: Modified abdominoplasty can be used as an alternative, low morbid approach in dealing with selected patients with difficult stoma problems. PMID- 20718833 TI - Double jeopardy: pyogenic liver abscess and massive secondary rectal haemorrhage after rubber band ligation of haemorrhoids. PMID- 20718834 TI - Immunohistochemical analysis of tumour regression grade for rectal cancer after neoadjuvant chemoradiotherapy. AB - AIM: Tumour regression grade (TRG) as defined by Rodel et al. has been used as an independent prognostic factor for rectal carcinoma after preoperative treatment by chemoradiotherapy (CRT). Determination of TRG 2 and 3, semiquantitatively defined as more or less than 50% tumour regression, respectively, does not appear to correlate with prognosis. The purpose of this study was to find an immunohistochemical pattern to permit improved stratification of intermediate responders defined by disease free (DFS) and overall survival (OS). METHOD: Immunohistochemistry of EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), CD133 antibody, p53 antibody and Ki67 antibody was evaluated using tissue microarrays (TMA) on post-treatment surgical specimens from 88 patients. CD133 expression was confirmed in the whole section when available. RESULTS: At a median follow-up of 40 months, TRG was found to be an independent predictor of DFS (P = 0.05) and OS (P = 0.001) but no differences were found between TRG 2 and 3 in terms of DFS (P = 0.74) or OS (P = 0.41). The results of TMA showed an immunohistochemically poor prognostic profile for intermediate responders configured by negativity of CD133 expression. However, when examining CD133 expression in the whole section, there was an intermediate correlation with TMA and the prognostic significance was lost. CONCLUSION: The results did not confirm the value of immunohistochemistry in predicting the prognosis of patients with rectal cancer following neoadjuvant chemoradiotherapy. This questions the accuracy of TMA in detecting CD133 expression in this setting. PMID- 20718835 TI - Prognostic significance of high-grade dysplasia in colorectal adenomas. AB - AIM: Colonoscopy to detect and remove polyps has contributed to a reduction in colorectal carcinoma. Three-year follow up is recommended for patients considered to be at high risk (at least three adenomas, adenoma >= 1 cm, villous or high grade features). Our study focused on patients diagnosed with high-grade dysplasia with regard to initial management and follow up. METHOD: A search of patients who had had endoscopic removal of a high-grade adenoma was carried out. Patients with the following were excluded: follow up of < 1 year, polyposis syndromes, prior colon cancer and a diagnosis of adenocarcinoma within 6 months following initial diagnosis. RESULTS: Eighty-three patients treated between 1999 and 2007 for high-grade dysplasia (HGD) in a colorectal adenoma were identified. Over a median follow-up period of 4 years, 53 (64%) developed further adenomatous polyps. Among these, 7% had an adenoma with HGD or an adenocarcinoma. In all these patients, the initial high-grade adenoma was > 1 cm in diameter. Initial follow-up colonoscopy was performed on average 7 months following the initial diagnosis. Ten per cent of patients underwent prophylactic segmental resection, and 6% received argon laser therapy. CONCLUSION: The study demonstrates that patients who have a colorectal adenoma > 1 cm with HGD may be at high risk of developing further adenomas with HGD or carcinoma. Close follow up is warranted. PMID- 20718836 TI - Where does pelvic nerve injury occur during rectal surgery for cancer? AB - AIM: Optimal treatment of rectal adenocarcinoma involves total mesorectal excision with nerve-preserving dissection. Urinary and sexual dysfunction is still frequent following these procedures. Improved knowledge of pelvic nerve anatomy may help reduce this and define the key anatomical zones at risk. METHOD: The MEDLINE database was searched for available literature on pelvic nerve anatomy and damage after rectal surgery using the key words 'autonomic nerve', 'pelvic nerve', 'colorectal surgery', and 'genitourinary dysfunction'. All relevant French and English publications up to May 2010 were reviewed. Reviewed data were illustrated using 3D reconstruction of the foetal pelvis. RESULTS: The ligation of the inferior mesenteric artery and dissection of the retrorectal space can cause damage to the superior hypogastric plexus and/or hypogastric nerve. Anterolateral dissection in the 'lateral ligament' area and division of Denonvilliers' fascia can damage the inferior hypogastric plexus and efferent pathways. Perineal dissection can indirectly damage the pudendal nerve. CONCLUSIONS: In most cases, the pelvic nerves can be preserved during rectal surgery. Complete oncological resection may require dissection close to the nerves where the tumour is located anterolaterally where it is fixed and when the pelvis is narrow. PMID- 20718837 TI - Sacral nerve stimulation for faecal incontinence: results from a single centre over a 10-year period. AB - AIM: Sacral nerve stimulation (SNS) is considered a first-line surgical treatment option for faecal incontinence. There is little information on long-term results. The results of SNS for faecal incontinence performed at a single centre over a 10 year period are reported. METHOD: A cohort analysis of consecutive patients treated with SNS for faecal incontinence over a 10-year period was carried out. Data were collected prospectively using bowel habit diaries and St Mark's and Cleveland Clinic incontinence scores. Treatment success was defined as a >50% reduction in episodes of faecal incontinence compared with baseline. RESULTS: Temporary SNS was performed in 118 patients, and 91 (77%) were considered suitable for chronic stimulation. The median period of follow up was 22 (1-138) months. Seventy patients were followed for 1 year with success in 63 (90%). Of 18 patients followed for 5 years, 15 (83%) reported continued success, 11 (61%) maintained full efficacy, 4 (22%) reported some loss, and 3 (17%) reported complete loss. Three patients with a 10-year follow up had no loss in efficacy. Overall, complete loss of efficacy was observed in 14 (16%) patients at a median of 11.5 months following implantation. A further 5 (6%) patients showed deterioration with time. In 9 (47%), no reason for the deterioration in symptoms could be identified. CONCLUSIONS: SNS can be effective for up to 10 years. Some patients experience deterioration in symptoms over time. The reasons for this are often not evident. PMID- 20718838 TI - Single incision laparoscopic colon surgery. Is the ride worth the curve? PMID- 20718839 TI - Commentary on 'Survival of patients with pseudomyxoma peritonei treated by serial debulking'. PMID- 20718841 TI - Cervical cancer screening in Mediterranean countries: implications for the future. AB - Prompted by feedback from the 34th European Congress of Cytology (ECC), the practice of including a special symposium in the programme was continued in the 35th ECC in Lisbon (2009) by arranging a satellite symposium entitled 'Cervical Cancer Screening in the Mediterranean Countries'. Because of the importance to the future of this discipline, it was felt appropriate to summarize the highlights of this symposium here. Cervical cancer prevention strategies in the countries participating in the symposium (Portugal, Spain, Italy, Croatia, Greece and Turkey) appear to be highly variable. As yet, none of these countries can demonstrate a fully implemented national screening programme, but all are in different phases of designing and/or setting up such a programme, which is important. At present, the time-honoured concept of cervical cancer prevention by Pap smear screening is under review, because prophylactic human papillomavirus (HPV) vaccines demonstrate a potential to prevent the vast majority (albeit not all) of cases of cervical cancer in the foreseeable future. Cervical cancer screening is still needed in this emerging era of HPV vaccination, but clearly the existing screening strategies must be modified to provide a cost-effective combination of vaccination and screening. If the currently evaluated new screening strategies, such as HPV testing followed by cytology triage, become a reality, there is the likelihood that the Pap test will have only a secondary role, subordinate to HPV testing. Supporters of this scenario claim that Pap test performance will deteriorate in vaccinated populations. Reduced positive predictive value (PPV), due to lower disease prevalence, is inevitable, however, and this would also affect HPV tests. Any decline in sensitivity and specificity depends on human performance, and as such is avoidable by taking appropriate preventive measures. As clinical cytologists, we should focus attention on minimizing the risk to the Pap test of falling sensitivity because of unfamiliarity with abnormal cells, and also of reduced specificity if the fear of missing significant disease leads to overcalling of benign abnormalities. PMID- 20718842 TI - Aortic and mitral valve stenosis with regurgitation: not due to rheumatic heart disease. AB - The patient is a 13-year-old Mexican-American immigrant who had no previous medical care. Upon arrival to the United States she was diagnosed with severe mitral valve stenosis and regurgitation. In addition she had severe aortic stenosis with mild to moderate aortic valve regurgitation, which was thought to be rheumatic heart disease. On the basis of the clinical and echocardiographic findings she was taken to the operating room for both mitral and aortic valve replacement. Her operation was complicated by the discovery that her aorta was completely calcified, as were her coronary arteries, mitral valve and aortic valve. She underwent aortic and mitral valve replacement as well as replacement of her aortic arch. Her coronary arteries were patch augmented and reimplanted into the newly created ascending aorta. Based on the pathologic examination of the surgical tissue a diagnosis of Gaucher disease was made. PMID- 20718843 TI - Differentiation of the left- from right-side ventricular septum in acute anterior myocardial infarction by tissue Doppler imaging. AB - OBJECTIVES: This study was to evaluate the longitudinal and radial function of the left- and right-side ventricular septum (Ls and Rs) in patients with acute anterior myocardial infarction (AMI) by tissue Doppler imaging. METHODS: Thirty patients with anterior ST-elevation AMI and revascularization and 20 age-matched normal subjects were enrolled as controls. The longitudinal and radial systolic tissue velocity (TV), strain rate (SR) and strain (E) of both Ls and Rs were assessed. RESULTS: In normal, there were no significant differences of longitudinal TV, SR and E between the Ls and Rs. The radial TV was same directed, but larger in Ls than Rs (P < 0.001). The radial SR and E were positive values of Ls and negative values of Rs, but the degrees were similar in both sides. In AMI, longitudinal and radial TV were significantly decreased in both sides. However, longitudinal and radial SR and E were significantly decreased in Ls only (P < 0.001 in all). Fourteen patients with AMI who showed no functional recovery had more reduced radial E of Ls (3.9 +/- 1.5% vs. 5.5 +/- 2.1%, P = 0.02), but not longitudinal E of Ls than the other 16 patients with recovery. CONCLUSION: This study showed the ventricular septum can be functionally differentiated the Ls from the Rs, which can be well demonstrated by SR imaging. The impairment of radial rather than longitudinal function of the Ls was related to no functional recovery. PMID- 20718844 TI - Resource allocation for efficient environmental management. AB - Environmental managers must decide how to invest available resources. Researchers have previously determined how to allocate conservation resources among regions, design nature reserves, allocate funding to species conservation programs, design biodiversity surveys and monitoring programs, manage species and invest in greenhouse gas mitigation schemes. However, these issues have not been addressed with a unified theory. Furthermore, uncertainty is prevalent in environmental management, and needs to be considered to manage risks. We present a theory for optimal environmental management, synthesizing previous approaches to the topic and incorporating uncertainty. We show that the theory solves a diverse range of important problems of resource allocation, including distributing conservation resources among the world's biodiversity hotspots; surveillance to detect the highly pathogenic avian influenza H5N1 virus in Thailand; and choosing survey methods for the insect order Hemiptera. Environmental management decisions are similar to decisions about financial investments, with trade-offs between risk and reward. PMID- 20718845 TI - Testing the Janzen-Connell mechanism: pathogens cause overcompensating density dependence in a tropical tree. AB - The Janzen-Connell hypothesis is a leading explanation for plant-species diversity in tropical forests. It suggests that specialized natural enemies decrease offspring survival at high densities beneath parents, giving locally rarer species an advantage. This mechanism, in its original form, assumes that density dependence is overcompensating: mortality must be disproportionately high at the highest densities, with few offspring recruiting below their parents. We tested this assumption using parallel shadehouse and field density-series experiments on seedlings of a tropical tree, Pleradenophora longicuspis. We found strong, overcompensating mortality driven by fungal pathogens, causing 90% (shadehouse) or 100% (field) mortality within 4 weeks of germination, and generating a negative relationship between initial and final seedling densities. Fungicide treatment led to much lower, density-independent, mortality. Overcompensating mortality was extremely rapid, and could be missed without detailed monitoring. Such dynamics may prevent dead trees from being replaced by conspecifics, promoting coexistence as envisioned by the Janzen-Connell hypothesis. PMID- 20718846 TI - Trade-offs and the evolution of life-histories during range expansion. AB - During range-advance, individuals on the expanding edge of the population face a unique selective environment. In this study, we use a three-trait trade-off model to explore the evolution of dispersal, reproduction and competitive ability during range expansion. We show that range expansion greatly affects the evolution of life-history traits due to differing selection pressures at the front of the range compared with those found in stationary and core populations. During range expansion, dispersal and reproduction are selected for on the expanding population front, whereas traits associated with fitness at equilibrium density (competitive ability) show dramatic declines. Additionally, we demonstrate that the presence of a competing species can considerably reduce the extent to which dispersal is selected upwards at an expanding front. These findings have important implications for understanding both the rate of spread of invasive species and the range-shifting dynamics of native species in response to climate change. PMID- 20718847 TI - Endocrine autoimmune disease: genetics become complex. AB - The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed. PMID- 20718848 TI - Value of exercise echocardiography for predicting mortality in elderly patients. AB - BACKGROUND: Elderly patients with suspected or known coronary artery disease are often referred for pharmacological stress testing. Data on the value of exercise echocardiography (ExEcho) for predicting outcome (particularly all-cause mortality) in these patients are scarce. METHODS: Peak treadmill ExEcho was performed in 2159 patients >= 70 years of age with known or suspected coronary artery disease. Left ventricular wall motion was evaluated at baseline and with exercise, and the increase in wall motion score index from rest to peak exercise (DeltaWMSI) was calculated. Ischaemia was diagnosed when new or worsening wall motion abnormalities developed with exercise. The end points were all-cause mortality and major cardiac events (cardiac death or myocardial infarction). RESULTS: Ischaemia developed in 844 patients (38.6%) during exercise. Over a mean follow-up of 3.5 +/- 3.1 years, 439 deaths occurred. The cumulative 5-year mortality rate was 29.3% in patients with ischaemia versus 16.8% in those without ischaemia (P < 0.001). After covariate adjustment, DeltaWMSI remained an independent predictor of mortality [hazard ratio (HR) 2.37, 95% confidence interval (CI) 1.66-3.39, P < 0.001] and major cardiac events (HR 3.48, 95% CI 2.11-5.74, P < 0.001). These results remained significant even in patients with chronotropic incompetence. When added to a model with clinical, resting echocardiographic and exercise electrocardiogram variables, ExEcho results provided incremental value for the prediction of both end points (P < 0.001). CONCLUSIONS: ExEcho is feasible in elderly patients with suspected or known coronary artery disease and provides useful information for risk stratification in these patients. PMID- 20718849 TI - Active matrix metalloproteinase-2 upregulation in the abdominal skin of patients with direct inguinal hernia. AB - BACKGROUND: Prior studies suggest impaired collagen metabolism involving the whole abdominal wall including the skin in patients with abdominal hernia. We compared expression patterns of matrix metalloproteinase-2 (MMP-2) and its modulators membrane type-1-matrix metalloproteinase (MT-1 MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the skin of patients with and without primary inguinal hernia. MATERIALS AND METHODS: Skin biopsy specimens from abdominal wall incisions were obtained during surgery from patients with direct inguinal hernia, indirect inguinal hernia or without hernia (controls). MMP-2, MT-1 MMP and TIMP-2 expression were determined using immunocytochemistry and immunoblotting in intact tissue and in cultured fibroblasts isolated from the biopsies. The degradation activity of MMP-2 was semiquantitatively determined using zymography. RESULTS: Significantly greater active MMP-2 expression was observed in skin fibroblasts obtained from patients with direct hernia compared with controls. MT1-MMP expression was directly correlated with MMP-2 expression with most intense staining produced in patients with direct or indirect inguinal hernia. TIMP-2, was maximally expressed in the control group, with significantly diminished expression levels recorded in the hernia groups. CONCLUSIONS: Our findings indicate active MMP-2 upregulation in the abdominal skin of patients with direct inguinal hernia. This metalloproteinase plays a role in matrix degradation, weakening the abdominal wall. Skin disorders and previously described transversalis fascia defects in these patients could point to a systemic collagen metabolism abnormality as a risk factor for direct hernia. PMID- 20718850 TI - Interactions among gender, age, hypertension and C-reactive protein in coronary vasospasm. AB - BACKGROUND: Coronary vasospasm (CVsp) has been reported to be an inflammatory disease, reflected by elevated high-sensitivity C-reactive protein (hs-CRP). We investigated the interactions among gender, age, hypertension and hs-CRP in patients with CVsp. MATERIALS AND METHODS: We retrospectively examined 722 Taiwanese patients with or without CVsp during an 8-year period. None of the patients had obstructive coronary artery disease. Serum hs-CRP levels were examined in a subset of 375 patients to evaluate the interactions of hs-CRP with gender, age, smoking and hypertension in the development of CVsp. RESULTS: In women, only the highest hs-CRP tertile (> 3 mg L-1) was independently associated with CVsp. In men, age > 58 years and the highest hs-CRP tertile were independently associated with CVsp. In women, elevated risk was only demonstrated in patients <= 58 years of age with hs-CRP levels in the highest tertile. In men, a positively monotonic trend was demonstrated between hs-CRP levels and CVsp in those > 58 years of age. The odds ratios of CVsp in both women and men with hs CRP in the highest tertile reduced from 6.01 to 1.48 and 6.35-2.69 respectively, if they had hypertension. CONCLUSION: The relationship between hs-CRP and CVsp differed between men and women. Our findings that there is a non-threshold model in men and a threshold model in women provide evidence that more smokers in men (life-style) and age (induction time) contribute to the natural history of CVsp development. The negative effect of hypertension on CVsp suggests that the pathogenesis of CVsp differs from that of coronary atherosclerosis. PMID- 20718851 TI - Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force. AB - BACKGROUND: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. METHODS: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. RESULTS AND CONCLUSIONS: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress. PMID- 20718852 TI - Commentary: Genetic news between ventricle and nose (Commentary on Poon et al.). PMID- 20718854 TI - Perinatal development of inhibitory synapses in the nucleus tractus solitarii of the rat. AB - The nucleus tractus solitarii (NTS) plays a key role in the central control of the autonomic nervous system. In adult rats, both GABA and glycine are used as inhibitory neurotransmitter in the NTS. Using a quantitative morphological approach, we have investigated the perinatal development of inhibitory synapses in the NTS. The density of both inhibitory axon terminals and synapses increased from embryonic day 20 until the end of the second postnatal week (postnatal day 14). Before birth, only GABAergic axon terminals developed and their number increased during the first postnatal week. Mixed GABA/glycine axon terminals appeared at birth and their number increased during the first postnatal week. This suggests the development of a mixed GABA/glycine inhibition in parallel to pure GABA inhibition. However, whereas GABAergic axon terminals were distributed throughout the NTS, mixed GABA/glycine axon terminals were strictly located in the lateral part of the NTS. Established at birth, this specific topography remained in the adult rat. From birth, GABA(A) receptors, glycine receptors and gephyrin were clustered in inhibitory synapses throughout the NTS, revealing a neurotransmitter-receptor mismatch within the medial part of the NTS. Together these results suggest that NTS inhibitory networks develop and mature until postnatal day 14. Developmental changes in NTS synaptic inhibition may play an important role in shaping neural network activity during a time of maturation of autonomic functions. The first two postnatal weeks could represent a critical period where the impact of the environment influences the physiological phenotypes of adult rats. PMID- 20718853 TI - Identification of a Chr 11 quantitative trait locus that modulates proliferation in the rostral migratory stream of the adult mouse brain. AB - Neuron production takes place continuously in the rostral migratory stream (RMS) of the adult mammalian brain. The molecular mechanisms that regulate progenitor cell division and differentiation in the RMS remain largely unknown. Here, we surveyed the mouse genome in an unbiased manner to identify candidate gene loci that regulate proliferation in the adult RMS. We quantified neurogenesis in adult C57BL/6J and A/J mice, and 27 recombinant inbred lines derived from those parental strains. We showed that the A/J RMS had greater numbers of bromodeoxyuridine-labeled cells than that of C57BL/6J mice with similar cell cycle parameters, indicating that the differences in the number of bromodeoxyuridine-positive cells reflected the number of proliferating cells between the strains. AXB and BXA recombinant inbred strains demonstrated even greater variation in the numbers of proliferating cells. Genome-wide mapping of this trait revealed that chromosome 11 harbors a significant quantitative trait locus at 116.75 +/- 0.75 Mb that affects cell proliferation in the adult RMS. The genomic regions that influence RMS proliferation did not overlap with genomic regions regulating proliferation in the adult subgranular zone of the hippocampal dentate gyrus. On the contrary, a different, suggestive locus that modulates cell proliferation in the subgranular zone was mapped to chromosome 3 at 102 +/- 7 Mb. A subset of genes in the chromosome 11 quantitative trait locus region is associated with neurogenesis and cell proliferation. Our findings provide new insights into the genetic control of neural proliferation and an excellent starting point to identify genes critical to this process. PMID- 20718855 TI - Developmental increase in D1-like dopamine receptor-mediated inhibition of glutamatergic transmission through P/Q-type channel regulation in the basal forebrain of rats. AB - Whole-cell patch-clamp recordings of non-N-methyl-d-aspartate glutamatergic excitatory postsynaptic currents (EPSCs) were carried out from cholinergic neurons in slices of basal forebrain (BF) of developing rats aged 21-42 postnatal days to elucidate postnatal developmental change in Ca(2+) channel subtypes involved in the transmission as well as that in dopamine D(1)-like receptor mediated presynaptic inhibition. The amplitude of EPSCs was inhibited by bath application of omega-conotoxin GVIA (omega-CgTX; 3 microM) or omega-agatoxin-TK (omega-Aga-TK; 200 nM) throughout the age range examined, suggesting that multiple types of Ca(2+) channel are involved in the transmission. The EPSC fraction reduced by omega-CgTX decreased with age, whereas that reduced by omega Aga-TK increased. Inhibition of the EPSCs by a D(1)-like receptor agonist, SKF 81297 (SKF; 30 microM) increased with age in parallel with the increase in omega Aga-TK-induced inhibition. An activator of the adenylyl cyclase (AC) pathway, forskolin (FK; 10 microM) inhibited the EPSCs, and FK-induced inhibition also increased with age in parallel with the increase in SKF-induced inhibition. Throughout the age range examined, SKF showed no further inhibitory effect on the EPSCs after omega-Aga-TK- or FK-induced effect had reached steady-state. These findings suggest that D(1)-like receptor-mediated presynaptic inhibition of glutamate release onto cholinergic BF neurons increases with age, and that the change is coupled with a developmental increase in the contribution of P/Q-type Ca(2+) channels as well as a developmental increase in AC pathway contribution. PMID- 20718856 TI - Cerebellar Golgi cells in the rat receive convergent peripheral inputs via a lateral reticular nucleus relay. AB - Golgi cells are important players in the function of the cerebellar cortex, controlling the flow of incoming information from mossy fibres to the granule cells, which excite other cortical neurons. We recently showed that in anaesthetized rats most Golgi cells respond to stimulation of afferents from a very wide peripheral receptive field with a long-lasting depression of firing. These responses are mediated via a crossed ascending afferent pathway but the supraspinal part of this pathway is unknown. Here we have examined the hypothesis that the lateral reticular nucleus, a brainstem nucleus with known broad afferent convergence that projects mossy fibres to much of the cerebellum, is involved. First, we showed that single-pulse electrical microstimulation within the lateral reticular nucleus can elicit long-lasting depressions in Golgi cells, which are qualitatively similar to those evoked by peripheral afferent stimulation. Second, we showed that the amplitude of the depressions of Golgi cell firing evoked by peripheral stimulation can be reduced by pharmacological manipulation of the lateral reticular nucleus, either ipsilateral or contralateral to the stimulus site, with local injections of either the GABA(A) receptor agonist muscimol or the AMPA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione. This evidence suggests that the lateral reticular nucleus is a relay nucleus in the brainstem for peripheral afferent information in a pathway that generates Golgi cell long lasting depression responses. PMID- 20718857 TI - Stability of subicular place fields across multiple light and dark transitions. AB - Although hippocampal CA1 place cells can be strongly modulated by visual inputs, the effect of visual modulation on place cells in other areas of the hippocampal formation, such as the subiculum, has been less extensively explored. Here, we investigated the role of visual inputs on the activity of subicular place cells by manipulating ambient light levels while freely-moving rats foraged for food. Rats were implanted with tetrodes in the dorsal subiculum and units were recorded while the animal performed a pellet-chasing task during multiple light-to-dark and dark-to-light transitions. We found that subicular place fields presented a somewhat heterogeneous response to light-dark transitions, with 45% of pyramidal units showing stable locational firing across multiple light-dark-light transitions. These data suggest that visual inputs may participate in spatial information processing by the subiculum. However, as a plurality of units was stable across light-dark transitions, we suggest that the subiculum supports, probably in association with the grid cells of the entorhinal cortex, the neurocognitive processing underlying path integration. PMID- 20718858 TI - Unitized representation of paired objects in area 35 of the macaque perirhinal cortex. AB - The perirhinal cortex, which is critical for long-term stimulus-stimulus associative memory, consists of two cytoarchitectonically distinct subdivisions: area 35 (A35) and area 36 (A36). Previous electrophysiological studies suggested that macaque A36 is involved in both association and retrieval processes during a visual pair-association task. However, the neuronal properties of macaque A35 have never been examined because A35 is located in a very narrow region, which makes it difficult to systematically record single-unit activity from there. In the present study, we overcame this technical difficulty for targeting A35 by combining magnetic resonance imaging-guided in-vivo localization with postmortem histological localization. This two-track approach enabled us to record from 181 A35 neurons in two macaque monkeys while they performed a pair-association task. Among these neurons, 64 showed stimulus-selective responses during the cue period (cue-selective neurons), whereas 18 did during the delay period (delay-selective neurons). As in A36, the responses of cue-selective neurons in A35 to paired associates were correlated. In both areas, these correlations were stronger in neurons showing delay selectivity than in those without delay selectivity. Notably, delay-selective neurons in A35 responded similarly to the optimal stimulus and its paired associate, whereas delay-selective neurons in A36 discriminated between them. However, these neurons in both areas discriminated the primary pair, consisting of the optimal stimulus and its paired associate, from other pairs, indicating that selectivity across pairs was maintained between the two areas. These results suggest that delay-selective neurons in A35 represent these paired stimuli as a single unitized item rather than two associated items. PMID- 20718859 TI - Staphylococcus aureus elongation factor G--structure and analysis of a target for fusidic acid. AB - Fusidic acid (FA) is a bacteriostatic antibiotic that locks elongation factor G (EF-G) on the ribosome in a post-translocational state. It is used clinically against Gram-positive bacteria such as pathogenic strains of Staphylococcus aureus, but no structural information has been available for EF-G from these species. We have solved the apo crystal structure of EF-G from S. aureus to 1.9 A resolution. This structure shows a dramatically different overall conformation from previous structures of EF-G, although the individual domains are highly similar. Between the different structures of free or ribosome-bound EF-G, domains III-V move relative to domains I-II, resulting in a displacement of the tip of domain IV relative to domain G. In S. aureus EF-G, this displacement is about 25 A relative to structures of Thermus thermophilus EF-G in a direction perpendicular to that in previous observations. Part of the switch I region (residues 46-56) is ordered in a helix, and has a distinct conformation as compared with structures of EF-Tu in the GDP and GTP states. Also, the switch II region shows a new conformation, which, as in other structures of free EF-G, is incompatible with FA binding. We have analysed and discussed all known fusA-based fusidic acid resistance mutations in the light of the new structure of EF-G from S. aureus, and a recent structure of T. thermophilus EF-G in complex with the 70S ribosome with fusidic acid [Gao YG et al. (2009) Science326, 694-699]. The mutations can be classified as affecting FA binding, EF-G-ribosome interactions, EF-G conformation, and EF-G stability. PMID- 20718860 TI - High diversity of polyketide synthase genes and the melanin biosynthesis gene cluster in Penicillium marneffei. AB - Despite the unique phenotypic properties and clinical importance of Penicillium marneffei, the polyketide synthase genes in its genome have never been characterized. Twenty-three putative polyketide synthase genes and two putative polyketide synthase nonribosomal peptide-synthase hybrid genes were identified in the P. marneffei genome, a diversity much higher than found in other pathogenic thermal dimorphic fungi, such as Histoplasma capsulatum (one polyketide synthase gene) and Coccidioides immitis (10 polyketide synthase genes). These genes were evenly distributed on the phylogenetic tree with polyketide synthase genes of Aspergillus and other fungi, indicating that the high diversity was not a result of lineage-specific gene expansion through recent gene duplication. The melanin biosynthesis gene cluster had gene order and orientations identical to those in the Talaromyces stipitatus (a teleomorph of Penicillium emmonsii) genome. Phylogenetically, all six genes of the melanin-biosynthesis gene cluster in P. marneffei were also most closely related to those in T. stipitatus, with high bootstrap supports. The polyketide synthase gene of the melanin-biosynthesis gene cluster (alb1) in P. marneffei was knocked down, which was accompanied by loss of melanin pigment production and reduced ornamentation in conidia. The survival of mice challenged with the alb1 knockdown mutant was significantly better than those challenged with wild-type P. marneffei (P < 0.005). The sterilizing doses of hydrogen peroxide, leading to a 50% reduction in survival of conidia, were 11 min for wild-type P. marneffei and 6 min for the alb1 knockdown mutant of P. marneffei, implying that the melanin-biosynthesis gene cluster contributed to virulence through decreased susceptibility to killing by hydrogen peroxide. PMID- 20718861 TI - Proteolysis of Pseudomonas exotoxin A within hepatic endosomes by cathepsins B and D produces fragments displaying in vitro ADP-ribosylating and apoptotic effects. AB - To assess Pseudomonas exotoxin A (ETA) compartmentalization, processing and cytotoxicity in vivo, we have studied the fate of internalized ETA with the use of the in vivo rodent liver model following toxin administration, cell-free hepatic endosomes, and pure in vitro protease assays. ETA taken up into rat liver in vivo was rapidly associated with plasma membranes (5-30 min), internalized within endosomes (15-60 min), and later translocated into the cytosolic compartment (30-90 min). Coincident with endocytosis of intact ETA, in vivo association of the catalytic ETA-A subunit and low molecular mass ETA-A fragments was observed in the endosomal apparatus. After an in vitro proteolytic assay with an endosomal lysate and pure proteases, the ETA-degrading activity was attributed to the luminal species of endosomal acidic cathepsins B and D, with the major cleavages generated in vitro occurring mainly within domain III of ETA-A. Cell free endosomes preloaded in vivo with ETA intraluminally processed and extraluminally released intact ETA and ETA-A in vitro in a pH-dependent and ATP dependent manner. Rat hepatic cells underwent in vivo intrinsic apoptosis at a late stage of ETA infection, as assessed by the mitochondrial release of cytochrome c, caspase-9 and caspase-3 activation, and DNA fragmentation. In an in vitro assay, intact ETA induced ADP-ribosylation of EF-2 and mitochondrial release of cytochrome c, with the former effect being efficiently increased by a cathepsin B/cathepsin D pretreatment. The data show a novel processing pathway for internalized ETA, involving cathepsins B and D, resulting in the production of ETA fragments that may participate in cytotoxicity and mitochondrial dysfunction. PMID- 20718862 TI - Specific cleavage of the DNase-I binding loop dramatically decreases the thermal stability of actin. AB - Differential scanning calorimetry was used to investigate the thermal unfolding of actin specifically cleaved within the DNaseI-binding loop between residues Met47-Gly48 or Gly42-Val43 by two bacterial proteases, subtilisin or ECP32/grimelysin (ECP), respectively. The results obtained show that both cleavages strongly decreased the thermal stability of monomeric actin with either ATP or ADP as a bound nucleotide. An even more pronounced difference in the thermal stability between the cleaved and intact actin was observed when both actins were polymerized into filaments. Similar to intact F-actin, both cleaved F actins were significantly stabilized by phalloidin and aluminum fluoride; however, in all cases, the thermal stability of the cleaved F-actins was much lower than that of intact F-actin, and the stability of ECP-cleaved F-actin was lower than that of subtilisin-cleaved F-actin. These results confirm that the DNaseI-binding loop is involved in the stabilization of the actin structure, both in monomers and in the filament subunits, and suggest that the thermal stability of actin depends, at least partially, on the conformation of the nucleotide binding cleft. Moreover, an additional destabilization of the unstable cleaved actin upon ATP/ADP replacement provides experimental evidence for the highly dynamic actin structure that cannot be simply open or closed, but rather should be considered as being able to adopt multiple conformations. PMID- 20718863 TI - Mouse cytosolic sulfotransferase SULT2B1b interacts with cytoskeletal proteins via a proline/serine-rich C-terminus. AB - Cytosolic sulfotransferase (SULT) SULT2B1b had previously been characterized as a cholesterol sulfotransferase. Like human SULT2B1, mouse SULT2B1b contains a unique, 31 amino acid C-terminal sequence with a proline/serine-rich region, which is not found in members of other SULT families. To gain insight into the functional relevance of this proline/serine-rich region, we constructed a truncated mouse SULT2B1b lacking the 31 C-terminal amino acids, and compared it with the wild-type enzyme. Enzymatic characterization indicated that the catalytic activity was not significantly affected by the absence of those C terminal residues. Glutathione S-transferase pulldown assays showed that several proteins interacted with mouse SULT2B1b specifically through this C-terminal proline/serine-rich region. Peptide mass fingerprinting revealed that of the five SULT2B1b-binding proteins analyzed, three were cytoskeletal proteins and two were cytoskeleton-binding molecular chaperones. Furthermore, wild-type mouse SULT2B1b, but not the truncated enzyme, was associated with the cytoskeleton in experiments with a cytoskeleton-stabilizing buffer. Collectively, these results suggested that the unique, extended proline/serine-rich C-terminus of mouse SULT2B1b is important for its interaction with cytoskeletal proteins. Such an interaction may allow the enzyme to move along microfilaments such as actin filaments, and catalyze the sulfation of hydroxysteroids, such as cholesterol and pregnenolone, at specific intracellular locations. PMID- 20718864 TI - A novel prokaryotic L-arginine:glycine amidinotransferase is involved in cylindrospermopsin biosynthesis. AB - We report the first characterization of an L-arginine:glycine amidinotransferase from a prokaryote. The enzyme, CyrA, is involved in the pathway for biosynthesis of the polyketide-derived hepatotoxin cylindrospermopsin from Cylindrospermopsis raciborskii AWT205. CyrA is phylogenetically distinct from other amidinotransferases, and structural alignment shows differences between the active site residues of CyrA and the well-characterized human L-arginine:glycine amidinotransferase (AGAT). Overexpression of recombinant CyrA in Escherichia coli enabled biochemical characterization of the enzyme, and we confirmed the predicted function of CyrA as an L-arginine:glycine amidinotransferase by (1) H NMR. As compared with AGAT, CyrA showed narrow substrate specificity when presented with substrate analogs, and deviated from regular Michaelis-Menten kinetics in the presence of the non-natural substrate hydroxylamine. Studies of initial reaction velocities and product inhibition, and identification of intermediate reaction products, were used to probe the kinetic mechanism of CyrA, which is best described as a hybrid of ping-pong and sequential mechanisms. Differences in the active site residues of CyrA and AGAT are discussed in relation to the different properties of both enzymes. The enzyme had maximum activity and maximum stability at pH 8.5 and 6.5, respectively, and an optimum temperature of 32 degrees C. Investigations into the stability of the enzyme revealed that an inactivated form of this enzyme retained an appreciable amount of secondary structure elements even on heating to 94 degrees C, but lost its tertiary structure at low temperature (T(max) of 44.5 degrees C), resulting in a state reminiscent of a molten globule. CyrA represents a novel group of prokaryotic amidinotransferases that utilize arginine and glycine as substrates with a complex kinetic mechanism and substrate specificity that differs from that of the eukaryotic L-arginine:glycine amidinotransferases. PMID- 20718865 TI - Conformation-dependent hydride transfer in neuronal nitric oxide synthase reductase domain. AB - Calmodulin (CaM) activates the constitutive isoforms of mammalian nitric oxide synthase by triggering electron transfer from the reductase domain FMN to the heme. This enables the enzymes to be regulated by Ca(2+) concentration. CaM exerts most of its effects on the reductase domain; these include activation of electron transfer to electron acceptors, and an increase in the apparent rate of flavin reduction by the substrate NADPH. It has been shown that the former is caused by a transition from a conformationally locked form of the enzyme to an open form as a result of CaM binding, improving FMN accessibility, but the latter effect has not been explained satisfactorily. Here, we report the effect of ionic strength and isotopic substitution on flavin reduction. We found a remarkable correlation between the rate of steady-state turnover of the reductase domain and the rate of flavin reduction over a range of different ionic strengths. The reduction of the enzyme by NADPH was biphasic, and the amplitudes of the phases determined through global analysis of stopped-flow data correlated with the proportions of enzyme known to exist in the open and closed conformations. The different conformations of the enzyme molecule appeared to have different rates of reaction with NADPH. Thus, proximity of FMN inhibits hydride transfer to the FAD. In the CaM-free enzyme, slow conformational motion (opening and closing) limits turnover. It is now clear that this motion also controls hydride transfer during steady-state turnover, by limiting the rate at which NADPH can access the FAD. PMID- 20718866 TI - Catalytic digestion of human tumor necrosis factor-alpha by antibody heavy chain. AB - It has long been an important task to prepare a catalytic antibody capable of digesting a targeting crucial protein that controls specific life functions. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine and an important molecule concerned with autoimmune diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease, and Crohn's disease. A mAb (ETNF-6 mAb) raised against human TNF-alpha was prepared, and the steric conformation was created by using molecular modeling after the cDNA was sequenced. The heavy chain (ETNF-6-H) of the mAb was considered to possess a catalytic triad-like structure in the complementarity determining regions (CDRs). As a result, ETNF-6-H exhibited a peptidase and a protease activity. In fact, ETNF-6-H predominantly cleaved the Ser5-Arg6 bond of TNF-alpha at the first step, resulting in the generation of a fragment of ~ 17 kDa. This fragment was digested to a smaller molecule of 15 kDa by scission of the Gln21-Ala22 bond. The intermediate product was further converted into a fragment of 13.3 kDa by successive cleavage of the Leu36-Leu37 and Asn39-Gly40 bonds. The heavy chain possessed a protease activity against TNF alpha with a multicleavage site. PMID- 20718867 TI - Small-molecule modulators of zymogen activation in the fibrinolytic and coagulation systems. AB - The coagulation and fibrinolytic systems are central to the hemostatic mechanism, which works promptly on vascular injury and tissue damage. The rapid response is generated by specific molecular interactions between components in these systems. Thus, the regulation mechanism of the systems is programmed in each component, as exemplified by the elegant processes in zymogen activation. This review describes recently identified small molecules that modulate the activation of zymogens in the fibrinolytic and coagulation systems. PMID- 20718868 TI - Induction of Kruppel-like factor 4 by high-density lipoproteins promotes the expression of scavenger receptor class B type I. AB - Kruppel-like factor 4 (KLF4) is an evolutionarily conserved zinc finger containing transcription factor. In the present study, peripheral blood mononuclear cells and phorbol 12-myristate 13-acetate-differentiated THP-1 cells were treated with oxidized low-density lipoproteins and high-density lipoproteins to determine the expression of KLF4 and scavenger receptor class B type I (SR BI). A full-length cDNA of KLF4 or short interference RNA against KLF4 was transfected into THP-1 cells, and the subsequent expressions of SR-BI were analysed by real-time PCR and western blot. The binding and transcriptional activities of KLF4 to the SR-BI promoter were detected by electrophoretic mobility shift assay, chromatin immunoprecipitation assay and luciferase reporter assay. The results showed that induction of KLF4 by high-density lipoproteins could promote the expression of SR-BI, resulting from the binding to putative KLF4 binding element on the promoter of SR-BI. All results indicate a potential function of KLF4 in the pathogenesis of atherosclerosis through the regulation effect on atherosclerotic-related genes. PMID- 20718869 TI - Microarray analysis of a microbe-mineral interaction. AB - The weathering of volcanic minerals makes a significant contribution to the global silicate weathering budget, influencing carbon dioxide drawdown and long term climate control. Basalt rocks may account for over 30% of the global carbon dioxide drawdown in silicate weathering. Micro-organisms are known to play a role in rock weathering yet the genomics and genetics of biological rock weathering are unknown. We apply DNA microarray technology to determine putative genes involved in weathering using the heavy metal-resistant organism, Cupriavidus metallidurans CH34; in particular we investigate the sequestering of iron. The results show that the bacterium does not depend on siderophores. Instead, the up regulation of porins and transporters which are employed concomitantly with genes associated with biofilm formation suggests that novel passive and active iron uptake systems are involved. We hypothesize that these mechanisms induce rock weathering by changes in chemical equilibrium at the microbe-mineral interface, reducing the saturation state of iron. We also demonstrate that low concentrations of metals in the basalt induce heavy metal-resistant genes. Some of the earliest environments on the Earth were volcanic. Therefore, these results not only elucidate the mechanisms by which micro-organisms might have sequestered nutrients on the early Earth but also provide an explanation for the evolution of multiple heavy metal resistance genes long before the creation of contaminated industrial biotopes by human activity. PMID- 20718870 TI - Prevalence of dental myths, oral hygiene methods and tobacco habits in an ageing North Indian rural population. AB - BACKGROUND AND OBJECTIVES: Though increased emphasis is being given to expanding dental care facilities and awareness in Indian villages, the target population is unfortunately less literate and financially-equipped compared to their urban counterparts. This study attempted to evaluate dental myths, oral hygiene methods and beliefs, and tobacco habits present in a rural ageing population. MATERIAL AND METHODS: The study area consisted of a group of 10 villages, situated in the district of Lucknow, Uttar Pradesh, India. The sample comprised 681 people aged 50 years or above. The subjects were questioned about dental myths, tobacco habits and oral hygiene methods and then divided into groups on the basis of age, gender, and educational status. Mean values, standard deviation, chi-square test, t-test and p values were used to obtain inter-group comparisons. RESULTS: Forty percent of the subjects considered oral hygiene unnecessary, with 61% relying on simple mouth rinsing for maintaining oral hygiene, 48% either smoked and chewed tobacco or both and 81% had one or more dental myth. CONCLUSION: The results showed that the rural ageing population is deprived and a targeted programme to spread scientific dental practices to them is necessary. PMID- 20718871 TI - Update on tumours of the adrenal cortex, phaeochromocytoma and extra-adrenal paraganglioma. AB - This review covers aspects of adrenal cortical tumours, phaeochromocytoma and extra-adrenal paragangliomas. Relevant clinical and epidemiological information is included. It is now known that about 30% of paragangliomas occur in a familial setting and these new aspects of the genetic background are presented. The main diagnostic problem in both groups of tumours is the recognition of malignant potential. The uses and limitations of multifactorial histological assessment in diagnosis and prognosis are discussed. Finally, data on the molecular changes associated with tumorigenesis and tumour progression are highlighted, and how this information may contribute in future to diagnosis and prognosis. PMID- 20718872 TI - Desmoplasia: not always a bad thing. AB - Desmoplasia describes a histological pattern characterized by a hyalinized stroma and a minimal cellular infiltrate. In non-cutaneous neoplasms, this pattern of stromal response is classically associated with malignancy, whereas in cutaneous pathology, desmoplasia is observed in malignant as well as benign neoplasms. Given this, the obvious question is whether desmoplasia associated with a benign neoplasm is any different from that associated with malignant tumours. Is the stromal response a mere epiphenomenon, or does it actually contribute to the biological behaviour of the neoplasm? What happens at the tumour-host interface? Which molecules are involved in mediating the desmoplastic reaction pattern? This review is an attempt to answer these questions. Examples of benign and malignant cutaneous neoplasms associated with the desmoplastic reaction pattern will be included. PMID- 20718873 TI - A new allele, HLA-B*4212, identified in a Brazilian volunteer bone marrow donors by sequence-based typing. AB - Here we report the discovery of a novel HLA-B allele, named B*4212 in a Brazilian volunteer bone marrow donor. The new sequence has nucleotide variation at position 496 (T->G) as compared with B*4201. This variation results in a conservative amino acid substitution from valine to glycine at codon 165 of exon 3. PMID- 20718874 TI - Stability and robustness of blood variables in an antidoping context. AB - INTRODUCTION: With the setting up of the newly Athlete's Biological Passport antidoping programme, novel guidelines have been introduced to guarantee results beyond reproach. We investigated in this context, the effect of storage time on the variables commonly measured for the haematological passport. We also wanted to assess for these variables, the within and between analyzer variations. METHODS: Blood samples were obtained from top level male professional cyclists (27 samples for the first part of the study and 102 for the second part) taking part to major stage races. After collection, they were transported under refrigerated conditions (2 degrees C < T < 12 degrees C), delivered to the antidoping laboratory, analysed and then stored at approximately 4 degrees C to conduct analysis at different time points up to 72 h after delivery. A mixed model procedure was used to determine the stability of the different variables. RESULTS: As expected haemoglobin concentration was not affected by storage and showed stability for at least 72 h. Under the conditions of our investigation, the reticulocytes percentage showed a much better stability than previous published data (> 48 h) and the technical comparison of the haematology analyzer demonstrated excellent results. CONCLUSION: In conclusion, our data clearly demonstrate that as long as the World Anti-Doping Agency's guidelines are followed rigorously, all blood results reach the quality level required in the antidoping context. PMID- 20718875 TI - The new haematology analyzer DxH 800: an evaluation of the analytical performances and leucocyte flags, comparison with the LH 755. AB - INTRODUCTION: The analytical performance and the abnormality messages on differential (flags) of the new analyzer Beckman Coulter DxH 800 were compared with those of the LH 755. METHODS: First, we evaluated the accuracy of the results of the DxH 800, in comparison with the LH 755, in 125 samples without alarm using unflagged sample results on both analyzers. Second, flagged samples on the LH 755 but not flagged by the DxH 800 were evaluated by flow cytometry for accuracy of the DxH 800 results. Finally, we evaluated the sensitivity and specificity of abnormality messages on differential given by the analyzers, in comparison with manual blood smears. RESULTS: The correlation coefficients (R) for complete blood count parameters and differential demonstrated that the DxH 800 results were similar to that of LH 755. Excellent correlation coefficients between DxH 800 and flow cytometry results were found for white blood cell count (R = 0.985, n = 31), platelet count (R = 0.976, n = 51) and nucleated red blood cells (R = 0.966, n = 37). The overall performance showed an increased sensitivity (0.892) and specificity (0.864) of the flags on DxH 800 when compared to the LH 755 (0.846 and 0.733, respectively). CONCLUSION: The DxH 800 provides reliable results and increases laboratory efficiency by reducing working time and costs associated with the optical validation of the results. PMID- 20718877 TI - UK National Clinical Guidelines in Paediatric Dentistry: treatment of traumatically intruded permanent incisor teeth in children. PMID- 20718878 TI - Guideline for the use of fissure sealants including management of the stained fissure in first permanent molars. PMID- 20718879 TI - British Society of Paediatric Dentistry: a policy document on management of caries in the primary dentition. PMID- 20718881 TI - Addiction medicine: a new medical specialty in a new age of medicine. PMID- 20718882 TI - Management strategies for recurrent vasovagal syncope. AB - Vasovagal syncope (VVS) is the commonest cause of recurrent syncope and has a high level of morbidity in both young and elderly patients. Diagnosis and treatment are often unsatisfactory despite the fact that syncope has a lifetime cumulative incidence of 35%. A detailed history can often yield an accurate diagnosis in most young patients. Older patients are more likely to present in an atypical manner and although the yield is low, a more comprehensive diagnostic assessment may be needed. It is important to identify patients with low supine systolic blood pressure who are prone to recurrent VVS. These patients represent a distinct subtype of VVS and may respond to a tailored therapeutic approach. Treatment options for VVS are limited because of a paucity of randomized trials. The backbone of therapy is educating the patient, avoiding precipitating factors, maintaining hydration and the application of physical counter-pressure manoeuvres. Drug therapy is rarely warranted; however, fludrocortisone, alpha agonists, such as midodrine and dihydroergotamine, and selective serotonin reuptake inhibitors may be helpful in some patients. Permanent cardiac pacing is rarely needed and randomized trials do not support its use. PMID- 20718883 TI - Comparison of the distribution of citations received by articles published in high, moderate, and low impact factor journals in clinical medicine. AB - BACKGROUND: Whether the journal impact factor (JIF) indicator reflects the number of citations to an average article of a journal in different subject categories is controversial. We sought to further investigate this issue in general and internal medicine journals. METHODS: We selected to evaluate three journals of the above subject category, in each of three different JIF levels (high: 15.5 28.6, moderate: 4.4-4.9 and low: 1.6). Using the Scopus database, we retrieved the original research articles (after detailed screening) and review articles (as classified by Scopus) that were published in the selected journals in 2005 along with the number of citations they received in 2006 and 2007. We pooled the citations for articles of the same type in journals with the same JIF level into distinct variables. RESULTS: There was no marked association between the distribution of citations per article published in general medical journals and their JIF. All distributions studied were skewed to the right (higher number of citations). Specifically, 16-22% of the original research articles accounted for 50% of the total citations to this type of article for all three categories of studied journals; 34-37% of original research articles accounted for 75% of citations. The respective values for review articles were 12-18% and 29-39%. CONCLUSION: The distribution of citations received by articles published in high, moderate and low impact factor journals in clinical medicine seems similar. The JIF is not an accurate indicator of the citations the average article receives; articles published in low impact factor journals can still be highly cited and vice versa. PMID- 20718884 TI - A quantity survey of intravenous administration of metronidazole in its different forms in a tertiary teaching hospital. AB - The aim of this paper is to examine the prescribing patterns and cost of various formulations of metronidazole in a hospital setting over a 3-month period. Oral metronidazole has high bioavailability (98.9%) with peak plasma concentrations averaged at 2.3 h after dosing. Despite the high bioavailability of oral metronidazole, many patients continue to receive metronidazole intravenously when they are suitable for oral preparation. An audit of 120 consecutive patients prescribed metronidazole was conducted at the Liverpool Hospital, NSW, from March to July 2005. There were 65 men and 55 women (age 18-93). Of the 120 patients, 16 were on oral, 1 on rectal and 103 were on intravenous metronidazole. Treatment was initiated based on clinical diagnoses. Potential pathogens were subsequently identified on only 21 occasions. The use of metronidazole as an oral preparation was contraindicated in 27 patients (22.5%) who were nil-by-mouth. Of these, rectally administered metronidazole was contraindicated in only eight patients. The average course of intravenous metronidazole was 8.0 +/- 9.7 days (mean +/- SD). The total number of intravenous metronidazole treatment days was 824. Oral metronidazole would have been possible in 618 out of the 824 days. The estimated cost to administer each dose of oral, suppository and intravenous forms of metronidazole is $A0.11, $A1.34 and $A6.09 respectively. Thus, substantial savings could be achieved if oral metronidazole were to be administered whenever possible. The early use of oral or rectal metronidazole should be encouraged when there are no clinical contraindications. PMID- 20718885 TI - Rapid and sequential desensitization to both aspirin and clopidogrel. AB - Hypersensitivity reactions to aspirin and clopidogrel are 2.5% and 1%, respectively. Dual anti-platelet therapy with these drugs is effective in preventing thrombosis following deployment of stents for cerebrovascular and cardiovascular syndromes. Desensitization therapy with both aspirin and clopidogrel may be required for patients undergoing stent implantation that have experienced hypersensitivity to these agents. We report the case of a 58-year-old woman who developed urticaria and angioedema following aspirin therapy for ischaemic cerebrovascular disease. She developed an identical reaction after clopidogrel was subsequently administered. Investigations revealed the presence of an internal carotid artery aneurysm that required deployment of a stent. Rapid desensitization to aspirin over 5.5 h followed 3 days later by rapid desensitization to clopidogrel over 2.5 h was successfully performed prior to stenting. After 4 months she has tolerated this dual anti-platelet therapy without any adverse reaction. Rapid and sequential desensitization to both aspirin and clopidogrel can be successfully performed for patients who require stent deployment but have hypersensitivity to both these anti-platelet agents. PMID- 20718886 TI - Ectopic splenomegaly. PMID- 20718887 TI - Parenchymal neurocysticercosis. PMID- 20718888 TI - Organ donation in Australia. PMID- 20718890 TI - Emergency department management of exacerbation of chronic obstructive pulmonary disease: low compliance or real world? PMID- 20718892 TI - End-of-life decision-making in patients with locked-in syndrome. PMID- 20718893 TI - e-Health: a step forward but not without risk. PMID- 20718894 TI - Dental implants in patients with rheumatoid arthritis: clinical outcome and peri implant findings. AB - PURPOSE: Implant prosthodontic treatment outcomes for patients suffering from autoimmune rheumatoid arthritis (RA) with or without concomitant connective tissue diseases (CTD) were evaluated. MATERIAL AND METHODS: Thirty-four female patients' (25 isolated RA; nine RA+CTD) implant survival/success rate, peri implant conditions (marginal bone loss, pocket depth, plaque index, gingiva index and bleeding index) and incidence of prosthodontic maintenance were retrospectively evaluated. RESULTS: Implants evaluated presented a high implant survival (100%) and a 3.5-year success (93.8%) rate during the follow-up programme (mean 47.6 month) without difference between isolated RA (94.6%) and RA and concomitant CTD (92.3%), respectively. In isolated RA, acceptable marginal bone resorption (mean: 2.1 mm; SD: 0.5 mm), pocket depth (mean: 2.8 mm; SD:3.2 mm) and healthy soft-tissue conditions (plaque/bleeding/gingiva index Grade 0 in 80%) were noticed. However, patients with RA+CTD presented increased bone resorption (mean: 3.1 mm; SD: 0.7 mm) and more vulnerable soft-tissue conditions (higher bleeding index) differing significantly to patients with isolated RA (p<0.01). Peri-implant parameters were significantly influenced by the patients' underlying disease (RA, RA+CTD; Kruskal-Wallis test, Jonckheere-Terpstra test). CONCLUSIONS: In contrast to isolated RA, in RA patients with concomitant CTD, differences in the peri-implant parameters such as pronounced marginal bone resorption and bleeding may be anticipated and appear to be significantly influenced by the patients' underlying disease. PMID- 20718895 TI - Serum levels of interleukin-10 and tumour necrosis factor-alpha in chronic periodontitis. AB - AIMS: To investigate, using a cross-sectional study design, whether the extent of periodontal inflammation associates with the serum levels of cytokine interleukin (IL)-10 and tumour necrosis factor (TNF)-alpha and their ratio. MATERIAL AND METHODS: The study group consisted of 61 subjects with chronic periodontitis and 30 control subjects with minimally inflamed periodontal tissues. Probing pocket depth (PD), bleeding on probing (BOP) and periodontal attachment level (AL) were measured. The serum IL-10 (pg/ml) and TNF-alpha (U/l) levels were analysed using enzyme-linked immunosorbent assays. After categorization of the subjects, associations between serum IL-10 and TNF-alpha levels and the extent of periodontal inflammation were studied using linear regression models adjusted for age, gender, body mass index and smoking. RESULTS: A negative, partly dose dependent association existed between the extent of BOP, PD >= 4 mm and AL >= 4 mm and serum IL-10 level. The subjects in the periodontitis group presented significantly higher serum TNF-alpha levels and their TNF-alpha/IL-10 ratio was approximately threefold when compared with the ratio in the control group. CONCLUSIONS: The significantly higher serum TNF-alpha/IL-10 ratio in the subjects with chronic periodontitis when compared with the ratio in the controls is indicative of a stronger systemic pro-inflammatory state in chronic periodontitis. PMID- 20718897 TI - The importance of attached nail plate epithelium in the diagnosis of nail apparatus melanoma. PMID- 20718898 TI - Baldy. PMID- 20718900 TI - Meyerson-Phenomenon hides a nevus flammeus. AB - Facial eczema is a common disease in daily dermatological practice. The cause of facial eczema is often atopic dermatitis or allergic contact dermatitis. Usually, the eczema resolves with correct topical treatment and by avoiding allergic trigger factors. A 49-year-old woman presented with persistent eczema on her forehead which recurred over decades despite correct topical therapy. A skin biopsy revealed the astonishing diagnosis of a nevus flammeus with an overlying eczema known as the Meyerson phenomenon. The Meyerson phenomenon is often described in children with nevi flammei suffering from atopic dermatitis - in adults the phenomenon is rarely recognized as a reason for eczema. We show the interesting case of an adult woman with the Meyerson phenomenon on a nevus flammeus and discuss the possible pathomechanisms. PMID- 20718901 TI - Oral ivermectin for head lice: a comparison with 0.5 % topical malathion lotion. AB - BACKGROUND: Reports of treatment failure of head lice have become increasingly common. Oral ivermectin has been proposed as a potential alternative for the treatment of head lice infestation. The aim of this study was to compare the efficacy of oral ivermectin with topical malathion lotion in the treatment of head lice. PATIENTS AND METHODS: Eighty apparently healthy children with head lice infestation were randomly assigned to 2 groups, with 40 patients in each. The first group received oral ivermectin as a single dose of 200 MUg/kg and the second group received single topical application of malathion lotion 0.5%. Follow up visits were done at days 8, 15 and 29. A second dose of either drug was given at day 8 in case of treatment failure. RESULTS: After a single dose, complete cure was achieved in 77.5% and 87.5% of ivermectin and malathion groups respectively. After the second dose for nonresponders, the cure rate increased to 92.5% in the ivermectin group and 95% in the malathion group. No major adverse effects were observed in either group. CONCLUSIONS: Oral ivermectin is a promising effective approach for the treatment of head lice and could be an ideal substitute for conventional pediculicides. PMID- 20718902 TI - Plasma medicine: possible applications in dermatology. AB - As a result of both the better understanding of complex plasma phenomena and the development of new plasma sources in the past few years, plasma medicine has developed into an innovative field of research showing high potential. While thermal plasmas have long been used in various medical fields (for instance for cauterization and sterilization of medical instruments), current research mainly focuses on application of non-thermal plasmas. Experiments show that cold atmospheric plasmas (CAPs) allow efficient, contact-free and painless disinfection, even in microscopic openings, without damaging healthy tissue. Plasmas influence biochemical processes and offer new possibilities for the selective application of individually designable medically active substances. In dermatology, new horizons are being opened for wound healing, tissue regeneration, therapy of skin infections, and probably many more diseases. First clinical trials show the efficacy and tolerability of plasma in treating infected chronic wounds. A major task will be the introduction of plasma into clinical medicine and, simultaneously, the further investigation of the mechanisms of action of plasma at the cellular level. PMID- 20718904 TI - Editorial: at the bifurcation of the last frontiers. AB - The concept of coronary angioplasty percutaneous coronary intervention (PCI) was pioneered by Andreas Gruntzig. Since then, several modifications, innovative devices, techniques, and advances have revolutionized the practice of interventional cardiology. Coronary bifurcation and chronic total occlusion are the last two frontiers that continue to challenge the skills of the interventional cardiologists. Proceedings of the second Bifurcation Summit held from November 26 to 28, 2009 in Nanjing, China are published in this symposium. In a general review, the state of the art in management of bifurcation lesion is summarized in the statement of the "Bifurcation Club in KOKURA." A new-presented concept was the "extension distance" between the main vessel and the sidebranch ostia and its association with restenosis. The results of two studies on shear stress (SS) after PCI showed that contradictory lower SS after stenting was associated with lower in-stent restenosis. There was better fractional flow reserve after double kissing crush technique than provisional one-stent technique. There was also lower rate of stent thrombosis after bifurcation stenting with excellent final angiographic results. In a negative note, the SYNTAX score had no predictive values on trifurcated left main stenting. In summary, different aspects of percutaneous management for bifurcated lesion are described seen from different perspectives and evidenced by novel techniques and strategies. PMID- 20718905 TI - Recent perspective on coronary bifurcation intervention: statement of the "Bifurcation Club in KOKURA". AB - The treatment of coronary bifurcation lesion remains a challenging issue even in the drug-eluting stent era. Frequent restenosis and stent thrombosis have been recently shown to be related not only to geometrical gap or stent structural deformation but also to rheological disturbance. Low wall shear stress at the lateral side of the bifurcation is likely to cause atherosclerotic changes due to easy access of the macrophages that induce chemical mediators. The turbulent flow over stent metal may facilitate accumulation of platelets, which results in thrombosis. The jailed strut and excess metal overlap may increase these risks. Since dramatic changes of the coronary flow pattern at the bifurcation are closely related to the genesis of atherosclerosis, future bifurcation intervention technique should be considered to restore the original physiological state as well as the anatomical structure. This article summarizes the global consensus of the members of the Asian Bifurcation Club and European Bifurcation Club at the KOKURA meeting. It also provides a perspective of basic sciences relating to bifurcation anatomy, physiology, and pathology, in the search for a best strategy for bifurcation intervention. PMID- 20718906 TI - Stent thrombosis following 2 drug-eluting stent implantations for coronary bifurcation lesion: a single-center analysis. AB - BACKGROUND: The incidence of stent thrombosis (ST) following 2 drug-eluting stent (DES) implantations for coronary bifurcation lesions needs to be identified. METHODS: From April 2004 to April 2009, 705 consecutive patients with true bifurcation lesions who underwent a double stenting procedure with DES at the Fu Wai Hospital were analyzed. RESULTS: Six (0.85%) patients had a definite ST, all of them had an early (4 acute and 2 subacute) definite ST. Probable ST occurred in 4 patients; in all of these cases, the event occurred early and was adjudicated because of the occurrence of sudden death within 30 days of the procedure. Therefore, a total of 10/705 (1.42%) patients had a definite or probable ST. Possible stent thrombosis was adjudicated only in 1 patient 371 days after the initial PCI in whom the cause of death was unexplained. Compared to the patients without definite and probable ST, patients with definite and probable ST were older, had more unstable angina, lower LVEF, and more left main bifurcation lesions (63.2 +/- 8.9 vs. 56.8 +/- 10.9 yrs; P = 0.049, 100% vs. 64.7%; P = 0.018, 50.6 +/- 9.9 vs. 60.3 +/- 12.4%; P = 0.019 and 70.0% vs. 36.1%; P = 0.043). Logistic analysis results indicated that only LVEF (OR 0.92, 95% CI 0.87 0.93; P = 0.017) was associated with definite and probable ST. CONCLUSIONS: The present study indicates that modern 2-DES technique for bifurcation lesions was comparatively safe with a low incidence of ST. PMID- 20718907 TI - Incomplete aneurysm coverage after patent foramen ovale closure in patients with huge atrial septal aneurysm: effects on left atrial functional remodeling. AB - BACKGROUND: Large devices are often implanted to treat patent foramen ovale (PFO) and atrial septal aneurysm (ASA) with increase risk of erosion and thrombosis. Our study is aimed to assess the impact on left atrium functional remodeling and clinical outcomes of partial coverage of the approach using moderately small Amplatzer ASD Cribriform Occluder in patients with large PFO and ASA. METHODS: We prospectively enrolled 30 consecutive patients with previous stroke (mean age 36 +/- 9.5 years, 19 females), significant PFO, and large ASA referred to our center for catheter-based PFO closure. Left atrium (LA) passive and active emptying, LA conduit function, and LA ejection fraction were computed before and after 6 months from the procedure by echocardiography. The preclosure values were compared to values of a normal healthy population of sex and heart rate matched 30 patients. RESULTS: Preclosure values demonstrated significantly greater reservoir function as well as passive and active emptying, with significantly reduced conduit function and LA ejection fraction, when compared normal healthy subjects. All patients underwent successful transcatheter closure (25 mm device in 15 patients, 30 mm device in 6 patients, mean ratio device/diameter of the interatrial septum = 0.74). Incomplete ASA coverage in both orthogonal views was observed in 21 patients. Compared to patients with complete coverage, there were no differences in LA functional parameters and occlusion rates. CONCLUSIONS: This study confirmed that large ASAs are associated with LA dysfunction. The use of relatively small Amplatzer ASD Cribriform Occluder devices is probably effective enough to promote functional remodeling of the left atrium. PMID- 20718908 TI - Case series are no substitute for randomised placebo-controlled trials for determination of treatment efficacy. PMID- 20718909 TI - Radiological review of intercostal artery: Anatomical considerations when performing procedures via intercostal space. AB - INTRODUCTION: The aim of this study was to closely examine the course of the intercostal arteries within the intercostal spaces particularly with regard to where the arteries were located in relation to their adjacent ribs. The degree of tortuosity of the arteries was also examined, along with anatomical differences in different age groups. METHODS: A total of 81 patients between the age of 30 and 90 years who had underwent a CT examination of the chest for any indication were included in the study. All studies were performed on a dual source 64 slice CT (Siemens Definition Erlangen Germany). Analysis of the intercostal arteries was performed on a CT workstation using volume rendered 3D reconstructions F, or each patient the 10'n intercostals pacesb ilaterally were examined for the course and tortuosity of the intercostal arteries. RESULTS: The ICA is located relatively inferiorly in the intercostal space at costovertebral junction and it gradually becomes more superiorly positioned within the intercostal space it as courses laterally. This finding was consistent in all age groups. In addition, analysis of the data demonstrated increasing intercostal artery tortuosity with advancing age. CONCLUSION: In this study we have examined the course of the posterior intercostal arteries using MDCT. This study confirms the classical description of the course of ICA. We have shown that in the medial chest, posteriorly, the artery is located in the inferior half of the intercostal space. As it moves away from the costovertebral junction it travels closer to the inferior border of the rib above and reaches the intercostal groove. We have also shown that the artery tends to be more tortuous in elderly patients, decreasing the area of "safe" space for interventions. Both of these findings are relevant to radiologists and non-radiologists performing interventional procedures via the intercostal space. PMID- 20718910 TI - Long-term outcomes of vertebroplasty for osteoporotic compression fractures. AB - INTRODUCTION: This study aimed to determine outcomes of percutaneous vertebroplasty for osteoporotic vertebral compression fractures (VCFs). METHODS: Prospective assessment of short-term (20 years). The readers were asked to either 'clear' or 'call back' cases depending on need for further workup, and at post-baseline reads to indicate whether each case was 'new' or 'old' (i.e. remembered from prior read). Two sets were presented only at baseline (40 cases per reader), and were used to calculate the reader's false recollection rate. Three sets were repeated post-baseline once or twice (100 cases per reader). Reading conditions were standardised. RESULTS: Memory performance differed markedly between readers. The number of correctly remembered cases (of 100 'old' cases) had a median of 10.5 and range of 0-58. The observed number of false recollections (of 40 'totally new' cases) had a median of 2 and range of 0 17. Diagnostic performance measures were mean (range): sensitivity 0.68 (0.54 0.81); specificity 0.82 (0.74-0.91); positive predictive value (PPV) 0.55 (0.50 0.65); negative predictive value (NPV) 0.89 (0.86-0.93) and accuracy 0.78 (0.76 0.83). Confidence intervals (CIs; 95%) for each reader overlapped for all the diagnostic parameters, indicating a lack of statistically significant difference between the readers at the 5% level. The most sensitive and the most specific reader showed a trend away from each other on sensitivity, specificity, NPV and PPV; their accuracies were 0.76 and 0.82, respectively, and their accuracy 95% CIs overlapped considerably. Correlation analysis by reader showed no association between observed memory performance and any of the diagnostic accuracy measures in our group of readers. In particular, there was no correlation between diagnostic accuracy and memory performance. CONCLUSION: There was no association between visual memory performance and diagnostic accuracy as a screening mammographer in our group of eight representative readers. Whether a radiologist has a good or a bad visual memory for cases, and in particular mammograms, should not impact on his or her performance as a radiologist and mammogram reader. PMID- 20718912 TI - Pilot comparison of F-fluorocholine and F-fluorodeoxyglucose PET/CT with conventional imaging in prostate cancer. AB - INTRODUCTION: Conventional imaging (CI) is known to have limitations with respect to staging of patients with primary or relapsed prostate cancer. Positron emission tomography/computed tomography (PET/CT) with (18)F-flurodeoxyglucose (FDG) is also often suboptimal because of low tracer avidity, but (18)F fluorocholine (FCH) appears to be a promising alternative molecular imaging probe. We report a prospective pilot study of PET/CT comparing both tracers for staging and restaging of patients with prostate cancer. METHODS: Sixteen prostate cancer patients were evaluated (7 for staging and 9 for restaging). All patients also underwent CI, comprising at least an abdominopelvic CT and a bone scan. All imaging results and other relevant data were extracted from the imaging reports and medical charts. RESULTS: Based on all imaging-detected disease sites, both FCH-PET/CT and FDG-PET/CT (79%) were more sensitive than CI (14%), with the highest number of sites of nodal and distant disease on FCH PET/CT. FCH-PET/CT alone would have provided sufficient clinical information to form an appropriate management plan in 88% of cases, as compared with 56% for CI. CONCLUSION: FCH PET/CT has the potential to impact on the management of patients with prostate cancer significantly more often than CI. PMID- 20718913 TI - Enlarged hilar and mediastinal lymph nodes in chronic obstructive pulmonary disease. AB - INTRODUCTION: To evaluate the frequency of enlarged hilar or mediastinal lymph nodes in patients suffering from chronic obstructive pulmonary disease (COPD). METHODS: In a retrospective study, 89 patients with proven COPD were analysed. Exclusion criteria were history of malignant disease or clinical evidence of pneumonia. Prevalence, size, and localisation of enlarged lymph nodes were assessed by multi-slice computed tomography (MSCT) and correlated with the clinical stages following the GOLD classification as well as the MSCT findings of bronchitis and emphysema. RESULTS: 44/89 (49%) of our patients showed enlarged lymph nodes. Lymph node enlargement was more often seen in the mediastinum (48%) than the hilar region (20%). The most common localisation of enlarged mediastinal lymph nodes was the regional station 7 following the ATS mapping (infracarinal). Patients with a stage I following the GOLD classification showed enlarged lymph nodes in 49% (18/37), stage II in 46% (12/26), stage III in 58% (7/12) and stage IV in 50% (7/14). These findings did not differ significantly (P > 0.05). Severe airway wall thickening (42/89) was significantly more often associated with an increase of nodal enlargement (64%) (P < 0.05). CONCLUSION: The present study demonstrates that enlarged hilar and mediastinal lymph nodes may occur in a rather high percentage of patients suffering from COPD, especially in those with the MSCT finding of severe bronchitis. PMID- 20718914 TI - Retrospective audit of the investigation of patients with suspected acute subarachnoid haemorrhage. AB - INTRODUCTION: Recommended investigational care (RIC) of emergency department (ED) patients with suspected subarachnoid haemorrhage comprises lumbar puncture (LP) to detect xanthochromia if the preceding CT scan is negative. METHODS: Retrospective audit of the investigational care of 100 consecutive ED patients presenting with possible subarachnoid haemorrhage. RESULTS: Of the 100 patients, 91 had negative CT, and 36 (39.6%) of these patients had an LP performed to detect xanthochromia (i.e. RIC). Fifty-five of 91 (60.4%) patients did not receive RIC. Of the 55 patients who did not receive RIC, 25 (45.5%) had a documented senior clinical decision not to perform an LP; 15 (27.3%) had no documented reason; five (9.1%) refused consent; two (3.6%) had an LP but no xanthochromia requested, one patient did not have an LP because of technical issues, six patients underwent CT angiography (CTA), and one patient underwent magnetic resonance angiography (MRA), in the absence of a LP, following a negative CT. Two patients underwent CTA following a negative xanthochromia result. Patients admitted to the emergency extended care unit had 6.85 times the odds of receiving RIC (95% CI 2.20-21.4). CONCLUSIONS: Fifty-five (55) of 91 (60%) ED patients did not receive RIC. Fifteen of the 55 did not have any documented justification for not performing an LP with xanthochromia testing. Admission to an emergency extended care unit was a predictor of receiving RIC. Inappropriate use of CTA and MRA was identified. These findings have important implications for patient safety. Multifaceted strategies are required to close this evidence-practice gap. PMID- 20718915 TI - Role of FDG PET/CT in imaging of renal lesions. AB - Focal incidental renal lesions are commonly encountered on positron emission tomography (PET)/computed tomography (CT) imaging. The vast majority of these lesions are benign. However, the interpretation of renal lesions can be problematic if the imaging criteria of simple cysts are not met. Limited literature exists on the characterisation of renal masses with metabolic imaging. The purpose of this article is to focus on the imaging features of benign and malignant renal masses with PET/CT. The lesions discussed include renal cyst, angiomyolipoma, oncocytoma, renal cell carcinoma, renal metastases and other infiltrating neoplastic processes affecting the kidney. Both the anatomical and metabolic features which characterise these benign and malignant entities are described. We emphasise the importance of viewing the CT component to identify the typical morphological features and discuss how to best use hybrid imaging for management of renal lesions. Metabolic imaging has a promising role in the imaging of renal lesions and can help prevent unnecessary biopsies and ensure optimal management of suspicious lesions. PMID- 20718916 TI - Fusion of high b-value diffusion-weighted and T2-weighted MR images improves identification of lymph nodes in the pelvis. AB - Accurate identification of lymph nodes facilitates nodal assessment by size, morphological or MR lymphographic criteria. We compared the MR detection of lymph nodes in patients with pelvic cancers using T2-weighted imaging, and fusion of diffusion-weighted imaging (DWI) and T2-weighted imaging. Twenty patients with pelvic tumours underwent 5-mm axial T2-weighted and DWI (b-values 0-750 s/mm(2)) on a 1.5T system. Fusion images of b = 750 s/mm(2) diffusion-weighted MR and T2 weighted images were created. Two radiologists evaluated in consensus the T2 weighted images and fusion images independently. For each image set, the location and diameter of pelvic nodes were recorded, and nodal visibility was scored using a 4-point scale (0-3). Nodal visualisation was compared using Relative to an Identified Distribution (RIDIT) analysis. The mean RIDIT score describes the probability that a randomly selected node will be better visualised relative to the other image set. One hundred fourteen pelvic nodes (mean 5.9 mm; 2-10 mm) were identified on T2-weighted images and 161 nodes (mean 4.3 mm; 2-10 mm) on fusion images. Using fusion images, 47 additional nodes were detected compared with T2-weighted images alone (eight external iliac, 24 inguinal, 12 obturator, two peri-rectal, one presacral). Nodes detected only on fusion images were 2-9 mm (mean 3.7 mm). Nodal visualisation was better using fusion images compared with T2-weighted images (mean RIDIT score 0.689 vs 0.302). Fusion of diffusion weighted MR with T2-weighted images improves identification of pelvic lymph nodes compared with T2-weighted images alone. The improved nodal identification may aid treatment planning and further nodal characterisation. PMID- 20718917 TI - The CT and F-FDG PET/CT appearance of primary renal malignant fibrous histiocytoma. AB - Renal malignant fibrous histiocytoma (MFH) is a rare, primary renal tumour. Imaging findings of renal MFH, including ultrasound, CT and MRI, have, however, been reported. As to the best of our knowledge (18)F-FDG PET/CT imaging of renal MFH has not been previously reported, we present the CT and (18)F-FDG PET/CT appearance of a pathologically proven primary renal MFH. PMID- 20718918 TI - Comparison of a Commonwealth-initiated regional radiation oncology facility in Toowoomba with a Queensland Health facility. AB - The aim was to compare a private Commonwealth-initiated regional radiation oncology facility in Toowoomba with a Queensland Health facility (QHF) in Brisbane. The comparison concentrated on staffing, case mix and operational budgets, but was not able to look at changes in access to services. Data were collected from the two facilities from January 2008 to June 2008 inclusive. A number of factors were compared, including case mix, staffing levels, delay times for treatment, research, training and treatment costs. The case mix between the two areas was similar with curative treatments making up just over half the work load in both centres and two-thirds the work being made up of cancers of breast and prostate. Staffing levels were leaner in Toowoomba, especially in the areas of nursing, administration and trial coordinators. Research activity was slightly higher in Toowoomba. The average medicare cost per treatment course was similar in both centres ($5000 per course). Total costs of an average treatment including patient, State and Commonwealth costs, showed a 30% difference in costing favouring Toowoomba. This regional radiation oncology centre has provided state of-the-art cancer care that is close to home for patients living in the Darling Downs region. Both public and private patients have been treated with modest costs to the patient and significant savings to QH. The case mix is similar to the QHF, and there has been significant activity in clinical research. A paperless working environment is one factor that has allowed staffing levels to be reduced. Ongoing support from Governments are required if private facilities are to participate in important ongoing staff training. PMID- 20718919 TI - Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: A dosimetric study using helical tomotherapy. AB - INTRODUCTION: The study aims to assess the feasibility of dosimetrically sparing the limbic circuit during whole brain radiation therapy (WBRT) and prophylactic cranial irradiation (PCI). METHODS AND MATERIALS: We contoured the brain/brainstem on fused MRI and CT as the target volume (PTV) in 11 patients, excluding the hippocampus and the rest of the limbic circuit, which were considered organs at risk (OARs). PCI and WBRT helical tomotherapy plans were prepared for each patient with a 1.0-cm field width, pitch = 0.285, initial modulation factor = 2.5. We attempted to spare the hippocampus and the rest of the limbic circuit while treating the rest of the brain to 30 Gy in 15 fractions (PCI) or 35 Gy in 14 fractions (WBRT) with V(100) >or= 95%. The quality of the plans was assessed by calculating mean dose and equivalent uniform dose (EUD) for OARs and the % volume of the PTV receiving the prescribed dose, V(100). RESULTS: In the PCI plans, mean doses/EUD were: hippocampus 12.5 Gy/14.23 Gy, rest of limbic circuit 17.0 Gy/19.02 Gy. In the WBRT plans, mean doses/EUD were: hippocampus 14.3 Gy/16.07 Gy, rest of limbic circuit 17.9 Gy/20.74 Gy. The mean V(100) for the rest of the brain (PTV) were 94.7% (PCI) and 95.1% (WBRT). Mean PCI and WBRT treatment times were essentially identical (mean 15.23 min, range 14.27-17.5). CONCLUSIONS: It is dosimetrically feasible to spare the hippocampus and the rest of the limbic circuit using helical tomotherapy while treating the rest of the brain to full dose. PMID- 20718920 TI - Use of 3D imaging and awareness of GEC-ESTRO recommendations for cervix cancer brachytherapy throughout Australia and New Zealand. AB - INTRODUCTION: A 2005 survey of practices indicated limited use of three dimensional (3D) imaging modalities and planning methods in cervix cancer brachytherapy in Australia and New Zealand. However, advancing technologies and published recommendations are influencing change. This survey aims to identify both changes in practice and awareness and uptake of Groupe European de Curietherapie of the European Society for Therapeutic Radiology and Oncology (GEC ESTRO) recommendations. METHODS: A survey was emailed to all radiotherapy departments with brachytherapy facilities. Twenty departments practise brachytherapy for cancer of the cervix. The survey consisted of five questions enquiring about use and type of 3D imaging; rate of reimaging and replanning; and contouring, prescribing and reporting practices. RESULTS: A 100% response rate was obtained. Sixty-five per cent of departments use 3D CT imaging to plan brachytherapy insertions. Thirty per cent of departments use two-dimensional (2D) x-rays. Four departments (20%) use a combination of imaging modalities including CT, ultrasound and MRI. Sixty-five per cent of departments reimage and replan for each insertion. Four departments (20%) contour, prescribe dose and report treatment according to GEC-ESTRO recommendations. CONCLUSIONS: There has been a marked increase in the use of 3D imaging and awareness of GEC-ESTRO recommendations. Implementation and reporting of image-based gynaecological brachytherapy is strongly dependent on local resources and infrastructure. PMID- 20718921 TI - Paediatric nasopharyngeal rhabdomyosarcoma: A case series and literature review. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue tumour in children, with the head and neck region accounting for 35-40% of cases. Nasopharyngeal RMSs tend to grow rapidly and invade adjacent structures. Both the Intergroup Rhabdomyosarcoma Studies and the European Studies have established that the ideal management of this disease is multimodal, using a combination of surgery, chemotherapy and radiotherapy. This case series examines the role of radiotherapy in the management of paediatric nasopharyngeal RMSs, with particular reference to long-term morbidity and disease-free survival. The cases of five children with nasopharyngeal RMS were reviewed and a systematic review of the literature contained in the PubMed databases was conducted to establish 24 individually detailed cases. Management in all patients was multimodal, using a combination of chemotherapy, radiotherapy as well as surgery. External beam radiotherapy is an integral component of treatment for nasopharyngeal RMSs. With more patients surviving for longer periods, more long-term sequelae of radiotherapy have been reported. Complications include sensorineural deafness, endocrine manifestations following radiation of the pituitary gland, cranial nerve palsies, second malignancies within the radiation field, cataract formation, retinopathy and growth disturbance. Morbidity from radiotherapy may be considerable and depends on the field and dose of radiation. Current advances in radiotherapy are aimed at improving the rate of tumour control and reducing such complications. Recent improvements in imaging and conformal techniques have the potential to reduce the morbidity associated with radiotherapy in this cohort. PMID- 20718922 TI - Strategies to successfully publish your first manuscript. AB - Applying published evidence is fundamental to the practice of medicine. However, the steps needed to undertake scientific research and generate a manuscript of publishable quality are often overwhelming for junior doctors. Undertaking research and publishing these findings are complementary. Clinicians often present research at college or scientific meetings as oral or poster presentations. Yet despite this, most research is not subsequently submitted for peer review publication in a scientific journal. Reasons put forward for research not being published include lack of time, ongoing study, difficulties with co authors and a negative study. A lack of experience in the actual process of writing and publishing is also likely to be a contributing factor. The steps required in writing a successful manuscript are multiple and clinicians often lack awareness of the specific formatting requirements for submission to a scientific journal such as JMIRO. The aim of this article is to provide information for clinicians inexperienced in writing and submitting a manuscript with the intent of achieving a publication. It is not meant to be a step-by-step recipe in doing this but a guide as to what is required. PMID- 20718923 TI - "Advantage of optimizing V-V timing in cardiac resynchronization therapy devices" by Dr. Duvall. PMID- 20718924 TI - Compliance with topical nasal medication--an evaluation in children with rhinitis. AB - It is our impression that children with rhinitis often dislike or struggle with the administration of topical nasal sprays and drops. This study aims to investigate children's acceptance of topical nasal sprays/drops, and to identify patient factors that may affect their acceptance. An interview (by WYZI) questionnaire survey was carried out on parents/guardians of children aged 1-15 with rhinitis, where information on the diagnosis and treatment, patients' use and responses to these medications, and their preferred treatment routes were collected. Two hundred questionnaires were completed, of which 194 were valid for analysis. The mean age of patients was 7.54 yr; male to female ratio was 1:1.6, and Chinese made up the majority (62.4%). About one quarter (24.7%) of children disliked the use of topical nasal sprays/drops sufficiently to affect compliance with the medication. Furthermore, of those who could indicate their preferred route of drug administration (n = 75), 73% indicated a preference for oral medication, while only 11% preferred the nasal route. Topical nasal sprays/drops were more acceptable in older children (7-15 yr) compared to the younger ones (1 6 yr) (OR = 2.383, CI 1.223-4.644). The acceptance of nasal sprays/drops was not associated with gender, ethnic group, concurrent use by other family members, length and amount of usage, and the response to therapy. A substantial proportion of children prescribed topical nasal sprays/drops did not find it acceptable. Age played a significant factor to the acceptance of the use of topical nasal sprays/drops. PMID- 20718925 TI - How to diagnose psychogenic and functional breathing disorders in children and adolescents. AB - Psychogenic and functional breathing disorders are common and affect mostly children and adolescents, resulting in considerable morbidity and contributing significantly to patient and physician cost and frustration. The most common non organic clinical entities are psychogenic cough, throat clearing tic, sighing dyspnoea, hyperventilation syndrome, and vocal cord dysfunction. Combinations of organic respiratory diseases and psychogenic aspects can coincide. The mainstay of the diagnosis of psychogenic and functional breathing disorders is full and meticulously taken history. A list of possible questions is presented. Furthermore, the value of a thorough physical examination is often underestimated. If a diagnosis cannot be made clear enough by history taking and examination alone, some baseline instrumental diagnostics are meaningful. An interview with an experienced clinical psychologist and a visit at the physiotherapist may add further information in some cases. Criteria, which differentiate psychogenic or functional breathing symptoms from organic ones, include no nocturnal symptoms, mostly no typical trigger factors, symptoms may occur suddenly and even at rest, speaking is possible without problems and there are normal diagnostic results during episodes of symptoms. Intensive efforts should be made to diagnose psychogenic and functional symptoms, because this will reduce or eliminate harm, prevent stigmatization and fixation of symptoms and disease, allow an untroubled life (including sports), and prevent patients from undergoing unnecessary and potentially harmful therapies. PMID- 20718926 TI - Asthma severity in childhood, untangling clinical phenotypes. AB - Assessment of childhood asthma severity and asthma control encompasses heterogeneous clinical presentations. The relationship between patterns of asthma symptoms and objective measurements is poorly defined in paediatric asthma. This study includes 115 asthmatic schoolchildren, of which 31 were at inclusion defined as Problematic severe asthma because of inadequate asthma control in the presence of high-dose inhaled corticosteroid (HD-ICS) treatment and at least one other asthma controller drug. Two partially overlapping clinical outcomes were defined irrespective of severity classification (Exacerbations and Chronic persistent asthma) in patients with uncontrolled asthma. The same symptom criteria were used as for Problematic severe asthma, but disregarding current medication. Lung function, exhaled nitric oxide (FE(NO)), bronchial hyperresponsiveness, allergic sensitization and Quality of life (QoL) in the symptom subgroups were compared to children with well-controlled asthma. Multifactor analysis was performed to assess the relative explanatory power of clinical asthma presentations and of HD-ICS treatment on objective measurements. Whereas children included in the Exacerbations subgroup had objective features similar to patients with well-controlled asthma, the Chronic persistent asthma subgroup demonstrated significantly reduced lung function, increased immunoglobin E, allergic poly-sensitization and impaired QoL, similar to that in patients pre defined as Problematic severe asthma. The presence of chronic asthma symptoms was a significant explanatory factor for reduced lung function, QoL and increased FE(NO) in multifactor analysis. Differences in objective measurements suggest that children with Chronic persistent asthma and those who are symptomatic predominantly during exacerbations may represent distinct phenotypes of childhood asthma with different clinical prognoses. PMID- 20718927 TI - Five-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents. AB - The efficacy and safety of five-grass pollen 300IR sublingual immunotherapy (SLIT) tablets (Stallergenes SA, France) have previously been demonstrated in paediatric patients. This report presents additional data concerning efficacy at pollen peak, efficacy and safety according to age, nasal and ocular symptoms, use of rescue medication, satisfaction with treatment and compliance. Children (5-11 yr) and adolescents (12-17 yr) with grass pollen-allergic rhinoconjunctivitis were included in a multinational, randomized, double-blind, placebo-controlled study and received either a 300IR five-grass pollen tablet or placebo daily in a pre- (4 months) and co-seasonal protocol. The severity of six symptoms (sneezing, rhinorrhoea, nasal congestion, nasal and ocular pruritis, and tearing) was scored, and rescue medication use was recorded daily during the pollen season. Patient satisfaction was recorded at the season end. A total of 161 children and 117 adolescents were evaluated (n = 267). 300IR SLIT was effective over the whole season (p = 0.0010) and at the pollen peak (p = 0.0009). The adjusted mean difference between 300IR and placebo groups was significant for both nasal (p = 0.0183) and ocular (p < 0.0001) symptoms. Rescue medication use was statistically lower in the SLIT group during the pollen season and at the pollen peak (both p < 0.05). More patients in the SLIT group were satisfied with their treatment compared to placebo (83.2% vs. 68.1%, p = 0.0030), and compliance was high (SLIT 93.9% of patients were compliant, placebo 94.8% of patients were compliant). SLIT was well tolerated by children and adolescents. 300IR five-grass pollen tablets are effective and safe during the pollen season and at the pollen peak in children and adolescents with grass pollen rhinoconjunctivitis. PMID- 20718928 TI - Immune regulatory cytokines in the milk of lactating women from farming and urban environments. AB - Children living on farms have fewer allergies. It is unclear whether breastfeeding in different environments contributes to preventing allergies by exposing offspring to different cytokines that can modulate immune responses. The aim of this study was to quantify and compare levels of Transforming Growth Factor-beta1 (TGF-beta1) and Interleukin-10 (IL-10) in the colostrum and mature milk of mothers living in towns at sea level (references) and mothers on farms. Milk samples were collected within 3 days postpartum (colostrum) and at the first month of the baby's life (mature milk). Sixty-nine reference mothers and 45 farm mothers participated in the study. TGF-beta1 concentrations were significantly higher both in the colostrum (p < 0.05) and in mature milk (p < 0.05) of farm mothers. In the reference mothers, a significant decrease in TGF-beta1 concentrations was observed between colostrum (650, range 0-8000 pg/ml) and mature milk (250, range 0-8000 pg/ml) (p < 0.05). In farm mothers, TGF-beta1 concentrations were 1102 pg/ml (range 0-14,500) in colostrum and remained high in mature milk (821 pg/ml, range 0-14,650). IL-10 concentrations were higher in the mature milk of farm mothers (p < 0.05). No significant differences in IL-10 were observed between colostrum and mature milk in the control group (15 pg/ml, range 0-1800, and 0 pg/ml, range 0-230) or in farm mothers (9.5 pg/ml, range 0-1775, and 14.2 pg/ml, range 0-930), respectively. Exposure to a farm environment is associated with higher concentrations of TGF-beta1 and IL-10 in breast milk when compared to exposure to an urban environment. Higher cytokine concentrations in breast milk may influence early modulation of the development of an immune response, leading to a reduced prevalence of allergy-related diseases in farm children. PMID- 20718929 TI - Timing of infection and development of wheeze, eczema, and atopic sensitization during the first 2 yr of life: the KOALA Birth Cohort Study. AB - To investigate if infections in pregnancy and very early in life present a risk for wheezing, eczema, or atopic sensitization in later infancy. A total of 2319 children enrolled before birth in the KOALA Birth Cohort Study were followed during their first 2 yr of life using repeated questionnaires. Information was obtained on common colds, fever, and diarrhea with fever as well as on wheeze and eczema at ages 3 and 7 months and 1 and 2 yr, respectively. Blood samples were collected from 786 children at age 2 yr for specific immunoglobulin E analyses. Children with a common cold [adjusted odds ratio (aOR) 2.03 95% CI 1.21-3.41] or fever episode (aOR 1.81 95% CI 1.10-2.96) in the first 3 months of life had a higher risk of new onset wheeze in the second year of life compared to children who had not. For children with diarrhea with fever in the first 3 months of life, the aOR for new onset wheeze in the second year of life was 3.94 (95% CI 1.36 11.40) compared to children without diarrhea. Infections becoming clinically manifest during the first 3 months of life may be a general marker for a wheezy phenotype. PMID- 20718930 TI - NF-kappaB is not directly responsible for photoresistance induced by fractionated light delivery in HT-29 colon adenocarcinoma cells. AB - Our recent study follows up an earlier one which demonstrated hypericin-mediated photocytotoxic effects on HT-29 adenocarcinoma cells by light fractionation with a longer dark pause between two unequal light doses (Sackova, A. [2005] Photochem. Photobiol.81, 1411-1416). Here, we present closer study on events invoked by sublethal light dose (1 J cm(-2)) during the period of 6 h that is sufficient to invoke resistance to second lethal dose (11 J cm(-2)). First, we proved that the dark pause of 6 h, but not 1 h, resulted in better cell survival with suppressed phosphatidylserine externalization, decreased reactive oxygen species production and hypericin content as well as altered expression of HSP70, GRP94, clusterin, nuclear factor (NF)-kappaB, IkappaB-alpha or Mcl-1. NF-kappaB activity assay confirmed activation of this early-response pathway. However, inhibition of IkappaB (IKK) kinase by parthenolide by stopping NF-kappaB release from the complex with IkappaB did not prevent onset of resistance, but it invoked some resistance even in groups with shorter, 1 h dark pause. Therefore, we predict involvement of another signaling pathway, located upstream from NF kappaB, responsible for onset of resistance to photodynamic therapy with hypericin in colon adenocarcinoma cells HT-29. PMID- 20718931 TI - Chronic stroke recovery after combined BCI training and physiotherapy: a case report. AB - A case of partial recovery after stroke and its associated brain reorganization in a chronic patient after combined brain computer interface (BCI) training and physiotherapy is presented. A multimodal neuroimaging approach based on fMRI and diffusion tensor imaging was used to investigate plasticity of the brain motor system in parallel with longitudinal clinical assessments. A convergent association between functional and structural data in the ipsilesional premotor areas was observed. As a proof of concept investigation, these results encourage further research on a specific role of BCI on brain plasticity and recovery after stroke. PMID- 20718932 TI - Switch-specific and general preparation map onto different ERP components in a task-switching paradigm. AB - We examined whether the cue-locked centroparietal positivity is associated with switch-specific or general preparation processes. If this positivity (300-400 ms) indexes switch-specific preparation, faster switch trials associated with smaller RT switch cost should have a larger positivity as compared to slower switch trials, but no such association should be evident for repeat trials. We extracted ERP waveforms corresponding to semi-deciles of each participant's RT distribution (i.e., fastest to slowest 5% of trials) for switch and repeat conditions. Consistent with a switch-specific preparation process, centroparietal positivity amplitude was linked to slower RT and larger RT switch cost for switch but not repeat trials. A later pre-target negativity (500-600 ms) was inversely correlated with RT for both switch and repeat trials, consistent with a general anticipatory preparation processes. PMID- 20718933 TI - Efficient and cost-effective estimation of the influence of respiratory variables on respiratory sinus arrhythmia. AB - Researchers are interested in respiratory sinus arrhythmia (RSA) as an index of cardiac vagal activity. Yet, debate exists about how to account for respiratory influences on quantitative indices of RSA. T. Ritz, M. Thons, and B. Dahme (2001) developed a within-individual correction procedure by which the effects of respiration on RSA may be estimated using regression models. We replicated their procedure substituting a spectral high-frequency measure of RSA for a time-domain statistic and a respiratory belt's relative measure of tidal volume for the direct assessment provided by a pneumotachograph. The standardized slopes from the respiratory belt and pneumotachography-derived regression equations (estimated across a 6-min paced breathing protocol) were positively correlated (r=0.93, p<.001); correlations were similar across 2- and 4-min time courses parsed from the 6-min protocol. Our results offer methodological alternatives to the research community. PMID- 20718934 TI - Effects of visual and verbal presentation on cognitive load in vigilance, memory, and arithmetic tasks. AB - Degree of pupil dilation has been shown to be a valid and reliable measure of cognitive load, but the effect of aural versus visual task presentation on pupil dilation is unknown. To evaluate effects of presentation mode, pupil dilation was measured in three tasks spanning a range of cognitive activities: mental multiplication, digit sequence recall, and vigilance. Stimuli were presented both aurally and visually, controlling for all known visual influences on pupil diameter. The patterns of dilation were similar for both aural and visual presentation for all three tasks, but the magnitudes of pupil response were greater for aural presentation. Accuracy was higher for visual presentation for mental arithmetic and digit recall. The findings can be accounted for in terms of dual codes in working memory and suggest that cognitive load is lower for visual than for aural presentation. PMID- 20718935 TI - Health-illness transition among persons using advanced medical technology at home. AB - This study aimed to elucidate meanings of health-illness transition experiences among adult persons using advanced medical technology at home. As an increasing number of persons perform self-care while using different sorts of advanced medical technology at home, knowledge about health-illness transition experiences in this situation may be useful to caregivers in supporting these patients. A qualitative design was used. Five women and five men, all of whom performed self care at home, either using long-term oxygen therapy from a ventilator or oxygen cylinder, or performing peritoneal or haemodialysis, were interviewed. Ethics committee approval was obtained. Informed consent was received from all participants, and ethical issues concerning their rights in research were raised. The interviews were analysed using a phenomenological hermeneutical methodology, including both an inductive and a deductive structural analysis. This method offers possibilities to obtain an increased understanding by uncovering a deeper meaning of lived experiences through interviews transcribed as texts. The health illness transition for adult persons in this context was found to mean a learning process of accepting, managing, adjusting and improving daily life with technology, facilitated by realizing the gain from technology at home. Further, the meaning of the health-illness transition experience was interpreted as contentment with being part of the active and conscious process towards transcending into a new state of living, in which the individual and the technology were in tune. The healthy transition experience was characterized by human growth and becoming. This study elucidates one meaning of health-illness transition experiences in relation to the use of advanced medical technology on a more generic level, independent of the specific type of technology used. A positive attitude towards technology at home facilitates the transition. PMID- 20718936 TI - Improved genotyping of the human minor histocompatibility antigen HB-1 by polymerase chain reaction with sequence-specific primers using a complementary oligonucleotide. AB - Single nucleotide polymorphisms of minor histocompatibility antigens (mHags) have been genotyped by allele-specific polymerase chain reaction with sequence specific primers (PCR-SSP). Because discriminating the genotype of HB-1 Y by PCR SSP under various PCR conditions was difficult, we optimized the use of oligonucleotides complementary to the allele-specific forward primer to improve the specificity of the HB-1 Y PCR-SSP. Specific allele discrimination was possible with an annealing temperature between 61 degrees C and 63 degrees C and in the presence of a threefold excess of a 15-bp complementary oligonucleotide. In conclusion, the inclusion of a complementary oligonucleotide in the PCR-SSP assay may improve its specificity and selectivity for genotyping several mHags for which optimizing PCR conditions have been difficult. PMID- 20718937 TI - Cells with hematopoietic activity in the mouse placenta reside in side population. AB - The discovery of a major hematopoietic stem cell pool in midgestation mouse embryo has defined the placenta as an important hematopoietic anatomical site. In this study, we examined the flow cytometric pattern of mouse placenta cells on embryonic days (E) 10.5 to E15.5, in view of CD45 and c-Kit expression. We also determined which population of these cells shows differentiation potential toward multiple hematopoietic lineages by performing coculture with OP9 stromal cells and colony-forming assay in methylcellulose. Only CD45(+)c-Kit(+) population showed the ability to form hematopoietic colonies including multiple lineages. To distinguish which fraction of placenta cells have the hematopoietic activity, we used GFP transgenic mice in which the fetal part of the placenta is GFP positive and the maternal part is GFP negative. E11.5 and E13.5 CD45(+)c-Kit(+) placental cells that have ability to form hematopoietic colonies are the fetal GFP positive placental cells. E11.5 and E13.5 CD45(+)c-Kit(+) placental cells that have an ability to form hematopoietic colonies mainly reside in Hoechst dye-effluxing side population area (SP). Taken together, in the placenta of mouse embryo, we conclude that SP cells in the CD45(+)c-Kit(+) fetal placental cells have the ability to form hematopoietic colonies. PMID- 20718938 TI - SUMOylation negatively regulates transcriptional and oncogenic activities of MafA. AB - Dysregulated expression of Maf proteins (namely c-Maf, MafA and MafB) leads to multiple myeloma in humans and oncogenic transformation of chicken embryonic fibroblasts. Maf proteins are transcriptional activators of tissue-specific gene expression and regulators of cell differentiation. For example, MafA is a critical regulator of crystallin genes and the lens differentiation program in chickens. In mammals, MafA is essential for the development of mature insulin producing beta-cells of pancreas. It has been shown that MafA protein stability is regulated by phosphorylations at multiple serine and threonine residues. Here, we report that Maf proteins are also post-translationally modified by small ubiquitin-like modifier (SUMO) proteins at a conserved lysine residue in the amino-terminal transactivator domain. A SUMOylation-deficient mutant of MafA (K32R) was more potent than wild-type MafA in transactivating luciferase reporter construct driven by alphaA-crystallin or insulin gene promoter. In ovo electroporation into developing chicken embryo showed that the K32R mutant induced ectopic delta-crystallin gene expression more efficiently than the wild type MafA. We also demonstrated that the K32R mutant had enhanced ability to induce colony formation of a chicken fibroblast cell line DF-1. Therefore, SUMOylation is a functional post-translational modification of MafA that negatively regulates its transcriptional and transforming activities. PMID- 20718940 TI - Meeting report from the Third Global Workshop on Melanoma. PMID- 20718939 TI - Chromatin dynamics mediated by histone modifiers and histone chaperones in postreplicative recombination. AB - Eukaryotic chromatin is regulated by chromatin factors such as histone modification enzymes, chromatin remodeling complexes and histone chaperones in a variety of DNA-dependent reactions. Among these reactions, transcription in the chromatin context is well studied. On the other hand, how other DNA-dependent reactions, including postreplicative homologous recombination, are regulated in the chromatin context remains elusive. Here, histone H3 Lys56 acetylation, mediated by the histone acetyltransferase Rtt109 and the histone chaperone Cia1/Asf1, is shown to be required for postreplicative sister chromatid recombination. This recombination did not occur in the cia1/asf1-V94R mutant, which lacks histone binding and histone chaperone activities and which cannot promote the histone acetyltransferase activity of Rtt109. A defect in another histone chaperone, CAF-1, led to an increase in acetylated H3-K56 (H3-K56-Ac) dependent postreplicative recombination. Some DNA lesions recognized by the putative ubiquitin ligase complex Rtt101-Mms1-Mms22, which is reported to act downstream of the H3-K56-Ac signaling pathway, seem to be increased in CAF-1 defective cells. Taken together, these data provide the framework for a postreplicative recombination mechanism controlled by histone modifiers and histone chaperones in multiple ways. PMID- 20718941 TI - Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis. AB - We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with Nras(Q61K) to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4(R24C) did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4(R24C) mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression. PMID- 20718942 TI - The effects of glucagon-like peptide 2 on enteric neurons in intestinal inflammation. AB - BACKGROUND: Intestinal inflammation alters the structure and function of the enteric nervous system (ENS). Glucagon-like peptide 2 (GLP-2) reduces intestinal inflammation and has trophic effects on isolated neurons. This study examined the effects of GLP-2 treatment on the submucosal plexus of rat colon in the trinitrobenzene sulfonic acid (TNBS) model of colitis. METHODS: After administration of TNBS or saline/ethanol for controls, animals were allocated to treatment with GLP-2 (50 MUg kg-1 day-1, s.c.) or sham injection of vehicle, twice daily. Animals were monitored, following clinical parameters, and killed on day 5. The number of neuronal cell bodies per ganglion was quantified using immunohistochemistry on submucosal whole mount preparations, with further characterization of specific subpopulations using antibodies against vasoactive intestinal polypeptide (VIP), neuronal nitric oxide synthase (nNOS), and enteric glial cells with glial fibrillary acid protein and S100. KEY RESULTS: Glucagon like peptide 2 treatment was associated with a significant amelioration of weight loss, and reduced neutrophil infiltration and microscopic colitis scores in the TNBS animals. Inflammation resulted in a loss of enteric neurons in submucosal ganglia; GLP-2 treatment restored the enteric neuronal populations to normal. In control, non-inflamed animals, GLP-2 treatment increased the number of VIP expressing neurons per ganglion; in TNBS-treated animals, GLP-2 prevented an inflammation-induced reduction in the numbers of VIP expressing neurons per ganglion. Glucagon-like peptide 2 did not change the numbers of nNOS neurons or enteric glial cells in either the control, or inflamed state. CONCLUSIONS & INFERENCES: These findings show that GLP-2 increased the number of VIP expressing neurons in normal animals, and prevents the inflammation-induced loss of neurons in the colonic submucosal ganglia, with an increase in the proportion of VIP expressing neurons. They suggest that GLP-2 may have a role in protecting or regulating the circuitry of the ENS under basal and inflamed states. PMID- 20718943 TI - The traditional antidiarrheal remedy, Garcinia buchananii stem bark extract, inhibits propulsive motility and fast synaptic potentials in the guinea pig distal colon. AB - BACKGROUND: Garcinia buchananii bark extract is a traditional African remedy for diarrhea, dysentery, abdominal discomfort, and pain. We investigated the mechanisms and efficacy of this extract using the guinea pig distal colon model of gastrointestinal motility. METHODS: Stem bark was collected from G. buchananii trees in their natural habitat of Karagwe, Tanzania. Bark was sun dried and ground into fine powder, and suspended in Krebs to obtain an aqueous extract. Isolated guinea pig distal colon was used to determine the effect of the G. buchananii bark extract on fecal pellet propulsion. Intracellular recording was used to evaluate the extract action on evoked fast excitatory postsynaptic potentials (fEPSPs) in S-neurons of the myenteric plexus. KEY RESULTS: Garcinia buchananii bark extract inhibited pellet propulsion in a concentration-dependent manner, with an optimal concentration of ~10 mg powder per mL Krebs. Interestingly, washout of the extract resulted in an increase in pellet propulsion to a level above basal activity. The extract reversibly reduced the amplitude of evoked fEPSPs in myenteric neurons. The extract's inhibitory action on propulsive motility and fEPSPs was not affected by the opioid receptor antagonist, naloxone, or the alpha- 2 adrenoceptor antagonist, yohimbine. The extract inhibited pellet motility in the presence of gamma-aminobutyric acid (GABA), GABA(A) and GABA(B) receptor antagonists picrotoxin and phaclofen, respectively. However, phaclofen and picrotoxin inhibited recovery rebound of motility during washout. CONCLUSIONS & INFERENCES: Garcinia buchananii extract has the potential to provide an effective, non-opiate antidiarrheal drug. Further studies are required to characterize bioactive components and elucidate the mechanisms of action, efficacy, and safety. PMID- 20718944 TI - The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients. AB - BACKGROUND: Visceral hypersensitivity to distension is thought to play an important role in the pathophysiology of the irritable bowel syndrome (IBS). Cannabinoids are known to decrease somatic pain perception, but their effect on visceral sensitivity in IBS remains unclear. Therefore, we evaluated the effect of the mixed CB(1) /CB(2) receptor agonist delta-9-tetrahydrocannabinol (Delta(9) -THC, dronabinol) on rectal sensitivity. METHODS: Ten IBS patients and 12 healthy volunteers (HV) underwent a barostat study to assess rectal sensitivity using an intermittent pressure-controlled distension protocol before and after sigmoid stimulation. Repetitive sigmoid stimulation is a validated method to increase visceral perception in IBS patients, consisting of a 10-min period of 30 s stimuli (60 mmHg), separated by 30 s of rest (5 mmHg). The effect of placebo and Delta(9) -THC (5 and 10 mg in healthy volunteers and 10 mg in IBS patients) on rectal sensitivity was evaluated on respectively three and two separate days in a double blind, randomized, crossover fashion. KEY RESULTS: All participants (HV and IBS) reported central side effects during the highest dose of Delta(9) -THC, most frequently increased awareness of the surrounding, light-headedness and sleepiness, whereas no side effects where reported during placebo. Although blood pressure was not affected, heart rate increased in both HV and IBS, but was most pronounced in IBS patients. The cannabinoid agonist Delta(9) -THC did not alter baseline rectal perception to distension compared to placebo in HV or IBS patients. Similarly, after sigmoid stimulation there were no significant differences between placebo and Delta(9) -THC in sensory thresholds of discomfort. CONCLUSIONS & INFERENCES: These findings imply that Delta(9) -THC does not modify visceral perception to rectal distension and argue against (centrally acting) CB agonists as tool to decrease visceral hypersensitivity in IBS patients. PMID- 20718945 TI - Appearance and disappearance of functional gastrointestinal disorders in patients with eating disorders. AB - BACKGROUND: Functional gastrointestinal disorders or 'functional gastrointestinal disorder-like' symptoms (FGIDs) occur commonly in eating disorders (ED), but it is not known if these disorders are stable over time. The aims were to evaluate the turnover of FGIDs in patients with ED, and to relate this turnover to changes in body mass index (BMI), ED behaviors, and psychological variables. METHODS: Patterns and repeated measures analysis of presence of individual FGIDs and regional FGID categories (esophageal, gastroduodenal, bowel, and anorectal) in ED patients (n = 73) at admission to hospital and at 12-month follow-up, using change in BMI and ED behaviors as between patient variables. KEY RESULTS: Functional gastrointestinal disorders prevalence was 97% at admission and 77% at follow-up. The only individual FGIDs to decrease over time were functional heartburn (admission 53%, follow-up 23%) and functional dysphagia (21%, 7%). There was significant patient variation in the disappearance, persistence, and appearance of both individual FGIDs and FGID regional categories. Twenty-five (34%) of patients acquired at least one new FGID regional category at follow-up. There was no relationship between changes in BMI, self-induced vomiting, laxative use, binge eating, anxiety, depression, somatization, and the turnover of individual or regional FGIDs. CONCLUSIONS & INFERENCES: Functional gastrointestinal disorders remain common after 12 months in patients with an ED. Considerable turnover of the FGIDs occurs, however, and the appearance of new FGIDs is not restricted to the original FGID regional category. There is no apparent relationship between the turnover of the FGIDs and ED behaviors, psychological variables or body weight change. These findings have implications for the clinical evaluation and management of FGIDs in ED patients. PMID- 20718946 TI - Perception of dysphagia: lack of correlation with objective measurements of esophageal function. AB - BACKGROUND: The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically-induced esophageal hypocontractility, and in patients with gastro-esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). METHODS: Combined manometry-impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5-point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. KEY RESULTS: In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. CONCLUSIONS & INFERENCES: There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity. PMID- 20718947 TI - Clustering of protein families into functional subtypes using Relative Complexity Measure with reduced amino acid alphabets. AB - BACKGROUND: Phylogenetic analysis can be used to divide a protein family into subfamilies in the absence of experimental information. Most phylogenetic analysis methods utilize multiple alignment of sequences and are based on an evolutionary model. However, multiple alignment is not an automated procedure and requires human intervention to maintain alignment integrity and to produce phylogenies consistent with the functional splits in underlying sequences. To address this problem, we propose to use the alignment-free Relative Complexity Measure (RCM) combined with reduced amino acid alphabets to cluster protein families into functional subtypes purely on sequence criteria. Comparison with an alignment-based approach was also carried out to test the quality of the clustering. RESULTS: We demonstrate the robustness of RCM with reduced alphabets in clustering of protein sequences into families in a simulated dataset and seven well-characterized protein datasets. On protein datasets, crotonases, mandelate racemases, nucleotidyl cyclases and glycoside hydrolase family 2 were clustered into subfamilies with 100% accuracy whereas acyl transferase domains, haloacid dehalogenases, and vicinal oxygen chelates could be assigned to subfamilies with 97.2%, 96.9% and 92.2% accuracies, respectively. CONCLUSIONS: The overall combination of methods in this paper is useful for clustering protein families into subtypes based on solely protein sequence information. The method is also flexible and computationally fast because it does not require multiple alignment of sequences. PMID- 20718948 TI - Enhancement of solubility in Escherichia coli and purification of an aminotransferase from Sphingopyxis sp. MTA144 for deamination of hydrolyzed fumonisin B(1). AB - BACKGROUND: Fumonisin B(1) is a cancerogenic mycotoxin produced by Fusarium verticillioides and other fungi. Sphingopyxis sp. MTA144 can degrade fumonisin B(1), and a key enzyme in the catabolic pathway is an aminotransferase which removes the C2-amino group from hydrolyzed fumonisin B(1). In order to study this aminotransferase with respect to a possible future application in enzymatic fumonisin detoxification, we attempted expression of the corresponding fumI gene in E. coli and purification of the enzyme. Since the aminotransferase initially accumulated in inclusion bodies, we compared the effects of induction level, host strain, expression temperature, solubility enhancers and a fusion partner on enzyme solubility and activity. RESULTS: When expressed from a T7 promoter at 30 degrees C, the aminotransferase accumulated invariably in inclusion bodies in DE3 lysogens of the E. coli strains BL21, HMS174, Rosetta 2, Origami 2, or Rosetta gami. Omission of the isopropyl-beta-D-thiogalactopyranoside (IPTG) used for induction caused a reduction of expression level, but no enhancement of solubility. Likewise, protein production but not solubility correlated with the IPTG concentration in E. coli Tuner(DE3). Addition of the solubility enhancers betaine and sorbitol or the co-enzyme pyridoxal phosphate showed no effect. Maltose-binding protein, used as an N-terminal fusion partner, promoted solubility at 30 degrees C or less, but not at 37 degrees C. Low enzyme activity and subsequent aggregation in the course of purification and cleavage indicated that the soluble fusion protein contained incorrectly folded aminotransferase. Expression in E. coli ArcticExpress(DE3), which co-expresses two cold-adapted chaperonins, at 11 degrees C finally resulted in production of appreciable amounts of active enzyme. Since His tag-mediated affinity purification from this strain was hindered by co-elution of chaperonin, two steps of chromatography with optimized imidazole concentration in the binding buffer were performed to obtain 1.45 mg of apparently homogeneous aminotransferase per liter of expression culture. CONCLUSIONS: We found that only reduction of temperature, but not reduction of expression level or fusion to maltose-binding protein helped to produce correctly folded, active aminotransferase FumI in E. coli. Our results may provide a starting point for soluble expression of related aminotransferases or other aggregation-prone proteins in E. coli. PMID- 20718949 TI - Asthma in changing environments--chances and challenges of international research collaborations between South America and Europe--study protocol and description of the data acquisition of a case-control-study. AB - BACKGROUND: Asthma in children is an emerging public health problem in South America. So far, research in this part of the world is limited. This paper presents the methodology and description of the data acquisition of an asthma case-control study conducted in the Central South of Chile. METHODS/DESIGN: A hospital-based case-control study about asthma (188 cases, 294 controls) in children (6-15 years) was carried out in Valdivia, Chile between November 2008 and December 2009. Data on asthma risk factors were collected by computer assisted personal interview using validated questions from e.g. ISAAC phase II. Data on household dust exposure (endotoxin, allergen analyses), skin prick tests to most common allergens, stool examinations for parasitic infection, and blood samples (total IgE, genetics) were collected. Additionally, 492 randomly chosen blood donors were recruited in order to assess allele frequencies in the population of Valdivia. DISCUSSION: Overall 1,173 participants were contacted. Response was 82% among cases and 65% among controls. Atopic sensitization was high (78% among cases, 47% among controls). Cases had a statistically significantly (p < .0001) increased self-reported 12-month prevalence of symptoms of rhinitis (82% vs. 51%) and wheeze (68% vs. 16%). The study is well placed to address current hypotheses about asthma and its correlates in the South American context. Results of this study might help develop novel, innovative and individualized prevention strategies in countries in transition with respect to the South American context. PMID- 20718951 TI - Synchronous perforation of a duodenal and gastric ulcer: a case report. AB - INTRODUCTION: Peritonitis due to peptic ulcer perforation is a surgical emergency with a high risk of mortality and morbidity. CASE PRESENTATION: We present a rare case of a 54-year-old Caucasian man who underwent an emergency laparotomy for peritonitis caused by perforation of two peptic ulcers. The first was located on the anterior wall of the duodenum and the second was posterior, pre-pyloric, close to the lesser curvature. CONCLUSION: To the best of our knowledge, this is only the second report in the medical literature of a simultaneous perforation of two peptic ulcers; though rare, every surgeon performing open or laparoscopic repair of a perforated peptic ulcer should be aware of the possibility of simultaneous perforation. PMID- 20718950 TI - Trichostatin A and 5-azacytidine both cause an increase in global histone H4 acetylation and a decrease in global DNA and H3K9 methylation during mitosis in maize. AB - BACKGROUND: Modifications of DNA and histones in various combinations are correlated with many cellular processes. In this study, we investigated the possible relationship between histone H4 tetraacetylation, DNA methylation and histone H3 dimethylation at lysine 9 during mitosis in maize root meristems. RESULTS: Treatment with trichostatin A, which inhibits histone deacetylases, resulted in increased histone H4 acetylation accompanied by the decondensation of interphase chromatin and a decrease in both global H3K9 dimethylation and DNA methylation during mitosis in maize root tip cells. These observations suggest that histone acetylation may affect DNA and histone methylation during mitosis. Treatment with 5-azacytidine, a cytosine analog that reduces DNA methylation, caused chromatin decondensation and mediated an increase in H4 acetylation, in addition to reduced DNA methylation and H3K9 dimethylation during interphase and mitosis. These results suggest that decreased DNA methylation causes a reduction in H3K9 dimethylation and an increase in H4 acetylation. CONCLUSIONS: The interchangeable effects of 5-azacytidine and trichostatin A on H4 acetylation, DNA methylation and H3K9 dimethylation indicate a mutually reinforcing action between histone acetylation, DNA methylation and histone methylation with respect to chromatin modification. Treatment with trichostatin A and 5-azacytidine treatment caused a decrease in the mitotic index, suggesting that H4 deacetylation and DNA and H3K9 methylation may contain the necessary information for triggering mitosis in maize root tips. PMID- 20718952 TI - Mycotic aneurysm of the inferior gluteal artery caused by non-typhi Salmonella in a man infected with HIV: a case report. AB - INTRODUCTION: Non-typhi Salmonellae infections represent major opportunistic pathogens affecting human immunodeficiency virus-infected individuals residing in sub-Saharan Africa. To the best of our knowledge, we report the first documented case in the medical literature of a Salmonella-induced mycotic aneurysm involving an artery supplying the gluteal region. CASE PRESENTATION: A 37-year-old black, Kenyan man, infected with human immunodeficiency virus with a CD4 count of 132 cells per microliter presented with a pulsatile gluteal mass and debilitating pain progressing over one week. He was receiving prophylaxis with trimethoprim sulfamethoxazole. Aspiration of the mass yielded gross blood. An ultrasound examination revealed a 37 ml vascular structure with an intra-luminal clot. Upon exploration, a true aneurysm of the inferior gluteal artery was identified and successfully resected. A culture of the aspirate grew a non-typhi Salmonellae species. Following resection, he was treated with oral ciprofloxacin for 10 weeks. He later began anti-retroviral therapy. Forty-two months after the initial diagnosis, he remained alive and well. CONCLUSIONS: Clinicians caring for patients infected with human immunodeficiency virus in Africa and other resource limited settings should be aware of the invasive nature of Salmonella infections and the potential for aneurysm formation in unlikely anatomical locations. Rapid initiation of appropriate anti-microbial chemotherapy and surgical referral is needed. Use of trimethoprim-sulfamethoxazole prophylaxis does not routinely prevent invasive Salmonella infections. PMID- 20718954 TI - Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report. AB - INTRODUCTION: We report the development of acute lymphoblastic leukemia in a patient in whom temozolomide was used for the treatment of a brain tumor. Unlike that of other alkylating agents, the leukemogenic potential of temozolomide is considered to be very low, and very rarely are such cases reported. CASE PRESENTATION: A 26-year-old Pakistani man who was treated for glioblastoma with temozolomide in an adjuvant setting was diagnosed to have acute lymphoblastic leukemia one year after stopping temozolomide. CONCLUSION: Temozolomide is a highly active agent, used in the management of high-grade brain neoplasms. The agent is generally regarded to be safe, with an acceptable safety profile. Very few cases of myelodysplasia associated with temozolomide use have been reported. We report here the first case of acute lymphoblastic leukemia, which developed in a young man about one year after he finished taking temozolomide. This should provide further insight into a possible toxicity profile of this alkylating agent. This finding should be of interest to physicians in general and to medical oncologists in particular. PMID- 20718953 TI - Asymmetric localization of Arabidopsis SYP124 syntaxin at the pollen tube apical and sub-apical zones is involved in tip growth. AB - BACKGROUND: The continuous polarized vesicle secretion in pollen tubes is essential for tip growth but the location of endo- and exocytic sub-domains remains however controversial. In this report we aimed to show that Arabidopsis thaliana syntaxins are involved in this process and contribute to spatially define exocytosis and membrane recycling. RESULTS: Using GFP-fusion constructs, we imaged the distribution of pollen-specific (AtSYP124) and non-pollen syntaxins (AtSYP121 and AtSYP122) in transiently transformed Nicotiana tabacum pollen tubes. All three proteins associate with the plasma membrane and with apical vesicles indicating a conserved action mechanism for all SYPs. However, the GFP tagged SYP124 showed a specific distribution with a higher labelling at the plasma membrane flanks, 10-25 mum behind the apex. This distribution is affected by Ca2+ fluxes as revealed by treatment with Gd3+ (an inhibitor of extracellular Ca2+ influx) and TMB-8 (an inhibitor of intracellular Ca2+ release). Both inhibitors decreased growth rate but the distribution of SYP124 at the plasma membrane was more strongly affected by Gd3+. Competition with a related dominant negative mutant affected the specific distribution of SYP124 but not tip growth. In contrast, co-expression of the phosphatidylinositol-4-monophosphate 5-kinase 4 (PIP5K4) or of the small GTPase Rab11 perturbed polarity and the normal distribution of GFP-SYP but did not inhibit the accumulation in vesicles or at the plasma membrane. CONCLUSIONS: The results presented suggest that in normal growing pollen tubes, a net exocytic flow occurs in the flanks of the tube apex mediated by SYP124. The specific distribution of SYP124 at the plasma membrane is affected by changes in Ca2+ levels in agreement with the importance of this ion for exocytosis. Apical growth and the specific localization of SYP124 were affected by regulators of membrane secretion (Ca2+, PIP5K4 and Rab11) but competition with a dominant negative mutant affected only SYP distribution. These data thus suggest that syntaxins alone do not provide the level of specificity that is required for apical growth and that additional signalling and functional mechanisms are required. PMID- 20718955 TI - Integrative inference of gene-regulatory networks in Escherichia coli using information theoretic concepts and sequence analysis. AB - BACKGROUND: Although Escherichia coli is one of the best studied model organisms, a comprehensive understanding of its gene regulation is not yet achieved. There exist many approaches to reconstruct regulatory interaction networks from gene expression experiments. Mutual information based approaches are most useful for large-scale network inference. RESULTS: We used a three-step approach in which we combined gene regulatory network inference based on directed information (DTI) and sequence analysis. DTI values were calculated on a set of gene expression profiles from 19 time course experiments extracted from the Many Microbes Microarray Database. Focusing on influences between pairs of genes in which one partner encodes a transcription factor (TF) we derived a network which contains 878 TF - gene interactions of which 166 are known according to RegulonDB. Afterward, we selected a subset of 109 interactions that could be confirmed by the presence of a phylogenetically conserved binding site of the respective regulator. By this second step, the fraction of known interactions increased from 19% to 60%. In the last step, we checked the 44 of the 109 interactions not yet included in RegulonDB for functional relationships between the regulator and the target and, thus, obtained ten TF - target gene interactions. Five of them concern the regulator LexA and have already been reported in the literature. The remaining five influences describe regulations by Fis (with two novel targets), PhdR, PhoP, and KdgR. For the validation of our approach, one of them, the regulation of lipoate synthase (LipA) by the pyruvate-sensing pyruvate dehydrogenate repressor (PdhR), was experimentally checked and confirmed. CONCLUSIONS: We predicted a set of five novel TF - target gene interactions in E. coli. One of them, the regulation of lipA by the transcriptional regulator PdhR was validated experimentally. Furthermore, we developed DTInfer, a new R-package for the inference of gene-regulatory networks from microarrays using directed information. PMID- 20718956 TI - Calculation of accurate small angle X-ray scattering curves from coarse-grained protein models. AB - BACKGROUND: Genome sequencing projects have expanded the gap between the amount of known protein sequences and structures. The limitations of current high resolution structure determination methods make it unlikely that this gap will disappear in the near future. Small angle X-ray scattering (SAXS) is an established low resolution method for routinely determining the structure of proteins in solution. The purpose of this study is to develop a method for the efficient calculation of accurate SAXS curves from coarse-grained protein models. Such a method can for example be used to construct a likelihood function, which is paramount for structure determination based on statistical inference. RESULTS: We present a method for the efficient calculation of accurate SAXS curves based on the Debye formula and a set of scattering form factors for dummy atom representations of amino acids. Such a method avoids the computationally costly iteration over all atoms. We estimated the form factors using generated data from a set of high quality protein structures. No ad hoc scaling or correction factors are applied in the calculation of the curves. Two coarse-grained representations of protein structure were investigated; two scattering bodies per amino acid led to significantly better results than a single scattering body. CONCLUSION: We show that the obtained point estimates allow the calculation of accurate SAXS curves from coarse-grained protein models. The resulting curves are on par with the current state-of-the-art program CRYSOL, which requires full atomic detail. Our method was also comparable to CRYSOL in recognizing native structures among native-like decoys. As a proof-of-concept, we combined the coarse-grained Debye calculation with a previously described probabilistic model of protein structure, TorusDBN. This resulted in a significant improvement in the decoy recognition performance. In conclusion, the presented method shows great promise for use in statistical inference of protein structures from SAXS data. PMID- 20718957 TI - In vivo expression of innate immunity markers in patients with Mycobacterium tuberculosis infection. AB - BACKGROUND: Toll-like receptors (TLRs), Coronin-1 and Sp110 are essential factors for the containment of Mycobacterium tuberculosis infection. The purpose of this study was to investigate the in vivo expression of these molecules at different stages of the infection and uncover possible relationships between these markers and the state of the disease. METHODS: Twenty-two patients with active tuberculosis, 15 close contacts of subjects with latent disease, 17 close contacts of subjects negative for mycobacterium antigens and 10 healthy, unrelated to patients, subjects were studied. Quantitative mRNA expression of Coronin-1, Sp110, TLRs-1,-2,-4 and -6 was analysed in total blood cells vs an endogenous house-keeping gene. RESULTS: The mRNA expression of Coronin-1, Sp110 and TLR-2 was significantly higher in patients with active tuberculosis and subjects with latent disease compared to the uninfected ones. Positive linear correlation for the expression of those factors was only found in the infected populations. CONCLUSIONS: Our results suggest that the up-regulation of Coronin-1 and Sp110, through a pathway that also includes TLR-2 up-regulation may be involved in the process of tuberculous infection in humans. However, further studies are needed, in order to elucidate whether the selective upregulation of these factors in the infected patients could serve as a specific molecular marker of tuberculosis. PMID- 20718959 TI - Detectability of Plasmodium falciparum clones. AB - BACKGROUND: In areas of high transmission people often harbour multiple clones of Plasmodium falciparum, but even PCR-based diagnostic methods can only detect a fraction (the detectability, q) of all clones present in a host. Accurate measurements of detectability are desirable since it affects estimates of multiplicity of infection, prevalence, and frequency of breakthrough infections in clinical drug trials. Detectability can be estimated by typing repeated samples from the same host but it has been unclear what should be the time interval between the samples and how the data should be analysed. METHODS: A longitudinal molecular study was conducted in the Kassena-Nankana district in northern Ghana. From each of the 80 participants, four finger prick samples were collected over a period of 8 days, and tested for presence of different Merozoite Surface Protein (msp) 2 genotypes. Implications for estimating q were derived from these data by comparing the fit of statistical models of serial dependence and over-dispersion. RESULTS: The distribution of the frequencies of detection for msp2 genotypes was close to binomial if the time span between consecutive blood samples was at least 7 days. For shorter intervals the probabilities of detection were positively correlated, i.e. the shorter the interval between two blood collections, the more likely the diagnostic results matched for a particular genotype. Estimates of q were rather insensitive to the statistical model fitted. CONCLUSIONS: A simple algorithm based on analysing blood samples collected 7 days apart is justified for generating robust estimates of detectability. The finding of positive correlation of detection probabilities for short time intervals argues against imperfect detection being directly linked to the 48-hour periodicity of P. falciparum. The results suggest that the detectability of a given parasite clone changes over time, at an unknown rate, but fast enough to regard blood samples taken one week apart as statistically independent. PMID- 20718958 TI - Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment. AB - Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life.The treatment in this age-group is non pharmacological and aims at promoting changes in lifestyle. However, pharmacological treatments are indicated in special situations.The major goals in dietary treatments are not only limited to weight loss, but also to an improvement in the quality of life. Modification of risk factors associated to comorbidities, personal satisfaction of the child or adolescent and trying to establish healthy life habits from an early age are also important. There is a continuous debate on the best possible exercise to do, for children or adolescents, in order to lose weight. The prescription of physical activity to children and adolescents requires extensive integrated work among multidisciplinary teams, patients and their families, in order to reach therapeutic success.The most important conclusion drawn from this symposium was that if the growing prevalence of overweight and obesity continues at this pace, the result will be a population of children and adolescents with metabolic syndrome. This would lead to high mortality rates in young adults, changing the current increasing trend of worldwide longevity. Government actions and a better understanding of the causes of this problem must be implemented worldwide, by aiming at the prevention of obesity in children and adolescents. PMID- 20718960 TI - Factors associated with excessively lengthy treatment of tuberculosis in the eastern Paris region of France in 2004. AB - BACKGROUND: Few data are available on prescriber adherence to tuberculosis (TB) treatment guidelines. In particular, excessively long treatment carries a risk of avoidable adverse effects and represents a waste of healthcare resources. We examined factors potentially associated with excessively long treatment. METHODS: We reviewed the medical records of patients diagnosed with TB in 2004 in the eastern Paris region. Sociodemographic and clinical factors associated with excessively long treatment were identified by logistic regression analyses. Based on contemporary guidelines, excessively long treatment was defined as more than 6 months of a four-drug regimen for thoracic TB with full sensitive strains, and more than 12 months for patients with extrathoracic TB. RESULTS: Analyses concerned 478 patients with a median age of 36.0 +/- 13.5 years, of whom 48% were living in precarious conditions (i.e. poor living conditions and/or no health insurance), 80% were born abroad, and 17% were HIV-seropositive. TB was restricted to the chest in 279 patients (isolated pulmonary, pleuropulmonary, and isolated pleural TB in 245, 13, and 21 patients, respectively), exclusively extrathoracic in 115 patients, and mixed in the remaining 84 patients. Treatment was prescribed by a chest specialist in 211 cases (44.1%) and 295 patients (61.7%) were managed in a single institution. The treatment duration complied with contemporary guidelines in 316 cases (66.1%) and was excessively long in 162 cases (33.9%). The median duration of excessively long treatment was 313 days (IQR: 272-412). In multivariate analysis, isolated thoracic TB, previous TB, HIV infection, a prescriber other than a chest specialist, and management in more than one healthcare center during treatment were independently associated with excessively lengthy treatment. CONCLUSION: One-third of TB patients received excessively long treatment, reflecting inadequate awareness of management guidelines or unwillingness to implement them. PMID- 20718961 TI - Atypical presentation of acute pancreatitis in a man with pancreatic insufficiency and cystic fibrosis: a case report. AB - INTRODUCTION: Whether acute pancreatitis can occur in pancreatically insufficient individuals with cystic fibrosis remains a matter of debate. CASE PRESENTATION: We describe a case of acute pancreatitis occurring in a 52-year-old Caucasian Australian man with moderately severe cystic fibrosis lung disease and pancreatic insufficiency. An inflammatory mass within the head of his pancreas was confirmed using computed tomography, magnetic resonance imaging and pancreatic biopsy, but serum amylase and lipase remained normal throughout the acute phase of his illness. His symptoms and the pancreatic mass resolved following the insertion of a biliary stent and the introduction of ursodeoxycholic acid. CONCLUSION: Our case report highlights the potential for acute pancreatitis to occur in patients with pancreatic insufficiency and cystic fibrosis. We further demonstrate that conventional biochemical markers that are normally assessed to confirm the diagnosis may not be of particular use. As patients with cystic fibrosis survive into their fourth and fifth decades of life, atypical presentations of acute pancreatitis may become more common. PMID- 20718962 TI - Protective effects of a gastrointestinal agent containing Korean red ginseng on gastric ulcer models in mice. AB - BACKGROUND: Korean red ginseng (KRG) is a ginseng that has been cultivated and aged for 4-6 years or more, and goes through an extensive cleaning, steaming and drying process. KRG contains more than 30 kinds of saponin components and has been reported as having various biological properties, such as anti-fatigue action, immune restoration, and neurovegetative effect. The purpose of this study was to assess the effects of a KRG-containing drug (KRGCD) on gastric ulcer models in mice. METHODS: Stomach ulcers were induced by oral ingestion of hydrochloride (HCl)/ethanol or indomethacin. Treatment with KRGCD (30, 100, and 300 mg/kg, p.o.) occurred 1 hr before the ulcer induction. Effect of KRGCD on anti-oxidant activity and gastric mucosal blood flow with a laser Doppler flowmeter in mice stomach tissue was evaluated. RESULTS: KRGCD (100 and 300 mg/kg, p.o.) significantly decreased ethanol- and indomethacin-induced gastric ulcer compared with the vehicle-treated (control) group. KRGCD (100 and 300 mg/kg) also decreased the level of thiobarbituric acid reactive substance (TBARS) and increased gastric mucosal blood flow compared with the control group. CONCLUSIONS: These results suggest that the gastroprotective effects of KRGCD on mice ulcer models can be attributed to its ameliorating effect on oxidative damage and improving effect of gastric mucosal blood flow. PMID- 20718963 TI - The ethics of human volunteer studies involving experimental exposure to pesticides: unanswered dilemmas. AB - The controversy about the use of data from human volunteer studies involving experimental exposure to pesticides as part of regulatory risk assessment has been widely discussed, but the complex and interrelated scientific and ethical issues remain largely unresolved. This discussion paper, generated by authors who comprised a workgroup of the ICOH Scientific Committee on Rural Health, reviews the use of human experimental studies in regulatory risk assessment for pesticides with a view to advancing the debate as to when, if ever, such studies might be ethically justifiable. The discussion is based on three elements: (a) a review of discussion papers on the topic of human testing of pesticides and the positions adopted by regulatory agencies in developed countries; (b) an analysis of published and unpublished studies involving human testing with pesticides, both in the peer-reviewed literature and in the JMPR database; and (c) application of an ethical analysis to the problem. The paper identifies areas of agreement which include general principles that may provide a starting point on which to base criteria for judgements as to the ethical acceptability of such studies. However, the paper also highlights ongoing unresolved differences of opinion inherent in ethical analysis of contentious issues, which we propose should form a starting point for further debate and the development of guidelines to achieve better resolution of this matter. PMID- 20718964 TI - Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. AB - BACKGROUND: Over the last few decades, research regarding the age of onset of schizophrenia and its relationship with other clinical variables has been incorporated into clinical practices. However, reports of potential differences in demographic and clinical characteristics between early- and adult-onset schizophrenia spectrum disorders have been controversial. Thus, this study aims to assess differences in demographic and clinical characteristics correlated with age of illness onset in schizophrenia spectrum disorders. METHODS: Data were collected from 104 patients with schizophrenia and schizoaffective disorder. Diagnosis was made via structured clinical interviews. Assessments of psychiatric symptoms and social and global functioning were completed. The effect of age of onset on demographic and clinical variables was examined using correlation analyses and binary logistic regression models. We chose 17 years of age as the cut-off for early-onset schizophrenia spectrum disorders based on a recent clinical consensus. We further investigated differences in the severity of psychopathology and other clinical variables between the early- and adult-onset groups. RESULTS: The binary logistic regression analysis showed that age of onset was significantly related to the cognitive component of the Positive and Negative Syndrome Scale (PANSS) (odds ratio, OR = 0.58; 95% confidence interval, CI = 0.872-0.985; p < 0.001) and Barratt Impulsiveness Scale (BIS) score (OR = 0.94; 95% CI = 0.447-0.744; p = 0.015). Patients with early onset of schizophrenia spectrum disorders had significantly greater levels of cognitive impairment and higher impulsivity. There were significant differences between several demographic and clinical variables, including the negative symptom component of the PANSS (p < 0.001), cognitive component of the PANSS (p < 0.001), BIS score (p = 0.05), and psychological domain of quality of life (QOL) (p = 0.05), between patients with early- and adult-onset schizophrenia spectrum disorders, having controlled for the effect of the current age and duration of illness. CONCLUSIONS: Our findings support the hypothesis of an influence of age of onset on illness course in patients with schizophrenia spectrum disorders. This finding may in fact be part of a separate domain worthy of investigation for the development of interventions for early symptoms of schizophrenia. PMID- 20718965 TI - Practical screening of purified cellobiohydrolases and endoglucanases with alpha cellulose and specification of hydrodynamics. AB - BACKGROUND: It is important to generate biofuels and society must be weaned from its dependency on fossil fuels. In order to produce biofuels, lignocellulose is pretreated and the resulting cellulose is hydrolyzed by cellulases such as cellobiohydrolases (CBH) and endoglucanases (EG). Until now, the biofuel industry has usually applied impractical celluloses to screen for cellulases capable of degrading naturally occurring, insoluble cellulose. This study investigates how these cellulases adsorb and hydrolyze insoluble alpha-cellulose - considered to be a more practical substrate which mimics the alkaline-pretreated biomass used in biorefineries. Moreover, this study investigates how hydrodynamics affects cellulase adsorption and activity onto alpha-cellulose. RESULTS: First, the cellulases CBH I, CBH II, EG I and EG II were purified from Trichoderma reesei and CBH I and EG I were utilized in order to study and model the adsorption isotherms (Langmuir) and kinetics (pseudo-first-order). Second, the adsorption kinetics and cellulase activities were studied under different hydrodynamic conditions, including liquid mixing and particle suspension. Third, in order to compare alpha-cellulose with three typically used celluloses, the exact cellulase activities towards all four substrates were measured.It was found that, using alpha-cellulose, the adsorption models fitted to the experimental data and yielded parameters comparable to those for filter paper. Moreover, it was determined that higher shaking frequencies clearly improved the adsorption of cellulases onto alpha-cellulose and thus bolstered their activity. Complete suspension of alpha-cellulose particles was the optimal operating condition in order to ensure efficient cellulase adsorption and activity. Finally, all four purified cellulases displayed comparable activities only on insoluble alpha cellulose. CONCLUSIONS: alpha-Cellulose is an excellent substrate to screen for CBHs and EGs. This current investigation shows in detail, for the first time, the adsorption of purified cellulases onto alpha-cellulose, the effect of hydrodynamics on cellulase adsorption and the correlation between the adsorption and the activity of cellulases at different hydrodynamic conditions. Complete suspension of the substrate has to be ensured in order to optimize the cellulase attack. In the future, screenings should be conducted with alpha-cellulose so that proper cellulases are selected to best hydrolyze the real alkaline pretreated biomass used in biorefineries. PMID- 20718966 TI - Recovery after caesarean birth: a qualitative study of women's accounts in Victoria, Australia. AB - BACKGROUND: The caesarean section rate is increasing globally, especially in high income countries. The reasons for this continue to create wide debate. There is good epidemiological evidence on the maternal morbidity associated with caesarean section. Few studies have used women's personal accounts of their experiences of recovery after caesarean. The aim of this paper is to describe women's accounts of recovery after caesarean birth, from shortly after hospital discharge to between five months and seven years after surgery. METHOD: Women who had at least one caesarean birth in a tertiary hospital in Victoria, Australia, participated in an interview study. Women were selected to ensure diversity in experiences (type of caesarean, recency), caesarean and vaginal birth, and maternal request caesarean section. Interviews were audiotaped and transcribed verbatim. A theoretical framework was developed (three Zones of clinical practice) and thematic analysis informed the findings. RESULTS: Thirty-two women were interviewed who between them had 68 births; seven women had experienced both caesarean and vaginal births. Three zones of clinical practice were identified in women's descriptions of the reasons for their first caesareans. Twelve women described how, at the time of their first caesarean section, the operation was performed for potentially life-saving reasons (Central Zone), 11 described situations of clinical uncertainty (Grey Zone), and nine stated they actively sought surgical intervention (Peripheral Zone).Thirty of the 32 women described difficulties following the postoperative advice they received prior to hospital discharge and their physical recovery after caesarean was hindered by a range of health issues, including pain and reduced mobility, abdominal wound problems, infection, vaginal bleeding and urinary incontinence. These problems were experienced across the three zones of clinical practice, regardless of the reasons women gave for their caesarean. CONCLUSION: The women in this study reported a range of unanticipated and unwanted negative physical health outcomes following caesarean birth. This qualitative study adds to the existing epidemiological evidence of significant maternal morbidity after caesarean section and underlines the need for caesarean section to be reserved for circumstances where the benefit is known to outweigh the harms. PMID- 20718968 TI - Do differences in the administrative structure of populations confound comparisons of geographic health inequalities? AB - BACKGROUND: Geographical health inequalities are naturally described by the variation in health outcomes between areas (e.g. mortality rates). However, comparisons made between countries are hampered by our lack of understanding of the effect of the size of administrative units, and in particular the modifiable areal unit problem. Our objective was to assess how differences in geographic and administrative units used for disseminating data affect the description of health inequalities. METHODS: Retrospective study of standard populations and deaths aggregated by administrative regions within 20 European countries, 1990-1991. Estimated populations and deaths in males aged 0-64 were in 5 year age bands. Poisson multilevel modelling was conducted of deaths as standardised mortality ratios. The variation between regions within countries was tested for relationships with the mean region population size and the unequal distribution of populations within each country measured using Gini coefficients. RESULTS: There is evidence that countries whose regions vary more in population size show greater variation and hence greater apparent inequalities in mortality counts. The Gini coefficient, measuring inequalities in population size, ranged from 0.1 to 0.5 between countries; an increase of 0.1 was accompanied by a 12-14% increase in the standard deviation of the mortality rates between regions within a country. CONCLUSIONS: Apparently differing health inequalities between two countries may be due to differences in geographical structure per se, rather than having any underlying epidemiological cause. Inequalities may be inherently greater in countries whose regions are more unequally populated. PMID- 20718967 TI - Structure and evolution of Apetala3, a sex-linked gene in Silene latifolia. AB - BACKGROUND: The evolution of sex chromosomes is often accompanied by gene or chromosome rearrangements. Recently, the gene AP3 was characterized in the dioecious plant species Silene latifolia. It was suggested that this gene had been transferred from an autosome to the Y chromosome. RESULTS: In the present study we provide evidence for the existence of an X linked copy of the AP3 gene. We further show that the Y copy is probably located in a chromosomal region where recombination restriction occurred during the first steps of sex chromosome evolution. A comparison of X and Y copies did not reveal any clear signs of degenerative processes in exon regions. Instead, both X and Y copies show evidence for relaxed selection compared to the autosomal orthologues in S. vulgaris and S. conica. We further found that promoter sequences differ significantly. Comparison of the genic region of AP3 between the X and Y alleles and the corresponding autosomal copies in the gynodioecious species S. vulgaris revealed a massive accumulation of retrotransposons within one intron of the Y copy of AP3. Analysis of the genomic distribution of these repetitive elements does not indicate that these elements played an important role in the size increase characteristic of the Y chromosome. However, in silico expression analysis shows biased expression of individual domains of the identified retroelements in male plants. CONCLUSIONS: We characterized the structure and evolution of AP3, a sex linked gene with copies on the X and Y chromosomes in the dioecious plant S. latifolia. These copies showed complementary expression patterns and relaxed evolution at protein level compared to autosomal orthologues, which suggests subfunctionalization. One intron of the Y-linked allele was invaded by retrotransposons that display sex-specific expression patterns that are similar to the expression pattern of the corresponding allele, which suggests that these transposable elements may have influenced evolution of expression patterns of the Y copy. These data could help researchers decipher the role of transposable elements in degenerative processes during sex chromosome evolution. PMID- 20718969 TI - Imatinib induced severe skin reactions and neutropenia in a patient with gastrointestinal stromal tumor. AB - BACKGROUND: Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST). The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression. However, imatinib can be associated with diverse adverse events, which has limited its use. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST. CASE PRESENTATION: A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant. An abdominal CT scan revealed a 20 x 19 cm intraabdominal mass with tumor invasion into the peritoneum. Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT. The patient was diagnosed with unresectable GIST. Imatinib 400 mg/day was started. The patient tolerated the first eight weeks of treatment. However, about three months later, the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash. The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care. However, the skin lesions recurred whenever the patient received imatinib over 100 mg/day. Therefore, imatinib 100 mg/day was maintained. Despite the low dose imatinib, follow up CT showed a marked partial response without grade 3 or 4 toxicities. CONCLUSION: The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug. PMID- 20718971 TI - Inhibition of allogeneic inflammatory responses by the Ribonucleotide Reductase Inhibitors, Didox and Trimidox. AB - BACKGROUND: Graft-versus-host disease is the single most important obstacle facing successful allogeneic stem cell transplantation (SCT). Even with current immunosuppressive therapies, morbidity and mortality rates are high. Current therapies including cyclosporine A (CyA) and related compounds target IL-2 signaling. However, although these compounds offer great benefit, they are also associated with multiple toxicities. Therefore, new compounds with a greater efficacy and reduced toxicity are needed to enable us to overcome this hurdle. METHODS: The allogeneic mixed lymphocyte reaction (MLR) is a unique ex vivo method to study a drug's action on the initial events resulting in T-cell activation and proliferation, synonymous to the initial stages of tissue and organ destruction by T-cell responses in organ rejection and Graft-versus-host disease. Using this approach, we examined the effectiveness of two ribonucleotide reductase inhibitors (RRI), Didox and Trimidox, to inhibit T-cell activation and proliferation. RESULTS: The compounds caused a marked reduction in the proliferative responses of T-cells, which is also accompanied by decreased secretion of cytokines IL-6, IFN-gamma, TNF-alpha, IL-2, IL-13, IL-10 and IL-4. CONCLUSIONS: In conclusion, these data provide critical information to justify further investigation into the potential use of these compounds post allogeneic bone marrow transplantation to alleviate graft-versus-host disease thereby achieving better outcomes. PMID- 20718970 TI - A knowledge management tool for public health: health-evidence.ca. AB - BACKGROUND: The ultimate goal of knowledge translation and exchange (KTE) activities is to facilitate incorporation of research knowledge into program and policy development decision making. Evidence-informed decision making involves translation of the best available evidence from a systematically collected, appraised, and analyzed body of knowledge. Knowledge management (KM) is emerging as a key factor contributing to the realization of evidence-informed public health decision making. The goal of health-evidence.ca is to promote evidence informed public health decision making through facilitation of decision maker access to, retrieval, and use of the best available synthesized research evidence evaluating the effectiveness of public health interventions. METHODS: The systematic reviews that populate health evidence.ca are identified through an extensive search (1985-present) of 7 electronic databases: MEDLINE, EMBASE, CINAHL, PsycINFO, Sociological Abstracts, BIOSIS, and SportDiscus; handsearching of over 20 journals; and reference list searches of all relevant reviews. Reviews are assessed for relevance and quality by two independent reviewers. Commonly used public health terms are used to assign key words to each review, and project staff members compose short summaries highlighting results and implications for policy and practice. RESULTS: As of June 2010, there are 1913 reviews in the health-evidence.ca registry in 21 public health and health promotion topic areas. Of these, 78% have been assessed as being of strong or moderate methodological quality. Health-evidence.ca receives approximately 35,000 visits per year, 20,596 of which are unique visitors, representing approximately 100 visits per day. Just under half of all visitors return to the site, with the average user spending six minutes and visiting seven pages per visit. Public health nurses, program managers, health promotion workers, researchers, and program coordinators are among the largest groups of registered users, followed by librarians, dieticians, medical officers of health, and nutritionists. The majority of users (67%) access the website from direct traffic (e.g., have the health-evidence.ca webpage bookmarked, or type it directly into their browser). CONCLUSIONS: Consistent use of health-evidence.ca and particularly the searching for reviews that correspond with current public health priorities illustrates that health-evidence.ca may be playing an important role in achieving evidence-informed public health decision making. PMID- 20718972 TI - Interaction of silver nanoparticles with Tacaribe virus. AB - BACKGROUND: Silver nanoparticles possess many unique properties that make them attractive for use in biological applications. Recently they received attention when it was shown that 10 nm silver nanoparticles were bactericidal, which is promising in light of the growing number of antibiotic resistant bacteria. An area that has been largely unexplored is the interaction of nanomaterials with viruses and the possible use of silver nanoparticles as an antiviral agent. RESULTS: This research focuses on evaluating the interaction of silver nanoparticles with a New World arenavirus, Tacaribe virus, to determine if they influence viral replication. Surprisingly exposing the virus to silver nanoparticles prior to infection actually facilitated virus uptake into the host cells, but the silver-treated virus had a significant reduction in viral RNA production and progeny virus release, which indicates that silver nanoparticles are capable of inhibiting arenavirus infection in vitro. The inhibition of viral replication must occur during early replication since although pre-infection treatment with silver nanoparticles is very effective, the post-infection addition of silver nanoparticles is only effective if administered within the first 2-4 hours of virus replication. CONCLUSIONS: Silver nanoparticles are capable of inhibiting a prototype arenavirus at non-toxic concentrations and effectively inhibit arenavirus replication when administered prior to viral infection or early after initial virus exposure. This suggests that the mode of action of viral neutralization by silver nanoparticles occurs during the early phases of viral replication. PMID- 20718974 TI - Diverse accumulation of several dehydrin-like proteins in cauliflower (Brassica oleracea var. botrytis), Arabidopsis thaliana and yellow lupin (Lupinus luteus) mitochondria under cold and heat stress. AB - BACKGROUND: Dehydrins represent hydrophilic proteins acting mainly during cell dehydration and stress response. Dehydrins are generally thermostable; however, the so-called dehydrin-like (dehydrin-related) proteins show variable thermolability. Both groups immunoreact with antibodies directed against the K segment of dehydrins. Plant mitochondrial dehydrin-like proteins are poorly characterized. The purpose of this study was to extend previous reports on plant dehydrins by comparing the level of immunoprecipitated dehydrin-like proteins in cauliflower (Brassica oleracea var. botrytis), Arabidopsis thaliana and yellow lupin (Lupinus luteus) mitochondria under cold and heat stress. RESULTS: All the analyzed plant species showed constitutive accumulation of thermostable mitochondrial putative dehydrins ranging from 50 to 70 kDa. The mitochondrial dehydrin-like proteins observed in cauliflower and Arabidopsis ranged from 10 to 100 kDa and in lupin imbibed seeds and hypocotyls--from 20 to 90 kDa. Cold treatment increased mainly the accumulation of 10-100 kDa cauliflower and Arabidopsis dehydrin-like proteins, in the patterns different in cauliflower leaf and inflorescence mitochondria. However, in lupin mitochondria, cold affected mainly 25-50 kDa proteins and seemed to induce the appearance of some novel dehydrin-like proteins. The influence of frost stress on cauliflower leaf mitochondrial dehydrin- like proteins was less significant. The impact of heat stress was less significant in lupin and Arabidopsis than in cauliflower inflorescence mitochondria. Cauliflower mitochondrial dehydrin-like proteins are localized mostly in the mitochondrial matrix; it seems that some of them may interact with mitochondrial membranes. CONCLUSIONS: All the results reveal an unexpectedly broad spectrum of dehydrin-like proteins accumulated during some abiotic stress in the mitochondria of the plant species analyzed. They display only limited similarity in size to those reported previously in maize, wheat and rye mitochondria. Some small thermolabile dehydrin-like proteins were induced under stress conditions applied and therefore they are likely to be involved in stress response. PMID- 20718975 TI - Landmine injuries at the Emergency Management Center in Erbil, Iraq. AB - BACKGROUND: Landmines can cause death, injury and disability in addition to many indirect public health consequences. This study aimed at understanding the trends, demography and other epidemiological characteristics of hospitalized landmine injured patients in Erbil governorate. METHODS: The case records of landmine injured patients who had been admitted to the Emergency Management Centre in Erbil city from July 1998 to July 2007 were reviewed and descriptively analyzed. RESULTS: Two hundred eighty five landmine injured patients were admitted to the center, their mean +/- SD age was 26.5 +/- 13.2 years (range 6-71 years), 95.1% were males, nearly 50% were between 19 to 35 years of age and 96.8% were civilians. Around 72% of victims sustained limb amputations; 58.6% lower limb and 13.3% upper limb out of the total. The hospital mortality rate was 2.1%. The number of admissions for landmine injury was steadily decreasing between July 1998 and July 2001, followed by prominent increase between July 2002 and July 2003. The highest proportion of admissions occurred in summer (35.4%) and majority of incidents occurred along the borders with Iran and Turkey (61.8%). CONCLUSION: Civilian male adolescents and young adults constituted the majority of hospitalized landmine victims in Erbil governorate. While a high proportion of victims sustained lower limb amputations, upper limb amputations particularly among children and injury to head and face were relatively common which might be attributed to handling explosives. This emphasizes the need to examine the reasons behind handling explosives. PMID- 20718976 TI - Profiling alumni of a Brazilian public dental school. AB - BACKGROUND: Follow-up studies of former students are an efficient way to organize the entire process of professional training and curriculum evaluation. The aim of this study was to identify professional profile subgroups based on job-related variables in a sample of former students of a Brazilian public dental school. METHODS: A web-based password-protected questionnaire was sent to 633 registered dentists who graduated from the Federal University of Goias between 1988 and 2007. Job-related information was retrieved from 14 closed questions, on subjects such as gender, occupational routine, training, profits, income status, and self perception of professional career, generating an automatic database for analysis. The two-step cluster method was used for dividing dentists into groups on the basis of minimal within-group and maximal between-group variation, using job related variables to represent attributes upon which the clustering was based. RESULTS: There were 322 respondents (50.9%), predominantly female (64.9%) and the mean age was 34 years (SD = 6.0). The automatic selection of an optimal number of clusters included 289 cases (89.8%) in 3 natural clusters. Clusters 1, 2 and 3 included 52.2%, 30.8% and 17.0% of the sample respectively. Interpretation of within-group rank of variable importance for cluster segmentation resulted in the following characterization of clusters: Cluster 1 - specialist dentists with higher profits and positive views of the profession; Cluster 2 - general dental practitioners in small cities; Cluster 3 - underpaid and less motivated dentists with negative views of the profession. Male dentists were predominant in cluster 1 and females in cluster 3. One-way Anova showed that age and time since graduation were significantly lower in Cluster 2 (P < 0.001). Alternative solutions with 4 and 5 clusters revealed specific discrimination of Cluster 1 by gender and dental education professionals. CONCLUSIONS: Cluster analysis was a valuable method for identifying natural grouping with relatively homogeneous cases, providing potentially meaningful information for professional orientation in dentistry in a variety of professional situations and environments. PMID- 20718977 TI - Community-based prevention leads to an increase in condom use and a reduction in sexually transmitted infections (STIs) among men who have sex with men (MSM) and female sex workers (FSW): the Frontiers Prevention Project (FPP) evaluation results. AB - BACKGROUND: India has an estimated 2.0 million to 3.1 million people living with HIV; it has the highest number of HIV-positive people in Asia and ranks third in the world. The Frontiers Prevention Project (FPP) was implemented in 2002 to conduct targeted prevention intervention geared towards female sex workers (FSW) and men who have sex with men (MSM) in the state of Andhra Pradesh (AP). This paper reports the overall changes in behaviour and STI outcomes between 2003/4 and 2007 and also describes the changes attributed to the FPP. METHODS: The evaluation used two cross-sectional surveys among MSM and FSW at 24 sites in AP. Surveys were implemented using a similar methodology. Univariate analyses were conducted by comparing means: baseline vs. four-year follow-up and FPP vs. non FPP. For both MSM and FSW, random and fixed-effects logit regression models at the site level were estimated for condom use with last partner, syphilis sero positivity and HSV 2 sero-positivity. In addition, for FSW we estimated models for condom use with regular partner, and for MSM we estimated models for condom use with last female partner. RESULTS: Among MSM, fixed-effects analysis revealed that FPP was positively correlated with the probability of condom use with last female sexual partner and negatively correlated with the individual probability of sero-positivity to syphilis and HSV 2. Among FSW, the FPP intervention was significantly correlated with increased condom use with regular partners and with lower probability of STI sero-positivity. DISCUSSION: Important changes in behaviours related to an increase in prevention activities translated to reductions in STI sero-prevalence in AP, India. In contrast with non-FPP sites, the FPP sites experienced an intense community approach as part of the FPP intervention, and the general increase in condom use and its effect on STI sero prevalence reflected the efficacy of these intense prevention activities focused on key populations in AP. PMID- 20718978 TI - Does pleural fluid appearance really matter? The relationship between fluid appearance and cytology, cell counts, and chemical laboratory measurements in pleural effusions of patients with cancer. AB - BACKGROUND: Previous reports have suggested that the appearance of pleural effusions (i.e., the presence or absence of blood) might help to establish the etiology of the effusions. This study explores the relationship between pleural fluid appearance and the results of chemical and cytological analyses in a group of patients with recurrent symptomatic pleural effusions and a diagnosis of cancer. METHODS: Medical records were reviewed from all 390 patients who were diagnosed with cancer, who underwent thoracentesis before placement of an intrapleural catheter (IPC) between April 2000 and January 2006. Adequate information for data analysis was available in 365 patients. The appearance of their pleural fluid was obtained from procedure notes dictated by the pulmonologists who had performed the thoracenteses. The patients were separated into 2 groups based on fluid appearance: non-bloody and bloody. Group differences in cytology interpretation were compared by using the chi square test. Cellular counts, chemical laboratory results, and survival after index procedure were compared by using the student's t test. RESULTS: Pleural fluid cytology was positive on 82.5% of the non-bloody effusions and on 82.4% of the bloody ones. The number of red blood cells (220.5 x 103/microL vs. 12.3 x 103/microL) and LDH values (1914 IU/dl vs. 863 IU/dl) were statistically higher in bloody pleural effusions. CONCLUSION: The presence or absence of blood in pleural effusions cannot predict their etiology in patients with cancer and recurrent symptomatic pleural effusions. PMID- 20718979 TI - Strengthening the emergency healthcare system for mothers and children in The Gambia. AB - A system to improve the management of emergencies during pregnancy, childbirth, infancy and childhood in a region of The Gambia (Brikama) with a population of approximately 250,000 has been developed.This was accomplished through formal partnership between the Gambian Ministry of Health, the World Health Organisation, Maternal Childhealth Advocacy International and the Advanced Life Support Group.Since October 2006, the hospital in Brikama has been renovated and equipped and more efficiently provided with emergency medicines. An emergency ambulance service now links the community with the hospital through a mobile telephone system. Health professionals from community to hospital have been trained in obstetric, neonatal and paediatric emergency management using skills' based education. The programme was evaluated in log books detailing individual resuscitations and by external assessment.The hospital now has constant water and electricity, a functioning operating theatre and emergency room; the maternity unit and children's wards have better emergency equipment and there is a more reliable supply of oxygen and emergency drugs, including misoprostol (for treating post partum haemorrhage) and magnesium sulphate (for severe pre eclampsia). There is also a blood transfusion service.Countrywide, 217 doctors, nurses, and midwives have undergone accredited training in the provision of emergency maternal, newborn and child care, including for major trauma. 33 have received additional education through Generic Instructor Courses and 15 have reached full instructor status. 83 Traditional Birth Attendants and 48 Village Health Workers have been trained in the recognition and initial management of emergencies, including resuscitation of the newborn. Eleven and ten nurses underwent training in peri-operative nursing and anaesthetics respectively, to address the acute shortage required for emergency Caesarean section.Between May 2007 and March 2010, 109 patients, mostly pregnant mothers, were stabilised and transported to hospital by the new emergency ambulance service.293 resuscitation attempts were documented in personal logbooks.A sustainable system for better managing emergencies has been established and is helping to negate the main obstacle impeding progress: the country's lack of available trained medical and nursing staff. However, insufficient attention was paid to improving staff morale and accommodation representing significant failings of the programme. PMID- 20718980 TI - Coverage statistics for sequence census methods. AB - BACKGROUND: We study the statistical properties of fragment coverage in genome sequencing experiments. In an extension of the classic Lander-Waterman model, we consider the effect of the length distribution of fragments. We also introduce a coding of the shape of the coverage depth function as a tree and explain how this can be used to detect regions with anomalous coverage. This modeling perspective is especially germane to current high-throughput sequencing experiments, where both sample preparation protocols and sequencing technology particulars can affect fragment length distributions. RESULTS: Under the mild assumptions that fragment start sites are Poisson distributed and successive fragment lengths are independent and identically distributed, we observe that, regardless of fragment length distribution, the fragments produced in a sequencing experiment can be viewed as resulting from a two-dimensional spatial Poisson process. We then study the successive jumps of the coverage function, and show that they can be encoded as a random tree that is approximately a Galton-Watson tree with generation dependent geometric offspring distributions whose parameters can be computed. CONCLUSIONS: We extend standard analyses of shotgun sequencing that focus on coverage statistics at individual sites, and provide a null model for detecting deviations from random coverage in high-throughput sequence census based experiments. Our approach leads to explicit determinations of the null distributions of certain test statistics, while for others it greatly simplifies the approximation of their null distributions by simulation. Our focus on fragments also leads to a new approach to visualizing sequencing data that is of independent interest. PMID- 20718981 TI - Are chest compressions safe for the patient reconstructed with sternal plates? Evaluating the safety of cardiopulmonary resuscitation using a human cadaveric model. AB - BACKGROUND: Plate and screw fixation is a recent addition to the sternal wound treatment armamentarium. Patients undergoing cardiac and major vascular surgery have a higher risk of postoperative arrest than other elective patients. Those who undergo sternotomy for either cardiac or major vascular procedures are at a higher risk of postoperative arrest. Sternal plate design allows quick access to the mediastinum facilitating open cardiac massage, but chest compressions are the mainstay of re-establishing cardiac output in the event of arrest. The response of sternal plates and the chest wall to compressions when plated has not been studied. The safety of performing this maneuver is unknown. This study intends to demonstrate compressions are safe after sternal plating. METHODS: We investigated the effect of chest compressions on the plated sternum using a human cadaveric model. Cadavers were plated, an arrest was simulated, and an experienced physician performed a simulated resuscitation. Intrathoracic pressure was monitored throughout to ensure the plates encountered an appropriate degree of force. The hardware and viscera were evaluated for failure and trauma respectively. RESULTS: No hardware failure or obvious visceral trauma was observed. Rib fractures beyond the boundaries of the plates were noted but the incidence was comparable to control and to the fracture incidence after resuscitation previously cited in the literature. CONCLUSIONS: From this work we believe chest compressions are safe for the patient with sternal plates when proper plating technique is used. We advocate the use of this life-saving maneuver as part of an ACLS resuscitation in the event of an arrest for rapidly re-establishing circulation. PMID- 20718982 TI - Rapid method for determination of DNA repair capacity in human peripheral blood lymphocytes amongst smokers. AB - BACKGROUND: DNA repair capacity is an important determinant of susceptibility to cancer. The hOGG1 enzyme is crucial for repairing the 8-oxoguanine lesion that occurs either as a byproduct of oxidative metabolism or as a result of exogenous sources such as exposure to cigarette smoke. It has been previously reported that smokers with low hOGG1 activity had significantly higher risk of developing lung cancer as compared to smokers with high hOGG1 activity. METHODS: In the current study we elucidate the association between plasma levels of 8-OHdG and the OGG1 repair capacity. We used the commercially available 8-OHdG ELISA (enzyme-linked immunosorbent assay), the Comet assay/FLARE hOGG1 (Fragment Length Analysis by Repair Enzymes) assay for quantification of the levels of 8-OHdG and measured the constitutive, induced and unrepaired residual damage, respectively. We compared the DNA repair capacity in peripheral blood lymphocytes following H2O2 exposure in 30 lung cancer patients, 30 non-, 30 former and 30 current smoker controls matched by age and gender. RESULTS: Our results show that lung cancer cases and current smoker controls have similar levels of 8-OHdG lesions that are significantly higher compared to the non-smokers controls. However, lung cancer cases showed significantly poorer repair capacity compared to all controls tested, including the current smokers controls. After adjustment for age, gender and family history of smoking-related cancer using linear regression, we observed a 5-fold increase in risk of lung cancer associated with high levels of residual damage/reduced repair capacity. Reduced OGG1 activity could be expected to be a risk factor in other smoking-related cancers. CONCLUSION: Our study shows that the Comet/FLARE assay is a relatively rapid and useful method for determination of DNA repair capacity. Using this assay we could identify individuals with high levels of residual damage and hence poor repair capacity who would be good candidates for intensive follow-up and screening. PMID- 20718983 TI - Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial. AB - BACKGROUND: Recent studies have questioned our previous understanding on the effect of nitrous oxide on muscle relaxants, since nitrous oxide has been shown to potentiate the action of bolus doses of mivacurium, rocuronium and vecuronium. This study was aimed to investigate the possible effect of nitrous oxide on the infusion requirements of cisatracurium. METHODS: 70 ASA physical status I-III patients aged 18-75 years were enrolled in this randomized trial. The patients were undergoing elective surgery requiring general anesthesia with a duration of at least 90 minutes. Patients were randomized to receive propofol and remifentanil by target controlled infusion in combination with either a mixture of oxygen and nitrous oxide (Nitrous oxide/TIVA group) or oxygen in air (Air/TIVA group). A 0.1 mg/kg initial bolus of cisatracurium was administered before tracheal intubation, followed by a closed-loop computer controlled infusion of cisatracurium to produce and maintain a 90% neuromuscular block. Cumulative dose requirements of cisatracurium during the 90-min study period after bolus administration were measured and the asymptotic steady state rate of infusion to produce a constant 90% block was determined by applying nonlinear curve fitting to the data on the cumulative dose requirement during the study period. RESULTS: Controller performance, i.e. the ability of the controller to maintain neuromuscular block constant at the setpoint and patient characteristics were similar in both groups. The administration of nitrous oxide did not affect cisatracurium infusion requirements. The mean steady-state rates of infusion were 0.072 +/- 0.018 and 0.066 +/- 0.017 mg * kg-1 * h-1 in Air/TIVA and Nitrous oxide/TIVA groups, respectively. CONCLUSIONS: Nitrous oxide does not affect the infusion requirements of cisatracurium. TRIAL REGISTRATION: ClinicalTrials.gov NCT01152905; European Clinical Trials Database at http://eudract.emea.eu.int/2006 006037-41. PMID- 20718985 TI - What is behind smoker support for new smokefree areas? National survey data. AB - BACKGROUND: Some countries have started to extend indoor smokefree laws to cover cars and various outdoor settings. However, policy-modifiable factors around smoker support for these new laws are not well described. METHODS: The New Zealand (NZ) arm of the International Tobacco Control Policy Evaluation Survey (ITC Project) derives its sample from the NZ Health Survey (a national sample). From this sample we surveyed adult smokers (n = 1376). RESULTS: For the six settings considered, 59% of smokers supported at least three new completely smokefree areas. Only 2% favoured smoking being allowed in all the six new settings. Support among Maori, Pacific and Asian smokers relative to European smokers was elevated in multivariate analyses, but confidence intervals often included 1.0.Also in the multivariate analyses, "strong support" by smokers for new smokefree area laws was associated with greater knowledge of the second-hand smoke (SHS) hazard, and with behaviours to reduce SHS exposure towards others. Strong support was also associated with reporting having smokefree cars (aOR = 1.68, 95% CI = 1.21 - 2.34); and support for tobacco control regulatory measures by government (aOR = 1.63, 95% CI = 1.32 - 2.01). There was also stronger support by smokers with a form of financial stress (not spending on household essentials). CONCLUSIONS: Smokers from a range of population groups can show majority support for new outdoor and smokefree car laws. Some of these findings are consistent with the use of public health strategies to support new smokefree laws, such as enhancing public knowledge of the second-hand smoke hazard. PMID- 20718984 TI - The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition. AB - BACKGROUND: Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs are able to proliferate and self-renew extensively due to their ability to express anti-apoptotic and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate CSCs might have significant clinical implications. The objectives of this study were to examine the molecular mechanisms by which epigallocathechin gallate (EGCG) inhibits stem cell characteristics of prostate CSCs, and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. RESULTS: Our data indicate that human prostate cancer cell lines contain a small population of CD44+CD133+ cancer stem cells and their self-renewal capacity is inhibited by EGCG. Furthermore, EGCG inhibits the self-renewal capacity of CD44+alpha2beta1+CD133+ CSCs isolated from human primary prostate tumors, as measured by spheroid formation in suspension. EGCG induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2, survivin and XIAP in CSCs. Furthermore, EGCG inhibits epithelial-mesenchymal transition by inhibiting the expression of vimentin, slug, snail and nuclear beta-catenin, and the activity of LEF-1/TCF responsive reporter, and also retards CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Interestingly, quercetin synergizes with EGCG in inhibiting the self-renewal properties of prostate CSCs, inducing apoptosis, and blocking CSC's migration and invasion. These data suggest that EGCG either alone or in combination with quercetin can eliminate cancer stem cell-characteristics. CONCLUSION: Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities will be beneficial for prostate cancer prevention and/ortreatment. PMID- 20718986 TI - Inflammatory myofibroblastic pseudotumour of the liver in association with gall stones - a rare case report and brief review. AB - Inflammatory myofibroblastic pseudotumours of the liver are rare tumour-like lesions that can mimic malignant liver neoplasms. The symptoms and radiological findings of this rare tumour can pose diagnostic difficulties. We describe a 69 year-old gentleman who was admitted to our department with symptoms suggestive of acute cholecystitis. Ultrasonography and computed tomography of the liver raised the possibility of metastatic liver disease. A core biopsy of the liver was performed to confirm the diagnosis of liver metastasis. Unexpectedly it showed no evidence of malignancy but instead revealed an inflammatory myofibroblastic pseudotumour of the liver. This case report highlights the diagnostic dilemma that arose due to the similarity of appearances between the two pathological entities on imaging and this stresses the need for accurate histological diagnosis so as to avoid unnecessary surgical intervention. To the best of our knowledge, only a minority of cases are reported in the literature associating a hepatic inflammatory myofibroblastic pseudotumour with gall stones. PMID- 20718987 TI - RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma. AB - BACKGROUND: Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells. RESULTS: Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. CONCLUSION: In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma. PMID- 20718988 TI - Hidden Markov model speed heuristic and iterative HMM search procedure. AB - BACKGROUND: Profile hidden Markov models (profile-HMMs) are sensitive tools for remote protein homology detection, but the main scoring algorithms, Viterbi or Forward, require considerable time to search large sequence databases. RESULTS: We have designed a series of database filtering steps, HMMERHEAD, that are applied prior to the scoring algorithms, as implemented in the HMMER package, in an effort to reduce search time. Using this heuristic, we obtain a 20-fold decrease in Forward and a 6-fold decrease in Viterbi search time with a minimal loss in sensitivity relative to the unfiltered approaches. We then implemented an iterative profile-HMM search method, JackHMMER, which employs the HMMERHEAD heuristic. Due to our search heuristic, we eliminated the subdatabase creation that is common in current iterative profile-HMM approaches. On our benchmark, JackHMMER detects 14% more remote protein homologs than SAM's iterative method T2K. CONCLUSIONS: Our search heuristic, HMMERHEAD, significantly reduces the time needed to score a profile-HMM against large sequence databases. This search heuristic allowed us to implement an iterative profile-HMM search method, JackHMMER, which detects significantly more remote protein homologs than SAM's T2K and NCBI's PSI-BLAST. PMID- 20718989 TI - rSW-seq: algorithm for detection of copy number alterations in deep sequencing data. AB - BACKGROUND: Recent advances in sequencing technologies have enabled generation of large-scale genome sequencing data. These data can be used to characterize a variety of genomic features, including the DNA copy number profile of a cancer genome. A robust and reliable method for screening chromosomal alterations would allow a detailed characterization of the cancer genome with unprecedented accuracy. RESULTS: We develop a method for identification of copy number alterations in a tumor genome compared to its matched control, based on application of Smith-Waterman algorithm to single-end sequencing data. In a performance test with simulated data, our algorithm shows >90% sensitivity and >90% precision in detecting a single copy number change that contains approximately 500 reads for the normal sample. With 100-bp reads, this corresponds to a ~50 kb region for 1X genome coverage of the human genome. We further refine the algorithm to develop rSW-seq, (recursive Smith-Waterman-seq) to identify alterations in a complex configuration, which are commonly observed in the human cancer genome. To validate our approach, we compare our algorithm with an existing algorithm using simulated and publicly available datasets. We also compare the sequencing-based profiles to microarray-based results. CONCLUSION: We propose rSW-seq as an efficient method for detecting copy number changes in the tumor genome. PMID- 20718990 TI - Nanofibers and nanoparticles from the insect-capturing adhesive of the Sundew (Drosera) for cell attachment. AB - BACKGROUND: The search for naturally occurring nanocomposites with diverse properties for tissue engineering has been a major interest for biomaterial research. In this study, we investigated a nanofiber and nanoparticle based nanocomposite secreted from an insect-capturing plant, the Sundew, for cell attachment. The adhesive nanocomposite has demonstrated high biocompatibility and is ready to be used with minimal preparation. RESULTS: Atomic force microscopy (AFM) conducted on the adhesive from three species of Sundew found that a network of nanofibers and nanoparticles with various sizes existed independent of the coated surface. AFM and light microscopy confirmed that the pattern of nanofibers corresponded to Alcian Blue staining for polysaccharide. Transmission electron microscopy identified a low abundance of nanoparticles in different pattern form AFM observations. In addition, energy-dispersive X-ray spectroscopy revealed the presence of Ca, Mg, and Cl, common components of biological salts. Study of the material properties of the adhesive yielded high viscoelasticity from the liquid adhesive, with reduced elasticity observed in the dried adhesive. The ability of PC12 neuron-like cells to attach and grow on the network of nanofibers created from the dried adhesive demonstrated the potential of this network to be used in tissue engineering, and other biomedical applications. CONCLUSIONS: This discovery demonstrates how a naturally occurring nanofiber and nanoparticle based nanocomposite from the adhesive of Sundew can be used for tissue engineering, and opens the possibility for further examination of natural plant adhesives for biomedical applications. PMID- 20718991 TI - Development of a universal psycho-educational intervention to prevent common postpartum mental disorders in primiparous women: a multiple method approach. AB - BACKGROUND: Prevention of postnatal mental disorders in women is an important component of comprehensive health service delivery because of the substantial potential benefits for population health. However, diverse approaches to prevention of postnatal depression have had limited success, possibly because anxiety and adjustment disorders are also problematic, mental health problems are multifactorially determined, and because relationships amongst psychosocial risk factors are complex and difficult to modify. The aim of this paper is to describe the development of a novel psycho-educational intervention to prevent postnatal mental disorders in mothers of firstborn infants. METHODS: Data from a variety of sources were synthesised: a literature review summarised epidemiological evidence about neglected modifiable risk factors; clinical research evidence identified successful psychosocial treatments for postnatal mental health problems; consultations with clinicians, health professionals, policy makers and consumers informed the proposed program and psychological and health promotion theories underpinned the proposed mechanisms of effect. The intervention was pilot-tested with small groups of mothers and fathers and their first newborn infants. RESULTS: What Were We Thinking! is a psycho-educational intervention, designed for universal implementation, that addresses heightened learning needs of parents of first newborns. It re-conceptualises mental health problems in mothers of infants as reflecting unmet needs for adaptations in the intimate partner relationship after the birth of a baby, and skills to promote settled infant behaviour. It addresses these two risk factors in half-day seminars, facilitated by trained maternal and child health nurses using non-psychiatric language, in groups of up to five couples and their four-week old infants in primary care. It is designed to promote confidence and reduce mental disorders by providing skills in sustainable sleep and settling strategies, and the re-negotiation of the unpaid household workload in non-confrontational ways. Materials include a Facilitators' Handbook, creatively designed worksheets for use in seminars, and a book for couples to take home for reference. A website provides an alternative means of access to the intervention. CONCLUSIONS: What Were We Thinking! is a postnatal mental health intervention which has the potential to contribute to psychologically-informed routine primary postnatal health care and prevent common mental disorders in women. PMID- 20718992 TI - Undergraduate medical student perceptions and use of Evidence Based Medicine: a qualitative study. AB - BACKGROUND: Many medical schools teach the principles of Evidence Based Medicine (EBM) as a subject within their medical curriculum. Few studies have explored the barriers and enablers that students experience when studying medicine and attempting to integrate EBM in their clinical experience. The aim of this study was to identify undergraduate medical student perceptions of EBM, including their current use of its principles as students and perceived future use as clinicians. METHODS: Third year medical students were recruited via email to participate in focus group discussions. Four focus groups were conducted separately across four hospital sites. All focus groups were conducted by the same facilitator. All discussions were transcribed verbatim, and analysed independently by the two authors according to the principles of thematic analysis. RESULTS: Focus group discussions were conducted with 23 third-year medical students, representing three metropolitan and one rural hospital sites. Five key themes emerged from the analysis of the transcripts: (1) Rationale and observed use of EBM in practice, (2) Current use of EBM as students, (3) Perceived use of EBM as future clinicians, (4) Barriers to practicing EBM, and (5) Enablers to facilitate the integration of EBM into clinical practice. Key facilitators for promoting EBM to students include competency in EBM, mentorship and application to clinical disciplines. Barriers to EBM implementation include lack of visible application by senior clinicians and constraints by poor resourcing. CONCLUSIONS: The principles and application of EBM is perceived by medical students to be important in both their current clinical training and perceived future work as clinicians. Future research is needed to identify how medical students incorporate EBM concepts into their clinical practice as they gain greater clinical exposure and competence. PMID- 20718993 TI - Phenotypic plasticity in the range-margin population of the lycaenid butterfly Zizeeria maha. AB - BACKGROUND: Many butterfly species have been experiencing the northward range expansion and physiological adaptation, probably due to climate warming. Here, we document an extraordinary field case of a species of lycaenid butterfly, Zizeeria maha, for which plastic phenotypes of wing color-patterns were revealed at the population level in the course of range expansion. Furthermore, we examined whether this outbreak of phenotypic changes was able to be reproduced in a laboratory. RESULTS: In the recently expanded northern range margins of this species, more than 10% of the Z. maha population exhibited characteristic color pattern modifications on the ventral wings for three years. We physiologically reproduced similar phenotypes by an artificial cold-shock treatment of a normal southern population, and furthermore, we genetically reproduced a similar phenotype after selective breeding of a normal population for ten generations, demonstrating that the cold-shock-induced phenotype was heritable and partially assimilated genetically in the breeding line. Similar genetic process might have occurred in the previous and recent range-margin populations as well. Relatively minor modifications expressed in the tenth generation of the breeding line together with other data suggest a role of founder effect in this field case. CONCLUSIONS: Our results support the notion that the outbreak of the modified phenotypes in the recent range-margin population was primed by the revelation of plastic phenotypes in response to temperature stress and by the subsequent genetic process in the previous range-margin population, followed by migration and temporal establishment of genetically unstable founders in the recent range margins. This case presents not only an evolutionary role of phenotypic plasticity in the field but also a novel evolutionary aspect of range expansion at the species level. PMID- 20718995 TI - The opportunities for and obstacles against prevention: the example of Germany in the areas of tobacco and alcohol. AB - BACKGROUND: Recent years have seen a growing research and policy interest in prevention in many developed countries. However, the actual efforts and resources devoted to prevention appear to have lagged well behind the lip service paid to the topic. DISCUSSION: We review the evidence on the considerable existing scope for health gains from prevention as well as for greater prevention policy efforts in Germany. We also discuss the barriers to "more and better" prevention and provide modest suggestions about how some of the obstacles could be overcome. SUMMARY: In Germany, there are substantial health gains to be reaped from the implementation of evidence-based, cost-effective preventive interventions and policies. Barriers to more prevention include social, historical, political, legal and economic factors. While there is sufficient evidence to scale up prevention efforts in some public health domains in Germany, in general there is a comparative shortage of research on non-clinical preventive interventions. Some of the existing barriers in Germany are at least in principle amenable to change, provided sufficient political will exists. More research on prevention by itself is no panacea, but could help facilitate more policy action. In particular, there is an economic efficiency-based case for public funding and promotion of research on non-clinical preventive interventions, in Germany and beyond, to confront the peculiar challenges that set this research apart from its clinical counterpart. PMID- 20718994 TI - Detection of hepatitis B virus DNA among accepted blood donors in Nanjing, China. AB - BACKGROUND: Posttransfusion hepatitis B virus (HBV) infection still occurs although its incidence has been substantially reduced since the introduction of screening of hepatitis B surface antigen (HBsAg) in blood donors. This study aimed to investigate the occult HBV infection in accepted blood donors in Nanjing, China. RESULTS: The lower detection limit of the nested PCR in this study was estimated to be 20 copies/ml HBV DNA. The positive rate of occult HBV infection was 0.13% (5 of 2972) in the accepted blood donors. Sequencing data showed that the amplified HBV sequences were not identical each other and to the known sequences cloned in our laboratory, excluding the false-positive caused by cross-contamination. Phylogenetic analysis showed that the HBV in all five donors was genotype B; a single base deletion was detected in the S region of HBV DNA from one donor, and no mutation was observed in the "a" determinant of HBsAg from four other donors. All five donors were negative for anti-HBs and one was positive for anti-HBc. CONCLUSIONS: The prevalence of occult HBV infection in the accepted blood donors in Nanjing, China is relatively high. The data would be meaningful in adapting strategy to eliminate posttransfusion HBV infection in China. PMID- 20718996 TI - Including the public in pandemic planning: a deliberative approach. AB - BACKGROUND: Against a background of pandemic threat posed by SARS and avian H5N1 influenza, this study used deliberative forums to elucidate informed community perspectives on aspects of pandemic planning. METHODS: Two deliberative forums were carried out with members of the South Australian community. The forums were supported by a qualitative study with adults and youths, systematic reviews of the literature and the involvement of an extended group of academic experts and policy makers. The forum discussions were recorded with simultaneous transcription and analysed thematically. RESULTS: Participants allocated scarce resources of antiviral drugs and pandemic vaccine based on a desire to preserve society function in a time of crisis. Participants were divided on the acceptability of social distancing and quarantine measures. However, should such measures be adopted, they thought that reasonable financial, household and psychological support was essential. In addition, provided such support was present, the participants, in general, were willing to impose strict sanctions on those who violated quarantine and social distancing measures. CONCLUSIONS: The recommendations from the forums suggest that the implementation of pandemic plans in a severe pandemic will be challenging, but not impossible. Implementation may be more successful if the public is engaged in pandemic planning before a pandemic, effective communication of key points is practiced before and during a pandemic and if judicious use is made of supportive measures to assist those in quarantine or affected by social isolation measures. PMID- 20718997 TI - Poverty and fever vulnerability in Nigeria: a multilevel analysis. AB - BACKGROUND: Malaria remains a major public health problem in Sub Saharan Africa, where widespread poverty also contribute to the burden of the disease. This study was designed to investigate the relationship between the prevalence of childhood fever and socioeconomic factors including poverty in Nigeria, and to examine these effects at the regional levels. METHODS: Determinants of fever in the last two weeks among children under five years were examined from the 25004 children records extracted from the Nigeria Demographic and Health Survey 2008 data set. A two-level random effects logistic model was fitted. RESULTS: About 16% of children reported having fever in the two weeks preceding the survey. The prevalence of fever was highest among children from the poorest households (17%), compared to 15.8% among the middle households and lowest among the wealthiest (13%) (p<0.0001). Of the 3,110 respondents who had bed nets in their households, 506(16.3%) children had fever, while 2,604(83.7%) did not. (p=0.082). In a multilevel model adjusting for demographic variables, fever was associated with rural place of residence (OR=1.27, p<0.0001, 95% CI: 1.16, 1.41), sex of child: female (OR=0.92, p=0.022, 95% CI: 0.859, 0.988) and all age categories (>6 months), whereas the effect of wealth no longer reached statistical significance. CONCLUSION: While, overall bednet possession was low, less fever was reported in households that possessed bednets. Malaria control strategies and interventions should be designed that will target the poor and make an impact on poverty. The mechanism through which wealth may affect malaria occurrence needs further investigation. PMID- 20718999 TI - Probable tacrolimus toxicity from tibolone co-administration in a woman: a case report. AB - INTRODUCTION: Tibolone is a synthetic steroid, used with increasing frequency to treat symptoms of menopause, including patients with solid-organ transplants who are taking concurrent immune suppression. To the best of our knowledge, there are no reported drug interactions between tibolone and tacrolimus, one of the principal immune suppressants used in kidney transplantation. CASE PRESENTATION: We report the case of a 49-year-old Caucasian woman who had received a kidney transplant and who developed acute kidney injury secondary to tacrolimus toxicity 10 days after starting tibolone therapy. No alternative causes were found. Tibolone is known to be a weak competitive inhibitor of CYP3A4, which is involved in tacrolimus metabolism. CONCLUSIONS: Despite a careful evaluation, no alternative reason was found for the acute kidney injury, and her kidney function returned to the previous baseline within several days of cessation of the medication, and with no other specific treatment. Using the Drug Interaction Probability Scale we conclude that she experienced a probable drug interaction. We believe that transplant clinicians should utilise frequent therapeutic drug monitoring of tacrolimus in patients starting or stopping tibolone therapy. PMID- 20718998 TI - Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer is a complex genetic disorder that is characterized by rapid progression, invasiveness, resistance to treatment and high molecular heterogeneity. Various agents have been used in clinical trials showing only modest improvements with respect to gemcitabine-based chemotherapy, which continues to be the standard first-line treatment for this disease. However, owing to the overwhelming molecular alterations that have been reported in pancreatic cancer, there is increasing focus on targeting molecular pathways and networks, rather than individual genes or gene-products with a combination of novel chemotherapeutic agents. METHODS: Cells were transfected with small interfering RNAs (siRNAs) targeting the individual CK2 subunits. The CK2 protein expression levels were determined and the effect of its down-regulation on chemosensitization of pancreatic cancer cells was investigated. RESULTS: The present study examined the impact on cell death following depletion of the individual protein kinase CK2 catalytic subunits alone or in combination with gemcitabine and the molecular mechanisms by which this effect is achieved. Depletion of the CK2alpha or -alpha' subunits in combination with gemcitabine resulted in marked apoptotic and necrotic cell death in PANC-1 cells. We show that the mechanism of cell death is associated with deregulation of distinct survival signaling pathways. Cellular depletion of CK2alpha leads to phosphorylation and activation of MKK4/JNK while down-regulation of CK2alpha' exerts major effects on the PI3K/AKT pathway. CONCLUSIONS: Results reported here show that the two catalytic subunits of CK2 contribute differently to enhance gemcitabine-induced cell death, the reduced level of CK2alpha' being the most effective and that simultaneous reduction in the expression of CK2 and other survival factors might be an effective therapeutic strategy for enhancing the sensitivity of human pancreatic cancer towards chemotherapeutic agents. PMID- 20719000 TI - Interleukin-27 acts on hepatic stellate cells and induces signal transducer and activator of transcription 1-dependent responses. AB - BACKGROUND: Interleukin (IL)-27 is a cytokine belonging to the IL-6/IL-12 cytokine family that is secreted by activated macrophages and dendritic cells and which strongly acts on T-cells and cells of the innate immune system. Not much is known about possible effects of IL-27 on other cell types. It signals via the common IL-6-type-cytokine receptor chain gp130 and the IL-27-specific chain WSX 1. We previously described that IL-27 also stimulates hepatoma cells and primary hepatocytes. The aim of this study was to investigate whether IL-27 would also act on hepatic stellate cells (HSC), the second most abundant hepatic cell type, which would demonstrate a more general role of this cytokine in the liver. RESULTS: Using a human HSC line and primary rat HSC we investigated the signalling characteristics of IL-27 in these cells. We show that IL-27 activates signal transducer and activator of transcription (STAT) 1 and to a minor extent STAT3 in a human HSC cell line and that it leads to the induction of STAT1 target genes such as interferon response factor-1, myxovirus resistance A and STAT1 itself. Similarly we find that IL-27 also elicits STAT1-dependent responses in primary rat HSC. CONCLUSIONS: We provide the first evidence for a function of IL 27 in HSC and show that its responses resemble Interferon-gamma-like functions in these cells. Our data suggests that IL-27 may play an important role in the context of liver inflammation by acting on the different liver cell types. PMID- 20719002 TI - [A woman with a duodenal prolapse]. AB - A 83-year-old woman suffering from Alzheimer s disease, was admitted to the hospital because of a rectal prolapse for which she underwent a perineal rectosigmoidectomy (Altemeier's procedure). In less then three months the patient was readmitted because of a massive small intestinal prolapse through a rectal perforation at the site of the previous anastomosis. PMID- 20719001 TI - Chaperone expression profiles correlate with distinct physiological states of Plasmodium falciparum in malaria patients. AB - BACKGROUND: Molecular chaperones have been shown to be important in the growth of the malaria parasite Plasmodium falciparum and inhibition of chaperone function by pharmacological agents has been shown to abrogate parasite growth. A recent study has demonstrated that clinical isolates of the parasite have distinct physiological states, one of which resembles environmental stress response showing up-regulation of specific molecular chaperones. METHODS: Chaperone networks operational in the distinct physiological clusters in clinical malaria parasites were constructed using cytoscape by utilizing their clinical expression profiles. RESULTS: Molecular chaperones show distinct profiles in the previously defined physiologically distinct states. Further, expression profiles of the chaperones from different cellular compartments correlate with specific patient clusters. While cluster 1 parasites, representing a starvation response, show up regulation of organellar chaperones, cluster 2 parasites, which resemble active growth based on glycolysis, show up-regulation of cytoplasmic chaperones. Interestingly, cytoplasmic Hsp90 and its co-chaperones, previously implicated as drug targets in malaria, cluster in the same group. Detailed analysis of chaperone expression in the patient cluster 2 reveals up-regulation of the entire Hsp90-dependent pro-survival circuitries. In addition, cluster 2 also shows up regulation of Plasmodium export element (PEXEL)-containing Hsp40s thought to have regulatory and host remodeling roles in the infected erythrocyte. CONCLUSION: In all, this study demonstrates an intimate involvement of parasite-encoded chaperones, PfHsp90 in particular, in defining pathogenesis of malaria. PMID- 20719003 TI - [Acute compartment syndrome following the International Four Days Marches Nijmegen]. AB - Acute compartment syndrome of the anterior and lateral compartment of the lower right leg was diagnosed in a 47-year-old woman after she had taken part in the 'International Four Days Marches Nijmegen', the Netherlands. Initially a fasciotomy was carried out, but later resection of the entire peroneus musculature was also required as it had become necrotic. Acute compartment syndrome of the lower leg is a potentially limb threatening condition, requiring emergency surgical treatment. Known causes are high-energy impact, and reperfusion after vascular procedures, but it can also be caused by prolonged stress such as during sustained walking. Although it is rare, the possibility of acute compartment syndrome of the lower leg should be borne in mind when making a diagnosis in patients presenting with pain after prolonged repetitive stress. PMID- 20719004 TI - [A child with an oesophageal foreign body for 1.5 years]. AB - A 2-year-old boy presented with a 1.5-year history of recurrent cough, wheeze and feeding problems. An x-ray of the thorax and an oesophagogram showed constriction of the trachea and proximal portion of the oesophagus. On endoscopy a foreign body was found, embedded in extensive granulation tissue. This could only be removed surgically via oesophagotomy, and turned out to be a plastic toy coin. PMID- 20719006 TI - [CT colonography as first-line diagnostic procedure in patients with bowel symptoms]. AB - OBJECTIVE: To investigate in how many patients with bowel or abdominal complaints, referred by the primary care physician (PCP) for exclusion of colorectal carcinoma (CRC), the more invasive colonoscopy could be avoided on the basis of the findings of CT colonography. DESIGN: Retrospective, descriptive. METHODS: All consecutive patients who underwent CT colonography in our centre on the request of their PCP from December 2006 to June 2009 were included. Demographic and referral data were collected. CT colonography results were described according to the 'CT Colonography Reporting and Data System'. We also investigated how many patients had to undergo colonoscopy in the 6 months following CT colonography. RESULTS: 398 patients (154 men and 244 women) with a median age of 61 years (range: 22-91) were included. Follow-up colonoscopy was indicated by CT colonography in 30 patients (7.5%) for suspected colorectal carcinoma, polyps > 10 mm, or 3 or more polyps 6-9 mm in size. In 33 patients (8.3%) follow-up colonoscopy or CT colonography was indicated for 1 or 2 polyps 6 9 mm in size, or suspicious lesions. 11 of these patients (2.8%) underwent colonoscopy. In 335 patients (84.2%) polyps > 6 mm or malignancies could be excluded. 18 of these patients (4.5%) still had a colonoscopy. In total, colonoscopy was spared in 341 patients (85.7%). Significant or potentially significant extra-colonic pathological abnormalities were found in 63 patients (15.8%). CONCLUSION: Our results support the theory that in the vast majority of patients with low or moderate suspicion of CRC referred by their PCP, invasive colonoscopy could be avoided, because CRC and polyps could be excluded by CT colonography. CT colonography could be a valuable additional diagnostic tool in primary care. PMID- 20719005 TI - [Effect of surgical treatment on patients with cerebral palsy: improvement of manual dexterity but not of perceived competence]. AB - OBJECTIVE: To examine the relationship between impaired manual dexterity and perceived competence in children with cerebral palsy and the effect of surgical intervention, with the question whether the perceived competence is applicable as an outcome measure for surgical reconstruction of hand function. METHOD: The Dutch version of the Michigan Hand Outcomes Questionnaire (MHQ-DLV) for perceived manual dexterity and the Dutch version of the Harter Scales for perceived competence were used in a sample of 25 children and adolescents with hemiplegic cerebral palsy of the spastic type. 10 patients underwent surgical treatment to improve hand function. In this 'surgical group' both questionnaires were repeated at least one year postoperatively. RESULTS: Perceived manual dexterity was low (mean MHQ-DLV-score: 63.2; SD: 18.9), as were the scores of perceived overall competence (2.92; SD: 0.84), social competences (2.66; SD: 0.92) and athletic competences (2.29; SD: 0.79). There was no correlation between the degree of perceived impairment in manual dexterity and the perceived competence (r = -0.16; p = 0.43). After surgical reconstruction manual dexterity improved (mean increase in score: 24; SD: 10.4; p < 0.01), but perceived competence did not improve (p = 0.39). CONCLUSION: Children with cerebral palsy and impaired manual dexterity did have a lower perceived competence than children without this disorder. The extent to which manual dexterity was impaired did not correlate with the extent to which perceived competence was lowered. Surgical intervention substantially improved perceived manual dexterity, but perceived competence did not improve. Perceived competence does not seem to be applicable as an outcome measure for surgical reconstruction of manual dexterity. PMID- 20719007 TI - [Angio-oedema and urticaria as side effects of frequently used drugs]. AB - Angio-oedema and urticaria can be symptoms of both allergic (IgE-mediated) and non-allergic drug hypersensitivity reactions. Non-allergic drug reactions, that may have a similar clinical presentation as allergic drug reactions, are not caused by an IgE-mediated immune mechanism. Because of unfamiliarity with non allergic drug reactions and the unclear time course between drug use and reactions, the relationship with the responsible drug is often not recognized, leading to unnecessary patient risks. In the present article three patients with angio-oedema and urticaria as side effects of frequently used drugs (ACE inhibitors, NSAIDs and betalactams) are presented and discussed. Patient A was a 69-year-old man with ACE-inhibitor induced angio-oedema. Patient B was a 40-year old woman with urticaria and angio-oedema after ingestion of a NSAID caused by a non-allergic drug reaction. Patient C was a 54-year-old woman who developed an anaphylactic shock because of a type I allergy to betalactams. PMID- 20719008 TI - [Patients should be involved in the development of indicators]. AB - Various generic and disease-specific instruments have been developed to measure quality of life. In a recent study the results of 3 standardized quality of life questionnaires were compared with qualitative research consisting of open interviews among 343 patients with inoperable lung cancer. The questionnaires did not fully cover all the factors that caused distress in lung cancer patients. For example, about a quarter of patients reported an overall form of distress instead of specific problems at some time point. In addition, 27% reported some element of their contact with the health care system as distressing. These aspects are not covered in quality of life questionnaires. Patients should always be involved in the development of questionnaires measuring quality of life or quality of care from the patients' perspective. PMID- 20719009 TI - [Patellofemoral pain: physiotherapy and surgery]. AB - Patellofemoral pain is common and difficult to treat. The consensus is that a non surgical treatment is the preferred first choice. Watchful waiting is advocated and the value of physiotherapy as such is unclear. Recent research published in the Netherlands shows that supervised and protocolized intensive physiotherapy is more effective for treating patellofemoral pain syndrome than supervised waiting. In selected patients with recurrent patella dislocation or severe pain caused by radiologically proven maltracking, surgical intervention is indicated. PMID- 20719010 TI - [Iron deficiency anaemia due to a matriptase-2 mutation]. AB - A 36-year old female patient who had had iron deficiency anaemia since her childhood showed no clear response to oral iron treatment. Elevated serum hepcidin levels were found after excluding other causes of iron deficiency. This is in contrast to what is expected in iron deficiency anaemia and indicates a primary defect in hepcidin regulation. Indeed, in the search for a defect in genes coding for hepcidin-regulating proteins the patient was found to be compound heterozygous for two different mutations in the TMPRSS6 gene. This leads to a dysfunctional matriptase-2 protein for which the gene codes. Consequently, liver cells cannot inhibit hepcidin production in the presence of low serum iron levels. High hepcidin levels result in less iron being absorbed from the bowel than is necessary for erythropoiesis. Therefore, patients with matriptase-2 deficiency respond poorly to oral iron treatment and have to be treated with intravenous iron. PMID- 20719011 TI - [Inflammatory bowel disease and Clostridium difficile: be prepared]. AB - In this report we describe 3 female patients, aged 38, 29 and 91, with inflammatory bowel disease (IBD) and suffering from an episode of abdominal symptoms and diarrhoea. This raised suspicion of a flare-up of IBD, but all three proved to have Clostridium difficile-associated disease (CDAD). This diagnosis led to a change in management, medication being changed from ciprofloxacin into metronidazole in 2 patients. Patients known to have IBD often present with abdominal pain and diarrhoea. In such a situation an exacerbation of the IBD usually seems most likely. However, an infection with C. difficile always has to be considered, since this infection can mimic a flare-up of IBD. There is a rising incidence of C. difficile in patients with IBD. C. difficile infections in IBD-patients tend to run a more severe course. Therefore, early diagnosis of CDAD in IBD patients is important and has distinct therapeutic implications. PMID- 20719012 TI - [The premenstrual syndrome]. AB - Premenstrual syndrome (PMS) is characterised by the occurrence of physical and psychological symptoms during the luteal phase of almost every menstrual cycle. These symptoms disappear at the beginning of menstruation, and a symptom-free period of at least a week ensues. Premenstrual dysphoric disorder (PMDD) is a variation of PMS, with predominantly psychological symptoms. The aetiology of PMD and PMDD is not known. A possible explanation however is an abnormal, stronger reaction to physiologically normal hormonal fluctuations. Diagnosing PMS and PMDD requires prospective daily monitoring of symptoms over at least two menstrual cycles. No effective medication for the treatment of PMS has been registered in the Netherlands. In randomized placebo-controlled trials selective serotonin reuptake inhibitors and oral contraceptives containing drosperinone have been found to have a positive effect on the physical and psychological symptoms of PMS and PMDD. PMID- 20719013 TI - [Hepatocellular carcinoma: the significance of cirrhosis for treatment and prognosis--retrospective study]. AB - OBJECTIVE: To determine whether the presence of liver cirrhosis was related to the treatment options and survival of patients with hepatocellular carcinoma (HCC). DESIGN: Retrospective. METHOD: A status investigation of all HCC patients who were treated in the period 2000-2007 at the Erasmus MC Hospital, Rotterdam, was performed. The treatments were analysed and the disease-free and total survival rate were calculated. RESULTS: HCC was diagnosed in 461 patients during the study period. Cirrhosis was present in 295 patients (64%). Treatment with curative intent was pursued in 184 patients through partial liver resection, orthotopic liver transplantation or radiofrequency ablation. The group of patients without cirrhosis contained significantly more women (38% versus 18%) (p < 0.001), showed less hepatitis B or C infection (34% versus 74%) (p < 0.001) and had a larger median tumour size (80 mm (range: 3-227) versus 35 mm (range: 8 200)) (p < 0.001). Patients without cirrhosis were mainly treated by partial liver resection (37% versus 10%) (p < 0.001) and less by liver transplantation (1% versus 13%) (p < 0.001) or radiofrequency ablation (5% versus 16%) (p = 0.001). Median follow-up was 31 months (range: 1-108). Without stratification according to treatment, the overall 3-year survival in patients with non cirrhotic and cirrhotic HCC was 30% and 32%, respectively (difference not significant). Patients who had undergone potential curative treatment in cirrhotic or non-cirrhotic livers had a 3-year survival rate of 54% and 59%, respectively (difference not significant). The recurrence rate of HCC without cirrhosis was 39%, of which 31% in the first year. The recurrence rate with cirrhosis was 37%, of which 23% in the first year (difference not significant). CONCLUSION: The presence of liver cirrhosis was strongly associated with treatment options for patients with HCC but not with the prognosis for a recurrence of HCC or the survival rate following potential curative treatment. PMID- 20719014 TI - [Torsion of the gallbladder]. AB - An 18-year-old male presented at the casualty department with acute right upper abdominal pain. Laboratory examinations showed no abnormalities apart from a mildly elevated leukocyte count. Ultrasound examination revealed hydrops of the gallbladder, with thickening of the wall, with no indication of gallstones. Laparoscopy revealed a necrotic gallbladder due to torsion. The gallbladder was successfully removed. Torsion of the gallbladder is a rare condition, in which the organ twists on its longitudinal axis. It is found primarily in patients under 18 years or over 65 years of age. Laboratory and radiological investigations usually reveal non-specific abnormalities, which means that a correct diagnosis is made preoperatively in < 10% of patients. Treatment of choice is an emergency cholecystectomy. The prognosis is excellent with adequate treatment. PMID- 20719015 TI - [Postmortem explantation of an implantable defibrillator or pacemaker]. AB - Implantations of implantable defibrillators (ICDs) have increased dramatically over the last few years and pacemaker implantations stay at a high level. Therefore the question often arises as to what to do after the death of a patient with an ICD or pacemaker. There are medical aspects to this issue as well as legal and environmental issues that need to be addressed. If the deceased is to be cremated, an implantable device needs to be explanted and this is also preferable in the case of a burial. Safety measures have to be taken when an implantable defibrillator is removed. There are no legal regulations in the Netherlands about who is responsible for explantation of cardiac devices but in most cases it will be done by the treating physician or a funeral director. Explantation requires a number of instruments: gloves, a scalpel, blunt scissors, insulated tongs, suture set and sticking plaster. PMID- 20719016 TI - [Omeprazole of limited value in crying babies]. AB - OBJECTIVE: To determine the role of omeprazole treatment in crying infants under the age of 1 year in whom acid gastroesophageal reflux is suspected and to study the evidence for efficacy, prescribing behaviour and side effects of this medicine, which is not registered for use in infants. DESIGN: Literature study. METHOD: To assess efficacy we conducted a study of the literature using PubMed with the search terms 'gastro-esophageal reflux disease', 'crying', 'adverse drug reactions' and 'omeprazole', in the age category 'all infants 0-23 months' We used the medicine prescription database Interactie DataBase to assess prescribing data and studied reports of suspected side effects of omeprazole in children younger than 1 year to the Lareb Netherlands pharmacovigilance centre. RESULTS: We found 139 articles including 32 clinical trials. In only 3 of these was the efficacy of omeprazole studied in children under the age of 1 year. These studies showed that there was an effect on the acidity of the stomach, but not on symptoms. Although many side effects may occur during the use of omeprazole, few suspected side effects were reported to the Lareb Netherlands pharmacovigilance centre. Omeprazole is supplied in 10 mg amounts and it is therefore difficult to adjust dose to weight. Pharmacoepidemiological data show therefore that nearly all children receive 10 mg or multiples thereof. Given the age and corresponding weights we expected doses of 4-20 mg/day to be prescribed. CONCLUSION: It is uncertain whether acid reflux is the cause of crying in babies and, if reflux is suspected, whether omeprazole is the preferred treatment. PMID- 20719017 TI - [Vertebroplasty: a treatment option for osteoporotic compression fractures]. AB - Percutaneous vertebral augmentation, with percutaneous vertebroplasty (PVP) as its most widely used variant, is currently the only intervention for painful osteoporotic compression fractures. This procedure offers immediate and substantial pain relief in over 80% of treated patients with a low reported complication rate (< 1.6%). A large number of studies have shown promising results and the superiority of this treatment over conservative treatment has been established. Results of the first two, long-awaited, placebo-controlled trials were unexpected: improvement after PVP was similar to improvement after placebo treatment. Limitations in the design of both trials prevented widespread implementation of the results. We believe that PVP cannot be regarded as an obsolete treatment as long as patients are carefully selected. Patients with persistent (over 2 months) and painful osteoporotic vertebral fractures have been shown to benefit from vertebroplasty and are therefore suitable candidates for this procedure, which, in these cases, can prevent complications due to long-term disabling pain. PMID- 20719018 TI - [Vertebroplasty? Don't do it]. PMID- 20719019 TI - [Two doctors with itchy bumps]. AB - After visiting Portugal, two medical residents developed lineary rashes on their arms. In this rash, vesiculas developed, which ruptured, leaving crustae that disappeared after a few weeks. The cause was Thaumetopoea Processionea (oak processionary caterpillar). PMID- 20719020 TI - From the editor: a personal coda. PMID- 20719021 TI - Should empathic development be a priority in biomedical ethics teaching? A critical perspective. PMID- 20719022 TI - Medical humanities: an e-module at the University of Manchester. PMID- 20719023 TI - Teaching military medical ethics: another look at dual loyalty and triage. PMID- 20719024 TI - Medical readers' theater as a teaching tool. PMID- 20719025 TI - The unique nature of clinical ethics in allied health pediatrics: implications for ethics education. PMID- 20719026 TI - What health science students learn from playing a standardized patient in an ethics course. PMID- 20719027 TI - Medical student attitudes about bioethics. PMID- 20719028 TI - Saving and ignoring lives: physicians' obligations to address root social influences on health--moral justifications and educational implications. PMID- 20719029 TI - Rural healthcare ethics: no longer the forgotten quarter. PMID- 20719030 TI - The humanities and the future of bioethics education. PMID- 20719031 TI - The Case: A Son's Refusal. PMID- 20719037 TI - Relational autonomy and multiculturalism. PMID- 20719038 TI - Lifestyle: Bioethics at a critical juncture. PMID- 20719039 TI - Sweden asks: Should convicted murderers practice medicine? PMID- 20719040 TI - The persistence of physician-parent conflicts. PMID- 20719041 TI - Does executive impairment define a frontal variant of Alzheimer's disease? AB - BACKGROUND: People with Alzheimer's disease (AD) who present with prominent frontal features such as a dysexecutive syndrome may be difficult to differentiate clinically from subjects with frontotemporal lobar degeneration (FTLD). This study was performed to improve the differential diagnosis between AD and FTLD and to better characterize the AD subgroup with greater executive dysfunction. METHODS: Using a well-defined prospectively studied cohort of cognitively impaired subjects, which included those with AD and with FTLD, we nominated a frontal variant of AD (FvAD) group as those AD subjects with the lowest quartile of scores on the Frontal Assessment Battery (FAB), indicating greatest executive dysfunction, and compared them with the rest of the AD cases (whom we called the AD group) and those with FTLD across several baseline variables including cognitive, functional and behavioral scales. We also compared the changes from baseline for these three groups at 6 and 12 months. Additionally, we controlled for dementia severity by matching AD and FTLD cases on a functional scale, the SMAF, and repeated the same comparisons with these severity-matched groups. RESULTS: The 114 FvAD subjects had a mean age of 78.1 years and Mini-mental State Examination (MMSE) scores of 16.6, and the (remaining) AD group had a mean age of 78.4 years and MMSE of 22.4. There were 30 FTLD subjects with a mean age at baseline of 70.9 years and a mean baseline MMSE of 23.4. The FvAD group was significantly more severely impaired than the other two groups on all baseline assessments except the behavioral scale, the Neuropsychiatric Inventory (NPI), where there was insignificantly less impairment than in the FTLD group. In the analysis of subjects matched at baseline for functional impairment, the FvAD and FTLD groups were not significantly different on most assessment scales although on the FAB, clock-drawing and MMSE the FvAD subjects were still significantly more impaired. These two severity-matched groups were also similar in other baseline characteristics except for older age and less psychotropic use in the FvAD group. The severity-matched FvAD group was significantly different from the AD group in almost all assessment scales. All three unmatched and matched groups declined similarly over 12 months. CONCLUSIONS: When groups were not matched for baseline severity, the use of the FAB defined a group of AD subjects with greater executive dysfunction that were distinguished from both the remainder of the AD and FTLD subjects in almost all domains except behavioral disturbance and probably were just more severely affected AD subjects. The FAB is thus more useful as a marker of dementia severity than as a scale to detect a frontal variant of AD or to distinguish AD from FTLD. Controlling for severity, however, did allow the definition of a subgroup of AD subjects that more closely resembled FTLD subjects than the remainder of the AD subjects. It is proposed that subjects with dementia presenting with greater executive impairment but without prominent behavioral symptoms are likely to have AD rather than FTLD, especially if they are quite functionally impaired. With time FTLD subjects develop increasing executive dysfunction and increasingly resemble the more severely affected AD subjects. PMID- 20719042 TI - Behaviorally spontaneous confabulation in limbic encephalitis: the roles of reality filtering and strategic monitoring. AB - Behaviorally spontaneous confabulation is characterized by a confusion of reality evident in currently inappropriate acts that patients justify with confabulations and in disorientation. Here, we describe a 38-year-old woman lawyer hospitalized because of non-herpetic, presumably autoimmune, limbic encephalitis. For months, she considered herself at work and desperately tried to respect her falsely believed professional obligations. In contrast to a completely erroneous concept of reality, she did not confabulate about her remote personal past. In tasks proposed to test strategic retrieval monitoring, she produced no confabulations. As expected, she failed in tasks of reality filtering, previously shown to have high sensitivity and specificity for behaviorally spontaneous confabulation and disorientation: she failed to suppress the interference of currently irrelevant memories and she had deficient extinction capacity. The observation underscores the special status of behaviorally spontaneous confabulation among confabulatory phenomena and of reality filtering as a thought control mechanism. We suggest that different processes may underlie the generation of false memories and their verbal expression. We also emphasize the need to present theories of confabulation together with experimental tasks that allow one to empirically verify the theories and to explore underlying physiological mechanisms. PMID- 20719046 TI - Evaluation of the bioconjugation efficiency of different quantum dots as probes for immunostaining tumor-marker proteins. AB - The differing bioconjugation efficiencies of quantum dots (QDs) are a practical obstacle to their popularization. Differences in bioconjugation efficiency based on immunostaining the same targeted molecules using different batches of QDs need to be evaluated prior to their application. In this paper, a quantitative method for evaluating the efficiency of QDs in staining tissues has been developed based on Hadamard transform (HT) spectral imaging. Proliferating cell nuclear antigens (PCNA) in breast cancer tissues were labeled with bioconjugated QD bioprobes using a 454 nm laser as the light source for fluorescence spectral imaging. Four dimensional (4D) spectral imaging analysis of PCNA in cell nuclei was carried out using HT spectral microscopy based on immunostaining with different batches of QDs. The fluorescence intensity distributions in the cell nuclei were collected from the 4D images. Based on the information obtained from microscopic spectra and 4D images, differences in the bioconjugation efficiency among different batches of QDs were evaluated. The results demonstrate that it is possible to maintain uniform bioconjugation efficiencies with different QD bioconjugation processes in order to obtain accurate and reliable results in biomedical analysis and cancer diagnosis. PMID- 20719043 TI - Inhibitory control and psychopathology: a meta-analysis of studies using the stop signal task. AB - The Stop Signal Task (SST) is a measure that has been used widely to assess response inhibition. We conducted a meta-analysis of studies that examined SST performance in patients with various psychiatric disorders to determine the magnitude and generality of deficient inhibition. A five-item instrument was used to assess the methodological quality of studies. We found medium deficits in stop signal reaction time (SSRT), reflecting the speed of the inhibitory process, for attention-deficit hyperactivity disorder (ADHD) (g = 0.62), obsessive compulsive disorder (OCD) (g = 0.77) and schizophrenia (SCZ) (g = 0.69). SSRT was less impaired or normal for anxiety disorder (ANX), autism, major depressive disorder (MDD), oppositional defiant disorder/conduct disorder (ODD/CD), pathological gambling, reading disability (RD), substance dependence, and Tourette syndrome. We observed a large SSRT deficit for comorbid ADHD + RD (g = 0.82). SSRT was less than moderately impaired for ADHD + ANX and ADHD + ODD/CD. Study quality did not significantly affect SSRT across ADHD studies. This confirms an inhibition deficit in ADHD, and suggests that comorbid ADHD has different effects on inhibition in patients with ANX, ODD/CD, and RD. Further studies are needed to firmly establish an inhibition deficit in OCD and SCZ. PMID- 20719047 TI - Experimental study of NaCl aqueous solutions by Raman spectroscopy: towards a new optical sensor. AB - Raman spectroscopy was used to study the NaCl aqueous solutions around the solid liquid phase transition. Special attention was devoted to the modification induced by the salt on the OH stretching band of water. Investigations were carried out in the temperature range between -21 and 10 degrees C, for concentrations from 0 to 200 g/L. We demonstrated that micro-Raman spectroscopy can be used as a marker, allowing the determination of the salt concentration of an aqueous solution with an error close to +/-5%. PMID- 20719049 TI - Directed calcium chloride coalescence method for preparation of silver nanocubes. AB - Controlling the size, shape, and structure of metal nanoparticles is very important because of the strong correlation between these parameters and their resulting optical, electrical, and catalytic properties. This paper describes a directed calcium chloride coalescence method, based upon incubating a silver colloid with an aqueous solution of CaCl(2), for preparation of silver nanocubes with a particle size of 270 to 950 nm. The method avoids the use of nonvolatile surfactants and polymers, which may be adsorbed onto the silver nanocubes and interfere with their possible applications in catalysis and analytical devices based on surface-enhanced Raman scattering (SERS) spectroscopy. The nanocubes show good SERS activity in the presence of adsorbed 4-mercaptobenzoic acid (4 MBA) with excitation at 632.8 nm, and the enhancement factor reaches approximately 7 x 10(5). The nanocubes are produced in a simple and cost effective way, and they are expected to play an important role in the development of SERS-based analytical devices. The method may represent a novel route for preparation of metal nanocubes, which is a subject of intense interest. PMID- 20719048 TI - Surface-enhanced Raman scattering detection and tracking of nanoprobes: enhanced uptake and nuclear targeting in single cells. AB - We describe the development and application of a co-functionalized nanoprobe and biodelivery platform combining a nuclear targeting peptide (NTP) for improved cellular uptake and intracellular targeting with p-mercaptobenzoic acid (pMBA) as a surface-enhanced Raman scattering (SERS) reporter for tracking and imaging. The nuclear targeting peptide, an HIV-1 protein-derived TAT sequence, has been previously shown to aid entry of cargo through the cell membrane via normal cellular processes, and furthermore, to localize small cargo to the nucleus of the cell. Previous work in our lab has verified cell uptake and distribution of the nanoprobes in clinically relevant mouse and human cell lines. In this work, two-dimensional SERS mapping was used to track the spatial and temporal progress of nanoparticle uptake in PC-3 human prostate cells and to characterize localization at various time points, demonstrating the potential for an intracellularly targeted multiplexed nanobiosensing system with excellent sensitivity and specificity. Silver nanoparticles co-functionalized with the TAT peptide showed greatly enhanced cellular uptake over the control nanoparticles lacking the targeting moiety. The ability to detect and monitor nanoprobe trafficking using SERS spectroscopy offers an improved alternative over previous tracking and detection methods such as light microscopy and fluorescence methods. The development of multifunctional nanoconstructs for intracellular delivery has potential clinical applications in early detection and selective treatment of disease in affected cells. Other applications include use in basic research aimed at understanding the inner workings of living cells and how they respond to chemical and biological stimuli. PMID- 20719050 TI - Variability in Raman spectra of single human tumor cells cultured in vitro: correlation with cell cycle and culture confluency. AB - In this work we investigate the capability of Raman microscopy (RM) to detect inherent sources of biochemically based spectral variability between single cells of a human tumor cell line (DU145) cultured in vitro. Principal component analysis (PCA) is used to identify differences in single-cell Raman spectra. These spectral differences correlate with (1) cell cycle progression and (2) changing confluency of a cell culture during the first 3 to 4 days after sub culturing. Cell cycle regulatory drugs are used to synchronize the cell cycle progression of cell cultures, and flow cytometry is used to determine the cell cycle distribution of cell cultures at the time of Raman analysis. Spectral variability arising from cell cycle progression is (1) expressed as varying intensities of protein and nucleic acid features relative to lipid features, (2) well correlated with known biochemical changes in cells as they progress through the cell cycle, and (3) shown to be the most significant source of inherent spectral variability between cells. Furthermore, the specific biomolecules responsible for the observed spectral variability due to both cell cycle progression and changes in cell culture confluency can be identified in the first and second components of principal component analysis (PCA). Our characterization of the inherent sources of variability in Raman spectra of single human cells will be useful for understanding subtle spectral differences in RM studies of single cells. PMID- 20719051 TI - A prototype hand-held Raman sensor for the in situ characterization of meat quality. AB - As a tool for the in situ characterization of meat quality, a hand-held Raman sensor head using an excitation wavelength of 671 nm was developed. A microsystem based external cavity diode laser module was integrated into the sensor head and attached to a Raman probe, which is equipped with lens optics for excitation and signal collection as well as a Raman filter stage for Rayleigh rejection. The Raman signal was guided by an optical fiber to the detection unit, which was in the initial phase a laboratory spectrometer with a charge-coupled device (CCD) detector. The laser and the sensor head were characterized in terms of stability and performance for in situ Raman investigations. Raman spectra of meat were obtained with 35 mW within 5 seconds or less, ensuring short measuring times for the hand-held device. In a series of measurements with raw and packaged pork meat, the Raman sensor head was shown to detect microbial spoilage on the meat surface, even through the packaging foil. PMID- 20719052 TI - Identification of a mixed microparticle by combined microspectroscopic techniques: a real forensic case study in the biopharmaceutical industry. AB - Identification of foreign microparticles in drug products is one of the first steps in evaluating the nature of particle contamination and its consequences for product quality. To characterize various foreign particles, we use spectral database search methods as well as a number of microscopic and microspectroscopic techniques. Here, we report a case study involving the identification and root cause investigation of a microparticle consisting of four compounds. Foreign microparticles consisting of mixtures pose unique challenges for identification as their spectra are difficult to interpret and general database searches usually return unsatisfactory results. Moreover, sample separation through purification and other manipulations is time consuming and often difficult for these microparticles due to their small sizes and the limited quantities of the components. Here we demonstrate an applicable methodology that combines multiple microscopic and microspectroscopic techniques to identify a heterogeneous microparticle without the need for sample purification or chemical separation. This methodology primarily combines Raman, infrared, and energy dispersive X-ray microspectroscopic techniques to obtain complementary spectral information for the identification of heterogeneous particles. With this methodology, the mixed microparticle investigated in this study was determined to consist of polyisobutylene, hydrated magnesium silicate, titanium dioxide, and silica, likely originating from the vial stopper material. PMID- 20719053 TI - Fourier transform infrared microspectroscopy of endocarditis vegetation. AB - The objectives of this work were to compare the infrared spectra of bacterial endocarditis vegetation with those of native valvular tissue and the infrared spectra of vegetation bacterial masses with those of surrounding vegetation tissue. Streptococcal aortic endocarditis was induced in three rabbits. Vegetation slices were cryo-sectioned for study by Fourier transform infrared (FT IR) microspectroscopy. Valvular apparatus, vegetation, and bacterial masses within the vegetation were localized on hematoxylin and eosin (H&E) stained contiguous slices. Infrared images of whole vegetations and images of bacterial masses were acquired with apertures set to 80 x 80 and 20 x 20 microm, respectively. Valvular apparatus and vegetation showed different infrared spectra, mainly in the amide I and amide II bands (1674-1518 cm(-1)), and at about 1450, 1400, 1340, 1280, 1240, 1200, 1080, and 1030 cm(-1). Valvular collagen, elastin, and proteoglycans may explain these differences. Bacterial masses and surrounding vegetation showed different infrared patterns, mainly in the amide I and amide II bands and in the 1142-991 cm(-1) carbohydrate spectral range. Bacterial nucleic acids and polysaccharides may partly explain these differences. Study of experimental endocarditis vegetation using FT-IR microspectroscopy distinguishes (1) the vegetation from the valvular tissue, and (2) the bacterial masses from the surrounding tissue. This study demonstrates for the first time that FT-IR microspectroscopy is able to detect bacterial growth in infected tissue. FT-IR microspectroscopy appears to be a useful tool for investigation of the biochemical structure of endocarditis vegetation. PMID- 20719054 TI - Stopped-flow ultra-rapid-scanning Fourier transform infrared spectroscopy on the millisecond time scale. AB - Full-range mid-infrared spectra were measured during the reaction of CpCo(CO)(2) with nitrosyl chloride by interfacing a rapid-mixing stopped-flow device with an ultra-rapid-scanning Fourier transform infrared (FT-IR) spectrometer having a temporal resolution of 5 ms. Changes to the data acquisition hardware of this spectrometer now allow a sequence of well over 2000 spectra to be collected without interruption. Two transient species were observed spectroscopically during the first 500 ms of the reaction of CpCo(CO)(2) with nitrosyl chloride. The shortest-lived species that was observed, [CpCo(CO)(2)(NO)](+), had a half life of approximately 20 ms at 25 degrees C and approximately 70 ms at 10 degrees C. This intermediate transformed into a longer-lived (approximately 0.5 s) intermediate, CpCo(NO)Cl. Potential intermediate species with one CO and one NO ligand, such as [CpCo(CO)(NO)](+) and CpCo(CO)(NO)Cl, were not observed, although the possibility that they exist cannot be ruled out. PMID- 20719055 TI - Conformation of poly(ethylene oxide) chains in clay galleries. AB - The conformation and arrangement of poly(ethylene oxide) (PEO) chains in clay galleries is still controversial. In our work, various spectroscopic methods have been used to explore the conformation of PEO in clay galleries. The melt intercalation process is investigated using variable-temperature Raman spectroscopy. It is found that the sharp peak at 860 cm(-1) appears with an increase of the intercalation time, suggesting the formation of a crown-ether like association between the cations and the PEO oxygen atoms. Two-dimensional infrared correlation analysis also suggests the presence of the crown-ether-like association between them. Therefore, a distorted helical conformation may be a more accurate way to describe the conformation of the PEO chains in the clay galleries, and a single-layer arrangement is suggested. PMID- 20719057 TI - Ultraviolet-visible absorption and luminescence properties of quinacridone-barium sulfate solid mixtures. AB - The absorption and emission spectral features of the dye quinacridone (QA) have been studied in solution and in the solid phase. In the solid phase, QA has been investigated as pure microcrystalline powder and mixed with barium sulfate (BaSO(4)) in different mass percentages. Two kinds of QA-BaSO(4) mixtures have been prepared: physical blends of the two microcrystalline powders, and mixtures with gum arabic as binder. The latter was used in painting mock-ups. Luminescence properties of the mixtures have been investigated using both steady-state and time-resolved techniques. The prepared samples have allowed the Kubelka-Munk correction model, formulated for the emission spectra, to be tested. Moreover, the luminescence decay profiles have been analyzed using the maximum entropy method (MEM) and the nonlinear least-squares method. All the results obtained highlight how physical (self-absorption) and chemical (composition of the microenvironment) factors can influence the spectral and kinetic properties of dyes. These factors should always be taken into account in the diagnostic activity applied to works of art. PMID- 20719056 TI - Fluorescence instrument response standards in two-photon time-resolved spectroscopy. AB - We studied the fluorescence properties of several potential picosecond lifetime standards suitable for two-photon excitation from a Ti:sapphire femtosecond laser. The fluorescence emission of the selected fluorophores (rose bengal, pyridine 1, and LDS 798) covered the visible to near-infrared wavelength range from 550 to 850 nm. We suggest that these compounds can be used to measure the appropriate instrument response functions needed for accurate deconvolution of fluorescence lifetime data. Lifetime measurements with multiphoton excitation that use scatterers as a reference may fail to properly resolve fluorescence intensity decays. This is because of the different sensitivities of photodetectors in different spectral regions. Also, detectors often lose sensitivity in the near-infrared region. We demonstrate that the proposed references allow a proper reconvolution of measured lifetimes. We believe that picosecond lifetime standards for two-photon excitation will find broad applications in multiphoton spectroscopy and in fluorescence lifetime imaging microscopy (FLIM). PMID- 20719058 TI - Complexation of europium(III) with the zwitterionic form of amino acids studied with ultraviolet-visible and time-resolved laser-induced fluorescence spectroscopy. AB - The complex formation of europium(III) with the zwitterionic form of amino acids (alanine, phenylalanine, and threonine) has been studied in aqueous solution. Measurements were performed at I = 0.1 M (NaCl/NaClO(4)), room temperature, and trace metal concentrations in the range of pH 2 to 8 using ultraviolet-visible (UV-Vis) and time-resolved laser-induced fluorescence spectroscopy (TRLFS). While complexation leads to a significant luminescence enhancement in the emission spectrum of the metal ion, absorption in the UV-Vis spectrum of the amino acid (AA) decreases. As zwitterionic species (AAH), all three ligands form weak complexes with 1:1 stoichiometry and a general formula of EuAAH(3+) with the metal. The complex stability constants were determined to be log K approximately 1 for all complexes, indicating the negligible contribution of the amino acid side chain to the complex formation reaction. PMID- 20719059 TI - Detection of cotton lint trash within the ultraviolet-visible spectral range. AB - Cotton lint trash is a serious problem in the textile industry. The principle upon which this research is based is that different materials have different spectral absorption, excitation, and emission characteristics. Although white light imaging is widely used to detect colored foreign-matter contaminants, or "trash", it is almost useless for detecting white trash. The objective of the research described in this paper was to achieve the best trash detection result possible in the spectral range from 250 to 850 nm. Diffuse reflection spectroscopy indicated that the differences in gray value between lint and white trash become significant in the ultraviolet (UV) range, especially from 250 to 350 nm. Fluorescence spectroscopy gave reliable evidence that the UV-induced fluorescence intensity of white trash is much stronger than that of lint. To detect several types of trash simultaneously, the interaction of white-light imaging and UV-induced fluorescence imaging was studied. To avoid the spectral interference caused by white light in fluorescence imaging, a novel method--an alternating imaging detection method--is proposed. Experiments indicated that the advantages of both white-light imaging and UV-induced fluorescence imaging were preserved in the method. The novel method could effectively detect both colored and white trash in real time. This method can also be applied to trash detection in seed cotton, wool, tea leaf, and tobacco leaf. PMID- 20719060 TI - Heterogeneous thermal-lens immunoassay for small organic compounds: determination of 4-aminophenol. AB - 4-Aminophenol was selected as a model hapten for thermal-lens detection in a heterogeneous indirect immunoassay for small organic compounds. The assay is based on the competition of the free hapten and 4-aminophenol labeled with tetramethyl rhodamine isothiocyanate (TRITC) for rabbit anti-4-aminophenol antibodies (4-AP-GA-BSA) immobilized on a transparent poly(ethylene terephthalate) plate. The amount of the colored analyte was directly measured by thermal lensing at the plate surface. The developed method is specific for 4 aminophenol. The limit of detection is 2 x 10(-7) M, which corresponds to the absolute amount of 3 x 10(-11) mol of 4-aminophenol. The sensitivities of the developed thermal-lens and fluorescence-based measurements of the immunoassay under the same conditions are in good agreement with the expected and discussed theoretical sensitivities of photothermal and fluorescence measurements. PMID- 20719061 TI - Rapid simultaneous determination of four non-steroidal anti-inflammatory drugs by means of derivative nonlinear variable-angle synchronous fluorescence spectrometry. AB - A rapid, simple, and inexpensive spectrofluorimetric method has been proposed for the simultaneous quantification of diflunisal, salicylic acid, fenoprofen, and 6 methoxy-2-naphthylacetic acid (6MNA). First-derivative nonlinear variable-angle synchronous fluorescence spectrometry has been developed to improve the selectivity of fluorescence measurements without loss of sensitivity. It allows the simultaneous determination of different substances in a mixture from a single spectrum based on a single scan. The analyses were performed in an ethanol-water (70%) medium at a pH of 9.2, adjusted by using ammonium/ammonia (0.5 M) as a buffer solution. The linear concentration ranges are 30.0-100.0, 100.0-600.0, 50.0-150.0, and 30.0-100.0 ng/mL for salicylic acid, fenoprofen, diflunisal, and 6-methoxy-2-naphthylacetic acid, respectively, at lambda(ex)/lambda(em) = 281.1/423.6, 241.2/301.2, 284.1/403.8, and 268.7/339.6 nm, respectively. Analytical parameters of the proposed method were calculated according to the error propagation theory. The sensitivity, repeatability, reproducibility, and limits of detection achieved with the proposed method are adequate for the determination of these anti-inflammatory drugs. PMID- 20719062 TI - On the use of overtone and combination bands for the analysis of the CaSO4-H2O system by mid-infrared reflection spectroscopy. AB - With the aim of characterizing ground preparations of paintings by infrared reflection spectroscopy, the CaSO(4)-H(2)O system (gypsum/bassanite/anhydrite) has been re-investigated, evaluating and assigning the SO(4)(2-) and OH overtone and combination bands, respectively, in the ranges 1900-2700 cm(-1) and 5000-6000 cm(-1) resulting from reflection and high concentration transmission spectra. The second-order modes have been proven to be highly specific, reliable, and less affected by overlap with bands of organic binders and can hence be exploited for the identification of the sulfate hydration phase using infrared (IR) reflection spectroscopy. Subsequently, the characterization and identification of hydration phases in unknown sulfate-based ground preparations on authentic artworks have been carried out noninvasively by fiber-optic reflection IR spectroscopy and on cross-sections by infrared reflection micro-spectroscopy. The spectroscopic data collected both on standards and artworks have been cross-validated by X-ray diffraction. PMID- 20719063 TI - Effective suppression of stray light in rotational coherent anti-stokes Raman spectroscopy using an angle-tuned short-wave-pass filter. AB - Stray light interference is a common problem in spontaneous rotational Raman spectroscopy and rotational coherent anti-Stokes Raman spectropscopy (CARS). The reason is that the detected spectrum appears in the spectral vicinity of the probe beam wavelength, and stray light at this wavelength from optics and surfaces is hard to suppress. In this Note, efficient suppression of stray light is demonstrated for rotational CARS measurements using a commercially available short-wave-pass filter. By angle-tuning this filter with a specified cut-off wavelength at 561 nm, the cut-off wavelength could be tuned to a desired spectral position so that more than 80% transmission is achieved as close as 15 cm(-1) (approximately 0.4 nm) from the probe beam wavelength of 532.0 nm, while the intensity at this wavelength is suppressed by two orders of magnitude. PMID- 20719064 TI - MAPC transplantation confers a more durable benefit than AC133+ cell transplantation in severe hind limb ischemia. AB - There is a need for comparative studies to determine which cell types are better candidates to remedy ischemia. Here, we compared human AC133(+) cells and multipotent adult progenitor cells (hMAPC) in a mouse model reminiscent of critical limb ischemia. hMAPC or hAC133(+) cell transplantation induced a significant improvement in tissue perfusion (measured by microPET) 15 days posttransplantation compared to controls. This improvement persisted for 30 days in hMAPC-treated but not in hAC133(+)-injected animals. While transplantation of hAC133(+) cells promoted capillary growth, hMAPC transplantation also induced collateral expansion, decreased muscle necrosis/fibrosis, and improved muscle regeneration. Incorporation of differentiated hAC133(+) or hMAPC progeny into new vessels was limited; however, a paracrine angio/arteriogenic effect was demonstrated in animals treated with hMAPC. Accordingly, hMAPC-conditioned, but not hAC133(+)-conditioned, media stimulated vascular cell proliferation and prevented myoblast, endothelial, and smooth muscle cell apoptosis in vitro. Our study suggests that although hAC133(+) cell and hMAPC transplantation both contribute to vascular regeneration in ischemic limbs, hMAPC exert a more robust effect through trophic mechanisms, which translated into collateral and muscle fiber regeneration. This, in turn, conferred tissue protection and regeneration with longer term functional improvement. PMID- 20719065 TI - Evaluation of alginate microspheres for mesenchymal stem cell engraftment on solid organ. AB - Mesenchymal stem cells (MSCs) may be used as a cell source for cell therapy of solid organs due to their differentiation potential and paracrine effect. Nevertheless, optimization of MSC-based therapy needs to develop alternative strategies to improve cell administration and efficiency. One option is the use of alginate microencapsulation, which presents an excellent biocompatibility and an in vivo stability. As MSCs are hypoimmunogenic, it was conceivable to produce microparticles with [alginate-poly-L-lysine-alginate (APA) microcapsules] or without (alginate microspheres) a surrounding protective membrane. Therefore, the aim of this study was to determine the most suitable microparticles to encapsulate MSCs for engraftment on solid organ. First, we compared the two types of microparticles with 4 * 10(6) MSCs/ml of alginate. Results showed that each microparticle has distinct morphology and mechanical resistance but both remained stable over time. However, as MSCs exhibited a better viability in microspheres than in microcapsules, the study was pursued with microspheres. We demonstrated that viable MSCs were still able to produce the paracrine factor bFGF and did not present any chondrogenic or osteogenic differentiation, processes sometimes reported with the use of polymers. We then proved that microspheres could be implanted under the renal capsule without degradation with time or inducing impairment of renal function. In conclusion, these microspheres behave as an implantable scaffold whose biological and functional properties could be adapted to fit with clinical applications. PMID- 20719066 TI - In vitro differentiated adult human liver progenitor cells display mature hepatic metabolic functions: a potential tool for in vitro pharmacotoxicological testing. AB - The potential use of stem/progenitor cells as alternative cell sources to mature hepatocytes remains basically dependent on their ability to exhibit some, if not all, the metabolic liver functions. In the current study, four major liver functions were investigated in adult derived human liver stem/progenitor cell (ADHLSCs) populations submitted to in vitro hepatogenic differentiation: gluconeogenesis, ammonia detoxification, and activity of phase I and phase II drug-metabolizing enzymes. These acquired hepatic activities were compared to those of primary adult human hepatocytes, the standard reference. Amino acid content was also investigated after hepatogenic differentiation. Differentiated ADHLSCs display higher de novo synthesis of glucose correlated to an increased activity of glucose-6 phosphatase and mRNA expression of key related enzymes. Differentiated ADHLSCs are also able to metabolize ammonium chloride and to produce urea. This was correlated to an increase in the mRNA expression of relevant key enzymes such arginase. With respect to drug metabolism, differentiated ADHLSCs express mRNAs of all the major cytochromes investigated, among which the CYP3A4 isoform (the most important drug-metabolizing enzyme). Such increased expression is correlated to an enhanced phase I activity as independently demonstrated using fluorescence-based assays. Phase II enzyme activity and amino acid levels also show a significant enhancement in differentiated ADHLSCs. The current study, according to data independently obtained in different labs, demonstrates that in vitro differentiated ADHLSCs are able to display advanced liver metabolic functions supporting the possibility to develop them as potential alternatives to primary hepatocytes for in vitro settings. PMID- 20719067 TI - Use of perfluorodecalin for pancreatic islet culture prior to transplantation: a liquid-liquid interface culture system--preliminary report. AB - Although the issue remains controversial, short-term culture is probably beneficial for islet graft quality. However, significant islet loss is invariably observed. This is related to reduced survival of large islets, which is compromised by hypoxia under standard culture conditions. We aimed to develop a method of culture, which would avoid exposure to relative hypoxia and hence maintain the quality of islets. Isolated rat islets cultured for 48 h in a liquid liquid interface culture system (LICS) with a perfluorocarbon were compared to islets cultured under standard (C1) and suboptimal conditions (C2). Islets were tested for viability and response to a glucose challenge, and a marginal mass was transplanted into syngeneic diabetic recipients. The viability of islets after 24 h culture in LICS was higher than in C1 and C2 groups (89.0% vs. 77.5% and 64.6%, respectively) and decreased with time to reach 79.0%, 62.9%, and 53.4% after 72-h culture. The stimulation index in LICS-cultured islets was also significantly higher than in C1 and C2 groups (12.3 +/- 0.4 vs. 5.8 +/- 0.5 and 4.1 +/- 0.2, respectively). Following transplantation of LICS-cultured islets 50% of recipients were rendered normoglycemic compared with 14.3% and 31.3% for C2 and fresh islets, respectively. Our liquid-liquid interface culture system using perfluorodecalin provides optimized culture conditions, which preserve both islet viability and their ability to engraft successfully after intraportal transplantation and could be used for islet transportation. PMID- 20719068 TI - Assessment of human islet labeling with clinical grade iron nanoparticles prior to transplantation for graft monitoring by MRI. AB - Ex vivo labeling of islets with superparamagnetic iron oxide (SPIO) nanoparticles allows posttransplant MRI imaging of the graft. In the present study, we compare two clinical grade SPIOs (ferucarbotran and ferumoxide) in terms of toxicity, islet cellular uptake, and MRI imaging. Human islets (80-90% purity) were incubated for 24 h with various concentrations of SPIOs (14-280 MUg/ml of iron). Static incubations were performed, comparing insulin response to basal (2.8 mM) or high glucose stimulation (16.7 mM), with or without cAMP stimulation. Insulin and Perl's (assessment of iron content) staining were performed. Electronic microscopy analysis was performed. Labeled islets were used for in vitro or in vivo imaging in MRI 1.5T. Liver section after organ removal was performed in the same plane as MRI imaging to get a correlation between histology and radiology. Postlabeling islet viability (80 +/- 10%) and function (in vitro static incubation and in vivo engraftment of human islets in nude mice) were similar in both groups. Iron uptake assessed by electron microscopy showed iron inclusions within the islets with ferucarbotran, but not with ferumoxide. MRI imaging (1.5T) of phantoms and of human islets transplanted in rats, demonstrated a strong signal with ferucarbotran, but only a weak signal with ferumoxide. Signal persisted for >8 weeks in the absence of rejection. An excellent correlation was observed between radiologic images and histology. The hepatic clearance of intraportally injected ferucarbotran was faster than that of ferumoxide, generating less background. A rapid signal decrease was observed in rejecting xenogeneic islets. According to the present data, ferucarbotran is the most appropriate of available clinical grade SPIOs for human islet imaging. PMID- 20719069 TI - Intravital two-photon microscopy assessment of renal protection efficacy of siRNA for p53 in experimental rat kidney transplantation models. AB - Renal ischemia-reperfusion (I/R) injury, which is unavoidable in renal transplantation, frequently influences both short- and long-term allograft survival. Despite decades of laboratory and clinical investigations, and the advent of renal replacement therapy, the overall mortality rate due to acute tubular injury has changed little. I/R-induced DNA damage results in p53 activation in proximal tubule cells (PTC), leading to their apoptosis. Therefore, we examined the therapeutic effect of temporary p53 inhibition in two rat renal transplantation models on structural and functional aspects of injury using intravital two-photon microscopy. Nephrectomized Sprague-Dawley rats received syngeneic left kidney transplantation either after 40 min of intentional warm ischemia or after combined 5-h cold and 30-min warm ischemia of the graft. Intravenously administrated siRNA for p53 (siP53) has previously been shown to be filtered and reabsorbed by proximal tubular epithelial cells following the warm ischemia/reperfusion injury in a renal clamp model. Here, we showed that it was also taken up by PTC following 5 h of cold ischemia. Compared to saline-treated recipients, treatment with siP53 resulted in conservation of renal function and significantly suppressed the I/R-induced increase in serum creatinine in both kidney transplantation models. Intravital two-photon microscopy revealed that siP53 significantly ameliorated structural and functional damage to the kidney assessed by quantification of tubular cast formation and the number of apoptotic and necrotic tubular cells and by evaluation of blood flow rate. In conclusion, systemic administration of siRNA for p53 is a promising new approach to protect kidneys from I/R injury in renal transplantation. PMID- 20719070 TI - Impact of escaped bone marrow mesenchymal stromal cells on extracardiac organs after intramyocardial implantation in a rat myocardial infarction model. AB - Cell escape occurs after intramyocardial injection for treatment of myocardial infarction (MI) and then the migrated cells might be entrapped by extracardiac organs. We investigated the fate of migrated bone marrow-derived mesenchymal stromal cells (MSCs) and their impact on lung, liver, and spleen. MI model was created by coronary artery ligation in female Lewis rats. Three weeks after the ligation, bromodeoxyuridine (BrdU)-labeled male MSCs were directly injected into the infarcted area in the cell transplantation group (n = 22). The same volume of phosphate-buffered solution (PBS) was injected in the control group (n = 21). In the sham group (n = 10) intramyocardial injection of the same volume of PBS was performed in healthy rats. Four weeks later, echocardiography was performed and the cell retention was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry study was performed to identify the migrated cells. Heart function was improved after the cell injection. qRT-PCR results showed the percentage of retained cells in heart, spleen, liver, and lung ranked 3.63 +/- 0.48%, 0.77 +/- 0.13%, 0.68 +/- 0.10%, 0.62 +/- 0.11%, respectively, after cell transplantation. The implanted MSCs that escaped to liver, spleen, and lung did not differentiate into fibroblast, myofibroblast, or alveolar epithelial cells. However, the migrated MSCs in liver expressed functional hepatocyte marker. In conclusion, cell migration after intramyocardial injection did not result in deterioration of lung, liver, and spleen function. Our study might pave the way for new safety investigation of emerging cell resources and their impact on target and untargeted organs. PMID- 20719071 TI - Late passage human fibroblasts induced to pluripotency are capable of directed neuronal differentiation. AB - It is possible to generate induced pluripotent stem (iPS) cells from mouse and human somatic cells by ectopic expression of defined sets of transcription factors. However, the recommendation that somatic cells should be utilized at early passages for induced reprogramming limits their therapeutic application. Here we report successful reprogramming of human fibroblasts after more than 20 passages in vitro, to a pluripotent state with four transcription factors: Oct4, Sox2, Klf4, and c-Myc. The late passage-derived human iPS cells resemble human embryonic stem cells in morphology, cell surface antigens, pluripotent gene expression profiles, and epigenetic states. Moreover, these iPS cells differentiate into cell types representative of the three germ layers in teratomas in vivo, and directed neuronal differentiation in vitro. PMID- 20719072 TI - Delivery of a therapeutic protein by immune-privileged Sertoli cells. AB - Immune-privileged Sertoli cells survive long term after allogeneic or xenogeneic transplantation without the use of immunosuppressive drugs, suggesting they could be used as a vehicle to deliver therapeutic proteins. As a model to test this, we engineered Sertoli cells to transiently produce basal levels of insulin and then examined their ability to lower blood glucose levels after transplantation into diabetic SCID mice. Mouse and porcine Sertoli cells transduced with a recombinant adenoviral vector containing furin-modified human proinsulin cDNA expressed insulin mRNA and secreted insulin protein. Transplantation of 5-20 million insulin-expressing porcine Sertoli cells into diabetic SCID mice significantly decreased blood glucose levels in a dose-dependent manner, with 20 million Sertoli cells decreasing blood glucose levels to 9.8 +/- 2.7 mM. Similar results were obtained when 20 million insulin-positive, BALB/c mouse Sertoli cells were transplanted; blood glucose levels dropped to 6.3 +/- 2.4 mM and remained significantly lower for 5 days. To our knowledge, this is the first study to demonstrate Sertoli cells can be engineered to produce and secrete a clinically relevant factor that has a therapeutic effect, thus supporting the concept of using immune-privileged Sertoli cells as a potential vehicle for gene therapy. PMID- 20719073 TI - Body mass index reflects islet isolation outcome in islet autotransplantation for patients with chronic pancreatitis. AB - Total pancreatectomy with autologous islet cell transplantation (TP with AIT) is an effective treatment for chronic pancreatitis patients with severe abdominal pain. Body mass index (BMI) of the pancreatic donor is proven to be a useful predictor for islet isolation and transplantation outcomes in allogenic islet transplantation. However, the association between BMI and islet isolation outcome and/or metabolism after AIT was previously unclear. Twelve patients who received TP with AIT at our hospital were included in this study. All pancreata were preserved with both pancreatic ductal injection and oxygen-charged static two layer method using ET-Kyoto solution. The cohort was divided into two groups: low BMI group (BMI <23 kg/m(2), n=5) and high BMI group (BMI >=23, n=7). The high BMI group had a significantly higher islet yield per gram than the low BMI group both in pancreas postdigestion and in final product (postdigestion: 7330 +/- 539 vs. 3509 +/- 563 IE/g; p<0.001; final product: 6555 +/- 585 vs. 3476 +/- 546 IE/g; p=0.004). For islet yield in final product per patient body weight, the high BMI group also had significantly higher islet yield than the low BMI group (7997 +/- 779 vs. 4175 +/- 750 IE/kg, p=0.007). Insulin independence rate in the high BMI group (71%) was also higher than that low BMI group (40%), but it did not reach statistical significance. Pancreata from patients with higher BMI could obtain higher islet yield in the setting of autologous islet cell transplantation for chronic pancreatitis. PMID- 20719074 TI - Bone marrow and pancreatic islets: an old story with new perspectives. AB - In the past years, in the field of beta-cell replacement for diabetes therapy, the easy availability of bone marrow (BM) and the widely consolidated clinical experience in the field of hematology have contributed to the development of strategy to achieve donor-specific transplantation tolerance. Recently, the potential role of BM in diabetes therapy has been reassessed from a different point of view. Diverse groups investigated the contribution of BM cells to beta cell replacement as direct differentiation into insulin-producing cells. More importantly, while direct differentiation is highly unlikely, a wide array of experimental evidences indicates that cells of BM origin are capable of facilitating the survival or the endogenous regeneration of beta-cells through an as yet well-defined regeneration process. These new experimental in vitro and in vivo data will expand in the near future the clinical trials involving BM or BM derived cells to cure both type 1 and type 2 diabetes in humans. In this review we recapitulate the history of use of BM in diabetes therapy and we provide clinically relevant actual information about the participation of BM and BM derived stem cells in islet cell regeneration processes. Furthermore, new aspects such as employing BM as "feeder tissue" for pancreatic islets and new clinical use of BM in diabetes therapy are discussed. PMID- 20719075 TI - Characterization of tolerance induction through prenatal marrow transplantation: the requirement for a threshold level of chimerism to establish rather than maintain postnatal skin tolerance. AB - Hematopoietic chimerism resulting from prenatal marrow transplantation does not consistently result in allotolerance for unidentified causes. In a C57BL/6-into FVB/N murine model, we transplanted T-cell-depleted adult marrow on gestational day 14 to elucidate the immunological significance of chimerism towards postnatal tolerance. Postnatally, chimerism was examined by flow cytometry, and tolerance by skin transplantation and mixed lymphocyte reaction. Regulatory T cells were quantified by FoxP3 expression. Peripheral chimerism linearly related to thymic chimerism, and predicted the degree of graft acceptance with levels >3% at skin placement, yielding consistent skin tolerance. Low- and high-level chimeras had lower intrathymic CD3(high) expression than microchimeras or untransplanted mice. Regardless of the skin tolerance status in mixed chimeras, donor-specific alloreactivity by lymphocytes was suppressed but could be partially restored by exogenous interleukin-2. Recipients that lost peripheral chimerism did not accept donor skin unless prior donor skin had engrafted at sufficient chimerism levels, suggesting that complete tolerance can develop as a consequence of chimerism related immunosuppression of host lymphocytes and the tolerogenic effects of donor skin. Thus, hematopoietic chimerism exerted immunomodulatory effects on the induction phase of allograft tolerance. Once established, skin tolerance did not fade away along with spontaneous regression of peripheral and tissue chimerism, as well as removal of engrafted donor skin. Neither did it break following in vivo depletion of increased regulatory T cells, and subcutaneous interleukin-2 injection beneath the engrafted donor skin. Those observations indicate that the maintenance of skin tolerance is multifaceted, neither solely dependent upon hematopoietic chimerism and engrafted donor skin nor on the effects of regulatory T cells or clonal anergy. We conclude that hematopoietic chimerism generated by in utero hematopoietic stem cell transplantation is critical to establish rather than maintain postnatal skin tolerance. Therefore, the diminution of hematopoietic chimerism below a threshold level does not nullify an existing tolerance state, but lessens the chance of enabling complete tolerance. PMID- 20719076 TI - Pancreatic islet culture and preservation strategies: advances, challenges, and future outlook. AB - Postisolation islet survival is a critical step for achieving successful and efficient islet transplantation. This involves the optimization of islet culture in order to prolong survival and functionality in vitro. Many studies have focused on different strategies to culture pancreatic islets in vitro through manipulation of culture media, surface modified substrates, and the use of various techniques such as encapsulation, embedding, scaffold, and bioreactor culture strategies. This review aims to present and discuss the different methodologies employed to optimize pancreatic islet culture in vitro as well as address their respective advantages and drawbacks. PMID- 20719077 TI - Lack of evidence for recipient precursor cells replenishing beta-cells in transplanted islets. AB - Bone marrow and tissue precursor cells have been postulated to replenish grafts of transplanted islets. Several investigators have reported that bone marrow cells can promote the regeneration of injured islets. In this study, we investigated the potential of recipient-derived precursor cells to form new pancreatic endocrine cells in islet grafts transplanted under the kidney capsule. Mouse insulin promoter (MIP)-green fluorescence protein (GFP) mice, which express GFP only in beta-cells, or beta-actin GFP mice, which express GFP ubiquitously, were used to determine if the recipient-derived cells differentiate into beta cells or other types of endocrine cells. We transplanted MIP-GFP islets into wild type mice, wild-type islets into MIP-GFP mice, beta-actin GFP islets into wild type mice, and wild-type islets into beta-actin GFP mice. beta-Actin GFP bone marrow cells were then injected into wild-type mice to evaluate the potential role of bone marrow stem cells to provide new islet cells to the graft. No beta cells with green fluorescence were seen in the graft when wild-type islets were transplanted into MIP-GFP mice. When wild-type islets were transplanted into beta actin GFP mice, no beta-cells with GFP staining could be identified in the grafts. Similarly, no endocrine cells with GFP staining could be identified in the grafts after injection of beta-actin GFP bone marrow cells into wild-type islet-transplanted wild-type mice. This study provides further support for the concept that recipient precursor cells do not produce new beta-cells in grafts of transplanted islets. PMID- 20719079 TI - Suspension culture of mammalian cells using thermosensitive microcarrier that allows cell detachment without proteolytic enzyme treatment. AB - Microcarriers are used to expand anchorage-dependent cells in large-scale suspension bioreactors. Proteolytic enzyme treatment is necessary to detach cells cultured on microcarriers for cell harvest or scale-up, but the enzyme treatment damages the cells and extracellular matrices and complicates the culture process. Here, we fabricated thermosensitive microcarriers from which cells can be detached by temperature change without proteolytic enzyme treatment. A thermosensitive polymer, poly-N-isopropylacrylamide (pNIPAAm), was incorporated on the surface of Cytodex-3(r) microcarriers. pNIPAAm-grafted microcarriers allowed human bone marrow-derived mesenchymal stem cells (hBMMSCs) to adhere, spread, and grow successfully on the microcarriers as nongrafted microcarriers did. By dropping temperature below 32 degrees C, more than 82.5% of hBMMSCs were detached from pNIPAAm-grafted microcarriers. The trypsin treatment for cell detachment induced apoptosis and death of some of the detached cells, but cell detachment from pNIPAAm-grafted microcarriers by temperature change significantly reduced the apoptosis and cell death. pNIPAAm-grafted microcarriers can significantly reduce cell extracellular matrix damage in the cell detachment process and simplify the cell detachment process by avoiding proteolytic enzyme treatment. pNIPAAm-grafted microcarriers would be valuable to a variety of potential fields demanding a large amount of cells without cell damage, such as cell therapy, tissue engineering, and other biological and clinical applications. PMID- 20719078 TI - Antiproinflammatory effects of iodixanol (OptiPrep)-based density gradient purification on human islet preparations. AB - Islet isolation and purification using a continuous density gradient may reduce the volume of tissue necessary for implantation into patients, therefore minimizing the risks associated with intraportal infusion in islet transplantation. On the other hand, the purification procedure might result in a decreased number of islets recovered due to various stresses such as exposure to cytokine/chemokine. While a Ficoll-based density gradient has been widely used in purification for clinical trials, purification with iodixanol (OptiPrep) has been recently reported in islet transplant series with successful clinical outcomes. The aim of the current study was to compare the effects of the purification method using OptiPrep-based and Ficoll-based density gradients. Human islet isolations were performed using a modified automated method. After the digestion phase, pre-purification digests were divided into two groups and purified using a semiautomated cell processor with either a continuous Ficoll- or OptiPrep-based density gradient. The quantity, purity, viability, and cellular composition of islet preparations from each group were assessed. Cytokine/chemokine and tissue factor production from islet preparations after 48-h culture were also measured. Although islet purity, post-purification IEQ, islet recovery rate, FDA/PI, and fractional beta-cell viability were comparable, beta-cell mass after 48-h culture significantly improved in the OptiPrep group when compared to the Ficoll group. The production of cytokine/chemokine including IL-1beta, TNF-alpha, IFN-gamma, IL 6, IL-8, MIP-1beta, MCP-1, and RANTES but not tissue factor from the OptiPrep group was significantly lower during 48-h culture after isolation. Each preparation contained the similar number of ductal cells and macrophages. Endotoxin level in both gradient medium was also comparable. The purification method using OptiPrep gradient media significantly reduced cytokine/chemokine production but not tissue factor from human islet preparations and improved beta cell survival during pretransplant culture. Our results suggest that the purification method using OptiPrep gradient media may be of assistance in increasing successful islet transplantation. PMID- 20719080 TI - A neuroregenerative human ensheathing glia cell line with conditional rapid growth. AB - Ensheathing glia have been demonstrated to have neuroregenerative properties but this cell type from human sources has not been extensively studied because tissue samples are not easily obtained, primary cultures are slow growing, and human cell lines are not available. We previously isolated immortalized ensheathing glia by gene transfer of BMI1 and telomerase catalytic subunit into primary cultures derived from olfactory bulbs of an elderly human cadaver donor. These cells escape the replicative senescence characteristic of primary human cells while conserving antigenic and neuroregenerative properties of ensheathing glia, but their low proliferative rate in culture complicates their utility as cell models and their application for preclinical cell therapy experiments. In this study we describe the use of a conditional SV40 T antigen (TAg) transgene to generate human ensheathing glia cell lines, which are easy to maintain due to their robust growth in culture. Although these fast growing clones exhibited polyploid karyotypes frequently observed in cells immortalized by TAg, they did not acquire a transformed phenotype, all of them maintaining neuroregenerative capacity and antigenic markers typical of ensheathing glia. These markers were also retained even after elimination of the TAg transgene using Cre/LoxP technology, although the cells died shortly after, confirming that their survival depended on the presence of the immortalizing genes. We have also demonstrated here the feasibility of using these human cell lines in animal models by genetically marking the cells with GFP and implanting them into the injured spinal cord of immunosuppressed rats. Our conditionally immortalized human ensheathing glia cell lines will thus serve as useful tools for advancing cell therapy approaches and understanding neuroregenerative mechanisms of this unique cell type. PMID- 20719082 TI - Establishment of a Brazilian line of human embryonic stem cells in defined medium: implications for cell therapy in an ethnically diverse population. AB - Pluripotent human embryonic stem (hES) cells are an important experimental tool for basic and applied research, and a potential source of different tissues for transplantation. However, one important challenge for the clinical use of these cells is the issue of immunocompatibility, which may be dealt with by the establishment of hES cell banks to attend different populations. Here we describe the derivation and characterization of a line of hES cells from the Brazilian population, named BR-1, in commercial defined medium. In contrast to the other hES cell lines established in defined medium, BR-1 maintained a stable normal karyotype as determined by genomic array analysis after 6 months in continuous culture (passage 29). To our knowledge, this is the first reported line of hES cells derived in South America. We have determined its genomic ancestry and compared the HLA-profile of BR-1 and another 22 hES cell lines established elsewhere with those of the Brazilian population, finding they would match only 0.011% of those individuals. Our results highlight the challenges involved in hES cell banking for populations with a high degree of ethnic admixture. PMID- 20719081 TI - Long-term contribution of human bone marrow mesenchymal stromal cells to skeletal muscle regeneration in mice. AB - Mesenchymal stromal cells (MSCs) are attractive for cellular therapy of muscular dystrophies as they are easy to procure, can be greatly expanded ex vivo, and contribute to skeletal muscle repair in vivo. However, detailed information about the contribution of bone marrow (BM)-derived human MSCs (BM-hMSCs) to skeletal muscle regeneration in vivo is very limited. Here, we present the results of a comprehensive study of the fate of LacZ-tagged BM-hMSCs following implantation in cardiotoxin (CTX)-injured tibialis anterior muscles (TAMs) of immunodeficient mice. beta-Galactosidase-positive (beta-gal(+)) human-mouse hybrid myofibers (HMs) were counted in serial cross sections over the full length of the treated TAMs of groups of mice at monthly intervals. The number of human cells was estimated using chemiluminescence assays. While the number of human cells declined gradually to about 10% of the injected cells at 60 days after transplantation, the number of HMs increased from day 10 onwards, reaching 104 +/ 39.1 per TAM at 4 months postinjection. beta-gal(+) cells and HMs were distributed over the entire muscle, indicating migration of the former from the central injection site to the ends of the TAMs. The identification of HMs that stained positive for human spectrin suggests myogenic reprogramming of hMSC nuclei. In summary, our findings reveal that BM-hMSCs continue to participate in the regeneration/remodeling of CTX-injured TAMs, resulting in +/-5% HMs at 4 months after damage induction. Moreover, donor-derived cells were shown to express genetic information, both endogenous and transgenic, in recipient myofibers. PMID- 20719083 TI - Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. AB - Despite advances in wound closure techniques and devices, there is still a critical need for new methods of enhancing the healing process to achieve optimal outcomes. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. Adipose-derived stem cells (ASCs) hold great promise for wound healing, because they are multipotential stem cells capable of differentiation into various cell lineages and secretion of angiogenic growth factors. The aim of this study was to evaluate the benefit of ASCs on wound healing and then investigate the probable mechanisms. ASCs characterized by flow cytometry were successfully isolated and cultured. An excisional wound healing model in rat was used to determine the effects of locally administered ASCs. The gross and histological results showed that ASCs significantly accelerated wound closure in normal and diabetic rat, including increased epithelialization and granulation tissue deposition. Furthermore, we applied GFP-labeled ASCs on wounds to determine whether ASCs could differentiate along multiple lineages of tissue regeneration in the specific microenvironment. Immunofluorescent analysis indicated that GFP-expressing ASCs were costained with pan-cytokeratin and CD31, respectively, indicating spontaneous site-specific differentiation into epithelial and endothelial lineages. These data suggest that ASCs not only contribute to cutaneous regeneration, but also participate in new vessels formation. Moreover, ASCs were found to secret angiogenic cytokines in vitro and in vivo, including VEGF, HGF, and FGF2, which increase neovascularization and enhance wound healing in injured tissues. In conclusion, our results demonstrate that ASC therapy could accelerate wound healing through differentiation and vasculogenesis and might represent a novel therapeutic approach in cutaneous wounds. PMID- 20719084 TI - Efficacy of periodontal stem cell transplantation in the treatment of advanced periodontitis. AB - Periodontitis is the most common cause for tooth loss in adults and advanced types affect 10-15% of adults worldwide. The attempts to save tooth and regenerate the periodontal apparatus including cementum, periodontal ligament, and alveolar bone reach to the dental tissue-derived stem cell therapy. Although there have been several periodontitis models suggested, the apical involvement of tooth root is especially challenging to be regenerated and dental stem cell therapy for the state has never been investigated. Three kinds of dental tissue derived adult stem cells (aDSCs) were obtained from the extracted immature molars of beagle dogs (n = 8), and ex vivo expanded periodontal ligament stem cells (PDLSCs), dental pulp stem cells (DPSCs), and periapical follicular stem cells (PAFSCs) were transplanted into the apical involvement defect. As for the lack of cementum-specific markers, anti-human cementum protein 1 (rhCEMP1) antibody was fabricated and the aDSCs and the regenerated tissues were immunostained with anti CEMP1 antibody. Autologous PDLSCs showed the best regenerating capacity of periodontal ligament, alveolar bone, and cementum as well as peripheral nerve and blood vessel, which were evaluated by conventional and immune histology, 3D micro CT, and clinical index. The rhCEMP1 was expressed strongest in PDLSCs and in the regenerated periodontal ligament space. We suggest here the PDLSCs as the most favorable candidate for the clinical application among the three dental stem cells and can be used for treatment of advanced periodontitis where tooth removal was indicated in the clinical cases. PMID- 20719085 TI - Therapeutic effects of umbilical cord blood-derived mesenchymal stem cell transplantation in experimental lupus nephritis. AB - Mesenchymal stem cells (MSCs) have been shown to possess immunomodulatory properties. Systemic lupus erythematosus is an autoimmune disease that results in nephritis and subsequent destruction of renal microstructure. We investigated whether transplantation of human umbilical cord blood-derived MSCs (uMSCs) is useful in alleviating lupus nephritis in a murine model. It was found that uMSCs transplantation significantly delayed the development of proteinuria, decreased anti-dsDNA, alleviated renal injury, and prolonged the life span. There was a trend of decreasing T-helper (Th) 1 cytokines (IFN-gamma, IL-2) and proinflammatory cytokines (TNF-alpha, IL-6, IL-12) and increasing Th2 cytokines (IL-4, IL-10). The in vitro coculture experiments showed that uMSCs only inhibited lymphocytes and splenocytes proliferation but not mesangial cells. Long term engraftment of uMSCs in the kidney was not observed either. Together, these findings indicated that uMSCs were effective in decreasing renal inflammation and alleviating experimental lupus nephritis by inhibiting lymphocytes, inducing polarization of Th2 cytokines, and inhibition of proinflammatory cytokines production rather than direct engraftment and differentiating into renal tissue. Therapeutic effects demonstrated in this preclinical study support further exploration of the possibility to use uMSCs from mismatched donors in lupus nephritis treatment. PMID- 20719086 TI - Transplantation of insulin-producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. AB - Diabetes mellitus can be treated with islet transplantation, although there is a scarcity of donors. This study investigated whether human mesenchymal stem cells (MSCs) from umbilical cord stroma could be induced to differentiate into insulin producing cells and the effects of retro-orbital injection of human insulin producing cells for the treatment of nonobese diabetic (NOD) mice. MSCs were isolated from human umbilical cord stroma and induced to differentiate into insulin-producing cells using differentiation medium. Differentiated cells were evaluated by immunocytochemistry, RT-PCR, and real-time PCR. C-peptide release, both spontaneous and after glucose challenge, was measured by ELISA. Insulin producing cells were then transplanted into NOD mice. Blood glucose levels and body weights were monitored weekly. Human nuclei and C-peptide were detected in mouse livers by immunohistochemistry. Pancreatic beta-cell development-related genes were expressed in the differentiated insulin-producing cells. Differentiated cells' C-peptide release in vitro increased after glucose challenge. Further, in vivo glucose tolerance tests showed that blood sugar levels decreased after the cells' transplantation into NOD mice. After transplantation, insulin-producing cells containing human C-peptide and human nuclei were located in the liver. Thus, we demonstrated that differentiated insulin-producing cells from human umbilical cord stromal MSCs transplanted into NOD mice could alleviate hyperglycemia in diabetic mice. PMID- 20719087 TI - Amniotic membrane application reduces liver fibrosis in a bile duct ligation rat model. AB - Biliary fibrosis and resultant cirrhosis are among the most common outcomes of chronic liver diseases. Currently, liver transplantation remains the only effective treatment. In seeking alternative therapeutic approaches, we focused on the potential use of the human amniotic membrane (AM). Indeed, AM has gained increasing importance for its antiscarring, anti-inflammatory, and wound-healing properties, as well as for the multipotent differentiation ability and immunomodulatory features of AM-derived cells. Intriguingly, we have recently demonstrated that placenta-derived cells reduce lung fibrosis in bleomycin treated mice, and that AM patches reduce postischemic cardiac injury in rats. Hence, we have now investigated the effects of human AM on biliary fibrosis induced in rats through the bile duct ligation (BDL) procedure. A fragment of human AM was applied onto the liver surface after BDL and the effects on fibrosis establishment and progression were evaluated at different time points in comparison with fibrosis progression in control BDL rats. The degree of liver fibrosis was first assessed by the semiquantitative Knodell scoring system and, thereafter, by digital image morphometric analysis to quantify the area occupied by ductular reaction, activated myofibroblasts, and collagen deposition. We demonstrated a significant reduction in the severity of BDL-induced fibrosis in AM-treated rats. Indeed, while fibrosis progressed rapidly in control BDL rats, leading to cirrhosis within 6 weeks, AM-treated rats showed confined fibrosis at the portal/periportal area with no signs of cirrhosis, and a reduction in collagen deposition to about 50% of levels observed in control BDL rats. In addition, the AM was able to significantly slow the gradual progression of the ductular reaction and reduce, at all time points, the area occupied by activated myofibroblasts. These findings suggest that human AM, when applied as a patch onto the liver surface, might inhibit fibrosis progression in BDL-injured livers, and could protect against hepatic damage associated with fibrotic degeneration. PMID- 20719088 TI - Combined application of neutrophin-3 gene and neural stem cells is ameliorative to delay of denervated skeletal muscular atrophy after tibial nerve transection in rats. AB - Examination of the therapeutic efficacy of neural stem cells (NSCs) has recently become the focus of much investigation. In this study we present an insight of the effects of combined application with neurotrophin-3 (NT-3) and NSCs that derived from rat embryo spinal cord on delaying denervated skeletal muscular atrophy after tibial nerve was severed. NT-3 gene was amplified by PCR and subcloned into lentiviral vector pWPXL-MOD to construct a lentiviral expression vector pWPXL-MOD-NT-3. A positive clone expressing NT-3 (named NSCs-NT-3) was obtained and used for differentiation in vitro and transplantation. Sixty adult rats, whose tibial nerves were sectioned, were divided into two groups: one grafted with NSCs-NT-3 (experimental group, n = 30) and the other with NSCs transfected by pWPXL-MOD (control group, n = 30). The cell survival and differentiation, NT-3 gene expression, and effect of delaying denervated skeletal muscular atrophy were examined through immunohistostaining, RT-PCR, Western blot, electrophysiological analysis, and mean cross-sectional area (CSA) of gastrocnemius, respectively. The results show that the NT-3 gene, which is comprised of 777 bp, was cloned and significantly different expression were detected between NSCs and NSCs-NT-3 in vitro. Quantitative analysis of the choline acetyltransferase (ChAT) immunopositive cells revealed a significant increase in experimental group compared to the control group 4 weeks after implantation (p < 0.01). Twelve weeks after transplantation, the ChAT immunopositive cells were detected near the engrafted region only in experimental group. Furthermore, the effect in delaying denervated skeletal muscular atrophy is indicated in the EMG examination and mean CSA of gastrocnemius. These findings suggest that the neural stem cells expressing NT-3 endogenously would be a better graft candidate for the delay of denervated skeletal muscular atrophy. PMID- 20719089 TI - Regional transient portal ischemia and irradiation as preparative regimen for hepatocyte transplantation. AB - Hepatocyte transplantation is regarded as a promising option to correct hereditary metabolic liver disease. This study describes a novel method involving regional transient portal ischemia (RTPI) in combination with hepatic irradiation (IR) as a preparative regimen for hepatocyte transplantation. The right lobules of rat livers (45% of liver mass) were subjected to RTPI of 30-120 min. Liver specimens and serum samples were analyzed for transaminase levels, DNA damage, apoptosis, and proliferation. Repopulation experiments involved livers of dipeptidylpeptidase IV (DPPIV)-deficient rats preconditioned with RTPI (60-90 min) either with or without prior partial hepatic IR (25 Gy). After reperfusion intervals of 1 and 24 h, 12 million wild-type (DPPIV positive) hepatocytes were transplanted into recipient livers via the spleen. RTPI of 60-90 min caused limited hepatic injury through necrosis and induced a distinct regenerative response in the host liver. Twelve weeks following transplantation, small clusters of donor hepatocytes were detected within the portal areas. Quantitative analysis revealed limited engraftment of 0.79% to 2.95%, whereas control animals (sham OP) exhibited 4.16% (determined as relative activity of DPPIV when compared to wild-type liver). Repopulation was significantly enhanced (21.43%) when IR was performed prior to RTPI, optimum preconditioning settings being 90 min of ischemia and 1 h of reperfusion before transplantation. We demonstrate that RTPI alone is disadvantageous to donor cell engraftment, whereas the combination of IR with RTPI comprises an effective preparative regimen for liver repopulation. The method described clearly has potential for clinical application. PMID- 20719091 TI - Optimal time point for neuronal generation of transplanted neural progenitor cells in injured spinal cord following root avulsion. AB - Root avulsion of the brachial plexus results in a progressive and pronounced loss of motoneurons. Cell replacement strategies have therapeutic potential in the treatment of motoneuron degenerative neurological disorders. Here, we transplanted spinal cord-derived neural progenitor cells (NPCs) into the cervical ventral horn of adult rats immediately, 2 weeks, or 6 weeks after root avulsion to determine an optimal time scale for the survival and differentiation of grafted cells. We showed that grafted NPCs survived robustly at all three time points and there was no statistical difference in survival rate. Interestingly, however, transplantation at 2 weeks postavulsion significantly increased the neuronal differentiation of transplanted NPCs compared to transplantation immediately or at 6 weeks postavulsion. Moreover, only NPCs transplanted at 2 weeks postavulsion were able to differentiate into choline acetyltransferase (ChAT)-positive neurons. Specific ELISAs and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that expression levels of BDNF and GDNF were significantly upregulated in the ventral cord at 2 weeks postavulsion compared to immediately or at 6 weeks postavulsion. Our study suggests that the cervical ventral horn at 2 weeks postavulsion both supports neuronal differentiation and induces region-specific neuronal generation possibly because of its higher expression of BDNF and GDNF. PMID- 20719092 TI - Beneficial effect of autologous transplantation of endothelial progenitor cells on steroid-induced femoral head osteonecrosis in rabbits. AB - Femoral head osteonecrosis (ON) is a serious complication of steroid administration. We examined whether implantation of autologous bone marrow derived endothelial progenitor cells (EPCs) can augment neovascularization and bone regeneration in steroid-induced osteonecrosis of the femoral head. Forty 12 week-old male New-Zealand white rabbits were divided into group I (left untreated, n=12), group II (core decompression, n=12), and group III (core decompression + autologous EPCs implantation, n=16) after receiving an established inductive protocol for inducing steroid-associated ON. Four weeks later, these rabbits were euthanized, bilateral femora were dissected for Micro CT-based microangiography to assess vascularization, and then the osteonecrotic changes and repair processes were examined histopathologically. Quantitative analysis showed that new vessel formation in group III was significantly greater compared with other groups at 4 weeks after treatment. The histologic and histomorphometric analyses revealed that the new bone volume was significantly higher in group III than in groups I and II 4 weeks after treatment. A combination of EPCs and core decompression enhances the neovascularization and bone regeneration in rabbit steroid-induced femoral head ON. Local implantation of EPCs may provide a novel and effective therapeutic option for early corticosteroid-induced ON. PMID- 20719093 TI - Bone marrow mononuclear cells increase retinal ganglion cell survival and axon regeneration in the adult rat. AB - The central nervous system (CNS) of adult mammals generally does not regenerate, and many studies have attempted to identify factors that could increase neuroprotection and/or axonal outgrowth after CNS lesions. Using the optic nerve crush of rats as a model for CNS injury, we investigated the effect of intravitreal transplantation of syngeneic bone-marrow mononuclear cells (BMMCs) on the survival of retinal ganglion cells (RGC) and on the regeneration of optic axons. Control animals received intravitreal saline injections after lesion. Injections of BMMCs resulted in a 1.6-fold increase in the number of RGCs surviving 14 days after injury. The BMMC-treated animals also had increased numbers of axons, which grew up to 1.5 mm from the crush site, and also had reduced Muller glia activation. Analysis of mRNAs in all conditions revealed an increase in levels of fibroblast growth factor 2 (FGF-2) mRNA in treated animals 14 days after injury. To investigate whether the regenerated axons could reach the brain, we retrograde labeled the RGCs by injecting a lipophilic tracer into the superior colliculus. We also analyzed the expression of NGFI-A in the superficial layers of the superior colliculus as a possible marker of synaptic input from RGC axons. We found evidence that more RGCs were able to reach the brain after treatment and we showed that NGFI-A expression was higher in the treated animals 60 days after injury. These results demonstrate that transplant of BMMCs can increase neuroprotection and neuroregeneration after injury in a model of optic nerve crush, and these effects could be mediated by FGF-2. PMID- 20719094 TI - Targeting uncoupling protein-2 improves islet graft function. AB - Preserving and enhancing the primary function of transplanted islets is not only crucial for improving the outcome of the islet transplantation, but is also important for reducing the islet mass required to achieve insulin independence. Uncoupling protein 2 (UCP2) is a member of the uncoupling protein family, which is localized to the inner mitochondrial membrane and negatively regulates insulin secretion in the pancreatic beta-cells. In this study, we assessed the importance of UCP2 in improving islet graft primary function by using UCP2 gene-knockout (UCP2-KO) mice in a syngeneic islet transplantation model. Islets were isolated from UCP2-KO or wild-type (WT) C57BL/6J mice. The effects of deficiency of UCP2 on islet transplantation and islet function were determined. Two hundred islets from UCP2-KO, but not from WT, donors were capable of completely restoring normoglycemia in 1 week in all syngeneic diabetic recipients. Islets harvested from UCP2-KO mice secreted onefold more insulin in GSIS assay than that from WT mice, and maintained normal GSIS after 72-h exposure to high glucose challenge. In addition, UCP2-KO islets expressed twofold higher Bcl-2 mRNA than that from WT islets, and were resistant to high glucose and proinflammatory cytokine induced death. Our study explored a potential mechanism that may explain the benefit of UCP2-KO islets in islet transplantation. Targeting UCP2 may provide a novel strategy to improve primary function of transplanted islets and reduce the number of islets required in transplantation. PMID- 20719095 TI - Transplantation of olfactory ensheathing cells as adjunct cell therapy for peripheral nerve injury. AB - Traumatic events, such as work place trauma or motor vehicle accident violence, result in a significant number of severe peripheral nerve lesions, including nerve crush and nerve disruption defects. Transplantation of myelin-forming cells, such as Schwann cells (SCs) or olfactory ensheathing cells (OECs), may be beneficial to the regenerative process because the applied cells could mediate neurotrophic and neuroprotective effects by secretion of chemokines. Moreover, myelin-forming cells are capable of bridging the repair site by establishing an environment permissive to axonal regeneration. The cell types that are subject to intense investigation include SCs and OECs either derived from the olfactory bulb or the olfactory mucosa, stromal cells from bone marrow (mesenchymal stem cells, MSCs), and adipose tissue-derived cells. OECs reside in the peripheral and central nervous system and have been suggested to display unique regenerative properties. However, so far OECs were mainly used in experimental studies to foster central regeneration and it was not until recently that their regeneration promoting activity for the peripheral nervous system was recognized. In the present review, we summarize recent experimental evidence regarding the regenerative effects of OECs applied to the peripheral nervous system that may be relevant to design novel autologous cell transplantation therapies. PMID- 20719096 TI - Bridging the rural-urban divide. PMID- 20719097 TI - Property and privacy paradigms of "marketable spit": an ethical and legal counterpart to blood? AB - Major advances in the testing of oral fluid (e.g., saliva) may lead to the diagnosis and treatment of previously undiagnosed conditions and may enable dentists to manage oral disease more effectively. Such use of another body fluid, blood, is already well established. Blood is a complex tissue that has been extensively researched and is now used for a wide variety of diagnostic tests. It is also regarded as a form of property with ethical and legal dimensions. If saliva is to fulfill a similar role, it should perhaps be granted those same protections. This paper advances the concept that saliva should be considered a form of property, possibly within personal biological materials law. The emerging potential for the development of marketable products from oral fluids raises the issue of protecting the research participant's ethical and legal rights. In particular, violation of privacy and genetic discrimination may arise from the testing of salivary DNA. Respect for autonomy requires that the clinician inform a patient or research participant about his or her rights to property and privacy as these may pertain to oral fluid. PMID- 20719098 TI - Comparative translucency of esthetic composite resin restorative materials. AB - OBJECTIVE: To evaluate the translucency of currently available composites classified by their respective manufacturers as "opaque," "dentin," "body" (or "universal") and "enamel" materials. MATERIALS AND METHODS: Four disk-shaped specimens were produced using a split-ring mould (13 mm in diameter and 2 mm in thickness) from each of 39 proprietary composite restorative materials. Enamel and dentin samples of equivalent thickness were obtained from extracted human teeth. Colour values for lightness (L*), red-green chromatic coordinate (a*) and blue-yellow chromatic coordinate (b*) were recorded against standard white and black backgrounds with a Minolta CR-300 chroma meter under the standard illuminant D65. Translucency parameter values were calculated and compared using analysis of variance and the Tukey test, with significance set at p < 0.05. RESULTS: A continuum of values for the translucency parameter was obtained, ranging from the most opaque (Filtek Supreme Plus A2D) to the most translucent (Ceram X Duo E2). In general, "opaque" and "dentin" composites yielded relatively low translucency values, "body" (or "universal") composites yielded intermediate values, and "enamel" composites yielded relatively high values. However, the boundaries between these categories were not distinct, and there was some overlap. The mean value of the translucency parameter for human enamel was within the range of values for "enamel" shade composites. The individual values for specimens of human dentin were more variable (i.e., greater standard deviation around the mean) than those for human enamel. The mean value obtained for dentin was intermediate between the ranges for composites with low and intermediate translucency. CONCLUSIONS: The various categories of composite from different manufacturers yielded a wide range of translucency, with minimal distinction between the extremes in adjacent categories. The measured translucency values provided more information than the respective category types. Knowledge of the relative translucency and opacity of different commercial materials can assist clinicians in the choice of composite for clinical use. PMID- 20719099 TI - A patient treated for lymphoma with chemotherapy is now interested in a dental implant. If her lymphoma recurs, will there be any ramifications for the implant? PMID- 20719100 TI - How do I evaluate a patient with a swollen lip? PMID- 20719101 TI - Factors affecting the energy delivered to simulated class I and class v preparations. AB - PURPOSE: To determine the effect of operator, curing light and preparation location, as well as any correlations among these variables, on the amount of light energy delivered to simulated cavity preparations. MATERIALS AND METHODS: Each of 10 dentists and 10 fourth-year dental students light-cured a Class I preparation in tooth 26 and a Class V preparation in tooth 37 in a dental mannequin head. The operators exposed each preparation for 10 seconds with each of 3 LED-based curing lights (Bluephase G2 on high power, Demi and VALO on standard power). Each operator also used the VALO unit in the plasma mode for 2 sequential 3-second curing cycles. For each combination of operator, curing light and preparation, the irradiance (mW/cm(2)) received at the base of the preparation was measured with a laboratory-grade spectroradiometer, and software was used to calculate the energy density delivered in real time. The statistical analysis included 3-way analysis of variance (ANOVA) and the Fisher protected least significant difference (PLSD) test for post hoc pairwise comparisons. RESULTS: There was a large qualitative and quantitative variation in the irradiance delivered to the preparations by each operator. Three-way ANOVA showed no statistically significant differences between dentists and dental students in terms of the amount of energy delivered (p = 0.90). However, there were statistically significant differences in energy delivered by the various curing lights (p < 0.001) and between the 2 preparation locations (p < 0.001). According to the Fisher PLSD test for post hoc pairwise comparison of means, the VALO unit used in the plasma mode for two 3-second curing cycles delivered the most energy (16.4 +/- 3.1 J/cm(2)) to the Class I preparation, and the same light used for 10 seconds in the standard mode delivered the least amount of energy (9.9 +/- 2.4 J/cm(2)) (p < 0.001). For the Class V preparation, the VALO unit used in the plasma mode for two 3-second curing cycles delivered the most energy (12.5 +/- 4.0 J/cm(2)), and the Demi unit, used for 10 seconds, delivered the least energy (7.4 +/- 2.5 J/cm(2)). CONCLUSIONS: The energy delivered by a curing light to a preparation in a simulated clinical environment was affected by the operator's light-delivery technique, the choice of curing light and the location of the preparation. PMID- 20719102 TI - Sjogren syndrome: reduced quality of life as an oral-systemic consequence. PMID- 20719103 TI - Light energy matters. PMID- 20719104 TI - Trends in the study of Aboriginal health risks in Canada. AB - OBJECTIVE: To identify trends in the study of health risk in peer-reviewed and grey literature in Canadian Aboriginal populations from 1960 to 2007. STUDY DESIGN: Systematic literature review and analysis. METHODS: Peer-reviewed literature was searched using 5 electronic library databases. The grey literature was searched using 3 online search engines, 4 agency websites and 2 online compiled databases. The search terms used were "Canada," synonyms for Canadian Aboriginal peoples and "risk." Citations were screened for relevance to Aboriginal populations and risks to aspects of human health. RESULTS: Both literatures show an exponential growth in risk-focused study of Canadian Aboriginal health issues over time. There is a geographic foci in the North with the Prairies and the West under-represented. Risk is most commonly used in relation to general health, environmental, zoonotic infections and chronic diseases in the peer-reviewed literature, and general health or environment in the grey literature. Most publications in both literatures are on generalized Aboriginal populations. When specified, a larger proportion of the publications relate to First Nations people, followed by Inuit. Little literature exists on Metis health risks in Canada. CONCLUSIONS: There has been an increase in publications about Aboriginal health risk in Canada over time. Trends reflect a research focus on the North and an increased interest in environment and health issues. Greater attention to mental health, addictions and Metis health is required. The increasing use of a risk-based analytical focus has potential implications for understanding the nature of Aboriginal health today and in the future. PMID- 20719105 TI - Survival of head and neck cancer in Greenland. AB - OBJECTIVES: Head and neck cancer is frequent in the Inuit population of Greenland and is characterized by a very high incidence of Epstein-Barr virus associated nasopharyngeal carcinoma (NPC). However, information on the treatment and survival of Inuit head and neck cancer patients is practically non-existent. The aim of this study, therefore, was to analyse the epidemiological pattern, time course and survival of head and neck cancer patients in Greenland. STUDY DESIGN: Retrospective register-based study. METHODS: The Danish Civil Registration System, the Danish Cancer Registry and hospital-based registries were used to identify all patients resident in Greenland diagnosed with head and neck cancer during the period 1994-2003. Data were analysed with regard to clinical characteristics, treatment delay and survival. RESULTS: A total of 125 patients were identified. The age-standardized incidence rate for all head and neck cancer cases was 28/100,000 for males and 19/100,000 for females. High incidence rates were found for NPC and oral cancers. Of all cancers, 47% were stage IV at the time of diagnosis, while 61% of all NPC's were stage IV. The median delay from date of first symptom to treatment was 248 days for all cancers. The overall crude 5-year survival rate for all sites together was 35% and for NPC 20%. CONCLUSION: Survival of head and neck cancer in Greenland is very low. Delays in treatment and inadequate follow-up on treatment complications are probable causes. The improvements in treatment for NPC and other head and neck cancer cases over the last decades are yet to be seen in this Inuit population. PMID- 20719106 TI - Prevalence of gestational diabetes mellitus among women born in Greenland: measuring the effectiveness of the current screening procedure. AB - OBJECTIVES: To estimate the prevalence of gestational diabetes mellitus (GDM) among Greenlanders and to evaluate the quality of the current screening procedure for gestational diabetes. STUDY DESIGN: Observational retrospective study of consecutive birth-log data and medical records on pregnant women who had given birth in Nuuk during 2008. METHODS: Information about maternal weight, weight gain in pregnancy, height, blood pressure, result of oral glucose tolerance test, family history of diabetes, smoking and alcohol habits, ethnicity, delivery and birth weight and length was collected for women who had given birth in Nuuk, Greenland, during 2008. RESULTS: A total of 233 women born in Greenland who had given birth to a singleton in Nuuk 2008 were included in the study. Of those, 37% were defined as having a high risk for GDM and thus met the screening criteria for GDM used in Greenland. However, only 54% of those women were screened. The prevalence of gestational diabetes was calculated to be 4.3% among high-risk Greenlandic pregnant women (2/46) (95% CI 0-10.0%). CONCLUSIONS: Despite a suboptimal screening rate, the prevalence of GDM among Greenlanders seems to be relatively low and Greenlanders may thus be less prone to develop GDM. However, diabetes mellitus is a relatively new disease in Greenland, and glucose intolerance in pregnancy is more likely to affect the next generation. The screening rate is suboptimal, and it is recommended that the screening procedure be optimized in order to find and treat all women with GDM. The number of screened women compared to the number of births occurring annually could be used as an indicator of screening efficacy. Diabetes prevention initiatives should be given high priority to avoid high rates of GDM in the future, as increasing prevalence of the disease is now seen worldwide, regardless of race. PMID- 20719108 TI - Depression and anxiety in the reindeer-herding Sami population of Sweden. AB - OBJECTIVES: The objective of this study was to investigate symptoms and predicting factors of depression and anxiety among reindeer-herding Sami in Sweden. STUDY DESIGN: A total of 319 reindeer-herding Sami (168 men, 151 women) were compared with urban and rural reference populations comprising 1,393 persons (662 men, 731 women). METHODS: A cross-sectional questionnaire study on mental health, which included the Hospital Anxiety and Depression Scale (HADS). Data were analysed with regard to population, gender, age group, education and work related stress. RESULTS: The Sami population disclosed higher mean values for both depression and anxiety than the reference groups, with Sami men reporting the highest rates. Work-related stress was associated with anxiety and depression in the Sami group. CONCLUSIONS: By comparing Sami men and women with reference groups of men and women living in urban and rural areas in northern Sweden, this study identified that reindeer-herding Sami men require special attention with regard to mental health problems. PMID- 20719107 TI - Individual saturated fatty acids are associated with different components of insulin resistance and glucose metabolism: the GOCADAN study. AB - OBJECTIVES: Type 2 diabetes and the consumption of saturated fatty acids (FAs) are on the rise among Alaska Inuits. This analysis, based on a cross-sectional study, explores the possible associations of saturated FA content in red blood cells (RBCs) and parameters of glucose metabolism in a sample of Alaska Natives. STUDY DESIGN AND METHODS: The sample included 343 women and 282 men aged 35-74. Statistical analyses explored the associations of selected RBC (myristic, palmitic and stearic acids) FAs with fasting glucose (plasma), fasting insulin (plasma), 2h glucose (2-hour glucose tolerance test), 2h insulin and homeostasis model assessment (HOMA) index. The models included sex and glucose metabolism status as fixed factors and age, body mass index (BMI), waist circumference, physical activity (METS) and FA content in RBCs as covariates. Measures of insulin, glucose and HOMA index were used as dependent variables. RESULTS: Myristic acid was positively associated with fasting insulin (beta=0.47, p<0.001), 2h insulin (beta=0.53, p=0.02) and HOMA index (beta=0.455, p<0.001). Palmitic acid was associated with 2h glucose (beta=2.3*10(-2), p<0.001) and 2h insulin (beta=5.6*10(-2), p=0.002) and stearic acid was associated with fasting glucose (beta=4.8*10(-3), p=0.006). CONCLUSIONS: These results strongly support the hypothesis that saturated fatty acids are associated with insulin resistance and glucose intolerance and that saturated fatty acids are significant risk factors for type 2 diabetes. PMID- 20719109 TI - [Role of Precision Radiotherapy for the Curable Non-small Cell Lung Cancer.]. PMID- 20719110 TI - [Consolidation treatment for non-small cell lung cancer.]. PMID- 20719111 TI - [Identification and Functional Analysis of A Novel Candidate Oncogene RAP2B in Lung Cancer.]. AB - BACKGROUND: RAP2B is one of the 50 novel candidate genes cloned from the differential expression cDNA libraries constructed in lung cancer cells. Though RAP2B contains conserved domain and belongs to Ras superfamily, the function of RAP2B in carcinogenesis is still poorly understood. The aim of this study is to explore the roles of RAP2B gene in carcinogenesis. METHODS: RT-PCR was applied to examine transcriptional status of RAP2B in the tumor and corresponding adjacent tissues collected from 27 patients with lung squamous cell carcinoma. RAP2B expression plasmid was constructed and transfected into Rat1 cells to evaluate the in vitro transformation ability through colony formation assay. Reporter gene assay was performed to reveal the relationship between RAP2B gene and NF-kappaB pathway. RESULTS: About 67% (18/27) of tumor tissues show higher mRNA expression than that in the corresponding adjacent normal tissues. Typical transforming focus formation was observed in Rat1 cells which were transfected with RAP2B gene. The reporter gene assay data showed that RAP2B activated NF-kappaB pathway more than 3 folds compared with the mock vector. CONCLUSIONS: RAP2B may be a novel candidate oncogene that plays important roles in carcinogenesis through activation of NF-kappaB pathway. PMID- 20719112 TI - [Transfection of Axin Gene Down-regulates Expressions of beta-catenin and TCF-4 and Inhibits the Proliferation and Invasive Ability of Lung Cancer Cells.]. AB - BACKGROUND: Axin is an important negative regulator of Wnt signaling pathway. It can induce the phosphorylation and degradation of beta-catenin. The reduced expression of axin or high expression of beta-catenin and TCF-4 were associated with malignant proliferation in many tumors. The aim of this study is to examine the relationships among the expressions and locations of axin, beta-catenin and other relevant molecules, and the roles of axin on proliferation, invasive ability and apoptosis of lung cancer cells. METHODS: The axin cDNA was transfected into lung cancer BE1 cell line which has very low axin expression. The levels of expression and location of axin, beta-catenin and TCF-4 before and after transfection were detected using immunofluorescence. The mRNA levels of expression of axin, beta-catenin and TCF-4 were examined using reverse transcription-polymerase chain reaction (RT-PCR). The apoptosis, proliferation and invasive ability of lung cancer cells before and after transfection were examined with flow cytometry, MTT and transwell methods. RESULTS: After transfection of axin gene into BE1 cells (BE1-axin cells), axin mRNA and protein were overexpressed significantly. Meanwhile, the protein expression of beta catenin and mRNA expression of TCF-4 were decreased significantly in BE1-axin cells than that in BE1 or vector control cells. The flow cytometry revealed that the apoptosis rate of BE1-axin cells was enhanced, but MTT and Transwell assay indicated that the proliferation and invasive ability were decreased significantly in BE1-axin cells than those in BE1 or vector control cells. CONCLUSIONS: The overexpression of axin could down-regulate the protein expression of beta-catenin and the transcription of TCF-4, and inhibit the proliferation and invasive ability of lung cancer cells. PMID- 20719113 TI - [Screening and Identification of Non-Small-Cell Lung Cancer Associated Antigen with SEREX.]. AB - BACKGROUND: Currently, there are only limited number of diagnostic tumor markers for non-small-cell lung cancer (NSCLC). The aim of this study is to screen and identify non-small-cell lung cancer associated antigens, by using of cancer sera containing antibodies which react with autologous cellular antigens (tumor associated antigens TAAs), which can be used in NSCLC early screening or target treatment. METHODS: Two T7 phage display cDNA libraries were panning against the sera from 24 patients with NSCLC. Then the enriched libraries were screened with the pool of sera from NSCLC patients, the positive clones encoding antigenic genes were obtained after screening, and the nucleotide sequences of positive were identified and analyzed with BLAST software in GenBank. RESULTS: After immunoscreen two T7 phage display cDNA libraries with serum from patients with NSCLC, thirty-one positive clones were obtained and sequence results showed they were derive from 15 genes, 12 of 15 genes were homologous to the genes known in GenBank, such as RHOA, ITGB4, and HNRNPA2/B1 et al . The other three genes expressed sequence tags (ESTs) were not found in GenBank. CONCLUSIONS: Fifteen NSCLC associated antigen genes and three candiated gene were obtained by SEREX from T7 phage display cDNA libraries. PMID- 20719114 TI - [High expression of twist is positively correlated with the differentiation of lung cancer.]. AB - BACKGROUND: Twist has been identified as a promoting factor for epithelialmesenchymal transition (EMT), which enhances the metastatic potential of cancer. The aim of this study is to detect the expression of Twist in lung cancer tissues and cell lines, and analyze its relationship with clinicopathologic characteristics and biological behavior of lung cancer. METHODS: Twist expression was examined in 68 lung cancer specimens and 8 normal lung specimens using immunohistochemistry (S-P method). Expression levels of Twist1 and Twist2 mRNA were detected using transcription-polymerase chain reaction (RT-PCR) in HBE and 8 lung cancer cell lines. Immunofluorescence was used to detect the Twist protein expression levels and subcellular localization in lung cancer cells and HBE (human normal bronchi epithelium) cells. RESULTS: Among 68 lung cancer specimens, 9 samples showed weak expression of Twist 13.24% (9 of 68), 75.00% (51 of 68) lung cancer specimens showed moderate to strong Twist staining whereas 8 corresponding normal lung specimens showed weak staining extent. Twist expression level was positively correlated with differentiation (P =0.002) and age (P =0.012). Twist1 and Twist2 mRNA expression levels were incompatible in different histology types. The fluorescence signal of Twist protein was conspicuous in lung squamous cell carcinoma cells and adencarcinoma cells, primarily in cytoplasm, but low in HBE. CONCLUSIONS: High expression of Twist in lung cancer was associated with differentiation. Twist could be used as a valuable biomarker to evaluate the progression of lung cancer. PMID- 20719116 TI - [Abnormal Expression of p120-catenin and E-cadherin Is Significantly Correlated with Malignant Phenotype of Human Lung Cancer.]. AB - BACKGROUND: To explore the correlation between p120-catenin (p120ctn) and small GTPases in human lung cancer, and their effect on the cell-cell adhesion, we examined the expression patterns of p120ctn and Rac1, which is the core member of small GTPases, and their correlation with clinicopathological factors. METHODS: S P immunohistochemistry, Western Blot, and RT-PCR were used to detect the expression patterns of p120ctn and Rac1 in 138 patients with non-small cell lung cancer (NSCLC) and two kinds of homologous lung cancer cell lines. We also used an in vitro model to evaluate their expression, and to determine whether protein expression correlated with the invasive capacity of lung cancer cell lines. RESULTS: In lung cancer, the levels of protein and mRNA expression of p120ctn were significantly lower than normal lung tissue, and Rac1 was also found to be higher in tumor tissue than in normal lung tissue. A correlation between abnormal p120ctn and overexpression of Rac1 (Correlation coefficient=0.720, P <0.001) was also associated with malignancy of lung cancer, such as poor differentiation (P =0.022), high TNM stage (P =0.010), and lymph node metastasis (P =0.009) in NSCLC patients. Abnormal expression of p120ctn and overexpression of Rac1 was significantly associated with the high metastatic capacity of BE1 cells. CONCLUSIONS: Abnormal p120ctn expression correlates with Rac1 overexpression, which contributes to the malignancy-related of NSCLC. PMID- 20719115 TI - [A new serum biomarker for lung cancer - transthyretin.]. AB - BACKGROUND: Lung cancer is the leading cause of cancer death worldwide and very few specific biomarkers could be used in clinical diagnosis at present. The aim of this study is to find novel potential serum biomarkers for lung cancer using Surface Enhanced Laser Desorption/Ionization (SELDI) technique. METHODS: Serum sample of 227 cases including 146 lung cancer, 13 pneumonia, 28 tuberculous pleurisy and 40 normal individuals were analyzed by CM10 chips. The candidate biomarkers were identified by ESI/MS-MS and database searching, and further confirmed by immunoprecipitation. The same sets of serum sample from all groups were re-measured by ELISA assay. RESULTS: Three protein peaks with the molecular weight 13.78 kDa, 13.90 kDa and 14.07 kDa were found significantly decreased in lung cancer serum compared to the other groups and were all automatically selected as specific biomarkers by Biomarker Wizard software. The candidate biomarkers obtained from 1-D SDS gel bands by matching the molecular weight with peaks on CM10 chips were identified by Mass spectrometry as the native transthyretin (nativeTTR), cysTTR and glutTTR, and the identity was further validated by immunoprecipitation using commercial TTR antibodies. Downregulated of TTR was found in both ELISA and SELDI analysis. CONCLUSIONS: TTRs acted as the potentially useful biomarkers for lung cancer by SELDI technique. PMID- 20719117 TI - [The Relationship between the PI3K/Akt/mTOR Signal Transduction Pathway and Non small Cell Lung Cancer.]. AB - BACKGROUND: It has been known that abnormality of PI3K/Akt/mTOR signal pathway plaied an important role in the oncogenesis of lung cancer. In this study, we tried to detect the mRNA expression levels of VEGF, PI3K, Akt, mTOR gene, the key genes of PI3K/Akt/mTOR signal pathway, in human non-small cell lung cancer (NSCLC) tissue and explore the relationship between PI3K/Akt/mTOR signaling pathway and non-small cell lung cancer. METHODS: Lung cancer tissue specimens were obtained from 40 patients. Adjacent-tumor NSCLC tissues from the 30 patients were served as control. The RT-PCR technique was used to detect the VEGF, PI3K, Akt, mTOR gene expression levels. RESULTS: The average mRNA expression levels of VEGF, PI3K, Akt, mTOR gene in lung cancer were (40+/-59)%, (61+/-23)%, (77+/-32)% and (43+/-21)% respectively, while the mRNA expression levels of VEGF, PI3K, Akt, mTOR genes in adjacent-tumor tissue were (16+/-40)%, (23+/-16)%, (10+/-12)% and (20+/-17)%, respectively. All the levels of VEGF, PI3K, Akt, mTOR gene expression in NSCLC were significantly higher than that in adjacent-tumor lung tissue (P <0.01). CONCLUSIONS: Our preliminary data have demonstrated that PI3K/Akt/mTOR signaling pathway is activated in the tumor cells of NSCLC. The activated PI3K/Akt/mTOR signaling pathway might be an important role in the pathogenesis of NSCLC. PMID- 20719118 TI - [Expression and Significance of Stem Cell Markers CK19, Notch3, CD133, P75NTR, STRO-1 and ABCG2 in Pulmonary Squamous Carcinomas.]. AB - BACKGROUND: Increasing reports showed that some tumor stem cells were selfrenewal and multi-lineage differentiated in tumors, similar to the normal stem cells in human body. The aim of this study is to observe the expression of stem cell markers in lung squamous carcinoma tissues. METHODS: Fifty-four lung cancer specimens from surgery were analyzed for CK19, Notch3, CD133, P75NTR, STRO-1 and ABCG2 expression by using S-P immunohistochemistry. In addition, ten normal lung tissue samples were included as control. RESULTS: CK19, Notch3, CD133 and ABCG2 were expressed in 54 Lung cancer tissues, without expression of P75NTR and STRO 1. The expression rate of CK19, Notch3, CD133 and ABCG2 was 66.67% (36/54), 87.04% (47/54), 50% (27/54), and 61.11% (33/54) respectively. The levels of expression of Notch3, CD133 and ABCG2 were significantly lower in high differentiation group than those in moderate and low differentiation group (P <0.05). The levels of expression of CK19, CD133 and ABCG2 were significantly higher in lymph node metastasis group than those in non-metastasis group (P <0.05). The percentage of total positive cells of four stem cell markers in serial tissue sections was lower than 2%. CONCLUSIONS: There was expression of some stem cell markers in pulmonary squamous carcinomas, and there was relationship between expression degree with differentiation degree and lymph node metastasis. PMID- 20719119 TI - [The quantitative analysis of the oxidants/antioxidants in the tissues of lung cancer patients.]. AB - BACKGROUND: The relationship between antioxidants and tumor was gradually paid attention. The changes of activities and the levels of expression mRNA and protein of oxidants and antioxidants, were evaluated in 113 lung tumor and 64 tumor-free lung tissues collected between the years 2006 and 2007 from 113 individuals with surgically resectable lung cancer in order to understand the mechanism of the onset and development of lung cancer. METHODS: The activities of TSOD, MnSOD, CuZnSOD, GPx, H2O2 and MDA were determined by chromometry. MnSOD, CuZnSOD mRNA and protein expression levels were evaluated by Reverse transcription polymerase chain reaction and Western Blot analysis in tumor tissues, as well as corresponding control tissues. RESULTS: Comparing with the levels of these indexes in the tumor-free tissues, the activities of TSOD, CuZnSOD, GPx were higher, H2O2 and MDA were lower in the tumor tissues (P <0.05 or P <0.01). Comparing with the group of the squamous cell carcinoma, H2O2, MDA were higher in the tumor tissues of the group of adenocarcinoma (P <0.05 or P <0.01). There was less MnSOD mRNA and protein in tumor than in tumor-free lung. The contents of CuZnSOD mRNA and protein in tumor were less than those in tumor free lung tissue (P <0.01). CONCLUSIONS: The imbalance between the oxidants and antioxidants exists in the tissues of patients with lung cancer. The imbalance may have some relationship with the onset and development of lung cancer. PMID- 20719120 TI - [The clinical analysis of first-line palitaxel plus platinum-based chemotherapy to treat elderly non-small cell lung cancer.]. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) are more common in elderly people. The elderly patients are usually intolerable to platinum-based chemotherapy for other accompanying diseases. But many recent researches show the age factor is not the absolute contraindication. The aim of this study is to compare the toxic effects, disease progression time and overall survival time between advanced NSCLC patients 60 or older than 60 and younger than 60 who are administrated with palitaxel plus platinum-based agents. METHODS: One hundred and ninety two patients were retrospectively divided into two groups according to the age of 60. The regimen is palitaxel (175 mg per square meter on day 1) combined with cisplatin (75 mg per square meter on day1)/carboplatin (ar an area under the curve of 5 mg per millimeter per minute on day 1), 3-4 weeks per cycle. RESULTS: The respond rate in groups >=60 and <60 were 22.34% vs 24.49%, median time to progression were 4.1 months vs 4.4 months; median overall survival time were 11.8 months vs 12.4 months; one, two and three-year survival rate were 52.1% vs 54.1%, 19.1% vs 20.4%, 9.6% vs 11.2%, respectively, there are no statistical difference. The most common grade 3 or 4 adverse events between groups >=60 and <60 were neutropenia (21.27% and 16.32%, respectively), thrombocytopenia (4.26% and 2.04%), there were no statistical difference. Nonhaematologial toxicities are mild. CONCLUSIONS: Palitaxel plus platinum-based chemotherapy in elderly patients is effective and tolerable. PMID- 20719121 TI - [Simultaneous Surgical Treatment of Non-small Cell Lung Cancer and Off-pump Coronary Artery bypass Grafting.]. AB - BACKGROUND: Patients with resectable lung cancer and unstable coronary heart disease are at high risks of postoperative death or severe cardioovascular complications. They always pose a therapeutic challenge for thoracic surgeons. The aim of this study is to summarize clinical experience of radical lung resection for cancer with simultaneous off-pump coronary artery bypass grafting. METHODS: Seven patients who suffered from non small cell lung cancer concomitant arrhythmia, unstable angina and recent history of myocardial infarction had been carried out simultaneous radical lobectomy and off-pump coronary artery bypass grafting. Preoperative 6 patients had been confirmed to be misfit for either coronary arterioplasty or stent implanting by performing the coronary angiography. One patient had undergone stenting before the lung cancer had been diagnosed. The procedure through median sternotomy performed offpump coronary artery bypass grafting preceded lobectomy and mediastinal lymphadenectomy. Left upper lobectomy was performed in 2 patients, right upper lobectomy was performed in 1 patient, right upper and middle lobectomy was performed in one patient, video thoracoscopy assisted left lower lobectomy was performed in 1 patient, right lower lobectomy was performed in 2 patients. RESULTS: There was no death of patient in hospital, however, a patient died 7th month postoperatively because of cerebrovascular accident. Atrial fibrillation was observed postoperatively in 1 patient. Five patients were diagnosed as squamous cell lung cancer by pathology examination, and 2 patients were adenocarcinoma. Follow-up ranging from 2 months to 59 monthswas available for these patients postoperatively. None of the patients showed evidence of angina and myocardial infarction after surgery. In one patient, who underwent left superior lobectomy, local recurrence was found at 19 months after surgery. CONCLUSIONS: In selected patients, simultaneous radical lung resection and off-pump coronary artery bypass grafting is a safe and effective treatment when unstable coronary heart disease and lung cancer coexist. The therapeutic strategy may decrease the incidence of postoperative complications. PMID- 20719122 TI - [Advances of maintenance therapy on advanced non-small cell lung cancer.]. PMID- 20719123 TI - [Advances of peripheral blood micrometastases in non-small cell lung cancer.]. PMID- 20719124 TI - [New broncoscope techniques for the early diagnosis of central lung cancer.]. PMID- 20719125 TI - [Expression of Copper-Transporting P-Type Adenosine Triphosphatase (ATP7B) Correlates with Cisplatin-Resistance in Human Lung Adenocarcinoma Cell Line A549.]. AB - BACKGROUND: Cisplatin is the basic chemotherapy agent of lung carcinoma, and cisplatin-resistance mostly leads to the failing of chemotherapy in the patients. The aim of this study is to investigate the relationship between the expression of copper-transporting P-type adenosine triphosphatase (ATP7B) and cisplatinresistance in different cisplatin-resistant A549 cells. METHODS: Three differently cisplatin-resistant A549 sublines (A549/DDP0.5, A549/DDP1.0, A549/DDP2.0) were established from their parental human lung adenocarcinoma cell line A549 which was sensitive to cisplatin, by gradually increasing concentration of cisplatin. The resistance indexes of all the sublines were checked by MTT method. The levels of ATP7B mRNA and protein were measured by RT-PCR and Western Blot respectively in all the cell lines. RESULTS: The resistance indexes of the three cisplatin-resistant sublines were 1.7, 3.2 and 5.2 respectively (P <0.001), and the levels of ATP7B mRNA were 1.6, 4.9 and 10.1 folds compared to the parental A549 cells (P <0.001). Meanwhile, expression of ATP7B protein was enhanced in the three cisplatin-resistant sulines corresponding to their cisplatin-resistance. CONCLUSIONS: Expression of ATP7B correlates with cisplatin resistance in A549 cells, and maybe ATP7B contributes to acquisition of cisplatin resistance. PMID- 20719126 TI - [One Case Report of Thin-walled-cavity Lung Cancer Causing Pneumopericardium.]. PMID- 20719127 TI - [Advances of molecular etiology on lung cancer in non smokers.]. PMID- 20719128 TI - End of life experience of symptom cluster and their management in Hong Kong chinese patients with lung cancer who receive palliative radiotherapy. AB - Breathlessness, fatigue, and anxiety are distressing symptoms for patients with advanced lung cancer, however, they are not relieved by palliative RT and are often viewed as neglected areas of clinical practice. This paper aims to review definitions of, and explore patients' experiences of, breathlessness, fatigue, and anxiety. Further, it will outline existing approaches, both pharmacological and non-pharmacological, to treat them. Current treatments and perceptions of these symptoms will be discussed in the context of Hong Kong health care service. The review of literature also shows that breathlessness, fatigue and anxiety appears to have similar emotional origins. A contemporary approach of using a common pyschoeducational intervention to treat these symptoms together as a cluster in end of life care will be discussed. PMID- 20719129 TI - [Ablation of p120-Catenin Altering the Activity of Small GTPase in Human Lung Cancer Cells.]. AB - BACKGROUND: p120-catenin (p120(ctn)), a member of the Armadillo gene family, has emerged as an important modulator of small GTPase activities. Therefore, it plays novel roles in tumor malignant phenotype, such as invasion and metastasis, whose mechanism are not well clarified yet. The aim of this study is to explore the roles of p120ctn on the regulation of small GTP family members in lung cancer and the effects to lung cancer invasions and metastasis. METHODS: After p120(ctn) was knocked down by siRNA, in vivo and in vitro analysis was applied to investigate the role and possible mechanism of p120(ctn) in lung cancer, such as Western Blot, pull-down analysis, and nude mice models. RESULTS: p120(ctn) depletion inactivated RhoA, with the the activity of Cdc42 and Rac1 increased, the invasiveness of lung cancer cells was promoted both in vitro and in vivo. CONCLUSIONS: p120(ctn) gene knockdown enhances the metastasis of lung cancer cells, probably by altering expression of small GTPase, such as inactivation of RhoA and activation of Cdc42/Rac1. PMID- 20719130 TI - [The Expression and Significance of Annexin II in Lung Squamous Cell Cancer and Adenocarcinom.]. AB - BACKGROUND: Annexin II is a calcium-dependent phosphnolipid-binding protein that plays a role in many cellular functions. It has been proven that annexin II has been involved in many human cancers. The aim of this study is to examine the expression of annexin II in lung cancer tissues, and analyze the correlations between annexin II and clinicopathological parameters. METHODS: Annexin II expression was examined in 110 lung cancer specimens using immunohistochemistry (SP method). Western Blot was used to detect the expression of annexin II in lung cancer tissues and the corresponding normal lung tissues. RESULTS: Among 110 lung cancer specimens, 67 samples showed positive expression of annexin II (60.9%). It showed membranous staining in lung squamous cell carcinoma. The positive membranous expression and cytoplasmic expression of annexin II in lung adenocarcinoma mainly showed membranous staining. Annexin II expression level was positively correlated with lymphoid node metastasis (P =0.008) and TNM stages (P =0.002). There was expression of annexin II in both lung cancer tissues and the corresponding normal lung tissues, and in lung cancer tissues, the total levels of annexin II proteins were significantly higher than that in the corresponding normal lung tissues (P <0.001). CONCLUSIONS: The expression of annexin II positively may correlated with lung squamous cell carcinoma and adenocarcinoma development. PMID- 20719131 TI - [Meta Analysis of Association between Polymorphisms in Promoter Region of MMPs gene and Risk of Lung Cancer.]. AB - BACKGROUND: Lung cancer is one of the most common cancers worldwide, especially in China. It has been proved that matrix metalloproteases (MMPs) play a key role in malignant cell metastasis. There have been a considerable number of studies investigating MMP polymorphisms in relation to various cancers. However, the associations of MMP polymorphisms with risk of lung cancer are lack of consistency. The aim of this study is to assess the association of MMP polymorphisms with risk of lung cancer by conducting a Meta -analysis from all eligible casecontrol studies published to date. METHODS: To identify all studies that examined the association of polymorphisms in the promoter of MMP1, MMP2 and MMP9 with lung cancer, we conducted a computerized literature search of PubMed and MEDLINE database (before March, 2009). Two investigators independently extracted the data and reached a consensus on all items. RESULTS: Eight case control studies, including 4 467 lung cancer cases and 4 051 controls, were selected for Meta -analysis to better assess the purported associations of common MMPs polymorphisms with risk of lung cancer. Our results suggest that MMP2 735C/T polymorphism is significantly modified risk of lung cancer. Comparing with the wild -735C allele, the variant T allele decreased risk of developing lung cancer (OR=0.72, 95%CI: 0.61-0.85, P =0.0001). Other polymorphisms, including MMP1 -1607 1G/2G, MMP2 -1306C/T and MMP9 -1562C/T, are not associated with risk of lung cancer. CONCLUSIONS: The present study indicates that the MMP2 -735C/T polymorphism is associated with the risk of lung cancer. Lager studies should be required to warrant the association of MMP9 -1562C/T polymorphism with risk of lung cancer. PMID- 20719132 TI - [Prognostic Analysis of ERCC1, RRM1 and p53 Expressions in Postoperative Stage I II Lung Cancer.]. AB - BACKGROUND: Cisplatin is an important drug in lung cancer chemotherapy. It has been proven that ERCC1, RRM1, p53 expressions were related to resistance to platinum and prognosis of the patcents with lung cancer. The aim of this study is to analyze the association of the expression of ERCC1, RRM1, p53 with postoperative survival in patients with stage I-II non-small-cell lung cancer (NSCLC), and to explore the relationship between the expression of ERCC1, RRM1, p53 and resistance to cisplatin. METHODS: A total of 75 patients with stage I-II NSCLC receiving radical resection from Feb. 1992 to Jan. 1994 were followed up. Postoperative patients with stage I were randomized two groups (chemo and non chemo groups). All patients with stage II received adjuvant cisplatinbased chemotherapy. Immunohistochemical staining was used to detect the expression of ERCC1, RRM1, p53 in paraffinembedded specimens. RESULTS: In stage I NSCLC, the prognosis of the patients with high expression of ERCC1 (High-ERCC1) was better than those with low expression of ERCC1 (Low-ERCC1). 1, 3, 5-year survival rate in the patients with high expression of ERCC1 was 100.00%, 91.30%, 86.74% and in those with Low-ERCC1 was 96.43%, 60.71%, 57.14%, respectively (P =0.0058). The patients with High- ERCC1 had a better survival rate than those with Low-ERCC1 in stage I NSCLC without chemotherapy. MST in high and low expression of ERCC1 was 72.00(+) months and 64.67 months, respectively (P =0.0327). In contrary to stage I NSCLC, the patients with had a better survival rate than those with in stage II. MST was 60.00(+) months in stage II patients with low expression of ERCC1, but MST was only 25.50 months with (P =0.0442). The postoperative survival of NSCLC patients was not any statistical different between with high expression and low expression of RRM1 and p53. CONCLUSIONS: High expression of ERCC1 is a better independent prognostic factor in stage I NSCLC patients. Cisplatin-base chemotherapy prolongs survival in stage II NSCLC patients with. Adjuvant chemotherapy regimen is determined according to ERCC1 expression levels in resected NSCLC. PMID- 20719133 TI - [Expression of Integrins and Extracellular Matrix Proteins in Non-small Cell Lung Cancer: Correlation with Tumor Metastasis and Prognosis.]. AB - BACKGROUND: As invasion and metastasis of cancer seriously threaten human's life, it is of more important clinical significance to understand and evaluate the biologic behavior of cancer correctly. Abnormal expression of integrin and ECM proteins play an important role in invasion and metastasis of cancer. The objective of this study is to analyze the expression of the integrin alpha5, beta1 and ECM proteins in patients with NSCLC and its correlation with lymph node (LN) metastasis as well as prognosis, and to evaluate its roles in the metastasis of tumor. METHODS: The expression of integrin alpha5, beta1 and collagen type IV, fibronectin, tenascin was determined by immunohistochemistry. The relationship was analysized that between integrin alpha5, beta1 and ECM proteins expression and clinico-pathologic parameters especially LN metastasis and prognosis. RESULTS: The expression of collagen type IV was negatively correlated with LN metastasis, and positively to prognosis of patients; The expression of integrin alpha5, beta1 was positively correlated with LN metastasis, and integrin alpha5 was negatively to prognosis of patients. The expression of integrin alpha5 was positively correlated with the expression of integrin beta1, and negatively with the expression of collagen type IV. The expression of collagen type IV in stage I disease P-TNM stage was remarkably higher than that in stage III disease and poordifferentiated disease (P <0.001), but integrin alpha5, beta1 was significantly higher than that in stage III disease and poordifferentiated disease. CONCLUSIONS: Increased expression of integrin alpha5, beta1 and decreased expression of ECM significantly correlated with LN metastasis of NSCLC. Integrin alpha5 and collagen type IV are prognosic factors in patients with NSCLC. PMID- 20719134 TI - [Effects of Expression of ERCC1, RRM1 on Survival Trend of Lung Cancer with Cisplatin Combine Gemcitabine Chemotherapy after Surgical Resection.]. AB - BACKGROUND: It has been proved that the chemotherapy respouse was related to the expression levels of tumor genes in lung cancer. The aim of this study was to explor the relationship of ERCC1, RRM1 expression and the benefits from postoperative cisplatin combined with gemcitabine (GP) chemotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: All 57 postoperative patients with stage II-IV NSCLC were entered into the study, and 39 cases of patients were at least received 2 cycles of cisplatin combind with gemcitabine chemotherapy, 18 cases with no chemotherapy. Immunohistochemistry was performed in paraffin embedded tumor specimens to investigate ERCC1, RRM1 expression. Cox proportional regression analysis was used to screen independent prognostic risk factors for survival. Comparisons of the median survival time among groups were based on Kaplan-Meier analysis. RESULTS: Cox regression analyses showed that the extent of tumor resection, chemotherapy after surgical resection and expressions of ERCC1 were independent prognostic factors. In the group of high expression of ERCC1, the median survival time of postoperative chemotherapy patients and control were 42 and 12 months respectively (P =0.018). In the group with low expression of ERCC1, the median survival time of postoperative chemotherapy patients and control were 23 and 21 months respectively (P =0.088). However, In the group of high expression of RRM1, the median survival time of postoperative chemotherapy patients and control were 28 and 21 months respectively (P =0.092). In the group with low expression of RRM1, the median survival time of postoperative chemotherapy patients and control were 42 and 22 months respectively (P =0.010). CONCLUSIONS: The NSCLC patients with high expression of ERCC1 and low expression of RRM1 get more probablely benefits from postoperative cisplatin combine gemcitabine chemotherapy. PMID- 20719135 TI - [Cryosurgery Combined with Radioactive Seeds and Release-controlled Chemical Drugs Implantation for the Treatment of Lung Carcinoma.]. AB - BACKGROUND: It is very difficult for cryosurgery to ablate all tumors because of its large volume and irregular shape. It is a complementary method for chemo radioactive concurrent therapy to treat tumor remains. The aim of this study is to evaluate the application, security and effectiveness of Argon-Helium cryosurgery combined with radioactive seeds/release-controlled drugs implantation for percutaneous treatment of pulmonary neoplasma by CT guidance. METHODS: Lung cryosurgery and radioactive seeds and release-controlled drugs implantation were sequentially performed in 20 cases with 16 primary lung cancer and 4 secondary lung cancer. Side effects were observed during cryosurgery and seeds implantation. RESULTS: (3.4+/-0.2) cryoprobes were inserted into a nodule which is average (5.8+/-0.5) cm in diameter in 20 cases with 21 tumors. 85.6%+/-2.4% of tumor size had been ablated for each procedure. Haemoptysis occurred in 80% patients after cryosurgery, and disappeared in a week. Pneumothroax happened in 15% patients and recovered in a short time without special treatment. Absorption fever occurred in 20% patients and returned to normal in a week. (23.4+/-1.4) radioactive seeds and (8.3+/-1.2) drug-released drugs were percutaneously inserted into the 21 remaining tumors in a week after cryosurgery and 4 tumors (<2 cm in diameter) without cryosurgery. There were no severe side effects directly related to the procedures except 3 had slight nausea. The medium survive time was 16 months and average survive time was (14.0+/-2.6) months. More than 60% of patients survived more than 1 year. CONCLUSIONS: Cryosurgery is a rapid modality for the debulking of pulmoanry tumor and concurrent therapy of radioactive seeds and release-controlled drugs implantation could effectively treat the remaining tumor. It is a rapid and effective method for the treatment of advanced stage lung cancer. PMID- 20719136 TI - [Erlotinib in the Second/Third Line Treatment of Patients with Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: Erlotinib is a targeted drug for non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy, influencing factors and toxicity of erlotinib in patients with NSCLC. METHODS: Patients with NSCLC who had been previously treated with at least one course of platinum based chemotherapy received 150 mg oral doses of erlotinib once daily until disease progression. Response rate, progression free survival, overall survival and toxicity profile were analyzed. Kaplan-Meier methods was used to analyze the survival rate. Cox regression was used to define the predictive factors. RESULTS: Forty-eight patients were enrolled into the study from Dec, 2005 to Sep, 2006. We followed up these patients until 08.Dec.2008. Median follow up time was 30 months. The compliance rate was 100%. The median symptom improving time was 7 days. Partial response 33.4% (16/48), stable disease 22.9% (11/48), and progressive disease 43.7% (21/48). Response rate was 33.4% (16/48). Disease control rate was 56.3% (27/48). One and two-year progression-free survival rates and overall survival rates were 25%(events 36), 8.3% (events 40) and 43.8% (death 27), 20.8% (death 38); three-year overall survival 5.6%. The median progression free survival time and median overall survival time was 5 months and 8 months, respectively. Performance status was the only predictor for overall survival in the Cox model (P <0.001). Skin toxicity (grade 1 to 3) was found in 93.7% patients. One patient discontinued erlotinib because of perianal abscess. CONCLUSIONS: Erlotinib is another effective drug for patients with previously chemotherapy advanced NSCLC and accepted toxicity profile. PMID- 20719137 TI - [The Value of (18)F-FDG PET in Predicting the Prognosis of NSCLC.]. AB - BACKGROUND: (18)F-FDG PET has been widely applied in the diagnosis, treatment evaluation and following up of NSCLC. But the usefulness of PET in the prognosis predicting of NSCLC is uncertain. The purpose of the study is to investigate the value of (18)F-FDG PET in the prognosis of NSCLC. METHODS: The value of SUV of primary and metastasis lesions to the prognosis of NSCLC were analyzed. RESULTS: SUV of primary lesions, all the metastasis lesions and hilar and/or mediastinal metastatic lymphnodes were (6.3+/-3.2), (4.3+/-3.1) and (4.6+/-3.4) respectively. Overall survival (OS) of patients whose SUV of primary lesions>= 7 and< 7 ones were 26.1 and 38.7 months (P =0.02). OS of patients whose SUV of lymphnodes metastasis>= 5 and< 5 ones were 17.0 and 28.9 months (P <0.001). Kaplen-Meier survival analysis revealed that SUV of primary lesions>= 7, SUV of lymphnodes metastasis>= 5, cancer stage, pathological status of tumor, differentiation of tumor, receiving surgery or not, numbers of organs that had metastasis, lymphnodes metastasis positive or not in PET scan, bone metastasis positive or not in PET scan were prognostic factors of NSCLC. Multivariate analysis suggested that tumor metastasis positive or not at PET scan, receiving surgery or not and the differentiation status was well-differentiated or not are independent prognostic factors of NSCLC patients. CONCLUSIONS: SUV of primary lesions and hilar and/or mediastinal lymphnodes in newly diagnosed NSCLC can be prognostic factors for NSCLC patients. PMID- 20719138 TI - [Application of Flexi-rigid Thoracoscopy Under Local Anesthesia to Diagnose Malignant Pleural Effusion.]. PMID- 20719139 TI - [Correlation between the Quantifiable Parameters of Whole Solitary Pulmonary Nodules Perfusion Imaging Derived with Dynamic CT and Nodules Size.]. AB - BACKGROUND: The solitary pulmonary nodules (SPNs) is one of the most common findings on chest radiographs. The blood flow patterns of the biggest single SPNs level has been studied. This assessment may be only a limited sample of the entire region of interest (ROI) and is unrepresentative of the SPNs as a volume. Ideally, SPNs volume perfusion should be measured. The aim of this study is to evaluate the correlation between the quantifiable parameters of SPNs volume perfusion imaging derived with 16-slice spiral CT and 64-slice spiral CT and nodules size. METHODS: Sixty-five patients with SPNs (diameter<=3 cm; 42 malignant; 12 active inflammatory; 11 benign) underwent multi-location dynamic contrast material-enhanced serial CT scanning mode with stable table were performed; The mean values of valid sections were calculated, as the quantifiable parameters of volume SPNs perfusion imaging derived with 16-slice spiral CT and 64-slice spiral CT. The correlation between the quantifiable parameters of SPNs volume perfusion imaging derived with 16-slice spiral CT and 64-slice spiral CT and nodules size were assessed by means of linear regression analysis. RESULTS: No significant correlations were found between the nodules size and each of the peak height (PHSPN) (32.15 Hu+/-14.55 Hu),ratio of peak height of the SPN to that of the aorta (SPN-to-A ratio) (13.20+/-6.18)%, perfusion (PSPN) (29.79+/-19.12) mLmin(-1)100 g(-1) and mean transit time (12.95+/-6.53) s (r =0.081, P =0.419; r =0.089, P =0.487; r =0.167, P =0.077; r =0.023, P =0.880). CONCLUSIONS: No significant correlations were found between the quantifiable parameters of SPNs volume perfusion imaging derived with 16-slice spiral CT and 64-slice spiral CT and nodules size. PMID- 20719140 TI - [Surgical Treatment for Non-small-cell Lung Cancer in Patients over 70 Years Old.]. PMID- 20719141 TI - [Gefitinib in Advanced Non-small-cell Lung Cancer.]. PMID- 20719142 TI - [Detection of markers for lymph nodes metastasis in lung cancer.]. PMID- 20719143 TI - [Advances in sputum cytological test for the diagnosis of lung cancer.]. PMID- 20719144 TI - [Advances in lung cancer immunotherapy.]. PMID- 20719145 TI - [Advance in the detection of circulating tumour cells in patients with lung cancer.]. PMID- 20719146 TI - [Endostar Combined GC in the Treatment of Advanced Non-small Cell Lung Cancer.]. PMID- 20719147 TI - [Analysis of differential gel electrophoresis of paclitaxol resistant and sensitive lung adenocarcinoma cells' secretome.]. AB - BACKGROUND: Paclitaxol (PTX) resistance is one of main factors which affect the outcome of chemotherapy of lung adenocarcinoma. The aim of this study is to compare the secreted protein expression profiles between Paclitaxol (PTX) resistant and sensitive lung adenocarcinoma cells by proteomic research method, so as to provide evidence of choosing individual chemotherapy drugs in clinical treatment. METHODS: Total secreted proteins extracted from a PTX sensitive cell line A549 and a PTX resistant cell line A549-Taxol were separated by fluorscent differential gel electrophoresis (DIGE). High quality 2-DE profiles were obtained and analyzed by Decyder 6.5 analysis software to screen differentially expressed protein spots. Those spots were identified by mass spectrometry. RESULTS: 2-DE patterns of lung adenocarcinoma cells with high-resolution and reproducibility were obtained. 76 significantly differentially expressed protein spots were screened, 19 proteins were identified by mass spectrometry. The identified proteins could be classified into different catogories: metabolic enzyme, extracellular matrix (ECM) degradation enzyme, cytokine, signal transducer, cell adhesion, and so on. CONCLUSIONS: Multiple secreted proteins related to chemoresistance of A549-Taxol cells were identified in this study for the first time. The results presented here would provide clues to identify new serologic chemoresistant biomarkers of NSCLC. PMID- 20719148 TI - [P120-catenin Isoforms 1A and 3A Differently Affect the Expression of E-cadherin and beta-catenin in Lung Cancer Cells.]. AB - BACKGROUND: Different isoforms of p120-catenin (p120(ctn)), the members of catenin family, are variably expressed in different tissues and cells. These isoforms may confer different properties with respect to cell adhesion and migration, but this concept needs experimental evidence. METHODS: To more precisely define their biological roles, we stably transfected isoforms 1A and 3A into the lung cancer cell lines A549 and NCI-H460, which had low expression of p120(ctn). Using RT-PCR, Western Blot, and Transwell, we testified their impact on the expression of E-cadherin, beta-catenin, and the invasiveness of lung cancer cells. RESULTS: Expression of isoform 1A of p120(ctn) upregulated E cadherin and beta-catenin, as well as the ability of cells to invasion. In contrast, overexpression of isoform 3A had a smaller influence on invasion. CONCLUSIONS: P120(ctn) isoforms 1A and 3A may differently regulate the invasive, adhesive of lung cancer cells through distinct regulation of the expression of E cadherin and beta-catenin. PMID- 20719149 TI - [The Role of Matrine and Mitogen-Ativated Protein Kinase/Extracellular Signal Regulated Kinase Signal Transduction in the Inhibition of the Proliferation and Migration of Human Umbilical Veins Endothelial Cells Induced by Lung Cancer cells.]. AB - BACKGROUND: Matrine, one of the major alkaloid components of the traditional Chinese medicine Sophora roots, has a wide range of pharmacological effects including anti-inflammatory activities, growth inhibition and induction of cell differentiation and apoptosis. Motigen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) has found to be a crucial signaling pathway in endothelial cells. The aim of this study is to investigate the role of Matrine and MAPK/ERK signal transduction in the inhibition of the proliferation and migration of human umbilical veins endothelial cells (HUVECs) induced by lung cancer cells. METHODS: HUVECs were cultured with A549CM. Mat or PD98059 (i.e PD), specific inhibitor of MAPK/ERK, was added into the A549CM. The proliferation of the HUVECs was measured by cell counting. The migration of the HUVECs was observed by wound healing assay. The expression levels of ERK and p ERK protein were detected by Western Blot analysis. RESULTS: On 24 hours after intervention, the A549CM significantly stimulated the proliferation, migration and expression of p-ERK of HUVECs. Compared with the A549CM group, Mat significantly inhibited the proliferation, migration and p-ERK expression of HUVECs induced by A549CM. While PD only decreased the proliferation and p-ERK expression of HUVECs induced by A549CM. PD had no effect in the migration of HUVECs. CONCLUSIONS: The results demonstrated that Mat and PD98059 can effectively decrease proliferation and expression of p-ERK of HUVECs induced by A549CM. Furthermore Mat can also inhibit migration of HUVECs induced by A549CM that did not changed by PD98059. These data implied that suppressing MAPK/ERK signal transduction may play the crucial role in resisting lung cacinoma angiogenesis with Mat. PMID- 20719151 TI - [Effects of Methylation of FHIT Gene on it's Protein and mRNA Expression in Non small Cell Lung Cancer.]. AB - BACKGROUND: Fragile histidine triad (FHIT) is a new tumor suppressor gene, whose promoter methylation plays an important role in carcinogenesis. The aim of this study is to explore the effects of CpG island methylation on protein and mRNA expression of FHIT in non-small cell lung cancer, and the roles of FHIT gene in pathogenesis of NSCLC. METHODS: Methylation and protein expression and transcriptional level of FHIT gene were detected by methylationspecific PCR, Western Blot and RT-PCR in 52 tumor tissues and normal tissues of NSCLC. RESULTS: Methylation in the tumor samples was detected at 38.46%, whereas it occurred at lower frequencies (7.69%) in the corresponding normal lung tissues. Protein expression frequencies was 28.8% in the tumor samples, whereas it was 88.5% in the corresponding normal lung tissues. MRNA expression frequencies was 51.9% in the tumor samples and 100% in the corresponding normal lung tissues. CONCLUSIONS: In NSCLC, FHIT gene promoter methylation frequency was significantly increased with decreased expression, suggesting that FHIT promoter methylation plays a role in lung cancer carcinogenesis. PMID- 20719150 TI - [Establishment of a Novel Chinese Human Lung Adenocarcinoma Cell Line CPA-Yang1 which Produces Highly Bone Metastases in Immunodeficient Mice.]. AB - BACKGROUND: Lung cancer is a common malignancy and is the major determinant of overall cancer mortality worldwidely. Approximately 70% of lung cancer patients will die from metastatic diseases. The aim of this study is to establish a Chinese lung adenocarcinoma cell line with high metastasis potency for exploring the mechanism of occurrence and development in lung cancer. METHODS: The cell came from the pericardial effusion of a fifty-year old male patient with lung adenocarcinoma and the cells in primary culture were obtained successfully. Immunodeficient mice tumorigenicity was assayed. The cell growth curve was mappinged. Analysis of chromosome karyotype was tested. Tumor marker was detected by radioimmunoassay. The gene expression was measured by real-time quantitative PCR. RESULTS: The first passage cells were planted in immunodeficient mice subcutaneously and the tumorigenesis rate was 100% as well as later passages. Under the microscope, the cell showed larger and semi-suspension, semi-adherence. Approximately 0.8*10(6) cancerous cells were injected into left cardiac ventricle or tail vein of immunodeficient mice resulted start to appear lower limb paralysis and spine swelling deformation in the mice after inoculation two-three weeks. The bone metastasis rate was 90% in the tumor bearing mice by bone scintigraphy and pathology and only pulmonary metastasis 10% at the same time. The chromosome karyotype analysis of the cells was sub-triploid. The tumor marker CEA was detected in higher secretion by radioimmunoassay in the cell culture suspension. Quantitative real-time PCR was used to examined and compared SPC-A-1 lung adenocarcinoma, VEGF-C, IL-6, IL-8, genes were overexpressed. The novel cell line was named CPA-Yang1. CONCLUSIONS: Tne novel strain CPA-Yang1 is an parental cell with characteristics of bone metastasis of Chinese lung adenocarcinoma. It has stable traits, highly metastatic ability and a good experimental model for lung cancer research. PMID- 20719152 TI - [Analysis of Differentially Expressed Proteins in Self-Paired Sera of Advanced Non-small Cell Lung Cancer Patients Responsive to Gefinitib.]. AB - BACKGROUND: All the advanced NSCLC patients that received EGFR-TKI therapy will eventually relapse after a period of efficacy. The aim of this study is to investigate the serum biomarkers as potential predictive factors for the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in advanced non-small cell lung cancer. METHODS: Twenty self paired serum samples were collected from 9 advanced NSCLC patients that evaluated as disease control (SD or PR) after gefinitib therapy, at the time points of before and after gefinitib treatment but 2 weeks before being evaluated as disease progress. All samples were pre-separated by WCX microbeads, and then detected on the MALDI-TOF-MS platform of Bruker Autoflex. ClinProTools (Version: 2.1) was used to analyze the differentially expressed proteins. RESULTS: There were 7 protein peaks (m/z), 3 242.09, 8 690.36, 2 952.64, 3 224.04, 1 450.51, 1 887.8 and 3 935.73 found statistically differentially expressed between the self paired samples. Three proteins (3 242.09, 2 952.64 and 3 224.04) were down regulated and four proteins (8 690.36, 1 450.51, 1 887.8 and 3 935.73) up regulated in gefinitib treated sera. CONCLUSIONS: The data here suggest that several specific protein peaks might indicate gefinitib resistance, yet the identities of these proteins and the mechanisms underlying the responsiveness to gefinitib treatment need further investigation. PMID- 20719153 TI - [The Correlation between CT Characteristics of Non-small Lung Cancer and the Performance of (18)F-FDG PET and the Expression of Glut1 Protein.]. AB - BACKGROUND: Glut1 is the main carrier which intervenes the glucose uptake of cell, and the expression of Glut1 was positively correlated to the uptake of FDG. The aim of this study is to select the CT characteristics and clinicopathological parameters which can reflect the levels of glucose metabolism of human non-small lung cancer (NSLC). METHODS: Thirty-three cases of the NSLC (squamous carcinoma 11 cases and adenocarcinoma 22 cases) have undergone the scanning of FDG PET/CT before operation. The tumor pathological classification, degree of differentiation and lymph node metastasis were collected. The CT characteristics which included the diameter, deep lobulation, thin and short spiculation, spinous protuberance, cavity sign, vessel convergence sign and pleural retraction sign were described. Tracer uptake of suspected lesions was assessed by visual assessment and quantitatively by the maximum standardized uptake values (SUVmax). The expression of Glut1 which were examined by means of SP immunohistochemical technique was also analyzed. RESULTS: The positive rate of Glut1 was 66.67% (squamous carcinoma was 90.91% and adenocarcinoma was 54.55%). The positive rate of Glut1 and SUVmax of squamous carcinoma were significant higher than adenocarcinoma (Pbilateral=0.037, Punilateral=0.045). Through visual assessment and SUVmax, the uptake and the positive rate of Glut1 which size >=2 cm were higher than the size <2 cm (Pbilateral=0.002, Pbilateral=0.001, Punilateral=0.049). The uptake intense of FDG was related to the thin and short spiculation through visual assessment (Pbilateral=0.006). CONCLUSIONS: The study suggested that the levels of glucose metabolism of squamous carcinoma higher than adenocarcinoma, the diameter upper than 2 cm and the thin and short speculation were higher. PMID- 20719154 TI - [Evaluation of Three-Dimensional Reconstruction CT in Percutaneous Radiofrequency Ablation (RFA) of the Unresectable Lung Tumor with a Clustered Electrode.]. AB - BACKGROUND: Radiofrequency ablation (RFA) of lung tumours has recently received much attention for the promising results achieved. Here, to evaluate the value of three-dimensional reconstruction CT in radiofrequency ablation (RFA) of advanced non-small cell lung cancer. METHODS: Sixty-six cases of advanced non-small cell lung cancer with 68 lesions (2 patients had 2 lesion treated in one session) were underwent three-dimensional reconstruction CT-giuded percutaneous RFA therapy. To evaluate short-term therapeutic effect of lung tumors using spiral CT scanning in 1-3 months after RFA to investigate the alterations of tumor size and density pre and post-procedure, and complications, to observe the short-term curative effect. RESULTS: Our experiences have shown an initial increase in lesion size at immediate follow-up CT. The density of 64 lesions was lowered (94.1%) and 4 lesion is increased (5.9%) at immediate and one month follow-up CT. SPECT scan findings that 82.4% (56/68) cases of FDG uptake in tumors after RFA with tumor/non-tumor of lower than 2.5 at one month follow-up. The change in treated lesion size over time, radiologically assessed through measurements of the lesions on axial CT scans in the lung window setting no lesions had complete response, 50 lesions (73.5%) had partial response, 2 lesions with stable disease, 6 lesions showed progressive disease at 3 month follow-up CT. SPECT scan findings that 79.4% (54/68) cases of FDG uptake in tumors after RFA with tumor/non-tumor of lower than 2.5 at 3 month follow-up. CONCLUSIONS: The percutaneous RFA therapy under the guidance of three-dimensional reconstruction CT scan is safe and effective, with few complications, and can serve as a new method to the treatment of advanced non-small cell lung cancers. PMID- 20719155 TI - [Clinical observation on the target therapy of rh-endostin, combined with chemotherapy in advanced non-small cell lung cancer.]. AB - BACKGROUND: The chemotherapy of advanced non-small cell lung cancer is in a Bottleneck. The target therapy of Anti-angiogenesis gradually shows an advantage in the therapy of patients with advanced NSCLC. To investigate the short-term efficacy, safety and the quality of life of the target therapy of rh-Endostin combined with chemotherapy in patients with advanced NSCLC. METHODS: Sixty-two advanced NSCLC patients were randomly divided into either the trial group with chemotherapy plus rh-Endostin or control group with chemotherapy alone. The efficacy and toxicity were evaluated after 2 cycles according to RECIST criteria. RESULTS: The trial groups efficiency rate was 46.87%, while the control group was 26.66%, there was no significant differences of two groups (Chi-square=1.912, P=0.166). The clinical benefit rate was 81.25% in the trial group and 53.33% in control group. There was significant difference of the clinical benefit rate between the trial group and the control group (Chi-square=4.3185, P=0.0377). The score of quality of life in the trial group was significantly higher than that the control group after the treatment (Chi-square=11.233, P=0.0008). There was no significant difference of incidence of toxicities between the trial group and the control group (P>0.05). CONCLUSIONS: Rh-Endostin combined with chemotherapy was effective, reasonable, safe and well tolerated for advanced NSCLC. PMID- 20719156 TI - [Expression and Clinical Significance of Heparanase and Ki-67 in Non-small Cell Lung Cancer.]. AB - BACKGROUND: It has been proven that heparanase and Ki-67 had relationship with occurrence and metastasis in lung cancer. The aim of this work was to investigate the expressions of heparanase and Ki-67 and to explore their clinical significance and mutual relations in non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical method was used to detect the heparanase and Ki-67expression in the routinely paraffin-embedded sections of surgical specimen of 70 cases with NSCLC and 20 ones with normal lung tissues. RESULTS: Heparanase and Ki-67 were highly expressed in lung cancer tissues (72.9% and 85.7%) while negative in epithelia of normal lung tissues. The expression of heparanase was significantly correlated with TNM stage (P=0.044) and lymphatic metastasis (P=0.001). The expression of Ki-67 was significantly correlated with tumor size (P=0.03) and histology type (P=0.001) and differentiation (P=0.01) and lymphatic metastasis (P=0.01) and TNM stage (P=0.043). The expression of heparanase and Ki-67 was no significant difference (P=0.323). CONCLUSIONS: Heparanase and Ki-67 were involved in the occurrence and development of lung cancer and they may predict patients prognosis, while the expression of heparanase and Ki-67 had no association with NSCLC, which may contribute to the different mechanisms involved in tumor occurrence and development. PMID- 20719157 TI - [Clinical Observation of Erlotinib in the Treatment of Elderly Patients with Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: About 80% lung cancer is non-small cell lung cancer (NSCLC) and more than 70% are in advanced stage. The aim of this study is to evaluate the clinical efficacy and the side effects of erlotinib in the treatment of elderly patients with advanced non-small cell lung cancer. METHODS: Twenty-nine patients with advanced non-small cell lung cancer were treated with erlotinib 150 mg/d, then the adverse reaction and clinical efficacy were recorded during 3 months. RESULTS: Total 29 patients were evaluated for efficacy. The total rate of effect was 20.69%, including 1 case CR, 5 cases PR, 9 cases SD and 14 cases PD. We compared the effective rate of stage III with IV. There were no significant difference between the effective rate of stage III and IV (P=0.337). The main side effects were rash (37.93%), diarrhea (17.24%) and vomiting (6.9%) and most side effects were grade I and II. CONCLUSIONS: Erlotinib for elderly patients with advanced non-small cell lung cancer have better effective and less toxic effects and the further clinical study should be warranted. PMID- 20719158 TI - [Genome wide association study on lung cancer.]. PMID- 20719159 TI - [The Advances of Anti-angiogenesis and Normalization of Tumor Vasculature.]. PMID- 20719160 TI - [The principles and methods in surgical treatment of lung cancer patients with lymph node dissection.]. PMID- 20719161 TI - [Application of RNAi Technology in Cancer Therapy.]. PMID- 20719162 TI - [Research Advance on the Role of IGF Network in Non-small Cell Lung Cancer.]. PMID- 20719163 TI - [Targeted therapy for advanced non-small cell lung cancer in the elderly.]. PMID- 20719164 TI - [Pulmonary injury of commonly used antineoplastic drug.]. PMID- 20719166 TI - [Combined lung large cell and sarcomatoid carcinoma.]. PMID- 20719165 TI - [Combined Bronchoscopic Interventions with Percutaneous Implantations of Radioactive Seeds & Release-controlled Chemical Drugs for Treatment of Patients with Papillary Thyroid Carcinoma and Invasion of Trachea.]. PMID- 20719167 TI - Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer. AB - The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC) patients. CYP3A4(*)16B polymorphism was associated with decreased metabolism of irrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN 38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1(*)28 and UGT1A1(*)6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin) are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinucleotide repeat (CA-SSR) showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR promoter activity. EGFR gene mutations and polymorphisms were also associated with EGFR kinase inhibitors response and toxicity. PMID- 20719168 TI - [Antiangiogenic Effect of Oyster Polypeptide (OPP).]. AB - BACKGROUND: Drugs which block tumor angiogenesis will be likely effective towards inhibiting tumor growth for angiogenesis being a prerequisite for tumor growth and metastasis. Therefore, antiangiogenesis has become a promising strategy for the treatment of cancer. Investigation on both antiangiogenic effect and mechanism(s) of oyster polypeptide (OPP) were performed via experiments of chicken embryos model in vivo and human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: The methods employed in experiment were chorioallantoic membrane (CAM) angiogenesis in chicken embryos in vivo, MTT cell survival assay, flat plate scarification, transwell plates assay, matrigel-induced tube formation assay and transmission electron microscope et al. and the OPP's effects on angiogenesis was observed. RESULTS: Study showed that treatment with OPP resulted in significant inhibition of chorioallantoic membrane (CAM) angiogenesis in chicken embryos. MTT cell survival assay showed that treatment with OPP resulted in strong inhibition of HUVECs growth, with an IC50 of 400 mug/mL. Flat plate scarification suggested that OPP (200 mug/mL, 400 mug/mL and 800 mug/mL) distinctly inhibited HUVECs' migration (18.75%, 37.93%, 74.07% respectively, treatment for 12 h). Treatment with OPP of different concentrations (200 mug/mL, 400 mug/mL and 800 mug/mL) significantly reduced the density of the migration cells by 15.5%, 37.2% and 67.24% (P<0.05) respectively. Matrigel-induced tube formation assay showed that OPP resulted in striking inhibition of tube formation of 52.43%, 84.47% and 96.12% (P<0.01) at 200 mug/mL, 400 mug/mL and 800 mug/mL (treatment for 10 h) respectively. In addition, the apoptotic analysis by transmission electron microscope showed that OPP (400 mug/mL, treatment for 48 h) distinctly induced HUVECs' apoptosis. CONCLUSIONS: This study strikingly showed that OPP could inhibit angiogenesis through its effects on vascular endothelial cells directly and the inhibition of their proliferation, migration, angiogenic ability, and induction of their apoptosis might be the antiangiogenic mechanism of OPP. PMID- 20719169 TI - [The Relationship between the Status of Human Papillomavirus 16/18 Infection and the Expression of Bcl-2 and Bax in Squamous Cell Carcinomas of the Lung.]. AB - BACKGROUND: The relationship between the virus and carcinomas has attracted attention and China may be highly infected-District with HPV. It was unclear that whether there has been HPV infection in squamous cell carcinomas and the occurrence and development of lung cancer has the relation with HPV. This experiment applied situ hybridization and immunohistochemical techniques. This study is to investigate the relationship between the status of HPV16/18 infection between the expression of Bcl-2 and Bax in squamous cell carcinomas of the lung. METHODS: In 44 patients with squamous cell carcinomas of the lung, HPV 16/18 DNA was examined by in situ hybridization, expression of Bcl-2 and Bax was revealed by immunohistochemistry and koilocytes was detected in carcinomas tissues by morphologic examination. RESULTS: Of 44 patients with squamous cell carcinomas of the lung, 12 (27.27%) were found to be HPV negative. Twenty-three (52.27%) were found to be integrated form HPV, 9 (20.45%) were found to be large number of episomal form and a few integrated form HPV. And no simplex episomal form HPV was found. HPV 16/18 DNA could not be detected in 15 non-carcinomas tissues. A significantly higher 16/18 DNA positive rates in carcinomas tissues compared to non-carcinomas tissues (P<0.001). Of 44 patients, 20 (45.5%) were found to be Bcl 2 positive. There were significantly difference between integrated and other form HPV 16/18 in expression of Bcl-2 (P<0.05). CONCLUSIONS: HPV infection might be a particular agent in patient with squamous cell carcinomas of the lung. The levels of expression of Bcl-2 were significant higher in HPV positive patients than patients with HPV negative or episomal form HPV in squamous cell carcinomas of the lung. PMID- 20719170 TI - [The Expression Status of 11 Genes, Located at the Commonly Deleted Region 3p21.3, in Non-small Cell Lung Cancer.]. AB - BACKGROUND: The deletion of allele located at 3p21.3 region is found in 50%-80% of nonsmall cell lung cancer (NSCLC), suggesting that this region might harbor some tumor suppressor genes (TSGs). It is anticipated that some TSGs closely related to NSCLC carcinogenesis might be found by screening the expression of genes, located at the commonly deleted region 3p21.3, in NSCLC. METHODS: Semi quantitative reverse transcription-polymerase chain reaction (RT-PCR) and related statistical analysis were applied to examine the expression status of 11 genes closely related to tumor selected from 3p21.3 by bioinformatics in 16 NSCLC biopsies. RESULTS: No expression or down-regulation of RASSF1A, GNAT1, SEMA3B, SEMA3F, Blu were observed in 43.8% (7/16), 37.5% (6/16), 62.5% (10/16), 50% (8/16), 56.3% (9/16) respectively, in NSCLC tissues (P<0.05). No difference was found in another six genes (ZNF35, NPRL2, LTF, AUXD1, BAP1 and FUS1) from 11 genes in NSCLC and matched tumor-adjacent normal tissues. CONCLUSIONS: Several genes identified from 3p21.3 may play a certain role in NSCLC carcinogenesis. PMID- 20719171 TI - [The Expression and Biological Significance of PD-L1 on Lung Cancer Cell Lines.]. AB - BACKGROUND: Tumor-associated PD-L1 expression was recently shown to promote T cell apoptosis and proposed as a potential mechanism of immune evasion by tumors. On the basis of the ability of tumor-associated PD-L1 to mediate activated T-cell death, it is likely that manipulation of the PD-L1 pathway at defined time points during the development of the T-cell antitumor immune response can enhance the efficacy of T-cell-based immunotherapy. Here, the levels of expression of PD-L1 on lung cancer cell lines and its role in interaction of CTL and target cells was investigated. METHODS: Human PBMC derived DCs were loaded with apoptotic tumor cells and stimulated by CD40 mAb (5C11). Tumor specific CTL was generated in vitro by autologous T cells co-cultured with mature DCs. Expression of PD-L1 on lung cancer cell lines H1299 and A549 were analyzed by FCM. JAM assay was used to detect the cytolytic activity of CTL with or without blocking PD-L1 by PD-L1 mAb respectively. The concentrations of IFN-gamma in supernatants from distinct groups were analyzed by ELISA. RESULTS: Tumor cells-loaded mature DCs could induce the generation of the tumor specific CTL. Expression of PD-L1 was low on A549 cell, but high on H1299 cell. Blockade of PD-L1 on A549 could not improve cytolytic effect of CTL on target cells and IFN-gamma production, but fragmentation of H1299 cells and IFN-gamma production were significantly enhanced by the combination of PD-L1 mAb and CTL. CONCLUSIONS: Expression of PD-L1 on lung cancer cell line can decrease the cytolytic effect of CTL on target cells. PMID- 20719172 TI - Heparanase expression correlates with angiogenesis and lymphangiogenesis in human lung cancer. AB - BACKGROUND: Heparanase has been thought to be a good molecular marker of tumor, and the heparanase expression level was correlated closely with tumor metastasis. In this study, we investigate the effects of heparanase on angiogenesis and lymphangiogenesis of lung cancer and the relationship between heparanase expression and vascular endothelial growth factor (VEGF), vascular endothelial growth factor-C (VEGF-C). METHODS: Immunohistochemistry was used to detect the expression of heparanase, VEGF, VEGF-C protein and microvascular density (MVD), lymphatic vessel density (LVD) in 115 cases of non-small cell lung cancer (NSCLC) and 45 cases of adjacent normal tissue samples. RESULTS: Our results showed that heparanase expression was significantly increased in 91 (79.13%) of the 115 cases and correlated with lymph node metastasis (node positive rate 87.0%; node negative rate 36.8%; P=0.003). Heparanase positive expression cases have significantly higher concentration of microvascular density (MVD) and lymphatic vessel density (LVD) as compared with heparanase negative expression cases (P<0.01, P<0.01, respectively), heparanase expression was significantly correlated with VEGF, VEGF-C expression in NSCLC. CONCLUSIONS: Heparanase overexpression was associated with angiogenesis and lymphangiogenesis of lung cancer, targeting of heparanase may represent a significant therapeutic potential for lung cancer. PMID- 20719173 TI - [A Meta-analysis of Platinum Plus Taxanes Regimen on Treating Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: The platinum-based plus a third-generation agent doublet chemotherapy regimen has been recommended as the standard first-line chemotherapy for advanced NSCLC by ASCO and NCCN. This study was aimed to evaluate the clinical efficacy and side effects of the Platinum plus Taxanes or other novel agent. METHODS: The databases PubMed, CENTRAL, EMBASE and Chinese Biomedical Literature database were retrieved by using the key words "non small cell lung cancer" or "Carcinoma, Non Small Cell Lung" so as to search the studies about the randomized controlled clinical trials, which compared Platinum plus Taxanes with Platinum plus other novel agents. A meta-analysis was conducted and the quality scores were evaluated according to the improved Jadad's score. RESULTS: Nine randomized controlled clinical trials with 4 703 patients were included. The overall response rate and 1 year survival rate of the two groups were not significantly different (RR=1.00, 95%CI: 0.91-1.11, P=0.95; RR=0.98, 95%CI: 0.84-1.15, P=0.83). The incidence rate of grade 3-4 leukopenia, neutropenia, anemia, nausea and vomiting in TP is much lower than that in platinum plus other novel agent. Sub-group analysis showed that the overall response rate and 1 year survival rate of TP aren't statistically different from NP or GP. The incidence rate of grade 3-4 leukopenia, neutropenia and anemia in TP is statistically lower than that in NP. The incidence rate of grade 3-4 anemia and thrombocytopenia in TP is statistically lower than that in GP. CONCLUSIONS: The clinical efficacy of TP and platinum plus other novel agent is quite similar, but quite different from each other in side effects, which provides important evidence on selecting individual chemotherapy regimen. PMID- 20719174 TI - [Expression and Clinical Significance of ABCC10 in the Patients with Non-small Cell Lung Cancer.]. AB - BACKGROUND: Multidrug resistance (MDR) is the main reason of the failure of chemotherapy in lung cancer. The MDR mechanism in lung cancer is complex, which relates to sorts of drug resistant genes. ABCC10 is a recently identified member of a subset of the C family of ATP-binding cassette (ABC) transporters. The drug resistance capability of ABCC10 has been partly determined. The aim of the study is to investigate the expression of ABCC10 in non small cell lung cancer (NSCLC) and normal tissues, and analyze the relationship between ABCC10 expression level and clinical features, such as TNM stages, histological types and pathological grades. METHODS: The expression of ABCC10 was detected in squamous cell carcinoma, adenocarcinoma and normal lung tissues by immunohistochemistry. Then the statistical analysis was performed. RESULTS: The expression of ABCC10 was mainly located in cell membrane and cytoplasm. There were significant differences between the expression of ABCC10 in NSCLC and normal tissues (P<0.01). The positive rates in squamous cell carcinoma and adenocarcinoma were 73.26% and 81.16%, respectively with significant differences (P<0.05). There were significant differences among histological grades in squamous cell carcinoma (P<0.01). There were significant differences among histological grades and TNM stages respectively in adenocarcinoma (P<0.01). CONCLUSIONS: ABCC10 is overexpressed in NSCLC. The expression of ABCC10 in adenocarcinoma is higher than that in squamous cell carcinoma. The expression in adenocarcinoma is correlated to pathological grades and TNM stages. The results of this study would be benefit for further study of ABCC10 in tumor and its chemoresistance. PMID- 20719175 TI - [The Study on Gene Amplification of EGFR in Bronchioloalveolar Carcinoma and Conventional Adenocarcinoma of the Lung.]. AB - BACKGROUND: Patients with adenocarcinoma of the lung have disproportionately response to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). The aim of this study is to analyze the difference of EGFR gene amplification in bronchioloalveolar carcinoma (BAC), adenocarcinma mixed subtype and conventional adenocarcinoma of the lung and provide some information to clinical therapies. METHODS: Lung cancer cases were collected and reviewed from the archives of the Department of Pathology, Chinese PLA General Hospital during the time period from 2004 to 2006. The definite diagnosis of BAC based on 2004 WHO classification of lung tumors was made by two pathologists. Fluorescence in situ hybridization (FISH) was performed to detect EGFR gene amplification in pure BAC, adenocarcinma mixed subtype and conventional adenocarcinoma. RESULTS: Conventional adenocarcinoma had higher EGFR amplification compared with pure BAC and adenocarcinma mixed subtype (Chi-square=11.632, P<0.05). EGFR gene amplification was found in 45.45% of conventional adenocarcinoma, 14.81% in pure BACs, and 22.58% in adenocarcinma mixed subtype. EGFR gene amplification was observed as scattered signals in most cases. CONCLUSIONS: EGFR gene amplification was seen more frequently in the invasive components than in BAC. EGFR gene amplification might be associated with the development of adenocarcinoma of the lung. PMID- 20719176 TI - [Irinotecan/cisplatin versus Etoposide/cisplatin for Patients with Extensive Stage Small Cell Lung Cancer: A Systematic Review.]. AB - BACKGROUND: It is unclear whether etoposide/cisplatin (EP) regimen is the optimal chemotherapy regimen in the treatment patients with extensive small cell lung cancer (SCLC), this study was aimed to evaluate the efficacy and safety of patients with extensive SCLC treated with irinotecan/cisplatin (IP) versus EP. METHODS: We searched EMBASE, PubMed, the Cochrane Library, China journal full text database (CJFD), Chinese scientific journal full-text database (CSJD), Chinese biomedicine literature database (CBM) for randomized controlled trials comparing IP with EP regimens. Two reviewers independently assessed the quality of included studies and extracted data. We analyzed the data using Review Manager (version 5.0). RESULTS: Four randomized controlled trials totaling 1 180 patients were included. The results of meta analysis were as follows: there was no significant difference between IP regimen and EP regimens in one year survive rate (RR=1.22, 95%CI: 0.97-1.54), two year survive rate (RR=2.26, 95%CI: 0.46 11.21). There was significant difference between IP regimen and EP regimens in overall response rate (RR=1.13, 95%CI: 1.03-1.25), grade 3/4 neutropenia (RR=0.48, 95%CI: 0.34-0.69), thrombopenia (RR=0.23, 95%CI: 0.15-0.36), grade 3 anemia (RR=0.55, 95%CI: 0.40-0.77), grade 3/4 diarrhea (RR=9.56, 95%CI: 4.91 18.59), grade 3 nausea/vomiting (RR=1.70, 95%CI: 1.19-2.43). CONCLUSIONS: There is no significant difference between IP group and EP group with regard to one year survive rate, two year survive rate, but IP regimen improves reponse rate. IP regimen has less hematologic & greater gastrointestinal toxicity compared with EP, EP regimen remain the main standard chemotherapy in the treatment extensive small cell lung cancer due to cheapness, they still need to be confirmed by randomized controlled trials. PMID- 20719177 TI - [Clinicopathological Research and Expression of PTEN/PI3K/Akt Signaling Pathway in Non-small Cell Lung Cancer.]. AB - BACKGROUND: It has been known that abnormality of PTEN/PI3K/Akt signal pathway played an important role in initiation of some malignant tumors. The aim of this study is to examine the expression and clinicopathological significance of PTEN, PI3K and Akt in non-small cell lung cancer (NSCLC). METHODS: Expression levels of PTEN, PI3K and Akt protein were determined using immunohistochemistry S-P in 61 specimens of NSCLC with follow-up. RESULTS: (1)The levels of PTEN protein was higher than that of control group, and levels of PI3K and Akt protein were lower than that of control group; (2)Expression of PTEN and PI3K were related to histotype, clinical stage, lymphonode metastasis and survival rate; Expression of Akt was related to clinical stage, lymphonode metastasis and survival rate; (3)The Cox Monovariable Analyses revealed that both smoking and negative expression of PTEN were the risking factors on the death of the NSCLC patients after surgery; (4)The expression of PTEN protein was negatively correlated to that of PI3K and Akt respectively, while the expression of PI3K was positively correlated to that of Akt. CONCLUSIONS: In NSCLC, the lack of PTEN induced up regulation of PI3K and Akt, which demonstrated that PTEN/PI3K/Akt signaling pathway contributed to the tumorigenesis and development of NSCLC. They could be used as the indicators of prognosis and targets of therapy. PMID- 20719178 TI - [The Clinical Applications of Combined HBV Approach to Chemotherapy for Non-small Cell Lung Cancer while Adoption of Antivirus Therapy.]. AB - BACKGROUND: Lung cancer has become the most serious malignant tumor threating the human beings' health and life, and chemotherapy postponing or suspending contributes to one of the prognostic causes. In this research, we try to explore the importance of combined HBV approach to chemotherapy for non-small cell lung cancer while adoption of antivirus therapy. METHODS: Select 60 cases of patients suffering from combined HBV IIIA non-small cell lung cancer, who were divided into two groups, the experimental group and control group. For the experimental group, a NP-approach chemotherapy was adopted along with addition of Lamivudine (NP+Lam group), while for the control group, only NP-approach was applied (NP group), in order to compare whether there would be any statistical difference between the two groups in terms of damage to the functions of liver and immune system as well as reactivation of HBV. RESULTS: The blood serum of the patients from both of the two groups rises, with the NP group being prominently higher than the NP+Lam group on an average (P<0.05). Upon completion of the chemotherapy, the percentage of CD3(+)/CD4(+) and CD4(+)/ CD8(+) decreases. As the percentage of CD8(+) increases, the differences in these items turn out to be marked (P<0.05). The reactivation of HBV and postponing or suspending of the chemotherapy are also find prominently different (P<0.05). CONCLUSIONS: It is necessary to use antiviral therapy while the patents with combined non-small cell lung cancer receive therapy. PMID- 20719179 TI - [Brain radiotherapy combined with sequential chemotherapy in non-small-cell lung cancer patients with brain metastases.]. AB - BACKGROUND: Brain irradiation is the traditional treatment for NSCLC patients with brain metastases, whereas combined with chemotherapy is the nowadays treatment direction. Since sequential/maintenance chemotherapy has shown promising results in advanced NSCLC, we carried out the study to explore the role of sequential chemotherapy combined with brain radiotherapy in patients with brain metastases. METHODS: Treatment naive NSCLC patients with brain metastases sequentially received the 3 chemotherapy regimens TP-NP-GP. The TP regimen consisted of Paclitaxol 175 mg/m(2) d1, Cisplatin 20 mg/m(2) d1-5. The NP regimen consisted of Nevalbine 25 mg/m(2) d1 and 8, Cisplatin 20 mg/m(2) d1-5. The GP regimen consisted of Gemcitabine 1 g/m(2) d1 and 8, Cisplatin 20 mg/m(2) d1-5. All regimens were repeated every 3 weeks. Each regimen was executed for at least 2 cycles and no more than 4 cycles. RESULTS: The response rates of TP, NP and GP sequentially used were 41.2%, 35.6% and 27.8% respectively for the out brain lesions and 60.8% for the brain lesions combining with brain irradiation. Median survival time was 14.7 months and the 1, 2 and 3 year overall survivals were 67.8%, 20.6% and 1.3% respectively. CONCLUSIONS: The 3rd generation regimen-based sequential chemotherapy combined with WBRT was effective for NSCLC patients with brain metastasis with an encouraging survival and acceptable tolerability. PMID- 20719180 TI - [The pitfall of transbronchial lung biopsy in the small cell carcinoma--attach 64 cases immunohistochemistry research.]. AB - BACKGROUND: It is very difficult to make diagnosis on the HE section to small cell lung carcinoma by bronchoscopic and easy to make misdiagnosis, we can avoid this by using immunohistochemical staining to diagnose differentially among the small cell carcinoma, poorly differentiated squamous cell carcinoma, atypical form carcinoid and lymphoma. METHODS: 64 cases of lung biopsy by bronchoscopic were consistency with small cell carcinoma and stained by immunochemistry for Ki67, CD56, TTF-1, CgA, Syn, P63, CK5/6, LCA, 34betaE12. RESULTS: For the 64 cases, we diagnosed 61 cases to the small cell carcinoma, 1 case to the poorly differentiated squamous cell carcinoma and 2 cases to the atypical carcinoid after IHC stain. CONCLUSIONS: It is the different therapy among the small cell carcinoma, poorly differentiated squamous cell carcinoma, atypical form carcinoid and lymphoma, so we can identify the diagnosis and differential diagnosis with IHC thoroughly, accordingly decrease incidence of misdiagnosis. PMID- 20719181 TI - [Diagnosis and Management of Chylothorax after resection of Lung Cancer.]. AB - BACKGROUND: With the development of lung cancer surgery, the rate of chylothorax after resection of lung cancer had an increasing trend year by year. The aim of this study is to explore the diagnosis and management of postoperative chylothorax for resection of lung cancer by analysis 1472 cases lung cancer patients who underwent radical resection of lung cancer at our department in the past 7 year. METHODS: Clinical date of 17 patients with lung cancer who had postoperative chylothorax were analyzed retrospectively. RESULTS: Seventeen cases were treated by conservative treatment, among them 16 case were cured, one case was failure by conservative treatment and was cured by tieing off the ductusthoracious. CONCLUSIONS: The occurrence of chylothorax has a correlation with the TNM stages and operation site of lunge cancer, in the management of postoperative chylothorax, adopting correct measures promptly can reach good therapeutic effect. PMID- 20719182 TI - [A Functional Domain Analysis of the BAG Family Proteins and the Relationship with Human Malignancy.]. PMID- 20719183 TI - [The Roles of P120-catenin and the Ttranscriptional Factor Kaiso for the Tumor.]. PMID- 20719184 TI - [p300/CBP and Lung Cancer.]. PMID- 20719185 TI - [Advances of eIF4E Gene and Research in Lung Cancer.]. PMID- 20719186 TI - [Advances in serum tumor markers of lung cancer.]. PMID- 20719187 TI - [Selection of Therapy Method for Stage III Non Small Cell Lung Cancer after Induction Chemotherapy.]. AB - BACKGROUND: It is the main choice that neoadjust chemotherapy following surgery and induction chemotherapy following radiation therapy for locally advanced lung cancer. The aim of this study is to explore the selection of operation or synchronous radiotherapy and chemotherapy for stage III non small cell lung cancer (NSCLC) after induction chemotherapy. METHODS: After two cycles of induction chemotherapy, patients with stage III NSCLC were divided at random into synchronous radiotherapy and chemotherapy group or operation therapy group for therapy by the chemotherapy effect PR or CR, or estimated complete excision; and patients accepting complete excision operation continuously accepted two cycles of chemotherapy according to original proposal. RESULTS: Total 71 patients with stage III NSCLC entered therapy group after induction chemotherapy. Where, 37 patients accepted synchronous radiotherapy and chemotherapy, and 34 patients accepted operation. The 1-year, 2-year, and 3-year survival rate of synchronous radiotherapy and chemotherapy group was 78.4%, 40.5% and 23.4% respectively, while that of operation group was 81.1%, 39.5% and 35.1% respectively. The medium survival of the two groups was 18.0+/-2.4 and 23.0+/-1.6 respectively, and there was no statistical difference (P=0.23) in survival rate. The disease-free survival rate of synchronous radiotherapy and chemotherapy group and operation group was 14.0+/-1.7 months and 19.0+/-3.2 months respectively (P=0.044), and obviously, there was statistical difference. CONCLUSIONS: After induction chemotherapy, patients with stage III NSCLC could select operation therapy and synchronous radiotherapy and chemotherapy. Where, synchronous radiotherapy and chemotherapy is relatively safe, but the adverse reaction can't be ignored. Operation therapy has higher risk and difficulty for induction chemotherapy, but has shown its superiority in disease-free survival. PMID- 20719188 TI - [Microinvasive technique for postoperative early bronchial stump fistula.]. AB - BACKGROUND: Although Bronchial stump fistula after pneumonectomy is a rare, but has serious complications. The main reason is that encapsulated fluid or blood around bronchial stump forms and infects. We used CT localization chest drainage and direct vision-assisted thoracoscopic chest drainage techniques to treat early fistula and observe their clinical efficacy. METHODS: Between October 2003 and July 2008, 12 patients with early bronchial stump fistula were recognized, and underwent CT localization chest drainage and direct vision-assisted thoracoscopic chest drainage techniques. RESULTS: After treatment, patients' clinic symptom were relieved, and fistula healed. CONCLUSIONS: Early recognization and treatment of bronchial stump fistula by microinvasive technique, could achieve a satisfactory clinical efficacy. PMID- 20719189 TI - Genetic fingerprint concerned with lymphatic metastasis of human lung squamous cancer. AB - BACKGROUND: With the most recent introduction of microarray technology to biology, it becomes possible to perform comprehensive analysis of gene expression in cancer cell. In this study the laser microdissection technique and cDNA microarray analysis were combined to obtain accurate molecular profiles of lymphatic metastasis in patients with lung squamous cell carcinoma. METHODS: Primary lung squamous cancer tissues and regional lymph nodes were obtained from 10 patients who underwent complete resection of lung cancer. According to the source of lung cancer cells, the samples were classified into three groups: the primary tumor with lymphatic metastasis (TxN+, n=5), the primary tumor without lymphatic metastasis (TxN-, n=5) and matched tumor cells from metastatic lymph nodes (N+, n=5). Total RNA was extracted from laser microdissected tumor samples. Adequate RNA starting material of mRNA from primary tumor or metastatic nodes were labeled and then hybridized into the same microarray containing 6 000 known, named human genes/ESTs. After scanning, data analysis was performed using GeneSpring6.2. RESULTS: A total of 37 genes were found to be able to separate TxN+ from TxN-. TxN+ have higher levels of genes concerned with structural protein, signal transducer, chaperone and enzyme. TxN- have higher levels of genes coding for cell cycle regulator, transporter, signal transducer and apoptosis regulator. Interestingly, there were no differentially expressed genes between N+ and TxN+. CONCLUSIONS: The acquisition of the metastatic phenotype might occur early in the development of lung squamous cancer. We raise the hypothesis that the gene-expression signature described herein is valuable to elucidate the molecular mechanisms regarding lymphatic metastasis and to look for novel therapeutic targets. PMID- 20719190 TI - [hsa-miR-125a-5p Enhances Invasion Ability in Non-Small Lung Carcinoma Cell Lines.]. AB - BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNAs that posttranscriptionally regulate gene expression by partially binding complementary to target sites in mRNAs. Although some impaired miRNA regulations have been observed in many human cancers, the functions of miR-125a are still unclear. The aim of this study is to investigate the expression of hsa-miR-125a-5p in NSCLC cell lines and the relationship between hsa-miR-125a-5p and the invasion of lung cancer cells. METHODS: The expression of hsa-miR-125a-5p and the effectiveness for a given period time after being transfected sense hsa-miR-125a-5p 2'-O-methyl oligonucleotide, which were 24 h, 36 h, 48 h, 60 h and 72 h, were examined by realtime PCR. Meanwhile, we investigated the modification of invasive ability in A549 and NCI-H460 cells by transwell. RESULTS: Real-time PCR showed that hsa-miR 125a-5p was poorly-expressed in 6 lung cancer cell lines, especially in LH7, NCI H460, SPC-A-1 and A549. The highest expression of hsa-miR-125a-5p occurred in the cells transfected with sense hsa-miR-125a-5p 2'-O-methyl oligonucleotide 36 h. Furthermore, the invasive abilities of A549 and NCI-H46O were enhanced by up regulating hsa-miR-125a-5p. CONCLUSIONS: hsa-miR-125a-5p was poorly-expressed in lung cancer cells and it could enhance lung cancer cell invasion by up-regulating hsa-miR-125a-5p. PMID- 20719191 TI - [Effects of EPO Gene on Growth and Apoptosis of Lung Adenocarcinoma Cell Line A549.]. AB - BACKGROUND: Published data on the association between erythropoietin (EPO) and cancer cell are inconclusive. The aim of this study is to investigate the effect of erythropoietin (EPO) on the growth and survival of lung adenocarcinoma cell line A549. METHODS: The recombinant plasmid pcDNA3.1(-)-hEPO was constructed and transfected into A549 cells by liposome protoco1. The Levels of EPO in culture supernatant were detected by ELISA. Effects of EPO gene on growth and survival of the transfected cells were evaluated by MTT assay and flow cytometry (FCM ). Levels of vascular endothelial growth factor (VEGF) were also evaluated by ELISA. RESULTS: The recombinant eukaryotic expression vector pcDNA3.1(-)-hEPO was successfully constructed. The growth of cells in hEPO transfected cells was significantly inhibited after transfection (P<0.01). More cells were blocked in S phase in hEPO transfected group compared with control group (P<0.05), and the apoptotic rate were also significantly higher than those of their controls (P<0.01). Levels of VEGF in hEPO transfected cells were significantly lower than controls (P<0.01). CONCLUSIONS: Exogenous EPO gene expression in A549 cells can induce cell growth inhibition and apoptosis of A549 cells, and expression of VEGF can also be inhibited. PMID- 20719192 TI - [Effect of Suture Lines on Lung Adenocarcinoma Cell in vitro.]. AB - BACKGROUND: The interaction of cell and medical biomaterial is one of the significant factors to affect clinical application of medical biomaterial. This research is to investigate three of suture lines how to affect the proliferation and cell cycle of Lung Adenocarcinoma cell A549. METHODS: Three of suture lines are respectively cultivated with Lung Adenocarcinoma cell A549, after of 72 hours, to detect absorptance of each groups by MTT method in order to reflect the proliferation of Lung Adenocarcinoma cell A549 and to detect percentage of G1 period cell and S period cell of each of groups by flow cytometry. RESULTS: Different of suture lines have effect differently on the proliferation and cell cycle of Lung Adenocarcinoma cell A549 (P<0.05). The effect of absorbent suture line on the proliferation and cell cycle of Lung Adenocarcinoma cell A549 is strong, the effect of chorda serica chirurgicalis is medium, the effect of slide wire is poor. Different length of each suture line have effect differently on the proliferation and cell cycle of Lung Adenocarcinoma cell A549 (P<0.05). CONCLUSIONS: Three of suture line materials have different effect on the proliferation and cell cycle of Lung Adenocarcinoma cell A549, to reflect dose effect relation. PMID- 20719193 TI - [Screening of Highly-expressed-HMGB1-Gene Human Lung Cancer Cell Lines.]. AB - BACKGROUND: Lung cancer is a type of malignant tumor which threats human health and life. Its morbidity might increase dramatically in a long period. Lung cancer is the leading cause of cancer-related death all over the world. HMGB1 (high mobility group box B 1) is a non-histone chromosome binding protein in the cells. It takes part in many biological processes including genes transcription and DNA repair. HMGB1 overexpression can result in cell apoptosis, differentiation, migration and proliferation. The main purpose of this study was to detect the HMGB1 expression of 4 lung cancer cell lines in order to select the most suitable cell line to do the work next step. METHODS: Four lung cancer cell lines were cultured by normal method, Western blot and real-time quantitative PCR were used to verify the levels of expression of HMGB1. The cell line which HMGB1 over expressed was selected. RESULTS: HMGB1 expressed in all 4 lung cancer cell lines, the cell line L9981 was the most highly expressed cell line (P<0.001). CONCLUSIONS: All 4 lung cancer cell lines expree HMGB1 gene. As the HMGB1 overexpression cell line, L9981 is an ideal material for follow-up research. PMID- 20719194 TI - [A Novel Method for Detecting p53 Autoantibodies in Sera of Patients with NSCLC.]. AB - BACKGROUND: Serum autoantibody detection is useful means for the early diagnosis and prognosis of cancer. So our objective was to synthesize peptide array to analyse p53 autoantibodies in the sera of patients with non small cell lung cancer (NSCLC). METHODS: Cellulose-bound overlapping peptides (12 mers) derived from p53 wild type protein were synthesized using SOPTs synthesis technique by an AutoSpot robot -ASP SL (Intavis, Germany). The membrane was incubated with 1/400 dilutions of p53 monoclonal antibody (Sc-53394) to establish a new approach to detect p53 antibody, and the epitopes of the p53 monoclonal antibody is already known. We analysed the p53 autoantibodies from the sera of NSCLC and controls by peptide array and ELISA. RESULTS: We synthesized on cellulose membranes twelve amino-acid overlapping peptides which included all of the sequences of the polypeptide chain of p53. The p53 autoantibody was positive in seven cases of thirty patients sera with NSCLC and was negative in sera of the controls, with the same result of ELISA CONCLUSIONS: The peptide array could be applied not only to detect the autoantibodies in the sera of patients with lung cancer, but also to map the epitopes of the autoantibodies which might be useful for the early diagnosis and prognosis of cancer. PMID- 20719195 TI - [A Prospective Randomized Study of Adjuvant Chemotherapy in Resected Stage IIIA N2 Non-small Cell Lung Cancer.]. AB - BACKGROUND: Lung cancer is one of the leading cause of cancer-related death around the world. Surgery is the primary treatment for patients with stage I, II, or IIIA non-small cell lung cancer (NSCLC). However, longterm survival of NSCLC patients after surgery alone is largely unsatisfactory. We undertook to determine whether adjuvant vinorelbine/paclitaxel plus carboplatin prolong overall survival among patients with completely resected stage IIIA-N2 nonsmall cell lung cancer. METHODS: We randomly assigned patients with completely resected stage IIIA-N2 non small cell lung cancer to vinorelbine/paclitaxel plus carboplatin or to observation RESULTS: A total of 150 patients (1999-2003) underwent randomization to vinorelbine/paclitaxel plus carboplatin (79 patients) or observation. In both groups, the median age was 57 years, 73 percent were male, and 28 percents had squamous carcinoma. Chemotherapy caused neutropenia in 82 percents of patients (including grade 3 and 4 neutropenia in 42 percent) and there was no treatment related death observed in this trial. After median follow-up of 39 months (range 1-110), overall survival was significantly prolonged in the chemotherapy group as compared with the observation group (33 months versus 24 months, Chi square=4.363, P=0.037), as was disease-free survival (32 months versus 20 months, Chi-square=5.413, P=0.020). Five-year overall survival rates were 31.1 percent and 19.1 percent, respectively. CONCLUSIONS: Adjuvant vinorelbine/paclitaxel plus carboplatin have an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected stage IIIA-N2 non-small cell lung cancer. PMID- 20719196 TI - [Expression and its Clinical Significance of NOK, EGFR in NSCLC.]. AB - BACKGROUND: NOK (Novel Oncogene with Kinase-domain) is a newly identified receptor protein-tyrosine kinases (RPTKs) subfamily, which possesses strong oncogenic potential including enhancing cell transformation, tumorigenesis, invasion and metastasis. However, NOK protein lacks extracellular domain, and how the NOK is activated by the membrane receptor and the expression of NOK in non small cell lung cancer (NSCLC) are not clear. Our aim of this study was to investigate the expressions of NOK, EGFR proteins in NSCLC. METHODS: The expression rates of NOK, EGFR proteins in 155 cases with NSCLC was deteced by immunohistochemical stain; The clinical correlations between two proteins were analyzed by statistics. RESULTS: The NOK positive expression was mainly located in cytoplasm and EGFR was mainly located in the plasma membrane and cytoplasm. NOK, EGFR proteins were high expressed in NSCLC and there were extremely differences comparing the expression of NOK, EGFR proteins in squamous cell lung cancer, lung adenocarcinoma with those in corresponding normal tissue respectively (P<0.001); and there were no significant differences between the two kinds of the cancers for their comparison of NOK, EGFR expression (P=0.099; P=0.23); however, there were significant differences for NOK and EGFR expression among histological grades and TNM stages in squamous cell lung cancers, lung adenocarcinoma (P<0.01). There were correlation between positive and intensity of NOK and EGFR expression in whatever total NSCLC or squamous cell lung cancer or lung adenocarcinoma (P<0.001), while the correlation coefficients(rs) were 0742, 0.722, 0.756 respectively. CONCLUSIONS: The NOK proteins are highly expressed in the NSCLC, and the expression rates of NOK proteins are correlated with the cancers' histological grades and TNM stages, which may be concern with tumorgenesis and progression; the positive expression rate and intensity of NOK protein correlate well with the expression of EGFR protein in NSCLC, which the activation of NOK probably owe to EGFR activation, all that would provide evidence for further study on the effective mechanism of NOK in the tumorigenesis or tumor progression. PMID- 20719197 TI - [Analysis of Subclassification by Size and Survival-associated Factors of Stage I Non-small Cell Lung Cancer.]. AB - BACKGROUND: The sixth edition of TNM system is hard to illuminate the survival of different tumor load precisely. This retrospective study attempted to evaluate the prognostic clinicopathologic features of non-small cell lung cancer (NSCLC). Especially we subclassified tumor sizes to validate the new T classification of international union against cancer (UICC). METHODS: We reviewed the clinical data of 327 stage I NSCLC with complete resection. Survival was analysed by Kaplan Meier method and Log-rank test. The multivariate analysis was performed with Cox's proportion risk model. RESULTS: The 5-year survival rate of poorly differentiated histologic grade and moderate-well differentiated histologic grade were 60.49% and 73.98% respectively (P=0.02574); The 5-year survival rate of preoperative anemia or not were 64.44% and 73.00% (P=0.0182); Tumor size was divided into <=2 cm, 2.1 cm-3 cm, 3.1 cm-5 cm and 5.1 cm-7 cm with 5-year survival rate of 86.30%, 72.73%, 62.50% and 58.33% respectively (P<0.0001). CONCLUSIONS: Histologic grade, preoperative anemia and tumor size are the independent prognostic factors in complete resection of stage I NSCLC. The patients with moderate-well differentiated histologic grade, non-preoperative anemia and smaller tumor size have longer survival time. Changes in tumor size classification are to subclassify into<=2 cm, 2.1 cm-3 cm, and 3.1 cm-5 cm, which is consistent with new T-staging system protocol of UICC. PMID- 20719198 TI - [Expression and Clinical Significance of TTF-1 and p63 in NSCLC.]. AB - BACKGROUND: To detect the expressions of thyroid transcription factor-1 (TTF-1) and p63 in non-small cell lung cancer (NSCLC) and to evaluate their clinical significance. METHODS: The expression of TTF-1 and p63 from 404 NSCLC and 28 benign pulmonary disease (BPD) tissue specimens were detected by immunohistochemical EnVision two-step method, together with their clinicopathologic data. RESULTS: The positive rate of TTF-1 and p63 protein in NSCLC tissues was 51.7% (209/404) and 37.9% (153/404), respectively, while negative in the BPD group. There was overexpression of TTF-1 in female gender and non-smoking history (P<0.001) and asymptomatic patients (P=0.015). It was more frequently in adenocarcinoma (AdC) with sensitivity of 84.1% and specificity of 89.8%, especially in well or moderately differentiated AdC (P<0.001). The positive rate of p63 was closely related with male gender and smoking history (P<0.001). Its sensitivity and specificity to squamous cell carcinoma (SCC) was 95.5% and 98.8%, respectively, which was positively correlated with differentiation of SCC (P=0.008), but negatively with tumor stage (P=0.002). Logistic multivariate analysis showed smoking history and histological type were significantly associated with TTF-1 and p63 expression. 93.1% of those represent TTF-1(+)/p63(-) were AdC, while 98.6% of TTF-1(-)/p63(+) were SCC. p63 expression was negatively correlated with TTF-1 (P<0.001). CONCLUSIONS: TTF-1 and p63 might be effective bio-markers for AdC and SCC in NSCLC. They may be a useful marker panel for the identification and differential of lung cancer. PMID- 20719199 TI - [Therapeutic efficacy of Traditional Vein Chemotherapy and Bronchial Arterial Infusion Combining with CIKs on III Stage Non-small Cell Lung Cancer.]. AB - BACKGROUND: The therapeutic efficacy of late lung-cancer was very poor, and cytokine-induced killer cells (CIK) were paid more attention to treat non-small cell lung cancer (NSCLC). The aim of this study is to get insight into the role of bronchial arterial infusion bronchial arterial infusion (BAI) plus CIK about NSCLC by comparing therapeutic efficacy among BAI, traditional vein chemotherapy and BAI plus CIK, for late NSCLC. METHODS: A total of 120 patients were enrolled in this study, dividing randomly into three groups: bronchial arterial infusion (BAI), traditional vein chemotherapy and BAI plus CIK. Clinical effects and side effects were estimated after two period of therapy. RESULTS: The effective rate (CR+PR%) of combined group is higher than the traditional vein chemotherapy group (66.67%, n=39) and there are significant differences (Chi-square=4.721, P=0.03); The side effect of rate of BAI plus CIK group is significantly lower than the traditional vein chemotherapy group, and so did the non-bone marrow inhibition side effects (P<0.05). The tumor progression rate (PD%) of bronchial arterial infusion (BAI) group is higher than combined group (Chi-square=4.287, P=0.038). There was no difference between the traditional vein chemotherapy group and combined group (Chi-square=0.082, P=0.775). CONCLUSIONS: Bronchial Artery Infusion combined with cytokine-induced killer cells is an ideal, safety, effective comprehensive treatment method for late stage lung cancer. PMID- 20719200 TI - [The Expression of hTERT mRNA and p16 Protein in Non-small Cell Lung Cancer.]. AB - BACKGROUND: hTERT and p16 are involved in oncogenesis and development of tumor. The aim of this study is to investigate the expression of human telomerase reverse transcriptase (hTERT) and p16 in non-small cell lung cancer (NSCLC). METHODS: The quantitative reverse transcription-polymerase chain reaction (RT qPCR) and immunohistochemistry were applied to detect the hTERT and p16 in tissue of 21 cases of lung benign diseases and 117 of non-small cell lung cancer and adjacent tissues, respectively. RESULTS: hTERT mRNA levels from NSCLC in 117 patients and normal lung tissue in 21 normal controls were 2.937+/-0.836 and 2.042+/-0.378, respectively (t=-5.242, P<0.01). Expression of p16 protein was observed in 85.7% of normal tissues, while 47.9% of lung cancer tissues showed p16 protein expression (P=0.004). The expression of hTERT mRNA was significantly correlated with the histology (P<0.05); the expression of p16 protein was significantly correlated with the clinical stage, degree of differentiation and lymph node metastasis (P<0.05). The significant correlation between the expression of hTERT and p16 (P<0.05). CONCLUSIONS: The hTERT may be useful in clinical diagnosis of NSCLC. Expression of hTERT and p16 is related to the carcinogenesis and development of NSCLC. PMID- 20719201 TI - [Three Dimensional Conformal Radiotherapy Combined with Concurrent Chemotherapy for Stage III Non-small Cell Lung Cancer.]. AB - BACKGROUND: The outcome of treatment for stage III non-small cell lung cancer (NSCLC) by radiotherapy plus concurrent chemotherapy is poor. This study was aimed to investigate the feasibility of three-dimensional conformal radiotherapy (3D-CRT) plus concurrent cisplatin-based chemotherapy on the patients with stage III non-small cell lung cancer. METHODS: 88 cases with stage III NSCLC from August 2004 to June 2007 were divided randomly into concurrent group and 3D-CRT alone group RESULTS: The overall response rate (CR+PR) in concurrent group and 3D CRT alone group were 90.9% and 68.2% respectively (P<0.05). The 1, 2, 3-year overall survival rate in concurrent group and 3D-CRT alone group were 68.8%, 35.1%, 19.7% and 38.9%, 22.8%, 12.4% respectively. The median survival was 18.8 months, and 12.6 months, respectively, and the difference of the toxicity (except leukocytopenia) was not statistically significant in two groups (P>0.05). CONCLUSIONS: 3D-CRT combined with concurrent chemotherapy has better response and shorter treatment course than the 3DCRT alone, and increases the overall survival, so it is the best method for the treatment stage III NSCLC. PMID- 20719202 TI - [Clinical Significance of CK20, CK19, CEA mRNAs in Peripheral Blood from Lung Cancer Patients.]. AB - BACKGROUND: The tumor cells may disseminate into circulation even in early stages. However, the numbers of such cells are so small that they cannot be detected by conventional diagnostic methods. Developments in molecular technology have made it possible to detect small numbers of tumor cells in peripheral blood. In this study, 83 preoperative peripheral blood samples from patients with lung cancer were analyzed for the determination of CEA, CK19, and CK20 mRNA expression in peripheral blood, and its clinical significance was evaluated. METHODS: Nested reverse transcriptasepolymerase chain reaction (nested RT-PCR) was used to analyze CEA, CK19, and CK20 mRNA expression in peripheral blood. Fresh tumor tissues from patients with esophageal cancer (n=15) were used as a positive control, and blood samples from 15 healthy volunteers as a negative control. RESULTS: Among 83 blood samples from patients with lung cancer, the expression of CK20, CK19 and CEA mRNA was 41.0%, 36.1% and 48.2%, respectively. 73.5% were positive for at least one markers for these three genes, and were significantly correlated with the metastasis of the cancer (P<0.05), but had no correlation with age and sex. In primary esophageal tumors, 15 tumor tissues were all positive for CEA, CK19, and CK20 mRNA. 2 of 15 blood samples from healthy donors were positive for CK19 and CEA mRNA, and 1 of 15 blood sample positive for CK20 mRNA. CONCLUSIONS: The three markers of CK20, CK19 and CEA mRNA could be the target genes in detecting circulating tumor cells in peripheral blood from patients with lung cancer. The combined detection of CK20, CK19 and CEA mRNA by RT-PCR assay may contribute to the PCR positivity and sensitivity, and CK20, CK19, CEA mRNA expression increase the specificity. PMID- 20719203 TI - [Surgical treatment of superior vena cava syndrome caused by thoracic cancers.]. PMID- 20719204 TI - [Advances of MicroRNA in Lung Cancer.]. PMID- 20719206 TI - [Advances on micrometastasis of Non-small Cell Lung Cancer.]. PMID- 20719205 TI - [Advance on the Role of Mitogen-activated Protein Kinase (MAPK) Signal Pathway in Non-small Cell Lung Cancer.]. PMID- 20719207 TI - [Advances in Anti-tumor Activity of Indole-3-carbinol.]. PMID- 20719208 TI - [Advance of treatment of small cell lung cancer in 2009 american society of clinical oncology annual meeting.]. PMID- 20719209 TI - [Correlation between Changes in Serum Level of CEA and CYFRA 21-1 and Objective Response of Chemotherapy.]. AB - BACKGROUND: Serum levels of tumor markers are associated with tumor metabolism or apoptosis, changes of which after chemotherapy may reflect tumor response to treatment. The aim of this study was to assess the predictive role of changes in serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced non-small cell lung cancer. METHODS: Changes in serum levels of CEA and CYFRA 21-1 were investigated retrospectively after one cycle of chemotherapy in 42 patients with advanced NSCLC. Correlations between the changes and radiological objective response were analyzed. RESULTS: After two cycles of chemotherapy, radiological objective response rate was 28.6%. At baseline, gender, age, clinical stage, serum levels of CEA and CYFRA 21-1 were not different between patients with objective response (OR) and no response (NR). After one cycle of chemotherapy, compared to baseline level, declines in serum levels of CEA and CYFRA 21-1 were observed in patients with OR, but have no statistical significance. In contrast, reduction of CEA and CYFRA 21-1 over baseline after one cycle of chemotherapy showed statistically significant difference between OR and NR. When reduction percentages of CEA and CYFRA 21-1 were used to predict objective response of chemotherapy, the area under the ROC curve (AUC) was 0.875 for CEA and 0.919 for CYFRA 21-1. According to the ROC curve, a 22% reduction of CEA yielded a sensitivity of 58.3% and a specificity of 97%, 51% reduction of CYFRA 21-1 with a sensitivity of 83.3% and a specificity of 93.3%. When above reduction percentages were used as cutoffs for prediction of radiological objective response, combination of the CEA and CYFRA 21-1 yielded a sensitivity of 91.7% and a specificity of 86.7%. CONCLUSIONS: Reduction percentages of CEA and CYFRA 21-1 during chemotherapy could be used to evaluate chemotherapy efficacy in patients with advanced NSCLC. The cutoffs of reduction percentage need further research. PMID- 20719210 TI - Cervical cancer vaccine development. AB - Cervical cancer is initiated by infection of cervical epithelium with human papillomavirus. Vaccines have been developed, incorporating papillomavirus viral capsids and alum based adjuvants. In extensive clinical trials these vaccines have been shown safe and effective in preventing infection with, and disease caused by, the papillomavirus genotypes they incorporate, in women not already infected. These vaccines have the potential to reduce the global burden of cervical cancer by up to 70%. PMID- 20719211 TI - Cancers attributable to human papillomavirus infection. AB - Although the human papillomavirus (HPV) vaccine was introduced primarily as a cervical cancer prevention vaccine, HPV has a causal role in several types of cancer. This article reviews the epidemiological evidence for the role of HPV in human cancer, and describes Australian trends in these cancers. HPV is a necessary cause of cervical cancer. The currently vaccine-preventable subtypes of HPV 16 and 18 are responsible for ~70% of cervical cancer. The introduction of an organised Pap smear program in Australia led to a steep decline in incidence over the past decades. HPV can be detected in ~40% and 70% of vulval and vaginal cancers respectively. Rates of these cancers have been stable over the past 20 years. The prevalence of HPV in penile cancer is ~50% and incidence has not recently changed. For anal cancer, ~85% of cases are HPV positive, and incidence has increased significantly in both men and women over the past 20 years. In the oral cavity, ~35% of oropharyngeal cancers and ~25% of other oral cavity cancers are HPV positive. The incidence of HPV-related oral cavity and oropharyngeal cancers is increasing, whereas incidence at HPV-unrelated sites is decreasing. Overall, 1154 HPV-related cancer cases were potentially preventable by vaccination. If HPV-related cancers at non-cervical sites are prevented by vaccination, then a similar number of cancer cases will be prevented as in the cervix. However, almost one-quarter of the potentially preventable cancer cases are in men, who are not included in the current national immunisation program. PMID- 20719212 TI - Estimating the prevalence of and treatment patterns for juvenile onset recurrent respiratory papillomatosis in Australia pre-vaccination: a pilot study. AB - BACKGROUND: Recurrent respiratory papillomatosis (RRP) causes serious morbidity. RRP in Australia may be eliminated in the near future following the implementation of a national vaccination program using a human papillomavirus (HPV) vaccine that protects against infection with HPV types 6 and 11, those responsible for RRP. Baseline data on RRP prevalence and disease burden in Australia are lacking. METHODS: Three study methods were used to estimate the burden of juvenile onset RRP in Australia. We conducted a retrospective chart review of RRP cases treated at The Children's Hospital at Westmead over 10 years, examined the coding of these cases, and then calculated and applied the positive predictive value of the codes to national data to estimate the prevalence of RRP in Australia. We also conducted an online survey of otolaryngologists in Australia who manage RRP. RESULTS: Nineteen patients were treated at the hospital over 10 years, involving 359 admissions. We estimate that between 33 and 56 RRP cases aged <20 are being treated nationally per year (0.6-1.1 per 100 000 persons), with children 5-9 years having a higher estimated rate of 1.2-1.8 per 100 000. Among 39 otolaryngologists treating juvenile onset RRP, the majority (73%) treated RRP in a paediatric tertiary hospital, and used the microdebrider for ablation of lesions. CONCLUSIONS: Our estimates of RRP disease burden agree with international estimates. As a small number of clinicians treat RRP nationally, we believe that establishment of a national RRP register is both feasible and necessary to monitor the impact of vaccination. PMID- 20719213 TI - Human papillomavirus vaccine introduction in Vietnam: formative research findings. AB - BACKGROUND: Formative research is a useful tool for designing new health interventions. This paper presents key findings from formative research conducted in Vietnam to guide human papillomavirus (HPV) vaccine introduction. METHODS: We explored the sociocultural environment, health system capacity and the policy making process using a combined quantitative and qualitative methodology. Data collection was done through literature review, in-depth interviews, focus group discussions, observation checklists and a structured questionnaire on knowledge, attitudes and practices. Populations of interest included 11- to 14-year-old girls, their parents, community leaders, teachers, health workers, health and education officials, and policy-makers at all levels. RESULTS: Although HPV vaccines are new, we found high potential acceptance among parents and girls. HPV vaccine introduction was also favourably supported by health professionals if assurances for system preparedness, e.g. cold chain and human resources, were made. There were no significant barriers from the policy perspective that would prevent the introduction of a new vaccine. However, several concerns related to this new vaccine would need to be adequately addressed before implementation. CONCLUSION: Our findings provide options for potential vaccine delivery strategies, appropriate communication strategies and targeted advocacy strategies to introduce HPV vaccines in the Vietnamese context. PMID- 20719214 TI - 'It's a logistical nightmare!' Recommendations for optimising human papillomavirus school-based vaccination experience. AB - INTRODUCTION: To date, no published studies examine procedural factors of the school-based human papillomavirus (HPV) vaccination program from the perspective of those involved. This study examines the factors that were perceived to impact optimal vaccination experience. METHODS: Schools across Sydney were selected to reflect a range of vaccination coverage at the school level and different school types to ensure a range of experiences. Semi-structured focus groups were conducted with girls; and one-on-one interviews were undertaken with parents, teachers and nurses until saturation of data in all emergent themes was reached. Focus groups and interviews explored participants' experiences in school-based HPV vaccination. Transcripts were analysed, letting themes emerge. RESULTS: Themes related to participants' experience of the organisational, logistical and procedural aspects of the vaccination program and their perceptions of an optimal process were organised into two categories: (1) preparation for the vaccination program and (2) vaccination day strategies. In (1), themes emerged regarding commitment to the process from those involved, planning time and space for vaccinations, communication within and between agencies, and flexibility. In (2), themes included vaccinating the most anxious girls first, facilitating peer support, use of distraction techniques, minimising waiting time girls, and support staff. DISCUSSION: A range of views exists on what constitutes an optimal school-based program. Several findings were identified that should be considered in the development of guidelines for implementing school-based programs. Future research should evaluate how different approaches to acquiring parental consent, and the use of anxiety and fear reduction strategies impact experience and uptake in the school-based setting. PMID- 20719216 TI - Low rates of free human papillomavirus vaccine uptake among young women. AB - OBJECTIVE: To determine uptake of quadrivalent human papillomavirus recombinant vaccine (quadrivalent; Gardasil((R)), Merck, New Jersey, USA) offered under optimal conditions to women 18 to 24 years of age, and to identify predictors of uptake. METHODS: Young women (n = 209) were recruited from a university health clinic. After completing a self-administered questionnaire, women received a free voucher for the entire vaccine series. RESULTS: Only 59 women (28.2%) who were offered this free service completed the series. Just over half (50.7%) received the first dose. Of those, 78.3% returned to receive the second and 55.7% returned for the third. Young women who felt their mothers might not want them to be vaccinated were much less likely to complete the series compared with those who felt their mothers would 'definitely' want them to be vaccinated (P = 0.0002). Also, young women who indicated that they would take the time to return to the clinic for doses two and three were far more likely to complete the series (P = 0.0004). Several measures failed to achieve even bivariate significance with vaccine uptake, including being sexually active in the past 12 months, ever having a Pap test or an abnormal Pap test result, and ever having a sexually transmissible infection. CONCLUSIONS: Even under ideal conditions, uptake of Gardasil among women 18-24 years of age may be quite low. Maternal endorsement and young women's perceptions about the time needed to return for subsequent doses are important determinants of vaccine uptake. Fortunately, these two determinants lend themselves to intervention efforts. PMID- 20719215 TI - Scaling up human papillomavirus vaccination: a conceptual framework of vaccine adherence. AB - This review article provides a conceptual framework for human papillomavirus (HPV) vaccine acceptance and adherence, with a focus on improving understanding of the sociocultural factors impacting vaccine adherence behaviour. We include a systematic review of the slowly expanding literature on HPV vaccine acceptability and uptake in developed nations, as well as the relatively few publications from poorer nations, where more than 80% of global cervical cancer related deaths occur and where the vaccine will probably have the largest impact. We suggest that this conceptual framework will not only improve our understanding of HPV vaccine uptake and adherence, but it may also guide future sociobehavioural research geared towards improving adherence to the HPV vaccine and other multi step vaccines in a young population at risk for sexually transmissible infections. PMID- 20719217 TI - National survey of general practitioners' experience of delivering the National Human Papillomavirus Vaccination Program. AB - BACKGROUND: Between 2007 and 2009, Australian general practitioners (GPs) were involved in implementing a population-based human papillomavirus (HPV) vaccination program. We investigated GPs' experiences of delivering the HPV vaccine to women aged 18-26. METHODS: We posted a survey to 1000 GPs. The survey was informed by 12 domains incorporating constructs from psychological theories that focus on individual and environmental barriers and facilitators to effective implementation of evidence-based practice by health professionals. RESULTS: The response rate was 32%. The 298 vaccinating GPs were positive about HPV vaccine implementation as part of their professional role as a worthwhile initiative within existing general practice infrastructure. They had more negative views about some aspects of program organisation, such as the timelines and potential adverse impacts on cervical screening rates. Vaccine safety was not a key concern. Actual levels of knowledge about HPV were moderate (mean score 3.41 out of 6 (s.d. 0.99)) and contrasted with self-rated knowledge, which was high (93% perceived their knowledge to be adequate). Notably, there were unrealistic expectations about the likely reduction in Pap abnormalities due to vaccination, which is important to clarify to avoid loss of confidence in the vaccine when this reduction does not eventuate. CONCLUSIONS: Australian GPs viewed HPV vaccination of women aged 18-26 years as an integrated part of their routine practice, with positive attitudes regarding its benefits and achievability. GPs are well placed to implement mass immunisation programs as long as they are supported by effective and timely communication strategies and resources. PMID- 20719218 TI - Knowledge of human papillomavirus (HPV) and the HPV vaccine in a national sample of Australian men and women. AB - BACKGROUND: Human papillomavirus (HPV) knowledge has rarely been investigated in the context of a national vaccination program. The present study investigated HPV knowledge after the introduction of a national HPV vaccination program in Australia using a national sample of men and women. METHODS: Questions assessing HPV knowledge were part of a broader national study of health and relationships administered via a computer-assisted telephone interview. These findings are from wave four of the study, conducted between 2007 and 2008. Knowledge questions about HPV included its association with cervical cancer, genital warts and abnormal Pap tests. RESULTS: A total of 2634 women and 2556 men between the ages of 18 and 70 were interviewed. Overall, 62.8% (95% confidence interval (CI): 60.8 64.7%) of women and 38.3% (95% CI: 36.3-40.4%) of men had heard of HPV. Of these, 66.0% (95% CI: 64.1-67.9%) correctly answered that HPV is associated with cervical cancer, 50.2% (95% CI: 48.2-52.1%) answered that HPV is associated with abnormal Pap tests and 44.5% (95% CI: 42.5-46.5%) answered that HPV causes warts. Predictors of good knowledge included being female, aged between 26 and 45, holding higher education levels and older age at first sex. Ever having a Pap test was also associated with awareness about HPV. CONCLUSION: One of the highest levels of knowledge about HPV in Australia to date is reported in the present study. Knowledge about the association between HPV and cervical cancer was particularly high, especially when compared with knowledge of the association with genital warts. This appears to be a consequence of the marketing of the HPV vaccine as a vaccination against cervical cancer. PMID- 20719219 TI - Human papillomavirus vaccine acceptability among a national sample of adult women in the USA. AB - BACKGROUND: In the USA, the human papillomavirus (HPV) vaccine is currently licensed for 9-26-year-old females, but licensure for women over 26 years is being considered. The aim of the current study was to investigate the association of sociodemographic and health-related factors to HPV vaccine acceptability among adult women. METHODS: The current study utilised a nationally representative sample of women (n = 1323) aged 27-55 living in the USA, with an oversampling of black and Latina women. A multiple item measure of HPV vaccine acceptability across varying cost and location-of-availability (clinic only v. any local pharmacy) conditions was the main outcome measure. General linear modelling was used to analyse the association of vaccine cost, location availability, and sociodemographic and health-related variables with vaccine acceptability. RESULTS: Vaccine cost had the strongest association with acceptability [F (2, 1249) = 832.1; P < 0.0001]; however, factors such as religiosity, political views, a history of various negative sexual health outcomes and previous flu shot receipt were also associated with acceptability. Location availability had a statistically significant but modest effect, with a slight preference shown for health clinic availability. CONCLUSIONS: Adult women had generally high levels of HPV vaccine acceptability, but were greatly influenced by cost of the vaccine. Women who had experienced negative sexual health outcomes due to HPV-specific infection rated the vaccine as more acceptable, perhaps due to distress associated with those outcomes. PMID- 20719220 TI - Monitoring the control of human papillomavirus (HPV) infection and related diseases in Australia: towards a national HPV surveillance strategy. AB - This paper describes a possible multifaceted approach to human papillomavirus (HPV) related surveillance in Australia following implementation of a national HPV vaccination program. We describe eight main components: monitoring of vaccine coverage, vaccine safety, type-specific HPV infection surveillance, cervical cytology (Pap screening) coverage and screen detected lesion prevalence, cervical cancer incidence and mortality, genital wart incidence, incidence of recurrent respiratory papillomatosis, and knowledge, attitudes and beliefs about HPV and HPV vaccination. Australia is well placed to monitor the impact of its HPV vaccination program as well as to measure vaccine effectiveness with existing HPV vaccines, cervical screening and cancer registries. PMID- 20719221 TI - Human papillomavirus vaccine safety in Australia: experience to date and issues for surveillance. AB - Australia was one of the first countries to licence a quadrivalent human papillomavirus (HPV) vaccine, rapidly followed by a federally funded program of universal vaccination of a broad age group of females through schools (12 to 18 years) and primary care (19 to 26 years). As of August 2009, more than 5.8 million doses of Gardasil((R)) (quadrivalent; Merck, New Jersey, USA) have been distributed in Australia and a total of 1394 suspected adverse events following immunisation (AEFI) have been reported to the passive surveillance system. Most reports are of common and expected reactions. Case series of more uncommon and serious AEFI, both known to be potentially vaccine related (anaphylaxis, conversion disorders and lipoatrophy) and otherwise (multiple sclerosis and pancreatitis) have been published. PMID- 20719222 TI - What can surveillance of genital warts tell us? AB - In this Review, we describe the recent epidemiology of genital warts and postulate what the future may hold as a result of the introduction of the quadrivalent human papillomavirus (HPV) vaccine. HPV types 6 or 11 are responsible for most cases and they develop in about two-thirds of women a few months after HPV 6 or 11 infections are first detected by polymerase chain reaction. Surveillance data, cohort studies and cross-sectional surveys suggest that the annual incidence of genital warts exceeds 1% and serological studies suggest cumulative risk up to 40 years of age for HPV 6 or 11 is over 25%. The quadrivalent HPV vaccine is highly effective against genital warts and Australian surveillance data in the 2 years after the introduction of the vaccine have shown large declines in younger women and to a lesser degree heterosexual men. No significant changes in older women or men who have sex with men were seen. Given the success of Australia's catch-up program it will not be long before we know if the basic reproductive number for genital warts holds the prospect of elimination. However, if genital warts stabilise at a lower, but not very low, rate we will know that elimination will not be possible without vaccination of males. PMID- 20719223 TI - Cytology and cervical cancer surveillance in an era of human papillomavirus vaccination. AB - Cytological and cancer surveillance will provide the most effective indications of short-term effects and long-term outcomes of the introduction of the human papillomavirus (HPV) vaccine in Australia. This article outlines how this surveillance is proposed to occur through the established national monitoring mechanisms of the National Cervical Screening Program in the annual Australian Institute of Health and Welfare (AIHW) publication 'Cervical screening in Australia'. Cytological surveillance will be possible principally through cytology data provided annually by the state and territory cervical cytology registers, and it is expected that these data will provide the earliest and most comprehensive indications of effects from the HPV vaccine. Some potential issues in interpreting these data are also discussed, including the potentially confounding effects of the introduction of new National Health and Medical Research Council guidelines 'Screening to prevent cervical cancer: guidelines for the management of asymptomatic women with screen-detected abnormalities' some 9 months before the introduction of the vaccine. Cancer surveillance over the long term will be possible using cervical cancer incidence data reported annually for the National Cervical Screening Program in 'Cervical screening in Australia' using data sourced from the Australian Cancer Database. In a final discourse, the HPV vaccine and cervical screening are discussed concurrently, and the importance of continued cervical screening in the HPV vaccine era emphasised. PMID- 20719224 TI - Quality assessment for human papillomavirus testing. AB - There are over 30 commercial, as well as numerous in-house assays, available for human papillomavirus testing. Laboratories performing such assays would need to assess accuracy and reproducibility of their results by incorporating ongoing internal control as well as participating in external quality-assurance schemes (EQAS) as part of their quality assurance program. Several EQAS are available and participation in which is a requirement for laboratories engaged in HPV testing. It is important that laboratories select the appropriate panels for detection of targeted types covered by assay used. Failure to do so can possibly alter patient management and increase the cost of treatment. PMID- 20719225 TI - US physicians' intentions regarding impact of human papillomavirus vaccine on cervical cancer screening. AB - BACKGROUND: US cervical cancer screening recommendations have not changed since the human papillomavirus (HPV) vaccine introduction in 2006, but epidemiological and cost-effectiveness studies indicate that recommendations will need to change for fully vaccinated women. We evaluated physician intentions regarding HPV vaccine's impact on future screening. METHODS: A nationally representative sample of 1212 primary care physicians was surveyed in 2006-2007 (response rate: 67.5%). Our study included 1114 physicians who provided Pap testing. Questions covered Pap test screening practices and intentions regarding HPV vaccine's impact on screening. Distribution differences were assessed using chi(2) statistics; multivariate analyses were performed. RESULTS: Overall, 40.7% (95% confidence interval (CI): 37.6-43.8%) of physicians agreed that the HPV vaccine will affect screening initiation, and 38.2% (35.0-41.5%) agreed that vaccination will affect screening frequency. Significant differences in responses were found by specialty; internists were more likely to agree that vaccination would impact screening than other specialties. Belief in the effectiveness of new screening technologies was associated with intention to change screening initiation (odds ratio (OR) = 1.66 (1.20-2.31)) and frequency (OR = 1.99 (1.40-2.83)). Adherence to current Pap test screening interval guidelines was associated with intention to change screening frequency (OR = 1.39 (1.01-1.91)). CONCLUSIONS: Many providers anticipate adjusting screening for vaccinated women, but a significant group believes nothing will change or are unsure. The present study provides important baseline data on intentions in the period preceding widespread vaccine diffusion and may help explain current and future trends in practice patterns. PMID- 20719226 TI - Audit of paired anal cytology and histopathology outcomes in patients referred to a public sexual health clinic. AB - BACKGROUND: The level of agreement between anal cytology and histopathology is not clear with only a few studies evaluating the reliability of anal specimen reporting. Australian data in relation to this are limited. METHODS: The results of paired anal cytology and histopathology specimens received between 2002 and 2008 from patients who were referred within the sexual health clinic were retrieved from the anatomical pathology database. A total of 248 paired samples from 154 (21 females, 133 males) participants were extracted. Concurrent high risk human papilloma virus (hrHPV) DNA assay and HIV status for the study group were also collected. Data were tabulated according to reported grade of squamous abnormality based on the Bethesda system. Using the biopsy result as the gold standard the specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) for cytology were calculated and the association between grade of abnormality, HIV status and hrHPV infection estimated. RESULTS: Concordance between cytology and histology showed that in 204 (85%) paired samples both tests were categorised as abnormal (Kappa statistic 0.73, P = 0.013). The cytology result showed a sensitivity of 96%, specificity 14%, PPV 89% and NPV 31% when compared with histopathology. HrHPV assay was positive in 192 (80%) samples. High-grade squamous abnormalities were reported in biopsy specimens from 60% (n = 42/67) of HIV-positive subjects and 25% (n = 22/87) of HIV-negative subjects. HIV-positive individuals were more likely to be hrHPV positive, odds ratio (OR) 6.21 [95% confidence interval (CI) 2.69 to 14.34], when compared with HIV-negative subjects. CONCLUSION: Anal cytology is highly sensitive for the detection of abnormal squamous cells. While cytology has low specificity for predicting the grade of abnormality compared with biopsy outcome, its application as a screening method in asymptomatic at risk populations warrants further study. PMID- 20719227 TI - A brief history of economic evaluation for human papillomavirus vaccination policy. AB - BACKGROUND: This commentary discusses key issues for health economic evaluation and modelling, applied to human papillomavirus (HPV) vaccine programs. METHODS: We outline some of the specific features of HPV disease and vaccination, and associated policy questions in light of a literature search for economic evaluations on HPV vaccination. RESULTS: We observe that some policy questions could not be reliably addressed by many of the 43 published economic evaluations we found. Despite this, policy making on universal HPV vaccination followed shortly after vaccine licensure in many developed countries, so the role economic evaluation played in informing these decisions (pre-dating 2008) seems to have been fairly limited. For more recent decisions, however, economic evaluation is likely to have been used more widely and more intensively. CONCLUSIONS: We expect future cost-effectiveness analyses to be more instrumental in policy making regarding vaccines covering more HPV types, therapeutic HPV vaccines, and novel diagnostic tests for biomarkers of HPV infection and disease integrated with cervical screening programs. PMID- 20719228 TI - Models of cervical screening in the era of human papillomavirus vaccination. AB - Epidemiologic and economic evaluation using simulation modelling can support complex policy decisions, and is an important tool in predicting the future interaction between human papillomavirus vaccination and cervical screening. Several categories of screening program evaluation are of interest, including: (1) changes to screening considered over the short term, over which the effects of vaccination should be confined to the youngest age groups (<30 years old); (2) the medium and long-term effect of vaccination on the screening program; and (3) changes to screening in context of vaccination. This review considers some of the policy questions in each category and discusses the modelling implications, with particular focus on the Australian context. PMID- 20719229 TI - Unresolved questions concerning human papillomavirus infection and transmission: a modelling perspective. AB - Mathematical transmission models are widely used to forecast the potential impact of interventions such as vaccination and to inform the development of health policy. Effective vaccines are now available for the prevention of cervical cancer and other diseases attributable to human papillomavirus (HPV). Considerable uncertainties remain regarding the characterisation of HPV infection and its sequelae, infectivity, and both vaccine-conferred and naturally-acquired immunity. In this review, we discuss the key knowledge gaps that impact on our ability to develop accurate models of HPV transmission and vaccination. PMID- 20719230 TI - Promising strategies for cervical cancer screening in the post-human papillomavirus vaccination era. AB - Human papillomavirus (HPV) vaccination is expected to reduce the burden of cervical cancer in most settings; however, it is also expected to interfere with the effectiveness of screening. In the future, maintaining Pap cytology as the primary cervical screening test may become too costly. As the prevalence of cervical dysplasias decreases, the positive predictive value of the Pap test will also decrease, and, as a result, more women will be referred for unnecessary diagnostic procedures and follow-up. HPV DNA testing has recently emerged as the most likely candidate to replace cytology for primary screening. It is less prone to human error and much more sensitive than the Pap smear in detecting high-grade cervical lesions. Incorporating this test would improve the overall quality of screening programs and allow spacing out screening tests, while maintaining safety and lowering costs. Although HPV testing is less specific than Pap cytology, this issue could be resolved by reserving the latter for the more labour-efficient task of triaging HPV-positive cases. Because most HPV-positive smears would contain relevant abnormalities, Pap cytology would be expected to perform with sufficient accuracy under these circumstances. HPV Pap triage would also provide a low-cost strategy to monitor long-term vaccine efficacy. Although demonstration projects could start implementing HPV testing as a population screening tool, more research is needed to determine the optimal age to initiate screening, the role of HPV typing and other markers of disease progression, and appropriate follow-up algorithms for HPV-positive and Pap-negative women. PMID- 20719231 TI - Global reduction of cervical cancer with human papillomavirus vaccines: insights from the hepatitis B virus vaccine experience. AB - BACKGROUND: Worldwide, prophylactic vaccines against two major human cancers are now commercially available: hepatitis B virus (HBV) vaccines (first licensed in 1982) against primary hepatocellular carcinoma and human papillomavirus (HPV) vaccines (first licensed 2006) against cervical cancer. Initial implementation strategies for HBV vaccination were not successful in preventing disease in the community: it took 15 years for significant global reduction in the burden of this disease. METHODS: We compare and contrast HBV vaccine experiences to challenges for successful global HPV vaccination strategies, and make recommendations accordingly. RESULTS: Lessons from HBV immunisation for successful outcomes with HPV immunisation showed that several factors need to be met: (i) the engagement of key stakeholders in all aspects of planning and delivery of HPV vaccine strategies; (ii) understanding the specific characteristics of targeted population groups; (iii) global cooperation and support with WHO recommendations; (iv) Government supported mass immunization programs and cooperation between public and private entities; (v) affordable HPV vaccines for some regions; (vi) culturally appropriate and diverse public education programs in targeted health promotion strategies; (vii) pro-active health providers and parents in encouraging adolescents to undertake HPV vaccination; and (vii) eventual immunisation of infants. CONCLUSIONS: The key to success will be affordable, readily deliverable HPV vaccines to young girls as universal campaigns. PMID- 20719232 TI - Role of the nurse immuniser in implementing and maintaining the National Human Papillomavirus 'Cervical Cancer' Vaccine rollout through a school-based program in Victoria. AB - In an effort to understand the strengths and limitations of current approaches to human papillomavirus vaccine (HPV) delivery in schools, we conducted an audit of nurse immunisers (NI). In this survey of 159 Victorian NI, the NI perceived that knowledge, safety and side effects were among the most important issues raised by parents, schoolgirls, and teachers in the school setting. The most common concern identified by NIs was the physical layout of the vaccination setting (41%), followed by safety, then knowledge of the vaccine. There is a need for ongoing assessment of factors that improve or impede the delivery of HPV vaccines. PMID- 20719233 TI - Human papillomavirus (HPV) vaccine acceptance and perceived effectiveness, and HPV infection concern among young New Zealand university students. AB - Two-hundred undergraduate students completed an anonymous questionnaire after viewing a human papillomavirus (HPV) vaccine television commercial. Eight-four percent of participants would accept a free HPV vaccine, whereas 47% were unconcerned about future personal HPV infection risk. Males were less likely to accept a free HPV vaccine and to be concerned about future personal HPV infection risk. Perceived HPV vaccine effectiveness was significantly greater among participants who had previously heard of the vaccine and who knew that HPV is sexually transmitted. More education on the role of sexual behavioural characteristics of both males and females in HPV transmission is necessary to promote awareness and concern of personal HPV infection risk and acceptance of HPV vaccination. PMID- 20719235 TI - Human CD133-derived bone marrow stromal cells establish ectopic hematopoietic microenvironments in immunodeficient mice. AB - Cultured adherent bone marrow stromal cells (BMSCs) are capable of forming ectopic hematopoietic microenvironments (HMEs) in immunodeficient mice. However, the cell surface phenotype of the native bone marrow stem/progenitor cell that gives rise to BMSCs that support hematopoiesis remains poorly defined. We recently reported the derivation of human BMSC-like cells (CD133BMSCs) by magnetic cell sorting against Prominin-1 (CD133), an epitope expressed by embryonic, fetal, and adult stem cells. Here we demonstrate that CD133BMSCs are capable of forming ectopic HMEs. Cultured adherent CD133BMSCs derived from sorted CD133-positive cells lacked CD133 expression, but were uniformly positive for CD146, an epitope recently described to identify self-renewing osteoprogenitor cells that could transfer the HME. CD133BMSCs were genetically-tagged by lentivirus, expanded, and seeded into HA/TCP/fibrin constructs that were implanted subcutaneously. After 60days, CD133BMSCs produced human osteocytes, osteoblasts, adipocytes, and reticular cells that supported murine hematopoiesis. CD133BMSCs that were not transduced with lentivirus also formed HMEs. Control constructs seeded with human dermal fibroblasts formed connective tissue, but failed to form HMEs. Our data indicate that CD133 expression identifies a native human bone marrow stem/progenitor cell that gives rise to BMSCs capable of forming the HME. PMID- 20719234 TI - Probing membrane topology of the antimicrobial peptide distinctin by solid-state NMR spectroscopy in zwitterionic and charged lipid bilayers. AB - Distinctin is a 47-residue antimicrobial peptide, which interacts with negatively charged membranes and is active against Gram-positive and Gram-negative bacteria. Its primary sequence comprises two linear chains of 22 (chain 1) and 25 (chain 2) residues, linked by a disulfide bridge between Cys19 of chain 1 and Cys23 of chain 2. Unlike other antimicrobial peptides, distinctin in the absence of the lipid membrane has a well-defined three-dimensional structure, which protects it from protease degradation. Here, we used static solid-state NMR spectroscopy in mechanically aligned lipid bilayers (charged or zwitterionic) to study the topology of distinctin in lipid bilayers. We found that this heterodimeric peptide adopts an ordered conformation absorbed on the surface of the membrane, with the long helix (chain 2), approximately parallel to the lipid bilayer (~5 degrees from the membrane plane) and the short helix (chain 1) forming a ~24 degrees angle with respect to the bilayer plane. Since the peptide does not disrupt the macroscopic alignment of charged or zwitterionic lipid bilayers at lipid-to-protein molar ratio of 50:1, it is possible that higher peptide concentrations might be needed for pore formation, or alternatively, distinctin elicits its cell disruption action by another mechanism. PMID- 20719236 TI - Ephrinb3 induces mesostriatal dopaminergic projection to the striatum. AB - Dopaminergic neurons in midbrain are subdivided into three subsets, forming mesostriatal, mesocortical and mesolimbic projections, respectively. The molecular mechanism specifying mesostriatal projection, which is important for understanding the pathogenesis of Parkinson's disease, remains unclear. To probe the role of axon guide molecule Ephrinb3 in inducing mesostriatal projection, we labeled mesostriatal and mesocortical subset DA neurons with fluorescent microspheres, and purified these subpopulation cells with fluorescence-activated cell sorting (FACS). Moreover, real-time PCR was performed to address the expression of Ephrinb3 in mesostriatal DA neurons, and fluorescence in situ hybridization (FISH) was used to further verify the expression of Ephrinb3 in labeled neurons. The results showed that mesostriatal DA neurons were successfully isolated with retrograde labeling and FACS. Real-time PCR showed that the expression of Ephrinb3 was higher in mesostriatal DA neurons than in mesocortical neurons. Also, Ephrinb3 could be detected in labeled neurons with FISH. Our results indicate that Ephrinb3 is directly involved in the specificity of mesostriatal projection. PMID- 20719237 TI - Application of maximin correlation analysis to classifying protein environments for function prediction. AB - More and more protein structures are being discovered, but most of these still have little functional information. Based on the assumption that structural resemblance would lead to functional similarity, researchers computationally compare a new structure with functionally annotated structures, for high throughput function prediction. The effectiveness of this approach depends critically upon the quality of comparison. In particular, robust classification often becomes difficult when a function class is an aggregate of multiple subclasses, as is the case with protein annotations. For such multiple-subclass classification problems, an optimal method termed the maximin correlation analysis (MCA) was proposed. However, MCA has never been applied to automated protein function prediction although MCA can minimize the misclassification risk in the correlation-based nearest neighbor classification, thus increasing classification accuracy. In this article, we apply MCA to classifying three dimensional protein local environment data derived from a subset of the protein data bank (PDB). In our framework, the MCA-based classifier outperformed the compared alternatives by 7-19% and 6-27% in terms of average sensitivity and specificity, respectively. Given that correlation-based similarity measures have been widely used for mining protein data, we expect that MCA would be employed to enhance other types of automated function prediction methods. PMID- 20719238 TI - Intermediate structure between chromatin fibers and chromosome revealed by mechanical stretching and SPM measurement. AB - The morphology of chromosomes (certain rod-shaped structures) is highly reproducible despite the high condensation of chromatin fibers (~1 mm) into chromosomes (~1 MUm). However, the mechanism underlying the condensation of chromatin fibers into chromosomes is unclear. We assume that investigation of the internal structure of chromosomes will aid in elucidating the condensation process. In order to observe the detailed structure of a chromosome, we stretched a human chromosome by using a micromanipulator and observed its morphology along the stretched region by scanning probe microscopy (SPM). We found that the chromosome consisted of some fibers that were thicker than chromatin fibers. The found fiber was composed of approximately 90-nm-wide beads that were linked linearly. To explore the components of the fiber, we performed immunofluorescence staining of the stretched chromosome. Fluorescence signals of topoisomerase (Topo) IIalpha, which is known to interact with and support chromatin fibers, and DNA were detected both on the found fiber and beads. Furthermore, after micrococcal nuclease and trypsin treatments, the fibers were found to be mechanically supported by proteins. These results suggest that chromosome comprises an intermediate structure between chromatin fibers and chromosomes. PMID- 20719239 TI - Silver nanoparticle applications and human health. AB - Nanotechnology is rapidly growing with nanoparticles produced and utilized in a wide range of commercial products throughout the world. For example, silver nanoparticles (Ag NP) are used in electronics, bio-sensing, clothing, food industry, paints, sunscreens, cosmetics and medical devices. These broad applications, however, increase human exposure and thus the potential risk related to their short- and long-term toxicity. A large number of in vitro studies indicate that Ag NPs are toxic to the mammalian cells derived from skin, liver, lung, brain, vascular system and reproductive organs. Interestingly, some studies have shown that this particle has the potential to induce genes associated with cell cycle progression, DNA damage and apoptosis in human cells at non-cytotoxic doses. Furthermore, in vivo bio-distribution and toxicity studies in rats and mice have demonstrated that Ag NP administered by inhalation, ingestion or intra-peritoneal injection were subsequently detected in blood and caused toxicity in several organs including brain. Moreover, Ag NP exerted developmental and structural malformations in non-mammalian model organisms typically used to elucidate human disease and developmental abnormalities. The mechanisms for Ag NP induced toxicity include the effects of this particle on cell membranes, mitochondria and genetic material. This paper summarizes and critically assesses the current studies focusing on adverse effects of Ag NPs on human health. PMID- 20719240 TI - Eye movements during reading of randomly shuffled text. AB - In research on eye-movement control during reading, the importance of cognitive processes related to language comprehension relative to visuomotor aspects of saccade generation is the topic of an ongoing debate. Here we investigate various eye-movement measures during reading of randomly shuffled meaningless text as compared to normal meaningful text. To ensure processing of the material, readers were occasionally probed for words occurring in normal or shuffled text. For reading of shuffled text we observed longer fixation times, less word skippings, and more refixations than in normal reading. Shuffled-text reading further differed from normal reading in that low-frequency words were not overall fixated longer than high-frequency words. However, the frequency effect was present on long words, but was reversed for short words. Also, consistent with our prior research we found distinct experimental effects of spatially distributed processing over several words at a time, indicating how lexical word processing affected eye movements. Based on analyses of statistical linear mixed-effect models we argue that the results are compatible with the hypothesis that the perceptual span is more strongly modulated by foveal load in the shuffled reading task than in normal reading. Results are discussed in the context of computational models of reading. PMID- 20719242 TI - Drug targeting to the kidney: Advances in the active targeting of therapeutics to proximal tubular cells. AB - Activated signaling cascades in the proximal tubular cells of the kidneys play a crucial role in the development of tubulointerstitial fibrosis. Inhibition of these signaling cascades with locally delivered therapeutics is an attractive approach to minimize the risk of unwanted side effects and to enhance their efficacy within the renal tissue. This review describes the potential avenues to actively target drugs to proximal tubular cells by recognition of internalizing receptors and how drug carriers can reach this cell type from either the apical or basolateral side. Important characteristics of drug carrier systems such as size and charge are discussed, as well as linking technologies that have been used for the coupling of drugs to the presented carrier systems. Lastly, we discuss the cellular handling of drugs by proximal tubular cells after their delivery to the kidneys. PMID- 20719243 TI - Cytotoxicity of eight cigarette smoke condensates in three test systems: comparisons between assays and condensates. AB - Cytotoxic properties of tobacco smoke are associated with chronic tobacco-related diseases. The cytotoxicity of tobacco smoke can be tested with short-term predictive assays. In this study, we compare eight mainstream cigarette smoke condensates (CSCs) from commercial and experimental cigarettes in three different cytotoxicity assays with unique and overlapping endpoints. The CSCs demonstrated cytotoxicity in all assays. In the multiple cytotoxicity endpoint (MCE) assay with TK-6 cells, the cigarette varieties that had the highest EC50s for reduced cell growth also showed a positive dose-response relationship for necrotic cells. In the IdMOC multiple cell-type co-culture (MCTCC) system, all CSCs reduced the viability of the cells. Low concentrations of some CSCs had a stimulatory effect in lung microvascular endothelial cells and small airway epithelial cells. In the neutral dye assay (NDA), except for a 100% flue-cured tobacco CSC, there was little consistency between CSCs producing morphological evidence of moderate or greater toxicity and the CSCs with the lowest EC50s in the MCE or MCTCC assays. Overall, cigarettes made with flue-cured tobacco were the most cytotoxic across the assays. When results were expressed on a per-mg of nicotine basis, lower tar cigarettes were the most cytotoxic in primary human respiratory cells. PMID- 20719244 TI - Drosophila as a model to study age-related neurodegenerative disorders: Alzheimer's disease. AB - Alzheimer's Disease (AD) is the most common cause of dementia in the aging population. Although a variety of drug treatments can delay the onset of disease or temporarily reduce its severity, there is currently no cure or effective long term treatment. This therapeutic void in part reflects an incomplete understanding of the biochemical pathogenesis of this disease. Model organisms, including invertebrates, have been extensively utilized to gain insight into the molecular and cellular mechanisms underlying disease. Here, we will describe how Drosophila has been used to study the function of genes associated with AD and to develop models of this devastating disease. PMID- 20719241 TI - Strategies to inhibit viral protein nuclear import: HIV-1 as a target. AB - Nuclear import is a critical step in the life cycle of HIV-1. During the early (preintegration) stages of infection, HIV-1 has to transport its preintegration complex into the nucleus for integration into the host cell chromatin, while at the later (postintegration) stages viral regulatory proteins Tat and Rev need to get into the nucleus to stimulate transcription and regulate splicing and nuclear export of subgenomic and genomic RNAs. Given such important role of nuclear import in HIV-1 life cycle, this step presents an attractive target for antiviral therapeutic intervention. In this review, we describe the current state of our understanding of the interactions regulating nuclear import of the HIV-1 preintegration complex and describe current approaches to inhibit it. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import. PMID- 20719245 TI - Skin and brain age together: The role of hormones in the ageing process. AB - The importance of the endocrine environment in the initiation of the ageing process has been elucidated in several in vivo and in vitro studies. Changes in endocrine pathways accompany healthy ageing, these include the growth hormone/insulin-like growth factor-I axis (somatopause) and that of sexual hormones, namely estradiol (menopause), testosterone (andropause), and dehydroepiandrosterone and its sulphate (adrenopause). The clinical significance of these changes is variable and results in morphological and functional alterations of all organ systems including the skin and the central nervous system. Moreover, the pathogenesis of age-associated diseases such as epithelial skin cancer and neurodegenerative diseases has been partly attributed to the lack of hormones. Several studies have been conducted in an attempt to reverse the ageing process and clinical signs by substitution of the serum hormone levels in older individuals, however the benefits of hormone replacement therapy, if any, are still controversial. On the other hand, recent data suggest that skin is a window to the human organism and represents an adequate model for ageing research, also implying the use of skin samples for evaluating the ageing status of the central nervous system. PMID- 20719246 TI - Gastro-intestinal delivery of influenza subunit vaccine formulation adjuvanted with Gram-positive enhancer matrix (GEM) particles. AB - In this study, a liquid formulation of influenza subunit vaccine admixed with Gram-positive enhancer matrix (GEM) particles as adjuvant was delivered to upper and lower parts of intestinal tract. The aim was to determine the most effective immunization site in the intestines. Mice were vaccinated with a liquid formulation of GEM and influenza subunit vaccine orally and rectally. The oral administration of the vaccine with GEM particles induced a better systemic and mucosal immune response than oral (vaccine only) and rectal (with and without adjuvant) immunizations. Rectal administration elicited high IgG1 responses but little IgG2a, indicating a Th2 dominated immune response. In contrast, the oral immunization with GEM particles elicited a balanced IgG1 and IgG2a response. In conclusion, our results demonstrate that GEM-adjuvanted influenza vaccine should be targeted to the upper part of the intestinal tract. PMID- 20719247 TI - Rheological and syringeability properties of highly concentrated human polyclonal immunoglobulin solutions. AB - This study of highly concentrated polyvalent immunoglobulin solutions, IgG, aimed at analyzing the relationships between protein concentration and aggregation on the one hand and viscosity on the other hand. Viscosity variations as a function of IgG concentration showed two well-defined behaviours: a Newtonian behaviour for low-concentrated solutions and a shear-thinning behaviour for highly concentrated ones. The viscosity data fitted very well with the Mooney model, suggesting the absence of intermolecular interactions in the IgG solutions that behaved like a non-interacting suspension of hard particles. The polyclonal nature of IgG seems to prevent intermolecular interaction. The shape factor, determined from Mooney fitting, revealed a non-spherical shape of the polyclonal IgG molecules. The rheological properties were also correlated with the injection force (F) through hypodermic needles by syringeability tests. Here, F was mainly affected by three parameters: the solution viscosity, the injection flow rate, and the needle characteristics. In fact, syringeability tests showed that F increased with IgG concentration and flow rate and decreased with the internal diameter of the needle. A zone for optimal injection conditions was then identified taking into account the different affecting parameters and mainly a maximum force for manual injection, which was fixed at 30N. PMID- 20719248 TI - Molecular manipulation associated with disulfide bond formation to enhance the stability of recombinant therapeutic protein. AB - Cys27 in the extracellular domain of human CD83 (hCD83ext), a potential therapeutic protein, was identified as a target for molecular manipulation. Two Escherichia coli strains of BL21(DE3) and Origami B(DE3), respectively, with a reducing and an oxidative cytoplasm were used as the expression host to produce the Cys27 mutants. It was observed that Cys27 was involved in the in vivo formation of intramolecular disulfide bonds when hCD83ext was expressed in Origami B(DE3). The Origami-derived protein products had a higher tendency than the BL21-derived counterparts for multimerization via the in vitro formation of intermolecular disulfide bonds. Various analyses were conducted to identify the structural differences among these mutant variants. Most importantly, molecular stability was enhanced by the Cys27 mutations since the Cys27 mutants derived from either BL21 or Origami were much less susceptible to degradation compared to wild-type hCD83ext. This study highlights the implications of aberrant disulfide bond formation on the production of therapeutic proteins. PMID- 20719249 TI - Maximum likelihood based classification of electron tomographic data. AB - Classification and averaging of sub-tomograms can improve the fidelity and resolution of structures obtained by electron tomography. Here we present a three dimensional (3D) maximum likelihood algorithm--MLTOMO--which is characterized by integrating 3D alignment and classification into a single, unified processing step. The novelty of our approach lies in the way we calculate the probability of observing an individual sub-tomogram for a given reference structure. We assume that the reference structure is affected by a 'compound wedge', resulting from the summation of many individual missing wedges in distinct orientations. The distance metric underlying our probability calculations effectively down-weights Fourier components that are observed less frequently. Simulations demonstrate that MLTOMO clearly outperforms the 'constrained correlation' approach and has advantages over existing approaches in cases where the sub-tomograms adopt preferred orientations. Application of our approach to cryo-electron tomographic data of ice-embedded thermosomes revealed distinct conformations that are in good agreement with results obtained by previous single particle studies. PMID- 20719250 TI - Regulation of virulence factors, carbon utilization and virulence by SNF1 in Cryptococcus neoformans JEC21 and divergent actions of SNF1 between cryptococcal strains. AB - We describe here the functions of a Snf1/AMPK homolog in the human pathogenic yeast Cryptococcus neoformans, strain JEC21. We found that JEC21 SNF1 is a key regulator for the biosynthesis of the major virulence factors, stress resistance and alternative carbon source utilization. Disruption of JEC21 SNF1 results in defects of laccase activity and capsule production, sensitivity to cation stress. Especially, we found that JEC21 SNF1 is essential for growth at elevated temperature and for thermotolerance. To our knowledge, a role for Snf1 proteins in thermotolerance has not been reported. Furthermore, we observed a functional divergence between JEC21 SNF1 and its equivalent from serotype A strain H99. A high temperature is needed for H99 SNF1 to function in stress response and carbon source preference, but not for the JEC21 SNF1. Our results confirmed a critical role of JEC21 SNF1 in regulation of stress response and virulence. Revelation of divergent actions of SNF1 may help to understand the evolution of cryptococcal pathogenesis and provides insights into the strain-associated biosynthesis of virulence factors. PMID- 20719251 TI - Diversification and evolution of the avirulence gene AVR-Pita1 in field isolates of Magnaporthe oryzae. AB - Rice blast disease is the single most destructive plant disease that threatens stable rice production worldwide. Race-specific resistance to the rice blast pathogen has not been durable and the mechanism by which the resistance is overcome remains largely unknown. Here we report the molecular mechanisms of diversification and the instability of the avirulence gene AVR-Pita1 in field strains of Magnaporthe oryzae interacting with the host resistance gene Pi-ta and triggering race-specific resistance. Two-base-pair insertions resulting in frame shift mutations and partial and complete deletions of AVR-Pita1 were identified in virulent isolates. Moreover, a total of 38 AVR-Pita1 haplotypes encoding 27 AVR-Pita1 variants were identified among 151 avirulent isolates. Most DNA sequence variation was found to occur in the exon region resulting in amino acid substitution. These findings demonstrate that AVR-Pita1 is under positive selection and mutations of AVR-Pita1 are responsible for defeating race-specific resistance in nature. PMID- 20719252 TI - Direct, real-time measurement of shear stress-induced nitric oxide produced from endothelial cells in vitro. AB - Nitric oxide (NO) produced by the endothelium is involved in the regulation of vascular tone. Decreased NO production or availability has been linked to endothelial dysfunction in hypercholesterolemia and hypertension. Shear stress induced NO release is a well-established phenomenon, yet the cellular mechanisms of this response are not completely understood. Experimental limitations have hindered direct, real-time measurements of NO under flow conditions. We have overcome these challenges with a new design for a parallel-plate flow chamber. The chamber consists of two compartments, separated by a Transwell(r) membrane, which isolates a NO recording electrode located in the upper compartment from flow effects. Endothelial cells are grown on the bottom of the membrane, which is inserted into the chamber flush with the upper plate. We demonstrate for the first time direct real-time NO measurements from endothelial cells with controlled variations in shear stress. Step changes in shear stress from 0.1 dyn/cm(2) to 6, 10, or 20 dyn/cm(2) elicited a transient decrease in NO followed by an increase to a new steady state. An analysis of NO transport suggests that the initial decrease is due to the increased removal rate by convection as flow increases. Furthermore, the rate at which the NO concentration approaches the new steady state is related to the time-dependent cellular response rather than transport limitations of the measurement configuration. Our design offers a method for studying the kinetics of the signaling mechanisms linking NO production with shear stress as well as pathological conditions involving changes in NO production or availability. PMID- 20719254 TI - Comparison of long-term humoral memory development after immunisation against Neisseria meningitidis B or diphtheria toxoid. AB - Since genome sequence data became available there has been a marked increase in number of protein antigens that have been suggested as prospective vaccine components against Neisseria meningitidis B (MenB). Few studies have addressed the mechanisms by which meningococcal vaccines generate and sustain immunological memory. The goal of this study was to compare the B-cell response (antibody secreting cells [ASC], memory B cell and IgG) evoked by a MenB vaccine (VA-MENGOC BC((r))) with the B-cell response to diphtheria toxoid (DT) induced by a successful vaccine (Diphtheria-Tetanus-Pertussis [DTP]). The results showed different kinetics of specific ASC response after the primary and booster immunisations. Concerning the specific ASC kinetics, MenB vaccine induced a strong primary response, but the recall response showed a limited power over time. In contrast, DTP primary ASC response was weaker than the booster responses. We observed an increase in the relative percent of memory B cells after 1, 2 and 3 doses of MenB vaccine (mean of 0.8%, 1.3% and 1.6%, respectively) but without statistical significance. Similar frequencies were detected after boosting given at 4 months (mean of 1.3%) or 6 months (mean of 0.9%) following the third dose. DT specific memory B cell response showed a slight lower magnitude after the primary immunisation schedule (mean of 1.2% after the third dose) compared with the MenB response. However, a stronger memory B cell response was induced by booster doses of DTP vaccine at 4 months (mean of 1.9%) or 6 months (mean of 1.9%). The kinetics of specific IgG induced by both vaccines was similar, suggesting that memory B cells were responsible for the strong antibody response seen after the booster vaccination. PMID- 20719253 TI - Budesonide versus placebo in high-risk population with screen-detected lung nodules: rationale, design and methodology. AB - BACKGROUND: Screening-CT is able to discover small peripheral lung nodules. The nature of these nodules is uncertain but it is reasonable that some of them, in particular the non-solid ones, could represent precancerous lesions. A previous trial showed a reduction in size of peripheral nodules by inhaled budesonide in subjects with bronchial dysplasia. OBJECTIVE: The primary objective of the study was the evaluation of the effect of budesonide as a chemopreventive agent for lung lesions. The primary endpoint was the modification of lung lesions at ld-CT scan (according to RECIST criteria) after one year of treatment in a person specific analysis. METHODS: We performed a randomized, double-blind, placebo controlled trial to evaluate whether inhaled budesonide was able to reduce size and number of persistent, undetermined CT-detected lung nodules in high-risk asymptomatic subjects currently undergoing a five-year CT scan screening program at the European Institute of Oncology. RESULTS: Trial enrollment started in April 2006 and ended in July 2007 with the randomization of 202 current or former smokers with stable CT-detected lung nodules set to receive budesonide 800 MUg or placebo twice daily for 12 months. CONCLUSION: Our trial represents the first phase II study of a chemopreventive intervention focusing on the peripheral lung, where the majority of lung cancers arise. The research was nested into a screening project with clear advantages in participant accrual and reduction of costs. This paper describes the rationale and design of the study, thus focusing on the methodology and operational aspects of the clinical trial. (Clinicaltrials.gov number. NCT00321893). PMID- 20719255 TI - Weathering a "perfect storm" in surgical education. PMID- 20719256 TI - Surgical residency, class of 2010: the kids are all right. PMID- 20719257 TI - Endoscopic therapy as a first-line therapy for pancreatic-pleural fistula. PMID- 20719259 TI - One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome-MEN 2C? PMID- 20719260 TI - One hundred and seven member family with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome-MEN 2C? PMID- 20719261 TI - Microtubules: in vivo. Preface. PMID- 20719262 TI - Determination of microtubule dynamic instability in living cells. AB - The precise regulation of microtubules and their dynamics is critical for cell cycle progression, cell signaling, intracellular transport, cell polarization, and organismal development. For example, mitosis, cell migration, and axonal outgrowth all involve rapid and dramatic changes in microtubule organization and dynamics. Microtubule-associated proteins (MAPs) such as MAP2 and tau (Bunker et al., 2004; Dhamodharan and Wadsworth, 1995) and microtubule-interacting proteins such as stathmin, the kinesin MCAK, and EB1 (Cassimeris, 1999; Moore and Wordeman, 2004; Ringhoff and Cassimeris, 2009; Rusan et al., 2001) as well as numerous clinically approved or experimental anti-mitotic drugs including the taxanes, vinca alkaloids, and colchicine-like compounds modulate microtubule dynamic in cells (Jordan, 2002; Jordan and Kamath, 2007). In this chapter, we describe methods to analyze the dynamic instability of microtubules in living cells by microscopy of microinjected or expressed fluorescent tubulin, time-lapse microscopy, and analysis of time-dependent microtubule length changes. PMID- 20719263 TI - Analysis of microtubule polymerization dynamics in live cells. AB - The spatiotemporal regulation of intracellular microtubule polymerization dynamics, by numerous microtubule-associated proteins and other mechanisms, is central to many cell processes. Here, we give an overview and practical guide on how to acquire and analyze time-lapse sequences of dynamic microtubules in live cells by either fluorescently labeling entire microtubules or by utilizing proteins that specifically associate only with growing microtubule ends and summarize the strengths and weaknesses of different approaches. We give practical recommendations for imaging conditions, and discuss important limitations of such analysis that are dictated by the maximum achievable spatial and temporal sampling frequencies. PMID- 20719264 TI - The use of fluorescence redistribution after photobleaching for analysis of cellular microtubule dynamics. AB - Microtubules (MTs) are highly dynamic polymers that serve as tracks for vesicular movement during interphase and as structural components of the mitotic spindle, which is used to segregate the genetic material. MT dynamics are highly regulated wherein MTs turnover differentially between interphase and mitosis. Within the mitotic spindle, there are distinct classes of MTs with different dynamic properties. To understand how cellular proteins regulate the dynamics of MTs, it is necessary to have methods to assess their turnover properties. In this chapter we present approaches to assess MT dynamics in cultured mammalian cells using fluorescence redistribution after photobleaching. We include a discussion of cell culture and imaging conditions that maintain cell viability. We also provide an extensive discussion of both data collection and analysis that are utilized to estimate the turnover dynamics of MTs. PMID- 20719265 TI - Kinetochore-microtubule dynamics and attachment stability. AB - Mitosis is the process by which a cell divides its genetic material equally into two daughter cells. Successful division requires that the two identical sister chromatids of a mitotic chromosome attach to the plus-ends of spindle microtubules (MTs) via their kinetochores, which are large protein structures built on centromeric DNA. Attachments between kinetochores and MTs must be persistent so that forces can be generated for chromosome movements, but at the same time they must be compliant, because attached MT plus-ends continuously polymerize and depolymerize to provide force for chromosome congression to the spindle equator. Both the attachment stability of kinetochore-MTs and the degree of dynamic instability exhibited by kinetochore-MTs must be precisely controlled to avoid errors in chromosome segregation. This chapter provides an overview of techniques used in cultured mammalian cells that measure stability and polymerization/depolymerization dynamics of kinetochore-MTs during mitosis. PMID- 20719266 TI - Photoactivatable green fluorescent protein-tubulin. AB - Direct observations of live cells expressing fluorescently tagged tubulin have led to important advances in our understanding of mitosis. A limitation of this approach is that all of the cells' microtubules are fluorescent and thus observation of the behavior of specific subsets of microtubules is precluded. To address this problem, we have tagged tubulin with a photoactivatable variant of green fluorescent protein (PA-GFP), thereby allowing one to follow the behavior of a subset of tagged molecules in the cell. Here, we describe methods to tag and express proteins with PA-GFP, locally photoactivate the recombinant protein and record the dynamic behavior of the photoactivated molecules in live cells. Use of photoactivatable proteins is a powerful approach to examine dynamic processes, including spindle formation, in diverse cells. PMID- 20719267 TI - Microtubule dynamics at the cell cortex probed by TIRF microscopy. AB - Total internal reflection fluorescence (TIRF) microscopy is a technique that allows selective excitation of fluorescence at a liquid/solid interface within a short distance from the boundary. The penetration depth of TIRF microscopy depends on the angle of illumination resulting in a range of depths, which typically vary from approximately similar 70-200 nm up to reverse approximately 500 nm. The advantages of TIRF microscopy include excellent signal-to-noise ratio, high sensitivity, low photobleaching, and low photodamage. TIRF microscopy is widely used for studying cell adhesion, exo- and endocytosis, and the dynamics of plasma membrane-associated molecules. TIRF microscopy can also be applied for selective visualization of any other cellular processes that occur near the basal membrane even if their localization is not restricted to this part of the cell. For example, microtubules are distributed throughout the cytoplasm, but the use of TIRF microscopy makes it possible to visualize specifically the microtubule subpopulation in the vicinity of the basal cortex and thus study cortical microtubule attachment and stabilization, interactions between microtubules and matrix adhesion structures, and the behavior of specific molecules involved in these processes. In this chapter we describe the application of a commercially available setup to analyze microtubule behavior in live mammalian cells using TIRF microscopy. PMID- 20719268 TI - Microtubule dynamics in dendritic spines. AB - Neuronal microtubules recently emerged as temporal and spatial regulators of dendritic spines, the major sites of excitatory synaptic input. By imaging microtubules in cultured mature primary hippocampal neurons using fluorescently tagged tubulin and microtubule plus-end binding (EB) protein EB3, dynamic microtubules were found to regularly depart from the dendritic shaft and enter dendritic spines. Evidence indicates that microtubule invasions into spines regulate spine actin dynamics and induce transient morphological changes, such as the formation of spine head protrusion and spine growth. Because alterations in spine morphology play an important role in synaptic plasticity and have been linked to learning and memory formation, it is possible that dynamic microtubules are engaged in adaptive processes in the adult brain. This chapter provides detailed methods for live imaging of dynamic microtubules in mature hippocampal neurons in culture. We describe protocols for culturing and transfecting mature hippocampal neurons and visualizing microtubules and microtubule plus-EB proteins by total internal reflection fluorescence microscopy and spinning disk confocal microscopy. PMID- 20719269 TI - Protein micropatterns: A direct printing protocol using deep UVs. AB - The described protocol is a simple method to make protein micropatterns with a micron size resolution. It can be applied to control cell shape and adhesive geometry, and also for any other assay requiring protein patterning. It is based on the use of a photomask with microfeatures to locally irradiate with deep UV light (below 200 nm) an antifouling substrate, making it locally adsorbing for proteins. The entire process can be subdivided into three main parts. The first part describes the design of a photomask. The second part describes the passivation (antifouling treatment) of the substrate, its irradiation, and the binding of proteins. The entire process can be completed in a couple of hours. It requires no expensive equipment and can be performed in any biology lab. The last part describes cell deposition on the micropatterned substrate. We also provide a discussion with pitfalls and alternative techniques adapted to various substrates, including silicone elastomers. PMID- 20719270 TI - New and old reagents for fluorescent protein tagging of microtubules in fission yeast; experimental and critical evaluation. AB - The green fluorescent protein (GFP) has become a mainstay of in vivo imaging in many experimental systems. In this chapter, we first discuss and evaluate reagents currently available to image GFP-labeled microtubules in the fission yeast Schizosaccharomyces pombe, with particular reference to time-lapse applications. We then describe recent progress in the development of robust monomeric and tandem dimer red fluorescent proteins (RFPs), including mCherry, TagRFP-T, mOrange2, mKate, and tdTomato, and we present data assessing their suitability as tags in S. pombe. As part of this analysis, we introduce new PCR tagging cassettes for several RFPs, new pDUAL-based plasmids for RFP-tagging, and new RFP-tubulin strains. These reagents should improve and extend the study of microtubules and microtubule-associated proteins in S. pombe. PMID- 20719271 TI - Optical trapping and laser ablation of microtubules in fission yeast. AB - Manipulation has been used as a powerful investigation technique since the early history of biology. Every technical advance resulted in more refined instruments that led to the discovery of new phenomena and to the solution of old problems. The invention of laser in 1960 gave birth to what is now called optical manipulation: the use of light to interact with matter. Since then, the tremendous progress of laser technology made optical manipulation not only an affordable, reliable alternative to traditional manipulation techniques but disclosed also new, intriguing applications that were previously impossible, such as contact-free manipulation. Currently, optical manipulation is used in many fields, yet has the potential of becoming an everyday technique in a broader variety of contexts. Here, we focus on two main optical manipulation techniques: optical trapping and laser ablation. We illustrate with selected applications in fission yeast how in vivo optical manipulation can be used to study organelle positioning and the force balance in the microtubule cytoskeleton. PMID- 20719272 TI - A fast microfluidic temperature control device for studying microtubule dynamics in fission yeast. AB - Recent development in soft lithography and microfluidics enables biologists to create tools to control the cellular microenvironment. One such control is the ability to quickly change the temperature of the cells. Genetic model organism such as fission yeast has been useful for studies of the cell cytoskeleton. In particular, the dynamic microtubule cytoskeleton responds to changes in temperature. In addition, there are temperature-sensitive mutations of cytoskeletal proteins. We describe here the fabrication and use of a microfluidic device to quickly and reversibly change cellular temperature between 2 degrees C and 50 degrees C. We demonstrate the use of this device while imaging at high resolution microtubule dynamics in fission yeast. PMID- 20719273 TI - Microtubule-dependent spatial organization of mitochondria in fission yeast. AB - The microtubule cytoskeleton has an important role in the control of mitochondrial distribution in higher eukaryotes. In humans, defects in axonal mitochondrial transport are linked to neurodegenerative diseases. This chapter highlights fission yeast Schizosaccharomyces pombe as a powerful genetic model system for the study of microtubule-dependent mitochondrial movement, dynamics and inheritance. PMID- 20719274 TI - Microscopy methods for the study of centriole biogenesis and function in Drosophila. AB - Centrosomes regulate cell motility, adhesion, and polarity in interphase and participate in spindle formation in mitosis. They are composed of two centrioles, which are microtubule-based structures, and a proteinaceous matrix recruited by those, called pericentriolar material. Centrioles are also necessary for the nucleation of the axoneme, the microtubule inner structure of cilia and flagella. The fruit fly, Drosophila melanogaster, has played an important role in the study of cell biology processes and their contextualization in a variety of developmental phenomena. In this chapter, we describe immunofluorescence and electron microscopy methods used to study Drosophila early embryogenesis and spermatogenesis. These methods have been widely used to study centriole assembly and its function as a centrosome organizer during mitotic and meiotic cell divisions and as an axoneme nucleator in the formation of flagella. PMID- 20719275 TI - Drosophila S2 cells as a model system to investigate mitotic spindle dynamics, architecture, and function. AB - In order to perpetuate their genetic content, eukaryotic cells have developed a microtubule-based machine known as the mitotic spindle. Independently of the system studied, mitotic spindles share at least one common characteristic--the dynamic nature of microtubules. This property allows the constant plasticity needed to assemble a bipolar structure, make proper kinetochore-microtubule attachments, segregate chromosomes, and finally disassemble the spindle and reform an interphase microtubule array. Here, we describe a variety of experimental approaches currently used in our laboratory to study microtubule dynamics during mitosis using Drosophila melanogaster S2 cells as a model. By using quantitative live cell imaging microscopy in combination with an advantageous labeling background, we illustrate how several cooperative pathways are used to build functional mitotic spindles. We illustrate different ways of perturbing spindle microtubule dynamics, including pharmacological inhibition and RNA interference of proteins that directly or indirectly impair microtubule dynamics. Additionally, we demonstrate the advantage of using fluorescent speckle microscopy to investigate an intrinsic property of spindle microtubules known as poleward flux. Finally, we developed a set of laser microsurgery-based experiments that allow, with unique spatiotemporal resolution, the study of specific spindle structures (e.g., centrosomes, microtubules, and kinetochores) and their respective roles during mitosis. PMID- 20719276 TI - Assessment of mitotic spindle phenotypes in Drosophila S2 cells. AB - The Drosophila S2 cell line is popularly used to study mitosis. In this cell line, multiple genes can be easily and efficiently knocked down by RNA interference (RNAi), and the associated mitotic phenotypes can be assessed with high-resolution microscopy after immunofluorescence or in a living cell. However, compared to untransformed cells in wild-type organisms such as yeasts or worms, mitosis in the S2 cell line is more variable and often looks abnormal even in RNAi-untreated cells. Therefore, in order to judge whether a phenotype is derived from RNAi of the target gene or is simply a variation of control cells, it is critical to prepare proper control samples and perform objective imaging and image analysis. Here, we discuss how bona fide mitotic phenotypes associated with RNAi can be identified, avoiding selecting false positives, in S2 cells. PMID- 20719277 TI - Analysis of microtubules in budding yeast. PMID- 20719278 TI - Imaging and analysis of the microtubule cytoskeleton in giardia. AB - Giardia intestinalis, a common parasitic protist, possesses a complex microtubule cytoskeleton critical for cellular function and transitioning between the cyst and trophozoite life cycle stages. The giardial microtubule cytoskeleton is comprised of highly dynamic and stable structures. Novel microtubule structures include the ventral disc that is essential for the parasite's attachment to the intestinal villi to avoid peristalsis. The completed Giardia genome combined with new molecular genetic tools and live imaging will aid in the characterization and analysis of cytoskeletal dynamics in Giardia. Fundamental areas of giardial cytoskeletal biology remain to be explored and knowledge of the molecular mechanisms of cytoskeletal functioning is needed to better understand Giardia's unique biology and pathogenesis. PMID- 20719279 TI - Live cell-imaging techniques for analyses of microtubules in Dictyostelium. AB - Dictyostelium amoebae provide a popular model system for analyses of cell and cytoskeletal dynamics. Yet, the sensitivity of Dictyostelium cells to phototoxic effects, their rapid cell movement, and the extraordinary motility of their microtubule system are specific challenges for live cell imaging. The protocols outlined in this chapter are optimized to minimize these challenges, using Dictyostelium cells expressing green fluorescent tubulin or microtubule plus-end markers such as TACC. We describe suitable specimen preparations, treatments with microtubule-depolymerizing drugs, and applicable settings on wide-field and confocal microscopy systems for four-dimensional time-lapse and fluorescence recovery after photobleaching analyses of microtubule dynamics. PMID- 20719280 TI - Imaging of mitotic spindle dynamics in Caenorhabditis elegans embryos. AB - Development of the nematode Caenorhabditis elegans is highly reproducible, and the cell division patterns are virtually invariant. Transparency of the eggshell and cells enables the observation of intracellular events with a high temporal and spatial resolution. These unique features, along with the sophisticated genetic techniques, make this organism one of the most attractive model systems for dissecting regulatory mechanisms of dynamic cellular behaviors, such as mitosis, at an organismal level. In this chapter, we describe immunofluorescence and live imaging methods for analyzing mitotic spindle regulation. In particular, we present the use of double- or triple-labeled fluorescent strains for high resolution two-dimensional and three-dimensional live imaging to analyze dynamic behaviors of mitotic spindles. PMID- 20719281 TI - Microtubule dynamics in plant cells. AB - This chapter describes some of the choices and unavoidable compromises to be made when studying microtubule dynamics in plant cells. The choice of species still depends very much on the ability to produce transgenic plants and most work has been done in the relatively small cells of Arabidopsis plants or in tobacco BY-2 suspension cells. Fluorescence-tagged microtubule proteins have been used to label entire microtubules, or their plus ends, but there are still few minus-end markers for these acentrosomal cells. Pragmatic decisions have to be made about probes, balancing the efficacy of microtubule labeling against a tendency to overstabilize and bundle the microtubules and even induce helical plant growth. A key limitation in visualizing plant microtubules is the ability to keep plants alive for long periods under the microscope and we describe a biochamber that allows for plant cell growth and development while allowing gas exchange and reducing evaporation. Another major difficulty is the limited fluorescence lifetime and we describe imaging strategies to reduce photobleaching in long-term imaging. We also discuss methods of measuring microtubule dynamics, with emphasis on the behavior of plant-specific microtubule arrays. PMID- 20719282 TI - Melanophores for microtubule dynamics and motility assays. AB - Microtubules (MTs) are cytoskeletal structures essential for cell division, locomotion, intracellular transport, and spatial organization of the cytoplasm. In most interphase cells, MTs are organized into a polarized radial array with minus-ends clustered at the centrosome and plus-ends extended to the cell periphery. This array directs transport of organelles driven by MT-based motor proteins that specifically move either to plus- or to minus-ends. Along with using MTs as tracks for cargo, motor proteins can organize MTs into a radial array in the absence of the centrosome. Transport of organelles and motor dependent radial organization of MTs require MT dynamics, continuous addition and loss of tubulin subunits at minus- and plus-ends. A unique experimental system for studying the role of MT dynamics in these processes is the melanophore, which provides a useful tool for imaging of both dynamic MTs and moving membrane organelles. Melanophores are filled with pigment granules that are synchronously transported by motor proteins in response to hormonal stimuli. The flat shape of the cell and the radial organization of MTs facilitate imaging of dynamic MT plus ends and monitoring of their interaction with membrane organelles. Microsurgically produced cytoplasmic fragments of melanophores are used to study the centrosome-independent rearrangement of MTs into a radial array. Here we describe the experimental approaches to study the role of MT dynamics in intracellular transport and centrosome-independent MT organization in melanophores. We focus on the preparation of cell cultures, microsurgery and microinjection, fluorescence labeling, and live imaging of MTs. PMID- 20719283 TI - Imaging cilia in zebrafish. AB - Research focused on cilia as extremely important cellular organelles has flourished in recent years. A thorough understanding of cilia regulation and function is critical, as disruptions of cilia structure and/or function have been linked to numerous human diseases and disorders. The tropical freshwater zebrafish is an excellent model organism in which to study cilia structure and function. We can readily image cilia and their motility in embryonic structures including Kupffer's vesicle during somite stages and the pronephros from 1 day postfertilization onward. Here, we describe how to image cilia by whole-mount immunofluorescence, transverse cryosection/immunohistochemistry, and transmission electron microscopy. We also describe how to obtain videos of cilia motility in living embryos. PMID- 20719284 TI - Modeling microtubule-mediated forces and centrosome positioning in Caenorhabditis elegans embryos. AB - Microtubules and associated motor proteins are the major generators and mediators of the forces that organize the functional positioning of intracellular structures. The positioning of the centrosomes is a primary target for microtubule-mediated organization. The positioning of the centrosomes further defines the positionings of nucleus, mitotic spindles, and other organelles. Numerical modeling is an effective means by which we can further understand the physical mechanisms underlying microtubule-mediated centrosome positioning. Here, we summarize how we formulated the biophysical properties of microtubules in order to construct a numerical model of centrosome positioning in Caenorhabditis elegans embryos. Microtubules elongate and shrink in a stochastic manner, in a process known as "dynamic instability." Upon association with the cell cortex or motor proteins, microtubules mediate pushing and pulling forces. These forces move the centrosome, which is located at the minus-end of the microtubules, to the right place with the right timing. We discuss how the modeling efforts complement experimental knowledge and allow us to evaluate the sufficiency of various candidate hypotheses. PMID- 20719285 TI - Cryo-electron tomography of cellular microtubules. AB - Microtubules are intrinsically dynamic structures. In the cellular environment many proteins and protein complexes are associated with microtubules that influence or functionalize microtubule dynamics. Therefore, investigation of the structure and dynamics of microtubules with their associated complexes inside the cellular environment lies at the heart of fully understanding their function. Cryo electron microscopy has been essential in structural microtubule research since the atomic structure of tubulin and the structure of microtubules were unraveled using this technique. Furthermore, the specific structures at the microtubule ends linked to the growing or shrinking states were also detected by cryo electron microscopy. Electron microscopy studies on microtubules were mainly performed in vitro but microtubules can also be investigated inside cells, using cryo electron tomography. Cryo electron tomography is an important tool in structural biology research because it enables visualization of single and unique protein complexes in a cellular environment and at a molecular resolution. Cryo electron tomography is a three-dimensional (3D) imaging technique in which electron microscopy tomographic imaging is performed on cryogenically cooled, vitrified specimens after which the object is computationally reconstructed. Here, I describe the materials and methods for cryo electron tomography of microtubules and in whole cells, describing cell growth, specimen vitrification, localization of microtubules, cryo electron tomography recording, tomographic image reconstruction, and 3D visualization techniques. PMID- 20719286 TI - Automated identification of microtubules in cellular electron tomography. AB - We describe a method for automatically finding the location and conformations of microtubules in tomograms of high-pressure frozen, freeze substituted cells. Our approach uses two steps: a preprocessing step that finds locations in the tomograms that are likely to lie inside microtubules and a tracking step that uses the preprocessed data to identify the trajectories of individual microtubules. We test this method on a reconstruction of a Caenorhabditis elegans mitotic spindle and we compare our results with those obtained by a human expert who manually segmented the same data. At present, the method could be used to assist the analysis of large-scale tomography reconstructions. With further improvements, it may be possible to reliably segment cellular tomograms without human intervention. PMID- 20719287 TI - Quality control in single-molecule studies of kinesins and microtubule-associated proteins. AB - Commercial microscopes capable of single-molecule experiments have made it simple for researchers to adopt these powerful techniques. This chapter is meant to help newcomers assess whether their data is of sufficient quality to warrant time intensive analysis. Two problems can hamper single-molecule experiments: (1) non specific aggregation of the proteins of interest and (2) detection thresholds from a poor microscope setup. I outline four steps that researchers can take to overcome these problems and convince themselves that they are observing bona fide single molecules. PMID- 20719288 TI - Response-repetition effects in task switching with and without response execution. AB - Previous research into the mechanisms of task switching has shown that repeating the same response in a different task context is associated with costs. To investigate whether such response-repetition costs occur even when the first of the two responses is not overtly executed, we used a variant of the change-signal paradigm. Subjects responded to a first stimulus by pressing a left or right response key. In half of the trials, a second stimulus occurred after a variable, adaptively adjusted delay, indicating to abandon the first response, and only respond to the second stimulus using another set of left and right response keys. In Experiment 1, different tasks had to be performed with the first and second stimulus (task-switch condition); in Experiment 2, the same task had to be performed with both stimuli (task-repetition condition). Response-repetition costs were obtained in Experiment 1, and response-repetition benefits in Experiment 2. Importantly, these costs and benefits were obtained even when the first of the two responses had not been overtly executed. The data support the idea that interference of task-specific response codes occurs at the level of abstract response codes. Interference of such response codes occurs even when the responses are not overtly executed. PMID- 20719289 TI - Normative longitudinal maternal sleep: the first 4 postpartum months. AB - OBJECTIVE: To describe the normative course of maternal sleep during the first 4 months postpartum. STUDY DESIGN: Sleep was objectively measured using continuous wrist actigraphy. This was a longitudinal, field-based assessment of nocturnal sleep during postpartum weeks 2 through 16. Fifty mothers participated during postpartum weeks 2 through 13; 24 participated during postpartum weeks 9 through 16. RESULTS: Maternal nocturnal sleep time was 7.2 (SD +/- 0.95) hours and did not change significantly across postpartum weeks 2 through 16. Maternal sleep efficiency did improve across weeks 2 (79.7%; SD +/- 5.5) through 16 (90.2%; SD +/- 3.5) as a function of decreased sleep fragmentation across weeks 2 (21.7; SD +/- 5.2) through 16 (12.8; SD +/- 3.3). CONCLUSION: Though postpartum mothers' total sleep time was higher than expected during the initial postpartum months, this sleep was highly fragmented (similar to fragmenting sleep disorders) and inefficient. This profile of disturbed sleep should be considered in intervention designs and family leave policies. PMID- 20719290 TI - Prediction of spontaneous preterm birth in asymptomatic twin pregnancies using the change in cervical length over time. PMID- 20719292 TI - The relationship between amniotic fluid levels of brain-type natriuretic peptide and recipient cardiomyopathy in twin-twin transfusion syndrome. AB - OBJECTIVE: We sought to evaluate amniotic fluid brain natriuretic peptide (BNP) levels as a biomarker of recipient twin (RT) cardiomyopathy (RTCM) in twin-twin transfusion syndrome. STUDY DESIGN: Amniotic fluid samples were obtained from 157 twin-twin transfusion syndrome RTs and from 6 singletons (controls) from 2007 through 2009. N-terminal prohormone BNP (NT-proBNP) levels were quantified by enzyme-linked immunosorbent assay. RTCM was classified as mild (IIIA), moderate (IIIB), or severe (IIIC) by fetal echocardiography. The relationship between NT proBNP and RTCM was evaluated using analysis of variance. The ability of NT proBNP to predict moderate or greater RTCM was evaluated by receiver operating characteristic analysis. RESULTS: There is a significant positive correlation between NT-proBNP levels and worsening RTCM (r = 0.33; P < .001). NT-proBNP thresholds of 569 fmol/mg and 369 fmol/mg had a sensitivity of 70% and 87%, and specificity of 67% and 42%, respectively, in predicting moderate or greater RTCM. CONCLUSION: This is the first large case series that demonstrates a relationship between NT-proBNP and RTCM. This pathophysiologic insight supports ongoing efforts to develop screening biomarkers. PMID- 20719293 TI - Beta 2 adrenergic agents and autism. PMID- 20719294 TI - The effect of magnesium sulfate on the activity of matrix metalloproteinase-9 in fetal cord plasma and human umbilical vein endothelial cells. AB - OBJECTIVE: Clinical evidence suggests that magnesium sulfate may reduce the risk of fetal neurologic injury in preterm delivery. Matrix metalloproteinase-9 (MMP 9) levels are elevated in preterm labor patients. There is evidence that MMP-9 may break down the blood-brain barrier in humans, causing cytokine mediated cell injury. Our objective was to determine whether the addition of magnesium sulfate attenuates activity of MMP-9, a complex zinc-dependent enzyme, in fetal cord plasma. STUDY DESIGN: We collected cord plasma in 6 term, unlabored patients. Using enzyme-linked immunosorbent assay, we measured the activity of MMP-9 with varying concentrations of magnesium sulfate added in vitro. Results were verified using a human umbilical cord vein endothelial cell (HUVEC) line. RESULTS: Addition of physiologic doses of magnesium sulfate (0.07 mg/mL) resulted in a 25% decrease in active MMP-9 (P = .03). In a HUVEC line, magnesium sulfate resulted in a 32% decrease in MMP-9 activity (P = .00012). CONCLUSION: The addition of magnesium sulfate attenuated MMP-9 activity in cord plasma and in a HUVEC line. PMID- 20719295 TI - Inner segment/outer segment junction assessed by spectral-domain optical coherence tomography in patients with idiopathic epiretinal membrane. AB - PURPOSE: To evaluate the anatomic features of the photoreceptor inner/outer segment (IS/OS) junction before and after surgery by spectral-domain optical coherence tomography in patients undergoing idiopathic epiretinal membrane (ERM) surgery and to correlate these features with the functional outcomes. DESIGN: Prospective, cohort study. METHODS: We prospectively studied 45 eyes of 45 patients with idiopathic epiretinal membrane who had a preoperative visual acuity of 20/32 or less and were scheduled to undergo transconjunctival 25-gauge vitrectomy. The patients were divided into 2 groups based on the preoperative structural integrity of the IS/OS junction: the intact IS/OS junction group and the disrupted IS/OS junction group. Changes in the IS/OS junction and best corrected visual acuity were compared between 2 groups before and at 3, 6, and 12 months after surgery. RESULTS: A total of 45 patients were recruited for this study. There were 34 eyes with an intact IS/OS junction (group 1) and 11 eyes with a disrupted or irregular IS/OS junction (group 2), as determined before surgery. Significantly better postoperative best-corrected visual acuity was seen in group 1 as compared with that in group 2 at 3, 6, and 12 months after the surgery (P < .001). Significant improvement of visual acuity was also seen in group 1 when compared to group 2 (P < .05). Of the 34 eyes in group 1, 17 (50%) showed disruption of the IS/OS junction at 3 months after surgery, although this disruption was only transient and resolved completely by 12 months after the surgery. However, none of the eyes from group 2 showed a normal appearance of the IS/OS junction at any time point during the study period of 1 year. CONCLUSIONS: The IS/OS junction can recover in eyes with preoperative intact IS/OS junction as assessed over a follow-up period of 1 year after surgery. Preoperative integrity of the IS/OS junction may be an important prognostic factor for better visual recovery and better improvement of the postoperative best-corrected visual acuity after epiretinal membrane surgery. PMID- 20719296 TI - Long-term temporal changes of macular thickness and visual outcome after vitrectomy for idiopathic epiretinal membrane. AB - PURPOSE: To evaluate the long-term correlation of visual outcome and macular thickness after vitrectomy for idiopathic epiretinal membrane and to identify prognostic factors for good visual outcome. DESIGN: Retrospective, observational case series. METHODS: We reviewed the records of 52 patients with idiopathic epiretinal membrane who were treated with vitrectomy and could be followed up for more than 12 months. The main outcome measures were best-corrected visual acuity (BCVA) and central macular thickness at baseline; at 1, 3, 6, and 12 months after surgery; and at the final follow-up visit. The correlation between BCVA and central macular thickness was analyzed and the receiver operating characteristic curve analysis was performed to obtain cutoff values for visual prognosis. RESULTS: Most of the changes in BCVA and central macular thickness took place during the first 3 months and reached a plateau at 12 months after surgery. Despite the lack of changes in BCVA after 12 months of follow-up, significant reduction in central macular thickness could still be observed over 12 months after surgery. The final BCVA was correlated significantly with preoperative BCVA and central macular thickness and early postoperative central macular thickness. Among them, the postoperative central macular thickness at 1 month showed the largest area under the receiver operating characteristic curve. CONCLUSIONS: Given the removal of the confounding effect of cataract, postoperative follow-up of 12 months may be sufficient to reach the final BCVA after surgery. However, more time is needed to achieve final central macular thickness. Because of the significant correlation between final BCVA and early postoperative central macular thickness, serial optical coherence tomography images in the early postoperative period were needed to predict visual outcome after epiretinal membrane removal. PMID- 20719297 TI - The posterior limb in the medial canthal tendon in asians: does it exist? AB - PURPOSE: To analyze the medial canthal tendon and to clarify the true anatomic nature of the posterior limb of this tendon. DESIGN: Observational anatomic study. METHODS: Eleven postmortem eyelids of 9 Asian cadavers (6 right and 5 left eyes; age average, 77.2 years) were analyzed. Axial sections in parallel to the eyelid margin starting at 1 mm above the upper eyelid margin were made. The sliced specimens were dehydrated and embedded in paraffin, cut into 7-MUm thickness sections, and stained with Masson trichrome. To demonstrate the hardness felt when the Horner muscle is pulled, 3 additional postmortem eyelids of 2 Asians (2 right and 1 left eyes; age, 70 and 75 years at death) were analyzed. The pulling process was documented with a video camera. RESULTS: The posterior limb of the medial canthal tendon was not detected in any of the specimens. The Horner muscle originated via its tendon from the posterior lacrimal crest and the anterior area of the medial orbital wall. The lacrimal diaphragm around the posterior lacrimal crest ran almost parallel to the Horner muscle and usually was difficult to distinguish from the tendon of the Horner muscle. The medial check ligament supported the posterior aspect of the Horner muscle and was inserted into the medial orbital wall. The hard sensation that was felt when the Horner muscle was pulled was demonstrated in the video. CONCLUSIONS: The posterior limb of the medial canthal tendon was not detected in any of the specimens. This anatomic structure seems to be a part of the Horner muscle. PMID- 20719298 TI - A randomized intraindividual comparison of the accommodative performance of the bag-in-the-lens intraocular lens in presbyopic eyes. AB - PURPOSE: To compare the accommodative performance of the Morcher BioComFold Type 89A bag-in-the-lens intraocular lens (IOL) with a conventional in-the-bag control IOL in presbyopic eyes. DESIGN: Prospective, randomized clinical trial with intraindividual comparison. METHODS: SETTING: Department of Ophthalmology, St. Thomas' Hospital, London, United Kingdom. STUDY POPULATION: Fifty-two eyes of 26 patients with bilateral age-related cataracts. INTERVENTION: Phacoemulsification cataract extraction with implantation of a bag-in-the-Lens and a control IOL, the Alcon AcrySof SA60AT (Alcon Laboratories, Fort Worth, Texas, USA), randomized to either eye. MAIN OUTCOME MEASURES: Axial IOL shift stimulated by physiologic (near visual effort) and pharmacologic (pilocarpine and cyclopentolate) accommodative stimulation was measured objectively with partial coherence interferometry. Other outcome measures were objective and subjective accommodation, logarithm of the minimal angle of resolution distance-corrected near visual acuity, and defocus curves. RESULTS: Three months after surgery, axial IOL shift stimulated by near visual effort measured -5.9 +/- 10.3 MUm in bag-in-the-lens eyes versus -8.4 +/- 12.8 MUm in control eyes (P = .37), that stimulated by pilocarpine measured 20.2 +/- 165.6 MUm versus 50.4 +/- 164.4 MUm (P = .36), and that stimulated by cyclopentolate measured -65.8 +/- 64.3 MUm versus -54.0 +/- 37.5 MUm (P = .34), respectively (n = 25). Objective accommodation measured 0.03 +/- 0.18 diopters (D) in bag-in-the-lens eyes versus 0.08 +/- 0.21 D in control eyes (P = .40), whereas subjective accommodation measured 2.48 +/- 0.72 D versus 2.45 +/- 0.80 D (P = .75), respectively. Distance corrected near visual acuity and defocus curves showed no difference between IOLs. CONCLUSIONS: The bag-in-the-lens IOL demonstrated negligible axial shift and objective accommodation with physiologic near visual stimulation. The IOL shift demonstrated with pilocarpine also was clinically insignificant. The bag-in the-lens IOL showed no accommodative or near visual advantage over a conventional in-the-bag IOL, despite its unique capsular fixation method. This provides further evidence that the focus-shift principle fails to produce clinically significant IOL movement. PMID- 20719299 TI - Multicenter survey with a systematic overview of acute-onset endophthalmitis after transconjunctival microincision vitrectomy surgery. AB - PURPOSE: To explore the incidence and visual outcomes of acute-onset endophthalmitis after transconjunctival microincision vitrectomy surgery (MIVS). DESIGN: Retrospective, interventional, multicenter survey with a systematic review. METHODS: A clinical database search was performed at 27 institutions involving 43 868 consecutive patients who underwent vitrectomy between November 2003 and October 2008 to identify all patients with endophthalmitis after vitrectomy. A systematic review of studies reporting the endophthalmitis rates after MIVS versus 20-gauge vitrectomy was conducted to assess the pooled incidence rates of postvitrectomy endophthalmitis. RESULTS: The endophthalmitis rates from the multicenter survey were 0.034% (10 cases per 29 030 eyes) after 20 gauge vitrectomy and 0.054% (8 cases per 14 838 eyes) after MIVS, with no significant (P = .603) differences between groups. Although the incidence in 25 gauge cases (6 per 8238 eyes; 0.073%) was greater than in 23-gauge cases (2 per 6600 eyes; 0.030%), the difference was not significant (P = 0.451). Of 8 eyes in which endophthalmitis developed after MIVS, 6 eyes (75%) had a final visual acuity of 0.5 or better, and none lost light perception. By combining the results of 7 studies, including the current multicenter survey, meta-analyses from a total of 77 956 cases at the baseline showed that the pooled endophthalmitis rates after MIVS (0.08%; 95% confidence interval, 0.030% to 0.164%) and after 20 gauge vitrectomy (0.030%; 95% confidence interval, 0.012% to 0.048%) did not differ significantly (P = .207, pooled risk difference; 0.0005 [95% confidence interval, -0.0002 to 0.0012]). CONCLUSIONS: The incidence of postvitrectomy endophthalmitis was low with no significant differences between MIVS and 20-gauge vitrectomy. PMID- 20719300 TI - Polypoidal choroidal vasculopathy masquerading as neovascular age-related macular degeneration refractory to ranibizumab. AB - PURPOSE: To report a neovascular age-related macular degeneration pattern refractory to ranibizumab. DESIGN: Retrospective, observational case series. METHODS: Between March and May 2009, cases with neovascular age-related macular degeneration refractory to ranibizumab were investigated with indocyanine green angiography. We identified 12 eyes of 12 patients with polypoidal choroidal vasculopathy. Refractory to treatment were defined cases with persistent subretinal or intraretinal fluid, or both, after 3 or more consecutive monthly ranibizumab injections regardless of best-corrected visual acuity. RESULTS: All patients identified were white, of whom 6 were male. Mean age +/- standard deviation at presentation was 75 +/- 5.6 years (range, 64 to 81 years); diagnosis, based on fluorescein angiography, comprised occult choroidal neovascularization (CNV) in 8 eyes, and 1 case each of classic-no-occult CNV, minimally classic CNV, predominantly classic CNV, and retinal angiomatous proliferation. Eight cases had switched from courses of other therapy (5 pegaptanib, 1 photodynamic therapy, 1 photodynamic therapy then pegaptanib, 1 bevacizumab). After a mean follow-up of 10.2 +/- 4.8 months (range, 3 to 18 months) and 7.6 +/- 3.9 ranibizumab injections (range, 3 to 14 injections), indocyanine green angiography revealed polypoidal choroidal vasculopathy lesions in all cases. CONCLUSIONS: Neovascular age-related macular degeneration refractory to a course of ranibizumab injections may harbor polypoidal choroidal vasculopathy. In such cases, indocyanine green angiography is a valuable tool for revealing polypoidal lesions. PMID- 20719301 TI - Intravitreal ranibizumab for choroidal neovascularization in angioid streaks. AB - PURPOSE: To analyze retrospectively the efficacy of intravitreal ranibizumab injections for the management of choroidal neovascularization (CNV) in patients with angioid streaks. DESIGN: Nonrandomized, double-center, retrospective, interventional case series. METHODS: A consecutive series of patients affected with CNV associated with angioid streaks were treated with intravitreal ranibizumab injections (0.5 mg/0.05 mL). Best-corrected visual acuity, fundus photography results, optical coherence tomography (OCT) results, and fluorescein angiography results were examined before and after treatment. The primary end point was the percentage of eyes with stable or improved visual acuity at the end of follow-up. Secondary end points were the percentage of eyes with stable or decreased macular thickness on optical coherence tomography and the percentage of eyes with persistent leakage on fluorescein angiography at the last follow-up examination. RESULTS: Thirty-five eyes of 27 patients were treated with repeated intravitreal ranibizumab injections (mean, 5.7 injections; range, 2 to 14 injections) for a mean of 24.1 months (range, 6 to 37 months). At the end of follow-up, visual acuity was stabilized or improved in 30 (85.7%) of 35 eyes. Macular thickness had stabilized or decreased in 18 (51.5%) of 35 eyes. At the last follow-up examination, on fluorescein angiography, no further leakage was observed in 23 (65.7%) of 35 eyes. CONCLUSIONS: In this large series of angioid streaks-associated CNV, ranibizumab injections allowed stabilization of visual acuity. Ranibizumab seems to be a safe therapeutic option in CNV associated with angioid streaks. PMID- 20719302 TI - Scale for photographic grading of vitreous haze in uveitis. AB - PURPOSE: To validate a scale for grading vitreous haze in uveitis using digitized photographs and standardized scoring. DESIGN: Evaluation of clinical research methodology. METHODS: Calibrated Bangerter diffusion filters inducing incremental decrements of spatial contrast were placed in front of the camera lens while photographing a normal eye to simulate vitreous haze. The photographs were digitized and an ordinal scale was created from 0 (none) to 8 (highest level of opacification at which fundus details could be seen). The scale steps correspond approximately to decimal Snellen visual acuities of 1.0, 0.8, 0.4, 0.2, 0.1, 0.04, 0.02, 0.01, and 0.002, with approximately 0.3 log step between each step. For validation, digitized fundus photographs of uveitis patients were displayed on a computer monitor for comparison with the standard photos. Three observers graded the test set twice under standard conditions. Interobserver and intraobserver variability and kappa values for agreement greater than chance were calculated. RESULTS: Variance component analysis determined that 87.7% of the variance in grades was attributable to the test item rather than to grader or session. The intraclass correlation between graders and grading sessions varied from 0.84 to 0.91. Simple agreement within 1 grade between graders and sessions occurred in 90 +/- 5.5% of gradings. kappa values averaged 0.91, which is considered near perfect. CONCLUSIONS: A 9-step photographic scale was designed to standardize the grading of vitreous haze in uveitis patients using fundus photographs. The scale is potentially adaptable to clinical trials in uveitis. PMID- 20719304 TI - Structure of the O-polysaccharide of Cronobacter sakazakii O1 containing 3-(N acetyl-l-alanyl)amino-3,6-dideoxy-d-glucose. AB - The O-polysaccharide (O-antigen) was released by mild acid hydrolysis of the lipopolysaccharide of Cronobacter sakazakii ATCC 29544(T) (serotype O1) and studied by composition analysis and Smith degradation, in addition to 1D and 2D (1)H and (13)C NMR spectroscopy. The following structure of the pentasaccharide repeating unit of the O-polysaccharide was established: [Formula: see text] where d-Qui3NAcyl stands for 3-(N-acetyl-l-alanyl)amino-3,6-dideoxy-d-glucose. The same composition but a different structure has been reported earlier for the O polysaccharide of C. sakazakii 3290 [MacLean, L. L.; Pagotto, F.; Farber, J. M.; Perry, M. B. Biochem. Cell Biol.2009, 87, 459-465]. PMID- 20719303 TI - Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. AB - BACKGROUND: Although inflammatory activity is known to play a role in depression, no work has examined whether experimentally induced systemic inflammation alters neural activity that is associated with anhedonia, a key diagnostic symptom of depression. To investigate this, we examined the effect of an experimental inflammatory challenge on the neural correlates of anhedonia-namely, reduced ventral striatum (VS) activity to reward cues. We also examined whether this altered neural activity related to inflammatory-induced increases in depressed mood. METHODS: Participants (n = 39) were randomly assigned to receive either placebo or low-dose endotoxin, which increases proinflammatory cytokine levels in a safe manner. Cytokine levels were repeatedly assessed through hourly blood draws; self-reported and observer-rated depressed mood were assessed regularly as well. Two hours after drug administration, neural activity was recorded as participants completed a task in which they anticipated monetary rewards. RESULTS: Results demonstrated that subjects exposed to endotoxin, compared with placebo, showed greater increases in self-reported and observer-rated depressed mood over time, as well as significant reductions in VS activity to monetary reward cues. Moreover, the relationship between exposure to inflammatory challenge and increases in observer-rated depressed mood was mediated by between group differences in VS activity to anticipated reward. CONCLUSIONS: The data reported here show, for the first time, that inflammation alters reward-related neural responding in humans and that these reward-related neural responses mediate the effects of inflammation on depressed mood. As such, these findings have implications for understanding risk of depression in persons with underlying inflammation. PMID- 20719305 TI - Solid-phase synthesis of a pentavalent GalNAc-containing glycopeptide (Tn antigen) representing the nephropathy-associated IgA hinge region. AB - Incomplete or aberrant glycosylation leading to Tn antigen (GalNAcalpha1-Ser/Thr) expression on human glycoproteins is strongly associated with human pathological conditions, including tumors, certain autoimmune diseases, such as the idiopathic IgA nephropathy, and may modulate immune homeostasis. In addition, the Tn antigen is highly expressed by certain pathogens and plays a role in host-pathogen interactions. To enable experimental approaches to study interactions of the Tn antigen with the immune system and analyze anti-Tn antibody responses in infection or disorders, we generated a Tn-expressing resource that can be used for high-throughput screening. In consideration of IgA nephropathy in which the hinge region is incompletely glycosylated, we used this hinge sequence that encodes five potential glycosylation sites as the ideal template for the synthesis of a Tn antigen-expressing glycopeptide. Inclusion of an N-terminal biotin in the peptide enabled binding to streptavidin-coated ELISA plates as monitored using Helix pomatia agglutinin or anti-Tn monoclonal antibody. We also found that the biotinylated IgA-Tn peptide is a functional acceptor for beta1-3 galactosylation using recombinant T-synthase (beta1-3-galactosyltransferase). Besides its immunochemical functionality as a possible diagnostic tool for IgA nephropathy, the peptide is an excellent substrate for glycan elongation and represents a novel template applicable for glycan-antigen-associated diseases. PMID- 20719306 TI - Clinicopathologic features and genotyping of patients with chronic HBV infection in the Upper Egypt. AB - The aim of this study was to determine the clinicopathologic features and Hepatitis B virus genotypes in HBV-infected patients in the Upper Egypt. Eighty three HBsAg-positive patients (28 carriers, 14 with chronic hepatitis, 32 with liver cirrhosis and 9 with hepatocellular carcinoma) were enrolled. Blood was collected and serum samples obtained were screened for Hepatitis markers genotyping was conducted for 6 HBV genotypes (A through F) using a method for genotyping HBV by primer specific polymerase chain reaction. Genotype D was the only genotype detected in different clinical forms of chronic HBV infection (carriers, chronic hepatitis, cirrhosis and hepatocellular carcinoma) and, in all patients who had elevated or normal alanine aminotransferase levels and in all ages. HBeAg was absent in 78 patients suggesting the presence of pre-core or core mutations. Positive correlation was found among serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), histological activity index and grade of hepatitis. This study provides the first indication about the clinicopathologic features of HBV-infected patients in the Upper Egypt. It also reports the predominance of genotype D in this region. PMID- 20719307 TI - Opening a window on attention: documenting and simulating recovery from simultanagnosia. AB - Simultanagnosia is a disorder of visual attention: the inability to see more than one object at one time. Some hypothesize that this is due to a constriction of the visual "window" of attention. Little is known about how simultanagnosics explore complex stimuli and how their behaviour changes with recovery. We monitored the eye movements of simultanagnosic patient SL to see how she scans social scenes shortly after onset of simultanagnosia (Time 1) and after some recovery (Time 2). At Time 1 SL had an abnormally low proportion of fixations to the eyes of the people in the scenes. She made a significantly larger proportion of fixations to the eyes at Time 2. We hypothesized that this change was related to an expansion of her restricted window of attention. Previously we simulated SL's behaviour in healthy subjects by having them view stimuli through a restricted viewing window. We used this simulation paradigm here to test our expanding window hypothesis. Subjects viewing social scenes through a larger window allocated more fixations to the eyes of people in the scenes than subjects viewing scenes through a smaller window, supporting our hypothesis. Recovery in simultanagnosia may be related to the expansion of the restricted attentional window that characterizes the disorder. PMID- 20719309 TI - Methylation patterns of Brahma during spermatogenesis and oogenesis: potential implications. AB - To compare methylation profiles and expression levels of Brahma at different stages of spermatogenesis, and to identify the methylation pattern during oogenesis, we analyzed gene expression and methylation patterns in murine germ cells at various developmental stages. The methylation levels of CpG islands within Brahma increased during spermatogenesis and decreased during oogenesis. This change in methylation pattern correlates with the change in expression of Brahma during spermatogenesis. As the degree of methylation increases, the expression decreases. The change in methylation is opposite during oogenesis, which suggests opposite expression levels. PMID- 20719310 TI - Successful pelvic abscess drainage by cecal biopsies in Crohn's disease. PMID- 20719308 TI - Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort. AB - OBJECTIVE: To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism and the PROGINS allele. DESIGN: Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies. SETTING: An international ovarian cancer consortium including studies from Australia, Europe, and the United States. PATIENT(S): Five thousand eight hundred twelve white female controls, of whom 348 had endometriosis, from eight ovarian cancer case control studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotypes for the +331C/T single nucleotide polymorphism and PROGINS allele and a history of endometriosis. RESULT(S): The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (odds ratio=0.65; 95% confidence interval: 0.43-0.98), whereas there was no association between the PROGINS allele and endometriosis (odds ratio=0.94, 95% confidence interval 0.76-1.16). CONCLUSION(S): Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced progesterone (P) receptor A to P receptor B ratio, and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease. PMID- 20719311 TI - A comment on the "robust stability analysis of fractional order interval polynomials", by Nusret Tan et al. AB - It is shown that Theorem 3 in the article mentioned in the title is not true and some modification is suggested to eliminate the mistake. PMID- 20719312 TI - Prenatal diagnosis of warfarin embryopathy using three-dimensional ultrasound. PMID- 20719313 TI - The effect of altered loading following rotator cuff tears in a rat model on the regional mechanical properties of the long head of the biceps tendon. AB - Biceps tendon pathology is a common clinical problem often seen in conjunction with rotator cuff tears. A previous study found detrimental changes to biceps tendons in the presence of rotator cuff tears in a rat model. Therefore, the objective of this study was to utilize this model along with models of altered loading to investigate the effect of altered loading on the initiation of these detrimental changes. We created supraspinatus and infraspinatus rotator cuff tears in the rat and followed these tears with either increased or decreased loading. Mechanical properties were determined along the length of the biceps tendon 4 and 8 weeks following injury. At the insertion site, stiffness increased with decreased loading, while detrimental changes were seen with increased loading 4 weeks following detachments. Increased loading resulted in decreased mechanical properties along the entire tendon length at both time points. Decreased loading resulted in both increased and decreased tendon properties at different regions of the tendon at 4 weeks, but by 8 weeks, there were no differences between decreased loading and detachment alone. We could not conclude where changes begin in the tendon with altered loading, but did demonstrate that regional differences exist. These results support that there is an effect of altered loading, as decreased loading resulted in variable changes at 4 weeks that were no different from detachment alone by 8 weeks, and increased loading resulted in detrimental properties along the entire length at both 4 and 8 weeks. PMID- 20719314 TI - The biomechanical effects of limb lengthening and botulinum toxin type A on rabbit tendon. AB - Numerous studies have examined the effects of distraction osteogenesis (DO) on bone, but relatively fewer have explored muscle adaptation, and even less have addressed the concomitant alterations that occur in the tendon. The purpose herein was to characterize the biomechanical properties of normal and elongated rabbit (N = 20) tendons with and without prophylactic botulinum toxin type A (BTX A) treatment. Elastic and viscoelastic properties of Achilles and Tibialis anterior (TA) tendons were evaluated through pull to failure and stress relaxation tests. All TA tendons displayed nonlinear viscoelastic responses that were strain dependent. A power law formulation was used to model tendon viscoelastic responses and tendon elastic responses were fit with a microstructural model. Distraction-elongated tendons displayed increases in compliance and stress relaxation rates over undistracted tendons; BTX-A administration offset this result. The elastic moduli of distraction-lengthened TA tendons were diminished (p = 0.010) when distraction was combined with gastrocnemius (GA) BTX-A administration, elastic moduli were further decreased (p = 0.004) and distraction following TA BTX-A administration resulted in TA tendons with moduli not different from contralateral control (p > 0.05). Compared to contralateral control, distraction and GA BTX-A administration displayed shortened toe regions, (p = 0.031 and 0.038, respectively), while tendons receiving BTX-A in the TA had no differences in the toe region (p > 0.05). Ultimate tensile stress was unaltered by DO, but stress at the transition from the toe to the linear region of the stress-stretch curve was diminished in all distraction-elongated TA tendons (p < 0.05). The data suggest that prophylactic BTX-A treatment to the TA protects some tendon biomechanical properties. PMID- 20719315 TI - Local dynamic stability of amputees wearing a torsion adapter compared to a rigid adapter during straight-line and turning gait. AB - Lower limb amputees have decreased balance during daily ambulation compared to nonamputees. An optimally compliant torsion adapter, which enables transverse plane rotation at the socket-pylon junction may reduce limb asymmetries and improve comfort leading to increased confidence and stability during gait. The purpose of this study was to determine if the presence of a torsion adapter affects amputee sensitivity to local perturbations (local dynamic stability) during straight-line walking and during a turning task. Ten unilateral transtibial amputees were fit with a torsion and rigid adapter in random order and blinded to the condition. After a 3-week acclimation period, kinematic data were collected while subjects walked in a straight-line on a treadmill and around a 1-m radius circular path at constant speed. Maximum finite-time Lyapunov exponents (lambda), an estimator of local dynamic stability, were calculated for the amputee's sagittal plane hip, knee and ankle angles for each condition. The prosthetic limb lambda was greater during a turn compared to straight-line walking, suggesting amputees are less stable while turning. There were no statistically significant differences found in lambda between adapters during both walking conditions, suggesting the torsion adapter had no effect on amputee stability; however, high inter-subject variability due to the examined population and turning task may have masked a small decrease in prosthetic limb hip and knee stability for the torsion adapter during straight-line gait. Therefore, the torsion adapter's added degree of freedom may have a small adverse effect on prosthetic limb stability during straight-line walking and no effect on turning. PMID- 20719316 TI - Letter to the Editor regarding "all joint moments significantly contribute to trunk angular acceleration". PMID- 20719317 TI - Partial medial meniscectomy and rotational differences at the knee during walking. AB - Loss of meniscal function due to injury or partial meniscectomy is common and represents a significant risk factor for premature osteoarthritis. The menisci can influence the transverse plane movements (anterior-posterior (AP) translation and internal-external (IE) rotation) of the knee during walking. While walking is the most frequent activity of daily living, the kinematic differences at the knee during walking associated with the meniscal injury are not well understood. This study examined the influence of partial medial meniscectomy (PMM) on the kinematics and kinetics of the knee during the stance phase of gait by testing the differences in anterior-posterior translation, internal-external rotation, knee flexion range of movement, peak flexion/extension moments, and adduction moments between the PMM and healthy contralateral limbs. Ten patients (45+/-9 years old, height 1.75+/-0.06m, weight 76.7+/-13.5kg) who had undergone partial medial meniscectomy (33+/-100 months post-op) in one limb with a healthy contralateral limb were tested during normal walking. The contralateral limb was compared to a matched control group and no differences were found. The primary kinematic difference was a significantly greater external rotation (3.2 degrees ) of the tibia that existed through stance phase, with 8 of 10 subjects demonstrating the same pattern. The PMM subjects also exhibited significantly lower peak flexion and extension moments in their PMM limbs. The altered rotational position found likely results in changes of tibio-femoral contact during walking and could cause the type of degenerative changes found in the articular cartilage following meniscal injury. PMID- 20719318 TI - Determination of organic priority pollutants and emerging compounds in wastewater and snow samples using multiresidue protocols on the basis of microextraction by packed sorbents coupled to large volume injection gas chromatography-mass spectrometry analysis. AB - This paper describes the development and validation of a new procedure for the simultaneous determination of 41 multi-class priority and emerging organic pollutants in water samples using microextraction by packed sorbent (MEPS) followed by large volume injection-gas chromatography-mass spectrometry (LVI-GC MS). Apart from method parameter optimization the influence of humic acids as matrix components on the extraction efficiency of MEPS procedure was also evaluated. The list of target compounds includes polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), phthalate esters (PEs), nonylphenols (NPs), bisphenol A (BPA) and selected steroid hormones. The performance of the new at-line microextraction-LVI-GC-MS protocol was compared to standard solid phase extraction (SPE) and LVI-GC-MS analysis. LODs for 100 mL samples (SPE) ranged from 0.2 to 736 ng L(-1) were obtained. LODs for 800 microL of sample (MEPS) were between 0.2 and 266 ng L(-1). In the case of MEPS methodology even a sample volume of only 800 microL allowed to detect the target compounds. These results demonstrate the high sensitivity of both procedures which permitted to obtain good recoveries (>75%) for all cases. The precision of the methods, calculated as relative standard deviation (RSD) was below 21% for all compounds and both methodologies. Finally, the developed methods were applied to the determination of target analytes in various samples, including snow and wastewater. PMID- 20719319 TI - A multiple-function stationary phase based on perhydro-26-membered hexaazamacrocycle for high-performance liquid chromatography. AB - A perhydro-26-membered hexaazamacrocycle-based silica (L(1)GlySil) stationary phase for high-performance liquid chromatography (HPLC) was prepared using 3 glycidoxypropyltrimethoxysilane as coupling reagent. The structure of new material was characterized by infrared spectroscopy, elemental analysis and thermogravimetric analysis. The chromatographic performance and retention mechanism of the new phase were evaluated in reversed-phase (RP) and normal-phase (NP) modes using different solute probes including aromatic compounds, organophosphorus pesticides, carbamate pesticides and phenols. The results showed that L(1)GlySil was a sort of multimode-bonded stationary phase with excellent chromatographic properties. The new phase could provide various action sites for different solutes, such as hydrophobic, hydrogen bonding, pi-pi, dipole-dipole interactions and acid-base equilibrium. The presence of phenyl rings, secondary amino groups and alkyl linkers in the resulting material made it suitable for the separation of above-mentioned analytes by multimode retention mechanisms. PMID- 20719320 TI - Adsorption equilibria of proline in hydrophilic interaction chromatography. AB - The adsorption behavior of proline under hydrophilic interaction chromatography conditions was investigated from six aqueous solutions of acetonitrile. Proline adsorption isotherms were recorded at each mobile phase composition by frontal analysis and inverse method. The BET model was found to be the best choice to describe the nonlinear behavior of proline adsorption under hydrophilic interaction chromatography conditions. The adsorption isotherm parameters were derived from two independent parameter estimation methods. The parameters derived from regression analysis of the frontal analysis data and from overloaded elution bands were found to be in good agreement with the excess isotherm of water. The mobile phase composition at which the maximum excess adsorption of water was observed corresponded to the maximum saturation capacity measured for proline. PMID- 20719321 TI - Thermodynamic and kinetic study of chiral separations of coumarin-based anticoagulants on derivatized amylose stationary phase. AB - Thermodynamic and kinetic studies are performed on amylose derivatized with tris (3,5-dimethylphenyl carbamate) stationary phase for the chiral separation of coumarin-based anticoagulants. Polar-organic eluents that contain acetonitrile as bulk solvent with modifiers such as methanol, i-butanol, t-butanol, and tetrahydrofuran are used in the study. Temperature is varied from 5 to 45 degrees C at constant pressure of 1500psi. In general, both retention and enantioselectivity decrease as the temperature increases and as hydrogen bond donating ability of the modifiers increases. The van't Hoff plots are found to show both linear and non-linear behavior. The non-linear plots are believed to be the result of conformational changes in the derivatized amylose phase and are observed around room temperature. The retention behavior in acetonitrile mobile phase provides a linear enthalpy-entropy compensation plot, indicating that all coumarins may have a similar retention mechanism. In contrast, enthalpy-entropy compensation is not observed for warfarin and coumatetralyl enantiomers when separated with different organic modifiers in the mobile phase. The kinetic data indicate that the rate of sorption is always greater than the rate of desorption. An increase in the concentration of alcohol modifiers causes an increase in the desorption rate constant. In contrast, an increase in the concentration of tetrahydrofuran causes a decrease in the desorption rate constant. This effect is most significant for the second eluted enantiomer of coumatetralyl, for which the desorption rate is 36 times slower than the first eluted enantiomer. PMID- 20719322 TI - Solvent-based de-emulsification dispersive liquid-liquid microextraction combined with gas chromatography-mass spectrometry for determination of trace organochlorine pesticides in environmental water samples. AB - In this work, we propose solvent-based de-emulsification dispersive liquid-liquid microextraction (SD-DLLME) as a simple, rapid and efficient sample pretreatment technique for the extraction and preconcentration of organochlorine pesticides (OCPs) from environmental water samples. Separation and analysis of fifteen OCPs was carried out by gas chromatography-mass spectrometry (GC/MS). Parameters affecting the extraction efficiency were systematically investigated. The detection limits were in the range of 2-50 ng L(-1) using selective ion monitoring (SIM). The precision of the proposed method, expressed as relative standard deviation, varied between 3.5 and 10.2% (n=5). Results from the analysis of spiked environmental water samples at the low-ppb level met the acceptance criteria set by the EPA. PMID- 20719323 TI - Separation of honokiol and magnolol by intermittent counter-current extraction. AB - Recently, intermittent counter-current extraction (ICcE) has been developed and shown its advantage in improving resolution between targeted compounds. However, how to choose suitable parameters to increase the throughput has not been systematically studied yet. In present work, we first calculated theoretically the conditions to carry out ICcE elution mode. Then, honokiol and magnolol were separated as model compounds using ICcE elution mode to confirm our conclusion. After parameters like sample concentration and sample feed were optimized in analytical high-performance counter-current chromatography (HPCCC), the separation process was scaled up to preparative HPCCC successfully. 12.8 g honokiol and 16.1g magnolol were separated from 30 g mixture with purities of 98.6% and 93.7%. And the throughput of target isolation of ICcE elution mode was at least 3.75 x higher than isocratic elution mode with the same HPCCC instruments. Our results confirmed our theory calculation and demonstrated the enormous potential of ICcE on preparative separation of binary mixture. PMID- 20719324 TI - Isolation of a polysaccharide with anticancer activity from Auricularia polytricha using high-speed countercurrent chromatography with an aqueous two phase system. AB - Polysaccharides from a crude extract of Auricularia polytricha were separated by high-speed countercurrent chromatography (HSCCC). The separation was performed with an aqueous two-phase system of PEG1000-K2HPO4-KH2PO4-H2O (0.5:1.25:1.25:7.0, w/w). The crude sample (2.0 g) was successfully separated into three polysaccharide components of AAPS-1 (192 mg), AAPS-2 (137 mg), and AAPS-3 (98 mg) with molecular weights of 162, 259, and 483 kDa, respectively. These compounds were tested for growth inhibition of transplanted S180 sarcoma in mice. AAPS-2 had an inhibition rate of 40.4%. The structure of AAPS-2 was elucidated from partial hydrolysis, periodate oxidation, acetylation, methylation analysis, and NMR spectroscopy (1H, 13C). These results showed AAPS-2 is a polysaccharide with a backbone of (1-->3)-linked-beta-d-glucopyranosyl and (1-->3, 6)-linked-beta-D glucopyranosyl residues in a 2:1 ratio, and has one terminal (1-->)-beta-D glucopyranosyl at the O-6 position of (1-->3, 6)-linked-beta-D-glucopyranosyl of the main chain. PMID- 20719325 TI - A facile synthesis method to silica coated CdSe/ZnS nanocomposites with tuneable size and optical properties. AB - A facile method for the preparation of single Quantum Dots (QDs) in silica spheres with tunable size and optical property has been developed. A time interval addition of silica precursor method has been used to increase the size of the silica shell and in parallel tuning the photoluminescence property. The resulting CdSe/ZnS/SiO(2) nanocomposites were characterized by transmission electron microscopy, photoluminescence spectroscopy and zeta-potential measurements. Since for different applications of silica coated core-shell nanoparticles, control over the thickness of the shell in parallel with tuning on the optical property of the final product required, these study could pave the way for the application of this nanocomposites in different fields like photonic crystals, biolabeling, etc. PMID- 20719326 TI - Thermo-sensitive amphiphilic supramolecular assembly based on cyclodextrin inclusion. AB - The ionic self-assembled organic microrods are obtained through complexing two functional molecules, sodium deoxycholate and 1-adamantanamine hydro-chloride. Meanwhile, the amphiphilicity of the complex could be changed by a supramolecular approach with cyclodextrin (CD) inclusion to obtain a thermo-sensitive system. The microrod morphology and structure are characterized by optical microscopy, scanning electron microscopy, single crystal analysis and X-ray powder diffraction. The mechanism of thermo-sensitivity induced by beta-CD inclusion complex is discussed in view of dynamic balance between the host beta-CDs and guest molecules. Experimental results indicate the feasibility of single crystal culture in ionic self-assembly and potential application of CDs in thermo sensitive supramolecular systems. PMID- 20719327 TI - Superparamagnetic nanoclusters coated with oleic acid bilayers for stabilization of emulsions of water and oil at low concentration. AB - Emulsions of water and dodecane with drop sizes down to 1 microm were stabilized with 30-100 nm interfacially active nanoclusters of sub-15 nm iron oxide primary particles at an extremely low loading of 0.14 wt.%. The nanoclusters, coated with a bilayer of oleic acid, formed stable dispersions in water at pH 7-10. The phase behavior and droplet morphologies of the emulsions of water and dodecane were tuned with pH. The oil/water emulsions at pH 9-10 were converted to middle phase emulsions at pH 6-7 and water/oil emulsions as the pH was further lowered. The magnetization per gram of Fe is similar for the nanoclusters and the primary particles, indicating the spacing between the particles is sufficient to avoid magnetic coupling. The larger volume of nanoclusters relative to the individual primary particles is beneficial for magnetomotive sensing applications including imaging of oil reservoirs, as it increases the force on the particles for a given magnetic field. PMID- 20719328 TI - In situ synthesis of highly luminescent glutathione-capped CdTe/ZnS quantum dots with biocompatibility. AB - This paper focuses on the in situ synthesis of novel CdTe/ZnS core-shell quantum dots (QDs) in aqueous solution. Glutathione (GSH) was used as both capping reagent and sulfur source for in situ growth of ZnS shell on the CdTe core QDs. The maximum emission wavelengths of the prepared CdTe/ZnS QDs can be simply tuned from 569 nm to 630 nm. The PL quantum yield of CdTe/ZnS QDs synthesized is up to 84%, larger than the original CdTe QDs by around 1.7 times. The PL lifetime results reveal a triexponential decay model of exciton and trap radiation behavior. The average exciton lifetime at room temperature is 17.1 ns for CdTe (2.8 nm) and 27.4 ns for CdTe/ZnS (3.7 nm), respectively. When the solution of QDs is dialyzed for 3 h, 1.17 ppm of Cd(2+) is released from CdTe QDs and 0.35 ppm is released from CdTe/ZnS. At the dose of 120 microg/ml QDs, 9.5% of hemolysis was induced by CdTe QDs and 3.9% was induced by CdTe/ZnS QDs. These results indicate that the synthesized glutathione-capped CdTe/ZnS QDs are of less toxicity and better biocompatibility, so that are attractive for use in biological detection and related fields. PMID- 20719329 TI - Sodium montmorillonite silylation: unexpected effect of the aminosilane chain length. AB - In this work, the silylation of sodium montmorillonite (Na-MMT) was performed in glycerol using 3-aminopropyltriethoxysilane, N-(2-aminoethyl)-3 aminopropyltrimethoxysilane and 3-[2-(2-aminoethylamino)ethylamino]-propyl trimethoxysilane. The effects on the d-spacing of sodium montmorillonite (Na-MMT) upon reaction with three aminosilanes of different chain length were studied in details by combining experimental and computational techniques. Infrared spectroscopy was used to monitor the grafting process, while the degree of grafting was calculated using thermogravimetric analysis. X-ray diffraction experiments were carried out to evaluate the shift of the (0 0 1) basal spacing. It was found that the degree of silylation of Na-MMT increases with increasing the length of the aminosilane organic moieties, the overall aminosilane concentration, and temperature. The same beneficial effects were observed on the silicate d-spacing, as its value increases with increasing silane concentration and reaction temperature. Remarkably, however, increasing the length of the organic chains in the silane modifiers resulted in decreasing values of the Na MMT interlayer distance. A rationale for this behavior is proposed on the basis of atomistic molecular dynamics simulation evidences. PMID- 20719330 TI - Secondary and primary repolarization changes in left ventricular hypertrophy: a model study. AB - The contributions of reduced conduction velocity (CV) and prolonged action potential duration (APD) to QT interval prolongation and T wave and T vector loop morphology in left ventricular hypertrophy (LVH) were studied using an analytical computer model. Three types of anatomic LVH were simulated: concentric and eccentric hypertrophy, and left ventricular dilatation. In each LVH type, depolarization changes were simulated by CV slowing and primary repolarization changes by APD prolongation. Both CV slowing and APD prolongation prolonged the QT interval; however, the secondary and primary repolarization changes differed in additional electrocardiogram (ECG) characteristics creating specific vectorcardiographic/ECG patterns. The secondary repolarization changes were characterized by prolonged QT interval, accompanied by pronounced QRS changes, including increased maximum spatial QRS vector magnitude, prolonged QRS duration, QRS morphology consistent with intraventricular conduction delay, lower values of the T/QRS duration ratio, increased maximum spatial T vector magnitude, narrow and prolonged discordant T vector loops, and discordant tall T waves creating a pattern of ST strain in the precordial ECG leads. QT prolongation in primary repolarization changes was accompanied with inconsiderable changes of QRS amplitude and duration, higher values of the T/QRS duration ratio, widened rounded T loops, and notched or bifid T waves in left precordial leads of the 12 lead ECG. These simulation data are consistent with the accumulated evidence suggesting that LVH induces changes in CV and APD. Our results emphasize the need for simultaneous consideration of morphologic QRS and T wave patterns together with QT prolongation in clinical evaluation of LVH. PMID- 20719331 TI - Implantable and surface electrocardiography: complementary technologies. AB - Combining information obtained from the surface electrocardiogram and implantable devices represents an emerging trend in electrocardiology. Important potential applications include ischemia detection and localization, continuous monitoring of cardiac cycle parameters, and telemedicine. This article presents an overview of these emerging applications, focusing on our recent studies that combine the electrograms obtained from body surface and implantable devices to reconstruct a full 12-lead electrocardiogram from the implanted device. These technologies have broad application for detection of ischemia, improvement of the accuracy of ischemic localization, and rhythm discrimination. PMID- 20719332 TI - Interlead difference between T-peak to T-end intervals in resynchronization patients with an implantable cardioverter-defibrillator. AB - BACKGROUND: The effectiveness of cardiac resynchronization therapy (CRT) in preventing sudden cardiac death is controversial. Epicardial left ventricular pacing reverses the direction of activation of the left ventricular wall from the epicardium to the endocardium. We evaluated whether the interlead difference between T-peak to T-end (Tp-e) intervals determined by a 187-channel repolarization interval-difference mapping electrocardiograph (187-ch RIDM-ECG) is related to the occurrence of ventricular tachyarrhythmia requiring implantable cardioverter-defibrillator (ICD) therapy in heart failure patients receiving CRT with a defibrillator (CRT-D). METHODS AND RESULTS: Repolarization interval difference mapping electrocardiograph (187-channel) was performed on 61 patients who received CRT-D. Twenty-one patients experienced appropriate ICD therapy. The interlead difference between corrected recovery time intervals was not significantly different between patients with and without appropriate ICD therapy (98 +/- 24 milliseconds versus 88 +/- 24 milliseconds). The interlead difference between corrected Tp-e intervals was significantly higher in patients with appropriate ICD therapy than in those without (88 +/- 22 milliseconds versus 59 +/- 23 milliseconds, P < .001). CONCLUSION: The interlead difference between corrected Tp-e intervals determined by 187-ch RIDM-ECG may be related to appropriate ICD therapy in heart failure patients receiving CRT-D. PMID- 20719333 TI - Improving contemporary algorithms for implantable cardioverter-defibrillator function. AB - Implantable cardioverter-defibrillators (ICDs) have been shown in various clinical trials to prevent mortality from sudden cardiac death due to unstable rhythms or ventricular fibrillation. Modern ICDs use sophisticated algorithms to not only deliver therapy on the detection of a malignant rhythm but also reduce the incidence of inappropriate shocks through rhythm discrimination. Current algorithms for detection of malignant rhythms use sophisticated techniques such as real-time processing and analysis of electrograms from a transvenous lead system. The Rhythm ID feature in Boston Scientific ICDs is an example of one such algorithm used for rhythm discrimination. Rhythm ID uses the vector timing and correlation algorithm, which incorporates both timing as well as morphology information for supraventricular tachycardia discrimination. Clinical trials demonstrated high sensitivity and specificity of this feature in discriminating between ventricular tachycardia and supraventricular tachycardia (results published previously). On detection of the unknown rhythm (when the ventricular tachycardia rate detection criteria is met), the vector timing and correlation algorithm compares the unknown rhythm beat-by-beat to a stored template of normal sinus rhythm. The feature correlation coefficient computed over more than 8 points in the time-aligned signals is used for the comparison. The specific discrimination procedure of Rhythm ID depends on the mode (VR or DR) and on whether the test rhythm is an initial detected rhythm or a postshock rhythm. The normal sinus rhythm template against which the suspected rhythm is compared can be periodically updated. This article will cover some of the key aspects of the Rhythm ID feature's decision-making process and the algorithm for template update. The results of previously published clinical studies involving the algorithm's performance also will be reviewed. PMID- 20719334 TI - Automatic detection and quantification of sleep apnea using heart rate variability. AB - Detection of sleep apnea using electrocardiographic (ECG) parameters is noninvasive and inexpensive. Our approach is based on the hypothesis that the patient's sleep-wake cycle during episodes of sleep apnea modulates heart rate (HR) oscillations. These HR oscillations appear as low-frequency fluctuations of instantaneous HR (IHR) and can be detected using HR variability analysis in the frequency domain. The purpose of this study was to evaluate the efficacy of our ECG-based algorithm for sleep apnea detection and quantification. The algorithm first detects normal QRS complexes and R-R intervals used to derive IHR and to estimate its spectral power in several frequency ranges. A quadratic classifier, trained on the learning set, uses 2 parameters to classify the 1-minute epoch in the middle of each 6-minute window as either apneic or normal. The windows are advanced by 1-minute steps, and the classification process is repeated. As a measure of quantification, the algorithm correctly classified 84.7% of all the 1 minute epochs in the evaluation database; and as a measure of the accuracy of apnea classification, the algorithm correctly classified all 30 test recordings in the evaluation database either as apneic or normal. Our sleep apnea detection algorithm based on analysis of a single-lead ECG provides accurate apnea detection and quantification. Because of its noninvasive and low-cost nature, this algorithm has the potential for numerous applications in sleep medicine. PMID- 20719335 TI - QT restitution properties of middle-aged women with different exercise capacities. AB - BACKGROUND: Framingham Study data indicate an incremental risk of cardiovascular death in relation to low exercise capacity in women. The reason for death is still not clear. METHODS: QT restitution properties in 80 middle-aged women were investigated to confirm whether the cardiac restitution property was affected by the exercise capacity. Exercise tests were performed according to the Bruce protocol. Seventy cases were divided into the low-exercise capacity group (LEC group) and high-exercise capacity group (HEC group) by median exercise capacities. Sequential QT intervals and their preceding TQ intervals were measured, and the QT restitution curve (QTRC) was constructed. Two exponential equations were used to match the data and calculate the maximum slope (Smax) of QTRC, respectively. RESULTS: With elevation in the exercise level, the women in the LEC group had a higher change rate of QT intervals (41 +/- 10 vs 29 +/- 3 ms/Met, P = .001) and TQ intervals (46 +/- 12 vs 41 +/- 7 ms/Met, P = .046); and the ratio of QT interval alterations to TQ interval alterations increased (0.41 +/- 0.09 vs 0.36 +/- 0.07, P = .003). The Smax of the QTRC in the LEC group was higher than that in the HEC group (1.43 +/- 0.44 vs 1.13 +/- 0.34, P = .002). There was an inverse relationship between Smax and exercise capacity (r = -0.43, P = .001). CONCLUSION: Middle-aged women with low exercise capacity have steeper QTRCs than those with high exercise capacity, denoting a more unstable alternation of QT interval with elevation in exercise level. PMID- 20719336 TI - Transient peaked T waves during exercise stress testing: an unusual manifestation of reversible cardiac ischemia. AB - A 57-year-old man presented with atypical upper body pain, initially attributed to musculoskeletal etiology. After analgesic failure, an exercise myocardial perfusion imaging was performed. During stress testing, patient's pain was reproduced, accompanied by prominent T-wave peaking with minor J-point elevation. T-wave amplitude decreased at the end of the recovery phase when his chest pain completely resolved. The myocardial perfusion imaging revealed extensive reversible ischemia of the septum and apical walls. Subsequent coronary arteriography demonstrated a 99% stenosis of the left anterior descending artery that was stented. Patient has remained asymptomatic since. We conclude that transient peaked T waves with minor J-point elevation during exercise may be an unusual electrocardiographic manifestation of reversible cardiac ischemia. PMID- 20719337 TI - The role of inhibitory control in behavioral and physiological expressions of toddler executive function. AB - A total of 81 toddlers (24-27months of age) participated in a biobehavioral investigation of inhibitory control. Maternal report measures of inhibitory control were related to laboratory tasks assessing inhibitory abilities under conditions of conflict, delay, and compliance challenge as well as toddler verbal ability. In addition, unique variance in inhibitory control was explained by task related changes in brain electrical activity at lateral frontal scalp sites as well as concurrent inhibitory task performance. Implications regarding neural correlates of executive function during early development and a central organizing role of inhibitory processing during toddlerhood are discussed. PMID- 20719338 TI - Pathophysiology of inflammation and tissue injury in multiple sclerosis: what are the targets for therapy. AB - Many new therapies have become available for multiple sclerosis patients during the last decade. They are mainly effective in the early relapsing stage of the disease. Despite this undisputed progress, there are still major deficits in the treatment of the patients. Effective anti-inflammatory treatments profoundly decrease disease activity, although this may occur on the expense of a partially impaired immune surveillance of the central nervous system. Furthermore, the clinical outcome of recent trials does not always meet the expectations of the neuroimmunological community. This suggests that preclinical testing in experimental models, although useful and necessary, has its limitations. For treatment of the progressive stage of the disease blood brain barrier penetration of drugs appears to be one crucial issue. Additionally, little is known on the immunological mechanisms of slow burning inflammation present in the brain of patients with progressive MS. Finally, it is suggested that neuroprotective strategies, which target mitochondrial injury and its downstream effects on neurons and axons are promising future therapeutic options. PMID- 20719339 TI - Impaired response inhibition in ill Gulf War veterans. AB - Poor performance on tasks requiring response inhibition has been observed among chronically ill veterans of the 1991 Persian Gulf War. Semantic difficulties have also been reported. We collected event-related potential (ERP) and behavioral data from 25 Gulf War veterans who complained of cognitive difficulties and from 23 matched controls, who were deployed but not symptomatic, while they performed a GO-NOGO task that required both a semantic decision and inhibitory processing. A significantly greater false-alarm rate among the ill veterans was accompanied in the ERP data by significantly reduced amplitude in the NOGO P3, consistent with previous ERP studies of other patient groups that have shown poor inhibitory response performance. This supports the contention that the ill veterans' deficit lies more in inhibiting than in detecting task-related differences in the stimuli. PMID- 20719340 TI - Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. AB - PURPOSE: We characterized and compared the impact of clinical phenotypic associations between interstitial cystitis/painful bladder syndrome and controls in relation to potentially related conditions, particularly irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. MATERIALS AND METHODS: Female patients with interstitial cystitis/painful bladder syndrome and controls with no interstitial cystitis/painful bladder syndrome completed a biopsychosocial phenotyping questionnaire battery which included demographics/history form, self-reported history of associated conditions, and 10 validated questionnaires focused on symptoms, suffering/coping and behavioral/social factors. RESULTS: Questionnaires were completed by 205 patients with interstitial cystitis/painful bladder syndrome and 117 controls matched for age. Prevalence of self-reported associated condition diagnosis in interstitial cystitis/painful bladder syndrome vs controls was irritable bowel syndrome 38.6% vs 5.2%, fibromyalgia 17.7% vs 2.6% and chronic fatigue syndrome 9.5% vs 1.7% (all p <0.001). In the interstitial cystitis/painful bladder syndrome cohort 50.3% reported no other associated condition, 24.4% had interstitial cystitis/painful bladder syndrome + irritable bowel syndrome only, 2.5% had interstitial cystitis/painful bladder syndrome + fibromyalgia only, 1.5% had interstitial cystitis/painful bladder syndrome + chronic fatigue syndrome only, while 20.2% had multiple associated conditions. As the number of associated conditions increased (ie localized, regional, systemic), pain, stress, depression and sleep disturbance increased while social support, sexual functioning and quality of life deteriorated. Anxiety and catastrophizing remained increased in all groups. Symptom duration was associated with this apparent phenotypic progression. CONCLUSIONS: Irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome are more prevalent in patients with interstitial cystitis/painful bladder syndrome than in asymptomatic control subjects, and result in significant impact. There are at least 3 distinct clinical phenotypes based on identification of overlapping syndrome patterns. A suggestion that remains to be proven with longitudinal studies is that there may be progression over time from an organ centric to a regional and finally to a systemic pain syndrome with progression of symptom severity, and deterioration of cognitive and psychosocial parameters. PMID- 20719341 TI - Percutaneous renal cryoablation: local control at mean 26 months of followup. AB - PURPOSE: We retrospectively determined the efficacy of percutaneous renal cryoablation based on a mean followup of more than 2 years. MATERIALS AND METHODS: Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act compliant retrospective study. Informed consent was waived. From March 2003 through March 2007, 91 patients with 93 tumors underwent 92 percutaneous cryoablation procedures. Technical success was defined as extension of the ice ball beyond the tumor margin and post ablation images showing no contrast enhancement in the area encompassing the original tumor within 3 months of the procedure. Local tumor progression was defined as new enhancement in the ablated tumor or an increase in ablated tumor size beyond 3 months after the procedure. Complications were defined using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. RESULTS: Mean followup was 26 months (range 5 to 61, SD +/-13) and mean tumor size was 3.4 cm (range 1.5 to 7.3, SD +/-1.2). Major complications occurred in 6 of 91 patients (7%) or after 8 of 92 (9%) procedures. Technically successful ablation was performed in the treatment of 89 of the 93 (96%) tumors or 87 of the 91 patients (96%). Of the 83 tumors with followup longer than 3 months only a single case (1%) of local tumor progression occurred. Overall local control was achieved in 86 of 91 (95%) patients or 88 of 93 (95%) tumors. CONCLUSIONS: Midterm followup of percutaneous renal cryoablation shows durability of this treatment method with a low incidence of tumor recurrence beyond 3 months. PMID- 20719342 TI - Profile of the brushite stone former. AB - PURPOSE: The incidence of brushite stones has increased during the last 3 decades and we report our experience with brushite stone formers. MATERIALS AND METHODS: From 1996 to 2008 we identified 82 patients with brushite urinary calculi. After institutional review board approval a review of our prospectively collected database was performed. RESULTS: There were 54 (65.9%) male and 28 (34.1%) female stone formers. Mean age was 44 years (range 4 to 84). Prior stone events were reported by 69 (84.1%) patients with 54 (78.3%) having received shock wave lithotripsy. Bilateral calculi were present in 28 (34.1%) patients. Mean stone area was 29.2 mm(2) (range 2 to 130). Surgery was performed in 80 patients including 63 (76.8%) percutaneous nephrolithotomy, 8 (9.8%) ureteroscopy, 3 (3.7%) shock wave lithotripsy, and 6 (7.3%) ureteroscopy and percutaneous nephrolithotomy. After primary and secondary procedures 76 (92.7%) patients were rendered stone-free. Metabolic urine studies were available in 45 patients. All patients demonstrated 1 or more abnormalities, with hypercalciuria (greater than 250 mg daily for women and greater than 275 mg daily for men) in 38 (80.9%), urine pH greater than 6.2 in 29 (61.7%), urine volume less than 2 l in 27 (57.4%), hypocitraturia (less than 320 mg daily) in 22 (46.8%), hyperuricosuria (greater than 750 mg daily in women, greater than 800 mg daily in men) in 8 (17%) and hyperoxaluria (greater than 32 mg daily in women and greater than 43 mg daily in men) in 5 (10.6%). Recurrent stone events occurred in 31 (37.8%) patients at a mean of 33 (range 2 to 118) months from treatment. CONCLUSIONS: Brushite stone formers are a treatment challenge. Almost a third will present with bilateral stones and the stone burden is sizeable. Nearly 80% of patients report having prior shock wave lithotripsy and recurrent stone events occurred approximately 3 years after treatment. All patients with brushite stones in this cohort had an underlying metabolic abnormality and specifically brushite stones should be heralded as a marker for hypercalciuria. Based on these data we recommend all brushite stone formers undergo 24-hour urine studies and have close long-term followup. PMID- 20719344 TI - Screening of PAH-degrading bacteria in a mangrove swamp using PCR-RFLP. AB - There are abundant PAH-degrading bacteria in mangrove sediments, and it is very important to screen the high efficiency degraders in order to perform bioremediation of PAH polluted environments. In order to obtain the more highly efficient PAH-degrading bacteria from a mangrove swamp, we first obtained 62 strains of PAH-degrading bacteria using traditional culture methods and based on their morphological characteristics. We then used the modern molecular biological technology of PCR-RFLP, in which the 16S rDNA of these strains were digested by different enzymes. Based on differences in the PCR-RFLP profiles, we obtained five strains of phenanthrene-degrading bacteria, five strains of pyrene-degrading bacteria, four strains of fluoranthene-degrading bacteria, five strains of benzo[a]pyrene-degrading bacteria and two strains of mixed PAH-degrading bacteria (including phenanthrene, pyrene, fluoranthene and benzo[a]pyrene). Finally, a total of 14 different PAH-degrading bacteria were obtained. The 16S rDNA sequences of these strains were aligned with the BLAST program on the NCBI website and it was found that they belonged to the alpha-proteobacteria and gamma proteobacteria, including four strains, where the similarities were no more than 97% and which were suspected therefore to be new species. This study indicated that PCR-RFLP was a very important method to screen degrading-bacteria, and also a significant molecular biological tool for the rapid classification and accurate identification of many different strains. On the other hand, it also showed that rich bacterial resources existed in mangrove areas, and that exploring and developing the functional microorganism from these mangrove areas would have wide use in the study of bioremediation of contaminated environments in the future. PMID- 20719343 TI - Post World War II orcharding creates present day DDT-problems in The Sorfjord (Western Norway)--a case study. AB - The Sorfjord has a long history of agriculture and industry, and environmental monitoring has been conducted for decades, comprising analyses of contaminants in mussel, fish and sediments. DDT was used as an insecticide in orchards surrounding the fjord between World War II and 1970. Since the early 1990 s, elevated concentrations of DDT were found in mussels and fish. Unexpectedly, DDT concentrations increased towards present day, despite the discontinuation of use. The highest concentrations in mussels (in 2006) corresponded to about two orders of magnitude higher than background. Analyses of sediment core sections also indicated increased input towards present day. Shifts in climatic parameters, as well as increased amounts of soil dissolved organic carbon following a decline in atmospheric sulphate deposition may have contributed to this phenomenon. We warrant the need for increased knowledge of the effects of alterations in variables acting regionally and globally on the disposition of contaminants in ecosystems. PMID- 20719345 TI - High serum concentrations of pentosidine, an advanced glycation end product, are associated with low normal value of ankle-brachial index in apparently healthy men. AB - The ankle-brachial index (ABI) is widely used for peripheral arterial disease screening and is associated with future cardiovascular events. Pentosidine, an advanced glycation end product, accumulates with age and in diabetes and end stage renal disease; but the significance of elevated serum pentosidine is not well known. We investigated the relationship of the ABI to circulating pentosidine concentrations as well as other atherogenic factors in apparently healthy men. The study group consisted of a total of 170 apparently healthy men (age, 55 +/- 9 years). Serum pentosidine concentrations were measured by enzyme linked immunosorbent assay. The mean ABI and pentosidine concentrations of the whole study group were 1.16 +/- 0.07 (range, 0.98-1.35) and 36.1 +/- 10.6 ng/mL (range, 11.2-81.0), respectively. Univariate analysis showed that the ABI was inversely correlated with pentosidine (P = .0004), small low-density lipoprotein (LDL) cholesterol (P = .017), LDL cholesterol (P = .019), apolipoprotein B (P = .024), fasting insulin (P = .028), very small LDL cholesterol (P = .036), difference in ABIs between legs (P = .037), malondialdehyde-modified LDL (P = .044), and homeostasis model assessment of insulin resistance (P = .047). Stepwise multiple linear regression analysis revealed that increased pentosidine, fasting insulin, small LDL cholesterol, difference in ABIs between legs, difference in systolic blood pressure between arms, and reduced body mass index were independent determinants of reduced ABI (adjusted R(2) = 0.237, P < .0001). Serum pentosidine was an important, independent determinant of ABI in healthy men. Subjects with an ABI less than 1.10 showed higher pentosidine concentrations. PMID- 20719346 TI - Comparison of the perforation rate for acute appendicitis between nationals and migrants in Taiwan, 1996-2001. AB - OBJECTIVE: Immigrant populations have grown rapidly in recent years in many countries. Immigrant-related healthcare issues have thus become more and more important. The aim of this study was to assess any possible disparity in access to care between migrants and nationals under the national health insurance (NHI) system in Taiwan. STUDY DESIGN: Retrospective population-based observational study. METHODS: National population-based data on patients aged >=20 years in Taiwan under the NHI programme were studied. The frequency of use and expenditure on ambulatory care, inpatient care and emergency care were analysed separately. Ruptured appendicitis was also analysed as an outcome indicator for access to care. Logistic regression and two-part models were applied. RESULTS: Overall, migrants had a lower rate of healthcare utilization than nationals, and this gap remained consistent from 1996 to 2001. However, using ruptured appendicitis as the outcome indicator, no significant overall difference in access to care was found between nationals and migrants under the NHI programme in Taiwan (odds ratio 1.01, 95% confidence interval 0.93~1.11). CONCLUSION: This study found that although migrants had a lower rate of healthcare utilization than nationals, their rate of adverse outcome was similar to nationals when they faced an acute, non-selective emergency condition such as appendicitis. The findings suggest that the use of more dimensional indicators may help to avoid possible misleading inferences on the variation in access to health care in Taiwan. PMID- 20719347 TI - IFN-g response to vaccination against tuberculosis in dairy heifers under commercial settings. AB - The purpose was to determine IFN-g release as a response to vaccination against tuberculosis in dairy heifers under commercial settings. Four-hundred pregnant heifers from ten herds were randomly allocated into four groups: (1) unvaccinated, (2) BCG vaccinated, (3) BCG vaccinated plus a CFPP400 MUg+polygen boost, and (4) BCG vaccinated plus a CFP200 MUg+polygen boost, under a completely randomized blocks design. A dose of 106CFU of BCG was delivered SC in the neck, then blood samples were taken at days 0, 30, 120, 210, 300 and 720 to estimate IFN-g release in response to bovine-PPD antigen. No significant difference (P > 0.05) was observed in IFN-g release between groups at days 0 and 120. At days 30 and 210, vaccinated groups show higher IFN-g release than the control group but only difference of group 3 was significant (P < 0.05). At day 300, group 1 showed significantly higher IFN-g release. No significant difference was observed at day 720. Using IFN-g release as a surrogate for vaccine efficacy, BCG plus a boost with CFP or CFPP combined with an adjuvant that improves cellular immune response has the potential to protect cattle against tuberculosis for moderate periods of time in vaccinated cattle under commercial settings. PMID- 20719348 TI - Prophylactic total gastrectomy for individuals with germline CDH1 mutation. AB - BACKGROUND: Germline mutation of the CDH1 gene, which encodes for the E-cadherin adhesion protein, is rare but confers an estimated lifetime risk of hereditary diffuse gastric cancer of 87%. Fewer than 100 prophylactic total gastrectomies have been reported for this condition. METHODS: Patients with germline CDH1 mutation who underwent multidisciplinary counseling followed by prophylactic total gastrectomy were reviewed. RESULTS: Ten patients (6 male, 4 female) with a median age of 42 years (range, 26-51) underwent prophylactic total gastrectomy between 2006 and 2009. Of the 6 families represented, there were 4 missense, 1 frameshift, and 1 splice site mutation. Median time from genetic testing to surgery was 3 months (range, 1-7). All patients had an upper endoscopy before surgery, identifying only 1 patient with a focus of diffuse gastric cancer. After prophylactic total gastrectomy, extensive pathologic analysis demonstrated that 9 patients had up to 77 foci of noninvasive cancer, and 2 of these patients had 4 12 foci of T1 invasive cancer. Median operative time was 213 minutes; there were no anastomotic leaks, and the length of stay was 7-8 days. One patient had a complication within 30 days (pulmonary embolism), and 3 patients had late complications (2 small bowel obstructions and 1 anastomotic stricture). Median weight loss at 6 months was 19%. CONCLUSION: The majority of patients with germline CDH1 mutation have foci of noninvasive or invasive gastric cancer by middle age. Serial upper endoscopies provide inadequate screening. Prophylactic total gastrectomy is the procedure of choice for definitive treatment. PMID- 20719349 TI - Different patterns of cancer incidence among African American and Caucasian renal allograft recipients. AB - BACKGROUND: Little data are available regarding cancer incidence in separately analyzed African American renal allograft recipients, with no study examining in detail the incidence and relative distribution of individual post-transplant malignancies versus those occurring in Caucasians. METHODS: We compared the incidence of nonskin cancer occurring in 495 African Americans transplanted at our center from 1984 to 2007 and followed through June 2009 with that occurring in 11,155 patients in the Canadian Organ Replacement Registry transplanted from 1981 to 1998 and followed through December 1999, of which 97% were Caucasian. RESULTS: Despite a shorter follow-up, the overall incidence of nonskin cancer, as well as that of prostate, renal cell, pancreatic, and esophageal cancer, was significantly higher in the African American group. Cancers of the prostate and pancreas comprised a significantly higher fraction of neoplasms occurring in the African American group, whereas lip cancer did so in the Canadian Organ Replacement Registry group. CONCLUSION: In our pilot study, the overall incidence of nonskin cancers was higher in African American versus Caucasian renal allograft recipients, reflecting a significantly different relative distribution of cancer types that follows cancer incidence trends by race in the general population in several but not all cases. If verified in subsequent studies, these findings have important implications with regard to the need for transplant programs to tailor cancer education and pretransplant and post-transplant surveillance appropriately to the African American patient. PMID- 20719350 TI - A statewide consortium of surgical care: a longitudinal investigation of vascular operative procedures at 16 hospitals. AB - BACKGROUND: Regional surgical quality improvement consortiums are becoming more common. Herein we have reported the effectiveness of a statewide consortium focusing on open vascular operative procedures. METHODS: The statewide Michigan Surgical Quality Consortium was established in 2005 with 16 hospitals that report cases of vascular open operative intervention, in a sampling manner consistent with the private sector National Surgical Quality Improvement Program. Data are abstracted by onsite trained nurses using defined and validated pre-, peri-, and postoperative variables with 30-day follow-up. Outpatient and emergent cases were excluded. We compared outcomes over the course of the consortium (era I, April 2005-March 2007; era II, April 2007-March 2008) via univariate and multivariate techniques. RESULTS: Era I (n = 2,453) and era II (n = 3,409) cases were similar in age (mean, 68 years), gender (61% male), relative value units (mean, 21), and distribution of Current Procedural Terminology codes. Duration of stay and operative time decreased by 15% and 11%, respectively, when comparing era I with era II (P < .001). Mortality at 30 days was not different between eras I and II (2.7% vs 2.5%; P = NS), but morbidity was decreased (15.8% vs 13.8%; P = .02). Specific decreases were noted in sepsis and pulmonary, but not cardiac or renal, complications. When evaluating both eras, modifiable variables (able to be altered by the surgeon) for morbidity included increased length of operation (odds ratio [OR], 1.004; 95% confidence interval [CI], 1.003-1.005; P < .0001), hypertension (OR, 1.46; 95% CI, 1.03-2.1; P = .03), and blood transfusion (OR, 2.8; 95% CI, 2.04-3.88; P < .0001). However, anemic patients (11%; hematocrit <30) who were transfused were less likely to suffer morbidity (OR, 56; 95% CI, 0.47-0.67; P < .0001) than those transfused who were not anemic. The absolute 2% reduction in complications led to a $172 cost savings for the payers per patient in era II compared with era I. CONCLUSION: A statewide quality-of-care consortium with timely feedback of data was associated with decreased morbidity over a relatively short follow-up period in vascular patients. Focusing on best processes in real-world practice, such as appropriate transfusion and length of operation, may further improve vascular surgical outcomes. PMID- 20719351 TI - Progressive postinjury thrombocytosis is associated with thromboembolic complications. AB - BACKGROUND: Our previous investigation demonstrated that despite routine chemoprophylaxis, thrombelastography, which is a comprehensive test measuring the viscoelastic properties of blood, identified a hypercoagulable state in a cohort of critically ill surgical patients that was associated with thromboemobolic events. Furthermore, because thrombelastography allows for the comprehensive assessment of coagulation status, this work suggested that platelet hyperactivity is a component of the hypercoagulable state. We hypothesized that progressive postinjury thrombocytosis contributes to a hypercoagulable state that is associated with thrombelastography. METHODS: One thousand four hundred and forty severely injured patients surviving >48 h were entered into a database prospectively over 12 years. The variables that were evaluated in associated with thrombocytosis (platelet count >450,000) included age, Injury Severity Score, packed red blood cell transfusions in 12 h, and thromboemobolic complications (TE) (deep venous thrombosis, pulmonary embolus, mesenteric thrombosis, stroke, and arterial thrombosis). The time frame for the development of thrombocytosis was assessed at greater or less than 7 days postinjury. Logistic regression was used to identify the independent variables predictive of thrombocytosis and to adjust the association of thrombocytosis with TE for other risk factors. C statistic was used to assess the discriminative power of thrombocytosis for prediction of TE. RESULTS: The mean age was 37.4 +/- 0.4 years. The Injury Severity Score was 29.3 +/- 0.3, and mean red blood cell transfusions in 12 h was 4.4 +/- 0.2 units. Injury via blunt force occurred in 76% of patients, and 72% of patients were male. Thrombocytosis was identified in 447 (31%) patients and was noted almost exclusively >7 days postinjury (98%). TE developed in 35 (8%) of the 447 patients with thrombocytosis, compared with 45 (4.5%) of the remaining 993 patients who did not develop thrombocytosis. Persistent thrombocytosis >7 days was associated with TE (P > .0001). Logistic regression analysis indicated that when adjusted for intensive care unit duration of stay, transfusions, age, and Injury Severity Score, patients with sustained thrombocytosis more than 3 days were noted to have a 1.4 * increased risk of TE (odds ratio, 1.12; 95% confidence interval, 1.04-1.2; P = .002; C-statistic = 0.82). CONCLUSION: Persistent thrombocytosis in critically injured patients receiving routine chemoprophylaxis is associated with thrombotic complications. Subsequent investigation is warranted to differentiate enzymatic from platelet hypercoagulability to ascertain the role of antiplatelet therapy for prevention of TE. PMID- 20719352 TI - Intestinal malrotation: varied clinical presentation from infancy through adulthood. AB - BACKGROUND: The purpose of this study was to determine the incidence and clinical presentation of intestinal malrotation from infancy through adulthood by examining the experience of a single institution caring for patients of all ages with this condition. METHODS: We conducted a retrospective review on all patients diagnosed with intestinal malrotation at Massachusetts General Hospital between 1992 and 2009. Patient demographics, clinical history, diagnostic tests, operative procedures, and outcome variables were recorded. Patients were divided into 3 age groups: infants (<1 year), children (1-18 years), and adults (18 years). RESULTS: We identified 170 patients, of whom 31% were infants, 21% were children, and 48% were adults. Infants nearly always presented with emesis (93%), whereas adults most commonly presented with abdominal pain (87%), and less often with emesis (37%) or nausea (31%). The incidence of volvulus declined with age, from 37% to 22% to 12%, in each of the 3 age groups, respectively. Although infants were most often diagnosed within hours or days of symptom onset, 59% of children and 32% of adults experienced symptoms for years before diagnosis. Upper gastrointestinal series was the most common imaging study performed in infants and children, but was replaced by abdominal computed tomography in adults. All infants and children underwent a Ladd's procedure, compared with only 61% of adults. The majority of patients experienced resolution of symptoms after operative intervention, although this decreased slightly with age. CONCLUSION: Intestinal malrotation can occur in patients of any age and, in contrast with traditional teaching, nearly half of these patients may present during adulthood. An increased awareness of this entity and an understanding of its varied presentation at different ages may reduce time to diagnosis and improve patient outcome. PMID- 20719354 TI - Terrestrial and oceanic influence on spatial hydrochemistry and trophic status in subtropical marine near-shore waters. AB - Terrestrial and oceanic influences like groundwater discharges and/or oceanic upwelling define the hydrochemical and biological characteristics of near-shore regions. In karst environments, such as the Yucatan Peninsula (SE Mexico), the balance between these two influences on spatial and temporal scales is poorly understood. This study focused on near-shore waters within 200 m offshore along the Yucatan coast. The trophic status and hydrochemical zones of the study area were determined as a function of physical and nutrient data collected from 2005 to 2006. The main terrestrial influence was groundwater discharge, while the most important marine influence was related to seasonal changes in water turbulence. Spatial differences (p < 0.05) were observed among salinity, light extinction coefficient (k), NO(3)(-), NH(4)(+), and Chl-a. Seasonal differences were observed for all variables except for k. During the dry season, terrestrial influences are the dominant factor on near-shore hydrochemistry. The region around Dzilam exhibited the maximum influence of groundwater discharge estimated by salinity dissolution (delta). During the rainy and "nortes" seasons, there is a balance between oceanic and terrestrial influences. The trophic status measured using the TRIX index, indicated that near-shore waters were mainly oligo mesotrophic; with a meso-eutrophic status in areas with documented anthropogenic impacts. Four hydrological zones were identified by a Canonical Variate Analysis (CVA) using salinity, NO(2)(-), k and NH(4)(+) as the main discriminating variables. Zones I and II showed almost pristine conditions, with well-balanced terrestrial-oceanic influences. In Zone III, terrestrial influences such as groundwater discharges and inland pollution suggesting human impacts were dominant respect to the effects of oceanic influences like upwelling and sediment resuspension caused by winds and oceanic currents. Zone IV received enhanced groundwater and associated nutrients. Anthropogenic activities have led to ecosystem degradation but the speed at which this occurs depends on local and regional characteristics. Therefore, this study has defined those characteristics so as to enact better management policies. PMID- 20719353 TI - Replication of the hepatitis B virus requires a calcium-dependent HBx-induced G1 phase arrest of hepatocytes. AB - Chronic HBV infections cause hepatocellular carcinoma (HCC). Activities of the HBV HBx protein regulate HBV replication and may contribute to the development of HCC. We previously reported that HBx causes primary rat hepatocytes to exit G0 but stall in G1 phase of the cell cycle; entry into G1 stimulated HBV replication. We now report that the activity of the mitochondria permeability transition pore is required for HBx regulation of cell cycle proteins and HBV replication in primary rat hepatocytes, that progression from G0 to G1 stimulates HBV polymerase activity, and that HBV replication is facilitated by the HBx induced G1 arrest. HBx stimulation of HBV replication was linked to elevation of the R2 subunit of ribonucleotide reductase. Our studies suggest that HBx uses mitochondrial-dependent calcium signaling to cause hepatocytes to exit G0 but stall in G1 and that this HBx activity alters the cellular environment and stimulates HBV replication. PMID- 20719355 TI - Assessing the fate and transformation by-product potential of trenbolone during chlorination. AB - Chlorine disinfection is an effective means for managing microbiological activity during drinking water treatment and can eliminate a number of known organic contaminants. Trenbolone is an androgenic steroidal hormone used primarily as a growth stimulant in the animal feedstock industry and has been found in waterways downstream of such operations. Due to its relatively stable environmental presence, trenbolone may migrate downstream where it can impact drinking water resources. Trenbolone was exposed to hypochlorite under various reaction conditions to determine its stability and the scope of its transformation by products. The results indicate trenbolone is highly reactive in the presence of hypochlorite and results in an extensive number of transformation by-products. Continued exposure to hypochlorite resulted in a highly dynamic system involving secondary transformations of most of the initial by-products. The results indicate the reactivity of trenbolone is affected by pH and alters the distribution of observed transformation by-products. PMID- 20719356 TI - Removal of steroid estrogens in carbonaceous and nitrifying activated sludge processes. AB - A carbonaceous (heterotrophic) activated sludge process (ASP), nitrifying ASP and a nitrifying/denitrifying ASP have been studied to examine the role of process type in steroid estrogen removal. Biodegradation efficiencies for total steroid estrogens (Sigma(EST)) of 80 and 91% were recorded for the nitrifying/denitrifying ASP and nitrifying ASP respectively. Total estrogen biodegradation (Sigma(EST)) was only 51% at the carbonaceous ASP, however, the extent of biodegradation in the absence of nitrification clearly indicates the important role of heterotrophs in steroid estrogen removal. The low removal efficiency did not correlate with biomass activity for which the ASP(carbonaceous) recorded 80 microg kg(-1) biomass d(-1) compared to 61 and 15 microg kg(-1) biomass d(-1) at the ASP(nitrifying) and ASP(nitrifying/denitrifying) respectively. This finding was explained by a moderate correlation (r(2)=0.55) between total estrogen loading (Sigma(EST) mgm( 3)d(-1)) and biomass activity (microg Sigma(EST) degraded kg(-1) d(-1)) and has established the impact of loading on steroid estrogen removal at full-scale. At higher solids retention time (SRT), steroid estrogen biodegradation of>80% was observed, as has previously been reported. It is postulated that hydraulic retention time (HRT) is as important as SRT as this governs both reaction time and loading. This observation is based on the high specific estrogen activity determined at the ASP(carbonaceous) plant, the significance of estrogen loading and the positive linear correlation between SRT and HRT. PMID- 20719357 TI - Growth and photosynthetic responses of the cordgrass Spartina maritima to CO2 enrichment and salinity. AB - Future climatic scenarios combine increasing concentrations of atmospheric CO(2) and rising sea levels. Spartina maritima is a C(4) halophyte that is an important pioneer and ecosystem engineer in salt marshes of the Atlantic coast of southern Europe. A glasshouse experiment investigated the combined effects on its growth and photosynthetic apparatus of approximately doubling CO(2) concentration (from 380 to 700 MUmol mol(-1)) at a range of salinity (0, 171 and 510 mM NaCl). We measured relative growth rates, gas exchange, chlorophyll fluorescence parameters, photosynthetic pigment concentrations, and total ash, Na(+), K(2+), Ca(2+) and N concentrations. Elevated CO(2) stimulated growth of S. maritima by c. 65% at all external salinities; this growth enhancement was associated with greater net photosynthetic rate (A) and improved leaf water relations. A increased despite a drop in stomatal conductance in response to 700 MUmol mol(-1) CO(2). CO(2) and salinity had a marked overall effect on the photochemical (PSII) apparatus and the synthesis of photosynthetic pigments. Phi(PSII) values at midday decreased significantly with external salinity in plants grown at 380 MUmol mol(-1) CO(2); and F(v)/F(m) and Phi(PSII) values were higher at 700 MUmol mol(-1) CO(2) in presence of NaCl. Plant nutrient concentrations declined under elevated CO(2), which can be ascribed to the dilution effect caused by an increase in biomass. The results suggest that the productivity S. maritima and the ecosystem services it provides will increase in likely future climatic scenarios. PMID- 20719358 TI - Optically stimulated luminescence dating of cave deposits at the Xiaogushan prehistoric site, northeastern China. AB - The Xiaogushan cave site is one of the most important prehistoric sites in North China. The stone and bone artifacts found in the cave are similar to European contemporaneous artifacts. Cave deposits consist of five layers that have been dated from 46,353 +/- 1179 to 4229 +/- 135 cal. yr BP, using radiocarbon dating techniques on charcoal and bone samples collected from Layers 2-5. In this paper, optically stimulated luminescence (OSL) techniques were applied to date six samples taken from Layers 1-3. The luminescence properties of the fine-grained and coarse-grained quartz extracts indicate that the materials are suitable for OSL dating using a single-aliquot regeneration-dose (SAR) protocol. The OSL ages obtained are broadly consistent with the stratigraphy and the associated calibrated radiocarbon ages. The dating results show that the cave was first occupied by humans about 70 ka. The human occupation of the cave may be related to climate change. An occupation hiatus is inferred to between ~ 17 to ~ 10 ka. The stone and bone artifacts found in Layers 2 and 3 may indicate the Middle to Upper Paleolithic transitions in the region. PMID- 20719359 TI - Mandibular molar root morphology in Neanderthals and Late Pleistocene and recent Homo sapiens. AB - Neanderthals have a distinctive suite of dental features, including large anterior crown and root dimensions and molars with enlarged pulp cavities. Yet, there is little known about variation in molar root morphology in Neanderthals and other recent and fossil members of Homo. Here, we provide the first comprehensive metric analysis of permanent mandibular molar root morphology in Middle and Late Pleistocene Homo neanderthalensis, and Late Pleistocene (Aterian) and recent Homo sapiens. We specifically address the question of whether root form can be used to distinguish between these groups and assess whether any variation in root form can be related to differences in tooth function. We apply a microtomographic imaging approach to visualise and quantify the external and internal dental morphologies of both isolated molars and molars embedded in the mandible (n=127). Univariate and multivariate analyses reveal both similarities (root length and pulp volume) and differences (occurrence of pyramidal roots and dental tissue volume proportion) in molar root morphology among penecontemporaneous Neanderthals and Aterian H. sapiens. In contrast, the molars of recent H. sapiens are markedly smaller than both Pleistocene H. sapiens and Neanderthals, but share with the former the dentine volume reduction and a smaller root-to-crown volume compared with Neanderthals. Furthermore, we found the first molar to have the largest average root surface area in recent H. sapiens and Neanderthals, although in the latter the difference between M(1) and M(2) is small. In contrast, Aterian H. sapiens root surface areas peak at M(2). Since root surface area is linked to masticatory function, this suggests a distinct occlusal loading regime in Neanderthals compared with both recent and Pleistocene H. sapiens. PMID- 20719360 TI - Tree-ring C-H-O isotope variability and sampling. AB - In light of the proliferation of tree-ring isotope studies, the magnitude and cause of variability of tree-ring delta(13)C, delta(18)O and delta(2)H within individual trees (circumferential) and among trees at a site is examined in reference to field and laboratory sampling requirements and strategies. Within this framework, this paper provides a state-of-knowledge summary of the influence of "juvenile" isotope effects, ageing effects, and genetic effects, as well as the interchangeability of species, choice of ring segment to analyze (whole ring, earlywood or latewood), and the option of sample pooling. The range of isotopic composition of the same ring among trees at a site is ca. 1-30/00 for delta(13)C, 1-40/00 delta(18)O, and 5-300/00 for delta(2)H, whereas the circumferential variability within a tree is lower. A standard prescription for sampling and analysis does not exist because of differences in field environmental circumstances and mixed findings represented in relevant published literature. Decisions in this regard will usually be tightly constrained by goals of the study and project resources. Sampling 4-6 trees at a site while avoiding juvenile effects in rings near the pith seems to be the most commonly used methodology, and although there are some reasoned arguments for analyzing only latewood and developing separate isotope records from each tree, the existence of some contradictory findings together with efforts to reduce cost and effort have prompted alternate strategies (e.g., most years pooled with occasional analysis of rings in the sequence separately for each tree) that have produced useful results in many studies. PMID- 20719361 TI - Polar organic and inorganic markers in PM10 aerosols from an inland city of China -seasonal trends and sources. AB - Polar organic compounds and elements were quantified in PM(10) aerosols collected in urban and rural areas of Baoji, an inland city of China, during winter and spring 2008. Concentrations of biomass burning markers and high molecular weight n-alkanoic acids (HMW, >C(22:0)) were heavily increased in winter. In contrast, sugars presented in higher levels in the spring, among which sucrose was the most abundant with an average of 219ngm(-3) in winter and 473ngm(-3) in spring respectively. This suggests enhanced biotic activity in the warm season, whereas no obvious trend was observed for sugar alcohols, concentrations of the three sugar alcohols in spring were only 0.94-2.3 times as those in winter, indicating a second pathway of their formation other than fungal spores in cold season. Major crustal elements (i.e., Fe, K, Mn and Ti) in PM(10) aerosols were also observed in larger concentrations in spring samples than those in winter due to an enhancement of coarse particles from soil minerals. By using principal component analysis (PCA) and positive matrix factorization (PMF), sources and their contributions to the PM components were also investigated in this study. Four factors were extracted with both models, and the sources represented by different factors were based on the highest loaded marker species as follows: factor 1, soil and road dust (Fe, Sr and Ti); factor 2, biomass burning (levoglucosan, galactosan and syringic acid); factor 3, microbial emissions (fructose and sucrose); and factor 4, fossil fuel combustion and fungal spores influence (Pb, Zn, arabitol and mannitol). The high correlation between PM(10) and factor 1 suggested that PM(10) pollution in Baoji was dominated by soil and dust re-suspension. PMID- 20719362 TI - Levels and patterns of Persistent Organic Pollutants (POPS) in selected food items from Northwest Russia (1998-2002) and implications for dietary exposure. AB - Residues of persistent organic pollutants (POPs) were analysed in 70 selected food items from Northwest Russia in 1998-2002. Levels of PCBs ranged from 0.2 to 16ng/g wet weight (ww) in dairy products and fats, 0.2 to 23ng/g ww in meat products, 0.5 to 16ng/g ww in eggs and 0.3 to 30ng/g ww in fish. High levels of DDT (16ng/g ww) were found in locally produced butter from Kola Peninsula, in pork fat from Arkhangels region (10 to 130ng/g ww) and in some fish samples from White Sea and Kargopol region (17 and 30ng/g ww). Findings of low DDE/DDT ratios in many of the studied food items indicated recent contamination to DDTs. Mean levels of sum TEQs(WHO1998) of dioxin-like mono-ortho PCBs: PCBs 105, 118, 156 and 157 (?mo-PCBs-TEQs(WHO1998)) were highest in dairy products, chicken eggs and fish, with levels of 0.292, 0.245 and 0.254pg/g ww, respectively. The estimated daily intake (EDI) for ?mo-PCBs-TEQs(WHO1998) was 0.74pg/kgbw/day and in the same range as in Sweden and Denmark. Fish, dairy products, eggs and meat were the main contributors to the EDI of ?mo-PCBs-TEQs(WHO1998). The EDIs of DDTs, HCHs and HCB were several times higher than in Sweden and Denmark. Consumption of meat and poultry were important sources for intake of DDTs and HCHs, respectively. Contamination of animal feed and agricultural practice were assumed the most important causes for the results in the present study. However, increased control on maximum residue levels in food and feed may have resulted in large changes on levels and patterns of POPs in food in the studied areas. PMID- 20719363 TI - A mild and rare form of Klippel-Trenaunay syndrome presenting with urethral bleeding due to penile hemangioma. AB - Klippel-Trenaunay syndrome (KTS) is characterized by a triad of cutaneous port wine capillary malformations, hemihypertrophy, and varicose veins. Intermittent gross painless hematuria is usually the first clinical sign. An 8-year-old boy with multiple hemangiomas, including glans penis, and associated with KTS presented with urethral bleeding. Radiologic and endoscopic evaluation revealed neither intra-abdominal nor intravesical hemangioma. Urethral bleeding was thought to be related to glanular hemangioma extending to the anterior penile urethra. Although we were able to manage the case conservatively, many patients require endoscopic or surgical interventions. Radiologic and endoscopic evaluations and careful follow-up is essential for diagnosis and prompt treatment. PMID- 20719364 TI - Three-dimensional anatomy of the pelvic bone in bladder exstrophy: comparison between patients managed with osteotomy and pubic symphysis internal fixation using metal plates. AB - OBJECTIVES: To compare intrapelvic osseous dimensions in classic bladder exstrophy patients who underwent pelvic osteotomy and pubic symphysis internal fixation, using metal plates without osteotomy by defining intrapelvic angles and distances using three-dimensional computed tomography scan (3D-CT). METHODS: Fourteen exstrophy patients who were operated with osteotomy (OST) and 19 patients who had undergone pubic approximation using metal plates (PLT) were enrolled in this study. 3D-CT was performed to measure 8 intrapelvic angles and 9 distances. In addition, a 3D-CT image of control group of 14 age- and sex-matched patients and the preoperative data of 12 cases (6 patients in each group) were considered to compare the bony aspects of exstrophy patients before and 6 months after surgery. RESULTS: Sacroiliac joint angle, pubococcygeal angle, ischiopubic angle, pubic diastasis, and inter-triradiate distance were different from controls in both techniques. Iliac wing angle, however, was at near normal values in PLT group. The result of before-after comparison revealed significant changes in iliac wing angle, sacroiliac joint angle, and pubic diastasis in both groups. CONCLUSIONS: Our study suggests that internal fixation of pubic arch using metal plates in bladder exstrophy may be as effective as the currently accepted osteotomy-containing techniques from the standpoint of intrapelvic osseous dimensions and angles. Modification of our new pubic approximation technique is essential to better recapitulate the anatomy of the normal bony pelvis. PMID- 20719365 TI - Determinants of performing radical prostatectomy pelvic lymph node dissection and the number of lymph nodes removed in elderly men. AB - OBJECTIVE: Controversy persists regarding the adequacy of pelvic lymph node dissection (PLND) and cancer control when comparing minimally invasive radical prostatectomy (MIRP) and open radical prostatectomy (RRP). We characterized determinants of performance and extent of PLND during radical prostatectomy in elderly men. METHODS: A population-based study was conducted comprised of 5448 men >=65 years undergoing RRP and MIRP during 2004 to 2006 from Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data. Multivariable logistic regression was used to assess the effect of demographic and tumor characteristics, surgical approach, and surgeon volume on the likelihood of performing PLND. RESULTS: PLND was performed for 87.6% vs. 38.3% of men undergoing RRP vs. MIRP (P <.001). Among RRP, 82.6% vs. 4.6% underwent extended vs. limited PLND, with a median yield of 4 vs. 3 lymph nodes (P <.001). Median MIRP PLND yield was 3 lymph nodes. In adjusted analyses, men undergoing RRP vs. MIRP (odds ratio [OR] 16.7; 95% confidence interval [CI], 11.1-25.0), those with few vs. multiple comorbidities (OR 1.4, 95% CI 1.02-1.91), intermediate (OR 1.87; 95% CI 1.48-2.37), and high (OR 2.77; 95% CI 2.02-3.78) vs. low-risk features, and men treated by high-volume surgeons (OR 1.008; 95% CI 1.004-1.011) were more likely to undergo PLND. Conversely, Hispanic (OR 0.68, 95% CI 0.49-0.96) vs. white men were less likely to undergo PLND. CONCLUSIONS: Independent of tumor characteristics, men undergoing RRP vs. MIRP were more likely to undergo PLND with greater lymph node yield and racial variation observed. Further studies are needed to determine the appropriate use of PLND. PMID- 20719366 TI - Multidetector computed tomography: role in determination of urinary stones composition and disintegration with extracorporeal shock wave lithotripsy--an in vitro study. AB - OBJECTIVES: To evaluate the ability of noncontrast computed tomography (NCCT) to predict stone composition and fragility for treatment with extracorporeal shock wave lithotripsy (SWL). METHODS: A total of 103 stones from patients who had undergone different open surgical procedures were scanned with a 64 detector row helical computed tomography (CT) scanner using 1-mm collimation at 2 energy levels of 80 and 120 kV. The chemical compositions of the urinary stones were assessed on the basis of the differences in the densities measured in Hounsfield units (HU). Stones were then broken in an electromagnetic lithotripter until complete fragmentation, and number of shock waves was counted. RESULTS: After exclusion of the groups with few calculi, 46 pure stones (18 uric acid, 22 calcium oxalate monohydrate, 6 struvite) and 48 mixed stones were included in the statistical analysis. For measurements at 120-kV, 80-kV, and dual-energy CT values, the overall difference between the densities of the stones was statistically significant; however there was a cross-over in densities between all stone groups. There were significant positive correlations at 120-kV, 80-kV, and dual-energy CT values between stone density and number of shock waves required for complete fragmentation. Stones with HU >1000 required statistically significant higher number of shock waves. CONCLUSIONS: Multidetector CT is not an accurate method for detection of human stone compositions; however a high stone CT attenuation value is s significant predictor of failure to fragment renal stones by SWL. PMID- 20719367 TI - Loss of muscarinic and purinergic receptors in urinary bladder of rats with hydrochloric acid-induced cystitis. AB - OBJECTIVES: To clarify the basic mechanism involved in the pathophysiology of cystitis by characterizing the urodynamic parameters, pharmacologically relevant (muscarinic and purinergic) receptors, and the in vivo release of adenosine triphosphate (ATP) in the bladder of hydrochloric acid (HCl)-treated rats. METHODS: The muscarinic and purinergic receptors in rat tissue were measured by radioreceptor assays using (N-methyl-3H) scopolamine methyl chloride ([3H]NMS) and alphabeta-methylene-ATP (2,8-3H) tetrasodium salt ([3H]alphabeta-MeATP), respectively. The urodynamic parameters and ATP levels were measured using a cystometric method and the luciferin-luciferase assay, respectively. RESULTS: In the HCl-treated rats, the micturition interval and micturition volume were significantly (48% and 55%, respectively, P <.05) decreased and the number of micturitions was significantly (3.2-fold, P <.05) increased compared with those of the control rats. The maximal number of binding sites for [3H]NMS and [3H]alphabeta-MeATP was significantly (55% and 72%, respectively, P <.001) decreased in the bladder of HCl-treated rats, suggesting downregulation of both muscarinic and purinergic receptors. In the HCl-treated rats, the inhibition constant, K(i), values for oxybutynin, solifenacin, and darifenacin were significantly (1.3-1.4-fold, P <.05) increased, but those for tolterodine and AF DX116 were unchanged. Similarly, the inhibition constant for A-317491, pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium, and MRS2273 was significantly (5.5, 11, and 7.6-fold, respectively, P <.001) increased. Furthermore, the in vivo release of ATP was significantly (P <.05) enhanced in the HCl-treated rat bladder. CONCLUSIONS: Both muscarinic and purinergic mechanisms might be, at least in part, associated with the urinary dysfunction due to cystitis. PMID- 20719368 TI - Enhanced transrectal ultrasound modalities in the diagnosis of prostate cancer. AB - Standard grayscale transrectal ultrasound has a poor sensitivity for detection of prostate cancer. Saturation biopsy schemes have improved prostate cancer detection rates over standard template biopsy schemes, but carry additional morbidity and cost. Enhanced ultrasound modalities (EUM), including color and power Doppler, contrast-enhancement, harmonic and flash replenishment imaging, and elastography have demonstrated improved prostate cancer detection. EUM targeting areas with increased or abnormal vascularity or firmness for biopsy offer improved prostate cancer detection. EUM, detect prostate cancer more efficiently than standard ultrasound guided biopsies. These emerging technologies may potentially augment standard prostate biopsy in clinical practice. PMID- 20719369 TI - Patterns of recurrence and role of adjuvant chemotherapy in stage II-IV serous ovarian borderline tumors. AB - OBJECTIVE: The objective of this study was to evaluate patterns of recurrence and prognostic factors as well as the role of adjuvant chemotherapy in stage II-IV ovarian SBT. METHODS: We performed a retrospective review of all patients with advanced-stage SBT treated at our institution from 1979 to 2008. Advanced stage was defined as FIGO stage II-IV. Progression-free survival (PFS) was defined as the time of diagnosis to time of recurrence/death or last follow-up. Kaplan-Meier method was used to report the PFS rate. RESULTS: A total of 80 stage II-IV patients were identified, of which 15 (19%) were stage II, 63 (79%) were stage III, and 2 (2.5%) were stage IV. The site of metastasis was pelvis in 15 patients (19%), omentum in 29 patients (36%), isolated lymph nodes in 2 patients (2.5%), lung in 1 patient (1%), axilla in 1 patient (1%), and multiple sites in 32 patients (40%). With a median follow-up of 4.8 years, 17 patients (21%) developed recurrent disease. Only patients with metastasis to the omentum or multiple sites developed recurrent disease. Of the 65 stage III/IV patients, 17 patients (26%) received adjuvant chemotherapy following diagnosis. The 3-year progression-free survival (PFS) was 89.9% (95% CI, 77.3-95.7) for patients who did not receive adjuvant chemotherapy compared with 70.6% (95% CI, 43.1-86.6) for patients who received adjuvant chemotherapy. CONCLUSIONS: While advanced-stage ovarian SBT generally has a good prognosis, nearly 21% of patients develop recurrent disease with intermediate follow-up. It is unclear from these data if adjuvant chemotherapy influenced PFS. PMID- 20719370 TI - Class III NSRH: oncological outcome in 170 cervical cancer patients. AB - OBJECTIVE: To analyze local recurrence rate (LRR), morbidities and oncologic outcome of class III nerve-sparing radical hysterectomy. PATIENTS AND METHODS: 170 consecutive class III NSRH cases were performed. Nineteen patients were addressed directly to surgery whilst neoadjuvant chemotherapy was administered in 151 patients. The majority of patients had SCC (75%). The median follow-up was 31 months. RESULTS: The mean age was 50 [27-78] years. Mean post-operative hospital stay was 7 [3-16] days. 2 intraoperative complications occurred. Operating time and blood loss was similar to the state-of-the-art of conventional radical hysterectomy. Overall G3-4 complication rate was 8.2 % (14/170). Early G3-4 complication rate was 3.5% (6/170). Late G3-4 complication rate was: 4.7%. (8/170). Positive pelvic nodes were noted in 31 patients (18.2%). Vagina and parametrial involvement were present in 38 (22%) and 27 (15.8%) patients, respectively. LRR was 10% (17/170). The sites of relapse were: 12 pelvic, 5 vaginal. There were 9 patients DOD. The 2-year and 5-year DFS rates were 89% and 81%, respectively. Univariate and multivariate analysis identified vagina involvement and postoperative treatment as significant prognostic factors. CONCLUSIONS: The oncologic results of NSRH were similar to the state-of-the-art of conventional radical hysterectomy. Two years DFS in relation to FIGO stage of disease was 92.3, 89.2 and 86.1 % respectively for IB1, IB2, IIB comparable to literature data. The early and late complications rate related to autonomic injury was significantly lower. The nerve-sparing technique should be considered in all cervical cancer patients addressed to surgery. PMID- 20719371 TI - Primary giant cell malignant fibrous histiocytoma of the ovary: case report and review of the literature. PMID- 20719372 TI - Gynecologic Oncology Group (GOG) Report. PMID- 20719373 TI - Added value of IgE detection to rApi m 1 and rVes v 5 in patients with Hymenoptera venom allergy. PMID- 20719374 TI - Invariant natural killer T cells and asthma: immunologic reality or methodologic artifact? PMID- 20719375 TI - Levels of circulating IL-33 and eosinophil cationic protein in patients with hypereosinophilia or pulmonary eosinophilia. PMID- 20719376 TI - Extending the actor-partner interdependence model to include cross-informant data. AB - This paper illustrates an extension of the APIM technique within a path analysis framework by using cross-informant data on the outcome variable. Data for the current study were derived from a sample of young adult heterosexual couples who had been in a romantic relationship for at least four months (N = 115 couples). The findings from the current study indicate that romantic relationship satisfaction is associated with externalizing behavior problems among both females and males, but that both dyadic data and cross-informant reports are needed to understand this association. Not considering dyadic or cross-informant data may lead to different, and potentially misleading, claims. The findings from the current study provide clear evidence that incorporating cross-informant data in dyadic data analyses provides important new insights into understanding the association between romantic relationship functioning and individual outcomes. PMID- 20719377 TI - Gout therapeutics: new drugs for an old disease. AB - The approval of febuxostat, a non-purine-analogue inhibitor of xanthine oxidase, by the European Medicines Agency and the US Food and Drug Administration heralds a new era in the treatment of gout. The use of modified uricases to rapidly reduce serum urate concentrations in patients with otherwise untreatable gout is progressing. Additionally, advances in our understanding of the transport of uric acid in the renal proximal tubule and the inflammatory response to monosodium urate crystals are translating into potential new treatments. In this Review, we focus on the clinical trials of febuxostat. We also review results from studies of pegloticase, a pegylated uricase in development, and we summarise data for several other pipeline drugs for gout, such as the selective uricosuric drug RDEA594 and various interleukin-1 inhibitors. Finally, we issue a word of caution about the proper use of the new drugs and the already available drugs for gout. At a time of important advances, we need to recommit ourselves to a rational approach to the treatment of gout. PMID- 20719378 TI - The effect of the local delivery of alendronate on human adipose-derived stem cell-based bone regeneration. AB - Recent studies have shown that alendronate (Aln) enhances the osteogenesis of osteoblasts and bone marrow mesenchymal stem cells. In this study, we hypothesize that Aln may act as an osteo-inductive factor to stimulate the osteogenic differentiation of human adipose-derived stem cells (hADSCs) for bone regeneration. The in vitro effect of Aln (1-10 MUM) on the osteogenic ability of hADSCs was evaluated by examining mineralization and alkaline phosphatase (ALP) activity. Bone morphogenetic protein 2 (BMP2) expression was measured using a real-time polymerase chain reaction and western blot analysis. Our results indicated that 5 MUM Aln was sufficient to enhance BMP2 expression, ALP activity and mineralization in hADSCs. The in vivo effect of locally administered Aln on bone repair was examined in a rat critical-sized (7-mm) calvarial defect that was implanted with a hADSC-seeded poly(lactic-co-glycolic acid) (PLGA) scaffold. Aln (5 MUM/100 MUl/day) was injected locally into the defect site for one week. New bone formation was evaluated by radiographic and histological analyses at 8 and 12 weeks post-implantation. The expression levels of human BMP2 (hBMP2) and hADSC localization in defect sites were examined using immunohistochemistry analysis and fluorescent in situ hybridization, respectively. Results showed that local treatment of Aln on hADSC-seeded PLGA scaffolds at week 12 had a maximal effect on bone regeneration, enhancing mineralization and bone matrix formation. In addition, hADSCs and hBMP2 were also detected at the defect sites. These results demonstrated that local delivery of Aln, a potent osteo-inductive factor, enhances hADSC osteogenesis and bone regeneration. PMID- 20719379 TI - Osteogenic differentiation of intact human amniotic membrane. AB - Tissue engineering strategies usually require cell isolation and combination with a suitable biomaterial. Human amniotic membrane (AM) represents a natural two layered sheet comprising cells with proven stem cell characteristics. In our approach, we evaluated the differentiation potential of AM in toto with its sessile stem cells as alternative to conventional approaches requiring cell isolation and combination with biomaterials. For this, AM-biopsies were differentiated in vitro using two osteogenic media compared with control medium (CM) for 28 days. Mineralization and osteocalcin expression was demonstrated by (immuno)histochemistry. Alkaline phosphatase (AP) activity, calcium contents and mRNA expression of RUNX2, AP, osteopontin, osteocalcin, BMP-2 (bone morphogenetic protein), and BMP-4 were quantified and AM viability was evaluated. Under osteogenic conditions, AM-biopsies mineralized successfully and by day 28 the majority of cells expressed osteocalcin. This was confirmed by a significant rise in calcium contents (up to 27.4 +/- 6.8 mg/dl d28), increased AP activity, and induction of RUNX2, AP, BMP-2 and BMP-4 mRNA expression. Relatively high levels of viability were retained, especially in osteogenic media (up to 78.3 +/- 19.0% d14; 62.9 +/- 22.3% d28) compared to CM (42.2 +/- 15.2% d14; 35.1 +/- 8.6% d28). By this strategy, stem cells within human AM can successfully be driven along the osteogenic pathways while residing within their natural environment. PMID- 20719380 TI - Transparent magnetic photoresists for bioanalytical applications. AB - Microfabricated devices possessing magnetic properties are of great utility in bioanalytical microdevices due to their controlled manipulation with external magnets. Current methods for creating magnetic microdevices yield a low transparency material preventing light microscopy-based inspection of biological specimens on the structures. Uniformly transparent magnetic photoresists were developed for microdevices that require high transparency as well as consistent magnetism across the structure. Colloidal formation of 10 nm maghemite particles was minimized during addition to the negative photoresists SU-8 and 1002F through organic capping of the nanoparticles and utilization of solvent-based dispersion techniques. Photoresists with maghemite concentrations of 0.01-1% had a high transparency due to the even dispersal of maghemite nanoparticles within the polymer as observed with transmission electron microscopy (TEM). These magnetic photoresists were used to fabricate microstructures with aspect ratios up to 4:1 and a resolution of 3 MUm. Various cell lines showed excellent adhesion and viability on the magnetic photoresists. An inspection of cells cultured on the magnetic photoresists with TEM showed cellular uptake of magnetic nanoparticles leeched from the photoresists. Cellular contamination by magnetic nanoparticles was eliminated by capping the magnetic photoresist surface with native 1002F photoresist or by removing the top layer of the magnetic photoresist through surface roughening. The utility of these magnetic photoresists was demonstrated by sorting single cells (HeLa, RBL and 3T3 cells) cultured on arrays of releasable magnetic micropallets. 100% of magnetic micropallets with attached cells were collected following release from the array. 85-92% of the collected cells expanded into colonies. The polymeric magnetic materials should find wide use in the fabrication of microstructures for bioanalytical technologies. PMID- 20719381 TI - The formation of protein concentration gradients mediated by density differences of poly(ethylene glycol) microspheres. AB - A critical element in the formation of scaffolds for tissue engineering is the introduction of concentration gradients of bioactive molecules. We explored the use of poly(ethylene glycol) (PEG) microspheres fabricated via a thermally induced phase separation to facilitate the creation of gradients in scaffolds. PEG microspheres were produced with different densities (buoyancies) and centrifuged to develop microsphere gradients. We previously found that the time to gelation following phase separation controlled the size of microspheres in the de-swollen state, while crosslink density affected swelling following buffer exchange into PBS. The principle factors used here to control microsphere densities were the temperature at which the PEG solutions were reacted following phase separation in aqueous sodium sulfate solutions and the length of the incubation period above the 'cloud point'. Using different temperatures and incubation times, microspheres were formed that self-assembled into gradients upon centrifugation. The gradients were produced with sharp interfaces or gradual transitions, with up to 5 tiers of different microsphere types. For proof-of concept, concentration gradients of covalently immobilized proteins were also assembled. PEG microspheres containing heparin were also fabricated. PEG-heparin microspheres were incubated with fluorescently labeled protamine and used to form gradient scaffolds. The ability to form gradients in microspheres may prove to be useful to achieve better control over the kinetics of protein release from scaffolds or to generate gradients of immobilized growth factors. PMID- 20719382 TI - Delineating parameters of iron overload in MDS patients treated with deferasirox. PMID- 20719383 TI - Alloreactive natural killer cells in hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia can play a major role in reducing the risk of relapse by inducing a graft versus leukemia (GVL) effect. Here, we review the effectiveness of mismatching inhibitory killer cell-immunoglobulin-like receptors (KIR) on donor natural killer (NK) cells as a mechanism for GVL. We review the range of KIR and the importance of T cell and NK cell content of the graft, together with considerations of the graft source. Further understanding of conditioning and mechanisms to reduce graft versus host disease (GVHD) will improve our ability to manipulate NK cells in HSCT. PMID- 20719384 TI - Abused and neglected children in court: knowledge and attitudes. AB - OBJECTIVE: After maltreated children are taken into protective custody, dependency courts determine the children's placements. Many, if not most, maltreated children never attend their dependency court hearings. We had the rare opportunity to interview children in a jurisdiction where children regularly attend their detention hearings in dependency court. Our main goals were to assess maltreated children's knowledge and attitudes about their court experiences and identify predictors thereof. We also examined if the maltreated children desired greater participation in dependency court decisions. METHODS: Immediately after attending their dependency court hearings, 7- to 10-year-olds were interviewed about their knowledge of, attitudes concerning, and participation in dependency court. Information was also extracted from the children's dependency court files. RESULTS: Lack of understanding and negative attitudes were common. Age predicted court knowledge, and age, anxiety, court knowledge, abuse type, and criminal court referral predicted attitudes. Qualitative findings included that a substantial minority of children did not feel believed or listened to, and most children wanted to return home. CONCLUSIONS: This research is relevant to current debates about the extent to which children should be involved in legal decisions. The results suggest that maltreated children may profit from greater understanding of dependency court. Moreover, the findings indicate that children often wish to have greater influence in dependency court decisions. POLICY IMPLICATIONS: Professionals should consider providing children involved in dependency court hearings with age appropriate information about the legal proceedings. Children may also benefit in dependency hearings from the opportunity, directly or indirectly (through their attorneys), to give voice to their wishes and needs. PMID- 20719385 TI - Therapeutic efficacy of silymarin and naringenin in reducing arsenic-induced hepatic damage in young rats. AB - We investigated the effects of silymarin and naringenin in counteracting arsenic induced hepatic oxidative stress post exposure. Male wistar rats were chronically exposed to sodium arsenite for eight months followed by oral treatment with silymarin and naringenin (50 mg/kg each) for 15 consecutive days to evaluate hepatic damage and antioxidant potential. Our results demonstrate a significant decrease in hepatic GSH levels, SOD and catalase activities and an increase in GST and TBARS levels after arsenic administration. Silymarin or naringenin administration increased GSH levels and was beneficial in the recovery of altered SOD and catalase activity besides significantly reducing blood and tissue arsenic concentration. Our results point to the antioxidant potential of these flavonoids, which might be of benefit in the clinical recovery of subject exposed to arsenic. These flavonoids can be incorporated into the diet or co-supplemented during chelation treatment, and thus may afford a protective effect against arsenite-induced cytotoxicity. PMID- 20719386 TI - DNA damage and metal accumulation in four tissues of feral Octopus vulgaris from two coastal areas in Portugal. AB - The alkaline comet assay has been employed for the first time to estimate the basal DNA damage in the digestive gland, gills, kidney and gonads of Octopus vulgaris. Octopuses were captured in two coastal areas adjacent to the cities of Matosinhos (N) and Olhao (S), Portugal. The area of Matosinhos is influenced by discharges of the Douro River, city of Porto, industries and intensive agriculture, while Olhao is an important fisheries port. Previous works point to contrasting metal availability in the two coastal areas. Among the analysed tissues digestive gland presented the highest levels of Zn, Cu, Cd and Pb. Tissues of specimens from Matosinhos exhibited high levels of Cd and from Olhao enhanced Pb concentrations. The DNA damages in digestive gland, gills and kidney were more accentuated in specimens from Matosinhos than from Olhao, suggesting a stronger effect of contaminants. Elevated strand breakages were registered in digestive gland, recognised for its ability to store and detoxify accumulated metals. The DNA damages in kidney, gills and gonads were lower, reflecting reduced metal accumulation or efficient detoxification. The broad variability of damages in the three tissues may also mirror tissue function, specific defences to genotoxicants and cell-cycle turnover. PMID- 20719387 TI - Assessment of wastewater effluent quality in Thessaly region, Greece, for determining its irrigation reuse potential. AB - The objective of the present study is to assess wastewater effluent quality in Thessaly region, Greece, in relation to its physicochemical and microbiological burden as well as its toxic potential on a number of organisms. Wastewater may be used for agricultural as well as for landscape irrigation purposes; therefore, its toxicity potential is quite important. Thessaly region has been chosen since this region suffers from a distinct water shortage in summer period necessitating alternative water resources. During our research, treated effluents from four wastewater treatment plants operating in the region (Larissa, Volos, Karditsa, and Tirnavos) were tested for specific physicochemical and microbiological parameters [biochemical oxygen demand (BOD(5)), chemical oxygen demand (COD), total suspended solids (TSS), pH, electrical conductivity, selected metals presence (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn, As), and fecal coliforms' (FC) number]. The effluents were also tested for their toxicity using two different bioassays (Daphnia magna immobilization test and Phytotoxkit microbiotest). The findings were compared to relative regulations and guidelines regarding wastewater reuse for irrigation. The results overall show that secondary effluents in Thessaly region are generally acceptable for reuse for irrigation purposes according to limits set by legislation, if effective advanced treatment methods are applied prior to reuse. However, their potential toxicity should be closely monitored, since it was found that it may vary significantly in relation to season and location, when indicator plant and zooplankton organisms are used. PMID- 20719388 TI - Toxicity of aqueous extract of Euphorbia tirucalli latex on catfish, Heteropneustes fossilis. AB - A four-day static renewal acute toxicity test was performed to determine the LC(50) value of aqueous extract of Euphorbia tirucalli latex for the freshwater fish, Heteropneustes fossilis. The LC(50) values, their upper and lower confidence limits and slope functions were calculated. The LC(50) values for aqueous extract of E. tirucalli latex at various exposure periods are 3.450 MUl/L for 24 h, 2.516 MUl/L for 48 h, 1.623 MUl/L for 72 h and 1.315 MUl/L for 96 h. The toxicity of aqueous extract of E. tirucalli latex exhibits a positive correlation between fish mortality and exposure periods. It is concluded that latex of E. tirucalli has higher piscicidal activity as compared with other synthetic pesticides, organophosphates and pyrethroids for the fish H. fossilis. Hence, adequate precautions must be exercised when E. tirucalli latex is being used near fish-inhabiting water reservoirs. PMID- 20719389 TI - Solitary lytic skull lesion revealing an eosinophilic granuloma in an adult. PMID- 20719390 TI - [Nontumoral bilateral occlusion of the Monro foramina]. PMID- 20719391 TI - The iron complex of Dp44mT is redox-active and induces hydroxyl radical formation: an EPR study. AB - Iron chelation therapy was initially designed to alleviate the toxic effects of excess iron evident in iron-overload diseases. However, some iron chelator-metal complexes have also gained interest due to their high redox activity and toxicological properties that have potential for cancer chemotherapy. This communication addresses the conflicting results published recently on the ability of the iron chelator, Dp44mT, to induce hydroxyl radical formation upon complexation with iron (B.B. Hasinoff and D. Patel, J Inorg. Biochem.103 (2009), 1093-1101). This previous study used EPR spin-trapping to show that Dp44mT-iron complexes were not able to generate hydroxyl radicals. Here, we demonstrate the opposite by using the same technique under very similar conditions to show the Dp44mT-iron complex is indeed redox-active and induces hydroxyl radical formation. This was studied directly in an iron(II)/H(2)O(2) reaction system or using a reducing iron(III)/ascorbate system implementing several different buffers at pH 7.4. The demonstration by EPR that the Dp44mT-iron complex is redox active confirms our previous studies using cyclic voltammetry, ascorbate oxidation, benzoate hydroxylation and a plasmid DNA strand-break assay. We discuss the relevance of the redox activity to the biological effects of Dp44mT. PMID- 20719392 TI - Zinc(II) tweezers containing artificial peptides mimicking the active site of phosphotriesterase: the catalyzed hydrolysis of the toxic organophosphate parathion. AB - Two new ligand-containing histidine based on N,N',N"-tris(N-benzyl-L histidinyl)tri(2-aminoethyl)amine, L(1), namely N,N',N"-tris[(1S)-2-methoxy-2-oxy 1-(1-benzylimidazol-4-ylmethyl)]nitrilotriacetamide L(2) and N,N',N"-tris{N benzyl-N-[N-benzyl-N-(N-benzyl-L-histidinyl)-L-histidinyl]-L-histidinyl}tri(2 aminoethyl)amine L(3) were prepared. Zinc(II) binding studies by these ligand systems were analyzed by means of potentiometric and (1)H NMR titrations in aqueous methanol (33 % v/v). Subsequently their zinc(II) complexes [L(1)Zn(H(2)O)](ClO(4))(2) x HClO(4) (1), [L(2)Zn(OH(2))](ClO(4))(2) x H(2)O (2), and ([L(3)Zn(3)(H(2)O)(3)](ClO(4))(6).3HClO(4)x 5H(2)O (3), respectively were synthesized and characterized. The reactivity of the trinuclear complex (3) toward the hydrolysis of the toxic organophosphate parathion was investigated and compared with that of the mononuclear reference complex (1). From the pH dependence of the apparent rate constants, and the deprotonation constant (pK(a)) of the coordinated water molecules in (1), the active species were confirmed to be {[HL(1)Zn(OH)](2+)/[L(1)Zn(H(2)O)](2+)} at pH 8.5. The trizinc complex (3) effects hydrolysis of parathion, with three times rate enhancement over the mononuclear (1), indicating that cooperative action of the three zinc centers is limited. PMID- 20719393 TI - Impulsivity and suicidality: the mediating role of painful and provocative experiences. AB - BACKGROUND: Multiple studies have reported a link between high levels of impulsivity and suicidal behavior. Joiner's (2005) explanation for this link is that impulsive individuals have a greater tendency to experience painful and provocative events that habituate them to fear and pain, which leads to an acquired capability for engaging in suicidal behavior. METHODS: Study 1 tested Joiner's (2005) hypothesis in a sample of 182 undergraduate students who completed self-report questionnaires on impulsivity, frequency of painful and provocative events, and acquired capability for suicide. In addition to self report, pain tolerance (an aspect of acquired capability for suicide) was measured with a pressure algometer. Study 2 sought to replicate our findings from Study 1 in a sample of 516 clinical outpatients using a multi-faceted measure of impulsivity. RESULTS: Consistent with prediction, product of coefficients tests for mediation (MacKinnon et al., 2002) revealed that impulsivity has an indirect relationship with acquired capability for suicidal behavior, and that this relationship is mediated by painful and provocative events. LIMITATIONS: Data from our studies are cross-sectional in nature, which does not allow for conclusions about the temporal ordering of our variables. In addition, self report was used to measure most variables. Future research may benefit from a longitudinal design and the inclusion of other modes of assessment (e.g., behavioral measures of impulsivity). CONCLUSIONS: Our findings suggest that the link between impulsivity and suicidal behavior occurs because impulsive people tend to have a greater capability for suicidal behavior, which they have acquired through experiencing painful and provocative events. PMID- 20719394 TI - Association of seasonality and premenstrual symptoms in bipolar I and bipolar II disorders. AB - BACKGROUND: Although seasonal affective disorder and premenstrual syndrome (PMS) are frequently observed in mood disorders, little is known as to whether lifetime traits of seasonality and premenstrual distress are related to bipolar disorder independent of mood episodes. This study aimed at investigating these two cyclic traits with respect to bipolar I and II disorders as well as evaluating the association between them. METHODS: Subjects included 61 female patients with bipolar I or II disorders and 122 healthy women. Seasonality and premenstrual symptoms were measured retrospectively on a lifetime basis using the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Premenstrual Symptoms Screening Tool (PSST). RESULTS: Patients showed higher global seasonality scores on the SPAQ compared to the normal controls. Further, the patient-control difference was more prominent in cases of bipolar II disorder (p<0.0001) than in bipolar I disorder (p=0.001). The prevalence of moderate to severe PMS as indicated on the PSST was also significantly higher in bipolar II disorder patients (51.6%) as compared to controls (19.7%). A significant association between seasonality and PMS was observed in both patient and control groups. CONCLUSIONS: The results suggested that female patients with bipolar disorder experience seasonal and premenstrual changes in mood and behavior regardless of their mood episodes, and traits of seasonality and PMS are associated with each other. A common biological mechanism of these two cyclic conditions may be involved in the development of the cyclicity of bipolar disorder. PMID- 20719395 TI - Behavior problems at ages 6 and 11 and high school academic achievement: longitudinal latent variable modeling. AB - Previous studies documented long-run effects of behavior problems at the start of school on academic achievement. However, these studies did not examine whether the observed effects of early behavior problems are explained by more proximate behavior problems, given the tendency of children's behavior problems to persist. Latent variable modeling was applied to estimate the effects of behavior problems at ages 6 and 11 on academic achievement at age 17, using data from a longitudinal study (n=823). Behavior problems at ages 6 and 11, each stage independently of the other, predicted lower math and reading test scores at age 17, controlling for intelligence quotient (IQ), birth weight, maternal characteristics, family and community environment, and taking into account behavior problems at age 17. Behavior problems at the start of school, independent of later behavior problems, exert lingering effects on achievement by impeding the acquisition of cognitive skills that are the foundation for later academic progress. PMID- 20719396 TI - Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (Oncorhynchus mykiss). AB - The pregnane X receptor (PXR) belongs to the nuclear hormone receptor (NR) superfamily and is commonly described as a xenophore or a pharmacophore, as it can be activated by a wide array of xenobiotics, including numerous pharmaceuticals and other environmental pollutants. The PXR regulates expression of e.g. cytochrome P450 3A (CYP3A) and the P-glycoprotein (P-gp) that are involved in excretion of lipophilic xenobiotics and endobiotics. A full length PXR cDNA was isolated from rainbow trout liver and it was expressed in a descending order of magnitude in liver>intestine>kidney>heart. A rainbow trout PXR reporter assay was developed and a suite of pharmaceuticals and other xenobiotics were screened. However, no specific activation of rainbow trout PXR was observed with the substances tested. Interactions of prototypical PXR agonists on PXR signaling in rainbow trout were further investigated in cells of hepatic origin exposed in vitro and in juvenile rainbow trout exposed in vivo. The rainbow trout hepatoma cell line (RTH-149), displayed 600 times lower expression of CYP3A mRNA compared to primary cultures of hepatocytes, and did not respond to treatment with either pregnenolone 16alpha-carbonitrile (PCN), ketoconazole (KCZ) or rifampicin (RIF), which implies a non-functional PXR in this cell line. Exposure of hepatocytes to PCN and lithocholic acid (LA), resulted in a weak concentration-dependent induction of CYP3A and P-gp mRNA levels, though, exposure to the higher concentration of LA (50 MUM) decreased PXR mRNA levels. Exposure to dexamethasone (DEX) resulted in a decrease in PXR mRNA, without affecting CYP3A mRNA levels in hepatocytes in vitro. Injections of rainbow trout in vivo with 1 mg LA/kg fish resulted in a slight (albeit not significant) increase in CYP3A mRNA levels without affecting PXR mRNA levels. Although, injection with 10mg omeprazole (OME)/kg fish had no effect on PXR and CYP3A mRNA levels, a 60% inhibition of CYP3A enzyme activities was evident. An in vitro screening of the chemicals used showed that OME and RIF acted as weak CYP3A inhibitors whereas LA and DEX did not affect the CYP3A activity. In contrast, PCN acted as an activator of the CYP3A enzyme activity in vitro. Taken together, these data show that some prototypical PXR agonists weakly affect PXR activation in rainbow trout. Besides, some of these agonists have a stronger effect on the CYP3A catalyst. This study demonstrates the importance of investigation effects of pharmaceuticals on the PXR signaling pathway in non-target animals such as fish. PMID- 20719397 TI - Oral exposure of adult zebrafish (Danio rerio) to 2,4,6-tribromophenol affects reproduction. AB - The bromophenol 2,4,6-tribromophenol (TBP) is widely used as an industrial chemical, formed by degradation of tetrabromobisphenol-A, and it occurs naturally in marine organisms. Concentrations of TBP in fish have been related to intake via feed, but little is known about effects on fish health after oral exposure. In this study, we exposed adult male and female zebrafish (Danio rerio) to TBP via feed in nominal concentrations of 33, 330, and 3300 MUg/g feed (or control feed) for 6 weeks to assess the effects of TBP on reproductive output, gonad morphology, circulatory vitellogenin levels, and early embryo development. The aim was also to investigate the extent to which TBP was metabolised to 2,4,6 tribromoanisole (TBA) in dietary exposed zebrafish, and the amounts of TBP and TBA found in offspring. After 6 weeks of exposure, we found about 3% of the daily dose of TBP in adult fish and the mean concentration of TBA was 25-30% of the TBP concentration. TBP and TBA were detected in offspring with wet weight-based egg/fish concentration ratios well below one. Exposure to TBP significantly reduced the fertilization success and disturbed the gonad morphology, i.e. fewer spermatid cysts in males and increased presence of atretic follicles and oocytes with decreased vitellogenesis in females. In females, the disturbed gonad morphology was accompanied by increased levels of circulating vitellogenin. Significant effects were observed at 3300 MUg/g feed. Offspring early development was not significantly affected, but yolk-sac oedema tended to increase in frequency in exposed groups with time. Our results show that dietary exposure to TBP, at concentrations found in marine organisms that are part of the natural diet of wild fish, can interfere with reproduction in zebrafish. We also observed low accumulation from feed of TBP in zebrafish and biotransformation of TBP to TBA. This is the first paper showing gonadal histopathological changes and effects on fertility in TBP exposed fish. PMID- 20719399 TI - Targeting cancer cells with nucleic acid aptamers. AB - Aptamers are short, structured, single-stranded RNA or DNA ligands that bind with high affinity to their target molecules, which range from small chemicals to large cell-surface and transmembrane proteins. Aptamers are now emerging as promising molecules to target specific cancer epitopes in clinical diagnosis and therapy. Furthermore, because of their high specificity and low toxicity, aptamers might be considered as the compounds-of-choice for in vivo cell recognition. Specific cancer cell recognition could be capitalized upon for delivering therapeutic nanoparticles, small interfering RNA bioconjugates, chemotherapeutic cargos or molecular imaging probes. In this article, we review recent advances in the use of aptamers for in vivo cancer cell recognition, with a particular focus on novel applications of aptamers for targeting the cell surface. PMID- 20719401 TI - Development of an online automatic diagnostic reference levels management system for digital radiography: a pilot experience. AB - The diagnostic reference levels (DRLs) concept is a methodology proposed by the International Commission on Radiological Protection (ICRP) for identifying any unusual high patient doses involved in radiological examinations. However, some challenges are anticipated in the DRLs concept including resource demand for running the audit cycle by individual imaging departments and availability of DRLs. The objective of this study was to develop an online automatic DRLs management system for digital radiography (DR) with the aim of addressing the challenges of the DRLs obligation. An online automatic DRLs management system for DR composed of freeware was developed. The system was tested with 75 DR images. This pilot experience shows that the system successfully addresses the challenges in the DRLs management, i.e. resource demand for running the audit cycle by individual imaging departments and availability of DRLs. It can provide at a low cost an efficient and effective solution to the implementation of regular audits of patient doses using DR in busy clinical departments. It can also contribute to the development of DRLs at local and national levels. In this way, any unacceptable radiological practice (examination used unjustified high radiation dose) can be identified. PMID- 20719400 TI - Clinical determinants of aspirin resistance in diabetes. AB - Recent studies indicate that not all diabetic subjects benefit from aspirin therapy. Our objective is to characterize diabetic subjects with aspirin resistance using urine thromboxane, and VerifyNow measures. Our results suggest that cardiovascular disease, microalbuminuria, poor diabetes control, and increased waist circumference help identify aspirin resistance in diabetes. PMID- 20719403 TI - Reorganization of photosystem II is involved in the rapid photosynthetic recovery of desert moss Syntrichia caninervis upon rehydration. AB - The moss Syntrichia caninervis (S. caninervis) is one of the dominant species in biological soil crusts of deserts. It has long been the focus of scientific research because of its ecological value. Moreover, S. caninervis has a special significance in biogenesis research because it is characterized by its fast restoration of photosynthesis upon onset of rehydration of the desiccated organism. In order to study the mechanisms of rapid photosynthetic recovery in mosses upon rewatering, we investigated the kinetics of the recovery process of photosynthetic activity in photosystem (PS) II, with an indirect assessment of the photochemical processes based on chlorophyll (Chl) fluorescence measurements. Our results showed that recovery can be divided into two phases. The fast initial phase, completed within 3 min, was characterized by a quick increase in maximal quantum efficiency of PSII (F(v)/F(m)). Over 50% of the PSII activities, including excitation energy transfer, oxygen evolution, charge separation, and electron transport, recovered within 0.5 min after rehydration. The second, slow phase was dominated by the increase of plastoquinone (PQ) reduction and the equilibrium of the energy transport from the inner antenna to the reaction center (RC) of PSII. Analysis of the recovery process in the presence of 3-(3,4 dichlorophenyl)-1,1-dimethyl urea (DCMU) revealed that blocking the electron transport from Q(A) to Q(B) did not hamper Chl synthesis or Chl organization in thylakoid membranes under light conditions. A de novo chloroplast protein synthesis was not necessary for the initial recovery of photochemical activity in PSII. In conclusion, the moss's ability for rapid recovery upon rehydration is related to Chl synthesis, quick structural reorganization of PSII, and fast restoration of PSII activity without de novo chloroplast protein synthesis. PMID- 20719402 TI - Analysis of the signaling pathways regulating Src-dependent remodeling of the actin cytoskeleton. AB - Cell adhesion to the extracellular matrix is mediated by adhesion receptors, mainly integrins, which upon interaction with the extracellular matrix, bind to the actin cytoskeleton via their cytoplasmic domains. This association is mediated by a variety of scaffold and signaling proteins, which control the mechanical and signaling activities of the adhesion site. Upon transformation of fibroblasts with active forms of Src (e.g., v-Src), focal adhesions are disrupted, and transformed into dot-like contacts known as podosomes, and consisting of a central actin core surrounded by an adhesion ring. To clarify the mechanism underlying Src-dependent modulation of the adhesive phenotype, and its influence on podosome organization, we screened for the effect of siRNA-mediated knockdown of tyrosine kinases, MAP kinases and phosphatases on the reorganization of the adhesion-cytoskeleton complex, induced by a constitutively active Src mutant (SrcY527F). In this screen, we discovered several genes that are involved in Src-induced remodeling of the actin cytoskeleton. We further showed that knockdown of Src in osteoclasts abolishes the formation of the podosome-based rings and impairs cell spreading, without inducing stress fiber development. Our work points to several genes that are involved in this process, and sheds new light on the molecular plasticity of integrin adhesions. PMID- 20719404 TI - Head and neck squamous cell carcinoma from an unknown primary site. AB - BACKGROUND: The purpose of this study is to present our experience treating patients with squamous cell carcinoma (SCC) from an unknown head and neck primary site and to determine whether a policy change eliminating the larynx and hypopharynx from the radiotherapy (RT) portals has impacted outcome. METHODS: One hundred seventy-nine patients received definitive RT with or without a neck dissection for SCC from an unknown head and neck primary site. RT was delivered to the ipsilateral neck alone or both sides of the neck and, usually, the potential mucosal primary sites. The median mucosal dose was 5670 cGy. The median neck dose was 6500 cGy. One hundred nine patients (61%) received a planned neck dissection. RESULTS: Mucosal control at 5 years was 92%. The mucosal control rate in patients with RT limited to the nasopharynx and oropharynx was 100%. The 5 year neck-control rates were as follows: N(1), 94%; N(2a), 98%; N(2b), 86%; N(2c), 86%; N(3), 57%; and overall, 81%. The 5-year cause-specific survival rates were as follows: N(1), 94%; N(2a), 88%; N(2b), 82%; N(2c), 71%; N(3), 48%; and overall, 73%. The 5-year overall survival rates were as follows: N(1), 50%; N(2a), 70%; N(2b), 59%; N(2c), 45%; N(3), 34%; and overall, 52%. Eleven patients (7%) developed severe complications. CONCLUSION: RT alone or combined with neck dissection results in a high probability of cure with a low risk of severe complications. Eliminating the larynx and hypopharynx from the RT portals did not compromise outcome and likely reduces treatment toxicity. PMID- 20719405 TI - A case of cochlear implantation in a patient with Paget disease. PMID- 20719406 TI - A silicone nasal swab for the treatment of severe and recalcitrant epistaxis in hereditary hemorrhagic telangiectasia: an alternative to surgical nostril closure. AB - BACKGROUND: Epistaxis is the most common symptom in patients with hereditary hemorrhagic telangiectasia (HHT). In severely affected cases, cessation of the nasal airflow seems to be the only long-term effective treatment. Such procedure deeply affects patient's quality of life (QoL) and is sometimes refused. METHODS: This study investigated the effectiveness of a tailored silicone nasal swab on 2 patients affected by HHT and severe epistaxis. RESULTS: In both cases, we observed a good clinical effect, with significant reduction of epistaxis and improved QoL. CONCLUSIONS: Our preliminary results indicate that the silicone nasal swab can be considered an effective way of treating severe epistaxis in patients with HHT. Its advantages, in terms of maintained airflow patency, reversibility, and improved QoL, are highlighted. PMID- 20719407 TI - Animal model of radiogenic bone damage to study mandibular osteoradionecrosis. AB - OBJECTIVE: The objective of the study was to create an animal model to study mandibular osteoradionecrosis (ORN) using high-dose rate (HDR) brachytherapy. METHODS: Ten Sprague-Dawley male rats were used in this study. Six rats received a single dose of 30 Gy using an HDR remote afterloading machine via a brachytherapy catheter placed along the left hemimandible. The remaining 4 rats served as controls with catheter placement without radiation (sham). On the day following irradiation or sham, all 3 left mandibular molars were atraumatically extracted. Twenty-eight days after irradiation, mandibles were examined using nondecalcified histology with sequential fluorochrome labeling, decalcified histology, and micro-computed tomography scanning. RESULTS: Irradiated rats demonstrated exposed bone at the extraction sockets, whereas the control animals had complete mucosalization. Alopecia was also seen in the irradiated group. Both histologic and radiologic analyses of the mandible specimens demonstrated a reduction in bone formation in the radiated mandibles as compared with controls. CONCLUSIONS: Our HDR brachytherapy model incorporating postradiation dental extractions has successfully demonstrated reproducible radiogenic mandibular bone damage analogous to the clinical ORN. Although clinical criteria continue to be used today in describing ORN, this model can serve as a platform for future studies to define ORN and delineate its pathogenesis. PMID- 20719408 TI - No association between DNA repair gene XRCC1 and amyotrophic lateral sclerosis. AB - Reduced DNA repair capacity may play a role in amyotrophic lateral sclerosis (ALS) etiology. We examined the association between ALS risk and single nucleotide polymorphisms (SNPs) in the gene x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) utilizing data from a case-control study and 2 genome-wide association studies (the study of Irish Amyotrophic Lateral Sclerosis and the National Institute of Neurological Disorders and Stroke (NINDS) genome-wide study in Amyotrophic Lateral Sclerosis and Neurologically Normal Controls). Our results did not show any differences in the frequency of XRCC1 gene polymorphisms between ALS patients and controls free of any neurological disease. PMID- 20719409 TI - Associations between nutritional status, weight loss, radiotherapy treatment toxicity and treatment outcomes in gastrointestinal cancer patients. AB - BACKGROUND & AIMS: Patients with gastrointestinal cancers are susceptible to nutritional deterioration which may be compounded by radiotherapy treatment toxicities. This study aimed to determine whether nutritional status at radiotherapy commencement or changes in nutritional status throughout radiotherapy were associated with treatment toxicity and outcomes in gastrointestinal cancer patients. METHODS: Seventy-three gastrointestinal cancer patients receiving curative radiotherapy underwent medical record audits assessing body weight, radiotherapy toxicity, unplanned treatment breaks or hospital admissions and completion of prescribed treatment/s. Nutritional status was assessed in a subset of patients (n = 11) using the Patient-Generated Subjective Global Assessment tool. RESULTS: Seventy-five percent of patients lost weight throughout radiotherapy. Weight loss was significantly greater in patients experiencing unplanned radiotherapy breaks (-3.1% vs -1.6%, p < 0.05) and in patients not completing prescribed chemotherapy (-3.3% vs -1.6%, p < 0.05). Toxicity severity was strongly correlated with Patient-Generated Subjective Global Assessment score (rho = 0.839, p < 0.001) and was increased in patients experiencing unplanned admissions compared to those without admission (42.1% vs 9.3% with grade 3 toxicity respectively, p < 0.001). CONCLUSIONS: Deterioration in nutritional status during radiotherapy (as measured by weight loss) may be associated with poorer short-term treatment outcomes in gastrointestinal cancer patients. Patient numbers were too small to definitively determine the effect of nutritional status at radiotherapy commencement or changes in nutritional status throughout radiotherapy (defined by PG-SGA) on treatment outcomes. Further research is required to investigate this in larger, longer-term studies. PMID- 20719410 TI - Parenteral branched-chain amino acids for hepatic encephalopathy. What is the grade of recommendation? PMID- 20719411 TI - The 2009 ESPEN Sir David Cuthbertson. Citrulline: a new major signaling molecule or just another player in the pharmaconutrition game? AB - Citrulline (CIT) is synthesized from arginine (ARG) and glutamine in enterocytes and metabolized by the kidneys into arginine, which is available for peripheral tissues. Thus CIT, rather than ARG, could be a limiting amino acid (AA) in situations of intestinal failure. This was verified in a rat model of short bowel syndrome. The effects of CIT were further tested in renutrition of malnourished rats and in healthy volunteers fed a hypoproteic diet. CIT supplementation improved protein synthesis (PS) and ARG availability more than ARG itself, which is explained by the fact that CIT, unlike ARG, is very efficiently transported into enterocytes and escapes hepatic uptake. Action of CIT on PS is mediated through the mTOR pathway. A key issue is why CIT should stimulate PS. CIT could be a counterpart of leucine, with leucine stimulating PS in the postprandial state, while CIT acts when protein intake is low or nil to maintain PS at a minimal level compatible with life. CIT could also be a safe way to deliver ARG to endothelial and immune cells, and can certainly prevent excessive uncontrolled nitric oxide production. PMID- 20719412 TI - Association of omega-3 fatty acids and homocysteine concentrations in pre eclampsia. AB - BACKGROUND & AIMS: The present study examines the associations of folic acid, vitamin B12 and omega-3 fatty acids and increased homocysteine which are implicated in the pathology of pre-eclampsia. METHODS: 49 Pre-eclamptic and 57 normotensive women were recruited at Bharati hospital, Pune, India. Plasma folate, vitamin B12, homocysteine and erythrocyte omega-3 and omega-6 fatty acids were analyzed. RESULTS: Homocysteine concentrations were higher in pre-eclamptic than in normotensive women (14.28+/-7.31 vs. 11.03+/-4.38 MUmol/l, p<0.01) despite similar levels of folic acid and vitamin B12. In the pre-eclamptic group, plasma folate levels were positively associated with erythrocyte omega-6 fatty acids (p<0.05) while erythrocyte docosahexaenoic acid levels were negatively associated with plasma homocysteine levels (p<0.01). CONCLUSIONS: Our study provides evidence for the associations of altered omega-3 fatty acids especially docosahexaenoic acid and the resultant increased homocysteine concentrations in pre-eclampsia. Future studies need to examine if docosahexaenoic acid supplementation during pregnancy reduces homocysteine levels and ameliorates the risk of developing pre-eclampsia. PMID- 20719413 TI - The prevalence of malnutrition and the evolution of nutritional status in patients with moderate to severe forms of Crohn's disease treated with Infliximab. AB - BACKGROUND & AIMS: Malnutrition is variably encountered in adult patients with Crohn's disease. We evaluated the nutritional status at the beginning and during Infliximab treatment in patients with Crohn's disease. METHODS: Patients with moderate/severe flares of disease treated with Infliximab for induction and maintenance of remission were included in a prospective observational study. Body Mass Index and Nutritional Risk Index were calculated in each patient at 0, 6 weeks and than every 8 weeks for one year. RESULTS: From 30 patients treated with Infliximab 59.3% had low BMI, 35.7% being undernourished. The severity of Crohn's disease did not correlate with low BMI but did correlate with Nutritional Risk Index (p = 0.001). In all patients that responded to Infliximab treatment progressive weight gain was observed, all but one patient reaching normal BMI after one year. Mean weight gain was significantly more elevated (p = 0.001) and time needed to reach normal BMI was longer in the undernutrition group (p = 0.01). Clinical remission was the principal factor associated with weight gain (p = 0.001), while there was no influence of endoscopic remission on nutritional status. CONCLUSIONS: In patients with moderate/severe forms of Crohn's disease malnutrition is frequently encountered. Induction and maintenance treatment with Infliximab determines weight gain and corrects malnutrition in all patients with clinical remission. PMID- 20719414 TI - National survey of the use and application of leeches in oral and maxillofacial surgery in the United Kingdom. AB - We investigated the use of leeches by oral and maxillofacial surgeons to establish whether they are used according to a standard protocol, and to ascertain whether clinicians Knew which leeches they are using and from where they are sourced. A self-designed questionnaire sent to 154 oral and maxillofacial surgery units in the United Kingdom included questions about the use of leeches, whether a protocol was followed, the number and type used, and their source. Of the 74 (48%) returned, 13 units (18%) used leeches, most commonly for the salvage of free flaps (n=7). Twelve units had no protocol for their application, and five respondents were either incorrect or did not know the type of leech that was used. The study shows that further education and support may be necessary in the application of leeches within the speciality, and that a protocol is needed for their use. PMID- 20719415 TI - Rare case of bizarre parosteal osteochondromatous proliferation presenting in the zygoma. AB - Bizarre parosteal osteochondromatous proliferation is a rare benign lesion that tends to occur within the bones of the hands and feet. To our knowledge this is the third published case of its occurrence in the head region. We report the case of a 31-year-old man with an eight-month history of an asymptomatic, slowly enlarging lump on the right zygomatic area diagnosed as bizarre parosteal osteochondromatous proliferation. Diagnosis depends on specific radiological and histopathological features. Treatment is by complete excision, and recurrence has been reported in up to 50% of cases. Awareness of the condition will expedite its correct diagnosis and management. PMID- 20719416 TI - Use of n-butyl 2-cyanoacrylate tissue adhesive to splint traumatised teeth in the emergency department. AB - The splinting of traumatised teeth can be difficult in the emergency department where access to dentally trained clinicians and equipment may be limited. We report the use of a readily available medical tissue adhesive (n-butyl 2 cyanoacrylate) as a material for temporary dental splinting, and discuss its suitability for the task. PMID- 20719417 TI - A brain abscess following dental extractions in a patient with hereditary hemorrhagic telangiectasia. AB - Oral and maxillofacial surgeons must be aware of the potentially life-threatening complications of dental extractions in patients with hereditary haemorrhagic telangiectasia because of their high prevalence of pulmonary arteriovenous fistulas. Despite the lack of evidence-based guidelines, antibiotic cover should be given to patients with HHT who require oral surgery according to the same rules as those used for patients at high risk of bacterial endocarditis. PMID- 20719418 TI - Risk, theory, social and medical models: a critical analysis of the concept of risk in maternity care. AB - BACKGROUND: there is an on-going debate about perceptions of risk and risk management in maternity care. OBJECTIVES: to provide a critical analysis of the risk concept, its development in modern society in general and UK maternity services in particular. Through the associated theory, we explore the origins of the current preoccupation with risk. Using Pickstone's historical phases of modern health care, the paper explores the way maternity services changed from a social to a medical model over the twentieth century and suggests that the risk agenda was part of this process. KEY CONCLUSIONS: current UK maternity services policy which promotes normality contends that effective risk management screens women suitable for birth in community maternity units (CMUs) or home birth: however, although current policy advocates a return to this more social model, policy implementation is slow in practice. IMPLICATIONS FOR PRACTICE: the slow implementation of current maternity policy in is linked to perceptions of risk. We content that intellectual and social capital remains within the medical model. PMID- 20719419 TI - RHIZOtest: a plant-based biotest to account for rhizosphere processes when assessing copper bioavailability. AB - The ability of the free ion activity model (FIAM), the terrestrial biotic ligand model (TBLM), the diffusive gradients in thin films (DGT) technique and a plant based biotest, the RHIZOtest, to predict root copper (Cu) concentration in field grown durum wheat (Triticum turgidum durum L.) was assessed on 44 soils varying in pH (3.9-7.8) and total Cu (32-184 mg kg(-1)). None of the methods adequately predicted root Cu concentration, which was mainly correlated with total soil Cu. Results from DGT measurements and even more so FIAM prediction were negatively correlated with soil pH and over-estimated root Cu concentration in acidic soils. TBLM implementation improved numerically FIAM prediction but still failed to predict adequately root Cu concentration as the TBLM formalism did not considered the rhizosphere alkalisation as observed in situ. In contrast, RHIZOtest measurements accounted for rhizosphere alkalisation and were mainly correlated with total soil Cu. PMID- 20719420 TI - Gene transcription profiles, global DNA methylation and potential transgenerational epigenetic effects related to Zn exposure history in Daphnia magna. AB - A reduced level of DNA methylation has recently been described in both Zn-exposed and non-exposed offspring of Daphnia magna exposed to Zn. The hypothesis examined in this study is that DNA hypomethylation has an effect on gene transcription. A second hypothesis is that accumulative epigenetic effects can affect gene transcription in non-exposed offspring from parents with an exposure history of more than one generation. Transcriptional gene regulation was studied with a cDNA microarray. In the exposed and non-exposed hypomethylated daphnids, a large proportion of common genes were similarly up- or down-regulated, indicating a possible effect of the DNA hypomethylation. Two of these genes can be mechanistically involved in DNA methylation reduction. The similar transcriptional regulation of two and three genes in the F0 and F1 exposed daphnids on one hand and their non-exposed offspring on the other hand, could be the result of a one-generation temporary transgenerational epigenetic effect, which was not accumulative. PMID- 20719421 TI - Alterations to proteome and tissue recovery responses in fish liver caused by a short-term combination treatment with cadmium and benzo[a]pyrene. AB - The livers of soles (Solea senegalensis) injected with subacute doses of cadmium (Cd), benzo[a]pyrene (B[a]P), or their combination, were screened for alterations to cytosolic protein expression patterns, complemented by cytological and histological analyses. Cadmium and B[a]P, but not combined, induced hepatocyte apoptosis and Kupfer cell hyperplasia. Proteomics, however, suggested that apoptosis was triggered through distinct pathways. Cadmium and B[a]P caused upregulation of different anti-oxidative enzymes (peroxiredoxin and glutathione peroxidase, respectively) although co-exposure impaired induction. Similarly, apoptosis was inhibited by co-exposure, to which may have contributed a synergistic upregulation of tissue metalloproteinase inhibitor, beta-actin and a lipid transport protein. The regulation factors of nine out of eleven identified proteins of different types revealed antagonistic or synergistic effects between Cd and B[a]P at the prospected doses after 24 h of exposure. The results indicate that co-exposure to Cd and B[a]P may enhance toxicity by impairing specific responses and not through cumulative damage. PMID- 20719422 TI - 'All in the same boat'? Patient and carer attitudes to peer support and social comparison in Motor Neurone Disease (MND). AB - This paper explores attitudes to peer support among people with Motor Neurone Disease (MND) and their family carers. It reports findings from a secondary analysis of data from two UK interview studies conducted by the authors. The process of secondary analysis is reported in detail. 48 people with MND and 22 carers were interviewed in 2005-2007. The authors identified narrative extracts on peer support from their own datasets and exchanged them for independent thematic analysis. Subsequent discussion, drawing on literature on support groups and social comparison, led to an exploration of two overarching themes: valuing camaraderie and comparison, and choosing isolation. Findings suggest that social comparison theory is a useful framework for analysing attitudes to MND support groups, but that on its own it is insufficient. 'Valuing camaraderie and comparison' explains how support groups offer practical and social support, as well as beneficial opportunities for social comparison. Seeing others coping well with the condition can provide hope, while downward comparison with those worse off can also make people feel better about their own situation. However, most people are also shocked and saddened by seeing others with the condition. Tension of identity can occur when group membership starts to define the individual as 'a person with MND, rather than the person I am that happens to have MND'. Choosing isolation can be a deliberate defensive strategy, to protect oneself from witnessing one's possible future. Levels of involvement may change over time as people struggle with their changing needs and fears. PMID- 20719423 TI - Linking two opposites of pregnancy loss: Induced abortion and infertility in Yoruba society, Nigeria. AB - Involuntary infertility and induced abortion exist on opposite sides of the spectrum: the first being the unwanted loss of childbearing potential while the second is the intentional termination of pregnancy. However, this paper proposes that these two poles of pregnancy loss are in fact related in Yoruba society, Nigeria. This argument is supported by qualitative and quantitative data drawn from an applied research project in communities and health institutions of Lagos State, from 1996 to 1999, where a total of 693 women recounted 1114 personal abortion experiences, and 233 women shared their experiences of fertility problems. Study statistics show that 37% of secondary infertility was most probably the result of induced abortion and that half of women with abortion complications interviewed in a referral hospital will have fertility problems. This paper provides insight into the reasons why single and married women decide to abort, and use unsafe methods, despite awareness of the serious health risks, including infertility. This is paradoxical given that fear of infertility is a major reason why women do not use modern contraceptives when trying to prevent unwanted pregnancy. By analysing the relations between infertility and abortion within the socio-cultural, economic, and services-related structures that influence women's decisions, this paper suggests ways of addressing the problems related to both types of pregnancy loss. PMID- 20719424 TI - [Anatomical snuffbox lipoma causing nervous compression. A case report]. AB - Lipomas are rarely localized at the hand, and more unfrequently at the anatomical snuffbox. We report a case of a lipoma that compressed the lateral branch of the superficial sensory branch of the radial nerve. PMID- 20719425 TI - Compatible solutes: Thermodynamic properties and biological impact of ectoines and prolines. AB - Compatible solutes like ectoine and its derivatives are deployed by halophile organisms as osmolytes to sustain the high salt concentration in the environment. This work investigates the relation of the thermodynamic properties of compatible solutes and their impact as osmolytes. The ectoines considered in this work are ectoine, hydroxyectoine, and homoectoine. Besides solution densities (15-45 degrees C) and solubilities in water (3-80 degrees C), component activity coefficients in the aqueous solutions were determined in the temperature range between 0 and 50 degrees C. The latter is important for adjusting a certain water activity and therewith a respective osmotic pressure within a cell. The characteristic effect of ectoines is compared to that of prolines, as well as to that of incompatible solutes as salts and urea. The experimental results show that the influence on the activity (coefficient) of water is quite different for compatible and incompatible solutes: whereas compatible solutes cause decreasing water activity coefficients, incompatible solutes lead to an increase in water activity coefficients. Based on this quantity, the paper discusses the impact of various osmolytes on biological systems and contributes to the explanation why some osmolytes are more often and at other temperatures used than others. Moreover, it was found that the anti-stress effect of an osmolyte is weakened in the presence of a salt. Finally, it is shown that the thermodynamic properties of compatible solutes can be modeled and even predicted using the thermodynamic model PC-SAFT (Perturbed-Chain Statistical Associating Fluid Theory). PMID- 20719426 TI - Budding of giant unilamellar vesicles induced by an amphitropic protein beta2 glycoprotein I. AB - beta(2)-glycoprotein I (beta(2)GPI) is a plasma protein capable of binding reversibly to membranes, and is classified among the amphitropic proteins. Part of the protein intercalates into the outer membrane leaflet, altering the difference between the preferred areas of the membrane leaflets, which results in membrane shape transformations. Budding, as a specific example of such shape transformations, was studied using giant unilamellar vesicles. Our aim was to identify the vesicle parameters that influence the degree of membrane budding by studying this process qualitatively and quantitatively. A simple theoretical model has been developed and assessed against the experimental observations. The results show that beta(2)GPI binds in a concentration dependent manner, causing transitions between vesicle shapes with increasing numbers of buds. Higher numbers of buds are characteristic of larger and/or more flaccid vesicles. When the vesicle membrane is strained, a higher beta(2)GPI concentration is needed to produce the same effects as on the unstrained vesicle. Vesicles were found to be highly individual in their behaviour, so each was treated individually. Specific vesicle behaviour was found to be the consequence of the neck between the main vesicle body and the buds, which could be either open, closed for the exchange of solution, or closed for the exchange of both solution and membrane. PMID- 20719427 TI - Comparison between ozone and ultrasound disintegration on sludge anaerobic digestion. AB - This paper deals with the comparison of ultrasound (mechanical) and ozone (chemical) pre-treatment on the performances of excess sludge semi-continuous digestion. Sludge solubilisation has been investigated by varying specific energy input. For each pre-treatment, long anaerobic digestion tests were carried out by two parallel digesters: one reactor, as control unit, was fed with untreated waste activated sludge, and the other one was fed with disintegrated sludge. To evaluate and compare the efficacy of both pre-treatments, the specific energy was maintained approximately the same. The digestion tests were carried out to investigate the feasibility of anaerobic digestion performance (total biogas production, volatile solids removal, sludge dewaterability) and to assess the heat balance. Results obtained from the digestion of sonicated sludge at 4% disintegration degree (~ 2500 kJ/kg TS) showed that the ultrasound pre-treatment may be effective both in increasing VS destruction (+19%) and cumulative biogas production (+26%). On the contrary, the digestion test with ozonized sludge (ozone dose of 0.05 g O(3)/g TS corresponding to ~ 2000 kJ/kg TS) did not indicate a significant improvement on the digestion performances. By doubling the ozone dose an improvement in the organics removal and cumulative biogas production was observed. Relevant differences in terms of colloidal charge and filterability were discussed. PMID- 20719428 TI - Regulatory requirements and tools for environmental assessment of hazardous wastes: understanding tribal and stakeholder concerns using Department of Energy sites. AB - Many US governmental and Tribal Nation agencies, as well as state and local entities, deal with hazardous wastes within regulatory frameworks that require specific environmental assessments. In this paper we use Department of Energy (DOE) sites as examples to examine the relationship between regulatory requirements and environmental assessments for hazardous waste sites and give special attention to how assessment tools differ. We consider federal laws associated with environmental protection include the National Environmental Policy Act (NEPA), the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response Compensation and Liability Act (CERCLA), as well as regulations promulgated by the Nuclear Regulatory Commission, Tribal Nations and state agencies. These regulatory regimes require different types of environmental assessments and remedial investigations, dose assessments and contaminant pathways. The DOE case studies illustrate the following points: 1) there is often understandable confusion about what regulatory requirements apply to the site resources, and what environmental assessments are required by each, 2) the messages sent on site safety issued by different regulatory agencies are sometimes contradictory or confusing (e.g. Oak Ridge Reservation), 3) the regulatory frameworks being used to examine the same question can be different, leading to different conclusions (e.g. Brookhaven National Laboratory), 4) computer models used in support of groundwater models or risk assessments are not necessarily successful in convincing Native Americans and others that there is no possibility of risk from contaminants (e.g. Amchitka Island), 5) when given the opportunity to choose between relying on a screening risk assessments or waiting for a full site-specific analysis of contaminants in biota, the screening risk assessment option is rarely selected (e.g. Amchitka, Hanford Site), and finally, 6) there needs to be agreement on whether there has been adequate characterization to support the risk assessment (e.g. Hanford). The assessments need to be transparent and to accommodate different opinions about the relationship between characterizations and risk assessments. This paper illustrates how many of the problems at DOE sites, and potentially at other sites in the U.S. and elsewhere, derive from a lack of either understanding of, or consensus about, the regulatory process, including the timing and types of required characterizations and data in support of site characterizations and risk assessments. PMID- 20719429 TI - Stiletto stabbing: penetrating injury to the hypothalamus with hyperacute diabetes insipidus. AB - Diabetes insipidus (DI) is a well documented complication observed after traumatic head injuries. We report a case of hyperacute onset DI in a 19-year-old male who sustained a hypothalamic-pituitary injury when he was stabbed in the head with a 30-cm long thin-bladed knife. At CT, our patient showed significant hemorrhagic contusions of the lower hypothalamus. He developed polydipsia, polyuria, and mild hypernatremia in the Emergency Department. Diagnostic digital subtraction angiography showed a hypervascular congestive pituitary gland with prominent draining veins. On the third day his hypernatremia became severe (183mEq/L). He was managed with parenteral fluids and a regimen of intranasal DDAVP (1-desamino 8-d-arginine vasopressin), leading to improved plasmatic sodium levels, urine output, and urinary specific gravity. In patients presenting with hyperacute posttraumatic DI, emergency room physicians and neurosurgeons should rule out direct injury to the hypothalamus and/or the posterior lobe of the pituitary, and initiate early pharmacological treatment. PMID- 20719430 TI - Laboratory confirmed polymethyl-methacrylate (Palacos)-hypersensitivity after cranioplasty. AB - Polymethyl-methacrylate (PMMA) as part of bone cement is a widely used material in the context of orthopaedic implants and also in cranioplasty. Although PMMA is characterised by excellent biocompatibility with low intrinsic toxicity and inflammatory activation, a minor portion of patients develop allergic reactions. We present the case of a 39-year-old woman with an increasing headache and a corresponding erythema over the parieto-occipital cranioplasty, which was performed 42 days prior using a PMMA compound. A patch test specific for bone cement components confirmed the diagnosis of a PMMA delayed-type hypersensitivity reaction. The prevalence of allergic reactions to bone cement components are known to vary from between 0.6% and 1.6%, however no adequate, pre-interventional diagnostic tool is currently available. Therefore, physicians are required to consider this differential diagnosis even after an extremely delayed onset of symptoms. This case describes the first ever-reported case in the literature of hypersensitivity to bone cement cranioplasty. PMID- 20719431 TI - Impact of long-term reclaimed wastewater irrigation on agricultural soils: a preliminary assessment. AB - The effect of reclaimed wastewater irrigation on the alteration of soil properties and accumulation of trace metals in soil profiles was investigated by monitoring different plots from Palmdale, California that had been irrigated with effluents for various lengths of time (3, 8, and 20 years, respectively). The non effluent-irrigated plot served as the control and provided reference "background" values. Total metals at different soil depths were analyzed by acid digestion, and EDTA-extractable metals were analyzed as available fraction. Results show that soil pH values were significantly (p<0.05) lowered in plots with 20-year irrigation to a depth of 140 cm, while EC was elevated for all three plots compared with control. OM, TC and TN contents increased in the top 10-cm soil layers in plots with 8- and 20-year effluent irrigation. Irrigation with effluents also increased both the total and EDTA-extractable metals in the fields. It showed that long-term effluent irrigation could be of agricultural interest due mainly to its organic matter concentrations and nutrients input, however, trace contaminants such as heavy metals in the upper horizons may be accumulated, which may eventually lead to deterioration of soil and groundwater quality and affect the sustainability of land-based disposal of effluent. PMID- 20719432 TI - Explosion characteristics of flammable organic vapors in nitrous oxide atmosphere. AB - Despite unexpected explosion accidents caused by nitrous oxide have occurred, few systematic studies have been reported on explosion characteristics of flammable gases in nitrous oxide atmosphere compared to those in air or oxygen. The objective of this paper is to characterize explosion properties of mixtures of n pentane, diethyl ether, diethylamine, or n-butyraldehyde with nitrous oxide and nitrogen using three parameters: explosion limit, peak explosion pressure, and time to the peak explosion pressure. Then, similar mixtures of n-pentane, diethyl ether, diethylamine, or n-butyraldehyde with oxygen and nitrogen were prepared to compare their explosion characteristics with the mixtures containing nitrous oxide. The explosion experiments were performed in a cylindrical vessel at atmospheric pressure and room temperature. The measurements showed that explosion ranges of the mixtures containing nitrous oxide were narrow compared to those of the mixtures containing oxygen. On the other hand, the maximum explosion pressures of the mixtures containing nitrous oxide were higher than those of the mixtures containing oxygen. Moreover, our experiments revealed that these mixtures differed in equivalence ratios at which the maximum explosion pressures were observed: the pressures of the mixtures containing nitrous oxide were observed at stoichiometry; in contrast, those of the mixtures containing oxygen were found at fuel-rich area. Chemical equilibrium calculations confirmed these behaviors. PMID- 20719433 TI - Temporal daily associations between pain and sleep in adolescents with chronic pain versus healthy adolescents. AB - Adolescents with chronic pain frequently report sleep disturbances, particularly short sleep duration, night wakings, and poor sleep quality. Prior research has been limited by assessment of subjectively reported sleep only and lack of data on daily relationships between sleep and pain. The current study utilized multilevel modeling to compare daily associations between sleep and pain in adolescents with chronic pain and healthy adolescents. Ninety-seven adolescents (n=39 chronic pain; n=58 healthy) aged 12-18, 70.1% female participated. Adolescents completed pain diary ratings (0-10 NRS) and actigraphic sleep monitoring for 10 days. Actigraphic sleep variables (duration, efficiency, WASO) and self-reported sleep quality were tested as predictors of next-day pain, and daytime pain was tested as a predictor of sleep that night. Effects of age, gender, study group, and depressive symptoms on daily associations between sleep and pain were also tested. Multivariate analyses revealed that nighttime sleep (p<.001) and minutes awake after sleep onset (WASO) (p<.05) predicted next-day pain, with longer sleep duration and higher WASO associated with higher pain. Contrary to hypotheses, neither nighttime sleep quality nor sleep efficiency predicted pain the following day. The interaction between nighttime sleep efficiency and study group was significant, with adolescents with pain showing stronger associations between sleep efficiency and next-day pain than healthy participants (p=.05). Contrary to hypotheses, daytime pain did not predict nighttime sleep. Daily associations between pain and sleep suggest that further work is needed to identify specific adolescent sleep behaviors (e.g., compensatory sleep behaviors) that may be targeted in interventions. PMID- 20719434 TI - Postnatal blockade of androgen receptors or aromatase impair the expression of stress hypothalamic-pituitary-adrenal axis habituation in adult male rats. AB - Sex steroid hormones during development permanently alter, or organize, the brain and behavior, while during adulthood they act to reversibly modulate, or activate, physiology and behavior. Testosterone exerts both organizational and activational effects on the magnitude of the hypothalamic-pituitary-adrenal (HPA) axis response to acute stress. What has never been approached is how testosterone can organize habituation of the HPA axis, in which stress induced elevations in ACTH and corticosterone release decline over repeated exposures to the same stimulus. In the current study we examined HPA responses to repeated psychogenic stress in 65-day-old, adult male rats that received subcutaneous capsules containing the antiandrogen flutamide or the aromatase inhibitor 1,4,6 androstatriene-3,17-dione (ATD), introduced within 12h of birth and removed on day 21 of weaning. An additional group of castrated, adult male rats were used to differentiate organizational from activational effects of testosterone. All treatment groups displayed smaller declines in ACTH in response to repeated restraint compared to control animals. Remarkably, the normal decline in corticosterone failed to occur in flutamide- and ATD-treated animals. By contrast, males that were castrated as adults showed a significant reduction in corticosterone after repeated stress. Taken together, these findings underscore an organizing influence of both androgen receptors and estrogen conversion on HPA habituation to repeated psychogenic stress, which appears to occur independent of the activational effects of testosterone. PMID- 20719435 TI - Anxiety sensitivity, distress tolerance, and discomfort intolerance in relation to coping and conformity motives for alcohol use and alcohol use problems among young adult drinkers. AB - Anxiety sensitivity, distress tolerance, and discomfort intolerance have been identified as important factors related to alcohol use motives and alcohol related problems. Yet, these variables are highly correlated and little work has delineated whether these psychological vulnerability factors are differentially related to alcohol use motives and problems. To fill this gap in the existing literature, the present study evaluated whether anxiety sensitivity, distress tolerance, and discomfort intolerance were differentially related to high-risk alcohol use motives (i.e., coping and conformity motives) and alcohol use problems among 224 young adult, current drinkers (52.3% women; M(age)=21.18, SD=7.08). Results indicated that distress tolerance, but not anxiety sensitivity or discomfort intolerance, was significantly related to coping motives for alcohol use. Additionally, anxiety sensitivity, but not distress tolerance or discomfort intolerance, was significantly related to conformity motives for drinking. For both sets of analyses, the observed significant effects were evident above and beyond the variance accounted for by alcohol consumption level, smoking rate, negative affectivity, and non-criterion alcohol use motives. Additionally, discomfort intolerance and anxiety sensitivity each predicted alcohol use problems; effects were not attributable to negative affectivity, cigarettes smoked per day, or shared variance with distress tolerance. Findings are discussed in relation to the role of emotional sensitivity and intolerance in terms of the motivational bases for alcohol use and alcohol use problems among young adult drinkers. PMID- 20719436 TI - Lupus erythematosus. Are residential insecticides exposure the missing link? AB - Although the etiology of systemic lupus erythematosus (SLE) remains to be fully elucidated, it is now apparent that multiple genetic and environmental factors are at play. Because lupus has a strong female preponderance, several studies have examined the role of female hormones in disease etiology. Yet this knowledge has not helped to explain lupus etiology or to prevent it. Estrogens exist not only as natural or drug compounds, but also as environmental chemical contaminant and women are highly exposed to all of them. Estrogenic activity has been found in a number of pesticides including pyrethroids that are largely used in the household. Although there is only a small amount of published data examining a possible causal relationship between lupus and pesticides it can be hypothesized that pesticides, in particular insecticides, through their estrogenic activity and capacity to induce oxidative stress provoke autoimmune reaction influencing lupus development. PMID- 20719437 TI - Double conflicts model and anxiety ratification therapy hypotheses of obsessive compulsive disorder. AB - In-depth researches on the psychopathology of obsessive-compulsive disorder (OCD) have been made in the cognitive-behavioral domain. However, some questions about the symptoms have not been properly answered yet. Studies from other domains also shed light on the psychopathology of OCD. The most inspiring ones are studies on psychological trauma which have probed into the mechanism of intrusions, and studies on emotion regulation which have investigated how behavioral emotion expressions are shaped. In this paper, we analyze the roles of psychological trauma and emotion regulation in OCD and propose a double conflicts model. In the model, it is hypothesized that information conflict and motivational conflict, which are called "core conflicts", are key factors in the psychopathology of OCD, and that obsessions and compulsions arise within two associated loops. Anxiety ratification therapy hypothesis is further put forward, which emphasizes the acceptance of all aspects of anxiety, including the behavioral responses and the accompanying new information, and sets the modification of the basic assumptions as the goal of treatment. Although the model provides comprehensive explanation for many symptoms, the assumptions on which the model is based are in need of confirmation. The therapy is tailored for OCD, but its operability and effect should be monitored closely. PMID- 20719438 TI - Lack of association between age at menarche and age at menopause: Pro-Saude Study, Rio de Janeiro, Brazil. AB - OBJECTIVE: To investigate the association between age at menarche and age at menopause among Brazilian women. METHODS: This study is based on cross-sectional data obtained in 1999 from technical and administrative employees who were recruited for participation at the Pro-Saude cohort study in Rio de Janeiro, Brazil. The final study population consisted of 1462 women. Participants completed a self-administered multidimensional questionnaire. In addition to the study exposure (age at menarche) and outcome (age at menopause) variables, the following independent variables were selected: parity; schooling; self-classified race; use of oral contraceptives; smoking; and body mass index (BMI). Median ages at natural menopause and the survival curves were estimated by the Kaplan-Meier method. To estimate the association between age at menarche and age at natural menopause, a Cox semi-parametric model was fitted. Women who were still menstruating, who had undergone surgery for the removal of the uterus or ovaries, or who were in perimenopause were censored. RESULTS: Natural menopause occurred in 205 women. The median and mode for natural menopause were 51.7 and 50 years of age, respectively. In the multivariate analysis, no statistically significant association was observed between age at menarche and age at menopause (HR: 1.01; 95% CI: 0.93-1.11). CONCLUSION: In the current study, the hypothesis of an association between age at menarche and age at natural menopause was not confirmed. Specific studies on the determinants of age at menopause should be conducted, due to the importance of menopause in the causality of diseases with high case mortality rate. PMID- 20719439 TI - A forensic approach to fatal dog attacks. A case study and review of the literature. AB - The authors present a case of a 45-year-old man who was found dead on the grounds of an abandoned military base. His body was discovered lying face down in a large pool of partially desiccated blood with signs of having been dragged. On-site examination revealed severe injuries to the face, neck and head, the result of having been attacked by a pack of dogs. A multi-disciplinary approach, including autopsy findings, histological examination, and bite mark analysis was performed. Photos of the injuries were taken using the specific photographic recommendations of the American Board of Forensic Odontology (ABFO). Comparisons between dental casts obtained from the dogs, and the inflicted wounds were made, resulting in positive correlations of injuries and the dental casts of three of the five dogs involved, suggesting that these dogs were probably the more active participants in the attack. This paper also highlights the ever-growing problems posed by stray dogs which tend to live under certain conditions: hunger; thirst; compromised health status; possible feelings of being threatened. At times they are also feral. This situation poses a threat to humans who come into contact with them. PMID- 20719440 TI - Gastrointestinal hypomotility: an under-recognised life-threatening adverse effect of clozapine. AB - AIM: To highlight some problems that may occur when investigating clozapine associated deaths including (i) that death may be related to gastrointestinal hypomotility and (ii) that post-mortem blood clozapine and norclozapine concentrations may not reflect ante-mortem concentrations. CASE REPORTS: A 41 year-old male died 40 min after admission to hospital as a result of aspiration complicating severe, clozapine-induced constipation. At post-mortem the small bowel was dilated and contained bloodstained mucus, particularly within the jejunum. The large bowel was considerably dilated and contained large quantities of foul-smelling, bloodstained fluid and a small amount of stool. Its lining was focally congested, but there was no other obvious abnormality. Analysis of serum obtained on admission revealed clozapine and norclozapine concentrations of 0.56 and 0.43 mg/L, respectively, whereas post-mortem femoral whole blood obtained <34 h after death showed clozapine and norclozapine concentrations of 3.73 and 1.75 mg/L, respectively. In 6 out of a further 12 clozapine-associated deaths investigated 2002-9 there were reports of gastrointestinal tract problems of varying severity. CONCLUSIONS: Severe constipation or paralytic ileus in clozapine-treated patients may lead to intestinal necrosis and/or perforation, or pulmonary aspiration. In some such cases the immediate cause of death may be obvious, but in others only careful assessment of the clinical course of the terminal illness may reveal gastrointestinal hypomotility as a likely underlying cause of death. PMID- 20719441 TI - Classification of OPP adhesive tapes according to pyrogram of adhesives. AB - Pressure sensitive adhesives (PSAs) of colorless and transparent oriented polypropylene (OPP) adhesive tapes were analyzed by pyrolysis/gas chromatography/mass spectrometry (Py/GC/MS). The PSAs were acrylic and rubber based PSAs and the tapes were classified according to total ion current (TIC) chromatograms of the PSAs. The main pyrolyzates of the acrylic PSAs were decomposition products of monomers, monomers, dimmers and trimers. Those of the rubber-based PSAs were the monomers of elastomers, and subtle peaks observed were the pyrolyzates of tackifiers and volatile additives in the TIC chromatograms. Small differences were observed among the classifications of the acrylic PSAs by Py/GC/MS, attenuated total reflection Fourier transform infrared (ATR FT-IR) and Matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS). The classification of the rubber-based PSAs by Py/GC/MS and that by ATR FT-IR were the same, and a slight difference was observed between those by Py/GC/MS and MALDI MS. PMID- 20719442 TI - Forensic molecular pathology of violent deaths. AB - In forensic pathology, while classical morphology remains a core procedure to investigate deaths, a spectrum of ancillary procedures has been developed and incorporated to detail the pathology. Among them, postmortem biochemistry is important to investigate the systemic pathophysiological changes involved in the dying process that cannot be detected by morphology. In addition, recent advances in molecular biology have provided a procedure to investigate genetic bases of diseases that might present with sudden death, which is called 'molecular autopsy'. Meanwhile, the practical application of RNA analyses to postmortem investigation has not been accepted due to rapid decay after death; however, recent experimental and practical studies using real-time reverse transcription PCR have suggested that the relative quantification of mRNA transcripts can be applied in molecular pathology for postmortem investigation of deaths, which may be called 'advanced molecular autopsy'. In a broad sense, forensic molecular pathology implies applied medical sciences to investigate the genetic basis of diseases, and the pathophysiology of diseases and traumas leading to death at a biological molecular level in the context of forensic pathology. The possible applications include analyses of local pathology, including tissue injury, ischemia/hypoxia and inflammation at the site of insult or specific tissue damage from intoxication, systemic responses to violence or environmental hazards, disorders due to intoxication, and systemic pathophysiology of fatal process involving major life-support organs. A review of previous studies suggests that systematic postmortem quantitative analysis of mRNA transcripts can be established from multi-faceted aspects of molecular biology and incorporated into death investigations in forensic pathology, to support and reinforce morphological evidence. PMID- 20719443 TI - Development of latent fingerprint by ZnO deposition. AB - Vacuum metal deposition (VMD) utilizing sequential Au and Zn depositions has been an effective technique to develop latent fingerprint on plastic surfaces. A simplified vacuum deposition process was conducted to develop fingerprint in this study. While pure ZnO was thermally evaporated in a vacuum system, ZnO could condense on polyethylene terephthalate (PET) surface. Direct deposition of ZnO, without applying Au seeding, yielded normal development of latent fingerprint. The development of aged fingerprint by ZnO deposition was more effective than that by Au/Zn VMD. PMID- 20719444 TI - Value of multislice computed tomography in the diagnosis of acute mesenteric ischemia. AB - OBJECTIVE: To define the value of multislice computed tomography (CT) in the diagnosis of acute mesenteric ischemia (AMI). MATERIALS AND METHODS: Two hundred patients (age range: 20-92 years) who were referred to the emergency CT department with a clinical suspicion of AMI were prospectively included in the study. CT examinations were performed with a multislice (16) CT scanner and the protocol included pre-contrast, arterial and venous phase acquisitions. Images were evaluated by using multiplanar reconstruction, maximum intensity projection and volume-rendering techniques at the CT workstation. RESULTS: Ninety-four patients (47%) underwent surgery for AMI or for other causes of acute abdominal pain. One hundred-six patients (53%) were followed conservatively according to clinical, radiologic and laboratory findings. Of the 94 patients who underwent surgery, 49 (25%) were found to have AMI. All of these 49 patients with a proven AMI diagnosis were diagnosed with CT. In the other 45 patients who underwent surgery, CT findings were negative for AMI. None of the patients, who were followed conservatively, were eventually diagnosed as having AMI except 1 patient. This patient was unfit for surgery although his clinical and radiologic findings were consistent with AMI and died in 3 days. The sensitivity and specificity values of CT for the detection of AMI were calculated to be 100% for each. CONCLUSIONS: Multislice CT is an effective imaging technique for the diagnosis of AMI with excellent sensitivity and specificity values. PMID- 20719445 TI - Reliable low-cost capillary electrophoresis device for drug quality control and counterfeit medicines. AB - The proportion of counterfeit medicines is dramatically increasing these last few years. According to numerous official sources, in some pharmaceutical wholesalers in African countries, the proportion has reached 80%. Unfortunately, this situation is far to be improved due to lack of suitable analytical equipment allowing rapid actions of the Regulatory Agencies based on scientific consideration, at affordable cost and all over the drug supply chain. For that purpose, a network group considered that mater by building a low-cost original capillary electrophoresis (CE) equipment equipped with a new deep UV detector based on LED technology. The generic conditions for analysis were investigated: capillary zone electrophoresis (CZE) performed at acidic pH for basic drug molecules (i.e., quinine, highly used as the last antimalarial rampart), basic pH for compounds such as furosemide (a common diuretic drug) and at neutral pH for a well known antibiotic combination, trimethoprim/sulfamethoxazol. To evaluate the ability of the CE equipment for quantification, a full validation and a method comparison study were carried out for the CZE method dedicated to quinine determination. The validation involved the use of accuracy profile and total error concept to monitor the adequacy of the results obtained by the new prototype. The method comparison was based on the Bland and Altman approach by comparing results obtained by the low-cost CE and a conventional set-up. Subsequent validation studies were realized with neutral and acidic drug molecules, each focusing on a single concentration level calibration curve in order to maintain as low as possible the expenses due to reagents and thus the cost of analysis, as important advantages of CE for drug quality control. PMID- 20719446 TI - Micellar electrokinetic chromatography method development for determination of impurities in ritonavir. AB - Ritonavir is a synthetic peptidomimetic human immunodeficiency virus (HIV) protease inhibitor employed in the treatment of AIDS since 1996. Synthetic precursors are potential impurities in the final product. In the present work a micellar electrokinetic chromatography (MEKC) method for the separation of Ritonavir from three available synthetic precursors was developed. The optimized separation is performed in a background electrolyte composed of sodium tetraborate (pH 9.6; 15mM) containing sodium dodecylsulfate (30mM) and acetonitrile (18%, v/v). Mass spectrometry was used to confirm the identity of the tested substances. Good repeatability was observed for migration time (RSD about 0.4%) and peak area (RSD about 0.8%). The limits of detection (LOD) obtained allow the determination of two of the impurities at levels as low as 0.005% m/m, and one at a level of 0.3% m/m. PMID- 20719447 TI - Application and potential of capillary electroseparation methods to determine antioxidant phenolic compounds from plant food material. AB - Antioxidants are one of the most common active ingredients of nutritionally functional foods which can play an important role in the prevention of oxidation and cellular damage inhibiting or delaying the oxidative processes. In recent years there has been an increased interest in the application of antioxidants to medical treatment as information is constantly gathered linking the development of human diseases to oxidative stress. Within antioxidants, phenolic molecules are an important category of compounds, commonly present in a wide variety of plant food materials. Their correct determination is pivotal nowadays and involves their extraction from the sample, analytical separation, identification, quantification and interpretation of the data. The aim of this review is to provide an overview about all the necessary steps of any analytical procedure to achieve the determination of phenolic compounds from plant matrices, paying particular attention to the application and potential of capillary electroseparation methods. Since it is quite complicated to establish a classification of plant food material, and to structure the current review, we will group the different matrices as follows: fruits, vegetables, herbs, spices and medicinal plants, beverages, vegetable oils, cereals, legumes and nuts and other matrices (including cocoa beans and bee products). At the end of the overview, we include two sections to explain the usefulness of the data about phenols provided by capillary electrophoresis and the newest trends. PMID- 20719448 TI - Determination of pKa values of benzimidazole derivatives from mobility obtained by capillary electrophoresis. AB - Dissociation constants of benzimidazole derivatives have been determined using capillary zone electrophoresis (CZE). Since CZE is a separation method, high purity and known concentration for the samples is not necessary because only mobilities are measured. The precision of pK(a) measurements of seven compounds is useful to observe pK(a) shifts induced by chemical variations. Some of them were compared to potentiometry and spectroscopy experiments. Good correlated pK(a) values are observed between the three analytical techniques. PMID- 20719449 TI - Altered levels of nucleoside metabolite profiles in urogenital tract cancer measured by capillary electrophoresis. AB - Metabolic profiles of nucleosides studied on the level of urine are closely related to the pathophysiological status of the organism. Posttranscriptional modifications of RNA (mostly tRNA) in cell nucleus are responsible for change of nucleoside levels during malignant disease. In this paper, 256 metabolite profiles from 160 urogenital tract cancer patients and 96 healthy controls, composed of 19 nucleosides were collected and studied with the application of such an approach. This approach comprised of the analysis of urine extracts and the investigation of collected nucleoside and modified nucleoside profiles by advanced statistical data processing tools such as principal component analysis (PCA), hierarchical cluster analysis (HCA), K-Nearest Neighbor method (kNN) and partial least squares-discriminant analysis with probabilistic function (p-PLS DA). It has been shown that alterations of metabolite profiles in cancer diseases are mainly expressed by the fold change of the urine levels of most nucleosides. In addition, observed metabolite-to-metabolite ratios differ in urogenital cancer patients compared to healthy controls. The obtained relationships between urinary nucleoside profiles and the presence of cancer diseases have been evaluated. Discrimination of the cancer patients and the non-cancer healthy subjects is with 76.5% sensitivity and 80.2% specificity. The presented results prove the usefulness of the metabolomic approach in studying urinary nucleoside profiles with high diagnostic potency in urogenital cancer diseases. Profiles of urinary nucleosides might be employed as a reliable and convenient tool in the diagnostics of urogenital tract cancer diseases. PMID- 20719450 TI - Metabolomic approach to the nutraceutical effect of rosemary extract plus Omega-3 PUFAs in diabetic children with capillary electrophoresis. AB - Type 1 diabetes mellitus is a major endocrine disorder, affecting approximately 5% of the world's population. It not only leads to hyperglycaemia but also causes many complications, and numerous studies have demonstrated that oxidative stress contributes to these complications. As a new strategy to improve the oxidative damage in diabetes, interest has grown in the usage of natural antioxidants, even more in the long term. Among them, Rosmarinus officinalis (rosemary) has been widely accepted as one of the species with the highest antioxidant activity. In addition, omega-3 polyunsaturated fatty acids were efficient in delaying and decreasing cardiovascular risk factors associated with diabetes. Type 1 diabetic children and the corresponding controls were enrolled in the assay. The aim was evaluating the effect of a special additive containing rosemary extract, vitamin E and PUFAs added to their standard diet through the meat. In the analytical point of view, a metabolomic approach with CE-UV was used to detect possible differences in urine of diabetic children as compared to controls. After the application of the appropriate multivariate statistical tools, clear differences could be observed between treated and non-treated diabetic children and some of the metabolites associated could be identified. This was specially challenging as most of the clinical biochemical parameters measured by target analysis showed no differences between the groups. PMID- 20719451 TI - Analysis of biological samples by capillary electrophoresis with laser induced fluorescence detection. AB - In this paper an overview is provided on practical difficulties as well as applications of capillary electrophoresis coupled to laser induced fluorescence detection methods in the field of analysis of biological samples. Various methodological approaches elaborated for determination of small molecules, peptides and proteins are outlined. Besides giving an overview on detection based on native fluorescence, immune and enzyme assays, the main focus is the problematics of sample derivatization and achievable detection sensitivities in the analysis of real biological samples. The characteristics and applicability of the most commonly used labeling reagents are discussed in details. PMID- 20719452 TI - Preface. PMID- 20719453 TI - Method development and validation of capillary sodium dodecyl sulfate gel electrophoresis for the characterization of a monoclonal antibody. AB - A capillary sodium dodecyl sulfate gel electrophoresis (cSDS) method has been developed and qualified for purity and impurity analysis of monoclonal antibodies. This method was optimized and qualified for the analysis of monoclonal antibody (mAb1) under reduced and non-reduced conditions. Some of the sample preparation parameters including sample buffer pH, incubation temperature and duration, alkylation conditions with iodoacetamide (IAM), and reduction conditions with 2-mercaptoethanol (2-ME) were optimized. It was observed that under slightly acidic conditions (pH 5.5-6.5) the thermally induced fragmentation of non-reduced mAb1 was greatly decreased. As such, a citrate-phosphate buffer at pH 6.5 was used for sample preparation to replace the original Beckman sample buffer (pH 9.0). The optimal sample preparation conditions were found to be as follows: (1) incubation temperature and duration (reduced and non-reduced), 65 degrees C for 5 min; (2) alkylation condition, 10 microL of 0.25 M IAM; (3) reduction condition, 10 microL of 5-fold diluted 2-ME. The method was qualified by evaluating specificity, accuracy, precision, limit of quantitation (LOQ), and linearity. The method exhibited no interference from sample buffer matrix. The method was found to be linear, accurate, and precise in the range of 0.25 3.0mg/mL protein concentration. The LOQ of the method was determined to be 0.02 mg/mL for reduced and non-reduced mAb1. In addition, some aspects of sample stability were examined during qualification. PMID- 20719454 TI - Screening alpha-glucosidase inhibitors from traditional Chinese drugs by capillary electrophoresis with electrophoretically mediated microanalysis. AB - In the present study, we report the study by a combination of electrophoretically mediated microanalysis method with a partial technique for screening alpha glucosidase inhibitors from 21 traditional Chinese drugs. In the setup, substrates and enzymes were introduced into the capillary as distinct plugs, the electrophoretic conditions for enzyme reaction and separation of substrates and products were different in the composition and pH of the background electrolyte, which make more enzyme reactions possible. Part of the capillary was filled with the optimal buffer for the enzyme reaction, whereas the rest was filled with the background electrolyte optimal for the separation of substrates and products. With the optimal condition, the Michaelis-Menten constant and the inhibitive mechanism of acarbose were studied, which were in the same range as previous literature data. Furthermore, the inhibitory ratios of enzymatic activity (IRE) of 21 traditional Chinese drugs were determined. The classical method has superiorities over traditional assay methods, which not only minimizes the false positive results but also simplifies the experimental processes. It could be used for screening inhibitors in natural extract. PMID- 20719455 TI - Improvement of a capillary electrophoresis/frontal analysis (CE/FA) method for determining binding constants: discussion on relevant parameters. AB - Drug-plasma protein interactions have a significant impact on both pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) and pharmacodynamics (pharmacological effects). Therefore, it is of high interest to evaluate this binding during the drug development process. Capillary electrophoresis (CE) is an interesting analytical tool for drug-protein binding characterization because it consumes a relatively low amount of reagents and enables assays that can be carried out under near-physiological conditions. The most interesting mode of CE for the study of biomolecular interactions is CE/frontal analysis (CE/FA). However, some confusion in how to conduct CE/FA experiments has emerged in the literature. The present study examines, using research into drug-albumin interactions as an example, the most important steps to take into consideration when building up new CE/FA binding assays. These include the following: choosing the buffer and applied voltage; evaluating protein adsorption onto the capillary wall; choosing the injection volume; choosing the drug and protein concentrations; and, finally, verifying the co migration of the protein and drug-protein complex. The experimental part of the present report can serve as a checklist for developing the key parameters that need to be addressed for successful and reliable interaction studies. In a second time, short-end injection was used to enhance throughput. The strengths of the binding constants (K(a)) for nine selected drugs (basic, neutral, and acidic substances) to albumin, which is the most important plasma protein, were from logK(a) 2.9 to 5.4. These values were compared to those obtained with validated methods and good agreement was achieved. PMID- 20719456 TI - Separation and determination of four ganoderic acids from dried fermentation mycelia powder of Ganoderma lucidum by capillary zone electrophoresis. AB - Ganoderic acids (GAs) were bioactive secondary metabolites produced by a traditional mushroom Ganoderma lucidum. We describe a simple and efficient method for the separation and quantitative determination of four GAs, namely Ganoderic acid T (GA-T), Ganoderic acid Mk (GA-Mk), Ganoderic acid Me (GA-Me) and Ganoderic acid S (GA-S) from dried triterpene-enriched extracts of G. lucidum mycelia powder by capillary zone electrophoresis (CZE). Under the optimum conditions, the four GAs reached the baseline separation in 9 min with Glycyrrhetinic acid (GTA) as internal standard. The four GAs and internal standard (GTA) were detected at a wavelength 245 nm. All calibration curves showed good linearity (r(2)>0.9958) within test ranges. Limit of detection (LOD) and limit of quantification (LOQ) were less than 0.6 and 1.8 microg/mL, respectively. The relative standard deviation (R.S.D.) values of precision and recoveries were less than 5% and recoveries ranged from 91.4% to 103.6%. This was the first report on simultaneous determination of the four GAs and the results provided a firm basis for the trace analysis of GAs in dried fermentation mycelia powder of G. lucidum with high accuracy. PMID- 20719457 TI - Chiral separation of econazole using micellar electrokinetic chromatography with hydroxypropyl-gamma-cyclodextrin. AB - A cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) method with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) as chiral selector for the enantiomeric separation of econazole is reported. Enantioseparation of econazole was successfully achieved by the optimized CD-MEKC system containing 40mM HP gamma-CD, 50mM SDS and 20mM phosphate buffer (pH 8) solution with an analysis time of less than 9min. Calibration curves were linear for the two stereoisomers of econazole (r(2)>0.998). Good repeatabilities in the migration time, peak area and peak height were obtained in terms of RSD% ranging from 0.30 to 7.67%. Combination of solid-phase extraction (SPE) procedure using diol column and the CD-MEKC method was successfully applied to the determination of econazole in a formulated cream sample. PMID- 20719458 TI - 1H NMR spectroscopic studies on human seminal plasma: a probative discriminant function analysis classification model. AB - Traditional seminal fluid-based clinical descriptors used to predict infertility and sub-fertility have shortcomings, including lack of insight into the underlying pathology. These methods are also time-consuming and labor-intensive. To address these limitations, (1)H nuclear magnetic resonance (NMR) spectroscopy was used to identify and classify signature biomarkers. Semen samples collected from 60 healthy, fertile men and from 125 infertile (normozoospermic and oligozoospermic) patients. Lactate, alanine, choline, citrate, glycerophosphocholine (GPC), glutamine, tyrosine, histidine, phenylalanine, and uridine were measured by (1)H NMR spectroscopy. The sperm concentration, motility, lipid peroxidation, and total protein were evaluated with standard laboratory methods in the same samples. NMR-quantified metabolites and clinical laboratory data were analyzed, separately, through linear multivariate discriminant function analysis (DFA) to determine the signature descriptors for each group. DFA reveals that alanine, citrate, GPC, tyrosine, and phenylalanine can be used to determine infertility. DFA-based classification demonstrated high accuracy (92.4% by NMR and 94.1% by clinical laboratory method) in differentiating healthy controls from infertile patients. This statistical analysis was also able to accurately classify normozoospermic to oligozoospermic samples (92.9% by NMR and 92.6% by clinical laboratory method). In conclusion, (1)H NMR-based metabolic screening appears to be a promising, rapid, and non invasive approach to probing infertility that has similar sensitivity and specificity to the tedious laboratory method. PMID- 20719459 TI - Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of artemether and lumefantrine in human plasma: application for a pharmacokinetic study. AB - A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC ESI-MS/MS) method for the simultaneous quantitation of artemether and lumefantrine in human plasma was developed and validated. Artesunate was used as an internal standard (IS). The analytes were extracted by a protein precipitation procedure and separated on a reversed-phase Zorbax SB-Ciano column with a mobile phase composed of methanol and 10mM aqueous ammonium acetate containing 0.2% (v/v) acetic acid and 0.1% (v/v) formic acid. Multiple reaction monitoring was performed using the transitions m/z 316 -> m/z 267, m/z 530 -> m/z 348 and m/z 402 -> m/z 267 to quantify artemether, lumefantrine and artesunate, respectively. Calibration curves were constructed over the range of 10-1000 ng/mL for artemether and 10-18,000 ng/mL for lumefantrine. The lower limit of quantitation was 10 ng/mL for both drugs. The mean R.S.D. values for the intra-run precision were 2.6% and 3.0% and for the inter-run precision were 3.6% and 4.6% for artemether and lumefantrine, respectively. The mean accuracy values were 102.0% and 101.2% for artemether and lumefantrine, respectively. No matrix effect was detected in the samples. The validated method was successfully applied to determine the plasma concentrations of artemether and lumefantrine in healthy volunteers, in a one-dose pharmacokinetic study, over the course of 11 days. PMID- 20719460 TI - A stability-indicating liquid chromatographic method for Lomustine. AB - A simple, inexpensive and rapid liquid chromatography (LC) method has been developed for the quantitative determination of Lomustine, an chemotherapy drug. Degradation studies were performed on the bulk drug by heating to 60 degrees C, exposure to UV light at an energy of 200 Wh/m(2)and to visible light at an illumination of not less than 1.2 million lux hours, acid (0.1N hydrochloric acid), base (0.1N sodium hydroxide) aqueous hydrolysis and oxidation with 6.0% (v/v) hydrogen peroxide. Good resolution between the peaks corresponding to impurities produced during synthesis, degradation products and the analyte was achieved on a Symmetry C 8 LC column using a mobile phase consisting of a mixture of aqueous potassium dihydrogen phosphate and acetonitrile. The degradation samples were assayed against the reference standard of Lomustine and the mass balance in each case was close to 99.9%. Validation of the method was carried out as per International Conference on Harmonization (ICH) requirements. PMID- 20719461 TI - Bringing gender sensitivity into healthcare practice: a systematic review. AB - OBJECTIVE: Despite the body of literature on gender dimensions and disparities between the sexes in health, practical improvements will not be realized effectively as long as we lack an overview of the ways how to implement these ideas. This systematic review provides a content analysis of literature on the implementation of gender sensitivity in health care. METHODS: Literature was identified from CINAHL, PsycINFO, Medline, EBSCO and Cochrane (1998-2008) and the reference lists of relevant articles. The quality and relevance of 752 articles were assessed and finally 11 original studies were included. RESULTS: Our results demonstrate that the implementation of gender sensitivity includes tailoring opportunities and barriers related to the professional, organizational and the policy level. As gender disparities are embedded in healthcare, a multiple track approach to implement gender sensitivity is needed to change gendered healthcare systems. CONCLUSION: Conventional approaches, taking into account one barrier and/or opportunity, fail to prevent gender inequality in health care. For gender sensitive health care we need to change systems and structures, but also to enhance understanding, raise awareness and develop skills among health professionals. PRACTICE IMPLICATIONS: To bring gender sensitivity into healthcare practice, interventions should address a range of factors. PMID- 20719462 TI - The effect of spousal communication on contraceptive use in Central Terai, Nepal. AB - OBJECTIVE: Family planning has several social and health benefits; it can reduce maternal mortality and the number of unplanned pregnancies, as well as increase educational and economic opportunities. Utilizing quantitative data from an endline household survey (July 2009) and data from focus group discussions, the Centre for Development and Population Activities (CEDPA) seeks to determine whether spousal communication increases contraceptive use among married women of child-bearing age in Nepal's Central Terai region. METHODS: Quantitative household survey and qualitative focus group discussions. RESULTS: Women who discuss family planning with their husbands (OR=7.254), perceive husband approval on family planning (OR=5.558) and have born a son (OR=2.239) are more likely to use a modern contraceptive method. Qualitative data show that several other considerations can be motivating factors for contraceptive uptake. CONCLUSION: While results do not explain the direction of causality, it is clear that spousal discussion and partner approval are significant in a woman's decision to use modern contraceptives in the Central Terai region of Nepal. PRACTICE IMPLICATIONS: More research needs to be conducted on the effect of spousal communication and contraceptive use, in particular, the role of frequency, quality, and content of spousal communication, as well as individual motivations. PMID- 20719463 TI - "There is nothing to worry about": gynecologists' counseling on mammography. AB - OBJECTIVE: In Germany, approximately 10 million women between the ages of 50 and 69 are eligible for biennial mammography screening. Mammography is at the center of much controversy, however, which means gynecologists must provide women considering mammography with sufficient and transparent information. The present study analyzed the information gynecologists share with a person seeking advice about the benefit and harms of mammography screening. METHOD: To receive realistic data, we called 20 gynecologists practicing in different large cities across Germany and took telephone counseling sessions on the benefit and harms of mammography. RESULTS: The majority of gynecologists described mammography as safe and scientifically well grounded. Harms were rarely mentioned or described as negligible. A minority of gynecologists provided numerical information; when they did, they often quantified the benefit using relative risk reduction and harms using absolute risk increase. CONCLUSION: A sample of German gynecologists was not able to correctly and transparently communicate the benefit and harms of mammography screening to a patient. PRACTICE IMPLICATION: Gynecologists should be taught how to understand and transparently explain medical risk information in simple terms. PMID- 20719464 TI - A nationwide survey of standardized patients: who they are, what they do, and how they experience their work. AB - OBJECTIVE: Standardized or simulated patients are widely used in medical training, however, little is known about these individuals and their work experience. The current study was designed to describe the SP workforce and gain insight into the routine tasks, challenges and rewards associated with their work. METHODS: Using the full 2005 membership list (n=450) of Association of Standardized Patient Educators (ASPE), one SP educator for each medical school across all states was identified, representing a total of 87 different medical schools. Fifty-seven (65%) of the SP educators approached agreed to participate in the study and distribute surveys to 10 SPs in each program. RESULTS: 255 (45%) of the distributed surveys were returned representing the experience of SPs in 57 medical schools across all 6 ASPE geographic regions. Specifics in regard to work scheduling and compensation are reported with some regional differences noted in pay. On the whole, SPs were highly satisfied with their work, but roughly half reported some difficulty with elements of case mastery and providing feedback to learners. CONCLUSION: SP satisfaction is high but challenges in case mastery and feedback tasks are evident. PRACTICE IMPLICATIONS: Meeting training needs can enhance the utility and effectiveness of this workforce. PMID- 20719465 TI - Heparin versus bivalirudin for carotid artery stenting using proximal endovascular clamping for neuroprotection: results from a prospective randomized study. AB - BACKGROUND: General recommendations indicate that, during a carotid artery stenting (CAS), sufficient unfractionated heparin (UFH) has to be given to maintain the activated clotting time between 250 to 300 seconds. Bivalirudin use is able to reduce postprocedural bleedings in percutaneous interventions when compared with UFH. The study purpose was to evaluate, in a randomized study, the safety and efficacy of bivalirudin versus heparin during CAS, using proximal endovascular occlusion (PEO) as a distal protection device. METHODS: From January 2006 to December 2009, 220 patients undergoing CAS using PEO have been randomly assigned to one of the study arms (control arm: 100 UI/kg UFH or bivalirudin arm: 0.75 mg/kg intravenous bolus and intraprocedural infusion at 1.75 mg/kg/h). RESULTS: Procedural success was achieved in all the patients. No episodes of intraprocedural thrombosis occurred. One major stroke occurred in the bivalirudin arm, and two minor strokes occurred, one in each group. A significant difference in the incidence of postprocedural bleedings was observed between the study groups; bivalirudin use was associated with reduced number of bleedings according to Thrombolysis In Myocardial Infarction criteria. CONCLUSIONS: The use of bivalirudin should be considered a safe and effective anticoagulation regimen during CAS, using PEO as a distal protection device. Bivalirudin use is associated with a reduced incidence of bleedings. PMID- 20719466 TI - Evidence for markers of hypoxia and apoptosis in explanted human carotid atherosclerotic plaques. AB - OBJECTIVE: Apoptosis and inflammation are important features of atherosclerotic plaques. We investigated whether a common signal molecule can trigger these two apparently separate pathways. Hypoxia inducible factor (HIF-1alpha) is known to participate in atherosclerosis and to stimulate apoptosis signal-regulating kinase 1 (ASK-1), one of the mitogen-activated protein kinases, which is activated by various extracellular stimuli and involved in a variety of cellular function. METHODS: We tested carotid artery specimens from 50 subjects who underwent angioplasty and five age-matched controls for either Western blot or histologic analysis. The hypoxic status was investigated by means of HIF-1alpha expression in carotid specimens. RESULTS: HIF-1alpha was significantly upregulated in carotid specimens with respect to controls (P < .05), ASK-1 was detected in plaques of any composition from lipidic to calcific, and this expression increased with the stage of the plaque and with the expression of inflammatory (p-ERK, RANK-L, OPG) and apoptotic molecules (caspase 9, p-p-38, and p-JNK). CONCLUSION: Our data suggest that hypoxia is the key regulating factor that triggers inflammation as well as apoptosis in the human atherosclerotic plaque. PMID- 20719467 TI - Reducing venous stasis ulcers by fifty percent in 10 years: the next steps. PMID- 20719469 TI - Assessment of the perforators of anterolateral thigh flaps using 64-section multidetector computed tomographic angiography in head and neck cancer reconstruction. AB - BACKGROUND: The anterolateral thigh (ALT) flap is a frequent choice for free flap transfer in head and neck cancer reconstruction because of its versatility. Preoperative mapping of the perforator pedicles of an ALT flap is still a challenge because of variations in vasculature. Although computed tomographic angiography (CTA) is used increasingly to evaluate the peripheral vasculature, the use of this method for evaluating the perforators of an ALT flap has not been described in detail. METHODS: From September 2008 to March 2009, 32 patients underwent preoperative CTA before free ALT flap transfer for head and neck cancer reconstruction. The perforators were marked on a 64-section multidetector CT image for each patient. The preoperatively mapped perforators were compared with the actual intraoperative findings. Flap success rates and associated morbidity and complications were recorded. RESULTS: Preoperative CTA identified major variations in perforators. Eighty-four were found by preoperative CTA; 64 of these were mapped to be explored during the operation, and 13 additional perforators were identified during surgery. The accuracy rate of identifying the branching origin of the ALT perforators was 98% (63/64). All of the ALT flaps survived except for one with necrosis (survival rate 97%). There was no donor site morbidity. CONCLUSIONS: Preoperative mapping of perforators by CTA proved valuable in free ALT flap transfer and shortened the operation time significantly. This modality provides useful information for head and neck cancer reconstruction in difficult cases, especially in patients with large or through and-through defects that might need multiple perforators in flap design. PMID- 20719470 TI - Objective interpretation of dobutamine stress echocardiography by diastolic dyssynchrony imaging: a practical approach. AB - BACKGROUND: Postsystolic shortening is a sensitive maker of myocardial ischemia. The aim of this study was to investigate whether diastolic dyssynchrony imaging is useful for the objective interpretation of dobutamine stress echocardiography. METHODS: Postsystolic shortening was detected by using tissue Doppler imaging displacement timing analysis: the delays of the displacement peaks from end systole were displayed from green to red, depending on the preset time window on diastolic dyssynchrony imaging. Dobutamine stress echocardiography was performed in 59 patients with suspected coronary artery disease who presented with normal left ventricular wall motion at rest (age range, 44-83 years; 20 women). The optimal time windows for diastolic dyssynchrony imaging at rest and at peak dobutamine were determined by receiver operating characteristic analysis by measuring the delays of the displacement peaks in the left ventricular myocardial segments. Diastolic dyssynchrony imaging was performed using time windows of 100 msec at rest and 80 msec at peak dobutamine. The diagnostic power of diastolic dyssynchrony imaging was assessed with quantitative coronary angiography as the gold standard (>50% diameter stenosis) both at rest and at peak dobutamine. RESULTS: Coronary artery disease was present in 37 patients (63%). Diastolic dyssynchrony imaging at peak dobutamine predicted the presence of coronary artery disease with sensitivity of 89%, specificity of 77%, predictive accuracy of 85%, positive predictive value of 79%, and negative predictive value of 81%. Diastolic dyssynchrony imaging at rest yielded sensitivity of 62%, specificity of 73%, predictive accuracy of 66%, positive predictive value of 79%, and negative predictive value of 53%. Importantly, diastolic dyssynchrony imaging demonstrated excellent intraindividual (97%) and interindividual (90%) agreement. CONCLUSION: Diastolic dyssynchrony imaging is useful in the objective interpretation of dobutamine stress echocardiography. PMID- 20719471 TI - Standing on the promises: first wave validation reports of the Patient-Reported Outcome Measurement Information System. PMID- 20719472 TI - Weighted index explained more variance in physical function than an additively scored functional comorbidity scale. AB - OBJECTIVE: 1) examine association between the Functional Comorbidity Index (FCI) and discharge functional status (FS); 2) examine impact of FCI on FS when added to comprehensive models; and 3) compare additive FCI with weighted FCI and list of condition variables (list). STUDY DESIGN AND SETTING: Patients were drawn from Focus On Therapeutic Outcomes, Inc. (FOTO) database (1/1/06-12/31/07). FS collected using computer adaptive tests. Linear regression examined association between FCI and FS. Three methods of including functional comorbidities (FC) were compared. RESULTS: Relationship between FCI and FS varied by group (range, 0.02 0.9). Models with weighted index or list had similar R2. Weighted FCI or list increased R2 of crude models by <0.01 for cervical, shoulder, and lumbar; by 0.01 for wrist/hand, knee, and foot/ankle; by 0.02 for hip; by 0.03 for elbow; and by 0.08 for neurological. Addition of FCI to comprehensive models added <0.01 to R2 (all groups). Weighted FCI increased R2 by <0.01 for cervical, lumbar, and shoulder; by 0.01 for wrist/hand, hip, knee, and foot/ankle; by 0.02 for elbow; and by 0.04 for neurological; whereas list increased R2 by <0.01 for cervical, shoulder, and lumbar; by 0.01 for knee and foot/ankle; by 0.02 for elbow, wrist/hand, and hip; and by 0.05 for neurological. CONCLUSION: List of comorbidities or weighted FCI is preferable to using additive FCI. PMID- 20719473 TI - Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: results from Kochi RYOMA study. AB - OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with a broad spectrum of clinical features. Although gender may be one of the important modifying factors in HCM, there has been little information on gender differences. METHODS: We investigated gender-specific differences in the clinical features of HCM in a community-based Japanese population. We established cardiomyopathy registration in Kochi Prefecture named Kochi RYOMA study consisting of 9 hospitals as an unselected regional Japanese population. RESULTS: 261 patients with diagnosis of HCM were registered. At registration, 88 patients (34%) were women. Female patients were more frequently diagnosed as having HCM at >=65 years (41% versus 27%) and had a higher ratio of familial HCM (35% versus 19%). More female patients had diagnosis of HCM due to cardiac symptoms (64% versus 40%) and were symptomatic both at diagnosis and at registration. Although the prevalence of atrial fibrillation was not different between males and females, embolic events occurred less frequently in female patients at registration than in male patients (2% versus 10%). In female patients, there were more obstructive HCM patients and fewer patients with apical HCM. Left ventricular and left atrial diameters were smaller and fractional shortening was higher in females than in males. CONCLUSIONS: The manifestations of HCM in unselected Japanese patients differed in men and women, which suggest that hormonal, social, and genetic factors may influence the clinical presentation of HCM. PMID- 20719474 TI - Increased schedule-induced polydipsia in the rat following subchronic treatment with MK-801. AB - Primary polydipsia, defined as excessive fluid intake not explained by medical causes, has been reported to occur in over 20% of chronically ill psychiatric inpatients and is especially common in schizophrenic populations. We tested the hypothesis that in an animal model of schizophrenia-like symptoms (subchronic injections of MK-801, 0.5 mg/kg twice daily for 7 days) an increase in the acquisition of schedule-induced polydipsia (SIP) will occur. Young adult, male rats acquired SIP when food-restricted and placed on a non-contingent fixed-time 1-min food schedule. In comparison with saline-treated control animals, subchronic MK-801 treatment significantly increased SIP. These findings suggest an animal model of polydipsia associated with schizophrenia in humans. PMID- 20719475 TI - Relationships between perceptions of the family environment and of negative life events in recent-onset schizophrenia patients. PMID- 20719476 TI - Searching for the role of membrane sphingolipids in selectivity of antitumor ether lipid-edelfosine. AB - Edelfosine is a synthetic antitumor lipid of high selectivity. Its activity on membrane level inspired the investigations on edelfosine-lipid interactions to verify, which of the membrane components may be responsible for the selectivity of this drug. Because of overexpression of gangliosides in tumor progression and the ability of edelfosine to insert into membrane rafts, we have chosen two sphingolipids, i.e. sphingomyelin and ganglioside to investigate in mixtures with edelfosine. It was found that edelfosine shows strong affinity to ganglioside in contrast to sphingomyelin. Differences in the interactions of edelfosine with sphingolipids were analyzed from the point of view of the structure and shape of the interacting molecules. The comparison of the results with those previously reported for edelfosine mixed with other membrane components, allowed us to suggest that gangliosides may be considered as target molecules attracting edelfosine to tumor cells. PMID- 20719477 TI - Preparation and physicochemical characterization of naproxen-PLGA nanoparticles. AB - Naproxen is a non-steroidal anti-inflammatory drug which can be used for the treatment of inflammatory disorders like uveitis and arthirit rheumatoid. The aim of the present study was to investigate the physicochemical characteristics of naproxen-PLGA nanoparticles. The nanoparticles of naproxen with PLGA were formulated using the solvent evaporation/extraction technique (the single emulsion technique). Several process parameters i.e., drug/polymer ratio, aqueous phase volume and speed of homogenization were considered with the aim of achieve optimal preparation conditions. The physicochemical characteristics of nanoparticles were studied applying particle size analysis, differential scanning calorimetry, X-ray crystallography, Fourier transform infrared spectroscopy and scanning electron microscopy. The release rate of naproxen from various drug/polymer nanoparticles was investigated as well. All the prepared formulations using PLGA resulted in nano-range size particles (352-571 nm) with spherical smooth morphology. The nanoparticles of naproxen-PLGA displayed lower crystallinity with no chemical interactions between the drug and polymer molecules. The nanoparticles exhibited the slower release of drug in comparison with the intact drug and the physical mixtures. According of these findings, formulation of the naproxen-PLGA nanoparticles was able to improve the physicochemical characteristics of the drug and possibly will increase the anti inflammatory effects of drug following its ocular or intra-joint administration. PMID- 20719478 TI - Graphene oxide sheet-prussian blue nanocomposites: green synthesis and their extraordinary electrochemical properties. AB - A facile and green method for the synthesis of graphene oxide sheets (GOs) prussian blue nanocomposites has been presented via a spontaneous redox reaction in a aqueous solution containing FeCl3, K3[Fe(CN)6] and graphene oxide sheets. Electrochemical property investigation demonstrates PB nanocubes formed on the surface of GOs retain their excellent electrochemical activity and the GOs can enhance the electron transfer between PB and GC electrode. Moreover, the obtained nanocomposites even have shown a higher sensitivity toward the electrocatalytical reduction of H2O2 than that of multiwalled carbon nanotube/PB nanocomposites. Given their extraordinary electrochemical properties and the green preparation, as-prepared GO-PB nanocomposites have great potential in the field of electrochemical sensor and biofuel cell. PMID- 20719479 TI - Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC. AB - Packaging small drug molecules, such as non-steroidal anti-inflammatory drugs (NSAIDs) into nanoparticulate systems has been reported as a promising approach to improve the drug's bioavailability, biocompatibility and safety profiles. In the last 20 years, lipid nanoparticles (lipid dispersions) entered the nanoparticulate library as novel carrier systems due to their great potential as an alternative to other systems such as polymeric nanoparticles and liposomes for several administration routes. For ocular instillation nanoparticulate carriers are required to have a low mean particle size, with the lowest polydispersity as possible. The purpose of this work was to study the combined influence of 2 level, 4-factor variables on the formulation of flurbiprofen (FB), a lipophilic NSAID, in lipid carriers currently named as nanostructured lipid carriers (NLC). NLC were produced with stearic acid (SA) and castor oil (CO) stabilized by Tween(r) 80 (non-ionic surfactant) in aqueous dispersion. A 2(4) full factorial design based on 4 independent variables was used to plan the experiments, namely, the percentage of SA with regard to the total lipid, the FB concentration, the stabilizer concentration, and the storage conditions (i.e., storage temperature). The effects of these parameters on the mean particle size, polydispersity index (PI) and zeta potential (ZP) were investigated as dependent variables. The optimization process was achieved and the best formulation corresponded to the NLC formulation composed of 0.05 (wt%) FB, 1.6 (wt%) Tween(r) 80 and a 50:50 ratio of SA to CO, with an average diameter of 288 nm, PI 0.245 of and ZP of -29 mV. This factorial design study has proven to be a useful tool in optimizing FB loaded NLC formulations. Stability of the optimized NLC was predicted using a TurbiScanLab(r) and the ocular tolerance was assessed in vitro and in vivo by the Eytex(r) and Draize test, respectively. The developed systems were shown physico chemically stable with high tolerance for eye instillation. PMID- 20719480 TI - Dynamic rheological properties of plant cell-wall particle dispersions. AB - The rheological behaviour of plant cell-wall particle dispersions was investigated using dynamic oscillatory measurements. Two starting plant materials, broccoli stem and carrot were used and two types of particles were obtained by mechanically shearing blanched (80 degrees C, 10 min) or cooked (100 degrees C, 15 min) plant tissues. Blanching resulted in cell-wall particles made up of a collection of clusters of cells with an average particles size of ~200 MUm, while cooking generated nearly all single-cell particles with an average particle size of ~80 MUm. The rheological measurements showed that in the range of weight concentrations considered (~0.5% to ~8%) the dispersions behaved as elastic materials with the elastic modulus G' higher than G" within the frequency range (0.01-10 Hz). This study shows that the behaviour of the complex modulus G* as a function of the effective volume fraction phi can be modelled using different theoretical equations. To do so, it is assumed that below a critical volume fraction phic a network of plant cell-wall particles was formed and G* as a function of phi obeys a power-law relationship. However above phic, where the particles were highly packed, G* could be modelled using theoretical equations developed for concentrated emulsions and elastic particle dispersions. PMID- 20719481 TI - [Drugs news]. PMID- 20719482 TI - [French guidelines for sweat test practice and interpretation for cystic fibrosis neonatal screening]. AB - These guidelines aim to standardize the standard operating procedures for the sweat test in newborn cystic fibrosis (CF) screening. They have been implemented by the national Neonatal Screening working group of the French Federation for Cystic Fibrosis. It is recommended that the sweat test be performed when the infant weighs more than 3 kg and is at least 3 weeks of age. Sweat gland secretion is stimulated by transdermal administration of pilocarpine by iontophoresis. Sweat is preferentially collected in a Macroduct coil. Diagnosis of CF is based on the sweat chloride level. A sweat chloride level below 30 mmol/l very probably rules out CF; 60 mmol/l or higher supports the diagnosis of CF. Values between 30 and 60 mmol/l are considered abnormal. PMID- 20719483 TI - [Pylephlebitis in the child: a challenging diagnosis]. AB - Pylephlebitis or septic thrombophlebitis of the portomesenteric veins is a complication of intra-abdominal infections. The disease is rare in children and the diagnosis is often delayed. The morbidity of pylephlebitis is relatively low, although there is a risk of residual thrombosis. We report on 2 cases of pylephlebitis in a 12-year-old girl and a 13-year-old boy, following undiagnosed appendicitis. In the 1st case, the young girl had been misdiagnosed with Salmonella infection and was given antibiotics; in the 2nd case, the boy had retrocecal appendicitis that was clinically subacute. An accurate diagnosis was finally made in both cases by CT scan. Both children evolved satisfactorily following appendectomy, long-term antibiotics, and anticoagulation. Clinically, the severe sepsis associated with pylephlebitis is at the forefront. Physical examination is often normal and therefore of little help; the knowledge of a preceding abdominal infection leads to further radiological investigations. Biologically, there are pronounced signs of infection. CT is the preferred exam for diagnosing pylephlebitis, as it can also show the underlying cause of the intra-abdominal sepsis or possible complications. Doppler sonography is recommended more for follow-up of the portal vein thrombosis. Treatment of pylephlebitis associated with appendicitis always includes long-term antibiotics. An appendectomy is always performed either at the time of diagnosis or later. The need for anticoagulation therapy in children is controversial. However, most pediatricians recommend its use, beginning as soon as possible, to be continued until normalization of portal vein flow. PMID- 20719484 TI - [Consequences for the newborn of alcohol consumption during pregnancy]. AB - BACKGROUND: This paper aims at showing the immediate and long-term consequences affecting newborns whose mothers did not reduce or stop their consumption of alcohol when they were pregnant; these women were chosen among women who also used psychoactive substances. METHODS: A retrospective cohort was constituted of babies who were found to have been exposed in utero to one or more legal or illegal psychoactive substance(s) and who were born or hospitalized between 1999 and 2008 in a hospital near Paris. Among the cohort of 170 babies, 56 had mothers who had not modified their alcohol consumption when they were pregnant, 30 had mothers who had reduced their alcohol consumption, and 84 had mothers who declared having been abstinent. RESULTS: The babies born to mothers who did not modify their alcohol consumption when pregnant were more likely to be premature (30%) and hospitalized in the neonatology hospital unit (60.7%). They needed specific care for durations significantly longer than the babies exposed in utero to other psychoactive substances (P<0.005). They were more often diagnosed with fetal alcohol spectrum disorders (18%) and placed in a foster family (18%). CONCLUSION: Given the negative consequences on the babies born to mothers who do not modify their alcohol consumption when pregnant, these mothers should be identified and provided with better care. The successful strategies for early therapeutic interventions used in other countries should be studied as examples. This would make it possible to reduce the enormous financial, material and human costs that are a direct consequence of alcohol consumption during pregnancy. PMID- 20719485 TI - [Childhood epilepsy with centrotemporal spikes in Marrakech]. PMID- 20719486 TI - [Evaluation of language at 6 years in children born prematurely without cerebral palsy: prospective study of 55 children]. AB - OBJECTIVES: Very premature birth carries a high risk of neurocognitive disabilities and learning disorders. Acquiring sufficient speech skills is crucial to good school performance. METHODS: A prospective study was conducted in 2006 to evaluate speech development in 55 children born very prematurely in 2000 at the Rouen Teaching Hospital (Rouen, France), free of cerebral palsy, compared to 6-year-old born at full term. A computerized speech assessment tool was used (Bilan Informatise du Langage Oral, BILO II). RESULTS: In the premature-birth group, 49 % of 6-year-old had at least 1 score below the 25th percentile on 1 of the 8 BILO II tests. Significant speech impairments were noted for 2 components of speech, namely, comprehension and phonology. Oral comprehension scores no higher than the 10th percentile were obtained by 23 % of prematurely born children (P<0.02 vs controls). On word repetition tasks used to test phonology, 21 % of prematurely born children obtained scores no higher than the 10th percentile (P<0.01 vs controls). An evaluation of sensorimotor language prerequisites (constraints) in 30 of the 55 prematurely born children showed significant differences with the controls for word memory, visual attention, and buccofacial praxis. CONCLUSION: The speech development impairments found in 6 year-old born very prematurely suggest a distinctive pattern of neurodevelopmental dysfunction that is consistent with the motor theory of speech perception. PMID- 20719487 TI - Pelvic exenterative surgery for palliation of malignant disease in the robotic era. AB - A Medline-based literature review was carried out of the surgical management of advanced pelvic cancers and the effect of minimally invasive technology in this setting to review the current status of exenterative surgery for advanced pelvic malignancies. Palliation and/or resection of advanced pelvic cancer affecting one or more pelvic compartments offers benefit and improved quality of life in carefully selected patients. This complex surgery is best carried out by experienced multidisciplinary teams after meticulous preoperative staging and assessment. Survival rates at 5 years are between 25 and 40% in the absence of metastatic disease and between 18 and 24 months in the palliative setting. Open surgery remains the gold standard approach, but emerging reports of laparoscopic and robotically assisted laparoscopic techniques may be feasible in highly selected individuals. PMID- 20719489 TI - Effect of sex and dietary fat intake on the fatty acid composition of phospholipids and triacylglycerol in rat heart. AB - Variations in the fatty acid composition of lipids in the heart alter its function and susceptibility to ischaemic injury. We investigated the effect of sex and dietary fat intake on the fatty acid composition of phospholipids and triacylglycerol in rat heart. Rats were fed either 40 or 100g/kg fat (9:1 lard:soybean oil) from weaning until day 105. There were significant interactive effects of sex and fat intake on the proportions of fatty acids in heart phospholipids, dependent on phospholipid classes. 20:4n-6, but not 22:6n-3, was higher in phospholipids in females than males fed a low, but not a high, fat diet. There was no effect of sex on the composition of triacylglycerol. These findings suggest that sex is an important factor in determining the incorporation of dietary fatty acids into cardiac lipids. This may have implications for sex differences in susceptibility to heart disease. PMID- 20719490 TI - Lactate dehydrogenase as prognostic factor in limited and extensive disease stage small cell lung cancer - a retrospective single institution analysis. AB - PURPOSE: The aim of this retrospective study is to present data on clinical significance of lactate dehydrogenase (LDH) serum levels in an unselected contemporary patient population with small cell lung cancer (SCLC) in limited disease (LD) and extensive disease stage (ED). PATIENTS AND METHODS: From June 2004 to June 2008, our electronic database including all in-patient and out patient contacts was searched for patients with newly diagnosed LD and ED SCLC. 397 cases were identified. We collected data on patient characteristics including clinical performance status and LDH serum levels, metastatic sites, efficacy of first line chemotherapy and survival. RESULTS: In both limited and extensive disease SCLC, elevated LDH serum levels resulted in significantly shorter median survival. The effect was most pronounced if levels were 300 U/l or higher. In patients with limited disease and normal LDH levels, median survival was 18.0 months. If LDH was higher than 300 U/l, overall survival was reduced to 12 months. In cases with extensive disease, overall survival was significantly lower in patients with elevated LDH serum levels with an additional reduction in overall survival in patients with LDH levels above 300 U/l. (7.0 vs. 12.0 months, p = <0.001). Multivariate Cox regression analyses revealed LDH levels to be an independent predictor of mortality after adjustment for age and Performance Status in LD and ED SCLC (HR 1.003, p = 0.017; HR 1.001, p = 0.002 respectively). However, categorizing LDH levels revealed no significant difference in LD SCLC. CONCLUSION: In our contemporary comprehensive patient population, LDH is proved to be a strong, independent predictive factor of median survival in patients with LD and ED SCLC. PMID- 20719491 TI - Peroxygenase based sensor for aromatic compounds. AB - We report on the redox behaviour of the peroxygenase from Agrocybe aegerita (AaeAPO) which has been electrostatically immobilized in a matrix of chitosan embedded gold nanoparticles on the surface of a glassy carbon electrode. AaeAPO contains a covalently bound heme-thiolate as the redox active group that exchanges directly electrons with the electrode via the gold nanoparticles. The formal potential E degrees ' of AaeAPO in the gold nanoparticles-chitosan film was estimated to be -(286+/-9) mV at pH 7.0. The heterogeneous electron transfer rate constant (k(s)) increases from 3.7 in the scan rate range from 0.2 to 3.0 V s(-1) and level off at 63.7 s(-1). Furthermore, the peroxide-dependent hydroxylation of aromatic compounds was applied to develop a sensor for naphthalene and nitrophenol. The amperometric measurements of naphthalene are based on the indication of H(2)O(2) consumption. For the chitosan-embedded gold nanoparticle system, the linear range extends from 4 to 40 MUM naphthalene with a detection limit of 4.0 MUM (S/N=3) and repeatability of 5.7% for 40 MUM naphthalene. PMID- 20719492 TI - Sensitive voltammetric sensor for the determination of oxidative DNA damage in calf thymus DNA. AB - A simple and reliable method based on voltammetry is proposed for the determination of oxidative DNA damage by the simultaneous determination of guanine and 8-hydroxygunine using single-walled carbon nanotubes modified edge plane pyrolytic graphite electrode (SWNT/EPPGE). In acid-hydrolyzed calf thymus DNA, two well-defined peaks at ~312 and ~502 mV corresponding to the oxidation of 8-hydroxyguanine and guanine, respectively in phosphate buffer solution (PBS) of pH 7.2 were observed in square wave voltammetry. Remarkable enhancement in the oxidation peak current of both the compounds was observed along with the negative shift of peak potentials using SWNT/EPPGE as compared to bare EPPGE. The detection limits of guanine and 8-hydroxyguanine were calculated to be 0.05*10( 9) and 0.01*10(-9) mol L(-1), respectively. The limits of quantification were found as 0.17*10(-9) and 0.34*10(-10) mol L(-1) for guanine and 8-hydroxyguanine, respectively. PMID- 20719493 TI - Biosensors coated with sulfated polysaccharides for the detection of hepatocyte growth factor/scatter factor in cell culture medium. AB - Process control methods for cell culture bioreactors include on-line monitoring of protein concentrations. Bioreactor samples typically contain high amounts of different proteins. The direct detection of a single protein in this complex medium is a challenging task within the development of biosensors with label-free detection. We introduce the development of a mass-sensitive biosensor based on surface acoustic waves (SAW) for the detection of hepatocyte growth factor/scatter factor (HGF/SF) in the serum containing medium of a miniaturized bioreactor for culturing hepatocytes. The specificity of the biosensor was obtained following two approaches. In the first approach, antibodies against HGF (anti-HGF) were immobilized covalently via an intermediate layer of dicarboxy polyethylene glycol on the biosensor surface. In the second approach, dextran sulfate and fucoidan were used as sensor coatings exploiting the fact that HGF binds specifically to those sulfated polysaccharides. Performing HGF assays, similar results were obtained using biosensors coated with dextran sulfate and biosensors coated with anti-HGF. Even higher sensor signals were obtained using biosensors coated with fucoidan, particularly at 37 degrees C. Therefore, biosensor coatings based on biospecific sulfated polysaccharides offer a simple and cost-saving alternative compared to the commonly used coating with antibodies. PMID- 20719494 TI - Bacteriorhodopsin-based photo-electrochemical cell. AB - A simple solution-based electrochemical cell has been constructed and successfully employed in the detection of the photoelectric response upon photoexcitation of bacteriorhodopsin (bR) without external bias. Commercially available indium tin oxide (ITO) glasses served as the optical windows and electrodes. Small amounts of bR suspensions (~100 MUL) were utilized as the photovoltaic medium to generate the proton gradient between two half-cells separated by a molecular porous membrane. Continuous broadband visible light (lambda>380 nm) and a short-pulse 532-nm laser were employed for the photoexcitation of bR. Upon the modulated cw broadband irradiation, an instantaneous rise and decay of the current was observed. Our observations of the pH-dependent photocurrent are consistent with previous reports in a bR thin film configuration, which also showed a polarity inversion at pH 5-6. This is due to the change of the priority of the proton release and proton uptake in the photocycle of bR. Studies on the ionic strength effect were also carried out at different KCl concentrations, which resulted in the acceleration of the rise and decay of the photoelectric response. This was accompanied by a decrease in the stationary photocurrent at higher KCl concentrations in the broadband excitation experiments. The solution-based electrochemical cell uses aqueous medium, which is required for the completion of the bR proton pumping function. Due to the generation of the stationary current, it is advantageous to convert solar energy into electricity without the need of film-based photovoltaic devices with external bias. PMID- 20719495 TI - Hybridisation thermodynamic parameters allow accurate detection of point mutations with DNA microarrays. AB - We consider mixtures of two DNA sequences t and t' differing by a single nucleotide, which are analyzed by an Agilent custom DNA microarray. In particular we focus on the case in which t, the "wild type", is predominantly abundant and t' the "mutant" is at very low concentrations compared to t. We show that by using appropriately designed arrays it is possible to accurately quantify the presence of t' even at low relative concentrations (~1%). The detection method is based on thermodynamic models of DNA hybridisation and on the analysis of a large number of hybridisation intensities from probes containing one or two mismatches with respect to t and t'. PMID- 20719496 TI - Versatile label free biochip for the detection of circulating tumor cells from peripheral blood in cancer patients. AB - The isolation of circulating tumor cells (CTCs) using microfluidics is attractive as the flow conditions can be accurately manipulated to achieve an efficient separation. CTCs are rare events within the peripheral blood of metastatic cancer patients which makes them hard to detect. The presence of CTCs is likely to indicate the severity of the disease and increasing evidences show its use for prognostic and treatment monitoring purposes. We demonstrated an effective separation using a microfluidic device to utilize the unique differences in size and deformability of cancer cells to blood cells. Using physical structures placed in the path of blood specimens in a microchannel, CTCs which are generally larger and stiffer are retained while most blood constituents are removed. The placements of the structures are optimized by computational analysis to enhance the isolation efficiency. With blood specimens from metastatic lung cancer patients, we confirmed the successful detection of CTCs. The operations for processing blood are straightforward and permit multiplexing of the microdevices to concurrently work with different samples. The microfluidic device is optically transparent which makes it simple to be integrated to existing laboratory microscopes and immunofluorescence staining can be done in situ to distinguish cancer cells from hematopoietic cells. This also minimizes the use of expensive staining reagents, given the small size of the microdevice. Identification of CTCs will aid in the detection of malignancy and disease stage as well as understanding the phenotypic and genotypic expressions of cancer cells. PMID- 20719497 TI - Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer. AB - PURPOSE: The aim of this prospective study was to assess the incidence of extra axillary lymph node involvement on baseline FDG PET/CT in patients with stage II III breast cancer scheduled for neo-adjuvant chemotherapy. METHODS: Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique. RESULTS: Sixty patients were included. In 17 patients (28%) extra axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group). CONCLUSIONS: FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management. PMID- 20719498 TI - Nuclear S100A4 is a novel prognostic marker in colorectal cancer. AB - Current staging classifications in colorectal cancer are not able to accurately predict patient outcome, and the need for novel prognostic markers is evident. S100A4 is a Ca(2+)-binding protein which promotes metastasis in several tumour types, and the aim of the present study was to investigate the prognostic impact of S100A4 expression in colorectal cancer. Two hundred and forty two patients with curatively resected adenocarcinoma of the colon or rectum were prospectively included in the study at the time of surgery. S100A4 expression was analysed by immunohistochemistry, and associations with clinicopathological variables and patient outcome were investigated. Nuclear expression of S100A4 was observed in 29% and cytoplasmic expression was observed in 64% of the tumours. In univariate analysis, nuclear S100A4 was a negative predictor of metastasis-free (P=0.006) and overall survival (P=0.01), whereas cytoplasmic S100A4 was not associated with patient outcome. In multivariate analysis, nuclear localisation was inversely associated with metastasis-free (P=0.03) and overall survival (P=0.02). Interestingly, the prognostic impact was largely confined to TNM stage II, and stage II patients with tumours expressing nuclear S100A4 had a similar prognosis as stage III patients. In conclusion, nuclear expression of S100A4 is a novel prognostic marker in colorectal cancer, and the prognostic value in TNM stage II suggests that nuclear S100A4 could be used in the stratification of stage II patients for adjuvant treatment. PMID- 20719499 TI - Decision making in surgical oncology. AB - Decisions in surgical oncology are increasingly being made by multi-disciplinary teams (MDTs). Although MDTs have been widely accepted as the preferred model for cancer service delivery, the process of decision making has not been well described and there is little evidence pointing to the ideal structure of an MDT. Performance in surgery has been shown to depend on non-technical skills, such as decision making, as well as patient factors and the technical skills of the healthcare team. Application of this systems approach to MDT working allows the identification of factors that affect the quality of decision making for cancer patients. In this article we review the literature on decision making in surgical oncology and by drawing from the systems approach to surgical performance we provide a framework for understanding the process of decision making in MDTs. Technical factors that affect decision making include the information about patients, robust ICT and video-conferencing equipment, a minimum dataset with expert review of radiological and pathological information, implementation and recording of the MDTs decision. Non-technical factors with an impact on decision making include attendance of team members at meetings, leadership, teamwork, open discussion, consensus on decisions and communication with patients and primary care. Optimising these factors will strengthen the decision making process and raise the quality of care for cancer patients. PMID- 20719500 TI - Application of a novel method for optimization of bioemulsan production in a miniaturized bioreactor. AB - A novel and economical method was used to optimize bacterial growth and bioemulsan production. Acinetobacter calcoaceticus PTCC 1641 was applied in an innovated synthetic medium comprised whey and mineral salt medium (MSM) in ratio of 1:1 in a shaken flask bioreactor. The optimum inoculum size, shaking frequency rate and filling volume (V(L)) using ventilation flasks were investigated that resulted in 5 vol.%, 300 rpm and 15 ml), respectively. The surface tension decreased around 48% during bioemulsan production. Due to determine bioemulsan properties, the reliability of blood agar method was confirmed as well. PMID- 20719501 TI - Cadmium(II) sequestration characteristics by two isolates of Synechocystis sp. in terms of exopolysaccharide (EPS) production and monomer composition. AB - We investigated cadmium(II) resistance and its association with exopolysaccharide (EPS) production in cyanobacteria. Increased EPS production was associated with Cd(II) resistance. The most resistant isolate, Synechocystis sp. BASO670, secreted the greatest amount of EPS (548 mg/L). EPS production by Synechocystis sp. BASO670 and Synechocystis sp. BASO672 was increased following exposure to 15 and 35 ppm Cd(II). Monomer composition of EPS belonging to each isolate was changed after Cd(II) treatment. Uronic acid contents of Cd(II) treated cells were higher than control cells of each isolate. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis confirmed that a considerable amount of metals had precipitated on the cell surface. Fourier transform infrared (FT-IR) spectrum analysis of EPSs belonging to both isolates indicated the presence of C-H and C-O group, which may serve as binding sites for divalent cations. PMID- 20719502 TI - Effect of ultrasonic pre-treatment on low temperature acid hydrolysis of oil palm empty fruit bunch. AB - Various pre-treatment techniques change the physical and chemical structure of the lignocellulosic biomass and improve hydrolysis rates. The effect of ultrasonic pre-treatment on oil palm empty fruit bunch (OPEFB) fibre prior to acid hydrolysis has been evaluated. The main objective of this study was to determine if ultrasonic pre-treatment could function as a pre-treatment method for the acid hydrolysis of OPEFB fibre at a low temperature and pressure. Hydrolysis at a low temperature was studied using 2% sulphuric acid; 1:25 solid liquid ratio and 100 degrees C operating temperature. A maximum xylose yield of 58% was achieved when the OPEFB fibre was ultrasonicated at 90% amplitude for 45min. In the absence of ultrasonic pre-treatment only 22% of xylose was obtained. However, no substantial increase of xylose formation was observed for acid hydrolysis at higher temperatures of 120 and 140 degrees C on ultrasonicated OPEFB fibre. The samples were then analysed using a scanning electron microscope (SEM) to describe the morphological changes of the OPEFB fibre. The SEM observations show interesting morphological changes within the OPEFB fibre for different acid hydrolysis conditions. PMID- 20719503 TI - Design and synthesis of new adamantyl-substituted antileishmanial ether phospholipids. AB - A series of new 2-[3-(2-alkyloxy-ethyl)-adamantan-1-yl]-ethoxy substituted ether phospholipids was synthesized and their antileishmanial activity was evaluated against Leishmania infantum amastigotes. The majority of the new analogues were significantly less cytotoxic than miltefosine while, antiparasitic activity depended on the length of the 2-alkyloxy substituent. The most potent compounds were {2-[[[3-(2-hexyloxy-ethyl)-adamant-1-yl]-ethoxy]hydroxyphosphinyloxy]ethyl} Nu,Nu,Nu-trimethyl-ammonium inner salt (5b) and {2-[[[3-(2-octyloxy-ethyl) adamant-1-yl]-ethoxy]hydroxyphosphinyloxy]ethyl}-Nu,Nu,Nu-trimethyl-ammonium inner salt (5c). PMID- 20719504 TI - Lactarane sesquiterpenoids from Lactarius subvellereus and their cytotoxicity. AB - Subvellerolactones B (1), D (2), and E (3), structurally unusual lactarane sesquiterpenoids, were isolated from the fruiting bodies of Lactarius subvellereus together with four known lactarane sesquiterpenes (4-7). The chemical structures and stereochemistries of compounds 1-3 were determined on the basis of spectroscopic analyses, including 1D and 2D NMR experiments and a convenient Mosher ester procedure. Subvellerolactone B (1) exhibited cytotoxicity against the A549, SK-MEL-2, and HCT-15 cell lines with IC50 values of 26.5, 18.3, and 14.2 microM, respectively, and subvellerolactones D (2) and E (3) showed cytotoxicity against the A549 and HCT-15 cell lines (IC50 (2): 25.1 and 17.8 microM, and IC50 (3): 19.6 and 28.7 microM, respectively). PMID- 20719505 TI - Synthesis, proapoptotic screening, and structure-activity relationships of novel aza-lupane triterpenoids. AB - Apoptosis is a highly regulated process by which excessive cells are eliminated in order to maintain normal cell development and tissue homeostasis. Resistance to apoptosis often contributes to failure in cancer prevention and treatment. Apoptotic cell death regulators are considered important targets for discovery and development of new therapeutic agents in oncology research. A class of novel aza-lupane triterpenoids were designed, synthesized, and evaluated for antitumor activity against a panel of cancer cell lines of different histogenic origin and for ability to induce apoptosis. 3,30-Bis(aza) derivatives were identified not only to possess improved cytotoxicity compared to the natural product betulinic acid but also to affect cell death predominantly via apoptosis, whereas the mono(aza) derivatives apparently triggered cell death via different, non apoptotic pathway(s). PMID- 20719506 TI - Structure-activity relationship study of glaziovianin A against cell cycle progression and spindle formation of HeLa S3 cells. AB - Various derivatives of glaziovianin A, an antitumor isoflavone, were synthesized, and the cytotoxicity of each against HeLa S3 cells was investigated. Compared to glaziovianin A, the O7-allyl derivative was found to be more cytotoxic against HeLa S3 cells and a more potent M-phase inhibitor. PMID- 20719507 TI - Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles as dual serotonin 5-HT2C and 5-HT6 receptor ligands. AB - Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro pyrazino[1,2-a]indole scaffold, which is based on intramolecular C-H insertion of a carbene. The compounds act as dual serotonin 5-HT2C- and 5-HT6-ligands. PMID- 20719508 TI - Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H) yl)acetamide vasopressin V3 (V1b) receptor antagonists. AB - The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics. PMID- 20719509 TI - SAR development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as kappa opioid receptor antagonists. Part 2. AB - Further structure activity relationship studies on a previously reported 8 azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated. PMID- 20719510 TI - Synthesis of cholestane glycosides bearing OSW-1 disaccharide or its 1-->4-linked analogue and their antitumor activities. AB - For further structure-activity relationship (SAR) research of OSW saponins, a cholestane glycoside, namely 3beta, 16beta, 26-trihydroxycholest-5-en-22-one 16-O (2-O-4-methoxybenzoyl-beta-D-xylopyranosyl)-(1-->3)-2-O-acetyl-alpha-L arabinopyranoside (1) together with two 1-->4-linked disaccharide analogues (2 and 3) were synthesized. Their cytotoxic activities were evaluated by the standard MTT assay. Compound 1 showed potent cytotoxicity against five types of human tumor cells, with IC50 ranging between 1.3 and 73 nM. PMID- 20719511 TI - Identification and hit-to-lead optimization of a novel class of CB1 antagonists. AB - The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat. PMID- 20719512 TI - Calcium oscillations, G1 phase duration and neurogenesis timing. PMID- 20719513 TI - The effects of surface slope on multi-segment foot kinematics in healthy adults. AB - Previous work evaluating the effects of surface slope on gait has focused on lower extremity kinematics and kinetics. However, an assessment of multi-segment foot kinematics during walking on inclined and declined ramps has not been previously reported. Sagittal ankle motion using a single rigid body foot model and three-dimensional hindfoot and forefoot kinematics for 24 healthy adults (16 females and 8 males, average age 25.5 +/- 4.4 years) were compared during level surface, inclined surfaces of 3%, 6%, 9% and 12% grade and a declined surface of approximately 7.5% grade at a constant speed using a standard treadmill. Significant differences in peak hindfoot plantarflexion, sagittal plane range of motion and time of peak dorsiflexion, plantarflexion, varus and valgus were seen between surface slope conditions. Significant changes were also seen in forefoot plantarflexion and sagittal plane range of motion however the maximum difference between conditions was less than 3 degrees . These results indicate that foot mechanics can be significantly altered when ambulating on ramps in healthy adults. Specifically, treadmill protocols which incorporate different surface slopes often encountered during ambulation of daily living, may provide an improved technique in evaluating a patient's ability to function in the community. PMID- 20719514 TI - A novel device for improving marker placement accuracy. AB - BACKGROUND: Repeatability of marker placement has been acknowledged as a major factor affecting the reliability of multi-segment foot models. A novel device is proposed that is intended to reduce marker placement error and its effect on the reliability of inter-segmental foot kinematic data is investigated. METHOD: The novel device was tested on eight healthy subjects. Landmarks were identified and indicated on the subject's foot at the start of testing using pen, and these points were used to guide placement. Markers were twice attached by a podiatrist using a standard approach, and twice by a researcher who used the novel device. Replacement accuracy and the kinematic reliability of the foot model data for both techniques were analysed. RESULTS: The mean marker placement variability using the novel device placement device was 1.1mm (SD 0.28) compared to 1.4mm (SD 0.23) when using standard placement techniques. Results suggest that these reductions in placement error tended to improve the overall reliability of the multi-segment data from the foot model. DISCUSSION: The novel device is a simple and inexpensive tool for improving the placement consistency of skin-mounted markers. PMID- 20719516 TI - Nuclear export of mRNA. AB - The nuclear export of mRNA, in which Mex67-Mtr2 mediates movement of mature transcripts through nuclear pores, represents the culmination of the nuclear portion of the gene expression pathway. Nuclear export is closely integrated with transcription and processing, and is based on forming a messenger ribonucleoprotein (mRNP) export complex in the nucleus that is able to diffuse back and forth through the pores. Directionality is imposed by remodelling of the mRNP in the cytoplasm, thereby removing key transport-related proteins and preventing its return to the nucleus. The nuclear and cytoplasmic steps of this pathway, in which Mex67-Mtr2 and Nab2 are added and removed, are crucial, and both involve remodelling of the mRNP, which is mediated by DEAD-box helicases together with adaptor and accessory proteins. Recent structural and cell biology results provide key information that should enable development of a detailed understanding of this central cellular process at a molecular level. PMID- 20719515 TI - Immunohistochemical analysis of developmental neural antigen expression in the balloon cells of focal cortical dysplasia. AB - Balloon cells (BC) are the histological hallmarks of focal cortical dysplasia (FCD). Expression of the neural stem cell surface marker CD133 and other developmental markers was studied in the BC of FCD using formalin-fixed paraffin embedded tissue from nine patients with FCD. Labeling indexes were calculated for all antibodies. BC were easily identified at the gray-white matter junction and they extended into the white matter. Immunoreactivity in BC was found for the following antigens in nine patients: CD133 (six patients; 22.2 +/- 7.7%), CD34 (two patients; 0.4 +/- 0.3%), nestin (nine patients; 37.6 +/- 8.5%), vimentin (eight patients; 59.2 +/- 8.7%), glial fibrillary acid protein (six patients; 34.3 +/- 10.4%), microtubule-associated protein 2 (four patients; 8.3 +/- 5.0%), neurofilament-middle/high (five patients; 10.2 +/- 4.6%) and synaptophysin (three patients; 4.2 +/- 3.3%). Neuronal nuclei (NeuN, neuron specific nuclear protein) was not expressed in BC of any patient. The results of this study suggest that BC in patients with FCD originate from glioneuronal precursor cells and that developmental defects of neuronal and glial specifications are important in the histogenesis of FCD. PMID- 20719517 TI - Reference axes for comparing the motion of knee replacements with the anatomic knee. AB - In the literature, different methods have been used to describe the motion of the anatomic knee and total knee replacements (TKR). The major goal of this study was to identify the most suitable methods for comparing TKR motion with that of the anatomic knee, whether for the purpose of developing new TKR designs, or evaluating existing ones. A further goal was to specify a testing methodology which would apply the methodology and represent a wide range of activities. Six knee specimens were tested in a Desktop Knee Machine, where different sequences of compressive, shear, and torque loads were applied at a full range of flexion angles. Data from a typical total knee was obtained by analysis. The motion results were displayed using different reference axes, specifically the circular axis, the epicondylar axis, the line joining the contact points, and the line joining the lowest lateral and medial femoral condylar points. It was concluded that the circular axis was the most generally applicable choice of a key femoral axis, for comparing the rigid body motion of a total knee with anatomic data, but that the actual contact points had important significance in full extension and in high flexion. PMID- 20719518 TI - Extracellular matrix content of ruptured anterior cruciate ligament tissue. AB - Anterior cruciate ligaments (ACLs) can rupture with simple movements, suggesting that structural changes in the ligament may reduce the loading capacity of the ligament. We aimed to investigate if proteoglycan and collagen levels were different between ruptured and non-ruptured ACLs. We also compared changes in ruptured tissue over time. During arthroscopic knee reconstruction surgery 24 ruptured ACLs were collected from participants (10 females; 14 males; mean age 24 years). Four non-ruptured ACLs were obtained from participants undergoing total knee replacement surgery (one female, three males; mean age 66 years). Western blot analysis was used to characterise core proteins of aggrecan, versican, decorin and biglycan and glycosaminoglycan assays were also conducted. Collagen levels were measured by hydroxyproline (OHPr) assays. Significantly lower levels of collagen, were found in ruptured ACL compared to non-ruptured ACL (p=0.004). Lower levels of both small and large proteoglycans were found in ruptured than non-ruptured ACLs. No correlation was found between time since rupture and proteoglycan or collagen levels. Ruptured ACLs had less collagen and proteoglycans than non-ruptured ACLs. These changes indicate either extracellular matrix protein levels were reduced prior to rupture or levels decreased immediately after rupture. It is possible that the composition and structure of ACLs that rupture are different to normal ACLs, potentially reducing the tissue's ability to withstand loading. An enhanced understanding of the aetiology of ACL injury could help identify individuals who may be predisposed to rupture. PMID- 20719519 TI - What activities do patients with patellar instability perceive makes their patella unstable? AB - Patellar instability is a disabling musculoskeletal condition. Whilst previous texts have suggested that twisting activities may cause patients to experience instability symptoms, no studies have assessed which activities are related to the patient's perceived instability. The purpose of this study was to determine which activities and with what frequency patients with patellar instability symptoms, perceive their patella to be unstable. Ninety patients referred because of recurrent patellar instability were asked to assess the frequency with which they perceived patellar instability for 19 everyday and sporting activities. The results indicated that sporting and multi-directional twisting activities were more frequently related to patellar instability symptoms, compared to lower energy, uni-planar activities. Females and those without a family history of patellar instability reported more frequent patellar instability symptoms, compared to males, or those with a family history of this disorder. Further study is now recommended to determine whether these results reflect that of patients with milder subluxation disorders, and whether factors such as hypermobility have an impact on perceived patellar instability for this patient group. PMID- 20719520 TI - Variations in dynamic knee valgus and gluteus medius onset timing in non-athletic females related to hormonal changes during the menstrual cycle. AB - It has been suggested that activities of daily living could contribute to the occurrence of ACL injury in females. Currently, no studies have focused on the lower extremity behavior of a non-athletic population to compare or understand the lower extremity adeptness towards daily movements that mimic athletic tasks. Our hypothesis was that increased knee valgus angles would occur during the late follicular phase of the menstrual cycle accompanied by different onset timing of the gluteus medius muscle. In a controlled laboratory study, 23 non-athletic collegiate females participated and 15 subjects comprised the final sample for statistical analysis. Subjects performed a single leg drop landing maneuver while 3-D knee kinematics and gluteus medius muscle onset timing were assessed throughout three distinct phases of the menstrual cycle, confirmed by blood hormone analysis. In general, knee valgus angles were significantly less in the luteal phase compared to both follicular phases (p<0.005), while differences were not observed for gluteus medius onset timing (p=0.936). As a decreased knee joint valgus angle was observed during the luteal phase, it was hypothesized that the hormone progesterone could significantly influence knee kinematics during a dynamic task. However, such influence was not observed for gluteus medius EMG onset timing as a significant correlation between gluteus medius onset timing and knee valgus angle could not be determined. PMID- 20719521 TI - 3D representation of the surface topography of normal and dysplastic trochlea using MRI. AB - The three-dimensional (3D) image of the articular surface topography of the normal and the dysplastic trochlea has not been defined. The aim of this study was to represent both the normal and dysplastic trochlear geometry in 3D using magnetic resonance imaging (MRI). Using the segmentation software program Amira (Mercury Computer Systems, Inc., Chelmsford, USA) we created 3D reconstructions of the distal femur bone and cartilage using MRI scans. Bone and cartilage of the distal femur were traced slice by slice in the acquisitioned dimension while the Amira program reconstructed the 3D model. This model was then transferred to the Rhinoceros 4.0 software (Robert McNeel & Associates, Seattle, USA) for measuring. Using this system a non-invasive 3D representation of the articular cartilage and bone of the normal trochlea and depiction of different types of trochlear dysplasia were possible. Potential advantages of these MRI measurements are assessment of the 3D articular cartilage of the whole trochlea and the bony contours on the same image, no imaging errors from joint malpositioning, no ionizing radiation, precise preoperative planning according to the documented pathomorphology, and comparison between the preoperative and the postoperative shapes. The disadvantages include higher costs compared to radiography or CT scans, and time consuming reconstruction, making them currently a research tool. PMID- 20719522 TI - A case for one-stage revision in infected total knee arthroplasty? AB - Infection in total knee replacement is a rare but devastating complication. The current literature tends to support a two-stage revision as definitive treatment of established deep infection. Despite the fact that single stage revision is a well recognised treatment for the infected hip replacement, it has not gained the same level of support in the knee. This article reviews the literature of two stage and single stage revision and reports the senior author's experience with the latter. PMID- 20719523 TI - Supramolecular protamine/Gd-loaded liposomes adducts as relaxometric protease responsive probes. AB - A new approach to enzyme-responsive MRI agents based on the use of liposomes loaded with a high number of paramagnetic metal complexes (Gd-HPDO3A) is presented. It relies on the disruption of low relaxivity aggregates formed by liposomes and a macromolecular substrate that is selectively cleaved by the enzyme of interest. The interaction of anionic liposomes composed of POPC:CHOL:DPGS and the cationic protein protamine yields a poorly soluble supramolecular assembly endowed with a low relaxivity. The action of the serine protease trypsin causes the digestion of protamine and the consequent de-assembly of the supramolecular adduct. The process is accompanied by an overall relaxation enhancement of solvent water protons as consequence of the dissolution of the aggregated liposomes. The observed increase of relaxivity is linearly dependent on the enzyme concentration. An illustrative example of the possible use of the herein presented responsive agent has been reported. It consists of the entrapment of the supramolecular assembly in alginate microcapsules that have often been used as envelopes for in vivo applications of stem cells and pancreatic islets. The change in the observed longitudinal relaxation rate R(1) (leading to an hyperintense signal in the corresponding MR images) may act as a sensor of the protease activity in the biological environment in which the capsules is located. PMID- 20719524 TI - Structure-activity relationships of mononuclear metal-thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities. AB - A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four functionalized furyl-thiosemicarbazones (NT1-4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L)2Cl2] or [M(L)Cl2] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure-activity relationship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC50 of 4.6 microM) and antiamoebic (NT2Pd, IC50 of 0.6 microM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the proliferation of these parasites at concentrations that are not cytotoxic to mammalian cells. PMID- 20719525 TI - Visualization of the flagellar surface of protists by atomic force microscopy. AB - In many cells, motility is mediated by flagellar beating. Protist parasites are capable of highly coordinated motility which contributes to their pathogenicity in mammalian hosts. Understanding the structural aspects of the flagellum may be important to the identification of novel targets for therapeutic intervention. Our group used atomic force microscopy (AFM) to examine the ultrastructure of Trypanosoma cruzi, obtaining valuable information on the organisation of the flagellar sub-structure. AFM images revealed novel flagellar components such as the presence of periodically-spaced protrusions organised along a flagellar furrow and oriented through the major flagellar axis between the axoneme and the paraflagellar rod. The nature and functional role of this structure are still unknown, although the hypothesis that the furrow might physically separate the two distinct domains of the flagellar membrane that comprise the surface of the axoneme and the paraflagellar rod (PFR) has been raised. To test whether the furrow was present or not only in PFR-bearing flagella, different protists containing or lacking the PFR, were analysed by AFM. Analysis of T. cruzi, Trypanosoma brucei and Herpetomonas megaseliae, which present distinct PFRs, showed similar and equivalent furrows along the main axis of their flagella, whereas Crithidia deanei, Giardia lamblia and Tritrichomonas foetus (in which the PFR is reduced or absent) lacked a furrow. Our results strongly suggest that the flagellar furrow is a characteristic feature of PFR-containing flagella and opens new perspectives for its functional role in the definition of sub-domains on the flagellar membrane. PMID- 20719526 TI - The disequilibrium between 210Po and 210Pb in raw and drinking waters. AB - Many countries have to monitor and control the radioactivity in drinking waters in order to ensure compliance with the requirements of their respective regulations. Among radionuclides responsible for this radioactivity there are (210)Po and (210)Pb, which are usually not in radioactive equilibrium in waters. This paper deals with the analysis of this disequilibrium and the way that the water treatment plants affect it. To do this, (210)Po and (210)Pb activity concentrations were measured in raw and drinking water. The measurements were performed by alpha-particle spectrometry and gas flow proportional counting and the corresponding formulae for uncertainties and detection limits are presented. The values obtained show that the Po/Pb ratio is lower in surface than in ground waters. Regarding water treatment, this ratio adopts values lower in drinking water than in raw waters. In any case, for the waters analysed in this work the committed effective doses due to these radionuclides, are negligible. PMID- 20719527 TI - Secondary correction of bilateral cleft lip nose deformity - Clinical and three dimensional observations on pre- and postoperative outcome. AB - PURPOSE: The purpose of this study was to describe the clinical and three dimensional (3D) outcomes following secondary correction of bilateral cleft lip and nose by reverse-U incision, nasal tip cartilage graft, and medial-upward advancement of bilateral nasolabial components with vestibular expansion with a free mucosal graft. PATIENTS AND METHODS: Secondary correction of the bilateral cleft lip and nose deformity was performed on 11 patients with complete bilateral cleft lip, alveolus and palate (BCLP). In four patients with an extremely short columella, an inferiorly based small pedicle flap from rim skin rotating into the columella base was included to elongate the columella length. Pre- and postoperative nasal forms were recorded using photos and 3D data taken serially. RESULTS: The nasal forms and lateral profiles were improved in all patients postoperatively. The pre- and postoperative 3D colour images demonstrated satisfactorily elongated columella length, symmetrically increased nasal tip projection, and enlarged alar groove. No serious complications were observed postoperatively. CONCLUSIONS: Our secondary correction technique of the bilateral cleft lip and nose will provide successful results producing an adequate nasal tip projection and alar forms without damaging the upper lip tissue in patients with BCLP. PMID- 20719528 TI - Early stage de-etiolation increases the ferulic acid content in winter triticale seedlings under full sunlight conditions. AB - In the presented work an attempt has been made to estimate the phenolics content and its implication for the protection of the photosynthetic apparatus in course of a plant's de-etiolation. The experiments were carried out on two genotypes of winter triticale varying in their resistance to drought. The activity of the photosynthetic apparatus was monitored by taking measurements of chlorophyll fluorescence and chlorophyll/carotenoids content. Analyses of the total pool of phenolic compounds and ferulic acid as well as l-phenylalanine ammonia lyase activity were completed. The first illuminations of etiolated seedlings induced a chlorophyll synthesis, which was followed by the increasing activity of the photosynthetic apparatus in both studied genotypes. Piano exhibited a higher values of the maximum quantum efficiency of photosystem II primary photochemistry during de-etiolation than Imperial. These results may just indicate that for Imperial, the delivery of photons to the reaction centres exceeded the capacity of the photosynthetic apparatus to transduce this energy via electron transport. An increase in the content of ferulic acid was more noticeable for Piano and seems to be a consequence of adaptation to the new light conditions. It should be taken into account, that an increase of ferulic acid content during early stage of de-etiolation, may limit the photoinhibition of photosynthesis whenever radiation is excessive for the photosynthetic apparatus. PMID- 20719529 TI - Hepatic and biliary damage after transarterial chemoembolization for malignant hepatic tumors: incidence, diagnosis, treatment, outcome and mechanism. AB - OBJECTIVE: To provide an overview of recent studies on transarterial chemoembolization-related hepatic and biliary damage (TRHBD) in patients with malignant hepatic tumors (MHT) and to explore the reasons for TRHBD. METHODS: Literature on the treatments for MHT by TACE was sought in PubMed and the related information was summarized. RESULTS: TRHBD is found to occur in the hepatic parenchymal cells, biliary tree and blood-vascular system. The damage is mainly due to ischemia resulting from embolic materials such as gelatin sponge and lipiodol. In addition, clinicians' skill levels in non-superselective catheterization, the health condition of the patients, and the chemical agents used may also be related to the damage. Most of the deterioration can be reversed if the patients are diagnosed and treated properly and promptly. CONCLUSIONS: Understanding the mechanisms of TRHBD more comprehensively is helpful in developing effective methods for prevention and treatment. PMID- 20719530 TI - Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer. AB - Colorectal cancer (CRC) treatment has evolved significantly over the last ten years with the use of active chemotherapeutic agents including fluoropyrimidines, oxaliplatin and irinotecan plus targeted monoclonal antibodies bevacizumab, cetuximab and panitumumab. The addition of newer chemotherapeutic agents and targeted therapies has improved patient outcomes at the cost of increased toxicity with not all patients benefiting from these treatments. It is necessary for clinicians to more accurately predict clinical outcomes particularly in the predominantly elderly CRC patient population. This review aims to summarise existing data regarding the use of clinical and laboratory variables plus molecular markers in predicting response, survival and toxicity to chemotherapy agents and targeted monoclonal antibodies currently used in the treatment of CRC. PMID- 20719531 TI - Cerebrospinal fluid ferritin level, a sensitive diagnostic test in late presenting subarachnoid hemorrhage. AB - The workup of patients with suspected subarachnoid hemorrhage (SAH) presenting late is complicated by a loss of diagnostic sensitivity of computed tomography (CT) brain imaging and cerebrospinal fluid (CSF) bilirubin levels. In this prospective longitudinal study of CSF ferritin levels in SAH, serial CSF samples from 14 patients with aneurysmal SAH requiring extraventricular drainage (EVD) were collected. The control group comprised 44 patients presenting with headache suspicious of SAH. Nine patients underwent a traumatic spinal tap. CSF ferritin levels were significantly higher in the patients with SAH compared with controls (P < .0001). The upper reference range of CSF ferritin is 12 ng/mL, and there was no significant difference between the traumatic and normal spinal taps (mean, 9.0 ng/mL vs 3.9 ng/mL; P = .59). CSF ferritin levels increased after SAH, from an average of 65 ng/mL on day 1 to 1750 ng/mL on day 11 (P < .01). Both the Fisher and Columbia CT scores were significantly correlated with CSF ferritin level. The increase in CSF ferritin level after SAH and possibly may provide additional diagnostic information in patients with suspected SAH who present late to the clinic. PMID- 20719533 TI - Common carotid artery aneurysm revealing Takayasu's arteritis. AB - Takayasu's arteritis (TA) is a chronic inflammatory disease of unknown etiology affecting large vessels, most markedly the aorta and its branches. Stroke or transient ischemic attack may occur in TA due to either the occlusion or embolic material originating from the inflammatory region of the vessel. Extracranial carotid aneurysms caused by TA are extremely rare and usually appear at advanced stages of the disease. A 27-year-old woman presented with carotidynia and a left laterocervical mass. Ultrasonography of the bilateral carotid arteries revealed an aneurysm of the left common carotid artery. The patient fulfilled the diagnostic criteria for TA. Extracranial carotid artery aneurysm could be an initial manifestation of this disease. The diagnosis of TA was made on the basis of the presence of systemic inflammatory reaction and the anatomic locations of the affected arteries-the common carotid artery in a young woman. Surgery with stent placement can be a successful long-term treatment. PMID- 20719532 TI - Poststroke aphasia recovery assessed with functional magnetic resonance imaging and a picture identification task. AB - Stroke patients often display deficits in language function, such as correctly naming objects. Our aim was to evaluate the reliability and the patterns of poststroke language recovery using a picture identification task during functional magnetic resonance imaging (fMRI) at 4 T. Four healthy subjects and 4 subjects with left middle cerebral artery stroke with chronic (>1 year) aphasia were enrolled in the study. In each subject, 10 fMRI scans were performed over a 10-week period using a picture-identification task. The active condition involved presenting subject with a panel of 4 figures (eg, drawings of 4 animals) every 6 seconds and asking the subject to indicate which figure matched the written name in the center. The control condition was a same/different judgment task with pairs of geometric figures (squares, octagons, or combination) presented every 6 seconds. Thirty-second active/control blocks were repeated 5 times each, and responses were recorded. The stoke subjects and controls had similar demographic characteristics, including age (46 vs 53 years), personal handedness (Edinburg Handedness Inventory, 89 vs 95), familial handedness (93 vs 95), and years of education (14.3 vs 14.8). For the active condition, the controls performed better than the stroke subjects (97.7% vs 89.1%; P < .001); the 2 groups performed similarly for the control condition (99.5% vs 98.8%; P = .23). On fMRI, the controls exhibited bilateral, L > R positive blood oxygenation level-dependent (BOLD) activations in frontal and temporal language areas and symmetric retrosplenial and posterior cingulate areas and symmetric negative BOLD activations in bilateral frontotemporal language networks. In contrast, the stroke subjects exhibited positive BOLD activations predominantly in peristroke areas and negative BOLD activations in the unaffected (right) hemisphere. Both groups displayed high activation reliability (as measured by the intraclass correlation coefficient [ICC]) in the left frontal and temporal language areas, although in the stroke subjects the ICC in the frontal regions was spread over a much larger peristroke area. This study documents the utility of the picture identification task for poststroke language recovery evaluation. Our data suggest that adult stroke patients use functional peristroke areas to perform language functions. PMID- 20719534 TI - Factors associated with misdiagnosis of acute stroke in young adults. AB - Misdiagnosis or delayed diagnosis of acute ischemic stroke can result in neurologic worsening or a missed opportunity for thrombolysis. Because stroke in young adults is less common than stroke in the elderly, we sought to determine clinical characteristics associated with misdiagnosis of stroke in young adults. Patients from the prospectively maintained Young Stroke Registry in our comprehensive stroke center were reviewed. Demographic information, past medical history, presentation within the 3-hour time window, and outcomes were assessed. We compared patients misdiagnosed and those correctly diagnosed to identify factors associated with misdiagnosis of acute stroke. A total of 57 patients aged 16-50 were enrolled in the registry during 2001-2006. Eight patients (14%; 4 men and 4 women; mean age, 38 years) were misdiagnosed. Seven of these 8 patients were discharged from the emergency department initially. Patients age <35 years (P = .05) and patients with posterior circulation stroke (P = .006) were more likely to be misdiagnosed. All 8 misdiagnosed patients were initially evaluated at hospitals that were not certified primary stroke centers. Patients presenting with vertebrobasilar territory ischemia have a greater rate of misdiagnosis. Our study demonstrates the increasing need for "young stroke awareness" among emergency department personnel. Initial misdiagnosis can potentially lead to a lost opportunity for thrombolysis in otherwise good candidates. PMID- 20719535 TI - Factors predicting outcome in stroke patients treated with 0.6 mg/kg alteplase: evidence from the Japan Alteplase Clinical Trial (J-ACT). AB - The aim of the present study was to identify factors associated with functional outcome, mortality, and symptomatic intracranial hemorrhage (sICH) in patients from the Japan Alteplase Clinical Trial (J-ACT) data set with ischemic stroke treated with intravenous (IV) 0.6 mg/kg alteplase within 3 hours after onset. The patient sample comprised 103 patients from the J-ACT, a multicenter, single-dose, open-label cohort study conducted to verify the efficacy and safety of IV 0.6 mg/kg alteplase in treating acute hemispheric stroke. The effects of 21 patient baseline characteristics on a favorable outcome (as evaluated by modified Rankin scale [mRS] score of 0-1 after 3 months), death within 3 months, and incidence of sICH within 36 hours after the start of treatment were examined by univariate analysis and stepwise logistic regression analysis. The baseline characteristics associated with a favorable outcome in univariate analysis included age and National Institutes of Health Stroke Scale (NIHSS) score. The factors associated with death included age and the NIHSS score. No factors were significantly associated with sICH. In stepwise logistic regression analysis, age and NIHSS score significantly predicted both favorable outcome and death. No factors significantly predicted sICH. Age and baseline NIHSS score were independent predictors for both favorable outcome and death. Although these factors are consistent with those found to be predictors in studies on IV 0.9 mg/kg alteplase, there were no factors predicting outcomes specific for IV 0.6 mg/kg alteplase. PMID- 20719536 TI - Alberta Stroke Program Early CT Score (ASPECTS) in patients with wake-up stroke. AB - One-quarter of ischemic strokes occur during sleep, and affected patients are excluded from thrombolytic therapy because of an unknown time of stroke onset. It has been suggested that early ischemic changes detected on computed tomography (CT) are similar in patients with acute stroke and patients who recently awoke with stroke. We compared head CT scans using the Alberta Stroke Program Early CT Score (ASPECTS) in patients who were likely to suffer their stroke during sleep (awoke group) and a control group of patients with stroke of known onset time. Patients were recruited from a prospectively collected acute stroke database. The awoke group was defined as all ischemic stroke patients who were "last seen normal" more than 4 hours ago, arrived between 4 a.m. and 10 a.m., and underwent head CT within 15 hours of the time last seen normal. The control group was randomly selected from patients who underwent head CT within 4 hours of stroke onset. The ASPECTS evaluations were performed by investigators blinded to patient group and time of onset. A modified Rankin Scale (mRS) score was available in 15 awoke patients and 46 control patients at 90 days after stroke. Twenty-eight awoke patients and 68 control patients had suitable imaging for the ASPECTS. Baseline demographic characteristics and risk factors were similar in the 2 groups. The dichotomized ASPECTS analysis (<=7 vs 8-10) showed no significant differences between the groups. ASPECTS was 8-10 in 89.3% the awoke group and 95.6% in the control group (P=.353). There was a trend toward higher 90-day mRS score (0-1) in the awoke group versus controls (73% vs 45%; P=.079). Initial ASPECTS was similar in patients with wake-up stroke and those with 4 hours of symptoms. This suggests that a subset of wake-up stroke patients might be suitable for thrombolytic therapy. PMID- 20719537 TI - Lack of international consensus on ethical aspects of acute stroke trials. AB - Acute stroke trials are becoming increasingly multinational. Working toward a shared ethical standard for acute stroke research necessitates evaluating the degree of consensus among international researchers. We surveyed all 275 coinvestigators and coordinators who participated in the AbESTT II study (evaluating abciximab vs placebo) about their experience with their local institutional review board (IRB) or equivalent, as well as, about their personal beliefs regarding the ethical aspects of acute stroke trials. A total of 90 coinvestigators from 15 different countries responded to our survey. Among the IRBs represented by the responding coinvestigators, only 18% allowed surrogate consent to be obtained over the phone. Although 52% allowed the participation of subjects with aphasia, only 5% allowed the participation of subjects with neglect/hemi-inattention. The National Institutes of Health Stroke Scale score was deemed adequate to establish decisional capacity based on language by 62% of the coinvestigators and 36% of the IRBs. A belief that IRB regulations cause unnecessary delays and fear in relatives/patients was reported by 67% of coinvestigators, and the belief that granting an exemption from informed consent under specific circumstances is appropriate was reported by 41%. There appears to be considerable international diversity in the ethical priorities and informed consent standards among different IRBs and investigators in stroke research. The stroke community should make an attempt to standardize the consent process used in research. Given the critical nature of the time to treatment in stroke care, these standards should be integrated into current frameworks of clinical care and research. The absence of an ethical consensus can become a barrier to advancing stroke treatment internationally. PMID- 20719538 TI - Presenting symptoms and onset-to-arrival time in patients with acute stroke and transient ischemic attack. AB - Delayed arrival to the emergency department (ED) precludes most stroke patients from receiving thrombolytic treatment. Our objective in this study was to examine the association between presenting symptoms and onset-to-arrival time (ie, time between onset of symptoms to arrival at the ED) in a statewide stroke registry. Demographics, clinical data, and presenting symptoms were collected for patients with acute stroke or symptomatic transient ischemic attack (TIA) admitted to 15 Michigan hospitals (n = 1922). Polytomous logistic regression models were developed to test the association between presenting symptoms and onset-to arrival time (classified as <2 hours, 2-6 hours, or >6 hours/unknown). Onset-to arrival time was <2 hours in 19% of the patients, 2-6 hours in 22%, and >6 hours/unknown in 59%. Unilateral symptoms (reported by 40%) and speech difficulties (reported by 22%) were associated with increased likelihood of arriving within 2 hours (unilateral: adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.1-1.9; speech: aOR, 1.6; 95% CI, 1.2-2.2). Difficulty with walking, balance, or dizziness (12%), confusion (9%), loss of consciousness (6.7%) and falls (3.4%) were associated with lower likelihood of arriving within 2 hours (walking: aOR, 0.7; 95% CI, 0.4-1.0; confusion: aOR, 0.5; 95% CI, 0.3 0.8; consciousness: aOR, 0.5; 95% CI, 0.1-0.9; falls: aOR, 0.4; 95% CI, 0.3-0.9). Presenting symptoms were strongly associated with time of arrival; patients with unilateral symptoms and speech difficulties were more likely to seek care early. Future studies should consider including more specific patient-level data to identify psychosocial and behavioral aspects of recognition and action to stroke symptoms. PMID- 20719539 TI - Effect of combined treatment with curcumin and candesartan on ischemic brain damage in mice. AB - The combined effects of curcumin and candesartan were investigated in brain ischemia induced by middle cerebral artery (MCA) occlusion (MCAO). Male mice were classified into 5 groups. The mice were killed 24 hours after MCAO, and each group was divided into 2 halves. In one half, brain homogenate was collected for antioxidant enzyme activity determination, and in the other half, samples were obtained for red color intensity determination in brain slices. The untreated group exhibited significantly reduced cerebral blood flow, increased lipid peroxide levels and heart rate, decreased superoxide dismutase (SOD) and glutathione-S-transferase (GST) activity, and reduced red color intensity compared with the sham group. Combination treatment with curcumin and candesartan significantly restored SOD and GST activity, thiobarbituric acid reactive substances, heart rate, blood flow, and red color intensity compared with the untreated group. The use of each drug alone significantly restored SOD and blood flow compared with the sham and untreated groups, heart rate decreased with curcumin alone, and red color intensity and nitric oxide level increased with candesartan alone. These results indicate that curcumin synergistically enhances the inhibitory action of candesartan on brain ischemia through suppression of blood flow changes and oxidative stress via antioxidant properties, suggesting beneficial combined effects of curcumin and candesartan on ischemic brain damage. PMID- 20719540 TI - National sex-specific trends in hospital-based stroke rates. AB - Mounting regional and national evidence suggests a decline in primary in-hospital stroke diagnoses. However, these data do not include secondary diagnoses of stroke, and little is known about whether this decline varies significantly by sex. Compared with men, women are less likely to have optimal control of stroke risk factors, which may be leading to less impressive declines in stroke incidence in women. This study evaluated sex trends in hospital-based stroke diagnoses in the United States. The study was a time-trend analysis by sex of national age-adjusted rates of primary or secondary hospital-based stroke diagnosis per 100,000 persons (identified by ICD-9 procedure codes) among patients for 1997-2006 using data from all US states contributing to the Nationwide Inpatient Sample. Adjustments were made to correct for some inaccuracies in diagnostic codes. Between 1997 and 2006, total hospital-based stroke diagnoses decreased from 680,607 to 609,359. The age-adjusted hospital based stroke diagnosis rate per 100,000 persons decreased in a roughly linear pattern from 282.7 to 210.4 in men (26%; P < .001) and from 240.5 to 184.7 in women (23%; P < .05). The average rate of decrease (slope) in hospital-based stroke diagnosis rates was greater in men than in women (-8.7 vs -7.5 per 100,000 persons; P = .003). Age-adjusted rates of hospital-based stroke diagnoses have decreased substantially in the United States during the last decade, but slightly less so in women. These results are generally encouraging, but nonetheless indicate that more intensive preventive efforts are warranted to completely eliminate sex disparities in stroke occurrence. PMID- 20719542 TI - One-lung ventilation for radiofrequency ablation of pulmonary lesions out of the surgical area: a secure option. PMID- 20719541 TI - Low patient enrollment sites in multicenter randomized clinical trials of cerebrovascular diseases: associated factors and impact on trial outcomes. AB - Wide variability in patient enrollment among participating sites is a common phenomenon in multicenter trials. We examined stroke trial-related factors associated with the proportion of sites with low patient enrollment and the effect of these low-enrollment sites on trial outcome. We identified efficacy clinical trials enrolling patients with cerebrovascular diseases between 1980 and 2008 using an electronic database. The trials included in our analyses were multicenter randomized controlled trials (RCTs) comparing efficacy endpoints between two or more treatment groups and having >5 sites. Sites enrolling <10 patients or <2% of total trial patients were defined as low- enrollment sites. Trials were classified into tertiles based on the proportion of low-enrollment sites. Factors associated with trials that could be ascertained through a systematic review of published data were identified and examined. The association between low enrollment and a conclusive trial designation (defined by the ability to reject the primary null hypothesis either at or before target enrollment or demonstrate equivalence/noninferiority with adequate statistical power, depending on the initial design) was assessed using a multivariate logistic regression model. We identified 51 trials that met the inclusion criteria and provided information regarding patients enrolled per center. A total of 3059 participating centers enrolled a total of 53,742 trial participants; 78% of the participating sites enrolled <2% of trial participants. Trials enrolling acute stroke patients (within 24 hours of symptom onset) or those evaluating endovascular/surgical intervention had a higher proportion of low-enrollment sites (<10 patients per site). Studies with a higher proportion of low-enrollment sites were more likely to target acute stroke patients and less likely to randomize >=1000 patients, use general efficacy endpoints, and stratify by site. There was no association between the studies with a higher proportion of low-enrollment sites and designation as a conclusive trial. A better understanding of factors associated with low-enrollment sites in clinical trials and the impact on a trial's ability to demonstrate conclusive outcomes may lead to strategies to make trial enrollments more efficient and cost-effective. PMID- 20719543 TI - Usefulness of sirolimus-based immunosuppression in ameliorating pre-transplant renal dysfunction in patients with Chagas' heart disease. PMID- 20719544 TI - Descartes discarded? Introspective self-awareness and the problems of transparency and compositionality. AB - What has the self to be like such that introspective awareness of it is possible? The paper asks if Descartes's idea of an inner self can be upheld and discusses this issue by invoking two principles: the phenomenal transparency of experience and the semantic compositionality of conceptual content. It is assumed that self awareness is a second-order state either in the domain of experience or in the domain of thought. In the former case self-awareness turns out empty if experience is transparent. In the latter, it can best be conceived of as a form of mental quotation. Various proposed analyses of direct and indirect quotation are discussed and tested regarding their applicability to thought. It is concluded that, on the assumption of compositionality, the inner self is only insofar accessible to awareness as it has an accessible phonological (or otherwise subsymbolic) structure, as apparently only inner speech does. PMID- 20719545 TI - Malignancy detection in digital mammograms: important reader characteristics and required case numbers. AB - RATIONALE AND OBJECTIVES: To determine the relationship between heightened levels of reader performance and reader practice in terms of number of cases read and previous experience. MATERIALS AND METHODS: A test set of mammograms was developed comprising 50 cases. These cases consisted of 15 abnormals (biopsy proven) and 35 normals (confirmed at subsequent rescreen). Sixty-nine breast image readers reviewed these cases independently and their performance was measured by recording their individual receiver operating characteristic score (area under the curve), sensitivity, and specificity. These measures of performance were then compared to a range of factors relating to the reader such as years of certification and reporting, number of cases read per year, previous experiences, and satisfaction levels. Correlation analyses using Spearman methods were performed along with the Mann-Whitney test to detect differences in performance between specific reader groups. RESULTS: Improved reader performance was found for years certified (P = .004), years of experience (P = .0001), and hours reading per week (P = .003) shown by positive statistical significant relationships with Az values (area under receiver operating characteristic curve). Statistical comparisons of Az values scored for individuals who read varying number of cases per year showed that those individuals whose annual mammographic case load was 5000 or more (P = .03) or between 2000 and 4999 (P = .05), had statistically significantly higher scores than those who read less than 1000 cases per year. CONCLUSION: The results of this study have shown variations in reader performance relating to parameters of reader practice and experience. Levels of variance are shown and potential acceptance levels for diagnostic efficacy are proposed which may inform policy makers, judicial systems and public debate. PMID- 20719546 TI - Inhibition effects of high mechanical index ultrasound contrast on hepatic metastasis of cancer in a rat model. AB - RATIONAL AND OBJECTIVES: The liver is the most common organ for tumor metastasis. The development of new methods to depress hepatic metastasis is of great importance in improving survival. The aim of this study was to observe the effects of high-mechanical index ultrasound contrast on hepatic metastasis of colorectal cancer. MATERIALS AND METHODS: Hepatic metastasis models were established by injecting human colon carcinoma LoVo cells into the spleens of Sprague-Dawley rats. The rats were divided into a control group, a microbubble plus ultrasound group, a simple ultrasound group, and a simple microbubble group. The ultrasound contrast agent SonoVue (1 mL/kg) was injected via the tail vein, and high-mechanical index ultrasound contrast (frequency, 1.5 MHz; mechanical index, 1.7) was performed on the spleen intermittently for 2 minutes. The animals were sacrificed after 10 days, and the sizes and number of hepatic metastases were measured and compared. Histologic pathology and splenic ultrastructure were observed. RESULTS: The number and sizes of hepatic metastases patently decreased in rats in the microbubble plus ultrasound group (P < .01). There were no obvious differences among the control group, simple ultrasound group, and simple microbubble group in hepatic metastases (P > .05). Histologic pathology showed that the number of tumor cells in the spleens decreased considerably, and massive necroses, hemorrhages, and thrombi were observed in the tumor and spleen tissues of rats in the microbubble plus ultrasound group. Transmission electron microscopy showed that the mitochondria of tumor cells and endothelial cells were clearly swelled, and there were gaps among endothelial cells and platelets aggregated in capillary vessels. CONCLUSION: This research shows that intermittent high-mechanical index ultrasound contrast may inhibit the hepatic metastasis of cancer in a rat model. PMID- 20719547 TI - In vitro assessment of poly-iodinated triglyceride reconstituted low-density lipoprotein: initial steps toward CT molecular imaging. AB - RATIONALE AND OBJECTIVES: Targeted molecular probes offer the potential for greater specificity in cancer imaging with contrast-enhanced computed tomography (CT). We investigate a low-density lipoprotein (LDL) nanoparticle loaded with poly-iodinated triglyceride (ITG) in a proof of concept study of targeted x-ray imaging. LDLs are targeted to the LDL cell surface receptor (LDLR), which is overexpressed in several tumor types. The LDL-LDLR pathway presents a high capacity and self-renewing transport system for molecular imaging in CT. MATERIALS AND METHODS: ITG was synthesized and loaded into the core of LDL particles to form a reconstituted nanoparticle, hereafter referred to as (rITG)LDL. Particle size was measured by dynamic light scattering. The x-ray attenuation of the (rITG)LDL solution was measured with CT imaging and signal enhancement was calibrated for equivalent iodine concentration. Cultured human hepatoblastoma G2 (HepG2) cells, which overexpress LDLR, were incubated with (rITG)LDL with or without native LDL. The cells were imaged with CT to characterize particle sequestration. RESULTS: Reconstitution of LDL with ITG was successful and did not compromise the targeting function of the particle. Measurement of the x-ray attenuation properties of the (rITG)LDL solution revealed an effective iodine concentration of 0.78 mg/mL. In vitro studies of HepG2 cells demonstrated a significant increase in CT image intensity over control cells when incubated with (rITG)LDL. CONCLUSION: The in vitro results of this study suggest that (rITG)LDL can provide adequate image enhancement for CT molecular imaging. Potential applications include breast imaging and small animal imaging at low x-ray energies. In vivo experiments will be required to verify that tumor uptake of (rITG)LDL is sufficient for enhanced detection. Use at higher x-ray energies, as used in conventional CT, will require a further increase in iodine loading. PMID- 20719548 TI - Part one: for the motion: A randomised controlled trial is the best way to determine whether endovascular repair is the preferred management strategy in patients with a ruptured aortic aneurysm. PMID- 20719549 TI - Is duplex ultrasound scanning for peripheral arterial disease of the lower limb a non-invasive alternative or an adjunct to angiography? PMID- 20719550 TI - Treatment of mycotic aneurysms with involvement of the abdominal aorta: single centre experience in 44 consecutive cases. AB - OBJECTIVE: To review our management of mycotic aneurysms involving the abdominal aorta over the past 2 decades to assess the safety and efficacy of in-situ and extra-anatomic repair combined with antibiotic treatment. MATERIALS AND METHODS: From March 1990 to August 2008, 44 patients with a mycotic aneurysm involving the abdominal aorta were treated at our University Hospital. For all patients, we recorded the aetiology, clinical findings and anatomic location of the aneurysm, as well as bacteriology results, surgical and antibiotic therapy and morbidity and mortality. RESULTS: Twenty-one (47.7%) of the mycotic aneurysms had already ruptured at the time of surgery. Free rupture was present in nine patients (20.5%). Contained rupture was observed in 12 patients (27.3%). Urgent surgery was performed in 18 cases (40.9%). Revascularisation was achieved by in-situ reconstruction in 37 patients (84.1%), while extra-anatomic reconstruction was performed in six patients (13.6%). One patient (2.3%) was treated with a combined in-situ and extra-anatomic reconstruction. In one case (2.3%), endovascular aneurysm repair (EVAR) was performed. In-hospital mortality was 22.7%, 50% in the extra-anatomic reconstruction group and 18.9% in the in-situ repair group. One third (33.3%) of our patients, who presented with a ruptured mycotic aneurysm died in the peri-operative period. This mortality was 13% in the patient-group presenting with an intact aneurysm. Of the 34 surviving patients, 12 patients (27.3% of surviving patients died after discharge from our hospital. In half of these patients, an acute cardiac event was to blame. Three patients (8%) showed re-infection after in-situ reconstruction. CONCLUSION: Management of mycotic aortic aneurysms remains a challenging problem. The results of surgery depend on many factors. In our experience, in-situ repair remains a feasible and safe treatment option for patients who are in good general condition at the time of surgery. PMID- 20719551 TI - Continuous monitoring and quantification of multiple parameters of daily physical activity in ambulatory Duchenne muscular dystrophy patients. AB - Multiple motor function and strength assessment tools exist for the evaluation of neuromuscular diseases, but most do not directly assess functional ability in the patients' daily physical activity in their home environment. In this study our aim was to assess: 1) the feasibility and accuracy of physical activity monitoring during two days in a home environment of five DMD patients using a non commercialized monitor containing a 3D accelerometer and a gyroscope, 2) if a difference in the physical activity parameters could be measured before and one month after starting prednisolone. We reliably quantified the time spend sitting, standing, lying, walking, the number of steps taken, the cadence, the number of walking episodes and their duration as well as how these were distributed over the day. Parameters possibly reflecting endurance, such as the duration of the walking episodes or the succession of two or three walking episodes lasting more than 30 s were the most improved after prednisolone treatment. This degree of detailed determination of physical activity in a home environment has not been previously reported in neuromuscular disorders to our knowledge and some of the reported parameters are potential new outcome measures in clinical trials. PMID- 20719552 TI - Cysteinyl-leukotriene receptor antagonism blunts the acute hypotensive response to endotoxin in cats. AB - This study evaluated the effects of a cysteinyl-leukotriene-1 (cys-LT(1)) receptor antagonist, zarfirlukast, during feline endotoxemia. Six adult, sexually intact male cats received either placebo or zarfirlukast (10mg, PO) and endotoxin (2 MUg/kg/h q 6h) in a cross-over design. Rectal temperature, heart rate, systolic arterial blood pressure, plasma tumor necrosis factor (TNF) activity, interleukin (IL)-6 concentration and urine cys-LT to creatinine ratio were evaluated. The rectal temperature, plasma TNF activity and IL-6 concentrations were significantly higher and systolic arterial blood pressure and heart rate significantly lower after endotoxin infusion. Cats treated with zafirlukast had a significantly higher blood pressure at 4h (P=0.002) compared to placebo. Urine cys-LT to creatinine ratio was significantly greater in the cats treated with zafirlukast compared to placebo (P=0.02). Zafirlukast administration ameliorated the acute hypotensive response to endotoxin in cats, but failed to significantly alter rectal temperature, heart rate or production of TNF and IL-6. PMID- 20719553 TI - Ultrasound promoted synthesis of quinolines using basic ionic liquids in aqueous media as a green procedure. AB - The basic ionic liquid (BIL) based on imidazolum cation efficiently catalyzes the condensation reaction of isatin with ketones by ultrasonic irradiation in aqueous media for quinoline synthesis. When two different alpha-protons are available in a ketone, a mixture of two quinolines is obtained. In this method, one of the quinolines with high selectivity is produced. Another significant advantage of this method is omission of subsidiary reactions, such as aldol condensation. Compared with conventional methods, the main advantages of the present procedure are its being a green method, its milder conditions, necessary shorter reaction time, and its higher yields and selectivity without the need for a transition metal catalyst. The use of BILs and ultrasound promoted this protocol under room temperature. By changing the type of BILs, ultrasonic irradiation time, and ultrasonic frequency, synthesis of quinolines is manageable. PMID- 20719554 TI - Acute homocysteine rise after repeated levodopa application in patients with Parkinson's disease. PMID- 20719555 TI - Neighbourhood design and fear of crime: a social-ecological examination of the correlates of residents' fear in new suburban housing developments. AB - This study explored the relationship between neighbourhood design and residents' fear of crime in new suburban housing developments. Self-report and objective data were collected as part of the RESIDential Environments (RESIDE) Project. A neighbourhood form index based on the planning and land-use characteristics that draw people into public space, facilitate pedestrian movement and ensure the presence of 'territorial guardians' was developed for each participant (n=1059) from objective environmental data. With each additional index attribute, the odds of being fearful reduced (trend test p value=0.001), and this persisted even after progressive adjustment for demographics, victimisation, collective efficacy and perceived problems. The findings support the notion that a more walkable neighbourhood is also a place, where residents feel safer, and provides further evidence endorsing a shift away from low density, curvilinear suburban developments towards more walkable communities with access to shops, parks and transit. PMID- 20719556 TI - Spatial and sex differences in AIDS mortality in Chiang Rai, Thailand. AB - Aggregate mortality data do not tell us if AIDS mortality is uniformly reduced or if there is spatial differentiation. A total of 2432 male and 1864 female deaths (2000-2004) from AIDS in Chiang Rai are used to detect mortality clusters. Both male and female clusters are more or less in the same location implying similar risk factors; however, male clusters remain more prevalent as male patients are likely to be slower in getting treatment. The findings indicate non-random clustering and confirm that although mortality rates are significantly reduced in most areas some sub-districts need attention for follow-up public health efforts. PMID- 20719557 TI - Epidemiology of hand, foot, and mouth disease and genotype characterization of Enterovirus 71 in Jiangsu, China. AB - BACKGROUND: In the spring of 2008, an EV71-caused hand, foot, and mouth disease (HFMD) outbreak occurred in Fuyang city, Anhui Province, China. Jiangsu Province that borders Auhui to the east is presumed as a key station for the spread of EV71 to other regions of the Yangtze River Delta. OBJECTIVES: To investigate the HFMD prevalence in Zhenjiang city of Jiangsu from May 2008 to October 2009, and the epidemic origin of EV71 circulating in Jiangsu. STUDY DESIGN: During May 2008 and October 2009, a total of 6324 HFMD cases in Zhenjiang, Jiangsu, were investigated. Sixty throat specimens were randomly selected from different patients, and 28 nucleotide sequences of EV71 VP1 regions were successfully determined by RT-nested-PCR and sequencing. EV71 genotypes were characterized by phylogenetic analyses. RESULTS: The incidence rate of HFMD was highest in the period of March-July and in the 1-4 years old age groups. Intriguingly, there was a slight predominance for boys and for children living in rural areas in HFMD infection. Phylogenetic analyses indicated that all Jiangsu EV71 strains and most China strains belonged to subgenotype C4a. CONCLUSION: The C4a was the most prominent EV71 subgenotype circulating in China. Routine HFMD surveillance should be focused on the period of March-July, and more prevention efforts should be aimed at 1-4 years old children. Moreover, government efforts are urgently needed to improve public health condition and medical service quality in rural areas. PMID- 20719558 TI - Test-retest reliability of the speech-evoked auditory brainstem response. AB - OBJECTIVE: The speech-evoked auditory brainstem response (ABR) provides an objective measure of subcortical encoding of complex acoustic features. However, the intrasubject reliability of this response in both optimal and challenging listening conditions has not yet been systematically documented. This study aimed to evaluate test-retest reliability of the speech-evoked ABR in young adults. METHODS: In each of two sessions, ABRs were obtained with: (1) a 170 ms /da/ syllable presented in quiet as well as 2-talker and 6-talker babble background noise conditions and (2) a 40 ms /da/ syllable presented in quiet. Test-retest reliability of the responses was analyzed in the frequency and time domains. RESULTS: The speech-evoked ABR does not vary significantly across sessions within individuals on measures of temporal encoding (i.e., peak latencies, stimulus-to response and response-to-response measures), frequency representation and response magnitude. CONCLUSIONS: The subcortical auditory pathway produces a response to a complex sound that is stable and replicable from session to session. SIGNIFICANCE: By demonstrating the high degree of replicability in optimal and challenging listening conditions, the applicability of the speech evoked ABR may be increased to examining a range of auditory processing abilities in clinical and research settings. PMID- 20719559 TI - Development of neonatal seizure detectors: an elusive target and stretching measuring tapes. PMID- 20719560 TI - Application of nonlinear dynamics analysis in assessing unconsciousness: a preliminary study. AB - OBJECTIVES: To quantify the degree of unconsciousness with EEG nonlinear analysis and investigate the change of EEG nonlinear properties under different conditions. METHODS: Twenty-one subjects in persistent vegetative state (PVS), 16 in minimally conscious state (MCS) and 30 normal conscious subjects (control group) with brain trauma or stroke were involved in the study. EEG was recorded under three conditions: eyes closed, auditory stimuli and painful stimuli. EEG nonlinear indices such as Lempel-Ziv complexity (LZC), approximate entropy (ApEn) and cross-approximate entropy (cross-ApEn) were calculated for all the subjects. RESULTS: The PVS subjects had the lowest nonlinear indices followed by the MCS subjects and the control group had the highest. The PVS and MCS group had poorer response to auditory and painful stimuli than the control group. Under painful stimuli, nonlinear indices of subjects who recovered (REC) increased more significantly than non-REC subjects. CONCLUSIONS: With EEG nonlinear analysis, the degree of suppression for PVS and MCS could be quantified. The changes of brain function for unconscious subjects could be captured by EEG nonlinear analysis. SIGNIFICANCE: EEG nonlinear analysis could characterise the changes of brain function for unconscious state and might have some value in predicting prognosis of unconscious subjects. PMID- 20719561 TI - Masseter muscle function after percutaneous balloon compression of trigeminal ganglion for the treatment of trigeminal neuralgia: a neurophysiological follow up study. AB - OBJECTIVE: We aimed to evaluate by longitudinal neurophysiological examinations the natural course of masseter muscle weakness that developed after percutaneous balloon compression (PBC) of the trigeminal ganglion for the treatment of idiopathic trigeminal neuralgia. METHODS: The affected side of 15 patients (mean age 69.5+/-4.5 years) who underwent unilateral PBC were studied before, 1 month, 6 months and 12 months after surgery by means of: (1) motor evoked potentials (MEPs) of the masseter muscle elicited by transcranial magnetic stimulation of the contralateral motor cortex and of the ipsilateral trigeminal motor branch; and (2) concentric needle electromyography of masseter muscle. RESULTS: The latencies of MEPs' to cortical and nerve stimulation became significantly prolonged 1 month after PBC, whereas, thereafter, they demonstrated a gradual shortening towards preoperative values. The interference electromyographic pattern 1 month post-PBC study was reduced in all patients, but it improved in follow-up, returning 12-months postoperatively to complete in 13 and nearly complete in two patients. CONCLUSION: Masseter muscle weakness should be expected in all cases after PBC of the trigeminal ganglion. SIGNIFICANCE: As verified by repeated studies, the results of which favoured a focal demyelination process of trigeminal motor branch, muscle dysfunction appears to be reversible over a period of 6-12 months. PMID- 20719562 TI - Current trends in biodegradable polyhydroxyalkanoates. AB - The microbial polyesters known as polyhydroxyalkanoates (PHAs) positively impact global climate change scenarios by reducing the amount of non-degradable plastic used. A wide variety of different monomer compositions of PHAs has been described, as well as their future prospects for applications where high biodegradability or biocompatibility is required. PHAs can be produced from renewable raw materials and are degraded naturally by microorganisms that enable carbon dioxide and organic compound recycling in the ecosystem, providing a buffer to climate change. This review summarizes recent research on PHAs and addresses the opportunities as well as challenges for their place in the global market. PMID- 20719563 TI - Does CPAP treatment in mild obstructive sleep apnea affect blood pressure? AB - OBJECTIVES: Obstructive sleep apnea (OSA) is associated with significant cardiovascular (CV) morbidity. Continuous positive airway pressure (CPAP) is the standard treatment for moderate to severe OSA, resulting in a reduction in CV morbidity. No studies have compared CV outcomes between CPAP and no CPAP in mild OSA (5>or=AHI<15). METHODS: Retrospective cohort study of subjects (age>or=18) with mild OSA diagnosed between 2004 and 2006. Subjects with a history of hypertension, angina, stroke and smoking were excluded. Subjects were stratified into two groups: CPAP (n=93) or no CPAP (n=162). The mean blood pressures (MBP) were compared 2 years after the diagnosis of OSA was established. RESULTS: Unmatched for covariates (age, sex, BMI, neck circumference, AHI, arousal index and family h/o CV disorders), subjects with mild OSA on CPAP had a 1.97 point reduction, and no CPAP resulted in a 9.61 point elevation (p<0.0001) in MBP. With propensity score matching for covariates, the mean difference in MBP was -1.97 (95% CI: -14.03, -9.92; p<0.0001) with a sensitivity analysis of 2.646. CONCLUSION: This study shows an elevation of the MBP in mild OSA patients who were not treated with CPAP. CPAP treatment in mild OSA patients decreased the MBP over a 2-year period. PMID- 20719565 TI - Analysis of the products of cryoprecipitation: RiCoF is deficient in cryosupernatant plasma. AB - INTRODUCTION: Cryoprecipitate and its byproduct, cryosupernatant plasma (CSP) have been used to treat specific medical diseases such as hemophilia, von Willebrand disease and thrombotic thrombocytopenia purpura. Cryoprecipitate is also widely used to prepare fibrin glue. In many instances, it is given to augment fresh frozen plasma when patients are bleeding. However, the full range of constituents of cryoprecipitate and CSP are not widely appreciated. METHODS: To determine the concentration of the various constituents in plasma and its frozen fractions, we measured levels of Factor VIII, von Willebrand factor antigen, fibrinogen, Factor V, ATIII, functional and antigenic proteins C and S, plasminogen, Total protein, fibronectin, Factor XIII, RiCoF and von Willebrand factor multimers in the starting plasma, the cryoprecipitate and the CSP produced from the plasma in each of the blood groups. RESULTS: While only 4% of the plasma proteins cryoprecipitate, there is considerable enrichment of Factor VIII, von Willebrand factor and RiCoF. However, cryoprecipitate contains only 27% of the plasma fibrinogen and has low levels of Factor V, protein S, protein C, ATIII and plasminogen. Factor VIII and von Willebrand factor are much reduced in the cryosupernatant plasma (0.20 U/ml and 0.16 U/ml) and there is virtually no ristocetin cofactor activity. This is consistent with the absence of the higher molecular weight multimers of VWF found in CSP. The ADAMTS-13 levels are the same as in plasma. All levels vary between blood groups. CONCLUSIONS: While cryoprecipitate is relatively enriched in certain factors, the process does not result in concentration of other coagulation factors so cryoprecipitate cannot be used for the replacement of protein C, protein S or Factor V. SCP is deficient in RiCoF. PMID- 20719564 TI - Acute myocardial rescue with endogenous endothelial progenitor cell therapy. AB - PURPOSE: Post-myocardial infarction heart failure is a major health concern with limited therapy. Molecular revascularisation utilising granulocyte-macrophage colony stimulating factor (GMCSF) mediated endothelial progenitor cell (EPC) upregulation and stromal cell derived factor-1alpha (SDF) mediated myocardial EPC chemokinesis, may prevent myocardial loss and adverse remodelling. Vasculogenesis, viability, and haemodynamic improvements following therapy were investigated. PROCEDURES: Lewis rats (n=91) underwent LAD ligation and received either intramyocardial SDF and subcutaneous GMCSF or saline injections at the time of infarction. Molecular and haemodynamic assessments were performed at pre determined time points following ligation. FINDINGS: SDF/GMCSF therapy upregulated EPC density as shown by flow cytometry (0.12+/-0.02% vs. 0.06+/-0.01% circulating lymphocytes, p=0.005), 48hours following infarction. A marked increase in perfusion was evident eight weeks after therapy, utilising confocal angiography (5.02+/-1.7*10(-2)MUm(3)blood/MUm(3)myocardial tissue vs. 2.03+/ 0.710(-2)MUm(3)blood/MUm(3)myocardial tissue, p=0.00004). Planimetric analysis demonstrated preservation of wall thickness (0.98+/-0.09mm vs. 0.67+/-0.06mm, p=0.003) and ventricular diameter (7.81+/-0.99mm vs. 9.41+/-1.1mm, p=0.03). Improved haemodynamic function was evidenced by echocardiography and PV analysis (ejection fraction: 56.4+/-18.1% vs. 25.3+/-15.6%, p=0.001; pre-load adjusted maximal power: 6.6+/-2.6mW/MUl(2) vs. 2.7+/-1.4mW/MUl(2), p=0.01). CONCLUSION: Neovasculogenic therapy with GMCSF-mediated EPC upregulation and SDF-mediated EPC chemokinesis maybe an effective therapy for infarct modulation and preservation of myocardial function following acute myocardial infarction. PMID- 20719566 TI - Complete androgen insensitivity syndrome: an anatomic evaluation and sexual function questionnaire pilot study. AB - PURPOSE: To further characterize the anatomy and sexual function of women with CAIS compared to normal females, and assess the utility of magnetic resonance imaging (MRI) to distinguish anatomical differences. MATERIALS AND METHODS: In a prospective cohort pilot study, five individuals with androgen insensitivity syndrome and six, normal, nulliparous women underwent an interview, physical examination, questionnaire completion and MRI of the pelvis. Statistical analysis was performed with emphasis on determining significant differences in anatomical findings and sexual satisfaction. RESULTS: MRI demonstrated statistically significant differences in vaginal depth and size that were not confirmed on physical exam. MRI and physical exam demonstrated a non-significant difference in average phallic thickness between the two groups, although the CAIS group clitoral width tended to be smaller. Physical exam demonstrated a higher average erect height and longer arm span in the CAIS patients but this was not statistically significant. No significant differences were noted in categories designed to assess satisfaction with ability to achieve orgasm, vaginal appearance and frequency of sexual intercourse between the two groups. CONCLUSIONS: The women with CAIS were as satisfied with sexual function as were the women within the control group. Physical exam and MRI did not find any statistically significant clinically relevant differences between the two groups. PMID- 20719567 TI - Adolescent girls with disorders of sex development: A needs analysis of transitional care. AB - OBJECTIVE: To collect information on clinical concerns relating to adolescent girls with disorders of sex development (DSD) during the process of transition from paediatric-to-adult clinical services. SUBJECTS AND METHODS: This was a prospective audit of the clinical indications for referral and on-going clinical needs for all girls aged 12-20 years seen in a specialist DSD clinic over a 6 month period. Clinical needs were classified according to level of urgency using a simple 'traffic light' classification: green for low, amber for moderate, and red for high. RESULTS: Fifty girls were seen during the study period and all were referred from paediatric services. Patients may have had one or more indication(s) for referral to the adult clinic and these were: urology/gynaecology (70%), endocrinology (42%) and psychology (14%). The most common indication for on-going clinical input was psychology, with 46% of patients requiring monitoring and intervention. Of the 14 patients (28%) classified red suggesting they had an urgent clinical need, psychology was a major factor in all but one patient. CONCLUSION: Clinicians working with adolescents with DSD need to develop a co-ordinated programme for transitional care that recognises the importance of psychological input within the multi disciplinary team. PMID- 20719568 TI - Executive cognitive function and food intake in children. AB - OBJECTIVE: The current study investigated relations among neurocognitive skills important for behavioral regulation, and the intake of fruit, vegetables, and snack food in children. DESIGN: Participants completed surveys at a single time point. SETTING: Assessments took place during school. PARTICIPANTS: Participants were 107 fourth-grade children from a large US city. Ninety-one percent were Latino, and 4% were African-American, which represented school ethnic distribution. MAIN OUTCOME MEASURE(S): Independent variable included was self reported executive cognitive function (ECF). Dependent variables included self reported fruit, vegetable, and snack food intake. ANALYSES: Primary analyses general linear regression models covarying for appropriate demographic variables. RESULTS: Analyses demonstrated that ECF proficiency was negatively related to snack food intake, but was not significantly related to fruit and vegetable intake. CONCLUSIONS AND IMPLICATIONS: Since ECF is correlated with snack food intake, future studies may consider assessing the potential of enhancing ECF in health promotion interventions. PMID- 20719569 TI - Natural killer cell receptor--repertoire and functions after induction therapy by polyclonal rabbit anti-thymocyte globulin in unsensitized kidney transplant recipients. AB - Polyclonal rabbit anti-thymocyte globulin (rATG) is widely used in solid organ transplantation (SOT) as induction therapy or to treat corticosteroid-resistant rejection. In vivo, the effect of rATG on natural killer (NK) cells has not been studied. These cells are of particular relevance after SOT because classical immunosuppressive drugs do not inhibit or even can activate NK cells. A cohort of 20 recipients at low immunological risk, that had been receiving rATG as induction therapy, was analyzed for receptor repertoire, cytotoxicity and capacity of NK cells to secrete IFN-gamma before kidney transplantation and at different time points thereafter. NK cells expressed fewer killer-cell immunoglobulin-like receptors (KIR), fewer activating receptors NKG2D, but more inhibitory receptor NKG2A compatible with an immature phenotype in the first 6 months post transplantation. Both cytotoxicity of NK cells and the secretion of IFN-gamma were preserved over time after transplantation. PMID- 20719570 TI - Benign childhood epilepsy with centrotemporal spikes and the multicomponent model of attention: a matched control study. AB - Although the high risk of cognitive impairments in benign childhood epilepsy with centrotemporal spikes (BCECTS) is now well established, there is no clear definition of a uniform neurocognitive profile. This study was based on a neuropsychological model of attention that assessed various components of attention in 21 children with BCECTS and 21 healthy children. All participants were tested with a computerized test battery using the multicomponent model of attention performance. In comparison with healthy participants, the children with BCECTS showed significant impairment in the measure of selectivity and in one measure of intensity of attention (arousal). Our results did not correlate with the electroclinical variables of age at onset of seizures and spike index on sleep EEGs. To the best of our knowledge, this is the first study in which the multicomponent model of attentional function has been used in children with BCECTS to provide a clearer neuropsychological profile of these patients. PMID- 20719571 TI - Introduction and first validation of EpiTrack Junior, a screening tool for the assessment of cognitive side effects of antiepileptic medication on attention and executive functions in children and adolescents with epilepsy. AB - OBJECTIVE: Maximum seizure control, preservation of cognition, and prevention of developmental hindrance are major aims of the pharmacological treatment of children and adolescents with epilepsy. Herewith we introduce the junior version of EpiTrack, a 12- to 15-minute screening test for monitoring the cognitive effects of antiepileptic drug treatment in children and adolescents aged 6 to 18. METHODS: The test, which comprises six subtests (Speed, Flexibility, Planning, Response Inhibition, Word Fluency, Working Memory), was administered to 277 children and adolescents aged 6-18 years, 111 of whom were retested after an interval of 3 months. For the first clinical validation, 155 patients (46% idiopathic/benign, 62% seizure free) were evaluated. RESULTS: Standardization and correction for age resulted in a mean score of 33 +/- 2 points, which was no longer correlated with age (r=0.005). The retest practice effect was 0.7 +/- 2 points, and the reliability r(tt)=0.78. Factor analysis indicated one executive factor in controls and patients. In the epilepsy group, 50% of the patients were impaired (controls 14%). Number of antiepileptic drugs, use/no use of individual drugs, type of epilepsy, earlier age at onset, generalized tonic-clonic seizures, and history of febrile seizures made a difference in test performance. For patients and controls, EpiTrack scores reflected parents' performance ratings and the children's needs for extra education. CONCLUSION: The junior version of EpiTrack appears to be a valid and reliable screening tool for the assessment of executive functions in children and adolescents. Future studies with a repeated measurement design must show how well this tool is suited for the tracking of cognitive effects of antiepileptic drug treatment. PMID- 20719572 TI - The relationships among medicine symptom distress, self-efficacy, patient provider relationship, and medication compliance in patients with epilepsy. AB - The purpose of this study was to investigate the relationships among medicine symptom distress, self-efficacy, patient-provider relationship, and medication compliance in patients with epilepsy. Patients with epilepsy (n=357) were recruited using convenience sampling from three medical centers in northern Taiwan. Results showed significant differences in relationships between medication compliance and the following factors: gender, employment status, comorbid chronic diseases, self-driving, daily drug dosing frequency, seizure after a missed dose, and self-efficacy. Logistic regression analysis indicated that comorbid chronic disease, self-driving, seizure after a missed dose, and self-efficacy were significantly associated with medication compliance. These data suggest that health care providers of patients with epilepsy pay more attention to treatment of comorbid chronic diseases, the safety issues of self driving, seizures occurring after missed doses, and awareness of self-efficacy. PMID- 20719573 TI - Will the new antiseizure devices fill the gap between drugs and surgery? Treating the brain as a "black box". AB - An informed answer to the question Will the new antiseizure devices fill the gap between drugs and surgery? requires that the therapeutic ratio and the devices' capacity to cost-effectively decrease disease burden globally be considered. Regarding therapeutic ratio, the answer is likely Yes, if and only if, and at a minimum, all relevant seizure variables are quantified, the spatiotemporal behavior of seizures at short and long time scales is better understood, and statistical analyses of efficacy conform to and address the multidimensional, complex nature of seizures. Regarding the capacity of devices to cost-effectively decrease disease burden globally, the answer is likely No, unless: (1) cost effectiveness is demonstrable and maximal, which requires that devices become the sole therapy; (2) seizure comorbidities are prevented or their seriousness is reduced; (3) patients with pharmacoresistant seizures may rejoin society's mainstream; and (4) disruptive (revolutionary) conceptual and technological advances materialize. PMID- 20719574 TI - Treatment strategies in the postictal state. AB - Postictal behaviors and symptoms often require special assessment and treatment. We review risk factors for postictal delirium and psychosis and management of agitated and confused behaviors in patients after seizures. Medical and emergency staff require careful training to manage behaviors associated with postictal delirium and psychosis in order to protect patients while their confusion resolves. Treatment of postictal states requires recognition of underlying neurological and systemic disorders associated with seizures and delirium such as metabolic disorders and nonconvulsive seizures. There is incomplete information about the causes and optimal treatments for seizure-related psychosis, however, postictal behaviors can usually be managed safely. PMID- 20719575 TI - Reirradiation of head and neck cancer with high-dose-rate brachytherapy: a customizable intraluminal solution for postoperative treatment of tracheal mucosa recurrence. AB - PURPOSE: Delivering adequate dose to tracheal mucosa recurrence after multiple prior courses of surgery and radiation presented a challenge for radiation delivery. Tumor bed location and size, combined with previous doses to surrounding areas, complicated the use of external beam therapy with either photons or electrons. High-dose-rate (HDR) brachytherapy was explored to provide sufficient dose coverage. METHODS AND MATERIALS: A 45-year-old gentleman presented with recurrent head and neck cancer. After undergoing additional excision of gross tumor in the tracheal region, radiation was recommended to improve local control. The region of residual tumor was confined to a small superficial lesion at the posterior-superior aspect of the trachea, involving mucosa located along the bend of the trachea, immediately deep to the stoma. External beam treatment was discussed but was not recommended based on recurrence location in the prior radiation field and patient's flexed chin position. HDR technique with a custom applicator was preferred. RESULTS: A three-dimensional HDR plan based on computed tomography used a single catheter optimized to cover gross tumor volume as delineated by physician. Prescribed dose was 5 Gy/fraction for six fractions (two fractions/wk). The applicator position was verified daily with computed tomography and physician setup approval before treatment. The patient was positioned on a wing board to allow access to the stoma. HDR brachytherapy was well tolerated. CONCLUSIONS: Intraluminal HDR brachytherapy is a viable option for providing dose to region inside tracheal stoma. Advantages over photon and electron beam therapy include reduced dose to surrounding tissues previously irradiated, skin dose, and reproducibility of treatment delivery. PMID- 20719576 TI - Accelerated partial breast irradiation using the strut-adjusted volume implant single-entry hybrid catheter in brachytherapy for breast cancer in the setting of breast augmentation. AB - PURPOSE: Accelerated partial breast irradiation (APBI) has gained popularity as an alternative to adjuvant whole breast irradiation; however, owing to limitations of delivery devices for brachytherapy, APBI has not been a suitable option for all the patients. This report evaluates APBI using the strut-adjusted volume implant (SAVI) single-entry catheter to deliver brachytherapy for breast cancer in the setting of an augmented breast. METHODS AND MATERIALS: The patient previously had placed bilateral subpectoral saline implants; stereotactic core biopsy revealed estrogen receptor- and progesterone receptor-positive ductal carcinoma in situ of intermediate nuclear grade. The patient underwent needle localized segmental mastectomy of her left breast; pathologic specimen revealed no residual malignancy. An SAVI 8-1 device was placed within the segmental resection cavity. Treatment consisted of 3.4 Gy delivered twice a day for 5 days for a total dose of 34 Gy. Treatments were delivered with a high-dose-rate (192)Ir remote afterloader. RESULTS: Conformance of the device to the lumpectomy cavity was excellent at 99.2%. Dosimetric values of percentage of the planning target volume for evaluation receiving 90% of the prescribed dose, percentage of the planning target volume for evaluation receiving 95% of the prescribed dose, volume receiving 150% of the prescribed dose, and volume receiving 200% of the prescribed dose were 97.1%, 94.6%, 22.7 cc, and 11.6 cc, respectively. Maximum skin dose was 115% of the prescribed dose. The patient tolerated treatment well with excellent cosmetic results, and limited acute and late toxicity at 8 weeks and 6 months, respectively. CONCLUSIONS: Breast augmentation should not be an exclusion criterion for the option of APBI. The SAVI single-entry catheter is another option to successfully complete APBI using brachytherapy for breast cancer in the setting of an augmented breast. PMID- 20719577 TI - Isolated noradrenergic failure in adult-onset autosomal dominant leukodystrophy. AB - We evaluated the autonomic control of the cardiovascular system and the skin innervation of a patient from a new Italian family with a genetically proven diagnosis of adult-onset autosomal dominant leukodystrophy (ADLD) due to lamin B1 gene duplication. Cardiovascular reflexes and pharmacological assessment indicated a selective sympathetic failure, sparing cardiovagal function. Microneurography revealed absent sympathetic activity. The evaluation of autonomic innervation of skin annexes showed severely depleted and morphologically abnormal noradrenergic dopamine-beta-hydroxylase (DbetaH) immunoreactive fibres with preserved cholinergic vasoactive intestinal polypeptide (VIP) immunoreactive fibres. This peculiar autonomic dysfunction may represent a hallmark for ADLD. PMID- 20719578 TI - Hypercholesterolemia magnitude increases sympathetic modulation and coagulation in LDLr knockout mice. AB - We investigated the effects of low lipoprotein receptor deficiency in cholesterol blood concentrations, blood pressure, hemostatic factors, and the autonomic nervous system in three groups: control mice fed standard diet (CO, n=9), lipoprotein receptor-deficient mice (LDLr(-/-), n=9) fed standard diet (LDLr-S) or hypercholesterolemic diet (LDLr-H, n=8). Frequency domain analysis of heart rate and blood pressure variability was performed with an autoregressive algorithm. The spectral components were expressed in absolute (s(2) or mmHg(2)) and normalized units. Spontaneous baroreflex sensitivity (BRS) was estimated by alpha index, defined as square root ratio between low frequency power in blood pressure variability and heart rate variability. LDLr/- mice presented a significant increase in the cholesterol blood concentration (mean+/-SD; mg/dl; LDLr-S=202.01+/-34.38 and LDLr-H=530.7+/-75.17) compared to CO (79.2+/-13.6), p=0.001. The receptor deletion was associated with a heart rate variability reduction (p=0.013). The BRS was reduced (p<0.05) in LDLr-S and LDL-H (mean+/-SD: 0.96+/-0.39 and 0.59+/-0.34, respectively) compared to CO (4.02+/-1.92). Moreover, hypercholesterolemic diet significantly increased the cardiac sympathetic modulation (0V pattern of symbolic analysis: mean+/-SD, CO=8.04+/ 4.53; LDLr-S=16.49+/-4.52 and LDLr-H=21.80+/-8.24, p=0.006). The 0V pattern was statically correlated to coagulation factor VII (r=0.555, p=0.0208). In LDLr-H, the concentration (interquartile range) of plasmatic fibrinogen and hemostatic factors VII (2.8-3.3) and XII (1.1-1.3) were increased compared to CO (0.9-1.1and 0.9-1.0, respectively) and LDLr-S (0.7-1.0 and 0.8-0.9, respectively) (p<0.004 for FVII and p<0.006 for FXII). Taken together, the results indicate that plasmatic cholesterol magnitude is determinant to increase the coagulation and the sympathetic modulation. PMID- 20719579 TI - Acute superoxide scavenging restores depressed baroreflex sensitivity in renovascular hypertensive rats. AB - In some pathological conditions such as hypertension, there is an impairment in the autonomic control of blood pressure resulting in changes in baroreflex sensitivity. In the present study we tested the hypothesis that acute superoxide scavenging would restore the reduced baroreflex sensitivity in renovascular hypertension. Male Wistar rats underwent 2-Kidney-1-Clip (2K1C) or sham surgery and were maintained untouched for six weeks to develop hypertension. After six weeks, animals from the 2K1C group were hypertensive when compared to the sham group (165+/-9 vs. 108+/-7mm Hg, P<0.05). As a proof of principle for the hypertension model adopted, animals from the 2K1C group presented increased non clipped kidney and cardiac mass index and reduced clipped kidney mass index. Regarding baroreflex, 2K1C rats presented diminished baroreflex sensitivity when compared to the sham group (2K1C+saline: -1.61+/-0.15 vs. sham+saline: -2.79+/ 0.24bpm mm Hg(-1), p<0.05). Moreover, acute administration of Vitamin C (150mg/Kg, i.v.) restored baroreflex sensitivity in 2K1C rats (2K1C+Vit C: 3.08+/-0.37 vs. 2K1C+saline: -1.61+/-0.15bpm mm Hg(-1), p<0.05). Furthermore, administration of apocynin (30MUg/Kg, i.v.), a NADPH oxidase inhibitor, also improved baroreflex sensitivity in the 2K1C group (2K1C+apocynin: -2.81+/-0.24 vs. 2K1C+saline: -1.61+/-0.15bpm mm Hg(-1), p<0.05). In addition, autonomic blockade with either methylatropine or propranolol reduced the changes in heart rate to the same extent in all groups suggesting that improved baroreflex sensitivity by antioxidants were mediated by improvement in autonomic function. Taken together, these data suggest that NADPH oxidase-derived reactive oxygen species are involved in the blunted baroreflex sensitivity in renovascular hypertension and that acute scavenging of superoxide restores baroreflex sensitivity. PMID- 20719581 TI - Development and validation of a nylon6 nanofibers mat-based SPE coupled with HPLC method for the determination of docetaxel in rabbit plasma and its application to the relative bioavailability study. AB - A simple and sensitive HPLC method was established and validated for the determination of docetaxel (DTX) in rabbit plasma. Biosamples were spiked with paclitaxel (PCX) as an internal standard (I.S.) and pre-treated by solid-phase extraction (SPE). The SPE procedure followed a simple protein digestion was based on nylon6 electrospun nanofibers mats as sorbents. Under optimized conditions, target analytes in 500 microL of plasma sample can be completely extracted by only 2.5mg nylon6 nanofibers mat and eluted by 100 microL solvent. The HPLC separation was obtained on C18 column and UV detector was used to quantify the target analytes. The extraction recovery was more than 85%; the standard curve was linear over the validated concentrations range of 10-5000 ng/mL and the limit of detection was 2 ng/mL. The inter-day coefficient of variation (CV%) of the calibration standards was below 5.0% and the mean accuracy was in the range of 92.8-113.4%. Moreover, analysing quality control plasma samples in 3 days, the results showed that the method was precise and accurate, for the intra- and inter day CV% within 10% and the accuracy from 96.0% to 114.0%. The developed and validated method was successfully applied to relative bioavailability study for the preclinical evaluation of a new injectable DTX-sulfobutyl ether beta cyclodextrin (DTX-SBE-beta-CD) inclusion complex freeze-dried powder (test preparation), compared with the reference preparation (DTX injection, Taxotere) in healthy rabbits. On the basis of the mean AUC(0-t) and AUC(0-infinity), the relative bioavailability of the test preparation was found to be 113.1%. PMID- 20719580 TI - Measurement of menadione in urine by HPLC. AB - Menadione is a metabolite of vitamin K that is excreted in urine. A high performance liquid chromatography (HPLC) method using a C(30) column, post-column zinc reduction and fluorescence detection was developed to measure urinary menadione. The mobile phase was composed of 95% methanol with 0.55% aqueous solution and 5% DI H(2)O. Menaquinone-2 (MK-2) was used as an internal standard. The standard calibration curve was linear with a correlation coefficient (R(2)) of 0.999 for both menadione and MK-2. The lower limit of quantification (LLOQ) was 0.3pmole menadione/mL urine. Sample preparation involved hydrolysis of menadiol conjugates and oxidizing the released menadiol to menadione. Using this method, urinary menadione was shown to increase in response to 3 years of phylloquinone supplementation. This HPLC method is a sensitive and reproducible way to detect menadione in urine. PMID- 20719582 TI - Development of an LC-MS/MS assay to determine plasma pharmacokinetics of the radioprotectant octadecenyl thiophosphate (OTP) in monkeys. AB - Octadecenyl thiophosphate (OTP), a synthetic analogue of the lysophospholipid growth factor lysophosphatidic acid (LPA), significantly reduces mortality following a lethal dose of LD(80/30) radiation exposure in a mouse model of whole body irradiation. To facilitate dose scaling between species, we developed a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) for the preclinical pharmacokinetic characterization of OTP in monkeys. Sample extraction was carried out using a butanol based liquid-liquid extraction method. A partially deuterated OTP analogue was used as internal standard (IS). OTP and IS were separated by reversed-phase liquid chromatography on a C-8 column using 10mM ammonium acetate and acetonitrile. A triple quadrupole mass spectrometer operating in the negative electrospray ionization mode with multiple reaction monitoring was used to detect OTP and IS transitions of m/z 363.1-->95.0 and 403.1-->95.0. The method was applied to determine pharmacokinetic parameters in monkeys receiving a single oral OTP dose (3mg/kg). OTP is readily absorbed with a relatively long half-life which supports further preclinical testing of OTP as a radioprotectant in monkeys. PMID- 20719583 TI - Analysis of the antiviral drugs acyclovir and valacyclovir-hydrochloride in tsetse flies (Glossina pallidipes) using LC-MSMS. AB - A new simple, sensitive and precise liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of valacyclovir-HCl and acyclovir in tsetse flies (Glossina pallipides). Tsetse flies were extracted by ultrasonication with acidified methanol/acetonitrile, centrifuged and cleaned up by solid phase dispersion using MgSO(4) and MSPD C(18) material. Samples were analysed using a Waters Alliance 2695 series HPLC with a C(18) Gemini analytical column (150 mm x 4.6 mm x 5 microm) and a guard cartridge column connected to a Waters Quattro-Micro triple-quadrupole mass spectrometer. The isocratic mobile phase consisted of methanol:acetonitrile:water (60:30:10, v/v/v) plus formic acid (0.1%) at a flow rate of 0.25 ml/min. The precursor>product ion transition for valacyclovir (m/z 325.1>152) and acyclovir (m/z 226.1>151.9) were monitored in positive electrospray multiple reaction monitoring mode. The method was validated at fortification levels of 0.5, 1 and 2 microg/g. The range of calibration for both drugs was 0.45-4.5 microg/g. The overall accuracy of the method was 92% for valacyclovir and 95% for acyclovir with corresponding within-laboratory reproducibilities of 4.4 and 3.4%, respectively. Mean recoveries were above 80% for both drugs and repeatability ranged from 0.7 to 6.1%. For both drugs the limits of detection and quantification were 0.0625 and 0.2 microg/g, respectively. The method was applied in experiments on the mass rearing of tsetse flies for sterile insect technique (SIT) applications, in which the flies were fed with blood meals containing acyclovir or valcyclovir-HCl prior to analysis to assess effects on Glossina pallidipes Salivary Gland Hypertrophy syndrome. PMID- 20719584 TI - Did African Americans experience the 'Antebellum Puzzle'? Evidence from the United States Colored Troops during the Civil War. AB - The "Antebellum Puzzle" has been the subject of comment since the 1980s. It involves the paradox that, although the American economy was experiencing rapid economic growth in the several decades prior to the Civil War (1861-1865), the stature of native-born white males had been declining for the birth cohorts from the late 1820s. This was also true for free blacks (Komlos, 1992), but was apparently not true for slaves. This paper uses a sample of 8592 adult back males who were recruits to the United States Colored Troops during the Civil War. They were recruited significantly among ex-slaves. Recruits from the birth cohorts of 1838-1842 were then linked to characteristics of their counties of birth from the 1840 and 1850 U.S. Censuses. Unlike slaves in the coastal manifests, these African American recruits showed evidence of a decline in heights from the birth cohorts of the 1820s onwards. Unlike the native-white recruits, however, the characteristics of their counties of birth had relatively less power in explaining differences in heights. There was some support for the mortality hypothesis, but the nutrition hypothesis needs to be interpreted in light of the fact that slave owners has a strong interest in monitoring and controlling the diet of their slaves. PMID- 20719586 TI - Clinical inertia in management of T2DM. AB - Diabetes is highly prevalent and serious chronic debilitating disease and reported to be the fourth main cause of death in Europe. Despite extensive evidence of benefits of tight glycemic control, large proportions of people with diabetes do not achieve target glycemic control. One major reason for this is clinical inertia which is "recognising the problem but failure to act" by health care professionals in primary care. The key issues in the management of people with T2DM include early detection of problems, realistic goal setting, improved patient adherence, better knowledge and understanding of pharmacotherapeutic treatment options and prompt intervention. Health care professionals must need to overcome clinical inertia and need to intensify therapy in an appropriate and timely manner. PMID- 20719587 TI - Validation of a modelling approach for estimating the likely effectiveness of cancer screening using cancer data on prevalence screening and incidence. AB - PURPOSE: This study aims to validate a biostatistical approach to predict the likely effectiveness of screening in reducing advanced disease in the absence of data on incident screen and interval cancers. METHODS: We derived the predicted relative reduction in advanced stage disease following screening from the expected proportion of advanced disease following screening and the observed proportion of advanced disease detected clinically among the controls. We compared the predicted estimates to those observed in a randomised trial. RESULTS: Using our method, the predicted estimates of relative reduction in node positive breast cancer following screening were comparable to the observed estimates for the age groups 50-59 and 60-69 in the screening study (predicted 32% vs. observed 40% (p=0.274) and predicted 34% vs. observed 45% (p=0.068), respectively). However, for the age groups 40-49 and 70-74 the predicted values were overestimates of the likely effectiveness of screening compared to the observed values (predicted 38% vs. observed 16% (p=0.014) and predicted 34% vs. observed 0% (p=0.001), respectively). CONCLUSION: When the number of cancer cases is more than hundred, the method of prediction using only prevalence screen data may be accurate. Where cancers are less common, for example in small populations or young age groups, further data from interval cancers or incidence screens may be necessary. PMID- 20719588 TI - Basic position of the Japan Prosthodontic Society with respect to the policy statement on TMD by the American Association for Dental Research (AADR). PMID- 20719589 TI - Keeping score of coronary artery disease using cardiac CT angiography: can reasonable experts agree? PMID- 20719590 TI - Quantification of human dynamic muscle fatigue by electromyography and kinematic profiles. AB - We wished to quantify the dynamic muscle fatigue by electromyographic (EMG) and kinematic parameters during uphill walking (5 km/h, 25%). The muscle coordination between biceps femoris, semitendinosus, vastus lateralis, gastrocnemius medialis, soleus, and tibialis anterior was evaluated by measuring (a) the period from onset of the EMG burst to heel contact, and (b) duration of the EMG burst. The muscle activity of the individual bursts was evaluated by the root mean-square (RMS), the mean power frequency (MPF), and the averaged EMG profile during one stride cycle. The most pronounced differences at the start and end of the endurance test were observed in the semitendinosus and the biceps femoris. The gastrocnemius was recruited substantially closer to heel contact, but no changes were noted in the soleus. The RMS and duration of the EMG burst were changed significantly for the vastus lateralis. The overall pattern of the kinematic profiles (position, and velocity) for the upper and lower leg remained constant, although the muscle activity and coordination changed. During dynamic muscle fatigue, a complex interaction between muscle coordination and muscle performance was noted, but how the central nervous system control this interaction is not known. PMID- 20719591 TI - Soleus H-reflex tests in spasticity and dystonia: A computerized analysis. AB - In 54 healthy individuals, and in 25 spastic and 7 dystonic subjects, soleus H reflex vibratory inhibition, H M ratio, and homonymous recovery curves obtained at two stimulus intensity levels were investigated in the same subject. In spasticity, the most prominent changes consist of a diminution of the vibratory inhibition at stimulus intensities lower than needed for a maximum H-reflex and an increase in the H M ratio. These results suggest that presynaptic inhibition is reduced mainly at low-intensity levels and that excitability of motoneurons is increased. Recovery curves in spasticity do not show such significant changes as found for the recruitment curves. In dystonia, prominent changes occur in the late facilitatory phase of the recovery curve obtained at 0.5 H(max) stimulus intensity, suggesting increased interneuronal activity. Vibratory suppression may be diminished, but H M ratio is unaltered. A multivariate analysis was used to identify variables that discriminated between control, spastic, and dystonic subjects. The analysis yielded two canonical variables that are a linear combination of four H-reflex variables that contribute significantly to the group classification. Based on these two canonical variables, each group can be properly differentiated quantitatively. PMID- 20719592 TI - Indices of muscle fatigue. AB - Myoelectric signal variables and mechanical variables are known to change during sustained voluntary or electrically elicited contractions. These phenomena reflect changes in the properties of the muscle fiber and its membrane. Such changes are generally called "fatigue." Muscle fiber conduction velocity and myoelectric signal spectral parameters (mean and median frequency) show a linear or curvilinear decrease in time, depending on the level of voluntary or electrically elicited contraction. Amplitude paramaters [average rectified value (ARV) and root mean-square (RMS) value] and force often show a dome-shaped pattern with respect to time. In previous research, these patterns have been fitted with least-square regression curves or lines whose parameters (decrement, time constant, initial slope) have been considered indicators of the amount and rate of muscle property changes and therefore of ongoing fatigue. A new index of fatigue is proposed in this work. The product of a reference value (e.g., the first value of the time series) and the time of observation defines a reference rectangle. The area between the upper side of such rectangle and the experimental data points is divived by the area of the reference rectangle to provide this index. This area ratio index may be computed either as an attribute of a contraction or as a function of time; it is regression-free, it is dimensionless, it varies between 0 and 1 for decreasing patterns, it is negative for increasing patterns, and it is little affected by experimental point fluctuations except for the value that defines the reference rectangle. With respect to other indices, the area ratio index provides a quantitative approach to fatigue that is consistent with the intuitive definition of fatigue. If applied to different myoelectric signal variables, the resulting area ratios may be interpreted as the components of a fatigue vector. PMID- 20719593 TI - Phase-dependent preferential activation of the soleus and gastrocnemius muscles during hopping in humans. AB - The electromyographic (EMG) activation patterns of the medial gastrocnemius (MG) and soleus (SOL) muscles were studied in 10 normal male subjects during hopping on a force-plate with special reference to three different phases of the movement: (a) precontact phase (PRE), (b) eccentric or stretching phase (ECC), and (c) concentric or shortening phase (CON). In a randomized order, each subject performed hopping on two legs with a minimal ground contact time, either with maximal frequency (FAST), maximal height (MAX) or at a constant frequency of 2 Hz (2HZ). The simultaneously digitized MG and SOL EMG activities were full-wave rectified and subjected to phase-dependent averaging that allowed repeated bursts of EMG signals during a hopping trial to be aligned in time and integrated with respect to mechanical events. Such analyses demonstrated that both these muscles were activated to a similar extent and in advance ( approximately 45 ms) of onset of ground contact during FAST hopping. Similarly, no significant differences in the integrated EMG activities (IEMGs) were observed between the MG and SOL during the CON phases of 2HZ and MAX conditions. During the PRE and ECC phases of MAX and 2HZ hopping, however, a significantly higher IEMG was noted in MG than in SOL (e.g., for the PRE: 13.3 +/- 1.4 vs. 4.7 +/- 1.0 muV . s, p < 0.01 for 2HZ and 12.6 +/- 1.3 vs. 4.7 +/- 1.2 muV . s, p < 0.01 for MAX). These results provide EMG evidence that preferential and movement phase-dependent neuromuscular activation exists within the ankle extensor synergy in humans. PMID- 20719594 TI - Topical anesthetic-induced improvements in the mobility of patients with muscular hypertonicity: Preliminary results. AB - Application of a topical anesthetic on the skin of the upper and lower limbs of chronic stroke and head-trauma patients induced considerable improvement in limb mobility within 30 min. We hypothesize that the augmentation of joint mobility and reduction in muscle rigidity are the result of desensitization of skin receptors that interact with the motor system. Physical therapy exercises performed during the effective period of the anesthetic rendered long-lasting improvement in the patients' ability to move their upper limbs and ambulate more effectively. PMID- 20719595 TI - Electromyography profiles of knee joint musculature during pivoting: Changes induced by anterior cruciate ligament deficiency. AB - Anterior cruciate ligament (ACL) insufficiency and associated rotational instability of the knee joint is a potentially disabling condition. In particular, anterior-posterior laxity increases when the ACL is damaged and decreases with contraction of the hamstring musculature. Because laxity is controllable with muscle activity, comparison of muscular synergy patterns between groups of subjects with ACL-deficient and uninjured knees may identify compensatory mechanisms that could influence therapeutic procedures. All participants selected were between 18 and 40 years of age and had clinical or surgical documentation of ACL deficiency. Each subject was asked to walk and pivot with a stride time of 1 s on a 12-m walkway. The right and left foot contact patterns and linear envelopes (LE) from the surface electromyographic (EMG) patterns of the gastrocnemius (GS), medial and lateral hamstring, rectus femoris (RF), and vastus lateralis (VL) were measured. Results from 15 subjects with uninjured knees and 12 subjects with ACL-deficient knees showed significant differences between their muscle synergy patterns. The types of differences observed depended on the stride period. All muscles within the ACL-deficient population showed some periods of abnormal activity. The differences in synergies indicate that there is a tendency for a greater net posterior force, flexor moment, and external rotation moment to be produced on the tibia during the time when most external rotation occurs to compensate for the mechanical actions of the lost ligament. PMID- 20719596 TI - EMG-force relations of a single skeletal muscle acting across a joint: Dependence on joint angle. AB - The electromyogram (EMG)-force relations of a single skeletal muscle (soleus) acting on a joint set isometrically at various flexion angles was studied using electrical nerve stimulation as the experimental method. The EMG-force relationships were linear at extremes of joint extension and became progressively nonlinear as the flexion angle increased. Joint angles at extreme extension showed the least passive and active force whereas their corresponding EMG versus force relations were linear. At extremes of joint flexion large passive force was accompanied by minimal active force. The largest active forces were recorded at midrange of the joints' excursion (90 degrees ). The source of the increasing nonlinearity was traced to large variability in the active and passive muscle forces as a function of joint angle, excluding all but minor variability in the EMG with joint position. We concluded that length-dependent variations of active and passive forces of the muscle (length-tension relations) compounded with the variation of its moment arm when acting across the joint require major consideration in biomechanical studies in which EMG is used to represent muscle force indirectly. PMID- 20719597 TI - New method for expressing F-wave data as conduction velocity. AB - A method for expressing F-wave data as a conduction velocity (normalized F-wave conduction velocity, NFCV) is described for the median, ulnar, peroneal, and posterior tibial nerves. Surface measurements routinely performed for calculation of motor conduction velocity (MCV) are used together with F-wave latency and a compensation factor (CF) to calculate a "velocity" easily comparable (normalized) to the MCV. Significant correlations between segmental "limb lengths" and whole 'extremity lengths" are shown. High correlations between NFCV and MCV are shown in a normal population, implying that NFCV is a valid descriptor of nerve conduction although it is not the true F-wave conduction velocity. The NFCV is shown to be more sensitive to age than F-wave latency or MCV, implying that NFCV potentially may be used as a sensitive indicator of motor nerve pathology. PMID- 20719598 TI - Technique for detecting MUAP propagation from high-threshold motor units. AB - A technique was developed to identify the propagation pattern of high-threshold motor unit action potentials (MUAPs) in human skeletal muscles. A linear surface array and a selective needle electrode were used simultaneously for detection of myoelectric signals during a constant-force isometric voluntary contraction. The needle signals were decomposed into trains of single MUAPs and were used to trigger-average the surface signals. After averaging 16 channels of surface signals derived with the linear array electrode, we obtained the propagation of single MUAPs along the muscle fibers. The special quadrifilar needle electrode and the algorithm for decomposing the needle signals made it possible to detect high-threshold MUs recruited at 0.86). However, IEMG normalized to another exercise was characterized by poor reliability (ICCs < 0.34), even when determined as the reliability of data averaged over two occasions. Regardless of whether absolute or normalized IEMG was used, 95% confidence intervals were wide, suggesting that precise, interday prediction of an individual's performance using the present protocol is questionnable. PMID- 20719671 TI - The assessment of motor recovery: A new look at an old problem. AB - After nervous system damage, functional recovery usually occurs. It is of great clinical importance to follow the course of recovery and, when possible, predict the extent. This measurement and prediction of recovery is one of the main challenges facing clinicians today. The majority of assessment procedures currently employed, however, are impairment-oriented; that is, these procedures are oriented primarily at the disease or organ level. Until now, few procedures have been available that focus at the disability or behavioural level. This lack of disability-oriented assessment procedures hinders the development and evaluation of rehabilitation programmes, as impairment-oriented assessment scores have little relevance for the prediction of daily functioning. In this paper, a preliminary task-set is presented that may function as an impetus for the development of novel disability-oriented assessment procedures in neurological rehabilitation. Motor behaviour is not assessed in vacuo, rather as the end result of a continuous interaction between motor, sensory and cognitive processes. With this task set, it is possible to evaluate the changing influence of sensory and cognitive factors on the quality of motor performance over time. These changes, it is argued, are a crucial component of functional recovery. PMID- 20719672 TI - Electromyographic evidence of delayed fatigue-induced sarcolemmal excitability impairment in McArdle's disease. AB - Loss of sarcolemmal excitability is an early sign of fatigue in exercising muscle. This can be determined from a decreasing muscle fibre conduction velocity (MFCV). Underlying causes are still unclear. Three McArdle's disease patients and seven healthy controls performed sustained isometric ischaemic biceps brachii exercise until exhaustion. Each subject participated in three tests: at 40%, at 80% and at 100% of the maximal voluntary contraction (MVC). Analysis was done over the period in which the force level was maintained at 40% and 80% MVC, and over the period during loss of force at all three levels. We found that, in contrast to the occurrence of an immediately starting and ongoing decrease of MFCV in controls, a delayed onset of this decrease was observed in patients with McArdle's disease. Only during the loss of force phase was the MFCV decrease similar in patients and controls. The early occurrence of an MFCV decrease in controls appears to be related to the accumulation of lactic acid, which is virtually absent in the patient group. During force loss, different (additional) mechanisms must be responsible for the MFCV decrease in patients and, most probably, in controls as well. PMID- 20719673 TI - The effects of muscle length and force output on the EMG power spectrum of the erector spinae. AB - In many skeletal muscles the myoelectric power spectrum median frequency (MF) increases with increasing force output, possibly reflecting the greater size and conduction velocity of the later-recruited (fast twitch) fibres. Muscles, such as the erector spinae, in which fast twitch fibres are smaller than slow twitch, may display an atypical relationship between force output and median frequency. The present study sought to investigate this possibility. Ten healthy men held forces ranging from 20-80% maximal voluntary contraction (MVC) of the back extensors for 4-6 s, at muscle lengths corresponding to 30, 60 and 90% of the lumbar spine's range of flexion (ROF). MF was determined from surface electromyograms recorded from thoracic and lumbar regions of the erector spinae. In each region, MF was significantly higher at 30% ROF (short muscle length) than at 60 or 90% ROF (P < 0.005) and slightly (but not significantly) higher at 60 than 90% ROF. The muscle length effect on MF may reflect a reduction in conduction velocity of the stretched and narrowed muscle fibres. Force output had a significant effect on MF (P < 0.0004), although the shape of the relationship differed between the two levels of the erector spinae: in the thoracic region MF increased with force up to 40-50% MVC and then levelled off, whereas in the lumbar region MF was relatively stable up to 30-40% MVC and then declined with increasing force. The results suggest that the mean fibre size of the later recruited motor units is, in the thoracic region, larger, and in the lumbar region, smaller, than that of the earlier-recruited motor units. PMID- 20719674 TI - Motor unit discharge during muscular after-contraction. AB - Discharges of single motor units (MUs) in human triceps brachii and deltoid muscle were recorded using needle electromyography during after-contraction and voluntary contraction performed either against a small elastic load or under isometry. The steady-state firing rate of the MUs was lower under after contraction than during voluntary movement of comparable amplitude and time course (or isometric force level), whereas variability of interspike intervals was similar under the two conditions. In the tibialis anterior muscle (where after-contraction was lacking), a weak voluntary contraction preceded by sustained strong voluntary effort also showed lower firing rate of MUs as compared to similar voluntary movement performed after a rest period. We concluded that sustained contraction gave rise to peripheral potentiation of contractile properties of the muscle, irrespective of whether it was proximal or distal, whereas after-contraction was due to a central tonic drive that differed for proximal and distal muscles. PMID- 20719675 TI - Moment-angle relationship at lower limb joints during human walking at different velocities. AB - The coupling between joint kinematics and kinetics during level walking was analysed by plotting joint angles vs. joint moments about the hip, knee and ankle in nine normal male subjects walking at three different velocities. The curves obtained were reproducible, and variability among subjects was relatively low. Counterclockwise loops corresponded to energy produced, and clockwise loops to energy absorbed at the joint; both loops are described in different phases of the stride cycle. At increasing walking velocity some of the loops narrowed, thus revealing the possibility of energy recovery. Analysis of individual diagrams revealed that consistent portions of the moment-angle loops can be described as a sequence of quasi-constant slope phases, separated by transition periods where quasi-isometric changes in joint moment occur. This figure, which was particularly evident of the hip and ankle joints, is reminiscent of a mechanical system with elastic components, which, in different phases of the rhythmic locomotion activity, moves along discrete status levels characterized by specific length-tension relationships. Implications of the above results in terms of the neurol control of joint properties during active movement are discussed. PMID- 20719676 TI - Modelling the triceps surae muscle-tendon complex for the estimation of length changes during walking. AB - The triceps surae muscle-tendon complex has been modelled by many authors seeking to estimate the change in muscle length that occurs in locomotion. The objective of the present study is to assess to what extent the commonly adopted assumptions of foot rigidity and pure sagittal motion are acceptable. A model of the triceps surae muscle-tendon complex was implemented by taking into account all possible movements between forefoot and rear foot. Length and velocity curves from a 3 dimensional gait analysis were obtained from six normal subjects. The angle between forefoot and rear foot proved to be changeable with stride (11.8 degrees +/- 4.7 SE). The effect on the length and velocity estimation was analysed by comparing the curves obtained by our model to those obtained by a model in which the foot is considered to be a rigid body. Significant differences were found for the soleus muscle length at late stance/early swing and late swing phases, and for the soleus muscle velocity at early stance phase. The length and velocity curves were also compared to curves calculated on a pure sagittal projection. No changes were observed, except for an offset of 1-3 mm caused by the general external rotation of the foot (which is also present in standing). The curves appeared superimposable when referred to the standing upright position. Care needs to be taken, however, when extending the above results to the clinical application, where foot deformity and deviation from a normal pattern of motion can occur. PMID- 20719677 TI - Contractile properties of human ankle muscles determined by a systems analysis method for the EMG-force relationship. AB - In order to determine painlessly and non-invasively the contractile properties of human skeletal muscles, the systems analysis method was applied to the relationship between the electromyogram (EMG) of agonist muscles and the isometric force produced by the voluntary contraction of the ankle plantarflexors and dorsiflexors. The subject's task was to produce force impulses at six different ankle positions for both muscles. The EMG(input)-force(output) relationship was approximated using the linear second-order system, and the contraction time (CT), half-relaxation time (HRT) and impulse response (IMP) were estimated. CT, HRT and IMP were found to increase as the muscles were stretched. The CT and HRT were longer for the plantarflexors than for the dorsiflexors, except at extremely plantarflexed positions. These results show qualitative agreement with results obtained by supramaximal electrical stimulation. It is suggested that the method of systems analysis is useful in identifying differences in muscle contractile properties under various force-production conditions. PMID- 20719678 TI - Myoelectric activity during voluntary elbow movements in above-elbow amputees. AB - This study is concerned with the analysis of myoelectric activity in the biceps and triceps muscles of unilateral above-elbow (AE) amputees during voluntary fast elbow movements. The signal patterns obtained from each subject's remnant limb were analysed and compared with similar acquired muscle patterns from the sound arm. Our findings, in agreement with suggestions from the literature, show that a significant portion of the so-called triphasic muscle patterns still occur in the remnant limbs of amputees, and therefore, are generated without the use of proprioceptive and sensory feedback. Although the patterns show some unexplained inconsistencies in timing and duration, the results indicate that for traumatic amputees the loss of an arm does not mean that remnant muscle contractions lose their relation to previous movements. In addition, congenital amputees did not show phasic patterns during voluntary fast elbow movements. PMID- 20719679 TI - Velocity-dependent muscle strategy during plantarflexion in humans. AB - This work examines the relative contribution of the triceps surae heads and the tibialis anterior (TA) to tension development with reference to voluntary plantarflexion at various velocities and at two articular positions of the knee joint (extended and flexed at 90 degrees ). Subjects were instructed to perform plantarflexion at various submaximal and maximal velocities with no intention of stopping the movement. Voluntary electromyographic (EMG) activity was recorded and the amplitude, duration and integral were analysed. Integrated EMG (IEMG) was normalized with respect to duration. The maximal M wave and the Hoffmann (H) reflex elicited by electrical stimulation of the tibial nerve were recorded in the triceps surae to estimate the effects in gastrocnemii (G) length and motoneuron excitability differences, respectively, in the two knee positions. The results indicate that: (a) although the largest EMG activity was recorded in the extended limb, the greatest maximal velocities were performed in the flexed knee position; (b) with increasing velocity of movement, all triceps surae muscles showed enhanced IEMG activities; (c) at a low velocity of movement the soleus (So1) G IEMG ratio was larger in the flexed compared to the extended knee; and (d) with increasing velocity, co-activation of agonist and antagonist muscles appeared. It is concluded that the larger maximal velocity of movement observed in the flexed compared to the extended knee was not primarily related to the neural command of the different triceps surae components, but rather to their mechanical properties. Furthermore, co-activation of agonist and antagonist muscles may contribute to the performance of the contractile strategy during rapid movements. PMID- 20719680 TI - The effects of normalization method on antagonistic activity patterns during eccentric and concentric isokinetic knee extension and flexion. AB - The purpose of this study was to compare different normalization methods of electromyographic (EMG) activity of antagonists during isokinetic eccentric and concentric knee movements. Twelve women performed three maximum knee extensions and flexions isometrically and at isokinetic concentric and eccentric angular velocities of 30 degrees .s(-1), 90 degrees .s(-1), 120 degrees .s(-1) and 150 degrees .s(-1). The EMG activity of the vastus lateralis, rectus femoris, vastus medialis and hamstrings was recorded. The antagonist integrated IEMG values were normalized relative to the EMG of the same muscle during an isometric maximal action (static method). The values were also expressed as a percentage of the EMG activity of the same muscle, at the same angle, angular velocity and muscle action (dynamic method) when the muscle was acting as an agonist. Three-way analysis of variance (ANOVA) designs indicated significantly greater IEMG normalized with the dynamic method compared to the EMG derived using the static method (P < 0.05). These differences were more evident at concentric angular velocities and at the first and last 20 degrees of the movement. The present findings demonstrate that the method of normalization significantly influences the conclusions on antagonistic activity during isokinetic maximum voluntary efforts. The dynamic method of normalization is more appropriate because it considers the effects of muscle action, muscle length and angular velocity on antagonist IEMG. PMID- 20719681 TI - Force-dependent changes in movement-related cortical potentials. AB - The purpose of this study was to compare movement-related cortical potentials (MRCPs) associated with different levels of isometric contractions by elbow flexors. Eight healthy, right-handed male subjects participated in this study and performed different levels (10 and 50% of maximal voluntary contraction) of isometric contractions by the right elbow flexors. Electroencephalogram (EEG) signals were recorded from Fz, C3, Cz and C4 of the international 10 20 system. Motor potential (MP) amplitudes (from -200 to approximately -50 ms before force onset) for C3 associated with both force generations was significantly greater (P < 0.01) than those for C4, indicating that contralateral predominance of MRCP was observed in the right arm flexion. In Fz, the potentials of negative slope (NS') (from -600 to approximately -200 ms) and MPs for 50% MVC were significantly greater than those of 10% MVC. In Cz, the MP associated with 50% MVC revealed a significantly greater (P < 0.05) value than that with 10% MVC. In C3 and C4, the MP associated with 50% MVC tended to be greater than that with 10% MVC, but no statistically significant differences were found. These force-dependent changes in MRCPs imply increased activation of neural circuits involved in motor preparation and initiation. It is therefore suggested that the larger potentials from Fz and Cz for 50% MVC compared with 10% MVC reflect a greater activation of supplementary motor area for the preparation of the larger force generation. PMID- 20719682 TI - The relationship between the soleus H-reflex amplitude and vibratory inhibition in controls and spastic subjects. I. Experimental results. AB - The effect of continuous Achilles tendon vibration on the soleus H-reflex amplitude was quantified over the entire H-reflex recruitment trajectory in 30 controls and 33 patients with spasticity in the lower limbs. The results show that with increasing stimulus intensities, vibratory inhibition of the Hreflex initially increases, then subsequently decreases. This is probably a direct consequence of how the activation thresholds of the motoneurons are distributed over the motoneuron pool. In patients, vibratory inhibition of the H-reflex was less over the entire recruitment trajectory than in controls. The decrease in vibratory inhibition in spasticity is commonly attributed to a decrease in presynaptic inhibition or post-activation depression. However, the average Hreflex threshold was lower in the patients, suggesting a decrease of the motoneuron activation thresholds. A lower reflex threshold in spasticity, therefore, may contribute to the observed reduction of vibratory inhibition. PMID- 20719683 TI - The relationship between the soleus H-reflex amplitude and vibratory inhibition in controls and spastic subjects. II. Computer model. AB - A computer model is presented that describes soleus H-reflex recruitment as a function of electric stimulus intensity. The model consists of two coupled non linear transfer functions. The first transfer function describes the activation of muscle spindle (Ia) afferent terminals as a function of the electric stimulus intensity; whereas the second describes the activation of a number of motoneurons as a function of the number of active Ia afferent terminals. The effect of change in these transfer functions on the H-reflex recruitment curve is simulated. In spastic patients, a higher average maximal H-response amplitude is observed in combination with a decreased H-reflex threshold. Vibration of the Achilles tendon reduces the H-reflex amplitude, presumably by reducing the excitatory afferent input. Vibratory inhibition is diminished in spasticity. In the model, the afferent-motoneuron transfer function was modified to represent the possible alterations occurring in spasticity. The simulations show that vibratory suppression of the H-reflex is determined only in part by the inhibition level of the afferent input. With a constant level of presynaptic inhibition, the suppression of reflexes of different sizes may vary. A lowering of the motoneuron activation thresholds in spastic patients will directly contribute to a decrease of vibratory inhibition in spasticity. PMID- 20719684 TI - Dependence of average muscle fibre conduction velocity on voluntary contraction force. AB - Average muscle fibre conduction velocity (CV) measured with multichannel surface electrodes decreases with time during sustained isometric contraction. Based on this property, CV is considered a candidate for an objective index to localized muscular fatigue. CV, however, also depends on many other factors that include muscle temperature and voluntary contraction force. In this paper, the effect of contraction force on CV was studied by defining not only the target force level but also the whole force trajectory. The contraction was isometric and lasted 14 s. The target force was set at four levels from 30% to 90% of the maximal voluntary contraction (MVC). Three typical muscles were studied in seven healthy male subjects. In the vastus lateralis, CV increased with contraction force in many cases. In the biceps brachii, CV decreased rapidly with time before the contraction force reached the target levels of 70% or 90% MVC. At these force levels, CV was smaller than that at 50% MVC. CV in the biceps consequently showed no apparent dependence on the contraction force. The tibialis anterior showed intermediate change in CV between the vastus lateralis and the biceps brachii. These results indicate that CV basically increases with contraction force, but this relationship becomes unclear when CV decreases rapidly with time. PMID- 20719686 TI - Editorial Fatigue in functional electrical stimulation in spinal cord injury. PMID- 20719685 TI - EMG-Feedback from two muscles in postural reactions: A new pocket device for the patient-therapist pair. PMID- 20719687 TI - The effects of fatigue on the torque-frequency curve of the human paralysed soleus muscle. AB - An advanced understanding of the torque-generating properties of the chronically paralysed soleus muscle may be instrumental in developing improved methods to activate human paralysed muscle. We established the shape of the torque-frequency curve before and after fatigue of the human paralysed soleus muscle. After fatigue, the normalized torque-frequency curve was shifted to the right, suggesting a higher frequency was required to generate the same relative torque. Low frequency fatigue (LFF) consisting of reduced torques at low frequencies and normal torques at higher frequencies was demonstrated. Conversely, the acutely paralysed soleus muscle was found to be fatigue-resistant and showed no shift in the torque-frequency curve. The muscle activation history (potentiation), LFF, and changing contractile speeds may affect the torque-frequency curve after fatigue. These factors may also play an important role in the development of optimal methods to activate paralysed muscle to attenuate fatigue. PMID- 20719688 TI - Fatigue in human thenar muscles paralysed by spinal cord injury. AB - Muscle fatigue (force loss) induced by constant frequency stimulation (36 Hz) and variable rate stimulation (36 Hz to 18 Hz over 60 s) were compared in six individuals with thenar muscles which were paralysed by chronic cervical spinal cord injury (SCI), and in six volunteers with no known neurological disorder. The variable stimulation rate pattern represented the general decline in thenar motor unit firing rates recorded during 60 s maximum voluntary contractions performed by the able-bodied (AB) subjects. Constant and variable rate stimulation produced similar resultant force declines, as measured from abduction and flexion force components. However, significant force loss always occurred earlier and was of greater magnitude in SCI subjects, irrespective of the stimulation pattern (all, P < 0.01). Because more force was generally lost in one force component versus the other, the direction of the resultant force could also change with fatigue. The recordings from SCI participants were also contaminated by spontaneous motor unit activity, spasms and F responses. The stimulation frequency needed to produce half-maximum tetanic force increased for SCI subjects after fatigue, so higher, not lower stimulation frequencies were needed to produce any given submaximal force. Therefore, to match stimulation rate to changes in muscle contractile properties, these parameters have to be monitored and controlled on line. The fatigue during each stimulation protocol, and for each subject population, was attributed primarily to contractile failure because any decrements in M-wave amplitude or area recovered completely within the first minute whereas twitch and tetanic forces remained somewhat depressed. PMID- 20719689 TI - Surface EMG as a fatigue indicator during FES-induced isometric muscle contractions. AB - The electromyogram (EMG) signal has potential as an indicator of stimulated muscle fatigue in applications of functional electrical stimulation (FES). In particular, it could be used to detect near lower limb collapse due to the associated muscle fatigue in FES-aided standing systems and thereby prevent falling. Surface EMG measurement, however, is hampered by stimulation artifact during FES. Modified surface stimulation and EMG detection equipment were designed and built to minimize this artifact and to permit detection of the electrical signal generated by the muscle during contraction. Artifact reduction techniques included shorting stimulator output leads between stimulus pulses and limiting and blanking slew rate in the EMG processing stage. Isometric fatigue experiments were performed by stimulating the quadriceps muscle of 20 able-bodied (a total of 125 trials) and three spinal cord injured (18 trials) subjects. Fatigue-tracking performance indicators were derived from the root-mean-square (RMS) of the EMG amplitude and from the median frequency (MF) of the EMG power spectral content. The results demonstrate that reliable fatigue tracking indicators for practical FES applications will be difficult to obtain, but that amplitude-based measures in spinal cord injured subjects show promise. PMID- 20719690 TI - Detection and prediction of FES-induced fatigue. AB - The estimation of externally elicited muscle forces is important for the better control of a functional electrical stimulation (FES)-assistive system. Various techniques of signal processing are presented, all with only one aim, to determine the correlation between the decrease of muscle force after continuous stimulation and surface recordings of the evoked potentials. Wrist flexor muscles were stimulated under isometric conditions, and surface electromyography (sEMG) was used to record wrist joint torque in both able-bodied and spinal cord injured volunteers. The joint torque was determined from recordings of the force generated by the wrist flexors, with the forearm immobilized. The sEMG was recorded utilizing a preamplifier with a stimulation artefact suppression circuitry. The signal was processed in the time and frequency domains, and analysed vs time, as well as in the state space formed by the wrist torque and evoked potential. The torque vs sEMG curves were used to establish the relationship that can be used for detection of the decrease of the force associated with FES-induced muscle fatigue. Among seven different techniques of sEMG processing the best correlation was found between the median frequency and force changes. The phase plane plot was fitted with an exponential curve, and the parameters obtained from the fitting were used to determine two events: prediction of the onset of fatigue and detection of fatigue. This suggests that it is possible to use the processed sEMG as a trigger signal to change the pattern of stimulation and allow the muscle to recover while resting, or to inform the user that the muscle force will soon drop rapidly. The recovery of the muscle force and sEMG was also analysed to learn more about the mechanisms that may be responsible for FES-induced fatigue. This technique offers simple on-off type feedback capability for fatigue detection in FES applications. PMID- 20719691 TI - Muscle fatigue in interrupted stimulation: Effect of partial recovery on force and EMG dynamics. AB - Muscle fatigue is a major problem in functional electrical stimulation (FES); the understanding of fatigue and recovery processes is thus of great interest. In interrupted stimulation, fatigue and recovery occur in sequence, and the history dependency of the muscle's response to FES becomes significant. In this work, the force and electromyographical (EMG) fatigue characteristics of FES-activated paralysed muscles were studied, both in the initially unfatigued state (primary fatigue) and in the reactivated state, after rest periods of prescribed durations (post-recovery fatigue). Because the data were collected over weeks, longitudinal studies were also made to account for long-term training effects of the muscle. Mechanical and myoelectric profiles, the latter derived from the M-wave, were obtained from the right quadriceps of two paraplegic subjects under isometric stimulation. Force was found to correlate highly with peak-to-peak amplitude of the EMG M-wave. Training did not affect this correlation, but as the recovery duration increased, the force-EMG curves became less concave. Training was found to increase the muscle force and EMG peak-to-peak amplitude, as well as the residual force achieved, but it had no noticeable effects on the M-wave duration parameters. Both the force and EMG parameters demonstrated substantial recovery within the first 3 min of rest, and exhibited a consistent tendency to level off for higher periods of rest. After comparing this finding to those expected from previous metabolic models, it was concluded from the subjects studied and model developed that, in addition to metabolic factors, electrolytic factors may be significant in governing the dynamics of fatigue and recovery. PMID- 20719692 TI - The influence of voluntary upper body exercise on the performance of stimulated paralysed human quadriceps. AB - In this study the influence of voluntary upper body exercise on the performance of stimulated paralysed human quadriceps was investigated in five subjects with spinal cord lesions in the thoracic spine. The experimental setup consisted of computer-controlled stimulation of the quadriceps using electrodes on the surface of the skin, a dynamometer for isometric or isokinetic loading of the lower leg, and a rowing ergometer for upper body exercise. In all subjects, quadriceps fatigue tests were conducted to study the influence of upper body exercise on knee torque during sustained continuous or intermittent stimulation of quadriceps. The relative asymptotic torque appeared to be significantly higher with the presence of upper body exercise than without. This was consistently found both between trials (starting with or without upper body exercise) as well as within trials, when upper body exercise was started or stopped during the trial. No significant influence of upper body exercise on the time constant of initial torque decline was found. PMID- 20719693 TI - The relationships between movement-related cortical potentials and motor unit activity during muscle contraction. AB - This study investigated the relationship between movement-related cortical potentials (MRCP) and motor unit (MU) activity during muscle contractions. Ten right-handed, healthy males performed three motor tasks which were designed to bring about three different MU recruitment patterns while eliciting identical terminal force levels. In task I, the subjects were asked to perform 'shots' of self-paced isometric elbow flexion at 20% of maximal voluntary contraction (MVC). In task II, subjects performed 'holds' and maintained a constant isometric contraction for 2 s. In task III, task II was again performed while circulation was occluded prior to and during the trials. The arterial occlusion was induced by a pressure cuff around the upper-arm which was inflated to 200 mmHg for 5 min before the trials. Electroencephalogram (EEG) signals were recorded from scalp electrodes 2 s before and 2 s after the initiation of the motor tasks. The myoelectric (EMG) signals from the biceps brachii were recorded together with the force measurement. These simultaneously recorded EEG, EMG and force data were time-locked to the onset of force (1% of the target force) by an on-line computer system and then averaged for 50 trials for each subject. Grand average data indicated that there were no significant differences in the grand mean force levels exerted among the three tasks. The averaged EMG amplitude during force output in task III, however, was significantly (P < 0.001) greater than those in task II. The significantly greater EMG amplitude on the identical force output that was observed may thus be due to progressive recruitment of additional MU to compensate for the deficit in force development during trials with arterial occlusion. The averaged mean MRCP amplitudes after the onset of movement (AM potentials) were significantly (P < 0.001) greater in order of tasks III, II and I at all electrode locations (C3, Cz, C4). Our data suggest that the mean amplitude of AM potentials was related to MU activity, i.e., the higher the negativity of AM potentials, the greater the MU activity. PMID- 20719694 TI - Normality and stationarity of EMG signals of elbow flexor muscles during ramp and step isometric contractions. AB - The purpose of this study was to test the stationarity and normality of electromyographic (EMG) signals obtained while exerting isometric contractions: (a) where a steady force level is maintained (step contractions); and (b) where the force level is increased linearly over time (ramp contractions). Ramp elbow flexions were performed from 0 to 100% of the maximum voluntary contraction (MVC) in a 5-s period. For the step contractions, four force levels (20, 40, 60 and 80% MVC) were maintained for a period of 3 s each. EMG signals of the biceps brachii (BB) and brachioradialis (BR) muscles of 16 subjects were recorded with surface electrodes and digitized at a sampling frequency of 2000 Hz. Tests of normality (Shapiro-Wilk test) and stationarity (reverse arrangement test) were performed locally on short finite time records (512-ms windows). Results show that, in general, EMG signals present a non-Gaussian amplitude distribution and are stationary. Furthermore, the amplitude distribution characteristics and the stationarity of the signal were not dependent on the muscle investigated, nor on the type of contraction or force level tested. The finding of local stationarity for both tasks is important, because it suggests that performing standard spectral analysis is applicable for both step and ramp contractions. It also allows a direct comparison between results obtained under both conditions. PMID- 20719695 TI - Consistency of multi-channel surface EMG recordings: Application in spinal cord injured subjects. AB - We evaluated the consistency of serial polyelectromyographic recordings of altered motor control in spinal cord injured (SCI) individuals. Using 12 pairs of surface electrodes placed over major muscle groups of lower limb and trunk, we examined voluntary and involuntary and phasic and tonic features of motor control using a standardized protocol for brain motor control assessment (BMCA). The surface electromyographic (EMG) data were digitized and analysed on the basis of the root mean square (RMS) envelope of activity, with the exception of phasic tendon tap responses which were evaluated from full bandwidth EMG data. The average amplitudes of responses were calculated. The median correlation of the results from two successive examinations 1-2 weeks apart for all subjects was 0.98. Further analysis was based on ratios of corresponding elements from the two studies. Noise from null responses was suppressed by incorporating a threshold parameter T set to 1 muV(RMS). With this value, pairs of studies in 52 subjects were virtually identical (mean ratio of 1.02 +/- 0.1). Z-scores from two case studies in which pharmacological and physiological interventions changed motor control demonstrated the utility of the procedure. This method offers a reliable and appropriate means of studying altered motor control which is sensitive to changes induced after interventions. PMID- 20719696 TI - The effect of muscle length on electrically elicited muscle vibrations in the in situ cat soleus muscle. AB - The effects of length changes in the in-situ cat soleus muscle on vibromyographic (VMG) signals were assessed using electrical stimulation of the soleus nerve in three adult male cats. Force and VMG signals were measured using an E-shaped force transducer and a miniature, unidirectional accelerometer, respectively. In each test, the soleus nerve was stimulated for 6 s at rates ranging from 4 to 35 Hz, and at two to four ankle angles (80-140 degrees ). The force of the soleus muscle increased with increasing muscle length and stimulation rates. For a given sub-tetanic frequency of stimulation, the root mean square (RMS) values of the VMG signal were larger at intermediate muscle lengths than at both the longest and the shortest muscle lengths. There was a continuous increase in the RMS of the VMG signal with decreasing muscle length when the contraction was tetanic. There was a trend towards an increase in the median frequency (MDF) of the VMG signal with increasing muscle length. The results of this study support the idea that the amplitude and frequency content of the VMG signal during electrically elicited muscle contractions are directly affected by changes in the mechanical properties (i.e. the stiffness and the active and passive tension) of muscle caused by length changes. PMID- 20719697 TI - Extent of muscle inhibition as a function of knee angle. AB - The present study was aimed at assessing muscle inhibition (MI) of the quadriceps muscles of healthy subjects as a function of knee angle. The extent of muscle activation and of twitch potentiation following maximal contractions at different knee angles were investigated. Six males and four females (mean age 29.5 +/- 6.2 yr) performed three maximal isometric knee extensions on a KinCom dynamometer with the right and left legs at 15, 30, 45, 60 and 90 degrees from full extension. MI was assessed using the interpolated twitch technique. This technique requires surface stimulation of the femoral nerve during the maximal contractions. MI was estimated by the amount of extra torque evoked by the superimposed twitch. Electromyographical (EMG) activity of the vastus lateralis muscle was measured in order to estimate muscle activation. Twitch potentiation was assessed at 5, 20, 60 and 120 s after the maximal contractions by applying a single electrical twitch to the relaxed muscle. Results revealed a strong dependency of MI on the knee angle tested; MI increased with increasing muscle lengths and was almost three times higher at 60 degrees than at 15 degrees of full extension. Muscle activation measured as the root mean square (RMS) values of the vastus lateralis EMG was the same for four out of the five muscle lengths measured; at a knee angle of 90 degrees , the RMS values were significantly higher. Twitch potentiation was observed at all knee angles following maximal contractions. Potentiation was highest immediately after contraction (i.e. 5 s after), and the amount of potentiation did not depend on the knee angle. Muscle activation and twitch potentiation only accounted for a small percentage of the differences in MI as a function of knee angle. It is suggested that increased patellofemoral pressure and increased ligament strain, which are highest between 45 and 60 degrees of full extension, might be responsible for the high MI measured at these knee angles. It is further hypothesized that the differences in MI as a function of muscle length are also associated with the shortening of the contractile elements during contractions, and the concomitant loss in force potential; a phenomenon which is probably more pronounced at short compared to long muscle lengths. PMID- 20719698 TI - A validation of techniques using surface EMG signals from dynamic contractions to quantify muscle fatigue during repetitive tasks. AB - The purpose of the current study was to determine the validity of quantifying biceps brachii fatigue with dynamic measures of surface electromyo-graphic (EMG) mean power frequency (MPF) through comparisons with the well-established isometric methodology. Subjects performed repetitive elbow flexion-extension movements with a hand held load of 7 kg until volitional exhaustion. Elbow joint angle and biceps brachii EMG signals were recorded continuously during the fatiguing movement (in 250-ms segments) and during isometric, isotonic contractions (in 1000-ms segments) performed at a 90 degrees flexion angle before and after the trial. The MPF and average EMG amplitude (AEMG) were also calculated with each sample, and a polynomial regression analysis was used to characterize the time history of changes and to determine the rested and fatigued values for the dynamic EMG with: (a) all dynamic samples above 5% MVC and (b) only samples where the elbow joint was between 80 degrees and 100 degrees of flexion. There was a significant increase in AEMG and a decrease in MPF for the isometric contractions and both dynamic methods. When compared to dynamic values at rest and fatigue, the isometric AEMG and MPF were substantially lower and slightly higher, respectively. No significant differences were observed between the AEMG or MPF results from the two methods of processing the dynamic EMG. The decreases in MPF ranged from 25% to 29% and did not differ between methods. The absolute and relative increases in isometric AEMG were substantially lower than with both dynamic methods. The current results support the use of MPF values from surface EMG signals recorded during dynamic contractions to quantify fatigue of the biceps brachii muscle. The proposed methodology can be used to monitor fatigue continuously throughout a dynamic movement with minimal disturbance to the task being performed and without the need to monitor joint angles. PMID- 20719699 TI - Correspondence between the directional patterns of hip muscle activation and their mechanical action in man. AB - The hypothesis that the pattern of muscle activation during a static voluntary effort exerted in different directions is oriented in the direction of the muscle's mechanical action was evaluated. The electromyographical (EMG) activation patterns of five hip muscles (gluteus medius, rectus femoris, tensor fasciae latae, gracilis and semitendinosus) and one knee muscle (vastus lateralis) were characterized in 11 normal subjects during static efforts at the hip joint. Subjects were asked to generate torques (10 and 20 Nm) in 24 directions covering 360 degrees at increments of 15 degrees in the transverse plane of the femur whereas torques at the knee were to be kept at zero. Using vector summation of the rectified EMGs, a mean angular value of muscle activation was calculated for each muscle across subjects. It was observed that the mean angular values of muscles acting at the hip were significantly oriented, whereas the activity of the vastus lateralis was not significantly oriented. In addition, the angular values of activation of the rectus femoris, tensor fasciae latae and semitendinosus muscles were not significantly different from the direction of mechanical action of these respective muscles as determined using a biomechanical model of the hip. However, the angular values of the gluteus medius and gracilis activations were found to be significantly different from their anatomical line of action. The angular values of activation of two muscles (rectus femoris and gluteus medius) were also compared to the mechanical pulling direction of these muscles as determined following electrical stimulation of the recorded muscle regions. The analysis revealed that the angular value of the gluteus medius and rectus femoris during voluntary static efforts at the hip was not significantly different from the direction of mechanical action of these muscles as determined by the electrical stimulation. In general, these results support the hypothesis that the degree of a muscle's activation in one direction is determined as a function of its mechanical action. PMID- 20719701 TI - Erratum. PMID- 20719700 TI - Impaired balance control in paraplegic subjects. AB - Postural muscle use during sitting balance control was studied in persons with a complete thoracic spinal cord injury (SCI). It was hypothesized that these subjects use non-postural muscles such as the latissimus dorsi (LD) and trapezius pars ascendens (TPA) to restore sitting balance, whereas non-SCI subjects primarily use their erector spinae (ES). This adaptive postural strategy in SCI subjects presupposes stabilizing effects of the scapular protractors, such as the pectoralis major (PM) and the serratus anterior (SA), on the shoulder girdle. Sitting balance was perturbed systematically in three groups of either low thoracic SCI, high thoracic SCI or non-SCI participants. Centre of pressure changes and activity of the LD, TPA, PM, SA, ES and oblique abdominal (OA) muscles were measured during task execution. Because non-SCI subjects differ from SCI subjects in their ability to tilt their pelvis during sitting, the correlation between pelvic movement and postural changes during task execution was also investigated. Results indicate that high thoracic SCI subjects use their LD, TPA, PM, SA and high thoracic part of the ES more in situations of similarly perturbed sitting balance than non-SCI subjects. Differences are smaller in the low thoracic SCI group. A kinematic concept combining alternative postural muscle activity and altered movement in thoracic SCI subjects is discussed. PMID- 20719702 TI - Stimulation frequency history alters length-force characteristics of fully recruited rat muscle. AB - Effects of stimulation frequency history on length-force characteristics were determined for rat medial gastrocnemius muscle (GM). The peripheral nerve was stimulated supramaximally according to two stimulation protocols. First, a complete set of length-force data were obtained by stimulating the nerve with a decreasing stimulation frequency (DSF) staircase composed of five successive pulse trains (200 ms each) of 100-, 50-, 40-, 30- and 15-Hz stimulation. Then length-force data were obtained using constant stimulation frequency (CSF; during the isometric contraction inter-stimulus interval was constant). The acquisition order of a complete set of length-force data was: first 15-Hz, then 30-, 40-, 50- and finally 100-Hz stimulation. For all DSF conditions, both optimum muscle length as well as active slack length were shifted significantly (P < 0.05) to lower muscle length with respect to CSF. Muscle length range between active slack and optimum length for all DSF conditions was increased significantly with respect to CSF. DSF thus caused a marked shift of the length-force relationship to lower muscle length compared to the CSF-dependent length-force relationship. As a result of this shift, muscle force enhancement (potentiation) was non linearly related to muscle length; force enhancement decreased exponentially with increasing muscle length. In addition, DSF-dependent length-force characteristics are not scaled and shifted versions of those for CSF. Possible factors affecting these length-force characteristics are higher intracellular calcium concentration, myosin light chain phosphorylation, fatigue during sustained contractions, interaction between aponeurosis and fibre length, distribution of fibre mean sarcomere length with respect to muscle length, and muscle length changes during unfused tetanic contractions. It is concluded that length-force characteristics of rat GM are dependent on both short-term stimulation frequency history as well as stimulation frequency per se. PMID- 20719703 TI - Cocontraction in three age groups of children during treadmill locomotion. AB - This study attempted to assess and compare the amount of cocontraction present in thigh and leg muscles in three groups of children during treadmill walking and running. Thirty children, aged 7-8 (n = 10), 10-12 (n = 10) and 15-16 (n = 10) years, performed 4-min bouts of submaximal treadmill exercise at two walking and four running speeds, assigned in a randomized order. Three seconds of EMG data were collected during the final minute of each bout from the vastus lateralis (VL), hamstrings (H), tibialis anterior (TA) and soleus (S). The processed linear envelopes of VL and H, and likewise of TA and S, were overlapped and a cocontraction index calculated (area of overlap divided by the number of data points) for thigh and leg segments, respectively. Cocontraction was highest for the youngest children and lowest for the oldest, for both thigh and leg, whether expressed in terms of absolute speed or as a percentage of each child's VO(2 max). Larger amounts of cocontraction may help to explain the higher metabolic cost of locomotion for younger children, when compared with adolescents and adults. PMID- 20719704 TI - Myoelectric and mechanical changes elicited by ischemic preconditioning in the feline hindlimb. AB - Tourniquet use is fraught with potential complications. For example, ischemia produced by the tourniquet may lead to nerve and muscle injuries. One technique shown in cardiovascular and free-flap surgery to improve the viability of muscle subjected to ischemia is preconditioning. This technique involves an initial brief period of ischemia, followed by reperfusion before a prolonged ischemic episode. The purpose of this study was to explore ischemic preconditioning as a method to reduce tourniquet-related morbidity. In six cats, one leg was preconditioned by 10 min of tourniquet-induced ischemia followed by 10 min of reperfusion. The contralateral limb was not preconditioned. Both limbs underwent 1 h of tourniquet inflation followed by a 2-h recovery period. Isometric force and electromyographic (EMG) amplitude were recorded throughout the procedure at 20-min intervals in both medial gastrocnemius muscles. Analysis of variance (ANOVA) with repeated measures shows that, after 60 min of tourniquet application, maximal isometric force was significantly larger in the preconditioned group. Furthermore, the EMG amplitude during recovery was found to be significantly larger in the preconditioned limbs. These results suggest that preconditioning improves skeletal muscle viability in vivo. Further research is needed, however, to assess the long-term effects of this technique, and to delineate appropriate preconditioning protocols that would improve surgical outcome without significantly increasing the complexity of the procedures. PMID- 20719705 TI - Surface EMG modifications after eccentric exercise. AB - The possibility that the surface electromyographic signal (sEMG) from exercised muscle would show significant changes to demonstrate muscle damage after eccentric contraction (EC) was tested in this study. The experiment lasted five consecutive days. On the first day, six sedentary adult subjects performed two rounds of 35 ECs with the biceps brachii of the non-dominant arm, the other arm being used as control. Individual muscle soreness was assessed on a subjective scale. The analysis of sEMG was performed on the signal recorded during isometric contractions at 80% and 50% of maximal voluntary contraction (MVC), choosing root mean square (RMS) and median frequency (MDF) as synthetic sEMG parameters. MVC was also recorded, and plasma levels of creatine kinase were determined in four subjects. The most important findings which resulted from this study were: (a) spectral parameters are less sensitive to error introduced by electrode repositioning than time domain parameters, and are more sensitive to EC-induced sEMG changes than RMS; (b) a significant shift of MDF power spectra towards low frequencies at 80% and 50% MVC (20% and 5% of decay, respectively) was evident as early as 1 h after EC on the exercised arm; and (c) MDF follows the evolution of muscle damage. We concluded from these results that MDF is suitable for the early and non-invasive detection of sEMG changes induced by EC. In addition, we found further evidence that the observed modifications result from a selective or prevalent damage of type 2B muscle fibres. PMID- 20719706 TI - An analysis of greyhound gait using wavelets. AB - In this paper we present a method of analysing gait of quadrupedal animals using wavelets. Time series data such as joint trajectories can be decomposed by the discrete wavelet transform to represent components of different frequency bandwidth. Differences between two similar trajectories can be detected by comparing the components of the same bandwidth. We analysed kinematic data of the hindlimbs of three greyhounds with normal gait and with tibial nerve paralysis. Abnormalities in the gait patterns were detected and quantified by comparing the energy contribution of the components that were present at the same level of the wavelet transform. PMID- 20719707 TI - Superficial granulomatous pyoderma with ocular involvement. PMID- 20719708 TI - IL-15 in HIV infection: pathogenic or therapeutic potential? AB - Recent studies have shown that interleukin-15 (IL-15) is produced during acute HIV and SIV infection, and may impact viremia and viral set point. This is further supported by the findings that administration of IL-15 during acute SIV infection dramatically increases viral set point. Although the role of intrinsic IL-15 during chronic infection is much less defined, in vivo administration of IL 15 does not increase viral replication in SIV-infected animals. Recent data also suggest that IL-15 acts, not only on CD8+ T cells and natural killer cells, but also on effector memory CD4+ T cells. IL-15 clearly expands very different CD4+ T cell subpopulations than IL-2 in SIV-infected animals, and may be useful for the restoration of effector memory CD4+ T cells that are depleted early in HIV and SIV infection. Understanding IL-15's role in SIV infection may help us to design novel therapeutic approaches to HIV infection. PMID- 20719709 TI - Role of IL-12 in HIV infection and vaccine. AB - Among cytokines that dictate the fate of developing immune responses, IL-12 represents an important nexus for the development of type I cell-mediated immune responses (CMI). This factor is primarily produced by monocytic cell lineages in response to stimuli such as pathogen-associated molecular patterns, dictating the development of naive T cells as they differentiate into antigen-specific T cells. HIV infection results in an early loss of effective TH1 prototype CMI when such responses appear to be precisely the type of CMI needed to control the virus and a host of opportunistic pathogens. Besides CD4 T cell loss, much of the muted IL 12 response has been attributed to direct effects of HIV or its proteins on antigen-presenting cells, while T and NK cell responses to IL-12 appear maintained during chronic HIV infection. However, while IL-12 therapy is unlikely to provide major benefits in the context of an established HIV infection, IL-12 preconditioning of monkeys during acute SIV infection markedly delayed disease progression. These findings suggest that IL-12 may serve as a critical vaccine adjuvant, and as treatment for particular opportunistic agents or neoplasm such as Kaposi's sarcoma; it has already shown promising results in the context of HIV infection. PMID- 20719710 TI - Cytokines and the pathogenesis of HIV infection. PMID- 20719711 TI - IL-17 and HIV pathogenesis. PMID- 20719712 TI - Downregulation of HD-PTP by high magnesium concentration: novel insights into magnesium-induced endothelial migration. AB - Magnesium promotes endothelial migration, an event which is orchestrated by a complex interplay between protein tyrosine kinases and phosphatases. We found that high extracellular concentrations of magnesium do not modulate the levels and the activation of FAK and Src, two tyrosine kinases involved in driving cell migration. Interestingly, we show that magnesium induced-endothelial motility correlates with the downregulation of HD-PTP, a potential tyrosine phopshatase previously shown to be involved in modulating cell migration. The decreased amounts of HD-PTP are not dependent upon transcriptional mechanisms. In contrast to Fibroblast Growth Factor-induced HD-PTP downregulation, the proteasome seems not to be involved in regulating HD-PTP levels in endothelial cells cultured in high magnesium containing medium. Our results indicate that, in the presence of high magnesium concentrations, endothelial cells are stimulated to migrate through complex mechanisms involving also HD-PTP. PMID- 20719713 TI - [SCHIZOBANK - The Hungarian national schizophrenia biobank and its role in schizophrenia research and in personalized medicine]. AB - Delineating the pathogenesis of multifactorial diseases is a major challenge of the postgenomial era. Genetic factors are known to play an important role in the pathogenesis of certain psychiatric disorders as well as in the development of adverse reactions to psychoactive drugs. Containing large numbers of samples and linking them clinical data, biobanks are gaining importance in the studies of chronic multifactorial diseases. Several biobanks are under establishment in Hungary. The first initiative to collect samples in neurological and psychiatric disorders was the NEPSYBANK coordinated by the Hungarian Society of Clinical Neurogenetics. The national biobank network is currently established by the NEKIFUT project of the National Office of Research and Technology. In this article we describe the structure, logistics and informatical background of the national schizophrenia biobank (SCHIZOBANK). The initiative of the SCHIZOBANK originates from a consortium in which academy and health industry partners are collecting biological materials and data in five major psychiatric center under the coordination of the Medical and Health Science Center of the University of Debrecen. We review other international schizophrenia biobanks as well. Major strength of the SCHIZOBANK is the collection of very detailed phenotypic data and of RNA and plasma both in psychotic and non-psychotic state of the patient which permits longitudinal follow-up and the study of both static and dynamically changing transcriptomic, proteomic and metabolomic markers. The collection of the SCHIZOBANK is available not only to consortial partners but to other national and international research groups as well. PMID- 20719714 TI - [Evaluating the benefits of mammographic breast cancer screening]. AB - Mammographic breast cancer screening is one of the most popular cancer death preventive programs worldwide, as well as in Hungary. Breast cancer mortality and incidence started to decrease some years after international introduction of the screening program. The role played by mammography in the advantageous turn is not known. Potential points in evaluating the benefits of a screening program are reviewed. We focus on the average lifetime gain, which is 1 to 3 weeks in case of mammography, according to age groups. PMID- 20719715 TI - [Symptoms of hepatocellular carcinoma. Laboratory tests used for its diagnosis and screening]. AB - Early stage hepatocellular carcinoma is a symptom-free disease. Local and general symptoms occur due to the growth of the tumor tissue and the infiltration of the surrounding blood vessels. Illness progression is indicated by the development of abdominal discomfort, cachexia, therapy-resistant decompensation of previously compensated cirrhosis and in severe cases, the thrombosis of the portal vein or the hepatic veins. Characteristic laboratory findings are the quickly deteriorating blood and liver function tests results, the occurrence of haemostatic disorders and occasional hypoglycemia and/or hypercalcemia. To clarify the etiology and to identify high risk patients, we need to differentiate alcohol-, drug- or chemical-induced hepatic disorders, viral hepatitis B, C and Delta, metabolic disorders and non-alcoholic steatohepatitis. In the case of focal hepatic lesions, persistently elevated alfa fetoprotein levels have a high diagnostic value. At levels over 200 ng/ml, the positive predictive value is >90%. Other, less commonly measured biomarkers are the glycosilated alfa fetoprotein-L3 and the vitamin K-deficiency induced des-gamma-carboxy prothrombin. The risk of tumor occurrence is multiple in patients with HbeAg positive chronic hepatitis B if the virus is of genotype C with mutations in the 1762 and 1764 locations of the core promoter region. Abdominal ultrasound and measurement of alfa fetoprotein is recommended every 6 months for high risk individuals, or every 3-4 months over an 18-24 months period for patients with hepatic lesions of <1cm and of unknown malignancy. PMID- 20719716 TI - [Prevalence of microalbuminuria and its clinical correlation with other risk factors of cardiovascular diseases]. AB - Degree of albuminuria is a sensitive parameter to estimate cardiovascular risk and endothelial dysfunction. Large epidemiological studies proved higher amount of protein in the urine in diabetic and hypertensive patients. Measurement of albuminuria is not a part of the daily routine in Hungarian primary care nowadays. Authors used a simple screening tests and confirmed higher incidence of microalbuminuria in patients with diabetes, hypertension, as well in patients with increased waist circumference, especially in women. Authors suggest this screening test to general practitioners and family physicians to use in their daily cardiovascular care and preventive practice. PMID- 20719717 TI - [Role of rosuvastatin in current lipid-lowering therapy]. AB - Statins are the most widely used lipid-lowering therapy. Among them, the rosuvastatin can be well tolerated and effectively helps to reach LDL-cholesterol goals in primary and secondary cardiovascular prevention. In addition, rosuvastatin reduces triglyceride and high-sensitivity C-reactive protein level and increases high-density lipoprotein (HDL) cholesterol, too. Imaging studies demonstrated that rosuvastatin therapy can not only reduce atherosclerosis progression but might induce its regression too. PMID- 20719718 TI - [Role of fatty liver in metabolic syndrome]. AB - Epidemiological studies in humans have documented an association between visceral obesity and cardiovascular risk factors such as dyslipidemia, insulin resistance, and type 2 diabetes mellitus. Recently, attention has been focused on the excessive accumulation of triglycerides in the liver as part of metabolic syndrome. It appears that fat accumulation in the liver is associated with several features of insulin resistance even in normal-weight and moderately overweight people. PMID- 20719719 TI - [Comments on the topic of female fertility preservation]. PMID- 20719720 TI - Endoclamp balloon visualization and automatic placement system. AB - OBJECTIVES: Aortic occlusion is one of the most important open discussions in minimally invasive cardiac surgery. Different techniques can be employed, and all have benefits and drawbacks. The objective of our work is to improve the safety of internal aortic occlusion with the Port Access technique, which employs an endoclamp balloon catheter. We propose a combined information and positioning system based on augmented reality technology and robotics in which the position of the balloon can be seen at all times and can be automatically controlled by a robotic actuator. METHODS: The system was designed by a multidisciplinary team of engineers, medical doctors, and human factor specialists in a human-centered design approach. We measure the balloon position in real time with a magnetic tracking system. This position is superimposed on a 3-dimensional scan of the patient's thorax, with the balloon in the artery shown at all times. The position measurement is also used to control the robotic catheter inserter that places and maintains the balloon position at a specified target. The system was evaluated in 2 user studies that compared it with other visual aids. RESULTS: The user tests have shown that the system effectively supports the surgeon in the placement task, with an increase in placement accuracy and a reduction in time compared with the current visualization technique. The users also rated the system as supporting them well. CONCLUSIONS: The clinical feasibility of the system was proved. The system provides better visualization and position control and can effectively increase the safety of the procedure. This system has the potential of making Port Access a more attractive technique. PMID- 20719721 TI - Readmission to the intensive care unit after fast-track cardiac surgery: an analysis of risk factors and outcome according to the type of operation. AB - INTRODUCTION: In the present study, we investigated risk factors for intensive care unit (ICU) readmission after fasttrack cardiac surgery and analyzed outcome data according to the type of surgical procedure. METHODS: Between 1999 and 2008, we prospectively enrolled 4270 consecutive patients who underwent isolated coronary artery bypass grafting (CABG) (CABG group, n = 3754), isolated valve surgery (valve group, n = 353), or combined CABG and valve surgery (CABG + valve group, n = 163) in the study. RESULTS: Ninety-eight patients (2.2%) were readmitted to the ICU. Of these patients, 73 were in the CABG group (1.9% of this group), 16 were in the valve group (4.5%), and 9 were in the CABG + valve group (5.5%). The main reason for ICU readmission in all groups was respiratory distress. A multivariate analysis showed that the independent risk factors for ICU readmission in the CABG group were an age >65 years (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.5-5.4; P = .001), peripheral arterial disease (OR, 2.7; 95% CI, 1.2-6.1; P = .016), and drainage >500 mL (OR, 2.5; 95% CI, 1.2 5.1; P = .009). The independent risk factors for the valve group included only preoperative congestive heart failure (OR, 3.9; 95% CI, 1.3-11.7; P = .01). No independent risk factor was defined for the CABG + valve group. Mortality was significantly higher among the readmitted patients in all groups. CONCLUSIONS: The risk factors for readmission after cardiac surgery with fast-track recovery may differ according to the type of operation. A strict control of volume balance and blood transfusion may further help prevent the occurrence of the most frequent cause of readmission, respiratory failure. PMID- 20719722 TI - The nonselective beta-blocker carvedilol suppresses apoptosis in human cardiac tissue: a pilot study. AB - BACKGROUND: Cardioplegia and reperfusion of the myocardium may be associated with cardiomyocyte apoptosis and subsequent myocardial injury. To establish a pharmacologic strategy for the prevention of these events, this study aimed to verify the reliability of our human cardiac model and to evaluate the antiapoptotic properties of the nonselective beta-blocker carvedilol during simulated cardioplegia and reperfusion ex vivo. METHODS: Cardiac biopsies were retrieved before induction of cardiopulmonary bypass from the auricle of the right atrium of patients undergoing elective coronary artery bypass grafting. Biopsies were exposed to ex vivo conditions of varying periods of cardioplegia/reperfusion (30/10 minutes, 60/20 minutes, 120/40 minutes). Group I was the untreated control (n = 15), group II was the treated control (cardioplegia/reperfusion, n = 15), and group III was the experimental group (cardioplegia/reperfusion plus carvedilol, n = 15). Immunostaining for antibodies to activated caspase 3 and poly(ADP-ribose) polymerase 1 (PARP-1) cleavage was used to detect apoptosis. RESULTS: The percentage of apoptotic cardiomyocytes was significantly lower (P < .05) in group I than in group II, revealing a time dependent increase. In group III, carvedilol treatment suppressed apoptosis significantly (P < .05). CONCLUSION: Carvedilol significantly suppresses apoptosis in our ex vivo setting. This finding warrants further studies to evaluate the potential beneficial effects of carvedilol in suppressing ischemia/reperfusion injury in clinical settings. PMID- 20719723 TI - Efficacy of propafenone hydrochloride in preventing postoperative atrial fibrillation after coronary artery bypass grafting. AB - BACKGROUND: Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass grafting (CABG), and the incidence of postoperative AF (PAF) is estimated to range from 10% to 40%. PAF is a serious complication that is related to unstable hemodynamics, development of embolisms, patient discomfort, and increased medical costs associated with the prolongation of hospital stay. Sometimes, immediate attention is also necessary. In this study, we assessed the efficacy of treatment with the antiarrhythmic drug propafenone hydrochloride, which was administered in the early postoperative period, in preventing the development of PAF, and we attempted to identify risk factors for PAF. MATERIALS AND METHODS: The subjects were 78 patients who underwent isolated off-pump CABG between July 2007 and October 2008. We conducted the study by dividing the patients into 2 groups, a group of 26 patients who received propafenone hydrochloride (P group) and a control group of 52 patients who did not receive this drug (C group). The patients in the P group were given propafenone hydrochloride (150-450 mg/day orally) for 10 days, starting on the day after surgery, and were observed for the development of AF by means of continuous 12-lead electrocardiographic monitoring. Development of AF was defined as AF that lasted grade II (n = 17), perforation (n = 8), and paravalvular leakage (n = 1). Eleven transitoric ischemic attacks, 2 strokes, and 1 cerebral bleeding event were recorded. In echocardiography, the transvalvular pressure gradient changed from 10.55 to 15.02 (P = .004), 19.9 mmHg (P = .056), and 37 mmHg (not applicable) after 5, 10, and 15 years, respectively. Mean HG regurgitation was grade 0.49 before discharge and increased to 1.0 (P < .001), 0.91, and 2.5 after 5, 10, and 15 years, respectively. Ejection fraction increased from 61.9% to 64% after 5 years and to 66% after 10 years (P = .021) and then decreased to 63.5% after 15 years. CONCLUSIONS: Comparing HG with other valve prostheses, survival and graft durability seem to be confirmed. They are vulnerable to infections. The hemodynamic performance is good, and hemorrhagic or thrombo-embolic events are rare. PMID- 20719727 TI - The effect of statin therapy on stimulation of endothelium-derived nitric oxide before and after coronary artery bypass surgery. AB - BACKGROUND: The purpose of this study was to determine the effects of statins on endothelium-derived nitric oxide (NO) levels during coronary artery bypass grafting (CABG) surgery. METHODS: In a prospective study, 130 patients with coronary artery disease were randomized according to preoperative atorvastatin treatment. The patients in group 1 took 40 mg atorvastatin daily for at least 1 month preoperatively, and those in group 2 took no atorvastatin preoperatively. Plasma nitrite and nitrate were measured at baseline and after inducing reactive hyperemia, both before and after surgery. Reactive hyperemia was induced by placing a blood pressure cuff on the upper forearm, inflating it for 5 minutes at 250 mm Hg, and then rapidly deflating the cuff. Blood was collected from the radial artery on the same side 2 minutes after cuff deflation. Plasma levels of total cholesterol, triglycerides, and high- and low-density lipoproteins were measured and analyzed for correlations with NO. RESULTS: The mean (+/-SD) baseline plasma NO levels before operation were as follows: group 1, 33.97 +/- 18.27 nmol/L; group 2, 24.24 +/- 8.53 nmol/L (P < .001). A significant difference between the 2 groups in plasma NO levels was observed after preoperative reactive hyperemia induction: group 1, 56.43 +/- 15.03 nmol/L; group 2, 43.12 +/- 10.67 nmol/L (P < .001). Two hours after cardiopulmonary bypass (CPB), we observed no significant differences in plasma NO levels, either at baseline (group 1, 11 +/- 3.41 nmol/L; group 2, 9 +/- 5.51 nmol/L) or after reactive hyperemia (group 1, 17.98 +/- 6.77 nmol/L; group 2, 18.00 +/- 6.47 nmol/L). A correlation with preoperative nitroglycerine use was observed (P = .007; r = 0.23). Linear regression analysis (F = 1.463; R = 0.314; R2 = 0.099; P = .16) indicated that the only significant correlation was with preoperative nitroglycerine use (P = .007; t = 2.746). CONCLUSIONS: Preoperative atorvastatin treatment in patients with coronary artery disease increases plasma NO levels before and after reactive hyperemia prior to surgery. CABG surgery with CPB significantly impairs endothelial-derived NO levels, with or without preoperative atorvastatin treatment. Preoperative nitroglycerine use is correlated with higher NO levels after CABG. PMID- 20719728 TI - Mitral annular remodeling to treat functional mitral regurgitation: a pilot acute study in a canine model. AB - BACKGROUND: The aim of this study was to evaluate the feasibility and efficacy of the injection of a nonabsorbable substance into the base of the left ventricle (LV) to treat functional mitral regurgitation (MR). METHODS: Tyramine-based hyaluronan hydrogel was injected into the base of the LV of the beating heart in a canine model of rapid ventricular pacing-induced functional MR (n = 4). The severity of MR was evaluated by epicardial echocardiography before and after hydrogel injection. RESULTS: The injection improved MR grade from 3.4 +/- 0.8 to 1.3 +/- 0.5 (P = .006) without inducing hemodynamic instability or any evidence of myocardial ischemia. We noted significant decreases in the septal-lateral dimension at the mitral annulus (3.4 +/- 0.4 cm to 2.9 +/- 0.3 cm; P = .039) and MR volume (20.6 +/- 7.3 mm3 to 5.2 +/- 2.2 mm3; P = .044). CONCLUSIONS: A novel treatment consisting of hydrogel injection into the base of the LV between the 2 papillary muscles was found to be feasible and effective for reducing functional MR in a canine model. PMID- 20719729 TI - Balloon occlusion of the ascending aorta without hypothermic circulatory arrest in valve surgery for patients with a porcelain aorta. AB - Severe calcification of the ascending aorta and the aortic arch complicates cardiac surgery. The optimal approach in such patients is unknown. Four valve surgeries were performed with balloon occlusion without hypothermic circulatory arrest. All patients had femoral arterial cannulation, and all 3 patients who required an aortotomy had right axillary artery cannulation as well. A balloon catheter was inserted just proximal to the brachiocephalic artery via a purse string stitch. Good cardiac arrest was obtained in all cases, and a good bloodless field was obtained in all 3 aortic valve cases. There were no balloon related complications. The patients all showed good postoperative courses. Balloon occlusion of the ascending aorta without circulatory arrest is effective for performing a rapid and less invasive surgery that is not significantly different from the usual valve surgery. PMID- 20719730 TI - Steal from skeletonized internal thoracic artery graft during hemodialysis after coronary artery bypass grafting. AB - BACKGROUND: We used transthoracic Doppler echocardiography to evaluate the potential for flow variation in a skeletonized internal thoracic artery (ITA) graftc ipsilateral to an upper-extremity arteriovenous fistula during postoperative hemodialysis. METHODS: Between October 2008 and May 2009, 7 patients in chronic hemodialysis underwent coronary artery bypass grafting. We selected 5 of these patients according to the following inclusion criteria: patients who were undergoing chronic hemodialysis via a left upper-extremity arteriovenous fistula and in whom the skeletonized left ITA was anastomosed to the left anterior descending artery as an in situ graft; the right ITA was not used as a graft; postoperative multidetector computed tomography evaluation of the coronary artery demonstrated patency of the left ITA. The following parameters were calculated at baseline, after the dialysis pump was on, before the pump was turned off, and after the pump was off: peak systolic velocity, end diastolic velocity, time-averaged mean velocity, pulsatility index, and ITA diameter. Flow was calculated with the following formula: Flow = Time-Averaged Mean Velocity x (Half the Diameter of the ITA)2 x 60 x pi. RESULTS: When the hemodialysis pump was started, there was a significant reduction in the flow of the left ITA (P = .01), whereas there was no variation in the flow of the right ITA (P = .54). During dialysis, no patients experienced hypotension, arrhythmia, or angina. Just after the end of dialysis, the left ITA flow significantly increased (P = .01). CONCLUSIONS: Flow reduction of the ITA graft ipsilateral to an upper-extremity arteriovenous fistula develops during postoperative hemodialysis, even when the skeletonization technique is used. PMID- 20719731 TI - Tranexamic Acid in cardiac surgery and postoperative seizures: a case report series. AB - With the recent withdrawal of the antifibrinolytic aprotinin from the market, tranexamic acid (TxA) has become more widely used. This change has led to increasing concern about the side-effect profile of TxA, particularly the incidence of postoperative seizures. In this case series, we describe 7 patients over an 18-month period who had open-chamber cardiac surgery and developed seizures in the postoperative period. This incidence is increased compared with that of a cohort of patients in the previous 36 months who did not receive TxA (0.66% versus 0%; P < .05). The exact mechanism of TxA-induced seizures is thought to be via inhibition of gamma-aminobutyric acid receptors in neurons. Data from the neurosurgical literature show a well-established link between this antifibrinolytic and seizures. There is now increasing awareness of this association in cardiac surgery, particularly when high TxA doses are used. PMID- 20719732 TI - Simultaneous operation in a patient with coronary heart disease, abnormal orifice of coronary arteries, morgagni hernia, atrial septal defect, and pericardial and pleural agenesis. AB - A 68-year-old male patient with acute coronary syndrome was referred to our center. He also received a diagnosis of diaphragmatic hernia after a clinical examination. The patient underwent a simultaneous aorta coronary bypass operation and repair of the congenital diaphragm hernia. During the operation, the patient was observed to have an atrial septal defect. Our handling of the case is discussed in light of the literature. PMID- 20719733 TI - Dealing with a septal hematoma after switch operation with ventricular septal defect closure. AB - We report the case of a 7-day-old boy who underwent operation for transposition of the great arteries with a ventricular septal defect. An intraseptal hematoma occurred postoperatively. Because of the rarity of this complication, the optimal strategy for treating this problem is not known. We opted for a conservative approach. In the "Discussion," we elaborate on the existing literature. PMID- 20719734 TI - Single-stage repair of aneurysm of the ascending aorta associated with aortic coarctation. AB - A 38-year-old man with a history of uncontrolled hypertension was investigated for atypical chest pains and found to have an aneurysm of the ascending aorta and a coexisting coarctation of the aorta. The timing and sequence of surgical repair of these 2 pathologies are controversial. We report an elective single-stage operation in which the ascending aorta was replaced and an extracardiac bypass from the ascending to the descending aorta was performed with excellent results. PMID- 20719735 TI - Accessory mitral valve causing left ventricular outflow tract obstruction. AB - We studied the clinical characteristics and operative treatment of left ventricular outflow tract obstruction (LVOTO) caused by a congenital accessory mitral valve (AMV). Two patients were admitted to our department. Preoperatively, case 1 was diagnosed as congenital heart disease with severe LVOTO and an anterior mitral valve cleft. The patient in case 2 had a congenital atrial septal defect combined with AMV and mild LVOTO, as well as mild mitral valve regurgitation. In case 1, LVOTO was caused by a type I (fixed) AMV. In case 2, the AMV was type II (mobile type). Both AMV were resected, and the concomitant cardiac disorders were treated simultaneously. The operations were successful, and the LVOTO almost disappeared. Patients with LVOTO caused by AMV should undergo operation for removal of the accessory valve. These patients should be followed up and observed periodically by Doppler echocardiography to identify any aggravation of the LVOTO. PMID- 20719736 TI - Dynamic aortic pouch: a rare etiology of aortic regurgitation. AB - The causes of aortic regurgitation (AR) include rheumatic heart disease, infective endocarditis, and various congenital and degenerative defects. We report an unusual case of AR in a 72-year-old man due to an aortic root pouch. The diagnosis AR was made by cardiac echocardiography, and the cause was revealed by cardiac catheterization and 64-slice cardiac computed tomography. During aortic valve replacement, a saccular pouch between the noncoronary cusp and the right coronary cusp of the aortic valve was noted. PMID- 20719737 TI - Large-sized bilateral axillary artery aneurysms in a patient with marfan syndrome: a case report. AB - A 46-year-old man presented with large bilateral aneurysm of the axillary arteries combined with Marfan syndrome. Treatment consisted of axillary aneurysm resection and vessel replacement. Postoperative computed tomographic angiography confirmed good flow in the bilateral axillary artery, and the patient recovered without complication. PMID- 20719738 TI - Delayed ascending aortic dissection following off-pump coronary bypass surgery in preexisting stanford B dissection. AB - Delayed ascending aortic dissection following coronary artery bypass surgery is a rare but lethal complication. We present the case of a 54-year-old man with a delayed acute Stanford A aortic dissection following an off-pump coronary artery bypass surgery in preexisting chronic type B disease. Such a case of an iatrogenic acute aortic dissection poses a significant challenge and dilemma in choosing the best technique for coronary revascularization in this group of patients. The pathophysiology and technical options are discussed. PMID- 20719739 TI - Online social and professional support for smokers trying to quit: an exploration of first time posts from 2562 members. AB - BACKGROUND: Both intratreatment and extratreatment social support are associated with increased rates of smoking cessation. Internet-based social support groups have the capability of connecting widely dispersed groups of people trying to quit smoking, making social support available 24 hours a day, seven days a week, at minimal cost. However, to date there has been little research to guide development of this particular feature of Web-assisted tobacco interventions (WATIs). OBJECTIVE: Our objectives were to compare the characteristics of smokers who post in an online smoking cessation support group with smokers who do not post, conduct a qualitative analysis of discussion board content, and determine the time it takes for new users to receive feedback from existing members or moderators. METHODS: Data were collected from StopSmokingCenter.net version 5.0, a WATI equipped with an online social support network moderated by trained program health educators that was operational from November 6, 2004, to May 15, 2007. Demographic and smoking characteristics for both users and nonusers of the online social support network were analyzed, and qualitative analyses were conducted to explore themes in message content. Posting patterns and their frequency were also analyzed. RESULTS: During the study period, 16,764 individuals registered; of these, 70% (11,723) reported being American. The mean age of registrants was 38.9 years and 65% (10,965) were female. The mean number of cigarettes smoked was 20.6 per day. The mean score for the 41% (6849) of users who completed the Fagerstrom Test for Nicotine Dependence was 5.6. Of all registered members, 15% (2562) made at least one post in the online social support network; 25% of first posts received a response from another member within 12 minutes, 50% within 29 minutes. The most frequent first posts were from recent quitters who were struggling with their quit attempts, and most responses were from members who had quit for a month or more. Differences in demographic and smoking characteristics between members who posted on the support group board at least once and those who did not post were statistically but not clinically significant. CONCLUSIONS: Peer responses to new users were rapid, indicating that online social support networks may be particularly beneficial to smokers requiring more immediate assistance with their cessation attempt. This function may be especially advantageous for relapse prevention. Accessing this kind of rapid in-person support from a professional would take an inordinate amount of time and money. Further research regarding the effectiveness of WATIs with online social support networks is required to better understand the contribution of this feature to cessation, for both active users (posters) and passive users ("lurkers") alike. PMID- 20719740 TI - Feasibility of internet-based health-related quality of life data collection in a large patient cohort. AB - BACKGROUND: Patient registries are commonly used to track survival and medical outcomes in large cohorts. However, large-scale collection of health-related quality of life (HRQOL) data is more challenging because such data must be collected directly from patients. Internet-based HRQOL questionnaires are a potential solution, allowing home data collection with immediate storage in a central database. OBJECTIVES: Our objectives were to investigate the sociodemographic predictors of Internet use and willingness to convey HRQOL information over the Internet in a Canadian tertiary care patient population and to determine whether Internet use patterns of tertiary care patients differ from those of the general Canadian population. Additionally, we sought to identify the success of home completion of Internet-based HRQOL questionnaires, as well as factors hindering home completion. METHODS: We surveyed 644 patients at the Toronto General and St. Michael's Hospitals from November 2003 through July 2006 within a prospective, longitudinal cohort study of HRQOL in patients with lung disease or lung transplants. Using multiple logistic regression, we assessed patient age, gender, rurality, marital status, and employment or education status as potential sociodemographic predictors of having an Internet-accessible home computer, using email at least weekly, and willingness to complete a quality of life questionnaire over the Internet. Patients electing to complete questionnaires over the Internet were followed from September 2005 through March 2008 to assess completion of HRQOL questionnaires from home, identify barriers for noncompletion, and determine sociodemographic predictors for home completion. RESULTS: Of the 644 patients, the median age was 51 years, with a similar number of males and females. Most were urban Ontario residents, were unemployed, and were married or in a common-law relationship. Having an Internet-accessible home computer was reported by 79.7% (513/644) of patients and use of email at least weekly by 66.5% (414/623) of patients. A majority of patients (57.1% 368/644) were willing to complete HRQOL questionnaires over the Internet via an emailed link. Of the participating 644 patients, 368 elected to complete future questionnaires from home and, as part of a gradual roll-out of the home HRQOL questionnaire, 211 were sent emails inviting them to do so. Of the invited patients, 78% (165/211) completed at least one questionnaire from home. The most common reason for noncompletion was a lack of or an inability to find time to complete the questionnaire. No statistically significant sociodemographic predictors of Internet use were associated with completion or noncompletion of questionnaires from home. CONCLUSIONS: Home, Internet-based HRQOL assessment is feasible in tertiary care patient populations with a high predicted rate of Internet usage based on sociodemographic parameters. A large minority of patients were unwilling or unable to take part in home HRQOL assessments indicating that alternative methods of data collection are still required. However, the majority of patients electing to complete home HRQOL assessments went on to do so over the Internet. PMID- 20719741 TI - A CUG codon adapted two-hybrid system for the pathogenic fungus Candida albicans. AB - The genetics of the most common human pathogenic fungus Candida albicans has several unique characteristics. Most notably, C. albicans does not follow the universal genetic code, by translating the CUG codon into serine instead of leucine. Consequently, the use of Saccharomyces cerevisiae as a host for yeast two-hybrid experiments with C. albicans proteins is limited due to erroneous translation caused by the aberrant codon usage of C. albicans. To circumvent the need for heterologous expression and codon optimalization of C. albicans genes we constructed a two-hybrid system with C. albicans itself as the host with components that are compatible for use in this organism. The functionality of this two-hybrid system was shown by successful interaction assays with the protein pairs Kis1-Snf4 and Ino4-Ino2. We further confirmed interactions between components of the filamentation/mating MAP kinase pathway, including the unsuspected interaction between the MAP kinases Cek2 and Cek1. We conclude that this system can be used to enhance our knowledge of protein-protein interactions in C. albicans. PMID- 20719742 TI - Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes. AB - A series of oligodeoxyribonucleotides and oligoribonucleotides containing single and multiple tricyclo(tc)-nucleosides in various arrangements were prepared and the thermal and thermodynamic transition profiles of duplexes with complementary DNA and RNA evaluated. Tc-residues aligned in a non-continuous fashion in an RNA strand significantly decrease affinity to complementary RNA and DNA, mostly as a consequence of a loss of pairing enthalpy DeltaH. Arranging the tc-residues in a continuous fashion rescues T(m) and leads to higher DNA and RNA affinity. Substitution of oligodeoxyribonucleotides in the same way causes much less differences in T(m) when paired to complementary DNA and leads to substantial increases in T(m) when paired to complementary RNA. CD-spectroscopic investigations in combination with molecular dynamics simulations of duplexes with single modifications show that tc-residues in the RNA backbone distinctly influence the conformation of the neighboring nucleotides forcing them into higher energy conformations, while tc-residues in the DNA backbone seem to have negligible influence on the nearest neighbor conformations. These results rationalize the observed affinity differences and are of relevance for the design of tc-DNA containing oligonucleotides for applications in antisense or RNAi therapy. PMID- 20719743 TI - Anti-tumor activity of splice-switching oligonucleotides. AB - Alternative splicing has emerged as an important target for molecular therapies. Splice-switching oligonucleotides (SSOs) modulate alternative splicing by hybridizing to pre-mRNA sequences involved in splicing and blocking access to the transcript by splicing factors. Recently, the efficacy of SSOs has been established in various animal disease models; however, the application of SSOs against cancer targets has been hindered by poor in vivo delivery of antisense therapeutics to tumor cells. The apoptotic regulator Bcl-x is alternatively spliced to express anti-apoptotic Bcl-x(L) and pro-apoptotic Bcl-x(S). Bcl-x(L) is upregulated in many cancers and is associated with chemoresistance, distinguishing it as an important target for cancer therapy. We previously showed that redirection of Bcl-x pre-mRNA splicing from Bcl-x(L) to -x(S) induced apoptosis in breast and prostate cancer cells. In this study, the effect of SSO induced Bcl-x splice-switching on metastatic melanoma was assessed in cell culture and B16F10 tumor xenografts. SSOs were delivered in vivo using lipid nanoparticles. Administration of nanoparticle with Bcl-x SSO resulted in modification of Bcl-x pre-mRNA splicing in lung metastases and reduced tumor load, while nanoparticle alone or formulated with a control SSO had no effect. Our findings demonstrate in vivo anti-tumor activity of SSOs that modulate Bcl-x pre-mRNA splicing. PMID- 20719744 TI - PmiRKB: a plant microRNA knowledge base. AB - MicroRNAs (miRNAs), one type of small RNAs (sRNAs) in plants, play an essential role in gene regulation. Several miRNA databases were established; however, successively generated new datasets need to be collected, organized and analyzed. To this end, we have constructed a plant miRNA knowledge base (PmiRKB) that provides four major functional modules. In the 'SNP' module, single nucleotide polymorphism (SNP) data of seven Arabidopsis (Arabidopsis thaliana) accessions and 21 rice (Oryza sativa) subspecies were collected to inspect the SNPs within pre-miRNAs (precursor microRNAs) and miRNA-target RNA duplexes. Depending on their locations, SNPs can affect the secondary structures of pre-miRNAs, or interactions between miRNAs and their targets. A second module, 'Pri-miR', can be used to investigate the tissue-specific, transcriptional contexts of pre- and pri miRNAs (primary microRNAs), based on massively parallel signature sequencing data. The third module, 'MiR-Tar', was designed to validate thousands of miRNA target pairs by using parallel analysis of RNA end (PARE) data. Correspondingly, the fourth module, 'Self-reg', also used PARE data to investigate the metabolism of miRNA precursors, including precursor processing and miRNA- or miRNA*-mediated self-regulation effects on their host precursors. PmiRKB can be freely accessed at http://bis.zju.edu.cn/pmirkb/. PMID- 20719745 TI - Heart rate influence on incidence of cardiovascular disease among adults in China. AB - BACKGROUND: Higher heart rate is associated with mortality, whereas its association with clinical cardiovascular events is much more challenged. METHODS: A prospective study was conducted for 169,871 Chinese adults >=40 years in 1991 and followed during 1999-2000 with a response rate of 93.4%. Hazard ratios (HRs) were estimated by Cox proportional hazard regression model. Cardiovascular disease (CVD) was defined as diagnosis of acute myocardial infarction or stroke or death due to CVD (International Classification of Diseases, Ninth Revision: 390.0-398.9, 401.0-429.9 and 430.0-438.9). RESULTS: After an average of 8.3 years' follow-up (836,811 person-years), 6837 participants (3932 men, 2905 women) developed CVD. Compared with the participants with heart rate 60-74 beats per minute (bpm), heart rate 75-89 and >=90 bpm in men increased the risk of CVD after multivariate adjustment, with corresponding HRs [95% confidence intervals (CIs)] 1.12 (1.04-1.20) and 1.32 (1.18-1.47). Heart rate >=90 bpm increased women's risk of CVD with HR (95% CI) 1.23 (1.09-1.38). Heart rate >=75 bpm in men increased the risk of heart disease. Heart rate >=90 bpm increased the risks of coronary heart disease (CHD) and stroke in men, and the risks of heart disease and CHD in women. CONCLUSIONS: Elevated heart rate was associated with high CVD incidence in Chinese adults. This suggests that higher heart rate might be a risk marker for CVD in Chinese adults. PMID- 20719746 TI - Prenatal smoking exposure and offspring stress coping in late adolescence: no causal link. AB - BACKGROUND: In utero exposure to tobacco smoking has been suggested to cause persistent alterations in cognitive functioning. We examined if mothers' smoking during pregnancy (SDP) is associated with long-term impairment in offspring stress coping and the causal mechanism behind a possible link. METHODS: We used a large cohort (n = 187,106) of young males in Sweden (mean age = 18.2 years), who underwent a semi-structured psychological assessment in 1997-2006, including an evaluation of stress coping ability, as part of the compulsory military conscript examination. We compared differentially exposed siblings within nuclear families and cousins in extended families and used multilevel structural equation models to disentangle genetic from environmental contributions to the association between SDP and stress coping. RESULTS: SDP and offspring stress coping was moderately strongly associated when comparing unrelated individuals [regression coefficient (b) = -0.38 on a nine-point scale; 95% confidence interval (CI) -0.40 to -0.36, P < 0.0001]. In contrast, it disappeared when siblings were compared (b = 0.11; 95% CI -0.01 to 0.23, P = 0.071). This familial confounding was entirely due to genetic influences. CONCLUSIONS: SDP is an established risk factor for pregnancy- and birth-related complications. However, we found no long-term effect of SDP on offspring stress coping. Rather, the observed association was due to familial confounding of genetic origin; women prone to SDP also transmit genes to their children that are associated with poorer coping with stress. PMID- 20719748 TI - Synergistic inhibition of glycinergic transmission in vitro and in vivo by flavonoids and strychnine. AB - The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signaling in spinal cord, brain stem, and higher central nervous system regions. The flavonoids quercetin and genistein have been identified previously as promising GlyR antagonists in vitro, but their detailed mechanism of action was not known. Here, inhibition of recombinant human alpha1 GlyRs in HEK 293 cells by genistein, quercetin, and strychnine was studied using whole-cell recording techniques. The interaction of several inhibitors applied alone or in combination was analyzed using a minimum mechanism of receptor activation and inhibition. Receptor inhibition in vivo was studied in a mouse model of strychnine toxicity. Genistein, quercetin, and strychnine were noncompetitive GlyR inhibitors. The inhibitory potency of one flavonoid (either genistein or quercetin) was not affected by simultaneous application of the other, suggesting that both flavonoids target the same site on the receptor. In combination with strychnine, flavonoid inhibition was augmented, indicating that strychnine binds to a position on the receptor physically distant from the flavonoid site. Potentiation of strychnine inhibition by flavonoids was also observed in vivo, where harmless doses of flavonoids enhanced strychnine toxicity in mice. Thus, in vitro and in vivo studies demonstrated a true synergism between flavonoids and strychnine for GlyR inhibition. The mechanism-based approach used here allows a rapid analysis of the effects of single drugs versus drug combinations. PMID- 20719749 TI - Discriminating between different acute chemical toxicities via changes in the daphnid metabolome. AB - Currently, there is widespread interest in exploiting "omics" approaches to screen the toxicity of chemicals, potentially enabling their rapid categorization into classes of defined mode of action (MOA). Direct infusion Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) metabolomics provides a sensitive and nontargeted analysis of potentially a thousand endogenous metabolites. Our previous work has shown that mass spectra can be recorded from whole-organism homogenate or hemolymph of single adult Daphnia magna. Here we develop multivariate models and discover perturbations to specific metabolic pathways that can discriminate between the acute toxicities of four chemicals to D. magna using FT-ICR MS metabolomics. We focus on model toxicants (cadmium, fenvalerate, dinitrophenol, and propranolol) with different MOAs. First, we confirmed that a toxicant-induced metabolic effect could be determined for each chemical in both the hemolymph and the whole-organism metabolome, with between 9 and 660 mass spectral peaks changing intensities significantly, dependent upon toxicant and sample type. Subsequently, supervised multivariate models were built that discriminated significantly all four acute metabolic toxicities, yielding mean classification error rates (across all classes) of 3.9 and 6.9% for whole organism homogenates and hemolymph, respectively. Following extensive peak annotation, we discovered toxicant-specific perturbations to putatively identified metabolic pathways, including propranolol-induced disruption of fatty acid metabolism and eicosanoid biosynthesis and fenvalerate-induced disruption of amino sugar metabolism. We conclude that the metabolic profiles of whole-daphnid homogenates are more discriminatory for toxicant action than hemolymph. Furthermore, our findings highlight the capability of metabolomics to discover early-event metabolic responses that can discriminate between the acute toxicities of chemicals. PMID- 20719750 TI - Cobalt-Induced lung injury and hypoxia-inducible factor 1 alpha. PMID- 20719751 TI - An evaluation of a personal electronic device to enhance self-monitoring adherence in a pediatric weight management program using a multiple baseline design. AB - OBJECTIVE: To examine the effectiveness of a personal electronic device (PED) in order to improve adherence to self-monitoring of dietary intake and physical activity. METHOD: The impact of a PED on adherence to self-monitoring goals was examined in a multiple baseline design across three overweight adolescents. During baseline, a traditional paper-and-pencil method of self-monitoring was utilized. The subsequent study phase introduced a PED for self-monitoring. Percent self-monitoring goal attainment was the outcome of interest. RESULTS: During baseline, attainment of self-monitoring goals was low for all three participants (3-4%). Each subject's percent attainment of self-monitoring goal increased upon the introduction of the PED. For two of the three subjects this increase was stable (~75 and 100%) post-intervention. For the third subject the increase in percent attainment of self-monitoring goal was more variable but remained above baseline levels. CONCLUSION: PEDs have potential for improving self-monitoring in the context of behavioral weight management treatment for adolescents. PMID- 20719752 TI - Adolescent and parent perceptions of patient-centered communication while managing type 1 diabetes. AB - OBJECTIVE: To examine whether adolescents' and parents' perceptions of patient centered communication (PCC) with the physician may be associated with aspects of patient empowerment (e.g., perceptions of competence) and diabetes management (i.e., adherence and HbA1c). METHODS: One hundred and ninety adolescents with type 1 diabetes and their parents rated perceptions of PCC following a clinic visit and completed measures of competence, illness perceptions, self-efficacy, and adherence in the weeks following their clinic visit, and again 6 months later. Metabolic control was indexed from medical records. RESULTS: Higher levels of PCC with physicians were associated cross-sectionally and longitudinally with greater perceptions of control and competence for both adolescents and parents. Mediation analyses indicated that PCC was indirectly related to subsequent adherence and metabolic control through perceptions of the adolescent's competence in diabetes management. CONCLUSIONS: Perceptions of PCC with healthcare providers may empower adolescents and parents in their diabetes management. PMID- 20719753 TI - Feeling of burden, psychological distress, and anxiety among primary caregivers of children with home enteral nutrition. AB - OBJECTIVE: To examine the relationship between several psychological factors and the feeling of burden experienced by caregivers of children with home enteral nutrition. METHODS: Fifty-six mothers of pediatric patients with chronic diseases requiring long-term home enteral nutrition were recruited. They were asked to respond to specific questionnaires about their anxiety symptoms (State-Trait Anxiety Inventory), psychological distress (SCL-90-R) and feeling of burden (Zarit-scale). RESULTS: Caregivers' feeling of burden was found to be statistically associated to psychological distress (r = .516, p < .001) and trait anxiety (r = .376, p = .005). No significant differences were found between the type of diagnosis and caregiver burden. Regression analysis indicated psychological distress has a partial mediational effect in the relationship between trait anxiety and caregivers' burden. CONCLUSIONS: Psychological distress and anxiety show a positive correlation with caregivers' feeling of burden, and may disrupt family well-being. Early identification of high-risk situations is essential in order to plan specific psychosocial aid efficiently. PMID- 20719758 TI - When should precaution prevail? Interests in (public) health, the risk of harm and xenotransplantation. PMID- 20719759 TI - Expression and regulation of GPAT isoforms in cultured human keratinocytes and rodent epidermis. AB - Phospholipids are required for epidermal lamellar body formation. Glycerol 3 phosphate acyltransferases (GPATs) catalyze the initial step in the biosynthesis of glycerolipids. Little is known about the expression and regulation of GPATs in epidermis/keratinocytes. Here, we demonstrate that GPAT 1, 3, and 4 are expressed in epidermis/keratinocytes, whereas GPAT2 is not detected. In mouse epidermis, GPAT 3 and 4 are mainly localized to the upper layers whereas GPAT1 is found in both the upper and lower layers. GPAT1 and 3 mRNA increase during fetal rat epidermal development. No change in GPAT expression was observed in adult mice following acute permeability barrier disruption. Calcium-induced human keratinocyte differentiation increased GPAT3 mRNA whereas both GPAT1 and 4 mRNA levels decreased. In parallel, total GPAT activity increased 2-fold in differentiated keratinocytes attributable to an increase in N-ethylmaleimide (NEM) sensitive GPAT activity localized to microsomes with little change in NEM resistant activity, consistent with an increase in GPAT3. Furthermore, PPARgamma or PPARdelta activators increased GPAT3 mRNA, microsomal GPAT activity, and glycerol lipid synthesis without affecting the expression of GPAT1 or 4. Finally, both PPARgamma and PPARdelta activators increased GPAT3 mRNA via increasing its transcription. Thus, multiple isoforms of GPAT are expressed and differentially regulated in epidermis/keratinocytes. PMID- 20719760 TI - Comprehensive analysis of the major lipid classes in sebum by rapid resolution high-performance liquid chromatography and electrospray mass spectrometry. AB - Sebum is a complex lipid mixture that is synthesized in sebaceous glands and excreted on the skin surface. The purpose of this study was the comprehensive detection of the intact lipids that compose sebum. These lipids exist as a broad range of chemical structures and concentrations. Sebum was collected with SebuTape(TM) from the foreheads of healthy donors, and then separated by HPLC on a C8 stationary phase with sub 2 um particle size. This HPLC method provided high resolution and excellent reproducibility of retention times (RT). Compound mining was performed with time of flight (TOF) and triple quadrupole (QqQ) mass spectrometers (MS), which allowed for the classification of lipids according to their elemental composition, degree of unsaturation, and MS/MS fragmentation. The combination of the two MS systems detected 95 and 29 families of triacylglycerols (TAG) and diacylglycerols (DAG), respectively. Assignment was carried out regardless of positional isomerism. Among the wax esters (WE), 28 species were found to contain the 16:1 fatty acyl moiety. This method was suitable for the simultaneous detection of squalene and its oxygenated derivative. A total of 9 cholesterol esters (CE) were identified and more than 48 free fatty acids (FFA) were detected in normal sebum. The relative abundance of each individual lipid within its own chemical class was determined for 12 healthy donors. In summary, this method provided the first characterization of the features and distribution of intact components of the sebum lipidome. PMID- 20719761 TI - Module-based prediction approach for robust inter-study predictions in microarray data. AB - MOTIVATION: Traditional genomic prediction models based on individual genes suffer from low reproducibility across microarray studies due to the lack of robustness to expression measurement noise and gene missingness when they are matched across platforms. It is common that some of the genes in the prediction model established in a training study cannot be matched to another test study because a different platform is applied. The failure of inter-study predictions has severely hindered the clinical applications of microarray. To overcome the drawbacks of traditional gene-based prediction (GBP) models, we propose a module based prediction (MBP) strategy via unsupervised gene clustering. RESULTS: K means clustering is used to group genes sharing similar expression profiles into gene modules, and small modules are merged into their nearest neighbors. Conventional univariate or multivariate feature selection procedure is applied and a representative gene from each selected module is identified to construct the final prediction model. As a result, the prediction model is portable to any test study as long as partial genes in each module exist in the test study. We demonstrate that K-means cluster sizes generally follow a multinomial distribution and the failure probability of inter-study prediction due to missing genes is diminished by merging small clusters into their nearest neighbors. By simulation and applications of real datasets in inter-study predictions, we show that the proposed MBP provides slightly improved accuracy while is considerably more robust than traditional GBP. AVAILABILITY: http://www.biostat.pitt.edu/bioinfo/ CONTACT: ctseng@pitt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20719762 TI - Methylene blue-mediated photodynamic inactivation as a novel disinfectant of enterovirus 71. AB - OBJECTIVES: We tested whether methylene blue, an inexpensive and safe photosensitizer, is feasible for photodynamic inactivation of enterovirus 71 (EV71) in the environment. METHODS: By escalating light doses and photosensitizer concentrations, photoinactivation of EV71 and other enteroviruses was examined in vitro. Viral transmission in the environment was simulated with a neonatal mouse model in vivo. Possible mechanisms were analysed with alterations of viral DNA and proteins after treatments. RESULTS: Photodynamic inactivation of EV71 in suspensions occurred in a dose-dependent manner. The optimal condition for photoinactivating EV71 required a light dose of 200 J/cm(2) in the presence of methylene blue. This photodynamic condition was also able to inactivate other enteroviruses, including poliovirus 1 and coxsackieviruses A2, A3, A16 and B3. In an imitation environment, EV71 spread on a solid surface was inactivated by methylene blue-mediated photodynamic inactivation and prevented EV71 transmission to mice. Western blot and RT-PCR analysis indicated that both the viral proteins and the genome were disrupted after photodynamic inactivation. CONCLUSIONS: Methylene blue-mediated photodynamic inactivation may provide a novel way to eliminate environmentally contaminated sources of EV71 to prevent infection. PMID- 20719763 TI - Rifampicin enhances activity of daptomycin and vancomycin against both a polysaccharide intercellular adhesin (PIA)-dependent and -independent Staphylococcus epidermidis biofilm. AB - OBJECTIVES AND METHODS: This study addressed the efficacy of daptomycin, vancomycin, rifampicin, daptomycin/rifampicin and vancomycin/rifampicin against a polysaccharide intercellular adhesin (PIA)-dependent and -independent Staphylococcus epidermidis biofilm using flow cell and guinea pig tissue cage models. RESULTS: The flow cell model of both PIA-dependent and -independent biofilms demonstrated that the viable cell count after treatment with daptomycin/rifampicin was significantly lower (P<0.05) than after treatment with vancomycin, vancomycin/rifampicin, daptomycin or rifampicin alone. To validate these observations, a guinea pig tissue cage model was used. The results demonstrated that the addition of rifampicin to daptomycin or vancomycin sterilized 5/6 tissues cages colonized with S. epidermidis 1457 (PIA producing). Similar results were noted with S. epidermidis 1457 icaADBC::dhfr (non-PIA producing), where daptomycin/rifampicin and vancomycin/rifampicin sterilized 5/6 and 6/6 tissue cages, respectively. There was no statistical difference in comparison with the no-treatment control when both 1457 and 1457 icaADBC::dhfr were treated with vancomycin and daptomycin alone. Furthermore, treatment with rifampicin alone sterilized 5/6 and 3/6 1457 and 1457 icaADBC::dhfr tissue cages, respectively. CONCLUSIONS: Interpretation of these data suggests that rifampicin is highly active against S. epidermidis biofilms and both vancomycin and daptomycin are effective at reducing the subpopulation of bacteria that develop rifampicin resistance. PMID- 20719764 TI - Anti-tubercular screening of natural products from Colombian plants: 3 methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis. AB - OBJECTIVES: New anti-mycobacterial entities with novel mechanisms of action are clinically needed for treating resistant forms of tuberculosis. The purpose of this study was to evaluate anti-tubercular activity and selectivity of seven recently isolated natural products from Colombian plants. METHODS: MICs were determined using a liquid medium growth inhibition assay for Mycobacterium tuberculosis H(37)Rv and both solid and liquid media growth inhibition assays for Mycobacterium bovis BCG. Escherichia coli growth inhibition and mammalian macrophage cell toxicity were evaluated to establish the degree of selectivity of the natural product against whole cell organisms. Enzymatic inhibition of ATP dependent MurE ligase from M. tuberculosis was assayed using a colorimetric phosphate detection method. The most active compound, 3-methoxynordomesticine hydrochloride, was further investigated on M. bovis BCG for its inhibition of sigmoidal growth, acid-fast staining and viability counting analysis. RESULTS: Aporphine alkaloids were found to be potent inhibitors of slow-growing mycobacterial pathogens showing favourable selectivity and cytotoxicity. In terms of their endogenous action, the aporphine alkaloids were found inhibitory to M. tuberculosis ATP-dependent MurE ligase at micromolar concentrations. A significantly low MIC was detected for 3-methoxynordomesticine hydrochloride against both M. bovis BCG and M. tuberculosis H(37)Rv. CONCLUSIONS: Considering all the data, 3-methoxynordomesticine hydrochloride was found to be a potent anti tubercular compound with a favourable specificity profile. The alkaloid showed MurE inhibition and is considered an initial hit for exploring related chemical space. PMID- 20719765 TI - Evidence for multiple group 1 late embryogenesis abundant proteins in encysted embryos of Artemia and their organelles. AB - The presence of late embryogenesis abundant (LEA) proteins in plants and animals has been linked to their ability to tolerate a variety of environmental stresses. Among animals, encysted embryos of the brine shrimp Artemia franciscana are among the most stress resistant eukaryotes, and for that reason it is considered to be an extremophile. The study presented here demonstrates that these embryos contain multiple group 1 LEA proteins with masses of 21, 19, 15.5 and 13 kDa. The LEA proteins first appear in diapause-destined embryos, beginning at ~4 days post fertilization, but not in nauplii-destined embryos. After resumption of embryonic development, the LEA proteins decline slowly in the desiccation resistant encysted stages, then disappear rapidly as the embryo emerges from its shell. LEA proteins are absent in fully emerged embryos, larvae and adults. They are abundant in mitochondria of encysted embryos, but barely detectable in nuclei and absent from yolk platelets. LEA proteins were also detected in dormant embryos of six other species of Artemia from hypersaline environments around the world. This study enhances our knowledge of the group 1 LEA proteins in stress tolerant crustacean embryos. PMID- 20719766 TI - Function of GRAS proteins in root nodule symbiosis is retained in homologs of a non-legume, rice. AB - Root nodule (RN) symbiosis in legumes shares genes involved in the early signaling pathway with more ancient arbuscular mycorrhiza (AM) symbiosis, which is widespread in higher plants. The non-legume homologs of such genes have been well documented to be not only essential for the AM symbiosis in non-legume mycorrhizal plants but also functional in the RN symbiosis in legume plants. In contrast, it has not been investigated in detail whether RN symbiosis-specific genes, which are not essential for AM symbiosis, are functionally conserved in non-legumes. Two GRAS-domain transcription factors, NSP1 and NSP2, have been shown to be required for RN symbiosis, but not for AM symbiosis. In this study, we demonstrated that their homologs, OsNSP1 and OsNSP2, from rice are able to fully rescue the RN symbiosis-defective phenotypes of the mutants of corresponding genes in the model legume, Lotus japonicus. Our results indicate that some of the genes essential for RN symbiosis conserve their functions in homologs from non-legumes, which do not nodulate. PMID- 20719767 TI - Abstracts of the British Geriatrics Society Spring Meeting. April 22-24, 2010. Edinburgh, Scotland, United Kingdom. PMID- 20719769 TI - Taxonomic counts of cognition in the wild. AB - In 1985, Kummer & Goodall pleaded for an ecology of intelligence and proposed that innovations might be a good way to measure cognition in the wild. Counts of innovation per taxonomic group are now available in hundreds of avian and primate species, as are counts of tactical deception, tool use and social learning. Robust evidence suggests that innovation rate and its neural correlates allow birds and mammals to cope better with environmental change. The positive correlations between taxonomic counts, and the increasing number of cognitive and neural measures found to be associated with ecological variables, suggest that domain general processes might be more pervasive than previously thought in the evolution of intelligence. PMID- 20719770 TI - Ancient death-grip leaf scars reveal ant-fungal parasitism. AB - Parasites commonly manipulate host behaviour, and among the most dramatic examples are diverse fungi that cause insects to die attached to leaves. This death-grip behaviour functions to place insects in an ideal location for spore dispersal from a dead body following host death. Fossil leaves record many aspects of insect behaviour (feeding, galls, leaf mining) but to date there are no known examples of behavioural manipulation. Here, we document, to our knowledge, the first example of the stereotypical death grip from 48 Ma leaves of Messel, Germany, indicating the antiquity of this behaviour. As well as probably being the first example of behavioural manipulation in the fossil record, these data support a biogeographical parallelism between mid Eocene northern Europe and recent southeast Asia. PMID- 20719771 TI - Brothers delay menarche and the onset of sexual activity in their sisters. AB - The higher costs of sons compared with daughters extends to a negative effect of brothers on the lifetime reproductive success of their siblings in subsistence and preindustrial societies. In societies with fewer resource constraints, one might expect that these effects would be limited or non-existent. This study investigates the costs of brothers and sisters in a contemporary western society of adult Australians. Girls with elder brothers had a delayed age at menarche. Younger brothers were associated with delayed onset of sexual activity in sisters, but not in brothers. Neither younger nor elder brothers influenced fitness parameters (number of pregnancies, number of children, age at first pregnancy or age at first birth) in siblings of either sex. This study provides evidence that brothers negatively affect their sisters' onset of reproductive maturity and sexual activity; however, this delay is not associated with a fitness cost in contemporary Australia. We suggest this is due to the long period of independence prior to child bearing. PMID- 20719768 TI - Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. AB - The identification and production of recombinant morphogens and growth factors that play key roles in tissue regeneration have generated much enthusiasm and numerous clinical trials, but the results of many of these trials have been largely disappointing. Interestingly, the trials that have shown benefit all contain a common denominator, the presence of a material carrier, suggesting strongly that spatio-temporal control over the location and bioactivity of factors after introduction into the body is crucial to achieve tangible therapeutic effect. Sophisticated materials systems that regulate the biological presentation of growth factors represent an attractive new generation of therapeutic agents for the treatment of a wide variety of diseases. This review provides an overview of growth factor delivery in tissue engineering. Certain fundamental issues and design strategies relevant to the material carriers that are being actively pursued to address specific technical objectives are discussed. Recent progress highlights the importance of materials science and engineering in growth factor delivery approaches to regenerative medicine. PMID- 20719772 TI - Adaptive auditory risk assessment in the dogbane tiger moth when pursued by bats. AB - Moths and butterflies flying in search of mates risk detection by numerous aerial predators; under the cover of night, the greatest threat will often be from insectivorous bats. During such encounters, the toxic dogbane tiger moth, Cycnia tenera uses the received intensity, duration and emission pattern of the bat's echolocation calls to determine when, and how many, defensive ultrasonic clicks to produce in return. These clicks, which constitute an acoustic startle response, act as warning signals against bats in flight. Using an integrated test of stimulus generalization and dishabituation, here we show that C. tenera is able to discriminate between the echolocation calls characteristic of a bat that has only just detected it versus those of a bat actively in pursuit of it. We also show that C. tenera habituates more profoundly to the former stimulus train ('early attack') than to the latter ('late attack'), even though it was initially equally responsive to both stimuli. Matched sensory and behavioural data indicate that reduced responsiveness reflects habituation and is not merely attributable to sensory adaptation or motor fatigue. In search of mates in the face of bats, C. tenera's ability to discriminate between attacking bats representing different levels of risk, and to habituate less so to those most dangerous, should function as an adaptive cost-benefit trade-off mechanism in nature. PMID- 20719773 TI - The evolution of punishment through reputation. AB - Punishment of non-cooperators has been observed to promote cooperation. Such punishment is an evolutionary puzzle because it is costly to the punisher while beneficial to others, for example, through increased social cohesion. Recent studies have concluded that punishing strategies usually pay less than some non punishing strategies. These findings suggest that punishment could not have directly evolved to promote cooperation. However, while it is well established that reputation plays a key role in human cooperation, the simple threat from a reputation of being a punisher may not have been sufficiently explored yet in order to explain the evolution of costly punishment. Here, we first show analytically that punishment can lead to long-term benefits if it influences one's reputation and thereby makes the punisher more likely to receive help in future interactions. Then, in computer simulations, we incorporate up to 40 more complex strategies that use different kinds of reputations (e.g. from generous actions), or strategies that not only include punitive behaviours directed towards defectors but also towards cooperators for example. Our findings demonstrate that punishment can directly evolve through a simple reputation system. We conclude that reputation is crucial for the evolution of punishment by making a punisher more likely to receive help in future interactions, and that experiments investigating the beneficial effects of punishment in humans should include reputation as an explicit feature. PMID- 20719774 TI - Running backwards: soft landing-hard takeoff, a less efficient rebound. AB - Human running at low and intermediate speeds is characterized by a greater average force exerted after 'landing', when muscle-tendon units are stretched ('hard landing'), and a lower average force exerted before 'takeoff', when muscle tendon units shorten ('soft takeoff'). This landing-takeoff asymmetry is consistent with the force-velocity relation of the 'motor' (i.e. with the basic property of muscle to resist stretching with a force greater than that developed during shortening), but it may also be due to the 'machine' (e.g. to the asymmetric lever system of the foot operating during stance). Hard landing and soft takeoff-never the reverse-were found in running, hopping and trotting animals using diverse lever systems, suggesting that the different machines evolved to comply with the basic force-velocity relation of the motor. Here we measure the mechanical energy of the centre of mass of the body in backward running, an exercise where the normal coupling between motor and machine is voluntarily disrupted, in order to see the relevance of the motor-machine interplay in human running. We find that the landing-takeoff asymmetry is reversed. The resulting 'soft landing' and 'hard takeoff' are associated with a reduced efficiency of positive work production. We conclude that the landing takeoff asymmetry found in running, hopping and trotting is the expression of a convenient interplay between motor and machine. More metabolic energy must be spent in the opposite case when muscle is forced to work against its basic property (i.e. when it must exert a greater force during shortening and a lower force during stretching). PMID- 20719775 TI - How the insect immune system interacts with an obligate symbiotic bacterium. AB - The animal immune system provides defence against microbial infection, and the evolution of certain animal-microbial symbioses is predicted to involve adaptive changes in the host immune system to accommodate the microbial partner. For example, the reduced humoral immune system in the pea aphid Acyrthosiphon pisum, including an apparently non-functional immune deficiency (IMD) signalling pathway and absence of peptidoglycan recognition proteins (PGRPs), has been suggested to be an adaptation for the symbiosis with the bacterium Buchnera aphidicola. To investigate this hypothesis, the interaction between Buchnera and non-host cells, specifically cultured Drosophila S2 cells, was investigated. Microarray analysis of the gene expression pattern in S2 cells indicated that Buchnera triggered an immune response, including upregulated expression of genes for antimicrobial peptides via the IMD pathway with the PGRP-LC as receptor. Buchnera cells were readily taken up by S2 cells, but were subsequently eliminated over 1-2 days. These data suggest that Buchnera induces in non-host cells a defensive immune response that is deficient in its host. They support the proposed contribution of the Buchnera symbiosis to the evolution of the apparently reduced immune function in the aphid host. PMID- 20719776 TI - Intra-locus sexual conflict and sexually antagonistic genetic variation in hermaphroditic animals. AB - Intra-locus sexual conflict results when sex-specific selection pressures for a given trait act against the intra-sexual genetic correlation for that trait. It has been found in a wide variety of taxa in both laboratory and natural populations, but the importance of intra-locus sexual conflict and sexually antagonistic genetic variation in hermaphroditic organisms has rarely been considered. This is not so surprising given the conceptual and theoretical association of intra-locus sexual conflict with sexual dimorphism, but there is no a priori reason why intra-locus sexual conflict cannot occur in hermaphroditic organisms as well. Here, I discuss the potential for intra-locus sexual conflict in hermaphroditic animals and review the available evidence for such conflict, and for the existence of sexually antagonistic genetic variation in hermaphrodites. I argue that mutations with asymmetric effects are particularly likely to be important in mediating sexual antagonism in hermaphroditic organisms. Moreover, sexually antagonistic genetic variation is likely to play an important role in inter-individual variation in sex allocation and in transitions to and from gonochorism (separate sexes) in simultaneous hermaphrodites. I also describe how sequential hermaphrodites may experience a unique form of intra locus sexual conflict via antagonistic pleiotropy. Finally, I conclude with some suggestions for further research. PMID- 20719777 TI - Genetic and 'cultural' similarity in wild chimpanzees. AB - The question of whether animals possess 'cultures' or 'traditions' continues to generate widespread theoretical and empirical interest. Studies of wild chimpanzees have featured prominently in this discussion, as the dominant approach used to identify culture in wild animals was first applied to them. This procedure, the 'method of exclusion,' begins by documenting behavioural differences between groups and then infers the existence of culture by eliminating ecological explanations for their occurrence. The validity of this approach has been questioned because genetic differences between groups have not explicitly been ruled out as a factor contributing to between-group differences in behaviour. Here we investigate this issue directly by analysing genetic and behavioural data from nine groups of wild chimpanzees. We find that the overall levels of genetic and behavioural dissimilarity between groups are highly and statistically significantly correlated. Additional analyses show that only a very small number of behaviours vary between genetically similar groups, and that there is no obvious pattern as to which classes of behaviours (e.g. tool-use versus communicative) have a distribution that matches patterns of between-group genetic dissimilarity. These results indicate that genetic dissimilarity cannot be eliminated as playing a major role in generating group differences in chimpanzee behaviour. PMID- 20719778 TI - Divergence and ontogenetic coupling of larval behaviour and thermal reaction norms in three closely related butterflies. AB - Genetic trade-offs such as between generalist-specialist strategies can be masked by changes in compensatory processes involving energy allocation and acquisition which regulation depends on the state of the individual and its ecological surroundings. Failure to account for such state dependence may thus lead to misconceptions about the trade-off structure and nature of constraints governing reaction norm evolution. Using three closely related butterflies, we first show that foraging behaviours differ between species and change remarkably throughout ontogeny causing corresponding differences in the thermal niches experienced by the foraging larvae. We further predicted that thermal reaction norms for larval growth rate would show state-dependent variation throughout development as a result of selection for optimizing feeding strategies in the respective foraging niches of young and old larvae. We found substantial developmental plasticity in reaction norms that was species-specific and reflected the different ontogenetic niche shifts. Any conclusions regarding constraints on performance curves or species-differentiation in thermal physiology depend on when reaction norms were measured. This demonstrates that standardized estimates at single points in development, or in general, allow variation in only one ecological dimension, may sometimes provide incomplete information on reaction norm constraints. PMID- 20719779 TI - Pre-implantation implantable cardioverter defibrillator concerns and Type D personality increase the risk of mortality in patients with an implantable cardioverter defibrillator. AB - AIMS: Little is known about the influence of psychological factors on prognosis in implantable cardioverter defibrillator (ICD) patients. We examined the influence of the distressed personality (Type D) and pre-implantation device concerns on short-term mortality in ICD patients. METHODS AND RESULTS: Consecutively implanted ICD patients (N = 371; 79.5% men) completed the Type D Scale and the ICD Patient Concerns questionnaire prior to implantation and were followed up for short-term mortality. The prevalence of Type D was 22.4%, whereas 34.2% had high levels of ICD concerns. The incidence of mortality was higher in Type D vs. non-Type D patients [13.3% vs. 4.92%; hazard ratio (HR): 2.74; 95% confidence interval (CI): 1.24-6.03] and in patients with high vs. low levels of ICD concerns (11.0% vs. 4.5%; HR: 2.38; 95% CI: 1.08-5.23). Type D personality (HR: 2.79; 95% CI: 1.25-6.21) and high levels of ICD concerns (HR: 2.38; 95% CI: 1.06-5.34) remained independent predictors of mortality in separate analyses, adjusting for sex, age, ICD indication, coronary artery disease, and shocks. Patients with clustering of both Type D personality and high levels of pre implantation concerns (HR: 3.86; 95% CI: 1.64-9.10) had a poorer survival compared with patients with one or none of these risk markers in adjusted analysis. Shocks during the follow-up period were also associated with mortality (HR: 3.09; 95% CI: 1.36-7.04). CONCLUSION: Patients with a distressed personality and high levels of pre-implantation device-related concerns had a poorer prognosis, independent of other risk markers including shocks. This subgroup of patients should be identified in clinical practice and would likely benefit from a combined distress management programme and cardiac rehabilitation. PMID- 20719780 TI - Cryoablation: how to improve results in atrioventricular nodal reentrant tachycardia ablation? AB - Ablation for atrioventricular nodal reentry tachycardia is very effective, with a potential for damage to the normal conduction system. Cryoablation is an alternative, as it allows cryomapping, which permits assessment of slow pathway elimination at innocent freezing temperatures, avoiding permanent damage to the normal conduction system. It is associated with shorter radiation times and the absence of heart block in all published data. We discuss in this overview different approaches of cryoenergy delivery (focusing on spot catheter ablation), and how lesion formation is influenced by catheter tip size, application duration, and freezing rate. Some advantages of cryoenergy are explained. Whether these features also apply for an approach with a cryoballoon, e.g. for atrial fibrillation is unclear. PMID- 20719781 TI - Doubly robust estimation of attributable fractions. AB - The attributable fraction (AF) is a widely used measure to assess the impact of an exposure on a disease. It is commonly estimated through maximum likelihood, which requires a regression model for the outcome. Recently, it was demonstrated that the AF can also be estimated through inverse probability weighting, which requires a model for the exposure. In this paper, we derive doubly robust estimators for the AF. These estimators require one model for the outcome and one model for the exposure and are consistent if either model is correct, not necessarily both. We consider both cohort/cross-sectional studies and case control studies. PMID- 20719782 TI - Constrained inference in mixed-effects models for longitudinal data with application to hearing loss. AB - In medical studies, endpoints are often measured for each patient longitudinally. The mixed-effects model has been a useful tool for the analysis of such data. There are situations in which the parameters of the model are subject to some restrictions or constraints. For example, in hearing loss studies, we expect hearing to deteriorate with time. This means that hearing thresholds which reflect hearing acuity will, on average, increase over time. Therefore, the regression coefficients associated with the mean effect of time on hearing ability will be constrained. Such constraints should be accounted for in the analysis. We propose maximum likelihood estimation procedures, based on the expectation-conditional maximization either algorithm, to estimate the parameters of the model while accounting for the constraints on them. The proposed methods improve, in terms of mean square error, on the unconstrained estimators. In some settings, the improvement may be substantial. Hypotheses testing procedures that incorporate the constraints are developed. Specifically, likelihood ratio, Wald, and score tests are proposed and investigated. Their empirical significance levels and power are studied using simulations. It is shown that incorporating the constraints improves the mean squared error of the estimates and the power of the tests. These improvements may be substantial. The methodology is used to analyze a hearing loss study. PMID- 20719783 TI - Thoracic empyema in high-risk patients: conservative management or surgery? AB - We retrospectively analyzed the data of 119 patients who were treated for empyema thoracis from 1999 to 2007. There were 87 men with a mean age of 63.9 years (range, 19-79 years) and 32 women with a mean age 55.2 years (range, 26-78 years). The empyema was right-sided in 73 patients and left-sided in 46. The etiology was parapneumonic in 43.7% of cases, postoperative in 42.0%, posttraumatic in 11.8%, and due to other causes in 2.5%. Eight (6.7%) patients underwent surgery on admission because of unstable clinical status; all 8 survived. Fibrinolysis was used in 111 (93.3%) patients; of these, 88 (73.9%) were successfully treated by intrapleural urokinase instillation, and 23 (19.4%) failed treatment and underwent surgery. All 88 patients who had successful fibrinolytic therapy survived, they accounted for 1.8% of the morbidity. In the 23 patients who underwent surgery after failed treatment, there were 3 deaths, accounting for 2.7% overall mortality and 6.3% morbidity. Treating thoracic empyema in patients with significant comorbidities is challenging. Intrapleural urokinase administration might be beneficial in high-risk patients, but in those without significant comorbidities, early surgery may be considered. PMID- 20719784 TI - Blood pressure variability in patients with diabetes mellitus. AB - Reduced arterial compliance in patients with diabetes mellitus has been shown in several studies, but it has not been significantly associated with either atherosclerosis or vessel wall thickness. Blood pressure variability is still poorly explored in diabetic patients. The aim of this study was to compare blood pressure variability and arterial compliance in patients with type 2 diabetes mellitus and controls matched for sex, age, and weight. Arterial compliance was measured and noninvasive 24-h ambulatory blood pressure monitoring was performed in 18 diabetic patients and 18 controls. There was significantly higher 24-h systolic blood pressure variability (17.7 +/- 6.8 vs. 14.6 +/- 2.6 mm Hg), diastolic blood pressure variability (15.6 +/- 7.1 vs. 11.4 +/- 3.1 mm Hg), and mean arterial blood pressure variability (14.8 +/- 7.0 vs. 11.1 +/- 2.9) in diabetic patients. Systolic, diastolic, and mean arterial blood pressure variability was significantly higher during daytime but not night time in diabetic patients compared to controls. Diabetic patients also had significantly reduced small artery compliance, but no differences in large artery compliance, cardiac output, or systemic vascular resistance. The findings suggest that hyperglycemia may affect the compliance of the vascular system, resulting in high blood pressure fluctuations. PMID- 20719785 TI - Absence of calcium channel alpha1C-subunit mutation in human atrial fibrillation. AB - L-type voltage-gated calcium channel mutation or phenotypical variation resulting from alternative splicing has been associated with sudden arrhythmogenic death and heart failure. Changes in calcium current density, protein and mRNA expression have been associated with atrial fibrillation. We studied human atrium harvested from 16 cardiac surgery patients (coronary bypass and/or valve procedures) for mutation of Ca(v)1.2 alpha(1C) (the main pore-forming subunit of L-type voltage-gated calcium channel) for an association with atrial fibrillation. Seven patients had persistent atrial fibrillation and one was resuscitated from ventricular arrhythmia. Clinical data were collected and prospectively updated for the development of arrhythmia. Four (25%) patients had new-onset postoperative paroxysmal atrial fibrillation. DNA from all atrial specimens was amplified, extracted, and sequenced. The alpha(1C)-subunit mutation was absent in all specimens obtained from all patients, regardless of heart rhythm. This suggests that atrial fibrillation is not associated with loss-of function mutation of the main pore-forming subunit of the L-type voltage-gated calcium channel. PMID- 20719786 TI - Clinical outcomes of medical treatment of acute type A intramural hematoma. AB - A retrospective study was performed in 30 patients who were treated for type A intramural hematoma from 1999 to 2008, of whom 24 were initially treated without surgical intervention. These 24 patients were followed up for 3.3 +/- 3.5 years (range, 0 days to 10.0 years). Four hospital deaths occurred (hospital mortality, 16.7%), there were 2 late deaths, and 2 other patients needed an operation during the follow-up period. The event-free survival rate (freedom from death or surgery) at 5 years was significantly lower in patients with maximal aortic diameter > or =48 mm than in those with diameters <48 mm (28.6% +/- 17.1% vs. 88.2% +/- 7.8%). Maximal aortic diameter > or =48 mm and computed tomography findings of a small intimal defect were significant predictors of rupture or progression of ascending aortic dissection. The outcome of medical treatment for type A intramural hematoma was acceptable during both the early and late periods, but patients with a relatively large aortic diameter or an intimal defect in the ascending aorta have a high probability of adverse outcome, and must be considered for surgery. PMID- 20719787 TI - Role of vacuum in methicillin-resistant deep sternal wound infection. AB - Between January 2002 and January 2009, 39 patients with post-cardiotomy staphylococcal deep sternal wound infection were treated primarily by a vacuum assisted closure method (group A). Results were compared with those of 30 patients with staphylococcal deep sternal wound infection who received closed mediastinal irrigation with antibiotics (group B). The prevalence of methicillin resistance was similarly high in both groups (64.1% in A, 56.7% in B). One group B patient died during treatment. The median healing time was significantly shorter at 13 days in group A (mean, 13.5 +/- 3.2 days) compared to 18 days (mean, 21.2 +/- 16.4 days) in group B. Deep sternal wound infection did not recur after vacuum treatment, while 7 (24%) patients in group B suffered a recurrence. Hospital stay was significantly shorter in group A (median, 30.5 days; mean, 32.2 +/- 11.3 days vs. median, 45 days; mean, 49.2 +/- 19.3 days). The significantly shorter healing time with vacuum-assisted closure was confirmed in both methicillin-sensitive (12 vs. 17 days) and methicillin-resistant infections (14 vs. 21 days). Hospital stay remained significantly shorter in group A (35 vs. 46 days) when only methicillin-resistant deep sternal wound infection was considered. PMID- 20719788 TI - Revisiting the prone position in video-assisted thoracoscopic surgery. AB - The fully prone position, once used in surgery for chronic inflammatory lung diseases, has become obsolete. In the last 2 years, a modified semiprone position was used for video-assisted thoracoscopic surgery in 358 patients undergoing lobectomy with mediastinal complete lymphadenectomy The ports were placed with the patient in the lateral decubitus position. The patient was rotated 45-60 degrees towards the surgeon, giving enhanced exposure of the posterior mediastinum, esophagus, subcarinal and paratracheal spaces, due to displacement of the lung under gravity away from the operative field. This position is safe, well-tolerated, and allows more ergonomic and anatomical placement of the ports. PMID- 20719789 TI - Sternotomy approach for modified Blalock-Taussig shunt: is it a safe option? AB - Central aorta-pulmonary artery shunts have fallen into disfavor because of shunt thrombosis and congestive heart failure, and a modified Blalock-Taussig shunt via thoracotomy can lead to pulmonary artery hypoplasia and distortion. We reviewed the outcomes of a modified Blalock-Taussig shunt by a sternotomy approach in 20 infants from July 2007 to October 2009. Their mean age was 5.79 months, and median weight was 5.4 kg. A 4-mm graft was placed in 11 patients, a 5-mm graft in 8, and a 3.5-mm graft in 1. There was no incidence of sepsis, seroma, or phrenic nerve palsy. There was one hospital death. The mean hospital stay was 10.4 +/- 4.3 days (range, 8-15 days). The mean oxygen saturation at discharge was 89% (range, 81%-93%). The sternotomy approach is technically easier to perform, cosmetically preferable, and probably hemodynamically superior. Correction of branch pulmonary stenosis is easily incorporated into this procedure. The theoretical disadvantage of this method is a potential technical difficulty with sternal reentry for subsequent procedures. PMID- 20719790 TI - Congenital right pulmonary artery-to-left atrial fistula. AB - A 23-year-old man presented with cyanosis since birth. Precordial echocardiography failed to detect any structural heart abnormality except for enlarged left atrium. Pulmonary angiography revealed a type I right pulmonary artery-to-left atrial fistula. Simple ligation of the fistula without cardiopulmonary bypass was performed successfully, and the cyanosis disappeared postoperatively. PMID- 20719791 TI - Successful surgical repair of complete sternal cleft in an adult. AB - We describe direct repair of congenital complete sternal cleft in a 35-year-old woman, using titanium plates fixed by pre-drilled screws to the manubrium and costal cartilages. This provided excellent protective and cosmetic results. PMID- 20719792 TI - Double-outlet right ventricle with extremely rare conotruncal morphology. AB - We describe an extremely rare form of double-outlet right ventricle in a 1-year old boy who had l-malposition of the great arteries with the definitive conotruncal features of false Taussig-Bing heart. Extraordinary conotruncal morphology raised several surgical options, however, the definitive anatomical repair was achieved by an arterial switch operation with a baffle from a ventricular septal defect to the pulmonary artery. PMID- 20719793 TI - Critical stenosis of pulmonary homograft induced by Surgicel in Ross procedure. AB - Surgicel is bio-absorbable cellulose used to control bleeding. A 52-year-old woman with severe aortic valve regurgitation and aortic dilatation underwent the Ross procedure and ascending aortic replacement. After 48 h, she suffered severe hypotension and hypoxemia. Arteriography revealed stenosis of the pulmonary homograft, which required urgent re-intervention. Extrinsic compression of the posterior wall of the homograft due to Surgicel was found. PMID- 20719794 TI - Partial resection of mitral leaflets during mitral valve replacement. AB - Usually, after mitral leaflet tissue is resected, artificial chordae are used to obtain papillary muscle-to-mitral annulus continuity so as to preserve left ventricular performance. A modified technique that does not require resection of the posterior mitral leaflet and permits implantation of an adequate size of prosthesis is described. PMID- 20719795 TI - Warm pediatric cardiac surgery: European experience. AB - Cold pediatric cardiac surgery has been a dogma for 50 years. However, the beneficial effects of cold perfusion are counterbalanced by the drawbacks of hypothermia. Thus, we propose a major paradigm shift from hypothermic surgery to warm perfusion and intermittent warm blood cardioplegia. This approach gives satisfactory results even with prolonged aortic crossclamp times. The major advantages are reduced time to extubation and shorter intensive care unit stay. Warm pediatric surgery is an anecdotal phenomenon no more; over 10,000 procedures have been carried out in Europe. All types of cardiopathy have been treated, including arterial switch, total pulmonary anomalous venous return, interruption of the aortic arch, and hypoplastic left heart syndrome. Once surgeons decide to shift from hypothermia to normothermia, they never decide to shift back to hypothermia. This fact is evidence of the satisfactory clinical outcome obtained with this technique. The technique and the composition of microplegia is identical in all European centers, the only variable factor being the interval between microplegia injections, which varies from 10 to 25 min. We hope that the increasing interest in pediatric warm surgery will hearten new candidates. PMID- 20719796 TI - Superior vena cava syndrome due to giant aortic aneurysm. PMID- 20719797 TI - Three-dimensional angiography of aberrant segmental vein of right upper lobe. PMID- 20719798 TI - Complete tracheal disruption by motor-saw. PMID- 20719799 TI - Long-term results of mitral balloon valvuloplasty. PMID- 20719800 TI - Pressure-regulated tepid blood reperfusion in patients undergoing emergency coronary revascularization after myocardial infarction. PMID- 20719801 TI - Minimally invasive approach for congenital cardiac defects. PMID- 20719803 TI - Theories of the policy process in health promotion research: a review. AB - The Ottawa Charter laid the ground work for a new research and practice agenda by urging health promoters to advocate for healthy public policies. After more than 20 years, it is now time to reflect on the state of policy research in health promotion and to examine how rigorously theories are applied. The review of the literature was conducted on 11 peer-reviewed journals. The journals were selected for their solid track record in publishing health promotion articles and by using a set of pre-defined inclusion and exclusion criteria. The articles, published between January 1986 and June 2006, were searched using Medline and CINAHL databases. The selected papers feature search terms related to 'politics', 'policy', 'advocacy' and 'coalition'. We examined the theoretical grounding of each paper and whether it focuses on policy content (e.g. nature, impact, evolution of the policy), policy processes (e.g. advocacy capacity building and strategies) or theoretical/methodological issues in policy analysis. This review demonstrates that policy research in health promotion is still largely an a theoretical enterprise. Out of the 119 articles that were found eligible, 39 did apply to some degree a theoretical framework, of which 21 referred to a theoretical framework from political science. We conclude that the field has yet to acknowledge critical concepts that would help to shed light on the policy process, and that validated rigorous theoretical frameworks to inform research and practice are hardly applied. Recommendations are formulated to improve policy research in health promotion. PMID- 20719804 TI - Effects of capsazepine, a transient receptor potential vanilloid type 1 antagonist, on morphine-induced antinociception, tolerance, and dependence in mice. AB - BACKGROUND: Repeated morphine treatment has been shown to induce transient receptor potential vanilloid type 1 (TRPV1) expression in the spinal cord, dorsal root ganglion (DRG), and sciatic nerve of a rat model. Increased TRPV1 expression may therefore play a role in morphine tolerance. In this study, we evaluated the hypothesis that blockage of TRPV1 may be useful as an adjunctive pain management therapy. We investigated whether blockage of TRPV1 by capsazepine, a TRPV1 antagonist, affected antinociception, development of tolerance, and physical dependence on morphine in mice. METHODS: Institute of Cancer Research mice were pretreated with capsazepine and post-treated with morphine acutely and repeatedly. Antinociception and its tolerance were assessed using the hot-plate test. Morphine dependence was examined through the manifestation of withdrawal symptoms induced by naloxone in morphine-dependent mice. RESULTS: Acute capsazepine treatment (5 mg kg-1, i.p.) potentiated the antinociceptive effects of morphine, as measured by the hot-plate test. Repeated co-treatment of capsazepine (2.5 mg kg-1 i.p.) with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. The development of morphine dependence was also reduced by capsazepine (1.25 or 2.5 mg kg-1 i.p.). CONCLUSIONS: Our results suggest that TRPV1 antagonists can be used adjunctively to morphine treatment because they strengthen morphine antinociception and prevent the development of tolerance, and also physical dependence, on morphine. PMID- 20719805 TI - Advanced maternal age and the risk of perinatal death due to intrapartum anoxia at term. AB - BACKGROUND: Advanced maternal age is associated with higher risks of intrapartum complications. However, the effect of maternal age on the risk of perinatal death due to these complications is unclear. The aim of the present study was to determine the association between maternal age and delivery-related perinatal death at term. METHODS: In this retrospective cohort study, birth records of 1,043,002 singleton term infants with cephalic presentation were analysed excluding anomalous and antepartum losses in Scotland between 1985 and 2004. Linked Scottish national registries of pregnancy outcome data and perinatal death data were used. The event was delivery-related perinatal death (ie, intrauterine fetal death during labour or death of the infant in the first 4 weeks of life), plus a subgroup ascribed to intrapartum anoxia. RESULTS: There were 803 delivery related perinatal deaths, with 490 due to intrapartum anoxia (4.7 per 10,000 births) and 313 (3.0 per 10,000 births) due to non-anoxic causes. Compared to women aged 25-34, women aged 40 and above had a twofold risk of delivery-related perinatal death at term (adjusted OR 2.20, 95% CI 1.42 to 3.40). The excess was explained by increased risk of death due to intrapartum anoxia. Among women in labour at term, age greater than 40 was independently associated with risk of anoxic death among primiparous (adjusted OR 5.34, 95% CI 2.34 to 12.20) and multiparous women (adjusted OR 2.14, 95% CI 0.99 to 4.60). CONCLUSIONS: Advanced maternal age is associated with an increased risk of death due to intrapartum anoxia at term. PMID- 20719806 TI - Ethnic differences in stillbirth and early neonatal mortality in The Netherlands. AB - BACKGROUND: Ethnic disparities in perinatal mortality are well known. This study aimed to explore the contribution of demographic, socioeconomic, health behavioural and pre-existent medical risk factors among different ethnic groups on fetal and early neonatal mortality. METHODS: We assessed perinatal mortality from 24.0 weeks' gestation onwards in 554 234 singleton pregnancies of nulliparous women in the linked Netherlands Perinatal Registry over the period 2000-2006. Logistic regression modelling was used. RESULTS: Considerable ethnic differences in perinatal mortality exist especially in fetal mortality. Maternal age, socioeconomic status and pre-existent diseases could not explain these ethnic differences. Late booking visit could explain some differences. Compared with the Dutch, African women had an increased fetal mortality risk of OR 1.7 (95% CI 1.4 to 2.1); South Asian women, 1.8 (1.4 to 2.3); other non-Western women, 1.3 (1.1 to 1.6) and Turkish/Moroccan women, 1.3 (1.1 to 1.4). The risk on early neonatal mortality was only increased in other non-Western women, OR 1.3 (1.0 to 1.8). Ethnic differences were even present in the women without risk factors including preterm births. Mortality risk for East Asian and other Western women was lower or comparable with the Dutch. CONCLUSION: Important ethnic differences in fetal mortality exist, especially among women of African and South Asian origin. Ethnic minorities should be more acquainted with the significance of early start of prenatal care. Tailored prenatal care for women with African and South Asian origin seems necessary. More research on underlying cause of deaths is needed by ethnic group. PMID- 20719807 TI - Which measure of quality of life performs best in older age? A comparison of the OPQOL, CASP-19 and WHOQOL-OLD. AB - BACKGROUND: Most measures of quality of life (QoL) are based on 'expert' opinions. This study describes a new measure of QoL in older age, the Older People's QoL Questionnaire (OPQOL), which is unique in being derived from the views of lay people, cross-checked against theoretical models for assessment of comprehensiveness. Its performance was assessed cross-sectionally and longitudinally. It was compared with two existing QoL measures in the cross sectional studies in order to identify the optimal measure for use with older populations. METHODS: Data were taken from three surveys of older people living at home in Britain in 2007-2008: one population survey of people aged 65+, one focused enumeration survey of ethnically diverse older people aged 65+, one follow-up of a population survey of people aged 65+ at baseline in 1999/2000. Measures were QoL (using OPQOL, Control, Autonomy, Satisfaction, Pleasure--19 items (CASP-19), World Health Organization Quality of Life questionnaire--version for older people (WHOQOL-OLD)), health, social and socioeconomic circumstances. The CASP-19 and WHOQOL-OLD were not administered to the longitudinal sample in order to reduce respondent burden. RESULTS: Psychometric tests were applied to each QoL measure. The OPQOL, CASP-19 and WHOQOL-OLD performed well with the cross sectional samples; however, only the OPQOL met criteria for internal consistency in the Ethnibus samples. CONCLUSION: The OPQOL is of potential value in the outcome assessment of health and social interventions, which can have a multidimensional impact on people's lives. Further research is needed to examine whether differences by ethnicity reflect real differences in QoL, methodological issues, variations in expectations or cultural differences in reporting. PMID- 20719808 TI - Comparison of oral and computerized versions of the word memory test. AB - A computer-administered version of the Word Memory Test (WMT) was compared with the orally administered version in two clinical samples to assess equivalency of the two versions. The two samples included inpatients at an epilepsy center (n = 67) and forensic and clinical referrals to a private practice (n = 58). A randomized procedure was used to assign participants to either version of the WMT. Only the results of the WMT primary effort measures were analyzed. Between group comparisons of the WMT effort measures were conducted using Mann-Whitney nonparametric analysis. No significant differences were found between versions for several diagnostic subgroups. The data generally support equivalency of the orally administered version and the computerized version of the WMT effort measures in a mixed outpatient sample. PMID- 20719809 TI - Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit? AB - BACKGROUND: Limited data exist concerning the need for luteal support in clomiphene citrate-stimulated intrauterine insemination (IUI) cycles. The addition of progesterone became an established clinical practice, despite the absence of evidence of effectiveness. METHODS: A prospective randomized controlled trial was performed in a tertiary referral centre to assess the effect of intravaginal micronized progesterone as luteal support on the probability of ongoing pregnancy in patients stimulated with clomiphene citrate for IUI. Normo ovulatory women, <= 36 years of age, undergoing ovarian stimulation with clomiphene citrate (50 mg) for IUI (n = 468) were randomized during the period from September 2008 to December 2009. Patients were randomized, either to receive luteal phase support (n = 243) in the form of vaginal micronized progesterone in three separate doses (200 mg, 3 times a day), or to the control group who did not receive luteal phase support (n = 225). RESULTS: Data from 400 women were analysed. Following the first interim analysis, the study was prematurely cancelled as an extremely low total pregnancy rate was found. No difference was observed in ongoing pregnancy between patients who did, or did not, receive vaginal progesterone as luteal support [8.7% (17/196) versus 9.3% (19/204), respectively, P = 0.82; difference -0.6%, 95% confidence interval (CI): -6.4, 5.2]. Additionally, the early pregnancy loss rate did not differ between groups (1.5% progesterone group versus 2% no progesterone group, P = 0.78; difference 0.5%, 95% CI: -3.6, 2.7). CONCLUSIONS: Routine supplementation of the luteal phase with vaginal progesterone does not seem to improve pregnancy rates in normo ovulatory women stimulated with clomiphene citrate for IUI. Clinical trials.gov:NCT01046708. PMID- 20719810 TI - 'Daddy ran out of tadpoles': how parents tell their children that they are donor conceived, and what their 7-year-olds understand. AB - BACKGROUND: The present study explored the process of disclosure in gamete donation families in the UK. METHODS: Interviews were conducted with 23 mothers and 15 fathers who had told their 7-year-old child about the nature of their conception. Twelve children were interviewed about what they understood and how they felt about their donor conception (DC). RESULTS: The majority of families had disclosed by the age of four and mothers were found to be the main disclosers. Although some parents expressed concerns about the disclosure, the majority did not experience difficulties. No child responded to disclosure in a negative way. Seven-year-old children showed little understanding of their DC, despite parents starting the process of disclosure before the age of four. CONCLUSIONS: In spite of mothers' concerns about disclosing DC to their children, children responded to disclosure in a neutral way and most parents did not find disclosure to be problematic. PMID- 20719811 TI - Measuring patient-centredness, the neglected outcome in fertility care: a random multicentre validation study. AB - BACKGROUND: High-quality fertility care should be effective and safe, but also patient-centred. However, a suitable instrument for measuring patient-centredness is lacking. This study aims to develop and validate an instrument that can reliably measure patient-centredness in fertility care: patient-centredness questionnaire-infertility (PCQ-infertility). METHODS: The PCQ's content, addressing 53 care aspects, was generated by seven focus groups with 54 infertile patients. Besides background questions, the questionnaire included one 'experience item' and one 'importance item' for each care aspect. Thirty Dutch fertility clinics were invited to participate in the validation study. The questionnaire was sent at random to 1200 infertile couples. Psychometric tests included inter-item and reliability analyses. Importance scores were calculated. The discriminative power was determined using multilevel analysis. RESULTS: The questionnaire was completed by 888 infertile couples (net response 75%) from 29 clinics. The ultimate PCQ-infertility, comprising 46 items and seven subscales, appeared reliable and valid for measuring patient-centredness in fertility care. Of the seven subscales, 'communication' received the best ratings and 'continuity' the worst. 'Honesty and clearness on what to expect from fertility care' appeared most important to patients. Significant differences between clinics were found, even after case-mix adjustment. CONCLUSION: This study resulted in a valid, reliable and strongly discriminating instrument for measuring patient-centredness in fertility care. The PCQ-infertility can identify shortcomings on patient-centredness and can be adopted for quality improvement. Therefore, fertility care can now be monitored and benchmarked on patient centredness, as well as on live birth and complication rates. PMID- 20719812 TI - Breast cancer characteristics are modified by first trimester human placenta: in vitro co-culture study. AB - BACKGROUND: Pregnant women with breast cancer present with a more advanced disease compared with non-pregnant women. Nevertheless, breast cancer metastasis to the placenta is rare. Trophoblast/tumor implantations share the same biochemical mediators, while only the first is stringently controlled. We hypothesized that the same mechanisms that affect/restrain placental implantation may inhibit metastatic growth in the placenta. We aimed to analyze the effects of human placenta on breast cancer cells. METHODS: First trimester human placental explants were co-cultured with MCF-7/T47D-eGFP tagged cells. Following culture, placenta/cancer cells/both were fixed, paraffin embedded and sliced for immunohistochemical analysis or sorted by their eGFP expression for future analysis. The tested parameters were: proliferation (immunohistochemistry)/cell cycle (FACS), apoptosis (immunohistochemistry/FACS), cell count/adhesion/distribution around the placenta (cell sorter, visual observation and counting), matrix metalloproteinase activity (zymogram) and estrogen receptor (ER) expression (western blotting, immunohistochemistry). RESULTS: Reduced breast cancer cell numbers (45%?, 48%? for MCF-7/T47D, respectively, P < 0.05) were observed near the placenta. The placenta elevated MCF-7 sub-G1 phase and modestly elevated apoptosis (3-17%? for T47D/MCF-7, respectively, P < 0.05). Our findings demonstrate breast cancer cell migration from the placenta as: (i) T47D/MCF-7 cells changed their morphology to that of motile cells; (ii) elevated MMPs activity was found in the co-culture; (iii) placental soluble factors detached breast cancer cells; and (4) the placenta reduced MCF-7/T47D cells' ER expression (a characteristic of motile cells). CONCLUSIONS: MCF-7/T47D cells are eliminated from the placental surroundings. Analyzing the causes of these phenomena may suggest biological pathways for this event and raise new therapeutic targets. PMID- 20719813 TI - Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin. AB - BACKGROUND: The LH surge promotes ovulation via activation of multiple signaling networks in the ovarian follicle. Studies in animal models have shown the importance of LH-induced activation of the epidermal growth factor (EGF)signaling network in critical peri-ovulatory events. We investigated the biological significance of regulatory mechanisms mediated by EGF-like growth factors during LH stimulation in humans. METHODS: We characterized the EGF signaling network in mature human ovarian follicles using in vivo and in vitro approaches. Amphiregulin (AREG) levels were measured in 119 follicular fluid (FF) samples from IVF/ICSI patients. Biological activity of human FF was assessed using in vitro oocyte maturation, cumulus expansion and cell mitogenic assays. RESULTS: AREG is the most abundant EGF-like growth factor accumulating in the FF of mature follicles of hCG-stimulated patients. No AREG was detected before the LH surge or before hCG stimulation of granulosa cells in vitro, demonstrating that the accumulation of AREG requires gonadotrophin stimulation. Epiregulin and betacellulin mRNA were detected in both human mural and cumulus granulosa cells, although at significantly lower levels than AREG. FF from stimulated follicles causes cumulus expansion and oocyte maturation in a reconstitution assay. Immunodepletion of AREG abolishes the ability of FF to stimulate expansion (P < 0.0001) and oocyte maturation (P < 0.05), confirming the biological activity of AREG. Conversely, mitogenic activity of FF remained after depletion of AREG, indicating that other mitogens accumulate in FF. FF from follicles yielding an immature germinal vesicle oocyte or from an oocyte that develops into an aberrant embryo contains lower AREG levels than that from follicles yielding a healthy oocyte (P = 0.008). CONCLUSIONS: EGF-like growth factors play a role in critical peri-ovulatory events in humans, and AREG accumulation is a useful marker of gonadotrophin stimulation and oocyte competence. PMID- 20719814 TI - Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids. AB - BACKGROUND: The relationship between fibroids and infertility remains an unsolved question, and management of intramural fibroids is controversial. During the implantation phase, uterine peristalsis is dramatically reduced, which is thought to facilitate embryo implantation. Our aims were to evaluate (i) the occurrence and frequency of uterine peristalsis in infertile women with intramural fibroids and (ii) whether the presence of uterine peristalsis decreases the pregnancy rate. METHODS: Ninety-five infertile patients with uterine fibroids were examined using magnetic resonance imaging (MRI). Inclusion criteria were as follows: (i) presence of intramural fibroids, excluding submucosal type; (ii) no other significant infertility factors (excluding endometriosis); and (iii) regular menstrual cycles, and MRI performed at the time of implantation (luteal phase day 5-9). The frequency of junctional zone movement was evaluated using cine-mode display MRI. After MRI, patients underwent infertility treatment for up to 4 months, and the pregnancy rate was evaluated prospectively. RESULTS: Fifty-one patients fulfilled the inclusion criteria, and 29 (57%) and 22 (43%) patients were assigned to the low (0 or 1 time/3 min) or high frequency (>= 2 times/3 min) uterine peristalsis group, respectively. Endometriosis incidence was the same in both groups. Ten out of the 29 patients (34%) in the low-frequency group achieved pregnancy, compared with none of the 22 patients (0%) in the high-frequency group (P< 0.005). Comparing pregnant and non-pregnant cases, 4 of 10 patients (40%) and 9 of 41 patients (22%), respectively, had endometriosis (not significant). CONCLUSIONS: A higher frequency of uterine peristalsis during the mid-luteal phase might be one of the causes of infertility associated with intramural-type fibroids. PMID- 20719815 TI - A qualitative study exploring perceptions and experiences of patients and clinicians of palliative medicine outpatient clinics in different settings. AB - Palliative care exists in a variety of settings and palliative care teams form many guises within this. A Palliative Medicine Outpatient Clinic (PMOC) exists to meet the flexible provision of the needs and preferences of individuals within whatever care setting they reside. This explorative study used a qualitative methodology, capturing patients' actual experience of care in preference to their satisfaction, as this is a more accurate measure of how and what patients judge as important in their healthcare. The overall themes in this paper point to the 'value' that patients perceived from attending the PMOC and how important the clinics were to clinicians that provided the care. The clinic facilitates much more than symptom control and here lies the challenge in how we convert the very positive experience of individuals into a language of outcome measures that captures the 'essence' of our work in this fiscally driven health economy. PMID- 20719816 TI - Disease trajectories and ACT/RCPCH categories in paediatric palliative care. AB - The objective of this study was to provide a preliminary description of trajectories of life-limiting conditions (LLCs) using qualitative experiential data. Semi-structured interviews were conducted with families of children with LLCs, selected to encompass all Association for Children's Palliative Care (ACT)/Royal College of Paediatrics and Child Health (RCPCH) categories, using a schedule developed from focus groups of professionals. Thirty out of 76 families agreed to participate. Four of these were unsuitable. In nine out of 26 families, their child had died. In eight out of the 26, two individuals were interviewed. Twenty-four mothers, nine fathers, one sibling and two foster-carers were interviewed in total. The interview schedule was developed from data from four themed focus groups, comprising 25 professionals from 14 backgrounds. Thirty-four milestones in five phases were identified: Diagnosis, Loss of normality, Adjusting to new normality, Palliative phase and Death. Many milestones were common to all categories, suggesting that the ACT/RCPCH system encompasses related conditions. Others occurred in only some, suggesting trajectories in the categories are distinct. Significant themes emerging from qualitative data were: becoming expert in their child, concerns about service provision, information needs and relationships with health professionals. By presenting qualitative descriptive data regarding the lived experience of families of children with LLCs, this study provides preliminary evidence that the ACT/RCPCH categories are suitable tools for research and service development. PMID- 20719817 TI - The acute effects of smokeless tobacco on central aortic blood pressure and wave reflection characteristics. AB - The main objectives of this study were to examine the acute effect of a single dose of smokeless tobacco (ST) on central aortic blood pressure and wave reflection characteristics. Fifteen apparently healthy male subjects (aged 30.6 +/- 6.2 y) were given a 2.5 g oral dose of ST after baseline measurements were recorded. Pulse wave analysis using radial artery applanation tonometry was performed in triplicate at baseline (0 min) and at 10-min intervals during (10, 20 and 30 min) and after (40, 50 and 60 min) ST use. An acute dose of ST was associated with a significant increase in heart rate (HR), central aortic systolic and diastolic blood pressure, peripheral brachial systolic and diastolic blood pressure, and aortic augmentation index normalized to a fixed heart rate of 75 bpm (AIx@75). Furthermore, ejection duration and round trip travel time of the reflected pressure wave (Deltat(p)) were significantly decreased as a result of one time ST use. As a result of changes in aortic pressure wave reflection characteristics, there was a significant increase in wasted left ventricular pressure energy (LVE(w)) and the tension-time index (TTI) as a result of ST use. In conclusion, one time use of ST elicits significant transient increases in HR, central aortic pressures, AIx@75, the TTI and LVE(w). Chronic users subjected to decades of elevated central pressures and left ventricular work may have an increased cardiovascular risk as central aortic pressures are even more strongly related to cardiovascular outcomes than peripheral blood pressures. PMID- 20719818 TI - Nanoparticle-induced pulmonary toxicity. AB - In recent decades, advances in nanotechnology engineering have given rise to the rapid development of many novel applications in the biomedical field. However, studies into the health and safety of these nanomaterials are still lacking. The main concerns are the adverse effects to health caused by acute or chronic exposure to nanoparticles (NPs), especially in the workplace environment. The lung is one of the main routes of entry for NPs into the body and, hence, a likely site for accumulation of NPs. Once NPs enter the interstitial air spaces and are quickly taken up by alveolar cells, they are likely to induce toxic effects. In this review, we highlight the different aspects of lung toxicity resulting from NP exposure, such as generation of oxidative stress, DNA damage and inflammation leading to fibrosis and pneumoconiosis, and the underlying mechanisms causing pulmonary toxicity. PMID- 20719819 TI - Study on ASTC-a-1 cells labeled with superparamagnetic iron oxide and its magnetic resonance imaging. AB - The aim of this preliminary study is to explore the feasibility of incorporating superparamagnetic iron oxide (SPIO) with poly-L-lysine (PLL) for labeling and magnetic resonance imaging (MRI) of human lung adenocarcinoma cells. Endorem (5 200 microg/mL) was incubated with ASTC-a-1 cells in the presence of PLL (1.5 microg/mL) for 0.5-24 h. The presence of SPIO in labeled cells was examined by Prussian blue stain. The effects of SPIO on cell proliferation, reactive oxygen species (ROS) generation and the mitochondria were also examined. In vitro MRI of SPIO-PLL-labeled cells was performed using a clinical 1.5 T MRI system. The labeling efficiency of >99% could be achieved after incubating for 0.5 h with 25 microg/mL of SPIO in the presence of PLL (1.5 microg/mL). Higher concentrations of SPIO (e.g. >50 microg/mL) could induce significant cell death, which might be mediated by changes in intracellular ROS level and mitochondrial membrane potential. In vitro MRI showed the decrease in MRI signal intensity on T(1)WI, T(2)WI and T(2)*WI sequences. In conclusion, MRI can trace SPIO-labeled cancer cells according to changes in T(1)WI, T(2)WI and T(2)*WI sequences. It should be noted that at higher concentrations, SPIO can cause cell damage. PMID- 20719820 TI - Effects of a high-intensity task-oriented training on gait performance early after stroke: a pilot study. AB - OBJECTIVE: To investigate the feasibility and the effects on gait of a high intensity task-oriented training, incorporating a high cardiovascular workload and large number of repetitions, in patients with subacute stroke, when compared to a low intensity physiotherapy-programme. DESIGN AND SUBJECTS: Randomized controlled clinical trial: Forty-four patients with stroke were recruited at 2 to 8 weeks after stroke onset. MEASURES: Maximal gait speed assessed with the 10 metre timed walking test (10MTWT), walking capacity assessed with the six-minute walk test (6MWT). Control of standing balance assessed with the Berg Balance Scale and the Functional Reach test. Group differences were analysed using a Mann Whitney U-test. RESULTS: Between-group analysis showed a statistically significant difference in favour of the high intensity task-oriented training in performance on the 10MTWT (Z = -2.13, P = 0.03) and the 6MWT (Z = -2.26, P = 0.02). No between-group difference were found for the Berg Balance Scale (Z = 0.07, P = 0.45) and the Functional Reach test (Z = -0.21, P = 0.84). CONCLUSION: A high-intensity task-oriented training programme designed to improve hemiplegic gait and physical fitness was feasible in the present study and the effectiveness exceeds a low intensity physiotherapy-programme in terms of gait speed and walking capacity in patients with subacute stroke. In a future study, it seems appropriate to additionally use measures to evaluate physical fitness and energy expenditure while walking. PMID- 20719821 TI - A case of prostatic adenocarcinoma with aberrant p63 expression: presentation with detailed immunohistochemical study and FISH analysis. AB - Prostate carcinomas showing aberrant diffuse-nuclear p63 expression are extremely rare, and there is only 1 article in the literature reporting a series of 21 such cases. We document an additional case of p63-positive prostatic adenocarcinoma in a 60-year-old man, whose diagnosis was difficult. The patient was found to have an elevated prostate-specific antigen (PSA) level at a general health check-up and was referred to the hospital. His serum PSA was 4.2 ng/mL. Digital rectal examination and transrectal ultrasonography did not reveal a lesion. Transrectal needle biopsy of the prostate detected atypical, small prostatic glands suspected for adenocarcinoma at 2 cores. However immunohistochemistry showed nuclear p63 expression in the suspicious glands. Repeat biopsy revealed only high-grade prostatic intraepithelial neoplasia. In the third transrectal biopsy, finding of the same atypical glands showing perineural invasion facilitated the diagnosis of malignancy. The patient underwent a radical prostatectomy. Five different small tumor foci were seen in the prostate after pathological evaluation, one of which was p63 positive and the others p63 negative. The largest of the classic p63 negative tumors showed a TMPRSS2-ERG translocation by fluorescent in situ hybridization while the p63-positive tumor did not. The authors submit that this subtype (p63-positive prostate adenocarcinoma) should be listed among the recognized rare variants of prostatic adenocarcinoma. PMID- 20719822 TI - Interpreting composite outcomes in trials. PMID- 20719823 TI - Inconsistent reporting of surrogate outcomes in randomised clinical trials: cohort study. AB - OBJECTIVE: To assess if authors of randomised clinical trials convey the fact that they have used surrogate outcomes and discussed their validity. DESIGN: Cohort study. SETTING: Six major general medical journals. PARTICIPANTS: Randomised clinical trials published in 2005 and 2006 that used a surrogate as a primary outcome. RESULTS: Of 626 published randomised clinical trials, 109 (17%) used a surrogate as a primary outcome. Of these trials, 62 (57%, 95% confidence interval 47% to 67%) clearly reported that the primary outcome was a surrogate. Only 38 (35%, 26% to 45%) also discussed the validity of the surrogate. CONCLUSION: Only about one third of authors of randomised clinical trials that used a surrogate as a primary outcome reported adequately on the surrogate. Better reporting is needed. PMID- 20719824 TI - Can user charges make health care more efficient? AB - Sarah Thomson, Thomas Foubister, and Elias Mossialos explain why charging patients for health services we want them to use makes little economic sense. PMID- 20719825 TI - Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. AB - OBJECTIVE: To study how composite outcomes, which have combined several components into a single measure, are defined, reported, and interpreted. DESIGN: Systematic review of parallel group randomised clinical trials published in 2008 reporting a binary composite outcome. Two independent observers extracted the data using a standardised data sheet, and two other observers, blinded to the results, selected the most important component. RESULTS: Of 40 included trials, 29 (73%) were about cardiovascular topics and 24 (60%) were entirely or partly industry funded. Composite outcomes had a median of three components (range 2-9). Death or cardiovascular death was the most important component in 33 trials (83%). Only one trial provided a good rationale for the choice of components. We judged that the components were not of similar importance in 28 trials (70%); in 20 of these, death was combined with hospital admission. Other major problems were change in the definition of the composite outcome between the abstract, methods, and results sections (13 trials); missing, ambiguous, or uninterpretable data (9 trials); and post hoc construction of composite outcomes (4 trials). Only 24 trials (60%) provided reliable estimates for both the composite and its components, and only six trials (15%) had components of similar, or possibly similar, clinical importance and provided reliable estimates. In 11 of 16 trials with a statistically significant composite, the abstract conclusion falsely implied that the effect applied also to the most important component. CONCLUSIONS: The use of composite outcomes in trials is problematic. Components are often unreasonably combined, inconsistently defined, and inadequately reported. These problems will leave many readers confused, often with an exaggerated perception of how well interventions work. PMID- 20719826 TI - Foreign body inhalation in children. PMID- 20719827 TI - Lost without translation? PMID- 20719828 TI - Implication of oxygen-regulated protein 150 (ORP150) in apoptosis induced by proteasome inhibitors in human thyroid cancer cells. AB - CONTEXT: The inhibition of the 26S proteasome may lead to endoplasmic reticulum stress, which has been shown to be implicated in the antitumoral effects of proteasome inhibitors. Oxygen-regulated protein 150 (ORP150) is an inducible endoplasmic reticulum chaperone that is up-regulated after numerous cellular insults and has a cytoprotective role for the maintenance of cellular viability. OBJECTIVE: The purpose of this study was to determine the involvement of ORP150 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibition. DESIGN: The effects of proteasome inhibition on the expression of ORP150 were analyzed using real-time RT-PCR and Western blot. To ascertain the effect of ORP150, cells were transfected with ORP150 plasmid or small interfering RNA (siRNA) against ORP150, apoptotic cells, and induction of CCAAT/enhancer-binding protein homologous transcription factor (CHOP) mediated by proteasome inhibition were investigated. RESULTS: ORP150 was induced in thyroid cancer cells after proteasome inhibition. Suppression of activating transcription factor 4 expression by siRNA inhibited the up-regulation of ORP150 mediated by proteasome inhibitors. siRNA for ORP150 stimulated MG132-mediated apoptosis and induction of CHOP, a transcription factor with apoptosis-inducing activity. In contrast, ORP150-overexpressing cells demonstrated less susceptibility to MG132-induced apoptosis and displayed less up-regulation of CHOP. In addition, the sensitizing effect of small interfering ORP150 on apoptosis was suppressed by siRNA for CHOP. CONCLUSIONS: These results suggest that up-regulation of ORP150 in thyroid cancer cells inhibits MG132-induced apoptosis via suppression of CHOP induction, thereby decreasing the potential antitumor activity of MG132. PMID- 20719829 TI - A nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia. AB - CONTEXT: Vitamin D may be important in the pathogenesis of severe preeclampsia. Given the few effective preventive strategies for severe preeclampsia, studies establishing this link are needed so that effective interventions can be developed. OBJECTIVE: Our objective was to assess whether midgestation vitamin D deficiency is associated with development of severe preeclampsia. DESIGN AND SETTING: We conducted a nested case-control study of pregnant women who had previously given blood for routine genetic multiple marker screening and subsequently delivered at a tertiary hospital between January 2004 and November 2008. PATIENTS: Participants included women with singleton pregnancies in the absence of any chronic medical illnesses. From an overall cohort of 3992 women, 51 cases of severe preeclampsia were matched by race/ethnicity with 204 women delivering at term with uncomplicated pregnancies. Banked maternal serum was used to measure maternal 25-hydroxyvitamin D [25(OH)D]. MAIN OUTCOME MEASURE: The main outcome was severe preeclampsia. RESULTS: Midgestation maternal 25(OH)D concentration was lower in women who subsequently developed severe preeclampsia compared with controls [median (interquartile range), 75 (47-107) nmol/liter vs. 98 (68-113) nmol/liter; P = 0.01]. Midgestation maternal 25(OH)D of less than 50 nmol/liter was associated with an almost 4-fold odds of severe preeclampsia (unadjusted odds ratio, 3.63; 95% confidence interval, 1.52-8.65) compared with midgestation levels of at least 75 nmol/liter. Adjustment for known confounders strengthened the observed association (adjusted odds ratio, 5.41; 95% confidence interval, 2.02-14.52). CONCLUSION: Maternal midgestation vitamin D deficiency was associated with increased risk of severe preeclampsia. Vitamin D deficiency may be a modifiable risk factor for severe preeclampsia. PMID- 20719830 TI - Serum levels of anti-Mullerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 Turner syndrome patients. AB - CONTEXT: In adult women, anti-Mullerian hormone (AMH) is related to the ovarian follicle pool. Little is known about AMH in girls. OBJECTIVE: The objective of the study was to provide a reference range for AMH in girls and adolescents and to evaluate AMH as a marker of ovarian function. SETTING: The study was conducted at a tertiary referral center for pediatric endocrinology. MAIN OUTCOME MEASURES: We measured AMH in 926 healthy females (longitudinal values during infancy) as well as in 172 Turner syndrome (TS) patients according to age, karyotype (A: 45,X; B: miscellaneous karyotypes; C: 45,X/46,XX), and ovarian function (1: absent puberty; 2: cessation of ovarian function; 3: ongoing ovarian function). RESULTS: AMH was undetectable in 54% (38 of 71) of cord blood samples (<2; <2-15 pmol/liter) (median; 2.5th to 97.5th percentile) and increased in all (37 of 37) infants from birth to 3 months (15; 4.5-29.5 pmol/liter). From 8 to 25 yr, AMH levels were stable (19.9; 4.7-60.1 pmol/liter), with the lower level of the reference range clearly above the detection limit. AMH levels were associated with TS-karyotype groups (median A vs. B: <2 vs. 3 pmol/liter, P = 0.044; B vs. C: 3 vs. 16 pmol/liter, P < 0.001) as well as with ovarian function (absent puberty vs. cessation of ovarian function: <2 vs. 6 pmol/liter, P = 0.004; cessation of ovarian function vs. ongoing ovarian function: 6 vs. 14 pmol/liter, P = 0.001). As a screening test of premature ovarian failure in TS, the sensitivity and specificity of AMH less than 8 pmol/liter was 96 and 86%, respectively. CONCLUSION: AMH seems to be a promising marker of ovarian function in healthy girls and TS patients. PMID- 20719831 TI - Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. AB - CONTEXT: We have previously shown that enhancing brain insulin signaling by intranasal administration of a single dose of the hormone acutely reduces food intake in young men but not women, whereas its improving effects on spatial and working memory are restricted to young women. OBJECTIVE: Against the background of animal studies suggesting that low estrogen concentrations are a prerequisite for the anorexigenic impact of central nervous insulin, we extended our foregoing study by assessing intranasal insulin effects in postmenopausal women with comparatively low estrogen concentrations, expecting them to be more sensitive than young women to the anorexigenic effects of the hormone. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: In a within-subject, double-blind comparison performed at the University of Lubeck, 14 healthy postmenopausal women (body mass index, 23.71+/-0.6 kg/m2; age, 57.61+/-1.14 yr) were intranasally administered 160 IU regular human insulin or vehicle. MAIN OUTCOME MEASURES: Subjects performed a working memory task (digit span) and a hippocampus-dependent visuospatial memory task. Subsequently, free-choice food intake from an ad libitum breakfast buffet was measured. RESULTS: Contrary to expectations, results in postmenopausal women mirrored those found in young women (22.44+/-0.63 yr), i.e. insulin administration did not affect food intake (P>0.46), but did enhance performance in the prefrontal cortex-dependent working memory task (P<0.05). CONCLUSIONS: Low estrogen levels as present in postmenopausal women do not modulate the effects of intranasal insulin in females, suggesting that in humans as opposed to rats, estrogen signaling does not critically alter central nervous system sensitivity to the effects of insulin on energy homeostasis and cognition. PMID- 20719832 TI - Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 5 1/2 years: millennium cohort study. AB - CONTEXT: Transient hypothyroxinemia is the commonest thyroid dysfunction of premature infants, and recent studies have found adverse associations with neurodevelopment. The validity of these associations is unclear because the studies adjusted for a differing range of factors likely to influence neurodevelopment. OBJECTIVE: The aim was to describe the association of transient hypothyroxinemia with neurodevelopment at 5.5 yr corrected age. DESIGN: We conducted a follow-up study of a cohort of infants born in Scotland from 1999 to 2001 <=34 wk gestation. MAIN OUTCOME MEASURES: We measured scores on the McCarthy scale adjusted for 26 influences of neurodevelopment including parental intellect, home environment, breast or formula fed, growth retardation, and use of postnatal drugs. RESULTS: A total of 442 infants <=34 wk gestation who had serum T(4) measurements on postnatal d 7, 14, or 28 and 100 term infants who had serum T(4) measured in cord blood were followed up at 5.5 yr. Infants with hypothyroxinemia (T(4) level <= 10th percentile on d 7, 14, or 28 corrected for gestational age) scored significantly lower than euthyroid infants (T(4) level greater than the 10th percentile and less than the 90th percentile on all days) on all McCarthy scales, except the quantitative. After adjustment for confounders of neurodevelopment, hypothyroxinemic infants scored significantly lower than euthyroid infants on the general cognitive and verbal scales. CONCLUSIONS: Our findings do not support the view that the hypothyroxinemic state, in the context of this analysis, is harmless in preterm infants. Many factors contribute both to the etiology of hypothyroxinemia and neurodevelopment; strategies for correction of hypothyroxinemia should acknowledge its complex etiology and not rely solely on one approach. PMID- 20719833 TI - Association between change in body composition and change in inflammatory markers: an 11-year follow-up in the Whitehall II Study. AB - CONTEXT: Obesity is associated with low-grade inflammation, but the long-term effects of weight change on inflammation are unknown. OBJECTIVE: The aim was to examine the association of change in weight, body mass index (BMI), and waist circumference with change in C-reactive protein (CRP) and IL-6 and to assess whether this association is modified by baseline obesity status. DESIGN AND SETTING: The design was a prospective cohort study among civil servants (the Whitehall II Study, UK). We used data from two clinical screenings carried out in 1991-1993 and 2002-2004 (mean follow-up, 11.3 yr). PARTICIPANTS: We studied 2496 men and 1026 women [mean age, 49.4 (sd=6.0) yr at baseline] with measurements on inflammatory markers and anthropometry at both baseline and follow-up. MAIN OUTCOME MEASURES: We measured change in serum CRP and IL-6 during follow-up. RESULTS: The mean increases in CRP and IL-6 were 0.08 [95% confidence interval (CI), 0.07-0.09] mg/liter and 0.04 (95% CI, 0.03-0.05) pg/ml per 1-kg increase in body weight during follow-up. Study members with a BMI less than 25 kg/m2 at baseline had an average increase in CRP of 0.06 (95% CI, 0.05-0.08) mg/liter per 1-kg increase in body weight, whereas the increase in those who were overweight (25<=BMI<30 kg/m2) and obese (BMI>=30 kg/m2) was greater: 0.08 (95% CI, 0.06 0.09) mg/liter and 0.11 (95% CI, 0.07-0.14) mg/liter, respectively (P value for interaction=0.002). Similar patterns were observed for changes in BMI and waist circumference. CONCLUSIONS: Those who were overweight or obese at baseline had a greater absolute increase in CRP per unit increase in weight, BMI, and waist circumference than people who were normal weight. PMID- 20719834 TI - High-molecular-weight adiponectin and the risk of type 2 diabetes in the ARIC study. AB - CONTEXT: Adiponectin, synthesized by adipocytes, has been shown to be a predictor of type 2 diabetes. Adiponectin circulates in plasma as three oligomeric isoforms. High-molecular-weight (HMW) adiponectin is thought to be the most biologically active form of adiponectin in terms of glucose homeostasis. OBJECTIVE: Our objective was to investigate whether HMW adiponectin is more strongly associated with incident diabetes than is total adiponectin. DESIGN: A nested case-cohort study was conducted in a population-based cohort of 9740 middle-aged, initially healthy, white and African-American participants of the Atherosclerosis Risk in Communities (ARIC) study followed for up to 9 yr. Plasma total and HMW adiponectin were measured by ELISA in 550 incident diabetes cases and 540 noncases. RESULTS: Overall hazard ratios (95% confidence intervals) for developing diabetes for those in the fourth (vs. the first) quartile of total adiponectin, HMW adiponectin, and the ratio of HMW to total were 0.40 (0.25 0.64), 0.38 (0.23-0.63), and 0.65 (0.42-0.99), respectively, after adjustment for age, sex, ethnicity, study center, parental history of diabetes, hypertension, body mass index, and waist-to-hip ratio and 0.52 (0.32-0.85), 0.51 (0.31-0.86), and 0.77 (0.50-1.20), respectively, after additional adjustment for inflammation score (a score composed of six inflammation markers) and fasting insulin. When further adjusting for baseline fasting glucose, the graded associations were attenuated substantially and lost their gradation. CONCLUSIONS: In this community based sample of U.S. adults, higher total and HMW adiponectin concentrations were similarly associated with a lower incidence of diabetes over 9 yr of follow-up. PMID- 20719836 TI - Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. AB - CONTEXT: Appetite-related hormones may play an important role in weight regain after obesity therapy. OBJECTIVE: Our objective was to investigate the potential involvement of ghrelin, leptin, and insulin plasma levels in weight regain after a therapeutic hypocaloric diet. DESIGN: A group of obese/overweight volunteers (49 women and 55 men; 35 +/- 7 yr; 30.7 +/- 2.4 kg/m(2)) followed an 8-wk hypocaloric diet (-30% energy expenditure) and were evaluated again 32 wk after treatment. Body weight as well as plasma fasting ghrelin, leptin, and insulin concentrations were measured at three points (wk 0, 8, and 32). RESULTS: After the 8-wk hypocaloric diet, the average weight loss was -5.0 +/- 2.2% (P < 0.001). Plasma leptin and insulin concentrations decreased significantly, whereas ghrelin levels did not markedly change. In the group regaining more than 10% of the weight loss, leptin levels were higher (P < 0.01), whereas ghrelin levels were lower (P < 0.05). No differences were observed in insulin levels. Weight regain at wk 32 was negatively correlated with ghrelin and positively associated with leptin levels at baseline (wk 0) and endpoint (wk 8). These outcomes showed a gender-specific influence, being statistically significant among men for ghrelin and between women for leptin. Moreover, a decrease in ghrelin after an 8-wk hypocaloric diet was related to an increased risk for weight regain (odds ratio = 3.109; P = 0.008) whereas a greater reduction in leptin (odds ratio = 0.141; P = 0.001) was related to weight-loss maintenance. CONCLUSIONS: Subjects with higher plasma leptin and lower ghrelin levels at baseline could be more prone to regain lost weight, and hormones levels could be proposed as biomarkers for predicting obesity-treatment outcomes. PMID- 20719835 TI - High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. AB - CONTEXT: Cross-sectional epidemiological studies have found that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of certain fragility fractures despite normal or elevated bone mineral density (BMD). OBJECTIVE: In this study, high-resolution peripheral quantitative computed tomography was applied to characterize cortical and trabecular microarchitecture and biomechanics in the peripheral skeleton of female patients with T2DM. DESIGN AND SETTING: A cross-sectional study was conducted in patients with T2DM recruited from a diabetic outpatient clinic. PARTICIPANTS: Elderly female patients (age, 62.9 +/- 7.7 yr) with a history of T2DM (n = 19) and age- and height-matched controls (n = 19) were recruited. OUTCOME MEASURES: Subjects were imaged using high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Quantitative measures of volumetric (BMD), cross-sectional geometry, trabecular and cortical microarchitecture were calculated. Additionally, compressive mechanical properties were determined by micro-finite element analysis. RESULTS: Compared to the controls, the T2DM cohort had 10% higher trabecular volumetric BMD (P < 0.05) adjacent to the cortex and higher trabecular thickness in the tibia (13.8%; P < 0.05). Cortical porosity differences alone were consistent with impaired bone strength and were significant in the radius (>+50%; P < 0.05), whereas pore volume approached significance in the tibia (+118%; P = 0.1). CONCLUSION: The results of this pilot investigation provide a potential explanation for the inability of standard BMD measures to explain the elevated fracture incidence in patients with T2DM. The findings suggest that T2DM may be associated with impaired resistance to bending loads due to inefficient redistribution of bone mass, characterized by loss of intracortical bone offset by an elevation in trabecular bone density. PMID- 20719837 TI - Recombinant human GH replacement therapy in children with pseudohypoparathyroidism type Ia: first study on the effect on growth. AB - CONTEXT: Since the identification of GH deficiency due to resistance to GHRH in patients with pseudohypoparathyroidism type Ia (PHP-Ia), no study investigated the effects of recombinant human GH (rhGH) therapy on height velocity (HV) in these patients. OBJECTIVES, PATIENTS AND METHODS: To address this question, eight prepubertal PHP-Ia children with GH deficiency (seven girls and one boy, aged 5.8 12 yr) underwent a 3- to 8-yr treatment with rhGH. Height and HV were measured before and at 6-month intervals during therapy. Nine sex- and age-matched children with idiopathic GH deficiency were monitored during rhGH therapy for comparison. RESULTS: In PHP-Ia children, height sd scores increased from -2.4 +/- 0.58 to -1.8 +/- 0.47 (P = 0.04) after 12 months, this increase being maintained after the second (-1.6 +/- 0.6) and third (-1.15 +/- 0.6) year of therapy, similarly to what recorded in children with idiopathic GH deficiency. The HV and HV sd scores after 3 yr maintained a significant increase from 3.5 +/- 0.6 to 7.0 +/- 0.9 cm/yr (P < 0.0001) and from -2.8 +/- 0.8 to +2.2 +/- 1.0 (P < 0.0001), respectively. Six patients treated for 4-8 yr had a reduced pubertal spurt and did not improve their near-adult height, with the only exception of one patient in whom estrogen production was blocked by GnRH analogs. CONCLUSIONS: We report the first study on the efficacy of rhGH replacement therapy in prepubertal children with PHP-Ia and provide indication that treatment of GH deficiency should be started soon due to the rather limited time window for a potentially effective therapy. PMID- 20719838 TI - Clinical Review#: The diagnosis and management of central hypoadrenalism. AB - CONTEXT: Adrenal failure secondary to hypothalamo-pituitary disease is a common clinical problem which has serious repercussions. It is essential to perform validated diagnostic procedures and manage such patients with clear objectives and based on well-established replacement programs. EVIDENCE ACQUISITION: PubMed was searched for all data reflecting pituitary hypoadrenalism dating back to 1960 in order to establish a published database. EVIDENCE SYNTHESIS: The results from published studies were assessed in the light of the author's extensive personal experience dating back some 30 yr in clinical endocrinology, in an attempt to provide clear diagnostic and management advice. CONCLUSIONS: While much of the physiology of the hypothalamo-pituitary-adrenal axis is well understood, its clinical assessment and diagnostic procedures to establish the need for replacement are still far from perfect, and to a certain extent clinical judgement is still vital. In terms of replacement therapies, these are still far from optimal in terms of quality of life and mortality, although they are increasingly being based on objective evidence rather than established practice. However, it is anticipated that newer replacement protocols will improve a situation that has previously changed little for many years. PMID- 20719840 TI - Low-grade albuminuria is associated with carotid intima-media thickness in Chinese type 2 diabetic patients. AB - CONTEXT: Low-grade albuminuria was reported to be associated with cardiovascular risk factors. Our present study showed a significant association between low grade urinary albumin-to-creatinine ratio (ACR) and elevated carotid intima-media thickness (CIMT) in type 2 diabetic patients. OBJECTIVE: The objective of this study is to evaluate the association between low-grade albuminuria and CIMT in type 2 diabetic patients. DESIGN, SETTING, PARTICIPANTS, AND MEASURES: A cross sectional study was performed in 760 type 2 diabetic patients (age range, 29-76 yr) with normoalbuminuria from Shanghai, China. A first-voided early morning spot urine sample was obtained for urinary albumin and creatinine measurements. CIMT was measured using high-resolution B-mode ultrasonography. RESULTS: CIMT, as well as body mass index, glycated hemoglobin A1c, systolic and diastolic blood pressure, and serum triglycerides, progressively increased across the sex specific quartiles of ACR (all P < 0.05). Compared with the patients in the lowest quartile, those in the third and the highest quartiles had significantly higher levels of CIMT (0.87 and 0.91 vs. 0.79 mm, P = 0.0025 and <0.0001, respectively). A fully adjusted logistic regression analysis revealed that compared with the patients in the lowest quartile of ACR, those in the third and the highest quartiles had 1.98- to 2.76-fold increased risk of elevated CIMT. CONCLUSIONS: In type 2 diabetic patients, slightly elevated ACR level, which was below the current cutoff point of microalbuminuria, was associated with higher CIMT after adjustments of conventional cardiovascular risk factors. The results implied that low-grade albuminuria might be an early marker for the detection of cardiovascular disease in type 2 diabetic patients. PMID- 20719839 TI - Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. AB - CONTEXT: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. OBJECTIVE: Our objective was to establish the health status of adults with CAH. DESIGN AND SETTING: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. PATIENTS: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18-69) years. MAIN OUTCOME MEASURES: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. RESULTS: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. CONCLUSIONS: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required. PMID- 20719841 TI - The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance. AB - INTRODUCTION: The age-specific prevalence of polycystic ovaries (PCO), as defined by the Rotterdam criteria, among normal ovulatory women, has not yet been reported. It is also uncertain whether these women differ from their peers in the hormonal or metabolic profile. METHODS: A total of 262 ovulatory Caucasian women aged 25-45 yr, enrolled in a community-based ovarian aging study (OVA), underwent transvaginal ultrasound assessment of ovarian volume and antral follicle count (AFC) in the early follicular phase and were categorized as to whether they met the Rotterdam definition of PCO by AFC (>=12 in one ovary) and/or by volume (>10 cm(3) for one ovary). The effect of age on prevalence of PCO was assessed. Serum hormones and metabolic measures were compared between women meeting each element of the Rotterdam criterion and those without PCO using age-adjusted linear regressions. RESULTS: The prevalence of PCO by AFC was 32% and decreased with age. Those with PCO by AFC had lower FSH; higher anti-Mullerian hormone, estrone, dehydroepiandrostenedione sulfate, and free androgen index; and slightly higher total testosterone than those without PCO. However, slightly higher body mass index and waist circumference were the only metabolic differences. Women with PCO by volume had higher anti-Mullerian hormone and free androgen index but did not differ in any other hormonal or metabolic parameter. DISCUSSION: PCO is a common, age-dependent finding among ovulatory women. These women lack the metabolic abnormalities seen in PCO syndrome. Isolated PCO in an ovulatory woman is not an indication for metabolic evaluation. PMID- 20719842 TI - An "unforeseen" complication of urinary tract infection in a patient with diabetes. PMID- 20719843 TI - Making decisions for people with dementia who lack capacity: qualitative study of family carers in UK. AB - OBJECTIVE: To identify common difficult decisions made by family carers on behalf of people with dementia, and facilitators of and barriers to such decisions, in order to produce information for family carers about overcoming barriers. DESIGN: Qualitative study to delineate decision areas through focus groups and complexity of decision making in individual interviews. SETTING: Community settings in London. PARTICIPANTS: 43 family carers of people with dementia in focus groups and 46 carers who had already made such decisions in individual interviews. RESULTS: Family carers identified five core problematic areas of decision making: accessing dementia related health and social services; care homes; legal financial matters; non-dementia related health care; and making plans for the person with dementia if the carer became too ill to care for them. They highlighted the difficulties in making proxy decisions, especially against active resistance, and their altered role of patient manager while still a family member. Families devised strategies to gain agreement in order to ensure that the person with dementia retained dignity. CONCLUSIONS: The following strategies helped with implementation of decisions: introducing change slowly; organising legal changes for the carer as well as the patient; involving a professional to persuade the patient to accept services; and emphasising that services optimised, not impeded, independence. To access services, carers made patients' general practice appointments, accompanied them to the surgery, pointed out symptoms, gained permission to receive confidential information, asked for referral to specialist services, and used professionals' authority to gain patients' agreement. End of life decisions were particularly difficult. They were helped by knowledge of the person with dementia's previous views, clear prognostic information, and family support. Information sheets to help carers to overcome barriers to proxy decision making have been developed; their impact in practice has yet to be evaluated. PMID- 20719851 TI - Contemporary castration: why the modern day eunuch remains invisible. PMID- 20719852 TI - UN fears disease outbreak as result of Darfur camp blockade. PMID- 20719853 TI - Pakistan sees first suspected cases of cholera. PMID- 20719854 TI - The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. AB - Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T3. In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T3 required for UCP1 expression. T3 actions are mediated by thyroid hormone nuclear T3 receptors (TR), TRalpha and TRbeta. Studies in mice suggest that TRbeta is required for UCP1 induction, whereas TRalpha regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T3 vs. specific TRbeta1 and TRalpha1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nm). GC-1 at low doses (0.2-10 nm) was less potent than T3, increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T3, GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The alpha1- and alpha2-adrenergic D2 responses increased using high T3 doses. In summary, T3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TRbeta1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T3 on TRbeta1. PMID- 20719855 TI - Type 3 deiodinase deficiency causes spatial and temporal alterations in brain T3 signaling that are dissociated from serum thyroid hormone levels. AB - The type 3 deiodinase (D3) is an enzyme that inactivates thyroid hormones (TH) and is highly expressed during development and in the central nervous system. D3 deficient (D3KO) mice develop markedly elevated serum T(3) level in the perinatal period. In adulthood, circulating T(4) and T(3) levels are reduced due to functional deficits in the thyroid axis and peripheral tissues (i.e. liver) show evidence of decreased TH action. Given the importance of TH for brain development, we aimed to assess TH action in the brain of D3KO mice at different developmental stages and determine to what extent it correlates with serum TH parameters. We used a transgenic mouse model (FINDT3) that expresses the reporter gene beta-galactosidase (beta-gal) in the central nervous system as a readout of local TH availability. Together with experiments determining expression levels of TH-regulated genes, our results show that after a state of thyrotoxicosis in early development, most regions of the D3KO brain show evidence of decreased TH action at weaning age. However, later in adulthood and in old age, the brain again manifests a thyrotoxic state, despite reduced serum TH levels. These region specific changes in brain TH status during the life span of the animal provide novel insight into the important role of the D3 in the developing and adult brain. Our results suggest that, even if serum concentrations of TH are normal or low, impaired D3 activity may result in excessive TH action in multiple brain regions, with potential consequences of altered neural function that may be of clinical relevance to neurological and neuroendocrine disorders. PMID- 20719856 TI - Magmas, a gene newly identified as overexpressed in human and mouse ACTH secreting pituitary adenomas, protects pituitary cells from apoptotic stimuli. AB - Pituitary tumors are mostly benign, being locally invasive in 5-35% of cases. Deregulation of several genes has been suggested as a possible alteration underlying the development and progression of pituitary tumors. We here report the identification of a cDNA, corresponding to Magmas gene (mitochondria associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction), which is highly expressed in two different ACTH-secreting mouse pituitary adenoma cell lines as compared with normal pituitary as well as in two thirds of 64 examined pituitary adenomas as compared with human normal pituitary. Tim 16, the mitochondrial protein encoded by Magmas, was indeed expressed in a mouse ACTH-secreting pituitary adenoma cell line, AtT-20 D16v-F2 cells, in a subcellular compartment likely corresponding to mitochondria. Magmas silencing determined a reduced rate of DNA synthesis, an accumulation in G1 phase, and a concomitant decrease in S phase in At-T20 D16v-F2 cells. Moreover, Magmas-silenced cells displayed basal caspase 3/7 activity and DNA fragmentation levels similar to control cells, which both increased under proapoptotic stimuli. Our data demonstrate that Magmas is overexpressed in mouse and human ACTH secreting pituitary adenomas. Moreover, our results show that Magmas protects pituitary cells from apoptosis, suggesting its possible involvement in neoplastic transformation. PMID- 20719857 TI - The immune signaling molecule 4-1BB stimulation reduces adiposity, insulin resistance, and hepatosteatosis in obese mice. AB - Immune cells (e.g. macrophages and T cells) in adipose tissue play a crucial role in the development of obesity-induced inflammation and metabolic disorders. Here we report findings suggesting that the immune signaling molecule 4-1BB/CD137 is a novel target for treatment of obesity and metabolic disorders. 4-1BB stimulation with agonistic antibody reduced body weight and adiposity and markedly improved glucose intolerance and hepatosteatosis in diet-induced obese mice and genetically obese/diabetic mice. Increases in lymphoid T cell expansion/activation and adipose/hepatic CD8+ T cell recruitment were evident in the anti-4-1BB antibody-treated obese mice. Glycolysis, beta-oxidation, and oxygen consumption rates also increased in the treated mice. These findings suggest that 4-1BB-stimulation accompanied by CD8+ T cell expansion/activation enhances glucose/lipid metabolism, leading to increased energy expenditure. Manipulation of 4-1BB may provide a unique immunological strategy against obesity and metabolic disorders. PMID- 20719858 TI - Fructose-1,6-bisphosphatase regulates glucose-stimulated insulin secretion of mouse pancreatic beta-cells. AB - Pancreatic beta-cells can precisely sense glucose stimulation and accordingly adjust their insulin secretion. Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme, but its physiological significance in beta-cells is not established. Here we determined its physiological role in regulating glucose sensing and insulin secretion of beta-cells. Considerable FBPase mRNA was detected in normal mouse islets and beta-cell lines, although their protein levels appeared to be quite low. Down-regulation of FBP1 in MIN6 cells by small interfering RNA could enhance the glucose-stimulated insulin secretion (GSIS), whereas FBP1-overexpressing MIN6 cells exhibited decreased GSIS. Inhibition of FBPase activity in islet beta-cells by its specific inhibitor MB05032 led to significant increase of their glucose utilization and cellular ATP to ADP ratios and consequently enhanced GSIS in vitro. Pretreatment of mice with the MB05032 prodrug MB06322 could potentiate GSIS in vivo and improve their glucose tolerance. Therefore, FBPase plays an important role in regulating glucose sensing and insulin secretion of beta-cells and serves a promising target for diabetes treatment. PMID- 20719859 TI - Regulation of adipocyte differentiation by activation of serotonin (5-HT) receptors 5-HT2AR and 5-HT2CR and involvement of microRNA-448-mediated repression of KLF5. AB - Retrovirus insertion-mediated random mutagenesis was applied in 3T3-L1 preadipocyte cells to better understand the molecular basis of obesity (the expansion of individual adipocytes). We found that tryptophan hydroxylase-1, a rate-limiting enzyme for the synthesis of serotonin (5-HT), is expressed in adipocytes and is required for their differentiation. A 5-HT type 2A receptor (5 HT(2A)R) antagonist, ketanserin, and a 5-HT(2c)R antagonist, SB-242084, inhibited adipocyte differentiation. Because 5-HT(2c)R mRNA levels are up-regulated during adipocyte differentiation and micro-RNA (miR)-448 is located in the fourth intron of Htr2c, we also studied the role of miR-448 in 3T3-L1 cells. Through a bioinformatics approach, Kruppel-like factor 5 (KLF5) was identified as a potential target of miR-448. Using a luciferase reporter assay, we confirmed that miR-448 targets the Klf5 3'-intranslated region. Overexpression of miR-448 reduced the expression of Klf5 and adipocyte differentiation, which was confirmed by the reduced expression of adipogenic genes and triglyceride accumulation. To examine the loss of miR-448 function, we constructed a decoy gene that had tandem complementary sequences for miR-448 in the 3'-untranslated region of a luciferase gene under the control of a cytomegalovirus promoter. When the miR-448 decoy gene was introduced into 3T3-L1 preadipocytes, KLF5 was up-regulated and triglyceride concentration was increased. In this study, we identified the regulation of adipocyte differentiation by 5-HT, 5-HT(2A)R, and 5-HT(2C)R. miR-448-mediated repression of KLF5 was identified as a negative regulator for adipocyte differentiation. PMID- 20719860 TI - Subunit interactions influence TSHR multimerization. AB - The TSH receptor (TSHR) is the key molecule influencing thyroid growth and development and is an antigenic target in autoimmune thyroid disease. The TSHR exists in monomeric and multimeric forms, and it has been shown previously that multimeric complexes of the TSHR preferentially localize in lipid rafts. However, unlike other glycoprotein hormone receptors, the TSHR exists in several forms on the cell membrane due to intramolecular cleavage of its ectodomain, which causes the production of alpha- and beta-subunits of various lengths. After cleavage and reduction of disulfide bonds, alpha-subunits consisting of the receptor ectodomain may be lost from the cell surface by receptor shedding, leading to accumulation of excess beta-subunits within the membrane. Because cell surface expression of these various forms of the TSHR is critical to receptor signaling and autoimmune responses, we set out to model the influence of beta-subunits on full-length TSHRs. To study this interaction, we generated three truncated ectodomain beta-subunits linked to green fluorescent protein (named beta-316, 366, and -409) as examples of native cleaved forms of the TSHR. These constructs were transfected into human embryonic kidney 293 cells in the presence and absence of the full-length receptor. Whereas the beta-316 and beta-366 forms showed cell surface expression, the expression of beta-409 was primarily intracellular. Cotransfection of the beta-subunits with a full-length hemagglutinin-tagged wild-type (WT) receptor (HT-WT-TSHR) in both transient and stable systems caused a significant decrease in surface expression of the full length WT receptors. This decrease was not seen with control plasmid consisting of a plasma membrane-targeted protein tagged to red fluorescent protein. To ascertain if this response was due to homointeraction of the truncated beta constructs with the WT-TSHRs, we immunoprecipitated membranes prepared from the cotransfected cells using antihemagglutinin and then probed with anti-green fluorescent protein. These studies confirmed dimerization of the beta-subunits with the WT full-length receptor, and this interaction was further observed in vivo by fluorescence resonance energy transfer. We then studied the functional consequences of this interaction on TSHR signaling by examining Galphas-mediated signals. The well-expressed truncated constructs, when coexpressed with full length TSHR, did not alter constitutive cAMP levels, but there was a significant decrease in TSH-induced cAMP generation. Furthermore, we observed that truncated beta-316 and beta-366 had faster internalization rate, which may lead to a significant decrease in the expression of the full-length receptor on the cell surface, thus contributing to the decreased signaling response. However, the decrease in surface receptors may also be due to inhibition of newly formed receptors reaching the surface as result of receptor-receptor interaction. It is well known that under normal physiological conditions both cleaved and uncleaved TSHR forms coexist on the cell surface of normal thyrocytes. Our studies allow us to conclude, therefore, that multimerization of cleaved/ truncated forms of the beta-subunits with the full-length TSHR has a profound influence on TSHR internalization and signaling. Hence, the degree of intramolecular cleavage must also modulate TSHR signaling. PMID- 20719861 TI - Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. AB - Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has sitosterolemia. Thus, whole genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients. PMID- 20719862 TI - New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8. AB - Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (beta = 0.23 SD, P = 4.4 * 10(-9)) and rs1536482 (beta = 0.22 SD, P = 7.1 * 10(-8)) for which the closest candidate genes (although >=90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 * 10(-4)) but COL5A1 remained a suggestive association in the combined sample (beta = 0.16 SD, P = 1.1 * 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (beta = 0.13 SD, P = 5.1 * 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (beta = 0.14 SD, P = 3.5 * 10(-9)). The third new locus (rs6496932), on 15q25.3 (beta = 0.13, P = 1.4 * 10(-8)), was within a wide linkage disequilibrium block extending into the 5' end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus. PMID- 20719864 TI - Acoustic evidence for positional and complexity effects on children's production of plural -s. AB - PURPOSE: Some variability in children's early productions of grammatical morphemes reflects phonological factors. For example, production of 3rd person singular -s is increased in utterance-final versus utterance-medial position and in simple versus cluster codas (e.g., sees vs. hits). Understanding the factors that govern such variability is an important step toward modeling developmental processes. In this study, the authors examined the generality of these effects by determining whether position and coda complexity influence production of plural s, which phonologically manifests the same as 3rd person singular -s. METHOD: The authors used an elicited imitation task to examine the speech of 16 two-year olds. Eight plural nouns (half contained simple codas, half contained cluster codas) were elicited utterance-medially and utterance-finally. Acoustic analysis of each noun was used to identify acoustic cues associated with coda production. RESULTS: Results showed that plural production was more robust in utterance-final versus utterance-medial position but equally robust in simple versus cluster codas. CONCLUSIONS: These findings extend positional effects on morpheme production to plural -s. An effect of coda complexity was not observed for plural but was observed for 3rd person singular, which raises the possibility that the morphological representation proper influences the degree to which phonological factors affect morpheme production. PMID- 20719863 TI - Chk1-dependent constitutive phosphorylation of BLM helicase at serine 646 decreases after DNA damage. AB - BLM helicase, the protein mutated in Bloom syndrome, is involved in signal transduction cascades after DNA damage. BLM is phosphorylated on multiple residues by different kinases either after stress induction or during mitosis. Here, we have provided evidence that both Chk1 and Chk2 phosphorylated the NH(2) terminal 660 amino acids of BLM. An internal region within the DExH motif of BLM negatively regulated the Chk1/Chk2-dependent NH(2)-terminal phosphorylation event. Using in silico analysis involving the Chk1 structure and its known substrate specificity, we predicted that Chk1 should preferentially phosphorylate BLM on serine 646 (Ser(646)). The prediction was validated in vitro by phosphopeptide analysis on BLM mutants and in vivo by usage of a newly generated phosphospecific polyclonal antibody. We showed that the phosphorylation at Ser(646) on BLM was constitutive and decreased rapidly after exposure to DNA damage. This resulted in the diminished interaction of BLM with nucleolin and PML isoforms, and consequently decreased BLM accumulation in the nucleolus and PML nuclear bodies. Instead, BLM relocalized to the sites of DNA damage and bound with the damage sensor protein, Nbs1. Mutant analysis confirmed that the binding to nucleolin and PML isoforms required Ser(646) phosphorylation. These results indicated that Chk1-mediated phosphorylation on BLM at Ser(646) might be a determinant for regulating subnuclear localization and could act as a marker for the activation status of BLM in response to DNA damage. PMID- 20719865 TI - The main concept analysis in cantonese aphasic oral discourse: external validation and monitoring chronic aphasia. AB - PURPOSE: The 1st aim of this study was to further establish the external validity of the main concept (MC) analysis by examining its relationship with the Cantonese Linguistic Communication Measure (CLCM; Kong, 2006; Kong & Law, 2004) an established quantitative system for narrative production-and the Cantonese version of the Western Aphasia Battery (CAB; Yiu, 1992). The 2nd purpose of the study was to evaluate how well the MC analysis reflects the stability of discourse production among chronic Cantonese speakers with aphasia. METHOD: Sixteen participants with aphasia were evaluated on the MC analysis, CAB, and CLCM in the summer of 2008 and were subsequently reassessed in the summer of 2009. They encompassed a range of aphasia severity (with an Aphasia Quotient ranging between 30.2/100 and 94.8/100 at the time of the 1st evaluation). RESULTS: Significant associations were found between the MC measures and the corresponding CLCM indices and CAB performance scores that were relevant to the presence, accuracy, and completeness of content in oral narratives. Moreover, the MC analysis was found to yield comparable scores for chronic speakers on 2 occasions 1 year apart. CONCLUSION: The present study has further established the external validity of MC analysis in Cantonese. Future investigations involving more speakers with aphasia will allow adequate description of its psychometric properties. PMID- 20719866 TI - The primacy of priming in grammatical learning and intervention: a tutorial. AB - PURPOSE: The author presents a tutorial on structural priming and its relevance to the study of grammatical development and language intervention. METHOD: The findings from structural priming studies are examined from the standpoint of the types of changes that occur in participants' language use, the contexts in which these changes occur, and the effects of these changes on participants' language knowledge. Details of children's grammatical development and language intervention are then considered in light of these findings. RESULTS: Evidence from the structural priming literature provides insight into the transition from early conservative grammatical use to broader abstract grammatical use in young children, and suggests ways in which language intervention activities can be modified to promote greater grammatical change in children with language impairments. CONCLUSIONS: Structural priming is not divorced from everyday language use. Evidence from priming research can be put to use in the study of children's grammatical development and in shaping the methods that are used to facilitate children's grammatical abilities. PMID- 20719867 TI - Gesture and motor skill in relation to language in children with language impairment. AB - PURPOSE: To examine gesture and motor abilities in relation to language in children with language impairment (LI). METHOD: Eleven children with LI (aged 2;7 to 6;1 [years;months]) and 16 typically developing (TD) children of similar chronological ages completed 2 picture narration tasks, and their language (rate of verbal utterances, mean length of utterance, and number of different words) and gestures (coded for type, co-occurrence with language, and informational relationship to language) were examined. Fine and gross motor items from the Battelle Developmental Screening Inventory (J. Newborg, J. R. Stock, L. Wneck, J. Guidubaldi, & J. Suinick, 1994) and the Child Development Inventory (H. R. Ireton, 1992) were administered. RESULTS: Relative to TD peers, children with LI used gestures at a higher rate and produced greater proportions of gesture-only communications, conventional gestures, and gestures that added unique information to co-occurring language. However, they performed more poorly on measures of fine and gross motor abilities. Regression analyses indicated that within the LI but not the TD group, poorer expressive language was related to more frequent gesture production. CONCLUSIONS: When language is impaired, difficulties are also apparent in motor abilities, but gesture assumes a compensatory role. These findings underscore the utility of including spontaneous gesture and motor abilities in clinical assessment of and intervention for preschool children with language concerns. PMID- 20719868 TI - Measuring goodness of story narratives. AB - PURPOSE: The purpose of this article was to evaluate a new measure of story narrative performance: story completeness. It was hypothesized that by combining organizational (story grammar) and completeness measures, story "goodness" could be quantified. METHOD: Discourse samples from 46 typically developing adults were compared with those from 24 adults with acquired brain injuries. Story retellings were elicited and analyzed for episode structure (story grammar). Each story was also evaluated for the presence of 5 key components, yielding the story completeness score. Story goodness was quantified by combining the story grammar and completeness measures using a 2-coordinate grid system. A multivariate analysis of variance was performed as well as correlational analyses between the story grammar and story completeness scores. RESULTS: There were significant group differences on both story grammar and story completeness. Moderate correlations were noted between the 2 measures, suggesting that the indices were not entirely measuring the same abilities. Plotting the 2 sets of scores into quadrants discriminated the comparison group and the group with brain injury into 4 distinct categories of story "goodness." CONCLUSION: The combination of measures provided a more accurate depiction of discourse performance than either measure alone. Results suggest the measure is sensitive, is reliable, and has potential utility for investigating discourse deficits in clinical populations. PMID- 20719869 TI - Oral narrative skills in French adults who are functionally illiterate: linguistic features and discourse organization. AB - PURPOSE: To investigate the nature and extent of oral language difficulties encountered by adults who are functionally illiterate. METHOD: Fifty-two men and women identified as functionally illiterate, together with a group of control individuals of comparable age, sex, and socioprofessional background, produced a narrative intended for an absent recipient based on a sequence of pictures featuring a cast of 3 protagonists. All narratives were transcribed in their entirety and coded in terms of linguistic features and discourse organization. RESULTS: As a group, the participants who were illiterate had great difficulty handling morphosyntactic rules, referential cohension, and the narrative schema. Furthermore, a qualitative analysis highlighted considerable interindividual variability in narrative styles, reflecting different types of difficulties. CONCLUSIONS: Individuals who have not succeeded in learning to read also have impaired oral language abilities. This may affect different aspects of communication skills to a greater or lesser extent. These results have implications for teaching written language to adult learners. PMID- 20719870 TI - The role of pragmatic language use in mediating the relation between hyperactivity and inattention and social skills problems. AB - PURPOSE: In the present study, the authors explored whether pragmatic language use was associated with, and perhaps accounted for, the social skills problems that children with varying levels of hyperactivity and inattention experience. METHOD: A community sample of 54 children aged 9-11 years participated. Pragmatic language use, hyperactivity and inattention, and social skills were examined utilizing data collected from standardized parent-report rating scales. RESULTS: Pragmatic language use fully mediated the relation between hyperactivity and social skills problems and partially mediated the relation between inattention and social skills problems. Further, pragmatic language use provided a unique contribution in the estimate of children's social skills of 21.6% above and beyond the contribution of hyperactivity and 17.2% above and beyond the contribution of inattention. CONCLUSIONS: Possible explanations for these mediation results are discussed in terms of children with attention deficit/hyperactivity disorder and the problems that they experience with social relations. PMID- 20719871 TI - Psycholinguistic profiling differentiates specific language impairment from typical development and from attention-deficit/hyperactivity disorder. AB - PURPOSE: Practitioners must have confidence in the capacity of their language measures to discriminate developmental language disorders from typical development and from other common disorders. In this study, psycholinguistic profiles were collected from 3 groups: children with specific language impairment (SLI), children with attention-deficit/hyperactivity disorder (ADHD), and children with typical development (TD). The capacity of different language indices to successfully discriminate SLI cases from TD and ADHD cases was examined through response operating characteristics curves, likelihood ratios, and binary logistic regression. METHOD: The Test of Early Grammatical Impairment (Rice & Wexler, 2001a), Dollaghan and Campbell's (1998) nonword repetition task, Redmond's (2005) sentence recall task, and the Test of Narrative Language (Gillam & Pearson, 2004) were administered to 60 children (7-8 years of age). RESULTS: Diagnostic accuracy was high for all 4 psycholinguistic measures, although modest reductions were observed with the SLI versus ADHD discriminations. Classification accuracy associated with using the Test of Early Grammatical Impairment and the Sentence Recall task was equivalent to using all 4 measures. IMPLICATIONS: Outcomes confirmed and extended previous investigations, documenting high levels of diagnostic integrity for these particular indices and supporting their incorporation into eligibility decisions, differential diagnosis, and the identification of comorbidity. PMID- 20719872 TI - Predictors of morphosyntactic growth in typically developing toddlers: contributions of parent input and child sex. AB - PURPOSE: Theories of morphosyntactic development must account for between-child differences in morphosyntactic growth rates. This study extends Legate and Yang's (2007) theoretically motivated cross-linguistic approach to determine if variation in properties of parent input accounts for differences in the growth of tense productivity. METHOD: Fifteen toddlers (and parents) participated. None were producing tense morphemes productively at 21 months. Two dependent measures of morphosyntactic growth between 21 and 30 months were used: empirical Bayes linear coefficients at 21 months and predicted productivity scores at 30 months. Predictor variables included child sex, vocabulary, and mean length of utterance as well as 4 measures of parent language input at 21 months. RESULTS: Input informativeness for tense was the most consistent predictor of morphosyntactic growth, explaining 28.3% of the unique variance in children's linear growth coefficients at 21 months and 23.0% of the unique variance in predicted tense productivity scores at 30 months. General input measures were unrelated. Child sex explained an additional 24.7% of the variance in early linear growth. Child vocabulary at 21 months did not explain a significant proportion of unique variance. CONCLUSION: The findings provide evidence that input informativeness, an abstract and distributed property of input, contributes to morphosyntactic growth. PMID- 20719873 TI - Feasibility, efficacy, and social validity of home-based storybook reading intervention for children with language impairment. AB - PURPOSE: This study evaluated the feasibility, efficacy, and social validity of a parent-implemented intervention for promoting print knowledge in preschoolers with language impairment. METHOD: This trial involved 62 children and their parents. Each dyad completed a 12-week intervention program. Parents in the treatment group implemented print-focused reading sessions; parents in two comparison groups implemented sessions focused on either storybook pictures (picture-focused condition) or phonological concepts (sound-focused condition). RESULTS: Many parents completed the program successfully, but attrition was high; 23% of families dropped out of the program. Children who remained in the treatment group demonstrated significantly greater gains on 1 of 2 measures of print knowledge compared with those in the picture-focused condition but not the sound-focused condition. Parents generally reported favorable impressions of the program, although several aspects of the program received higher ratings from parents in the print-focused group. CONCLUSION: Study results raise questions about the feasibility of home-based intervention for some families; future research that examines the characteristics of families that may affect completion are needed. The causal effects of print-focused reading sessions are promising for addressing children's print-concept knowledge but not alphabet knowledge. Home-based reading intervention has considerable social validity as a therapeutic approach. PMID- 20719874 TI - Using aided AAC models, recasts, and contrastive targets to teach grammatical morphemes to children who use AAC. AB - PURPOSE: The purpose of the investigation was to evaluate the effects of using aided augmentative and alternative communication (AAC) modeling and recasting on the expression of grammatical morphemes with children who used AAC. METHOD: A single-subject, multiple-probe, across-targets design was used for the study. Three participants were each taught to use 3 grammatical structures. Intervention consisted of aided AAC models and recasts during storybook reading tasks. RESULTS: All three children readily began using the targeted grammatical morphemes. However, none of the participants maintained use of the first morpheme. Error analyses revealed that the children either omitted the targeted morpheme or replaced it with another morpheme. To address this issue, a second intervention phase was implemented for the targets that were not maintained. During this phase, various grammatical morphemes were contrasted with each other (e.g., past tense -ed vs. possessive 's). Following the second intervention phase, participants maintained all targets. CONCLUSIONS: Aided AAC models and recasts may be used as part of intervention packages designed to help children acquire production of grammatical morphemes; however, it is important to provide contrasts of grammatical forms to ensure acquisition. Theoretical and clinical implications are discussed. PMID- 20719875 TI - Getting past the RNA world: the initial Darwinian ancestor. AB - A little-noted result of the confirmation of multiple premises of the RNA-world hypothesis is that we now know something about the dawn organisms that followed the origin of life, perhaps over 4 billion years ago. We are therefore in an improved position to reason about the biota just before RNA times, during the era of the first replicators, the first Darwinian creatures on Earth. An RNA congener still prominent in modern biology is a plausible descendent of these first replicators. PMID- 20719878 TI - The 'Ajuda Paralyses': history of a neuropsychiatric debate in mid-19th-century Portugal. AB - The second half of the 19th century witnessed an increasing interest in neurology and psychiatry by Portuguese physicians, in parallel with the overall development of these disciplines in other countries. This process is reflected in the numerous case report publications as well as in debates taking place at the Lisbon Society of Medical Sciences, the major scientific forum of that time. The 'Ajuda Paralyses' were a mysterious succession of epidemics that occurred during 1860-64 in the Ajuda asylum for cholera and yellow fever orphans, which were extensively discussed during 1865-66 by Bernardino Antonio Gomes, Antonio Maria Barbosa, Abel Jordao and Eduardo Motta. Studying this debate helps understand the initial stages of development and the great interest that 'nervous diseases' had for Portuguese clinicians in the mid-19th century and possibly provides one of the first modern descriptions of nutrition-related polyradiculoneuropathy and the ocular findings associated with avitaminosis A. This debate took place at a decisive time for the scientific development of neurology and psychiatry, concurrent with the widespread application of the clinical-anatomical method and neuropathology to the study of diseases of the nervous system, which would set the foundations for our own modern pathophysiological framework. Therefore, the 'Ajuda paralyses' debate also provides a good basis for a discussion on the evolution of the concepts of hysteria and psychosomatic disease and the description of peripheral neuropathy from among a wealth of other entities that did not withstand the test of science. PMID- 20719876 TI - Oncogenes and tumor suppressor genes. AB - Breast cancer progression involves multiple genetic events, which can activate dominant-acting oncogenes and disrupt the function of specific tumor suppressor genes. This article describes several key oncogene and tumor suppressor signaling networks that have been implicated in breast cancer progression. Among the tumor suppressors, the article emphasizes BRCA1/2 and p53 tumor suppressors. In addition to these well characterized tumor suppressors, the article highlights the importance of PTEN tumor suppressor in counteracting PI3K signaling from activated oncogenes such as ErbB2. This article discusses the use of mouse models of human breast that recapitulate the key genetic events involved in the initiation and progression of breast cancer. Finally, the therapeutic potential of targeting these key tumor suppressor and oncogene signaling networks is discussed. PMID- 20719879 TI - Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. AB - The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 +/- 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 +/- 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R2(adjusted) = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R2(adjusted) = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain. PMID- 20719877 TI - Noncoding RNPs of viral origin. AB - Like their host cells, many viruses produce noncoding (nc)RNAs. These show diversity with respect to time of expression during viral infection, length and structure, protein-binding partners and relative abundance compared with their host-cell counterparts. Viruses, with their limited genomic capacity, presumably evolve or acquire ncRNAs only if they selectively enhance the viral life cycle or assist the virus in combating the host's response to infection. Despite much effort, identifying the functions of viral ncRNAs has been extremely challenging. Recent technical advances and enhanced understanding of host-cell ncRNAs promise accelerated insights into the RNA warfare mounted by this fascinating class of RNPs. PMID- 20719880 TI - Factors influencing left ventricular mass regression in patients with primary aldosteronism post adrenalectomy. AB - BACKGROUND: Primary aldosteronism (PA) is a type of secondary hypertension with prominent left ventricular hypertrophy (LVH). Unilateral aldosterone-producing adenoma (APA) is the most common subtype that can be cured by adrenalectomy. OBJECTIVE: To investigate left ventricular structural change after surgery and the factors associated with the degree of LVH regression in patients with PA. METHODS: We performed a retrospective analysis in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database, including demography, biochemical data, echocardiography and medication. RESULTS: From July 1994 to January 2007, 20 patients (8 men) with APA receiving adrenalectomy and having pre- and postoperative echocardiography were selected. After 21 +/- 19 months post operation, the left ventricular wall thickness and left ventricular mass index (LVMI) decreased significantly. The decrease of LVMI is significant only in patients who had LVH before operation. In analysis of factors associated with net LVMI decrease (DeltaLVMI; post-operative LVMI - pre-operative LVMI), only pre operative LVMI (r = -.783, p < .001), and DeltaSBP (r = .472, p = .036) significantly correlated with DeltaLVMI. In conclusion, LVH in PA could be significantly reversed by adrenalectomy. Pre-operative LVMI and DeltaSBP were associated with the degree of LVMI decrease. CONCLUSION: LVH in PA could be significantly reversed by adrenalectomy. Pre-operative LVMI and DeltaSBP were associated with the degree of LVMI decrease. PMID- 20719881 TI - Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. AB - BACKGROUND: The electropathological substrate of persistent atrial fibrillation (AF) in humans is largely unknown. The aim of this study was to compare the spatiotemporal characteristics of the fibrillatory process in patients with normal sinus rhythm and long-standing persistent AF. METHODS AND RESULTS: During cardiac surgery, epicardial mapping (244 electrodes) of the right atrium (RA), the left lateral wall (LA), and the posterior left atrium (PV) was performed in 24 patients with long-standing persistent AF. Twenty-five patients with normal sinus rhythm, in whom AF was induced by rapid pacing, served as a reference group. A mapping algorithm was developed that separated the complex fibrillation process into its individual elements (wave mapping). Parameters used to characterize the substrate of AF were (1) the total length of interwave conduction block, (2) the number of fibrillation waves, and (3) the ratio of block to collision of fibrillation waves (dissociation index). In 4403 maps of persistent AF, no evidence for the presence of stable foci or rotors was found. Instead, many narrow wavelets propagated simultaneously through the atrial wall. The lateral boundaries of these waves were formed by lines of interwave conduction block, predominantly oriented parallel to the atrial musculature. Lines of block were not fixed but continuously changed on a beat-to-beat basis. In patients with persistent AF, the total length of block in the RA was more than 6-fold higher than during acute AF (median, 21.1 versus 3.4 mm/cm(2); P<0.0001). The highest degree of interwave conduction block was found in the PV area (33.0 mm/cm(2)). The number of fibrillation waves during persistent AF was 4.5/cm(2) compared with 2.3 during acute AF, and the dissociation index was 7.3 versus 1.5 (P<0.0001). The interindividual variation of these parameters among patients was high. CONCLUSIONS: Electric dissociation of neighboring atrial muscle bundles is a key element in the development of the substrate of human AF. The degree of the pathological changes can be measured on an individual basis by electrophysiological parameters in the spatial domain. PMID- 20719882 TI - The relationship between body composition and structural changes at the knee. AB - OBJECTIVE: Obesity is an important risk factor for knee OA. Evidence suggests that fat and muscle have differential effects on the pathogenesis of disease. The aim of this study was to examine the relationship between body composition and knee structure, including knee cartilage volume, defects and bone marrow lesions (BMLs). METHODS: A total of 153 subjects aged 25-60 years, 81% females, were recruited across a range of BMI (18-55 kg/m2) for a study examining the relationship between obesity and musculoskeletal disease. MRI was performed of the dominant knee. Cartilage volume, defects and BMLs were measured using validated methods. Body composition was measured using dual X-ray absorptiometry. RESULTS: There was an 81 (95% CI: 69, 94) mm3 increase in cartilage volume for every 1 kg increase in skeletal muscle mass. Fat mass was not significantly associated with cartilage volume. Fat mass, but not skeletal muscle mass, was a risk factor for cartilage defects and BMLs. For every 1 kg increase in total body fat there was an increased risk of cartilage defects (OR=1.31, 95% CI: 1.04, 1.64) and BMLs (OR=1.09, 95% CI: 1.01, 1.18). CONCLUSIONS: In this relatively healthy population, fat mass was associated with increased cartilage defects and BMLs, which are features of early knee OA. In contrast, skeletal muscle mass was positively associated with cartilage volume, which may be due to coinheritance, a commonality of environmental factors associated with cartilage accrual or a protective effect of increased muscle. PMID- 20719883 TI - Magnetic resonance imaging and musculoskeletal ultrasonography detect and characterize covert inflammatory arthropathy in systemic sclerosis patients with arthralgia. AB - OBJECTIVES: Arthropathy, particularly synovial inflammation in SSc, is not well characterized. We explored the role of MRI and musculoskeletal ultrasonography (MSUS) in detecting and characterizing synovial inflammation in SSc patients with arthralgia while comparing the two imaging modalities. METHODS: Seventeen SSc patients with arthralgia and no overt inflammatory arthritis had a baseline MSUS of their hands. Six months later, 13 unselected patients had a second MSUS and 8 of these 13 patients also had MRI with gadolinium of their most symptomatic hand. RESULTS: Of the eight patients undergoing MRI scan, all (100%) patients had synovitis and 88% of patients had tenosynovitis. MRI also showed erosions in 75% of patients. On MSUS, on baseline and second scans, tenosynovitis was seen in 46% and 47% of the patients and synovitis in 6% and 23%, respectively. No erosions were identified. Applying the RAMRIS system (a semi-quantitative MRI scoring system used in RA), the mean values for synovitis, oedema and erosions fell within the range seen in RA. CONCLUSIONS: This study demonstrates the presence of a persistent inflammatory, erosive, peripheral arthropathy, similar to that seen in RA, in SSc patients with arthralgia without overt inflammatory joint disease. While both MRI and MSUS are useful in characterizing synovial inflammation in SSc, MRI is clearly more sensitive than MSUS in this setting. Further studies to establish the clinical and radiological musculoskeletal outcomes over time in this group of patients are required in order to identify the appropriate management of arthralgia in SSc. PMID- 20719884 TI - Crucial roles for protein kinase C isoforms in tumor-specific killing by apoptin. AB - The chicken anemia virus-derived protein apoptin induces apoptosis in a variety of human malignant and transformed cells but not in normal cells. However, the mechanisms through which apoptin achieves its selective killing effects are not well understood. We developed a lentiviral vector encoding a green fluorescent protein-apoptin fusion gene (LV-GFP-AP) that can efficiently deliver apoptin into hematopoietic cells. Apoptin selectively killed the human multiple myeloma cell lines MM1.R and MM1.S, and the leukemia cell lines K562, HL60, U937, KG1, and NB4. In contrast, normal CD34(+) cells were not killed and maintained their differentiation potential in multilineage colony formation assays. In addition, dexamethasone-resistant MM1.R cells were found to be more susceptible to apoptin induced cell death than the parental matched MM1.S cells. Death susceptibility correlated with increased phosphorylation and activation of the apoptin protein in MM1.R cells. Expression array profiling identified differential kinase profiles between MM1.R and MM1.S cells. Among these kinases, protein kinase Cbeta (PKCbeta) was found by immunoprecipitation and in vitro kinase studies to be a candidate kinase responsible for apoptin phosphorylation. Indeed, shRNA knockdown or drug-mediated inhibition of PKCbeta significantly reduced apoptin phosphorylation. Furthermore, apoptin-mediated cell death proceeded through the upregulation of PKCbeta, activation of caspase-9/3, cleavage of the PKCdelta catalytic domain, and downregulation of the MERTK and AKT kinases. Collectively, these results elucidate a novel pathway for apoptin activation involving PKCbeta and PKCdelta. Further, they highlight the potential of apoptin and its cellular regulators to purge bone marrow used in autologous transplantation for multiple myeloma. PMID- 20719885 TI - A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor infiltrating lymphocytes and favors tumor rejection in mice. AB - Human CD8(+) tumor-infiltrating T lymphocytes (TIL), in contrast with CD8(+) blood cells, show impaired IFN-gamma secretion on ex vivo restimulation. We have attributed the impaired IFN-gamma secretion to a decreased mobility of T-cell receptors on trapping in a lattice of glycoproteins clustered by extracellular galectin-3. Indeed, we have previously shown that treatment with N acetyllactosamine, a galectin ligand, restored this secretion. We strengthened this hypothesis here by showing that CD8(+) TIL treated with an anti-galectin-3 antibody had an increased IFN-gamma secretion. Moreover, we found that GCS-100, a polysaccharide in clinical development, detached galectin-3 from TIL and boosted cytotoxicity and secretion of different cytokines. Importantly, we observed that not only CD8(+) TIL but also CD4(+) TIL treated with GCS-100 secreted more IFN gamma on ex vivo restimulation. In tumor-bearing mice vaccinated with a tumor antigen, injections of GCS-100 led to tumor rejection in half of the mice, whereas all control mice died. In nonvaccinated mice, GCS-100 had no effect by itself. These results suggest that a combination of galectin-3 ligands and therapeutic vaccination may induce more tumor regressions in cancer patients than vaccination alone. PMID- 20719887 TI - Kienbock's disease. PMID- 20719886 TI - Circulating levels of the innate and humoral immune regulators CD14 and CD23 are associated with adult glioma. AB - Allergy history has been consistently inversely associated with glioma risk. Two serologic markers, soluble CD23 (sCD23) and soluble CD14 (sCD14), are part of the innate and adaptive humoral immune systems and modulate allergic responses in opposite directions, with sCD23 enhancing and sCD14 blunting inflammatory responses. We measured sCD23 and sCD14 in serum from blood that was drawn at a single time point from 1,079 glioma patients postdiagnosis and 736 healthy controls. Glioma was strongly associated with high sCD14 [highest versus lowest quartile odds ratio (OR), 3.94; 95% confidence interval (95% CI), 2.98-5.21] and low sCD23 (lowest versus highest quartile OR, 2.5; 95% CI, 1.89-3.23). Results were consistent across glioma histologic types and grades, but were strongest for glioblastoma. Whereas temozolomide treatment was not associated with either sCD14 or sCD23 levels among cases, those taking dexamethasone had somewhat lower sCD23 levels than those not taking dexamethasone. However, sCD23 was associated with case status regardless of dexamethasone treatment. These results augment the long observed association between allergies and glioma and support a role for the innate and adaptive humoral functions of the immune system, in particular immunoregulatory proteins, in gliomagenesis. PMID- 20719888 TI - A unique case of partial, radial-sided lunatomalacia. PMID- 20719889 TI - Radial wedge osteotomy for IIIB Kienbock's disease in cerebral palsy: a case report. PMID- 20719890 TI - An unusual forearm injury - with subluxation of both radioulnar joints. PMID- 20719891 TI - Dorsal spur causing block to wrist extension: unusual complication of distal radial fracture fixation using a palmar locking plate. PMID- 20719892 TI - Schwannomatosis affecting all three major nerves in the same upper extremity. PMID- 20719893 TI - Compression of the ulnar nerve in Guyon's canal by an angioleiomyoma. PMID- 20719894 TI - Foreign body migration within the flexor sheath. PMID- 20719895 TI - Metastases to the finger masquerading as flexor tenosynovitis. PMID- 20719896 TI - Atypical anatomy of the median nerve in the carpal tunnel - a potential pitfall. PMID- 20719897 TI - Subungual keratoacanthoma: the importance of accurate diagnosis. PMID- 20719900 TI - The carbon footprint of a renal service in the United Kingdom. AB - BACKGROUND: Anthropogenic climate change presents a major global health threat. However, the very provision of healthcare itself is associated with a significant environmental impact. Carbon footprinting techniques are increasingly used outside of the healthcare sector to assess greenhouse gas emissions and inform strategies to reduce them. AIM: This study represents the first assessment of the carbon footprint of an individual specialty service to include both direct and indirect emissions. METHODS: This was a component analysis study. Activity data were collected for building energy use, travel and procurement. Established emissions factors were applied to reconcile this data to carbon dioxide equivalents (CO(2)eq) per year. RESULTS: The Dorset Renal Service has a carbon footprint of 3006 tonnes CO(2)eq per annum, of which 381 tonnes CO(2)eq (13% of overall emissions) result from building energy use, 462 tonnes CO(2)eq from travel (15%) and 2163 tonnes CO(2)eq (72%) from procurement. The contributions of the major subsectors within procurement are: pharmaceuticals, 1043 tonnes CO(2)eq (35% of overall emissions); medical equipment, 753 tonnes CO(2)eq (25%). The emissions associated with healthcare episodes were estimated at 161 kg CO(2)eq per bed day for an inpatient admission and 22 kg CO(2)eq for an outpatient appointment. CONCLUSION: These results suggest that carbon-reduction strategies focusing upon supply chain emissions are likely to yield the greatest benefits. Sustainable waste management and strategies to reduce emissions associated with building energy use and travel will also be important. A transformation in the way that clinical care is delivered is required, such that lower carbon clinical pathways, treatments and technologies are embraced. The estimations of greenhouse gas emissions associated with outpatient appointments and inpatient stays calculated here may facilitate modelling of the emissions of alternative pathways of care. PMID- 20719901 TI - Angiosarcoma of the breast. PMID- 20719903 TI - Chemoimmunotherapy reduces the progression of multiple myeloma in a mouse model. AB - Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of malignant plasma cells in the bone marrow. Recently, we showed a correlation between increased ratios of functional regulatory T cells (Treg) and disease progression in a unique mouse model that mimics the human disease. Cyclophosphamide (CYC) is a cytotoxic alkylating agent widely used in chemotherapeutic regimens. Low-dose CYC was previously reported to selectively reduce Treg levels and to contribute to immunostimulation. Our objectives were (a) to determine whether treatment using a low-dose CYC could reduce MM progression and (b) to further characterize the modes of action underlying these effects. We found that both low- and high-dose CYC given to sick mice with hind limb paralysis resulted in the disappearance of the paralysis, the replacement of plasma tumor cells in the bone marrow by normal cell populations, and a significant prolongation of survival. However, only low-dose CYC treatment decreased the incidence of MM. Low-dose CYC rendered Tregs susceptible to apoptosis because of the downregulation of Bcl-xL and CTLA-4 in these cells, and a decreased production of interleukin 2 by effector CD4 cells. Moreover, using this treatment, we noted the recovery of IFN-gamma-producing natural killer T cells and maturation of dendritic cells. Treatment of tumor-bearing mice with repeated administrations of low-dose CYC at longer time intervals (coinciding with the blocked renewal of Tregs) resulted in reduced tumor load, and the prevention or delay of disease recurrence, thereby breaking immune tolerance against MM tumor cells. PMID- 20719902 TI - Body size and incident colorectal cancer: a prospective study of older women. AB - Obesity is a controversial risk factor for colorectal cancer (CRC) in older women. We evaluated associations between multiple body size parameters and incident CRC in the prospective, population-based Iowa Women's Health Study (IWHS). IWHS participants, ages 55 to 69 years, provided data regarding height; weight; weight at ages 50, 40, 30, 18 years; hip circumference; and waist circumference at baseline (1986). Derived variables included body mass index (BMI), waist-to-hip ratio (WHR), and "overweight years" (OWY; conceptually similar to cigarette pack-years). Incident CRC cases (n = 1,464) were ascertained from the State Health Registry of Iowa, through 2005. Multivariable Cox regression models were fit to estimate body size-associated CRC risks. Among 36,941 women (619,961 person-years), baseline height, weight, BMI, hip circumference, waist circumference, and WHR were all positively associated with incident CRC (P(trend) <= 0.003 for each). Baseline BMI yielded the highest CRC risk estimates (obese III versus normal, RR = 1.56; 95% CI = 1.10-2.22; P(trend) < 0.001) and was more closely associated with distal than proximal tumors (P(trend) < 0.001 versus 0.06). Conversely, height was more closely associated with proximal than distal tumors (P(trend) < 0.001 versus 0.04). Other body size parameters were less predictive of incident CRC. These data strongly support a positive association between increased body size and CRC risk among older women. Further investigation of when increased body size has the greatest effect on CRC risk (i.e., early adulthood versus later adulthood) might also be informative, particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis. PMID- 20719904 TI - Health care reform: a view from abroad. PMID- 20719905 TI - Multiple pleuropericardial implants of thymoma after videothoracoscopic resection. AB - The case of a 49-year-old man with multiple pleuropericardial implants of B2 thymoma is reported. Two years earlier, the patient had undergone left videothoracoscopic (VATS) resection of a 6-cm thymoma in another hospital. The operative report describes a technically correct procedure with morcellation of the lesion within a retrieval thoracoscopic bag. Through a standard thoracotomy, 11 implants were resected with macroscopically complete tumor removal. The origin of cell spillage was ascribed to manipulation of the thymoma during VATS resection. PMID- 20719906 TI - Large primary cardiac sarcoma on the left ventricular free wall: is total excision contraindicated? AB - A case of a large primary cardiac sarcoma on the left ventricular free wall is reported. Although the definitive diagnosis of this tumor was not made preoperatively, total excision was planned for rapid diagnosis and optimal procedure. However, the operation was discontinued due to intraoperative diagnosis of malignancy. As a result, the patient suffered from the symptoms of cardiac tamponade caused by the large tumor. We discuss the surgical strategy to provide therapeutic benefit for possible patients in the future. In conclusion, an aggressive attempt at volume reduction such as cardiac autotransplantation may relieve the symptoms, even though such surgery would only be palliative. PMID- 20719907 TI - A population-based study on the risks of cervical lesion and human papillomavirus infection among women in Beijing, People's Republic of China. AB - BACKGROUND: Few population-based studies have investigated premalignant and malignant cervical abnormalities in Beijing. METHODS: A total of 6,385 randomly selected sexually active women were interviewed and examined. Cervical lesion was diagnosed using cytology and histology. High-risk human papillomavirus (HPV) was detected by the second-generation hybrid capture test and typed by gene chip of DNA from paraffin-embedded tissue. RESULTS: The cervical lesion prevalence diagnosed by histology was 5.8%. High-risk HPV overall prevalence was 9.9%, 50.5% with cervical lesion and 7.4% without cervical lesion. High-risk HPV DNA load increased with increasing degree of lesions. HPV 16 was the most common type (26.5%) among women with cervical lesion, followed by HPV 58 (8.8%), HPV 33 (7.8%), and HPV 56 (5.3%). Women under 50 years of age, married status, pregnancy and delivery status, couple's sexual behavior, contraceptive history, columnar ectopy, and bacterial vaginosis or trichomonas vaginitis history were more risk factors for HPV infection. Factors for cervical lesion were similar, but in comparison with HPV infection, all associations were weakened. Only middle-aged women, husband's sexual partners, oral contraceptives, columnar ectopy, and history of trichomonas vaginitis remained associated with cervical lesion. CONCLUSION: In Beijing, the prevalence of cervical lesion and high-risk HPV is higher than estimated in previous reports. HPV 16, 58, and 33 were the most prevalent types. This is relevant for work related to cervical cancer vaccination. IMPACT: The study was conducted to understand the current status and epidemiologic characteristics of women with cervical lesion and HPV infection in Beijing. PMID- 20719908 TI - Carbamazepine but not valproate induces CYP2A6 activity in smokers with mental illness. AB - BACKGROUND: Antiepileptic drugs (AED) are being increasingly used in the management of serious mental illness, but their effects on nicotine metabolism have not been studied. METHODS: This study investigated the effects of three AEDs (carbamazepine, oxcarbazepine, and valproic acid) on nicotine and nicotine metabolite levels in 149 smokers with schizophrenia and bipolar disorder who participated in an afternoon blood draw for nicotine, cotinine, and 3' hydroxycotinine (3HC). The ratio of 3HC to cotinine was calculated as a marker of CYP2A6 metabolic activity. Among the participants, 8 smokers were taking carbamazepine, 6 were taking oxcarbazepine, and 40 were taking valproic acid. RESULTS: The 3HC/cotinine ratio was significantly higher in individuals taking carbamazepine or oxcarbazepine (combined, n = 14) versus those not taking either (mean 0.993 versus 0.503; P < 0.001). The cotinine/cigarette per day ratio was significantly lower in individuals taking carbamazepine or oxcarbazepine. The 3HC/cotinine ratios were also significantly higher in the subgroup of individuals taking carbamazepine (n = 8) versus those not taking it. There were no significant differences in nicotine or cotinine levels or 3HC/cotinine ratios in individuals taking valproic acid versus those not taking it. We conducted backward stepwise linear regression models to identify predictors of the log transformed 3HC/cotinine ratios. Taking carbamazepine and number of cigarettes smoked per day were significant determinants of log 3HC/cotinine. CONCLUSIONS: Carbamazepine likely induces hepatic metabolism via CYP2A6 and is associated with increased 3HC/cotinine ratios. IMPACT: Increased nicotine metabolism in individuals using AED has implications for increased smoking behavior and exposure to more tobacco toxins, which warrants further study. PMID- 20719909 TI - Does Ravitch legend turn back? PMID- 20719910 TI - Improving results with additional technique. PMID- 20719911 TI - Simvastatin inhibits aortic valve calcification in hypercholesterolemic rabbits. PMID- 20719912 TI - Statins may not prevent structural valve degeneration of aortic bioprosthetic valves, but should probably be prescribed to patients undergoing heart valve surgery nonetheless. PMID- 20719913 TI - Primary pleomorphic liposarcoma: a rare mediastinal tumor. PMID- 20719914 TI - Acute aortic syndrome: have we always got a precise diagnosis? PMID- 20719915 TI - Multidetector computed tomography scanning is still the gold standard for diagnosis of acute aortic syndromes. PMID- 20719916 TI - Transoesophageal echocardiography and oesophageal perforation. PMID- 20719917 TI - The adaptive significance of unproductive alternative splicing in primates. AB - Alternative gene splicing is pervasive in metazoa, particularly in humans, where the majority of genes generate splice variant transcripts. Characterizing the biological significance of alternative transcripts is methodologically difficult since it is impractical to assess thousands of splice variants as to whether they actually encode proteins, whether these proteins are functional, or whether transcripts have a function independent of protein synthesis. Consequently, to elucidate the functional significance of splice variants and to investigate mechanisms underlying the fidelity of mRNA splicing, we used an indirect approach based on analyzing the evolutionary conservation of splice variants among species. Using DNA polymerase beta as an indicator locus, we cloned and characterized the types and frequencies of transcripts generated in primary cell lines of five primate species. Overall, we found that in addition to the canonical DNA polymerase beta transcript, there were 25 alternative transcripts generated, most containing premature terminating codons. We used a statistical method borrowed from community ecology to show that there is significant diversity and little conservation in alternative splicing patterns among species, despite high sequence similarity in the underlying genomic (exonic) sequences. However, the frequency of alternative splicing at this locus correlates well with life history parameters such as the maximal longevity of each species, indicating that the alternative splicing of unproductive splice variants may have adaptive significance, even if the specific RNA transcripts themselves have no function. These results demonstrate the validity of the phylogenetic conservation approach in elucidating the biological significance of alternative splicing. PMID- 20719918 TI - Subribosomal particle analysis reveals the stages of bacterial ribosome assembly at which rRNA nucleotides are modified. AB - Modified nucleosides of ribosomal RNA are synthesized during ribosome assembly. In bacteria, each modification is made by a specialized enzyme. In vitro studies have shown that some enzymes need the presence of ribosomal proteins while other enzymes can modify only protein-free rRNA. We have analyzed the addition of modified nucleosides to rRNA during ribosome assembly. Accumulation of incompletely assembled ribosomal particles (25S, 35S, and 45S) was induced by chloramphenicol or erythromycin in an exponentially growing Escherichia coli culture. Incompletely assembled ribosomal particles were isolated from drug treated and free 30S and 50S subunits and mature 70S ribosomes from untreated cells. Nucleosides of 16S and 23S rRNA were prepared and analyzed by reverse phase, high-performance liquid chromatography (HPLC). Pseudouridines were identified by the chemical modification/primer extension method. Based on the results, the rRNA modifications were divided into three major groups: early, intermediate, and late assembly specific modifications. Seven out of 11 modified nucleosides of 16S rRNA were late assembly specific. In contrast, 16 out of 25 modified nucleosides of 23S rRNA were made during early steps of ribosome assembly. Free subunits of exponentially growing bacteria contain undermodified rRNA, indicating that a specific set of modifications is synthesized during very late steps of ribosome subunit assembly. PMID- 20719919 TI - Regulatory RNAs derived from transfer RNA? AB - Four recent studies suggest that cleavages of transfer RNAs generate products with microRNA-like features, with some evidence of function. If their regulatory functions were to be confirmed, these newly revealed RNAs would add to the expanding repertoire of small noncoding RNAs and would also provide new perspectives on the coevolution of transfer RNA and messenger RNA. PMID- 20719920 TI - A comprehensive survey of 3' animal miRNA modification events and a possible role for 3' adenylation in modulating miRNA targeting effectiveness. AB - Animal microRNA sequences are subject to 3' nucleotide addition. Through detailed analysis of deep-sequenced short RNA data sets, we show adenylation and uridylation of miRNA is globally present and conserved across Drosophila and vertebrates. To better understand 3' adenylation function, we deep-sequenced RNA after knockdown of nucleotidyltransferase enzymes. The PAPD4 nucleotidyltransferase adenylates a wide range of miRNA loci, but adenylation does not appear to affect miRNA stability on a genome-wide scale. Adenine addition appears to reduce effectiveness of miRNA targeting of mRNA transcripts while deep-sequencing of RNA bound to immunoprecipitated Argonaute (AGO) subfamily proteins EIF2C1-EIF2C3 revealed substantial reduction of adenine addition in miRNA associated with EIF2C2 and EIF2C3. Our findings show 3' addition events are widespread and conserved across animals, PAPD4 is a primary miRNA adenylating enzyme, and suggest a role for 3' adenine addition in modulating miRNA effectiveness, possibly through interfering with incorporation into the RNA-induced silencing complex (RISC), a regulatory role that would complement the role of miRNA uridylation in blocking DICER1 uptake. PMID- 20719921 TI - Phosphorylation-state-dependent regulation of NMDA receptor short-term plasticity modifies hippocampal dendritic Ca2+ transients. AB - N-methyl-D-aspartate (NMDA) receptor-mediated currents are enhanced by phosphorylation. We have investigated effects of phosphorylation-dependent short term plasticity of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) on the induction of long-term depression (LTD). We confirmed in whole cell clamped CA1 pyramidal neurons that LTD is induced by pairing stimulus protocols. However, after serine-threonine phosphorylation was modified by postsynaptic introduction of a protein phosphatase-1 (PP1) inhibitor, the same pairing protocol evoked long-term potentiation (LTP). We determined effects of modification of phosphatase activity on evoked NMDA EPSCs during LTD induction protocols. During LTD induction, using a protocol pairing depolarization to -40 mV and 0.5 Hz stimulation, NMDA receptor-mediated EPSCs undergo a short-term enhancement at the start of the protocol. In neurons in which PP1 activity was inhibited, this short-term enhancement was markedly amplified. We then investigated the effect of this enhancement on Ca(2+) entry during the start of the LTD induction protocol. Enhancement of NMDA receptor-mediated responses was accompanied by an amplification of induction protocol-evoked Ca(2+) transients. Furthermore, this amplification required synaptic activation during the protocol, consistent with an enhancement of Ca(2+) entry mediated by NMDA receptor activation. The sign of NMDA receptor-mediated long-term plasticity, whether potentiation or depression depends on the amplitude of the synaptic Ca(2+) transient during induction. We conclude that short-term phosphorylation-dependent plasticity of the NMDA receptor-mediated EPSCs contributes significantly to the effect of phosphatase inhibition on the subsequent induction of LTD or LTP. PMID- 20719923 TI - Equal degrees of object selectivity for upper and lower visual field stimuli. AB - Functional MRI (fMRI) studies of the human object recognition system commonly identify object-selective cortical regions by comparing blood oxygen level dependent (BOLD) responses to objects versus those to scrambled objects. Object selectivity distinguishes human lateral occipital cortex (LO) from earlier visual areas. Recent studies suggest that, in addition to being object selective, LO is retinotopically organized; LO represents both object and location information. Although LO responses to objects have been shown to depend on location, it is not known whether responses to scrambled objects vary similarly. This is important because it would suggest that the degree of object selectivity in LO does not vary with retinal stimulus position. We used a conventional functional localizer to identify human visual area LO by comparing BOLD responses to objects versus scrambled objects presented to either the upper (UVF) or lower (LVF) visual field. In agreement with recent findings, we found evidence of position-dependent responses to objects. However, we observed the same degree of position dependence for scrambled objects and thus object selectivity did not differ for UVF and LVF stimuli. We conclude that, in terms of BOLD response, LO discriminates objects from non-objects equally well in either visual field location, despite stronger responses to objects in the LVF. PMID- 20719924 TI - Neural substrate of an increase in sensory sampling triggered by a motor command in a gymnotid fish. AB - Despite recent advances that have elucidated the effects of collateral of motor commands on sensory processing structures, the neural mechanisms underlying the modulation of active sensory systems by internal motor-derived signals remains poorly understood. This study deals with the neural basis of the modulation of the motor component of an active sensory system triggered by a central motor command in a gymnotid fish. In Gymnotus omarorum, activation of Mauthner cells, a pair of reticulospinal neurons responsible for the initiation of escape responses in most teleosts, evokes an abrupt and prolonged increase in the rate of the electric organ discharge (EOD), the output signal of the electrogenic component of the active electrosensory system. We show here that prepacemaker neural structures (PPs) that control the discharge of the command nucleus for EODs are key elements of this modulation. Retrograde labeling combined with injections of glutamate at structures that contain labeled neurons showed that PPs are composed of a bilateral group of dispersed brain stem neurons that extend from the diencephalon to the caudal medulla. Blockade of discrete PPs regions during the Mauthner cell-initiated electrosensory modulation indicate that the long duration of this modulation relied on activation of diencephalic PPs, whereas its peak amplitude depended on the recruitment of medullary PPs. Temporal correlation of motor and sensory consequences of Mauthner cell activation suggests that the Mauthner cell-initiated enhancement of electrosensory sampling is involved in the selection of escape trajectory. PMID- 20719922 TI - Molecular layer inhibitory interneurons provide feedforward and lateral inhibition in the dorsal cochlear nucleus. AB - In the outer layers of the dorsal cochlear nucleus, a cerebellum-like structure in the auditory brain stem, multimodal sensory inputs drive parallel fibers to excite both principal (fusiform) cells and inhibitory cartwheel cells. Cartwheel cells, in turn, inhibit fusiform cells and other cartwheel cells. At the microcircuit level, it is unknown how these circuit components interact to modulate the activity of fusiform cells and thereby shape the processing of auditory information. Using a variety of approaches in mouse brain stem slices, we investigated the synaptic connectivity and synaptic strength among parallel fibers, cartwheel cells, and fusiform cells. In paired recordings of spontaneous and evoked activity, we found little overlap in parallel fiber input to neighboring neurons, and activation of multiple parallel fibers was required to evoke or alter action potential firing in cartwheel and fusiform cells. Thus neighboring neurons likely respond best to distinct subsets of sensory inputs. In contrast, there was significant overlap in inhibitory input to neighboring neurons. In recordings from synaptically coupled pairs, cartwheel cells had a high probability of synapsing onto nearby fusiform cells or other nearby cartwheel cells. Moreover, single cartwheel cells strongly inhibited spontaneous firing in single fusiform cells. These synaptic relationships suggest that the set of parallel fibers activated by a particular sensory stimulus determines whether cartwheel cells provide feedforward or lateral inhibition to their postsynaptic targets. PMID- 20719925 TI - Short-duration epileptic discharges show a distinct phase preference during ongoing hippocampal slow oscillations. AB - Non-REM (slow-wave) sleep has been shown to facilitate temporal lobe epileptiform events, whereas REM sleep seems more restrictive. This state-dependent modulation may be the result of the enhancement of excitatory synaptic transmission and/or the degree of network synchronization expressed within the hippocampus of the temporal lobe. The slow oscillation (SO), a ~1 Hz oscillatory pattern expressed during non-REM sleep and urethane anesthesia, has been recently shown to facilitate the generation, maintenance, and propagation of stimulus-evoked epileptiform activity in the hippocampus. To further address the state-dependent modulation of epileptic activity during the SO, we studied the properties of short-duration interictal-like activity generated by focal application of penicillin in the hippocampus of urethane-anesthetized rats. Epileptiform spikes were larger but only slightly more prevalent during the SO as opposed to the theta (REM-like) state. More notably, however, epileptic spikes had a significant tendency to occur just following the peak negativity of ongoing SO cycles. Because of the known phase-dependent changes in 1) synaptic excitability (just following the positive peak of the SO) and 2) network synchronization (during the negative peak of the SO), these results suggest that it is the synchrony and not the changes in synaptic excitability that lead to the facilitation of epileptiform activity during sleep-like slow wave states. PMID- 20719926 TI - Representation of eye position in the human parietal cortex. AB - Neurons that signal eye position are thought to make a vital contribution to distinguishing real world motion from retinal motion caused by eye movements, but relatively little is known about such neurons in the human brain. Here we present data from functional MRI experiments that are consistent with the existence of neurons sensitive to eye position in darkness in the human posterior parietal cortex. We used the enhanced sensitivity of multivoxel pattern analysis (MVPA) techniques, combined with a searchlight paradigm, to isolate brain regions sensitive to direction of gaze. During data acquisition, participants were cued to direct their gaze to the left or right for sustained periods as part of a block-design paradigm. Following the exclusion of saccade-related activity from the data, the multivariate analysis showed sensitivity to tonic eye position in two localized posterior parietal regions, namely the dorsal precuneus and, more weakly, the posterior aspect of the intraparietal sulcus. Sensitivity to eye position was also seen in anterior portions of the occipital cortex. The observed sensitivity of visual cortical neurons to eye position, even in the total absence of visual stimulation, is possibly a result of feedback from posterior parietal regions that receive eye position signals and explicitly encode direction of gaze. PMID- 20719928 TI - Estimating network parameters from combined dynamics of firing rate and irregularity of single neurons. AB - High firing irregularity is a hallmark of cortical neurons in vivo, and modeling studies suggest a balance of excitation and inhibition is necessary to explain this high irregularity. Such a balance must be generated, at least partly, from local interconnected networks of excitatory and inhibitory neurons, but the details of the local network structure are largely unknown. The dynamics of the neural activity depends on the local network structure; this in turn suggests the possibility of estimating network structure from the dynamics of the firing statistics. Here we report a new method to estimate properties of the local cortical network from the instantaneous firing rate and irregularity (CV(2)) under the assumption that recorded neurons are a part of a randomly connected sparse network. The firing irregularity, measured in monkey motor cortex, exhibits two features; many neurons show relatively stable firing irregularity in time and across different task conditions; the time-averaged CV(2) is widely distributed from quasi-regular to irregular (CV(2) = 0.3-1.0). For each recorded neuron, we estimate the three parameters of a local network [balance of local excitation-inhibition, number of recurrent connections per neuron, and excitatory postsynaptic potential (EPSP) size] that best describe the dynamics of the measured firing rates and irregularities. Our analysis shows that optimal parameter sets form a two-dimensional manifold in the three-dimensional parameter space that is confined for most of the neurons to the inhibition-dominated region. High irregularity neurons tend to be more strongly connected to the local network, either in terms of larger EPSP and inhibitory PSP size or larger number of recurrent connections, compared with the low irregularity neurons, for a given excitatory/inhibitory balance. Incorporating either synaptic short-term depression or conductance-based synapses leads many low CV(2) neurons to move to the excitation-dominated region as well as to an increase of EPSP size. PMID- 20719927 TI - Endogenous inhibition of the trigeminally evoked neurotransmission to cardiac vagal neurons by muscarinic acetylcholine receptors. AB - Stimulation of the nasal mucosa by airborne irritants or water evokes a pronounced bradycardia accompanied by peripheral vasoconstriction and apnea. The dive response, which includes the trigeminocardiac reflex, is among the most powerful autonomic responses. These responses slow the heart rate and reduce myocardial oxygen consumption. Although normally cardioprotective, exaggeration of this reflex can be detrimental and has been implicated in cardiorespiratory diseases, including sudden infant death syndrome (SIDS). An essential component of the diving response and trigeminocardiac reflex is activation of the parasympathetic cardiac vagal neurons (CVNs) in the nucleus ambiguus that control heart rate. This study examined the involvement of cholinergic receptors in trigeminally evoked excitatory postsynaptic currents in CVNs in an in vitro preparation from rats. CVNs were identified using a retrograde tracer injected into the fat pads at the base of the heart. Application of the acetylcholinesterase inhibitor neostigmine significantly decreased the amplitude of glutamatergic neurotransmission to CVNs on stimulation of trigeminal fibers. Whereas nicotine did not have any effect on the glutamatergic responses, the muscarinic acetylcholine receptor (mAChR) agonist bethanechol significantly decreased the excitatory neurotransmission. Atropine, an mAChR antagonist, facilitated these responses indicating this trigeminally evoked brain stem pathway in vitro is endogenously inhibited by mAChRs. Tropicamide, an m4 mAChR antagonist, prevented the inhibitory action of the muscarinic agonist bethanechol. These results indicate that the glutamatergic synaptic neurotransmission in the trigeminally evoked pathway to CVNs is endogenously inhibited in vitro by m4 mAChRs. PMID- 20719929 TI - Ca2+-dependent and Na+-dependent K+ conductances contribute to a slow AHP in thalamic paraventricular nucleus neurons: a novel target for orexin receptors. AB - Thalamic paraventricular nucleus (PVT) neurons exhibit a postburst apamin resistant slow afterhyperpolarization (sAHP) that is unique to midline thalamus, displays activity dependence, and is abolished in tetrodotoxin. Analysis of the underlying sI(AHP) confirmed a requirement for Ca(2+) influx with contributions from P/Q-, N-, L-, and R subtype channels, a reversal potential near E(K)(+) and a significant reduction by UCL-2077, barium or TEA, consistent with a role for K(Ca) channels. sI(AHP) was significantly reduced by activation of either the cAMP or the protein kinase C (PKC) signaling pathway. Further analysis of the sAHP revealed an activity-dependent but Ca(2+)-independent component that was reduced in high [K(+)](o) and blockable after Na(+) substitution with Li(+) or in the presence of quinidine, suggesting a role for K(Na) channels. The Ca(2+) independent sAHP component was selectively reduced by activation of the PKC signaling pathway. The sAHP contributed to spike frequency adaptation, which was sensitive to activation of either cAMP or PKC signaling pathways and, near the peak of membrane hyperpolarization, was sufficient to cause de-inactivation of low threshold T-Type Ca(2+) channels, thus promoting burst firing. PVT neurons are densely innervated by orexin-immunoreactive fibers, and depolarized by exogenously applied orexins. We now report that orexin A significantly reduced both Ca(2+)-dependent and -independent sI(AHP), and spike frequency adaptation. Furthermore orexin A-induced sI(AHP) inhibition was mediated through activation of PKC but not PKA. Collectively, these observations suggest that K(Ca) and K(Na) channels have a role in a sAHP that contributes to spike frequency adaptation and neuronal excitability in PVT neurons and that the sAHP is a novel target for modulation by the arousal- and feeding-promoting orexin neuropeptides. PMID- 20719930 TI - Visuomotor velocity transformations for smooth pursuit eye movements. AB - Smooth pursuit eye movements are driven by retinal motion signals. These retinal motion signals are converted into motor commands that obey Listing's law (i.e., no accumulation of ocular torsion). The fact that smooth pursuit follows Listing's law is often taken as evidence that no explicit reference frame transformation between the retinal velocity input and the head-centered motor command is required. Such eye-position-dependent reference frame transformations between eye- and head-centered coordinates have been well-described for saccades to static targets. Here we suggest that such an eye (and head)-position-dependent reference frame transformation is also required for target motion (i.e., velocity) driving smooth pursuit eye movements. Therefore we tested smooth pursuit initiation under different three-dimensional eye positions and compared human performance to model simulations. We specifically tested if the ocular rotation axis changed with vertical eye position, if the misalignment of the spatial and retinal axes during oblique fixations was taken into account, and if ocular torsion (due to head roll) was compensated for. If no eye-position dependent velocity transformation was used, the pursuit initiation should follow the retinal direction, independently of eye position; in contrast, a correct visuomotor velocity transformation would result in spatially correct pursuit initiation. Overall subjects accounted for all three components of the visuomotor velocity transformation, but we did observe differences in the compensatory gains between individual subjects. We concluded that the brain does perform a visuomotor velocity transformation but that this transformation was prone to noise and inaccuracies of the internal model. PMID- 20719931 TI - Hypertension induced by angiotensin II and a high salt diet involves reduced SK current and increased excitability of RVLM projecting PVN neurons. AB - Although evidence indicates that activation of presympathetic paraventricular nucleus (PVN) neurons contributes to the pathogenesis of salt-sensitive hypertension, the underlying cellular mechanisms are not fully understood. Recent evidence indicates that small conductance Ca(2+)-activated K(+) (SK) channels play a significant role in regulating the excitability of a key group of sympathetic regulatory PVN neurons, those with axonal projections to the rostral ventrolateral medulla (RVLM; i.e., PVN-RVLM neurons). In the present study, rats consuming a high salt (2% NaCl) diet were made hypertensive by systemic infusion of angiotensin II (AngII), and whole cell patch-clamp recordings were made in brain slice from retrogradely labeled PVN-RVLM neurons. To determine if the amplitude of SK current was altered in neurons from hypertensive rats, voltage clamp recordings were performed to isolate SK current. Results indicate that SK current amplitude (P < 0.05) and density (P < 0.01) were significantly smaller in the hypertensive group. To investigate the impact of this on intrinsic excitability, current-clamp recordings were performed in separate groups of PVN RVLM neurons. Results indicate that the frequency of spikes evoked by current injection was significantly higher in the hypertensive group (P < 0.05-0.01). Whereas bath application of the SK channel blocker apamin significantly increased discharge of neurons from normotensive rats (P < 0.05-0.01), no effect was observed in the hypertensive group. In response to ramp current injections, subthreshold depolarizing input resistance was greater in the hypertensive group compared with the normotensive group (P < 0.05). Blockade of SK channels increased depolarizing input resistance in normotensive controls (P < 0.05) but had no effect in the hypertensive group. On termination of current pulses, a medium afterhyperpolarization potential (mAHP) was observed in most neurons of the normotensive group. In the hypertensive group, the mAHP was either small or absent. In the latter case, an afterdepolarization potential (ADP) was observed that was unaffected by apamin. Apamin treatment in the normotensive group blocked the mAHP and revealed an ADP resembling that seen in the hypertensive group. We conclude that diminished SK current likely underlies the absence of mAHPs in PVN RVLM neurons from hypertensive rats. Both the ADP and greater depolarizing input resistance likely contribute to increased excitability of PVN-RVLM neurons from rats with AngII-Salt hypertension. PMID- 20719932 TI - BDNF evokes release of endogenous cannabinoids at layer 2/3 inhibitory synapses in the neocortex. AB - The neurotrophin brain-derived neurotrophic factor (BDNF) is a potent regulator of inhibitory synaptic transmission, although the locus of this effect and the underlying mechanisms are controversial. We explored a potential interaction between BDNF and endogenous cannabinoid (endocannabinoid) signaling because activation of type 1 cannabinoid (CB1) receptors potently regulates gamma aminobutyric acid (GABA) release and both trkB tyrosine kinase receptors and CB1 receptors are highly expressed at synapses in neocortical layer 2/3. Here, we found that the effects of BDNF at inhibitory cortical synapses are mediated by the release of endocannabinoids acting retrogradely at presynaptic CB1 receptors. Specifically, acute application of BDNF rapidly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) via postsynaptic trkB receptor activation because intracellular delivery of the tyrosine kinase inhibitor K252a completely blocked the BDNF effect. Although triggered by postsynaptic trkB activation, BDNF exposure decreased presynaptic release probability, as evidenced by increases in the paired-pulse ratio and coefficient of variation of evoked responses. In addition, BDNF decreased the frequency but not the amplitude of action potential-independent miniature IPSCs and BDNF did not alter the postsynaptic response to locally applied GABA. These results suggest that BDNF induces the release of a retrograde messenger from the postsynaptic cell that regulates presynaptic neurotransmitter release. Consistent with a role for endocannabinoids as the retrograde signal, the effect of BDNF on IPSCs was blocked by CB1 receptor antagonists and was occluded by a cannabinoid receptor agonist. Furthermore, inhibiting endocannabinoid synthesis or transport also disrupted the BDNF effect, implicating postsynaptic endocannabinoid release triggered by BDNF. PMID- 20719933 TI - Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. AB - PURPOSE: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression. EXPERIMENTAL DESIGN: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis. RESULTS: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival. CONCLUSIONS: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants. PMID- 20719934 TI - Successful treatment of melanoma brain metastases with adoptive cell therapy. AB - PURPOSE: To determine the objective response rate and response duration of melanoma brain metastases to adoptive cell therapy (ACT) with autologous antitumor lymphocytes plus interleukin-2 following a lymphodepleting preparative regimen. METHODS: Between 2000 and 2009, 264 patients with metastatic melanoma received ACT, consisting of cyclophosphamide and fludarabine with or without total body irradiation, followed by the infusion of autologous tumor-infiltrating lymphocytes (TIL) or autologous peripheral blood lymphocytes retrovirally transduced to express a T-cell receptor (TCR) that recognized the melanocyte differentiation antigens gp-100 or MART-1. From this group, 26 patients were retrospectively identified to have had untreated brain metastases and extracranial disease before receiving ACT. The response rate and duration of melanoma brain metastases, as well as the overall response rate, response duration, and survival for these patients, are presented. RESULTS: Seventeen of these 26 patients received ACT with TIL. Seven of these patients (41%) achieved a complete response in the brain, and six patients achieved an overall partial response. In the nine patients that received TCR-transduced lymphocytes, two patients achieved a complete response in the brain (22%) and one of these two achieved an overall partial response. One patient developed a tumor-associated subarachnoid hemorrhage during the thrombocytopenic phase of therapy and had an uneventful metastatectomy. CONCLUSION: ACT with a nonmyeloablative preparative regimen using either TIL- or TCR gene-transduced cells and interleukin-2 can mediate complete and durable regression of melanoma brain metastases. This strategy can be used safely in selected patients with metastatic melanoma to the brain. PMID- 20719935 TI - Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer. AB - BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. PATIENTS AND METHODS: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. RESULTS: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin induced DNA cross-links following administration of gemcitabine. CONCLUSION: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule. PMID- 20719936 TI - Pregnane X receptor is SUMOylated to repress the inflammatory response. AB - Long-term treatment of patients with the macrolide antibiotic and prototypical activator of pregnane X receptor (PXR) rifampicin (Rif) inhibits the inflammatory response in liver. We show here that activation of the inflammatory response in hepatocytes strongly modulates SUMOylation of ligand-bound PXR. We provide evidence that the SUMOylated PXR contains SUMO3 chains, and feedback represses the immune response in hepatocytes. This information represents the first step in developing novel pharmaceutical strategies to treat inflammatory liver disease and prevent adverse drug reactions in patients experiencing acute or systemic inflammation. These studies also provide a molecular rationale for constructing a novel paradigm that uniquely defines the molecular basis of the interface between PXR-mediated gene activation, drug metabolism, and inflammation. PMID- 20719937 TI - The D prostanoid receptor agonist BW245C [(4S)-(3-[(3R,S)-3-cyclohexyl-3 hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid] inhibits fibroblast proliferation and bleomycin-induced lung fibrosis in mice. AB - Prostaglandin (PG) D(2) exerts contrasting activities in the inflamed lung via two receptors, the D prostanoid receptor (DP) and the chemoattractant receptor homologous molecule expressed on T helper 2 lymphocytes. DP activation is known mainly to inhibit proinflammatory cell functions. We tested the effect of a DP specific agonist, (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4 imidazolidineheptanoic acid (BW245C), on pulmonary fibroblast functions in vitro and in a mouse model of lung fibrosis induced by bleomycin. DP mRNA expression was detected in cultured mouse lung primary fibroblasts and human fetal lung fibroblasts and found to be up- and down-regulated by interleukin-13 and transforming growth factor (TGF)-beta, respectively. Although micromolar concentrations of BW245C and PGD(2) did not affect mouse fibroblast collagen synthesis or differentiation in myofibroblasts, they both inhibited fibroblast basal and TGF-beta-induced proliferation in vitro. The repeated administration of BW245C (500 nmol/kg body weight instilled transorally in the lungs 2 days before and three times per week for 3 weeks) in bleomycin-treated mice significantly decreased both inflammatory cell recruitment and collagen accumulation in the lung (21 days). Our results indicate that BW245C can reduce lung fibrosis in part via its activity on fibroblast proliferation and suggest that DP activation should be considered as a new therapeutic target in fibroproliferative lung diseases. PMID- 20719938 TI - Induction of intestinal multidrug resistance-associated protein 2 by glucagon like Peptide 2 in the rat. AB - The effects of glucagon-like peptide 2 (GLP-2) on expression and activity of jejunal multidrug resistance-associated protein 2 (Mrp2; Abcc2) and glutathione transferase (GST) were evaluated. After GLP-2 treatment (12 MUg/100 g b.wt. s.c., every 12 h, for 5 consecutive days), Mrp2 and the alpha class of GST proteins and their corresponding mRNAs were increased, suggesting a transcriptional regulation. Mrp2 was localized at the apical membrane of the enterocyte in control and GLP-2 groups, as detected by confocal immunofluorescence microscopy. As a functional assay, everted intestinal sacs were incubated in the presence of 1-chloro-2,4-dinitrobenzene in the mucosal compartment, and the glutathione conjugated derivative, dinitrophenyl-S-glutathione (DNP-SG; model Mrp2 substrate), was detected in the same compartment by high-performance liquid chromatography. A significant increase in apical secretion of DNP-SG was detected in the GLP-2 group, consistent with simultaneous up-regulation of Mrp2 and GST. GLP-2 also promoted an increase in cAMP levels as detected in homogenates of intestinal mucosa. Treatment of rats with 2',3'-dideoxyadenosine (DDA), a specific inhibitor of adenylyl cyclase, abolished the increase in cAMP levels and Mrp2 protein promoted by GLP-2, suggesting cAMP as a mediator of Mrp2 modulation. Increased expression of Mrp2 and cAMP levels in response to GLP-2 occurred not only at the tip but also at the middle region of the villus, where constitutive expression of Mrp2 is normally low. In conclusion, our study suggests a role for GLP-2 in the prevention of cell toxicity of the intestinal mucosa by increasing Mrp2 chemical barrier function. PMID- 20719939 TI - Modulation of hepatic cytochrome P450s by Citrobacter rodentium infection in interleukin-6- and interferon-{gamma}-null mice. AB - After infection with Citrobacter rodentium, murine hepatic cytochrome P450 (P450) mRNAs are selectively regulated. Several serum proinflammatory cytokines are elevated, the most abundant being interleukin-6 (IL6). To elucidate the role of cytokines in the regulation of P450s during infection, we orally infected wild type, IL6(-/-), or interferon-gamma(-/-) [IFNgamma(-/-)] female C57BL/6J mice with C. rodentium and analyzed hepatic P450 expression 7 days later. The majority of P450 mRNAs were equally affected by infection in each genotype, indicating that IL6 and IFNgamma are not the primary mediators of P450 down-regulation in this disease model. The down-regulation of CYP3A11 and CYP3A13 and induction of CYP2D9 mRNAs were attenuated in the IL6(-/-) mice, suggesting a role of IL6 in the regulation of only these P450s. Similar evidence implicated IFNgamma in the regulation of CYP2D9, CYP2D22, CYP3A11, CYP3A25, and CYP4F18 mRNAs in C. rodentium infection and CYP2B9, CYP2D22, and CYP2E1 in the bacterial lipopolysaccharide model of inflammation. This is the first indication of an in vivo role for IFNgamma in hepatic P450 regulation in disease states. The deficiency of IL6 or IFNgamma affected serum levels of the other cytokines. Moreover, experiments in cultured hepatocytes demonstrated that tumor necrosis factor alpha (TNFalpha) is the most potent and efficacious of the cytokines tested in the regulation of murine P450 expression. It is therefore possible that part of the IFNgamma(-/-) and IL6(-/-) phenotypes could be attributed to the reduced levels of TNFalpha and part of the IFNgamma(-/-) phenotype could be caused by reduced levels of IL6. PMID- 20719940 TI - Histone deacetylase: a potential therapeutic target for fibrotic disorders. AB - Histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. In the past several years, the role of HDACs in cancer initiation and progression, as well as the therapeutic effects of HDAC inhibitors in various types of cancer, has been well studied. Recent studies indicated that HDAC activity is also associated with the development and progression of some chronic diseases characterized by fibrosis, including chronic kidney disease, cardiac hypertrophy, and idiopathic pulmonary fibrosis. Here, we review what is known about HDACs in the progression of tissue fibrosis and the potential applications of HDAC inhibitors in the treatment of disorders associated with fibroblast activation and proliferation. PMID- 20719941 TI - Swine influenza H1N1 virus induces acute inflammatory immune responses in pig lungs: a potential animal model for human H1N1 influenza virus. AB - Pigs are capable of generating reassortant influenza viruses of pandemic potential, as both the avian and mammalian influenza viruses can infect pig epithelial cells in the respiratory tract. The source of the current influenza pandemic is H1N1 influenza A virus, possibly of swine origin. This study was conducted to understand better the pathogenesis of H1N1 influenza virus and associated host mucosal immune responses during acute infection in humans. Therefore, we chose a H1N1 swine influenza virus, Sw/OH/24366/07 (SwIV), which has a history of transmission to humans. Clinically, inoculated pigs had nasal discharge and fever and shed virus through nasal secretions. Like pandemic H1N1, SwIV also replicated extensively in both the upper and lower respiratory tracts, and lung lesions were typical of H1N1 infection. We detected innate, proinflammatory, Th1, Th2, and Th3 cytokines, as well as SwIV-specific IgA antibody in lungs of the virus-inoculated pigs. Production of IFN-gamma by lymphocytes of the tracheobronchial lymph nodes was also detected. Higher frequencies of cytotoxic T lymphocytes, gammadelta T cells, dendritic cells, activated T cells, and CD4+ and CD8+ T cells were detected in SwIV-infected pig lungs. Concomitantly, higher frequencies of the immunosuppressive T regulatory cells were also detected in the virus-infected pig lungs. The findings of this study have relevance to pathogenesis of the pandemic H1N1 influenza virus in humans; thus, pigs may serve as a useful animal model to design and test effective mucosal vaccines and therapeutics against influenza virus. PMID- 20719942 TI - Murine cytomegalovirus perturbs endosomal trafficking of major histocompatibility complex class I molecules in the early phase of infection. AB - Murine cytomegalovirus (MCMV) functions interfere with protein trafficking in the secretory pathway. In this report we used Deltam138-MCMV, a recombinant virus with a deleted viral Fc receptor, to demonstrate that MCMV also perturbs endosomal trafficking in the early phase of infection. This perturbation had a striking impact on cell surface-resident major histocompatibility complex class I (MHC-I) molecules due to the complementary effect of MCMV immunoevasins, which block their egress from the secretory pathway. In infected cells, constitutively endocytosed cell surface-resident MHC-I molecules were arrested and retained in early endosomal antigen 1 (EEA1)-positive and lysobisphosphatidic acid (LBPA) negative perinuclear endosomes together with clathrin-dependent cargo (transferrin receptor, Lamp1, and epidermal growth factor receptor). Their progression from these endosomes into recycling and degradative routes was inhibited. This arrest was associated with a reduction of the intracellular content of Rab7 and Rab11, small GTPases that are essential for the maturation of recycling and endolysosomal domains of early endosomes. The reduced recycling of MHC-I in Deltam138-MCMV-infected cells was accompanied by their accelerated loss from the cell surface. The MCMV function that affects cell surface-resident MHC-I was activated in later stages of the early phase of viral replication, after the expression of known immunoevasins. MCMV without the three immunoevasins (the m04, m06, and m152 proteins) encoded a function that affects endosomal trafficking. This function, however, was not sufficient to reduce the cell surface expression of MHC-I in the absence of the transport block in the secretory pathway. PMID- 20719943 TI - RNA structures required for production of subgenomic flavivirus RNA. AB - Flaviviruses are a group of single-stranded, positive-sense RNA viruses causing ~100 million infections per year. We have recently shown that flaviviruses produce a unique, small, noncoding RNA (~0.5 kb) derived from the 3' untranslated region (UTR) of the genomic RNA (gRNA), which is required for flavivirus-induced cytopathicity and pathogenicity (G. P. Pijlman et al., Cell Host Microbe, 4: 579 591, 2008). This RNA (subgenomic flavivirus RNA [sfRNA]) is a product of incomplete degradation of gRNA presumably by the cellular 5'-3' exoribonuclease XRN1, which stalls on the rigid secondary structure stem-loop II (SL-II) located at the beginning of the 3' UTR. Mutations or deletions of various secondary structures in the 3' UTR resulted in the loss of full-length sfRNA (sfRNA1) and production of smaller and less abundant sfRNAs (sfRNA2 and sfRNA3). Here, we investigated in detail the importance of West Nile virus Kunjin (WNV(KUN)) 3' UTR secondary structures as well as tertiary interactions for sfRNA formation. We show that secondary structures SL-IV and dumbbell 1 (DB1) downstream of SL-II are able to prevent further degradation of gRNA when the SL-II structure is deleted, leading to production of sfRNA2 and sfRNA3, respectively. We also show that a number of pseudoknot (PK) interactions, in particular PK1 stabilizing SL-II and PK3 stabilizing DB1, are required for protection of gRNA from nuclease degradation and production of sfRNA. Our results show that PK interactions play a vital role in the production of nuclease-resistant sfRNA, which is essential for viral cytopathicity in cells and pathogenicity in mice. PMID- 20719944 TI - The C-terminal alpha-helix domain of apolipoprotein E is required for interaction with nonstructural protein 5A and assembly of hepatitis C virus. AB - We have recently demonstrated that human apolipoprotein E (apoE) is required for the infectivity and assembly of hepatitis C virus (HCV) (K. S. Chang, J. Jiang, Z. Cai, and G. Luo, J. Virol. 81:13783-13793, 2007; J. Jiang and G. Luo, J. Virol. 83:12680-12691, 2009). In the present study, we have determined the molecular basis underlying the importance of apoE in HCV assembly. Results derived from mammalian two-hybrid studies demonstrate a specific interaction between apoE and HCV nonstructural protein 5A (NS5A). The C-terminal third of apoE per se is sufficient for interaction with NS5A. Progressive deletion mutagenesis analysis identified that the C-terminal alpha-helix domain of apoE is important for NS5A binding. The N-terminal receptor-binding domain and the C terminal 20 amino acids of apoE are dispensable for the apoE-NS5A interaction. The NS5A-binding domain of apoE was mapped to the middle of the C-terminal alpha helix domain between amino acids 205 and 280. Likewise, deletion mutations disrupting the apoE-NS5A interaction resulted in blockade of HCV production. These findings demonstrate that the specific apoE-NS5A interaction is required for assembly of infectious HCV. Additionally, we have determined that using different major isoforms of apoE (E2, E3, and E4) made no significant difference in the apoE-NS5A interaction. Likewise, these three major isoforms of apoE are equally compatible with infectivity and assembly of infectious HCV, suggesting that apoE isoforms do not differentially modulate the infectivity and/or assembly of HCV in cell culture. PMID- 20719945 TI - The F gene of the Osaka-2 strain of measles virus derived from a case of subacute sclerosing panencephalitis is a major determinant of neurovirulence. AB - Measles virus (MV) is the causative agent for acute measles and subacute sclerosing panencephalitis (SSPE). Although numerous mutations have been found in the MV genome of SSPE strains, the mutations responsible for the neurovirulence have not been determined. We previously reported that the SSPE Osaka-2 strain but not the wild-type strains of MV induced acute encephalopathy when they were inoculated intracerebrally into 3-week-old hamsters. The recombinant MV system was adapted for the current study to identify the gene(s) responsible for neurovirulence in our hamster model. Recombinant viruses that contained envelope associated genes from the Osaka-2 strain were generated on the IC323 wild-type MV background. The recombinant virus containing the M gene alone did not induce neurological disease, whereas the H gene partially contributed to neurovirulence. In sharp contrast, the recombinant virus containing the F gene alone induced lethal encephalopathy. This phenotype was related to the ability of the F protein to induce syncytium formation in Vero cells. Further study indicated that a single T461I substitution in the F protein was sufficient to transform the nonneuropathogenic wild-type MV into a lethal virus for hamsters. PMID- 20719946 TI - Histone deacetylases and the nuclear receptor corepressor regulate lytic-latent switch gene 50 in murine gammaherpesvirus 68-infected macrophages. AB - Gammaherpesviruses are important oncogenic pathogens that transit between lytic and latent life cycles. Silencing the lytic gene expression program enables the establishment of latency and a lifelong chronic infection of the host. In murine gammaherpesvirus 68 (MHV68, gammaHV68), essential lytic switch gene 50 controls the interchange between lytic and latent gene expression programs. However, negative regulators of gene 50 expression remain largely undefined. We report that the MHV68 lytic cycle is silenced in infected macrophages but not fibroblasts and that histone deacetylases (HDACs) mediate silencing. The HDAC inhibitor trichostatin A (TSA) acts on the gene 50 promoter to induce lytic replication of MHV68. HDAC3, HDAC4, and the nuclear receptor corepressor (NCoR) are required for efficient silencing of gene 50 expression. NCoR is critical for transcriptional repression of cellular genes by unliganded nuclear receptors. Retinoic acid, a known ligand for the NCoR complex, derepresses gene 50 expression and enhances MHV68 lytic replication. Moreover, HDAC3, HDAC4, and NCoR act on the gene 50 promoter and are recruited to this promoter in a retinoic acid responsive manner. We provide the first example of NCoR-mediated, HDAC-dependent regulation of viral gene expression. PMID- 20719947 TI - Epstein-Barr virus nuclear antigen 1 Hijacks the host kinase CK2 to disrupt PML nuclear bodies. AB - Latent Epstein-Barr virus (EBV) infection is an important causative factor in the development of several cancers, including nasopharyngeal carcinoma (NPC). The one EBV protein expressed in the nucleus of NPC cells, EBNA1, has been shown to disrupt promyelocitic leukemia (PML) nuclear bodies (NBs) by inducing the degradation of PML proteins, leading to impaired DNA repair and increased cell survival. Although EBNA1-mediated PML disruption is likely to be an important factor in the development of NPC, little is known about its mechanism. We now show that an interaction between EBNA1 and the host CK2 kinase is crucial for EBNA1 to disrupt PML bodies and degrade PML proteins. EBNA1 increases the association of CK2 with PML proteins, thereby increasing the phosphorylation of PML proteins by CK2, a modification that is known to trigger the polyubiquitylation and degradation of PML. The interaction between EBNA1 and CK2 is direct and occurs through the beta regulatory subunit of CK2 and EBNA1 amino acids 387 to 394. The binding of EBNA1 to the host ubiquitin specific protease USP7 has also been shown to be important for EBNA1-mediated PML disruption. We show that EBNA1 also increases the occupancy of USP7 at PML NBs and that CK2 and USP7 bind independently and simultaneously to EBNA1 to form a ternary complex. The combined results indicate that EBNA1 usurps two independent cellular pathways to trigger the loss of PML NBs. PMID- 20719948 TI - A conserved domain in the coronavirus membrane protein tail is important for virus assembly. AB - Coronavirus membrane (M) proteins play key roles in virus assembly, through M-M, M-spike (S), and M-nucleocapsid (N) protein interactions. The M carboxy-terminal endodomain contains a conserved domain (CD) following the third transmembrane (TM) domain. The importance of the CD (SWWSFNPETNNL) in mouse hepatitis virus was investigated with a panel of mutant proteins, using genetic analysis and transient-expression assays. A charge reversal for negatively charged E(121) was not tolerated. Lysine (K) and arginine (R) substitutions were replaced in recovered viruses by neutrally charged glutamine (Q) and leucine (L), respectively, after only one passage. E121Q and E121L M proteins were capable of forming virus-like particles (VLPs) when coexpressed with E, whereas E121R and E121K proteins were not. Alanine substitutions for the first four or the last four residues resulted in viruses with significantly crippled phenotypes and proteins that failed to assemble VLPs or to be rescued into the envelope. All recovered viruses with alanine substitutions in place of SWWS residues had second site, partially compensating, changes in the first TM of M. Alanine substitution for proline had little impact on the virus. N protein coexpression with some M mutants increased VLP production. The results overall suggest that the CD is important for formation of the viral envelope by helping mediate fundamental M-M interactions and that the presence of the N protein may help stabilize M complexes during virus assembly. PMID- 20719949 TI - Dissociation of paramyxovirus interferon evasion activities: universal and virus specific requirements for conserved V protein amino acids in MDA5 interference. AB - The V protein of the paramyxovirus subfamily Paramyxovirinae is an important virulence factor that can interfere with host innate immunity by inactivating the cytosolic pathogen recognition receptor MDA5. This interference is a result of a protein-protein interaction between the highly conserved carboxyl-terminal domain of the V protein and the helicase domain of MDA5. The V protein C-terminal domain (CTD) is an evolutionarily conserved 49- to 68-amino-acid region that coordinates two zinc atoms per protein chain. Site-directed mutagenesis of conserved residues in the V protein CTD has revealed both universal and virus-specific requirements for zinc coordination in MDA5 engagement and has also identified other conserved residues as critical for MDA5 interaction and interference. Mutation of these residues produces V proteins that are specifically defective for MDA5 interference and not impaired in targeting STAT1 for proteasomal degradation via the VDC ubiquitin ligase complex. Results demonstrate that mutation of conserved charged residues in the V proteins of Nipah virus, measles virus, and mumps virus also abolishes MDA5 interaction. These findings clearly define molecular determinants for MDA5 inhibition by the paramyxovirus V proteins. PMID- 20719950 TI - Apoptosis of hepatitis B virus-infected hepatocytes prevents release of infectious virus. AB - Apoptosis of infected cells is critically involved in antiviral defense. Apoptosis, however, may also support the release and spread of viruses. Although the elimination of infected hepatocytes is required to combat hepatitis B virus (HBV) infection, it is still unknown which consequences hepatocyte apoptosis has for the virus and whether or not it is advantageous to the virus. To study this, we designed a cell culture model consisting of both HBV-producing cell lines and primary human hepatocytes serving as an infection model. We showed that the release of mature, enveloped virions was 80% to 90% reduced 24 h after the induction of apoptosis in HBV-replicating hepatoma cells or HBV-infected hepatocytes. Importantly, HBV particles released from apoptotic hepatocytes were immature and nonenveloped and proved not to be infectious. We found an inverse correlation between the strength of an apoptotic stimulus and the infectivity of the virus particles released: the more potent the apoptotic stimulus, the higher the ratio of nonenveloped capsids to virions and the lower their infectivity. Furthermore, we demonstrated that HBV replication and, particularly, the expression of the HBx protein transcribed from the viral genome during replication do not sensitize cells to apoptosis. Our data clearly reject the hypothesis that the apoptosis of infected hepatocytes facilitates the propagation of HBV. Rather, these data indicate that HBV needs to prevent the apoptosis of its host hepatocyte to ensure the release of infectious progeny and, thus, virus spread in the liver. PMID- 20719951 TI - Culturing the unculturable: human coronavirus HKU1 infects, replicates, and produces progeny virions in human ciliated airway epithelial cell cultures. AB - Culturing newly identified human lung pathogens from clinical sample isolates can represent a daunting task, with problems ranging from low levels of pathogens to the presence of growth suppressive factors in the specimens, compounded by the lack of a suitable tissue culture system. However, it is critical to develop suitable in vitro platforms to isolate and characterize the replication kinetics and pathogenesis of recently identified human pathogens. HCoV-HKU1, a human coronavirus identified in a clinical sample from a patient with severe pneumonia, has been a major challenge for successful propagation on all immortalized cells tested to date. To determine if HCoV-HKU1 could replicate in in vitro models of human ciliated airway epithelial cell cultures (HAE) that recapitulate the morphology, biochemistry, and physiology of the human airway epithelium, the apical surfaces of HAE were inoculated with a clinical sample of HCoV-HKU1 (Cean1 strain). High virus yields were found for several days postinoculation and electron micrograph, Northern blot, and immunofluorescence data confirmed that HCoV-HKU1 replicated efficiently within ciliated cells, demonstrating that this cell type is infected by all human coronaviruses identified to date. Antiserum directed against human leukocyte antigen C (HLA-C) failed to attenuate HCoV-HKU1 infection and replication in HAE, suggesting that HLA-C is not required for HCoV HKU1 infection of the human ciliated airway epithelium. We propose that the HAE model provides a ready platform for molecular studies and characterization of HCoV-HKU1 and in general serves as a robust technology for the recovery, amplification, adaptation, and characterization of novel coronaviruses and other respiratory viruses from clinical material. PMID- 20719952 TI - HIV controllers with HLA-DRB1*13 and HLA-DQB1*06 alleles have strong, polyfunctional mucosal CD4+ T-cell responses. AB - A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4+ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8+ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4+ T cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the rectal mucosa of 28 "controllers" (viral load [VL] of <2,000 copies/ml), 14 "noncontrollers" (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had higher magnitude Gag-specific mucosal CD4+ T-cell responses than individuals on HAART (P<0.05), as measured by their ability to produce gamma interferon (IFN-gamma), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha), and macrophage inflammatory protein 1beta (MIP-1beta). The frequency of polyfunctional mucosal CD4+ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P<0.05). Controllers with the strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4+ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4+ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8+ T-cell response (Spearman's r=0.43, P=0.005), suggesting that increased CD4+ T-cell "help" may be important in maintaining strong CD8+ T-cell responses in the gut of HIV controllers. PMID- 20719953 TI - Poxvirus complement control proteins are expressed on the cell surface through an intermolecular disulfide bridge with the viral A56 protein. AB - The vaccinia virus (VACV) complement control protein (VCP) is an immunomodulatory protein that is both secreted from and expressed on the surface of infected cells. Surface expression of VCP occurs though an interaction with the viral transmembrane protein A56 and is dependent on a free N-terminal cysteine of VCP. Although A56 and VCP have been shown to interact in infected cells, the mechanism remains unclear. To investigate if A56 is sufficient for surface expression, we transiently expressed VCP and A56 in eukaryotic cell lines and found that they interact on the cell surface in the absence of other viral proteins. Since A56 contains three extracellular cysteines, we hypothesized that one of the cysteines may be unpaired and could therefore form a disulfide bridge with VCP. To test this, we generated a series of A56 mutants in which each cysteine was mutated to a serine, and we found that mutation of cysteine 162 abrogated VCP cell surface expression. We also tested the ability of other poxvirus complement control proteins to bind to VACV A56. While the smallpox homolog of VCP is able to bind VACV A56, the ectromelia virus (ECTV) VCP homolog is only able to bind the ECTV homolog of A56, indicating that these proteins may have coevolved. Surface expression of poxvirus complement control proteins may have important implications in viral pathogenesis, as a virus that does not express cell surface VCP is attenuated in vivo. This suggests that surface expression of VCP may contribute to poxvirus pathogenesis. PMID- 20719954 TI - Kaposi's sarcoma-associated herpesvirus inhibits interleukin-4-mediated STAT6 phosphorylation to regulate apoptosis and maintain latency. AB - Cytokine-mediated JAK/STAT signaling controls numerous important biologic responses like immune function, cellular growth, and differentiation. Inappropriate activation of this signaling pathway is associated with a range of malignancies. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious viral agent associated with Kaposi's sarcoma and may also contribute to B-cell disorders, which include primary effusion lymphoma (PEL) and multicentric Castleman's disease. However, regulation of cytokine-mediated lymphocytic immune response by KSHV is not fully understood. In this report, we demonstrate that KSHV suppresses the interleukin-4 (IL-4)-stimulated immune response of B lymphocyte activation and cell proliferation. Moreover, we show that the latency associated nuclear antigen (LANA) encoded by KSHV is essential for viral blocking of IL-4-induced signaling. LANA reduces phosphorylation of the signal transducers and activators of transcription 6 (STAT6) on Y-641 and concomitantly its DNA binding ability. Importantly, knockdown of endogenous STAT6 dramatically increases the sensitivity of PEL cells to low-serum stress or chemical-mediated cellular apoptosis and reactivation of KSHV from latent replication. Thus, these findings suggest that the IL-4/STAT6 signaling network is precisely controlled by KSHV for survival, maintenance of latency, and suppression of the host cytokine immune response of the virus-infected cells. PMID- 20719955 TI - Proteasome activator REGgamma enhances coxsackieviral infection by facilitating p53 degradation. AB - Coxsackievirus B3 (CVB3) is a small RNA virus associated with diseases such as myocarditis, meningitis, and pancreatitis. We have previously demonstrated that proteasome inhibition reduces CVB3 replication and attenuates virus-induced myocarditis. However, the underlying mechanisms by which the ubiquitin/proteasome system regulates CVB replication remain unclear. In this study, we investigated the role of REGgamma, a member of the 11S proteasome activator, in CVB3 replication. We showed that overexpression of REGgamma promoted CVB3 replication but that knockdown of REGgamma led to reduced CVB3 replication. We further demonstrated that REGgamma-mediated p53 proteolysis contributes, as least in part, to the proviral function of REGgamma. Although total protein levels of REGgamma remained unaltered after CVB3 infection, virus infection induced a redistribution of REGgamma from the nucleus to the cytoplasm, rendering an opportunity for a direct interaction of REGgamma with viral proteins and/or host proteins (e.g., p53), which controls viral growth and thereby enhances viral infectivity. Further analyses suggested a potential modification of REGgamma by SUMO following CVB3 infection, which was verified by both in vitro and in vivo sumoylation assays. Sumoylation of REGgamma may play a role in its nuclear export during CVB3 infection. Taken together, our results present the first evidence that the host REGgamma pathway is utilized and modified during CVB3 infection to promote efficient viral replication. PMID- 20719957 TI - Evaluation of the cobas 4800 CT/NG test for detecting Chlamydia trachomatis and Neisseria gonorrhoeae. AB - OBJECTIVES: To investigate the performance of the fully automated cobas 4800 CT/NG test for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. METHODS: The study was conducted using 900 clinical specimens (496 urine and 404 swab specimens) for C trachomatis testing, of which 498 specimens (318 urine and 180 swab specimens) were also tested for N gonorrhoeae. The results of the cobas 4800 CT/NG test were compared with those obtained from the Roche COBAS AMPLICOR CT/NG and COBAS TaqMan CT assays. N gonorrhoeae-positive specimens were further tested using in-house, real-time PCR assays. A panel of 223 Neisseria isolates was used to further investigate the performance of the cobas 4800 N gonorrhoeae assay. RESULTS: For urine specimens, the sensitivity, specificity and negative and positive predictive values of the cobas 4800 CT/NG test were 94.5%, 99.5%, 98.8% and 97.7%, respectively, for C trachomatis, and 92.9%, 100%, 99.7% and 100%, respectively, for N gonorrhoeae. For swab specimens, the sensitivity, specificity and negative and positive predictive values were 92.0%, 100%, 99.5% and 100%, respectively, for C trachomatis, and 100%, 99.4%, 100% and 90.0%, respectively, for N gonorrhoeae. All N gonorrhoeae isolates were positive and all non-gonococcal Neisseria strains were negative by the cobas 4800 N gonorrhoeae assay. CONCLUSIONS: The cobas 4800 CT/NG test is suitable for high through-put identification of C trachomatis and N gonorrhoeae infections. PMID- 20719956 TI - Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance. AB - The HIV gp41 N-trimer pocket region is an ideal viral target because it is extracellular, highly conserved, and essential for viral entry. Here, we report on the design of a pocket-specific D-peptide, PIE12-trimer, that is extraordinarily elusive to resistance and characterize its inhibitory and structural properties. D-peptides (peptides composed of D-amino acids) are promising therapeutic agents due to their insensitivity to protease degradation. PIE12-trimer was designed using structure-guided mirror-image phage display and linker optimization and is the first D-peptide HIV entry inhibitor with the breadth and potency required for clinical use. PIE12-trimer has an ultrahigh affinity for the gp41 pocket, providing it with a reserve of binding energy (resistance capacitor) that yields a dramatically improved resistance profile compared to those of other fusion inhibitors. These results demonstrate that the gp41 pocket is an ideal drug target and establish PIE12-trimer as a leading anti HIV antiviral candidate. PMID- 20719958 TI - MAP1B regulates axonal development by modulating Rho-GTPase Rac1 activity. AB - Cultured neurons obtained from MAP1B-deficient mice have a delay in axon outgrowth and a reduced rate of axonal elongation compared with neurons from wild type mice. Here we show that MAP1B deficiency results in a significant decrease in Rac1 and cdc42 activity and a significant increase in Rho activity. We found that MAP1B interacted with Tiam1, a guanosine nucleotide exchange factor for Rac1. The decrease in Rac1/cdc42 activity was paralleled by decreases in the phosphorylation of the downstream effectors of these proteins, such as LIMK-1 and cofilin. The expression of a constitutively active form of Rac1, cdc42, or Tiam1 rescued the axon growth defect of MAP1B-deficient neurons. Taken together, these observations define a new and crucial function of MAP1B that we show to be required for efficient cross-talk between microtubules and the actin cytoskeleton during neuronal polarization. PMID- 20719959 TI - Par6 alpha interacts with the dynactin subunit p150 Glued and is a critical regulator of centrosomal protein recruitment. AB - The centrosome contains proteins that control the organization of the microtubule cytoskeleton in interphase and mitosis. Its protein composition is tightly regulated through selective and cell cycle-dependent recruitment, retention, and removal of components. However, the mechanisms underlying protein delivery to the centrosome are not completely understood. We describe a novel function for the polarity protein Par6alpha in protein transport to the centrosome. We detected Par6alpha at the centrosome and centriolar satellites where it interacted with the centriolar satellite protein PCM-1 and the dynactin subunit p150(Glued). Depletion of Par6alpha caused the mislocalization of p150(Glued) and centrosomal components that are critical for microtubule anchoring at the centrosome. As a consequence, there were severe alterations in the organization of the microtubule cytoskeleton in the absence of Par6alpha and cell division was blocked. We propose a model in which Par6alpha controls centrosome organization through its association with the dynactin subunit p150(Glued). PMID- 20719960 TI - Integrin-mediated cell attachment induces a PAK4-dependent feedback loop regulating cell adhesion through modified integrin alpha v beta 5 clustering and turnover. AB - Cell-to-extracellular matrix adhesion is regulated by a multitude of pathways initiated distally to the core cell-matrix adhesion machinery, such as via growth factor signaling. In contrast to these extrinsically sourced pathways, we now identify a regulatory pathway that is intrinsic to the core adhesion machinery, providing an internal regulatory feedback loop to fine tune adhesion levels. This autoinhibitory negative feedback loop is initiated by cell adhesion to vitronectin, leading to PAK4 activation, which in turn limits total cell vitronectin adhesion strength. Specifically, we show that PAK4 is activated by cell attachment to vitronectin as mediated by PAK4 binding partner integrin alphavbeta5, and that active PAK4 induces accelerated integrin alphavbeta5 turnover within adhesion complexes. Accelerated integrin turnover is associated with additional PAK4-mediated effects, including inhibited integrin alphavbeta5 clustering, reduced integrin to F-actin connectivity and perturbed adhesion complex maturation. These specific outcomes are ultimately associated with reduced cell adhesion strength and increased cell motility. We thus demonstrate a novel mechanism deployed by cells to tune cell adhesion levels through the autoinhibitory regulation of integrin adhesion. PMID- 20719961 TI - Activation of Akt is essential for the propagation of mitochondrial respiratory stress signaling and activation of the transcriptional coactivator heterogeneous ribonucleoprotein A2. AB - Mitochondrial respiratory stress (also called mitochondrial retrograde signaling) activates a Ca(2+)/calcineurin-mediated signal that culminates in transcription activation/repression of a large number of nuclear genes. This signal is propagated through activation of the regulatory proteins NFkappaB c-Rel/p50, C/EBPdelta, CREB, and NFAT. Additionally, the heterogeneous ribonucleoprotein A2 (hnRNPA2) functions as a coactivator in up-regulating the transcription of Cathepsin L, RyR1, and Glut-4, the target genes of stress signaling. Activation of IGF1R, which causes a metabolic switch to glycolysis, cell invasiveness, and resistance to apoptosis, is a phenotypic hallmark of C2C12 myoblasts subjected to mitochondrial stress. In this study, we report that mitochondrial stress leads to increased expression, activation, and nuclear localization of Akt1. Mitochondrial respiratory stress also activates Akt1-gene expression, which involves hnRNPA2 as a coactivator, indicating a complex interdependency of these two factors. Using Akt1(-/-) mouse embryonic fibroblasts and Akt1 mRNA-silenced C2C12 cells, we show that Akt1-mediated phosphorylation is crucial for the activation and recruitment of hnRNPA2 to the enhanceosome complex. Akt1 mRNA silencing in mtDNA-depleted cells resulted in reversal of the invasive phenotype, accompanied by sensitivity to apoptotic stimuli. These results show that Akt1 is an important regulator of the nuclear transcriptional response to mitochondrial stress. PMID- 20719962 TI - Sprouty proteins inhibit receptor-mediated activation of phosphatidylinositol specific phospholipase C. AB - Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signaling; however, their exact mechanism of action remains incompletely understood. We identified phosphatidylinositol-specific phospholipase C (PLC) gamma as a partner of the Spry1 and Spry2 proteins. Spry-PLCgamma interaction was dependent on the Src homology 2 domain of PLCgamma and a conserved N-terminal tyrosine residue in Spry1 and Spry2. Overexpression of Spry1 and Spry2 was associated with decreased PLCgamma phosphorylation and decreased PLCgamma activity as measured by production of inositol (1,4,5)-triphosphate (IP(3)) and diacylglycerol, whereas cells deficient for Spry1 or Spry1, -2, and -4 showed increased production of IP(3) at baseline and further increased in response to growth factor signals. Overexpression of Spry 1 or Spry2 or small-interfering RNA mediated knockdown of PLCgamma1 or PLCgamma2 abrogated the activity of a calcium dependent reporter gene, suggesting that Spry inhibited calcium-mediated signaling downstream of PLCgamma. Furthermore, Spry overexpression in T-cells, which are highly dependent on PLCgamma activity and calcium signaling, blocked T cell receptor-mediated calcium release. Accordingly, cultured T-cells from Spry1 gene knockout mice showed increased proliferation in response to T-cell receptor stimulation. These data highlight an important action of Spry, which may allow these proteins to influence signaling through multiple receptors. PMID- 20719963 TI - The sodium/proton exchanger NHE8 regulates late endosomal morphology and function. AB - The pH and lumenal environment of intracellular organelles is considered essential for protein sorting and trafficking through the cell. We provide the first evidence that a mammalian NHE sodium (potassium)/proton exchanger, NHE8, plays a key role in the control of protein trafficking and endosome morphology. At steady state, the majority of epitope-tagged NHE8 was found in the trans-Golgi network of HeLa M-cells, but a proportion was also localized to multivesicular bodies (MVBs). Depletion of NHE8 in HeLa M-cells with siRNA resulted in the perturbation of MVB protein sorting, as shown by an increase in epidermal growth factor degradation. Additionally, NHE8-depleted cells displayed striking perinuclear clustering of endosomes and lysosomes, and there was a ninefold increase in the cellular volume taken up by LAMP1/LBPA-positive, dense MVBs. Our data points to a role for the ion exchange activity of NHE8 being required to maintain endosome morphology, as overexpression of a nonfunctional point mutant protein (NHE8 E225Q) resulted in phenotypes similar to those seen after siRNA depletion of endogenous NHE8. Interestingly, we found that depletion of NHE8, despite its function as a sodium (potassium)/proton antiporter, did not affect the overall pH inside dense MVBs. PMID- 20719967 TI - Stigma and discrimination of mental health problems: workplace implications. PMID- 20719964 TI - SPG20 protein spartin is recruited to midbodies by ESCRT-III protein Ist1 and participates in cytokinesis. AB - Hereditary spastic paraplegias (HSPs, SPG1-46) are inherited neurological disorders characterized by lower extremity spastic weakness. Loss-of-function SPG20 gene mutations cause an autosomal recessive HSP known as Troyer syndrome. The SPG20 protein spartin localizes to lipid droplets and endosomes, and it interacts with tail interacting protein 47 (TIP47) as well as the ubiquitin E3 ligases atrophin-1-interacting protein (AIP)4 and AIP5. Spartin harbors a domain contained within microtubule-interacting and trafficking molecules (MIT) at its N terminus, and most proteins with MIT domains interact with specific ESCRT-III proteins. Using yeast two-hybrid and in vitro surface plasmon resonance assays, we demonstrate that the spartin MIT domain binds with micromolar affinity to the endosomal sorting complex required for transport (ESCRT)-III protein increased sodium tolerance (Ist)1 but not to ESCRT-III proteins charged multivesicular body proteins 1-7. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells by small interfering RNA significantly decreases the number of cells where spartin is present at midbodies. Depletion of spartin does not affect Ist1 localization to midbodies but markedly impairs cytokinesis. A structure-based amino acid substitution in the spartin MIT domain (F24D) blocks the spartin-Ist1 interaction. Spartin F24D does not localize to the midbody and acts in a dominant negative manner to impair cytokinesis. These data suggest that Ist1 interaction is important for spartin recruitment to the midbody and that spartin participates in cytokinesis. PMID- 20719968 TI - Dame Carol Black. The report on Attitudes and Barriers to Employment in HIV positive patients. PMID- 20719969 TI - The journal in the 1980s. PMID- 20719970 TI - Employers--aren't they all the same? PMID- 20719971 TI - Dame Laura Knight Ruby Loftus screwing a Breech-ring 1943. PMID- 20719972 TI - Why I became a second hand bookseller: part 2. PMID- 20719973 TI - Fibroblast growth factor-10 signals development of von Brunn's nests in the exstrophic bladder. AB - von Brunn's nests have long been recognized as precursors of benign lesions of the urinary bladder mucosa. We report here that von Brunn's nests are especially prevalent in the exstrophic bladder, a birth defect that predisposes the patient to formation of bladder cancer. Cells of von Brunn's nest were found to coalesce into a stratified, polarized epithelium which surrounds itself with a capsule like structure rich in types I, III, and IV collagen. Histocytochemical analysis and keratin profiling demonstrated that nested cells exhibited a phenotype similar, but not identical, to that of urothelial cells of transitional epithelium. Immunostaining and in situ hybridization analysis of exstrophic tissue demonstrated that the FGF-10 receptor is synthesized and retained by cells of von Brunn's nest. In contrast, FGF-10 is synthesized and secreted by mesenchymal fibroblasts via a paracrine pathway that targets basal epithelial cells of von Brunn's nests. Small clusters of 10pRp cells, positive for both FGF 10 and its receptor, were observed both proximal to and inside blood vessels in the lamina propria. The collective evidence points to a mechanism where von Brunn's nests develop under the control of the FGF-10 signal transduction system and suggests that 10pRp cells may be the original source of nested cells. PMID- 20719974 TI - Role of the Rhesus glycoprotein, Rh B glycoprotein, in renal ammonia excretion. AB - Rh B glycoprotein (Rhbg) is a member of the Rh glycoprotein family of ammonia transporters. In the current study, we examine Rhbg's role in basal and acidosis stimulated acid-base homeostasis. Metabolic acidosis induced by HCl administration increased Rhbg expression in both the cortex and outer medulla. To test the functional significance of increased Rhbg expression, we used a Cre-loxP approach to generate mice with intercalated cell-specific Rhbg knockout (IC-Rhbg KO). On normal diet, intercalated cell-specific Rhbg deletion did not alter urine ammonia excretion, pH, or titratable acid excretion significantly, but it did decrease glutamine synthetase expression in the outer medulla significantly. After metabolic acidosis was induced, urinary ammonia excretion was significantly less in IC-Rhbg-KO than in control (C) mice on days 2-4 of acid loading, but not on day 5. Urine pH and titratable acid excretion and dietary acid intake did not differ significantly between acid-loaded IC-Rhcg-KO and C mice. In IC-Rhbg-KO mice, acid loading increased connecting segment (CNT) cell and outer medullary collecting duct principal cell Rhbg expression. In both C and IC-Rhbg-KO mice, acid loading decreased glutamine synthetase in both the cortex and outer medulla; the decrease on day 3 was similar in IC-Rhbg-KO and C mice, but on day 5 it was significantly greater in IC-Rhbg-KO than in C mice. We conclude 1) intercalated cell Rhbg contributes to acidosis-stimulated renal ammonia excretion, 2) Rhbg in CNT and principal cells may contribute to renal ammonia excretion, and 3) decreased glutamine synthetase expression may enable normal rates of ammonia excretion under both basal conditions and on day 5 of acid loading in IC-Rhbg-KO mice. PMID- 20719975 TI - Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection. AB - The capacity of renin-angiotensin system (RAS) inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is started. A multimodal intervention is required to afford renoprotection in overt diabetic nephropathy. Here we assessed the effects of maximal RAS inhibition by angiotensin-converting enzyme (ACE) inhibitor plus angiotensin II type 1 receptor blocker (ARB) in combination with statin in rats with overt diabetic nephropathy. Uninephrectomized rats made diabetic by streptozotocin were orally treated from 4 (when proteinuria and renal lesions had developed) to 8 mo with vehicle, lisinopril plus candesartan, lisinopril plus candesartan plus rosuvastatin, or rosuvastatin alone. Systolic blood pressure increased in diabetic rats and was significantly lowered by combined therapies. Dual RAS blockade significantly reduced proteinuria compared with vehicle. Addition of statin further lowered proteinuria to control levels. Glomerulosclerosis was ameliorated by RAS inhibitors or statin, and regression was achieved by the addition of statin. Loss of podocytes of diabetic rats was limited by ACE inhibitor plus ARB while normalized by the three drugs. Defective nephrin expression of diabetes was increased by dual RAS blockade or statin and restored by the triple therapy. Tubular damage, interstitial inflammation, and expression of the fibrotic markers transforming growth factor (TGF)-beta1 and phosphorylated Smad 2/3 in tubuli were significantly reduced by the triple regimen. These data suggest a strategy to target proteinuria to try to achieve regression of renal disease in diabetic patients who do not fully benefit from RAS inhibition alone. PMID- 20719976 TI - Cytoglobin, a novel globin, plays an antifibrotic role in the kidney. AB - Cytoglobin (Cygb), a novel member of the globin superfamily, is expressed by fibroblasts in various organs. However, its function remains unknown. Because of its localization, we speculated that a biological role of Cygb may be related to fibrogenesis. To clarify the role of Cygb in kidney fibrosis, we employed the remnant kidney model in rats. Immunohistochemical analysis showed an increase in Cygb expression in parallel with disease progression. To investigate the functional consequence of Cygb upregulation, we established transgenic rats overexpressing rat Cygb. Overexpression of Cygb improved histological injury, preserved renal function, and ameliorated fibrosis, as estimated by the accumulation of collagen I and IV as well as Masson trichrome staining. These protective effects of Cygb were associated with a decrease in nitrotyrosine deposition in the kidney and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion as a marker of oxidative stress. We also performed in vitro studies utilizing a rat kidney fibroblast cell line transiently overexpressing Cygb, an inducible kidney cell transfected with Cygb, and primary cultured fibroblasts isolated from the kidneys of the transgenic rats. These different experimental systems consistently showed that Cygb inhibited collagen synthesis. Furthermore, mutant disruption of heme in Cygb that impaired its antioxidant properties led to the loss of antifibrotic effects, suggesting that Cygb reduces fibrosis via a radical scavenging function. In conclusion, we showed that Cygb plays an important role in protection of the kidney against fibrosis via the amelioration of oxidative stress both in vitro and in vivo. Cygb might represent a good therapeutic target in chronic kidney disease. PMID- 20719977 TI - Constitutive endocytosis and recycling of NKCC2 in rat thick ascending limbs. AB - The Na-K-2Cl cotransporter (NKCC2) mediates NaCl absorption by the thick ascending limb of Henle's loop (THAL). Exocytosis and endocytosis regulates surface expression of most transporters. However, little is known about the mechanism of NKCC2 trafficking in the absence of stimulating hormones and whether this mechanism contributes to regulation of steady-state surface expression of apical NKCC2 in the THAL. We tested whether NKCC2 undergoes constitutive endocytosis that regulates steady-state surface NKCC2 and NaCl reabsorption in THALs. We measured steady-state surface NKCC2 levels and the rate of NKCC2 endocytosis by surface biotinylation and Western blot and confocal microscopy of isolated perfused rat THALs. We observed constitutive NKCC2 endocytosis over 30 min that averaged 21.5 +/- 2.7% of the surface pool. We then tested whether methyl-beta-cyclodextrin (MbetaCD), a compound that inhibits endocytosis by chelating membrane cholesterol, blocked NKCC2 endocytic retrieval. We found that 30-min treatment with MbetaCD (5 mM) blocked NKCC2 endocytosis by 81% (P < 0.01). Blockade of endocytosis by MbetaCD induced accumulation of NKCC2 at the apical membrane as demonstrated by a 60 +/- 16% (P < 0.05) increase in steady-state surface expression and enhanced apical surface NKCC2 immunostaining in isolated, perfused THALs. Acute treatment with MbetaCD did not change the total pool of NKCC2. MbetaCD did not affect NKCC2 trafficking when it was complexed with cholesterol before treatment. Inhibition endocytosis with MbetaCD enhanced NKCC2 dependent NaCl entry by 57 +/- 16% (P < 0.05). Finally, we observed that a fraction of retrieved NKCC2 recycles back to the plasma membrane (36 +/- 7%) over 30 min. We concluded that constitutive NKCC2 trafficking maintains steady-state surface NKCC2 and regulates NaCl reabsorption in THALs. These are the first data showing an increase in apical membrane NKCC2 in THALs by altering the rates of constitutive NKCC2 trafficking, rather than by stimulation of hormone-dependent signaling. PMID- 20719978 TI - A single residue in transmembrane domain 11 defines the different affinity for thiazides between the mammalian and flounder NaCl transporters. AB - Little is known about the residues that control the binding and affinity of thiazide-type diuretics for their protein target, the renal Na(+)-Cl(-) cotransporter (NCC). Previous studies from our group have shown that affinity for thiazides is higher in rat (rNCC) than in flounder (flNCC) and that the transmembrane region (TM) 8-12 contains the residues that produce this difference. Here, an alignment analysis of TM 8-12 revealed that there are only six nonconservative variations between flNCC and mammalian NCC. Two are located in TM9, three in TM11, and one in TM12. We used site-directed mutagenesis to generate rNCC containing flNCC residues, and thiazide affinity was assessed using Xenopus laevis oocytes. Wild-type or mutant NCC activity was measured using (22)Na(+) uptake in the presence of increasing concentrations of metolazone. Mutations in TM11 conferred rNCC an flNCC-like affinity, which was caused mostly by the substitution of a single residue, S575C. Supporting this observation, the substitution C576S conferred to flNCC an rNCC-like affinity. Interestingly, the S575C mutation also rendered rNCC more active. Substitution of S575 in rNCC for other residues, such as alanine, aspartate, and lysine, did not alter metolazone affinity, suggesting that reduced affinity in flNCC is due specifically to the presence of a cysteine. We conclude that the difference in metolazone affinity between rat and flounder NCC is caused mainly by a single residue and that this position in the protein is important for determining its functional properties. PMID- 20719979 TI - Hyperaldosteronism in Klotho-deficient mice. AB - Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25-dihydroxyvitamin-D(3) [1,25(OH)(2)D(3)]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca(2+) reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klotho(hm) mice and wild-type mice (klotho(+/+)) were subjected to a normal (D(+)) or vitamin D deficient (D(-)) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D(-/+)). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D(3,) adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca(2+), phosphate and Na(+), but not K(+) concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca(2+)-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D(3) in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span. PMID- 20719980 TI - Shear stress increases nitric oxide production in thick ascending limbs. AB - We showed that luminal flow stimulates nitric oxide (NO) production in thick ascending limbs. Ion delivery, stretch, pressure, and shear stress all increase when flow is enhanced. We hypothesized that shear stress stimulates NO in thick ascending limbs, whereas stretch, pressure, and ion delivery do not. We measured NO in isolated, perfused rat thick ascending limbs using the NO-sensitive dye DAF FM-DA. NO production rose from 21 +/- 7 to 58 +/- 12 AU/min (P < 0.02; n = 7) when we increased luminal flow from 0 to 20 nl/min, but dropped to 16 +/- 8 AU/min (P < 0.02; n = 7) 10 min after flow was stopped. Flow did not increase NO in tubules from mice lacking NO synthase 3 (NOS 3). Flow stimulated NO production by the same extent in tubules perfused with ion-free solution and physiological saline (20 +/- 7 vs. 24 +/- 6 AU/min; n = 7). Increasing stretch while reducing shear stress and pressure lowered NO generation from 42 +/- 9 to 17 +/- 6 AU/min (P < 0.03; n = 6). In the absence of shear stress, increasing pressure and stretch had no effect on NO production (2 +/- 8 vs. 8 +/- 8 AU/min; n = 6). Similar results were obtained in the presence of tempol (100 MUmol/l), a O(2)(-) scavenger. Primary cultures of thick ascending limb cells subjected to shear stresses of 0.02 and 0.55 dyne/cm(2) produced NO at rates of 55 +/- 10 and 315 +/ 93 AU/s, respectively (P < 0.002; n = 7). Pretreatment with the NOS inhibitor l NAME (5 mmol/l) blocked the shear stress-induced increase in NO production. We concluded that shear stress rather than pressure, stretch, or ion delivery mediates flow-induced stimulation of NO by NOS 3 in thick ascending limbs. PMID- 20719981 TI - Direct demonstration of tubular fluid flow sensing by macula densa cells. AB - Macula densa (MD) cells in the cortical thick ascending limb (cTAL) detect variations in tubular fluid composition and transmit signals to the afferent arteriole (AA) that control glomerular filtration rate [tubuloglomerular feedback (TGF)]. Increases in tubular salt at the MD that normally parallel elevations in tubular fluid flow rate are well accepted as the trigger of TGF. The present study aimed to test whether MD cells can detect variations in tubular fluid flow rate per se. Calcium imaging of the in vitro microperfused isolated JGA glomerulus complex dissected from mice was performed using fluo-4 and fluorescence microscopy. Increasing cTAL flow from 2 to 20 nl/min (80 mM [NaCl]) rapidly produced significant elevations in cytosolic Ca(2+) concentration ([Ca(2+)](i)) in AA smooth muscle cells [evidenced by changes in fluo-4 intensity (F); F/F(0) = 1.45 +/- 0.11] and AA vasoconstriction. Complete removal of the cTAL around the MD plaque and application of laminar flow through a perfusion pipette directly to the MD apical surface essentially produced the same results even when low (10 mM) or zero NaCl solutions were used. Acetylated alpha-tubulin immunohistochemistry identified the presence of primary cilia in mouse MD cells. Under no flow conditions, bending MD cilia directly with a micropipette rapidly caused significant [Ca(2+)](i) elevations in AA smooth muscle cells (fluo-4 F/F(0): 1.60 +/- 0.12) and vasoconstriction. P2 receptor blockade with suramin significantly reduced the flow-induced TGF, whereas scavenging superoxide with tempol did not. In conclusion, MD cells are equipped with a tubular flow-sensing mechanism that may contribute to MD cell function and TGF. PMID- 20719982 TI - Polycystic kidney disease in Han:SPRD Cy rats is associated with elevated expression and mislocalization of SamCystin. AB - Polycystic kidney disease (PKD) in Han:SPRD Cy rats is caused by a missense mutation in Anks6 (also called Pkdr1), leading to an R823W substitution in SamCystin, a protein that contains ankyrin repeats and a sterile alpha motif (SAM). The cellular function of SamCystin and the role of the Cy (R823W) mutation in cyst formation are unknown. In normal SPRD rats, SamCystin was found to be expressed in proximal tubules and glomeruli; protein expression was highest at 7 days of age and declined by ~50-60% at 45-84 days of age. In Cy/+ and Cy/Cy kidneys, expression of SamCystin was lower than in +/+ kidneys at 3 and 7 days but became elevated at 21 days. Immunohistochemical analysis revealed that SamCystin was distributed on the brush border of proximal tubules in normal rat kidneys. In Cy/+ kidneys, there were robust SamCystin staining in cyst-lining epithelial cells and loss of apical localization, and increased number of PCNA positive cells in cyst-lining epithelia. Verapamil, an L-type Ca(2+) channel blocker, accelerated PKD progression in this model and caused a further increase in the expression and abnormal distribution of SamCystin. We conclude that aberrant expression and mislocalization of R823W SamCystin lead to increased cell proliferation and renal cyst formation. PMID- 20719983 TI - Effect of revaccination using different schemes among adults with low or undetectable anti-HBs titers after hepatitis B virus vaccination. AB - Our objective was to investigate the effect of various reimmunization schemes for hepatitis B in adults with low or undetectable anti-HBs titers. Over 2 years, 10 MUg of Saccharomyces cerevisiae-recombinant hepatitis B virus (HBV) vaccine (synthesized in China) was used in at least one standardized scheme to immunize 2,310 healthy male and nonpregnant female adults. Of these, 240 subjects tested negative for hepatitis B markers. These 240 subjects were equally divided into 4 groups. The first group, designated Engerix-40, was revaccinated with 40 MUg Engerix-B; the second, Engerix-20, was revaccinated with 20 MUg Engerix-B; the third, Chinese-20, was revaccinated with 20 MUg Chinese-made yeast-recombinant vaccine; and the last group, Chinese-10, was revaccinated with 10 MUg Chinese made yeast-recombinant vaccine. Blood samples were collected before and 1, 2, 8, and 12 months after the first injection. The anti-HBs-positive conversion rates of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than that of the Chinese-10 group (P < 0.01). Over time, the anti-HBs conversion rate increased in all groups, but values were significantly different from those for the other groups only in the Chinese-10 group (P < 0.001). The anti-HBs geometric mean titers (GMTs) of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than in the Chinese-10 group (P < 0.05). Increased doses raise and maintain anti HBs titers in subjects with low or undetectable titers after HBV vaccination. PMID- 20719984 TI - Field evaluation of the efficacy of Mycobacterium bovis bacillus Calmette-Guerin against bovine tuberculosis in neonatal calves in Ethiopia. AB - In developing countries, the conventional test and slaughter strategy for the control of bovine tuberculosis is prohibitively expensive, and alternative control methods such as vaccination are urgently required. In this study, the efficacy of Mycobacterium bovis bacillus Calmette-Guerin (BCG) for protection against bovine tuberculosis (bTB) was evaluated in Holstein calves under field conditions in Ethiopia. Thirteen neonatally vaccinated and 14 control calves were exposed for 10 to 23 months to skin test reactor cows. Gamma interferon (IFN gamma) testing, comparative intradermal tuberculin testing, postmortem examination, and bacteriological culture were used for the evaluation of BCG efficacy. The overall mean pathology score was significantly (P < 0.05) higher in control calves than in vaccinated calves. Culture positivity for Mycobacterium bovis was higher in the control calves than in the vaccinated calves, and significantly more BCG-vaccinated animals would have passed a standard meat inspection (P = 0.021). Overall, the protective efficacy of BCG was between 56% and 68%, depending on the parameters selected. Moreover, by measuring gamma interferon responses to the antigens ESAT-6 and CFP-10, which are present in M. bovis but absent from BCG, throughout the experiment, we were able to distinguish between vaccinated animals that were protected against bTB and those animals that were not protected. In conclusion, the present trial demonstrated an encouraging protective effect of BCG against bTB in a natural transmission setting in Ethiopia. PMID- 20719985 TI - Monofunctional and polyfunctional CD8+ T cell responses to human herpesvirus 8 lytic and latency proteins. AB - Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. It is postulated that CD8(+) T cell responses play an important role in controlling HHV-8 infection and preventing development of disease. In this study, we investigated monofunctional and polyfunctional CD8(+) T cell responses to HHV-8 lytic proteins gB (glycoprotein B) and K8.1 and latency proteins LANA-1 (latency-associated nuclear antigen-1) and K12. On the basis of our previous findings that dendritic cells (DC) reveal major histocompatibility complex (MHC) class I epitopes in gB, we used a DC-based system to identify 2 novel epitopes in gB, 2 in K8.1, 5 in LANA 1, and 1 in K12. These new HHV-8 epitopes activated monofunctional and polyfunctional CD8(+) T cells that produced various combinations of gamma interferon, interleukin 2, tumor necrosis factor alpha, macrophage inhibitory protein 1beta, and cytotoxic degranulation marker CD107a in healthy HHV-8 seropositive individuals. We were also able to detect HHV-8-specific CD8(+) T cells in peripheral blood samples using HLA A*0201 pentamer complexes for one gB epitope, one K8.1 epitope, two LANA-1 epitopes, and one K12 epitope. These immunogenic regions of viral lytic and latency proteins could be important in T cell control of HHV-8 infection. PMID- 20719986 TI - Serological protection induced by Haemophilus influenzae Type B conjugate vaccine in Mexican children: is a booster dose of the vaccine needed? AB - We determined the seroprevalence of protective antibodies against Hib in Mexican children under the age of five using a standardized enzyme-linked immunosorbent assay. Hib antibodies (>= 0.15 MUg/ml) were present in 95.34% (+/-1.14% [seroprevalence +/- standard error]) of samples. Fewer children aged 30 to 47 months had protective Hib antibody levels (91.45% +/- 2.60%) than children from 12 to 29 and 48 to 59 months (97.3% +/- 1.34% and 97.44% +/- 1.80%, respectively). PMID- 20719987 TI - Characterization of Erysipelothrix species isolates from clinically affected pigs, environmental samples, and vaccine strains from six recent swine erysipelas outbreaks in the United States. AB - The aim of this study was to characterize Erysipelothrix sp. isolates from clinically affected pigs and their environment and compare them to the Erysipelothrix sp. vaccines used at the sites. Samples were collected during swine erysipelas outbreaks in vaccinated pigs in six Midwest United States swine operations from 2007 to 2009. Pig tissue samples were collected from 1 to 3 pigs from each site. Environmental samples (manure, feed, central-line water, oral fluids, and swabs collected from walls, feed lines, air inlets, exhaust fans, and nipple drinkers) and live vaccine samples were collected following the isolation of Erysipelothrix spp. from clinically affected pigs. All Erysipelothrix sp. isolates obtained were further characterized by serotyping. Selected isolates were further characterized by PCR assays for genotype (E. rhusiopathiae, E. tonsillarum, Erysipelothrix sp. strain 1, and Erysipelothrix sp. strain 2) and surface protective antigen (spa) type (A, B1, B2, and C). All 26 isolates obtained from affected pigs were E. rhusiopathiae, specifically, serotypes 1a, 1b, 2, and 21. From environmental samples, 56 isolates were obtained and 52/56 were E. rhusiopathiae (serotypes 1a, 1b, 2, 6, 9, 12, and 21), 3/56 were Erysipelothrix sp. strain 1 (serotypes 13 and untypeable), and one was a novel species designated Erysipelothrix sp. strain 3 (serotype untypeable). Four of six vaccines used at the sites were commercially available products and contained live E. rhusiopathiae serotype 1a. Of the remaining two vaccines, one was an autogenous live vaccine and contained live E. rhusiopathiae serotype 2 and one was a commercially produced inactivated vaccine and was described by the manufacturer to contain serotype 2 antigen. All E. rhusiopathiae isolates were positive for spaA. All Erysipelothrix sp. strain 1 isolates and the novel Erysipelothrix sp. strain 3 isolate were negative for all currently known spa types (A, B1, B2, and C). These results indicate that Erysipelothrix spp. can be isolated from the environment of clinically affected pigs; however, the identified serotypes in pigs differ from those in the environment at the selected sites. At one of the six affected sites, the vaccine strain and the isolates from clinically affected pigs were of homologous serotype; however, vaccinal and clinical isolates were of heterologous serotype at the remaining five sites, suggesting that reevaluation of vaccine efficacy using recent field strains may be warranted. PMID- 20719988 TI - Identification of Mycobacterium tuberculosis antigens of high serodiagnostic value. AB - Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis, with several million new cases detected each year. Current methods of diagnosis are time-consuming and/or expensive or have a low level of accuracy. Therefore, new diagnostics are urgently needed to address the global tuberculosis burden and to improve control programs. Serological assays remain attractive for use in resource-limited settings because they are simple, rapid, and inexpensive and offer the possibility of detecting cases often missed by routine sputum smear microscopy. The aim of this study was to identify M. tuberculosis seroreactive antigens from a panel of 103 recombinant proteins selected as diagnostic candidates. Initial library screening by protein array analysis and enzyme-linked immunosorbent assay (ELISA) identified 42 antigens with serodiagnostic potential. Among these, 25 were novel proteins. The reactive antigens demonstrated various individual sensitivities, ranging from 12% to 78% (specificities, 76 to 100%). When the antigens were analyzed in combinations, up to 93% of antibody responders could be identified among the TB patients. Selected seroreactive proteins were used to design 3 new polyepitope fusion proteins. Characterization of these antigens by multiantigen print immunoassay (MAPIA) revealed that the vast majority of the TB patients (90%) produced antibody responses. The results confirmed that due to the remarkable variation in immune recognition patterns, an optimal multiantigen cocktail should be designed to cover the heterogeneity of antibody responses and thus achieve the highest possible test sensitivity. PMID- 20719989 TI - Rinderpest virus expressing enhanced green fluorescent protein as a separate transcription unit retains pathogenicity for cattle. AB - A full-length DNA clone of a virulent strain of rinderpest virus was constructed with the gene for the enhanced green fluorescent protein (eGFP) inserted as a separate transcription unit between the P and M genes. Rescue of the virus from the modified clone using reverse genetics generated a virus that grew to the same levels as the virus rescued from the unmodified DNA clone in cell culture. The recombinant virus expressed eGFP to a high level and was used to follow virus replication in real-time using live-cell imaging. Cattle infected with both the recombinant wild-type virus and the recombinant eGFP expressing virus developed clinical disease similar to that of the wild-type natural virus isolate. Detection of virus in circulating peripheral blood leukocytes was equivalent to that of the animals infected with the wild-type virus. The high level of expression of soluble eGFP by this virus allowed us to detect viral replication in infected animals by confocal microscopy. Imaging vibrating microtome sections by confocal microscopy provided good preservation of tissue and cellular architecture as well as revealing the sites of replication of the virus in different tissues of infected animals. PMID- 20719990 TI - Influence of human immunodeficiency virus and CD4 count on the prevalence of human papillomavirus in heterosexual couples. AB - This study investigated the impact of human immunodeficiency virus (HIV) infection on genital human papillomavirus (HPV) in heterosexual couples. More HIV positive men and women had genital HPV compared with HIV-negative men (77 vs 49%; P<0.001) and women (74 vs 36%; P<0.001). More men and women with partners who were HPV positive had HPV genital infection compared with those with HPV-negative partners (for men, 72% compared with 40%; P<0.001). Men with HIV-positive female partners were at greater risk of high-risk HPV and low-risk HPV (LR HPV) infection compared with men with HIV-negative female partners. This risk increased with decreasing CD4 count { >= 350 ml-1: odds ratio [OR ], 2.37 [95% confidence interval (CI), 1.47-3.83]; < 350 ml-1: OR, 3.02 [95 % CI, 1.86-4.9]}. Conversely, the risk of HPV of any type was not found to differ between women with an HIV-positive or HIV-negative male partner. In men, HIV infection and female partner HIV-positive status were both associated with a higher risk of type-specific HPV concordance with their sexual partner, though the associations were not significant for LR HPV. In women, HIV infection and low CD4 count were significantly associated with increased risk of type-specific HPV concordance, but male partner HIV-positive status was not significantly associated with this concordance. In conclusion, male genital HPV prevalence and type-specific sharing were influenced by their own HIV-positive status and that of their female partner. In contrast, female genital HPV prevalence and HPV type-specific sharing were determined by their own HIV-positive status and not by that of their male partner. PMID- 20719991 TI - Evaluation of a modified vaccinia virus Ankara (MVA)-based candidate pandemic influenza A/H1N1 vaccine in the ferret model. AB - The zoonotic transmissions of highly pathogenic avian influenza viruses of the H5N1 subtype that have occurred since 1997 have sparked the development of novel influenza vaccines. The advent of reverse genetics technology, cell-culture production techniques and novel adjuvants has improved the vaccine strain preparation, production process and immunogenicity of the vaccines, respectively, and has accelerated the availability of pandemic influenza vaccines. However, there is still room for improvement, and alternative vaccine preparations can be explored, such as viral vectors. Modified vaccinia virus Ankara (MVA), originally developed as a safe smallpox vaccine, can be exploited as a viral vector and has many favourable properties. Recently, we have demonstrated that an MVA-based vaccine could protect mice and macaques against infection with highly pathogenic influenza viruses of the H5N1 subtype. In the present study, recombinant MVA expressing the haemagglutinin (HA) gene of pandemic influenza A/H1N1 virus was evaluated in the ferret model. A single immunization induced modest antibody responses and afforded only modest protection against the development of severe disease upon infection with a 2009(H1N1) strain. In contrast, two immunizations induced robust antibody responses and protected ferrets from developing severe disease, confirming that MVA is an attractive influenza vaccine production platform. PMID- 20719992 TI - Proteomic analysis of Glossina pallidipes salivary gland hypertrophy virus virions for immune intervention in tsetse fly colonies. AB - Many species of tsetse flies (Diptera: Glossinidae) can be infected by a virus that causes salivary gland hypertrophy (SGH). The genomes of viruses isolated from Glossina pallidipes (GpSGHV) and Musca domestica (MdSGHV) have recently been sequenced. Tsetse flies with SGH have reduced fecundity and fertility which cause a serious problem for mass rearing in the frame of sterile insect technique (SIT) programmes to control and eradicate tsetse populations in the wild. A potential intervention strategy to mitigate viral infections in fly colonies is neutralizing of the GpSGHV infection with specific antibodies against virion proteins. Two major GpSGHV virion proteins of about 130 and 50 kDa, respectively, were identified by Western analysis using a polyclonal rabbit antibody raised against whole GpSHGV virions. The proteome of GpSGHV, containing the antigens responsible for the immune-response, was investigated by liquid chromatography tandem mass spectrometry and 61 virion proteins were identified by comparison with the genome sequence. Specific antibodies were produced in rabbits against seven candidate proteins, including the ORF10/C-terminal fragment, ORF47 and ORF96 as well as proteins involved in peroral infectivity PIF-1 (ORF102), PIF 2 (ORF53), PIF-3 (ORF76) and P74 (ORF1). Antiserum against ORF10 specifically reacted to the 130 kDa protein in a Western blot analysis and to the envelope protein of GpSGHV, detected by using immunogold-electron microscopy. This result suggests that immune intervention of viral infections in colonies of G. pallidipes is a realistic option. PMID- 20719993 TI - Suppression of human immunodeficiency virus type 1 replication in macrophages by commensal bacteria preferentially stimulating Toll-like receptor 4. AB - Protection from primary human immunodeficiency virus type 1 (HIV-1) infection has not yet been accomplished by vaccines inducing HIV-1-specific acquired immunity. Nevertheless, it has been reported that a small subgroup of women remain resistant to HIV-1 infection under natural conditions. If similar conditions can be induced in uninfected individuals, it will contribute the first line of protection against HIV-1 infection, and also improve the effects of anti-HIV-1 vaccines. We reasoned that innate immunity may be involved in the resistance to HIV-1 infection, and investigated the effects of various Toll-like receptor (TLR) ligands and commensal bacteria on HIV-1 replication in macrophages, one of the initial targets of HIV-1 infection and also the main mediators of innate immunity. We established the HIV-1 reporter monocytic cell line, THP-1/NL4-3luc, which could be differentiated into macrophage-like cells in vitro. In these cells, stimulation of TLR3 and TLR4 by their ligands suppressed HIV-1 expression partly through type I interferon (IFN). Among the commensal bacteria tested, Escherichia coli, Veillonella parvula and Neisseria mucosa suppressed HIV-1 expression, whereas Lactobacillus acidophilus, Prevotella melaninogenica, P. bivia and Mycobacterium smegmatis enhanced it. The bacteria with suppressive effects preferentially stimulated TLR4, whereas the ones with enhancing effects stimulated TLR2. Neutralizing antibodies against TLR4 and IFN-alpha/beta receptor abrogated bacterially mediated HIV-1 suppression. Suppressive effects of E. coli, V. parvula and N. mucosa on HIV-1 replication were reproducible in primary monocyte-derived macrophages following acute HIV-1 infection. These findings suggest that certain commensal bacteria preferentially stimulating TLR4 potentially produce local environments resistant to HIV-1 infection. PMID- 20719994 TI - Experimental oral infection of bluetongue virus serotype 8 in type I interferon receptor-deficient mice. AB - The identification of transmission routes for bluetongue virus (BTV) is essential to improve the control of the disease. Although BTV is primarily transmitted by several species of Culicoides biting midges, there has been evidence of transplacental and oral transmission. We now report that IFNAR((-/-)) mice are susceptible to oral infection by BTV-8. Viraemia, clinical manifestations and tissue lesions are similar to those in intravenously infected mice. In addition, we show that the oral cavity and oesophagus are susceptible to BTV infection and replication, suggesting that these organs are possible entry routes during BTV oral infection. PMID- 20719995 TI - The nature nursing quality of work life: an integrative review of literature. AB - Studies that have examined the nursing quality of work life (QWL) have not been systematically reviewed in the recent years. Thus, the current study was aimed to identify the predictors of the nurses' QWL and determine the definitions of QWL for nurses. The authors used an integrative review of the literature and identified six themes as the major predictors of the nurses' QWL: leadership and management style/decision-making latitude, shift working, salary and fringe benefits, relationship with colleagues, demographic characteristics, and workload/job strain. Although different researchers had varied perspectives on the QWL in nursing, most viewed QWL as a subjective phenomenon that is influenced by personal feeling and perceptions. A closer review of definitions of QWL indicated that some authors considered QWL as an "outcome," whereas others saw it as a "process." Further research needs to be conducted to determine the relative importance of QWL predictors, and implementation programs to improve the QWL. PMID- 20719996 TI - Creative partnerships for funding nursing research. AB - The Small Business Innovation Research (SBIR) program and the Small Business Technology Transfer Research (STTR) program are two federal funding mechanisms that some nurses in academic positions have used to support research and development of innovative nursing products or services. Both the SBIR and STTR mechanisms are excellent sources of funding for nurse researchers who want to capitalize on relationships with small businesses or obtain seed money to fund high-risk projects with potential to attract new venture capital. This article provides an overview of National Institutes of Health (NIH)-funded SBIR and STTR programs and summarizes similarities and differences between the programs. The article also describes unique features of NIH SBIR and STTR funding mechanisms that differentiate them from other R-series funding mechanisms, reviews evaluation criteria for SBIR and STTR projects, and discusses critical partners and resources for proposal development. Finally, the article describes characteristics of successful partnerships and provides examples of SBIR/STTR funded projects. PMID- 20720000 TI - Impact Factor number reflects sustained high quality. PMID- 20720002 TI - A dual interface determines the recognition of RNA polymerase II by RNA capping enzyme. AB - RNA capping enzyme (CE) is recruited specifically to RNA polymerase II (Pol II) transcription sites to facilitate cotranscriptional 5'-capping of pre-mRNA and other Pol II transcripts. The current model to explain this specific recruitment of CE to Pol II as opposed to Pol I and Pol III rests on the interaction between CE and the phosphorylated C-terminal domain (CTD) of Pol II largest subunit Rpb1 and more specifically between the CE nucleotidyltransferase domain and the phosphorylated CTD. Through biochemical and diffraction analyses, we demonstrate the existence of a distinctive stoichiometric complex between CE and the phosphorylated Pol II (Pol IIO). Analysis of the complex revealed an additional and unexpected polymerase-CE interface (PCI) located on the multihelical Foot domain of Rpb1. We name this interface PCI1 and the previously known nucleotidyltransferase/phosphorylated CTD interface PCI2. Although PCI1 and PCI2 individually contribute to only weak interactions with CE, a dramatically stabilized and stoichiometric complex is formed when PCI1 and PCI2 are combined in cis as they occur in an intact phosphorylated Pol II molecule. Disrupting either PCI1 or PCI2 by alanine substitution or deletion diminishes CE association with Pol II and causes severe growth defects in vivo. Evidence from manipulating PCI1 indicates that the Foot domain contributes to the specificity in CE interaction with Pol II as opposed to Pol I and Pol III. Our results indicate that the dual interface based on combining PCI1 and PCI2 is required for directing CE to Pol II elongation complexes. PMID- 20720003 TI - The gene encoding the hematopoietic stem cell regulator CCN3/NOV is under direct cytokine control through the transcription factors STAT5A/B. AB - Cytokines control the biology of hematopoietic stem cells (HSCs) and progenitor cells in part through the transcription factors STAT5A/B. To investigate the target genes of STAT5A/B activated by cytokines in HSCs and progenitors, we performed microarray analyses using Lineage(-) Sca-1(+) c-Kit(+) (KSL) cells in the presence and absence of STAT5A/B. Stimulation with a mixture containing IL-3, IL-6, stem cell factor, thrombopoietin, and Flt3 ligand induced Ccn3/Nov mRNA over 100-fold in WT (control) but not Stat5a/b-null KSL cells. CCN3/NOV is a positive regulator of human HSC self-renewal and development of committed blood cells. Without stimulation, the Ccn3/Nov signal level was low in control KSL cells similar to Stat5a/b-null KSL cells. To determine which cytokine activates the Ccn3/Nov gene, we analyzed Lineage(-) c-Kit(+) (KL) and 32D cells using quantitative PCR and ChIP assays. Although stimulation with a mixture lacking IL 3 prevented the induction of Ccn3/Nov in control KL cells, IL-3 alone could induce Ccn3/Nov mRNA in control KL and 32D cells. ChIP assays using 32D cells revealed IL-3-induced binding of STAT5A/B to a gamma-interferon-activated sequences site in the Ccn3/Nov gene promoter. This is the first report that Ccn3/Nov is directly induced by cytokines through STAT5A/B. PMID- 20720004 TI - Activator-dependent p300 acetylation of chromatin in vitro: enhancement of transcription by disruption of repressive nucleosome-nucleosome interactions. AB - Condensation of chromatin into higher order structures is mediated by intra- and interfiber nucleosome-nucleosome interactions. Our goals in this study were to determine the impact specific activator-dependent histone acetylation had on chromatin condensation and to ascertain whether acetylation-induced changes in chromatin condensation were related to changes in RNA polymerase II (RNAPII) activity. To accomplish this, an in vitro model system was constructed in which the purified transcriptional activators, Tax and phosphorylated CREB (cAMP response element-binding protein), recruited the p300 histone acetyltransferase to nucleosomal templates containing the human T-cell leukemia virus type-1 promoter sequences. We find that activator-dependent p300 histone acetylation disrupted both inter- and intrafiber nucleosome-nucleosome interactions and simultaneously led to enhanced RNAPII transcription from the decondensed model chromatin. p300 histone acetyltransferase activity had two distinct components: non-targeted, ubiquitous activity in the absence of activators and activator dependent activity targeted primarily to promoter-proximal nucleosomes. Mass spectrometry identified several unique p300 acetylation sites on nucleosomal histone H3 (H3K9, H3K27, H3K36, and H3K37). Collectively, our data have important implications for understanding both the mechanism of RNAPII transcriptional regulation by chromatin and the molecular determinants of higher order chromatin structure. PMID- 20720005 TI - N-type calcium channel in the pathogenesis of experimental autoimmune encephalomyelitis. AB - One of the family of voltage-gated calcium channels (VGCC), the N-type Ca(2+) channel, is located predominantly in neurons and is associated with a variety of neuronal responses, including neurodegeneration. A precise mechanism for how the N-type Ca(2+) channel plays a role in neurodegenerative disease, however, is unknown. In this study, we immunized N-type Ca(2+) channel alpha(1B)-deficient (alpha(1B)(-/-)) mice and their wild type (WT) littermates with myelin oligodendrocyte glycoprotein 35-55 and analyzed the progression of experimental autoimmune encephalomyelitis (EAE). The neurological symptoms of EAE in the alpha(1B)(-/-) mice were less severe than in the WT mice. In conjunction with these results, sections of the spinal cord (SC) from alpha(1B)(-/-) mice revealed a reduction in both leukocytic infiltration and demyelination compared with WT mice. No differences were observed in the delayed-type hypersensitivity response, spleen cell proliferation, or cytokine production from splenocytes between the two genotypes. On the other hand, Western blot array analysis and RT-PCR revealed that a typical increase in the expression of MCP-1 in the SC showed a good correlation with the infiltration of leukocytes into the SC. Likewise, immunohistochemical analysis showed that the predominant source of MCP-1 was activated microglia. The cytokine-induced production of MCP-1 in primary cultured microglia from WT mice was significantly higher than that from alpha(1B)(-/-) mice and was significantly inhibited by a selective N-type Ca(2+) channel antagonist, omega-conotoxin GVIA or a withdrawal of extracellular Ca(2+). These results suggest that the N-type Ca(2+) channel is involved in the pathogenesis of EAE at least in part by regulating MCP-1 production by microglia. PMID- 20720006 TI - Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. AB - Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that preferentially targets motor neurons. It was recently found that dominant mutations in two related RNA-binding proteins, TDP-43 (43-kDa TAR DNA-binding domain protein) and FUS/TLS (fused in sarcoma/translated in liposarcoma) cause a subset of ALS. The convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations are suggestive of a functional relationship; however, whether or not TDP-43 and FUS/TLS operate in common biochemical pathways is not known. Here we show that TDP-43 and FUS/TLS directly interact to form a complex at endogenous expression levels in mammalian cells. Binding was mediated by an unstructured TDP 43 C-terminal domain and occurred within the context of a 300-400-kDa complex that also contained C-terminal cleavage products of TDP-43 linked to neuropathology. TDP-43 C-terminal fragments were excluded from large molecular mass TDP-43 ribonucleoprotein complexes but retained FUS/TLS binding activity. The functional significance of TDP-43-FUS/TLS complexes was established by showing that RNAi silencing of either TDP-43 or FUS/TLS reduced the expression of histone deacetylase (HDAC) 6 mRNA. TDP-43 and FUS/TLS associated with HDAC6 mRNA in intact cells and in vitro, and competition experiments suggested that the proteins occupy overlapping binding sites. The combined findings demonstrate that TDP-43 and FUS/TLS form a functional complex in intact cells and suggest that convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations may reflect their participation in common biochemical processes. PMID- 20720007 TI - TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a molecule capable of initiating the release of intracellular Ca(2+) required for many essential cellular processes. Recent evidence links two-pore channels (TPCs) with NAADP induced release of Ca(2+) from lysosome-like acidic organelles; however, there has been no direct demonstration that TPCs can act as NAADP-sensitive Ca(2+) release channels. Controversial evidence also proposes ryanodine receptors as the primary target of NAADP. We show that TPC2, the major lysosomal targeted isoform, is a cation channel with selectivity for Ca(2+) that will enable it to act as a Ca(2+) release channel in the cellular environment. NAADP opens TPC2 channels in a concentration-dependent manner, binding to high affinity activation and low affinity inhibition sites. At the core of this process is the luminal environment of the channel. The sensitivity of TPC2 to NAADP is steeply dependent on the luminal [Ca(2+)] allowing extremely low levels of NAADP to open the channel. In parallel, luminal pH controls NAADP affinity for TPC2 by switching from reversible activation of TPC2 at low pH to irreversible activation at neutral pH. Further evidence earmarking TPCs as the likely pathway for NAADP-induced intracellular Ca(2+) release is obtained from the use of Ned-19, the selective blocker of cellular NAADP-induced Ca(2+) release. Ned-19 antagonizes NAADP activation of TPC2 in a non-competitive manner at 1 MUM but potentiates NAADP activation at nanomolar concentrations. This single-channel study provides a long awaited molecular basis for the peculiar mechanistic features of NAADP signaling and a framework for understanding how NAADP can mediate key physiological events. PMID- 20720008 TI - Time of day and nutrients in feeding govern daily expression rhythms of the gene for sterol regulatory element-binding protein (SREBP)-1 in the mouse liver. AB - Sterol regulatory element-binding protein-1 (SREBP-1) plays a central role in transcriptional regulation of genes for hepatic lipid synthesis that utilizes diet-derived nutrients such as carbohydrates and amino acids, and expression of SREBP-1 exhibits daily rhythms with a peak in the nocturnal feeding period under standard housing conditions of mice. Here, we report that the Srebp-1 expression rhythm shows time cue-independent and Clock mutation-sensitive circadian nature, and is synchronized with varied photoperiods apparently through entrainment of locomotor activity and food intake. Fasting caused diminution of Srebp-1 expression, while diabetic db/db and ob/ob mice showed constantly high expression with loss of rhythmicity. Time-restricted feedings during mid-light and mid-dark periods exhibited differential effects, the latter causing more severe damping of the oscillation. Therefore, "when to eat in a day (the light/dark cycle)," rather than "whenever to eat in a day," is a critical determinant to shape the daily rhythm of Srebp-1 expression. We further found that a high-carbohydrate diet and a high-protein diet, as well as a high-fat diet, cause phase shifts of the oscillation peak into the light period, underlining the importance of "what to eat." Daily rhythms of SREBP-1 protein levels and Akt phosphorylation levels also exhibited nutrient-responsive changes. Taken together, these findings provide a model for mechanisms by which time of day and nutrients in feeding shape daily rhythms of the Srebp-1 expression and possibly a number of other physiological functions with interindividual and interdaily differences in human beings and wild animals subjected to day-by-day changes in dietary timing and nutrients. PMID- 20720009 TI - Transmembrane segments prevent surface expression of sodium channel Nav1.8 and promote calnexin-dependent channel degradation. AB - The voltage-gated sodium channel (Na(v)) 1.8 contributes substantially to the rising phase of action potential in small dorsal root ganglion neurons. Na(v)1.8 is majorly localized intracellularly and its expression on the plasma membrane is regulated by exit from the endoplasmic reticulum (ER). Previous work has identified an ER-retention/retrieval motif in the first intracellular loop of Na(v)1.8, which prevents its surface expression. Here we report that the transmembrane segments of Na(v)1.8 also cause this channel retained in the ER. Using transferrin receptor and CD8alpha as model molecules, immunocytochemistry showed that the first, second, and third transmembrane segments in each domain of Na(v)1.8 reduced their surface expression. Alanine-scanning analysis revealed acidic amino acids as critical factors in the odd transmembrane segments. Furthermore, co-immunoprecipitation experiments showed that calnexin interacted with acidic amino acid-containing sequences through its transmembrane segment. Overexpression of calnexin resulted in increased degradation of those proteins through the ER-associated degradation pathway, whereas down-regulation of calnexin reversed the phenotype. Thus our results reveal a critical role and mechanism of transmembrane segments in surface expression and degradation of Na(v)1.8. PMID- 20720010 TI - ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells. AB - Loss of the q22 band of chromosome 16 is a frequent genetic event in breast cancer, and the candidate tumor suppressor gene, ATBF1, has been implicated in breast cancer by genomic deletion, transcriptional down-regulation, and association with better prognostic parameters. In addition, estrogen receptor (ER)-positive breast cancer expresses a higher level of ATBF1, suggesting a role of ATBF1 in ER-positive breast cancer. In this study, we examined whether and how ATBF1 affects the ER function in breast cancer cells. We found that ATBF1 inhibited ER-mediated gene transcription, cell growth, and proliferation in ER positive breast cancer cells. In vitro and in vivo immunoprecipitation experiments revealed that ATBF1 interacted physically with the ER and that multiple domains in both ATBF1 and ER proteins mediated the interaction. Furthermore, we demonstrated that ATBF1 inhibited ER function by selectively competing with the steroid receptor coactivator AIB1 but not GRIP1 or SRC1 for binding to the ER. These findings not only support the concept that ATBF1 plays a tumor-suppressive role in breast cancer, they also provide a mechanism for how ATBF1 functions as a tumor suppressor in breast cancer. PMID- 20720011 TI - Factors from human embryonic stem cell-derived fibroblast-like cells promote topology-dependent hepatic differentiation in primate embryonic and induced pluripotent stem cells. AB - The future clinical use of embryonic stem cell (ESC)-based hepatocyte replacement therapy depends on the development of an efficient procedure for differentiation of hepatocytes from ESCs. Here we report that a high density of human ESC-derived fibroblast-like cells (hESdFs) supported the efficient generation of hepatocyte like cells with functional and mature hepatic phenotypes from primate ESCs and human induced pluripotent stem cells. Molecular and immunocytochemistry analyses revealed that hESdFs caused a rapid loss of pluripotency and induced a sequential endoderm-to-hepatocyte differentiation in the central area of ESC colonies. Knockdown experiments demonstrated that pluripotent stem cells were directed toward endodermal and hepatic lineages by FGF2 and activin A secreted from hESdFs. Furthermore, we found that the central region of ESC colonies was essential for the hepatic endoderm-specific differentiation, because its removal caused a complete disruption of endodermal differentiation. In conclusion, we describe a novel in vitro differentiation model and show that hESdF-secreted factors act in concert with regional features of ESC colonies to induce robust hepatic endoderm differentiation in primate pluripotent stem cells. PMID- 20720012 TI - A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5-p25 hyperactivity and tau hyperphosphorylation. AB - The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by Abeta peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or Abeta induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys(245)-Ala(277). p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced Abeta(1-42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases. PMID- 20720013 TI - Structure of hepatitis E virion-sized particle reveals an RNA-dependent viral assembly pathway. AB - Hepatitis E virus (HEV) induces acute hepatitis in humans with a high fatality rate in pregnant women. There is a need for anti-HEV research to understand the assembly process of HEV native capsid. Here, we produced a large virion-sized and a small T=1 capsid by expressing the HEV capsid protein in insect cells with and without the N-terminal 111 residues, respectively, for comparative structural analysis. The virion-sized capsid demonstrates a T=3 icosahedral lattice and contains RNA fragment in contrast to the RNA-free T=1 capsid. However, both capsids shared common decameric organization. The in vitro assembly further demonstrated that HEV capsid protein had the intrinsic ability to form decameric intermediate. Our data suggest that RNA binding is the extrinsic factor essential for the assembly of HEV native capsids. PMID- 20720014 TI - Regulation of constitutive cargo transport from the trans-Golgi network to plasma membrane by Golgi-localized G protein betagamma subunits. AB - Observations of Golgi fragmentation upon introduction of G protein betagamma (Gbetagamma) subunits into cells have implicated Gbetagamma in a pathway controlling the fission at the trans-Golgi network (TGN) of plasma membrane (PM) destined transport carriers. However, the subcellular location where Gbetagamma acts to provoke Golgi fragmentation is not known. Additionally, a role for Gbetagamma in regulating TGN-to-PM transport has not been demonstrated. Here we report that constitutive or inducible targeting of Gbetagamma to the Golgi, but not other subcellular locations, causes phospholipase C- and protein kinase D dependent vesiculation of the Golgi in HeLa cells; Golgi-targeted beta(1)gamma(2) also activates protein kinase D. Moreover, the novel Gbetagamma inhibitor, gallein, and the Gbetagamma-sequestering protein, GRK2ct, reveal that Gbetagamma is required for the constitutive PM transport of two model cargo proteins, VSV-G and ss-HRP. Importantly, Golgi-targeted GRK2ct, but not a PM-targeted GRK2ct, also blocks protein transport to the PM. To further support a role for Golgi localized Gbetagamma, endogenous Gbeta was detected at the Golgi in HeLa cells. These results are the first to establish a role for Golgi-localized Gbetagamma in regulating protein transport from the TGN to the cell surface. PMID- 20720015 TI - Structure and functional analysis of LptC, a conserved membrane protein involved in the lipopolysaccharide export pathway in Escherichia coli. AB - LptC is a conserved bitopic inner membrane protein from Escherichia coli involved in the export of lipopolysaccharide from its site of synthesis in the cytoplasmic membrane to the outer membrane. LptC forms a complex with the ATP-binding cassette transporter, LptBFG, which is thought to facilitate the extraction of lipopolysaccharide from the inner membrane and release it into a translocation pathway that includes the putative periplasmic chaperone LptA. Cysteine modification experiments established that the catalytic domain of LptC is oriented toward the periplasm. The structure of the periplasmic domain is described at a resolution of 2.2-A from x-ray crystallographic data. The periplasmic domain of LptC consists of a twisted boat structure with two beta sheets in apposition to each other. The beta-sheets contain seven and eight antiparallel beta-strands, respectively. This structure bears a high degree of resemblance to the crystal structure of LptA. Like LptA, LptC binds lipopolysaccharide in vitro. In vitro, LptA can displace lipopolysaccharide from LptC (but not vice versa), consistent with their locations and their proposed placement in a unidirectional export pathway. PMID- 20720016 TI - Cpl-7, a lysozyme encoded by a pneumococcal bacteriophage with a novel cell wall binding motif. AB - Bacteriophage endolysins include a group of new antibacterials reluctant to development of resistance. We present here the first structural study of the Cpl 7 endolysin, encoded by pneumococcal bacteriophage Cp-7. It contains an N terminal catalytic module (CM) belonging to the GH25 family of glycosyl hydrolases and a C-terminal region encompassing three identical repeats of 42 amino acids (CW_7 repeats). These repeats are unrelated to choline-targeting motifs present in other cell wall hydrolases produced by Streptococcus pneumoniae and its bacteriophages, and are responsible for the protein attachment to the cell wall. By combining different biophysical techniques and molecular modeling, a three-dimensional model of the overall protein structure is proposed, consistent with circular dichroism and sequence-based secondary structure prediction, small angle x-ray scattering data, and Cpl-7 hydrodynamic behavior. Cpl-7 is an ~115-A long molecule with two well differentiated regions, corresponding to the CM and the cell wall binding region (CWBR), arranged in a lateral disposition. The CM displays the (betaalpha)(5)beta(3) barrel topology characteristic of the GH25 family, and the impact of sequence differences with the CM of the Cpl-1 lysozyme in substrate binding is discussed. The CWBR is organized in three tandemly assembled three-helical bundles whose dispositions remind us of a super-helical structure. Its approximate dimensions are 60 * 20 * 20 A and presents a concave face that might constitute the functional region involved in bacterial surface recognition. The distribution of CW_7 repeats in the sequences deposited in the Entrez Database have been examined, and the results drastically expanded the antimicrobial potential of the Cpl-7 endolysin. PMID- 20720017 TI - Structure and function of the hetero-oligomeric cysteine synthase complex in plants. AB - Cysteine synthesis in bacteria and plants is catalyzed by serine acetyltransferase (SAT) and O-acetylserine (thiol)-lyase (OAS-TL), which form the hetero-oligomeric cysteine synthase complex (CSC). In plants, but not in bacteria, the CSC is assumed to control cellular sulfur homeostasis by reversible association of the subunits. Application of size exclusion chromatography, analytical ultracentrifugation, and isothermal titration calorimetry revealed a hexameric structure of mitochondrial SAT from Arabidopsis thaliana (AtSATm) and a 2:1 ratio of the OAS-TL dimer to the SAT hexamer in the CSC. Comparable results were obtained for the composition of the cytosolic SAT from A. thaliana (AtSATc) and the cytosolic SAT from Glycine max (Glyma16g03080, GmSATc) and their corresponding CSCs. The hexameric SAT structure is also supported by the calculated binding energies between SAT trimers. The interaction sites of dimers of AtSATm trimers are identified using peptide arrays. A negative Gibbs free energy (DeltaG = -33 kcal mol(-1)) explains the spontaneous formation of the AtCSCs, whereas the measured SAT:OAS-TL affinity (K(D) = 30 nm) is 10 times weaker than that of bacterial CSCs. Free SAT from bacteria is >100-fold more sensitive to feedback inhibition by cysteine than AtSATm/c. The sensitivity of plant SATs to cysteine is further decreased by CSC formation, whereas the feedback inhibition of bacterial SAT by cysteine is not affected by CSC formation. The data demonstrate highly similar quaternary structures of the CSCs from bacteria and plants but emphasize differences with respect to the affinity of CSC formation (K(D)) and the regulation of cysteine sensitivity of SAT within the CSC. PMID- 20720018 TI - gamma-Tocotrienol but not gamma-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents. AB - Although gamma-tocotrienol (T3), a vitamin E isolated primarily from palm and rice bran oil, has been linked with anticancer activities, the mechanism of this action is poorly understood. In this study, we investigated whether gamma-T3 can modulate the STAT3 cell signaling pathway, closely linked to inflammation and tumorigenesis. We found that gamma-T3 but not gamma-tocopherol, the most common saturated form of vitamin E, inhibited constitutive activation of STAT3 in a dose and time-dependent manner, and this inhibition was not cell type-specific. gamma T3 also inhibited STAT3 DNA binding. This correlated with inhibition of Src kinase and JAK1 and JAK2 kinases. Pervanadate reversed the gamma-T3-induced down regulation of STAT3 activation, suggesting the involvement of a protein-tyrosine phosphatase. When examined further, we found that gamma-T3 induced the expression of the tyrosine phosphatase SHP-1, and gene silencing of the SHP-1 by small interfering RNA abolished the ability of gamma-T3 to inhibit STAT3 activation, suggesting a vital role for SHP-1 in the action of gamma-T3. Also gamma-T3 down modulated activation of STAT3 and induced SHP-1 in vivo. Eventually, gamma-T3 down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of the cell cycle, and induction of apoptosis. This vitamin also sensitized the tumor cells to the apoptotic effects of thalidomide and bortezomib. Overall, our results suggest that gamma-T3 is a novel blocker of STAT3 activation pathway both in vitro and in vivo and thus may have potential in prevention and treatment of cancers. PMID- 20720019 TI - Nuclear-localized calcineurin homologous protein CHP1 interacts with upstream binding factor and inhibits ribosomal RNA synthesis. AB - Calcineurin homologous protein 1 (CHP1) is a widely expressed, 22-kDa myristoylated EF-hand Ca(2+)-binding protein that shares a high degree of similarity with the regulatory B subunit of calcineurin (65%) and with calmodulin (59%). CHP1 localizes to the plasma membrane, the Golgi apparatus, and the nucleus and functions to regulate trafficking of early secretory vesicles, activation of T cells, and expression and transport of the Na-H exchanger NHE1. Although CHP1 contains nuclear export signals, whether its nuclear and cytoplasmic localization is regulated and has distinct functions remain unknown. We show that CHP1 is predominantly in the nucleus in quiescent fibroblasts, is translocated to cytoplasmic compartments with growth medium, and that translocation is inhibited by mutations in the nuclear export motifs. In a screen for proteins co-precipitating with CHP1 in quiescent cells we identified the upstream binding factor UBF, a DNA-binding protein and component of the RNA polymerase I complex regulating RNA synthesis. The CHP1-UBF interaction is restricted to the nucleus and inhibited by Ca(2+). Nuclear retention of CHP1 attenuates the abundance of UBF in the nucleolus and inhibits RNA synthesis when quiescent cells are transferred to growth medium. These data show UBF as a newly identified CHP1-binding protein and regulation of RNA synthesis as a newly identified function for nuclear-localized CHP1, which is distinct from CHP1 functions in the cytosol. PMID- 20720020 TI - CTX-M1 ESBL-producing Klebsiella pneumoniae subsp. pneumoniae isolated from cases of bovine mastitis. PMID- 20720021 TI - Poor positive accuracy of QuickVue rapid antigen tests during the influenza A (H1N1) 2009 pandemic. AB - We assessed the accuracy of positive QuickVue rapid influenza virus antigen test results. Using reverse transcription (RT)-PCR as the gold standard, 17 (37.8%) of 45 QuickVue-positive specimens were determined to be false positives. We report an unexpectedly high rate of false-positive QuickVue results during a period of high influenza A (H1N1) 2009 virus prevalence. PMID- 20720022 TI - Mycoplasma genitalium PCR: does freezing of specimens affect sensitivity? AB - Mycoplasma genitalium is an established cause of sexually transmitted infections. Studies of disease associations are often performed on archived specimens, but little is known about the effect of storage of specimens on the detection of M. genitalium. Genital swab and first-void urine specimens submitted for detection of M. genitalium were tested on the day of receipt. Remnants of positive original specimens as well as DNA preparations were stored at -20 degrees C for up to 18 months. A total of 361 M. genitalium-positive specimens were available. PCR after repeat DNA preparation was performed for 262 specimens. The sensitivity after repeat DNA preparation was 90%, and the median decrease in DNA load was 155 genome equivalents (geq) (P < 0.0001). For 327 specimens, PCR could be repeated on the primary DNA preparation. The sensitivity of PCR after storage was 95%, and the median decrease in DNA load was 13.5 geq (P < 0.0001). The specimens yielding negative results at repeat testing had a significantly lower median DNA load in the primary analysis than those with a repeat positive test (P < 0.0001). For 228 specimens, PCR could be performed both on the primary DNA preparation and after repeat DNA preparation. The median DNA load was lower after repeat DNA extraction than after repeat testing of the stored DNA extract (P < 0.0001). In conclusion, the M. genitalium DNA load as well as the detection rate decreased after storage. This was more pronounced in clinical specimens stored frozen than in stored DNA extracts, particularly in those with an initial low DNA load. PMID- 20720023 TI - Assessment of Clostridium difficile infections by quantitative detection of tcdB toxin by use of a real-time cell analysis system. AB - We explored the use of a real-time cell analysis (RTCA) system for the assessment of Clostridium difficile toxins in human stool specimens by monitoring the dynamic responses of the HS27 cells to tcdB toxins. The C. difficile toxin caused cytotoxic effects on the cells, which resulted in a dose-dependent and time dependent decrease in cell impedance. The RTCA assay possessed an analytical sensitivity of 0.2 ng/ml for C. difficile toxin B with no cross-reactions with other enterotoxins, nontoxigenic C. difficile, or other Clostridum species. Clinical validation was performed on 300 consecutively collected stool specimens from patients with suspected C. difficile infection (CDI). Each stool specimen was tested in parallel by a real-time PCR assay (PCR), a dual glutamate dehydrogenase and toxin A/B enzyme immunoassay (EIA), and the RTCA assay. In comparison to a reference standard in a combination of the three assays, the RTCA had a specificity of 99.6% and a sensitivity of 87.5% (28 of 32), which was higher than the EIA result (P = 0.005) but lower than the PCR result (P = 0.057). In addition, the RTCA assay allowed for quantification of toxin protein concentration in a given specimen. Among RTCA-positive specimens collected prior to treatment with metronidazole and/or vancomycin, a significant correlation between toxin protein concentrations and clinical CDI severities was observed (R(2) = 0.732, P = 0.0004). Toxin concentrations after treatment (0.89 ng/ml) were significantly lower than those prior to the treatment (15.68 ng/ml, Wilcoxon P = 0.01). The study demonstrates that the RTCA assay provides a functional tool for the potential assessment of C. difficile infections. PMID- 20720024 TI - Multiplex blood PCR in combination with blood cultures for improvement of microbiological documentation of infection in febrile neutropenia. AB - The frequent lack of microbiological documentation of infection by blood cultures (BC) has a major impact on clinical management of febrile neutropenic patients, especially in cases of unexplained persistent fever. We assessed the diagnostic utility of the LightCycler SeptiFast test (SF), a multiplex blood PCR, in febrile neutropenia. Blood for BC and SF was drawn at the onset of fever and every 3 days of persistent fever. SF results were compared with those of BC, clinical documentation of infection, and standard clinical, radiological, and microbiological criteria for invasive fungal infections (IFI). A total of 141 febrile neutropenic episodes in 86 hematological patients were studied: 44 (31%) microbiologically and 49 (35%) clinically documented infections and 48 (34%) unexplained fevers. At the onset of fever, BC detected 44 microorganisms in 35/141 (25%) episodes. Together, BC and SF identified 78 microorganisms in 61/141 (43%) episodes (P = 0.002 versus BC or SF alone): 12 were detected by BC and SF, 32 by BC only, and 34 by SF only. In 19/52 (37%) episodes of persistent fever, SF detected 28 new microorganisms (7 Gram-positive bacterial species, 15 Gram negative bacterial species, and 6 fungal species [89% with a clinically documented site of infection]) whereas BC detected only 4 pathogens (8%) (P = 0.001). While BC did not detect fungi, SF identified 5 Candida spp. and 1 Aspergillus sp. in 5/7 probable or possible cases of IFI. Using SeptiFast PCR combined with blood cultures improves microbiological documentation in febrile neutropenia, especially when fever persists and invasive fungal infection is suspected. Technical adjustments may enhance the efficiency of this new molecular tool in this specific setting. PMID- 20720025 TI - The (1,3){beta}-D-glucan test as an aid to early diagnosis of invasive fungal infections following lung transplantation. AB - The Fungitell assay for (1,3)beta-D-glucan (BG) detection in serum has been evaluated in patients with invasive fungal infections (IFIs) and healthy controls and for the early diagnosis of IFI in cancer patients. We evaluated the BG assay for the detection of IFI in lung transplant recipients. Serial serum samples were prospectively collected from patients undergoing lung transplants at Duke Hospital. Fungal infections were classified according to revised European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. A receiver operator characteristic (ROC) curve was generated; possible causes for false-positive and false-negative tests were investigated by linear regression analysis. Seven hundred fifty-six serum specimens from 59 subjects without IFI and 41 specimens from 14 patients with proven or probable IFI were tested. The area under the ROC curve was 0.69. Based on a 60-pg/ml positive cutoff, per patient sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 64%, 9%, 14%, and 50%, respectively; per-test estimates were 71%, 59%, 9%, and 97%, respectively. The majority (92%) of patients not diagnosed with an IFI had at least one BG level of >=60 pg/ml, and 90% had at least one BG level of >=80 pg/ml. Respiratory colonization with mold and hemodialysis significantly affected mean BG levels. In conclusion, the accuracy of the BG test is marginal and its utility as a tool for the early diagnosis of IFI is questionable in the lung transplant population. Although the NPV of the BG test is high, the low PPV limits its utility as a screening tool for early diagnosis of IFI. PMID- 20720026 TI - Critical stages of extracting DNA from Aspergillus fumigatus in whole-blood specimens. AB - A standardized protocol for extracting DNA from Aspergillus fumigatus has been proposed by the European Aspergillus PCR Initiative (EAPCRI). Using meta regression analysis, the EAPCRI showed certain stages of the process to be critical to providing a satisfactory analytical sensitivity. The study investigated each step of the EAPCRI protocol by elimination and monitored the influence on Aspergillus PCR performance. PMID- 20720027 TI - Use of FTA cards for direct sampling of patients' lesions in the ecological study of cutaneous leishmaniasis. AB - The FTA card (Whatman) was assessed for its utility as a molecular epidemiological tool in collecting samples from patients with leishmaniasis in Peru because the card has a variety of merits; it is less invasive for patients and easy to handle for both physicians and other medical personnel for sample collection or diagnosis, in addition to its simplicity and easy countrywide and/or intercountry transportation for analysis. Samples were collected from 132 patients suspected of having leishmaniasis, and Leishmania species were successfully identified in samples from 81 patients in 15 departments of Peru by cytochrome b and mannose phosphate isomerase gene analyses. Of these, 61.7% were identified as Leishmania (Viannia) peruviana, 22.2% as L. (V.) braziliensis, 12.3% as L. (V.) guyanensis, 2.5% as L. (V.) shawi, and 1.2% as L. (V.) lainsoni. The three predominant species, L. (V.) peruviana, L. (V.) braziliensis, and L. (V.) guyanensis, were mainly found in the Andean highlands, in the tropical rainforest, and in northern and central rainforest regions, respectively. This is the first time L. (V.) shawi has been identified outside Brazil. The present study showed that the FTA card will be a useful tool for the ecological study of different forms of leishmaniasis. Furthermore, collecting samples directly from patients' lesions by using the FTA card eliminates (i) the possibility of contamination of Leishmania isolates during short- and/or long-term passages of culture in vitro in each laboratory and (ii) pain and suffering of patients from taking samples by skin biopsy. PMID- 20720028 TI - Strains of Mycobacterium tuberculosis from western Maharashtra, India, exhibit a high degree of diversity and strain-specific associations with drug resistance, cavitary disease, and treatment failure. AB - We performed spoligotyping of Mycobacterium tuberculosis isolates from 833 systematically sampled pulmonary tuberculosis (TB) patients in urban Mumbai, India (723 patients), and adjacent rural areas in western India (110 patients). The urban cohort consisted of two groups of patients, new cases (646 patients) and first-time treatment failures (77 patients), while only new cases were recruited in the rural areas. The isolates from urban new cases showed 71% clustering, with 168 Manu1, 62 CAS, 22 Beijing, and 30 EAI-5 isolates. The isolates from first-time treatment failures were 69% clustered, with 14 Manu1, 8 CAS, 8 Beijing, and 6 EAI-5 isolates. The proportion of Beijing strains was higher in this group than in urban new cases (odds ratio [OR], 3.29; 95% confidence limit [95% CL], 1.29 to 8.14; P = 0.003). The isolates from rural new cases showed 69% clustering, with 38 Manu1, 7 CAS, and 1 EAI-5 isolate. Beijing was absent in the rural cohort. Manu1 was found to be more common in the rural cohort (OR, 0.67; 95% CL, 0.42 to 1.05; P = 0.06). In total, 71% of isolates were clustered into 58 spoligotypes with 4 predominant strains, Manu1 (26%), CAS (9%), EAI-5 (4%), and Beijing (4%), along with 246 unique spoligotypes. In the isolates from urban new cases, we found Beijing to be associated with multidrug resistance (MDR) (OR, 3.40; 95% CL, 1.20 to 9.62; P = 0.02). CAS was found to be associated with pansensitivity (OR, 1.83; 95% CL, 1.03 to 3.24; P = 0.03) and cavities as seen on chest radiographs (OR, 2.72; 95% CL, 1.34 to 5.53; P = 0.006). We recorded 239 new spoligotypes yet unreported in the global databases, suggesting that the local TB strains exhibit a high degree of diversity. PMID- 20720029 TI - Polymicrobial bloodstream infection with Eggerthella lenta and Desulfovibrio desulfuricans. AB - The advancement in culture identification methods has made possible the culture and identification of slow-growing anaerobic bacteria in clinical samples. Here, we describe a case of polymicrobial bloodstream infection (BSI) caused by Eggerthella lenta and Desulfovibrio desulfuricans, identified by API 20A and Vitek 2 systems and by 16S rRNA sequencing. PMID- 20720030 TI - Development of a rapid ATP bioluminescence assay for biocidal susceptibility testing of rapidly growing mycobacteria. AB - An ATP-based biocide susceptibility assay for mycobacteria was developed by optimizing the cell lysis and assay conditions. Compared to the conventional agar plating method, the assay was rapid (1.5 h) and showed high sensitivity and specificity as determined by receiver operating characteristic (ROC) analysis. The test species, Mycobacterium immunogenum, M. chelonae, and M. abscessus, showed various susceptibilities to the glutaraldehyde- and isothiazolone-based test biocides. PMID- 20720031 TI - Performance of version 2.0 of the Cobas AmpliPrep/Cobas TaqMan real-time PCR assay for hepatitis B virus DNA quantification. AB - The detection and quantification of hepatitis B virus (HBV) DNA are essential for the diagnosis and treatment of chronic HBV infection. The use of real-time PCR assays for HBV DNA quantification is strongly recommended. The goal of this study was to evaluate the intrinsic characteristics and clinical performance of version 2.0 (v2.0) of the Cobas AmpliPrep/Cobas TaqMan (CAP/CTM) assay, a fully automated platform for HBV DNA quantification in serum or in plasma with a claimed lower limit of detection of 20 IU/ml and a claimed upper limit of quantification of 1.7 * 10(8) IU/ml. The specificity of the assay was 99% (95% confidence interval, 94.7 to 100%). Intra-assay and interassay coefficients of variation ranged from 0.21% to 2.67% and from 0.65% to 2.25%, respectively. The calibration of the assay was found to be satisfactory. Study of blood specimens from patients infected with HBV genotypes A to F showed good correspondence between HBV DNA levels measured by the CAP/CTM v2.0 assay, version 1.0 of the same assay, and the third-generation "branched DNA" assay. The CAP/CTM v2.0 assay quantified HBV DNA levels in serum or plasma from the same patients equally. In conclusion, the new version of the CAP/CTM assay is sensitive, specific, and reproducible. It accurately quantifies HBV DNA levels in patients chronically infected with HBV genotypes A to F. Improvements made to ensure equal quantification of HBV DNA in serum and plasma have been successful. Overall, the CAP/CTM assay, version 2.0, is well suited to monitoring clinical HBV DNA levels according to current clinical practice guidelines. PMID- 20720032 TI - Simultaneous genotyping and quantification of hepatitis B virus for genotypes B and C by real-time PCR assay. AB - Hepatitis B virus (HBV) is an important cause of human chronic liver diseases and is a major public health problem. Viral load and HBV genotype play critical roles in determining clinical outcomes and response to antiviral treatment in hepatitis B patients. Viral genotype detection and quantification assays are currently in use with different levels of effectiveness. In this study, the performance of a real-time genotyping and quantitative PCR (GQ-PCR)-based assay was evaluated. Through the use of genotype-specific primers and probes, this assay provides simultaneous identification and quantification of genotypes B and C in a single reaction. Our GQ-PCR correctly identified all predefined genotypes B and C, and no cross-reaction between genotypes B and C were observed. The GQ-PCR identified more cases of HBV infections with mixed genotypes B and C than direct sequencing did. Samples from 127 HBV-infected Chinese patients were genotyped with GQ-PCR, revealing 56.7% HBV as genotype B, 13.4% as genotype C, and 29.8% as mixed genotypes B and C. This assay provides a reliable, efficient, and cost-effective means for quantification of the B and C genotypes of HBV in single or mixed infections. This assay is suitable for sequential monitoring of viral load levels and for determining the relationship between the genotype viral load and stage of disease in Asians. PMID- 20720033 TI - Containment of bioaerosol infection risk by the Xpert MTB/RIF assay and its applicability to point-of-care settings. AB - The recently introduced Xpert MTB/RIF assay (Xpert) has point-of-care potential, but its capacity for biohazard containment remained to be studied. We compared the bioaerosols generated by the Xpert assay to acid-fast bacillus (AFB) microscope slide smear preparation. The Xpert assay sample treatment reagent (SR) was also studied for its sterilizing capacity, stability, and effect on assay sensitivity after prolonged treatment. During the preparation of AFB smears, sputum samples spiked with Mycobacterium bovis BCG at 5 * 10(8) CFU/ml produced 16 and 325 CFU/m(3) air measured with an Andersen impactor or BioSampler, respectively. In contrast, neither the sample preparation steps for the Xpert assay nor its automated processing produced any culturable bioaerosols. In testing of SR sterilizing capacity, clinical sputum samples from strongly smear positive tuberculosis patients treated with SR at a 2:1 ratio eliminated Mycobacterium tuberculosis growth in all but 1/39 or 3/45 samples cultured on solid or liquid medium, respectively. These few unsterilized samples had a mean 13.1-day delay in the time to positive culture. SR treatment at a 3:1 ratio eliminated growth in all samples. SR retained a greater than 6-log-unit killing capacity despite storage at temperatures spanning 4 to 45 degrees C for at least 3 months. The effect of prolonged SR sample treatment was also studied. Spiked sputum samples could be incubated in SR for up to 3 days without affecting Xpert sensitivity for M. tuberculosis detection and up to 8 h without affecting specificity for rifampin resistance detection. These results suggest that benchtop use of the Xpert MTB/RIF assay limits infection risk to the user. PMID- 20720034 TI - Electronic-nose technology using sputum samples in diagnosis of patients with tuberculosis. AB - We investigated the potential of two different electronic noses (EN; code named "Rob" and "Walter") to differentiate between sputum headspace samples from tuberculosis (TB) patients and non-TB patients. Only samples from Ziehl-Neelsen stain (ZN)- and Mycobacterium tuberculosis culture-positive (TBPOS) sputum samples and ZN- and culture-negative (TBNEG) samples were used for headspace analysis; with EN Rob, we used 284 samples from TB suspects (56 TBPOS and 228 TBNEG samples), and with EN Walter, we used 323 samples from TB suspects (80 TBPOS and 243 TBNEG samples). The best results were obtained using advanced data extraction and linear discriminant function analysis, resulting in a sensitivity of 68%, a specificity of 69%, and an accuracy of 69% for EN Rob; for EN Walter, the results were 75%, 67%, and 69%, respectively. Further research is still required to improve the sensitivity and specificity by choosing more selective sensors and type of sampling technique. PMID- 20720035 TI - Biodistribution and uptake of 3'-deoxy-3'-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model. AB - (18)F-3'-Deoxy-3'-fluorothymidine ((18)F-FLT) is a PET tracer that accumulates in proliferating tissues. The current study was undertaken to determine whether equilibrative nucleoside transporter 1 (ENT1) is important for (18)F-FLT uptake in normal tissues and tumors. METHODS: ENT1-knockout (ENT1(-/-)) mice were generated and compared with wild-type (ENT1(+/+)) mice using small-animal (18)F FLT PET. In addition, ENT1(+/+) mice were also injected with the ENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside phosphate (NBMPR-P) at 1 h before radiotracer injection, followed by (18)F-FLT small-animal PET. Tissues of interest were analyzed for thymidine kinase 1 and nucleoside transporters by immunoblotting and immunohistochemistry, respectively, and plasma thymidine levels were analyzed by liquid chromatography-mass spectrometry. Human lung carcinoma A549 cells were stably transfected with pSUPER-producing short-hairpin RNA against human ENT1 (hENT1) or a scrambled sequence with no homology to mammalian genes (A549-pSUPER-hENT1 and A549-pSUPER-SC, respectively). Cultured transfected cells were characterized for hENT1 transcript levels and (18)F-FLT uptake using real-time polymerase chain reaction and (3)H-FLT uptake assays, respectively. Transfected A549 cells were grown as xenograft tumors in NIH-III mice, which were analyzed by (18)F-FLT small-animal PET. RESULTS: Compared with noninjected ENT1(+/+) mice, ENT1(+/+) mice injected with NBMPR-P and ENT1(-/-) mice displayed a reduced percentage injected dose per gram (%ID/g) for (18)F-FLT in the blood (84 and 81%, respectively) and an increased %ID/g for (18)F-FLT in the spleen (188 and 469%, respectively) and bone marrow (266 and 453%, respectively). ENT1(-/-) mice displayed 1.65-fold greater plasma thymidine levels than did ENT1(+/+) mice. Spleen tissue from ENT1(+/+) and ENT1(-/-) mice displayed similar thymidine kinase 1 protein levels and significant concentrative nucleoside transporter 1 and 3 staining. Compared with A549-pSUPER-SC cells, A549 pSUPER-hENT1 cells displayed 0.45-fold hENT1 transcript levels and 0.68-fold (3)H FLT uptake. Compared with A549-pSUPER-SC xenograft tumors, A549-pSUPER-hENT1 xenograft tumors displayed 0.76-fold %ID/g values (ex vivo gamma-counts) and 0.65 fold maximum standardized uptake values (PET image analysis) for (18)F-FLT uptake at 1 h after tracer injection. CONCLUSION: Loss of ENT1 activity significantly affected (18)F-FLT biodistribution in mice and (18)F-FLT uptake in xenograft tumors, suggesting that nucleoside transporters are important mediators of (18)F FLT uptake in normal and transformed cells. PMID- 20720036 TI - 18F-FDG PET after 2 cycles of ABVD predicts event-free survival in early and advanced Hodgkin lymphoma. AB - Our objective was to assess the prognostic value of (18)F-FDG PET after 2 cycles of chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in Hodgkin lymphoma (HL) patients overall and in subgroups of patients with early and advanced stages and with low and high risks according to the International Prognostic Score (IPS). METHODS: One hundred fifteen patients with newly diagnosed HL were prospectively included in the study. All underwent standard ABVD therapy followed by consolidation radiotherapy in cases of bulky disease. After 2 cycles of ABVD, the patients were evaluated with PET (PET2). Prognostic analysis compared the 3-y event-free survival (EFS) rate to the PET2 results, clinical data, and IPS. RESULTS: Of the 104 evaluated patients, 93 achieved complete remission after first-line therapy. During a median follow-up of 36 mo, relapse or disease progression was seen in 22 patients. Treatment failure was seen in 16 of the 30 PET2-positive patients and in only 6 of the 74 PET2-negative patients. PET2 was the only significant prognostic factor. The 3-y EFS was 53.4% for PET2-positive patients and 90.5% for PET2-negative ones (P < 0.001). When patients were categorized according to low or high IPS risk and according to early or advanced stage of disease, PET2 was also significantly associated with treatment outcome. CONCLUSION: PET2 is an accurate and independent predictor of EFS in HL. A negative interim (18)F-FDG PET result is highly predictive of treatment success in overall HL patients, as well as in subgroups with early or advanced-stage disease and with low or high IPS risk. PMID- 20720038 TI - Cellular dosimetry using the Geant4 Monte Carlo toolkit. PMID- 20720039 TI - The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. AB - Animal experiments suggest that 2 different types of activated microglia (AMG) cells occur in the brain after a stroke: local AMG in the area of the infarct and remote AMG, which occurs along affected fiber tracts. We used (11)C-PK11195 PET to image AMG in vivo after stroke in humans in a prospective longitudinal study to investigate the temporal dynamics of AMG and relate local and remote AMG activity to pyramidal tract (PT) damage using diffusion tensor imaging (DTI). METHODS: Eighteen patients underwent DTI-MRI, (11)C-PK11195 PET, and behavioral testing within 2 wk and 6 mo of acute subcortical stroke. In 12 patients, the PT was affected by the stroke (PT group), and in 6 patients it was not (non-PT group). Standardized volumes of interest (VOIs) were placed along the PT at the level of the brain stem, semioval center, and infarct. Tracer uptake ratios (ipsilateral to contralateral) were calculated for each VOI and related to tract damage (measured as fractional anisotropy ratio) and clinical outcome. Six controls underwent the same protocol but only once. RESULTS: In both patient groups, local AMG activity in the infarct was increased initially and significantly decreased over the follow-up period. In contrast, remote AMG was detected only in the PT group in the brain stem along the affected tract and persisted during follow-up. No AMG was observed retrograde to the lesion at any time. Remote AMG activity along the affected PT in the brain stem correlated with initial PT damage as measured by DTI in the same tract portion. Local AMG activity in the infarct correlated with anterograde PT damage only at follow-up. After controlling for PT damage, initial AMG activity in the brain stem showed a positive correlation with clinical outcome, whereas persisting AMG activity in the infarct tended to be negatively correlated. CONCLUSION: DTI-guided (11)C PK11195 PET in acute subcortical stroke demonstrates differential temporal dynamics of local and remote AMG. Activity of both types related to anterograde PT damage as measured by DTI and might contribute differently to clinical outcome. PMID- 20720042 TI - Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV 133): a novel vesicular monoamine transporter 2 imaging agent. AB - Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-(18)F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-FP-(+)-dihydrotetrabenazine [DTBZ] or (18)F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use. METHODS: Nine healthy human subjects (mean age +/- SD, 58.6 +/- 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 +/- 22.9 MBq of (18)F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs. RESULTS: The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% +/- 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 +/- 23.8 microGy/MBq, was the pancreas. The effective dose equivalent and effective dose for (18)F-AV-133 were 36.5 +/- 2.8 and 27.8 +/- 2.5 microSv/MBq, respectively. These values are comparable to those reported for any other (18)F-labeled radiopharmaceutical. CONCLUSION: (18)F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans. PMID- 20720043 TI - 11C-dihydrotetrabenazine beta-cell imaging. PMID- 20720044 TI - VQ/SPECT. PMID- 20720045 TI - Quantitative assessment of hypoxia kinetic models by a cross-study of dynamic 18F FAZA and 15O-H2O in patients with head and neck tumors. AB - Several kinetic models have been proposed to assess the underlying oxygenation status behind hypoxia tracer uptake and have shown advantages, compared with static analysis, in discriminating hypoxic regions. However, the quantitative assessment of mathematic models that take into consideration clinical applications and their biologic nature is still challenging. We performed a feasibility study to assess hypoxia kinetic models using voxelwise cross-analysis between the uptake of the perfusion tracer (15)O-H(2)O and the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA). METHODS: Five patients with advanced head and neck cancer were included. For each patient, dynamic sequences of (15)O-H(2)O for 5 min and (18)F-FAZA for 60 min were acquired consecutively after injections of approximately 1 GBq and 300 MBq of each tracer, respectively. The compartment model, Thorwarth model, Patlak plot, Logan plot, and Cho model were applied to model the process of tracer transport and accumulation under hypoxic conditions. The standard 1-tissue-compartment model was used to compute a perfusion map for each patient. The hypoxia kinetic models were based on the assumption of a positive correlation between tracer delivery and perfusion and a negative (inverse) correlation between tracer accumulation (hypoxia) and perfusion. RESULTS: Positive correlations between tracer delivery and perfusion were observed for the Thorwarth and Cho models in all patients and for the reversible and irreversible 2-compartment models in 4 patients. Negative correlations between tracer accumulation and perfusion were observed for the reversible 2-compartment model in all patients and for the irreversible 2 compartment model and Cho model in 4 patients. When applied to normal skeletal muscle, the smallest correlation variance over all 5 patients was observed for the reversible 2-compartment model. CONCLUSION: Hypoxia kinetic modeling delivers different information from static measurements. Different models generate different results for the same patient, and they even can lead to opposite physiologic interpretations. On the basis of our assessment of physiologic precision and robustness, the reversible 2-compartment model corresponds better to the expectations of our assumptions than the other investigated models. PMID- 20720046 TI - Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. AB - The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in the brain. Animal and postmortem human data suggest that mutant huntingtin represses CB1 transcription. Our aim was to measure CB1 levels in the brains of Huntington disease (HD) patients in vivo. METHODS: Twenty symptomatic HD patients and 14 healthy controls underwent PET with the novel CB1 ligand N-[2 (3-cyano-phenyl)-3-(4-(2-(18)F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2 pyridyloxy)-2-methylproponamide. RESULTS: We observed a profound decrease of CB1 availability throughout the gray matter of the cerebrum, cerebellum, and brain stem in HD patients, even in early disease stages. Disease burden ([number of CAG repeats in the HTT gene - 35.5] x age) was inversely correlated with CB1 availability in the prefrontal and premotor cortex. CONCLUSION: The profound early and widespread reduction of CB1 availability in vivo is consistent with the hypothesis that mutant huntingtin represses CB1 transcription. This is the first, to our knowledge, in vivo demonstration of disturbance of the endocannabinoid system in a human neurologic disease. PMID- 20720047 TI - PET/CT colonography. PMID- 20720048 TI - PET imaging of norepinephrine transporter-expressing tumors using 76Br-meta bromobenzylguanidine. AB - Meta-iodobenzylguanidine (MIBG) labeled with (123)I or (131)I has been widely used for the diagnosis and radiotherapy of norepinephrine transporter (NET) expressing tumors. However, (123)I/(131)I-MIBG has limitations for detecting small lesions because of its lower spatial resolution than PET tracers. In this study, meta-bromobenzylguanidine (MBBG) labeled with (76)Br (half-life, 16.1 h), an attractive positron emitter, was prepared and evaluated as a potential PET tracer for imaging NET-expressing tumors. METHODS: (76)Br-MBBG was prepared by a halogen-exchange reaction between the (76)Br and iodine of nonradioactive MIBG. The stability of MBBG was evaluated in vitro and in vivo by high-performance liquid chromatography analysis. Cellular uptake studies with or without NET inhibitors were performed in NET-positive PC-12 cell lines. Biodistribution studies were performed in PC-12 tumor-bearing nude mice by administration of a mixed solution of MBBG, MIBG, and (18)F-FDG. The tumor was imaged using (76)Br MBBG and (18)F-FDG with a small-animal PET scanner. RESULTS: MBBG was stable in vitro, but some time-dependent dehalogenation was observed after administration in mice. MBBG showed high uptake in PC-12 tumor cells that was significantly decreased by the addition of NET inhibitors. In biodistribution studies, MBBG showed high tumor accumulation (32.0 +/- 18.6 percentage injected dose per gram at 3 h after administration), and the tumor-to-blood ratio reached as high as 54.4 +/- 31.9 at 3 h after administration. The tumor uptake of MBBG correlated well with that of MIBG (r = 0.997) but not with that of (18)F-FDG. (76)Br-MBBG PET showed a clear image of the transplanted tumor, with high sensitivity, which was different from the lesion shown by (18)F-FDG PET. CONCLUSION: (76)Br-MBBG showed high tumor accumulation, which correlated well with that of MIBG, and provided a clear PET image. These results indicated that (76)Br-MBBG would be a potential PET tracer for imaging NET-expressing neuroendocrine tumors and could provide useful information for determining the indications for (131)I-MIBG therapy. PMID- 20720049 TI - Different modes of transport for 3H-thymidine, 3H-FLT, and 3H-FMAU in proliferating and nonproliferating human tumor cells. AB - The basis for the use of nucleoside tracers in PET is that activity of the cell growth-dependent enzyme thymidine kinase 1 is the rate-limiting factor driving tracer retention in tumors. Recent publications suggest that nucleoside transporters might influence uptake and thereby affect the tracer signal in vivo. Understanding transport mechanisms for different nucleoside PET tracers is important for evaluating clinical results. This study examined the relative role of different nucleoside transport mechanisms in uptake and retention of [methyl (3)H]-3'-deoxy-3'-fluorothymidine ((3)H-FLT), [methyl-(3)H]-thymidine ((3)H thymidine), and (3)H-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil ((3)H-FMAU). METHODS: Transport of (3)H-FLT, (3)H-thymidine, and (3)H-FMAU was examined in a single human adenocarcinoma cell line, A549, under both nongrowth and exponential-growth conditions. RESULTS: (3)H-Thymidine transport was dominated by human equilibrative nucleoside transporter 1 (hENT1) under both growth conditions. (3)H-FLT was also transported by hENT1, but passive diffusion dominated its transport. (3)H-FMAU transport was dominated by human equilibrative nucleoside transporter 2. Cell membrane levels of hENT1 increased in cells under exponential growth, and this increase was associated with a more rapid rate of uptake for both (3)H-thymidine and (3)H-FLT. (3)H-FMAU transport was not affected by changes in growth conditions. All 3 tracers concentrated in the plateau phase, nonproliferating cells at levels many-fold greater than their concentration in buffer, in part because of low levels of nucleoside metabolism, which inhibited tracer efflux. CONCLUSION: Transport mechanisms are not the same for (3)H thymidine, (3)H-FLT, and (3)H-FMAU. Levels of hENT1, an important transporter of (3)H-FLT and (3)H-thymidine, increase as proliferating cells enter the cell cycle. PMID- 20720050 TI - 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. AB - We aimed to evaluate (68)Ga-DOTATATE PET/CT for the early prediction of time to progression and clinical outcome after a first cycle of peptide receptor radionuclide treatment (PRRT) in a cohort of patients with well-differentiated neuroendocrine tumors. METHODS: Thirty-three consecutive patients (22 men and 11 women; mean age +/- SD, 57.8 +/- 12.1 y) were investigated at baseline and again 3 mo after initiation of the first cycle of PRRT. (68)Ga-DOTATATE receptor expression was assessed using 2 measures of standardized uptake value (SUV): maximum SUV (SUV(max)) and tumor-to-spleen SUV ratio (SUV(T/S)). Percentage change in SUV scores after PRRT relative to baseline (DeltaSUV) was calculated. After completing 1-3 cycles of PRRT, patients entered the follow-up study, for estimation of time to progression. According to the Response Evaluation Criteria in Solid Tumors, progression was defined on the basis of contrast-enhanced CT. Clinical symptoms, as well as the tumor markers chromogranin A and neuron specific enolase, were also recorded during regular follow-up visits. RESULTS: The 23 of 31 patients with decreased SUV(T/S) after the first PRRT cycle had longer progression-free survival than did the 8 of 31 patients with stable or increased scores (median survival not reached vs. 6 mo, P = 0.002). For the 18 of 33 patients showing a reduction in SUV(max), there was no significant difference in progression-free survival (median survival not reached vs. 14 mo, P = 0.22). Multivariate regression analysis identified SUV(T/S) as the only independent predictor for tumor progression during follow-up. In the 17 of 33 patients with clinical symptoms before PRRT, DeltaSUV(T/S) correlated with clinical improvement (r = 0.52, P < 0.05), whereas DeltaSUV(max) did not (r = 0.42, P = 0.10). Changes in the tumor markers (chromogranin A and neuron-specific enolase) did not predict DeltaSUV scores, clinical improvement, or time to progression. CONCLUSION: Decreased (68)Ga-DOTATATE uptake in tumors after the first cycle of PRRT predicted time to progression and correlated with an improvement in clinical symptoms among patients with well-differentiated neuroendocrine tumors; DeltaSUV(T/S) was superior to DeltaSUV(max) for prediction of outcome. PMID- 20720051 TI - Functional imaging to differentiate pulmonary carcinoids. PMID- 20720052 TI - Excessive aortic inflammation in chronic obstructive pulmonary disease: an 18F FDG PET pilot study. AB - Chronic obstructive pulmonary disease (COPD) patients exhibit increased cardiovascular risk, even after controlling for smoking. Inflammation may underlie this observation. METHODS: We measured vascular inflammation in both COPD patients and controls using (18)F-FDG PET/CT. Aortic inflammation was expressed as the target-to-background ratio (TBR) of the standardized uptake value in 7 COPD patients, 5 metabolic syndrome patients, and 7 ex-smokers. RESULTS: Abdominal aortic mean TBR (+/-SD) was greater in COPD patients than in ex-smoker controls (1.60 +/- 0.13 vs. 1.34 +/- 0.15, P = 0.0001). Aortic arch and abdominal aorta mean TBRs were higher in metabolic syndrome patients than in COPD patients (aortic arch, 1.80 +/- 0.18 vs. 1.53 +/- 0.18, P = 0.001, and abdominal aorta, 1.71 +/- 0.14 vs. 1.60 +/- 0.13, P = 0.001). CONCLUSION: COPD patients exhibited aortic inflammation that fell between the aortic inflammation exhibited by ex-smokers and that by metabolic syndrome patients. This may in part explain the increased risk of cardiovascular disease in COPD patients. PMID- 20720053 TI - Multimodality imaging of gene transfer with a receptor-based reporter gene. AB - Gene therapy trials have traditionally used tumor and tissue biopsies for assessing the efficacy of gene transfer. Noninvasive imaging techniques offer a distinct advantage over tissue biopsies in that the magnitude and duration of gene transfer can be monitored repeatedly. Human somatostatin receptor subtype 2 (SSTR2) has been used for the nuclear imaging of gene transfer. To extend this concept, we have developed a somatostatin receptor-enhanced green fluorescent protein fusion construct (SSTR2-EGFP) for nuclear and fluorescent multimodality imaging. METHODS: An adenovirus containing SSTR2-EGFP (AdSSTR2-EGFP) was constructed and evaluated in vitro and in vivo. SCC-9 human squamous cell carcinoma cells were infected with AdEGFP, AdSSTR2, or AdSSTR2-EGFP for in vitro evaluation by saturation binding, internalization, and fluorescence spectroscopy assays. In vivo biodistribution and nano-SPECT imaging studies were conducted with mice bearing SCC-9 tumor xenografts directly injected with AdSSTR2-EGFP or AdSSTR2 to determine the tumor localization of (111)In diethylenetriaminepentaacetic acid (DTPA)-Tyr3-octreotate. Fluorescence imaging was conducted in vivo with mice receiving intratumoral injections of AdSSTR2, AdSSTR2-EGFP, or AdEGFP as well as ex vivo with tissues extracted from mice. RESULTS: The similarity between AdSSTR2-EGFP and wild-type AdSSTR2 was demonstrated in vitro by the saturation binding and internalization assays, and the fluorescence emission spectra of cells infected with AdSSTR2-EGFP was almost identical to the spectra of cells infected with wild-type AdEGFP. Biodistribution studies demonstrated that the tumor uptake of (111)In-DTPA-Tyr3-octreotate was not significantly different (P > 0.05) when tumors (n = 5) were injected with AdSSTR2 or AdSSTR2-EGFP but was significantly greater than the uptake in control tumors. Fluorescence was observed in tumors injected with AdSSTR2-EGFP and AdEGFP in vivo and ex vivo but not in tumors injected with AdSSTR2. Although fluorescence was observed, there were discrepancies between in vivo imaging and ex vivo imaging as well as between nuclear imaging and fluorescent imaging. CONCLUSION: These studies showed that the SSTR2-EGFP fusion construct can be used for in vivo nuclear and optical imaging of gene transfer. PMID- 20720054 TI - Reproducibility of 18F-FDG and 3'-deoxy-3'-18F-fluorothymidine PET tumor volume measurements. AB - The objective of this study was to establish the repeatability and reproducibility limits of several volume-related PET image-derived indices-namely tumor volume (TV), mean standardized uptake value, total glycolytic volume (TGV), and total proliferative volume (TPV)-relative to those of maximum standardized uptake value (SUV(max)), commonly used in clinical practice. METHODS: Fixed and adaptive thresholding, fuzzy C-means, and fuzzy locally adaptive Bayesian methodology were considered for TV delineation. Double-baseline (18)F-FDG (17 lesions, 14 esophageal cancer patients) and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) (12 lesions, 9 breast cancer patients) PET scans, acquired at a mean interval of 4 d and before any treatment, were used for reproducibility evaluation. The repeatability of each method was evaluated for the same datasets and compared with manual delineation. RESULTS: A negligible variability of less than 5% was measured for all segmentation approaches in comparison to manual delineation (5%-35%). SUV(max) reproducibility levels were similar to others previously reported, with a mean percentage difference of 1.8% +/- 16.7% and 0.9% +/- 14.9% for the (18)F-FDG and (18)F-FLT lesions, respectively. The best TV, TGV, and TPV reproducibility limits ranged from -21% to 31% and -30% to 37% for (18)F-FDG and (18)F-FLT images, respectively, whereas the worst reproducibility limits ranged from -90% to 73% and -68% to 52%, respectively. CONCLUSION: The reproducibility of estimating TV, mean standardized uptake value, and derived TGV and TPV was found to vary among segmentation algorithms. Some differences between (18)F-FDG and (18)F-FLT scans were observed, mainly because of differences in overall image quality. The smaller reproducibility limits for volume-derived image indices were similar to those for SUV(max), suggesting that the use of appropriate delineation tools should allow the determination of tumor functional volumes in PET images in a repeatable and reproducible fashion. PMID- 20720056 TI - Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y SIR spheres: radiobiologic considerations. AB - Radioactive (90)Y-selective internal radiation (SIR) sphere therapy is increasingly used for the treatment of nonresectable hepatocellular carcinoma (HCC). However, the maximum delivered dose is limited by severe injury to the nontarget tissue, including liver parenchyma. Our study aimed to implement radiobiologic models for both tumor control probability (TCP) and normal-tissue complication probability (NTCP) to describe more effectively local response and the liver toxicity rate, respectively. METHODS: Patients with documented HCC, adequate bone marrow parameters, and regular hepatic and pulmonary function were eligible for the study. Patients who had pulmonary shunt greater than 20% of (99m)Tc-labeled macroaggregated albumin or any uncorrectable delivery to the gastrointestinal tract, reverse blood flow out of the liver, or complete portal vein thrombosis were excluded. Patients received a planned activity of the (90)Y SIR spheres, determined using the empiric body surface area method. The dose distribution was determined using posttreatment (3-dimensional) activity distribution and Monte Carlo dose voxel kernel calculations, and the mean doses to healthy liver and tumor were calculated for each patient. Response was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) and recommendations of the European Association for the Study of the Liver (EASL). Criteria were used to assess possible liver toxicities. The parameters of TCP and NTCP models were established by direct maximization of the likelihood. RESULTS: Seventy-three patients were treated. With an average dose of 110 Gy to the tumor, complete or partial response was observed in 74% and 55% of patients according to the EASL guideline and RECIST, respectively, and the predicted TCPs were 73% and 55%, respectively. With a median liver dose of 36 Gy (range, 6-78 Gy), the >or=grade 2 (G2), >or=grade 3 (G3), and >or=grade 4 (G4) liver toxicities were observed in 32% (23/73), 21% (15/73), and 11% (8/73) of patients, respectively. The parameters describing the >or=G2 liver toxicity data using the NTCP model were a tolerance dose of the whole organ leading to a 50% complication probability of 52 Gy (95% confidence interval, 44-61 Gy) and a slope of NTCP versus dose of 0.28 (95% confidence interval, 0.18-0.60), assuming n = 1. CONCLUSION: The radiobiologic approach, based on patient-specific dosimetry, could improve the (90)Y-microsphere therapeutic approach of HCC, maintaining an acceptable liver toxicity. PMID- 20720057 TI - Assessment of islet specificity of dihydrotetrabenazine radiotracer binding in rat pancreas and human pancreas. AB - Vesicular monoamine transporter 2 (VMAT2) is a putative molecular target for the quantitative imaging of pancreatic beta-cell mass by PET. The VMAT2 PET tracer (11)C-dihydrotetrabenazine ((11)C-DTBZ) exhibits high pancreatic uptake that is reduced in type 1 diabetes. The aim of this study was to assess the islet and VMAT2 specificity of DTBZ binding in the pancreas. METHODS: The biodistribution of (11)C-DTBZ in rats was determined 10 and 60 min after injection. The localization of DTBZ radioactivity in rat and human pancreatic tissue sections was investigated by autoradiography. Saturation and competition binding assays were performed with (3)H-DTBZ and sections of rat pancreatic and control tissues. The binding of (11)C-DTBZ in pancreatic sections from rats with streptozotocin induced diabetes was compared with that in control rats. RESULTS: The values for the pancreatic uptake of (11)C-DTBZ (percentage injected dose per gram of tissue) were 3.0 at 10 min and 2.7 at 60 min. At 10 min, pancreatic radioactivity was heterogeneously distributed, with higher levels toward the head of the pancreas (head-to-tail ratio, 1.7). No such gradient was observed in pancreatic sections incubated with (11)C-DTBZ and (3)H-DTBZ in vitro. In rats, (11)C-DTBZ and (3)H DTBZ binding in pancreatic islets did not exceed binding in the exocrine pancreas. Saturable (3)H-DTBZ binding was observed in the rat brain striatum (dissociation constant [K(d)], 1.3 nM) and the bovine adrenal medulla (K(d), 3.3 nM), whereas in the rat pancreas, (3)H-DTBZ binding was nonsaturable. Competition binding with (3)H-DTBZ and VMAT2 antagonists also indicated that DTBZ binding in the rat pancreas was nonspecific and did not represent binding to VMAT2. Nonspecific pancreatic (11)C-DTBZ binding was lower in rats with streptozotocin induced diabetes than in control rats. In sections of human pancreas, a subset of pancreatic islets were weakly but VMAT2-specifically labeled with (3)H-DTBZ. CONCLUSION: The results showed that the pancreatic uptake of (11)C-DTBZ is mainly due to nonspecific binding in the exocrine pancreas and suggested that the reduction in pancreatic (11)C-DTBZ binding observed in type 1 diabetes is not specific for the loss of beta-cell mass. PMID- 20720058 TI - The effect of posttherapy 131I SPECT/CT on risk classification and management of patients with differentiated thyroid cancer. AB - The objective of this study was to determine whether posttherapy (131)I SPECT/CT changed the need for additional cross-sectional imaging or modified the American Thyroid Association risk of recurrence classification. We performed planar imaging and SPECT/CT in a consecutive series of patients after (131)I therapy. METHODS: Planar imaging and SPECT/CT were performed on 148 consecutive patients with thyroid carcinoma (125 papillary, 2 follicular, 8 Hurthle cell, and 13 poorly differentiated) approximately 5 d after the therapeutic administration of 1,739-8,066 MBq (47-218 mCi) of (131)I. The indication for treatment was postsurgical ablation (n = 109) or recurrent or metastatic disease with rising thyroglobulin levels (n = 39). SPECT/CT scans were obtained for all subjects for 1 bed position (38 cm), which included the neck and upper chest. Additional SPECT/CT scans of the abdomen or pelvis were acquired if suggestive findings were noted on planar images. All patients were treated in real time, according to the standard of care in our practice. At that time, clinical decisions regarding thyroid tumor classification were made by our multidisciplinary group based on all data, including operative findings, pathology, imaging, and thyroglobulin levels. In a retrospective analysis, planar and SPECT/CT images were interpreted independently, and sites of uptake were categorized as likely benign, malignant, or equivocal. An experienced thyroid endocrinologist used a combination of surgical histopathology and scan findings to determine whether additional cross sectional imaging was required and determined if the imaging findings changed the patient's risk category. RESULTS: In 29 patients, 61 additional cross-sectional imaging studies were avoided using SPECT/CT, compared with medical decision making based on the planar images alone. In 7 of 109 postsurgical patients, SPECT/CT findings changed the initial American Thyroid Association risk of recurrence classification. The sensitivity of planar imaging and SPECT/CT for identification of focal (131)I uptake in the thyroid bed was similar in the postsurgical and recurrence cohorts. For metastatic disease in the neck, characterization of (131)I uptake by SPECT/CT in the postsurgical group was significantly better than that by planar scanning (P < 0.01). Among the 109 postsurgical patients, the characterization of iodine uptake in the lung, liver, and bone was also more accurate using SPECT/CT than planar scanning (P < 0.01). The CT portion of SPECT/CT demonstrated non-iodine-avid lesions in 32 of 148 patients. CONCLUSION: SPECT/CT data provided information that reduced the need for additional cross-sectional imaging in 29 patients (20%) and significantly altered the initial risk of recurrence estimates in 7 of 109 patients (6.4%), thereby altering patient management recommendations with regard to frequency and intensity of follow-up studies. PMID- 20720059 TI - Is 18F-FDG PET/CT useful for the early prediction of histopathologic response to neoadjuvant erlotinib in patients with non-small cell lung cancer? AB - Early prediction of treatment response is of value in avoiding the unnecessary toxicity of ineffective treatment. The objective of this study was to prospectively evaluate the role of integrated (18)F-FDG PET/CT for the early identification of response to neoadjuvant erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. METHODS: From October 2006 to March 2009, 23 patients with non-small cell lung cancer eligible for surgical resection were evaluated for this study. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. (18)F-FDG PET/CT was performed before and at 1 wk after the administration of erlotinib. Changes in tumor (18)F-FDG uptake during treatment were measured by standardized uptake values and assessed prospectively according to the criteria of the European Organization for Research and Treatment of Cancer. Patients with a decrease in standardized uptake values of 25% or more after 1 wk were classified as "metabolic responders." The metabolic response was compared with the pathologic response, obtained by histopathologic examination of the resected specimen. RESULTS: Following the (18)F-FDG PET/CT criteria of the European Organization for Research and Treatment of Cancer, 6 patients (26%) had a partial response within 1 wk, 16 patients (70%) had stable disease, and 1 patient (4%) had progressive disease. The median percentage of necrosis in the early metabolic responder group was 70% (interquartile range, 30%-91%), and the median percentage of necrosis in the nonresponder group was 40% (interquartile range, 20%-50%; P = 0.09). The kappa-agreement between the metabolic and pathologic responders was 0.55 (P = 0.008). CONCLUSION: The results of this study suggest that early during the course of epidermal growth factor receptor tyrosine kinase inhibitor therapy, (18)F-FDG PET/CT can predict response to erlotinib treatment in patients with non-small cell lung cancer. PMID- 20720060 TI - Molecular imaging of the dopamine transporter. AB - The dopamine transporter (DAT) is a transmembrane protein responsible for reuptake of dopamine from the synaptic cleft and termination of dopaminergic transmission. Several radioligands are available for DAT imaging with SPECT and PET. This review summarizes the main SPECT and PET radioligands and the main applications of DAT imaging in neuropsychiatric disorders. PMID- 20720062 TI - Additional gains with time-of-flight PET at high counting rates: lessons learned from early time-of-flight PET systems. PMID- 20720064 TI - Science to practice: can CT be performed for multicolor molecular imaging? AB - In an animal model of atherosclerosis, it was shown that multispectral computed tomography (CT) used with two radiologic contrast agents (gold and iodine) can depict macrophages, vascularization, and calcification separately and simultaneously during only one scanning examination. PMID- 20720065 TI - MR imaging of the sonographically indeterminate adnexal mass. AB - Magnetic resonance (MR) imaging of the sonographically indeterminate adnexal mass can be used to guide patient care and reduce the costs of investigation and treatment. Most indeterminate masses result from common benign conditions, and women with such masses can avoid unnecessary or inappropriate surgery. For the minority of women in whom indeterminate masses are malignant, use of MR imaging rather than a "wait and watch" strategy of interval re-examination with ultrasonography offers a more timely diagnosis. There are simple diagnostic steps in the MR imaging assessment that direct a problem-solving, tailored approach based on signal characteristics and morphology. PMID- 20720066 TI - Thin-section CT of the lungs: the Hinterland of normal. AB - Thin-section computed tomography (CT) of the lungs was introduced more than 20 years ago and has an established role in the assessment of patients who are known to have, or are suspected of having, diffuse lung disease. Thin-section CT can demonstrate very early disease, sometimes in individuals without symptoms or pulmonary function test abnormalities. Such sensitivity comes at a price because it may be difficult to distinguish thin-section CT findings that lie within the normal range from those that represent early, but important, disease. This review examines particular thin-section CT findings that occupy the gray area between unequivocal health and definite disease, with a particular focus on the effects of cigarette smoking and aging. PMID- 20720067 TI - Contrast-enhanced dedicated breast CT: initial clinical experience. AB - PURPOSE: To quantify contrast material enhancement of breast lesions scanned with dedicated breast computed tomography (CT) and to compare their conspicuity with that at unenhanced breast CT and mammography. MATERIALS AND METHODS: Approval of the institutional review board and the Radiation Use Committee and written informed consent were obtained for this HIPAA-compliant study. Between September 2006 and April 2009, 46 women (mean age, 53.2 years; age range, 35-72 years) with Breast Imaging Reporting and Data System category 4 or 5 lesions underwent unenhanced breast CT and contrast material-enhanced breast CT before biopsy. Two radiologists independently scored lesion conspicuity for contrast-enhanced breast CT versus mammography and for contrast-enhanced breast CT versus unenhanced breast CT. Mean lesion voxel intensity was measured in Hounsfield units and normalized to adipose tissue intensity on manually segmented images obtained before and after administration of contrast material. Regression models focused on conspicuity and quantified enhancement were used to estimate the effect of pathologic diagnosis (benign vs malignant), lesion type (mass vs calcifications), breast density, and interradiologist variability. RESULTS: Fifty-four lesions (25 benign, 29 malignant) in 46 subjects were analyzed. Malignant lesions were seen significantly better at contrast-enhanced breast CT than at unenhanced breast CT (P < .001) or mammography (P < .001). Malignant calcifications (malignant lesions manifested mammographically as microcalcifications only, n = 7) were seen better at contrast-enhanced breast CT than at unenhanced breast CT (P < .001) and were seen similarly at contrast-enhanced breast CT and mammography. Malignant lesions enhanced 55.9 HU +/- 4.0 (standard error), whereas benign lesions enhanced 17.6 HU +/- 6.1 (P < .001). Ductal carcinoma in situ (n = 5) enhanced a mean of 59.6 HU +/- 2.8. Receiver operating characteristic curve analysis of lesion enhancement yielded an area under the receiver operating characteristic curve of 0.876. CONCLUSION: Conspicuity of malignant breast lesions, including ductal carcinoma in situ, is significantly improved at contrast-enhanced breast CT. Quantifying lesion enhancement may aid in the detection and diagnosis of breast cancer. PMID- 20720068 TI - Frequency and importance of small amount of isolated pelvic free fluid detected with multidetector CT in male patients with blunt trauma. AB - PURPOSE: To retrospectively determine the frequency and importance of a small amount of isolated pelvic free fluid seen at multidetector computed tomography (CT) in male patients who have blunt trauma without an identifiable cause. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirement for informed consent was waived for this HIPAA-compliant study. One thousand male patients with blunt trauma who underwent abdominopelvic CT at a level 1 trauma center between January 2004 and June 2006 were entered into this study. The CT images of the 1000 patients were reviewed independently by two abdominal radiologists. CT scan assessment included evaluation for presence or absence of pelvic free fluid, any traumatic or nontraumatic cause of the free fluid, pelvic free fluid attenuation and volume measurements, and determination of the location of pelvic free fluid. Interobserver agreement was determined with kappa statistics, and the Student t test was used to assess differences in the mean volume and mean attenuation of the pelvic free fluid in the patients with and those without injury. RESULTS: Pelvic free fluid was identified in 10.2% (102 of 1000) of patients. A small amount of isolated pelvic free fluid without any identifiable cause was identified in 4.8% (48 of 1000) of patients by reader 1 and in 5.0% (50 of 1000) of patients by reader 2 (kappa value, 0.76) and was located at or below the level of the third sacral vertebral body in all 49 patients with isolated pelvic free fluid. The mean volume and mean attenuation of the small amount of isolated pelvic free fluid were 2.3 mL +/- 1.5 (standard deviation) and 8.1 HU +/- 3.9, respectively. None of the patients in this group had an undiagnosed bowel and/or mesenteric injury. CONCLUSION: In male patients with blunt trauma, a small amount of isolated pelvic free fluid with attenuation equal to that of simple fluid and located in the deep region of the pelvis likely is not a sign of bowel and/or mesenteric injury. PMID- 20720069 TI - Intraindividual comparison of gadoxetate disodium-enhanced MR imaging and 64 section multidetector CT in the Detection of hepatocellular carcinoma in patients with cirrhosis. AB - PURPOSE: To prospectively compare gadoxetate disodium-enhanced magnetic resonance (MR) imaging with multiphasic 64-section multidetector computed tomography (CT) in the detection of hepatocellular carcinoma (HCC) in patients with cirrhosis. MATERIALS AND METHODS: Institutional review board approval and informed patient consent were obtained for this prospective study. Fifty-eight patients (39 men, 19 women; mean age, 63 years; age range, 35-84 years) underwent gadoxetate disodium-enhanced MR imaging and multiphasic 64-section multidetector CT. The imaging examinations were performed within 30 days of each other. The two sets of images were qualitatively analyzed in random order by three independent readers in a blinded and retrospective fashion. Using strict diagnostic criteria for HCC, readers classified all detected lesions with use of a four-point confidence scale. The reference standard was a combination of pathologic proof, conclusive imaging findings, and substantial tumor growth at follow-up CT or MR imaging (range of follow-up, 90-370 days). The diagnostic accuracy, sensitivity, and positive predictive value were compared between the two image sets. Interreader variability was assessed. The accuracy of each imaging method was determined by using an adjusted modified chi(2) test. RESULTS: Eighty-seven HCCs (mean size +/- standard deviation, 1.8 cm +/- 1.5; range, 0.3-7.0 cm) were confirmed in 42 of the 58 patients. Regardless of lesion size, the average diagnostic accuracy and sensitivity for all readers were significantly greater with gadoxetate disodium enhanced MR imaging (average diagnostic accuracy: 0.88, 95% confidence interval [CI]: 0.80, 0.97; average sensitivity: 0.85, 95% CI: 0.74, 0.96) than with multidetector CT (average diagnostic accuracy: 0.74, 95% CI: 0.65, 0.82; average sensitivity: 0.69, 95% CI: 0.59, 0.79) (P < .001 for each). No significant difference in positive predictive value was observed between the two image sets for each reader. Interreader agreement was good to excellent. CONCLUSION: Compared with multiphasic 64-section multidetector CT, gadoxetate disodium enhanced MR imaging yields significantly higher diagnostic accuracy and sensitivity in the detection of HCC in patients with cirrhosis. PMID- 20720071 TI - Allogeneic renal graft rejection in a rat model: in vivo MR imaging of the homing trait of macrophages. AB - PURPOSE: To evaluate the feasibility of MR imaging to depict the in vivo recruitment of superparamagnetic iron oxide (SPIO)-labeled macrophages and to aid diagnosis of graft rejection in kidney transplantation. MATERIALS AND METHODS: This study was approved by the institution's committee on animal research. Eighteen male Lewis rats received a kidney transplant; 12 had an F344 rat donor and six had a Lewis rat donor. Peritoneal macrophages were harvested from thioglycollate-treated Lewis rats, cultured, and labeled with SPIO. After resuspension of macrophages in a concentration of 1 x 10(7) cells per milliliter of Hanks balanced salt solution, 5 x 10(6) of SPIO-labeled macrophages was administered through the tail vein 2 or 5 days after transplantation in each group. The transplanted kidneys were imaged on a 4.7-T MR imager 24 hours after macrophage administration. The Wilcoxon signed rank test was performed for evaluating the differences between the relative signal intensity (SI) before and after SPIO-labeled macrophage administration. RESULTS: A low-SI zone was predominantly noted in the medulla of the transplanted kidneys, and the relative SI decreased significantly from 1.40 to 0.53 (P < .001) in the allogeneic transplants following SPIO-labeled macrophage administration 5 days after the allogeneic transplantation. In the syngeneic group, the lower-SI zone was not noted in the grafts. At histopathologic examination, the lower-SI zone corresponded to the distribution of the SPIO-labeled macrophages. CONCLUSION: This study demonstrates that the homing of intravenously administered SPIO labeled macrophages can be monitored in the allograft rejection model on in vivo MR images. PMID- 20720070 TI - Renal mass biopsy to guide treatment decisions for small incidental renal tumors: a cost-effectiveness analysis. AB - PURPOSE: To evaluate the effectiveness, cost, and cost-effectiveness of using renal mass biopsy to guide treatment decisions for small incidentally detected renal tumors. MATERIALS AND METHODS: A decision-analytic Markov model was developed to estimate life expectancy and lifetime costs for patients with small (< or = 4-cm) renal tumors. Two strategies were compared: renal mass biopsy to triage patients to surgery or imaging surveillance and empiric nephron-sparing surgery. The model incorporated biopsy performance, the probability of track seeding with malignant cells, the prevalence and growth of benign and malignant tumors, treatment effectiveness and costs, and patient outcomes. An incremental cost-effectiveness analysis was performed to identify strategy preference under a willingness-to-pay threshold of $75,000 per quality-adjusted life-year (QALY). Effects of changes in key parameters on strategy preference were evaluated in sensitivity analysis. RESULTS: Under base-case assumptions, the biopsy strategy yielded a minimally greater quality-adjusted life expectancy (4 days) than did empiric surgery at a lower lifetime cost ($3466), dominating surgery from a cost effectiveness perspective. Over the majority of parameter ranges tested in one way sensitivity analysis, the biopsy strategy dominated surgery or was cost effective relative to surgery based on a $75,000-per-QALY willingness-to-pay threshold. In two-way sensitivity analysis, surgery yielded greater life expectancy when the prevalence of malignancy and propensity for biopsy-negative cancers to metastasize were both higher than expected or when the sensitivity and specificity of biopsy were both lower than expected. CONCLUSION: The use of biopsy to guide treatment decisions for small incidentally detected renal tumors is cost-effective and can prevent unnecessary surgery in many cases. PMID- 20720072 TI - Do patients with structural abnormalities of the shoulder experience pain after MR arthrography of the shoulder? AB - PURPOSE: To assess the pain course after intraarticular injection of a gadolinium containing contrast material admixed with anesthetic for magnetic resonance (MR) arthrography of the shoulder in relation to internal derangements of the shoulder. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this study. The study sample consisted of 655 consecutive patients (249 female, 406 male; median age, 54 years) referred for MR arthrography of the shoulder. Pain level was measured at baseline, directly after intraarticular injection of the gadolinium-containing contrast material admixed with anesthetic, 4 hours after injection, 1 day (18-30 hours) after injection, and 1 week (6-8 days) after injection with a visual analog scale (range, 0-10). MR arthrography was used to assess the following internal derangements: lesions of the rotator cuff tendons and long biceps tendon, adhesive capsulitis (frozen shoulder), fluid in the subacromial bursa, labral tears, and osteoarthritis of the glenohumeral joint. History of shoulder surgery was recorded. Linear regression models were calculated for the dependent variable (difference between follow-up pain and baseline pain), with the independent variable grouping adjusted for age and sex. RESULTS: There was no significant association between pain level over time and internal derangements of the shoulder, nor was there significant association between pain level over time in patients with a history of shoulder surgery and patients without a history of shoulder surgery. CONCLUSION: Neither internal derangements nor prior surgery have an apparent effect on the pain course after MR arthrography of the shoulder. PMID- 20720073 TI - Value of cerebral microhemorrhages detected with susceptibility-weighted MR Imaging for prediction of long-term outcome in children with nonaccidental trauma. AB - PURPOSE: To determine the prevalence of parenchymal brain microhemorrhages (MHs) in infants with nonaccidental trauma (NAT) by using susceptibility-weighted (SW) magnetic resonance (MR) imaging and to assess whether the presence of MH results in improved prediction of the long-term neurologic outcome. MATERIALS AND METHODS: A retrospective case-control analysis of the data for 101 children aged 1-32 months with forensic pediatric specialist-confirmed NAT was performed with institutional review board approval. Sixty-two patients were boys (mean age, 8.4 months +/- 7.4 [standard deviation]), and 39 were girls (mean age, 7.4 months +/- 7.8). The imaging findings and clinical data of the children who were examined with SW imaging were collected. Exclusion criteria included pre-existing cognitive delays, central nervous system malformations, previous brain injuries, and/or birth before 30 weeks gestation. Dichotomized long-term neurologic outcomes (good [normal, mild disability, or moderate disability] versus poor [severe disability, vegetative state, or death]) at greater than or equal to 6 months (mean, 33 months; range 6-95 months) were available for 53 patients (36 boys [mean age, 7.3 months +/- 5.9]; 17 girls [mean age, 7.4 months +/- 7.9]; overall range, 2-32 months). Logistic regression was used to determine whether the presence of SW imaging-depicted MH, as compared with other radiologic findings, resulted in improved prediction of long-term neurologic outcome. RESULTS: Imaging findings showed that of the 101 patients, 29 (29%) had MH at SW imaging, 66 (65%) had extraaxial hemorrhages, 52 (51%) had retinal hemorrhages, and 35 (35%) had evidence of acute ischemic injury. A significantly larger number of children with poor outcomes than children with good outcomes had brain MH (nine of 14 vs seven of 39; P = .001) and ischemic injury (13 of 14 vs 17 of 39; P = .006). Logistic regression analysis revealed presence of MH at SW imaging followed by acute ischemic injury, initial Glasgow Coma Scale score, and age-to be the most significant single variable in the final model, with an overall predictive accuracy of 92.5%. CONCLUSION: Presence of intraparenchymal brain MH in children with NAT, as detected on SW images, correlates with significantly poor long-term neurologic outcome, improves outcome prediction compared with the predictions made by using other tested clinical and imaging findings, and is most predictive when combined with presence of ischemic injury. PMID- 20720074 TI - Ruptured intracranial aneurysms: factors affecting the rate and outcome of endovascular treatment complications in a series of 782 patients (CLARITY study). AB - PURPOSE: To analyze the clinical and anatomic factors that affect the occurrence and outcome of complications (thromboembolic events and intraoperative rupture) in the endovascular treatment of ruptured intracranial aneurysms in a large multicenter series, the CLARITY study (Clinical and Anatomic Results in the Treatment of Ruptured Intracranial Aneurysms). MATERIALS AND METHODS: This study was approved by the institutional review boards of the participating centers, and written informed consent was obtained from all patients. In the CLARITY series, 782 patients (314 men, 468 women; age range, 19-80 years, mean age, 51.3 years +/ 13.2 [standard deviation]) with 782 ruptured aneurysms underwent endovascular treatment for ruptured intracranial aneurysms at 20 institutions. Uni- and multivariate analyses were performed to determine factors (demographic characteristics, risk factors, anatomic factors, and therapeutic factors) that affect the occurrence of treatment-related complications. RESULTS: A higher rate of thromboembolic events was observed in patients with aneurysms larger than 10 mm (28.0% vs 10.7% in patients with aneurysms < or =10 mm, P < .001), in smokers (16.1% vs 10.1% in nonsmokers, P = .015), and in patients with aneurysms with a neck larger than 4 mm (20.8% vs 11.0% in aneurysms with a neck < or =4 mm, P = .004).The frequency of intraoperative rupture was higher in patients with middle cerebral artery (MCA) aneurysms (8.5% vs 3.7% in patients without MCA aneurysms, P = .029), in patients younger than 65 years (5.0% vs 0.8% in patients older than 65 years, P = .032), and in patients without hypertension (5.4% vs 1.5% in patients with hypertension, P = .017). CONCLUSION: The rate of thromboembolic events in the endovascular treatment of ruptured aneurysms is significantly affected by aneurysm size and neck size but not by aneurysm location. Conversely, the rate of intraoperative rupture is significantly affected by aneurysm location but not aneurysm size. PMID- 20720075 TI - Brain temperature measured by using proton MR spectroscopy predicts cerebral hyperperfusion after carotid endarterectomy. AB - PURPOSE: To determine whether brain temperature measured by using preoperative proton magnetic resonance (MR) spectroscopy could help identify patients at risk for cerebral hyperperfusion after carotid endarterectomy (CEA). MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Acquisition of proton MR spectroscopic data by using point-resolved spectroscopy without water suppression was performed before CEA in the bilateral cerebral hemispheres of 84 patients with unilateral internal carotid artery stenosis (> or =70%) and without contralateral internal carotid artery steno-occlusive disease. Brain temperature was calculated from the chemical shift difference between water and N-acetylaspartate signals at proton MR spectroscopy. Cerebral blood flow (CBF) was also measured by using single photon emission computed tomography and N isopropyl-p-[(123)I]-iodoamphetamine before and immediately after CEA and on the 3rd postoperative day. The relationship between each variable and the development of post-CEA hyperperfusion (CBF increase > or = 100% compared with preoperative values) was evaluated with univariate statistical analysis followed by multivariate analysis. RESULTS: A linear correlation was observed between preoperative brain temperature difference (the value in the affected hemisphere minus the value in the contralateral hemisphere) and increases in CBF immediately after CEA (r = 0.763 and P < .001) when the preoperative brain temperature difference was greater than 0. Cerebral hyperperfusion immediately after CEA was observed in nine patients (11%). Elevated preoperative brain temperature difference was the only significant independent predictor of post-CEA hyperperfusion. When elevated brain temperature difference was defined as a marker of hemodynamic impairment in the affected cerebral hemisphere, use of preoperative brain temperature difference resulted in 100% sensitivity and 87% specificity, with a 47% positive predictive value and a 100% negative predictive value for the prediction of post-CEA hyperperfusion. Hyperperfusion syndrome developed on the 3rd and 4th postoperative days in two of the nine patients who exhibited hyperperfusion immediately after CEA. CONCLUSION: Brain temperature measured by using preoperative proton MR spectroscopy may help identify patients at risk for post-CEA cerebral hyperperfusion. PMID- 20720076 TI - Relative capability of MR imaging and FDG PET to depict changes associated with prodromal and early Alzheimer disease. AB - PURPOSE: To quantify the effect sizes of regional metabolic and morphometric measures in patients with preclinical and mild Alzheimer disease (AD) to aid in the identification of noninvasive biomarkers for the early detection of AD. MATERIALS AND METHODS: The study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from each participant or participant's legal guardian. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging data were analyzed from 80 healthy control (HC) subjects, 68 individuals with AD, and 156 with amnestic mild cognitive impairment (MCI), 69 of whom had single-domain amnestic MCI. Regions of interest (ROIs) were derived after coregistering FDG PET and MR images by using high-throughput, subject specific procedures. The Cohen d effect sizes were calculated for 42 predefined ROIs across the brain. Statistical comparison of the largest overall effect sizes for MR imaging and PET was performed. Metabolic effect sizes were determined with and without accounting for regional atrophy. Discriminative accuracy of ROIs showing the largest effect sizes were compared by calculating receiver operating characteristic curves. RESULTS: For all disease groups, the hippocampus showed the largest morphometric effect size and the entorhinal cortex showed the largest metabolic effect size. In mild AD, the Cohen d effect size for hippocampal volume (1.92) was significantly larger (P < .05) than that for entorhinal metabolism (1.43). Regression of regional atrophy substantially reduced most metabolic effects. For all group comparisons, the areas under the receiver operating characteristic curves were significantly larger for hippocampal volume than for entorhinal metabolism. CONCLUSION: The current results show no evidence that FDG PET is more sensitive than MR imaging to the degeneration occurring in preclinical and mild AD, suggesting that an MR imaging finding may be a more practical clinical biomarker for early detection of AD. PMID- 20720077 TI - Loaded cartilage T2 mapping in patients with hip dysplasia. AB - PURPOSE: To evaluate the change in cartilage T2 values with loading in patients with hip dysplasia. MATERIALS AND METHODS: Fifteen patients with hip dysplasia and nine asymptomatic healthy volunteers were evaluated between April 2008 and February 2009. All subjects provided written informed consent before participation in this prospective, institutional review board-approved study. Midcoronal T2 mapping of hips was performed under unloaded and loaded conditions (with 50% body weight) at 3.0-T magnetic resonance (MR) imaging. Loading was achieved with a mechanical loading system. T2 values under unloaded conditions and the change in T2 values at the weight-bearing area of the acetabular and femoral cartilage with loading were compared between normal and dysplastic hips. The change in T2 with loading was correlated with the patient's age and body mass index as well as with the center-edge angle determined on conventional radiographs. RESULTS: The decrease in cartilage T2 at the outer superficial zones of the acetabular cartilage with loading was significantly greater in patients with hip dysplasia than in healthy volunteers: The mean T2 change with loading was -7.6% +/- 10.6 (+/-standard deviation) for dysplastic hips and 1.2% +/- 10.9 for normal hips (P = .04). Among patients with hip dysplasia, there was a positive correlation between the center-edge angle on anteroposterior radiographs and T2 changes with loading at the outer deep zones of the acetabular cartilage. CONCLUSION: Cartilage T2 mapping with loading during MR imaging enabled the detection of site-specific changes in cartilage T2 in dysplastic hips. PMID- 20720078 TI - Dual-source parallel radiofrequency excitation body MR imaging compared with standard MR imaging at 3.0 T: initial clinical experience. AB - PURPOSE: To prospectively compare the image quality and homogeneity of magnetic resonance (MR) images obtained by using a dual-source parallel radiofrequency (RF) excitation body MR imaging system with parallel transmission and independent RF shimming with the image quality and homogeneity of single-source MR images obtained by using standard sequences for routine clinical use in patients at 3.0 T. MATERIALS AND METHODS: After institutional review board approval and informed patient consent were obtained, a dual-source parallel RF excitation 3.0-T MR system with independent RF shimming and parallel transmission technology was used to examine 28 patients and was compared with a standard 3.0-T MR system with single RF transmission. The RF power was distributed to the independent ports of the system body coil by using two RF transmission sources with full software control, enabling independent control of the phase and amplitude of the RF waveforms. Axial T2-weighted fast spin-echo (SE) and diffusion-weighted (DW) liver images, axial T2-weighted fast SE pelvic images, and sagittal T1- and T2 weighted fast SE spinal images were obtained by using dual- and single-source RF excitation. Two radiologists independently evaluated the images for homogeneity and image quality. Statistical significance was calculated by using the nonparametric Wilcoxon signed rank test. Interobserver agreement was determined by using Cohen kappa and Kendall tau-b tests. RESULTS: Image quality comparisons revealed significantly better results with dual-source rather than single-source RF excitation at T2-weighted liver MR imaging (P = .001, kappa = 1.00) and better results at DW liver imaging at a statistical trend level (P = .066, tau-b > 0.7). Owing to reduced local energy deposition, fewer acquisitions and shorter repetition times could be implemented with dual-source RF excitation pelvic and spinal MR imaging, with image acquisition accelerating by 18%, 33%, and 50% compared with the acquisitions with single-source RF excitation. Image quality did not differ significantly between the two MR techniques (P > .05, tau-b > 0.5). CONCLUSION: Dual-source parallel RF excitation body MR imaging enables reduced dielectric shading, improved homogeneity of the RF magnetic induction field, and accelerated imaging at 3.0 T. PMID- 20720079 TI - Low yield of chest radiography in a large tuberculosis screening program. AB - PURPOSE: To assess the frequency and spectrum of abnormalities on routine screening chest radiographs in the pre-employment evaluation of health care workers with positive tuberculin skin test (TST) results. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant retrospective study and waived the need for written informed patient consent. Chest radiographic reports of all 2586 asymptomatic individuals with positive TST results who underwent pre-employment evaluation between January 1, 2003, and December 31, 2007, were evaluated to determine the frequency of detection of evidence of active tuberculosis (TB) or latent TB infection (LTBI) and the spectrum of imaging findings. All chest radiographs interpreted as positive were reviewed by an experienced board-certified radiologist. If there was a discrepancy between the two readings, a second experienced radiologist served as an independent and final arbiter. Any follow-up chest radiographs or computed tomographic images that had been acquired by employee health services or by the employee's private physician as a result of a suspected abnormality detected at initial screening were also evaluated. RESULTS: Of the 159 (6.1%) chest radiographic examinations that yielded abnormal results, there were no findings that were consistent with active TB. There were 92 cases of calcified granulomas, calcified lymph nodes, or both; 25 cases of apical pleural thickening; 16 cases of fibrous scarring; and 31 cases of noncalcified nodules. All cases of fibrous scarring involved an area smaller than 2 cm(2). All noncalcified nodules were 4 mm in diameter or smaller, with the exception of one primary lung malignancy and one necrotizing granuloma (negative for acid-fast bacilli) that grew Mycobacterium kansasii on culture. CONCLUSION: Universal chest radiography in a large pre-employment TB screening program was of low yield in the detection of active TB or increased LTBI reactivation risk, and it provided no assistance in deciding which individuals to prioritize for LTBI treatment. PMID- 20720081 TI - Case 161: hydatid disease with water lily sign manifesting as a soft-tissue mass in the calf of a child. PMID- 20720082 TI - Primary end-point error. PMID- 20720083 TI - Evidence-based data for abandoning unselective daily chest radiographs in Intensive Care Units. PMID- 20720084 TI - Imaging expertise in critical care units. PMID- 20720085 TI - Traumatic dural venous sinus thrombosis in high-risk acute blunt head trauma patients. PMID- 20720086 TI - Comment on parameters of low-grade glioma as predictors. PMID- 20720087 TI - Aortopathy in bicuspid aortic valve disease: is it really congenital? PMID- 20720088 TI - Impact of first- and second-line treatment for Hodgkin's lymphoma on the incidence of AML/MDS and NHL--experience of the German Hodgkin's Lymphoma Study Group analyzed by a parametric model of carcinogenesis. AB - BACKGROUND: Using a parametric carcinogenesis model, we disentangle the superimposing effects of primary and relapse therapies of Hodgkin's disease on secondary neoplasias. PATIENTS AND METHODS: We analyze eight randomized trials of the German Hodgkin's lymphoma study group [5357 individuals, 67 secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and 97 secondary non Hodgkin's lymphoma (NHL)]. Primary therapies were divided into four groups: radiotherapy alone, moderately dosed COPP/ABVD-like chemotherapies for intermediate and advanced stages and BEACOPP escalated. RESULTS: For secondary AML/MDS, the hazards after primary therapies are proportional (maximum at 3.4 years), while the hazard after relapse therapy is more peaked (maximum at 1.8 years). Intermediate and advanced stage chemotherapy resulted in a cumulative risk of 1.5%, while the risk after BEACOPP escalated is higher (4.4%, P = 0.004) and comparable with that after relapse therapy (4.5%). For secondary NHL, there are no differences in cumulative risk between the primary therapies (2.9%), while the risk after relapse therapy is increased (6.6%, P = 0.002). CONCLUSIONS: BEACOPP escalated moderately increases the risk of secondary AML/MDS but not NHL. No differences were found between other chemotherapies of advanced stages and intermediate stages. Secondary AML/MDS occurs faster after relapse treatment than after primary treatment. PMID- 20720090 TI - Pitfalls in comparing breast cancer survival of elderly patients between hospitals without comorbidity or cause of death data. PMID- 20720089 TI - Recall pneumonitis during systemic treatment with sunitinib. PMID- 20720091 TI - Detection of airborne bacteria in a German turkey house by cultivation-based and molecular methods. AB - Today's large-scale poultry production with densely stocked and enclosed production buildings is often accompanied by very high concentrations of airborne microorganisms leading to a clear health hazard for employees working in such environments. Depending on the expected exposure to microorganisms, work has to be performed under occupational safety conditions. In this study, turkey houses bioaerosols were investigated by cultivation-based and molecular methods in parallel to determine the concentrations and the composition of bacterial community. Results obtained with the molecular approach showed clearly its applicability for qualitative exposure measurements. With both, cultivation-based and molecular methods species of microorganism with a potential health risk for employees (Acinetobacter johnsonii, Aerococcus viridans, Pantoea agglomerans, and Shigella flexneri) were identified. These results underline the necessity of adequate protection measures, including the recommendation to wear breathing masks during work in poultry houses. PMID- 20720092 TI - The osmolyte trimethylamine N-oxide (TMAO) increases the proteolytic activity of botulinum neurotoxin light chains A, B, and E: implications for enhancing analytical assay sensitivity. AB - Botulism, the disease caused by botulinum neurotoxins (BoNTs), secreted by the spore-forming, anaerobic bacteria Clostridium botulinum, has been associated with food poisoning for centuries. In addition, the potency of BoNTs coupled with the current political climate has produced a threat of intentional, malicious poisoning by these toxins. The ability to detect and measure BoNTs in complex matrixes is among the highest research priorities. However, the extreme potency of these toxins necessitates that assays be capable of detecting miniscule quantities of these proteins. Thus, signal-boosting strategies must be employed. A popular approach uses the proteolytic activity of the BoNT light chain (LC) to catalyze the cleavage of synthetic substrates; reaction products are then analyzed by the analytical platform of choice. However, BoNT LCs are poor catalysts. In this study, the authors used the osmolyte trimethylamine N-oxide (TMAO) to increase the proteolytic activities of BoNT LCs. Their data suggest that concentrated solutions of TMAO induce complete folding of the LCs, resulting in increased substrate affinity and enhanced enzyme turnover. The authors observed increases in catalysis for BoNT serotypes A, B, and E, and this increased proteolytic activity translated into substantial increases in analytical assay sensitivity for these medically relevant toxins. PMID- 20720093 TI - Time and intensity factors in identification of components of odor mixtures. AB - Identification of odors of compounds introduced into changeable olfactory environments is the essence of olfactory coding, which focuses perception on the latest stimulus with the greatest salience. Effects of stimulus intensity and adapting time on mixture component identification after adapting with one component were each studied in 10 human subjects. Odors of 1 and 5 mM vanillin (vanilla) and phenethyl alcohol (rose) were identified, with adapting time varied by sniffing naturally once or twice, or sniffing 5 times, once every 2 s. Odors of water-adapted single compounds were identified nearly perfectly (94%), self adapted to 51% but did not cross-adapt (94%), showing the 2 compounds had quickly adapting independent odors. Identifications of the vanilla and rose odors in water-adapted mixtures were reduced to 59% and 79%, respectively. Following single-component adaptation, the average 33% identification of odors of adapted (ambient) mixture components contrasted with the greater average 86% identification of new unadapted (extra) mixture components. Identifications were lower for 1 than 5 mM components when concentrations were not matched, and ambient component identifications were lower after 10-s adaptation than after 1 or 2 sniffs. Rapid selective adaptation and mixture component suppression manipulate effective intensity to promote emergence of characteristic odor qualities in dynamic natural settings. PMID- 20720094 TI - Promoting knowledge of cancer prevention and screening in an underserved Hispanic women population: a culturally sensitive education program. AB - This article aims to measure the baseline knowledge of cancer prevention, screening, and early detection practices, to understand the barriers to cancer screening and sources of health information; and to evaluate the effectiveness of a culturally sensitive education program in an underserved Hispanic women population. A total of 180 women participated. Pre- and postsurveys were administered. Multivariate analysis was used to analyze the impact of program on knowledge and to determine factors affecting learning. Results showed Significant overall improvement in knowledge of cancer symptoms (1.85 baseline vs. 3.67 postintervention, p < .001), knowledge of risk-reducing behaviors (2.71 vs. 4.81, p < .001); and effect on planned behavior (89% planned to follow screening guidelines). Higher incomes and younger age are associated with better learning. Major barriers to cancer screening were financial limitations and lack of knowledge. The intervention was effective in promoting awareness and knowledge of cancer screening and prevention. Programs aimed at reducing cancer incidence and mortality should recognize the importance of cultural sensitivity and facilitating access to screening tests. PMID- 20720095 TI - Pilot test of a peer-led small-group video intervention to promote mammography screening among Chinese American immigrants. AB - This study evaluated the feasibility, acceptability, and potential effect of a small-group video intervention led by trained Chinese American lay educators who recruited Chinese American women not up to date on mammography screening. Nine lay educators conducted 14 Breast Health Tea Time Workshops in community settings and private homes that started with watching a culturally tailored video promoting screening followed by a question-and-answer session and distribution of print materials. Many group attendees did not have health insurance or a regular doctor, had low levels of income, and were not proficient in English. Forty-four percent of the attendees reported receipt of a mammogram within 6 months after the small-group session, with higher odds of screening among women who had lived in the United States less than 10% of their lifetime. Four of the educators were very interested in conducting another group session in the next 6 months. PMID- 20720096 TI - Postpartum smoking abstinence and smoke-free environments. AB - The purpose of this exploratory study was to describe factors that contribute to successful postpartum smoking abstinence among women who quit smoking during pregnancy. Research questions addressed the primary motivators and lifestyle characteristics of women who do not return to postpartum smoking. Participants were recruited from a feasibility study (N = 16) based on their ability to remain smoke free for at least 6 months following delivery. Individual interviews were analyzed using content analysis strategies. Women's narratives described the process of postpartum smoking abstinence. Four themes emerged: (a) child's health as the primary motivator, (b) demanding a smoke-free home or environment, (c) smoking perception changes from one of primarily comfort to one of disgust, and (d) viewing abstinence as a lifelong change. Clinical implications include educating families about the effects of smoke-free environments on the health of their children while redirecting smoking habits with healthy behaviors. PMID- 20720097 TI - Addressing sexual health in Florida youth: improving communication, collaboration, and consensus building among providers. AB - The purpose of this article is to describe (a) the Finding Common Ground Summits conducted in Florida during 2005-2006 with the objective of improving communication, collaboration, and consensus building among organizations interested in reducing sexual health risk behaviors among youth; (b) the attitudes of Summit participants; and (c) the impact of this exploratory initiative. The 196 participants, invited to participate by the Florida Department of Education, included individuals working in both school and community human sexuality education and promotion programs. Participants completed an initial survey just before the one-day Summits identifying attitudes and beliefs toward sexuality education. They were sent a Web survey approximately 6 months after the Summit to assess outcomes (n = 64). Frequencies and MANOVAs were conducted to assess differences on the attitude scale items between those identifying as supporters of abstinence-only, abstinence-based, and comprehensive sexuality education. The majority of participants believed sexuality education should be taught, gained an understanding of providers with varying philosophies, and wanted to continue collaborative efforts. This initial pilot project was successful in improving communication, collaboration, and consensus building among sexuality education providers, although future efforts are needed and encouraged as risky sexual behaviors among youth remain high. PMID- 20720098 TI - Birth order and risk of non-hodgkin lymphoma--true association or bias? AB - There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983-2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL. PMID- 20720099 TI - Validity of recall of tobacco use in two prospective cohorts. AB - This project studied the convergent validity of current recall of tobacco-related health behaviors, compared with prospective self-report collected earlier at two sites. Cohorts were from the Oregon Research Institute at Eugene (N = 346, collected 19.5 years earlier) and the University of Pittsburgh, Pennsylvania (N = 294, collected 3.9 years earlier). Current recall was examined through computer assisted interviews with the Lifetime Tobacco Use Questionnaire from 2005 through 2008. Convergent validity estimates demonstrated variability. Validity estimates of some tobacco use measures were significant for Oregon subjects (age at first cigarette, number of cigarettes/day, quit attempts yes/no and number of attempts, and abstinence symptoms at quitting; all P < 0.03). Validity estimates of Pittsburgh subjects' self-reports of tobacco use and abstinence symptoms were significant (P < 0.001) for all tobacco use and abstinence symptoms and for responses to initial use of tobacco. These findings support the utility of collecting recalled self-report information for reconstructing salient lifetime health behaviors and underscore the need for careful interpretation. PMID- 20720100 TI - In snow's footsteps: Commentary on shoe-leather and applied epidemiology. AB - The term shoe-leather epidemiology is often synonymous with field epidemiology or intervention epidemiology. All 3 terms imply investigations initiated in response to urgent public health problems and for which the investigative team does much of its work in the field (i.e., outside the office or laboratory). Alexander D. Langmuir is credited with articulating the concept of disease surveillance as it is applied to populations rather than individuals. He also founded the Epidemic Intelligence Service (EIS) Program in 1951, a 2-year training experience in applied epidemiology that places professionals in the field, domestically and internationally, in real-life situations. Today, 70-90 EIS officers are assigned each year to Centers for Disease Control and Prevention programs and to state and local health departments to meet the broad spectrum of challenges in chronic disease, injury prevention, violence, environmental health, occupational safety and health, and maternal and child health, as well as infectious diseases. Throughout their assignments, EIS officers are encouraged to strive for analytic rigor as well as public health consequence, which requires technical competence blended with good judgment and awareness of context. Effective applied epidemiologists must have skills beyond just epidemiology to improve a population's health; the field of applied epidemiology requires multiple team members, all having different but complementary skills, to be effective. PMID- 20720101 TI - Measurement error of dietary self-report in intervention trials. AB - Dietary intervention trials aim to change dietary patterns of individuals. Participating in such trials could impact dietary self-report in divergent ways: Dietary counseling and training on portion-size estimation could improve self report accuracy; participant burden could increase systematic error. Such intervention-associated biases could complicate interpretation of trial results. The authors investigated intervention-associated biases in reported total carotenoid intake using data on 3,088 breast cancer survivors recruited between 1995 and 2000 and followed through 2006 in the Women's Healthy Eating and Living Study, a randomized intervention trial. Longitudinal data from 2 self-report methods (24-hour recalls and food frequency questionnaires) and a plasma carotenoid biomarker were collected. A flexible measurement error model was postulated. Parameters were estimated in a Bayesian framework by using Markov chain Monte Carlo methods. Results indicated that the validity (i.e., correlation with "true" intake) of both self-report methods was significantly higher during follow-up for intervention versus nonintervention participants (4-year validity estimates: intervention = 0.57 for food frequency questionnaires and 0.58 for 24 hour recalls; nonintervention = 0.42 for food frequency questionnaires and 0.48 for 24-hour recalls). However, within- and between-instrument error correlations during follow-up were higher among intervention participants, indicating an increase in systematic error. Diet interventions can impact measurement errors of dietary self-report. Appropriate statistical methods should be applied to examine intervention-associated biases when interpreting results of diet trials. PMID- 20720102 TI - Ectopic Reelin induces neuronal aggregation with a normal birthdate-dependent "inside-out" alignment in the developing neocortex. AB - Neurons in the developing mammalian neocortex form the cortical plate (CP) in an "inside-out" manner; that is, earlier-born neurons form the deeper layers, whereas later-born neurons migrate past the existing layers and form the more superficial layers. Reelin, a glycoprotein secreted by Cajal-Retzius neurons in the marginal zone (MZ), is crucial for this "inside-out" layering, because the layers are inverted in the Reelin-deficient mouse, reeler (Reln(rl)). Even though more than a decade has passed since the discovery of reelin, the biological effect of Reelin on individual migrating neurons remains unclear. In addition, although the MZ is missing in the reeler cortex, it is unknown whether Reelin directly regulates the development of the cell-body-sparse MZ. To address these issues, we expressed Reelin ectopically in the developing mouse cortex, and the results showed that Reelin caused the leading processes of migrating neurons to assemble in the Reelin-rich region, which in turn induced their cell bodies to form cellular aggregates around Reelin. Interestingly, the ectopic Reelin-rich region became cell-body-sparse and dendrite-rich, resembling the MZ, and the late born neurons migrated past their predecessors toward the central Reelin-rich region within the aggregates, resulting in a birthdate-dependent "inside-out" alignment even ectopically. Reelin receptors and intracellular adaptor protein Dab1 were found to be necessary for formation of the aggregates. The above findings indicate that Reelin signaling is capable of inducing the formation of the dendrite-rich, cell-body-sparse MZ and a birthdate-dependent "inside-out" alignment of neurons independently of other factors/structures near the MZ. PMID- 20720103 TI - Separable prefrontal cortex contributions to free recall. AB - In everyday life, we often must remember the past in the absence of helpful cues in the environment. In these cases, the brain directs retrieval by relying on internally maintained cues and strategies. Free recall is a widely used behavioral paradigm for studying retrieval with minimal cue support. During free recall, individuals often recall semantically related items consecutively--an effect termed semantic clustering--and previous studies have sought to understand clustering to gain leverage on the basic mechanisms supporting strategic recall. Successful recall and semantic clustering depend on the prefrontal cortex (PFC). However, as a result of methodological limitations, few functional magnetic resonance imaging (fMRI) studies have assessed the neural mechanisms at encoding that support subsequent recall, and none have tested the event-related correlates of recall itself. Thus, it remains open whether one or several frontal control mechanisms operate during encoding and recall. Here, we applied a recently developed method (Oztekin et al., 2010) to assess event-related fMRI signal changes during free recall. During encoding, dorsolateral prefrontal cortex (DLPFC) activation was predictive of subsequent semantic clustering. In contrast, subregions of ventrolateral prefrontal cortex (VLPFC) were predictive of subsequent recall, whether clustered or nonclustered, and were inversely associated with clustering during recall. These results suggest that DLPFC supports relational processes at encoding that are sufficient to produce category clustering effects during recall. Conversely, controlled retrieval mechanisms supported by VLPFC support item-specific search during recall. PMID- 20720104 TI - Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. AB - The abnormal spine morphology found in fragile X syndrome (FXS) is suggestive of an error in the signaling cascades that organize the actin cytoskeleton. We report here that physiological activation of the small GTPase Rac1 and its effector p-21 activated kinase (PAK), two enzymes critically involved in actin management and functional synaptic plasticity, is impaired at hippocampal synapses in the Fmr1-knock-out (KO) mouse model of FXS. Theta burst afferent stimulation (TBS) caused a marked increase in the number of synapses associated with phosphorylated PAK in adult hippocampal slices from wild-type, but not Fmr1 KO, mice. Stimulation-induced activation of synaptic Rac1 was also absent in the mutants. The polymerization of spine actin that occurs immediately after theta stimulation appeared normal in mutant slices but the newly formed polymers did not properly stabilize, as evidenced by a prolonged vulnerability to a toxin (latrunculin) that disrupts dynamic actin filaments. Latrunculin also reversed long-term potentiation when applied at 10 min post-TBS, a time point at which the potentiation effect is resistant to interference in wild-type slices. We propose that a Rac>PAK signaling pathway needed for rapid stabilization of activity induced actin filaments, and thus for normal spine morphology and lasting synaptic changes, is defective in FXS. PMID- 20720105 TI - The development of the corpus callosum in the healthy human brain. AB - The corpus callosum changes structurally throughout life, but most dramatically during childhood and adolescence. Even so, existing studies of callosal development tend to use parcellation schemes that may not capture the complex spatial profile of anatomical changes. Thus, more detailed mapping of callosal growth processes is desirable to create a normative reference. This will help to relate and interpret other structural, functional, and behavioral measurements, both from healthy subjects and pediatric patients. We applied computational surface-based mesh-modeling methods to analyze callosal morphology at extremely high spatial resolution. We mapped callosal development and explored sex differences in a large and well matched sample of healthy children and adolescents (n = 190) aged 5-18 years. Except for the rostrum in females, callosal thickness increased across the whole surface, with sex- and region specific rates of growth, and at times shrinkage. The temporally distinct changes in callosal thickness are likely to be a consequence of varying degrees of axonal myelination, redirection, and pruning. Alternating phases of callosal growth and shrinkage may reflect a permanent adjustment and fine-tuning of fibers connecting homologous cortical areas during childhood and adolescence. Our findings emphasize the importance of taking into account sex differences in future studies, as existing developmental effects might remain disguised (or biased toward the effect of the dominant sex in unbalanced statistical designs) when pooling male and female samples. PMID- 20720106 TI - Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat. AB - The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network. PMID- 20720107 TI - The alpha-syntrophin PH and PDZ domains scaffold acetylcholine receptors, utrophin, and neuronal nitric oxide synthase at the neuromuscular junction. AB - At the neuromuscular junction (NMJ), the dystrophin protein complex provides a scaffold that functions to stabilize acetylcholine receptor (AChR) clusters. Syntrophin, a key component of that scaffold, is a multidomain adapter protein that links a variety of signaling proteins and ion channels to the dystrophin protein complex. Without syntrophin, utrophin and neuronal nitric oxide synthase mu (nNOSmu) fail to localize to the NMJ and the AChRs are distributed abnormally. Here we investigate the contribution of syntrophin domains to AChR distribution and to localization of utrophin and nNOSmu at the NMJ. Transgenic mice expressing alpha-syntrophin lacking portions of the first pleckstrin homology (PH) domain (DeltaPH1a or DeltaPH1b) or the entire PDZ domain (DeltaPDZ) were bred onto the alpha-syntrophin null background. As expected the DeltaPDZ transgene did not restore the NMJ localization of nNOS. The DeltaPH1a transgene did restore postsynaptic nNOS but surprisingly did not restore sarcolemmal nNOS (although sarcolemmal aquaporin-4 was restored). Mice lacking the alpha-syntrophin PDZ domain or either half of the PH1 domain were able to restore utrophin to the NMJ but did not correct the aberrant AChR distribution of the alpha-syntrophin knock out mice. However, mice expressing both the transgenic DeltaPDZ and the transgenic DeltaPH1a constructs did restore normal AChR distribution, demonstrating that both domains are required but need not be confined within the same protein to function. We conclude that the PH1 and PDZ domains of alpha syntrophin work in concert to facilitate the localization of AChRs and nNOS at the NMJ. PMID- 20720109 TI - Lobster attack induces sensitization in the sea hare, Aplysia californica. AB - Studies of the neural mechanisms of learning, especially of sensitization, have benefitted from extensive research on the model species, Aplysia californica (hereafter Aplysia). Considering this volume of literature on mechanisms, it is surprising that our understanding of the ecological context of sensitization in Aplysia is completely lacking. Indeed, the widespread use of strong electric shock to induce sensitization (an enhancement of withdrawal reflexes following noxious stimulation) is completely unnatural and leaves unanswered the question of whether this simple form of learning has any ecological relevance. We hypothesized that sublethal attack by a co-occurring predator, the spiny lobster, Panulirus interruptus, might be a natural sensitizing stimulus. We tested reflex withdrawal of the tail-mantle and head of individual Aplysia before and after attack by lobsters. Lobster attack significantly increased the amplitude of both reflexes, with a temporal onset that closely matched that observed with electric shock. This result suggests that electric shock may indeed mimic at least one naturally occurring sensitizing stimulus, suggesting, for the first time, an ecological context for this well studied form of learning. PMID- 20720108 TI - Mechanisms of regulation of oligodendrocyte development by p38 mitogen-activated protein kinase. AB - Many extracellular and intrinsic factors regulate oligodendrocyte development, but their signaling pathways remain poorly understood. Although the p38 mitogen activated protein kinase (MAPK)-dependent pathway is implicated in oligodendrocyte progenitor cell (OPC) lineage progression, its molecular targets involved in myelinogenesis are mostly unidentified. We have analyzed mechanisms by which p38MAPK regulates oligodendrocyte development and demonstrate that p38MAPK inhibition prevents OPC lineage progression and inhibits MBP (myelin basic protein) promoter activity and Sox10 function. In white-matter tissue, differential levels of MAPK phosphorylation are observed in oligodendrocyte lineage cells. Phosphorylated p38MAPK was found in CC1- and CNP-expressing differentiated oligodendrocytes of the adult brain and was temporally associated with a decline in the levels of phosphorylated extracellular signal-regulated kinase (ERK) in cells of this lineage. PDGF stimulates the phosphorylation of ERK, p38MAPK, and c-Jun N-terminal kinase (JNK), and p38MAPK inhibition was associated with increased ERK, JNK, and c-Jun phosphorylation. In the presence of PDGF, simultaneous inhibition of p38MAPK and either MAPK kinase (MEK) or JNK significantly alleviates the repression of myelin gene expression and lineage progression induced by p38MAPK inhibition alone. Dominant-negative c-Jun reverses the inhibition of myelin promoter activity by active MEK1 or dominant-negative p38MAPKalpha mutants, and phosphorylated c-Jun was detected at the MBP promoter after p38MAPK inhibition, indicating c-Jun as a negative mediator of p38MAPK action. Our findings indicate that p38MAPK activity in the brain supports myelin gene expression through distinct mechanisms via positive and negative regulatory targets. We show that oligodendrocyte differentiation involves p38-mediated Sox10 regulation and cross talk with parallel ERK and JNK pathways to repress c-Jun activity. PMID- 20720110 TI - The muscarinic long-term enhancement of NMDA and AMPA receptor-mediated transmission at Schaffer collateral synapses develop through different intracellular mechanisms. AB - We had described a muscarinic-mediated long-term synaptic enhancement at Schaffer collateral synapses caused by the insertion of AMPARs in spines of rat hippocampal CA1 pyramidal neurons that requires Ca(2+) release from IP3-sensitive stores (Fernandez de Sevilla et al., 2008). We now show that this AMPA-mediated LTP(IP3) is precisely matched by an amplification of NMDAR-mediated transmission. The enhanced AMPAR transmission involves SNARE protein activity and CaMKII activation. The amplification of NMDA transmission requires combined CaMKII, PKC, and SRC kinase activity without detectable surface incorporation of NMDARs, suggesting that changes in receptor properties mediate this process. The enhanced AMPAR- and NMDAR-mediated transmission markedly reduce the induction threshold of "Hebbian" LTP. We conclude that both modes of glutamatergic synaptic potentiation may play a critical functional role in the regulation of the learning machinery of the brain by adding flexibility to the demands of the hippocampal network. PMID- 20720111 TI - Role of aberrant striatal dopamine D1 receptor/cAMP/protein kinase A/DARPP32 signaling in the paradoxical calming effect of amphetamine. AB - Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine insensitive DAT that is functional but with reduced dopamine uptake function. DAT CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8 dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels. PMID- 20720112 TI - Impaired speech repetition and left parietal lobe damage. AB - Patients with left hemisphere damage and concomitant aphasia usually have difficulty repeating others' speech. Although impaired speech repetition, the primary symptom of conduction aphasia, has been associated with involvement of the left arcuate fasciculus, its specific lesion correlate remains elusive. This research examined speech repetition among 45 stroke patients who underwent aphasia testing and MRI examination. Based on lesion-behavior mapping, the primary structural damage most closely associated with impaired speech repetition was found in the posterior portion of the left arcuate fasciculus. However, perfusion-weighted MRI revealed that tissue dysfunction, in the form of either frank damage or hypoperfusion, to the left inferior parietal lobe, rather than the underlying white matter, was associated with impaired speech repetition. This latter result suggests that integrity of the left inferior parietal lobe is important for speech repetition and, as importantly, highlights the importance of examining cerebral perfusion for the purpose of lesion-behavior mapping in acute stroke. PMID- 20720113 TI - Longitudinal evidence for functional specialization of the neural circuit supporting working memory in the human brain. AB - Although children perform more poorly than adults on many cognitive measures, they are better able to learn things such as language and music. These differences could result from the delayed specialization of neural circuits and asynchronies in the maturation of neural substrates required for learning. Working memory--the ability to hold information in mind that is no longer present in the environment--comprises a set of cognitive processes required for many, if not all, forms of learning. A critical neural substrate for working memory (the prefrontal cortex) continues to mature through early adulthood. What are the functional consequences of this late maturation for working memory? Using a longitudinal design, we show that although individuals recruit prefrontal cortex as expected during both early and late adolescence during a working memory task, this recruitment is correlated with behavior only in late adolescence. The hippocampus is also recruited, but only during early, and not late, adolescence. Moreover, the hippocampus and prefrontal cortex are coactive in early adolescence regardless of task demands or performance, in contrast to the pattern seen in late adolescents and adults, when these regions are coactive only under high task demands. Together, these data demonstrate that neural circuitry underlying working memory changes during adolescent development. The diminishing contribution of the hippocampus in working memory function with age is an important observation that informs questions about how children and adults learn differently. PMID- 20720114 TI - The scaffold protein NHERF2 determines the coupling of P2Y1 nucleotide and mGluR5 glutamate receptor to different ion channels in neurons. AB - Expressed metabotropic group 1 glutamate mGluR5 receptors and nucleotide P2Y1 receptors (P2Y1Rs) show promiscuous ion channel coupling in sympathetic neurons: their stimulation inhibits M-type [Kv7, K(M)] potassium currents and N-type (Ca(V)2.2) calcium currents (Kammermeier and Ikeda, 1999; Brown et al., 2000). These effects are mediated by G(q) and G(i/o) G-proteins, respectively. Via their C-terminal tetrapeptide, these receptors also bind to the PDZ domain of the scaffold protein NHERF2, which enhances their coupling to G(q)-mediated Ca(2+) signaling (Fam et al., 2005; Paquet et al., 2006b). We investigated whether NHERF2 could modulate coupling to neuronal ion channels. We find that coexpression of NHERF2 in sympathetic neurons (by intranuclear cDNA injections) does not affect the extent of M-type potassium current inhibition produced by either receptor but strongly reduced Ca(V)2.2 inhibition by both P2Y1R and mGluR5 activation. NHERF2 expression had no significant effect on Ca(V)2.2 inhibition by norepinephrine (via alpha(2)-adrenoceptors, which do not bind NHERF2), nor on Ca(V)2.2 inhibition produced by an expressed P2Y1R lacking the NHERF2-binding DTSL motif. Thus, NHERF2 selectively restricts downstream coupling of mGluR5 and P2Y1Rs in neurons to G(q)-mediated responses such as M-current inhibition. Differential distribution of NHERF2 in neurons may therefore determine coupling of mGluR5 receptors and P2Y1 receptors to calcium channels. PMID- 20720115 TI - The postsynaptic adenomatous polyposis coli (APC) multiprotein complex is required for localizing neuroligin and neurexin to neuronal nicotinic synapses in vivo. AB - Synaptic efficacy requires that presynaptic and postsynaptic specializations align precisely and mature coordinately. The underlying mechanisms are poorly understood, however. We propose that adenomatous polyposis coli protein (APC) is a key coordinator of presynaptic and postsynaptic maturation. APC organizes a multiprotein complex that directs nicotinic acetylcholine receptor (nAChR) localization at postsynaptic sites in avian ciliary ganglion neurons in vivo. We hypothesize that the APC complex also provides retrograde signals that direct presynaptic active zones to develop in register with postsynaptic nAChR clusters. In our model, the APC complex provides retrograde signals via postsynaptic neuroligin that interacts extracellularly with presynaptic neurexin. S-SCAM (synaptic cell adhesion molecule) and PSD-93 (postsynaptic density-93) are scaffold proteins that bind to neuroligin. We identify S-SCAM as a novel component of neuronal nicotinic synapses. We show that S-SCAM, PSD-93, neuroligin and neurexin are enriched at alpha3*-nAChR synapses. PSD-93 and S-SCAM bind to APC and its binding partner beta-catenin, respectively. Blockade of selected APC and beta-catenin interactions, in vivo, leads to decreased postsynaptic accumulation of S-SCAM, but not PSD-93. Importantly, neuroligin synaptic clusters are also decreased. On the presynaptic side, there are decreases in neurexin and active zone proteins. Further, presynaptic terminals are less mature structurally and functionally. We define a novel neural role for APC by showing that the postsynaptic APC multiprotein complex is required for anchoring neuroligin and neurexin at neuronal synapses in vivo. APC human gene mutations correlate with autism spectrum disorders, providing strong support for the importance of the association, demonstrated here, between APC, neuroligin and neurexin. PMID- 20720117 TI - Reward changes salience in human vision via the anterior cingulate. AB - Reward-related mesolimbic dopamine steers animal behavior, creating automatic approach toward reward-associated objects and avoidance of objects unlikely to be beneficial. Theories of dopamine suggest that this reflects underlying biases in perception and attention, with reward enhancing the representation of reward associated stimuli such that attention is more likely to be deployed to the location of these objects. Using measures of behavior and brain electricity in male and female humans, we demonstrate this to be the case. Sensory and perceptual processing of reward-associated visual features is facilitated such that attention is deployed to objects characterized by these features in subsequent experimental trials. This is the case even when participants know that a strategic decision to attend to reward-associated features will be counterproductive and result in suboptimal performance. Other results show that the magnitude of visual bias created by reward is predicted by the response to reward feedback in anterior cingulate cortex, an area with strong connections to dopaminergic structures in the midbrain. These results demonstrate that reward has an impact on vision that is independent of its role in the strategic establishment of endogenous attention. We suggest that reward acts to change visual salience and thus plays an important and undervalued role in attentional control. PMID- 20720116 TI - Structural dynamics of synapses in vivo correlate with functional changes during experience-dependent plasticity in visual cortex. AB - The impact of activity on neuronal circuitry is complex, involving both functional and structural changes whose interaction is largely unknown. We have used optical imaging of mouse visual cortex responses and two-photon imaging of superficial layer spines on layer 5 neurons to monitor network function and synaptic structural dynamics in the mouse visual cortex in vivo. Total lack of vision due to dark-rearing from birth dampens visual responses and shifts spine dynamics and morphologies toward an immature state. The effects of vision after dark rearing are strongly dependent on the timing of exposure: over a period of days, functional and structural changes are temporally related such that light stabilizes spines while increasing visually driven activity. The effects of long term light exposure can be partially mimicked by experimentally enhancing inhibitory signaling in the darkness. Brief light exposure, however, results in a rapid, transient, NMDA-dependent increase of cortical responses, accompanied by increased dynamics of dendritic spines. These findings indicate that visual experience induces rapid reorganization of cortical circuitry followed by a period of stabilization, and demonstrate a close relationship between dynamic changes at single synapses and cortical network function. PMID- 20720118 TI - Nuclear factor kappaB controls acetylcholine receptor clustering at the neuromuscular junction. AB - At the vertebrate neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is stimulated by motor neuron-derived glycoprotein Agrin and requires a number of intracellular signal or structural proteins, including AChR associated scaffold protein Rapsyn. Here, we report a role of nuclear factor kappaB (NF-kappaB), a well known transcription factor involved in a variety of immune responses, in regulating AChR clustering at the NMJ. We found that downregulating the expression of RelA/p65 subunit of NF-kappaB or inhibiting NF kappaB activity by overexpression of mutated form of IkappaB (inhibitor kappaB), which is resistant to proteolytic degradation and thus constitutively keeps NF kappaB inactive in the cytoplasma, impeded the formation of AChR clusters in cultured C2C12 muscle cells stimulated by Agrin. In contrast, overexpression of RelA/p65 promoted AChR clustering. Furthermore, we investigated the mechanism by which NF-kappaB regulates AChR clustering. Interestingly, we found that downregulating the expression of RelA/p65 caused a marked reduction in the protein and mRNA level of Rapsyn and upregulation of RelA/p65 enhanced Rapsyn promoter activity. Mutation of NF-kappaB binding site on Rapsyn promoter prevented responsiveness to RelA/p65 regulation. Moreover, forced expression of Rapsyn in RelA/p65 downregulated muscle cells partially rescued AChR clusters, suggesting that NF-kappaB regulates AChR clustering, at least partially through the transcriptional regulation of Rapsyn. In line with this notion, genetic ablation of RelA/p65 selectively in the skeletal muscle caused a reduction of AChR density at the NMJ and a decrease in the level of Rapsyn. Thus, NF-kappaB signaling controls AChR clustering through transcriptional regulation of synaptic protein Rapsyn. PMID- 20720119 TI - Spectral integration in primary auditory cortex attributable to temporally precise convergence of thalamocortical and intracortical input. AB - Primary sensory cortex integrates sensory information from afferent feedforward thalamocortical projection systems and convergent intracortical microcircuits. Both input systems have been demonstrated to provide different aspects of sensory information. Here we have used high-density recordings of laminar current source density (CSD) distributions in primary auditory cortex of Mongolian gerbils in combination with pharmacological silencing of cortical activity and analysis of the residual CSD, to dissociate the feedforward thalamocortical contribution and the intracortical contribution to spectral integration. We found a temporally highly precise integration of both types of inputs when the stimulation frequency was in close spectral neighborhood of the best frequency of the measurement site, in which the overlap between both inputs is maximal. Local intracortical connections provide both directly feedforward excitatory and modulatory input from adjacent cortical sites, which determine how concurrent afferent inputs are integrated. Through separate excitatory horizontal projections, terminating in cortical layers II/III, information about stimulus energy in greater spectral distance is provided even over long cortical distances. These projections effectively broaden spectral tuning width. Based on these data, we suggest a mechanism of spectral integration in primary auditory cortex that is based on temporally precise interactions of afferent thalamocortical inputs and different short- and long-range intracortical networks. The proposed conceptual framework allows integration of different and partly controversial anatomical and physiological models of spectral integration in the literature. PMID- 20720121 TI - Stability of the visual world during eye drift. AB - We are normally not aware of the microscopic eye movements that keep the retinal image in motion during visual fixation. In principle, perceptual cancellation of the displacements of the retinal stimulus caused by fixational eye movements could be achieved either by means of motor/proprioceptive information or by inferring eye movements directly from the retinal stimulus. In this study, we examined the mechanisms underlying visual stability during ocular drift, the primary source of retinal image motion during fixation on a stationary scene. By using an accurate system for gaze-contingent display control, we decoupled the eye movements of human observers from the changes in visual input that they normally cause. We show that the visual system relies on the spatiotemporal stimulus on the retina, rather than on extraretinal information, to discard the motion signals resulting from ocular drift. These results have important implications for the establishment of stable visual representations in the brain and argue that failure to visually determine eye drift contributes to well known motion illusions such as autokinesis and induced movement. PMID- 20720120 TI - Intrinsic circuit organization and theta-gamma oscillation dynamics in the entorhinal cortex of the rat. AB - A thorough knowledge of the intrinsic circuit properties of the entorhinal cortex (EC) and the temporal dynamics these circuits support is essential for understanding how information is exchanged between the hippocampus and neocortex. Using intracellular and extracellular recordings in the anesthetized rat and anatomical reconstruction of single cells, we found that EC5 and EC2 principal neurons form large axonal networks mainly within their layers, interconnected by the more vertically organized axon trees of EC3 pyramidal cells. Principal cells showed layer-specific unique membrane properties and contributed differentially to theta and gamma oscillations. EC2 principal cells were most strongly phase modulated by EC theta. The multiple gamma oscillators, present in the various EC layers, were temporally coordinated by the phase of theta waves. Putative interneurons in all EC layers fired relatively synchronously within the theta cycle, coinciding with the maximum power of gamma oscillation. The special wiring architecture and unique membrane properties of EC neurons may underlie their behaviorally distinct firing patterns in the waking animal. PMID- 20720122 TI - Motoneurons dedicated to either forward or backward locomotion in the nematode Caenorhabditis elegans. AB - Multifunctional motoneurons and muscles, which are active during forward and backward locomotion are ubiquitous in animal models. However, studies in the nematode Caenorhabditis elegans suggest that some locomotor motoneurons are necessary only for forward locomotion (dorsal B-motoneurons, DB), while others (dorsal A-motoneurons, DA) are necessary only for backward locomotion. We tested this hypothesis directly by recording the activity of these motoneurons during semirestrained locomotion. For this purpose, we used epifluorescence imaging of the genetically encoded calcium sensor cameleon, expressed in specific motoneurons, while monitoring locomotor behavior through the microscope condenser using a second camera. We found that ventral and dorsal B-motoneurons (DB and VB) were coactive during forward locomotion while ventral A-motoneurons (VA) were only active during backward locomotion. The signals we recorded correlated with the direction of locomotion but not with the faster undulatory cycles. To our knowledge, these are the first recordings of motoneuron activity in C. elegans and the only direction-dedicated motoneurons described to date. PMID- 20720123 TI - A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. AB - We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD. PMID- 20720124 TI - Sonic hedgehog guides post-crossing commissural axons both directly and indirectly by regulating Wnt activity. AB - After midline crossing, axons of dorsolateral commissural neurons turn rostrally into the longitudinal axis of the spinal cord. In mouse, the graded distribution of Wnt4 attracts post-crossing axons rostrally. In contrast, in the chicken embryo, the graded distribution of Sonic hedgehog (Shh) guides post-crossing axons by a repulsive mechanism mediated by hedgehog-interacting protein. Based on these observations, we tested for a possible cooperation between the two types of morphogens. Indeed, we found that Wnts also act as axon guidance cues in the chicken spinal cord. However, in contrast to the mouse, Wnt transcription did not differ along the anteroposterior axis of the spinal cord. Rather, Wnt function was regulated by a gradient of the Wnt antagonist Sfrp1 (Secreted frizzled related protein 1) that in turn was shaped by the Shh gradient. Thus, Shh affects post-crossing axon guidance both directly and indirectly by regulating Wnt function. PMID- 20720126 TI - Repeated stress impairs endocannabinoid signaling in the paraventricular nucleus of the hypothalamus. AB - Endocannabinoids (eCBs) are ubiquitous retrograde signaling molecules in the nervous system that are recruited in response to robust neuronal activity or the activation of postsynaptic G-protein-coupled receptors. Physiologically, eCBs have been implicated as important mediators of the stress axis and they may contribute to the rapid feedback inhibition of the hypothalamic-pituitary-adrenal axis (HPA) by circulating corticosteroids (CORTs). Understanding the relationship between stress and eCBs, however, is complicated by observations that eCB signaling is itself sensitive to stress. The mechanisms that link stress to changes in synaptic eCB signaling and the impact of these changes on CORT mediated negative feedback have not been resolved. Here, we show that repetitive immobilization stress, in juvenile male rats, causes a functional downregulation of CB(1) receptors in the paraventricular nucleus of the hypothalamus (PVN). This loss of CB(1) receptor signaling, which requires the activation of genomic glucocorticoid receptors, impairs both activity and receptor-dependent eCB signaling at GABA and glutamate synapses on parvocellular neuroendocrine cells in PVN. Our results provide a plausible mechanism for how stress can lead to alterations in CORT-mediated negative feedback and may contribute to the development of plasticity of HPA responses. PMID- 20720125 TI - Implicit perceptual anticipation triggered by statistical learning. AB - Our environments are highly regular in terms of when and where objects appear relative to each other. Statistical learning allows us to extract and represent these regularities, but how this knowledge is used by the brain during ongoing perception is unclear. We used rapid event-related fMRI to measure hemodynamic responses to individual visual images in a continuous stream that contained sequential contingencies. Sixteen human observers encountered these statistical regularities while performing an unrelated cognitive task, and were unaware of their existence. Nevertheless, the right anterior hippocampus showed greater hemodynamic responses to predictive stimuli, providing evidence for implicit anticipation as a consequence of unsupervised statistical learning. Hippocampal anticipation based on predictive stimuli correlated with subsequent processing of the predicted stimuli in occipital and parietal cortex, and anticipation in additional brain regions correlated with facilitated object recognition as reflected in behavioral priming. Additional analyses suggested that implicit perceptual anticipation does not contribute to explicit familiarity, but can result in predictive potentiation of category-selective ventral visual cortex. Overall, these findings show that future-oriented processing can arise incidentally during the perception of statistical regularities. PMID- 20720127 TI - Direction-selective ganglion cells show symmetric participation in retinal waves during development. AB - Direction-selective ganglion cells (DSGCs) fire robustly for stimuli moving along one direction of motion and are strongly inhibited by stimuli moving in the opposite, or null, direction. In contrast to direction-selective neurons in primary visual cortex, a role for neural activity in the development of direction selective retinal circuits has not been established. Direction-selective responses are detected at eye opening, before which spontaneous correlated activity known as retinal waves provide directional input to ganglion cells. Indeed, we observed a significant bias in wave propagation along the nasal over temporal direction. Using simultaneous calcium imaging and cell-attached recordings from three genetically labeled DSGC types in mice, we observed that all three DSGC types fire action potentials during retinal waves. However, we found that the direction of wave propagation did not influence DSGC spiking. These results indicate that the mechanisms guiding the formation of the asymmetric inhibition underlying direction selectivity in the retina are not dependent upon the directional properties of retinal waves. PMID- 20720128 TI - Presynaptic kainate receptor activation preserves asynchronous GABA release despite the reduction in synchronous release from hippocampal cholecystokinin interneurons. AB - Inhibitory synaptic transmission in the hippocampus in mediated by a wide variety of different interneuron classes which are assumed to play different roles in network activity. Activation of presynaptic kainate receptors (KARs) has been shown to reduce inhibitory transmission but the interneuron class(es) at which they act is only recently beginning to emerge. Using paired recordings we show that KAR activation causes a decrease in presynaptic release from cholecystokinin (CCK)- but not parvalbumin-containing interneurons and that this decrease is observed when pyramidal cells, but not interneurons, are the postsynaptic target. We also show that although the synchronous release component is reduced, the barrage of asynchronous GABA release from CCK interneurons during sustained firing is unaffected by KAR activation. This indicates that presynaptic KARs preserve and act in concert with asynchronous release to switch CCK interneurons from a phasic inhibition mode to produce prolonged inhibition during periods of intense activity. PMID- 20720129 TI - A temporal hierarchy for conspecific vocalization discrimination in humans. AB - The ability to discriminate conspecific vocalizations is observed across species and early during development. However, its neurophysiologic mechanism remains controversial, particularly regarding whether it involves specialized processes with dedicated neural machinery. We identified spatiotemporal brain mechanisms for conspecific vocalization discrimination in humans by applying electrical neuroimaging analyses to auditory evoked potentials (AEPs) in response to acoustically and psychophysically controlled nonverbal human and animal vocalizations as well as sounds of man-made objects. AEP strength modulations in the absence of topographic modulations are suggestive of statistically indistinguishable brain networks. First, responses were significantly stronger, but topographically indistinguishable to human versus animal vocalizations starting at 169-219 ms after stimulus onset and within regions of the right superior temporal sulcus and superior temporal gyrus. This effect correlated with another AEP strength modulation occurring at 291-357 ms that was localized within the left inferior prefrontal and precentral gyri. Temporally segregated and spatially distributed stages of vocalization discrimination are thus functionally coupled and demonstrate how conventional views of functional specialization must incorporate network dynamics. Second, vocalization discrimination is not subject to facilitated processing in time, but instead lags more general categorization by approximately 100 ms, indicative of hierarchical processing during object discrimination. Third, although differences between human and animal vocalizations persisted when analyses were performed at a single-object level or extended to include additional (man-made) sound categories, at no latency were responses to human vocalizations stronger than those to all other categories. Vocalization discrimination transpires at times synchronous with that of face discrimination but is not functionally specialized. PMID- 20720130 TI - Age-related deterioration of rod vision in mice. AB - Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and, more specifically, photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid-deficiency hypothesis, we compared the morphological and functional properties of rods of adult and aged B6D2F1/J mice. We found that the number of rods and the length of their outer segments were significantly reduced in 2.5-year-old mice compared with 4-month-old animals. Aging also resulted in a twofold reduction in the total level of opsin in the retina. Behavioral tests revealed that scotopic visual acuity and contrast sensitivity were decreased by twofold in aged mice, and rod ERG recordings demonstrated reduced amplitudes of both a- and b-waves. Sensitivity of aged rods determined from single-cell recordings was also decreased by 1.5-fold, corresponding to not more than 1% free opsin in these photoreceptors, and kinetic parameters of dim flash response were not altered. Notably, the rate of rod dark adaptation was unaffected by age. Thus, our results argue against age-related deficiency of 11-cis-retinal in the B6D2F1/J mouse rod visual cycle. Surprisingly, the level of cellular dark noise was increased in aged rods, providing an alternative mechanism for their desensitization. PMID- 20720131 TI - Precise spatiotemporal patterns among visual cortical areas and their relation to visual stimulus processing. AB - Visual processing shows a highly distributed organization in which the presentation of a visual stimulus simultaneously activates neurons in multiple columns across several cortical areas. It has been suggested that precise spatiotemporal activity patterns within and across cortical areas play a key role in higher cognitive, motor, and visual functions. In the visual system, these patterns have been proposed to take part in binding stimulus features into a coherent object, i.e., to be involved in perceptual grouping. Using voltage sensitive dye imaging (VSDI) in behaving monkeys (Macaca fascicularis, males), we simultaneously measured neural population activity in the primary visual cortex (V1) and extrastriate cortex (V2, V4) at high spatial and temporal resolution. We detected time point population events (PEs) in the VSDI signal of each pixel and found that they reflect transient increased neural activation within local populations by establishing their relation to spiking and local field potential activity. Then, we searched for repeating space and time relations between the detected PEs. We demonstrate the following: (1) spatiotemporal patterns occurring within (horizontal) and across (vertical) early visual areas repeat significantly above chance level; (2) information carried in only a few patterns can be used to reliably discriminate between stimulus categories on a single-trial level; (3) the spatiotemporal patterns yielding high classification performance are characterized by late temporal occurrence and top-down propagation, which are consistent with cortical mechanisms involving perceptual grouping. The pattern characteristics and the robust relation between the patterns and the stimulus categories suggest that spatiotemporal activity patterns play an important role in cortical mechanisms of higher visual processing. PMID- 20720133 TI - Commentary on an article by Christopher J. Lenarz, MD, et Al.: "Timing of wound closure in open fractures based on cultures obtained after debridement". PMID- 20720132 TI - Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. AB - Glutamate is the major excitatory neurotransmitter in the brain. The NMDA subtype of glutamate receptors (NMDAR) is known to mediate many physiological neural functions. However, excessive activation of NMDARs contributes to neuronal damage in various acute and chronic neurological disorders. To avoid unwanted adverse side effects, blockade of excessive NMDAR activity must therefore be achieved without affecting its physiological function. Memantine, an adamantane derivative, has been used for the treatment of Alzheimer's disease with an excellent clinical safety profile. We previously showed that memantine preferentially blocked neurotoxicity mediated by excessive NMDAR activity while relatively sparing normal neurotransmission, in part because of its uncompetitive antagonism with a fast off-rate. Here, using rat autaptic hippocampal microcultures, we show that memantine at therapeutic concentrations (1-10 microM) preferentially blocks extrasynaptic rather than synaptic currents mediated by NMDARs in the same neuron. We found that memantine blocks extrasynaptic NMDAR mediated currents induced by bath application of 100 microM NMDA/10 microM glycine with a twofold higher potency than its blockade of the NMDAR component of evoked EPSCs (EPSCs(NMDAR)); this effect persists under conditions of pathological depolarization in the presence of 1 mm extracellular Mg(2+). Thus, our findings provide the first unequivocal evidence to explain the tolerability of memantine based on differential extrasynaptic/synaptic receptor blockade. At therapeutic concentrations, memantine effectively blocks excessive extrasynaptic NMDAR-mediated currents, while relatively sparing normal synaptic activity. PMID- 20720134 TI - Comparison of a standard and a gender-specific posterior cruciate-substituting high-flexion knee prosthesis: a prospective, randomized, short-term outcome study. AB - BACKGROUND: Recently, much debate has focused on the effect of gender-specific total knee arthroplasty. The purpose of the present study was to compare clinical and radiographic results as well as femoral component fit in patients receiving either a standard posterior cruciate-substituting LPS-Flex or gender-specific posterior cruciate-substituting LPS-Flex total knee prosthesis. METHODS: Sequential simultaneous bilateral total knee arthroplasty was performed for eighty-five patients (170 knees). Eighty-five women (mean age, 69.7 years) received a standard LPS-Flex prosthesis in one knee and a gender-specific LPS Flex prosthesis in the contralateral knee. The mean duration of follow-up was 2.13 years. At each follow-up, the Knee Society score, the Hospital for Special Surgery knee score, the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score, and radiographs were evaluated. The aspect ratio of the distal part of the femur was compared with those of the standard LPS-Flex prosthesis and the gender-specific LPS-Flex prosthesis. RESULTS: The mean postoperative Knee Society scores (95.5 points in the standard implant group, compared with 96.5 points in the gender-specific implant group) and Hospital for Special Surgery knee scores (90.7 points in the standard implant group, compared with 91.2 points in the gender-specific implant group) were similar in both groups. The mean postoperative WOMAC score was 36.6 points. Postoperatively, the mean ranges of knee motion in the supine position (125 degrees in the standard implant group, compared with 126 degrees in the gender-specific implant group), patient satisfaction (8.3 points in the standard implant group, compared with 8.1 points in the gender-specific implant group), and radiographic results were similar in both groups. The femoral component in the standard implant group fit significantly better than that in the gender-specific implant group (p < 0.0001). CONCLUSIONS: The present study did not show any clinical benefits of a gender specific LPS-Flex total knee prosthesis at the time of short-term follow-up. Longer follow-up is needed to determine whether there will be an advantage in terms of longer-term function. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. PMID- 20720135 TI - Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. AB - BACKGROUND: The purpose of this study was to compare the outcomes of treatment with bone marrow aspirate concentrate, a simple, one-step, autogenous, and arthroscopically applicable method, with the outcomes of microfracture with regard to the repair of full-thickness cartilage defects in an equine model. METHODS: Extensive (15-mm-diameter) full-thickness cartilage defects were created on the lateral trochlear ridge of the femur in twelve horses. Bone marrow was aspirated from the sternum and centrifuged to generate the bone marrow concentrate. The defects were treated with bone marrow concentrate and microfracture or with microfracture alone. Second-look arthroscopy was performed at three months, and the horses were killed at eight months. Repair was assessed with use of macroscopic and histological scoring systems as well as with quantitative magnetic resonance imaging. RESULTS: No adverse reactions due to the microfracture or the bone marrow concentrate were observed. At eight months, macroscopic scores (mean and standard error of the mean, 9.4 + or - 1.2 compared with 4.4 + or - 1.2; p = 0.009) and histological scores (11.1 + or - 1.6 compared with 6.4 + or - 1.2; p = 0.02) indicated improvement in the repair tissue in the bone marrow concentrate group compared with that in the microfracture group. All scoring systems and magnetic resonance imaging data indicated that delivery of the bone marrow concentrate resulted in increased fill of the defects and improved integration of repair tissue into surrounding normal cartilage. In addition, there was greater type-II collagen content and improved orientation of the collagen as well as significantly more glycosaminoglycan in the bone marrow concentrate-treated defects than in the microfracture-treated defects. CONCLUSIONS: Delivery of bone marrow concentrate can result in healing of acute full-thickness cartilage defects that is superior to that after microfracture alone in an equine model. CLINICAL RELEVANCE: Delivery of bone marrow concentrate to cartilage defects has the clinical potential to improve cartilage healing, providing a simple, cost-effective, arthroscopically applicable, and clinically effective approach for cartilage repair. PMID- 20720136 TI - The modified oblique keller capsular interpositional arthroplasty for hallux rigidus. AB - BACKGROUND: Hallux rigidus is a common problem characterized by localized osteoarthritis and limited range of motion of the hallux. First metatarsophalangeal joint arthrodesis has been the accepted procedure for the treatment of late-stage disease. Despite the success of arthrodesis, some patients object to the notion of eliminating motion at the metatarsophalangeal joint. For this reason, motion-sparing procedures such as the modified oblique Keller capsular interpositional arthroplasty have been developed. METHODS: We compared a cohort of ten patients (ten toes) who had undergone the modified Keller arthroplasty with a group of twelve patients (twelve toes) who had undergone a first metatarsophalangeal joint arthrodesis at an average of sixty three and sixty-eight months, respectively. Clinical outcomes were evaluated, and range of motion, great toe dynamometer strength, plantar pressures, and radiographs were assessed. RESULTS: Clinical outcome differences existed between the groups, with the American Orthopaedic Foot and Ankle Society score being significantly higher for the arthroplasty group than for the arthrodesis group. The arthroplasty group had a mean of 54 degrees of passive and 30 degrees of active range of motion of the first metatarsophalangeal joint. The plantar pressure data revealed significantly higher pressures in the arthrodesis group under the great toe but not under the second metatarsal head. CONCLUSIONS: The modified oblique Keller capsular interpositional arthroplasty appears to be a motion-sparing procedure with clinical outcomes equivalent to those of arthrodesis, and it is associated with a more normal pattern of plantar pressures during walking. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence. PMID- 20720137 TI - Pelvic inlet and outlet radiographs redefined. AB - BACKGROUND: Musculoskeletal plain radiographic imaging protocols are typically predicated on orthogonal views of the bone or joint being evaluated. Pelvic injury has been evaluated with 45 degrees inlet and 45 degrees outlet radiographs. While these views are perpendicular to each other, they may not be in the best plane to evaluate pelvic injury because of variable lumbopelvic anatomy. We hypothesized that inlet and outlet radiographic views optimized to examine the clinically relevant osseous landmarks vary substantially from routine 45 degrees inlet and outlet views. METHODS: Sixty-eight consecutive patients without pelvic ring disruption who had undergone routine axial pelvic computed tomography scans were retrospectively identified. The optimal inlet and outlet angles required to profile the clinically relevant pelvic anatomy were quantified for each patient with use of sagittal computed tomography reconstructions. RESULTS: The optimal inlet angle to profile the anterior body of S1 required an average caudal tilt of 21 degrees . The average outlet angle (cephalad tilt) perpendicular to the body of S1 was 63 degrees and perpendicular to S2 was 57 degrees . The optimal angles were the same for male and female patients and for patients with normal and dysmorphic pelves and were independent of patient age. CONCLUSIONS: Screening inlet and screening outlet radiographs made at 25 degrees and 60 degrees , respectively, are recommended to provide accurate profiles of the clinically relevant posterior osseous pelvic anatomy. PMID- 20720138 TI - Obesity, age, sex, diagnosis, and fixation mode differently affect early cup failure in total hip arthroplasty: a matched case-control study of 4420 patients. AB - BACKGROUND: Studies about the influence of patient characteristics on mechanical failure of cups in total hip replacement have applied different methodologies and revealed inconclusive results. The fixation mode has rarely been investigated. Therefore, we conducted a detailed analysis of the influence of patient characteristics and fixation mode on cup failure risks. METHODS: We conducted a case-control study of total hip arthroplasties in 4420 patients to test our hypothesis that patient characteristics of sex, age, weight, body mass index, and diagnosis have different influences on risks for early mechanical failure in cemented and uncemented cups. RESULTS: Women had significantly reduced odds for failure of cups with cemented fixation (odds ratio = 0.59; 95% confidence interval, 0.43 to 0.83; p = 0.002) and uncemented fixation (odds ratio = 0.63; 95% confidence interval, 0.5 to 0.81; p = 0.0003) compared with that for men (odds ratio = 1). Each additional year of patient age at the time of surgery reduced the failure odds by a factor of 0.98 for both cemented cups (odds ratio = 0.98; 95% confidence interval, 0.96 to 0.99; p = 0.016) and uncemented cups (odds ratio = 0.98; 95% confidence interval, 0.97 to 0.99; p = 0.0002). In patients with cemented cups, the weight group of 73 to 82 kg had significantly lower failure odds (odds ratio = 0.63; 95% confidence interval, 0.4 to 0.98) than the lightest (<64 kg) weight group or the heaviest (>82 kg) weight group (odds ratios = 1.00 and 1.07, respectively). No significant effects of weight were noted in the uncemented group. In contrast, obese patients (a body mass index of >30 kg/m(2)) with uncemented cups had significantly elevated odds relative to patients with a body mass of <25 kg/m(2) (odds ratio = 1.41; 95% confidence interval, 1.03 to 1.91) for early failure of the cups compared with an insignificant effect in the cemented arm of the study. Compared with osteoarthritis as the reference diagnosis (odds ratio = 1), developmental dysplasia (odds ratio = 0.52; 95% confidence interval, 0.28 to 0.97) and hip fracture (odds ratio = 0.38; 95% confidence interval, 0.16 to 0.92) were significantly protective in cemented cups. CONCLUSIONS: Female sex and older age have similarly protective effects on the odds for early failure of cemented and uncemented cups. Although a certain body-weight range has a significant protective effect in cemented cups, the more important finding was the significantly increased risk for failure of uncemented cups in obese patients. Patients with developmental dysplasia and hip fracture were the only diagnostic groups with a significantly decreased risk for cup failure, but only with cemented fixation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence. PMID- 20720139 TI - Influence of obesity on femoral osteolysis five and ten years following total hip arthroplasty. AB - BACKGROUND: The most important long-term complication following total hip arthroplasty is periprosthetic femoral osteolysis. A sizeable proportion of patients who undergo arthroplasty are obese. While patient activity, implant type, and quality of fixation are known risk factors for osteolysis, the literature concerning obesity is sparse and controversial. Our primary objective was to evaluate the influence of obesity on the risk of osteolysis five and ten years after primary total hip arthroplasty with a cemented stem. Secondary objectives were to evaluate clinical outcome and patient satisfaction. METHODS: We conducted a prospective cohort study of patients undergoing hip arthroplasty with a third-generation stem-cementing technique from 1996 to 2003. All patients were seen at five or ten years postoperatively. Radiographs and information regarding body-mass index (<25 kg/m(2) = normal weight, 25 to 29.9 kg/m(2) = overweight, and > or = 30 kg/m(2) = obese) and activity were obtained. Activity was assessed with use of the University of California at Los Angeles (UCLA) activity scale. Osteolysis was assessed radiographically. Clinical outcome measurements included the Harris hip and Merle d'Aubigne and Postel scores. RESULTS: Our study included 503 arthroplasties in 433 patients; the results of 241 (47.9%) of the arthroplasties were evaluated at five years and the results of 262 (52.1%), at ten years. Osteolysis was identified around forty-four stems, with twenty-four (13.3%) in 181 hips of normal-weight patients, eleven (5.4%) in 205 hips of overweight patients, and nine (7.7%) in 117 hips of obese patients. Normal-weight patients had the highest activity level (mean UCLA activity scale score [and standard deviation], 5.5 + or - 2.0 points), and obese patients had the lowest (mean UCLA activity scale score, 5.0 + or - 1.7 points). When adjusted for activity, cementing quality, and patient age and sex, the risk of osteolysis in obese patients was not increased as compared with that for overweight patients (adjusted odds ratio, 1.4; 95% confidence interval, 0.6 to 3.7), whereas the risk of femoral osteolysis in normal-weight patients was found to be significantly higher than that in overweight patients (adjusted odds ratio, 2.6; 95% confidence interval, 1.2 to 5.7). Clinical outcomes were similar among the groups. CONCLUSIONS: We found no increased risk of osteolysis around a cemented femoral stem in obese patients five and ten years after primary total hip arthroplasty. The highest prevalence of osteolysis was observed in normal-weight patients. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions to Authors for a complete description of levels of evidence. PMID- 20720140 TI - A postfracture initiative to improve osteoporosis management in a community hospital in ontario. AB - BACKGROUND: Screening programs to manage osteoporosis in fracture clinic environments have had varying success in terms of increasing rates of investigation and initiation of treatment for the disease. METHODS: We determined rates of postfracture investigation and care for osteoporosis in patients screened through a coordinator-based initiative in a community hospital fracture clinic. A coordinator screened outpatients, educated them about osteoporosis, advised them to see their family physician for assessment and/or treatment, and performed follow-up at six months. Men who were fifty years of age or older and women who were forty years of age or older and had a fragility fracture were eligible. RESULTS: Of 505 patients enrolled at baseline, 332 (66%) returned the follow-up questionnaire; 51% of those patients reported having had a bone mineral density test after screening and 26% had initiated first-line treatment (35% if the patients who had already initiated treatment at baseline were excluded) and an additional 23% were continuing treatment since baseline. After adjustment for demographic and baseline variables, patients who had initiated first-line treatment after screening were 4.15 times more likely to have had a bone mineral density test after screening than patients who had never initiated treatment and 11.67 times more likely to have had a bone mineral density test after screening than patients who had continued treatment since baseline. CONCLUSIONS: A coordinator-based osteoporosis screening program was associated with osteoporosis investigation and treatment. A postfracture bone mineral density test was highly associated with treatment initiation. PMID- 20720141 TI - The offset of the tibial shaft from the tibial plateau in Chinese people. AB - BACKGROUND: Long-stem tibial components are available for complex primary and revision total knee arthroplasties. Most of the stems' designs are based on anatomic data from Western populations. We conducted a morphologic study to determine the relationship of the tibial shaft to the tibial plateau in Chinese people. METHODS: We included knees from fifty Chinese individuals (twenty-five females and twenty-five males) in this study. On magnetic resonance imaging scans of the tibial plateau and the proximal part of the tibial shaft of each lower limb, the distance between the axis of the tibial shaft and the center of the tibial plateau was measured and was defined as the offset of the tibial shaft from the tibial plateau at three resection levels: the first just distal to the subchondral bone of the medial tibial plateau, the second 5 mm distal to it, and the third 10 mm distal to it. The dimensions of the tibial plateau were measured as well. RESULTS: At the first, second, and third resection levels, the mean tibial shaft offsets (and standard deviations) from the center of the tibial plateau were, respectively, 7.23 + or - 2.44 mm (3.40 + or - 1.94 mm of mediolateral offset and 6.22 + or - 2.05 mm of anteroposterior offset), 6.33 + or - 2.26 mm (3.14 + or - 2.04 mm of mediolateral offset and 5.24 + or - 1.96 mm of anteroposterior offset), and 4.75 + or - 2.07 mm (2.68 + or - 1.91 mm of mediolateral offset and 3.46 + or - 2.03 mm of anteroposterior offset). At each resection level, the mean offset in the male group was significantly larger than that in the female group. CONCLUSIONS: There is a large variation in the offset of the tibial shaft from the tibial plateau in Chinese people. The axis of the tibial shaft is located anterolateral to the center of the tibial plateau in this population. CLINICAL RELEVANCE: The use of an anterolaterally offset tibial keel or stem seems more suitable for Chinese patients undergoing primary or revision total knee arthroplasty. PMID- 20720142 TI - The "docking" method for periprosthetic humeral fracture after total elbow arthroplasty: a case report. PMID- 20720143 TI - Giant calcified thoracic disc herniation in a child: a case report and review of the literature. PMID- 20720144 TI - Surgery was superior to physiotherapy for small and medium-size rotator cuff tears. PMID- 20720145 TI - Osteochondral autologous transplantation was more effective than microfracture for osteochondritis dissecans in children younger than eighteen years. PMID- 20720146 TI - Arthroscopic decompression with acromioplasty and structured exercise was no more effective and was more expensive than exercise alone. PMID- 20720148 TI - What's New in Spine Surgery. PMID- 20720149 TI - Strong population genetic structure in a broadcast-spawning Antarctic marine invertebrate. AB - Although studies of population genetic structure are commonplace, a strong bias exists toward species from low latitudes and with relatively poor dispersal capabilities. Consequently, we used 280 amplified fragment length polymorphism bands to explore patterns of genetic differentiation among 8 populations of a high latitude broadcast-spawning marine mollusc, the Antarctic limpet Nacella concinna. Over 300 individuals were sampled along a latitudinal gradient spanning the Antarctic Peninsula from Adelaide Island to King George Island (67 degrees 62 degrees S), then to Signy Island (60 degrees S) and South Georgia (54 degrees S). Populations from the Antarctic Peninsula exhibited little genetic structure but were themselves strongly differentiated from both Signy and South Georgia. This finding was analytically highly robust and implies the presence of significant oceanographic barriers to gene flow in a species long regarded as a classic example of a widely dispersing broadcast spawner. PMID- 20720150 TI - Cdc14: a highly conserved family of phosphatases with non-conserved functions? AB - CDC14 was originally identified by L. Hartwell in his famous screen for genes that regulate the budding yeast cell cycle. Subsequent work showed that Cdc14 belongs to a family of highly conserved dual-specificity phosphatases that are present in a wide range of organisms from yeast to human. Human CDC14B is even able to fulfill the essential functions of budding yeast Cdc14. In budding yeast, Cdc14 counteracts the activity of cyclin dependent kinase (Cdk1) at the end of mitosis and thus has important roles in the regulation of anaphase, mitotic exit and cytokinesis. On the basis of the functional conservation of other cell-cycle genes it seemed obvious to assume that Cdc14 phosphatases also have roles in late mitosis in mammalian cells and regulate similar targets to those found in yeast. However, analysis of the human Cdc14 proteins (CDC14A, CDC14B and CDC14C) by overexpression or by depletion using small interfering RNA (siRNA) has suggested functions that are quite different from those of ScCdc14. Recent studies in avian and human somatic cell lines in which the gene encoding either Cdc14A or Cdc14B had been deleted, have shown - surprisingly - that neither of the two phosphatases on its own is essential for viability, cell-cycle progression and checkpoint control. In this Commentary, we critically review the available data on the functions of yeast and vertebrate Cdc14 phosphatases, and discuss whether they indeed share common functions as generally assumed. PMID- 20720151 TI - Control of Notch-ligand endocytosis by ligand-receptor interaction. AB - In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1(WT)) in the absence of active Notch signaling. Both Jagged1(WT) and Jagged1(Ndr) interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1(WT) showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1(WT), but not Jagged1(Ndr), trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1(WT) in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1(Ndr) did not exert a dominant-negative effect over Jagged1(WT) in terms of receptor activation. Finally, in Jag1(Ndr/Ndr) mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1(Ndr) ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands. PMID- 20720152 TI - Cytoskeletal dysfunction dominates in DAP12-deficient osteoclasts. AB - Despite evidence that DAP12 regulates osteoclasts, mice lacking the ITAM-bearing protein exhibit only mild osteopetrosis. Alternatively, Dap12(-/-) mice, also lacking FcRgamma, are severely osteopetrotic, suggesting that FcRgamma compensates for DAP12 deficiency in the bone-resorbing polykaryons. Controversy exists, however, as to whether these co-stimulatory molecules regulate differentiation of osteoclasts or the capacity of the mature cell to degrade bone. We find that Dap12(-/-) osteoclasts differentiate normally when generated on osteoblasts but have a dysfunctional cytoskeleton, impairing their ability to transmigrate through the osteoblast layer and resorb bone. To determine whether the FcRgamma co-receptor, OSCAR mediates osteoclast function in the absence of DAP12, we overexpressed OSCAR fused to FLAG (OSCAR-FLAG), in Dap12(-/-) osteoclasts. OSCAR-FLAG partially rescues the abnormal cytoskeleton of Dap12(-/-) osteoclasts grown on bone, but not those grown on osteoblasts. Thus, cytoskeletal dysfunction, and not arrested differentiation, is the dominant consequence of DAP12 deficiency in osteoclasts. The failure of osteoblasts to normalize Dap12(-/ ) osteoclasts indicates that functionally relevant quantities of OSCAR ligand do not reside in bone-forming cells. PMID- 20720154 TI - NUMTs in the sponge genome reveal conserved transposition mechanisms in metazoans. AB - The transposition of parts of the mitochondrial (mt) genetic material into the nuclear genome (NUMTs) occurs in a wide range of eukaryotes. Here, we show that NUMTs exist for nearly all regions of the mt genome in the demosponge Amphimedon queenslandica, a representative of the oldest phyletic lineage of animals. Because the sponge NUMTs are small and noncoding, and transposed via a DNA intermediate, as in eumetazoans, we infer that the transpositonal processes underlying NUMT formation in contemporary animals existed in their most recent common ancestor. In contrast to most bilaterians, Amphimedon NUMTs are inserted into regions of high gene density. Given the common features of metazoan NUMTs, the reduction in animal mt genome sizes relative to other eukaryotes may be the product of the mt DNA transposition mechanisms that evolved along the metazoan stem. PMID- 20720153 TI - Protein mobilities and P-selectin storage in Weibel-Palade bodies. AB - Using fluorescence recovery after photobleaching (FRAP) we measured the mobilities of EGFP-tagged soluble secretory proteins in the endoplasmic reticulum (ER) and in individual Weibel-Palade bodies (WPBs) at early (immature) and late (mature) stages in their biogenesis. Membrane proteins (P-selectin, CD63, Rab27a) were also studied in individual WPBs. In the ER, soluble secretory proteins were mobile; however, following insertion into immature WPBs larger molecules (VWF, Proregion, tPA) and P-selectin became immobilised, whereas small proteins (ssEGFP, eotaxin-3) became less mobile. WPB maturation led to further decreases in mobility of small proteins and CD63. Acute alkalinisation of mature WPBs selectively increased the mobilities of small soluble proteins without affecting larger molecules and the membrane proteins. Disruption of the Proregion-VWF paracrystalline core by prolonged incubation with NH(4)Cl rendered P-selectin mobile while VWF remained immobile. FRAP of P-selectin mutants revealed that immobilisation most probably involves steric entrapment of the P-selectin extracellular domain by the Proregion-VWF paracrystal. Significantly, immobilisation contributed to the enrichment of P-selectin in WPBs; a mutation of P-selectin preventing immobilisation led to a failure of enrichment. Together these data shed new light on the transitions that occur for soluble and membrane proteins following their entry and storage into post-Golgi-regulated secretory organelles. PMID- 20720155 TI - MicroRNA171c-targeted SCL6-II, SCL6-III, and SCL6-IV genes regulate shoot branching in Arabidopsis. AB - MicroRNAs (miRNAs) are ~21-nucleotide noncoding RNAs that play critical roles in regulating plant growth and development through directing the degradation of target mRNAs. Axillary meristem activity, and hence shoot branching, is influenced by a complicated network that involves phytohormones such as auxin, cytokinin, and strigolactone. GAI, RGA, and SCR (GRAS) family members take part in a variety of developmental processes, including axillary bud growth. Here, we show that the Arabidopsis thaliana microRNA171c (miR171c) acts to negatively regulate shoot branching through targeting GRAS gene family members SCARECROW LIKE6-II (SCL6-II), SCL6-III, and SCL6-IV for cleavage. Transgenic plants overexpressing MIR171c (35Spro-MIR171c) and scl6-II scl6-III scl6-IV triple mutant plants exhibit a similar reduced shoot branching phenotype. Expression of any one of the miR171c-resistant versions of SCL6-II, SCL6-III, and SCL6-IV in 35Spro-MIR171c plants rescues the reduced shoot branching phenotype. Scl6-II scl6 III scl6-IV mutant plants exhibit pleiotropic phenotypes such as increased chlorophyll accumulation, decreased primary root elongation, and abnormal leaf and flower patterning. SCL6-II, SCL6-III, and SCL6-IV are located to the nucleus, and show transcriptional activation activity. Our results suggest that miR171c targeted SCL6-II, SCL6-III, and SCL6-IV play an important role in the regulation of shoot branch production. PMID- 20720156 TI - OAK-based cochleates as a novel approach to overcome multidrug resistance in bacteria. AB - Antibiotic resistance has become a worldwide medical problem. To find new ways of overcoming this phenomenon, we investigated the role of the membrane-active oligo acyl-lysyl (OAK) sequence C(12)K-7alpha(8), in combination with essentially ineffective antibiotics. Determination of minimal inhibitory concentration (MIC) against gram-negative multidrug-resistant strains of Escherichia coli revealed combinations with sub-MIC OAK levels that acted synergistically with several antibiotics, thus lowering their MICs by several orders of magnitude. To shed light into the molecular basis for this synergism, we used both mutant strains and biochemical assays. Our results suggest that bacterial sensitization to antibiotics was derived mainly from the OAK's capacity to overcome the efflux enhanced resistance mechanism, by promoting backdoor entry of otherwise excluded antibiotics. To facilitate simultaneous delivery of the pooled drugs to an infection site, we developed a novel OAK-based cochleate system with demonstrable stability in whole blood. To assess the potential therapeutic use of such cochleates, we performed preliminary experiments that imitate systemic treatment of neutropenic mice infected with lethal inoculums of multidrug resistance E. coli. Single-dose administration of erythromycin coencapsulated in OAK-based cochleates has decreased drug toxicity and increased therapeutic efficacy in a dose-dependent manner. Collectively, our findings suggest a potentially useful approach for fighting efflux-enhanced resistance mechanisms. PMID- 20720157 TI - Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. AB - Hypopituitary Ames dwarf mice were injected either with growth hormone (GH) or thyroxine for a 6-wk period to see whether this intervention would reverse their long life span or the resistance of their cells to lethal stresses. Ames dwarf mice survived 987 +/- 24 d (median), longer than nonmutant control mice (664 +/- 48), but GH-injected dwarf mice did not differ from controls (707 +/- 9). Fibroblast cells from Ames dwarf mice were more resistant to cadmium than cells from nonmutant controls (LD(50) values of 9.98 +/- 1.7 and 3.9 +/- 0.8, respectively), but GH injections into Ames dwarf mice restored the normal level of cadmium resistance (LD(50)=5.8 +/- 0.9). Similar restoration of normal resistance was observed for fibroblasts exposed to paraquat, methyl methanesulfonate, and rotenone (P<0.05 in each case for contrast of GH-treated vs. untreated dwarf mice; P<0.05 for dwarf vs. nonmutant control mice.) T4 injections into Ames dwarf mice, in contrast, did not restore normal life span. We conclude that the remarkable life-span extension of Ames dwarf mice, and the stress resistance of cells from these mice, depends on low levels of GH exposure in juvenile and very young adult mice. PMID- 20720158 TI - Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. AB - Acetaminophen [N-acetyl-p-aminophenol (APAP)] is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, we hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1 deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use. PMID- 20720159 TI - Functional role of gangliotetraosylceramide in epithelial-to-mesenchymal transition process induced by hypoxia and by TGF-{beta}. AB - The epithelial-to-mesenchymal transition (EMT) is a basic cellular process that plays a key role in normal embryonic development and in cancer progression/metastasis. Our previous study indicated that EMT processes of mouse and human epithelial cells induced by TGF-beta display clear reduction of gangliotetraosylceramide (Gg4) and ganglioside GM2, suggesting a close association of glycosphingolipids (GSLs) with EMT. In the present study, using normal murine mammary gland (NMuMG) cells, we found that levels of Gg4 and of mRNA for the UDP-Gal:beta1-3galactosyltransferase-4 (beta3GalT4) gene, responsible for reduction of Gg4, were reduced in EMT induced by hypoxia (~1% O(2)) or CoCl(2) (hypoxia mimic), similarly to that for TGF-beta-induced EMT. An increase in the Gg4 level by its exogenous addition or by transfection of the beta3GalT4 gene inhibited the hypoxia-induced or TGF-beta-induced EMT process, including changes in epithelial cell morphology, enhanced motility, and associated changes in epithelial vs. mesenchymal molecules. We also found that Gg4 is closely associated with E-cadherin and beta-catenin. These results suggest that the beta3GalT4 gene, responsible for Gg4 expression, is down-regulated in EMT; and Gg4 has a regulatory function in the EMT process in NMuMG cells, possibly through interaction with epithelial molecules important to maintain epithelial cell membrane organization. PMID- 20720160 TI - p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues. AB - This study aimed to determine the mechanisms responsible for long-term tissue damage following radiation injury. We irradiated p21-knockout (p21(-/-)) and wild type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored the mechanisms of radiation-induced mesenchymal stem cell (MSC) dysfunction in isolated bone marrow-derived cells. p21 expression was chronically elevated >200 fold in irradiated tissues. Loss of p21 function resulted in a >4-fold increase in the number of skin MSCs remaining after radiation. p21(-/-) mice had significantly less radiation damage, including 6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate (P<0.01). Irradiated p21(-/-) MSCs had 4-fold increased potential for bone or fat differentiation, 4-fold greater proliferation rate, and nearly 7-fold lower senescence as compared to WT MSCs (P<0.01). Ectopic expression of p21 in knockout cells decreased proliferation and differentiation potential and recapitulated the WT phenotype. Loss of p21 function markedly decreases the deleterious effects of radiation injury in mesenchyme-derived tissues and preserves tissue-derived MSCs. In addition, p21 is a critical regulator of MSC proliferation, differentiation, and senescence both at baseline and in response to radiation. PMID- 20720161 TI - SHIP negatively regulates Flt3L-derived dendritic cell generation and positively regulates MyD88-independent TLR-induced maturation. AB - We demonstrate herein that SHIP negatively regulates the proliferation, differentiation, and survival of FL-DCs from BM precursors, as shown by a more rapid appearance and higher numbers of CD11c(+) DCs from SHIP-/- cultures as well as increased survival of mature FL-DCs in the absence of Flt3L. This increased survival, which is lost with low levels of the PI3K inhibitor, LY, correlates with an enhanced constitutive activation of the Akt pathway. Interestingly, however, these SHIP-/- FL-DCs display a less-mature phenotype after TLR ligand stimulation, as far as MHCII, CD40, and CD86 are concerned. Unexpectedly, SHIP-/- FL-DCs activated with TLR ligands, which use MyD88-independent pathways, are markedly impaired in their ability to stimulate Ag-specific T cell proliferation, and SHIP-/- FL-DCs activated by TLRs, which exclusively use the MyD88-dependent pathway, are as capable as WT FL-DCs. There is also a more pronounced T(H)1 skewing by the SHIP-/- FL-DCs than by WT FL-DCs, which is consistent with our finding that SHIP-/- FL-DCs secrete higher levels of IL-12 and TNF-alpha in response to LPS or dsRNA than their WT counterparts. These results suggest that SHIP negatively regulates FL-DC generation but positively regulates the maturation and function of FL-DCs induced by TLRs, which operate via MyD88 independent pathways. PMID- 20720162 TI - Hijacked phagosomes and leukocyte activation: an intimate relationship. AB - Intracellular pathogens have developed different strategies to survive within host cells. For example, these pathogens might interfere with the biogenesis of phagolysosomes, thereby forming replicative vacuoles. Although the complex mechanisms used by pathogens to hijack the biogenesis of phagolysosomes have been elucidated in naive leukocytes, the role of leukocyte activation in this process has not yet been investigated. Leukocytes are known to be activated by cytokines, and several reports have demonstrated that several cytokines modulate the endocytic pathway and thereby, affect phagosome biogenesis. These observations provide molecular evidence that endocytosis can be regulated by the immune environment. In this review, we highlight the effect of leukocyte activation by cytokines on the endocytic pathway and on phagosome biogenesis. We briefly describe the mechanism of phagolysosome formation before focusing on the strategies used by two bacterial pathogens, Coxiella burnetii and Mycobacterium tuberculosis, to hijack phagolysosome biogenesis. Finally, we emphasize the effect of leukocyte activation on the endocytic pathway and on phagolysosome formation, which has not been highlighted to date. PMID- 20720163 TI - miRNA-based mechanism for the commitment of multipotent progenitors to a single cellular fate. AB - When stem cells and multipotent progenitors differentiate, they undergo fate restriction, enabling a single fate and blocking differentiation along alternative routes. We herein present a mechanism whereby such unequivocal commitment is achieved, based on microRNA (miRNA)-dependent repression of an alternative cell fate. We show that the commitment of monocyte RAW264.7 progenitors to active macrophage differentiation involves rapid up-regulation of miR-155 expression, which leads to the suppression of the alternative pathway, namely RANK ligand-induced osteoclastogenesis, by repressing the expression of MITF, a transcription factor essential for osteoclast differentiation. A temporal asymmetry, whereby miR-155 expression precedes and overrides the activation of the osteoclast transcriptional program, provides the means for coherent macrophage differentiation, even in the presence of osteoclastogenic signals. Based on these findings, we propose that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation. PMID- 20720164 TI - Quantitative 3D elemental microtomography of Cyclotella meneghiniana at 400-nm resolution. AB - X-ray fluorescence tomography promises to map elemental distributions in unstained and unfixed biological specimens in three dimensions at high resolution and sensitivity, offering unparalleled insight in medical, biological, and environmental sciences. X-ray fluorescence tomography of biological specimens has been viewed as impractical-and perhaps even impossible for routine application due to the large time required for scanning tomography and significant radiation dose delivered to the specimen during the imaging process. Here, we demonstrate submicron resolution X-ray fluorescence tomography of a whole unstained biological specimen, quantifying three-dimensional distributions of the elements Si, P, S, Cl, K, Ca, Mn, Fe, Cu, and Zn in the freshwater diatom Cyclotella meneghiniana with 400-nm resolution, improving the spatial resolution by over an order of magnitude. The resulting maps faithfully reproduce cellular structure revealing unexpected patterns that may elucidate the role of metals in diatom biology and of diatoms in global element cycles. With anticipated improvements in data acquisition and detector sensitivity, such measurements could become routine in the near future. PMID- 20720165 TI - The chemokine IL8 is up-regulated in bovine endometrial stromal cells by the BoHV 4 IE2 gene product, ORF50/Rta: a step ahead toward a mechanism for BoHV-4 induced endometritis. AB - Postpartum infections of the endometrium and metritis are common causes of delayed conception and infertility in cattle. These infections are characterized by inflammation of the endometrium and secretion of the chemokine interleukin 8 (IL8), which attracts granulocytes to the endometrium. Bovine herpesvirus 4 (BoHV 4) is tropic for the endometrium and the only virus consistently associated with postpartum metritis. The BoHV-4 Immediate Early 2 (IE2) gene is the first viral gene transcribed by host cells after infection, and the IE2 gene product, ORF50/Rta, transactivates host cell genes. The present study tested the hypothesis that ORF50/Rta transactivates the IL8 gene promoter during BoHV-4 infection of bovine endometrial stromal cells (BESCs). Infection of primary BESCs with BoHV-4 stimulated IL8 gene promoter activity and IL8 protein secretion. However, IL8 production was dependent on the transcription of viral genes, because psoralen/ultraviolet cross-linking of the viral DNA abrogated the response to BoHV-4 infection. Furthermore, IL8 promoter serial deletion analysis revealed a specific region responsive to ORF50/Rta. These observations may represent an endometrial defense mechanism against viral infection or a virulence mechanism by which viral replication stimulates chemokine secretion to attract more susceptible host cells to the endometrium. PMID- 20720166 TI - Characterization of the effects of prolactin in gonadotroph target cells. AB - Hyperprolactinemia is a major cause of infertility, brought about by inhibition of gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus and impairment of luteinizing hormone (LH) output from the pituitary gland. However, whereas the actions of prolactin (PRL) within the brain have been investigated extensively, its specific effects at the level of pituitary gonadotroph target cells remain unclear. Here, we provide evidence that the actions of PRL within the gonadotroph are more complex than originally envisaged. Using a gonadotroph cell monoculture, the first series of experiments showed that PRL is, paradoxically, a potent stimulator of LH release, with a three- to fourfold increase in LH values at hyperprolactinemic concentrations of PRL. Conversely, PRL dose-dependently modulated the LH secretory response to GnRH in a biphasic manner, with classical suppression of LH output only detected under a narrow dose range. In contrast, at all doses tested, PRL blocked the LHB mRNA response to the secretagogue. Subsequent studies revealed that the stimulatory effects of PRL on LH release are not mediated by the conventional cytokine receptor pathways but, rather, by a novel JAK2-PIK3-PKC-dependent signaling cascade. Moreover, the experiments showed that these actions of PRL within gonadotroph cells are controlled by dopamine, the main hypothalamic inhibitory regulator of PRL release in vivo. Our findings have unraveled specific actions of PRL within the gonadotroph and the cell-signaling interactions that ultimately underlie hyperprolactinemia-induced infertility. PMID- 20720167 TI - Metastasis tumor antigen 2 (MTA2) is involved in proper imprinted expression of H19 and Peg3 during mouse preimplantation development. AB - The epigenetic mechanisms involved in establishing and maintaining genomic imprinting are steadily being unmasked. The nucleosome remodeling and histone deacetylation (NuRD) complex is implicated in regulating DNA methylation and expression of the maternally expressed H19 gene in preimplantation mouse embryos. To dissect further the function of the NuRD complex in genomic imprinting, we employed an RNA interference (RNAi) strategy to deplete the NuRD complex component Metastasis Tumor Antigen 2 (MTA2). We found that Mta2 is the only zygotically expressed Mta gene prior to the blastocyst stage, and that RNAi mediated knockdown of Mta2 transcript leads to biallelic H19 expression and loss of DNA methylation in the differentially methylated region in blastocysts. In addition, biallelic expression of the paternally expressed Peg3 gene, but not Snrpn, is also observed in blastocysts following Mta2 knockdown. Loss of MTA2 protein does not result in a decrease in abundance of other NuRD components, including methyl-binding-CpG-binding domain protein 3 (MBD3), histone deacetylases 1 and 2 (HDACs 1 and 2), and chromodomain helicase DNA-binding protein 4 (CHD4). Taken together, our results support a role for MTA2 within the NuRD complex in genomic imprinting. PMID- 20720168 TI - Novel method of gene transfer in birds: intracytoplasmic sperm injection for green fluorescent protein expression in quail blastoderms. AB - This study was conducted to establish a new method of avian transgenesis by intracytoplasmic sperm injection (ICSI). First, we evaluated the fertilization ability of quail oocytes after microinjection of Triton X-100 (TX-100)-treated quail sperm with PLCZ cRNA. The quail oocytes were cultured for 24 h, and blastoderm development was examined by histological observation. The TX-100 treatment induced damage to the quail sperm membrane and interfered with fertilization of oocytes injected with sperm. On the other hand, when quail oocytes were injected with TX-100-treated sperm and PLCZ cRNA simultaneously, 43.5% (10/23) of the oocytes developed into blastoderms. This rate of development was comparable to that for oocytes injected with sperm without TX-100 treatment but with PLCZ cRNA (6 [42.9%] of 14). Second, we evaluated the rate of transduction of the enhanced green fluorescent protein (EGFP) gene in quail oocytes injected with TX-100-treated sperm and PLCZ cRNA. The EGFP expression was assessed by histological observation of fluorescence emission in the embryos. The intracytoplasmic injection of sperm without TX-100 treatment but with PLCZ cRNA and EGFP vector induced blastoderm development in 40% (4/10) of the oocytes, but those oocytes showed no fluorescence emission. In contrast, the intracytoplasmic injection of TX-100-treated sperm and PLCZ cRNA induced blastoderm development in 43.8% (7/16) of the oocytes, and, importantly, 85.7% (6/7) of oocytes showed fluorescence emission. In addition, PCR analysis detected GFP fragments in 50% (3/6) of GFP-expressing blastoderms. These results indicate that this ICSI method with additional treatments described herein may be the first step toward the production of transgenic birds. PMID- 20720169 TI - Is FAS/Fas ligand system involved in equine corpus luteum functional regression? AB - Proapoptotic factor Fas ligand (FASL) and its cell surface receptor FAS are tumor necrosis factor superfamily members that trigger apoptosis in different cell types. However, their influence on luteal steroidogenesis is not clearly understood. The aim of the present work was to determine (i) the presence of the cytokine FASL and its receptor FAS in the mare's corpus luteum (CL) throughout the luteal phase, as well as (ii) the influence of FASL alone, or together with the cytokines tumor necrosis factor alpha (TNF) and interferon gamma (IFNG), on equine luteal cell production of luteotrophic and luteolytic factors, cell viability, and apoptosis. FASL and FAS protein expression and mRNA transcription were evaluated in different luteal stages of the equine CL by Western blotting and real-time PCR assays, respectively. Protein expression and FASL mRNA transcription increased in the late CL. Also, FAS and FASL proteins were present in large steroidogenic and endothelial CL cells throughout the luteal phase, as demonstrated by immunohistochemistry. Equine luteal cells isolated from midluteal phase CL were stimulated without (control) or with exogenous cytokines: FASL (10 ng/ml); TNF+IFNG (10 ng/ml each; positive control) or FASL+TNF+IFNG (10 ng/ml each). FASL clearly inhibited in vitro progesterone and prostaglandin E(2) (PGE(2)) production by equine luteal cells but increased prostaglandin F(2alpha) (PGF(2alpha)). Furthermore, FASL effect on equine luteal cell viability depended on the presence of cytokines TNF and IFNG. In conclusion, this study shows the presence of FASL and FAS in the equine CL and suggests their importance in functional luteolysis. PMID- 20720170 TI - Analysis of the rice mitochondrial carrier family reveals anaerobic accumulation of a basic amino acid carrier involved in arginine metabolism during seed germination. AB - Given the substantial changes in mitochondrial gene expression, the mitochondrial proteome, and respiratory function during rice (Oryza sativa) germination under anaerobic and aerobic conditions, we have attempted to identify changes in mitochondrial membrane transport capacity during these processes. We have assembled a preliminary rice mitochondrial carrier gene family of 50 members, defined its orthology to carriers of known function, and observed significant changes in microarray expression data for these rice genes during germination under aerobic and anaerobic conditions and across rice development. To determine if these transcript changes reflect alteration of the carrier profile itself and to determine which members of the family encode the major mitochondrial carrier proteins, we analyzed mitochondrial integral membrane protein preparations using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and peptide mass spectrometry, identifying seven distinct carrier proteins. We have used mass spectrometry-based quantitative approaches to compare the abundance of these carriers between mitochondria from dry seeds and those from aerobic- or anaerobic germinated seeds. We highlight an anaerobic-enhanced basic amino acid carrier and show concomitant increases in mitochondrial arginase and the abundance of arginine and ornithine in anaerobic-germinated seeds, consistent with an anaerobic role of this mitochondria carrier. The potential role of this carrier in facilitating mitochondrial involvement in arginine metabolism and the plant urea cycle during the growth of rice coleoptiles and early seed nitrate assimilation under anaerobic conditions are discussed. PMID- 20720171 TI - Stacking multiple transgenes at a selected genomic site via repeated recombinase mediated DNA cassette exchanges. AB - Recombinase-mediated DNA cassette exchange (RMCE) has been successfully used to insert transgenes at previously characterized genomic sites in plants. Following the same strategy, groups of transgenes can be stacked to the same site through multiple rounds of RMCE. A gene-silencing cassette, designed to simultaneously silence soybean (Glycine max) genes fatty acid omega-6 desaturase 2 (FAD2) and acyl-acyl carrier protein thioesterase 2 (FATB) to improve oleic acid content, was first inserted by RMCE at a precharacterized genomic site in soybean. Selected transgenic events were subsequently retransformed with the second DNA construct containing a Yarrowia lipolytica diacylglycerol acyltransferase gene (DGAT1) to increase oil content by the enhancement of triacylglycerol biosynthesis and three other genes, a Corynebacterium glutamicum dihydrodipicolinate synthetase gene (DHPS), a barley (Hordeum vulgare) high lysine protein gene (BHL8), and a truncated soybean cysteine synthase gene (CGS), to improve the contents of the essential amino acids lysine and methionine. Molecular characterization confirmed that the second RMCE successfully stacked the four overexpression cassettes to the previously integrated FAD2-FATB gene silencing cassette. Phenotypic analyses indicated that all the transgenes expressed expected phenotypes. PMID- 20720172 TI - 13C-tracer and gas chromatography-mass spectrometry analyses reveal metabolic flux distribution in the oleaginous microalga Chlorella protothecoides. AB - The green alga Chlorella protothecoides has received considerable attention because it accumulates neutral triacylglycerols, commonly regarded as an ideal feedstock for biodiesel production. In order to gain a better understanding of its metabolism, tracer experiments with [U-(13)C]/[1-(13)C]glucose were performed with heterotrophic growth of C. protothecoides for identifying the metabolic network topology and estimating intracellular fluxes. Gas chromatography-mass spectrometry analysis tracked the labeling patterns of protein-bound amino acids, revealing a metabolic network consisting of the glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle with inactive glyoxylate shunt. Evidence of phosphoenolpyruvate carboxylase, phosphoenolpyruvate carboxykinase, and malic enzyme activity was also obtained. It was demonstrated that the relative activity of the pentose phosphate pathway to glycolysis under nitrogen limited environment increased, reflecting excess NADPH requirements for lipid biosynthesis. Although the growth rate and cellular oil content were significantly altered in response to nitrogen limitation, global flux distribution of C. protothecoides remained stable, exhibiting the rigidity of central carbon metabolism. In conclusion, quantitative knowledge on the metabolic flux distribution of oleaginous alga obtained in this study may be of value in designing strategies for metabolic engineering of desirable bioproducts. PMID- 20720173 TI - Nucleus raphe pallidus participates in midbrain-medullary cardiovascular sympathoinhibition during electroacupuncture. AB - We have shown that electroacupuncture (EA) inhibits sympathoexcitatory rostral ventrolateral medulla (rVLM) neurons and reflex responses following activation of a long-loop pathway in the arcuate nucleus and ventrolateral periaqueductal gray (vlPAG). Additionally, EA at P 5-6 acupoints (overlying the median nerve) activates serotonin-containing neurons in the nucleus raphe pallidus (NRP), which, in turn, inhibit rVLM neurons. Although direct projections from the vlPAG to the rVLM exist, it is uncertain whether an indirect pathway through the NRP serves an important role in vlPAG-rVLM cardiovascular modulation. Therefore, the splanchnic nerve (SN) was stimulated to induce cardiovascular sympathoexcitatory reflexes, and EA was applied at P 5-6 acupoints in alpha-chloralose-anesthetized cats. A single-barreled recording electrode was inserted into the NRP or rVLM. Microinjection of DL-homocysteic acid (DLH) into the vlPAG increased the NRP neuronal response to SN stimulation (5 +/- 1 to 12 +/- 2 spikes/30 stim). Likewise, EA at P 5-6 for 30 min increased the NRP response to SN stimulation (3 +/- 1 to 10 +/- 2 spikes/30 stim), an effect that could be blocked by microinjection of kynurenic acid (KYN) into the caudal vlPAG. Furthermore, the reflex increase in blood pressure induced by application of bradykinin to the gallbladder and the rVLM cardiovascular presympathetic neuronal response to SN stimulation was inhibited by injection of DLH into the vlPAG, a response that was reversed by injection of KYN into the NRP. These results indicate that EA activates the vlPAG, which excites the NRP to, in turn, inhibit rVLM presympathetic neurons and reflex cardiovascular sympathoexcitatory responses. PMID- 20720174 TI - PGC-1alpha increases PDH content but does not change acute PDH regulation in mouse skeletal muscle. AB - The aim of this study was to test whether the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)1alpha regulates the content of pyruvate dehydrogenase (PDH)-E1alpha and influences PDH activity through regulation of pyruvate dehydrogenase kinase-4 (PDK4) expression and subsequently PDH phosphorylation. PGC-1alpha whole body knockout (KO), muscle specific PGC-1alpha overexpressing mice (MCK PGC-1alpha), and littermate wild type (WT) mice underwent two interventions known to affect PDH. Quadriceps muscles were removed from fed and 24-h fasted mice as well as at 6 h of recovery after 1-h running and from mice that did not run acutely. PDH-E1alpha protein content and PDH-E1alpha phosphorylation were lower in PGC-1alpha KO and higher in MCK PGC-1alpha mice at rest, but, while MCK PGC-1alpha had higher PDK4 protein content, KO of PGC-1alpha had no effect on PDK4 protein content. The differences in phosphorylation partly vanished when expressing phosphorylation relative to the PDH-E1alpha content with only a maintained elevated phosphorylation in MCK PGC-1alpha mice. Fasting upregulated PDK4 protein in PGC-1alpha KO, MCK PGC 1alpha and WT mice, but this was not consistently associated with increased PDH E1alpha phosphorylation. Downregulation of the activity of PDH in the active form (PDHa) at 6-h recovery from exercise in both the PGC-1alpha KO and MCK PGC-1alpha mice and the association between PDH-E1alpha phosphorylation and PDHa activity in PGC-1alpha KO mice indicate that PGC-1alpha is not required for these responses. In conclusion, PGC-1alpha regulates PDH-E1alpha protein content in parallel with mitochondrial oxidative proteins, but does not seem to influence PDH regulation in mouse skeletal muscle in response to fasting and in recovery from exercise. PMID- 20720175 TI - Effect of metabolic acidosis on neonatal proximal tubule acidification. AB - The serum bicarbonate in neonates is lower than adults due in large part to a lower rate of proximal tubule acidification. It is unclear if the neonatal proximal tubule is functioning at maximal capacity or if the proximal tubule can respond to metabolic acidosis as has been described in adult proximal tubules. We find that neonatal mouse brush-border membranes have a lower Na(+)/H(+) exchanger (NHE) 3 protein abundance (neonate 0.11 +/- 0.05 vs. adult 0.64 +/- 0.07; P < 0.05) and a higher NHE8 protein abundance (neonate 1.0 +/- 0.01 vs. adult 0.13 +/ 0.09; P < 0.001) compared with adults. To examine if neonates can adapt to acidosis, neonatal mice were gavaged with either acid or vehicle for 4 days, resulting in a drop in serum bicarbonate from 19.5 +/- 1.0 to 8.9 +/- 0.6 meq/l (P < 0.001). Proximal convoluted tubule Na(+)/H(+) exchanger activity (dpH(i)/dt) was 1.68 +/- 0.19 pH units/min in control tubules and 2.49 +/- 0.60 pH units/min in acidemic neonatal mice (P < 0.05), indicating that the neonatal proximal tubule can respond to metabolic acidosis with an increase in Na(+)/H(+) exchanger activity. Similarly, brush-border membrane vesicles from neonatal rats had an increase in Na(+)/H(+) exchanger activity with acidemia that was almost totally inhibited by 10(-6) M 5-(N-ethyl-n-isopropyl)-amiloride, a dose that has little effect on NHE3 but inhibits NHE8. There was a significant increase in both NHE3 (vehicle 0.35 +/- 0.07 vs. acid 0.73 +/- 0.07; P < 0.003) and NHE8 brush-border membrane protein abundance (vehicle 0.41 +/- 0.05 vs. acid 0.73 +/- 0.06; P < 0.001) in acidemic mouse neonates compared with controls. A comparable increase in NHE3 and NHE8 was found in neonatal rats with acidosis. In conclusion, the neonatal proximal tubule can adapt to metabolic acidosis with an increase in Na(+)/H(+) exchanger activity. PMID- 20720176 TI - Muscle protein synthesis and gene expression during recovery from aerobic exercise in the fasted and fed states. AB - The purpose of this investigation was to assess mixed-muscle fractional synthesis rate (FSR) and the expression of genes involved in skeletal muscle remodeling after aerobic exercise in the fasted and fed states. Eight recreationally active males (25 +/- 1 yr; Vo(2 max): 52 +/- 2 ml.kg(-1).min(-1)) performed 60-min of cycle ergometry at 72 +/- 1% Vo(2 max) on two occasions in a counter-balanced design. Subjects ingested a noncaloric placebo (EX-FAST) or a beverage containing (per kg body wt): 5 kcal, 0.83 g carbohydrate, 0.37 g protein, and 0.03 g fat (EX FED) immediately and 1 h after exercise. FSR was assessed at rest and following exercise with the use of a l-[ring (2)H(5)]-phenylalanine infusion combined with muscle biopsies at 2 and 6 h postexercise. mRNA expression was assessed at 2 and 6 h postexercise via real-time RT-PCR. FSR was higher (P < 0.05) after exercise in both EX-FAST (0.112 +/- 0.010%.h(-1)) and EX-FED (0.129 +/- 0.014%.h(-1)) compared with rest (0.071 +/- 0.005%.h(-1)). Feeding attenuated the mRNA expression (P < 0.05) of proteolytic factors MuRF-1 (6 h) and calpain-2 (2 and 6 h) postexercise but did not alter FOXO3A, calpain-1, caspase3, or myostatin mRNA expression compared with EX-FAST. Myogenic regulatory factor (MRF4) mRNA was also attenuated (P < 0.05) at 2 and 6 h postexercise in EX-FED compared with EX-FAST. These data demonstrate that a nonexhaustive bout of aerobic exercise stimulates skeletal muscle FSR in the fasted state and that feeding does not measurably enhance FSR between 2 and 6 h after aerobic exercise. Additionally, postexercise nutrient intake attenuates the expression of factors involved in the ubiquitin proteosome and Ca(2+)-dependent protein degradation pathways. These data provide insight into the role of feeding on muscle protein metabolism during recovery from aerobic exercise. PMID- 20720177 TI - High-NaCl intake impairs dynamic autoregulation of renal blood flow in ANG II infused rats. AB - The aim of this study was to investigate dynamic autoregulation of renal blood flow (RBF) in ANG II-infused rats and the influence of high-NaCl intake. Sprague Dawley rats received ANG II (250 ng.kg(-1).min(-1) sc) or saline vehicle (sham) for 14 days after which acute renal clearance experiments were performed during thiobutabarbital anesthesia. Rats (n = 8-10 per group) were either on a normal (NNa; 0.4% NaCl)- or high (HNa; 8% NaCl)-NaCl diet. Separate groups were treated with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol; 1 M in drinking water). Transfer function analysis from arterial pressure to RBF in the frequency domain was used to examine the myogenic response (MR; 0.06-0.09 Hz) and the tubuloglomerular feedback mechanism (TGF; 0.03-0.06 Hz). MAP was elevated in ANG II-infused rats compared with sham groups (P < 0.05). RBF in ANG II HNa was reduced vs. sham NNa and sham HNa (6.0 +/- 0.3 vs. 7.9 +/- 0.3 and 9.1 +/- 0.3 ml.min(-1).g kidney wt(-1), P < 0.05). transfer function gain in ANG II HNa was significantly elevated in the frequency range of the MR (1.26 +/- 0.50 dB, P < 0.05 vs. all other groups) and in the frequency range of the TGF (-0.02 +/- 0.50 dB, P < 0.05 vs. sham NNa and sham HNa). Gain values in the frequency range of the MR and TGF were significantly reduced by tempol in ANG II-infused rats on HNa diet. In summary, the MR and TGF components of RBF autoregulation were impaired in ANG II HNa, and these abnormalities were attenuated by tempol, suggesting a pathogenetic role for superoxide in the impaired RBF autoregulatory response. PMID- 20720178 TI - Effects of blebbistatin and Ca2+ concentration on force produced during stretch of skeletal muscle fibers. AB - When activated muscle fibers are stretched at low speeds [<= 2 optimal length (L(o))/s], force increases in two phases, marked by a change in slope [critical force (P(c))] that happens at a critical sarcomere length extension (L(c)). Some studies attribute P(c) to the number of attached cross bridges before stretch, while others attribute it to cross bridges in a pre-power-stroke state. In this study, we reinvestigated the mechanisms of forces produced during stretch by altering either the number of cross bridges attached to actin or the cross-bridge state before stretch. Two sets of experiments were performed: 1) activated fibers were stretched by 3% L(o) at speeds of 1.0, 2.0, and 3.0 L(o)/s in different pCa(2+) (4.5, 5.0, 5.5, 6.0), or 2) activated fibers were stretched by 3% L(o) at 2 L(o)/s in pCa(2+) 4.5 containing either 5 MUM blebbistatin(+/-) or its inactive isomer (+/+). All stretches started at a sarcomere length (SL) of 2.5 MUm. When fibers were activated at a pCa(2+) of 4.5, P(c) was 2.47 +/- 0.11 maximal force developed before stretch (P(o)) and decreased with lower concentrations of Ca(2+). L(c) was not Ca(2+) dependent; the pooled experiments provided a L(c) of 14.34 +/- 0.34 nm/half-sarcomere (HS). P(c) and L(c) did not change with velocities of stretch. Fibers activated in blebbistatin(+/-) showed a higher P(c) (2.94 +/- 0.17 P(o)) and L(c) (16.30 +/- 0.38 nm/HS) than control fibers (P(c) 2.31 +/- 0.08 P(o); L(c) 14.05 +/- 0.63 nm/HS). The results suggest that forces produced during stretch are caused by both the number of cross bridges attached to actin and the cross bridges in a pre-power-stroke state. Such cross bridges are stretched by large amplitudes before detaching from actin and contribute significantly to the force developed during stretch. PMID- 20720179 TI - Amino acid substitutions in the FXYD motif enhance phospholemman-induced modulation of cardiac L-type calcium channels. AB - We have found that phospholemman (PLM) associates with and modulates the gating of cardiac L-type calcium channels (Wang et al., Biophys J 98: 1149-1159, 2010). The short 17 amino acid extracellular NH(2)-terminal domain of PLM contains a highly conserved PFTYD sequence that defines it as a member of the FXYD family of ion transport regulators. Although we have learned a great deal about PLM dependent changes in calcium channel gating, little is known regarding the molecular mechanisms underlying the observed changes. Therefore, we investigated the role of the PFTYD segment in the modulation of cardiac calcium channels by individually replacing Pro-8, Phe-9, Thr-10, Tyr-11, and Asp-12 with alanine (P8A, F9A, T10A, Y11A, D12A). In addition, Asp-12 was changed to lysine (D12K) and cysteine (D12C). As expected, wild-type PLM significantly slows channel activation and deactivation and enhances voltage-dependent inactivation (VDI). We were surprised to find that amino acid substitutions at Thr-10 and Asp-12 significantly enhanced the ability of PLM to modulate Ca(V)1.2 gating. T10A exhibited a twofold enhancement of PLM-induced slowing of activation, whereas D12K and D12C dramatically enhanced PLM-induced increase of VDI. The PLM-induced slowing of channel closing was abrogated by D12A and D12C, whereas D12K and T10A failed to impact this effect. These studies demonstrate that the PFXYD motif is not necessary for the association of PLM with Ca(V)1.2. Instead, since altering the chemical and/or physical properties of the PFXYD segment alters the relative magnitudes of opposing PLM-induced effects on Ca(V)1.2 channel gating, PLM appears to play an important role in fine tuning the gating kinetics of cardiac calcium channels and likely plays an important role in shaping the cardiac action potential and regulating Ca(2+) dynamics in the heart. PMID- 20720180 TI - Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. AB - Various uremic toxins accumulate in patients with chronic renal failure (CRF) and one of them is indoxyl sulfate, which accelerates the progression of CRF through unknown mechanisms. The present study investigates how indoxyl sulfate promotes CRF using the proximal tubular cell line HK-2 and CRF rats. Indoxyl sulfate inhibited serum-induced cell proliferation and promoted the activation of senescence-associated beta-galactosidase, a marker of cellular senescence, and the expression of alpha-smooth muscle actin (alpha-SMA), a marker of fibrosis, through inducing p53 expression and phosphorylation. Pifithrin-alpha, p-nitro, a p53 inhibitor, blocked these effects. Indoxyl sulfate evoked reactive oxygen species (ROS), and the antioxidant N-acetylcysteine inhibited indoxyl sulfate induced p53 expression and phosphorylation, as well as indoxyl sulfate-induced alpha-SMA expression. We previously demonstrated that although cellular senescence and fibrosis are detectable in the kidneys of CRF rats, the oral adsorbent AST-120 repressed these effects. Here, we found that beta galactosidase, p53 and alpha-SMA were expressed and colocalized in the renal tubules of CRF rats, whereas AST-120 decreased the expression of these genes. Taken together, these findings indicate that indoxyl sulfate induces the expression and phosphorylation of p53 though ROS production, thus inhibiting cell proliferation and promoting cellular senescence and renal fibrosis. PMID- 20720181 TI - ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes. AB - The number of intermediate-conductance, Ca(2+)-activated K(+) channels (KCa3.1) present at the plasma membrane is deterministic in any physiological response. However, the mechanisms by which KCa3.1 channels are removed from the plasma membrane and targeted for degradation are poorly understood. Recently, we demonstrated that KCa3.1 is rapidly internalized from the plasma membrane, having a short half-life in both human embryonic kidney cells (HEK293) and human microvascular endothelial cells (HMEC-1). In this study, we investigate the molecular mechanisms controlling the degradation of KCa3.1 heterologously expressed in HEK and HMEC-1 cells. Using immunofluorescence and electron microscopy, as well as quantitative biochemical analysis, we demonstrate that membrane KCa3.1 is targeted to the lysosomes for degradation. Furthermore, we demonstrate that either overexpressing a dominant negative Rab7 or short interfering RNA-mediated knockdown of Rab7 results in a significant inhibition of channel degradation rate. Coimmunoprecipitation confirmed a close association between Rab7 and KCa3.1. On the basis of these findings, we assessed the role of the ESCRT machinery in the degradation of heterologously expressed KCa3.1, including TSG101 [endosomal sorting complex required for transport (ESCRT)-I] and CHMP4 (ESCRT-III) as well as VPS4, a protein involved in the disassembly of the ESCRT machinery. We demonstrate that TSG101 is closely associated with KCa3.1 via coimmunoprecipitation and that a dominant negative TSG101 inhibits KCa3.1 degradation. In addition, both dominant negative CHMP4 and VPS4 significantly decrease the rate of membrane KCa3.1 degradation, compared with wild-type controls. These results are the first to demonstrate that plasma membrane associated KCa3.1 is targeted for lysosomal degradation via a Rab7 and ESCRT dependent pathway. PMID- 20720182 TI - Ionic currents in intimal cultured synoviocytes from the rabbit. AB - Hyaluronan, a joint lubricant and regulator of synovial fluid content, is secreted by fibroblast-like synoviocytes lining the joint cavity, and secretion is greatly stimulated by Ca(2+)-dependent protein kinase C. This study aimed to define synoviocyte membrane currents and channels that may influence synoviocyte Ca(2+) dynamics. Resting membrane potential ranged from -30 mV to -66 mV (mean 45 +/- 8.60 mV, n = 40). Input resistance ranged from 0.54 GOmega to 2.6 GOmega (mean 1.28 +/- 0.57 GOmega; nu = 33). Cell capacitance averaged 97.97 +/- 5.93 pF. Voltage clamp using C(s+) pipette solution yielded a transient inward current that disappeared in Ca(2+)-free solutions and was blocked by 1 MUM nifedipine, indicating an L-type calcium current. The current was increased fourfold by the calcium channel activator FPL 64176 (300 nM). Using K(+) pipette solution, depolarizing steps positive to -40 mV evoked an outward current that showed kinetics and voltage dependence of activation and inactivation typical of the delayed rectifier potassium current. This was blocked by the nonspecific delayed rectifier blocker 4-aminopyridine. The synoviocytes expressed mRNA for four Kv1 subtypes (Kv1.1, Kv1.4, Kv1.5, and Kv1.6). Correolide (1 MUM), margatoxin (100 nM), and alpha-dendrotoxin block these Kv1 subtypes, and all of these drugs significantly reduced synoviocyte outward current. The current was blocked most effectively by 50 nM kappa-dendrotoxin, which is specific for channels containing a Kv1.1 subunit, indicating that Kv1.1 is critical, either as a homomultimeric channel or as a component of a heteromultimeric Kv1 channel. When 50 nM kappa dendrotoxin was added to current-clamped synoviocytes, the cells depolarized by >20 mV and this was accompanied by an increase in intracellular calcium concentration. Similarly, depolarization of the cells with high external potassium solution caused an increase in intracellular calcium, and this effect was greatly reduced by 1 MUM nifedipine. In conclusion, fibroblast-like synoviocytes cultured from the inner synovium of the rabbit exhibit voltage dependent inward and outward currents, including Ca(2+) currents. They thus express ion channels regulating membrane Ca(2+) permeability and electrochemical gradient. Since Ca(2+)-dependent kinases are major regulators of synovial hyaluronan secretion, the synoviocyte ion channels are likely to be important in the regulation of hyaluronan secretion. PMID- 20720183 TI - Dose-dependent regulation of primitive erythroid maturation and identity by the transcription factor Eklf. AB - The primitive erythroid (EryP) lineage is the first to differentiate during mammalian embryogenesis. Eklf/Klf1 is a transcriptional regulator that is essential for definitive erythropoiesis in the fetal liver. Dissection of the role(s) of Eklf within the EryP compartment has been confounded by the simultaneous presence of EryP and fetal liver-derived definitive erythroid (EryD) cells in the blood. To address this problem, we have distinguished EryP from their definitive counterparts by crossing Eklf(+/-) mutant and epsilon globin::histone H2B-GFP transgenic mice. Eklf-deficient EryP exhibit membrane ruffling and a failure to acquire the typical discoidal erythroid shape but they can enucleate. Flow cytometric analyses of H2B-GFP(+) EryP revealed that Eklf heterozygosity results in the loss of Ter119 surface expression on EryP but not on EryD. Null mutation of Eklf resulted in abnormal expression of a range of surface proteins by EryP. In particular, several megakaryocyte markers were ectopically expressed by maturing Eklf-null EryP. Unexpectedly, the platelet tetraspanin CD9 was detected on nucleated wild-type EryP but not on mature EryD and thus provides a useful marker for purifying circulating EryP. We conclude that Eklf gene dosage is crucial for regulating the surface phenotype and molecular identity of maturing primitive erythroid cells. PMID- 20720184 TI - Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. AB - Serial quantitation of BCR-ABL mRNA levels is an important indicator of therapeutic response for patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, but there is substantial variation in the real-time quantitative polymerase chain reaction methodologies used by different testing laboratories. To help improve the comparability of results between centers we sought to develop accredited reference reagents that are directly linked to the BCR-ABL international scale. After assessment of candidate cell lines, a reference material panel comprising 4 different dilution levels of freeze-dried preparations of K562 cells diluted in HL60 cells was prepared. After performance evaluation, the materials were assigned fixed percent BCR-ABL/control gene values according to the International Scale. A recommendation that the 4 materials be established as the first World Health Organization International Genetic Reference Panel for quantitation of BCR ABL translocation by real-time quantitative polymerase chain reaction was approved by the Expert Committee on Biological Standardization of the World Health Organization in November 2009. We consider that the development of these reagents is a significant milestone in the standardization of this clinically important test, but because they are a limited resource we suggest that their availability is restricted to manufacturers of secondary reference materials. PMID- 20720185 TI - Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy. AB - Extracorporeal photochemotherapy (ECP) is widely used to treat cutaneous T-cell lymphoma, graft-versus-host disease, and allografted organ rejection. Its clinical and experimental efficacy in cancer immunotherapy and autoreactive disorders suggests a novel mechanism. This study reveals that ECP induces a high percentage of processed monocytes to enter the antigen-presenting dendritic cell (DC) differentiation pathway, within a single day, without added cytokines, as determined by enhanced expression of relevant genes. The resulting DCs are capable of processing and presentation of exogenous and endogenous antigen and are largely maturationally synchronized, as assessed by the level of expression of costimulatory surface molecules. Principal component analysis of the ECP induced monocyte transcriptome reveals that activation or suppression of more than 1100 genes produces a reproducible distinctive molecular signature, common to ECP-processed monocytes from normal subjects, and those from patients. Because ECP induces normal monocytes to enter the DC differentiation pathway, this phenomenon is independent of disease state. The efficiency with which ECP stimulates new functional DCs supports the possibility that these cells participate prominently in the clinical successes of the treatment. Appropriately modified by future advances, ECP may potentially offer a general source of therapeutic DCs. PMID- 20720186 TI - Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant. AB - In vivo targeting of C-type lectin receptors is an effective strategy for increasing antigen uptake and presentation by dendritic cells (DCs). To induce efficient immune response, glycosylated tumor-associated Tn antigens were used to target DCs through binding to macrophage galactose-type lectin (MGL). The capacity of Tn-glycosylated antigens-and the multiple antigenic glycopeptide Tn3 therapeutic candidate vaccine-to target mouse and human MGL(+) DCs are demonstrated, especially regarding dermal DCs. In mice, MGL(+) CD103(-) dermal DCs efficiently captured and processed glycosylated Tn antigen in vivo, inducing a potent major histocompatibility complex (MHC) class II-restricted T-cell response. Intradermal immunization with Tn-glycopeptides induced high levels of Th2 cytokines-even in the presence of unmethylated cytosine-phosphate-guanosine and was associated with increased expansion of the germinal center B-cell population. Therefore, MGL acts as an efficient endocytic antigen receptor on dermal DCs in vivo, able to prime Tn-specific T- and B-cell responses. Moreover, even in the absence of adjuvant, immunization with this glycosidic Tn-based vaccine induced high levels of anti-Tn antibody responses, recognizing human tumor cells. In vivo DC-targeting strategies, based on Tn-MGL interactions, constitute a promising strategy for enhancing antigen presentation and inducing potent antibody response. PMID- 20720187 TI - MicroRNA expression in maturing murine megakaryocytes. AB - MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell autonomously. PMID- 20720188 TI - Ischemic diffusion lesion reversal is uncommon and rarely alters perfusion diffusion mismatch. AB - OBJECTIVE: The use of diffusion-weighted imaging (DWI) to define irreversibly damaged infarct core is challenged by data suggesting potential partial reversal of DWI abnormalities. However, previous studies have not considered infarct involution. We investigated the prevalence of DWI lesion reversal in the EPITHET Trial. METHODS: EPITHET randomized patients 3-6 hours from onset of acute ischemic stroke to tissue plasminogen activator (tPA) or placebo. Pretreatment DWI and day 90 T2-weighted images were coregistered. Apparent reversal of the acute ischemic lesion was defined as DWI lesion not incorporated into the final infarct. Voxels of CSF at follow-up were subtracted from regions of apparent DWI lesion reversal to adjust for infarct atrophy. All cases were visually cross checked to exclude volume loss and coregistration inaccuracies. RESULTS: In 60 patients, apparent reversal involved a median 46% of the baseline DWI lesion (median volume 4.9 mL, interquartile range 2.6-9.5 mL) and was associated with less severe baseline hypoperfusion (p < 0.001). Apparent reversal was increased by reperfusion, regardless of the severity of baseline hypoperfusion (p = 0.02). However, the median volume of apparent reversal was reduced by 45% when CSF voxels were subtracted (2.7 mL, interquartile range 1.6-6.2 mL, p < 0.001). Perfusion-diffusion mismatch classification only rarely altered after adjusting the baseline DWI volume for apparent reversal. Visual comparison of acute DWI to subacute DWI or day 90 T2 identified minor regions of true DWI lesion reversal in only 6 of 93 patients. CONCLUSIONS: True DWI lesion reversal is uncommon in ischemic stroke patients. The volume of apparent lesion reversal is small and would rarely affect treatment decisions based on perfusion-diffusion mismatch. PMID- 20720189 TI - CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease. AB - OBJECTIVE: Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease. METHODS: A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid beta 1 42 (Abeta(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time. RESULTS: Lower baseline CSF Abeta(1-42) was associated with more rapid cognitive decline. Subjects with CSF Abeta(1-42) levels <=192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline. CONCLUSIONS: Reduced CSF Abeta(1 42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD. PMID- 20720190 TI - Lifestyles of the young and migrainous. PMID- 20720191 TI - An unfavorable lifestyle and recurrent headaches among adolescents: the HUNT study. AB - OBJECTIVES: To examine the relationship between recurrent headache disorders (i.e., migraine and tension-type headache) and lifestyle factors (overweight, low physical activity, and smoking) in an unselected population study among adolescents. METHODS: In this cross-sectional study from Norway, a total of 5,847 students were interviewed about headache complaints and completed a comprehensive questionnaire including items concerning physical activity and smoking. In addition, they underwent a clinical examination with height and weight measurements. Adolescents with high physical activity who were not current smokers and not overweight were classified as having a good lifestyle status. These students were compared to those with 1 or more of the negative lifestyle factors present in regard to headache diagnosis and headache frequency. RESULTS: In adjusted multivariate analyses, recurrent headache was associated with overweight (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.2-1.6, p < 0.0001), low physical activity (OR = 1.2, 95% CI 1.1-1.4, p = 0.002), and smoking (OR = 1.5, 95% CI 1.3-1.7, p < 0.0001). The prevalence of OR increased with more than 1 negative lifestyle factor present, evident for headache diagnoses and frequency. CONCLUSION: The results from the present study show that overweight, smoking, or low physical activity are independently and in combination associated with recurrent headache among adolescents. The associations observed and the additive effect of these negative lifestyle factors on the prevalence of recurrent headache indicates possible targets for preventive measures. PMID- 20720192 TI - Tregs and human atherothrombotic diseases: toward a clinical application? PMID- 20720193 TI - Notch leads lymphatics and links them to blood vessels. PMID- 20720194 TI - Osteoprotegerin: a biomarker with many faces. PMID- 20720195 TI - Sonic hedgehog signaling induces vascular smooth muscle cell proliferation via induction of the G1 cyclin-retinoblastoma axis. AB - OBJECTIVE: Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in the pathogenesis of intimal hyperplasia, the main cause of restenosis following vascular reconstruction. Here, the impact of sonic hedgehog (Shh)/Gli family zinc finger 2 (Gli2) signaling on VSMC proliferation was assessed. METHODS AND RESULTS: Increased Shh signaling was detected in VSMCs in the neointima of vein grafts obtained from mice undergoing restenosis. Comparable results were found in primary cultured human VSMCs (hVSMCs) obtained from patients undergoing coronary bypass surgery, which were used to further assess the impacts of Shh signaling on VSMC proliferation. Inhibition of Shh signaling in hVSMCs through treatment with cyclopamine or knockdown of Gli2 results in G(1) arrest and reduced cyclin D1, cyclin E, and phosphorylated retinoblastoma (pRB) levels. In contrast, activation of Shh/Gli2 signaling in hVSMCs results in increased levels of G(1) cyclins and promotes G(1)-S transition. Stimulation of hVSMC proliferation by Shh is abolished by cyclin D1 knockdown. CONCLUSIONS: Combined, these results demonstrate that Shh/Gli2 signaling stimulates VSMC proliferation via regulation of the G(1) cyclin-retinoblastoma axis and suggest that antagonists that target the Shh pathway may be therapeutically beneficial in the prevention of intimal hyperplasia. PMID- 20720196 TI - Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. AB - The ability of the in vitro mammalian cell tests currently used to identify genotoxins has been shown to be limited by a high rate of false-positive results, triggering further unnecessary testing in vivo. During an European Centre for the Validation of Alternative Methods workshop on how to improve the specificity of these assays, testing at high concentrations was identified as one possible source of false positives. Thus far, Organisation for Economic Co-operation and Development genotoxicity test guidelines have required testing of chemicals using mammalian cells in vitro should be undertaken to concentrations as high as 10 mM (5000 MUg/ml). Recently, a draft revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use genotoxicity test guidelines has recommended that testing concentrations should be reduced to 1 mM (500 MUg/ml). To assess the impact that this lowering would have on the outcome of in vitro genotoxicity testing, we established a database of 384 chemicals classified as rodent carcinogens and reported Ames test results and the test concentrations that produced positive results in the mouse lymphoma assay (MLA), in vitro chromosome aberration (CA) assay and in vitro micronucleus test. Genotoxicity testing results were illustrated for 229 and 338 compounds in the MLA and in vitro CA assay, respectively. Of these test compounds, 62.5% produced positive results in the MLA, of which 20.3% required testing between 1 and 10 mM. A total of 58.0% produced positive results in in vitro CA assays, of which 25.0% required testing between 1 and 10 mM. If the testing concentration limit for mammalian cell assays was reduced to 1 mM, 24 (6.25%) potential carcinogens would not be detected in any part of the standard in vitro genotoxicity test battery (Ames test, MLA and in vitro CA assay). Further re-evaluation and/or retest of these compounds by Kirkland and Fowler [Kirkland, D. and Fowler, P. (2010) Further analysis of Ames negative rodent carcinogens that are only genotoxic in mammalian cells in vitro at concentrations exceeding 1 mM, including retesting of compounds of concern. Mutagenesis 25, 539-553] suggest that the current 10 mM top concentration can be reduced without any loss of sensitivity in detecting rodent carcinogens. PMID- 20720197 TI - Further analysis of Ames-negative rodent carcinogens that are only genotoxic in mammalian cells in vitro at concentrations exceeding 1 mM, including retesting of compounds of concern. AB - In the analysis by Parry et al. [Parry, J. M., Parry, E., Phrakonkham, P. and Corvi, R. (2010) Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. Mutagenesis, 25, 531-538], 24 rodent carcinogens that were negative in the Ames test were identified that were only positive in mammalian cell tests at concentrations between 1 and 10 mM. These carcinogens can be subdivided into four groups as follows: (1) probable non genotoxic (non-mutagenic) carcinogens, tumour promoters or negative for genotoxicity in vivo (n=10); (2) questionable carcinogens (n=4); (3) carcinogens with a probable genotoxic mode of action (n=5); (4) compounds where carcinogenicity or in vivo genotoxicity is unknown or unclear (n=5). It is not expected that in vitro mammalian cell tests should give positive results with Group 1 chemicals. Within Groups 2-4, five chemicals were considered a low priority because they could be detected using modified conditions because genotoxicity was associated with precipitate or pH shifts or because non-standard metabolism was required. The remaining nine chemicals were therefore considered most critical in terms of detection of genotoxic activity in mammalian cells. Daminozide was also included because it may have given positive responses between 1 and 10 mM. Many of the reported studies could have given positive results only at >1 mM because 'old' protocols were followed. These 10 chemicals have therefore been retested using modern protocols. Some were negative even up to 10 mM. Others were positive at concentrations <1 mM. Only methylolacrylamide was positive at a concentration >1 mM (2 mM = 202 MUg/ml). Low-molecular weight substances may therefore require concentrations >1 mM, but further work is needed. Based on this analysis, it is concluded that the 10 mM upper limit in mammalian cell tests can be lowered without any loss of sensitivity in detecting genotoxic rodent carcinogens. A new limit of 1 mM or 500 MUg/ml, whichever is the higher, is proposed. PMID- 20720198 TI - Pronounced virus-dependent activation drives exhaustion but sustains IFN-gamma transcript levels. AB - During many chronic infections, the responding CD8 T cells become exhausted as they progressively lose their ability to elaborate key effector functions. Unlike prototypic memory CD8 cells, which rapidly synthesize IFN-gamma following activation, severely exhausted T cells fail to produce this effector molecule. Nevertheless, the ontogeny of exhausted CD8 T cells, as well as the underlying mechanisms that account for their functional inactivation, remains ill defined. We have used cytokine reporter mice, which mark the transcription of IFN-gamma mRNA by the expression of Thy1.1, to decipher how activation events during the early stages of a chronic infection dictate the development of exhaustion. We show that virus-specific CD8 T cells clearly respond during the early stages of chronic lymphocytic choriomeningitis virus infection, and that this early T cell response is more pronounced than that initially observed in acutely infected hosts. Thus, exhausted CD8 T cells appear to emerge from populations of potently activated precursors. Unlike acute infections, which result in massive expansion of the responding T cells, there is a rapid attenuation of further expansion during chronic infections. The exhausted T cells that subsequently emerge in chronically infected hosts are incapable of producing the IFN-gamma protein. Surprisingly, high levels of the IFN-gamma transcript are still present in exhausted cells, demonstrating that ablation of IFN-gamma production by exhausted cells is not due to transcriptional silencing. Thus, posttranscription regulatory mechanisms likely disable this effector module. PMID- 20720199 TI - IFN regulatory factor 3 contributes to the host response during Pseudomonas aeruginosa lung infection in mice. AB - Pseudomonas aeruginosa is a major opportunistic pathogen. However, host defense mechanisms involved in P. aeruginosa lung infection remain incompletely defined. The transcription factor IFN regulatory factor 3 (IRF3) is primarily associated with host defense against viral infections, and a role of IRF3 in P. aeruginosa infection has not been reported previously. In this study, we showed that IRF3 deficiency led to impaired clearance of P. aeruginosa from the lungs of infected mice. P. aeruginosa infection induced IRF3 translocation to the nucleus, activation of IFN-stimulated response elements (ISRE), and production of IFN beta, suggesting that P. aeruginosa activates the IRF3-ISRE-IFN pathway. In vitro, macrophages from IRF3-deficient mice showed complete inhibition of CCL5 (RANTES) and CXCL10 (IP-10) production, partial inhibition of TNF, but no effect on CXCL2 (MIP-2) or CXCL1 (keratinocyte-derived chemokine) in response to P. aeruginosa stimulation. In vivo, IRF3-deficient mice showed complete inhibition of CCL5 production and partial or no effects on production of other cytokines and chemokines in the bronchoalveolar lavage fluids and lung tissues. Profiling of immune cells in the airways revealed that neutrophil and macrophage recruitment into the airspace was reduced, whereas B cell, T cell, NK cell, and NKT cell infiltration was unaffected in IRF3-deficient mice following P. aeruginosa lung infection. These data suggest that IRF3 regulates a distinct profile of cytokines and chemokines and selectively modulates neutrophil and macrophage recruitment during P. aeruginosa infection. Thus, IRF3 is an integral component in the host defense against P. aeruginosa lung infection. PMID- 20720201 TI - MEKK3 overexpression contributes to the hyperresponsiveness of IL-12 overproducing cells and CD4+ T conventional cells in nonobese diabetic mice. AB - Elevated IL-12 production and higher rate of CD4(+) T conventional (Tconv) cell proliferation in NOD mice have been implicated in the progression of type 1 diabetes. However, the underlying mechanisms remain largely unknown, even though enhanced activation of the IkappaB kinase (IKK)/NF-kappaB pathway has been revealed to mediate IL-12 overproduction. In this study, we report that deviated p38 MAPK activation also contributes to elevated IL-12 production with a mechanism involving MAPK-activated protein kinase-2-mediated stabilization of IL 12p40 mRNA. Aberrant p38 activation induced by various inflammatory stimuli in IL 12-overproducing cells is not due to defective MAPK phosphatase-1 induction in NOD mice. Deviated IKK and MAPKs activation also occurs in NOD CD4(+) Tconv cells, which is associated with higher rates of proliferation. All of the above evidence suggests that the signaling defects occur at the level of MAPK kinase kinase (MAK3K or MEKK). Further exploration shows that MEKK3, but not other MAP3Ks, is overexpressed in NOD IL-12-overproducing cells and CD4(+) Tconv cells independent of autoimmune inflammation. MEKK3 knockdown leads to reversal of the deviated IKK and MAPKs activation, resulting in reduced IL-12 production and decreased CD4(+) Tconv cell proliferation. Thus, this study provides a molecular mechanism of the hyperresponsiveness of IL-12-overproducing cells and CD4(+) Tconv cells in NOD mice. PMID- 20720200 TI - An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. AB - The aryl hydrocarbon receptor (AHR) has been known to cause immunosuppression after binding dioxin. It has recently been discovered that the receptor may be central to T cell differentiation into FoxP3(+) regulatory T cells (Tregs) versus Th17 cells. In this paper, we demonstrate that kynurenine, the first breakdown product in the IDO-dependent tryptophan degradation pathway, activates the AHR. We furthermore show that this activation leads to AHR-dependent Treg generation. We additionally investigate the dependence of TGF-beta on the AHR for optimal Treg generation, which may be secondary to the upregulation of this receptor that is seen in T cells postexposure to TGF-beta. These results shed light on the relationship of IDO to the generation of Tregs, in addition to highlighting the central importance of the AHR in T cell differentiation. All tissues and cells were derived from mice. PMID- 20720202 TI - Chemerin contributes to inflammation by promoting macrophage adhesion to VCAM-1 and fibronectin through clustering of VLA-4 and VLA-5. AB - Chemerin is a potent macrophage chemoattractant protein. We used murine peritoneal exudate cells (PECs) in adhesion, flow cytometry, and confocal microscopy assays to test the hypothesis that chemerin can also contribute to inflammation by promoting macrophage adhesion. Chemerin stimulated the adhesion of PECs to the extracellular matrix protein fibronectin and to the adhesion molecule VCAM-1 within a minute, with an EC(50) of 322 and 196 pM, respectively. Experiments using pertussis toxin and PECs from ChemR23(-/-) mice demonstrated that chemerin stimulated the adhesion of macrophages via the Gi protein-coupled receptor ChemR23. Blocking Abs against integrin subunits revealed that 89% of chemerin-stimulated adhesion to fibronectin was dependent on increased avidity of the integrin VLA-5 (alpha(5)beta(1)) and that 88% of adhesion to VCAM-1 was dependent on increased avidity of VLA-4 (alpha(4)beta(1)). Although chemerin was unable to induce an increase in integrin affinity as judged by the binding of soluble ligand, experiments using confocal microscopy revealed an increase in valency resulting from integrin clustering as the mechanism responsible for chemerin-stimulated macrophage adhesion. PI3K, Akt, and p38 were identified as key signaling mediators in chemerin-stimulated adhesion. The finding that chemerin can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules, taken together with its ability to promote chemotaxis, suggests a novel role for chemerin in the recruitment and retention of macrophages at sites of inflammation. PMID- 20720203 TI - P2Y2 receptor regulates VCAM-1 membrane and soluble forms and eosinophil accumulation during lung inflammation. AB - ATP has been defined as a key mediator of asthma. In this study, we evaluated lung inflammation in mice deficient for the P2Y(2) purinergic receptor. We observed that eosinophil accumulation, a distinctive feature of lung allergic inflammation, was defective in OVA-treated P2Y(2)-deficient mice compared with OVA-treated wild type animals. Interestingly, the upregulation of VCAM-1 was lower on lung endothelial cells of OVA-treated P2Y(2)(-/-) mice compared with OVA treated wild type animals. Adhesion assays demonstrated that the action of UTP on leukocyte adhesion through the regulation of endothelial VCAM-1 was abolished in P2Y(2)-deficient lung endothelial cells. Additionally, the level of soluble VCAM 1, reported as an inducer of eosinophil chemotaxis, was strongly reduced in the bronchoalveolar lavage fluid (BALF) of P2Y(2)-deficient mice. In contrast, we observed comparable infiltration of macrophages and neutrophils in the BALF of LPS-aerosolized P2Y(2)(+/+) and P2Y(2)(-/-) mice. This difference could be related to the much lower level of ATP in the BALF of LPS-treated mice compared with OVA-treated mice. Our data define P2Y(2) as a regulator of membrane and soluble forms of VCAM-1 and eosinophil accumulation during lung inflammation. PMID- 20720204 TI - Nonmalignant clonal expansions of memory CD8+ T cells that arise with age vary in their capacity to mount recall responses to infection. AB - Immune responsiveness declines with age in part due to the development of CD8(+) T cell clonal expansions (TCEs) that can dominate the peripheral T cell pool. Although some TCEs arise due to persistent Ag stimulation from chronic infections, others arise in the apparent absence of chronic infection. We have recently shown that this latter class of TCEs can arise over time from the memory CD8(+) T cell pool established by an acute viral infection. Unlike TCEs driven by chronic infections, these age-related TCEs do not display the phenotypic and in vitro functional characteristics of exhausted cells. However, the rate at which these age-related TCEs develop from the memory CD8(+) T cell pool, as well as their ability to mount a recall response to secondary pathogen challenge in vivo, is not known. In this study, we analyzed large cohorts of mice over time for the development of TCE following Sendai virus infection and found a progressive increase in the appearance of TCEs, such that most mice showed evidence of TCE within the memory T cell pool by 2 y postinfection. Using a dual adoptive transfer approach to address the recall potential of virus-specific TCEs, we also demonstrate that most TCEs examined are poorly responsive to a secondary infection. Therefore, we provide evidence that the development of TCE is a common occurrence due to the progressive dysregulation of the virus-specific memory T cell pool with age, but many TCEs are profoundly defective in their ability to mediate recall responses. PMID- 20720205 TI - Proximal events in 7,12-dimethylbenz[a]anthracene-induced, stromal cell-dependent bone marrow B cell apoptosis: stromal cell-B cell communication and apoptosis signaling. AB - Intercellular communication is an essential process in stimulating lymphocyte development and in activating and shaping an immune response. B cell development requires cell-to-cell contact with and cytokine production by bone marrow stromal cells. However, this intimate relationship also may be responsible for the transfer of death-inducing molecules to the B cells. 7,12 Dimethylbenz[a]anthracene (DMBA), a prototypical polycyclic aromatic hydrocarbon, activates caspase-3 in pro/pre-B cells in a bone marrow stromal cell-dependent manner, resulting in apoptosis. These studies were designed to examine the hypothesis that an intrinsic apoptotic pathway is activated by DMBA and that the ultimate death signal is a DMBA metabolite generated by the stromal cells and transferred to the B cells. Although a loss of mitochondrial membrane potential did not occur in the DMBA/stromal cell-induced pathway, cytochrome c release was stimulated in B cells. Caspase-9 was activated, and formation of the apoptosome was required to support apoptosis, as demonstrated by the suppression of death in Apaf-1(fog) mutant pro-B cells. Investigation of signaling upstream of the mitochondria demonstrated an essential role for p53. Furthermore, DMBA-3,4 dihydrodiol-1,2-epoxide, a DNA-reactive metabolite of DMBA, was sufficient to upregulate p53, induce caspase-9 cleavage, and initiate B cell apoptosis in the absence of stromal cells, suggesting that production of this metabolite by the stromal cells and transfer to the B cells are proximal events in triggering apoptosis. Indeed, we provide evidence that metabolite transfer from bone marrow stromal cells occurs through membrane exchange, which may represent a novel communication mechanism between developing B cells and stromal cells. PMID- 20720206 TI - Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. AB - Cerebral malaria is a severe complication of malaria. Sequestration of parasitized RBCs in brain microvasculature is associated with disease pathogenesis, but our understanding of this process is incomplete. In this study, we examined parasite tissue sequestration in an experimental model of cerebral malaria (ECM). We show that a rapid increase in parasite biomass is strongly associated with the induction of ECM, mediated by IFN-gamma and lymphotoxin alpha, whereas TNF and IL-10 limit this process. Crucially, we discovered that host CD4(+) and CD8(+) T cells promote parasite accumulation in vital organs, including the brain. Modulation of CD4(+) T cell responses by helminth coinfection amplified CD4(+) T cell-mediated parasite sequestration, whereas vaccination could generate CD4(+) T cells that reduced parasite biomass and prevented ECM. These findings provide novel insights into immune-mediated mechanisms of ECM pathogenesis and highlight the potential of T cells to both prevent and promote infectious diseases. PMID- 20720207 TI - Inflammatory effects of ex vivo human Th17 cells are suppressed by regulatory T cells. AB - Th17 cells are proinflammatory cells associated with many immune-mediated diseases. Major factors limiting the study of human Th17 cells are the lack of an accepted method for their in vitro differentiation or for isolation of a homogenous population of Th17 cells that do not cosecrete IFN-gamma. To overcome these hurdles, we established a novel method to isolate in vivo differentiated Th17 cells from peripheral blood by sorting CD161(+)CCR4(+)CCR6(+)CXCR3(-)CD4(+) T cells. The resulting cells produce high levels of IL-17 but not IFN-gamma, express high levels of retinoic acid-related orphan receptor variant 2, and maintain this phenotype upon expansion. Ex vivo Th17 cells exhibit a low cytotoxic potential and are hyporesponsive to polyclonal anti-CD3/anti-CD28 stimulation. Importantly, ex vivo Th17 cells were susceptible to suppression by both naive and memory regulatory T cells (Tregs), which inhibited production of IL-17, IL-22, and CXCL8. Moreover, Tregs suppressed the antifibrotic effects of Th17 cells in a wound-healing model. These findings provide new tools for the study of normal and pathological functions of bona fide Th17 cells in humans. They also provide new insight into the cross-talk between Th17 cells and immune and nonimmune cells, and they establish the paradigm that adoptive Treg-based therapies may effectively limit Th17-mediated inflammation. PMID- 20720208 TI - Interference with dendritic cell populations limits early antigen presentation in chronic gamma-herpesvirus-68 infection. AB - A critical factor influencing the ability of the host to mount a robust immune response against a virus depends on the rapid recruitment of dendritic cells (DCs) presenting Ags. From the outset, this step sets the tempo for subsequent activation of virus-specific T cells. Despite this, how induction of the immune response might be modified by pathogens with the capacity to establish persistence is unclear. In this study, we have characterized the in vivo influence of murine gamma-herpesvirus K3-mediated interference with MHC class I in DCs that drive the initial adaptive immune response. We observed that gamma herpesvirus could interfere with the very earliest phase of Ag presentation through K3 by directly targeting migratory and lymph node-resident DCs. These results show that a pathogen with the capacity to interfere with early Ag presentation can establish suboptimal conditions for rapid induction of the adaptive immune response and thus favor establishment of viral persistence. PMID- 20720209 TI - Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice. AB - Tumor cell vaccination with irradiated autologous tumor cells is a promising approach to activate tumor-specific T cell responses without the need for tumor Ag identification. However, uptake of dying cells by dendritic cells (DCs) is generally a noninflammatory or tolerizing event to prevent the development of autoreactive immune responses. In this study, we describe the mechanisms that confer the potent T cell priming capacity of a recently identified a population of DCs (merocytic DCs [mcDCs]) that potently primes both CD8(+) and CD4(+) T cells to cell-associated Ags upon uptake of apoptotic cells. mcDCs acquired cell associated materials through a process of merocytosis that is defined by the uptake of small particles that are stored in nonacidic compartments for prolonged periods, sustained Ag presentation, and the induction of type I IFN. T cells primed by mcDCs to cell-associated Ags exhibit increased primary expansion, enhanced effector function, and increased memory formation. By using transgenic T cell transfer models and endogenous models, we show that treatment of tumor bearing mice with mcDCs that have been exposed to dying tumor cells results in tumor suppression and increased host survival through the activation of naive tumor-specific CD8(+) T cells as well as the reinvigoration of tumor-specific T cells that had been rendered nonresponsive by the tumor in vivo. The potent capacity of mcDCs to prime both CD4(+) and CD8(+) T cells to cell-associated Ags under immunosuppressive conditions makes this DC subset an attractive target for tumor therapies as well as interventional strategies for autoimmunity and transplantation. PMID- 20720210 TI - Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. AB - Mucosal (nasal or oral) administration of anti-CD3 mAb is effective in ameliorating animal models of autoimmunity (experimental autoimmune encephalomyelitis, diabetes, and lupus) by inducing LAP(+) regulatory T cells. We tested this approach in an arthritis model using type II collagen. We found that nasal anti-CD3 was more effective than oral anti-CD3 in attenuating the development of arthritis. Nasal anti-CD3 induced a LAP(+) regulatory T cell that secreted high levels of IL-10 and suppressed collagen-specific T cell proliferation and anti-collagen Ab production. However, neither nasal nor oral anti-CD3 attenuated disease when given to animals with ongoing arthritis, and this was associated with a lack of induction of LAP(+) regulatory T cells. We found, however, that coadministration of a novel emulsome adjuvant, which enhances Th2 responses, resulted in the induction of LAP(+) regulatory T cells and suppression of ongoing arthritis by both nasal and oral anti-CD3. Suppression of arthritis by mucosal anti-CD3 was associated with less joint damage, a decrease of TNF-alpha and IFN-gamma mRNA expression in joints, and a reduction in anti-collagen Abs. These results demonstrate that mucosal anti-CD3 therapy may serve as a therapeutic approach in arthritis and that the biologic effect is enhanced by an emulsome-based adjuvant. PMID- 20720211 TI - CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype. AB - Expression of CCR6 and its ligand, CCL20, are increased in the colon of humans with inflammatory bowel diseases and mice with experimental colitis; however, their role in disease pathogenesis remains obscure. In this study, we demonstrate a role for CCR6 on regulatory T (Treg) cells in the T cell-transfer model of colitis. Rag2(-/-) mice given Ccr6(-/-)CD4(+)CD45RB(high) T cells had more severe colitis with increased IFN-gamma-producing T cells, compared with the mice given wild-type cells. Although an equivalent frequency of induced/acquired Treg (iTreg) cells was observed in mesenteric lymph nodes and colon from both groups, the suppressive capacity of Ccr6(-/-) iTreg cells was impaired. Cotransfer studies of wild-type or Ccr6(-/-) Treg cells with CD4(+)CD45RB(high) T cells also showed a defect in suppression by Ccr6(-/-) Treg cells. CCR6(+) Treg cells were characterized as Ag-activated and IL-10-producing in the steady-state and preferentially migrated to the colon during inflammation. Thus, we conclude that CCR6 expression on Treg cells was required for the full function of Treg cell mediated suppression in the T cell-transfer model of colitis. CCR6 may contribute to the regulation of colitis by directing its function in Ag-specific, IL-10 producing iTreg cells to the inflamed colon. PMID- 20720212 TI - Overexpression of TGF-beta 1 gene induces cell surface localized glucose regulated protein 78-associated latency-associated peptide/TGF-beta. AB - TGF-beta plays a crucial role in immune regulation. It has been reported that pro TGF-beta, latency-associated peptide (LAP), latent TGF-beta and/or active TGF beta (LAP/TGF-beta) is localized on the cell surface of Foxp3(+) regulatory T cells. However, the molecular mechanism(s) of how LAP/TGF-beta is anchored on the cell membrane is unknown. In this study, we show that forced expression of human TGF-beta(1) gene by retrovirus transduction into P3U1 mouse myeloma cells, and other cell types including murine CD4(+)CD25(-) T cells, makes these cells surface LAP/TGF-beta-positive. The surface LAP/TGF-beta contains high glycosylated, furin-processed latent TGF-beta, which is different from the low glycosylated, furin-unprocessed intracellular form or the high-glycosylated, furin-unprocessed secreted form. Furthermore, surface LAP/TGF-beta forms a complex with the molecular chaperone glucose-regulated protein 78 (GRP78, also known as BiP), and knockdown of GRP78 reduced the expression levels of surface LAP/TGF-beta. GRP78, however, is not involved in GARP-mediated surface LAP/TGF beta. Our results suggest that GRP78 provides an additional surface localization mechanism for LAP/TGF-beta, which may play an important role in controlling TGF beta activity. PMID- 20720213 TI - Manual and automated office measurements in relation to awake ambulatory blood pressure monitoring. AB - BACKGROUND: Automated blood pressure (BP) devices are commonly used in doctor's offices. How BP measured on these devices relates to ambulatory BP monitoring is not clear. OBJECTIVE: To assess how well office-based manual and automated BP predicts ambulatory BP. METHODS: Using data on 654 patients, we assessed how well sphygmomanometer measurements and measurements taken with an automated device (BpTRU) predicted results on ambulatory BP monitoring. We assess positive and negative predictive values and overall accuracy. We look at different cut-points for systolic (130, 135 and 140 mmHg) and diastolic (80, 85 and 90 mmHg) BP. RESULTS: A single automated office BP (AOBP) assessment provides superior predictive values and overall accuracy compared to three manual office BP assessments. For systolic BP, the predictive values are <=69% for any of the cut points while the positive predictive values for the single automated measurement is between 80.0% and 86.9% and the overall accuracy gets as high as 74% for the 130 mmHg cut-point. For diastolic BP, the automated readings are also more predictive but in this case, it is the negative predictive values that are better, as well as the overall accuracy. CONCLUSIONS: Based on the results, we suggest that 135/85 mmHg continue to be used as the cut-point defining high BP with the BpTRU device. However, future research might suggests that values in a grey zone between 130-139 mmHg systolic and 80-89 mmHg diastolic be confirmed using ambulatory BP monitoring. As well, three AOBP assessments might produce much greater accuracy than the single AOBP assessment used in the study. PMID- 20720214 TI - 360 Degrees of human subjects protections in community-engaged research. AB - With the introduction of the new National Institutes of Health Roadmap in 2003, there has been a growing emphasis on translational research. Translational research challenges current human subjects protections guidelines that were written in the 1970s and were focused on the protection of the individual participant in a clinical drug trial. Community engagement requires a critical examination of the range of risks that may arise when communities are both participants and partners in research, in order to promote appropriate and effective protection of human subjects as individuals and members of communities. Given that the principal investigator has ultimate responsibility for ensuring the ethical integrity of the research, researchers should be aware of the human subjects protections delineated in the federal regulations that must be fulfilled and the other entities that can help ensure human subjects protections. PMID- 20720215 TI - Are herbal medicines ripe for the cancer clinic? AB - The use of complementary and alternative medicine (CAM) has become a core component of the daily challenges faced when treating cancer patients. PHY906 is a formulation of four herbal compounds traditionally used to treat nausea, vomiting, cramping, and diarrhea. Diarrhea is one of the major side effects of the cancer drug irinotecan. In this issue of Science Translational Medicine, Lam and colleagues report that administration of PHY906 with irinotecan in a mouse model of colon cancer resulted in a synergistic reduction in tumor burden, maintenance of body weight, and stem cell regeneration in the intestinal mucosa. Yet when considering CAM use in the treatment of cancer patients, one must take into account reproducibility of preclinical findings in clinical practice, quality assurance of herbal products, and potential toxicities associated with alternative therapies. PMID- 20720216 TI - The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. AB - PHY906, a four-herb Chinese medicine formula first described 1800 years ago, decreases gastrointestinal toxicity induced by the chemotherapeutic drug CPT-11 (irinotecan), as shown in a phase I/II clinical study. Similarly, in a murine colon 38 allograft model, PHY906 increased the antitumor activity of CPT-11 while decreasing animal weight loss caused by CPT-11. Here, we have further examined the effect of PHY906 on the intestinal toxicity caused by CPT-11 in mice. PHY906 did not protect against the initial DNA damage and apoptosis triggered by CPT-11 in the intestine, but by 4 days after CPT-11 treatment, PHY906 had restored the intestinal epithelium by promoting the regeneration of intestinal progenitor or stem cells and several Wnt signaling components. PHY906 also potentiated Wnt3a activity in human embryonic kidney-293 cells. Furthermore, PHY906 exhibited anti inflammatory effects in mice by decreasing the infiltration of neutrophils or macrophages, tumor necrosis factor-alpha expression in the intestine, and proinflammatory cytokine concentrations in plasma. Chemical constituents of PHY906 potently inhibited nuclear factor kappaB, cyclooxygenase-2, and inducible nitric oxide synthase. Our results show that the herbal medicine PHY906 can counteract the toxicity of CPT-11 via several mechanisms that act simultaneously. PMID- 20720217 TI - Multivalent integrin-specific ligands enhance tissue healing and biomaterial integration. AB - Engineered biointerfaces covered with biomimetic motifs, including short bioadhesive ligands, are a promising material-based strategy for tissue repair in regenerative medicine. Potentially useful coating molecules are ligands for the integrins, major extracellular matrix receptors that require both ligand binding and nanoscale clustering for maximal signaling efficiency. We prepared coatings consisting of well-defined multimer constructs with a precise number of recombinant fragments of fibronectin (monomer, dimer, tetramer, and pentamer) to assess how nanoscale ligand clustering affects integrin binding, stem cell responses, tissue healing, and biomaterial integration. Clinical-grade titanium was grafted with polymer brushes that presented monomers, dimers, trimers, or pentamers of the alpha(5)beta(1) integrin-specific fibronectin III (7 to 10) domain (FNIII(7-10)). Coatings consisting of trimers and pentamers enhanced integrin-mediated adhesion in vitro, osteogenic signaling, and differentiation in human mesenchymal stem cells more than did surfaces presenting monomers and dimers. Furthermore, ligand clustering promoted bone formation and functional integration of the implant into bone in rat tibiae. This study establishes that a material-based strategy in which implants are coated with clustered bioadhesive ligands can promote robust implant-tissue integration. PMID- 20720219 TI - Different populations of circulating endothelial cells in patients with age related macular degeneration: a novel insight into pathogenesis. AB - PURPOSE: Circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) may serve as novel markers of endothelial dysfunction. The presence and clinical implications of CECs and the expression of endothelin (ET)-1, one of the most potent vasoconstrictors, have not been evaluated in patients with the neovascular form of age-related macular degeneration (AMD). This study was conducted to determine the different populations of endothelial cells (ECs) in the peripheral blood of AMD patients and to correlate these findings with the expression of ET-1 and the cytokines and growth factors responsible for EC migration and function. METHODS: Peripheral blood samples were collected from 29 patients with diagnosed neovascular AMD and from 38 healthy control subjects. CD133(-)CD144(+) CECs and CD34(+)CD133(+)CD144(+) EPCs were counted and analyzed by flow cytometry. The intracellular expression of ET-1 in peripheral blood nuclear cells (PBNCs) was studied by using qRT-PCR, Western blot, and immunocytofluorescence assays, and ET-1, IGF-1, VEGF, SDF-1, and HGF plasma concentrations were measured in enzyme-linked immunosorbent assays. RESULTS: Increased CECs and EPCs were found in the AMD patients compared with the counts in healthy individuals. The expression of intracellular ET-1 was significantly elevated in PBNCs from the AMD patients compared with the control subjects. In addition a significantly higher plasma concentration of IGF-1 was observed, but a lower SDF-1 level in the group of AMD patients. CONCLUSIONS: These findings suggest that circulating endothelial cells, together with high ET-1 content, may contribute to the development of AMD. Further prospective investigations on the mechanism involved may be relevant to the potential treatment of this disease. PMID- 20720218 TI - Oxygen distribution in the human eye: relevance to the etiology of open-angle glaucoma after vitrectomy. AB - PURPOSE: Vitrectomy, when followed by cataract surgery, increases the risk of open-angle glaucoma. This study was conducted in patients to determine whether these procedures are associated with increased exposure of the trabecular meshwork to oxygen. METHODS: Oxygen distribution was recorded with a fiberoptic probe in patients undergoing surgery for cataract, glaucoma, or retinal disease. pO(2) was measured beneath the central cornea, in the mid-anterior chamber, and in the anterior chamber angle. In patients who were pseudophakic or were scheduled for cataract extraction, pO(2) was also measured in the posterior chamber and near the lens. RESULTS: Eyes with no previous cataract or vitrectomy surgery had steep oxygen gradients in the aqueous humor between the cornea and lens. pO(2) was low in the posterior chamber and near the lens. Previous vitrectomy was associated with significantly increased pO(2) in the posterior chamber. Eyes with previous cataract surgery had significantly elevated pO(2) only in the posterior chamber and in front of the intraocular lens (IOL). Eyes that had both vitrectomy and previous cataract surgery had increased pO(2) in the posterior chamber, anterior to the IOL, and in the anterior chamber angle. pO(2) in the posterior chamber and the anterior chamber angle correlated strongly. CONCLUSIONS: Oxygen metabolism by the lens and cornea establishes oxygen gradients in the anterior segment. Vitrectomy and cataract surgery increase pO(2) in the anterior chamber angle, potentially damaging trabecular meshwork cells. We propose that oxygen levels in the anterior chamber angle are strongly influenced by oxygen derived from the ciliary body circulation. PMID- 20720221 TI - Biocidal efficacy of silver-impregnated contact lens storage cases in vitro. AB - PURPOSE: Silver-impregnated contact lens (CL) storage cases are designed to reduce microbial contamination during use, but there are limited data on their effectiveness. This study evaluated early antimicrobial activity of silver impregnated CL cases and silver-release characteristics in vitro. METHODS: Three silver-impregnated CL storage cases-MicroBlock (CIBA Vision, Atlanta, GA), i clean (Sauflon Pharmaceuticals Ltd., London, UK), and Nano-case (Marietta Vision, Marietta, GA)-were evaluated. Test organisms included the ISO14729 panel and two clinical isolates, Delftia acidovorans and Stenotrophomonas maltophilia. Each well of the case was challenged with 2 mL of the organism in phosphate-buffered saline at 10(3), 10(4), 10(5), and 10(6) CFU/mL. Survivors were recovered after 6, 10, and 24 hours' incubation at 25 degrees C. Inductively coupled plasma mass spectrometry was used to quantify the release of silver from the cases for similar incubation conditions and for time points up to 28 days. RESULTS: Significant differences in antimicrobial activity were observed between cases (P <= 0.001). Activity was apparent only after 24 hours. MicroBlock showed the highest activity against Pseudomonas aeruginosa (2.4 +/- 0.5 log reduction at 10(6)), Serratia marcescens (3.3 +/- 0.9 log reduction at 10(6)), D. acidovorans (2.8 +/- 0.1 log reduction at 10(3)), and Fusarium solani (0.5 +/- 0.2 at 10(3)). The i-clean case was most effective against Staphylococcus aureus (5.4 +/- 1.1 log reduction), whereas Nano-case showed the greatest activity against S. maltophilia (0.2 +/- 0.3 log reduction at 10(3)). MicroBlock was the only case to demonstrate silver release over 28 days. CONCLUSIONS: Current silver-impregnated CL storage cases show variation in their in vitro antimicrobial activity. Broadly, the MicroBlock case demonstrated robust activity against most Gram negative bacteria, whereas the i-clean case was more effective against S. aureus. Silver-release data suggest different modes of action for different cases. PMID- 20720220 TI - Cone degeneration following rod ablation in a reversible model of retinal degeneration. AB - PURPOSE: Amphibian retinas regenerate after injury, making them ideal for studying the mechanisms of retinal regeneration, but this leaves their value as models of retinal degeneration in question. The authors asked whether the initial cellular changes after rod loss in the regenerative model Xenopus laevis mimic those observed in nonregenerative models. They also asked whether rod loss was reversible. METHODS: The authors generated transgenic X. laevis expressing the Escherichia coli enzyme nitroreductase (NTR) under the control of the rod specific rhodopsin (XOP) promoter. NTR converts the antibiotic metronidazole (Mtz) into an interstrand DNA cross-linker. A visually mediated behavioral assay and immunohistochemistry were used to determine the effects of Mtz on the vision and retinas of XOPNTR F1 tadpoles. RESULTS: NTR expression was detected only in the rods of XOPNTR tadpoles. Mtz treatment resulted in rapid vision loss and near complete ablation of rod photoreceptors by day 12. Muller glial cell hypertrophy and progressive cone degeneration followed rod cell ablation. When animals were allowed to recover, new rods were born and formed outer segments. CONCLUSIONS: The initial secondary cellular changes detected in the rodless tadpole retina mimic those observed in other models of retinal degeneration. The rapid and synchronous rod loss in XOPNTR animals suggested this model may prove useful in the study of retinal degeneration. Moreover, the regenerative capacity of the Xenopus retina makes these animals a valuable tool for identifying the cellular and molecular mechanisms at work in lower vertebrates with the remarkable capacity of retinal regeneration. PMID- 20720222 TI - Association of interferon-gamma, interleukin-10, and tumor necrosis factor-alpha gene polymorphisms with occurrence and severity of Eales' disease. AB - PURPOSE: Eales' disease (ED) is an idiopathic retinal vasculitis characterized by capillary nonperfusion and neovascularization. Previous reports on ED demonstrated that T-cell-mediated immunoresponse and differential cytokine production in inflammatory and angiogenic stage seem to influence the extent and severity of this disease. Therefore, the purpose of this study is to investigate the influence of cytokine gene polymorphisms on occurrence and severity of ED. METHODS: One hundred twenty-one patients with ED were recruited from an Eastern Indian population and compared with 223 matched healthy control subjects. Genotyping of IFN-gamma, IL-10, and TNF-alpha were performed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). RESULTS: A statistically significant association was found between the IL-10 -1082AA (P = 0.002), TNF-alpha -308AA (P = 0.0017) genotypes and the IL-10 ATA haplotype (P = 0.0123) and the occurrence of ED. In addition IL-10 -1082GG (P = 0.0005), TNF alpha -308GG (P < 0.0001) genotype were found to be protective against disease occurrence. A synergistically low IL-10/high TNF-alpha genotype increased the risk of development (P < 0.0001) and the severity (P = 0.019) of ED. CONCLUSIONS: These data suggest that a low IL-10-expressing and high TNF-alpha-expressing genotype of the host can influence the occurrence and severity of outcome of ED. PMID- 20720223 TI - Submacular DL-alpha-aminoadipic acid eradicates primate photoreceptors but does not affect luteal pigment or the retinal vasculature. AB - PURPOSE: Macular telangiectasia type 2 (MT2) is a condition of uncertain etiology characterized by retinal vascular abnormalities, depletion of luteal pigment, and photoreceptor loss. To model this condition, the authors recently used a purportedly glial-selective toxin, DL-alpha-aminoadipic acid (DL-alpha-AAA), to test the effect of Muller cell disruption on the blood-retinal barrier in rats. In this study, they investigated macular changes after subretinal injection of DL alpha-AAA in monkeys. METHODS: Various doses of DL-alpha-AAA were injected beneath the macula in eight monkey eyes. Eyes were examined by multifocal electroretinography (mfERG), optical coherence tomography (OCT), fundus autofluorescence, color photography, and fluorescein angiography. Five months after injection, eyes were examined by histology and immunohistochemistry for changes in photoreceptors and the retinal glia. In vitro studies evaluated the effect of DL-alpha-AAA on 661W cone photoreceptor viability. RESULTS: Subretinal injection of DL-alpha-AAA resulted in virtually complete ablation of photoreceptors in the injected area, as shown by OCT and histology, and severely impaired mfERG responses. Muller cells, albeit activated, survived the injury. Macular pigment remained unchanged in the central fovea. Subretinal injection of DL-alpha-AAA did not induce vascular leakage, though it increased the fundus autofluorescence. DL-alpha-AAA had a dose-dependent toxic effect on 661W photoreceptors. CONCLUSIONS: Submacular injection of DL-alpha-AAA induced severe damage to photoreceptors but failed to eliminate Muller cells in monkeys. Central macular pigment persisted despite loss of photoreceptors, and the retinal vasculature was unaffected. These observations may have significance in studying the roles of different cellular components in the pathogenesis of MT2. PMID- 20720225 TI - Spatiotemporal properties of multipeaked electrically evoked potentials elicited by penetrative optic nerve stimulation in rabbits. AB - PURPOSE: To investigate the spatiotemporal properties of the cortical responses elicited by intraorbital optic nerve (ON) stimulation with penetrating electrodes as means of designing optimal stimulation strategies for an ON visual prosthesis. METHODS: The ON of rabbits was exposed by orbital surgery for electrical stimulation. Craniotomy was performed to expose the visual cortex contralateral to the operated eye. Electrically evoked potentials (EEPs) were recorded by an electrode array positioned on the visual cortex. RESULTS: There were primarily four components (N1, P1, P2, P3) in EEPs with implicit times of 8.0 +/- 0.6, 11.3 +/- 1.3, 20.5 +/- 1.4, and 26.9 +/- 1.5 ms, respectively, when the ON was stimulated by penetrating electrodes. The thresholds to elicit these components were different, and the higher thresholds were seen with slower cortical components. The corresponding thresholds were 13.8 +/- 3.1 MUA for N1, 21.8 +/- 4.7 MUA for P1, 36.4 +/- 11.4 MUA for P2, and 68.4 +/- 17.2 MUA for P3. The time courses of the EEP components were also distinct. The locations of EEPs with the maximum P1 amplitude showed a spatial correspondence to the ON stimulation sites. Different profiles of cortical responses could be discriminated when the ON stimulation sites were separated by 150 MUm. CONCLUSIONS: Multiple components with different properties were elicited in EEPs when the ON was stimulated by penetrating electrodes. Retinotopic and localized stimulation could be achieved with this stimulating approach. PMID- 20720224 TI - Temporal interactions during paired-electrode stimulation in two retinal prosthesis subjects. AB - PURPOSE: Since 2002, six blind patients have undergone implantation of an epiretinal 4 * 4 electrode array designed to directly stimulate the remaining cells of the retina after severe photoreceptor degeneration due to retinitis pigmentosa. This study was conducted to investigate how the brightness of percepts is affected by pulse timing across electrodes in two of these patients. METHODS: Subjects compared the perceived brightness of a standard stimulus (synchronous pulse trains presented across pairs of electrodes) to the perceived brightness of a test stimulus (pulse trains across the electrode pair phase shifted by 0.075, 0.375, 1.8, or 9 ms). The current amplitude necessary for each phase-shifted test stimulus to match the brightness of the standard was determined. RESULTS: Depending on the electrode pair, interactions between electrodes were either facilitatory (the perceived brightness produced by stimulating the pair of electrodes was greater than that produced by stimulating either electrode alone) or suppressive (the perceived brightness produced by stimulating the pair of electrodes was less than that produced by stimulating either electrode alone). The amount of interaction between electrodes decreased as a function of increased separation both in time (the phase-shift between pulse trains) and space (center-to-center distance between the electrode pair). CONCLUSIONS: For visual prostheses to represent visual scenes that are changing in both space and time requires the development of spatiotemporal models describing the effects of stimulation across multiple electrodes. During multielectrode stimulation, interactions between electrodes have a significant influence on subjective brightness that includes both facilitatory and suppressive effects, and these interactions can be described with a simple computational model. (ClinicalTrials.gov number, NCT00279500.). PMID- 20720226 TI - Diabetic macular edema: fundus autofluorescence and functional correlations. AB - PURPOSE: Diabetic macular edema (DME) shows variable clinical characteristics with unpredictable results to local treatment, probably reflecting different phenotypes. The purpose of this study was to evaluate the role of structural and functional macular imaging in the characterization of DME patterns. METHODS: One hundred fifty-one eyes of 92 diabetic patients with untreated clinically significant macular edema (CSME) underwent best corrected visual acuity (BCVA) determination (logMAR), slit lamp biomicroscopy; fluorescein angiography; optical coherence tomography (OCT; mean central retinal thickness [CRT], volume, and DME pattern); fundus autofluorescence (FAF; absent or increased [i]FAF, single or multiple spots; iFAF area quantification); and microperimetry. Linear correlation, data agreement and three-way analysis of covariance were used for statistics. RESULTS: Thirty-five (23.2%) eyes had normal FAF; and 116 eyes had iFAF: 48 (31.8%) single-spot iFAF, 68 (45%) multiple-spot iFAF. Retinal sensitivity in areas with iFAF was 11.5+/-5.3 dB (vs. 15.1+/-3.9 dB in normal areas, P<0.005). Retinal sensitivity of the central field was 15.1+/-3.9 dB in normal FAF, 12.4+/-4.8 dB in single-spot iFAF and 11.4+/-4.9 dB in multiple-spot iFAF (P<0.05). OCT CRT and volume were not significantly different between the FAF groups. OCT volume correlated to OCT CRT (r=0.68), retinal sensitivity in iFAF (r=-0.50) and BCVA (r=0.42). Cystoid OCT pattern and FA edema patterns correlated with iFAF presence (P<0.0001). CONCLUSIONS: In CSME, FAF correlates better with OCT patterns and central field microperimetry rather than with visual acuity. FAF is a rapid, noninvasive technique that may give new insight into the evaluation of DME. The validity of FAF in the follow-up and treatment outcomes in DME remain to be assessed. PMID- 20720227 TI - Cataract surgery induces retinal pro-inflammatory gene expression and protein secretion. AB - PURPOSE: To investigate the effect(s) of cataract surgery on the expression of pro-inflammatory genes and proteins in the retina using an experimental rodent model. METHODS: An extracapsular lens extraction was performed in one eye of C57BL/6 mice (n = 24); the contralateral unoperated eyes (n = 24) as well as eyes from unoperated animals (n = 9) served as controls. The neurosensory retina and retinal pigment epithelium (RPE)/choroid were collected postoperatively. Expression of genes involved in the acute inflammatory/injury response, including IL-1beta, fibroblast growth factor, transforming growth factor beta, chemokine CCL2, SDF-1, and complements C3, C4, and factor B (CFB), were examined by real time PCR and, selectively, by immunohistochemistry. RESULTS: The expression of IL 1beta and CCL2 genes was markedly upregulated (>20-fold, P < 0.01) in the neurosensory retina 30 minutes postoperatively and maintained for the 2-week postoperative period of observation; IL-1beta expression was also upregulated in RPE/choroid. The expression of complement C3 (>5-fold) and CFB (>30-fold) genes in the neurosensory retina was also significantly upregulated (P < 0.01 in both cases). Increased IL-1b, CCL2, and CFB as well as enhanced C5b-9 immunostaining were observed by confocal microscopy. CONCLUSIONS: In rodents, lens extraction elicited an acute pro-inflammatory gene and protein response in the posterior segment of the eye, indicating induction of the inflammasome as well as complement activation, as occurs in the "danger" response. A similar response in humans might explain the pathogenesis of cataract surgery-associated retinal complications such as cystoid macular edema. PMID- 20720228 TI - The transition zone between healthy and diseased retina in patients with retinitis pigmentosa. AB - PURPOSE: To describe the structural changes in the transition zone from relatively healthy retinal regions to severely affected regions in patients with retinitis pigmentosa (RP) using frequency domain optical coherence tomography (fdOCT). METHODS: FdOCT line scans of the horizontal meridian were obtained from one eye of 13 patients with RP and 30 control subjects. The patients had normal or near normal foveal sensitivities and visual field diameters >=10 degrees . Using a computer-aided manual segmentation procedure, the locations at which the outer segment (OS) and outer nuclear layer plus outer plexiform layer (ONL+) thicknesses fell below the 95% confidence interval of the controls were measured, as were the locations at which the OS layer disappeared and the locations at which the ONL+ was reduced to an asymptotically small thickness. RESULTS: The progression from healthy to severely affected regions followed a common pattern in most patients. Region A, the central region including the foveal center, had normal OS and ONL+ thickness. Region B had abnormal OS but normal ONL+ thickness. Region C had abnormal but measurable OS and ONL+ thicknesses. In Region D, the OS layer disappeared, as did the IS/OS line, and the ONL+ thickness decreased further. In Region E, the ONL+ reached an asymptotic thickness. CONCLUSIONS: The structural changes in the transition zone followed an orderly progression from a thinning of the OS layer, to a thinning of the ONL+, to a loss of the OS layer, to an ONL+ reduced to an asymptotically small level. PMID- 20720229 TI - Calibration of the TonoLab tonometer in mice with spontaneous or experimental glaucoma. AB - PURPOSE: To measure the accuracy of TonoLab (TioLat, Helsinki, Finland) tonometry in mice with spontaneous or induced experimental glaucoma. METHODS: Chronic intraocular pressure (IOP) elevation was induced in one eye of 32 mice by injection of polystyrene beads and viscoelastic material. Three to 6 weeks later, the eyes were cannulated and manometrically set to 10, 20, 30, 40, or 50 mm Hg. The mice were 8-week and 8-month-old C57BL/6, 8-week-old DBA/2J, and 8-week-old CD1. The TonoLab calibration was also tested on five aged DBA/2J mice with spontaneous glaucoma. The relation of the TonoLab reading to manometric IOP was evaluated in multivariate linear regression models with axial length, IOP history, and mouse strain as independent variables. RESULTS: The slope of the relationship between TonoLab and manometric IOP in all the mice was 0.998, with an intercept of 2.3 mm Hg (adjusted R in univariate regression = 0.86). Neither the mice with bead-induced glaucoma nor those with spontaneous glaucoma (older DBA/2J mice) differed significantly from the control animals in having an excellent correlation between TonoLab and manometer IOP. Longer and wider mouse eyes had slightly higher tonometrically measured IOP, whether glaucomatous or control (multivariate regression, adjusted R(2) = 0.90, P < 0.0001). There was no difference in tonometric accuracy among the three mouse strains: CD1, C57BL/6, and DBA/2J, nor between 8-week and 8-month-old C57BL/6 mice (multivariate regression, P = 0.32). CONCLUSIONS: The TonoLab accurately reflects IOP in both normal mice and in eyes of mice with experimental or spontaneous glaucoma, with no detectable effect of age. PMID- 20720230 TI - Removal of biofilm from contact lens storage cases. AB - PURPOSE: Lens case hygiene practices are important in maintaining safe contact lens wear. However, the effectiveness of various lens case cleaning practices have not been evaluated and compared. This in vitro study aimed to evaluate and compare the efficacy of cleaning practices that are most commonly carried out by lens wearers and recommended by practitioners. METHODS: Pseudomonas aeruginosa 122, Serratia marcescens ATCC 13880, and Staphylococcus aureus ATCC 6538 were the challenge bacteria for biofilm formation on unused lens cases from two different manufacturers. After establishment of the biofilm, each lens case was subjected to one of the six cleaning regimens: "rinsed," "rubbed and rinsed," "air-dried," "soaked in a multipurpose contact lens solution," "tissue-wiped," and "lids recapped." The level of residual biofilm was quantified at the end of each cleaning regimen. The efficacy of each cleaning regimen was then compared. RESULTS: Mechanical rubbing and wiping of lens cases were the most effective cleaning regimen tested in reducing biofilm. Soaking lenses in disinfecting solution for 6 hours removed the majority of biofilm from lens cases. Rinsing lens cases alone provided only minimal efficacy in reducing biofilm. Air-drying or recapping the cases with the lid without any other additional cleaning methods were the least efficient at removing biofilm. CONCLUSIONS: Based on this study, digital rubbing and rinsing and/or wiping the lens cases with tissue is recommended. Air-drying or recapping the lens case lids after use without any additional cleaning methods should be discouraged with non-antimicrobial lens cases. PMID- 20720231 TI - The elastin fiber system between and adjacent to collector channels in the human juxtacanalicular tissue. AB - PURPOSE: To determine the composition and investigate the elastin fiber system in the juxtacanalicular tissue adjacent to and between collector channel orifices in normal human eyes. METHODS: Normal human eyes (71.0 +/- 8.6 years; mean +/- SD; n = 4) were perfusion fixed at low (10 mm Hg) and high pressure (20 mm Hg) with 3% paraformaldehyde/0.1 M phosphate buffer. Frontal serial sections were cut from paraffin blocks, and regions with and without collector channels were selected. Sections were stained using Weigert's resorcin-fuchsin stain with oxidation. Immunohistochemistry was performed using antibodies against elastin, fibrillin-1, and microfibrillar-associated protein-1/2. RESULTS: Elastin, elaunin, and oxytalan fibers were identified within the juxtacanalicular tissue of the inner and outer walls in low- and high-pressure eyes. These fibers were found at collector channel orifices, between collector channels, and within collector channel walls. Fibrillin-1 was located at the base and lateral edges of Schlemm's canal endothelial cells. Microfibrillar-associated protein-1/2 was found with elastin-like fibers at the base of Schlemm's canal endothelium cells, in the juxtacanalicular tissue, and in the uveal region. CONCLUSIONS: Elastin, elaunin, oxytalan, and elastin-associated proteins fibrillin-1 and microfibrillar associated protein-1/2 were identified within the juxtacanalicular tissue of the inner and outer walls and within collector channel walls of human eyes perfused at low and high pressure. No differences in labeling patterns for elastin, elaunin, and oxytalan were found in the juxtacanalicular tissue adjacent to or between collector channel orifices. The elastin fiber system appears to have a significant role in the support and distensibility of the juxtacanalicular region under collector channels. PMID- 20720232 TI - Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. AB - PURPOSE: To investigate the effects of fasudil, a Rho-associated coiled coil forming protein kinase (ROCK) inhibitor, on normal or impaired optic nerve head (ONH) blood flow in a rabbit model. METHODS: ONH blood flow was measured by laser speckle flowgraphy. Changes in ONH blood flow were examined during a continuous intravenous infusion of fasudil with and without the application of N(G)-nitro-L arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Effects of topical fasudil on ONH blood flow were investigated in normal eyes or models of ocular circulation impairment induced by the application of endothelin (ET)-1. Visual-evoked potentials (VEPs) and morphologic and histologic changes were also analyzed in the ET-1-injected eyes. RESULTS: A continuous intravenous infusion of fasudil had no significant effect on normal ONH blood flow, yet it prevented or improved the ONH blood flow impairment induced by the intravenous injection of L NAME. Repeated intravitreal injections of ET-1 twice a week for 4 weeks decreased the ONH blood flow, prolonged the VEPs' implicit time, enlarged the optic cup, and decreased retinal ganglion cells. Multiple doses of topical fasudil ameliorated the ONH impairments caused by ET-1. CONCLUSIONS: These results show that systemic or topical fasudil suppresses impairment of ONH blood flow, function, and morphology induced by L-NAME or ET-1. A ROCK inhibitor can be useful for the treatment of impaired ONH blood flow. PMID- 20720233 TI - Stakeholders urge overhaul of REMS programs: Standardization, better access, less paperwork sought. PMID- 20720234 TI - Government incentivizes hospitals to use EHR technology in meaningful ways. PMID- 20720235 TI - Pharmacy makes inroads in medical home movement. PMID- 20720237 TI - Best-of-breed versus integrated systems. PMID- 20720238 TI - Followership: Nontraditional leadership roles for new practitioners. PMID- 20720239 TI - Improving patient safety with intelligent infusion devices. PMID- 20720240 TI - Drug interactions and toxicities associated with the antiviral management of cytomegalovirus infection. AB - PURPOSE: Drug interactions and toxicities associated with the antiviral management of cytomegalovirus (CMV) infection are described. SUMMARY: The use of current antiviral treatments for CMV in patients undergoing solid organ or hematopoietic stem cell transplantation is categorically characterized by high toxicity profiles and drug-drug interactions. The consequences of hematologic toxicities may be manifested clinically in several ways, including increased rates of infections and bleeding, more pronounced bone marrow suppression, and the development of anemia. Moreover, patients undergoing solid organ or stem cell transplantation have difficulty tolerating the nephrotoxic effects of current treatments, because their renal function is often already compromised by infection, sepsis, or the administration of other commonly used nephrotoxic drugs. Patients undergoing transplantation have an especially high risk of drug interactions, because multiple drugs are often administered to prevent allograft rejection, to treat or prevent infection, to control pain, and to treat a number of possible comorbid conditions. Commonly used antiviral agents for the management of CMV infection include cidofovir, CMV i.v. immunoglobulin, foscarnet, ganciclovir, and valganciclovir. Drug interactions associated with the use of ganciclovir and foscarnet sodium are numerous and potentially dangerous. At this time, such toxicities are managed by dosage adjustments, temporary discontinuations of medications, and careful monitoring of the patient. CONCLUSION: Clinically important drug-drug interactions can occur in immunocompromised transplant recipients who are treated for CMV infection. Because of the high toxicity and narrow therapeutic range of the antiviral medications available for CMV management, patients should be carefully monitored for any potential adverse effects from such interactions. PMID- 20720241 TI - Elevated international normalized ratio associated with concomitant warfarin and erlotinib. AB - PURPOSE: The case of a patient who developed elevated International Normalized Ratio (INR) values after concomitant administration of warfarin and erlotinib is reported. SUMMARY: A 47-year-old Caucasian man with a history of atrial fibrillation, anxiety, and a 40-pack-year smoking history was diagnosed with advanced, moderately differentiated adenocarcinoma of the lung. Soon after being diagnosed with non-small-cell lung cancer, warfarin was initiated for the treatment of a venous thromboembolism. The patient's warfarin dosage was adjusted to reach a target INR of 2-3. His INR was relatively stable (2.1-3.2) for at least eight weeks before erlotinib was added to the chemotherapy regimen. The patient developed a well-disseminated rash and diarrhea soon after starting erlotinib. Seven days after the initiation of erlotinib therapy, the patient's INR value increased from 2.8 to 5.3, with no concurrent changes in warfarin dosage, other medications, or diet. After withholding two doses of warfarin, the patient's INR value increased to 9.1, and the patient developed an elbow hematoma. His anticoagulation was rapidly reversed with the administration of subcutaneous phytonadione. The patient elected to discontinue erlotinib nine days after its initiation. The next day, his INR value was 2.4. The patient returned to the hematology-oncology clinic for follow-up two days later, where his INR was found to be 0.9. CONCLUSION: Concomitant administration of erlotinib and warfarin resulted in an increase in INR values in a 47-year-old man with advanced lung cancer. PMID- 20720242 TI - Pattern of clopidogrel use in hospitalized patients receiving percutaneous coronary interventions. AB - PURPOSE: The pattern of clopidogrel loading in patients who had undergone percutaneous coronary intervention (PCI) was studied in a retrospective analysis of clinical records. METHODS: A database of deidentified electronic medical records from hospitals and hospital-affiliated outpatient facilities throughout the United States was analyzed for PCI patients with or without a diagnosis of acute coronary syndrome (ACS) who received clopidogrel loading doses of > or =300 mg between 48 hours before and 6 hours after PCI. A high dose was defined as > or =600 mg, and pretreatment was defined as more than 6 hours before PCI for 300-599 mg and 2 or more hours before PCI for > or =600 mg. RESULTS: Among 6253 PCI patients who met the criteria, there were 2331 with a diagnosis of ACS (ACS-PCI) and 3922 without an ACS diagnosis (elective PCI). Of the ACS-PCI patients, 1359 had ST-segment elevation myocardial infarction (STEMI) and 972 had unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI). A majority of ACS-PCI patients (57%) received a > or =600-mg loading dose, 34% received a 300-mg loading dose, and the rest received a loading dose between 300 and 600 mg. Loading consisted of a single bolus in 75% of patients, two doses in 21.5%, and three or more doses in 3.1%. The first dose was during or after PCI in 56% of the UA/NSTEMI group and in 71% of both the elective PCI and STEMI groups. Among the UA/NSTEMI group, only 33% met criteria for pretreatment. CONCLUSION: Reported practice patterns of clopidogrel administration before PCI for UA/NSTEMI were not consistent with evidence generated from published clinical trials and guidelines. Recommended pre-treatment with clopidogrel was frequently not practiced. PMID- 20720243 TI - Impact of postoperative venous thromboembolism on Medicare recipients undergoing total hip replacement or total knee replacement surgery. AB - PURPOSE: The impact of postoperative venous thromboembolism (VTE) during initial hospitalization for total hip replacement (THR) or total knee replacement (TKR) surgery was assessed. METHODS: Using Medicare Provider Analysis and Review files, patients who underwent THR, TKR, or hip fracture surgery from 2005 to 2007 were identified using appropriate procedure codes from the International Classification of Diseases, 9th Revision, Clinical Modification. Medicare managed care patients were excluded from the study. Eligible patients were classified as having had deep venous thrombosis (DVT), pulmonary embolism (PE), DVT and PE, or no VTE during their initial hospitalization. Risk adjustment was performed using propensity score matching. Medicare cost, cost to beneficiaries, and cost to primary payers were analyzed to determine risk-adjusted differences in outcome measures, including mortality, rehospitalization, bleeding, length of stay, and total health care expenditures related to VTE events. RESULTS: A total of 170,047 patients were identified. Postoperative VTE events occurred in 3,014 patients (1.77%) during their initial hospitalization. Risk-adjusted mortality rates were three to four times higher for patients with VTE compared with those without VTE. Patients with VTE were more likely to be rehospitalized and experience bleeding within 30 days. Risk-adjusted differences in annual mean cost, including Medicare cost and costs to beneficiaries and primary payers, were significantly greater for patients with VTE. CONCLUSION: Patients who developed VTE after THR or TKR had a higher likelihood of mortality, bleeding, and rehospitalization; were hospitalized longer; and incurred higher costs to Medicare, Medicare beneficiaries, and private payers compared with patients without VTE. PMID- 20720244 TI - Continuous quality improvement using intelligent infusion pump data analysis. AB - PURPOSE: The use of continuous quality-improvement (CQI) processes in the implementation of intelligent infusion pumps in a community teaching hospital is described. SUMMARY: After the decision was made to implement intelligent i.v. infusion pumps in a 413-bed, community teaching hospital, drug libraries for use in the safety software had to be created. Before drug libraries could be created, it was necessary to determine the epidemiology of medication use in various clinical care areas. Standardization of medication administration was performed through the CQI process, using practical knowledge of clinicians at the bedside and evidence-based drug safety parameters in the scientific literature. Post implementation, CQI allowed refinement of clinically important safety limits while minimizing inappropriate, meaningless soft limit alerts on a few select agents. Assigning individual clinical care areas (CCAs) to individual patient care units facilitated customization of drug libraries and identification of specific CCA compliance concerns. Between June 2007 and June 2008, there were seven library updates. These involved drug additions and deletions, customization of individual CCAs, and alterations of limits. Overall compliance with safety software use rose over time, from 33% in November 2006 to over 98% in December 2009. Many potentially clinically significant dosing errors were intercepted by the safety software, prompting edits by end users. Only 4-6% of soft limit alerts resulted in edits. CONCLUSION: Compliance rates for use of infusion pump safety software varied among CCAs over time. Education, auditing, and refinement of drug libraries led to improved compliance in most CCAs. PMID- 20720245 TI - Impact of telepharmacy in a multihospital health system. AB - PURPOSE: The impact of telepharmacy in a multihospital health system was evaluated. SUMMARY: Telepharmacy services were implemented at five hospitals within a Catholic, nonprofit, integrated delivery network health system. Telepharmacy services were provided by seven pharmacists employed by the health system. Using a virtual private network or terminal server, pharmacists directly accessed hospital servers and information systems to conduct their work. Telephone calls were automatically routed to the telepharmacist so that handling of nursing and other calls would be transparent to staff. Hours of telepharmacy service were 5 p.m. to 2 a.m. Monday through Friday evenings at four of the hospitals and 8 p.m. to 10 p.m. at the rural hospital. Order-processing time for routine orders was reduced from 26.8 to 14 minutes (p < 0.0001), while stat order processing was shortened from 11.6 to 8.8 minutes (p = 0.007). For routine orders, turnaround times greater than 60 minutes became almost nonexistent after telepharmacy services were implemented. The number of clinical interventions documented increased by 42%, from 619 to 881, equivalent to a net annualized saving of $1,132,144. A significant improvement in nurses' global satisfaction with pharmacist availability for unit consultations was reported (3.0 versus 4.0 on a 5.0 Likert scale; p = 0.028). CONCLUSION: The implementation of telepharmacy services in a multihospital health system expanded hours of service, improved the speed of processing of physician medication orders, and increased clinical pharmacy services and cost avoidance. Surveys of health care staff found that telepharmacy services were well received. PMID- 20720246 TI - Assessing the value of services provided by pharmacy faculty on a contractual basis. PMID- 20720247 TI - Establishment of a national pharmacy practice residency program in Saudi Arabia. PMID- 20720248 TI - The relationship of systemic right ventricular function to ECG parameters and NT proBNP levels in adults with transposition of the great arteries late after Senning or Mustard surgery. AB - AIMS: Heart failure is common late after Senning or Mustard palliation of transposition of the great arteries (TGA). Although cardiac magnetic resonance (CMR) is the gold standard for evaluating systemic right ventricular performance, additional information regarding heart failure status might be gleaned from the surface ECG and circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. The interrelationships between these heart failure markers were examined in adults late after Mustard and Senning surgery. METHODS: Thirty-five consecutive adults with Senning or Mustard repair of TGA attending a dedicated congenital heart failure clinic were studied. Assessment included symptom assessment, venous blood sampling for measurement of circulating NT-proBNP levels, surface 12-lead ECG and CMR for the assessment of right ventricular systolic function and determination of indexed right ventricular volumes. RESULTS: Mean age was 29 +/- 6.5 years, 54% had undergone Mustard surgery. Compared with those with uncomplicated surgery, patients with complex surgical history had higher NT-proBNP levels (55 +/- 26 vs 20 +/- 35 pmol/l; p=0.002) and longer QRS duration (116 +/- 28 ms vs 89 +/- 11 ms; p=0.0004) while showing no difference in New York Heart Association class and right ventricular function. There was a significant relationship between diastolic and systolic right ventricular volumes and both NT-proBNP levels (r=0.43, p=0.01; r=0.53, p=0.001, respectively) and QRS duration (r=0.47, p=0.004; r=0.53, p=0.001, respectively). CONCLUSIONS: Circulating NT-proBNP levels and several surface ECG parameters constitute safe, cost-effective and widely available surrogate markers of systemic right ventricular function and provide additional information on heart failure status. Both measures hold promise as prognostic markers and their association with long-term outcome should be determined. PMID- 20720249 TI - Long-term clinical outcome of extensive pulmonary vein isolation-based catheter ablation therapy in patients with paroxysmal and persistent atrial fibrillation. AB - OBJECTIVE: To examine the long-term clinical outcomes of patients undergoing catheter ablation (CA) for either paroxysmal (PAF) or persistent atrial fibrillation (PsAF) using an extensive pulmonary vein isolation (EPVI)-based strategy. METHODS AND RESULTS: 574 patients (61 +/- 9 years; 449 men) with drug refractory PAF or PsAF underwent CA. Ipsilateral pulmonary veins (PVs) were isolated with extensive antral ablation. A cavotricuspid isthmus line with bidirectional conduction block was created and all non-PV triggers of AF ablated at the index procedure. Left atrial linear ablation was performed in patients with PsAF if AF remained inducible. Patients with recurrent atrial arrhythmias had previous lesions assessed and consolidated. With mean follow up of 27 +/- 14 months after the final procedure, 480 patients (83.6%) were in sinus rhythm without antiarrhythmic drugs (1.4 +/- 0.6 procedures). The single procedure success rate without antiarrhythmic drugs was 65.5%. A late recurrence (>6 months after the initial procedure) and very late recurrence (>12 months) were seen in 1.6% and 1.7% of patients, respectively. All patients with a late recurrence had PV reconnection, with one patient also demonstrating a non-PV trigger. In comparison, non-PV triggers of AF accounted for 85.7% of very late recurrences with no evidence of PV reconduction. CONCLUSIONS: EPVI-based CA is effective in maintaining sinus rhythm in patients with PAF and PsAF over the long term. Recurrent AF after 1 year is mainly due to non-PV triggers, suggestive of an ongoing pathological process. PMID- 20720250 TI - Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction. AB - BACKGROUND: Measurement of the degree of aortic valve calcification (AVC) using electron beam computed tomography (EBCT) is an accurate and complementary method to transthoracic echocardiography (TTE) for assessment of the severity of aortic stenosis (AS). Whether threshold values of AVC obtained with EBCT could be extrapolated to multislice computed tomography (MSCT) was unclear and AVC diagnostic value in patients with low ejection fraction (EF) has never been specifically evaluated. METHODS: Patients with mild to severe AS underwent prospectively within 1 week MSCT and TTE. Severe AS was defined as an aortic valve area (AVA) of less than 1 cm(2). In 179 patients with EF greater than 40% (validation set), the relationship between AVC and AVA was evaluated. The best threshold of AVC for the diagnosis of severe AS was then evaluated in a second subset (testing set) of 49 patients with low EF (<=40%). In this subgroup, AS severity was defined based on mean gradient, natural history or dobutamine stress echocardiography. RESULTS: Correlation between AVC and AVA was good (r=-0.63, p<0.0001). A threshold of 1651 arbitrary units (AU) provided 82% sensitivity, 80% specificity, 88% negative-predictive value and 70% positive-predictive value. In the testing set (patients with low EF), this threshold correctly differentiated patients with severe AS from non-severe AS in all but three cases. These three patients had an AVC score close to the threshold (1206, 1436 and 1797 AU). CONCLUSIONS: In this large series of patients with a wide range of AS, AVC was shown to be well correlated to AVA and may be a useful adjunct for the evaluation of AS severity especially in difficult cases such as patients with low EF. PMID- 20720251 TI - Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. AB - OBJECTIVES: In patients with aortic stenosis (AS) left ventricular (LV) myocardial growth may exceed individual needs to compensate LV haemodynamic load leading to inappropriately high LV mass (iLVM), a condition at high risk of adverse cardiovascular events. The prognostic impact of iLVM was determined in 218 patients with asymptomatic severe AS. METHODS: iLVM was recognised when the measured LV mass exceeded 10% of the expected value predicted from height, sex and stroke work (prognostic cut-off assessed by a specific ROC analysis). For assessment of outcome, the endpoint was defined as death from all causes, aortic valve replacement or hospital admission for non-fatal myocardial infarction and/or congestive heart failure. RESULTS: At the end of follow-up (22+13 months) complete clinical data were available for 209 participants (mean age 75+11 years). A clinical event occurred in 81 of 121 patients (67%) with iLVM and in 26 of 88 patients (30%) with appropriate LV mass (aLVM) (p<0.001). Event-free survival in patients with aLVM and iLVM was 78% vs 56% at 1-year, 68% vs 29% at 3 year and 56% vs 10% at 5-year follow-up, respectively (all p<0.01). Cox analysis identified iLVM as a strong predictor of adverse outcome (Exp beta 3.08; CI 1.65 to 5.73) independent of diabetes, transaortic valve peak gradient and extent of valvular calcification. Among patients with LV hypertrophy, those with iLVM had a risk of adverse events 4.5-fold higher than counterparts with aLVM. CONCLUSIONS: iLVM is common in patients with asymptomatic severe AS and is associated with an increased rate of cardiovascular events independent of other prognostic covariates. PMID- 20720252 TI - The extent to which chaperone policies are used in acute hospital trusts in England. AB - OBJECTIVE: To determine whether the Ayling Inquiry's recommendations (2004) concerning chaperone policy implementation in acute hospital trusts in England has been implemented. METHODS: A quantitative questionnaire based on the Ayling Inquiry was posted to medical directors of all acute hospital trusts in England during December 2005 to March 2006 to determine whether their trusts had implemented the inquiry's recommendations by 1 December 2005. The same questionnaire was resent between December 2007 and March 2008 to determine whether their trusts had implemented the inquiry's recommendations by 1 December 2007. RESULTS: The total response rates were 59.4% and 47.7% for the first and second cohorts, respectively. The percentage of trusts having a chaperone policy increased from 41.3% in December 2005 to 56.5% in December 2007. By the end of 2007, 17.3% had accredited training for chaperones, 57.7% had a management lead and 71.2% of trusts formally investigated a breach of the chaperone policy, the latter being a fall from 88.4% in December 2005. Informing patients verbally of the policy was the most common method of distributing the information in both cohorts. By 1 December 2007, 50.0% of trusts did not use any resources towards their chaperone policy. Of the trusts without a chaperone policy by 1 December 2007, 52.5% intend to start a policy. CONCLUSION: Despite a public inquiry, only a small majority of acute trusts in England have a chaperone policy in place, which may have severe medico-legal repercussions in the future. Commencing a chaperone policy is a must for acute trusts and regular auditing necessary to ensure recommendations be maintained. PMID- 20720253 TI - Strabismus and discrimination in children: are children with strabismus invited to fewer birthday parties? AB - AIM: To determine the social acceptance of children with strabismus by their peers and to determine the age at which the negative impact of strabismus on psychosocial interactions emerges. METHODS: Photographs of six children were digitally altered in order to create pictures of identical twins except for the position of the eyes (orthotropic, exotropic and exotropic) and the colour of the shirt. One hundred and eighteen children aged 3-12 years were asked to select, for each of the six twin pairs, one of the twins to invite to their birthday party. The grouping of the pictures and the composition of the twin pairs were determined by Latin squares. RESULTS: Children younger than 6 years old did not make any significant distinctions between orthotropic children and children with strabismus. Respondents aged 6 years or older invited children with a squint to their birthday parties significantly less often than orthotropic children. The authors found no impact (p>0.1) of gender, of the colour of the shirt or of the type of strabismus, but did find a highly significant impact of age on the number of invited children with strabismus. CONCLUSIONS: Children aged 6 years or older with a visible squint seem to be less likely to be accepted by their peers. Because this negative attitude towards strabismus appears to emerge at approximately the age of 6 years, corrective surgery for strabismus without prospects for binocular vision should be performed before this age. PMID- 20720254 TI - Antioxidant-rich spice added to hamburger meat during cooking results in reduced meat, plasma, and urine malondialdehyde concentrations. PMID- 20720255 TI - Eating in the absence of hunger in adolescents: intake after a large-array meal compared with that after a standardized meal. AB - BACKGROUND: Eating in the absence of hunger (EAH) is typically assessed by measuring youths' intake of palatable snack foods after a standard meal designed to reduce hunger. Because energy intake required to reach satiety varies among individuals, a standard meal may not ensure the absence of hunger among participants of all weight strata. OBJECTIVE: The objective of this study was to compare adolescents' EAH observed after access to a very large food array with EAH observed after a standardized meal. DESIGN: Seventy-eight adolescents participated in a randomized crossover study during which EAH was measured as intake of palatable snacks after ad libitum access to a very large array of lunch type foods (>10,000 kcal) and after a lunch meal standardized to provide 50% of the daily estimated energy requirements. RESULTS: The adolescents consumed more energy and reported less hunger after the large-array meal than after the standardized meal (P values < 0.001). They consumed ~70 kcal less EAH after the large-array meal than after the standardized meal (295 +/- 18 compared with 365 +/- 20 kcal; P < 0.001), but EAH intakes after the large-array meal and after the standardized meal were positively correlated (P values < 0.001). The body mass index z score and overweight were positively associated with EAH in both paradigms after age, sex, race, pubertal stage, and meal intake were controlled for (P values <= 0.05). CONCLUSION: EAH is observable and positively related to body weight regardless of whether youth eat in the absence of hunger from a very large-array meal or from a standardized meal. This trial was registered at clinicaltrials.gov as NCT00631644. PMID- 20720256 TI - Plasma vitamin D and mortality in older men: a community-based prospective cohort study. AB - BACKGROUND: Vitamin D status is known to be important for bone health but may also affect the development of several chronic diseases, including cancer and cardiovascular diseases, which are 2 major causes of death. OBJECTIVE: We aimed to examine how vitamin D status relates to overall and cause-specific mortality. DESIGN: The Uppsala Longitudinal Study of Adult Men, a community-based cohort of elderly men (mean age at baseline: 71 y; n = 1194), was used to investigate the association between plasma 25-hydroxyvitamin D [25(OH)D] and mortality. Total plasma 25(OH)D was determined with HPLC atmospheric pressure chemical ionization mass spectrometry. Proportional hazards regression was used to compute hazard ratios (HRs). RESULTS: During follow-up (median: 12.7 y), 584 (49%) participants died. There was a U-shaped association between vitamin D concentrations and total mortality. An approximately 50% higher total mortality rate was observed among men in the lowest 10% (<46 nmol/L) and the highest 5% (>98 nmol/L) of plasma 25(OH)D concentrations compared with intermediate concentrations. Cancer mortality was also higher at low plasma concentrations (multivariable-adjusted HR: 2.20; 95% CI: 1.44, 3.38) and at high concentrations (HR: 2.64; 95% CI: 1.46, 4.78). For cardiovascular death, only low (HR: 1.89; 95% CI: 1.21, 2.96) but not high (HR: 1.33; 95% CI: 0.69, 2.54) concentrations indicated higher risk. CONCLUSIONS: Both high and low concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality. Low concentrations are associated with cardiovascular mortality. PMID- 20720257 TI - Effect of lysine supplementation on health and morbidity in subjects belonging to poor peri-urban households in Accra, Ghana. AB - BACKGROUND: Lysine affects diarrhea and anxiety via effects on serotonin receptors, enhanced intestinal repair, and sodium chloride-dependent opioid peptide transport. OBJECTIVE: The objective was to investigate the effects of lysine supplementation on morbidity, growth, and anxiety in children and adults of peri-urban areas of Accra, Ghana. DESIGN: In a double-blind randomized trial, the effect of lysine supplementation (1 g lysine/d) compared with that of placebo was examined in 2 groups of men, women, and children (n = 271). Primary outcomes included diarrheal and respiratory morbidity, growth, and anxiety and complement C3, C-reactive protein, serum cortisol, transferrin, and ferritin values. Independent-sample t tests, odds ratios, generalized estimating equations, 4 parameter sinusoid regression, and generalized linear models were used. RESULTS: Thirty percent of men, 50% of women, and 15% of children were at risk of lysine inadequacy. Supplementation in children reduced diarrheal episodes [19 lysine, 35 placebo; odds ratio (OR): 0.52; 95% CI: 0.29, 0.92; P = 0.046] and the total number of days ill (21 lysine, 47 placebo; OR: 0.44; 95% CI: 0.26, 0.74; P = 0.034). Mean days ill per child per week (0.058 +/- 0.039 lysine, 0.132 +/- 0.063 placebo; P = 0.017) were negatively associated with weight gain with control for baseline weight and study group (P = 0.04). Men had fewer coryza episodes (23 lysine, 39 placebo; OR: 0.60; 95% CI: 0.36, 1.01; P = 0.05), total number of days ill (lysine: 130; placebo: 266; OR: 0.51; 95% CI: 0.28, 0.93; P = 0.03), and mean days ill per person per week (lysine: 0.21 +/- 0.23; placebo: 0.41 +/- 0.35; P = 0.04). Serum ferritin (P = 0.045) and C-reactive protein (P = 0.018) decreased in lysine-supplemented women but increased in placebo-supplemented women. CONCLUSION: Lysine supplementation reduced diarrheal morbidity in children and respiratory morbidity in men in Ghana. PMID- 20720258 TI - The cost of US foods as related to their nutritive value. AB - BACKGROUND: Comparisons of the cost of different foods relative to their energy and nutritive value were conducted in the 1800s by the US Department of Agriculture (USDA). OBJECTIVE: The objective was to reestablish the relations between food cost, energy, and nutrients by using contemporary nutrient composition and food prices data from the USDA. DESIGN: The USDA Food and Nutrient Database for Dietary Studies 1.0 (FNDDS 1.0) and the Center for Nutrition Policy and Promotion food prices database were used for analysis. For 1387 foods, key variables were as follows: energy density (kcal/g), serving size (g), unit price ($/100 g), serving price ($/serving), and energy cost ($/kcal). A regression model tested associations between nutrients and unit price ($/100 g). Comparisons between food groups were tested by using one-factor analyses of variance. Relations between energy density and price within food groups were tested by using Spearman's correlations. RESULTS: Grains and fats food groups supplied the lowest-cost dietary energy. The energy cost for vegetables was higher than that for any other food group except for fruit. Serving sizes increased with water content and varied inversely with energy density of foods. The highest prices per serving were for meats, poultry, and fish, and the lowest prices per serving were for the fats category. Although carbohydrates, sugar, and fat were associated with lower price per 100 g, protein, fiber, vitamins, and minerals were associated with higher price per 100 g, after adjustment for energy. CONCLUSIONS: Grains and sugars food groups were cheaper than vegetables and fruit per calorie and were cheaper than fruit per serving. These price differentials may help to explain why low-cost, energy-dense foods that are nutrient poor are associated with lower education and incomes. PMID- 20720259 TI - Oral administration of glucagon-like peptide 1 or peptide YY 3-36 affects food intake in healthy male subjects. AB - BACKGROUND: Peripheral infusion of glucagon-like peptide 1 (GLP-1) or peptide YY 3-36 (PYY3-36) reduces food intake in healthy, obese, and diabetic subjects. In vivo, both peptides are cosecreted from intestinal L cells; GLP-1 is subject to rapid breakdown by dipeptidyl peptidase IV, and together with PYY3-36 it is likely to be degraded in the liver before entering the systemic circulation. The largest concentrations are observed in the splanchnic blood rather than in the systemic circulation. OBJECTIVE: In contrast with peripheral infusion, oral delivery of sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) mimics endogenous secretion. We aimed to investigate how this affects food intake. DESIGN: Twelve healthy male subjects were studied in a randomized, double-blind, placebo-controlled, 4-way crossover trial. Each subject received in random order 2.0 mg GLP-1, 1.0 mg PYY3-36, or 2.0 mg GLP-1 plus 1.0 mg PYY3-36; the peptides were mixed with SNAC. The placebo treatment was the delivery agent alone. Food intake during an ad libitum test meal was measured. RESULTS: Both peptides were rapidly absorbed from the gut, leading to plasma concentrations several times higher than those in response to a normal meal. GLP-1 alone, but not PYY3-36, reduced total energy intake significantly, with marked effects on glucose homeostasis. Coadministration of both peptides reduced total energy intake by 21.5% and fullness at meal onset (P < 0.05) but not total 24-h energy intake. CONCLUSION: The results show a marked effect of orally administered GLP-1 and PYY3-36 on appetite by showing enhanced fullness at meal onset and reduced energy intake. This trial was registered at clinicaltrials.gov as NCT00822705. PMID- 20720260 TI - Estrogen induces distinct patterns of microRNA expression within the mouse uterus. AB - Control of estrogenic activity within the uterus is evident as unopposed estrogen action is associated with endometrial pathologies such as endometriosis and endometrial carcinoma. MicroRNAs (miRNAs) have emerged as important posttranscriptional regulators, which are postulated to fine-tune the actions of steroids in many systems including the uterus. The objective of the current study was to examine uterine expression of miRNAs in response to estrogen treatment within the mouse uterus using an ovariectomized, steroid-reconstituted mouse model. MicroRNA microarray analysis and subsequent quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) verification revealed that expression of mirn155, mirn429, and mirn451 was significantly increased by estrogen administration whereas mirn181b and mirn204 expression was significantly reduced. Pretreatment with the estrogen receptor (ER) antagonist ICI 182,780 confirmed that estrogen regulation was mediated via the classical ER pathway. This study demonstrates that estrogen regulates specific miRNAs within the murine uterus, which may participate in posttranscriptional regulation of estrogen regulated genes. PMID- 20720262 TI - 17alpha-Hydroxylase (CYP17) expression and subsequent androstenedione production in the human ovary. AB - Traditionally, in women, only the theca cells in the ovary and the zona reticularis layer of the adrenal cortex are believed to synthesize androgens. Interestingly, their neighboring cell layers, the granulosa cells and the zona glomerulosa cells, respectively, do not produce androgens. Recent literature has highlighted the role of the activator protein (AP-1) transcription factor, c-Fos, in the dynamics of this structural and functional relationship. Differential expression of c-Fos is believed to result in distinct patterns of steroidogenesis among these compartments in both the ovary and the adrenal glands. Clinically, deficient c-Fos levels have been implicated in the pathogenesis of polycystic ovary syndrome (PCOS). In this review, we discuss the pivotal role of c-Fos in controlling the expression of CYP17 and hence androgen production in various organ systems throughout the human body. PMID- 20720261 TI - Basal and steroid hormone-regulated expression of CXCR4 in human endometrium and endometriosis. AB - Endometriosis is associated with activation of local and systemic inflammatory mechanisms, including increased levels of chemokines and other proinflammatory cytokines. We have previously reported increased gene expression of chemokine receptor 4 (CXCR4), the receptor for CXCL12, in lesions of the rat model of endometriosis. The CXCR4-CXCL12 axis has been shown to have both immune (HIV infection, lymphocyte chemotaxis) and nonimmune functions, including roles in tissue repair, angiogenesis, invasion, and migration. There is evidence indicating that these mechanisms are also at play in endometriosis; therefore, we hypothesized that activation of the CXCR4-CXCL12 axis could be responsible, at least in part, for the survival and establishment of endometrial cells ectopically. Immunohistochemistry (IHC) showed that CXCR4 protein levels were significantly higher in endometriotic lesions compared to the endometrium of controls. Next, we determined basal gene and protein expression of CXCR4 and CXCL12 and regulation by estradiol (E2) and/or progesterone (P4) in endometrial cell lines using quantitative polymerase chain reaction (qPCR), and Western blots. Basal CXCR4 gene expression levels were higher in epithelial versus stromal cells; conversely, CXCL12 was expressed at higher levels in stromal vs epithelial cells. CXCR4 gene expression was significantly downregulated by ovarian steroid hormones in endometrial epithelial. These data suggest that steroid modulation of CXCR4 is defective in endometriosis, although the specific mechanism involved remains to be elucidated. These findings have implications for future therapeutic strategies specifically targeting the inflammatory component in endometriosis. PMID- 20720265 TI - Kava hepatotoxicity--a clinical review. AB - This review critically analyzes the clinical data of patients with suspected kava hepatotoxicity and suggests recommendations for minimizing risk. Kava is a plant (Piper methysticum) of the pepper family Piperaceae, and its rhizome is used for traditional aqueous extracts in the South Pacific Islands and for commercial ethanolic and acetonic medicinal products as anxiolytic herbs in Western countries. A regulatory ban for ethanolic and acetonic kava extracts was issued in 2002 for Germany on the basis of reports connecting liver disease with the use of kava, but the regulatory causality assessment was a matter of international discussions. Based on one positive reexposure test with the kava drug, it was indeed confirmed that kava is potentially hepatotoxic. In subsequent studies using a structured, quantitative and hepatotoxicity specific causality assessment method in 14 patients with liver disease described worldwide, causality for kava +/- comedicated drugs and dietary supplements including herbal ones was highly probable (n = 1), probable (n = 4) or possible (n = 9) regarding aqueous extracts (n = 3), ethanolic extracts (n = 5), acetonic extracts (n = 4), and mixtures containing kava (n = 2). Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements comprizing herbal ones in most of the 14 patients. Hepatotoxicity occurred independently of the used solvent, suggesting poor kava raw material quality as additional causative factor. In conclusion, in a few individuals kava may be hepatotoxic due to overdose, prolonged treatment, comedication, and probably triggered by an unacceptable quality of the kava raw material; standardization is now required, minimizing thereby hepatotoxic risks. PMID- 20720263 TI - Regulation of caveolin-1 expression and phosphorylation by VEGF in ovine amnion cells. AB - Vascular endothelial growth factor (VEGF) has been implicated in the regulation of vesicular transport of amniotic fluid via caveolae across the amnion. This study tested the hypothesis that VEGF regulates caveolar function by stimulating caveolin-1 expression and phosphorylation in ovine amniotic epithelial cells (oAECs). Using primary cultures of oAECs, caveolin-1 was identified by immunofluorescent staining. Caveolin-1 messenger RNA (mRNA) abundance was determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and protein by Western blotting. The effects of VEGF( 165) on caveolin-1 expression and phosphorylation were determined. Caveolin-1 immunoreactivity was detected in oAECs. In response to 10 ng/mL VEGF( 165), caveolin-1 mRNA levels increased whereas the protein levels were unaffected. Furthermore, VEGF stimulated caveolin 1 phosphorylation, an effect abrogated by the inhibition of c-Src protein kinase. These data suggest that VEGF upregulates caveolin-1 activity through c-Src signaling pathways. Our observations support the hypothesis that VEGF regulates amniotic fluid transport across the amnion by stimulating caveolin-1 activity to mediate caveolar function in amnion cells. PMID- 20720266 TI - Visceral adipose tissue visfatin in nonalcoholic fatty liver disease. AB - BACKGROUND: Visfatin is a novel adipocytokine predominantly expressed and secreted by visceral adipose tissue. It is realized for its multiple functions of central importance in NAD biosynthesis, innate immunity and inflammation. Its phosphoribosyl transferase activity regulates cellular energetics and NAD dependent enzymes such as SIRTUINS. Although its expression in various tissues and circulating levels are documented, visceral visfatin levels in Nonalcoholic fatty liver disease (NAFLD) patients have not been reported. OBJECTIVE: The aim of the present study was to assess visceral adipose tissue visfatin levels in NAFLD. Materials and methods. A total of 115 patients undergoing diagnostic laparoscopy were recruited in the study and categorized into two groups based on standard criteria for NAFLD. Visceral adipose tissue TNF-a, IL-6 and visfatin levels were measured by ELISA. Blood glucose, lipids, liver enzymes and non esterified fatty acids (NEFA) were estimated using standard procedures. Formalin fixed, Hematoxylene Eosin stained liver biopsy specimens were examined for the presence of steatosis and the degree of steatosis was ascertained as per Brunt.s classification. RESULTS: The visceral visfatin level declined significantly (P < 0.001) in all groups of NAFLD as compared to non NAFLD group, while plasma NEFA level increased with progressive steatosis (P < 0.02). Significant increase in TNF a was observed in all groups of NAFLD, while IL-6 increased in NASH only. CONCLUSION: A significant decline in visceral adipose tissue visfatin level was found to be associated with degree of steatosis in NAFLD patients. PMID- 20720267 TI - Short and long term outcome of kidney transplanted patients with chronic viral hepatitis B and C. AB - INTRODUCTION: Liver disease related to chronic viral hepatitis is a major cause of morbidity and mortality in renal transplant patients. There is no agreement upon the influence of chronic hepatitis B (HBV) and hepatitis C (HCV) infection in patient and graft survival. AIMS: The aim of the study was to evaluate the influence of HBV and HCV on patient and graft short and long term survival, in the patients transplanted at our institution. MATERIALS AND METHODS: We evaluated the influence of antiHCV and HBsAg status (positive vs. negative); sex; age (> 49 years vs. < 49 years at transplantation); time on dialysis (> 3 vs. < 3 years); acute rejection; kind of graft (deceased vs. living donor, and kidney versus kidney and pancreas); number of transplantations; use of induction immunosuppression; and maintenance immunosuppression treatment (comparing the traditional triple therapy containing azathioprine, cyclosporine and prednisone vs. newer regimens which include tacrolimus, mycophenolate mofetil, sirolimus, etc) on the survival, long term and within the first month of transplantation, of the graft and the patients transplanted in our Institution between January 1991 and August 2009. RESULTS: We included 542 patients, 60% males. median age of 42.03 years (SD 13.06 years). 180 patients (33%) were antiHCV positive and 23 (4%) were HBsAg positive. AntiHCV positive, traditional triple therapy and acute rejection were associated with diminished graft survival. Older age, antiHCV positive, HBsAg positive, deceased donor, kidney-pancreas transplantation and traditional triple therapy were associated with diminished patient survival. Traditional triple therapy was associated with diminished one month graft survival; and older age and antiHCV positive were associated with diminished one month patient survival. CONCLUSION: In our experience, antiHCV positive status was associated with diminished long term patient and graft survival, and diminished six month graft survival; and HBsAg positive was associated with diminished patient survival. PMID- 20720268 TI - Clinical outcomes of liver transplantation for polycystic liver disease: a single center experience. AB - Polycystic liver disease (PLD) is a celiopathy characterized by progressive growth of multiple hepatic cysts. In a minority of patients, severe symptomatic hepatomegaly necessitates liver transplantation (LT). The purpose of this study is to describe the postoperative and long-term outcomes of all patients transplanted for PLD at our center. All patients who underwent LT for PLD were identified through our database. Using patient charts, data were extracted on patient demographics and medical history, postoperative surgical and medical complications, length of hospitalization, prevalence of chronic kidney failure, and patient and graft survival. Subjects were contacted in April 2010 to verify their survival and confirm their need, if any, for hemodialysis and/or kidney transplantation. Descriptive statistics for patient and graft survival were performed. From 1993 to 2010, 14 subjects underwent LT and 1 subject underwent combined kidney and LT; all subjects were female and the mean age was 49.0 years. 10 (66.7%) subjects had polycystic kidney disease. Patients experienced a high rate of vascular complications, including hepatic artery thrombosis (HAT) or stenosis in 3 (20%) and 2 (13.3%) subjects, respectively. One subject had early graft loss due to HAT and underwent re-transplantation. The mean length of hospitalization was 18.8 days. After a mean of 66.8 months of follow-up (3-200), 13 (86.7%) subjects are alive with satisfactory graft function, and no patients had renal failure. In conclusion, patients who underwent LT for PLD had a high rate of postoperative vascular complications. However, long-term patient and graft survival, and kidney function, is excellent. PMID- 20720269 TI - Prevalence of type 2 diabetes mellitus and chronic liver disease: a retrospective study of the association of two increasingly common diseases in Mexico. AB - BACKGROUND: Recent studies have demonstrated a relationship between insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The aim of this study was to determine the prevalence of T2DM among patients with liver disease. METHODS: A retrospective study was performed by examining the charts of patients who presented with a diagnosis of liver disease at a university hospital between January 2006 and April 2010. RESULTS: Liver disease was found in 129 patients. The most prevalent liver disease was cirrhosis, with 61 patients (47.2%), 44 patients had hepatitis C virus (34.1%) and 28 patients had hepatocellular carcinoma (21.7%). T2DM was diagnosed in 30 patients, 18 of whom were male (18/60; 30%) and 12 of whom were female (12/69; 17.4%). Only liver cirrhosis was significantly related to T2DM (21 of 61 patients; 34.4%, p < 0.004). CONCLUSIONS: The prevalence of T2DM among patients with liver disease (23.2%) is well established and similar to that reported in Western and some Eastern countries. PMID- 20720270 TI - Comparison of acoustic radiation force impulse imaging (ARFI) to liver biopsy histologic scores in the evaluation of chronic liver disease: A pilot study. AB - BACKGROUND AND AIMS: Acoustic Radiation Force Impulse Imaging (ARFI) is a novel non invasive technique studying the localized mechanical properties of tissue by utilising short, high intensity acoustic pulses (shear wave pulses) to assess the mechanical response (tissue displacement), providing a measure of tissue elasticity. The aim of this study is to investigate the feasibility of ARFI imaging as a non-invasive method for the assessment of liver fibrosis compared to liver biopsy scores. MATERIALS AND METHODS: A prospective blind comparison study of ARFI elastography (Virtual Touch Imaging., ACUSON S2000 Ultrasound Unit, Siemens, Mountain View CA) in a consecutive series of patients who underwent liver biopsy for assessment of fibrosis in chronic liver disease. ARFI shear-wave propagation velocity was measured in meters per second. Mean ARFI velocities were compared with both Batts-Ludwig (F0 to F4) and Modified Ishak scores (F0 to F4) for fibrosis in liver biopsy findings. Twenty-one patients with chronic liver disease (Hepatitis C (HCV) =16, Hepatitis B (HBV) = 1, both HCV and HBV = 1 Alcoholic liver disease (ALD) = 1, others = 2) underwent ARFI and liver biopsy on the same day. RESULTS: The Spearman correlation coefficients between the median values of the ARFI measurements and the histological fibrosis stage of the Modified Ishak score and Batts-Lud- (3) wig score were both highly significant (p < 0.01) with rho = 0.69 and rho = 0.72 respectively. The median ARFI (total 180 replications; minimum 5, maximum 10 measurements per patients) velocities for our study population range from 0.92 to 4.17 m/sec. Areas under the receiver operating characteristic curve for the accuracy of ARFI imaging was 1.00 and 0.35, for the diagnosis of moderate fibrosis (histologic fibrosis stage, F (3) 2) and 0.85 and 0.85 respectively for Ishak and Batts-Ludwig score, for the diagnosis of cirrhosis. CONCLUSION: ARFI imaging has a strong correlation with the fibrosis stage of both Batts-Ludwig and shak score in chronic liver disease. It.s accuracy in prediction of severe fibrosis and cirrhosis is maximal in comparison with earlier stages. PMID- 20720271 TI - Congenital absent of inferior vena cava. PMID- 20720272 TI - The CT Quadrate lobe hot spot sign. AB - Intense enhancement of the quadrate lobe in the arterial phase may be seen on computed tomography in patients of superior vena cava syndrome. We present this imaging finding in a case of lymphoma causing superior vena cava syndrome and discuss the physiological cause and importance of this sign. PMID- 20720273 TI - NISCH syndrome with hypothyroxinemia. AB - Neonatal Ichthyosis Sclerosing Cholangitis (NISCH) syndrome is a rare autosomal recessive condition characterized by ichthyosis, sclerosing cholangitis and alopecia. Only 5 patients have been described till now. We report a patient presenting with clinical characteristics of NISCH syndrome and hypothyroxinemia. PMID- 20720274 TI - Platelet count/spleen diameter ratio as a predictor of esophageal varices in cirrhotic patients. PMID- 20720276 TI - A rare case of recurrent prolonged hepatotoxicity due to ornidazole. PMID- 20720277 TI - Cefuroxime axetil-induced liver failure. PMID- 20720278 TI - Early warning of liver disease in diabetics. PMID- 20720281 TI - Towards multifocal ultrasonic neural stimulation: pattern generation algorithms. AB - Focused ultrasound (FUS) waves directed onto neural structures have been shown to dynamically modulate neural activity and excitability, opening up a range of possible systems and applications where the non-invasiveness, safety, mm-range resolution and other characteristics of FUS are advantageous. As in other neuro stimulation and modulation modalities, the highly distributed and parallel nature of neural systems and neural information processing call for the development of appropriately patterned stimulation strategies which could simultaneously address multiple sites in flexible patterns. Here, we study the generation of sparse multi-focal ultrasonic distributions using phase-only modulation in ultrasonic phased arrays. We analyse the relative performance of an existing algorithm for generating multifocal ultrasonic distributions and new algorithms that we adapt from the field of optical digital holography, and find that generally the weighted Gerchberg-Saxton algorithm leads to overall superior efficiency and uniformity in the focal spots, without significantly increasing the computational burden. By combining phased-array FUS and magnetic-resonance thermometry we experimentally demonstrate the simultaneous generation of tightly focused multifocal distributions in a tissue phantom, a first step towards patterned FUS neuro-modulation systems and devices. PMID- 20720282 TI - Tracking burst patterns in hippocampal cultures with high-density CMOS-MEAs. AB - In this work, we investigate the spontaneous bursting behaviour expressed by in vitro hippocampal networks by using a high-resolution CMOS-based microelectrode array (MEA), featuring 4096 electrodes, inter-electrode spacing of 21 um and temporal resolution of 130 us. In particular, we report an original development of an adapted analysis method enabling us to investigate spatial and temporal patterns of activity and the interplay between successive network bursts (NBs). We first defined and detected NBs, and then, we analysed the spatial and temporal behaviour of these events with an algorithm based on the centre of activity trajectory. We further refined the analysis by using a technique derived from statistical mechanics, capable of distinguishing the two main phases of NBs, i.e. (i) a propagating and (ii) a reverberating phase, and by classifying the trajectory patterns. Finally, this methodology was applied to signal representations based on spike detection, i.e. the instantaneous firing rate, and directly based on voltage-coded raw data, i.e. activity movies. Results highlight the potentialities of this approach to investigate fundamental issues on spontaneous neuronal dynamics and suggest the hypothesis that neurons operate in a sort of 'team' to the perpetuation of the transmission of the same information. PMID- 20720283 TI - Applications of tissue heterogeneity corrections and biologically effective dose volume histograms in assessing the doses for accelerated partial breast irradiation using an electronic brachytherapy source. AB - A low-energy electronic brachytherapy source (EBS), the model S700 Axxent x-ray device developed by Xoft Inc., has been used in high dose rate (HDR) intracavitary accelerated partial breast irradiation (APBI) as an alternative to an Ir-192 source. The prescription dose and delivery schema of the electronic brachytherapy APBI plan are the same as the Ir-192 plan. However, due to its lower mean energy than the Ir-192 source, an EBS plan has dosimetric and biological features different from an Ir-192 source plan. Current brachytherapy treatment planning methods may have large errors in treatment outcome prediction for an EBS plan. Two main factors contribute to the errors: the dosimetric influence of tissue heterogeneities and the enhancement of relative biological effectiveness (RBE) of electronic brachytherapy. This study quantified the effects of these two factors and revisited the plan quality of electronic brachytherapy APBI. The influence of tissue heterogeneities is studied by a Monte Carlo method and heterogeneous 'virtual patient' phantoms created from CT images and structure contours; the effect of RBE enhancement in the treatment outcome was estimated by biologically effective dose (BED) distribution. Ten electronic brachytherapy APBI cases were studied. The results showed that, for electronic brachytherapy cases, tissue heterogeneities and patient boundary effect decreased dose to the target and skin but increased dose to the bones. On average, the target dose coverage PTV V(100) reduced from 95.0% in water phantoms (planned) to only 66.7% in virtual patient phantoms (actual). The actual maximum dose to the ribs is 3.3 times higher than the planned dose; the actual mean dose to the ipsilateral breast and maximum dose to the skin were reduced by 22% and 17%, respectively. Combining the effect of tissue heterogeneities and RBE enhancement, BED coverage of the target was 89.9% in virtual patient phantoms with RBE enhancement (actual BED) as compared to 95.2% in water phantoms without RBE enhancement (planned BED). About 10% increase in the source output is required to raise BED PTV V(100) to 95%. As a conclusion, the composite effect of dose reduction in the target due to heterogeneities and RBE enhancement results in a net effect of 5.3% target BED coverage loss for electronic brachytherapy. Therefore, it is suggested that about 10% increase in the source output may be necessary to achieve sufficient target coverage higher than 95%. PMID- 20720284 TI - Polymer gel dosimeters with enhanced sensitivity for use in x-ray CT polymer gel dosimetry. AB - A primary limitation of current x-ray CT polymer gel dosimetry is the low contrast, and hence poor dose resolution, of dose images produced by the system. The low contrast is largely due to the low-dose sensitivity of current formulations of polymer gel for x-ray CT imaging. This study reports on the investigation of new dosimeter formulations with improved dose sensitivity for x ray CT polymer gel dosimetry. We incorporate an isopropanol co-solvent into an N isopropylacrylamide-based gel formulation in order to increase the total monomer/crosslinker concentration (%T) within the formulation. It is shown that gels of high %T exhibit enhanced dose sensitivity and dose resolutions over traditional formulations. The gels are shown to be temporally stable and reproducible. A single formulation (16%T) is used to demonstrate the capabilities of the x-ray CT polymer gel dosimetry system in measuring known dose distributions. A 1 L gel volume is exposed to three separate irradiations: a single-field percent depth dose, a two-field 'cross' and a three-field 'test case'. The first two irradiations are used to generate a dose calibration curve by which images are calibrated. The calibrated images are compared with treatment planning predictions and it is shown that the x-ray CT polymer gel dosimetry system is capable of capturing spatial and dose information accurately. The proposed new gel formulation is shown to be sensitive, stable and to improve the dose resolution over current formulations so as to provide a feasible gel for clinical applications of x-ray CT polymer gel dosimetry. PMID- 20720285 TI - A coordinated molecular 'fishing' mechanism in heterodimeric kinesin. AB - Kar3 is a kinesin motor that facilitates chromosome segregation during cell division. Unlike many members of the kinesin superfamily, Kar3 forms a heterodimer with non-motor protein Vik1 or Cik1 in vivo. The heterodimers show ATP-driven minus-end directed motility along a microtubule (MT) lattice, and also serve as depolymerase at the MT ends. The molecular mechanisms behind this dual functionality remain mysterious. Here, a molecular mechanical model for the Kar3/Vik1 heterodimer based on structural, kinetic and motility data reveals a long-range chemomechanical transmission mechanism that resembles a familiar fishing tactic. By this molecular 'fishing', ATP-binding to Kar3 dissociates catalytically inactive Vik1 off MT to facilitate minus-end sliding of the dimer on the MT lattice. When the dimer binds the frayed ends of MT, the fishing channels ATP hydrolysis energy into MT depolymerization by a mechanochemical effect. The molecular fishing thus provides a unified mechanistic ground for Kar3's dual functionality. The fishing-promoted depolymerization differs from the depolymerase mechanisms found in homodimeric kinesins. The fishing also enables intermolecular coordination with a chemomechanical coupling feature different from the paradigmatic pattern of homodimeric motors. This study rationalizes some puzzling experimental observation, and suggests new experiments for further elucidation of the fishing mechanism. PMID- 20720286 TI - The impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model. AB - Microbubble-mediated disruption of the blood-brain barrier (BBB) for targeted drug delivery using focused ultrasound shows great potential as a therapy for a wide range of brain disorders. This technique is currently at the pre-clinical stage and important work is being conducted in animal models. Measurements of standing waves in ex vivo rat skulls were conducted using an optical hydrophone and a geometry dependence was identified. Standing waves could not be eliminated through the use of swept frequencies, which have been suggested to eliminate standing waves. Definitive standing wave patterns were detected in over 25% of animals used in a single study. Standing waves were successfully eliminated using a wideband composite sharply focused transducer and a reduced duty cycle. The modified pulse parameters were used in vivo to disrupt the BBB in a rat indicating that, unlike some other bioeffects, BBB disruption is not dependent on standing wave conditions. Due to the high variability of standing waves and the inability to correctly estimate in situ pressures given standing wave conditions, attempts to minimize standing waves should be made in all future work in this field to ensure that results are clinically translatable. PMID- 20720287 TI - A respiratory latent variable model for mechanically measured heartbeats. AB - The effect of respiration on heartbeats in a mechanically measured cardiac signal was noticed already in the first respiratory ballistocardiography studies in the 1920s. The effect was described as a modulation of the heartbeat amplitude, and that view has persisted. Although a reasonable approximation, amplitude modulation is not an accurate description of the respiratory effect. In this paper, the respiratory variation is described with a linear latent variable model, where the direction of variation can be distinct from the direction of amplitude. The model was evaluated with seven ballistocardiograms from three healthy test subjects. Based on a Bayesian information criterion analysis, it was found to describe the variation accurately in all the cases. As the modelling of the heartbeat shape is improved, existing heartbeat detection methods can be made more accurate by applying the proposed model. PMID- 20720289 TI - Cardiac magnetic field mapping quantified by Kullback-Leibler entropy detects patients with coronary artery disease. AB - Cardiac magnetic field mapping (CMFM) is a noninvasive method to determine cardiac electrical activity. We analysed the utility of CMFM for the detection of patients with coronary artery disease (CAD) without subjecting them to stress. We studied 59 healthy control subjects and 101 patients with CAD without previous myocardial infarction (MI). The heart's magnetic field was recorded over the anterior chest wall using a multichannel magnetic measurement system with axial second-order gradiometers. The evaluation of CMFM was based on comparison of the 'ideal' group mean maps of young healthy subjects and maps of examined individuals. Three measures of similarity were considered: Kullback-Leibler (KL) entropy, normalized residual magnetic field strength and deviations in the magnetic field map orientation. The mean values of these parameters during the depolarization and repolarization were used for further classification with the help of logistic regression. The feature set based on the KL-entropy demonstrated the best classification results (sensitivity/specificity of 85/80%), followed by the residual feature (85/75%) and the magnetic field orientation feature (80/73%) sets. The forward stepwise technique was applied to select the best set of features from the combined feature set. Two parameters were selected, namely the KL-entropy for the repolarization period and the residual parameter for the depolarization period. The classification based on these parameters demonstrated a sensitivity of 88% and a specificity of 88% for the distinction of CAD patients from the control subjects. The area under the receiver operator curve was 94%. Hence, we suggest that CMFM evaluation based on KL-entropy is a promising technique to identify patients with CAD. PMID- 20720288 TI - Synthetic ECG generation and Bayesian filtering using a Gaussian wave-based dynamical model. AB - In this paper, we describe a Gaussian wave-based state space to model the temporal dynamics of electrocardiogram (ECG) signals. It is shown that this model may be effectively used for generating synthetic ECGs as well as separate characteristic waves (CWs) such as the atrial and ventricular complexes. The model uses separate state variables for each CW, i.e. P, QRS and T, and hence is capable of generating individual synthetic CWs as well as realistic ECG signals. The model is therefore useful for generating arrhythmias. Simulations of sinus bradycardia, sinus tachycardia, ventricular flutter, atrial fibrillation and ventricular tachycardia are presented. In addition, discrete versions of the equations are presented for a model-based Bayesian framework for denoising. This framework, together with an extended Kalman filter and extended Kalman smoother, was used for denoising the ECG for both normal rhythms and arrhythmias. For evaluating the denoising performance, the signal-to-noise ratio (SNR) improvement of the filter outputs and clinical parameter stability were studied. The results demonstrate superiority over a wide range of input SNRs, achieving a maximum 12.7 dB improvement. Results indicate that preventing clinically relevant distortion of the ECG is sensitive to the number of model parameters. Models are presented which do not exhibit such distortions. The approach presented in this paper may therefore serve as an effective framework for synthetic ECG generation and model based filtering of noisy ECG recordings. PMID- 20720290 TI - Tracking time-varying cerebral autoregulation in response to changes in respiratory PaCO2. AB - Cerebral autoregulation has been studied by linear filter systems, with arterial blood pressure (ABP) as the input and cerebral blood flow velocity (CBFV-from transcranial Doppler Ultrasound) as the output. The current work extends this by using adaptive filters to investigate the dynamics of time-varying cerebral autoregulation during step-wise changes in arterial PaCO(2). Cerebral autoregulation was transiently impaired in 11 normal adult volunteers, by switching inspiratory air to a CO(2)/air mixture (5% CO(2), 30% O(2) and 65% N(2)) for approximately 2 min and then back to the ambient air, causing step-wise changes in end-tidal CO(2) (EtCO(2)). Simultaneously, ABP and CBFV were recorded continuously. Simulated data corresponding to the same protocol were also generated using an established physiological model, in order to refine the signal analysis methods. Autoregulation was quantified by the time-varying phase lead, estimated from the adaptive filter model. The adaptive filter was able to follow rapid changes in autoregulation, as was confirmed in the simulated data. In the recorded signals, there was a slow decrease in autoregulatory function following the step-wise increase in PaCO(2) (but this did not reach a steady state within approximately 2 min of recording), with a more rapid change in autoregulation on return to normocapnia. Adaptive filter modelling was thus able to demonstrate time-varying autoregulation. It was further noted that impairment and recovery of autoregulation during transient increases in EtCO(2) occur in an asymmetric manner, which should be taken into account when designing experimental protocols for the study of autoregulation. PMID- 20720291 TI - Oriented cube-on-cube nanocrystal assembly of SrTiO3 tubules. AB - We report on an unusual crystallization phenomenon that results in the self assembly of sub-micron tubules of crystalline SrTiO(3). The deposition of the tubular structures was done in the pores of anodized aluminum oxide templates by the electrophoretic deposition of SrTiO(3) sols and subsequent annealing. Homogeneous nucleation inside the pores produces a critical number of crystallites leading to their self-organization when the nanocrystals reach sizes that equal the mean free distances between the nuclei. Due to steric constraints the crystals start to organize in order to most efficiently fill the available surface of the pore walls. This process leads to the formation of domains containing a large number of idiomorphic SrTiO(3) nano-cubes that are self aligned into almost perfect cube-on-cube and cube-to-wall registry, which makes up the walls of the tubules. The described mechanism shows the ability of nanocrystals with well defined morphologies to adapt spatial constraints and self organize into desired geometries. PMID- 20720292 TI - Artificial granularity in two-dimensional arrays of nanodots fabricated by focused-electron-beam-induced deposition. AB - We have prepared 2D arrays of nanodots embedded in an insulating matrix by means of focused-electron-beam-induced deposition using the W(CO)(6) precursor. By varying the deposition parameters, i.e. the electron beam current and energy and the raster constant, we obtain an artificial granular material with tunable electrical properties. The analysis of the temperature dependence of the conductivity and of the current-voltage characteristic suggests that the transport mechanism is governed by electron tunneling between artificial grains. In order to understand the nature of the granularity and thus the microstructural origin of the electronic transport behavior, we perform TEM and micro-Raman investigations. Independent of the deposition parameters, TEM measurements show that the dots are constituted of amorphous tungsten carbide clusters embedded in an amorphous carbonaceous matrix. Micro-Raman spectra show two peaks, around 690 and 860 cm(-1) associated with the W-C stretching modes. Higher frequency peaks give information on the composition of the matrix. In particular, we measure a peak at about 1290 cm(-1), which is associated with sp(3) carbon bonds. Furthermore we detect the so-called D and G peaks, at about 1350 and 1560 cm(-1), associated with the vibration modes of the sp(2) carbon bonds. The analysis of the position of the peaks and of their relative intensity suggests that the composition of the matrix is between nanocrystalline graphite and amorphous carbon. PMID- 20720293 TI - Development of chitosan-coated gold nanoflowers as SERS-active probes. AB - Surface-enhanced Raman scattering (SERS) has been intensely researched for many years as a potential technique for highly sensitive detection. This work, through the reduction of HAuCl(4) with pyrrole in aqueous solutions, investigated a facile one-pot synthesis of flower-like Au nanoparticles with rough surfaces. The formation process of the Au nanoflowers (AuNFs) was carefully studied, and a spontaneous assembly mechanism was proposed based on the time-course experimental results. The key synthesis strategy was to use pyrrole as a weak particle stabilizing and reducing agent to confine crystal growth in the limited ligand protection region. The nanometer-scale surface roughness of AuNFs provided several hot spots on a single particle, which significantly increased SERS enhancement. Good biocompatible stable Raman-active probes were synthesized by coating AuNFs with chitosan. The conservation of the SERS effects in living cells suggested that the chitosan-capped AuNFs could be suitable for highly sensitive detection and have potential for targeting of tumors in vivo. PMID- 20720294 TI - Inertially assisted nanoscale self-assembly. AB - We present a simple and versatile method for integrating submicron objects onto pre-determined locations on a substrate. The method relies on augmenting inertial forces using centrifugal motion and geometric constraints to guide the placement of submicron objects on a substrate with minimal requirements for surface engineering and binding chemistries. Here, we demonstrate the utility of the method for placing gold particles, metal nanorods and inorganic nanocrystals. The method has demonstrated high yield of self-assembly for submicron particles with a variety of shapes and sizes. We have been able to get a near-perfect yield for filling hundreds of traps with nanoparticles in only 20 min. Two hundred nanometer diameter nanorods were self-assembled into an array of 256 traps on the template with 92% yield. 1.4 microm and 300 nm sodium chloride crystals were self assembled in arrays of 7000 and 576 traps, respectively, with near-perfect yield in filling each site. Due to its convenient set-up and high performance, inertially assisted self-assembly can be easily adopted and used for a variety of integration needs on the submicron scale. PMID- 20720295 TI - Mesoporous silica nanotubes hybrid membranes for functional nanofiltration. AB - The development of nanofiltration systems would greatly assist in the production of well-defined particles and biomolecules with unique properties. We report a direct, simple synthesis of hexagonal silica nanotubes (NTs), which vertically aligned inside anodic alumina membranes (AAM) by means of a direct templating method of microemulsion phases with cationic surfactants. The direct approach was used as soft templates for predicting ordered assemblies of surfactant/silica composites through strong interactions within AAM pockets. Thus, densely packed NTs were successfully formed in the entirety of the AAM channels. These silica NTs were coated with layers of organic moieties to create a powerful technique for the ultrafine filtration. The resulting modified-silica NTs were chemically robust and showed affinity toward the transport of small molecular particles. The rigid silica NTs inside AAM channels had a pore diameter of A nonsynonymous polymorphism was associated with birth weight and 21-day body weight (P < 0.05), while g.7944 A>T was associated with 46-day body weight. Linkage and radiation hybrid mapping assigned SLC6A14 to a region around SW1522 on SSCXp13, which did not fall in the confidence interval of the quantitative trait locus (QTL) for growth and fatness traits on SSCX in the resource population. These results indicate that SLC6A14 is not a positional candidate gene for the QTL affecting fatness and growth traits in pigs. PMID- 20720305 TI - Chromosome rearrangements and survival of androgenetic rainbow trout (Oncorhynchus mykiss). AB - The purpose of this work was to quantify the impact of spontaneous and X radiation-induced chromosome rearrangements on survival rate of androgenetic rainbow trout (Oncorhynchus mykiss). Various doses of X irradiation (50, 150, 250, 350 Gy) were used for inactivation of nuclear DNA in oocytes. After the irradiation, eggs were inseminated with normal sperm from 4 males derived from a strain characterized by Robertsonian rearrangements and length polymorphism of the Y chromosome. The haploid zygotes were exposed to a high hydrostatic pressure (7000 psi) to duplicate the paternal DNA. Neither Robertsonian chromosome polymorphism nor the Y chromosome morphology impaired the viability of the androgenetic embryos and alevins. Moreover, survival of eyed embryos of the androgenetic rainbow trout increased significantly with increasing doses of oocyte X irradiation. After 6 months of rearing, only specimens from the 250 and 350 Gy variants survived. The number of fingerlings with remnants of the maternal genome in the forms of chromosome fragments was higher in the 250 Gy group. Intraindividual variation of chromosome fragment number was observed, and some individuals exhibited haploid/diploid mosaicism and body malformations. Individuals irradiated with less than 250 Gy died, presumably because of the conflict between intact paternally derived chromosomes and the residues of maternal genome in the form of chromosome fragments. PMID- 20720306 TI - Chromosomal assignment of R-spondin genes in the donkey (Equus asinus, 2n = 62). AB - R-spondins constitute a recently discovered small family of growth factors, and the evidence of their role in several developmental pathways is growing fast. In this work we describe the chromosomal location of the four RSPO genes in the donkey. Using horse BACs, we localized RSPO1 on EAS 5q23, RSPO2 on EAS 12q13, RSPO3 on EAS 24q26, and RSPO4 on EAS 15p13. Moreover, RSPO2, RSPO3, and RSPO4 are the first genes mapped on donkey chromosomes 12, 24, and 15, respectively. PMID- 20720307 TI - Prostaglandin-endoperoxide synthase genes COX1 and COX2 - novel modifiers of disease severity in cystic fibrosis patients. AB - Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among Caucasians caused by a mutation in the CFTR gene. However, the clinical outcome of CF pulmonary disease varies remarkably even in patients with the same CFTR genotype. This has led to a search for genetic modifiers located outside the CFTR gene. The aim of this study was to evaluate the effect of functional variants in prostaglandin-endoperoxide synthase genes (COX1 and COX2) on the severity of lung disease in CF patients. To the best of our knowledge, it is the first time when analysis of COX1 and COX2 as potential CF modifiers is provided. The study included 94 CF patients homozygous for F508del mutation of CFTR. To compare their clinical condition, several parameters were recorded, e.g. a unique clinical score: disease severity status (DSS). To analyse the effect of non-CFTR genetic polymorphisms on the clinical course of CF patients, the whole coding region of COX1 and selected COX2 polymorphisms were analysed. Statistical analysis of genotype-phenotype associations revealed a relationship between the heterozygosity status of identified polymorphisms and better lung function. These results mainly concern COX2 polymorphisms: -765G>C and 8473T>C. The COX1 and COX2 polymorphisms reducing COX protein levels had a positive effect on all analysed clinical parameters. This suggests an important role of these genes as protective modifiers of pulmonary disease in CF patients, due to inhibition of arachidonic acid conversion into prostaglandins, which probably reduces the inflammatory process. PMID- 20720308 TI - DNA methylation analysis of a de novo balanced X;13 translocation in a girl with abnormal phenotype: evidence for functional duplication of the whole short arm of the X chromosome. AB - We report on a 13-month-old girl showing dysmorphic features and a delay in psychomotor development. She was diagnosed with a balanced de novo translocation 46,X,t(X;13)(p11.2;p13) and non-random inactivation of the X chromosome. FISH analysis, employing the X chromosome centromere and XIST-region-specific probes, showed that the XIST locus was not involved in the translocation. Selective inactivation of paternal X, which was involved in translocation, was revealed by the HUMARA assay. The pattern of methylation of 5 genes located within Xp, which are normally silenced on an inactive X chromosome, corresponded to an active (unmethylated) X chromosome. These results revealed that in our proband the X chromosome involved in translocation (Xt) was preferentially inactivated. However, genes located on the translocated Xp did not include XIST. This resulted in functional Xp disomy, which most probably accounts for the abnormal phenotype in our patient. PMID- 20720309 TI - An age-related decrease in factor V Leiden frequency among Polish subjects. AB - Factor V Leiden (G1691A FV mutation) is a widely acknowledged risk factor of deep vein thrombosis, including pulmonary embolism as the most serious complication. However, its high prevalence of ~5%in the Caucasian population might be related to an unknown evolutionary advantage. It might exert a beneficial effect on the carrier, e.g. protecting women from excessive bleeding during labour or allowing increased survival in severe sepsis or with other inflammatory diseases. The aim of our study was to verify or contradict the hypothesis of a favourable association between the A allele (A1691) and longevity in the Polish population. For this purpose, the G1691A mutation was analyzed by PCR-RFLP in 1016 Poles: 400 neonates (187 female and 312 male), 184 healthy adults (129 female and 55 male), and 432 long-lived individuals (age >=95 years: 343 women and 89 men). Frequencies of G1691A carriers and the A1691 allele in long-lived individuals (0.2% and 0.1%, respectively) were significantly lower than in neonates (4.2% and 2.2%, respectively) and adults (3.3% and 1.6%). The frequency of the G1691A factor V Leiden mutation decreased with age, which indicates a shorter survival time among A1691 allele carriers in the Polish population. PMID- 20720310 TI - Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population. AB - Single-nucleotide polymorphisms in genes involved in DNA-damage-induced responses are reported frequently to be a risk factor in various cancer types. Here we analysed polymorphisms in 5 genes involved in DNA repair (XPD Asp312Asn and Lys751Gln, XRCC1 Arg399Gln, APE1 Asp148Glu, NBS1 Glu185Gln, and XPA G-4A) and in a gene involved in regulation of the cell-cycle (CCND1 A870G). We compared their frequencies in groups of colon, head and neck, and breast cancer patients, and 2 healthy control groups: (1) matched healthy Polish individuals and (2) a NCBI database control group. Highly significant differences in the distribution of genotypes of the APE1, XRCC1 and CCND1 genes were found between colon cancer patients and healthy individuals. The 148Asp APE1 allele and the 399Gln XRCC1 allele apparently increased the risk of colon cancer (OR = 1.9-2.3 and OR = 1.5 2.1, respectively). Additionally, frequencies of XPD genotypes differed between healthy controls and patients with colon or head and neck cancer. Importantly, no differences in the distribution of these polymorphisms were found between healthy controls and breast cancer patients. The data clearly indicate that the risk of colon cancer is associated with single-nucleotide polymorphism in genes involved in base-excision repair and DNA-damage-induced responses. PMID- 20720311 TI - Gene expression profiling in peripheral blood nuclear cells in patients with refractory ischaemic end-stage heart failure. AB - Functional analysis of up- and down-regulated genes might reveal whether peripheral blood cells may be considered as a material of diagnostic or prognostic value in patients with end-stage heart failure (HF). The aim of the present study was to compare the transcriptomic profile of peripheral blood nuclear cells from 6 male patients with ischaemic end-stage HF with those of 6 male patients with asymptomatic cardiac dysfunction. The expression of genes in peripheral blood nuclear cells in both groups of patients was measured using whole-genome oligonucleotide microarrays utilizing 35 035 oligonucleotide probes. Microarray analyses revealed 130 down-regulated genes and 15 up-regulated genes in the patients with end-stage HF. Some of the down-regulated genes belonged to the pathways that other studies have shown to be down-regulated in cardiomyopathy. We also identified up-regulated genes that have been correlated with HF severity (CXCL16) and genes involved in the regulation of expression of platelet activation factor receptor (PTAFR, RBPSUH, MCC, and PSMA7). In conclusion, the identification of genes that are differentially expressed in peripheral blood nuclear cells of patients with HF supports the suggestion that this diagnostic approach may be useful in searching for the molecular predisposition for development of severe refractory HF in patients with post infarction asymptomatic abnormalities and remodelling of the left ventricle. These results need further investigation and validation. PMID- 20720312 TI - Importance of eps genes from Bacillus subtilis in biofilm formation and swarming. AB - Unicellular organisms naturally form multicellular communities, differentiate into specialized cells, and synchronize their behaviour under certain conditions. Swarming, defined as a movement of a large mass of bacteria on solid surfaces, is recognized as a preliminary step in the formation of biofilms. The main aim of this work was to study the role of a group of genes involved in exopolysaccharide biosynthesis during pellicle formation and swarming in Bacillus subtilis strain 168. To assess the role of particular proteins encoded by the group of epsI-epsO genes that form the eps operon, we constructed a series of insertional mutants. The results obtained showed that mutations in epsJ-epsN, but not in the last gene of the eps operon (epsO), have a severe effect on pellicle formation under all tested conditions. Moreover, the inactivation of 5 out of the 6 genes analysed caused total inhibition of swarming in strain 168 (that does not produce surfactin) on LB medium. Following restoration of the sfp gene (required for production of surfactin, which is essential for swarming of the wild-type bacteria), the sfp+ strains defective in eps genes (except epsO) generated significantly different patterns during swarming on synthetic B medium, as compared to the parental strain 168 sfp+. PMID- 20720313 TI - Campylobacter protein oxidation influences epithelial cell invasion or intracellular survival as well as intestinal tract colonization in chickens. AB - The Dsb family of redox proteins catalyzes disulfide bond formation and isomerization. Since mutations in dsb genes change the conformation and stability of many extracytoplasmic proteins, and since many virulence factors of pathogenic bacteria are extracytoplasmic, inactivation of dsb genes often results in pathogen attenuation. This study investigated the role of 2 membrane-bound oxidoreductases, DsbB and DsbI, in the Campylobacter jejuni oxidative Dsb pathway. Campylobacter mutants, lacking DsbB or DsbI or both, were constructed by allelic replacement and used in the human intestinal epithelial T84 cell line for the gentamicin protection assay (invasion assay) and chicken colonization experiments. In C. coli strain 23/1, the inactivation of the dsbB or dsbI gene separately did not significantly affect the colonization process. However, simultaneous disruption of both membrane-bound oxidoreductase genes significantly decreased the strain's ability to colonize chicken intestines. Moreover, C. jejuni strain 81-176 with mutated dsbB or dsbI genes showed reduced invasion/intracellular survival abilities. No cells of the double mutants (dsbB- dsbI-) of C. jejuni 81-176 were recovered from human cells after 3 h of invasion. PMID- 20720315 TI - Structural transitions in solids. PMID- 20720316 TI - Crystal fingerprint space--a novel paradigm for studying crystal-structure sets. AB - The initial aim of the crystal fingerprint project was to solve a very specific problem: to classify and remove duplicate crystal structures from the results generated by the evolutionary crystal-structure predictor USPEX. These duplications decrease the genetic diversity of the population used by the evolutionary algorithm, potentially leading to stagnation and, after a certain time, reducing the likelihood of predicting essentially new structures. After solving the initial problem, the approach led to unexpected discoveries: unforeseen correlations, useful derived quantities and insight into the structure of the overall set of results. All of these were facilitated by the project's underlying idea: to transform the structure sets from the physical configuration space to an abstract, high-dimensional space called the fingerprint space. Here every structure is represented as a point whose coordinates (fingerprint) are computed from the crystal structure. Then the space's distance measure, interpreted as structure 'closeness', enables grouping of structures into similarity classes. This model provides much flexibility and facilitates access to knowledge and algorithms from fields outside crystallography, e.g. pattern recognition and data mining. The current usage of the fingerprint-space model is revealing interesting properties that relate to chemical and crystallographic attributes of a structure set. For this reason, the mapping of structure sets to fingerprint space could become a new paradigm for studying crystal-structure ensembles and global chemical features of the energy landscape. PMID- 20720317 TI - Addressing chemical diversity by employing the energy landscape concept. AB - Exploring the structural diversity of a chemical system rests on three pillars. First, there is the global exploration of its energy landscape that allows one to predict which crystalline modifications can exist in a chemical system at a given temperature and pressure. Next, there is the development of new synthesis methods in solid-state chemistry, which require only very low activation energies such that even metastable modifications corresponding, for example, to minima on the landscape surrounded by low barriers can be realized. Finally, there is the theoretical design of optimal synthesis routes, again based on the study of the system's energy landscape. In this paper the energy landscape approach to the prediction of stable and metastable compounds as a function of temperature and pressure is presented, with a particular focus on possible phase transitions. Furthermore, several examples are presented, where such predicted compounds were subsequently successfully synthesized, often employing a newly developed synthesis method, low-temperature atom-beam deposition. PMID- 20720314 TI - Bacterial diversity in the rumen of Indian Surti buffalo (Bubalus bubalis), assessed by 16S rDNA analysis. AB - Bacterial communities in buffalo rumen were characterized using a culture independent approach for a pooled sample of rumen fluid from 3 adult Surti buffaloes. Buffalo rumen is likely to include species of various bacterial phyla, so 16S rDNA sequences were amplified and cloned from the sample. A total of 191 clones were sequenced and similarities to known 16S rDNA sequences were examined. About 62.82% sequences (120 clones) had >90% similarity to the 16S rDNA database sequences. Furthermore, about 34.03% of the sequences (65 clones) were 85-89% similar to 16S rDNA database sequences. For the remaining 3.14%; the similarity was lower than 85% Phylogenetic analyses were also used to infer the makeup of bacterial communities in the rumen of Surti buffalo. As a result, we distinguished 42 operational taxonomic units (OTUs) based on unique 16S r DNA sequences: 19 OTUs affiliated to an unidentified group (45.23% of total OTUs), 11 OTUs of the phylum Firmicutes, also known as the low G+C group (26.19%), 7 OTUs of the Cytophaga-Flexibacter-Bacteroides phylum (16.66%), 4 OTUs of Spirochaetes (9.52%), and 1 OTU of Actinobacteria (2.38%). These include 10 single-clone OTUs, so Good's coverage (94.76%) of 16S rRNA libraries indicated that sequences identified in the libraries represent the majority of bacterial diversity present in rumen. PMID- 20720318 TI - Integral modeling approach to study the phase behavior of complex solids: application to phase transitions in MgSiO3 pyroxenes. AB - A combination of electronic structure calculations, classical molecular dynamics simulations and metadynamics is proposed to study the phase behavior of complex crystals. While the former provide accurate energetics for thermodynamic properties, molecular dynamics and metadynamics simulations may reveal new metastable phases and provide insight into mechanisms and kinetics of the respective structural transformations. Here, different simulation methods are used to investigate the polymorphism of MgSiO(3) pyroxenes (enstatites) up to high pressures and temperatures. A number of displacive phase transitions are observed within the three basic structure types clino-, ortho- and protoenstatite using classical molecular dynamics simulations. Transitions between these types require a change of stacking order, which is modeled using a combination of molecular dynamics and metadynamics. PMID- 20720319 TI - Interactive visualization of quantum-chemistry data. AB - Simulation and computation in chemistry studies have improved as computational power has increased over recent decades. Many types of chemistry simulation results are available, from atomic level bonding to volumetric representations of electron density. However, tools for the visualization of the results from quantum-chemistry computations are still limited to showing atomic bonds and isosurfaces or isocontours corresponding to certain isovalues. In this work, we study the volumetric representations of the results from quantum-chemistry computations, and evaluate and visualize the representations directly on a modern graphics processing unit without resampling the result in grid structures. Our visualization tool handles the direct evaluation of the approximated wavefunctions described as a combination of Gaussian-like primitive basis functions. For visualizations, we use a slice-based volume-rendering technique with a two-dimensional transfer function, volume clipping and illustrative rendering in order to reveal and enhance the quantum-chemistry structure. Since there is no need to resample the volume from the functional representations for the volume rendering, two issues, data transfer and resampling resolution, can be ignored; therefore, it is possible to explore interactively a large amount of different information in the computation results. PMID- 20720320 TI - Polarization effects and phase equilibria in high-energy-density polyvinylidene fluoride-based polymers. AB - Using first-principles calculations, the phase diagrams of polyvinylidene fluoride (PVDF) and its copolymers under an applied electric field are studied and phase transitions between their nonpolar alpha and polar beta phases are discussed. The results show that the degree of copolymerization is a crucial parameter controlling the structural phase transition. In particular, for tetrafluoroethylene (TeFE) concentration above 12%, PVDF-TeFE is stabilized in the beta phase, whereas the alpha phase is stable for lower concentrations. As larger electric fields are applied, domains with smaller concentrations (< or = 12%) undergo a transition from the alpha to the beta phase until a breakdown field of approximately 600 MV m(-1) is reached. These structural phase transitions can be exploited for efficient storage of electrical energy. PMID- 20720321 TI - Mode crystallography of distorted structures. AB - The description of displacive distorted structures in terms of symmetry-adapted modes is reviewed. A specific parameterization of the symmetry-mode decomposition of these pseudosymmetric structures defined on the setting of the experimental space group is proposed. This approach closely follows crystallographic conventions and permits a straightforward transformation between symmetry-mode and conventional descriptions of the structures. Multiple examples are presented showing the insight provided by the symmetry-mode approach. The methodology is shown at work, illustrating its various possibilities for improving the characterization of distorted structures, for example: detection of hidden structural correlations, identification of fundamental and marginal degrees of freedom, reduction of the effective number of atomic positional parameters, quantitative comparison of structures with the same or different space group, detection of false refinement minima, systematic characterization of thermal behavior, rationalization of phase diagrams and various symmetries in families of compounds etc. The close relation of the symmetry-mode description with the superspace formalism applied to commensurate superstructures is also discussed. Finally, the application of this methodology in the field of ab initio or first principles calculations is outlined. At present, there are several freely available user-friendly computer tools for performing automatic symmetry-mode analyses. The use of these programs does not require a deep knowledge of group theory and can be applied either a posteriori to analyze a given distorted structure or a priori to parameterize the structure to be determined. It is hoped that this article will encourage the use of these tools. All the examples presented here have been worked out using the program AMPLIMODES [Orobengoa et al. (2009). J. Appl. Cryst. 42, 820-833]. PMID- 20720322 TI - Diffusion-equation method for crystallographic figure of merits. AB - Global optimization methods play a significant role in crystallography, particularly in structure solution from powder diffraction data. This paper presents the mathematical foundations for a diffusion-equation-based optimization method. The diffusion equation is best known for describing how heat propagates in matter. However, it has also attracted considerable attention as the basis for global optimization of a multimodal function [Piela et al. (1989). J. Phys. Chem. 93, 3339-3346]. The method relies heavily on available analytical solutions for the diffusion equation. Here it is shown that such solutions can be obtained for two important crystallographic figure-of-merit (FOM) functions that fully account for space-group symmetry and allow the diffusion-equation solution to vary depending on whether atomic coordinates are fixed or not. The resulting expression is computationally efficient, taking the same order of floating-point operations to evaluate as the starting FOM function measured in terms of the number of atoms in the asymmetric unit. This opens the possibility of implementing diffusion-equation methods for crystallographic global optimization algorithms such as structure determination from powder diffraction data. PMID- 20720323 TI - Geometric parameters of isotropic ensembles of right cylinders from the small angle-scattering correlation function. AB - The scattered intensity of ensembles of right homogeneous quasi-diluted cylinders with constant oval right section (RS) and volume fraction phi are analyzed using the small-angle-scattering (SAS) correlation function (CF) gamma(r) = gamma(r, phi) in the isotropic two-phase approximation. A relation between the CF of the cylinder RS, beta(0)(r), and the CF of the single cylinder of height H, gamma(0)(r, H), allows the calculation of the explicit cylinder parameters of height, surface area, RS surface area, RS perimeter and volume. This is accomplished by evaluating the first two derivatives of gamma(0)(r) at r = 0. Without the assumption of an oval RS, neither H nor the RS surface area can be uniquely determined. PMID- 20720324 TI - Space fullerenes: a computer search for new Frank-Kasper structures. AB - A Frank-Kasper structure is a 3-periodic tiling of the Euclidean space E3 by tetrahedra such that the vertex figure of any vertex belongs to four specified patterns with, respectively, 20, 24, 26 and 28 faces. Frank-Kasper structures occur in the crystallography of metallic alloys and clathrates. A new computer enumeration method has been devised for obtaining Frank-Kasper structures of up to 20 cells in a reduced fundamental domain. Here, the 84 obtained structures have been compared with the known 27 physical structures and the known special constructions by Frank-Kasper-Sullivan, Shoemaker-Shoemaker, Sadoc-Mosseri and Deza-Shtogrin. PMID- 20720325 TI - A special class of simple 24-vertex polyhedra and tetrahedrally coordinated structures of gas hydrates. AB - It is established that the eight-dimensional lattice E(8) and the Mathieu group M(12) determine a unique sequence of algebraic geometry constructions which define a special class of simple 24-vertex, 14-face polyhedra with four-, five- and six-edge faces. As an example, the graphs of the ten stereohedra that generate most known tetrahedrally coordinated water cages of gas hydrates have been derived a priori. A structural model is proposed for the phase transition between gas hydrate I and ice. PMID- 20720326 TI - On R factors for dynamic structure crystallography. AB - In studies of dynamic changes in crystals in which induced metastable species may have lifetimes of microseconds or less, refinements are most sensitive if based on the changes induced in the measured intensities. Agreement factors appropriate for such refinements, based on the ratios of the intensities before and after the external perturbation is applied, are discussed and compared with R factors commonly applied in static structure crystallography. PMID- 20720328 TI - Making green jobs safe. PMID- 20720329 TI - Mood change and perception of workload in Australian midwives. AB - Investigations of mood and workload in health care settings have focussed primarily on nurses and junior doctors. Given the critical shortfall in the Australian midwifery workforce, and the specialised nature of midwifery as an occupation, it is important to understand how mood and workload are experienced by midwives. Twenty midwives (18F, 2M) in an Australian metropolitan hospital completed logbooks assessing daily fluctuations in subjective mood and workload. Participants also provided information about history of psychopathology and sleep quality. Results revealed that midwives were relatively stable in terms of mood but did experience increased fear and decreased happiness when at work. Further, workload factors significantly predicted mood at work. Specifically, when participants felt that their work was more demanding and frustrating and required more effort, or when they felt that they could not accomplish all that was expected, mood was negatively influenced. This supports the connection between workload and negative mood change in healthcare. Given the potential for mood to influence a multitude of functions relevant to safety, performance and psychosocial wellbeing it is important to understand the factors which influence mood, particularly in light of the current shortfall in the Australian healthcare workforce. PMID- 20720330 TI - Less quick returns--greater well-being. AB - The aim of this study was to design ergonomically improved shift schedules for nurses in primary health care shift work in order to enhance their health and well-being. The main change made was the reduction of quick returns (i.e., no more morning shifts immediately after an evening shift) in order to ensure more recovery time between work shifts. Six municipal hospital units participated in the intervention. Our aim was to maintain or improve the well-being and work ability of aged workers. The subjects (n=75) were divided into three age groups: 20-40, 41-52, and 53-62 yr. The introduction of more recovery time between evening and morning shifts significantly improved the subjects' sleep and alertness, well-being at work, perceived health, and leisure-time activities independently of their age. The effect on social and family life was also positive. Working in shifts was the most disruptive for the youngest group of nurses. The Work Ability Index score depended on the age group: it was lowest among the oldest age group, and did not change during the intervention. Ergonomic working time arrangements show positive effects on the well-being of health care workers of all ages. PMID- 20720331 TI - Work schedules and health behavior outcomes at a large manufacturer. AB - There is evidence that work schedules may influence rates of unhealthy behaviors, suggesting that addressing work schedule challenges may improve health. Health Risk Assessment (HRA) survey responses were collected during 2000-2008 in a multinational chemical and coatings manufacturer. Responses of 26,442 were sufficiently complete for analysis. Rates of smoking, lack of exercise, moderate to high alcohol use, obesity (BMI > or = 30), and short sleep duration were compared by work schedule type (day, night, or rotating shift) and daily work hours (8, 10, or 12 h). Prevalence rate ratios (RRs) were calculated, adjusting for age group, sex, marital/living status, job tenure, and occupational group. The reference group was 8-h day shift employees. Overall prevalence rates were: sleep duration of 6 h or less per night 47%, smoking 17.3%, no exercise 22.0%, BMI > or = 30 28.3%, and moderate to heavy alcohol consumption 22.2%. Statistically significant RRs include the following: Short sleep duration: 10 h rotating shift (RR=1.6), 12 h day and 12 h rotating shifts (RR=1.3); Smoking: 12 h day and rotating shifts (RR=1.6), 10 and 12 h night and 8 h rotating shift (RR=1.4); No exercise: 8, 10, and 12 h rotating shifts (RR=1.2 to 1.3), 12 h day schedules (RR=1.3). Obesity (BMI > or = 30): 8 and 10 h night shifts (RR=1.3 and 1.4, respectively). PMID- 20720332 TI - Staying safe in the jungles of Borneo: five studies of fatigue and cultural issues in remote mining projects. AB - The global mining industry keeps expanding, and projects are often started in areas previously considered too remote. Due to worker beliefs about safety, and the diversity of cultures in remote projects, the measurement and management of human fatigue is complex. This paper reports on five studies from companies in Kalimantan, the Indonesian part of the island of Borneo, where workers had been killed in likely fatigue-related accidents. Mixed-method approaches, involving qualitative, semi-quantitative, and quantitative measures were used. Participants were 20-45 yr old, had homes of 4.7 people (SD +/- 1.8), shared income outside of the house in 80% of cases, travelled < or = 3 d each-way between blocks of shifts. A major output was a set of camp standards to help ensure recovery sleep. Another requirement identified was access to leave when family members died, since not attending death ceremonies caused a lot of stress and made recovery and safe work less possible. Demanding work conditions and long work hours were also problematic in some operations. Safety systems should better consider fatigue in accidents/incidents and link its data with hours of work information. The interaction of cultures, stress, sleep, fatigue, safety and individual differences must be more effectively addressed in remote mining camps. PMID- 20720333 TI - Characteristics and effects of suicide prevention programs: comparison between workplace and other settings. AB - The present study reviews the literature on suicide prevention programs conducted in the workplace and other settings, namely school, the community, medical facilities, jail, and the army, by conducting an electronic literature search of all articles published between 1967 and November 2007. From a total of 256 articles identified, various contents of suicide prevention programs were determined, and in 34 studies, the effect of programs was evaluated. A review of the literature reveals that the common contents of suicide prevention programs in the workplace and other settings are education and training of individuals, development of a support network, cooperation from internal and external resources, as well as education and training of managers and staff. Although the characteristic contents of suicide prevention programs at the workplace aimed at improving personnel management and health care, screening and care for high-risk individuals, as well as improvement of building structures, were not described. Although a reduction in undesirable attitudes and an increase in mental health knowledge and coping skills in the workplace are in agreement with findings in other settings, suicide rate, suicide-associated behavior, and depression, which were assessed in other settings, were not evaluated in the three studies targeting the workplace. PMID- 20720334 TI - Reduction of adsorption capacity of coconut shell activated carbon for organic vapors due to moisture contents. AB - In occupational hygiene, activated carbon produced from coconut shell is a common adsorbent material for harmful substances including organic vapors due to its outstanding adsorption capacity and cost advantage. However, moisture adsorption of the carbon generally decreases the adsorption capacity for organic vapors. In a previous report, we prepared several coconut shell activated carbons which had been preconditioned by equilibration with moisture at different relative humidities and measured the breakthrough times for 6 kinds of organic vapor, in order to clarify the effect of preliminary moisture content in activated carbon on the adsorption capacity in detail. We found that the relative percent weight increase due to moisture adsorption of the carbon specimen had a quantitative effect, reducing the breakthrough time. In this report, we carried out further measurements of the effect of moisture content on the adsorption of 13 kinds of organic vapor, and investigated the relationship between moisture adsorption and the reduction of the breakthrough time of activated carbon specimens. We also applied the data to the Wood's breakthrough time estimation model which is an extension of the Wheeler-Jonas equation. PMID- 20720335 TI - Assessment of human color discrimination based on illuminant color, ambient illumination and screen background color for visual display terminal workers. AB - Human performance on color discrimination in visual display terminals may be affected by illuminant colors, the level of ambient illumination and background colors of the monitor. Few studies have focused on this topic. This study investigated human color discrimination ability in a simulated control room. Ten subjects were recruited as participants to perform a series of experimental tasks. A complete factorial (2 x 3 x 3) within-subject design was used. The independent variables were three illuminant colors (red, blue, and white), two ambient illumination levels (50 lux and 300 lux), and three background colors (black, blue and brown); the three dependent variables were the color discrimination ability (error scores), completion time and subject preference. The results showed that the illuminant colors and the screen background colors both significantly influenced human color discrimination ability (p<0.01). The result of this research can be used in control room design when considering the effect of color. PMID- 20720336 TI - Waist circumference can predict the occurrence of multiple metabolic risk factors in middle-aged Japanese subjects. AB - Visceral obesity is associated with the clustering of metabolic risk factors and the incidence of cardiovascular events. However, the association between the waist circumference values and the metabolic risk factors has not been fully established in Japanese middle-aged subjects. We examined the data from 6,033 Japanese middle-aged subjects aged 40-59 yr (4,599 male and 1,434 female). Metabolic risk factors such as high blood pressure, dyslipidemia, and glucose intolerance were identified according to the diagnostic criteria for metabolic syndrome in Japan. Numbers of metabolic risk factors were significantly associated with the waist circumference values in both male and female subjects. The prevalence of subjects with multiple (two or more) metabolic risk factors was 29.7% and 7.4% in male and female, respectively. According to receiver operating characteristic analysis, the cut-off values of waist circumference with the maximal sensitivity plus specificity to predict the presence of multiple metabolic risk factors were 86 cm and 81 cm in male and female, respectively. These values were in agreement with the diagnostic criteria for metabolic syndrome in Japanese male, but not in female. In conclusion, the waist circumference values can predict the presence of multiple metabolic risk factors in Japanese middle-aged subjects. PMID- 20720337 TI - Characteristics of multiwall carbon nanotubes for an intratracheal instillation study with rats. AB - Much concern has been raised over the health consequences of workers exposed to carbon nanotubes. In order to characterize multi-wall carbon nanotubes (MWCNT) suspended in a phosphate-buffered saline containing 0.1% Tween 80 for an intratracheal instillation study. Length and width distributions of the MWCNT fibers, dispersion of MWCNT in the suspension and in the lung tissue and the MWCNT contents of metal impurities were investigated. Arithmetic mean length and width of the MWCNT fibers as measured on scanning electron microscope (SEM) photographs were 5.0 microm and 88 nm, respectively, and fibers longer than 5.0 microm were 38.9% of all fibers measured. Dynamic light scattering size measurement revealed that 5-min ultrasonication, together with addition of Tween 80 into the suspension, decreased the hydrodynamic diameters of the agglomerated MWCNT to those of finer particles below 1.0 microm. SEM observation showed good dispersion of MWCNT in the suspension, and in the alveoli on Day 1 after instillation. Concentration of iron, chromium and nickel in the MWCNT were 4,400, 48 and 17 ppm (wt/wt), respectively, all of which were below levels that would elicit positive pulmonary toxic responses to these metals. The results suggest that well-dispersed, long and thin MWCNT fibers exhibit asbestos-like pathogenicity in the lung. PMID- 20720338 TI - Logical consideration on lockout and trapped key interlock for machine. AB - "Lockout" is an important method for hazardous energy control to protect humans working at a place where they may be injured by unexpected release of hazardous energy. Actually, this administrative control is used in order to compensate for the incompleteness of the ZMS (Zero Mechanical State). This paper proposes the basic requirements for the "Lockout" used for machine maintenance work by applying the "principle of safety confirmation". In view of the above, the relation of "locking up the power switch in the OFF position", "withdrawing and possessing the key for hostage control" and "unlocking the movable guard for accessing to the working space" of the "trapped key interlock", which is alternative to "Lockout", should be made unate in terms of system. This paper formulates these interrelations, presents them in the form of interlock structure, and shows an example of configuration that can meet the required safety functions. PMID- 20720339 TI - Brief hourly exercise during night work can help maintain workers' performance. AB - Increased night work is an important issue because of its implications on workers' health, safety and performance. This study examined the effects of brief hourly exercise as a countermeasure against the adverse effects of night work, especially for workers requiring sustained attention while working in a prolonged sitting posture. During simulated night work (22:00-08:00), participants were required to follow an hourly schedule comprising a 30-min task, 15-min test and 15-min break. The study included 2 experimental conditions: (1) hourly exercise (HE; hourly exercise for 3 min during breaks) and (2) control (without exercise during breaks). Throughout the test period, work performance in the last 10 min of each 30-min task was better under the HE condition than under the control condition (p<0.01). During the second half of the test period, exercise showed an effect on sustained attention (p=0.02). Parasympathetic nerve activity under the HE condition was less than that under the control condition (p<0.01). However, exercise was not effective in reducing subjective fatigue and sleepiness. These results suggest that brief hourly exercise acts as a restraint on parasympathetic nerve activity and is capable of sustaining attention levels during the circadian rhythm nadir that occurs during early morning. PMID- 20720340 TI - Analysis of aerosol emission and hazard evaluation of electrical discharge machining (EDM) process. AB - The safety and environmental aspects of a manufacturing process are important due to increased environmental regulations and life quality. In this paper, the concentration of aerosols in the breathing zone of the operator of Electrical Discharge Machining (EDM), a commonly used non traditional manufacturing process is presented. The pattern of aerosol emissions from this process with varying process parameters such as peak current, pulse duration, dielectric flushing pressure and the level of dielectric was evaluated. Further, the HAZOP technique was employed to identify the inherent safety aspects and fire risk of the EDM process under different working conditions. The analysis of aerosol exposure showed that the concentration of aerosol was increased with increase in the peak current, pulse duration and dielectric level and was decreased with increase in the flushing pressure. It was also found that at higher values of peak current (7A) and pulse duration (520 micros), the concentration of aerosols at breathing zone of the operator was above the permissible exposure limit value for respirable particulates (5 mg/m(3)). HAZOP study of the EDM process showed that this process is vulnerable to fire and explosion hazards. A detailed discussion on preventing the fire and explosion hazard is presented in this paper. The emission and risk of fire of the EDM process can be minimized by selecting proper process parameters and employing appropriate control strategy. PMID- 20720342 TI - Efficacy of cognitive behavioral therapy training using brief e-mail sessions in the workplace: a controlled clinical trial. AB - In the present study, we conducted a clinical controlled trial to evaluate the effects of cognitive behavioral therapy (CBT) training in improving depression and self-esteem in workers. A total of 261 workers were assigned to either an intervention group (n=137) or a waiting-list group (n=124). The intervention group was offered participation in a group session with CBT specialists and three e-mail sessions with occupational health care staff. Between-group differences in the change in Center for Epidemiologic Studies Depression Scale (CES-D) and Self Esteem Scale from baseline to three months after the end of training were assessed by analysis of covariance. All subjects in the intervention group completed the group session and 114 (83%) completed the three e-mail sessions. CES-D score decreased by 2.21 points in the intervention group but increased by 0.12 points in the control group, a significant difference of -2.33 points (95% confidence interval: -3.89 to-0.77; p<0.001). The between-group difference in change of self-esteem scores was not significant. Results of the present study suggest that CBT training cooperatively provided by CBT specialists and occupational health care staff using brief e-mail is effective in improving feelings of depression in workers. PMID- 20720341 TI - Risk for non-obese Japanese workers to develop metabolic syndrome. AB - With regard to metabolic syndrome-related risks (MS risks), obese workers have been the focus of attention, and less attention has been paid to non-obese subjects as if they were free from the risks. The present analysis was initiated to know if no-obesity means no-MS risks. Participants of the study were 804 male workers, who showed no pathological findings in 12 MS-related and other health parameters in 2003, and had complete sets of data in 2008. They were classified by BMI in 2003 into lean (< 18.5), normal (> or = 18.5 to < 25) and obese groups (> or =25). Proportion of MS in 2008 was examined by use of the second phase of MS criteria. Proportions for the lean, normal and obese subjects who met MS criteria in 2008 were 3.2, 4.8 and 5.3%, respectively, with no significant difference in proportions among them. In the non-obese (i.e., lean+normal) group, age was not significantly influential to increase BMI. Thus, the MS risk exists even in non-obese young workers. Anti-MS effort should be directed not only to obese but to non-obese workers, and care should be extended irrespective of ages. PMID- 20720343 TI - Job strain among rubber-glove-factory workers in central Thailand. AB - Job strain has become a major concern because of its potential impacts on worker well-being and performance. This cross-sectional study aimed to assess the prevalence of, and examine factors associated with, job strain among workers in a rubber-glove factory, in a central province of Thailand. A total of 200 workers aged 18-55 yr, who had worked at the factory for at least 6 months, completed the Job Content Questionnaire (JCQ) (Thai Version). Two of 5 scales in the JCQ were used to measure job strain, i.e.; job control and psychological job demand. The prevalence of job strain was 27.5%. Multiple logistic regression analysis indicated two variables significantly associated with job strain: low supervisor social support (adjusted OR=3.08; 95%CI: 1.38-6.91) and high job insecurity (adjusted OR=2.25; 95%CI: 1.04-4.88). Effective training for supervisors, to create good relationships among workers and supervisors, and ensuring steady and secure jobs for good employees, are necessary. PMID- 20720344 TI - Weight loss approach during routine follow-up is effective for obstructive sleep apnea hypopnea syndrome subjects receiving nasal continuous positive airway pressure treatment. AB - The present study investigated the effectiveness of a weight loss program during routine medical follow-up with regularity on promoting weight reduction in obese obstructive sleep apnea hypopnea syndrome (OSAHS) subjects receiving continuous positive airway pressure treatment (CPAP). A total of 10 male obese OSAHS subjects treated with CPAP were enrolled in the present study that was an intervention study without a control and had a pre-post test study design. The age was 50.7 (7.8) (mean (SD)) years, and body mass index was 30.7 (2.5) kg/m(2). A 4-month weight loss program was developed, using a combined approach of diet and physical activity based on individual counseling with behavioral approach. At 4 months, weight was significantly decreased compared with the baseline value (88.4 (8.9) kg to 86.9 (8.8) kg, p=0.005), and the mean weight loss was a 1.7% decrease from the baseline. There was significantly higher percent weight loss in the group with a CPAP duration < 30 months, than in the group > or = 30 months (2.7 (1.6) % vs. 0.6 (0.5) %, p=0.032). The present study shows that a weight loss program may be useful in reducing weight for male obese OSAHS subjects treated with CPAP. PMID- 20720345 TI - Assessment of coronary artery flow velocity pattern as a long-term predictor of left ventricular function and cardiac events after percutaneous coronary intervention in anterior acute myocardial infarction. AB - BACKGROUND: Coronary flow velocity (CFV) can be used to assess short-term left ventricular function recovery and the clinical prognosis of patients with acute myocardial infarction (AMI). We evaluated CFV as a predictor of long-term left ventricular function recovery and cardiac events in patients with anterior wall AMI. METHODS AND RESULTS: CFV pattern of the distal left anterior descending (LAD), wall motion score index (WMSI) and left ventricular ejection fraction (LVEF) were recorded at the points of time within 24 hours, 3 days, 6 months, and 3 years after percutaneous coronary intervention (PCI) in 50 consecutive patients with anterior wall AMI. The clinical data were collected. Patients were divided into two groups based on diastolic deceleration time (DDT) 3 days after PCI. Compared with 3 days, LVEF and WMSI in group A (DDT>600 ms, n=20) improved in 6 months and 3 years (p<0.01), but they were unchanged in group B (DDT< or =600 ms, n=30). The incidence of cardiac events was higher in group B than in group A during 6 months (p<0.01).With a 3-year follow up, the incidence of chronic heart failure was higher in group B than in group A (p=0.009). CONCLUSION: CFV could be used as a predictor of long-term left ventricular function recovery and cardiac events in patients with anterior wall AMI. PMID- 20720346 TI - Computed tomography and scintigraphy vs. cardiac catheterization for coronary disease screening prior to noncardiac surgery. AB - OBJECTIVE: The goal of this study was to investigate the utility of multidetector row computed tomography (MDCT) and adenosine triphosphate stress cardiac single photon emission computed tomography (ATP-SPECT) in evaluating coronary artery disease (CAD) in patients scheduled for non-cardiac surgery. PATIENTS AND METHODS: We routinely performed echocardiography and exercise stress electrocardiography as preoperative cardiac screening examinations for patients scheduled for non-cardiac surgery under general anesthesia. Of 848 consecutive preoperative patients (Non-invasive Group), 49 patients with abnormalities of these screening examinations had MDCT and ATP-SPECT. Of 809 consecutive preoperative patients studied at an earlier time (Invasive Group), 58 patients with abnormalities of these screening examinations had cardiac catheterization as an additional cardiac examination. RESULTS: The number of patients in the non invasive and invasive subgroups having additional screening examinations was comparable, and there was no significant difference in perioperative cardiac events between the two subgroups. Based on results of the additional tests in the two subgroups, preoperative prophylactic invasive treatment for CAD was carried out in a small number of patients, again with no significant differences between the groups. However, total medical expenses for the additional cardiac examinations were significantly reduced in the non-invasive subgroup compared with the invasive subgroup (140,030+/-34,800 vs. 187,170+/-26,120 yen, respectively, p=0.0002). CONCLUSION: Non-invasive examination prior to noncardiac surgery using MDCT and ATP-SPECT in a subgroup of patients suspected of having CAD appears to be a useful screening procedure. Compared with invasive cardiac catheterization, CT testing has comparable diagnostic utility without an increase in perioperative cardiac events, and in addition, it has an improved cost-benefit profile. PMID- 20720347 TI - Quality of warfarin control affects the incidence of stroke in elderly patients with atrial fibrillation. AB - OBJECTIVE: Adjusted-dose warfarin therapy can prevent stroke in patients with atrial fibrillation. However, the quality of the warfarin control may be considered to be important for elderly patients. methods: We followed 188 patients (age > or =70 years) with atrial fibrillation (warfarin, 120 patients; non-warfarin, 68 patients) for 2 years. Their warfarin control was assessed by time in therapeutic range (TTR) for an international normalized ratio of prothrombin time of 1.6-2.6, based on the Japanese guidelines of anticoagulation for elderly patients with atrial fibrillation. RESULTS: Stroke occurred in 23 patients (12.2%). In warfarin-treated patients, receiver-operator characteristic (ROC) curves suggested that patients with TTR >68% had anticoagulation benefit. In the ROC curves for prediction of stroke, the area under the curve of TTR was 0.709 (95% confidence interval, 0.585 to 0.834; p=0.02). The sensitivity and specificity of TTR < or =68% were 91.7% and 54.0%, respectively. Kaplan-Meier curves showed that the event-free ratio of stroke was significantly higher in patients who achieved this cut-off of TTR. CONCLUSION: The results suggest that the quality of warfarin control is directly associated with the incidence of stroke in elderly patients. PMID- 20720348 TI - Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients. AB - OBJECTIVE: To evaluate the effects of one year of treatment with sibutramine plus L-carnitine compared to sibutramine on body weight, glycemic control, and insulin resistance state in type 2 diabetic patients. METHODS: Two hundred and fifty-four patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) >8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg plus L carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP). RESULTS: There was a decrease in body weight, BMI, HbA(1c), FPI, HOMA-IR, and RBP-4 in both groups, even when the values obtained with sibutramine plus L-carnitine were lower than the values obtained in sibutramine group. There was a faster decrease of FPG, PPG, TC, LDL C, resistin and Hs-CRP with sibutramine plus L-carnitine even when no differences between the two groups were obtained. Furthermore, only sibutramine plus L carnitine improved Tg, and visfatin. CONCLUSION: Sibutramine plus L-carnitine gave a faster improvement of lipid profile, insulin resistance parameters, glycemic control, and body weight compared to sibutramine. PMID- 20720349 TI - Significant impairment of left atrial function in patients with cardioembolic stroke caused by paroxysmal atrial fibrillation. AB - OBJECTIVE: Patients with cardioembolic stroke (CE) caused by paroxysmal atrial fibrillation (Paf) sometimes show normal sinus rhythm on admission, which makes it difficult to diagnose them as having CE. The present study examined the differences in echocardiographic findings between patients with CE caused by Paf (the Paf-CE group) and those with non-cardiogenic embolic ischemic stroke (the Non-CE group). METHODS: We examined thirty-two patients with embolic ischemic stroke presenting with a normal sinus rhythm upon admission to our hospital; 13 patients in the Paf-CE group and 19 patients in the Non-CE group. During admission, all patients underwent transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) at a normal sinus rhythm. The left atrial dimension, left ventricular end-diastolic dimension and left ventricular ejection fraction were measured using TTE. The left atrial appendage peak flow velocity (LAAPV), spontaneous echo-contrast in the left atrium (LASEC) and thrombus in the left atrium were evaluated using TEE. RESULTS: Among the clinical background characteristics, hypertension was significantly more frequent in the Non-CE group than in the Paf-CE group (p<0.01). Congestive heart failure was significantly more frequent in the Paf-CE group than in the Non-CE group (p<0.05). LAAPV was significantly lower in the Paf-CE group than in the Non-CE group (34.7 cm/s vs. 64.0 cm/s, p<0.01), and the LASEC grade was significantly higher in the Paf-CE group than in the Non-CE group (p<0.01). A thrombus in the left atrium was detected in two patients in the Paf-CE group, but no thrombi were detected in any of the patients in the Non-CE group. CONCLUSION: Echocardiographic evaluation is useful, as the above data indicate that the left atrial function is apparently impaired in patients with CE caused by Paf, even in a patient with an apparently normal sinus rhythm. PMID- 20720350 TI - The nosocomial transmission of Helicobacter cinaedi infections in immunocompromised patients. AB - BACKGROUND: We encountered 15 cases of Helicobacter cinaedi (H. cinaedi) infection between March and July 2008. PATIENT, METHOD, AND RESULT: The underlying diseases were hematological malignancies in a majority of cases, many of which received chemotherapy. All patients had a fever. The fever was followed by cellulitis in three, a skin rash in six, pain in the lower limbs in three, and diarrhea in three cases. We analyzed the bacterial 23S rRNA genes. The fifteen strains were divided according to base sequence into Groups A, B, and C, respectively. All four cases in Group A were women and all ten in Group C were men, indicating that the gender of the patient corresponded precisely to the genotypes of the separated bacilli in these two groups. These findings also suggested the strong possibility of nosocomial spread. CONCLUSION: It is highly likely that H. cinaedi infections have been overlooked due to the difficulties encountered in culturing the bacterium. The possibility of septicemia caused by H. cinaedi should be suspected especially in immunocompromised patients such as those undergoing chemotherapy, with symptoms such as fever, rash, arthritis, cellulitis, leg pain, and other systemic or local symptoms. PMID- 20720351 TI - A case of severe thrombocytopenia in a patient with chronic hepatitis C caused by a single administration of pegylated interferon alpha 2a subsequent to 48 weeks of pegylated interferon alpha 2b plus ribavirin therapy. AB - A 54-year-old female with chronic hepatitis C developed severe thrombocytopenia after a single administration of Peg-IFN alpha 2a subsequent to 48 weeks of Peg IFN alpha-2b plus ribavirin therapy. The platelet count decreased from 11.3 x 10(4) /mm(3) to 1.6 x 10(4) /mm(3). Blood test and bone marrow aspiration examination indicated that an immunological mechanism was considered for the etiology of platelet decrease. Fifty mg of prednisolone was administered and the platelet count gradually increased to the normal range. This case is very instructive since severe thrombocytopenia did not occur during 48 weeks of Peg IFN alpha-2b plus ribavirin therapy, but occurred after a single subcutaneous administration of Peg-IFN alpha-2a during a subsequent course. PMID- 20720352 TI - Triple synchronous primary cancers of rectum, thyroid, and uterine cervix detected during the workup for hematochezia. AB - Multiple primary cancers are defined as multiple occurrences of malignant neoplasm of different histologic origin in the same individual. The synchronous occurrence of triple distinct cancers in the same patient is very rare. Herein, we report an extremely rare case of synchronous triple primary cancers of the rectum, thyroid gland and uterine cervix; all were detected during the work-up for hematochezia. To the best of our knowledge, this is the first such report in the medical literature. PMID- 20720353 TI - A case of solid pseudopapillary neoplasm of the pancreas presenting with left sided extrahepatic portal hypertension. AB - A 53-year-old woman was referred to our hospital for management of gastric varices that ran transversely across the greater curvature of the gastric body, detected during routine upper gastrointestinal endoscopy. CT identified a low density calcified mass near the tail of the pancreas and the splenic hilum. Based on the results of radiographic and pathological investigations, the tumor was diagnosed as solid pseudopapillary neoplasm (SPN), and the gastric varices were considered to have developed secondary to occlusion of the splenic vein by the tumor mass. This is a rare case of SPN associated with splenic vein occlusion and left-sided extrahepatic portal hypertension. PMID- 20720354 TI - A case of IgA-related enteropathy complicated with gastrointestinal bleeding and progressive IgA nephropathy: a possible variant Henoch-Schonlein purpura? AB - Here, we report an adult patient with IgA-related enteropathy complicated with massive intestinal bleeding and acute renal failure, but without skin lesions. Surgical resection of the small intestine and steroid pulse therapy was performed. Histopathology revealed significant deposition of IgA and C3 in the small vessels of the intestine and the kidney mesangium. Although skin purpura was absent, the histopathology and clinical manifestations suggested that the pathophysiology was similar to Henoch-Schonlein purpura (HSP), implying IgA related enteropathy as a subclass of HSP. Retrospective analysis indicates that terminal ileum lesions may be a poor prognostic indicator. PMID- 20720355 TI - Chylous ascites and chylothorax: an unusual manifestation of cardiac amyloidosis. AB - Restrictive cardiomyopathy is an extremely rare cause of massive chylous ascites and chylothorax. We report a 56-year-old man patient who presented with chylous ascites and bilateral chylothorax; 12-lead electrocardiography and echocardiography revealed restrictive cardiomyopathy. Endomyocardial biopsy disclosed amyloidosis. PMID- 20720356 TI - Premature atrial contraction induces torsades de pointes in a patient of Takotsubo cardiomyopathy with QT prolongation. AB - Although the prognosis for patients with stress-induced cardiomyopathy (Takotsubo cardiomyopathy) is relatively good, some patients with this syndrome develop torsades de pointes, which can be fatal. The present report describes a patient with Takotsubo cardiomyopathy and torsades de pointes induced by premature atrial contraction associated with QT interval prolongation, hypokalemia and hypomagnesemia. PMID- 20720357 TI - Stenotrophomonas maltophilia endocarditis of prosthetic mitral valve. AB - We present a 78-year-old woman with prosthetic valve endocarditis due to Stenotrophomonas maltophilia (S. maltophilia) 3 years after mitral valve replacement. Administration of sulfamethoxazole-trimethoprim was effective; however, it was discontinued because of side effects, which led to failure of antibiotic therapy. Complications of multiple cerebral infarction and paravalvular abscess developed. Although the prosthetic valve was removed 50 days after admission, she died 4 months after surgery. S. maltophilia has been increasingly being considered as a serious nosocomial pathogen. S. maltophilia endocarditis is rare; however, it should be recognized as a possible life threatening disease in patients with prosthetic valve. PMID- 20720358 TI - Acute right heart failure and achalasia-like syndrome in a patient with limited cutaneous systemic sclerosis and primary biliary cirrhosis. AB - We report a case of a 63-year-old woman who developed acute right heart failure and an achalasia-like syndrome with limited cutaneous systemic sclerosis (lcSSc) and primary biliary cirrhosis. Intravenous administration of diuretics improved her acute heart failure. Anti-centromere antibodies and anti-mitochondria antibodies were present. A coronary angiogram and a Swan-Ganz catheter revealed no abnormalities. Thallium-201 scan at rest demonstrated mild perfusion defects in both the apex and the anteroseptal and the inferior myocardium. A cine esophagram revealed an achalasia-like syndrome. Though rare, physicians should be aware that some patients with lcSSc may develop acute right heart failure or achalasia-like syndrome. PMID- 20720359 TI - A case of tuberculous peritonitis in a hemodialysis patient with high serum soluble interleukin-2 receptor and CA-125 levels. AB - A hemodialysis patient with tuberculous peritonitis with hypercalcemia and high serum soluble interleukin-2 receptor (sIL-2R) and CA-125 levels is reported. An 82-year-old woman who had been on hemodialysis therapy for 6 years was admitted to our hospital for evaluation and treatment of hypercalcemia. Laboratory examination and radiologic studies revealed markedly increased serum sIL-2R and CA-125 levels and exudative ascites, with high levels of adenosine deaminase (ADA) and CA-125, which was suggestive of malignancy or tuberculosis. She was finally diagnosed as having tuberculous peritonitis based on positivity for Mycobacterium tuberculosis in ascitic fluid. The ascites subsided with normalization of hypercalcemia and a marked decrease in serum sIL-2R and CA-125 levels in response to anti-tuberculosis treatment. This case indicates that serum sIL-2R and CA-125 levels can rise to levels suggestive of malignancy in tuberculous peritonitis, and that they can be used to monitor the response to anti-tuberculosis treatment. PMID- 20720360 TI - Early diagnosis and treatment may prevent the development of complications in an adult patient with glycogen storage disease type Ia. AB - Type Iota(a) glycogen storage disease (GSD Iota(a)) is caused by the deficiency of glucose-6-phosphatase activity, which results in metabolic disorder and organ failure, including renal failure. GSD Iota(a) patients are generally diagnosed at a median age of 6 months. However, we report a 20-year-old Japanese female with newly diagnosed GSD Iota(a) . The renal disorder of GSD Iota(a) is considered to be produced by glomerular hyperfiltration, TGF-beta expression which is induced by renin-angiotensin-aldosterone system (RAS) and uric acid, and the increase in both small dense LDL and modified LDL which is characteristic of GSD Iota(a) as well as hypertriglyceridemia. With the administration of intensive therapies, including angiotensin type 1-receptor blocker and some lipid lowering drugs, along with traditional dietary therapy, daily proteinuria of the patient improved from 2.1 g to 0.78 g. Although the patients of GSD Iota(a) should receive an early and accurate diagnosis and effective therapies before the age of 1 year, the combination of traditional dietary therapies and intensive therapies may have therapeutic potential for the complications of adult patients. In this report, we describe the management of renal disease and the characteristic features of this metabolic disorder. PMID- 20720361 TI - An autopsy case of disseminated cryptococcosis manifesting as acute diarrhea in a patient with primary biliary cirrhosis. AB - A 58-year-old woman with an 18-year history of primary biliary cirrhosis was admitted because of pneumococcal pneumonia. She was treated with antibiotics and mechanical ventilation. After the pneumonia improved, she developed severe watery diarrhea. Although vancomycin was administered enterally, the diarrhea persisted. She died of multiple organ failure within 16 days of the onset of diarrhea. An autopsy showed intracapillary cryptococci in the systemic organs, especially in the intestinal tract. The cause of diarrhea was considered to be extensive intestinal mucosal necrosis due to disseminated cryptococcosis. This is a rare case of cryptococcal infection manifesting as acute diarrhea. PMID- 20720362 TI - Ehlers-Danlos syndrome type IV, vascular type, which demonstrated a novel point mutation in the COL3A1 gene. AB - Ehlers-Danlos syndrome type IV (EDS type IV), vascular type, an autosomal dominant disorder caused by a mutation of the type III procollagen gene (COL3A1) is the most severe form of EDS and often presents with aortic hemorrhage or organ perforation. This report discusses a male patient with EDS type IV with dyspnea due to hemopneumothorax. He had thin skin and hypermobile joints and was clinically confirmed as having EDS type IV. The diagnosis was genetically confirmed by a mutation c.2528 G>A (p.Gly843Glu) in the COL3A1 gene. The position of the mutation has never been reported. PMID- 20720363 TI - CD3- and CD4-positive plasmablastic lymphoma: a literature review of Japanese plasmablastic lymphoma cases. AB - Plasmablastic lymphoma (PBL) is a very rare and recently-described subtype of diffuse large B-cell lymphoma. A maxillary tumor in an 84-year-old HIV-negative Japanese-man was referred. The biopsied specimen showed a diffuse proliferation of mature plasma cells, expressing CD3 (+), CD4 (+), CD20 (-), CD138 (+) and EBER (+) by immunohistochemistry. He was diagnosed as a plasmablastic lymphoma; radiation therapy (RT) was started, but the response to the RT was only a partial response. To our knowledge, this is the first report of a patient with PBL expressing CD3 and CD4. PMID- 20720364 TI - Hyponatremic encephalopathy after excessive water ingestion prior to pelvic ultrasound: neuroimaging findings. AB - We report two patients with acute hyponatremic encephalopathy which developed after massive water ingestion for pelvic ultrasound and emphasize the findings of magnetic resonance (MR) imaging including diffusion-weighted imaging (DWI). Both subjects had completely recovered within 24 hours following fluid restriction and salt replacement. MR imaging revealed cortical sulcal narrowing, restricted diffusion and sulcal T2 hyperintensity along with diffuse pial enhancement suggesting diffuse cerebral cortical cytotoxic edema and blood-brain barrier breakdown. In addition to the first illustration of multimodality MR imaging features of water-intoxication, these two cases also highlight the need for standardized practice on the quantity of water intake recommended to distend the bladder for pelvic ultrasound, especially in patients at risk for serum inappropriate ADH syndrome-related hyponatremia. PMID- 20720365 TI - Herbal medicine-induced meningitis-retention syndrome. AB - A 73-year-old woman developed subacute meningitis-retention syndrome (MRS), dermatitis, and latent pneumonitis likely due to the herbal medicines Shinbu-Tou and Rikkunshi-Tou. The responsible site of lesions for urinary retention seemed to be the spinal micturition pathways and, to a lesser extent, the sacral spinal cord. All of her clinical manifestations were successfully ameliorated within three weeks of discontinuation of the herbal remedies. PMID- 20720366 TI - Pulmonary Mycobacterium parascrofulaceum infection as an immune reconstitution inflammatory syndrome in an AIDS patient. AB - Nontuberculous mycobacterial (NTM) infection in HIV (human immunodeficiency virus)-infected patients who have started highly active antiretroviral therapy (HAART) is well known to be one scenario of immune reconstitution inflammatory syndrome (IRIS). We encountered the first case in Japan of an HIV-infected patient with pulmonary Mycobacterium parascrofulaceum infection as IRIS. A 34 year-old man with acquired immunodeficiency syndrome (AIDS) was receiving highly active antiretroviral therapy. Lymphadenopathy was observed at the left pulmonary hilum. IRIS was suspected and thoracoscopic surgery was performed to diagnose the cause of lymphadenopathy. Granulomas were observed histologically, and M. parascrofulaceum was cultured. This organism was susceptible to Clarithromycin, rifampicin and levofloxacin. After the operation and without treatment, recurrence of M. parascrofulaceum infection was not observed. M. parascrofulaceum was isolated from several clinical specimens for the first time in 2004. To date, only five cases have been reported. PMID- 20720367 TI - A case of fever of unknown origin: co-existence of Kikuchi-Fujimoto disease and acute disseminated encephalomyelitis (ADEM). AB - It is believed that viral infections and the hyperimmune reaction due to these infections are involved in the etiology of Kikuchi-Fujimoto Disease (KFD), a rare cause of fever of unknown origin. Axillary lymphadenopathy and neurologic involvement are rare in KFD. We present a patient diagnosed with KFD histopathologically during an investigation of the origin of fever and axillary lymphadenopathy. Subsequently, incidental sinus aspergilloma was diagnosed radiologically in the patient and acute disseminated encephalitis developed during follow-up. This report aims to draw attention to the co-existence of KFD and Acute Disseminated Encephalomyelitis, two diseases of which the origins are not clear. PMID- 20720368 TI - Sickle cell trait as a cause of splenic infarction while climbing Mt. Fuji. AB - We report a 38-year-old mestizo man with the sudden onset of left upper abdominal pain while climbing Mt. Fuji, which is the highest mountain in Japan. Enhanced computed tomography showed splenic infarction. Although his peripheral blood smear was normal, a hemoglobin S level of 40% established the diagnosis of sickle cell trait (SCT). This trait is common worldwide, but is not well recognized by doctors in Japan because no Japanese patients with SCT have been reported. However, in Japan it is important to consider SCT when assessing foreign patients with splenic infarction. PMID- 20720369 TI - A swollen index finger as a presentation of thyroid dermopathy. PMID- 20720370 TI - Hypokalemic myopathy due to excessive consumption of cola. PMID- 20720371 TI - Black thyroid. PMID- 20720372 TI - Primary ciliary dyskinesia demonstrating atypical presentation of Kartagener's syndrome. PMID- 20720373 TI - Smokers are over-represented in subjects with ahaptoglobinemia in Ghana. AB - AIM: Smoking has been established as a major risk factor for cardiovascular disease. It causes oxidative stress and sub-clinical inflammation, which undermine the antioxidant defense system of the body. We reasoned that natural antioxidant defense systems may be compromised in smokers. To this end, we examined whether haptoglobin (Hp), a potent antioxidant, is impacted negatively by smoking. METHODS: Study participants consisted of 121 current smokers and 105 healthy non-smokers without diabetes and without blood smear-positive P. falciparum. Smokers were defined as individuals who smoke at least 1 cigarette a week and are current smokers (occasional and regular). Baseline demographics, hematological indices, lipid profiles, blood pressure, lactate dehydrogenase activity and haptoglobin phenotypes were determined. RESULTS: Ahaptoglobinemia was found to be highly overrepresented in smokers (odds ratio (OR)=3.1, 95% confidence interval (CI)=1.5-6.5, p=0.002). This observation was not attributed to intravascular hemolysis. Hp2-2 phenotype was found to be under represented in smokers (OR=0.53, 95% CI=0.28-0.99, p=0.05). Smoking was confirmed to augment hypertension (diastolic blood pressure (DBP) and systolic blood pressure (SBP) in male smokers (p=0.0001). Interestingly, however, this appeared not to be related to lipid metabolism, as HDL was elevated (p=0.0007) while LDL was decreased (p=0.004) in smokers within the study population. CONCLUSION: We conclude that smoking is a risk factor for ahaptoglobinemia, which will impact negatively on anti-oxidant defenses and augment pro-oxidative stress effects. PMID- 20720374 TI - Inhibitory effects of cilostazol on proliferation of vascular smooth muscle cells (VSMCs) through suppression of the ERK1/2 pathway. AB - AIM: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and VSMCs. Cilostazol is a phosphodiesterase (PDE) 3 inhibitor that increases intracellular cAMP levels and decreases intracellular Ca(2+) levels, inhibiting platelet aggregation and inducing vasodilatation. Cilostazol is also known to have an inhibitory effect on the proliferation of VSMCs, but the anti-proliferative mechanism of cilostazol in VSMCs has not yet been established. In the present study, we investigated whether the anti-proliferative mechanism of cilostazol is associated with the suppression of extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3 kinase (PI3K) signaling pathways. METHODS: To confirm the anti-proliferative effects of cilostazol on VSMCs, VSMCs were induced to proliferate by serum-induced mitogenesis and then were treated with cilostazol for 24 h. And, to investigate whether the anti-proliferative mechanism of cilostazol in VSMCs involves the suppression of the ERK and PI3K pathways, expression of the phosphorylated forms of ERK1/2, Raf, Akt, and glycogen synthase kinase (GSK)-3 were evaluated by western blot. RESULTS: Cilostazol inhibited VSMC proliferation in a dose dependent manner. Phosphorylated ERK1/2 and Raf were significantly reduced in a dose-dependent manner, whereas phosphorylated Akt and GSK-3 were not changed. CONCLUSION: These results suggest that suppression of the ERK pathway but not the PI3K pathway is an important mechanism in the anti-proliferative effect of cilostazol on VSMCs. PMID- 20720375 TI - Dietary soybean phospholipids increase the oxidative stability of lipids extracted from fish fillets. AB - We previously reported that the feeding of soybean phospholipids to fish increased the storage stability of n-3 polyunsaturated fatty acids (PUFA)-rich fish fillets. In this study, we examined the storage stability of lipids extracted from fish fed a diet containing soybean phospholipids and fish oil. Rainbow trout were divided into two groups, and were fed an either 2.5% soybean phospholipids (test) or no phospholipids (control) containing diet for 4 weeks. Lipids were extracted from fish fillets after the feeding period, and were subjected to an oxidation test. Lipids extracted from the fillets of fish in the test group exhibited lower values of oxygen absorption than those in the control group, and the degradation of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) was inhibited. Higher percentages of DHA and EPA were bound to phosphatidylcholine and phosphatidylethanolamine in the extracted lipids in the test group than in the control group. These results indicate that the oxidative stability of lipids extracted from fish fed soybean phospholipids is high, and that the higher percentages of DHA and EPA in PC and PE may have resulted in the higher stability of the lipids extracted from fish fillet. PMID- 20720376 TI - The mechanism of weight-loss promoting effects of oil heated with vegetable protein. AB - We have previously reported that a soy oil-containing experimental diet (fat-free AIN93G containing oil thermally processed with soybean protein followed by filtration), inhibited body weight increases without any adverse effects when given ad libitum to male Wistar rats for 12 weeks. In the present paper, the mechanism of weight-loss promoting effects was investigated. Fasted 10-week-old rats were fed a slurry composed of AIN93G (fat-free), Cr(2)O(3) (marker), water, and 7 wt% soy oil or fresh oil (control) and sacrificed at 20, 60, 90, 120, 150, 210, 270 or 360 min. The stomach, small intestine, cecum, colon and feces were then collected to determine the distribution of the slurry in the digestive tract. The results indicated that the content was transferred faster from stomach to small intestine in the soy oil group than in the control group. Fecal excretion (derived from a commercial standard diet ingested before slurry administration) in the soy oil group was significantly higher than in the control group. Digestive enzyme activities, lipase, sucrose, and maltose, were not inhibited by soy oil. In addition, feces collected in the 12-week feeding experiment were more in the dry weight and contained higher levels of nitrogen and water in the soy oil group than in the control group, revealing that an increased amount of nutrition was continuously excreted in the former group. The above-described findings suggest that soy oil stimulated peristalsis of the gastrointestinal tract and that colon contents are actively excreted, resulting in safe and steady body weight decreases. PMID- 20720377 TI - Rheological behavior of polyoxyethylene phytosterol-polyoxyethylene cholesterol/tetraethylene glycol monododecyl ether/water systems. AB - We have studied the rheological properties of mixtures of polyoxyethylene (10 mol) phytosterol (PhyEO(10)) and polyoxyethylene (10 mol) cholesterol (ChEO(10)) mixed in different ratios along with tetraethylene glycol monododecyl ether (C(12)EO(4)) surfactants in water. Addition of C(12)EO(4) to the aqueous solution of a mixture of (PhyEO(10) + ChEO(10)) results in one-dimensional micellar growth and formation of viscoelastic solution of entangled wormlike micelles. Steady shear rheological measurements show the Newtonian flow behavior at low shear-rate region and non-Newtonian flow behavior at higher shear-rate for viscous samples. The dynamic rheological data of the viscoelastic samples indicate the plateau modulus (G(o)) increases monotonically with C(12)EO(4) concentration and relaxation time (tau(R)) display a maximum at a composition corresponding to the viscosity maximum. The prepared viscoelastic sample in mixed nonionic surfactant systems has potential applications in cosmetic formulation. PMID- 20720378 TI - Evaluation of detergency using artificially soiled multifiber fabrics. AB - The evaluation of textile detergency was carried out using artificially soiled multifiber adjacent fabric (MFF) composed of six different warp regions. The MFF soiled with model water-soluble, oily or particulate contaminant was cleaned in water, water/ethanol (1/1 in volume ratio), ethanol and n-decane with the stirring as a mechanical action. The detergency of the each fiber region was determined from the change in surface reflectance of the corresponding region due to cleaning. The soil removal was strongly dependent on contaminant, fiber and liquid species, indicating that the detergency was dominated by the dissolution of the contaminant into the washing liquid and the affinity between the contaminant and the fiber surface. The addition of alkali and surfactant to water or the solubilization of water into n-decane considerably increased the soil removal. The experimental results were not in contradiction with common and well known knowledge about textile washing. Therefore, the artificially soiled MFF can be utilized for the detergency evaluation for textiles. PMID- 20720379 TI - A novel synthesis of SO(3)H type gemini surfactant having semifluoroalkyl group as hydrophobic group. AB - In this work, novel SO(3)H type Gemini surfactants having semifluoroalkyl group (RfCH(2)CH-: Rf = C(4)F(9), C(6)F(13), C(8)F(17)) as hydrophobic group were successively synthesized by the radical addition of fluoroalkyl to 1,4-pentadiene using fluoroalkyl iodide and AIBN as initiator, and the following thiocyanization (-SCN), conversion to -SH, and oxidation to SO(3)H as hydrophilic group. Similarly, the common 1+1 type semifluoroalkyl surfactants having SO(3)H were synthesized. Surfactant properties of their sodium salts (cmc, gamma(cmc), pC(20), Gamma(cmc), and A) were investigated by measuring surface tension. As expected, the cmc value of Gemini surfactant whose fluoroalkyl is C(4)F(9) was more than one order of magnitude smaller than that of the corresponding 1+1 type. Other properties also showed the excellent efficiency of Gemini structure to reduce the surface tension. PMID- 20720380 TI - Enzymatic conversion of diacetylated sophoroselipid into acetylated glucoselipid: surface-active properties of novel bolaform biosurfactants. AB - Sophoroselipids (SL) are bolaform biosurafactants which are abundantly produced by microorganisms from renewable resources. In this study, four kinds of bolaform biosurfactants were produced, and these derivatives were chemoenzymatically synthesized from "acid form" diacetylated SL (SLdiAc), which are preferentially produced by Candida floricola TM 1502 which was newly found in our group. The effects of the structure of sugar moiety on their surface-active properties were investigated by surface tension measurement. After microbial production of SLdiAc from oleic acid/glucose, SLdiAc was converted into acetylated glucoselipid (GLAc). Among twelve species of glucosidases, pectinase and pectolyase including polygalacturonase were found to cleave the beta-1,2-glycosidic linked disaccharide, especially pectolyase produced GLAc effectively at 40 degrees C and pH 4.0. The structure of the major component of purified GLAc was assigned as 17- [(beta-D-glucopyranosyl)oxy]-cis-9-octadecenoate 6'-acetate by using NMR analyses, MALDI-TOF/MS and GC-MS. Glucoselipid (GL) without acetyl group was also enzymatically converted from SL obtained from alkaline hydrolysis of SLdiAc. Interestingly, the estimated CMC values of SLdiAc, SL, GLAc, GL indicated almost the same values despite their difference in hydrophilic structure. Although the difference in monosaccaride and disaccharide also did not affect gammaCMC, the presence of acetyl group on sugar moiety was found to lower the gammaCMC value slightly, suggesting that the acetyl group on produced bolaform biosurfactant is likely to play more important role to reduce the free energy of air/water interface. PMID- 20720381 TI - Hepatic function and lipid metabolism are modulated by short-term feeding of cholesterol oxidation products in rats. AB - Dietary cholesterol oxidation products (COPs) modulate various metabolic processes, particularly lipid metabolism. In this study, we observed that dietary COPs perturbed hepatic function, linoleic acid desaturation, and cholesterol catabolism in rats that were fed with diets containing 0.5% COPs for a short duration (7 days). The rats (age, 8 weeks) were fed American Institute of Nutrition (AIN)-purified diets containing 0.5% cholesterol or 0.5% COPs for 7 days. The glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) levels were significantly high in rats fed with dietary COPs, but no such increase was observed in rats fed with dietary cholesterol, thereby indicating that dietary COPs may impair the hepatic function. The mRNA expression levels of Delta6 desaturase in the liver were significantly increased by dietary COPs, while these levels were significantly decreased by dietary cholesterol. However, the mRNA expression level of cholesterol 7alpha-hydroxylase (CYP7A1) in the liver was significantly decreased by dietary COPs and significantly increased by dietary cholesterol. Therefore, dietary COPs may modulate lipid metabolic processes such as linoleic acid desaturation and cholesterol catabolism even when they are consumed for a short duration. Hence, processed animal foods containing COPs should be consumed with caution. PMID- 20720382 TI - Rapid quantitative analysis of sphingolipids in seafood using HPLC with evaporative light-scattering detection: its application in tissue distribution of sphingolipids in fish. AB - Sphingolipids are ubiquitous in all eukaryotic organisms and known to be essential constituents of cellular membranes. Recently, various physiological functions of dietary sphingolipids, such as preventing cancer, improving skin barrier and contributing to central nervous system myelination have been demonstrated. To characterize the sphingolipids from fish as food components, tissue distribution of sphingomyelin and glycosylceramide (ceramide monohexoside, CMH) in fish were determined in this study. We established a rapid, accurate and effective method for separation, purification and determination of sphingolipids by using high-performance liquid chromatography with evaporative light-scattering detector (ELSD-HPLC). Sphingolipids were extracted and quantified from pacific saury (Cololabis saira). Sphingomyelin in different tissues of Cololabis saira ranged from 2.5 +/- 0.2 mg/g to 27.6 +/- 2.1 mg/g, the content in brain was the highest, followed by eyes, and CMH contents were less than 23.0 +/- 2.4 mg/g in all tissues. These results revealed that fish contained CMH and sphingomyelin as same levels as most of the terrestrial organisms and suggested marine organisms could be used as a potential source of precious and useful complex lipids. PMID- 20720383 TI - Incretin-based therapies: review of the outpatient literature with implications for use in the hospital and after discharge. AB - A large percentage of critically ill adult inpatients have type 2 diabetes, which may be undiagnosed or uncontrolled during hospitalization. Hyperglycemia complicates the therapeutic management of inpatients and leads to adverse outcomes, and intensive glycemic control with insulin reduces morbidity and mortality. Insulin therapy, however, is labor-intensive and time-consuming. More important, long-standing protocols such as the sliding scale do not provide adequate glucose control. Although more research is needed to determine the best methods for treating hyperglycemia in-hospital, the importance of achieving better glycemic control while reducing the risk of hypoglycemia has been demonstrated. Post-discharge diabetes care is equally important, as it is essential in improving long-term outcomes after a hospital stay. Hospital care providers can play an important role in effective antihyperglycemic regimens in patients with diabetes prior to discharge. Post-discharge management is a formidable challenge because of the availability of an array of oral antidiabetes agents, including metformin, sulfonylureas, and thiazolidinediones, each with distinct therapeutic and adverse event profiles. Incretin-based therapies offer a potentially useful option for post-discharge therapy, and possibly for inpatient diabetes treatment. Incretins are effective, safe, and well-tolerated; they are easier for patients to use compared with insulin injections (eg, continual glucose monitoring is not required); and they may provide long-term improvement of cardiovascular parameters and beta-cell function. This review examines the challenges to achieving glycemic control in the hospital setting and summarizes clinical data on the efficacy and safety of incretin-based therapies in their use in the hospital and after discharge. PMID- 20720384 TI - Association of seminal plasma motility inhibitors/semenogelins with sperm in asthenozoospermia-infertile men. AB - Seminal plasma motility inhibitors (SPMIs) are proteinase-resistant fragments of semenogelin I and II (Sgs), which are the major proteins of semen coagulum. SPMIs inhibit the motility of spermatozoa, and Sgs are thought to be natural regulators of human sperm function. The mechanism underlying sperm motility regulation and its association with defective motility in infertile men remain unclear. The purpose of this study was to investigate the association between SPMIs and spermatozoa in infertile men with asthenozoospermia. Fifty-four semen samples from 37 asthenozoospermic patients and 17 samples from 9 normal healthy subjects were analyzed. Spermatozoa, washed by Percoll density gradients, were immunostained with anti-SPMI antibody and subjected to flow cytometric analysis. The proportion of spermatozoa labeled with the antibody and the average intensity of fluorescence labeling per spermatozoa were analyzed in relation to the parameters used for semen analysis. A significant negative correlation was found between sperm motility and the proportion (R = -0.68) and intensity (R = -0.38) of labeling. These results suggest that SPMIs remain on the sperm surface after liquefaction. This might account for some disorders of sperm motility observed in infertile men with asthenozoospermia. PMID- 20720385 TI - Assessment of the expression of IRbeta, IRS-1, IRS-2 and IGF-IRbeta in a rat model of intrauterine growth restriction. AB - OBJECTIVE: To investigate glomerular development and expression of insulin and insulin-like growth factor receptors in an experimental model of intrauterine growth restriction (IUGR). MATERIAL AND METHODS: We studied three groups of Sprague-Dawley fetuses: IUGR - restricted by ligation of the right uterine artery; C-IUGR - left horn controls, and EC - external controls (non manipulated). Body and organs were weighed, and glomerular number and volume were analyzed. Expression of IRbeta, IRS-1, IRS-2 and IGF-IRbeta was analyzed in liver, intestine and kidneys by immunoblotting. RESULTS: Organ/body weight ratios were similar. In IUGR, glomerular number and volume were increased compared to C IUGR and EC (p<0.001). In the IUGR liver, increases were found in IGF-IRbeta compared to C-IUGR and EC; IRbeta compared to EC, and IRS-2 compared to C-IUGR. However, decreases in IRbeta were noted in IUGR compared to C-IUGR; IRS-1 compared to C-IUGR and EC, and IRS-2 compared to EC. In IUGR intestine, increases were detected in IRbeta, IRS-1 and IGF-IRbeta compared to C-IUGR and EC. In IUGR kidneys, increases were observed in IRbeta and IGF-IRbeta compared to C-IUGR and EC, and IRS-1 compared to EC. Decreased IRS-2 in the intestine and kidney were noticed in IUGR compared to C-IUGR and EC. CONCLUSION: IUGR fetuses had less glomeruli and alterations in insulin receptors, which may be associated with an increased risk of disease occurrence in adulthood. PMID- 20720386 TI - Mobile phones: a role in teaching dermatology? PMID- 20720387 TI - Pyoderma gangrenosum of the eyelid: report of two cases and review of the literature. AB - Pyoderma gangrenosum (PG) of the eyelid is extremely rare, and its proper management is essential for the preservation of visual function. Here, we report 2 cases of PG of the eyelid with intraorbital involvement. In both cases, the skin and intraorbital lesions improved after systemic immunosuppressive therapies; however, corneal perforation occurred in 1 case. In order to assess the clinical features of PG of the eyelid and to obtain clues for optimal treatment, we reviewed 15 well-documented cases in the literature, including the present cases. Corneal perforation occurred in 4 cases and defective ocular motility in 1 case. Three patients eventually underwent enucleation of the affected eye. Our cases and the literature review clearly indicate that MRI is a powerful tool for evaluating the extent of extracutaneous PG lesions around the eye and that early diagnosis and immediate immunosuppressive therapy are crucial for the preservation of visual acuity. PMID- 20720388 TI - Does basal cell carcinoma belong to the spectrum of sorafenib-induced epithelial skin cancers? AB - The multikinase inhibitor sorafenib is therapeutically used in various malignancies. Multiple cutaneous side effects are well described but recent reports indicated a possible association of epithelial skin cancer growth during sorafenib therapy. To our knowledge, few cases of actinic keratoses and variants of squamous cell carcinomas associated with sorafenib have been published. We report 2 patients who developed a basal cell carcinoma (BCC) while treated with sorafenib. Interestingly BCC is a tumor which has not been described yet in association with sorafenib therapy. The tumors were excised completely. After termination of sorafenib treatment, no new BCCs or other epithelial skin cancers occurred. There is accumulating evidence in the literature that sorafenib and possibly other targeted agents are associated with an increased occurrence of epithelial skin cancers. These observations are summarized here and complemented by the new observation that also BCCs might be associated with sorafenib therapy. The pathogenetic mechanisms are unclear so far but induction of the mitogen activated protein kinase pathway in wild-type RAF cells by RAF inhibitors might play a role. Patients should be informed of this possible side effect and undergo regular dermatological controls before and during sorafenib therapy. PMID- 20720389 TI - Prenatal diagnosis of persistent urogenital sinus with duplicated hydrometrocolpos and ascites--a case report. AB - We report a successful case of persistent urogenital sinus associated with a duplicated nonsyndromic form of hydrometrocolpos and ascites diagnosed prenatally. Though urogenital malformations are extremely rare and variable in presentation, the conjugation of those anomalies in a newborn is reported here for the first time. Prenatal ultrasound diagnosis was suspected at 25 weeks' gestation and MRI imaging supported the diagnosis. Periodic ultrasound surveillance was conducted until birth at 35 weeks' gestation by cesarean section. The presumptive diagnosis was confirmed after birth. One month later, the newborn underwent reconstructive surgical intervention with good outcome. PMID- 20720390 TI - Autoimmune bullous skin diseases occurring under anti-tumor necrosis factor therapy: two case reports. AB - BACKGROUND: Anti-tumor necrosis factor (TNF) agents are increasingly being used for a rapidly expanding number of rheumatic and systemic diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The use of anti-TNF agents has been associated with more and more cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. OBSERVATIONS: We report 2 cases of autoimmune bullous skin disease occurring in patients undergoing TNF-targeted therapy: a bullous pemphigoid and a pemphigus foliaceus. Both patients were treated by anti-TNF agents for rheumatoid arthritis and showed improvement following interruption of that treatment. Here, we discuss the relationship between anti-TNF therapy and the occurrence of autoimmune bullous disease. CONCLUSION: Anti-TNF agents should be considered as a potential cause of drug-induced autoimmune bullous skin disease. PMID- 20720391 TI - Activin A in carcinoid heart disease: a possible role in diagnosis and pathogenesis. AB - BACKGROUND/AIMS: Carcinoid heart disease (CHD), a complication of neuroendocrine tumors (NETs), is characterized by right heart fibrotic lesions. Though serotonin is likely involved, the pathogenesis of CHD remains unclear. Cytokines and growth factors with fibrogenic properties may play a role. We sought to examine the relationship between plasma levels of fibrogenic cytokines and growth factors and CHD, both to provide further insight into possible biomarkers of CHD as well as into the possible pathogenesis of CHD. METHODS: Plasma samples obtained from 71 patients with NETs and 18 controls were analyzed using enzyme immunoassays. All patients underwent echocardiography. RESULTS: 15 patients (21%) had CHD, all of whom had carcinoid syndrome compared to 82% of those without CHD. CHD patients were older (p = 0.01), had larger (p = 0.007) and more numerous liver metastases (p = 0.04), and had elevated 24-hour urinary 5-hydroxyindoleacetic acid (U-5HIAA) (p = 0.03) and serum chromogranin A levels (p = 0.02). CHD patients had higher plasma levels of C-reactive protein (p = 0.03), osteoprotegerin (p = 0.005), and activin A (p = 0.005) than patients without CHD. A significant direct correlation between activin A and U-5HIAA levels was observed in the total patient group (r = 0.30, p = 0.02). Activin A >=0.34 ng/ml (odds ratio (OR) 5.35 [1.01; 28.17], p = 0.048) and age >=69.5 (OR 6.10 [1.60; 23.24], p = 0.008) were independent predictors of CHD. Activin A levels were elevated to the same degree in both early and advanced CHD. Activin A >=0.34 ng/ml had 87% sensitivity and 57% specificity for detecting CHD (p = 0.006). CONCLUSION: Elevated plasma activin A levels are associated with the presence of CHD. PMID- 20720392 TI - Cross-cultural considerations in administering the center for epidemiologic studies depression scale. AB - BACKGROUND: Cultural biases may affect the individual responses to questionnaires for depression and thus confound the international or multiethnic researches on depression. OBJECTIVE: We compared the diagnostic accuracy of the Center for Epidemiologic Studies Depression Scale (CES-D) for major depressive disorder (MDD) in late life between Korean and US Caucasian elderly. METHODS: This study included 332 US Caucasian MDD patients, 116 Korean MDD patients, 125 US Caucasian nondepressed subjects and 700 Korean nondepressed subjects. Differential item functioning and factor analyses were conducted to examine the differences in the response patterns to the CES-D between the US Caucasian and Korean elderly. Diagnostic accuracy of the CES-D for MDD was compared using the area under the receiver-operating characteristic curves (AUC). RESULTS: The Korean elderly were more likely to endorse 6 items compared to the US Caucasians, and the US Caucasian elderly were more likely to endorse 5 items compared to the Koreans. The factor solutions from both ethnic groups were not comparable since the congruence coefficient for the second factor was below 0.46 and that for the first factor did not reach 0.90. The AUC of the CES-D for MDD in Koreans (AUC = 0.850, 95% CI = 0.801-0.899) was significantly smaller than that in US Caucasians (AUC = 0.973, 95% CI = 0.960-0.987), and the optimal cutoff score of the CES-D in the Korean elderly (21/22) was 2 times higher than that in the US Caucasian elderly (10/11). CONCLUSION: Cross-cultural issues may significantly influence the diagnostic accuracy of depression questionnaires and thus should be considered more carefully than before in both clinical and research settings on multiethnic populations. PMID- 20720393 TI - Addition of color Doppler to the routine obstetric sonographic survey aids in the detection of pulmonic stenosis. AB - OBJECTIVE: Most fetuses with congenital heart disease (CHD) occur in women that are not at increased risk, and since it is impractical to perform detailed fetal echocardiography on everyone, detection of CHD relies mainly on routine second trimester fetal anatomic surveys. We therefore attempted to improve the detection rate of CHD at the time of routine second trimester obstetrical sonography in low risk patients. METHODS: This was a retrospective review of an 18-month period in which color Doppler was added to the standard grey scale evaluation of the fetal heart at the time of our routine second trimester anatomic surveys that we performed on fetuses at low risk for CHD. Cases in which CHD was suspected were reviewed with special attention to those in which abnormalities on color Doppler were the primary finding. RESULTS: CHD was suspected in 17 of 1,766 (1%) routine fetal anatomic surveys that we performed between 16 and 22 weeks. There were 13 cases with findings on grey scale, and 4 cases (24%) that relied on findings with color Doppler, as the grey scale evaluation was normal or near normal. Of these 4 cases, 3 had critical pulmonic stenosis requiring balloon valvuloplasty shortly after birth; the fourth case had a mildly dysplastic pulmonic valve that did not require intervention in the immediate newborn period. CONCLUSIONS: The addition of color Doppler evaluation of the fetal heart to routine obstetrical sonographic structural surveys in low-risk patients aids in the detection of pulmonic stenosis. PMID- 20720394 TI - DNA methylation patterns of metaphase chromosomes in human preimplantation embryos. AB - We performed a stage-by-stage study of DNA methylation patterns in metaphase chromosomes from blastomeres of triploid and abnormal diploid human embryos. QFH banded homologous parental chromosomes differ in their DNA methylation patterns at the metaphase of the 1st cleavage division. Chromosomes of both parental genomes are gradually demethylated at subsequent cleavages, undergoing hemimethylation in 2-cell embryos. At the 4-cell stage hypomethylated chromosomes initially appear and are further registered until the blastocyst stage. The proportion of hemimethylated and hypomethylated chromosomes varies between the blastomeres since the 4-cell stage with no preference for certain chromosomes to be hemi- or hypomethylated demonstrates random segregation of hypomethylated, undermethylated and methylated chromatids during cell cleavage. By the blastocyst stage the chromosomes acquire band- and, thus, chromosome-specific methylation patterns, with 5-methylcytosine-rich DNA preferentially accumulated in R- and T bands and in the short arms of acrocentric chromosomes. Thus, demethylaton and remethylation of parental genomes of human embryos proceeds in the same manner from the 1st metaphase stage up to the blastocyst. These processes involve all chromosomes and all bands from each chromosome and lead to establishment of chromosome-specific DNA methylation patterns by the blastocyst stage with no differences between homologous chromosomes. PMID- 20720395 TI - Molecular cytogenetic characterization of the genome organization of the 6-banded armadillo (Euphractus sexcinctus). AB - Xenarthra, as the probable earliest offshoot of the placental tree, represents a key taxon for understanding mammalian phylogeny. To gain further insight into the chromosomal evolution and genome organization of the xenarthrans, we have established the first genome-wide comparative chromosome map between human and the 6-banded armadillo (Euphractussexcinctus, 2n = 58), a basal species on the Xenarthra branch, by reciprocal cross-species chromosome painting. In total, 22 human autosomal paints revealed 41 homologous segments in the euchromatic genome of E. sexcinctus. Our results provide further support for the notion that the 2 human homologous segmental associations, i.e. HSA 2/8 and 7a/10p, could constitute the synapomorphies that unite the xenarthrans. Moreover, we propose that the putative ancestral Xenarthra karyotype closely resemble the 2n = 54 karyotype of the E. sexcinctus, consisting of the equivalents of HSA1p, 1q, 2a, 2b, 2c/8c, 3/21, 4a, 4b/8b, 5, 6a, 6b, 7a/10p, 7b/16p, 8a, 9, 10q, 11, 12a/22a, 12b/22b, 13, 14/15, 16q/19q, 17, 18, 19p, 20, and X. In addition, we have analysed the C-banding patterns of E. sexcinctus, and cloned, FISHmapped and sequenced 7 novel repetitive DNA segments, providing further information on the complexity of genome architecture of E. sexcinctus. PMID- 20720396 TI - Trichilemmal cyst nevus with a sebaceous nevus component. AB - A 23-year-old man with a typical trichilemmal cyst nevus is reported. This recently described disorder is sufficiently characteristic to differentiate it from sebaceous nevus, nevus comedonicus, porokeratotic eccrine nevus, nevus corniculatus, follicular basaloid hamartoma, Munro's nevus and Gardner's syndrome. PMID- 20720397 TI - No neocentric activity on Aegilops markgrafii chromosome E. AB - Classical neocentromeres, proven mainly in Poaceae species, cause meiotic drive in higher plants. Here I present data indicating that the morphological stretching of a chromatin domain at the long arm of Aegilops markgrafii chromosome E during meiosis is not due to a supposed neocentric activity. The stretching is visible at the alien univalent in metaphase I and anaphase I pollen mother cells of Triticum aestivum--Ae. markgrafii monosomic addition line E and at one univalent of the 49-chromosome-containing plants containing the haploid Ae. markgrafii genome added to wheat. The absence of both centromeric histone variant CENH3 and attachment of spindle fibers, proven by immunostaining with antibodies against CENH3 and tubulin, respectively, revealed that the univalent elongation of chromosome E is not caused by a classical plant neocentromere. PMID- 20720398 TI - Sequence analysis and mapping of the Sry gene in species of the subfamily Arvicolinae (rodentia). AB - The rodent subfamily Arvicolinae, which contains about 125 species, presents some interesting exceptions concerning Sry, the sex determining gene in mammals. In some species multiple Sry copies have been described on the Y chromosome and in the Iberian vole, Microtus cabrerae, several Sry sequences have been cloned and mapped not only on the Y but also on the X chromosome. Here we present a comparative analysis of Sry sequences from a total of 22 species. Our study demonstrates for the first time that for most North American species, as previously reported for the European species, multiple copies of the Sry gene exist on the Y chromosome. Furthermore, we have sequenced and analyzed the full sequence of Sry from several European species, showing that the sequence and structure of the gene in this group of species present the main features described for Sry in other mammals. Finally, FISH analyses on some of these species demonstrated that all Sry sequences, despite their functional status, mapped on the euchromatic short arm of the Y chromosome. PMID- 20720399 TI - Choose your country to preserve your quality of life. PMID- 20720400 TI - Regional variation in health status among chronic obstructive pulmonary disease patients. AB - BACKGROUND: Little is known about geographic differences in health status among patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: The aim of this study was to examine regional variations in self-reported health status of COPD patients at 7 Veterans Affairs clinics. METHODS: The Ambulatory Care Quality Improvement Project was a multicenter, randomized trial conducted from 1997 to 2000 that evaluated a quality improvement intervention in the primary care setting. Four thousand and nine participants with COPD (age >=45 years) completed the Seattle Obstructive Lung Disease Questionnaire (SOLDQ) and 2,991 also completed the Medical Outcomes Study 36-item short form (SF-36). The unadjusted maximal difference in health status scores is reported as the ratio of the highest and lowest site prevalence. We report the maximal site difference in mean health status scores after adjusting for demographics, comorbidities, utilization, medication use and clinic factors. RESULTS: Subjects were predominantly older (66.5 +/- 9.2 years) Caucasian (83.2%) men (97.9%). After adjustment, the maximal site difference for each health status score was significant (p < 0.01) but larger for the SOLDQ (physical 11.2, emotional 9.7, coping skills 7.6) than for the SF-36 (physical component summary 4.7, mental component summary 2.6). Most of the health status variation was explained by individual or clinic level factors, not clinic site. CONCLUSIONS: Our models explained <30% of variation in health status measures; therefore, future studies should consider additional predictors of health status such as physical performance, social determinants of health, COPD treatment and environmental factors. Despite its limitations, this study suggests a need to consider regional differences in health status when comparing COPD health outcomes in diverse geographic areas. PMID- 20720401 TI - An intergenerational approach in the promotion of balance and strength for fall prevention - a mini-review. AB - The risk of sustaining a fall is particularly high in children and seniors. Deficits in postural control and muscle strength either due to maturation, secular declines or biologic aging are two important intrinsic risk factors for falls. During life span, performance in variables of static postural control follows a U-shaped curve with children and seniors showing larger postural sway than healthy adults. Measures of dynamic postural control (i.e. gait speed) as well as isometric (i.e. maximal strength) and dynamic muscle strength (i.e. muscular power) follow an inverted U-shaped curve during life span, again with children and seniors showing deficits compared to adults. There is evidence that particularly balance and resistance training are effective in counteracting these neuromuscular constraints in both children and seniors. Further, these training regimens are able to reduce the rate of sustaining injuries and falls in these age groups. An intergenerational intervention approach is suggested to enhance the effectiveness of these training programs by improving compliance and increasing motivation of children and seniors exercising together. Thus, the objectives of this mini-review are: (1) to describe the epidemiology and etiology of falls in children and seniors; (2) to discuss training programs that counteract intrinsic fall risk factors by reducing the rate of falling, and (3) to present an intergenerational approach that has the potential to make training programs even more effective by including children and seniors together in one exercise group. PMID- 20720402 TI - Using targeted spirometry to reduce non-diagnosed chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is increasing worldwide and thus its associated morbidity and mortality. However, COPD often goes undiagnosed. OBJECTIVES: We evaluated the rate of non-diagnosed irreversible airway obstruction (AO) and characterized this patient group. We further assessed the possible effects of conducting targeted spirometry in a population sample in Salzburg, Austria, as part of the Burden of Obstructive Lung Disease (BOLD) study. METHODS: 1,258 adults >=40 years of age completed a questionnaire and performed spirometry before and after bronchodilator therapy (post-BD). Irreversible AO was defined as post-BD FEV(1)/FVC below the lower limit of normal; we used the FEV(1)% predicted (pred.) to further grade the disease. Participants without a physician diagnosis of COPD who reported respiratory symptoms and a history of risk factors (ever smoking or occupational risk) were defined as eligible for targeted spirometry. RESULTS: 85.9% (171/199) of the participants with irreversible AO did not report a prior diagnosis of COPD. Non diagnosed AO was inversely related to severity, age, self-reported prior respiratory diseases and cough as a respiratory symptom. 343 participants were eligible for targeted spirometry and irreversible AO was present in 86 (25.1%) participants. Therefore, targeted spirometry could reduce the underdiagnosis of irreversible AO of any severity by 50.3% (86 of 171). The diagnosis of 1 person with FEV(1) <80% pred. would require spirometry in 8.4 subjects (95% confidence interval 6.2-11.1). CONCLUSION: Although several factors are associated with non diagnosed AO, spirometry in individuals with respiratory symptoms and exposure to risk factors could reduce undiagnosed irreversible AO by half. PMID- 20720403 TI - Response to dasatinib in a patient with concomitant chronic myeloid leukemia and chronic lymphocytic leukemia. AB - While chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are common diseases in the elderly, they rarely occur simultaneously in the same patient. Here we present the case of a 77-year-old patient diagnosed with CML in the chronic phase who showed an optimal response to 400 mg/day of imatinib. This patient progressed to Binet B-CLL with an 11q22.3 deletion and CD38 positivity in the 4th month of treatment. During the follow-up, his lymphocyte number doubled in <6 months. Based on previous reports, dasatinib was chosen instead of imatinib. After 6 months of treatment with 100 mg/day of dasatinib, the patient demonstrated a partial response, characterized by the regression of lymph node enlargement, a hemoglobin level of 10.7 g/dl, neutrophils of 1.7 * 10(9)/l, a 82% reduction in the lymphocyte number and an increase in cytotoxic CD8+ and large granular lymphocytes. This partial response has persisted to the present time. While little data have been published regarding the in vitro effect of dasatinib monotherapy for CLL, this case report provides some evidence of the clinical activity of dasatinib in CLL. PMID- 20720404 TI - Effects of paricalcitol and enalapril on atherosclerotic injury in mouse aortas. AB - AIMS: This study investigated the protective effect of vitamin D analog paricalcitol combined with angiotensin-converting enzyme inhibitor (enalapril) on aortic oxidative injury in atherosclerotic mice. METHODS: Female mice were treated for 16 weeks as follows: (1) ApoE deficient + vehicle, (2) ApoE deficient + paricalcitol (200 ng 3 times a week), (3) ApoE deficient + enalapril (30 mg/l in drinking water), (4) ApoE deficient + paricalcitol + enalapril, and (5) wild type controls. RESULTS: ApoE-deficient mice developed hypertension which was prevented by enalapril or enalapril + paricalcitol treatment but not by paricalcitol treatment. Histology showed atherosclerotic plaque in the aorta of ApoE-deficient mice which was prevented by paricalcitol, enalapril, and paricalcitol + enalapril treatments. Aortic malondialdehyde levels, NADPH oxidase subunit p22(phox), manganese-superoxide dismutase (Mn-SOD), inducible nitric oxide synthase, monocyte chemoattaractant protein-1, tumor necrosis factor (TNF) alpha, and cyclooxygenase-2 protein expressions increased, whereas glutathione levels, CuZn-SOD, and endothelial protein expressions decreased in ApoE-deficient mice compared to controls. Treatment with paricalcitol and enalapril alone or in combination protected the inflammatory and oxidative endothelial injury of the aorta in atherosclerotic mice. CONCLUSION: Combination therapy affords greater protection against aortic inflammatory and oxidative injury in atherosclerosis than monotherapy. PMID- 20720405 TI - Heritability of renal function and inflammatory markers in adult male twins. AB - BACKGROUND: Loss of renal function is accompanied by a progressive increase in markers of inflammation; it is unknown whether they share common genetic pathways. STUDY DESIGN: We evaluated the shared heritability of estimated glomerular filtration rate (eGFR) and markers of inflammation and endothelial activation in 524 twin males from the Vietnam Era Twin Registry; 9 twins were excluded due to incomplete or incorrect data. Models were adjusted for age, race, body mass index, smoking, hypertension, diabetes mellitus, prior coronary artery disease and intercurrent medications. RESULTS: The mean eGFR was 89 +/- 13 ml/min/1.73 m2 (range 35-146); eGFR, intracellular adhesion molecule (ICAM) and TNF-alpha receptor (TNF-alphaR) were moderately heritable (all ~50%), while IL-6 receptor (IL-6R) and P-selectin were highly heritable (68 and 76%, respectively). IL-6R and TNF-alphaR showed a significant inverse association with eGFR (p = 0.04 and p < 0.0001) while the association with ICAM and P-selectin was direct (p = 0.001 and p = 0.06). Bivariate structural equation models showed that the association between eGFR and biomarkers was due to unique environmental factors and there were no shared genetic pathways. CONCLUSION: We found no shared genetic pathways between renal function and inflammation. Thus, increased inflammation represents a response to declining renal function rather than being a mechanism contributing to renal deterioration. PMID- 20720407 TI - Contribution of angiogenic factors in a rat model of pre-eclampsia. AB - BACKGROUND/AIMS: Pre-eclampsia is a disorder that results in significant feto maternal complications with yet no definitive pharmacologic intervention. One postulated etiologic mechanism is an imbalance between circulating pro-angiogenic and anti-angiogenic factors. We investigated these factors sequentially throughout pregnancy (19-21 days) in our rat model of pre-eclampsia, which involves the imposition of excessive volume expansion. METHODS: We evaluated the status of the pro-angiogenic and anti-angiogenic factors at the following time points: 3-5, 7-10 and 17-20 days of gestation. RESULTS: We have previously determined that the urinary excretion of the circulating bufodienolide, marinobufagenin, is elevated at the 3- to 5-day time period, prior to the advent of hypertension and proteinuria. At 3-5 days of pregnancy, there was no evidence of angiogenic imbalance in the normal pregnant (NP) and 'pre-eclamptic' (PDS) rats. At the 7- to 10-day time point, plasma PlGF was greater in the NP rats than in the PDS group (p < 0.05). The plasma sFlt-1/PlGF ratio in the PDS animals was greater than that in the NP rats (p < 0.05). The placental sFlt-1 and sFlt-1/PlGF ratio were greater in the PDS rats than in NP rats (p < 0.05). These changes were also present at the 17- to 20-day time point in both plasma and placenta. The administration of resibufogenin, an antagonist of marinobufagenin, early in pregnancy, prevented angiogenic imbalance. CONCLUSION: We conclude that angiogenic imbalance plays a role in the pathogenesis of pre-eclampsia in this rat model. Furthermore, the earliest event in the pathogenetic sequence appears to be the secretion and elaboration of marinobufagenin. PMID- 20720408 TI - Horizontal semicircular canal benign paroxysmal positional vertigo: effectiveness of two different methods of treatment. AB - The aim of this study is to compare the results obtained using 2 methods of treatment for horizontal semicircular canal benign paroxysmal positional vertigo (HSC-BPPV): the barbecue maneuver + forced prolonged position (FPP) versus the Gufoni maneuver. In a randomized prospective clinical trial, we recruited 147 patients affected by HSC-BPPV. The primary outcome was the absence of vertigo and nystagmus upon application of the supine roll test during the follow-up examination. A statistical evaluation was performed in order to assess whether any parameters (e.g. age, duration of nystagmus and symptoms) could influence in any way the results obtained with the 2 methods of treatment. One hundred and three of the 147 patients affected by HSC-BPPV had the geotropic form and 44 had the apogeotropic type. We were able to transform 29 cases of HSC-BPPV from apogeotropic to geotropic. Finally, we obtained a group of 112 patients who were randomized either to the barbecue + FPP procedure (54 patients) or to the Gufoni maneuver (58 patients). The most evident result is the higher percentage of success (statistically significant) with the Gufoni maneuver at the first session of treatment (86 vs. 61%). The final control showed that 44 out of 54 (81%) patients treated with the barbecue maneuver + FPP were symptom free compared to 54 out of 58 (93%) treated with the Gufoni maneuver. Both the barbecue maneuver + FPP and the Gufoni maneuver are valid methods for treating HSC-BPPV (geotropic forms). However, our results also indicate that the Gufoni maneuver has a significant advantage: the success rate shown at the follow-up, although without statistical significance, is undoubtedly higher (93 vs. 81%). This result, together with the fact that it is very easy to perform and that patient compliance is better, make the Gufoni maneuver the method of choice in HSC-BPPV treatment. PMID- 20720406 TI - Blockade of osteopontin inhibits glomerular fibrosis in a model of anti glomerular basement membrane glomerulonephritis. AB - BACKGROUND: In our rat model for anti-GBM GN, severe fibrosis follows glomerular inflammation. A potential role of extracellular matrix protein osteopontin (OPN) in glomerular fibrosis was investigated. METHODS: Neutralizing OPN antiserum or control normal serum was injected into the experimental rats at late inflammatory/early fibrotic stage. Glomerular inflammation and fibrosis were determined. RESULTS: OPN antiserum treatment had little effect on glomerular inflammation. However, the antiserum treatment resulted in a significant reduction in number of fibrotic glomeruli (50% of the controls). Histology observation showed that fibrotic tissue in glomeruli of the antiserum treated rats was mild and poorly developed. OPN antiserum treatment resulted in downregulated glomerular expression of collagen 1alpha1; collagen deposition in the antiserum treated rats reduced to <30% of that for normal serum controls. CONCLUSION: Neutralization of OPN inhibited progression of fibrosis in vivo when given at early fibrotic stage. Thus, OPN may be a therapeutic target for glomerular fibrosis. PMID- 20720409 TI - Associations of local release of inflammatory biomarkers during carotid artery stenting with plaque echogenicity and calcification. AB - BACKGROUND AND PURPOSE: The purpose of this study is to evaluate whether release of inflammatory markers locally from an atherosclerotic plaque after carotid artery stenting (CAS) is associated with plaque echogenicity and calcification. METHODS: The study consisted of 36 patients with 42 severely stenotic carotid arteries who underwent CAS with the distal balloon occlusion. Before CAS, the plaque echogenicity was evaluated by acoustic densitometry and the distribution of calcification was investigated. Systemic blood samples were obtained from the aorta before CAS and local blood samples under distal balloon occlusion just after CAS. RESULTS: The interleukin (IL)-6 and osteopontin (OPN) levels markedly increased at the plaque site in comparison to the systemic values (p < 0.001). Moreover, the local IL-18 level slightly increased compared to the systemic values. In contrast, the local high-sensitive C-reactive protein level slightly decreased. The local matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP-1 and soluble intercellular adhesion molecule 1 levels were not changed. The levels of local IL-6 release were associated with lower echogenicity and less calcification (p < 0.05), while those of local OPN release were independent of plaque characteristics. CONCLUSIONS: Our observations show that IL-6 and OPN were released from carotid stenotic lesions after CAS. The association between high levels of IL-6 release and lower plaque echogenicity and less plaque calcification suggests that IL-6 is prone to be released from vulnerable carotid plaques after CAS. PMID- 20720410 TI - Detection of paroxysmal atrial fibrillation in acute stroke patients. AB - BACKGROUND: Atrial fibrillation (AF) is a frequent cause of stroke, but detecting paroxysmal AF (pAF) poses a challenge. We investigated whether continuous bedside ECG monitoring in a stroke unit detects pAF more sensitively than 24-hour Holter ECG, and tested whether examining RR interval dynamics on short-term ECG recordings using an automated screening algorithm (ASA) for pAF detection is a useful tool to predict the risk of pAF outside periods of manifest AF. METHODS: Patients >60 years with acute ischemic stroke or transient ischemic attacks (TIA) were prospectively enrolled unless initial ECG revealed AF or they had a history of paroxysmal or persistent AF. ASA was performed on 1- to 2-hour ECG recordings in the emergency room and patients were classified into 5 risk categories for pAF. All patients underwent continuous bedside ECG monitoring for >48 h. Additionally, 24-hour Holter ECG was performed. RESULTS: 136 patients were enrolled (median age: 72 years, male: 58.8%). In 29 (21.3%), pAF was newly diagnosed by continuous bedside ECG monitoring. pAF increased with age (p = 0.031). Median time to first pAF detection on continuous bedside ECG monitoring was 36 h. In 16 patients, pAF was detected by continuous bedside ECG monitoring prior to the performance of 24-hour Holter ECG. Thirteen of the remaining patients were pAF positive on continuous bedside ECG monitoring, but 24-hour Holter detected only 3 patients. Accordingly, the sensitivity of 24-hour Holter was 0.23. Sensitivity of higher-risk categories of ASA compared to continuous bedside ECG monitoring was 0.72, and specificity 0.63. CONCLUSION: Continuous bedside ECG monitoring is more sensitive than 24-hour Holter ECG for pAF detection in acute stroke/TIA patients. Screening patients for pAF outside AF episodes using ASA requires further development. PMID- 20720411 TI - Ischemic stroke in young Asian women: risk factors, subtypes and outcome. AB - BACKGROUND AND OBJECTIVE: The objective of our study was to describe risk factors, mechanisms and outcome of young Asian women with ischemic stroke. METHODS: Twelve tertiary-care centers in 8 Asian countries participated. Women aged 15-45 years were included if they had an ischemic stroke supported by neuroimaging. Data on age, risk factor history, stroke mechanism and discharge status were collected. RESULTS: A total of 958 subjects were included, their mean age was 34 years. Large-vessel thrombosis comprised 24%, cerebral venous thrombosis 21%, cardioembolism 19% and small-vessel thrombosis 15%. The stroke risk factors included hypertension (29%), diabetes (14%), pregnancy (11%), valvular heart disease (10%) and cigarette smoking (3%). Anemia was found in 42%, and mortality was 4%; at discharge, 17% had modified Rankin score (mRS) >4 and 83% mRS 0-3. CONCLUSION: Unlike among Caucasians, large-vessel thrombosis, cerebral venous thrombosis and cardioembolism are common among young Asian women with stroke. A high proportion are pregnancy-related. More studies are needed. PMID- 20720412 TI - Health-related quality of life in patients with subarachnoid haemorrhage. AB - BACKGROUND: Aneurysmal subarachnoid haemorrhage (SAH) is a devastating disease with high mortality and disability. The data from large longitudinal studies on health-related quality of life (HRQoL) in patients with SAH are limited. The objective was to investigate HRQoL in patients after SAH and to identify predictors of HRQoL. METHODS: 113 patients with aneurysmal SAH were assigned to either neurosurgery (n = 57) or endovascular coiling (n = 56). Clinical assessments (Barthel Index, modified Rankin Scale) and evaluation of HRQoL [36 Item Short-Form Survey, EuroQol (EQ5D), EQ visual analogue scale (EQ VAS)] were performed at discharge, and at 6 and 12 months of follow-up. Independent predictors of HRQoL were determined using multiple regression analysis. RESULTS: HRQoL in SAH patients was considerably reduced compared to the normal population. At discharge, 92.2% of the patients had moderate or severe problems on the EQ5D. The EQ VAS score was 57.8 +/- 19.3. However, HRQoL still showed improvement from 3 months up to 1 year. At 12 months after SAH, the EQ VAS score was approximately 12-14% higher than at discharge. The independent predictors of decreased HRQoL included female gender, severe SAH, functional disability, depression, a lower level of education and the lack of a stable partnership. CONCLUSIONS: The long term HRQoL outcome after SAH is unfavourable. HRQoL outcome measures should be included in future studies to provide better evidence of the long-term outcomes after SAH. In addition, the independent determinants of HRQoL identified in this study should be considered in the healthcare programmes aimed at increasing the HRQoL in SAH survivors. PMID- 20720413 TI - Coexisting small vessel disease predicts poor long-term outcome in stroke patients with intracranial large artery atherosclerosis. AB - BACKGROUND AND PURPOSES: Until now, limited data are available about the potential effect of coexisting small vessel disease (SVD) on the long-term outcome of stroke patients with intracranial large artery atherosclerosis (ILAA). METHODS: A prospective study was performed on 293 patients with symptomatic ILAA, who were divided into 4 groups (group I, single intracranial large artery atherosclerosis (SILAA) without SVD; group II, multiple intracranial large arteries atherosclerosis (MILAA) without SVD; group III, SILAA with SVD; group IV, MILAA with SVD) and followed up for recurrent stroke or death. RESULTS: The 3 year cumulative risks of recurrent stroke were 18% for SILAA without SVD, 38% for MILAA without SVD, 21% for SILAA with SVD and 34% for MILAA with SVD. The 3-year cumulative risks of death were 6, 7, 20 and 22%, respectively. Compared with SILAA without SVD, more recurrent stroke occurred in MILAA without SVD (log-rank 3.83; p = 0.050) and MILAA with SVD (log-rank 7.79; p = 0.014), and the higher risk of death (log-rank 9.472; p = 0.002) was found in group MILAA with SVD. A Cox proportional-hazards regression model showed that MILAA with SVD may be a predictor of recurrent stroke (hazard ratio 2.001; 95% CI 1.108-3.934; p = 0.044), and a borderline predictor for death (hazard ratio 3.180; 95% CI 0.895 10.987; p = 0.073). CONCLUSION: Coexisting SVD is very common and may predict poor outcome in stroke patients with symptomatic ILAA. PMID- 20720414 TI - Functional outcome after stroke in patients with aphasia and neglect: assessment by the motor and cognitive functional independence measure instrument. AB - BACKGROUND: The role of neuropsychological deficits in predicting functional outcome in patients with aphasia and neglect at the end of rehabilitation after stroke has been poorly investigated. This was the aim of this prospective study evaluated using a Functional Independence Measure (FIM) instrument. METHODS: Patients with a primary diagnosis of cerebrovascular accident [125 patients with aphasia, 45 with neglect and 131 without either aphasia or neglect (WAN)] were enrolled. Backward multiple linear regression analysis was used to predict motor and cognitive FIM, discharge destination, and length of stay. The independent variables were age, gender, aphasia, stroke type, stroke lesion size, comorbidity, bladder catheter, stroke severity, trunk control test, initial motor FIM, and committed caregiver identified on admission to rehabilitation. RESULTS: At the end of rehabilitation, patients with neglect had significantly lower final motor FIM scores and lower daily efficiency improvement in motor FIM scores compared with those with aphasia (both p < 0.001) and WAN (both p < 0.001). Patients with aphasia showed lower final cognitive FIM scores compared with those with neglect (p < 0.001) and those without deficits (p < 0.001). Neglect was a predictor of final motor FIM (beta = -0.24) and efficiency in motor FIM (beta = 0.29), while aphasia was a predictor of final cognitive FIM (beta = -0.54). Neglect and aphasia did not differ and were not predictors of discharge destination and length of stay. CONCLUSIONS: Patients with neglect have lower motor FIM scores if compared with those with aphasia, while patients with aphasia have lower cognitive FIM scores. Neglect is a predictor of motor FIM, while aphasia is a predictor of cognitive FIM scores. PMID- 20720415 TI - Striking increases in carotid artery wall thickness in healthy subjects. AB - BACKGROUND: Atherosclerosis has long been thought to develop over time in a linear manner from gradual wall thickening to advanced thick lesions. However, evidence has emerged indicating a phasic rather than linear progression with time. A major reason for this non-linear pattern appears to be the occurrence of hemorrhages in the arterial wall, although data on this issue are still scarce. We studied the occurrence of temporarily impressive thickenings of the carotid arterial wall in a cohort of healthy postmenopausal women who were followed up for 3 years with regular carotid ultrasound examinations. METHODS: The women were the European participants of a randomized placebo-controlled trial into the effect of hormone replacement therapy on progression of carotid intima-media thickness (CIMT). For a period of 3 years, the women underwent a standardized carotid ultrasound protocol every 6 months. Common, bifurcation and internal carotid segments were scanned on both sides, stored on videotape, and the near and far wall CIMT was measured on defined angles and segments, also in areas of plaque. Adverse events were routinely recorded. At the completion of the study, all segment-specific measurements were evaluated for outliers. Images were retrieved from videotape and evaluated whether the outlier resulted from a real morphological change or 'measurement error'. RESULTS: The 509 healthy postmenopausal women, free from previous symptomatic cardiovascular disease, underwent 3,812 carotid ultrasound scans during the study, and 44,924 carotid segments were evaluated. In 203 segments of 188 participants outliers were observed. True morphological changes were found in 12 participants, equivalent to a 3-year risk of 2.4%. These changes did not give rise to clinical symptoms. In the 6 women of whom we had follow-up measurements, the changes were reversed within 6-12 months. CONCLUSION: We observed acute increases in CIMT among 2.4% of healthy postmenopausal European women followed for 3 years. When assuming these were the result of vessel wall hemorrhages, our findings add to the body of evidence suggesting that vessel wall hemorrhages contribute to atherosclerosis development and also appear to occur clinically silent. PMID- 20720416 TI - Serotype distribution and antimicrobial resistance of adult Streptococcus pneumoniae clinical isolates over the period 2001-2008 in Crete, Greece. AB - BACKGROUND: We report on the serotype distribution and the antimicrobial susceptibility patterns (ASP) to 19 antibiotics of 195 Streptococcus pneumoniae isolates (41 invasive) collected over the period 2001-2008 from adult patients. MATERIAL AND METHODS: Pneumococcal isolates were serotyped by the Quellung reaction, and ASP testing was performed using E-test. RESULTS: Isolates with intermediate and high-level resistance to penicillin increased from 17 and 12.4% over the period 2001-2004 to 31.1 and 16.7% over the years 2005-2008, respectively (p = 0.03). Macrolide resistance increased from 27.6 to 38.9%, but this was not significant (p = 0.13), while resistance to trimethoprim sulfamethoxazole did not change over time, with approximately one fourth of the isolates being resistant. Only one isolate was resistant to fluoroquinolones. Multi-resistance was observed among 42 (58.1%) penicillin non-susceptible strains. The isolates tested belonged to 20 different serotypes. Serotypes 19F and 19A were the most common among penicillin-resistant isolates. The currently licensed 23-valent pneumococcal polysaccharide vaccine covered 98.4% of all 186 typeable S. pneumoniae strains. CONCLUSION: Our study emphasizes the importance of continued serotyping and surveillance of antimicrobial susceptibility of all S. pneumoniae clinical isolates, especially invasive ones, in order to guide the clinician in the choice of appropriate empirical antibiotic therapy for serious pneumococcal infections. PMID- 20720417 TI - Evaluation of anti-quorum-sensing activity of edible plants and fruits through inhibition of the N-acyl-homoserine lactone system in Chromobacterium violaceum and Pseudomonas aeruginosa. AB - BACKGROUND: To find out an alternative strategy to antibiotic usage against bacterial infection. MATERIALS AND METHODS: The purpose of this study is to describe the quorum-sensing (QS) inhibitory activity of edible plants and fruits against N-acyl-homoserine lactone (AHL)-mediated violacein production in Chromobacterium violaceum and virulence factor expression in Pseudomonas aeruginosa PAO1. RESULTS: Aqueous extracts of Ananas comosus (Bromeliaceae), Musa paradiciaca (Musaceae), Manilkara zapota (Sapotaceae) and Ocimum sanctum (Lamiaceae) were prepared and anti-QS activity of each extract was tested against AHL-mediated phenotypic expressions of C. violaceum and PAO1. Most of these extracts showed significant reduction in AHL-mediated violacein production in C. violaceum as well as pyocyanin pigment, staphylolytic protease, elastase production and biofilm formation in PAO1. However, these extracts were not inhibitory to bacterial growth, revealing that the QS inhibition by the extracts is not related to static or killing effects on the bacteria. CONCLUSIONS: The present study identified the anti-QS activity of A. comosus, M. paradiciaca, M. zapota and O. sanctum. An AHL-inactivating compound from these plant sources can be used as an alternative to antibiotic compounds to prevent AHL-mediated bacterial infection in higher organisms. PMID- 20720418 TI - Prospective study of vinorelbine and capecitabine combination therapy in Chinese patients with metastatic breast cancer pretreated with anthracyclines and taxanes. AB - AIMS: This phase II study prospectively evaluated the feasibility of vinorelbine in combination with capecitabine in Chinese patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. METHODS: Vinorelbine (25 mg/m(2) intravenous infusion on days 1 and 8) and capecitabine (1,000 mg/m(2) b.i.d., days 1-14) were administered to eligible MBC patients previously treated with anthracyclines and taxanes every 3 weeks for up to 6 cycles, until disease progression or unacceptable toxicity. The primary endpoint was objective response. RESULTS: Seventy-two patients were enrolled. In total, 297 cycles were given (median 4 cycles, range 2-6). The overall response rate was 45.8% (95% CI 34.2-57.4%), including 5 complete (6.9%) and 28 partial responses (38.9%). With median follow-up of 22 months, median time to progression was 7.7 months (95% CI 5.5-10.0) and median survival was 26.1 months (95% CI 19.6-32.6). The response rate was 53.8% in patients resistant to anthracyclines and taxanes combination. The most common hematologic adverse events were leukopenia (81.9%) with grade 3/4 incidence of 41.7%; nausea was the most frequent non-hematologic toxicity (62.5%). Hand-foot syndrome occurred in 12.5% of patients, and diarrhea was rare. CONCLUSIONS: Capecitabine 1,000 mg/m(2) b.i.d. combined with vinorelbine 25 mg/m(2) is an effective and safe treatment for MBC patients, no matter if anthracycline and taxane pretreated or resistant. PMID- 20720419 TI - Difficulties in the treatment of intestinal amoebiasis in mentally disabled individuals at a rehabilitation institution for the intellectually impaired in Japan. AB - BACKGROUND: A mass Entamoeba histolytica infection recurred despite repeated treatments with metronidazole at a rehabilitation institution for individuals with intellectual impairments. METHODS: Diloxanide furoate was administered to improve intractable intestinal amoebiasis after a recurring amoebic infection that tends to occur via coprophagy in mentally disabled individuals infected with E. histolytica at an institution (the prevalence rate and positive serology rate were 38.2 and 67.1%, respectively). The therapeutic effect of the drugs was judged by microscopic stool examination and an E. histolytica antigen detection kit. RESULTS: The mass infection was eliminated through the administration of metronidazole and subsequent use of diloxanide furoate. CONCLUSIONS: Combination therapy successfully cured and prevented transmission of the mass E. histolytica infection at the institution. PMID- 20720420 TI - Water immersion-induced skin wrinkling is related to heart rate variability. AB - Water immersion-induced skin wrinkling (WISW) is dependent on intact peripheral sympathetic function. WISW was hypothesized to reflect autonomic function in subjects without peripheral neuropathy. We prospectively studied 70 healthy subjects (aged 31 +/- 8 years, 63% females) without cardiovascular risk factors or neurological disease. All subjects underwent short-term heart rate variability (HRV) studies. Time and frequency domain variables were derived including the HRV index. WISW was graded using a previously validated scale of 1-4 of which 18.6% of subjects exhibited grade 1 (minimal) WISW and 35.7% had grade 2 WISW. On multivariate analysis using the HRV index, WISW was independently related to height and the HRV index. We conclude that WISW is related to central autonomic function. PMID- 20720421 TI - A retrospective longitudinal study of caries development in an Australian Aboriginal birth cohort. AB - There are a limited number of longitudinal investigations that examine the progression of dental disease in an indigenous population. Dental examinations of a cohort of indigenous Australians born in Darwin (Australia) between 1987 and 1990 were conducted at ages 6-8 and 11-13 years as part of the Child Dental Health Survey, and 18-20 years as part of the longstanding prospective Aboriginal Birth Cohort (ABC) study. Data was available at all ages for 145 participants. The percent DMFT >0 increased from 17.2 to 44.1 to 81.4%, representing a linear trajectory, whereas mean DMFT increased from 0.3 to 1.0 to 5.6, representing an exponential trajectory. Both trends were significant. At age 18-20 years, the percent DMFT >0 among ABC study participants was 1.2 times that of their counterparts at a national level. The differences were more marked when dental caries severity was considered, with mean DMFT among 18- to 20-year-old ABC study participants being 1.7 times that of similarly aged adults at a national level. Most of this disparity was constituted by the decayed component, with ABC study participants having eight times the mean DT of their national-level counterparts. The findings indicate that Aboriginal young adults in this birth cohort experience a disproportionate amount of dental disease relative to their non indigenous counterparts, and that this pattern is consistent across the life course. PMID- 20720423 TI - Tau-proteins as gender-specific state markers in amnestic mild cognitive impairment. AB - BACKGROUND/AIMS: Our purpose was to assess whether cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) reflect trait or state of disease in patients with AD and amnestic mild cognitive impairment (aMCI). METHODS: Analysis of CSF levels of A-beta-(1, 42), total tau and phospho-tau-181 (t-tau and p-tau-181), cognitive scaling with the cognitive part of the Alzheimer's Disease Assessment Scale and detailed neuropsychological testing including the California Verbal Learning Test (CVLT) and the Visual Reproduction Test from the Wechsler Memory Scale (WMS). RESULTS: We assessed healthy elderly controls, patients with aMCI (Petersen criteria; n = 62; age 67.9 +/- 7.6 years; MMSE score = 28.0 +/- 1.6; mean +/- standard deviation) and patients with AD (DSM-IV and NINCDS-ADRDA criteria; n = 106; age = 71.8 +/- 7.5 years; MMSE score >=20, 23.7 +/- 2.4) from an outpatient memory clinic. In the aMCI subjects, but not in the controls or patients with AD, the CVLT and the WMS scores correlated with the levels of t-tau and p-tau-181. More specifically, the CSF levels of p-tau-181 and t-tau correlated with the CVLT score in females and WMS score in males. CONCLUSIONS: Neurochemical markers of AD are gender-specific state markers in aMCI. This forms the basis for future preventive studies aiming at delaying manifest AD. PMID- 20720422 TI - Snacking habits and caries in young children. AB - Dental caries is caused by a combination of infection and diet. This disease, if left untreated, may lead to pain, and impair the quality of life, nutritional status and development of young children. The objective was to investigate the association between snacking and caries in a population at high risk of dental caries. American preschool children (n = 1,206) were recruited in the offices of paediatricians. Data on sociodemographic characteristics, oral hygiene, breast feeding, use of bottle and snacking were collected by questionnaire. Plaque presence, the number of teeth and their caries status (deft) were scored. The children sampled were 61% Black, 27% White and 10% Asian. Of the 1- to 2-, 2- to 3- and 3- to 4-year-old children, 93.8, 82.4 and 77.3% were caries free, and their mean caries scores were 0.16, 0.58 and 0.93, respectively. Multivariate partial least squares (PLS) modelling revealed plaque presence, lowest income, descriptors for tooth exposure time (number of teeth and age) and cariogenic challenge (total intake of sugar-containing snacks and chips/crisps, and chips intake with a sugar-containing drink) to be associated with more caries. These differences were also found in univariate analyses; in addition, children who continued breast-feeding after falling asleep had significantly higher deft values than those who did not. PLS modelling revealed that eating chips clustered with eating many sweet snacks, candies, popcorn and ice cream. We conclude that, in addition to the traditional risk indicators for caries - presence of plaque, sugar intake and socioeconomic status -, consumption of chips was associated with caries in young children. PMID- 20720424 TI - Two-year treatment with cyclosporine microemulsion for responder myasthenia gravis patients. AB - BACKGROUND: Cyclosporine (CsA) microemulsion pre-concentrate (MEPC) is a potential steroid-sparing agent for myasthenia gravis (MG) patients; however, there is a paucity of information on the long-term use of CsA MEPC in these patients. OBJECTIVES: We examined the efficacy and safety of CsA MEPC therapy administered to MG patients in a 2-year prospective open trial. METHODS: From Hanamaki General Hospital and Keio University Hospital, 28 patients provided informed consent. They were enrolled in a prospective open study of CsA MEPC for the initial 6-month observation period; after this 9 were defined as poor responders and excluded from the long-term analysis. RESULTS: The proportion of patients with minimal manifestations or pharmacologic remission status increased significantly. Among 18 patients taking oral prednisolone, 16 (88.9%) achieved a >or=50% reduction in prednisolone dose. Time to attain the minimal quantitative MG (QMG) score (4.2 +/- 2.6) was 4.2 +/- 4.2 months. Time to attain the minimal dose of prednisolone (2.9 +/- 3.1 mg/day) was 9.3 +/- 6.9 months. The dose of CsA MEPC was reduced to 2.6 mg/kg/day 2 years after starting the drug. Both total and ocular QMG scores were significantly decreased at 6 months and were generally maintained thereafter. The dose of prednisolone was significantly reduced at 1 year, and further reduced at 2 years. BMI decreased significantly, and 9 of 12 (75%) patients complaining of moon face reported that this had resolved on exit. All patients tolerated CsA MEPC without significant side effects. CONCLUSION: CsA MEPC therapy in responder MG patients suppressed disease severity, reduced steroid requirements, and alleviated steroid-related side effects. These findings should be confirmed by prospective controlled double-blind trials. PMID- 20720425 TI - Incidental multiple intracerebral foreign bodies. PMID- 20720426 TI - The relationship between insulin resistance and hypercoagulability in acute ischemic stroke. AB - AIM: Insulin resistance has effects on the coagulation system, which is important in the acute phase of infarct. We examined the relationships between insulin resistance, hemostatic markers and stroke severity in acute ischemic stroke patients. METHODS: Protein C (PC), protein S (PS), fibrinogen, von Willebrand factor and antithrombin III (AT III) were studied in 75 acute ischemic stroke patients with and without insulin resistance. RESULTS: The PC and PS levels of insulin-resistant patients were significantly lower than those of non-insulin resistant patients (PC: 87 +/- 19.23 vs. 97.89 +/- 13.3%, p = 0.007; PS: 84.75 +/ 15.72 vs. 93.21 +/- 15.02%, p = 0.02), and both of the anticoagulants were correlated with the homeostasis model assessment (HOMA; r = -0.339, p = 0.003 and r = -0.481, p = 0.000, respectively). Additionally, the NIH Stroke Scale (NIHSS) score correlated negatively with PS (r = -0.329, p = 0.004) and AT III levels (r = -0.235, p = 0.04). The parameters with positive correlations with NIHSS were fibrinogen (r = 0.270, p = 0.019), fasting glucose (r = 0.358, p = 0.008) and HOMA (r = 0.286, p = 0.013). CONCLUSIONS: The significant associations between insulin resistance and hemostatic markers may be relevant to stroke severity by causing a procoagulant tendency in acute ischemic stroke. PMID- 20720427 TI - Association of hospital arrival time with modified rankin scale at discharge in patients with acute cerebral infarction. AB - This study evaluated the time interval from the development or recognition of a symptom to hospital arrival and investigated its association with the modified Rankin Scale (mRS) at discharge in patients with acute cerebral infarction. A registry was established with ischemic stroke patients admitted to an academic medical center in Korea from January 2005 to March 2009. The time interval between symptom onset and hospital arrival was recorded for each patient and analyzed along with the patient's clinical characteristics and mRS at discharge. Regardless of initial severity at admission, mRS was significantly different between two groups of hospital arrival: within 3 h and beyond 3 h. Multiple regression analysis also showed more positive mRS scores for patients within the 3-hour arrival, controlling for other significant factors. The findings provided patients' initiatives for early hospital arrival. PMID- 20720428 TI - Late sequelae of whiplash injury with dissection of cervical arteries. AB - BACKGROUND/AIMS: The objective of our study was to estimate the incidence of posttraumatic dissections of cervical arteries in patients with whiplash injury acquired in a car accident. METHODS AND PATIENTS: We performed a retrospective analysis of medical records of 500 patients with whiplash injury acquired in car accidents between 1996 and 2005 and searched for dissections of cervical arteries occurring within 12 months after injury. RESULTS: Eight cases of cervical arterial dissection occurred within 12 months following whiplash injury. In 7 cases (87.5%), the dissection was complicated by brain infarction. The incidence of posttraumatic dissections after whiplash injuries was much higher than the overall incidence of cervical arterial dissections in the general population (1.6 vs. 0.0041%). The risk of cerebrovascular events was still increased 4-12 months after whiplash injury (0.6 vs. 0.003075% in the general population). CONCLUSIONS: There is an increased risk of posttraumatic dissection and cerebrovascular events within 12 months after whiplash injury. Car accident is an important risk factor for arterial dissections. The victims of car accidents should be screened for arterial dissections. The results of this study should be more thoroughly investigated in a prospective trial of car accident victims as a risk factor for arterial dissections. PMID- 20720429 TI - Liver transplantation in swine without venovenous bypass. AB - INTRODUCTION: A model of orthotopic liver transplantation in swine was developed to investigate an advanced reperfusion approach. Thereby, we consciously disclaim otherwise commonly practiced venovenous bypass during the recipient operation. MATERIAL AND METHODS: Ten liver transplantations were performed according to the described technique without using venovenous bypass. In each swine the observation period was 48 h. RESULTS: All transplantations were carried out after a median cold ischemic time of 307.5 min (295-340); the median warm ischemic time in these cases was 25 min (20-32). Eight of 10 swine survived 48 h after the operation. CONCLUSION: Orthotopic liver transplantations in the recipient swine are feasible even without using venovenous bypass. PMID- 20720430 TI - Effect of intravenous morphine comedication on bile duct visualization, diameter and volume applying intravenous CT cholangiography in a porcine liver model. AB - BACKGROUND/AIMS: To determine whether intravenous morphine comedication improves bile duct visualization, diameter and/or volume applying intravenous CT cholangiography in a porcine liver model. METHODS: 12 Landrace pigs underwent intravenous CT cholangiography. Eight minutes after initiation of the contrast material infusion, either morphine sulfate (n = 6 animals) or normal saline (n = 6 animals) was administered. Eighteen consecutive CT scans of the liver were acquired with 2-min intervals starting with initiation of the contrast material infusion. Maximum bile duct visualization scores, diameters and volumes and time to maximum bile duct visualization scores, diameters and volumes were determined. RESULTS: Maximum bile duct visualization scores, diameters and volumes and time to maximum bile duct visualization scores, diameters and volumes were not significantly different when the morphine group was compared to the normal saline group. Maximum bile duct visualization scores ranged between 4.00 +/- 0.00 and 2.83 +/- 1.47. Maximum bile duct diameters ranged between 6.77 +/- 0.40 and 2.10 +/- 1.35 mm. Maximum bile duct volume was 16.41 +/- 7.33 ml in the morphine group and 16.79 +/- 5.65 ml in the normal saline group. CONCLUSION: Intravenous morphine comedication failed to improve bile duct visualization and to increase bile duct diameter and volume applying CT cholangiography. PMID- 20720431 TI - Aneurysm-express: human abdominal aortic aneurysm wall expression in relation to heterogeneity and vascular events - rationale and design. AB - OBJECTIVE: Elective repair of abdominal aortic aneurysms (AAA) is associated with significant morbidity and mortality. Large amounts of AAA tissue are necessary to assess heterogeneity among AAA and to correct for potential confounders such as known risk factors. The Aneurysm-express study aims to identify different types of AAA using inflammatory markers in the aneurysm wall that predict postoperative cardiovascular adverse events and mortality, therefore allowing individual risk assessment. METHODS: The Aneurysm-express is an ongoing prospective cohort study including AAA patients undergoing open repair. At baseline, blood is drawn, relevant clinical data are collected and the standard diagnostic modalities are performed. During surgery a specimen of the ventral AAA wall is collected and processed to study protein expressions and histology. INTERIM RESULTS: The study commenced in 2003 in 2 medical centers and currently holds information and material of >300 AAA patients, making it the largest reported aneurysm biobank. Patients are followed for 3 years after surgery for occurring cardiovascular events. The current mean follow-up is 2.1 +/- 1.3 years with an event rate of 27%. CONCLUSION: The large amount of structurally stored tissue and blood combined with clinical characteristics and follow-up provide an excellent soil for indepth pathophysiological analyses, with assessment of AAA heterogeneity in combination with postoperative clinical outcome. PMID- 20720432 TI - Evaluation of male inter-troop transfer as a mating strategy among ring-tailed lemurs on St. Catherines Island, USA. AB - One commonly cited function of dispersal is to increase mating opportunities. In this study, I evaluated the hypothesis that male inter-troop transfer is used as a mating strategy in ring-tailed lemurs, Lemur catta, on St. Catherines Island (SCI), Ga., USA. I measured male mating success and inter-troop transfer behavior across 5 years in a population consisting of 4 lemur groups on SCI. Data strongly supported dispersal as a successful mating strategy of natal males, because these males did not mate within their natal groups, but always mated in their new groups of entry. For secondary male dispersal (transfers between 2 non-natal groups), data on 2 males collected in breeding seasons immediately prior to and following transfer show that their individual mating success measures increased following a transfer. Data revealed that among non-natal males, high-ranking males on SCI were more likely to transfer between groups than lower-ranking males, which is somewhat contrary to the more common trend among primates of lower-ranking males transferring more frequently. In sum, male primary dispersal appears to function as a mating strategy among male L. catta on SCI, with indications that secondary dispersal may also be successful at increasing male mating success. PMID- 20720433 TI - General derivation of the sets of pedigrees with the same kinship coefficients. AB - Quantification of kinships between two individuals using unlinked autosomal markers rests upon the identity-by-descent (IBD) probabilities among their four alleles at a locus because they determine the algebraic expressions of the joint genotypic probabilities. Nevertheless, some pedigrees share the same IBD probabilities and are therefore indistinguishable using those markers. Examples of these pedigrees were previously described, such as the case of half-siblings, grandparent-grandchild and avuncular, but a general analysis has not been attempted. The aim of this study is to present a systematic and mathematically supported framework where considering unlinked autosomal markers complete sets of indistinguishable pedigrees linking two non-inbred individuals are generally derived. In our work, complete sets of pedigrees with the same IBD partitions are formally established and mathematically treated, considering kinships linking any pair of non-inbred individuals, whether they are related just maternally or paternally, or both. Moreover, general expressions for IBD partitions, and consequently for joint genotypic probabilities, are derived considering a simple counting rule based on two 'atom' pedigrees: parent-child and full-siblings. Besides the theoretical formalization of the problem, the developed framework has potential applications in forensics as well as in breeding strategies design and in conservation studies. PMID- 20720434 TI - Expression of novel podocyte-associated proteins sult1b1 and ankrd25. AB - BACKGROUND/AIMS: Podocytes have a unique function in the renal ultrafiltration that is achieved by expressing proteins that are highly specific to podocytes. In this study, we identified two novel podocyte-associated proteins. METHODS: The expression of sult1b1 and ankrd25 in mouse tissues was studied by RT-PCR. The protein expression was studied by generating polyclonal antibodies that were used in Western blotting and immunohistochemistry. RESULTS: By RT-PCR we detected sult1b1 expression only in glomerular, liver and brain tissues. By immunohistochemistry, sult1b1 was detected in the kidney exclusively in the Golgi apparatus of the podocyte. No expression outside the glomerulus was observed in the kidney. The ankrd25 transcript was detected in most mouse tissues analyzed by RT-PCR. In the kidney, however, immunohistochemistry showed that this protein was expressed only by podocyte, mesangial, and smooth muscle cells. In podocytes, ankrd25 was localized to foot processes. CONCLUSIONS: Identification of these two novel glomerulus-associated proteins opens up possibilities to investigate their role in the renal filter physiology and diseases. We speculate that sult1b1 may be involved in the sulfonylation of podocyte protein podocalyxin, whereas ankrd25 may contribute to controlling actin dynamics in podocyte foot processes. PMID- 20720435 TI - CCL5, CXCL10 and CXCL11 chemokines in patients with active and stable relapsing remitting multiple sclerosis. AB - OBJECTIVE: Chemokines are involved in the migration of inflammatory cells to the central nervous system in multiple sclerosis (MS). The aim of our study was to estimate the concentrations of CCL5, CXCL10 and CXCL11 in serum and cerebrospinal fluid (CSF) samples of relapsing-remitting MS (RRMS) patients during both relapse and stable disease, and to compare the results with those of controls. We also decided to evaluate the effect of methylprednisolone (MP) therapy on CCL5, CXCL10 and CXCL11 serum concentrations in MS patients with relapse. METHODS: The study groups consisted of 17 RRMS patients during relapse, 30 RRMS patients in remission and 25 patients with tension headache with no symptoms of inflammatory disease as controls. In the group of relapsing MS patients, blood samples were obtained before steroid therapy and after a 5-day treatment with MP at a dose of 1 g i.v. once daily. Chemokine levels were measured by ELISA. RESULTS: CXCL10 levels were significantly higher in the CSF of MS patients both during relapse (mean +/- SD, 298.2 +/- 143.8 pg/ml) and stable disease (323.7 +/- 183 pg/ml) in comparison with the control group (152.4 +/- 97.7 pg/ml; p < 0.001). CSF levels of CCL5 were significantly higher in relapsing MS patients (8.74 +/- 6.18 pg/ml) in comparison with stable MS patients (4.4 +/- 3.9 pg/ml, p = 0.005). CXCL11 levels of MS patients did not significantly differ from control values. There was no effect of MP therapy on serum levels of CCL5, CXCL10 and CXCL11. CONCLUSIONS: These observations suggest involvement of CXCL10 and CCL5 but not CXCL11 in the pathogenesis of MS. CCL5 may induce the recruitment of inflammatory cells in acute-stage MS. PMID- 20720436 TI - Integrin beta1 subunit signaling is involved in the directed migration of human retinal pigment epithelial cells following electric field stimulation. AB - AIMS: Direct current electric fields (EFs) can induce directed cell migration in a wide variety of cells, and this has been proven to be of importance in wound healing. Here we observed the effects of EFs on cultured human retinal pigment epithelial (RPE) cells and explored the possible involvement of integrin beta1 subunit signaling in the process. METHODS: Cultured human RPE cells were exposed to an EF at 5 V/cm for 3 h. The rate and directionality of cell migration were quantified. The distribution of integrin beta1 subunit was measured by immunohistochemistry and the expression of integrin beta1 subunit and phosphorylated focal adhesion kinase (FAK) was determined by PCR and Western blotting. Experiments were performed in the presence or absence of anti-integrin beta1 subunit antibody. RESULTS: During exposure to an EF at 5 V/cm for 3 h, the separated human RPE cells and wounded RPE monolayer demonstrated a cathodal directed migration. The distribution of integrin beta1 subunit in the cells was also polarized to the cathode, and the expression in mRNA and its protein level were obviously increased. Furthermore, exposure to EFs of 5 V/cm triggered the phosphorylation of FAK in human RPE cells. In contrast, blocking of integrin beta1 subunit suppressed the directed migration of RPE cells and reduced the activation of FAK in EFs. CONCLUSIONS: These findings indicate that EF exposure results in directed migration of the separated RPE cells and RPE monolayer. These effects may partially act through the activation of integrin beta1 subunit signaling. PMID- 20720437 TI - Estimating the rate of non-participation and its influence on the study results: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study report 32. AB - PURPOSE: To report the non-participation rates in a cross-sectional study, compare participants with non-participants, elucidate barriers for non-response and evaluate the influence of non-responders on the outcome measure. METHODS: The Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study had 2 steps in which non- participation was possible. Step 1 was an estimation of fasting blood sugar at the participants' homes, and step 2 a base hospital examination. The sociodemographic information was collected at the time of enumeration. The barriers against participation were noted at refusal. The data of the participants were compared with the urban Tamil Nadu population data from the 2001 census. RESULTS: The non-participation rate was 3.6% in the field (step 1), and 13.9% at the base hospital (step 2). At step 1, older men and unemployed women had a lesser odds ratio for non-participation than younger age groups. At step 2, employment was significant for non-participation in men, and age between 50 and 59 years, illiteracy and unemployment in women. CONCLUSION: The barriers against participation differed between steps 1 and 2. The study participants were similar to the population of urban Tamil Nadu. Hence, the results of the study can be generalized to the urban Indian population. PMID- 20720438 TI - Evaluation of the role of vascular endothelial growth factor in diabetic retinopathy. AB - PURPOSE: The study is aiming at investigating the correlation between vascular endothelial growth factor (VEGF) as an angiogenic factor and diabetic retinopathy in type 2 diabetic patients and the effect of panretinal coagulation and glycemic control on VEGF. METHODS: The study included 30 patients of type 2 diabetes, 10 of them did not suffer from any of the vascular complications of type 2 diabetes mellitus (group 1), 10 patients had nonproliferative diabetic retinopathy (group 2), 10 patients had proliferative diabetic retinopathy (PDR) (group 3) and (group 4), as well as 10 healthy subjects that served as control group. All participants were subjected to complete clinical examination including ophthalmic and medical examination, laboratory investigations comprising complete blood count, liver function test, serum creatinine, 24-hour urinary albumin excretion, lipid profile, fasting and 2-hour postprandial blood glucose, HbA(1C) and serum VEGF. RESULTS: The study reported a highly significant increase in the serum VEGF in the diabetic patients compared to the control group (p < 0.001), and there was also a highly significant increase in the serum VEGF in the patients with PDR versus nonproliferative diabetic retinopathy (40.55 +/- 8.28 vs. 20.3 +/- 2.45, p < 0.001). There was a reduction in the serum VEGF in a group of diabetic patients with poor glycemic control when their diabetic state corrected through 4 months of follow-up was highly significant (17.29 +/- 1.61 before vs. 9.39 +/- 0.82 after control p < 0.001) as well as the reduction in the serum VEGF which was observed in a group of patients with PDR when proper panretinal photocoagulation (PRP) was applied to their retinae with 4 months of follow-up (40.55 +/- 8.28 before vs. 21.15 +/- 1.76 after PRP, p < 0.001). CONCLUSION: Serum VEGF is significantly increased in diabetic patients, especially those with PDR, and this elevation of VEGF was reduced in uncontrolled diabetic patients with proper gycemic control, and in patients with PDR with proper PRP, indicating that VEGF is an angiogenic factor that reflects the degree of neovascularization in diabetic complications. PMID- 20720439 TI - Redundant mechanisms for vascular growth factors in retinopathy of prematurity in vitro. AB - BACKGROUND: Current treatments for retinopathy of prematurity (ROP) targeting single vascular growth factors are ineffective in preventing neoangiogenesis. METHODS: We investigated the redundant/compensatory mechanisms between vascular growth factors in ROP. Cultured retinal vascular endothelial cells under CoCl2 induced hypoxia were transfected with recombinant adeno-associated virus type 2 vascular endothelial growth factor (VEGF) or pGIPZ-VEGF RNA interference to up- and downregulate VEGF expression, respectively. At 48 h after transfection, basic fibroblast growth factor (bFGF) and angiopoietin 1 (ANG1) gene expression as well as mitotic cycle changes were analyzed in the cells and correlated with the change in VEGF expression. RESULTS: Compared with the normal control group 1, at 30 min, 12 h and 24 h, the expressions of VEGF, bFGF and ANG1 in the hypoxia control group 2 were significantly higher. In the highly expressing VEGF group (group 3), the expressions of bFGF and ANG1 were downregulated, while in the low expressing VEGF group 4, the expressions of bFGF and ANG1 were significantly upregulated. In the bevacizumab treatment group 5, the expressions of VEGF, bFGF and ANG1 were similar to those in group 2, and the difference was not significant. CONCLUSIONS: A compensatory mechanism (redundancy) exists between vascular growth factors in ROP. Such a phenomenon could partially explain why the inhibition of a single growth factor cannot effectively prevent the recurrence of neovascularization in ROP. A more effective strategy for treating ROP may be to inhibit VEGF and its redundant pathways. PMID- 20720440 TI - 'Do not put off the writing ... unpublished work effectively does not exist!'. An Interview with Clem W. Imrie, Emeritus Professor of Surgery, West of Scotland Pancreatic Unit, Royal Infirmary, Glasgow, UK. [Interviewed by Martin E Fernandez Zapico]. AB - In this interview, Professor Clem W. Imrie shares with Pancreatology his life experience as a surgeon and scientist in pancreatic research. He is a world recognized pancreatologist for his contribution to the understanding of pancreatic diseases; his work on the characterization of pathogenesis as well as the treatment of pancreatitis has been seminal. and IAP. PMID- 20720443 TI - Diabetes mellitus in pancreatic cancer and the need for diagnosis of asymptomatic disease. AB - Pancreatic cancer is strongly associated with the development of hyperglycemia, peripheral insulin resistance and diabetes mellitus, especially when presented as new-onset diabetes mellitus. Peripheral insulin resistance and hyperinsulinemia have been suggested to promote growth of pancreatic cancer cells, and therefore a relation between long-standing diabetes mellitus type 2 and pancreatic cancer has been implied. Epidemiological studies, though, give incongruent results to this problem. There are data supporting a tumor-derived influence on glucose metabolism, insulin secretion and eventually the development of diabetes mellitus in early stages of pancreatic cancer. The only possibility for curative intent in pancreatic cancer is to diagnose the disease before symptoms occur. Patients with newly diagnosed diabetes mellitus type 2 or hyperglycemia as a risk group have been recommended for primary screening for pancreatic cancer. To date, there is no specific biomarker to identify patients with an asymptomatic pancreatic cancer. The review discuss the relationship between pancreatic cancer and diabetes mellitus and the possibility of secondary screening of patients with newly diagnosed diabetes mellitus type 2 or hyperglycemia in an artificial neural network. PubMed was searched for articles using the Mesh term 'pancreatic neoplasms' combined with 'insulin resistance' and 'glucose metabolism disorders'. Additional articles were retrieved through hyperlinks and by manually searching reference lists in original published articles. In total 36 articles were systematically reviewed. and IAP. PMID- 20720442 TI - Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer. AB - The calcineurin-responsive nuclear factor of activated T cells (NFAT) family of transcription factors was originally identified as a group of inducible nuclear proteins, which regulate transcription during T lymphocyte activation. However, following their initial discovery, a multitude of studies quickly established that NFAT proteins are also expressed in cells outside the immune system, where they participate in the regulation of the expression of genes influencing cell growth and differentiation. Ectopic activation of individual NFAT members is now recognized as an important aspect for oncogenic transformation in several human malignancies, most notably in pancreatic cancer. Sustained activation of the Ca(2+)/calcineurin/NFAT signaling pathway has emerged as a powerful regulatory principle governing pancreatic cancer cell growth. Activated NFAT proteins form complexes with key oncogenic proteins to regulate the transcription of master cell cycle regulators and proteins with functions in cell survival, migration and angiogenesis. This review pays particular attention to recent advances in our understanding of how the NFAT transcription pathway controls gene expression during development and progression of pancreatic cancer. and IAP. PMID- 20720444 TI - DNA mutational differences in cytological specimens from pancreatic cancer and cholangiocarcinoma. AB - BACKGROUND/AIMS: Preoperative distinction between pancreatic cancer (PC) and extrahepatic cholangiocarcinoma (CC) is desirable due to diverging management options, and to optimize enrollment into neoadjuvant trials. METHODS: A single center retrospective study of patients with PC or CC was undertaken. Four blinded pathologists reviewed all cases and reached a consensus diagnosis (PC or CC). Microdissection-based multiple microsatellite loss analysis and direct sequencing of K-ras oncogene was performed and compared for PC and CC. RESULTS: Of 33 cases studied (17 males; 16 PC, 17 CC; 10 with primary sclerosing cholangitis), a K-ras mutation was present in 14/16 (87.5%) PC and 1/17 (5.9%) CC cases (p < 0.001), sensitivity and specificity were 87.5 and 94%, respectively. The mean fractional mutational rate was higher in PC (0.51; 95% CI 0.45-0.58) compared to CC (0.34; 95% CI 0.28-0.39, p < 0.001). CONCLUSIONS: The presence of a K-ras mutation in cytology specimens distinguishes PC from CC in this study. and IAP. PMID- 20720445 TI - Endoscopic retrograde cholangiopancreatography and manometry findings in 1,241 idiopathic pancreatitis patients. AB - BACKGROUND: 10-30% of patients with pancreatitis are classified as idiopathic after the initial evaluation. Our aim was to assess the diagnostic yield of endoscopic retrograde cholangiopancreatography (ERCP) and sphincter of Oddi manometry in patients with idiopathic pancreatitis in a tertiary referral center. METHODS: A single-center, retrospective study analyzing the ERCP and manometry results of 1,241 patients who were classified as having idiopathic pancreatitis based upon their initial evaluation. RESULTS: A single episode of pancreatitis occurred in 20.4%, acute recurrent pancreatitis in 56.3% and chronic pancreatitis in 23.3% of the patients undergoing ERCP. Sphincter of Oddi dysfunction was found in 40.3% and pancreas divisum in 18.8% of the patients. Biliary stone disease was found in 3.0%. Intraductal papillary mucinous neoplasms were identified in 52 patients with increasing frequency in older age groups. The overall diagnostic yield of ERCP and sphincter of Oddi manometry to elucidate a potential cause of pancreatitis was 65.8%. Of these, 91.9% patients had findings amenable to endoscopic therapy. The complication rate was 11.5%. CONCLUSIONS: In this large series, ERCP with manometry frequently identified conditions which probably caused or contributed to the idiopathic pancreatitis. Long-term studies are awaited to determine outcomes after correctable factors are addressed. and IAP. PMID- 20720446 TI - Incidence, etiology and prognosis of first-time acute pancreatitis in young patients: a population-based cohort study. AB - BACKGROUND/AIMS: The etiology of acute pancreatitis (AP) seems to have changed during the last two decades, and since detection of mutations in the gene for cationic trypsinogen(PRSS1) causing hereditary pancreatitis some patients formerly diagnosed with idiopathic AP (IAP) turn out to have a genetic cause. METHODS: Data on patients <30 years of age, diagnosed with AP identified in the Danish National Registry of Patients, were retrieved. Patients previously diagnosed with IAP were offered genetic counseling and testing for mutations in the PRSS1, the Serine Protease Inhibitor Kazal type1 (SPINK1) and the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR). RESULTS: The standardized incidence ratio (SIR) of AP increased from 3.56 per 100,000 person years in the period 1980-1984 to 6.43 in 2000-2004 (p < 0.01). The SIR of women surpassed that of men in 1999. Among patients with former IAP, 3 had hereditary pancreatitis, 3 CFTR and 4 SPINK1 mutations after re-evaluation. CONCLUSION: The incidence of AP, especially in women, increased over time. More patients had gallstone-related and less alcohol-related AP in the period 1999-2004 compared to 1980-1999. Genetic causes of AP were found in 32% of those tested with IAP and as a minimum estimation in 4% of the total cohort. and IAP. PMID- 20720447 TI - Helicobacter pylori in autoimmune pancreatitis and pancreatic carcinoma. AB - BACKGROUND: Helicobacter pylori has been suggested to be involved in pancreatic diseases, namely autoimmune pancreatitis and pancreatic carcinoma. We investigated the presence of conserved sequences of Helicobacter in pancreatic tissue and pancreatic juice from patients with chronic nonautoimmune and autoimmune pancreatitis as well as pancreatic ductal adenocarcinoma (PDAC). METHODS: 35 pancreatic juices collected during routine endoscopic retrograde cholangiopancreatography and 30 pancreatic tissues were studied. Nested PCR was used to detect H. pylori in the isolated DNA samples. In order to exclude a methodological bias, the samples were analyzed blindly in 2 different laboratories using either conventional or LightCycler PCR for H. pylori urease A and 16S ribosomal DNA. RESULTS: In the pancreas of 11 patients with autoimmune pancreatitis, no H. pylori DNA could be detected. Further, in none of the other tissue samples of chronic pancreatitis or PDAC could we detect any Helicobacter sequences. Out of the pancreatic juice samples, none demonstrated either of the 2 Helicobacter gene sequences investigated. CONCLUSION: Despite good scientific reasoning for an involvement of Helicobacter in pancreatic diseases, a direct infection of the microbial agent seems unlikely. Rather, the pathomechanism must involve molecular mimicry in autoimmune pancreatitis, or the transformation of nitric food constituents to nitrosamines in pancreatic cancer. and IAP. PMID- 20720449 TI - Circulating levels of visfatin, resistin and pro-inflammatory cytokine interleukin-8 in acute pancreatitis. AB - BACKGROUND: Resistin and visfatin, hormones produced by adipose tissue, have pro inflammatory potential; however, their role in acute pancreatitis (AP) has been investigated only rarely. METHODS: The study group comprised 32 patients with alcoholic AP and 30 controls. In all cases AP was classified as C according to Balthazar's CT score and as severe according to Ranson's criteria. The serum level of visfatin, resistin, and interleukin(IL)-8 immunoassays were measured by ELISA on admission and on the third and fifth day of hospitalization. RESULTS: On the admission day serum resistin and IL-8 concentrations in AP patients were significantly higher than in controls and they further increased on the third and fifth day of hospitalization. On the admission day serum visfatin levels in AP patients were significantly higher than in controls and further increased on the third day of hospitalization. On the fifth day the levels decreased; however, they were still higher than on admission. The correlation between visfatin and resistin as well as between C-reactive protein and visfatin, resistin and IL-8 levels has been found. CONCLUSION: In the course of AP, visfatin and resistin levels increase in parallel with C-reactive protein. We speculate that those parameters may provide an additional tool for the prognosis and monitoring of AP. and IAP. PMID- 20720450 TI - Polymorphisms of beta defensins are associated with the risk of severe acute pancreatitis. AB - AIMS: Bacterial translocation from the intestinal tract plays an important role in severe acute pancreatitis (AP). Human beta-defensins are a family of antimicrobial peptides present at the mucosal surface. The aim of this study was to investigate the relevance of single nucleotide polymorphisms (SNPs) in the DEFB1 gene and copy number polymorphisms of the DEFB4 genes in AP. METHODS: 124 AP patients (30 with mild and 94 with severe disease) and 100 healthy controls were enrolled in the study. Three SNPs of the DEFB1 gene [G-20A (c.-20G->A), C 44G (c.-44C->G) and G-52A (c.-52G->A)] were genotyped by Custom TaqMan assay. The DEFB4 gene copy number was determined by means of a TaqMan real-time PCR assay. RESULTS: Significantly higher frequencies of the AA genotype of G-20A (c.-20G->A) and the AA genotype of G-52A (c.-52G->A) were observed among the patients with severe AP (SAP) compared with the healthy controls (38 vs. 20 and 41 vs. 18%, respectively). The GG protective genotype of C-44G (c.-44C->G) SNP was much less frequent (1%) among the patients than among the controls (9%). A higher frequency of a lower (<4) copy number of the DEFB4 gene was observed in the patients with SAP compared with the healthy controls (62 vs. 24%, respectively). CONCLUSIONS: The variations in the genes encoding human beta-defensin-1 and -2 may be associated with the risk of SAP. and IAP. PMID- 20720448 TI - Pancreatic function in carboxyl-ester lipase knockout mice. AB - BACKGROUND/AIMS: CEL-MODY is a monogenic form of diabetes and exocrine pancreatic insufficiency due to mutations in the carboxyl-ester lipase (CEL) gene. We aimed to investigate endocrine and exocrine pancreatic function in CEL knockout mice (CELKO). METHODS: A knockout mouse model with global targeted deletion of CEL was investigated physiologically and histopathologically, and compared to littermate control CEL+/+ mice at 7 and 12 months on normal chow and high-fat diets (HFD), i.e. 42 and 60% fat by calories. RESULTS: CELKO+/+ and -/- mice showed normal growth and development and normal glucose metabolism on a chow diet. Female CEL-/ mice on 60% HFD, on the other hand, had increased random blood glucose compared to littermate controls (p = 0.02), and this was accompanied by a reduction in glucose tolerance that did not reach statistical significance. In these mice there was also islet hyperplasia, however, alpha- and beta-islet cells appeared morphologically normal and pancreatic exocrine function was also normal. CONCLUSION: Although we observed mild glucose intolerance in female mice with whole-body knockout of CEL, the full phenotype of human CEL-MODY was not reproduced, suggesting that the pathogenic mechanisms involved are more complex than a simple loss of CEL function. and IAP. PMID- 20720452 TI - Radical surgery for pancreatic malignancy in the elderly. AB - BACKGROUND: Improving life expectancy is associated with increasing incidence of pancreatic cancer. We reviewed morbidity and mortality in patients aged 65 years and older undergoing curative intent surgery in two centers in the Czech Republic. METHODS: Data were retrieved by retrospective analysis of the medical records over the period 2000-2007. In total, 60 patients were included. The mean age was 71 years (median 70 years; range 65-85 years). Most patients (43, 72%) underwent hemipancreatoduodenectomy, combined in 4 with portomesenterial vessel resection. Twelve patients (20%) had distal pancreatectomy and 5 patients (8%) total pancreatectomy. RESULTS: Overall morbidity was 28%. Only 10 patients (18%) developed serious surgical complications in terms of pancreatic leak (5, 8%), biliary leak (2, 3%), and intra-abdominal inflammatory collection (4, 7%). Four patients (6.6%) died within 30 days. The 1-year survival was 62.8%. CONCLUSION: We can conclude that age per se is not a contraindication to surgery. Patient's overall general condition, co-existing co-morbidities, and ability to get over with any potential complications are more important. and IAP. PMID- 20720451 TI - Distal pancreatectomy for body-tail pancreatic cancer: is there a role for celiac axis resection? AB - BACKGROUND/AIMS: Body-tail pancreatic cancer is an aggressive disease with a low resectability rate and a poor prognosis. Celiac axis invasion usually contraindicates resection. The aim of this study was to analyze the feasibility of distal pancreatectomy (DP) with celiac axis resection (DP-CAR) for locally advanced body-tail pancreatic cancer. METHODS: All DPs performed between January 1989 and December 2007 were considered. DP and DP-CAR were reviewed for pre-, intra- and postoperative data. An extensive, detailed literature review on DP and DP-CAR was also performed. RESULTS: DP was performed in 49 of our patients, and 745 cases were retrieved from the literature. The overall morbidity and mortality rates were 32.0 and 3.0%, respectively. We performed DP-CAR in 5 patients with no mortality but 80% morbidity. A further 90 patients were retrieved from the literature. Arterial reconstruction was needed in 1/5 of our patients and in 13/90 of patients in the literature. Collaterals from superior mesenteric artery maintained adequate hepatic artery blood flow in the remaining 81 patients. The overall morbidity and mortality rates were 40.6 and 2.1%, respectively. The median survival ranged between 4.5 and 25 months after DP and was 13 months after DP-CAR. CONCLUSIONS: DP-CAR improves resectability without increasing the mortality rate. The complication rate after DP-CAR was higher than after DP, but still within the range of extended DP. DP-CAR should be considered for the inclusion among the 'extended' procedures for the treatment of body-tail pancreatic cancers invading the celiac axis. and IAP. PMID- 20720453 TI - Modulation of C6 Glioma Cell Proliferation by Ureido-Calix[8]arenes. AB - Calixarenes are synthetic macrocyclic compounds that may serve as scaffolds for biologically active molecules and have been proposed as potential anticancer agents. We synthesized a ureido-calix[8]arene carrying N-acetyl-D-glucosamine residue (compound 1) and had previously demonstrated that it inhibits C6 glioma cell migration and proliferation, with divergent mechanisms. In the present work we explored in more detail the antiproliferative effect of compound 1, comparing it to related compounds lacking either the sugar moieties (compound 2), the multiple ureido groups (compound 3) or both (compound 4). The results show that the action of compound 1 is independent of the N-acetyl-D-glucosamine residues, requires the presence of multiple ureido groups and does not seem to involve focal adhesion kinase signaling. Inhibition of proliferation is reduced by preincubation with epidermal growth factor (EGF) and vascular endothelial growth factor (20 ng/ml) with compound 1, and extracellular-related kinase phosphorylation is reduced by treatment with compound 1 in both basal and EGF stimulated conditions, suggesting that the observed effect depends on a direct interference with growth factor signaling. PMID- 20720454 TI - Positive effect of HPA lanolin versus expressed breastmilk on painful and damaged nipples during lactation. AB - Painful and/or damaged nipples associated with breastfeeding are common and represent a challenge for both the persons experiencing nipple pain and/or trauma and for those providing treatment. However, evidence-based data has been insufficient to demonstrably minimize these common reasons for failure to initiate or continue successful breastfeeding. The aim of this study was to evaluate the efficacy of specific-grade highly purified anhydrous (HPA) lanolin versus expressed breastmilk (EBM) for the treatment of painful and damaged nipples associated with breastfeeding in a prospective controlled clinical trial evaluating 84 lactating mothers. Nipple trauma and healing rates were rated by the Nipple Trauma Score. Nipple pain intensity was assessed on a visual analog scale. Outcome parameters were in favor of the HPA lanolin group, reaching statistical significance for healing rates, nipple trauma and nipple pain. In our study, we found HPA lanolin more effective than EBM, inducing faster healing of nipple trauma (absolute risk reduction of 0.43) and reducing nipple pain (absolute risk reduction of 0.61 on day 3). We concluded that HPA lanolin, combined with breastfeeding education, was more effective than EBM, combined with breastfeeding education, in reducing nipple pain and promoting healing of nipple trauma. PMID- 20720455 TI - Resistance of liposomal sunscreen formulations against plain water as well as salt water exposure and perspiration. AB - The present in vivo investigation using a total of 30 healthy adult volunteers with Fitzpatrick skin type II examines the persistent efficacy of sunscreens using liposomal suspensions as the vehicle. Based on the COLIPA guidelines, the protective effect of a single application of 4 different liposomal sunscreen formulations (sun protection factors, SPFs: 50+, 30, 25 and 15) against sunburn at the recommended amount of 2 mg/cm(2) was determined after exposure of the skin to plain water and salt water and after profuse perspiration. Under the influence of plain water, salt water and sweating, the SPF values of sunscreen 1 (labeled SPF of 50+) were reduced only marginally to 97, 96 and 99%, respectively, those of sunscreen 2 (labeled SPF of 30) to 97, 96 and 99%, respectively, those of sunscreen 3 (labeled SPF of 25) to 90, 83 and 91%, respectively, and those of sunscreen 4 (labeled SPF of 15) to 96, 96 and 95%, respectively. This set of data shows that despite plain water and salt water immersion or profuse sweating, the liposomal sunscreen formulation may deliver a long-lasting protective effect in everyday situations encountered by outdoor workers or during leisure activities. PMID- 20720457 TI - A novel regulator (USP10) of p53: Implications for tumor suppression and therapeutic targeting. PMID- 20720456 TI - Phosphatidylinositol 4-phosphate 5-kinase alpha is induced in ganglioside stimulated brain astrocytes and contributes to inflammatory responses. AB - In brain tissue, astrocytes play defensive roles in central nervous system integrity by mediating immune responses against pathological conditions. Type I phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K alpha) that is responsible for production of phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) regulates many important cell functions at the cell surface. Here, we have examined whether PIP5K alpha is associated with astrocyte inflammatory responses. Gangliosides are releasable from damaged cell membranes of neurons and capable of inducing inflammatory responses. We found that treatment of primary cultured astrocytes with gangliosides significantly enhanced PIP5K alpha mRNA and protein expression levels. PI(4,5)P2 imaging using a fluorescent tubby (R332H) expression as a PI(4,5)P2-specific probe showed that ganglioside treatment increased PI(4,5)P2 level. Interestingly, microRNA-based PIP5K alpha knockdown strongly reduced ganglioside-induced transcription of proinflammatory cytokines IL-1 beta and TNFalpha. PIP5K alpha knockdown also suppressed ganglioside-induced phosphorylation and nuclear translocation of NF-kappaB and the degradation of I kappaB-alpha, indicating that PIP5K alpha knockdown interfered with the ganglioside-activated NF-kappaB signaling. Together, these results suggest that PIP5K alpha is a novel inflammatory mediator that undergoes upregulation and contributes to immune responses by facilitating NF-kappaB activation in ganglioside-stimulated astrocytes. PMID- 20720458 TI - Preventive care is the wave of the future. PMID- 20720459 TI - Using inflammatory markers as a diagnostic tool. PMID- 20720460 TI - Nurses in government can shape NP practice. PMID- 20720461 TI - Pharmaceutical reduction of breast cancer risk. PMID- 20720463 TI - New treatment for von Willebrand disease. PMID- 20720465 TI - Exploring sexuality & quality of life in women after breast cancer surgery. PMID- 20720467 TI - Take chest pain to heart. PMID- 20720468 TI - Polycystic ovary syndrome: recognize and intervene early. PMID- 20720470 TI - Risk factors for catheter-associated bloodstream infections in a Pediatric Cardiac Intensive Care Unit. AB - BACKGROUND: Catheter-associated bloodstream infections (CA-BSIs) are an important complication of care in children hospitalized with complex congenital heart disease; however, little is known about risk factors for CA-BSI in these patients. METHODS: We conducted a retrospective nested case-control study in the 26-bed Cardiac Intensive Care Unit (CICU) at the Children's Hospital of Philadelphia.We identified all primary CA-BSIs in the CICU between January 1, 2004 and June 30, 2005. Controls were selected from rosters of CICU patients that were admitted during the same time period. Incidence density sampling was used to match cases and controls on time at risk. Data on demographic features and clinical characteristics were abstracted from the medical record. In addition, detailed data on exposures to medical devices, interventions, and therapeutic agents were gathered during a 4-day period immediately before the onset of infection (cases) or study entry (controls). RESULTS: We identified 59 children who developed a CA-BSI. The median time from catheter insertion to onset of infection was 9 days. Over half of infections were caused by gram positive organisms. On multivariable analysis, only tunneled catheters emerged as an independent risk factor for infection. CONCLUSION: In this study population, tunneled catheters were associated with a higher risk of CA-BSI, possibly because of the catheter material. Additionally, we did not find that the burden of catheters and medical devices was associated with an increased risk of infection. Because most CA-BSIs in our study population occurred > or =7 days after catheter insertion, strict attention to aseptic technique when using or dressing a catheter might reduce CA-BSI rates in the pediatric CICU. PMID- 20720471 TI - Role of human coronavirus NL63 in hospitalized children with croup. AB - BACKGROUND: Human coronavirus NL63 (HCoV-NL63) has recently been implicated as a common cause of croup in children. This study was performed to evaluate viruses associated with croup in children, with an emphasis on HCoV-NL63. METHODS: Nasopharyngeal aspirates were prospectively collected from 182 children hospitalized with croup at Seoul National University Bundang Hospital from January 2005 to June 2009. Multiplex reverse-transcriptase polymerase chain reaction was conducted for detection of 11 respiratory viruses, and medical records were reviewed. RESULTS: Viruses were identified in 147 (80.8%) of the 182 croup patients. The 3 most commonly detected viruses were parainfluenza virus type 1 (PIV1) in 44 (24.2%) patients, HCoV-NL63 in 30 (16.5%) patients, and influenza A virus in 25 (13.7%) patients. Other detected viruses were rhinovirus in 22 (12.1%) patients, PIV type 3 and respiratory syncytial virus in 15 (8.2%) patients, human bocavirus in 8 (4.4%) patients, and several others in a few patients. Coinfections with > or = 2 viruses were found in 20 (11%) patients. HCoV-NL63 was identified primarily in winter, which coincides with the peak occurrence of croup. Patients with HCoV-NL63 infection were younger than those who were positive for PIV1 (median age 13 months versus 21 months, P = 0.006) and had shorter fever duration than influenza A virus infection (median 1.5 days versus 4 days, P = 0.000). CONCLUSIONS: PIV1 and HCoV-NL63 were most commonly associated with patients who were hospitalized with croup. HCoV-NL63 is prevalent in winter and is associated with younger age and with shorter fever duration. PMID- 20720472 TI - Staphylococcus aureus pathogenesis: secretion systems, adhesins, and invasins. PMID- 20720473 TI - Purpose and design of antimicrobial stewardship programs in pediatrics. PMID- 20720474 TI - A four-week-old infant with an intracardiac mass. PMID- 20720475 TI - Pediatric acute pancreatitis related to tigecycline. PMID- 20720476 TI - Use of abacavir in 30 HIV-infected children from Durban, South Africa: report from a pilot study. PMID- 20720477 TI - A presumed tubercular choroiditis based on interferon-gamma release assay and response to therapy. PMID- 20720478 TI - Reconstruction of pancreatic duct for previous Puestow operation for an islet autotransplantation. PMID- 20720479 TI - Low variability of intraindividual longitudinal leukocyte gene expression profiling cardiac allograft rejection scores. PMID- 20720480 TI - Malakoplakia-induced diarrhea in a kidney transplant recipient. PMID- 20720481 TI - Intravascular route is not superior to an intraperitoneal route for in utero transplantation of human hematopoietic stem cells and engraftment in sheep. PMID- 20720482 TI - Acute sickle hepatic crisis after liver transplantation in a patient with sickle beta-thalassemia. PMID- 20720483 TI - Initial experience with a technique for wound closure after cardiac device implantation designed to reduce infection and minimize tissue scar formation. AB - Infection is a well-recognized complication that can occur after the implantation of cardiac devices such as pacemakers and implantable cardioverter defibrillators (ICDs). Reported infection rates after new device implantation are reported to be around 1%, while infection rates after device generator replacements are higher with a reported average of up to 4-5% per year. Here we report our experience using a modified plastic surgical technique for cardiac device wound closure designed to both reduce infections and enhance cosmetic outcomes. Patients were recruited from among those individuals undergoing routine cardiac device implantation (either new or replacement) at our institution. A total of 124 patients were included in the study. There were 74 women and 48 men, mean age 58 +/- 16 years. There were 74 new pacemaker implants and 27 pacemaker generator replacements. There were 17 new ICD generator implants and 6 ICD generator reimplants. Mean follow-up time was 15 +/- 16 months. During the follow-up period, there have been no device infections nor any wound dehiscences observed. Each patient felt that the scar was cosmetically acceptable. Two patients developed mild rashes to the clear plastic adhesive that resolved after removal. The modified wound closure technique described above appears to minimize cardiac device wound infections while facilitating cosmetically acceptable wound scar formation. PMID- 20720484 TI - Use of heptaminol hydrochloride for catecholamine weaning in septic shock. AB - We analyze in the current study the impact of heptaminol hydrochloride (Heptamyl) administration in patients with septic shock requiring adrenergic support on the duration of vasopressor infusion and on catecholamine delay weaning. In this prospective study were included 49 nonconsecutive patients with septic shock requiring vasopressor infusion and with stable hemodynamic parameters during more than 24 hours. All these patients were included in a random way to receive or not heptaminol hydrochloride. The primary end point was the effect of heptaminol hydrochloride administration on duration of weaning, defined as cessation of vasopressor support. There were 32 males (65%) and 17 females (35%). The mean age (+/- standard deviation) was 53.9 +/- 22.2 years. Norepinephrine was the most commonly used vasopressor agent (73.4%). The comparison between two groups (with and without heptaminol hydrochloride) showed that two groups had the same epidemiologic, clinical, and biologic findings on intensive care unit admission. In our study, we found that the introduction of Heptamyl was associated with a quick decrease of dose of dopamine and norepinephrine in comparison with the Heptamyl-free group. By comparing the two groups, we found that the delay of catecholamine weaning was significantly faster for the dopamine (P = 0.008) and noradrenalin (P = 0.001) in the Heptamyl group. Finally, the intensive care unit mortality rate and the hospital mortality rate were significantly lower in the Heptamyl group. Our study shows a reduction in norepinephrine and dopamine weaning duration in septic patients enrolled in the heptaminol hydrochloride group. PMID- 20720485 TI - The effect of statin therapy on ventricular tachyarrhythmias: a meta-analysis. AB - The objective of this study was to assess whether statin therapy is associated with a reduction in ventricular tachyarrhythmias. Statins have been shown to be beneficial beyond their cholesterol-lowering effects. These pleiotropic effects have been implicated in the protection against atrial fibrillation and the reduction in appropriate implantable cardioverter-defibrillator therapy in patients with coronary artery disease. This meta-analysis was conducted to evaluate whether statins were associated with a reduction in ventricular tachyarrhythmias in patients with coronary artery disease or nonischemic cardiomyopathy. The Medline and Cochrane databases were searched for studies in human subjects published in the English language between 1985 and February 2010. Studies were included in our analysis if they provided data regarding the association between the use of statins and the incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with coronary artery disease or nonischemic cardiomyopathy. The occurrence of ventricular arrhythmias was defined as the VT/VF occurrence or appropriate implantable cardioverter defibrillator therapy for VT/VF. Of the 166 identified articles, nine prospective studies with 150,953 patients enrolled met our inclusion criteria and were included in this analysis. Using a random effects model, statin therapy was associated with a 31% reduction in the risk of VT/VF when compared with the group not on statin therapy (pooled relative risk = 0.69, 95% confidence interval, 0.58 0.83; heterogeneity I2 = 57.3%). There was a low likelihood of publication bias in this analysis (Egger's test P = 0.957). Statin use in patients with coronary artery disease or nonischemic cardiomyopathy is associated with a 31% reduction in the development of ventricular tachyarrhythmias. PMID- 20720486 TI - Efficacy of hybrid therapy in the form of right atrial ablation and adjunctive therapy in refractory atrial fibrillation in symptomatic patients. AB - Symptomatic atrial fibrillation is often treated with antiarrhythmic drugs. Responsiveness is poor and adverse effects common. Nonpharmacologic treatments consisting of the Maze procedure and catheter-based pulmonary vein isolation are highly successful but invasive with complications. Right atrial ablation is relatively simple in comparison. Success ranges between 20% and 80%. Some studies have shown improved response when combined with antiarrhythmic drugs (AADs). We performed a review of available literature to determine the efficacy of hybrid therapy in the form of right atrial ablation, AAD with cardioversion, and pacing in reducing atrial fibrillation burden. All human studies studying efficacy of right atrial ablation and postablation AAD therapy in refractory atrial fibrillation were considered. The primary outcome was reduction of atrial fibrillation burden. The secondary outcome was significant adverse events. We searched Medline, EMBASE, CINAHL, and Cochrane databases. Data collection, analysis, and selection of studies were done independently by two review authors. We included six studies with variable numbers of participants and outcomes. We defined success of hybrid therapy as reduced burden of atrial fibrillation. Total subjects studied was 189, 26% female and 74% male. Average age was 58 years. Left atrial diameter was less than 5 cm and mean ejection fraction was 64%. Mean atrial fibrillation duration was 3.35 years. Most patients had failed at least two AADs. Hybrid therapy was successful in 82% patients. All forms of hybrid therapy consisting of right atrial ablation and AAD therapy seem to be reasonably effective in relief of symptoms from refractory atrial fibrillation with minimal side effects; however, much larger randomized trials need to be performed before a significant superiority of any one may be established. PMID- 20720487 TI - Innate immunity, allergy and atopic dermatitis. AB - PURPOSE OF REVIEW: We review here the recent discoveries in innate immunity that shed light on the pathophysiology of atopic dermatitis. RECENT FINDINGS: The mechanisms that promote the enhanced susceptibility to cutaneous infections in atopic dermatitis are complex interactions among several factors. They include skin barrier dysfunction, reduced skin lipid content, and abnormalities of the innate immune response. Some of the innate immune defects observed in atopic dermatitis are primary defects, such as epithelial barrier defects and defects in signaling or expression of innate receptors. Others may be secondary to the effects of the adaptive immune response. For example, deficiencies in antimicrobial peptides may be due to the overexpression of T helper 2 cytokines such as interleukin-4 and interleukin-13. However, how all components interact with each other remains to be fully investigated. SUMMARY: To break this vicious circle, a multiprolonged approach directed at healing or protecting the skin barrier and addressing the immune dysregulation is necessary to improve and control the disease. PMID- 20720488 TI - Atopic keratoconjunctivitis and atopic dermatitis. AB - PURPOSE OF REVIEW: This review will focus on the diagnostic features of atopic keratoconjunctivitis (AKC), its relationship to atopic dermatitis, the immunopathogenesis, and therapy, and will include strategies used for the management of severe disease unresponsive to conventional therapy. RECENT FINDINGS: Recent research has demonstrated the importance of various cytokines (IL-33), proteins (thymic stromal lymphopoetin) and effector cells (conjunctival epithelial cells, eosinophils and basophils) in the pathogenesis of chronic ocular inflammation. Current evidence supports the use of tacrolimus and cyclosporin A, topically or systemically, as well tolerated and effective steroid sparing agents. SUMMARY: Recalcitrant AKC may be a blinding condition. Understanding the immunopathogenesis of atopic dermatitis and AKC has already influenced therapy and is essential to the development of future immunomodulatory treatments. The successful management of AKC requires the use of topical cromones, antihistamines and calcineurin inhibitors. Severely affected patients also require systemic immunosuppressive therapy. The current challenge is to find more specific topical and systemic immunomodulatory therapies with a better side effect profile. PMID- 20720489 TI - Treatment of seasonal allergic conjunctivitis with ophthalmic corticosteroids: in search of the perfect ocular corticosteroids in the treatment of allergic conjunctivitis. AB - PURPOSE OF REVIEW: Corticosteroids are an effective short-term treatment option for seasonal allergic conjunctivitis (SAC). Their use has been limited due to their side effects and has led to the development of modified 'soft', 'smart' ophthalmic corticosteroid formulations that retain their anti-inflammatory mechanism of action with an improved safety profile. RECENT FINDINGS: Similar to the development of the prodrug concept for the nose and lung that led to the development of ciclesonide, a chloromethyl-ester group substitution at the carbon 20 (C-20) position of the traditional corticosteroid has led to the development of a family of potential ophthalmic corticosteroids including loteprednol etabonate that has demonstrated similar efficacy to the C-20 ketone corticosteroids in the treatment of the signs and symptoms of ocular allergies, but less likely to induce elevations in intraocular pressure (IOP) or the formation of cataracts. The C-20 ester corticosteroid, loteprednol etabonate has been designed to be rapidly converted to an inactive, nontoxic metabolite, thus minimizing adverse effects, and loteprednol etabonate (0.2%) is currently the only ophthalmic corticosteroid specifically developed for and approved by the Food and Drug Administration for treatment of SAC. SUMMARY: The development of modified or soft, smart corticosteroids such as loteprednol etabonate provides an avenue for expanding the treatment of the inflammation associated with signs and symptoms in patients with chronic forms or severe acute exacerbations of allergic conjunctivitis. Modified corticosteroids are an effective and well tolerated option for the short-term treatment of the inflammation and signs and symptoms associated with SAC. PMID- 20720491 TI - The evolution and clinical impact of human leukocyte antigen technology. AB - PURPOSE OF REVIEW: As human leukocyte (HLA) antigen and antibody testing has evolved, typing, screening, and crossmatching assays have become exquisitely specific and sensitive. How best to use this information is a focal point of the transplant community and of this review. RECENT FINDINGS: Driven by advances in technology, two major changes in the transplant community recently occurred. Firstly, the United Network for Organ Sharing mandated the use of cPRA to replace the more subjective panel reactive antibody value. Secondly, the virtual crossmatch (vXM) became a reality. The vXM categorizes sensitized patients as compatible or incompatible with their donors by predicting the likelihood of a positive crossmatch. Although the use of cPRA and vXM represents major progress in organ allocation algorithms, there are compelling issues that must be addressed. These include defining appropriate threshold values for antibody assignment and recognizing the relevance of antibodies to HLA-Cw*, HLA-DQ*, and HLA-DP*. SUMMARY: Undoubtedly, molecular HLA-typing and solid-phase antibody detection assays have revolutionized clinical histocompatibility testing. These new testing methodologies have had a major impact in both allocation and outcome of transplanted kidneys. However, even these new methodologies are not flawless and pose new challenges to the transplant community. PMID- 20720490 TI - Resident intimal dendritic cells and the initiation of atherosclerosis. AB - PURPOSE OF REVIEW: To highlight the fact that regional differences in the normal arterial intima are critical to atherosclerotic lesion formation driven by systemic risk factors. RECENT FINDINGS: At arterial curvatures, bifurcations and branches unique hemodynamics influence endothelial cell signaling and gene expression patterns, which create a proinflammatory environment, with low-grade recruitment of monocytes and accumulation of cells with dendritic features in the intima. Upon induction of hypercholesterolemia, these resident intimal dendritic cells initiate atherosclerosis by rapidly engulfing lipid and becoming the first foam cells in nascent lesions. This step precedes endothelial cell activation and increased monocyte recruitment. SUMMARY: The unique features of the arterial intima at atherosclerosis-susceptible sites do not lead to disease under normal physiological conditions, but this intimal environment promotes the initiation of atherogenesis upon induction of systemic risk factors such as hypercholesterolemia. PMID- 20720492 TI - Heart transplantation. AB - PURPOSE OF REVIEW: This paper briefly and subjectively reviews a number of the modest or tentative, but noteworthy, advances in heart transplantation that have been made during the past 18 months or so. RECENT FINDINGS: The advances reviewed concern the selection of recipients, the management of the heart transplantation waiting list, the management of donors, post-heart transplant monitoring of immunological status, the early diagnosis of rejection, the role of mammalian target of rapamycine inhibitors and induction agents, and the definition and grading of cardiac allograft vasculopathy. SUMMARY: The findings reviewed indicate progress in the clarification of issues that were in most cases already being investigated. Further studies will in general be needed before corresponding measures are adopted in clinical practice. PMID- 20720493 TI - Pharmacogenetics in immunosuppressants: impact on dose requirement of calcineurin inhibitors in renal and liver pediatric transplant recipients. AB - PURPOSE OF REVIEW: Calcineurin inhibitors (CNI) are the mainstay immunosuppressive therapy in pediatric solid organ transplantation. These drugs have narrow therapeutic window, and continuous therapeutic drug monitoring is required to keep blood levels within the therapeutic range. Personalization of immunosuppressive therapy according to the genetic profile may provide a way to optimize drug dosing from the first day of transplantation. In this review, we will highlight the recent pharmacogenetic studies of CNIs in pediatric renal and liver transplantation. RECENT FINDINGS: CNIs are metabolized by CYP3A4 and CYP3A5. In the intestine, the absorption of these drugs is limited by the P glycoprotein efflux transporter. Most of the pediatric studies showed an association between CYP3A5 genetic variation and CNI dosing. Carriers of the wild type allele (CYP3A5*1) required higher doses of CNIs as compared with individuals homozygous to the variant CYP3A5*3 allele. CYP3A4 and ABCB1 (encoding P glycoprotein) genetic variations did not show an association with CNI dosing. SUMMARY: The pharmacogenetics of CNIs has been widely investigated in adults, little is known about this field in the pediatric groups. Prospective studies are needed to elucidate the effect of genetic variations on CNI drug dosing and to investigate their impact on short and long-term clinical outcome. PMID- 20720494 TI - Allergic bronchopulmonary aspergillosis and Aspergillus infection in cystic fibrosis. AB - PURPOSE OF REVIEW: Recent literature on Aspergillus fumigatus infection and allergy in cystic fibrosis have expanded our understanding of many aspects of allergic bronchopulmonary aspergillosis, and bring new attention to A. fumigatus airways infection and A. fumigatus allergy without allergic bronchopulmonary aspergillosis (ABPA). RECENT FINDINGS: ABPA, A. fumigatus infection and A. fumigatus allergy without ABPA all likely worsen cystic fibrosis (CF) lung disease. Studies examining utility of new serologic assays for diagnosing ABPA include evaluations of standardized measurement of A. fumigatus-specific IgG, serum chemokine TARC levels, and recombinant A. fumigatus allergens; as yet, none appear ideal. Although oral glucocorticoids remain primary therapy, toxicity and incomplete control have led to an ongoing search for further safe and effective agents including itraconazole and voriconazole, intravenous pulse methylprednisolone, nebulized amphotericin B and omalizumab. Little controlled treatment data is available. SUMMARY: Diagnosis of CF-ABPA remains difficult, but improvements in serologic assays are occurring. Treatment remains in many cases unsatisfactory, and new agents offer promise but await proper controlled trials of safety and efficacy. A. fumigatus airway infection and A. fumigatus allergy without ABPA are emerging as further complications of A. fumigatus respiratory colonization in patients with CF, but prospective studies are needed to corroborate largely retrospective findings. PMID- 20720495 TI - Animal models of scleroderma: fresh insights. AB - PURPOSE OF REVIEW: Recent years have seen the advent and progress in our understanding of fibrosis and vasculopathy in systemic sclerosis, scleroderma (SSc) largely mediated through the development and study of novel animal models. The most well studied animal models of SSc involve the bleomycin model of induced fibrosis and the Tsk/+ model. However, even though these models provide useful insights into the pathogenesis of fibrosis and vasculopathy, they do not mimic the disease accurately. RECENT FINDINGS: Several mouse models have been developed that have specifically focused on the vasculopathy of SSc and have yielded relevant insights into this disorder further highlighting the novel mechanisms that may be responsible for this pathological feature. Furthermore, the contribution of the innate immune system mediated by the inflammasome in the induction of fibrosis has also demonstrated significant insights, possibly implicating an etiological mechanism of SSc. And recent transgenic or knockout animal models have emphasized the relevance of macrophage chemoattractant protein 1 (MCP-1), alpha-melanocyte stimulating hormone (alpha-MSH), and peroxisome proliferator-activated receptor-gamma (PPARgamma) in fibrosis. SUMMARY: Recent advances in animal models of SSc have elucidated the involvement of relevant proteins that appear to mediate vasculopathy and also implicated the involvement of the innate immune system in fibrosis. These models have identified novel therapeutic targets that may lead to more effective treatments for this incurable disease. PMID- 20720496 TI - Less is not always more: sugammadex and the risk of under-dosing. PMID- 20720497 TI - Increased coronary artery calcium score and noncalcified plaque among HIV infected men: relationship to metabolic syndrome and cardiac risk parameters. AB - OBJECTIVE: In this study, the effects of traditional cardiac risk factors on coronary artery calcium (CAC) score and presence of plaque, including noncalcified plaque, measured by computed tomography coronary angiography, were compared among HIV-infected and non-HIV-infected subjects, with respect to the presence of the metabolic syndrome (MS). DESIGN AND METHODS: HIV-infected men recruited for the presence of the MS (HIV + MS, n = 27) were compared with 2 control groups, HIV-infected men recruited without regard to metabolic criteria (HIV, n = 87), and HIV-negative control men (C, n = 40), also recruited without regard to any metabolic criterion. RESULTS: All 3 groups were similar in age, demographic parameters, and smoking. MS was seen in 100% of the HIV + MS group, compared with 28% in the HIV-infected control group and 11% in the HIV-negative controls. HIV + MS subjects had higher mean CAC score than HIV-infected controls (72 +/- 25 vs. 30 +/- 8, P = 0.04, HIV + MS vs. HIV) and HIV-negative controls (72 +/- 25 vs. 18 +/- 7; P = 0.02, HIV + MS vs. C). With respect to CAC, only the HIV + MS group had increased CAC compared with non-HIV. In contrast, both HIV groups demonstrated an increased prevalence of plaque [63% vs. 38%, P = 0.04 (HIV + MS vs. C) and 59% vs. 38%, P = 0.02, (HIV vs. C)] and increased number of noncalcified plaque segments compared with the HIV-negative group [1.26 +/- 0.31 vs. 0.45 +/- 0.16, P = 0.01 (HIV + MS vs. C); 1.02 +/- 0.18 vs. 0.45 +/- 0.16, P = 0.04 (HIV vs. C)]. Plaque and noncalcified plaque did not differ significantly between the HIV groups. CONCLUSIONS: Metabolic abnormalities in HIV patients are specifically associated with increased coronary artery calcification, whereas HIV itself or other factors may be associated with the development of noncalcified lesions. PMID- 20720498 TI - Involvement of prostaglandin F2alpha in preeclamptic human umbilical vein vasospasm: a role of prostaglandin F and thromboxane A2 receptors. AB - OBJECTIVE: Preeclampsia is characterized by hypertension and proteinuria developing after 20 weeks of gestation. Increased vasoconstriction can be one of the major underlying pathophysiological event in this syndrome. We examined the role of vasoconstrictor prostanoid, prostaglandin F2alpha (PGF2alpha) in preeclamptic and normotensive human umbilical veins. METHODS: Umbilical veins were set up in organ bath. The concentration-response curves of PGF2alpha (endogenous agonist of prostaglandin F receptor) and fluprostenol (prostaglandin F receptor selective agonist) were determined in normal and preeclamptic veins either in the absence or presence of BAY u3405 (thromboxane A2 receptor selective antagonist). PGF2alpha and its major metabolite concentrations were measured by enzyme immunoassay kit. The expression of vasoconstrictor prostanoid receptors was determined by western blot. RESULTS: The concentration-dependent contractions to PGF2alpha and fluprostenol were significantly increased in umbilical vein preparations derived from preeclamptic women compared with those of normotensives. Increased reactivity was related with enhanced sensitivity to these spasmogens in preeclamptic veins. BAY u3405 (10 MUmol/l) did not modify the responsiveness to PGF2alpha in normal umbilical veins whereas moderately reduced the contractions in preeclamptic preparations. Serum concentrations of PGF2alpha and its major metabolite, 13,14-dihydro-15-keto-PGF2alpha, were comparable between preeclamptics and normotensives whereas the metabolite concentration was elevated in umbilical cord serum of preeclamptics. 13,14-dihydro-15-keto PGF2alpha, release was also increased in umbilical vein preparations of preeclamptic women. An increased prostaglandin F receptor protein expression was determined whereas EP3 and thromboxane A2 protein expressions were unchanged in preeclamptic umbilical veins. CONCLUSION: Prostaglandin F and thromboxane A2 receptors activation by PGF2alpha could be involved in umbilical vasospasm observed in preeclampsia. PMID- 20720499 TI - Blood pressure and survival in long-term hemodialysis patients with and without polycystic kidney disease. AB - BACKGROUND: In maintenance dialysis patients, low blood pressure (BP) values are associated with higher death rates when compared with normal to moderately high values. This 'hypertension paradox' may be related to comorbid conditions. Dialysis patients with polycystic kidney disease (PKD) usually have a lower comorbidity burden and greater survival. We hypothesized that in PKD dialysis patients, a representative of a healthier dialysis patient population, high BP is associated with higher mortality. METHODS: Time-dependent survival models including after multivariate adjustment were examined to assess the association between prehemodialysis and posthemodialysis BP and all-cause mortality in a 5 year cohort of 67 085 non-PKD and 1579 PKD hemodialysis patients. RESULTS: In PKD patients, low prehemodialysis and posthemodialysis SBPs were associated with increased mortality, whereas high prehemodialysis DBP was associated with greater survival. Fully adjusted death hazard ratios (and 95% confidence levels) for prehemodialysis and posthemodialysis BP of less than 120 mmHg (reference 140 to <160 mmHg) were 1.30 (1.06-1.92) and 1.45 (1.04-2.02), respectively, and for prehemodialysis DBP of 80 mmHg or more (reference 70 to <80 mmHg) was 0.68 (0.49 0.93, all P values <0.05). Similar associations were observed in non-PKD patients. In pooled analyses, within each commensurate BP stratum, PKD patients exhibited superior survival to non-PKD patients. CONCLUSION: Among hemodialysis patients, those with PKD display a similar BP paradox as those without PKD, even though within each BP category PKD patients maintain superior survival. Randomized clinical trials are needed to define optimal blood pressure targets in the hemodialysis population. PMID- 20720500 TI - Glomerular hemodynamics and arterial function in normal individuals. AB - OBJECTIVE: To determine the relationship between arterial function (stiffness and wave reflection) and glomerular hemodynamics. METHODS: In 49 healthy normotensive individuals, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by urinary clearances of 99mTC-DTPA and 131I-hippuran, respectively. Filtration fraction was computed as GFR/ERPF. Arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV). Wave reflection was evaluated by carotid augmentation index (AIx), reflection magnitude and the round trip travel time of the pressure wave. RESULTS: PWV and round-trip travel time were not independently correlated with any renal hemodynamic parameter or urinary albumin-creatinine ratio (UACR). AIx and reflection magnitude were directly correlated with filtration fraction (r = 0.35 and 0.37, respectively) and UACR (r = 0.43 and 0.53, respectively). When the population was divided into quartiles of reflection magnitude, filtration fraction and UACR progressively increased from the lowest to the highest quartile and after adjustment for age, mean arterial pressure, heart rate but also sex for UACR (P linear trend = 0.031 and 0.001, respectively). CONCLUSION: It is suggested that in normal individuals, the amplitude of wave reflection but not arterial stiffness is associated with signs evocative of increased glomerular pressure (filtration fraction and UACR), independently of systemic blood pressure. PMID- 20720501 TI - Human umbilical cord-derived mesenchymal stromal cells differentiate into functional Schwann cells that sustain peripheral nerve regeneration. AB - Human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) that are available from cell banks can be induced to differentiate into various cell types, thereby making them practical potential sources for cell-based therapies. In injured peripheral nerves, Schwann cells (SCs) contribute to functional recovery by supporting axonal regeneration and myelin reconstruction. Here, we first demonstrate a system to induce UC-MSCs to differentiate into cells with SC properties (UC-SCs) by treatment with beta-mercaptoethanol followed by retinoic acid and a set of specific cytokines. The UC-SCs are morphologically similar to SCs and express SC markers, including P0, as assessed by immunocytochemistry and reverse transcription polymerase chain reaction. Transplantation of UC-SCs into transected sciatic nerves in adult rats enhanced nerve regeneration. The effectiveness of UC-SCs for axonal regeneration was comparable to that of authentic human SCs based on histological criteria and functional recovery. Immunohistochemistry and immunoelectron microscopy also demonstrated myelination of regenerated axons by UC-SCs. These findings indicate that cells with SC properties and with the ability to support axonal regeneration and reconstruct myelin can be successfully induced from UC-MSCs to promote functional recovery after peripheral nerve injury. This system may be applicable for the development of cell-based therapies. PMID- 20720502 TI - Leucine-rich repeat kinase 2 is associated with the endoplasmic reticulum in dopaminergic neurons and accumulates in the core of Lewy bodies in Parkinson disease. AB - Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequent genetic cause of Parkinson disease (PD). To understand the role of LRRK2 in the neuropathology of PD, we investigated the protein expression in a healthy brain and brains from patients with PD and its subcellular localization in dopaminergic neurons. LRRK2 was found to be widely expressed in healthy adult brain, including areas involved in PD. By double fluorescent staining, we found that endogenous LRRK2 is colocalized with the endoplasmic reticulum (ER) markers Neurotrace and KDEL in human dopaminergic neurons. Labeling of brain sections with anti-LRRK2 and anti-alpha-synuclein antibodies revealed localization of LRRK2 in the core of 24% of Lewy bodies (LBs) in the substantia nigra and 11% of LBs in the locus coeruleus in idiopathic PD patients. The percentage was increased to 50% in both areas in a patient with the G2019S LRRK2 mutation. The finding of ER localization suggests the possibility that LRRK2 is involved in the ER stress response and could account for the susceptibility to neuronal degeneration of LRRK2 mutation carriers. The localization of LRRK2 protein in the core of a subset of LBs demonstrates the contribution of LRRK2 to LB formation and disease pathogenesis. PMID- 20720503 TI - Axonal pathology precedes demyelination in a mouse model of X-linked demyelinating/type I Charcot-Marie Tooth neuropathy. AB - The X-linked demyelinating/type I Charcot-Marie-Tooth neuropathy (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32. Connexin32 is expressed by myelinating Schwann cells and forms gap junctions in noncompact myelin areas, but axonal involvement is more prominent in X-linked compared with other forms of demyelinating Charcot-Marie-Tooth disease. To clarify the cellular and molecular mechanisms of axonal pathology in CMT1X, we studied Gjb1-null mice at early stages (i.e. 2-4 months old) of the neuropathy, when there is minimal or no demyelination. The diameters of large myelinated axons were progressively reduced in Gjb1-null mice compared with those in wild-type littermates. Furthermore, neurofilaments were relatively more dephosphorylated and more densely packed starting at 2 months of age. Increased expression of beta-amyloid precursor protein, a marker of axonal damage, was also detected in Gjb1-null nerves. Finally, fast axonal transport, assayed by sciatic nerve ligation experiments, was slower in distal axons of Gjb1-null versus wild-type animals with reduced accumulation of synaptic vesicle-associated proteins. These findings demonstrate that axonal abnormalities including impaired cytoskeletal organization and defects in axonal transport precede demyelination in this mouse model of CMT1X. PMID- 20720504 TI - Response of human oligodendrocyte progenitors to growth factors and axon signals. AB - We examined the effects of growth factors and axonal signals on the differentiation of human fetal and adult oligodendrocyte progenitor cells (OPCs) and determined whether these effects translated into enhanced axonal ensheathment. Only small numbers of fetal OPCs grown in defined medium expressed the oligodendroglial lineage markers Olig2 and O4. The combination of platelet derived growth factor-AA and basic fibroblast growth factor enhanced proliferation of Olig2-positive and O4-positive cells; a combination of brain derived neurotrophic factor and insulin-like growth factor 1 promoted O4-positive cell differentiation, galactocerebroside expression, and morphological complexity. Coculturing with rodent dorsal root ganglion neurons in defined medium alone enhanced OPC differentiation and myelin basic protein expression. The addition of brain-derived neurotrophic factor/insulin-like growth factor 1 further enhanced differentiation, axonal attachment and ensheathment, and clustering of the contactin-associated protein Caspr and Na+ channels. By contrast, most adult OPCs were O4 positive and Olig2 positive in defined medium; both brain-derived neurotrophic factor/insulin-like growth factor 1 and platelet derived growth factor-AA/basic fibroblast growth factor promoted their myelin basic protein expression and membrane sheet formation; coculture with dorsal root ganglion neurons further increased myelin basic protein expression. Growth factors also enhanced attachment of adult OPCs to axons, but their capacity to ensheath axons was lower than that of fetal OPCs. These results demonstrate that fetal and adult OPCs show measurable responses to selected growth factors and axon signals that correlate with their capacity for axon ensheathment. The distinct properties of fetal and adult OPCs may be related to differences in their chronological age and initial differentiation states. PMID- 20720506 TI - Hyperdopaminergic status in experimental Huntington disease. AB - Huntington disease has been linked to increased dopaminergic neurotransmission in the striatum, and clinical studies have demonstrated that the associated chorea can be treated with dopamine antagonist or dopamine-depleting drugs. The origin of this hyperdopaminergic status is unknown. Because substantia nigra pars compacta and the ventral tegmental area are the main sources of striatal dopamine input, we hypothesized that changes in these regions relate to striatal dopaminergic alterations. Here, in a recently generated transgenic rat Huntington disease model that shows progressive striatal neurodegeneration and chorea, we found evidence of increased dopamine levels in the striatum. We also demonstrate more dopaminergic cells in the substantia nigra pars compacta and ventral tegmental area in these rats. These results suggest that increased striatal dopamine comes from these 2 main nuclei, and that it is not necessarily related to shrinkage of the striatum. The findings implicate increased dopamine input from these nuclei in the pathogenesis of chorea in Huntington disease. PMID- 20720505 TI - TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. AB - Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of beta-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43-positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease. PMID- 20720507 TI - Novel characterization of monocyte-derived cell populations in the meninges and choroid plexus and their rates of replenishment in bone marrow chimeric mice. AB - The mouse dura mater, pia mater, and choroid plexus contain resident macrophages and dendritic cells (DCs). These cells participate in immune surveillance, phagocytosis of cellular debris, uptake of antigens from the surrounding cerebrospinal fluid and immune regulation in many pathologic processes. We used Cx3cr1 knock-in, CD11c-eYFP transgenic and bone marrow chimeric mice to characterize the phenotype, density and replenishment rate of monocyte-derived cells in the meninges and choroid plexus and to assess the role of the chemokine receptor CX3CR1 on their number and tissue distribution. Iba-1 major histocompatibility complex (MHC) Class II CD169 CD68 macrophages and CD11c putative DCs were identified in meningeal and choroid plexus whole mounts. Comparison of homozygous and heterozygous Cx3cr1 mice did not reveal CX3CR1 dependancy on density, distribution or phenotype of monocyte-derived cells. In turnover studies, wild type lethally irradiated mice were reconstituted with Cx3cr1/-positive bone marrow and were analyzed at 3 days, 1, 2, 4 and 8 weeks after transplantation. There was a rapid replenishment of CX3CR1-positive cells in the dura mater (at 4 weeks) and the choroid plexus was fully reconstituted by 8 weeks. These data provide the foundation for future studies on the role of resident macrophages and DCs in conditions such as meningitis, autoimmune inflammatory disease and in therapies involving irradiation and hematopoietic or stem cell transplantation. PMID- 20720508 TI - Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease. AB - Motor dysfunction, cognitive impairment, and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1, and Lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the Lin7 homolog b ([Lin7b] also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. Lin7 homolog b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth, and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD. PMID- 20720510 TI - US pharmacists' effect as team members on patient care: systematic review and meta-analyses. AB - BACKGROUND: One approach postulated to improve the provision of health care is effective utilization of team-based care including pharmacists. OBJECTIVE: The objective of this study was to conduct a comprehensive systematic review with focused meta-analyses to examine the effects of pharmacist-provided direct patient care on therapeutic, safety, and humanistic outcomes. METHODS: The following databases were searched from inception to January 2009: NLM PubMed; Ovid/MEDLINE; ABI/INFORM; Health Business Fulltext Elite; Academic Search Complete; International Pharmaceutical Abstracts; PsycINFO; Cochrane Database of Systematic Reviews; National Guideline Clearinghouse; Database of Abstracts of Reviews of Effects; ClinicalTrials.gov; LexisNexis Academic Universe; and Google Scholar. Studies selected included those reporting pharmacist-provided care, comparison groups, and patient-related outcomes. Of these, 56,573 citations were considered. Data were extracted by multidisciplinary study review teams. Variables examined included study characteristics, pharmacists' interventions/services, patient characteristics, and study outcomes. Data for meta-analyses were extracted from randomized controlled trials meeting meta analysis criteria. RESULTS: A total of 298 studies were included. Favorable results were found in therapeutic and safety outcomes, and meta-analyses conducted for hemoglobin A1c, LDL cholesterol, blood pressure, and adverse drug events were significant (P < 0.05), favoring pharmacists' direct patient care over comparative services. Results for humanistic outcomes were favorable with variability. Medication adherence, patient knowledge, and quality of life-general health meta-analyses were significant (P < 0.05), favoring pharmacists' direct patient care. CONCLUSIONS: Pharmacist-provided direct patient care has favorable effects across various patient outcomes, health care settings, and disease states. Incorporating pharmacists as health care team members in direct patient care is a viable solution to help improve US health care. PMID- 20720509 TI - Brain aquaporin-4 in experimental acute liver failure. AB - Intracranial hypertension caused by brain edema and associated astrocyte swelling is a potentially lethal complication of acute liver failure (ALF). Mechanisms of edema formation are not well understood, but elevated levels of blood and brain ammonia and its by-product glutamine have been implicated in this process. Since aquaporin-4 (AQP4) has been implicated in brain edema in other conditions, we examined its role in a rat model of ALF induced by the hepatotoxin thioacetamide. Rats with ALF showed increased AQP4 protein in the plasma membrane (PM). Total tissue levels of AQP4 protein and mRNA levels were not altered, indicating that increased AQP4 is not transcriptionally mediated but likely reflects a more stable anchoring of AQP4 to the PM and/or interference with its degradation. An increase inAQP4 immunoreactivity in thePM was observed in perivascular astrocytes in ALF. Rats with ALF also showed increased levels of alpha-syntrophin, a protein involved in anchoringAQP4 to perivascular astrocytic end-feet. Increased AQP4 andalpha-syntrophin levels were inhibited by L-histidine, an inhibitor of glutamine transport into mitochondria, suggesting a role for glutamine in the increase of PM levels of AQP4. These results indicate that increased AQP4 PM levels in perivascular astrocytic end-feet are likely critical to the development of brain edema in ALF. PMID- 20720511 TI - Estradiol gel 0.1% relieves vasomotor symptoms independent of age, ovarian status, or uterine status. AB - OBJECTIVE: Data from a pivotal efficacy trial have been reanalyzed to explore the impact of age, uterine status, and ovarian status on the efficacy of estradiol gel 0.1% (Divigel) for the treatment of moderate to severe vasomotor symptoms associated with menopause. METHODS: Post hoc analyses were performed on data from a phase III clinical trial of estradiol gel 0.1%. These analyses explored the effects of age (<50, 50-59, >=60 y) and uterine and ovarian status (intact or absent) on the change from baseline to week 12 in the frequency and severity of moderate to severe vasomotor symptoms. The effects of age, uterine status, and ovarian status were investigated for each individual dose (1.0, 0.5, and 0.25 g) of estradiol gel 0.1% (separately and pooled) compared with those of placebo. RESULTS: Treatment with any dose of estradiol gel 0.1% reduced both the frequency and severity of moderate to severe vasomotor symptoms from baseline regardless of age, uterine status, or ovarian status. Women 50 years or older, regardless of uterine or ovarian status, treated with estradiol gel 0.1% showed improvement in vasomotor symptoms compared with women given matched placebo. No interactions were detected between estradiol gel 0.1% treatment and age, uterine status, or ovarian status on vasomotor symptom frequency or severity. CONCLUSIONS: Estradiol gel 0.1% treatment numerically decreased the frequency and severity of vasomotor symptoms in healthy, postmenopausal women independent of age, uterine status, or ovarian status. To our knowledge, these data are the first to directly explore the effects of age, hysterectomy, and oophorectomy on the efficacy of transdermal estrogen therapy. PMID- 20720512 TI - Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve. AB - The pathogenesis of stroke involves inflammation, apoptosis, and excitotoxicity, which is mediated in part by neuronal NO synthase (nNOS) activation. Ghrelin, an endogenous 28-amino acid peptide, is shown to exert antiapoptotic and anti inflammatory properties. However, the effect of ghrelin in permanent focal cerebral ischemia and the role of the vagus nerve in its action remain unknown. To study this, male adult Sprague-Dawley rats underwent right-sided permanent middle cerebral artery occlusion (MCAO) with or without prior bilateral truncal vagotomy. This was followed by infusion of 4 nmol human ghrelin as treatment or saline as vehicle. Neurological deficit was assessed at 24 h after MCAO. Rats were killed thereafter, and brains were rapidly removed and analyzed for infarct size, markers of inflammation, excitotoxicity, and apoptosis. Compared with vehicle treatment, human ghrelin treatment in vagus nerve-intact rats after MCAO showed marked reduction in neurological deficit by 57% and infarct size by 25%. Middle cerebral artery occlusion resulted in increases in cerebral TNF-alpha, IL 6, neutrophil trafficking, matrix metalloproteinase 9 and nNOS gene expression, nitrotyrosine, and apoptosis. Human ghrelin treatment in vagus nerve-intact rats significantly decreased the above measurements. Human ghrelin treatment also improved 7-day survival and significantly decreased neurological deficit over the entire 7 days after MCAO in vagus nerve-intact rats compared with vehicle. Prior vagotomy, however, blunted human ghrelin's neuroprotective effects on neurological deficit, infarct size, TNF-alpha, neutrophil trafficking, nitrotyrosine, and apoptosis. Human ghrelin is thus a neuroprotective agent that inhibits inflammation, nNOS activity, and apoptosis in focal cerebral ischemia through a vagal pathway. PMID- 20720514 TI - Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS induced systemic inflammation in a rat model. AB - Septic shock is characterized by systemic inflammation and can lead to hemorrhage and necrosis in multiple organs. Septic shock is one of the leading causes of death. Studies have reported that septic shock is strongly associated with coagulation abnormality. The adenosine diphosphate (ADP) receptor antagonist, clopidogrel sulfate (CS), inhibits platelet function. Thus, we hypothesized that CS could inhibit LPS-induced systemic inflammation in a rat model. Male Wistar rats weighing 250 to 300 g received an LPS injection, followed 6 h later by filtration leukocytapheresis or mock treatment for 30 min under sevoflurane anesthesia. Five days before LPS injection, rats were given an oral dose of water or CS (10 mg/kg body weight). Levels of proinflammatory markers were determined in serum and tissue samples, and high-mobility group box 1 (HMGB1) expression was evaluated in lung and liver tissues. Compared with LPS-treated rats, induction of cytokines (IL-6 and TNF-alpha) was reduced in rats pretreated with CS. In addition, histological changes observed in lung and liver tissue samples of LPS treated rats were attenuated in CS-pretreated rats. Clopidogrel sulfate pretreatment also reduced LPS-induced HMGB1 expression in lung and liver tissues. Collectively, our findings demonstrate that CS pretreatment may have value as a new therapeutic tool against systemic inflammation. PMID- 20720513 TI - Injury induces early activation of T-cell receptor signaling pathways in CD4+ regulatory T cells. AB - Although it is known that injury enhances the regulatory activity of CD4 regulatory T cells (Tregs), the cellular and molecular mechanisms responsible for injury-induced Treg activation remain unclear. This study was designed to investigate and compare injury-induced T-cell receptor (TCR) signaling in Tregs, non-Tregs, and CD8 T cells. Specifically, we used phospho-flow cytometry to measure the expression and phosphorylation of ZAP-70, protein kinase C theta, nuclear factor of activated T cells, and glycogen synthase kinase 3beta in FoxP3 Tregs versus FoxP3 non-Tregs versus CD8 T cells. Groups of male C57BL/6J mice underwent burn or sham injury, and lymph nodes and spleens were harvested at early time points-15, 30, 60, 120, and 240 min-to measure TCR signaling. As early as 15 min after burn injury, we observed a significant upregulation and phosphorylation of ZAP-70, protein kinase C theta, nuclear factor of activated T cells, and glycogen synthase kinase 3beta in Tregs prepared from injury-site draining lymph nodes. Burn injury did not activate TCR signaling in Tregs from the spleen or in CD4 non-Tregs and CD8 T cells. In conclusion, the results of this study demonstrate that burn injury activates TCR signaling in Tregs, but not non-Tregs or CD8 T cells. These findings suggest that injury provides an early TCR-activating signal to Tregs and supply new insights into how injury influences the adaptive immune system. PMID- 20720515 TI - Combination of imipenem and TAK-242, a Toll-like receptor 4 signal transduction inhibitor, improves survival in a murine model of polymicrobial sepsis. AB - Sepsis is characterized by an excessive host response to infection. Toll-like receptors (TLRs) are essential for triggering this type of host immune response. Toll-like receptor 4 mediates recognition of LPS from gram-negative bacteria and is an important initiator of sepsis. In the present study, we evaluated the efficacy of TAK-242, a novel TLR4 signal transduction inhibitor, in a murine cecal ligation and puncture (CLP) model. Treatment with TAK-242 (10 mg/kg i.v.) in combination with imipenem (1 mg/kg s.c.) 1 h after CLP significantly increased the survival rates of mice from 17% to 50% (P <= 0.01) and suppressed CLP-induced increases in serum levels of IL-1[beta], IL-6, IL-10, and macrophage inflammatory protein 2 by 64%, 73%, 79%, and 81%, respectively (P <= 0.025). Additionally, coadministration of TAK-242 with imipenem after CLP significantly inhibited CLP induced decreases in blood platelet counts by 37% (P <= 0.025) and increases in serum levels of alanine aminotransferase by 32% (P <= 0.025) and blood urea nitrogen by 43% (P <= 0.025). TAK-242 at a dose of 10 mg/kg had no effect on bacterial counts in blood, suggesting that it does not affect blood bacteria spread. These results indicate that TAK-242 shows therapeutic effects in murine polymicrobial sepsis, and it may be a potential therapeutic agent for the treatment of sepsis. PMID- 20720516 TI - Plasma clozapine and norclozapine in patients prescribed different brands of clozapine (Clozaril, Denzapine, and Zaponex). AB - To investigate the bioequivalence of the three clozapine brands licensed in the United Kingdom, we compared plasma clozapine and norclozapine in therapeutic drug monitoring samples from patients switched from Clozaril to either Denzapine or Zaponex tablets. For Clozaril/Denzapine, the median prescribed clozapine dose was 450 mg/day (range, 125-850 mg/day) (n = 66) and the median time between samples was 16 weeks. The Clozaril/Zaponex comparison (n = 57) was not dose-controlled; the median Clozaril dose was 450 mg/day (range, 150-900 mg/day) and the median Zaponex dose 400 mg/day (range, 100-850 mg/day). The median time between samples was 19 weeks. There was no significant difference in mean plasma clozapine and norclozapine concentration before and after switching in either case, although some individual results showed clinically relevant concentration differences. Plasma norclozapine showed greater reproducibility between samples than clozapine. The different brands of clozapine available in the United Kingdom show bioequivalence. Nevertheless, careful monitoring of mental state, smoking habit, adherence, and of possible life-threatening adverse effects is mandatory if the drug is to be used safely. PMID- 20720517 TI - The convergence of therapeutic drug monitoring and pharmacogenetic testing to optimize efavirenz therapy. AB - The aim of this study was to show the benefits of combining therapeutic drug monitoring (TDM) and pharmacogenetic analyses to optimize efavirenz (EFV) therapy. Patients were selected to minimize nongenetic differences between patients: 32 HIV adherent patients without drug interactions treated with an EFV nonindividualized dose over at least 1 year and included in a TDM program were genotyped according to minimum steady-state concentrations (C ss min). The EFV plasma concentrations (n = 158) were quantified by high-performance liquid chromatography-ultraviolet, and genetic polymorphisms were analyzed using the PHARMAchip. Central nervous system side effects were assessed systematically. Genetic polymorphisms were detected in 79.2% of patients with EFV Css min outside the therapeutic range (1-4 mg/L), showing the high diagnostic efficacy of combining TDM with pharmacogenetic testing. CYP2B6 (516 G>T) polymorphisms were associated with a significant decrease in EFV plasma clearance in 80% of the poor metabolizer patients (G/T, T/T). All homozygous patients had C ss min greater than 4 mg/L, 75% of them showing central nervous system side effects. For such patients, pharmacogenetic testing with TDM could be advantageous because the polymorphism is a determinant of these circumstances and TDM would allow reductions in dose to be specified without assuming an equal dose for any given genotype. In fact, poor metabolizer patients required less than a 600 mg standard starting dose, implying that if CYP2B6 screening were available, EFV therapy could be started at 400 mg and later TDM-individualized. The results of this study clarify the genotype versus phenotype debate for optimizing drug therapy. Pharmacogenetic testing together with TDM links genotype to phenotypic differences in drug concentrations and adverse events, providing additional support for dosage adjustment and a more efficient use of both approaches. As genotype screens become cheaper, and in combination with TDM, adjusting dosages in the light of genetic polymorphisms will become a reality. PMID- 20720518 TI - Differences in clearance of mycophenolic acid among renal transplant recipients, hematopoietic stem cell transplant recipients, and patients with autoimmune disease. AB - For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients. PMID- 20720519 TI - An enzyme-linked immunosorbent assay to study bevacizumab pharmacokinetics. AB - INTRODUCTION: Bevacizumab is an antivascular endothelial growth factor humanized monoclonal antibody used to inhibit angiogenesis in cancer. It displays an important interindividual pharmacokinetic variability, which could explain part of the interindividual differences in clinical response. Therefore, an assay to measure bevacizumab serum concentrations is needed. METHODS: An enzyme-linked immunosorbent assay was developed using microtiter plates sensitised with vascular endothelial growth factor 165, a recombinant form of vascular endothelial growth factor. Lower and upper limits of quantitation as well as limit of detection were determined. Eight calibrators and three quality controls, with concentrations of 5 mg/L, 30 mg/L, and 75 mg/L, were tested on five occasions initially and on five subsequent occasions. Trough and peak serum concentrations of bevacizumab were measured in patients with metastatic colorectal cancer. Bevacizumab concentrations were described using a two compartment population pharmacokinetic model with first-order constants. RESULTS: Imprecision and accuracy of calibrators and quality controls were 20% or less, except for the zero calibrator. The limit of detection was 0.033 mg/L. Lower and upper limits of quantitation were 5 and 75 mg/L, respectively. A total of 175 blood samples was available for analysis from 16 patients. Median (range) trough and peak concentrations during the treatment were 47.2 (9.6-106.9) mg/L and 159.3 (33.0-327.3) mg/L, respectively. CONCLUSION: This method is rapid, accurate, reproducible, and may be useful for pharmacokinetic and pharmacokinetic pharmacodynamic studies as well as in therapeutic drug monitoring of bevacizumab. PMID- 20720520 TI - Clinician ordering practices for voriconazole therapeutic drug monitoring: experiences of a referral laboratory. AB - Monitoring of serum voriconazole concentrations has been proposed to optimize therapeutic effect and minimize toxicity. However, little is known about the clinical use of voriconazole therapeutic drug monitoring (TDM) by treating physicians. Four hundred seventy-eight episodes corresponding with 161 adult patients (mean three TDM episodes per patient; range 1-31, at a mean interval 43.6 days [range 1-266] between repetitions) performed at a state reference laboratory in Australia during a 30-month period were reviewed. Information about voriconazole dose was provided on only nine (1.9%) request forms. Timing of voriconazole TDM in relation to the previous dose was stated in 189 (39%) episodes and corresponded with peak measurements in 16; interval measurements (taken on average 3.3 [range 3-10.5] hours from the preceding dose) in 15; and trough measurements in 158 episodes. Of the 158 trough concentration measurements, only 66 (42%) were between 1 and 5.5 mg/L, the suggested therapeutic range. Similarly, only 33% (98 of 298) of all the random TDM episodes achieved voriconazole concentrations greater than 2.05 mg/L, previously associated with favorable outcomes. Compared with trough TDM, random episodes were significantly more likely to result in undetectable (less than 0.1 mg/L) concentrations (45 of 298 [15.1%] versus 12 of 158 [7.6%]; P = 0.021, odds ratio 2.16, 95% confidence interval: 1.11-4.22). Among patients with multiple TDM episodes, there was no correlation between the initial and final trough or between the initial and final random concentrations. Only 44% (eight of 18) of patients with multiple trough TDM had final concentration within 1 to 5.5 mg/L; and only 26% (15 of 58) of patients with multiple random TDM had final concentration greater than 2.05 mg/L. Adoption of consistent and clear guidelines on voriconazole TDM use and education of physicians ordering the test is required because the majority of testing performed was inappropriate and prone to suboptimal interpretation. PMID- 20720521 TI - Solid-phase synthesis of oligodeoxynucleotides containing N4-[2-(t butyldisulfanyl)ethyl]-5-methylcytosine moieties. AB - An efficient route for the synthesis of the phosphoramidite derivative of 5 methylcytosine bearing a tert-butylsulfanyl group protected thiol is described. This building block is used for the preparation of oligonucleotides carrying a thiol group at the nucleobase at the internal position of a DNA sequence. The resulting thiolated oligonucleotides are useful intermediates to generate oligonucleotide conjugates carrying molecules of interest at internal positions of a DNA sequence. PMID- 20720522 TI - Urinary granzyme A mRNA is a biomarker to diagnose subclinical and acute cellular rejection in kidney transplant recipients. AB - The distinction between T-cell-mediated rejection (TCMR) and other causes of kidney transplant dysfunction such as tubular necrosis requires biopsy. Subclinical rejection (SCR), an established risk factor for chronic allograft dysfunction, can only be diagnosed by protocol biopsy. A specific non-invasive biomarker to monitor immunological graft status would facilitate diagnosis and treatment of common transplantation-related complications. To identify possible markers, we measured urinary mRNA levels of several cytolytic proteins by quantitative PCR. Our cohort of 70 renal transplant recipients had biopsy proven type I and type II TCMR, acute tubular necrosis, SCR, calcineurin inhibitor toxicity, cytomegalovirus infection, and stable graft function with normal histology. Granzyme A (GzmA) mRNA was significantly higher in subclinical and acute cellular rejection compared to patients with stable grafts or those with tubular necrosis with 80% sensitivity and up to 100% specificity. Granzyme B and perforin mRNA levels could significantly discriminate acute rejection from stable or tubular necrosis, but were not significantly elevated during SCR. Importantly, only GzmA mRNA remained below detection limits from grafts that were stable and most with tubular necrosis. Hence, the presented data indicate that urinary GzmA mRNA levels may entail a diagnostic non-invasive biomarker to distinguish patients with subclinical and acute cellular rejection from those with tubular necrosis or stable grafts. PMID- 20720523 TI - BK channels and a new form of hypertension. AB - Large, Ca-activated K channels (BK) are comprised of an alpha pore (BKalpha) and one of four beta subunits (BKbeta1-4). When the gene for BKbeta1 is knocked out (BKbeta1-KO), the result is increased myogenic tone of vascular smooth muscle and hypertension. We reexamined whether the hypertension is entirely due to increased vascular tone, because most monogenic forms of hypertension have renal origins and BKbeta1 resides in renal connecting tubule (CNT) cells. Moreover, BKbeta1 is localized in the adrenal glands, where it may control production of aldosterone. This review will summarize our report that a majority of the hypertension of BKbeta1-KO is the result of insufficient handling of dietary K, resulting in increased plasma K and hyperaldosteronism, the latter promoting Na and fluid retention. The fluid retention and hypertension are exacerbated by a high-K diet and reduced by eplerenone, an aldosterone receptor inhibitor. Genetic knockout of BKbeta4 (BKbeta4-KO), which resides in intercalated cells, also exhibits deficient K excretion, fluid retention, and mild hypertension that is not exacerbated when animals are treated with a high-K diet. These results show that the hypertension associated with BKbeta1-KO occurs because of enhanced fluid retention, as well as because of the previously described vascular dysfunction. PMID- 20720524 TI - Sub-nephrotoxic doses of gentamicin predispose animals to developing acute kidney injury and to excrete ganglioside M2 activator protein. AB - We studied whether nephrotoxic drug administration sensitizes to acute renal failure (ARF) by administering a sub-nephrotoxic dose of gentamicin. This pre treatment sensitized animals with no sign of renal injury to develop ARF when exposed to a second potential nephrotoxic drug, also given at sub-nephrotoxic doses that would be otherwise harmless to non-sensitized animals. We identified urinary ganglioside M2 activator protein (GM2AP) as a biomarker of an enhanced sensitivity to suffer ARF following sub-nephrotoxic treatment with gentamicin. Sub-nephrotoxic gentamicin did not alter renal GM2AP gene expression or protein levels, determined by reverse transcriptase-PCR, western blot, and immunostaining, nor was its serum level modified. The origin of increased GM2AP in the urine is thought to be a defective tubular handling of this protein as a consequence of gentamicin action. Hence, markers of acquired sensitivity may improve the prevention of ARF by enhancing our capacity to monitor for this condition, in a preemptive manner. PMID- 20720525 TI - Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells. AB - The two hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and -independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis. In order to better understand the regulation of hypoxia inducible genes, we determined the expression of FIH1 in the kidney and its functional role in isolated renal cells. FIH1 was expressed only in distal tubules and in podocytes, thus showing a very distinct expression pattern, partially overlapping with sites of HIF-1alpha expression. In tubular cells, RNA silencing of FIH1 caused transcriptional activation of HIF target genes during hypoxia. In contrast, FIH1 silencing in podocytes enhanced transcription of hypoxia-inducible genes in an HIF-independent manner. Using the anti-Thy.1 rat model of glomerulonephritis, we found a gradual decrease of glomerular FIH1 expression during disease progression paralleled by an increase in hypoxia inducible genes including CXCR4, a mediator of glomerular inflammation. Thus, FIH1 appears to be a suppressor of oxygen-dependent genes in the kidney, operating through HIF-dependent and -independent mechanisms. PMID- 20720526 TI - Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients. AB - We sought to examine the impact of asymptomatic bacteriuria on renal transplant outcome by retrospectively analyzing 189 renal transplant recipients for whom systematic screening uncovered 298 episodes of asymptomatic bacteriuria in 96 recipients. These patients were treated and all were followed for 36 months. Significant risk factors included female gender, glomerulonephritis as the disease that led to transplantation, and double renal transplant. There were no differences in serum creatinine, creatinine clearance, or proteinuria between patients with and without bacteriuria. The incidence of pyelonephritis in these patients was 7.6 episodes per 100 patient-years compared with 1.07 in those without asymptomatic bacteriuria. Between two to five and more than five bacteriuria episodes were significant independent factors associated with pyelonephritis whereas more than five episodes was a significant independent factor associated with rejection. Thus, we found no differences in renal function prognosis between patients who do not develop asymptomatic bacteriuria and those uncovered by systematic screening and who received treatment following kidney transplantation. Despite this treatment, the incidence of pyelonephritis was much higher in the group of patients with detected asymptomatic bacteriuria. PMID- 20720527 TI - Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone. AB - We studied here the independent roles of angiotensin II and aldosterone in regulating the sodium chloride cotransporter (NCC) of the distal convoluted tubule. We adrenalectomized three experimental and one control group of rats. Following surgery, the experimental groups were treated with either a high physiological dose of aldosterone, a non-pressor, or a pressor dose of angiotensin II for 8 days. Aldosterone and both doses of angiotensin II lowered sodium excretion and significantly increased the abundance of NCC in the plasma membrane compared with the control. Only the pressor dose of angiotensin II caused hypertension. Thiazides inhibited the sodium retention induced by the angiotensin II non-pressor dose. Both aldosterone and the non-pressor dose of angiotensin II significantly increased phosphorylation of NCC at threonine-53 and also increased the intracellular abundance of STE20/SPS1-related, proline alanine rich kinase (SPAK). No differences were found in other modulators of NCC activity such as oxidative stress responsive protein type 1 or with-no-lysine kinase 4. Thus, our in vivo study shows that aldosterone and angiotensin II independently increase the abundance and phosphorylation of NCC in the setting of adrenalectomy; effects are likely mediated by SPAK. These results may explain, in part, the hormonal control of renal sodium excretion and the pathophysiology of several forms of hypertension. PMID- 20720528 TI - Kidney function and risk triage in adults: threshold values and hierarchical importance. AB - In this study, we attempted to identify threshold values for kidney function measures that maximally discriminate short-term mortality, to identify major population segments in which these thresholds apply, and to classify the hierarchical rank of the thresholds when other classic risk factors are also considered. To do this we retrospectively identified estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (ACR) thresholds to maximize sensitivity and specificity predictions for death in non institutionalized NHANES III participants, representative of the United States population from 1988 to 1994 and followed through 2000. In a classification tree excluding dichotomizing variables, age 57 years was initially selected; ACR appeared in the second round and eGFR in the third. The prognostic discrimination of optimum eGFR and ACR thresholds exceeded those of commonly advocated public health screening measures, such as LDL cholesterol and fasting blood glucose, with body mass index appearing in the third round, and smoking and LDL cholesterol in the fourth. In a tree permitting dichotomizing variables, the ACR, systolic blood pressure, and glucose first appeared in the third round, with eGFR, smoking, and LDL in the fourth. Thus, the albumin-creatinine ratio and eGFR may be at least as efficient for survival-based clinical triage as most other classic risk factors. PMID- 20720529 TI - National Kidney Foundation consensus conference on cardiovascular and kidney diseases and diabetes risk: an integrated therapeutic approach to reduce events. AB - Cardiovascular disease (CVD) is the most common cause of death in industrialized nations. Type 2 diabetes is a CVD risk factor that confers risk similar to a previous myocardial infarction in an individual who does not have diabetes. In addition, the most common cause of chronic kidney disease (CKD) is diabetes. Together, diabetes and hypertension account for more than two-thirds of CVD risk, and other risk factors such as dyslipidemia contribute to the remainder of CVD risk. CKD, particularly with presence of significant albuminuria, should be considered an additional cardiovascular risk factor. There is no consensus on how to assess and stratify risk for patients with kidney disease across subspecialties that commonly treat such patients. This paper summarizes the results of a consensus conference utilizing a patient case to discuss the integrated management of hypertension, kidney disease, dyslipidemia, diabetes, and heart failure across disciplines. PMID- 20720530 TI - Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. AB - IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4 related tubulointerstitial nephritis.' PMID- 20720531 TI - WASH-world action on salt and health. AB - There is overwhelming evidence that our current high-salt intake is the major factor increasing blood pressure (BP) and, thereby, a major cause of cardiovascular disease and kidney disease worldwide. A reduction in salt intake to the recommended level of <5-6 g/day is very beneficial, and could prevent millions of deaths each year and make major savings for healthcare services. Several countries, e.g., Finland and the UK, have already reduced the amount of salt being consumed by a combined policy of getting the food industry to decrease the amount of salt added to foods, clear labelling on food products, and increasing public awareness of the harmful effects of salt on health. Many other developed countries, e.g., Australia, Canada, and the US, are also stepping up their activities. The major challenge now is to spread this out worldwide, particularly to developing countries where ~80% of global BP-related disease burden occurs. In many developing countries, most of the salt consumed comes from salt added during cooking or from sauces; therefore, public health campaigns are needed to encourage consumers to use less salt. A modest reduction in salt intake across the whole population will result in major improvements in public health and have huge economic benefits in all countries around the world. World Action on Salt and Health (WASH) is a coalition of health professionals from different countries who know very well the harm of high BP and has a major role in implementing changes in their own countries. We welcome nephrologists to join (http://www.worldactiononsalt.com). PMID- 20720534 TI - Abnormal responses to monetary outcomes in cortex, but not in the basal ganglia, in schizophrenia. AB - Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear. In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain or avoid the indicated loss. Group differences in blood-oxygen-level-dependent responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC). Significant group by outcome valence interactions were observed in the medial and lateral PFC, lateral temporal cortex, and amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients. Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms. PMID- 20720535 TI - Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. AB - Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 MUg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety. PMID- 20720536 TI - DNA methylation regulates cocaine-induced behavioral sensitization in mice. AB - The behavioral sensitization produced by repeated cocaine treatment represents the neural adaptations underlying some of the features of addiction in humans. Cocaine administrations induce neural adaptations through regulation of gene expression. Several studies suggest that epigenetic modifications, including DNA methylation, are the critical regulators of gene expression in the adult central nervous system. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and consequent promoter region hypermethylation is associated with transcriptional silencing. In this study a potential role for DNA methylation in a cocaine-induced behavioral sensitization model in mice was explored. We report that acute cocaine treatment caused an upregulation of DNMT3A and DNMT3B gene expression in the nucleus accumbens (NAc). Using methylated DNA immunoprecipitation, DNA bisulfite modification, and chromatin immunoprecipitation assays, we observed that cocaine treatment resulted in DNA hypermethylation and increased binding of methyl CpG binding protein 2 (MeCP2) at the protein phosphatase-1 catalytic subunit (PP1c) promoter. These changes are associated with transcriptional downregulation of PP1c in NAc. In contrast, acute and repeated cocaine administrations induced hypomethylation and decreased binding of MeCP2 at the fosB promoter, and these are associated with transcriptional upregulation of fosB in NAc. We also found that pharmacological inhibition of DNMT by zebularine treatment decreased cocaine-induced DNA hypermethylation at the PP1c promoter and attenuated PP1c mRNA downregulation in NAc. Finally, zebularine and cocaine co-treatment delayed the development of cocaine-induced behavioral sensitization. Together, these results suggest that dynamic changes of DNA methylation may be an important gene regulation mechanism underlying cocaine-induced behavioral sensitization. PMID- 20720537 TI - Deep brain stimulation in clinical practice and in animal models. PMID- 20720538 TI - Graphene as a subnanometre trans-electrode membrane. AB - Isolated, atomically thin conducting membranes of graphite, called graphene, have recently been the subject of intense research with the hope that practical applications in fields ranging from electronics to energy science will emerge. The atomic thinness, stability and electrical sensitivity of graphene motivated us to investigate the potential use of graphene membranes and graphene nanopores to characterize single molecules of DNA in ionic solution. Here we show that when immersed in an ionic solution, a layer of graphene becomes a new electrochemical structure that we call a trans-electrode. The trans-electrode's unique properties are the consequence of the atomic-scale proximity of its two opposing liquid solid interfaces together with graphene's well known in-plane conductivity. We show that several trans-electrode properties are revealed by ionic conductance measurements on a graphene membrane that separates two aqueous ionic solutions. Although our membranes are only one to two atomic layers thick, we find they are remarkable ionic insulators with a very small stable conductance that depends on the ion species in solution. Electrical measurements on graphene membranes in which a single nanopore has been drilled show that the membrane's effective insulating thickness is less than one nanometre. This small effective thickness makes graphene an ideal substrate for very high resolution, high throughput nanopore-based single-molecule detectors. The sensitivity of graphene's in-plane electronic conductivity to its immediate surface environment and trans-membrane solution potentials will offer new insights into atomic surface processes and sensor development opportunities. PMID- 20720539 TI - Mediator and cohesin connect gene expression and chromatin architecture. AB - Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin loading factor Nipbl is associated with mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell. PMID- 20720540 TI - Single-atom-resolved fluorescence imaging of an atomic Mott insulator. AB - The reliable detection of single quantum particles has revolutionized the field of quantum optics and quantum information processing. For several years, researchers have aspired to extend such detection possibilities to larger-scale, strongly correlated quantum systems in order to record in situ images of a quantum fluid in which each underlying quantum particle is detected. Here we report fluorescence imaging of strongly interacting bosonic Mott insulators in an optical lattice with single-atom and single-site resolution. From our images, we fully reconstruct the atom distribution on the lattice and identify individual excitations with high fidelity. A comparison of the radial density and variance distributions with theory provides a precise in situ temperature and entropy measurement from single images. We observe Mott-insulating plateaus with near zero entropy and clearly resolve the high-entropy rings separating them, even though their width is of the order of just a single lattice site. Furthermore, we show how a Mott insulator melts with increasing temperature, owing to a proliferation of local defects. The ability to resolve individual lattice sites directly opens up new avenues for the manipulation, analysis and applications of strongly interacting quantum gases on a lattice. For example, one could introduce local perturbations or access regions of high entropy, a crucial requirement for the implementation of novel cooling schemes. PMID- 20720541 TI - Comprehensive methylome map of lineage commitment from haematopoietic progenitors. AB - Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions. PMID- 20720542 TI - Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. AB - The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume regulation in animal cells. Crystal structures of the potassium-bound form of the pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain. Here we show that this element is a key regulator of a previously unrecognized ion pathway. Current models of P-type ATPases operate with a single ion conduit through the pump, but our data suggest an additional pathway in the Na(+)/K(+) ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely to apply to the H(+)/K(+)-ATPase and the Ca(2+)-ATPase. PMID- 20720543 TI - Postgenomic chemical biology. AB - Chemical biology contributions will become increasingly important as we enter the second decade of the postgenomic era. PMID- 20720545 TI - Post-translational modifications: A shift for the O-GlcNAc paradigm. PMID- 20720546 TI - Metalloenzymes: Natural product nitrosation. PMID- 20720547 TI - Chemical ecology: Reprogramming a termite monarchy. PMID- 20720548 TI - Screening: Your brain on drugs. PMID- 20720551 TI - Combined blockade of beta- and alpha1-adrenoceptors in left ventricular remodeling induced by hypertension: beneficial or not? PMID- 20720552 TI - Left ventricular global systolic dysfunction has a significant role in the development of diastolic heart failure in patients with systemic hypertension. AB - Regional left ventricular (LV) systolic dysfunction has been identified in diastolic heart failure (DHF). However, the relationship between regional or global LV systolic function and heart failure symptoms in DHF has not been evaluated in detail. The present study evaluates such relationships in patients with systemic hypertension (HT) and DHF. We assessed LV systolic and diastolic function in 220 consecutive patients with systemic HT and in 30 normal individuals (Control) using Doppler echocardiography. Patients with HT were assigned to groups with DHF, asymptomatic diastolic dysfunction (ADD) and no diastolic dysfunction (Simple HT). Ejection fraction in DHF was significantly decreased (63+/-8%) compared with the Control, Simple HT and ADD groups (67+/-5, 66+/-7 and 68+/-8%, respectively). Isovolumetric contraction time in DHF (70+/-30 msec) was significantly increased compared with those in the ADD, Simple HT and Control groups (31+/-17, 31+/-15 and 30+/-19 msec, respectively). Mitral annular systolic velocities were significantly decreased in the DHF and ADD groups (6.4+/ 1.5 and 7.2+/-1.3 cm sec-1, respectively) compared with those in the Simple HT and Control groups (8.5+/-1.8 and 8.4+/-3.0 cm sec-1, respectively), and in the DHF group compared with the ADD group. LV global systolic dysfunction has a significant role in the development of heart failure symptoms associated with DHF in patients with systemic HT. PMID- 20720553 TI - Interaction between exercise and hypertension in spontaneously hypertensive rats: a meta-analysis of experimental studies. AB - The effect of exercise on the progression of hypertension and development of heart failure has been extensively studied in spontaneously hypertensive rats (SHRs), but results published thus far have not revealed a clear picture. Studies differ with respect to the age and sex of rats, duration of exercise and exercise protocols. This study was aimed to examine the influence of age at the start of exercise and the effect of the duration of exercise on blood pressure and hypertrophy, which has not been previously investigated. We identified 18 reports in the literature (with a total of about 410 rats) that investigated the effect of exercise on SHR. A reduction in blood pressure was observed in rats that started exercise protocols in the pre-hypertensive or very early hypertensive state, but not in older rats. Exercise lowered the heart weight-to-body weight ratio in rats starting exercise at a very early age, but not in rats at an advanced age. A reduction in blood pressure was observed in animals that had a short period of training, but the effect was lost when the duration of exercise was prolonged. Exercise reduced resting heart rates in all groups and increased the heart weight-to-body weight ratio in groups that were exposed to free running wheels, but not in rats that performed treadmill exercise. In conclusion, exercise per se does not reduce blood pressure in SHR with established hypertension and may increase the incidence of myocardial hypertrophy, depending on the form of exercise. PMID- 20720554 TI - Differences in the prevalence of metabolic syndrome and levels of C-reactive protein after puerperium in women with hypertensive disorders during pregnancy. AB - To measure high-sensitivity C-reactive protein (hsCRP) levels and to assess the presence of metabolic syndrome (MS) after puerperium in women diagnosed with various hypertensive disorders during pregnancy (HDP), a consecutive, cross sectional case study at the 15th week after gestation. The sample consisted of 264 women who were admitted to a women's hospital. The diagnoses consisted of transient gestational hypertension (TGH=43.2%), preeclampsia (PC=29.5%), chronic hypertension (CH=20.1%) and PC superimposed on CH (7.2%). A diagnosis of previous hypertension was present in 45.8% of the CH group. The prevalence of MS was 16.7% (CH=42.1%, TGH=13.9%, PC=4.1%, P<0.001). The average hsCRP levels for the CH, TGH and PC groups were 3.79 +/- 2.76, 3.55 +/- 3.15 and 2.89 +/- 3.02, respectively (P=0.040). The levels of hsCRP were higher in women with MS (4.71 +/- 3.15 vs. 3.01 +/- 2.88 mg l(-1) in those without MS, P<0.001), and they increased when a higher number of MS criteria was fulfilled (P<0.001). The results demonstrated a positive correlation between hsCRP levels and body mass index (BMI) (r=0.46), waist circumference (r=0.50) or the number of fulfilled MS criteria (r=0.56). The results suggest differences in vascular risk that depend on the type of HDP and on the prevalence of MS. The prevalence of MS was notably higher in the CH group, intermediate among the TGH group and much lower in the PC group. Differences in hsCRP levels also depended on the type of HDP (higher levels in CH and TGH patients in comparison with PC patients). Women with MS had higher hsCRP levels compared with women without MS, and the levels correlated with the number of MS criteria fulfilled. This result suggests that subclinical inflammatory status is correlated with the number of MS components present. Furthermore, hsCRP levels increased with increasing BMIs and waist circumferences. PMID- 20720555 TI - Therapeutic implications of high-dose angiotensin receptor blocker monotherapy in mild-to-moderate hypertensive patients. PMID- 20720556 TI - Polymorphisms of the endothelial nitric oxide synthase gene in breast cancer: a genetic association study and meta-analysis. AB - The endothelial nitric oxide synthase gene (NOS3) has been proposed as a candidate gene for breast cancer (BC), however, the specific role of variants and haplotypes has not been clarified. We examined the association of two polymorphisms (4b/a and G894T) and their haplotypes in a case-control sample of 306 patients with BC and in 131 healthy females. In addition, a meta-analysis of studies investigating association between NOS3 polymorphisms and BC was conducted. The single locus analysis for the two polymorphisms revealed an association only for the 4b/a polymorphism, but adjustment for age diminished this association (odds ratio (OR) (95% confidence interval)=0.98 (0.34-2.81)). The analysis of haplotypes showed an association for two haplotypes involving the 894T allele (bT and aT) (P<0.05). The meta-analysis for both polymorphisms produced nonsignificant associations without significant heterogeneity. A positive association was detected for the promoter T786C polymorphism (pooled OR=1.51 (1.07-2.12)), but this comparison was based on few studies. The available evidence from our study and the meta-analysis cannot support a major contributory role of these common NOS3 polymorphisms in BC, although future larger studies may help in drawing safer conclusions about the genetics of BC. PMID- 20720557 TI - A novel homozygous MMP2 mutation in a patient with Torg-Winchester syndrome. AB - Torg-Winchester syndrome (OMIM 259600) is an autosomal recessive multicentric osteolysis disorder. Mutations in the gene for matrix metalloproteinase 2 (MMP2) are involved in its pathogenesis. This is the first report of Torg-Winchester syndrome in east Asians. A 31-year-old female Korean patient had the typical clinical phenotypes of the syndrome, including shortening of trunk and limbs and severe osteolysis resulting in extremely small hands and feet. In addition, she had cord compression at the cervico-medullary junction, as well as lumbar dural ectasia. Molecular analysis revealed a novel homozygous missense mutation of MMP2, c.1217G>A (p.G406D). Gelatin zymography demonstrated a complete loss of the MMP2 activity of the mutation. Our results provide insights into the clinical and radiological features and pathogenic mechanisms of the syndrome. PMID- 20720558 TI - Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. AB - Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P=0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P=0.015). Moreover, previous studies have shown that the ABCG2 421C>A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C>A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients. PMID- 20720559 TI - Approaches to quality management and accreditation in a genetic testing laboratory. AB - Medical laboratories, and specifically genetic testing laboratories, provide vital medical services to different clients: clinicians requesting a test, patients from whom the sample was collected, public health and medical-legal instances, referral laboratories and authoritative bodies. All expect results that are accurate and obtained in an efficient and effective manner, within a suitable time frame and at acceptable cost. There are different ways of achieving the end results, but compliance with International Organization for Standardization (ISO) 15189, the international standard for the accreditation of medical laboratories, is becoming progressively accepted as the optimal approach to assuring quality in medical testing. We present recommendations and strategies designed to aid genetic testing laboratories with the implementation of a quality management system, including key aspects such as document control, external quality assessment, internal quality control, internal audit, management review, validation, as well as managing the human side of change. The focus is on pragmatic approaches to attain the levels of quality management and quality assurance required for accreditation according to ISO 15189, within the context of genetic testing. Attention is also given to implementing efficient and effective quality improvement. PMID- 20720560 TI - Safety and efficacy of coenzyme Q10 supplementation in early chronic Peyronie's disease: a double-blind, placebo-controlled randomized study. AB - No oral medication has proved to be clearly beneficial for Peyronie's disease (PD). We investigated the safety and efficacy of coenzyme Q(10) (CoQ(10)) supplementation in patients with early chronic PD. We conducted a randomized clinical trial of 186 patients with chronic early PD. Patients were randomly assigned to either 300 mg CoQ(10) daily (n=93) or similar regimen of placebo (n=93) for 24 weeks. Erectile function (EF), pain during erection, plaque volume, penile curvature and treatment satisfaction using patient versions of the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire were assessed at baseline and every 4 weeks during study period. EF was assessed using International Index of Erectile Function (IIEF-5), and pain was evaluated with a visual analog scale (VAS, 0-10). All patients also responded to a Global Assessment Question, 'Has the treatment you have been taking during this study improved your erections?' After 24 weeks, mean IIEF-5 score, mean VAS score and mean EDITS score improved significantly in patients receiving CoQ(10) (all P<0.01). Mean plaque size and mean penile curvature degree were decreased in the CoQ(10) group, whereas a slight increase was noted in the placebo group (both P=0.001). Mean index of IIEF-5 in 24-week treatment period was 17.8 +/- 2.7 in the CoQ(10) group and 8.8 +/- 1.5 in the placebo group (P=0.001). Of the patients in CoQ(10) group, 11 (13.6%) had disease progression vs 46 (56.1%) in placebo group (P=0.01). In patients with early chronic PD, CoQ(10) therapy leads plaque size and penile curvature reduction and improves EF. PMID- 20720561 TI - Functional correction of type VII collagen expression in dystrophic epidermolysis bullosa. AB - Functional defects in type VII collagen, caused by premature termination codons on both alleles of the COL7A1 gene, are responsible for the severe autosomal recessive types of the skin blistering disease, recessive dystrophic epidermolysis bullosa (RDEB). The full-length COL7A1 complementary DNA (cDNA) is about 9 kb, a size that is hardly accommodated by therapeutically used retroviral vectors. Although there have been successful attempts to produce functional type VII collagen protein in model systems of RDEB, the risk of genetic rearrangements of the large repetitive cDNA sequence may hamper the clinical application of full length COL7A1 cDNA in the human system. Therefore, we used trans-splicing to reduce the size of the COL7A1 transcript. Retroviral transduction of RDEB keratinocytes with a 3' pre-trans-splicing molecule resulted in correction of full-length type VII collagen expression. Unlike parental RDEB keratinocytes, transduced cells displayed normal morphology and reduced invasive capacity. Moreover, transduced cells showed normal localization of type VII collagen at the basement membrane zone in skin equivalents, where it assembled into anchoring fibril-like structures. Thus, using trans-splicing we achieved correction of an RDEB phenotype in vitro, which marks an important step toward its application in gene therapy in vivo. PMID- 20720562 TI - Resveratrol targets transforming growth factor-beta2 signaling to block UV induced tumor progression. AB - Resveratrol (RES) is a potent anti-cancer agent. We have previously reported that RES arrests the growth of invasive human A431 squamous cell carcinoma (SCC) cells. In this study, we show that oral administration of RES to highly tumor susceptible p53(+/-)/SKH-1 mice markedly delayed UV-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to SCCs. Transforming growth factor-beta2 (TGF-beta2) was predominantly overexpressed in UV-induced SCCs and its expression was diminished in RES-treated SCCs/skin. In addition to the inhibition of TGF-beta2 expression, RES increased the level of epithelial cadherin. This RES-mediated TGF-beta2 downregulation led to the inhibition of both TGF-beta2/Smad-dependent and -independent pathways, and suppressed the invasiveness of A431 cells. Addition of TGF-beta2, but not TGF-beta1, rescued the RES-mediated downregulation of p-extracellular signal-regulated kinases 1/2, p Smad3, and alpha-smooth muscle actin. The protein kinase B (Akt) substrate cAMP response-binding protein (pCREB) transcription factor is known to regulate TGF beta2 expression, and RES treatment decreased phosphorylation of Akt and pCREB. Expression of constitutively active Akt blocked RES inhibition of CREB and TGF beta2, and rescued RES inhibition of cellular invasiveness. Our data indicate that RES suppresses UV-induced malignant tumor progression in p53(+/-)/SKH-1 mice and that RES-inhibited invasiveness of human A431 SCC cells appears to occur, in part, through the Akt-mediated downregulation of TGF-beta2. PMID- 20720563 TI - Generation of antibodies of distinct subclasses and specificity is linked to H2s in an active mouse model of epidermolysis bullosa acquisita. AB - Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease, characterized by antibodies to type VII collagen (COL7). EBA can be induced in mice by immunization with a fragment of the non-collagenous 1 domain of murine COL7. Contrary to other autoimmune diseases, e.g., rheumatoid arthritis, little is known about the genetic susceptibility for EBA. We therefore used the EBA mouse model to address the hypothesis that disease induction depends on the major histocompatibility complex (MHC) haplotype. Mice from different inbred strains were immunized with recombinant murine COL7. Five distinct responses were observed: induction of (i) severe disease in SJL/J (H2s) and female MRL/MpJ (H2k), (ii) mild and transient disease in C57Bl/10.s (H2s), (iii) microscopic blistering in DBA/1J (H2q), (iv) only presence of non-pathogenic autoantibodies in C57Bl/6J (H2b), NZM2410/J (H2z), BXD2 (H2b), and male MRL/MpJ, and (v) complete resistance to EBA in NOD/ShiLtJ (H2g7) and C57Bl/10.q (H2q) mice. Overall, susceptibility to EBA was strongly associated with H2s. In addition, the diseased phenotype was associated with autoantibodies to specific regions of COL7. Our findings show that induction of antibodies with a distinct specificity is linked to the MHC haplotype in experimental EBA. Furthermore, our data are the basis for future studies with the goal of identifying non-MHC EBA susceptibility genes. PMID- 20720564 TI - Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNlambda) in cutaneous lupus erythematosus. AB - Type I IFNs (IFNalpha/beta) have been shown to have a central role in the pathophysiology of lupus erythematosus (LE). The recently discovered type III IFNs (IFNlambda1/IL29, IFNlambda2/IL28a, IFNlambda3/IL28b) share several functional similarities with type I IFNs, particularly in antiviral immunity. As IFNlambdas act primarily on epithelial cells, we investigated whether type III IFNs might also have a role in the pathogenesis of cutaneous LE (CLE). Our investigations demonstrate that IFNlambda and the IFNlambda receptor were strongly expressed in the epidermis of CLE skin lesions and related autoimmune diseases (lichen planus and dermatomyositis). Significantly enhanced IFNlambda1 could be measured in the serum of CLE patients with active skin lesions. Functional analyses revealed that human keratinocytes are able to produce high levels of IFNlambda1 but only low amounts of IFNalpha/beta/gamma in response to immunostimulatory nuclear acids, suggesting that IFNlambda is a major IFN produced by these cells. Exposure of human keratinocytes to IFNlambda1 induced the expression of several proinflammatory cytokines, including CXCL9 (CXC-motiv ligand 9), which drive the recruitment of immune cells and are associated with the formation of CLE skin lesions. Our results provide evidence for a role of type III IFNs in not only antiviral immunity but also autoimmune diseases of the skin. PMID- 20720565 TI - FcgammaRIIA and FcgammaRIIIB are required for autoantibody-induced tissue damage in experimental human models of bullous pemphigoid. PMID- 20720566 TI - Association between the germline MC1R variants and somatic BRAF/NRAS mutations in melanoma tumors. PMID- 20720567 TI - Contact between dermal papilla cells and dermal sheath cells enhances the ability of DPCs to induce hair growth. AB - We previously showed that cultured rat dermal papilla cells (DPCs) retain their hair-inducing capacity on afollicular epidermal cell (EPCs). Here, we examined the hair growth-inducing capacity of differently subcultured DPCs by transplanting them, along with rat EPCs, onto the backs of nude mice (graft chamber assay). DPCs at passage (p) ?6 (DPCs(p?6) or, more generally, low-passage DPCs) induced hair formation. However, DPCs(p>30) (high-passage DPCs) had no such activity and induced only subepidermal hair follicles (HFs) that were not encapsulated by the dermal sheath (DS). Thus, we examined the effect of DS cells (DSCs(p=1)) on the ability of DPCs(p=60) to induce hair growth by testing a mixture of these two cell types (cotransplant) in the graft chamber assay, in which DSCs(p=1) and DPCs(p=60) were labeled with enhanced green fluorescent protein (EGFP) and 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI), respectively. These cotransplants generated hairs as actively as did DPCs(p=6) transplants. Their HFs were encapsulated with EGFP(+)-DS and had DPs consisting largely of EGFP(+)-DPCs (47%) and DiI(+)-DPCs (43%), indicating a major contribution of DSC(p=1)-derived DPCs to HF induction. In addition, the results of in vitro coculture of DPCs(p=60) and DSCs(p=1) suggest that high passage DPCs stimulate the expression of certain trichogenic genes in DSCs. PMID- 20720568 TI - Quality of life in alopecia areata: a study of 60 cases. PMID- 20720569 TI - Antibody-based proteomics: fast-tracking molecular diagnostics in oncology. AB - The effective implementation of personalized cancer therapeutic regimens depends on the successful identification and translation of informative biomarkers to aid clinical decision making. Antibody-based proteomics occupies a pivotal space in the cancer biomarker discovery and validation pipeline, facilitating the high throughput evaluation of candidate markers. Although the clinical utility of these emerging technologies remains to be established, the traditional use of antibodies as affinity reagents in clinical diagnostic and predictive assays suggests that the rapid translation of such approaches is an achievable goal. Furthermore, in combination with, or as alternatives to, genomic and transcriptomic methods for patient stratification, antibody-based proteomics approaches offer the promise of additional insight into cancer disease states. In this Review, we discuss the current status of antibody-based proteomics and its contribution to the development of new assays that are crucial for the realization of individualized cancer therapy. PMID- 20720572 TI - Antihypertensive treatment and control in a large primary care population of 21 167 patients. AB - The efficacy of antihypertensive drug therapy is undisputed, but observational studies show that few patients reach a target blood pressure <140/90 mm Hg. However, there is limited data on the drug prescribing patterns and their effectiveness in real practice. This retrospective observational survey of electronic patient records extracted data from 24 Swedish primary health-care centres, with a combined registered population of 330 000 subjects. We included all patients > 30 years with a recorded diagnosis of hypertension who consulted the centres in 2005 or 2006 (n=21 167). Main outcome measures were systolic and diastolic blood pressures, and prescribed antihypertensive drug classes. Only 27% had a blood pressure <140/90 mm Hg. The number of prescribed drugs increased with age, except among the oldest (> 90 years). Only 29% of patients given monotherapy had a blood pressure <140/90 mm Hg. Women more often received diuretics (52 vs 42%), and less often angiotensin-converting enzyme inhibitors (22 vs 33%) and calcium channel blockers (26 vs 31%) than men. beta-Blockers and diuretics were the most common drug classes prescribed, independent of comorbidity. In conclusion, one out of four primary care patients with hypertension reach target blood pressure. More frequent use of drug combinations may improve blood pressure control. PMID- 20720571 TI - Molecular imaging by mass spectrometry--looking beyond classical histology. AB - Imaging mass spectrometry (IMS) using matrix-assisted laser desorption ionization (MALDI) is a new and effective tool for molecular studies of complex biological samples such as tissue sections. As histological features remain intact throughout the analysis of a section, distribution maps of multiple analytes can be correlated with histological and clinical features. Spatial molecular arrangements can be assessed without the need for target-specific reagents, allowing the discovery of diagnostic and prognostic markers of different cancer types and enabling the determination of effective therapies. PMID- 20720573 TI - The effect of feto-maternal size and childhood growth on left ventricular mass and arterial stiffness in Afro-Caribbean children. AB - We hypothesized that maternal size, fetal size and childhood growth are associated with childhood blood pressure, left ventricular mass (LVM) and arterial stiffness. The Vulnerable Windows Cohort is a longitudinal study of 569 mothers and their offspring. Anthropometry was measured on each child at birth, at 6 weeks, once in 3 months upto 2 years and then every 6 months. Blood pressure and body composition were assessed in 185 children (age 11.5 years) and echocardiography performed. LVM was not associated with maternal size after adjustment for child's weight. LVM was significantly associated with faster growth in childhood and with current weight, fat mass and lean mass. Systolic blood pressure was not related to maternal, fetal or newborn anthropometry, but was positively associated with infant and childhood growth, as well as current body size and fat mass. The pulse pressure/stroke volume ratio (an index of arterial stiffness) was inversely associated with maternal size, placental volume at 20 weeks, fetal size at 35 weeks and childhood growth even after adjustment for current weight. In conclusion, LVM in childhood is positively associated with maternal height, child's current size and rate of growth. Arterial stiffness is inversely related to maternal, fetal and placental size as well as growth throughout childhood. PMID- 20720574 TI - E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models. AB - The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis. PMID- 20720570 TI - Functional proteomics to dissect tyrosine kinase signalling pathways in cancer. AB - Advances in the generation and interpretation of proteomics data have spurred a transition from focusing on protein identification to functional analysis. Here we review recent proteomics results that have elucidated new aspects of the roles and regulation of signal transduction pathways in cancer using the epidermal growth factor receptor (EGFR), ERK and breakpoint cluster region (BCR)-ABL1 networks as examples. The emerging theme is to understand cancer signalling as networks of multiprotein machines which process information in a highly dynamic environment that is shaped by changing protein interactions and post translational modifications (PTMs). Cancerous genetic mutations derange these protein networks in complex ways that are tractable by proteomics. PMID- 20720576 TI - Long-term, antidiabetogenic effects of GLP-1 gene therapy using a double stranded, adeno-associated viral vector. AB - Diabetes is characterized by insulin resistance and a reduction in insulin secretion, leading to progressive beta-cell failure and loss of beta-cell mass. Its central therapeutic issues are how to restore glucose responsiveness of beta cells to normal and counteract defects in insulin secretion. Native glucagon-like peptide-1 (GLP-1), which makes beta-cells competent and diabetic beta-cells specifically more sensitive to glucose, has a major drawback of rapid inactivation. In this study, we describe the construction and analysis of a GLP-1 plasmid and double-stranded, adeno-associated viral (dsAAV) expression vector to overcome both the rapid degradation of native GLP-1 and limitations of gene therapy using standard single-stranded AAV. Our study results demonstrate that fasting blood glucose levels of db/db obese mice decreased significantly up to 4 months after a single injection of dsAAV GLP-1, and both insulin and circulating GLP-1 levels increased in dsAAV GLP-1-infected mice. These results demonstrate that dsAAV GLP-1 has long-term, efficient transgene expression with minimal toxicity and cellular immune responses. This study suggests that GLP-1 produced by dsAAV may be an alternative to the continuous infusions required for GLP-1 peptide therapy or daily injections of GLP-1. PMID- 20720575 TI - Inhibition of the IKK/NF-kappaB pathway by AAV gene transfer improves muscle regeneration in older mdx mice. AB - The IkappaB kinase (IKKalpha, beta and the regulatory subunit IKKgamma) complex regulates nuclear factor of kappaB (NF-kappaB) transcriptional activity, which is upregulated in many chronic inflammatory diseases. NF-kappaB signaling promotes inflammation and limits muscle regeneration in Duchenne muscular dystrophy (DMD), resulting in fibrotic and fatty tissue replacement of muscle that exacerbates the wasting process in dystrophic muscles. Here, we examined whether dominant negative forms of IKKalpha (IKKalpha-dn) and IKKbeta (IKKbeta-dn) delivered by adeno-associated viral (AAV) vectors to the gastrocnemius (GAS) and tibialis anterior (TA) muscles of 1, 2 and 11-month-old mdx mice, a murine DMD model, block NF-kappaB activation and increase muscle regeneration. At 1 month post treatment, the levels of nuclear NF-kappaB in locally treated muscle were decreased by gene transfer with either AAV-CMV-IKKalpha-dn or AAV-CMV-IKKbeta-dn, but not by IKK wild-type controls (IKKalpha and beta) or phosphate-buffered saline (PBS). Although treatment with AAV-IKKalpha-dn or AAV-IKKbeta-dn vectors had no significant effect on muscle regeneration in young mdx mice treated at 1 and 2 months of age and collected 1 month later, treatment of old (11 months) mdx with AAV-CMV-IKKalpha-dn or AAV-CMV-IKKbeta-dn significantly increased levels of muscle regeneration. In addition, there was a significant decrease in myofiber necrosis in the AAV-IKKalpha-dn- and AAV-IKKbeta-dn-treated mdx muscle in both young and old mice. These results demonstrate that inhibition of IKKalpha or IKKbeta in dystrophic muscle reduces the adverse effects of NF-kappaB signaling, resulting in a therapeutic effect. Moreover, these results clearly demonstrate the therapeutic benefits of inhibiting NF-kappaB activation by AAV gene transfer in dystrophic muscle to promote regeneration, particularly in older mdx mice, and block necrosis. PMID- 20720577 TI - Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver. AB - A novel class of PEGylated polyacridine peptides was developed that mediate potent stimulated gene transfer in the liver of mice. Polyacridine peptides, (Acr X)(n)-Cys-polyethylene glycol (PEG), possessing 2-6 repeats of Lys-acridine (Acr) spaced by either Lys, Arg, Leu or Glu, were Cys derivatized with PEG (PEG(5000 kDa)) and evaluated as in vivo gene transfer agents. An optimal peptide of (Acr Lys)(6)-Cys-PEG was able to bind to plasmid DNA (pGL3) with high affinity by polyintercalation, stabilize DNA from metabolism by DNAse and extend the pharmacokinetic half-life of DNA in the circulation for up to 2 h. A tail vein dose of PEGylated polyacridine peptide pGL3 polyplexes (1 MUg in 50 MUl), followed by a stimulatory hydrodynamic dose of normal saline at times ranging from 5 to 60 min post-DNA administration, led to a high level of luciferase expression in the liver, equivalent to levels mediated by direct hydrodynamic dosing of 1 MUg of pGL3. The results establish the unique properties of PEGylated polyacridine peptides as a new and promising class of gene delivery peptides that facilitate reversible binding to plasmid DNA, protecting it from DNase in vivo resulting in an extended circulatory half-life, and release of transfection competent DNA into the liver to mediate a high-level of gene expression upon hydrodynamic boost. PMID- 20720579 TI - A libelous state of affairs. PMID- 20720578 TI - Endofungal bacterium controls its host by an hrp type III secretion system. AB - Burkholderia rhizoxinica and Rhizopus microsporus form a unique symbiosis in which intracellular bacteria produce the virulence factor of the phytopathogenic fungus. Notably, the host strictly requires endobacteria to sporulate. In this study, we show that the endofungal bacteria possess a type III secretion system (T3SS), which has a crucial role in the maintenance of the alliance. Mutants defective in type III secretion show reduced intracellular survival and fail to elicit sporulation of the host. Furthermore, genes coding for T3SS components are upregulated during cocultivation of the bacterial symbiont with their host. This is the first report on a T3SS involved in bacterial-fungal symbiosis. Phylogenetic analysis revealed that the T3SS represents a prototype of a clade of yet uncharacterized T3SSs within the hrp superfamily of T3SSs from plant pathogenic microorganisms. In a control experiment, we demonstrate that under laboratory conditions, rhizoxin production was not required for establishment of the symbiotic interaction. PMID- 20720580 TI - Improving the performance of enteric vaccines in the developing world. AB - Vaccines against important enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in some populations. The application of new technologies and diverse scientific disciplines are needed to realize the promise of truly universal and effective solutions to combat those and other enteric diseases. PMID- 20720581 TI - The complement receptor CD46 tips the scales in T(H)1 self-control. PMID- 20720582 TI - All GOD's creatures got dedicated mucosal immunity. PMID- 20720583 TI - A toxin-sensitive receptor able to reduce immunopathology. PMID- 20720584 TI - Innate sensing of nickel. PMID- 20720587 TI - Therapy: Vitamin B6, B9 and B12 in diabetic nephropathy--beware. PMID- 20720588 TI - Diabetes: Shining a light: the role of vitamin D in diabetes mellitus. PMID- 20720589 TI - Pituitary gland: New consensus in acromegaly: criteria for cure and control. PMID- 20720586 TI - Complement: a key system for immune surveillance and homeostasis. AB - Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease. PMID- 20720590 TI - Diabetes: Treatment of diabetes mellitus: new tricks by an old player. PMID- 20720591 TI - Pharmacotherapy: ACCORD Blood Pressure and ACCORD Lipid: how low can we go? PMID- 20720592 TI - Phenylketonuria: a 21st century perspective. AB - Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future. PMID- 20720593 TI - Hyaluronan stimulates mobilization of mature hematopoietic cells but not hematopoietic progenitors. AB - Hyaluronan (HA) is expressed by cells in bone marrow where it contributes to the regulation of hematopoietic homeostasis. In this study, we have demonstrated that exogenous low molecular weight HA (LMW HA) polymers mobilize leukocytes, but not hematopoietic progenitor cells, to peripheral blood within a 3 hour time period following HA administration. Mobilization of leukocytes correlated with increased extracellular MMP-9 concentrations induced by LMW HA, but not high molecular weight (HMW) HA. In contrast, HMW HA up-regulated TIMP-1 expression in bone marrow cells. In vitro, HMW HA did not influence SDF-1 - mediated chemotaxis of hematopoietic progenitors, whereas LMW HA polymers demonstrated inhibitory activity. These findings suggest that the effects of HA on cell motility depend on the size of the HA polymers and on the type of target cells. PMID- 20720595 TI - Neurotrophin in obstetrics and gynaecology. AB - Since Rita Levi Montalcini and Stanley Cohen received Nobel Prize for their pioneering work on nerve growth factor (NGF), its role in female reproductive system has been reinforced in last two decades. The neurotrophins (NT) including nerve growth factor (NGF) are a family of related growth factors and their respective receptor tyrosine kinases that are of major importance in the regulation of neuronal survival and differentiation. While role of NGF in mast cell-mediated egg implantation and inhibition of rejection were primary concern at their time, in the ovary NGF can help in the differentiation process by which ovarian follicles become responsive to gonadotrophins. They help in follicular maturation, steroid secretion and ovulation in the ovary, by inducing the FSH receptor (FSHR). Due to the pleiotropism, NGF is mandatory for the success of pregnancy, while progesterone helping to maintain local levels of NGF in utero. In endometriosisi and polycystic ovarian disease it has major role to play. An autocrine role of NGF in breast cancer and epithelial ovarian cancer (EOC) is evident now. Thus its study will infuse new insight in diseases of both obstetrics and gynaecology. PMID- 20720594 TI - Alpha 7 subunit of nAChR regulates migration of human mesenchymal stem cells. AB - The efficient migration of mesenchymal stem cells (MSCs) to diseased tissues is required for the fulfillment of their regenerative potential. Recruitment of circulating cells into the damaged tissues is regulated by a complex network, which includes the non-neural cholinergic system. We found that human MSCs (hMSCs) express nicotinic acetylcholine receptor subunits alpha 7, beta 2 and beta 4. The receptor agonist nicotine caused calcium (Ca(++)) influx into hMSCs suggesting that the calcium ion channel alpha 7 homopolymer mediated this response. While high concentrations of nicotine (10(5)M) induced hMSC apoptosis, physiological concentrations (10(7)M) did not interfere with cell survival. At non-toxic concentrations, nicotine increased spontaneous migration of hMSCs, whereas chemotaxis of hMSCs toward C3a and bFGF in vitro and migration of intravenously infusion hMSCs into bone marrow and spleen in vivo were inhibited. The antagonist for the alpha 7 homopolymer, bungarotoxin, blocked the inhibitory effect of nicotine on chemotactic factor-induced migration of hMSCs. These findings reveal an involvement of the non-neural cholinergic system in regulation of hMSC migration. PMID- 20720596 TI - Sca-1 / c-Kit receptor expression and apoptosis pattern in ENU induced MDS mice. AB - The bone marrow is the major site of haemopoiesis in adult human. It contains cells that represent the stages in the development of different types of blood cells e.g. myelocytes, metamyelocytes, erythroblasts, reticulocytes, and other lymphoid progenies etc. Bone marrow failure is primarily the result of a specific failure of bone marrow precursor cells to produce mature cells. N-ethyl N-nitroso urea (ENU) is one of the most potent mutagens that can create an abnormal bone marrow microenvironment by causing defect in haematopoietic stem cell maturation cascade. ENU is easy to administer in mouse, and some probable mutations can be helpful to create models of human diseased conditions like Myelodysplastic syndrome (MDS). MDS is considered as an intravascular bone marrow disorder, a combined structural-functional abnormality wherein the differentiation procedure of the bone marrow stem cell is either incomplete or defective. We assumed that Myelodysplastic syndrome stands in between an inhibitory cellular pattern and a positive overshoot of abnormal differentiations representing an unknown juncture where the mystery of aplasia and leukemia hide back. Instead of using a transgenic mouse model, we attempted to develop an experimentally induced murine model of preleukemia or human MDS like disease model. In doing so ENU has been administered i.p and the animals were examined on thirtieth day and peripheral blood haemogram was documented. Upon registering the appearance of abnormal peripheral blood scenario, the changes in the intravascular bone marrow (BM) architecture, cell surface receptor expression, e.g. Sca-1, c-Kit and the early and late phase apoptic patterns were noted. The results represented an interesting correlation in between bone marrow architecture, early stem cell receptor and apoptic marker expression resembling human MDS. PMID- 20720597 TI - Life chances going up in smoke. PMID- 20720598 TI - Is bowel cancer screening important for Maori? PMID- 20720599 TI - Trends in survival and life expectancy by ethnicity, income and smoking in New Zealand: 1980s to 2000s. AB - BACKGROUND: Survival and life expectancy are commonly used metrics to describe population health. There are two objectives to this paper: (1) to provide an explanation of methods and data used to develop New Zealand life-tables by ethnic, income and smoking groups; and (2) to compare cumulative survival and life expectancy trends in these subpopulations. METHOD: We generated sex-specific life-tables for seven subpopulations: ethnicity (Maori and non-Maori); income tertiles; smoking (never and current); and two-way combinations (ethnicity by income; ethnicity by smoking; and smoking by income). This was repeated for five census-mortality cohorts (1981-84, 1986-89, 1991-94, 1996-99, and 2001-04). The method used to create the life-tables brings together three pieces of information: (1) the official Statistics New Zealand (SNZ) life-tables by year and sex; (2) the proportionate distribution of the total population by subpopulation (e.g. smoking prevalence); and (3) estimates of the differences in subpopulation mortality rates (from the New Zealand Census-Mortality Study [NZCMS]). RESULTS: Survival and life expectancy improved in all subpopulations across the five census cohorts. However, improvements were greater in non-Maori compared to Maori and high income compared to low income subpopulations. This led to widening of the gap in life expectancy between 1981 and 2001 between Maori and non-Maori (males), which increased from 5.4 years in 1981 to 9.0 in 2001 and between low income and high income which increased from 4.4 in 1981 to 6.5 in 2001 for males. The gap in life expectancy between current and never smokers in 1996 was 7.6 in males and 6.7 in females. However, the size of this gap varied by ethnicity: 7.3 and 6.2 for non-Maori males and females, and 4.3 and 3.9 for Maori male and females. Correspondingly, the gap in life expectancy between Maori and non-Maori is greater among never smokers (9.7 and 8.4 for males and females) than among current smokers (4.3 and 6.6 for males and females). CONCLUSION: Life tables have been successfully developed for subpopulations in New Zealand, and provide an alternative understanding of health and life in New Zealand over the past 20 years. Ethnic and income gaps in life expectancy have widened, and perhaps surprising results were found for smoking by ethnicity. These life-tables provide an important basis for subpopulation modelling and projections, and are freely available to researchers. PMID- 20720600 TI - If nobody smoked tobacco in New Zealand from 2020 onwards, what effect would this have on ethnic inequalities in life expectancy? AB - BACKGROUND: Smoking contributes to the 7 to 8 year gap between Maori and non Maori life expectancy (2006 Census). To inform current discussions by policy makers on tobacco control, we estimate life-expectancy in 2040 for Maori and non Maori, never-smokers and current-smokers. If nobody smoked tobacco from 2020 onwards, then life expectancy in 2040 will be approximated by projected never smoker life expectancy. METHOD: Life-tables by sex/ethnicity/smoking status for 1996-99 were estimated by merging official Statistics New Zealand life-tables, census data and linked census-mortality rate estimates. We specified six modelling scenarios, formed by combining two options for future per annum declines in mortality rates among never-smokers (1.5%/2.5% and 2.0%/3.5% for non Maori/Maori; i.e. assuming a return to long-run trends of closing ethnic gaps as in pre-1980s decades), and three options for future per annum reductions in the mortality rate difference comparing current to never-smokers (0%, 1% and 2%). RESULTS: In 1996-1999, current smokers had an estimated 3.9 to 7.4 years less of life expectancy relative to never-smokers. This smoking difference in life expectancy was less among Maori than among non-Maori. If the 2006 census smoking prevalence remains unchanged into the future, we estimate the difference in 2040 between Maori and non-Maori life expectancy will range from 1.8 to 6.1 years across the six scenarios and two sexes (average 3.8). If nobody smokes tobacco from 2020 onwards, we estimate additional gains in life expectancy for Maori ranging from 2.5 to 7.9 years (average 4.7) and for non-Maori ranging from 1.2 to 5.4 years (average 2.9). Going smokefree as a nation by 2020, compared to no change from the 2006 Census population smoking prevalence, will close ethnic inequalities in life expectancy by 0.3 to 4.6 years (average 1.8 years; consistently greater for females). DISCUSSION: If smoking persists at current rates it will become an even greater constraint on life expectancy improvements for New Zealanders in the future. Continued increases in life expectancy, and closing of the Maori:non-Maori gaps in life expectancy, would be greatly assisted by the end of tobacco smoking in Aotearoa-New Zealand by 2020. PMID- 20720602 TI - The prevalence of colorectal adenomas in Maori and New Zealand Europeans parallels colorectal cancer rates. AB - BACKGROUND: New Zealand (NZ) has a high incidence of colorectal cancer (CRC). Maori have a documented incidence that is approximately half that found in NZ Europeans, possibly the result of under-reporting. AIM: To determine and compare the prevalence of colorectal adenomas in Maori and NZ European patients. METHODS: Colonoscopy records from the Middlemore Colonoscopy Audit Database between 1 July 2001 and 31 December 2005 were reviewed. Studies performed for indications associated with an increased risk of colorectal polyps were excluded from the analysis. Patient demographics, including self-identified ethnicity, and number and location of colonic polyps were recorded. All polyp histology was reviewed. RESULTS: Data was analysed from 2842 colonoscopies--2523 were NZ Europeans (mean age 67 yrs) and 319 were Maori patients (mean age 60.6 yrs). To adjust for age, a comparison of data between 40 and 59 years was undertaken. In 643 (81.2%) NZ Europeans, polyps were identified in 213 (33.1%). In the 149 (18.8%) Maori patients, polyps were identified in 35 (23.5%) p=0.029. The comparative rates of adenomas in NZ Europeans and Maori were 16.7% and 8.7% respectively (p=0.019; 8% difference, CI=2.3-13.9%). CONCLUSION: The prevalence of colorectal adenomas in Maori is approximately half that found in NZ Europeans. This mirrors the reported difference in CRC incidence between these groups and lends support to this being a real finding and not a bias in the manner in which the data has been collected. PMID- 20720601 TI - Ethnic counts on mortality and census data 2001-06: New Zealand census-mortality study update. AB - AIM: To provide an update for the assessment of discrepancies in ethnicity counts in the 2001 census and mortality data for the 2004-2006 period. METHODS: 2001 census anonymously and probabilistically linked to 5 years of subsequent mortality data (135,849 eligible mortality records), allowing a comparison of ethnicity recording for the years 2001-2004 and 2004-2006. RESULTS: Using a total definition of ethnicity, census and mortality counts agree reasonably well in 2004-06 and resemble comparisons in 2001-04, except at younger ages where counts for Pacific and Asian ethnicities are up to a third less for mortality data. Due to multiple ethnicities being more commonly recorded on census data, sole ethnicity counts are generally greater on mortality than census data, particularly for Maori ethnicity. CONCLUSION: Similar to 2001-2004, there is little bias in ethnic group counts between census and mortality data when using total ethnicity. Calculations of mortality rates by ethnicity using unlinked census and mortality data and a total definition of ethnicity should be unbiased. These results support ongoing use of the census definition of ethnicity on all health datasets. PMID- 20720603 TI - Orbital infection in New Zealand: increased incidence due to socioeconomic deprivation and ethnicity. AB - AIM: This study aimed to identify the relationship between the incidence of orbital infection, ethnicity and socioeconomic deprivation in New Zealand. METHOD: Cases admitted to all public hospitals in New Zealand with the ICD-10 diagnosis of acute inflammation of the orbit for a 9-year period were retrieved from the National Minimum Data Set. Incidence rates of acute infection of the orbit were correlated with socioeconomic deprivation (measured by New Zealand Deprivation Index) and ethnicity. RESULTS: There were 530 cases admitted with acute orbital inflammation over a 9-year period from 1 July 2000 to 30 June 2009. This study identified a significant association between orbital infection incidence and socioeconomic deprivation and ethnicity. Cases in the moderate deprivation group had 1.5 times the rate of the least deprived group and the most deprived group had 2.9 times the rate of orbital infection of the least deprived group. Maori had 1.9 times the rate of the European group, and Pacific people had 3.6 times the rate of European group. CONCLUSION: Greater socioeconomic deprivation, and ethnicity was associated with an increased incidence of orbital infection in New Zealand. The reasons why these associations exist are currently not clear. PMID- 20720604 TI - Patients "falling through the cracks". The Canterbury Charity Hospital: initial progress report. AB - AIM: To present the early experience of establishing a community-funded and volunteer-staffed hospital in Christchurch, New Zealand. This was to provide free selected elective healthcare services to patients in the Canterbury region who were otherwise unable to access treatment in the public health system or afford private healthcare. METHODS: Data were reviewed relating to the establishment, financing, staffing and running of the Canterbury Charity Hospital. Details were provided of patients referred by their general practitioners who were seen and treated during the first two and a half years of function. RESULTS: Canterbury Charity Hospital Trust, established in 2004, completed the purchase of a residential villa in 2005 and converted it into the Canterbury Charity Hospital, which performed its first operations in 2007. By the end of December 2009, 115 volunteer health professionals and 79 non-medical volunteers had worked at the Hospital, provided a total of 966 outpatient clinic appointments, of which 609 were initial assessments, and performed 610 surgical procedures. Funding of $NZ4.3 million (end of last financial year) came from fundraising events, donations, grants and interest from investments. There has been no government funding. CONCLUSIONS: There is a substantial unmet need for elective healthcare in Canterbury, and this has, in part, been addressed by the recently established Canterbury Charity Hospital. The overwhelming community response we have experienced in Canterbury raises the question of whether the current public health system needs attention to be re-focused on unmet need. We contend that unless this occurs it might be necessary to establish charity-type hospitals elsewhere throughout the country. PMID- 20720605 TI - Health, inequality and the politics of genes. AB - Research into the possible genetic basis of health inequalities between different ethnic or racial groups raises many scientific, ethical and political concerns. Proponents of such research point to the possible benefits for marginalised groups of understanding genetic influences on health outcomes; opponents indicate the potential social costs, citing historical use of Darwinian concepts to explain and justify inequalities between different peoples. Many health researchers may avoid the subject due to its potential for controversy--e.g. the recent media furore over the so-called 'warrior gene', and its apparent genetic explanations for negative health and social statistics among Maori. This article argues for a more nuanced account of the evolutionary history of marginalised groups such as Maori, one that accepts the possibility of relevant genetic differences between sub-populations, but which also acknowledges genuine ethical and political concerns. Such an account may assist health researchers in addressing the politically sensitive subject of 'race' and social inequality. PMID- 20720606 TI - Integrated systems to improve care for very high intensity users of hospital emergency department and for long-term conditions in the community. AB - Adult patients who are very high intensity users of hospital emergency departments (VHIU) have complex medical and psychosocial needs. Their care is often poorly coordinated and expensive. Substantial health and social resources may be available to these patients but it is ineffective for a variety of reasons. In 2009 Counties Manukau District Health Board approved a business case for a programme designed to improve the care of VHIU patients identified at Middlemore Hospital. The model of care includes medical and social review, a multidisciplinary planning approach with a designated 'navigator' and assertive follow-up, self and family management, and involvement of community based organisations, primary care and secondary care. The model has been organised around geographic localities and alongside other initiatives. An intermediate care team has been established to attend to the current presenting problems, however the main emphasis is on optimising ongoing care and reducing subsequent admissions especially by connecting patients with primary health care. This whole process could be driven by the primacy care sector in due course. The background and initial experience with implementation are described. PMID- 20720607 TI - Sulphasalazine lung toxicity: report of two cases. PMID- 20720608 TI - A case of acupuncture-induced pneumothorax. PMID- 20720609 TI - Medical image. A case of nonresolving pneumonia. Cryptogenic organising pneumonia. PMID- 20720610 TI - Medical image. A case of recurrent hypoglycaemia. Insulinoma. PMID- 20720611 TI - Interprofessional learning in medical education in New Zealand. AB - This article considers interprofessional learning initiatives in the context of undergraduate and postgraduate education and the continuing professional development of doctors and other health professionals. The evidence for and challenges to delivering interprofessional education are discussed along with current interprofessional education initiatives in Aotearoa/New Zealand and Australia. Many opportunities exist for health professionals to work together more effectively. We all want the best outcomes for our patients and good working relationships, but often we work and learn in professional silos. This paper explores the policy drivers for interprofessional learning (IPL), provides evidence for what works, identifies some of the challenges and shares examples of how health professionals in New Zealand are implementing IPL initiatives: aimed at improving health outcomes and facilitating well-functioning workplaces for all members of the health care team. PMID- 20720612 TI - The Unfortunate Experiment debate: Manning response to Chalmers. PMID- 20720613 TI - A response to Professor Bryder's comments on 'Consequences in women of participating in a study of the natural history of cervical intraepithelial neoplasia 3'. PMID- 20720614 TI - Response to the Missing Manuscript editorial. PMID- 20720615 TI - Congratulations to the NZMJ for the Unfortunate Experiment theme issue. PMID- 20720616 TI - Smoker (mis)perceptions associated with pack colouring: national survey data. PMID- 20720617 TI - Legal blood alcohol limit: has New Zealand missed a golden opportunity? PMID- 20720618 TI - Choice of metal and wavelength for surface-plasmon resonance sensors: some considerations. PMID- 20720621 TI - Of optics and opticists. PMID- 20720619 TI - Patents. AB - 5,005,928; 5,005,958; 5,007,432; 5,007,689; 5,007,691; 5,007,692; 5,007,709; 5,007,711; 5,007,729; 5,009,233; 5,009,484; 5,009,494; PMID- 20720622 TI - Optimization of partial adaptive optics. PMID- 20720624 TI - Grating method for determining the absolute angle of incidence of ellipsometric samples in remote locations. PMID- 20720623 TI - Improved chopper mask for the dayglow photometer. PMID- 20720625 TI - Echelle grisms: an old challenge to the electromagnetic theory of gratings now resolved. PMID- 20720626 TI - Fiber-interferometric measurement of the heat-transfer coefficient of a plate. PMID- 20720627 TI - Fabry-Perot fiber-optic sensors in full-scale fatigue testing on an F-15 aircraft. PMID- 20720628 TI - Design for an all-reflection Michelson interferometer. PMID- 20720629 TI - Modified technique for calibrating Fabry-Perot interferometers. PMID- 20720630 TI - Wedge-shaped polyethylene far-infrared windows. PMID- 20720631 TI - Monte Carlo simulations of laser Doppler blood-flow measurements in tissue: Comment. PMID- 20720632 TI - Monte Carlo simulations of laser Doppler blood-flow measurements in tissue: reply to comment. PMID- 20720633 TI - Some reflections about a high-resolution spectrograph. PMID- 20720634 TI - Low-cost, high-resolution, single-structure array telescopes for imaging of low Earth-orbit satellites. AB - Telescopes that are designed for the unconventional imaging of near-Earth satellites must follow unique design rules. The costs must be reduced substantially over those of the conventional telescope designs, and the design must accommodate a technique to circumvent atmospheric distortion of the image. Apertures of 12 m and more along with altitude-altitude mounts that provide high tracking rates are required. A novel design for such a telescope, optimized for speckle imaging, has been generated. Its mount closely resembles a radar mount, and it does not use the conventional dome. Costs for this design are projected to be considerably lower than those for the conventional designs. Results of a design study are presented with details of the electro-optical and optical designs. PMID- 20720635 TI - Near-infrared attenuation of Saharan dust at the Tenerife and La Palma observatories. AB - The 150-km optical path between the astronomical observatories of Izana on Tenerife and Roque de Los Muchachos on La Palma provides an optimum scenario for on-ground tests of optical communication systems for intersatellite communications. We present calculations of the effects of Saharan dust invasions one of the most significant disturbances in this region-on the optical attenuation in the 780-880-nm spectral band. PMID- 20720636 TI - Three-element stressed Ge:Ga photoconductor array for the infrared telescope in space. AB - A stressed Ge:Ga photoconductor array with three elements applied to the Infrared Telescope in Space satellite was fabricated and tested in experiments at 2.0 K in very low-photon-influx conditions (~ 10(5) photons/s). Stress was applied to three Ge:Ga detectors in a series by a stable and compact stressing apparatus by using cone-disk springs. The cutoff wavelength was ~ 180 microm. Responsivity was ~ 100 A/W, and the product of quantum efficiency and photoconductive gain, etaG, was ~ 1 with a chopping frequency of 2 Hz. The noise equivalent power was <5 x 10(-18) W/Hz((1/2)) when low-noise transimpedance amplifiers were used. A slow transient response and a nonlinear response that was dependent on the background photon influx were observed in the experiments. The latter showed that the etaG had a time constant tau(c) that was proportional to N(ph)(-(1/2)). PMID- 20720637 TI - Silicon photodiode self-calibration using white light for photometric standards: theoretical analysis. AB - A method is proposed in which the responsivity (A/Im) for the photometric quantity of a silicon photodiode, which is combined with a V(lambda) filter of a known spectral transmittance, can be directly self-calibrated by measuring the surface reflectance and the recombination losses of the photodiode for white light. The derived equation for this method assumes approximations that can cause systematic errors. A computer simulation was made to quantify these errors, and an accuracy of better than 0.2% was predicted. Although experimental validation is necessary, this method is promising as a new, practical method for high accuracy photometric standards. PMID- 20720638 TI - Infrared ellipsometer for the study of surfaces, thin films, and superlattices. AB - An automatic infrared ellipsometer for the study of surface and interface phenomena has been constructed. The system is based on a Fourier transform spectrometer that we equipped with an ellipsometer unit. Polarizers and analyzers are of the ion-etched wire-grid type. Their rotation is governed by means of a computer-controlled stepping-motor system. A discussion of calibration procedures for the infrared range is given, and special attention is given to the problem of selecting the best measurement strategy. The polarization state of the reflected beam is determined by measuring the intensity at 72 regularly spaced polarizer/analyzer settings. It is found that the effects of interferometric polarization, beam wandering, and detector dichroism cannot be neglected. However, these error sources have been eliminated by analyzing the zeroth, second, and fourth harmonic components of the azimuthally recorded intensity. Both the multiplex advantage of Fourier transform spectroscopy and the phase sensitivity ofellipsometry are combined in this instrument. Measurements on superconducting films, superlattices, and doped GaAs films are reported. PMID- 20720639 TI - Method for azimuthal alignment in fixed-angle ellipsometry. AB - Our objective is to develop a method for azimuthal alignment of the polarizer analyzer in fixed-angle ellipsometry systems in which measurement of the light intensity in the straight-through mode is not possible. An analytical technique has been developed that allows the determination of the reference positions of the polarizer and analyzer through the use of reflection measurements from a dielectric sample at a single angle of incidence. The method was verified by using both a high-temperature unit and a room-temperature reflectometer system. In these cases the real part of the refractive index of the test sample was inferred with accuracy to within 0.5% and 1.7%, respectively. In addition the sensitivity of the technique to the polarizer-analyzer setting was assessed. PMID- 20720640 TI - Separation by ion implantation of oxygen (SIMOX) structures: estimating thicknesses. AB - The propagation of errors in the model parameters is compared for cases that analyze a simple separation by ion implantation of oxygen structure by using reflectometry and ellipsometry. Both methods give comparable values for the layer thicknesses. Both the radius of convergence and the values of uncertainty tend to be larger with reflectometry than with ellipsometry. PMID- 20720641 TI - Fringe localization control in holographic interferometry. AB - The practical use of holographic interferometry in nondestructive testing leads to many situations in which the characteristics of the fringe patterns make the observation and subsequent interpretation of the fringes difficult. Fringe control may then be employed to correct the troublesome parameters, the most commonly treated of which is fringe spacing. To gain more powerful control, a novel method is presented here that also permits one to change the localization of the fringe pattern. General vectorial expressions are derived that relate a tilt in the reference beam to a change in the fringe localization. Moreover the changes introduced into the fringe vector by this tilt can be suppressed by an adequate shift of the illumination beam focus. Some illustrative examples for a plane object are presented. PMID- 20720642 TI - Infrared-photodetector background-current estimation. AB - A method is described for facilitating the estimation of the background current that is generated by an infrared photodetector, based on the development of an idealized rectangular photon-responsivity spectrum that incorporates the detailed influence of the actual responsivity spectrum within the values of its predetermined parameters. Background currents may then be calculated algebraically without undue loss of precision by use of standard blackbody radiation formulas. Values of the parameters defining the idealized spectrum are derived for the majority of photodetectors in common use today, including silicide Schottky-barrier devices, and are applied within several examples of background-current estimation. PMID- 20720643 TI - Bandpass design-applications to nonnormal incidence. AB - A five-cavity bandpass is designed. The spectral transmittance simulates a Chebyshev polynomial. The same principles are used to design a bandpass that resides in a cemented cube at a 45 degrees angle of incidence that has minimal polarization splitting. PMID- 20720644 TI - General analysis of two-mirror relay systems. AB - The general two-mirror system used at finite conjugates is examined here. Relations for first-order geometric properties and third-order aberrations are given in terms of five design parameters: object distance, image distance, exit pupil size, and the two mirror magnifications. The conditions for aplanatic solutions are derived for conic mirrors. The curvatures of the astigmatic image surfaces are given, and the condition for anastigmatic solutions is derived. The relations are applied to infinite conjugate systems and spherical mirror systems as special cases. PMID- 20720645 TI - Accurate measurement of the dihedral angle of a corner cube. AB - The alignment of a corner cube affects the measurement of its dihedral angle. For 5 deg of tilt, the error is up to 7%, depending on the orientation of the tilt. A vector model is devised to derive formulas that take misalignment into account for both solid and hollow corner cubes. When the wave-front tilt caused by the dihedral angle error is not much greater than that caused by the surface figure, because of vignetting for a tilting illumination, the surface figure of the cube facet makes varying contributions to the wave-front tilt for different incident angles. Simulations and experimental results are presented. PMID- 20720646 TI - Theoretical study of birefringent filters as intracavity wavelength selectors. AB - A detailed theoretical study of the transmission function of birefringent filters using exact 4 x 4 matrix formalisms is presented. The Brewster-angle effect for the filters acting as intracavity wavelength selectors is also analyzed. Finally, the change in phase of the transmitted wave is calculated and the resonance condition of a cavity with a birefringent-type selector is obtained. The results are compared with those obtained from the usual Jones method. PMID- 20720647 TI - Highly stable, monochromatic and tunable optical radiation source and its application to high accuracy spectrophotometry. AB - An optical radiation source has been developed by coupling a dye laser to a small integrating sphere with an optical fiber. The radiant power from this source, which is monochromatic and spectrally tunable, has been stabilized to +/-0.02%. Nonuniformities in the emitted optical radiation field caused by speckle have been overcome by vibrating the fiber at ultrasonic frequencies. The source has been successfully used in a spectrophotometer to measure the transmittance of a large lens with an uncertainty of +/-0.01%, and the spectral responsivity of a filter radiometer with an uncertainty of +/-0.04%. PMID- 20720648 TI - Double-layer broadband antireflection coatings for grazing incidence angles. AB - This paper presents the methodology for the design of double-layer antireflection (AR) coatings forgrazing incidence angles for a given state of polarization. The designs are based on commonly used thin-film materials with the optical constants that can be realized by using standard evaporation techniques. The performance of some AR stacks has been computed, and the effect on spectral reflectance with variation in the thickness of the high-index layer, angle of incidence, and the refractive indices of the materials used for the inner and outer layers has been studied with a view to selecting a suitable design that gives the lowest reflectance over the widest wavelength range. The AR stacks show a reflectance of <0.5% over most parts of the visible and near-infrared regions of the spectrum. PMID- 20720649 TI - Calibration of Kodak 101 x-ray film. AB - Kodak 101-01 and 101-07 x-ray film was calibrated by using the soft x rays at lambda >/= 10 A emitted by a laser-produced plasma. The results for films fabricated in different batches are presented. PMID- 20720650 TI - Transmission-grating velocimetric technique for common objects. AB - An optical technique to detect the velocity of a moving object that has a brightness distribution is presented. We show theoretically and experimentally that the amplitude of the detected signal in transmission-grating velocimetry is proportional to the Fourier component of the object spectrum at the spatial frequency of the grating. This fact can be used advantageously to sense the velocities of moving objects of any shape in one pass through the detector's field of view. Results of the application of this method to measure the velocities of some common outdoor moving objects are also presented. PMID- 20720651 TI - Spatial-light-modulator-based electro-optical imaging system. AB - We describe a novel electro-optical system that can image objects over a long range of distance without involving any mechanical movement. PMID- 20720652 TI - Image logic algebra and its optical implementations. AB - A generic language for optical parallel processing image logic algebra (ILA), is proposed. In ILA a neighborhood configuration pattern (NCP) is introduced, and image transformations are defined by the use of NCP operations. The comprehensive relationship of ILA to symbolic substitution, optical array logic, mathematical morphology, and binary image algebra are clarified. Furthermore, an architecture that is suited for ILA and its optical implementations is proposed. PMID- 20720653 TI - Optical interconnects using top-surface-emitting microlasers and planar optics. AB - Optical interconnections made using two-dimensional arrays of top-surface emitting microlasers and integrated free-space optics are discussed for use in chip-to-chip communications. A demonstration setup with a 2 x 2 array of lasers is presented. System parameters, such as light efficiency, the number of data channels, thermal effects, power requirements, and the issue of hybrid integration of laser chips with passive optics, are considered. PMID- 20720654 TI - Large interconnects in photorefractives: grating erasure problem and a proposed solution. AB - The known problem of grating erasure in photorefractive-based holographic optical interconnects can lead to limitations in the density of the system. This problem is analyzed for an architecture that uses spatially multiplexed beams (to eliminate cross erasure) and angularly multiplexed input beams to record multiplexed gratings in a bismuth silicon oxide (BSO) crystal to interconnect three beams to an array of 8 x 8 (64) detectors. Drawbacks of the time-exposure technique, which compensates for erasure, are analyzed. A novel photorefractive based interconnect architecture is proposed, which uses holograms and read beams that are segregated to minimize erasure during recording and reading. PMID- 20720655 TI - Novelty imaging system with a desired long-time scale using BaTiO(3) and a controlled shutter sequence. AB - A novelty imaging system using photorefractive crystal BaTiO(3) and a controlled shutter sequence, which can be applied to the slow-motion detection of the object, is proposed. In this system the observation time scale is set to the desired long value uninfluenced by the time constant of the crystal that is used. This system utilizes a photorefractive beam-fanning effect in the BaTiO(3) crystal, so it is constructed simply by using only the object beam without suffering from the external disturbance that is intrinsic when the reference beam is used. Moreover, the visibility for an opaque object is also maintained by the use of an additional random-phase plate. We examine the basic characteristics and determine the appropriate conditions of the system. PMID- 20720656 TI - Multitarget data association using an optical neural network. AB - A neural network solution to the data association problem in multitarget tracking is presented. It uses position and velocity measurements of the targets over two consecutive time frames. A quadratic neural energy function, which is suitable for an optical processing implementation, results. Simulation resultsusing realistic target trajectories with target measurement noise including platform movement or jitter are presented. The results show that the network performs well when track data are corrupted by significant noise. Several possible optical neural network architectures to implement this algorithm are discussed, including a new all-optical matrix-vector multiplication approach. The matrix structure is employed to allow binary-ternary spatial light modulators to be used. PMID- 20720657 TI - Direct measurement of the electrogyratory effect in bismuth silicon oxide. AB - A direct measurement of the electrogyratory effect in bismuth silicon oxide is performed at wavelengths of 633, 543, and 442 nm. We experimentally measured the electrogyratory effect separately from the electro-optic effect. For externally applied electric fields ranging from 0 to 60 kV/cm, the contribution due to the electrogyratory effect is found to be negligible with respect to the contribution due to the electro-optic effect. Since devices employing bismuth silicon oxide typically require applied electric fields in this range, the electric field dependence of the rotary power is shown not to perturb the desired operation. PMID- 20720658 TI - Computer-generated holograms: application to intensity variable and wavelength demultiplexing holograms. AB - We report two kinds of Fresnel-type computer-generated hologram, namely, an intensity variable hologram and a wavelength demultiplexing hologram. The former shows that diffraction intensity can be controlled almost independently by the spatial frequencies of the holograms. The latter shows wavelength demultiplexing holograms. Combining the former intensity-controlled holograms, uniform diffraction intensity of different wavelengths can be realized. PMID- 20720659 TI - Effects and correction of magneto-optic spatial light modulator phase errors in an optical correlator. AB - Here we study the optical phase errors introduced into an optical correlator by the input and filter plane magneto-optic spatial light modulators. We measure and characterize the magnitude of these phase errors, evaluate their effects on the correlation results, and present a means of correction by a design modification of the binary phase-only optical-filter function. The efficacy of the phase correction technique is quantified and is found to restore the correlation characteristics to those obtained in the absence of errors, to a high degree. The phase errors of other correlator system elements are also discussed and treated in a similar fashion. PMID- 20720660 TI - Spherical particle sizing by optical correlation using ternary phase-amplitude filters. AB - Computer simulations and experimental data are presented for various ternary phase-amplitude filters used to size opaque spherical particles. We first report on nearly unlimited spatial frequency ternary phase-amplitude filters derived directly from the classical matched filter for opaque spherical particles in the size range of 100 to 400 microm. Next we investigate the increasing influence of the cutoff frequency on the optical correlator as the particles become smaller. Using limited-order ternary phase-amplitude filters, we report on sizing opaque spherical particles in the size ranges of 100 to 400, 15 to 100, and 5 to 25 microm. PMID- 20720661 TI - Real-time fingerprint verification system. AB - Access to security spaces and the verification of credit cards require, ideally, a simple and inexpensive system that combines accuracy with a high resistance to compromise. We have been investigating such a system. This system incorporates a novel fingerprint input arrangement that permits the use of optical pattern recognition for fingerprint verification in real time. Test results together with design considerations are reported. PMID- 20720662 TI - Improved space-marching algorithm for strong acousto-optic interaction of arbitrary fields. AB - We present a modification of the beam-propagation algorithm that avoids computer intensive processing of the sound carrier and instead deals with the slowly varying complex sound profile only. Our three test cases of Gaussian beams with different waists, strongly interacting with a two-dimensional sound column, show excellent agreement with the analytical treatment and with physical experiments performed in our laboratory. PMID- 20720663 TI - Automatic specklegram fringe analysis by using symmetry evaluation of the Theta scanning function. AB - New approaches are applied to overcome the difficulty of accurate angle measurements in specklegram information processing by introducing a prism rotator for compensation and by using symmetry evaluation. Together with slit scanning and the fast Fourier transform procedure, speckle random noise has been effectively suppressed, and accurate measurements of Theta and s are achieved. The method we present makes it possible to process the specklegram information automatically. The experimental setup is described in detail. The principles and experimental curves are given. PMID- 20720664 TI - Three-dimensional phase-contrast imaging by a computed-tomography microscope. AB - We report a technique for measuring the three-dimensional variation of refractive indices in a microscopic sample. The technique is an adaptation of optical computed tomography and is effective in measuring the three-dimensional refractive-index distribution of a nonabsorbing microscopic sample. Our report also includes a discussion of the conditions for the unambiguous application of the technique as well as results of experiments conducted with Aspergillus oryzae (commonly known as green mold) as the sample. PMID- 20720665 TI - Electro-optic Fabry-Perot pixels for phase-dominant spatial light modulators. AB - A theoretical analysis of phase enhancement by resonant Fabry-Perot picture elements in III-V semiconductor spatial light modulators (SLM's) is presented. For 90% reflecting electrodes, a phase modulation of 0.7pi rad is found in transmission when the electro-optic input phase is 0.06pi rad. Implementation of this resonant phase-dominant SLM in a 1.5-microm-thick AlGaAs/GaAs multiple quantum well (MQW) structure is proposed. Field effects and carrier-induced electro-optic effects are suggested for the MQW's. PMID- 20720668 TI - Astrophysics. PMID- 20720666 TI - Patents. AB - 4,991,926; 4,997,245; 4,997,246; 4,997,249; 4,998,791; 4,998,794; 5,000,531; 5,005,927; 5,007,065; 5,007,694; 5,009,502; 5,011,250. PMID- 20720669 TI - Joule-level tunable single-frequency Nd:glass laser. PMID- 20720670 TI - Stimulated Brillouin scattering phase conjugation of an amplified hydrogen fluoride laser beam. AB - Optical phase conjugation through stimulated Brillouin scattering was used to correct phase aberrations on a beam that was double passed through a pulsed hydrogen fluoride laser amplifier. PMID- 20720671 TI - Observation of the 8-microm N(2)O(5) thermal emission feature in the stratosphere: comment. AB - The measurement of N(2)O(5) by Evans [Appl. Opt. 25, 1866-1868 (1986)] contains several serious errors. A reanalysis of the published infrared spectra gives the more realistic error bar of +/-45%. PMID- 20720672 TI - Least-squares error analysis of the 1985 N(2)O(5) observation: reply. AB - A least-squares fitting analysis of the original 1985 observed N(2)O(5) spectrum was conducted. By the method of random number noise enhancement, the error that is due to random noise was estimated to be 8.3%, consistent with the original published error estimate of 10%. PMID- 20720673 TI - Single-mode fibers used as confocal microscope pinholes. AB - Conventional clear-aperture pinholes in confocal microscopes can be replaced by single-mode optical fibers, thereby reducing alignment and dust accumulation problems and providing greater flexibility for optical and electronic hardware placement. PMID- 20720674 TI - Frequency-modulation spectroscopy for trace species detection: theory and comparison among experimental methods. AB - A variety of frequency-modulation methods for high-sensitivity absorption detection of gas-phase species has evolved in recent years. The distinctions among these methods are mostly semantic. The mathematical derivations for wavelength-modulation spectroscopy and one- and two-tone frequency-modulation spectroscopies are presented; a common terminology is used to permit a comprehensive comparison of predicted detection sensitivities. Applying this formalism, I compare the optimum detection sensitivities of these different methods for a typical laser system, using the same parameters. As long as residual amplitude modulation is minimized by proper adjustment of the detection phase angle, high-frequency wavelength modulation and one- and two-tone frequency modulation methods all achieve approximately the same sensitivities. The choice among techniques is most strongly driven by the individual laser tuning characteristics, the absorption linewidth, and the detection bandwidth. It is shown that excess laser noise cannot always be excluded from consideration, even at megahertz detection frequencies. Also, detection at harmonics of the modulation or beat frequency may present certain advantages in minimizing residual amplitude-modulation noise. PMID- 20720675 TI - Frequency modulation and wavelength modulation spectroscopies: comparison of experimental methods using a lead-salt diode laser. AB - Wavelength modulation spectroscopy (WMS) and one-tone and two-tone frequency modulation spectroscopy (FMS) are compared by measuring the minimum detectable absorbances achieved using a mid-IR lead-salt diode laser. The range of modulation and detection frequencies spans over 5 orders of magnitude. The best results, absorbances in the low-to-mid 10(-7) range in a 1-Hz bandwidth, are obtained by using high-frequency WMS (10-MHz detection frequency) and are limited by detector thermal noise. This sensitivity can provide species detection limits well below 1 part per billion for molecules with moderate line strengths if multiple-pass cells are used. High-frequency WMS is also tested by measuring the absorbance due to tropospheric N(2)O at 1243.795 cm(-1). WMS at frequencies < 100 kHz is limited by laser excess (1/f) noise. Both of the FMS methods, which require modulating the laser at frequencies >/= 150 MHz, give relatively poor results due to inefficient coupling of the modulation waveform to the laser current. The re ults obtained agree well with theory. We also discuss the sensitivity limitations due to interference fringes from unintentional etalons and the effectiveness of etalon reduction schemes. PMID- 20720676 TI - Polarized spectral emittance from periodic micromachined surfaces: IV. Undoped silicon: Normal direction in deep lamellar gratings. AB - Experimental results of thermal emittance from deep gratings are presented along with a theoretical discussion. We have found that for a certain grating geometry thermal emission peaks coincide with the cutoff frequencies of slab waveguides. The coincidence was found with s- but not p-polarized emission. This suggests that coupling between grating fins for s-polarized emission is small. It was also found that emission peaks do not correlate directly with the well-known grating equation for these deep gratings. PMID- 20720677 TI - Diffuse nonlinearity with a thermal gradient in waveguide prism coupling. AB - Prism coupling of radiation inside a linear film over a nonlinear substrate is studied with a numerical method, showing that the change of coupling as a function of the input power in the case of a quasi-continuous operation (thermal nonlinearity) is influenced by a thermal gradient generated in the linear film. A comparison with experimental data confirms these calculations. PMID- 20720678 TI - Small-frequency-shift stimulated-four-photon mixing in optical fibers: optimum phase-matching conditions. AB - When the frequency shift of amplified Stokes and anti-Stokes waves in stimulated four-photon mixing processes is small, the equations governing the interaction can be simplified, and the general case of depleted pump power can be solved analytically. This yields expressions for the phase mismatch as a function of pump power required for maximum amplification of the generated frequencies. PMID- 20720679 TI - Passive optical fiber star coupler. AB - A fused polymer optical fiber star coupler utilizing a new fabrication technology has been developed. The uncladded fibers over the coupling region are fused together by a heat shrink sleeve. Low-cost star couplers with large port numbers, low excess losses, and high-uniformity variation are realized. PMID- 20720680 TI - Multimode fiber-optic broad spectral band interferometer. AB - We have developed techniques that permit broad spectral band interference fringes to be observed on a mode-by-mode basis, using long lengths of few-mode fiber without the detrimental effects of incoherent modal superimposition. Modes are spatially by a cladding etching technique. Mode orientation and polarization are preserved by using elliptical core fibers. PMID- 20720681 TI - Effective-index method and coupled-mode theory for almost-periodic waveguide gratings: a comparison. AB - Contradirectional propagation through active, first-order, almost-periodic, corrugated waveguide gratings is analyzed by using both coupled-mode theory and a combined effective-index/impedance-matching matrix technique. For TE-mode operation, which is near the first-order Bragg wavelength, the equivalence of the two techniques is analytically demonstrated for shallow surface corrugations. PMID- 20720682 TI - Aberrations of a multipass matrix system. AB - A three-objective multipass matrix system has been theoretically analyzed with respect to the aberrations of the third order. An expression has been derived in the three-dimensional coordinate system relating the position of a point in the output slit to that of a point in the input slit, depending on the construction peculiarities of the system given and the parameters of the matrix of intermediate images. Conditions of image focusing upon the input slit and astigmatism compensation have been derived. Relationships to determine the field curvature and distortion have been derived. PMID- 20720683 TI - Optical tracking of single Brownian particles. AB - A random access scanning microscope system was built to track the Brownian motion of submicrometer colloidal particles in all three dimensions. Transverse tracking resolutions of 20 nm were achieved for 1-ms clock rates. Based on mean-square displacements, the diffusion coefficient and hence the size of the individual particles was determined. Even better size resolution was demonstrated through the measurement of an axial drift motion, which was induced by radiation pressure. This experiment was simplified, if the particles could be trapped transversally by ponderomotive optical forces. The degree of trapping was directly observable from histograms of particle positions. PMID- 20720684 TI - Automated analysis of multiple-pulse particle image velocimetry data. AB - An application of multiple-pulse particle image velocimetry to the study of particle motion in a two-phase flow through a cylindrical tube bank is described. An algorithm is developed that automatically analyzes the digital, multiply exposed pictures of this flow and determines the particle trajectories, using a linear particle image tracking method. From these trajectories particle velocities as well as points of impact and angles of incidence and rebound for particles that collide with the cylinder surfaces are determined. This algorithm is sufficiently rapid that data can be collected and analyzed contemporaneously. PMID- 20720685 TI - Theory of mesospheric sodium fluorescence excited by pulse trains. AB - We describe a two-level model for the mesospheric sodium resonance fluorescence excited by a train of pulses. For pulse durations that are short compared with the 16-ns natural lifetime, population-rate equations are inadequate and must be replaced by density-matrix (Bloch) equations. We briefly contrast these two approaches and discuss several issues associated with pulse-train excitation. Analytical approximations to averages over atomic velocities and the transverse spatial profile of the laser are described. Estimates of return photon numbers for trains of pulses, ranging in duration from tens of picoseconds to half a nanosecond, are made and these estimates are compared with those of more conventional long-pulse lidar schemes. Roughly similar photon numbers are predicted for both long and short pulses whenever their average intensities are comparable. For average intensities, less than ~ 10 W/cm(2), trains of asymptotically equal to 0.5-ns pulses yield greater photon returns than trains of asymptotically equal to 30-ps pulses. For larger intensities the reverse can be true. PMID- 20720686 TI - Effects of speckle on the range precision of a scanning lidar. AB - The dynamic speckle generated by a scanning lidar is a major contributor to the range precision for long transmitter pulses, such as those for a linear frequency modulation-chirp waveform. The linear portion of the speckle-phase variations is automatically compensated, and the range precision is significantly improved, when an upchirp and downchirp pair is transmitted simultaneously, combined with a proper demodulation process. This concept was verified through a laboratory demonstration. The effect of speckle-amplitude variations on the compressed-pulse waveform is also investigated. PMID- 20720687 TI - Remote detection of methane with a 1.66-microm diode laser. AB - High-sensitivity real-time remote detection of methane in air with a 1.66-microm distributed-feedback diode laser operating at room temperature is demonstrated by laboratory simulations. The laser current was modulated at a high frequency of ~5 MHz, and the laser-center frequency was locked onto a methane-absorption line. The laser light directed toward the probed region was received after one-way transmission or further reflection from a topographic target. The methane absorption was detected by the second-harmonic component in the optical-power variation. The minimum-detectable concentration-path-length product in the transmission scheme was 0.3 part in 10(6) m for a signal averaging time of 1.3 s. In the reflection scheme, the amount of methane could be measured from the ratio of the fundamental and second-harmonic signal intensities independently of the received power. PMID- 20720688 TI - Spectroscopy of methane using a Nd:YAG laser at 1.34 microm. AB - We present measurements of the absorption coefficient of methane in the v(2) + 2v(3) band obtained with a neodymium:yttrium aluminum garnet (Nd:YAG) laser tuned by the use of an intracavity etalon to 7472 cm(-1) (1.3383 microm). The linewidth of the laser was shown to be comparable to that of the pressure-broadened methane feature while the absorption coefficient of methane at 1-atm pressure was measured to be 0.59 m(-1) atm(-1). These basic findings indicate that a practical methane detection system using laser radar (lidar) based on a Nd:YAG laser may be possible. PMID- 20720689 TI - Bioluminescence estimation from ocean in situ irradiances. AB - An algorithm is developed for estimating the spatial location and magnitude of a bioluminescent radiation source from measurements of the in situ irradiance and scalar irradiance at two depths. The algorithm is based on the principle of photon conservation. The most direct application of the algorithm requires that the absorption coefficient be known, but the algorithm is useful even if that coefficient is unknown. Numerical tests and an error analysis have been done to test the algorithm numerically. In addition we show that if the estimated source magnitude is nearly constant, that value can be used to estimate the vertical attenuation coefficient of the radiation field. PMID- 20720690 TI - Laser Raman sensor for measurement of trace-hydrogen gas. AB - A new optical hydrogen sensor based on spontaneous Raman scattering of laser light has been designed and constructed for rugged field use. It provides good sensitivity (better than 100 parts in 10(6)), rapid response (several seconds), and the inherent Raman characteristics of linearity and background gas independence of the signal. Efficient light collection and discrimination by using fast optics and a bandpass interference filter compensate for the inefficiency of the Raman-scattering process. A multipass optical cavity with a Herriott-type configuration provides intense illumination from an air-cooled cw gas laser. The observed performance is in good agreement with the theoretical signal and noise level predictions. PMID- 20720691 TI - Tunable ultraviolet femtosecond pulses at kilohertz repetition rates. AB - Femtosecond pulses, tunable between 250 and 400 nm, are generated at a pulse repetition rate of 8 kHz by two methods, sum-frequency generation and second harmonic generation. Both methods produce pulse energies ranging from ~ 10 pJ at 280 and 380 nm to 40 nJ at 310 nm. Between 250 and 280 nm, sum-frequency generation produces pulses with energies significantly greater than those produced by second-harmonic generation. The measured pulse duration at 310 nm is 180 fs. PMID- 20720692 TI - Interference effects in reticon photodiode array detectors. AB - A detector system incorporating the Reticon RL1024S photodiode array has been constructed at the National Oceanic and Atmospheric Administration Aeronomy Laboratory as part of a double spectrograph to be used to study the Earth's atmosphere from ground-based and aircraft-based platforms. To determine accurately the abundances of atmospheric trace gases, this new system must be able to measure spectral absorptions as small as 0.02%. The detector, manufactured by EG&G Reticon, exhibits superior signal-to-noise characteristics at the light levels characteristic of scattered skylights, but interference in the passivating layer (a thin layer of SiO(2) that is deposited during the manufacture to protect the silicon active area from water vapor) causes major problems in achieving the required precision. The mechanism of the problems and the solution we have implemented are described in detail. PMID- 20720693 TI - Fiber-optic particle size monitor based on white-light scattering. AB - A new fiber-optic particle size monitor for in situ measurement based on white light scattering is presented. The particle size is determined from the ratio of two scattered light intensities taken at two wavelength bands. By using white light scattering, the proper wavelength bands in the broad spectral region can be selected in accordance with the particle size that is to be measured. Then the measurable particle size range can be expanded and the particle size can be measured precisely. The performance of this particle size monitor is theoretically discussed, and experimental data from polystyrene latex suspensions are shown to confirm its operation. PMID- 20720694 TI - Fizeau digital interferometry with a diffraction-generated spherical wave for testing focusing optics. AB - A sufficiently small, reflective spherical particle at the focus of a test lens can replace the spherical autostigmatizing mirror in Fizeau digital interferometry, which is used for testing focusing optics. This small particle serves as a secondary coherent point source in the test arm and generates by diffraction a spherical wave that is used to produce the test beam. The relationships between the diffraction-generated wave and the size and shape of the diffracting element are discussed and also used to properly select the diffracting element. Experimental results confirm that the new technique has high accuracy. PMID- 20720695 TI - Fringe pattern in holographic interferometry for thermal expansion characterization of isotropic bodies. AB - The fringe pattern produced in a double-exposure hologram by thermal expansion of isotropic flat plates is theoretically attained and experimentally checked. The change of fringe shape as a function of the observation distance is analyzed. PMID- 20720696 TI - Zeeman laser interferometer errors for high-precision measurements. AB - We present a theoretical analysis of the errors of a Zeeman laser interferometer due to the nonorthogonally elliptic polarizations of laser modes. The polarizations make the measured Doppler frequency-shift signal become a modulated and nonharmonic signal and make the phase shift unstable and nonrepeatable when the signal is measured by a phasemeter. If the orthogonality error between two major axes of the laser polarizations is 6 degrees , the relative errors of the phasemeter output will exceed 200% when the measured phase shift is changed from 16.2 degrees to +3.5 degrees . We also introduce a way to eliminate the errors. PMID- 20720697 TI - Infrared optical constant determination of weakly absorbing dielectric thin films. AB - Simple approximate relations are given for the reflectance of a weakly absorbing dielectric layer deposited as a quarter wave or a half-wave upon transparent and metallic substrates. These approximated relations are used in the infrared to calculate the optical constants n and k and the inhomogeneity partial differentialn of the index n of a material deposited as a thin film. A high degree of accuracy is sought for k. Two examples are given for ZnS and ThF(4) in the 3-11-microm spectral range. PMID- 20720698 TI - Differential confocal scanning microscope with a two-mode optical fiber. AB - A novel technique for obtaining differential images with a scanning microscope by using a two-mode optical fiber is proposed. It is shown that both the differential amplitude and the differential phase images can be obtained by adjusting the differential phase delay between the fiber modes. The technique is demonstrated experimentally, and differential images of a specimen consisting of sharp edges in both amplitude and phase reflectivity are presented. PMID- 20720699 TI - Reflection scanning microscopy. AB - To image nontransparent samples we have utilized a special type of scanning-probe microscope that is referred to here as a reflection scanning microscope. The reflection scanning microscope provides a method for producing a scanned point light source as well as a system for collecting the light that is reflected by the sample. The system, which uses an optical fiber coupler, is easily installed on an existing photon scanning tunneling microscope. A calculation of the coupling coefficient between the natural propagation mode of the optical fiber and the light that is reflected by the sample is presented along with a comparison between calculated and measured values of the intensity of the light that is detected. Several images of different samples are presented that show the actual resolution of the microscope. PMID- 20720700 TI - Thermal modeling studies of organic compact disk-writable media. AB - The marking response of optical data storage structures is controlled by the interplay of optical and thermal effects. Relatively simple analytical expressions were derived that provided a qualitative and semiquantitative description of the optical and thermal characteristics of an organic dye-based optical recording medium. These were used to explain various phenomena that were observed during recording experiments that were performed on compact disk writable media and to evolve a new understanding of the mark formation process. PMID- 20720701 TI - Three-dimensional sensing of rough surfaces by coherence radar. AB - We introduce a three-dimensional sensor designed primarily for rough objects that supplies an accuracy that is limited only by the roughness of the object surface. This differs from conventional optical systems in which the depth accuracy is limited by the aperture. Consequently, our sensor supplies high accuracy with a small aperture, i.e., we can probe narrow crevices and holes. The sensor is based on a Michelson interferometer, with the rough object surface serving as one mirror. The small coherence length of the light source is used. While scanning the object in depth, one can detect the local occurrence of interference within the speckles emerging from the object. We call this method coherence radar. PMID- 20720702 TI - Picosecond (picoframe) framing camera evaluations. AB - Detailed theoretical evaluations of picoframe-I- and II-type framing cameras are presented, and predicted performance characteristics are compared with experimental results. The methods of theoretical simulations are described, and a suite of computer programs was developed. The theoretical analyses indicate that the existence of fringe fields in the vicinity of the deflectors is the main factor that limits the dynamic spatial resolutions and frame times of these particular designs of framing camera, and possible refinements are outlined. PMID- 20720703 TI - Achieving a given reflectance for unpolarized light by controlling the incidence angle and the thickness of a transparent thin film on an absorbing substrate: application to energy equipartition in the four-detector photopolarimeter. AB - At a given wavelength lambda we determine all possible solution pairs (?, zeta) of the incidence angle ? and the thickness zeta of a transparent thin film on an absorbing substrate that achieve a given unpolarized light reflectance R(u). The trajectory of the point that represents a solution pair in the zeta, ? plane depends on the optical properties of the film and substrate and on whether R(u) is greater than or less than the normal-incidence reflectance -R(0) of the bare substrate. When R(u) > - R(0), the specified reflectance is achieved over a limited range of ?. At the least possible incidence angle, the film thickness is approximately ? th wave. As an application we consider SiO(2) films on Si detectors that produce R(u). = 0.75, 0.6667, and 0.50 at lambda = 337 and 633 nm. If the first three detectors of the four-detector photopolarimeter (FDP) are coated to have these reflectance levels, with the reflectance diminishing in the direction of propagation of the light beam, and the last detector is antireflection coated (e.g., with a quarter-wave Si(3)N(4) layer), equipartition of energy among the four detectors is accomplished for incident unpolarized light. Such a condition is desirable in the operation of the FDP. The ellipsometric parameters of the coated surfaces and the FDP instrument matrix are also calculated. PMID- 20720704 TI - Aberration-corrected aspheric grating designs for the Lyman/Far-Ultraviolet Spectroscopic Explorer high-resolution spectrograph: a comparison. AB - Two approaches to reducing the optical aberrations of concave diffraction gratings have been studied to obtain candidate grating designs for the Lyman/Far Ultraviolet Spectroscopic Explorer mission. The first approach involves shaping the grating substrate while using straight and equally spaced grooves. The second approach involves using a gating substrate with a relatively simple figure and holographically controlling the groove curvature and spacing. We analyze and compare specific designs derived from both approaches. PMID- 20720705 TI - Aberration-corrected aspheric gratings for far-ultraviolet spectrographs: holographic approach. AB - Two approaches to reducing the optical aberrations of concave diffraction gratings have been studied: holographically controlling the groove curvature and spacing, and shaping the optical substrate while keeping the grooves straight and equally spaced. We develop the theory of ellipsoidal holographic diffraction gratings and apply this theory to Rowland circle spectrographs. We show that ellipsoidal holographic gratings used in second order can yield high spectral resolutions across the spectral band. These gratings may be suitable for use in far-ultraviolet Rowland spectrographs with small bandpasses. PMID- 20720707 TI - Yield analysis of multilayer optical coatings. AB - Yield is defined as the ratio of the number of devices that satisfy a particular technical specification to the total number of devices produced. For coated optical devices, random layer thickness variations decrease the yield. Variations in refractive index can also affect yields, but in this work we assume that changes in index are not as important as changes in thickness. A graphic method of yield analysis for optical coatings is presented. This method probes the sensitivity of the device performance against thickness variations and translates it into yield figures. Five examples of this analysis are provided including spectral and nonspectral applications. PMID- 20720706 TI - Measuring absolute diffuse reflectance in the ultraviolet. PMID- 20720708 TI - Characterization of x-ray transmission gratings. AB - Self-supporting transmission gratings with periods of 1 microm or below are used in combination with grazing-incidence telescopes in celestial x-ray astronomy. They can be produced with sizes up to only a few cm(2); therefore, several hundreds or even thousands of individual elements are needed in order to cover the aperture of a telescope. This large number leads to the problem of characterization of the gratings regarding their x-ray performance. We demonstrate that spectrometry in the resonance domain using H polarization is a suitable method for the determination of the grating wire profile and deviations of the grating surface from a plane. Although developed originally for microwave applications it can be shown that the methods of strict solution of the Helmholtz equation are able to explain even small effects related to imperfections of periodic submicrometer structures. PMID- 20720709 TI - In situ performance tests of soft-x-ray multilayer mirrors exposed to synchrotron radiation from a bending magnet. AB - The performance of soft-x-ray multilayer mirrors of Mo/Si, Rh/Si, and Ru/Si has been tested in situ during ~ 15-h exposure to white synchrotron radiation from a bending magnet of the Photon Factory (Tsukuba, Japan) ring. The power density on the sample surface was ~ 0.14 W/mm(2). The tests were made by measuring the intensity of the reflected beam from the test mirrors with a detector unit consisting of a carbon filter and an aluminum cathode. The detector unit served as an effective narrow-band detector for the intense radiation of 85-105 eV reflected from the test mirrors. The Mo/Si and Rh/Si multilayer mirrors were found to be quite stable against continuous irradiation, whereas the Ru/Si multilayer mirror showed a definite decrease in the reflected-beam intensity. PMID- 20720710 TI - Visibility-dependent depth of focus for incoherent sinusoidal sources. AB - A visibility-dependent depth of focus is developed for incoherent sinusoidal sources. This analysis is based on a derived relationship between the visibility and the optical transfer function (OTF). The formalism developed is general for any aperture topology and arbitrary orientation of sinusoidal sources. To illustrate the application of the method the cases of an annular aperture and a Gaussian aperture are analyzed. It is found that as the level of defect of defocus increases, the maximum visibility for which a particular spatial frequency can be resolved decreases. PMID- 20720711 TI - Guiding and concentrating hard x-rays by using a flexible hollow-core tapered glass fiber. AB - A 1.6-m-long, flexible, hollow glass fiber with a gradually diminishing bore diameter has been used efficiently to compress the size of an x-ray beam as it reflects from the inside walls of the fiber by total external reflection. The transmission characteristics of the fiber are reported for monochromatic synchrotron radiation of 8.04, 13, and 20 keV, as well as for CuKalpha radiation from a conventional x-ray tube. Intensity enhancements as large as 10 that correspond to a transmission efficiency of 54% were observed. The high efficiency of this prototype fiber supports the idea that this confinement technique should yield intensity gains of many orders of magnitude as the optimal fiber design is achieved. PMID- 20720712 TI - Path matching in holography for short coherence-length lasers. AB - A simple technique is described to match the optical path lengths in holography. PMID- 20720713 TI - Particle image velocimetry: three-dimensional fluid velocity measurements using holographic recording and optical correlation. AB - We report on an original use of optical correlation techniques and holographic recording to provide three-dimensional velocity vector information from particle image velocimetry. PMID- 20720714 TI - Holographic optical element for projection of stereo images. AB - We present a holographic element, capable of projecting dynamic stereoimages and allowing the observer to see through the device, forpossible use as a heads-up display in aircraft. PMID- 20720715 TI - Single-beam digital holographic contouring. AB - A method for digital holographic contouring that uses a diffraction grating to generate the reference beam and to introduce adequate phase delay in the object beam is described. PMID- 20720716 TI - Effects of thresholding level variation in fringe binarization of multiobject joint transform correlation. AB - It is possible to improve the fringe binarization method of joint transform correlation by choosing a suitable threshold level. PMID- 20720717 TI - Bispectral magnitude and phase recovery using a wide bandwidth acousto-optic processor. AB - A hybrid optical-digital processor has been developed that computes both the magnitude and phase of the bispectrum for wide bandwidth (10 MHz to 1 GHz) rf signals. The overall optical architecture is that of a modified Mach-Zehnder interferometer that contains three acousto-optic modulators and appropriate transforming lenses. The intensity distribution in the output plane of the interferometer contains an interference term that represents the real part of the bispectrum multiplied by a spatial carrier (the interference fringes). To isolate the bispectrum information, the output image is digitized and digitally filtered. The imaginary part of the bispectrum is obtained by Hilbert transforming the real part, and then computing the bispectrum magnitude and phase. The processor is tested with four different combinations of rf test signals. Each signal has a bandwidth of either 6 or 12 MHz. Test results that illustrate the performance of the processor in the recovery of magnitude and phase information for the bispectrum of quadratically related signals are presented. PMID- 20720718 TI - Optical correlator production system neural net. AB - A new neural net is described that can easily and cost-effectively accommodate multiple objects in the field of view in parallel. The use of a correlator achieves shift invariance and accommodates multiple objects in parallel. Distortion-invariant filters provide aspect-invariant distortion. Symbolic encoding, the use of generic object parts, and a production system neural net allow large class problems to be addressed. Optical laboratory data on the production system inputs are provided and emphasized. Test data assume binary inputs, although analog (probability) input neurons are possible. PMID- 20720719 TI - High-resolution contact Denisyuk holography. AB - The configurations, to assure high resolution in contact Denisyuk holography, are investigated by varying the construction and the viewing angles in the recording and the reconstruction setups, respectively. A range of optimized angles, obtained with Agfa 8E75 HD plates is given. These results are compared with another holographic material. To introduce this holographic technique in medical diagnostics, we made holograms of various stained-tissue samples. These holograms have been improved by the selection of tissue-staining dyes and their concentrations. PMID- 20720720 TI - Edge-illuminated holograms. AB - Design and construction considerations and performance characteristics of edge illuminated holograms are described. The display system layouts presented are compact, monolithic, and achromatic, and the light usage efficiency is improved by recycling the undiffracted hologram-illuminating beam. PMID- 20720721 TI - Laser structuralization of gelatin with acrylic acid compound for producing high resolution sensitive media for hologram optics. AB - The properties of laser (He-Ne) structuralization of gelatin films with acrylic acid compounds (amides and salts) for producing high-resolution sensitive media for hologram optics are discussed. PMID- 20720722 TI - Simulated annealing of binary holograms for the interconnection of single-mode structures. AB - The simulated annealing algorithm is applied to the design of binary holographic optical elements for the connection of single-mode structures. The system energy used with the simulated annealing algorithm is the absolute square of the overlap between the transmitted wave front and the modal characteristics of the receiving device; the system variables are the binary states of the hologram pixels. The plausibility of the obtained binary patterns is discussed for examples involving plane and spherical modal characteristics. The ability of the annealing process to avoid local minimum trapping is demonstrated. PMID- 20720723 TI - Optical coordinate transformations. AB - A novel technique for designing holographic optical elements that can perform general types of coordinate transformation is presented. The design is based on analytic ray-tracing techniques for finding the grating vector of the element, from which the holographic grating function is obtained as a solution of a Poissonlike equation. The grating function can be formed either as a computer generated or as a computer-originated hologram. The design and realization procedure are illustrated for a specific holographic element that performs a logarithmic coordinate transformation on two-dimensional patterns. PMID- 20720724 TI - Synthesis of diffractive optical bar codes. AB - A new type of diffractive optical bar code (DOBC) is proposed. Rather than scanning directly, the DOBC is coherently illuminated, and the first diffraction order is sensed. The spacing between the bars is chosen so that the thresholded diffraction pattern yields a specified binary code. Two approaches are investigated for synthesis of the DOBC: phase shaping and a gradient-based, nonlinear, constrained optimization technique. The two design methods are compared based on numerical results, and the validity of the overall design approach is verified by optically sensing the diffraction patterns for a number of fabricated DOBC's. PMID- 20720725 TI - Model-based frequency response characterization of a digital-image analysis system for epifluorescence microscopy. AB - We describe a model-based method for estimating the spatial frequency response of a digital-imaging system (e.g., a CCD camera) that is modeled as a linear, shift invariant image acquisition subsystem that is cascaded with a linear, shift variant sampling subsystem. The method characterizes the twodimensional frequency response of the image acquisition subsystem to beyond the Nyquist frequency by accounting explicitly for insufficient sampling and the sample-scene phase. Results for simulated systems and a real CCD-based epifluorescence microscopy system are presented to demonstrate the accuracy of the method. PMID- 20720726 TI - Gray-image processing using optical array logic. AB - A method for digital image processing that uses optical array logic (OAL) is presented. Parallel thresholding and digital filtering are demonstrated. OAL is a promising computational paradigm for digital optical computing based on parallel neighborhood operations for two two-dimensional binary images. In the proposed method, virtual processing elements are assumed on an image plane and a gray pixel in an original gray image is stored in each processing element. Efficient gray-image processing can be achieved by data manipulation in the virtual processing elements and in the data communication among them by using OAL. Several simulation results are presented. Finally, hardware requirements for the developed algorithms and their capabilities are discussed. PMID- 20720727 TI - Multiple-filter approach to phase retrieval from modulus data. AB - A new approach is given for the problem of reconstruction of phase from modulus data. A set of Wiener-filter functions is formed that multiply, in turn, displaced versions of the modulus data (in frequency space) such that the sum is a minimum L(2)-error norm solution for the object. The modulus data are permitted to contain both noise and signal (object) components. The required statistics are power spectra of the signal and noise, and correlations between modulus data at given frequencies and complex object spectral values at adjacent frequencies. In a numerical simulation, a 3 x 3 filter array is used to reconstruct any member of an object class consisting of 16 pictures of space shuttles in various combinations. The 16 pictures are used as a learning set to form the required power spectra and correlations mentioned above. Reconstructions are formed in the presence of data noise, data gaps, and filter-construction noise, in varying amounts. Results are encouraging in that the space shuttle images are always recognizable. PMID- 20720728 TI - Advanced distortion-invariant minimum average correlation energy (MACE) filters. AB - The original minimum average correlation energy (MACE) filter is addressed by using a new database (strategic relocatable objects, missile launchers) and including noise performance, depression angle, and resolution effects on the number of training set images that are required. Major attention is given to our new MACE filter algorithms for distortion-invariant pattern recognition: shifted MACE filters (to suppress large false correlation peaks), minimum variance-MACE filters (for improved noise performance), multiple symbolic encoded filters (to reduce the effect of false correlation peaks), and Gaussian-MACE filters (to improve noise performance and intraclass recognition and reduce the training set size). PMID- 20720729 TI - Iterative optimization algorithms for filter generation in optical correlators: a comparison. AB - A general approach to the implementation of highly selective spatial filters for pattern recognition leads to a nonlinear optimization problem. Three optimization algorithms, hill climbing (direct search), simulated annealing, and the genetic algorithm, were investigated for implementation on hybrid electro-optical systems. Experimental results indicate the substantial superiority of the genetic algorithm in terms of operating speed and performance quality. PMID- 20720730 TI - Phase extraction pattern recognition. AB - Phase extraction pattern recognition is a special case of nonlinear matched filtering. The phase extraction procedure is executed on the input function's Fourier transform as well as on the filter function's Fourier transform, both of which are manipulated for correlation purposes. This novel process is examined theoretically, by computer simulations and laboratory experiments. The implementation of a coherent electro-optical phase extraction pattern recognition system demonstrates the advantages of this new approach. PMID- 20720731 TI - Integral logarithmic transform: theory and applications. AB - Integral logarithmic transforms (LT's) are defined for both one- and two dimensional input functions. These have the desirable properties of linearity and invariance to scale change of the input. One of the two-dimensional LT's is additionally invariant to rotation. The LT's are conveniently inverted by simple differentiation. Also, they are amenable to optical analog implementation by using incoherent light and simple collimating lenses. As an application, the problem of noise suppression of an arbitrarily scaled image, by using Wiener filtering, is considered. Use of the LT of the image data as a preprocessing step permits the creation of a single Wiener filter optimized for use at all scales of magnification. Finally, application to a problem of character recognition and matched filtering is proposed. PMID- 20720732 TI - One-dimensional tomography: a comparison of Abel, onion-peeling, and filtered backprojection methods. AB - It is shown that the Abel inversion, onion-peeling, and filtered backprojection methods can be intercompared without assumptions about the object being deconvolved. If the projection data are taken at equally spaced radial positions, the deconvolved field is given by weighted sums of the projections divided by the data spacing. The weighting factors are independent of the data spacing. All the methods are remarkably similar and have Abelian behavior: the field at a radial location is primarily determined by the weighted differences of a few projections around the radial position. Onion-peeling and an Abel inversion using two-point interpolation are similar. When the Shepp-Logan filtered backprojection method is reduced to one dimension, it is essentially identical to an Abel inversion using three-point interpolation. The weighting factors directly determine the relative noise performance: the three-point Abel inversion is the best, while onion peeling is the worst with approximately twice the noise. Based on ease of calculation, robustness, and noise, the three-point Abel inversion is recommended. PMID- 20720733 TI - Technique for visualizing vaporlines emanating from water droplets. PMID- 20720734 TI - Near-resonance excitation of dielectric spheres with plane waves and off-axis Gaussian beams. PMID- 20720735 TI - Electronic versus thermal response for nonlinear prism coupling. PMID- 20720736 TI - Attenuation due to diffusion of water vapor in As(2)S(3) fiber. PMID- 20720737 TI - Impurity fluorescence in fluorozirconate fibers. PMID- 20720738 TI - Determination of alcohol partial molar volumes from single-droplet gravimetric and optical resonance data. PMID- 20720739 TI - Rotational and vibrational dependences of collisional linewidths in the nnu(2)-(n 1)nu(2) hot bands of H2O from Fourier-transform flame spectra. AB - The collisional widths of ~ 160 transitions belonging mainly to the 2nu(2)-nu(2), 3nu(2)-2nu(2), and 4nu(2)-3nu(2) hot bands of the H(2)(16)O molecule have been measured on Fourier-transform air-methane flame spectra at 2000 K and analyzed, showing a strong decrease in the collisional widths when the rotational quantum number J increases, as well as a nonnegligible decrease of the collisional widths when the nu(2) vibrational quantum number increases. PMID- 20720740 TI - Eigenmodes of misaligned unstable optical resonators with circular mirrors. AB - It is shown numerically that the diffractive transverse (Fox-Li) eigenmodes supported by an unstable cavity with tilted end mirrors can be computed by expanding these modes in terms of the fully aligned (aberration-free) eigenmodes of the same cavity. Circular mirror resonators are considered in which the aligned cavity eigenmodes can be decomposed into different azimuthal components. The biorthogonality property of the aligned cavity eigenmodes is used to obtain the coefficients in the modal expansion of the misaligned modes. Results are given for two different resonators: a conventional hard-edge unstable cavity with a small tilt of the output coupler and one that uses a graded reflectivity output mirror with a small tilt of the primary mirror. It is shown that the series expansion of the misaligned modes in terms of the aligned modes converges, and the converged eigenvalues are virtually identical to those computed by using the Prony method. Symmetry considerations and other new insights into the effects of a mirror tilt on the modes of a resonator are also discussed. PMID- 20720741 TI - Cyclic shearing interferometer for collimating short coherence-length laser beams. AB - Until now there has not been an accurate method for measuring the radius of curvature, R, of a short coherence-length light source, such as a short-pulse or broadband laser. We show that the easily aligned cyclic shearing interferometer (CSI) solves this problem. The CSI produces a stable fringe pattern from which R can be determined and can be used on beams with short coherence times down to 300 fs because the two beams in the interferometer follow nearly the same path. Comparison with data from a broadband XeCl laser (30-ps coherence time) confirms that the CSI performs as theory predicts. PMID- 20720742 TI - Direct generation of circularly polarized pulse from a transversely excited atmospheric CO(2) laser by injection locking. AB - The injection technique was applied to the generation of a circularly polarized pulse, with an energy of more than 5 J, directly from a transversely excited atmospheric CO(2) laser oscillator. PMID- 20720743 TI - Experimental verification of a theoretical model for continuous wave energy transfer dye mixture lasers in the near infrared. AB - We report the experimental verification of a simulation model for cw energy transfer dye lasers. Experimentals results obtained with Rhodamine 610 (donor) and Nile Blue 690 (acceptor) confirm theoretical model predictions. PMID- 20720744 TI - Spectral equalization and autosweeping effects in a pulsed dye laser with an intracavity photorefractive element. AB - A pulsed dye laser with an intracavity photorefractive element is reported. It is shown that the element can be used for storage of spectral information. New effects for this system such as spectral equalization and oscillation-frequency autosweeping are demonstrated. PMID- 20720745 TI - Scalable single-frequency diode-pumped ring laser. AB - A diode-pumped discrete-element ring laser that can be end pumped simultaneously along two intersecting axes is described. The maximum power obtained was 493-mW single frequency at 1.06 microm. A demonstration of cw and Q-switched operations was performed for the fundamental and second harmonic, and a second-harmonic conversion efficiency of 43% was obtained. This ring laser is shown to incorporate significant advantages in terms of alignment and scalability. PMID- 20720746 TI - Large temporal stretching of ultrashort pulses. AB - We demonstrate the stretching of 100- fs pulses by a factor of 12,000, using standard-size optical elements. These stretched pulses are then amplified and recompressed to their initial duration. PMID- 20720747 TI - Index profile of multilayer fibers of an elliptical cross-section. AB - A mathematical formula is derived from the multiple-beam Fizeau fringers crossing an elliptical multilayer fiber. A formula for the two-beam interference fringes crossing this fiber is also given. A model that divides the elliptical fiber cross-section into elliptical zones of constant refractive index is assumed. The index profile of the poly(aryl-ether-ether-ketone) fiber is calculated by using the mathematical formulas. Microinterferograms of both the multiple-beam Fizeau fringes and the totally duplicated image of the fiber from a two-beam intereference microscope are used for the determination of the refractiveindex profile of the fiber. The cross-sectional shape is determined from the diffraction pattern of a He-Ne laser beam. Microinterferograms are given for illustration. PMID- 20720748 TI - Parametric analysis of elasto-optic birefringent axis alignment in eccentrically coated polarization-maintaining optical fiber. AB - When high-birefringent fibers are used in polarization-sensitive devices, one must ensure the proper alignment of the optical axes. One nondestructive alignment method involves squeezing the fiber and noting the change in the resultant birefringent axes. We use the finite-element method to determine the change in the principal stress direction, and, hence, the extrinsic birefringent axis orientation, as a function of the fiber coating eccentricity. Fiber eccentricity can shift the extrinsic birefringent axis by more than 1.5 degrees , whch becomes important in high-performance device applications. PMID- 20720749 TI - Temperature and strain sensitivities of high-birefringence elliptical fibers. AB - We have analyzed and calculated the temperature and strain sensitivities of a high-birefringence double-clad elliptical fiber. We propose a method to minimize these sensitivities without increasing the fiber size or weight; this is achieved by selecting suitable fiber parameters-core ellipticity, refractive index difference, and thickness of the inner cladding. In addition, we discuss the design of temperature- or strain-insensitive fibers which may be used in polarimetric strain or temperature sensors. This method may also be used to minimize or enhance other external effects. PMID- 20720750 TI - Scaling rules for transverse magnetic waves propagating in nonlinear thin-film optical waveguides. AB - For TM-polarized waves, a mode power measure is applied to characterize nonlinear thin-film optical waveguides in an approach analogous to that we recently proposed for TE-polarized waves. For design conditions in which all the guided waves are induced by the nonlinearity of the film, we study how the power level threshold needed for wave propagation differs between the TE and the TM modes of polarization. Since our description is based on universal parameters, our results are applicable to different geometries of waveguides through simple scaling rules. PMID- 20720751 TI - Low-loss in-line microfilter fabricated by precision trench machining. AB - A machining technique has been developed that enables a narrow, smooth damage free walled trench to be cut into an optical fiber engraved in a silica substrate by using a fine silica powder effect. This technique allows a very low insertion loss (0.21 dB) in-line microfilter to be made by inserting a thin filter plate into a trench cut into an optical fiber already fixed to a substrate. PMID- 20720752 TI - Method for measuring the mode-index ratio of two regions in a planar waveguide. AB - A method for measuring the mode-index ratio n of two regions of a planar waveguide with an accuracy of better than 2 in 10(5) is presented. Simple and reliable techniques were utilized to produce two contiguous waveguides, with different refractive indices, on a common substrate. The two waveguiding regions were fabricated both in LiNbO(3) and in BK-7 glass by using titanium indiffusion followed by a proton-exchange (TIPE) process and a two-step Ag(+)/Na(+) ion exchange technique, respectively. The measured mode-index ratios obtained by our method agreed well with values obtained with the conventional prism-coupling technique. PMID- 20720753 TI - Measurement of triplet optical densities of organic compounds in the presence of photodecomposition. AB - We have developed a method to measure triplet optical densities OD(r)(lambda) when considerable photodecomposition is present. The method is demonstrated on Coumarin 120. By focusing an UV cw laser beam on a sample with the aid of a lens, high triplet optical densities OD(T)(lambda) can be recorded. However, the excitation of organic compounds with light causes varying degrees of photodecomposition. In order to take photodecomposition into account, one records triplet optical-density values as well as the accumulation of absorbing photoproducts as a function of time. Turning off the cw laser excitation, one records the accumulation of photoproducts only. Separating the two processes, one can determine how the triplet optical density OD(T) declines as a function of time t. The obtained curve can be expressed with an equation that appears to decline exponentially with time. This allows one to extrapolate back to t = 0 and recover OD(T) when there was no photodecomposition. The extrapolated OD(T) values are used to obtain triplet-extinction coefficients (T)(lambda) by McClure's method of Coumarin 120. PMID- 20720755 TI - Achromatic interferometer for imaging through turbulence. AB - An achromatic two-grating interferometer is used for imaging through inhomogeneities. Theoretical and experimental results for a two-point object are presented. PMID- 20720754 TI - Simulation of mirages. AB - A mirage is seen when atmospheric refraction distorts or displaces an image. We describe a mirage simulator that uses digital imaging equipment to generate mirage images from normal photographs. The simulation program relocates horizonal image lines into positions that they appear to occupy, according to rays traced from observer to object. Image-brightness adjustments are not required; we show that, while the atmosphere can change the size or shape of an object, it does not change its apparent brightness. The realistic quality of the computed images makes this simulator a useful tool in mirage analysis. PMID- 20720756 TI - Comparisons of indicatrices of desert and urban areas obtained from Landsat MSS data. AB - The indicatrices of ground glass surfaces were obtained as a measurement of their roughness and expressed by the Minnaert constant k. The indicatrices were also obtained for downtown areas of San Francisco and Berkeley and the desert areas in Nevada and California by using Landsat multispectral scanner (MSS) data with varying Sun elevations. The values of k for each training area were obtained. Finally the biconical spectral reflectance of sand collected from the desert of the training areas was measured in the laboratory, and the computed values of k were compared with those derived from the Landsat MSS data. PMID- 20720757 TI - Covariance of the received intensity of a partially coherent laser speckle pattern in the turbulent atmosphere. AB - A theoretical expression for the covariance of the received intensity of a partially coherent laser speckle pattern after propagation through the turbulent atmosphere is developed. It is shown that the atmospheric perturbation on a partially coherent speckle pattern can be decomposed into a coherent term and an incoherent term. The dependence of contributions of these components on the level of turbulence, vacuum speckle-contrast ratio, and detector spacing is studied in detail and the results are compared with the available experimental data. PMID- 20720758 TI - Raman scattering in ocean optics: quantitative assessment of internal radiant emission. AB - Raman-scattering activity in clear ocean waters is further documented from Monte Carlo simulations and optical data that are collected in the Sargasso Sea. A method is proposed, based on the anomalous absorption coefficient for a nonconservative irradiance field, to assess the percentile composition of internal radiant emission for the irradiance field at any depth. PMID- 20720759 TI - Light scattering from the volume of optical thin films: theory and experiment. AB - A theoretical model is presented that describes the volume scattering in thin optical films, particularly in typical columnar structures. It is based on a first-order perturbation theory that concerns the fluctuation of the dielectric permittivity in the film. For evaporated PbF(2) films that show a pronounced columnar morphology, angular as well as total integrated scattering measurements at lambda = 633 nm have been performed on a special layer design to suppress roughness-induced scattering. A comparison of the predicted theoretical and the measured experimental values leads to such structural parameters as packing density and the evolutionary exponent of the columns. PMID- 20720760 TI - Transient thermal-lensing effects on the performance of repetitively pulsed solid state lasers. AB - A computational model was developed to predict solid-state laser performance in the start-up transient regime of a repetitive pulse operation. Laser output in this regime is sensitive to the interaction of rate-equation, thermal-transport, and beam-propagation effects. A high-repetition-rate operation produces pulse trains that decay at a rate determined by the competition between energy deposition in the rod and surface cooling. Selected pulses in a train turn on and off as the repetition rate is increased because of the varying residual population inversion between pulses. PMID- 20720761 TI - Frequency-doubled and Q-switched 946-nm Nd:YAG laser pumped by a diode-laser array. AB - A Q-switched 946-nm Neodymium:yttrium aluminum garnet (Nd:YAG) laser pumped by a diode-laser array has been developed. At room temperature, pulses with 4.9-microj energy and 68.5-ns pulse duration were observed. When the temperature of the Nd:YAG crystal was lowered to 5 degrees C, the duration of the pulses was reduced to 62 ns, giving rise to peak powers of 76 W. By focusing the Q-switched pulses into a 5-mm-long potassium niobate crystal, second-harmonic generation produced blue light pulses at 473 nm of 42-ns duration and 22-W peak power. The pulse repetition rate was kept at 1.5 kHz throughout. PMID- 20720762 TI - Coherence length modulation of a multimode laser diode in a dual Michelson interferometer configuration. AB - The use of a multimode (compact-disk type) laser diode in a dual Michelson interferometer arrangement is investigated, both theoretically and experimentally, by using the technique of coherence length modulation. A reproducible way of shifting the interference regions is considered for the potential use of the technique in optical sensors, for flow or distance measurement. PMID- 20720763 TI - Fiber-optic fan-beam absorption tomography. AB - An absorption tomography instrument that is capable of acquiring 100 projections of 100 elements each in less than 200 ns is described. The instrument uses time multiplexed, fiber-optic fan-beam sources that are sequentially activated in groups to reduce greatly the total number of detectors required for achieving a given resolution. The quantitative details required to tailor this instrument to a particular application are presented. A single-fiber prototype was used to verify the design and establish its sensitivity. The sensitivity is limited by laser-speckle noise. The fiber-optic fan-beam generator can produce an interdetector correlation of the projection noise, reducing the effect of this noise on the reconstruction. The noise is measured as a function of optic-fiber stability and size, laser bandwidth and mode stability, and detector size. PMID- 20720764 TI - Patents. AB - 5,015,053; 5,016,950; 5,016,954; 5,018,801; 5,016,953; 5,016,977; 5,016,994; 5,018,838; 5,022,727. PMID- 20720765 TI - Of optics and opticists. PMID- 20720766 TI - Bragg diffraction technique for the concentration of hard x-rays for space astronomy. AB - Results of an investigation that was devoted to determining whether the Bragg diffraction technique can be used for the concentration of hard x rays (> 10 keV) are reported. Our final goal was to develop a hard x-ray concentrator for space astronomy. General formulas for the reflecting power of the mirrors are given, and criteria for optimizing the integrated reflectivity are derived. An application of these optimization criteria is presented to evaluate the performances that can be expected of a particular configuration of the Bragg concentrator for space astronomy. PMID- 20720767 TI - Reduced light-scattering properties for mixtures of spherical particles: a simple approximation derived from Mie calculations. AB - The reduced scattering cross section per unit of volume Sigma'(s) identical withSigma(s)(1 - g) is an important parameter to describe light propagation in media with scattering and absorption. Mie calculations of the asymmetry factor g for nonabsorbing spheres and Q(sca), the ratio of the scattering cross section Sigma(s) and the particle cross section, show that Q(sca)(1 - g) = 3.28x(0.37)(m 1)(2.09) is true to within a few percent, when the Mie parameters for relative refractive index m and size x are in the ranges of 1 < m /= 3) shuffle interconnections. AB - The need for d-dimensional (d >/= 3) interconnection patterns occurs if d dimensional data cubes have to be interconnected. The formal definition of such patterns, presented here, is based on the mixed radix numbering of the d-tuple data points. Because each coordinate of a d-dimensional data cube may be factorized in a different way, a family of interconnection patterns is obtained that increases with respect to the dimension of the data cubes. The properties of d-dimensional patterns are analyzed, and their realization in the frequency domain is described. Methods for the three-dimensional layout of the patterns are presented. The application of d-dimensional patterns within multistage interconnection networks is discussed. PMID- 20720808 TI - Transformation of three-dimensional shuffle patterns. AB - Formulas are presented for the transformation of three-dimensional shuffle patterns into the twodimensional domain. The results are applied to the transformation of the interstage patterns of three-dimensional multistage interconnection networks into their isomorphic two-dimensional patterns (and vice versa). This paper explains material in J. Giglmayr, "Classification scheme for 3 D shuffle interconnection patterns," Appl. Opt. 28, 3120-3128 (1989) and corrects some algebraic results. PMID- 20720809 TI - Analysis of cross talk in volume holographic interconnections. AB - We utilize a novel multiple-scattering formalism to study cross-talk effects in volume holographic interconnections. Specifically, we explore the composition of that cross talk and evaluate its maximum expected values as functions of various design parameters such as dynamic range, minimum separation between interconnections, and hologram size. Examples are given for canonic interconnections that involve two superposed gratings, but the analysis and results are relevant to a broader class of high-capacity interconnects. PMID- 20720810 TI - Concept for an optical bus-type interconnection network. AB - A concept for parallel optoelectronic bus-type interconnections (many participants-many participants) is given. The choices between multimode and single-mode fan-ins in free-space optical systems are discussed. When one single space-invariant multiple beam-splitting system is used for fan-out and fan-in simultaneously, the energy requirements for communications scale with 2N (for N participants on each busline), which is compared with N(2) for space-variant systems. A simple demonstration experiment with a Dammann grating used as a multiple beam splitter is shown, and in a design example the theoretical performance is discussed. PMID- 20720811 TI - Optical interconnects based on arrays of surfaceemitting lasers and lenslets. AB - A compact free-space optical system that uses arrays of surface-emitting lasers and lenslets for chip-to-chip and board-to-board optical communication is described. A seven-channel optical interconnect has been demonstrated at 300 Mbits/s per channel, and we describe how such a system can be expanded to several hundred channels while its compactness and alignability are retained. PMID- 20720812 TI - Fiber-optic acoustic Fourier transducer for audio sound processing. AB - We demonstrate a fiber-optic acoustic transducer operating in the audio-frequency regime. The device is made of an array of 120 multimode optical fibers and a photorefractive novelty filter. Each fiber in the array acts as a cantilevered mechanical resonator. The resonant frequencies of the fibers logarithmically sample the acoustic spectrum from approximately 100 Hz to 5 kHz. Laser light is injected into all fibers simultaneously and is reflected from the end of each fiber. An optical novelty filter extracts the acoustic information from the reflected light. The output of the novelty filter is essentially a Fourier transform of the acoustic signal. The background intensity in the transducer output corresponds to a driving amplitude of approximately 50 A. We describe holographic storage of complex sound patterns that use a LiNbO(3) crystal and an acoustic transducer. PMID- 20720813 TI - Iterative image processing using a cavity with a phase-conjugate mirror. AB - We describe an optical image processing system with regenerative feedback that utilizes a cavity with a phase-conjugate mirror. The system's characteristics and limitations are discussed, and its application to the implementation of iterative recovery algorithms (e.g., Gerchberg algorithm) is considered and demonstrated experimentally. PMID- 20720814 TI - Performance analysis of Givens rotation-integrated optical interdigitated electrode cross-channel Bragg diffraction devices: extrinsic and inherent errors. AB - The effects of extrinsic and inherent errors are analyzed for the integrated optical Givens rotation device. The extrinsic errors, caused by inaccurate voltage applied to the grating and inaccurate detection, are found to be important. The inherent errors caused by the propagation of these inaccuracies are detailed in algorithms for analog norm computation and in the QR algorithm for numerical linear algebra. A calibration procedure is developed to eliminate most of the errors. PMID- 20720815 TI - Design and performance of a programmable spatial CCD filter. AB - Parallel signal preprocessing techniques in an image plane, as suggested by the mechanism of human vision, are used to improve the performance of a solid-state imaging sensor. In this paper a 3 x 3 neighborhood operator, by which the gray level of a particular pixel in a transformed image can be determined from the gray levels of the corresponding pixel and its neighborhood in the original image by using appropriate algorithms, is discussed. Dynamic trade-off of signal-to noise ratio for resolution depending on the light level is realized by combining a newly designed CCD spatial filter with variable weighting circuitry. Improvement in sensitivity by as much as 11 dB at low light levels and edge enhancement at high light levels is obtained only by varying the weighting circuit gain. The design concepts and circuit layouts are also shown together with the performance data on test imagery. PMID- 20720816 TI - Real-time parallel optical logic operation using photorefractive two-wave mixing and fringe-shifting techniques. AB - The coupling effect between phase and intensity in photorefractive two-wave mixing in a Bi(12)SiO(20) crystal is demonstrated. By using interference fringe shifting techniques that are executed by a Mach-Zehnder interferometer, an optical parallel logic operation system that is based on the coupling effect is implemented. PMID- 20720817 TI - Hybrid optical-electronic logic gates in complementary metal-oxide semiconductor very-large-scale integration. AB - Photodiodes are integrated into complementary metal-oxide semiconductor very large-scale integration logic circuits to provide a hybrid interface between parallel-optical and electronic computing formats. This permits direct parallel transfer from an optical processor or storage element to a standard electronic system. The optical input beams may be viewed as control signals or as logical inputs that increase the system complexity and permit direct interaction of the electronic logic circuits with the optical beam states. Applications of the approach include hybrid optical-electronic logic gates, optical control of electronic data paths, and optically reconfigured very-large-scale integration circuits. PMID- 20720818 TI - Stable photorefractive square-law conversion using moving grating techniques. AB - We demonstrate a technique by which the temporal oscillations in the response of a photorefractive square-law converter, a recently developed high-contrast spatial light modulator, may be removed. This technique uses the translation of an amplitude grating incoherently imaged upon a photorefractive crystal to obtain a moving intensity pattern within the material. We thus obtain running-wave effects similar to those seen by previous investigators writing photorefractive gratings by using the interference of two coherent frequency-shifted beams. We show both theoretically and experimentally that the criteria for removing temporal oscillations simultaneously yields a significant improvement in the diffractionefficiency of the square-law converter. PMID- 20720819 TI - Electrophotochromic gratings in photorefractive Bi(12)TiO(20) crystals. AB - We present the first experimental demonstration of quasi-permanent holographic recordings in Bi(12)TiO(20) crystals through what is to our knowledge a new electrophotochromic effect. This arises from spatial redistribution of some centers that are different from photorefractive centers. Light diffracted from this photochromic grating records a secondary photorefractive hologram. Interaction between both gratings results in asymmetric polarization properties and reversible electric field enhancement of diffracted beams. PMID- 20720821 TI - Thickness measurement for volume holograms by analysis of first-order diffraction. AB - We present a method for measuring the thickness of volume holograms by analyzing the variations of the diffraction efficiency as a function of angle of incidence. This method can be justified theoretically within the Born approximation for gratings with small modulation. But we prove experimentally that the method can work surprisingly well even for strongly modulated volume holograms. The principle of the method consists of the determination of angles of incidence for which the first-order diffraction efficiency takes its extreme (maxima and minima) values: these angles are related to the thickness of the grating. PMID- 20720820 TI - Real-time fingerprint sensor using a hologram. AB - A holographic fingerprint sensor has been developed for a system that identifies a person by his or her fingerprints. The sensor uses a laser as its light source and consists of a light-conducting plate, which is a transparent glass plate with a plain grating-type hologram, and a focusing lens system just under the hologram. Since the sensor uses a plane-parallel plate, all the optical paths from each point of a fingerprint to the hologram are equal, and a bright fingerprint can be created without the trapezoidal distortion that is inherent in conventional prism-type sensors. PMID- 20720822 TI - Realization of perfect shuffle and inverse perfect shuffle transforms with holographic elements. AB - Techniques for implementing perfect shuffle and inverse perfect shuffle operations with the aid of a single holographic optical element are presented. The element is composed of subholographic lenses which operate on a different input area. For the inverse perfect shuffle operation, polarization coding is added in order to separate the input into distinct groups. Experimental results illustrating the effectiveness of the proposed techniques are given. PMID- 20720823 TI - Digital pure shear-strain moire patterns. AB - A method of constructing digital shear-strain moire patterns with pure shear strain fringes is proposed here with the help of digital image processing techniques and moire carrier patterns of rotation. This method is developed from a digital pure secondary moire pattern method. The pure shear-strain moire patterns do not require a high fringe density of primary moire patterns. It can give the shear-strain values at every point over the whole field and give the visible distribution of the shear-strain field. PMID- 20720824 TI - Binary phase-only filter associative memory. AB - An associative memory is implemented by using a binary phase-only filter as the memory element in a two-focal-length (2-f) correlator architecture. A sharp autocorrelation peak, combined with the 2-f architecture, allows the noise to be separated adequately from the signal such that a simple plane mirror can be used in the correlation plane instead of a nonlinearity. PMID- 20720825 TI - Minimum noise and correlation energy optical correlation filter. AB - A new distortion-invariant optical correlation filter to produce easily detectable correlation peaks in the presence of noise and clutter and to provide better intraclass recognition is presented. The basic ideas of the minimum variance synthetic discriminant function correlation filter (which minimizes noise variance in the output correlation peak/plane) and the minimum average correlation energy filter (which minimizes the average correlation plane energy over all the training images) are unified in a new filter that produces sharp correlation peaks while maintaining an acceptable signal-to-noise ratio in the correlation plane output. This new minimum noise and correlation energy filter approach introduces the concept of using the spectral envelope of the training images and the noise power spectrum to obtain a tight bound to the energy minimization problem that is associated with distortion-invariant filters in noise while allowing the user a variable parameter to adjust depending on the noise or clutter that is expected. We present the mathematical basis for the minimum noise and correlation energy filter and the initial simulation results. PMID- 20720826 TI - Biological photochrome bacteriorhodopsin and its genetic variant Asp96 ? Asn as media for optical pattern recognition. AB - The biological photochrome bacteriorhodopsin (BR) is contained within the purple membrane (PM) of Halobacterium halobium. Artificial derivatives with improved optical properties can be generated by genetic methods and isolated from mutated halobacterial strains. The use of PM films that contain wild-type BR and BR variants as real-time recording media for various holographic applications has been reported previously, and the advantages of BR variants have been demonstrated. The high reversibility (>> 10(5) record/erase cycles), the fast time scale of its photoconversions (femtoseconds to milliseconds), and the large photochromic shift ( approximately 160 nm) occurring during its photocycle make it a promising material for real-time applications. A dual-axis joint-Fourier transform (DA-JFT) correlator is used to demonstrate the applicability of PM films in holographic pattern recognition. One major advantage of PM films in this application is their high spatial resolution of more than 5000 lines/mm. Severe restrictions on the overall performance of the DA-JFT correlator system are caused by scattered light and result in a low signal-to-noise ratio. Since PM patches typically have a diameter in the range of the visible wavelengthsthat are used for hologram recording, light scattering is an intrinsic problem of PM films. The polarization recording properties of PM films are employed to overcome this problem. More than 20-fold improvement of the signal-to-noise ratio in the DA-JFT correlator output is obtained. PMID- 20720827 TI - Response of an acousto-optic device with feedback to time-varying inputs. AB - We investigate the response of an acousto-optic bistable device to time-varying acoustic inputs. The device is justifiably modeled by a two-hump one-dimensional autonomous nonlinear map in which the (implied) map period is determined by the feedback time of the device. Our newly added time-varying input has a period much greater than the feedback time and for simplicity is taken in the form of a periodic square pulse. We use numerical simulation and a matrix method to predict the general behavior of the output intensity at specific instants of time. Background knowledge, viz., general comments on the nature of oneand two-hump one dimensional maps and their distinction, is also presented in a unified fashion to aid in the understanding of the dynamics of the device. We find that novel changes of the output period can occur for significant feedback amplitudes, and that these changes can be sensitively controlled. PMID- 20720829 TI - Contrast of the vibration fringes in time-averaged electronic speckle-pattern interferometry: effect of speckle averaging. AB - This paper presents a detailed investigation of the effect of speckle averaging in electronic speckle-pattern interferometric fringes. The theory states that the constrast of the resultant smoothed fringes increases as the number of frames is increased. It is shown that the contrast of the fringes is optimized with a limited number of superpositions, and further addition results in the reduction of speckle noise with the contrast remaining almost the same. The contrast of the fringes obtained with pi and pi/2 phase-stepping methods with speckle averaging is also discussed. Both theoretical and experimental results are presented in this paper. PMID- 20720828 TI - Effect of disk birefringence on a differential magneto-optic readout. AB - The performance of a magneto-optic readout system can be degraded by a phase shift between two basic polarization components of a readout beam. One source of this phase shift is undesired birefringence in the substrate of an optical disk. The effect of disk birefringence on the signal-to-noise ratio of a differential magneto-optic readout is evaluated. It is shown that this effect may be represented by two parameters J(2) and J(3) that depend only on the birefringence and the numerical aperture of a beam illuminating the disk. Previous papers on this subject either presented involved, open-form expressions for the differential magneto-optic readout or assumed that the beam illuminating the disk is collimated. Here simple closed-form formulas are derived by using parameters J(2) and J(3). The effects of system conditions that can interact with the disk birefringence, such as an imbalance between the differential data detectors, are also considered. PMID- 20720830 TI - Fluorescence imaging for machine vision. AB - Suitable illumination is a crucial aspect in the successful solution of machine vision problems. In this research we used objective image evaluation techniques and found that fluorescence imaging is superior to conventional illumination for acquiring images of integrated circuit lead bonds. This is an interesting and surprising finding, since there was no a priori reason to expect that any part of the bond would contain fluorescent components. Consequently, fluorescence imaging should be considered as an option in designing machine vision systems, especially if conventional illumination systems do not produce images of adequate quality. In this research we discovered a novel and effective method for threshold selection. PMID- 20720831 TI - Nasa patter. PMID- 20720832 TI - Comparison of calculated aerosol backscatter at 9.1- and 2.1-microm wavelengths. AB - Calculated aerosol backscatter for three common atmospheric aerosol compositions is higher at 2.1 microm than at 9.1 microm for low backscatter conditions and almost comparable for high backscatter conditions. PMID- 20720833 TI - Performance of an etalon-stabilized tunable diode laser system. AB - A wavelength-stabilized tunable diode laser and a reflective optical system can produce fringe-free spectra with a noise level of 10(-5) absorbance units and a precision of 10(-5) cm(-1) in the wave-number scale. PMID- 20720834 TI - Frequency match of the Nd:YAG laser at 1.064 microm with a line in CO(2). AB - We report on the measurement of a frequency match between the oscillation frequency of the Nd:YAG laser at 1.064 microm and a line in the vibration rotation spectrum of the CO(2) molecule. The line occurs near the center of the Nd:YAG gain profile and is inferred to be narrow from a knowledge of the CO(2) molecular structure. The significance of the frequency match lies in its application as a reference for absolute-frequency stabilization of the Nd:YAG laser. PMID- 20720835 TI - Spot-size measurement of an intense CO(2) laser beam. AB - The determination of a high-power CO(2) laser beam spot size is described. The method consists of measuring burn pattern radii in holographic emulsion as a function of laser pulse energy. PMID- 20720836 TI - Synchronization of a laser diffraction drop sizing technique with intermittent spray systems. AB - A precise synchronization scheme for a laser diffraction technique (Malvern system) is developed by employing laser light extinction as an instantaneous trigger source. PMID- 20720838 TI - Relationship between backscattering and extinction coefficients of aerosols with application to turbid atmosphere: erratum. PMID- 20720837 TI - Infrared polarization signature from cirrus clouds. AB - Maximum infrared polarization signature of up to 1% is predicted in tropical subvisual cirrus involving randomly oriented ice crystals, based on radiative transfer calculations. PMID- 20720839 TI - Stable isotope analysis using tunable diode laser spectroscopy. AB - Measurements of ratios of stable isotopes are used in such diverse fields as petroleum prospecting, medical diagnostics, and planetary exploration. The narrow emission linewidth available from tunable diode lasers permits high-resolution infrared absorption measurements of closely spaced isotopic rovibrational lines. Our dual beam spectrometer uses the sweep integration technique in a spectral region where adjacent spectral lines are of approximately equal absorbance at the expected isotopic abundances. The experimental results reported here indicate that isotopic ratios of carbon in carbon dioxide can be measured to an accuracy of better than 0.4%. This laser spectroscopic technique offers an alternative to the mass spectrometric technique for in situ isotopic analysis in field studies, as well as flight and space applications. PMID- 20720840 TI - Measurements of collisional linewidths in the nu(2) band of H(2)O from Fourier transformed flame spectra. AB - The collisional widths of more than 200 transitions belonging to the v(2) band of the H(2)O molecule were measured by using the Fourier-transformed spectra of an air-methane flame at 2000 K. A nonlinear least-squares method was used to determine the line widths for a wide range of J (up to 28) and K(a) (up to 14) quantum number values. Finally, an analysis of the results as functions of J and K(a) is presented. PMID- 20720841 TI - Phase errors on interferograms: influence on the determination of positions, intensities, and widths of lines in the infrared. AB - The effect of a phase error on line parameter measurements by using Fourier transform spectra is studied, showing that, to obtain accurate results without modifying the interferogram, it is necessary to adjust a computed spectrum to an experimental spectrum in which the phase error is taken into account. PMID- 20720842 TI - Diffractive analysis of annular resonators. AB - The modal properties of annular resonators are investigated by using an approximate version of the Kirchhoff-Fresnel integral. It is shown that the radial diffraction of a thin annular beam with a large inside radius is similar to that of a cylindrical field distribution. This permits the formal demonstration of the equivalence that exists between large Fresnel number annular resonators and infinite strip resonators. The model explains the properties of annular resonators that have been observed either experimentally or numerically by others, such as the lack of azimuthal discrimination. PMID- 20720843 TI - Analytic eigenmode solution for the self-filtering unstable resonator. AB - An analytic solution for the bare cavity eigenmodes of a nonsymmetric self filtering unstable resonator is obtained by a modal expansion in prolate functions, which is a complete and orthogonal set of eigenmodes for a symmetric confocal stable resonator. An accurate representation within the aperture is shown to require only three terms. An efficient use of Gaussian quadrature for the various calculations is described. PMID- 20720844 TI - Optical absorption at 1.06 microm in highly deuterated potassium dihydrogen phosphate. AB - We have determined the relationship between residual proton (hydrogen) concentration and optical absorption at 1.06 microm in highly deuterated potassium dihydrogen phosphate (KDP). The proton concentration was determined by nuclear magnetic resonance (NMR) spectroscopy and the absorbance was measured by calorimetry. We obtained a hydrogen concentration dependence of 396 +/- 55 parts in 10(6) (ppm) cm(-1)/% hydrogen for the o- (ordinary-) polarized absorbance at 1.064 microm, and 45 +/- 7 ppm cm(-1)/% hydrogen for the e- (extraordinary) polarization. In addition, the KDP crystals we tested have residual (hydrogen independent) o- and e-polarized absorbances of 958 +/- 228 ppm cm(-1) and 343 +/- 28 ppm cm(-1), respectively, whose origin is unknown. We also found that the crystal deuterium-hydrogen (D-H) ratio can be related to the D-H ratio of the growth solution by a simple ideal mixture model with a segregation coefficient of 0.684 +/- 0.044. PMID- 20720845 TI - Toric unstable CO(2) laser resonator: an experimental study. AB - The output characteristics of a toric unstable resonator fitted to a multichannel stripline excitation system are presented. The resonator is shown to possess the usual advantages of a conventional unstable resonator plus the ability to modify the profile of the output beam by a simple change in the coupling aperture. Laser output parameters have been studied as a function of coupling fraction, magnification, and internal loss factors. Variations in the focal spot size as a function of the coupling aperture as well as resonator alignment sensitivity and polarization properties have been investigated. PMID- 20720846 TI - Gas contaminant effects in discharge-excited KrF lasers. AB - Infrared, ultraviolet, and mass spectrometers are used to study the evolution of gaseous impurities as a function of time in a discharge-excited KrF laser. The major contaminants detected, listed in order of prominence, are HF, CF(4), COF(2), SiF(4), and CO(2). The effect of each of these individual impurities on the laser performance is measured, and the results are used in a simple model that accurately predicts the decrease in laser output power with time. Techniques for improving the gas lifetime in KrF lasers are alsodiscussed. PMID- 20720847 TI - Cavity-mode identification of fluorescence and lasing in dye-doped microdroplets. AB - Recent advances in an aerosol-generation technique have permitted the accurate identification of optical resonance-mode features of micrometer-sized freely falling droplets for several different optical processes. Both input and output resonant features of fluorescence and lasing from dye-doped microdroplets were assigned to specific spherical cavity modes by using two independent procedures: (1) by matching observed fixed-angle elastic laser light scattering as a function of droplet size to calculated scattering intensities from the Lorenz-Mie theory, and (2) by matching observed resonance peaks to computed cavity-mode positions by automated correlation. Agreement between these two complementary techniques establishes high confidence in the resulting mode identifications. Assignments of observed emission peaks provide insight into droplet-emission mechanisms. PMID- 20720848 TI - Injection-locking of gain-guided diode laser arrays: influence of the master beam shape. AB - According to a previously reported model [IEEE J. Quantum Electron. 27, 396 (1991)], the properties of injection-locked gain-guided diode laser arrays depend on the geometric characteristics of the master beam, such as the size of its waist and its incidence angle. Experimentally, two injection configurations are of particular interest: the focused injection, in which the master beam is focused on one stripe of the slave array, and the wide-beam injection, in which the master beam is shone on the whole or a part of the width of the array. We investigate experimentally and compare these two configurations. In particular, we show that, in agreement with our theory, changing the geometry of the master beam greatly alters the far-field patterns, the locking bandwidth, and the spectrum of the locked array. We also compare the injection angle sensitivity and the beam-steering properties of the two configurations. Observations confirm our predictions, and optimal configurations are proposed. PMID- 20720849 TI - Pump wavelength tuning of a near-infrared optical parametric oscillator. AB - Optical parametric conversion in a potassium titanyl phosphate crystal with a tunable alexandrite laser was investigated as a function of pump wavelengths in the 700-800-nm region. Threshold energies and slope efficiencies for a doubly resonant oscillator configuration were measured for pump wavelengths of 744, 766, and 780 nm. Phase-matching conditions and a theoretical analysis using Sellmeier's equations provide good agreement with experimentally measured values of signal and idler wavelengths as a function of the pump wavelengths. PMID- 20720850 TI - Manchester encoder-decoder for optical data communication links. AB - A new encoder-decoder (CODEC) design of a Manchester coding scheme suitable for optical data communication links is presented. The design is simple and uses off the-shelf digital electronic components and subsystems. The CODEC can be used for high data rate transmissions, typical of opticalfiber systems and local area networks. The decoder is insensitive to variations in the clock rates within the range of +/-33%, whereas the encoder, which is a simple XOR logic gate, is not affected by clock variations. During high-frequency operation (e.g., at 100 MHz), the CODEC can be operated at a wide range of frequencies (from 66.6 to 133.3 MHz) without modification to the CODEC circuitry. Furthermore, the CODEC can be made to operate at any data rate by a simple change of a single capacitor or a single resistor in the decoder circuit. The CODEC was built in the laboratory by using transistor-transistor logicintegrated circuits. It was experimentally found that with this decoder the transmitted data, as well as the cloc, can be recovered from the Manchester coded signal without being affected by clock variations within the designed range. PMID- 20720851 TI - Time-resolved identification of modes and measurement of intermodal dispersion in optical fibers. AB - Picosecond pulses from a tunable mode-locked visible dye laser are injected into a 603-m few-mode optical fiber. Measurements of the output power temporal profile with 35-ps resolution show six clearly resolved modes. Time-profile measurements over a two-dimensional array of points in the fiber output far field yield a picture of each mode that identifies it. Measurements as a function of wavelength and fitting to waveguide dispersion calculations are used to model the fiber core refractive-index profile. As a result for the nominal step-index fiber used in this work, the presence of an index dip at the center of the core was detected. PMID- 20720852 TI - Analysis of etching-induced birefringence changes in elliptic core fibers. AB - A mathematical model is presented that predicts birefringence changes in an optical fiber as the cladding is removed. This model approximates a highly elliptical fiber core with a rectangular dielectric waveguide. The birefringence calculations obtained with the model compare well with experimental evidenceobtained with real-time birefringence monitoring during cladding removal by chemical etching. The information is used to control the amount of cladding removed from a D fiber to within approximately 0.05 microm for use in the production of passive optical fiber components. PMID- 20720853 TI - Transformation of paraxial beams in arbitrary multimode parabolic-index fiber tapers by using a quantum-theoretical approach. AB - The transformation of Gauss-Laguerre beams with a spherical wave front in a parabolic-index taper as well as the mode-coupling coefficients between the beams and the modes of the fiber behind the taper was analytically investigated in paraxial approximation by using a quantum-theoretical formalism. The taper model that is used here has an infinitely extended parabolic-index profile with an arbitrary longitudinal variation. For such taper elements we have demonstrated some matching and mode-filtering properties, which may be useful for different applications. PMID- 20720854 TI - Fiber ring resonator with power exchange between polarization modes: experiment. AB - Experimental results on the characteristics of a new type of fiber ring resonator made with polarizationpreserving fiber are reported. By using a splice inside the loop and crossing the fiber birefringent axes at the splice, we obtain greatly improved thermal stability. Further, by analyzing the output polarization state along the birefringent axes of the fiber, we obtain improved fringe modulation depth, additional improvement in thermal stability, and a simultaneous resonant peak and resonant dip output. A theoretical model is described that gives good agreement with the experiment. PMID- 20720855 TI - 40-GHz bandwidth InGaAs/InAlAs multiple quantum well optical intensity modulator. AB - High-speed waveguide InGaAs/InAIAs multiple quantum well (MQW) optical intensity modulators are demonstrated. To minimize the modulator capacitance, an undoped InAIAs cladding layer is added over the MQW core layer in the optical waveguide. In addition, polyimide is spin coated under the bonding pad. As a result, a very wide bandwidth in excess of 40 GHz is developed with a driving voltage of 6 V for a 10-dB extinction ratio and a linewidth broadening factor alpha of < 1.0 at an operating wavelength of 1.54 microm. The frequency response of the modulator is limited by the device capacitance and inductance. PMID- 20720856 TI - Low-pressure chemical vapor deposition silicon-oxynitride films for integrated optics. AB - The low-pressure chemical vapor deposition of silicon-oxynitride films for applications as integrated optical waveguides on silicon substrates, using gas compositions of SiH(2)Cl(2)-NH(3)-N(2)O, SiH(2)Cl(2)-NH(3)-O(2) and SiH(4)-NH(3) O(2), has been investigated with respect to deposition rate, uniformity, reproducibility in the 1.46-2 index range, and propagating loss. The best results were obtained with the SiH(2)Cl(2)-NH(2)-O(2) reaction, which provides a deposition rate up to 30 nm/min and a thickness variation across a wafer below 3% at propagation losses below 0.5 dB/cm. PMID- 20720857 TI - Optical loss measurement of low-loss thin-film waveguides by photographic analysis. AB - Photographic film was used to measure low intensities of guided light scattered from three different thin-film optical waveguides. The technique is shown to permit measurement of optical loss down to 0.07 dB/cm. The method involves the taking of a photograph of a guided light beam (lambda = 632.8 nm) and the use of a microdensitometer to measure the two-dimensional scattered intensity profile. The sensitivity of the photographic film permits the measurement of low light levels, and the beam profile information permits the evaluation of the uniform scattering assumption. The technique can be adapted to channel waveguide loss by using high-definition photographic film. Additionally, the use of infrared sensitive film can permit the technique to measure loss in the infrared. PMID- 20720858 TI - New type of photothermal spectroscopic technique. AB - We propose a new type of photothermal spectroscopic technique. The experimental setup is simple and the experiment can be readily carried out, even in the difficult environments that are often required for opticaland surface studies of materials. Features of the method proposed here are nondestructive and noncontact; in addition, the simplicity of our design enables us easily to make the system resistant to vibration and drift, which leads to a high signal-to noise ratio of the photothermal signal. A few experiments have been conducted to demonstrate the utilization of the method, e.g., a quantum-radiative efficiency of surface polaritons in an air-Ag film-BK-7 prism geometry has been evaluated. PMID- 20720859 TI - Integrating cavity absorption meter. AB - Scattering effects have always been an important systematic problem in absorption measurements. A new integrating cavity absorption meter has been developed that, in principle, is rigorously independent of scattering effects. The theoretical basis for this integrating cavity device is developed and applied to a generic experimental device: a one-dimensional model is described that demonstrates qualitatively the observed deviations from ideal; details of an actual device are provided; and experimental results for the absorption coefficient of aqueous solutions with various absorptions and with various concentrations of scatterers are presented. PMID- 20720860 TI - Characterization of the accretion of material by microparticles using resonant ellipsometry. AB - An optical technique to characterize the accretion of material by microparticles is described. Experiments on the absorption of water vapor by single levitated polystyrene microparticles are reported as examples of an application of the technique. The optical resonant frequencies of the microparticles are perturbed by the accretion of material and the observed shifts are used to characterize the growth. This technique, resonant ellipsometry, makes use of the polarization character of optical resonant modes to distinguish particle swelling from surface layer formation. The experimental results indicate that water vapor absorbed by polystyrene microparticles diffuses primarily into the particle bulk. PMID- 20720861 TI - Experimental apparatus for measurement of the angular, polarization, and wavelength dependence of light scattering from the visible to the infrared in bulk glass samples. AB - Previous measurements of light scattering on bulk glass samples were made primarily at visible wavelengths. The scattering loss at longer wavelengths was then estimated by extrapolating the visible results, assuming a lambda(-4) (Rayleigh) dependence. This method can lead to a substantial uncertainty in the scattering loss at long wavelengths (> 2 mum). We have therefore constructed an experimental apparatus that measures the angular dependence of light scattered in both the Rayleigh and the Mie regimes from bulk glass samples at wavelengths between 0.6 and 2.6 microm. We have also developed a method of analysis of the angular scattering of both vertically and horizontally polarized beams to determine the Rayleigh ratios and dissymmetry factors as a function of wavelength. The average size of the scattering sites can be estimated in the range of 0.02 to 2.0 mum. PMID- 20720862 TI - Improved method of loss measurement for optical waveguides by use of a rectangular glass probe. AB - The use of a glass-plate probe of rectangular shape is proposed for the measurement of transmission loss in optical waveguides. The light-collecting window is of a thin, rectangular shape and is perpendicular to the light streak, while the conventional fiberglass probe has a small circular face. This transversely elongated form results in a great improvement of mechanical tolerance for the probe movement in the vertical as well as in the transverse direction. A theoretical investigation also presents a reasonable agreement with the experiments. PMID- 20720863 TI - Computation of small-scale velocity turbulence and its effect on optical scintillations and stimulated thermal Rayleigh scattering. AB - Coherent high-power light beams propagating long distances through turbulent fluids are subject to many kinds of scattering effects; among these are small scale thermal index instabilities, in which the fluid is heated by the small fraction of light that is absorbed, amplifying the pre-existing index fluctuations and producing small-angle stimulated thermal Rayleigh scattering. Turbulent velocity fluctuations can inhibit the rate of growth of these instabilities by dispersing the thermal perturbations created by the beam. Methods for computing the turbulent diffusion of the heating perturbations, compatible with fast-Fourier-transform beam propagation computations, are presented. Propagation calculations of scintillation coherence times and small scale velocity turbulence thresholds for stimulated thermal Rayleigh scattering are included. PMID- 20720864 TI - High-spectral-resolution fluorescence light detection and ranging for mesospheric sodium temperature measurements. AB - The principle and practice of narrow-band light detection and ranging (lidar) for temperature measurements are discussed, with emphasis on a new two-frequency technique for measuring mesospheric Na temperature and density profiles. The uniqueness of this narrow-band lidar lies in the transmitter whose line-shape function can be measured directly. The frequency of the laser output can be monitored simultaneously during data acquisition with Doppler-free fluorescence spectroscopy by using a laboratory Na cell. These measurement techniques along with the procedures for data analysis are described in detail. At present the absolute temperature accuracy at the Na layer peak is +/-3 K (+/-4 K) with a vertical resolution of 1 km and an integration period of 5 min (2.5 min). Potential applications and furtherimprovements in this lidar technique are also discussed. PMID- 20720865 TI - Seasonal and geographic variations in imaginary refractive index of atmospheric particulate matter. AB - Samples of atmospheric particulate matter were collected on cellulose membrane filters at selected locations in Europe during 1976 and 1977 as part of an international cooperative atmospheric characterization program. These samples are analyzed for imaginary refractive index in the 0.3-1.7-microm spectral region. These data are used to determine the range of variability of the imaginary refractive index and are examined for seasonal variations. These data are discussed in the light of results of analysis of samples collected from other parts of the world and samples that were analyzed as a function of particle size. PMID- 20720866 TI - Ultraviolet and visible imaginary refractive index of strongly absorbing atmospheric particulate matter. AB - Determinations of the imaginary refractive index in the ultraviolet and visible spectral regions as determined from diffuse reflectance measurements are presented. Materials examined are carbon black and oxides of iron, lead, mercury, copper, manganese, and vanadium along with lead iodide and iron sulfide. PMID- 20720867 TI - Diffuse reflectance of the ocean: influence of nonuniform phytoplankton pigment profile. AB - For interpretating remotely sensed diffuse reflectance of stratified case 1 waters, Gordon and Clark [Appl. Opt. 19, 3428 (1980)] suggested that the reflectance of a stratified ocean is identical to that of a hypothetical homogeneous ocean with a phytoplankton pigment concentration (?C?) that is a depthweighted average of the actual depth-varying concentration [C(z)]. However, this hypothesis has not been tested experimentally or theoretically. In this paper, the hypothesis is examined with Monte Carlo simulations of radiative transfer in case 1 waters by using a refined bio-optical model of the inherent optical properties of the medium. This bio-optical model, which includes separate plankton and detrital particle absorption and scattering, parameterized by the pigment concentration, is presented and tuned to Morel's statistical analysis of the average diffuse attenuation coefficient over the euphotic zone. It provides a reasonable fit to diffuse attenuation and reflectance data of individual stations. The tratification model of Morel and Berthon [Limnol. Oceanogr. 34, 1545 (1989)] characteristic of open ocean case 1 waters and a synthetic model of somewhat stronger stratification (maximum stratification of the pigment concentration |dC/dz| asymptotically equal to 0.43 mg/m(3)/m) are tested first. Two scenarios are used to relate the inherent optical properties to the pigment profile. In the first, the particle absorption and the scattering coefficients covary with C(z) and simulations show that the maximum error in the hypothesis is less, similar 2-3% for the pigment profiles considered. In contrast, in the second scenario, the particle absorption coefficient was permitted to covary with C(z), but the scattering coefficient was independent of depth. Here, errors in the hypothesis of as much as 22% were observed for the stronger stratifications. Finally, a synthetic example of strong stratification |dC/dz|, as large as 8.9 mg/m(3)/m) is examined, and errors in the hypothesis of the order of 20-25% are found when both the particle absorption and the scattering covary with C; however, for the depth-independent particle scattering case, the hypothesis can lead to large errors in R. Interestingly, for both scenarios, the ratio of reflectances at two wavelengths shows a much smaller deviation from the hypothesis than the reflectance itself. PMID- 20720868 TI - Synthesis of integral transform solutions for the reconstruction of particle-size distributions from forward-scattered light. AB - Five integral transform solutions to the Fredholm integral equation that describes the forward-scattering properties of the distributions of spherical particles in the Fraunhofer diffraction regime have been studied. We have systematically reformulated the family of solutions, including four derivations by three other research groups and one developed as part of this work, using a standardized notation. This synthesis elucidates the mathematical interrelationships and fosters an understanding of the inversion performance of the five solutions. Finally a series of numerical experiments was carried out to demonstrate the relative performance of the techniques when applied to identical sets of simulated forward-scattering signatures. PMID- 20720869 TI - Transmission of a pulsed thin light beam through thick turbid media: experimental results. AB - Experimental results of light pulse transmission through thick turbid media are presented. Measurements have been carried out on polystyrene latex spheres by using a picosecond thin laser beam and a streak camera system. The results show that the shape of the received pulse depends mostly on the transport mean free path and on the absorption coefficient of the medium, indicating that both the absorption coefficient and the asymmetry factor of the scattering function can be obtained from the pulse shape. The results also show that a detectable amount of received photons follows trajectories near the source receiver line even for large values of optical depth, indicating the potential of a time-gated scanning imaging system to detect absorbing structures inside thick turbid media. PMID- 20720870 TI - Observation of suppression of morphology-dependent resonances in singly levitated micrometer-sized droplets. AB - Suppression of morphology-dependent resonances of the light elastically scattered by a laser-illuminated, micrometer-sized droplet is reported. A single nonabsorbing droplet is levitated by using an electrodynamic quadrupole trap, and the scattered light is monitored as the droplet slowly evaporates. The size of the droplet is approximated by using the instability characteristics of the electrodynamic trap. To determine the refractive index and droplet radius precisely, the experimental scattering curve is fitted to a scattering curve that is generated from Mie theoretical calculations. The procedure is then repeated for absorbing droplets. The quality factor Q of each experimental resonance is determined and used to quantify the suppression effect. A dramatic suppression of narrow resonances occurs with increased absorption, whereas little or no effect is seen in moderate to broad resonances. PMID- 20720871 TI - Modified Langley plot method for measuring the spectral aerosol optical thickness and its daily variations. AB - A method of obtaining the spectral aerosol optical thickness that uses a multispectral instrument and a crude instrument with one spectral band only, here the blue at 450 nm, is presented. The instrument in the blue range is calibrated from a stratospheric balloon. The method is shown to be efficient by using experimental data collected in West Africa, where the daily variations of the aerosol optical thicknesses are large because of frequent dust storms and where the classic Langley plot method could not be used. PMID- 20720872 TI - Processes of excitation and deactivation of excitation energy in organic wavelength transformers cooperating with solar photovoltaic cells. AB - The measurements of maximal power increase of silicon photovoltaic cells coated with polymethyl methacrylate foil containing Rhodamine-6G were carried out. The photoelements were irradiated from the solar radiation simulator. Two different amplification values were obtained: ~ 20% and 50%. An equation that describes the change of photoluminescence intensity as a function of fluorescent molecules and that takes into account the reabsorption and secondary fluorescence is derived. The expression obtained is compared with the results of photoluminescence measurements for Rhodamine-6G and 2,5-bis[5'-tert-butylbenzoxazol-(2')]-thiopen; good agreement is evident. PMID- 20720873 TI - Patents. AB - 4,989,959; 4,991,923; 5,009,243; 5,010,770; 5,011,265; 5,013,131; 5,013,133; 5,013,134; 5,013,136; 5,013,139; 5,013,142; 5,013,143; 5,014,709; 5,015,049; 5,015,052; 5,018,803; 5,020,888; 5,020,910; 5,022,726; 5,022,730; 5,022,743. PMID- 20720874 TI - Lens design: an introduction. PMID- 20720875 TI - Null lens design techniques. AB - There are a surprising number of discrete, well-corrected null lens designs with just two elements for testing a large, fast-speed parabolic mirror from its center of curvature. Some design techniques are discussed for generating these solutions, which may be applicable to the design of null lenses for other mirror shapes. Without examining these multiple solutions, which differ greatly in performance, there is no way to know if the optimum configuration has been found. PMID- 20720876 TI - Distortion-adjusting optical elements. AB - Distortion can be corrected in an image by placing a fourth-order aspheric optical element near the image plane. Moving the aspheric surface longitudinally changes the amount of distortion that is added by the aspheric surface without changing the paraxial image. Third-order astigmatism limits the performance of distortion correctors and may be eliminated by adding another fourth-order aspheric surface. Example elements were fabricated by diamond turning and were shown to introduce distortion without significantly degrading image quality. Three arrangements of distortion correctors are discussed: a single-element planoaspheric arrangement, an antisymmetric two-element arrangement, and a biaspheric arrangement in which distortion is not adjustable. PMID- 20720877 TI - Tertiary-spectrum manipulation in apochromats. AB - By combining achromatic and superachromatic lens groups we may achieve improved tertiary-spectrum residuals in apochromatic systems. The application of this technique is reported. The significance of a secondary spectrum and a tertiary spectrum in lens design is also reviewed. PMID- 20720878 TI - Gaussian beam parameters that use Coddington-based Y-NU paraprincipal ray tracing. AB - A method is described for modeling a Gaussian beam that travels along an axial or oblique path of a principal ray in a meridional plane. The method uses paraprincipal rays, which are traced adjacent to the principal ray by using a Y NU ray trace procedure that is based on Coddington's equations. Formulas are given that relate the parameters of the Gaussian beam to the heights and slopes of the paraprincipal rays. Two ray trace examples are provided. PMID- 20720879 TI - Exact sine condition in the presence of spherical aberration. AB - Considering the real pupil curvatures, a new exact sine condition in the presence of spherical aberration is derived and its validity is confirmed by ray traces. This sine condition is useful for lens design and lens evaluation. PMID- 20720880 TI - Evaluation of optical aberrations in point images. AB - Merit figures that are based on ray aberrations give different results from those based on wave-front aberrations. Here Zernike polynomials and a set of orthogonal polynomials that are based on the wave-front slope are used to study the transition from physical optics to geometrical optics. A knife-edge energy distribution is used to evaluate point images that are derived from both physical optics and geometrical optics. Parameters that are obtained from this evaluation are the radius of the major axis and the eccentricity of the irradiance distribution. A direct comparison of geometrical and physical aberrations through tenth order is made, based on geometrical-physical spot size, with the magnitude of the aberrations chosen in the transition region between physical and geometrical optics. Spot diagrams and diffraction images are shown side by side to the same scale with the diffraction images matched in exposure. This comparison shows that spot size, as determined by knife-edge scans, is a consistent measure of image quality for both spot diagrams and diffraction images. Furthermore spot size is a valid figure of merit down to the diffraction limit. PMID- 20720881 TI - Least-squares fitting of orthogonal polynomials to the wave-aberration function. AB - The wave-aberration function of systems with circular and square apertures can be expanded in terms of Zernike and Legendre polynomials. The polynomial terms form orthogonal sets; therefore each coefficient independently determined by an integral satisfies the principle of least squares. To evaluate the integral the pupil is divided into small areas where the wave-aberration function is approximated by the first three terms of a Taylor series expansion: the optical path difference and components of geometric aberration. In final form the coefficients are expressed by the sum of three bilinear terms by combining three matrices and six vectors. The former depend on the construction parameters and the latter on the ray pattern. PMID- 20720882 TI - Algorithm for determination of the diffraction focus in the presence of small aberrations. AB - The diffraction focus (or best focus) is calculated for an optical system that contains small aberrations. By assuming that the wave aberration function is known with respect to an arbitrary point in the image region, we obtained simple analytical expressions of the diffraction focus coordinates for any geometry of the pupil. The method can be easily worked out on a computer by ray tracing. A comparison is done with the method that is based on the displacement theorem. PMID- 20720883 TI - Multidimensional quadratic extrapolation method for the correction of aberrations in lens systems. AB - An interactive optical design tool that is based on multidimensional quadratic extrapolation is described. This technique extends the radius of convergence of the aberration manipulation process, provides strategic information about the correctability of the aberrations at each stage in iteration, and is computationally simple. A quadratic approximation to each of the nonlinearly varying aberrations, which are initially based on one relatively remote linearly predicted point in solution space, allows the step length of this differential improvement method to be extended over that which is possible with local derivative techniques. The basic mathematical method works with an equal number of defects and variables, and to involve all the relevant constructional parameters of an optical system these are grouped or linked together on the basis of an assumption about their combined ability to correct the chosen aberrations. Examples are given. PMID- 20720884 TI - Solution of the damped least-squares problem by using a combination of eigenvalue and singular value decompositions. AB - A combination of eigenvalue and singular value decompositions are used to solve the normal equation. An aspheric lens design that uses a 14-term power series aspheric for each surface is presented. PMID- 20720885 TI - Ray tracing kinoform lens surfaces. AB - An exact ray trace (Snell's law of refraction) of discontinuous surfaces of kinoform lenses (surface relief lenses) is used to evaluate optical performance when used alone or when used in conjunction with conventional optical surfaces. A phase-based merit function that is generated by ray tracing is useful for the design and optimization of such systems including color correction. This ray trace approach can also explain and evaluate the dual focal length features of kinoform lens designs. PMID- 20720886 TI - Modeling diffraction efficiency effects when designing hybrid diffractive lens systems. AB - We investigated the design of two broadband hybrid diffractive-refractive optical systems, a landscape lens, and a Schmidt telescope. The systems were achromatized by using the characteristically large negative dispersion of kinoforms. In the scalar wave regime kinoforms can approach 100% efficiency but only for one object point and wavelength. We evaluated polychromatic image quality, accounting for diffraction efficiency, by constructing weighted geometric point-spread functions from several diffracted orders and then calculating modulation transfer functions (MTF's). The MTF's of the hybrid achromats were improved at high spatial frequencies but were reduced at low frequencies because of diffraction into nondesign orders. PMID- 20720887 TI - Design of infrared hybrid refractive-diffractive lenses. AB - Hybrid refractive-diffractive elements offer a similar level of aberration control to the conventional doublet with approximately half the volume of material. The design principles of infrared elements are discussed. It is shown that, in order to match the performance of the conventional doublet, a general meniscus hybrid with an aspheric surface is required. The potential advantages are illustrated to good effect by a series of design examples, including a Petzval objective for the 3-5-microm band. PMID- 20720888 TI - Ray tracing through systems containing holographic optical elements. AB - While the subject of tracing finite rays through an optical system containing holographic optical elements (HOE's) has been widely discussed in scientific literature, the actual mechanism for determining the direction of a ray leaving a generalized HOE appears not to have been addressed in any great depth. Here a detailed description of a practical method that uses a lookup table approach for tracing finite rays through such systems is presented. Furthermore, the construction geometry is not limited to an arrangement whereby only perfect reference and object beams are used to produce the HOE. PMID- 20720889 TI - Design of zoom system by the varifocal differential equation. I. AB - A new concept on differential movements for moving lens components is given. A unified varifocal differential equation is derived. The solvable region, solution exchange, quickly varifocal curve, etc., are discussed in detail. Some important types of zoom systems are discussed from the point of view of the varifocal differential equation. PMID- 20720890 TI - Mechanically compensated zoom lenses with a single moving element. AB - A methodology has been investigated that offers a possible means of determining regions of potential solution space for the basic imaging problem where it is asserted that not more than two generic lenses are needed to solve the problem, if it is solvable at all. When this methodology was expanded to encompass zoom lenses, it was discovered that certain conditions exist that indicated that it may be possible to design a mechanically compensated zoom lens with only one moving lens element. To illustrate this finding, an infrared zoom lens was designed and is presented. The mitigation of mechanical tolerances that is common to mechanically compensated zoom lens systems may be realized as a consequence of this new optical configuration. PMID- 20720891 TI - Design of zoom lens systems that use gradient-index materials. AB - Some effective uses of the radial gradient-index (GRIN) lens in zoom lens systems are presented and lens design examples are shown. Also the effective Abbe number of a cemented GRIN lens is discussed and it is shown that a radial GRIN lens with uncommon dispersion can be replaced by a cemented radial GRIN lens with common dispersion. PMID- 20720892 TI - Aberration analysis in aerial images formed by lithographic lenses. AB - A test procedure for the final assembly of lenses that does not need exposed photographic plates is introduced. It is based on the metrological simulation of optical ray tracing. A measuring example illustrates its suitability for ultraviolet optical systems in particular. The measuring apparatus displays the distortion vectors directly in the aerial image, gives a wave-front analysis, and performs an analogous distortion analysis. PMID- 20720893 TI - Optical design of two spectrographs for the Canada-France-Hawaii telescope. AB - Optical designs of two new spectrographs for the Canada-France-Hawaii telescope Cassegrain focus are described. Also given is a summary of the design procedure using the Dominion Astrophysical Observatory optical design code OPTESA (optical system optimization by educated simulated annealing). The f/2.8 multiobject spectrograph has a field of view of 10 min of-arc, whereas the f/10 subsecond of arc imaging spectrograph has a field of view of 3 armin. They are to be commissioned in 1991. PMID- 20720895 TI - Wide-field f /3.5 Rosin camera. AB - Modification of Rosin's [J. Opt. Soc. Am. 51, 331-335 (1961)] simple design yields an f/3.5 camera that gives 2.5-arcsec resolution over a flat field that is 5 degrees in diameter. PMID- 20720894 TI - Polarization aberration analysis of the advanced x-ray astrophysics facility telescope assembly. AB -

The advanced x-ray astrophysics facility (AXAF) telescope consists of six concentric paraboloid-hyperboloid pairs of mirrors that operate near grazing incidence. Because of the substantial polarization effects at large angles of incidence there has been concern regarding the feasibility of doing polarimetry near the telescope focal plane. The primary mirror is shown to act as a tangentially directed half-wave linear retarder and to almost completely depolarize the linearly polarized component of the light. The secondary mirror introduces an additional half-wave of linear retardance. The two-mirror telescope assembly acts as a tangentially directed one-wave linear retarder. Each mirror depolarizes alone but together the two-mirror assembly preserves the polarization state. The net instrumental polarization effects are small and polarimetry is feasible with AXAF.

The polarization aberration function for the telescope is derived by using Jones calculus. Polarization aberration functions are used to calculte the effect of instrumental polarization on the transmitted wave front and the polarization state that is due to the primary mirror and the telescope assembly.

PMID- 20720896 TI - Optical design with Wood lenses 1: infinite conjugate systems. AB - Spherical aberration in a flat-surfaced radial gradient-index lens (a Wood lens) with a parabolic-index profile can be corrected by altering the profile to include higher-order terms. However, this results in a large amount of third order coma. An alternative method of aberration correction similar to that used in the catadioptric Schmidt system is presented. A Wood lens with a parabolic index profile is used to provide all or most of the optical power. Coma is corrected by stop shifting, and spherical aberration is corrected by placing a powerless Wood lens corrector plate at the stop. PMID- 20720897 TI - Aberrations of a horizontal-vertical depolarizer. AB - We use ray-trace equations for uniaxial birefringent materials to derive third order estimates for aberrations that are produced in imaging through uniaxial plates and horizontal-vertical (HV) depolarizers. An HV depolarizer is a spatial pseudodepolarizer; it converts a uniform input polarization state into a continuum of spatially varying polarization states in an output beam. An HV depolarizer consists of two birefringent wedges whose crystal axes are crossed at 90 degrees . The interface between the wedges is inclined, which leads to a spatially varying retardance that provides the spatial pseudodepolarization. In HV depolarizers, spherical aberration, astigmatism, and image doubling are the principal aberrations for on-axis objects. Only spherical aberration occurs in isotropic plates, while the presence of birefringent wedges introduces astigmatism and image doubling. It is shown that image separation is proportional tothe magnitude of the retardance variation. Image separation is independent of the thickness, wedge angle, and refractive indices that are used to achieve this variation. A computer program is used to perform an exact birefringent ray trace and produces spot diagrams that confirm the aberration estimates. PMID- 20720898 TI - Ultraviolet angular response of cesium-telluride photocathodes. AB - Photoelectric emission is matched to optical absorption through the use of thin film equations to explain the variation in angular response of alkali-bearing photocathodes at angles of incidence from 0 to 60 degrees . The nearly exact match shows that the relationship between optical absorption and photoemission is linear. This matching ability also permits direct determination of the optical constants of an unknown film and in addition permits the calculation of the quantum efficiency of the absorbing layer. PMID- 20720899 TI - Electromagnetic scattering of two-dimensional surface-relief dielectric gratings. AB - We employed the rigorous vector coupled-wave theory [J. Opt. Soc. Am. 73, 1105 (1983)] to analyze the electromagnetic scattering from two dimensional (2-D) surface-relief dielectric gratings. A shoot-back method was developed for the numerical solution of the resulting coupled differential equations. This method allowed numerical solutions to be found for grating structures of arbitrary profiles and relatively deep grooves. It was most suitable where the grating medium refractive index was not too large and where only a small number of propagating orders existed. Experiments confirmed the numerically predicted reflectivities for 2-D surface-relief dielectric sinusoidal gratings. Reflectivity measurements were made on 2-D sinusoidal gratings fabricated on photoresist and on polycarbonate. The grating periodicities were of the order of 3000 lines/mm such that only the zero-order diffracted waves were propagating in the incident region, and possibly a few forward orders in the transmission region. The embossing technique that was used for replicating the grating patterns from photoresist onto polycarbonate proved to be a feasible method for the production of such gratings. PMID- 20720900 TI - Spectral line-shape distortions in Michelson interferometers due to off-focus radiation source. AB - When the radiation source in a Michelson interferometer is placed in front of or behind the focal plane of the collimator, distortions arise in the spectral line shapes. The appearance and behavior of these distortions in a cube-corner interferometer are treated in this work. We shall also present a simple and fast method to calculate the true line position of a distorted line, and an easy rule of thumb to connect the off-focus shift and the amount of distortion. Calculation of the phase-error curves in the signal domain is treated as well. This calculation gives a possibility of correcting the distorted interferogram. PMID- 20720901 TI - Nonimaging light concentration using total internal reflection films. AB - We present a method of fabricating nonimaging light concentrators from total internal reflection film. A prototype has been made and tested and found to operate in agreement with predictions of ray-tracing codes. The performance of the prototype is comparable with that of concentrators made from specular reflecting materials. PMID- 20720902 TI - Oxygen-ion beam polishing of a 5-cm-diameter diamond film. AB - A 5-cm diameter, 1-microm (peak to valley) rough diamond film has been polished to optical quality by an oxygen-ion beam. The rms and peak-to-valley roughness values of the polished surface have been lowered to 5.5 and 55.4 nm, respectively. Reactive ion beam polishing provides a low-temperature (140 degrees C), noncontact, and precisely controllable approach to improving the surface quality of diamond films. This progress is essential to the use of diamond coatings in optical applications. PMID- 20720904 TI - Optical properties of diffractive, bifocal, intraocular lenses. AB - The resolution of diffractive, bifocal, intraocular lenses was studied with regard to pupil displacement and diameter size through computer simulations, bench measurements, and patient vision-acuity measurements. Good agreement was obtained between these three methods of investigation. In particular, we find that pupil displacements of the order of 1 mm reduce the resolution considerably for these lenses. PMID- 20720903 TI - Ronchi and Hartmann tests with the same mathematical theory. AB - A common mathematical model is established for the Ronchi and Hartmann tests and for interpretation of the Ronchigrams as level curves of the components of the transversal aberrations. With the same point of view, a Hartmanngram is regarded as two 90 degrees crossed null Ronchi gratings. A simple and direct method is also developed for calculating Ronchigrams for the cases of centered and off-axis conic sections with the point light source at any location. PMID- 20720905 TI - 4x4 optical packet switching of asynchronous burst optical packets with a prototype, 4x4 label processing and switching sub-system. AB - We report a prototype, 4x4 (4 input/4 output) label processing and switching sub system for 10-Gb/s asynchronous burst variable-length optical packets. With the prototype, we perform a 4x4 optical packet switching demonstration, achieving error-free (BER<10(-12)) label processing and switching operation for all possible input/output combinations (16 switching paths) simultaneously. Power consumption and latency of the entire, self-contained sub-system is 83 W (includes fan power) and 300 ns, respectively. PMID- 20720906 TI - Two-photon fluorescence correlation microscopy combined with measurements of point spread function; investigations made in human skin. AB - Two-photon excitation fluorescence correlation spectroscopy (TPFCS) has been applied in connection to measurements of the point spread function (PSF) for quantitative analysis of sulphorhodamine B (SRB) in excised human skin. The PSF was measured using subresolution fluorescent beads embedded in the skin specimen. The PSF, measured as full width at half maximum (FWHM) was found to be 0.41 +/- 0.05 microm in the lateral direction, and 1.2 +/- 0.4 microm in the axial direction. The molecular diffusion of SRB inside the skin ranged between 0.5 and 15.0 x 10(-8) cm(2)/s. The diffusion coefficient is not dependent on depths down to 40 microm. The fluorophores were found to accumulate on the upper layers of the skin. This work is the first TPFCS study in human skin. The results show that TPFCS can be used for quantitative analyses of fluorescent compounds in human skin. PMID- 20720907 TI - All-silicon and in-line integration of variable optical attenuators and photodetectors based on submicrometer rib waveguides. AB - We demonstrate a monolithic integration of variable optical attenuators (VOAs) and photodetectors (PDs) based on submicrometer silicon (Si) rib waveguide with p i-n diode structure for near infrared (NIR) light. To make the Si PD absorptive for NIR, we introduced lattice defects at the rib core by means of argon ion implantation. At reverse bias of 5 V, the PD exhibits dark current of approximately 1 nA, responsivity of approximately 65 mA/W at 1560-nm wavelength, and a 3-dB cut-off frequency of approximately 350 MHz, while the VOA shows approximately 100 MHz. The PD has an absorption coefficient as low as approximately 0.5 cm(-1), which is favorable for an in in-line PD configuration, where the PD absorbs a small portion of the optical power. For DC light, the PD precisely detects the optical power attenuated by the VOA with a detection range of over 40 dB. The 3-dB cut-off frequency of synchronous operation between the VOA and PD is approximately 50 MHz, which is limited by RF noise originating from the VOA drive current. Putting an isolation groove between the VOA and PD is effective for avoiding performance degradation in DC and RF operation. PMID- 20720908 TI - Observation of light-by-light polarization control and stabilization in optical fibre for telecommunication applications. AB - In many photonics applications, especially in optical fibre based systems, the state of polarization of light remains so far an elusive uncontrolled variable, which can dramatically affect the performances of that systems and which one would like to control as finely as possible. Here, we experimentally demonstrate light-by-light polarization control via a nonlinear effect occurring in single mode optical fibre. We observe a polarization attraction and stabilization of a 10 Gbit/s optical telecommunication signal around 1550 nm. We also validate the potentiality of the device to annihilate very fast nanosecond polarization bursts. This result confirms yet another fascinating possibility to all-optical control the light properties in optical fibre. PMID- 20720909 TI - Iterative method for zero-order suppression in off-axis digital holography. AB - We propose a method to suppress the so-called zero-order term in a hologram, based on an iterative principle. During the hologram acquisition process, the encoded information includes the intensities of the two beams creating the interference pattern, which do not contain information about the recorded complex wavefront, and that can disrupt the reconstructed signal. The proposed method selectively suppresses the zero-order term by employing the information obtained during wavefront reconstruction in an iterative procedure, thus enabling its suppression without any a priori knowledge about the object. The method is analyzed analytically and its convergence is studied. Then, its performance is shown experimentally. Its robustness is assessed by applying the procedure on various types of holograms, such as topographic images of microscopic specimens or speckle holograms. PMID- 20720910 TI - Phase-transparent flexible waveband conversion of 43 Gb/s RZ-DQPSK signals using multiple-QPM-LN waveguides. AB - We report phase-transparent waveband conversion with polarization insensitivity based on second harmonic (SH) wave pumped difference frequency generation (DFG) using multiple-quasi-phase-matched LiNbO(3) (QPM-LN) waveguides. Flexible waveband conversion is demonstrated over the entire C-band using a tunable DFB-LD array (TLA) as a pump source for a multiple-QPM-LN waveguide. The penalty free waveband conversion of 43 Gb/s return-to-zero differential quadrature phase-shift keying (RZ-DQPSK) waveband signals is successfully achieved. PMID- 20720911 TI - Gouy shift correction for highly accurate refractive index retrieval in time domain terahertz spectroscopy. AB - Terahertz spectroscopic measurements are usually performed in focused beam geometry while the standard routine for the retrieval of the sample refractive index assumes plane-wave approximation. In this paper we propose a model for the transmission function which accounts for spatially limited Gaussian terahertz beams. We demonstrate experimentally its validity and applicability for an accurate extraction of the refractive index from experimental data. PMID- 20720912 TI - Rotation-invariant target recognition in LADAR range imagery using model matching approach. AB - Shape index is introduced to explore the target recognition problem from laser radar (Ladar) range imagery. A raw Ladar scene range image is transformed into a height-range image and a horizontal-range image. Then they are compared with a model library in which every model target includes six selected samples based on the principles of raising recognition rate and shortening computation time. We experimentally demonstrate that the proposed recognition approach can resolve the out-of-plane and rotation-invariant target recognition problem with a high recognition rate. PMID- 20720913 TI - High order resonances between core mode and cladding supermodes in long period fiber gratings inscribed in photonic bandgap fibers. AB - High order resonances between fundamental core mode and cladding LP(01) supermodes are demonstrated in long period fiber gratings (LPFGs) inscribed in all-solid photonic bandgap fibers for the first time to our knowledge. The resonance wavelengths of the LPFGs calculated by way of photonic bandgap theory agree with the experimental results. The temperature responses of these resonance peaks have been theoretically and experimentally investigated. In addition, the mechanism of LPFG formation has been researched deeply through coupled-mode theory (CMT) and the cutback experiments. PMID- 20720914 TI - Quasi-whispering gallery modes of exciton-polaritons in a ZnO microrod. AB - We report the photoluminescence (PL) investigations of quasi-whispering gallery mode (quasi-WGM) polaritons in a ZnO microrod at room temperature. By using the confocal micro-PL spectroscopic technique, we observe the clear optical quasi WGMs. These quasi-WGMs appeared in the ultraviolet (UV) emission region where the cavity modes strongly couple with excitons and form polaritons. The quasi-WGMs polaritons can be well described by the plane wave interference and the coupling oscillator model. PMID- 20720915 TI - Sub-wavelength light localization in nanorod chain enhances second-harmonic generation. AB - We demonstrate that nonlinear dielectric nanorod chains enhance the second harmonic generation by taking advantage of subwavelength light confinement. We report a conversion efficiency higher than 10% for only 200 W input pump peak power in a 20 nanorod chain possessing a nonlinear susceptibility chi(2) = 10 pm/V. This giant frequency conversion is shown to originate from a lateral squeezing of the fundamental guided mode and from the combination of slow light at both frequencies omega and 2 omega. These results open an interesting route for the design of highly integrated efficient nonlinear devices. PMID- 20720916 TI - Some features of the photonic crystal fiber temperature sensor with liquid ethanol filling. AB - We introduce a novel photonic crystal fiber (PCF) temperature sensor that is based on intensity modulation and liquid ethanol filling of air holes with index guiding PCF. The mode field, the effective refractive index and the confinement loss of PCF were all found to become highly temperature-dependent when the thermo optic coefficient of the liquid ethanol used is higher than that of silicon dioxide and this temperature dependence is an increasing function of the d/Lambda ratio and the input wavelength. All the experiments and simulations are discussed in this paper and the temperature sensitivity of transmission power was experimentally determined to be 0.315 dB/ degrees C for a 10-cm long PCF. PMID- 20720917 TI - Subwavelength electromagnetic dynamics in stacked complementary plasmonic crystal slabs. AB - Resonant electromagnetic fields in stacked complementary plasmonic crystal slabs (sc-PlCSs) are numerically explored in subwavelength dimensions. It is found that the local plasmon resonances in the sc-PlCSs are composite states of locally enhanced electric and magnetic fields. Two sc-PlCSs are analyzed in this paper and it is shown that each sc-PlCS realizes a resonant electromagnetic state suggested by one of Maxwell equations. It is moreover clarified that the local plasmons open efficient paths of Poynting flux, those result in high-contrast polarized transmission. PMID- 20720919 TI - Experimental verification of sparse frequency linearly frequency modulated ladar signals modeling. AB - We present the results of an experiment designed to verify the results of a previously published theoretical model that predicts the range resolution and peak-to-side lobe ratio of sparse frequency linearly frequency modulated (SF-LFM) ladar signals. We use two ultra stable diode lasers which are frequency locked and can be current tuned in order to adjust the difference frequency between the two lasers. The results of the experiment verify the previously developed model proving that SF-LFM ladar signals have the ability to increase the range resolution of a ladar system without the need for larger bandwidth modulators. Finally we simulate a target at a range of approximately 150 meters through the use of a fiber optic delay line, and demonstrate the ability of SF-LFM ladar signals to detect a target at range. PMID- 20720920 TI - Extremely large-mode-area photonic crystal fibre with low bending loss. AB - We report on the design of a novel flexible very large mode area photonic crystal fibre for short pulse high peak power fibre laser and beam delivery applications. This fibre has an extremely large mode area exceeding 2500 microm(2) when kept straight and over 1000 microm(2) when bent over a 10 cm radius at a wavelength of 1064 nm. In addition our fibre exhibits very small fundamental mode bending loss below 10(-2) dB/m. The large difference between the propagation loss levels of fundamental and higher order modes forces efficient single-mode guidance in the fibre core while bent. This allows using the fibre to build compact high power laser systems. The paper further explores the major features of this fibre including: the dependence of the mode field area on the fibre core shape, the influence of the bending radius and of the bending direction as well as the impact of manufacturing tolerances on the fibre specifications. PMID- 20720921 TI - Coherence of particulate beam attenuation and backscattering coefficients in diverse open ocean environments. AB - We present an extensive data set of particle attenuation (c(p)), backscattering (b(bp)), and chlorophyll concentration (Chl) from a diverse set of open ocean environments. A consistent observation in the data set is the strong coherence between c(p) and b(bp) and the resulting constancy of the backscattering ratio (0.010 +/- 0.002). The strong covariability between c(p) and b(bp) must be rooted in one or both of two explanations, 1) the size distribution of particles in the ocean is remarkably conserved and particle types responsible for c(p) and b(bp) covary, 2) the same particle types exert influence on both quantities. Therefore, existing relationships between c(p) or Chl:c(p) and phytoplankton biomass and physiological indices can be conceptually extended to the use of b(bp). This finding lends support to use of satellite-derived Chl and b(bp) for investigation of phytoplankton biomass and physiology and broadens the applications of existing ocean color retrievals. PMID- 20720922 TI - Noise performance of optical fiber transmission links that use non-degenerate cascaded phase-sensitive amplifiers. AB - Based on semi-classical theory, the noise performance of a multi-span fiber optical transmission system employing a cascaded phase-insensitive amplifier (PIA) and phase-sensitive amplifiers (PSAs) is investigated. Compared with the pure-PIA and pure-PSA based in-line amplification schemes, the copier + PSA scheme is found to improve the system NF by up to 6 and 3 dB, respectively, in an optimized long-haul fiber link. In addition, this cascaded configuration will significantly relax the requirement for accurate phase- and wavelength-locking which is rigorously needed in the pure-PSA configuration. This scheme is also modulation-format independent. As a proof of concept, the NF of a fiber parametric amplifier based copier + PSA cascade with inter-stage attenuation representing the fiber link is measured, which shows a 1.8-dB total NF improvement over the conventional EDFA cascade. PMID- 20720923 TI - On-chip optical interconnection by using integrated III-V laser diode and photodetector with silicon waveguide. AB - On-chip integration of III-V laser diodes and photodetectors with silicon nanowire waveguides is demonstrated. Through flip-chip bonding of GaInNAs/GaAs laser diodes directly onto the silicon substrate, efficient heat dissipation was realized and characteristic temperatures as high as 132K were achieved. Spot-size converters for the laser-to-waveguide coupling were used, with efficiencies greater than 60%. The photodetectors were fabricated by bonding of InGaAs/InP wafers directly to silicon waveguides and formation of metal-semiconductor-metal structures, giving responsivities as high as 0.74 A/W. Both laser diode and the photodetector were integrated with a single silicon waveguide to demonstrate a complete on-chip optical transmission link. PMID- 20720924 TI - Experimental detection of optical vortices with a Shack-Hartmann wavefront sensor. AB - Laboratory experiments are carried out to detect optical vortices in conditions typical of those experienced when a laser beam is propagated through the atmosphere. A Spatial Light Modulator (SLM) is used to mimic atmospheric turbulence and a Shack-Hartmann wavefront sensor is utilised to measure the slopes of the wavefront surface. A matched filter algorithm determines the positions of the Shack-Hartmann spot centroids more robustly than a centroiding algorithm. The slope discrepancy is then obtained by taking the slopes measured by the wavefront sensor away from the slopes calculated from a least squares reconstruction of the phase. The slope discrepancy field is used as an input to the branch point potential method to find if a vortex is present, and if so to give its position and sign. The use of the slope discrepancy technique greatly improves the detection rate of the branch point potential method. This work shows the first time the branch point potential method has been used to detect optical vortices in an experimental setup. PMID- 20720925 TI - 1550 nm high contrast grating VCSEL. AB - We demonstrate an electrically pumped high contrast grating (HCG) VCSEL operating at 1550 nm incorporating a proton implant-defined aperture. Output powers of >1 mW are obtained at room temperature under continuous wave operation. Devices operate continuous wave at temperatures exceeding 60 degrees C. The novel device design, which is grown in a single epitaxy step, may enable lower cost long wavelength VCSELs. PMID- 20720926 TI - Femtosecond multi-filamentation control by mixture of gases: towards synthesised nonlinearity. AB - We have investigated femtosecond multi-filamentation process in a mixture of gases controlling the concentration of atoms versus molecules in the gas cell. The experimental results show that this control could provide a new freedom degree to deterministic spatial distribution control of the multiple filaments. Our simulation indicates surprisingly that only difference of the gases nonlinearity (referred to as "synthesised nonlinearity") is sufficient to be responsible for this control. This study opens the way to provide few-cycle pulses spatial distributed source for spatially encoded measurements and experiments. PMID- 20720927 TI - Highly-stable monolithic femtosecond Yb-fiber laser system based on photonic crystal fibers. AB - A self-starting, passively stabilized, monolithic all-polarization- maintaining femtosecond Yb-fiber master oscillator / power amplifier with very high operational and environmental stability is demonstrated. The system is based on the use of two different photonic crystal fibers. One is used in the oscillator cavity for dispersion balancing and nonlinear optical limiting, and another one is used for low-nonlinearity final pulse recompression. The chirped-pulse amplification and recompression of the 232-fs, 45-pJ/pulse oscillator output yields a final direct fiber-end delivery of 7.3-nJ energy pulses of around 297 fs duration. Our laser shows exceptional stability. No Q-switched modelocking events were detected during 4-days long observation. An average fluctuation of only 7.85 x 10(-4) over the mean output power was determined as a result of more than 6 hours long measurement. The laser is stable towards mechanical disturbances, and maintains stable modelocking in the temperature range of at least 10 - 40 (0)C. PMID- 20720928 TI - Observation of four-wave mixing in slow-light silicon photonic crystal waveguides. AB - Four-wave mixing is observed in a silicon W1 photonic crystal waveguide. The dispersion dependence of the idler conversion efficiency is measured and shown to be enhanced at wavelengths exhibiting slow group velocities. A 12-dB increase in the conversion efficiency is observed. Concurrently, a decrease in the conversion bandwidth is observed due to the increase in group velocity dispersion in the slow-light regime. The experimentally observed conversion efficiencies agree with the numerically modeled results. PMID- 20720929 TI - Wave propagation retrieval method for chiral metamaterials. AB - In this paper we present the wave propagation method for the retrieving of effective properties of media with circularly polarized eigenwaves, in particularly for chiral metamaterials. The method is applied for thick slabs and provides bulk effective parameters. Its strong sides are the absence of artificial branches of the refractive index and simplicity in implementation. We prove the validity of the method on three case studies of homogeneous magnetized plasma, bi-cross and U-shaped metamaterials. PMID- 20720930 TI - Study of water concentration measurement in thin tissues with terahertz-wave parametric source. AB - Water concentration and distribution in biotissues are important factors in many applications. THz-wave is a viable tool for water content measurement due to its highly sensitivity to water. In this study, the measuring errors of water concentration using THz-wave induced by transmittance and sample thickness were analyzed theoretically. The chosen basis for sample thickness and measuring THz frequency were presented theoretically. Measurements of the water two-dimensional mapping in different animal tissue samples were demonstrated experimentally, which clearly shows the spatial distribution of the tissues. PMID- 20720931 TI - Application theory of scattering and coupled mode analysis for liquid crystal diffractive grating. AB - This work presents a detailed analysis of a liquid crystal (LC) phase diffraction grating based on a approach combining vector theory of scattering and coupled mode analysis. In general, the coupled mode analysis gives a solution for the diffracted field regardless of aperture and the polarization state of the incident light. However, the aperture of the incident light defines the angular selectivity of the diffraction grating as well as the distribution of the intensity of the diffractive maximums. The solution of the vector theory of scattering in combination with the coupled mode analysis for diffraction of the light beam with finite aperture has allowed one to optimize the parameters of the high efficiency diffractive LC grating. The analytic solutions here were verified with experimental results for a reverse-twisted LC grating and a comparison with the standard Gooch-Tarry's method, which typically applied for a twisted nematic LC display. PMID- 20720933 TI - Structurally-tolerant vertical directional coupling between metal-insulator-metal plasmonic waveguide and silicon dielectric waveguide. AB - Vertical directional coupling between a metal-insulator-metal (MIM) plasmonic waveguide and a conventional dielectric waveguide is investigated. The coupling length, extinction ratio, insertion loss and coupling efficiency of the hybrid coupler are analyzed. As an example, when the separation between the two waveguides is 250 nm, a maximum coupling efficiency of 73%, an insertion loss of 1.4 dB and an extinction ratio of 16 dB can be achieved at a coupling length of 4.5 microm at 1.55 microm wavelength. A particular feature of this hybrid coupler is that it is highly tolerant to the structural parameters of the plasmonic waveguide and the misalignment between the two waveguides. The performance of this hybrid coupler as a TM polarizer is also analyzed and a maximum extinction ratio of 44 dB and an insertion loss of -0.18 dB can be obtained. The application of this hybrid coupler includes the signal routing between plasmonic waveguides and dielectric waveguides in photonic integrated circuits and the polarization control between TE and TM modes. In addition, it provides an approach for efficiently exciting MIM plasmonic modes with conventional dielectric modes. PMID- 20720932 TI - Mid-infrared characterization of solution-processed As2S3 chalcogenide glass waveguides. AB - An etch-free and cost-effective deposition and patterning method to fabricate mid infrared chalcogenide glass waveguides for chemical sensing applications is introduced. As(2)S(3) raised strip optical waveguides are produced by casting a liquid solution of As(2)S(3) glass in capillary channel molds formed by soft lithography. Mid-IR transmission is characterized by coupling the output of a quantum cascade (QC) laser (lambda = 4.8 microm) into the 40 microm wide by 10 microm thick multi-mode waveguides. Loss as low as 4.5 dB/cm is achieved using suitable substrate materials and post-processing. Optical absorption and surface roughness measurements indicate that the solution-processed films are of sufficient quality for optical devices and are promising for further development of waveguide-based mid-IR elements. PMID- 20720934 TI - First demonstration of long-haul transmission using silicon microring modulators. AB - We report error-free long-haul transmission of optical data modulated using a silicon microring resonator electro-optic modulator with modulation rates up to 12.5 Gb/s. Using bit-error-rate and power penalty characterizations, we evaluate the performance of this device with varying modulation rates, and perform a comparative analysis using a commercial electro-optic modulator. We then experimentally measure the signal integrity degradation of the high-speed optical data with increasing propagation distances, induced chromatic dispersions, and bandwidth-distance products, showing error-free transmission for propagation distances up to 80 km. These results confirm the functional ubiquity of this silicon modulator, establishing the potential role of silicon photonic interconnects for chip-scale high-performance computing systems and memory access networks, optically-interconnected data centers, as well as high-performance telecommunication networks spanning large distances. PMID- 20720935 TI - Tuning the extraordinary transmission in a metallic/dielectric CDC hole array by changing the temperature. AB - Tunable extraordinary transmission via changing temperature of a porous metallic layer on top of a thin layer of dielectric strontium titanate (STO) was studied. The metallic layer has a through-hole array and each hole has a circular converging-diverging channel (CDC) shape, which induces the excitation of surface plasmon polaritons (SPPs) and then results in a controllable extraordinary optical transmission in the terahertz (THz) frequency range. We used a three dimensional (3D) finite element method to analyze the transmission characteristics of the structure. Location and magnitude of the transmission peaks can be adjusted by hole size, converging angle, and thicknesses of metal and STO layers. Remarkably, the suggested structure presents a strong transmission dependency on temperature, which offers a new approach to actively and externally tune the transmission. This new design could lead to a family of temperature-sensitive devices working in the THz frequency range, promising in many applications including photonics, nanolithography, imaging, and sensing. PMID- 20720936 TI - Time-resolved surface plasmon polariton coupled exciton and biexciton emission. AB - We discuss the coupling between optically excited semiconductor nanocrystals (NC) and thin metal films in both the single and multi-exciton regime. Using time resolved photoluminescence spectroscopy, we determine the decay dynamics of free space and surface plasmon polariton (SPP) coupled emission. The two dynamics are found to be distinctly different at very small NC-metal separations and at photon energies close to the SPP resonance frequency. A comparison with numerical calculations allow us to conclude that the difference in emission dynamics is associated with the different interactions of parallel and perpendicular dipole emitters with lossy surface waves. Experiments at high excitation densities reveal that the coupling to SPPs and lossy surface waves is identical for excitons and biexcitons. PMID- 20720937 TI - Pupil coding masks for imaging polychromatic scenes with high resolution and extended depth of field. AB - An algorithm for the design of imaging systems with circular symmetry that exhibit high resolution as well as extended depth of field for polychromatic incoherent illumination is presented. The approach provides a significant improvement over a publication [1] where the design was carried for a single wavelength. The approach is based on searching for a binary phase pupil mask that provides imaging with the highest cut-off spatial frequency, while assuring a desired contrast value over a given depth of field. Simulations followed by experimental results are provided. PMID- 20720938 TI - Electroluminescence from n-In2O3:Sn randomly assembled nanorods/p-SiC heterojunction. AB - Room-temperature electroluminescence (EL) has been realized from Sn-doped In(2)O(3) (In(2)O(3):Sn) nanorods. Heterojunction light-emitting diode (LED) was formed by depositing a layer of randomly packed n-In(2)O(3):Sn nanorods onto a p type 4H-SiC substrate. It is found that the emission intensity of the heterojunction LED under forward bias can be maximized by doping the In(2)O(3) nanorods with 3 mol. % of Sn. Furthermore, two emission peaks of the EL spectra are observed at approximately 395 and approximately 440 nm. These ultraviolet and visible peaks are attributed to the radiative recombination at Sn induced and intrinsic defect states of the In(2)O(3):Sn nanorods. PMID- 20720939 TI - Controlled light-pulse propagation via dynamically induced double photonic band gaps. AB - We analyze the optical response of a standing-wave driven four-level atomic system with double dark resonances. Fully developed double photonic band gaps arise as a result of periodically modulated refractive index within the two electromagnetically induced transparency widows. We anticipate that the dynamically induced band gaps can be used to coherently control the propagation of light-pulses with different center frequencies and may have applications in all-optical switching and routing for quantum information networks. PMID- 20720940 TI - Domain wall characterization in ferroelectrics by using localized nonlinearities. AB - In this paper, a method of domain wall characterization in ferroelectrics through Cherenkov second harmonic generation by localized nonlinearities is proposed. By this method, domain wall width is estimated to be less than 10nm. High spatial angular resolution of about 10 mrad in the experiment reveals the fine structures of the domain walls. Combined with scanning techniques, this method can reconstruct domain wall patterns with high resolution. This method has advantages of being nondestructive, noncontact, in situ as well as of high resolution. PMID- 20720941 TI - 1 x 2 precise electro-optic switch in periodically poled lithium niobate. AB - A 1 x 2 precise electro-optic switch was demonstrated in a periodically poled lithium niobate crystal. In the experiment, the optical signal was shifted to different channels by adjusting external applied electric fields. The bandwidth of the working wavelength for the switch is nearly 2 nm, which makes this device has large tolerance to the drift of the working wavelength in the practical applications. Theoretical discussion about 1 x 2 precise electro-optic switch based on this structure is also presented. PMID- 20720942 TI - Planar and ridge waveguides formed in LiNbO3 by proton exchange combined with oxygen ion implantation. AB - We report on the fabrication of planar and ridge waveguides in lithium niobate by proton exchange combined with oxygen ion implantation. The implanted energy ranges from 600 to 1400 keV with a dose of 1 x 10(15) ions/cm(2). The modes in proton exchanged waveguide can be modulated by O ion implantation. There are different damage profiles in proton-exchanged and ion-implanted waveguides in Rutherford backscattering/channeling spectra. The refractive index profile in single-mode waveguide in lithium niobate has been obtained based on Intensity Calculation Method. Also ridge waveguide was fabricated on the basis of planar waveguide by Ar ion beam etching. The measured near-field intensity distributions of the ridge waveguide modes show a reasonable agreement with the simulated ones. The estimated propagation loss was approximately 2.2 dB/cm. PMID- 20720943 TI - Demonstration of a low V pi L modulator with GHz bandwidth based on electro-optic polymer-clad silicon slot waveguides. AB - We demonstrate a near-infrared electro-optic modulator with a bandwidth of 3 GHz and a V(pi)L figure of merit of 0.8 V-cm using a push-pull configuration. This is the highest operating speed achieved in a silicon-polymer hybrid system to date by several orders of magnitude. The modulator was fabricated from a silicon strip loaded slot waveguide and clad in a nonlinear polymer. In this geometry, the electrodes form parts of the waveguide, and the modulator driving voltage drops across a 200 nm slot. PMID- 20720944 TI - Fast noncontact measurements of tablet dye concentration. AB - A non-contact, non-destructive technique for estimating the dye concentration of a tablet is presented. These measurements are performed by an optoelectronic system capable for fast acquisition of two-dimensional distribution of reflection spectra with high spatial resolution by using a subspace vector model of surface reflection. Vector components representing compressed spectral data are used directly (without reconstruction of the reflection spectra) for discrimination of tablets with small dye-concentration difference. Analysis of the data obtained after tablet illumination by 7 mutually orthogonal spectral functions allows us to find a single optimal spectral function which is enough for estimating the dye concentration. Using the optimal spectral function, either the mean concentration of riboflavin or distribution of the concentration over the tablet surface can be evaluated with high rate which ensures application of the technique for online quality control of each tablet. PMID- 20720945 TI - Magneto-optical effects in interacting localized and propagating surface plasmon modes. AB - We report that the effect of an external magnetic field on the propagation of surface plasmons can be effectively modified through the coupling between localized (LSP) and propagating (SPP) surface plasmons. When these plasmon modes do not interact, the main effect of the magnetic field is a modification of the wavevector of the SPP mode, leaving the LSP virtually unaffected. Once both modes start to interact, there is a strong variation of the magnetic field induced modification of the SPP dispersion curve and, simultaneously, the LSP mode becomes sensitive to the magnetic field. PMID- 20720946 TI - TM-wave propagation controlled by split ring resonator array. AB - We propose a new approach to control the propagation of electromagnetic (EM) wave with certain polarization by a split ring resonator (SRR) array. Interactions between SRR and the EM wave in the array are analyzed and it is found that the H field is always perpendicular to the SRR plane around the magnetic resonance frequency. Based on this property, a semicircular waveguide is designed to realize a 180 degrees bending with high performance. The structure of this approach is simple and feasible, providing an alternative way to construct bending waveguide with low loss. PMID- 20720947 TI - High-resolution methods for fluorescence retrieval from space. AB - The retrieval from space of a very weak fluorescence signal was studied in the O(2)A and O(2)B oxygen atmospheric absorption bands. The accuracy of the method was tested for the retrieval of the chlorophyll fluorescence and reflectance terms contributing to the sensor signal. The radiance at the top of the atmosphere was simulated by means of a commercial radiative-transfer program at a high resolution (0.1 cm(-1)). A test data set was generated in order to simulate sun-induced chlorophyll fluorescence at the top of the canopy. Reflectance terms were spectrally modeled using cubic splines and fluorescence by means of the sum of two Voigt functions. Sensor radiance residual minimization was performed in the presence of a multiplicative noise, thus ensuring that the sensor simulations were realistic. The study, which focused on the possibility of retrieving fluorescence with an accuracy better than 10%, was performed for instrument resolutions ranging from about 0.4 cm(-1) to 2 cm(-1) in order to test the algorithm for the characteristics of existing and planned hyper-spectral sensors. The algorithm was also used to retrieve fluorescence in the single O(2)A band at the OCO and TANSO-FTS instrument spectral resolutions. PMID- 20720948 TI - Detecting quantum coherence of Bose gases in optical lattices by scattering light intensity in cavity. AB - We propose a new method of detecting quantum coherence of a Bose gas trapped in a one-dimensional optical lattice by measuring the light intensity from Raman scattering in cavity. After pump and displacement process, the intensity or amplitude of scattering light is different for different quantum states of a Bose gas, such as superfluid and Mott-Insulator states. This method can also be useful to detect quantum states of atoms with two components in an optical lattice. PMID- 20720949 TI - Implementation of a cost-effective optical comb source in a WDM-PON with 10.7 Gb/s data to each ONU and 50 km reach. AB - The performance of a cost-effective optical comb source using commercial off the shelf (COTS) components in a WDM passive optical network is demonstrated. Eight comb modes are individually modulated at 10.7 Gb/s and transmitted over 50 km of single mode fiber for downlink transmission. Error free performance is obtained for each comb line and a maximum performance difference of 1.4 dB is experienced between the eight channels. Colorless operation of the optical network unit is achieved by utilizing an integrated module consisting of a tunable laser and an electro-absorption modulator as an uplink transmitter. Finally the predicted downstream performance of the system, when all the channels are transmitted simultaneously, is numerically simulated. PMID- 20720950 TI - Anomalous group velocity at the high energy range of a 3D photonic nanostructure. AB - We report on a study of electromagnetic waves propagation in thin periodically ordered photonic nanostructures in the spectral range where the light wavelength is on the order of the lattice parameter. The vector KKR method we use allows us to determine the group index from finite photonic structures including extinction providing confirmation of recently emerged results. We show that for certain frequencies the group velocity of opal slabs can either be superluminal or approach zero depending on the crystal thickness and the unavoidable presence of losses. In some cases, group velocity can be negative. Such behavior can be clearly attributed to the finite character of the three-dimensional structure and reproduces previously reported experimental observations. Calculations show that contrary to the predictions of extraordinary group velocity reductions for infinite periodic structures, the group velocity of real opals may exhibit strong fluctuations at the high energy range. Hence, a direct identification between the calculated anomalous group velocities, for an actual opal film, and the predicted propagating low dispersion modes for an ideal infinite ordered structure seems difficult to establish. PMID- 20720951 TI - Performance characteristics of a continuous-wave compact widely tunable external cavity interband cascade lasers. AB - We present the design and performance of a novel broadly tunable continuous-wave external-cavity interband cascade laser (ECicL). The ICL die growth and fabrication, as well as the external cavity geometry are described. Tuning across the 3.2-3.35 microm wavelength range, limited by the gain width of the ICL active medium, is achieved at a maximum power level of 4 mW. PMID- 20720952 TI - Polymer-composite fibers for transmitting high peak power pulses at 1.55 microns. AB - Hollow-core photonic bandgap fibers (PBG) offer the opportunity to suppress highly the optical absorption and nonlinearities of their constituent materials, which makes them viable candidates for transmitting high-peak power pulses. We report the fabrication and characterization of polymer-composite PBG fibers in a novel materials system, polycarbonate and arsenic sulfide glass. Propagation losses for the 60 microm-core fibers are less than 2dB/m, a 52x improvement over previous 1D-PBG fibers at this wavelength. Through preferential coupling the fiber is capable of operating with over 97% the fiber's power output in the fundamental (HE(11)) mode. The fiber transmitted pulses with peak powers of 11.4 MW before failure. PMID- 20720953 TI - Measured comparison of the crossover periods for mid- and long-wave IR (MWIR and LWIR) polarimetric and conventional thermal imagery. AB - We report the results of a multi-day diurnal study in which polarimetric and conventional thermal imagery is recorded in the mid- and long-wave IR to identify and compare the respective time periods in which minimum target contrast is achieved. The data shows that the chief factors affecting polarimetric contrast in both wavebands are the amount of thermal emission from the objects in the scene and the abundance of MWIR and LWIR sources in the optical background. In particular, it has been observed that the MWIR polarimetric contrast was positively correlated to the presence of MWIR sources in the optical background, while the LWIR polarimetric contrast was negatively correlated to the presence of LWIR sources in the optical background. PMID- 20720954 TI - Triple-frequency symmetric subtraction scheme for nonresonant background suppression in coherent anti-Stokes Raman scattering (CARS) microscopy. AB - We report a unique triple-frequency symmetric subtraction scheme to effectively remove the nonresonant background in coherent anti-Stokes Raman scattering (CARS) microscopy. Theoretical and experimental studies show that this unique scheme has an optimal performance for high contrast vibrational imaging, particularly useful when the resonant signal was larger than or comparable to the nonresonant background. PMID- 20720955 TI - Phase-sensitive imaging of diffracted light by single nanoslits: measurements from near to far field. AB - We perform phase-sensitive imaging of optical wavefront emanating from a single nanoslit and propagating into free space by using scattering type near-field scanning optical microscope combined with an optical interferometer. By analyzing polarization resolved optical amplitudes and phases, the propagation directions of surface waves are determined and the phase difference between two orthogonal polarization components of the surface wave are discussed for increasing distance from the slit. PMID- 20720956 TI - Detection of colored nanomaterials using evanescent field-based waveguide sensors. AB - We have developed an optical system designed for detecting colored nanomaterials in aqueous solutions, using the concept of evanescent-field-coupled waveguide mode sensors. In this study, we found that the waveguide modes induced in the sensor are intrinsically sensitive to a change in optical absorption, or a 'change in color'. The system detects less than one gold nanoparticle (diameter: 20 nm) adsorbed per square micrometer. It is also demonstrated that significant signal enhancement due to adsorption of molecules is achieved using a dye. The developed sensor rarely suffers from a drawback of impurity adsorption. The system is expected to be applied as an effective sensing tool for metal colloids, nanoparticles, and colored biomolecules in solution. PMID- 20720957 TI - Design and characterization of a micron-focusing plasmonic device. AB - We design and experimentally demonstrate a focusing plasmonic device consisting of a central slit surrounded by the grooves with the fixed width and depth in Au/Cr metal layers. By modulating the phases of the radiation lights decoupled by the grooves from surface plasmon polaritons waves, the focal length can be controlled in the range of several wavelengths. A micron-focusing device is fabricated by the focused ion beam and the focusing performance is characterized using the scanning near-field optical microscope. The experimental results show a significant focusing effect and have agreement with the theoretical analysis and simulation results. Such a focusing plasmonic device with the predicted focal length has potential practical applications in integrated photonics due to the simplicity of the design and fabrication. PMID- 20720958 TI - Near-zero dispersion, highly nonlinear lead-silicate W-type fiber for applications at 1.55 microm. AB - We report the design, fabrication and characterization of a lead-silicate glass highly nonlinear W-type fiber with a flattened and near-zero dispersion profile in the 1.55 microm region. The fiber was composed of three types of commercial lead silicate glasses. Effectively single-mode guidance was observed in the fiber at 1550 nm. The nonlinear coefficient and the propagation loss at this wavelength were measured to be 820 W(-1)km(-1) and 2.1 dB/m, respectively. Investigations of the Brillouin threshold revealed no evidence of stimulated Brillouin scattering for continuous wave signal powers up to 29 dBm in a 2m sample of the fiber. A broadband dispersion measurement confirmed the near-zero dispersion values and the flat dispersion profile around 1550 nm, in good agreement with our simulations. Efficient four-wave-mixing, tunable across the whole C-band, was demonstrated in a 2.2m length of the fiber. PMID- 20720959 TI - Hidden progress: broadband plasmonic invisibility. AB - One of the key challenges in current research into electromagnetic cloaking is to achieve invisibility at optical frequencies and over an extended bandwidth. There has been significant progress towards this using the idea of cloaking by sweeping under the carpet of Li and Pendry. Here, we show that we can harness surface plasmon polaritons at a metal surface structured with a dielectric material to obtain a unique control of their propagation. We exploit this control to demonstrate both theoretically and experimentally cloaking over an unprecedented bandwidth (650-900 nm). Our non-resonant plasmonic metamaterial is designed using transformational optics extended to plasmonics and allows a curved reflector to mimic a flat mirror. Our theoretical predictions are validated by experiments mapping the surface light intensity at a wavelength of 800 nm. PMID- 20720960 TI - Stimulated Brillouin scattering based in-band OSNR monitoring technique for 40 Gbps and 100 Gbps optical transparent networks. AB - We demonstrate experimentally and numerically that the SBS based in-band OSNR monitoring technique can be used for dual polarization signals. We also present novel approach for a drastic enhancement of the sensitivity monitoring range by intentionally adding in-band ASE noise into the signal. Numerical results are provided for 44.6 Gbps DPSK, 44.6 Gbps DQPSK and 112 Gbps Dual Polarization (DP-) QPSK signals, with both 100 GHz and 50 GHz channel spacing scenarios. PMID- 20720961 TI - Tunable Fabry-Perot interferometer from ferroelectric polymer based on surface energy modification. AB - Surface energy modification was utilized in the fabrication of hollow transmission Fabry-Perot interferometer (FPI) for the first time. Polydimethylsiloxane (PDMS) was used to modify the surface energy of substrate for the self-assembly of poly(vinylidenefluoride-trifluoroethylene) [P(VDF-TrFE)] 70/30 mol% copolymer film on given areas, which is simple and low destructive for the photoelectric device. A strain of 7.12% under a field of 22.3 MV/m was observed from the copolymer film, which led to the FPI with a tunable range of 54 nm at wavelength of 604 nm. PMID- 20720962 TI - Efficient planar fiber-to-chip coupler based on two-stage adiabatic evolution. AB - A new, efficient adiabatic in-plane fiber-to-chip coupler design is proposed. In this design, the light from the fiber is coupled into a low-index waveguide with matching mode size. The mode is first adiabatically reduced in size with a rib taper, and then transferred into a high-index (e.g. silicon) waveguide with an inverse taper. The two-stage design allows to reduce the coupler length multiple times in comparison with pure inverse taper-based couplers of similar efficiency. The magnitude of length reduction increases with the refractive index of the low index waveguide and the fiber mode size. PMID- 20720963 TI - Improving the lateral resolution of a multi-sensor profile measurement method by non-equidistant sensor spacing. AB - We present a method to enhance the achievable lateral resolution of a multi sensor scanning profile measurement method. The relationship between the profile measurement method considered and established shearing techniques is illustrated. Simulation and measurement results show that non-equidistant sensor spacing can improve the lateral resolution significantly. PMID- 20720964 TI - Fourier domain mode-locked swept source at 1050 nm based on a tapered amplifier. AB - While swept source optical coherence tomography (OCT) in the 1050 nm range is promising for retinal imaging, there are certain challenges. Conventional semiconductor gain media have limited output power, and the performance of high speed Fourier domain mode-locked (FDML) lasers suffers from chromatic dispersion in standard optical fiber. We developed a novel light source with a tapered amplifier as gain medium, and investigated the FDML performance comparing two fiber delay lines with different dispersion properties. We introduced an additional gain element into the resonator, and thereby achieved stable FDML operation, exploiting the full bandwidth of the tapered amplifier despite high dispersion. The light source operates at a repetition rate of 116 kHz with an effective average output power in excess of 30 mW. With a total sweep range of 70 nm, we achieved an axial resolution of 15 microm in air (approximately 11 microm in tissue) in OCT measurements. As our work shows, tapered amplifiers are suitable gain media for swept sources at 1050 nm with increased output power, while high gain counteracts dispersion effects in an FDML laser. PMID- 20720965 TI - Gradual loss of polarization in light scattered from rough surfaces: electromagnetic prediction. AB - Electromagnetic theory is used to calculate the gradual loss of polarization in light scattering from surface roughness. The receiver aperture is taken into account by means of a multiscale spatial averaging process. The polarization degrees are connected with the structural parameters of surfaces. PMID- 20720966 TI - A ray-transfer-matrix model for hybrid fiber Fabry-Perot sensor based on graded index multimode fiber. AB - A theoretical model based on the ray-transfer-matrix method is developed for explaining the principle of a graded-index multimode fiber (GI-MMF) based hybrid fiber Fabry-Perot (GI-FFP) sensor. It is verified by the numerical simulations and experimental results that the high fringe contrast of the reflective spectrum of the sensor is due to the periodic self-focusing effect of the GI-MMF. The influence of the GI-MMF length on the shape of reflective spectrum and corresponding maximum fringe contrast are investigated. Experimental results are in good agreement with the theory. A typical GI-FFP sensor is fabricated and its response to the external refractive index is measured with a maximum sensitivity of approximately 160 dB/RIU (Refractive Index Unit). PMID- 20720967 TI - Determination of the time origin by the maximum entropy method in time-domain terahertz emission spectroscopy. AB - We have developed a scheme for determining the time origin by the maximum entropy method (MEM) in time-domain terahertz (THz) emission spectroscopy. By applying the MEM to trial damped sinusoidal waveforms, we confirmed that the MEM gives true phase shifts across the resonance features and that its inherent uncertainty in determining the time origin is +/-15 fs for 100-fs-class excitation/sampling optical pulses. Furthermore, when the MEM was applied to a THz waveform recorded experimentally with a finite sampling interval for the Bloch oscillation in a semiconductor superlattice, a misplacement of the time origin was indeed detected with an accuracy limited by the worse of the MEM inherent uncertainty and the sampling interval. PMID- 20720968 TI - Ultrahigh-Q one-dimensional photonic crystal nanocavities with modulated mode-gap barriers on SiO2 claddings and on air claddings. AB - We report designs for a silicon-on-insulator (SOI) one-dimensional (1D) photonic crystal (PhC) nanocavity with modulated mode-gap barriers based on the lowest dielectric band. These cavities have an ultrahigh theoretical quality factor (Q) of 10(7)-10(8) while maintaining a very small modal volume of 0.6-2.0 (lambda/n)(3), which are the highest Q for any nanocavities with SiO(2) under cladding. We have fabricated these SOI 1D-PhC cavities and confirmed that they exhibited a Q of 3.6 x 10(5), which is also the highest measured Q for SOI-type PhC nanocavities. We have also applied the same design to 1D PhC cavities with air claddings, and found that they exhibit a theoretical quality factor higher than 10(9). The fabricated air-cladding 1D Si PhC cavities have showed a quality factor of 7.2 x 10(5), which is close to the highest Q value for 1D PhC cavities. PMID- 20720969 TI - Simultaneous multi-channel CMW-band and MMW-band UWB monocycle pulse generation using FWM effect in a highly nonlinear photonic crystal fiber. AB - We propose and experimentally demonstrate a scheme to simultaneously realize multi-channel centimeter wave (CMW) band and millimeter wave (MMW) band ultra wideband (UWB) monocycle pulse generation using four wave mixing (FWM) effect in a highly nonlinear photonic crystal fiber (HNL-PCF). Two lightwaves carrying polarity-reversed optical Gaussian pulses with appropriate time delay and another lightwave carrying a 20 GHz clock signal are launched into the HNL-PCF together. By filtering out the FWM idlers, two CMW-band UWB monocycle signals and two MMW band UWB monocycle signals at 20 GHz are obtained simultaneously. Experimental measurements of the generated UWB monocycle pulses at individual wavelength, which comply with the FCC regulations, verify the feasibility and flexibility of proposed scheme for use in practical UWB communication systems. PMID- 20720970 TI - Surface integral equation formulation for the analysis of left-handed metamaterials. AB - A surface integral equation (SIE) formulation is applied to the analysis of electromagnetic problems involving three-dimensional (3D) piecewise homogenized left-handed metamaterials (LHM). The resulting integral equations are discretized by the well-known method of moments (MoM) and solved via an iterative process. The unknowns are defined only on the interfaces between different media, avoiding the discretization of volumes and surrounding space, which entails a drastic reduction in the number of unknowns arising in the numerical discretization of the equations. Besides, the SIE-MoM formulation inherently includes the radiation condition at infinity, so it is not necessary to artificially include termination absorbing boundary conditions. Some 3D numerical examples are presented to confirm the validity and versatility of this approach on dealing with LHM, also providing some intuitive verifications of the singular properties of these amazing materials. PMID- 20720971 TI - Hybrid continuous wave terahertz spectroscopy. AB - We propose a hybrid architecture for continuous wave terahertz spectroscopy employing a conventional two color photomixing system combined with a quasi time domain spectrometer, driven by a multimode laser diode. This approach fuses high spectral intensity with broadband frequency information and overcomes the ambiguity of standard continuous wave thickness measurements. PMID- 20720972 TI - Compact Bragg grating with embedded metallic nano-structures. AB - A compact Bragg grating with embedded gapped metallic nano-structures is proposed and investigated theoretically. The Bragg grating consists of periodic planar metallic strips embedded in a dielectric waveguide. The grating exhibits distinct polarization characteristics due to its underlying working mechanisms of the metallic nano-strips. The grating can be considered as insulator-metal-insulator surface plasmonic polariton waveguide grating with improved light confinement for TM polarized waves. For the TE waves, significant field mismatch between metal and non-metal sections of the grating results in strong reflection. Comparison with the conventional deeply-etched grating on the same waveguide structures reveals interesting characteristics. It is concluded that the two types of grating structures share similar guidance, reflection and loss mechanisms for the TE modes. The spectral characteristics and their dependences on grating duty cycle are drastically different for the TM modes, mainly due to the SPP effect for the metal. Although the proposed grating performs slightly worse comparing to the deeply-etched grating for TE waves, its fabrication process should be easier since there will be no narrow trench (in sub-microns) deep-etching process (up to a few microns in depth) involved. PMID- 20720973 TI - Jitter-free multi-layered nanoparticles optical storage disk with buffer ring. AB - A multi-layered nanoparticles optical disk has been developed for a jitter-free high-density data storage system. The disk has nano structures composed of 300-nm diameter photosensitive particles and 30-nm-width non-photosensitive buffer rings around them. With the buffer rings into the nanoparticles disk, a conventional confocal microscope equipped with a low numerical aperture (NA) objective picked up a particle's shape signal to generate a synchronous signal on its own. In the three-dimensional structured disk proposed, no electronically-produced reference signal is necessary for clock data recover (CDR); no jitter occurs in data decoding. PMID- 20720974 TI - Effect of dielectric constant tuning on a photonic cavity frequency and Q-factor. AB - For practical applications in quantum electrodynamics, it has been proposed to produce frequency tuning or Q-switching by dynamically changing the dielectric constant around a nano-cavity. Local changes in the dielectric constant of a photonic cavity with finite-lifetime, may affect not only the frequency of electromagnetic cavity modes but also their quality-factor (Q). Thus, it is important to have prediction capability regarding the combined effect of these changes. Here perturbation theory, usually applied to eigenmodes with real eigenvalues, is formulated in the complex domain, in which the eigen-frequency imaginary part is related to the Q-factor. Normalizable leaky modes, and bi orthogonality in a finite volume are the basis for such a formulation. We introduce such capabilities by presenting semi-analytical expressions of first order perturbation analysis for a 3D cavity with radiation losses. The obtained results are in good agreement with numerical calculations. PMID- 20720976 TI - Generation of frequency-modulated sub-terahertz signal using microwave photonic technique. AB - We present a photonic technique for generating a frequency- modulated sub terahertz signal for non-destructive or noninvasive sensing and imaging applications. Large frequency deviation was achieved by using optical phase modulation and heterodyne photomixing with an uni-travelling photodetector. The operation principle is theoretically derived and explained. In addition, the generation of 350-GHz frequency- modulated sub-terahertz signal with 6.7-GHz frequency deviation is experimentally demonstrated, and the possibility of frequencies up to 1 THz and wider frequency deviations is discussed. PMID- 20720975 TI - Characterizing accuracy of total hemoglobin recovery using contrast-detail analysis in 3D image-guided near infrared spectroscopy with the boundary element method. AB - The quantification of total hemoglobin concentration (HbT) obtained from multi modality image-guided near infrared spectroscopy (IG-NIRS) was characterized using the boundary element method (BEM) for 3D image reconstruction. Multi modality IG-NIRS systems use a priori information to guide the reconstruction process. While this has been shown to improve resolution, the e(R)ect on quantitative accuracy is unclear. Here, through systematic contrast-detail analysis, the fidelity of IG-NIRS in quantifying HbT was examined using 3D simulations. These simulations show that HbT could be recovered for medium sized (20mm in 100mm total diameter) spherical inclusions with an average error of 15%, for the physiologically relevant situation of 2:1 or higher contrast between background and inclusion. Using partial 3D volume meshes to reduce the ill-posed nature of the image reconstruction, inclusions as small as 14 mm could be accurately quantified with less than 15% error, for contrasts of 1.5 or higher. This suggests that 3D IG-NIRS provides quantitatively accurate results for sizes seen early in treatment cycle of patients undergoing neoadjuvant chemotherapy when the tumors are larger than 30 mm. PMID- 20720977 TI - Highly efficient phosphorescent organic light-emitting diode with a nanometer thick Ni silicide/polycrystalline p-Si composite anode. AB - A phosphorescent organic light-emitting diode (PhOLED) with a nanometer-thick (approximately 10 nm) Ni silicide/ polycrystalline p-Si composite anode is reported. The structure of the PhOLED is Al mirror/ glass substrate / Si isolation layer / Ni silicide / polycrystalline p-Si/ V(2)O(5)/ NPB/ CBP: (ppy)(2)Ir(acac)/ Bphen/ Bphen: Cs(2)CO(3)/ Sm/ Au/ BCP. In the composite anode, the Ni-induced polycrystalline p-Si layer injects holes into the V(2)O(5)/ NPB, and the Ni silicide layer reduces the sheet resistance of the composite anode and thus the series resistance of the PhOLED. By adopting various measures for specially optimizing the thickness of the Ni layer, which induces Si crystallization and forms a Ni silicide layer of appropriate thickness, the highest external quantum efficiency and power conversion efficiency have been raised to 26% and 11%, respectively. PMID- 20720978 TI - Packet QoS level classifier based on optical binary priority comparison. AB - Next generation High-Speed optical packet switching networks require components capable of classifying incoming packet into the appropriate priority queue according to the service class of the packet. For the first time, we proposed an all-optical packet QoS (Quality of Service) level classifier employing a sequential binary packet priority comparator, which is implemented using the SOA based optical logic gates. The performance of the optical binary packet priority comparator was verified experimentally at 1 Gbit/s showing that the proposed scheme can operate higher data rates. These packet level classifier structures are attractive for all-optical network and applications. PMID- 20720979 TI - Thickness dependence of the terahertz response in (110)-oriented GaAs crystals for electro-optic sampling at 1.55 microm. AB - We experimentally study the thickness dependence of the terahertz (THz) response in {110}-oriented GaAs crystals for free space electro-optic sampling at 1.55 microm. The THz response bandwidths are analyzed and simulated under phase matching condition with a model frequency response function. The results indicate that the detection bandwidth increases from 2 THz to 3 THz when the thickness of GaAs is reduced from 2 mm to 1 mm. Below 1 mm, the detected bandwidth is increasingly limited by the emitter characteristics and the finite probe pulse duration. The broadest bandwidth in experiment reaches 3.3 THz when using a 0.2 mm thick crystal, while it exceeds 5 THz in theory. The THz response sensitivity was studied experimentally and modeled taking into account the absorption of the THz radiation in the GaAs crystal. While absorption was found to be negligible for the crystal thickness range studied here, strong saturation is predicted theoretically for crystal thicknesses exceeding 5 mm. PMID- 20720980 TI - Bowtie nano-aperture as interface between near-fields and a single-mode fiber. AB - We present the development and study of a single bowtie nano-aperture (BNA) at the end of a monomode optical fiber as an interface between near-fields/nano optical objects and the fiber mode. To optimize energy conversion between BNA and the single fiber mode, the BNA is opened at the apex of a specially designed polymer fiber tip which acts as an efficient mediator (like a horn optical antenna) between the two systems. As a first application, we propose to use our device as polarizing electric-field nanocollector for scanning near-field optical microscopy (SNOM). However, this BNA-on-fiber probe may also find applications in nanolithography, addressing and telecommunications as well as in situ biological and chemical probing and trapping. PMID- 20720981 TI - A practical nanofabrication method: surface plasmon polaritons interference lithography based on backside-exposure technique. AB - For the experiments of surface plasmon polaritons (SPPs) interference lithography based on attenuated total reflection-coupling mode to be done conveniently, we introduce a backside-exposure technique in this paper. The physical mechanisms of SPPs interference with the backside -exposure method are studied and the interference fringes with feature size below 65 nm are experimentally obtained. The technique can be used to fabricate nanostructures conveniently with large area, and avoids the difficulties for seeking high refractive prism and matching fluid. PMID- 20720982 TI - Spectrally resolved laser ranging with frequency combs. AB - The multiheterodyne beatnote between two frequency combs having pulses sliding one with respect to another is used to perform spectrally resolved ranging of diffuse reflectors at short distances. The sliding comb sources are generated using one mode-locked laser and a two-beam interferometer, but two properly controlled lasers could be used as well. A pseudo-random binary modulation of the pulses is used to increase the non-ambiguous range. Ranging with a spatial resolution of 21 cm and a spectral resolution of 10 cm(-1) over a 200 cm(-1) spectral range is demonstrated. PMID- 20720983 TI - Direct patterning in sub-surface of stainless steel using laser pulses. AB - This paper reports for the first time on the direct creating microcavities in sub surface of stainless steel using a single Nd:YAG laser pulse. The low peak power density is used in the process, which is in the order of 1 MW/cm(2). The formation of the microcavities in the sub-surface of stainless steel is an evidence of volume expulsion during laser-metal interaction. Direct patterning in the sub-surface of stainless steel is demonstrated by realizing a series of microcavities to form a pre-designed pattern. Potential applications of sub surface patterning in metal, such as security marking, micro-heater, micro insulator and micro-sensor, are discussed. PMID- 20720984 TI - X-ray phase contrast microscopy at 300 nm resolution with laboratory sources. AB - We report the performance of an X-ray phase contrast microscope for laboratory sources with 300 nm spatial resolution. The microscope is based on a commercial X ray microfocus source equipped with a planar X-ray waveguide able to produce a sub-micrometer x-ray beam in one dimension. Phase contrast images of representative samples are reported. The achieved contrast and resolution is discussed for different configurations. The proposed approach could represent a simple, inexpensive, solution for sub-micrometer resolution imaging with small laboratory setups. PMID- 20720985 TI - Nanostructure-enhanced laser tweezers for efficient trapping and alignment of particles. AB - We propose and demonstrate a purely optical approach to trap and align particles using the interaction of polarized light with periodic nanostructures to generate enhanced trapping force. With a weakly focused laser beam, we observed efficient trapping and transportation of polystyrene beads with sizes ranging from 10 mum down to 190 nm as well as cancer cell nuclei. In addition, alignment of non spherical dielectric particles to a 1-D periodic nanostructure was achieved with low laser intensity without attachment to birefringent crystals. Bacterial cells were trapped and aligned with incident optical intensity as low as 17 microW/microm(2). PMID- 20720986 TI - Parallel scanning-optical nanoscopy with optically confined probes. AB - We report the imaging of sub-diffraction limited features using an optical probe generated by focusing a round spot at one wavelength, lambda(1) = 405 nm, and a ring-shaped spot at a second wavelength, lambda(2) = 532 nm, onto a thin photochromic layer that coats the nanostructures. Illumination at lambda(2) turns the photochromic layer opaque to lambda(1) everywhere except at the centre of the ring, where the illumination at lambda(1) penetrates and probes the underlying nanostructure. We confirm that this optically confined probe increases image contrast and is able to resolve features smaller than the far-field diffraction limit. Furthermore, by using an array of dual-wavelength diffractive microlenses, we demonstrate the feasibility of parallelizing this approach. Compared to previous approaches, our technique is not limited to fluorescence imaging. PMID- 20720987 TI - Complex sub-laser-cycle electron dynamics in strong-field nonsequential triple ionization. AB - Using the full three-dimensional classical ensemble model, we have investigated nonsequential triple ionization (NSTI) of Ne by intense linearly polarized laser fields systematically. Trajectory back analysis enables us to identify the various NSTI channels at different intensities in an intuitive way. The momentum distributions of the triply ionized ions calculated by this model agree well with the experimental results over a wide range of laser intensities [J. Phys. B 41, 081006 (2008)]. With this classical model we achieve insight into the complex sub laser-cycle dynamics of the correlated three electrons in NSTI. PMID- 20720988 TI - Highly efficient Yb:YAG channel waveguide laser written with a femtosecond-laser. AB - Using a femtosecond Ti:Sapphire laser, micro-tracks of material damage were written into Yb:YAG crystals. Waveguiding was achieved in a channel between pairs of tracks with guiding losses of 1.3 dB/cm at a wavelength of 1063 nm, due to a stress induced change of the refractive index. Pumped at a wavelength of 941 nm, highly efficient laser oscillation in a Yb:YAG channel waveguide at a wavelength of 1030 nm was demonstrated. An output power of 0.8 W at 1.2 W of launched pump power was achieved, resulting in a record slope efficiency of 75%. PMID- 20720989 TI - Numerical methods for modeling photonic-crystal VCSELs. AB - We show comparison of four different numerical methods for simulating Photonic Crystal (PC) VCSELs. We present the theoretical basis behind each method and analyze the differences by studying a benchmark VCSEL structure, where the PC structure penetrates all VCSEL layers, the entire top-mirror DBR, a fraction of the top-mirror DBR or just the VCSEL cavity. The different models are evaluated by comparing the predicted resonance wavelengths and threshold gains for different hole diameters and pitches of the PC. The agreement between the models is relatively good, except for one model, which corresponds to the effective index method. The simulation results elucidate the strength and weaknesses of the analyzed methods; and outline the limits of applicability of the different models. PMID- 20720990 TI - Structural color in Myxomycetes. AB - In this paper we report evidence of structural color in Myxomycetes, a group of eukaryotic microorganisms with an uncertain taxonomic position. We investigated the Diachea leucopoda, which belongs to the Physarales order, Myxomycetes class, and found that its peridium -protective layer that encloses the mass of spores- is basically a corrugated layer of a transparent material, which produces a multicolored pointillistic effect, characteristic of this species. Scanning (SEM) and transmission (TEM) electron microscopy techniques have been employed to characterize the samples. A simple optical model of a planar slab is proposed to calculate the reflectance. The chromaticity coordinates are obtained, and the results confirm that the color observed is a result of an interference effect. PMID- 20720991 TI - Planar photonic crystal cavities with far-field optimization for high coupling efficiency and quality factor. AB - Different types of planar photonic crystal cavities aimed at optimizing the far field emission pattern are designed and experimentally assessed by resonant scattering measurements. We systematically investigate the interplay between achieving the highest possible quality (Q) factor and maximizing the in- and out coupling efficiency into a narrow emission cone. Cavities operate at telecommunications wavelengths, i.e. around approximately 1.55 microm, and are realized in silicon membranes. A strong modification of the far-field emission pattern, and therefore a substantial increase of the coupling efficiency in the vertical direction, is obtained by properly modifying the holes around L3, L5 and L7 type PhC cavities, as we predict theoretically and show experimentally. An optimal compromise yielding simultaneously a high Q-factor and a large coupling to the fundamental cavity mode is found for a L7-type cavity with a measured Q congruent with 62000, whose resonant scattering efficiency is improved by about two orders of magnitude with respect to the unmodified structure. These results are especially useful for prospective applications in light emitting devices, such as nano-lasers or single-photon sources, in which vertical in- and out coupling of the electromagnetic field is necessarily required. PMID- 20720992 TI - Performance analysis of the attenuation-partition based iterative phase retrieval algorithm for in-line phase-contrast imaging. AB - The phase retrieval is an important task in x-ray phase contrast imaging. The robustness of phase retrieval is especially important for potential medical imaging applications such as phase contrast mammography. Recently the authors developed an iterative phase retrieval algorithm, the attenuation-partition based algorithm, for the phase retrieval in inline phase-contrast imaging [1]. Applied to experimental images, the algorithm was proven to be fast and robust. However, a quantitative analysis of the performance of this new algorithm is desirable. In this work, we systematically compared the performance of this algorithm with other two widely used phase retrieval algorithms, namely the Gerchberg-Saxton (GS) algorithm and the Transport of Intensity Equation (TIE) algorithm. The systematical comparison is conducted by analyzing phase retrieval performances with a digital breast specimen model. We show that the proposed algorithm converges faster than the GS algorithm in the Fresnel diffraction regime, and is more robust against image noise than the TIE algorithm. These results suggest the significance of the proposed algorithm for future medical applications with the x ray phase contrast imaging technique. PMID- 20720993 TI - Fourier transform demodulation of pixelated phase-masked interferograms. AB - Recently a new type of spatial phase shifting interferometer was proposed that uses a phase-mask over the camera's pixels. This new interferometer allows one to phase modulate each pixel independently by setting the angle of a linear polarizer built in contact over the camera's CCD. In this way neighbor pixels may have any desired (however fixed) phase shift without cross taking. The standard manufacturing of these interferometers uses a 2x2 array with phase-shifts of 0, pi/2, pi, and 3 pi/2 radians. This 2x2 array is tiled all over the video camera's CCD. In this paper we propose a new way to phase demodulate these phase-masked interferograms using the squeezing phase-shifting technique. A notable advantage of this squeezing technique is that it allows one the use of Fourier interferometry wiping out the detuning error that most phase shifting algorithms suffers. Finally we suggest the use of an alternative phase-mask to phase modulate the camera's pixels using a linear spatial carrier along a given axis. PMID- 20720994 TI - Generation of 30-fs ultraviolet pulses by four-wave optical parametric chirped pulse amplification. AB - We report on the generation of approximately 30-fs ultraviolet pulses with approximately 10 microJ energy by means of four-wave optical parametric chirped pulse amplification in fused silica. The four-wave optical parametric amplifier is pumped by the second-harmonic of the Ti:sapphire laser and is seeded by visible broadband chirped signal pulses. The idler pulses are produced in the ultraviolet by four-wave mixing and are compressed in a medium with normal group velocity dispersion. PMID- 20720995 TI - Brillouin amplification in phase coherent transfer of optical frequencies over 480 km fiber. AB - We describe the use of fiber Brillouin amplification (FBA) for the coherent transmission of optical frequencies over a 480 km long optical fiber link. FBA uses the transmission fiber itself for efficient, bi-directional coherent amplification of weak signals with pump powers around 30 mW. In a test setup we measured the gain and the achievable signal-to-noise ratio (SNR) of FBA and compared it to that of the widely used uni-directional Erbium doped fiber amplifiers (EDFA) and to our recently built bi-directional EDFA. We measured also the phase noise introduced by the FBA and used a new and simple technique to stabilize the frequency of the FBA pump laser. We then transferred a stabilized laser frequency over a wide area network with a total fiber length of 480 km using only one intermediate FBA station. After compensating the noise induced by the fiber, the frequency is delivered to the user end with an uncertainty below 2 x 10(-18) and an instability sigma y(tau) = 2 x 10(-14) /(tau/s). PMID- 20720996 TI - Characterization of bending losses for curved plasmonic nanowire waveguides. AB - We characterize bending losses of curved plasmonic nanowire waveguides for radii of curvature ranging from 1 to 12 microm and widths down to 40 nm. We use near field measurements to separate bending losses from propagation losses. The attenuation due to bending loss is found to be as low as 0.1 microm(-1) for a curved waveguide with a width of 70 nm and a radius of curvature of 2 microm. Experimental results are supported by Finite Difference Time Domain simulations. An analytical model developed for dielectric waveguides is used to predict the trend of rising bending losses with decreasing radius of curvature in plasmonic nanowires. PMID- 20720997 TI - Light scattering, field localization and local density of states in co-axial plasmonic nanowires. AB - Based on analytical scattering theory, we develop a multipolar expansion method to investigate systematically the near-field enhancement, far-field scattering and Local Density of States (LDOS) spectra in concentric metal-insulator-metal (MIM) cylindrical nanostructures, or coaxial plasmonic nanowires (CPNs). We demonstrate that these structures support distinctive plasmonic resonances with strongly reduced scattering in the far-field zone and significant electric field enhancement in deep sub-wavelength dielectric regions. Additionally, we study systematically the effects of geometrical parameters and dielectric index on the near-field and far-field plasmonic response of CPNs in the visible and near infrared spectral range. Finally, we demonstrate that CPNs provide a convenient approach for engineering strong (almost three orders of magnitude) LDOS enhancement in sub-wavelength dielectric gaps at multiple frequencies. These results enable the engineering of multiband optical detectors and CPNs-based light emitters with simultaneously enhanced excitation and emission rates for nanoplasmonics. PMID- 20720998 TI - Micromachined lens microstages for two-dimensional forward optical scanning. AB - This work presents a novel approach for a miniaturized optical scanning module based on lateral and piston motion of two commercial lenses by MEMS actuation. Two aspheric glass lenses of 1 mm diameter are assembled on two electrostatically actuated microstages moving along perpendicular axes to tilt optical path. The compact integration secures the effective beam aperture of 0.6 mm within the device width of 2 mm. The lens mass provides high-Q motions at low operating voltages of DC 5 V and AC 10 V, i.e., the lateral angle of 4.6 degrees at 277 Hz and the vertical angle of 5.3 degrees at 204 Hz. The device can provide a new direction for miniaturizing laser scanning based endoscopes or handheld projectors. PMID- 20720999 TI - Wavelength-dependent transmission through sharp 90 degrees bends in sub wavelength metallic slot waveguides. AB - In this paper, we present a comprehensive numerical study of the wavelength dependence of transmission through sharp 90 degrees bends in metallic slot waveguides with sub-wavelength localization and varying geometrical parameters. In particular, it is demonstrated that increasing the plasmon wavelength results in a significant increase (up to nearly 100%) of transmission through the bend, combined with a reduction in the mode asymmetry in the second arm of the bend. The mode asymmetry and its relaxation are explained by interference of the transmitted mode with non-propagating and leaky modes generated at the bend. Comparison with the two-dimensional case of a metal-dielectric-metal waveguide is also conducted, showing significant differences for the slot waveguides based on the presence of different non-propagating and leaky modes. PMID- 20721000 TI - Subwavelength grating crossings for silicon wire waveguides. AB - We report on the design, simulation and experimental demonstration of a new type of waveguide crossing based on subwavelength gratings in silicon waveguides. We used 3D finite-difference time-domain simulations to minimize loss, crosstalk and polarization dependence. Measurement of fabricated devices show that our waveguide crossings have a loss as low as -0.023 dB/crossing, polarization dependent loss of < 0.02 dB and crosstalk <-40 dB. PMID- 20721001 TI - Enhanced fast light in microfiber ring resonator with a Sagnac loop reflector. AB - We fabricate a microfiber knot-type ring resonator with a Sagnac loop reflector, and control the light velocity using the device. In this structure, light is reflected by the Sagnac loop and passes through the ring resonator twice. Thus, it possesses doubled transmission and group delay comparing with the microfiber ring resonator without the Sagnac loop. We experimentally demonstrate pulse advancement in an under-coupled microfiber knot-type ring resonator with a Sagnac loop reflector. In the experiment, a maximum of approximately 25 ps pulse advancement was achieved for a 5-Gb/s RZ signal. PMID- 20721002 TI - 3D integration of photonic crystal devices: vertical coupling with a silicon waveguide. AB - Two integrated devices based on the vertical coupling between a photonic crystal microcavity and a silicon (Si) ridge waveguide are presented in this paper. When the resonator is coupled to a single waveguide, light can be spectrally extracted from the waveguide to free space through the far field emission of the resonator. When the resonator is vertically coupled to two waveguides, a vertical add-drop filter can be realized. The dropping efficiency of these devices relies on a careful design of the resonator. In this paper, we use a Fabry-Perot (FP) microcavity composed of two photonic crystal (PhC) slab mirrors. Thanks to the unique dispersion properties of slow Bloch modes (SBM) at the flat extreme of the dispersion curve, it is possible to design a FP cavity exhibiting two quasi degenerate modes. This specific configuration allows for a coupling efficiency that can theoretically achieve 100%. Using 3D FDTD calculations, we discuss the design of such devices and show that high dropping efficiency can be achieved between the Si waveguides and the PhC microcavity. PMID- 20721003 TI - Coherent optical spectroscopy of a hybrid nanocrystal complex embedded in a nanomechanical resonator. AB - We have theoretically investigated a hybrid nanocrystal complex consisted of a metal nanoparticle (MNP) and a semiconductor quantum dot (SQD) embedded in a nanomechanical resonator in the simultaneous presence of a strong control field and a weak probe field. It is shown that the resonance amplification peak of the probe spectrum will enhance dramatically due to the coupling of the plasmon, exciton and nanomechanical resonator. The enhancement increases significantly with decreasing the distance between the metal nanoparticle and a quantum dot, which implies the strong plasmon enhancement effect in this coupled system. The results obtained here may have the potential applications such as tunable Raman lasers and bio-sensors. PMID- 20721004 TI - Spectral phase transfer to ultrashort UV pulses through four-wave mixing. AB - Transfer of spectral phase from near infrared ultrashort pulses to deep ultraviolet (UV) sub-30-fs pulses through four-wave mixing process is demonstrated. Micro joule UV pulses at 237 nm were generated by nonlinear mixing of second harmonic pulses of Ti:sapphire laser output and near infrared pulses from a noncollinear optical parametric amplifier. Chirp of the near infrared pulse was transferred to the UV pulse with the opposite sign. A positively chirped near infrared pulse was used for generating a negatively chirped UV pulse, which was compressed down to 25 fs by a magnesium fluoride window. PMID- 20721005 TI - High power red and near-IR generation using four wave mixing in all integrated fibre laser systems. AB - We demonstrate high power generation of visible red and near IR light by four wave mixing in photonic crystal fibres (PCFs) pumped at 1064 nm with picosecond pulses (30 - 80 ps). 30% conversion efficiency is demonstrated in a single pass using fibre lengths less than 1 m, with signal wavelengths from 650 nm to 820 nm selectable by choice of PCF. An all fibre integrated system delivers 2.16 W at 740 nm with a pulse repetition frequency of 20 MHz. We discuss the overall parameter space for this type of wavelength conversion in PCF with different fibre designs suitable for delivering a particular wavelength at low or high power. PMID- 20721006 TI - Quantum-correlated photon pair generation in chalcogenide As2S3 waveguides. AB - We theoretically investigate the generation of quantum-correlated photon pairs through spontaneous four-wave mixing in chalcogenide As(2)S(3) waveguides. For reasonable pump power levels, we show that such photonic-chip-based photon-pair sources can exhibit high brightness (approximately 1 x 10(9) pairs/s) and high correlation (approximately 100) if the waveguide length is chosen properly or the waveguide dispersion is engineered. Such a high correlation is possible in the presence of Raman scattering because the Raman profile exhibits a low gain window at a Stokes shift of 7.4 THz, though it is constrained due to multi-pair generation. As the proposed scheme is based on photonic chip technologies, it has the potential to become an integrated platform for the implementation of on-chip quantum technologies. PMID- 20721007 TI - High index contrast polymer waveguide platform for integrated biophotonics. AB - We present detailed characterization of a unique high-index-contrast integrated optical polymer waveguide platform where the index of the cladding material is closely matched to that of water. Single-mode waveguides designed to operate across a large part of the visible spectrum have been fabricated and waveguide properties, including mode size, bend loss and evanescent coupling have been modeled using effective-index approximation, finite-element and finite-difference time domain methods. Integrated components such as directional couplers for wavelength splitting and ring resonators for refractive-index or temperature sensing have been modeled, fabricated and characterized. The waveguide platform described here is applicable to a wide range of biophotonic applications relying on evanescent-wave sensing or excitation, offering a high level of integration and functionality. The technology is biocompatible and suitable for wafer-level mass production. PMID- 20721008 TI - Highly flexible polymeric optical waveguide for out-of-plane optical interconnects. AB - In this paper, we reported high speed optical test on polymeric optical waveguide array with embedded 45 masculine micro-mirrors on flexible substrate for out-of plane optical interconnects. The waveguide array was bent with curvature ranging from 61 mm to 5mm. As the bending radius decreases, the average insertion loss increases from 3.4 dB to 7.7 dB for single-mode fiber (SMF) coupling and from 5.5 dB to 7.9 dB for multi-mode fiber (MMF) coupling, respectively. Eye-diagrams under such bending conditions show that the Q factor decreases from 8.0 to 6.1 and the calculated bit error rate (BER) increases from 10(-16) to 10(-10) at 10 Gbps. PMID- 20721009 TI - High-resolution, high-reflectivity operation of lamellar multilayer amplitude gratings: identification of the single-order regime. AB - High resolution while maintaining high peak reflectivities can be achieved for Lamellar Multilayer Amplitude Gratings (LMAG) in the soft-x-ray (SXR) region. Using the coupled waves approach (CWA), it is derived that for small lamellar widths only the zeroth diffraction order needs to be considered for LMAG performance calculations, referred to as the single-order regime. In this regime, LMAG performance can be calculated by assuming a conventional multilayer mirror with decreased density, which significantly simplifies the calculations. Novel analytic criteria for the design of LMAGs are derived from the CWA and it is shown, for the first time, that the resolution of an LMAG operating in the single order regime is not limited by absorption as in conventional multilayer mirrors. It is also shown that the peak reflectivity of an LMAG can then still be as high as that of a conventional multilayer mirror (MM). The performance of LMAGs operating in the single-order regime are thus only limited by technological factors. PMID- 20721010 TI - Chromatic dispersion compensation in coherent transmission system using digital filters. AB - We present a comparative analysis of three popular digital filters for chromatic dispersion compensation: a time-domain least mean square adaptive filter, a time domain fiber dispersion finite impulse response filter, and a frequency-domain blind look-up filter. The filters are applied to equalize the chromatic dispersion in a 112-Gbit/s non-return-to-zero polarization division multiplexed quadrature phase shift keying transmission system. The characteristics of these filters are compared by evaluating their applicability for different fiber lengths, their usability for dispersion perturbations, and their computational complexity. In addition, the phase noise tolerance of these filters is also analyzed. PMID- 20721011 TI - Optical channel waveguides in Nd:LGS laser crystals produced by proton implantation. AB - Optical channel waveguides have been produced for the first time in Nd:LGS multi functional laser crystals by using proton implantation. The obtained good guiding performance exhibits the well-confined modal fields in the waveguiding structures. The confocal fluorescence images of the obtained waveguides have revealed that the photoluminescence properties of the Nd(3+) ions have been well preserved in the waveguide's active volume, which suggests promising applications as multi-functional integrated laser generation elements. These images have been also used to elucidate the spatial distribution of lattice damage and distortion caused by the implantation process, which are both mainly located at the nuclear collision region. PMID- 20721012 TI - Terahertz inverse synthetic aperture radar (ISAR) imaging with a quantum cascade laser transmitter. AB - A coherent transceiver using a THz quantum cascade (TQCL) laser as the transmitter and an optically pumped molecular laser as the local oscillator has been used, with a pair of Schottky diode mixers in the receiver and reference channels, to acquire high-resolution images of fully illuminated targets, including scale models and concealed objects. Phase stability of the received signal, sufficient to allow coherent image processing of the rotating target (in azimuth and elevation), was obtained by frequency-locking the TQCL to the free running, highly stable optically pumped molecular laser. While the range to the target was limited by the available TQCL power (several hundred microwatts) and reasonably strong indoor atmospheric attenuation at 2.408 THz, the coherence length of the TQCL transmitter will allow coherent imaging over distances up to several hundred meters. Image data obtained with the system is presented. PMID- 20721013 TI - Impact of phase to amplitude noise conversion in coherent optical systems with digital dispersion compensation. AB - The impact of phase to amplitude noise conversion for QPSK, 16-QAM, and 64-QAM coherent optical systems are investigated with electronically-compensated chromatic dispersion (CD). The electronic equalizer is shown to convert the phase noise from the local oscillator (LO) to amplitude noise, limiting the amount of CD that can ideally be compensated digitally. The simulation results demonstrate that the performance of coherent systems can significantly be degraded with digitally compensated CD and LO phase noise. The maximum tolerable LO linewidth is also investigated for the different modulation formats and found to become increasingly stringent for longer transmission distance and higher symbol rate. PMID- 20721014 TI - Ultra-large multi-region photon sieves. AB - A novel method of designing ultra-large photon sieves in visible regime with multi-region structure is proposed and experimentally demonstrated. Design principle that is based on both phase matching and total pinhole area matching among regions is introduced. The focusing properties of the multi-region structure and the conventional monolithic structure of the same numerical aperture in terms of energy efficiency and the sidelobe suppression are compared. Two photon sieves of focal length 500 mm and diameters 50mm and 125 mm with respectively 3 and 4 regions at working wavelength 632.8 nm are fabricated using UV lithography to validate the proposed method. Good performance of the multi region photon sieves are evaluated by imaging test. The extension of the proposed method suggests a new concept of ring-to-ring design in terms of pinhole size and density of each individual ring for photon sieves with superior suppressed sidelobes towards ultra-large dimension, high numerical aperture that can be implemented with UV lithography which is otherwise impossible with e-beam technique. PMID- 20721015 TI - Time-resolved diffusing wave spectroscopy with a CCD camera. AB - We show how time-resolved measurements of the diffuse light transmitted through a thick scattering slab can be performed with a standard CCD camera, thanks to an interferometric protocol. Time-resolved correlations measured at a fixed photon transit time are also presented. The high number of pixels of the camera allows us to attain a quite good sensitivity for a reasonably low acquisition time. PMID- 20721016 TI - Anomalous refractive effects in honeycomb lattice photonic crystals formed by holographic lithography. AB - We have investigated for the first time the anomalous refractive effects of a photonic crystal (PhC) formed by holographic lithography (HL) with triangular rods arranged in a honeycomb lattice in air. Possibilities of left-handed negative refraction and superlens are discussed for the case of TM2 band with the index contrast n = 3.4:1. In contrast to the conventional honeycomb PhC made of regular rods in air, the HL PhCs show left-handed negative refraction over a wider and higher frequency range with high transmissivity (>90%), and the effective indices quite close to -1 for a wide range of incident angles with a larger all-angle left-handed negative refraction (AALNR) frequency range (Deltaomega/omega approximately 14.8%). Calculations and FDTD simulations demonstrate the high-performance negative refraction properties can happen in the holographic structures for a wide filling ratio and can be modulated by changing the filling ratio easily. PMID- 20721017 TI - Improvement of delay-bandwidth product in photonic crystal slow-light waveguides. AB - We report new results about the improvement of delay-bandwidth product in photonic crystal slow light waveguides. Previous studies have obtained large delay-bandwidth product at the price of small average group index. It is pointed out here that the radius and the distance between the two boundary rows of holes have a key contribution for delay-bandwidth product. We show the possibility of improving this factor of merit meanwhile maintaining the same group index. We succeed in improving normal delay-bandwidth product from 0.15 to 0.35, keeping at the same time the group index unchanged at high value of 90. This optimization approach may be applicable for previous flat band slow light devices. PMID- 20721018 TI - Diode-pumped gigahertz femtosecond Yb:KGW laser with a peak power of 3.9 kW. AB - We present a diode-pumped Yb:KGW laser with a repetition rate of 1 GHz and a pulse duration of 281 fs at a wavelength of 1041 nm. A high brightness distributed Bragg reflector tapered diode laser is used as a pump source. Stable soliton modelocking is achieved with a semiconductor saturable absorber mirror (SESAM). The obtained average output power is 1.1 W and corresponds to a peak power of 3.9 kW and a pulse energy of 1.1 nJ. With harmonic modelocking we could increase the pulse repetition rate up to 4 GHz with an average power of 900 mW and a pulse duration of 290 fs. This Yb:KGW laser has a high potential for stable frequency comb generation. PMID- 20721019 TI - Optical gain, spontaneous and stimulated emission of surface plasmon polaritons in confined plasmonic waveguide. AB - We develop a theoretical model to compute the local density of states in a confined plasmonic waveguide. Based on this model, we derive a simple formula with a clear physical interpretation for the lifetime modification of emitters embedded in the waveguide. The gain distribution within the active medium is then computed following the formalism developed in a recent work [Phys. Rev. B 78, 161401 (2008)], by taking rigorously into account the pump irradiance and emitters lifetime modifications in the system. We finally apply this formalism to describe gain-assisted propagation in a dielectric-loaded surface plasmon polariton waveguide. PMID- 20721020 TI - Silver square nanospirals mimic optical properties of U-shaped metamaterials. AB - We present a study of the optical properties of three-armed square nanospirals made of silver and realized as nanostructured thin films with Glancing Angle Deposition. Calculation of current flows in the nanospirals show excited resonant modes resembling those observed in U-shaped resonators. Four principal resonances were determined: near 200 THz and 480 THz for one polarization and 250 THz and 650 THz for the polarization orthogonal to the first one. In particular, a mode with anti-parallel current flow in opposite arms, associated with the observed resonance near 650 THz, indicates the existence of a magnetic-like resonance in the square nanospiral arrays. The robustness of the resonances against variations in the structural parameters of the nanospirals was investigated. This study revealed that the main parameter driving the position of the resonances was the overall dimension of the nanospiral, directly related to the length of their arms. Optical properties of a sample were measured by generalized spectroscopic ellipsometry at near-normal incidence, and evidence conversion between polarization states even for light polarized in the plane containing one of the arms in agreement with the numerical study. The measurements compared favorably to the results of the numerical simulations taking into account the disorder in the sample. PMID- 20721021 TI - 167 W, power scalable ytterbium-doped photonic bandgap fiber amplifier at 1178 nm. AB - An ytterbium-doped photonic bandgap fiber amplifier operating at the long wavelength edge of the ytterbium gain band is investigated for high power amplification. The spectral filtering effect of the photonic bandgap efficiently suppresses amplified spontaneous emission at the conventional ytterbium gain wavelengths and thus enables high power amplification at 1178 nm. A record output power of 167 W, a slope efficiency of 61% and 15 dB saturated gain at 1178 nm have been demonstrated using the ytterbium-doped photonic bandgap fiber. PMID- 20721022 TI - Geometry-dependent terahertz emission of silicon nanowires. AB - THz emission was observed from the vertically aligned silicon nanowire (Si NW) arrays, upon the excitation using a fs Ti-sapphire laser pulse (800 nm). The Si NWs (length = 0.3 approximately 9 microm) were synthesized by the chemical etching of n-type silicon substrates. The THz emission exhibits significant length dependence; the intensity increases sharply up to a length of 3 mum and then almost saturates. Their efficient THz emission is attributed to strong local field enhancement by coherent surface plasmons, with distinctive geometry dependence. PMID- 20721023 TI - Thermoreflectance characterization of beta-Ga2O3 thin-film nanostrips. AB - Nanostructure of beta-Ga(2)O(3) is wide-band-gap material with white-light emission function because of its abundance in gap states. In this study, the gap states and near-band-edge transitions in beta-Ga(2)O(3) nanostrips have been characterized using temperature-dependent thermoreflectance (TR) measurements in the temperature range between 30 and 320 K. Photoluminescence (PL) measurements were carried to identify the gap-state transitions in the beta-Ga(2)O(3) nanostrips. Experimental analysis of the TR spectra revealed that the direct gap (E(0)) of beta-Ga(2)O(3) is 4.656 eV at 300 K. There are a lot of gap-state and near-band-edge (GSNBE) transitions denoted as E(D3), E(W1), E(W2), E(W3), E(D2), EDBex, E(DB), E(D1), E(0), and E(0)' can be detected in the TR and PL spectra at 30 K. Transition origins for the GSNBE features in the beta-Ga(2)O(3) nanostrips are respectively evaluated. Temperature dependences of transition energies of the GSNBE transitions in the beta-Ga(2)O(3) nanostrips are analyzed. The probable band scheme for the GSNBE transitions in the beta-Ga(2)O(3) nanostrips is constructed. PMID- 20721024 TI - Bandwidth enhancement of injection-locked distributed reflector lasers with wirelike active regions. AB - The modulation bandwidth enhancement of distributed reflector (DR) lasers with wirelike active regions utilizing optical injection locking is demonstrated both theoretically and experimentally. By the rate equation analysis, it is shown that DR lasers with wirelike active regions realize a low optical injection power and a large bandwidth enhancement under small operation currents. Experimentally, the small-signal bandwidth is increased to >15 GHz at a bias current of 5 mA, which is 4 times smaller than that for conventional edge-emitting lasers. A large signal modulation at 10 Gbps is also performed at the same bias current of 5 mA and voltage swing of 0.4 V(pp), and error-free detection was confirmed under the low-power conditions. PMID- 20721025 TI - Surface plasmon resonance enhanced photoconductivity in Cu nanoparticle films. AB - We describe an all-electrical plasmon detection based on the near field coupling between plasmons and percolating electrons. It is the technique to electrically detect the local field enhancement from randomly distributed Cu nanoparticles coupled to a plasmon resonance. In addition, we revealed that plasmon-sensitivity is maximized at the percolation threshold, the minimum Cu particle surface coverage which can make the percolation path through the particles. Our detectors have a simple structure for easy fabrication and a high level of sensitivity to plasmon resonance. PMID- 20721026 TI - Diffractive phase-shift lithography photomask operating in proximity printing mode. AB - A phase shift proximity printing lithographic mask is designed, manufactured and tested. Its design is based on a Fresnel computer-generated hologram, employing the scalar diffraction theory. The obtained amplitude and phase distributions were mapped into discrete levels. In addition, a coding scheme using sub-cells structure was employed in order to increase the number of discrete levels, thus increasing the degree of freedom in the resulting mask. The mask is fabricated on a fused silica substrate and an amorphous hydrogenated carbon (a:C-H) thin film which act as amplitude modulation agent. The lithographic image is projected onto a resist coated silicon wafer, placed at a distance of 50 microm behind the mask. The results show a improvement of the achieved resolution--linewidth as good as 1.5 microm--what is impossible to obtain with traditional binary masks in proximity printing mode. Such achieved dimensions can be used in the fabrication of MEMS and MOEMS devices. These results are obtained with a UV laser but also with a small arc lamp light source exploring the partial coherence of this source. PMID- 20721027 TI - Inhibition of the two-photon absorption response exhibited by a bilayer TiO2 film with embedded Au nanoparticles. AB - We use two different synthesis approaches for the preparation of TiO(2) films in order to study their resulting third order optical nonlinearity, and its modification by the inclusion of Au nanoparticles in one of the samples. An ultrasonic spray pyrolysis method was used for preparing a TiO(2) film in which we found two-photon absorption as a dominant nonlinear effect for 532 nm and 26 ps pulses; and a purely electronic nonlinearity at 830 nm for 80 fs pulses. A strong optical Kerr effect and the inhibition of the nonlinear optical absorption in 532 nm can be obtained for the first sample if Au nanoparticles embedded in a second TiO(2) film prepared by a sol-gel technique are added to it. We used an optical Kerr gate, z-scan, a multi-wave mixing experiment and an input-output transmittance experiment for measuring the optical nonlinearities. PMID- 20721028 TI - Numerical implementation of a VCSEL-based stochastic logic gate via polarization bistability. AB - We study the interplay of polarization bistability, spontaneous emission noise and aperiodic current modulation in vertical cavity surface emitting lasers (VCSELs). We demonstrate the phenomenon of logic stochastic resonance (LSR), by which the laser gives robust and reliable logic response to two logic inputs encoded in an aperiodic signal directly modulating the laser bias current. The probability of a correct response is controlled by the noise strength, and is equal to 1 in a wide region of noise strengths. LSR is associated with optimal noise-activated polarization switchings (the so-called "inter-well" dynamics if one considers the VCSEL as a bistable system described by a double-well potential) and optimal sensitivity to spontaneous emission in each polarization (the "intra-well" dynamics in the double-well potential picture). The robust nature of LSR in VCSELs offers interesting perspectives for novel applications and provides yet another example of a driven nonlinear optical system where noise can be employed constructively. PMID- 20721029 TI - Frequency-agile THz-wave generation and detection system using nonlinear frequency conversion at room temperature. AB - A surface-emitting THz parametric oscillator is set up to generate a narrow linewidth, nanosecond pulsed THz-wave radiation. The THz-wave radiation is coherently detected using the frequency up-conversion in MgO: LiNbO(3) crystal. Fast frequency tuning and automatic achromatic THz-wave detection are achieved through a special optical design, including a variable-angle mirror and 1:1 telescope devices in the pump and THz-wave beams. We demonstrate a frequency agile THz-wave parametric generation and THz-wave coherent detection system. This system can be used as a frequency-domain THz-wave spectrometer operated at room temperature, and there are a high possible to develop into a real-time two dimensional THz spectral imaging system. PMID- 20721030 TI - Emission properties of electrically pumped triangular shaped microlasers. AB - We study the emission properties of electrically pumped triangular-shaped microlasers with rounded corners. We find no signs of directional emission for the relatively large cavities (dimension approximately 100 microm) used in our experiments, in full agreement with ray simulation results. The broad emission characteristics that we observe can be fine-tuned by adjusting the resonator geometry as is verified through simulations which might prove useful for applications in optical devices. PMID- 20721031 TI - Enhancing and redirecting carbon nanotube photoluminescence by an optical antenna. AB - We observe the angular radiation pattern of single carbon nanotubes' photoluminescence in the back focal plane of a microscope objective and show that the emitting nanotube can be described by a single in-plane point dipole. The near-field interaction between a nanotube and an optical antenna modifies the radiation pattern that is now dominated by the antenna characteristics. We quantify the antenna induced excitation and radiation enhancement and show that the radiative rate enhancement is connected to a directional redistribution of the emission. PMID- 20721032 TI - Giant nonlinear response of terahertz nanoresonators on VO2 thin film. AB - We report on an order of magnitude enhanced nonlinear response of vanadium dioxide thin film patterned with nanoresonators--nano slot antennas fabricated on the gold film. Transmission of terahertz radiation, little affected by an optical pumping for the case of bulk thin film, can now be completely switched-off: DeltaT/T approximately -0.9999 by the same optical pumping power. This unprecedentedly large optical pump-terahertz probe nonlinearity originates from the insulator-to-metal phase transition drastically reducing the antenna cross sections of the nanoresonators. Our scheme enables nanoscale-thin film technology to be used for all-optical switching of long wavelength light. PMID- 20721034 TI - High-sensitivity 10 Gbps Ge-on-Si photoreceiver operating at lambda approximately 1.55 microm. AB - We present a high-sensitivity photoreceiver based on a vertical- illumination type 100% Ge-on-Si photodetector. The fabricated p-i-n photodetector with a 90 microm-diameter mesa shows the -3 dB bandwidth of 7.7 GHz, and the responsivity of 0.9 A/W at lambda approximately 1.55 microm, corresponding to the external quantum efficiency of 72%. A TO-can packaged Ge photoreceiver exhibits the sensitivity of -18.5 dBm for a BER of 10(-12) at data rate of 10 Gbps. This result proves the capability of a cost-effective 100% Ge-on-Si photoreceiver which can readily replace the III-V counterparts for optical communications. PMID- 20721033 TI - Laser absorption spectroscopy of water vapor confined in nanoporous alumina: wall collision line broadening and gas diffusion dynamics. AB - We demonstrate high-resolution tunable diode laser absorption spectroscopy (TDLAS) of water vapor confined in nanoporous alumina. Strong multiple light scattering results in long photon pathlengths (1 m through a 6 mm sample). We report on strong line broadening due to frequent wall collisions (gas-surface interactions). For the water vapor line at 935.685 nm, the HWHM of confined molecules are about 4.3 GHz as compared to 2.9 GHz for free molecules (atmospheric pressure). Gas diffusion is also investigated, and in contrast to molecular oxygen (that moves rapidly in and out of the alumina), the exchange of water vapor is found very slow. PMID- 20721035 TI - Generation of continuously tunable fractional optical orbital angular momentum using internal conical diffraction. AB - When a left-circularly polarised Gaussian light beam, which has spin angular momentum (SAM) J(sp) = sigmah = 1h per photon, is incident along one of the optic axes of a slab of biaxial crystal it undergoes internal conical diffraction and propagates as a hollow cone of light in the crystal. The emergent beam is a superposition of equal amplitude zero and first order Bessel like beams. The zero order beam is left-circularly polarised with zero orbital angular momentum (OAM) J(orb) = [see text]h = 0, while the first order beam is right-circularly polarized but carries OAM of J(orb) = 1h per photon. Thus, taken together the two beams have zero SAM and J(orb) = (1/2)h per photon. In this paper we examine internal conical diffraction of an elliptically polarised beam, which has fractional SAM, and demonstrate an all-optical process for the generation light beams with fractional OAM up to +/- 1h. PMID- 20721036 TI - Transflective display using a polymer-stabilized blue-phase liquid crystal. AB - A wide view, submillisecond response, and single-cell-gap transflective display using a blue-phase liquid crystal (BPLC) is proposed. To balance the optical phase retardation between transmissive (T) and reflective (R) regions, in-plane protrusion electrodes are formed with different gaps in the two regions. This display exhibits reasonably high optical efficiency and well matched voltage dependent transmittance and reflectance curves. Using biaxial films and broadband wide-view circular polarizers, the viewing angle with 100:1 contrast ratio is obtained over the entire viewing cone in the T region, and 10:1 over 50 degrees in the R region. The potential application is emphasized. PMID- 20721037 TI - Optical switching of near infrared light transmission in metamaterial-liquid crystal cell structure. AB - A metamaterial-liquid crystal cell structure is fabricated with the metamaterial as one of the liquid crystal alignment layers. Nano-sized double-split ring resonator in the metamaterial accommodates two distinct resonances in the near infrared regime. By adopting an azo-nematic liquid crystal in a twisted nematic liquid crystal cell structure, a photo-isomerization process is utilized to achieve an optical switching of light transmissions between two resonances. A single device of the metamaterial-liquid crystal cell structure has a potential application in the photonic switching in optical fiber telecommunications. PMID- 20721038 TI - Pixel level optical-transfer-function design based on the surface-wave interferometry aperture. AB - The design of optical transfer function (OTF) is of significant importance for optical information processing in various imaging and vision systems. Typically, OTF design relies on sophisticated bulk optical arrangement in the light path of the optical systems. In this letter, we demonstrate a surface-wave-interferometry aperture (SWIA) that can be directly incorporated onto optical sensors to accomplish OTF design on the pixel level. The whole aperture design is based on the bull's eye structure. It composes of a central hole (diameter of 300 nm) and periodic groove (period of 560 nm) on a 340 nm thick gold layer. We show, with both simulation and experiment, that different types of optical transfer functions (notch, highpass and lowpass filter) can be achieved by manipulating the interference between the direct transmission of the central hole and the surface wave (SW) component induced from the periodic groove. Pixel level OTF design provides a low-cost, ultra robust, highly compact method for numerous applications such as optofluidic microscopy, wavefront detection, darkfield imaging, and computational photography. PMID- 20721039 TI - Nanoparticle-doped polyimide for controlling the pretilt angle of liquid crystals devices. AB - The pretilt angles of liquid crystal molecules can be controlled by using conventional polyimide (PI) alignment material doped with different concentrations of Polyhedral Oligomeric Silsequioxanes (POSS) nanoparticles, which have been observed to spontaneously induce vertical alignment. The addition of POSS in the homogenous PI changes the surface energy of the alignment layer and generates a variable pretilt angle. Experimental results demonstrate that the pretilt angle thetap is a function of the POSS concentration, and can be tuned continuously over the range of 0 degrees 10(8) with a small mode volume V. The resulting Q(2)/V-ratio is among the highest realized for optical microresonators and allows us to observe bistable behavior at very low powers. We report single-wavelength all-optical switching via the Kerr effect at a record-low threshold of 50 microW. Moreover, an advantageous mode geometry enables the coupling of two tapered fiber waveguides to a bottle mode in an add drop configuration. This allows us to route a CW optical signal between both fiber outputs with high efficiency by varying its power level. Finally, we demonstrate that the same set-up can also be operated as an optical memory. PMID- 20721165 TI - Liquid-crystal micropolarimeter array for full Stokes polarization imaging in visible spectrum. AB - In this paper, we describe the design, modeling, fabrication, and optical characterization of the first micropolarimeter array enabling full Stokes polarization imaging in visible spectrum. The proposed micropolarimeter is fabricated by patterning a liquid-crystal (LC) layer on top of a visible-regime metal-wire-grid polarizer (MWGP) using ultraviolet sensitive sulfonic-dye-1 as the LC photoalignment material. This arrangement enables the formation of either micrometer-scale LC polarization rotators, neutral density filters or quarter wavelength retarders. These elements are in turn exploited to acquire all components of the Stokes vector, which describes all possible polarization states of light. Reported major principal transmittance of 75% and extinction ratio of 1100 demonstrate that the MWGP's superior optical characteristics are retained. The proposed liquidcrystal micropolarimeter array can be integrated on top of a complementary metal-oxide-semiconductor (CMOS) image sensor for real-time full Stokes polarization imaging. PMID- 20721166 TI - Interferometric characterization of a sub-wavelength near-infrared negative index metamaterial. AB - Negative phase advance through a single layer of near-IR negative index metamaterial (NIM) is identified through interferometric measurements. The NIM unit cell, sub-wavelength in both the lateral and light propagation directions, is comprised of a pair of Au strips separated by two dielectric and one Au film. Numerical simulations show that the negative phase advance through the single layer sample is consistent with the negative index exhibited by a bulk material comprised of multiple layers of the same structure. We also numerically demonstrate that the negative index band persists in the lossless limit. PMID- 20721167 TI - Dynamics of a paired optical vortex generated by second-harmonic generation. AB - We study the dynamics of a paired optical vortex (OV) generated by second harmonic generation (SHG) using sub-picosecond pulses. By changing the position of a thin nonlinear crystal along the propagation direction, we observe a rotation of two vortices with changing separation distance. The dynamics is well explained by SHG with a beam walk-off, which introduces a contamination of zero order Laguerre-Gaussian beam (LG(0)) together with topological charge doubling. The quantitative analysis indicates that the rotation angle of the OVs manifests the Gouy phase while the splitting provides the walk-off angle of the crystal. We also show that the subtraction of LG(0) is realized by the superposition of LG(0) with an anti-balanced phase in the pump. PMID- 20721168 TI - Particle-swarm-optimization-assisted rate equation modeling of the two-peak emission behavior of non-stoichiometric CaAl(x)Si((7-3x)/4)N3:Eu2+ phosphors. AB - We examined non-stoichiometric CaAl(x)Si((7-3x)/4)N(3):Eu(2+) phosphors that were intentionally prepared with x = 0.7-1.3 to identify the origin of the deconvoluted Gaussian components that constitute the emission spectra of stoichiometric CaAlSiN(3):Eu(2+) phosphors. The Al/Si molar ratio around the Eu(2+) activator caused the deconvoluted Gaussian peaks. The Eu(2+) activator sites in Al-rich environments gave rise to the lower-energy emission peak, while those in Si-rich environments were related to the higher-energy emission peaks. Active energy transfer from the Eu(2+) activator site in the Si-rich environment to the Eu(2+) activator site in the Al-rich environment was confirmed. Particle swarm optimization was employed to estimate the nine unknown decision parameters that control the energy transfer process. All of the decision parameters were estimated within the range of reasonable values. PMID- 20721169 TI - Tensor factorization for model-free space-variant blind deconvolution of the single- and multi-frame multi-spectral image. AB - The higher order orthogonal iteration (HOOI) is used for a single-frame and multi frame space-variant blind deconvolution (BD) performed by factorization of the tensor of blurred multi-spectral image (MSI). This is achieved by conversion of BD into blind source separation (BSS), whereupon sources represent the original image and its spatial derivatives. The HOOI-based factorization enables an essentially unique solution of the related BSS problem with orthogonality constraints imposed on factors and the core tensor of the Tucker3 model of the image tensor. In contrast, the matrix factorization-based unique solution of the same BSS problem demands sources to be statistically independent or sparse which is not true. The consequence of such an approach to BD is that it virtually does not require a priori information about the possibly space-variant point spread function (PSF): neither its model nor size of its support. For the space-variant BD problem, MSI is divided into blocks whereupon the PSF is assumed to be a space invariant within the blocks. The success of proposed concept is demonstrated in experimentally degraded images: defocused single-frame gray scale and red-green blue (RGB) images, single-frame gray scale and RGB images blurred by atmospheric turbulence, and a single-frame RGB image blurred by a grating (photon sieve). A comparable or better performance is demonstrated in relation to the blind Richardson-Lucy algorithm which, however, requires a priori information about parametric model of the blur. PMID- 20721170 TI - Highly sensitive bending sensor based on Er3+-doped DBR fiber laser. AB - A short cavity Er(3+)-doped distributed-Bragg-reflector (DBR) fiber laser with a low polarization beat frequency has been demonstrated for bending measurement. The polarization beat frequency of the DBR laser is extremely sensitive to bending and can measure curvature changes as small as 1.8 x 10(-2) m(-1). Excellent agreement between experimental and theoretical results was obtained for bending curvatures from 0 m(-1) to 58.8 m(-1) with corresponding changes in beat frequency from 18.6 MHz to 253 MHz. The sensor is insensitive to temperature fluctuations and has a temperature coefficient of the beat frequency of -25.4 kHz/degrees C, making the temperature compensation unnecessary in most practical applications. The very low beat frequency of the DBR fiber laser makes frequency down-conversion unnecessary. This can greatly simplify the demodulation scheme and thus, allow the realization of low-cost but highly sensitive optical bending sensor systems. PMID- 20721172 TI - Electrically tunable photonic true-time-delay line. AB - We present a new application of the acousto-optic superlattice modulation of a fiber Bragg grating based on the dynamic phase and group delay properties of this fiber-optic component. We demonstrate a tunable photonic true-time-delay line based on the group delay change of the light reflected from the grating sidebands. The delay is electrically tuned by adjusting the voltage applied to a piezoelectric transducer that generates the acoustic wave propagating along the grating. In our experiments, a true-time delay of 400 ps is continuously adjusted (300 ps within the 3 dB amplitude range of the first sideband), using a 12 cm long uniform grating. PMID- 20721171 TI - Design of an integrated hardware interface for AOSLO image capture and cone targeted stimulus delivery. AB - We demonstrate an integrated FPGA solution to project highly stabilized, aberration-corrected stimuli directly onto the retina by means of real-time retinal image motion signals in combination with high speed modulation of a scanning laser. By reducing the latency between target location prediction and stimulus delivery, the stimulus location accuracy, in a subject with good fixation, is improved to 0.15 arcminutes from 0.26 arcminutes in our earlier solution. We also demonstrate the new FPGA solution is capable of delivering stabilized large stimulus pattern (up to 256 x 256 pixels) to the retina. PMID- 20721173 TI - Fifteen terawatt picosecond CO2 laser system. AB - The generation of a record peak-power of 15 TW (45 J, 3 ps) in a single CO(2) laser beam is reported. Using a master oscillator-power amplifier laser system, it is shown that up to 100 J of energy can be extracted in a train of 3 ps laser pulses separated by 18 ps, a characteristic time of the CO(2) molecule. The bandwidth required for amplifying the short injected laser pulse train in a 2.5 atm final CO(2) amplifier is provided by field broadening of the medium at intensities of up to 140 GW/cm(2). The measured saturation energy for 3 ps pulses is 120 mJ/cm(2) which confirms that energy is simultaneously extracted from six rovibrational lines. PMID- 20721174 TI - Optical transmission anomalies in a double-layered metallic slit array. AB - We theoretically predicted the existence of an anomalous optical transmittance dip, which must be observed for a metamaterial structure with two metallic slabs with cut-through slit arrays of a constant period d under a normal incident condition. By changing the relative lateral displacement l between the two slabs, the dip frequency varies across that of a so-called Rayleigh-Wood's (RW) anomaly frequency. The mechanism of this anomaly is quite different from that of the RW anomaly and interpreted in terms of the interference between the propagating and evanescent waves. For the present double-layered system, furthermore, it is suggested that the RW anomaly vanishes for l = 0 and d/2. In experiments in the terahertz region, we observe that the fundamental features agree with these theoretical predictions. PMID- 20721175 TI - Anomalous behavior in length distributions of 3D random Brownian walks and measured photon count rates within observation volumes of single-molecule trajectories in fluorescence fluctuation microscopy. AB - Based on classical mean-field approximation using the diffusion equation for ergodic normal motion of single 24-nm and 100-nm nanospheres, we simulated and measured molecule number counting in fluorescence fluctuation microscopy. The 3D measurement set included a single molecule, or an ensemble average of single molecules, an observation volume DeltaV and a local environment, e.g. aqueous solution. For the molecule number N << 1 per DeltaV, there was only one molecule at a time inside DeltaV or no molecule. The mean rate k of re-entries defined by k = N/tau(dif) was independent of the geometry of DeltaV but depended on the size of DeltaV and the diffusive properties tau(dif). The length distribution l of single-molecule trajectories inside DeltaV and the measured photon count rates I obeyed power laws with anomalous exponent kappa =-1.32 approximately -4/3. PMID- 20721176 TI - Impact of the MAI and beat noise on the performance of OCDM/WDM Optical Packet Switches using Gold codes. AB - Recent advances in optical devices greatly enhance the feasibility of Optical Code Division Multiplexing/Wavelength Division Multiplexing (OCDM/WDM) Optical Packet Switch. In this paper, the performance of an OCDM/WDM switch is investigated when impairment due to both Multiple Access Interference and Beat noise are taken into account. Analytical models are proposed to dimension the switch resources as the number of optical codes carried on each wavelength and the number of needed optical converters. The Packet Loss Probability due to output packet contentions is evaluated as a function of the main switch and traffic parameters when Gold coherent optical codes are adopted. When the available bandwidth is fixed for the WDM/OCDM signal, due to a statistical multiplexing effect, we show that the use of more length codes and fewer wavelengths lead to lower packet loss probability, especially for low offered traffic. PMID- 20721177 TI - Power efficient subcarrier modulation for intensity modulated channels. AB - We compare formats for optical intensity modulation limited by thermal noise with the assumption of having ideal devices. At the same bitrate and bandwidth, a hitherto unknown format turns out to be more power efficient than known formats. This new modulation, which is a hybrid between on-off keying and phase-shift keying, belongs to the subcarrier modulation family. At asymptotically high signal-to-noise ratios, this hybrid scheme has a 1.2 dB average electrical power gain and 0.6 dB average optical power gain compared to OOK, while it has a 3.0 dB average electrical power gain and 2.1 dB average optical power gain compared to subcarrier QPSK. PMID- 20721178 TI - Tunable band-pass plasmonic waveguide filters with nanodisk resonators. AB - A novel and simple plasmonic filter based on metal-insulator-metal plasmonic waveguides with a nanodisk resonator is proposed and investigated numerically. By the resonant theory of disk-shaped nanocavity, we find that the resonance wavelengths can be easily manipulated by adjusting the radius and refractive index of the nanocavity, which is in good agreement with the results obtained by finite-difference time-domain (FDTD) simulations. In addition, the bandwidths of resonance spectra are tunable by changing the coupling distance between the nanocavity and waveguides. This result achieved by FDTD simulations can be accurately analyzed by temporal coupled mode theory. Our filters have important potential applications in high-density plasmonic integration circuits. PMID- 20721179 TI - Polarization demultiplexing in Stokes space. AB - A technique is demonstrated for polarization demultiplexing of arbitrary complex modulated signals. The technique is based entirely on the observation of samples in Stokes space, does not involve demodulation and is modulation format independent. The data in Stokes space is used to find the best fit plane and the normal to it which contains the origin. This normal identifies the two orthogonal polarization states of transmission and the desired polarization alignment transformation matrix. The technique is verified experimentally and is compared with the constant modulus algorithm. PMID- 20721180 TI - Fishnet metamaterials--rules for refraction and limits of homogenization. AB - The perfectly conducting stacked fishnet metamaterial is studied in this paper. The analysis is based on a combination of the mode matching method together with the generalized eigenvalue problem, and takes into account wave propagation along all three Cartesian axes. The analysis has been developed for a fishnet of square lateral periodicity and for two particular polarizations, namely TE and TM, corresponding to the two most common excitations. The 1D and 2D dispersion characteristics are calculated for both polarizations, showing that the TM waves undergo negative refraction in a narrow frequency band just below Wood's anomaly, whereas TE polarized waves exhibit ordinary positive refraction. Finally, possible homogenization of the fishnet metamaterial is considered, showing that only for small angles of incidence and in the immediate vicinity of Wood's anomaly can the fishnet be seen as homogenizable uniaxial medium. PMID- 20721181 TI - An efficient approach for investigating surface plasmon resonance in asymmetric optical fibers based on birefringence analysis. AB - We have analytically investigated the polarization dependence of surface plasmon resonance in fiber structures having strong asymmetry. From our simulation experiments it is found that the resonance wavelength coincides with the zero birefringence point of two degenerate modes, consequently demonstrating a new approach through which one can accurately locate the resonance peak of the system without having to analyze the loss spectrum. Results obtained using the new technique also reveal better performance in terms of accuracy and computation efficiency. Application of this approach in the analysis of refractive index and pressure sensors based on the single core D-shaped and symmetric multiple air hole fibers respectively is presented as a demonstration. The proposed technique, which primarily involves the search of zero-birefringence point, may be generalized for the study of other plasmonic waveguide structures. PMID- 20721182 TI - Low-loss hybrid plasmonic waveguide with double low-index nano-slots. AB - A hybrid plasmonic waveguide with double low-index nano-slots is introduced. The fabrication is simple and compatible with the standard processes for SOI wafers. The theoretical investigation shows that the present hybrid plasmonic waveguide has a low loss and consequently a relatively long propagation distance (at the order of several tens of lambda). For TE polarization, there is a strong field enhancement in the double nano-slots. More power is confined in the low-index nano-slots for a smaller core width. For a 50 nm-wide hybrid plasmonic waveguide with double 10 nm-wide slots, the power confinement factor in the nano-slots is as high as 85% and the effective area is as small as 0.007 microm(2) at 1550 nm. Consequently, the power density in the nano-slots becomes very high, e.g., >120 microm(-2), which is very desired for many applications. For the present hybrid plasmonic waveguide, the lateral dimension could be less than 50 nm and the calculated decoupled separation for two parallel identical waveguides is only 0.62 microm, which is helpful to realize photonic integration circuits with ultra high integration density. PMID- 20721183 TI - Metal microneedle fabrication using twisted light with spin. AB - Microneedle fabrication on a metal surface based on laser ablation using twisted light with spin was demonstrated, for the first time. The resulting needle showed a height of at least 10 microm above the target surface and a tip diameter of less than 0.3 microm. We also demonstrated the fabrication of a two-dimensional 5 x 6 microneedle array. The needles were uniformly well shaped with an average length and tip diameter of about 10 and 0.5 microm, respectively. PMID- 20721184 TI - Modeling of the angular tolerancing of an effective medium diffractive lens using combined finite difference time domain and radiation spectrum method algorithms. AB - A new rigorous vector-based design and analysis approach of diffractive lenses is presented. It combines the use of two methods: the Finite-Difference Time-Domain for the study in the near field, and the Radiation Spectrum Method for the propagation in the far field. This approach is proposed to design and optimize effective medium cylindrical diffractive lenses for high efficiency structured light illumination systems. These lenses are realised with binary subwavelength features that cannot be designed using the standard scalar theory. Furthermore, because of their finite and high frequencies characteristics, such devices prevent the use of coupled wave theory. The proposed approach is presented to determine the angular tolerance in the cases of binary subwavelength cylindrical lenses by calculating the diffraction efficiency as a function of the incidence angle. PMID- 20721185 TI - Phase contrast optical tweezers. AB - In this paper, for the first time, we report on systematic theoretical and experimental investigation of Phase Contrast Optical Tweezers (PCOT) which could be an indispensable tool for micromanipulation of the transparent micro and nano objects such as biological tissues and vesicles. The quadrant photodiode detection scheme and the power-spectrum calibration method is shown to be valid for this case. We have shown that the phase objective with new designed phase plates can provide nearly aberration-free condition at a desired depth. This could be a valuable advantage for simultaneous in-depth micro-manipulations and visualization of the sample. PMID- 20721186 TI - Multi-peak electromagnetically induced transparency (EIT)-like transmission from bull's-eye-shaped metamaterial. AB - We investigate the electromagnetic response of the concentric multi-ring, or the bull's eye, structure as an extension of the dual-ring metamaterial which exhibits electromagnetically-induced transparency (EIT)-like transmission characteristics. Our results show that adding inner rings produces additional EIT like peaks, and widens the metamaterial's spectral range of operation. Analyses of the dispersion characteristics and induced current distribution further confirmed the peak's EIT-like nature. Impacts of structural and dielectric parameters are also investigated. PMID- 20721187 TI - Theory of passively mode-locked photonic crystal semiconductor lasers. AB - We report the first theoretical investigation of passive mode-locking in photonic crystal mode-locked lasers. Related work has investigated coupled-resonator optical-waveguide structures in the regime of active mode-locking [Opt. Express 13, 4539-4553 (2005)]. An extensive numerical investigation of the influence of key parameters of the active sections and the photonic crystal cavity on the laser performance is presented. The results show the possibility of generating stable and high quality pulses in a large parameter region. For optimized dispersion properties of the photonic crystal waveguide cavity, the pulses have sub picosecond widths and are nearly transform limited. PMID- 20721188 TI - Signal, noise, and bias for a broadband, division-of-amplitude Stokes polarimeter. AB - We analyze estimation error as a function of spectral bandwidth for division-of amplitude (DoAm) Stokes polarimeters. Our approach allows quantitative assessment of the competing effects of noise and deterministic error, or bias, as bandwidth is varied.We use the signal-to-rms error (SRR) as a metric. Rather than calculating the SRR of the estimated Stokes parameters themselves, we use the singular-value decomposition to calculate the SRRs of the coefficients of the measured data vector projected onto the measurement matrix left singular vectors.We argue that calculating the SRRs for left singular vector coefficients will allow development of reconstruction filters to minimize Stokes estimation error. For the example case of a source with constant polarization over a relatively wide band, we show that as the spectral filter bandwidth is increased to include wavelengths significantly different than the design wavelength, the SRRs of the estimated left singular vector coefficients will a.) increase monotonically if relatively few photo-detection events (PDEs) are recorded, b.) after a sharp peak close to the design wavelength, decrease monotonically if relatively many PDEs are recorded, and c.) have well-defined maxima for nominal PDE counts. Given some idea of the source brightness relative to detector noise, one can specify a spectral filter bandwidth minimizing the variance and bias effects and optimizing Stokes parameter estimation. Our approach also allows one to specify the bandwidth over which the response of "achromatic" optics must be reasonably invariant with wavelength for rms Stokes estimation error to remain below some desired maximum. Finally, we point out that our method can be generalized not only to other types of polarimeters, but also to any sensing scheme that can be represented by a linear system for limiting values of a certain parameter. PMID- 20721189 TI - Parametric blind-deconvolution algorithm to remove image artifacts in hybrid imaging systems. AB - Hybrid imaging systems employing cubic phase modulation in the pupil-plane enable significantly increased depth of field, but artifacts in the recovered images are a major problem. We present a parametric blind-deconvolution algorithm, based on minimization of the high-frequency content of the restored image that enables recovery of artifact-free images for a wide range of defocus. We show that the algorithm enables robust matching of the image recovery kernel with the optical point-spread function to enable, for the first time, optimally low noise levels in recovered images. PMID- 20721190 TI - Estimation of displacement derivatives in digital holographic interferometry using a two-dimensional space-frequency distribution. AB - The paper introduces a two-dimensional space-frequency distribution based method to directly obtain the unwrapped estimate of the phase derivative which corresponds to strain in digital holographic interferometry. In the proposed method, a two-dimensional pseudo Wigner-Ville distribution of the reconstructed interference field is evaluated and the peak of the distribution provides information about the phase derivative. The presence of a two-dimensional window provides high robustness against noise and enables simultaneous measurement of phase derivatives along both spatial directions. Simulation and experimental results are presented to demonstrate the method's applicability for phase derivative estimation. PMID- 20721191 TI - Wavelength multicasting in silicon photonic nanowires. AB - We demonstrate a scalable, energy-efficient, and pragmatic method for high bandwidth wavelength multicasting using FWM in silicon photonic nanowires. We experimentally validate up to a sixteen-way multicast of 40-Gb/s NRZ data using spectral and temporal responses, and evaluate the resulting data integrity degradation using BER measurements and power penalty performance metrics. We further examine the impact of this wavelength multicasting scalability on conversion efficiency. Finally, we experimentally evaluate up to a three-way multicast of 160-Gb/s pulsed-RZ data using spectral and temporal responses, representing the first on-chip wavelength multicasting of pulsed-RZ data. PMID- 20721192 TI - Femtosecond laser-assisted selective infiltration of microstructured optical fibers. AB - A new method of selectively infiltrating microstructured optical fibers with the assistance of femtosecond laser micromachining is presented. With this technique, any type of air-holes in the cross-section of the microstructured optical fibers can be selectively infiltrated with liquids, which opens up a highly efficient, precise, flexible and reliable way of selective infiltrating and has high potential in the fabrication of novel hybrid-structured optical fibers and the devices based on them. PMID- 20721193 TI - Laser cooling of a semiconductor load to 165 K. AB - We demonstrate cooling of a 2 micron thick GaAs/InGaP double-heterostructure to 165 K from ambient using an all-solid-state optical refrigerator. Cooler is comprised of Yb(3+)-doped YLF crystal, utilizing 3.5 Watts of absorbed power near the E4-E5 Stark manifold transition. PMID- 20721194 TI - Eight-channel reconfigurable microring filters with tunable frequency, extinction ratio and bandwidth. AB - We demonstrate an eight-channel reconfigurable optical filter on a silicon chip. It consists of cascaded microring resonators and integrated compact heaters. With an embedded Mach-Zehnder (MZ) arm coupling to a microring resonator, the important parameters of a filter such as center frequency, extinction ratio and bandwidth can be controlled simultaneously for purposes of filtering, routing and spectral shaping. Thus our device could potentially be useful in dense wavelength division multiplexing (DWDM) and radio frequency arbitrary waveform generation (RFAWG). Multichannel filter response was successfully tuned to match the International Telecommunication Unit (ITU) grid with 50, 100 and 200 GHz in channel spacing. Programmable channel selectivity was demonstrated by heating the MZ arm, and continuous adjustment of through-port extinction ratio from 0 dB to 27 dB was achieved. Meanwhile, the 3 dB bandwidth in the drop port changed from 0.12 nm to 0.16 nm. The device had an ultra-compact footprint (1200 microm x 100 microm) excluding the metal leads and contact pads, making it suitable for large scale integration. PMID- 20721195 TI - A WDM-PON with an 80 Gb/s capacity based on wavelength-locked Fabry-Perot laser diode. AB - We investigate a high capacity WDM-PON based on wavelength-locked Fabry-Perot laser diodes. A color-free transmission of 2.5 Gb/s per channel is achieved with a polarization independent F-P LD and a decision threshold control circuit at the receiver. Then, we demonstrate an 80 Gb/s capacity (2.5 Gb/s x 32 channels) WDM PON with transmission length of 20 km. We also investigate impairments in transmission. PMID- 20721196 TI - Temporally focused femtosecond laser pulses for low numerical aperture micromachining through optically transparent materials. AB - Temporal focusing of spatially chirped femtosecond laser pulses overcomes previous limitations for ablating high aspect ratio features with low numerical aperture (NA) beams. Simultaneous spatial and temporal focusing reduces nonlinear interactions, such as self-focusing, prior to the focal plane so that deep (approximately 1 mm) features with parallel sidewalls are ablated at high material removal rates (25 microm(3) per 80 microJ pulse) at 0.04-0.05 NA. This technique is applied to the fabrication of microfluidic devices by ablation through the back surface of thick (6 mm) fused silica substrates. It is also used to ablate bone under aqueous immersion to produce craniotomies. PMID- 20721197 TI - Weaving the invisible thread: design of an optically invisible metamaterial fibre. AB - We present the design of an invisible metamaterial fibre operating at optical frequencies, which could be fabricated by adapting existing fibre drawing techniques. The invisibility is realised by matching the refractive index of the metamaterial fibre with the surroundings. We present a general recipe for the fabrication of such fibres, and numerically characterise a specific example using hexagonally arranged silver nanowires in a silica background. We find that invisibility is highly sensitive to details of the metamaterial boundary, a problem that is likely to affect most invisibility and cloaking schemes. PMID- 20721198 TI - Highly sensitive and spatially resolved polyvinyl alcohol/acrylamide photopolymer for real-time holographic applications. AB - By employing low molecular-weight polyvinyl alcohol (PVA) as binder, the spatial resolution of a red-sensitive PVA/acrylamide based photopolymer are improved from 1000 lines/mm to 3000 lines/mm. By increasing the ambient temperature during the holographic recording, the photosensitivity of photopolymer is also increased about 5 times. The optimized photopolymer system has high capacity such as high photosensitivity (8 mJ/cm(2)), high spatial resolution (over 3000 lines/mm) and high diffraction efficiency (over 94%). To our knowledge, its holographic recording performance is the best of ever reported PVA/acrylamide based photopolymer systems. It has good application prospects in real-time holographic interferometry, holographic storage and holographic display. PMID- 20721199 TI - 40-80-160 GHz tunable mode-locked semiconductor fiber laser incorporating a nonlinear optical loop mirror. AB - We demonstrate a tunable mode-locked semiconductor fiber laser incorporating a nonlinear optical loop mirror and synchronized to an external optical signal at 40 GHz, 80 GHz, and 160 GHz. The laser generates sech(2) pulses as short as 2.0 ps, 1.7 ps, and 1.3 ps at 40 GHz, 80 GHz, and 160 GHz, respectively, and is tunable within the C-band. The maximum root-mean-square timing jitter of the laser is 580 fs at 40 GHz and 80 GHz. PMID- 20721200 TI - Optical phase conjugation in phase-modulated transmission systems: experimental comparison of different nonlinearity-compensation methods. AB - We experimentally compare the effectiveness of three different optical-phase conjugation-based nonlinearity-compensation strategies on a transmission system employing phase-modulated signals, and hence affected by the Gordon-Mollenauer effect. We demonstrate that it is possible to obtain significant nonlinearity compensation, but that no improvement is obtained using configurations specifically aimed at the compensation of the nonlinear phase noise. PMID- 20721201 TI - Development of a 3D artificial compound eye. AB - In this research paper, in a major departure from conventional 2D micromachining processes, design and fabrication of a 3D compound eye system consisting of a 3D microprism array, an aperture array, and a microlens array were investigated. Specifically, the 3D microprism array on a curved surface was designed to steer the incident light from all three dimensions to a 2D plane for image formation. For each microprism, there is a corresponding microlens to focus the refracted light on the image plane. An aperture array was also implemented between the microprism array and the microlens array to eliminate cross-talk among the neighboring channels. In this system, 601 individual micro-assemblies consisting of microprisms and microlenses were constructed in a 20 mm diameter area. In this configuration, the maximum light deviation angle was determined to be 18.43 degrees. This research demonstrated an innovative and integrated approach to fabricating true 3D micro and meso scale optical structures. This work also validated the feasibility of using ultraprecision machining process for 3D microoptical device fabrication. The technology demonstrated in this research has high potentials in optical sensing, vision research and many other optical and photonic applications. PMID- 20721202 TI - Bandwidth-efficient phase modulation techniques for stimulated Brillouin scattering suppression in fiber optic parametric amplifiers. AB - Two novel bandwidth efficient pump-dithering Stimulated Brillouin Scattering (SBS) suppression techniques are introduced. The techniques employ a frequency hopped chirp and an RF noise source to impart phase modulation on the pumps of a two pump Fiber Optical Parametric Amplifier (FOPA). The effectiveness of the introduced techniques is confirmed by measurements of the SBS threshold increase and the associated improvements relative to the current state of the art. Additionally, the effect on the idler signal integrity is presented as measured following amplification from a two pump FOPA employing both techniques. The measured 0.8 dB penalty with pumps dithered by an RF noise source, after accruing 160 ps/nm of dispersion with 38 dB conversion gain in a two-pump FOPA is the lowest reported to date. PMID- 20721203 TI - Subwavelength focusing of light in the planar anisotropic metamaterials with zone plates. AB - We present here a structure with just a single slit covering the planar anisotropic metamaterial. The metamaterial has hyperbolic dispersion and can be realized using metal-dielectric multilayers. The structure combines the focusing performance of the zone plates and subwavelength resolution of the anisotropic metamaterials so that subwavelength focal spots can be obtained at the focal plane. The relationship between the focal spot size and slit width has been investigated, and a resolution of 36 nm about 1/10 of 365 nm incident wavelength is obtained with a 100 nm wide single slit. PMID- 20721204 TI - Carpet cloaking on a dielectric half-space. AB - Carpet cloaking is proposed to hide an object on a dielectric half-space from electromagnetic (EM) detection. A two-dimensional conformal transformation specified by an analytic function is utilized for the design. Only one nonsingular material parameter distribution suffices for the characterization. The cloaking cover situates on the dielectric half-space, and consists of a lossless upper part for EM wave redirection and an absorbing bottom layer for inducing correct reflection coefficient and absorbing transmission. Numerical simulations with Gaussian beam incidence are performed for verification. The broadband behavior of the carpet cloaking is also illustrated. PMID- 20721205 TI - Photonic crystal biosensor based on angular spectrum analysis. AB - The need for cost effective and reliable biosensors in e.g. medical applications is an ever growing and everlasting one. Not only do we strive to increase sensitivity and detection limit of such sensors; ease of fabrication or implementation are equally important. In this work, we propose a novel, photonic crystal based biosensor that is able to operate at a single frequency, contrary to resonance based sensors. In a certain frequency range, guided photonic crystal modes can couple to free space modes resulting in a Lorentzian shape in the angular spectrum. This Lorentzian can shift due to refractive index changes and simulations have shown sensitivities of 65 degrees per refractive index unit and more. PMID- 20721206 TI - Self-referenced characterization of optical frequency combs and arbitrary waveforms using a simple, linear, zero-delay implementation of spectral shearing interferometry. AB - We discuss a simple, linear, zero-delay implementation of spectral shearing interferometry for amplitude and phase characterization of optical frequency comb sources and arbitrary waveforms. We demonstrate this technique by characterizing two different high repetition rate (approximately 10 GHz) frequency comb sources, generated respectively by strong external and intracavity phase modulation of a continuous-wave laser. This technique is easy to implement, requiring only an intensity modulator and an optical spectrum analyzer (OSA), and is demonstrated to work at average power levels down to 100 nW (10 aJ/pulse at 10 GHz). By exploiting the long coherence lengths of these frequency combs and the self referenced nature of the measurement, we also demonstrate a simple single-ended measurement of dispersion and dispersion slope in long lengths of fiber (>25 km). PMID- 20721207 TI - Time-dependent theoretical model for terahertz wave detector using a parametric process. AB - We have presented a time-dependent theoretical model to describe the time behavior of a quasi-monochromatic nanosecond terahertz detector reported by Guo et al. [Appl. Phys. Lett. 93, 021106 (2008)]. The temporal input-output characteristic of the detector is investigated numerically by taking the system parameters close to the experimental ones, and the calculated pulse width for the incident terahertz wave agrees well with the experimental one. Our results demonstrate that the energy and width of an output idler wave pulse are proportional to those of the incident terahertz wave pulse. This study provides a strict theoretical basis and could be used to guide the design and optimization for the highly sensitive coherent terahertz detector. PMID- 20721208 TI - Optical characterization of coupled resonator slow-light rib waveguides. AB - We report on the design, fabrication and optical characterization of a slow light waveguide created using a linear array of coupled resonators in a large cross section rib waveguide. Structures with as many as 25 high aspect ratio resonators are experimentally investigated. The measured propagation loss, group velocity, and delay-bandwidth product (DBP) are presented. The metric DBP/unit loss is also introduced, with a value 38/dB. Finally we discuss a method for further reducing loss in the slow-light rib waveguide. PMID- 20721209 TI - Analysis of resonant optical gyroscopes with two input/output waveguides. AB - Rotation sensitivity of optical gyroscopes with ring resonators and two input/output waveguides in a coplanar add-drop filter configuration is studied. First, the gyroscope with a single resonator is analyzed, which is shown to have slightly higher sensitivity than the one with one waveguide. Next, the sensor with two identical resonators coupled through waveguides is investigated, which turns out to have half the sensitivity of the one with a single resonator when compared for the same footprints. The last point is valid when the resonators have the same coupling coefficients to the waveguides in the sensor with two resonators. PMID- 20721210 TI - Enhancing the efficiency of slit-coupling to surface-plasmon-polaritons via dispersion engineering. AB - We describe a simple method for enhancing the efficiency of coupling from a free space transverse-magnetic (TM) plane-wave mode into a surface-plasmon-polariton (SPP) mode. The coupling structure consists a metal film with a dielectric-filled slit and a planar, dielectric layer on the slit-exit side of the metal film. By varying the dielectric layer thickness, the wavevector of the SPP mode on the metal surface can be tuned to match the wavevector magnitude of the modes emanating from the slit exit, enabling high-efficiency radiation coupling into the SPP mode at the slit exit. An optimal dielectric layer thickness of approximately 100 nm yields a visible-frequency SPP coupling efficiency approximately 4 times greater than the SPP coupling efficiency without the dielectric layer. Commensurate coupling enhancement is observed spanning the free space wavelength range 400 nm < or = lambda(0) < or = 700 nm. We map the dependence of the SPP coupling efficiency on the slit width, the dielectric-layer thickness, and the incident wavelength to fully characterize this SPP coupling methodology. PMID- 20721211 TI - Dynamic axial stabilization of counter-propagating beam-traps with feedback control. AB - Optical trapping in a counter-propagating (CP) beam-geometry provides unique advantages in terms of working distance, aberration requirements and intensity hotspots. However, its axial performance is governed by the wave propagation of the opposing beams, which can limit the practical geometries. Here we propose a dynamic method for controlling axial forces to overcome this constraint. The technique uses computer-vision object tracking of the axial position, in conjunction with software-based feedback, for dynamically stabilizing the axial forces. We present proof-of-concept experiments showing real-time rapid repositioning coupled with a strongly enhanced axial trapping for a plurality of particles of varying sizes. We also demonstrate the technique's adaptability for real-time reconfigurable feedback-trapping of a dynamically growing structure that mimics a continuously dividing cell colony. Advanced implementation of this feedback-driven approach can help make CP-trapping resistant to a host of perturbations such as laser fluctuations, mechanical vibrations and other distortions emphasizing its experimental versatility. PMID- 20721212 TI - In situ monitoring of the acetylene decomposition and gas temperature at reaction conditions for the deposition of carbon nanotubes using linear Raman scattering. AB - To understand the reaction mechanisms taking place by growing carbon nanotubes via the catalytic chemical vapor deposition process, a strategy to monitor in situ the gas phase at reaction conditions was developed applying linear Raman spectroscopy. The simultaneous determination of the gas temperature and composition was possible by a new strategy of the evaluation of the Raman spectra. In agreement to the well-known exothermic decomposition of acetylene, a gas temperature increase was quantified when acetylene was added to the incident flow. Information about exhaust gas recirculation and location of the maximal acetylene conversion was derived from the composition measurements. PMID- 20721213 TI - Plasmonically induced transparent magnetic resonance in a metallic metamaterial composed of asymmetric double bars. AB - We demonstrate that the trapped magnetic resonance mode can be induced in an asymmetric double-bar structure for electromagnetic waves normally incident onto the double-bar plane, which mode otherwise cannot be excited if the double bars are equal in length. By adjusting the structural geometry, the trapped magnetic resonance becomes transparent with little resonance absorption when it happens in the dipolar resonance regime, a phenomenon so-called plasmonic analogue of electromagnetically induced transparency (EIT). This planar EIT-like metamaterial offers a great geometry simplification by combining the radiant and subradiant resonant modes in a single double-bar resonator. PMID- 20721214 TI - Ultra-low voltage, ultra-small mode volume silicon microring modulator. AB - We show GHz modulation in a 2.5 microm radius silicon micro-ring, with only 150 mV peak-peak drive voltage and an electro-optic modal volume of only 2 microm(3). The swing voltage and the micro-ring modulator are the smallest demonstrations so far in silicon. The presented approach lays the ground work for a new class of high speed low voltage modulators enabling, seamless integration of nanophotonics with low voltage digital CMOS nano-electronics. PMID- 20721215 TI - Generation of hybrid polarization-orbital angular momentum entangled states. AB - Hybrid entangled states exhibit entanglement between different degrees of freedom of a particle pair and thus could be useful for asymmetric optical quantum network where the communication channels are characterized by different properties. We report the first experimental realization of hybrid polarization orbital angular momentum (OAM) entangled states by adopting a spontaneous parametric down conversion source of polarization entangled states and a polarization-OAM transferrer. The generated quantum states have been characterized through quantum state tomography. Finally, the violation of Bell's inequalities with the hybrid two photon system has been observed. PMID- 20721216 TI - Determination of paraxial image plane location by using Ronchi test. AB - A method to determine the location of the paraxial image plane of an imaging system is discussed. This method uses a recently developed quantitative Ronchi test and is different in that the location of paraxial image plane of the system can be determined from the measured Ronchigrams alone. We validate the location determined by the method by modifying the optical setup and comparing the retrieved f-number of the system to the theoretical prediction. PMID- 20721217 TI - A bridge between the single-photon and squeezed-vacuum states. AB - The two modes of the Einstein-Podolsky-Rosen quadrature entangled state generated by parametric down-conversion interfere on a beam splitter of variable splitting ratio. Detection of a photon in one of the beam splitter output channels heralds preparation of a signal state in the other, which is characterized using homodyne tomography. By controlling the beam splitting ratio, the signal state can be chosen anywhere between the single-photon and squeezed state. PMID- 20721218 TI - Ultrafast time domain demonstration of bulk magnetization precession at zero magnetic field ferromagnetic resonance induced by terahertz magnetic field. AB - We report the first observation of sub-terahertz bulk-magnetization precession, using terahertz time-domain spectroscopy. The magnetization precession in gallium substituted epsilon-iron oxide nano-ferromagnets under zero magnetic field is induced by the impulsive magnetic field of the THz wave through the gyromagnetic effect. Just at the resonance frequency, the linear to circular polarized wave conversion is realized. This is understood as the free induction decay signal radiated from a rotating magnetic dipole corresponding to the natural resonance. Furthermore, this demonstration reveals that the series of gallium-substituted epsilon-iron oxide nano-ferromagnets is very prospective for magneto-optic devices, which work at room temperature without external magnetic field, in next generation wireless communication. PMID- 20721219 TI - Rare earth doped ring-shaped luminescent micro-composites on patterned ferroelectrics. AB - Ferroelectric domain patterns are used as templates on which rare earth doped high refractive index nanoparticles activated with trivalent rare earth ions (RE(3+)) are selectively assembled on domain surfaces with a specific polarization. Two-dimensional luminescent heterostructures, with sizes and geometries defined by the ferroelectric patterning are achieved. The process of incorporation and consolidation of the optically active nanoparticles into the alternate domain structures leads to luminescent ring-shaped arrangements with innovative geometries and to a micrometer spatial control of the trivalent rare earth ion emitters. Multicolor emission systems and the possibility of chromatic switching at the micrometer scale among the three different compounds forming the two dimensional structure is demonstrated. PMID- 20721220 TI - High-efficiency fiber-to-chip grating couplers realized using an advanced CMOS compatible silicon-on-insulator platform. AB - A new generation of Silicon-on-Insulator fiber-to-chip grating couplers which use a silicon overlay to enhance the directionality and thereby the coupling efficiency is presented. Devices are realized on a 200 mm wafer in a CMOS pilot line. The fabricated fiber couplers show a coupling efficiency of -1.6 dB and a 3 dB bandwidth of 80 nm. PMID- 20721221 TI - Dynamic line-by-line pulse shaping with GHz update rate. AB - We introduce a novel scheme for dynamic line-by-line pulse shaping with GHz update rates. Four lines of an optical frequency comb source are used to injection-lock four individual VCSEL, which are subsequently electrically modulated at 0.4 to 1 GHz through current modulation. This concept could be considered a completely new way of pulse shaping as the light is not simply modified, but rather regenerated with the desired properties. We also discuss an important drawback of line-by-line pulse shapers that ultimately limits the modulation speed capability. PMID- 20721222 TI - Synchronization of random bit generators based on coupled chaotic lasers and application to cryptography. AB - Random bit generators (RBGs) constitute an important tool in cryptography, stochastic simulations and secure communications. The later in particular has some difficult requirements: high generation rate of unpredictable bit strings and secure key-exchange protocols over public channels. Deterministic algorithms generate pseudo-random number sequences at high rates, however, their unpredictability is limited by the very nature of their deterministic origin. Recently, physical RBGs based on chaotic semiconductor lasers were shown to exceed Gbit/s rates. Whether secure synchronization of two high rate physical RBGs is possible remains an open question. Here we propose a method, whereby two fast RBGs based on mutually coupled chaotic lasers, are synchronized. Using information theoretic analysis we demonstrate security against a powerful computational eavesdropper, capable of noiseless amplification, where all parameters are publicly known. The method is also extended to secure synchronization of a small network of three RBGs. PMID- 20721223 TI - Highly efficient hybrid light-emitting device using complex of CdSe/ZnS quantum dots embedded in co-polymer as an active layer. AB - We propose a highly efficient hybrid light-emitting device (LED) with a single active layer where CdSe/ZnS quantum dots (QDs) are dispersed as a guest material in a conjugated polymer (co-polymer) matrix used for a host material. In our structure, the QDs act on light-emitting chromophores by trapping the migrating excitons in the co-polymer matrix via Forster energy transfer, and improve the charge balance within the co-polymer by trapping the injected electron carriers. Experimental results show that the electroluminescent properties highly depend on the doping density of the QDs within the co-polymer matrix, where the luminance as well as the external current efficiency are initially enhanced with increasing the concentration of the dispersed QDs in the co-polymer solution, and then such properties are degraded due to aggregation of the QDs. We can get the maximum brightness of 9,088 cd/m(2) and the maximum external current efficiency of 7.5 cd/A in mixing ratio of the QDs by 1.0 wt%. The external current efficiency is enhanced by over 15 times and the turn-on voltage is reduced in comparison with the corresponding values for a reference device that uses only a co-polymer as an active layer. PMID- 20721224 TI - Optimization of metallic microheaters for high-speed reconfigurable silicon photonics. AB - The strong thermooptic effect in silicon enables low-power and low-loss reconfiguration of large-scale silicon photonics. Thermal reconfiguration through the integration of metallic microheaters has been one of the more widely used reconfiguration techniques in silicon photonics. In this paper, structural and material optimizations are carried out through heat transport modeling to improve the reconfiguration speed of such devices, and the results are experimentally verified. Around 4 micros reconfiguration time are shown for the optimized structures. Moreover, sub-microsecond reconfiguration time is experimentally demonstrated through the pulsed excitation of the microheaters. The limitation of this pulsed excitation scheme is also discussed through an accurate system-level model developed for the microheater response. PMID- 20721225 TI - Analytical study of pulse amplification in silicon Raman amplifiers. AB - The nonlinear process of stimulated Raman scattering is important for silicon photonics as it enables optical amplification and lasing. To understand the dynamics of silicon Raman amplifiers (SRAs), a numerical approach is generally employed, even though it provides little insight into the contribution of different SRA parameters to the signal amplification process. In this paper, we solve the coupled pump-signal equations analytically under realistic conditions, and derive an exact formula for the envelope of a signal pulse when picosecond optical pulses are amplified inside a SRA pumped by a continuous-wave laser beam. Our solution is valid for an arbitrary pulse shape and fully accounts for the Raman gain-dispersion effects, including temporal broadening and group-velocity reduction (a slow-light effect). It can be applied to any pumping scenario and leads to a simple analytic expression for the maximum optical delay produced by the Raman dispersion in a unidirectionally pumped SRA. We employ our analytical formulation to study the evolution of optical pulses with Gaussian, exponential, and Lorentzian shapes. The ability of a Gaussian pulse to maintain its shape through the amplifier makes it possible to realize soliton-like propagation of chirped Gaussian pulses in SRAs. We obtain analytical expressions for the required linear chirp and temporal width of a soliton-like pulse in terms of the net signal gain and the Raman-dispersion parameter. Our results are useful for optimizing the performance of SRAs and for engineering controllable signal delays. PMID- 20721226 TI - Thickness and refractive index measurement of a silicon wafer based on an optical comb. AB - We have proposed and demonstrated a novel method that can determine both the geometrical thickness and refractive index of a silicon wafer at the same time using an optical comb. The geometrical thickness and refractive index of a silicon wafer was determined from the optical thickness using phase information obtained in the spectral domain. In a feasibility test, the geometrical thickness and refractive index of a wafer were measured to be 334.85 microm and 3.50, respectively. The measurement uncertainty for the geometrical thickness was evaluated as 0.95 microm (k = 1) using a preliminary setup. PMID- 20721227 TI - A novel ECDM-OFDM-PON architecture for next-generation optical access network. AB - This paper proposes a novel architecture for next-generation passive optical network (PON) based on electrical code division multiplexing orthogonal frequency division multiplexing (ECDM-OFDM) access. The feasibility of bidirectional transmission with the same wavelength has been experimentally demonstrated under this architecture. An error-free transmission of two PON channels has been successfully demonstrated in the experiment. PMID- 20721228 TI - Diode pumped passively mode-locked Yb:SSO laser with 2.3 ps duration. AB - This paper reports on a diode-pumped picosecond passively mode-locked Yb:SSO laser. Pulses as short as 2.3 ps with a repetition rate of 53 MHz were generated, without extra negative dispersion elements. The output power achieved 1.87 W at a pump power of 11.5 W. Continuous-wave operation and wavelength tuning were examined. The CW operation achieved 3.55 W output power with a slope efficiency of 44.5%; its tuning can cover the range of 1034.0-1089.7 nm. PMID- 20721229 TI - High displacement sensitivity in asymmetric plasmonic nanostructures. AB - The strong couplings between two asymmetric plasmonic nanostructures can lead to ultra-sensitive optical responses when their separation changes. We employ electromagnetic numerical simulations to study the displacement sensitivity of two kinds of plasmonic systems: (1) a split-ring resonator and a metal rod; (2) two metal rods of asymmetric lengths. Structural asymmetry makes antiparallel current interactions possible and greatly enhances the sensitivity to 5%/nm for normalized frequency changes and 29%/nm for normalized transmittance changes. These are the highest displacement sensitivity among all physical systems investigated so far. In addition, we also find that these systems display a universal scaling curve independent of their shapes or dimensions. These asymmetric plasmonic nanostructures will open widespread applications from strain mapping, surface wave or heat wave imaging, optomechanical sensing, to environmental detections. PMID- 20721230 TI - Supercontinuum generation with optical vortices. AB - We employ an optical vortex beam for the generation of femtosecond supercontinuum in a solid state medium. We demonstrate that the continuum generation process is initiated by the filamentation of the vortex, resulting in a spatially divergent continuum. Despite the strong self-focusing and the formation of multiple hot spots along the vortex ring, the singularity is preserved in both the near- and far-fields. PMID- 20721231 TI - One-dimensional hard x-ray field retrieval using a moveable structure. AB - We present a technique that allows measuring the field of an x-ray line focus using far-field intensity measurements only. One-dimensional phase retrieval with transverse translation diversity is used to recover a hard x-ray beam focused by a compound kinoform lens. The reconstruction is found to be in good agreement with independent knife-edge scan measurements taken at separated planes. The approach avoids the need for measuring the beam profile at focus and allows narrower beams to be measured than the traditional knife-edge scan. PMID- 20721232 TI - Laser-induced phase transitions of Ge2Sb2Te5 thin films used in optical and electronic data storage and in thermal lithography. AB - Amorphous thin films of Ge(2)Sb(2)Te(5), sputter-deposited on a ZnS-SiO(2) dielectric layer, are investigated for the purpose of understanding the structural phase-transitions that occur under the influence of tightly-focused laser beams. Selective chemical etching of recorded marks in conjunction with optical, atomic force, and electron microscopy as well as local electron diffraction analysis are used to discern the complex structural features created under a broad range of laser powers and pulse durations. Clarifying the nature of phase transitions associated with laser-recorded marks in chalcogenide Ge(2)Sb(2)Te(5) thin films provides useful information for reversible optical and electronic data storage, as well as for phase-change (thermal) lithography. PMID- 20721233 TI - Biochemical sensing with a polymer-based micromachined Fabry-Perot sensor. AB - A white-light source operated polymer-based micromachined Fabry-Perot biochemical sensor is reported. As a refractive-index sensitive optical sensor, its transducing signal varies upon the changes of the effective refractive index in the Fabry-Perot cavity. This sensor is fabricated from PDMS and glass. More specifically, this sensor is a micromachined Fabry-Perot interferometer (microFPI) and is fabricated by bonding a glass substrate and the soft lithographically patterned PDMS. Several biochemicals have been detected with the microFPI biochemical sensors. Measurements show that rabbit IgG at a concentration of as low as 5 to 50 ng/ml can be detected even without any performance optimization of the devices. PMID- 20721234 TI - Synthesis of ZnO nanoflowers and their wettabilities and photocatalytic properties. AB - By combing laser direct writing and hydrothermal growth, we demonstrate the growth of three-dimensional flowerlike ZnO nanostructures from aqueous solution. Our approach offers synthetic flexibility in controlling film architecture, coating texture and crystallite size. The wettability is studied by measurement of time-dependent contact angles in the as-grown samples. In addition, superior photocatalytic activity of the flowerlike ZnO nanostructures in the degradation of Rhodamine B is investigated as well. The influence factors and formation mechanism of the flowerlike ZnO nanostructures are also analyzed and discussed. PMID- 20721235 TI - Non-Markovian dynamics of a microcavity coupled to a waveguide in photonic crystals. AB - In this paper, the non-Markovian dynamics of a microcavity coupled to a waveguide in photonic crystals is studied based on a semi-finite tight binding model. Using the exact master equation, we solve analytically and numerically the general and exact solution of the non-Markovain dynamics for the cavity coupled to the waveguide in different coupling regime. A critical transition is revealed when the coupling increases between the cavity and the waveguide. In particular, the cavity field becomes dissipationless when the coupling strength goes beyond a critical value, as a manifestation of strong non-Markovian memory effect. The result also indicates that the cavity can maintain in a coherent state with arbitrary small number of photons when it strongly couples to the waveguide at very low temperature. These properties can be measured experimentally through the photon current flowing over the waveguide in photonic crystals. PMID- 20721236 TI - Near-field THz imaging of free induction decay from a tyrosine crystal. AB - We demonstrate images of free induction decay (FID) signals from a grain of tyrosine in the near-field of the THz frequency region. By combining electro optic sampling with a charge-coupled-device (CCD) camera, our near-field THz microscope allows us to visualize the electric field blinking with the FID signal with spatial resolution of better than 70 microm. The oscillating frequency of the FID signal centered at approximately 1 THz corresponds to the vibrational mode of the tyrosine crystal. These results confirm that the THz near-field microscope can take spectroscopic images with subwavelength spatial resolution (approximately lambda/4). PMID- 20721237 TI - Multi-wavelength fiber optical parametric oscillator with ultra-narrow wavelength spacing. AB - We propose a novel multi-wavelength fiber optical parametric oscillator (MW-FOPO) based on a ring cavity. A highly nonlinear fiber and a Mach-Zehnder interferometer formed by two 3-dB optical couplers are used as the gain medium and the comb filter, respectively. Multi-wavelength lasing of the MW-FOPO with an ultra-narrow wavelength spacing of about 0.08 nm is achieved. The output spectrum of the MW-FOPO covers a wavelength regime from 1510 nm to 1615 nm (for lasing wavelengths with the power that exceeds -60 dBm). The stability of the MW-FOPO is discussed and experimentally demonstrated. A comparison of the output spectra between the MW-FOPO and the multi-wavelength Erbium-doped fiber laser is also presented. PMID- 20721238 TI - Mathematic models for a ray tracing method and its applications in wireless optical communications. AB - This paper presents a new ray tracing method, which contains a whole set of mathematic models, and its validity is verified by simulations. In addition, both theoretical analysis and simulation results show that the computational complexity of the method is much lower than that of previous ones. Therefore, the method can be used to rapidly calculate the impulse response of wireless optical channels for complicated systems. PMID- 20721239 TI - Time-domain measurement of optical transport in silicon micro-ring resonators. AB - We perform time-domain measurements of optical transport dynamics in silicon nano photonic devices. Using pulsed optical excitation the thermal and carrier induced optical nonlinearities of micro-ring resonators are investigated, allowing for identification of their individual contributions. Under pulsed excitation build up of free carriers and heat in the waveguides leads to a beating oscillation of the cavity resonance frequency. When employing a burst of pulse trains shorter than the carrier life-time, the slower heating effect can be separated from the faster carrier effect. Our scheme provides a convenient way to thermally stabilize optical resonators for high-power time-domain applications and nonlinear optical conversion. PMID- 20721240 TI - Shifted angular spectrum method for off-axis numerical propagation. AB - A novel method is proposed for simulating free-space propagation from an input source field to a destination sampling window laterally shifted from that in the source field. This off-axis type numerical propagation is realized using the shifted-Fresnel method (Shift-FR) and is very useful for calculating non-paraxial and large-scale fields. However, the Shift-FR is prone to a serious problem, in that it causes strong aliasing errors in short distance propagation. The proposed method, based on the angular spectrum method, resolves this problem. Numerical examples as well as the formulation are presented. PMID- 20721241 TI - Dynamics of single-layer polymer breath figures. AB - A single-layer of breath figure pattern was explored via the dynamical optical images and the temperature evolution. The pattern was prepared with the solution of carbon disulfide (CS(2)) dissolved 1% weight concentration of polystyrene. The evaporation of CS(2) was considered to be the most important role to the formation of the breath figure pattern. The understanding of the breath figures pattern will promote the technique to fabricating an imprinted template with demanded hexagonal structures. PMID- 20721242 TI - Ultrafast temporal pulse shaping via phase-sensitive three-wave mixing. AB - It is well-known that the process of optical parametric amplification (OPA) can be sensitive to the phases of the incident waves. In OPA realized by three-wave mixing, injection of all three waves into the same mode with appropriate phase relationship results in amplification of the signal phase, with an associated deamplification of the signal energy. Prospects for the use of this technique in the temporal domain for shaping ultrashort laser pulses are analyzed using a numerical model. Several representative pulse shaping capabilities of this technique are identified, which can significantly augment the performance of common passive pulse shaping methods operating in the Fourier domain. It is found that the use of phase-sensitive OPA shows a potential for significant compression of approximately 100 fs pulses, steepening of the rise time of ultrashort pulses, and production of pulse doublets and pulse trains. It is also shown that the group velocity mismatch can assist the shaping process. Such pulse shaping capabilities are found to be within reach of this technique in common nonlinear optical crystals pumped by pulses available from compact femtosecond chirped pulse amplification laser systems. PMID- 20721243 TI - Flow-assisted single-beam optothermal manipulation of microparticles. AB - An optothermal tweezer was developed with a single-beam laser at 1550 nm for manipulation of colloidal microparticles. Strong absorption in water can thermally induce a localized flow, which exerts a Stokes' drag on the particles that complements the gradient force. Long-range capturing of 6 microm polystyrene particles over approximately 176 microm was observed with a tweezing power of approximately 7 mW. Transportation and levitation, targeted deposition and selective levitation of particles were explored to experimentally demonstrate the versatility of the optothermal tweezer as a multipurpose particle manipulation tool. PMID- 20721244 TI - Error-free demodulation of pixelated carrier frequency interferograms. AB - Recently, pixelated spatial carrier interferograms have been used in optical metrology and are an industry standard nowadays. The main feature of these interferometers is that each pixel over the video camera may be phase-modulated by any (however fixed) desired angle within [0,2pi] radians. The phase at each pixel is shifted without cross-talking from their immediate neighborhoods. This has opened new possibilities for experimental spatial wavefront modulation not dreamed before, because we are no longer constrained to introduce a spatial carrier using a tilted plane. Any useful mathematical model to phase-modulate the testing wavefront in a pixel-wise basis can be used. However we are nowadays faced with the problem that these pixelated interferograms have not been correctly demodulated to obtain an error-free (exact) wavefront estimation. The purpose of this paper is to offer the general theory that allows one to demodulate, in an exact way, pixelated spatial-carrier interferograms modulated by any thinkable two-dimensional phase carrier. PMID- 20721245 TI - Femtowatt-light-level phase measurement of slow light pulses via beat-note interferometer. AB - We report on an experimental demonstration of applying the beat-note interferometer to simultaneously measure the phase and amplitude variations of light pulses after propagating through an electromagnetically induced transparency medium at femtowatt-light levels. Furthermore, we observe that the measured phase noise approaches the shot-noise level arising from the fluctuations of detected photons. PMID- 20721246 TI - [Effect of integrin-linked kinase on the growth of prostate cancer in nude mice]. AB - OBJECTIVE: To investigate the effect of the integrin-linked kinase (ILK) small interfering RNA (siRNA) on prostate cancer in nude mice by orthotopic injection of human cell line DU145. METHODS: The cultured human cell line DU145 was knocked down for ILK using a siRNA .Cellular ILK expression was quantified by RT-PCR and Western blot analysis. Moreover, cell attachment, invasiveness and microfilament dynamics assays were performed. Furthermore, the impact of the ILK siRNA on the prostate cancer was tested using a nude mice model in which prostate cancer was induced by orthotopic injection of human prostate cancer cell line DU145.Gross tumor volume of prostate in nude mice,cell differentiation,the state of apoptosis and proliferation were tested after 5 weeks of injection. RESULTS: The expression of ILK was suppressed significantly by siRNA, cellular mRNA and protein of ILK decreased 87% and 81% separately. The knockdown of ILK also induced the attachment and invasiveness of DU145 cell growing down. The tumor volume, cell differentiation, apoptosis index and proliferation index of prostate in nude mice of ILK siRNA orthotopic injection model were significantly smaller, better, increased and decreased separately than those in control group. CONCLUSION: Targeting inhibition of ILK not only decreases attachment and invasiveness of human DU145 cells, but also suppresses the growth and development of prostate cancer of orthotopic injection human DU145 cell line model in nude mice. PMID- 20721247 TI - [Clinical utility of fluorescence in situ hybridization improves the sensitivity in the diagnosis of upper urinary tract urothelial carcinoma]. AB - OBJECTIVE: To assess the clinical utility of a fluorescence in situ hybridization (FISH) assay as a non-invasive method for diagnosing and monitoring urothelial carcinoma (UC) in the upper urinary tract (UUT). METHODS: Urine specimens from 63 consecutive patients with UUT-UC and 69 controls with benign disease were analyzed by means of cytology and FISH. For FISH analysis, labeled probes specific for chromosomes 3, 7, and 17 and for the p16 (9p21) gene were used to assess chromosomal abnormalities indicative of malignancy.Sensitivity and specificity of both techniques were determined and compared. The frequency of chromosomal aberrations of malignant cells from UUT-UC was also determined. RESULTS: Of 63 patients with UUT-UC, FISH affords an overall sensitivity of 84.1% (53/63), the figure being 71.4% (20/28) for PTa and PT1 tumors,94.3% (33/35) for PT2-4 tumors. The sensitivities of urine cytology were 35.7% (10/28) for PTa and PT1 tumor,45.7% (16/35)for PT2-4 tumors,with an overall sensitivity of 41.3% (26/63). The sensitivities of the two methods for the low grade tumors were 80% (20/25) and 44% (11/25), and for high grade tumors were 86.8% (33/38) and 39.5% (15/38), respectively. Specificities for FISH and urine cytology were 91.3% (63/69) and 94.2% (65/69)respectively. CONCLUSION: According to the results,the sensitivity of FISH for the detection of UUT-UC is superior to that of urine cytology and the specificities of FISH and urine cytology are not significantly different. FISH can promote the diagnosis of UUT-UC, especially for the low stage and low grade cases,it may be a new promising non-invasive method for the diagnosis of UUT-UC. PMID- 20721248 TI - [CMTM5 inhibits the tumor cell behavior of prostate cancer by downregulation of HER2]. AB - OBJECTIVE: To discover whether there is any other pathway than EGFR which has interaction with HER2 that makes a different down stream on cancer manners and whether CMTM5 plays a role in HER2 related tumor performance. METHODS: HER2 and CMTM5 were detected on prostate cancer tissue chip using IHC. The protein levels of HER2, Cyclin D1 and CMTM5 were compared had with or without CMTM5 plasmid transfection on PC3 cell line to insure their relationship. RESULTS: The author demonstrated that the HER2 had been up regulated in prostate cancer epithelium while CMTM5 down regulated. Overexpression of CMTM5 in PC3 could lower the HER2 and Cyclin D1 protein level. CONCLUSION: The results suggest that in prostate cancer HER2 has a different partner in the signaling transduction other than EGFR as in a traditional pathway. CMTM5 may have a chance to be chosen as the next potential treatment bio-target of prostate cancer. PMID- 20721249 TI - [Effects of clinically effective dose of lovastatin on prostate cancer PC3 cells]. AB - OBJECTIVE: To investigate the effects of clinically achievable dose of lovastatin on prostate cancer PC3 cells. METHODS: PC3 prostate cancer cells were treated with dimethyl sulfoxide(DMSO),or lovastain only,or lovastatin with mevalonic acid for 24, 48 and 72 hours respectively. MTT assay was used to detect the cell viability. By means of [3H] thymidine incorporation tests, the effects of lovastatin on cell proliferation were analyzed. Western blot was used to detect activated casepase3, caspase7, and cleaved PARP (cPARP), the important molecules on the apoptosis pathway. RESULTS: Cell proliferation of PC3 was significantly inhibited by 39.29%[(63.69%+/-3.69%) vs (102.98%+/-6.84%), P=0.000] after 48 h treatment with lovastatin at its clinically achievable dose of 2 micromol/L. After 72 hours the cell proliferation was inhibited by 44.24% [(52.79%+/-9.88% ) vs (97.03%+/-0.87%), P=0.048]. The cell number was also markedly decreased (4.86x10(5)+/-0.10x10(5)) vs (9.66x10(5)+/-0.10x10(5)), P=0.000] after 72 h treatment at this low concentration of 2 micromol/L. The viability of PC3 cells was significantly decreased 50.12% (56.52%+/-6.40%) vs (106.64%+/-5.27%), P=0.000] and 60.05% (41.99%+/-11.64%) vs (102.94%+/-8.49%), P=0.000] after 48 h and 72 h treatment, respectively. In addition, 2 micromol/L lovastatin induced activation of casepase7 and led the death substrate PARP to cleavage. CONCLUSION: Clinically achievable dose of lovastatin inhibits prostate cancer PC3 cell proliferation and induces PC3 cell apoptosis. PMID- 20721250 TI - [Clinical study on intermittent hormonal therapy for patients with prostate cancer]. AB - OBJECTIVE: To investigate the effect of intermittent hormonal therapy (IHT) for patients with different stage/grade prostate cancer (PCa). METHODS: The number of cycles and the duration of ON/OFF therapy for 45 PCa patients receiving IHT were observed. Maximal androgen blockade (MAB) therapies were used for six to nine months, and then stopped until the serum prostate specific antigen (PSA) was decreased below 0.2 microg/L, which lasted for three months. It was decided whether MAB went on according to the level of PSA. RESULTS: The average follow-up time was 40.7+/-13.4 months. Forty-one patients started the second cycle of treatment, of whom, 8 became androgen-independent and 7 were at T3-4M0 or M1 stages and the Gleason scores were above 8. Sixteen patients entered the third cycle, of whom, 14 were at lower than stage III and 13 had the Gleason scores below 7. From the first to the fourth courses of treatment, the average intervals were 8.7+/-5.4 (47.1%), 8.4+/-4.9 (49.3%), 7.0+/-3.4 (43.7%), and 3.7+/ 0.6(42.5%) months respectively. Five patients developed bone metastasis. No one died up to now. According to the evaluation criteria, patients were divided into tolerance (n=16) and intolerance groups (n=29). Compared with the intolerance group, the patients who tolerated the treatment well had lower Gleason scores (P=0.002), lower PSA levels (P=0.053) and lower tumor stages (P=0.001). There was no evidence that age, lymph node metastasis, bone metastasis and the state of recurrence were associated with an increased risk of the outcome. Non-conditional Logistic regression analysis showed that the proportion of patients at stage IV was the only independent risk factor for the tolerance of the treatment (OR=12.113, 95%CI 1.330-110.312, P=0.027). CONCLUSION: Intermittent hormonal therapy is more effective and proper for the patient with highly differentiated tumor and at lower stages (< or = III). The patients who progressed to hormone independence are mostly at stage IV with poorly differentiated tumor. Intermittent hormone therapy could be more adaptive for the patients at lower than stage III. PMID- 20721251 TI - [Impact of prostate volume on the diagnostic value of prostate cancer with different biopsy strategies]. AB - OBJECTIVE: To assess impact of different prostate biopsy strategies according to prostate volume on tumor detection. METHODS: A total of 323 consecutive men with suspected prostate cancer were included in the study. Indications for transrectal ultrasound guided prostate biopsy were: abnormal digital rectal examination (DRE, 52 cases) and/or a total prostate specific antigen (PSA) over 4.0 microg/L (305 cases). In the subjects, their ages were between 49 years and 90 years, the mean: 69 years; PSAs were between 0.6 microg/L and 142.5 microg/L, the mean: 20.8 microg/L; and the prostate volumes were between 12.3 mL and 255.5 mL, the mean: 60.4 mL. Transrectal ultrasound guided prostate biopsy of 13 core scheme was conducted in each patient. The cancer detection rate for each biopsy core was calculated. The sensitivities of different combinations of biopsy cores were compared with a 13 core biopsy protocol and the prostate volumes were divided into two groups (<50 mL and >or=50 mL). The optimum number of biopsy cores was determined in patients with different prostate volumes. RESULTS: Of the 323 patients 120 (37.2%) were positive for prostate cancer. Compared to the patients with a prostate volume<50 mL, cancer detection rates of 13 core biopsy protocol in the patients with a prostate volume>or=50 mL decreased significantly (51.0% vs 26.1%). In patients with a prostate volume smaller than 50 mL, the 8 core biopsy protocol consisting of the apex, mid gland, base, lateral mid gland or of the apex, mid gland, lateral mid gland, lateral base of the prostate revealed the results similar to those of the 13 core biopsy protocol (sensitivities: 98.6% and 97.3%, both P>0.05). In the larger prostate volume group, 10 core biopsy protocol that included cores at the apex, mid gland, base, lateral mid gland and lateral base detected 97.6% of cancers (P>0.05). CONCLUSION: Patients with larger prostates have lower cancer detection rates. For patients with prostate volume smaller than 50 mL, 8 core biopsy protocol consisting of the apex, mid gland, base, lateral mid gland or of the apex, mid gland, lateral mid gland, lateral base of the prostate can be used since it reveals results similar to those of 13 core biopsy protocol. 10 core biopsy protocol that includes cores at the apex, mid gland, base, lateral mid gland and lateral base can be used for patients with prostate volumes larger than 50 mL. PMID- 20721252 TI - [Changes in clinical features of inpatients with prostate cancer in the past 11 years]. AB - OBJECTIVE: To investigate changes of the stage, age of onset, and prostate specific antigen (PSA) level of prostate cancer with socioeconomic development and medicare promotion. METHODS: The medical records of 784 inpatients with prostate cancer were analyzed retrospectively, who were diagnosed in Peking University First Hospital from 1997 to 2007. According to the time of diagnosis, all the patients were sorted into three groups: earlier group (1997-2001), intermediate group (2002-2004), and contemporary group (2005-2007). The tumor stages, ages, Gleason scores, and PSA levels of each group and of the three groups were compared to determine whether the discrepancies were significant. RESULTS: The discrepancies of ages, Gleason scores, and stages between earlier and intermediate groups were not significant. The differences of ages and stages between intermediate and contemporary groups were not significant, but the change of Gleason scores was significant. The discrepancies of Gleason scores and stages between earlier and contemporary groups were meaningful, but the change of ages was not significant. CONCLUSION: As time passes, PSA levels and tumor stages of prostate cancer patients show a descending trend, but the discrepancy of ages between the three groups is meaningless. The weight of low risk and intermediate risk groups in localized prostate cancer is becoming heavy. PMID- 20721253 TI - [Standardized diagnosis and treatment of azoospermia: a report of 1027 cases]. AB - OBJECTIVE: To constitute an appropriate procedure for clinical diagnosis and treatment for men with azoospermia in China. METHODS: Following a procedure which combined the recommendations from WHO, European Association of Urology (EAU), American Urological Association (AUA), American Society for Reproductive Medicine (ASRM) with our own experiences, 1 027 patients with azoospermia were divided into different subtypes according to patients' case histories and outcomes of various routine and specialized examinations. Then appropriate treatments were chosen according to the diagnostic subtypes. RESULTS: There were 516 cases of obstructive azoospermia, 315 of non-obstructive azoospermia and 150 of combined (obstructive and non-obstructive) azoospermia and 46 of azoospermia with special aetiology. Of the 96 patients who adopted surgical intervention, 28 underwent transurethral resection of the ejaculatory ducts, 10 vasovasostomy and 58 vasoepididymostomy. Of the 45 patients who adopted drug intervention, 16 with inflammatory obstructive azoospermia were treated with antibiotics and 29 with hypogonadotropic hypogonadism were treated with hormonal therapy. Of all the subjects, 789 patients chose in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and 142 chose artificial insemination of donor (AID) or adoption. CONCLUSION: (1) A standard procedure should be established for the diagnosis, classification and treatment of azoospermia; (2) Special examinations and treatments should be given to cases of azoospermia with special aetiology; (3) According to the diagnosis and the patients' conditions, the most appropriate treatment options should be recommended to them; (4) The hereditary factors in azoospermia should be seriously considered, and a genetic work-up and counseling should be offered in such cases. PMID- 20721254 TI - [Clinical efficacy and patient satisfaction with penile prosthesis implantation for the treatment of severe erectile dysfunction]. AB - OBJECTIVE: To investigate the clinical efficacy and patient and partner's satisfaction with penile prosthesis implantation (PPI) for treating Chinese patients with severe erectile dysfunction (SED). METHODS: One hundred and sixty eight SED patients were successfully treated by PPI from July 2000 to June 2010. Of the 146 (86.9%) patients who had been followed up over 6 months post operation, 36 (24.7%) had been implanted with one piece malleable prosthesis (AMS650) and 110 (75.3%) with three piece inflatable prosthesis (AMS700CXM).All the patients had been followed up by using international index of erectile dysfunction (IIEF5), Quality of Life Score (QOL) for evaluating clinical efficacy and using Visual Analogue Scale (VAS) for evaluating patient and partner's satisfaction and the duration of the follow-up was 6 to 119 months. RESULTS: The mean age of patients was 35.9+/-12.1 years(20 to 75 years), All the operations were successful and sexual intercourse with PPI was performed post 4 to 6 weeks without severe complications like infection and erosion. The prosthesis survive rate and frequent sexual intercourse rate were 98.6% and 87.7% respectively. IIEF5 scores pre and post PPI were 6.3+/- 1.7 and 21.3+/-1.6 respectively,the QOL scores pre and post PPI were 5.1+/-0.9 and 1.5+/-0.5 respectively, and both of them showed significant improvement (P<0.01). As for VAS, the patient and partner's overall satisfaction rates were 92.5% and 90.4% respectively. Moreover, better satisfaction was showed with AMS700CXM as compared with AMS650 (P<0.05) in patients with SED. CONCLUSION: PPI is the safe and effective treatment option for Chinese patients with SED. The AMS700CXM penile prosthesis is better than AMS650 for patients' overall satisfaction. PMID- 20721255 TI - [Correlation and risk factors between vascular endothelial dysfunction and erectile dysfunction]. AB - OBJECTIVE: To study the correlation between risk factors of vascular endothelial dysfunction and erectile dysfunction(ED). METHODS: The case history records levels of cholesterol,triglyceride and testicle, endothelial functions detected by using Doppler ultrasound and the risk factors of 134 ED patients were analyzed with those of 15 healthy men as the control group. RESULTS: We found that flow mediated dilation (FMD)<10% in 97 erectile dysfunction patients among the 134 cases was significantly different from that of the control group with no significant differences in cholesterol, triglyceride and testicle levels. Smoking and lack of exercise might be the high risk factors of vascular endothelial dysfunction. CONCLUSION: Erectile dysfunction may be linked to the impaired the endothelial function. PMID- 20721256 TI - [Corpus cavernosum-corpus spongiosum shunt plus intracavernous tunneling for the treatment of prolonged ischemic priapism]. AB - OBJECTIVE: To investigate the efficacy and safety of corpus cavernosum-corpus spongiosum shunt (CC-CSS) plus intracavernous tunneling(CC-CSS+ICT) for the treatment of prolonged ischemic priapism (PIP) were investigated. METHODS: Of 21 patients with PIP, 11 (Group A) underwent CC-CSS and 10 (Group B) CC-CSS+ICT surgery. The penile hardness score (PHS) and pain visual analogue score (PVAS) were used to assess the efficacy of the surgery. RESULTS: The erectile functions of the two groups were normal (IIEF5 23.6+/-1.1) before the onset of PIP, and the duration of PIP was (3.4+/-1.3) d. PHS 3.9+/-0.4, and PVAS 8.4+/-0.7. There was no statistical difference between the two groups (P>0.05). On 1, 3 and 5 days after the operation, the PHS and PVAS of Group B decreased significantly than those of Group A (P<0.05). CONCLUSION: CC-CSS+ICT could quickly restore penile detumescence and relieve pain as compared with CC-CSS, which might be a safe and effective method for the treatment of PIP. PMID- 20721257 TI - [Dapoxetine in treatment of premature ejaculation: a systematic review]. AB - OBJECTIVE: To assess the effectiveness of dapoxetine in the treatment of premature ejaculation. METHODS: Both English and Chinese studies involving men with prematrue ejaculation who were treated with dapoxetine from the Cochrane Library, MEDLINE, EMBASE and CNKI, CBM, VIP between 1979 and 2009.were included in the randomized controlled trials (RCTs) and the data processed by RevMan. RESULTS: Five RCTs involving 4433 patients were included in the Meta analysis, of which 3 were of grade A and 2 were of grade B according to the quality evaluation of methodology. Intravaginal ejaculatory latency time (IELT), patient-reported global impression of change (PGI), satisfaction with sexual intercourse (SWSI), perceived control over ejaculation (PCOE), personal distress related to ejaculation (PDRE) were used for assessment. Meta analysis based on included studies of patients having been treated with dapoxetine for 9-24 weeks showed that: (1) the difference of the patients' IELT between treatment group and control group was statistically significant [P<0.001, WMD (95%CI) was 1.38 (1.21,1.55)]; (2) the difference of the PGI of development in premature ejaculation between treatment group and control group was statistically significant [P<0.001, OR (95%CI) was 3.56 (2.60,4.88)]; (3) the difference of the patients' SWSI between treatment group and control group was statistically significant [P<0.001, OR (95%CI) was 3.85 (2.08,7.10)]; the difference of the patients' score of SWSI between treatment group and control group was statistically significant [P<0.001, WMD (95%CI) was 0.55 (0.48,0.62)]; (4) the difference of the patients' change of PCOE between treatment group and control group was statistically significant [P<0.001, OR (95%CI) was 2.87(2.30,3.58)]; the difference of the patients' score of PCOE between treatment group and control group was statistically significant [P<0.001, WMD (95%CI) was 0.63(0.49,0.78)]; (5) after being treated with dapoxetine for 9-24 weeks, the difference of the patients' change of PDRE between treatment group and control group was statistically significant [P<0.001, OR (95%CI) was 2.02 (1.69,2.42)]. All the RCTs reported the side effects of dapoxetine, but the results showed that there were no serious side effects of dapoxetine during the treatment period. CONCLUSION: The available evidence indicates that dapoxetine would improve the symptoms of premature ejaculation, prolong IELT over 9-24 weeks in men from a wide range of cultural backgrounds, and significantly improve all patients' reported outcomes and the patients' clinical global impressions of premature ejaculation, including more control, greater satisfaction, and less distress. PMID- 20721258 TI - [Establishment nephrolithiasis rat model induced by nanobacteria and analysis of stone formation]. AB - OBJECTIVE: To establish nephrolithiasis rat model induced by nanobacteria and to determine the relationship of nanobacteria with nephrolithiasis. METHODS: Thirty adult male SD rats were randomized into 3 groups (n=10 each): group A, given an intravenous injection of nanobacteria; group B, given an intravenous injection of nanobacteria and taken tetracycline; group C, as normal control. Eight weeks later, all rats were sacrificed and the kidneys were examined for pathology and the 24-h urine N-acetyl-beta-D-aminoglycoside enzyme (NAG) and lactate dehydrogenase (LDH) were detected. RESULTS: Histopathological studies revealed nanobacteria induced renal tubular crystallization, which was significantly different among the 3 groups (P=0.033). The crystallization was higher in group A than that in group B. The urinary NAG and LDH excretion were significantly different among the 3 groups (P<0.001). CONCLUSION: Nanobacteria may be involved in the pathogenesis of nephrolithiasis. Tetracycline may inhibit stone formation. PMID- 20721259 TI - [Effect of nanobacteria on cell damage and crystal retention in renal tubular epithelial cells]. AB - OBJECTIVE: To study the damage of nanobacteria on HK-2 cells, the possible principles, the effect of crystals (COM) adhering to HK-2 cells after the damage. METHODS: Four groups were chosen for the study: control group, NB group, nHAP group and COM group. Morphological changes of the HK-2 cells were observed after HE stain and with TEM after 12 hours and 24 hours. Meanwhile, the levels of H2O2, LDH, MDA and ATPases were surveyed after 6 hours,12 hours and 24 hours, respectively. And 6, 12, and 24 hours later, COM crystals were mixed into the culture fluids of each group. Then phalloidin-FITC was used to finish fluorescent staining of the cells. At last, the adhering effects of each group with the laser scanning confocal fluorescence microscope were observed and contrasted. RESULTS: After HE stain and with TEM: in NB and nHAP group, the shape of the cells changed, brush borders were arranged in disorder, vacuoles formed in the kytoplasms, the mitochondria became swelled up, the karyotheca dissolved and the nucleolus disappeared in some cells. After 24 hours, in NB group, the number of the cells in which the karyotheca dissolved was more than that in nHAP group. After 12 and 24 hours, the level of H2O2 in NB group was higher than that in control group and nHAP group; After 6 and 24 hours, the level of MDA in NB group was higher than that in control group and nHAP group; At each time point, there was no significant difference in the level of LDH between control group, nHAP group and NB group; After 12 hours, the activities of Na+/K+ ATPases in NB group and nHAP group were lower than those in control group. And after 24 hours, the activity of Na+/K+ ATPases in NB group was lower than that in control group; After 12 and 24 hours, the activities of Ca2+/Mg2+ ATPases in NB group was lower than those in control group. After 12 hours, the activity of Ca2+/Mg2+ ATPases in nHAP group was lower than that in control group. The observation with the laser scanning confocal fluorescence microscope: after 12 hours, showed that the number of the crystals adhering to the cells in NB group and COM group increased, and in COM group, some crystals had entered the cells; after 24 hours, the adhering effects of the crystals in NB and COM group were similar to those after 12 hours, but the number of adhered crystals was more than that after 12 hours; At each time point, there was no significant change in control and nHAP groups. CONCLUSION: Nanobacteria has a damage effect on HK-2 cells, the damage increases with the acting time expanding. The damage is more severe than that of nHAP. In the damage process of nanobacteria, the lipid peroxidation may play an important role. After the damage of nanobacteria, the adhering effect of the COM crystals to the cells increases observably, and the number of crystals adhering to the cells becomes more and more with the acting time expanding. Although nHAP also has a damage effect on HK-2 cells, it does not effect the adhering process. PMID- 20721260 TI - [Cultivation and morphology of nanobacteria in sera of patients with kidney calculi]. AB - OBJECTIVE: To detect, culture, and characterize the nanobacteria (NB) from sera of patients with kidney calculi in our department. METHODS: Blood samples of 24 patients with kidney calculi and of 3 healthy volunteers in our department were collected for NB culture in this study. We used immunohistochemistry, von kossa staining, scanning electron microscopy (SEM), transmission electron microscopy (TEM) to investigate the appearance and components of cultural NB. RESULTS: Twenty-two blood samples out of 24 (91.67%) showed growth of NB, while no NB were detected in volunteers' blood samples. The infection rate of stone group was obviously higher than that of healthy volunteers. After a 4-week culture period, the light microscope revealed coccoid-shaped NB with a diameter of 100-500 nm, which could be identified by immunohistochemistry and von kossa staining. SEM and TEM (negative staining) revealed NB with a hollow interior coated in needle-like apatite crystals. Such nanoparticles could bud-off new ones and therefore appeared like living organisms. CONCLUSION: NB can be identified from sera of most patients involved in kidney calculi. It may have intimate relation to the formation of kidney calculi because the infection rate of NB blood samples of stone patients was significantly higher than that of healthy volunteers. Immunohistochemistry, von kossa staining, SEM and TEM are special methods for identifying NB from different aspects. The appearance and character are important points to distinguish NB from other nano-sized particles. PMID- 20721261 TI - [Standard-tract percutaneous nephrolithotomy accessed by two-step dilation for 3052 patients]. AB - OBJECTIVE: To evaluate the efficacy and morbidity of 24F-tract percutaneous nephrolithotomy (PNL) accessed by two-step dilation. METHODS: A total of 3052 patients with 3 366 kidneys or upper ureter calculi underwent 24F-tract PNL accessed by two-step dilation between Aug., 2003 and Jan., 2008, including 108 patients with solitary kidney, 68 with kidney cysts, 44 with horseshoe kidney, 26 with vertebral column deformity, 24 with medullary sponge kidney and 1 transplanted kidney. Stone burdens were (47.2+/-35.6) mm in length. RESULTS: 99.4% of 3740 operations were successful in one-session access,in which 3348 PNLs were accessed by single tract (89.5%), 366 by double tracts (9.7%) and 26 by triple tracts (0.7%). The mean operating time was (68.4+/-30.9) min, the mean first accessing time were (17.6+/-11.1) min. and the mean calculi-dealing time were (35.0+/-55.3) min. The stone-free rate after one session operation was 100% for single calculus and 72.3% for multiple or staghorn calculi. of all the kidneys, 374 (11.1%) accepted another PNL to remove the residual calculi, and the last stone-free rate of PNL was 88.6%. During and after operation, 52 cases (1.4%) needed transfusion, 12 (0.3%) underwent selective embolization of renal artery and 1 (0.03%) accepted nephrectomy for bleeding control. No injury of organs occurred except for 3 cases with pneumatothorax and 19 (0.5%) with urinary extravazation. No septic shock occurred. CONCLUSION: 24F-tract PNL accessed by two-step dilation wtih ultrasound-guided puncture is effective and safe. PMID- 20721262 TI - [Analysis of serum electrolytes in urolithiasis patients]. AB - OBJECTIVE: To define the difference of serum calcium (Ca), phosphorus (P), potassium (K), sodium (Na), chlorine (Cl), carbon dioxide combining power (CO2CP), hydrogen ion concentration (pH) of urine and urine specific gravity (SG) between those patients suffering from urolithiasis and non-urolithiasis at the same time period. METHODS: Data from 1 164 patients admitted to the Department of Urology, Peking University People's Hospital from January, 2005 to July, 2007 were retrospectively reviewed. Seven hundred fourteen patients suffered from urolithiasis, and 450 patients were diagnosed as non-urolithiasis. Blood and urine were taken from the patient the next morning after admission. Serum levels of Ca, P, K, Na, Cl, CO2CP and urine pH and SG were checked by automatic biochemistry analyzer. The data were analyzed by software SPSS 13.0. RESULTS: Patients' ages in urolithiasis group varied from 5 to 87 years and the male to female ratio was 1.8:1. The patients in non-urolithiasis group aged from 12 to 94 years and the male to female ratio was 3.8:1. There was difference in the levels of serum Na, K, Cl, CO2CP, Ca and P between urolithiasis and non-urolithiasis groups (P<0.05). In male patients, serum Na, Ca and P levels in urolithiasis group were higher than those in non-urolithiasis group(P<0.05), serum K and urine pH levels were lower in urolithiasis group than those in non-urolithasis group (P<0.05). In female patients, serum Na level was higher in urolithiasis group than that in non-urolithiasis group (P=0.080). Logistic regression analysis showed that beta value of serum Na level in male and female group was 0.10 (P<0.01) and 0.09 (P=0.054) respectively. CONCLUSION: There was difference in serum electrolyte levels between urolithiasis group and non-urolithiasis group. The chang of serum Na level may play role in pathogenesis of urolithiasis. PMID- 20721263 TI - [Retroperitoneal laparoscopic adrenalectomy for larger adrenal tumor]. AB - OBJECTIVE: To evaluate the feasibility and safety of retroperitoneal laparoscopic adrenalectomy for larger adrenal tumor. METHODS: A retrospective cohort study of patients who underwent retroperitoneal laparoscopic adrenalectomy in a single unit from July 2004 to December 2008 was undertaken, in which 53 cases were divided into 2 groups according to size as estimated by group A [n=13; age: 45+/ 18 years; size: (7.6+/-1.2) cm, maximum diameter of tumor larger than 6 cm] and group B [n=40; age: (49+/-12) years; size: (4.0+/-0.9) cm, between 3 and 6 cm]. RESULTS: All procedures were performed successfully. In comparison between the 2 groups ,the mean operative time [(127+/-77) min vs (107+/-47) min, P<0.05] and estimated blood loss [(167+/- 223) mL vs (65+/-60) mL,P<0.01] had significant difference. The intraoperative complications and blood transfusion rate in group A were higher than those of group B (23% vs 12.5% and 15% vs 2.5%),no difference was noted in their hospital stay after operation [(7.1+/-1.1) d vs (5.5+/-0.7) d, P>0.05]. Group A was followed up for 25+/-14 months,during which time no local recurrence was noted in 8 cases, 3 cases were missed ,and 2 cases were alive with hydronephrosis. Group B was followed up for 29+/-14 months, during which time 30 cases were free, 9 cases were lost, and 1 case was found with real disfunction. The pathology of most tumors in group A included medullary lipoma(30.8%), pheochromocytoma(23%) and ganglioneuroma(23%), the others included adenoma(32.5%), pheochromocytoma(25%) and ganglioneuroma(17.5%) in group B. CONCLUSION: Retroperitoneal laparoscopic adrenalectomy has best value in patients with larger adrenal tumor and it is a minimally invasive and safe procedure for skillful surgeons in the treatment of tumor size larger than 6 cm. PMID- 20721264 TI - [Intravesical laparoscopic repair of vesicovaginal fistula]. AB - OBJECTIVE: To introduce a new technique to treat vesicovaginal fistula (VVF) with intravesical laparoscopic repair, and assess its safety and efficacy. METHODS: Four female patients with iatronic VVF were treated with intravesical laparoscopic method between October 2008 and March 2010. The second case underwent open surgery repair four months ago. All the fistulae were in posterior wall of bladder,with 0.8 cm, 1.0 cm, 1.2 cm and 0.5 cm in size respectively. One 10 mm superpubic trocar and 2.5 mm lateral trocars were placed in surgery. Carbon dioxide gas was used to distend the bladder. RESULTS: Four operations were completed successfully. The operative time was 80-140 min, and the blood loss was 50-100 mL. The indwelling catheter was removed after 4 weeks. All the patients were followed up for 1-8 months. Three patients showed no recurrence of fistula and had normal urination. One patient developed urinary leakage through the vagina again after 1 month. CONCLUSION: Intravesical laparoscopic technique is a safe and effective treatment with micro-trauma for iatrogenic VVF, but more clinical files are needed for further evaluation. PMID- 20721265 TI - [Diagnose and therapy for urinary tract endometriosis: a report of 22 cases]. AB - OBJECTIVE: To describe our diagnostic and therapeutic experience of patients with urinary tract endometriosis. METHODS: We performed a retrospective analysis of 22 cases of urinary tract endometriosis with histopathological results from 2001 to 2007. RESULTS: The mean patient age was 36.0 years. Of the 22 patients, 4 had bladder involvement and 18 ureteral involvement. In those with bladder endometriosis, the diagnosis was made by cystoscopy and biopsy in 4 patients. The treatments consisted of partial cystectomy in 3 patients and transurethral resection of the bladder in 1 patient. One of the patients who underwent transurethral resection of the bladder experienced 1 relapse. The relapse was treated with partial cystectomy. In the patients with ureteral endometriosis, the diagnosis was mainly established by ultrasound (18 cases), intravenous urography (11 cases), retrograde pyelography (7 cases), CT (14 cases) and MRI (5 cases). The treatments consisted of ureterolysis in 1 patient,ureteroneocystostomy in 4, and ureteral resection and end-to-end anastomosis in 13 of them. All the patients pathologic results were of endometriosis. CONCLUSION: Urinary tract endometriosis is an uncommon disease. Partial cystectomy should be considered as the therapeutic option for bladder endometriosis . For cases of ureteral endometriosis, the first technique depends on the location, extent and depth of the lesion. PMID- 20721266 TI - [Characteristics of renal hemorrhage after percutaneous nephrolithotomy and the timing of selective embolization: a report of 13 cases]. AB - OBJECTIVE: To investigate the characteristics of severe renal hemorrhage after percutaneous nephrolithotomy (PNL) and timing of selective transarterial embolization(TAE) . METHODS: Between May 2005 and March 2010, superselective renal angiography was used to control severe bleeding in 15 of 1418 cases (1520 PNL procedures, 1.06%). In the 15 cases, superselective renal angioembolization was used to control severe bleeding in 13 (0.92%) . The medical records of all the patients who underwent renal angiography and angioembolization were reviewed. RESULTS: Severe bleeding cases after PNL were divided into 3 types according to the clinical characteristics: type I (urgency type), type II (intermittence type) and type III (persistent slow type). There were 3 patients in type I, 6 in type II and 6 in type III. All the patients had a normal coagulation profile before surgery. A total of 11 patients (84.6%) underwent the first-time successful embolization and 2 (15.4%) the second-time successful embolization. The longer time between angioembolization and bleeding was, the more blood loss and transfusion volume were, except for 1 patient in type II . Temporality serum creatinine abnormality was found in 2 patients, one with a solitary kidney patient and the other with angioembolization for both renal bleeding. CONCLUSION: TAE is a minimally invasive, safe, simple, and highly effective modality for the management of post PNL renal bleeding. This option should be considered early in the management of these cases,especially for Urgency type bleeding. PMID- 20721267 TI - [Retropublic extraperitoneal laparoscopic prostatectomy with urethra preservation]. AB - OBJECTIVE: To explore the feasibility and superiority of retropubic extraperitoneal laparoscopic simple prostatectomy with prostatic urethra preservation to treat large volume benign prostatic hyperplasia(BPH) . METHODS: From January 2006 to August 2009, laparoscopic simple prostatectomy with prostatic urethra preservation was performed in 45 patients with symptomatic BPH,and the age of patients was 70.5+/-7.2 (range 47 to 83) years old. The transrectal ultrasound (TRUS) revealed BPH and calculated prostatic gland weight was 126.1+/-52.4 (range 62 to 365) g. There were 3 cases presented with bladder calculus and 1 case presented with bladder diverticulum. The technique included retropubic extraperitoneal space produced by balloon dilation, five trocars in a reverted U shape placed,transverse prostatic capsular incision made, subcapsular plane developed, prostatic adenoma removed while prostatic urethra preserved as well as prostatic capsule sutured. Demographic, perioperative and outcome data were recorded. RESULTS: No patient required conversion to open surgery. The mean operative time was 123.9+/-51.3 (range 37 to 270) minutes and the estimated blood loss was 230.6+/-194.5 (range 50 to 800) mL. Blood transfusion was not necessary in this group of patients. Bladder irrigation was not needed except for the initial 2 cases and the average Foley catheter duration was 7.5+/-3.5 (range 2 to 14) days. Significant improvement was noted in the maximum flow rate, the International Prostate Score Symptoms (IPSS) and the quality of life questionnaires (QOL) three months after surgery. The erectile function was preserved in all patients who were potent before surgery and the ejaculation maintained antegrade. No urinary incontinence was reported by patients. CONCLUSION: Laparoscopic simple prostatectomy with prostatic urethra preservation for large benign prostatic hyperplasia is feasible and reproducible. Postoperative bladder irrigation can be avoided and antegrade ejaculation is preserved. The patients have a shorter hospital stay and early return to normal activity. PMID- 20721268 TI - [Clinical application of subcutaneous nephrovesical bypass system]. AB - OBJECTIVE: To evaluated the subcutaneous nephrovesical bypass carried out in patients with ureter obstruction and improve the quality of life of patients with palliative definitive percutaneous nephrostomy. METHODS: A total of 36 patients with advanced cancer receiving 45 subcutaneous nephrovesical bypass tubes were included in the study. Uronephrosis ranged from 1.8-5.2 cm, serum creatinine 73 760 micromol/L,and glomerular filtration rate (GFR) 19-26 mL/min. The obstruction was proved to be complete by retrograde pyelography. The nephrovesical stents were inserted utilizing percutaneous access to both of the kidney and bladder,and a subcutaneous tunnel was created between the two sites. B-ultrasound, KUB (kidneys, ureters, and bladder), serum creatinine test and GFR were carried out 72 hours after operation. RESULTS: Urinary diversion operations were successful in the 36 patients, uronephrosis ranged from 0-1.8 cm, all stents were in position, serum creatinine 72-173 micromol/L, GFR 25-40 mL/min after the operation, and the bypass functioned well in 45 stents for 67 to 481 days of the follow-up. CONCLUSION: Subcutaneous nephrovesical bypass can protect renal function of patients suffering from ureteral obstruction by simple and minimum invasive operation; it can also reduce complications caused by percutaneous nephrostomy and improve the patient's life quality. PMID- 20721269 TI - [Development of remote wireless mobile voiding diary and a report of its objective voiding in 20 young people]. AB - OBJECTIVE: To find out the data of the micturitions in healthy young people with the remote & mobile voiding diary monitoring system. METHODS: Twenty healthy young people were studied and ten of them were female. The ages ranged from 22 to 35 years (the mean age: 27.4 years). The females were 22-33 years old (the mean age: 26.4 years ) and the males 24-35 years old (the mean age: 28.4 years). With the remote & mobile voiding diary monitoring system, their voiding information was collected. Through bluetooth, the voiding information was sent to the patient's intelligent cell phone from the collector, then stored directly by intelligent cell phone and wirelessly transmitted to the workstation in the hospital. All of them completed the voiding diaries for 7 days and the data were analyzed. RESULTS: The average micturition of the young healthy people was 5.6 times (3.4-7.4) per 24 hours,in which 5.3 (3.4-7.3) times were in the daytime and 0.3 (0-1.3)times in the night. The functional voiding volume was 318 mL (66-642 mL). The mean voiding volume in 24 hours was 1 724 mL (1152-2 415 mL), in which 1 289 mL (786-2 039 mL) was in the daytime and 435 mL (292-805 mL) in the night. The mean drinking volume was 1 022 mL (453-1 721 mL) in the daytime and 7 mL (0 43 mL) in the night. The nocturia index (Ni) was 1.03, the nocturnal polyuria index (NPi) 26%, and the nocturnal bladder capacity index (NBCi) 0.27. CONCLUSION: The remote & mobile voiding diary monitoring system can help us get the objective voiding information from young health people for the first time. It is reliable, maneuverable and can be widely used in clinical diagnosis. PMID- 20721270 TI - [A methodology study on flow cytometric analysis of cell DNA stained with DAPI and Hoechst33342]. AB - OBJECTIVE: To discuss a simple method for flow cytometric analysis of cell DNA stained with DAPI and Hoechst33342. METHODS: HT 29 cells stained with DAPI, Hoechst33342 or PI were measured by BD FACSAria and the percentages of cells in G0/G1, S and G2/M phases with three staining methods, then the results were analyzed and compared. Before measurement we monitored the quality of DNA analysis of flow cytometer through UV beads QC experiment and analyzed the standard chicken erythrocyte nuclei (CEN) and calf thymocyte nuclei (CTN) stained with DAPI and Hoechst33342. RESULTS: CV value of UV peak was 2.4 after QC experiments. There were 4 peaks on CEN histograms and the ratios of peak channel mean of G2/G1, G3/G1, and G4/G1 were about 2, 3, and 4 respectively. Both CV values of the first peak were 2.4. There were 2 peaks on CTN histograms and the ratio of peak channel mean of G2/G1 was 1.97, and CV value of G0/G1 2.4. The complete cell cycle of HT29 cells stained with DAPI, Hoechst33342 or PI was showed entirely, CV values were 3.40, 3.02 and 4.42, respectively, and the percentages of cells in G0/G1 were 60.86%, 60.22% and 60.81%,respectively, in S, 28.85%, 29.70% and 29.82%,respectively, and in G2/M, 10.29%, 9.09% and 9.37%, respectively. The results by the three methods showed no difference. CONCLUSION: This method for measurement of cellular DNA content is a simple and efficient approach to determining cell cycle and can be the first choice when using flow cytometer with 355 nm UV. PMID- 20721271 TI - [Advances in clinical study of nocturia]. AB - Nocturia is one of the most common reasons for interrupted sleep in general adult population. The condition affects both men and women, with an incidence that increases dramatically with age. Nocturia has a negative impact on quality of life, affecting both morbidity and mortality. International Continence Society (ICS) issued a report of terminology standardization in 2002, in which nocturia is defined as waking during the night at least once to urinate. Nocturia is a common complaint in elderly population. Although most cases of nocturia are assumed to be caused by urologic problems, the interacting effects of aging and sleep on renal and urinary function, in fact, cause nocturia in the elderly. Effective diagnosis of the condition is dependent on a clear understanding of its underlying etiology. Multiple factors may cause nocturia, such as behavioral or environmental factors and pathologic conditions. In general, the causes of nocturia fall into three categories: diurnal polyuria, nocturnal polyuria, and low bladder capacity. Careful evaluation of medications and underlying medical conditions is essential for the proper management of nocturia. A voiding diary is necessary to diagnose the syndrome of nocturnal polyuria, which is a common cause of nocturia. Addressing any underlying conditions that contribute to nocturia is the first step in treating the condition. Lifestyle and behavioral changes may provide benefit in some individuals, but for many cases, pharmacotherapy is the best option. Antimuscarinic agents are first-line therapies for overactive bladder and are often used in the management of nocturia. Current treatment options also include desmopressin, a synthetic analog of arginine vasopressin, which can increase urinary osmolality and decrease total urinary volume. The desmopressin therefore increases the length of time until the first nocturnal void and decreases the number of nocturnal voids, the NUV voided, and the percentage of urine voided at night. PMID- 20721272 TI - A case of critical aortic stenosis masquerading as acute coronary syndrome. AB - Serum cardiac troponins I and T are reliable and highly specific markers of myocardial injury. Studies have shown that at least 20% of patients with severe aortic stenosis have detectable serum troponins. This case report describes a patient who presented as suspected acute coronary syndrome with markedly elevated troponin levels, who was later found to have normal coronaries and critical aortic stenosis. This case highlights the need for comprehensive and accurate physical examination in patients who present with angina. Critical aortic stenosis may cause such severe subendocardial ischemia as to cause marked elevation in cardiac markers and mimic an acute coronary syndrome. Careful physical examination will lead to an earlier use of non invasive techniques, such as echocardiography to confirm the correct diagnosis and the avoidance of inappropriate treatments such as intravenous nitroglycerin and glycoprotein IIb/IIIa inhibitors. PMID- 20721274 TI - Echocardiographic Assessment of Left Ventricular Function in Type 1 Gaucher's Disease. AB - There is predominate opinion among physicians managing type 1 Gauchers' disease (GD) that cardiac involvement is not an issue in these patients. In order to follow this hypothesis, we prospectively investigated 15 adult imiglucerase treated type 1 GD patients by echocardiography, Doppler, and tissue Doppler echocardiography. This was a case-controlled study with 18 matched healthy volunteers. The obtained data was correlated with the levels of NT-proBNP (brain natriuretic peptide). None of the GD patients had clinical signs of heart disease. In 3 of the 15 patients, we observed echocardiographic signs of aortic and mitral valve calcification. The left ventricular systolic function was within normal limits. Compared to the control group, there was no statistically significant difference observed in the most sensitive indices of left ventricular diastolic function, parameter E(m) (P = .095), and E/E(m) ratio (P = .097), as demonstrated by tissue Doppler echocardiography. However, there was a positive correlation between the E/E(m) ratio and NT-proBNP plasma levels (P = .009). In conclusion, the prospective echocardiographic study of type 1 GD patients did not validate any left ventricular dysfunction. But, the E/E(m) ratio showed a strong statistical correlation with the most sensitive indicators of heart failure, NT proBNP. Research on larger groups of patients and the usage of even more sensitive methods as strain-rate imaging will be necessary to confirm eventual myocardial involvement in GD patients. PMID- 20721275 TI - Bevacizumab demonstrates prolonged disease stabilization in patients with heavily pretreated metastatic renal cell carcinoma: a case series and review of the literature. AB - There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC). These include the immunotherapeutics, alfa interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR) via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months) with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study. PMID- 20721273 TI - S-layer glycoproteins and flagellins: reporters of archaeal posttranslational modifications. AB - Many archaeal proteins undergo posttranslational modifications. S-layer proteins and flagellins have been used successfully to study a variety of these modifications, including N-linked glycosylation, signal peptide removal and lipid modification. Use of these well-characterized reporter proteins in the genetically tractable model organisms, Haloferax volcanii, Methanococcus voltae and Methanococcus maripaludis, has allowed dissection of the pathways and characterization of many of the enzymes responsible for these modifications. Such studies have identified archaeal-specific variations in signal peptidase activity not found in the other domains of life, as well as the enzymes responsible for assembly and biosynthesis of novel N-linked glycans. In vitro assays for some of these enzymes have already been developed. N-linked glycosylation is not essential for either Hfx. volcanii or the Methanococcus species, an observation that allowed researchers to analyze the role played by glycosylation in the function of both S-layers and flagellins, by generating mutants possessing these reporters with only partial attached glycans or lacking glycan altogether. In future studies, it will be possible to consider questions related to the heterogeneity associated with given modifications, such as differential or modulated glycosylation. PMID- 20721276 TI - Use of the 2-Pyridinealdoxime/N,N'-Donor Ligand Combination in Cobalt(III) Chemistry: Synthesis and Characterization of Two Cationic Mononuclear Cobalt(III) Complexes. AB - The use of 2-pyridinealdoxime (paoH)/N,N'-donor ligand (L-L) "blend" in cobalt chemistry has afforded two cationic mononuclear cobalt(III) complexes of the general type [Co(pao)(2)(L-L)](+), where L-L = 1,10-phenanthroline (phen) and 2,2'-bipyridine (bpy). The CoCl(2)/paoH/L-L (1 : 2 : 1) reaction system in MeOH gives complexes [Co(III)(pao)(2)(phen)]Cl.2H(2)O (1.2H(2)O) and [Co(III)(pao)(2)(bpy)]Cl.1.5MeOH (2.1.5MeOH). The structures of the complexes were determined by single-crystal X-ray crystallography. The Co(III) ions are six coordinate, surrounded by three bidentate chelating ligands, that is, two pao(-) and one phen or bpy. The deprotonated oxygen atom of the pao(-) ligand remains uncoordinated and participates in hydrogen bonding with the solvate molecules. IR data of the complexes are discussed in terms of the nature of bonding and the known structures. PMID- 20721277 TI - Modelling nonstationary gene regulatory processes. AB - An important objective in systems biology is to infer gene regulatory networks from postgenomic data, and dynamic Bayesian networks have been widely applied as a popular tool to this end. The standard approach for nondiscretised data is restricted to a linear model and a homogeneous Markov chain. Recently, various generalisations based on changepoint processes and free allocation mixture models have been proposed. The former aim to relax the homogeneity assumption, whereas the latter are more flexible and, in principle, more adequate for modelling nonlinear processes. In our paper, we compare both paradigms and discuss theoretical shortcomings of the latter approach. We show that a model based on the changepoint process yields systematically better results than the free allocation model when inferring nonstationary gene regulatory processes from simulated gene expression time series. We further cross-compare the performance of both models on three biological systems: macrophages challenged with viral infection, circadian regulation in Arabidopsis thaliana, and morphogenesis in Drosophila melanogaster. PMID- 20721278 TI - Synthesis, Structure, and Antiproliferative Activity of Three Gallium(III) Azole Complexes. AB - As part of our interest into the bioinorganic chemistry of gallium, gallium(III) complexes of the azole ligands 2,1,3-benzothiadiazole (btd), 1,2,3-benzotriazole (btaH), and 1-methyl-4,5-diphenylimidazole (L) have been isolated. Reaction of btaH or btd with GaBr(3) or GaCl(3) resulted in the mononuclear complexes [GaBr(3)(btaH)(2)] (1) and [GaCl(3)(btd)(2)] (2), respectively, while treatment of GaCl(3) with L resulted in the anionic complex (LH)(2)[GaCl(4)] (3). All three complexes were characterized by single-crystal X-ray crystallography and IR spectroscopy, while their antiproliferative activities were investigated against a series of human and mouse cancer cell lines. PMID- 20721279 TI - Primary stenting immediatly after surgery in occluded anastomoses of aortoaortic tube graft: a case report. AB - The conventional elective open procedures for abdominal aortic aneurysm repair are reliable and yield durable results. The aortoaortic tube graft has the lowest morbidity incidence when compared with different techniques. Albeit infrequent, thrombosis can be present in the first 30 days. Its treatment consists in thrombectomy and anastomosis evaluation, but with an increase in morbidity, especially in patients with urgent reintervention. This is a case report of a patient with aortoaortic tube graft, who present critical left limb ischemia immediately after surgical procedure. Angiography showed complete occlusion of left common iliac artery, affecting the distal graft anastomosis. The occlusion was resolved with endovascular treatment, and a noncovered, self-expanding, nitinol stent was deployed (primary stenting) covering the distal bypass anastomosis, with no complications and complete lower limb perfusion recovery. One month later, the patient was still asymptomatic, with distal pulse palpable and ankle-brachial index 1. PMID- 20721280 TI - Kinetic Studies and Mechanism of Hydrogen Peroxide Catalytic Decomposition by Cu(II) Complexes with Polyelectrolytes Derived from L-Alanine and Glycylglycine. AB - The catalytic decomposition of hydrogen peroxide by Cu(II) complexes with polymers bearing L-alanine (PAla) and glycylglycine (PGlygly) in their side chain was studied in alkaline aqueous media. The reactions were of pseudo-first order with respect to [H(2)O(2)] and [L-Cu(II)] (L stands for PAla or PGlygly) and the reaction rate was increased with pH increase. The energies of activation for the reactions were determined at pH 8.8, in a temperature range of 293-308 K. A suitable mechanism is proposed to account for the kinetic data, which involves the Cu(II)/Cu(I) redox pair, as has been demonstrated by ESR spectroscopy. The trend in catalytic efficiency is in the order PGlygly>PAla, due to differences in modes of complexation and in the conformation of the macromolecular ligands. PMID- 20721281 TI - Isolated ventricular noncompaction syndrome in a nigerian male: case report and review of the literature. AB - Isolated ventricular non-compaction cardiomyopathy (IVNC) is a rare, morphologically distinct primary genetic cardiomyopathy, which is now gaining prominence as an important differential diagnosis in patients presenting with cardiac failure. We describe a case report of a Nigerian male with facial dysmorphism presenting with cardiac failure. This is followed by a review of the literature with focus on the diagnosis of this condition, which may be difficult especially in non-Caucasian populations. PMID- 20721282 TI - Kinetics and Mechanisms of the Chromium(III) Reactions with 2,4- and 2,5 Dihydroxybenzoic Acids in Weak Acidic Aqueous Solutions. AB - The reactions of 2,4- and 2,5-dihydroxybenzoic acids (dihydroxybenzoic acid, DHBA) with chromium(III) in weak acidic aqueous solutions have been shown to take place in at least two stages. The first stage of the reactions has an observed rate constant k(1(obs)) = k(1)[DHBA] + C and the corresponding activation parameters are DeltaH(1(2,4)) ( not equal) = 49, 5 kJ/mol(-1), DeltaS(1(2,4)) ( not equal) = -103, 7 J mol(-1) K(-1), DeltaH(1(2,5)) ( not equal) = 60, 3 kJ/mol( 1), and DeltaS(1(2,5)) ( not equal) = -68, 0 J mol(-1) K(-1). These are composite activation parameters and the breaking of the strong intramolecular hydrogen bonding in the two ligands is suggested to be the first step of the (composite) first stage of the reactions. The second stage is ligand concentration independent and is thus attributed to a chelation process. The corresponding activation parameters are DeltaH(2(2,4)) ( not equal) = 45, 13 kJ/mol(-1), DeltaS(2(2,4)) ( not equal) = -185, 9 J mol(-1) K(-1), DeltaH(2(2,5)) ( not equal) = 54, 55 kJ/mol(-1), and DeltaS(2(2,5)) ( not equal) = -154, 8 J mol(-1) K(-1). The activation parameters support an associative mechanism for the second stage of the reactions. The various substitution processes are accompanied by proton release, resulting in pH decrease. PMID- 20721283 TI - Noninvasive demonstration of dual coronary artery fistulas to main pulmonary artery with 64-slice multidetector-computed tomography: a case report. AB - Coronary artery fistulas, including coronary pulmonary fistulas, are usually discovered accidently among the adult population when undergoing invasive coronary angiographies. We report here a 58-year-old woman with dual fistulas originating from the left anterior descending coronary artery and right coronary sinus to the main pulmonary artery, demonstrating noninvasively with multidetector-computed tomography (MDCT) and transthoracic echocardiography (TTE). PMID- 20721284 TI - A rare coronary anomaly: one ostium fits all. AB - Coronary anomalies affect a small percentage of the general population. A solitary coronary ostium in the absence of other major congenital anomalies is very rare. We describe a case of a patient, admitted to our cardiology department with an acute myocardial infarction. A coronary angiogram shows a solitary ostium originating from the right sinus of Valsalva with the left anterior descending coronary artery (LAD) ventral to the pulmonary artery and the circumflex artery (Cx) following its course retroaortically. The theoretical variant of this type of malformation has been described but has not been reported in a clinical case before. Coronary anomalies are usually detected during coronary angiography, but exact course determination and relationships are difficult to visualize. The use of cardiac computed tomography (CCT) allows visualization of the coronary anatomy in a 3-dimensional image and demonstrated an added value to coronary angiography. PMID- 20721285 TI - The chick as a model for the study of the cellular mechanisms and potential therapies for Alzheimer's disease. AB - While animal experiments have contributed much to our understanding of the mechanisms of Alzheimer's disease (AD), their value in predicting the effectiveness of treatment strategies in clinical trials has remained controversial. The disparity between the results obtained in animal models and clinical trials may in part be explained by limitations of the models and species specific differences. We propose that one trial passive avoidance in the day-old chick is a useful system to study AD because of the close sequence homologies of chick and human amyloid precursor protein (APP). In the chick, APP is essential for memory consolidation, and disrupting its synthesis or structure results in amnesia. RER, a tripeptide sequence corresponding to part of the growth domain of APP, can restore memory loss and act as a cognitive enhancer. We suggest that RER and its homologues may form the basis for potential pharmacological protection against memory loss in AD. PMID- 20721286 TI - Survey of the Factors Associated with a Woman's Choice to Have an Epidural for Labor Analgesia. AB - Objectives. The purpose of this study was to determine the factors associated with whether a woman received an epidural in labor and to determine the main source used to obtain information about labor epidurals. Methods. Over a one month period, we surveyed all patients who labored, the day after their delivery. We used multiple logistic regression to identify potential predictive factors after initial univariate analysis. Results. 320 women who met enrollment criteria delivered during the study period and 94% completed the study. Of the 302 patients surveyed, 80% received an epidural for labor. Univariate analysis showed the following variables were associated with whether women received an epidural (P < .01): partner preference, prior epidural, language, education, type of insurance, age, duration, and pitocin use. Using computed multiple logistic regression only partner preference and prior epidural were associated with whether women received an epidural. Conclusion. It was not surprising that a previous epidural was predictive of a patient receiving an epidural. The strong association with partner preference and epidural use suggests this is an important factor when counseling pregnant women with regard to their decision to have a labor epidural. PMID- 20721287 TI - Rikkunshito and ghrelin. AB - Rikkunshito is a popular Japanese traditional medicine that is prescribed in Japan to treat various gastrointestinal tract disorders. In a double-blind controlled study, rikkunshito significantly ameliorated dysmotility-like dyspepsia and brought about a generalized improvement in upper gastric symptoms such as nausea and anorexia when compared with a control group. Several studies in rats have shown enhanced gastric emptying and a protective effect on gastric mucosa injury with rikkunshito administration. In addition, rikkunshito in combination with an anti-emetic drug is effective against anorexia and vomiting that occur as adverse reactions to chemotherapy in patients with advanced breast cancer. However, the mechanism by which rikkunshito alleviates gastrointestinal disorders induced by anticancer agents remains unclear. It has recently been shown that rikkunshito ameliorates cisplatin-induced anorexia by mediating an increase in the circulating ghrelin concentration. Moreover, Fujitsuka et al. found that decreased contractions of the antrum and duodenum in rats treated with a selective serotonin reuptake inhibitor were reversed by rikkunshito via enhancement of the circulating ghrelin concentration. These findings show that rikkunshito may be useful for treatment of anorexia and may provide a new strategy for improvement of upper gastrointestinal dysfunction. PMID- 20721288 TI - Racial Disparities between the Sex Steroid Milieu and the Metabolic Risk Profile. AB - Aims and Method. The present study examined the relationship between the metabolic risk profile (MRP) and total testosterone (TT) and free testosterone using the free androgen index (FAI) and sex hormone binding globulin (SHBG) in 36 Caucasian American (CA) and 30 African-American (AA) women volunteering for a weight loss study. Results. After controlling for age, significant relationships were found between TT and diastolic blood pressure (P = .004 and P = .015 in CA and AA women, resp.). Additionally, total cholesterol (P = .003), low density lipoprotein cholesterol (P = .004), apolipoprotein B (P = .006), and the total cholesterol/high density lipoprotein cholesterol (P = .027) were significantly related to TT in AA women only. In CA women, similar measures of glucose/insulin status related to FAI, were also related to SHBG. In both CA and AA women, SHBG was related to waist (P = .031 and P = .022 resp.). Conclusion. Our findings showed racial disparities in the relationship between the sex steroid milieu and the MRP in overweight/obese CA and AA women. PMID- 20721289 TI - Prevention of dementia: focus on lifestyle. AB - The objective of this paper is to summarize current knowledge on the possible advantages of lifestyle interventions, with particular attention to physical fitness, cognitive activity, leisure and social activity as well as nutrition. There is a large amount of published papers providing partial evidence and asserting the need for immediate, appropriate preventive lifestyle measures against dementia and AD development. Nevertheless, there are currently great difficulties in drafting effective guidelines in this field. This depends mainly upon lack of randomized controlled trials assessing benefits versus risks of particular lifestyle interventions strategies. However, due to the rapid increase of dementia burden, lifestyle factors and their amelioration should be already made part of decision making in light of their health-maintaining effects while awaiting for results of well-designed large prospective cohort studies in dementia. PMID- 20721290 TI - Analgesic Efficacy of Pfannenstiel Incision Infiltration with Ropivacaine 7.5 mg/mL for Caesarean Section. AB - Background. Pain after Caesarean delivery is partly related to Pfannenstiel incision, which can be infiltrated with local anaesthetic solutions. Methods. A double- blind randomized control trial was designed to assess the analgesic efficacy of 7.5 mg/mL ropivacaine solution compared to control group, in two groups of one hundred and forty four parturients for each group, who underwent Caesarean section under spinal anaesthesia: group R (ropivacaine group) and group C (control group). All parturients also received spinal sufentanil (2.5 mug). Results. Ropivacaine infiltration in the Pfannenstiel incision for Caesarean delivery before wound closure leads to a reduction of 30% in the overall consumption of analgesics (348 550 mg for group R versus 504 426 mg for group C with P < .05), especially opioids in the first 24 hours, but also significantly increases the time interval until the first request for an analgesic (4 h 20 min +/- 2 h 26 for group R versus 2 h 42 +/- 1 h 30 for group C). The P values for the two groups were: P < .0001 for paracetamol, P < .0001 for ketoprofen and P for nalbuphine which was the most significant. There is no significant difference in the threshold of VAS in the two series. Conclusion. This technique can contribute towards a programme of early rehabilitation in sectioned mothers, with earlier discharge from the post-labour suite. PMID- 20721291 TI - Sustained self-regulation of energy intake: initial hunger improves insulin sensitivity. AB - Background. Excessive energy intake has been implicated in diabetes, hypertension, coronary artery disease, and obesity. Dietary restraint has been unsuccessful as a method for the self-regulation of eating. Recognition of initial hunger (IH) is easily learned, can be validated by associated blood glucose (BG) concentration, and may improve insulin sensitivity. Objective. To investigate whether the initial hunger meal pattern (IHMP) is associated with improved insulin sensitivity over a 5-month period. Methods. Subjects were trained to recognize and validate sensations of IH, then adjust food intake so that initial hunger was present pre-meal at each meal time (IHMP). The purpose was to provide meal-by-meal subjective feedback for self-regulation of food intake. In a randomised trial, we measured blood glucose and calculated insulin sensitivity in 89 trained adults and 31 not-trained controls, before training in the IHMP and 5 months after training. Results. In trained subjects, significant decreases were found in insulin sensitivity index, insulin and BG peaks, glycated haemoglobin, mean pre-meal BG, standard deviation of diary BG (BG as recorded by subjects' 7-day diary), energy intake, BMI, and body weight when compared to control subjects. Conclusion. The IHMP improved insulin sensitivity and other cardiovascular risk factors over a 5-month period. PMID- 20721292 TI - Ghrelin, des-acyl ghrelin, and obestatin: regulatory roles on the gastrointestinal motility. AB - Ghrelin, des-acyl ghrelin, and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. To examine the regulatory roles of these peptides, we applied the manometric measurement of gastrointestinal motility in freely moving conscious rat or mouse model. Ghrelin exerts stimulatory effects on the motility of antrum and duodenum in both fed and fasted state of animals. Des-acyl ghrelin exerts inhibitory effects on the motility of antrum but not on the motility of duodenum in the fasted state of animals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state but not in the fasted state of animals. NPY Y2 and Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptor in the brain may mediate the action of des-acyl ghrelin, whereas CRF type 1 and type 2 receptors in the brain may mediate the action of obestatin. Vagal afferent pathways might be involved in the action of ghrelin, but not involved in the action of des-acyl ghrelin, whereas vagal afferent pathways might be partially involved in the action of obestatin. PMID- 20721294 TI - Nanoparticulate radiolabelled quinolines detect amyloid plaques in mouse models of Alzheimer's disease. AB - Detecting aggregated amyloid peptides (Abeta plaques) presents targets for developing biomarkers of Alzheimer's disease (AD). Polymeric n-butyl-2 cyanoacrylate (PBCA) nanoparticles (NPs) were encapsulated with radiolabelled amyloid affinity (125)I-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) as in vivo probes. (125)I-CQ-PBCA NPs crossed the BBB (2.3 +/- 0.9 ID/g) (P < .05) in the WT mouse (N = 210), compared to (125)I-CQ (1.0 +/- 0.4 ID/g). (125)I-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1) versus WT (N = 38; 2.54 x 10(5) +/- 5.31 x 10(4) DLU/mm(2); versus 1.98 x 10(5) +/- 2.22 x 10(4) DLU/mm(2)) and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Abeta(42) peptide (N = 17; 7.19 x 10(5) +/- 1.25 x 10(5) DLU/mm(2)), versus WT (6.07 x 10(5) +/- 7.47 x 10(4) DLU/mm(2)). Storage phosphor imaging and histopathological staining of the plaques, Fe(2+) and Cu(2+), validated results. (125)I-CQ-PBCA NPs have specificity for Abeta in vitro and in vivo and are promising as in vivo SPECT ((123)I), or PET ((124)I) amyloid imaging agents. PMID- 20721293 TI - Evaluation of BACE1 Silencing in Cellular Models. AB - Beta-secretase (BACE1) is the major enzyme participating in generation of toxic amyloid-beta (Abeta) peptides, identified in amyloid plaques of Alzheimer's disease (AD) brains. Its downregulation results in decreasing secretion of Abeta. Thus, BACE1 silencing by RNAi represents possible strategy for antiamyloid therapy in the treatment of AD. In this study, a series of newly designed sequences of synthetic and vector-encoded siRNAs (pSilencer, pcPURhU6, and lentivirus) were tested against overexpressed and endogenous BACE1 in several cell lines and in adult neural progenitor cells, derived from rat hippocampus. SiRNAs active in human, mouse, and rat cell models were shown to diminish the level of BACE1. In HCN A94 cells, two BACE1-specific siRNAs did not alter the expression of genes of BACE2 and several selected genes involved in neurogenesis (Synapsin I, betaIII-Tubulin, Calbidin, NeuroD1, GluR2, CREB, MeCP2, PKR), however, remarkable lowering of SCG10 mRNA, coding protein of stathmin family, important in the development of nervous system, was observed. PMID- 20721295 TI - Emotion processing for arousal and neutral content in Alzheimer's disease. AB - Objective. To assess the ability of Alzheimer's disease (AD) patients to perceive emotional information and to assign subjective emotional rating scores to audiovisual presentations. Materials and Methods. 24 subjects (14 with AD, matched to controls for age and educational levels) were studied. After neuropsychological assessment, they watched a Neutral story and then a story with Emotional content. Results. Recall scores for both stories were significantly lower in AD (Neutral and Emotional: P = .001). CG assigned different emotional scores for each version of the test, P = .001, while ratings of AD did not differ, P = .32. Linear regression analyses determined the best predictors of emotional rating and recognition memory for each group among neuropsychological tests battery. Conclusions. AD patients show changes in emotional processing on declarative memory and a preserved ability to express emotions in face of arousal content. The present findings suggest that these impairments are due to general cognitive decline. PMID- 20721296 TI - Effect of microwave radiation on enzymatic and chemical Peptide bond synthesis on solid phase. AB - Peptide bond synthesis was performed on PEGA beads under microwave radiations. Classical chemical coupling as well as thermolysin catalyzed synthesis was studied, and the effect of microwave radiations on reaction kinetics, beads' integrity, and enzyme activity was assessed. Results demonstrate that microwave radiations can be profitably exploited to improve reaction kinetics in solid phase peptide synthesis when both chemical and biocatalytic strategies are used. PMID- 20721297 TI - Isolation and Characterization of a Defensin-Like Peptide (Coprisin) from the Dung Beetle, Copris tripartitus. AB - The antibacterial activity of immune-related peptides, identified by a differential gene expression analysis, was investigated to suggest novel antibacterial peptides. A cDNA encoding a defensin-like peptide, Coprisin, was isolated from bacteria-immunized dung beetle, Copris tripartitus, by using differential dot blot hybridization. Northern blot analysis showed that Coprisin mRNA was up-regulated from 4 hours after bacteria injection and its expression level was reached a peak at 16 hours. The deduced amino acid sequence of Coprisin was composed of 80 amino acids with a predicted molecular weight of 8.6 kDa and a pI of 8.7. The amino acid sequence of mature Coprisin was found to be 79.1% and 67.4% identical to those of defensin-like peptides of Anomala cuprea and Allomyrina dichotoma, respectively. We also investigated active sequences of Coprisin by using amino acid modification. The result showed that the 9-mer peptide, LLCIALRKK-NH(2), exhibited potent antibacterial activities against Escherichia coli and Staphylococcus aureus. PMID- 20721298 TI - Overweight among Four-Year-Old Children in Relation to Early Growth Characteristics and Socioeconomic Factors. AB - Objectives. To assess early growth characteristics and socioeconomic factors of children in relation to body mass index (BMI) and presence of overweight among four-year-old children. Methods. Two Child Health Centres (CHC) participated in the study. They were selected to obtain two populations of children featuring divergent socio-economic characteristics. Growth data registered at the CHCs from birth to the 4-year check-up were recovered. Overweight was defined by the BMI cut-offs established by IOTF. BMI values expressed as BMI standard deviation score (BMISDS) were used for analysis. Results. At the 4-year check-up, the BMISDS and the proportion of children with overweight (including the obese) were significantly higher in the district with lower socio-economic status. High BMI at birth and low socio-economic status of the population in the CHC-district were shown to be independent determinants for overweight and BMISDS at four years of age. Conclusions. More research is needed to understand the mechanisms and how intervention programs should be designed in order to prevent the development of overweight and obesity in children. PMID- 20721299 TI - Classification of upper limb motions from around-shoulder muscle activities: hand biofeedback. AB - Mining information from EMG signals to detect complex motion intention has attracted growing research attention, especially for upper-limb prosthetic hand applications. In most of the studies, recordings of forearm muscle activities were used as the signal sources, from which the intention of wrist and hand motions were detected using pattern recognition technology. However, most daily life upper limb activities need coordination of the shoulder-arm-hand complex, therefore, relying only on the local information to recognize the body coordinated motion has many disadvantages because natural continuous arm-hand motions can't be realized. Also, achieving a dynamical coupling between the user and the prosthesis will not be possible. This study objective was to investigate whether it is possible to associate the around-shoulder muscles' Electromyogram (EMG) activities with the different hand grips and arm directions movements. Experiments were conducted to record the EMG of different arm and hand motions and the data were analyzed to decide the contribution of each sensor, in order to distinguish the arm-hand motions as a function of the reaching time. Results showed that it is possible to differentiate hand grips and arm position while doing a reaching and grasping task. Also, these results are of great importance as one step to achieve a close loop dynamical coupling between the user and the prosthesis. PMID- 20721300 TI - Dynamics of Biomineralization and Biodemineralization. AB - In order to understand the fundamental processes leading to biomineralization, this chapter focuses on the earliest events of homo/heterogeneous nucleation from an initial supersaturated solution phase and subsequent growth involving various possible precursor phases (amorphous or crystalline) to the final mineral phase by specific template and other influences. We also discuss how the combination of macroscopic constant composition and microscopic atomic force microscopy provides insights into the physical mechanisms of crystal growth and phase stability and the influences of proteins, peptides or other small molecules.Biodemineralization reactions of tooth enamel and bone may be inhibited or even suppressed when particle sizes fall into certain critical nanoscale levels. This phenomenon actually involves particle-size-dependent critical conditions of energetic control at the molecular level. Clearly, this dissolution termination is a kinetic phenomenon and cannot be attributed to reaction retardation as a result of surface modification by additives. Almost all biomineralized structures are highly hierarchical at many different length scales. At the lowest level they often consist of tiny crystals, typically tens to hundreds of nanometers. This size is not arbitrary; rather, it seems to give biominerals such as bone and tooth remarkable physical characteristics. PMID- 20721302 TI - Koenigs et al. reply. PMID- 20721303 TI - The Effective Treatment of Juveniles Who Sexually Offend: An Ethical Imperative. AB - This article raises serious concerns regarding the widespread use of unproven interventions with juveniles who sexually offend and suggests innovative methods for addressing these concerns. Dominant interventions (i.e., cognitive-behavioral group treatments with an emphasis on relapse prevention) typically fail to address the multiple determinants of juvenile sexual offending and could result in iatrogenic outcomes. Methodologically sophisticated research studies (i.e., randomized clinical trials) are needed to examine the clinical and cost effectiveness of cognitive-behavioral group interventions, especially those delivered in residential settings. The moral and ethical mandate for such research is evident when considering the alternative, in which clinicians and society are willing to live in ignorance regarding the etiology and treatment of juvenile sexual offending and to consign offending youths to the potential harm of untested interventions. Encouraging signs of a changing ethical climate include recent federal funding of a randomized clinical trial examining treatment effectiveness with sexually offending youths and the introduction of separate (i.e., developmentally informed) clinical and legal interventions for juvenile vs. adult sexual offenders. PMID- 20721304 TI - Emotion (Dys)regulation and Links to Depressive Disorders. AB - Clinical depression is a significant mental health problem that is associated with personal suffering and impaired functioning. These effects underscore the continuing need for new approaches that can inform researchers and clinicians when designing interventions. We propose that individual differences in the self regulation of sadness and distress provide an important link between stress, depressed mood, and the onset of depressive disorder, and that if we have a better understanding of the ways children successfully manage negative emotions, we can better prevent and treat pediatric depression. In this article, we therefore examine the normative development of responses that children use to attenuate sadness, and aspects of the neurobiological infrastructure that both enable and constrain such self-regulatory efforts. We also address the emerging literature on affect regulation among children at familial risk for depressive disorders. We conclude that problems with adaptively self-regulating sadness and distress represent one pathway that can lead to juvenile-onset depression. And we need integrated, developmental studies of the psychosocial and neurobiological aspects of self-regulatory responses to sadness and distress in order to better understand this process, and to design age-sensitive intervention strategies for pediatric depression. PMID- 20721305 TI - Gender Role Conflict, Interest in Casual Sex, and Relationship Satisfaction Among Gay Men. AB - This study compared single (n = 129) and partnered gay men (n = 114) to determine if they differed in their concerns over traditional masculine roles and interest in casual sex, and to measure the relationship between concerns over masculine roles and interest in casual sex. Additionally, a regression model to predict relationship satisfaction was tested. Participants were recruited at two Southern California Gay Pride festivals. Group comparisons showed single men were more restrictive in their affectionate behavior with other men (effect-size r = .14) and were more interested in casual sex than partnered men (effect-size r = .13); and partnered men were more concerned with being successful, powerful, and competitive than single men (effect-size r = .20). Different masculine roles were predictive of interest in casual sex among the two groups of men. Finally, a hierarchical regression analysis found that interest in casual sex and the length of one's current relationship served as unique predictors of relationship satisfaction among the partnered gay men (Cohen's f(2) = .52). PMID- 20721301 TI - Single molecule transcription profiling with AFM. AB - Established techniques for global gene expression profiling, such as microarrays, face fundamental sensitivity constraints. Due to greatly increasing interest in examining minute samples from micro-dissected tissues, including single cells, unorthodox approaches, including molecular nanotechnologies, are being explored in this application. Here, we examine the use of single molecule, ordered restriction mapping, combined with AFM, to measure gene transcription levels from very low abundance samples. We frame the problem mathematically, using coding theory, and present an analysis of the critical error sources that may serve as a guide to designing future studies. We follow with experiments detailing the construction of high density, single molecule, ordered restriction maps from plasmids and from cDNA molecules, using two different enzymes, a result not previously reported. We discuss these results in the context of our calculations. PMID- 20721306 TI - Self-reports of Substance Abusers: The Relation between Social Desirability and Social Network Variables. AB - It is important to examine social desirability when interpreting self-report data from substance abusers. Social desirability is the tendency to respond on surveys that make people appear more favorable to others; thus, a strong desire for social approval is related to minimized reports of substance use. In the present study, the relationship between social desirability and different types of social support was examined within 582 residents of communal-living recovery homes (i.e., Oxford Houses). Although effect sizes were small, results may suggest that participants reported social network variables in a socially desirable manner; this tendency towards self-deception even predicted misrepresentations of these constructs eight months later. In addition, self-reports of the substance use habits of friends and family were more prone to social desirability than the reporting of other social network characteristics. Overall, it is suggested that social desirability might be taken into account when examining substance abusers' self-reports of social support variables. PMID- 20721308 TI - Identification of Small Molecule Inhibitors of Clostridium perfringens epsilon Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen. AB - The Clostridium perfringens epsilon toxin, a select agent, is responsible for a severe, often fatal enterotoxemia characterized by edema in the heart, lungs, kidney, and brain. The toxin is believed to be an oligomeric pore-forming toxin. Currently, there is no effective therapy for countering the cytotoxic activity of the toxin in exposed individuals. Using a robust cell-based high-throughput screening (HTS) assay, we screened a 151,616-compound library for the ability to inhibit epsilon-toxin-induced cytotoxicity. Survival of MDCK cells exposed to the toxin was assessed by addition of resazurin to detect metabolic activity in surviving cells. The hit rate for this screen was 0.6%. Following a secondary screen of each hit in triplicate and assays to eliminate false positives, we focused on three structurally-distinct compounds: an N-cycloalkylbenzamide, a furo[2,3-b]quinoline, and a 6H-anthra[1,9-cd]isoxazol. None of the three compounds appeared to inhibit toxin binding to cells or the ability of the toxin to form oligomeric complexes. Additional assays demonstrated that two of the inhibitory compounds inhibited epsilon-toxin-induced permeabilization of MDCK cells to propidium iodide. Furthermore, the two compounds exhibited inhibitory effects on cells pre-treated with toxin. Structural analogs of one of the inhibitors identified through the high-throughput screen were analyzed and provided initial structure-activity data. These compounds should serve as the basis for further structure-activity refinement that may lead to the development of effective anti-epsilon-toxin therapeutics. PMID- 20721307 TI - Rapid automatized naming as an index of genetic liability to autism. AB - This study investigated rapid automatized naming (RAN) ability in high functioning individuals with autism and parents of individuals with autism. Findings revealed parallel patterns of performance in parents and individuals with autism, where both groups had longer naming times than controls. Significant parent-child correlations were also detected, along with associations with language and personality features of the broad autism phenotype (retrospective reports of early language delay, socially reticent personality). Together, findings point towards RAN as a potential marker of genetic liability to autism. PMID- 20721309 TI - Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6 tetrahydropyridine-5-carboxylic acid diethylamides as Potential Anti-inflammatory Agents. AB - Fifteen novel 1-(substituted phenylcarbonyl/sulfonylamino)-1,2,3,6-tetrahydro- pyridine-5-carboxylic acid diethylamide (7, 15) were synthesized in fair to good yields via sodium borohydride reduction of the corresponding 1-(substituted phenylcarbonyl/ sulfonylimino)-3-diethylcarbamoyl pyridinium ylides (6, 14) in absolute ethanol. PMID- 20721311 TI - Finding Jumps in Otherwise Smooth Curves: Identifying Critical Events in Political Processes. AB - Many social processes are stable and smooth in general, with discrete jumps. We develop a sequential segmentation spline method that can identify both the location and the number of discontinuities in a series of observations with a time component, while fitting a smooth spline between jumps, using a modified Bayesian Information Criterion statistic as a stopping rule. We explore the method in a large-n, unbalanced panel setting with George W. Bush's approval data, a small-n time series with median DW-NOMINATE scores for each Congress over time, and a series of simulations. We compare the method to several extant smoothers, and the method performs favorably in terms of visual inspection, residual properties, and event detection. Finally, we discuss extensions of the method. PMID- 20721310 TI - Influences of School Latino Composition and Linguistic Acculturation on a Prevention Program for Youth. AB - This study examined how ethnic composition and linguistic acculturation within schools affected the efficacy of a youth substance use prevention model program. Data come from a randomized trial of the keepin' it REAL program, using a predominantly Mexican American sample of middle school students in Phoenix, Arizona. Schools were randomly assigned to a control group or to one of three culturally tailored intervention versions. We hypothesized that school ethnic and linguistic acculturation composition (percent Latino, percent non-English speaking at home) and individual level of linguistic acculturation jointly would moderate the efficacy of the prevention program, as indicated by students' alcohol, marijuana, and cigarette use. Using multilevel linear modeling and multiple imputation techniques to manage clustered data and attrition, results showed that desired program effects varied by the linguistic acculturation level of the school, the program version, and individual acculturation level. The Latino intervention version was more efficacious in schools with larger percentages of non-English speaking families, but only among less linguistically acculturated Latino students. There were no significant school level program effects connected to the percentage of Latino students at school, the other versions of the program, or among more linguistically acculturated students. PMID- 20721312 TI - Just-so Stories: Vaccines, Autism, and the Single-bullet Disorder. PMID- 20721313 TI - A novel model-free data analysis technique based on clustering in a mutual information space: application to resting-state FMRI. AB - Non-parametric data-driven analysis techniques can be used to study datasets with few assumptions about the data and underlying experiment. Variations of independent component analysis (ICA) have been the methods mostly used on fMRI data, e.g., in finding resting-state networks thought to reflect the connectivity of the brain. Here we present a novel data analysis technique and demonstrate it on resting-state fMRI data. It is a generic method with few underlying assumptions about the data. The results are built from the statistical relations between all input voxels, resulting in a whole-brain analysis on a voxel level. It has good scalability properties and the parallel implementation is capable of handling large datasets and databases. From the mutual information between the activities of the voxels over time, a distance matrix is created for all voxels in the input space. Multidimensional scaling is used to put the voxels in a lower dimensional space reflecting the dependency relations based on the distance matrix. By performing clustering in this space we can find the strong statistical regularities in the data, which for the resting-state data turns out to be the resting-state networks. The decomposition is performed in the last step of the algorithm and is computationally simple. This opens up for rapid analysis and visualization of the data on different spatial levels, as well as automatically finding a suitable number of decomposition components. PMID- 20721314 TI - Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. AB - Serotonin (5-HT) appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lacked acute effects on adult neurogenesis in many studies, which suggested a surprisingly long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late-stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT receptors. PMID- 20721315 TI - Shared Strategies for Behavioral Switching: Understanding How Locomotor Patterns are Turned on and Off. AB - Animals frequently switch from one behavior to another, often to meet the demands of their changing environment or internal state. What factors control these behavioral switches and the selection of what to do or what not to do? To address these issues, we will focus on the locomotor behaviors of two distantly related "worms," the medicinal leech Hirudo verbana (clade Lophotrochozoa) and the nematode Caenorhabditis elegans (clade Ecdysozoa). Although the neural architecture and body morphology of these organisms are quite distinct, they appear to switch between different forms of locomotion by using similar strategies of decision-making. For example, information that distinguishes between liquid and more solid environments dictates whether an animal swims or crawls. In the leech, dopamine biases locomotor neural networks so that crawling is turned on and swimming is turned off. In C. elegans, dopamine may also promote crawling, a form of locomotion that has gained new attention. PMID- 20721316 TI - CORTICAL SURFACE PARAMETERIZATION BY P-HARMONIC ENERGY MINIMIZATION. AB - Cortical surface parameterization has several applications in visualization and analysis of the brain surface. Here we propose a scheme for parameterizing the surface of the cerebral cortex. The parameterization is formulated as the minimization of an energy functional in the p(th) norm. A numerical method for obtaining the solution is also presented. Brain surfaces from multiple subjects are brought into common parameter space using the scheme. 3D spatial averages of the cortical surfaces are generated by using the correspondences induced by common parameter space. PMID- 20721318 TI - Audit of orthopaedic audits in an english teaching hospital: are we closing the loop? AB - BACKGROUND: Clinical audit is an important tool to improve patient care and outcomes in health service. A significant proportion of time and economic resources are spent on activities related to clinical audit. Completion of audit cycle is essential to confirm the improvements in healthcare delivery. We aimed this study to evaluate audits carried out within trauma and orthopaedic unit of a teaching hospital over the last 4 years, and establish the proportions which were re-audited as per recommendations. METHODS: Data was collected from records of the clinical audit department. All orthopaedic audit projects from 2005 to 2009 were included in this study. The projects were divided in to local, regional and national audits. Data regarding audit lead clinicians, completion and presentation of projects, recommendations and re-audits was recorded. RESULTS: Out of 61 audits commenced during last four years, 19.7% (12) were abandoned, 72.1% (44) were presented and 8.2 % (5) were still ongoing. The audit cycle was completed in only 29% (13) projects. CONCLUSION: Change of junior doctors every 4~6 months is related to fewer re-audits. Active involvement by supervising consultant, reallocation of the project after one trainee has finished, and full support of audit department may increase the ratio of completion of audit cycles, thereby improving the patient care. PMID- 20721317 TI - Clinical pharmacology and vascular risk. AB - Pharmacological treatment and several drugs of abuse have been associated with ischemic heart disease (IHD) and cerebrovascular diseases (CVD). However, there is a paucity of data on the independent risk of vascular disease (VD) associated with pharmacological treatment and no controlled trials demonstrating a reduction in risk with abstinence. Information about IHD and CVD-related drug abuse is mainly limited to epidemiological studies focused on urban populations. The potential link between some pharmacological treatments (estrogen, some oncologic drugs and some atypical antipsychotics) and cerebrovascular adverse events was analyzed, but disagreement about an association persists. Drugs of abuse, including cocaine, amphetamines and heroin, have been associated with an increased vascular risk. These drugs can cause abrupt changes in blood pressure, vasculitic-type changes, lead to embolization caused by infective endocarditis, and hemostatic and hematologic abnormalities that can result in increased blood viscosity and platelet aggregation. Long-term treatment strategies based on medication, psychological support, and outreach programs play an important role in treatment of drug dependency. In these last years public interest in risk factors for VD has been constantly increasing and the successful identification and management of pharmacological treatment and drug abuse can be challenging. One of the major public health issues for the future will be to focus more on new vascular risk factor recognition and management. The objective of this chapter is to review the relevance of IHD and CVD associated with various pharmacological treatments and drug abuse with focusing on ischemic disease. This chapter reports the clinical evidence of this association and analyzes the experimental role of new drugs as a growing risk factor of VD with the hypothetical new association. In conclusion, in this chapter great attention is paid to evaluating the scientific and real evidence of cerebrovascular effect and drug use and abuse so as to identify a new groups of "modifiable" risk factors. PMID- 20721319 TI - Two stage hip revision in periprosthetic infection: results of 41 cases. AB - BACKGROUND: two-stage revision is considered the best treatment approach for the eradication of chronic joint infection. We report the outcome of 41 consecutive patients with infected hip prostheses, treated between 2000 and 2005, with two stage revision using an antibiotic-loaded cement spacer. METHODS: Patients underwent a treatment protocol which included clinical and radiographic evaluation, laboratory investigations, hip aspiration, 99mTc-MDP and 99mTc leukocyte-labeled scintigraphy and intraoperative assessment. All patients were diagnosed with a late chronic infection and classified as B-host according to the Cierny-Mader classification system. 9 patients out of 41 (22%) required a second interim treatment period, with exchange of the spacer. The proportion of methicillin-resistant Staphylococcus was similar between the one-spacer group and two-spacer group (28% vs 33%), whereas the proportion of patients with three or more risk factors was significantly higher in the two-spacer group than in the one-spacer group (28% vs 55%, respectively). RESULTS: Forty patients had final reimplantation, one patient had a resection arthroplasty. At an average follow-up of 5.3 years no recurrence of infection occurred. The average post-operative Harris hip score improved from 41 to 80. CONCLUSIONS: In the treatment of two stage revision arthroplasty the adherence to the protocol proved to be effective for infection eradication and final reimplantation. PMID- 20721321 TI - Macrophage Response to UHMWPE Submitted to Accelerated Ageing in Hydrogen Peroxide. AB - Ultra-high molecular weight polyethylene (UHMWPE) has been the most commonly used bearing material in total joint arthroplasty. Wear and oxidation fatigue resistance of UHMWPE are regarded as two important properties to extend the longevity of knee prostheses. The present study investigated the accelerated ageing of UHMWPE in hydrogen peroxide highly oxidative chemical environment. The sliced samples of UHMWPE were oxidized in a hydrogen peroxide solution for 120 days with their total level of oxidation (Iox) characterized by Fourier Transformed Infrared Spectroscopy (FTIR). The potential inflammatory response, cell viability and biocompatibility of such oxidized UHMWPE systems were assessed by a novel biological in vitro assay based on the secretion of nitric oxide (NO) by activated murine macrophages with gamma interferon (IFN-gamma) cytokine and lipopolysaccharide (LPS). Furthermore, macrophage morphologies in contact with UHMWPE oxidized surfaces were analyzed by cell spreading-adhesion procedure using scanning electron microscopy (SEM). The results have given significant evidence that the longer the period of accelerated aging of UHMWPE the higher was the macrophage inflammatory equivalent response based on NO secretion analysis. PMID- 20721320 TI - Animal models of ischemic stroke. Part two: modeling cerebral ischemia. AB - Animal models of stroke provide an essential tool for the understanding of the complex cellular and molecular pathophysiology of stroke and for testing novel recanalyzing, neuroprotective, neuroregenerative or anti- inflammatory drugs in pre- clinical setting. Since the first description of the distal occlusion of the middle cerebral artery (MCA) in rats, different techniques and methods to induce focal and global ischemia of the brains have been developed and optimized. The different models, ranging from proximal to distal MCA occlusion to embolic and photothrombotic stroke vary widely in their ability to model human disease and in their application to the study of cell death, inflammation and neural repair. In the first part of the review animal models developed for studying stroke related risk factors are described while this section discusses specific models that have been created for mimicking different types of stroke, focal and global ischemia in an experimental setup. Advantages and limits and the potential of the diverse models for the study of novel therapies as well as for the study of basic pathophysiological mechanisms are explored. PMID- 20721322 TI - Histopomorphic evaluation of radiofrequency mediated debridement chondroplasty. AB - The use of radiofrequency devices has become widespread for surgical ablation procedures. When ablation devices have been deployed in treatment settings requiring tissue preservation like debridement chondroplasty, adoption has been limited due to the collateral damage caused by these devices in healthy tissue surrounding the treatment site. Ex vivo radiofrequency mediated debridement chondroplasty was performed on osteochondral specimens demonstrating surface fibrillation obtained from patients undergoing knee total joint replacement. Three radiofrequency systems designed to perform debridement chondroplasty were tested each demonstrating different energy delivery methods: monopolar ablation, bipolar ablation, and non-ablation energy. Treatment outcomes were compared with control specimens as to clinical endpoint and histopomorphic characteristics. Fibrillated cartilage was removed in all specimens; however, the residual tissue remaining at the treatment site displayed significantly different characteristics attributable to radiofrequency energy delivery method. Systems that delivered ablation-based energies caused tissue necrosis and collateral damage at the treatment site including corruption of cartilage Superficial and Transitional Zones; whereas, the non-ablation system created a smooth articular surface with Superficial Zone maintenance and without chondrocyte death or tissue necrosis. The mechanism of radiofrequency energy deposition upon tissues is particularly important in treatment settings requiring tissue preservation. Ablation-based device systems can cause a worsened state of articular cartilage from that of pre treatment. Non-ablation energy can be successful in modifying/preconditioning tissue during debridement chondroplasty without causing collateral damage. Utilizing a non-ablation radiofrequency system provides the ability to perform successful debridement chondroplasty without causing additional articular cartilage tissue damage and may allow for other cartilage intervention success. PMID- 20721323 TI - Application of autologous bone marrow derived mesenchymal stem cells to an ovine model of growth plate cartilage injury. AB - Injury to growth plate cartilage in children can lead to bone bridge formation and result in bone growth deformities, a significant clinical problem currently lacking biological treatment. Mesenchymal stem/stromal cells (MSC) offer a promising therapeutic option for regeneration of damaged cartilage, due to their self renewing and multi-lineage differentiation attributes. Although some small animal model studies highlight the therapeutic potential of MSC for growth plate repair, translational research in large animal models, which more closely resemble the human condition, are lacking. Our laboratory has recently characterised MSCs derived from ovine bone marrow, and demonstrated these cells form cartilage-like tissue when transplanted within the gelatin sponge, Gelfoam, in vivo. In the current study, autologous bone marrow MSC were seeded into Gelfoam scaffold containing TGF-beta1, and transplanted into a surgically created defect of the proximal ovine tibial growth plate. Examination of implants at 5 week post-operatively revealed transplanted autologous MSC failed to form new cartilage structure at the defect site, but contributed to an increase in formation of a dense fibrous tissue. Importantly, the extent of osteogenesis was diminished, and bone bridge formation was not accelerated due to transplantation of MSCs or the gelatin scaffold. The current study represents the first work that has utilised this ovine large animal model to investigate whether autologous bone marrow derived MSC can be used to initiate regeneration at the injured growth plate. PMID- 20721324 TI - Prevention strategies for cardioembolic stroke: present and future perspectives. AB - Atrial fibrillation (AF) is the most common cause of cardioembolism. An update on secondary prevention strategies, used to protect patients from the risk of stroke in many common cardiac conditions, is presented in the paper. The main line of actions of stroke prevention in cardioembolism is mostly connected with antithrombotic drugs, but also other, more invasive, techniques are quickly emerging. Also the classic pharmacological prevention with coumarins may soon be overcome by new generation anticoagulants. Is an aggressive treatment of Patent Foramen Ovale (PFO) always recommended? One of the main challenges of the future years will be to understand competitiveness between old and new preventive strategies. PMID- 20721325 TI - Prevalence of stroke in Restless Legs Syndrome: Initial Results Point to the Need for More Sophisticated Studies. AB - BACKGROUND: Recent studies suggest a potential relationship between Restless Legs Syndrome (RLS) and hypertension and heart disease. Acute clinical stroke has been linked to the immediate onset of RLS, and epidemiological studies suggest the possibility that RLS may also lead to stroke. METHODS: MRI scans from 26 RLS cases and 241 controls from the population based MEMO-Study (Memory and Morbidity in Augsburg Elderly) were assessed for the presence of clinical stroke, silent infarction, subcortical lesions and cortical atrophy. T1, T2, proton density images were obtained and infarcts and their characteristics were determined by visual inspection. RLS status was assessed according to the minimal criteria of the International RLS Study Group. Scans from the 26 RLS patients and a subset of 26 age and sex matched controls were reexamined by a separate rater using the same methodology. Descriptive statistics, logistic and linear regression models were used to determine the risk of the three types of CNS changes associated with RLS case status. RESULTS: Among the 267 participants there was no difference in the prevalence of cardiovascular diseases or risk factors between RLS patients and the 241 controls. The prevalences of cerebrovascular events of all types, were greater in RLS patients, as were the amounts of cortical atrophy and the volume of subcortical lesions. However, these differences were not statistically significant. When age, sex and co-morbidities were taken into account in a logistic regression model, there was a statistically non-significant greater risk for stroke (Odds Ratio 2.46 with 95% CI 0.97-6.28, p = .06) associated with RLS case status. CONCLUSIONS: Future similar studies need to be performed on younger patients without other potential vascular risk factors, using Flair images and computerized programs for detection of cerebral ischemia. Improved methods for detection may allow for a reasonable sample size. PMID- 20721326 TI - Anterior Cruciate Ligament Injury: Compensation during Gait using Hamstring Muscle Activity. AB - Previous research has shown that an increase in hamstring activation may compensate for anterior tibial transalation (ATT) in patients with anterior cruciate ligament deficient knee (ACLd); however, the effects of this compensation still remain unclear. The goals of this study were to quantify the activation of the hamstring muscles needed to compensate the ATT in ACLd knee during the complete gait cycle and to evaluate the effect of this compensation on quadriceps activation and joint contact forces. A two dimensional model of the knee was used, which included the tibiofemoral and patellofemoral joints, knee ligaments, the medial capsule and two muscles units. Simulations were conducted to determine the ATT in healthy and ACLd knee and the hamstring activation needed to correct the abnormal ATT to normal levels (100% compensation) and to 50% compensation. Then, the quadriceps activation and the joint contact forces were calculated. Results showed that 100% compensation would require hamstring and quadriceps activations larger than their maximum isometric force, and would generate an increment in the peak contact force at the tibiofemoral (115%) and patellofemoral (48%) joint with respect to the healthy knee. On the other hand, 50% compensation would require less force generated by the muscles (less than 0.85 of maximum isometric force) and smaller contact forces (peak tibiofemoral contact force increased 23% and peak patellofemoral contact force decreased 7.5% with respect to the healthy knee). Total compensation of ATT by means of increased hamstring activity is possible; however, partial compensation represents a less deleterious strategy. PMID- 20721327 TI - Intrinsic Factors Influencing the Infection by Helminth Parasites in Horses under an Oceanic Climate Area (NW Spain). AB - A coprological survey to determine the influence of some intrinsic factors (breed, age, and sex) on the infection by helminth parasites in equine livestock (n = 418) under an oceanic climate area (NW Spain) was conducted. Faecal samples were individually collected and analyzed by the coprological techniques. The main strongylid genera identified were Trichonema and Cyalocephalus spp (small strongyles) and Strongylus and Triodontophorus (large strongyles). The prevalence of gastrointestinal nematode was 89% (95% CI 86, 92) and 1% cestoda (0, 2). The percentage of horses with strongyloid parasites was 89% (86, 92), 11% (8, 14) for Parascaris, and 3% (1, 5) for Oxyuris. The highest prevalence for ascariosis was observed in the youngest horses (<3 years), for oxyurosis in the >10 years animals, and for strongylosis in the 3-10 years ones. Females were significantly more parasitized than males. A negative correlation between the age and the egg excretion of ascarids and strongyles was recorded. The autochthonous and the English Pure Blood horses were the most parasitized. We concluded that the infections by helminths, especially the strongyloids, are significantly common in the region, so that greater importance should be given to this situation. PMID- 20721329 TI - Molluscicidal Activity of Some Solanum Species Extracts against the Snail Biomphalaria alexandrina. AB - Background. Snails' species are associated with transmission parasitic disease as intermediate host. Biological control stands to be a better alternative to the chemical controls aimed against snails. The search of herbal preparations that do not produce any adverse effects in the non-target organisms and are easily biodegradable remains a top research issue for scientists associated with alternative molluscicides control. Method. Solvent extracts of fresh mature leaves of S. nigrum, S. villosum, and S. sinaicum were tested against Biomphalaria alexandrina, a common intermediate host of schistosoma mansoni. A phytochemical analysis of chloroform: ethanol extract was performed to search for active toxic ingredient. The lethal concentration was determined. Results. Extracts isolated from mature leaves of Solanum species were found to be having molluscicidal properties. S. nigrum extract was recorded as the highest mortality rate. When the mortality of different solvent extracts was compared, the maximum (P < .05) mortality was recorded at a concentration of 90 ppm of ethanol extract of S. nigrum. Conclusion. Extract of mature leaves of S. nigrum exhibited molluscicidal activity followed by S. sinaicum and the less one was S. villosum. The study provides considerable scope in exploiting local indigenous resources for snails' molluscicidal agents. PMID- 20721328 TI - Aspects of toxoplasma infection on the reproductive system of experimentally infected rams (ovis aries). AB - Eight reproductive rams with no prior reproductive disease were distributed into three groups of infection with T. gondii: GI, 3 rams, 2.0 x 10(5) P strain oocysts; GII, 3 rams, 1.0 x 10(6) RH strain tachyzoites; GIII, 2 control rams. Clinical parameters were measured and serological evaluations (IIF) were performed. Presence of the parasite in the semen was investigated by PCR and bioassay techniques. The rams presented clinical alterations (hyperthermia and apathy) related to toxoplasmosis in both groups infected with Toxoplasma gondii. All the inoculated rams responded to antigenic stimulus, producing antibodies against T. gondii from postinoculation day 5 onwards. In ovine groups I and II, the greatest titers observed were 1 : 4096 and 1 : 8192, respectively. In semen samples collected from these two groups, the presence of T. gondii was detected by bioassay and PCR. This coccidian was isolated (bioassay and PCR) in tissue pools (testicles, epididymis, seminal vesicle, and prostrate) from two rams infected presenting oocysts and in one presenting tachyzoites. PMID- 20721331 TI - Vaccine Efficacy of Bm86 Ortholog of H. a. anatolicum, rHaa86 Expressed in Prokaryotic Expression System. AB - The use of tick vaccine in controlling ticks and tick borne diseases has been proved effective in integrated tick management format. For the control of H. a. anatolicum, Bm86 ortholog of H. a. anatolicum was cloned and expressed as fusion protein in E. coli as E. coli-pETHaa86. The molecular weight of the rHaa86 was 97 kDa with a 19 kDa fusion tag of thioredoxin protein. The expressed protein was characterized immunologically and vaccine efficacy was evaluated. After 120 hours of challenge, only 26% tick could successfully fed on immunized animals. Besides significant reduction in feeding percentages, a significant reduction of 49.6 mg; P < .01 in the weight of fed females in comparison to the females fed on control animals was recorded. Following oviposition, a significant reduction of 68.1 mg; P < .05 in the egg masses of ticks fed on immunized animals in comparison to the ticks fed on control animals was noted. The reduction of number of females, mean weight of eggs, adult females and efficacy of immunogen were 73.8%, 31.3%, 15.8%, and 82.3%, respectively. The results indicated the possibility of development of rHaa86 based vaccine as a component of integrated control of tick species. PMID- 20721330 TI - Porcine cysticercosis in southeast Uganda: seroprevalence in kamuli and kaliro districts. AB - The recent recognition of neurocysticercosis as a major cause of epilepsy in Uganda and changes in pig demography have lead to a need to better understand the basic epidemiology of Taenia solium infections in pigs and humans. Human exposure is a function of the size of the animal reservoir of this zoonosis. This is the first field survey for porcine cysticercosis to investigate the prevalence of antigen-positive pigs across an entire rural district of south-east Uganda. In our field surveys, 8.6% of 480 pigs screened were seropositive for the parasite by B158/B60 Ag-ELISA. In addition, of the 528 homesteads surveyed 138 (26%) did not have pit latrines indicating a high probability of pigs having access to human faeces and thus T. solium eggs. This study thus indicates the need for better data on this neglected zoonotic disease in Uganda, with a particular emphasis on the risk factors for infection in both pigs and humans. In this regard, further surveys of pigs, seroprevalence surveys in humans and an understanding of cysticercosis-related epilepsy are required, together with risk factor studies for human and porcine infections. PMID- 20721332 TI - Primary prevention of first-ever stroke in primary health care: a clinical practice study based on medical register data in sweden. AB - Background. The aim of this study was to investigate whether established risk factors for stroke in patients admitted to health care for first-ever stroke had been detected and treated in primary health care. Methods. In a retrospective study in Nacka municipality, Stockholm County, Sweden, with about 70 000 inhabitants, we included all men and women admitted to health care due to first ever stroke between October 1999 and March 2001. Data on 187 such patients, with a mean age of 75 years, were obtained from medical registers. Main outcome measures were detection and treatment of risk factors for stroke including hypertension, diabetes, atrial fibrillation, smoking, alcohol abuse, and overweight/obesity. Results. In a majority of patients seen in primary health care with hypertension and diabetes, those risk factors were detected and treated (75.6% and 75.0%, resp.). Fewer patients with atrial fibrillation received treatment (60.9%). Treatment of lifestyle factors was difficult to assess because of lack of data in the medical records. Conclusions. Primary prevention of stroke in primary health care needs to be improved, especially when atrial fibrillation and lifestyle-related risk factors are present. Health policies need to target not only the public, but also general practitioners and other health care professionals. PMID- 20721333 TI - Circulating Antibodies to IDO/THO Pathway Metabolites in Alzheimer's Disease. AB - In Alzheimer's disease, indoleamine 2,3-dioxygenase and tryptophan hydroxylase are known to induce an overproduction of neurotoxic compounds, such as quinolinic acid and 3-hydroxykynurenine from the former, and 5-hydroxytryptophol and 5 methoxytryptophol from the latter. Other compounds, such as kynurenic acid, serotonin, and melatonin are produced via the same pathways. An improved ELISA method identified circulating antibodies directed against these compounds, linked to proteins, as previously described for other chronic diseases. This describes how only the A isotype of circulating immunoglobulins recognized a pattern of conjugated tryptophan metabolites in the sera of Alzheimer patients. These data indirectly confirmed the involvement of tryptophan derivatives in the pathogenic processes of Alzheimer's disease. Further studies are required to evaluate the relevance of these antibody patterns in monitoring this disease. PMID- 20721334 TI - Fecal occult blood test and gastrointestinal parasitic infection. AB - Stool specimens of 1238 workers in western region of Saudi Arabia were examined for infection with intestinal parasites and for fecal occult blood (FOB) to investigate the possibility that enteroparasites correlate to occult intestinal bleeding. Direct smears and formal ether techniques were used for detection of diagnostic stages of intestinal parasites. A commercially available guaiac test was used to detect fecal occult blood. 47.01% of the workers were infected with intestinal parasites including eight helminthes species and eight protozoan species. The results provided no significant evidence (P-value = 0.143) that intestinal parasitic infection is in association with positive guaiac FOB test. PMID- 20721335 TI - Effects of aquajogging in obese adults: a pilot study. AB - Aim and Method. To examine in obese people the potential effectiveness of a six week, two times weekly aquajogging program on body composition, fitness, health related quality of life, and exercise beliefs. Fifteen otherwise healthy obese persons participated in a pilot study. Results. Total fat mass and waist circumference decreased 1.4 kg (P = .03) and 3.1 cm (P = .005), respectively. The distance in the Six-Minute Walk Test increased 41 meters (P = .001). Three scales of the Impact of Weight on Quality of Life-Lite questionnaire improved: physical function (P = .008), self-esteem (P = .004), and public distress (P = .04). Increased perceived exercise benefits (P = .02) and decreased embarrassment (P = .03) were observed. Conclusions. Aquajogging was associated with reduced body fat and waist circumference and improved aerobic fitness and quality of life. These findings suggest the usefulness of conducting a randomized controlled trial with long-term outcome assessments. PMID- 20721336 TI - Dysphagia in stroke: a new solution. AB - Dysphagia is extremely common following stroke, affecting 13%-94% of acute stroke sufferers. It is associated with respiratory complications, increased risk of aspiration pneumonia, nutritional compromise and dehydration, and detracts from quality of life. While many stroke survivors experience a rapid return to normal swallowing function, this does not always happen. Current dysphagia treatment in Australia focuses upon prevention of aspiration via diet and fluid modifications, compensatory manoeuvres and positional changes, and exercises to rehabilitate paretic muscles. This article discusses a newer adjunctive treatment modality, neuromuscular electrical stimulation (NMES), and reviews the available literature on its efficacy as a therapy for dysphagia with particular emphasis on its use as a treatment for dysphagia in stroke. There is a good theoretical basis to support the use of NMES as an adjunctive therapy in dysphagia and there would appear to be a great need for further well-designed studies to accurately determine the safety and efficacy of this technique. PMID- 20721337 TI - Reconstruction-dependent recovery from anorexia and time-related recovery of regulatory ghrelin system in gastrectomized rats. AB - Gastrectomy reduces food intake and body weight (BW) hampering recovery of physical conditions. It also reduces plasma levels of stomach-derived orexigenic ghrelin. This study explored changes in orexigenic ghrelin system in rats receiving total gastrectomy with Billroth II (B-II) or Roux-en-Y (R-Y) method. Feeding and BW were reduced by gastrectomy and subsequently recovered to a greater extent with R-Y than B-II while plasma ghrelin decreased similarly. At postoperative 12th week, ghrelin contents increased in the duodenum and pancreas, plasma ghrelin levels increased upon fasting, and ghrelin injection promoted feeding but not in earlier periods. In summary, gastrectomized rats partially recover feeding and BW, in a reconstruction-dependent manner. At 12th week, ghrelin is upregulated in extra-stomach tissues, plasma ghrelin levels are physiologically regulated, and orexigenic effect of exogenous ghrelin is restored. This time-related recovery of ghrelin system may provide a strategy for promoting feeding, BW, and thereby physical conditions in gastrectomized patients. PMID- 20721339 TI - The Influence of Neocate in Paediatric Short Bowel Syndrome on PN Weaning. AB - Clinical management of short bowel syndrome remains a multistage process. Although PN is crucial, early introduction of enteral feeding is mandatory. We describe retrospectively 4 patients with an ultrashort bowel who could be weaned off PN on very short terms after introduction of an amino-acid-based formula (Neocate). Patient 1 had congenital short bowel with 50 cm small bowel and 30 cm colon. He had persistent diarrhoea on a semielementary formula. When Neocate was introduced he could be weaned from PN within 6 months. Patient 2 needed multiple surgical interventions because of NEC at D 27. He maintained 40 cm small bowel and an intact colon and remained PN dependent on semielemental formula. After introducing Neocate, PN could be weaned within 3 months. In the next 2 patients, Neocate was introduced as initial enteral feeding after bowel resection following antenatal midgut volvulus. Patient 3 had 20 cm small bowel and an intact colon. PN was weaned after 2 months. Patient 4 had 9 cm small bowel and an intact colon. PN was weaned after 13 months. In all patients Ileocaecal valve (ICV) was preserved. No consensus is reached on the type of formula to use for short bowel syndrome. Compared to recent data in the literature, the weaning period in these 4 patients was significantly shortened on an aminoacid based formula. The reason for this may lie in the antiallergic properties of this formula. We recommend the use of an amino-acid-based formula to induce earlier weaning of PN. PMID- 20721338 TI - Milk Products Containing Bioactive Tripeptides Have an Antihypertensive Effect in Double Transgenic Rats (dTGR) Harbouring Human Renin and Human Angiotensinogen Genes. AB - Tripeptides isoleucyl-prolyl-proline (IPP) and valyl-prolyl-proline (VPP) act as ACE inhibitors in vitro. Double transgenic rats (dTGR) harbouring human renin and human angiotensinogen genes develop malignant hypertension due to increased angiotensin II formation. The present study was aimed to evaluate possible antihypertensive effect of IPP and VPP in this severe model. Four-week-old dTGR were randomized in three groups to receive: (1) water (control), (2) fermented milk containing IPP and VPP, and (3) IPP and VPP dissolved in water for three weeks. Fermented milk, but not peptides in water, attenuated the development of hypertension in dTGR by 19 mmHg versus the control group (P = .023). In vitro vascular function tests showed that high concentrations of the peptides evinced ACE inhibitory properties. In other hypertension related variables, no significant differences between the treatment groups were found. In conclusion, fermented milk product containing IPP and VPP prevents development of malignant hypertension in an animal model. PMID- 20721340 TI - Effect of VPAC1 Blockade on Adipose Tissue Formation and Composition in Mouse Models of Nutritionally Induced Obesity. AB - Background. The pituitary adenylate cyclase activating polypeptide (PACAP) may affect adipogenesis and adipose tissue formation through interaction with its G protein-coupled receptor VPAC1. Methods. We have used a monoclonal antibody (MAb 23A11) blocking VPAC1 in mouse models of nutritionally induced obesity. Results. Administration of MAb 23A11 (25 mg/kg body weight i.p. twice weekly) to 5-week old male C57Bl/6 mice kept on a high-fat diet for 15 weeks had no significant effect on weight gain, nor on subcutaneous (SC) or gonadal (GON) adipose tissue mass, as compared to the control MAb 1C8. However, adipocyte hypertrophy was observed in SC adipose tissue of MAb 23A11 treated mice. In a second study, 24 weeks old obese mice were treated for 5 weeks with MAb 23A11, without effect on body weight or fat mass, as compared to treatment with MAb 1C8. In addition, MAb 23A11 had no significant effect on glucose tolerance or insulin resistance in lean or obese C57Bl/6 mice. Conclusion. Blocking VPAC1 does not significantly affect adipose tissue formation in mouse models of diet-induced obesity, although it may be associated with mild adipocyte hypertrophy. PMID- 20721341 TI - Ghrelin's Roles in Stress, Mood, and Anxiety Regulation. AB - Several studies suggest that the peptide hormone ghrelin mediates some of the usual behavioral responses to acute and chronic stress. Circulating ghrelin levels have been found to rise following stress. It has been proposed that this elevated ghrelin helps animals cope with stress by generating antidepressant-like behavioral adaptations, although another study suggests that decreasing CNS ghrelin expression has antidepressant-like effects. Ghrelin also seems to have effects on anxiety, although these have been shown to be alternatively anxiogenic or anxiolytic. The current review discusses our current understanding of ghrelin's roles in stress, mood, and anxiety. PMID- 20721342 TI - Neuronal models for studying tau pathology. AB - Alzheimer's disease (AD) is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing beta amyloid peptide and neurofibrillary tangles (NFTs), consisting of fibrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modified animals, which today include numerous mouse, fish, worm, and fly models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD. PMID- 20721343 TI - Lagochilascaris minor: Susceptibility and Resistance to Experimental Infection in Mice Is Independent of H-2 Haplotype and Correlates with the Immune Response in Immunized Animals. AB - Recently, we demonstrated that C57BL/6 mice are more susceptible to experimental lagochilascariosis than BALB/c mice. To investigate the pattern of infection and the role of the genetic background on susceptibility to infection, we studied experimental lagochilascariosis in H-2(a) identical B10.A and A/J mice. Infected B10.A mice had a lower survival ratio and more severe lesions in the lungs than did A/J mice. Splenocytes of A/J mice immunized with the crude extract of the parasite showed increased proliferation and produced a higher level of interleukin 10 and interferon-gamma in the presence of CE or concanavalin A when compared to B10.A mice. This suggests that resistance of A/J mice may be due to less severe lesions in lungs and other organs and a better immune response to parasite antigens. This paper provides evidence that major histocompatibility complex haplotype does not influence the survival to experimental infection with L. minor. PMID- 20721344 TI - Insulin therapy and body weight, body composition and muscular strength in patients with type 2 diabetes mellitus. AB - Aims. To determine the progression of body weight (BW) and body composition (BC) in patients with type 2 diabetes mellitus (T2D) on insulin therapy and the consequences on muscle strength (MS) as a reflect of free fat mass increases. Research design and methods. We analysed BC using air displacement plethysmography and MS by hand grip dynamometry in 40 T2D before and after three (M3) and six months (M6) of insulin therapy. Results. at baseline HbA1c was 9.76 +/-1.6% and BW was stable with fat mass (FM) 28 +/- 10.7 kg; and fat free mass (FFM) 52.4 +/- 11 kg; at M6, HbA1c improved to 7.56 +/- 0.8%; insulin doses tended to increase. BW gain at M6 was + 3.2 +/- 4.2 kg and with an increase of only 25% by M3; it was composed of FM, whereas FFM was unchanged. MS did not increase on insulin therapy. Conclusions. In T2D, BW gain was composed exclusively of FM with no improvement in MS. PMID- 20721345 TI - Preschool Participation and BMI at Kindergarten Entry: The Case for Early Behavioral Intervention. AB - Preschool years (ages 3-5) are a critical period in growth and development. Emerging studies suggest that preschool attendance may be linked to future weight, and perhaps obesity. This study examined relationships between public preschool attendance, demographic variables, and weight at kindergarten entry. Participants included 2,400 children entering kindergarten in 2006. Height and weight were used to calculate a child's BMI category based on CDC norms. At kindergarten entry, 17% of participants were overweight, and 18% were obese. Children attending a public preschool were at an increased risk for overweight (OR = 1.06) and obesity (OR = 1.34) at kindergarten entry, chi(2)(2) = 6.81, P = .03 relative to children who did not attend preschool. No significant trends relationships between demographics and weight status were found, but demographic variables are summarized descriptively. Policy and clinical implications are provided. PMID- 20721346 TI - Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation. AB - Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12-associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-beta1, and complement receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAM signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic activity of microglia via ITIM signaling. Moreover, microglial neurotoxicity is alleviated via interaction of Siglec-11 with sialic acids on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration triggered by chronic inflammation. PMID- 20721347 TI - The prokinetic face of ghrelin. AB - This review evaluated published data regarding the effects of ghrelin on GI motility using the PubMed database for English articles from 1999 to September 2009. Our strategy was to combine all available information from previous literature, in order to provide a complete structured review on the prokinetic properties of exogenous ghrelin and its potential use for treatment of various GI dysmotility ailments. We classified the literature into two major groups, depending on whether studies were done in health or in disease. We sub-classified the studies into stomach, small intestinal and colon studies, and broke them down further into studies done in vitro, in vivo (animals) and in humans. Further more, the reviewed studies were presented in a chronological order to guide the readers across the scientific advances in the field. The review shows evidences that ghrelin and its (receptor) agonists possess a strong prokinetic potential to serve in the treatment of diabetic, neurogenic or idiopathic gastroparesis and possibly, chemotherapy-associated dyspepsia, postoperative, septic or post-burn ileus, opiate-induced bowel dysfunction and chronic idiopathic constipation. Further research is necessary to close the gap in knowledge about the effect of ghrelin on the human intestines in health and disease. PMID- 20721348 TI - Self-Reported Psychosocial Health in Obese Patients before and after Weight Loss. AB - Psychosocial profiles were examined in 255 morbidly obese patients attending a hospital service offering access to standard weight loss therapies. 129 patients were reassessed after at least 6-month follow-up. At baseline, 51.8% and 32.7% of patients, respectively, had evidence of anxiety and depressive disorders, 24% had severe impairments in self esteem, and 29.7% had an increased risk of eating disorders. At follow-up, weight loss from baseline was significant in all 3 therapies: diet only is 0.74 +/- 1.8 kg; pharmacotherapy is 6.7 +/- 4.2 kg; and surgery is 20.1 +/- 13.6 kg. Anxiety scores improved in all three groups (P < .05). Patients having pharmacotherapy or surgery had significant improvements in physical and work function and public distress compared to those having dietary treatment only (P < .05). Our observational data suggest that weight management services can lead to psychosocial benefit in morbidly obese patients. Well designed studies are necessary to examine the link between weight loss and emotional health. PMID- 20721350 TI - Flaxseed ingestion alters ratio of enterolactone enantiomers in human serum. AB - Enterolactone (EL) is an enterolignan found in human subjects. In this pilot study, the enantiomeric ratios of serum EL were determined in serum from healthy adults during consumption of habitual diet, and after an 8-day supplementation with flaxseed (25 g/day). (-)EL dominated in all serum samples collected during habitual diet consumption. However, the ratio of (-)EL and (+)EL enantiomers differed markedly between individuals. Flaxseed ingestion increased significantly the proportion of (+)EL in all subjects. Moreover, a small but significant increase in serum (-)EL concentration was measured. After flaxseed ingestion, ( )EL concentrations correlated with those of (+)EL suggesting that the stereochemistry of the parent plant lignan in flaxseed is not a major determinant of EL formation in human subjects. Comparison of EL concentrations obtained with the validated chromatographic methods (HPLC-MS/MS, HPLC-CEAD, and GC-MS) and the time-resolved fluoroimmunoassay (TR-FIA) revealed that the immunoassay method underestimates human serum EL concentrations after the flaxseed ingestion. PMID- 20721351 TI - Differential expression of intestinal genes in opossums with high and low responses to dietary cholesterol. AB - High and low responding opossums (Monodelphis domestica) differ in their plasma very low density lipoprotein and low density lipoprotein (VLDL+LDL) cholesterol concentrations when they consume a high cholesterol diet, which is due in part to absorption of a higher percentage of dietary cholesterol in high responders. We compared the expression of a set of genes that influence cholesterol absorption in high and low responders fed a basal or a high cholesterol and low fat (HCLF) diet. Up-regulation of the ABCG5, ABCG8, and IBABP genes by the HCLF diet in high and low responders may reduce cholesterol absorption to maintain cholesterol homeostasis. Differences in expression of the phospholipase genes (PLA2 and PLB) and phospholipase activity were associated with differences in cholesterol absorption when opossums were fed cholesterol-enriched diets. Higher PLA2 and PLB mRNA levels and higher phospholipase activity may increase cholesterol absorption in high responders by enhancing the release of cholesterol from bile salt micelles for uptake by intestinal cells. PMID- 20721349 TI - CSF Biomarkers for Alzheimer's Disease Diagnosis. AB - Alzheimer's disease (AD) is the most common form of dementia that affects several million people worldwide. The major neuropathological hallmarks of AD are the presence of extracellular amyloid plaques that are composed of Abeta40 and Abeta42 and intracellular neurofibrillary tangles (NFT), which is composed of hyperphosphorylated protein Tau. While the amyloid plaques and NFT could define the disease progression involving neuronal loss and dysfunction, significant cognitive decline occurs before their appearance. Although significant advances in neuroimaging techniques provide the structure and physiology of brain of AD cases, the biomarker studies based on cerebrospinal fluid (CSF) and plasma represent the most direct and convenient means to study the disease progression. Biomarkers are useful in detecting the preclinical as well as symptomatic stages of AD. In this paper, we discuss the recent advancements of various biomarkers with particular emphasis on CSF biomarkers for monitoring the early development of AD before significant cognitive dysfunction. PMID- 20721352 TI - Xenon anesthesia improves respiratory gas exchanges in morbidly obese patients. AB - Background. Xenon-in-oxygen is a high density gas mixture and may improve PaO2/FiO2 ratio in morbidly obese patients uniforming distribution of ventilation during anesthesia. Methods. We compared xenon versus sevoflurane anesthesia in twenty adult morbidly obese patients (BMI > 35) candidate for roux-en-Y laparoscopic gastric bypass and assessed PaO2/FiO2 ratio at baseline, at 15 min from induction of anaesthesia and every 60 min during surgery. Differences in intraoperative and postoperative data including heart rate, systolic and diastolic pressure, oxygen saturation, plateau pressure, eyes opening and extubation time, Aldrete score on arrival to the PACU were compared by the Mann Whitney test and were considered as secondary aims. Moreover the occurrence of side effects and postoperative analgesic demand were assessed. Results. In xenon group PaO2-FiO2 ratio was significantly higher after 60 min and 120 min from induction of anesthesia; heart rate and overall remifentanil consumption were lower; the eyes opening time and the extubation time were shorter; morphine consumption at 72 hours was lower; postoperative nausea was more common. Conclusions. Xenon anesthesia improved PaO2/FiO2 ratio and maintained its distinctive rapid recovery times and cardiovascular stability. A reduction of opioid consumption during and after surgery and an increased incidence of PONV were also observed in xenon group. PMID- 20721353 TI - Ghrelin and functional dyspepsia. AB - The majority of patients with dyspepsia have no identifiable cause of their disease, leading to a diagnosis of functional dyspepsia (FD). While a number of different factors affect gut activity, components of the nervous and endocrine systems are essential for normal gut function. Communication between the brain and gut occurs via direct neural connections or endocrine signaling events. Ghrelin, a peptide produced by the stomach, affects gastric motility/emptying and secretion, suggesting it may play a pathophysiological role in FD. It is also possible that the functional abnormalities in FD may affect ghrelin production in the stomach. Plasma ghrelin levels are reported to be altered in FD, correlating with FD symptom score. Furthermore, some patients with FD suffer from anorexia with body-weight loss. As ghrelin increases gastric emptying and promotes feeding, ghrelin therapy may be a new approach to the treatment of FD. PMID- 20721354 TI - Lessons from Multicenter Studies on CSF Biomarkers for Alzheimer's Disease. AB - Several single-center studies have confirmed the usability of cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer's disease (AD), even in early disease stages. Large scale multicenter studies have principally confirmed this, although such studies have also indicated the presence of significant intercenter and interlaboratory variations in biomarker measurements. Such variations may hamper the development of biomarkers and their introduction into clinical routine practice. Recently a quality control program run by the Alzheimer's Association was started in order to harmonize procedures of laboratories world-wide. This program provides both standardized guide lines and external control CSF samples, and will allow longitudinal evaluation of laboratory performance. PMID- 20721355 TI - Brain Activation by Peptide Pro-Leu-Gly-NH(2) (MIF-1). AB - MIF-1 (Pro-Leu-Gly-NH(2)) is a tripeptide for which the therapeutic potential in Parkinson's disease and depression has been indicated by many studies. However, the cellular mechanisms of action of MIF-1 are not yet clear. Here, we show the specific brain regions responsive to MIF-1 treatment by c-Fos mapping, and determine the kinetics of cellular signaling by western blotting of pERK, pSTAT3, and c-Fos in cultured neurons. The immunoreactivity of c-Fos was increased 4 hours after MIF-1 treatment in brain regions critically involved in the regulation of mood, anxiety, depression, and memory. The number of cells activated was greater after peripheral treatment (intravenous delivery) than after intracerebroventricular injection. In cultured SH-SY5Y neuronal cells, c Fos was induced time- and dose-dependently. The activation of cellular c-Fos was preceded by a transient increase of mitogen-activated protein kinase pERK but a reduction of phosphorylated Signal Transducer and Activator of Transcription (pSTAT3) initially. We conclude that MIF-1 can modulate multiple cellular signals including pERK, and pSTAT3 to activate c-Fos. The cellular activation in specific brain regions illustrates the biochemical and neuroanatomical basis underlying the therapeutic effect of MIF-1 in Parkinson's disease and depression. PMID- 20721356 TI - Diet, Screen Time, Physical Activity, and Childhood Overweight in the General Population and in High Risk Subgroups: Prospective Analyses in the PIAMA Birth Cohort. AB - Objective. To prospectively identify behavioral risk factors for childhood overweight and to assess their relevance in high risk sub groups (children of mothers with overweight or low education). Methods. In the PIAMA birth cohort (n = 3963), questionnaire data were obtained at ages 5 and 7 on "screen time", walking or cycling to school, playing outside, sports club membership, fast food consumption, snack consumption and soft drink consumption. Weight and height were measured at age 8 years. Results. Screen time, but none of the other hypothesized behavioral factors, was associated with overweight (aOR 1.4 (CI: 1.2-1.6)). The adjusted population attributable risk fraction for screen time > 1 hr/day was 10% in the high risk and 17% in the low risk sub groups. Conclusion. Reduction of screen time to < 1 hr/day could result in a reduction of overweight prevalence in the order of 2 percentage points in both high and low risks sub groups. PMID- 20721358 TI - Hop and Acacia Phytochemicals Decreased Lipotoxicity in 3T3-L1 Adipocytes, db/db Mice, and Individuals with Metabolic Syndrome. AB - The plant-based compounds rho-iso-alpha acids (RIAA) from Humulus lupulus (hops) and proanthocyanidins (PAC) from Acacia nilotica have been shown to modulate insulin signaling in vitro. We investigated their effects on triglyceride (TG) deposition in 3T3-L1 adipocytes, glucose and insulin in obese mouse models, and metabolic syndrome markers in adults with metabolic syndrome. The combination of RIAA and PAC synergistically increased TG content and adiponectin secretion in 3T3-L1 adipocytes under hyperinsulinemic conditions and reduced glucose or insulin in obese mice. In a clinical trial, tablets containing 100 mg RIAA and 500 mg PAC or placebo were administered to metabolic syndrome subjects (3 tablets/day, n = 35; 6 tablets/day, n = 34; or placebo, n = 35) for 12 weeks. Compared to placebo, subjects taking 3 tablets daily showed greater reductions in TG, TG : HDL, fasting insulin, and HOMA scores. The combination of RIAA : PAC at 1 : 5 (wt : wt) favorably modulates dysregulated lipids in insulin resistance and metabolic syndrome. PMID- 20721357 TI - Ghrelin in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) often exhibit symptoms of anorexia and cachexia, which are associated with decreased quality of life and increased mortality. Chronic inflammation may be an important mechanism for the development of anorexia, cachexia, renal osteodystrophy, and increased cardiovascular risk in CKD. Ghrelin is a gastric hormone. The biological effects of ghrelin are mediated through the growth hormone secretagogue receptor (GHSR). The salutary effects of ghrelin on food intake and meal appreciation suggest that ghrelin could be an effective treatment for anorexic CKD patients. In addition to its appetite stimulating effects, ghrelin has been shown to possess anti-inflammatory properties. The known metabolic effects of ghrelin and the potential implications in CKD will be discussed in this review. The strength, shortcomings, and unanswered questions related to ghrelin treatment in CKD will be addressed. PMID- 20721359 TI - Effects of Peanut Processing on Masticatory Performance during Variable Appetitive States. AB - Background. Current evidence indicates that peanut consumption reduces cardiovascular disease risk, while posing little threat to positive energy balance. However, questions have been raised as to whether inter- and intraindividual variability in mastication in response to peanut form and processing properties may influence these health effects, since mastication has the potential to alter the bioaccessibility of nutrients within the nut matrix. Objective. To explore the relationship between peanut form and processing and masticatory function. Subjects/Methods. Thirty nine adults (16 M, 23 F; BMI: 30.4 +/- 4.0 kg/m(2); age: 27 +/- 8 y) with healthy dentition chewed four different forms of peanuts until they would normally swallow and then expectorated the bolus. Surface electromyograms (EMGs) were obtained from the masseter and temporalis muscles during chewing of the four test foods. The maximum and mean bite forces, duration of chewing sequence, number of chews, and total muscle work for the complete chewing cycle were measured on the integrated EMG in fasted and sated states. Results. While no significant differences were noted in response to appetitive state, peanut form and processing had a significant influence on masticatory efficiency, as measured by proportional particle size distributions. The processed peanuts (honey roasted, roasted salted, and roasted unsalted) were chewed significantly fewer times compared to the unprocessed form (raw). Further, the proportional particle sizes within the swallowing bolus were significantly larger for the processed forms compared to the unprocessed form. Conclusion. These observations may have implications for bioaccessibility of energy and cardioprotective nutrients as well as endocrine responses, following peanut consumption. PMID- 20721360 TI - The experience of being obese and the many consequences of stigma. AB - The present qualitative study aimed to explore how people experience their obesity and to explore the impact of this on their motivations to lose weight. Participants (n = 46) were either currently obese or had been obese and were interviewed about their experiences. Participants described the impact of obesity on aspects of their self-identity and used language such as "ugly", "freak", "hate", "blob", and "disgust" which reflected the pervasively negative impact of their weight. They highlighted a complex and often contradictory relationship with food and described how such negative experiences were created out of the dynamic between their obesity and a stigmatising social context. Some, however, suggested that such stigma could also have positive consequences by promoting and encouraging behaviour change. Many obese people, therefore, experience their weight in profoundly negative ways as a result of existing within a social context which stigmatises their condition. The results are discussed in terms of the costs and benefits of stigma and a balance between support, tolerance, and collusion in promoting weight loss. PMID- 20721362 TI - Unusual recognition of (n-Bu4N)2SO4 by a cyanuric acid based host via contact ion pair interactions. AB - A tripodal neutral receptor selectively binds tetrabutylammonium sulfate where anion is encapsulated in the cavity and cations are in close contact with the anion via C-H...O interactions. This organic cation capped sulfate-bowl exists both in solid and solution states and the sulfate assisted cap can be opened and closed reversibly with a temperature key. PMID- 20721361 TI - Global and national socioeconomic disparities in obesity, overweight, and underweight status. AB - Objective. To examine the association between socioeconomic factors and weight status across 53 countries. Methods. Data are cross-sectional and from the long version of the World Health Survey (WHS). There were 172,625 WHS participants who provided self-reported height and weight measures and sociodemographic information. The International Classification of adult weight status was used to classify participants by body mass index (BMI): (1) underweight (<18.5), (2) normal weight (18.5-24.9), (3) overweight (25.0-29.9), and (4) obese (>30.0). Multinomial regression was used in the analyses. Results. Globally, 6.7% was underweight, 25.7% overweight, and 8.9% obese. Underweight status was least (5.8%) and obesity (9.3%) most prevalent in the richest quintile. There was variability between countries, with a tendency for lower-income quintiles to be at increased risk for underweight and reduced risk for obesity. Conclusion. International policies may require flexibility in addressing cross-national differences in the socio-economic covariates of BMI status. PMID- 20721363 TI - Zirconate pyrochlores under high pressure. AB - Ab initio total-energy calculations and X-ray diffraction measurements have been combined to study the phase stability of zirconate pyrochlores (A(2)Zr(2)O(7); A = La, Nd and Sm) under pressures up to 50 GPa. Phase transformations to the defect-cotunnite structure are theoretically predicted at pressures of 22, 20 and 18 GPa, in excellent agreement with the experimentally determined values of 21, 22 and 18 GPa for La(2)Zr(2)O(7), Nd(2)Zr(2)O(7) and Sm(2)Zr(2)O(7), respectively. Analysis of the elastic properties indicates that elastic anisotropy may be one of the driving forces for the pressure-induced cubic-to noncubic phase transformation. PMID- 20721364 TI - Coating and dispersion of ceramic nanoparticles by UV-ozone etching assisted surface-initiated living radical polymerization. AB - Commercially available unmodified ceramic nanoparticles (NPs) in dry powder state were surface-modified and dispersed in almost single-crystal size. The surface initiated living radical polymerization after just UV-ozone soft etching enables one to graft polymers onto the surface of ceramic NPs and disperse them in solvents. Furthermore, a number of NPs were dispersed with single-crystal sizes. The technique developed here could be applied to almost all ceramic NPs including metal nitrides. PMID- 20721365 TI - From nucleation to nanowires: a single-step process in reactive plasmas. AB - This feature article introduces a deterministic approach for the rapid, single step, direct synthesis of metal oxide nanowires. This approach is based on the exposure of thin metal samples to reactive oxygen plasmas and does not require any intervening processing or external substrate heating. The critical roles of the reactive oxygen plasmas, surface processes, and plasma-surface interactions that enable this growth are critically examined by using a deterministic viewpoint. The essentials of the experimental procedures and reactor design are presented and related to the key process requirements. The nucleation and growth kinetics is discussed for typical solid-liquid-solid and vapor-solid-solid mechanisms related to the synthesis of the oxide nanowires of metals with low (Ga, Cd) and high (Fe) melting points, respectively. Numerical simulations are focused on the possibility to predict the nanowire nucleation points through the interaction of the plasma radicals and ions with the nanoscale morphological features on the surface, as well as to control the localized 'hot spots' that in turn determine the nanowire size and shape. This generic approach can be applied to virtually any oxide nanoscale system and further confirms the applicability of the plasma nanoscience approaches for deterministic nanoscale synthesis and processing. PMID- 20721366 TI - Insights into the capping and structure of MoS(2) nanotubes as revealed by aberration-corrected STEM. AB - Aberration-corrected electron microscopy (STEM-HAADF) has been used for the first time to understand the capping, nature and structure of the MoS(2) nanotubes. The MoS(2) nanotubes that have been obtained have various unusual faceted caps presumably arising from the presence of topological defects. A detailed study of the capping of the nanotubes, along with identification that the MoS(2) nanotubes are of the zigzag type have been carried out using both experimental and simulated STEM images. The presence of 3R-rhombohedral stacking of the MoS(2) nanotubes has been identified. PMID- 20721367 TI - Fabrication of membrane-type microvalves in rectangular microfluidic channels via seal photopolymerization. AB - Rectangular fluidic channels have rarely been used in microfluidic devices which use PDMS membrane-type microvalves, since the rectangular channel shape does not perfectly match the round shape of the membrane deformation. We present a polymer sealing method to fabricate PDMS membrane-type microvalves for rectangular microchannels. After fabricating the microfluidic device, photocurable oligomer is introduced into the fluidic channel and gas pressure is applied to the pneumatic channel to deform the membrane. The polymer seal is then locally polymerized by photolithography producing a structure matching the shape of the deformed membrane curvature. We compare the flow leakage between the membrane type microvalve with and without a polymer seal. We also demonstrate a micropump and droplet generator using this embedded polymer membrane-type microvalve in a rectangular microfluidic channel. This polymeric seal technique enables the use of easily fabricated rectangular channel membrane microvalves with all the functionality of their curved channel counterparts with negligible flow leakage. PMID- 20721368 TI - Bimetallic nickel-iridium nanocatalysts for hydrogen generation by decomposition of hydrous hydrazine. AB - Alloying Ni with Ir leads to the formation of highly active catalysts for complete decomposition of hydrous hydrazine with 100% H(2) selectivity at room temperature. Use of surfactants enhances the activity by suppressing the agglomeration of nanoparticles, but does not affect the bimetallic compositions of the nanoparticles. PMID- 20721369 TI - Confinement effects on alloy reactivity. AB - Density functional theory is used to characterize reactivity in systems confined between alloy surfaces separated by a gap from three to 10 A. It is found that the proximity of a second surface alters the geometric and electronic properties of the first one, and the changes are related to the nature of the interacting surfaces. These phenomena are explored by analysis of the dissociation of molecular oxygen and that of water in the confined systems. The results suggest that such confinement effects may be further designed for specific applications by tuning the alloy composition. PMID- 20721370 TI - Cations in control: crystal engineering polyoxometalate clusters using cation directed self-assembly. AB - The synthetic engineering of anionic polyoxometalate (POM) clusters with predefined properties tailored to specific applications is a great challenge using routine "one-pot" POM syntheses. Under such conditions, difficulties often arise from the multitude of complex reaction pathways and self-assembly processes occurring in solution. In this respect the major role of the charge balancing cations cannot be ignored, in fact such cations are crucial, both in the assembly of the building blocks, linkage to the overall cluster, and then assembly into the bulk material. Further, the role of the cation facilitating the selective crystallization of a particular cluster type cannot be divorced from the reaction process since the crystallization process itself can help pull "virtual" building blocks into being. This perspective briefly outlines our efforts towards engineering novel POM based materials, highlighting the use of large organic cations as "Shrink-wrapping" agents to isolate new POM clusters, frameworks and cage compounds. Central to this perspective is the hypothesis that, in the case of POM cluster assembly, the mechanism and various equilibria which define the clusters can be controlled by the selective crystallisation using cation control. Consequently, this indicates that the process of crystallisation can have a profound effect on self-assembly at the molecular level. We therefore propose that the crystallization process itself may define the molecular structure of the cluster leading to the conundrum, which came first, the cluster or the crystal of the cluster? PMID- 20721371 TI - The electrodeposition of copper from supercritical CO(2)/acetonitrile mixtures and from supercritical trifluoromethane. AB - The electrochemistry of [Cu(hfac)(2)], where hfac is hexafluoroacetylacetonate, and [Cu(MeCN)(4)](+) were investigated in liquid acetonitrile (MeCN), supercritical CO(2)/MeCN and supercritical trifluoromethane (CHF(3)) at 310-311 K and 17-20 MPa using either [NBu(n)(4)][BF(4)] or [NBu(n)(4)][B{3,5 (CF(3))(2)C(6)H(3)}(4)] as the supporting electrolyte. In liquid acetonitrile it is possible to deposit metallic Cu from both ([Cu(MeCN)(4)][BF(4)]) and [Cu(hfac)(2)] but voltammetry for the [Cu(hfac)(2)] system is more complex and there is evidence of stripping of the Cu by reaction with Cu(ii). Voltammetry of the two copper complexes in scCO(2)/MeCN showed typical plating and stripping features but with slightly increased diffusion limited currents for copper reduction due to the decreased viscosity of the supercritical solvent. In scCO(2)/MeCN the Cu(i) complex, tetrakis(acetonitrile)copper(i) tetrafluoroborate ([Cu(MeCN)(4)][BF(4)]), was found to produce better quality copper deposits than the Cu(ii) complex ([Cu(hfac)(2)]). The Cu(i) complex has the advantages that it is stable and does not undergo comproportionation with copper(0) and that its ligands are totally compatible with the scCO(2)/MeCN solvent system. The solubility of ([Cu(MeCN)(4)][BF(4)]) is limited in scCO(2)/MeCN but can be significantly improved by changing the anion for tetrakis[3,5 bis(trifluoromethyl)phenyl]borate ([B{3,5-(CF(3))(2)C(6)H(3)}(4)](-)). It was possible to deposit smooth copper films of high purity and low resistivity (down to 4.0 * 10(-6)Omega cm) from the Cu(i) complex. Copper was also deposited from supercritical CHF(3) using [Cu(hfac)(2)] as a precursor. Although the plating and stripping features in the voltammetry are complicated by the lack of cosolvent and electroreduction of the solvent or free ligands, it was possible to produce copper films with resistivities as low as 5.8 * 10(-6)Omega cm. PMID- 20721372 TI - Vesicular assemblies of modified Mn(12) single molecular magnets. AB - Fatty acid modified Mn(12) derivatives can self-assembly into vesicular structures in organic media. The vesicular assemblies have a sandwich structure with Mn(12) cluster separated by two alkyl chain layers. PMID- 20721373 TI - Hierarchical functionalisation of single-wall carbon nanotubes with DNA through positively charged pyrene. AB - A simple and efficient method to link reversibly DNA to SWNTs via electrostatic interaction is reported. The DNA/nanotube hybrids are characterised by a combination of gel electrophoresis and AFM. PMID- 20721374 TI - Hierarchically multifunctional TiO(2) nano-thorn membrane for water purification. AB - A novel TiO(2) nano-thorn membrane was assembled for concurrent filtration and photocatalytic oxidization to remove pollutants in water. This membrane has hierarchical porous and multifunctional properties, which provide these advantages: (1) producing water with high quality; (2) increasing water flux; and (3) eliminating membrane fouling. PMID- 20721375 TI - Dynamic saturation optical microscopy: employing dark-state formation kinetics for resolution enhancement. AB - Fluorescence microscopy has become one of the most rapidly developing observation techniques in the field of molecular biology, since its high sensitivity, contrast and labeling specificity together with being non-invasive fulfill the most important requirements of live cell imaging. The biggest limitation of the technique seems to be the spatial resolution which is, based on Abbe's diffraction law, restricted to some hundreds of nanometres. Recently, various approaches have been developed that overcome the limit imposed by the diffraction barrier and these methods currently lead the development in the field of fluorescence microscopy. In this contribution, we present dynamic saturation optical microscopy (DSOM)--a new technique that monitors the temporal decay of the excited singlet state due to a dark state formation. By mapping the intensity dependent decay kinetics, enhanced resolution images can be obtained. Generally, any dark state of fluorescent molecules can be employed in DSOM. Here, we focus our attention on triplet state formation. PMID- 20721376 TI - Self-reorganization of CdTe nanoparticles into two-dimensional Bi2Te3/CdTe nanosheets and their thermoelectrical properties. AB - A partial cation exchange reaction between CdTe nanoparticles and Bi(3+) ions gives rise to spontaneous formation of two-dimensional Bi(2)Te(3)/CdTe nanosheets. The average size and thickness of the nanosheets are around 200 and 6.9 nm, respectively. Both CdTe and Bi(2)Te(3), which are there as the form of nanoparticles with average sizes of 3.4 nm, are found to be homogenously distributed in the nanosheets. The Bi(2)Te(3)/CdTe nanosheets are further integrated into a pellet by using spark plasma sintering for optimizing thermoelectric performance. Compared with the bulk n-type Bi(2)Te(3), the pellets composed of Bi(2)Te(3)/CdTe nanosheets exhibit a considerably low thermal conductivity, 0.63 W m(-1) K(-1), and a slightly high Seebeck coefficient, -182.2 MUV K(-1), at room temperature. PMID- 20721377 TI - Water and ethanol desorption in the flexible metal organic frameworks, MIL-53 (Cr, Fe), investigated by complex impedance spectroscopy and density functional theory calculations. AB - The breathing behaviour of MIL-53(Cr) and MIL-53(Fe) upon water and ethanol desorption has been investigated by combining complementary experimental techniques including ThermoGravimetry Analysis (TGA), Differential Scanning Calorimetry (DSC) and Complex Impedance Spectroscopy (CIS). It was shown that two stages of solvent departure are involved in the desorption process, as revealed by (i) a change of the weight loss gradient in the TGA curve, (ii) the existence of a second endothermic peak in the DSC signal and (iii) a sudden drop and/or profile change of the ac conductivity in CIS. All these features are observed around a typical temperature T(c), for which the framework contractions, caused by the solvent desorption, occur. Moreover, it is shown that these modifications are more pronounced when the magnitude of the breathing is higher, as illustrated by the comparison of the water/MIL-53(Cr), ethanol/MIL-53(Cr) and water/MIL 53(Fe) systems. CIS data were further analyzed in the light of DFT calculations which provided the preferential arrangements of the molecules within the pores and the resulting host/guest interactions. It could then be proposed that (i) the polarization conductivity results from the local re-orientation of the MU(2)-OH dipoles bonded to the metal atom from the hybrid solid, i.e. Fe or Cr, and (ii) that dc conductivity, which can be ascribed to a proton propagation via a Grotthus mechanism, is favoured when the solvent molecules form strong hydrogen bonds between each other. PMID- 20721378 TI - In trap fragmentation and optical characterization of rotaxanes. AB - The first experiments on trapped rotaxanes are presented, combining collision induced fragmentation and in-trap laser spectroscopy. The intrinsic optical properties of three rotaxanes and their non-interlocked building blocks (thread and macrocycle) isolated in a quadrupolar ion trap are investigated. The excitation and relaxation processes under thermal activation as well as under photo-activation are addressed. The light and collision induced fragmentation pathways show that the degradation mechanisms occurring in the rotaxane are highly dependent on the nature of the thread. In the prospective of operating photoswitchable molecules, photo-activation is achieved in a controlled way by depositing photo-energy in the desired sub-unit of a mechanically interlocked structure. PMID- 20721379 TI - Asymmetric transfer hydrogenation of ketones catalyzed by rhodium complexes containing amino acid triazole ligands. AB - Active and selective catalysts for the asymmetric reduction of ketones, under transfer hydrogenation conditions, were obtained by combining [RhCl(2)Cp*](2), with a series of l-amino acid thioamide ligands functionalized with 1,2,3 triazoles. The obtained secondary alcohol products were formed with up to 93% ee. PMID- 20721380 TI - A chemistry/physics pathway with nanofibrous scaffolds for gene delivery. AB - This perspective is to introduce a new pathway for non-viral gene delivery by taking advantage of nanofibrous scaffolds as gene storage devices, gene carriers and homing devices. During gene delivery to the target, the DNA has to be protected in order to pass through a set of barriers before reaching the nucleus. The DNA can form a complex with polycations, and numerous publications exist on how to stabilize the DNA fragments by natural and synthetic materials. Electrospun nanofibrous scaffolds can be used to store the DNA, especially in the form of a more stabilized polyplex, and then to deliver the DNA (polyplex) to cells that are attached to the scaffold. While each essential step has been tested experimentally, the overall yet untested process, especially for in vivo experiments, may lead to a promising specific approach for gene/drug storage and delivery. The pathway described herein is based mainly on our understanding of the physics and chemistry of gene storage and delivery processes, in contrast to using pure biological concepts. Novel biodegradable, biocompatible nanofibrous materials with imbedded DNA (e.g., in the polyplex form) can then be designed to fabricate an intelligent scaffold for gene delivery. To achieve the above goal, the first step is to stabilize the DNA so that it can be incorporated into nanofibrous scaffolds. In this respect, we shall discuss the different methods of DNA/gene condensation and complex formation, and then explain the strategy used to incorporate DNA into electrospun nanofibers. Solvent-induced DNA condensation and then encapsulation were achieved. However, the released naked DNA was not sufficiently protected for gene transfection in cells. The objective of the current perspective is to suggest that, instead of the solvent-induced DNA condensation, one can combine the recently developed polyplex formation by using branched polyethyleneimine (bPEI). More importantly, free bPEI can be incorporated into the nanofibers separately so that during the gene delivery step, the presence of a predesigned amount of free bPEI can greatly increase the gene transfection efficiency, as has been reported recently by Chi Wu and his coworkers. Thus, a physics/chemistry-based pathway that utilizes nanofibrous scaffolds for gene delivery is within reach. PMID- 20721381 TI - Photoinduced electron transfer in thin films of porphyrin-fullerene dyad and perylenetetracarboxidiimide. AB - Photoinduced intra- and intermolecular electron transfer (ET) in thin films of porphyrin-fullerene dyad (P-F) and perylenetetracarboxidiimide (PTCDI) was studied by means of photoelectrical and spectroscopic methods. Films consisting of smooth 100 mol% layers of P-F and PTCDI were prepared by the Langmuir-Schafer (LS) technique and thermal evaporation, respectively. The time-resolved Maxwell displacement charge (TRMDC) and laser flash-photolysis methods were utilized to demonstrate photoinduced ET from P-F to PTCDI regardless of which chromophore is photoexcited. Finally, the information about the electron movement in the respective thin films was used to build a layered organic solar cell, whose internal quantum yield (Phi(I)) of collected charges was 13%. PMID- 20721382 TI - Microfluidic perfusion system for maintaining viable heart tissue with real-time electrochemical monitoring of reactive oxygen species. AB - A microfluidic device has been developed to maintain viable heart tissue samples in a biomimetic microenvironment. This device allows rat or human heart tissue to be studied under pseudo in vivo conditions. Effluent levels of lactate dehydrogenase and hydrogen peroxide were used as markers of damaged tissue in combination with in situ electrochemical measurement of the release of reactive oxygen species (ROS). The parameters for perfusion were optimized to maintain biopsies of rat right ventricular or human right atrial tissue viable for up to 5 and 3.5 hours, respectively. Electrochemical assessment of the oxidation current of total ROS, employing cyclic voltammetry, gave results in real-time that were in good agreement to biochemical assessment using conventional, off-chip, commercial assays. This proof-of-principle, integrated microfluidic device, may be exploited in providing a platform technology for future cardiac research, offering an alternative approach for investigating heart pathophysiology and facilitating the development of new therapeutic strategies. PMID- 20721383 TI - Multilayer gold nanoparticle-assisted thermal desorption ambient mass spectrometry for the analysis of small organics. AB - In this study, thermal desorption-based ambient mass spectrometry (TDAMS) for the analysis of small organics was explored. A layer-by-layer (LBL) self-assembled multilayer of a gold nanoparticle (AuNP)-based glass chip (Glass@AuNPs) with the absorption capacity in the near-infrared (NIR) region was used as the energy absorber and as the sample holder for sample deposition at ambient condition. An NIR laser diode (808 nm) was successfully employed as the thermal desorption source to liberate only small molecules from Glass@AuNPs chips. Followed by post ionization, the resultant ions were monitored by an ion trap mass spectrometer. Post-ionization was assisted by a spray consisting of 50% deionized water acetonitrile containing 0.1% acetic acid generated from a short tapered capillary by employing a high voltage (4 kV). Analytes with different polarities including small acids, amino acids, insecticides, and biodiesel samples such as ethyl esters can be directly analyzed using this approach. We demonstrated that this ambient mass spectrometric method was suitable for selectively analyzing small target organics directly from complex samples without any sample pretreatment. PMID- 20721384 TI - Selective adsorption of dithiolate-modified multi-wall carbon nanotubes onto alkanethiol self-assembled monolayers on Au(111). AB - Dithiolate-modified multi-wall carbon nanotubes (MWCNTs) adsorb selectively on the self-assembled monolayers (SAMs) of alkanethiols on a Au surface: the long dithiolates attached to the MWCNTs anchor the massive MWCNTs onto the Au surface by replacing the shorter thiolates of SAMs. PMID- 20721385 TI - Complete determination of natural site-specific enantio-isotopomeric excesses in linoleic acid using natural abundance deuterium 2D NMR in polypeptide mesophases. AB - NAD 2D NMR spectroscopy using chiral mesophases made of poly-gamma-benzyl-l glutamate and pyridine allowed us to evaluate, for the first time, the natural site-specific enantio-isotopomeric excesses at each methylene group of linoleic acid, a central, essential PUFA precursor of all conjugated triene fatty acids. PMID- 20721386 TI - Reactivity of an oxoboryl complex toward fluorinated aryl boron reagents. AB - X-Ray and IR data of unprecedented oxoboryl species indicate a significant alteration in the B[triple bond]O bond strength underlining the novel oxoboryl complexes' close relationship with the well investigated and important class of carbonyl complexes. PMID- 20721387 TI - Novel catanionic vesicles from calixarene and single-chain surfactant. AB - The mixed system between p-sulfonatocalix[4]arene and tetradecyltrimethylammonium bromide forms unilamellar vesicles after sonication of the aqueous dispersion. Furthermore these vesicles can be stored, without use of lyoprotectants, by lyophilization and then rehydration without change in size or shape. PMID- 20721388 TI - A detailed study of growth of nanostructured poly(aniline) particles in the light of thermodynamic interaction balance. AB - In this paper, various nanostructured poly(aniline) (PANI) particles have been prepared via redox polymerization of aniline in the presence of tri(ethylene glycol) bis(1,5-dihydroxy-naphthalene-2,6- disulfate) ether (TBE). The morphology evolution of the resulting PANI particles was carefully monitored by electron microscopy, clearly underlining the structure-directing role of TBE during the agglomeration of PANI primary nanoparticles (NPs) in the course of polymerization. Various interactions exerted on the PANI primary NPs were assessed based on extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, and the thermodynamic balance of these interactions was used to analyze the effect of the TBE concentration on the morphology of the nanostructured PANI particles. PMID- 20721389 TI - Differential capacitance of the double layer at the electrode/ionic liquids interface. AB - The differential capacitance of the electrical double layer at glassy carbon, platinum and gold electrodes immersed in various ionic liquids was measured using impedance spectroscopy. We discuss the influence of temperature, the composition of the ionic liquids and the electrode material on the differential capacitance/potential curves. For different systems these curves have various overall shapes, but all include several extremes and a common minimum near the open circuit potential. We attribute this minimum to the potential of zero charge (PZC). Significantly, the differential capacitance generally decreases if the applied potential is large and moving away from the PZC. This is attributed to lattice saturation [A. A. Kornyshev, J. Phys. Chem. B, 2007, 111, 5545] effects which result in a thicker double layer. The differential capacitance of the double layer grows and specific adsorption diminishes with increasing temperature. Specific adsorption of both cations and anions influences the shapes of curves close to the PZC. The general shape of differential capacitance/potential does not depend strongly on the identity of the electrode material. PMID- 20721390 TI - Multiple approaches to enantiopure spirocyclic benzofuranones using organocatalytic cascade reactions. AB - Three distinct aminocatalytic cascade reactions leading to enantiomerically pure spirocyclic benzofuranones have been devised, highlighting the ability of organocascade to generate high degrees of stereochemical and architectural complexity in a single chemical transformation. PMID- 20721391 TI - Synthesis, structures and spin crossover properties of infinite 3D frameworks of iron(II) containing organodinitrile bridging ligands. AB - Four new Fe(II) coordination polymers of formulation [Fe(L)(3)][MCl(4)](2), M = Fe(III), In(III) have been synthesized and structurally and magnetically characterized. They contain organodinitrile bridging ligands where L is 1,1' azobiscyclopentanecarbonitrile (ACCN) or 2,2'-azobisisobutyronitrile (AIBN). The compounds are [Fe(AIBN)(3)][InCl(4)](2) (1), [Fe(AIBN)(3)][FeCl(4)](2) (2), [Fe(ACCN)(3)][InCl(4)](2) (3), and [Fe(ACCN)(3)][FeCl(4)](2) (4). Compounds 1 and 2 were first reported many years ago, elsewhere, but not then structurally characterized. All four compounds adopt an "open framework" alpha-Po type 3D lattice structure with the [M(III)Cl(4)](-) anions held in the channels thereof. There are two crystallographically independent, distorted octahedral Fe(II)N(6) sites in 1 and 2, but only one Fe(II) site in 3 and 4. These are the first open framework systems containing covalently linked dinitrile bridging ligands and join a related class of [Fe(L)(3)](2+) frameworks known with ditriazole and ditetrazole linkers and exhibiting spin crossover behaviour. Indeed, compounds 1 and 2 display a 'half' spin transition in their magnetic susceptibility vs. temperature plots, this being due to the fact that only half of the Fe(II) d(6) centres in the framework changed spin from HS -> LS as the temperature decreased, as also evidenced by the structural details around the Fe(II) centres, determined below T(1/2) (118 and 170 K for 1 and 2, respectively). Mossbauer spectra confirmed these spin changes. The weak cooperativity between the SCO centres led to a lack of thermal hysteresis. When the ACCN ligand was used instead of the AIBN ligand, in compounds 3 and 4, only one crystallographically unique Fe(II) centre was observed in an otherwise similar framework. No SCO transition was observed in 3 and 4 as evidenced by temperature independent moment data, backed up by single crystal X-ray crystallographic analysis at 123 K. Thus the HS Fe(II) ions remain in this spin state at all temperatures, presumably because the ligand field, at the nitrile N-donors, is weaker in ACCN than in AIBN. In addition, the crystal structure of a minor phase of an aqua complex, [Fe(AIBN)(2)(H(2)O)(2)][FeCl(4)](2) (2a), obtained from the reaction that produced 2, showed a 2D layer motif, with trans-Fe(N)(4)(H(2)O)(2) ligation. PMID- 20721392 TI - A synthetic riboswitch with chemical band-pass response. AB - We designed a synthetic riboswitch containing an OFF and an ON riboswitch units fused in tandem. The resulting complex riboswitch functions as a chemical band pass filter circuit. PMID- 20721393 TI - A new tetrathiafulvalene-phenoxynaphthacenequinone dyad: switching on the intramolecular electron-transfer with UV light irradiation and metal ion coordination. AB - The metal ion-promoted intramolecular electron transfer within TTF-based dyad 1 containing a photochromic PNQ unit can be switched on with UV light irradiation by taking advantage of the photochromic feature of the PNQ unit and the fact that the trans and ana forms of PNQ show different electron accepting capacity. PMID- 20721394 TI - Purified rhodium edge states: undercoordination-induced quantum entrapment and polarization. AB - Artificial undercoordination of Rh atoms at a surface is indeed fascinating. It not only generates unusual energy states, but also differentiates the processes of catalytic reaction and growth nucleation at such atomic sites from those proceeding at a flat surface. Recent findings have stimulated the need a better understanding of the mechanism behind these observations. An X-ray photoelectron differential spectroscopy (XPDS) study reported herein reveals that the undercoordinated Rh atoms at step edges and the nearby missing-row vacancies generate two extra states in the 3d(5/2) band. These findings confirm theoretical [C. Q. Sun, Prog. Solid State Chem., 2007, 35, 1] expectations that the shorter and stronger bonds between undercoordinated atoms cause the local quantum entrapment of the core charge and the polarization of the otherwise conducting s electrons by the densely and deeply trapped core electrons. Therefore, the XPDS resolved low-energy component arises from quantum entrapment, while the high energy one arises from potential screening by polarization. PMID- 20721395 TI - An unusual discontinuity in the thermal spin transition in [Co(terpy)2][BF4]2. AB - Single crystal and powder samples of [Co(terpy)(2)][BF(4)](2) are low spin below 100 K but show a typically gradual thermal spin-transition on warming, centred near 270 K. However, the spin-crossover exhibits an unusual and pronounced discontinuity above room temperature, when the material is ca. 87% high-spin. A crystallographic study at nine temperatures between 30-375 K showed that the discontinuity is not caused by a phase transition or by changes in anion disorder. Rather, it may reflect the steric consequence of small changes in the nearest neighbour interactions between the cations as the spin transition progresses. PMID- 20721396 TI - Chiral Birch reduced tertiary phosphines: precursors to asymmetric 1,2 cyclohexenebis(tertiary phosphines). AB - The first examples of an optically active Birch reduced tertiary phosphine, viz. (R(P))-(cyclohexa-2,5-dienyl)(3-pentyl)phenylphosphine, and successful hydrophosphination of the related racemic ligand (+/-)-(cyclohexa-2,5-dienyl)(2 propyl)phenylphosphine with PHPh(2) in the presence of KOBu(t) in thf to give a 1,2-cyclohexenebis(tertiary phosphine), viz. (+/-)-1,2 C(6)H(8)(PPh(2))(PPhPr(i)), are described; as confirmed by crystal structure determinations of [SP-4-4-(S(P),S)]-chloro[(cyclohexa-2,5-dienyl)(3 pentyl)phenylphosphine][2-{1-(dimethylamino)ethyl}phenyl-C,N]palladium(II) and [SP-4-3-(+/-)]-dimethyl[(1-diphenylphosphino)(2 isopropylphenylphosphino)cyclohexene]platinum(II). PMID- 20721397 TI - On-demand generation of monodisperse femtolitre droplets by shape-induced shear. AB - We describe a method for creating discrete femtolitre-scale water-in-oil droplets on demand, based solely on a geometrically induced reduction in oil/water interfacial area at microfabricated junction orifices. This on-demand generation method is driven by self-shear of droplets due to interfacial tension induced forces resulting from a localized transition in microchannel height. The magnitudes of shear stresses involved appear to be significantly less than the shearing instabilities used to split off daughter droplets from aqueous mother plugs at microfabricated junctions in continuous water-in-oil segmented flows, which implies that this method may be better suited for studying biochemical reactions and reaction kinetics in droplets of decreased volume without loss of chemical reactivity due to redistribution of surfactant density used to passivate the oil/water interface. Predictable droplet generation rates under constant pressure conditions or the gated formation of one, two or more droplets at a time with fixed pressure pulses have been demonstrated in a similar manner to active on-demand droplet generation strategies, but with a simpler system not needing actuation and sensing equipment beyond a pressure regulator. PMID- 20721398 TI - Towards a quantitative description of solid electrolyte conductance switches. AB - We present a quantitative analysis of the steady-state electronic transport in a resistive switching device. The device is composed of a thin film of Ag(2)S (solid electrolyte) contacted by a Pt nano-contact acting as ion-blocking electrode, and a large-area Ag reference electrode. When applying a bias voltage both ionic and electronic transport occurs, and depending on the polarity it causes an accumulation of ions around the nano-contact. At small applied voltages (pre-switching) we observed this as a strongly nonlinear current-voltage curve, which is modeled using the Hebb-Wagner treatment for polarization of a mixed conductor. This model correctly describes the transport of the electrons within the polarized solid electrolyte in the steady-state up until the resistance switching, covering the entire range of non-stoichiometries, and including the supersaturation range just before the deposition of elemental silver. In this way, it is a step towards a quantitative understanding of the processes that lead to resistance switching. PMID- 20721399 TI - Activity-directed identification of maize kernel peroxidases associated with postharvest insect resistance. AB - Maize grain peroxidases are associated with insect resistance. In this study we present an activity directed approach for the identification of peroxidases localized in different grain tissues. With drastically reduced proteomic effort we could identify different peroxidases for maize weevil susceptible and resistant genotypes of maize. Our strategy also allows for the identification of previously unknown plant peroxidases. PMID- 20721400 TI - Negative ion formation in potassium-nitromethane collisions. AB - Ion-pair formation in gaseous nitromethane (CH(3)NO(2)) induced by electron transfer has been studied by investigating the products of collisions between fast potassium atoms and nitromethane molecules using a crossed molecular-beam technique. The negative ions formed in such collisions were analysed using time of-flight mass spectroscopy. The six most dominant product anions are NO(2)(-), O(-), CH(3)NO(2)(-), OH(-), CH(2)NO(2)(-) and CNO(-). By using nitromethane-d(3) (CD(3)NO(2)), we found that previous mass 17 amu assignment to O(-) delayed fragment, is in the present experiment may be unambiguously assigned to OH(-). The formation of CH(2)NO(2)(-) may be explained in terms of dissociative electron attachment to highly vibrationally excited molecules. PMID- 20721401 TI - Horseradish peroxidase-functionalized Pt hollow nanospheres and multiple redox probes as trace labels for a sensitive simultaneous multianalyte electrochemical immunoassay. AB - A novel strategy for a simultaneous multianalyte electrochemical immunoassay is proposed using thionine-labeled anti-AFP and ferrocene-labeled anti-CEA as tracers; each biorecognition event yielded a distinct voltammetric peak, whose position and size reflected the identify and level of the corresponding antigen. PMID- 20721402 TI - Additive coloring of thin, single crystalline MgO(001) films. AB - Electron bombardment of single-crystalline MgO(001) films has been shown to result in the formation of surface color centers. In this report we present an alternative way to produce surface color centers on single-crystalline MgO(001) films using additive Mg coloring. Electron paramagnetic resonance (EPR) spectroscopy was used to prove the formation of surface paramagnetic color centers upon deposition of small amounts of Mg on MgO(001) films at 50 K. With increasing coverage the number of Mg induced color centers rises up to a coverage of about 0.03 monolayers and thereafter decreases with increasing Mg coverage. At high coverage and low temperatures metallic Mg clusters nucleate on the surface of the MgO(001) film as shown by infrared (IR) spectroscopy using CO as a probe molecule. PMID- 20721403 TI - Conformational equilibria in vanillin and ethylvanillin. AB - The conformational equilibria of vanillin and ethylvanillin have been investigated in a supersonic jet expansion using rotational spectroscopy. Two conformers have been detected for each molecule, with a dominant O-H...O intramolecular hydrogen bond locking the local conformation of the hydroxyl and methoxy/ethoxy groups. As a consequence, the observed conformers of vanillin differ only in the orientation of the aldehyde group, either cis or trans with respect to the methoxy group. For ethylvanillin the ethoxy group would plausibly generate additional trans (in-plane) or gauche (out-of-plane) orientations. However, the two detected conformations exhibit only planar ethoxy trans arrangements, with the gauche forms most probably depopulated by collisional relaxation in the jet. Torsional tunneling effects due to internal rotation of the terminal methyl groups were not detectable, indicating internal rotation barriers above 12.3 kJ mol(-1). The conformational population ratios in the jet have been estimated from relative intensity measurements. Ab initio (MP2) and DFT calculations using B3LYP and the recent M05-2X empirical functional supplemented the experimental work, describing the rotational parameters, conformational landscape and the aldehyde and methyl internal rotation barriers in these molecules. PMID- 20721404 TI - MCD spectroscopy of hexanuclear Mn(III) salicylaldoxime single-molecule magnets. AB - The hexanuclear cages [Mn(6)O(2)(R-sao)(6)L(2)(EtOH)(x)(H(2)O)(y)] "Mn(6)" behave as single-molecule magnets (SMMs) below a characteristic blocking temperature. As with [Mn(12)O(12)(O(2)CR)(16)(H(2)O)(4)] "Mn(12)" the electronic absorption spectra are rather featureless, yielding little information on the electronic structure of the magnetic ions. Low temperature Magnetic Circular Dichroism (MCD) spectra afford greater resolution of the optical transitions and also probe the magnetic properties of the system. Both the ground state spin and blocking temperature of the Mn(6) cages are determined by subtle structural perturbations of a generic Mn(6)O(2) core. Absorbance and MCD spectra are reported for [Mn(6)O(2)(Et-sao)(6){O(2)CPh(Me)(2)}(2)(EtOH)(6)] (1), [Mn(6)O(2)(Et sao)(6){O(2)CPh}(2)(EtOH)(4)(H(2)O)(2)] (2), [Mn(6)O(2)(sao)(6){O(2)CPh}(2)(EtOH)(4)].EtOH (3) and the trinuclear precursor [Mn(3)O(Et-sao)(3)(MeOH)(3)](ClO(4)) (4) cast into polymer film. SMM behaviour has previously been observed using magnetic susceptibility measurements on powder and single-crystal samples. The ligand field environment of the magnetic ions is assumed to be similar in (1) and (2) and their different blocking temperatures are attributed to the magnitude of the effective exchange constant. The MCD spectra of (1) and (2), in which the ground state spin S = 12, show that the ligand field environments of the Mn ions are almost identical and that magnetic hysteresis persists for isolated molecules when crystal packing forces are removed. The subtle structural differences between (1) and (2) are manifested in the field dependence of the MCD response at different wavelengths that reflect changes in band polarisation. The MCD spectrum of (3) contains features not apparent in those of (1) and (2). These are attributed to 5-coordinate Mn(iii), which is unique to (3) among the compounds studied. (3) has ground state spin S = 4, a lower blocking temperature and consequently no observable hysteresis in the MCD down to 1.7 K. Comparison of the MCD spectra of (1)-(3) to that of (4) confirms the integrity of the Mn(6)O(2) core when these materials are cast into polymer film. PMID- 20721409 TI - In silico screening for unmonitored, potentially problematic high production volume (HPV) chemicals prone to sequestration in biosolids. AB - Thousands of high production volume (HPV) chemicals are used in the US at rates exceeding 450,000 kg (1 million pounds) per year, yet little is known about their fates during wastewater treatment and upon release into the environment. We utilized a recently introduced empirical model to predict the fraction of the mass loading (in raw sewage) that is expected to persist in digested sludge following conventional municipal treatment of chemical-laden sewage. The model requires only two readily available input parameters, a compound's log K(OW) value and a dimensionless curve fitting parameter (p(fit)). Following refinement of the fitting parameter and cross-validation of the model using the Jackknife method, we predicted the mass fractions of 207 hydrophobic HPV chemicals (log K(OW) of >= 4.0) that are expected to accumulate in digested municipal sludge during conventional wastewater treatment. Using this screening approach in conjunction with information from toxicity databases, we identified 11 HPV chemicals that are of potential concern due to (i) their propensity to accumulate and persist in sludge (>50% of mass loading), (ii) unfavorable ecotoxicity threshold values, and (iii) structural characteristics suggestive of environmental persistence following release of these HPV chemicals on land during biosolids recycling. The in silico screening approach taken in this study highlights existing environmental monitoring needs and may guide risk management strategies for biosolids disposal. PMID- 20721410 TI - Attenuated antiaggregation effects of magnetite nanoparticles in cerebrospinal fluid of people with Alzheimer's disease. AB - It is well known that oligomeric/aggregated amyloid beta peptides are a key player in the pathogenesis of Alzheimer's disease and that different nanoparticles influence oligomerization/aggregation processes in experiments in vitro. Our previous results demonstrated antiaggregation effects of magnetite nanoparticles in the case of protein lysozyme, however, they have yet to be supported by biological samples containing peptides/proteins preaggregated in vivo. In the study, Thioflavin T based fluorescence was evaluated on cerebrospinal fluid samples from people with Alzheimer's disease/multiple sclerosis and corresponding age-related controls using magnetite nanoparticles incubated for 24 h. Our results are as follows: (i) fluorescence of samples without nanoparticles was significantly higher in both older groups (old controls and people with Alzheimer's disease) than in those of younger (young controls and people with multiple sclerosis), (ii) nanoparticles did not markedly influence a fluorescence intensity in young people but eliminated it in both old groups; nevertheless, the effects of nanoparticles were significantly lower in patients with Alzheimer's disease then in the age-matched controls, and finally (iii) significant positive correlation was observed between fluorescence of samples without nanoparticles and levels of phospho-tau. Our results support studies reporting enhanced aggregation of different peptides/proteins occurring during normal aging and demonstrate for the first time that peptides/proteins preaggregated in vivo during Alzheimer's disease are more resistant to the antiaggregation effects of magnetite nanoparticles than those of age-matched controls. A significant correlation with phospho-tau levels indicate that the in vitro test with magnetite nanoparticles and Thioflavin T dye on cerebrospinal fluid could be sensitive to changes mediated by early Alzheimer's disease stages. PMID- 20721411 TI - High performance magnetically controllable microturbines. AB - Reported in this paper is two-photon photopolymerization (TPP) fabrication of magnetic microturbines with high surface smoothness towards microfluids mixing. As the key component of the magnetic photoresist, Fe(3)O(4) nanoparticles were carefully screened for homogeneous doping. In this work, oleic acid stabilized Fe(3)O(4) nanoparticles synthesized via high-temperature induced organic phase decomposition of an iron precursor show evident advantages in particle morphology. After modification with propoxylated trimethylolpropane triacrylate (PO(3)-TMPTA, a kind of cross-linker), the magnetic nanoparticles were homogeneously doped in acrylate-based photoresist for TPP fabrication of microstructures. Finally, a magnetic microturbine was successfully fabricated as an active mixing device for remote control of microfluids blending. The development of high quality magnetic photoresists would lead to high performance magnetically controllable microdevices for lab-on-a-chip (LOC) applications. PMID- 20721412 TI - Effects of the alkyl-chain length on the mixing state of imidazolium-based ionic liquid-methanol solutions. AB - Effects of the alkyl-chain length of the imidazolium cation on the mixing state of imidazolium-based ionic liquids, 1-alkyl-3-methylimidazolium (C(n)mim(+), the alkyl-chain lengths n of 4, 6, 8, 10, and 12) bis(trifluoromethanesulfonyl)amide (TFSA(-)), and methanol were investigated using small-angle neutron scattering (SANS), attenuated total reflectance infrared (ATR-IR), and NMR techniques. SANS measurements revealed that C(n)mim(+)TFSA(-) is heterogeneously mixed with methanol in the methanol mole fraction range of 0.8 <=x(CD(3)OD) <= 0.995. The heterogeneity of the C(n)mim(+)TFSA(-)-methanol solutions, except for C(4)mim(+)TFSA(-), is most enhanced at x(CD(3)OD) ~ 0.97 over the entire mole fraction range. Thus, the mole fraction at the maximum heterogeneity of the solutions is independent of the alkyl-chain length. In contrast, the magnitude of the maximum heterogeneity of the solutions is larger in the order of the alkyl chain length from n = 4 to 12. ATR-IR and NMR measurements showed that methanol molecules gradually form hydrogen bonds among them in the solutions with increasing x(CH(3)OH). In particular, the hydrogen-bonds among methanol molecules are conspicuously evolved in the solutions above x(CH(3)OH) ~ 0.8. The increase in the concentration of the hydrogen-bonded methanol with increasing x(CH(3)OH) does not significantly depend on the alkyl-chain length. According to these results, we concluded that the heterogeneity of C(n)mim(+)TFSA(-)-methanol solutions arises from polar domains composed of the imidazolium rings, TFSA(-), and methanol clusters and nonpolar domains formed by interaction among the alkyl chains of the imidazolium cations. PMID- 20721413 TI - Monitoring of pesticide residues in dairy cattle farms from NW Spain. AB - The consequences of the use of pesticides in agricultural activities for food and feed product safety are subjects of major concern. In the present work, simple and environmentally friendly methodologies were applied to the analysis of soil and cattle feed samples collected in dairy cattle farms from Galicia (NW Spain). This forms part of an integrated study aiming to investigate the global impact of the use of pesticides in such farms. The target compounds were 36 plant protection products belonging to different families. Organochlorine and organophosphorus pesticides were the most commonly detected compounds in the analyzed samples; pyrethroid and chloroacetanilide pesticides were also found in some of them, but not so frequently. Detected levels were rarely above the established legal limits. PMID- 20721414 TI - Highly efficient and enantioselective biotransformations of beta-lactam carbonitriles and carboxamides and their synthetic applications. AB - Catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase and amidase containing microbial whole cell catalyst, a number of racemic 1-arylmethyl- and 1 allyl-4-oxoazetidine-2-carbonitriles and carboxamides underwent efficient transformations under very mild conditions to produce enantiopure functionalized S-amide and R-acid products in excellent yields. While the nitrile hydratase showed good enzyme activity but virtually no enantioselectivity, the amidase displayed high R-enantioselectivity against almost all amide substrates tested. The synthetic applications of the resulting functionalized chiral beta-lactam derivatives were demonstrated by the facile preparation of beta-lactam-fused heterocyclic compounds. PMID- 20721415 TI - Notes on nursing: nurses making a difference in global health. PMID- 20721416 TI - Adaptation and validation of an oral anticoagulation measurement of treatment adherence instrument. AB - This methodological study adapted and analyzed the psychometric properties of the Measurement of Treatment Adherence (MTA) instrument for Brazilian users of oral anticoagulation therapy. Its final version was tested with 178 individuals. The average of answers for all questions ranged from 4.6 to 5.8 and 97.2% of the individuals were considered adherent. Moderate correlations were obtained between the adherence measure and the Mental health and Vitality domains of the SF-36. Cronbach's alpha was 0.60 and the ceiling effect occurred in answers to all items. These results indicate weak evidence of the validity, reliability and responsiveness of the MTA-adapted version for users of oral anticoagulant therapy. PMID- 20721417 TI - Clinical validation of impaired spirituality in patients with chronic renal disease. AB - This study aimed to identify and validate the defining characteristics of the nursing diagnosis Impaired spirituality. The methodological framework proposed by Fehring for the clinical validation of nursing diagnosis was used. The investigation was carried out in a dialysis clinic and had as participants 120 patients with chronic renal disease. Data were collected by two expert nurses, through interviews. The prevalence of the nursing diagnosis Impaired spirituality in the sample was 27.5%. It was found that the most frequent defining characteristics were Expresses behavioral changes: rage, Inability to express creativity, Questions suffering and Expresses alienation. The clinical validation of Impaired spirituality contributed to refine this diagnosis. Its identification in patients with chronic renal disease undergoing dialysis treatment can offer alternatives for a safer and more effective intervention, aiming at the satisfaction of the spiritual needs of these patients. PMID- 20721418 TI - Profile and severity of the patients of intensive care units: prospective application of the APACHE II index. AB - This study aimed to understand the profile and severity of patients in physiotherapy treatment after their admission to the intensive care unit (ICU) by applying the APACHE II index. One hundred and forty six subjects, with a mean age of 60.5 +/- 19.2 years, were evaluated. The APACHE II index was applied in the first 24 hours to evaluate the severity and mortality risk score. Patients were monitored until hospital discharge or death. The mean APACHE II score was 20+/ 7.3 with an estimated risk of death of 32.4% and observed mortality of 58.2%. The mean hospital stay was 27.8+/-25.2 days. The patients in physiotherapy at the institution studied were predominantly male, elderly, from the emergency service for treatment (non-surgical), and had clear severity, suggested by the APACHE II score and the observed mortality. PMID- 20721419 TI - The attitudes of nurses from an intensive care unit in the face of errors: an approach in light of bioethics. AB - This study analyzed the attitudes of nurses concerning the occurrence of errors in nursing procedures carried out in an Intensive Care Unit (ICU) based on the bioethics framework. This descriptive study with qualitative approach was carried out with 14 nurses from a private hospital in the city of Sao Paulo, Brazil. Results were analyzed according to Bardins proposal of content analysis. The resulting themes were: acknowledging ones fallibility; acknowledging and reporting errors; hiding errors. The nurses reports are based on considerations through the lens of bioethics: taking responsibility for an error implies acknowledging ones own vulnerabilities; acknowledging an error with responsibility implies ethical conditions in the relationships among those involved; and errors are in the context of a particular environment. This study enables re-thinking nursing practice based on bioethics, resorting to the analysis of errors focusing on the relationships between those involved. PMID- 20721420 TI - Nursing consultation protocol for patients after myocardial revascularization: influence on anxiety and depression. AB - The objective was to evaluate the influence of the Nursing Consultation Protocol in aspects of anxiety and depression in patients after myocardial revascularization using the Hospital Anxiety and Depression scale (HAD). A randomized clinical trial developed in the outpatient clinic of a public hospital in Fortaleza-Ceara. One hundred and forty six patients, who underwent myocardial revascularization, composed the population, providing the sample of 39 patients in the control group (CG) and 39 in the intervention group (IG). The results were presented in tables. Anxiety had a mean of 5.41 in the CG and a median of 5 and a mean in the IG of 5.21 and a median of 4. Depression predominated in the CG, with a mean 4.82 and a median of 4, while the IG had a mean of 3.79 and a median of 3. It was found that people monitored in accordance with the Nursing Consultation Protocol had a lower percentage of anxiety and depression after six months. PMID- 20721421 TI - Strengths and threats regarding the patients safety: nursing professionals opinion. AB - The aim of this research is to know the barriers and opportunities that nursing professionals detect in their clinical practice in order to develop the culture of patient safety and to identify future research lines. This qualitative study is based on the DELPHI method, with a group of 19 nursing professionals from education and care practice, involving both primary and specialized care. Weaknesses and threats revolve around five categories: profession, organization and infrastructure; indicators; communication and safety culture; and safety training. Opportunities to improve safety cover six categories: organizational change; promotion of the safety culture, professional training and development; relationship with the patients; research; and strategic planning. Work is needed to improve safety and nursing should be ready to assume this leadership. PMID- 20721422 TI - Methicillin resistant Staphylococcus aureus: knowledge and factors related to the nursing teams adherence to preventive measures. AB - This study evaluated the knowledge of a nursing team from a public hospital in the state of Sao Paulo, Brazil concerning preventive measures recommended in the care delivered to patients colonized with Methicillin Resistant Staphylococcus Aureus (MRSA) and, through the Health Beliefs Model, identified the factors influencing adherence or non-adherence to preventive measures. A total of 318 professionals from different units participated in the study. According to the analysis, the nursing teams knowledge and perception of MRSA susceptibility was limited, which indicates the need for actions to improve the understanding of preventive measures employed in the care delivered to patients colonized or infected by this microorganism. PMID- 20721423 TI - Prevalence of risk factors for breast neoplasm in the city of Maringa, Parana state, Brazil. AB - The aim of this study was to identify the prevalence of the risk factors for breast cancer among women between 40 and 69 years old in the city of Maringa, Parana State, Brazil. An analytical, exploratory and cross-sectional study was carried out through a population research at homes in Maringa. The sample was composed of 439 women between 40 and 69 years old. The data were collected by home interviews, stored using the Statistical Package for the Social Sciences (SPSS) software and presented in tables as absolute and relative frequency. The predominant ethnical group was Caucasian with an average age of 52 years. Among risk factors identified in the present study, an expressive number of overweight women were found. It is important and necessary to put in practice actions that identify the modifiable risk factors for the development of breast tumors in order to reduce morbidity and mortality levels due to this pathology. PMID- 20721424 TI - Health related quality of life of women with cervical cancer. AB - This cross-sectional study aimed to evaluate the health related quality of life (HRQoL) of women with cervical cancer and to identify predictors of quality of life. Between November 2008 and February 2009, 149 women were interviewed. The instrument Functional Assessment of Cancer Therapy-Cervix Cancer (FACT-Cx) was used to assess HRQoL and, in general, the scores obtained indicated positive evaluation. The items that showed negative evaluation were: I am interested in sex, I feel sexually attractive, I am afraid to have sex and My vagina feels too narrow or short. In multiple linear regression analysis, using the backward method, of the 18 independent variables, eight were predictive of HRQoL. Self perceived health status was the most influential factor. Special attention should be given to the sexual dysfunctions of these women after radiotherapy. PMID- 20721425 TI - Biological risk in nursing care provided in family health units. AB - There is very frequent exposure to potentially contaminated material in procedures performed by nursing professionals. This exploratory and descriptive study characterizes the potential risk of biological exposure in procedures performed by nursing professionals in ten Family Health units in Sao Carlos-SP, Brazil. We observed 238 procedures involving potential risk of contact with biological material, in which more than 90% involved the use of needles. The average rates of adherence to standard precautions were: 27.9% hand washing prior to procedures; 41.4% use of gloves; and 88.8% adequate disposal of piercing and cutting instruments. These professionals are subject to risks similar to those which hospital workers are also subjected, because they have a high risk of blood exposure and the frequency with which they handle needles is very high. PMID- 20721427 TI - Breast milk donation and social support: reports of women donors. AB - The study aimed to characterize the behavior of human milk donation and to describe the informal social and formal institutional support, according to reports from women donors. It is an exploratory, cross-sectional, descriptive study using domicile interviews based on structured and semi-structured scripts. The participants were 36 women enrolled in two human milk banks of the public health system of the Federal District. Statistical analysis of quantitative data and categorical content analysis of qualitative data were performed. Categories of reasons that most influenced the frequency of expressing were: food, time availability, negative emotions and fluid intake. The manual expressing technique was reported as predominant. The use of breast shells was cited by almost a third of the donors. Most frequent suggestions for improving institutional support were more attention and support from the milk banks for the donor. The study may serve as a stimulus for the implementation of technical and political strategies to encourage this practice. PMID- 20721426 TI - Factors associated to breastfeeding cessation before 6 months. AB - This research aimed to identify the determinants of full breastfeeding (FBF) and any breastfeeding (ABF) cessation before 6 months, through a six-month follow-up of 248 mothers going a postpartum visit. Data were collected by personal interview during the first month and telephone interviews at four and six months postpartum. Coxs proportional hazards model was used. Not having previous ABF experience, previous ABF duration 0.05) still had doubts about its use. Fluoxetine was the most prevalent antidepressant. Actions to improve knowledge concerning the use of antidepressant medications, their side and therapeutic effects, seem to be necessary and relevant. PMID- 20721433 TI - Psychosocial aspects of work and musculoskeletal disorders in nursing workers. AB - This study aimed to evaluate the association between psychological demands and control on work and the occurrence of musculoskeletal disorders among nursing workers. This cross-sectional study involved 491 nursing workers from a University hospital in Rio Grande do Sul. Brazilian versions of the Nordic Musculoskeletal Questionnaire and the Job Content Questionnaire were used. Among the participants, 96.3% reported some pain in any given part of the body last year, 73.1% in the last seven days and 65.8% reported difficulty in their daily routine. The chances of shoulder pain (OR=1.97; CI95%=1.07-3.64), in the thoracic spine (OR=1.83; CI95%=1.02-3.35) and in the ankles (OR=2.05; CI95%=1.05-4.02) were higher in the high work demand quadrant when compared to the low demand quadrant, after adjustments for potentially confusing factors Intervention measures in the organizational structure are needed, redefining demand levels and control at work. PMID- 20721434 TI - Assistance in family health from the perspective of users. AB - This descriptive exploratory study analyzed user satisfaction with the care received at a Family Health Unit in Ribeirao Preto, Brazil. In total, 40 users from families registered in the FHU were selected, using key informants and the snowball sampling technique, and interviewed. Thematic content analysis was used to analyze the empirical material. Interviewees were mostly female, over 50 years, resident in the catchment area of the unit for 10-30 years, had incomplete primary education and also did not perform work outside the home. The analysis identified three themes: access, team-user interaction and organization of work in the FHU. The subjects of this study expressed satisfaction with the accessibility provided together with the caring attention given to them, marked by a team-user interaction that takes place in a friendly and patience manner. Although not totally satisfied, the majority of users would recommend the health service to someone due to its quality. PMID- 20721435 TI - Burns in the domestic environment: characteristics and circumstances of accidents. AB - This study characterizes burn accidents in the domestic environment and identifies the circumstances of accidents affecting children, adults or elderly people who need supervision or care. Demographic data and burn characteristics of 61 domestic environment burn victims were collected. The family members of 13 children and one aged adult, who needed supervision or special care, were selected to answer a semi-structured interview. Two thematic groups were identified: social and environmental factors that might have contributed to the burn accidents and circumstances involving the accidents. Risk factors were: low socioeconomic and educational levels of mothers and those responsible for the children at the moment of the accident, small houses considering the number of occupants and unsafe kitchen equipment. Although cases of domestic violence were not identified there was neglect from caregivers. Health professionals should be attentive and investigate the circumstances of accidents involving vulnerable individuals. PMID- 20721436 TI - Profile of scientific and technological production in nursing education research groups in the south of Brazil. AB - This research aimed to present the profile of production of Nursing Education Research Groups (NERG) scientific and technological production in the South of Brazil. This documentary, quantitative, exploratory-descriptive retrospective research was guided by the active search for products in the Lattes curriculum of previously selected NERG researchers, based on the 2006 Census of the Research Group Directory/CNPq, between 1995 and 2008. The results indicated that the 18 NERG from southern Brazil produced 453 papers in proceedings, 371 book chapters, 206 books, 1,437 scientific articles and 08 technological products, but no patent was registered. NERGs scientific production in the research region has grown progressively over the past 14 years. To strengthen this structure, the establishment of collaborative networks can be used as a strategy, so that political-scientific joint actions in the sector can advance science and technology. PMID- 20721437 TI - Anthropology, health and illness: an introduction to the concept of culture applied to the health sciences. AB - This article presents a reflection as to how notions and behavior related to the processes of health and illness are an integral part of the culture of the social group in which they occur. It is argued that medical and health care systems are cultural systems consonant with the groups and social realities that produce them. Such a comprehension is fundamental for the health care professional training. PMID- 20721438 TI - Investment in nursing human assets: education and minds of the future. AB - This paper analyzes issues related to education, crises and changes in light of the postmodern order, emphasizing efforts towards human capital as the impetus to promote changes. Focusing on universities and organizations, we discuss the main five types of minds valued by modern and future societies, proposing investment in human assets through the use of strategies and technologies to ensure continuing education throughout life. PMID- 20721439 TI - The scientific study of happiness and health promotion: an integrative literature review. AB - The article aims to trace the profile of publications concerning the concept of subjective well-being (SWB), considered the scientific study of happiness, as well as discussing the impact of this accumulated understanding on health promotion. The revision was carried out in the databases PubMed, MedLine, PsycINFO, SciELO, LILACS and PEPSIC using the descriptor subjective well-being. Articles published in indexed periodicals between 1970 and 2008 were selected. From the inclusion/exclusion criteria 19 publications were selected in full for discussion. Of these, the majority were related to the health area and did not approach the concept of SWB directly, but touched on this together with the notions of well-being, satisfaction and quality of life. There were few publications that approached the term conceptually or that defined the instruments used for the assessment of SWB. Concluding, the results confirm the relevance of the theme for health promotion and the necessity of investigations related to the practices of health professionals. PMID- 20721440 TI - [Verotoxin-producing Escherichia coli: quantitative model of exposure and risk scenarios in cattle carcasses in Argentina]. AB - OBJECTIVES: Quantify contamination by verotoxin-producing Escherichia coli associated with hemolytic uremic syndrome (VTEC-HUS) in cattle carcasses and generate estimates of exposure in three likely scenarios. METHODS: A model was constructed of the frequency and magnitude of VTEC-HUS contamination from primary production to the removal of the carcasses from cold storage, based on the published scientific information, epidemiological data, and information from local experts. The probability distributions that best described each step in the process and scenarios were input to the @Risk program with multiple simulations using Monte Carlo analysis. Pearson s correlation test was used for the sensitivity analysis. RESULTS: The estimated frequency of carcasses with VTEC-HUS was 0.37 (95% CI: 0.26 to 0.58) and the final load of VTEC-HUS was 0.47 log CFU/carcass (95% CI: -2.46 to 3.62). The most closely related variables were the fattening system (r = -0.681) and the theoretical concentration of VTEC-HUS on the cattle's skin (r = 0.702). Vaccinating the animals reduced the frequency of VTEC-HUS in the carcasses by 54.1%, although there were no significant changes in the final VTEC-HUS load. Washing the carcasses reduced the final load by 0.42 log CFU/carcass compared with the baseline model, without any change in the frequency. A 50%-60% increase in the percentage of animals fattened in pens would increase the frequency of carcasses contaminated with VTEC-HUS by 15%-23%. CONCLUSIONS: Vaccinating the animals was the most effective scenario for reducing introduction of the bacteria in the beef production chain. Intensifying livestock production will increase the public health risk due to greater exposure to VTEC HUS. PMID- 20721441 TI - Enteroparasite contamination in peridomiciliar soils of two indigenous territories, State of Parana, southern Brazil. AB - OBJECTIVES: To determine 1) the degree of soil contamination by parasites; 2) the prevalence of contaminated samples; 3) the overall number of parasitic forms, by distance between the collection site and the domicile; 4) the mean number of parasite forms per peri-household area; and 5) the variables associated with the total number of parasite forms. METHODS: Soil samples were collected in the peridomicile of 18 (out of a total sample of 63) and 22 (out of 190) residences of the Faxinal and Ivai indigenous territories (ITs), respectively, from March 2005 through October 2006, and evaluated by the methods of Baermann, modified Faust et al., and Lutz. RESULTS: The overall prevalence of samples contaminated by enteroparasites of humans or of animals with zoonotic potential was 75.7% (84 out of 111) in Faxinal and 96.2% (127 out of 132) in Ivai. The most prevalent parasites were Ascaris spp., Isospora spp., and Toxocara spp. Positive statistical associations were observed between the number of parasitic forms per domicile and the following variables: time of year (season), the presence of bathrooms in the domicile, and the presence of excrement on peridomiciliar soil. CONCLUSIONS: The high level of soil contamination in Faxinal and Ivai 1) constitutes a potential source of parasitic infection and 2) suggests that the treatment of human and animal excreta continues to be inadequate. PMID- 20721442 TI - [Conceptual model for identifying factors relevant to the safety of children in school buses]. AB - OBJECTIVE: Prepare a conceptual model that facilitates understanding of the relationships between the variables that lead children to adopt postures in school transportation vehicles that increase injuries in traffic accidents. METHODS: For identification of the variables, direct information on school transportation was collected through focus groups, with bus aides and bus drivers, on-board filming during the transport of children, and recording of the dimensions of components in different types of school buses. The information collected was analyzed using the Atlas.ti v6 software and the construction of a model through deduction. RESULTS: Important relationships were found between adoption of potentially hazardous postures by children during transport to and from school and the seat and seat belt dimensions, the characteristics of the transportation service, and the role of bus aides. CONCLUSIONS: In order to adopt coherent interventions in school transportation safety, it is necessary to consider not only the technical aspects of the vehicle or posture that are controlled in crash tests but the specific variables of the activities that lead children to adopt postures that put them at greater risk of injury. PMID- 20721443 TI - Multigenerational inheritance and clinical characteristics of three large pedigrees with early-onset type 2 diabetes in Jamaica. AB - OBJECTIVE: To document the existence and clinical characteristics of three large families with multigenerational inheritance of early-onset type 2 diabetes in Jamaica. METHODS: Three probands from large families with multigenerational inheritance of early-onset type 2 diabetes in at least three generations were detected at the University Hospital of the West Indies in Jamaica. Each proband at the time of diagnosis was < 25 years of age, was lean, and did not require insulin therapy. Clinical, metabolic, and genetic assessments were undertaken to profile the diabetes in the three families. RESULTS: Three pedigrees--BK, SU, and CA--consisting of 38, 48, and 113 members, respectively, with multigenerational inheritance of early-onset type 2 diabetes in at least three generations, were investigated. The mean age at diagnosis of the three pedigrees was 31.5 +/- 2.9 years, with 10 persons detected below 25 years of age. Findings suggestive of overweight, insulin resistance, low insulin secretion, dyslipidemia, and mild intra-abdominal obesity were present. Islet cell antibodies and sequence variants in MODY1 to -6 genes were absent. CONCLUSIONS: Large families demonstrating multigenerational inheritance of diabetes and other characteristics consistent with early-onset type 2 diabetes are present in the Jamaican population. PMID- 20721444 TI - [Public financing of health research in five Latin American countries]. AB - OBJECTIVES: Describe the public subsystems of the national health research systems (SNIS) in five Latin American countries (Argentina, Bolivia, Chile, Paraguay, and Uruguay), emphasizing the types of institutional arrangements in place in each country to promote, develop, and sustain their SNIS, as well as explicit or implicit mechanisms for prioritizing health research projects. METHODS: The bodies responsible for managing the public resources allocated to finance health research projects in the five countries studied were identified. The types of projects financed were then analyzed-using a matrix constructed by area and object of study-, certain characteristics of the principal investigators, and the sums allocated between 2002 and 2006. RESULTS: Only the countries with greater resources or better developed networks of investigators have formal structures for allocating funds with regular calls for proposals and fixed rules. None of them has explicit comprehensive mechanisms for prioritizing health research. Moreover, the health research priorities in the countries vary widely. In this regard, it is significant that problems such as "nutrition and the environment" or "violence and accidents" receive little attention in most countries. The same holds true for a number of public health issues in some countries. In contrast, the research in the "hard sciences" absorbs up to one third of the total resources for research. CONCLUSIONS: Many questions arise about the ability of these countries to adapt and generate new knowledge, as well as the nearly nonexistent research on social, economic, and cultural determinants, or on health services and systems that have a high impact on groups with limited access to health care. Explicit priorities should be set with stakeholders for the health research agenda, and mechanisms should be adopted for monitoring and following up health research financing by subject and area of study. PMID- 20721445 TI - [Direct immunofluorescence assay performance in diagnosis of the Influenza A(H1N1) virus]. AB - By 25 April 2009, less than one month after the first human with Influenza A(H1N1) virus was detected in Mexico, the disease had already spread to more than 40 countries, with over 10,000 cases reported. Due to its unpredictability, this type of virus requires appropriate, reliable, and safe diagnostic methods that are also accessible to clinical laboratories. Through the analysis of 291 samples taken from patients with suspected Influenza A(H1N1) virus infection in Neuquen, Argentina, this study compares the two diagnostic methods used simultaneously: direct immunofluorescence assay (DFA) and real-time polymerase chain reaction (RT PCR). DFA had a sensitivity of 44.4%, a specificity of 99.6%, a positive predictive value of 95.2%, and a negative predictive value of 90.7%. Positive results obtained with this method can be considered true positives. A negative result does not rule out the presence of the virus. In this case, the sample should be examined by RT-PCR. Out of a total of 291 samples, there were 45 positive results with RT-PCR and 21 positive results with DFA. PMID- 20721446 TI - [Sporotrichosis: development and challenges of an epidemic]. AB - In the state of Rio de Janeiro, Brazil, sporotrichosis reached epidemic levels, involving humans and cats. Preliminary data indicate that approximately 2200 human cases were diagnosed between 1998 and December of 2009, and 3244 cats were treated. The geographic distribution of cases reveals a concentration in the City of Rio de Janeiro metropolitan area. The disease affects mostly women of a low socioeconomic status, aged 40 to 55 years, who work as housekeepers. Itraconazole has been the drug of choice for treatment. Although sporotrichosis does not usually affect organs other than the skin, mucosa, and subcutaneous tissue, it has an indirect social impact resulting from absenteeism, pain, and discomfort during the active disease stage, and the unpleasant appearance of the scars. In turn, systemic involvement is frequent in cats, leading to serious and difficult to treat forms of the disease and death. Considering that treatment time in animals is longer than in human beings, treating cats with sporotrichosis has been the greatest obstacle and the most important challenge for the control of this epidemic infection. PMID- 20721447 TI - [Rocky Mountain spotted fever in Brazil]. AB - Although the number of confirmed cases of spotted fever has been declining in Brazil since 2005, the mortality rate (20% to 30%) is still high in comparison to other countries. This high mortality rate is closely related to the difficulty in making the diagnosis and starting the correct treatment. Only two groups of antibiotics have proven clinical effectiveness against spotted fever: chloramphenicol and tetracyclines. Until recently, the use of tetracyclines was restricted to adults because of the associated bone and tooth changes in children. Recently, however, the American Academy of Pediatrics and various researchers have recommended the use of doxycycline in children. In more severe cases, chloramphenicol injections are often preferred in Brazil because of the lack of experience with injectable tetracycline. Since early diagnosis and the adequate drug treatment are key to a good prognosis, health care professionals must be better prepared to recognize and treat spotted fever. PMID- 20721448 TI - Needlestick injuries among sanitation workers in Mexico City. PMID- 20721449 TI - [Definitions, vaccines, and identification of the septic patient in pediatrics]. PMID- 20721450 TI - Maternal and congenital syphilis in Haiti: a big problem. PMID- 20721452 TI - [II Brazilian Guidelines on Acute Cardiac Insufficiency]. PMID- 20721453 TI - [Change the Qualis criteria!]. PMID- 20721454 TI - [How far are valid the consensus?]. PMID- 20721455 TI - Early marginal ulcer following Roux-en-Y gastric bypass under proton pump inhibitor treatment: prospective multicentric study. AB - CONTEXT: Causal factors of gastrojejunal ulcers after Roux-en-Y gastric bypass include peptic acid secretion from the gastric pouch. Esomeprazole is a potent inhibitor of acid secretion. OBJECTIVE: To assess the occurrence of dyspepsia and gastrojejunal ulcers within the first 2 months after Roux-en-Y gastric bypass during the use of esomeprazole. METHODS: One hundred eighteen morbid obese subjects were submitted to Roux-en-Y gastric bypass. Preoperative upper gastrointestinal tract endoscopy was negative for H. pylori. All subjects received esomeprazole for 60 days after surgery. RESULTS: Two weeks after surgery only 13 mild symptoms were reported. After 2 months, 17 also moderate complaints were registered. Endoscopy around the 60th day showed esophagitis in 10 (8.5%), hiatal hernia in 2 (1.7%), foreign body in the anastomotic line in 12 (10.2%) and gastrojejunal ulcers was observed in 9 (7.6%) subjects, 2 of which had a suture material or metallic staple granuloma in the gastrojejunostomy. Ten subjects took nonsteroidal anti-inflammatory drugs at least once during study, but none of them developed ulcer. None of the subjects with ulcer had dyspeptic symptoms. CONCLUSION: The incidence of ulcer in the gastrojejunal anastomosis within the first 2 months following Rouxen-Y gastric bypass under proton pump inhibitors is considerable. It was not related to the use of non-steroidal anti-inflammatory drugs, highlighting the possibility of ischemia and foreign body as causal factors. The ulcers were asymptomatic, and all post-surgical dyspeptic symptoms were moderate in severity. PMID- 20721456 TI - Surgical treatment of cystic neoplasms of the pancreas. AB - CONTEXT: Diagnosis and treatment of cystic neoplasms of the pancreas increased significantly in the last decades. There are only a few Brazilian publications on these tumors. The majority of them are limited to reports of one or few cases. OBJECTIVE: To present our experience with 27 patients with cystic neoplasms of the pancreas. METHODS: Demographic data, clinical manifestations, diagnostic exams, surgical procedures, postoperative complications, and follow-up data of 27 patients with cystic neoplasms of the pancreas were analyzed, according to the histological type of the tumor. RESULTS: There were 10 (37%) serous cystic tumors, 10 (37%) mucinous cystic tumors, 4 (15%) intraductal papillary mucinous tumors, and 3 (11%) solid pseudopapillary tumors or Frantz tumor. All serous cystic tumors, 6 (60%) mucinous tumors, 2 (50%) intraductal papillary mucinous tumors, and 2 (67%) solid pseudopapillary tumors were benign. The age of the patients varied from 31 to 82 years and all tumors were more common in female. Two patients had been treated previously as a pseudocyst. Surgical procedures depended on the location and extension of the tumor. Two patients underwent only laparotomy with tumor biopsy, one cholecystectomy with Roux-en-Y hepaticojejunostomy for jaundice treatment, 6 pancreatoduodenectomy, and 18 partial pancreatectomy. The most common postoperative complication was pancreatic fistula (n = 5; 19%). One patient died of necrotic pancreatitis. Of the 10 patients with serous cystic tumor, only 1 had tumor recurrence at the section border. The three patients with mucinous cystoadenocarcinoma in which was not possible to resect the tumor, died 6 to 24 months after laparotomy. The six patients with benign mucinous tumors did not have tumor recurrence. CONCLUSIONS: The most common cystic neoplasms of the pancreas are serous and mucinous cysts. These tumors are more frequent in female. Although almost all serous cysts are benign, 40% of mucinous cysts are malign. Misdiagnosis may delay appropriate treatment and increase mortality. PMID- 20721457 TI - Analysis of the immunohistochemical expressions of p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and their correlations with the prognostic factors. AB - CONTEXT: Search of tumors markers that allow treatment with higher survival rates, and indicate the response to treatment and recurrence of cancer OBJECTIVE: To analyze the immunoexpression of the proteins p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and correlate them with the clinical-pathological prognostic factors. METHOD: Tissue microarray paraffin blocks were made from colorectal adenocarcinoma tissue resected from 82 patients who had undergone surgery but not chemotherapy or radiotherapy, at "Hospital Sao Paulo", Sao Paulo, SP, Brazil, between 2002 and 2005. Thin sections (4 microm) were subjected to immunohistochemical reactions, and immunoexpression staining scores were obtained. The scores were correlated with the degree of cell differentiation, staging, disease-free interval, recurrence, survival and specific mortality. The study variables were analyzed using the chi-square and Kaplan-Meier tests to investigate associations with the markers. The significance of the differences between the curves of the disease-free interval and survival was analyzed using the Logrank and Wilcoxon tests. RESULTS: The immunohistochemical expression of p53 was positive in 70 tumors (85.4%) and negative in 12 (14.6%). The expression of bcl-2 was positive in 26 (31.7%) and negative in 56 (68.3%). The expression of Ki-67 was positive in 62 (75.6%) and negative in 20 (24.4%). There was no statistically significant correlation between the expressions of these markers separately or in conjunction, in relation to the degree of cell differentiation, staging, disease-free interval, survival and specific mortality. In relation to recurrence, there was a statistically significant correlation with positive expression of Ki-67 (P = 0.035). CONCLUSION: The immunohistochemical expression of Ki-67 in colorectal cancer is associated with recurrence of this disease. PMID- 20721458 TI - Analysis of the videolaparoscopy potentiality in the surgical treatment of the bowel obstruction. AB - CONTEXT: Laparotomy is the gold standard treatment of patients with intestinal obstruction without response to clinical management. Nowadays, literature has been demonstrating the feasibility of videolaparoscopy in the treatment of intestinal obstruction. OBJECTIVES: To report the clinical-epidemiological profile of patients with intestinal obstruction submitted to surgery and verify the presence of contraindications for laparoscopy. METHODS: It was done a observational, descriptive and retrospective study including adults patients with intestinal obstruction submitted to surgery at Hospital de Clinicas de Porto Alegre, RS, Brazil, between January of 2004 and October of 2008. RESULTS: It was included 135 patients in the study, with a total of 126 patients submitted to open surgery and 9 to laparoscopy. There was similar distribution between gender and the mean age was 59 years (SD +/- 16.9). The most frequent site of obstruction was the small bowel and the most frequent etiology was adhesions. Among the patients submitted to laparotomy, 75.4% presented with abdominal distention, 68.3% previous abdominal surgery, 11.9% body mass index >30 kg/m(2), 4.8% coagulopathy and 3.2% hemodynamic instability. Among the 135 patients, only 5 of them presented with none contraindications for videolaparoscopy. CONCLUSION: The epidemiological findings of this study are similar to the ones of the worldwide literature. Indications of videolaparoscopy in retrospective analyses have the limitation of subjective evaluation of intestinal obstruction, which was included in this study as a relative contraindication to laparoscopy. PMID- 20721459 TI - Oral taste recognition in health volunteers. AB - CONTEXT: Taste food recognition has an important role in the nutritional conditions and also allows protection of the organism integrity against foods potentially dangerous. OBJECTIVE: To investigate the presence of the selective taste regions on the tongue and also the palate participation in the oral taste definition. METHODS: A standard tongue divided in six regions was exposed with the four basic tastes (sweet, salted, sour and bitter), 10 times each. Thirteen volunteers were studied from both side and 34 only from one side, performing 240 tests with opened mouth and 240 with closing mouth, just after tongue sapid stimulation. A second group, with 12 volunteers, had its taste recognition studied, with and without palate isolation, using silicone prosthesis (n = 120). RESULTS: From results, chi-square (3x2) and (2x2), nonparametric independency test with P = 0.05 were obtained. CONCLUSIONS: Anterior, medium and posterior regions of the tongue, at both sides, had the same taste discriminative capacity. Nevertheless, closed mouth increased immediate and late recognition capacity by palate participation. It was possible to admit that palate participation increase the sapid perception in the mouth, by recruitment of the palate taste receptors and also by fluid compression and its scattering over tongue surface. PMID- 20721460 TI - Cost-effectiveness analysis on spinal anesthesia versus local anesthesia plus sedation for loop colostomy closure. AB - CONTEXT: Studies in the area of health economics are still poorly explored and it is known that the cost savings in this area is becoming more necessary, provided that strict criteria. OBJECTIVE: To perform a cost-effectiveness analysis of spinal anesthesia versus local anesthesia plus sedation for loop colostomy closure. METHODS: This was a randomized clinical trial with 50 patients undergoing loop colostomy closure either under spinal anesthesia (n = 25) or under local anesthesia plus sedation (n = 25). The duration of the operation, time spent in the post-anesthesia recovery room, pain, postoperative complications, length of hospital stay, laboratory and imaging examinations and need for rehospitalization and reoperation were analyzed. The direct medical costs were analyzed. A decision tree model was constructed. The outcome measures were mean cost and cost per local and systemic postoperative complications avoided. Incremental cost-effectiveness ratios were presented. RESULTS: Duration of operation: 146 +/- 111.5 min. vs 105 +/- 23.6 min. (P = 0.012); mean time spent in post-anesthesia recovery room: 145 +/- 110.8 min. vs 36.8 +/- 34.6 min. (P<0.001). Immediate postoperative pain was lower with local anesthesia plus sedation (P<0.05). Local and systemic complications were fewer with local anesthesia plus sedation (P = 0.209). Hospitalization + rehospitalization: 4.5 +/ 4.1 days vs 2.9 +/- 2.2 days (P<0.0001); mean spending per patient: R$ 5,038.05 vs 2,665.57 (P<0.001). Incremental cost-effectiveness ratio: R$ -474.78, indicating that the strategy with local anesthesia plus sedation is cost saving. CONCLUSION: In the present investigation, loop colostomy closure under local anesthesia plus sedation was effective and appeared to be a dominant strategy, compared with the same surgical procedure under spinal anesthesia. PMID- 20721461 TI - Insulin resistance index (HOMA-IR) in the differentiation of patients with non alcoholic fatty liver disease and healthy individuals. AB - CONTEXT: Due to its good correlation to glycemic clamp, HOMA-IR has been widely utilized as insulin resistance index in clinical and epidemiological studies involving non-alcoholic fatty liver disease carriers. However, values used for this parameter have shown large variability. OBJECTIVE: To identify the HOMA-IR cut value that best distinguishes non-diabetic non-alcoholic fatty liver disease patients from a control group. METHODS: One hundred sixteen non-alcoholic fatty liver disease patients were studied, diagnosed by clinical, biochemical, and liver image or biopsy criteria, and 88 healthy individuals, without any liver disease and testing for oral glucose tolerance within normality. These groups did not differ in age and gender. All were submitted to oral glucose tolerance test and blood samples were collected for glucose and insulin measurements by immunofluorometric method. HOMA-IR was calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. RESULTS: NAFLD patients showed higher insulin, glycemia, and HOMA-IR values than control group, even when excluding glucose intolerant and diabetes mellitus patients by their glycemic curves. HOMA-IR 75th percentile for control group was 1.78 and the best area under the curve index was obtained for HOMA-IR values of 2.0 [AUC= 0.840 (0.781-0.899 CI 95%), sensitivity (Se): 85%, specificity (Sp): 83%] while value 2.5 showed best specificity without important loss in sensitivity [AUC=0,831 (0.773-0.888) Se = 72%, Sp = 94%]. CONCLUSION: HOMA-IR values above or equal to 2.0 or 2.5 show enhanced diagnostic value in distinguishing non-alcoholic fatty liver disease carriers from control group individuals. PMID- 20721462 TI - Evaluation of the nonalcoholic fat liver disease fibrosis score for patients undergoing bariatric surgery. AB - CONTEXT: Morbidly obese patients have an increased risk for nonalcoholic fat liver disease. Its severe form, nonalcoholic steatohepatitis may cause liver fibrosis. The diagnosis of advanced fibrosis has great value during the pre operative evaluation for bariatric surgery. Currently, liver biopsy is the gold standard for diagnosis of liver fibrosis. OBJECTIVE: To evaluate the nonalcoholic fat liver disease fibrosis score in morbidly obese patients undergoing Roux-en-Y gastric bypass in our population. METHODS: One hundred fifty-eight morbidly obese patients that had undergone bariatric surgery were included. Age, body mass index, hyperglycemia, platelet count, albumin and AST/ALT ratio were applied to the score formula. Scores above 0.676 were indicative of advanced liver fibrosis and scores under -1,455 absence of advanced liver fibrosis. These scores were compared to liver biopsy findings. RESULTS: The presence of advanced fibrosis could be diagnosed with good accuracy, with a positive predictive value of 83.7%. The score had a higher accuracy to exclude advanced fibrosis with a negative predictive value of 97%. Twenty-five patients (16%) had scores between the cutoffs points and were identified as indeterminate. The score sensibility and specificity was 83% and 97% respectively. CONCLUSIONS: The nonalcoholic fat liver disease fibrosis score has high accuracy to identify and exclude advanced liver fibrosis in morbidly obese patients subjected to bariatric surgery. PMID- 20721463 TI - [Relationship between portal pressure gradient and ascites in cirrhotic patients]. AB - CONTEXT: Portal hypertension plays an important role in the pathogenesis of ascites. OBJECTIVES: To evaluate the hepatic venous pressure gradient and the presence of ascites in cirrhotic patients. METHODS: Eighty-three patients with cirrhosis were evaluated. All of the patients were submitted to ultrasonography to identify ascites and to a hepatic hemodynamic investigation to determine the hepatic venous pressure gradient. RESULTS: In the population evaluated, ascites was observed in 70 patients (84.3%), and the mean hepatic venous pressure gradient was 15.26 +/- 6.46 mm Hg. There was no statistically significant difference (P = 0.061) between the means of hepatic venous pressure gradient in patients with (14.70 +/- 6.43 mm Hg) and without ascites (18.64 +/- 5.78 mm Hg). When using a cut-off point of 8 mm Hg in order to assess the risk of developing ascites, patients with hepatic venous pressure gradient above 8 mm Hg were found to have a relative risk of 0.876 (CI = 0.74-1.03), (P = 0.446) of progressing to ascites. CONCLUSIONS: The pressure level of 8 mm Hg, as determined by the hepatic venous pressure gradient, does not define the presence or absence of ascites in the cirrhotic patient, and in view of the similarity between mean pressures in patients with or without peritoneal effusion, it is impossible to define a cut off point for the emergence of such complication. PMID- 20721464 TI - Clinical benefits after the implementation of a multimodal perioperative protocol in elderly patients. AB - CONTEXT: Multimodal protocol of perioperative care may enhance recovery after surgery. Based on evidence these new routines of perioperative care changed conventional prescriptions in surgery. OBJECTIVE: To evaluate the results of a multimodal protocol (ACERTO protocol) in elderly patients. METHODS: Non randomized historical cohort study was performed at the surgical ward of a tertiary university hospital. One hundred seventeen patients aged 60 and older were submitted to elective abdominal operations under either conventional (n = 42; conventional group, January 2004-June 2005) or a fast-track perioperative protocol named ACERTO (n = 75; ACERTO group, July 2005-December 2007). Main endpoints were preoperative fasting time, postoperative day of re-feeding, volume of intravenous fluids, length of hospital stay and morbidity. RESULTS: The implantation of the ACERTO protocol was followed by a decrease in both preoperative fasting (15 [8-20] vs 4 [2-20] hours, P<0.001) and postoperative day of refeeding (1st [1st-10th] vs 0 [0-5th] PO day; P<0.01), and intravenous fluids (10.7 [2.5-57.5] vs 2.5 [0.5-82] L, P<0.001). The changing of protocols reduced the mean length of hospital stay by 4 days (6[1-43] vs 2[1-97] days; P = 0.002) and surgical site infection rate by 85.7% (19%; 8/42 vs 2.7%; 2/75, P<0.001; relative risk = 1.20; 95% confidence interval = 1.03-1.39). Per-protocol analysis showed that hospital stay in major operations diminished only in patients who completed the protocol (P<0.01). CONCLUSION: The implementation of multidisciplinary routines of the ACERTO protocol diminished both hospitalization and surgical site infection in elderly patients submitted to abdominal operations. PMID- 20721465 TI - Comparative results of gastric submucosal injection with hydroxypropyl methylcellulose, carboxymethylcellulose and normal saline solution in a porcine model. AB - CONTEXT: Endoscopic mucosal resection is an established modality for excision of sessile lesions in the gastrointestinal tract. Submucosal fluid injection creates a cushion and may prevent thermal injury and perforation. OBJECTIVES: This blind study investigated the performance of three different solutions to create submucosal fluid cushions in porcine stomach. METHODS: Three solutions were injected in the stomach of nine pigs BR1: normal saline solution, carboxymethylcellulose 0.5% and hydroxypropyl methylcellulose 0.25%. In each pig, submucosal injections with 6 mL per test-solution were performed. One drop of methylene blue was added to all injections for better visualization. The time for the bleb to disappear was recorded. RESULTS: The overall median time of visible submucosal cushion was 37 minutes (range 12-60 min) for hydroxypropyl methylcellulose, 31 minutes for carboxymethylcellulose (range 10-43 min) and 19 minutes for normal saline solution (range 8-37 min). There was no statistically significant difference neither between normal saline solution and carboxymethylcellulose (P = 0.146) nor carboxymethylcellulose and hydroxypropyl methylcellulose (P = 0.119) but the median duration of hydroxypropyl methylcellulose was significantly longer than normal saline solution (P = 0.039). CONCLUSIONS: The length of hydroxypropyl methylcellulose submucosal fluid cushion is longer in comparison with normal saline solution. The median time for carboxymethylcellulose was not longer than normal saline solution. Hydroxypropyl methylcellulose, in the concentration of 0.25%, may be a durable alternative for submucosal injection. PMID- 20721466 TI - Intestinal permeability assessed by 51Cr-EDTA in rats with CCl4 - induced cirrhosis. AB - CONTEXT: The straight relationship between cirrhosis and impaired intestinal barrier has not been elucidated yet. OBJECTIVES: To verify (51)Cr-EDTA-intestinal permeability in rats with CCl(4)-induced cirrhosis and controls. METHOD: Fifty male Wistar rats weighing 150-180 g were separated in three groups: 25 animals received CCl(4) 0.25 mL/kg with olive oil by gavage with 12 g/rat/day food restriction for 10 weeks (CCl(4)-induced cirrhosis); 12 received the same food restriction for 10 weeks (CCl(4)-non exposed). Other 13 rats received indomethacin 15 mg/kg by gavage as positive control of intestinal inflammation. RESULTS: The median (25-75 interquartile range) (51)Cr-EDTA-IP values of cirrhotic and CCl(4)-non exposed rats were 0.90% (0.63-1.79) and 0.90% (0.60 1.52) respectively, without significant difference (P = 0.65). Animals from indomethacin group showed (51)Cr-EDTA-IP, median 7.3% (5.1-14.7), significantly higher than cirrhotic and CCl(4)-non exposed rats (P<0.001). CONCLUSION: This study showed the lack of difference between (51)Cr-EDTA-intestinal permeability in rats with and without cirrhosis. Further studies are necessary to better clarify the relationship between intestinal permeability and cirrhosis. PMID- 20721467 TI - [The effect of chronic ethanol consumption on duodenal absorption of iron in mice]. AB - CONTEXT: Alcoholists present an increase of iron hepatic concentration, although the responsible mechanisms for this deposition are still unknown. Despite the extensive literature related on the iron absorption in different pathological conditions, the effect of chronic ethanol consumption are still not conclusive and not completely understood. OBJECTIVE: To verify the effect of chronic ethanol ingestion on duodenal absorption of iron. METHODS: Ten male Swiss mice were divided into two groups: group 1 (n = 5) - control, and group 2 (n = 5) - water consumption with ethanol, as only water source. The animals were followed during 120 days. After this period, the duodenum was isolated and saline solution containing ascorbate of iron II in the 0,016 concentration of mg of iron element was infused. The effluent was collected in times 20, 40, 60, 80, 100 and 120 minutes. The results were analyzed by Mann-Whitney and Kruskal-Wallis tests. The significance was set for P<0.05. RESULTS: No difference was found between iron absorption as well as iron absorption curves in groups 1 and 2. CONCLUSION: The chronic consumption of ethanol did not alter iron absorption. PMID- 20721468 TI - Treatment of inflammatory bowel disease and pregnancy: a review of the literature. AB - CONTEXT: The inflammatory bowel disease is diagnosed frequently among woman of childbearing capacity. The management must be carefully because there are potential risks for the mother and fetus. RESULTS AND CONCLUSIONS: We review literature about the management of inflammatory bowel disease in pregnancy. Some studies are needed to ensure the best approach to inflammatory bowel disease in pregnant women. PMID- 20721469 TI - Variceal bleeding: consensus meeting report from the Brazilian Society of Hepatology. AB - In the last decades, several improvements in the management of variceal bleeding have resulted in a significant decrease in morbidity and mortality of patients with cirrhosis and bleeding varices. Progress in the multidisciplinary approach to these patients has led to a better management of this disease by critical care physicians, hepatologists, gastroenterologists, endoscopists, radiologists and surgeons. In this respect, the Brazilian Society of Hepatology has, recently, sponsored a consensus meeting in order to draw evidence-based recommendations on the management of these difficult-to-treat subjects. An organizing committee comprised of four people was elected by the Governing Board and was responsible to invite 27 researchers from distinct regions of the country to make a systematic review of the subject and to present topics related to variceal bleeding, including prevention, diagnosis, management and treatment, according to evidence-based medicine. After the meeting, all participants met together for discussion of the topics and the elaboration of the aforementioned recommendations. The organizing committee was responsible for writing the final document. The meeting was held at Salvador, May 6th, 2009 and the present manuscript is the summary of the systematic review that was presented during the meeting, organized in topics, followed by the recommendations of the Brazilian Society of Hepatology. PMID- 20721470 TI - Mutations of Bruton's tyrosine kinase gene in Brazilian patients with X-linked agammaglobulinemia. AB - Mutations in Bruton's tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA), which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in peripheral blood. We evaluated 5 male Brazilian patients, ranging from 3 to 10 years of age, from unrelated families, whose diagnosis was based on recurrent infections, markedly reduced levels of IgM, IgG and IgA, and circulating B cell numbers <2%. BTK gene analysis was carried out using PCR-SSCP followed by sequencing. We detected three novel (Ala347fsX55, I355T, and Thr324fsX24) and two previously reported mutations (Q196X and E441X). Flow cytometry revealed a reduced expression of BTK protein in patients and a mosaic pattern of BTK expression was obtained from mothers, indicating that they were XLA carriers. PMID- 20721471 TI - Lipopolysaccharide-induced expression of cell surface receptors and cell activation of neutrophils and monocytes in whole human blood. AB - Lipopolysaccharide (LPS) activates neutrophils and monocytes, inducing a wide array of biological activities. LPS rough (R) and smooth (S) forms signal through Toll-like receptor 4 (TLR4), but differ in their requirement for CD14. Since the R-form LPS can interact with TLR4 independent of CD14 and the differential expression of CD14 on neutrophils and monocytes, we used the S-form LPS from Salmonella abortus equi and the R-form LPS from Salmonella minnesota mutants to evaluate LPS-induced activation of human neutrophils and monocytes in whole blood from healthy volunteers. Expression of cell surface receptors and reactive oxygen species (ROS) and nitric oxide (NO) generation were measured by flow cytometry in whole blood monocytes and neutrophils. The oxidative burst was quantified by measuring the oxidation of 2',7'-dichlorofluorescein diacetate and the NO production was quantified by measuring the oxidation of 4-amino-5-methylamino 2',7'-difluorofluorescein diacetate. A small increase of TLR4 expression by monocytes was observed after 6 h of LPS stimulation. Monocyte CD14 modulation by LPS was biphasic, with an initial 30% increase followed by a 40% decrease in expression after 6 h of incubation. Expression of CD11b was rapidly up-regulated, doubling after 5 min on monocytes, while down-regulation of CXCR2 was observed on neutrophils, reaching a 50% reduction after 6 h. LPS induced low production of ROS and NO. This study shows a complex LPS-induced cell surface receptor modulation on human monocytes and neutrophils, with up- and down-regulation depending on the receptor. R- and S-form LPS activate human neutrophils similarly, despite the low CD14 expression, if the stimulation occurs in whole blood. PMID- 20721472 TI - A simple method to assess freezing of gait in Parkinson's disease patients. AB - Freezing of gait (FOG) can be assessed by clinical and instrumental methods. Clinical examination has the advantage of being available to most clinicians; however, it requires experience and may not reveal FOG even for cases confirmed by the medical history. Instrumental methods have an advantage in that they may be used for ambulatory monitoring. The aim of the present study was to describe and evaluate a new instrumental method based on a force sensitive resistor and Pearson's correlation coefficient (Pcc) for the assessment of FOG. Nine patients with Parkinson's disease in the "on" state walked through a corridor, passed through a doorway and made a U-turn. We analyzed 24 FOG episodes by computing the Pcc between one "regular/normal" step and the rest of the steps. The Pcc reached +/-1 for "normal" locomotion, while correlation diminished due to the lack of periodicity during FOG episodes. Gait was assessed in parallel with video. FOG episodes determined from the video were all detected with the proposed method. The computed duration of the FOG episodes was compared with those estimated from the video. The method was sensitive to various types of freezing; although no differences due to different types of freezing were detected. The study showed that Pcc analysis permitted the computerized detection of FOG in a simple manner analogous to human visual judgment, and its automation may be useful in clinical practice to provide a record of the history of FOG. PMID- 20721475 TI - Manson's schistosomiasis in the undernourished mouse: some recent findings. AB - This paper deals with current knowledge of the interrelationships between Schistosoma infection and malnutrition. It emphasizes the relevance of these investigations in the face of dynamic and evolving changes occurring in population diets and changes in the epidemiological patterns of schistosomiasis in endemic countries. The paper further discusses the basis for continuing the studies on this subject and the reasons why it represents a misunderstood association. This review also focuses on the cellular and humoral immune responses in the undernourished mouse model infected with Schistosoma mansoni, with updated information on the immune response in wild-type and iNOS knockout mice concerning soluble egg antigen specific antibodies and kinetics of IFN gamma, IL-4, IL-10 and IL-13 cytokines, in the chronic phase of Manson's schistosomiasis. There is indication that schistosome-infected undernourished mice are able to develop a humoral immune response, but antibody titres are much lower than in the control animals. Cytokine production (IFN-gamma, IL-4, IL-10) is lower in the undernourished mice, but as infection progresses to the chronic phase its kinetics run an antagonistic course when compared to that of well nourished animals. Marked variation in the secretion of IL-13 (a fibrogenic cytokine) could explain why undernourished mice do not develop liver "pipe-stem" fibrosis described in previous papers on well-nourished animals. PMID- 20721473 TI - Luteinizing hormone reduction by the male potency herb, Butea superba Roxb. AB - To determine if Butea superba Roxb., a traditional Thai male potency herb, has androgenic activity in 60-day-old male Wistar rats, we measured its effects on the pituitary-testicular axis and sex organs. Intact and orchidectomized adult male rats were subdivided into five groups (10 rats/group): distilled water, Butea superba (BS)-10, BS-50, BS-250, and testosterone propionate (TP). They received 0, 10, 50, and 250 mg.kg body weight(-1).day(-1) BS in distilled water by gavage and 6 mg.kg body weight(-1).day(-1) TP sc, respectively, during the 30 day treatment period. Blood was collected every 15 days and luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were measured. Changes of weight and histological appearance of sex organs were determined at the end of the 30-day treatment and 15-day post-treatment periods. TP treatment reduced serum FSH and LH levels and significantly increased the weight of the seminal vesicles and epididymis, in accordance with histopathological changes, in both intact and orchidectomized rats. No changes in serum testosterone, LH, and FSH levels were observed in any of the intact rats treated with BS, but a significant increase in seminal vesicle weight was observed only in the BS-250 group. Although a significant reduction in serum LH was detected in the BS-50 and BS-250 groups of orchidectomized rats, no significant change in weight or histology of sex organs was observed. Thus, we conclude that B. superba needs endogenous testosterone to work synergistically to stimulate the accessory sex organ of intact animals and can potentially exhibit an LH reduction effect in orchidectomized animals. PMID- 20721476 TI - The contributions of the Genome Project to the study of schistosomiasis. AB - In this paper we review the impact that the availability of the Schistosoma mansoni genome sequence and annotation has had on schistosomiasis research. Easy access to the genomic information is important and several types of data are currently being integrated, such as proteomics, microarray and polymorphic loci. Access to the genome annotation and powerful means of extracting information are major resources to the research community. PMID- 20721477 TI - Detection of IgG1 and IgG4 subtypes reactive against potato apyrase in schistosomiasis patients. AB - In this paper, we showed for the first time that the conserved domains within Schistosoma mansoni ATP diphosphohydrolase isoforms, shared with potato apyrase, possess epitopes for the IgG1 and IgG4 subtypes, as 24 (80%) of the 30 schistosomiasis patients were seropositive for this vegetable protein. The analyses for each patient cured (n = 14) after treatment (AT) with praziquantel revealed variable IgG1 and IgG4 reactivity against potato apyrase. Different antigenic epitopes shared between the vegetable and parasite proteins could be involved in susceptibility or resistance to S. mansoni AT with praziquantel and these possibilities should be explored. PMID- 20721478 TI - Antibody reactivity against potato apyrase, a protein that shares epitopes with Schistosoma mansoni ATP diphosphohydrolase isoforms, in acute and chronically infected mice, after chemotherapy and reinfection. AB - Schistosoma mansoni ATP diphosphohydrolase isoforms and potato apyrase share conserved epitopes. By enzyme-linked immunosorbent assays, elevated levels of IgM, IgG2a and IgG1 antibody reactivity against potato apyrase were observed in S. mansoni-infected BALB/c mice during the acute phase of infection, while only IgM and IgG1 antibody reactivity levels maintained elevated during the chronic phase of infection. Antibody reactivity against potato apyrase was monitored over an 11-month period in chronically-infected mice treated with oxamniquine. Eleven months later, the level of seropositive IgM decreased significantly (approximately 30%) compared to the level found in untreated, infected mice. The level of seropositive IgG1 decreased significantly four months after treatment (MAT) (61%) and remained at this level even after 11 months. The IgG2a reactivity against potato apyrase, although unchanged during chronic phase to 11 MAT, appeared elevated again in re-infected mice suggesting a response similar to that found during the acute phase. BALB/c mouse polyclonal anti-potato apyrase IgG reacted with soluble egg antigens probably due to the recognition of parasite ATP diphosphohydrolase. This study, for the first time, showed that the IgG2a antibody from S. mansoni-infected BALB mice cross-reacts with potato apyrase and the level of IgG2a in infected mice differentiates disease phases. The results also suggest that different conserved-epitopes contribute to the immune response in schistosomiasis. PMID- 20721479 TI - Seric chemokines and chemokine receptors in eosinophils during acute human schistosomiasis mansoni. AB - The recruitment of circulating eosinophils by chemokines and chemokine receptors plays an important role in the inflammation process in acute human schistosomiasis. Our main focus has been on the plasma chemokines (CXCL8/CCL2/CCL3/CCL24) and chemokine receptors (CCR2/CCR3/CCR5/CXCR1/CXCR2/CXCR3/CXCR4) expressed by circulating eosinophils from acute Schistosoma mansoni infected patients (ACT). Our studies compared ACT patients and healthy individuals as a control group. Our major findings demonstrated a plethora of chemokine secretion with significantly increased secretion of all chemokines analysed in the ACT group. Although no differences were detected for beta-chemokine receptors (CCR2, CCR3 and CCR5) or alpha chemokine receptors (CXCR3 and CXCR4), a significantly lower frequency of CXCR1+ and CXCR2+ eosinophils in the ACT group was observed. The association between chemokines and their chemokine receptors revealed that acutely infected schistosome patients displaying decreased plasma levels of CCL24 are the same patients who presented enhanced secretion of CCL3, as well as increased expression of both the CCR5 and CXCR3 chemokine receptors. These findings suggest that CCL24 may influence the kinetics of chemokines and their receptors and eosinophils recruitment during human acute schistosomiasis mansoni. PMID- 20721480 TI - Uptake of macromolecules by cercariae during skin penetration and transformation to schistosomula (Schistosoma mansoni). AB - Here, we observed the uptake of membrane-impermeant molecules by cercariae as they penetrate the skin and are transformed into schistosomula. We propose that membrane-impermeant molecules, Lucifer Yellow, Propidium iodide and Hoechst 33258 enter the parasite through both thenephridiopore and the surface membrane and then diffuse throughout the body of the parasite. We present a hypothesis that the internal cells of the body of the schistosomulum represent a new host parasite interface, at which skin-derived growth factors may stimulate receptors on internal membranes during transformation of the cercariae into the schistosomulum. PMID- 20721481 TI - CA88, a nuclear repetitive DNA sequence identified in Schistosoma mansoni, aids in the genotyping of nine Schistosoma species of medical and veterinary importance. AB - CA88 is the first long nuclear repetitive DNA sequence identified in the blood fluke, Schistosoma mansoni. The assembled S. mansoni sequence, which contains the CA88 repeat, has 8,887 nucleotides and at least three repeat units of approximately 360 bp. In addition, CA88 also possesses an internal CA microsatellite, identified as SmBr18. Both PCR and BLAST analysis have been used to analyse and confirm the CA88 sequence in other S. mansoni sequences in the public database. PCR-acquired nuclear repetitive DNA sequence profiles from nine Schistosoma species were used to classify this organism into four genotypes. Included among the nine species analysed were five sequences of both African and Asian lineages that are known to infect humans. Within these genotypes, three of them refer to recognised species groups. A panel of four microsatellite loci, including SmBr18 and three previously published loci, has been used to characterise the nine Schistosoma species. Each species has been identified and classified based on its CA88 DNA fingerprint profile. Furthermore, microsatellite sequences and intra-specific variation have also been observed within the nine Schistosoma species sequences. Taken together, these results support the use of these markers in studying the population dynamics of Schistosoma isolates from endemic areas and also provide new methods for investigating the relationships between different populations of parasites. In addition, these data also indicate that Schistosoma magrebowiei is not a sister taxon to Schistosoma mattheei, prompting a new designation to a basal clade. PMID- 20721482 TI - Schistosomal myeloradiculopathy in a low-prevalence area: 27 cases (14 autochthonous) in Campinas, Sao Paulo, Brazil. AB - Schistosomal myeloradiculopathy (SMR) is a form of schistosomiasis that is not linked with a high worm burden but rather is found in patients who have been sporadically exposed to Schistosoma mansoni. This paper aims to determine the occurrence of SMR in a low-endemic area with urban transmission in Campinas, Sao Paulo, Brazil. A retrospective study was performed, identifying confirmed cases in the two largest public hospitals on the region. Patients were diagnosed with SMR using standardised criteria, common clinical parameters, evidence of schistosomal infection and exclusion of other causes of myelopathy. A total of 27 patients were identified; 19 (85.2%) were men and four (14.8%) were women, ranging from 13-57 years of age (mean = 31.2; standard deviation = 12.8). Patients were classified as autochthonous (n = 14; 51.9%) or allochthonous (n = 11; 40.7%) and epidemiological data could not be obtained for two patients (7.4%). The clinical parameters of these patients were not different from previous studies. The sensitivity of serum immune reactions, cerebrospinal fluid immune reactions and parasitological stool examinations in identifying infected individuals was 87.5%, 93.8% and 40%, respectively. The epidemiological importance of these findings and their relationship with the control policies of schistosomiasis are discussed. PMID- 20721483 TI - Interobserver variability of ultrasound parameters in portal hypertension. AB - The aim of this study was to assess interobserver agreement of ultrasound parameters for portal hypertension in hepatosplenic mansonic schistosomiasis. Spleen size, diameter of the portal, splenic and superior mesenteric veins and presence of thrombosis and cavernous transformation were determined by three radiologists in blinded and independent fashion in 30 patients. Interobserver agreement was measured by the kappa index and intraclass correlation coefficient. Interobserver agreement was considered substantial (kappa = 0.714-0.795) for portal vein thrombosis and perfect (kappa = 1) for cavernous transformation. Interobserver agreement measured by the intraclass correlation coefficient was excellent for longitudinal diameter of the spleen (r = 0.828-0.869) and splenic index (r = 0.816-0.905) and varied from fair to almost perfect for diameter of the portal (r = 0.622-0.675), splenic (r = 0.573-0.913) and superior mesenteric (r = 0.525-0.607) veins. According to the results, ultrasound is a highly reproducible method for the main morphological parameters of portal hypertension in schistosomiasis patients. PMID- 20721484 TI - Imaging techniques and histology in the evaluation of liver fibrosis in hepatosplenic schistosomiasis mansoni in Brazil: a comparative study. AB - Few publications have compared ultrasound (US) to histology in diagnosing schistosomiasis-induced liver fibrosis (LF); none has used magnetic resonance (MR). The aim of this study was to evaluate schistosomal LF using these three methods. Fourteen patients with hepatosplenic schistosomiasis admitted to hospital for surgical treatment of variceal bleeding were investigated. They were submitted to upper digestive endoscopy, US, MR and wedge liver biopsy. The World Health Organization protocol for US in schistosomiasis was used. Hepatic fibrosis was classified as absent, slight, moderate or intense. Histology and MR confirmed Symmers' fibrosis in all cases. US failed to detect it in one patient. Moderate agreement was found comparing US to MR; poor agreement was found when US or MR were compared to histology. Re-classifying LF as only slight or intense created moderate agreement between imaging techniques and histology. Histomorphometry did not separate slight from intense LF. Two patients with advanced hepatosplenic schistosomiasis presented slight LF. Our data suggest that the presence of the characteristic periportal fibrosis, diagnosed by US, MR or histology, associated with a sign of portal hypertension, defines the severity of the disease. We conclude that imaging techniques are reliable to define the presence of LF but fail in grading its intensity. PMID- 20721485 TI - Acute schistosomiasis mansoni: revisited and reconsidered. AB - Acute schistosomiasis is a systemic hypersensitivity reaction against the migrating schistosomula and eggs. A variety of clinical manifestations appear during the migration of schistosomes in humans: cercarial dermatitis, fever, pneumonia, diarrhoea, hepatomegaly, splenomegaly, skin lesions, liver abscesses, brain tumours and myeloradiculopathy. Hypereosinophilia is common and aids diagnosis. The disease has been overlooked, misdiagnosed, underestimated and underreported in endemic areas, but risk groups are well known, including military recruits, some religious congregations, rural tourists and people practicing recreational water sports. Serology may help in diagnosis, but the finding of necrotic-exudative granulomata in a liver biopsy specimen is pathognomonic. Differentials include malaria, tuberculosis, typhoid fever, kala azar, prolonged Salmonella bacteraemia, lymphoma, toxocariasis, liver abscesses and fever of undetermined origin. For symptomatic hospitalised patients, treatment with steroids and schistosomicides is recommended. Treatment is curative in those timely diagnosed. PMID- 20721486 TI - Angiogenesis and schistosomiasis. AB - Angiogenesis has been recognised as a precursor of fibrosis in several pathologic conditions. Its participation has been demonstrated in schistosomiasis, both during periovular granuloma formation and in the genesis of schistosomal periportal fibrosis. Paradoxically, proliferation of new blood vessels, accompanied by production of vascular-endothelial growth factor, appeared prominent during fibrosis regression months after curative treatment of schistosomiasis. Thus, angiogenesis in schistosomiasis seems to have a two-way mode of action, participating both in fibrogenesis and in fibrosis degradation. Morphological observations presented here are in keeping with the possibility that, in the first case, angiogenesis allows pericytes to come in great numbers to the site of lesions and be detached from capillary walls and transformed into myofibroblasts, which are important extra-cellular matrix forming cells. During post-curative fibrosis regression, actin-containing pericytes appeared at various foci of tissue remodelling, especially at sites of repair of vascular lesions. The molecular and cell factors involved in both situations seem to be important subjects in need of further investigations and the schistosomiasis model certainly will be of great avail in this regard. PMID- 20721487 TI - Omental and pleural milky spots: different reactivity patterns in mice infected with Schistosoma mansoni reveals coelomic compartmentalisation. AB - In vertebrate animals, pleural and peritoneal cavities are repositories of milky spots (MS), which constitute an organised coelom-associated lymphomyeloid tissue that is intensively activated by Schistosoma mansoni infection. This study compared the reactive patterns of peritoneal MS to pleural MS and concluded from histological analysis that they represent independent responsive compartments. Whole omentum, lungs and the entire mediastinum of 54 S. mansoni-infected mice were studied morphologically. The omental MS of infected animals were highly activated, modulating from myeloid-lymphocytic (60 days of infection) to lymphomyeloid (90 days of infection) and lymphocytic or lymphoplasmacytic (160 days of infection) types. The non-lymphoid component predominated in the acute phase of infection and was expressed by monocytopoietic, eosinopoietic and neutropoietic foci, with isolated megakaryocytes and small foci of late normoblasts and mast cells. Nevertheless, pleural or thoracic MS of infected mice were monotonous, consisting of small and medium lymphocytes with few mast and plasma cells and no myeloid component. Our data indicate that compartmentalisation of the MS response is dependent on the lymphatic vascularisation of each coelomic cavity, limiting the effects or consequences of any stimulating or aggressive agents, as is the case with S. mansoni infection. PMID- 20721488 TI - Comparative randomised trial of high and conventional doses of praziquantel in the treatment of schistosomiasis mansoni. AB - The efficacy of oral praziquantel in the treatment of schistosomiasis has been considered low by most public health institutions. In this paper, we compared the efficacy of two dosages of praziquantel (80 mg/kg vs. 50 mg/kg) in patients with chronic schistosomiasis mansoni. Two hundred eighty-eight patients with schistosomiasis from a community in Brazil were randomly divided into two groups: 145 patients (Group 1) received 80 mg/kg body weight of oral praziquantel divided in two equal doses with 1 h interval and 143 patients (Group 2) received 50 mg/kg body weight of oral praziquantel. To keep the study masked, patients in Group 2 received placebo 1 h after the first dose. All patients were subjected to clinical and ultrasonographic examination. Cure assessment was performed by repeating two stool examinations, by a quantitative method, at 30, 90 and 180 days after treatment. The morbidity of schistosomiasis was low, with a few cases of light periportal thickening and 16 cases of mild splenomegaly. The cure rates were 89.7% for Group 1 and 83.9% for Group 2. There was no difference in the efficacy of both therapeutic dosages of praziquantel assayed. The adverse reactions were more frequent with higher dosage. PMID- 20721489 TI - Clinical and laboratory evaluation of schistosomiasis mansoni patients in Brazilian endemic areas. AB - A total of 60% of the territory of Alagoas (AL) is considered endemic for the occurrence of schistosomiasis and the classification of clinical forms of the disease are not known. This paper aimed to evaluate an endemic schistosomiasis population in AL, taking into account the prevalence, classification of the clinical forms and the results of laboratory analyses. The sample consisted of residents in endemic areas. The participants were submitted to a stool examination by the Kato-Katz technique and the diagnosis was based on the reading of two microscopic slides for each sample. The patients whose examinations were positive for schistosomiasis mansoni were submitted to a clinical examination and blood collection. Based on this examination, 8.11% of the study population were positive for schistosomiasis. The medium parasite load was 79.1 +/- 174.3 eggs. The intestinal (90.57%) and hepatointestinal (9.43%) forms were found at statistically significant levels (p < 0.001). The results of the present study update information on schistosomiasis in the city of Rio Largo. These data, although referring only to three locations in that city, suggest a decrease either in the parasite load or in the severity of clinical forms. PMID- 20721490 TI - Clinical-epidemiologic profile of the schistosomal myeloradiculopathy in Pernambuco, Brazil. AB - This was a retrospective descriptive study on a series of cases of schistosomal myeloradiculopathy (SMR) and the aim was to investigate the incidence of this disease and its clinical and epidemiological characteristics in cases diagnosed at three healthcare units in Pernambuco, Brazil between 1994-2006. The data were collected by reviewing the medical records from both the neurological and paediatric outpatient clinics and wards of the Hospital Clinics, Hospital of the Restoration and Pernambuco Mother and Child Institute. To gather the data, a spinal cord schistosomiasis evaluation protocol was used. The diagnoses were based on positive epidemiological evidence of schistosomiasis, clinical findings and laboratory tests (stool parasitological examination or rectal biopsies, magnetic resonance imaging findings and cerebrospinal fluid investigations). A total of 139 cases aged between 2-83 years were found. The most important determinants of SMR were male sex (66.2%), contact with fresh water (91%), origin in endemic regions (39.5%), lower-limb muscle weakness (100%), sensory level at the lower thoracic medulla (40.3%), myeloradicular form (76%) and presence of eggs in the stool parasitological examination (48%). This sample indicates the need for intervention policies guided by diagnostic standardization, thereby avoiding disease under-notification. PMID- 20721491 TI - Correlation of biological serum markers with the degree of hepatic fibrosis and necroinflammatory activity in hepatitis C and schistosomiasis patients. AB - Liver biopsy is the gold-standard method to stage fibrosis; however, it is an invasive procedure and is potentially dangerous. The main objective of this study was to evaluate biological markers, such as cytokines IL-13, IFN-gamma, TNF-alpha and TGF-beta, platelets, bilirubins (Bil), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total proteins, gamma-glutamil transferase (gamma-GT) and alkaline phosphatase (AP), that could be used to predict the severity of hepatic fibrosis in schistosomiasis and hepatitis C (HC) as isolated diseases or co-infections. The following patient groups were selected: HC (n = 39), HC/hepatosplenic schistosomiasis (HSS) (n = 19), HSS (n = 22) and a control group (n = 13). ANOVA and ROC curves were used for statistical analysis. P < 0.05 was considered significant. With HC patients we showed that TNF-alpha (p = 0.020) and AP (p = 0.005) could differentiate mild and severe fibrosis. With regard to necroinflammatory activity, AST (p = 0.002), gamma-GT (p = 0.034) and AP (p = 0.001) were the best markers to differentiate mild and severe activity. In HC + HSS patients, total Bil (p = 0.008) was capable of differentiating between mild and severe fibrosis. In conclusion, our study was able to suggest biological markers that are non-invasive candidates to evaluate fibrosis and necroinflammatory activity in HC and HC + HSS. PMID- 20721492 TI - Schistosoma mansoni: magnetic resonance analysis of liver fibrosis according to WHO patterns for ultrasound assessment of schistosomiasis-related morbidity. AB - For the last two decades, ultrasound (US) has been considered a surrogate for the gold standard in the evaluation of liver fibrosis in schistosomiasis. The use of magnetic resonance imaging (MRI) is not yet standardised for diagnosing and grading liver schistosomal fibrosis. The aim of this paper was to analyse MRI using an adaptation of World Health Organization (WHO) patterns for US assessment of schistosomiasis-related morbidity. US and MRI were independently performed in 60 patients (42.1 +/- 13.4 years old), including 37 men and 23 women with schistosomiasis. Liver involvement appraised by US and MRI was classified according to the WHO protocol from patterns A-F. Agreement between image methods was evaluated by kappa index (k). The correlation between US and MRI was poor using WHO patterns [k = 0.14; confidence interval (CI) 0.02; 0.26]. Even after grouping image patterns as "A-D", "Dc-E" and "Ec-F", the correlation between US and MRI remained weak (k = 0.39; CI 0.21; 0.58). The magnetic resonance adaptation used in our study did not confirm US classification of WHO patterns for liver fibrosis. PMID- 20721493 TI - Serum hyaluronan and collagen IV as non-invasive markers of liver fibrosis in patients from an endemic area for schistosomiasis mansoni: a field-based study in Brazil. AB - Non-invasive markers of fibrosis have been used to diagnose liver fibrosis in a variety of diseases. Hyaluronic acid (HA) and collagen IV (C-IV) levels were measured in the sera of patients from an endemic area for schistosomiasis in Brazil to diagnose and to rank the intensity of liver fibrosis. Seventy-nine adult patients with schistosomiasis, in the age range of 21-82 years (49 +/- 13.4) were submitted to clinical and ultrasonographic examinations. Ultrasound was employed to diagnose and categorise liver fibrosis according to World Health Organization patterns. Serum HA and C-IV levels were measured using commercial ELISA kits. Ultrasound revealed six patients with intense liver fibrosis, 21 with moderate, 23 with light and 29 without. Serum HA was able to separate individuals with fibrosis from those without (p < 0.001) and light from intense fibrosis (p = 0.029), but C-IV was not (p = 0.692). The HA diagnostic accuracy for fibrosis was 0.89. The 115.4 ng/mL cut-off level diagnosed patients with fibrosis (sensitivity 0.98, specificity 0.64). HA correlated positively with portal hypertension. Periportal fibrosis (subjective evaluation), age and collateral circulation predicted HA increase. In conclusion, we propose that serum HA can be used to identify patients with liver fibrosis in an endemic area for schistosomiasis mansoni in Brazil. PMID- 20721494 TI - Ultrasound in schistosomiasis mansoni. AB - We reviewed ultrasound features in patients with schistosomiasis mansoni. The alterations that we observed in acute and hepatosplenic schistosomiasis are described. The advantages and disadvantages of using ultrasound patterns in the evaluation of liver fibrosis are discussed. Other diseases that are important in the differential diagnosis of schistosomal liver fibrosis are presented. Ultrasound is an effective and flexible diagnostic tool in the evaluation of a variety of diseases. It presents no harmful effects to patients, allowing non invasive studies in hospitalized patients and in other facilities. PMID- 20721495 TI - Preliminary studies investigating the occurrence of Biomphalaria cousini in Brazil. AB - Specific genetic profiles of Brazilian Biomphalaria species were previously standardized by molecular taxonomy through the analysis of restriction fragments, which were generated by digesting the internal transcribed spacer region of rDNA with the DdeI endonuclease. Biomphalaria amazonica displayed three distinct profiles. To investigate these distinct profiles, the same molecular technique, polymerase chain reaction and restriction fragment length polymorphism, was used with different endonucleases. In addition, morphological data were also used to compare B. amazonica specimens that were collected from Brazil, Colombia and Bolivia. The morphological characters of Bolivian molluscs were similar to B. amazonica, displayed a molecular profile of five restriction fragments and morphological data, whereas the Colombian mollusc population showed morphological characters similar to Biomphalaria cousini and a molecular profile of three restriction fragments, similar to B. cousini. The Brazilian specimens showed the B. amazonica and B. cousini molecular profiles as well as a third profile, which resembled a combination of the Colombian and Bolivian molecular profiles. PMID- 20721496 TI - Susceptibility of Biomphalaria straminea from Peixe Angical dam, Tocantins, Brazil to infection with three strains of Schistosoma mansoni. AB - Environmental changes from water resource developmental projects affect the epidemiology of water-associated diseases, as well as malaria and schistosomiasis. Aiming to investigate the occurrence and distribution of freshwater snails of medical and veterinary importance in the area of influence of the Peixe Angical hydroelectric dam, a survey has been conducted over four years (2004-2008). The study has revealed the occurrence of populations of Biomphalaria straminea (Dunker) in all municipalities surrounding the lake. Studies on parasite-mollusc compatibility were undertaken using 35 populations of B. straminea, descendants of specimens obtained from that area and three strains of Schistosoma mansoni (Sambon) (BH, CM and CMO). The main results are as follows: (i) among the 1,314 specimens used, eight had been infected (infection index of 0.6%) with only the BH strain, (ii) for B. straminea populations, the mortality index was 6.8% and, depending on the strain used, the indexes were 4.6%, 8.49% and 19% with BH, CM and CMO strains, respectively, (iii) the infection indexes varied according to the B. straminea populations, ranging from 0-12.5% and (iv) the duration of the precercarial period varied from 25-49 days. These results, in addition to environmental and social changes that took place in the Peixe Angical dam region, indicate the possibility of B. straminea emerging as a schistosomiasis vector in this area. PMID- 20721497 TI - Carbohydrate metabolism alterations in Biomphalaria glabrata infected with Schistosoma mansoni and exposed to Euphorbia splendens var. hislopii latex. AB - This paper evaluates the alterations in the glycogen content of tissues (digestive gland and cephalopedal mass) and glucose in the haemolymph of Biomphalaria glabrata BH strain infected with Schistosoma mansoni BH strain and exposed to the latex of Euphorbia splendens var. hislopii. A reduction in the glycogen deposits was observed in infected snails exposed and not exposed to latex. However, the exposure to latex caused a greater depletion of the glycogen levels in both sites analysed, especially from the third week onward. The utilisation of latex as a molluscicide to control the population of infected B. glabrata selectively is proposed. PMID- 20721498 TI - Susceptibility and compatibility of Biomphalaria tenagophila from the Rio de la Plata basin with Schistosoma mansoni from Brazil. AB - Schistosomiasis has expanded to southern parts of Brazil. Between 2005-2007 the dispersion and the proliferation of Biomphalaria tenagophila was verified in the province of Corrientes near the Brazilian border. In order to study the possibility that schistosomiasis might spread into the basins of the Parana and Uruguay Rivers, 440 B. tenagophila collected from 10 populations groups were experimentally exposed to infection with Schistosoma mansoni of the SJ2 strain. Snails from five localities were susceptible. Frandsen's index (TCP/100) shows that those snails from Mirunga (11%), Aguacerito (2%) and Curupicay (2%) were Class I and not very compatible. Meanwhile, snails from Copra (6%) and Pay-Ubre (22%), in the Parana River basin, were Class II and poorly compatible. PMID- 20721499 TI - The effect of early infection with Echinostoma paraensei on the interaction of Schistosoma mansoni with Biomphalaria glabrata and Biomphalaria tenagophila. AB - Infection caused by the trematode Echinostoma paraensei has been shown to interfere in the natural resistance to infection by Schistosoma mansoni. Biomphalaria glabrata is susceptible to infection, while Taim isolate Biomphalaria tenagophila is resistant to infection by S. mansoni. These two snail species were assessed for infection with E. paraensei two days after exposure to S. mansoni miracidia. The number of B. tenagophila and B. glabrata infected with E. paraensei was lower in co-infected group, suggesting an antagonistic relationship. B. glabrata showed an increase in its susceptibility to S. mansoni, whereas B. tenagophila maintained its refractoriness to S. mansoni infection. Weekly comparisons made between the E. paraensei cercariae released from B. tenagophila and B. glabrata mono-infected snails revealed no quantitative differences. In contrast, S. mansoni cercariae released were higher in the B. glabrata co-infected group. Mortality rates were significantly greater in both species pertaining to co-infected group and unexpected mortalities were also observed in B. tenagophila exposed only to S. mansoni miracidia. Our study revealed that the B. tenagophila Taim isolate is susceptible to E. paraensei infection, although infection did not alter its resistance to S. mansoni infection. PMID- 20721500 TI - Phylogenetic analysis of Biomphalaria tenagophila (Orbigny, 1835) (Mollusca: Gastropoda). AB - Mitochondrial DNA of Biomphalaria tenagophila, a mollusc intermediate host of Schistosoma mansoni in Brazil, was sequenced and characterised. The genome size found for B. tenagophila was 13,722 bp and contained 13 messenger RNAs, 22 transfer RNAs (tRNA) and two ribosomal RNAs (rRNA). In addition to sequencing, the mitochondrial DNA (mtDNA) genome organization of B. tenagophila was analysed based on its content and localization of both coding and non-coding regions, regions of gene overlap and tRNA nucleotide sequences. Sequences of protein, rRNA 12S and rRNA 16S nucleotides as well as gene organization were compared between B. tenagophila and Biomphalaria glabrata, as the latter is the most important S. mansoni intermediate host in Brazil. Differences between such species were observed regarding rRNA composition. The complete sequence of the B. tenagophila mitochondrial genome was deposited in GenBank (accession EF433576). Furthermore, phylogenetic relationships were estimated among 28 mollusc species, which had their complete mitochondrial genome deposited in GenBank, using the neighbour joining method, maximum parsimony and maximum likelihood bootstrap. B. tenagophila was positioned at a branch close to B. glabrata and Pulmonata molluscs, collectively comprising a paraphyletic group, contrary to Opistobranchia, which was positioned at a single branch and constituted a monophyletic group. PMID- 20721501 TI - Evaluation of a linear spectral mixture model and vegetation indices (NDVI and EVI) in a study of schistosomiasis mansoni and Biomphalaria glabrata distribution in the state of Minas Gerais, Brazil. AB - This paper analyses the associations between Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) on the prevalence of schistosomiasis and the presence of Biomphalaria glabrata in the state of Minas Gerais (MG), Brazil. Additionally, vegetation, soil and shade fraction images were created using a Linear Spectral Mixture Model (LSMM) from the blue, red and infrared channels of the Moderate Resolution Imaging Spectroradiometer spaceborne sensor and the relationship between these images and the prevalence of schistosomiasis and the presence of B. glabrata was analysed. First, we found a high correlation between the vegetation fraction image and EVI and second, a high correlation between soil fraction image and NDVI. The results also indicate that there was a positive correlation between prevalence and the vegetation fraction image (July 2002), a negative correlation between prevalence and the soil fraction image (July 2002) and a positive correlation between B. glabrata and the shade fraction image (July 2002). This paper demonstrates that the LSMM variables can be used as a substitute for the standard vegetation indices (EVI and NDVI) to determine and delimit risk areas for B. glabrata and schistosomiasis in MG, which can be used to improve the allocation of resources for disease control. PMID- 20721502 TI - Schistosomiasis control program in the state of Minas Gerais in Brazil. AB - The Schistosomiasis Control Program (PCE) was implemented in Minas Gerais (MG) in 1984. In 1999, the state started the investigation and control of schistosomiasis in 470 municipalities. The aim of the present paper is to report the evolution of this Program from 1984-2007. The program included a coproscopic survey carried out in the municipalities of known endemic areas using a quantitative method. Positives were treated with praziquantel and given a program of health education. The information for this study was obtained from data collected and stored by the Health State Department. From 2003-2007, 2,643,564 stool examinations resulted in 141,284 positive tests for Schistosoma mansoni (5.3%). In the first evaluation after treatment, a decrease in the number of municipalities with prevalence over 10% was documented. In one village, selected for a more detailed evaluation, the percentage of positive tests decreased from 14.9% in the baseline survey to 5.3% after treatment. A reference centre for patients with severe schistosomiasis was created in Belo Horizonte, MG. Based on our findings, we believe that the implementation of PCE in MG is on the right path and in due time these new initiatives will provide desirable results. PMID- 20721503 TI - A geoprocessing approach for studying and controlling schistosomiasis in the state of Minas Gerais, Brazil. AB - Geographical information systems (GIS) are tools that have been recently tested for improving our understanding of the spatial distribution of disease. The objective of this paper was to further develop the GIS technology to model and control schistosomiasis using environmental, social, biological and remote sensing variables. A final regression model (R(2) = 0.39) was established, after a variable selection phase, with a set of spatial variables including the presence or absence of Biomphalaria glabrata, winter enhanced vegetation index, summer minimum temperature and percentage of houses with water coming from a spring or well. A regional model was also developed by splitting the state of Minas Gerais (MG) into four regions and establishing a linear regression model for each of the four regions: 1 (R(2) = 0.97), 2 (R(2) = 0.60), 3 (R(2) = 0.63) and 4 (R(2) = 0.76). Based on these models, a schistosomiasis risk map was built for MG. In this paper, geostatistics was also used to make inferences about the presence of Biomphalaria spp. The result was a map of species and risk areas. The obtained risk map permits the association of uncertainties, which can be used to qualify the inferences and it can be thought of as an auxiliary tool for public health strategies. PMID- 20721504 TI - The Estrada Real project and endemic diseases: the case of schistosomiasis, geoprocessing and tourism. AB - Geographical Information System (GIS) is a tool that has recently been applied to better understand spatial disease distributions. Using meteorological, social, sanitation, mollusc distribution data and remote sensing variables, this study aimed to further develop the GIS technology by creating a model for the spatial distribution of schistosomiasis and to apply this model to an area with rural tourism in the Brazilian state of Minas Gerais (MG). The Estrada Real, covering about 1,400 km, is the largest and most important Brazilian tourism project, involving 163 cities in MG with different schistosomiasis prevalence rates. The model with three variables showed a R(2) = 0.34, with a standard deviation of risk estimated adequate for public health needs. The main variables selected for modelling were summer vegetation, summer minimal temperature and winter minimal temperature. The results confirmed the importance of Remote Sensing data and the valuable contribution of GIS in identifying priority areas for intervention in tourism regions which are endemic to schistosomiasis. PMID- 20721505 TI - Rural tourism: a risk factor for schistosomiasis transmission in Brazil. AB - This paper reports an outbreak of acute schistosomiasis among 38 tourists who rented a country house in the district of Igarape, the metropolitan region of Belo Horizonte, Brazil, during a holiday period in 2006. A total number of 32 individuals were positive for Schistosoma mansoni. Results of stool examinations revealed individual S. mansoni egg counts per gram of faeces (epg) ranging from 4 768 epg with a geometric mean egg count of 45. The most frequent clinical symptoms were abdominal pain (78.1%), headache (75%), fever (65.6%), dry cough (65.2%) and both diarrhoea and asthenia (59.4%). A malacological survey of the area, where 22 specimens of Biomphalaria glabrata were collected, revealed three (13.6%) specimens eliminating Schistosoma cercariae. This investigation re confirms a recently described pattern of schistosomiasis infection, resulting in the acute form of the disease and connected to rural tourism, which contributes to the spread of the disease among the middle-class and into non-endemic areas. The lack of specific knowledge about acute schistosomiasis among health services causes an increased number of unnecessary diagnostic procedures and delays in accurate diagnosis and treatment, resulting in considerable discomfort for the patients. PMID- 20721506 TI - Schistosomiasis risk mapping in the state of Minas Gerais, Brazil, using a decision tree approach, remote sensing data and sociological indicators. AB - Schistosomiasis mansoni is not just a physical disease, but is related to social and behavioural factors as well. Snails of the Biomphalaria genus are an intermediate host for Schistosoma mansoni and infect humans through water. The objective of this study is to classify the risk of schistosomiasis in the state of Minas Gerais (MG). We focus on socioeconomic and demographic features, basic sanitation features, the presence of accumulated water bodies, dense vegetation in the summer and winter seasons and related terrain characteristics. We draw on the decision tree approach to infection risk modelling and mapping. The model robustness was properly verified. The main variables that were selected by the procedure included the terrain's water accumulation capacity, temperature extremes and the Human Development Index. In addition, the model was used to generate two maps, one that included risk classification for the entire of MG and another that included classification errors. The resulting map was 62.9% accurate. PMID- 20721507 TI - Current epidemiological status of schistosomiasis in the state of Pernambuco, Brazil. AB - Uncontrolled peripheral urbanisation coupled with environmental degradation has affected the status of schistosomiasis in Pernambuco (PE), Brazil. This endemic disease continues to perpetuate its transmission in rural areas and has also become a cause for concern in coastal towns of the state. The lack of basic infrastructure (sanitation and health programmes) to support the new urban areas leads to faecal contamination of natural aquatic environments, resulting in consequent infection of vector snails and the emergence of new sources of schistosomiasis transmission. In the present paper, we discuss the current epidemiological status of schistosomiasis in PE. We have consolidated and analysed information from parasitological, malacological and morbidity surveys undertaken by the group of researchers at the Laboratory of Schistosomiasis, Centro de Pesquisas Aggeu Magalhaes-Fiocruz. The results of our analysis show: (i) the maintenance of the levels of schistosomiasis in the rural Zona da Mata, PE, (ii) the record of the human cases of schistosomiasis and the foci of infected snails detected along the coast of PE through 2007, (iii) the high record of the severe clinical form of schistosomiasis in the metropolitan region of Recife (RMR) and (iv) new breeding sites of schistosomiasis vector snails that were identified in a 2008 survey covering the RMR and the coastal localities of PE. PMID- 20721508 TI - Spatial distribution of Schistosoma mansoni infection before and after chemotherapy with two praziquantel doses in a community of Pernambuco, Brazil. AB - Praziquantel chemotherapy has been the focus of the Schistosomiasis Control Program in Brazil for the past two decades. Nevertheless, information on the impact of selective chemotherapy against Schistosoma mansoni infection under the conditions confronted by the health teams in endemic municipalities remains scarce. This paper compares the spatial pattern of infection before and after treatment with either a 40 mg/kg or 60 mg/kg dose of praziquantel by determining the intensity of spatial cluster among patients at 180 and 360 days after treatment. The spatial-temporal distribution of egg-positive patients was analysed in a Geographic Information System using the kernel smoothing technique. While all patients became egg-negative after 21 days, 17.9% and 30.9% reverted to an egg-positive condition after 180 and 360 days, respectively. Both the prevalence and intensity of infection after treatment were significantly lower in the 60 mg/kg than in the 40 mg/kg treatment group. The higher intensity of the kernel in the 40 mg/kg group compared to the 60 mg/kg group, at both 180 and 360 days, reflects the higher number of reverted cases in the lower dose group. Auxiliary, preventive measures to control transmission should be integrated with chemotherapy to achieve a more enduring impact. PMID- 20721509 TI - The prevalence of schistosomiasis in school-aged children as an appropriate indicator of its prevalence in the community. AB - School-aged children (6-15 years) from the endemic area of Pernambuco were evaluated both as a target group for and an indicator of schistosomiasis control in the community. Parasitological data were drawn from baseline stool surveys of whole populations that were obtained to diagnose Schistosoma mansoni infection. Nineteen representative localities were selected for assessing the prevalence of schistosomiasis among individuals in the following age groups: 0-5, 6-15, 16-25, 26-40 and 41-80 years. For each locality, the prevalence in each age group was compared to that of the overall population using contingency table analysis. To select a reference group, the operational difficulties of conducting residential surveys were considered. School-aged children may be considered to be the group of choice as the reference group for the overall population for the following reasons: (i) the prevalence of schistosomiasis in this age group had the highest correlation with the prevalence in the overall population (r = 0.967), (ii) this age group is particularly vulnerable to infection and plays an important role in parasite transmission and (iii) school-aged children are the main target of the World Health Organization in terms of helminth control. The Schistosomiasis Control Program should consider school-aged children both as a reference group for assessing the need for intervention at the community level and as a target group for integrated health care actions of the Unified Health System that are focused on high-risk groups. PMID- 20721510 TI - Factors related to transmission of and infection with Schistosoma mansoni in a village in the South-eastern Region of Brazil. AB - In this transversal study, factors related to infection with and transmission of Schistosoma mansoni were explored. Based on stool examinations of two Kato-Katz smears of a single sample, the prevalences of schistosomiasis and geohelminths were established. In a multivariable analysis, sets of demographic, socio economic and water contact pattern variables were tested for strength of relation with infection. Males presented a 3.39-times higher risk for infection than females. The age groups between 10-19 years and 20-30 years showed risks of infection 7.1- and 7.5-times higher, respectively, than the control age group between 0-10 years. Individuals practicing leisure activities had a 1.96-times higher risk than those without these activities. The malacological survey identified snails of the species Biomphalaria glabrata, Biomphalaria straminea and Biomphalaria tenagophila. Two exemplars of B. glabrata (0.53%) proved positive for S. mansoni. The socio-economic improvements observed in the locality suggest a protective and preventive effect towards infection with schistosomiasis, which requires further investigation with a longitudinal and more detailed study design. Considering our findings, a proposal for an integrated control program should be based on two pillars: one horizontal, which involves social empowerment and health education, and another more vertical, which delivers treatment and infrastructure improvements. PMID- 20721511 TI - The role of population movement in the epidemiology and control of schistosomiasis in Brazil: a preliminary typology of population movement. AB - This paper examines recent developments in migration studies. It reviews literature related to the potential role of internal population movement in the occurrence of schistosomiasis in Brazil and modifies Prothero's typology of population movement for use in Brazil. This modified classification system may contribute to a better understanding of schistosome transmission as well as improved research and control programs. The results of this study indicate that population movement in Brazil primarily involves economically-motivated rural urban and interregional movement. However, several movement patterns have become increasingly important in recent years as a result of changing socioeconomic and urbanisation dynamics. These patterns include urban-urban, intracity and urban rural movement as well as the movement of environmental refugees and tourists. Little is known about the epidemiological significance of these patterns. This paper also highlights the role of social networks in the decision to migrate and to settle. Prothero's classic population movement typology categorises movement as either one-way migrations or circulations and examines them along spatial and temporal scales. However, the typology must be modified as epidemiological information about new patterns becomes available. This paper identifies areas that require further research and offers recommendations that can improve the measurement and spatial analysis of the relationship between population movement and schistosomiasis. PMID- 20721512 TI - Accessibility to and utilisation of schistosomiasis-related health services in a rural area of state of Minas Gerais, Brazil. AB - The objective of the present paper was to compare accessibility and utilisation of schistosomiasis diagnostic and treatment services in a small village and the surrounding rural area in northern part of the state of Minas Gerais Brazil. The study included 1,228 individuals: 935 central village residents and 293 rural residents of Sao Pedro do Jequitinhonha. Schistosoma mansoni infection rates were significantly higher in the central village than in the rural area during a survey in 2007 (44.3% and 23.5%, respectively) and during the 2002 schistosomiasis case-finding campaign (33.1% and 26.5%, respectively) (p < 0.001). However, during the 2002-2006 period, only 23.7% of the villagers and 27% of the rural residents obtained tests on their own from health centres, hospitals and private clinics in various nearby towns. In 2007, 63% of the villagers and 70.5% of the rural residents reported never having received treatment for schistosomiasis. This paper reveals considerable variation in the accessibility and utilisation of schistosomiasis-related health services between the central village and the rural area. A combination of low utilisation rates between 2002 2006 and persistently high S. mansoni infection rates suggest that the schistosomiasis control program must be more rapidly incorporated into the primary health services. PMID- 20721513 TI - Specific schistosomiasis treatment as a strategy for disease control. AB - The great hope for schistosomiasis treatment began with the development of oxamniquine and praziquantel. These drugs can be administered orally in a single dose and have a high curative power with minor side effects. In this study, we carried out a field experiment involving a population of 3,782 people. The population was examined at four localities in Minas Gerais within the valleys of the Doce and Jequitinhonha Rivers. In this cohort, there were 1,790 patients infected with Schistosoma mansoni (47.3%) and we showed that only 1,403 (78.4%) could be treated with oxamniquine in a single dose of 12.5-20 mg/kg orally. The other 387 (21.6%) were not treated during the first stage because of contraindications (pregnancy or impeditive diseases), absences or refusals. It was observed that, on average, 8.8-17% of the infected patients continued to excrete S. mansoni eggs at the end of the 2nd month after treatment and 30-32% of the cohort was infected by the end of the 24th month. In one of the areas that we followed-up for a total of 30 years, the prevalence of the infection with S. mansoni fell from 60.8-19.3% and the hepatosplenic form of the disease dropped from 5.8-1.3%. We conclude that specific treatment of schistosomiasis reduces the prevalence of infection in the short-term and the morbidity due to schistosomiasis in medium to long-term time frames, but does not help to control disease transmission. PMID- 20721514 TI - [Validation of a score for predicting bleeding events during acute coronary syndromes]. AB - BACKGROUND: bleeding is a major complication in patients treated for acute coronary syndromes (ACS) with antithrombotic and invasive therapies. Consequently, the benefit of such therapies should be balanced against the potential risk of hemorrhagic complications. Therefore, a score to estimate individual risk of bleeding might represent an important tool in clinical decision-making. OBJECTIVE: this study aims to create and validate a bleeding risk score for patients with ACS. METHODS: independent predictors of bleeding reported by the GRACE Registry were utilized. Variables with odds ratio (OR) > 2.5 in that Registry added 3 points (previous history of bleeding), OR = 1.5-2.4 added 2 points (creatinine clearance < 30 ml/min, female gender) and those with OR < 1.5 added 1 point (clearance between 30 and 60 ml/min, each 10 years of age>30, ST-deviation, peripheral artery disease and smoking). The score was validated in a cohort of 383 individuals with ACS. In-hospital bleeding was defined as hematocrit fall > 10%, blood transfusion > 2 units, intracerebral bleeding or fatal bleeding. RESULTS: the incidence of bleeding events was 3.1% and the score's C-statistics was 0.66 (95% CI = 0.52-0.80), indicating a predictive ability towards these events. Those with a score > 7 had 6% incidence of bleeding, compared with 1.9% if the score was < 7 (RR = 3.2; 95%CI = 1.04-9.9; p = 0.03). There was an interaction between a score > 7 and greater risk imposed by treatment with Clopidogrel (p = 0.02), IIb/IIIa blockers (p = 0.06) and surgical revascularization (p < 0.001). CONCLUSION: the score discriminates bleeding risk and is potentially useful in clinical decision-making during ACS. PMID- 20721515 TI - Lack of clopidogrel-statin interaction in patients undergoing coronary stent implantation. AB - BACKGROUND: Some studies have suggested reduced activity of clopidogrel on platelet activation and adherence in patients using statins. OBJECTIVE: To assess whether platelet activation and aggregation decrease with clopidogrel, and whether there is a reduction of the action of clopidogrel when associated with atorvastatin or simvastatin. METHODS: This prospective study included 68 patients with stable angina with previous use of simvastatin, atorvastatin, or no statin (control group), with previous elective indication of percutaneous coronary intervention (PCI). Platelet activation was analyzed by means of platelet count, levels of P-selectin and glycoprotein IIb/IIIa (with and without ADP stimulation) by flow cytometry. The findings were analyzed before and after percutaneous coronary intervention and the administration of clopidogrel. RESULTS: We observed reduction in platelet activity with use of clopidogrel. Furthermore, no differences were found between the variables analyzed to prove reduced activity of clopidogrel when combined with statins. We observed levels of p-selectin (pre angioplasty: 14.23 +/- 7.52 x 8.83 x 11.45 +/- 7.65 +/- 7.09; after angioplasty: 21.49 +/- 23.82 x 4 37 +/- 2.71 x 4.82 +/- 4.47, rho < 0.01) and glycoprotein IIb/IIIa (pre-angioplasty: 98.97 +/- 0.43 +/- 1.25 x 98.79 x 99.21 +/- 0.40 after angioplasty: 99.37 +/- 0.29 +/- 1.47 x 98.50 x 98.92 +/- 0.88, rho = 0.52), respectively, in the control, atorvastatin and simvastatin groups. CONCLUSION: We concluded that platelet activation decreases with administration of clopidogrel, and clopidogrel has no antiplatelet effect reduced in the presence of simvastatin or atorvastatin. PMID- 20721516 TI - Exercise chemosensitivity in heart failure: ventilatory, chronotropic and neurohormonal responses. AB - BACKGROUND: Heart failure (HF) is associated with resting increased peripheral and central chemosensitivity which may correlate with an increased ventilatory response to exercise. However, its sensitivity in HF during exercise was never really reported. OBJECTIVE: We tested if stimulation of central and peripheral chemoreceptors in HF patients could modulate ventilatory, chronotropic, and neurohormonal response during submaximal exercise. METHODS: We investigated central and peripheral chemosensitivity in 15 HF and 7 control (C) comparing response through three 6 minute walking tests conducted in a treadmill with : room air, hypoxia, and hypercapnia (in a randomic order). RESULTS: RR at room air C and HF was 17+/-2 and 22+/-2 (p<.0001); at hypoxia 17+/-1 and 23+/-2 (p<.02); at CO25% was 20+/-2 and 22+/-5 (p<.02). Tidal volume (TV) at room air was 1.25+/ 0.17 and 1.08+/-0.19 (p<.01); at hypoxia 1.65+/-0.34 and 1.2+/-0.2 (p<.0001); at CO25% 1.55+/-0.46 and 1.29+/-0.39 (p<.0001). At rest the increment in HF was higher for VE (C 33+/-40%, HF 62+/-94%, p<.01), HR(C 7+/-10%, HF 10+/-10%, p<0.05) at rest. During hypoxia exercise increment in HF was higher for RR (C 1+/ 4, HF 11+/-6,p<.05), HR (C 12+/-2, HF 14+/-3, p<.05), VE/VO2 (C -4+/-18%, HF 24+/ 21%, p<.01), HR/VO2 (C -26+/-11%, HF 11+/-5%, p<.01), VE/WD (C 36+/-10%, 46+/-14, p<.05%) and HR/WD (C 18+/-8%, HF 29+/-11, p<.01). During HF hypoxia exercise NO reduced, and IL-6, aldosterone levels increased. Neurohormonal levels unchanged in C. CONCLUSION: Exercise peripheral and central chemosensitivity are increased in HF and may modulate respiratory pattern, cardiac chronotropic, and neurohormonal activity during exercise. PMID- 20721517 TI - [Is it necessary to suspend betablockers in decompensated heart failure with low output?]. AB - BACKGROUND: there is evidence that the suspension of betablockers (BB) in decompensated heart failure may increase mortality. Dobutamine (dobuta) is the most commonly used inotrope in decompensation, however, BB and dobuta act with the same receptor with antagonist actions, and concurrent use of both drugs could hinder compensation. OBJECTIVE: to evaluate whether the maintenance of BB associated with dobuta difficults cardiac compensation. METHODS: we studied 44 patients with LVEF < 45% and the need for inotropics. Divided into three groups according to the use of BB. Group A (n=8): those who were not using BB at baseline; Group B (n=25): those who used BB, but was suspended to start dobuta; Group C (n = 11): those who used BB concomitant to dobuta. To compare groups, we used the Student t, Fisher exact and chi-square tests. Considered significant if p < 0.05. RESULTS: mean LVEF 23.8 +/- 6.6%. The average use of dobuta use was similar in all groups (p = 0.35), and concomitant use of dobutamine with BB did not increase the length of stay (BB 20.36 +/- 11.04 days vs without BB 28.37 +/- 12.76 days, p = NS). In the high dose, BB was higher in patients whose medication was not suspended (35.8 +/- 16.8 mg/day vs 23.0 +/- 16.7 mg/day, p = 0.004). CONCLUSION: maintaining BB associated with dobutamine did not increase the length of hospitalization and was not associated with the worst outcome. Patients who did not suspend BB were discharged with higher doses of the drug. PMID- 20721518 TI - [Body composition, biochemical and clinical changes of adolescents with excessive adiposity]. AB - BACKGROUND: adolescents with excess body fat and eutrophic had the same metabolic changes expected in obese individuals. OBJECTIVE: to evaluate body composition, anthropometric changes, biochemical and clinical characteristics of female adolescents. METHODS: a total of 113 adolescents from public schools in Vicosa, MG, divided into three groups: group 1 - consisting of eutrophic adolescents with excess body fat; group 2 - eutrophic with body fat within normal limits; and group 3 - with excess weight and body fat. Weight, height, waist and hip circumference, blood pressure were measured. The body mass index (BMI) and waist hip ratio were calculated. The percentage of body fat was obtained by bioelectrical impedance horizontally, following its own protocol for this evaluation. The assessment of the percentage of body fat and biochemistry was performed after 12 hours of fasting, and analyzed the lipid profile, blood glucose and insulin, homocysteine, leptin and C-reactive protein. Insulin resistance was calculated by HOMA index. RESULTS: the group of eutrophic adolescents, with higher adiposity, behaved in relation to blood pressure, HDL and glucose levels, similarly to adolescents who are overweight. It can be seen that the HOMA index, insulin and leptin increased with increasing body fat. More than half of adolescents had total cholesterol and CRP levels above recommended levels. The most obvious metabolic disorder related to the lipid profile for both groups studied. CONCLUSION: excess adiposity in normal weight adolescents may be related to clinical and biochemical changes similar to those found in adolescents who are overweight. PMID- 20721519 TI - Intermittent systolic overload promotes better myocardial performance in adult animals. AB - BACKGROUND: Corrected transposition of great arteries often evolves with right ventricular dysfunction. The ventricular preparation for anatomic correction in adult patients has produced disappointing results. OBJECTIVE: To assess right ventricular hypertrophy (RV) induced by conventional and intermittent pulmonary banding (PB) in adult animals. METHODS: Nineteen adult goats were divided into three groups: conventional (six animals), intermittent (six animals) and control (seven animals). The Conventional group underwent fixed PB with cardiac tape, while the intermittent group received PB adjustable device, which generated systolic overload for 12 hours, alternated with 12 hours of rest of RV. The pressures of the RV, pulmonary artery and aorta were measured throughout the study. Echocardiography was performed weekly. After four weeks, the animals were euthanized for morphological evaluation of the ventricles. The Control group was put to euthanasia for analysis at baseline. RESULTS: Pressure overload was lower in the intermittent group (p = 0.001), compared to the conventional group. There was an increase in the thickness of the RV of the Intermittent group measured by echocardiography compared to their baseline values (p < 0.05). The myocardial performance index in the RV group was better in the Intermittent group (p = 0.024), compared to the Conventional group. The groups stimulated showed increased muscle mass compared to the Control group (p = 0.001). There was no difference in myocardial water content. CONCLUSION: The intermittent BP developed hypertrophy of better performance, suggesting this protocol as the preferred method of ventricular preparation. PMID- 20721520 TI - Effects of the use of theoretical versus theoretical-practical training on CPR. AB - BACKGROUND: Theoretical knowledge and skill to perform good quality cardiopulmonary resuscitation (CPR) are essential for the survival of patients with sudden death. OBJECTIVE: To determine whether a theoretical course alone is sufficient to promote good quality CPR training and knowledge for health professionals in comparison to a theoretical-practical basic life support training. METHODS: Twenty volunteer nurses participated in the theoretical CPR and automated external defibrillation (AED) training by means of a theoretical class and video used in the Basic Life Support Training of the American Heart Association (BLS-AHA; group A). They were compared to other 26 health professionals who attended regular theoretical-practical BLS-AHA training (group B). After the training, the participants took theoretical and practical tests as recommended in BLS-AHA courses. The practical tests were recorded and were later scored by three experienced instructors. The theoretical test was a multiple choice test used in regular BLS-AHA courses. RESULTS: No difference was observed in the theoretical tests (p = ns). However, the practical tests were consistently worse in group A, as evaluated by the three examiners (p < 0.05). CONCLUSION: The use of CPR videos and theoretical training did not improve the individuals' psychomotor ability to perform good quality CPR; however, it may improve their cognitive ability (knowledge). Critical areas of intervention are the primary ABCD and the correct use of AED. PMID- 20721521 TI - Acute myocardial infarction in a patient with chronic myelocytic leukemia during chemotherapy with hydroxyurea. AB - BACKGROUND: Cardiac toxicity is a known side effect of chemotherapeutics such as 5-fluorouracil (5-FU) or cisplatin. Chest pain with ECG changes, arrhythmias, acute myocardial infarction (AMI), heart failure and sudden death have been described in the literature. CASE STUDY: We report the first case of AMI in a 59 year-old male patient with chronic myelocytic leukemia (CML) during chemotherapy with hydroxyurea. The patient was not affected by prior heart disease and did not reveal any classic risk factors for coronary heart disease. Because of the severe thrombocytopenia (23000/MUl), no acetylsalicylic acid (ASA) or clopidogrel were given but low dose heparin (400 U/h). Urgent coronary angiography revealed complete thrombotic occlusion of the proximal left descending coronary artery. CONCLUSION: This case reveals that AMI can occur during chemotherapy with hydroxyurea in patients without prior heart disease. The pathogenesis of this phenomenon remains hitherto unclear. Coronary artery spasm, lesions of the endothelium as well as coagulation disorders have been postulated to explain this side effect of hydroxyurea. PMID- 20721522 TI - [Self inflicting behavior in patients with borderline personality disorder : retrospective analysis of principles of plastic surgery therapy]. AB - One symptom of Borderline personality disorder is self inflicting behavior, especially cuts and thermal injuries in the upper extremity. Due to the complex underlying psychiatric disease, surgical treatment of these injuries can be tedious and frustrating; therefore it is sometimes necessary to differ from classical plastic surgery principals and to favorite a more conservative approach. In every case, close cooperation with psychiatrist is inalienable. PMID- 20721523 TI - [Treatment of metastatic melanoma with CTLA4 antibodies]. PMID- 20721524 TI - [Bilateral periorbital metastases of transtional cell carcinoma of the bladder]. AB - Bladder cancers account about 3% of malignant tumors and often metastasize to regional lymph nodes, liver, lungs and skeleton. Metastases in the area of the orbital region are very rare. When eyelid swelling, proptosis, diplopia, or ocular pain occurs, an underlying neoplastic process should always be suspected. Due to the rapid progression of orbital metastases, diagnosis and early initiation of palliative therapy is important. PMID- 20721525 TI - [Disorders of platelet function]. PMID- 20721526 TI - [Current aspects of anesthetic management in urological patients]. AB - Patients with coronary stents should take clopidogrel and acetylsalicylic acid for 4 weeks or 12 months after stenting. Stopping this medication early, e.g., for surgery, results in a 90-fold increase in the patient's risk for myocardial infarction from stent thrombosis. The mortality due to perioperative acute coronary syndrome clearly exceeds that due to perioperative bleeding complications. If oral medication resulting in platelet inhibition has to be paused "bridging" with short-acting, intravenous GPIIb/IIIa antagonists is possible. In recent years perioperative beta-blockade has been recommended for patients with high coronary vascular risk, and recently also for those with medium or low risk. Current studies, however, indicate that patients on beta blockers have increased perioperative mortality because of bradycardia, hypotension, and anemia. Therefore, anemia and hypotension should be rigorously avoided.Anesthetic management may have an influence on the postoperative course of cancer. Combined epidural-general anesthesia provides a benefit by minimizing the use of systemic opioids and volatile anesthetics. Presumably, this and a decreased response to surgical stress increase the ability of the patient's immune system to deal with cancer dissemination and micrometastasis. PMID- 20721527 TI - Living alone and deliberate self-harm: a case-control study of characteristics and risk factors. AB - BACKGROUND: An increasing proportion of the UK population live alone. Little is known about deliberate self-harm (DSH) patients who live alone. We conducted a study of the characteristics of DSH patients who live alone using data from the Oxford Monitoring System for Attempted Suicide. METHOD: Data on patients presenting to the general hospital in Oxford with an episode of DSH between 1993 and 2006 were analysed by gender and age group (15-24 years, 25-54 years and 55+ years) and according to whether or not they lived alone. RESULTS: In total, 1,163/7,865 (14.8%) patients lived alone. Having a problem with social isolation was more common in those living alone compared with those living with others, especially in those aged 55+ years. In the 25-54 years age group several variables concerning psychiatric problems were more common in those living alone, as was higher suicide intent associated with the current DSH episode and past DSH, and for females, repetition of DSH within 12 months. In patients aged 55+ years those living alone were more likely to have problems due to bereavement. Significantly more individuals living alone died from any cause. More also died by suicide, although the difference between the groups was non-significant after adjusting for age. CONCLUSIONS: These results have implications for psychiatric services assessing DSH patients who live alone, since, depending on the patient's age and living circumstances, different psychiatric and social interventions may be needed. Middle-aged DSH patients who live alone appear to be particularly vulnerable. DSH patients who live alone may not have supportive social networks and may be at increased risk of repetition of DSH and suicide. PMID- 20721528 TI - [Clinical pathway for total knee arthroplasty. I: Pathway conception and effect on functional quality of results]. AB - PURPOSE: The aim of the current study was to evaluate patient-centred and economic outcomes after introduction of a clinical pathway for total knee arthroplasty. METHODS: In a prospective trial two sequential cohorts of patients undergoing total knee arthroplasty were recruited. Baseline treatment was surveyed in cohort I and the clinical pathway was developed and evaluated in cohort II. Data from WOMAC, EQ-5D as well as partial cost data were collected. The study design was ratified by the local Independent Ethics Committee. RESULTS: There was an increase in WOMAC score of 39% for cohort I and 35% for cohort II in 3 months follow-up. Similar results were found for ED-5D with an increase of 30% for cohort I and 25% for cohort II. Partial cost rates could be lowered from 4303 EUR to 419 EUR. Despite this significant cost saving we were not able to improve the ratio of improvement in quality of life to costs. CONCLUSION: With the aid of a clinical pathway the process for implementation of a total knee arthroplasty was improved and treatment quality assured. PMID- 20721529 TI - Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury. AB - PURPOSE: Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended animation-like state induced by hydrogen sulfide (H2S) protects against hypoxia induced organ injury. We hypothesized that suspended animation is protective in VILI by reducing metabolism and thereby CO2 production, allowing for a lower respiratory rate while maintaining adequate gas exchange. Alternatively, H2S may reduce inflammation in VILI. METHODS: In mechanically ventilated rats, VILI was created by application of 25 cmH2O positive inspiratory pressure (PIP) and zero positive end-expiratory pressure (PEEP). Controls were lung-protective mechanically ventilated (13 cmH2O PIP, 5 cmH2O PEEP). H(2)S donor NaHS was infused continuously; controls received saline. In separate control groups, hypothermia was induced to reproduce the H2S-induced fall in temperature. In VILI groups, respiratory rate was adjusted to maintain normo-pH. RESULTS: NaHS dose dependently and reversibly reduced body temperature, heart rate, and exhaled amount of CO2. In VILI, NaHS reduced markers of pulmonary inflammation and improved oxygenation, an effect which was not observed after induction of deep hypothermia that paralleled the NaHS-induced fall in temperature. Both NaHS and hypothermia allowed for lower respiratory rates while maintaining gas exchange. CONCLUSIONS: NaHS reversibly induced a hypometabolic state in anesthetized rats and protected from VILI by reducing pulmonary inflammation, an effect that was in part independent of body temperature. PMID- 20721530 TI - Extracorporeal membrane oxygenation for severe influenza A (H1N1) acute respiratory distress syndrome: a prospective observational comparative study. AB - PURPOSE: To compare characteristics, clinical evolution and outcome in adult patients with influenza A (H1N1) acute respiratory distress syndrome (ARDS) treated with or without extracorporeal membrane oxygenation (ECMO). METHODS: A prospective observational study of patients treated in Marseille South Hospital from October 2009 to January 2010 for confirmed influenza A (H1N1)-related ARDS. Clinical features, pulmonary dysfunction and mortality were compared between patients treated with and without ECMO. RESULTS: Of 18 patients admitted, 6 were treated with veno-venous and 3 with veno-arterial ECMO after median (interquartile, IQR) duration of mechanical ventilation of 10 (6-96) h. Six ECMO were initiated in a referral hospital by a mobile team, a median (IQR) of 3 (2-4) h after phone contact. Before ECMO, patients had severe respiratory failure with median (IQR) PaO2 to FiO2 ratio of 52 (50-60) mmHg and PaCO2 of 85 (69-91) mmHg. Patients treated with or without ECMO had the same hospital mortality rate (56%, 5/9). Duration of ECMO therapy was 9 (4-14) days in survivors and 5 (2-25) days in non-survivors. Early improvement of PaO(2) to FiO2 ratio was greater in ECMO survivors than non-survivors after ECMO initiation [295 (151-439) versus 131 (106 144) mmHg, p < 0.05]. Haemorrhagic complications occurred in four patients under ECMO, but none required surgical treatment. CONCLUSIONS: ECMO may be an effective salvage treatment for patients with influenza A (H1N1)-related ARDS presenting rapid refractory respiratory failure, particularly when provided by a mobile team allowing early cannulation prior to transfer to a reference centre. PMID- 20721531 TI - Off-hours admission and mortality in two pediatric intensive care units without 24-h in-house senior staff attendance. AB - PURPOSE: To compare risk-adjusted mortality of children non-electively admitted during off-hours with risk-adjusted mortality of children admitted during office hours to two pediatric intensive care units (PICUs) without 24-h in-house attendance of senior staff. DESIGN: Prospective observational study, performed between January 2003 and December 2007, in two PICUs without 24-h in-house attendance of senior staff, located in tertiary referral children's hospitals in the Netherlands. METHODS: Standardized mortality rates (SMRs) of patients admitted during off-hours were compared to SMRs of patients admitted during office hours using Pediatric Index of Mortality (PIM1) and Pediatric Risk of Mortality (PRISM2) scores. Office hours were defined as week days between 8:00 a.m. and 6:00 p.m., with in-house attendance of senior staff, and off-hours as week days between 6:00 p.m. and 8:00 a.m., Saturdays, Sundays and public holidays, with one resident covering the PICU and senior staff directly available on-call. RESULTS: Of 3,212 non-elective patients admitted to the PICUs, 2,122 (66%) were admitted during off-hours. SMRs calculated according to PIM1 and PRISM2 did not show a significant difference with those of patients admitted during office hours. There was no significant effect of admission time on mortality in multivariate logistic regression with odds ratios of death in off hours of 0.95 (PIM1, 95% CI 0.71-1.27, p = 0.73) and 1.03 (PRISM2, 95% CI 0.76 1.39, p = 0.82). CONCLUSION: Off-hours admission to our PICUs without 24-h in house attendance of senior staff was not associated with higher SMRs than admission during office hours when senior staff were available in-house. PMID- 20721532 TI - Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kgamma) contributes to ventilator-induced lung injury and edema. AB - BACKGROUND: Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3 kinase gamma (PI3Kgamma) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kgamma or treated with PI3Kgamma inhibitors would be protected from ventilation-induced alveolar edema and lung injury. METHODS: Using an isolated and perfused lung model, wild-type (WT) and PI3Kgamma-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH2O and 0 cmH2O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH2O and -3 cmH2O PEEP (LOW STRESS). RESULTS: Compared with WT, PI3Kgamma-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kgamma-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kgamma wild-type lungs treated with AS605240, an inhibitor of PI3Kgamma kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs. CONCLUSIONS: Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti PI3Kgamma therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI. PMID- 20721533 TI - Postoperative red blood cell transfusion and morbid outcome in uncomplicated cardiac surgery patients. AB - OBJECTIVE: To evaluate postoperative red blood cell (RBC) transfusion and its association with postoperative cardiac events and multiorgan morbidity in uncomplicated cardiac surgery patients. METHODS: A cohort of 945 patients from the 5,436 coronary artery bypass grafting patients enrolled in the international Multicenter Study of Perioperative Ischemia (McSPI) Epidemiology II (EPI II) study was investigated. Inclusion criteria were low to moderate risk profile, postoperative hemoglobin level >= 10 g/dl, minimal postoperative blood loss, and no evidence of any morbid event on the day of surgery. RBC transfusion was assessed during the first 24 postoperative hours and cardiac as well as multiorgan outcomes from postoperative day 2 to hospital discharge. Multivariate analysis was applied to assess the effect of RBC transfusion on multiorgan outcomes. A secondary propensity score analysis was performed in 4,465 patients without early postoperative morbid outcomes. RESULTS: Transfused patients (193/945, 20.4%) were more likely to suffer cardiac events (P = 0.03), harvest site infection (P = 0.002), and composite morbidity outcome (P = 0.04). RBC transfusion was associated with cardiac events on multivariate as well as on propensity score analysis (adjusted odds ratio, 1.39; 95% confidence interval, 1.01-1.92; P = 0.04), and with harvest-site infection on multivariate analysis. Additionally, propensity score analysis suggested possible associations of RBC transfusion with increased risks for composite morbidity outcome and in-hospital mortality, renal morbidity, pneumonia, and mediastinitis. CONCLUSIONS: The data suggest a potential association between postoperative RBC transfusion and increased morbidity for cardiac surgery patients with low to moderate mortality risk profiles, adequate hemoglobin levels, and low bleeding rates. PMID- 20721534 TI - Neutrophil gelatinase-associated lipocalin clearance during veno-venous continuous renal replacement therapy in critically ill patients. PMID- 20721535 TI - Initial observations regarding free cortisol quantification logistics among critically ill children. AB - PURPOSE: Corticosteroid insufficiency may occur among critically ill patients, but the diagnosis remains controversial. Historically assessment of free cortisol (FC) by means of equilibrium dialysis (ED) has required large blood volumes and prolonged fractionation time preceding analysis. We hypothesized that temperature controlled centrifugal ultrafiltration with chemiluminescence immunoassay (CU/CI) would provide real-time FC data that highly correlated with ED/radioimmunoassay (ED/RI) or liquid chromatography/mass spectrometry (LC/MS) techniques. METHODS: We quantified and correlated baseline and corticotropin-stimulated TC and FC by means of CU/CI, ED/RI, and LC/MS among healthy adults and 37 critically ill children. RESULTS: Among critically ill children, FC was three- to fivefold higher than the healthy adults at baseline and increased another five- to eightfold following corticotropin administration. While TC increased approximately twofold following corticotropin administration, FC increased on average more than eightfold. Serum FC per CU/CI highly correlated with FC per ED/RI or LC/MS, but results were available in a fraction of the time. Children failing to increase TC by >9.0 MUg/dL (248 nM) following corticotropin demonstrated an appropriate FC increase. Nearly 50% of critically ill children exhibited FC <2.0 MUg/dL (55 nM). Neither FC nor TC concentrations correlated significantly with measures of illness severity. CONCLUSIONS: Quantification of FC utilizing CU/CI was fast (1-2 h) and results correlated highly with ED/RI or LC/MS methodologies. These data require validation with larger cohorts of healthy and critically ill children but indicate that real-time FC quantification is available to guide cortisol replacement therapy. PMID- 20721536 TI - Probiotics versus antibiotic decontamination of the digestive tract: infection and mortality. AB - PURPOSE: Selective decontamination of the digestive tract (SDD) has been shown to decrease the infection rate and mortality in intensive care units (ICUs); Lactobacillus plantarum 299/299v plus fibre (LAB) has been used for infection prevention and does not harbour the potential disadvantages of antibiotics. The objective was to assess whether LAB is not inferior to SDD in infection prevention. METHODS: Two hundred fifty-four consecutive ICU patients with expected mechanical ventilation >= 48 h and/or expected ICU stay >= 72 h were assigned to receive SDD: four times daily an oral paste (polymyxin E, gentamicin, amphotericin B), enteral solution (same antibiotics), intravenous cefotaxime (first 4 days) or LAB: two times daily L. plantarum 299/299v with rose-hip. RESULTS: The primary endpoint was infection rate. A difference <12% between both groups indicated non-inferiority of LAB. The trial was prematurely stopped after a study reporting increased mortality in critically ill pancreatitis patients receiving probiotics. No significant difference in infection rate [31% in the LAB group, 24% in the SDD group (OR 1.68, 95% CI 0.91-3.08; p = 0.10)] was found. ICU mortality was 26% and not significantly different between the LAB and SDD groups. Gram-positive cocci and Pseudomonas aeruginosa were significantly more frequently isolated from surveillance cultures in the SDD group compared to the LAB group (for sputum: 18 vs. 10% and 33 vs. 14%). Significantly more Enterobacteriaceae were found in the LAB group (23 vs. 50%). No increase in antibiotic resistance was found during and after SDD or LAB use. CONCLUSIONS: The trial could not demonstrate the non-inferiority of LAB compared with SDD in infection prevention. Results suggest no increased ICU mortality risk in the LAB group. PMID- 20721537 TI - Memantine shows promise in reducing gambling severity and cognitive inflexibility in pathological gambling: a pilot study. AB - RATIONALE: Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. Memantine, an N-methyl D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive decision making, suggesting it may help individuals with PG. OBJECTIVE: This study sought to examine the safety and efficacy of Memantine in PG. METHODS: Twenty-nine subjects (18 females) with DSM-IV PG were enrolled in a 10-week open label treatment study of memantine (dose ranging from 10 to 30 mg/day). Subjects were enrolled from January 2009 until April 2010. Change from baseline to study endpoint on the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) was the primary outcome measure. Subjects underwent pre- and post-treatment cognitive assessments using the stop-signal task (assessing response impulsivity) and the intra-dimensional/extra-dimensional (ID/ED) set shift task (assessing cognitive flexibility). RESULTS: Twenty-eight of the 29 subjects (96.6%) completed the 10-week study. PG-YBOCS scores decreased from a mean of 21.8 +/- 4.3 at baseline to 8.9 +/- 7.1 at study endpoint (p < 0.001). Hours spent gambling per week and money spent gambling both decreased significantly (p < 0.001). Subjects also demonstrated a significant improvement in ID/ED total errors (p = 0.037) at study endpoint. The mean effective dose of memantine was 23.4 +/- 8.1 mg/day. The medication was well-tolerated. Memantine treatment was associated with diminished gambling and improved cognitive flexibility. CONCLUSIONS: These findings suggest that pharmacological manipulation of the glutamate system may target both gambling and cognitive deficits in PG. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design. PMID- 20721538 TI - Chronic cannabis users show altered neurophysiological functioning on Stroop task conflict resolution. AB - RATIONALE: Chronic cannabis use has been related to deficits in cognition (particularly memory) and the normal functioning of brain structures sensitive to cannabinoids. There is increasing evidence that conflict monitoring and resolution processes (i.e. the ability to detect and respond to change) may be affected. OBJECTIVES: This study examined the ability to inhibit an automatic reading response in order to activate a more difficult naming response (i.e. conflict resolution) in a variant of the discrete trial Stroop colour-naming task. METHODS: Event-related brain potentials to neutral, congruent and incongruent trials were compared between 21 cannabis users (mean 16.4 years of near daily use) in the unintoxicated state and 19 non-using controls. RESULTS: Cannabis users showed increased errors on colour-incongruent trials (e.g. "RED" printed in blue ink) but no performance differences from controls on colour congruent (e.g. "RED" printed in red ink) or neutral trials (e.g. "*****" printed in green ink). Poorer incongruent trial performance was predicted by an earlier age of onset of regular cannabis use. Users showed altered expression of a late sustained potential related to conflict resolution, evident by opposite patterns of activity between trial types at midline and central sites, and altered relationships between neurophysiological and behavioural outcome measures not evident in the control group. CONCLUSIONS: These findings indicate that chronic use of cannabis may impair the brain's ability to respond optimally in the presence of events that require conflict resolution and hold implications for the ability to refrain from substance misuse and/or maintain substance abstention behaviours. PMID- 20721539 TI - Development of an enzymatic fiber-optic biosensor for detection of halogenated hydrocarbons. AB - An enzyme-based biosensor was developed by co-immobilization of purified enzyme haloalkane dehalogenase (EC 3.8.1.5) and a fluorescence pH indicator on the tip of an optical fiber. Haloalkane dehalogenase catalyzes hydrolytic dehalogenation of halogenated aliphatic hydrocarbons, which is accompanied by a pH change influencing the fluorescence of the indicator. The pH sensitivity of several fluorescent dyes was evaluated. The selected indicator 5(6)-carboxyfluorescein was conjugated with bovine serum albumin and its reaction was tested under different immobilization conditions. The biosensor was prepared by cross-linking of the conjugate in tandem with haloalkane dehalogenase using glutaraldehyde vapor. The biosensor, stored for 24 h in 50 mM phosphate buffer (pH 7.5) prior to measurement, was used after 15 min of equilibration, the halogenated compound was added, and the response was monitored for 30 min. Calibration of the biosensor with 1,2-dibromoethane and 3-chloro-2-(chloromethyl)-1-propene showed an excellent linear dependence, with detection limits of 0.133 and 0.014 mM, respectively. This biosensor provides a new tool for continuous in situ monitoring of halogenated environmental pollutants. PMID- 20721540 TI - Quantitative analysis of thymine with surface-enhanced Raman spectroscopy and partial least squares (PLS) regression. AB - Silver sol surface-enhanced Raman spectroscopy (SERS) was considered as a technique in the quantitative analysis of low-concentration thymine. Because of the poor stability and reproducibility of SERS signal, a polymer of polyacrylic acid sodium was selected as a stable medium to add into silver sol in order to obtain a surface-enhanced Raman spectroscopy signal. Assignments of Raman shift for solid thymine, SERS of thymine, and SERS of thymine containing stable medium were given. The comparison of Raman peaks between them showed that the addition of stable medium had a little influence on the SERS of thymine and is suitable for the quantitative analysis of low-concentration thymine. PMID- 20721541 TI - Tracking bacterial infection of macrophages using a novel red-emission pH sensor. AB - The relationship between bacteria and host phagocytic cells is key to the induction of immunity. To visualize and monitor bacterial infection, we developed a novel bacterial membrane permeable pH sensor for the noninvasive monitoring of bacterial entry into murine macrophages. The pH sensor was constructed using 2 dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF) as an electron withdrawing group and aniline as an electron-donating group. A piperazine moiety was used as the pH-sensitive group. Because of the strong electron-donating and withdrawing units conjugated in the sensing moiety M, the fluorophore emitted in the red spectral window, away from the autofluorescence regions of the bacteria. Following the engulfment of sensor-labeled bacteria by macrophages and their subsequent merger with host lysosomes, the resulting low-pH environment enhances the fluorescence intensity of the pH sensors inside the bacteria. Time-lapse analysis of the fluorescent intensity suggested significant heterogeneity of bacterial uptake among macrophages. In addition, qRT-PCR analysis of the bacterial 16 S rRNA gene expression within single macrophage cells suggested that the 16 S rRNA of the bacteria was still intact 120 min after they had been engulfed by macrophages. A toxicity assay showed that the pH sensor has no cytotoxicity towards either E. coli or murine macrophages. The sensor shows good repeatability, a long lifetime, and a fast response to pH changes, and can be used for a variety of bacteria. PMID- 20721542 TI - Improved detection following Neuro-Eye Therapy in patients with post-geniculate brain damage. AB - Damage to the optic radiation or the occipital cortex results in loss of vision in the contralateral visual field, termed partial cortical blindness or hemianopia. Previously, we have demonstrated that stimulation in the field defect using visual stimuli with optimal properties for blindsight detection can lead to increases in visual sensitivity within the blind field of a group of patients. The present study was aimed to extend the previous work by investigating the effect of positive feedback on recovery of visual sensitivity. Patients' abilities for detection of a range of spatial frequencies within their field defect were determined using a temporal two-alternative forced-choice technique, before and after a period of visual training (n = 4). Patients underwent Neuro Eye Therapy which involved detection of temporally modulated spatial grating patches at specific retinal locations within their field defect. Three patients showed improved detection ability following visual training. Based on our previous studies, we had hypothesised that should the occipital brain lesion extend anteriorly to the thalamus, little recovery would be expected. Here, we describe one such case who showed no improvements after extensive training. The present study provides further evidence that recovery (a) can be gradual and may require a large number of training sessions (b) can be accelerated using positive feedback and (c) may be less likely to take place if the occipital damage extends anteriorly to the thalamus. PMID- 20721543 TI - Magnetic resonance imaging features of the spinal cord in pediatric multiple sclerosis: a preliminary study. AB - INTRODUCTION: Spinal cord lesions in adults with multiple sclerosis (MS) are thought to contribute to disability. The magnetic resonance imaging (MRI) appearance and clinical correlates of spinal cord lesions in children with MS have not been reported. METHODS: T1-weighted pre- and post-gadolinium and T2 weighted TSE/FSE spine MR images of 36 children (age, 14.3 +/- 3.3) with relapsing-remitting MS (annualized relapse rate, 0.7; disease duration, 7.5 +/- 3.3 years) were analyzed for total lesion count, lesion location and length, intramedullary extent, and gadolinium enhancement. Clinical, demographic, laboratory, and MRI data were correlated. RESULTS: Lesions preferentially involved the cervical region, were predominantly focal, and involved only a portion of the transverse cord diameter. However, ten of 36 patients demonstrated longitudinally extensive lesions. Children with the highest clinical relapse rate also tended to have more spinal cord lesions and were more likely to accrue new lesions on serial spinal scans. CONCLUSION: These preliminary data suggest that MS lesions of the spinal cord in children are radiographically similar to that of adult-onset MS--supporting a common biology of pediatric- and adult-onset disease. However, children with relapsing-remitting MS can also develop longitudinally extensive lesions, suggesting that such lesions may be less specific for diseases such as neuromyelitis optica in pediatric patients. All patients recovered well from spinal cord attacks, and the presence of spinal cord lesions in the first few years of disease did not correlate with physical disability. Measures of spinal cord atrophy and longer periods of observation are required to determine the impact of spinal cord involvement in pediatric-onset MS. PMID- 20721544 TI - Comparing different MR angiography strategies of carotid stents in a vascular flow model: toward stent-specific recommendations in MR follow-up. AB - INTRODUCTION: Carotid artery stenting (CAS) requires adequate follow-up imaging to assess complications such as in-stent stenosis or occlusion. Options include digital subtraction angiography, CT angiography, ultrasound, and MR angiography (MRA), which may offer a non-invasive option for CAS follow-up imaging. The aim of this study was to assess contrast-enhanced MRA (CE-MRA) and three-dimensional time-of-flight MRA (3D-TOF) for visualization of the in-stent lumen in different carotid stents. METHODS: In this study, we compared CE-MRA and 3D-TOF of five different carotid stents (Guidant Acculink(r), Cordis Precise(r), Boston Wallstent(r), Abbot Vascular Xact(r), Cook Zilver(r)) in three diameters (4, 6, and 8 mm) using a vascular flow model at 3.0 T with the help of a recently developed carotid surface coil. Stent-related artifacts were objectively assessed by calculating artificial lumen narrowing (ALN) and relative in-stent signal (RIS). RESULTS: RIS and ALN depended heavily on stent type, stent diameter, and the employed MR sequence. ALN and RIS were relatively favorable for Acculink(r), Precise(r), and Zilver(r) stents with both CE-MRA and 3D-TOF. CE-MRA provided better results for the Wallstent, while the Xact stent was difficult to visualize with both MRA protocols. CONCLUSION: Both CE-MRA and 3D-TOF are viable options for depicting the in-stent lumen in carotid stents. For specific stents, 3D-TOF provided image quality comparable to CE-MRA and may thus be suitable for in vivo assessment. Development of stent-specific pathways for follow-up imaging seems advisable to address stent-related differences in image quality. PMID- 20721546 TI - Production of hexanoic acid from D-galactitol by a newly isolated Clostridium sp. BS-1. AB - In a study screening anaerobic microbes utilizing D: -galactitol as a fermentable carbon source, four bacterial strains were isolated from an enrichment culture producing H2, ethanol, butanol, acetic acid, butyric acid, and hexanoic acid. Among these isolates, strain BS-1 produced hexanoic acid as a major metabolic product of anaerobic fermentation with D: -galactitol. Strain BS-1 belonged to the genus Clostridium based on phylogenetic analysis using 16S rRNA gene sequences, and the most closely related strain was Clostridium sporosphaeroides DSM 1294(T), with 94.4% 16S rRNA gene similarity. In batch cultures, Clostridium sp. BS-1 produced 550 +/- 31 mL L-1 of H2, 0.36 +/- 0.01 g L-1 of acetic acid, 0.44 +/- 0.01 g L-1 of butyric acid, and 0.98 +/- 0.03 g L-1 of hexanoic acid in a 4-day cultivation. The production of hexanoic acid increased to 1.22 and 1.73 g L-1 with the addition of 1.5 g L-1 of sodium acetate and 100 mM 2-(N morpholino)ethanesulfonic acid (MES), respectively. Especially when 1.5 g L-1 of sodium acetate and 100 mM MES were added simultaneously, the production of hexanoic acid increased up to 2.99 g L-1. Without adding sodium acetate, 2.75 g L 1 of hexanoic acid production from D-galactitol was achieved using a coculture of Clostridium sp. BS-1 and one of the isolates, Clostridium sp. BS-7, in the presence of 100 mM MES. In addition, volatile fatty acid (VFA) production by Clostridium sp. BS-1 from D-galactitol and D: -glucose was enhanced when a more reduced culture redox potential (CRP) was applied via addition of Na2S.9H2O. PMID- 20721545 TI - Evolution of the Cinnamyl/Sinapyl Alcohol Dehydrogenase (CAD/SAD) gene family: the emergence of real lignin is associated with the origin of Bona Fide CAD. AB - Lignin plays a vital role in plant adaptation to terrestrial environments. The cinnamyl alcohol dehydrogenase (CAD) catalyzes the last step in monolignol biosynthesis and might have contributed to the lignin diversity in plants. To investigate the evolutionary history and functional differentiation of the CAD gene family, we made a comprehensive evolutionary analysis of this gene family from 52 species, including bacteria, early eukaryotes and green plants. The phylogenetic analysis, together with gene structure and function, indicates that all members of land plants, except two of moss, could be divided into three classes. Members of Class I (bona fide CAD), generally accepted as the primary genes involved in the monolignol biosynthesis, are all from vascular plants, and form a robustly supported monophyletic group with the lycophyte CADs at the basal position. This class is also conserved in the predicted three-dimensional structure and the residues constituting the substrate-binding pocket of the proteins. Given that Selaginella has real lignin, the above evidence strongly suggests that the earliest occurrence of the bona fide CAD in the lycophyte could be directly correlated with the origin of lignin. Class II comprises members more similar to the aspen sinapyl alcohol dehydrogenase gene, and includes three groups corresponding to lycophyte, gymnosperm, and angiosperm. Class III is conserved in land plants. The three classes differ in patterns of evolution and expression, implying that functional divergence has occurred among them. Our study also supports the hypothesis of convergent evolution of lignin biosynthesis between red algae and vascular plants. PMID- 20721548 TI - Perspectives to produce positively or negatively charged polyhydroxyalkanoic acids. AB - An overview is provided on the possibilities of producing positively and negatively charged poly(beta-hydroxyalkanoates), PHAs. A large variety of bacterial polyesters with functionalized terminal side chains can be produced in microbial fermentation processes by a direct polymerization of respective carbon sources, that is, carbon sources that carry functional groups in their omega position. However, charged PHAs are not accessible by a direct approach and must be synthesized via polymer-analogous reactions of functionalized bacterial polyesters. PHA polyanions are produced by converting the terminal functional groups into carboxylate groups, while PHA polycations are produced by introducing terminal amino groups. PHAs with terminal vinyl groups emerged as most suitable PHA precursors, as they can be produced in relatively high yields and the double bonds are sufficiently reactive. The oxidation of vinyl groups yields PHA polyanions. The conversion of terminal vinyl groups into epoxides with a subsequent ring-opening reaction with an amine yields PHA polycations. Other functionalized PHA that potentially lend themselves to polymer-analogous reactions are reviewed. PMID- 20721547 TI - Effects of calorie restriction on life span of microorganisms. AB - Calorie restriction (CR) in microorganisms such as budding and fission yeasts has a robust and well-documented impact on longevity. In order to efficiently utilize the limited energy during CR, these organisms shift from primarily fermentative metabolism to mitochondrial respiration. Respiration activates certain conserved longevity factors such as sirtuins and is associated with widespread physiological changes that contribute to increased survival. However, the importance of respiration during CR-mediated longevity has remained controversial. The emergence of several novel metabolically distinct microbial models for longevity has enabled CR to be studied from new perspectives. The majority of CR and life span studies have been conducted in the primarily fermentative Crabtree-positive yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, but studies in primarily respiratory Crabtree-negative yeast and obligate aerobes can offer complementary insight into the more complex mammalian response to CR. Not only are microorganisms helping characterize a conserved cellular mechanism for CR-mediated longevity, but they can also directly impact mammalian metabolism as part of the natural gut flora. Here, we discuss the contributions of microorganisms to our knowledge of CR and longevity at the level of both the cell and the organism. PMID- 20721550 TI - The effect of lipid content on the elemental composition and energy capacity of yeast biomass. AB - Oleaginous yeasts (18 strains) were grown in ethanol media under various cultivation conditions (33 biomass samples). It was found that lipid and lipid free fractions of dry biomass have elemental composition and biomass reductivity very close to values which can be considered as biological constants. The energy content of dry biomass strongly depended on the total lipid content. When the lipid content was 64%, the energy value of dry biomass reached 73% of diesel oil; therefore, oleaginous microorganisms can be a promising source of biodiesel fuel. The approach used in this work makes it possible to determine the energy value of biomass by its elemental composition without application of laborious and expensive calorimetric measurements of combustion heats. PMID- 20721549 TI - Microbial biodegradation of a novel fluorotelomer alcohol, 1H,1H,2H,2H,8H,8H perfluorododecanol, yields short fluorinated acids. AB - The accumulation of perfluorooctanoic acid (PFOA) has been detected in wildlife, soil, and water. Further, 8:2 fluorotelomer alcohol (8:2 FTOH) is used for the industrial synthesis of other fluorotelomer compounds, surfactants, and polymeric materials; however, it was recently found to be a potential source of PFOA contamination in the environment. 1H,1H,2H,2H,8H,8H-perfluorododecanol (degradable telomer fluoroalcohol (DTFA)), which is a newly developed fluorotelomer, contains the -CH2- group in the fluorinated carbon backbone, making it potentially degradable through biological reactions. In this study, we investigated the biodegradation of DTFA in a mixed bacterial culture obtained from activated sludge. Optimized quantitative liquid chromatography-mass spectrometry analysis of the predicted metabolites generated in the culture revealed accumulations of the transformation products from DTFA to 2H,2H,8H,8H PFDoA and 2H,8H,8H-2-PFUDoA via multiple processes. Furthermore, the production of short fluorinated compounds, perfluorobutanoic acid, perfluoropentanoic acid, and perfluoropentanedioic acid, which are believed to have lower accumulation potential and toxicity toward organisms than PFOA, was determined. PMID- 20721551 TI - Anatomic evaluation of the xiphoid process with 64-row multidetector computed tomography. AB - OBJECTIVE: The aim of this study was to evaluate the interindividual variations of the xiphoid process in a wide adult group using 64-row multidetector computed tomography (MDCT). MATERIALS AND METHODS: Included in the study were 500 consecutive patients who underwent coronary computed tomography angiography. Multiplanar reconstruction (MPR), maximum intensity projection (MIP) images on coronal and sagittal planes, and three-dimensional volume rendering (VR) reconstruction images were obtained and used for the evaluation of the anatomic features of the xiphoid process. RESULTS: The xiphoid process was present in all patients. The xiphoid process was deviated ventrally in 327 patients (65.4%). In 11 of these 327 patients (2.2%), ventral curving at the end of the xiphoid process resembled a hook. The xiphoid process was aligned in the same axis as the sternal corpus in 166 patients (33.2%). The tip of the xiphoid process was curved dorsally like a hook in three patients (0.6%). In four patients (0.8%), the xiphoid process exhibited a reverse S shape. Xiphoidal endings were single in 313 (62.6%) patients, double in 164 (32.8%), or triple in 23 (4.6%). Ossification of the cartilaginous xiphoid process was fully completed in 254 patients (50.8 %). In total, 171 patients (34.2%) had only one xiphoidal foramen and 45 patients (9%) had two or more foramina. Sternoxiphoidal fusion was present in 214 of the patients (42.8%). CONCLUSIONS: Significant interindividual variations were detected in the xiphoid process. Excellent anatomic evaluation capacity of MDCT facilitates the detection of variations of the xiphoid process as well as the whole ribcage. PMID- 20721552 TI - In vivo behaviour of low-temperature calcium-deficient hydroxyapatite: comparison with deproteinised bovine bone. AB - This study aims to evaluate in detail the biological osteoconductive properties of the low-temperature synthetic porous calcium-deficient hydroxyapatite and to compare it with the biological apatite. Bone reactions to granules of similar sizes of the low-temperature hydroxyapatite and commercially available non sintered deproteinized bovine bone were compared. Two different temperatures were used to fabricate two batches of newly developed porous hydroxyapatite with different carbonate groups content and specific surface area. The histological analysis of specimens with histomorphometry was performed at different time after in vivo implantation. Based on histological analysis, the level of bone formation in the spaces between the implanted granules and through the interconnected pores of all implanted materials within a cortical region (bone area ingrowth 72-85 %) was several-fold higher than within a cancellous bone site (bone area ingrowth 16 28 %) at three and six months after implantation. Within the cancellous bone site, bone coverage of the implanted material at six months was significantly higher in hydroxyapatite material fabricated using low-temperature synthesis and subsequent processing at 150 degrees C than in hydroxyapatite scaffold developed using low-temperature synthesis with subsequent processing at 700 degrees C or deproteinized bovine bone. According to our study, the bioactive properties of the low-temperature calcium-deficient hydroxyapatite are comparable with the biological apatite. The favourable influence of a high specific surface area of a low-temperature calcium-deficient hydroxyapatite on in vivo bone formation was emphasized. PMID- 20721553 TI - Denervation point for neuromuscular blockade on lateral pectoral nerves: a cadaver study. AB - PURPOSE: The objective of our study was to clarify the topography of the medial and lateral pectoral nerves (LPNs) and the vascularity in the infraclavicular fossa and to propose an ideal injection point for neuromuscular blockade of the pectoralis major (PM) muscle. METHODS: The pectoral muscles and their nerves were examined bilaterally on 10 formalin-fixed cadavers. The PM muscle was dissected from its clavicular origin and sternocostal attachments. It was reflected superolaterally to expose the pectoralis minor muscle and neurovascular bundle at the infraclavicular fossa. We took the measurements to identify a landmark point and reach the neurovascular bundle from an overlying point on the skin. RESULTS: The LPN was closely related to the thoracoacromial artery and veins on the lower surface of the PM muscle and was visible under the muscle fascia as a neurovascular bundle. The point where the pM line (perpendicular to midsternal line beginning from the inferior border of the jugular notch) transects the neurovascular bundle was sufficiently close to the point at which the neurovascular bundle enters the PM muscle. Hence, this point was determined as the denervation point in all cadaveric dissections. This denervation point is 2.81 +/- 0.33 cm distant vertically from the 1/3 medial part of the clavicle and 8.12 +/- 1.09 cm distant horizontally from the midsternal line. CONCLUSIONS: We have identified an injection point which may be and suitable and safe location to administer neuromuscular motor blockade of the pectoralis muscles with a percutaneous local anesthetic agent in some clinical pathologies requiring elective denervation. PMID- 20721554 TI - Dysmetabolic hyperferritinemia is associated with normal transferrin saturation, mild hepatic iron overload, and elevated hepcidin. AB - Hyperferritinemia is common in individuals with the metabolic syndrome (dysmetabolic hyperferritinemia), but its pathophysiology and the degree to which it reflects tissue iron overload remains unclear. We conducted a cross-sectional study evaluating ten cases with dysmetabolic hyperferritinemia for liver iron overload and compared their serum iron indices and urine hepcidin levels to healthy controls. Seven out of ten cases had mild hepatic iron overload by magnetic resonance imaging (MRI) (median, 75 micromol/g dry weight). Cases had higher serum ferritin than controls (median, 672 microg/L vs. 105 microg/L, p < 0.001), but the median transferrin saturation was not significantly different (38% vs. 36%, p = 0.5). Urinary hepcidin was elevated in dysmetabolic hyperferritinemia (median; 1,584 g/mg of creatinine vs. 799 ng/mg of creatinine, p = 0.05). Dysmetabolic hyperferritinemia is characterized by hyperferritinemia with normal transferrin saturation, elevated hepcidin levels, and mild liver iron overload in a subset of patients. PMID- 20721555 TI - Clinical efficacy of arsenic trioxide in a patient with acute promyelocytic leukemia with recurrent central nervous system involvement. PMID- 20721557 TI - Plasmodium vivax malaria-associated hemophagocytic lymphohistiocytosis in a young man with pancytopenia and fever. PMID- 20721556 TI - Concurrent p16 methylation pattern as an adverse prognostic factor in multiple myeloma: a methylation-specific polymerase chain reaction study using two different primer sets. AB - Disruption of cell cycle control genes, including p16, is known to contribute to the cancerogenesis of multiple myeloma (MM). We investigated the methylation status of p16 and its association with common cytogenetic changes, clinicolaboratory findings, and survival in MM. Methylation-specific polymerase chain reaction was performed in 99 newly diagnosed MM patients using two different sets of primers (p16M1 and p16M2). Four patterns of p16 promoter methylation were observed: (1) concurrent methylation of p16M1 and p16M2 (P1P2), 27.3%; (2) methylation of p16M1 alone (P1N2), 7.1%; (3) methylation of p16M2 alone (N1P2), 26.3%; and (4) no methylation (N1N2), 39.4%. Patients with p16P1P1 showed shorter survivals than those with the other methylation patterns (P1N2, N1P2, or N1N2; median survival, 12 vs. 43 months; P < 0.001), regardless of the treatment protocol. In a multivariate analysis, p16P1P2 was an independent prognostic factor of adverse outcome in MM. According to International Staging System (ISS), the study population could be divided into 21.2% (20/94) for stage I, 22.3% (21/94) for stage II, and 56.4% (53/94) for stage III (P = 0.003). ISS can divide patients into prognostic groups. Of note, in patients older than 60 years, ISS was not reflective of disease stage (P = 0.114). If p16P1P2 sets up as stage 4 of ISS, modified ISS could be a more reliable staging system irrespective of age in Korean MM patients (P = 0.003 and P = 0.004 in patients younger than 60 years and in patients older than 60 years, respectively). Our study suggests the potential use of p16 methylation status in predicting the outcome of MM patients and the applicability of demethylating agents in MM. PMID- 20721558 TI - [The current TNM system for gastrointestinal tumors part I]. AB - The present review describes the changes in the new 7th edition of the TNM system for tumors of the upper gastrointestinal tract. The description of esophageal tumor localization has been simplified and this new classification now includes tumors of the esophagogastric junction as well as the proximal 5 cm of the stomach. The regional lymph nodes of the esophagus now include celiac lymph nodes, a change which is important for therapeutic decision making. The categories T1 and T4 have been further subclassified. The N categorization now considers not only the presence of metastases but also the number of lymph node metastases within three categories. The T and N categories of stomach tumours (as well as the stage groups) have been modified to ensure a significantly better correlation to the prognosis. The number of lymph nodes has been adapted to 16 to classify pN0. Only slight modifications have been introduced in tumors of the small bowel. PMID- 20721559 TI - Molecular evaluation of 458 patients referred with a clinical diagnosis of familial Mediterranean fever in Scandinavia. PMID- 20721560 TI - Synovial fluid adenosine deaminase and high-sensitivity C-reactive protein activity in differentiating monoarthritis. AB - It is proposed that synovial fluid biomarkers may help in differentiating the type of arthritis. The aim of study is to determine whether synovial fluid adenosine deaminase (ADA) and high-sensitivity C-reactive protein (hs-CRP) can be useful in this regard. A total of 75 patients with knee monoarthritis that were admitted in Shahid Beheshti Kashan hospital in 2009 included in the study. There were 18 rheumatoid arthritis, 13 crystal-induced arthritis, 3 septic arthritis and 41 osteoarthritis. Inflammatory arthritis was diagnosed if more than 2,000 white blood cells existed in per milliliter of the synovial fluid. There was statistically significant difference in mean synovial fluid ADA and hs-CRP concentration between inflammatory (26.06 +/- 8.96 IU/l, 12.72 +/- 9.25 MUg/ml) and non-inflammatory arthritis (14.8 +/- 2.79 IU/l, 2.36 +/- 2.7 MUg/ml) (P values = 0.00, 0.00). There was statistically significant difference in mean synovial fluid ADA and hs-CRP concentration when rheumatoid arthritis (23.77 +/- 4.58 IU/l, 10.47 +/- 6.99 MUg/ml), crystal-induced arthritis (22.76 +/- 3.65 IU/l, 14.37 +/- 11.58 MUg/ml) and septic arthritis (49.66 +/- 8.96 IU/l, 18.25 +/ 5.37 MUg/ml) were compared with osteoarthritis (14.58 +/- 2.63 IU/l, 1.91 +/- 1.31 MUg/ml) (All P values = 0.00). There was statistically significant difference in mean synovial fluid ADA concentration between septic and rheumatoid arthritis and also between septic arthritis and crystal-induced arthritis (P values = 0.00, 0.00). This study showed that synovial fluid ADA and hs-CRP can properly differentiate inflammatory from non-inflammatory arthritis. Synovial fluid ADA is a useful marker in differentiating septic from rheumatoid and crystal-induced arthritis. PMID- 20721561 TI - Leucocyte profiles and corticosterone in chicks of southern rockhopper penguins. AB - The immune system is essential for health and survival of vertebrates, yet still little is known about the ontogeny of the immune system in wild birds. The southern rockhopper penguin (Eudyptes chrysocome chrysocome) is a semi-altricial seabird with a long developmental period and reversed hatching asynchrony, favouring the survival of B-chicks. We compared leucocyte counts and baseline corticosterone levels of southern rockhopper penguin chicks under different preconditions such as sex and origin from an A- or B-egg from 4 to 51 days of age. We conducted an experiment to compare leucocyte profiles and baseline corticosterone levels in A- and B-chicks in single-egg clutches as well as in B chicks from normal two egg-clutches (one A- and one B-egg). None of these treatments influenced leucocyte counts or corticosterone levels, indicating a similar investment in the immune system. Our main finding was an increase of leucocytes/10,000 erythrocytes with age, which was mainly caused by an increase in lymphocyte numbers. This suggests differential investment into acquired immunity at this stage of development. As the granulocyte/lymphocyte (G/L) ratio did not change with age or body condition, G/L ratios seem not to reflect stress caused by poor provisioning of penguin chicks. This was also reinforced by the decrease of plasma corticosterone levels with age. Body condition was negatively correlated with monocyte numbers, suggesting a poorer health status of penguin chicks in poorer body condition. Yet, there was no link between body condition and other leucocyte parameters, indicating that chicks in a good body condition did not additionally invest into their immune system. PMID- 20721562 TI - Isolated hypoganglionosis: systematic review of a rare intestinal innervation defect. AB - PURPOSE: Isolated hypoganglionosis (IH) is rare and resembles Hirschsprung's disease. The diagnosis by suction biopsy is difficult. A full-thickness biopsy is essential. Histological features of IH include sparse, small myenteric ganglia, low acetylcholinesterase activity in the lamina propria, and hypertrophy of muscularis mucosae and circular muscle. This review investigates the epidemiology, symptoms, diagnosis, and outcome of patients with IH. METHODS: A systematic review, using the keywords "isolated hypoganglionosis" and "intestinal hypoganglionosis" was performed. Publications were reviewed for epidemiology, histological methods, operative procedures, follow-up, and patient's outcome. RESULTS: Eleven publications from 1978 to 2009 reported 92 patients with IH (69 males and 23 females, age 4.85 years), presenting with constipation or enterocolitis. Diagnosis of IH was made by full-thickness biopsy and AChE staining in 91% of patients with additional staining in 82%; 54 patients had bowel resection and pull-through procedures; 11 patients had ileostomy or colostomy, and 2 had sphincter myectomy. Complications reported were enterocolitis, constipation, and residual disease. Seven patients (8%) died due to enterocolitis or short-bowel complications. CONCLUSION: This review confirms that diagnosis of IH is only possible by histochemical examination of a full thickness biopsy. Despite advanced age at diagnosis of IH, epidemiological and clinical data are similar to aganglionosis. PMID- 20721563 TI - Long-term results of stapled transanal rectal resection (STARR) for obstructive defecation syndrome. AB - BACKGROUND: Rectocele and distal rectal intussusception are organic causes of obstructive defecation syndrome and can be corrected surgically once conservative treatment remedies have been exhausted. Stapled transanal rectal resection (STARR) procedure was introduced as a new treatment approach. This study presents the first long-term results of this procedure. PATIENTS AND PROCEDURES: A STARR procedure was performed in 14 patients (two male, 12 female, age 53 +/- 12 years) between January 2003 and August 2005. The indication for surgery was a severe, conservatively treated stool evacuation disorder secondary to symptomatic rectocele and/or distal intussusception. RESULTS: The mean follow-up period was 68 +/- 10 (49-83) months. The defecation score (0-20 points) decreased from a preoperative 13.4 +/- 3.4 to 3.2 +/- 2.0 after 3 months and increased slightly to 4.7 +/- 3.4 by the time of the final examination. In 12 patients (85.7%), the obstructive defecation syndrome was significantly improved. These positive results were also maintained in the long-term. Five patients (38.5%) reported a slight worsening of continence in terms of urge incontinence. The most affected patients were those with preoperative normal continence. Procedure-related anal reoperations were required in two patients (14.3%). CONCLUSION: Even in long term, transanal rectal wall resection seems to be an effective therapy for obstructive defecation syndrome. However, it is associated with a substantial number of reoperations and in some patients with persistent urge incontinence. PMID- 20721564 TI - Breast milk tocopherol content during the first six months in exclusively breastfeeding Greek women. AB - PURPOSE: To determine tocopherol and fat content of Greek mother's milk during the first 6 months of exclusive breastfeeding and correlate with maternal diet characteristics. METHODS: Milk samples and dietary records were obtained by mothers at 1st (n = 64), 3rd (n = 39) and 6th (n = 23) month postpartum. Milk tocopherol content was determined by high-performance liquid chromatography method (HPLC) and fat content by the crematocrit method. RESULTS: Milk's alpha tocopherol content at 1st, 3rd and 6th month postpartum was 8.3 +/- 3.4, 8.1 +/- 4.2 and 8.5 +/- 4.7 MUmol/L, while total tocopherol values were 8.9 +/- 3.6, 8.7 +/- 4.6 and 9.5 +/- 5.6 MUmol/L, respectively, and were closely related to milk's fat content. No significant differences were observed for alpha- and total tocopherol content in breast milk among the three time points. Maternal vitamin E dietary intake was 7.2 +/- 3.7, 6.8 +/- 3.5 and 10.9 +/- 5.2 mg/day at 1st, 3rd and 6th month postpartum, respectively. Though vitamin E dietary intake was less than the recommended one, vitamin E content in breast milk was considered sufficient for infant needs. Milk tocopherol content was found to be associated only with mothers' total fat and saturated fat dietary intake. CONCLUSION: This study is among few in literature to determine tocopherol content of breast milk in European women and detect dietary factors that may influence its values. The only maternal dietary characteristic to affect breast milk tocopherol content was mothers' total fat intake, while tocopherol intake seems to have no effect. PMID- 20721565 TI - Cell type specific sequestration of choline acetyltransferase and tyrosine hydroxylase within Lewy bodies. AB - Lewy bodies (LBs), the pathological hallmark of Lewy body disease (LBD), contain alpha-synuclein, as well as other proteins. In this study, we examined the relationship of alpha-synuclein to two rate-limiting enzymes in neurotransmitter synthesis, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT). Double labeling immunohistochemistry for alpha-synuclein and TH revealed TH immunoreactivity within LBs in catecholaminergic neurons in the substantia nigra and locus coeruleus, but not within LBs in cholinergic neurons in the pedunculopontine nucleus and nucleus basalis of Meynert. In contrast, ChAT immunoreactivity within LBs was detected in cholinergic, but not within LBs in catecholaminergic neurons. The amygdala was devoid of TH and ChAT positive LBs, although a few Lewy neurites contained ChAT immunoreactivity. Further analysis revealed two distinct patterns of neurotransmitter immunoreactivity within LBs. One pattern had diffuse co-localization of TH or ChAT with alpha-synuclein as in cortical-type LBs, while the other had intense TH or ChAT immunoreactivity in the LB core surrounded by a peripheral rim of alpha-synuclein as in brainstem-type LBs. Levels of both TH and ChAT were higher in brainstem-type LBs than in the cytoplasm of the same neuron or in neurons from the same case devoid of LBs. Given the fact that LB-containing neurons have decreases in cytoplasmic TH and ChAT immunoreactivity, these results suggest LBs may disrupt cholinergic and catecholaminergic neurotransmitter production by sequestration of the rate limiting enzymes for acetylcholine and catecholamine synthesis. PMID- 20721566 TI - New neuropathological findings in Unverricht-Lundborg disease: neuronal intranuclear and cytoplasmic inclusions. AB - Unverricht-Lundborg disease (EPM1A), also known as Baltic myoclonus, is the most common form of progressive myoclonic epilepsy. It is inherited as an autosomal recessive trait, due to mutations in the Cystatin-B gene promoter region. Although there is much work on rodent models of this disease, there is very little published neuropathology in patients with EPM1A. Here, we present the neuropathology of a patient with genetically confirmed EPM1A, who died at the age of 76. There was atrophy and gliosis affecting predominantly the cerebellum, frontotemporal cortex, hippocampus and thalamus. We have identified neuronal cytoplasmic inclusions containing the lysosomal proteins, Cathepsin-B and CD68. These inclusions also showed immunopositivity to both TDP-43 and FUS, in some cases associated with an absence of normal neuronal nuclear TDP-43 staining. There were also occasional ubiquitinylated neuronal intranuclear inclusions, some of which were FUS immunopositive. This finding is consistent with neurodegeneration in EPM1A as at least a partial consequence of lysosomal damage to neurons, which have reduced Cystatin-B-related neuroprotection. It also reveals a genetically defined neurodegenerative disease with both FUS and TDP-43 related pathology. PMID- 20721568 TI - High medium-term survivorship and durability of Zweymuller-Plus total hip arthroplasty. AB - BACKGROUND AND PURPOSE: The Zweymuller-Plus system (SL-Plus stem, Bicon-Plus threaded cup) for primary total hip arthroplasty (THA) was introduced in 1993, as a successor of the Alloclassic THA with a few modifications in the conical stem shape and a new biconical threaded cup with a spherical shape. The medium-term performance of this system is not well established. To better understand the potential impact these design changes have had on (1) survivorship, (2) implant stability and (3) periprosthetic osteolysis, we studied patients who underwent THA using the SL-Plus stem and Bicon-Plus. METHODS: We retrospectively reviewed the cases of 148 patients (153 hips) who underwent Zweymuller-Plus primary THA after an average of 11 years. RESULTS: With revision for aseptic failure of biological fixation as the endpoint, survivorship was 98% for the stem and 100% for the cup. Focal osteolysis was observed in 6.6% of cups and 29% of stems. Four hips (2.6%) were revised because of aseptic failure of the biologic fixation and three hips (1.95%) for deep infection. As much as 146 stems and 149 cups were evaluated to be stable. CONCLUSION: Zweymuller-Plus THA resulted in high survivorship and durability at 11 years, although the rate of osteolysis around the stem indicated polyethylene wear. PMID- 20721567 TI - Surgical management of sternoclavicular septic arthritis. AB - INTRODUCTION: Septic arthritis of the sternoclavicular joint (SCJ) is a rare condition and has many diagnostic and therapeutic standards. The purpose of this study was to evaluate our experience with surgical and diagnostic management to provide a surgical pathway to help surgeons treat this disease. METHOD: We retrospectively reviewed five patients who were managed surgically between 1999 and 2007. All patients underwent structured diagnostic and treatment protocols. The functional outcome was evaluated using the Constant Score. PATIENTS: The patients had the following underlying medical conditions: laryngeal cancer, port explantation linked to a rectum carcinoma, spondylodiscitis, and brain stem infarct with reduced general condition; one patient had no underlying medical problems. Three patients underwent a simple incision, debridement and drainage, and two patients underwent an extended intervention with partial resection of the sternoclavicular joint. The mean duration of follow-up was 29 months (range 24-36 months). All patients had well-healed wounds without signs of reinfection. The Constant Score for the functional outcome at the time of the last follow-up was 76 points (range 67-93 points). All patients recovered completely from SCJ disease. CONCLUSION: Our recommendations for the management of septic arthritis of the sternoclavicular joint include standard treatment steps and assessments. The early stages of infection can be managed by simple incision, debridement and drainage. In advanced stages of infection, a more radical intervention is preferable. PMID- 20721569 TI - A simple and effective implant for displaced fractures of the greater tuberosity: the "Bamberg" plate. AB - Displaced fractures of the greater tuberosity are common findings in trauma surgical patients. Nevertheless, osteosynthesis of these fractures impairs the risk of secondary dislocation or secondary impingement due to the implant (e.g., 4.5 mm cancellous screws with spiked washers). We present an easy and simple technique/implant to perform an osteosynthesis of multiple-fractured greater tuberosity fractures. We use a self-adjusted calcaneus titanium plate (Litos) which is cut into a 6 or more holed small plate. In ten patients we had excellent postoperative outcomes with no complications and no secondary loss of reduction. The surgical technique is easy and efficient. PMID- 20721570 TI - Tackling the learning curve: comparison between the anterior, minimally invasive (Micro-hip(r)) and the lateral, transgluteal (Bauer) approach for primary total hip replacement. AB - BACKGROUND AND PURPOSE: There is still conflicting evidence about the true benefit of minimally invasive (MI) techniques in total hip replacement (THR). The aim of this prospective study was to evaluate the safeness of a MI approach during the learning curve of a single surgeon. Second, clinical and radiographic results among the MI THR group were compared with the results using a standard transgluteal (Bauer) approach. METHODS: 86 primary unilateral total hip arthroplasties (THAs) through a MI, anterior (Micro-hip((r))) approach were performed by a single senior surgeon (ES), representing a consecutive series of patients after beginning with the MI technique. Cases were compared to a matched cohort of patients who were treated with a standard transgluteal (Bauer) approach. Operation time, incision length, perioperative blood loss, haemoglobin level and blood transfusions were monitored. Complications were documented and followed up 1 year postoperatively. The Harris Hip Score (HHS), range of motion, use of analgetics, the Trendelenburg sign, sensibility of the lateral femoral cutaneous nerve and the acetabular/femoral component placement as well as potential heterotopic ossifications were analysed in both the groups after 12 months postoperatively. RESULTS: 74 MI THR patients and 60 standard THR patients were available for the one year follow-up. Operative time was significantly longer in the MI group, reduction in the haemoglobin level during the first 24 h was significant and the length of skin incision was significantly shorter. No significant differences were found for HHS, range of motion, use of analgetics, the Trendelenburg sign, and the acetabular/femoral component placement, heterotopic ossifications and intra- and postoperative complications. Sensibility of the lateral femoral cutaneous nerve was affected in three patients in the MI group. Radiographic evaluation revealed no component migration, implant subsidence or radiolucency signs in both the groups. DISCUSSION: Consistent with recent meta-analysis we found reduced blood loss, similar clinical/radiographic outcome and similar complication rates compared to standard THA. Our study shows, that MI THR is a safe procedure during the learning curve of an experienced surgeon. PMID- 20721571 TI - Fasciocutaneous free flap reconstruction for squamous cell carcinoma of the hypopharynx. AB - The purpose of this study was to examine functional and surgical outcomes after fasciocutaneous free flap reconstruction of the hypopharynx. A retrospective review of the records of 48 consecutive patients that underwent hypopharyngectomy and reconstruction using fasciocutaneous free flaps between 1996 and 2009 was performed. Flap donor sites included the radial forearm (n = 42), anterolateral thigh (n = 5), and lateral thigh (n = 1). There was no perioperative mortality, and the free flap survival rate was 95.8%. Five (10.4%) patients developed a postoperative pharyngocutaneous fistula. In three (6.3%) patients a stricture developed during the postoperative period. Forty-four (92%) patients were decannulated and maintained their voice. Forty-four (92%) patients were able to take oral nutrition, although 4 (8%) needed additional PEG-tube feeding. Five year overall and disease-specific survival rates were 56 and 61%, respectively. Functional reconstruction of extensive laryngohypopharyngeal defects can be achieved using fasciocutaneous free flaps with favorable functional and surgical results. PMID- 20721572 TI - Salvage surgery after locoregional failure in head and neck carcinoma patients treated with chemoradiotherapy. AB - With the increasing use of concomitant chemoradiotherapy (CCRT) in the treatment of advanced head and neck carcinoma, surgery has lost ground as the first therapy and is reserved as a salvage treatment in cases of locoregional failure. The objective of our study was to review our experience in patients who had a local or regional recurrence after treatment with CCRT. Thirty-two patients underwent salvage surgery after CCRT: 24 were treated with a local or locoregional resection and 8 patients with a neck dissection only. In patients who had surgery involving the primary location of the tumor, some kind of reconstruction was required in 83% of cases. One or more postoperative complications occurred in nine patients. The median hospital stay was 18.5 days. There was a significant difference in hospital stay in relation to the appearance of surgical complications. Five-year adjusted survival after salvage surgery was 34.2% (CI 95% 13.2-55.2%). Adjusted survival was related to the status of the resection margins and appearance of neck nodes with extracapsular spread in the neck dissection. In conclusion, salvage surgery after CCRT involves extensive resections, requiring reconstruction techniques with regional or microanastomosed free flaps in most cases, achieving acceptable outcomes. PMID- 20721573 TI - Relationship between tobacco consumption and health-related quality of life in adults living in a large metropolitan area. AB - The aim of this study was to analyze the relationship between health-related quality of life (HRQOL) and tobacco consumption in adult individuals (over the age of 15). The study was based on individual data from the City of Madrid Health Survey (ESCM05). Subjects were divided into three groups according to tobacco consumption: smokers, nonsmokers, and ex-smokers. HRQOL was measured using the COOP/WONCA quality-of-life vignettes. A multivariate adjustment with multinomial logistic regression was made, including the following as covariables: sociodemographic characteristics, comorbidities, drug use, and lifestyles. A total of 7341 individuals were interviewed (53.7% women), with an average age of 46.7 (SD = 19.02) years. The percentage of smokers was 27%, that of ex-smokers was 16.5%, and that of nonsmokers was 56.5%. There were no significant differences between smokers, ex-smokers, and nonsmokers in the raw scores obtained as totals from the COOP/WONCA questionnaire. Multivariate analysis revealed that smokers consume more antidepressant drugs (OR = 1.54, 95% CI = 1.09 2.16) and tranquilizers (OR = 1.91, 95% CI = 1.45-2.51), drink more alcohol (OR = 2.55, 95% CI = 2.11-3.08), get less physical exercise (OR = 1.33, 95% CI = 1.11 1.60), and have a lower quality of life (OR = 1.02, 95% CI = 1.00-1.04) than nonsmokers. Following adjustment for a significant number of covariables, sociodemographic as well as health-related, smokers consume more antidepressant drugs and tranquilizers, drink more alcohol, get less physical exercise, and demonstrate a lower HRQOL than nonsmokers. PMID- 20721574 TI - The clinical spectrum of late-onset Alexander disease: a systematic literature review. AB - Following the discovery of glial fibrillary acidic protein (GFAP) mutations as the causative factor of Alexander disease (AxD), new case reports have recently increased, prompting a more detailed comprehension of the clinical features of the three disease subtypes (infantile, juvenile and adult). While the clinical pattern of the infantile form has been substantially confirmed, the late-onset subtypes (i.e., juvenile and adult), once considered rare manifestations of AxD, have displayed a wider clinical spectrum. Our aim was to evaluate the clinical phenotype of the adult and juvenile forms by reviewing the previously reported cases. Data were collected from previously published reports on 112 subjects affected by neuropathologically or genetically proven adult and juvenile Alexander disease. Although the late-onset forms of AxD show a wide clinical variability, a common pattern emerges from comparing previously reported cases, characterized by pseudo-bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Late-onset AxD cases can no longer be considered as rare manifestations of the disease. The clinical pattern usually reflects the topographic localization of the lesions, with adult cases displaying a predominant infratentorial localization of the lesions. Juvenile cases show clinical and radiological features which are intermediate between adult and infantile forms. PMID- 20721576 TI - Serial testing with the interferon-gamma release assay in Portuguese healthcare workers. AB - OBJECTIVES: Evidence for the utility of the new Mycobacterium tuberculosis (MTB) specific IFN-gamma release assays in diagnosing latent tuberculosis infection (LTBI) is growing. However, data concerning conversion and reversion rates in serial testing of healthcare workers (HCWs) with an interferon-gamma release assay are sparse. METHODS: Between February 2007 and September 2009, 670 HCWs in the University Hospital of Porto, Portugal were tested at least twice with QuantiFERON-TB(r) Gold In-Tube (QFT) for LTBI. The tuberculin skin test (TST) was performed simultaneously. QFT was considered positive if INF-gamma >=0.35 IU/mL. TST conversion was defined as an increase >=10 or >=6 mm compared to a baseline TST <10 mm. RESULTS: The second QFT was positive in 4.8% of the 376 HCWs with an INF-gamma concentration at baseline below 0.1 IU/mL but in 48.8% of the 41 HCWs with an INF-gamma concentration of 0.2 to <0.35 IU/mL. Out of 74 HCWs with a baseline INF-gamma concentration >=3.0 IU/mL, 4 (5.4%) reversed while 27 out of 55 HCWs (49%) with a baseline INF-gamma concentration >=0.35 to <0.7 IU/mL reversed to a negative QFT. Those 61 HCWs with TST conversion (increase >=10 mm) were most often (78.7%) negative in both consecutive QFTs. CONCLUSION: Our data suggests the use of an uncertainty zone between 0.2 and 0.7 IU/mL in serial testing with QFT. As long as the knowledge regarding disease progression in QFT positive persons is limited, persons pertaining to this zone should be retested before being offered preventive chemotherapy. PMID- 20721577 TI - Hepatic progenitor cells in chronic hepatitis C: a phenomenon of older age and advanced liver disease. AB - Hepatic progenitor cells (HPC) appear in a variety of liver diseases. Their occurrence in chronic hepatitis C (CHC) remains unclear, and triggering factors have to be elucidated. The presence of HPC in CHC was examined in relation to histological and virological parameters and patient age. Fifty liver biopsies of HCV-infected patients were examined. The presence of HPC was evaluated by immunohistochemical expression of keratin 7 (K7). Double immunostaining with K7 and cell proliferation marker Ki-67 was undertaken. Ductular reaction at the limiting plate, mean number of isolated progenitor cells (IPC) and isolated ductular structures (IDS) were quantified. The predominant distribution pattern of IPC and IDS and the presence of K7(+) hepatocytes were registered. Relationship between ductular reaction, IPC, IDS, presence of K7(+) hepatocytes, and patient age, hepatitis grade and stage, HCV RNA, and HCV genotype was examined. Prominent ductular reaction and increased numbers of IPC and IDS correlated significantly with older age and severe fibrosis/cirrhosis. The above HPC subtypes were not proliferating. Periportal/periseptal distribution pattern of IPC and IDS and presence of K7(+) hepatocytes were significantly more frequent in advanced hepatitis stages and in patients older than 40 years. Intraparenchymal distribution pattern correlated with younger age, lobular activity, and early fibrosis stage. K7(+) hepatocytes were encountered almost exclusively in the periportal pattern and in the presence of interface hepatitis and were more frequent among HCV genotype-1 patients. HPC activation in CHC is a common but diverse phenomenon closely related to patient age and hepatitis stage. PMID- 20721578 TI - Modulation of immunity in mice with latent toxoplasmosis--the experimental support for the immunosuppression hypothesis of Toxoplasma-induced changes in reproduction of mice and humans. AB - The immunosuppression hypothesis suggests that the increased sex ratio in mice and women with latent toxoplasmosis, retarded embryonic growth in the early phases of pregnancy, prolonged pregnancy of Toxoplasma-infected women, and increased prevalence of toxoplasmosis in mothers of children with Down syndrome can be explained by the presumed immunosuppressive effects of latent toxoplasmosis. Here, we searched for indices of immunosuppression in mice experimentally infected with Toxoplasma gondii. Our results showed that mice in the early phase of latent infection exhibited temporarily increased production of interleukin (IL)-12 and decreased production of IL-10. In accordance with the immunosuppression hypothesis, the mice showed decreased production of IL-2 and nitric oxide and decreased proliferation reaction (synthesis of DNA) in the mixed lymphocyte culture in the early and also in the late phases of latent toxoplasmosis. Since about 30% of the world population are latently infected by T. gondii, the toxoplasmosis-associated immunosuppression might have serious public health consequences. PMID- 20721579 TI - Bilateral video-assisted thoracoscopic thymectomy has a surgical extent similar to that of transsternal extended thymectomy with more favorable early surgical outcomes for myasthenia gravis patients. AB - BACKGROUND: This study aimed to introduce the authors' surgical technique of bilateral video-assisted thoracoscopic thymectomy (BVT) and to compare their early surgical results between BVT and transsternal extended thymectomy (T3-b thymectomy) for patients with myasthenia gravis (MG). METHODS: The records of 114 patients who underwent either BVT (n = 55) or T3-b thymectomy (n = 59) for MG were reviewed retrospectively between January 2006 and November 2009. RESULTS: No surgical mortality or major morbidity occurred in either group. There was no conversion to open thymectomy, and no statistical difference was found in operation time between the two groups (112.2 +/- 26.2 min for BVT vs. 130.7 +/- 27.3 min for T-3b; p = 0.908). The duration of the chest tube, the length of the intensive care unit (ICU) or hospital stay, and the duration of opioid use for pain control were shorter in BVT group. The estimated blood loss and the total amount of drainage were greater in the T3-b thymectomy group. The specimen weights retrieved by BVT (72.5 +/- 61.6 g) were similar to those retrieved by T3 b thymectomy (74.1 +/- 38.2 g, p = 0.63) in nonthymomatous MG. CONCLUSIONS: The BVT was a safe procedure with a surgical extent and amount similar to those of T 3b thymectomy and less invasive for patients with MG. Long-term follow-up assessment and more extensive data are mandatory to verify the early surgical outcomes. PMID- 20721581 TI - Advances and high demands in totally robotic surgery for rectal cancer. PMID- 20721582 TI - Experience of 15 years using the 25-mm flexed end to end anastomosis anvil for safe transoral passage during intracorporeal circular-stapling gastrojejunostomy, esophagogastrostomy, and esophagojejunostomy. PMID- 20721583 TI - Reply to: Laparoscopic sleeve gastrectomy: a retrospective review of 1- and 2 year results. Surg Endosc 2010 (24):781-785. PMID- 20721585 TI - From napkin to new technology: 21st-century challenges for the surgeon-inventor. PMID- 20721584 TI - Implementation of colonoscopic process measures: does it improve quality? PMID- 20721586 TI - Hybrid NOTES transgastric cholecystectomy with reliable gastric closure: an animal survival study. AB - BACKGROUND: Secure transluminal closure remains the most fundamental barrier to safe translation of transgastric natural orifice transluminal endoscopic surgery (NOTES) procedures to humans. Obtaining optimal critical view of safety (CVS) is a prerequisite to performing cholecystectomy avoiding common bile duct injury. OBJECTIVES: (1) To evaluate feasibility and safety of hybrid transgastric NOTES cholecystectomy. (2) To evaluate feasibility and reliability of gastrotomy closure using a novel Over-The-Scope-Clip (OTSC; Ovesco) in survival porcine experiments. METHODS: Laparoscopic access to the abdominal cavity was obtained by two 2-mm and one umbilical optical trocar(s). Gastric access was created by balloon dilatation of a needle knife puncture up to 18 mm. Exposure of CVS was obtained and evaluated by aid of a 2-mm device. Subsequently the cystic duct and artery were clipped endoscopically. After laparoscopic dissection the specimen was extracted via the stomach. The gastrotomy was closed endoscopically using the OTSC. Necropsy was performed after 10 days with inspection of gastrotomy and peritoneal cavity for complications. Experiments were planned in 3 acute and 16 survival pigs. Main outcome parameters were documented exposure of CVS, successful cholecystectomy and closure, uncomplicated survival and histology confirmed full-thickness closure. RESULTS: In all 16 survival experiments CVS was obtained satisfactorily and hybrid cholecystectomy was successfully performed [100%; 95% confidence interval (CI): 81-100%]. Transgastric closure was endoscopically successful in all experiments in mean time of 7 min [standard deviation (SD) 3 min]. At necropsy 10 days after surgery there were no signs of (infectious) complications. Histology confirmed full-thickness healing with 100% success (95% CI: 81-100%). CONCLUSION: Hybrid transgastric NOTES cholecystectomy is feasible, safe and results in optimal CVS. Use of OTSC for gastrotomy closure is feasible, reliable and results in histology-proven full-thickness closure in survival porcine experiments. PMID- 20721587 TI - Fundus-first transumbilical single-incision laparoscopic cholecystectomy with a cholangiogram: a feasibility study. AB - BACKGROUND: An increasing number of techniques are emerging in the literature describing single-incision laparoscopic cholecystectomy (SILC). The advent of a new surgical approach is a reminder of the increase in bile duct injuries in the past when laparoscopic cholecystectomy was first introduced. With this in mind, the authors describe a safe and reproducible approach to SILC. METHODS: Between August 2008 and August 2009, 20 patients with symptomatic gallbladder disease underwent SILC using a totally transumbilical fundus-first approach with an intraoperative cholangiogram. Data including pain scores were collected prospectively. RESULTS: In this initial series, the median operative time was 103 min (range, 55-177 min), including the time for two patients undergoing additional procedures at the time of surgery. Intraoperative cholangiograms were completed for 18 of 19 patients. Additional ports were required in four patients for safe completion of the procedure. The mean pain score 12 h postoperatively was 2.5 on a visual analogue scale with a range of 0-10. There was no morbidity or mortality. CONCLUSION: According to the findings, SILC with an intraoperative cholangiogram can be performed safely using a fundus-first approach. However, for SILC to become the operation of choice for the treatment of gallbladder disease, evidence is required to demonstrate its advantage over laparoscopic cholecystectomy. PMID- 20721588 TI - New technologies for information retrieval to achieve situational awareness and higher patient safety in the surgical operating room: the MRI institutional approach and review of the literature. AB - BACKGROUND: Technical progress in the operating room (OR) increases constantly, but advanced techniques for error prevention are lacking. It has been the vision to create intelligent OR systems ("autopilot") that not only collect intraoperative data but also interpret whether the course of the operation is normal or deviating from the schedule ("situation awareness"), to recommend the adequate next steps of the intervention, and to identify imminent risky situations. METHODS: Recently introduced technologies in health care for real time data acquisition (bar code, radiofrequency identification [RFID], voice and emotion recognition) may have the potential to meet these demands. This report aims to identify, based on the authors' institutional experience and a review of the literature (MEDLINE search 2000-2010), which technologies are currently most promising for providing the required data and to describe their fields of application and potential limitations. RESULTS: Retrieval of information on the functional state of the peripheral devices in the OR is technically feasible by continuous sensor-based data acquisition and online analysis. Using bar code technologies, automatic instrument identification seems conceivable, with information given about the actual part of the procedure and indication of any change in the routine workflow. The dynamics of human activities also comprise key information. A promising technology for continuous personnel tracking is data acquisition with RFID. Emotional data capture and analysis in the OR are difficult. Although technically feasible, nonverbal emotion recognition is difficult to assess. In contrast, emotion recognition by speech seems to be a promising technology for further workflow prediction. CONCLUSION: The presented technologies are a first step to achieving an increased situational awareness in the OR. However, workflow definition in surgery is feasible only if the procedure is standardized, the peculiarities of the individual patient are taken into account, the level of the surgeon's expertise is regarded, and a comprehensive data capture can be obtained. PMID- 20721589 TI - Reply to 10.1007/s00464-009-0706-x (Vol 24, No 4, pp. 972-973): "Esophageal dilation after laparoscopic adjustable gastric banding". PMID- 20721590 TI - Comparison of electrode location between immediate postoperative day and 6 months after bilateral subthalamic nucleus deep brain stimulation. AB - OBJECTIVE: We compared the electrode positions of subthalamic nucleus (STN) deep brain stimulation (DBS) estimated at the immediate postoperative period with those estimated 6 months after surgery. METHODS: Brain CT scans were taken immediately and 6 months after bilateral STN DBS in 53 patients with Parkinson's disease. The two images were fused using the mutual information technique. The discrepancies of electrode positions in three coordinates were measured in the fused images, and the relationship with the pneumocephalus was evaluated. RESULTS: The average discrepancy of x- and y-coordinates of electrode positions at the level of STN (3.5 mm below the anterior commissure-posterior commissure line) were 0.6 +/- 0.5 mm (range, 0~2.1 mm) and 1.0 +/- 0.8 mm (range, 0~5.2 mm), respectively. The average discrepancy of z-coordinates of the electrode tips of the fused images was 1.0 +/- 0.8 mm (range, 0.1~4.0 mm). The volume of pneumocephalus (range, 0~76 ml) was correlated with the y-coordinate discrepancies (p < 0.005). CONCLUSION: The electrode positions in the immediate postoperative CT might have significant discrepancies with those in the CT taken at a stable period after STN DBS especially when there is a large amount of pneumocephalus. PMID- 20721591 TI - A novel monopartite dsRNA virus from rhododendron. AB - A dsRNA molecule of 3.4 kbp was extracted from two great rhododendron samples from Great Smoky Mountains National Park. Sequencing of this molecule suggests that it represents the genome of an undescribed virus, for which the provisional name rhododendron virus A (RhVA) is proposed. In phylogenetic analyses, this virus clustered together with southern tomato virus and related viruses, forming a coherent and distinct clade among dsRNA viruses. RhVA likely belongs to a yet to-be-established taxon of viruses with a non-segmented dsRNA genome. PMID- 20721592 TI - A comparison of methods for purification and concentration of norovirus GII-4 capsid virus-like particles. AB - Noroviruses (NoVs) are one of the leading causes of acute gastroenteritis worldwide. NoV GII-4 VP1 protein was expressed in a recombinant baculovirus system using Sf9 insect cells. Several methods for purification and concentration of virus-like particles (VLPs) were evaluated. Electron microscopy (EM) and histo blood group antigen (HBGA) binding assays showed that repeated sucrose gradient purification followed by ultrafiltration resulted in intact VLPs with excellent binding to H type 3 antigens. VLPs were stable for at least 12 months at 4 degrees C, and up to 7 days at ambient temperature. These findings indicate that this method yielded stable and high-quality VLPs. PMID- 20721593 TI - A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22. AB - Dentoleukoencephalopathies with autosomal recessive inheritance are very rare. Recently, a large inbred Syrian pedigree was reported with oligodontia in association with a degenerative neurologic condition characterized by progressive ataxia and pyramidal syndrome and abnormalities in the white matter and cortical atrophy. A whole-genome screening of this family using 382 microsatellite markers was completed, but no evidence was found of linkage to any chromosomal region. A genome-wide linkage analysis using the 260K single nucleotide polymorphism Affymetrix array was then undertaken and a maximum multipoint logarithm of the odds score of 5.66 (NPL score = 7.65) was detected on chromosome 10q22 region. This genomic interval contains 95 known genes including the Prosaposin gene (PSAP) responsible for metachromatic leukodystrophy, which was excluded. Seventeen additional candidate genes were tested and excluded. Sequencing of the whole candidate locus is in progress and should allow the identification of the causative gene in this rare disease, thereby improving the understanding of the physiopathology of this disease. PMID- 20721594 TI - Prevalence of anxiety and depression in osteoarthritis: use of the Hospital Anxiety and Depression Scale as a screening tool. AB - The aims of this study are to ascertain the prevalence of anxiety and depressive disorders in an outpatient population with osteoarthritis (OA), examine the interrelationships between severity of OA, pain, disability, and depression, and evaluate the Hospital Anxiety and Depression Scale (HADS) as a screening tool for this population. Patients with lower limb OA were evaluated with the Short Form McGill Pain and Present Pain Index Questionnaires, and a visual analogue scale, WOMAC Osteoarthritis Index-section C, and the HADS. Participants underwent a structured clinical interview by a liaison psychiatrist (AB). X-rays of affected joints were rated for disease severity. Fifty-four patients (42 females; mean age 63.3) were investigated. The prevalence of clinically significant anxiety and/or depression was 40.7% (95% confidence interval (CI), 27.6-55.0%). HADS was a good predictor of anxiety and depression with a sensitivity and specificity of 88% (95%CI, 64% to 99%) and 81% (95%CI, 65% to 92%), respectively. Pain correlated with HADS anxiety and depression scores (e.g. Rank correlation coefficients (Kendall's tau-b) between total HADS scores and Pain VAS scores 0.29; p=0.003). Disability was greater in patients with depression and/or anxiety (e.g. total HADS score; Kendall's rank correlation coefficient tau-b=0.26, p=0.007) OA severity as determined by radiological score was not a good predictor for anxiety nor depression and only weakly associated with disability. Anxiety and depression are very common in OA patients. HADS anxiety was a better predictor of diagnosed anxiety than HADS depression was of diagnosed depression. HADS is a valid and reliable screening instrument for detecting mood disorder, but not a diagnostic tool or a substitute for asking about symptoms of depression. The interrelationship between mental health, pain and disability is strong. We should therefore adopt a multidisciplinary approach to the management of OA. PMID- 20721595 TI - Full-thickness chest-wall resection followed by thorax reconstruction for recurrent malignant phyllodes tumor. AB - We present a case of a 39-year-old woman with a giant recurrent malignant phyllodes tumor accompanied with bleeding and infection. She underwent full thickness chest-wall resection. Bony thorax reconstruction and stabilization was accomplished using a Composix meshTM, and soft tissue reconstruction was performed with a musculocutaneous flap of latissimus dorsi muscle. The patient had a good postoperative outcome, and the surgical treatment remarkably improved her quality of life. Because chemotherapy and radiation are not established for treating malignant phyllodes tumors, an aggressive surgical approach should be considered for patients with a locally advanced malignant phyllodes tumor. PMID- 20721596 TI - Fractures in myelomeningocele. AB - BACKGROUND: In patients with myelomeningocele (MMC), a high number of fractures occur in the paralyzed extremities, affecting mobility and independence. The aims of this retrospective cross-sectional study are to determine the frequency of fractures in our patient cohort and to identify trends and risk factors relevant for such fractures. MATERIALS AND METHODS: Between March 1988 and June 2005, 862 patients with MMC were treated at our hospital. The medical records, surgery reports, and X-rays from these patients were evaluated. RESULTS: During the study period, 11% of the patients (n = 92) suffered one or more fractures. Risk analysis showed that patients with MMC and thoracic-level paralysis had a sixfold higher risk of fracture compared with those with sacral-level paralysis. Femoral neck z-scores measured by dual-energy X-ray absorptiometry (DEXA) differed significantly according to the level of neurological impairment, with lower z scores in children with a higher level of lesion. Furthermore, the rate of epiphyseal separation increased noticeably after cast immobilization. Mainly patients who could walk relatively well were affected. CONCLUSIONS: Patients with thoracic-level paralysis represent a group with high fracture risk. According to these results, fracture and epiphyseal injury in patients with MMC should be treated by plaster immobilization. The duration of immobilization should be kept to a minimum (<4 weeks) because of increased risk of secondary fractures. Alternatively, patients with refractures can be treated by surgery, when nonoperative treatment has failed. PMID- 20721597 TI - Adolescents with symptomatic laminolysis: report of two cases. AB - Retroisthmic cleft refers to a cleft in the lamina and is rarely reported. It was first described by Brocher, and later Wick et al. proposed the term "laminolysis" to describe the retroisthmic cleft by analogy with the nomenclature of the applied stress fracture of the pars interarticularis (spondylolysis) and the pedicle (pediculolysis). In this paper, we describe two adolescent sports players with symptomatic lumbar laminolysis. Both improved significantly after adequate conservative treatment. Knowledge of laminolysis in adolescent patients with low back pain is necessary to avoid overlooking it and late diagnosis. For correct diagnosis, multidetector three-dimensional computed tomography (CT) is suggested. In addition, magnetic resonance imaging (MRI) also allows detection of inflammation in the defects. PMID- 20721598 TI - Human skin penetration of a copper tripeptide in vitro as a function of skin layer. AB - OBJECTIVE AND DESIGN: Skin retention and penetration by copper applied as glycyl L-histidyl-L-lysine cuprate diacetate was evaluated in vitro in order to assess its potential for its transdermal delivery as an anti-inflammatory agent. MATERIALS AND METHODS: Flow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. copper tripeptide as permeant was applied on isolated stratum corneum, heat-separated epidermis and dermatomed skin and receptor fluid collected over 48 h in 4 h intervals using inductively coupled plasma mass spectrometry to analyze for copper in tissues and receptor fluid. RESULTS: The permeability coefficient of the compound through dermatomed skin was 2.43 +/- 0.51 * 10(-4) cm/h; 136.2 +/- 17.5 MUg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 97 +/- 6.6 MUg/cm(2) were retained as depot. CONCLUSIONS: Copper as tripeptide was delivered in potentially therapeutically effective amounts for inflammatory disease. PMID- 20721599 TI - Synthesis of optically pure S-sulfoxide by Escherichia coli transformant cells coexpressing the P450 monooxygenase and glucose dehydrogenase genes. AB - A cytochrome P450 monooxygenase (P450SMO) from Rhodococcus sp. can catalyze asymmetric oxygenation of sulfides to S-sulfoxides. However, P450SMO-catalyzed biotransformations require a constant supply of NAD(P)H, the expense of which constitutes a great hindrance for this enzyme application. In this study, we investigated the asymmetric oxygenation of sulfide to S-sulfoxide using E. coli cells, which co-express both the P450SMO gene from Rhodococcus sp. and the glucose dehydrogenase (GDH) gene from Bacillus subtilis, as a catalyst. The results showed that the catalytic performance of co-expression systems was markedly improved compared to the system lacking GDH. When using recombinant E. coli BL21 (pET28a-P450-GDH) whole cell as a biocatalyst, NADPH was efficiently regenerated when glucose was supplemented in the reaction system. A total conversion of 100% was achieved within 12 h with 2 mM p-chlorothioanisole substrate, affording 317.3 mg/L S-sulfoxide obtained. When the initial sulfide concentration was increased to 5 mM, the substrate conversion was also increased nearly fivefold: S-sulfoxide amounted to 2.5 mM (396.6 mg/L) and the ee value of sulfoxide product exceeded 98%. In this system, the effects of glucose concentration and substrate concentration were further investigated for efficient biotransformation. This system is highly advantageous for the synthesis of optically pure S-sulfoxide. PMID- 20721600 TI - Effects of vision and haptics on categorizing common objects. AB - Most research on object recognition and categorization centers on vision. However, these phenomena are likely influenced by the commonly used modality of touch. The present study tested this notion by having participants explore three dimensional objects using vision and haptics in naming and sorting tasks. Results showed greater difficulty naming (recognizing) and sorting (categorizing) objects haptically. For both conditions, error increased from the concrete attribute of size to the more abstract quality of predation, providing behavioral evidence for shared object representation in vision and haptics. PMID- 20721601 TI - QMOD: physically meaningful QSAR. AB - Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have utility in retrospective rationalization of activity patterns of substituents on a common scaffold, but are limited when either multiple scaffolds are present or when ligand alignment varies significantly based on structural changes. In addition, such methods generally assume independence and additivity of effect from scaffold substituents. Collectively, these non-physical modeling assumptions sharply limit the utility of widely used QSAR approaches for prospective prediction of ligand activity. The recently introduced Surflex-QMOD approach, by virtue of constructing physical models of binding sites, comes closer to a modeling approach that is congruent with protein ligand binding events. A set of congeneric CDK2 inhibitors showed that induced binding pockets can be quite congruent with the enzyme's active site but that model predictivity within a chemical series does not necessarily depend on congruence. Muscarinic antagonists were used to show that the QMOD approach is capable of making accurate predictions in cases where highly non-additive structure activity effects exist. The QMOD method offers a means to go beyond non causative correlations in QSAR analysis. PMID- 20721602 TI - Chloramphenicol acetyltransferase as selectable marker for plastid transformation. AB - Chloroplast transformation remains a demanding technique and is still restricted to relatively few plant species. The limited availability of selectable marker genes and the lack of selection markers that would be universally applicable to all plant species represent some of the most serious technical problems involved in extending the species range of plastid transformation. Here we report the development of the chloramphenicol acetyltransferase gene cat as a new selectable marker for plastid transformation. We show that, by selecting for chloramphenicol resistance, tobacco chloroplast transformants are readily obtained. Transplastomic lines quickly reach the homoplasmic state (typically in one additional regeneration round), accumulate the chloramphenicol acetyltransferase enzyme to high levels and transmit their plastid transgenes maternally into the next generation. No spontaneous antibiotic resistance mutants appear upon chloramphenicol selection. Several lines of evidence support the assumption that plant mitochondria are also sensitive to chloramphenicol suggesting that the chloramphenicol acetyltransferase may be a good candidate selectable marker for plant mitochondrial transformation. PMID- 20721604 TI - Multicomponent amorphous nanofibers electrospun from hot aqueous solutions of a poorly soluble drug. AB - PURPOSE: To design and fabricate multicomponent amorphous electrospun nanofibers for synergistically improving the dissolution rate and permeation profiles of poorly water-soluble drugs. METHODS: Nanofibers were designed to be composed of a poorly water soluble drug, helicid, a hydrophilic polymer polyvinylpyrrolidone as filament-forming matrix, sodium dodecyl sulfate as transmembrane enhancer and mannitol as taste masking agent, and were prepared from hot aqueous co-dissolving solutions of them. An elevated temperature electrospinning process was developed to fabricate the composite nanofibers, which were characterized using FESEM, DSC, XRD, ATR-FTIR, in vitro dissolution and permeation tests. RESULTS: The composite nanofibers were homogeneous with smooth surfaces and uniform structure, and the components were combined together in an amorphous state because of the favorable interactions such as hydrogen bonding, electrostatic interaction and hydrophobic interactions among them. In vitro dissolution and permeation tests demonstrated that the composite nanofibers had a dissolution rate over 26-fold faster than that of crude helicid particles and a 10-fold higher permeation rate across sublingual mucosa. CONCLUSIONS: A new type of amorphous material in the form of nanofibers was prepared from hot aqueous solutions of multiple ingredients using an electrospinning process. The amorphous nanofibers were able to improve the dissolution rate and permeation rate of helicid. PMID- 20721605 TI - PLGA erosion: solubility- or diffusion-controlled? AB - PURPOSE: To calculate the degradation time-dependent formation of water-soluble PLGA oligomers and to evaluate the relation between calculated oligomer formation and actual erosion of a PLGA-based delivery system. A proper model of the erosion process would be expected to facilitate forecasting of drug release profiles from PLGA matrices due to the close relationship of erosional mass loss and drug release described in the literature. METHODS: The molecular weight distribution (MWD), degradation and erosion behaviour of PLGA were characterized by gel permeation chromatography. RESULTS: PLGA was characterized by a lognormal distribution of mass fractions of individual molecular weights. Implementation of the pseudo-first-order reaction kinetics into the MWD function facilitated calculating the formation of water-soluble oligomers during degradation. The calculated soluble oligomer formation agreed excellently with measured erosional mass loss of a PLGA matrix in aqueous buffer, which suggested that the bulk erosion process was solely controlled by the kinetic of the formation of soluble oligomers and thus solubility-controlled and not diffusion-limited as conventionally assumed. CONCLUSION: The accurately calculated formation of soluble PLGA oligomers was in excellent agreement with the actual erosional mass loss of a PLGA matrix, suggesting that bulk erosion of PLGA represents a degradation-controlled dissolution process. PMID- 20721603 TI - Nanoparticle delivery systems in cancer vaccines. AB - Therapeutic strategies that involve the manipulation of the host's immune system are gaining momentum in cancer research. Antigen-loaded nanocarriers are capable of being actively taken up by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy by initiating a strong immunostimulatory cascade that results in potent antigen-specific immune responses against the cancer. Such carrier systems offer versatility in that they can simultaneously co-deliver adjuvants with the antigens to enhance APC activation and maturation. Furthermore, modifying the surface properties of these nanocarriers affords active targeting properties to APCs and/or enhanced accumulation in solid tumors. Here, we review some recent advances in these colloidal and particulate nanoscale systems designed for cancer immunotherapy and the potential for these systems to translate into clinical cancer vaccines. PMID- 20721606 TI - Dose dependent effect of C-type natriuretic peptide signaling in glycosaminoglycan synthesis during TGF-beta1 induced chondrogenic differentiation of mesenchymal stem cells. AB - Recent investigations credited important roles to C-type natriuretic peptide (CNP) signaling during chondrogenesis. This study investigated the putative role of CNP in transforming growth factor (TGF)-beta1 induced in vitro chondrogenic differentiation of mesenchymal stem cells (MSCs) in pellet culture. MSCs were derived from human trabecular bone and were characterized on the basis of their cell surface antigens and adipogenic, osteogenic, and chondrogenic differentiation potential. TGF-beta1 induced chondrogenic differentiation and glycosaminoglycan (GAG) synthesis was analyzed on the basis of basic histology, collagen type II, Sox 9 and aggrecan expressions, and Alcian blue staining. Results revealed that human trabecular bone-derived MSCs express CNP and NPR-B analyzed on the basis of RT-PCR and immunohistochemistry. In pellet cultures of MSCs TGF-beta1 successfully induced chondrogenic differentiation and GAG synthesis. RT-PCR analyses of both CNP and NPR-B during this process revealed an activation of this signaling pathway in response to TGF-beta1. Similar cultures induced with TGF-beta1 and treated with different doses of CNP showed that CNP supplementation at 10(-8) and 10(-7) M concentrations significantly increased GAG synthesis in a dose dependent manner, whereas at 10(-6) M concentration this stimulatory effect was diminished. In conclusion, CNP/NPR-B signaling pathway is activated during TGF-beta1 induced chondrogenic differentiation of human trabecular bone-derived MSCs and may strongly be involved in GAG synthesis during this process. This effect is likely to be a dose-dependent effect. PMID- 20721607 TI - Phenolic composition and antioxidant capacity of bilberry (Vaccinium myrtillus) leaves in Northern Europe following foliar development and along environmental gradients. AB - Bilberry is a characteristic field layer species in the boreal forests and is an important forage plant for herbivores of the North European ecosystem. Bilberry leaves contain high levels of phenolic compounds, especially hydroxycinnamic acids, flavonols, catechins, and proanthocyanidins. We investigated the phenolic composition of bilberry leaves in two studies, one following foliar development in forest and open areas, and the other along a wide geographical gradient from south to north boreal forests in Finland. An analysis of bilberry leaves collected in open and forest areas showed that major phenolic changes appeared in the first stages of leaf development, but, most importantly, synthesis and accumulation of flavonoids was delayed in the forest compared to the high light sites. Sampling along a geographical gradient in the boreal zone indicated that leaves from higher latitudes and higher altitudes had greater soluble phenolic and flavonol levels, higher antioxidant capacity, and lower contents of chlorogenic acid derivatives. The ecological significance of the results is discussed. PMID- 20721608 TI - Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes. AB - CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence. PMID- 20721609 TI - Possible difficult laryngoscopy caused by masticatory muscle tendon-aponeurosis hyperplasia: we anesthesiologists should be aware of this disease. AB - Masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) is a new disease entity characterized by limited mouth opening due to contracture of the masticatory muscles resulting from hyperplasia of tendons and aponeuroses. The other clinical feature is that the face of the patient with this disease displays a square mandible configuration. Muscle relaxants provide no relief for the limited mouth opening ability. Anesthesiologists need to suspect difficult airway when patients have limited mouth opening with square mandible configuration. MMTAH can therefore be a possible cause of difficult intubation. PMID- 20721610 TI - Accidental injection of remifentanil can cause a much more dangerous situation than the same dose of fentanyl. PMID- 20721611 TI - Care coordination for children with special health care needs: evaluation of a state experiment. AB - Care coordination (CC), a component of the medical home, may aid families who have children with special health care needs (CSHCN). Few data link CC to individual patient outcomes. To compare parent-reported outcomes for CSHCN receiving practice-based care coordination with those receiving standard care. This cross-sectional study examined two groups of CSHCN: one that received the services of a care coordinator for a year and one that did not. Parental surveys assessed: access to medical care, practice help and support, satisfaction with services, and parental mental and physical health. Associations between group status and parent-reported outcomes were assessed via regression analyses controlling for sociodemographic and health status variables. We also examined whether CC households who reported higher satisfaction with care had higher scores in the four domains. Parents in the care coordination group reported higher utilization of both primary care and specialist physicians, but did not report better practice help and support, better satisfaction with care, or better overall parental health. Parents in the care coordination group who reported being satisfied with their care rated their PCPs as more helpful than did the comparison families. Parents in this subgroup also reported significantly higher levels of care coordination than did parents in the comparison group. CSHCN appear to have higher PCP and specialist utilization when they receive supplemental care coordination. Additionally, those who are more satisfied with the care coordination they receive are happier with the assistance from their PCP and the overall care coordination provided. PMID- 20721612 TI - Consultative care coordination through the medical home for CSHCN: a randomized controlled trial. AB - The purpose of this study was to examine the impact of a care coordination intervention aimed at improving the medical home for children with special health care needs (CSHCN). 100 CSHCN referred by a Medicaid managed care plan were randomly assigned to a care coordination intervention or to a wait list comparison group that received standard care. For the intervention group, a care coordinator supported the medical home by consulting with primary care providers at multiple practices to develop an integrated, individualized plan to meet child and family needs. During the second phase of the study, the wait list comparison group received the 6-month intervention. At the end of 12 months, the two groups were combined to examine within subject differences (n = 61). Compared to the control group, participants in the initial intervention group reported a decreased need for information and improved satisfaction with mental health services and specialized therapies. This effect was replicated when the wait list control group received the intervention. Additional benefits were observed in the within subject analysis, including a decline in unmet needs, improved satisfaction with specialty care and care coordination, and improved ratings of child health and family functioning. This intervention improved outcomes for CSHCN and their families by supporting the efforts of primary care physicians to provide comprehensive and coordinated care through the medical home. The consulting care coordinator may provide an efficient and cost effective approach to enhancing the quality of care for CSHCN. PMID- 20721613 TI - Sharpening of directional selectivity from neural output of rabbit retina. AB - The estimation of motion direction from time varying retinal images is a fundamental task of visual systems. Neurons that selectively respond to directional visual motion are found in almost all species. In many of them already in the retina direction selective neurons signal their preferred direction of movement. Scientific evidences suggest that direction selectivity is carried from the retina to higher brain areas. Here we adopt a simple integrate and-fire neuron model, inspired by recent work of Casti et al. (2008), to investigate how directional selectivity changes in cells postsynaptic to directional selective retinal ganglion cells (DSRGC). Our model analysis shows that directional selectivity in the postsynaptic cells increases over a wide parameter range. The degree of directional selectivity positively correlates with the probability of burst-like firing of presynaptic DSRGCs. Postsynaptic potentials summation and spike threshold act together as a temporal filter upon the input spike train. Prior to the intricacy of neural circuitry between retina and higher brain areas, we suggest that sharpening is a straightforward result of the intrinsic spiking pattern of the DSRGCs combined with the summation of excitatory postsynaptic potentials and the spike threshold in postsynaptic neurons. PMID- 20721614 TI - How researchers define vulnerable populations in HIV/AIDS clinical trials. AB - In this study, we interviewed researchers, asking them to define vulnerable populations in HIV/AIDS clinical trials, and provide feedback on the federal regulations for three vulnerable populations. Interview data informed a conceptual framework, and were content analyzed to identify acceptability or disagreement with the regulations. Beginning with several characteristics of vulnerable enrollees identified by researchers, the conceptual framework illustrates possible scenarios of how enrollees could be considered vulnerable in clinical research. Content analysis identified barriers affecting HIV/AIDS researchers' ability to conduct clinical trials with pregnant women, prisoners, and children, for which the regulations specify additional protections. This study challenges current thinking about federal regulations' group-based approach to defining vulnerable populations. PMID- 20721615 TI - Risk factors for medication non-adherence in an HIV infected population in the Dominican Republic. AB - High levels of medication adherence are central to HIV treatment success. Barriers to medication adherence may differ by cultural setting. We aimed to determine risk factors for medication non-adherence in HIV infected individuals in the Dominican Republic. Adherence was measured in 300 individuals using a visual analog scale assessing the prior month and dichotomized at 95%. High levels of adherence were reported by 228 (76%). Risk factors for non-adherence included heavy alcohol use: 2.5 times odds (95% CI: 1.4-4.5), having children: 2.2 times higher odds (95% CI: 1.1-4.9) and perceptions of less social support related to adherence: 2 times higher odds (95% CI: 1.1-3.6). Culturally appropriate interventions are needed to address alcohol use, which is common in this setting. Parenting may represent a competing demand on time and resources and be an adherence barrier. Self-reported perceived lack of adherence support may be a useful marker for need for adherence interventions. PMID- 20721617 TI - Association between human papillomavirus and adenocarcinoma of rectum and recto sigmoid junction: a cohort study of 10,612 women in Taiwan. AB - This study aimed at assessing the association between the type-specific human papillomavirus (HPV) infection and the risk of adenocarcinoma of the rectum and recto-sigmoid junction. A total of 10,612 women aged 30-65 years old were enrolled from seven townships in Taiwan. Cervical cells collected at study entry were tested for 39 types of HPV infection by polymerase chain reactions and HPV blot kit. Newly developed adenocarcinomas of rectum and recto-sigmoid junction were ascertained through computerized linkage with national cancer registry profiles. An increased risk of adenocarcinomas of the rectum and recto-sigmoid junction was observed with HPV infection, showing a hazard ratio [HR] (95% confidence interval [CI]) of 1.99 (0.98-4.04) after adjustment for age and body mass index. The adjusted HR (95% CI) for the infection of HPV types other than 6 and 11 was 2.18 (1.04-4.60). Women with cervical infection of HPV types other than 6 and 11 at study entry may have an increased risk of adenocarcinomas of the rectum and recto-sigmoid junction, which deserves further validation by large scale studies. PMID- 20721616 TI - MC1R genotype may modify the effect of sun exposure on melanoma risk in the GEM study. AB - We investigated whether MC1R genotype modifies the effect of sun exposure on melanoma risk in 1,018 cases with multiple melanomas (MPM) and 1,875 controls with one melanoma (SPM). There was some suggestion that MC1R genotype modified the effect of beach and water activities on MPM risk: ORs were 1.94 (95% CI 1.40 2.70) for any activities for no R variants and 1.39 (95% CI 1.05-1.84) with R variants (R151C, R160W, D294H, and D84E) (p for interaction 0.08). MC1R modification of sun exposure effects appeared most evident for MPM of the head and neck: for early life ambient UV, the OR was 4.23 (95% CI 1.76-10.20) with no R and 1.04 (95% CI 0.40-2.68) with R (p for interaction = 0.01; p for three-way interaction = 0.01). Phenotype modified the effect of sun exposure and MPM in a similar manner. We conclude that MC1R and pigmentary phenotype may modify the effects of sun exposure on melanoma risk on more continuously sun-exposed skin. Possible explanations include that risk may saturate with higher sun sensitivity for melanomas on continuously sun-exposed sites but continue to increase as sun exposure increases with lower sun sensitivity, or that sun-sensitive people adapt their behavior by increasing sun protection when exposed. PMID- 20721618 TI - Association of creatin kinase B and peroxiredoxin 2 expression with age and embryo quality in cumulus cells. AB - PURPOSE: the purpose of this study was to identify age-related oocyte or embryo markers suitable for non-invasive analysis, as women over 38 years of age experience diminished pregnancy and ovulation rates. METHODS: we used real-time quantitative PCR to examine the gene expression profiles in cumulus cells acquired from older and younger age groups. We selected 11 genes involved in three functions that directly affect cellular aging: cell cycle control, apoptosis, and metabolism. RESULTS: CKB and PRDX2 were up-regulated in women older than 38 years, and the expression of these genes in cumulus cells was associated with embryo quality. In good-quality embryos, CKB expression was higher in the cumulus cells acquired from both older and younger age groups than in poor-quality embryos. CONCLUSIONS: these potential relationships among cumulus cell gene expression, oocyte quality, and age may expand our understanding of oogenesis and embryo development. CKB and PRDX2 may serve as biomarkers or therapeutic targets for the developmental potential of oocytes. PMID- 20721619 TI - Biochemical changes in plant leaves as a biomarker of pollution due to anthropogenic activity. AB - The air pollution due to anthropogenic activities seriously affected human life, vegetation, and heritage as well. The vegetation cover in and around the city mitigates the air pollution by acting as a sink for pollution. An attempt was made to evaluate biochemical changes occurred in four selected plant species, namely Azadirachta indica, Mangifera indica, Delonix regia, and Cassia fistula of residential, commercial, and industrial areas of Nagpur city in India. It was observed that the correlated values of air pollutants and plant leaves characteristics alter foliar biochemical features (i.e., chlorophyll and ascorbic acid content, pH and relative water content) of plants due to air pollution. The changes in air pollution tolerance index of plants was also estimated which revealed that these plants can be used as a biomarker of air pollution. PMID- 20721620 TI - Assessment of elemental distribution and trace element contamination in surficial wetland sediments, Southern Tibetan Plateau. AB - An investigation was performed to measure concentrations of major and trace elements in surficial wetland sediments in the southern Tibetan Plateau in order to assess the sediment quality. Results showed that most of elements have concentrations comparable to those of the Tibetan surface soil (TSS) except for As, Ca, Cs, Sr, and Cu. Correlation analysis indicated that most elements were highly associated with major crustal elements, suggestive of their common natural origin. Sediment quality assessment revealed that the wetlands are unpolluted with most of trace elements except for Cs and As, which are likely associated with organic matters and biological activities. Despite that the wetland sediments are minimally influenced by either local or long-transported anthropogenic pollutants, and no notable trace element pollutants were detected, As was found in elevated concentrations which far exceed the level above which harmful effects on wildlife and humans are likely to be observed. PMID- 20721621 TI - Mutational analysis of the carbohydrate binding activity of the tobacco lectin. AB - At present the three-dimensional structure of the tobacco lectin, further referred to as Nictaba, and its carbohydrate-binding site are unresolved. In this paper, we propose a three-dimensional model for the Nictaba domain based on the homology between Nictaba and the carbohydrate-binding module 22 of Clostridium thermocellum Xyn10B. The suggested model nicely fits with results from circular dichroism experiments, indicating that Nictaba consists mainly of beta-sheet. In addition, the previously identified nuclear localization signal is located at the top of the protein as a part of a protruding loop. Judging from this model and sequence alignments with closely related proteins, conserved glutamic acid and tryptophan residues in the Nictaba sequence were selected for mutational analysis. The mutant DNA sequences as well as the original Nictaba sequence have been expressed in Pichia pastoris and the recombinant proteins were purified from the culture medium. Subsequently, the recombinant proteins were characterized and their carbohydrate binding properties analyzed with glycan array technology. It was shown that mutation of glutamic acid residues in the C-terminal half of the protein did not alter the carbohydrate-binding activity of the lectin. In contrast, mutation of tryptophan residues in the N-terminal half of the Nictaba domain resulted in a complete loss of carbohydrate binding activity. These results suggest that tryptophan residues play an important role in the carbohydrate binding site of Nictaba. PMID- 20721622 TI - Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8). AB - Auto-antibodies induced by cancer represent promising sensitive biomarkers and probes to identify immunotherapeutic targets without immunological tolerance. Surprisingly few epitopes for such auto-antibodies have been identified to date. Recently, a cancer-specific syngeneic murine monoclonal antibody 237, developed to a spontaneous murine fibrosarcoma, was shown to be directed to murine podoplanin (OTS8) with truncated Tn O-glycans. Our understanding of such cancer specific auto-antibodies to truncated glycoforms of glycoproteins is limited. Here we have investigated immunogenicity of a chemoenzymatically produced Tn glycopeptide derived from the putative murine podoplanin O-glycopeptide epitope. We found that the Tn O-glycopeptide was highly immunogenic in mice and produced a Tn-glycoform specific response with no reactivity against unglycosylated peptides or the O-glycopeptide with extended O-glycan (STn and T glycoforms). The immunodominant epitope was strictly dependent on the peptide sequence, required Tn at a specific single Thr residue (Thr(77)), and antibodies to the epitope were not found in naive mice. We further tested a Tn O-glycopeptide library derived from human podoplanin by microarray analysis and demonstrated that the epitope was not conserved in man. We also tested human cancer sera for potential auto antibodies to similar epitopes, but did not detect such antibodies to the Tn library of podoplanin. The reagents and methods developed will be valuable for further studies of the nature and timing of induction of auto-antibodies to distinct O-glycopeptide epitopes induced by cancer. The results demonstrate that truncated O-glycopeptides constitute highly distinct antibody epitopes with great potential as targets for biomarkers and immunotherapeutics. PMID- 20721623 TI - Glutathione conjugates with dopamine-derived quinones to form reactive or non reactive glutathione-conjugates. AB - In this study we demonstrate for the first time that short-lived intermediate glutathione (GSH) conjugates (5-S-GSH-DA-o-quinone and 2-S-GSH-DA-o-quinone) must have first formed when GSH reacted with dopamine (DA)-derived DA-o-quinones without enzymatic catalysis in solutions. These intermediate GSH-conjugates are unstable and would finally transform into reactive or non-reactive GSH-conjugates dependent on ambient reductive forces. We demonstrated that, under sufficient reductive force, the intermediate GSH-conjugates could be reduced and transform into non-reactive 5-S-GSH-DA and 2-S-GSH-DA. However, under insufficient reductive forces, the intermediate GSH-conjugates could cyclize spontaneously to form reactive 7-S-GSH-aminochrome (7-S-GSH-AM). The 7-S-GSH-AM is so reactive and toxic that it could further conjugate with another GSH to form non-reactive 4,7 bi-GSH-5,6-dihydroindole in solutions. Furthermore 7-S-GSH-AM could abrogate tyrosinase activity rapidly and even inhibit proteasome activity in solutions. However, 7-S-GSH-AM could undergo automatically internal rearrangement and transform into non-reactive 7-S-GSH-5,6-dihydroindole if it had not conjugated with GSH. Therefore, insufficient ambient reductive force, such as decreased GSH concentration, could lead to decreased GSH detoxification efficiency for toxic DA quinones. Based on findings in this study, we propose two potential detrimental positive feedback loops involving accelerated DA oxidation, increased GSH consumption and impaired GSH detoxification efficiency, as the potential underlying chemical explanation for dopaminergic neuron degeneration in Parkinson's disease. PMID- 20721624 TI - Non-hepatic insults are common acute precipitants in patients with acute on chronic liver failure (ACLF). AB - INTRODUCTION: Acute-on-chronic liver failure (ACLF) is a newly coined term to describe simultaneous coexistence of two liver conditions, one of them being chronic or long-standing and the other acute or recent. There is limited data on the entity of ACLF. This study was performed to review our experience in ACLF patients from a tertiary care centre. PATIENTS AND METHODS: ACLF was defined as per the Asian Pacific Association for the Study of the Liver (APASL) criteria, except for including the non-hepatic insults as precipitating events. Based on the type of acute insult, patients were divided into type I (non hepatic injury) and type II (hepatic injury-further divided in to IIA-acute viral hepatitis (AVH) on underlying chronic liver disease (CLD), IIB-other acute hepatitic insults like drugs/toxins and IIC-same disease responsible for worsening). Patients were also analyzed for the mode of presentation, severity of liver illness, presence of acute kidney injury and other organ failure, hospital stay and final outcome. RESULTS: One hundred two patients with ACLF (85 males, mean age 44 +/- 12.5 years) were included in the study; they accounted for 49% of all liver failures and 27% of all admissions during the study period. Sixty patients (59%) had known cirrhosis whereas 42 (41%) patients presented for the first time as ACLF, unaware of the underlying CLD. Sixty-two (60%) patients had type I ACLF while 40 (40%) patients had type II ACLF. Infections (47%) were the most common non-hepatic causes of acute deterioration in type I ACLF. Amongst type II, acute viral hepatitis (IIA) accounted for six patients (4 hepatitis E virus, 2 hepatitis A virus) and type II C was the most common with alcoholic hepatitis accounting for 30 (29%) patients. Acute kidney injury was present in 47 (46%) and hypotension in 36 (35%) patients. Hypoxemia with ventilatory support was required in 22 (21%) patients. Mean hospital stay of patients was 9.7 +/- 6 days (2-27 days). Forty seven (46%) patients either died or left hospital in a very sick state. CONCLUSION: ACLF is a common problem in our clinical practice. Non-hepatic insults like non-hepatotropic infections/sepsis are common acute precipitating events. PMID- 20721625 TI - Combined effect of miR-146a rs2910164 G/C polymorphism and Toll-like receptor 4 +3725 G/C polymorphism on the risk of severe gastric atrophy in Japanese. AB - BACKGROUND: A G/C polymorphism in miRNA-146a (rs2910164) was shown to be associated with the risk of hepatocellular carcinoma. OBJECTIVE: This study aimed to examine the associations of the miR-146a G/C (rs2910164) and TLR4 +3725 G/C (rs11536889) polymorphisms with the risk of Helicobacter pylori (H. pylori) infection, gastric atrophy, and gastric cancer in a Japanese population. METHODS: Subjects for this study were 583 histologically diagnosed gastric cancer patients and age- and sex-frequency-matched 1,742 control outpatients (1,637 subjects were eligible for the analyses), who visited Aichi Cancer Center Hospital from the year 2001 to 2005. Serum pepsinogens were measured to evaluate gastric atrophy. RESULTS: When H. pylori-seropositive subjects or subjects with gastric atrophy were defined as H. pylori-infected subjects, the age- and sex-adjusted odds ratio (aOR) of severe gastric atrophy among the H. pylori infected was 1.44 (95% confidence interval [95% CI]=0.89-2.34, p=0.133) in G/G genotype of miR-146a polymorphism. When combined with TLR4 G/C polymorphism, the OR in those with miR 146a G/G and TLR4 G/C+C/C genotypes was significantly increased relative to those with miR-146a C/C+G/C and TLR4 G/G among the H. pylori-infected subjects: aOR=2.04 (95% CI=1.10-3.82, p=0.025). CONCLUSIONS: This study revealed the combined effect of miR-146a rs2910164 G/G and TLR4 +3725 C allele on the increased risk of severe gastric atrophy among the H. pylori-infected Japanese subjects. PMID- 20721626 TI - Role of a short-term stent-trial in a patient with biliary stricture and portal hypertensive biliopathy: long-term outcome result. AB - In portal hypertensive biliopathy (PHB) secondary to portal thrombosis, multiple factors can lead to symptoms and alteration of liver tests. The compression of the common bile duct (CBD) by peribiliary varices, portal vein thrombus or cavernoma, or the presence of biliary stone and an associated ischemic stricture are proposed to be involved in the pathogenesis of symptoms (jaundice, abdominal pain, fever) and alterations of liver tests. We present a case of a young HCV infected male patient in which multiple factors in PHB as mentioned above were present. Clinical and biochemical evaluations after a short-term biliary stent and after its removal (stent-trial) showed the major role of the ischemic associated stricture and rule out other factors in our patient. Long-term data support this result. PMID- 20721627 TI - Self-expandable metal stents (SEMS) can serve as a bridge to surgery or as a definitive therapy in patients with an advanced stage of cancer: clinical experience of a tertiary cancer center. AB - BACKGROUND: Self-expandable metal stents (SEMS) can be used to relieve benign and malignant colorectal obstruction. AIMS: The aim of this study was to determine the outcomes of SEMS for malignant colorectal obstruction. METHODS: Retrospective review was done of patients who underwent endoscopic SEMS placement from 2001 to 2007. RESULTS: Forty-six patients (23 M), mean age 60 years (range 24-82) underwent endoscopic SEMS placement. Cancer types included: 28 colorectal, and 18 metastatic cancers. The locations of the obstruction were as follows: two in the ascending colon, one in the hepatic flexure, three in the transverse colon, two in the splenic flexure, two in the descending colon, 26 in the sigmoid colon, and ten in the rectum. In 39 of the 46 cases (84.8%), placement of a single SEMS was successful covering the entire strictures, but in seven cases, two of the stents were placed in tandem resulting in adequate overage of stricture. Technical success was achieved in all cases. Clinical success was achieved in 39 out of 46 cases (84.8%). Two perforations were detected immediately and day 5 after SEMS placement, resulting in one death and one emergent surgery. Mean follow-up was 126 days (range 2-1,210). Twenty-eight of the 46 patients (61%) died during the follow-up period with the median overall survival being 3.52 months (95% CI: 2.34 4.41 months). CONCLUSIONS: Placement of SEMS for the treatment of colorectal obstruction is feasible and safe. In our institution, where SEMS are primarily used to palliate terminal disease, technical and clinical success rates were high without significant morbidity and mortality. On long-term follow-up, patients died from their advanced disease with infrequent recurrent obstruction or stent related complications. PMID- 20721628 TI - Fellow involvement during colonoscopy does not reduce adenoma detection rate. PMID- 20721630 TI - Use of 100 kV versus 120 kV in cardiac dual source computed tomography: effect on radiation dose and image quality. AB - To evaluate the effective radiation dose and image quality resulting from use of 100 vs. 120 kV among patients referred for cardiac dual source CT exam (DSCT). Prospective data was collected on 294 consecutive patients referred for DSCT. For each scan, a physician specializing in cardiac CT chose all parameters including tube current and voltage, axial versus helical acquisition, and use of tube current modulation. Lower tube voltage was selected for thinner patients or when lower radiation was desired for younger patients, particularly females. For each study, image quality (IQ) was rated on a subjective IQ score and contrast (CNR) and signal-to-noise (SNR) ratios were calculated. Tube voltage of 100 kV was used for 77 (26%) exams while 120 kV was used for 217 (74%) exams. Use of 100 kV was more common in thinner patients (weight 166 lbs vs. 199 lbs, P < .001). The effective radiation dose for the 100 and 120 kV scans was 8.5 and 15.4 mSv respectively. Among scans utilizing 100 and 120 kV, there was no difference in exam indication, use of beta blockers, heart rate, scan length and use of radiation saving techniques such as prospective ECG triggering and tube current modulation. The IQ score was significantly higher for 100 kV scans. While 100 kV scans were found to have higher image noise then those utilizing 120 kV, the contrast-to-noise and signal-to-noise were significantly higher (SNR: 9.4 vs. 8.3, P = .02; CNR: 6.9 vs. 6.0, P = .02). In selected non-obese patients, use of low kV results in a substantial reduction of radiation dose and may result in improved image quality. These results suggest that low kV should be used more frequently in non-obese patients. PMID- 20721631 TI - Explanatory pluralism in the medical sciences: theory and practice. AB - Explanatory pluralism is the view that the best form and level of explanation depends on the kind of question one seeks to answer by the explanation, and that in order to answer all questions in the best way possible, we need more than one form and level of explanation. In the first part of this article, we argue that explanatory pluralism holds for the medical sciences, at least in theory. However, in the second part of the article we show that medical research and practice is actually not fully and truly explanatory pluralist yet. Although the literature demonstrates a slowly growing interest in non-reductive explanations in medicine, the dominant approach in medicine is still methodologically reductionist. This implies that non-reductive explanations often do not get the attention they deserve. We argue that the field of medicine could benefit greatly by reconsidering its reductive tendencies and becoming fully and truly explanatory pluralist. Nonetheless, trying to achieve the right balance in the search for and application of reductive and non-reductive explanations will in any case be a difficult exercise. PMID- 20721633 TI - The impact of diabetes process and outcome quality measures on overall survival in patients with co-morbid colorectal cancer. AB - PURPOSE: To evaluate the effect of prevalent diabetes mellitus (DM) and quality of diabetes process and outcome measures on overall survival in colorectal cancer (CRC) patients. PATIENT AND METHODS: We conducted a retrospective cohort study among patients newly diagnosed with CRC. Kaplan-Meier analyses and Cox proportional hazard regression models were performed. Quality of diabetes process and outcomes measures in the year prior to CRC diagnosis were compared with those in the year after CRC diagnosis. RESULTS: Four hundred and seventy CRC patients were identified during the study period, including 122 (26%) patients with DM. Survival between diabetic and non-diabetic were not significantly different after stratifying by stage. In a multivariable model, only age (HR 1.04), stage 2 and 3 (HR 1.88), stage 4 (HR 4.26), and Deyo comorbidity score (HR 1.14) were significantly associated with increased risk of death. Overall, patients in this CRC cohort with DM had good to excellent diabetes quality of care in the year prior to diagnosis as evidenced by primary care and eye clinic visits, number of times diabetes intermediate outcomes were measured, and level of cholesterol (95.5 +/- 29.74) and hemoglobin A1c (7.2% + 1.4) control. After CRC diagnosis, there was no significant change in these quality of care indices compared to the year prior. CONCLUSIONS: Prevalent DM did not affect overall survival in this cohort of VA patients diagnosed with CRC. The quality of diabetes care prior to CRC diagnosis, which persisted after diagnosis, may have moderated the mortality effect of diabetes in this CRC cohort. PMID- 20721632 TI - Potential of magnetic resonance spectroscopy in assessing the effect of fatty acids on inflammatory bowel disease in an animal model. AB - People with inflammatory bowel disease (IBD) are at risk for developing colorectal cancer, and this risk increases at a rate of 1% per year after 8-10 years of having the disease. Saturated and omega-6 polyunsaturated fatty acids (PUFAs) have been implicated in its causation. Conversely, omega-3 PUFAs may have the potential to confer therapeutic benefit. Since proton magnetic resonance spectroscopy ((1)H MRS) combined with pattern recognition methods could be a valuable adjunct to histology, the objective of this study was to analyze the potential of (1)H MRS in assessing the effect of dietary fatty acids on colonic inflammation. Forty male Sprague-Dawley rats were administered one of the following dietary regimens for 2 weeks: low-fat corn oil (omega-6), high-fat corn oil (omega-6), high-fat flaxseed oil (omega-3) or high-fat beef tallow (saturated fatty acids). Half of the animals were fed 2% carrageenan to induce colonic inflammation similar to IBD. (1)H MRS and histology were performed on ex vivo colonic samples, and the (1)H MR spectra were analyzed using a statistical classification strategy (SCS). The histological and/or MRS studies revealed that different dietary fatty acids modulate colonic inflammation differently, with high-fat corn oil being the most inflammatory and high-fat flaxseed oil the least inflammatory. (1)H MRS is capable of identifying the biochemical changes in the colonic tissue as a result of inflammation, and when combined with SCS, this technique accurately differentiated the inflamed colonic mucosa based on the severity of the inflammation. This indicates that MRS could serve as a valuable adjunct to histology in accurately assessing colonic inflammation. Our data also suggest that both the type and the amount of fatty acids in the diet are critical in modulating IBD. PMID- 20721634 TI - Laparoscopic versus open appendectomy: an analysis of outcomes in 17,199 patients using ACS/NSQIP. AB - BACKGROUND: The current study was undertaken to evaluate the outcomes for open and laparoscopic appendectomy using the 2008 American College of Surgeons: National Surgical Quality Improvement Program (ACS/NSQIP) Participant Use File (PUF). We hypothesized that laparoscopic appendectomy would have fewer infectious complications, superior perioperative outcomes, and decreased morbidity and mortality when compared to open appendectomy. STUDY DESIGN: Using the Current Procedural Technology (CPT) codes for open (44950) and laparoscopic (44970) appendectomy, 17, 199 patients were identified from the ACS/NSQIP PUF file that underwent appendectomy in 2008. Univariate analysis with chi-squared tests for categorical data and t tests or ANOVA tests for continuous data was used. Binary logistic regression models were used to evaluate outcomes for independent association by multivariable analysis. RESULTS: Of the patients, 3,025 underwent open appendectomy and 14,174 underwent laparoscopic appendectomy. Patients undergoing laparoscopic appendectomy had significantly shorter operative times and hospital length of stay. They also had a significantly lower incidence of superficial and deep surgical site infections, wound disruptions, fewer complications, and lower perioperative mortality when compared to patients undergoing open appendectomy. CONCLUSIONS: Using the ACS/NSQIP PUF file, we demonstrate that laparoscopic appendectomy has better outcomes than open appendectomy for the treatment of appendicitis. While the operative treatment of appendicitis is surgeon specific, this study lends support to the laparoscopic approach for patients requiring appendectomy. PMID- 20721635 TI - Transcervical heller myotomy using flexible endoscopy. AB - INTRODUCTION: Esophageal achalasia is most commonly treated by laparoscopic myotomy. Transesophageal approaches using flexible endoscopy have recently been described. We hypothesized that using techniques and flexible instruments from our NOTES experience through a small cervical incision would be a safer and less traumatic route for esophageal myotomy. The purpose of this study was to evaluate the feasibility, safety, and success rate of using flexible endoscopes to perform anterior or posterior Heller myotomy via a transcervical approach. METHODS: This animal (porcine) and human cadaver study was conducted at the Legacy Research and Technology Center. Mediastinal operations on ten live, anesthetized pigs and two human cadavers were performed using standard flexible endoscopes through a small incision at the supra-sternal notch. The esophagus was dissected to the phreno esophageal junction using balloon dilatation in the peri-esophageal space followed by either anterior or posterior distal esophageal myotomy. Success rate was recorded of esophageal dissection to the diaphragm and proximal stomach, anterior and posterior myotomy, perforation, and complication rates. RESULTS: Dissection of the esophagus to the diaphragm and performing esophageal myotomy was achieved in 100% of attempts. Posterior Heller myotomy was always extendable onto the gastric wall, while anterior gastric extension of the myotomy was found to be more difficult (4/4 and 2/8, respectively; P = 0.061). CONCLUSION: Heller myotomy through a small cervical incision using flexible endoscopes is feasible. A complete Heller myotomy was performed with a higher success rate posteriorly possibly due to less anatomic interference. PMID- 20721637 TI - Insulin and chromium picolinate induce translocation of CD36 to the plasma membrane through different signaling pathways in 3T3-L1 adipocytes, and with a differential functionality of the CD36. AB - Chromium picolinate (CrPic) has been indicated to activate glucose transporter 4 (GLUT4) trafficking to the plasma membrane (PM) to enhance glucose uptake in 3T3 L1 adipocytes. In skeletal and heart muscle cells, insulin directs the intracellular trafficking of the fatty acid translocase/CD36 to induce the uptake of cellular long-chain fatty acid (LCFA). The current study describes the effects of CrPic and insulin on the translocation of CD36 from intracellular storage pools to the PM in 3T3-L1 adipocytes in comparison with that of GLUT4. Immunofluorescence microscopy and immunoblotting revealed that both CD36 and GLUT4 were expressed and primarily located intracellularly in 3T3-L1 adipocytes. Upon insulin or CrPic stimulation, PM expression of CD36 increased in a similar manner as that for GLUT4; the CrPic-stimulated PM expression was less strong than that of insulin. The increase in PM localization for these two proteins by insulin paralleled LCFA ([1-(14)C]palmitate) or [(3)H]deoxyglucose uptake in 3T3 L1 adipocytes. The induction of the PM expression of GLUT4, but not CD36, or substrate uptake by insulin and CrPic appears to be additive in adipocytes. Furthermore, wortmannin completely inhibited the insulin-stimulated translocation of GLUT4 or CD36 and prevented the increased uptake of glucose or LCFA in these cells. Taken together, for the first time, these findings suggest that both insulin and CrPic induce CD36 translocation to the PM in 3T3-L1 adipocytes and that their translocation-inducing effects are not additive. The signaling pathway inducing the translocations is different, apparently resulting in a differential activity of CD36. PMID- 20721638 TI - Enhancing effect of zinc on L-histidine transport in rat lung microvascular endothelial cells. AB - The aim of this study was to examine enhancing effect of L: -histidine into cultured rat lung microvascular endothelial cells (LMECs), which constitute the gas-blood barrier. Uptake of L: -histidine into LMECs markedly increased with the addition of ZnSO(4) (0.1 mmol/L), and this enhanced uptake of L: -histidine was drastically reduced in the presence of the Na(+)-independent system L substrate, 2-amino-2-norbornanecarboxylic acid (BCH). However, the uptake of L: -histidine together with ZnSO(4) was not reduced by the addition of metabolic inhibitor, 2,4 dinitrophenol, or sodium ion replacement. Moreover, the addition of the system N substrate, L: -glutamic acid gamma-monohydroxamate did not significantly decrease the uptake of L: -histidine with 143 mmol/L Na (+) + 1 mmol/L BCH. These results indicated that system-N transporter does not play a role in the uptake of L: histidine in the presence of ZnSO(4), suggesting that only system-L transporter is involved in the uptake of L: -histidine, although L: -histidine in the absence of ZnSO(4) was taken up by at least two pathways of Na(+)-dependent system-N and Na(+)-independent system-L processes into rat LMECs. The uptake of L: -histidine into rat LMECs in the presence of ZnSO(4) was also found to be unaffected by pH (5.0-7.4), indicating that uptake of L: -histidine into LMECs by the addition of zinc may not be involved in the H(+)-coupled transporters. PMID- 20721639 TI - Marginal zinc deficiency in pregnant rats impairs bone matrix formation and bone mineralization in their neonates. AB - Zinc (Zn) deficiency during pregnancy may result in a variety of defects in the offspring. We evaluated the influence of marginal Zn deficiency during pregnancy on neonatal bone status. Nine-week-old male Sprague-Dawley rats were divided into two groups and fed AIN-93G-based experimental diets containing 35 mg Zn/kg (Zn adequately supplied, N) or 7 mg Zn/kg (low level of Zn, L) from 14-day preconception to 20 days of gestation, that is, 1 day before normal delivery. Neonates were delivered by cesarean section. Litter size and neonate weight were not different between the two groups. However, in the L-diet-fed dam group, bone matrix formation in isolated neonatal calvaria culture was clearly impaired and was not recovered by the addition of Zn into the culture media. Additionally, serum concentration of osteocalcin, as a bone formation parameter, was lower in neonates from the L-diet-fed dam group. Impaired bone mineralization was observed with a significantly lower content of phosphorus in neonate femurs from L-diet fed dams compared with those from N-diet-fed dams. Moreover, Zn content in the femur and calvaria of neonates from the L-diet group was lower than that of the N diet-fed group. In the marginally Zn-deficient dams, femoral Zn content, serum concentrations of Zn, and osteocalcin were reduced when compared with control dams. We conclude that maternal Zn deficiency causes impairment of bone matrix formation and bone mineralization in neonates, implying the importance of Zn intake during pregnancy for proper bone development of offspring. PMID- 20721641 TI - Effects of the HIV-1 protein Tat on myocardial function and response to endotoxin. AB - HIV-1 infection has been associated with cardiomyopathy in a subset of patients. In order to determine whether HIV-1 alters myocardial function or the myocardial response to stress, transgenic mice that express the HIV-1 protein Tat were used. Heart function was assessed using the isolated working heart preparation. Response to infection was assessed by measuring heart function at various times after endotoxin administration. Since cytokines are implicated in myocardial dysfunction, plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL 6) and myocardial mRNA and protein levels of TNF-alpha and IL-6 were determined. Tat by itself did not cause myocardial dysfunction; however, 4 h after endotoxin, myocardial function was more severely compromised in the Tat mice than in control mice. Plasma TNF-alpha levels were elevated at 2 h and higher in the control group but myocardial levels were similar in the two groups. Plasma IL-6 was increased but myocardial levels were different only at 24 h at which time myocardial function was no longer depressed. Tat expression, by itself, did not impair intrinsic myocardial function but did increase myocardial injury induced by endotoxin. Although cytokines are associated with dysfunction, TNF-alpha and IL-6 were probably not responsible for the exaggerated dysfunction in Tat mice receiving endotoxin. PMID- 20721642 TI - Helicobacter pylori eradication: are we really all equal? A controlled study in native and immigrant population. AB - Italy's shift to a tertiary economy has modified the working market, concentrating demand also on unqualified one, which includes most immigrants. It is also well established that low socio-economical conditions are associated with an increased prevalence of H. pylori infection. The aims of this study were to compare: (1) the efficacy of a 7 days triple therapy in immigrant and in Italian patients; (2) the prevalence of PUD between these two groups of patients. A total of 116 consecutive immigrant and 112 Italian H. pylori infected patients were recruited between 2007 and 2008. Patients underwent (13)C-UBT, endoscopy with biopsies, and were offered a 7-day triple therapy. Eradication rate (ER) was assessed 8 weeks after the end of the treatment using (13)C-UBT. The two populations differed for median age (p < 0.01), prevalence of PUD (p < 0.01), and smoking status (p < 0.01). The ER according to the ITT analysis was 70% for Italian and 48.3% for immigrant (p < 0.01). Multivariate analysis including country of origin, sex, age, PUD, smoking, and alcohol status found that immigrant had an adjusted OR for not eradicating of 2.14 (p = 0.03). In immigrant patients resident in Italy, performance of triple therapy was lower than expected. Further studies are demanded to confirm and clarify these intriguing results. PMID- 20721640 TI - A new functional role of HIV-1 integrase during uncoating of the viral core. AB - An early and critical event of the human immunodeficiency virus type 1 (HIV-1) life cycle is uncoating of the viral core. Uncoating involves the disassembly of HIV-1 capsid (CA). The underlying mechanisms governing uncoating are poorly defined, and the role of viral and host factors in uncoating is not well understood. Cyclophilin A and TRIM5alpha are two cellular factors that interact with CA in exerting their effects on HIV-1 replication. Here, we review the current understanding of uncoating and the new functional role of HIV-1 IN during uncoating. PMID- 20721643 TI - The "antiphospholipid triangle" in an asymptomatic patient: a case report. PMID- 20721644 TI - Health care utilization following a non-urgent visit in emergency department and primary care. AB - Unscheduled visits to an emergency department (ED) or to primary care (PC) are often followed by further healthcare contacts. Present knowledge about predisposing factors and differences between healthcare levels is sparse. The objectives of this study were to describe and to analyze factors influencing subsequent healthcare contacts within 30 days following a non-urgent ED visit or an unscheduled visit in PC. In this prospective cohort study, subjects were identified and interviewed at the time of a non-urgent ED visit or unscheduled visits to PC. Data of all healthcare contacts during 1 month were collected. The probability of reattendance was analyzed regarding socio-demographic factors, previous and present health care utilization, the physicians' perceptions of the urgency of the visit, and appropriateness of its level of care. More than half of the patients in both settings had at least one contact with healthcare the following month. In 16% of the ED patients and 9% of PC patients, these contacts were to an ED. In the multivariate analysis, patients with regular monitoring of chronic disease were associated with an increased probability of having one or more physician visit the following month (OR 1.97 CI 95% 1.15-3.36). In conclusion, previous health care utilization was associated with an increased probability of one or more further physician visits the following month, regardless of the setting for the index visit or other patients characteristics. Physicians' perception of urgency did not influence the probability of further contacts. PMID- 20721645 TI - A rare cause of left upper quadrant abdominal pain. PMID- 20721646 TI - High-quality RNA preparation from Rhodosporidium toruloides and cDNA library construction therewith. AB - Oleaginous yeast Rhodosporidium toruloides is an excellent microbial lipid producer. Therefore, it is important to develop molecular biology tools to understand the basic mechanism for lipid accumulation and further manipulate the microorganism. High-quality RNA extraction from R. toruloides is particularly challenging due to high level of polysaccharides, lipids, and other secondary metabolites. To obtain an optimal protocol for RNA extraction from R. toruloides, four methods were evaluated. Large difference in RNA yield and quality among these protocols was found. The optimum method was modified RNAiso procedure, where RNA was isolated using liquid nitrogen-RNAiso method with salt precipitation and the addition of beta-mercaptoethanol. This method consistently recovered RNA in good quality with high yield. Around 297 MUg total RNA per gram of cells was obtained with an average purity measured as A260/A280 of 2.09. A titer of 105 cfu/ml could be harvested to construct a full-length cDNA library with the RNA sample in this quality. Electrophoresis gel analysis indicated the fragments ranged from 200 bp to 4.0 kb, with the average size of 1000 bp. Randomly picked clones showed the recombination efficiency at 80%. These results showed that RNA of R. toruloides was successfully extracted for the first time using the modified RNAiso method, and the cDNA library was appropriate for screening the genes related to lipid accumulation. PMID- 20721647 TI - Role of adenoidectomy in otitis media and respiratory function. AB - Adenoidectomy is among the most frequent surgical procedures performed on children. The rationale for adenoidectomy is to remove a chronically infected or enlarged and obstructing adenoid. Adenoidectomies are performed on children who have recurrent or chronic otitis media with effusion, on children with chronic rhinosinusitis, and on children with nasopharyngeal obstruction causing sleep disturbances and continuous mouth breathing. Various underlying factors that lead to adenoidectomy are also associated with asthma. Asthma is associated with recurrent respiratory tract infections predisposing individuals to recurrent or chronic otitis media and chronic rhinosinusitis. Children with asthma also have an increased risk of sleep-disordered breathing that is treated with adenoidectomy in the presence of nasopharyngeal obstruction. In nonasthmatic children, adenoidectomy does not influence the development of IgE-mediated allergy, bronchial hyperreactivity, or exhaled nitric oxide concentrations, all of which are surrogate asthma markers. Adenoidectomy in selected asthmatic children may relieve comorbidities associated with asthma. PMID- 20721648 TI - Bazex syndrome (acrokeratosis paraneoplastica) diagnosed in a patient with oral persistent ulcerations. AB - Paraneoplastic syndromes associated with head and neck cancer are rare and have been reported under dermatological, endocrine, hematological, neurological and rheumatological disorders. Bazex syndrome is an intriguing paraneoplasia that can be associated with head and neck squamous cell carcinomas. A range of symmetrical dermatological manifestations, with a clear predilection to extremities, that encompasses erythematous squamous plaques, skin scaling and nail dystrophy can provide a psoriasiform pattern in Bazex syndrome. In addition to these tricky clinical features, the rarity of the disease and the lack of understanding on Bazex syndrome generally make such cases to be mismanaged as psoriasis or lichen planus, causing an important delay in the diagnosis of the underlying malignancy. The authors describe a case of Bazex syndrome that occurred in a patient with a recently diagnosed tongue squamous cell carcinoma. Clinicians should consider paraneoplasia when assessing skin and/or oral persistent lesions. PMID- 20721649 TI - Development of sustained release capsules containing "coated matrix granules of metoprolol tartrate". AB - The objective of this investigation was to prepare sustained release capsule containing coated matrix granules of metoprolol tartrate and to study its in vitro release and in vivo absorption. The design of dosage form was performed by choosing hydrophilic hydroxypropyl methyl cellulose (HPMC K100M) and hydrophobic ethyl cellulose (EC) polymers as matrix builders and Eudragit(r) RL/RS as coating polymers. Granules were prepared by composing drug with HPMC K100M, EC, dicalcium phosphate by wet granulation method with subsequent coating. Optimized formulation of metoprolol tartrate was formed by using 30% HPMC K100M, 20% EC, and ratio of Eudragit(r) RS/RL as 97.5:2.5 at 25% coating level. Capsules were filled with free flowing optimized granules of uniform drug content. This extended the release period upto 12 h in vitro study. Similarity factor and mean dissolution time were also reported to compare various dissolution profiles. The network formed by HPMC and EC had been coupled satisfactorily with the controlled resistance offered by Eudragit(r) RS. The release mechanism of capsules followed Korsemeyer-Peppas model that indicated significant contribution of erosion effect of hydrophilic polymer. Biopharmaceutical study of this optimized dosage form in rabbit model showed 10 h prolonged drug release in vivo. A close correlation (R(2) = 0.9434) was established between the in vitro release and the in vivo absorption of drug. The results suggested that wet granulation with subsequent coating by fluidized bed technique, is a suitable method to formulate sustained release capsules of metoprolol tartrate and it can perform therapeutically better than conventional immediate release dosage form. PMID- 20721650 TI - Family functioning and weight loss in a sample of african americans and whites. AB - BACKGROUND: Traditionally, weight management behavioral research has focused on individual-level influences, with little attention given to interpersonal factors that relate to the family behavioral context. PURPOSE: This research examines the association between baseline family functioning scores and weight loss success in a sample of African Americans and Whites enrolled in a 20-week weight loss program with a weight loss goal of >= 4 kg. METHODS: Baseline surveys measuring six family functioning constructs were completed by 291 participants in a trial of weight loss maintenance. Analysis was limited to 217 participants in households with at least one other family member, and providing final weight measurements. We evaluated associations of family functioning, family composition, and demographic variables with weight loss success defined as losing >= 5% of initial body weight. Baseline predictors of weight loss success were determined using logistic regression analysis. RESULTS: Participants were on average 61 years of age with BMI of 34 kg/m(2); 57% were female and 75% self identified as African American. Sixty-two percent lost at least 5% of initial body weight. In bivariate analysis, weight loss success was associated with higher income and education (p < 0.01 and p = 0.05, respectively), ethnicity (p < 0.01), and the presence of a spouse (p = 0.01). After adjusting for socio demographic covariates in a multivariable model, the odds of weight loss success were independently influenced by a significant interaction between ethnicity and family cohesion (p < 0.01). CONCLUSIONS: These findings suggest that family context factors influence weight loss behaviors. PMID- 20721651 TI - Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. AB - INTRODUCTION: Uremic syndrome consists of nitrogenous waste retention, deficiency in kidney-derived hormones, and reduced acid excretion, and, if untreated, may progress to coma and eventual death. Previous experience suggests that oral administration of a probiotic formulation of selected microbial strains may extend renoprotection via intraintestinal extraction of toxic waste solutes in patients with chronic kidney disease (CKD)stages 3 and 4. This report presents preliminary data from a pilot study. METHODS: This was a 6-month prospective, randomized, double-blind, placebo-controlled crossover trial of a probiotic bacterial formulation conducted in four countries, at five institutions, on 46 outpatients with CKD stages 3 an nd 4: USA (n=10), Canada (n=113), Nigeria (n=115), and Argentina (n=8). Outcomes were compared using biochemical parameters:blood urea nitrogen (BUN), serum creatinine, and uric acid. General well-being was assessed as a secondary parameter by a quality of life (QQOL) questionnaire on a subjective scale of 1-10. RESULTS: Oral ingestion of probiotics (90 billion colony forming units [CFUs]/day) was well tolerated and safe during the entire trial period at all sites. BUN levels decreased in 29 patients (63%, P<0.05), creatinine levels decreased in 20 patients (43%, no statistical significance), and uric acid levels decreased in 15 patients (33%, no statistical significance). Almost all subjects expressed a perceived substantial overall improvement in QOL (86%, P<0.05). CONCLUSION: The main outcomes of this preliminary trial include a significant reduction of BUN, enhanced well-being, and absence of serious adverse effects, thus supporting the use of the chosen probiotic formulation for bowel-based toxic solute extraction. QOL and BUN levels showed statistically significant differences in outcome (P<0.05) between placebo and probiotic treatment periods at all four sites (46 patients). A major limitation of this trial is the small sample size nd elated inconsistencies. PMID- 20721652 TI - Stunned myocardium following acute spinal cord injury: Takotsubo cardiomyopathy after spinal hemorrhage. PMID- 20721654 TI - Melamine toxicity--stones vs. crystals. PMID- 20721655 TI - Acute oral potassium overdose: the role of hemodialysis. AB - INTRODUCTION: Hyperkalemia is a common condition, particularly in the setting of renal dysfunction. Hyperkalemia due to intentional oral potassium overdose is not commonly reported. CASE REPORT: We present a case of acute intentional potassium overdose in a patient with normal renal function resulting in significant hyperkalemia, with a maximum serum potassium concentration of 11 mEq/L. Despite an initial course complicated by various unstable cardiac rhythms, including ventricular tachycardia, ventricular fibrillation, and pulseless electrical activity, the patient was discharged from the hospital neurologically intact. Treatment for hyperkalemia included hemodialysis. DISCUSSION: The role of dialysis in potassium overdose is poorly defined. CONCLUSION: Based on this case and a review of the medical literature, we recommend hemodialysis for cases of potassium overdose with hemodynamic instability and significantly elevated serum potassium concentrations that do not respond promptly to medical therapy. Hemodialysis should also be considered in cases with underlying renal dysfunction. PMID- 20721656 TI - [Intralabyrinthine schwannomas]. AB - Schwannomas are benign neurogenic tumors arising from Schwann cells that usually form the myelin sheath of peripheral nerves. The typical localization of vestibular schwannomas is the internal auditory canal or the cerebellopontine angle. Intralabyrinthine lesions are extremely rare. Here we describe a series of four consecutive cases of intralabyrinthine schwannomas that were treated in the Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Bielefeld in Bielefeld, Germany. Therapeutic options are discussed and the literature is reviewed. PMID- 20721657 TI - [Acute hearing loss in the orchestral musician : Noise trauma or idiopathic sudden deafness?]. AB - During an orchestral performance musicians are exposed to high noise levels, which may exceed the intensity which could evoke hearing impairment after many years of exposure. From experience the degree of hearing loss in musicians is in general less than would be expected from the levels of exposure. The likelihood that an orchestral musician would develop a noise-induced hearing loss is much lower than for an industrial worker in a noise-intense factory. On the other hand it has to be considered that it is imperative for musicians to have non-impaired hearing to practise their profession. In some cases a sudden onset of hearing loss is traced to the noise stress of a loud performance. In such cases, the high noise levels predominantly produced by brass instruments or drums were assumed to be the cause. This publication presents five cases of expert opinions, where previous expert opinions had assumed noise or a blast trauma as the cause for the hearing loss. By careful analysis, a noise or a blast trauma was not regarded as probable in any of the cases. Interestingly, three of the five musicians had a normal contralateral hearing. In one case normal bilateral hearing was observed without the typical c(5) notch although the musician had been subject to noise stress in an orchestra for years. PMID- 20721658 TI - An evaluation of lead contamination in plastic toys collected from day care centers in the Las Vegas Valley, Nevada, USA. AB - Childhood exposure to environmental lead continues to be a major health concern. This study examined lead content within the plastic of children's toys collected from licensed day care centers in the Las Vegas valley, Nevada. It was hypothesized that the use of lead as a plastics stabilizer would result in elevated lead (>=600 ppm) in polyvinyl chloride plastics (PVC) compared to non PVC plastics. It was also hypothesized that, due to the use of lead chromate as a coloring agent, yellow toys would contain higher concentrations of lead (>=600 ppm) than toys of other colors. Toy samples were limited to those found in day care centers in Las Vegas, Nevada. 10 day care centers were visited and approximately 50 toy samples were taken from each center. Of the 535 toys tested, 29 contained lead in excess of 600 parts per million (ppm). Of those 29 toys, 20 were PVC and 17 were yellow. Both of the two hypotheses were strongly supported by the data. PMID- 20721659 TI - Functional and quality of life outcome of transobturator tape for treatment of female stress urinary. AB - INTRODUCTION AND HYPOTHESIS: this study aims to evaluate the functional outcome of transobturator tape (TOT) in treatment of female stress urinary incontinence (SUI) and its impact on patient quality of life (QoL). METHODS: sixty female patients with SUI underwent TOT operation, outside-in technique. Forty-eight patients completed the study. Clinical evaluation, urodynamics, and QoL using validated Arabic translation of the International Consultation on Incontinence Questionnaire-Short Form were done both preoperatively and 3, 6, and 12 months postoperatively. RESULTS: the mean follow-up was 16 months. The objective cure rate was 95.83%. There were no cases of urethral injury, bladder perforation, or thigh pain. De novo urgency and urge incontinence was observed in four patients (8.3%). No early or late outflow obstructive symptoms were noted. No difference was observed between pre- and postoperative filling cystometrogram and pressure flow studies. There was significant improvement in the postoperative QoL assessment. CONCLUSIONS: TOT (outside-in) appears to have no deleterious effect on storage and voiding functions. PMID- 20721660 TI - Comments on: epidemiological study of urge urinary incontinence and risk factors in China. PMID- 20721661 TI - Aldosterone and parathyroid hormone: a complex and clinically relevant relationship. PMID- 20721662 TI - Ejection time-corrected systolic velocity improves accuracy in the evaluation of myocardial dysfunction: a study in piglets. AB - This study aimed to assess the effect of correcting for the impact of heart rate (HR) or ejection time (ET) on myocardial velocities in the long axis in piglets undergoing hypoxia. The ability to eject a higher volume at a fixed ET is a characteristic of contractility in the heart. Systolic velocity of the atrioventricular annulus displacement is directly related to volume changes of the ventricle. Both ET and systolic velocity may be measured in a single heartbeat. In 29 neonatal pigs, systolic velocity and ET were measured with tissue Doppler techniques in the mitral valve annulus, the tricuspid valve annulus, and the septum. All ejection time corrected velocities (S((ET)), mean +/ SEM, cm/s) decreased significantly during hypoxia (S(mva(ET)) 15.5 +/- 0.2 to 13.2 +/- 0.3 (p < 0.001), S(septal(ET)) 9.9 +/- 0.1 to 7.8 +/- 0.2 (p < 0.001), S(tva(ET)) 12.1 +/- 0.2 to 9.8 +/- 0.3 (p < 0.001)). The magnitude of change from baseline to hypoxia was greater for ejection time corrected systolic velocities than for RR-interval corrected velocities (mean +/- SEM, cm/s); DeltaS(mva(ET)) 2.3 +/- 2.0 vs. DeltaS(mva(RR)) 1.6 +/- 1.1 (p = 0.02), DeltaS(septal(ET)) 2.1 +/ 1.0 vs. DeltaS(septal(RR)) 1.6 +/- 1.0 (p < 0.01), DeltaS(tva(ET)) 2.3 +/- 1.1 vs. DeltaS(tva(RR)) 1.8 +/- 1.3 (p = 0.04). The receiver operator characteristic (ROC) showed superior performance of S((ET)) compared with uncorrected velocities. The decrease in S((ET)) during hypoxia was not influenced by important hemodynamic determinants. ET-corrected systolic velocity improves accuracy and decreases variability in the evaluation of systolic longitudinal function and contractility during global hypoxia in neonatal pigs compared with systolic velocity alone. It is robust toward hemodynamic changes. This novel method has the potential of becoming a useful tool in clinical practice. PMID- 20721663 TI - A trick for dressing after liposuction. PMID- 20721664 TI - Local irrigation management institutions mediate changes driven by external policy and market pressures in Nepal and Thailand. AB - This article assesses the role of local institutions in managing irrigation water use. Fifty irrigation systems in each country were studied in Nepal and Thailand to compare the influence of local institutions on performance of irrigation systems amid changes in external policy and market pressures. Nepal's new irrigation policy after the re-instatement of multiparty democracy in 1990 emphasized participatory irrigation management transferring the management responsibility from state authorities to water users. The water user associations of traditional farmer-managed irrigation systems were formally recognized by requiring registration with related state authorities. In Thailand also government policies encouraged people's participation in irrigation management. Today water users are directly involved in management of even some large irrigation systems at the level of tertiary canals. Traditional communal irrigation systems in northern Thailand received support for system infrastructure improvement but have faced increased interference from government. In Thailand market development supported diversification in farming practices resulting in increased areas under high water-demanding commercial crops in the dry season. In contrast, the command areas of most irrigation systems in Nepal include cereal-based subsistence farming with only one-third having commercial farming. Cropping intensities are higher in Nepal than in Thailand reflecting, in part, differences in availability of land and management. In both countries local institutions play an important role in maintaining the performance of irrigation systems as external drivers and local contexts change. Local institutions have provided alternative options for irrigation water use by mediating external pressures. PMID- 20721665 TI - Toxicological effects of selective herbicides on plant growth promoting activities of phosphate solubilizing Klebsiella sp. strain PS19. AB - This study examines the effect of four herbicides, quizalafop-p-ethyl, clodinafop, metribuzin and glyphosate, on plant growth promoting activities like phosphate solubilization, siderophores, indole acetic acid, exo-polysaccharides, hydrogen cyanide and ammonia production by herbicide tolerant Klebsiella sp. strain PS19. The strain was isolated from mustard rhizosphere. The selected herbicides were applied two to three times at the recommended rates. Klebsiella sp. strain PS19 tolerated a concentration of 1600 MUg/ml each of quizalafop-p ethyl and clodinafop, and 3200 and 2800 MUg/ml of metribuzin and glyphosate, respectively. The activities of Klebsiella sp. strain PS19 observed under in vitro environment were persistent in the presence of all herbicides at lower rates. The plant growth promoting activities even-though decreased regularly, but was not lost completely, as the concentration of each herbicide was increased from the recommended to three times of higher doses. Among all herbicides, quizalafop-p-ethyl, generally, showed maximum toxicity to plant growth promoting activities of Klebsiella sp. strain PS19. As an example, 40, 80 and 120 MUg/l of quizalafop-p-ethyl added to liquid culture Pikovskaya medium, decreased phosphate solubilizing activity of strain PS19 by 93, 95 and 97%, respectively over untreated control. The study revealed that the higher rates of herbicides though decreased the plant growth promoting activity but it did not completely inhibit the metabolic activities of strain PS19. The herbicide tolerance together with growth promoting activities observed under herbicide stress suggests that Klebsiella sp. strain PS19 could be used as bacterial preparation for facilitating the growth and yields of crops even in soils polluted with herbicides. PMID- 20721666 TI - Increased immunogenicity to LipL32 of Leptospira interrogans when expressed as a fusion protein with the cholera toxin B subunit. AB - Leptospirosis is one of the most widespread zoonosis in the world. The development of a recombinant leptospira vaccine remains a challenge. In this study, we cloned the Leptospira interrogans open reading frame (ORF) coding the external membrane protein LipL32, an immunodominant antigen found in all pathogenic leptospira, downstream of the highly immunogenic cholera toxin B subunit (CTB) ORF. Expression and assembly of the CTB-LipL32 fusion protein into oligomeric structures of pentameric size were observed in soluble fractions by Western blot analysis. The CTB-LipL32 protein demonstrated strong affinity for monosialotetrahexosylgaglioside (GM1-ganglioside) in an enzyme-linked immunosorbent assay (ELISA), suggesting that the antigenic sites for binding and proper folding of the pentameric CTB structure were conserved. Furthermore, antisera against LipL32 also recognized the CTB-LipL32 fusion protein, suggesting that LipL32 also conserved its antigenic sites, a fact confirmed by an ELISA assay showing soluble CTB-LipL32 recognition by sera from convalescent patients. In addition, soluble CTB-LipL32 generated higher specific titers in mice immunized without external adjuvant than co-administration of CTB with LipL32. The data presented here provide support for CTB-LipL32 as a promising antigen for use in the control and study of leptospirosis. PMID- 20721667 TI - Evaluation of the use of selective PCR amplification of LPS biosynthesis genes for molecular typing of leptospira at the serovar level. AB - Leptospirosis is an important epidemic zoonosis worldwide. Currently, there are more than 250 Leptospira pathogenic serovars known that can potentially infect humans. Conventional classification of leptospires with the serovar as the basic taxon, based on serological recognition of lipopolysaccharide (LPS) composition does not correlate well with species determination, based on general genomic features. Here, we investigate the selective amplification of polymorphic regions from the LPS biosynthesis loci (rfb) as a potential tool for serovar typing of Leptospira interrogans species. Eight pairs of primers were designed to target six ORFs from the rfb operon with varying levels of sequence polymorphism. They were tested both separately and multiplexed. Half of these primer pairs produced serovar-specific amplicons, allowing the identification of some specific serovars and also groups of serovars. It was shown that the serovar classification of Leptospira can be accessed by selective amplification of rfb operons in some cases, which may permit a parallel between the serological and the genomic classifications of Leptospira. As a conclusion, the selective amplification of rfb generated promising and already useful results, but it appears necessary to characterize a larger variety of Leptospira genomes or rfb operons to fully develop this method. PMID- 20721669 TI - [Aims, implementation and impact of the Charter of rights for people in need of long-term care and assistance]. AB - All citizens have the right to dignified and respectful social care and assistance. The state and society as a whole have the responsibility to guarantee the realization of these rights. However, the question arises what is dignified and respectful long-term care and assistance for the individual? One possible answer is given by the German Charter of Rights for people in need of long-term care and assistance. The charter summarizes existing books of law such as the German Federal Constitution or the European Social Charter and translates them into a specific context of long-term care. It is written in a language easily understood by everyone and reflects the central situation of people in need of long-term care and assistance. It sets an explicit benchmark for health and social care in Germany. The Charter was developed in 2005 at the round table for long-term care, hosted by the Federal Ministry for Family Affairs, Senior Citizens, Women and Youth in collaboration with the Federal Ministry of Health and Social Security. The round table consisted of representatives of users, consumer groups and other stakeholders, but also of care providers and health and care insurance funds in Germany.Many institutions, such as residential homes and health care services have now successfully applied the Charter in their daily work and it has found its way into several books of law at national and regional levels. The following article gives an overview of the structure, content and intention of the Charter and also highlights examples of implementation and its effects on the care structure and daily work with people in need of long-term care. PMID- 20721668 TI - Pseudotumor cerebri. AB - INTRODUCTION: Pseudotumor cerebri is a condition characterized by raised intracranial pressure, normal CSF contents, and normal brain with normal or small ventricles on imaging studies. It affects predominantly obese women of childbearing age; however, its incidence seems to be increasing among adolescent and children. While among older children the clinical picture is similar to that of adults, younger children present demographic and clinical peculiarities. Different diagnostic criteria for adults and pre-pubertal children have been proposed. Etiology and pathogenesis are still unclear, particular concerning the role of obstruction to venous outflow. METHODS: An extensive literature review concerning all the aspects of pseudotumor cerebri has been performed, both among adults and pre-pubertal children. CONCLUSION: Pseudotumor cerebri is an avoidable cause of visual loss, both in adults and children. Few diagnostic measures are usually sufficient to determine the correct diagnosis. Since pseudotumor cerebri is a diagnosis of exclusion, the differential diagnosis work out is of special importance. Modern neuroimaging techniques, especially magnetic resonance imaging and magnetic resonance venography may clarify the role of obstruction to venous outflow in each case. Various therapeutic options are available: medical, surgical, and endovascular procedures may be used to prevent irreversible visual loss. Treatment is usually effective, and most patients will experience complete resolution of symptoms without persistent deficits. PMID- 20721670 TI - The role of lymphadenectomy in uterine carcinosarcomas (malignant mixed mullerian tumours): a critical literature review. AB - BACKGROUND: Uterine carcinosarcomas are rare and highly aggressive tumours. Although surgery is the cornerstone of treatment, the extent of the procedure remains controversial. We sought to evaluate the available literature data regarding the rationale of lymphadenectomy and its possible impact on survival. METHODS: A systematic Medline, PubMed and Scopus search with special focus on the publications of the last decade. RESULTS: Carcinosarcomas have similar clinical characteristics and behaviour with grade 3 endometrioid or aggressive variants of uterine adenocarcinoma. All studies have demonstrated that the FIGO stage of disease is the most important prognostic factor, followed by the depth of myometrial invasion, extra-uterine spread and positive peritoneal cytology. Moreover, lymph node involvement will be found in 14-38% of patients undergoing lymphadenectomy. This figure is similar to the one reported for endometrial carcinoma. Therefore, lymphadenectomy is mandatory for staging purposes. Regarding its impact on survival, the majority of studies confirm a significant survival benefit. The possible mechanisms for the improvement of survival from lymphadenectomy include removal of micro-metastatic foci, reduction of recurrence risk (removal of "target tissue") and mechanical circumvallate of the disease. Given that 5-38% of the patients will experience local recurrence and 30-83% distant metastases, lymphadenectomy reduces the risk of the first and identifies patients in advanced stage that may benefit from adjuvant chemotherapy, aiming to reduce the second and ultimately improve overall survival. CONCLUSIONS: Our review data fully justifies the rationale of lymphadenectomy, which beyond staging information seems to offer a measurable survival benefit. PMID- 20721671 TI - Nuclear pore biogenesis into an intact nuclear envelope. AB - Nuclear pore complexes (NPCs) serve as transport channels across the nuclear membrane, a double lipid bilayer that physically separates the nucleoplasm and cytoplasm of eukaryotic cells. New evidence suggests that the multiprotein nuclear pores also play a role in chromatin organization and gene expression. Given the importance of NPC function, it is not surprising that a growing list of human diseases and developmental defects have been linked to its malfunction. In order to fully understand the functional repertoire of NPCs and their essential role for nuclear organization, it is critical to determine the sequence of events that lead to the formation of nuclear pores. This is particularly relevant since NPC number, and possibly composition, are tightly linked to metabolic activity. Most of our knowledge is derived from NPC formation that occurs in dividing cells at the end of mitosis when the nuclear envelope (NE) and NPCs reform from disassembled precursors. However, NPC assembly also takes place during interphase into an intact NE. Importantly, this process is not restricted to dividing cells but also occurs during cell differentiation. Here, we will review aspects unique to this process, namely the regulation of nuclear expansion and the mechanisms of fusion between the outer and inner nuclear membranes. We will then discuss conserved and diverging mechanisms between post-mitotic and interphase assembly of the proteinaceous structure in light of recently published data. PMID- 20721672 TI - Measurement of the thickness and volume of adherent cells using transmission through-dye microscopy. AB - Cell volume is one of the basic characteristics of a cell and is being extensively studied in relationship to a variety of processes, such as proliferation, apoptosis, fertility, or locomotion. At the same time, its measurement under a microscope has not been well developed. The method we propose uses negative transmission contrast rendered to cells by a strongly absorbing dye present in the extracellular medium. Cells are placed in a shallow compartment, and a nontoxic and cell-impermeant dye, such as acid blue 9, is added to the medium. Transmission images are collected at the wavelength of maximum dye absorption (630 nm). Where the cell body displaces the dye, the thickness of the absorbing layer is reduced; thus, an increase in cell thickness produces brighter images and vice versa. The absolute values for cell thickness and volume can be easily extracted from the image by computing the logarithm of intensity and dividing it by the absorption coefficient. The method is fast, impervious to instability of the light source, and has a high signal-to-noise ratio; it can be realized either on a laser scanning or a conventional microscope equipped with a bandpass filter. For long-term experiments, we use a Bioptechs perfusion chamber fitted with a 0.03-mm spacer and an additional port to enable rapid switching of solutions. To show possible applications of this method, we investigated the kinetics of the cell volume response to a hypotonic buffer and to the apoptotic agents staurosporine and ionomycin. PMID- 20721675 TI - Anthropometric risk factors for elevated blood pressure in adolescents in Turkey aged 11-17. AB - To investigate the relationship between anthropometric parameters and elevated blood pressure in adolescents, we measured blood pressure (BP), height, weight, triceps skinfold (TSF) thickness, waist circumference (WC), and mid-upper-arm circumference (MUAC) in 2,860 student volunteers aged 11-17 years in Kayseri, Turkey. Waist-to-height ratio (WHtR), waist-to-arm-span ratio (WASR), body mass index (BMI), arm-fat area (AFA), and fat percentage (FP) were also calculated. Participants were divided into two groups: hypertensive [systolic blood pressure (SBP) or diastolic blood pressure (DBP) >= 95th percentiles, n = 246] and normotensives (SBP or DBP < 95th percentiles, n = 2614). Multiple logistic regression models were produced within these groups for the examined risk factors, and cutoff points were investigated for SBP or DBP >= 95th percentiles using receiver operating characteristics (ROC) analysis. BMI, WC, WHtR, WASR, MUAC, and BMI had statistically significant cutoffs among boys. Whereas BMI, WHtR, WASR, WC, MUAC, AFA, and TSF were statistically significant for girls younger than 15, only BMI and WC were statistically significant for participants older than 15. The independent risk factors for elevated BP were determined according to BMI and WC. Although several anthropometric measurements were significant in our participants, BMI and WC were significant among all participants irrespective of age and sex. PMID- 20721674 TI - Microvascular disease in children and adolescents with type 1 diabetes and obesity. AB - The incidence of type 1 diabetes (T1D) is increasing worldwide and is associated with a significant burden, mainly related to the development of vascular complications. Over the last decades, concomitant with the epidemic of childhood obesity, there has been an increasing number of cases of type 2 diabetes (T2D) among children and adolescents. Microvascular complications of diabetes, which include nephropathy, retinopathy and neuropathy, are characterized by damage to the microvasculature of the kidney, retina and neurons. Although clinically evident microvascular complications are rarely seen among children and adolescents with diabetes, there is clear evidence that their pathogenesis and early signs develop during childhood and accelerate during puberty. Diabetic vascular complications are often asymptomatic during their early stages, and once symptoms develop, there is little to be done to cure them. Therefore, screening needs to be started early during adolescence and, in the case of T2D, already at diagnosis. Identification of risk factors and subclinical signs of complications is essential for the early implementation of preventive and therapeutic strategies, which could change the course of vascular complications and improve the prognosis of children, adolescents and young adults with diabetes. PMID- 20721676 TI - Center of pressure excursion as a measure of balance performance in patients with non-specific low back pain compared to healthy controls: a systematic review of the literature. AB - Over the past 20 years, the center of pressure (COP) has been commonly used as an index of postural stability in standing. While many studies investigated COP excursions in low back pain patients and healthy individuals, no comprehensive analysis of the reported differences in postural sway pattern exists. Six online databases were systematically searched followed by a manual search of the retrieved papers. The selection criteria comprised papers comparing COP measures derived from bipedal static task conditions on a force-plate of non-specific low back pain (NSLBP) sufferers to those of healthy controls. Sixteen papers met the inclusion criteria. Heterogeneity in study designs prevented pooling of the data so only a qualitative data analysis was conducted. The majority of the papers (14/16, 88%) concluded that NSLBP patients have increased COP mean velocity and overall excursion as compared to healthy individuals. This was statistically significant in the majority of studies (11/14, 79%). An increased sway in anteroposterior direction was also observed in NSLBP patients. Patients with NSLBP exhibit greater postural instability than healthy controls, signified by greater COP excursions and a higher mean velocity. While the decreased postural stability in NSLBP sufferers further appears to be associated with the presence of pain, it seems unrelated to the exact location and pain duration. No correlation between the pain intensity and the magnitude of COP excursions could be identified. PMID- 20721677 TI - Does administration of non-steroidal anti-inflammatory drug determine morphological changes in adrenal cortex: ultrastructural studies. AB - Rofecoxib (Vioxx(c) made by Merck Sharp & Dohme, the USA) is a non-steroidal anti inflammatory drug which belongs to the group of selective inhibitors of cyclooxygenasis-2, i.e., coxibs. Rofecoxib was first registered in the USA, in May 1999. Since then the drug was received by millions of patients. Drugs of this group were expected to exhibit increased therapeutic action. Additionally, there were expectations concerning possibilities of their application, at least as auxiliary drugs, in neoplastic therapy due to intensifying of apoptosis. In connection with the withdrawal of Vioxx(c) (rofecoxib) from pharmaceutical market, attempts were made to conduct electron-microscopic evaluation of cortical part of the adrenal gland in preparations obtained from animals under influence of the drug. Every morning animals from the experimental group (15 rats) received rofecoxib (suspension in physiological saline)--non-steroidal anti-inflammatory drug (Vioxx(c), Merck Sharp and Dohme, the USA), through an intragastric tube in the dose of 1.25 mg during 8 weeks. In the evaluated material, there was found a greater number of secretory vacuoles and large, containing cholesterol and other lipids as well as generated glucocorticoids, lipid drops in cytoplasm containing prominent endoplasmic reticulum. There were also found cells with cytoplasm of smaller density--especially in apical and basal parts of cells. Mitochondria occasionally demonstrated features of delicate swelling. The observed changes, which occurred on cellular level with application of large doses of the drug, result from mobilization of adaptation mechanisms of the organism. PMID- 20721678 TI - A rare cause of dyspnea due to chylothorax. AB - We report the case of an 8-year-old boy who presented to the emergency department of another hospital and was referred to our pediatric intensive care unit with dyspnea and tachypnea of recent onset. The diagnosis of massive chylothorax with mediastinal shift was made on chest radiographs and CT scan. Initial investigations revealed no definite cause for the chylothorax. On later radiography and CT imaging with 3D surface rendering, a marked bone loss of the left ribs, clavicle, and shoulder joint was shown. The diagnosis of Gorham-Stout disease associated with chylothorax was suspected and histologically confirmed. PMID- 20721679 TI - Coarse-grained Brownian ratchet model of membrane protrusion on cellular scale. AB - Membrane protrusion is a mechanochemical process of active membrane deformation driven by actin polymerization. Previously, Brownian ratchet (BR) was modeled on the basis of the underlying molecular mechanism. However, because the BR requires a priori load that cannot be determined without information of the cell shape, it cannot be effective in studies in which resultant shapes are to be solved. Other cellular-scale models describing the protrusion have also been suggested for modeling a whole cell; however, these models were not developed on the basis of coarse-grained physics representing the underlying molecular mechanism. Therefore, to express the membrane protrusion on the cellular scale, we propose a novel mathematical model, the coarse-grained BR (CBR), which is derived on the basis of nonequilibrium thermodynamics theory. The CBR can reproduce the BR within the limit of the quasistatic process of membrane protrusion and can estimate the protrusion velocity consistently with an effective elastic constant that represents the state of the energy of the membrane. Finally, to demonstrate the applicability of the CBR, we attempt to perform a cellular-scale simulation of migrating keratocyte in which the proposed CBR is used for the membrane protrusion model on the cellular scale. The results show that the experimentally observed shapes of the leading edge are well reproduced by the simulation. In addition, The trend of dependences of the protrusion velocity on the curvature of the leading edge, the temperature, and the substrate stiffness also agreed with the other experimental results. Thus, the CBR can be considered an appropriate cellular-scale model to express the membrane protrusion on the basis of its underlying molecular mechanism. PMID- 20721680 TI - Favorable long-term outcome of low-grade oligodendrogliomas irrespective of 1p/19q status when treated without radiotherapy. AB - Despite the accumulating evidences of high chemosensitivity especially in anaplastic oligodendrogliomas with loss of chromosomes 1p and 19q, the optimal management strategy for low-grade tumors using the 1p/19q information remains controversial. We have treated all low-grade oligodendrogliomas by a chemotherapy preceding strategy without radiotherapy, and here we analyzed the survival outcomes of 36 consecutive patients in relation to 1p/19q status. The treatment protocol was as follows: (1) simple observation after gross total resection, and (2) modified PCV chemotherapy for postoperative residual tumors or recurrence after total resection. The 1p and 19q status were analyzed by fluorescence in situ hybridization. The median follow-up period was 7.5 years and no patient was lost during the follow-up periods. 1p/19q co-deletion was observed in 72% of the patients, and there was no significant association between 1p/19q co-deletion and chemotherapy response rate. The 5- and 10-year progression-free survival (PFS) rate was 75.1 and 46.9%, respectively, and the median PFS was 121 months for 1p/19q-deleted tumors and 101 months for non-deleted tumors (log-rank test: P = 0.894). Extent of surgery did not affect PFS (P = 0.685). In contrast, the elder patients (>50) had significantly shorter PFS (P = 0.0458). Recurrent tumors were well controlled by chemotherapy irrespective of 1p/19q status, and 35 out of 36 patients survived without receiving radiotherapy. The 5- and 10-year overall survival rates were 100 and 93.8%, respectively. Two of the patients in their sixties (29%) suffered from severe cognitive dysfunctions and marked brain atrophy following chemotherapy alone. These results show that low-grade oligodendrogliomas could be successfully treated by surgical resection and nitrosourea-based chemotherapy alone without radiotherapy irrespective of 1p/19q status. PMID- 20721681 TI - L-FABP T94A decreased fatty acid uptake and altered hepatic triglyceride and cholesterol accumulation in Chang liver cells stably transfected with L-FABP. AB - Liver fatty acid-binding protein (L-FABP, FABP1) is a highly conserved key factor in lipid metabolism. This study was undertaken to verify whether the T94A mutation in the L-FABP gene affects fatty acid uptake and intracellular esterification into specific lipid pools. Candidate SNPs were recreated using site-directed mutagenesis and tested for physical function in stably transfected Chang liver cell lines. We found that the T94A mutant of L-FABP lowered FFA uptake but had no effect on FFA efflux. L-FABP T94A-expressing cells showed decreased triglyceride content and increased cholesterol accumulation compared to the wild-type control for cells incubated with an FFA mixture (oleate: palmitate, 2:1 ratio). In conclusion, our study provided additional indications of the functional relevance of the L-FABP T94A SNP in hepatic fatty acid and lipid metabolism in humans. PMID- 20721682 TI - Up-regulation of stearoyl-CoA desaturase 1 and elongase 6 genes expression in rat lipogenic tissues by chronic food restriction and chronic food restriction/refeeding. AB - Successful treatment of obesity and related diseases by chronic food restriction requires the understanding of the effect of such nutritional therapy on the expression of genes which have been implicated to be involved in some diseases associated with obesity. The purpose of this study was to examine the effect of chronic food restriction and chronic food restriction/refeeding on lipogenic enzymes, especially the expression of genes encoding the stearoyl-CoA desaturase 1 (Scd1) and elongase6 (Elovl6) in rat liver and adipose tissue. We found that both chronic food restriction and chronic food restriction/refeeding caused increased expression of the Scd1 and Elovl6 genes in both the liver and adipose tissue. The increase was more pronounced in case of chronic food restriction/refeeding (several-fold increase) than that in chronic food restriction alone (two to threefold increase). Essentially, similar results were obtained when the expression of fatty acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and malic enzyme genes was studied. Moreover, we found that chronic food restriction and short-term fasting exert opposite effects on the expression of lipogenic enzymes genes. The increased expression of the genes encoding Scd1, Elovl6, and other key lipogenic enzymes may favor fat storage after chronic food restriction/refeeding and may be part of the molecular mechanism by which food restriction/refeeding increases body weight and enhances susceptibility to insulin resistance. PMID- 20721683 TI - Molecular identification of the gene encoding porcine tristetraprolin (TTP). AB - Tristetraprolin (TTP) is a CCCH tandem zinc finger protein that can bind to and destabilize certain mRNAs containing AU-rich element (ARE) binding sites. In this study, a novel porcine cDNA has been isolated by expressed sequence tag assembly and subsequently confirmed by RT-PCR analysis, and designated porcine TTP (poTTP). The open reading frame of the poTTP cDNA is 981 bp, encoding 326 amino acids. The poTTP gene is approximately 2.5 kb in size and contains a single intron. Southern blotting analysis demonstrated that it is a single copy gene. Real-time quantitative PCR analysis revealed that the poTTP gene is constitutively expressed in all detected tissues, and with the highest mRNA level in lymphoid tissues spleen and thymus. Recombinant His(6)-tagged poTTP protein and its two zinc finger mutants (C146G and H127I) were efficiently expressed and purified from Escherichia coli BL21 (DE3), respectively. In vitro, RNA electrophoretic mobility shift assay confirmed a direct interaction between poTTP protein and porcine TNF-alpha (poTNF-alpha) mRNA ARE probe; this interaction was eliminated when using either two zinc finger mutants of poTTP. Consistently, mutations within the ARE region prevented the binding interaction between recombinant poTTP protein and poTNF-alpha mRNA ARE probe. These results indicate that poTTP is an ARE-binding protein that might regulate the turnover of certain mRNAs in vivo. PMID- 20721684 TI - Effect of the redox state on HIV-1 tat protein multimerization and cell internalization and trafficking. AB - The redox state of the cysteine-rich region of the HIV Tat protein is known to play a crucial role in Tat biological activity. In this article, we show that Tat displays two alternative functional states depending on the presence of either one or three reduced sulphydryl groups in the cysteine-rich region, respectively. Using different approaches, a disulfide pattern has been defined for the Tat protein and a specific DTT-dependent breaking order of disulfide bonds highlighted. The Tat redox state deeply influences macrophage protein uptake. Immunoistochemistry analysis shows that the oxidized protein does not enter cells, whereas partially reduced protein reaches the cytosol and, to a limited extent, the nucleus. Finally electrophoretic analysis shows Tat high-molecular weight multi-aggregation, resulting in the loss of biological activity. This is due to strong electrostatic and metal-binding interactions, whereas Tat dimerization involves metal-binding interactions as well as disulfide bond formation. PMID- 20721685 TI - A comprehensive survey of Wireless Body Area Networks : on PHY, MAC, and Network layers solutions. AB - Recent advances in microelectronics and integrated circuits, system-on-chip design, wireless communication and intelligent low-power sensors have allowed the realization of a Wireless Body Area Network (WBAN). A WBAN is a collection of low power, miniaturized, invasive/non-invasive lightweight wireless sensor nodes that monitor the human body functions and the surrounding environment. In addition, it supports a number of innovative and interesting applications such as ubiquitous healthcare, entertainment, interactive gaming, and military applications. In this paper, the fundamental mechanisms of WBAN including architecture and topology, wireless implant communication, low-power Medium Access Control (MAC) and routing protocols are reviewed. A comprehensive study of the proposed technologies for WBAN at Physical (PHY), MAC, and Network layers is presented and many useful solutions are discussed for each layer. Finally, numerous WBAN applications are highlighted. PMID- 20721686 TI - Design and development of a Telephone-Linked Care (TLC) system to reduce impulsivity among violent forensic outpatients and probationers. AB - Forensic services face the challenge of reducing relapse among clients with a history of violent crime. An automated interactive voice response (IVR) service of the complex Telephone-Linked Care (TLC) type, with a focus on reducing impulsivity, could improve the adequacy of service responses to client needs. Theoretically based in Dialectical Behavior Therapy (DBT), Cognitive Behavior Therapy (CBT) and Motivational Interviewing (MI), the forensic TLC system offers interactive conversations on coping with the emotions of anger, shame and loneliness; activities of daily life such as getting out of bed, asking for help, visiting social services and taking medication; and other areas such as hearing voices, drinking alcohol and self-critical thoughts. We describe the user's flow through the system, with an in-depth synopsis of the hearing voices intervention. Issues regarding voluntary versus mandatory use of the system are addressed in connection with prospective introduction of the system in forensic settings. PMID- 20721687 TI - Boundary issues and multiple relationships in genetic counseling supervision: supervisor, non-supervisor, and student perspectives. AB - Boundary issues and multiple relationships potentially affect all supervision interactions. Boundary crossings are departures from the strictest professional role and may or may not benefit supervisees. Boundary violations are outside common practice and may place supervisees at significant risk. Multiple relationships occur when supervisors concurrently or consecutively hold two or more roles with supervisees. Studies in other fields indicate supervisors and supervisees may be uncertain about professional conduct regarding these issues. In this study, genetic counselor supervisors (n = 126), non-supervisors (n = 72), and genetic counseling students (n = 129) completed an anonymous survey investigating four major questions: 1) Are various boundary issues and multiple relationships perceived as differentially appropriate? 2) Do supervisor, non supervisor, and student perceptions differ? 3) What challenging situations have respondents experienced? and 4) What management strategies did they use? There was general agreement among groups in their appropriateness ratings of 56 hypothetical supervisor behaviors, although supervisor ratings tended to reflect stricter boundaries regarding the appropriateness of interactions than student ratings. A majority rated unavoidable boundary crossings and supervisor multiple relationships involving an academic relationship as most appropriate, and romantic/sexual multiple relationships and/or boundary violations as least appropriate. Analysis of respondents' actual challenging situations revealed many involved boundary violations, placed students at risk of harm, and often resulted in student compliance. PMID- 20721689 TI - Reconstructive surgery in young women with breast cancer. AB - Recovery of body image after mastectomy is essential for physical and mental quality of life. Partial or total mastectomy deformities can be reversed by reconstructive surgical procedures. Young women with breast cancer have specific characteristics related to the age of onset of the disease, prognosis and reconstructive expectations. Patient individualization is the key to a successful breast reconstruction. Autologous and prosthetic reconstruction are the two main techniques used for breast reconstruction. Each reconstructive technique has its own indications, advantages and limitations. Timing of the surgery is primarily determined by the requirement for adjuvant radiotherapy, so an immediate or a delayed approach can be recommended. In patients in whom the need for adjuvant radiotherapy is in doubt, a delayed-immediate approach is the best to optimize aesthetic and oncologic outcomes. Prophylactic mastectomy is also being indicated in a growing number of patients. In these patients it is important to choose a similar reconstructive procedure on both sides to achieve breast symmetry. PMID- 20721688 TI - Variability of NS1 proteins among H9N2 avian influenza viruses isolated in Israel during 2000-2009. AB - The main aims of the present study were to characterize NS1 protein from H9N2 avian influenza viruses (AIVs) isolated in Israel and to investigate the possibility to use NS1-based indirect ELISA. To achieve these purposes, the non structural gene (NS1) of 79 AIVs of the H9N2 subtype isolated in Israel in 2000 2009 was sequenced and genetically analyzed. The phylogenetic analysis demonstrated that four distinct introductions of H9N2 occurred in Israel during this period. Analysis of the inferred amino acid sequences of the NS1 proteins showed high, about 10%, differences between viruses of the 3rd and 4th introductions. Antibodies against NS1 protein in immune sera were tested by means of indirect ELISA using recombinant NS1 as antigen. Immune sera were obtained from experimentally H9N2-infected chicken after infection on 4, 7, 10, 14, and 21 days. All sera from chickens experimentally infected with 3rd- or 4th introduction AIV contained anti-NS1 antibodies that were detected by enzyme linked immunosorbent assay (NS1-ELISA) even though the recombinant NS1 used as antigen for NS1-ELISA differed significantly in its amino acid sequences from the NS1 protein of AIV that caused infection in experimental birds. These findings indicate that the sites of the NS1 protein by which viruses belonging to 3rd and 4th introduction are out of antigenic epitope positions were responsible for the results of NS1-based iELISA. PMID- 20721690 TI - Clinical significance of a serum CA 15-3 surge and the usefulness of CA 15-3 kinetics in monitoring chemotherapy response in patients with metastatic breast cancer. PMID- 20721691 TI - Ecotoxicological effects of rice field waters on selected planktonic species: comparison between conventional and organic farming. AB - The aim of this study was to assess the ecotoxicological effects of water coming from untreated organic and conventional rice field production areas in the Ebro Delta (Catalonia, Spain) treated with the herbicides oxadiazon, benzofenap, clomazone and bensulfuron-methyl and the fungicides carbendazim, tricyclazole and flusilazole. Irrigation and drainage channels of the study locations were also included to account for potential toxic effects of water coming in and out of the studied rice fields. Toxicity tests included four species (Pseudokirchneriella subcapitata, Desmodesmus subcapitatus, Chlorella vulgaris and Daphnia magna), three endpoints (microalgae growth, D. magna mortality and feeding rates), and two trophic levels: primary producers (microalgae) and grazers (D. magna). Pesticides in water were analyzed by solid phase extraction-liquid chromatography electrospray-tandem mass spectrometry (LC-ESI-MS/MS). Negative effects on algae growth and D. magna feeding rates were detected mainly after application of herbicides and fungicides, respectively, in the conventional rice field. Results indicated that most of the observed negative effects in microalgae and D. magna were explained by the presence of herbicides and fungicides. The above mentioned analyses also denoted an inverse relationship between phytoplankton biomass measured as chlorophyll a and herbicides. In summary, this study indicates that in real field situations low to moderate levels of herbicides and fungicides have negative impacts to planktonic organisms and these effects seem to be short lived. PMID- 20721692 TI - Expanded newborn screening in Greece: 30 months of experience. AB - In Greece, the National Newborn Screening Program was initiated in 1974 and is performed by the Institute of Child Health (ICH). However, there is a complete absence of conditions that have high rates of mortality and a relatively high prevalence listed in the Catalogue of Disorders screened by the ICH. Our laboratory has expanded the existing NBS program to include newborn screening for inborn errors of metabolism, screening for cystic fibrosis (the most common congenital disorder in the Greek population), congenital adrenal hyperplasia, and for biotinidase deficiency. From July 2007 to December 2009, 45,000 dried blood spots (DBS) were collected from infants born in Athens, Greece, and were analyzed. We present a report of our 30-month experience in the newborn screening area. The samples were tested for amino acidopathies, fatty acid oxidation disorders (FAOD), and organic acid metabolic disorders by applying flow injection analysis-electrospray ionization-tandem mass spectrometry (FIA-ESI-MS/MS); for cystic fibrosis by immunoreactive trypsinogen (IRT) measurement (time-resolved fluoroimmunoassay); for congenital adrenal hyperplasia by fluoroimmunoassay to measure the 17 hydroxy-progesterone level; and for biotinidase deficiency using a colorimetric method and a semiquantitative fluoroimmunoassay to determine biotinidase activity. Sample analysis resulted in establishing cutoff values for the respective disease markers for the first time in the Greek population. Four infants were identified with cystic fibrosis, two with congenital adrenal hyperplasia, two with phenylketonuria (PKU), one with medium-chain acyl CoA dehydrogenase deficiency (MCADD), and one with biotinidase deficiency. To the best of our knowledge, this is the first article reporting the status of expanded newborn screening in Greece. PMID- 20721693 TI - New calretinin-positive cells with polymorphous spines in the mouse forebrain during early postnatal ontogeny. AB - Immunohistochemical studies of calretinin (CR) in forebrain structures adjacent to the anterior horn of the lateral ventricle in adult mice allowed us to detect a population of previously unknown mono- and bipolar cells whose bodies and processes were coated with polymorphous spines (PS) (Morfologiya, 135, No. 3, 7 19 (2009)). CR-positive spiny (CR(+)PS) cells did not contain GAD67 and were located in the white matter and layers V-VI of the frontal area of the dorsomedial cortex close to the cingulum, the rostrodorsal part of the caudate putamen, the anterior olfactory nucleus, and the subependyma of the dorsolateral angle of the lateral ventricle. We report here studies of the distribution of these cells in seven-day-old mice. Comparative topographic analysis of definitive and early CR(+)PS cells showed that in seven-day-old mice, CR(+)PS cells were absent from the sites at which they were seen in adults, i.e., the anterior olfactory cortex, the cortical plate, and the inner part of the neostriatum. In addition, small numbers of CR(+)PS-like cells were seen at this age within the dorsal migration pathway, at the anterior margin of the neostriatum, along the dorsal border of the neostriatum with the corpus callosum, in the subependymal layer of the lateral wall of the lateral ventricle, and in the cingulum area. These data demonstrate that CR(+)PS cells may have a postnatal origin. Experiments to verify this hypothesis were performed using postnatal administration of bromodeoxyuridine (BrdU) to mice aged 2-4 days, followed by assessment of brain sections fixed at age 20 days. Double immunolabeling of sections for CR and BrdU demonstrated the presence of CR(+)PS cells containing postnatally supplied BrdU. These data provide evidence that at least some CR(+)PS cells undergo mitosis at postnatal age. In all probability, during the period from 7 to 20 days of postnatal development, CR(+)PS cells migrate to the sites that they occupy in adult animals. PMID- 20721694 TI - Patterns of referral and treatment of undescended testis: a 12-year experience in a single centre. AB - BACKGROUND: It is now recommended that orchidopexy be performed by 18 months. AIMS: To examine trends in the referral pattern and treatment of cryptorchidism in the south of Ireland. Secondly, to see how well EAU guidelines on orchidopexy management are being implemented in current practice. METHODS: A total of 145 orchidopexies performed over two periods, 1997-1998 (n = 31) and 2007-2008 (n = 114), were reviewed. RESULTS: There was a decrease in the mean age at referral, review in OPD and orchidopexy from 5.88, 6.26, and 6.98 years, respectively, in the first period, to 2.74, 3.45 and 4.1 years between 2007 and 2008. The proportion of boys having surgery before the age of 18 months was minimal and showed no improvement over time. CONCLUSIONS: Although there was a reduction in the age at orchidopexy, only a marginal number of boys underwent the surgery by 18 months of life. PMID- 20721695 TI - Interns as teachers of medical students: a pilot programme. AB - BACKGROUND: In recent years, rising numbers of medical students and an increasingly demanding clinical workload has put pressures on the educational systems for medical students in the hospital. Bedside teaching remains central to education, but tutorial delivery by registrars, tutors and consultants has proven to be increasingly difficult with the greater numbers of students now in the undergraduate system. AIMS: We have performed a pilot study to determine the feasibility of developing a Junior Tutor Programme, to assist in the delivery of tutorials to undergraduate medical students. METHODS: This was designed and delivered by interns under the supervision of the academic staff in the Departments of Medicine and Surgery in Connolly Hospital. The programme was evaluated by a questionnaire filled in by the students anonymously. RESULTS: A supervised programme of tutorials delivered by interns is a potentially useful way to ensure delivery of clinical teaching to undergraduate medical students. PMID- 20721696 TI - Are postoperative drains necessary with the Karydakis flap for treatment of pilonidal sinus? (Can fibrin glue be replaced to drains?) A prospective randomized trial. AB - PURPOSE: Different surgical techniques for pilonidal disease have been described in the literature. In this study, our aim was to evaluate the influence of routine cavity drainage in the Karydakis flap technique. METHODS: As much as 50 male patients with pilonidal sinus who underwent the Karydakis flap operation were evaluated prospectively.The patients were assigned randomly into two groups (Group 1 with suction drain; Group 2 fibrin glue). RESULTS: Fluid collection was encountered in 8 out of 50 patients (6.25%): 6 in Group 2 (24%) of which 4 experienced superficial, healed with simple dressing, the other 2 with substantial dehiscence healed with wound dressing; 2 in Group 1 (8%) were treated with wound punctures.There has been no recurrence in any of the patients during the follow-up period.The Karydakis flap operations can be performed with a near zero recurrence rate with the use of drains. CONCLUSION: We recommend the use of fibrin sealant with Karydakis flap procedure, but further studies are needed to confirm this conclusion. PMID- 20721697 TI - cagA and vacA status and influence of Helicobacter pylori infection on serum oxidative DNA damage in Iranian patients with peptic ulcer disease. AB - BACKGROUND: Infection with Helicobacter pylori strains may result in different pathological manifestations and increased oxidative stress leading to a strong inflammatory response in gastric mucosa. AIMS: The prevalence of cagA and vacA genes, proteins and the association of serum levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) with oxidative DNA damage were determined. METHODS: The presence of cagA gene and vacA alleles and IgG antibodies against CagA and VacA proteins were determined. Oxidative DNA damage status was determined using serum levels of 8 OHdG. RESULTS: Helicobacter pylori-positive, cagA-positive, and vacA alleles (s1 and m2) were predominant in all clinical outcomes. There was no significant association between prevalence of CagA and VacA status and clinical outcomes. The serum levels of 8-OHdG was at a higher level in H. pylori-positive patients. CONCLUSIONS: These virulence factors are not associated with the development of PUD in Iranian patients. H. pylori infection may be associated with increased serum 8-OHdG. PMID- 20721698 TI - Safety and tolerability of high-intensity anticoagulation with bivalirudin during neuroendovascular procedures. AB - BACKGROUND: Bivalirudin (Angiomax) is a direct thrombin inhibitor used in interventional cardiology due to its several distinct advantages over heparin, most notably a shorter half-life and a potentially superior safety profile. Bivalirudin is also safe to use in patients with active or remote heparin-induced thrombocytopenia. Our objective was to evaluate the safety and tolerability of high-intensity anticoagulation using bivalirudin during neuroendovascular procedures. METHODS: The bivalirudin dosing regimens reported in the cardiac literature were modified empirically for two different activated clotting time (ACT) target ranges. The low-dose protocol (ACT of 250 to 300 s) was used for embolization procedures and the high-dose protocol (ACT of 300-350) was employed for angioplasty and stent placement. The bivalirudin treated patients were matched for age, gender, and type of procedure with a random sample of patients who underwent neuroendovascular procedures with the standardized heparin protocol. The thromboembolic and hemorrhagic complications were compared between the two groups and bleeding complications were categorized as major (hemorrhage that was intra-cerebral or resulted in Hb decrease >= 5 g/dl), minor, or insignificant. RESULTS: Bivalirudin was used in 30 patients with high-dose and low-dose bivalirudin protocols used in 26 and 4 patients, respectively. These were compared to the 60 control patients who received heparin. There were no bleeding or thromboembolic complications in the bivalirudin treated patients; however one patient reported a transient headache. In patients treated with heparin, one bleeding complication of a groin hematoma was reported. Also one patient was found to have left-arm weakness following the procedure which was attributed to a new small middle cerebral artery ischemic event. CONCLUSIONS: Our data supports that bivalirudin usage is likely a safe alternative to heparin for high-intensity anticoagulation in neuroendovascular procedures. Further studies are required for more definitive comparisons for efficacy and cost-effectiveness between the two agents. PMID- 20721699 TI - The eschar of scrub typhus. PMID- 20721700 TI - Accidental inorganic mercury chloride poisoning in a 2-year old child. AB - Inorganic mercury poisoning is uncommon, but when it occurs it can result in severe, life threatening features and acute renal failure. A 2-year old well thriving child presented with alleged history of accidental ingestion of inorganic mercury chloride. He presented with evidence of corrosive trauma to the gastrointestinal tract mucosa, but with normal renal function at admission, which was managed with BAL and other supportive treatment. But he developed non oliguric renal failure after admission, which also improved gradually. On follow up, two months later, the patient's renal function was normal; indicating that renal failure caused by acute inorganic mercury poisoning produced no permanent renal damage. We have hereby presented a case of mercury intoxication in a 2-year old child, with an excellent clinical improvement and normalization of laboratory results. PMID- 20721702 TI - Abdominal epilepsy misdiagnosed as peptic ulcer pain. PMID- 20721701 TI - A clear CSF is not always a normal CSF: a case report of pneumococcal meningitis. AB - A normal initial cerebrospinal fluid (CSF) study has been traditionally used to exclude the potential diagnosis of bacterial meningitis. However, cases of pyogenic meningitis in the absence of CSF pleocytosis have been reported in which smears for gram stain or CSF culture revealed the diagnosis of meningitis. In the presence of clinical signs of meningitis, an abnormal initial CSF study indicates a diagnosis of bacterial meningitis but a normal result may not necessarily exclude it and therefore, should not delay early institution of appropriate antimicrobial therapy. PMID- 20721703 TI - Auditory neuropathy/Dys-synchrony in NICU high risk babies: results from a South Indian Hospital. PMID- 20721704 TI - Relapse of herpes simplex encephalitis presenting as choreoathetosis. AB - We report a case of herpes simplex virus (HSV) encephalitis (HSE) in an 11-year old boy who recovered with acyclovir therapy but developed relapse after 2 weeks. Choreoathetosis was the presenting feature of relapse. Response to antiinflammatory treatment was excellent. To the best of our knowledge, this is the first case of HSE relapse presenting with choreoathetosis reported from India. We describe the patient and review the literature on HSE and HSE relapse. PMID- 20721705 TI - Comet assay in neonatal sepsis. AB - OBJECTIVE: To determine whether the DNA damage detected using the Comet assay helps in the diagnosis of neonatal sepsis METHODS: Sepsis was diagnosed, based on clinical findings, laboratory findings and positive culture results, in 24 of the 48 newborns who participated in the study. Hematological parameters, baseline demographic data and genotoxic evaluation were investigated. RESULTS: There were no significant differences in hematological, demographic and genotoxic data between cases and controls. CONCLUSIONS: The Comet assay proved to be ineffective in the diagnosis of neonatal sepsis. PMID- 20721706 TI - RUNX2 polymorphisms associated with OPLL and OLF in the Han population. AB - BACKGROUND: Runt-related transcription factor 2 (RUNX2), BMP-2, COL6A1, and VDR are four genes that may be related to ossification of the spinal ligament. However, their pathogenetic relevance remains unclear. Most cases of ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) have been reported in Asian populations, but the polymorphic loci in these genes may vary among people of different races. PURPOSES: We identified (1) polymorphic loci in four genes (RUNX2, BMP-2, COL6A1, and VDR) in OPLL and OLF in Chinese Han patients and (2) identified loci related to these diseases. METHODS: We analyzed 19 single nucleotide polymorphisms (SNPs) in four candidate genes in 200 Han individuals (82 patients and 118 control subjects) by the Sequenom system. The genotype distribution and allele frequency of each SNP in the control and patient groups were compared. We then determined the relationships between the loci and the occurrence of OPLL and OLF. RESULTS: Genotyping showed RS1321075 and RS12333172 in RUNX2 differed between the patients and the control subjects. Both loci were located on chromosome 6 and exhibited linkage disequilibrium. One of the two blocks was a haplotype, thus suggesting a link between this block and increased incidence of OPLL and OLF. CONCLUSION: Although the detailed mechanism of the SNP is unclear, our data suggest RUNX2 could be responsible for ectopic bone formation in the spinal ligament in the Chinese Han population. However, we found no obvious connection between polymorphic loci of COLA1, BMP-2, and VDR and the diseases. CLINICAL RELEVANCE: Molecular genetic studies have identified several candidate genes that may be responsible for increased susceptibility to the diseases. Information regarding SNPs among the certain candidate genes may improve understanding of the disease and assist in developing new diagnostic gene tools during early episodes of the disease. PMID- 20721707 TI - Vitamin A supplementation for different periods alters rat vascular redox parameters. AB - Vitamin A plays physiological and antioxidants properties and is associated with protective effects on arterial level. However, deleterious effects have been reported, including those observed by our group, which has demonstrated pro oxidant properties in other systems. Therefore, it is needed to better understand the redox effects of retinoids on arterial system. Thus, our aim was to compare vascular redox parameters among animals supplemented or not with vitamin A. Eighty-five adult male rats were treated with different retinyl palmitate doses (1,000-9,000 IU kg(-1) day(-1)) or saline for 3 (25 rats, n=5 for each group), 7 (25 rats, n=5 for each group), and 28 (35 rats, n=7 for each group) days periods. Aorta artery was surgically removed, cleaned to remove the blood, and homogenized. It was evaluated thiobarbituric reactive species (TBARS), total reduced sulfhydryl (SH), and activities of superoxide dismutase (SOD) and catalase (CAT). Statistics were conducted by one-way ANOVA with Dunnet's post hoc and significance value of p<=0.05. About TBARS, we observed no modifications after 3 days, but a decrease after 7 days in all doses and after 28 days in three higher doses. The two higher doses yielded an increase on SH only after 3 days. SOD activity decreased in three higher doses after 3 days and in all doses after 28 days, but no modifications after 7 days, while CAT activity increased in all doses after 3 days, decreased in all doses after 7 days, and did not change after 28 days. In conclusion, vitamin A induces antioxidant status on vascular level. PMID- 20721708 TI - How to promote orthopedic basic science. PMID- 20721709 TI - Short-term postoperative mortality events in patients over 80 years of age with hip fracture: analysis at a single institution with limited medical resources. AB - BACKGROUND: Lethal events represent the most important complication in the treatment of hip fracture in elderly patients. Despite the increasing chance for treatment of such conditions, few data regarding risk factors associated with lethal events have been determined for ordinary hospitals with limited medical and human resources, particularly in Japan. METHODS: The incidence of postoperative lethal events and related preoperative risk factors in extremely elderly patients (>80 years) with hip fracture were retrospectively analyzed in our hospital for the past 2 years. RESULTS: Lethal events occurred in 11 (10.7%) of 103 patients within 3 months postoperatively. In both univariate and multivariate analyses, an elevated number of co-morbidities and preoperative respiratory dysfunction were identified as significant risk factors. Delay in surgery was not a risk factor for lethal events. CONCLUSIONS: A valid reason for delay is the need to stabilize concurrent medical conditions due to multiple co morbidities in extremely elderly patients with hip fracture. Considering the limited resources and extreme age of the subjects, the mortality rate in the present study was quite acceptable. Patients, families of patients, and physicians should recognize the increased risk of mortality for patients with significant risk factors in the surgical treatment of hip fracture. PMID- 20721710 TI - New treatment method for developmental dysplasia of the hips after walking age: arthroscopic reduction with limboplasty based on the findings of preoperative imaging. AB - BACKGROUND: What makes treatment choice for developmental dysplasia of the hips diagnosed after walking age difficult is the poor understanding of prereduction conditions that obstruct the reduction in spatial terms. To evaluate these problems, we employed subtraction three-dimensional imaging to search for the factors involved in intraarticular obstruction. On the basis of the findings of preoperative subtraction threedimensional imaging from computed tomography, we developed a new method, a minimum invasive arthroscopic reduction with limboplasty, for reduction of developmental dysplasia of the hips after walking age. The purposes of this report were to: (1) describe the technique of the arthroscopic procedure, and (2) evaluate our new method using radiographic parameters. METHODS: Ten patients with ten hips with developmental dysplasia after walking age treated by arthroscopic reduction with limboplasty were included in this study. The mean age of the patients at reduction was 22.6 months (range, 18.6-29.7 months); mean age at follow up was 7.2 years (range, 3.9-10.9 years); and mean follow up was 5.4 years (range, 1.7-9.0 years). These ten hips were evaluated using radiographic measurements. RESULTS: Moderate or severe avascular necrosis of the femoral head was not observed. Two hips that had a spherical-shaped head with minimal residual height loss or coxa magna were classified as Kalamchi and MacEwen grade 1. Additional surgery had been performed for two hips classified as Severin group 4 during the course of follow up. These two hips were classified as Severin group 1 at final examination. One more hip was classified as Severin group 4 at final examination, and additional surgery was recommended. The remaining seven hips (70%) therefore obtained good evaluations by arthroscopic reduction with limboplasty alone. CONCLUSIONS: We developed a new reduction method by using an arthroscopic procedure for the reduction of developmental dysplasia of the hips after walking age when this dysplasia failed to be reduced with nonoperative methods. The result of our new method is acceptable because good evaluations were obtained in 70% of hips 5.4 years after reduction by our new method alone. PMID- 20721711 TI - Reliability and validity of the Japanese Orthopaedic Association hip score. AB - BACKGROUND: The Japanese Orthopaedic Association (JOA) hip score has been widely used in Japan as a method to assess hip joint diseases. The JOA hip score consists of four subcategories: pain (Pain), range of motion (ROM), ability to walk (Gait), and activities of daily life (ADL). We present the first report to verify the reliability and validity of the JOA hip score. METHODS: A total of 123 patients with osteoarthritis of a unilateral hip and 29 patients with osteonecrosis of a unilateral hip were investigated. The JOA hip score was recorded by orthopedic surgeons in their offices. On the same day, each patient answered a Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (Japanese version 1.2) by himself or herself. The SF-36 survey measures eight subscales. The internal-consistency reliability of the JOA hip score was evaluated by Cronbach's coefficient alpha. The validity of the JOA hip score was tested by Spearman's correlation coefficients between the four subcategories of the JOA hip score and the eight SF-36 subscales. RESULTS: When patients with osteoarthritis with conservative treatment were assessed by the JOA hip score, Cronbach's coefficient alpha was 0.70, demonstrating internal-consistency reliability. However, when the JOA hip score was used for other groups, Cronbach's coefficient alpha was <0.70, demonstrating the lack of internal consistency reliability. Significant correlations were observed between Pain and bodily pain (r = 0.63), between Gait and physical functioning (PF) (r = 0.70), and between ADL and PF (r = 0.81), but not in any other combinations. CONCLUSIONS: We found that the JOA hip score is a reliable system only for patients with osteoarthritis of the hip with conservative treatment. The JOA hip score is a scaling system with convergent and discriminant validity for the assessment of physical function and pain. PMID- 20721712 TI - Long-term survivorship analysis of hip arthroplasty with vitallium mold cup. AB - BACKGROUND: Cup arthroplasty was used in the initial attempts to preserve the bone stock of the femoral head and neck for hip reconstruction. However, little conclusive data are available regarding its long-term survivorship. METHODS: We present a long-term survivorship analysis (mean follow-up, 19.3 years; range, 5 36.6 years) after vitallium mold arthroplasty in 77 secondary osteoarthritic hips. RESULTS: Kaplan-Meier survivorship analysis predicted a survival rate for vitallium mold arthroplasty of 81.6% (95% confidence interval [CI], 76.7-86.5) at 20 years and 59.1% (95% CI, 51.8-66.5) at 30 years, with conversion to total hip arthroplasty as the endpoint. The mean Merle d'Aubigne and Postel hip score showed a significant decrease in mobility from 4.12 (range, 3.18-5.86) 6 months after the operation to 3.19 (range, 1.7-4.6) at the last follow-up. No significant differences were observed for the pain score from 6 months after the operation (5.05; range, 4.2-5.9) to the last follow-up (4.46; range, 2.88-6.04)) or score for the ability to walk, from 6 months after the operation (2.5; range, 1.4-3.6) to the last follow-up (3.13; range, 1.59-4.67). Radiographically, the proximal and medial migration of the cup measured at the last follow-up was 10.4 +/- 5.4 mm (P < 0.01) and 0.2 +/- 2.1 mm (P > 0.05), respectively. CONCLUSIONS: Our results indicate inferior long-term survivorship after vitallium mold compared with that after Charnley low-friction arthroplasty. PMID- 20721713 TI - Crossover sign after rotational acetabular osteotomy for dysplasia of the hip. AB - BACKGROUND: This study was performed to evaluate whether the radiographic crossover sign influences the painful femoroacetabular impingement or the radiographic progression of osteoarthritis after rotational acetabular osteotomy (RAO). METHODS: A total of 104 patients (115 hips) with preosteoarthritis (pre OA) or early-stage OA of the hip due to dysplasia underwent RAO. Their mean age at the time of surgery was 34.7 years. The mean follow-up period was 13 years. Clinical follow-up was performed with the system of Merle d'Aubigne, and the impingement sign was evaluated. Radiographic analyses included the center-edge angle, acetabular roof angle, head lateralization index (HLI), joint congruency, crossover sign, posterior wall sign, acetabular index of depth to width, pistol grip deformity, and femoral head/femoral neck ratio. RESULTS: The mean clinical score improved significantly from 14.6 preoperatively to 17.0 at follow-up. The impingement sign at follow-up was observed in 14 hips (12.2%). The center-edge angle, acetabular roof angle, and head lateralization index (HLI) improved significantly after surgery. The crossover sign was observed in 8 hips (7.0%) preoperatively and in 49 hips (42.6%) postoperatively. The posterior wall sign was observed in 70 hips (60.9%) preoperatively and in 73 hips (63.5%) postoperatively. The impingement sign after RAO was positive significantly in the postoperative crossover sign-positive hips. Radiographic progression of OA was observed in 11 hips (crossover sign was positive in 7 hips and negative in 4 hips). The only factors significantly associated with radiographic progression after RAO were fair postoperative joint congruency and age at surgery. CONCLUSIONS: Although there was no significant radiographic progression of OA despite significant retroversion, anterior impingement and radiographic crossover sign after RAO are should be checked during the procedure. The goal of RAO should be correct alignment of the acetabulum including a correct version with a negative crossover sign. PMID- 20721714 TI - High-dose antibiotic infusion for infected knee prosthesis without implant removal. AB - BACKGROUND: Retention of a prosthesis represents an attractive surgical modality for the infected but well-fixed knee prosthesis because patients need to stay in bed after removal of all components. Some additional postoperative treatment would be needed, however, when treated only with debridement because of its low success rate. METHODS: In this study, intraarticular antibiotic infusion into the infected joints after debridement, while retaining the implants, was performed for six well-fixed total knee arthroplasties (TKAs), one revision TKA, and five tumor megaprostheses with an average follow-up period of 47.5 months (range 20-82 months). TKA patients with a polyethylene insert or those with all exchangeable components and all polyethylene parts in tumor megaprostheses underwent device removal and thorough debridement of the soft tissues. Subsequently, new polyethylene inserts were implanted in the TKA patients. The removed metallic prostheses were resterilized and reimplanted, and new polyethylene inserts were implanted in the tumor megaprostheses patients. The wound was closed in layers after insertion of a catheter percutaneously. The patients received organism specific intraarticular antibiotics through the catheter twice a day until the infection disappeared clinically. RESULTS: There was no recurrence of infection in the TKA and revision TKA patients. Four of five knees treated with tumor megaprostheses exhibited recurrence of the infection. Infection was finally healed, however, in all cases by the same treatment procedure. CONCLUSIONS: Although some patients experienced recurrence of infection, successful implant salvage was achieved in all cases with the same treatment procedure. Patients do not need to stay in bed during this treatment. Therefore, this method should be considered as one of the treatment options for infected knee prostheses. PMID- 20721715 TI - Association of serum carotenoids, retinol, and tocopherols with radiographic knee osteoarthritis: possible risk factors in rural Japanese inhabitants. AB - BACKGROUND: The consumption of antioxidant nutrients may influence the development and progression of osteoarthritis (OA). To determine the association between serum antioxidants and radiographic knee osteoarthritis, we undertook a cross-sectional investigation in a community-based study in Japan. METHODS: A total of 562 subjects (224 male, 338 female) > or = 40 years of age were enrolled in the Comprehensive Health Examination Program (CHEP, Yakumo Study) from 2003 to 2005. Subjects were categorized to the OA group (n = 140) if either knee was graded as Kellgren-Lawrence (K-L) grade > or = 2. The no-OA group was defined as showing radiographic findings of K-L 0 or 1 in either knee (n = 422). The serum levels of retinol, beta-/gamma-tocopherols, alpha-tocopherol, zeaxanthin/lutein, canthaxanthin, cryptoxanthin, lycopene, alpha-carotene, and beta-carotene were measured by high-performance liquid chromatography. The values of these antioxidants were divided into tertiles, and a logistic regression analysis was performed to analyze the association between them and radiographic knee OA, adjusting for potential confounders. RESULTS: Logistic regression analysis showed that compared to the lowest tertile of beta-/gamma-tocopherols the adjusted odds ratio (OR) was 0.52 [95% confidence interval (CI) 0.29-0.93] in the highest tertile; it also indicated a linear trend across tertiles. Furthermore, the adjusted OR was significantly decreased only in the middle tertile of alpha tocopherol (OR 0.51, 95% CI 0.29-0.90). We reevaluated any independent association for these tocopherols after adjustment by entering them into the model simultaneously. The significance of beta-/gamma-tocopherols was maintained. In contrast, no associations were found with any carotenoids or retinol. CONCLUSIONS: High serum values of beta-/gamma-tocopherols were found to be significantly associated with a low OR for radiographic knee osteoarthritis. The decreasing risk with a high serum value of beta-/gamma-tocopherols may support the possible protective effects against knee OA. PMID- 20721716 TI - Upper cervical spine injuries: age-specific clinical features. AB - BACKGROUND: There are few reports on the age-specific clinical features of upper cervical spine injury. To identify these age-specific changes, we reviewed 103 patients with upper cervical spine injury. METHODS: We subdivided the patients into four groups according to age: 12 patients were classified as old elderly (> or = 75 years), 18 patients as young elderly (65-74 years), 67 patients as young adults (18-64 years), and 6 patients as adolescents (< or = 17 years). Data were collected on injury etiology, mortality, neurological deficit, distribution and pattern of injury, degenerative changes of each joint in the upper cervical spine and disc in the cervical spine, and osteoporosis of the axis. RESULTS: The proportion of patients with a simple fall as the etiology of their injury showed a statistically significant trend to increase with aging. Although no specific distribution or pattern of injury was statistically elucidated, we were able to detect some common features. A high proportion of the old elderly group (5/12) had a type II odontoid fracture. Body fracture of the axis tends to be frequent in the young elderly and traumatic spondylolisthesis and hyperextension teardrop fracture to be frequent in the young adults. In adolescents, a traffic accident as an unbelted rear seat passenger was the most frequent etiology. Among the 103 patients, 16 died during the initial hospitalization. The mortality rate for upper cervical spine injury was similar in all groups. CONCLUSIONS: In the old elderly, stiffness of the lower cervical spine, caused by degenerative changes and osteopenia, might contribute to upper cervical spine injury in response to low-energy trauma. The disproportion of degenerative change in joints of the upper cervical spine might also contribute to the high frequency of type II odontoid fracture. In young adults, high-energy and hyperextension injury was the most frequent cause of upper cervical spine injury. PMID- 20721718 TI - Distal radius fracture arthroscopic intraarticular displacement measurement after open reduction and internal fixation from a volar approach. AB - BACKGROUND: The purpose of this study was to assess articular surface reduction arthroscopically after volar locked-plate fixation of distal radius fractures (DRFs) via fluoroscopyguided open reduction/internal fixation. We also aimed to develop preoperative radiographic criteria to help assist in determining which DRFs may need arthroscopic evaluation. METHODS: A total of 31 consecutive patients with DRF were prospectively enrolled. Posteroanterior (PA) and lateral radiographs as well as axial, coronal, and sagittal CT scans were obtained just after attempted reduction of the DRF. The widest articular displacement at the radiocarpal joint surface of the distal radius (preopD) was then measured using a digital radiography imaging system. The DRF was reduced under fluoroscopy, and a volar locked plate was applied. The degree of residual articular displacement was then measured arthroscopically, and the maximum displacement (postopD) was measured with a calibrated probe. RESULTS: Of the 31 patients, 7 had an arthroscopically assessed maximum postopD of > or = 2 mm after internal fixation. The correlation coefficients between each preopD and postopD of all radiographs and CTs were statistically significant. The cutoff values were 0.5 mm for PA radiographs, 2.10 mm for lateral radiographs, 2.15 mm for axial CT scans, 3.15 mm for coronal CT scans, and 1.20 mm for sagittal CT scans. All cutoff values for PA and lateral radiographs and for axial, coronal, and sagittal CT scans were unsuitable as screening criteria for arthroscopic reduction of DRF because of their low sensitivities and specificities. The cutoff value of the new preopD (the sum of the preopDs determined by lateral radiography and coronal CT scan) was 5.80 mm, and its sensitivity and specificity were 100% and 83.3%, respectively. CONCLUSIONS: Because a new preopD cutoff value of 5.80 mm is a good indicator for residual articular displacement after internal fixation of >2 mm, it is also a good indicator for the need for arthroscopic evaluation after internal fixation. PMID- 20721717 TI - Surgical correction of spinal deformity in patients with congenital muscular dystrophy. AB - BACKGROUND: Congenital muscular dystrophy (CMD), among the myopathic disorders is one form of flaccid neuromuscular disorder (NMD). Patients with NMD frequently develop progressive spinal deformity. For NMD patients who have a severe spinal deformity, sitting is often difficult and is accompanied by pain and breakdown of the skin. Spinal deformity surgery in these patients has been highly effective in stabilizing the spine, maintaining upright, comfortable sitting balance, and improving patients' quality of life. However, many studies have reported significant rates of peri/postoperative complications in these patients. To our knowledge, there has been no study on the results of spinal deformity surgery in patients with CMD. The purpose of this study was to review the clinical and radiological results of spinal deformity surgery in this group of patients with CMD. METHODS: Between 2004 and 2007, a total of 10 CMD patients underwent scoliosis surgery. There were three patients with Fukuyama CMD, three with Ullrich CMD, and 4 with nonsyndromic CMD (merosin-negative). They were nonambulatory. All the patients had standard posterior spinal fusion and pedicle screw-alone fixation from T3 or T4 to L5 for spinal deformity. Our inclusion criteria required that each patient (1) had considerable difficulty with sitting balance and pain or breakdown of the skin due to scoliosis; (2) was able to ventilate his or her lung autonomously; (3) was not ventilator-dependent; and (4) did not have cardiac failure. Sufficient informed consent was important, and the decision to perform surgery was made by the patient/family with sufficient preoperative informed consent. Patients were trained with inspiratory muscle training (IMT) using an inspiratory muscle trainer (Threshold IMT) for 6 weeks prior to surgery Cardiac function was assessed preoperatively. Pulmonary function tests were performed preoperatively and postoperatively. Radiographic assessments were performed on sitting anteroposterior (AP) and lateral radiographs. These assessments were made periodically. The Cobb angles of the curves and spinal pelvic obliquity (SPO) on the coronal plane, thoracic kyphosis, and lumbar lordosis were measured. The preoperative AP radiograph and side-bending films were examined to determine flexibility. Patients' and parents' satisfaction were surveyed by a self-completed questionnaire at the last follow-up. RESULTS: Percent forced vital capacity (%FVC) increased from a mean of 30% before IMT to a mean of 34% the day before surgery. The preoperative scoliosis was 75 degrees (range 61 degrees -95 degrees ). The scoliotic curvature on preoperative side bending films was 19 degrees (range 11 degrees -28 degrees ). All patients were extubated on the day of surgery. No patients developed cardiac or respiratory complications. The scoliotic curvature was 18 degrees (range 10 degrees -25 degrees ) immediately after surgery, and 19 degrees (range 12 degrees -27 degrees ) at the last follow-up. The pelvic obliquity improved from a mean of 17 degrees (range 14 degrees -20 degrees ) preoperatively to a mean of 6 degrees (range 4 degrees -9 degrees ) postoperatively and to 7 degrees (range 4 degrees -10 degrees ) at the last follow-up. Balanced sitting posture was achieved and maintained. On the sagittal plane, good reconstruction of sagittal plane alignment was recreated and maintained. There were no major complications or deaths. All patients/parents completed the outcome satisfaction questionnaire. Eight patients/parents were very satisfied and two were satisfied. CONCLUSIONS: Pedicle-screw-alone fixation and fusion to L5 was safe and effective in CMD patients with scoliosis of <95 degrees and pelvic obliquity of <20 degrees . Scoliosis curves were flexible (75% correction) on side-bending films preoperatively. Curve correction and maintenance of correction in the coronal and sagittal plane was excellent. The pelvic obliquity significantly improved. Balanced sitting posture was achieved and maintained in all patients. Our patients with CMD spinal deformity and a moderately and severely decreased FVC could be operated on safely and successfully with general anesthesia. All patients were extubated in the operating room. There were no major complications or deaths. We believe a FVC of <30% alone is not a predisposition to pulmonary complications. However, cardiomyopathy might be a determining risk of mortality, and we believe surgery for these patients should be avoided. Patients' and parents' satisfaction was high. PMID- 20721719 TI - Reliability, validity, and responsiveness of the Japanese version of the Patient Rated Wrist Evaluation. AB - BACKGROUND: The Patient-Rated Wrist Evaluation is a regionspecific, self administered questionnaire consisting of a pain scale (PRWE-P) and a functional scale (PRWE-F), with the latter consisting of specific function (PRWE-SF) and usual function (PRWE-UF). The PRWE was cross-culturally adapted from the original English version by the Impairment Evaluation Committee, Japanese Society for Surgery of the Hand (JSSH). The purpose of this study was to test the reliability, validity, and responsiveness of the Japanese version of PRWE (PRWE J). METHODS: A consecutive series of 117 patients with wrist disorders completed the PRWE-J, the JSSH version of the Disabilities of the Arm, Shoulder, and Hand (DASH-JSSH) questionnaire and the 36-Item Short-Form Health Survey (SF-36). Of the 117 patients, 71 were reassessed for test-retest reliability 1 or 2 weeks later. Reliability was investigated by reproducibility and internal consistency. To analyze the validity, a factor analysis (principal axis factoring) of PRWE-J and correlation coefficients between PRWE-J and DASH-JSSH were obtained. Responsiveness was examined by calculating the standardized response mean (SRM) (mean change/SD) and effect size (mean change/SD of baseline value) after open surgery in 50 patients. RESULTS: Cronbach's alpha coefficients for PRWE-P, PRWE F, and PRWE were 0.90, 0.95, and 0.95, respectively. The intraclass correlation coefficients (ICCs) for the same were 0.86, 0.93, and 0.92, respectively. Unidimensionality of PRWE-P was con-firmed. Bidimensionality of PRWE-F was confirmed and separated clearly into PRWE-SF and PRWE-UF. The correlation coefficients between PRWE-P and PRWE-F or DASH-JSSH were 0.63 or 0.63, respectively. The correlation coefficient between PRWE-F and DASH-JSSH was 0.80. The correlation coefficients between DASH-JSSH and PRWE-SF or PRWE-UF were 0.76 or 0.73, respectively. Moderate correlation was observed in "physical functioning" for SF-36 and PRWE-SF (r = -0.46), PRWE-F (r = -0.46), or PRWE (r = 0.46). The SRMs/effect sizes of PRWE-P, PRWE-F, or PRWE were respectively excellent: 1.7/2.2, 1.2/1.3, 1.6/1.9. CONCLUSIONS: The PRWE-J has evaluation capacities equivalent to those of the original PRWE. PMID- 20721720 TI - Differential onset patterns and causes of carpal tunnel syndrome after distal radius fracture: a retrospective study of 105 wrists. AB - BACKGROUND: It is well known that carpal tunnel syndrome (CTS) can occur in a wide range of time periods after distal radius fracture (DRF). Few studies have evaluated in detail the relationship between fracture and electrophysiological finding characteristics and time to onset of CTS after DRF. To clarify the characteristics of CTS after DRF, we classified a large number of clinical cases based on the period from the injury to onset of CTS. These cases were analyzed retrospectively. METHODS: We reviewed 105 wrists with CTS following DRF. Patients' ages ranged from 13 to 89 years. These 105 wrists were divided into three groups according to the period of post-fracture onset of CTS. Twenty-eight wrists were classified into the acute onset group (when the symptoms of CTS occurred within 1 week after fracture). Forty-seven wrists were classified into the subacute onset group (when symptoms of CTS occurred from 1 to 12 weeks after fracture). The remaining 30 wrists were classified into the delayed onset group (when symptoms of CTS occurred more than 12 weeks after fracture). Deformity of the distal radius on X-ray films was evaluated and distal motor latency (DML) of the median nerve was recorded to compare values among these three groups. RESULTS: In the acute onset group, 68% had an AO C-type fracture and 46% were caused by a high-energy injury. The percentage of this fracture pattern and mechanism was significantly higher in the acute onset group than in the other groups (P < 0.05; Kruskal-Wallis test). In the subacute onset and delayed onset groups, 79% and 63% had an A-type fracture and more than 90% were caused by a low energy injury. In the delayed onset group, the incidence of prolonged DML in the contralateral wrists was 71%, which was significantly higher than in the other two onset groups (P < 0.05; Kruskal- Wallis test). CONCLUSIONS: There were three onset patterns of CTS after DRF, and each CTS onset pattern had different etiologic mechanisms and different clinical features of CTS. In the acute onset group, a high-energy fracture pattern was associated with CTS. In the subacute and the delayed onset groups, lowenergy injury in elderly women was associated with CTS. Both deformity of the fracture and preexisting median nerve dysfunction were suggested as predisposing factor for CTS. PMID- 20721721 TI - Outcome of the functional treatment of first-time ankle inversion injury. AB - BACKGROUND: Avulsion fractures of the lateral malleoli in ankle inversion injuries are often undetected on routine radiographs. Undetected avulsion fractures have been managed as ankle sprain, which may affect the outcome of the treatment of the ankle sprain. The purposes of this study are to compare the outcomes of functional treatment between the first-time severe ligament injury and avulsion fracture of the lateral ankle, and to investigate how the anterior talofibular ligament (ATFL) view or the calcaneofibular ligament (CFL) view affects the diagnosis of the avulsion fracture and outcome of functional treatment of the ankle inversion injury. METHODS: A total of 276 consecutive patients with a first-time severe ankle inversion injury were classified into a ligament injury group (group I) or an avulsion fracture group (group II) on the basis of physical examination and radiographs. The patients with a negative finding on routine radiographs and a positive finding on the ATFL or CFL view derived from group II (group IIA). Age, sex, and activity level were analyzed. Patients were treated by stirrup splint. RESULTS: A total of 202 (73.2%) patients were in group I and 74 (26.8%) were in group II. In all, 50 patients in group II showed negative standard radiographs and a positive ATFL or CFL view. Altogether, 240 patients were followed up for at least 1 year and assessed clinically and radiographically. Differences in age, sex, and activity level before injury between groups were not statistically significant. Clinical and radiographic results of group II were inferior to those of group I. The outcome of group IIA was comparable to that of group I. CONCLUSIONS: The outcome of functional treatment of avulsion fracture was inferior to that of ligament injury. The ATFL and CFL views provide a more precise diagnosis but do not affect the outcome of the functional treatment. PMID- 20721722 TI - Proposed novel unified nomenclature for range of joint motion: method for measuring and recording for the ankles, feet, and toes. AB - The Ad Hoc Committee of Terminology of the Japanese Society for Surgery of the Foot (JSSF) proposes novel terminology for motion of the ankle, foot, and toe because there are some ambiguities in the current terminology. Articles were identified by searching the electronic databases of PubMed that compared definitions of American Orthopaedic Foot and Ankle Society (AOFAS), International Society of Biomechanics (ISB), and in the textbook of Kapandji as well as the American Academy of Orthopaedic Surgeons (AAOS). A total of 11 articles described the transverse (horizontal) plane motion in the hindfoot as external rotation/internal rotation and 10 as abduction/adduction. In all, 2 articles described the transverse (horizontal) plane motion in midfoot as external rotation/internal rotation and 10 as abduction/adduction. Another 4 articles described the transverse (horizontal) plane motion in the forefoot as external rotation/internal rotation and 8 as abduction/adduction. Altogether, 109 articles described the sagittal plane motion of the foot/ankle as dorsiflexion/plantarflexion and 20 as extension/flexion. In all, 99 articles described the frontal (coronal) plane motion of the foot/ankle as inversion/eversion and 4 as supination/pronation. Furthermore, 12 articles described the sagittal plane motion of toes as dorsiflexion/plantarflexion and 15 as extension/flexion. Another 16 articles described the frontal (coronal) plane motion of toes as supination/pronation and 1 as inversion/eversion. The transverse (horizontal) plane motion of the foot/ankle was defined as abduction/adduction in the hindfoot, midfoot, and forefoot; the sagittal plane motion of the foot/ankle was defined as dorsiflexion/plantarflexion; and the frontal (coronal) plane motion of the foot/ankle as inversion/eversion. The transverse (horizontal) plane motion of toes was defined as abduction/adduction; the sagittal plane motion of toes was defined as extension/flexion; and the frontal (coronal) plane motion of toes was defined as supination/pronation. PMID- 20721723 TI - Predictors of aggravation of cervical spine instability in rheumatoid arthritis patients: the large joint index. AB - BACKGROUND: Improved rheumatic drugs have provided significant benefits, but activities of daily living are not improved if spinal symptoms are overlooked. Furthermore, the appropriate timing for examining the cervical spine during follow-up is unclear. METHODS: To evaluate the relations of cervical spine instabilities and an index for cervical spine lesion in rheumatoid arthritis (RA) based on extremity radiographs, we examined preoperative radiographs of 100 RA patients who underwent total knee arthroplasty. Radiographic results for eight large joints (bilateral shoulders, elbows, hips, and knees) were graded as follows: Larsen grade > or = 2 for each joint was scored as 1 point, which we refer to as the "large joint index" (LJI), based on 0-8 points. The associations of radiographic cervical lesions with LJI, Ranawat class, the disease duration, RA drugs, or blood analysis data were evaluated. RESULTS: Atlantoaxial subluxation (AAS) (> or = 5 mm) was found in 45 patients, vertical subluxation (VS) (< or = 13 mm) in 42, a posterior atlantodental interval (PADI) (<14 mm) in 21, and subaxial subluxation (SAS) (> or = 3 mm) in 23. Most patients with a PADI < 14 mm (19/21, 90%) were complicated with both AAS and VS. LJI had a significant association with AAS (P < 0.0001), VS (P < 0.01), and PADI (P < 0.01). The PADI was significantly lower (P < 0.0001) and the LJI was significantly higher (P < 0.01) in patients of Ranawat class II compared to patients of Ranawat class I. The disease duration, age at surgery, and age at onset were also significantly associated with cervical instabilities. CONCLUSIONS: PADI should be recognized as a predictor of paralysis with anteroposterior instability and vertical and middle low cervical spine instability. The LJI proposed in this study has the possibility of being a predictor of cervical lesions. Patients with RA onset at a young age and a long disease duration also have a risk of progression of cervical spine instability. PMID- 20721724 TI - The usefulness of neutrophil CD64 expression in the diagnosis of local infection in patients with rheumatoid arthritis in daily practice. AB - BACKGROUND: The diagnosis of local infection in patients with rheumatoid arthritis (RA) is frequently difficult because clinical signs and symptoms and laboratory test results of local infection are also observed in arthritis of active RA. The need for a specific marker of infection is high in RA patients. The usefulness of neutrophil CD64 expression (CD64) to diagnose local musculoskeletal infection (local infection) and discriminate local infection from RA-related inflammation in RA patients was examined. METHODS: CD64 was measured by a quantitative method using flow cytometry in 61 RA patients in whom local infection was suspected, and the usefulness of CD64 was examined by comparing the findings with clinical results. RESULTS: There were 25 patients with local infection and 36 patients without infection. The median CD64 value the patients with local infection was 3148 molecules/cell (interquartile range [IQR], 2140 6231) and that of the patients without infection was 1106 molecules/cell (IQR, 804-1464) with a statistically significant difference (P < 0.0001). In contrast, no significant difference between the groups was observed in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell (WBC) count. The area under the curve of CD64 calculated by receiver operating characteristic curve analysis was larger than that of CRP, ESR, or WBC count, suggesting that CD64 has superior ability to discriminate of infection compared to these other markers. When the cutoff value of CD64 was set at 2000 molecules/cell, the sensitivity and specificity of CD64 for the detection of local infection in RA patients were 76.0% and 94.4%, respectively. CONCLUSIONS: CD64 is a useful marker in RA patients to discriminate local infection from RA-related inflammation. PMID- 20721725 TI - Clinical outcome following surgical intervention for a solitary bone cyst: emphasis on treatment by curettage and steroid injection. AB - BACKGROUND: Solitary bone cysts are benign, fluid-filled, expansive lesions in children. The success rate of bone consolidation in the case of a solitary bone cyst is unpredictable following steroid injection. METHODS: Among 24 patients with a solitary bone cyst, 11 (femur 8; pelvic bone 3) underwent curettage plus bone grafting for stabilization. The remaining 13 patients--8 long bones (humerus 6; femur 2) and 5 non-long bones (calcaneus 5)--underwent curettage plus steroid injections. RESULTS: Among the 11 patients, 2 treated by curettage plus bone grafting suffered recurrence and needed a second procedure. One of the 13 patients treated by curettage plus steroid injection as the initial treatment later developed a pathological fracture and underwent bone grafting. The remaining 12 patients treated by curettage plus steroid injection eventually achieved bone consolidation, after an average of 1.6 injections (range 1-3). One injection was enough to achieve bone consolidation in two of seven of the long bone cases (29%) and in all of the five non-long-bone cases. CONCLUSIONS: Steroid injection remains a useful method for treating solitary bone cysts owing to its low invasiveness. The very favorable results achieved in the five calcaneus cases following a single steroid injection may be attributable to curettage. Regardless of the relatively small number of cases, the different prognosis between long bones and the calcaneus following the same procedure suggests a varying pathogenesis and/or etiology among solitary bone cysts. PMID- 20721726 TI - Novel fully interconnected porous hydroxyapatite ceramic in surgical treatment of benign bone tumor. AB - BACKGROUND: Large bone defects remaining after curettage of benign bone tumors should be filled with a substitute to restore mechanical strength. In 2000, we developed a fully interconnected porous calcium hydroxyapatite ceramic (IPCHA, NEOBONE) and have utilized it as a bone substitute. IP-CHA has a finely organized, three-dimensional interconnecting pore structure. The large interconnecting channels (average diameter 40 microm) permit easy penetration of tissue into the deep pores, so IP-CHA can itself induce local bone repair processes. The purpose of this study was to evaluate the clinical outcomes with the use of IP-CHA as bone substitute after curettage of benign bone tumors. METHODS: We reviewed the results of 71 patients with benign bone tumors sequentially treated by curettage followed by implantation of IP-CHA between 2000 and 2006. There were 29 women and 42 men, with a mean age of 28 years. Assessment was based on radiography at each time point during the follow-up. Radiographic findings were classified into five stages: stage 0, no change; stage 1, slight bone formation; stage 2, moderate bone formation; stage 3, consolidation; stage 4, absorption. RESULTS: In 70 of 74 operated lesions, radiographs showed that implanted IP-CHA proceeded to stage 2 or more within an average of 8 months after the surgery. In addition, 17 lesions proceeded to stage 4 within 35 months after surgery, on average. However, there were 10 local recurrences, which is similar to the recurrence rate for such tumors treated with or without implantation of CHAs and reflects the biological nature of each tumor. CONCLUSIONS: In this study, we utilized IP-CHA as a bone substitute after curettage of benign bone tumors and demonstrated its usefulness in the clinical situation. IP-CHA comparatively exhibited excellent bone formation at an early stage although the problem of recurrence of the tumor remained. We conclude that IP-CHA is a useful bone substitute for the treatment of benign bone tumors. PMID- 20721727 TI - Effect of cyclic three-dimensional strain on cell proliferation and collagen synthesis of fibroblast-seeded chitosan-hyaluronan hybrid polymer fiber. AB - BACKGROUND: Tissue engineering techniques using biodegradable three-dimensional (3D) scaffolds with cultured cells offer more potential alternatives for the treatment of severe ligament and tendon injuries. In tissue engineering, one of the crucial roles of 3D scaffolds is to provide a temporary template with the biomechanical characteristics of the native extracellular matrix (ECM) until the regenerated tissue matures. The purpose of the present study was to assess the effect of various cyclic mechanical stresses on cell proliferation and ECM production in a 3D scaffold made from chitosan and hyaluronan for ligament and tendon tissue engineering. METHODS: Three-dimensional scaffolds seeded with rabbit patella tendon fibroblasts were attached to a bioreactor under various conditions: static group, no strain; stretch group, tensile strain; rotational group, rotational strain; combined group, rotational and tensile strain. In the Static group, 3 weeks of stationary culture was performed. In the remaining three groups, a loading regimen of 0.5 Hz for 18 h and then 6 h rest was carried out for 2 weeks after 1 week of static culture. The DNA content was determined to quantify cell proliferation. Real-time reverse transcription polymerase chain reaction analysis was performed to assess the mRNA levels of the ECM products. RESULTS: DNA content of the combined group was significantly higher than that of the static and stretch groups, and that of the rotational group was significant higher than that of the static and stretch groups at 21 days after cultivation. The mRNA level of types I and III collagen and fibromodulin in the combined group was significantly higher than that in the other three groups. The amount of collagen synthesis in the combined group was higher than that in the static group, but the difference was not significant. CONCLUSIONS: Multidimensional cyclic mechanical strain to mimic the physiological condition in vivo has the potential to improve or accelerate tissue regeneration in ligament and tendon tissue engineering using 3D scaffolds in vitro. PMID- 20721728 TI - Dorsoventral organization of sensory nerves in the lumbar spine as indicated by double labeling of dorsal root ganglion neurons. AB - BACKGROUND: Referred pain due to lumbar disc disorders can be analyzed using the stereoscopic structure of the peripheral sensory nervous system. The rostrocaudal structure has been clarified. The dorsoventral structure of the lumbar spine would be useful for mapping areas of pain perception in spinal disorders. METHODS: The neurotracer 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI) was applied to the lateral portion of the L5/6 intervertebral disc in rats to examine the dorsoventral organization of the sensory nervous system in the lumbar spine and related tissues. Fluorogold (FG) was applied to reference sites located at the spinous process of the L5 vertebra, the L5/6 facet joint, the psoas muscle at the L5 level, or the rectus abdominis muscle at the pubic symphysis. FG was also applied to the lateral portion of the disc (DiI application site) at L5 or at the L5 level as controls for the double labeling. Labeled neurons were counted in dorsal root ganglia (DRGs) from L1 through L4. RESULTS: The proportion of neurons double-labeled with DiI and FG in the total number of DiI-labeled and FG-labeled neurons was 32.9% in the control group; 0% in the spinous process, 0.6% in the facet joint, 2.3% in the psoas muscle, and 0.1% in the rectus abdominis muscle. DRG neurons with dichotomizing afferent fibers were most prevalent (2.3%) between the lateral disc and the psoas muscle at the groin; they were rare or absent between the disc and other reference sites. CONCLUSIONS: Dorsoventral organization of the primary sensory system in the lumbar body trunk was suggested from the proportion of DRG neurons with dichotomizing afferent fibers innervating the lumbar disc and other tissues. The present findings provide a pathomechanism of groin referred pain in lumbar disc disorders. PMID- 20721729 TI - Effect of estrogen on tissue elasticity of the ligament proper in rabbit anterior cruciate ligament: measurements using scanning acoustic microscopy. AB - BACKGROUND: Previous epidemiological studies revealed that anterior cruciate ligament (ACL) injuries were more frequently seen in female athletes than in male athletes. To elucidate the pathogenetic roles of estrogen in ACL ruptures, the elasticity of ACL tissue was measured using a scanning acoustic microscope (SAM) in an estrogen-controlled animal model. METHODS: A total of 40 ovariectomized Japanese white rabbits were randomly divided into four groups according to the administered dose of 17beta-estradiol (groups L, M, H, and C). Injection of 17beta-estradiol was performed 1, 2, 3, and 4 weeks after surgery, and doses in groups L, M, and H were 50, 100, and 500 microg/kg, respectively. Group C received no estradiol. Only groups L, M, and C were used for current analyses because their mean serum estrogen levels were within the physiological range (groups C, L, M, and H: 37, 50, 60, and 231 pg/ml, respectively). Five weeks after ovariectomy, the lateral portion of the ligament was harvested. Specimens were fixed with 10% neutralized formalin and embedded in paraffin. Then, 10 mum thick sections were cut perpendicular to the ligament fibers for routine histological staining and measurement with SAM. RESULTS: The mean tissue sound speeds of groups C, L, and M were 1727 +/- 32, 1683 +/- 53, and 1665 +/- 63 m/s, respectively. Group M presented significantly lower tissue sound speed than group C (P = 0.021). Furthermore, a negative correlation was found between the mean serum estrogen level and mean tissue sound speed of the ACL among all animals in groups C, L, and M (r = 0.47, P = 0.016). CONCLUSION: The results of the present study indicated that estrogen altered the tissue elasticity of rabbit ACL. Estrogen may constitute one of the pathogenetic factors in ACL rupture in female athletes. PMID- 20721730 TI - Sporadic osteogenesis imperfecta type V in an 11-year-old Japanese girl. PMID- 20721731 TI - Acute reconstruction of the medial collateral ligament of the elbow for severe valgus instability after anterior elbow dislocation. PMID- 20721732 TI - Multiple capillary hemangiomas of the cauda equina at a level of a single vertebra. PMID- 20721733 TI - C1/2 facet cyst revealed by facet joint arthrography. PMID- 20721734 TI - The identification of colon cancer susceptibility genes by using genome-wide scans. AB - Recent studies have indicated that in approximately 35% of all colorectal cancer (CRC) cases, the CRC was inherited. Although a number of high-risk familial variants have been identified, these mutations explain <6% of CRC cases; therefore, further genome-wide scans will need to be conducted in the future. There are two popular approaches to genome-wide scans, namely linkage and association. The linkage approach utilizes several hundred markers (typically between 300 and 500 markers) throughout the genome and identifies candidate regions shared among affected family members. Candidate regions are then scrutinized for the presence of susceptibility loci. Linkage studies require no prior information and can provide new avenues for future research, but the regions identified are often large and include many candidate genes. The second and more recent approach is the genome-wide association study (GWAS) in which hundreds of thousands of markers called single nucleotide polymorphisms (SNPs) are used to identify the SNPs associated with traits of interest by employing family-based or case-control association methods. GWAS studies require no prior information and, because they use hundreds of thousands of SNPs, they can target specific candidate genes and/or narrow regions for investigation. Study design considerations, methodology, and the execution of linkage and genome-wide association studies that use both family and case-control designs are covered in this chapter. PMID- 20721735 TI - Prioritizing candidate genetic modifiers of BRCA1 and BRCA2 using a combinatorial analysis of global expression and polymorphism association studies of breast cancer. AB - Epidemiological evidence from different studies has shown that genes harboring sequence variations may modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene-based approach or the development of large genome-wide association studies. However, both methods have notable limitations. This chapter describes a novel approach for analyzing gene expression differences to prioritize candidate modifier genes for single nucleotide polymorphism association studies. The advantage that gives this strategy an edge over other candidate gene-based studies is its potential to identify candidate genes that interact with exogenous risk factors to cause or modify cancer, without detailed a priori knowledge of the molecular pathways involved. PMID- 20721736 TI - Microarray-based comparative genomic hybridization (array-CGH) as a useful tool for identifying genes involved in Glioblastoma (GB). AB - Alterations in the genome that lead to changes in DNA sequence copy number are a characteristic of Glioblastomas (GBs). Microarray-based comparative genomic hybridization (array-CGH) is a high-throughput technology that allows the hybridization of genomic DNA onto conventional cDNA microarrays, normally used in expression profiling, to analyze genomic copy number imbalances. In this way, thousands of genes can be reviewed in a high resolution analysis to define amplicons and to identify? candidate genes showing recurrent genomic copy number changes in GB tumors. PMID- 20721737 TI - Multiplex Amplifiable Probe Hybridization (MAPH) methodology as an alternative to comparative genomic hybridization (CGH). AB - Genomic imbalances in locus copy-number are highly significant for the diagnosis and prognosis of cancer. Rapidly progressing DNA microarray technologies detect such pathogenic copy-number changes in the genome with high throughput, efficiency, and resolution. A variety of different microarray-based approaches have emerged, with array comparative genomic hybridization (array-CGH) being the method of choice in current clinical practice. Here we describe an alternative microarray-based technique called array-MAPH, derived from conventional Multiplex Amplifiable Probe Hybridization (MAPH).The main novelty of array-MAPH is the directed reduction of test DNA complexity prior to hybridization, yielding a mixture of specific probes, identical to target sequences on the microarray and thus increasing hybridization specificity. Unique amplifiable 400-600 bp fragments can be designed for any genomic region of interest, PCR-amplified, and spotted onto arrays as targets. The same sequences are combined into a probe mixture and hybridized to genomic DNA immobilized on a membrane. Bound probes are recovered by quantitative PCR and hybridized to the array. Array-MAPH can be used for the detection of small-scale copy-number changes, thereby providing new insights into the genetic basis of several diseases, including cancer. PMID- 20721738 TI - Utilizing Saccharomyces cerevisiae to identify aneuploidy and cancer susceptibility genes. AB - Cancers are commonly characterized as having an abnormal number of chromosomes, termed aneuploidy, which arise due to genomic instability. There is still debate over whether aneuploidy is a driving force of the disease or a resulting phenotype; however, the presence of aneuploidy can be used to grade the malignant potential of certain types of cancer. A simple hypothesis is that genome instability itself is tumorigenic in that it results in alterations in the number of chromosomes, which alters gene copy number and ultimately affects gene expression in cells.Many gene disruptions that result in a propensity for cells to become aneuploid were first identified through mutagenesis screens designed to generate null or missense mutations in haploid strains of Saccharomyces cerevisiae. In contrast, the susceptibility to develop cancer can be transmitted as an autosomal dominant trait with affected individuals being heterozygous carriers of null mutations. In this chapter, we will describe a technique that can be used to identify heterozygous mutations in dosage-sensitive genes that mediate genomic stability by performing genome-wide screens in yeast. PMID- 20721739 TI - Computational identification of cancer susceptibility loci. AB - The identification of novel cancer susceptibility syndromes and genes from very limited numbers of study individuals has become feasible through the use of high throughput genotype microarrays. With such an approach, highly sensitive genome wide computational methods are needed to identify the regions of interest. We have developed novel methods to identify and compare homozygous and compound heterozygous regions between cases and controls, to facilitate the identification of recessively inherited cancer susceptibility loci. As our approach is optimized for sensitivity, it creates many hits that may be unrelated to the phenotype of interest. We compensate for this compromised specificity by the automated use of additional sources of biological information along with a ranking function to focus on the most relevant regions. The methods are demonstrated here by comparing colorectal cancer patients to controls. PMID- 20721740 TI - Digital candidate gene approach (DigiCGA) for identification of cancer genes. AB - The candidate gene approach is one of the most commonly used methods for identifying genes underlying disease traits. Advances in genomics have greatly contributed to the development of this approach in the past decade. More recently, with the explosion of genomic resources accessible via the public Web, digital candidate gene approach (DigiCGA) has emerged as a new development in this field. DigiCGA, an approach still in its infancy, has already achieved some primary success in cancer gene discovery. However, a detailed discussion concerning the applications of DigiCGA in cancer gene identification has not been addressed. This chapter will focus on discussing DigiCGA in a generalized sense and its applications to the identification of cancer genes, including the cancer gene resources, application status, platform and tools, challenges, and prospects. PMID- 20721741 TI - The use of denaturing high performance liquid chromatography (DHPLC) for mutation scanning of hereditary cancer genes. AB - Denaturing high performance liquid chromatography (DHPLC) facilitates automated mutation scanning of PCR products with the ability to detect nearly 100% of sequence variants including single nucleotide substitutions and small insertions or deletions. It has particular application for genetic screening in inherited conditions; both for the initial identification of a mutation in disease carriers followed by sequence analysis, and for screening "at-risk" individuals prior to the development of disease in families with a known mutation. Specifically, in familial cancer syndromes, DHPLC has been reported as a genetic screening tool for the risk of developing breast and ovarian cancer (BRCA1), von Hippel Lindau disease (VHL), Cowden syndrome (PTEN), and Multiple Endocrine Neoplasia types 1 and 2 (MEN1 and RET). This chapter focuses on the methodologies specific to the WAVE System for Mutation Detection 2100 (Transgenomic Inc., Omaha, NE, USA) and highlights the use of Navigator software (Transgenomic Inc.), including data analysis with scatter graphs. PMID- 20721742 TI - Enhanced mismatch mutation analysis: simultaneous detection of point mutations and large scale rearrangements by capillary electrophoresis, application to BRCA1 and BRCA2. AB - We present the routine diagnostic application of EMMA (Enhanced Mismatch Mutation Analysis, Fluigent), a new, fast, reliable, and cost-effective method for mutation screening. This method is based on heteroduplex analysis by capillary electrophoresis and relies on the use of innovative matrices increasing the electrophoretic mobility differences between homoduplex and heteroduplex DNA, which is further enhanced by the addition of nucleosides in the separation matrix. Nucleosides interact with heteroduplex mismatched bases, hence increasing mobility difference with homoduplex. As separations are performed by multi capillary electrophoresis, it allows for high automation, low cost, and high throughput. Moreover, EMMA, in combination with limiting PCR conditions, can be used to achieve the simultaneous detection of point mutation and large scale rearrangement in a single run.We now report on the routine diagnostic use of this method for BRCA1 and BRCA2 screening. The coding sequence and exon-intron junctions of BRCA1 and BRCA2 were amplified in 24 multiplex PCRs using a single condition. PCRs were electrophoresed with a single analytical condition on an ABI3100, and data were analyzed using dedicated software (Emmalys).The strength of this new method relies on the following assets: (1) a single condition of analysis: modeling related to melting domain is not required (2) simultaneous detection of point mutations and large scale rearrangements, (3) optimized and ready-to-use polymer that can be used on various ABI sequencers, (4) easy to use, (5) low reagent costs, and (6) throughput. PMID- 20721743 TI - Economical protocol for combined single-strand conformation polymorphism and heteroduplex analysis on a standard capillary electrophoresis apparatus. AB - Combined single-strand conformational polymorphism (SSCP) and heteroduplex (HD) analysis (SSCP-HD) take advantage of parallel mutation detection in single-strand and duplex fraction during the single capillary electrophoresis (CE) run. The high mutation detection rate of individual SSCP and HD in CE guarantees almost a 100% success rate of combined SSCP-HD. Described here, the protocol for SSCP-HD CE does not require dedicated instrumentation but can be applied for any commonly available CE DNA analyzer. We focused mostly on the sample preparation step that is critical for the stability of generated fractions and reproducibility of a generated result. The application of universal primer for fluorescent labeling and omitting the PCR purification step also greatly reduce the cost of mutation detection by SSCP-HD-CE. PMID- 20721744 TI - Mutational screening of hMLH1 and hMSH2 that confer inherited colorectal cancer susceptibility using denature gradient gel electrophoresis (DGGE). AB - Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is primarily due to heterozygous germline mutations in one of the mismatch repair (MMR) genes. Mutation screening for MMR genes with various techniques revealed that the majority of mutations identified are small DNA variations (83.8% in hMLH1 and 73% in hMSH2). Denaturing gradient gel electrophoresis (DGGE) is a sensitive, robust and powerful technique to detect small nucleotide variations and has been used for mutation screening for many years. The separation principle of DGGE is based on the melting behaviour of DNA molecules. In a denaturing gradient acrylamide gel, double-stranded DNA is subjected to a denaturant environment and will melt in discrete segments called melting domains. The melting temperature (T (m)) of these domains is sequence-specific. Therefore, DNA containing a mutation will have a different mobility compared to the wild type. DGGE is the perfect method for mutation screening of large samples for unknown mutations. This is because it is user friendly, non-radioactive, cost-effective, less labour intensive and, more importantly, it is reliable and has a very high mutation detection rate. We have used DGGE to screen hMLH1 and hMSH2 mutations and have shown high detection rate. PMID- 20721745 TI - s-RT-MELT: a novel technology for mutation screening. AB - The fast growing understanding of genetic pathways that mediate cancer etiology, biology, and personalized medicine leads to an increasing need for extensive and reliable mutation screening on a population or on a single patient basis. Here we describe s-RT-MELT, a novel technology that enables expanded-throughput enzymatic mutation scanning in clinical cancer samples for germline or low-level somatic mutations, or for SNP genotyping. GC-clamp-containing PCR products from tumor and normal cells are hybridized to generate mismatches at the positions of mutations over one or multiple sequences in parallel. Mismatches are converted to double strand breaks using a DNA endonuclease (Surveyor), and poly A oligonucleotide tails are enzymatically attached at the position of the mutations. A novel application of PCR that operates at low denaturation temperatures enables the selective amplification of mutation-containing DNA fragments and high-throughput, closed-tube mutation scanning via melting curve analysis on conventional or nanotechnology real-time PCR platforms. We have applied s-RT-MELT in the screening of TP53 and EGFR mutations in cell lines and clinical samples and demonstrate its advantages for rapid, multiplexed mutation scanning in cancer. PMID- 20721746 TI - Zoom-in array comparative genomic hybridization (aCGH) to detect germline rearrangements in cancer susceptibility genes. AB - Disease predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements, including deletions or duplications that are challenging, to detect and characterize using standard PCR-based mutation screening methods. Such rearrangements range from single exons up to hundreds of kilobases of sequence in size. Array-based comparative genomic hybridization (aCGH) has evolved as a powerful technique to detect copy number alterations on a genome-wide scale. However, the conventional genome-wide approach of aCGH still provides only limited information about copy number status for individual exons. Custom-designed aCGH arrays focused on only a few target regions (zoom-in aCGH) may circumvent this drawback. Benefits of zoom-in aCGH include the possibility to target almost any region in the genome, and an unbiased coverage of exonic and intronic sequence facilitating convenient design of primers for sequence determination of the breakpoints. Furthermore, zoom-in aCGH can be streamlined for a particular application, for example, focusing on breast cancer susceptibility genes, with increased capacity using multiformat design. PMID- 20721747 TI - Development of a scoring system to screen for BRCA1/2 mutations. AB - Selection for genetic testing for pathogenic mutations in BRCA1 and BRCA2 is an important area of healthcare. While testing costs for mutational analysis are falling, costs of tests in North America remain in excess of $3,000. Most countries state that there should be at least a 10-20% likelihood of detecting a mutation in BRCA1 or BRCA2 within a family before mutational analysis is performed. A number of computer-based models have been developed to assess this likelihood, and these continue to be improved to incorporate mutation frequencies, breast cancer incidence and tumour histology. However, these can be time-consuming and difficult to use in a busy clinic. The Manchester scoring system was developed in 2003, and we have continued to validate its use in Western populations. The scoring system discriminates well at both the 10 and 20% threshold for testing and compares very well with more complex computer-based models. However, it should not be used in its current form in founder populations or populations with low incidence of breast cancer, although a lower points threshold could be used to determine an appropriate cut off. The development of the Manchester score and its comparison with other models will be described in this chapter. PMID- 20721749 TI - Functional analysis of human BRCA2 variants using a mouse embryonic stem cell based assay. AB - We describe here a comprehensive and reliable assay to test the functional significance of variants of unknown clinical significance (VUS) identified in the human breast cancer susceptibility gene, BRCA2. The assay is based on the ability of human BRCA2 to complement the loss of endogenous Brca2 in mouse embryonic stem cells. The procedure involves generation of a desired mutation in BRCA2 present in a bacterial artificial chromosome (BAC) and the introduction of the BAC into ES cells engineered for the assay. These ES cells have one null and one conditional allele of Brca2. First, the effect of the BRCA2 variants on the viability of ES cells is tested by Cre-mediated deletion of the conditional allele. Subsequently, variants that result in viable ES cells are examined for their effect on known functions of BRCA2 using a variety of functional assays such as sensitivity to genotoxic agents, in vivo and in vitro proliferation, effect on homologous recombination and genomic stability. The method described herein allows for the analysis of three to five sequence variants within 2-3 months. This approach can also be used for functional analysis of variants identified in other human disease genes that result in a phenotype detectable in ES cells. PMID- 20721748 TI - Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants. AB - The interpretation of the numerous sequence variants of unknown biological and clinical significance (UV for "unclassified variant") found in genetic screenings represents a major challenge in the molecular diagnosis of genetic disease, including cancer susceptibility. A fraction of UVs may be deleterious because they affect mRNA splicing. Here, we describe a functional splicing assay based on a minigene construct that assesses the impact of sequence variants on splicing. A genomic segment encompassing the variant sequence of interest along with flanking intronic sequences is PCR-amplified from patient genomic DNA and is cloned into a minigene vector. After transient transfection into cultured cells, the splicing patterns of the transcripts generated from the wild-type and from the variant constructs are compared by reverse transcription-PCR analysis and sequencing. This method represents a complementary approach to reverse transcription-PCR analyses of patient RNA, for the identification of pathogenic splicing mutations. PMID- 20721750 TI - Developing functional assays for BRCA1 unclassified variants. AB - Women with a family history of breast cancer have mutations in one of the breast cancer susceptibility genes, BRCA1 or BRCA2. Since the discovery of these two genes, around 100,000 women worldwide have undergone genetic testing. The decisions they make based on the results are usually life changing and may involve radical preventive surgeries such as prophylactic mastectomy and oophorectamy. However, not all mutations will lead to breast cancer, and to prevent unnecessary surgery, we are developing assays to determine which mutations adversely affect the functions of the protein encoded by the BRCA1 gene. The functions of BRCA1 are mediated by numerous interactions that are required for cell-cycle and centrosome control, transcriptional regulation and the DNA damage response. Missense mutations that perturb the interactions of BRCA1 will adversely affect these functions and are, therefore, likely to lead to breast cancer. Determining the effect missense mutations have on the interaction of BRCA1 with DNA will form the basis of the assay described in this chapter. PMID- 20721751 TI - Special issue for anthropology & medicine. PMID- 20721752 TI - The assemblage of compliance in psychiatric case management. AB - In the post-asylum era, case managers perform much of the face-to-face work of pharmaceutical compliance for people with severe and persistent mental illness. Their work demands careful orchestration of the assemblage of compliance, including the actual medications, the ideology of biopsychiatry, the division of professional labor, and certain mundane tools. Ethnographic vignettes from an Assertive Community Treatment (ACT) team show how case managers use this assemblage in their everyday routines, but also how it undercuts key elements of the original ACT mission. Reflecting its roots in the deinstitutionalization movement, the ACT model gives case managers limitless responsibilities for clients' lives, but then narrowly defines their role as the prosthetic extension of psychiatric authority. To produce compliance, case managers depend on the medication cassette, analyzed here as a human/non-human hybrid woven into their ordinary work. The medication cassette has pre-scripted uses that enlist clinicians in biopsychiatric thinking and also silently impose compliant behavior on clients. The elements in the assemblage of compliance depend on each other, but they do not form a seamless whole, as evidenced by the dilemmas and micropolitics of the clinical front-line. Theoretical notions of assemblages and technologies of compliance, drawn from science and technology studies, illuminate a core conundrum of practice in psychiatric case management. PMID- 20721753 TI - Inverting compliance, increasing concerns: aging, mental health, and caring for a trustful patient. AB - Why, after 40 years of intensive research, is adherence to treatment still an issue? This paper suggests a possible solution to an apparently unsolvable problem: reconceptualizing adherence. To understand how adherence can affect key personnel in any western health system, this study focuses on community nurses working with older mental health patients in Quebec. When they spoke about adherence, nurses presented an idealized image of the nurse-patient relationship, namely, the caring nurse and the trustful patient. However, this idealization cannot be reduced only to questions of power and paternalism. By reconceptualizing adherence as a 'matter of concern', health professionals and researchers alike might come to understand individual care situations within a broader notion of conflicts in patient care. PMID- 20721754 TI - Desire and disappointment: adolescent psychotropic treatment and adherence. AB - This paper situates medication adherence among adolescents in current cultural and political-economic debates about compliance/adherence and the formation of biomedical subjectivities. Building on prior work of the authors, this paper explores the role of desire in adherence to show how subjectivities are shaped by concordant, instrumental, or conditional forms of desire. Data is used to show how parents and adolescents compare the medicated self before and after, resulting in the formation of desire. It is argued that adherence is an outcome of desire: no desire, no adherence, or varying types of desire. Moreover, adherence is not a steady state. It is produced moment to moment as adolescents confront the desires of others. The study uses interview data to construct a case study of concordant desire, which is a form most likely to produce adherence. With concordant desire the medicated come to expect a future life on medication and a life where symptoms are stripped of their social and psychological meaning and significance. PMID- 20721755 TI - Self-compliance at 'Prozac campus'. AB - This paper focuses on psychiatric medication experiences among a sample of North American university students to explore a new cultural and social landscape of medication 'compliance.' In this landscape, patients assume significant personal decision-making power in terms of dosages, when to discontinue use and even what medications to take. Patients carefully monitor and regulate their moods, and actively gather and circulate newly legitimated blends of expert and experiential knowledge about psychiatric medications among peers, family members and their physicians. The medications too, take a vital role in shaping this landscape, and help to create the spaces for meaning-making and interpretation described and explored in this article. In concluding the article, the authors claim that two popular academic discourses in medical anthropology, one of patient empowerment and shared decision-making and the other of technologies of self and governmentality, may fail to account for other orders of reality that this paper describes - orders shaped and influenced by unconscious, unexpressed and symbolic motivations. PMID- 20721756 TI - Patient and practitioner noncompliance: rationing, therapeutic uncertainty, and the missing conversation. AB - Currently, the life expectancy of black Americans is about five years shorter than that of white Americans when factoring for gender. Poor patient compliance is often used as an explanation for why black people have worse health outcomes. The proof, however, is anecdotal and relies primarily on discourses about black people's general dysfunction. Black patients often respond in kind to problems they experience with health care access. They often conclude that the medical professionals they work with are racist. In most cases, neither of these explanations is correct. This paper argues that behavioral explanations for health care disparities shift attention away from structural issues, namely health care rationing and the limits of therapeutic medicine. The lack of an open discussion about the structural issues is part of the reason the goal initiated by the Clinton administration to end racial disparities by 2010, Healthy People 2010, largely failed. PMID- 20721757 TI - Extreme condition, extreme measures? Compliance, drug resistance, and the control of tuberculosis. AB - This paper explores the issue of compliance by focusing on the control of tuberculosis. In the last ten years, patient compliance in tuberculosis control has discursively shifted from 'direct observation' of therapy to more patient centred focus and support drawing on rights-based approaches in dealing with health care provision. At the same time, there has been an increased international concern with the rise of drug resistant forms of tuberculosis, and how to manage this. This paper looks at these issues and the tensions between them, by discussing the shift in discourses around the two and how they relate. Drawing on experience from work in Nepal, and its successful tuberculosis control programme, it looks at debates around this and how these two arenas have been addressed. The rise of increasingly drug resistant forms of tuberculosis has stimulated the development of new WHO and other guidelines addressing how to deal with this problem. The links between public health, ethics and legal mandate are presented, and the implications of this for controlling transmission of drug resistant disease, on the one hand, and the drive for greater patient support mechanisms on the other. Looking forwards to uncertain ethical and public health futures, these issues will be mediated by emergent WHO and international frameworks. PMID- 20721758 TI - Assessing the 'relative value' of diabetic patients treated through an incentivized, corporate compliance model. AB - Primary Care clinics in the United States continue to incentivize doctors to adhere to clinical guidelines regarding record keeping and managing specific patient disorders. This paper offers a case study of a US physician working in a system of total compliance. This narrative will illustrate how a specific system has emerged that pays doctors an end-of-year bonus for achieving compliance in four specific areas: record keeping, service hours, customer satisfaction surveys, and maintaining tight control of diabetic patients. In particular, special attention is paid to the emphasis on 'the numbers' within the corporate compliance model, and specifically, the relative value units (RVUs) used for structuring billing, labeling patients, and organizing the day-to-day activities of doctors. Although incentivized models of compliance have proved effective in managing both doctors and patients, especially in the UK, 'gaming' the system can occur. This paper identifies one example of how patients assume a hidden risk within this model by potentially being labeled noncompliant by having the wrong numbers, even when receiving good clinical care and acting medically compliant. PMID- 20721759 TI - Dangerous noncompliance: a narrative analysis of a CNN special investigation of mental illness. AB - Prevention of illness has become a central theme in debates over strategies to reduce healthcare costs. Severe mental illness poses a special challenge to the paradigm of rational prevention, the principal strategy of which is adherence to pharmacological therapies. With the contraction in the US of in-patient psychiatric care from the 1960s onwards, the mentally ill have become more visible among the homeless and among those caught up in the penal system. Their characteristic visibility contributes to their image as threatening. The perceived dangerousness and the combined societal and economic costs associated with the illness have generated a heightened, and in some venues even a sensationalized rhetoric surrounding the questions of responsibility and control, which we consider in terms of compliance. Using the linguistic method of discourse analysis, we analyze one high profile instance - an episode of CNN's 'Special Investigations Unit', which aired several times in the summer of 2007 - to demonstrate a narrative linking of the high social costs and failures associated with noncompliance and, therefore, the imperative of enforcing it for the safety of society. Through the semiotic reduction of a 'poetic parallelism', the episode reflects and reinforces existing cultural models for mental illness, including its status as straightforward biological disease amenable to pharmacological therapy but which remains uncontrolled due to widespread noncompliance. PMID- 20721760 TI - Inter-pill-ation and the instrumentalization of compliance. PMID- 20721761 TI - Dissociative tendencies and individual differences in high hypnotic suggestibility. AB - INTRODUCTION: Inconsistencies in the relationship between dissociation and hypnosis may result from heterogeneity among highly suggestible individuals, in particular the existence of distinct highly suggestible subtypes that are of relevance to models of psychopathology and the consequences of trauma. This study contrasted highly suggestible subtypes high or low in dissociation on measures of hypnotic responding, cognitive functioning, and psychopathology. METHODS: Twenty one low suggestible (LS), 19 low dissociative highly suggestible (LDHS), and 11 high dissociative highly suggestible (HDHS) participants were administered hypnotic suggestibility scales and completed measures of free recall, working memory capacity, imagery, fantasy-proneness, psychopathology, and exposure to stressful life events. RESULTS: HDHS participants were more responsive to positive and negative hallucination suggestions and experienced greater involuntariness during hypnotic responding. They also exhibited impaired working memory capacity, elevated pathological fantasy and dissociative symptomatology, and a greater incidence of exposure to stressful life events. In contrast, LDHS participants displayed superior object visual imagery. CONCLUSIONS: These results provide further evidence for two highly suggestible subtypes: a dissociative subtype characterised by deficits in executive functioning and a predisposition to psychopathology, and a subtype that exhibits superior imagery and no observable deficits in functioning. PMID- 20721762 TI - Does hemineglect affect visual mental imagery? Imagery deficits in representational and perceptual neglect. AB - To give new insight about the relationship between imagery processes and different types of hemispatial neglect, we assessed different mental imagery abilities in a sample of right- and left-brain-damaged patients. Furthermore, because of reports of a mental representation disorder for environments in patients affected by representational neglect we also tested their navigational imagery ability. We found that patients with no signs of perceptual or representational neglect performed flawlessly on our imagery tasks regardless of whether they had left- or right-sided lesions. By contrast, patients affected by neglect failed most of the tests; in particular, representational neglect patients failed one test of mental transformation and tests requiring the manipulation of cognitive maps. These results suggest there is a specific relationship between hemispatial neglect and deficits in visual mental imagery and demonstrate that the right hemisphere plays a specific role in visual mental imagery. PMID- 20721763 TI - Modelling the effects of condom use and antiretroviral therapy in controlling HIV/AIDS among heterosexuals, homosexuals and bisexuals. AB - A deterministic compartmental sex-structured HIV/AIDS model for assessing the effects of homosexuals and bisexuals in heterosexual settings in which homosexuality and bisexuality issues have remained taboo is presented. We extend the model to focus on the effects of condom use as a single strategy approach in HIV prevention in the absence of any other intervention strategies. Initially, we model the use of male condoms, followed by incorporating the use of both the female and male condoms. The model includes two primary factors in condom use to control HIV which are condom efficacy and compliance. Reproductive numbers for these models are computed and compared to assess the effectiveness of male and female condom use in a community. We also extend the basic model to consider the effects of antiretroviral therapy as a single strategy. The results from the study show that condoms can reduce the number of secondary infectives and thus can slow the development of the HIV/AIDS epidemic. Further, we note from the study that treatment of AIDS patients may enlarge the epidemic when the treatment drugs are not 100% effective and when treated AIDS patients indulge in risky sexual behaviour. Thus, the treatment with amelioration of AIDS patients should be accompanied with intense public health educational programs, which are capable of changing the attitude of treated AIDS patients towards safe sex. It is also shown from the study that the use of condoms in settings with the treatment may help in reducing the number of secondary infections thus slowing the epidemic. PMID- 20721764 TI - Modelling within host parasite dynamics of schistosomiasis. AB - Schistosomiasis infection is characterized by the presence of adult worms in the portal and mesenteric veins of humans as part of a complex migratory cycle initiated by cutaneous penetration of the cercariae shed by infected freshwater snails. The drug praziquantel is not always effective in the treatment against schistosomiasis at larvae stage. However, our simulations show that it is effective against mature worms and eggs. As a result, the study and understanding of immunological responses is key in understanding parasite dynamics. We therefore introduce quantitative interpretations of human immunological responses of the disease to formulate mathematical models for the within-host dynamics of schistosomiasis. We also use numerical simulations to demonstrate that it is the level of T cells that differentiates between either an effective immune response or some degree of infection. These cells are responsible for the differentiation and recruitment of eosinophils that are instrumental in clearing the parasite. From the model analysis, we conclude that control of infection is much attributed to the value of a function f, a measure of the average number of larvae penetrating a susceptible individual having hatched from an egg released by an infected individual. This agrees with evidence that there is a close association between the ecology, the distribution of infection and the disease. PMID- 20721765 TI - Inferences for joint modelling of repeated ordinal scores and time to event data. AB - In clinical trials and other follow-up studies, it is natural that a response variable is repeatedly measured during follow-up and the occurrence of some key event is also monitored. There has been a considerable study on the joint modelling these measures together with information on covariates. But most of the studies are related to continuous outcomes. In many situations instead of observing continuous outcomes, repeated ordinal outcomes are recorded over time. The joint modelling of such serial outcomes and the time to event data then becomes a bit complicated. In this article we have attempted to analyse such models through a latent variable model. In view of the longitudinal variation on the ordinal outcome measure, it is desirable to account for the dependence between ordered categorical responses and survival time for different causes due to unobserved factors. A flexible Monte Carlo EM (MCEM) method based on exact likelihood is proposed that can simultaneously handle the longitudinal ordinal data and also the censored time to event data. A computationally more efficient MCEM method based on approximation of the likelihood is also proposed. The method is applied to a number of ordinal scores and survival data from trials of a treatment for children suffering from Duchenne Muscular Dystrophy. Finally, a simulation study is conducted to examine the finite sample properties of the proposed estimators in the joint model under two different methods. PMID- 20721766 TI - Vocabulary used by sexual offenders: meaning and implications. AB - This paper examines how some sexual violence offenders use culturally acquired vocabularies to describe episodes of rape. The paper is based on an analysis of 12 accounts obtained from death-row inmates in Kenya who had been convicted of violent crimes and sexual violence. The accounts were elicited while conducting a larger study to explore the individual motivations, and social and cultural factors that predispose men to acts of rape. Findings suggest that some sex offenders are immersed in normative cultural expectations about sexuality and gender and that, within this framework, they endeavour to create a picture that shifts the blame from themselves to their victims. They attempt to foster the belief that women and girls, in one way or another, provoke rape. Such vocabularies are used to trivialise and neutralise instances of rape within the wider society. PMID- 20721767 TI - Inclusion and exclusion in mid-life lesbians' experiences of the Pap test. AB - Lesbians are said to feel excluded by sexual health messages that presume heterosexuality, a finding linked to lower levels of Papanicolaou (Pap) testing. This paper discusses a small, focused qualitative study based in Calgary, Canada that illuminated mid-life lesbians' experiences and perceptions of Pap testing and health. Participants indicated that they felt compelled and invited to access Pap testing by an inclusive discourse - that of 'mid-life', a period associated with an increased need for body surveillance. They also reflected upon aging as an experience of liberation, increased confidence and a time when they could 'catch up' on health and sexuality issues denied them in their younger days. On the other hand, there was significant uncertainty about Pap testing, human papillomavirus (HPV), cervical cancer and what kind of sexual healthcare is necessary for lesbians, which was reinforced by physician messages suggesting a reduced need for Pap testing when lesbian sexual identity was disclosed. In approaching mid-life lesbian healthcare, we suggest that greater analytical attention should be paid to the ways in which lesbian women are included, as much as excluded, in dominant sexual health scripts particularly by health providers who need to attend to women's diverse experiences and needs. PMID- 20721768 TI - Sexual communication among married couples in the context of a microbicide clinical trial and acceptability study in Pune, India. AB - Previous research in India indicates that there is little communication within marriage about sex. Lack of communication about safe sexual behaviours may increase couples' vulnerability to HIV. This study explores couple level sexual communication and socio-cultural norms that influence couples' communication about sex and its implications for HIV prevention. Data derive from in-depth interviews at two points in time with 10 couples. Secondary qualitative analyses of the interviews were conducted using inductive and deductive coding techniques. Half of the couples described improved communication about sex and HIV and AIDS after participation in the clinical trial and/or acceptability study, as well as increased sexual activity, improved relationships by alleviating doubts about their partner's fidelity and forgiving their partners. The findings show that creating safe spaces for couples where they can ask frank questions about HIV and AIDS, sex and sexuality potentially can improve couples' communication about sex and reduce their risk for HIV infection. PMID- 20721769 TI - Multiple concurrent thoughts: The meaning and developmental neuropsychology of working memory. AB - Working memory can be described as the small amount of information held in a readily accessible state, available to help in the completion of cognitive tasks. There has been considerable confusion among researchers regarding the definition of working memory, which can be attributed to the difficulty of reconciling descriptions from working memory researchers with very different theoretical orientations. Here I review theories of working memory and some of the main issues in the field, discuss current behavioral and neuropsychological research that can address these issues, and consider the implications for cognitive development. PMID- 20721770 TI - Comorbidity of ADHD and dyslexia. AB - Comorbidity of attention deficit hyperactivity disorder (ADHD) and reading disorder (RD) is frequent. Comorbid subjects show a neuropsychological profile characterized by failure of various cognitive functions with an additive-effect that can determine more severe functional deficits. Comorbid RD may be a marker for a group of children with ADHD with more severe cognitive deficits, and a worse neuropsychological, academic, and behavioral outcome. The article focuses on the link between RD and ADHD from an epidemiological, genetic, neurofunctional, neuropsychological, and therapeutic perspective and summarizes the characteristics of the comorbid phenotype. PMID- 20721771 TI - Two forms of implicit learning in childhood ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactivity mediated by frontal-striatal-cerebellar dysfunction. These circuits support implicit learning of perceptual-motor sequences but not visual-spatial context. ADHD and control children performed the Alternating Serial Reaction Time (ASRT) task, a measure of sequence learning, and the Contextual Cueing (CC) task, a measure of spatial contextual learning. Relative to controls, children with ADHD showed inconsistent ASRT learning but did not differ on CC learning. Thus, implicit sequence learning, a cognitive process mediated by frontal-striatal-cerebellar circuitry that is not under executive control, was atypical in ADHD. PMID- 20721772 TI - Childhood MS and ADEM: investigation and comparison of neurocognitive features in children. AB - Cognitive deficits in adult multiple sclerosis (MS) are well documented; however, little is known regarding cognitive impairments in similar childhood conditions. This study compared cognitive profiles of children aged 7-18 years with MS (N = 9) to those with acute disseminated encephalomyelitis (ADEM) (N = 9), a similar but monophasic condition. Individual profiles showed clinically relevant impairments across all cognitive domains evaluated. Differences in severity and spread were also found. Results suggest a gradient effect, with the transient white matter disruption in ADEM resulting in subtle cognitive impairments, while the multiple insults to white matter in childhood MS are associated with more severe sequelae. PMID- 20721773 TI - Sequence imitation and reaching measures of executive control: a longitudinal examination in the second year of life. AB - Despite increasing interest in the early development of executive control, few assessment tools are available for use in the second year of life. At 15 and 20 months, children completed a task battery that included reaching and sequence imitation tasks expected to require executive control. With age, children showed reduced perseveration and increased ability to resist interference across trials and from distractors. At each age, A-not-B with invisible displacement was correlated with one of the sequence imitation tasks modified to increase executive control demands. Correlations between child performance on individual tasks at 15 and 20 months were generally low. PMID- 20721774 TI - Affective and cognitive decision-making in adolescents. AB - Adolescents demonstrate impaired decision-making in emotionally arousing situations, yet they appear to exhibit relatively mature decision-making skills in predominantly cognitive, low-arousal situations. In this study we compared adolescents' (13-15 years) performance on matched affective and cognitive decision-making tasks, in order to determine (1) their performance level on each task and (2) whether performance on the cognitive task was associated with performance on the affective task. Both tasks required a comparison of choice dimensions characterized by frequency of loss, amount of loss, and constant gain. Results indicated that in the affective task, adolescents performed sub-optimally by considering only the frequency of loss, whereas in the cognitive task adolescents used relatively mature decision rules by considering two or all three choice dimensions. Performance on the affective task was not related to performance on the cognitive task. These results are discussed in light of neural developmental trajectories observed in adolescence. PMID- 20721775 TI - Age, sex, and pubertal phase influence mentalizing about emotions and actions in adolescents. AB - This study examined (1) emotional versus cognitive developmental trajectories and (2) the influence of age-extrinsic factors (i.e., sex and puberty). Using a cross sectional design, adolescents (N = 252) divided into four age-groups (ages 13, 15, 17, 19) performed two versions of a mentalizing task, about emotions and actions, as well as the Tower task. First, performance on all tasks improved linearly into late adolescence (age 19). Thus no differential trajectories were found for emotional versus cognitive development. Second, girls outperformed boys in mentalizing speed regarding both emotions and actions. In boys, a later pubertal phase was associated with increased mentalizing speed after controlling for age-group. PMID- 20721776 TI - Investigating the association between early life parental care and stress responsivity in adulthood. AB - We explored the associations between early life experience, endocrine regulation, psychological health, and hippocampal integrity in 37 elderly volunteers. Specifically, a neurodevelopmental and psychological mediation model was tested: Retrospective early life parental care was hypothesized to influence hippocampal integrity and the development of self-esteem. In turn, hippocampal volume (via modulation of hypothalamic-pituitary-adrenal axis negative feedback) and self esteem (via modulation of stress vulnerability) were suggested to influence the cortisol stress response. Results supported the two-mediator model. We propose that early life parental care impacts on an individual's developing brain and personality, which consequently contribute to the shaping of neuroendocrine stress responsivity. PMID- 20721777 TI - Neuropsychological differences among children with Asperger syndrome, nonverbal learning disabilities, attention deficit disorder, and controls. AB - Confusion is present as to possible diagnostic differences between Asperger syndrome (AS) and Nonverbal learning disabilities (NLD) and the relation of these disorders to attentional difficulties. Three-hundred and forty-five children participated in this study in 5 groups; NLD, AS, attention deficit hyperactivity disorder (ADHD): Combined type, ADHD: Inattentive type, and controls. The NLD group showed particular difficulty on visual-spatial, visual-motor, and fluid reasoning measures compared to the other groups. There was also a significant verbal-performance IQ split in this group related to difficulty in social functioning. This study extends the findings from previous studies and extends these findings to differences between AS and NLD groups. PMID- 20721780 TI - The relationship between post-traumatic stress disorder, depression, and lung disorders in Northern Plains and Southwest American Indians. AB - OBJECTIVE: Research within the past decade has suggested that mental disorders are associated with lung disorders. This study compared the association of lifetime post-traumatic stress disorder (PTSD) and lifetime major depression with lung disorders in two American Indian (AI) tribal communities. DESIGN: A total of 2622 tribal members (1414 in the Northern Plains and 1208 in the Southwest) aged 18-57 years completed an interview assessing psychiatric diagnoses and physical health, including lung disorders. Logistic regression analyses were used to estimate odds ratios for the association of PTSD and major depression with lung disorders. RESULTS: The prevalence of lung disorders was 17% (95% Confidence Interval [CI]: 15, 19) in the Northern Plains and 13% (95% CI: 11, 15) in the Southwest. In the Northern Plains, men with lung disorders had a higher prevalence of PTSD and major depression than men without lung disorders, and women with lung disorders had a higher prevalence of major depression than women without lung disorders. Neither PTSD nor major depression was associated with lung disorders in men or women living in the Southwest. In the Northern Plains, major depression remained significantly associated with lung disorders in both men (OR=3.1, 95% CI: 1.5, 6.4) and women (OR=2.2, 95% CI: 1.2, 4.1) even after adjusting for age, education, smoking, alcohol abuse, and PTSD. CONCLUSIONS: Depression, but not PTSD, was associated with lung disorders in AIs living in the Northern Plains. Differences between the Northern Plains and the Southwest underscore the importance of recognizing unique characteristics of tribes and tribal communities. The increasing prevalence of lung disorders in AIs heightens the need for further work to help explain social, cultural, and clinical determinants of these disorders and their associations to PTSD and depression, and ultimately to help provide more effective clinical treatment and preventive care. PMID- 20721781 TI - A comparison of multiple testing procedures for the gold standard non-inferiority trial. AB - For the three-arm parallel-group design, several procedures have been proposed in the literature to control for the multiple type I error when all groups are to be statistically compared. Mere statements regarding the rejection of the null hypotheses are not satisfactory, but instead confidence intervals are more desirable. For this purpose, the procedure by Koch and Rohmel (2004) is modified and the theoretical reasoning behind it is given. However, one combination of effects occurs where control of the multiple type I error cannot be guaranteed. This pathologic case is discussed theoretically and further investigated in a simulation study. PMID- 20721782 TI - Many-to-one comparison after sample size reestimation for trials with multiple treatment arms and treatment selection. AB - Sample size reestimation (SSRE) provides a useful tool to change the sample size when an interim look reveals that the original sample size is inadequate. To control the overall type I error, for testing one hypothesis, several approaches have been proposed to construct a statistic so that its distribution is independent to the SSRE under the null hypothesis. We considered a similar approach for comparisons between multiple treatment arms and placebo, allowing the change of sample sizes in all arms depending on interim information. A construction of statistics similar to that for a single hypothesis test is proposed. When the changes of sample sizes in different arms are proportional, we show that one-step and stepwise Dunnett tests can be used directly on statistics constructed in the proposed way. The approach can also be applied to clinical trials with SSRE and treatment selection at interim. The proposed approach is evaluated with simulations under different situations. PMID- 20721783 TI - An extension of Bayesian expected power and its application in decision making. AB - Whether and how to conduct a clinical study is one of the critical decisions to be made every day in the pharmaceutical industry. Robust measurements on the probability of success (POS) of a study are crucial in the decision-making process. Among many factors that can affect the POS, establishment of the statistical alternative hypothesis (H(1)) is arguably the most important consideration. The classical power is universally used for assessing the probability of H(1) being accepted, given a certain value of the parameter of interest. If H(1) is composite, power is often provided for a range of plausible values of the parameter to reflect our uncertainty about the parameter. This could become inconvenient for decision makers and potentially introduce biases into the decision-making process. This paper proposes an extension of Bayesian expected power (eBEP) as a single metric for assessing POS defined as the probability that H(1) is accepted in a study as a tool for decision-making. eBEP is convenient, driven by scientific evidence, and systematically integrates the uncertainty, thus facilitates robust decision-making. The computation procedure of eBEP via Monte Carlo methods is provided. The application of eBEP is illustrated using a real-life bioequivalence study. PMID- 20721784 TI - Statistical inference for tumor growth inhibition T/C ratio. AB - The tumor growth inhibition T/C ratio is commonly used to quantify treatment effects in drug screening tumor xenograft experiments. The T/C ratio is converted to an antitumor activity rating using an arbitrary cutoff point and often without any formal statistical inference. Here, we applied a nonparametric bootstrap method and a small sample likelihood ratio statistic to make a statistical inference of the T/C ratio, including both hypothesis testing and a confidence interval estimate. Furthermore, sample size and power are also discussed for statistical design of tumor xenograft experiments. Tumor xenograft data from an actual experiment were analyzed to illustrate the application. PMID- 20721785 TI - Comparison of measurements by multiple methods or instruments. AB - Much work has been done on comparison of one device with another, but the problem of comparing three or more devices is less well known. Most existing work has concentrated on the possibilities of a constant relative bias between the devices, or of different linear relationships with the underlying true value. These two possibilities are placed within a hierarchy of models extending them to settings with multiplicative interaction terms. These additional terms can capture departures such as outliers, variance changing with the analyte concentration, and different measurement variances between the devices. PMID- 20721786 TI - Bayesian versus frequentist hypotheses testing in clinical trials with dichotomous and countable outcomes. AB - In the problem of hypothesis testing, a question of practical importance is: When do Bayesian and frequentist methodologies suggest similar solutions? Substantial progress has been made for one-sided hypotheses on the parameters of continuous distributions. In this article, we study the problem of testing one-side hypotheses in binomial and Poisson trials, using Bayesian models with conjugate priors. By correctly choosing prior parameters, we can make the posterior probability smaller than, equal to, or larger than the frequentist p-value. The results are illustrated through simulation modeling and analysis of data from clinical trials. PMID- 20721787 TI - Mining pharmacovigilance data using Bayesian logistic regression with James-Stein type shrinkage estimation. AB - Spontaneous adverse event reporting systems are widely used to identify adverse reactions to drugs following their introduction into the marketplace. In this article, a James-Stein type shrinkage estimation strategy was developed in a Bayesian logistic regression model to analyze pharmacovigilance data. This method is effective in detecting signals as it combines information and borrows strength across medically related adverse events. Computer simulation demonstrated that the shrinkage estimator is uniformly better than the maximum likelihood estimator in terms of mean squared error. This method was used to investigate the possible association of a series of diabetic drugs and the risk of cardiovascular events using data from the Canada Vigilance Online Database. PMID- 20721788 TI - Retrospective robustness of the continual reassessment method. AB - We study model sensitivity of the continual reassessment method (CRM). The context is that of dose-finding designs where certain design parameters are fixed by the investigator. Although our focus is on the CRM (O'Quigley et al., 1990), the essential ideas can be applied to any sequential dose-finding method. It is expected that different choices of a model family and particular parameterizations will have an impact on performance. Assuming that the constraints outlined in Shen and O'Quigley (1996) are respected, large sample performance is unaffected. However small sample performance will be affected by these choices, which are to some degree arbitrary. This work focuses on the retrospective robustness of the CRM in practice. The question is not of a general theoretical nature where, in the background, we would want to consider large numbers of true potential situations. Instead, the question is raised in the specific context of any actual completed study and is the following: Would we have come to the same conclusion concerning the MTD had we worked with a design specified differently? The sequential nature of the CRM means that this question cannot be answered in any definitive way. We can, though, by appealing to the retrospective CRM (O'Quigley, 2005), provide consistent estimates of the relationships between the MTD and the chosen model. If these estimates suggest that changes in different family model parameters will be accompanied by changes in final recommendation, then we would not be confident in the reliability of the estimated MTD and more work would be needed. Also, of course, at the planning stage, prospective robustness could be studied by simulating trials using particular models and parameterizations. PMID- 20721789 TI - Sample size/power calculations for population pharmacodynamic experiments involving repeated-count measurements. AB - Repeated discrete outcome variables such as count measurements often arise in pharmacodynamic experiments. Count measurements can only take nonnegative integer values; this and correlation between repeated measurements from an individual make the design and analysis of repeated-count data special. Sample size/power calculation is an important part of clinical trial design to ensure adequate power for detecting significant effect, and it is often based on the procedure for analysis. This paper describes an approach for calculating sample size/power for population pharmacokinetic/pharmacodynamic experiments involving repeated count measurements modeled as a Poisson process based on mixed-effects modeling technique. The noncentral version of the Wald chi(2) test is used for testing parameter/treatment significance. The approach was applied to two examples and the results were compared to results obtained from simulations in NONMEM. The first example involves calculating the power of a design to detect parameter significance between two groups: placebo and treatment group. The second example involves characterization of the dose-efficacy relationship of oxybutynin using a mixed-effects modeling approach. Weekly urge urinary incontinence episodes (a discrete count variable) is the primary efficacy variable and is modeled as a Poisson variable. A prospective study based on two different formulations of oxybutynin was designed using published population pharmacokinetic/pharmacodynamic model. The results of simulation studies showed good agreement between the proposed method and NONMEM simulations. PMID- 20721790 TI - Determining a minimum clinically important difference between treatments for a patient-reported outcome. AB - Patient-reported outcomes are important for assessing the effectiveness of treatments in many disease areas. For this reason, many new instruments that capture patient-reported outcomes have been developed over the past several decades. With the development of each new instrument, there is the ensuing question of what constitutes a minimum clinically important difference between treatments when using the new instrument. In this paper we describe a method for estimating a minimum clinically important difference between treatments for a patient-reported outcome through a desired difference in response rates for a definition of a responder. As well as being of interest in its own right, the use of a minimum clinically important difference on the patient-reported outcome scale is likely to lead to sample size advantages. We illustrate the method with data on neuropathic pain when responder is defined by requiring at least some improvement in the Patient Global Impression of Change and when responder is defined by existing responder definitions. PMID- 20721791 TI - Bayesian adaptive dose-finding studies with delayed responses. AB - In recent years, Bayesian response-adaptive designs have been used to improve the efficiency of learning in dose-finding studies. Many current methods for analyzing the data at the time of the interim analysis only use the data from patients who have completed the study. Therefore, data collected at intermediate time points are not used for decision making in these studies. However, in some disease areas such as diabetes and obesity, patients may need to be studied for several weeks or months for a drug effect to emerge. Additionally, slow enrollment rates can limit the number of patients who complete the study in a given period of time. Consequently, at the time of an interim analysis, there may be only a small proportion (e.g., 20%) of patients who have completed the study. In this paper, we propose a new Bayesian prediction model to incorporate all the data (from patients who have completed the study and those who have not completed) to make decisions about the study at the interim analysis. Examples of decisions made at the interim analysis include adaptive treatment allocation, dropping nonefficacious dose arms, stopping the study for positive efficacy, and stopping the study for futility. The model is able to handle incomplete longitudinal data including missing data considered missing at random (MAR). A utility-function-based decision rule is also discussed. The benefit of our new method is demonstrated through trial simulations. Three scenarios are examined, and the simulation results demonstrate that this new method outperforms traditional design with the same sample size in each of these scenarios. PMID- 20721792 TI - Comment on: Cheng, Chow, Burt, and Cosmatos (2008). Statistical assessment of QT/QTc prolongation based on maximum of correlated normal random variables. Journal of Biopharmaceutical Statistics 18(3):494-501. PMID- 20721797 TI - Oxidative degradation of 2,6-dibromophenol using anion-exchange resin supported supramolecular catalysts of iron(III)-5,10,15,20-tetrakis (p hydroxyphenyl)porphyrin bound to humic acid prepared via formaldehyde and urea formaldehyde polycondensation. AB - An iron(III)-porphyrin catalyst, iron(III)-tetrakis(p-hydroxyphenyl)porphyrin (FeTHP), was introduced into a humic acid via a formaldehyde or urea-formaldehyde polycondensation reaction to stabilize the catalyst. The prepared supramolecular catalysts were then attached to Dowex-22, an anion-exchange resin. The oxidation of 2,6-dibromophenol (2,6-DBP) was then used, to evaluate the catalytic activities of the supported catalysts. The supported catalyst prepared via the urea-formaldehyde polycondensation reaction showed the highest catalytic activity of all catalysts tested. However, no debromination was observed under any conditions. To examine the reusability of the supported catalysts, they were evaluated on the basis of the decrease in the percent degradation of 2,6-DBP for the number times that they could be used. To determine why the catalytic activities decreased with increasing use, the surface of the supported catalysts were observed by scanning electron microscopy and energy dispersive X-ray spectrometry (SME-EDS) after each use. The poor reusability of the supported catalysts can be attributed to the fact that 2,6-DBP and/or brominated byproducts are tightly absorbed to the catalyst in the vicinity of the active site, which leads to inactivation of the supported catalysts. PMID- 20721798 TI - The effect of milk co-digested with dairy manure on biogas production and COD removal in batch processes. AB - Co-digestion of dairy manure with milk for biogas production was investigated in this study using batch experiments. Lab-scale digesters consisting of 500 mL flasks were employed (effective working volume: 300 mL) with temperature controlled at 37 degrees C. A total of eight treatments at different milk additions were examined, i.e., control (without milk), 1, 3, 5, 7, 9, 14, and 19%. The results showed that the cumulative biogas volume produced over the experimental period increased from around 4984 mL for the control to 10,228 mL for the 19% treatment. In parallel, the cumulative CH4 volume produced increased from 3306 mL to 6515 mL in the same treatment percentages. The high milk chemical oxygen demand (COD) had no negative impact on the final COD removal by the digestion process, evidenced by the observed good efficiencies of COD removal by 49.7, 50.5, 58.7, 49.0, 62.1, 68.4, 73.4, and 77.8% for the control, 1, 3, 5, 7, 9, 14, and 19% milk treatments. This clearly indicated that COD removal was improved with the increasing milk content in the co-digestion process. There was a good linear relationship between the peak biogas production rates and the increasing milk treatments, with a correlation coefficient of 0.9930 (R2=0.9861), meaning that about 98.6% of the increase in peak biogas production rate could be explained by the milk addition. The study has provided useful information that it is feasible and beneficial to enhance the overall biogas and CH4 productivities by batch co-digesting dairy manure with milk. PMID- 20721799 TI - Dow and Kaw,eff vs. Kow and Kaw degrees: acid/base ionization effects on partitioning properties and screening commercial chemicals for long-range transport and bioaccumulation potential. AB - A set of 543 ionizable commercial organic compounds with various acid/base functionalities and experimental octanol-water partitioning coefficients (log Kow) were obtained from the Canadian Domestic Substances List. Corresponding pH dependent octanol-water distribution coefficients (log Dow) and air-water partitioning coefficients (log Kaw,eff) were estimated using the SPARC software program, as were log Kow and log Kaw degrees values for the neutral forms of each chemical. Significant ionization dependent effects on chemical screening results at various pH values were obtained using established criteria for bioaccumulation potential (BAP) in aquatic organisms, terrestrial animals, and humans, as well as for atmospheric long range transport potential (LRTP). Future modelling efforts for environmental and toxicological screening of commercial chemicals should therefore explicitly include the influence of ionization for both weak and strong organic acids and bases on bioavailability and air-water mobility within the respective regulatory frameworks. Functional group specific sorption of both ionizable and neutral compounds to particulate and dissolved inorganic and organic matter will also affect chemical screening results for BAP and LRTP. More complex sorption related modelling in various types of representative aquatic systems also appears necessary to achieve reliable chemical screening results for commercial organic compounds. PMID- 20721800 TI - Replacement of chemical oxygen demand (COD) with total organic carbon (TOC) for monitoring wastewater treatment performance to minimize disposal of toxic analytical waste. AB - Chemical oxygen demand (COD) is widely used for wastewater monitoring, design, modeling and plant operational analysis. However this method results in the production of hazardous wastes including mercury and hexavalent chromium. The study examined the replacement of COD with total organic carbon (TOC) for general performance monitoring by comparing their relationship with influent and effluent samples from 11 wastewater treatment plants. Biochemical oxygen demand (BOD5) was also included in the comparison as a control. The results show significant linear relationships between TOC, COD and BOD5 in settled (influent) domestic and municipal wastewaters, but only between COD and TOC in treated effluents. The study concludes that TOC can be reliably used for the generic replacement of both COD (COD=49.2+3.00*TOC) and BOD5 (BOD5=23.7+1.68*TOC) in influent wastewaters but only for COD (COD=7.25+2.99*TOC) in final effluents. PMID- 20721801 TI - Physicochemical and geochemical characteristics of raw marine sediment used in fluoride removal. AB - The study was directed to use raw marine sediment in the removal of fluoride. The sediment was mainly composed of calcite, magnesium-calcite and aragonite. The effect of the initial fluoride concentration, pH and the contact time was studied at room temperature to determine the adsorption capacity of the sediment. The optimum adsorption capacity was observed at pH values of 5 and 6.2. The adsorption process was fast and the equilibrium was reached within 60 min. For fluoride solutions of 10 and 15 mg/L, 100% removal was obtained onto 0.1 g of raw marine sediment. Pseudo-first-order, pseudo-second-order, Elovich and intra particle diffusion equations were used to deduce the kinetic data. The adsorption mechanism was rather complex process, and the intra-particle diffusion was not the only rate-controlling step. The equilibrium data were tested using thirteen isotherm models (Langmuir, Freundlich, Tempkin, Dubinin-Radushkevich, Erunauer Emmett-Teller, Flory-Huggins, Non-ideal competitive adsorption, Generalized, Redlich Peterson, Khan, Sips, Koble Corrigan and Toth isotherm equations). Five different error functions were applied. For the sorption of fluoride process, the calculated activation energy and the free energy were of 0.707 and -14.491 kJ /mol, respectively. PMID- 20721802 TI - "Sports injuries in an America's Cup yachting crew: a 4-year epidemiological study covering the 2007 challenge"- a critical commentary. PMID- 20721804 TI - The first sight of love: Relationship-defining memories and marital satisfaction across adulthood. AB - The current study begins the exploration of relationship-defining memories (i.e., the first time someone met their spouse) across adulthood. Men and women ranging from 20 to 85 years old (N=267; M age=47.19) completed a measure of marital satisfaction, wrote a relationship-defining memory, and answered questions about the quality of their memory (i.e., vividness, valence, emotional intensity, and rehearsal). Data were collected online. Results indicate that individuals over 70 and those younger than 30 rehearsed relationship-defining memories most often. Women in midlife also reported more vivid memories. The quality of relationship defining memories also predicted marital satisfaction. Relationship-defining memories that were more vivid, positive, emotionally intense, and rehearsed related to higher marital satisfaction. Age and gender differences were minimal. Results are discussed in the context of the adaptive social function of autobiographical memories, such that these memories might have a role in influencing marital satisfaction across adulthood. PMID- 20721806 TI - Health in context. Abstracts of the 24th Annual Conference of the European Health Psychology Society. Cluj-Napoca, Romania. September 1-4, 2010. PMID- 20721805 TI - Recollective performance advantages for implicit memory tasks. AB - A commonly held assumption is that processes underlying explicit and implicit memory are distinct. Recent evidence, however, suggests that they may interact more than previously believed. Using the remember-know procedure the current study examines the relation between recollection, a process thought to be exclusive to explicit memory, and performance on two implicit memory tasks, lexical decision and word stem completion. We found that, for both implicit tasks, words that were recollected were associated with greater priming effects than were words given a subsequent familiarity rating or words that had been studied but were not recognised (misses). Broadly, our results suggest that non voluntary processes underlying explicit memory also benefit priming, a measure of implicit memory. More specifically, given that this benefit was due to a particular aspect of explicit memory (recollection), these results are consistent with some strength models of memory and with Moscovitch's (2008) proposal that recollection is a two-stage process, one rapid and unconscious and the other more effortful and conscious. PMID- 20721813 TI - Do you like me? Neural correlates of social evaluation and developmental trajectories. AB - Social acceptance is of key importance for healthy functioning. We used functional magnetic resonance imaging (fMRI) to examine age-related changes in the neural correlates of social acceptance and rejection processing. Participants from four age groups participated in the study: pre-pubertal children (8-10 years), early adolescents (12-14 years), older adolescents (16-17 years) and young adults (19-25 years). During the experiment, participants were presented with unfamiliar faces of peers and were asked to predict whether they expected to be liked or disliked by the other person, followed by feedback indicating acceptance or rejection. Results showed that activation in the ventral mPFC and striatum to social feedback was context-dependent; there was increased activation when participants had positive expectations about social evaluation, and increased activation following social acceptance feedback. Age-related comparisons revealed a linear increase in activity with age in these brain regions for positive expectations of social evaluation. Similarly, a linear increase with age was found for activation in the striatum, ventral mPFC, OFC, and lateral PFC for rejection feedback. No age-related differences in neural activation were shown for social acceptance feedback. Together, these results provide important insights in the developmental trajectories of brain regions implicated in social and affective behavior. PMID- 20721815 TI - American Society of Clinical Oncology--46th annual meeting. AB - The 46th Annual Meeting of the American Society of Clinical Oncology, held in Chicago, included topics covering new therapeutic developments in the field of oncology. This conference report highlights selected presentations on novel therapies for cancers including glioblastoma, breast cancer, myeloma, NSCLC and solid tumors. Investigational drugs discussed include rindopepimut and PF-299804 (both Pfizer Inc), entinostat (Syndax Pharmaceuticals Inc), panobinostat and NVP LDE-225 (both Novartis AG), CHR-3996 (Chroma Therapeutics Ltd), and HGS-1029 (Human Genome Sciences Inc). PMID- 20721814 TI - From observation to action simulation: the role of attention, eye-gaze, emotion, and body state. AB - This paper reviews recent aspects of my research. It focuses, first, on the idea that during the perception of objects and people, action-based representations are automatically activated and, second, that such action representations can feed back and influence the perception of people and objects. For example, when one is merely viewing an object such as a coffee cup, the action it affords, such as a reach to grasp, is activated even though there is no intention to act on the object. Similarly, when one is observing a person's behaviour, their actions are automatically simulated, and such action simulation can influence our perception of the person and the object with which they interacted. The experiments to be described investigate the role of attention in such vision-to-action processes, the effects of such processes on emotion, and the role of a perceiver's body state in their interpretation of visual stimuli. PMID- 20721816 TI - Society of Nuclear Medicine--57th annual meeting. AB - The 57th Annual Meeting of the Society of Nuclear Medicine, held in Salt Lake City, UT, USA, included topics covering new developments in imaging agents and radiopharmaceutical therapies in the field of nuclear medicine. This conference report highlights selected presentations related to imaging of the brain, the prediction of heart disease, and the detection and treatment of various cancers. Investigational drugs discussed include TF-2 plus [68Ga]IMP-288 and TF-2 plus [111In]IMP-288 (both Immunomedics Inc), [11C]PBR-170 (Royal Prince Alfred Hospital/Australian Nuclear Science & Technology Organization), [11C]LY-2795050 (Eli Lilly & Co), yttrium (90Y) clivatuzumab tetraxetan (Garden State Cancer Center/Immunomedics Inc), [18F]LMI-1195 (Lantheus Medical Imaging Inc), fluciclovine (18F) (GE Healthcare/Nihon Medi-Physics Co Ltd), [99mTc]MIP-1340 and [99mTc]MIP-1407 (both Molecular Insight Pharmaceuticals Inc). PMID- 20721817 TI - 32nd National Medicinal Chemistry Symposium--medicinal chemistry developments for neurodegeneration, diabetes and cancer. AB - The 32nd National Medicinal Chemistry Symposium, held in Minneapolis, MN, USA, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on NR2B subtype selective NMDA receptor antagonists from Merck; selective neuronal nitric oxide synthase inhibitors from Northwestern University; novel GPR119 agonists, suchas GSK-1292263A (GlaxoSmithKline plc), PSN-821 ((OSI) Prosidion) and MBX-2982 (Metabolex Inc); a small-molecule Bcl inhibitor,navitoclax (Abbott Laboratories); and p53-targeting agents from sanofi-aventis and Ascenta Therapeutics Inc, including AT-219. PMID- 20721818 TI - 32nd National Medicinal Chemistry Symposium--medicinal chemistry developments for cancer, and cardiovascular, metabolic and psychiatric disorders. AB - The 32nd National Medicinal Chemistry Symposium, held in Minneapolis, MN, USA, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on Hsp90 inhibitors and Hsp70 inducers, such as KU-32 and KU-174 (University of Kansas); natural products in drug design, such as minnelide (University of Minnesota) and tylocrebrine; novel compounds from Merck for metabolic and cardiovascular diseases, such as MK 7725, a series of DDP4 inhibitors and KV1.5 ion channel antagonists; and the discovery of the VEGFR2 kinase inhibitor AMG-429 (Amgen Inc). PMID- 20721819 TI - Cell-based assays--Informa Life Sciences' Fifth Annual Conference--Cell-based assays for compound screening and 3D assays. AB - Informa Life Sciences' Fifth Annual Conference on Cell-Based Assays, held in Cologne, Germany, included topics covering new technical developments in the field of cell-based assays. This conference report highlights selected presentations on cell-based assays for compound screening and 3D cell-based assays. PMID- 20721820 TI - Cell-based assays--Informa Life Sciences' Fifth Annual Conference--Label-free cell-based assays and high-content analysis in drug discovery. AB - Informa Life Sciences' Fifth Annual Conference on Cell-Based Assays, held in Cologne, Germany, included topics covering new technical developments in the field of cell-based assays. This conference report highlights selected presentations on label-free cell-based assays and the application of high-content analysis to drug discovery. PMID- 20721821 TI - Bangalore India Bio 2010. AB - The Bangalore India Bio 2010 conference, held in Bangalore, India, included topics covering new developments in the biopharma industry. This conference report highlights selected presentations on novel therapeutics for the treatment of cancer, including identification of novel benzimidazole, N-subsituted isatin and azetidine derivatives, and an Wnt antagonist. In addition, presentations from several biopharma companies and universities are highlighted, including Proteomics International Pty Ltd, Oxford BioMedica plc, AnaptysBio Inc, SIOGEN Biotech, RV College of Engineering and Indian Institute of Science. PMID- 20721822 TI - European Generic Medicines Association (EGA)--16th Annual Conference. AB - The 16th Annual Conference of the European Generic Medicines Association (EGA), held in Rome, included topics covering new developments and challenges in the generic medicines industry in Europe. This conference report highlights selected presentations on developments for generics in the Italian healthcare system, a summary of the EGA pharmaceutical sector inquiry on the delayed market entry of generics, developments and trends in the European generics market, the evolution and growth of the global generics industry, and a CEO perspective on the challenges facing the industry. PMID- 20721823 TI - Purines 2010: Adenine Nucleosides and Nucleotides in Biomedicine. AB - The Purines 2010: Adenine Nucleosides and Nucleotides in Biomedicine meeting, held in Tarragona, Spain, included topics covering new findings in the field of purinergic signaling and the development of purine-based drugs. This conference report highlights selected presentations on developments in purinerigic signaling, medicinal chemistry, the therapeutic potential of purine-based drugs, and the role of purines and adenosine receptors in neurodegenerative disorders, sickle cell disease, bone homeostasis, pulmonary fibrosis and pain. Investigational drugs discussed include CF-101 (Can-Fite BioPharma Ltd/NIH/Kwang Dong Pharmaceutical Co Ltd/Seikagaku Corp) and denufosol tetrasodium (Cystic Fibrosis Foundation Therapeutics Inc/Inspire Pharmaceuticals Inc). PMID- 20721824 TI - The Movement Disorder Society--14th International Congress of Parkinson's Disease and Movement Disorders. AB - The 14th International Congress of Parkinson's Disease and Movement Disorders, held in Buenos Aires, included topics covering new therapeutic developments in the field of Parkinson's disease and other movement disorders. This conference report highlights selected presentations on drug treatments for movement disorders, including safinamide (Merck Serono SA), PYM-50028 (Phytopharm plc), droxidopa, pardoprunox (Abbott Laboratories); treatment considerations for dystonia; exploiting existing drugs for new indications; and using genetics to assess drug therapy responses. PMID- 20721825 TI - Therapeutic bispecific antibodies: The selection of stable single-chain fragments to overcome engineering obstacles. AB - The clinical success of mAbs continues to reinforce antibody engineering as an essential tool for the development of biologics. Research focused on discovering the next generation of therapeutics has prompted a revisiting of the concept of bispecific antibodies (bsAbs). Recently, clinical programs investigating combinations of mAb therapies have renewed interest in the applications of bsAbs. However, because of challenges with production, efforts directed toward the development of bsAbs have yet to yield a product approved by the FDA. The current status of these proteins implies that the strategies for constructing therapeutic bsAbs will likely require a highly refined design plan at the outset of the engineering process. Antibody fragments are attractive building blocks for the assembly of bsAbs. Of the recombinant antibody fragments, single-chain variable fragments (scFvs) offer the advantage of expression as a single polypeptide, thereby greatly simplifying production. However, issues with stability have plagued these proteins and limit the application of scFvs as therapeutics. Recent advances in selection processes using display platforms have been reported that facilitate the 'evolution' of scFvs to obtain stabilities comparable with those of mAbs. The timely advances in scFv engineering parallel the resurgence of bsAbs and enable the construction of dual-targeting proteins that can be manufactured as therapeutics. PMID- 20721826 TI - The formulation and immunogenicity of therapeutic proteins: Product quality as a key factor. AB - The formation of anti-drug antibodies represents a risk that should be assessed carefully during biopharmaceutical drug product (DP) development, as such antibodies compromise safety and efficacy and may alter the pharmacokinetic properties of a compound. This feature review discusses immunogenicity issues in biopharmaceutical DP development, with a focus on product quality. Excipient induced and aggregate-induced immunogenicity are reviewed based on the concepts of 'aggregation-competent' species and 'provocative' aggregates. In addition, the influence of formulation parameters, such as particulates and contaminants appearing in the DP during processing and storage, on aggregate-induced immunogenicity are presented, including the role of fill-and-finish equipments and the effect of interactions with container materials. Furthermore, methods to detect and quantify aggregation and precursor conformational changes in a protein formulation are reviewed, and immunological mechanisms that may lead to aggregate induced immunogenicity are proposed and discussed. PMID- 20721827 TI - CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis. AB - CH-1504, being developed by Chelsea Therapeutics Inc under license from the University of South Alabama, is an orally available, metabolically inert antifolate, for the potential treatment of rheumatoid arthritis (RA). CH-1504 is an analog of methotrexate (MTX) but differs from the classical antifolates because of an improved safety and tolerability profile. A significant proportion of the toxicity profile of MTX can be attributed to its polyglutamylated and hydroxylated metabolites; therefore, metabolism-blocked antifolates, such as CH 1504, have been designed to prevent the accumulation of toxic metabolites. Preclinical studies and phase II clinical trials indicated that CH-1504 and MTX inhibit dihydrofolate reductase activity with equal potency. In a phase II, proof of-concept trial in patients with RA, CH-1504 was associated with improved tolerability and reduced hepatotoxicity as compared with MTX; in addition, improvements in the American College of Rheumatology response rates were similar following treatment with either CH-1504 or MTX. Furthermore, Chelsea Therapeutics are developing the L-isomer of CH-1504, CH-4051, which displays improved in vitro potency over with racemate and appears to be Chelsea Therapeutics' preferred candidate for future development. Inert antifolates appear to be a promising drug class for the treatment of RA because the disease-modifying properties of MTX are retained, but the therapeutic window of the inert antifolates is improved. However, further trials are required to establish the efficacy and long-term safety in a wider population of patients with RA. PMID- 20721829 TI - Antimicrobial peptides for leishmaniasis. AB - Leishmaniasis is a parasitic disease that is endemic to American, African, Asian and southern European countries. More than 350 million individuals in 88 countries are at risk of infection from this neglected tropical disease. No effective vaccinations are available against leishmaniasis, and control of the disease relies entirely on toxic drug treatments, some of which were developed as early as the 1940s. As parasite resistance becomes more prevalent, there is increasing concern that currently used drugs will soon become ineffective treatments. Consequently, an urgent need exists to develop new classes of compounds that are active against drug-resistant strains of Leishmania. This review summarizes research aimed at investigating the potential development of antimicrobial peptide-based antileishmanial agents. PMID- 20721828 TI - Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. AB - Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are beginning to reveal possible principles governing the biology of motor neuron selective vulnerability that implicate mitochondria and the mitochondrial permeability pore (mPTP). Proteins associated with the mPTP are known to be enriched in motor neurons and the genetic deletion of a major regulator of the mPTP has robust effects in ALS transgenic mice, delaying disease onset and extending survival. Thus, the mPTP is a rational, mechanism-based target for the development of drugs designed to treat ALS. Trophos SA has discovered olesoxime (TRO-19622), a small-molecule with a cholesterol-like structure, which has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. Olesoxime appears to act on mitochondria, possibly at the mPTP. Phase I clinical trials of olesoxime have been completed successfully. Olesoxime is well tolerated and achieves levels predicted to be clinically effective when administered orally. It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe. PMID- 20721830 TI - Diamidines for human African trypanosomiasis. AB - Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can penetrate the CNS. In this review, progress in the development of diamidines for the treatment of HAT is discussed. PMID- 20721832 TI - Optimal antiretroviral therapy: HIV-1 treatment strategies to avoid and overcome drug resistance. AB - Potent antiretroviral therapy (ART) has transformed HIV infection into a chronic manageable disease, but drug resistance remains a common problem that limits the effectiveness and clinical benefits of treatment. With increasing experience with ART, the understanding of viral dynamics of HIV improved, and researchers learned how challenging HIV can be to control. With new-class and new-generation drugs, it is hoped that the lessons learned will be useful for limiting drug resistance and optimizing the use of ART for long-term management of HIV infection. PMID- 20721833 TI - Cyclophilin inhibitors for the treatment of HCV infection. AB - Cyclophilins (Cyps) constitute one of the three families of peptidyl prolyl isomerase enzymes. CypA is the prototypical member of the Cyp family and is the predominant Cyp expressed in human cells. Recent studies indicate that CypA has an essential role in supporting HCV-specific RNA replication and protein expression. CypA interacts with several virally expressed proteins, including the non-structural (NS) proteins NS2, NS5A and NS5B, and may regulate diverse activities ranging from polypeptide processing to viral assembly. The introduction of non-immunosuppressive Cyp inhibitors into clinical trials confirms that Cyp inhibition is a valid strategy for developing novel therapeutics for the treatment of chronic HCV infection. This review describes the cyclophilin protein family and the potential roles played by cyclophilins in supporting HCV RNA replication and protein expression, as well as the initial clinical results obtained with a novel series of non-immunosuppressive cyclophilin inhibitors that established the clinical proof of concept for this emerging class of therapeutic agents. PMID- 20721834 TI - Cholera toxin B subunit modulation of mucosal vaccines for infectious and autoimmune diseases. AB - Parenteral vaccination is generally considered to be the most effective form of therapy for protection against infectious diseases. In recent years, vaccination at mucosal surfaces and combinatorial vaccination strategies that link immunostimulatory molecules to antigens have been developed to enhance vaccine efficacy. Prominent among immunological enhancement strategies are the bacterial A and B toxins, which include the cholera toxin (CT)A and CTB subunits. In contrast to the toxic CTA subunit, the non-toxic CTB subunit displays both carrier and immunostimulatory properties. When linked to pathogen antigens, CTB can impart immunostimulatory properties that are characteristic of the linked antigen. Vaccination strategies have also been broadened to include 'self' proteins applied for the immunological suppression of autoimmunity. When CTB is linked to an autoantigen, the outcome might be considered paradoxical. In type 1 diabetes, self proteins become strongly immunosuppressive, while cancer CTB autoantigen fusion proteins may exert a strong inflammatory response. This review discusses the immunostimulatory and immunosuppressive roles played by the CTB subunit in vaccine protection and therapy against infectious and autoimmune diseases. PMID- 20721835 TI - Outpatient parenteral antimicrobial therapy: Recent developments and future prospects. AB - Patients with serious infections requiring parenteral antimicrobial therapy are usually hospitalized for treatment. For certain conditions, however, administration of parenteral antibiotics outside the hospital setting may be safe, efficacious, convenient for patients and cost-beneficial. Outpatient parenteral antimicrobial therapy (OPAT) was developed in the US initially and its use has expanded globally during the past three decades. A wide variety of infections are amenable to treatment by OPAT. Once-daily agents such as ceftriaxone or teicoplanin and, more recently, antimicrobials such as ertapenem or daptomycin have been used for OPAT. The use of higher doses and less-frequent dosing of existing agents is being explored, and exciting new developments include the emergence of agents with broader-spectrum activity against drug resistant organisms and the use of antifungal agents in the OPAT setting. Future prospects in OPAT include the use of more recently launched drugs such as telavancin, as well as drugs in development, including dalbavancin (Durata Therapeutics Inc) and omadacycline (PTK-0796; Novartis AG/PARATEK Pharmaceuticals Inc). This review outlines recent developments in, and future prospects for, the antimicrobial agents used in OPAT. PMID- 20721836 TI - Cenicriviroc, an orally active CCR5 antagonist for the potential treatment of HIV infection. AB - Treatment of HIV-1-infected individuals is often complicated by the development of antiretroviral resistance, and novel antiretroviral agents with unique mechanisms of action and resistance profiles are needed to address this issue. CCR5 inhibitors represent a new class of antiretroviral agents that block the CCR5 receptor and prevent HIV-1 recognition and entry into CD4+ macrophages and T cells. Tobira Therapeutics Inc is developing cenicriviroc (TBR-652, formerly TAK 652), a potent inhibitor of CCR5-tropic HIV-1 replication. Cenicriviroc has good oral bioavailability, a long t1/2 that allows once-daily dosing, and has demonstrated excellent antiviral potency with minimal toxicity in in vitro studies and phase I clinical trials. Encouraging efficacy results have been reported from phase II clinical trials in patients with CCR5-tropic HIV-1. The drug is also an inhibitor of the CCR2 receptor, which is known to be associated with inflammatory-related disease states, leading to Tobira initiating a phase I clinical trial in patients with rheumatoid arthritis. Cenicriviroc is a promising CCR5 inhibitor with potentially important anti-inflammatory effects, and warrants further investigation. PMID- 20721831 TI - Brain dysfunction in the era of combination antiretroviral therapy: implications for the treatment of the aging population of HIV-infected individuals. AB - Improvements in the treatment of HIV infection and in the advancement of combination antiretroviral therapy (cART) have led to an increase in the number of individuals with HIV who are surviving to an older age. Preventing the development of neurocognitive abnormalities has become an increasingly important issue in this aging patient population, which is already at risk for cognitive impairment as a result of the neuropathological effects of HIV. cART has been critical in reducing the overall severity of HIV-associated neurocognitive disorders (HAND), but numerous challenges remain, as the prevalence of HAND continues to be high. There are several key areas in which treatment could be improved to reduce the incidence and severity of HAND. The use of well-tolerated cART medications that are able to penetrate the blood-brain barrier hold particular promise, as these agents may enable increased viral suppression in the parenchyma and may reduce neurocognitive dysfunction. In addition, the improved treatment of comorbid medical conditions that are common in patient populations with HIV (eg, HCV, liver failure and metabolic syndrome) is critical, as several of these conditions are known to have a significant effect on neural functions. Various research approaches indicate that the development of agents that control free radicals, neurotoxicity, proinflammatory processes and apoptosis may also have substantial potential in this field. PMID- 20721837 TI - Danoprevir, a small-molecule NS3/4A protease inhibitor for the potential oral treatment of HCV infection. AB - Danoprevir (ITMN-191; RG-7227), under development by InterMune Inc and Roche Holding AG, is a promising, potent NS3/4A protease inhibitor for the oral treatment of HCV infection. Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure. A phase Ib, 'IFN free' clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor RG-7128 (Pharmasset Inc/Roche Holding AG), was effective in reducing HCV-RNA levels in a large proportion of treatment-naive patients with HCV infection and in approximately half of previously non-responsive patients with HCV-1 infection, without resistance or safety concerns. In a phase IIb trial in treatment-naive patients with HCV-1 infection, danoprevir plus pegylated IFNalpha2a and ribavirin resulted in undetectable levels of HCV-RNA in the majority of patients, without any evidence of viral resistance; however, the high dose danoprevir arm was prematurely terminated because of grade 4 ALT elevations. Phase I trials have also demonstrated that ritonavir boosting improved the pharmacokinetic profile of danoprevir; therefore, at the time of publication, a phase IIb trial to evaluate ritonavir-boosted, low-dose danoprevir in combination with RG-7128 was planned. PMID- 20721838 TI - Vacc-4x, a therapeutic vaccine comprised of four engineered peptides for the potential treatment of HIV infection. AB - Vacc-4x is being developed by Bionor Immuno AS as a therapeutic vaccine to be used in conjunction with antiretroviral therapies by individuals infected with HIV. The vaccine is comprised of four synthetic peptides describing sequences from within the highly conserved HIV core protein p24, which are thought to induce T-cell-mediated responses. Vacc-4x was assessed in 51 patients infected with HIV in one phase I and one phase II clinical trial and was demonstrated to be safe and generally well tolerated with no significant adverse events. Promisingly, the vaccine was reported to induce cell-mediated immunity, with a third of vaccinees eligible for follow-up remaining off antiretroviral therapy and being essentially symptom-free 4 years after treatment. Nonetheless, without the inclusion of a placebo group, the data will be looked upon with a degree of skepticism in the scientific community. A phase IIb, placebo-controlled clinical trial to address this issue is currently ongoing, with data expected to become available by the end of 2010. If Vacc-4x vaccinees demonstrate significantly better responses than the placebo group in this trial, the prospects for Vacc-4x could be highly promising. PMID- 20721839 TI - [Visceral medicine 2010: interdisciplinary as well as individual]. PMID- 20721840 TI - [A prospective comparison of video colonoscopy and CT colonography in asymptomatic patients screened for colorectal cancer]. AB - BACKGROUND AND OBJECTIVE: It was the aim of this study to compare the sensitivity and specificity of low-dose CT colonography (CTC) with that of optical colonoscopy (OC) in asymptomatic patients undergoing these tests in a screening program for colonic cancer. PATIENTS AND METHODS: 58 patients (mean age 62.6 years) were included. They underwent low dose CTC and, immediately afterwards, colonoscopy. The colonoscopists were unaware of the CTC findings. A "second look" was performed if a lesion seen in CTC had been missed in the first colonoscopy. RESULTS: A total of 150 lesions were detected and histologically confirmed. 136 were found to be polypoid lesions, classified as either hyperplastic polyps (n = 66) or polyps with intraepithelial neoplasia (n = 70). In the per-patient analysis only 22.4 % of patients had no polypoid lesion, 27.6 % had at least one hyperplastic and 50.0 % had at least one adenomatous lesion. Sensitivity for adenomas of all size categories was calculated 55.7 % for CTC and 92.9 % for OC. This marked difference (both for the detection of individual lesions and the per patient analyses) does not reach significance in the two-sided McNemar test. CONCLUSIONS: There was a high prevalence of lesions with intraepithelial neoplasia in this screening group. OC had a higher sensitivity than CTC in the detection of lesions smaller than 10 mm. PMID- 20721842 TI - [70-year-old patient with chronic anemia. Gastric antral vascular ectasia; watermelon stomach]. PMID- 20721841 TI - [Unusual presentation of autoimmune pancreatitis type 1]. AB - HISTORY AND ADMISSION FINDINGS: A-51-year-old man presented with increasingly severe upper abdominal pain, in reduced general state and mild weight loss. Ten years before the patient had undergone a Kausch-Whipple procedure (pancreaticoduodenectomy) for an inflammatory mass in the pancreas, at that time histologically identified as an inflammatory tumour with chronic pancreatitis. Since then he has had repeated episodes of stenosis of the biliary-digestive anastomosis, associated with acute cholangitis. Laboratory findings on admission revealed liver function tests that were moderately (AST, ALT) or markedly elevated (GGT and AP). INVESTIGATIONS: Abdominal ultrasound revealed cuffing of the portal vein and its side-branches with low echogenicity. Magnetic resonance imaging showed periportal edema with irregular bile ducts. Initially the histological examination strongly suggested a peripheral malignant T-cell lymphoma. However, subsequent examination revealed a chronic IgG4-associated, lymphoplasmatic sclerosing inflammation of the biliary tract. TREATMENT AND COURSE: Histological re-examination of the 10-year-old pancreatic resection specimens also showed severe lymphoplasmatic infiltrates suggesting a pancreatic manifestation of an IgG4-associated systemic disease (ISD), known nowadays as an type 1 autoimmune pancreatitis (AIP). Based on the initial diagnosis of an invasive periphere malignant T-cell lymphoma of the liver a pre-phase treatment with vincristine, prednisolone followed by one cycle of CHOEP were administered. This resulted in complete remission of the patient's symptoms. Once the true diagnosis had been revised this treatment was immediately stopped. Since the patient remained symptom-free, the initially elevated laboratory parameters returned to normal and a remission of low echogenicity cuffing of the portal vein was observed and no further steroid treatment was administered. Ursodesocycholic acid was then given as the only drug, to prevent any further episodes of cholangitis. CONCLUSIONS: Autoimmune pancreatitis continues to be frequently unrecognized in clinical practice. But because it responds well to corticosteroids, this clinical entity should be considered in the differential diagnosis of unclear inflammatory changes and strictures of the pancreatic and biliary tracts or even, if necessary, looked for retrospectively in resected pancreas specimens. PMID- 20721843 TI - [Diagnosis and treatment of gastric cancer]. AB - From a global perspective, gastric cancer including cancer of the esophago gastric junction is the fourth most common malignant tumor and the second-most common cause of cancer-related death. Due to the lack of screening programs in Western countries, most gastric cancers are diagnosed in advanced stages. A sophisticated staging should include high-resolution computed tomography of the thorax, abdomen and pelvis and video-documented endoscopy and endoscopic ultrasound. In mucosal gastric cancer, endoscopic resection can replace surgical resection if specific criteria are present. In the stages II and III perioperative chemotherapy has been established as a standard of care and should be applied. In the metastatic setting, treatment goals are palliative. Chemotherapy can prolong survival, improve symptoms and can help to maintain a better quality of life. Combination chemotherapy including a platinum compound and a fluoropyrimidine regarded as standard. About 20 % of gastric cancers exhibit overexpression of the growth factor receptor family member Her2. Trastuzumab is a monoclonal antibody directed against Her2 and has shown to prolong survival when combined with cisplatin and 5-fluorouracil or capecitabine. PMID- 20721844 TI - [Personalized therapy of gastrointestinal cancers--possibilities and limitations]. AB - The aim of palliative chemotherapy is to increase survival whilst maintaining optimal quality of life for the individual patient. While the best use of traditional chemotherapeutical agents continues to be explored, the introduction of targeted therapies has significantly broadened the therapeutic options. Yet it is interesting to note that the results of current trials did not always confirm the underlying molecular concepts. Recent data have suggested that altered pathways underlie the development of cancer, not just altered genes. Thus an effective therapeutic agent will have to target pathophysiologically relevant signalling networks, rather than individual proteins. This review presents current concepts and problems of cancer treatment, highlighting results from recent clinical trials of colorectal and pancreatic cancer patients and to discuss the current understanding of the underlying mechanisms. PMID- 20721845 TI - [Drug therapy or surgical treatment of obesity--for drug therapy]. PMID- 20721846 TI - [Drug therapy or surgical treatment of obesity--for surgical treatment]. PMID- 20721847 TI - [Treatment of Crohn's disease: step-up or top-down?]. PMID- 20721848 TI - [Image quality in multidetector CT of paranasal sinuses: potential of dose reduction using an adaptive post-processing filter]. AB - PURPOSE: Evaluation of subjective image quality in dose-reduced multi-detector CT (MDCT) of paranasal sinuses using a 2D non-linear adaptive post-processing filter (2D-NLAF). MATERIALS AND METHODS: MDCT of paranasal sinuses was simulated using a human head phantom at a Somatom Sensation Cardiac 64 (Siemens, Erlangen). At constant collimation (64 * 0.6 mm) und pitch (p = 1), the tube current (50, 100, 200 mAs) and tube potential (80, 100, 120 kVp) were modified. The radiation exposure was represented by CTDIvol. Four independent blinded radiologists evaluated the image quality of axial 2 mm images and coronal reformations concerning the assessment of "fractures" and "soft tissue processes". The subjective image quality of original and post-processed images using a 2D-NLAF (SharpViewCT(r), Sweden) was graded on a 5-point scale ("1" excellent - "5" not adequate) and compared. RESULTS: Compared to the protocol with the best image quality (120kVp/ 200 mAs) 2D-NLAF led to a significant improvement in the subjective image quality at 100 kVp/ 100 mAs (score "1.4" with filter versus "2.2" without) and 120 kVp/ 50 mAs ("1.6" versus "2.0") (p < 0.03) particularly for high contrasts ("fractures", p < 0.001). In "soft tissue processes", 2D-NLAF provided improved quality from "2.1" to "1.4" (p < 0.04) at 100 kVp/ 100 mAs. Down to a CTDIvol of 8 mGy, the image quality was rated "good", and down to 5 mGy "diagnostic". CONCLUSION: The phantom study indicates a dose reduction potential in MDCT of paranasal sinuses up to 58% compared to a standard dose protocol using a 2D-NLAF without an essential loss of image quality. 2D-NLAF is particularly effective at 100 kVp/ 100 mAs and 120 kVp/ 50 mAs. PMID- 20721849 TI - Surgical correction and reconstruction of the nipple-areola complex: current review of techniques. AB - Nipple malformations are common congenital or acquired conditions that can have tremendous cosmetic, psychological, breast-feeding, sexual, and hygienic ramifications. Ideal reconstruction of the nipple-areola complex (NAC) requires symmetry in position, size, shape, texture, pigmentation, and permanent projection, and although many technical descriptions of NAC reconstruction exist in the medical literature, there are insufficient data presented to accurately compare outcomes. The current article comprises a thorough review of the literature, exploring the techniques described for NAC reconstruction, comparing reported outcomes and complications, and providing an evidence-based approach to NAC reconstruction. The findings of the review suggest that evidence regarding surgical correction of nipple deformity and complete NAC reconstruction is lacking, and loss of nipple projection over time is a pervasive problem common to all flap techniques. A combination of a single pedicle local flap with tattooing for complete NAC reconstruction is currently the most supported method; however, data concerning which type of reconstruction is best suited to immediate versus delayed and type of breast mound remain to be examined. PMID- 20721850 TI - [Mentally handicapped patients: a diagnostic challenge]. PMID- 20721871 TI - Photochemically crosslinked matrices of gelatin and fibrinogen promote rapid cell proliferation. AB - Here we report the use of a facile photochemical crosslinking method to fabricate stable polymer matrices from unmodified gelatin and fibrinogen. Gels were produced by covalent crosslinking of the proteins in a rapid photo-oxidative process, catalysed by a ruthenium metal complex and irradiation with visible light. For generation of macroporous, spongy matrices, the proteins and crosslinking reagents were mixed with catalase and hydrogen peroxide to achieve a foaming reaction, producing a stable, foamed matrix that was subsequently photo crosslinked. C2C12 cells were either seeded onto the matrices after photo-curing or embedded in the protein matrix prior to foaming and crosslinking. Cells seeded onto scaffolds post-curing showed high cell viability and rapid proliferation in vitro. For cells embedded in the matrix prior to crosslinking there was some loss of initial viability, but surviving cells were able to proliferate after a period of in vitro cultivation. The matrices were shown to be biocompatible when implanted into nude mice, with evidence of proliferation and differentiation of cells seeded into the scaffolds. The results are promising for further development of tissue-engineering scaffolds based on this ruthenium-catalysed photo-crosslinking method. PMID- 20721872 TI - Sixteen years of prenatal consultations for the N370S/N370S Gaucher disease genotype: what have we learned? AB - OBJECTIVE: Although prenatal diagnosis and genotyping are available for Gaucher disease, genetic counseling for an affected child's parents reflects the inability to predict disease course with certainty. The purpose of this survey is to ascertain disease status of children identified by prenatal screening. METHODS: All carrier couples for glucocerebrosidase mutations who were counseled at our large Gaucher Clinic were included; none had genotyped the fetus. Medical status of children was assessed by questionnaires and data were collected from clinic charts and/or telephone contact with the parents. RESULTS: Of 34 children born, 1 died in utero, 5 fetuses (N370S/N370S) aborted. Of 21 genotyped N370S/N370S, 7 children had Gaucher-like symptoms/signs but for only one child (two symptoms) were these ascribable to Gaucher disease; four children had non Gaucher symptoms/signs. CONCLUSION: Of 21 children whose parents pursued prenatal counseling for Gaucher disease and were found to have the N370S/N370S genotype, none has presented with severe disease with follow-up of 15 years. The Israeli experience shows that Gaucher disease N370S screening does not identify children requiring treatment, but rather leads to termination of asymptomatic fetuses; this may lead to reconsideration of guidelines regarding Gaucher screening. PMID- 20721873 TI - PAPP-A, free beta-hCG, and early fetal growth identify two pathways leading to preterm delivery. AB - OBJECTIVE: To evaluate early fetal growth and the biomarkers, pregnancy associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG), in relation to preterm delivery. METHODS: A cohort study of 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital between January 2005 and December 2007, was conducted. PAPP-A and free beta-hCG were measured in the first trimester. Early fetal growth was estimated by (GA(20)- GA(12))/Days(calendar), where GA(12) reflects the gestational age in days calculated from the crown-rump length at a 12-week scan, GA(20) reflects the gestational age in days calculated from the biparietal diameter at a 20-week scan, and Days(calendar) is the number of calendar days between the two scans. RESULTS: Low PAPP-A and low free beta-hCG were significantly associated with preterm delivery (<37 weeks). The association was even stronger when low PAPP-A and slow early fetal growth were combined, resulting in an adjusted odds ratio of 3.8 (95% CI, 1.6-8.7). Fast early fetal growth, but neither high PAPP-A nor high free beta-hCG, was significantly associated with preterm delivery. CONCLUSION: Two different biological pathways leading to spontaneous preterm delivery are suggested: fast early fetal growth and the combination of low PAPP-A and slow early fetal growth. PMID- 20721874 TI - Prenatal diagnosis of polysplenia syndrome associated with increased nuchal translucency. PMID- 20721875 TI - Distinction between fetal growth restriction and small for gestational age newborn weight enhances the prognostic value of low PAPP-A in the first trimester. PMID- 20721876 TI - Fetal cardiac tumors: a single-center experience of 40 cases. AB - OBJECTIVE: To determine the natural history and outcome of fetal cardiac tumors. METHODS: This was a retrospective cohort study of all prenatally detected cases of cardiac tumors at a tertiary cardiac care center. RESULTS: Forty fetuses were identified to have one or several cardiac tumors in association with fetal hydrops (18%), ventricular obstruction (30%) and/or arrhythmia (13%). Of 33 cases with rhabdomyoma, three patients elected to terminate the pregnancy, four offspring died at birth and 26 (79%) survived. On follow-up, 95% of all live-born cases with rhabdomyomas were free of cardiac symptoms but 88% had tuberous sclerosis. All three fetuses with teratoma presented with hydrops and none of them survived. In contrast, all three fetuses with cardiac fibroma are alive and have a biventricular physiology. One fetus with a large atrial hemangioendothelioma died in early infancy. Fetal or neonatal death was associated with an earlier cardiac anomaly diagnosis, earlier delivery, larger tumor size and fetal hydrops at presentation. CONCLUSIONS: The outcome of fetal cardiac tumors was predicted by the etiology and size of the cardiac mass and the presence of hydrops. Although most cardiac rhabdomyomas have a relatively benign perinatal course, the long-term prognosis is determined by the neurological manifestations associated with tuberous sclerosis. PMID- 20721877 TI - Bowel dilation as a predictor of adverse outcome in isolated fetal gastroschisis. AB - OBJECTIVES: This study was designed to evaluate bowel diameter as a predictor of adverse outcome in isolated fetal gastroschisis. METHODS: Retrospective study involving 94 singleton pregnancies. Ultrasound measurements of herniated bowel transverse diameter (BTD) were performed up to 3 weeks before delivery. Adverse outcome was intrauterine/neonatal death and/or bowel complications. RESULTS: Last BTD was recorded at 35.6 +/- 1.6 weeks and mean interval to delivery was 6.2 +/- 5.0 days. Intrauterine/neonatal death occurred in 10 (10.6%) cases; bowel complications were observed in 8 (8.5%). BTD >= 15, >= 20, >= 25, and >= 30 mm were found in 87, 46, 13, and 4% of pregnancies with a favorable outcome, respectively. BTD >= 25 mm sensitivity was 38%, and positive and negative predictive values were 38 and 87%. For BTD >= 30 mm, the values were 19, 50, and 85%. Observed/expected BTD ROC curve showed an area of 0.67, best cut-off value at 1.39; prediction values were similar to those for BTD >= 25 mm. Bowel dilatation was also significantly associated with lower rate of primary surgical closure, longer period to full oral feeding, and prolonged hospital stay. CONCLUSIONS: Bowel dilatation demonstrated up to 3 weeks before delivery is a predictor of intestinal complications and is associated with lower rate of primary surgical closure, longer period to achieve full oral feeding, and hospital stay. PMID- 20721878 TI - Fetal sex determination using circulating cell-free fetal DNA (ccffDNA) at 11 to 13 weeks of gestation. AB - OBJECTIVE: To examine the performance of a mass spectrometry-based detection platform using three Y-chromosome sequences for fetal sex determination from circulating cell-free fetal DNA (ccffDNA) in maternal blood in the first trimester of pregnancy. METHODS: We extracted ccffDNA for the determination of fetal sex from stored maternal plasma obtained at 11 to 13 weeks' gestation from singleton pregnancies with documented fetal gender. Mass spectrometry was used to examine 236 specimens for the presence of three Y-chromosome sequences (SRY, DBY and TTTY2). The sample was classified as male, female or inconclusive depending on the detection of three, one/none and two sequences, respectively. RESULTS: Three (1.3%) of the 236 cases were classified as invalid due to the absence of a well-defined spectral peak for TGIF and 22 (9.3%) were reported as inconclusive. In the 211 cases with a valid result, the fetal sex was correctly identified in 90 of 91 male babies and 119 of 120 female babies giving an accuracy of 99.1% and sensitivity and specificity for prediction of male fetuses of 98.9 and 99.2%, respectively. CONCLUSION: Fetal sex determination can be accurately determined from maternal ccffDNA in the first trimester of pregnancy using mass spectrometry analysis. PMID- 20721879 TI - The effect of fetal gender in predicting Down syndrome using long bone ultrasonographic measurements. AB - OBJECTIVE: To determine if fetal gender affects the screening efficiency of short femur and humerus lengths in the prediction of trisomy 21. METHODS: Retrospective cohort study of 62 111 patients presenting for ultrasound from 1990 to 2006. Short humerus and femur lengths were defined using (1) biparietal diameter (BPD) to femur/humerus length (FL/HL) ratios > 1.5 standard deviations above the mean, (2) the observed to expected (O/E) ratio of femur length <= 0.91 or humerus length <= 0.89, and (3) femur and humerus lengths < 5th percentile. The sensitivity, specificity, and likelihood ratios were calculated for the association of short FL/HL and trisomy 21 stratified by gender. RESULTS: Both BPD/long bone ratios as well as O/E ratios demonstrated a statistically significant higher specificity for the detection of trisomy 21 in female fetuses. This difference was most clinically significant when using the O/E ratio, which yielded a specificity of 82.6% in males and 90.6% in females for short femur, and 69.7% in males and 77.9% in females for short humerus, when these markers were evaluated as isolated findings. CONCLUSION: Gender-specific differences in the effectiveness of both short femur and humerus lengths for the prediction of trisomy 21 may exist, but their presence and magnitude are largely dependent on the formula used. PMID- 20721880 TI - Incorporation of fetal DNA detection assay in a noninvasive RhD diagnostic test. PMID- 20721881 TI - Split-screen video demonstration of sonography-guided muscle identification and injection of botulinum toxin. AB - A standardization of injection procedures for the various botulinum toxin (BoNT) indications has not been achieved to date. One established option to guide the therapist's needle is sonography guidance. It provides real-time visualization of the injection process, which is quick, allows perfect precision, and the procedure as such is painless. To demonstrate these qualities, we have recorded six split-screen video segments that show the handling of the probe and the needle during BoNT injections concurrently with the respective cross-sectional sonography recordings. The video sequences show differentiation of the pollicis longus muscle and individual finger flexor fascicles, needle tracking, and real time sonography-guided injection of the gastrocnemius, rectus femoris, and iliopsoas muscles. We hope this short presentation will help to encourage a more widespread use of the technique as well as further research on sonography guidance for precise delivery of BoNT injections to various target muscles. PMID- 20721882 TI - Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates. AB - The differentiation of embryonic or determined stem cell populations into adult liver fates under known conditions yields cells with some adult-specific genes but not others, aberrant regulation of one or more genes, and variations in the results from experiment to experiment. We tested the hypothesis that sets of signals produced by freshly isolated, lineage-dependent mesenchymal cell populations would yield greater efficiency and reproducibility in driving the differentiation of human hepatic stem cells (hHpSCs) into adult liver fates. The subpopulations of liver-derived mesenchymal cells, purified by immunoselection technologies, included (1) angioblasts, (2) mature endothelia, (3) hepatic stellate cell precursors, (4) mature stellate cells (pericytes), and (5) myofibroblasts. Freshly immunoselected cells of each of these subpopulations were established in primary cultures under wholly defined (serum-free) conditions that we developed for short-term cultures and were used as feeders with hHpSCs. Feeders of angioblasts yielded self-replication, stellate cell precursors caused lineage restriction to hepatoblasts, mature endothelia produced differentiation into hepatocytes, and mature stellate cells and/or myofibroblasts resulted in differentiation into cholangiocytes. Paracrine signals produced by the different feeders were identified by biochemical, immunohistochemical, and quantitative reverse-transcription polymerase chain reaction analyses, and then those signals were used to replace the feeders in monolayer and three-dimensional cultures to elicit the desired biological responses from hHpSCs. The defined paracrine signals were proved to be able to yield reproducible responses from hHpSCs and to permit differentiation into fully mature and functional parenchymal cells. CONCLUSION: Paracrine signals from defined mesenchymal cell populations are important for the regulation of stem cell populations into specific adult fates; this finding is important for basic and clinical research as well as industrial investigations. PMID- 20721883 TI - Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C. AB - Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting. CONCLUSION: All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C. American Association for the Study of Liver Diseases. PMID- 20721884 TI - The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. AB - This review focuses on the hypothesis that biliary HCO(3)(-) secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCO(3)(-) umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl(-)/ HCO(3)(-) exchange and HCO(3)(-) secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable biliary HCO(3)(-) umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO(3)(-) umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. PMID- 20721885 TI - Serum free light chain analysis. AB - In a variety of hematologic malignancies, immunoglobulin light chains (LC) are overproduced clonally and circulate without being linked by disulphide bonds to the immunoglobulin heavy chain. The recent development of a robust assay known as kappa and lambda "free" LC (FLC) to quantify the levels of these unbound LC in the serum, and thereby determine their ratio, has led to an explosion of studies that demonstrate its utility in a wide range of hematologic disorders. This article summarizes laboratory testing for serum FLC, with a particular focus on clinical applications for the test. PMID- 20721886 TI - An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era. AB - Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation. PMID- 20721887 TI - Striking morphology of leukemic phase of childhood peripheral T-cell lymphoma, not otherwise specified. PMID- 20721888 TI - Renal cell carcinoma and acute promyelocytic leukemia: a nonrandom association? PMID- 20721889 TI - Concurrent involved field radiation therapy and temsirolimus in refractory mantle cell lymphoma (MCL). PMID- 20721890 TI - MALT lymphoma and Kaposi sarcoma in an HIV-negative patient. AB - A 77-year-old caucasian man presented on March 2005 with important epigastric pain without any other significant history of gastritis. Patient refers a history of cutaneous Kaposi's sarcoma (KS) treated since 1974 with surgical excision or oncovorin topical injection. He underwent endoscopic evaluation showing a 1.5-cm ulcerated area at the gastric angulus, associated with edematous and erythematous nodular mucosa (Fig. 1). PMID- 20721891 TI - Severe thrombosis and acute thrombocytopenia in a cancer patient. PMID- 20721892 TI - Iron chelation therapy for patients with sickle cell disease and iron overload. PMID- 20721893 TI - Perfectionism and its relation to overevaluation of weight and shape and depression in an eating disorder sample. AB - OBJECTIVE: To examine the relative association between psychopathology (depression and overevaluation of weight and shape) and measures of perfectionism and self-criticism in an eating disorder sample. METHOD: Participants (n = 39) completed measures of independent variables (perfectionism and self-criticism) and dependent variables (depression and overevaluation of weight and shape). RESULTS: Simultaneous multiple regression analyses suggest that clinical perfectionism has a unique association with depression. Self-criticism and clinical perfectionism had a stronger association with overevaluation of weight and shape than other measures of perfectionism. DISCUSSION: Clinical perfectionism and self-criticism may be of more relevance than existing measures of multidimensional perfectionism in terms of explaining maintenance of depression and overevaluation of weight and shape. PMID- 20721894 TI - Development of emotion acceptance behavior therapy for anorexia nervosa: a case series. AB - This case series describes the development of a novel psychotherapeutic intervention for older adolescents and adults with anorexia nervosa (AN). Emotion acceptance behavior therapy (EABT) is based on a model that emphasizes the role of anorexic symptoms in facilitating avoidance of emotions. EABT combines standard behavioral interventions that are central to the clinical management of AN with psychotherapeutic techniques designed to increase emotion awareness, decrease emotion avoidance, and encourage resumption of valued activities and relationships outside the eating disorder. Five patients with AN aged 17-43 years were offered a 24-session manualized version of EABT. Four patients completed at least 90% of the therapy sessions, and three showed modest weight gains without return to intensive treatment. Improvements in depressive and anxiety symptoms, emotion avoidance, and quality of life also were observed. These results offer preliminary support for the potential utility of EABT in the treatment of older adolescents and adults with AN. PMID- 20721895 TI - Self-efficacy as a robust predictor of outcome in guided self-help treatment for broadly defined bulimia nervosa. AB - OBJECTIVE: To examine predictors of guided self-help (GSH) treatment outcome in bulimia nervosa (BN). METHOD: Data were included from 87 individuals who participated in one of two randomized controlled trials evaluating GSH interventions for BN. Participants received eight sessions of GSH over a 6- to 8 week period and were assessed at baseline, pretreatment, posttreatment, and 6 month follow-up. RESULTS: Motivation (confidence in ability to change) proved to be the most robust predictor of outcome, across three of the four outcome measures. Baseline measures of concern over mistakes perfectionism also uniquely predicted outcome at posttreatment. Posttreatment measures of stress, eating disorder-related automatic thoughts, and frequency of binge episodes predicted outcome at 6-month follow-up. DISCUSSION: This study suggests that tackling motivation early in therapy, with a particular focus on confidence in succeeding in change, could be of benefit to outcome in BN treatment. PMID- 20721896 TI - Associations between specific components of compulsive exercise and eating disordered cognitions and behaviors among young women. AB - OBJECTIVE: To explore the associations between specific elements of compulsive exercise and both eating-disordered cognitions and eating-disordered behaviors in a nonclinical sample of young women. METHOD: A sample of young women (n = 498) completed self-report measures of eating pathology (The Eating Disorders Examination Questionnaire) and a relatively new measure of Compulsive Exercise Test. RESULTS: Specific elements of compulsive exercise were associated with elevated levels of eating-disordered cognitions and increased frequency of eating disordered behaviors. DISCUSSION: These results support a multifunctional conceptualization of compulsive exercise, suggesting that some of the functionality of compulsive exercise may be akin to other forms of purging, and further supporting the notion of a possible functional equivalence between compulsive exercise and specific eating-disordered behaviors in terms of affect regulation. PMID- 20721898 TI - Dyskinesia-hyperpyrexia syndrome: another Parkinson's disease emergency. PMID- 20721897 TI - Microfluidic synthesis of composite cross-gradient materials for investigating cell-biomaterial interactions. AB - Combinatorial material synthesis is a powerful approach for creating composite material libraries for the high-throughput screening of cell-material interactions. Although current combinatorial screening platforms have been tremendously successful in identifying target (termed "hit") materials from composite material libraries, new material synthesis approaches are needed to further optimize the concentrations and blending ratios of the component materials. Here we employed a microfluidic platform to rapidly synthesize composite materials containing cross-gradients of gelatin and chitosan for investigating cell-biomaterial interactions. The microfluidic synthesis of the cross-gradient was optimized experimentally and theoretically to produce quantitatively controllable variations in the concentrations and blending ratios of the two components. The anisotropic chemical compositions of the gelatin/chitosan cross-gradients were characterized by Fourier transform infrared spectrometry and X-ray photoelectron spectrometry. The three-dimensional (3D) porous gelatin/chitosan cross-gradient materials were shown to regulate the cellular morphology and proliferation of smooth muscle cells (SMCs) in a gradient dependent manner. We envision that our microfluidic cross-gradient platform may accelerate the material development processes involved in a wide range of biomedical applications. PMID- 20721899 TI - A case of occupational peritoneal mesothelioma from exposure to tremolite-free chrysotile in Quebec, Canada: A black swan case. AB - BACKGROUND: Tremolite contamination has been proposed as the cause of mesothelioma in workers exposed to commercial chrysotile. The asbestos industry and scientists it has sponsored, for example, have argued that commercial chrysotile does not cause peritoneal mesothelioma. METHOD: Case report of peritoneal mesothelioma in a mill worker from a tremolite free Canadian mine. RESULTS: Reports from pathology and occupational health and safety panels conclude that this mill worker developed work-related peritoneal mesothelioma. CONCLUSION: Chrysotile without tremolite can cause peritoneal mesothelioma. PMID- 20721900 TI - Effects of a low intensity intervention to increase hearing protector use among noise-exposed workers. AB - BACKGROUND: Farm operators experience exposure to high noise and high prevalence of noise-induced hearing loss, but use of hearing protection in this worker group is low. The purpose of this study was to test a brief intervention to increase farm operators' use of hearing protection. METHODS: In this one-group pre- and post-test study, a random sample of 32 members of a farmers' organization was supplied a variety of hearing protectors. Participants received an assortment of hearing protectors by mail with manufacturer's instructions for use. RESULTS: Mean pre-intervention hearing protector use when in high noise in this group was 23% (SD 29). Of the 32 participants, 27 (84%) were exposed to hazardous noise during the study period. Post-intervention mean use of HPDs was 64%, an increase of 41% (t = 5.26, P < 000). CONCLUSION: Results of this study suggest that overall, hearing protectors were acceptable to farm operators, and that a brief mailed intervention is feasible. PMID- 20721901 TI - Does PTSD moderate the relationship between social support and suicide risk in Iraq and Afghanistan War Veterans seeking mental health treatment? AB - OBJECTIVE: This study examined posttraumatic stress disorder (PTSD) as a potential moderating variable in the relationship between social support and elevated suicide risk in a sample of treatment-seeking Iraq and Afghanistan War Veterans. METHOD: As part of routine care, self-reported marital status, satisfaction with social networks, PTSD, and recent suicidality were assessed in Veterans (N=431) referred for mental health services at a large Veteran Affairs Medical Center. Logistic regression analyses were conducted using this cross sectional data sample to test predictions of diminished influence of social support on suicide risk in Veterans reporting PTSD. RESULTS: Thirteen percent of Veterans were classified as being at elevated risk for suicide. Married Veterans were less likely to be at elevated suicide risk relative to unmarried Veterans and Veterans reporting greater satisfaction with their social networks were less likely to be at elevated risk relative to Veterans reporting lower satisfaction. Satisfaction with social networks was protective for suicide risk in PTSD and non PTSD cases, but was significantly less protective for veterans reporting PTSD. CONCLUSIONS: Veterans who are married and Veterans who report greater satisfaction with social networks are less likely to endorse suicidal thoughts or behaviors suggestive of elevated suicide risk. However, the presence of PTSD may diminish the protective influence of social networks among treatment-seeking Veterans. PMID- 20721902 TI - Potential use of Internet-based screening for anxiety disorders: a pilot study. AB - BACKGROUND: The Internet is a widely used resource for obtaining health information. Internet users are able to obtain anonymous information on diagnoses and treatment, seek confirmatory information, and are able to self-diagnose. We posted a self-report diagnostic screening questionnaire for DSM-IV anxiety and mood disorders (MACSCREEN) on our clinic website. METHOD: Three hundred and two individuals completed the MACSREEN. For those who qualified for a DSM-IV disorder, self-report symptom severity measures were completed for the specified disorder: Quick Inventory of Depressive Symptomatology, self-report, Social Phobia Inventory, GAD-7, Davidson Trauma Scale, Panic and Agoraphobia Scale, and Yale/Brown Obsessive Compulsive Scale, self-report. Cutoff scores for each self report measure were used to evaluate clinically significant symptom severity. Respondents were also asked to complete a series of questions regarding their use of the Internet for health information. RESULTS: The mean age of the MACSCREEN sample was 35.2 years (+/-13.9), where the majority (67.2%) were female. The most frequently diagnosed conditions were social phobia (51.0%), major depressive disorder (32.4%), and generalized anxiety disorder (25.5%). Sixty-five percent of the sample met criteria for at least one disorder. Most respondents reported completing the MACSCREEN, as they were concerned they had an anxiety problem (62.3%). The majority of respondents reported seeking health information concerning specific symptoms they were experiencing (54.6%) and were planning to use the information to seek further assessment (60.3%). CONCLUSION: Individuals with clinically significant disorder appear to be using the Internet to self diagnose and seek additional information. PMID- 20721903 TI - Relationship between respiratory, endocrine, and cognitive-emotional factors in response to a pharmacological panicogen. AB - BACKGROUND: The cholecystokinin agonist pentagastrin has been used to study panic attacks in the laboratory and to investigate hypothalamic-pituitary-adrenal axis activity. Its mechanism of panicogenesis remains unclear. Data from other models suggest that respiratory stimulation itself may induce panic, but pentagastrin's effects on respiration are not well established. Data from another model also suggest links between respiratory and HPA axis reactivity and cognitive modulation of both. To further explore these phenomena, we added respiratory measures to a study of cognitive modulation of HPA and anxiety responses to pentagastrin. METHODS: Healthy subjects received pentagastrin and placebo injections, with measurement of cortisol and subjective responses, on two different laboratory visits. They were randomly assigned to receive standard instructions or one of two versions of previously studied cognitive interventions (to either facilitate coping or increase sense of control), given before each visit. Capnograph measures of heart rate (HR), respiratory rate (RR), and end tidal pCO(2) were obtained on 24 subjects. RESULTS: Relative to placebo, pentagastrin induced a significant decline in pCO(2) with no change in RR. Cortisol and HR increased, as expected. Cognitive intervention reduced the hyperventilatory response to pentagastrin. CONCLUSIONS: Pentagastrin stimulates respiration, likely via increases in tidal volume. Respiratory stimulation could play a role in its panicogenic potency, though perhaps indirectly. As with HPA axis responses, higher-level brain processes may be capable of modulating pentagastrin-induced hyperventilation. This model may be useful for further study of cortical/cognitive control of interacting emotional, respiratory, and neuroendocrine sensitivities, with potential relevance to panic pathophysiology. PMID- 20721904 TI - Pardoprunox reverses motor deficits but induces only mild dyskinesia in MPTP treated common marmosets. AB - Long-acting full dopamine D(2) agonists produce less dyskinesia in 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and in Parkinson's disease than effective antiparkinsonian doses of levodopa. They do not however, prevent priming for dyskinesia expression on subsequent levodopa exposure. In contrast, the effects of partial D(2) receptor agonists on dyskinesia are unclear. We now examine the ability of the partial D(2) agonist pardoprunox (SLV308) to improve motor function and its propensity to prime for dyskinesia in drug naive, MPTP-treated common marmosets. Previously, drug naive, MPTP-treated common marmosets were treated with equivalent doses of either pardoprunox (SLV308) (0.1 mg/kg po), ropinirole (0.18 mg/kg po), or levodopa (10 mg/kg po BID) for 28 days. All treatments induced a similar reduction of motor disability. Dyskinesia induced by levodopa was of greater intensity than that following administration of either pardoprunox (SLV308) or ropinirole. Administration of pardoprunox (SLV308) resulted in dyskinesia that was less intense and of shorter duration than either ropinirole or levodopa. At the end of drug treatment, acute challenge with levodopa resulted in the expression of marked dyskinesia in animals that had previously received chronic levodopa or ropinirole treatment. However, animals previously treated with pardoprunox (SLV308) showed only mild dyskinesia in response to the levodopa challenge. These results suggest that the partial D(2) agonist pardoprunox (SLV308) is less likely to prime for dyskinesia or to lead to the expression of dyskinesia than either levodopa or full dopamine agonists. PMID- 20721905 TI - Racial differences in the diagnosis of Parkinson's disease--not just a North American issue. PMID- 20721907 TI - Posttraumatic stress and social anxiety: the interaction of traumatic events and interpersonal fears. AB - Posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD) are frequently comorbid among veteran and community samples. Several studies have demonstrated significant comorbidity between trauma, PTSD, and social anxiety (SA), and a growing number of studies have explored the nature of this association. Although a diagnosis of either PTSD or SAD alone can result in significant impairment in social and occupational functioning, these difficulties are often magnified in persons suffering from both disorders. This review describes the current state-of-the-art regarding the co-occurrence of trauma, PTSD, and SA. First, we provide an overview of empirical data on the prevalence of co-occurring trauma, PTSD, and SAD. Second, we describe possible explanatory models of the co-occurrence, with a specific focus on the shared vulnerability model. Third, we review the available empirical data addressing the postulates of this model, including both genetic and psychological vulnerabilities. Fourth, we describe additional factors-guilt, shame, and depressive symptoms-that may help to explain the co-occurrence of PTSD and SA. A better understanding of this complex relationship will improve the efficacy of treatment for individuals suffering from both disorders. We conclude with key areas for future research. PMID- 20721909 TI - Gender differences in depression and PTSD symptoms following combat exposure. AB - BACKGROUND: This research examined gender as a moderator of the association between combat exposure (CE) and depression as well as CE and PTSD symptoms among a nonclinical sample of Soldiers following deployment in support of operations in Afghanistan and Iraq. METHODS: Cases included 6,943 (516 women, 6,427 men) active duty Soldiers that were retrospectively analyzed from a pre- and post-deployment screening database at a large Army installation. RESULTS: Gender moderated the association between CE and depressive and PTSD symptoms such that higher levels of CE were more strongly associated with depression and PTSD symptoms in women compared to men. Female Soldiers also reported higher severity of depressive symptoms compared to male Soldiers, whereas men reported higher levels of CE and a greater number of previous deployments compared to women. CONCLUSIONS: CE was a stronger predictor of post-deployment depression and PTSD symptoms for women compared to men. These results provide evidence for gender-based differences in depression and PTSD risk. Screening for degree of CE in addition to symptoms associated with depression and PTSD can help with the care for service members who are returning from deployments to combat zones. PMID- 20721908 TI - Anxiety in medically ill children/adolescents. AB - Anxiety disorders are thought to be one of the most common psychiatric diagnoses in children/adolescents. Chronic medical illness is a significant risk factor for the development of an anxiety disorder, and the prevalence rate of anxiety disorders among youths with chronic medical illnesses is higher compared to their healthy counterparts. Anxiety disorders may develop secondary to predisposing biological mechanisms related to a child's specific medical illness, as a response to being ill or in the hospital, a threatening environment, as a result of other genetic and psychological factors, or as a combination of all these factors. Additionally, exposure to physical pain early in one's life and/or frequent painful medical procedures are correlated with fear and anxiety during subsequent procedures and treatments, and may lead to medical nonadherence and other comorbidities. Anxiety disorders can have serious consequences in children/adolescents with chronic and/or life-limiting medical illnesses. Therefore, proper identification and treatment of anxiety disorders is necessary and may improve not only psychiatric symptoms but also physical symptoms. Behavioral and cognitive methods as well as psychotropic medications are used to treat anxiety disorders in pediatric patients. We will review current treatments for anxiety in children/adolescents with medical illnesses and propose future research directions. PMID- 20721911 TI - Impaired finger dexterity in patients with parkinson's disease correlates with discriminative cutaneous sensory dysfunction. AB - To study the influence of discriminative cutaneous sensory dysfunction on impaired finger dexterity in Parkinson's disease (PD), we evaluated 48 right handed PD patients during a practically defined off-medication period and 24 healthy age-matched controls. With visual deprivation, a finger tapping task (FTT) was performed to assess the speed of simple repetitive finger movements and a coin rotation task (CRT) was used to assess finger dexterity. The tasks were performed with the right hand. We measured the somesthetic temporal discrimination threshold (sTDT) in the right index finger. The mean +/- SD FTT score of the patient group was lower than that of the control group (24.0 +/- 8.0 vs. 29.8 +/- 7.8; P < 0.01). The patient group performed worse on the CRT than the control group (8.5 +/- 3.5 vs. 12.6 +/- 1.7; P < 0.001). The mean sTDT value of the patient group was longer than that of the control group (124.0 +/- 44.8 vs. 78.1 +/- 26.2 ms; P < 0.001). The CRT scores correlated with the sTDT values (Pearson's correlation coefficient = -0.43; P < 0.01), but not with the Unified Parkinson's Disease Rating Scale (UPDRS) finger bradykinesia scores or FTT scores. Multiple regression analysis showed that the sTDT values (parameter estimate = -0.03, SE = 0.01; P < 0.01), but not patient age, UPDRS finger bradykinesia score, or FTT score, affected the CRT score. Slowness of simple repetitive finger movements did not have a strong impact on the impaired manual dexterity of PD. Discriminative sensory dysfunction and consequent abnormal sensorimotor integration seem to be involved in the impaired finger dexterity of PD. PMID- 20721910 TI - Clinical expression of LRRK2 G2019S mutations in the elderly. AB - Mutations in the leucine-rich repeat kinase 2 gene (LRRK2, PARK8) are the most commonly identified monogenic etiology of Parkinson disease (PD). Over represented in the Ashkenazi Jewish population, these mutations are transmitted in an autosomal dominant manner with age-dependent reduced penetrance. The natural history and penetrance of these mutations in the elderly is controversial and inadequately studied. We conducted a nested cohort study in a community-based aging study (the Einstein Aging Study). Six elderly, initially nonmanifesting carriers (NMC) of the LRKK2 G2019S mutation were identified (average age 82.1 +/- 7.0, range 72.7-90.8), and five had available longitudinal data. We matched five noncarrier controls to each NMC and followed them for an average of 4.7 years with annual cognitive and motor examinations. PD was identified in one NMC at age 95 and in no control subjects. The remaining carriers did not differ from controls on motor scores at baseline or follow-up. The baseline Unified Parkinson's Disease Rating Scale motor subscore (UPDRS-III) in cases was 6.2 +/- 6.9 (range 1-19) and in controls was 4.5 +/- 6.6 (1-30), P = 0.6; the mean difference in UPDRS-III slopes over time between cases and controls was 0.1 +/- 1.3 and was not statistically significant. Our data, while limited by a small sample size, show that in LRKK2 G2019S mutation carriers, phenoconversion to PD can occur late in life. However, most NMC have motor decline which is indistinguishable from their age mates, suggesting that the larger subset of elderly NMC is not on the motor trajectory to disease. PMID- 20721912 TI - Choreo-ballistic movements in a case carrying a missense mutation in syntaxin binding protein 1 gene. PMID- 20721913 TI - Comprehensive sequencing of the LRRK2 gene in patients with familial Parkinson's disease from North Africa. AB - The LRRK2 gene is a key player in Parkinson's disease (PD), however prevalence and pathogenicity of LRRK2 variants remain to be investigated in ethnically diverse populations. Herein, we performed comprehensive sequencing of the LRRK2 gene in 92 Tunisian probands with familial PD. We then performed an association study using all identified variants in a series of 167 Lrrk2 p.G2019S-negative patients with sporadic PD and 365 Lrrk2 p.G2019S-negative healthy control subjects, all from the same Arab-Berber ethnicity. We identified one novel coding substitution (p.M2408I) and 24 known coding changes. Only the Lrrk2 p.G2019S mutation segregated with disease within families and was found in 39% of familial probands. None of the variants displayed significant association with risk for sporadic PD, however a trend was observed for Lrrk2 p.Y2189C. The present study underscores the importance of the LRRK2 gene in the Tunisian PD population. PMID- 20721914 TI - Heart rate changes during freezing of gait in patients with Parkinson's disease. AB - Freezing of gait (FOG) is one of the most disabling symptoms that affect patients with Parkinson's disease (PD). Although the pathophysiology underlying FOG largely remains an enigma, several lines of evidence suggest that the autonomic nervous system might be involved. To this end, we tested the hypothesis that heart rate (HR) increases during FOG and, further, that HR increases just before FOG. To evaluate these hypotheses, 15 healthy older adults, 10 patients with PD who experienced FOG, and 10 patients who did not were studied. Patients with PD were tested during their "off" medication state. HR and HR variability were measured as subjects carried out tasks that frequently provoke FOG; 120 FOG episodes were evaluated. During FOG, HR increased (P = 0.001) by an average of 1.8 bpm, compared with HR measured before the beginning of FOG. HR also increased just before FOG, by 1 bpm (P < 0.0001). In contrast, during sudden stops and 180 degrees turns, HR decreased by almost 2 bpm (P < 0.0001). HR variability was not associated with FOG. To our knowledge, these findings are the first to document the association of FOG to autonomic system activation, as manifested by HR dynamics. One explanation is that the changes in HR before and during FOG may be a sympathetic response that, secondary to limbic activation, contributes to the development of freezing. Although further studies are needed to evaluate these associations, the current results provide experimental evidence linking impaired motor blockades to autonomic nervous system function among patients with PD. PMID- 20721915 TI - Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease. AB - Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth-Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 +/- 13.5) compared with all other groups (MC 13.8 +/- 11.9, NMC 19.6 +/- 13.0, controls 33.8 +/- 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 +/- 92.7). In MC (122.4 +/- 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 +/- 38.8) were comparable with controls (97.2 +/- 61.1). UPSIT and FM scores were correlated in the control (r = -0.305; P = 0.002) and the IPD group (r = -0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1-associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel. PMID- 20721916 TI - Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain). AB - The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson's disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counseling. A total of 59 sibships containing 244 individuals, with a total of 40 PD-affected relatives, were studied. Genetic testing for the R1441G mutation in the LRRK2 gene was performed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differences were found in penetrance. PMID- 20721917 TI - Risk for Parkinson's disease among patients with osteoarthritis: a Danish cohort study. AB - It has been suggested that use of nonsteroidal anti-inflammatory drugs (NSAID) protects against Parkinson's disease, although the results are not consistent. We investigated the risk for Parkinson's disease in patients with osteoarthritis, who are typically intensive users of NSAID. By using the files of the National Danish Hospital Register for the period 1977-2006, we identified a cohort of 134,176 patients with osteoarthritis severe enough to have required subsequent hip or knee implant surgery. The number of first hospital contacts for Parkinson's disease among cohort members in 1986-2007 was compared with that expected from the age-, gender- and period-specific hospital contact rates of the general Danish population, and standardized incidence ratios (SIRs) and associated 95% confidence intervals (CIs) were derived. Cohort members were also linked to the Danish Cancer Register to estimate the SIRs for colorectal and lung cancer. We observed a slightly increased risk for Parkinson's disease among patients with osteoarthritis and subsequent implant surgery (SIR, 1.07; 95% CI, 0.99-1.16). Decreased SIRs were found for both colorectal cancer (0.92; 95% CI, 0.88-0.97), consistent with a high prevalence of NSAID use among cohort members, and lung cancer (0.77; 95% CI, 0.73-0.80), indicating a lower prevalence of smoking than usual. Our results do not support the hypothesis that patients with prolonged use of NSAID and other analgesics are at reduced risk for Parkinson's disease. A possible lower smoking prevalence among patients with osteoarthritis might explain the slightly increased risk for Parkinson's disease. PMID- 20721919 TI - Alcohol in essential tremor and other movement disorders. AB - Many patients with essential tremor (ET) report transient improvement of symptoms after drinking alcohol. However, the brief duration of action, subsequent rebound, and the risk of developing alcohol addiction make the use of alcohol as a treatment for ET inappropriate. Whether excessive alcohol consumption is a risk for or a consequence of ET has been a subject of some controversy. In this review, we critically examine the mechanism of action of alcohol and its role in ET and other movement disorders. PMID- 20721918 TI - Risk and learning in impulsive and nonimpulsive patients with Parkinson's disease. AB - Relatively little is known about the interaction between behavioral changes, medication, and cognitive function in Parkinson's disease (PD). We examined working memory, learning and risk aversion in PD patients with and without impulsive or compulsive behavior (ICB) and compared the results with those in a group of age-matched control subjects. Parkinson patients with PD+ICB had poorer working memory performance than either controls or PD patients without ICB. PD+ICB patients also showed decreased learning from negative feedback and increased learning from positive feedback in off compared with on dopaminergic medication. This interaction between medication status and learning was the opposite of that found in the PD patients without a diagnosis of ICB. Finally, the PD group showed increased risk preference on medication relative to controls, and the subgroup of PD+ICB patients with pathological gambling were overall more risk prone than the PD group. Thus, medication status and an impulsive behavioral diagnosis differentially affect several behaviors in PD. PMID- 20721920 TI - A futility study of minocycline in Huntington's disease. AB - This study assessed the futility of proceeding with a Phase 3 clinical trial of minocycline as a disease-modifying treatment for Huntington's disease (HD). One hundred fourteen research participants with HD were randomized, 87 to minocycline (200 mg/d) and 27 to placebo. The change in Total Functional Capacity (TFC) score from baseline to Mo 18 was prespecified as the primary measure of HD progression. By using a futility design, we tested the null hypothesis that minocycline would reduce the mean decline in TFC score by at least 25% compared to a fixed value obtained from a historical database, with a one-tailed significance level of 10%. The placebo group was included to facilitate blinding. Rejection of the null hypothesis would discourage a major definitive trial of minocycline in HD. For the primary analysis, missing data were handled by carrying forward the last available observation; a secondary analysis used multiple imputations. The mean TFC decline in the minocycline group was 1.55 (SD 1.85), and futility was not declared (P = 0.12) for the primary analysis. When multiple imputation was used to handle missing data, the mean TFC decline in the minocycline group of 1.71 (SD 1.96, P = 0.07) suggested futility, as was the case for prespecified secondary outcome measures. There were no safety abnormalities attributable to minocycline. Based on the threshold of 25% improvement in TFC, further study of minocycline 200 mg/d in HD was not warranted. Futility designs aid in screening potential therapies for HD. PMID- 20721921 TI - Use of complementary and alternative therapies in outpatients with Parkinson's disease in Argentina. AB - We interviewed 300 patients (54.7% male; mean age was 65.8 +/- 9.5) attending the Movement Disorders Clinic at the Buenos Aires University Hospital to determine the prevalence of CATs use and their association with demographic, social, or disease-specific characteristics among patients with Parkinson's disease (PD) in Buenos Aires, Argentina. We found that 25.7% of the PD patients interviewed (77/300) stated they had used CATs to improve their PD symptoms whereas 38.0% (114/300) had used some CATs without any relation to PD, at least once in life. At the moment of the interview, CATs prevalence use was 50.6% in the former group and 25.0% in the latter. The use of CATs was much more frequent among women and more common in the 50- to 69-year age group. Friends and neighbors of the patients had most frequently recommended these therapies. No major association was observed between CATs use and the duration of the disease, side of initial involvement, PD phenotype, or the Hoehn and Yahr staging. Acupuncture, homeopathy, yoga, and therapeutic massage were the most widely used therapies. After the initiation of conventional treatment the use of massage, yoga, and acupuncture in patients using CATs to improve PD significantly increased. Neurologists should be aware and inquire about the use of CATs to rule out potentially harmful effects. PMID- 20721922 TI - Intraoperative local field recording for deep brain stimulation in Parkinson's disease and essential tremor. AB - Oscillations in the beta frequency range (beta-LFP) are widely distributed throughout the motor system, modulated by dopaminergic medications, and locally generated in the subthalamic nucleus (STN) and ventral intermediate nucleus of the thalamus (VIM). We investigated the feasibility of recording intraoperative beta-LFP signals and their descriptive summary statistics during surgeries for deep brain stimulation (DBS). beta-LFP from the microelectrode and stimulating lead were obtained from the STN in Parkinson's patients, and from the stimulating lead in the VIM of patients with Parkinson's disease or essential tremor. beta LFP power was obtained over 8 second epochs and displayed online as compressed spectral and density arrays and trend plots. In agreement with other studies, beta-LFP power along microelectrode penetrations was greater in the STN as compared to sites dorsal and ventral to the nucleus. Differences in beta-LFP power were also observed across the contacts of stimulating leads in the STN and VIM. The contact with greatest beta-LFP power was either the most effective contact for clinical stimulation or adjacent to it. These results were obtained from conventional power measurements, spectral displays, and trend plots with equipment commonly used for intraoperative neuromonitoring. We conclude that beta LFP is an accessible and easily recorded signal intraoperatively with potential usefulness for DBS lead localization and clinical programming of the stimulating lead. PMID- 20721923 TI - Hallervorden-Spatz disease: historical case presentation in the spotlight of nosological evolution. AB - Baron Dr. Ludo van Bogaert (1897-1989) authored more than 700 publications, gave countless lectures at Belgian and foreign universities and at international congresses, and trained more than 300 specialists from all over the world in the Bunge Institute. He filmed many of his patients suffering from movement disorders. Hallervorden-Spatz disease (HSD) was first described in 1922. The recognition of this well-defined syndrome was followed by several case reports published and in 1936, a new case was reported by Ludo van Bogaert and Clovis Vincent. To the best of our knowledge, this case report can be considered as the first filmed case of HSD. PMID- 20721924 TI - A comparison of two brief screening measures of cognitive impairment in Huntington's disease. AB - The goal of this study was to explore whether the Montreal Cognitive Assessment (MoCA), a new screening instrument, would be more sensitive to mild to moderate cognitive impairment in Huntington's disease (HD) than an established screening measure, the Mini Mental State Exam (MMSE). Our reasoning for this query is that the MoCA includes a broader range of test items and an additional assessment of executive functioning and attention compared with the MMSE. Using the receiver operating characteristic (ROC) analysis to examine performance of HD and control groups on both tests on overall scores and scores from various subdomains (i.e., visuospatial abilities) revealed that the MoCA achieved higher sensitivity without sacrificing specificity in many domains relative to the MMSE. PMID- 20721925 TI - Psychometric attributes of the rating scale for gait evaluation in Parkinson's disease. AB - BACKGROUND: The RSGE-PD-V2.0 is a specific measure for evaluation of gait impairment in PD. OBJECTIVE: To check the RSGE-PD-V2.0 metrics attributes. METHODS: In addition to demographic and historical data of PD, applied assessments were: Hoehn and Yahr staging (H&Y); impact in daily activities with Schwab and England scale (S&E); SCOPA Motor; mental status with Short portable mental status questionnaire (SPMSQ); quality of life with Parkinson's impact scale (PIMS), the Hamilton Depression Rating Scale-6 items (HDRS-6); and, the Clinical Impression of Severity Index-PD (CISI-PD). RESULTS: 151 PD patients were included (n = 102 (67.5%) were male). Most patients were in H&Y stage 3 (n = 78 (51.6%)). Mean of age and duration of disease was 68.4 and 7.6 years respectively. Mean values of L-Dopa doses was 652.6 mg/day. Mean values of SCOPA Motor were 29.1; SPMSQ: 1.8; HADS-6: 9.2; PIMS: 18.7;RSGE-PD-V2.0: 25.4; and, CISI-PD were 10.8. Full computable scores were 100%; Guttman's lambda, 0.954; and the item-total correlation, 0.408-0.830. Correlation coefficients (Spearman's rho) between RSGE-PD-V2.0 and H&Y, S&E, SCOPA Motor, PIMS and CISI-PD, were: 0.62; -0.75; 0.74; 0.46; and, 0.78 respectively. RSGE-PD-V2.0 scale significantly discriminated among PD severity levels (based on H&Y staging) Kruskal-Wallis (p < 0.000). CONCLUSIONS: Metric attributes of the RSGE-PD-V2.0 in this sample of study resulted in has sufficient and suitable satisfactory. We, therefore, believe that RSGE-PD-V2.0 is easy and a useful and recommendable specific tool for measuring gait disease in PD patients. PMID- 20721926 TI - The pattern of habitual sedentary behavior is different in advanced Parkinson's disease. AB - Physical behavior changes in Parkinson's disease (PD), however, objective evidence of this is lacking. This study explored methods to objectively quantify sedentary behavior (SB) in advanced PD with the aim of identifying changes that could impact on the burden of disease. We compared the SB of 17 PD (UPDRS III 29.1 +/- 5.5; disease duration 12.5 +/- 6.4; H&Y (3 & 4) and 17 aged and gender matched healthy subjects. SB was measured objectively over a 7 day period using the activPAL accelerometer. SB was defined as sitting or lying and described in terms of the volume and pattern of SB. Comparison between PD and controls showed that whilst there was no difference in the volume of sedentary time (P = 0.15), there was a significant difference in distribution (P < 0.01) and pattern of accumulation of sedentary time (P < 0.01). Bouts of SB in people with PD tend to last longer than that of controls, whilst the total time spent inactive is the same for the two groups. These results suggest that PD leads to a change in the pattern of SB but not the volume. This may be interpreted as a strategy to conserve energy to maximize function. Studying the pattern of SB appears promising and has the potential to help us to understand the impact of PD and the consequences of changes in SB on the burden of disease. PMID- 20721927 TI - Pantothenate kinase-associated neurodegeneration: novel mutations in the PANK2 gene in an Argentinean young woman. PMID- 20721928 TI - Substance abuse and movement disorders. AB - An array of movement disorders is associated with ethanol, illicit drugs, and tobacco. Heavy ethanol users experience withdrawal tremor and, less often, withdrawal parkinsonism, chorea, and myoclonus. Asterixis is a feature of hepatic failure. On the other hand, ethanol can ameliorate essential tremor and myoclonus dystonia. Among opioid drugs, meperidine can precipitate myoclonus. Severe parkinsonism affected users of a synthetic meperidine analog contaminated with 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Spongiform leukoencephalopathy, sometimes with chorea and myoclonus, occurred in inhalers of heroin vapor (chasing the dragon). Psychostimulants including cocaine acutely cause stereotypies and dyskinesias. Phencyclidine toxicity causes myoclonus. Tobacco use, on the other hand, protects against Parkinson's disease. Clinicians need to consider substance abuse in patients with unexplained movement disorders. PMID- 20721929 TI - Pilot trial of dialectical behavior therapy-enhanced habit reversal for trichotillomania. AB - BACKGROUND: Not all hair pullers improve acutely with cognitive-behavioral treatment (CBT) and few maintain their gains over time. METHODS: We conducted an open clinical trial of a new treatment that addresses affectively triggered pulling and emphasizes relapse prevention in addition to standard CBT approaches. Ten female participants satisfying DSM-IV criteria for trichotillomania (TTM) at two study sites received Dialectical Behavior Therapy (DBT)-enhanced CBT consisting of 11 weekly sessions and 4 maintenance sessions over the following 3 months. Independent assessors rated hair pulling impairment and global improvement at several study time points. Participants completed self-report measures of hair pulling severity and emotion regulation. RESULTS: Significant improvement in hair pulling severity and emotion regulation, as well as hair pulling impairment and anxiety and depressive symptoms, occurred during acute treatment and were maintained during the subsequent 3 months. Significant correlations were reported between changes in emotion regulation and hair pulling severity during both the acute treatment and maintenance phases. CONCLUSIONS: This study offers preliminary evidence for the efficacy of DBT-enhanced CBT for TTM and suggests the importance of addressing emotion regulation during TTM treatment. PMID- 20721930 TI - Evaluation of the FRAX and Garvan fracture risk calculators in older women. AB - Fracture risk calculators estimate the absolute risk of osteoporotic fractures. We investigated the performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal bone mineral density (BMD) for their age. Fractures were ascertained in women initially enrolled in a 5-year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T-score -1.3) were used to estimate fracture risk during follow-up using the FRAX and Garvan calculators. The FRAX-New Zealand tool was used both with and without baseline BMD. The discrimination of the calculators was assessed using the area under the curve (AUC) of receiver operating characteristic curves. The calibration was assessed by comparing estimated risk of fracture with fracture incidence across a range of estimated fracture risks and clinical factors. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67-0.70; osteoporotic fracture 0.62-0.64; any fracture 0.60-0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. In summary, none of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility. The calibration varied, suggesting that the calculators should be validated in local cohorts before clinical use. PMID- 20721931 TI - Low-trauma fractures indicate increased risk of hip fracture in frail older people. AB - This study aims to investigate the risk of subsequent fractures after low-trauma fracture in frail older people. A total of 1412 elderly residents (mean age 86.2 years, SD 7.0 years, female 77%) were recruited from aged care facilities in Australia. Residents were assessed and then followed for any fracture for 2 years and hip fractures for at least 5 years. Residents with and without a newly acquired fracture in the first 2 years were compared for risk of subsequent hip fracture. Residents with a nonhip fracture in the first 2 years had an increased risk of subsequent hip fracture for about 2.5 years, whereas those with a hip fracture had a similar risk over the whole period compared with those with no fracture. During these 2.5 years, 60, 28, and 6 subsequent hip fractures occurred in the nonfracture group (n = 953), the nonhip fracture group (n = 194), and the hip fracture group (n = 101), respectively, resulting in the probability of subsequent hip fracture of 8.0%, 19.9%, and 10.4%, respectively. Compared with the nonfracture group, the hazard ratio (HR) was 2.82 [95% confidence interval (CI) 1.73-4.59; p < .001] for the nonhip fracture group and 1.48 (95% CI 0.63 3.49, p = .37) for the hip fracture group after adjusting for age, sex, residence type, calcaneal broadband ultrasound attenuation, fracture history, weight, lower leg length, immobility, cognitive function, and medications. Frail institutionalized older people with newly acquired fractures are at increased risk of subsequent hip fracture for the next few years. Accordingly, despite their advanced age, they are a high-priority target group to investigate interventions that might reduce the risk of hip fracture. PMID- 20721932 TI - Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. AB - Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population-based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean +/- SEM) were significantly higher in men than women (33.3 +/- 1.0 pmol/L versus 23.7 +/- 0.6 pmol/L, p < .001). In pre- and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4- and 4.6-fold in the women and men, respectively. Moreover, for a given total-body bone mineral content, elderly subjects (age >= 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age-related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age-related impairment in bone formation. PMID- 20721933 TI - Lower trabecular volumetric BMD at metaphyseal regions of weight-bearing bones is associated with prior fracture in young girls. AB - Understanding the etiology of skeletal fragility during growth is critical for the development of treatments and prevention strategies aimed at reducing the burden of childhood fractures. Thus we evaluated the relationship between prior fracture and bone parameters in young girls. Data from 465 girls aged 8 to 13 years from the Jump-In: Building Better Bones study were analyzed. Bone parameters were assessed at metaphyseal and diaphyseal sites of the nondominant femur and tibia using peripheral quantitative computed tomography (pQCT). Dual energy X-ray absorptiometry (DXA) was used to assess femur, tibia, lumbar spine, and total body less head bone mineral content. Binary logistic regression was used to evaluate the relationship between prior fracture and bone parameters, controlling for maturity, body mass, leg length, ethnicity, and physical activity. Associations between prior fracture and all DXA and pQCT bone parameters at diaphyseal sites were nonsignificant. In contrast, lower trabecular volumetric BMD (vBMD) at distal metaphyseal sites of the femur and tibia was significantly associated with prior fracture. After adjustment for covariates, every SD decrease in trabecular vBMD at metaphyseal sites of the distal femur and tibia was associated with 1.4 (1.1-1.9) and 1.3 (1.0-1.7) times higher fracture prevalence, respectively. Prior fracture was not associated with metaphyseal bone size (ie, periosteal circumference). In conclusion, fractures in girls are associated with lower trabecular vBMD, but not bone size, at metaphyseal sites of the femur and tibia. Lower trabecular vBMD at metaphyseal sites of long bones may be an early marker of skeletal fragility in girls. PMID- 20721935 TI - Genetic profiling and individualized prognosis of fracture. AB - Fragility fracture is a serious public health problem in the world. The risk of fracture is determined by genetic and nongenetic clinical risk factors. This study sought to quantify the contribution of genetic profiling to fracture prognosis. The study was built on the ongoing Dubbo Osteoporosis Epidemiology Study, in which fracture and risk factors of 858 men and 1358 women had been monitored continuously from 1989 and 2008. Fragility fracture was ascertained by radiologic reports. Bone mineral density at the femoral neck was measured by dual energy X-ray absorptiometry (DXA). Fifty independent genes with allele frequencies ranging from 0.01 to 0.60 and relative risks (RRs) ranging from 1.01 to 3.0 were simulated. Three predictive models were fitted to the data in which fracture was a function of (1) clinical risk factors only, (2) genes only, and (3) clinical risk factors and 50 genes. The area under the curve (AUC) for model 1 was 0.77, which was lower than that of model II (AUC = 0.82). Adding genes into the clinical risk factors model (model 3) increased the AUC to 0.88 and improved the accuracy of fracture classification by 45%, with most (41%) improvement in specificity. In the presence of clinical risk factors, the number of genes required to achieve an AUC of 0.85 was around 25. These results suggest that genetic profiling could enhance the predictive accuracy of fracture prognosis and help to identify high-risk individuals for appropriate management of osteoporosis or intervention. PMID- 20721936 TI - Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants. AB - Cranial base abnormalities are an important complication of osteogenesis imperfecta (OI), a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. To elucidate which clinical characteristics are associated with the occurrence of cranial base abnormalities in OI, we compared cephalometric results of 187 OI patients (median age 12.0 years, range 3.4 to 47 years; 96 female) with those of 191 healthy subjects and related findings to clinical descriptors of the disease. Overall, 41 patients (22%) had at least one unambiguously abnormal skull base measure. Multivariate logistic regression analysis in patients with OI types I, III, and IV (n = 169) revealed that height Z-score [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.43-0.66, p < .001]--but not age, gender, scleral hue, lumbar spine areal bone mineral density, or a history of bisphosphonate treatment--was a significant independent determinant of skull base abnormalities. Among patients with a height Z-score below -3, 48% had a skull base abnormality regardless of whether they had received bisphosphonate treatment in the first year of life or not. Genotype phenotype correlations were evaluated in patients with detectable mutations in COL1A1 or COL1A2, the genes coding for collagen type I (n = 140). Skull base abnormalities were present in 6% of patients with haploinsufficiency (frameshift or nonsense) mutations, in 43% of patients with helical glycine substitutions caused by COL1A1 mutations, in 32% of patients with helical glycine substitutions owing to COL1A2 mutations, and in 17% of patients with splice-site mutations affecting either COL1A1 or COL1A2. However, multivariate logistic regression analysis showed that height Z-score but not the type of collagen type I mutation was independently associated with the prevalence of skull base abnormalities. In conclusion, this study shows that clinical severity of OI, as expressed by the height Z-score, was the strongest predictor of skull base abnormalities. We did not find evidence for the hypothesis that bisphosphonate treatment protects against skull base abnormalities. PMID- 20721934 TI - CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes osteoclastogenesis via induction of and interaction with dendritic cell-specific transmembrane protein (DC-STAMP). AB - CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes endochondral ossification. However, the role of CCN2 in the replacement of hypertrophic cartilage with bone is still unclear. The phenotype of Ccn2 null mice, having an expanded hypertrophic zone, indicates that the resorption of the cartilage extracellular matrix is impaired therein. Therefore, we analyzed the role of CCN2 in osteoclastogenesis because cartilage extracellular matrix is resorbed mainly by osteoclasts during endochondral ossification. Expression of the Ccn2 gene was upregulated in mouse macrophage cell line RAW264.7 on day 6 after treatment of glutathione S transferase (GST) fusion mouse receptor activator of NF-kappaB ligand (GST-RANKL), and a combination of recombinant CCN2 (rCCN2) and GST-RANKL significantly enhanced tartrate-resistant acid phosphatase (TRACP)-positive multinucleated cell formation compared with GST-RANKL alone. Therefore, we suspected the involvement of CCN2 in cell-cell fusion during osteoclastogenesis. To clarify the mechanism, we performed real-time PCR analysis of gene expression, coimmunoprecipitation analysis, and solid-phase binding assay of CCN2 and dendritic cell-specific transmembrane protein (DC-STAMP), which is involved in cell-cell fusion. The results showed that CCN2 induced and interacted with DC STAMP. Furthermore, GST-RANKL-induced osteoclastogenesis was impaired in fetal liver cells from Ccn2 null mice, and the impaired osteoclast formation was rescued by the addition of exogenous rCCN2 or the forced expression of DC-STAMP by a retroviral vector. These results suggest that CCN2 expressed during osteoclastogenesis promotes osteoclast formation via induction of and interaction with DC-STAMP. PMID- 20721937 TI - Prevalence of low bone mineral density in a low-income inner-city population. AB - Bone mineral density (BMD) is an important factor linked to bone health. Little is known of the prevalence of low BMD and its associated risk factors in an urban underserved population. Between 2001 and 2004, we recruited 338 subjects who completed drug use and medical history questionnaires, underwent hormonal measurements, and underwent whole-body dual-energy X-ray absorptiometry (DXA) for evaluation of BMD and body composition. Of these, 132 subjects had site-specific DXA (lumbar spine and hip) performed. Osteoporosis was defined as a T-score of 2.5 or less for men 50 years of age and older and postmenopausal women and a Z score of -2.0 or less in men younger than 50 years of age and premenopausal women at either the lumbar spine, total hip, or femoral neck, according to National Osteoporosis Foundation (NOF) guidelines. The cohort consisted of mostly African American, middle-aged people with a high prevalence of illicit drug use, 50% HIV(+), and 39% hepatitis C(+). Osteoporosis was identified in 22% of subjects (24 men, 5 women), with the majority of cases (90%) attributable to osteoporosis at the lumbar spine. Osteoporosis was more common in men than in women. Lower whole-body BMD among women was associated with multiple risk factors, but only with lower lean mass among men. Osteoporosis was highly prevalent in men, mainly at the spine. The risk factors for bone loss in this population need to be further clarified. Screening men for osteoporosis starting at age 50 might be warranted in this population given the multiple risk factors and the unexpectedly high prevalence of low BMD. PMID- 20721939 TI - Apple Down 152: a putative case of syphilis from sixth century AD Anglo-Saxon England. AB - This report describes a putative case of a treponemal infection observed on a skeleton of a young male adult from the Apple Down Anglo-Saxon cemetery dating to the sixth century AD, accompanied by grave goods indicative of a high status burial. The skeleton is well preserved and almost complete. The pathological evidence includes an extensive area of lytic destruction to the frontal bone of the skull, widespread profuse bilateral symmetrical periosteal reaction affecting scapulae, clavicles, arms, legs, hands, feet and ribs. There is also evidence of gummatous destruction on some of the long bones. Application of a differential diagnosis of all probable diseases exhibiting the individual symptoms leads to a clear conclusion that the person was infected with a treponemal pathogen. The skeleton shows none of the stigmata associated with the congenital form of treponemal disease. We propose that the evidence suggests a possible case of venereal syphilis rather than one of the endemic forms of treponemal disease. This diagnosis is based on the geographical pathogen range, the apparent low prevalence of the disease, significant social upheaval at the time, the high social status and early age of death of the individual. PMID- 20721940 TI - Phylogenetic analysis of the African papionin basicranium using 3-D geometric morphometrics: the need for improved methods to account for allometric effects. AB - The basicranium has been argued to contain a strong phylogenetic signal in previous analyses of primate cranial morphology. Therefore, further study of basicranial morphology may offer new insights into controversial phylogenetic relationships within primate groups. In this study, I apply 3-D geometric morphometric techniques in a phylogenetic analysis of the African papionin basicranium. The effects of allometry strongly influence African papionin basicranial morphology and, unless these size effects are controlled or eliminated, phylogenetic analyses suggest traditional phylogenetic groupings of small taxa (mangabeys) and large taxa (geladas, mandrills, drills, and baboons). When the effects of allometry are eliminated by excluding size-correlated principal components (PCs) or by regression analysis with retention of residuals, phylogenetic analyses of African papionin basicranial morphology are incongruent with recent molecular and morphological studies. By contrast, a cladistic analysis of basicranial characters using the narrow allometric coding method suggests the same phylogenetic relationships as recent molecular and morphological studies. These results suggest that important phylogenetic information is contained within the size-correlated data, and this information is being discarded during the attempt to eliminate the effects of body size. Future 3-D morphometric studies of phylogeny should focus on the development of new methodologies to adjust for allometric effects, as current techniques appear to be ill-equipped to deal with the case of a size-disparate, lower-level taxonomic group. PMID- 20721938 TI - Endocrinology of year-round reproduction in a highly seasonal habitat: environmental variability in testosterone and glucocorticoids in baboon males. AB - In conditions characterized by energetic constraints, such as in periods of low food availability, some trade-offs between reproduction and self-maintenance may be necessary; even year-round breeders may then be forced to exhibit some reproductive seasonality. Prior research has largely focused on female reproduction and physiology, and few studies have evaluated the impact of environmental factors on males. Here we assessed the effects of season and ambient temperatures on fecal glucocorticoid (fGC) and testosterone (fT) levels in male baboons in Amboseli, Kenya. The Amboseli basin is a highly challenging, semiarid tropical habitat that is characterized by strongly seasonal patterns of rainfall and by high ambient temperatures. We previously reported that female baboons were impacted by these challenging environmental conditions. We ask here whether male baboons in the same environment and groups as females exhibit similar physiological effects. We found that after accounting for male age and individual variability, males exhibited higher fGC levels and lower fT levels during the dry season than during the wet season. Furthermore, fT but not fGC levels were lower in months of high average daily maximum temperatures, suggesting a direct impact of heat on testes. Our results demonstrate that male baboons, like females, experience ecological stress that alters their reproductive physiology. The impact of the environment on male reproduction deserves more attention both in its own right and because alteration in male physiology may contribute to the reduction in female fertility observed inchallenging environments. PMID- 20721941 TI - Brief communication: Ectocranial suture closure in Pongo: pattern and phylogeny. AB - Ectocranial suture fusion patterns have been shown to contain biological and phylogenetic information. Previously the patterns of Homo, Pan, and Gorilla have been described. These data reflect the phylogenetic relationships among these species. In this study, we applied similar methodology to Pongo to determine the suture synostosis progression of this genus, and to allow comparison to previously reported data on other large-bodied hominoids. We hypothesized these data would strengthen the argument that suture synostosis patterns reflect the phylogeny of primate taxa. Results indicate that the synostosis of vault sutures in Pongo is similar to that reported for Gorilla (excluding Pan and Homo). However, the lateral-anterior pattern of fusion, in which there is a strong superior to inferior pattern, for Pongo is unique among these species, reflecting its phylogenetic distinctness among great ape taxa. PMID- 20721942 TI - Technical note: A method for assignment of the weight of characters. AB - The weight of characters is a crucial step in different population analyses. We propose a new formula to facilitate this while establishing a scale that follows the criteria of the probability of change in each character. This method is described for drawing of median-joining networks, yet it could also be used for other methods in which the weight of the characters is required. PMID- 20721943 TI - A weighted osteon morphotype score outperforms regional osteon percent prevalence calculations for interpreting cortical bone adaptation. AB - Using circularly polarized light microscopy,we described a weighted-scoring method for quantifying regional distributions of six secondary osteon morphotypes(Skedros et al.: Bone 44 (2009) 392-403). This osteon morphotype score (MTS) strongly correlated with "tension" and "compression" cortices produced by habitual bending. In the present study, we hypothesized that the osteon MTS is superior to a relatively simpler method based on the percent prevalence (PP) of these osteon morphotypes. This was tested in proximal femoral diaphyses of adult chimpanzees and habitually bent bones: calcanei from sheep, deer, and horses, radii from sheep and horses, and third metacarpals (MC3s) from horses. Sheep tibiae were examined because their comparatively greater torsion/shear would not require regional variations in osteon morphotypes. Predominant collagen fiber orientation (CFO), a predictor of regionally prevalent/predominant strain mode, was quantified as image gray levels (birefringence). Ten PP calculations were conducted. Although PP calculations were similar to the osteon MTS in corroborating CFO differences between "tension" and "compression" cortices of the chimpanzee femora and most of the habitually bent bones, PP calculations failed to show a compression/tension difference in equine MC3s and sheep radii. With the exception of the prevalence of the "distributed" osteon morphotype, correlations of PP calculations with CFO were weak and/or negative. By contrast, the osteon MTS consistently showed positive correlations with predominant CFO. Compared with the osteon MTS and predominant CFO, regional variations in PP of osteon morpho types are not stronger predictors of nonuniform strain distributions produced by bending. PMID- 20721944 TI - Reconstructing the population history of Nicaragua by means of mtDNA, Y chromosome STRs, and autosomal STR markers. AB - Before the arrival of the Spaniards in Nicaragua, diverse Native American groups inhabited the territory. In colonial times, Native Nicaraguan populations interacted with Europeans and slaves from Africa. To ascertain the extent of this genetic admixture and provide genetic evidence about the origin of the Nicaraguan ancestors, we analyzed the mitochondrial control region (HVSI and HVSII), 17 Y chromosome STRs, and 15 autosomal STRs in 165 Mestizo individuals from Nicaragua. To carry out interpopulation comparisons, HVSI sequences from 29 American populations were compiled from the literature. The results reveal a close relationship between Oto-manguean, Uto-Aztecan, Mayan groups from Mexico, and a Chibchan group to Nicaraguan lineages. The Native American contribution to present-day Nicaraguan Mestizos accounts for most of the maternal lineages, whereas the majority of Nicaraguan Y chromosome haplogroups can be traced back to a West Eurasian origin. Pairwise Fst distances based on Y-STRs between Nicaragua and European, African and Native American populations show that Nicaragua is much closer to Europeans than the other populations. Additionally, admixture proportions based on autosomal STRs indicate a predominantly Spanish contribution. Our study reveals that the Nicaraguan Mestizo population harbors a high proportion of European male and Native American female substrate. Finally, the amount of African ancestry is also interesting, probably because of the contribution of Spanish conquerors with North African genetic traces or that of West African slaves. PMID- 20721945 TI - Technical note: Enhancement of Scott's molar wear scoring method. AB - A method is described for orienting maxillary and mandibular molars in order to standardize the reporting of wear scores on quadrants of the occlusal surfaces (Scott: Am J Phys Anthropol 51 (1979) 213-217). The method, which was developed on an archeological sample from ancient Mendes, Egypt, further requires that quadrant scores be reported individually and sequentially for each tooth, rather than summed, in order to identify more easily differential and directional wear patterns. Intraobserver and interobserver error was found to be negligible when the appropriate diagrams and instructions were consulted. Thus, observer error does not add further to the potential for error associated with Scott's original scoring method. PMID- 20721947 TI - Bioarchaeological analysis of diet during the Coles Creek period in the southern Lower Mississippi Valley. AB - The timing of the dietary shift from foraging to maize agriculture, and the speed at which such practices were adopted, are important considerations in the cultural evolution of the New World. In the southern Lower Mississippi Valley, maize agriculture traditionally was believed to have been practiced during the Coles Creek period (A.D. 700-1200); however, direct evidence for maize is lacking in the archaeological record prior to A.D. 1000. The present study examines Coles Creek diet from a bioarchaeological perspective. Oral-health indicators, including abscesses, antemortem tooth loss, calculus, carious lesions, periodontal disease, and tooth wear, were evaluated in a regional, temporal context. Data were collected from 288 dentitions from eight sites in the southern Lower Mississippi Valley that range in date from 800 B.C. to A.D. 1200. The sample then was separated into Pre-Coles Creek and Coles Creek categories and statistical analyses were used to assess temporal variation in pathology load. Results indicate that pathology load in the Coles Creek sample is slightly heavier than the Pre-Coles Creek sample; however, the differences are not substantial. Furthermore, data suggest that regional differences in resource exploitation existed between the Lower Mississippi Valley and populations elsewhere in the eastern United States. Specifically, the presence of starchy native plants other than maize in the diet likely contributed to a high pathology load for early hunter-gatherers. Ultimately, data from this study complement the archaeological, botanical, and zooarchaeological records and indicate that Coles Creek subsistence was not based on maize agriculture. PMID- 20721946 TI - Age and individual foraging behavior predict tooth wear in Amboseli baboons. AB - Teeth represent an essential component of the foraging apparatus for any mammal, and tooth wear can have significant implications for survival and reproduction. This study focuses on tooth wear in wild baboons in Amboseli, southern Kenya. We obtained mandibular and maxillary tooth impressions from 95 baboons and analyzed digital images of replicas made from these impressions. We measured tooth wear as the percent dentine exposure (PDE, the percent of the occlusal surface on which dentine was exposed), and we examined the relationship of PDE to age, behavior, and life history variables. We found that PDE increased significantly with age for both sexes in all three molar types. In females, we also tested the hypotheses that long-term patterns of feeding behavior, social dominance rank, and one measure of maternal investment (the cumulative number of months that a female had dependent infants during her lifetime) would predict tooth wear when we controlled for age. The hypothesis that feeding behavior predicted tooth wear was supported. The percent of feeding time spent consuming grass corms predicted PDE when controlling for age. However, PDE was not associated with social dominance rank or maternal investment. PMID- 20721948 TI - Vertical nanowire architectures: statistical processing of porous templates towards discrete nanochannel integration. PMID- 20721949 TI - A light-activated theranostic nanoagent for targeted macrophage ablation in inflammatory atherosclerosis. AB - The synthesis and utility of a multimodal theranostic nanoagent based upon magnetofluorescent nanoparticles for the treatment of inflammatory atherosclerosis is described. These particles are modified with near-infrared fluorophores and light-activated therapeutic moieties, which allow for the optical determination of agent localization and phototoxic activation at spectrally distinct wavelengths. The resulting agent is readily taken up by murine macrophages in vitro and is highly phototoxic, with an LD(50) of 430 pM. Intravenous administration results in the localization of the nanoagent within macrophage-rich atherosclerotic lesions that can be imaged by intravital fluorescence microscopy. Irradiation of the atheroma with 650 nm light activates the therapeutic component and results in eradication of inflammatory macrophages, which may induce lesion stabilization. Importantly, these agents display limited skin photosensitivity, are highly efficacious, and provide an integrated imaging and therapeutic nanoplatform for atherosclerosis. PMID- 20721950 TI - Photocatalytic activity of protein-conjugated CdS nanoparticles. AB - Colloidal CdS nanoparticles are conjugated with a variety of proteins, including enhanced yellow fluorescent protein, tobacco etch virus protease (TEV), lysozyme, and bacterial cytochrome P450 CYP152A1, and the photochemical properties of the resulting conjugates are analyzed by EPR spectroscopy and hydroxyl radical specific fluorimetric assay. While irradiation of bare CdS colloids leads to photogeneration of hydroxyl and superoxide radicals, it is surprisingly observed that coating of the CdS particles with proteins effectively suppresses the production of these radical species and instead leads to increased formation of a long-lived reactive oxygen species, most likely H(2)O(2). A mechanism for the observed results is suggested. The empirical results are capitalized on for the assembly of a CdS-TEV nanohybrid, which shows significantly higher performance as a photocatalytic mediator for fatty acid hydroxylation by CYP152A1 than bare CdS nanoparticles. PMID- 20721951 TI - Strategy for the assembly of carbon nanotube-metal nanoparticle hybrids using biointerfaces. PMID- 20721952 TI - Poly(methacrylic acid) polymer hydrogel capsules: drug carriers, sub compartmentalized microreactors, artificial organelles. AB - Multilayered polymer capsules attract significant research attention and are proposed as candidate materials for diverse biomedical applications, from targeted drug delivery to microencapsulated catalysis and sensors. Despite tremendous efforts, the studies which extend beyond proof of concept and report on the use of polymer capsules in drug delivery are few, as are the developments in encapsulated catalysis with the use of these carriers. In this Concept article, the recent successes of poly(methacrylic acid) hydrogel capsules as carrier vessels for delivery of therapeutic cargo, creation of microreactors, and assembly of sub-compartmentalized cell mimics are discussed. The developed technologies are outlined, successful applications of these capsules are highlighted, capsules properties which contribute to their performance in diverse applications are discussed, and further directions and plausible developments in the field are suggested. PMID- 20721953 TI - Inhibition of hydroxyapatite nanoparticle-induced osteogenic activity in skeletal cells by adsorption of serum proteins. PMID- 20721954 TI - Acetochlor sorption and degradation in limestone subsurface and aquifers. AB - BACKGROUND: Acetochlor, introduced on the market in 1994, is used extensively worldwide, but sorption and degradation studies, including subsurface, are scarce, and there appear to be no such studies with aquifer sediment according to the present mini-review. Sorption, degradation and mineralisation of acetochlor were investigated in heterogeneous limestone down to 43 m below surface (mbs) in four European aquifers (1.7-59 mbs), both aerobic and anaerobic. RESULTS: Sorption revealed K(d) values of 3.39-4.96 L kg(-1) in topsoil, < 0.01-2.02 L kg( 1) in heterogeneous limestone, 0.06-0.72 L kg(-1) in aerobic aquifers and 1.03 4.60 L kg(-1) in microaerobic or anaerobic aquifers. The mineralisation half lives in the samples from 0.0-0.6 mbs were 0.8-2.1 years and 4.7-95 years in the unsaturated limestone samples from 1-43 mbs. Out of 22 samples from four different European aquifers, acetochlor was mineralised in five samples (half lives of 9-19 years), all from the same aquifer and core section (19.25-19.53 mbs). CONCLUSION: Sorption was weak in limestone and aerobic sandy aquifers, and strong in topsoils and in reduced sandy aquifers. Redox conditions controlled the extent of acetochlor sorption in aquifers, as reduced conditions induced increased sorption. Acetochlor was mineralised in deep subsurface, though slowly, and, as mineralisation is the only true removal mechanism in natural attenuation, even slow mineralisation in aquifers with long residence times can have a significant impact. PMID- 20721955 TI - The crux of the confusion about screening mammograms. PMID- 20721956 TI - Subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) prevents postoperative delayed gastric emptying. AB - BACKGROUND AND OBJECTIVES: Delayed gastric emptying (DGE) is one of main complications after pylorus-preserving pancreaticoduodenectomy (PPPD) with regional lymph node dissection (RLND). The aim of this study was to retrospectively investigate whether subtotal stomach-preserving PD (SSPPD) decreased incidence of DGE. METHODS: This study included 112 consecutive patients underwent PPPD (n = 48) or SSPPD (n = 64) with/without RLND. DGE was classified into three categories (grades A, B, and C) according to the guideline proposed by the International Study Group of Pancreatic Surgery. RESULTS: The incidence of DGE grade B/C in SSPPD with RLND (13.0%) was lower compared with that (34.8%) in PPPD with RLND (P = 0.0326). Consequently, the mean length of postoperative hospital stay of SSPPD with RLND group was significantly shorter than that of PPPD with RLND (P = 0.0476). CONCLUSIONS: SSPPD could be substituted for PPPD due to decreased postoperative DGE when RLND is involved. A randomized control trial of SSPPD versus PPPD should be considered. PMID- 20721957 TI - Differential proteomic profiling of chordomas and analysis of prognostic factors. AB - BACKGROUND: The recurrence rate of chordoma is high, and the prognosis is poor. METHODS: Differential proteomic analysis was performed on chordomas and adjacent normal tissues, with verification by Western blot. Protein expression was evaluated by immunohistochemistry of 37 chordomas. Association of candidate protein expression with clinical parameters, disease-free survival, and overall survival were analyzed. RESULTS: We identified 14 up-regulated and 5 down regulated proteins in chordomas. Expression of alpha enolase (ENO1), pyruvate kinase M2 (PKM2), and gp96 was higher in recurrences than in primary tumors. Univariate analysis showed that significantly adverse factors for disease-free survival were overexpression of ENO1 and PKM2, involvement of contiguous vertebral levels, and inadequate surgical margin at initial surgery. Inadequate surgical margin without radiotherapy, involvement of contiguous vertebral levels, and cervical spine location were adverse factors for overall survival. By multivariate analysis, independent adverse prognostic factors were inadequate surgical margin and involvement of multiple contiguous vertebral levels for recurrence; upper cervical spine location and involvement of contiguous vertebral levels for tumor-related death. Multivariate analysis failed to show the significance of the proteins. CONCLUSIONS: Involvements of multiple contiguous vertebral levels and upper cervical spine, rather than overexpression of ENO1, PKM2, or gp96, are independent prognostic indicators for chordomas. PMID- 20721958 TI - Incidental gallbladder cancer: analysis of surgical findings and survival. AB - BACKGROUND AND OBJECTIVES: Incidental gallbladder cancer (IGBCA) has risen worldwide and its prognosis depends on complete radical cholecystectomy (CRC). This study evaluated surgical findings during re-operation and survival of patients with IGBCA. METHODS: Demographics, surgical treatment, staging, and survival data for all IGBCA patients who underwent surgery at Instituto Oncologico Fundacion Arturo Lopez Perez (FALP) between 2000 and 2008 were analyzed. Differences between groups were analyzed by Student's t-test, Mann Whitney, chi-square, or Fisher log-rank tests. RESULTS: Forty-nine patients were studied (38 women/11 men, median age = 58 years). Pathology reports from cholecystectomy showed that 32 patients had a T2 tumor and 12 had positive resection margin. Thirty-six patients underwent surgical re-exploration and 20 underwent CRC; 10 with (+) residual disease and 10 with (-). For patients with at least T1b tumor, median survival was 28 months and 5-year disease-specific survival (DSS) was 29%. The 3-year DSS was 64% for CRC (-), 30% for CRC (+), and 8% for non-resected cases (P < 0.007). The 3-year DSS was better for patients with stage Ib than those with stages II and IV (P < 0.007). CONCLUSIONS: Patients with IGBCA have a high chance of intra-abdominal metastases or local residual disease. In CRC patients, intra-abdominal metastases were associated with a worse prognosis. PMID- 20721959 TI - Safety and potential benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal carcinomatosis from primary or recurrent ovarian cancer. AB - OBJECTIVES: To analyze the outcomes of cytoreductive surgery and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. METHODS: Fifty-three patients with peritoneal carcinomatosis from primary (45 cases) and recurrent (8 cases) ovarian cancer were previously treated by systemic chemotherapy with platinum and taxanes and then submitted to surgical cytoreduction and HIPEC (cisplatin and mitomycin-C) with a closed abdomen technique. The median follow-up period was 27 months (range: 3-107). RESULTS: At the end of operation a complete cytoreduction (CCR-0) was obtained in 37 patients (70%). Major morbidity occurred in 12 patients (23%); reoperation was necessary in 2 patients (4%), and no postoperative mortality was observed. Overall 5-year survival probability was 55%; it was 71% in CCR-0, 44% in CCR-1, and none in patients with CCR-2 or CCR-3 residual tumor (log-rank test: P = 0.017). The cumulative risk of recurrence in 37 CCR-0 cases was 54% at 5 years from operation. CONCLUSIONS: The results of our study indicate the feasibility and the potential benefit of a protocol including systemic chemotherapy, surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. A phase III trial to compare this approach with conventional treatment is needed. PMID- 20721960 TI - Survival after secondary cytoreduction for recurrent ovarian cancer: which are the prognostic factors? AB - OBJECTIVE: Significant controversy exists concerning the factors affecting survival after secondary cytoreduction (SCR) in recurrent ovarian cancer. This study aims to identify factors independently associated with survival after SCR. METHODS: We retrospectively retrieved 39 patients with recurrent ovarian cancer. All patients had been initially treated with primary cytoreduction in our institution and received platinum- and paclitaxel-based chemotherapy postoperatively. Disease-free interval (DFI) had to be longer than 6 months. A variety of clinicopathological factors were recorded. Multivariable Cox regression was performed to examine the associations of parameters with survival. RESULTS: Median survival was equal to 24 months, the median DFI was 22 months, and complete SCR had been achieved in 19/39 patients (48.7%, 95% CI: 32.4-65.2%). Higher number of recurrence sites, clear-cell histological type, and more advanced FIGO stage were independently associated with shorter survival; longer DFI was associated with longer survival. Noticeably, complete SCR lost its significance at the multivariable model, although it was associated with longer survival at the univariable analysis. CONCLUSIONS: Four factors seem capable of independently modifying survival after SCR: number of recurrence sites, DFI, FIGO stage, and clear cell histology. The two latter factors might reflect aggressive clinicopathological features of the tumor with long-term effect. PMID- 20721961 TI - Relation of MT1-MMP gene expression to outcomes in colorectal cancer. AB - BACKGROUND: Matrix metalloproteinases are members of a large family of endopeptidases that participate in the extracellular-matrix degradation that accompanies cancer cell invasion, metastasis and angiogenesis. The membrane-type 1 matrix metalloproteinase (MT1-MMP) gene has been reported in various cancers and is associated with tumor invasion and metastasis. This study examined the relation of the relative expression of MT1-MMP gene to clinicopathological factors and outcomes in patients with colorectal cancer (CRC). METHODS: We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated CRC. The relative expression levels of MT1-MMP mRNA in cancer and in normal adjacent mucosa were measured by quantitative real time reverse-transcriptase polymerase chain reaction. RESULTS: MT1-MMP gene expression was higher in cancer tissue than in adjacent normal mucosa. The level of MT1-MMP gene expression was not related to any clinicopathological factor. Overall survival at 5 years differed significantly between patients with high MT1 MMP gene expression and those with low expression. CONCLUSIONS: Overexpression of the MT1-MMP gene is considered a useful independent predictor of outcomes in patients with CRC. PMID- 20721962 TI - Activated carbon nanoparticles or methylene blue as tracer during video-assisted thoracic surgery for lung cancer can help pathologist find the detected lymph nodes. AB - BACKGROUND: To assess whether using methylene blue (MB) or activated carbon nanoparticles as tracer can increase the detected number of lymph nodes in the systematic nodal dissected tissue during Video-Assisted Thoracic Surgery (VATS) for non-small cell lung cancer. METHODS: Three groups of 20 patients each were obtained from randomization of 60 patients with NSCLC requiring VATS with systematic nodal dissection (SND) from February 2007 and December 2008, there were 17, 16, and 17 patients in group A (injection activated carbon nanoparticles), group B (injection MB), and group C (controls), respectively. RESULTS: There was difference of the total number of dissected lymph nodes per patient among three groups (P < 0.001). The total number of dissected LNs and mediastinal nodes per patient in group A and group B was more than in group C (P < 0.001). There were 20, 18, and 14 metastatic LNs dissected in 6, 6, and 7 patients of group A, B, and C, respectively. There was difference of total number of dissected metastatic LNs per patient among three groups (P = 0.002). CONCLUSIONS: MB can be as effective as activated carbon nanoparticles being tracer to increase the detected number of LNs in the systematic nodal dissected tissue during VATS for NSCLC. PMID- 20721963 TI - Atypical expression and distribution of embryonic stem cell marker, OCT4, in human lung adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: Lung cancer is one of the leading causes of cancer related deaths in the world. Although the origin still remains to be resolved, a prevailing hypothesis implies the involvement of cancer stem cells (CSCs) responsible for tumor initiation, maintenance, and progression. Embryonic stem cell marker, OCT4, encoding the spliced variants OCT4A and OCT4B, has recently been shown to have a dual role; as a potential adult stem cell marker and as a CSC marker in germline and somatic tumors. METHODS: We investigated the expression and intracellular distribution of OCT4A and OCT4B using flow cytometry, Western blot and quantitative RT-PCR analyses in normal and lung adenocarcinoma cell lines, primary cultures and tissue biopsies. RESULTS: We demonstrate for the presence of rare OCT4A(+) and OCT4B(+) cells in normal lung. Notably, we observed higher levels of expression and atypical cytoplasmic distribution of OCT4A and not OCT4B, in the malignant setting, strongly indicating an oncogenic role in lung adenocarcinoma. CONCLUSIONS: We postulate that OCT4A(+) cells are involved in the oncogenesis of lung adenocarcinoma. Identification of these cells and the biological processes vital for their subsistence, will guide the development of diagnostic and therapeutic clinical approaches with the goal of eliminating lung adenocarcinoma. PMID- 20721964 TI - Paraneoplastic glomerulopathy secondary to retroperitoneal sarcoma: a case report. AB - Glomerulopathy is a rare form of paraneoplastic disease. We present the second reported case of paraneoplastic glomerulopathy due to a retroperitoneal sarcoma. The patient presented with generalized edema and nephrotic syndrome. CT scan showed two large retroperitoneal masses. One large retroperitoneal mass was resected. Post-operatively, she developed kidney failure and biopsy showed minimal change disease. With steroid therapy, patient's symptoms went into remission. We hypothesize that minimal change paraneoplastic glomerulopathy developed due to damage from cytokines released from a T-cell mediated response to the malignancy. PMID- 20721965 TI - Use of sentinel lymph node biopsy for melanoma in children and adolescents. AB - BACKGROUND: Though sentinel lymph node biopsy (SLNB) is an integral component of melanoma staging, little is known about its use in children. METHODS: Patients (0 18 years) with melanoma diagnosed from 2003 to 2007 in the National Cancer Data Base were assessed. Logistic regression models were used to identify clinicopathologic, socioeconomic, and hospital factors associated with SLNB use and lymph node metastases (LNM). RESULTS: Of 671 children, 68.7% underwent SLNB. SLNB utilization rates were 39.9% for T1a patients and 87.6% for T1b-T3 patients. T1b-T3 patients were more likely to undergo SLNB if they were older (OR 4.86 95% CI: 1.88-12.59) or cared for at Children's hospitals (OR 2.43 95% CI: 1.09-5.40). T1b-T3 patients were less likely to undergo SLNB if uninsured (OR 0.25 95% CI: 0.08-0.76). Of those with SLNB, 118 (25.6%) had pathologically confirmed LNM. Patients were more likely to have LNM if younger (OR 3.19 95% CI: 1.20-8.51) or having higher T stage (OR 10.38 95% CI: 4.59-23.47). CONCLUSIONS: SLNB use for children with melanoma was associated with clinicopathologic, socioeconomic, and hospital factors. Younger patients have a higher likelihood of LNM but are the least likely to undergo SLNB. Though overall adherence appears high, there remains an opportunity for improved care for children with melanoma. PMID- 20721966 TI - Partner smoking characteristics: Associations with smoking and quitting among blue-collar apprentices. AB - BACKGROUND: Studies suggest that the social context of blue-collar workers contribute to their low smoking cessation rates. However, little is known on the effect of partner smoking and requests to quit on workers' cessation attempts. METHODS: Using data from a longitudinal smoking cessation intervention, multivariable logistic regression models were constructed to investigate the association of partner smoking characteristics with cessation among blue-collar apprentices. RESULTS: Smokers were more likely to have partners who smoke (OR 13.06; 95% CI 8.52-20.01). Partner's request to quit was associated with higher odds of smoking cessation at 1 month (OR 3.74; 95% CI 2.49-5.63) and 6 months (OR 1.90; 95% CI 1.06-3.41) post-intervention. Having a partner who smoked was associated with lower odds of smoking cessation at 1 month (OR 0.41; 95% CI 0.27 0.62), but not 6 months post-intervention. CONCLUSIONS: Results suggest that smoking cessation interventions that include partner support might improve cessation among blue-collar smokers. PMID- 20721967 TI - Work-relatedness of selected chronic medical conditions and workers' compensation utilization: National health interview survey occupational health supplement data. AB - BACKGROUND: An occupational health supplement (OHS) to the 1988 National Health Interview Survey (NHIS) bypassed many limitations of traditional occupational health surveillance systems, but the data collected about chronic work-related conditions have not yet been reported. METHODS: We calculated the prevalence and proportion of cases related to work for the aggregation of 13 chronic conditions included in the NHIS-OHS, and for 11 conditions individually. For each of nine conditions, and for the aggregation of all conditions, we also calculated the prevalence of workers' compensation claims filed. RESULTS: The overall prevalence of work-related chronic conditions was 7.5% (SE = 0.16). The work-related conditions with the highest prevalence were repeated trouble with the back/neck/spine (4.91%; SE = 0.13) and trouble hearing (1.14%; SE = 0.06). Overall, workers' compensation claims were filed for 39.0% (SE = 1.00) of work related cases. CONCLUSIONS: The burden of work-related illnesses in the US is substantial, and the workers' compensation system is underutilized. PMID- 20721968 TI - The estimated national burden of physical ergonomic hazards among US workers. AB - PURPOSE: To estimate the national burden of physical ergonomic hazards among working adults in the US. METHODS: We estimated the population prevalence of and the total number of workers who are exposed to physical ergonomic hazards, such as vibration, working in cramped space, kneeling, body bending or twisting, climbing, and repetitive motions using Occupational Information Network (O*NET) data and the Occupational Employment Statistics (OES) from the U.S. Bureau of Labor Statistics (BLS) stratified by occupation title. RESULTS: Repetitive motion was the most prevalent of all ergonomic hazards (27% of US workers are estimated to be exposed continually). Bending or twisting of the body more than half their time at work was also common, involving over 32 million US workers (25% of US workforce). Kneeling, crouching, stooping, or crawling was another ergonomic hazard that 14 million US workers perform more than half their time at work. Almost 4 million workers climb ladders, scaffolds, poles, etc. for more than half their time at work. We estimate that over 13 million workers (10% of US workforce) were exposed to cramped workspace that requires getting into awkward positions every day. Finally, about 3.5 million workers (2.7% of US workforce) were estimated to be exposed to whole body vibration every day. CONCLUSION: A large portion of the US work force is exposed to ergonomic hazards known to be associated with musculoskeletal disorders (MSDs). The occupations with the highest prevalence of each ergonomic hazard may be deserving of prompt efforts toward prevention of MSDs. PMID- 20721969 TI - Polymorphisms of methylenetetrahydrofolate reductase are associated with a high risk of nasopharyngeal carcinoma in a smoking population from Southern China. AB - Methylenetetrahydrofolate reductase (MTHFR) plays a central role in converting folate to a compound which serves as a methyl donor for DNA methylation, an epigenetic modification known to be dysregulated in carcinogenesis. This case control study assessed the contribution of MTHFR polymorphisms to the risk of nasopharyngeal carcinoma (NPC). MTHFR genotypes C677T and A1298C in 529 NPC patients and 577 frequency-matched controls were determined by PCR-based restriction fragment length polymorphism. We found a 1.57-fold increased risk of NPC in subjects with the MTHFR 1298AC genotype compared to subjects with the MTHFR 1298AA genotype. In addition, an elevated NPC risk was also found in subjects with both the MTHFR 677CT and 1298AC genotypes [odds ratio (OR) = 2.15, 95% confidence interval (CI) = 1.37-3.39] compared to subjects with the 677CC/1298AA genotypes. Furthermore, we observed an additive interaction between MTHFR polymorphisms and smoking status on the increased risk of NPC. The OR was 6.72 (95% CI = 1.85-24.48) among heavy smokers (pack-years >=15) carrying 677TT compared with nonsmokers carrying the 677CC genotype. The OR was 7.23 (95% CI = 4.22-12.38) or 12.75 (95% CI = 2.74-59.3) among subjects carrying the 1298AC or 1298CC genotype in heavy smokers (pack-years >=15) compared with 1298AA in nonsmokers. Our results provide the first molecular epidemiological evidence that MTHFR polymorphisms associate with the risk of NPC and this association is especially noteworthy in heavy smokers. PMID- 20721971 TI - Effects of dietary taurine on egg production, egg quality and cholesterol levels in Japanese quail. AB - BACKGROUND: Taurine is a semi-essential amino acid and has many biological properties. The objective of this study was to determine the effect of dietary supplementation with taurine on egg production, egg quality, and cholesterol level in serum and egg yolk of quails. A total of 108 quails aged 6 weeks were randomly allocated to three dietary treatments. Each treatment consisted of four replicates of nine quails. The diets were supplemented with 0, 100, and 500 mg kg(-1) of taurine for 8 weeks. RESULTS: Dietary 500 mg kg(-1) taurine significantly affected egg production rate and feed conversion ratio, but had no significant effects on body weight gain, feed consumption, or egg weight. Dietary taurine had no significant effect on egg quality parameters studied. Serum triglyceride concentration was reduced significantly with supplementation of taurine at 100 and 500 mg kg(-1). Egg yolk cholesterol content was reduced significantly, and the contents of serum taurine and egg yolk taurine were increased significantly with taurine supplementation at 500 mg kg(-1). CONCLUSION: Results of the present study indicated that adding 500 mg kg(-1) taurine reduced yolk cholesterol concentration and increased yolk taurine content without adverse effects on performance and egg quality of laying quails. PMID- 20721970 TI - Isosilybin A induces apoptosis in human prostate cancer cells via targeting Akt, NF-kappaB, and androgen receptor signaling. AB - Prostate cancer (PCA) is the second most malignancy in American men. Advanced stage PCA cells possess unlimited replication potential as well as resistance to apoptosis. Therefore, targeting survival mechanisms and activating apoptotic machinery in PCA cells using nontoxic phytochemicals is suggested as an attractive strategy against this deadly malignancy. In the present study, we assessed the effect of one such botanical agent, namely isosilybin A, on apoptotic machinery and key members of cell survival signaling [Akt, NF-kappaB, and androgen receptor (AR)] in different PCA cells. Results showed that isosilybin A (90-180 uM) treatment significantly induces apoptotic death by activating both extrinsic (increased level of DR5 and cleaved caspase 8) and intrinsic pathways (caspase 9 and 3 activation) of apoptosis in three different human PCA cell lines namely 22Rv1, LAPC4, and LNCaP. Further, isosilybin A treatment decreased the levels of phospho-Akt (serine-473), total Akt, and the nuclear levels of NF-kappaB constituents (p50 and p65). Isosilybin A treatment also decreased the AR and PSA level in 22Rv1, LAPC4, and LNCaP cells. Employing pan-caspase inhibitor (Z-VAD.fmk), we confirmed that isosilybin A-mediated decreased AR is independent of caspases activation. Temporal kinetics analysis showed that the primary effect of isosilybin A is on AR, as decrease in AR was evident much earlier (4 h) relative to caspase activation and apoptosis induction (12 h). Overall, our results demonstrated that isosilybin A activates apoptotic machinery in PCA cells via targeting Akt-NF-kappaB-AR axis; thereby, indicating a promising role for this phytochemical in the management of clinical PCA. PMID- 20721972 TI - Insecticide resistance in field populations of Bemisia tabaci (Hemiptera: Aleyrodidae) in West Africa. AB - BACKGROUND: The tobacco whitefly, Bemisia tabaci Gennadius (Hemiptera: Aleyrodidae), has developed a high degree of resistance to several chemical classes of insecticides throughout the world. To evaluate the resistance status in West Africa, eight insecticides from different chemical families were tested using the leaf-dip method on four field populations collected from cotton in Benin, Togo and Burkina Faso. RESULTS: Some field populations showed a significant loss of susceptibility to pyrethroids such as deltamethrin [resistance ratio (RR) 3-5] and bifenthrin (RR 4-36), to organophosphates (OPs) such as dimethoate (RR 8-15) and chlorpyrifos (RR 5-7) and to neonicotinoids such as acetamiprid (RR 7-8) and thiamethoxam (RR 3-7). Bemisia tabaci was also resistant to pymetrozine (RR 3-18) and to endosulfan (RR 14-30). CONCLUSION: The resistance of B. tabaci to pyrethroids and OPs is certainly due to their systematic use in cotton treatments for more than 30 years. Acetamiprid has been recently introduced for the control of whiteflies. Unfortunately, B. tabaci populations from Burkina Faso seem to be already resistant. Because cross resistance between these compounds has never been observed elsewhere, resistance to neonicotinoids could be due to the presence of an invasive B. tabaci biotype recently detected in the region. PMID- 20721973 TI - Impact of neonicotinoid insecticides on natural enemies in greenhouse and interiorscape environments. AB - The neonicotinoid insecticides imidacloprid, acetamiprid, dinotefuran, thiamethoxam and clothianidin are commonly used in greenhouses and/or interiorscapes (plant interiorscapes and conservatories) to manage a wide range of plant-feeding insects such as aphids, mealybugs and whiteflies. However, these systemic insecticides may also be harmful to natural enemies, including predators and parasitoids. Predatory insects and mites may be adversely affected by neonicotinoid systemic insecticides when they: (1) feed on pollen, nectar or plant tissue contaminated with the active ingredient; (2) consume the active ingredient of neonicotinoid insecticides while ingesting plant fluids; (3) feed on hosts (prey) that have consumed leaves contaminated with the active ingredient. Parasitoids may be affected negatively by neonicotinoid insecticides because foliar, drench or granular applications may decrease host population levels so that there are not enough hosts to attack and thus sustain parasitoid populations. Furthermore, host quality may be unacceptable for egg laying by parasitoid females. In addition, female parasitoids that host feed may inadvertently ingest a lethal concentration of the active ingredient or a sublethal dose that inhibits foraging or egg laying. There are, however, issues that require further consideration, such as: the types of plant and flower that accumulate active ingredients, and the concentrations in which they are accumulated; the influence of flower age on the level of exposure of natural enemies to the active ingredient; the effect of neonicotinoid metabolites produced within the plant. As such, the application of neonicotinoid insecticides in conjunction with natural enemies in protected culture and interiorscape environments needs further investigation. PMID- 20721974 TI - Amplification of CyclinL1 in uterine cervical carcinoma has prognostic implications. AB - The chromosomal 3q25.31 region was consistently amplified in primary cancer of cervix (CACX). CyclinL1 is a candidate gene of this region and already have been implicated as an oncogene in head and neck cancers. In this study, we aimed to investigate the involvement of CyclinL1 in cervical carcinogenesis and for this purpose its copy number variation (CNV) was studied in 23 cervical intraepithelial neoplasia (CIN) and 110 CACX samples. In CIN lesions CyclinL1 was not amplified; however, the amplification frequency was 16% (9/56) in stage I/II tumors which remained comparable during subsequent stages of tumorigenesis. This implied association of CyclinL1 amplification with development of early invasiveness. Quantitation of mRNA expression revealed 2.6 +/- 1.53-fold overexpression of this gene in primary CACX. The amplification/copy number gain of CyclinL1 and its mRNA profile were concordant, in tumors. Immunohistochemical (IHC) analysis in primary CACX, cell lines: SiHa and HeLa revealed intense nuclear expression of cyclinL1, which was further confirmed by Western blot in the cell lines. However 47% (7/15) CACX samples expressed high/intermediate level of cyclin L1. Kaplan-Meier survival analysis indicated CyclinL1 amplification as a determinant of poor patient outcome. Tumor radio-resistance developed as a consequence of CyclinL1 amplification. Cox multivariate analysis revealed that multiparous (>=5) CACX patients with amplified CyclinL1 locus along with advanced tumor stage (III/IV) had worst prognosis. Our data suggest importance of CyclinL1 in cervical carcinogenesis with its associated pathways viz: pre-mRNA splicing, cell-cycle regulation (G0/G1 and G2/M) being potential targets of therapeutic interventions in CACX. PMID- 20721975 TI - Association of a common AGO1 variant with lung cancer risk: a two-stage case control study. AB - Based on the important role of microRNA (miRNA) biosynthesis genes in carcinogenesis, we hypothesized that polymorphisms in the miRNA biosynthesis genes may modulate susceptibility to lung cancer. To test this hypothesis, we conducted a two-stage study to evaluate the associations between single nucleotide polymorphisms (SNPs) in the miRNA biosynthesis genes and the risk of lung cancer. In stage 1 of the study, 24 SNPs in the 11 miRNA biosynthesis genes (DROSHA, DGCR8, RAN, XPO5, DICER, AGO1, AGO2, HIWI, GEMIN3, GEMIN4, and TRBP) were genotyped in 100 lung cancer patients and 100 healthy controls using a sequenome mass spectrometry-based genotyping assay. One promising SNP (AGO1 rs636832A > G) was selected for stage 2 of the study, and genotyped by a melting curve analysis using fluorescence-labeled hybridization probes in an independent set of 552 cases and 552 controls. The AGO1 rs636832A > G exhibited highly consistent results between the two stages of the study. In combined analysis, the 636832A > G was associated with a significantly decreased risk of lung cancer in a dose-dependent manner (P(trend) = 6.0 * 10(-4)). Individuals with at least one rs636832G allele were at a significantly decreased risk of lung cancer compared with those with the AA genotype (adjusted odds ratio = 0.67, 95% confidence interval = 0.53-0.84, P = 4.0 * 10(-4)). This finding suggests that the AGO1 rs636832A > G might be a useful marker for determining the susceptibility to lung cancer and that the AGO1 gene might be involved in the development of lung cancer. PMID- 20721977 TI - The 2D:4D digit ratio is not a useful marker for prenatal famine exposure: Evidence from the Dutch hunger winter families study. AB - OBJECTIVES: Digit lengths, and in particular the ratio of the 2nd (2D) to 4th (4D) digit (2D:4D), are stable in adulthood and have been linked to characteristics thought to have developmental origins, but little research has focused on early life determinants of these measures. We examined whether exposure to acute famine during specific periods of gestation was associated with 2D, 4D or the 2D:4D ratio. METHODS: We studied men and women (1) born in one of three hospitals in western Netherlands whose mothers were exposed to a limited period of famine immediately prior to or during the pregnancy (n = 337); (2) born in the same hospitals to mothers not exposed to famine during the pregnancy (n = 271) or same-sex siblings of individuals in Groups 1 and 2 (n = 295). We measured 2D and 4D on both hands using calipers and computed the 2D:4D ratio. RESULTS: Mean 2D and 4D lengths were 73.5 (SD 5.1) and 75.0 (5.4) mm, respectively. The 2D:4D ratio was 0.981 (SD 0.030). Both 2D and 4D were associated with male gender and height (all P < 0.001), and weakly with BMI. The 2D:4D ratio was 0.0070 (95% confidence interval 0.0017, 0.0123) lower among males as compared with females, and was not significantly associated with height (0.0002 per cm; 95% -0.0001, 0.0005). The 2D:4D ratio was not significantly associated with exposure to famine, overall (-0.0010, 95% CI 0.0030, 0.0050) or within any period of gestation. CONCLUSIONS: The 2D:4D ratio is not significantly affected by prenatal exposure to famine and therefore is not a useful marker for generalized prenatal undernutrition. PMID- 20721978 TI - Secular change in the timing of dental root maturation in Portuguese boys and girls. AB - OBJECTIVES: In this study, we compare root formation in a modern sample of living Portuguese children (n = 521), between 6 and 18 years of age, with that of a similar sample of known sex and age Portuguese child skeletons (n = 114), who lived half a century earlier, to assess secular change in dental maturation. METHODS: The roots of seven developing permanent mandibular teeth were assessed for their maturation in both samples. The median age-of-attainment of root stages was calculated using logistic regression and compared between the samples. The potential influence of mortality bias in root development of the skeletal sample was tested. RESULTS: No mortality bias effect was detected. We find that the dentition of modern Portuguese boys and girls mature on average 1.22 years and 1.47 years earlier, respectively, compared to their counterparts born one half a century before. Our results also suggest that an earlier timing of attainment of root formation maturational stages was not accompanied by a change in the overall duration of root formation. CONCLUSIONS: We demonstrate a clear and consistent acceleration in dental root maturation due to secular changes and show that the plasticity in dental development in response to environmental factors is greater than previously thought. PMID- 20721979 TI - Nonmetric cranial variation of Jomon Japan: Implications for the evolution of eastern Asian diversity. AB - OBJECTIVES: The purpose of this study is to investigate the origin and expansion of the Jomon population, the Neolithic inhabitants of the Japanese archipelago, and peopling East/Northeast Asian region through a global comparison between the prehistoric samples from around the world. METHODS: R-matrix approach was applied to 20 nonmetric cranial traits for assessing the population structure and history of the Jomon. Pattern of ancient group relationships on a global scale was presented using network splitstree applied to distance matrix transformed from the R-matrix. RESULTS: The phenotypic variation is largest in Hokkaido region, followed by the regions of eastern Japan. The Chugoku region, the southwestern part of Japan, shows larger variance than eastern Japan. Global analyses including samples from Northeast Asia, Southeast Asia, Australia, West Asia, Europe, and North Africa dating roughly to the same chronological periods as those of the Jomon groups, indicate northern affinities of the Jomon and the distinction between Southeast and Northeast Asian series. CONCLUSION: The Jomon ancestors of the northern part of Japan might have expanded southward to Honshu Island with a series of bottlenecks. A possible gene flow from outside source or heterogeneous origin of western Jomon group was, at the same time, suggested. The network relationships of the Jomon with Northeast Asians and, to a lesser extent, with Southeast Asians based on the splitstree analysis may allow us to suppose that the Jomon may be one of the key populations for the studies of the evolution of eastern Asian diversity. PMID- 20721976 TI - The skinny on Slug. AB - The zinc finger transcription factor Slug (Snai2) serves a wide variety of functions in the epidermis, with roles in skin development, hair growth, wound healing, skin cancer, and sunburn. Slug is expressed in basal keratinocytes and hair follicles where it is important in maintaining epidermal homeostasis. Slug also helps coordinate the skin response to exogenous stimuli. Slug is rapidly induced by a variety of growth factors and injurious agents and Slug controls, directly or indirectly, a variety of keratinocyte responses, including changes in differentiation, adhesion, motility, and production of inflammatory mediators. Slug thus modulates the interactions of the keratinocyte with its environment and with surrounding cells. The function of Slug in the epidermis appears to be distinct from that of the closely related Snail transcription factor. PMID- 20721980 TI - Responsiveness of the reproductive axis to a single missed evening meal in young adult males. AB - OBJECTIVES: The male reproductive axis is responsive to energetic deficits, including multiday fasts, but little is known about brief periods of fasting (<24 hours). Reduced testosterone in low-energy balance situations is hypothesized to reflect redirection of resources from reproduction to survival. This study tests the hypothesis that testosterone levels decrease during a minor caloric deficiency by assessing the effects of a single missed (evening) meal on morning testosterone in 23 healthy male participants, age 19-36. METHODS: Participants provided daily saliva and urine samples for two baseline days and the morning following an evening fast (water only after 4 PM). Testosterone, cortisol, and luteinizing hormone were measured with enzyme immunoassays. RESULTS: Fasting specimens had significantly lower overnight urinary luteinizing hormone (P = 0.045) and morning salivary testosterone than baseline (P = 0.037). In contrast to morning salivary testosterone, there was a significant increase in overnight urinary testosterone (P = 0.000) following the evening fast, suggesting an increase in urinary clearance rates. There was a marginal increase in overnight urinary cortisol (P = 0.100), but not morning salivary cortisol (P = 0.589). CONCLUSION: These results suggest the male reproductive axis may react more quickly to energetic imbalances than has been previously appreciated. PMID- 20721981 TI - Maternal hemoglobin depletion in a settled northern Kenyan pastoral population. AB - OBJECTIVES: This study examines maternal hemoglobin depletion in a cross sectional sample of Ariaal women living in northern Kenya. Maternal hemoglobin depletion occurs when women do not have enough dietary iron to replace the high levels of iron allocated to the fetus during pregnancy. METHODS: To study this phenomenon, reproductive histories, socioeconomic status, anthropometry, and hemoglobin levels were collected from a cross-section of 200 lactating Ariaal women in northern Kenya. RESULTS: Ariaal women show increasing levels of hemoglobin with increasing time since birth and lower hemoglobin levels with increasing parity, indicating an incomplete repletion of dietary iron over women's reproductive lifetime. Women who lived in a more livestock-dependent village had higher hemoglobin levels and lower prevalence of clinical anemia than women who lived in villages more dependent on agriculture, indicating that differences in diet may alleviate the effects of iron depletion. CONCLUSIONS: These data demonstrate that Ariaal women are iron depleted due to pregnancy, incompletely replete hemoglobin during the course of lactation, and show depletion of hemoglobin with increasing parity. Women in this community may be able to improve their iron status through a greater reliance on food sources rich in dietary iron. PMID- 20721982 TI - Agent-based modeling of the spread of the 1918-1919 flu in three Canadian fur trading communities. AB - OBJECTIVES: Previous attempts to study the 1918-1919 flu in three small communities in central Manitoba have used both three-community population-based and single-community agent-based models. These studies identified critical factors influencing epidemic spread, but they also left important questions unanswered. The objective of this project was to design a more realistic agent based model that would overcome limitations of earlier models and provide new insights into these outstanding questions. METHODS: The new model extends the previous agent-based model to three communities so that results can be compared to those from the population-based model. Sensitivity testing was conducted, and the new model was used to investigate the influence of seasonal settlement and mobility patterns, the geographic heterogeneity of the observed 1918-1919 epidemic in Manitoba, and other questions addressed previously. RESULTS: Results confirm outcomes from the population-based model that suggest that (a) social organization and mobility strongly influence the timing and severity of epidemics and (b) the impact of the epidemic would have been greater if it had arrived in the summer rather than the winter. New insights from the model suggest that the observed heterogeneity among communities in epidemic impact was not unusual and would have been the expected outcome given settlement structure and levels of interaction among communities. CONCLUSIONS: Application of an agent-based computer simulation has helped to better explain observed patterns of spread of the 1918-1919 flu epidemic in central Manitoba. Contrasts between agent-based and population-based models illustrate the advantages of agent-based models for the study of small populations. PMID- 20721984 TI - Assessment and characterization of the diet of an isolated population in the Bolivian Andes. AB - OBJECTIVES: The goal of this research is to characterize the composition and nutrient adequacy of the diets in the northern region of the Department of Potosi, Bolivia. Communities in this semiarid, mountainous region are isolated and impoverished having the highest rates of child malnutrition and under-five mortality in the Americas. METHODS: A total of 2,222 twenty-four-hour dietary recalls were conducted in 30 communities during May and November 2006 and May and November 2007. Food composition data were compiled from diverse published sources and integrated with the recall data to estimate intakes of energy, protein, fat, carbohydrates, and seven micronutrients. Diets were characterized in terms of food sources, seasonality, and nutrient adequacy. RESULTS: The diet relies heavily on the potato and other tubers (54% of dietary energy) and grains (30% of dietary energy). Although crop production is seasonal, off-season consumption of chuno helps to minimize seasonal fluctuations in dietary energy intake. Despite relative monotony, intakes of iron, vitamin C, most B vitamins, and vitamin A in adults are probably adequate; riboflavin, calcium, and vitamin A intakes in children are low. Nevertheless, extremely low dietary fat intakes (approximately 3-9% of dietary energy from fat) likely prevent adequate absorption of fat soluble vitamins as well as lead to deficiencies of essential fatty acids. CONCLUSIONS: Dietary inadequacies, especially of fats, may explain much of the poor health observed in northern Potosi. An improved diet may be possible through increasing production and intake of local fat-rich food sources such as small animals. PMID- 20721986 TI - Breastfeeding and later psychosocial development in the Philippines. AB - OBJECTIVES: Evaluate whether breastfeeding (BF) duration predicts later psychosocial development (PD) in a large low socioeconomic status (SES) sample in the Philippines. METHODS: The sample consists of 2,752 children aged 5-6 years who were measured in 2004 as part of the Philippine government's Early Childhood Development Project. Duration of any BF was the primary independent variable in regression models predicting a cumulative index of PD that has been shown previously to predict school readiness. RESULTS: In this sample, mothers who breastfed their children for longer tended to have lower educational attainment and to come from lower income households. Despite this, BF duration was a positive predictor of future PD measured in late childhood, but only after adjustment for SES and related confounders. CONCLUSIONS: These findings add to growing evidence that BF could provide lasting economic and social benefits and underscore the importance of continuing current public health efforts to promote BF in the Philippines and across the globe. PMID- 20721985 TI - Blood lipids, infection, and inflammatory markers in the Tsimane of Bolivia. AB - OBJECTIVES: Little is known about blood cholesterol (blood-C) levels under conditions of infection and limited diet. This study examines blood-C and markers of infection and inflammation in the Tsimane of the Bolivian Amazon, indigenous forager farmers living in conditions that model preindustrial European populations by their short life expectancy, high load of infections and inflammation, and limited diets. METHODS: We use multivariate models to determine the relationships between lipid levels and markers of infection and inflammation. Adult Tsimane (N = 418, age 20-84) were characterized for blood lipids, cells, and inflammatory markers in relation to individual loads of parasites and village region. RESULTS: Most of the Tsimane (60%) carried at least one parasite species, averaging 1.3 species per person. Serum high-density lipoprotein cholesterol (HDL C), total cholesterol (total-C), and low-density lipoprotein cholesterol (LDL-C) were below the U.S. norms and varied inversely with markers of infection and inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), immunoglobulin (Ig) E and eosinophil count. Although no relationship of parasite load to blood-C was found, there was an association between anemia and parasite prevalence. CONCLUSIONS: We conclude that the highly infected environment of the Tsimane is related to low levels of blood total-C, HDL-C, and LDL-C. This may suggest a potential reason why arterial disease is largely absent in the Tsimane. PMID- 20721983 TI - Recommended levels and intensities of physical activity to avoid low cardiorespiratory fitness in European adolescents: The HELENA study. AB - OBJECTIVES: The purpose of this study was to determine the sex-specific physical activity (PA) intensity thresholds that best discriminate between unhealthy/healthy cardiorespiratory fitness (CRF). METHODS: Participants included 1,808 adolescents (964 girls), aged 12.5-17.5 years, from the HELENA study. We measured PA by accelerometer and calculated the time spent at light, moderate, vigorous, and moderate-to-vigorous (MVPA) intensities. CRF was assessed by the 20 m shuttle-run test. Adolescents were dichotomized (unhealthy/healthy) based on sex- and age-specific FITNESSGRAM standards. Receiver operating characteristic (ROC) analysis was used to determine thresholds that best discriminate between CRF categories. RESULTS: ROC analyses revealed that the PA thresholds that best discriminate between unhealthy/healthy CRF were >=152, >=33, >=13, and >=52 min/day in light, moderate, vigorous, and MVPA, respectively. In boys, the PA thresholds associated with a healthy CRF were >=37, >=19, and >=56 min/day in moderate, vigorous, and MVPA, respectively, whereas in girls were >=152, >=34, >=12, and >=51 min/day in light, moderate, vigorous, and MVPA, respectively. Spending at least 60 min/day in MVPA was also associated with a healthy CRF (odds ratios: 1.75, 1.94, and 1.57, all P < 0.05, for the whole sample, boys, and girls, respectively). CONCLUSIONS: This study shows sex- and intensity-specific PA thresholds to discriminate between adolescents with a healthy CRF from those with a less favorable or unhealthy CRF level. PMID- 20721987 TI - Bacterial olfaction. AB - Sensing their environment is a crucial ability of all life forms. In higher eukaryotes the sensing of airborne volatile compounds, or olfaction, is well developed. In plants, slime moulds and yeast there is also compelling evidence that these organisms can smell their environment and respond accordingly. Here we show that bacteria are also capable of olfaction. Bacillus licheniformis was able to sense airborne volatile metabolites produced by neighbouring bacterial cultures and cells could respond to this chemical information in a coordinated way. When Bacillus licheniformis was grown in a microtitre plate adjacent to a bacterial culture of the same or a different species, growing in complex medium, biofilm formation and pigment production were elicited by volatile molecules. A weaker response occurred in increasingly distant wells. The emitted volatile molecule was identified as ammonia. These data demonstrate that B. licheniformis has evolved the ability collect information about its environment from the surrounding air and physiologically respond to it in a manner similar to olfaction. This is the first time that a behavioural response triggered by odorant molecules received through the gas phase is described in bacteria. PMID- 20721989 TI - Mouse models and mouse supermodels. PMID- 20721988 TI - Cycling through metabolism. AB - Since the discovery of cyclins, the role of cell cycle regulators in the control of cell proliferation has been extensively studied. It is clear that proliferation requires an adapted metabolic response of the cells; hence the regulation of cell cycle must be linked to metabolic control. While at a much slower pace, the impact that the activities of cell cycle regulators such as cyclins, cyclin dependent kinases or E2F factor, transcription factor have on cell metabolism are also being uncovered. Here we will focus on recent data implicating cell cycle regulators in metabolic control, with particular attention to studies performed using mouse models. Furthermore, we will discuss the possible relevance of these findings in the context of metabolic disorders such as obesity or diabetes. PMID- 20721991 TI - Rhodium mediated C-H bond functionalisation leading to carboxylate derivatives. PMID- 20721992 TI - Coordination and dehydrogenation of amine-boranes at metal centers. AB - There have been a number of approaches developed for the catalyzed dehydrogenation of amine-boranes as potential dihydrogen sources for hydrogen storage applications in recent years. Key advances in this area have been recently made thanks to catalytic and stoichiometric studies. In this Minireview, the fate of amine-boranes upon coordination to a metal center is discussed with a particular emphasis on B-H activation pathways. We focus on the few cases in which coordination of the resulting dehydrogenated product could be achieved, which includes the coordination of aminoborane, the simplest unit resulting from dihydrogen release of ammonia-borane. PMID- 20721990 TI - Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens. AB - Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumour-initiation capacity in treated tumours. These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies. PMID- 20721993 TI - Structural characterization of a microperoxidase inside a metal-directed protein cage. PMID- 20721994 TI - Merging organocatalysis with an indium(III)-mediated process: a stereoselective alpha-alkylation of aldehydes with allylic alcohols. PMID- 20721996 TI - Uniform hollow carbon shells: nanostructured graphitic supports for improved oxygen-reduction catalysis. PMID- 20721995 TI - Polyfluorophores on a DNA backbone: sensors of small molecules in the vapor phase. PMID- 20721997 TI - Enantioselective addition of boronates to chromene acetals catalyzed by a chiral Bronsted acid/Lewis acid system. PMID- 20721998 TI - Infrared spectra of reactive species generated by flash pyrolysis in a free jet. PMID- 20721999 TI - Structural and potency relationships between scaffolds of compounds active against human targets. PMID- 20722000 TI - Exploring the limits of frustrated Lewis pair chemistry with alkynes: detection of a system that favors 1,1-carboboration over cooperative 1,2-P/B-addition. AB - The zirconocene complex [{(C6F5)2B-(CH2)3-Cp}(Cp-PtBu2)ZrCl2] (6; Cp=cyclo-C5H4) was prepared by hydroboration of [(allyl-Cp)(Cp-PtBu2)ZrCl2] (5) with HB(C6F5)2 ("Piers' borane"). It represents a frustrated Lewis pair (FLP) in which both the Lewis acid and the Lewis base were attached at the metallocene framework. Its reaction with 1-pentyne did not result in the 1,2-addition of or deprotonation reaction by the FLP, but rather in the 1,1-carboboration of the triple bond, thereby obtaining a Z/E mixture (1.2:1) of the respective organometallic substituted alkenes 7. The analogous reaction of 1-pentyne with the phosphorous free system [{(C6F5)2B-(CH2)3-Cp)}CpZrCl2] (9) gave the respective 1,1 carboboration products ((Z)-10/(E)-10~1.3:1). PMID- 20722001 TI - Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis. AB - Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of beta-catenin in diet-induced steatohepatitis, we recently found that liver-specific beta-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of beta-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 weeks. Chow-fed KO mice had higher serum and hepatic total bile acid levels and lower bile flow rate than WT mice. Expression levels of bile acid biosynthetic genes were lower and levels of major bile acid exporters were similar, which therefore could not explain the KO phenotype. Despite loss of the tight junction protein claudin-2, KO mice had preserved functional integrity of tight junctions. KO mice had bile canalicular morphologic abnormalities as evidenced by staining for F-actin and zona occludens 1. Electron microscopy revealed dilated and tortuous bile canaliculi in KO livers along with decreased canalicular and sinusoidal microvilli. KO mice on a cholic acid diet had higher hepatic and serum bile acid levels, bile ductular reaction, increased pericellular fibrosis, and dilated, misshapen bile canaliculi. Compensatory changes in expression levels of several bile acid transporters and regulatory genes were found in KO livers. CONCLUSION: Liver-specific loss of beta-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for beta catenin in biliary physiology. PMID- 20722002 TI - Relationship between age, skeletal site, and time post-ovariectomy on bone mineral and trabecular microarchitecture in rats. AB - The ovariectomized (OVX) rat is widely used in osteoporosis research, but no standard model exists. The individual effects of rat age, skeletal site, and time post-ovariectomy (post-OVX) on bone have been examined. However, the relationship between them is not yet fully explored. This study examined how various combinations of rat age, skeletal site, and time post-OVX affect bone mineral and microarchitecture. The rats used were 12 (n = 28), 24 (n = 28), and 44 (n = 31) weeks old. In each age group, approximately half underwent OVX and other half underwent Sham surgeries. Bone mineral (content and density) and trabecular morphology was assessed at 2, 5, 10, 15, 20, 25, and 30 weeks post-surgery. Sites examined included the proximal tibia, spine, distal femur, and proximal femur. Overall, the proximal tibia showed the earliest and greatest differences between OVX and Sham groups. The 24-week-old group showed the best osteoporotic response. The 12-week-old group showed growth effects, whilst the 44-week-old group showed aging effects. The response of certain sites to OVX was also found to depend on the rat age used. These findings may aid in explaining discrepancies reported in the literature as well as synergistic combinations that may signify advanced conditions. (c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:189-196, 2011. PMID- 20722004 TI - Publication of optimized multicolor immunofluorescence panels. PMID- 20722005 TI - OMIP-001: Quality and phenotype of Ag-responsive human T-cells. PMID- 20722006 TI - OMIP-002: Phenotypic analysis of specific human CD8+ T-cells using peptide-MHC class I multimers for any of four epitopes. PMID- 20722007 TI - OMIPs--Orchestrating multiplexity in polychromatic science. PMID- 20722008 TI - Ex vivo analysis of SIV-infected cells by flow cytometry. AB - Deciphering the complex interactions between human and simian immunodeficiency viruses (HIV/SIV) and their host cells is crucial to the development of improved therapies and vaccines. Investigating these relationships has been complicated by the inability to directly analyze infected cells among freshly isolated peripheral blood lymphocytes. Here, we describe a method to detect cells productively infected with SIVmac239 ex vivo from the blood or lymph nodes by flow cytometry. Using this method, we show a close correlation between the frequency of productively infected cells in both sample type and the plasma viral load. We define that the minimum threshold for detecting productively infected cells in lymph nodes by flow cytometry requires a plasma virus concentration of ~2.5 * 10(4) vRNA copy Equivalents (Eq)/ml. Conversely, an approximately 2 logs higher plasma viral load is needed to detect productively infected cells in the peripheral blood. This novel protocol provides a direct analytical tool to assess interactions between SIV and host cells, which is of key importance to investigators in AIDS research. PMID- 20722009 TI - Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts. AB - OBJECTIVE: The aim of this study was to determine whether there are differences in white matter integrity between systemic lupus erythematosus (SLE) patients and healthy controls, as determined using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging data. METHODS: Twelve patients with SLE (mean age 42 years [range 15-61 years]) diagnosed according to the American College of Rheumatology 1982 revised criteria for SLE and 28 healthy controls (mean age 46 years [range 21-61 years]) were included in the study. Magnetic resonance imaging was performed on a 3.0T scanner. Fractional anisotropy (FA) maps were calculated for each patient. TBSS analysis was used to compare the FA maps. The TBSS technique projects the FA data into a common space through the use of an initial approximate nonlinear registration, followed by projection onto an alignment-invariant tract representation (mean FA skeleton). The cluster results were corrected for multiple comparisons across space, and a threshold of significance of 0.05 was used. RESULTS: The white matter of tracts in the inferior fronto-occipital fasciculus, the fasciculus uncinatus, as well as the fornix, the posterior limb of the internal capsule (corticospinal tract), and the anterior limb of the internal capsule (anterior thalamic radiation) of patients with SLE showed reduced integrity as compared with normal subjects. CONCLUSION: In this preliminary study, the integrity of white matter tracts in areas around limbic structures and in the internal capsule was found to be reduced. Larger studies could improve our understanding of the pathologic mechanisms behind the reduced white matter tract integrity in SLE. PMID- 20722010 TI - Associations of cigarette smoking with rheumatoid arthritis in African Americans. AB - OBJECTIVE: To examine the associations of cigarette smoking with rheumatoid arthritis (RA) in African Americans, and to determine whether this association is impacted by the HLA-DRB1 shared epitope (SE). METHODS: Smoking status, cumulative smoking exposure, and SE status were determined in African American patients with RA and African American healthy controls. Associations of smoking with RA were examined using age- and sex-adjusted logistic regression analyses. Additive and multiplicative SE-smoking interactions were examined. RESULTS: After adjustment for age and sex, ever smoking (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.07, 1.97) and current smoking (OR 1.56, 95% CI 1.07, 2.26), relative to never smoking, were more common in African American patients with RA (n = 605) than in controls (n = 255). The association of smoking with RA was limited to those with a cumulative exposure exceeding 10 pack-years, associations that were evident both in autoantibody-positive and in autoantibody-negative disease. There was evidence of a significant additive interaction between SE status and heavy smoking (>=10 pack-years) in relation to RA risk (attributable proportion [AP] due to interaction 0.58, P = 0.007), with similar results for the additive interaction between SE status and ever smoking (AP 0.47, P = 0.006). There was no evidence of multiplicative interactions. CONCLUSION: Among African Americans, cigarette smoking is associated not only with the risk of autoantibody-positive RA but also with the risk of autoantibody-negative disease. The risk of RA attributable to smoking is limited to African Americans with more than 10 pack years of exposure and is more pronounced among individuals positive for the HLA DRB1 SE. PMID- 20722011 TI - Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. AB - OBJECTIVE: During inflammation in the joint, normal joint movements are usually painful. A neuronal mechanism for this form of mechanical hyperalgesia is the persistent sensitization of joint nociceptors to mechanical stimuli. Because tumor necrosis factor (TNF) is a major mediator of joint inflammation, we undertook the present study both to explore the potential of TNF to sensitize joint nociceptors to mechanical stimuli and to address the cellular mechanism involved. METHODS: In anesthetized rats, action potentials (APs) were recorded from sensory nociceptive Adelta fibers and C fibers supplying the knee joint. We monitored responses to rotation of the knee joint at innocuous and noxious intensities. TNF, etanercept, and a p38 inhibitor were injected into the knee joint, and the cyclooxygenase (COX) inhibitor diclofenac was administered intraperitoneally. APs were also recorded in isolated cultured dorsal root ganglion (DRG) neurons in order to test for changes in neuronal excitability induced by TNF. RESULTS: A single application of TNF into the normal knee joint caused a significant persistent sensitization of nociceptive sensory fibers to mechanical stimuli applied to the joint. This effect was dose dependent. It was prevented by coadministration of etanercept or by an inhibitor of p38, and it was attenuated by systemic application of a COX inhibitor. Patch clamp recordings from isolated DRG neurons showed a rapid increase in neuronal excitability induced by TNF. CONCLUSION: TNF can induce a long-lasting sensitization of joint nociceptors to mechanical stimuli and thus can induce long-lasting mechanical hyperalgesia in joints. TNF can act directly on neurons, underscoring its role as a sensitizing pain mediator. PMID- 20722012 TI - Transcriptional profiling of day 12 porcine embryonic disc and trophectoderm samples using ultra-deep sequencing technologies. AB - cDNA derived from trophectoderm (TE) and embryonic disc (ED) of a single day 12 porcine embryo was subjected to next-generation sequencing using the Illumina platform. The short sequencing reads from triplicate sequencing runs were aligned to a custom database designed to represent the known porcine transcriptome. As expected, genes involved in epithelial cell function and steroid biosynthesis were more abundant in cells from the TE; genes involved in maintenance of pluripotency and chromatin remodeling were more highly expressed in cells from the ED. Quantitative real-time PCR was used to confirm the validity of the approach. We conclude that gene expression profiles of even extremely small samples (=20-fold, and for a subset of them (NP-positive genes PAX1, FOXF1, HBB, CA12, and OVOS2; AC-positive genes GDF10, CYTL1, IBSP, and FBLN1), differential expression was confirmed by real-time quantitative PCR. Differentiated BM-MSCs and AD-MSCs demonstrated significant increases in the novel NP markers PAX1 and FOXF1. AD-MSCs lacked expression of the AC markers IBSP and FBLN1, whereas BM-MSCs lacked expression of the AC marker IBSP but expressed FBLN1. CONCLUSION: This study is the first to use gene expression profiling to identify the human NP cell phenotype. Importantly, these markers can be used to determine the in vitro differentiation of MSCs to an NP-like, rather than an AC like, phenotype. Interestingly, these results suggest that AD-MSCs may be a more appropriate cell type than BM-MSCs for use in engineering intervertebral disc tissue. PMID- 20722019 TI - Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. AB - OBJECTIVE: Prior research demonstrates that hydroxychloroquine (HCQ) lowers glycosylated hemoglobin (HbA(1c) ) in diabetes patients without rheumatic disease. We examined medical records of patients with diabetes mellitus (DM) and concomitant rheumatic illness to measure changes in HbA(1c) after starting HCQ or methotrexate (MTX). METHODS: We used electronic medical records to identify patients beginning treatment with either HCQ or MTX who had a diagnosis of DM (or a pretreatment HbA(1c) value of >=7%) and at least 1 HbA(1c) measurement both before and within 12 months after initiation of treatment. Using a structured medical record abstraction, we examined rheumatic disease diagnosis, cumulative steroid use, duration (months) between drug initiation and lowest HbA(1c) value, a change in DM medication, body mass index (BMI), age, and sex. Adjusted linear regression models determined changes in HbA(1c) from pretreatment values to the lowest posttreatment values within 12 months. RESULTS: We identified 45 patients taking HCQ and 37 patients taking MTX who met the inclusion criteria. Rheumatoid arthritis had been diagnosed in approximately half of the patients in each group. Age, sex, and mean pretreatment HbA(1c) levels were similar across groups. The mean BMI of those taking HCQ (35.4 kg/m(2) ) was slightly higher than that of those taking MTX (32.2 kg/m(2) ) (P = 0.13). Glucocorticoid use appeared more common in those taking MTX (46%) than in those taking HCQ (29%) (P = 0.17). The mean reduction in HbA(1c) from pretreatment values to the lowest posttreatment values was 0.66% (95% confidence interval [95% CI] 0.26, 1.05) in those taking HCQ compared with 0.11% (95% CI -0.18, 0.40) in those taking MTX. In fully adjusted analyses, the reduction in HbA(1c) among those taking HCQ was 0.54% greater than the reduction among those taking MTX (P = 0.041). CONCLUSION: HCQ initiation was associated with a significantly greater reduction in HbA(1c) as compared with MTX initiation among diabetes patients with rheumatic disease. PMID- 20722020 TI - Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients. AB - OBJECTIVE: To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients. METHODS: Twenty RA patients were treated with rituximab (cohort 1). Clinical response was defined as a decrease in the Disease Activity Score evaluated in 28 joints (DAS28) and as a response according to the European League Against Rheumatism (EULAR) criteria at week 12 and week 24. The presence of an IFN signature was analyzed in peripheral blood mononuclear cells by measuring the expression levels of 3 IFN response genes by quantitative polymerase chain reaction analysis. After comparison with the findings in healthy controls, patients were classified as having an IFN high or an IFN low signature. The data were confirmed in a second independent cohort (n = 31). Serum IFNalpha bioactivity was analyzed using a reporter assay. RESULTS: In cohort 1, there was a better clinical response to rituximab in the IFN low signature group. Consistent with these findings, patients with an IFN low signature had a significantly greater reduction in the DAS28 and more often achieved a EULAR response at weeks 12 and 24 as compared with the patients with an IFN high signature in cohort 2 versus cohort 1. The pooled data showed a significantly stronger decrease in the DAS28 in IFN low signature patients at weeks 12 and 24 as compared with the IFN high signature group and a more frequent EULAR response at week 12. Accordingly, serum IFNalpha bioactivity at baseline was inversely associated with the clinical response, although this result did not reach statistical significance. CONCLUSION: The type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA. This finding supports the notion that IFN signaling plays a role in the immunopathology of RA. PMID- 20722021 TI - Fasciitis as a common lesion of dermatomyositis, demonstrated early after disease onset by en bloc biopsy combined with magnetic resonance imaging. AB - OBJECTIVE: To investigate whether fasciitis is histopathologically demonstrable in patients with dermatomyositis (DM), and to analyze the process of inflammatory progression in myopathy accompanying DM. METHODS: STIR or fat-suppressed T2 weighted magnetic resonance imaging (MRI) and en bloc biopsy were performed in 14 patients with newly diagnosed adult-onset DM. The severity of inflammatory cell infiltration around the fascial and intramuscular small blood vessels was evaluated using the total vascular inflammation score (TVIS). RESULTS: In all patients, MRI revealed abnormal hyperintensity in the fascia and in marginal sites of the muscle, predominantly over central sites. En bloc biopsy revealed the presence of fasciitis in most of the patients, as shown by inflammatory infiltrates around the fascial small blood vessels. In those patients who underwent en bloc biopsy earlier than 2 months after the appearance of muscle symptoms, the TVIS of the fascia was significantly higher than the TVIS of the muscle. In contrast, in those patients who underwent en bloc biopsy >2 months after muscle symptom onset, the TVIS of the fascia did not differ significantly from the TVIS of the muscle. CONCLUSION: Fasciitis was histopathologically demonstrated in patients with newly diagnosed adult-onset DM as early as 2 months after the onset of muscle symptoms. These results indicate that fasciitis is a common lesion of DM and suggest that the fascial microvasculature is the primary site of inflammatory cell infiltration in DM. Fasciitis may contribute to muscle symptoms in patients with DM without myositis. PMID- 20722022 TI - CD248 and its cytoplasmic domain: a therapeutic target for arthritis. AB - OBJECTIVE: CD248 is a transmembrane glycoprotein expressed on the surface of activated perivascular and fibroblast-like cells. This study was undertaken to explore the function of CD248 and its cytoplasmic domain in arthritis. METHODS: Synovial tissue biopsy samples from healthy controls, from patients with psoriatic arthritis (PsA), and from patients with rheumatoid arthritis (RA) were stained for CD248. Transgenic mice that were CD248-deficient (CD248-knockout [CD248(KO/KO) ]) or mice with CD248 lacking the cytoplasmic domain (CD248(CyD/CyD) ) were generated. Collagen antibody-induced arthritis (CAIA) was induced in these mice and in corresponding wild-type (WT) mice as controls. Clinical signs and histologic features of arthritis were evaluated. Cytokine levels were determined by enzyme-linked immunosorbent assay, and the number of infiltrating inflammatory cells was quantified by immunohistochemistry. In vitro studies were performed with fibroblasts from CD248-transgenic mouse embryos to explain the observed effects on inflammation. RESULTS: Immunostaining of synovium from patients with PsA and patients with RA and that from mice after the induction of CAIA revealed strong CD248 expression in perivascular and fibroblast like stromal cells. CD248(KO/KO) and CD248(CyD/CyD) mice had less severe arthritis, with lower plasma levels of proinflammatory cytokines, as compared with WT controls. Moreover, the joints of these mice had less synovial hyperplasia, reduced accumulation of inflammatory cells, and less articular cartilage and bone damage. Tumor necrosis factor alpha-induced monocyte adhesion to CD248(CyD/CyD) fibroblasts was impaired. CD248(CyD/CyD) fibroblasts exhibited reduced expression of hypoxia-inducible factor 1alpha, placental growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9 activity in response to transforming growth factor beta. CONCLUSION: CD248 contributes to synovial hyperplasia and leukocyte accumulation in inflammatory arthritis, the effects of which are mediated partly via its cytoplasmic domain. CD248 is therefore a potential new target in the treatment of arthritis. PMID- 20722023 TI - Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease. AB - OBJECTIVE: To determine the significance of anti-U1 RNP antibodies in the cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD) who have central neuropsychiatric SLE (NPSLE). METHODS: The frequency of antinuclear antibodies including anti-U1 RNP antibodies in the sera and CSF of 24 patients with SLE and 4 patients with MCTD, all of whom had neuropsychiatric syndromes, was determined using an RNA immunoprecipitation assay and an enzyme-linked immunosorbent assay. The frequency of anti-U1 RNP antibodies in the CSF of patients with central NPSLE was examined, and the anti-U1 RNP index ([CSF anti-U1 RNP antibodies/serum anti-U1 RNP antibodies]/[CSF IgG/serum IgG]) was compared with CSF interleukin-6 (IL-6) levels and the albumin quotient (Qalb, an indicator of blood-brain barrier damage). CSF and serum antibodies against U1-70K, U1-A, and U1-C, including autoantigenic regions, were examined, and the U1-70K, U1-A, and U1-C indices as well as the anti-U1 RNP index were calculated. RESULTS: CSF anti-U1 RNP antibodies with an increased anti-U1 RNP index showed 64.3% sensitivity and 92.9% specificity for central NPSLE. The anti-U1 RNP index did not correlate with CSF IL-6 levels or the Qalb. The anti-U1-70K index was higher than the anti-U1-A and anti-U1-C indices in the CSF of anti-U1 RNP antibody-positive patients with central NPSLE. The major autoantigenic region for CSF anti-U1-70K antibodies appeared to be localized in U1-70K amino acid 141-164 residue within the RNA binding domain. CONCLUSION: The frequency of anti-U1 RNP antibodies in the CSF and the anti-U1 RNP index are useful indicators of central NPSLE in anti-U1 RNP antibody-positive patients. The predominance of anti-U1-70K antibodies in CSF suggests intrathecal anti-U1 RNP antibody production. PMID- 20722024 TI - Expansion of intestinal CD4+CD25(high) Treg cells in patients with ankylosing spondylitis: a putative role for interleukin-10 in preventing intestinal Th17 response. AB - OBJECTIVE: Subclinical gut inflammation has been demonstrated in patients with ankylosing spondylitis (AS). This study was undertaken to determine the frequency of regulatory CD4+CD25(high) T cells (Treg cells) and to evaluate Treg cell related cytokines (interleukin-2 [IL-2], transforming growth factor beta [TGFbeta], and IL-10) and transcription factors (FoxP3 and STAT-5) in the ileum of patients with AS. METHODS: Quantitative gene expression analysis, by reverse transcriptase-polymerase chain reaction, of Treg-related cytokines (IL-2, TGFbeta, and IL-10) and transcription factors (STAT-5 and FoxP3) was performed on ileal biopsy specimens from 18 patients with AS, 15 patients with active Crohn's disease (CD), and 15 healthy subjects. Tissue and circulating Treg cells were also analyzed by flow cytometry. RESULTS: A significant up-regulation of IL-2, TGFbeta, FoxP3, STAT-5, and IL-10 transcripts in the terminal ileum of AS patients displaying chronic ileal inflammation was observed. Flow cytometric analysis of Treg cells showed significant peripheral expansion in both patients with AS and chronic inflammation and patients with CD (mean +/- SD 1.08 +/- 0.4% and 1.05 +/- 0.3%, respectively) as compared with healthy subjects (0.25 +/- 0.12%) (P < 0.05). Interestingly, a 5-fold increase in the proportion of Treg cells was observed in the gut of patients with AS (5 +/- 3%) as compared with healthy subjects (1.2 +/- 0.4%) (P < 0.001), with 70-80% of these cells also producing IL-10. In vitro studies showed that blocking IL-10 was sufficient to induce Th17 polarization on lamina propria mononuclear cells isolated from AS patients. CONCLUSION: Our findings provide the first evidence that an active Treg cell response, mainly dominated by IL-10 production, occurs in the gut of AS patients and is probably responsible for the absence of a clear Th17 polarization in the ileum of AS patients. PMID- 20722025 TI - Exercise-induced pulmonary hypertension associated with systemic sclerosis: four distinct entities. AB - OBJECTIVE: Exercise-induced pulmonary hypertension (PH) may represent an early but clinically relevant phase in the spectrum of pulmonary vascular disease. There are limited data on the prevalence of exercise-induced PH determined by right heart catheterization in scleroderma spectrum disorders. We undertook this study to describe the hemodynamic response to exercise in a homogeneous population of patients with scleroderma spectrum disorders at risk of developing pulmonary vascular disease. METHODS: Patients with normal resting hemodynamics underwent supine lower extremity exercise testing. A classification and regression tree (CART) analysis was used to assess combinations of variables collected during resting right heart catheterization that best predicted abnormal exercise physiology, applicable to each individual subject. RESULTS: Fifty-seven patients who had normal resting hemodynamics underwent subsequent exercise right heart catheterization. Four distinct hemodynamic groups were identified during exercise: a normal group, an exercise-induced pulmonary venous hypertension (ePVH) group, an exercise out of proportion PH (eoPH) group, and an exercise induced PH (ePH) group. The eoPH and ePVH groups had higher pulmonary capillary wedge pressure (PCWP) than the ePH group (P < 0.05). The normal and ePH groups had exercise PCWP <=18 mm Hg, which was lower than that in the ePVH and eoPH groups (P < 0.05). During submaximal exercise, the transpulmonary gradient and pulmonary vascular resistance (PVR) were elevated in the ePH and eoPH groups as compared with the normal and ePVH groups (P < 0.05). CART analysis suggested that resting mean pulmonary artery pressure (mPAP) >=14 mm Hg and PVR >=160 dynes/seconds/cm(-5) were associated with eoPH and ePH (positive predictive value 89% for mPAP 14-20 mm Hg and 100% for mPAP >20 mm Hg). CONCLUSION: We characterized the exercise hemodynamic response in at-risk patients with scleroderma spectrum disorders who did not have resting PH. Four distinct hemodynamic groups were identified during exercise. These groups may have potentially different prognoses and treatment options. PMID- 20722026 TI - Efficacy, safety, and effects on blood pressure of naproxcinod 750 mg twice daily compared with placebo and naproxen 500 mg twice daily in patients with osteoarthritis of the hip: a randomized, double-blind, parallel-group, multicenter study. AB - OBJECTIVE: To test the superiority of naproxcinod compared with placebo in relieving the signs and symptoms of hip osteoarthritis and to assess the safety of naproxcinod and its effects on blood pressure. METHODS: In a 13-week, randomized, double-blind, parallel-group, multicenter study, 810 patients were randomized to receive either naproxcinod 750 mg twice daily, placebo, or naproxen 500 mg twice daily (2:2:1). Primary efficacy analyses compared naproxcinod and placebo using an analysis of covariance for 3 co-primary end points (the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain and function subscales and patient's overall rating of disease status). Safety assessments included adverse events and in-office blood pressure measurements. RESULTS: The least squares mean changes from baseline were significantly greater with naproxcinod than with placebo (P < 0.0001) and were similar to those with naproxen at week 13 for the WOMAC pain score (-25.81, -17.97, and -24.31 mm, respectively), the WOMAC function score (-22.24, -13.45, and -21.67 mm, respectively), and patient's rating of disease status (0.86, 0.51, and 0.82, respectively). Changes from baseline in systolic blood pressure were similar in the naproxcinod and placebo groups at weeks 2, 6, and 13 (differences between groups of 0.25, -0.45, and -0.11 mm Hg, respectively). Changes in the naproxen group were greater than those in the placebo group (differences of 3.11, 3.03, and 2.00 mm Hg, respectively). Systolic blood pressure increases >=10 mm Hg from baseline to week 13 occurred in 13.3%, 15.0%, and 20.3% of patients receiving naproxcinod, placebo, and naproxen, respectively. Naproxcinod and naproxen had similar adverse event and general safety profiles. CONCLUSION: The efficacy of naproxcinod for treating the signs and symptoms of hip osteoarthritis was statistically superior to that of placebo and similar to that of naproxen. Naproxcinod was well tolerated, with effects on systolic blood pressure similar to those of placebo. PMID- 20722028 TI - Clinical images: Divergent patterns of joint remodeling following effective urate lowering therapy in tophaceous gout. PMID- 20722029 TI - Risk factors for severe Muckle-Wells syndrome. AB - OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease resulting in excessive interleukin-1 release. It is unknown whether demographic, clinical, or laboratory characteristics at the time of diagnosis may identify patients who are at high risk for severe disease activity. This study was undertaken to analyze clinical and laboratory features of MWS, compare genetically defined subcohorts, and identify risk factors for severe MWS. METHODS: A multicenter cohort study of consecutive MWS patients was performed. Parameters assessed included clinical features, MWS Disease Activity Score (MWS DAS), inflammation markers, and cytokine levels. E311K mutation-positive patients were compared with E311K mutation-negative patients. Putative risk factors for severe MWS (defined as an MWS-DAS score of >=10) were assessed in univariate analyses, and significant predictors were entered into a multivariate model. RESULTS: Thirty-two patients (15 male and 17 female) were studied. The most frequent organ manifestations were musculoskeletal symptoms and eye and skin disorders. Renal disease and hearing loss were seen in >50% of the patients. Genetically defined subcohorts had distinct phenotypes. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis were female sex, hearing loss, musculoskeletal disease, increased erythrocyte sedimentation rate, and low hemoglobin level. Female sex and hearing loss remained significant after adjustment for age in a multivariate model (relative risk 1.8 and 2.6, respectively). CONCLUSION: MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high-risk group. PMID- 20722027 TI - Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain. AB - OBJECTIVE: To investigate the impact of an experimental model of osteoarthritis (OA) on spinal nociceptive processing and the role of the inhibitory endocannabinoid system in regulating sensory processing at the spinal level. METHODS: Experimental OA was induced in rats by intraarticular injection of sodium mono-iodoacetate (MIA), and the development of pain behavior was assessed. Extracellular single-unit recordings of wide dynamic range (WDR) neurons in the dorsal horn were obtained in MIA-treated rats and saline-treated rats. The levels of endocannabinoids and the protein and messenger RNA levels of the main synthetic enzymes for the endocannabinoids (N-acyl phosphatidylethanolamine phospholipase D [NAPE-PLD] and diacylglycerol lipase alpha [DAGLalpha]) in the spinal cord were measured. RESULTS: Low-weight (10 gm) mechanically evoked responses of WDR neurons were significantly (P < 0.05) facilitated 28 days after MIA injection compared with the responses in saline-treated rats, and spinal cord levels of anandamide and 2-arachidonoyl glycerol (2-AG) were increased in MIA treated rats. Protein levels of NAPE-PLD and DAGLalpha, which synthesize anandamide and 2-AG, respectively, were elevated in the spinal cords of MIA treated rats. The functional role of endocannabinoids in the spinal cords of MIA treated rats was increased via activation of cannabinoid 1 (CB(1) ) and CB(2) receptors, and blockade of the catabolism of anandamide had significantly greater inhibitory effects in MIA-treated rats compared with control rats. CONCLUSION: Our findings provide new evidence for altered spinal nociceptive processing indicative of central sensitization and for adaptive changes in the spinal cord endocannabinoid system in an experimental model of OA. The novel control of spinal cord neuronal responses by spinal cord CB(2) receptors suggests that this receptor system may be an important target for the modulation of pain in OA. PMID- 20722030 TI - Bone histomorphometric analysis of SAPHO syndrome with sternoclavicular hyperostosis. PMID- 20722031 TI - Long-term impact of delay in assessment of patients with early arthritis. AB - OBJECTIVE: During the last decade, rheumatologists have learned to initiate disease-modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed. METHODS: A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD-free remission, and the rate of joint destruction over 6 years followup were determined. RESULTS: The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in >=12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in <12 weeks. Older age, female sex, gradual symptom onset, involvement of the small joints, lower levels of C-reactive protein, and the presence of autoantibodies were associated with longer total delay. CONCLUSION: Only 31% of the RA patients were assessed in <12 weeks of symptom onset. Assessment in <12 weeks is associated with less joint destruction and a higher chance of achieving DMARD-free remission as compared with a longer delay in assessment. These results imply that attempts to diminish the delay in seeing a rheumatologist will improve disease outcome in patients with RA. PMID- 20722032 TI - Delay in receiving rheumatology care leads to long-term harm. PMID- 20722033 TI - The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1. AB - OBJECTIVE: To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA). METHODS: Published autoimmune disease genome-wide association studies were reviewed, and 519 single-nucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Meta-analysis results for the replicating loci included PTPN22 (rs6679677 [OR 1.58, P = 1.98 * 10(-12) ], rs2476601 [OR 1.64, P = 1.90 * 10(-13) ], and rs2488457 [OR 1.32, P = 6.74 * 10( 8) ]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 * 10(-9) ] and rs7234029 [OR 1.35, P = 1.86 * 10(-10) ]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 * 10(-6) ] and rs13143866 [OR 0.83, P = 1.95 * 10(-4) ]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 * 10(-6) ] and rs7574865 [OR = 1.31, P = 2.21 * 10(-6) ]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 * 10(-5) ]), COG6 (rs7993214 [OR = 0.76, P = 1.10 * 10(-5) ]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 * 10(-4) ]). These polymorphisms have been reported in diseases such as rheumatoid arthritis, type 1 diabetes mellitus, Crohn's disease, and multiple sclerosis. CONCLUSION: General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms. PMID- 20722034 TI - The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats. AB - OBJECTIVE: To explore the effect of bortezomib in splenocytes and fibroblast-like synoviocytes (FLS) and its in vivo potency in a rat model of adjuvant-induced arthritis (AIA), which resembles human rheumatoid arthritis (RA). METHODS: AIA was induced with Freund's complete adjuvant. Splenocyte and FLS proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively. The invasiveness of FLS from rats with AIA was tested in a Transwell system. The pattern of cytokine secretion was evaluated by cytometric bead array in splenocyte supernatants. Bortezomib was administered prophylactically or therapeutically, and arthritis was assessed clinically and histologically. Immunohistochemistry was performed for markers of inflammation and angiogenesis in joints. Hematologic and biochemical parameters were tested in peripheral blood (PB). Representative animals were examined by computed tomography (CT) scanning before and after bortezomib administration. The expression of Toll-like receptor 2 (TLR-2), TLR-3, and TLR-4 in PB and FLS was measured by real-time polymerase chain reaction, and alterations in specific cell populations in PB and spleen were determined by flow cytometry. RESULTS: In vitro, bortezomib exhibited significant inhibitory and proapoptotic activity in splenocytes and FLS from rats with AIA, altered the inflammatory cytokine pattern, and reduced the invasiveness of FLS from rats with AIA. In vivo, bortezomib significantly ameliorated disease severity. Remission was associated with improved histology and decreased expression of CD3, CD79a, CD11b, cyclooxygenase 1, and factor VIII in target tissues as well as down-regulation of TLR expression in PB and cultured FLS. CT scanning demonstrated a bone healing effect after treatment. CONCLUSION: Our findings suggest that bortezomib affects AIA in a pleiotropic manner and that this drug may be effective in RA. PMID- 20722035 TI - Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis. AB - OBJECTIVE: Interleukin-20 (IL-20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti-IL-20 antibody treatment would modulate the severity of the disease in a collagen induced arthritis (CIA) rat model. METHODS: We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti-IL-20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme linked immunosorbent assay. To analyze gene regulation by IL-20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL-17, and TNFalpha. We also used real-time quantitative polymerase chain reaction analysis and flow cytometry to determine IL-20-regulated RANKL in mouse osteoblastic MC3T3-E1 cells and Th17 cells. RESULTS: In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL-20, IL-1beta, IL-6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL-20 induced TNFalpha expression in SFs from rats with CIA. IL-20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells. CONCLUSION: Selectively blocking IL-20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL-20 is a novel target and that 7E may be a potential therapeutic agent for RA. PMID- 20722036 TI - A case of progressive multifocal leukoencephalopathy in a patient treated with infliximab. AB - We describe a 72-year-old white man with erosive rheumatoid arthritis in whom subacute neurologic and psychiatric symptoms developed after 3 years of treatment with infliximab, prednisone, and methotrexate. White matter demyelination was seen on magnetic resonance imaging of the brain, and progressive multifocal leukoencephalopathy (PML) was ultimately confirmed by brain biopsy. The patient was treated with supportive therapy and discontinuation of disease-modifying antirheumatic drugs, resulting in stabilization of the disease process. The patient survived, but neurologic and cognitive deficits persisted. The distribution and pathology of this patient's disease are unique from almost all reported incidents of oral methotrexate-associated leukoencephalopathy. The pathogenesis of disease may be linked to a T cell-mediated process that is potentially impacted by infliximab. This case provides the first reported evidence that PML can be seen in association with infliximab therapy. PMID- 20722037 TI - Clinical images: multi-modality imaging monitoring of anti-tumor necrosis factor alpha treatment at the joint and skin level in psoriatic arthritis. PMID- 20722038 TI - Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus. AB - OBJECTIVE: CXCR4 is a chemokine with multiple effects on the immune system. In murine lupus models, we demonstrated that monocytes, neutrophils, and B cells overexpressed CXCR4 and that its ligand, CXCL12, was up-regulated in diseased kidneys. We undertook this study to determine whether CXCR4 expression was increased in peripheral blood leukocytes from patients with systemic lupus erythematosus (SLE) and whether CXCL12 expression was increased in kidneys from patients with SLE. METHODS: Peripheral blood leukocytes from 31 SLE patients, 8 normal controls, and 9 patients with rheumatoid arthritis were prospectively analyzed by flow cytometry for CXCR4 expression. Biopsy samples (n = 14) from patients with lupus nephritis (LN) were immunostained with anti-CXCL12 antibody. RESULTS: CD19+ B cells and CD4+ T cells from SLE patients displayed a >2-fold increase (P = 0.0001) and >3-fold increase (P < 0.0001), respectively, in median CXCR4 expression compared with that in controls (n = 7-8). Moreover, CXCR4 expression on B cells was 1.61-fold higher in patients with SLE Disease Activity Index (SLEDAI) scores >10 (n = 8) than in patients with SLEDAI scores <=10 (n = 16) (P = 0.0008), 1.71-fold higher in patients with class IV LN (n = 5) than in patients with other classes of LN (n = 7) (P = 0.02), and 1.40-fold higher in patients with active neuropsychiatric SLE (NPSLE) (n = 6) than in patients with inactive NPSLE (n = 18) (P = 0.01). CXCL12 was significantly up-regulated in the tubules and glomeruli of kidneys in patients with LN (n = 14), with the percentage of positive cells correlating positively with the severity of LN. CONCLUSION: CXCR4 appears to be up-regulated in multiple leukocyte subsets in SLE patients. The heightened expression of CXCR4 on B cells in active NPSLE and of CXCL12 in nephritic kidneys suggests that the CXCR4/CXCL12 axis might be a potential therapeutic target for SLE patients with kidney and/or central nervous system involvement. PMID- 20722039 TI - The yeast ubiquitin-like domain protein Mdy2 is required for microtubule-directed nuclear migration and localizes to cytoplasmic granules in response to heat stress. AB - MDY2 encodes a ubiquitin-like (UBL)-domain protein necessary for efficient mating in Saccharomyces cerevisiae. Unlike most UBL proteins, Mdy2 is apparently not subject to C-terminal processing and is localized predominantly in the nucleus. Deletion of MDY2 is associated with a five- to seven-fold reduction in mating efficiency, mainly due to defects in nuclear migration and karyogamy at the prezygotic stage. Here, we looked for two potential interacting partners of Mdy2, investigated the function of Mdy2 in nuclear movement, determined the increased heat sensitivity defects of mdy2Delta mutants, and inspected localization of Mdy2. Coprecipitation studies show that Mdy2 associates with alpha-tubulin and with the microtubule (MT)-associated dynactin subunit p150(Glued)/Nip100. nip100Delta mutants exhibit no defects in nuclear migration or in MT length or orientation during shmooing growth. Deletion of MDY2 display small nuclear migration phenotype during vegetative growth and seems to exacerbate the defects in mitotic nuclear migration seen in the nip100Delta strain. Deletion of MDY2 increased heat sensitivity of the cells and these strains accumulate mitotic nuclear migration defects and shortened MTs under these conditions. GFP-Mdy2 proteins which are localized predominantly in the nucleus at permissive temperature are localized to cytoplasmic foci during heat shock. Colocalization studies revealed that heat stress-induced enrichment of Mdy2 in cytoplasmic foci merged mainly with stress granules marker Pab1. During glucose deprivation a minority of Mdy2 foci overlapped with P-bodies marker Dcp2, while most Mdy2 foci and Pab1 foci overlap. Accordingly, we propose that Mdy2 plays a critical role in the MT-dependent processes of karyogamy and stress response. PMID- 20722040 TI - Do spouses know how much fatigue, pain, and physical limitation their partners with rheumatoid arthritis experience? Implications for social support. AB - OBJECTIVE: To determine whether perceptions of clinical manifestations (fatigue, pain, and physical limitation) of rheumatoid arthritis (RA) differ between spouses and their partners with RA, and to determine whether the differences are associated with the perception of beneficial and problematic spousal social support. METHODS: English-speaking adults with RA of >= 6 months' duration and their spouses (n = 222 couples) completed standardized questionnaires for fatigue, pain, physical limitation, beneficial spousal support, and problematic spousal support. Spouses completed questionnaires based on their perception of their partner with RA. Agreement scores for fatigue, pain, and physical limitation were calculated by subtracting spouse scores from the scores of the partner with RA. Agreement levels were defined a priori: agreement (within +/- one-half of a minimum clinically important difference [MCID] unit), overestimator (< one-half an MCID), and underestimator (> one-half an MCID). Separate hierarchical linear regression models were used to measure the association between beneficial support and problematic support after adjusting for RA duration, physical health, sex, educational level, relationship duration, and satisfaction. RESULTS: Response rate for couples was 82%. Relative to participants with RA, spouses overestimated fatigue (26%), pain (29%), and physical limitation (39%), and underestimated fatigue (11%), pain (17%), and physical limitation (34%). After statistically controlling for demographic, disease, and psychosocial variables, participants with RA whose spouses underestimated fatigue received more problematic support (R(2) = 3.7%, P = 0.002), as did those whose spouses underestimated or overestimated physical limitation (R(2) = 3.4%, P = 0.017). CONCLUSION: Persons with RA perceived more problematic spousal support when their spouse underestimated fatigue, or underestimated or overestimated physical limitation levels. PMID- 20722041 TI - Ensuring quality of care through implementation of a competency-based musculoskeletal education framework. PMID- 20722042 TI - Emotional, physical, and sexual abuse in fibromyalgia syndrome: a systematic review with meta-analysis. AB - OBJECTIVE: To systematically assess the potential association of fibromyalgia syndrome (FMS) with emotional, physical, and sexual abuse. METHODS: The databases EMBase, Google Scholar, Medline, and PsycINFO (through April 2010) and the reference sections of original studies were searched for eligible studies. Eligible studies were cohort or case--control studies that assessed at least one type of emotional, physical, or sexual abuse in childhood or adulthood in patients with FMS and in controls. Two authors independently extracted descriptive, quality, and outcome data from included studies. Methodologic quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were pooled across studies by using the random-effects model. Heterogeneity was assessed by I(2) statistics. RESULTS: The search identified 18 eligible case-control studies with 13,095 subjects. There were significant associations between FMS and self-reported physical abuse in childhood (OR 2.49 [95% CI 1.81-3.42], I(2) = 0%; 9 studies) and adulthood (OR 3.07 [95% CI 1.01-9.39], I(2) = 79%; 3 studies), and sexual abuse in childhood (OR 1.94 [95% CI 1.36-2.75], I(2) = 20%; 10 studies) and adulthood (OR 2.24 [95% CI 1.07-4.70], I(2) = 64%; 4 studies). Study quality was mostly poor. Low study quality was associated with higher effect sizes for sexual abuse in childhood, but not with other effect sizes. CONCLUSION: The association of FMS with physical and sexual abuse could be confirmed, but is confounded by study quality. PMID- 20722043 TI - Visions: the art of science. PMID- 20722045 TI - Selective synthesis of N-alkyl hydroxylamines by hydrogenation of nitroalkanes using supported palladium catalysts. PMID- 20722044 TI - MLCK-independent phosphorylation of MLC20 and its regulation by MAP kinase pathway in human bladder smooth muscle cells. AB - Myosins are a superfamily of actin-based molecular motor proteins, which hydrolyze ATP and generate various forms of eukaryotic motility and muscle contraction. Myosin light chain 20 (MLC20) is small ring around the neck region of heavy chain of myosins. Phosphorylation of MLC20 is thought to play a key role in regulation of smooth muscle contraction. Calcium- and calmodulin-dependent myosin light chain kinase (MLCK) is considered the primary regulator of MLC20 phosphorylation. However, several observations in smooth muscle contraction cannot be explained by the mode of phosphorylation. By performing a series of experiments in vitro and in vivo, we report here MLCK-independent MLC20 phosphorylation. Gene expression study reveals that expression of MLCK in smooth muscles is inconsistent with MLC20 phosphorylation at Ser19. None of inactivating calmodulin/MLCK, depriving of calcium and silencing MLCK expression by siRNA blocks effectively the phosphorylation of MLC20 at Ser19. In addition, by overexpressing active human MAP (mitogen-activated protein)-ERK kinase kinase-1 (MEKK1) and blocking its downstream messengers, we have demonstrated a new regulatory system of MLC phosphorylation via MEKK1, which downregulates Ser19 phosphorylation of MLC20 through its downstream molecules, p38, JNK, and ERK in human bladder smooth muscle cells. PMID- 20722046 TI - Assessment of the natural history of forefoot bursae using ultrasonography in patients with rheumatoid arthritis: a twelve-month investigation. AB - OBJECTIVE: To determine the natural history and clinical significance of forefoot bursae over a 12-month period in patients with rheumatoid arthritis (RA). METHODS: Patients with RA (n=149) attending rheumatology outpatient clinics were assessed at baseline. A total of 120 participants, mean+/-SD age 60.7+/-12.1 years and mean+/-SD disease duration 12.99+/-10.4 years, completed the 12-month followup (98 women, 22 men, 93 rheumatoid factor positive, 24 rheumatoid factor negative, and 3 unknown). Musculoskeletal ultrasound (US) was used to identify forefoot bursae in all of the participants. Clinical markers of disease activity (well-being visual analog scale [VAS], erythrocyte sedimentation rate [ESR], C reactive protein [CRP] level, and Disease Activity Score in 28 joints [DAS28]) and foot symptoms on the Leeds Foot Impact Scale (LFIS) Questionnaire were recorded on both occasions. RESULTS: Presence of US-detectable forefoot bursae was identified in 93.3% of returnee (n=120) participants (individual mean 3.7, range 0-11) at baseline. Significant associations were identified between bursae presence and patient-reported foot impact for impairment/footwear (LFISIF ; baseline: r=0.226, P=0.013 and 12 months: r=0.236, P=0.009) and activity limitation/participation restriction (LFISAP; baseline: r=0.254, P=0.005 and 12 months: r=0.235, P=0.010). After 12 months, 42.5% of participants had an increase in the number of US-detectable forefoot bursae and 45% of participants had a decrease. Changes in bursae number significantly correlated with changes in LFISIF (r=0.216, P=0.018) and LFISAP (r=0.193, P=0.036). No significant associations were identified between changes in bursae and changes in global well being VAS, ESR, CRP level, or DAS28. CONCLUSION: The findings of this study suggest that forefoot bursae may regress or hypertrophy over time in patients with RA, and that these changes may be associated with self-reported foot impairment and activity restriction. PMID- 20722047 TI - Intravenous immunoglobulins for steroid-refractory esophageal involvement related to polymyositis and dermatomyositis: a series of 73 patients. AB - OBJECTIVE: To assess the long-term outcome of esophageal complications in the group of patients receiving intravenous immunoglobulins (IVIG) for the treatment of severe steroid-refractory esophageal involvement related to polymyositis/dermatomyositis (PM/DM). METHODS: We retrospectively reviewed the medical records of 73 patients (39 with PM, 34 with DM) with steroid-resistant esophageal involvement. Esophageal involvement was evaluated by clinical and manometric investigations. RESULTS: Seventy-three patients with steroid refractory esophageal involvement related to PM/DM received IVIG therapy (2 gm/kg monthly). The median interval between PM/DM diagnosis and the onset of esophageal complications was 6 months. The most common clinical manifestations revealing esophageal dysfunction were dysphagia (69.9%), coughing while eating (61.6%), and gastroesophageal reflux into the pharynx and/or mouth (34.2%). Twenty-five patients exhibited life-threatening esophageal complications requiring exclusive enteral feeding; 33 patients (45.2%) with esophageal impairment developed aspiration pneumonia. Sixty patients (82.2%) exhibited resolution of esophageal clinical manifestations, leading to a return to normal oral feeding and ablation of feeding enteral tubes. Four other patients (5.5%) improved, although they still experienced mild dysphagia intermittently. Because of impaired cricopharyngeal muscle relaxation, another patient successfully underwent cricopharyngeal myotomy. Eight patients died from aspiration pneumonia (n=6) and cancer (n=2). Muscle weakness, thoracic myopathy, and aspiration pneumonia were independent predictive factors of IVIG-treated esophageal complications in PM/DM patients. CONCLUSION: Our findings indicate that IVIG should be considered in life-threatening esophageal impairment complicating steroid-resistant PM/DM. We also suggest that combined therapy of IVIG and high-dose steroids may be the first-line therapy in PM/DM patients with life-threatening esophageal manifestations. PMID- 20722048 TI - Thyroid hormone and reproduction: regulation of estrogen receptors in goldfish gonads. AB - There is increasing evidence that thyroid hormones influence reproduction in vertebrates. However, little information is available on the mechanisms by which this happens. As a first step in determining these mechanisms, we test the hypothesis that the estrogen receptor subtypes (ERalpha, ERbeta-1, and ERbeta-2) are regulated by the thyroid hormone, (T(3)), in the gonads of goldfish. All three subtypes were down-regulated by T(3) in the testis or ovary. We also found evidence that T(3) decreased pituitary gonadotropin expression and decreased transcript for gonadal aromatase. Collectively, it appears that T(3) acts to diminish estrogen signaling by (1) decreasing pituitary LH expression and thus steroidogenesis, (2) down-regulating gonadal aromatase expression and thus decreasing estrogen synthesis from androgens, and (3) decreasing sensitivity to estrogen by down-regulating the ER subtypes. Goldfish are seasonal breeders, spawning once a year, and thus have two distinct periods of growth: somatic and reproductive. Circulating thyroid hormone levels have been found to increase just after spawning. Therefore, we propose that this may be an endocrine mechanism that goldfish use to switch their energy expenditure from reproductive to growth efforts in the goldfish. PMID- 20722049 TI - Induction of primordial germ cells from mouse induced pluripotent stem cells derived from adult hepatocytes. AB - Pluripotent stem cells can be established by various methods, but they share several cytological properties, including germ cell differentiation in vitro, independently of their origin. Although mouse induced pluripotent stem (iPS) cells can produce functional gametes in vivo, it is still unclear whether or not they have the ability to produce presumptive germ cells in vitro. Here, we show that mouse iPS cells derived from adult hepatocytes were able to differentiate into presumptive germ cells marked by mouse vasa homolog (Mvh) expression in feeder-free or suspension cultures. Embryoid body (EB) formation from iPS cells also induced the formation of round-shaped cells resembling immature oocytes. Mvh(+) cells formed clumps by co-aggregation with differentiation-supporting cells, and increased expression of germ cell markers was detected in these cell aggregates. Differentiation culture of presumptive germ cells from iPS cells could provide a conventional system for facilitating our understanding of the mechanisms underlying direct reprogramming and germline competency. PMID- 20722050 TI - Progressive drawing: A novel "lid-opener" and "monotony-breaker". AB - An innovative strategy called "progressive drawing" was used at the beginning (lid-opener) and later (monotony-breaker) during gross anatomy lectures. Diagrams were drawn on the classroom blackboard with anatomic structures added one by one. Students identified and labeled the diagrams and predicted the next structures to be drawn. Students felt that the strategy helped to activate prior knowledge, created interest in the current lecture, and made lecture sessions more interactive. The strategy has appeal for visual, auditory, read/write, and kinesthetic learners. PMID- 20722051 TI - IgG4-associated pouchitis. PMID- 20722052 TI - Role of different inflammatory and tumor biomarkers in the development of ulcerative colitis-associated carcinogenesis. AB - BACKGROUND: Colorectal cancer (CRC) is the most severe complication in inflammatory bowel disease (IBD). In the present study we investigated different mechanistic links between chronic colonic inflammation and its progression to adenocarcinoma. Along these lines, given that adrenomedullin (AM) has been implicated in carcinogenesis, we also analyzed changes in its colonic expression. METHODS: Mice were exposed to 5, 10, and 15 cycles of dextran sulfate sodium (DSS); each cycle consisted of 0.7% DSS for 1 week followed by distilled water for 10 days. After each period, macroscopic and histological studies, as well as characterization of inflammatory and tumor biomarkers, were carried out. RESULTS: The disease activity index (DAI) showed that the disease was present from the third cycle and it gradually increased during the course of DSS treatment. Macroscopic tumors were only seen after 15 cycles, and microscopic study showed that inflammation, dysplasia, and adenocarcinomas correlated with DSS cycles. beta-Catenin and proliferating cell nuclear antigen expressions progressively increased in animals treated with the different cycles of DSS. TNF-alpha and IFN gamma showed the highest production at the tenth cycle. COX-2, mPGES-1, and iNOS levels were also appreciably higher at the fifth and tenth cycles. Moreover, we observed a progressive enhancement in AM expression and changes in its intracellular location during the progression of the disease. CONCLUSIONS: Our results show an early induction of proinflammatory factors, which may contribute to the development of colon cancer, as well as demonstrate, for the first time, the expression of AM in IBD-derived CRC. PMID- 20722053 TI - Which magnetic resonance imaging findings accurately evaluate inflammation in small bowel Crohn's disease? A retrospective comparison with surgical pathologic analysis. AB - BACKGROUND: The aim was to evaluate the value of magnetic resonance imaging (MRI) findings in Crohn's disease (CD) in correlation with pathological inflammatory score using surgical pathology analysis as a reference method. METHODS: CD patients who were to undergo bowel resection surgery underwent MR enterography before surgery. The CD pathological inflammatory score of the surgical specimens was classified into three grades: mild or nonactive CD, moderately active CD, and severely active CD; fibrosis was also classified into three grades: mild, moderate, and severe. Mural and extramural MRI findings were correlated with pathological inflammatory and fibrosis grades. RESULTS: Fifty-three consecutive patients were included retrospectively. The mean delay between MRI and surgery was 24 days (range 1-90, median 14). The CD pathological inflammatory score was graded as follows: grade 0 (11 patients, 21%), grade 1 (15 patients, 28%), and grade 2 (27 patients, 51%). MRI findings significantly associated with pathological inflammatory grading were wall thickness (P < 0.0001), degree of wall enhancement on delayed phase (P < 0.0001), pattern of enhancement on both parenchymatous (P = 0.02), and delayed phase, (P = 0.008), T2 relative hypersignal wall (P < 0.0001), blurred wall enhancement (P = 0.018), comb sign (P = 0.004), fistula (P < 0.0001), and abscess (P = 0.049). The inflammation score correlated with the fibrosis score (r = 0.63, P = 0.0001). CONCLUSIONS: Our study identified MRI findings significantly associated with surgical pathological inflammation. These lesions are considered potentially reversible and may be efficiently treated medically. We also showed that fibrosis was closely and positively related to inflammation. PMID- 20722054 TI - Blockade of LTB(4) /BLT(1) pathway improves CD8(+) T-cell-mediated colitis. AB - BACKGROUND: Leukotriene B4 (LTB(4) ) has chemotactic properties for activated T cells expressing the high-affinity receptor BLT(1) . This study investigated whether the LTB(4) antagonist (CP-105,693), selective for BLT(1) receptor, could protect mice from colitis mediated by specific cytotoxic CD8(+) T lymphocytes (CTL). METHODS: Virus-specific colitis was induced in C57Bl/6 mice transferred with lymphoid cells from P14 TcR Tg mice which are specific to class I GP33 peptide of LCMV. Mice were immunized with GP33-pulsed dendritic cells and colitis was elicited by intrarectal administration of the peptide. Colitis was evaluated by body weight loss and macroscopic and histological analysis of colon. In vivo priming of specific CD8(+) CTL was determined using interferon (IFN)-gamma ELISPOT and in vivo CTL assays. In some experiments mice were treated with a selective LTB(4) receptor antagonist. RESULTS: Immunization with GP33-pulsed dendritic cells (DCs) induced priming of specific CD8(+) CTL, as shown by the presence of IFN-gamma-producing CD8(+) T cells in colon draining lymph nodes and in vivo CTL assays. Intrarectal challenge with GP33 induced severe colitis and recruitment of granzyme B(+) P14 CD8(+) cells in colon. Treatment with the specific LTB(4) receptor antagonist before elicitation of colitis reduced the severity of colitis and decreased the frequency of specific effectors. CONCLUSIONS: Colitis can be induced by IFN-gamma-producing cytotoxic CD8(+) CTL specific for viral antigen. Blockade of the LTB(4) /BLT(1) pathway by a selective BLT(1) receptor antagonist attenuates colitis by inhibiting CD8(+) effectors recruitment in colon. These data illustrate the therapeutic potential of LTB(4) receptor selective antagonists in protection from CD8(+) T-cell-mediated intestinal inflammation. PMID- 20722055 TI - Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid-refractory colitis. AB - BACKGROUND: Children with severe corticosteroid-resistant ulcerative colitis either need to undergo surgery or be treated with more intensive immunosuppression. Our aim was to characterize the short- and long-term outcomes and adverse events associated with the use of tacrolimus in a steroid-refractory pediatric population. METHODS: We retrospectively reviewed the medical records of 46 children with steroid-refractory colitis treated with tacrolimus at Children's Hospital Boston between 1994 and 2008. Oral tacrolimus was initiated at a dose of 0.1 mg/kg twice a day and titrated to yield trough levels of 10-15 ng/mL for induction, and 5-10 ng/mL once in remission. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. RESULTS: Ninety-three percent of patients were discharged without undergoing surgery. The median length of stay after starting tacrolimus was 10 days (range 4-37 days). The mean PUCAI score was 68 +/- 13 prior to initiating tacrolimus, and 27 +/- 18 at the time of hospital discharge. The probability of avoiding colectomy after starting tacrolimus was 40% at 26 months. The most common adverse events included hypertension (52%) and tremor (44%). There was one seizure and no deaths. CONCLUSIONS: Tacrolimus is useful as induction therapy in pediatric patients with corticosteroid-refractory colitis and side effects are generally mild and reversible. Despite these findings, many patients develop exacerbations of colitis upon transition to maintenance therapies. The long-term colectomy rate in this challenging population remains ~60% over time. PMID- 20722056 TI - Cytokine regulation of OCTN2 expression and activity in small and large intestine. AB - BACKGROUND: The organic cation transporter OCTN2 is located on the IBD5 risk allele and has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). OCTN2 is expressed in the apical membrane and transports many solutes including bacteria-derived mediators that may be involved in host-microbial interactions. To explore its role further, we examined potential regulatory factors in human IBD and in experimental models of OCTN2 expression. METHODS: Human colonic epithelial cells (Caco2BBE) were used to investigate the effects of inflammatory mediators on OCTN2 activity and expression. Apical membrane expression of OCTN2 was assessed by surface biotinylation. Rag-1(-/-) -deficient mice were used to determine the potential role of adaptive immune cells in the regulation of OCTN2 expression. C57Bl/6 mice were treated with the cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) to determine the effects on OCTN2 expression and activity. OCTN2 expression in human IBD specimens was assessed by Western blotting and immunohistochemistry. RESULTS: OCTN2 activity and expression are regulated by the state of intestinal inflammation. OCTN2 expression in colonic tissues of Rag-1(-/-) -deficient mice was reduced. Treatment with IFN-gamma and TNF-alpha increased intestinal OCTN2 expression, particularly in the colon. IFN-gamma increased both total and apical membrane expression of Caco2BBE OCTN2, whereas TNF-alpha stimulated apical expression. Colonic epithelial OCTN2 expression was increased in actively inflamed areas of both Crohn's disease and ulcerative colitis. CONCLUSIONS: Intestinal epithelial OCTN2 expression is increased by intestinal inflammation, most likely through increased levels of proinflammatory cytokines. These findings suggest that OCTN2 may participate to restoration of intestinal homeostasis under conditions of inflammation-associated stress. PMID- 20722057 TI - Amelioration of excess collagen IalphaI, fibrosis, and smooth muscle growth in TNBS-induced colitis in IGF-I(+/-) mice. AB - BACKGROUND: Strictures occur in ~ 30% of patients with Crohn's disease (CD) and are characterized by intestinal smooth muscle hyperplasia, hypertrophy, and fibrosis due to excess extracellular matrix production including collagen. Insulin-like growth factor-I (IGF-I) expression is increased in smooth muscle cells of the muscularis propria in CD and in animal models of CD, including trinitrobenzene sulfonic acid (TNBS)-induced colitis. While upregulated IGF-I is conjectured to cause smooth muscle cell growth and collagen production in the inflamed intestine, its role in the development of fibrosis has not been directly demonstrated. METHODS: Colitis was induced in IGF-I(+/-) or wildtype C57BL/6J mice by rectal administration of TNBS or ethanol vehicle. After 7 days, colonic smooth muscle cells were isolated and used to prepare RNA or protein lysates. Transcript levels of IGF-IEa, IGF binding protein (IGFBP)-3, IGFBP-5, TGF-beta1, and collagen IalphaI were measured by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Corresponding protein levels were measured by Western blot or enzyme-linked immunosorbent assay (ELISA). Fibrosis was measured using digital image analysis of Masson's trichrome-stained histologic sections. RESULTS: In IGF-I(+/-) mice, which express significantly lower levels of IGF-I than wildtype, the response to TNBS-induced colitis: upregulation of IGF-I, IGFBP 3, IGFBP-5 muscle growth, and collagen IalphaI expression, the resulting collagen deposition, and fibrosis are all significantly diminished compared to C57BL/6J wildtype controls. TGF-beta1 expression and its increase following TNBS administration are not altered in IGF-I(+/-) mice compared to wildtype. CONCLUSIONS: The findings indicate that IGF-I is a key regulator in intestinal smooth muscle hyperplasia and excess collagen production that leads to fibrosis and long term to stricture formation. PMID- 20722059 TI - Crohn's disease: ingested matter matters. PMID- 20722058 TI - Highlighting new phylogenetic specificities of Crohn's disease microbiota. AB - BACKGROUND: Recent studies suggest that gastrointestinal (GI) microbes play a part in the pathogenesis of Crohn's disease (CD). METHODS: Fecal samples were collected from 16 healthy individuals and 16 CD patients (age- and sex-matched). The DNA extracted from these samples were subjected to two different methods of microbiome analysis. Specific bacterial groups were quantified by real-time polymerase chain reaction (PCR) methods using primers designed using a high throughput in-house bioinformatics pipeline. The same DNA extracts were also used to produce fluorescently labeled cRNA amplicons to interrogate a custom-designed phylogenetic microarray for intestinal bacteria. RESULTS: Even though the intersubject variability was high, differences in the fecal microbiomes of healthy and CD patients were detected. Faecalibacterium prausnitzii and Escherichia coli were more represented in healthy and ileal CD patients, respectively. Additionally, probes specific for Ruminococcus bromii, Oscillibacter valericigenes, Bifidobacterium bifidum, and Eubacterium rectale produced stronger hybridization signals with the DNA samples from healthy subjects. Conversely, species overrepresented in CD patients were E. coli, Enterococcus faecium, and species from the Proteobacteria not normally found in the healthy human GI tract. Furthermore, we detected "healthy specific" molecular species or operational taxonomic units (OTUs) that are not closely related to any known species (Faecalibacterium, Subdoligranulum, and Oscillospora species), indicating that the phylogenetic dysbiosis is broader than at strain or species level. CONCLUSIONS: These two techniques of microbiome analysis provided a statistically robust new picture of the dysbiosis in fecal microbiota from ileal CD patients. Specifically, we identified a set of six species discriminant for CD, which provides a preliminary diagnostic tool. PMID- 20722060 TI - Different clinical characteristics in Hispanic and non-Hispanic whites with ileal pouch-anal anastomosis: a case-control study. AB - BACKGROUND: Inflammatory bowel disease (IBD) is increasingly diagnosed in ethnic and racial minorities. Ileal pouch-anal anastomosis (IPAA) has become the treatment of choice for ulcerative colitis (UC) patients requiring surgery. Few studies have characterized the natural history of IPAA and the pouch outcomes in the Hispanic American population. METHODS: Ethnicity was designated by self report and the Hispanics who had IPAA for UC were identified from a prospectively maintained database. Demographics, clinical characteristics, and pouch outcomes were compared between Hispanic and a sample of Non-Hispanic whites (1:4 ratio) randomly selected from the same database. Exclusion criteria were patients with a preoperative diagnosis of Crohn's disease or familial adenomatous polyposis, and patients of other ethnic groups. RESULTS: Thirty-six Hispanics with IPAA were identified. Hispanic patients were younger at UC diagnosis 23.1 +/- 13.1 vs. 30.4 +/- 12.6 yrs and at colectomy 31.9 +/- 13.9 vs. 38.8 +/- 13.8 yrs than controls. The interval between diagnosis and colectomy was comparable between the two groups. There were more uninsured in the Hispanic group than controls (13.9% vs. 2.8%). There were no significant differences in gender distribution, family history of IBD, smoking history, extent of UC, fulminant colitis, pouch configuration, stage of pouch, presence of extraintestinal manifestations, or concurrent autoimmune disorders. Pouch-related disorders and pouch failure were also similar. CONCLUSIONS: There appeared to be some difference in the preoperative characteristics of patients who underwent colectomy for UC between Hispanics and non-Hispanic whites, but outcomes after the restorative proctocolectomy with IPAA were comparable. Further studies are needed to characterize the natural history of UC and IPAA in the Hispanic population and the associated biosocioeconomic factors. PMID- 20722061 TI - Psychoneuroimmunologic factors in inflammatory bowel disease. AB - BACKGROUND: Bidirectional relationships between the immune system, nervous system, and psychological processes likely exist in inflammatory bowel disease (IBD) because stress can affect IBD, and IBD is associated with an increased risk of psychological difficulty. The field of psychoneuroimmunology (PNI) sheds light on specific mechanisms that are involved in these relationships, and this research can be applied specifically to IBD. The purpose of this article is to review research on PNI processes in IBD and provide recommendations for future research. METHODS: A literature search was conducted using the PubMed and PsychInfo computerized databases and bibliographies of relevant articles. RESULTS: The hypothalamic-pituitary-adrenal axis, sympathetic-adrenomedullary system, proinflammatory cytokines, substance P, and mast cells play roles in inflammatory processes in IBD. These processes also respond to stress, and they have been implicated in psychological problems in otherwise healthy individuals. These overlapping processes in inflammation and psychological function have received limited attention in IBD, but preliminary evidence suggests that these mechanisms may play a role in the psychological difficulty experienced by those with IBD. CONCLUSIONS: Several bidirectional PNI mechanisms overlap in IBD, suggesting ways that stress and psychological function can affect disease activity and, conversely, avenues by which the inflammation in IBD may contribute to psychological difficulty. More research on specific PNI processes is needed to fully understand these factors in IBD. PMID- 20722062 TI - Enteroantigen-presenting B cells efficiently stimulate CD4(+) T cells in vitro. AB - BACKGROUND: Presentation of enterobacterial antigens by antigen-presenting cells and activation of enteroantigen-specific CD4(+) T cells are considered crucial steps in inflammatory bowel disease (IBD) pathology. The detrimental effects of such CD4(+) T cells have been thoroughly demonstrated in models of colitis. Also, we have previously established an in vitro assay where murine enteroantigen specific colitogenic CD4(+) CD25(-) T cells are activated by splenocytes pulsed with an enterobacterial extract. METHODS: CD4(+) CD25(-) T cells were stimulated in vitro with various kinds of enterobacterial extract-pulsed antigen-presenting cells. T-helper phenotypes were detected by flow cytometry. RESULTS: We found that enteroantigen-pulsed splenic B cells possess a significantly higher and more sustained T cell stimulatory capacity than similarly pulsed splenic dendritic cells (DCs) measured by the level of enteroantigen-specific CD4(+) CD25(-) T cell proliferation. In support of this, we observed upregulation of classic maturation markers in B cells following incubation with enterobacterial antigens. Peritoneal and mesenteric lymph node-derived B cells were equally effective as enteroantigen presenting stimulator cells. B cells greatly expanded the number of stimulated CD4(+) T cells, which acquired a T(H) 2 phenotype. Interestingly, regulatory T cells were primarily activated by enteroantigen-pulsed B cells but not by similarly pulsed DCs. CONCLUSIONS: We conclude that B cells are superior stimulators of enteroantigen-specific CD4(+) T cells in vitro, favoring T(H) 2 polarization. Thus, enteroantigen-processing and -presentation by B cells instead of by DCs might have opposing consequences for IBD development. PMID- 20722063 TI - New therapeutic targets in ulcerative colitis: the importance of ion transporters in the human colon. AB - BACKGROUND: The absorption of water and ions (especially Na(+) and Cl(-)) is an important function of colonic epithelial cells in both physiological and pathophysiological conditions. Despite the comprehensive animal studies, there are only scarce available data on the ion transporter activities of the normal and inflamed human colon. METHODS: In this study, 128 healthy controls and 69 patients suffering from ulcerative colitis (UC) were involved. We investigated the expressional and functional characteristics of the Na(+)/H(+) exchangers (NHE) 1-3, the epithelial sodium channel (ENaC), and the SLC26A3 Cl(-)/HCO 3- exchanger downregulated in adenoma (DRA) in primary colonic crypts isolated from human biopsy and surgical samples using microfluorometry, patch clamp, and real time reverse-transcription polymerase chain reaction (RT-PCR) techniques. RESULTS: Data collected from colonic crypts showed that the activities of electroneutral (via NHE3) and the electrogenic Na(+) absorption (via ENaC) are in inverse ratio to each other in the proximal and distal colon. We found no significant differences in the activity of NHE2 in different segments of the colon. Surface cell Cl(-)/HCO 3- exchange is more active in the distal part of the colon. Importantly, both sodium and chloride absorptions are damaged in UC, whereas NHE1, which has been shown to promote immune response, is upregulated by 6-fold. CONCLUSIONS: These results open up new therapeutic targets in UC. PMID- 20722064 TI - The stress signal extracellular ATP modulates antiflagellin immune responses in intestinal epithelial cells. AB - BACKGROUND: Although intestinal epithelial cells (IECs) are continually exposed to commensal microbes, under healthy conditions they contribute to intestinal homeostasis while keeping inflammatory responses in check. In response to invading pathogens, however, IECs respond vigorously by producing inflammatory mediators. To better understand the signals that regulate the inflammatory responses of IECs, we investigated whether the danger signal ATP (which is released from injured cells) could alter responses to bacterial products. METHODS: We measured chemokine production from Caco-2 cells stimulated with the Toll-like receptor 5 agonist flagellin with or without ATP. ATP increased flagellin-induced IL-8 secretion but reduced CCL20 secretion via distinct signaling pathways. RESULTS: ATP-enhanced IL-8 production was only partly blocked by the P(2) receptor antagonist suramin and required activation of NF-kappaB while ATP-mediated reduction of CCL20 was completely blocked by suramin and required activation of ERK1/2. The effects of ATP on both chemokines required extracellular calcium but not phospholipase C, implicating P(2) X receptor involvement. To investigate how ATP alters IEC responses to bacterial products in vivo, mice receiving dextran sodium sulfate were given intrarectal flagellin with or without ATP. Addition of ATP to flagellin caused greater weight loss and increased antiflagellin antibody titers, as well as decreased colonic interferon gamma (IFN-gamma) and higher antiflagellin IgG1/IgG2 ratios, which indicate decreased Th1 polarization. CONCLUSIONS: Together, these data indicate that stress, in the form of extracellular ATP, reshapes both the inflammatory response of flagellin-stimulated IECs and downstream adaptive immunity, representing a possible strategy by which these cells differentiate between commensal and pathogenic bacteria. PMID- 20722065 TI - Factors impacting the results of interferon-gamma release assay and tuberculin skin test in routine screening for latent tuberculosis in patients with inflammatory bowel diseases. AB - BACKGROUND: Screening for latent tuberculosis (LTB) including chest x-ray, tuberculin skin test (TST), and facultative whole blood interferon-gamma assay (IGRA) is part of routine management in inflammatory bowel disease (IBD) patients before starting therapy with tumor necrosis factor (TNF)-alpha inhibitors. However, in patients with immunomodulators (IM) TST and IGRA might show limitations. METHODS: We aimed to evaluate the results from an IGRA (QuantiFERON TB Gold in Tube) and TST as well as their concordance in 208 consecutive IBD patients with indications for anti-TNF-alpha therapy. Associations of both tests with risk factors for LTB were determined by logistic regression. RESULTS: During screening, 149 patients (71.6%) were under IM therapy. In 26 (12.5%) patients TST was positive, whereas 15 (7.2%) patients showed a positive result from IGRA. IGRA failed on samples from 16/208 (7.7%) patients, resulting in 192/208 (92.3%) patients in whom results from both screening tests were available. Correlation between IGRA and TST results was fair (84.9%, kappa = 0.21). The presence of risk factors for LTB showed association with positive results of TST (odds ratio [OR] 3.7, 1.5-9.6) and IGRA (OR 3.5, 1.2-11.3). TST was associated furthermore with age (OR 1.06, 1.02-1.10) and signs indicative of LTB in chest x-ray (OR 4.9, 1.1 19.9). The IGRA was negatively influenced by IM therapy (OR 0.3, 0.1-0.9). CONCLUSION: Our study reveals that results of IGRA are negatively affected by IM therapy. Thus, current guidelines for TB screening prior anti-TNF-alpha therapy appear inaccurate in patients under IM. Therefore, LTB screening might be best performed prior to initiation of IM treatment. PMID- 20722066 TI - Role of PPARG gene variants in inflammatory bowel disease. PMID- 20722067 TI - Role of sensory neurons in colitis: increasing evidence for a neuroimmune link in the gut. AB - Growing evidence suggests a crucial involvement of extrinsic sensory neurons in the aberrant immune response in colitis. Activation of sensory neurons is accompanied by a release of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), which induce neurogenic inflammation characterized by vasodilatation, plasma extravasation, and leukocyte migration. Although the role of these neuropeptides in experimental colitis and human inflammatory bowel disease (IBD) remains controversial, numerous data indicate a functional role for sensory neurons. In fact, chemical desensitization or surgical denervation of sensory nerves were shown to attenuate experimental colitis. Furthermore, pharmacological blockade of the neurokinin-1 (NK1) receptor was demonstrated to be efficient in chemically induced mouse models of colitis, and, intriguingly, also in immune-mediated models of colitis (T-cell transfer colitis). Finally, the genetic deletion or pharmacological blockade of receptor channels such as TRPV1 and TRPA1 on nociceptive sensory neurons was also demonstrated to be effective in treating experimental colitis, supposedly by inhibiting neuropeptide release. In summary, we are only beginning to understand the mechanisms of how sensory neurons modulate immune cellular actions. These findings highlight a new role of sensory neurons in chronic intestinal inflammation and suggest new avenues for therapy of IBD. PMID- 20722068 TI - Recurrence rate of clostridium difficile infection in hospitalized pediatric patients with inflammatory bowel disease. AB - BACKGROUND: The incidence and associated morbidity of Clostridium difficile (CD) infection has been increasing at an alarming rate in North America. Clostridium difficile-associated diarrhea (CDAD) is the leading cause of nosocomial diarrhea in the USA. Patients with CDAD have longer average hospital admissions and additional hospital costs. Evidence has demonstrated that patients with inflammatory bowel disease (IBD) have a higher incidence of CD in comparison to the general population. The aim of this study was to compare the rate of recurrence of CD in hospitalized pediatric patients with IBD compared to hospitalized controls. The secondary aim was to evaluate whether infection with CD resulted in a more severe disease course of IBD. METHODS: This was a nested case control retrospective study of hospitalized pediatric patients. Diagnosis of CD was confirmed with stool Toxin A and B analysis. The following data were obtained from the medical records: demographic information, classification of IBD including location of disease, IBD therapy, and prior surgeries. In addition, prior hospital admissions within 1 year and antibiotic exposure were recorded. The same information was recorded following CD infection. Cases were patients with IBD and CD; two control populations were also studied: patients with CD but without IBD, and patients with IBD but without CD. RESULTS: For aim 1, a total of 111 eligible patients with IBD and CD infection and 77 eligible control patients with CD infection were included. The rate of recurrence of CD in the IBD population was 34% compared to 7.5% in the control population (P < 0.0001). In evaluating the effect of CD infection on IBD disease severity, we compared the 111 IBD patients with CD to a second control population of 127 IBD patients without CD. 57% of IBD-CD patients were readmitted with an exacerbation of disease within 6 months of infection with CD and 67% required escalation of therapy following CD infection, compared to 30% of IBD patients without CD (P < 0.001). Of the patients with IBD and CD, 44% of the cases were new-onset IBD, 63% were on immunosuppression therapy, and 33% were on gastric acid suppression prior to infection. In comparing the IBD-CD and control CD populations, there was no significant difference in antibiotic exposure: 33% of IBD patients and 26% of control patients were on antibiotics (P < 0.2). With regard to prior hospitalization, 10% of patients with IBD were hospitalized in the 30 days prior to infection in comparison to 27% of the control CD patients (P < 0.002). CONCLUSIONS: CD infection in patients with IBD results in a higher rate of recurrence and is associated with higher morbidity than the general population. Patients with IBD often required hospitalization and escalation of therapy following infection with CD, suggesting that CD resulted in increased severity of IBD disease. In addition, IBD patients were more likely develop community acquired CD, while the control patients developed nosocomial infections, indicating a higher susceptibility to CD infection in patients with IBD. PMID- 20722069 TI - Tumor necrosis factor-alpha represses the expression of NHE2 through NF-kappaB activation in intestinal epithelial cell model, C2BBe1. AB - BACKGROUND: High levels of proinflammatory cytokines are linked to pathogenesis of diarrhea in inflammatory bowel disease (IBD). Na(+) absorption is compromised in IBD. The studies were designed to determine the effect of tumor necrosis factor-alpha (TNF-alpha) on the expression and activity of NHE2, a Na(+) /H(+) exchanger (NHE) that is involved in transepithelial Na(+) absorption in intestinal epithelial cells. METHODS: NHE2 regulation was examined in TNF-alpha treated C2BBe1 cells by reverse-transcription polymerase chain reaction (RT-PCR), reporter gene assays, and Western blot analysis. NHE isoform activities were measured as ethyl-isopropyl-amiloride- and HOE694-sensitive (22) Na-uptake. In vitro and in vivo protein-DNA interactions were assessed by gel mobility shift assays and chromatin immunoprecipitation studies. RESULTS: TNF-alpha treatment of C2BBe1 cells led to repression of NHE2 promoter activity, mRNA, and protein levels; and inhibited both NHE2 and NHE3 mediated (22) Na-uptake. 5'-deletion analysis of the NHE2 promoter-reporter constructs identified basepair -621 to 471 as the TNF-alpha-responsive region (TNF-RE). TNF-alpha activated NF-kappaB subunits, p50 and p65, and their DNA-binding to a putative NF-kappaB motif within TNF-RE. Mutations in the NF-kappaB motif abolished NF-kappaB-DNA interactions and abrogated TNF-alpha-induced repression. Ectopic overexpression of NF-kappaB resulted in repression of NHE2 expression. Two functionally distinct inhibitors of NF-kappaB blocked the inhibitory effect of TNF-alpha. CONCLUSIONS: The human NHE2 isoform is a direct target of transcription factor NF-kappaB. TNF-alpha mediated activation of NF-kappaB decreases the expression and activity of NHE2 in the intestinal epithelial cell line, C2BBe1. These findings implicate NF-kappaB in the modulation of Na(+) absorption during intestinal inflammatory conditions such as IBD where a high level of TNF-alpha is detected. PMID- 20722070 TI - Directional differentiation of chicken primordial germ cells into adipocytes, neuron-like cells, and osteoblasts. AB - Primordial germ cells (PGCs) are useful for producing transgenic chickens and preserving genetic material in avian species. In this study, we investigated the in vitro differentiation potential of chicken PGCs into different cell types. For differentiation into adipocytes, chicken PGCs were cultured for 21 days in induction media containing dexamethasone, insulin and/or 3-isobutyl-1 methylxanthine (IBMX), and differentiation rates ranging from 74% to 91% were identified by oil red-O and alkaline phosphatase (ALP) staining. For differentiation into neuron-like cells, chicken PGCs were cultured for 3 or 7 days in the induction media containing retinoic acid (RA) and IBMX, and differentiation rates ranging from 71% to 87% were identified by toluidine blue staining and immunohistochemical staining. For differentiation into osteoblasts, chicken PGCs were cultured for 15 or 21 days in the induction media containing desamethasone, beta-glycerol phosphate and/or vitamin C, and differentiation rates ranging from 47% to 79% were confirmed by Von Kossa, cytochemical and immunohistochemical staining. These data suggest that, like mammalian PGCs, chicken PGCs can differentiate into different cell types in vitro. PMID- 20722072 TI - Origin of quantal size variation and high-frequency miniature postsynaptic currents at the Caenorhabditis elegans neuromuscular junction. AB - The neuromuscular junction (NMJ) of Caenorhabditis elegans has proved to be a very useful model synapse for investigating molecular mechanisms of synaptic transmission. Intriguingly, miniature postsynaptic currents (minis) at this synapse occur at an unusually high frequency (50-90 Hz in wild-type worms) and show large variation in quantal size (from <10 pA to >200 pA). It is important to understand the cellular and molecular bases for these properties of minis in order to interpret electrophysiological data from this synapse properly. Existing data suggest that several factors may contribute to the high frequency and quantal size variation, including 1) the establishment of multiple NMJs with each body-wall muscle cell, 2) diversity of postsynaptic receptors (two acetylcholine receptors and one GABA receptor), 3) association of one presynaptic site with several body-wall muscle cells, 4) effects of Ca(2+) at the presynaptic site, and 5) a possibly elevated (less negative) resting membrane potential in motoneurons. Neither the frequency nor the quantal size of minis is affected by electrical coupling of body-wall muscle cells. Furthermore, quantal size variation is not due to synchronized multivesicular release. Analyses of the C. elegans NMJ may lead to a better understanding of the mechanisms controlling the frequency and quantal size of minis of other synapses as well. PMID- 20722071 TI - Cerebral tissue repair and atrophy after embolic stroke in rat: a magnetic resonance imaging study of erythropoietin therapy. AB - Using magnetic resonance imaging (MRI) protocols of T(2)-, T(2)*-, diffusion- and susceptibility-weighted imaging (T2WI, T2*WI, DWI, and SWI, respectively) with a 7T system, we tested the hypothesis that treatment of embolic stroke with erythropoietin (EPO) initiated at 24 hr and administered daily for 7 days after stroke onset has benefit in repairing ischemic cerebral tissue. Adult Wistar rats were subjected to embolic stroke by means of middle cerebral artery occlusion (MCAO) and were randomly assigned to a treatment (n = 11) or a control (n = 11) group. The treated group was given EPO intraperitoneally at a dose of 5,000 IU/kg daily for 7 days starting 24 hr after MCAO. Controls were given an equal volume of saline. MRI was performed at 24 hr and then weekly for 6 weeks. MRI and histological measurements were compared between groups. Serial T2WI demonstrated that expansion of the ipsilateral ventricle was significantly reduced in the EPO treated rats. The volume ratio of ipsilateral parenchymal tissue relative to the contralateral hemisphere was significantly increased after EPO treatment compared with control animals, indicating that EPO significantly reduces atrophy of the ipsilateral hemisphere, although no significant differences in ischemic lesion volume were observed between the two groups. Angiogenesis and white matter remodeling were significantly increased and occurred earlier in EPO-treated animals than in the controls, as evident from T2*WI and diffusion anisotropy maps, respectively. These data indicate that EPO treatment initiated 24 hr poststroke promotes angiogenesis and axonal remodeling in the ischemic boundary, which may potentially reduce atrophy of the ipsilateral hemisphere. PMID- 20722073 TI - Different effects of erythropoietin in cisplatin- and docetaxel-induced neurotoxicity: an in vitro study. AB - Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) and docetaxel (DOCE) treatment. Erythropoietin (EPO) is a hematopoietic growth factor also displaying neurotrophic properties. Evidence suggests that EPO's neuroprotective action may rely on PI3K/AKT pathway activation; however, data regarding the EPO neuroprotective mechanism are still limited. This study evaluated the effect of EPO on organotypic cultures of rat dorsal root ganglia (DRG) and in primary cultures of DRG-dissociated sensory neurons exposed to CDDP- and DOCE-induced neurotoxicity, aiming to investigate EPO's neuroprotective mechanism. Subsequently, the levels of AKT expression and activation were analyzed by Western blot in neurons exposed to CDDP or DOCE; AKT's role was further evaluated by using a chemical inhibitor of AKT activation, wortmannin. In these models EPO, was protective against both CDDP- and DOCE induced cell death and against CDDP-induced neurite elongation reduction. A modulation of AKT activation was observed in CDDP-treated neurons, and the presence of wortmannin prevented EPO's neuroprotective action against CDDP toxicity but did not have any effect on EPO's protection against DOCE-induced toxicity, thus ruling out the PI3K-AKT pathway as the mechanism of EPO's effect in neuronal death prevention after DOCE exposure. Our results confirm in vitro the effectiveness of EPO as a neuroprotectant against both CDDP- and DOCE-induced neurotoxicity. In addition, a role of PI3K/AKT in EPO's protection against CDDP, but not against DOCE, neurotoxicity was shown, suggesting that alternative pathways could be involved in EPO's neuroprotective activity. PMID- 20722074 TI - Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling. AB - Wnt factors regulate neural stem cell development and neuronal connectivity. Here we investigated whether Wnt-3a and Wnt-3, expressed in the developing spinal cord, regulate proliferation and the neuronal differentiation of spinal cord neural precursors (SCNP). Wnt-3a promoted a sustained increase of SCNP proliferation and decreased the expression of cyclin-dependent kinase inhibitors. In contrast, Wnt-3 transiently enhanced SCNP proliferation and increased neurogenesis through beta-catenin signaling. Furthermore, both Wnt-3a and Wnt-3 stimulated neurite outgrowth in SCNP-derived neurons through beta-catenin- and TCF4-dependent transcription. Glycogen synthase kinase-3beta inhibitors mimicked Wnt signaling and promoted neurite outgrowth in established cultures. We conclude that Wnt-3a and Wnt-3 factors signal through the canonical Wnt/beta-catenin pathway to regulate different aspects of SCNP development. These findings may be of therapeutic interest for the treatment of neurodegenerative diseases and nerve injury. PMID- 20722075 TI - Regional and cellular distribution of mitochondrial ferritin in the mouse brain. AB - Iron and mitochondrial dysfunction are important in many neurodegenerative diseases. Several iron transport proteins have been identified that are associated with mitochondria, most recently mitochondrial ferritin. Here we describe the cellular distribution of mitochondrial ferritin in multiple regions of the brain in C57/BL6 mice. Mitochondrial ferritin was found in all regions of the brain, although staining intensity varied between regions. Mitochondrial ferritin was detected throughout the layers of cerebral cortex and in the cerebellum, hippocampus, striatum, choroid plexus, and ependymal cells. The cell type in the brain that stains most prominently for mitochondrial ferritin is neuronal, but oligodendrocytes also stain strongly in both gray matter and in white matter tracts. Mice deficient in H-ferritin do not differ in the mitochondrial ferritin staining pattern or intensity compared with C57/BL6 mice, suggesting that there is no compensatory expression of these proteins. In addition, by using inbred mouse strains with differing levels of iron content, we have shown that regional brain iron content does not affect expression of mitochondria ferritin. The expression of mitochondria ferritin appears to be more influenced by mitochondrial density. Indeed, at an intracellular level, mitochondrial ferritin immunoreaction product is strongest where mitochondrial density is high, as seen in the ependymal cells. Given the importance and relationship between iron and mitochondrial activity, understanding the role of mitochondrial ferritin can be expected to contribute to our knowledge of mitochondrial dysfunction and neurodegenerative disease. PMID- 20722076 TI - Environmental enrichment potentiates thalamocortical transmission and plasticity in the adult rat visual cortex. AB - It has been demonstrated that the complex sensorimotor and social stimulation achieved by rearing animals in an enriched environment (EE) can reinstate juvenile-like plasticity in the adult cortex. However, it is not known whether EE can affect thalamocortical transmission. Here, we recorded in vivo field potentials from the visual cortex evoked by electrical stimulation of the dorsal lateral geniculate nucleus (dLGN) in anesthetized rats. We found that a period of EE during adulthood shifted the input-output curves and increased paired-pulse depression, suggesting an enhanced synaptic strength at thalamocortical terminals. Accordingly, EE animals showed an increased expression of the vesicular glutamate transporter 2 (vGluT-2) in geniculocortical afferents to layer IV. Rats reared in EE also showed an enhancement of thalamocortical long term potentiation (LTP) triggered by theta-burst stimulation (TBS) of the dLGN. To monitor the functional consequences of increased LTP in EE rats, we recorded visual evoked potentials (VEPs) before and after application of TBS to the geniculocortical pathway. We found that responses to visual stimulation were enhanced across a range of contrasts in EE animals. This was accompanied by an up regulation of the intracortical excitatory synaptic marker vGluT-1 and a decrease in the expression of the vesicular GABA transporter (vGAT), indicating a shift in the excitation/inhibition ratio. Thus, in the adult rat, EE enhances synaptic strength and plasticity of the thalamocortical pathway associated with specific changes in glutamatergic and GABAergic neurotransmission. These data provide novel insights into the mechanisms by which EE shapes the adult brain. PMID- 20722078 TI - Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase-1 activation in macrophages. AB - Aeromonas hydrophila is a Gram-negative pathogen that causes serious infectious disease in humans. A. hydrophila induces apoptosis in infected macrophages, but the host proinflammatory responses triggered by macrophage death are largely unknown. Here, we demonstrate that the infection of mouse macrophages with A. hydrophila triggers the activation of caspase-1 and release of IL-1beta. Caspase 1 activation was abrogated in macrophages deficient in Nod-like receptor family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), but not NLR family, CARD domain containing 4 (NLRC4). The activation of the NLRP3 inflammasome was mediated by three cytotoxins (aerolysin, hemolysin and multifunctional repeat-in-toxin) produced by A. hydrophila. Our results indicated that the NLRP3 inflammasome senses A. hydrophila infection through the action of bacterial cytotoxins. PMID- 20722077 TI - Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells. AB - The initial requirement for the emergence of CMV-specific CD8(+) T cells is poorly understood. Mice deficient in the cosignaling TNF superfamily member, 4 1BB, surprisingly developed exaggerated early CD8(+) T-cell responses to mouse CMV (MCMV). CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations. Paradoxically, 4-1BB-deficient mice displayed reduced accumulation of memory CD8(+) T cells that expand during chronic/latent infection. Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4 1BBL. These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity. PMID- 20722079 TI - Anger and anxiety on the Gulf Coast. PMID- 20722080 TI - Medical ethics and the art of cardiovascular medicine. PMID- 20722081 TI - The ayes have it. PMID- 20722082 TI - [Accidental administration of toxic doses of intravenous adrenaline to a 5-month old infant]. PMID- 20722083 TI - At high running speeds, power developed each step during the push appears to be sustained by elastic energy. PMID- 20722084 TI - "Net advantage" is more rooted in sport than science. PMID- 20722085 TI - For forward running, study fore-aft forces. PMID- 20722087 TI - Safety in car design. PMID- 20722086 TI - A narrow focus on swing time and vertical ground reaction force. PMID- 20722088 TI - Certification. PMID- 20722089 TI - Diet and ischaemic heart disease. PMID- 20722090 TI - Beds for the dying. PMID- 20722091 TI - Image of Nursing. PMID- 20722092 TI - Acute hepatitis. PMID- 20722093 TI - Fish-hook in ano. PMID- 20722094 TI - Royal Commission on the N.H.S. PMID- 20722095 TI - At ground level. PMID- 20722096 TI - Hashimoto's disease. PMID- 20722097 TI - Planned home and hospital births in South Australia, 1991-2006: differences in outcomes. PMID- 20722098 TI - ESC tackles child congenital heart disease in poor countries. PMID- 20722100 TI - American Society of Clinical Oncology 2010 Annual Meeting update: summary of selected gynecologic cancer abstracts. PMID- 20722101 TI - RNAi screening of the kinome identifies modulators of cisplatin response in ovarian cancer cells. AB - OBJECTIVE: Ovarian cancer retains a poor prognosis among the female gynaecological malignancies. It constitutes about 3% of all malignancies in women and accounts for 5% of all female cancer related deaths. A standard treatment is cytoreductive surgery followed by adjuvant chemotherapy, and re-treatment with platinum based chemotherapy at the time of relapse. In order to improve cisplatin response in ovarian cancer cells, we utilized a high-throughput RNAi screening to identify kinase modulators. METHODS: A high-throughput RNAi screen was performed using a siRNA library targeting 572 kinases to identify potentiators of cisplatin response in the ovarian cancer cell line SKOV3. RESULTS: RNAi screening identified at least 55 siRNAs that potentiated the growth inhibitory effects of cisplatin in SKOV3 cells. Inhibition of ATR and CHK1 resulted in the greatest modulation of cisplatin response. Drug dose response of cisplatin in the presence of siRNA validated the effects of these target genes. To show that the siRNA data could be successfully translated into potential therapeutic strategies, CHK1 was further targeted with small molecule inhibitor PD 407824 in combination with cisplatin. Results showed that treatment of SKOV3 and OVCAR3 cells with CHK1 inhibitor PD 407824 led to sensitization of ovarian cancer cells to cisplatin. CONCLUSIONS: Our data provides kinase targets that could be exploited to design better therapeutics for ovarian cancer patients. We also demonstrate the effectiveness of high-throughput RNAi screening as a tool for identifying sensitizing targets to known and established chemotherapeutic agents. PMID- 20722102 TI - Risk factors for non-invasive lesions of the fallopian tube in BRCA mutation carriers. AB - OBJECTIVE: To identify risk factors for the presence of a non-invasive lesion of the fallopian tube in women with a BRCA1 or BRCA2 mutation. METHODS: 173 BRCA mutation carriers underwent a prophylactic salpingo-oophorectomy at the University Health Network, Toronto between 2000 and 2008 and were evaluated for the presence of a non-invasive lesion of the fallopian tube. Patients were classified as having p53 overexpression ("p53-signature"), a tubal intra epithelial carcinoma (TIC) or normal tubal epithelium. We obtained a risk factor questionnaire from all patients. We calculated odds ratios for several risk factors, comparing patients with a tubal abnormality to those with normal histology. RESULTS: Of the 173 patients, 43 (25%) were found to have a tubal lesion, including 23% of the BRCA1 mutation carriers and 27% of the BRCA2 mutation carriers. The prevalence of a non-invasive tubal lesion increased with age; an abnormality was present in 5% of women who had surgery before the age of 40 (1 of 12) and in 56% of women who underwent surgery at age 60 or above (6 of 13; p=0.004). A non-invasive lesion of either type was found in 31.2% of women with a BMI > 25 kg/m2) compared to 18.0% of patients with a BMI < 25 kg/m2 at the time of surgery (p=0.05). The average duration of oral contraceptive use among women with normal tubes was 6.0 years, compared to an average duration of 4.0 years for women with a p53 signature (p=0.09) and was 2.7 years for women with a TIC (p=0.0003). CONCLUSION: The prevalence of tubal p53 signature and TIC increases with age at salpingectomy and with BMI. Oral contraceptive use is associated with a decrease in the prevalence of TICs. PMID- 20722103 TI - Spurious pleocytosis. PMID- 20722179 TI - [Giant pseudo-aneurysm following Carol's surgery]. PMID- 20722180 TI - [Imaging diagnosis: Q & A. Thromboangitic coronary artery dissection]. PMID- 20722181 TI - Amenorrhoea. PMID- 20722182 TI - Further studies of agents isolated from tissue cultures inoculated with human leukaemic bone-marrow. PMID- 20722183 TI - Partial pituitary ablation with implants of gold-198 and yttrium-90 for Cushing's syndrome with associated adrenal hyperplasia. PMID- 20722185 TI - Intradermal B.C.G. vaccination by jet injection. PMID- 20722184 TI - Partial pituitary ablation with implants of gold-198 and yttrium-90 for acromegaly. PMID- 20722186 TI - Controlled trial of chlormethiazole in treatment of the alcoholic withdrawal phase. PMID- 20722187 TI - The effects of the National School Lunch Program on education and health. AB - This paper estimates the effects of participating in the National School Lunch Program in the middle of the 20th century on adult health outcomes and educational attainment. I utilize an instrumental variables strategy that exploits a change in the formula used by the federal government to allocate funding to the states. Identification is achieved by the fact that different birth cohorts were exposed to different degrees to the original formula and the new formula, along with the fact that the change of the formula affected states differentially by per capita income. Participation in the program as a child appears to have few long-run effects on health, but the effects on educational attainment are sizable. These results may suggest that subsidized lunches induced children to attend school but displaced food consumption from other sources. Alternatively, the program may have had short-run health effects that dissipated over time but that facilitated higher educational attainment. PMID- 20722188 TI - Chloromatous tumours in African children in Uganda. PMID- 20722189 TI - Complication following insertion of intrauterine contraceptive device. PMID- 20722190 TI - Transsexuality. PMID- 20722191 TI - Systemic reaction to bromsulphthalein. PMID- 20722192 TI - Sacro-iliac gout. PMID- 20722193 TI - Speech disorders in children-Part II. PMID- 20722194 TI - A Greenock family doctor looks back seven years. PMID- 20722195 TI - Cancer research. PMID- 20722196 TI - Circumcision. PMID- 20722197 TI - Barrier nursing. PMID- 20722198 TI - Dangers of radio-translucent dental plates. PMID- 20722199 TI - Electrical hazard. PMID- 20722200 TI - C.S.F.-protein fractions. PMID- 20722201 TI - B virus encephalomyelitis. PMID- 20722202 TI - Chalimony: seeking equity between parents of children with disabilities and chronic illnesses. PMID- 20722203 TI - An objective study of lumbar sympathectomy I. intermittent claudication. PMID- 20722204 TI - A penny saved can be a penalty earned: nursing homes, Medicaid planning, the Deficit Reduction Act of 2005, and the problem of transferring assets. PMID- 20722205 TI - Vascular responses in diabetic peripheral neuropathy. PMID- 20722206 TI - Diagnosis of hysteria. PMID- 20722207 TI - In vitro thrombosis and platelet aggregation in myocardial infarction. PMID- 20722208 TI - Hospital junior staff. PMID- 20722209 TI - Changing patterns of fracture in the dorsal and lumbar spine. PMID- 20722210 TI - Beta-adrenergic blockade in hypertrophic obstructive cardiomyopathy. PMID- 20722211 TI - Precautions against B virus infection. PMID- 20722212 TI - Erythrocyte sedimentation rate in elderly hospital in-patients. PMID- 20722213 TI - Rupture of the liver in an epileptic. PMID- 20722214 TI - Myasthenia gravis, Hashimoto's thyroiditis, and pernicious anaemia. PMID- 20722216 TI - Broadcast television for Doctors-a first evaluation. PMID- 20722217 TI - Aspirin and children. PMID- 20722218 TI - Epidermoid cholesteatoma. PMID- 20722219 TI - Coproporphyrin and oral contraceptives. PMID- 20722220 TI - Replacement arthroplasty. PMID- 20722222 TI - Time-expired senior registrars. PMID- 20722221 TI - Infections of the hand. PMID- 20722223 TI - Family Care Service Ltd. PMID- 20722224 TI - [From psychoanalysis to meta-analysis . . . and back]. PMID- 20722225 TI - Diagnosis and treatment of gastric gastrointestinal stromal tumor less than 5 cm in diameter. PMID- 20722226 TI - Planning responds to gender violence: evidence from Spain, Mexico and the United States. AB - Urban planning has been largely ineffective in addressing urban violence and particularly slow in responding to gender violence. This paper explores the public and private divide, structural inequalities, and issues of ethnicity and citizenship, in terms of their planning implications for gender violence. Drawing on evidence from Spain, Mexico and the United States, it examines how economic and social planning and gender violence intertwine. The three case studies demonstrate that the challenge is not only to break constructed structural inequalities and divisions between public and private spheres, but also to promote changes in the working models of institutions and organisations. PMID- 20722227 TI - Effects of urban growth controls on intercity commuting. AB - This paper presents an empirical study of the effects of urban growth controls on the intercity commuting of workers. Growth controls (land use regulations that attempt to restrict population growth and urban sprawl) have increased housing prices and diverted population growth to uncontrolled cities. It has been suggested that resulting changes in local labour supply might stimulate intercity commuting from uncontrolled to controlled cities. To test this hypothesis, a gravity model of commuting flows between places in California is estimated using alternative econometric methods (OLS, Heckman selection and count-data). The possibility of spatial dependence in commuting flows is also taken into consideration. Results suggest larger commuting flows to destination places that restrict residential growth. PMID- 20722228 TI - The West African medical staff and the administration of Imperial tropical medicine, 1902-14. AB - Established in 1902, the West African Medical Staff (WAMS) brought together the six medical departments of British West Africa. Its formation also followed the foundation of schools of tropical medicine in London and Liverpool. While the 'white' dominions were at the centre of Joseph Chamberlain's ambitions of erecting a system of imperial preference, the tropical colonies were increasingly tethered to the future security and prosperity of Greater Britain. Therefore, politicians and businessmen considered the WAMS and the new tropical medicine important first steps for making Britain's West African possessions healthier and more profitable regions of the empire. However, rather than realising these goals, significant structural barriers, and the self-interest and conservatism this helped breed among medical officers, made the application of even the most basic public health measures extremely challenging. Like many policies emanating from Whitehall during this period, what made the WAMS and the new tropical medicine thoroughly imperial was nothing accomplished in practice, but the hopes and aspirations placed in them. PMID- 20722229 TI - Effects of and protection from exposure to environmental factors. PMID- 20722230 TI - Is it appropriate to study the pharmacokinetics of drugs aimed at pregnant women in men? PMID- 20722231 TI - [Francis Harry Compton Crick (1916-2004)]. PMID- 20722232 TI - West side stories. Black women discuss life, family, and HIV. PMID- 20722233 TI - [14th Novak Traumatology Seminar 2009. 24-25 September, Brno]. PMID- 20722234 TI - [James Dewey Watson (1928)]. PMID- 20722235 TI - [Remembering Ferenc Alexander (1891-1964)]. PMID- 20722236 TI - [Andrew Fielding Huxley (1917)]. PMID- 20722237 TI - Booster shot. Despite a shortfall in patient-care revenue for the past 25 years, hospitals turned a profit thanks to investments and other revenue. AB - An analysis of hospital finances over the past 25 years shows a disconnect: The hospitals consistently lose money on patient care but make up for it in investment income. Healthcare economists see a danger in that situation. "I've always been a firm believer that the best way to ensure long-term financial sustainability is by demonstrating economic viability of your core service," says Louis Gapenski, left. PMID- 20722238 TI - Medium heat. Deals cooking, but not at projected sizzling pace. PMID- 20722239 TI - Boon to bottom line. Systems find ways to boost income in '09: reports. PMID- 20722240 TI - Healthy, wealthy and why. A strong job market help prolong life spans--just look at Japan. PMID- 20722241 TI - Accounting for nursing care. Researchers urge use of 'nursing intensity' data in hospital billing. PMID- 20722242 TI - Baby boomers court metabolic syndrome. PMID- 20722243 TI - Resistant disease or resistant patient: problems with adherence to cardiovascular medications in the elderly. AB - When faced with difficult-to-control cardiovascular risk factors, clinicians need to address the potential role of patient adherence to medication. Among the elderly in particular, careful consideration must be paid to accurately diagnosing an adherence problem in the context of often worsening atherosclerosis. This process includes moving beyond relying on clinical intuition to ascertain whether a patient has "real" (e.g., identifiable) reasons for suboptimal risk factor control and becoming comfortable using evidence-based questions and other ancillary data, when available, to more objectively identify patients with adherence issues. Once identified, a tailored search for an etiology that explores elderly specific patient, physician, and health care system factors needs to be conducted to understand why adherence is a problem for the patient. Finally, clinicians should employ simple tools and clear communication to work with patients and to help them overcome the relevant barriers. PMID- 20722244 TI - An evidence-based review of the AMA/AHA guideline for the primary prevention of ischemic stroke. AB - This article reviews and summarizes the American Heart Association/American Stroke Association guideline: Primary Prevention of Ischemic Stroke. It focuses on recommendations applicable to the geriatric population that may decrease patient risk of developing ischemic stroke. An approach focusing on assessing and treating modifiable risk factors is advised. PMID- 20722245 TI - Rheumatoid arthritis in elderly patients. AB - Rheumatoid arthritis (RA) in the geriatric population presents a unique challenge to treating clinicians. It can present as preexisting disease that may have been present for years or as a de novo onset of the illness. Diagnosis and management requires a detailed knowledge of the disease, its differential diagnoses, and the therapeutic options. A number of other diseases can mimic the illness and must be thoroughly evaluated to avoid serious consequences. New agents to treat RA are available that have shown promise in clinical trials and practice. Aggressive RA treatment should not be withheld in the geriatric population just because of advanced age, rather, treatment should be individualized, especially considering comorbidities and other factors that can specifically affect a patient's quality of life. Coordination of care among geriatricians and rheumatologists is the key to achieving optimal outcome. PMID- 20722246 TI - Persistent facial eruption. PMID- 20722247 TI - Toxoplasmosis in macropodids: a review. AB - Toxoplasmosis is a well-described disease entity that causes significant morbidity and mortality in both captive and free-ranging macropodids. The clinical presentation of toxoplasmosis in macropodids is variable, which reflects the multiple body systems affected by this disease. Animals may die without exhibiting premonitory signs or after the acute development of nonspecific signs of illness. In more chronic cases, clinical signs include neurologic deficits, blindness, respiratory signs, and, in some cases, diarrhea. Histologic lesions can be extensive and affect the pulmonary parenchyma, cardiac and skeletal muscle, lymph nodes, spleen, gastrointestinal tract, adrenal glands, pancreas, central nervous system, liver, and kidney. An antemortem diagnosis can be challenging, although a range of serologic tests are available. Treatment is frequently unrewarding, although recent evidence suggests that the anti-protozoal drug atovaquone may be effective in treating acute cases and eliminating infection. Attempts to vaccinate macropodids against toxoplasmosis have been unsuccessful, and preventive measures are limited to preventing exposure to sporulated oocysts in the environment. PMID- 20722248 TI - Evidence of antibiotic resistance in free-swimming, top-level marine predatory fishes. AB - Antibiotic resistance in bacteria is a growing problem in both human and veterinary medicine. Several studies documented the presence of resistant bacteria in humans, livestock, and domestic animals; however, limited research is available on the presence of antibiotic drug resistance in wildlife species. A cross-sectional study was conducted to estimate the prevalence of resistant bacteria collected from wild-caught, marine predatory fishes. Seven species of sharks and a single teleost species were opportunistically sampled from six different study sites in coastal Belize, coastal and nearshore waters of Louisiana, the Florida Keys, and Martha's Vineyard, Massachusetts. A total of 134 viable bacteria samples were isolated from the cloacal swabs of predatory fishes. Isolates were characterized by Gram-stain morphology and tested for resistance by using the Kirby-Bauer disc diffusion method. Thirteen drugs (penicillin G, piperacillin, ticarcillin, cefotaxime, ceftazidime, ceftiofur, amikacin, gentamicin, ciprofloxacin, enrofloxacin, doxycycline, chloramphenicol, and sulfamethoxazole) were selected for this study. Prevalence was calculated as the total number of isolates resistant to one or more drugs against the total number of samples in that study area or fish population. Sharks sampled in the Florida Keys exhibited the greatest resistance to a wide selection of drugs. Resistance to at least one drug was found in each of the six study sites and in all of the fish species sampled. Multidrug resistance was also documented in most of the study sites. Interspecific comparisons between redfish, Sciaenops ocellata, and sharks from Louisiana offshore waters (which represent species of the Carcharhinus genus) demonstrated a significantly higher prevalence in redfish, which may be because of the older age of the population. The findings of this study confirmed the presence of antibiotic-resistant bacteria in marine predatory fishes from multiple taxa and multiple geographic locations. PMID- 20722249 TI - Hematologic and plasma biochemistry values in white storks (Ciconia ciconia). AB - Hematologic and plasma biochemistry parameters of the white stork (Ciconia ciconia) were studied. Blood samples were taken from a total of 80 adult white storks kept in captivity in Hungarian zoos and bird repatriation stations, between 2002 and 2006. Hematologic (packed cell volume, 46.3% +/- 5.3%; hemoglobin concentration, 127.8 +/- 20.4 g/L; red blood cell counts, 2.28 +/- 0.35 10(12)/l/l; white blood cell counts, 21.6 +/- 4.2 10(9)/l/ l; heterophils, 61.0% +/- 9.8% [13.1 +/- 3.2 x 10(9)/L]; lymphocytes, 34.3% +/- 9.1% [7.4 +/- 2.5 x 10(9)/L]; monocytes, 3.44% +/- 2.3% [0.78 +/- 0.57 x 10(9)/L]; eosinophils 0.75% +/- 0.91% [0.16 +/- 0.21 x 10(9)/L]; basophils 0.38% +/- 0.56% [0.04 +/- 0.07 x 10(9)/L]) and plasma biochemistry values (aspartate aminotransferase, 267.5 +/- 145.8 U/L; L-gamma-glutamyltransferase, 47.6 +/- 49.3 U/L; lipase, 70.3 +/- 60.6 U/L; creatine kinase, 443.9 +/- 182.2 U/L; lactate dehydrogenase, 880.4 +/- 293.6 U/L; alkaline phosphatase, 177.5 +/- 116.6 U/L; amylase, 917.6 +/- 314.3 U/L; glutamate dehydrogenase, 7.3 +/- 4.0 U/L; total protein, 45.2 +/- 8.1 g/L; uric acid, 459.2 +/- 254.3 micromol/L; and bile acids, 46.3 +/- 20.5 micromol/L) were determined. The results obtained can be used as reference values, because there are no established values previously reported for adult white storks. PMID- 20722250 TI - Hypoaminoacidemia is not associated with ulcerative lesions in black rhinoceroses, Diceros bicornis. AB - Ulcerative oral and skin lesions have become an issue of concern for the health of the managed black rhinoceros (rhino) (Diceros bicornis) populations. Lesions exhibited by the black rhino are clinically similar to those observed in other species with superficial necrolytic dermatitis (SND). One biochemical alteration in dogs with SND is severe hypoaminoacidemia, and nearly all cases are fatal. The objective of this study was to determine if black rhinos with analogous lesions exhibit a similar hypoaminoacidemia. Amino acid concentrations were measured in monthly plasma samples collected for 1 yr from black rhinos with (n = 4) and without (n = 34) lesions clinically consistent with SND. The rhinos with skin and/or oral lesions were zoo born males, ages 2, 6, 17, and 23 yr, from four different facilities. Three rhinos recovered from skin (n = 2) and oral lesions (n = 1). However, the one male with both skin and oral lesions died with the disease. None of the affected black rhinos exhibited a decrease in any of the amino acids evaluated or for total amino acid concentrations (P > 0.05). Based on the absence of hypoaminoacidemia and the comparatively low mortality rate in rhinos with lesions, it appears that this syndrome is not entirely consistent with SND observed in other species. These data will be useful for future assessments of rhino nutritional status and other potential metabolic diseases. PMID- 20722251 TI - Immobilization of red fox (Vulpes vulpes) with medetomidine-ketamine or medetomidine-midazolam and antagonism with atipamezole. AB - Thirty-two free-ranging red foxes (Vulpes vulpes) were immobilized with one of three combinations: medetomidine (0.076 +/- 0.017 mg/kg) and ketamine (2.1 +/- 0.5 mg/kg; MK, n = 16), medetomidine (0.057 +/- 0.008 mg/kg) and low-dose midazolam (0.6 +/- 0.1 mg/kg; MM-0.5, n = 10), or medetomidine (0.067 +/- 0.012 mg/kg) and high-dose midazolam (1.3 +/- 0.2 mg/kg; MM-1, n = 6) by i.m. injection. Induction and recovery times were recorded. Pulse, respiratory rate, body temperature, systolic and diastolic blood pressure, and oxygen saturation were measured. Anesthesia depth indicators were observed. There was a significant difference between the MM-0.5 and the MM-1 groups regarding induction time, 8.1 +/- 2.1 min and 5.0 +/- 1.7 min, respectively. The MK induction time was 6.9 +/- 2.5 min, which was not significantly different from the other two groups. All combinations provided effective immobilization for at least 20-25 min. During immobilization, there were significant differences regarding rectal temperature, which was higher in the MK group; and blood pressure, which was higher in the MM 1 group. After administration of atipamezole at 5 mg per 1 mg medetomidine given, there was a significant difference between the groups in recovery time; MK foxes were standing within 3.9 +/- 1.7 min, MM-0.5 foxes within 10.6 +/- 4.5 min, and MM-1 foxes within 10.2 +/- 3.4 min. None of the combinations caused rough or prolonged recoveries. Subjectively, the MM groups had smoother and less ataxic recoveries than the MK group. In conclusion, the authors recommend the use of medetomidine at 0.07 mg/kg in combination with midazolam at 0.8 mg/kg or ketamine at 2 mg/kg for the immobilization of free-ranging red foxes. During immobilization, monitoring of body temperature and oxygenation is recommended. PMID- 20722252 TI - Fetal echocardiographic evaluation of the bottlenose dolphin (Tursiops truncatus). AB - In humans, fetal echocardiography represents the most important tool for the assessment of the cardiovascular well-being of the fetus. However, because of logistic, anatomic, and behavioral challenges, detailed fetal echocardiographic evaluation of marine mammals has not been previously described. Because the application of fetal echocardiography to cetaceans could have both clinical and academic importance, an approach to evaluating the fetal dolphin's cardiovascular status was developed with conventional, fetal echocardiographic techniques developed in humans. Eight singleton fetal bottlenose dolphins (Tursiops truncatus) were evaluated, each between 6 and 11 mo gestation; six fetuses underwent two fetal echocardiographic evaluations each, four at 3-mo intervals, and two at 0.5-mo intervals. Evaluations were performed without sedation, using conventional, portable ultrasound systems. Multiple transducers, probes, and maternal dolphin positions were used to optimize image quality. Fetal echocardiography included two-dimensional imaging and color flow mapping of the heart and great arteries, as well as pulsed Doppler evaluation of the umbilical artery and vein. Thorough evaluations of the fetal dolphins' cardiovascular status were performed, with the greatest resolution between 8 and 9 mo gestation. With the use of published human fetal echocardiographic findings for comparison, fetal echocardiography demonstrated normal structure and function of the heart and great arteries, including the pulmonary veins, inferior vena cava, right and left atria, foramen ovale, tricuspid and mitral valves, right and left ventricles, ventricular septum, pulmonary and aortic valves, main pulmonary artery and ascending aorta, and ductus arteriosus. Pulsed Doppler techniques demonstrated normal umbilical arterial and venous waveforms, and color flow mapping demonstrated absence of significant valvar regurgitation. Fetal echocardiography, particularly between 8 and 9 mo gestation, can provide a safe and detailed assessment of the cardiovascular status of the fetal bottlenose dolphin. PMID- 20722253 TI - Classification and prevalence of foot lesions in captive flamingos (Phoenicopteridae). AB - Foot lesions can compromise the health and welfare of captive birds. In this study, we estimated the prevalence of foot lesions in captive flamingos (Phoenicopteridae). The study was based on photos of 1,495 pairs of foot soles from 854 flamingos in 18 European and two Texan (USA) zoological collections. Methodology for evaluating flamingo feet lesions was developed for this project because no suitable method had been reported in the literature. Four types of foot lesions were identified: hyperkeratoses, fissures, nodular lesions, and papillomatous growths. Seven areas on each foot received a severity score from 0 to 2 for each type of lesion (0 = no lesion, 1 = mild to moderate lesion, 2 = severe lesion). The prevalence of birds with lesions (scores 1 or 2) were 100%, 87%, 17%, and 46% for hyperkeratosis, fissures, nodular lesions, and papillomatous growths, respectively. Birds with severe lesions (score 2) constituted 67%, 46%, 4%, and 12% for hyperkeratosis, fissures, nodular lesions, and papillomatous growths, respectively. Hyperkeratosis and nodular lesions were most prevalent on the base of the foot and the proximal portion of the digits, likely reflecting those areas bearing the most weight. The second and fourth digits were most affected with fissures and papillomatous lesions; these areas of the foot appear to be where the most flexion occurs during ambulation. The study demonstrates that foot lesions are highly prevalent and widely distributed in the study population, indicating that they are an extensive problem in captive flamingos. PMID- 20722254 TI - Comparison of the anesthetic effects of oral transmucosal versus injectable medetomidine in combination with tiletamine-zolazepam for immobilization of chimpanzees (Pan troglodytes). AB - Seventeen adult chimpanzees (Pan troglodytes) with an average age of 37 yr were immobilized with a combination of tiletamine-zolazepam (TZ) and medetomidine (MED) by one of two modes of delivery. Group A animals received the drug combination intramuscularly at 3 mg/kg and 0.05 mg/kg, respectively. Animals in group B received MED by oral transmucosal administration, meaning oral delivery with presumptive transmucosal absorption. MED at 0.1 mg/kg was mixed with marshmallow creme, and delivery was followed by 3 mg/kg of TZ intramuscularly. Chimpanzees from both groups were recovered after administration of atipamezole at 0.3 mg/kg intramuscularly. All chimpanzees were compliant with oral transmucosal drug administration, although two chimpanzees preferred oral MED mixed with applesauce. All animals exhibited some anxiety and excitatory behavior associated with darting, but this was reduced in group B, which was premedicated with oral transmucosal MED. The mean time from TZ administration to sedation sufficient for human contact was 16.4 and 14.7 min with and without oral transmucosal premedication, respectively. The mean time for recovery for those chimpanzees given oral transmucosal premedication was 13.8 min, which was significantly shorter than the time of recovery for the group not given oral premedication (P = 0.02). Oral transmucosal administration of MED provided light sedation in 16 of 17 chimpanzees to the level of arousable recumbency and a heavier sedation in one chimpanzee with no adverse side effects. TZ combined with MED by either oral transmucosal or injectable administration provided safe, heavy, long sedation with rapid, smooth, uneventful recoveries. PMID- 20722255 TI - Validation of a less invasive blood sampling technique in rabies serology using reduviid bugs (Triatominae, Hemiptera). AB - During serologic rabies surveys, bleeding is often difficult or almost impossible in small or endangered mammals such as bats. Therefore, the usefulness of an alternative, less invasive technique--that is, the use of blood-sucking reduviid bugs (Dipetalogaster maximus and Rhodnius prolixus)--was investigated. Bugs were used in combination with a conventional method (retro-orbitale bleeding) to obtain blood samples from the same individual NMRI-mice (Mus musculus) vaccinated against rabies. Rabies virus-neutralizing antibody (VNA) titers between paired blood samples obtained from the same mice were compared. The accuracy (between method comparison), precision (repeatability of results), and robustness (influence of digestion on blood parameter) of the bug method was evaluated. VNA titers in the blood sample obtained from the bugs' crops were equivalent to those from samples collected directly from the mice. No differences between samples taken from different bugs that had fed on the same mouse were noted. In addition, there were no changes in VNA titers in blood samples collected from the triatomine bugs for up to 4 hr after completion of the blood meal. This study demonstrates that the application of blood-sucking bugs offers a validated alternative for obtaining blood samples to determine rabies virus-neutralizing antibody titers and is highly suitable for animals with limited or no accessibility of veins by conventional sampling techniques. PMID- 20722256 TI - Ultrasound imaging of the inguinal region of adult male loggerhead sea turtles (Caretta caretta). AB - The biology and reproductive anatomy of male loggerhead sea turtles (Caretta caretta) have been difficult to study. The principle method for evaluation of the coelomic cavity in both adult and juvenile male sea turtles is celioscopy. The purpose of this study was to describe the technique and structures seen when scanning the inguinal region of live, wild-caught, adult male loggerhead sea turtles and to compare these findings to those resulting from celioscopy and necropsy. Twenty-one adult male loggerhead sea turtles were collected by trawling in the Cape Canaveral shipping channel in April 2007. All turtles were placed in dorsal recumbency and imaged with a Sonosite 180 Vet Plus (Sonosite, Inc., Bothell, Washington 98021, USA) and a microconvex, 4-7-MHz curvilinear array probe. The inguinal region was divided into four quadrants: cranial, lateral, medial, and caudal. Celioscopy was performed on 13 turtles, and biopsies were obtained of the testes and the epididymides to confirm correct identification of the structures. In the cranial aspect of the inguinal region, the urinary bladder and large and small intestines were identified. In the lateral inguinal region, the lung and kidney were seen. In the medial aspect of the inguinal region, the testis and epididymis were routinely identified. In the caudal aspect of the inguinal region, the coxofemoral joint was seen. A small learning curve was required; however, correlation with celioscopy and biopsy showed that consistent, repeatable identification of caudal coelomic structures was easily achieved. Ultrasound provided an inexpensive, rapid, noninvasive method to evaluate the reproductive anatomy of live-captured, male loggerhead sea turtles. PMID- 20722257 TI - Pulmonary carcinoma in a great horned owl (Bubo virginianus). AB - Pulmonary carcinoma was diagnosed in an 18+-year-old captive female great horned owl (Bubo virginianus). The owl presented with a history of progressive weakness and sudden onset of frank blood in the droppings. On physical examination, the owl had multiple white to yellow plaques in the oral cavity, decreased air sac sounds on the right side, dyspnea (during manual restraint), and reduced pectoral musculature. Whole-body radiographs revealed obliteration of the right-sided air sacs, a soft tissue plaque/density in the left caudal thoracic air sac, soft tissue opacity over the coelomic organs, and increased medullary opacity in the distal right humerus. The owl died during anesthetic recovery, and the body was submitted for necropsy. Although the clinical signs, physical examination results, radiographic signs, and gross pathology supported a diagnosis of mycotic infection, such as aspergillosis, histopathology confirmed pulmonary carcinoma with metastases to the air sacs and humerus. PMID- 20722258 TI - Coxiella burnetii abortion in captive dama gazelle (Gazella Dama) in the United Arab Emirates. AB - Abstract: Five cases of late-stage abortion in dama gazelle (Gazella dama) occurred in the United Arab Emirates. Histopathologic and molecular diagnostics found the abortions to be associated with Coxiella burnetii infection. Examination of the herd 6 mo later revealed a significant number of serologically positive animals but failed to detect the antigen in genital swabs. There are few reports in the literature of C. burnetii abortion in nondomestic ungulates and no published reports from the United Arab Emirates. PMID- 20722259 TI - Esophageal hiatal hernia in three exotic felines--Lynx lynx, Puma concolore, Panthera leo. AB - Hiatal hernia was diagnosed in three exotic felines-lynx (Lynx lynx), cougar (Puma concolore), and lion (Panthera leo). All cats had a history of anorexia. Thoracic and abdominal radiographs showed evidence of a soft tissue mass within the caudal mediastinum suggestive of a hiatal hernia in all animals. A barium esophagram was performed in one case. All animals underwent thoracic or abdominal surgery for hernia reduction. Surgical procedures included: intercostal thoracotomy with herniorrhaphy and esophagopexy (lynx and cougar), and incisional gastropexy (lion). Concurrent surgical procedures performed were gastrotomy for gastric foreign body removal and jejunostomy tube placement. Clinical signs related to the hiatal hernia disappeared after surgery and recurrence of signs was not reported for the time of follow-up. PMID- 20722260 TI - Melanocytic neoplasms in a black rhinoceros (Diceros bicornis) and an Indian rhinoceros (Rhinoceros unicornis). AB - Melanocytic neoplasms were diagnosed in a captive black rhinoceros (Diceros bicornis) and a captive Indian rhinoceros (Rhinoceros unicornis) from different facilities. The first case was a 10-yr-old, captive-born male black rhinoceros that presented with a small firm cutaneous mass on the dorsal midline. Aspirate cytology results were suggestive of a melanocytic neoplasm, and histologic examination of the excised mass confirmed a well-differentiated neoplasm with much pigment production, minimal anaplasia, and no mitotic figures. Several months after mass removal, a similar mass with identical histologic features was excised from the right medial thigh. The second case was a 28-yr-old, wild-born female Indian rhinoceros that presented with a draining wound at the coronary band of a rear digit. Histologic examination of a biopsy from this lesion revealed a melanocytic neoplasm with moderate cellular anaplasia, frequent mitoses, and scant pigment production. At necropsy, the tumor was found to ablate P3 and most deep tissues of the toe. No evidence of vascular invasion or metastasis was found. These two cases represent the only melanocytic neoplasms in Rhinoceridae reported in detail in the literature. PMID- 20722261 TI - Lysosomal storage disease in two presumed-related springboks (Antidorcas marsupialis). AB - In April 2007, two newborn springboks (Antidorcas marsupialis) from a zoo of southern France were found dead. Necropsy was performed on the two animals and revealed arthrogryposis, mild facial structural abnormalities, and bilateral enlargement of the kidneys with concurrent hydronephrosis in both newborns. Histopathologically, extensive cytoplasmic vacuolation of neurons in the central nervous system, thyroid follicular epithelium, renal tubular epithelium, enterocytes, hepatocytes, and ruminal epithelial cells was the most remarkable lesion in both animals. By electron microscopy, the vacuoles were membrane bound and contained scattered membranous and granular material within a primarily electron-lucent background. Hence, a diagnosis of lysosomal storage disease was established, with gross, histological, and ultrastructural features suggestive of an inherited form of mannosidosis. This report documents the first case of lysosomal storage disease in springboks. PMID- 20722262 TI - A case of metastatic uterine adenocarcinoma in a southern white rhinoceros (Ceratotherium simum simum). AB - A 39-yr-old, acyclic, uniparous, female white rhinoceros with a history of recurrent vaginal bleeding was euthanized following a period of respiratory distress and ill-thrift. The rhinoceros' uterus had previously been evaluated by ultrasound and diffuse endometrial hyperplasia and two benign uterine leiomyomas had been diagnosed. At necropsy examination, a large, infiltrative, metastatic uterine adenocarcinoma was found multifocally throughout the uterus, scattered within the peritoneal cavity, on the diaphragm, the splenic capsule, the pleural surface of the lung and mesenteric lymph nodes. A large volume (100 L) of ascites fluid was present in the abdominal and pleural cavities. PMID- 20722263 TI - Immobilization and intravenous anesthesia in a Sumatran rhinoceros (Dicerorhinus sumatrensis). AB - This paper reports in detail, for the first time, on two anesthetic procedures performed on a 15-yr-old, 530 kg, adult male Sumatran rhinoceros (Dicerorhinus sumatrensis). The anesthetic procedures were carried out in order to perform semen collection via electro-ejaculation, using well-established methods, and in order to examine and sample bilateral corneal opacities. Anesthesia for the first procedure was induced with a combination of 5 mg (0.0094 mg/kg) butorphanol tartrate and 5 mg (0.0094 mg/kg) detomidine hydrochloride administered intramuscularly. Subsequently, 0.74 mg (0.0014 mg/kg) etorphine and 3 mg (0.0057 mg/kg) acepromazine, with an additional 1.5 mg butorphanol (0.0028 mg/kg) and 1.5 mg (0.0028 mg/kg) detomidine, were administered intramuscularly. The second procedure was carried out using an intramuscular combination of butorphanol (0.019 mg/kg) and detomidine (0.019 mg/kg), followed by etorphine (0.0023 mg/kg) and acepromazine (0.009 mg/ kg). During the second procedure, the depth of anesthesia was managed with very small, supplemental intravenous doses of 50 mg ketamine (0.094 mg/kg). Sequential arterial blood gas analysis demonstrated respiratory acidosis with hypoxemia. Heart rate and respiratory rate ranged between 60-74 beats per minute (bpm), and 10-20 breaths per minute, respectively. Reversal after 100 min, with the intravenous administration of 150 mg (0.28 mg/kg) naltrexone and intravenous 20 mg (0.038 mg/kg) atipamezole, was uneventful and rapid, with the animal standing after 2 min. This combination provides satisfactory general anesthesia in this critically endangered species and will facilitate veterinary management of this species in captivity. PMID- 20722264 TI - Thyroid neoplasia in captive raccoons (Procyon lotor). AB - Two adult, spayed, female raccoons were diagnosed with thyroid neoplasia. One raccoon had a palpable, left-sided, nonfunctional thyroid adenocarcinoma which was treated with a thyroidectomy twice with local recurrence both times. After the second recurrence, pulmonary metastases were identified. A third thyroidectomy was performed, and a vascular access port was placed for administration of intravenous doxorubicin. The raccoon developed pancytopenia and became anorexic after chemotherapy, and the owner elected humane euthanasia. The second raccoon had nonpalpable, bilateral, functional follicular thyroid adenomatous hyperplasia and was treated with a right thyroidectomy and a partial left thyroidectomy, leaving behind the grossly normal portion of the left thyroid. However, the animal was still hyperthyroid after surgery and was then successfully managed with topical methimazole gel. Thyroid pathology has been documented in raccoons in Europe, but is not reported in the United States. Thyroid neoplasia in raccoons can occur as a nonfunctional adenocarcinoma, as is commonly reported in dogs, or as a functional adenoma, as is commonly reported in cats. Raccoons with adenocarcinomas should be evaluated for pulmonary metastasis. Methimazole gel may be a viable treatment option for raccoons with hyperthyroidism. PMID- 20722265 TI - Cerebral xanthomatosis in three green water dragons (Physignathus cocincinus). AB - Cerebral xanthomatosis was diagnosed in three female green water dragons (Physignathus cocincinus), all of which presented with progressive neurologic signs. No antemortem evidence for xanthomatosis was identified, but on postmortem examination cholesterol granulomas, composed of cholesterol clefts surrounded by macrophages and multinucleated giant cells, were found in the forebrain of each animal and were associated with significant displacement and pressure on the adjacent brain. Although the cause of xanthomatosis in these animals is unknown, nutrition and trauma may be involved in the pathogenesis of this condition. Cerebrum, cholesterol, green water dragon, Physignathus cocincinus, xanthoma. PMID- 20722266 TI - Serologic survey for selected infectious diseases in free-ranging Brazilian tapirs (Tapirus terrestris) in the cerrado of central Brazil. AB - From September 2000 to January 2002, a serologic survey was conducted in a population of free-ranging Brazilian tapirs (Tapirus terrestris) inhabiting Emas National Park and surrounding areas in Goias state, central Brazil, as part of an ecologic study. Ten tapirs were immobilized with a tiletamine-zolazepam combination, and blood samples were collected. All sera were negative for Leptospira spp., Brucella abortus, and equine infectious anemia; and one of 10 animals was positive for Toxoplasma gondii. This report represents the first serologic survey for selected infectious diseases in a free-ranging population of Brazilians tapirs in central Brazil. PMID- 20722267 TI - Chronic heart failure due to severe endocardiosis in a Gambian giant pouched rat (Cricetomys gambianus). AB - A 1.5-yr-old captive male Gambian giant pouched rat (Cricetomys gambianus) died after suffering from anorexia, weakness, and dyspnea for 3 wk. Thoracic radiographs of thorax and abdomen and computed tomography showed a severe biventricular enlargement of the heart and a moderate hepatomegaly. Necropsy revealed a severe, bilateral hypertrophic cardiomyopathy and dilation of the right ventricle due to multifocal bilateral, valvular endocardiosis of all atrioventricular valves and acute hepatic congestion. Histologically, the atrioventricular valves were multifocally thickened by a marked endocardiosis with stromal accumulation of Periodic acid-Schiff (PAS)-positive, mucinous material. Although common in dogs, endocardiosis has not been described in Nesomyidaes. As in other affected species, the pathogenesis of endocardiosis in this species remains unclear. PMID- 20722268 TI - Response to vaccination with a commercial inactivated rabies vaccine in a captive colony of Brazilian free-tailed bats (Tadarida brasiliensis). AB - A captive colony of Brazilian free-tailed bats (Tadarida brasiliensis) was vaccinated with a commercial monovalent inactivated rabies virus (RABV) vaccine (RABVAC 1). Baseline rabies virus neutralizing antibodies (VNA) and the response to vaccination were measured in 50 bats. Rabies VNA was detected in the plasma of 64% (27/42) of bats that had been vaccinated 1 yr prior, but only 19% (8/42) had levels considered adequate. Rabies VNA was detected in the plasma of 63% (5/8) of bats with no record of previous vaccination, suggesting natural RABV exposure before captivity. All bats demonstrated a VNA response by 10 days postvaccination, and baseline titer significantly predicted humoral response to vaccination. No adverse reactions to vaccination or clinical signs of RABV infection were observed in the bats during a 6-mo observation period. Annual vaccination may maintain immunity against RABV infection in captive colonies of bats. Bat, rabies virus, Tadarida brasiliensis, vaccination, virus neutralizing antibodies. PMID- 20722269 TI - Standardized protocols for plasma clearance of iohexol are not appropriate for determination of glomerular filtration rates in anesthetized California sea lions (Zalophus californianus). AB - Abstract: Plasma clearance of iohexol was evaluated in eight anesthetized California sea lions (Zalophus californianus), without evidence of renal dysfunction, to determine if the one-compartment model and the sample protocol used in dogs and cats could be applied to this species. Nonlinearity between samples in 75% (6/8) of sea lions voided those results. An additional two anesthetized sea lions were sampled at 5, 30, 45, 60, 120, 180, 240, and 360 min post iohexol injection and semi-logarithmic curves calculated. Plasma iohexol clearance values calculated by one-, two-, and noncompartment models were in poor agreement, suggesting that the standardized protocol described for dogs and cats cannot simply be applied to California sea lions, probably due to the effects of the dive reflex induced during anesthesia. PMID- 20722270 TI - Histologic structure of the uropygial gland of the osprey (Pandion haliaetus). AB - This study was performed to determine the histologic structure of the uropygial gland in an osprey. The gland was composed of two elongated lobes which were enclosed in a capsule of connective tissue. Each lobe of the gland had a large central cavity with one excretory duct. The secretory tubules consisted of four cell types: basal, intermediate, secretory, and degenerative. The intermediate cells in the osprey were few in number and did not form a layer, while secretory and degenerative cells consist of 2-3 strata, indicating a high level of lipogenesis. The membranes and peripheral cytoplasm of degenerative cells located in the base of the lobes revealed calcium (Ca2+) deposition and an intense acidophilic reaction. PMID- 20722271 TI - Treatment of an amelanotic melanoma using radiation therapy in a lesser Madagascar hedgehog tenrec (Echinops telfairi). AB - A 15-yr-old, male lesser Madagascar hedgehog tenrec (Echinops telfairi) presented with a mass caudal to the right ear. Cytology suggested a sarcoma. Surgical removal was attempted. Histology was consistent with a soft tissue sarcoma. The mass recurred within 331 days post operation. Radiation therapy was initiated. Computed tomography was used for staging in conjunction with three-dimensional computerized treatment planning software to permit accurate lesion localization and to optimize normal tissue sparing. A total dose of 6,480 cGy was administered in 24 fractions over 46 days. Transient hind limb paresis developed during the course of the radiation therapy, but resolved after 7 days with prednisone treatment. Minimal acute radiation toxicity was observed. The mass responded with at least a 90% reduction in volume following radiation treatment. The animal survived 266 days from the initiation of treatment. On necropsy, a small mass and granulation tissue were found at the site of the initial neoplasm, indicating good regional control of the tumor; however, extensive metastases to the spleen and liver were present. Immunohistochemically, the original, recurrent, and metastatic populations were strongly positive for HMB 45 and weakly positive for S-100, and the final diagnosis was metastatic amelanotic melanoma. PMID- 20722272 TI - Arcanobacterium pyogenes septicemia in a southern pudu (Pudu puda) following uterine prolapse. AB - A 14-year-old female pudu (Pudu puda) developed a uterine prolapse after unassisted parturition. The length of time between the prolapse and replacement of the organ was not known but was less than 24 hr. When the prolapse was first noticed, uterine tissue appeared undamaged and was immediately cleaned with antiseptic solution, handled carefully during replacement, and prophylactic antibiotic and anti-inflammatory drugs were given. The pudu appeared clinically normal until 4 days postpartum, when she developed clinical signs of tenesmus, dysuria, and a purulent discharge from the vulva. Despite further treatment, the animal was found dead 10 days postpartum, even though it had not shown any other signs of systemic illness. Gross and histologic lesions supported a diagnosis of septicemia secondary to metritis. Arcanobacterium pyogenes was isolated from lung, liver, and uterine exudate. PMID- 20722273 TI - Treatment of hypoxemia during anesthesia of brown bears (Ursus arctos). AB - This study assessed whether arterial oxygenation could be increased by treatment with intranasal oxygen supplementation in brown bears (Ursus arctos) with hypoxemia during anesthesia with medetomidine-zolazepam-tiletamine. Arterial blood samples were collected anaerobically from the femoral artery before and during oxygen supplementation. An oxygen flow rate of 2-5 L/min administered intranasally to brown bears weighing 12-120 kg markedly increased arterial oxygenation. Intranasal oxygen supplementation proved to be a simple and efficient method for treatment of hypoxemia in anesthetized bears. PMID- 20722274 TI - Systemic neosporosis in a white rhinoceros. AB - Neosporosis was diagnosed in a 16-year-old female white rhinoceros (Ceratotherium simum) that died suddenly without clinical signs. Histopathology revealed disseminated protozoan tachyzoites in liver, adrenal cortex, kidney, and intestine, with morphology compatible with either Toxoplasma or Neospora. The organism was identified as Neospora caninum with the use of primary rabbit anti N. caninum antibody immunohistochemistry and polymerase chain reaction. The exact source of infection remains unknown, but it is suspected that N. caninum oocysts were ingested from the soil. PMID- 20722275 TI - Fournier's gangrene syndrome in a chimpanzee (Pan troglodytes). AB - A 37-yr-old male chimpanzee (Pan troglodytes) was evaluated for intermittent diarrhea, scrotal swelling, and lethargy of 2 days duration. Physical examination revealed marked swelling of the scrotum and perineal tissues with mild pitting edema and crepitus. Computed tomography revealed a mixed gas and soft-tissue density extending from the caudal ventral subcutaneous tissues caudally to the scrotum and perineal tissues. Surgical exploration and castration were performed to establish drainage, and culture revealed a polymicrobial infection. A diagnosis of scrotal and fascial plane abscessation consistent with Fournier's gangrene was made. Although castration with open drainage was performed, the animal died 36 hr after surgery. Postmortem examination and histopathology revealed necrotizing fasciitis of the penis, vaginal tunic, and subcutaneous perineal and perianal tissues. PMID- 20722276 TI - Complication associated with abdominal surgical implantation of a radio transmitter in an American badger (Taxidea taxus). AB - Radio telemetry has greatly advanced the understanding of wild animal ecology. Telemetry studies must ensure that placement of transmitters does not influence the health and behavior of study animals. Here, 10 American badgers (Taxidea taxus) were implanted with beeswax-coated abdominal radio transmitters under general anesthesia and tracked for an average of 14 mo. Behavior and movements of all badgers indicated successful short-term recovery from implantation; however, three mortalities were observed between 5 mo and 15 mo after capture. Cause of death could not be determined for two badgers due to decomposition of the carcasses. A third badger that was recovered in good postmortem condition died from sepsis secondary to a transmitter-related omental torsion. This study indicates that there is some risk associated with abdominally implanted radio transmitters in badgers. Future studies involving implanted transmitters in mammals should focus on identifying safe and effective telemetry devices that do not affect the health of study animals. American badger, omental adhesion, peritoneal implant, telemetry, Taxidea taxus. PMID- 20722277 TI - Skin lesions associated with Demodex sp. in a llama (Lama glama). [corrected] AB - A 2.5-yr-old female llama (Lama glama) [corrected] with skin lesions was presented to the Animal Health Center in Seoul Grand Park Zoo, Korea. Mites of the genus Demodex in the absence of other mites or fungi were identified from the lesions by skin scrapings. The bodies were elongated, tapered, and 200-280 1m in length; four pairs of stumpy legs were present at the front of the body, and the striated opisthosoma constituted about half of the body length. Histologic examination of the skin biopsy showed typical folliculitis, hyperkeratinization of epidermis, and infiltration of inflammatory cells, consisting mainly of eosinophils and monocytes, in dermis. Although mites were undetected in the dilated hair follicles, the histologic features are consistent with descriptions of infestation by Demodex spp. This is believed to be the first case of skin lesions associated with Demodex sp. in L. glama. [corrected] Incidental findings were previously described in a different species of llamas (Lama glama) without any recognized symptoms. Treatment with amitraz (0.025%) eliminated the mites and resolved the clinical signs. PMID- 20722278 TI - Cryptococcus gattiivgi in a spinner dolphin (Stenella longirostris) from Hawaii. AB - A spinner dolphin (Stenella longirostris) was found stranded in Hawaii with cutaneous nodules and enlarged lymph nodes. Numerous Cryptococcus gattii VGI yeast were observed in multiple organs with minimal inflammation. This case represents the first reported infection of C. gattii in a dolphin from Hawaii. PMID- 20722279 TI - [Development of specific and degenerated primers to CesA genes encoding flax (Linum usitatissimum L.) cellulose synthase]. AB - Cellulose synthase catalytic subunit genes, CesA, have been discovered in several higher plant species, and it has been shown that the CesA gene family has multiple members. HVR2 fragment of these genes determine the class specificity of the CESA protein and its participation in the primary or secondary cell wall synthesis. The aim of this study was development of specific and degenerated primers to flax CesA gene fragments leading to obtaining the class specific HVR2 region of the gene. Two pairs of specific primers to the certain fragments of CesA-1 and CesA-6 genes and one pair of degenerated primers to HVR2 region of all flax CesA genes were developed basing on comparison of six CesA EST sequences of flax and full cDNA sequences of Arabidopsis, poplar, maize and cotton plants, obtained from GenBank. After amplification of flax cDNA, the bands of expected size were detected (201 and 300 b.p. for the CesA-1 and CesA-6, and 600 b.p. for the HVR2 region of CesA respectively). The developed markers can be used for cloning and sequencing of flax CesA genes, identifying their number in flax genome, tissue and stage specificity. PMID- 20722280 TI - [Transposition of the maize transposable element dSpm in transgenic sugar beets]. AB - Transgenic sugar beet plants carrying maize Spmn/dSpm transposable elements system have been constructed. Heterologous system of maize transposable elements Spm/dSpm was active in transgenic sugar beets that permits transposon-based gene tagging and obtaining of marker-free transgenic sugar beet. PMID- 20722281 TI - [Analysis of genetic variation in dogs (American Pit Bull Terrier breed) with high inbreeding level using microsatellite markers]. AB - The level of gene polymorphism of 10 microsatellite loci in 27 American Pit Bull Terrier dogs which have a high value of the percentage of blood and inbreeding coefficient achieved 43.8% was studied. The excess of heterozigosity over expected for this level of inbreeding coefficient was established. Suggestion that the high level of heterozigosity is the result of the selection against homozygotes was made. PMID- 20722282 TI - [Ploidy and genetic structure of hybrid populations of water frogs Pelophylax esculentus (L., 1758) complex (Amphibia, Ranidae) of Ukraine]. AB - The present study of green frog hybrid populations of Ukraine, including analysis of allozyme variability and planimetric analysis oferythrocytes size has confirmed that the unique region in this area is the Severski Donets basin The allopolyploid individuals there are met very frequently (5.7% of all investigated frogs). In other areas of Ukraine only two polyploid hybrids have been recorded. Beside that, one frog was defined as triploid Rana ridibundus. According to our investigations, all triploid hybrids from the Severski Donets basin are identified as P. esculentu (=lessonae)--2 ridibundus males. PMID- 20722283 TI - [Association of P-mobile element activity and DNA methylation pattern changes in the conditions of Drosophila melanogaster prolonged irradiation]. AB - Association of the radiosensitivity and epigenetic pattern DNA changes at the conditions of prolonged irradiation was investigated. Two laboratory Drosophila melanogaster strains (Canton-S and ri) irradiated for 20 generations to low doses rate (1.2 x 10(-1), 0.8 x 10(-8) and 0.12 x 10(-8) Gy/s) were used as experimental objects. DNA for the analysis was extracted separately for the flies of males and females. Restriction endonucleases Glul, Glal were used. Restriction analysis has shown that there are different DNA methylated patterns for males and females as for control and exposed variants. At the chronic irradiation there was the decline of methylation level at the enzymes Glul, Glal sites recognition. PMID- 20722284 TI - [Interaction of Ungernia victoris, Rhodiola rosea and Polyscias filicifolia plant extracts with bacterial cells]. AB - Components of three investigated plant extracts obtained from biomass of Ungernia victoris, Rhodiola rosea and Polyscias filicifolia cultivated cells interact with OmpC and OmpF proteins-porins and decrease their activity of as receptors in regard to OmpC- and OmpF-dependent bacteriophages. Entrance into cell of these components optimizes LPS synthesis and promotes increasing of receptor activity both itself LPS and OmpA and LamB proteins tightly connected with it. PMID- 20722285 TI - [MAST2-like protein kinase from grape vine Vitis vinifera: cloning of catalytic domain cDNA]. AB - The aim of our work is the identification of protein kinases phosphorylating microtubule proteins in plant cells. Using bioinformatic approach, we found genes of putative homologues of microtubule-associated mammalian protein kinase MAST2 in higher plant genomes. The gene of closest MAST2 homologue, putative protein, named GMLK (Grape MAST2-Like Kinase, A7NTE9_VITVI), was found in grape Vitis vinifera. We report here the cloning of cDNA of GMLK (A7NTE9) from Pinot Noir grape vine leaves. PMID- 20722286 TI - [Quantitative characters of male generative structures cells of wheat, rye and wheat-rye hybrids during microsporogenesis]. AB - The optical density indices of nucleoli and cytoplasm of male generative cells during microsporogenesis have been estimated for wheat, rye and F1 of wheat-rye hybrids using RNA staining. The correlation between RNA con tent in the nucleolus and the cytoplasm of investigated cells has been estimated. The dynamics of correlation between the nucleolus volume and RNA content in the nucleolus/ the cytoplasm has been shown for wheat and hybrids cells during microsporogenesis. The essential differences depending on genotype for quantitative karyometrical and cytochemical character expression have been determined for parental forms, as well as dependence of expression of these characters in the cells of FI wheat-rye hybrids on wheat maternal form. PMID- 20722287 TI - [Infection with Wolbachia does not influence crossing over in Drosophila melanogaster]. AB - The influence of infection with endosymbiotic bacteria Wolbachia on crossingover in Drosophila melanogaster between the white and cut genes in the X chromosome was studied. Reciprocal crosses have been conducted between infected and non infected fruit fly strains. The results showed no significant effect of Wolbachia infection on the crossingover rates in D. melanogaster between the white and cut genes in X-chromosome. PMID- 20722288 TI - [Site-specific recombinases in genetic engineering: modern in vivo technologies]. AB - Current advances in the field of site-specific recombinases (SSR) and their application for pro- and eukaryotic genomics are reviewed. Functions of SSR and main types of the genetic rearrangements they catalyze are outlined. Examples described in the review show the potential of SSR for studies of a diverse array of fundamental and applied problems, which are not easily solved (or not solved at all) with the help of other experimental approaches. Use of SSR for wider set of biological systems, generation of recombinases with a strict temporal and spatial control of their activity and search for SSR displaying new substrate specificity are major directions of development of SSR-based technology. PMID- 20722290 TI - The allure of an international locum opportunity. PMID- 20722289 TI - [Genetically programmed cell death: the basis of homeostasis and form of phytoimmunity response]. AB - This paper gives a brief overview of the recent ideas about programmed cell death including apoptosis in animals and plants. Comparison of these processes in animal and plant cells in terms of physiological features has been presented. Necrosis as a form of pathological, not genetically programmed cell death has been characterized. Reflections about the meaning (the need) of apoptosis in the formation of hypersensitive response in plants and the role of programmed cell death in joint relations between pathogens and plants have been considered. PMID- 20722291 TI - Globetrotting medicine. International locum tenens positions offer opportunities for adventure--and more. PMID- 20722292 TI - Novice leadership. An Army doctor learns to stop seeking popularity and earns respect in the process. PMID- 20722293 TI - Focused risk management battles tort reform storm. PMID- 20722294 TI - Finding joy in practice. PMID- 20722295 TI - Career contentment. PMID- 20722296 TI - 5 tips for achieving a work/life balance. PMID- 20722297 TI - Foster good patient relations by minimizing wait times. PMID- 20722298 TI - A model to optimise the requirements of lactating dairy cows for physically effective neutral detergent fibre. AB - This study modelled multiple physiological responses of dairy cows to physical and chemical characteristics of a diet aiming to optimise their requirements for physically effective neutral detergent fibre, expressed inclusive of particles dry matter > 8 mm (peNDF > 8). Extensive research data, comprising a wide range of feeding conditions (n = 64 studies and 257 different dietary treatments), were used to parameterise the model, while statistical modelling was used to account for the inter- and intra-experiment variation as well as to derive the model estimates. Physiological thresholds and 'safety limits' of peNDF > 8 for maintaining different physiological variables were derived using non-linear statistical modelling. Results showed that peNDF > 8 content in the diet is a key factor stimulating rumination activity, maintaining optimal ruminal pH and promoting fibre digestion. Modelling data with regard to the association of fibre digestion and time duration of ruminal pH < 5.8 and dietary peNDF > 8 suggests that feeding of less than 13.7% peNDF > 8 (the lower 'safety limit') is critical to prevent depression of fibre digestion in dairy cows. The study also indicated that the beneficial effects of peNDF > 8 on ruminal pH and fibre digestion can be at the expense of the dry matter intake (DMI) level of high-producing cows when the peNDF > 8 threshold of 14.9% in the diet is exceeded. In terms of the optimisation of peNDF > 8 requirements, the modelling data suggest that feeding of 17-18.5% peNDF > 8 can be beneficial in maintaining ruminal pH, while allowing a relatively high DMI (22.3-22.7 kg x d(-1)) for average high-producing dairy cows. PMID- 20722299 TI - Fermentative characteristics and fibrolytic activities of anaerobic gut fungi isolated from wild and domestic ruminants. AB - Fermentative characteristics and fibrolytic enzyme activities of anaerobic gut fungi from wild (17 isolates) and domestic ruminants (15 isolates) were examined. In a medium containing 0.5% wheat straw and 0.02% cellobiose as energy source, activities of carboxymethyl cellulase (CMCase), avicelase, xylanase, acetyl esterase and protease produced by the fungal isolates were investigated. Average activity of CMCase (17.4 vs. 8.25 mIU ml(-1)), acetyl esterase (134 vs. 57 mIU ml(-1)) and protease (4400 vs. 1683 mIU ml(-1)) were significantly higher in isolates from wild ruminants than those from domestic ruminants. Xylanase and avicelase activities were comparable. When compared irrespective of source, fungal isolates having monocentric growth pattern produced more fibrolytic enzymes than isolates having polycentric growth pattern. CMCase, xylanase, avicelase activities were highest in Neocallimastix isolates. Acetyl esterase activity was highest in Piromyces and Neocallimastix isolates. Protease activity was highest in Piromyces isolates followed closely by Neocallimastix isolates. Between isolates from wild and domestic ruminants few differences were observed in pattern of carbohydrate utilisation and end products of fermentation. Inter strain differences in the end product formation were apparent. All of the isolates produced acetate, lactate and formate; only a few isolates produced succinate. For isolation of superior fibrolytic isolates of anaerobic fungi, greater emphasis should be given to the screening of enzyme activities of isolates of genera Neocallimastix and Piromyces. PMID- 20722300 TI - Effect of weaning age on feed intake and ruminal fermentation patterns of calves fed a dry total mixed ration with ad libitum access to grass hay. AB - To study the effect of weaning age on average daily gain (ADG), dry matter intake (DMI) and ruminal fermentation, 10 rumen-cannulated male Holstein calves were randomly assigned to one of two treatments: (i) early weaned at 8 weeks of age (235 l milk); (ii) conventionally weaned at 12 weeks of age (347 l milk). Twice daily grass hay (9.0 MJ ME x kg(-1) DM) and a dry total mixed ration (TMR) (11.6 MJ ME x kg(-1) DM) containing 15% alfalfa hay and 85% concentrates were offered separately. Water was available ad libitum. Ruminal fluid was collected via cannulas at weeks 9, 11, 13 and 15, twice weekly just prior to as well as 1, 3, 5 and 7 h after morning feeding. Calves of both treatments achieved adequate ADG (947 vs. 959 g; p > 0.05). Just-weaned calves rapidly increased DMI (1.1-2.5 kg TMR and 2.4-3.6 kg TMR for early- and conventionally-weaned calves, respectively). From weeks 10-12 early-weaned calves consumed significantly more dry feed than conventionally-weaned calves (week 10: 2.5 vs. 1.6 kg/d; week 12: 3.4 vs. 2.4 kg/d). Early weaning stimulates DMI supporting ruminal fermentation intensity, indicated by lower ruminal pH. After weaning, only early-weaned calves achieved critical average ruminal pH (week 9: 5.7 vs. 6.0, p = 0.017; week 11: 5.9 vs. 6.2, p = 0.007). Experimental treatment did not affect the concentration of ruminal short-chain fatty acids (SCFA). For all calves, the effects of the concentrate-rich TMR were shown by a high SCFA level (daily average: 137-152 mmol x l(-1)) and an acetate to propionate to butyrate ratio between 51:36:9 and 54:33:10. PMID- 20722301 TI - Inulin and probiotics in newly weaned piglets: effects on intestinal morphology, mRNA expression levels of inflammatory marker genes and haematology. AB - The study aimed at determining the effect of inulin and/or a multispecies probiotic formulation on gastrointestinal tract (GIT) morphology, immunological and haematological parameters. Forty-eight newly weaned piglets were assigned to four feeding groups, receiving a standard basal diet (control), supplemented with 0.4% inulin, probiotics (1 x 10(9) CFU/kg as fed, enterococci, lactobacilli, bifidobacteria) or a combination of both (synbiotic). After four weeks of ad libitum feeding piglets were slaughtered and intestinal tissue samples were obtained for histometry. Additional tissue samples of the GIT, mesenteric lymph nodes, blood, liver and spleen were taken for mRNA expression analysis of cell turnover (CDK4, caspase3, IGF I), transcription factor NFkappaB and inflammatory marker genes (TNFalpha, TGFbeta). Changes in histometry occurred predominantly in the small intestine, showing higher jejunal villi when probiotics were administered alone (p < 0.10). Inulin decreased the number of acidic goblet cells in jejunal villi (p < 0.05), whereas probiotics increased neutral goblet cells in ileal villi (p < 0.05). Though inflammatory marker genes were uninfluenced by treatment in the proximal GIT, the colon showed downregulations induced by inulin (TNFalpha: p < 0.10, TGFbeta: p < 0.05). Gene expression of CDK4 was upregulated in the jejunum and of TGFbeta in the mesenteric lymph nodes in the probiotic groups. Interestingly, the probiotic group alone exhibited upregulations in cell turnover marker genes in the colon and blood. Furthermore, for numerous parameters, inulin and probiotics led to no synergistic but antagonistic interactions. PMID- 20722302 TI - Protein and energy metabolism of young male Wistar rats fed conjugated linoleic acid as structured triacylglycerol. AB - Twelve 4-week-old male Wistar rats weighing 100 g were fed diets semi-ad libitum for 22 d containing either 1.5% conjugated linoleic acid (CLA-diet) or high oleic sunflower oil (Control-diet). The CLA was structured triacylglycerol with predominantly cis-9, trans-11 and trans-10, cis-12 fatty acid isomers in the inner position and oleic acid in the other positions of the glycerol molecule. The rats were kept individually in metabolic cages. From days 8-16 energy, nitrogen (N) and carbon (C) balances as well as gas exchange measurements in open air circuit respiration chambers were performed. CLA had no significant influence on feed intake, daily gain in weight or feed conversion efficiency, but the digestibility of nutrients and energy was significantly reduced (except for fat). CLA did not affect N-balance, but reduced the level of daily retained fat (RQ method: 0.107 vs. 0.417 g/d, p < 0.01) and consequently energy retention in fat. This was explained by increased heat production (HP, RQ-method: 224.6 vs. 214.6 kJ/d, p < 0.001) caused by a higher fat oxidation (28.9% vs. 22.3%, p < 0.001) at the expense of oxidation of carbohydrates (65.6% vs. 71.4%, p < 0.001), while there was no significant effect on the oxidation of protein (5.5% vs. 6.3%). Consequently, the non-protein respiratory quotient (RQnp) was lower in the rats fed the CLA-diet than in the rats fed the Control-diet (0.907 vs. 0.928, p < 0.001). Plasma total lipids of the CLA-fed rats had higher concentrations of the cis-9, trans-11 than the trans-10, cis-12 CLA-isomer. This study shows that young male Wistar rats respond to CLA fed as structured triacylglycerol. PMID- 20722303 TI - Nucleotides in canine colostrum and milk at different stages of lactation. AB - The aim of this study was to investigate the presence of nucleotides in canine colostrum and milk during lactation. Colostrum and milk samples of 10 healthy bitches were collected manually from mammary glands and analysed for total milk solids, crude protein and adenosine 5'-monophosphate (AMP), cytidine 5' monophosphate (CMP), guanosine 5'-monophosphate (GMP) and uridine 5' monophosphate (UMP). We found that the total nucleotide content significantly (p < 0.05) increased during lactation, with UMP and CMP being the most abundant, while the AMP content was the lowest. The trend for CMP and UMP was opposite to that of other species, while AMP and GMP concentrations in bitch colostrum and milk were lower than those in other species. This is the first report on the presence of nucleotides in canine milk, and their occurrence could indicate a species-specific nucleotide metabolism or different secretory mechanisms. PMID- 20722304 TI - 'Don't forget about me'. What are you doing to provide access to your care? PMID- 20722305 TI - Loose lips ... it's time you create a social media policy for your practice. PMID- 20722306 TI - Say no to naysayers. PMID- 20722307 TI - So you thought you had HIPAA under control. PMID- 20722308 TI - Slather on the sunscreen. PMID- 20722310 TI - Quick death, slow death. I've learned from both. PMID- 20722309 TI - Your diet matters to your teeth and gums. PMID- 20722311 TI - Evidence-based review of interventions to improve palliation of pain, dyspnea, depression. AB - This review of the guideline developed by the Clinical Efficacy Subcommittee of the American College of Physicians and the accompanying systematic review offers clinicians evidence-based recommendations for palliative care. Seriously ill patients should be assessed for pain, dyspnea, and depression. Clinicians should use therapies of proven effectiveness to manage pain, depression, and dyspnea, including opioids in patients with unrelieved dyspnea and oxygen for short-term relief of hypoxemia. Clinicians should ensure that advance care planning, including completion of advance directives, occurs. PMID- 20722312 TI - Incorporating religion and spirituality to improve care for anxiety and depression in older adults. AB - Recent research has suggested that religion/spirituality may be linked to improved physical and emotional health, although the patient's motivation and method of using religious/spiritual beliefs appear to be a key factor in obtaining benefit. Studies have shown that there is a high level of religion/spirituality among older adults in the United States and significant patient-reported desire to include such beliefs in health care settings. This article provides a brief overview of the support for considering religion/spirituality in the health care of older adults and reviews potential drawbacks and methods for providers to assess and use patient beliefs to improve anxiety/depression. PMID- 20722313 TI - Implantable cardiac defibrillators and cardiac resynchronization therapy for heart failure in older adults. AB - Heart failure primarily affects older adults, but these patients are underrepresented in clinical trials. Implantable cardiac defibrillators have been shown in large trials to reduce mortality through primary and secondary prevention of cardiac arrest. It is not clear, however, whether older patients derive the same mortality benefit as younger patients. Cardiac resynchronization therapy improves exercise tolerance and quality of life, and decreases mortality and hospitalizations for younger and older patients with heart failure. Each of these devices is underused in older patients, especially in women and minorities. Physician recommendation for device placement requires a discussion of indication, risks, and benefits, as well as plans for deactivation in end-stage disease. PMID- 20722315 TI - Innovation. Virtual reality. PMID- 20722314 TI - Slightly sore, dark lesion on thigh. PMID- 20722316 TI - Human resources--mentoring: part 2. The benefit of experience. PMID- 20722317 TI - Innovation. Welcome to the wellbeing garden. PMID- 20722318 TI - Human capital theory: another way of valuing RNs knowledge. PMID- 20722319 TI - Fall risk assessment in the outpatient setting. PMID- 20722320 TI - Is there a role for 'wisdom workers' in professional nursing? PMID- 20722321 TI - Healing hands in Haiti. PMID- 20722322 TI - The ABC's for eliminating Clostridium difficile. PMID- 20722323 TI - Team building: a continuous challenge for today's nurse leaders. PMID- 20722324 TI - Cultures of candor. PMID- 20722325 TI - Cuts and child services. PMID- 20722326 TI - User involvement: children's participation in a parent-baby group. AB - According to the National Service Framework, children have a right to participate in the development of healthcare services and yet research suggests that young children are at risk of exclusion from user involvement initiatives. This paper outlines the findings of a participatory action research project conducted with families attending a health visitors' parent-baby group. A combination of participatory research methods were used to ascertain the infants' perspectives of the service and this led to a number of changes in terms of professional attitudes, service provision and working practices. Changes in professional attitudes included acknowledging the importance of social interaction to the children, recognising young children's views as embodied and produced within social interactions, and respecting children as active contributors and not simply as passive recipients of healthcare services. Changes in service provision resulted in redistributing resources, structures and spaces to take account of children's perspectives. Finally, reciprocity and responsiveness were seen as key components in enhancing young children's participation. PMID- 20722327 TI - Supporting emotional health and wellbeing: the Solihull Approach. AB - The quality of early relationships is an important factor in the development of emotional health and wellbeing. Yet in the UK, we do not integrate support for the relationship between the baby and parents into antenatal parentcraft. Neither do we provide enough focus on the relationship in basic and post-qualification training or support for practitioners to integrate working with the relationship into their practice. The Solihull Approach provides one model for working with the relationship between parents and the child and between the parents and practitioner. It integrates concepts from disparate academic fields that can focus a practitioner's work on supporting the relationship between parents and baby or child, whether individually or in a parenting group. PMID- 20722328 TI - A novel parent-supported emotional literacy programme for children. AB - This study explores whether a novel parent-supported emotional literacy programme called Parents And Children Together (PACT) is associated with improved social and emotional development for children compared to a standard curriculum. In eight schools in Cornwall, 686 children from Years 3 to 6 and their families participated in the PACT programme, and were compared with 212 peers from four demographically-matched schools who received a standard curriculum. Parents in intervention schools believed that the PACT programme had a significant positive impact on the social and emotional development of their children and improved the partnership with their child's school. Parental ratings of their child's emotional literacy was significantly higher after participation in the programme, and the children rated themselves significantly less likely to need further help in the future than those in the control schools. The implications for comprehensive mental health services are considered, and recommendations made for developing school and home-based emotional literacy programmes. Schools, particularly in deprived areas, should be supported to take part in PACT. School nurses and other community practitioners should play a leading role in these primary prevention and mental health improvement initiatives. PMID- 20722329 TI - Enuresis service review. PMID- 20722330 TI - Band 4 skill-mix staff. PMID- 20722331 TI - Tourette's: 20 CAMHS cases. PMID- 20722332 TI - Detecting neonatal jaundice. PMID- 20722333 TI - Building a better playground. PMID- 20722334 TI - The doctor is in--and online. PMID- 20722335 TI - The origin of cougar sex drives. PMID- 20722336 TI - The infection connection. Only a few months remain until voluntary participation in CDC's reporting network begins, and Medicare dollars are on the line. AB - Participation in the CDC's National Healthcare Safety Network is voluntary, but hospitals must be onboard by January 2011 for central line-associated bloodstrea infections, or they risk Medicare payment penalties. A similar requirement is in place for surgical-site infections starting in 2012. "We're very pleased with the announcement", regarding the two measures, said Russell Olmsted, president-elect of APIC. PMID- 20722337 TI - Rosier or rose-colored glasses? Critics take Obama administration to task on Medicare projections. PMID- 20722338 TI - Back in black. Not-for-profits see much better returns in '09: report. PMID- 20722339 TI - Financial failure not an option. NYC safety net hospitals can lead the way on reform but need some help. PMID- 20722340 TI - Hospital CEO turnover by state. Ranked by highest turnover percentages in 2009 for states with 30 or more hospitals. PMID- 20722342 TI - Inside the minds of animals. PMID- 20722341 TI - An Rx for the Army's wounded minds. PMID- 20722343 TI - Finding mom on facebook. PMID- 20722344 TI - Functional imaging of cognitive impairment in Parkinson's disease. AB - Parkinson's disease (PD) is known by most persons to be a neurodegenerative disorder that affects one's motor skills. However, the disease is also characterized by the less recognized cognitive symptoms, including deficits in executive functioning, as well as mood and behavioral problems, which are just as disabling and distressing as the motor symptoms. Imaging methods such as positron emission tomography (PET) have recently enhanced our understanding of cognitive disturbances in PD, and are reviewed in the current article. Furthermore, insights gained from the use of specific radiotracers in the dopaminergic and cholinergic neurotransmitter systems are discussed, as well as findings from in vivo detection of amyloid-beta. We will also discuss the potential use of a metabolic covariance network as a biomarker in clinical trials for the objective assessment of cognitive dysfunction in PD. PMID- 20722345 TI - A combined rTMS and ERP investigation of dorsolateral prefrontal cortex involvement in response inhibition. AB - The stop signal task is used to investigate inhibition of an initiated response. Converging evidence suggests that right inferior prefrontal cortex is involved in this behavior, although other regions in the prefrontal cortex have also been implicated. One technique used to determine the contribution of specific cortical regions to behavior is repetitive transcranial magnetic stimulation (rTMS). In the present study, fourteen subjects performed the stop signal task before and after receiving a train of rTMS to the left and right dorsolateral prefrontal cortex (DLPFC). The effects of rTMS were determined using event-related potential (ERP) measures that have been associated with response inhibition in previous studies. Stimulation of left and right DLPFC did not affect ERP measures of response inhibition. This negative finding is interpreted with caution, but is consistent with a recent study which found that stimulation of the same region had no effect on a behavioral measure of response inhibition. PMID- 20722346 TI - Quantitative electroencephalographic abnormalities in fibromyalgia patients. AB - There is increasing acceptance that pain in fibromyalgia (FM) is a result of dysfunctional sensory processing in the spinal cord and brain, and a number of recent imaging studies have demonstrated abnormal central mechanisms. The objective of this report is to statistically compare quantitative electroencephalogram (qEEG) measures in 85 FM patients with age and gender matched controls in a normative database. A statistically significant sample (minimum 60 seconds from each subject) of artifact-free EEG data exhibiting a minimum split-half reliability ratio of 0.95 and test-retest reliability ratio of 0.90 was used as the threshold for acceptable data inclusion. FM subject EEG data was compared to EEGs of age and gender matched healthy subjects in the Lifespan Normative Database and analyzed using NeuroGuide 2.0 software. Analyses were based on spectral absolute power, relative power and coherence. Clinical evaluations included the Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory and Fischer dolorimetry for pain pressure thresholds. Based on Z statistic findings, the EEGs from FM subjects differed from matched controls in the normative database in three features: (1) reduced EEG spectral absolute power in the frontal International 10-20 EEG measurement sites, particularly in the low to mid-frequency EEG spectral segments; (2) elevated spectral relative power of high frequency components in frontal/central EEG measurement sites; and (3) widespread hypocoherence, particularly in low- to mid-frequency EEG spectral segments, in the frontal EEG measurement sites. A consistent and significant negative correlation was found between pain severity and the magnitude of the EEG abnormalities. No relationship between EEG findings and medicine use was found. It is concluded that qEEG analysis reveals significant differences between FM patients compared to age and gender matched healthy controls in a normative database, and has the potential to be a clinically useful tool for assessing brain function in FM patients. PMID- 20722347 TI - Ictal bigeminy. AB - Seizures can influence cardiac autonomic function and cause abnormalities in the electrocardiogram (EKG). A case of stereotypical bigeminy during left temporal lobe seizures recorded in the epilepsy monitoring unit is presented. The mechanism is likely due to spread of the ictal discharge to primary visceromotor regions in the left insula (Island of Reil). This case illustrates the potential influence of ictal brain activity on cardiac electrophysiology. PMID- 20722348 TI - Electrophysiological characteristics of seizure clusters. AB - The phenomenon of temporal clustering of seizures is well known, but its effect on seizure localization has not been rigorously analyzed. The aim of our study was to assess electrophysiological localization during Video EEG (VEEG) monitoring in patients with intractable epilepsy demonstrating a cluster of seizures. The study was conducted on 203 intractable epilepsy patients, aged 2 to 60 years (19.96 +/- 10.87). Patients with unilateral temporal lobe epilepsy having clusters were compared with patients not having clusters, and the effect of clustering on concordance was addressed. Fully consistent localization was observed in 116 patients, partially consistent localization in 18 patients, and inconsistent localization in 19 patients. ANOVA did not reveal any significant difference in these groups (p=0.65). A total of 770 seizures recorded from 149 patients was analyzed for clustering effect. Clustering was present in 603/770 seizures pairs (78.31%). In the cluster group, 483 (80.09%) seizure pairs were concordant for seizure onset, while 98 (16.25%) were discordant and 22 (3.65%) were indeterminate. In the noncluster group, 134 (80.24%) seizure pairs were concordant for seizure onset, while 23 (13.77%) were discordant and 10 (5.98%) were indeterminate. The study found that cluster seizures occurring within an interseizure interval (ISI) less than 8 hours are independent and have the same localizing value as those seizures with longer ISIs. PMID- 20722349 TI - Hemispheric lateralization in benign focal epilepsy in childhood with centrotemporal spikes (BECTS). AB - Benign focal epilepsy in childhood with centrotemporal spikes (BECTS) is one of the most common forms of epilepsy. In adults there is a higher percentage of lateralized epileptic discharges in the left cerebral hemisphere; however, in children this pattern does not seem to have the same distribution. The objective of this study was to evaluate the lateralization of interictal spikes in children with BECTS in relation to the sex of the child and the age of onset of epilepsy. We studied the electroencephalograms (EEGs) of 114 children with a clinical diagnosis of BECTS according to ILAE. The results obtained from two EEGs, performed at intervals of 6 and 12 months, were correlated with the age of onset of the epileptic seizures and the sex of the child. There was no association between the onset of epileptic seizures and the age of the child (p=0.461). When we analyzed the relationship between laterality and sex we did not observe any difference in the first EEG (p = 0.767) results; however, in the results of the second EEG there was a difference (p = 0.002). In males, left and bilateral interictal spikes were predominant, and in females the right hemisphere showed predominant spikes and there were continuous spike-and-wave discharges during slow sleep (CSWSS). The analysis between laterality and a child's age did not show predominant interictal spikes in the hemispheres, except in males where there were predominant multifocal and generalized spikes, but not lateralization (p=0.011). The conclusion was that in BECTS the lateralization of interictal spikes was not consistent as described in adult patients, but there was a slight left hemispheric predominance in boys and right hemispheric predominance in girls. PMID- 20722350 TI - Dental hardware complicating diagnosis in refractory gelastic epilepsy secondary to hypothalamic hamartoma. AB - Hypothalamic hamartomas (HH) are developmental malformations of the hypothalamus associated with a potentially treatable epileptic encephalopathy, characterized by early onset gelastic seizures, the later development of multiple seizure types and progressive cognitive and behavioral decline. Surgical treatment of HH can lead to seizure control and improvement in the cognitive-behavioral syndrome. Video-EEG telemetry (VET) is often necessary to characterize the semiology of the seizures, but there are no specific interictal or ictal EEG pattems that will confirm the diagnosis. Magnetic resonance imaging (MRI) can identify HH and define their anatomy, but the imaging findings may be subtle and susceptible to artifactual contamination. We present a patient with intractable gelastic epilepsy in whom the diagnosis of HH was initially missed due to failure to recognize the clinical syndrome and contamination of the MRI images with dental hardware artifact. VET confirmed the clinical diagnosis and the HH was identified on MRI after the dental hardware was removed. VET should be performed to confirm seizure semiology in patients with suspected gelastic epilepsy. Establishing this diagnosis can subsequently direct the appropriate neuroradiological evaluation for HH and surgical treatment of these lesions. PMID- 20722351 TI - Neural correlates of error monitoring in an adult with Klinefelter's syndrome: a case report. AB - Studies have indicated that individuals with Klinefelter's syndrome (KS) exhibit deficits in executive functions. However, little attention has been paid to investigate control mechanism of executive functions, i.e., error monitoring, in individuals with KS. Two event-related potential (ERP) components, i.e., error related negativity (Ne/ERN) and error positivity (Pe), are the electrophysiological markers of error monitoring. This case report presents the findings of error monitoring from an adult with KS using the electrophysiological technique. This KS individual displayed small ERN and Pe amplitudes, suggesting that he may exhibit deficient error detection and reaction, a lack of conscious error recognition, and nonproficient adjustment after an error. The findings of this report should stimulate further study in error monitoring in individuals with KS. PMID- 20722352 TI - Noninvasive multimodal neuroimaging for Rasmussen encephalopathy surgery: simultaneous EEG-fMRI recording. AB - Rasmussen syndrome is characterized by continuous partial seizures with progressive neurological/cognitive impairment. Currently the only effective treatment is surgery (hemispherectomy). The objective of our study is to detect the exact epileptogenic focus through the analysis of multimodal noninvasive and innocuous functional neuroimaging. The subject is a 5-year-old female patient with Rasmussen encephalopathy. Continuous and simultaneous electroencephalography functional magnetic resonance imaging (EEG-fMRI) was recorded. The sources of background and paroxysmal activity of EEG were computed by low resolution electromagnetic tomography (LORETA). Image analysis (SPM: statistic parametric mapping) was obtained for the areas where statistically significant differences in the fMRI BOLD response were computed, and the results from both techniques were compared. The main source of paroxysmal activity by EEG analysis was found in the anterolateral left hemisphere, with a significant increase in absolute and relative energies of slow frequency bands (theta-delta): Z > or = 3. The fMRI BOLD signal (basal vs. paroxysmal activity) was significantly different in the same region (t-test > or = 2.39). The generators of propagated paroxysmal activity were found in similar areas for both techniques. In conclusion, simultaneous EEG-fMRI recording allows the analysis of two harmless functional neuroimaging techniques separately and together in the same time period. In our case, it allowed the accurate delineation of epileptogenic foci and areas of spread with high spatiotemporal resolution, which is crucial for epilepsy surgery. PMID- 20722353 TI - The yield of preoperative sequential routine scalp EEGs in patients who underwent anterior temporal lobectomy for mesial temporal sclerosis. AB - Mesial temporal lobe epilepsy syndrome (MTLES) is the most common surgically remediable epileptic syndrome in adults. Its diagnosis is easy when clinical history is supported by positive laboratory findings. However, routine EEG may not be informative in some patients, thus delaying accurate diagnosis. Therefore, we sought to determine how often routine EEGs displayed epileptiform discharges pre-operatively in a group of patients who underwent surgery for MTLES. Retrospectively, we reviewed the outpatient EEG records of MTLES patients who underwent surgery at our epilepsy center between 1997-2008 and had at least one routine pre-operative EEG recording in our outpatient laboratory. For each patient, serial EEGs were coded as normal, displaying nonspecific abnormalities or lateralized and localized interictal epileptiform discharges. Seventy patients were included in the study. We reviewed 230 EEGs. In almost half of the patients (47.1%) all EEGs were normal or revealed nonspecific findings. In patients who had >1 EEG, almost 3 EEGs had to be recorded to detect the epileptiform discharges for the first time and 6.23 years were needed to accomplish this. Sleep deprivation considerably increased the yield. In summary, patients who have a clinical history suggesting MTLES may need at least 3 routine scalp EEG recordings (with at least one of them after sleep deprivation) to detect epileptiform abnormalities and it may take much time. Therefore, a single prolonged outpatient video-EEG monitoring or an overnight inpatient monitoring might be reasonable alternatives to serial EEGs. PMID- 20722354 TI - Effectiveness of neurofeedback training as a treatment for opioid-dependent patients. AB - Neurofeedback (NF) training has been employed as a therapeutic method in substance-dependence disorder over the last three decades. The purpose of the present study was to examine the effectiveness of this method on improvement of comorbid neuro-psychological syndromes in opioid-dependence disorder. Psychopathological and craving dimensions and brain activity signals of 20 opioid dependent patients were measured using Symptom Checklist-90-Revised (SCL-90-R), Heroin Craving Questionnaire (HCQ), and Quantitative Electroencephalography (QEEG). All the patients were undergoing pharmacotherapy. They were assigned to two groups that were matched based on SCL-90-R scores, education and age. The experimental group received 30 sessions of NF training in addition to their medicine. The control group received only the usual pharmacotherapy. The probable changes were monitored by reappraisal of all the patients after the treatment. We hypothesized that patients in the experimental group would show more reduction in their comorbid syndromes. The Multivariate Analysis of Covariance (MANCOVA) showed that the experimental group, in comparison with control group, showed significantly more improvement in all three outcome measures. In the SCL-90-R, improvement was noted with the hypochondriacs, obsession, interpersonal sensitivity, aggression, psychosis, and general symptomatic indexes. In the HCQ, improvement was found in the anticipation of positive outcome, desire to use substance, and total average score. Finally, the QEEG showed positive changes in frontal, central and parietal delta, frontal and central theta, parietal alpha and frontal and central Sensory Motor Rhythm (SMR) amplitudes. This study suggests that NF can be used as a therapeutic method to ameliorate abnormalities related to opioid-dependence disorders. The results emphasize the importance of neuropsychological interventions in treatment of substance-dependence disorders. PMID- 20722355 TI - Thermally triggered cellular uptake of quantum dots immobilized with poly(N isopropylacrylamide) and cell penetrating peptide. AB - Thermally sensitive quantum dots (TSQDs) that exhibit an "on-demand" cellular uptake behavior via temperature-induced "shielding/deshielding" of cell penetrating peptides (CPP) on the surface were fabricated. Poly(N isopropylacrylamide) (PNIPAAm) (M(w) = 11.5K) and CPP were biotinylated at their terminal ends and co-immobilized on to the surface of streptavidin-coated quantum dots (QDs-Strep) through biotin-streptavidin interaction. The cellular contact of CPP was sterically hindered due to hydrated PNIPAAm chains below the lower critical solution temperature (LCST). In contrast, above the LCST, grafted PNIPAAm chains were collapsed to make CPP moieties resurfaced, leading to increased cellular uptake of QDs. The temperature-controlled "shielding/deshielding" of CPP was further applied for a thermally triggered siRNA delivery system, where biotinylated siRNA was additionally conjugated to the surface of TSQDs. The level of gene silencing was significantly enhanced by increasing temperature above the LCST due to the surface exposure of CPP. PMID- 20722356 TI - A facile "air-molding" method for nanofabrication. AB - In this letter, we demonstrate a spherical nanocavities fabrication using an "air molding" method, which is implemented by modulating the pressure difference across air-liquid interfaces in nanoholes on the mold. The cavities formation is theoretically considered and experimentally verified at macroscale first, and then a series of experiments are performed over a patterned surface with sub-300 nm holes by varying the pressure difference by sending a PDMS prepolymer coated mold into a vacuum chamber with changeable pressure. Results show that the air molding method for spherical cavities fabrication is feasible not only at macroscale, but also at the nanoscale when introducing a pressure difference across the air-liquid interface. And the cavities shape is easily controlled by modulating the pressure in the vacuum chamber. The spherical cavities in this paper have application potential in the optical field and in micro- and nanofluidics. PMID- 20722357 TI - Superamphiphiles based on charge transfer complex: controllable hierarchical self assembly of nanoribbons. AB - We have demonstrated a hierarchical self-assembly of the nanoribbons on the basis of the concept of a superamphiphile. A viologen-containing surfactant (RV) and a water-soluble electron donor, 6,8-dihydroxypyrene-1,3-disulfonic acid disodium (DHP), are mixed in water to form a charge transfer complex (RV-DHP), functionalizing as a superamphiphile. RV-DHP can self-assemble in water to form single-layer nanoribbon at pH 9. Moreover, upon pH stimulus, the self-assembling nanostructure can be tunable reversibly between single-layer and multilayer nanoribbons. This study represents a new example of hierarchical self-assembly of one-dimensional nanostructures, which may find potential applications in the area of smart nanodevices. PMID- 20722358 TI - Anharmonic electron-phonon coupling in condensed media: 1. Formalism. AB - Three different schemes for calculating anharmonic line shape functions are reported and discussed for the first time in this article using eigenstate representation. First, the linear dipole-moment time correlation function (DMTCF), homogeneous (single-site) absorption line shape function, and the respective Franck-Condon factors (FCF) are derived and explored as a molecule makes a transition from a harmonic to an anharmonic (Morse potential) electronic state. Second, the linear DMTCF, homogeneous absorption line shape function, and FCFs are also derived as a molecule makes a transition from one anharmonic to another linearly displaced anharmonic state; FCFs in this case are reported in an exact closed-form expressed in terms of Appell's hypergeometric function. Third, same as the latter set of results are reported but with both linearly displaced and distorted shape of the upper Morse potential. FCFs of the zero-phonon line in all three cases are reported. The first case is rather mathematically complex as a result of taking the overlap integral of the Morse oscillator eigenfunctions, whose spatial decay is a simple exponential, with those of harmonic oscillator, whose decay is a Gaussian. This form of a functional disparity gives rise to some challenges. Model calculations are presented and discussed. PMID- 20722359 TI - Novel melt-processable poly(ether ether ketone)(PEEK)/inorganic fullerene-like WS(2) nanoparticles for critical applications. AB - The combination of high-performance thermoplastic poly(ether ether ketone) (PEEK) with inorganic fullerene-like tungsten disulfide (IF-WS(2)) nanoparticles offers an attractive way to combine the merits of organic and inorganic materials into novel polymer nanocomposite materials. Here, we report the processing of novel PEEK/IF-WS(2) nanocomposites, which overcome the nanoparticle agglomerate formation and provide PEEK-particle interactions. The IF-WS(2) nanoparticles do not require exfoliation or modification, making it possible to obtain stronger, lighter materials without the complexity and processing cost associated with these treatments. The nanocomposites were fabricated by melt blending, after a predispersion step based on ball milling and mechanical treatments in organic solvent, which leads to the dispersion of individually IF-WS(2) nanoparticles in the PEEK matrix as confirmed by scanning electron microscopy. In order to determine the performance of the PEEK/IF-WS(2) nanocomposites for potential critical applications, particularly for the aircraft industry, we have extensively investigated these materials with a wide range of structural, thermal, and mechanical techniques using time-resolved synchrotron X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, dynamic-mechanical analysis, and tensile and impact tests as well as thermal measurements. Modulus, tensile strengh, thermal stability, and thermal conductivity of PEEK exhibited remarkable improvement with the addition of IF WS(2). PMID- 20722360 TI - Lowest electronic states of the CP47 antenna protein complex of photosystem II: simulation of optical spectra and revised structural assignments. AB - In this work, we present simulated steady-state absorption, emission, and nonresonant hole burning (HB) spectra for the CP47 antenna complex of photosystem II (PS II) based on fits to recently refined experimental data (Neupane et al. J. Am. Chem. Soc. 2010, 132, 4214). Excitonic simulations are based on the 2.9 A resolution structure of the PS II core from cyanobacteria (Guskov et al. Nat. Struct. Mol. Biol. 2009, 16, 334), and allow for preliminary assignment of the chlorophylls (Chls) contributing to the lowest excitonic states. The search for realistic site energies was guided by experimental constraints and aided by simple fitting algorithms. The following experimental constraints were used: (i) the oscillator strength of the lowest-energy state should be approximately <=0.5 Chl equivalents; (ii) the excitonic structure must explain the experimentally observed red-shifted (~695 nm) emission maximum; and (iii) the excitonic interactions of all states must properly describe the broad (non-line-narrowed, NLN) HB spectrum (including its antihole) whose shape is extremely sensitive to the excitonic structure of the complex, especially the lowest excitonic states. Importantly, our assignments differ significantly from those previously reported by Raszewski and Renger (J. Am. Chem. Soc. 2008, 130, 4431), due primarily to differences in the experimental data simulated. In particular, we find that the lowest state localized on Chl 526 possesses too high of an oscillator strength to fit low-temperature experimental data. Instead, we suggest that Chl 523 most strongly contributes to the lowest excitonic state, with Chl 526 contributing to the second excitonic state. Since the fits of nonresonant holes are more restrictive (in terms of possible site energies) than those of absorption and emission spectra, we suggest that fits of linear optical spectra along with HB spectra provide more realistic site energies. PMID- 20722361 TI - Formation of one-dimensional capped ZnO nanoparticle assemblies at the air/water interface. AB - The self-assembling behavior and microscopic structure of zinc oxide nanoparticle Langmuir-Blodgett monolayer films were investigated for the case of zinc oxide nanoparticles coated with a hydrophobic layer of dodecanethiol. Evolution of nanoparticle film structure as a function of surface pressure (pi) at the air water interface was monitored in situ using Brewster's angle microscopy, where it was determined that pi = 16 mN/m produced near-defect-free monolayer films. Transmission electron micrographs of drop-cast and Langmuir-Schaefer deposited films of the dodecanethiol-coated zinc oxide nanoparticles revealed that the nanoparticle preparation method yielded a microscopic structure that consisted of one-dimensional rodlike assemblies of nanoparticles with typical dimensions of 25 * 400 nm, encased in the organic dodecanethiol layer. These nanoparticle containing rodlike micelles were aligned into ordered arrangements of parallel rods using the Langmuir-Blodgett technique. PMID- 20722362 TI - Anharmonic RRKM calculation for the dissociation of (H(2)O)(2)H(+) and its deuterated species (D(2)O)(2)D(+). AB - Investigations on the dissociation kinetics of hydrated protonium ions, (H(2)O)(2)H(+) and their deuterated species (D(2)O)(2)D(+), are reported based on the harmonic and anharmonic oscillator model using the transition state theory and ab initio calculations. We find that the dissociation of (H(2)O)(2)H(+) and (D(2)O)(2)D(+) exhibits a distinct threshold behavior due to the existence of activation energies. Moreover, the deviation between the harmonic and anharmonic dissociation rate constants becomes larger in the high energy or temperature range, with the rate constants becoming unreasonably large under the harmonic oscillator model. The isotope effect is found to become more distinct but only in the case of the anharmonic oscillator model. These results show that the anharmonic Rice-Ramsperger-Kassel-Marcus (RRKM) theory can provide a reasonably good description for the dissociation of (H(2)O)(2)H(+) and (D(2)O)(2)D(+). Furthermore, a theoretical model to demonstrate the principle of vibrational predissociation spectroscopy (VPS) is established from the viewpoint of RRKM theory and applied in determining the experimental conditions and understanding the role of the dissociation rate constant k(E) played in the VPS experiment, using (H(2)O)(2)H(+) and (D(2)O)(2)D(+) as examples. PMID- 20722363 TI - Photophysics and photochemistry of the UV filter kynurenine covalently attached to amino acids and to a model protein. AB - The photophysics and photochemistry of kynurenine (KN) covalently bound to the amino acids lysine, cysteine, and histidine, the antioxidant glutathione, and the protein lysozyme have been studied by optical spectroscopy with femto- and nanosecond time resolution. The fluorescence quantum yield of the adducts of KN to amino acids is approximately 2 times higher than that of the free KN in solution; KN attached to protein exhibits a 7-fold increase in the fluorescence quantum yield. The S(1) state dynamics of KN-modified lysozyme reveals a multiphasic decay with a broad dispersion of time constants from 1 ps to 2 ns. An increase of the triplet yield of KN bound to lysozyme is also observed; the triplet state undergoes fast intramolecular decay. The obtained results reveal an increase of the photochemical activity of KN after its covalent attachment to amino acids and proteins, which may contribute to the development of oxidative stress in the human lenses-the main causative factor for the cataract onset. PMID- 20722364 TI - The effect of multiplicity on the size of iron(II) and the structure of iron(II) porphyrins. AB - The displacement of the iron(II) atom from the porphyrin plane in iron(II) porphyrin complexes is investigated with respect to the spin state of iron(II) employing density functional theory. In this study the quantum theory of atoms in molecules (QTAIM) is used to show that the atomic volume of iron is smaller in the quintet state of imidazolium ligated iron(II) porphyrin than in the triplet state. This is consistent with what has been found for free atoms and contradicts the original interpretation of structural studies with X-rays, which assumed that the out-of-plane displacement of iron from the porphyrin ring in the quintet state is due to the increased spatial size of the high-spin iron atom. The bonding environment of the iron atom is analyzed with respect to the electron density (rho) at the bond critical points (BCPs). It is found that in the quintet state, relative to the triplet state, there is a stronger bonding interaction between iron and the nitrogen atoms of the porphyrin despite a longer bond length. It has previously been suggested that the weakening of these bonds is the cause of the out-of-plane displacement of iron. Since this is not the case, this implies that the magnitude of the bonding interaction between the iron atom and the axial ligand has a more significant role in the domed structure of the quintet state. PMID- 20722365 TI - Conformational preferences of proline analogues with a fused benzene ring. AB - The intrinsic conformational preferences of indoline-2-carboxylic acid (Inc) and its alpha-methylated derivative (alphaMeInc) have been investigated using quantum mechanical calculations. Specifically, the behavior of their N-acetyl-N' methylamide derivatives, Ac-L-Inc-NHMe and Ac-L-alphaMeInc-NHMe, has been explored at the B3LYP/6-31+G(d,p) level. Such amino acids are analogues of proline and (alpha-methyl)proline, respectively, bearing a benzene ring fused to the C(gamma)-C(delta) bond of the five-membered pyrrolidine ring. The additional aromatic group has been shown to significantly restrict the conformational space available to these residues by reducing the flexibility of both the five-membered cycle and the peptide backbone. The fused benzene ring also plays a critical role in determining the cis-trans arrangement of the amide bond involving the pyrrolidine nitrogen, which is also modulated by the presence of the alpha-methyl group in the alphaMeInc derivative. Furthermore, the influence of the environment on the conformational propensities of these compounds has been evaluated by using both a self-consistent reaction field model and a recently developed interface in a hybrid QM/MM scheme, in which the solvent molecules are treated explicitly with classical mechanics while the solute is described by quantum mechanics at the density functional theory level. PMID- 20722366 TI - Synthesis and characterization of mixed methyl/allyl monolayers on Si(111). AB - The formation of mixed methyl/allyl monolayers has been accomplished through a two-step halogenation/alkylation reaction on Si(111) surfaces. The total coverage of alkylated Si, the surface recombination velocities, and the degree of surface oxidation as a function of time have been investigated using X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, and microwave conductivity measurements. The total coverage of alkyl groups, the rate of oxidation, and the surface recombination velocities of Si(111) terminated by mixed monolayers were found to be close to those observed for CH(3)-Si(111) surfaces. Hence, the mixed monolayer surfaces retained the beneficial properties of CH(3)-Si(111) surfaces while allowing for convenient secondary surface functionalization. PMID- 20722367 TI - Construction of peptoids with all trans-amide backbones and peptoid reverse turns via the tactical incorporation of N-aryl side chains capable of hydrogen bonding. AB - The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent interactions that direct local peptoid folding. We have found that simple, peptoid monomer model systems allow for the effective isolation of individual interactions within the peptoid backbone and side chains and can facilitate the study of the role of these interactions in restricting local peptoid conformation. Herein, we present an analysis of a set of peptoid monomers and an oligomer containing N-aryl side chains capable of hydrogen bonding with the peptoid backbone. These model peptoids were found to exhibit well-defined local conformational preferences, allowing for control of the omega, phi, and psi dihedral angles adopted by the systems. Fundamental studies of the peptoid monomers enabled the design and synthesis of an acyclic peptoid reverse-turn structure, in which N-aryl side chains outfitted with ortho-hydrogen bond donors were hypothesized to play a critical role in the stabilization of the turn. This trimeric peptoid was characterized by X-ray crystallography and 2D NMR spectroscopy and was shown to adopt a unique acyclic peptoid reverse-turn conformation. Further analysis of this turn revealed an n->pi*(C?O) interaction within the peptoid backbone, which represents the first reported example of this type of stereoelectronic interaction occurring exclusively within a polypeptoid backbone. The installation of N-aryl side chains capable of hydrogen bonding into peptoids is straightforward and entirely compatible with current solid-phase peptoid synthesis methodologies. As such, we anticipate that the strategic incorporation of these N-aryl side chains should facilitate the construction of peptoids capable of adopting discrete structural motifs, both turnlike and beyond, and will facilitate the continued development of well-folded peptoids. PMID- 20722368 TI - Dependence of the conformational isomerism in 1-n-butyl-3-methylimidazolium ionic liquids on the nature of the halide anion. AB - The conformational isomerism of the 1-n-butyl-3-methylimidazolium cation, [C(4)mim](+), in halide-based ionic liquids--[C(4)mim]Cl, [C(4)mim]Br, and [C(4)mim]I--was explored by Raman spectroscopy. The [C(4)mim](+) cation exhibits trans-gauche conformational isomerism with respect to the N1-C7-C8-C9 dihedral angle of its butyl chain. The thermodynamics of trans-gauche conversion were analyzed through the successful evaluation of the corresponding Gibbs free energy, Delta(iso)G degrees , enthalpy, Delta(iso)H degrees , and entropy, Delta(iso)S degrees , of conformational isomerization. The values of Delta(iso)G degrees obtained are small (a few units of kJ/mol) and show a slight negative variation with the decrease of the size of the halide anion. On the other hand, Delta(iso)H degrees and Delta(iso)S degrees values are positive for [C(4)mim]I and decrease with the anion size to yield negative values for [C(4)mim]Cl and [C(4)mim]Br. This suggests that the negative electrostatic field around the halide anions stabilizes the gauche isomer from an enthalpic point of view. In order to study the structure and ion-ion interactions in this type of ionic liquids, high-energy X-ray diffraction experiments were performed for [C(4)mim]Cl at different temperatures and for supercooled [C(4)mim][Br] at ambient temperature. Molecular dynamics (MD) simulations for these systems were also carried out at several temperatures. Delta(iso)G degrees and Delta(iso)H degrees values derived from the simulations qualitatively agree with the experimental ones. Experimental X-ray structure factors are also well reproduced by the simulations. The MD results also allowed the calculation of different spatial distribution functions (SDFs) for the three ionic liquids. Although all SDFs exhibit similar trends, [C(4)mim]I shows a reduced anion density facing the C(2) H atoms of the cation and enhanced anion densities above and below the imidazolium ring plane. This indicates that anions localized near the C(2)-H atoms of the cation can stabilize their gauche conformer, an effect that is stronger with smaller anions. This conclusion is also supported by ab initio calculations at the CCSD(T) level for isolated ion pairs. PMID- 20722369 TI - Design and assembly of new nonviral RNAi delivery agents by microwave-assisted quaternization (MAQ) of tertiary amines. AB - RNA interference (RNAi) is a gene-silencing phenomenon whereby double-stranded RNA (dsRNA) triggers the sequence-specific degradation of homologous mRNA. RNAi has been quickly and widely applied to discover gene functions and holds great potential to provide a new class of therapeutic agents. However, new chemistry and delivery approaches are greatly needed to silence disease-causing genes without toxic effects. We reasoned that conjugation of the cholesterol moiety to cationic lipids would enhance RNAi efficiencies and lower the toxic effects of lipid-mediated RNAi delivery. Here, we report the first design and synthesis of new cholesterol-conjugated cationic lipids for RNAi delivery using microwave assisted quaternization (MAQ) of tertiary amines. This strategy can be employed to develop new classes of nonviral gene delivery agents under safe and fast reaction conditions. PMID- 20722370 TI - Stereoselective alpha-aminoallylation of aldehydes with chiral tert butanesulfinamides and allyl bromides. AB - The combination of an aldehyde, an allylic bromide, and tert-butanesulfinamide in the presence of indium metal and titanium tetraethoxide allows straightforward access to homoallylamine derivatives in high yields and stereoselectivities. Moreover, the synthetic utility of the enantioenriched homoallylamine derived from n-decanal was illustrated in a concise synthesis of (+)-isosolenopsin. In this context, similar homoallylamines has been recently used by other groups in the synthesis of naturally occurring alkaloids. PMID- 20722371 TI - Heterogeneous chiral copper complexes of amino alcohol for asymmetric nitroaldol reaction. AB - Chiral amino alcohols supported on mesoporous silicas were synthesized and evaluated as a new class of chiral ligands in copper-catalyzed nitroaldol reaction under heterogeneous and mild reaction conditions. The activity and enantioselectivity of the present catalytic system is immensely influenced by the presence of achiral and chiral bases as an additive. The heterogenized chiral copper(II) complex of amino alcohol was found to be an effective recyclable catalyst for the nitroaldol reaction of different aldehydes such as aromatic, aliphatic, alicyclic, and alpha-beta unsaturated aldehydes to produce nitroaldol products with remarkably high enantioselectivity (>=99%) and yields. PMID- 20722372 TI - Structure of micelles formed by highly asymmetric polystyrene-b polydimethylsiloxane and polystyrene-b-poly[5-(N,N-diethylamino)isoprene] diblock copolymers. AB - The internal structure of polystyrene(PS)-shell micelles having core-forming blocks consisting of polydimethylsiloxane (PDMS) or poly[5-(N,N diethylamino)isoprene] (PAI) was determined in detail by accessing the multilevel structural organization using static and dynamic light scattering and small-angle X-ray scattering techniques. Well-defined PS-b-PDMS and PS-b-PAI diblock copolymers with molar masses in the range of 12.0k-18.2k g/mol were dispersed in cyclohexane, dimethylacetamide, or dimethylformamide. Colloidal nanoparticles exhibiting either swollen core with a large surface area per corona chain that enables the PS chains to assume a random coil conformation with gaussian statistics, or compact core and slightly stretched PS chains in the corona were obtained. Therefore, the results of this study provide an interesting alternative allowing for precise control of the core and corona properties of PS-b-PDMS and PS-b-PAI micelles in selective solvents. Admittedly, such differences in terms of micellar properties can dictate the potential of block copolymer micelles for generating thin films from preformed nano-objects, as well as the capability to function as nanoreactors in organic medium. PMID- 20722373 TI - Gold nanoframes: very high surface plasmon fields and excellent near-infrared sensors. AB - The sensing efficiency or factor of noble metal nanoparticles is defined as the wavelength shift of the surface plasmon resonance extinction peak position per unit change in the refractive index of the surrounding medium. The sensitivity of different shapes and sizes of gold nanoparticles has been studied by many investigators and found to depend on the plasmon field strength. As a result, the sensitivity factors were found to be larger for hollow nanoparticles than for solid ones of comparable dimensions. This is due to the strong plasmonic fields resulting from the coupling between the external and internal surface plasmon fields in the hollow nanoparticles. In the present paper, the sensitivity factors of a large number of gold nanoframes of different size and wall thickness have been determined by experimental and theoretical computation (using the discrete dipole approximation method). The dependence of the sensitivity factors and the plasmon field strength on the wall thickness and the size of the nanoframes has been determined and is discussed. The sensitivity factors are found to increase linearly with the aspect ratio (wall length/wall thickness) of the nanoframes and are especially sensitive to a decrease in the wall thickness. In comparison with other plasmonic nanoparticles, it is found that nanoframes have sensitivity factors that are 12, 7, and 3 times higher than those of gold nanospheres, gold nanocubes, and gold nanorods, respectively, as well as more than several hundred units higher than those of comparable-size gold nanocages. PMID- 20722374 TI - Real-time atmospheric chemistry field instrumentation. AB - Quantifying the concentrations of trace atmospheric species in complex, reactive, and constantly changing gas and particle mixtures is challenging. This article provides a broad overview of recent advances in instrumentation used for analyzing ambient gases and particles continuously and with fast time resolution during field campaigns. PMID- 20722375 TI - TiO2(B) nanoribbons as negative electrode material for lithium ion batteries with high rate performance. AB - Nanosized TiO(2)(B) has been investigated as a possible candidate to replace Li(4)Ti(5)O(12) or graphite as the negative electrode for a Li-ion battery. Nanoribbon precursors, classically synthesized in autogenous conditions at temperatures higher than 170 degrees C in alkaline medium, have been obtained, under reflux (T ~ 120 degrees C, P = 1 bar). After ionic exchange, these nanoribbons exhibit a surface area of 140 m(2) g(-1), larger than those obtained under autogenous conditions or by solid state chemistry. These nanoparticles transform after annealing to isomorphic titanium dioxide. They mainly crystallize as the TiO(2)(B) variety with only 5% of anatase. This quantification of the anatase/TiO(2)(B) ratio was deduced from Raman spectroscopy measurement. TEM analysis highlights the excellent crystallinity of the nanosized TiO(2)(B), crystallizing as 6 nm thin nanoribbons. These characteristics are essential in lithium batteries for a fast lithium ion solid state diffusion into the active material. In lithium batteries, the TiO(2)(B) nanoribbons exhibit a good capacity and an excellent rate capability (reversible capacity of 200 mA h g(-1) at C/3 rate (111 mA g(-1)), 100 mA h g(-1) at 15C rate (5030 mA g(-1)) for a 50% carbon black loaded electrode). The electrode formulation study highlights the importance of the electronic and ionic connection around the active particles. The cycleability of the nano-TiO(2)(B) is another interesting point with a capacity loss of 5% only, over 500 cycles at 3C. PMID- 20722376 TI - Improved synthesis of bis(borano)hypophosphite salts. AB - A synthesis of the bis(borano)hypophosphite anion with various counterions has been developed to make use of more benign and commercially available reagents. This method avoids the use of potentially dangerous reagents used by previous methods and gives the final products in good yield. Details of the crystal structure determination of the sodium salt in space group Ama2 are given using a novel computational technique combined with Rietveld refinement. PMID- 20722377 TI - Ultrasound-induced dissolution of lipid-coated and uncoated gas bubbles. AB - The 1.1 MHz ultrasound response of micrometer-scale perfluorobutane gas bubbles, coated with a mixture of 90 mol % saturated phospholipid (disteroylphosphatidylcholine, DSPC) or unsaturated phospholipid (dioleoylphosphatidylcholine, DOPC) and 10 mol % PEG-lipid, was studied by optical microscopy. Uncoated bubbles were also studied. Bubbles, resting buoyantly against the wall of a polystyrene cuvette, were exposed to brief pulses of ultrasound (~200 kPa amplitude) at a repetition rate of 25 Hz; images of the bubbles were taken after every other pulse. The coating had little effect on the initial response: large (>10 MUm diameter) bubbles showed no size change, while smaller bubbles rapidly shrank (or fragmented) to reach a stable or metastable diameter-ca. 2 MUm for coated bubbles and 4 MUm for uncoated bubbles. The coating had a significant effect on further bubble evolution: after reaching a metastable size, uncoated bubbles and DOPC-coated bubbles continued to shrink slowly and ultimately vanished entirely, while DSPC-coated bubbles did not change perceptibly during the duration of the exposure. Numerical modeling using the modified Herring equation showed that the size range in which DSPC bubbles responded does correspond well with the bubble resonance; the long-term stability of these bubbles may be related to the ability of the DSPC to form a two dimensional solid at ambient temperature or to phase separate from the PEG-lipid. PMID- 20722378 TI - Hydrogen-bonding-induced complexation of polydimethylsiloxane-graft-poly(ethylene oxide) and poly(acrylic acid)-block-polyacrylonitrile micelles in water. AB - Polydimethylsiloxane-graft-poly(ethylene oxide) (PDMS-g-PEO) copolymers form micelles in water with PDMS as the core and PEO as the corona. The introduction of poly(acrylic acid)-block-polyacrylonitrile (PAA-b-PAN) block copolymers in water leads to the formation of micellar complexes due to the hydrogen bonding between carboxyl groups and ether oxygens among the PAA and PEO chains in the corona of the micelles. The effects of pH, molar ratios (r) of PAA/PEO, and the standing time on the directly mixing these two micelles in water have been investigated using laser light scattering (LLS) and transmission electron microscopy (TEM). Our results showed that the complexation between PAA and PEO in the corona was greatly enhanced at a pH below 3.5. For a fixed pH value, the interactions between these two micelles in water were governed by the value of r. At r < ~0.6, mixing the two micelles in water resulted in a large floccule because the smaller PAA-b-PAN micelles act as physical cross-links, which are absorbed onto one PDMS-g-PEO micelle and simultaneously bonded to PEO chains on the other micelles, forming bridges and causing flocculation. At ~0.6 < r < ~1.2, the mixing led to stable micellar complexes with a layer of PAA-b-PAN micelles absorbed onto the initial PDMS-g-PEO micelles. At r > ~1.2, the resultant micellar complexes first remained stable, but they precipitated from solution after a long time standing. PMID- 20722379 TI - Porphyrin-fullerene, C60, cocrystallates: influence of C60 on the porphyrin ring conformation. AB - To examine the influence of fullerene on the macrocyclic ring conformation, crystal structures of a series of cocrystals of 2,3,5,10,12,13,15,20 octaphenylporphyrin, M(TPP)(Ph)(4) (M = 2H, Co(II), Cu(II)), and 2,312,13 tetramethyl-5,7,8,10,15,17,18,20-octaphenyl-porphinato copper(II), CuTPP(Ph)(4)(CH(3))(4), derivatives with fullerene, C(60), were elucidated. Furthermore, crystal structures of the parent porphyrins, M(TPP)(Ph)(4) (M = Co(II), Cu(II)) complexes, were also determined. All the cocrystals revealed one to-one stoichiometry between the porphyrin and C(60) and were free of lattice solvates. Porphyrin rings in M(TPP)(Ph)(4).C(60) cocrystals revealed significant distortion with the root-mean-square (rms) value as high as 0.265(2) A which is the average deviation of the 24 atoms core from the least-squares plane. Crystal structures of the parent M(TPP)(Ph)(4) (M = Co(II), Cu(II)) complexes indicated near planarity of the 24-atom core with the root-mean-square deviation value of 0.016(2) A. Molecular packing in the M(TPP)(Ph)(4).C(60) cocrystals showed essentially one-dimensional chains interconnected by weak interporphyrin and porphyrin-fullerene close contacts. The N(porphyrin)...C(C(60)) shortest distances between the H(2)(TPP)(Ph)(4) (M = 2H, Co(II), Cu(II)) and fullerene in the cocrystals are 3.031(5) A, 3.062(4) A, and 3.059(3) A, respectively. Similarly, close contact M...C distances in the M(TPP)(Ph)(4).C(60) (M = Co(II), Cu(II)) are 2.761(6) A and 2.886(3) A, respectively. In the Cu(TPP)(Ph)(4)(CH(3))(4).C(60) cocrystal, the shift of macrocyclic ring toward planarity was evidenced from the rms value of 0.236(2) A relative to that observed in CuTPP(Ph)(4)(CH(3))(4).CHCl(3) (0.391(2) A). The distortion of the macrocyclic ring in M(TPP)(Ph)(4).C(60) complexes was examined by normal coordinate-structure decomposition (NSD) analyses. Their out-of-plane displacement of the core atoms revealed predominant contribution being saddle (~95-96%) and gentle domed distortions (3-4%). In the case of M(TPP)(Ph)(4)(CH(3))(4).C(60) cocrystal, it showed mainly saddled (~83%), minimal ruffled (8%) and domed (8%) distortions of the macrocyclic ring. In-plane displacement on the 24-atom core of the porphyrin in these cocrystallates features generally a varying degree of N-str (B(1g)) and bre (A(1g)) distortions. PMID- 20722380 TI - Pd-catalyzed reaction of sterically hindered hydrazones with aryl halides: synthesis of tetra-substituted olefins related to iso-combretastatin A4. AB - PdCl(2)(MeCN)(2) in combination with dppp proved to be a powerful and efficient catalyst for the coupling of sterically hindered N-arylsulfonylhydrazones with aryl halides, thus providing a flexible and convergent access to tetrasubstituted olefins related to iso-combretastatin A4 in good yields. This new protocol has been applied successfully to the formal synthesis of biphenylisopropylidene 4 pyridine CYP17 inhibitor, 12b, of biological interest. PMID- 20722381 TI - Asymmetric synthesis of functionalized, monocyclic chlorocyclobutenes. AB - The selective synthesis of a variety of stereopure monocyclic chlorocyclobutenes is described. These derivatives could be coupled with Grignard reagents; two dienes from coupling with vinylmagnesium bromide reacted smoothly with maleic anhydride to yield illudol-related [4 + 2] cycloadducts. PMID- 20722382 TI - Copper(I)-secondary diamine complex-catalyzed enantioselective conjugate boration of linear beta,beta-disubstituted enones. AB - A copper(I)-chiral secondary diamine (L-e) complex catalyzes an enantioselective conjugate boration of beta,beta-disubstituted enones in high yields and up to 99% ee. Product chiral tertiary organoboronates can be converted to enantiomerically enriched cross-aldol products between ketones without any racemization. PMID- 20722383 TI - The electrical properties of biphenylenes. AB - The effect of the partial antiaromaticity of biphenylene on its substitution chemistry, its oxidation potential, and its single-molecule conductance is explored. Biphenylene and fluorene molecules with linkers of two amino groups or two cyclic thioether groups were synthesized and their conduction properties were investigated using scanning tunneling microscopy (STM) break-junction techniques and DFT calculations. Despite the partial antiaromaticity of biphenylene, which causes the biphenylenes to be much more easily oxidizable, no significant increase in molecular conductance was found. PMID- 20722384 TI - Convergent synthesis of trisubstituted Z-allylic esters by Wittig-Schlosser reaction. AB - beta-Lithiooxyphosphonium ylides, generated in situ from aldehydes and Wittig reagents, react readily with halomethyl esters to form trisubstituted Z-allylic esters. The methodology was applied to a total synthesis of the geranylgeraniol derived diterpene (6S,7R,Z)-7-hydroxy-2-((E)-6-hydroxy-4-methylhex-4-enylidene) 6,10-dimethylundec-9-enyl acetate (12). PMID- 20722385 TI - Dynamic ligand exchange in reactions of samarium diiodide. AB - Mechanistic studies show the importance of iodide displacement by additives that accelerate reactions of samarium diiodide. The key feature important for acceleration of reaction rate is the use of proton donors and other additives that have a high enough affinity for Sm(II) to displace iodide yet do not saturate the coordination sphere inhibiting substrate reduction. PMID- 20722386 TI - Highly alpha-selective hydrolysis of alpha,beta-epoxyalcohols using tetrabutylammonium fluoride. AB - We report a simple method for the highly regio- and stereoselective hydrolysis of alpha,beta-epoxyalcohols. Treatment of enantiopure epoxyalcohols derived from Sharpless epoxidation with TBAF/H(2)O resulted in exclusive ring opening at the normally disfavored alpha-position, providing access to arabino- or lyxo configured triols with full preservation of stereochemical purity. The method was applied in syntheses of 5-deoxy-l-arabinose (26) and a family of bicyclic acetals based on the insect pheromone hydroxybrevicomin (4). PMID- 20722387 TI - Pentagon-fused hollow fullerene in C78 family retrieved by chlorination. AB - C(78) is one of the most widely investigated higher fullerenes. Among its huge isomer family, only one non-IPR (IPR = isolated pentagon ring) cage, the C(2) symmetric (#22010)C(78), was previously stabilized by endohedral derivatization. Here we report a new C(1)-symmetric non-IPR hollow isomer, (#23863)C(78), which was captured as (#23863)C(78)Cl(8) and then subjected to a regioselective substitution reaction with benzyl hydroperoxide to form (#23863)C(78)(OOCH(2)C(6)H(5))Cl(7). The structural connectivity of (#23863)C(78), which contains a pair of fused pentagons, was confirmed by single crystal X-ray diffraction analysis of the (#23863)C(78)(OOCH(2)C(6)H(5))Cl(7) molecule, which shares the same fullerene core with (#23863)C(78)Cl(8); support for the structure is provided by comparable IR measurements and computation. Theoretical studies suggest that the differences in C-Cl bond length, intermediate stability, and steric effects of the involved molecules account for the chemical regioselectivity of the substitution reaction. PMID- 20722388 TI - Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp. AB - Stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a core bicyclo[2.2.2]diazaoctane ring system. These bioactive fungal secondary metabolites have a range of unusual structural and stereochemical features but their biosynthesis has remained uncharacterized. Herein, we report the first biosynthetic gene cluster for this class of fungal alkaloids based on whole genome sequencing of a marine-derived Aspergillus sp. Two central pathway enzymes catalyzing both normal and reverse prenyltransfer reactions were characterized in detail. Our results establish the early steps for creation of the prenylated indole alkaloid structure and suggest a scheme for the biosynthesis of stephacidin and notoamide metabolites. The work provides the first genetic and biochemical insights for understanding the structural diversity of this important family of fungal alkaloids. PMID- 20722389 TI - Trichohyalin is a potential major autoantigen in human alopecia areata. AB - Several lines of evidence support an autoimmune basis for alopecia areata (AA), a common putative autoimmune hair loss disorder. However, definitive support is lacking largely because the identity of hair follicle (HF) autoantigen(s) involved in its pathogenesis remains unknown. Here, we isolated AA-reactive HF specific antigens from normal human scalp anagen HF extracts by immunoprecipitation using serum antibodies from 10 AA patients. Samples were analyzed by LC-MALDI-TOF/TOF mass spectrometry, which indicated strong reactivity to the hair growth phase-specific structural protein trichohyalin in all AA sera. Keratin 16 (K16) was also identified as another potential AA-relevant target HF antigen. Double immunofluorescence studies using AA (and control sera) together with a monoclonal antibody to trichohyalin revealed that AA sera contained immunoreactivity that colocalized with trichohyalin in the growth phase-specific inner root sheath of HF. Furthermore, a partial colocalization of AA serum reactivity with anti-K16 antibody was observed in the outer root sheath of the HF. In summary, this study supports the involvement of an immune response to anagen-specific HFs antigens in AA and specifically suggests that an immune response to trichohyalin and K16 may have a role in the pathogenesis of the enigmatic disorder. PMID- 20722390 TI - Oxygen superbases as polar binding pockets in nonpolar solvents. AB - A novel class of chiral superbases derived from the 2,2'-bipyridyl-N,N'-dioxide skeleton are presented. Combined experimental and theoretical data reveal that their proton affinities are on the order of 1050 kJ mol(-1), with protonation occurring at the oxygen atoms in a chelating manner. In the free bases, the oxygen atoms form a strongly polar binding site hidden in a hydrophobic envelope formed by the hydrocarbon backbone of the superbases. This chiral molecular structure can entrap polar intermediates or polarized transition structures and stabilize them in nonpolar solvents. Specifically, this mode of catalysis is shown for the coupling of benzaldehyde and allyltrichlorosilane. PMID- 20722392 TI - Oysters produce an organic-inorganic adhesive for intertidal reef construction. AB - Coastal ecosystems rely upon oyster reefs to filter water, provide protection from storms, and build habitat for other species. From a chemistry perspective, few details are available to illustrate how these shellfish construct such extensive reef systems. Experiments presented here show that oysters generate a biomineralized adhesive material for aggregating into large communities. This cement is an organic-inorganic hybrid and differs from the surrounding shells by displaying an alternate CaCO(3) crystal form, a cross-linked organic matrix, and an elevated protein content. Emerging themes and unique aspects are both revealed when comparing oyster cement to the adhesives of other marine organisms. The presence of cross-linked proteins provides an analogy to mussel and barnacle adhesives whereas the high inorganic content is exclusive to oysters. With a description of oyster cement in hand we gain strategies for developing synthetic composite materials as well as a better understanding of the components needed for healthy coastal environments. PMID- 20722391 TI - Confocal imaging to quantify passive transport across biomimetic lipid membranes. AB - The ability of a molecule to pass through the plasma membrane without the aid of any active cellular mechanisms is central to that molecule's pharmaceutical characteristics. Passive transport has been understood in the context of Overton's rule, which states that more lipophilic molecules cross membrane lipid bilayers more readily. Existing techniques for measuring passive transport lack reproducibility and are hampered by the presence of an unstirred layer (USL) that dominates transport across the bilayer. This report describes assays based on spinning-disk confocal microscopy (SDCM) of giant unilamellar vesicles (GUVs) that allow for the detailed investigation of passive transport processes and mechanisms. This approach allows the concentration field to be directly observed, allowing membrane permeability to be determined easily from the transient concentration profile data. A series of molecules of increasing hydrophilicity was constructed, and the transport of these molecules into GUVs was observed. The observed permeability trend is consistent with Overton's rule. However, the values measured depart from the simple partition-diffusion proportionality model of passive transport. This technique is easy to implement and has great promise as an approach to measure membrane transport. It is optimally suited to precise quantitative measurements of the dependence of passive transport on membrane properties. PMID- 20722393 TI - In-tube extraction of volatile organic compounds from aqueous samples: an economical alternative to purge and trap enrichment. AB - A novel in-tube extraction device (ITEX 2) for headspace sampling was evaluated for GC/MS analysis of aqueous samples. Twenty compounds of regulatory and drinking water quality importance were analyzed, including halogenated hydrocarbons, BTEX compounds (benzene, toluene, ethylbenzene, xylenes), fuel oxygenates, geosmin, and 2-methylisoborneol. Five commercially available sorbent traps were compared for their compound specific extraction yield. On the basis of the results, a mixed bed trap was prepared and evaluated. The extraction parameters were optimized to yield maximum sensitivity within the time of a GC run, to avoid unnecessary downtime of the system. Method detection limits of 1-10 ng L(-1) were achieved for volatile organic compounds (VOCs), which is much lower than demands by regulatory limit values. The performance of the ITEX system is similar to that of purge and trap systems, but it requires lower sample volumes and is less prone to contamination, much simpler, more flexible, and affordable. Average relative standard deviations below 10% were achieved for all analytes, and recoveries from spiked tap water samples were between 90% and 103%, mostly. The extraction is nonexhaustive, removing a fraction of 7% to 55% of the target compounds, depending on the air-water partitioning coefficients. The method was also tested with nonsynthetic samples, including tap, pond, and reservoir water and different soft drinks. PMID- 20722394 TI - Microchip electrophoresis profiling of Abeta peptides in the cerebrospinal fluid of patients with Alzheimer's disease. AB - The preferential aggregation of Abeta1-42 in amyloid plaques is one of the major neuropathological events in Alzheimer's disease. This is accompanied by a relative reduction of the concentration of Abeta1-42 in the cerebrospinal fluid (CSF) of patients developing the signs of Alzheimer's disease. Here, we describe a microchip gel electrophoresis method in polydimethylsiloxane (PDMS) chip that enables rapid profiling of major Abeta peptides in cerebrospinal fluid. To control the electroosmotic flow (EOF) in the PDMS channel and also to reduce the adsorption of the peptides to the surface of the channel, a new double coating using poly(dimethylacrylamide-co-allyl glycidyl ether) (PDMA-AGE) and methylcellulose-Tween-20 was developed. With this method, separation of five synthetic Abeta peptides (Abeta1-37, Abeta1-38, Abeta1-39, Abeta1-40, and Abeta1 42) was achieved, and relative abundance of Abeta1-42 to Abeta1-37 could be calculated in different standard mixtures. We applied our method for profiling of Abeta peptides in CSF samples from nonAlzheimer patients and patients with Alzheimer's disease. Abeta peptides in the CSF samples were captured and concentrated using a microfluidic system in which magnetic beads coated with anti Abeta were self-organized into an affinity microcolumn under the a permanent magnetic field. Finally, we could detect two Abeta peptides (Abeta1-40 and Abeta1 42) in the CSF samples. PMID- 20722396 TI - Overview of high-resolution infrared measurement and analysis for atmospheric monitoring of halocarbons. AB - The current state of the art in recording and analyzing rotationally resolved vibration-rotation bands of atmospheric pollutant halocarbon species is reviewed. It is shown that in order to obtain molecular constants of sufficient accuracy to simulate the vibration-rotation structure over the range of atmospheric temperatures, it is necessary to obtain spectra at a range of temperatures using static cooling cells, supersonic jet expansions, and collisional cooling devices; employ sophisticated pattern recognition and analysis software; assign and fit spectral perturbations; and use spectral simulation and digital spectral subtraction (SASSI) to further simplify spectral bands for analysis. To demonstrate the techniques, an analysis of the nu(5) band of CH(37)ClF(2) in natural abundance is presented. PMID- 20722395 TI - Understanding the exceptional hydrogen-atom donor characteristics of water in Ti(III)-mediated free-radical chemistry. AB - In recent years solid evidence of HAT reactions involving water as hydrogen atom source have been presented. In this work we demonstrate that the efficiency of titanocene(III) aqua complexes as an unique class of HAT reagents is based on two key features: (a) excellent binding capabilities of water toward titanocene(III) complexes and (b) a low activation energy for the HAT step. The theory has predictive capabilities fitting well with the experimental results and may aid to find more examples of this remarkable radical reaction. PMID- 20722397 TI - Nickel(II)-dipeptidoamine-based tetrameric complex: structural study in solution and in solid state. AB - The coordination structure of M(4)L(4)H(-8) macromolecules (M = Ni(II), Cu(II), Pd(II)) containing small peptidic ligands (L = Xaa-His or Xaa-His-Yaa) has been predicted primarily on the basis of spectroscopic and potentiometric data in the literature. In this work, the neutral tetranuclear nickel(II) complex 1 formed with four double-deprotonated ligands (L = alpha-methyl-alanyl-histamine) was prepared, and its crystal structure was determined (C(36)H(56)N(16)Ni(4)O(4).4.5CH(3)OH.1.5H(2)O: a = 11.2645(4) A, b = 23.5003(8) A, c = 20.9007(7) A, beta = 102.321(1) degrees , monoclinic, P2(1)/c, Z = 4). In complex 1, the metal ions have a square planar geometry with 4N donor set consisting of the N-terminal amino nitrogen, the deprotonated amide nitrogen, the imidazole N(3) atom, and the deprotonated imidazole N(1) atom of the adjacent ligand. The latter nitrogen atom provides the connection of the four NiLH(-2) units forming a C(1) symmetrical saddle-like shape. The complexation of L with Ni(II) ion has been studied by a potentiometric method combined with UV-visible spectrophotometric titration. At pH 8.0, the predominant species is M(4)L(4)H(-8) with pK(4)(oligomerization) = 5.73. The tetranuclear structure of complex 1 was also studied in solution by (1)H and (13)C NMR spectroscopy suggesting a structure of symmetry S(4). DFT calculations on optimized structure in symmetry C(1) and S(4) have been performed to explain the observed differences in solution and in solid state. The nuclearity was also confirmed in solution by ESI-HRMS analysis. PMID- 20722398 TI - Characterization of uranyl(VI) nitrate complexes in a room temperature ionic liquid using attenuated total reflection-Fourier transform infrared spectrometry. AB - Room temperature ionic liquids form potentially important solvents in novel nuclear waste reprocessing methods, and the solvation, speciation, and complexation behaviors of actinides and lanthanides in room temperature ionic liquids is of current interest. In this study, the coordination environment of uranyl(VI) in solutions of the room temperature ionic liquid 1-butyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide containing either tetrabutylammonium nitrate or nitric acid was characterized using attenuated total reflection-Fourier transform infrared spectrometry. Both UO(2)(NO(3))(2) and UO(2)(NO(3))(3)(-) species were detected in solutions containing tetrabutylammonium nitrate. nu(as)(UO(2)) for these two species were found to lie at 951 and 944 cm(-1), respectively, while nu(as)(UO(2)) arising from uranyl(VI) coordinated by bis(trifluoromethylsulfonyl)imide anions in 1-butyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide was found to lie at 968 cm( 1). In solutions containing nitric acid, only UO(2)(NO(3))(2) was detected, due to the high water content. The UO(2)(NO(3))(+) species was not detected under the conditions used in this study. From the results shown here, we conclude that infrared spectroscopy forms a valuable addition to the suite of tools currently used to study the chemical behavior of uranyl(VI) in room temperature ionic liquids. PMID- 20722399 TI - Activation of Nrf2 by microcystin-LR provides advantages for liver cancer cell growth. AB - Microcystin-LR (MC-LR) is a potent heptapeptide hepatotoxin at high doses, but its underlying mechanism of promoting liver cell proliferation at low doses is unclear. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is key in mediating the protective antioxidant response against various environmental toxicants, but emerging data suggest that constitutive activation of Nrf2 contributes to a malignant phenotype. The purpose of this study was to characterize the interactions and effects of Nrf2 activation on cell proliferation induced by MC-LR treatment. Treatment of HepG2 and Hep3B cells with MC-LR resulted in significant increases in Nrf2-ARE binding activities in the nuclear fractions and upregulation of its downstream genes HO-1 and NQO1. A possible mechanism may be that MC-LR binds to the cytosolic regulator protein Keap1 to liberate Nrf2. Nrf2 knockdown inhibited MC-LR-induced cell proliferation and cell cycle progression. Together, these results indicate that MC-LR-induced upregulation of Nrf2 in cancer cells promotes liver cancer cell growth and suggest a positive role of Nrf2 in tumorigenesis. PMID- 20722400 TI - Ultracompact silicon/polymer laser with an absorption-insensitive nanophotonic resonator. AB - A planar nanophotonic Fabry-Perot-like resonator that can defy strong absorption of about 20 000 cm(-1) in the cavity material is demonstrated. Visible laser emission is observed from two silicon subwavelength-sized high index contrast gratings with embedded polymer gain material. The size of the laser is reduced by an order of magnitude compared to established designs based on photonic bandgap structures. As silicon constitutes the most common carrier for electronics, the cost-efficient integration of compact laser sources for visible wavelengths comes within reach. PMID- 20722401 TI - Plasmonic nanofocusing in a dielectric wedge. AB - We show that surface plasmon polaritons (SPPs) can be concentrated to subwavelength dimensions in a nanoscale dielectric wedge on a metal substrate. An adiabatic model explains how SPPs propagating on a Ag substrate covered with a thin Si film of slowly increasing thickness become highly confined inside the Si layer. Simulations predict strong subwavelength focusing near the surface plasmon resonance frequency. Unlike alternative strategies, this method does not require the nanoscale shaping of metal surfaces. PMID- 20722402 TI - Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus. AB - The expression of the gene products in many methicillin-resistant Staphylococcus aureus (MRSA) strains is regulated by the gene repressor BlaI. Here we show that BlaI is a mixture of monomer and dimer at in vivo concentrations, binds to the operator regions preferentially as a monomeric protein, and the measured dissociation constants and in vivo concentrations account for the basal level transcription of the resistance genes. These observations for the first time provide a quantitative picture of the processes that take place in the cytoplasm that lead to the induction of antibiotic resistance factors to counter the challenge by beta-lactams. PMID- 20722403 TI - Unique temperature-dependent supramolecular self-assembly: from hierarchical 1D nanostructures to super hydrogel. AB - Supramolecular self-assembly can not only lead to a better understanding of biological systems, but also can enable rational building of complex and functional materials. In this report, hierarchical one-dimensional (1D) architectures involving nanotubes, coiled-coil ropelike structures, nanohelices, and nanoribbons are created via lanthanum-cholate supramolecular self-assembly. These sophisticated self-assemblies are proven to be mediated by temperature. The entanglement of one-dimensional nanostructures is demonstrated to give rise to fascinating "super" hydrogel, which can realize water gelation at extremely low concentration. Unprecedented water gelation behaviors, that is, heating-enhanced stiffness and heating-promoted gelation, are found in lanthanum-cholate supramolecular hydrogel. The driving forces of self-assembled complex nanostructures and the unique role of temperature are also discussed. PMID- 20722404 TI - Structure and spectromagnetic properties of the superoxide radical adduct of DMPO in water: elucidation by theoretical investigations. AB - In the field of spin trapping chemistry, the design of more efficient radical traps can be assisted by the development of theoretical methods able to give a quantitative evaluation of the electron paramagnetic resonance (EPR) spectrum features of the spin-adduct radical, even before initiating the experimental work. The superoxide radical adduct of the 5,5-dimethyl-1-pyrroline-N-oxide nitrone (DMPO-OOH) has been reported in a huge number of papers devoted to the study of the oxidative stress. Here, we present for the first time the theoretical study of DMPO-OOH in an explicit water solution, based on the combined QM/MM//MD protocol we recently proposed, featuring a full coupling between the solute and all the explicit water molecules. Our results show that the DMPO-OOH EPR spectrum, whose interpretation is still debated, can be explained in the light of two sites in chemical exchange, in agreement with the most recent experimental data. Moreover, we demonstrate that each site consists of an equilibrium between the two main 5-membered ring conformations of DMPO-OOH. We provide also an analysis of the solvent contribution to the hyperfine coupling constants (hcc's) as well as an exhaustive study of the possible relationship between the hcc's and the main structural characteristics of DMPO-OOH. Our QM/MM//MD protocol appears thus to be an accurate theoretical tool allowing the investigation of the magnetic properties of large nitroxide spin adducts in complex environments. PMID- 20722405 TI - Benzothiadiazole-based D-pi-A-pi-D organic dyes with tunable band gap: synthesis and photophysical properties. AB - A series of symmetrical D-pi-A-pi-D molecules based on benzothiadiazole and oligo(thienylenevinylene)s were facilely developed. The investigation of their photophysical and electrochemical properties demonstrated that these compounds exhibited broad absorption covering the whole visible range with appropriate energy levels for light-harvesting donors. PMID- 20722406 TI - Thin-walled graphitic nanocages as a unique platform for amperometric glucose biosensor. AB - A thin-walled graphitic nanocages material with well-developed graphitic structure, large specific surface area and pronounced mesoporosity was synthesized and used to construct a sensing interface for an amperometric glucose biosensor, showing a high and reproducible sensitivity of 13.3 MUA mM(-1) cm(-2), linear dynamic range of 0.02-6.2 mM, and fast response time of 5 s. It was successfully used to accurately detect glucose in human serum with effective discrimination to common interference species such as dopamine, ascorbic acid, acetaminophen, and uric acid. PMID- 20722407 TI - One-way traffic of a viral motor channel for double-stranded DNA translocation. AB - Linear double-stranded DNA (dsDNA) viruses package their genome into a procapsid using an ATP-driven nanomotor. Here we report that bacteriophage phi29 DNA packaging motor exercises a one-way traffic property for dsDNA translocation from N-terminal entrance to C-terminal exit with a valve mechanism in DNA packaging, as demonstrated by voltage ramping, electrode polarity switching, and sedimentation force assessment. Without the use of gating control as found in other biological channels, the observed single direction dsDNA transportation provides a novel system with a natural valve to control dsDNA loading and gene delivery in bioreactors, liposomes, or high throughput DNA sequencing apparatus. PMID- 20722408 TI - Enhanced sequential carrier capture into individual quantum dots and quantum posts controlled by surface acoustic waves. AB - Individual self-assembled quantum dots and quantum posts are studied under the influence of a surface acoustic wave. In optical experiments we observe an acoustically induced switching of the occupancy of the nanostructures along with an overall increase of the emission intensity. For quantum posts, switching occurs continuously from predominantly charged excitons (dissimilar number of electrons and holes) to neutral excitons (same number of electrons and holes) and is independent of whether the surface acoustic wave amplitude is increased or decreased. For quantum dots, switching is nonmonotonic and shows a pronounced hysteresis on the amplitude sweep direction. Moreover, emission of positively charged and neutral excitons is observed at high surface acoustic wave amplitudes. These findings are explained by carrier trapping and localization in the thin and disordered two-dimensional wetting layer on top of which quantum dots nucleate. This limitation can be overcome for quantum posts where acoustically induced charge transport is highly efficient in a wide lateral matrix-quantum well. PMID- 20722409 TI - Detection of nucleic acids with graphene nanopores: ab initio characterization of a novel sequencing device. AB - We report an ab initio density functional theory study of the interaction of four nucleobases, cytosine, thymine, adenine, and guanine, with a novel graphene nanopore device for detecting the base sequence of a single-stranded nucleic acid (ssDNA or RNA). The nucleobases were inserted into a pore in a graphene nanoribbon, and the electrical current and conductance spectra were calculated as functions of voltage applied across the nanoribbon. The conductance spectra and charge densities were analyzed in the presence of each nucleobase in the graphene nanopore. The results indicate that due to significant differences in the conductance spectra the proposed device has adequate sensitivity to discriminate between different nucleotides. Moreover, we show that the nucleotide conductance spectrum is affected little by its orientation inside the graphene nanopore. The proposed technique may be extremely useful for real applications in developing ultrafast, low-cost DNA sequencing methods. PMID- 20722410 TI - Ordered nanostructures self-assembled from block copolymer tethered nanoparticles. AB - Combining the self-consistent field theory (SCFT) and the density functional theory (DFT), we investigated the self-assembly behavior of AB diblock copolymer tethered single spherical particle P (ABP molecules). Two cases were studied: one is where the particles are chemically neutral to both A and B blocks, and the other is where the particles are unfavorable to neither of the two blocks. For neutral particles, the ABP molecules self-assemble to typical equilibrium microstructures, such as lamellae and cylinders. The P particles are localized in B block domains, and the size of particles can influence the phase behavior. For unfavorable particles, the ABP molecules microphase separate to form distinct ordered structures. Hierarchical structures, such as cylinders with cylinders at the interfaces and lamellae with cylinders at the interfaces, were observed. These resulting hierarchical structures are mainly determined by two parameters: A block fraction f(A) and particle size R(P). On the basis of the calculation results, phase diagrams were constructed. PMID- 20722411 TI - New solvents designed on the basis of the molecular-microscopic properties of binary mixtures of the type (protic molecular solvent + 1-butyl-3 methylimidazolium-based ionic liquid). AB - The main purpose of this work is to analyze the microscopic feature of solvent systems resulting from the basis of binary mixtures formed by a protic molecular solvent (methanol, ethanol, propan-1-ol, propan-2-ol, and 2-ethoxyethanol) and a 1-butyl-3-methylimidazolium (bmim)-based ionic liquid (IL) cosolvent composed of different anions (tetrafluoroborate, hexafluorophosphate, chloride, and bromide). At the same time, a complementary aim is to evaluate the incidence of anion type on the solvation pattern. The empirical solvatochromic parameters E(T)(N), pi*, beta, and alpha were determined from the UV-vis solvatochromic shifts of adequate probes. The behavior of the solvent systems was analyzed according to their deviation from ideality. E(T)(N) polarity and pi* dipolarity/polarizability exhibit positive deviation from ideal behavior in all binary mixtures at the explored compositions. Moreover, E(T)(N) and alpha parameters display synergetic effects in some binary mixtures composed of tetrafluoroborate and hexafluorophosphate anions. The influence of anion nature on the response patterns is clearly manifested in the basicity beta and acidity alpha of the media. This is connected with the degree and type of interaction between the anions and the 1-butyl-3-methylimidazolium cation. The ion-pair character of the ionic liquids affects their interactions with a solute or a molecular solvent. The application of an appropriate preferential solvation model allowed us to obtain valuable information about solute-solvent and solvent-solvent interactions of the selected ionic liquid mixtures. It is possible to identify relevant mixtures paying particular attention to the most remarkable microscopic properties, the acidity and the basicity, in order to propose "new solvents". Thus, the solvating feature can be tailored selecting the molecular and/or the ionic component at a particular composition. A simplified combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K) equation is shown to satisfactorily predict the solvatochromic parameters within [protic molecular solvent + bmim based IL]. PMID- 20722412 TI - Design of a multifunctional nanohybrid system of the phytohormone gibberellic acid using an inorganic layered double-hydroxide material. AB - To offer a multifunctional and applicable system of the high-value biotechnological phytohormone gibberellic acid (GA), a nanohybrid system of GA using the inorganic Mg-Al layered double-hydroxide material (LDH) was formulated. The ion-exchange technique of LDH was applied to synthesize the GA-LDH hybrid. The hybrid structure of GA-LDH was confirmed by different spectroscopic techniques. The nanohybrid size was described by SEM to be ~0.1 MUm. The GA-LDH nanohybrid structure was the key parameter that controlled GA properties. The layered molecular structure of LDH limited the interaction of GA molecules in two dimensional directions. Accordingly, GA molecules did not crystallize and were released in an amorphous form suitable for dissolution. At various simulated soil solutions, the nanohybrids showed a sustained release process following Higuchi kinetics. The biodegradation process of the intercalated GA showed an extended period of soil preservation as well as a slow rate of degradation. PMID- 20722413 TI - Magnesium-dependent active-site conformational selection in the Diels-Alderase ribozyme. AB - The Diels-Alderase ribozyme, an in vitro-evolved ribonucleic acid enzyme, accelerates the formation of carbon-carbon bonds between an anthracene diene and a maleimide dienophile in a [4 + 2] cycloaddition, a reaction with broad application in organic chemistry. Here, the Diels-Alderase ribozyme is examined via molecular dynamics (MD) simulations in both crystalline and aqueous solution environments. The simulations indicate that the catalytic pocket is highly dynamic. At low Mg(2+) ion concentrations, inactive states with the catalytic pocket closed dominate. Stabilization of the enzymatically active, open state of the catalytic pocket requires a high concentration of Mg(2+) ions (e.g., 54 mM), with cations binding to specific phosphate sites on the backbone of the residues bridging the opposite strands of the pocket. The free energy profile for pocket opening at high Mg(2+) cation concentration exhibits a double minimum, with a barrier to opening of approximately 5.5 kJ/mol and the closed state approximately 3 kJ/mol lower than the open state. Selection of the open state on substrate binding leads to the catalytic activity of the ribozyme. The simulation results explain structurally the experimental observation that full catalytic activity depends on the Mg(2+) ion concentration. PMID- 20722414 TI - Side-chain conformational changes of transcription factor PhoB upon DNA binding: a population-shift mechanism. AB - Using molecular dynamics (MD) simulations and analyses of NMR relaxation order parameters, we investigated conformational changes of side chains in hydrophobic cores upon DNA binding for the DNA binding/transactivation domain of the transcription factor PhoB, in which backbone conformational changes upon DNA binding are small. The simulation results correlated well with experimental order parameters for the backbone and side-chain methyl groups, showing that the order parameters generally represent positional fluctuations of the backbone and side chain methyl groups. However, topological effects of the side chains on the order parameters were also found and could be eliminated using normalized order parameters for each amino acid type. Consistent with the NMR experiments, the normalized order parameters from the MD simulations showed that the side chains in one of the two hydrophobic cores (the soft core) were highly flexible in comparison with those in the other hydrophobic core (the hard core) before DNA binding and that the flexibility of the hydrophobic cores, particularly of the soft core, was reduced upon DNA binding. Principal component analysis of methyl group configurations revealed strikingly different side-chain dynamics for the soft and hard cores. In the hard core, side-chain configurations were simply distributed around one or two average configurations. In contrast, the side chains in the soft core dynamically varied their configurations in an equilibrium ensemble that included binding configurations as minor components before DNA binding. DNA binding led to a restriction of the side-chain dynamics and a shift in the equilibrium toward binding configurations, in clear correspondence with a population-shift model. PMID- 20722415 TI - Experimental evidence for heavy-atom tunneling in the ring-opening of cyclopropylcarbinyl radical from intramolecular 12C/13C kinetic isotope effects. AB - The intramolecular (13)C kinetic isotope effects for the ring-opening of cyclopropylcarbinyl radical were determined over a broad temperature range. The observed isotope effects are unprecedentedly large, ranging from 1.062 at 80 degrees C to 1.163 at -100 degrees C. Semiclassical calculations employing canonical variational transition-state theory drastically underpredict the observed isotope effects, but the predicted isotope effects including tunneling by a small-curvature tunneling model match well with experiment. These results and a curvature in the Arrhenius plot of the isotope effects support the recently predicted importance of heavy-atom tunneling in cyclopropylcarbinyl ring-opening. PMID- 20722416 TI - Correlation of active site metal content in human diamine oxidase with trihydroxyphenylalanine quinone cofactor biogenesis . AB - Copper-containing amine oxidases (CAOs) require a protein-derived topaquinone cofactor (TPQ) for activity. TPQ biogenesis is a self-processing reaction requiring the presence of copper and molecular oxygen. Recombinant human diamine oxidase (hDAO) was heterologously expressed in Drosophila S2 cells, and analysis indicates that the purified hDAO contains substoichiometric amounts of copper and TPQ. The crystal structure of a complex of an inhibitor, aminoguanidine, and hDAO at 2.05 A resolution shows that the aminoguanidine forms a covalent adduct with the TPQ and that the site is ~75% occupied. Aminoguanidine is a potent inhibitor of hDAO with an IC(50) of 153 +/- 9 nM. The structure indicates that the catalytic metal site, normally occupied by copper, is fully occupied. X-ray diffraction data recorded below the copper edge, between the copper and zinc edges, and above the zinc edge have been used to show that the metal site is occupied approximately 75% by copper and 25% by zinc and the formation of the TPQ cofactor is correlated with copper occupancy. PMID- 20722418 TI - Photocatalytic and conductive MWCNT/TiO2 nanocomposite thin films. AB - A conductive and photocatalytic nanocomposite thin film comprising multiwalled carbon nanotubes (MWCNTs) and TiO2 nanoparticles is fabricated based on layer-by layer (LbL) assembly in a nonpolar solvent, toluene. An amphiphilic surfactant, aerosol OT (AOT), is used to impart opposite surface charge onto MWCNTs and TiO2 in toluene. Our fabrication technique enables the incorporation of unoxidized MWCNTs into the nanocomposite thin films, and at the same time, provides a versatile method of fabricating conformal thin films over a large area. The physicochemical properties of MWCNT/TiO2 nanocomposite thin films, including composition and photocatalytic activity, can be varied by changing the concentration of AOT during assembly. The electrical properties of the nanocomposite film, specifically its sheet resistance and conductivity, can also be tuned through changing the assembly conditions. In addition, we demonstrate that the incorporation of MWCNTs within our films leads to a significant enhancement of the photocatalytic activity of TiO2. The conductivity and enhanced photocatalytic activity of MWCNT/TiO2 thin films make them promising for the generation of highly efficient dye-sensitized solar cells (DSSCs). PMID- 20722417 TI - pH-Sensitive siRNA nanovector for targeted gene silencing and cytotoxic effect in cancer cells. AB - A small interfering RNA (siRNA) nanovector with dual targeting specificity and dual therapeutic effect is developed for targeted cancer imaging and therapy. The nanovector is composed of an iron oxide magnetic nanoparticle core coated with three different functional molecules: polyethyleneimine (PEI), siRNA, and chlorotoxin (CTX). The primary amine group of PEI is blocked with citraconic anhydride that is removable at acidic conditions, not only to increase its biocompatibility at physiological conditions but also to elicit a pH-sensitive cytotoxic effect in the acidic tumor microenvironment. The PEI is covalently immobilized on the nanovector via a disulfide linkage that is cleavable after cellular internalization of the nanovector. CTX as a tumor-specific targeting ligand and siRNA as a therapeutic payload are conjugated on the nanovector via a flexible and hydrophilic PEG linker for targeted gene silencing in cancer cells. With a size of ~60 nm, the nanovector exhibits long-term stability and good magnetic property for magnetic resonance imaging. The multifunctional nanovector exhibits both significant cytotoxic and gene silencing effects at acidic pH conditions for C6 glioma cells, but not at physiological pH conditions. Our results suggest that this nanovector system could be safely used as a potential therapeutic agent for targeted treatment of glioma as well as other cancers. PMID- 20722419 TI - Contribution of amino acid region 659-663 of Factor Va heavy chain to the activity of factor Xa within prothrombinase . AB - Factor Va, the cofactor of prothrombinase, is composed of heavy and light chains associated noncovalently in the presence of divalent metal ions. The COOH terminal region of the heavy chain contains acidic amino acid clusters that are important for cofactor activity. In this work, we have investigated the role of amino acid region 659-663, which contains five consecutive acidic amino acid residues, by site-directed mutagenesis. We have generated factor V molecules in which all residues were mutated to either lysine (factor V(5K)) or alanine (factor V(5A)). We have also constructed a mutant molecule with this region deleted (factor V(Delta659-663)). The recombinant molecules along with wild-type factor V (factor V(WT)) were transiently expressed in mammalian cells, purified, and assessed for cofactor activity. Two-stage clotting assays revealed that the mutant molecules had reduced clotting activities compared to that of factor Va(WT). Kinetic analyses of prothrombinase assembled with the mutant molecules demonstrated diminished k(cat) values, while the affinity of all mutant molecules for factor Xa was similar to that for factor Va(WT). Gel electrophoresis analyses of plasma-derived and recombinant mutant prothrombin activation demonstrated delayed cleavage of prothrombin at both Arg(320) and Arg(271) by prothrombinase assembled with the mutant molecules, resulting in meizothrombin lingering throughout the activation process. These results were confirmed after analysis of the cleavage of FPR-meizothrombin. Our findings provide new insights into the structural contribution of the acidic COOH-terminal region of factor Va heavy chain to factor Xa activity within prothrombinase and demonstrate that amino acid region 659-663 from the heavy chain of the cofactor contributes to the regulation of the rate of cleavage of prothrombin by prothrombinase. PMID- 20722420 TI - Direct measurement of mercury(II) removal from organomercurial lyase (MerB) by tryptophan fluorescence: NmerA domain of coevolved gamma-proteobacterial mercuric ion reductase (MerA) is more efficient than MerA catalytic core or glutathione . AB - Aerobic and facultative bacteria and archaea harboring mer loci exhibit resistance to the toxic effects of Hg(II) and organomercurials [RHg(I)]. In broad spectrum resistance, RHg(I) is converted to less toxic Hg(0) in the cytosol by the sequential action of organomercurial lyase (MerB: RHg(I) -> RH + Hg(II)) and mercuric ion reductase (MerA: Hg(II) -> Hg(0)) enzymes, requiring transfer of Hg(II) from MerB to MerA. Although previous studies with gamma-proteobacterial versions of MerA and a nonphysiological Hg(II)-DTT-MerB complex qualitatively support a pathway for direct transfer between proteins, assessment of the relative efficiencies of Hg(II) transfer to the two different dicysteine motifs in gamma-proteobacterial MerA and to competing cellular thiol is lacking. Here we show the intrinsic tryptophan fluorescence of gamma-proteobacterial MerB is sensitive to Hg(II) binding and use this to probe the kinetics of Hg(II) removal from MerB by the N-terminal domain (NmerA) and catalytic core C-terminal cysteine pairs of its coevolved MerA and by glutathione (GSH), the major competing cellular thiol in gamma-proteobacteria. At physiologically relevant concentrations, reaction with a 10-fold excess of NmerA over HgMerB removes >=92% Hg(II), while similar extents of reaction require more than 1000-fold excess of GSH. Kinetically, the apparent second-order rate constant for Hg(II) transfer from MerB to NmerA, at (2.3 +/- 0.1) * 10(4) M(-1) s(-1), is ~100-fold greater than that for GSH ((1.2 +/- 0.2) * 10(2) M(-1) s(-1)) or the MerA catalytic core (1.2 * 10(2) M(-1) s(-1)), establishing transfer to the metallochaperone-like NmerA domain as the kinetically favored pathway in this coevolved system. PMID- 20722421 TI - A quantitative study of the effects of chaotropic agents, surfactants, and solvents on the digestion efficiency of human plasma proteins by trypsin. AB - Plasma biomarkers studies are based on the differential expression of proteins between different treatment groups or between diseased and control populations. Most mass spectrometry-based methods of protein quantitation, however, are based on the detection and quantitation of peptides, not intact proteins. For peptide based protein quantitation to be accurate, the digestion protocols used in proteomic analyses must be both efficient and reproducible. There have been very few studies, however, where plasma denaturation/digestion protocols have been compared using absolute quantitation methods. In this paper, 14 combinations of heat, solvent [acetonitrile, methanol, trifluoroethanol], chaotropic agents [guanidine hydrochloride, urea], and surfactants [sodium dodecyl sulfate (SDS) and sodium deoxycholate (DOC)] were compared with respect to their effectiveness in improving subsequent tryptic digestion. These digestion protocols were evaluated by quantitating the production of proteotypic tryptic peptides from 45 moderate- to high-abundance plasma proteins, using tandem mass spectrometry in multiple reaction monitoring mode, with a mixture of stable-isotope labeled analogues of these proteotypic peptides as internal standards. When the digestion efficiencies of these 14 methods were compared, we found that both of the surfactants (SDS and DOC) produced an increase in the overall yield of tryptic peptides from these 45 proteins, when compared to the more commonly used urea protocol. SDS, however, can be a serious interference for subsequent mass spectrometry. DOC, on the other hand, can be easily removed from the samples by acid precipitation. Examining the results of a reproducibility study, done with 5 replicate digestions, DOC and SDS with a 9 h digestion time produced the highest average digestion efficiencies (~80%), with the highest average reproducibility (<5% error, defined as the relative deviation from the mean value). However, because of potential interferences resulting from the use of SDS, we recommend DOC with a 9 h digestion procedure as the optimum protocol. PMID- 20722422 TI - Discovery of mitogen-activated protein kinase-interacting kinase 1 inhibitors by a comprehensive fragment-oriented virtual screening approach. AB - Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK1 could be useful for the treatment of cancers, we pursued a comprehensive virtual screening approach to rapidly identify pharmacological tools for target validation and to find optimal starting points for a plausible medicinal chemistry project. A collection of 1236 compounds, selected from a library of 42 168 compounds and a database of 18.8 million structures, were assayed. Of the identified hits, 26 were found to have IC(50) values less than 10 MUM (2.10% hit rate). The most potent compound had an IC(50) value of 117 nM, and 73.1% of these hits were fragments. The hits were characterized by a high ligand efficiency (0.32-0.52 kcal/mol per heavy atom). Ten different chemical scaffolds were represented, giving a chemotype/hit ratio of 0.38. PMID- 20722423 TI - Pre- and postnatal exposure to perfluorinated compounds (PFCs). AB - Perfluorinated compounds (PFCs) are a group of chemicals widely used for many applications. In this study PFCs were investigated in maternal blood during pregnancy (at two time points) (n = 40 and 38) and 6 months after delivery (n = 47), in cord blood (n = 33) and in blood of infants six (n = 40) and nineteen months (n = 24) after birth, and monthly in breast milk samples in Germany. Concentrations in maternal serum ranged from 0.5 to 9.4 MUg/L for perfluorooctane sulfonate (PFOS) and 0.7 to 8.7 MUg/L for perfluorooctanoic acid (PFOA). In cord serum, the values ranged from 0.3 to 2.8 MUg/L and from 0.5 to 4.2 MUg/L for PFOS and PFOA, respectively. The median results from serum at six and nineteen months of age were 3.0 and 1.9 MUg/L for PFOS and 6.9 and 4.6 MUg/L for PFOA, respectively. In breast milk samples, PFOS ranged from <0.03 to 0.11 MUg/L (median: 0.04 MUg/L), while PFOA was detected only in some samples as were all other PFCs. Overall, we found low levels of PFCs in cord sera and an increase in concentrations through the first months of infant life. Although the concentrations in breast milk were low, this intake led to a body burden at the age of six months similar to (PFOS) or higher than (PFOA) that found in adults. PMID- 20722426 TI - Replacement method and enhanced replacement method versus the genetic algorithm approach for the selection of molecular descriptors in QSPR/QSAR theories. AB - We compare three methods for the selection of optimal subsets of molecular descriptors from a much greater pool of such regression variables. On the one hand is our enhanced replacement method (ERM) and on the other is the simpler replacement method (RM) and the genetic algorithm (GA). These methods avoid the impracticable full search for optimal variables in large sets of molecular descriptors. Present results for 10 different experimental databases suggest that the ERM is clearly preferable to the GA that is slightly better than the RM. However, the latter approach requires the smallest amount of linear regressions and, consequently, the lowest computation time. PMID- 20722424 TI - Design, synthesis, and evaluation of 1,4,7,10-tetraazacyclododecane-1,4,7 triacetic acid derived, redox-sensitive contrast agents for magnetic resonance imaging. AB - The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive magnetic resonance imaging contrast agents are reported. The linkers were selected on the basis of computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r(1)) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 T. The DO3A complexes exhibited smaller r(1) values, in both bound and free states, than the DOTA complexes. PMID- 20722427 TI - Accelerated solvent extraction of lignin from Aleurites moluccana (Candlenut) nutshells. AB - Lignin from candlenut shells was isolated using an ethanol-water accelerated solvent extraction method. Yields (based on Klason lignin) increased from about 14 to 33% as temperature increased from 100 to 195 degrees C and were also influenced by the amount of aqueous acid used to precipitate lignin from the extraction liquor. These yields were higher than could be obtained using a conventional dioxane-water acidolysis method. The resulting lignin was characterized by IR, 31P NMR, and 1H-13C HMQC NMR spectroscopic techniques. The lignin contained predominantly guaiacyl units, and both the total hydroxyl group content and phenolic hydroxyl group content were high. PMID- 20722428 TI - Micellar crystallization with a hysteresis in temperature. AB - We have investigated the phase diagram of the triblock copolymer P123 solved in water by viscosity measurements for different concentrations and temperatures. The structures of the different phases were identified by surface sensitive neutron diffraction. We find a pronounced hysteresis between heating and cooling. During heating, a highly viscous crystalline fcc phase is found before melting occurs at 44 degrees C with a simultaneous drop in viscosity. Upon cooling, first a hexagonal phase with low viscosity develops followed by a highly viscous fcc phase. Phase diagrams for the heating and cooling cycle for different concentrations are provided. The hysteric behavior is discussed in relation to the shape of the micelles. PMID- 20722429 TI - Quantum mechanical reaction probability of triplet ketene at the multireference second-order perturbation level of theory. AB - Triplet ketene exhibits a steplike structure in the experimentally observed dissociation rates, but its mechanism is still unknown despite many theoretical efforts in the past decades. In this paper we revisit this problem by quantum mechanically calculating the reaction probability with multireference-based electronic structure theory. Specifically, we first construct an analytical potential energy surface of triplet state by fitting it to about 6000 ab initio energies computed at the multireference second-order Mller-Plesset perturbation (MRMP2) level. We then evaluate the cumulative reaction probability by using the transition state wave packet method together with an adiabatically constrained Hamiltonian. The result shows that the imaginary barrier frequency on the triplet surface is 328i cm-1, which is close to the CCSD(T) result (321i cm-1) but is likely too large for reproducing the experimentally observed steps. Indeed, our calculated reaction probability exhibits no signature of steps, reflecting too strong tunneling effect along the reaction coordinate. Nevertheless, it is emphasized that the flatness of the potential profile in the transition-state region (which governs the degree of tunneling) depends strongly on the level of electronic structure calculation, thus leaving some possibility that the use of more accurate theories might lead to the observed steps. We also demonstrate that the triplet potential surface differs significantly between the CASSCF and MRMP2 results, particularly in the transition-state region. This fact seems to require more attention when studying the "nonadiabatic" scenario for the steps, in which the crossing seam between S0 and T1 surfaces is assumed to play a central role. PMID- 20722430 TI - Phase-dependent lateral diffusion of alpha-tocopherol in DPPC liposomes monitored by fluorescence quenching. AB - The temperature-dependent fluorescence quenching of an amphiphilic palmitoyl derivative of 2,3-diazabicyclo[2.2.2]oct-2-ene (Fluorazophore-L) by alpha tocopherol (alpha-Toc) has been determined in liposomes composed of a saturated lipid, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). The mutual lateral diffusion coefficients (D(L)) were extracted according to a laterally diffusion controlled dynamic quenching model. Three distinct temperature regimes were identified: one between 65 and 39 degrees C, where the lateral diffusion coefficients were in the range of 10(-7) cm(2) s(-1) and the lifetime of the probe was monoexponential in the absence of alpha-Toc, a second one between 39 and 30 degrees C, where the lateral diffusion coefficients were in the range of 10(-8) cm(2) s(-1) and the lifetime of the probe was biexponential in the absence of alpha-Toc, and a third one below 30 degrees C, in which no diffusion was detectable, suggesting D(L) < 10(-9) cm(2)s (-1). These temperature domains were assigned, supported by differential scanning calorimetry (DSC) measurements, to the liquid-crystalline, ripple, and solid-gel phases of DPPC liposomes in the presence of the two additives. The absolute values of the individual lateral diffusion coefficients (taken as (1)/(2) of the D(L) values) of the Fluorazophore L/alpha-Toc (ca. 2.5 * 10(-7) cm(2) s(-1) at 52 degrees C) couple demonstrates that alpha-Toc does not diffuse at an unexpectedly high rate in comparison to the self-diffusion of DPPC (1.5 * 10(-7) cm(2) s(-1) at 52 degrees C). However, diffusion in DPPC liposomes is distinctly slower than that in POPC ones (e.g., D(L) = 4.9 * 10(-7) cm(2) s(-1) versus 6.4 * 10(-7) cm(2) s(-1) at 50 degrees C), with an activation energy of 49 +/- 5 kJ mol(-1) (value for POPC: 47 +/- 5 kJ mol(-1)), in the temperature range of the liquid-crystalline phase. Diffusion in the ripple phase, that is, below the main phase transition temperature, was found to be non-negligible, with an apparent activation energy of 175 +/- 50 kJ mol( 1). PMID- 20722431 TI - Oxidation-responsive micelles based on a selenium-containing polymeric superamphiphile. AB - We have fabricated a polymeric superamphiphile based on the electrostatic interaction between the double hydrophilic block copolymer of poly(ethylene glycol)-b-acrylic acid (PEG-b-PAA) and a selenium-containing surfactant (SeQTA). The polymeric superamphiphiles are able to self-assemble to form micelles in solution. The micelles can be disassembled with the addition of 0.1% H(2)O(2) because SeQTA is very sensitive to oxidation. The selenide group in SeQTA is oxidized into selenoxide (SeQTA-Ox) by H(2)O(2), which makes the surfactant more hydrophilic, thus leading to the disassembly of the micelles. In addition, small guest molecules such as fluorescein sodium can be loaded into the micelles made from the polymeric superamphiphiles and released in a controlled way under mild oxidation conditions. This study represents a new way to fabricate stimuli responsive superamphiphiles for controlled self-assembly and disassembly. PMID- 20722432 TI - Cooperatively enhanced ionic hydrogen bonds in Cl-(CH3OH)(1-3)Ar clusters. AB - Infrared predissociation (IRPD) spectra of Cl-(CH3OH)1-3Ar and Cl-(CH3OD)1-3Ar were obtained in the OH and CH stretching regions. The use of methanol-d1 was necessary to distinguish between CH stretches and hydrogen-bonded OH features. The spectra of Cl-(CH3OH)2-3Ar show intense features at frequencies lower than the CH stretches, indicating structures with very strong hydrogen bonds. These strong hydrogen bonds arise from structures in which a Cl-...methanol ionic hydrogen bond is cooperatively enhanced by the presence of a second shell and, in the case of Cl-(CH3OH)3Ar, a third shell methanol. The strongest hydrogen bond is observed in the Cl-(CH3OH)3Ar spectrum at 2733 cm-1, shifted a remarkable -948 cm 1 from the neutral, gas-phase methanol value. Harmonic, ab initio frequency calculations are not adequate in describing these strong hydrogen bonds. Therefore, we describe a simple computational approach to better approximate the hydrogen bond frequencies. Overall, the results of this study indicate that high energy isomers are very efficiently trapped using our experimental method of introducing Cl- into neutral, cold methanol-argon clusters. PMID- 20722433 TI - Ultralarge-area block copolymer lithography enabled by disposable photoresist prepatterning. AB - We accomplished truly scalable, low cost, arbitrarily large-area block copolymer lithography, synergistically integrating the two principles of graphoepitaxy and epitaxial self-assembly. Graphoepitaxy morphology composed of highly aligned lamellar block copolymer film that self-assembled within a disposable photoresist trench pattern was prepared by conventional I-line lithography and utilized as a chemical nanopatterning mask for the underlying substrate. After the block copolymer film and disposable photoresist layer were removed, the same lamellar block copolymer film was epitaxially assembled on the exposed chemically patterned substrate. Highly oriented lamellar morphology was attained without any trace of structure directing the photoresist pattern over an arbitrarily large area. PMID- 20722434 TI - Single-chain magnets constructed by using the strict orthogonality of easy planes: use of structural flexibility to control the magnetic properties. AB - A family of single-chain magnets (SCMs), of which the SCM character originated from the spatial arrangement of high spin Fe(II) ions with easy-plane anisotropy, was synthesized, and their magnetic properties were investigated. The chain complexes including alternating high-spin Fe(II) ions and low-spin Fe(III) ions, catena-[Fe(II)(ClO(4))(2){Fe(III)(bpca)(2)}]ClO(4).3MeNO(2) (1.3MeNO(2)), catena [Fe(II)(ClO(4))(H(2)O){Fe(III)((Me)L)(2)}](ClO(4))(2).2MeNO(2).H(2)O (2.2MeNO(2).H(2)O), catena [Fe(II)(ClO(4))(H(2)O){Fe(III)((Bu)L)(2)}](ClO(4))(2).3.5MeNO(2) (3.3.5MeNO(2)), and catena [{Fe(II)(ClO(4))(H(2)O)Fe(II)(H(2)O)(2)}(0.5){Fe(III)((Ph)L)(2)}](ClO(4))(2.5).4E NO(2) (4.4EtNO(2)), were synthesized with the use of bridging ligand Hbpca (bis (2-pyridylcarbonyl)amine)) and its derivatives of H(Me)L, H(Bu)L, and H(Ph)L each incorporating methyl, tert-butyl, or phenyl group on the 4-position of pyridyl ring. These complexes showed a typical ferrimagnetic behavior on direct current (dc) susceptibility data, and from an alternating current (ac) susceptibility measurements, SCM or superparamagnetic behaviors were confirmed with the Delta/k(B) values of 22.5(4), 21.8(18), and 28.8(3) K for 1.3MeNO(2), 2.2MeNO(2).H(2)O, and 3.3.5MeNO(2), of which the easy-axis anisotropy was originated from the orthogonal arrangement of easy-planes of Fe(II) ions. In the crystal structures, cylindrical voids were formed along the chain axis being surrounded by four chains in 1.3MeNO(2), 2.2MeNO(2).H(2)O, and 4.4EtNO(2) and two chains in 3.3.5MeNO(2), and solvent molecules as well as coordination-free perchlorate anions occupied these voids in a slightly different fashion depending on the complexes. 2.2MeNO(2).H(2)O maintains its chemical composition in a dried condition, whereas 1.3MeNO(2), 3.3.5MeNO(2), and 4.4EtNO(2) easily release solvent molecules to give 1, 3, and 4, respectively. 1 and 3 maintain the crystalline character showing slightly different X-ray diffraction (XRD) patterns from those of 1.3MeNO(2) and 3.3.5MeNO(2), and an enhancement of SCM character after release of the solvent molecules was observed for both. 4 lost crystalline character to become amorphous, and it lost the SCM character at the same time. PMID- 20722435 TI - Theoretical characterization of the F(2)O(3) molecule by coupled-cluster methods. AB - Coupled-cluster calculations with extended basis sets that include noniterative connected triple excitations (CCSD(T)) have been used to study the FOOOF isomer of F(2)O(3). Second-order Moller-Plessett perturbation theory (MP2) and density functional theory (B3LYP functional) calculations have also been performed for comparison. Two local minima of similar energy, namely, conformers of C(2) and C(s) symmetry have been located. Structures, harmonic vibrational frequencies, and standard enthalpies and free energies of formation have been calculated. The calculated bond lengths of F(2)O(3) are more characteristic of those in F(2)O and a "normal" peroxide than the unusual bond lengths in F(2)O(2). Both conformers have equal F-O and O-O bond lengths, contrary to a recent suggestion of an unsymmetrical structure. The harmonic vibrational frequencies can aid possible identification of gaseous F(2)O(3). The calculated Delta(f)H degrees and Delta(f)G degrees are 110 and 173 kJ mol(-1), respectively. These values are based on extrapolation of CCSD(T) results with augmented triple- and quadruple zeta basis sets and are expected to be within chemical accuracy (i.e., 1 kcal mol(-1) or 4 kJ mol(-1)). F(2)O(3) is calculated to be stable to decomposition to either FO + FOO or F(2) + O(3), but unstable to decomposition to its elements, to F(2)O(2) + (1)/(2)O(2), and to F(2)O + O(2). PMID- 20722436 TI - Poly(L-lactide)-vitamin E TPGS nanoparticles enhanced the cytotoxicity of doxorubicin in drug-resistant MCF-7 breast cancer cells. AB - Multiple drug resistance (MDR) seriously reduces the efficacy of many chemotherapeutic agents for cancer. P-Glycoprotein, an efflux pump overexpressed on the cell surface, plays an important role in drug resistance, but several surfactants, such as vitamin E TPGS, can inhibit P-glycoprotein. In this study, a polylactide-surfactant block copolymer poly(l-lactide)-vitamin E TPGS (PLA-TPGS) was synthesized using bidentate sulfonamide zinc ethyl complex as an efficient catalyst, and its self-assembled nanoparticles were used as carriers of doxorubicin. We first found that the activity of P-glycoprotein in drug-resistant breast cancer MCF-7/ADR cells was decreased after incubation with PLA-TPGS nanoparticles. In addition, the nuclear accumulation and cytotoxicity of doxorubicin were significantly increased by encapsulation into the nanoparticles. The enhanced efficacy of the doxorubicin-loaded PLA-TPGS nanoparticles may result from the combination of inhibition of efflux and increased entry of doxorubicin into the nucleus in drug-resistant MCF-7/ADR cells. Therefore, this innovative delivery system has potential to act as a nanomedicine for therapy of both drug sensitive and drug-resistant cancer. PMID- 20722437 TI - Deployment models for commercialized carbon capture and storage. AB - Even before technology matures and the regulatory framework for carbon capture and storage (CCS) has been developed, electrical utilities will need to consider the logistics of how widespread commercial-scale operations will be deployed. The framework of CCS will require utilities to adopt business models that ensure both safe and affordable CCS operations while maintaining reliable power generation. Physical models include an infrastructure with centralized CO(2) pipelines that focus geologic sequestration in pooled regional storage sites or supply CO(2) for beneficial use in enhanced oil recovery (EOR) and a dispersed plant model with sequestration operations which take place in close proximity to CO(2) capture. Several prototypical business models, including hybrids of these two poles, will be in play including a self-build option, a joint venture, and a pay at the gate model. In the self-build model operations are vertically integrated and utility owned and operated by an internal staff of engineers and geologists. A joint venture model stresses a partnership between the host site utility/owner's engineer and external operators and consultants. The pay to take model is turn key external contracting to a third party owner/operator with cash positive fees paid out for sequestration and cash positive income for CO(2)-EOR. The selection of a business model for CCS will be based in part on the desire of utilities to be vertically integrated, source-sink economics, and demand for CO(2)-EOR. Another element in this decision will be how engaged a utility decides to be and the experience the utility has had with precommercial R&D activities. Through R&D, utilities would likely have already addressed or at least been exposed to the many technical, regulatory, and risk management issues related to successful CCS. This paper provides the framework for identifying the different physical and related prototypical business models that may play a role for electric utilities in commercial-scale CCS. PMID- 20722438 TI - Quantum calculation of the second-order hyperpolarizability of chiral molecules in the "one-electron" model. AB - Quantum calculation of the hyperpolarizabilty tensor is carried out for chiral molecules displaying a "one-electron" chirality. Calculation is made possible by introducing a chiral perturbation term in the potential energy surface. We show that a one-electron chiral molecule is intrinsically nonlinear and diplays a nonzero electric chiral hyperpolarizability. Existence of magnetic contributions is discussed, and it is shown that higher-order perturbation terms are necessary to introduce such magnetic effects in the second-order hyperpolarizability. PMID- 20722439 TI - Capture and recovery of isobutane by electrothermal swing adsorption with post desorption liquefaction. AB - A bench-scale capture and recovery system to convert a low concentration organic gas to a liquid is described here. Adsorption of isobutane onto activated carbon fiber cloth (ACFC) followed by electrothermal desorption and subsequent liquefaction is demonstrated. Experimental conditions to condense desorbed isobutane were determined based on Dalton's law and Antoine's equation. Breakthrough curves for a gas stream containing 2000 ppm(v) isobutane in air adsorbing onto ACFC-15 demonstrate an adsorption capacity of 0.094 +/- 0.017 g of isobutane/g of ACFC with >98% capture efficiency. The system described here utilizes two adsorbers, which operate cyclically to allow for continuous treatment of the isobutane. Adsorption followed by electrothermal desorption provided a concentration ratio of 240, which facilitates condensation of the isobutane after compression and cooling and is an order of magnitude greater than what has been previously demonstrated. PMID- 20722440 TI - Oenothera paradoxa defatted seeds extract and its bioactive component penta-O galloyl-beta-D-glucose decreased production of reactive oxygen species and inhibited release of leukotriene B4, interleukin-8, elastase, and myeloperoxidase in human neutrophils. AB - In this study, we analyzed ex vivo the effect of an aqueous extract of Oenothera paradoxa defatted seeds on the formation of neutrophil-derived oxidants. For defining active compounds, we also tested lypophilic extract constituents such as gallic acid, (+)-catechin, ellagic acid, and penta-O-galloyl-beta-D-glucose and a hydrophilic fraction containing polymeric procyanidins. The anti-inflammatory potential of the extract and compounds was tested by determining the release from activated neutrophils of elastase, myeloperoxidase, interleukin-8 (IL-8), and leukotriene B4 (LTB4), which are considered relevant for the pathogenesis of cardiovascular diseases. The extract of O. paradoxa defatted seeds displays potent antioxidant effects against both 4beta-phorbol-12beta-myristate-alpha13 acetate- and formyl-met-leu-phenylalanine-induced reactive oxygen species production in neutrophils with IC50 values around 0.2 MUg/mL. All types of polyphenolics present in the extract contributed to the extract antioxidant activity. According to their IC50 values, penta-O-galloyl-beta-D-glucose was the more potent constituent of the extract. In cell-free assays, we demonstrated that this effect is partially due to the scavenging of O2- and H2O2 oxygen species. The extract and especially penta-O-galloyl-beta-D-glucose significantly inhibit elastase, myeloperoxidase IL-8, and LTB4 release with an IC50 for penta-O-galloyl beta-D-glucose of 17+/-1, 15+/-1, 6.5+/-2.5, and around 20 MUM, respectively. The inhibition of penta-O-galloyl-beta-D-glucose on reactive oxygen species and especially on O2- production, myeloperoxidase, and chemoattractant release may reduce the interaction of polymorphonuclear leukocyte with the vascular endothelium and by that potentially diminish the risk of progression of atherosclerosis development. PMID- 20722441 TI - Interfacial chemistry of poly(methyl methacrylate) arising from exposure to vacuum-ultraviolet light and atomic oxygen. AB - We herein report on the chemical and physical changes that occur in thin films of poly(methyl methacrylate), PMMA, induced by exposure to high-energy vacuum ultraviolet radiation and a supersonic beam of neutral, ground electronic state O((3)P) atomic oxygen. A combination of in situ quartz crystal microbalance and in situ Fourier-transform infrared reflection-absorption spectroscopy were used to determine the photochemical reaction kinetics and mechanisms during irradiation. The surface morphological changes were measured with atomic force microscopy. The results showed there was no enhancement in the mass loss rate during simultaneous exposure of vacuum ultraviolet (VUV) radiation and atomic oxygen. Rather, the rate of mass loss was impeded when the polymer film was exposed to both reagents. This study elucidates the kinetics of photochemical and oxidative reaction for PMMA, and shows that the synergistic effect involving VUV irradiation and exposure to ground state atomic oxygen depends substantially on the relative fluxes of these reagents. PMID- 20722442 TI - A versatile method for controlled synthesis of porous hollow spheres. AB - A versatile method was developed to synthesize nickel silicate, silica, and silica-nickel composite porous hollow spheres by using silica spheres as templates. In the preparation, silica spheres were treated with a mixture of NiSO(4).6H(2)O and NH(3).H(2)O. The nickel-based ingredient reacted with the silica to form a shell while the alkaline solution could remove the silica core, thus forming the nickel silicate hollow spheres. After these spheres were further treated with hydrogen in reduction or with HCl in etching, they became silica nickel hollow spheres or silica hollow spheres, respectively. The sizes of these hollow spheres depended on the concentration of the precursor. Our investigation also found that their surface properties or magnetic properties could be tailored by adjusting the fabrication parameters. PMID- 20722443 TI - Direct evidence of the role of ATPgammaS in the binding of single-stranded binding protein (Escherichia coli) and RecA to single-stranded DNA. AB - To gain insight into the influence of ATPgammaS on the competitive binding of RecA and single-stranded binding protein (SSB) on single-stranded DNA (ssDNA), AFM imaging was used to examine the three-dimensional structures of the different complexes formed by the binding of the two proteins on ssDNA in the presence and absence of ATPgammaS. In the presence of ATPgammaS, RecA attaches to ssDNA, displacing SSB, to form continuous binding regions that caused considerable elongation of the strand. When ATPgammaS is absent, RecA could not compete with SSB and only binds at a few sites that correspond to the vacancy in ssDNA left when SSB unbinds. These results provide direct evidence that, while SSB binding affinity to DNA is substantially higher than that of RecA, the presence of ATPgammaS is sufficient to alter the events and enable RecA coating of DNA. PMID- 20722444 TI - Electron capture dynamics of a water molecule connected to a cyclic water trimer: a direct ab initio MD approach. AB - Electron capture dynamics of the water tetramer (H(2)O)(n) (n = 4) have been investigated by means of a full-dimensional direct ab initio molecular dynamics (MD) method at the MP2/6-311++G(d,p) level. Two structural conformers (branched and cyclic forms of the water tetramer) were examined as neutral water tetramers. The structure of the branched form is that a dangling water molecule binds to the ring composed of a cyclic water trimer. In the case of electron capture of the branched form, first, an excess electron was trapped by the dangling water molecule. Next, rotation of the water molecule located in the ring occurred rapidly, while a hydrogen bond of the ring was broken. The branched structure was gradually changed to a linear one. This change was caused by the increase of the dipole moment of the neutral water tetramer oriented toward the excess electron. The time scale of hydrogen bond breaking and solvation of the excess electron were estimated to be 100 and 400 fs, respectively. In the case of the cyclic water tetramer, a planar structure was only changed to a slight bent form. The mechanism of electron capture of the water tetramer (mainly the branched form) was discussed on the basis of theoretical results. PMID- 20722445 TI - Heteropolynuclear gold complexes with metallophilic interactions: modulation of the luminescent properties. AB - Metalloligands of stoichiometry [AuCl(P-N)] have been obtained by the reaction of the heterofunctional phosphines P-N = PPh(2)py, PPh(2)CH(2)CH(2)py, or PPhpy(2) with [AuCl(tht)] (tht = tetrahydrothiophene). Reactions of these metalloligands with several metal compounds have afforded heteropolynuclear species which exhibit luminescent properties. The stoichiometries depend on the molar ratio and the heterometal. Thus, the reaction with [Cu(NCMe)(4)](+) in a molar ratio 2:1 gives the trinuclear compounds [Au(2)CuCl(2)(P-N)(2)](+), in which the structure and Au...Cu interactions depend on the phosphine ligand. With rhodium and iridium derivatives the reactivity is different leading to complexes of the type [AuMCl(2)(cod)(P-N)] for P-N = PPh(2)py, PPhpy(2), and [Au(2)M(2)Cl(cod)(2)(P N)(2)]Cl with PPh(2)CH(2)CH(2)py. Using [MCl(2)(NCPh)(2)] (M = Pd, Pt) in a 2:1 molar ratio yields [Au(2)MCl(4)(P-N)(2)] and in a 1:1 molar ratio [AuPdCl(3)(MU(3)-PPhpy(2))]. Several compounds have been characterized by X-ray diffraction showing in many cases short Au...M distances. The luminescence of these derivatives has been studied. The metalloligands display bands assigned to intraligand (IL) transitions. For the bimetallic (Au/M) systems the luminescence depends on the heterometal present and on the metallophilic interactions. The most important excitations in the relevant energy range were assigned essentially a MMLCT character (from Rh/Ir and Au to ligands) based on density functional theory (DFT) calculations in selected complexes. The luminescence behavior in Rh/Ir [AuMCl(2)(cod)(PPh(2)py)] complexes was interpreted on the basis of the different nature of the half occupied orbitals in the triplet state. PMID- 20722446 TI - Heterocyclic compounds and aromatic diglycosides from Bretschneidera sinensis. AB - Two new heterocyclic compounds, bretschneiderazines A and B (1, 2), three new aromatic diglycosides, bretschneiderosides A-C (3-5), and three known aromatic diglycosides, 6-8, were isolated from Bretschneidera sinensis. The structure of bretschneiderazine A (1) was confirmed by single-crystal X-ray diffraction analysis. Bretschneiderazine A (1) showed moderate activity against the NCI-H446 cell line. PMID- 20722447 TI - Asymmetrical [Ni(dmit)2]- arrangements induced by (1R,2R)-cyclohexanediammonium crown ether supramolecules. AB - Structurally flexible (1R,2R)-cyclohexanediammonium (CHDA(2+)) dication formed hydrogen-bonding supramolecules with [18]crown-6, benzo[18]crown-6 (B[18]crown 6), dibenzo[18]crown-6 (DB[18]crown-6), and dicyclohexano[18]crown-6 (DCH[18]crown-6) in [Ni(dmit)(2)](-) salts (dmit(2-) = 2-thioxo-1,3-dithiole-4,5 dithiolate). The two ammonium moieties of CHDA(2+) interacted with the crown ethers to form open-mouth-shaped sandwich-type cationic structures of (CHDA(2+))(crown ethers)(2), that is, (CHDA(2+))([18]crown-6)(2)[Ni(dmit)(2)](2)( )() (1), (CHDA(2+))(B[18]crown-6)(2)[Ni(dmit)(2)](2)(-)() (2), (CHDA(2+))(DB[18]crown-6)(2)[Ni(dmit)(2)](2)(-)() (3), and (CHDA(2+))(DCH[18]crown-6)(2)[Ni(dmit)(2)](2)(-)() (4). The chiral structure of CHDA(2+) induced asymmetrical [Ni(dmit)(2)](-) arrangements in the crystals. A large frequency and temperature dependence of the dielectric response was observed in (CHDA(2+))(B[18]crown-6)(2), due to the pendulum motion of the cyclohexane ring along the nitrogen-nitrogen direction of CHDA(2+). Since the inversion center of the [Ni(dmit)(2)](-) arrangements was lost in the unit cell due to the chiral space group, the salts 1-4 showed rather complicated magnetic behaviors. The temperature-dependent magnetic properties of salts 3 and 4 were explained by the sum of the Curie-Weiss and singlet-triplet thermal excitation models, with positive (ferromagnetic) and negative (antiferromagnetic) magnetic exchange energies, respectively. PMID- 20722448 TI - Pnictogen-hydride activation by (silox)3Ta (silox = (t)Bu3SiO); attempts to circumvent the constraints of orbital symmetry in N2 activation. AB - Activation of N(2) by (silox)(3)Ta (1, silox = (t)Bu(3)SiO) to afford (silox)(3)Ta?N-N?Ta(silox)(3) (1(2)-N(2)) does not occur despite DeltaG degrees (cald) = -55.6 kcal/mol because of constraints of orbital symmetry, prompting efforts at an independent synthesis that included a study of REH(2) activation (E = N, P, As). Oxidative addition of REH(2) to 1 afforded (silox)(3)HTaEHR (2-NHR, R = H, Me, (n)Bu, C(6)H(4)-p-X (X = H, Me, NMe(2)); 2-PHR, R = H, Ph; 2-AsHR, R = H, Ph), which underwent 1,2-H(2)-elimination to form (silox)(3)Ta?NR (1?NR; R = H, Me, (n)Bu, C(6)H(4)-p-X (X = H (X-ray), Me, NMe(2), CF(3))), (silox)(3)Ta?PR (1?PR; R = H, Ph), and (silox)(3)Ta?AsR (1?AsR; R = H, Ph). Kinetics revealed NH bond-breaking as critical, and As > N > P rates for (silox)(3)HTaEHPh (2-EHPh) were attributed to (1) DeltaG degrees (calc)(N) < DeltaG degrees (calc)(P) ~ DeltaG degrees (calc)(As); (2) similar fractional reaction coordinates (RCs), but with RC shorter for N < P~As; and (3) stronger TaE bonds for N > P~As. Calculations of the pnictidenes aided interpretation of UV-vis spectra. Addition of H(2)NNH(2) or H(2)N-N((c)NC(2)H(3)Me) to 1 afforded 1?NH, obviating these routes to 1(2)-N(2), and formation of (silox)(3)MeTaNHNH2 (4-NHNH(2)) and (silox)(3)MeTaNH(-(c)NCHMeCH(2)) (4-NH(azir)) occurred upon exposure to (silox)(3)Ta?CH(2) (1?CH(2)). Thermolyses of 4-NHNH(2) and 4-NH(azir) yielded [(silox)(2)TaMe](MU-N(alpha)HN(beta))(MU-N(gamma)HN(delta)H)[Ta(silox)(2)] (5) and [(silox)(3)MeTa](MU-eta(2)-N,N:eta(1)-C-NHNHCH(2)CH(2)CH(2))[Ta(kappa-O,C OSi(t)Bu(2)CMe(2)CH(2))(silox)(2)] (7, X-ray), respectively. (silox)(3)Ta?CPPh(3) (1?CPPh(3), X-ray) was a byproduct from Ph(3)PCH(2) treatment of 1 to give 1?CH(2). Addition of Na(silox) to [(THF)(2)Cl(3)Ta](2)(MU-N(2)) led to [(silox)(2)ClTa](MU-N(2)) (8-Cl), and via subsequent methylation, [(silox)(2)MeTa](2)(MU-N(2)) (8-Me); both dimers were thermally stable. Orbital symmetry requirements for N(2) capture by 1 and pertinent calculations are given. PMID- 20722449 TI - Dynamics of two-color two-photon excited fluorescence of p-terphenyl: determination and analysis of the molecular parameters. AB - We present the experimental and theoretical study of the two-photon excited polarized fluorescence of p-terphenyl dissolved in cyclohexane/paraffin. The fluorescence was produced within a two-color two-photon (2C2P) excitation scheme utilizing simultaneous absorption of two femtosecond laser pulses at 400 nm and at 800 nm with the total excitation energy of 4.649 eV. The fluorescence was detected by a time correlated single photon counting (TCSPC) system with two detectors. Using different combinations of the absorbed photon polarizations we extracted seven time-dependent molecular parameters from experiment that contain all information on the dynamics of the three-photon process under study. The analysis of the obtained molecular parameter values was based on the ab initio calculations of the vertical excitation energies and transition matrix elements in p-terphenyl and allowed for determination of the whole structure of the two photon absorption tensor, fluorescence lifetime, and the rotational correlation time. The obtained results imply that the fluorescence in the conditions of our experiment was governed mostly by the d(z) component of the fluorescence transition dipole moment that is parallel to the molecular long axis Z. The tensor was found to be symmetric. The two-photon excitation in p-terphenyl occurs simultaneously via two channels, one of them resulting in the population of the totally symmetric excited state and the other in the population of the nontotally symmetric excited state. Moreover, the energetically allowed pure electron transitions are dipole forbidden and become allowed by vibronic coupling. PMID- 20722450 TI - Modifying the wettability of surfaces by nanoparticles: experiments and modeling using the Wenzel law. AB - The control of the wettability by nanoparticles (NPs) was studied by treating lignin model surfaces with silica NPs at various NP concentrations. The experimental contact angles (CAs) were compared to a modified Wenzel equation, which takes into account the changes in the effective surface area and the surface roughness. The conclusion was drawn that the change of effective roughness is not visible, which implies that the NP-induced geometric heterogeneity is irrelevant for the CA change. This is attributed to dynamics of contact line in the weak pinning regime. PMID- 20722451 TI - Les Maitres de l'Orge: the proteome content of your beer mug. AB - The beer proteome has been evaluated via prior capture with combinatorial peptide ligand libraries (ProteoMiner as well as a homemade library of reduced polydispersity) at three different pH (4.0, 7.0, and 9.3) values. Via mass spectrometry analysis of the recovered fractions, after elution of the captured populations in 4% boiling SDS, we could categorize such species in 20 different barley protein families and 2 maize proteins, the only ones that had survived the brewing process (the most abundant ones being Z-serpins and lipid transfer proteins). In addition to those, we could identify 40 unique gene products from Saccharomyces cerevisiae, one from S. bayanus and one from S. pastorianus as routinely used in the malting process for lager beer. These latter species must represent trace components, as in previous proteome investigations barely two such yeast proteins could be detected. Our protocol permits handling of very large beer volumes (liters, if needed) in a very simple and user-friendly manner and in a much reduced sample handling time. The knowledge of the residual proteome in beers might help brewers in selecting proper proteinaceous components that might enrich beer flavor and texture. PMID- 20722456 TI - The first Asian Chemical Biology conference meets at Seoul National University. PMID- 20722458 TI - Acoustic spectroscopy of colloids dispersed in a polymer gel system. AB - The technique of acoustic spectroscopy offers some significant advantages over conventional techniques, such as dynamic light scattering and differential sedimentation (centrifugation), for the characterization of colloidal dispersions in that it does not require that the systems be highly dilute and transparent. Another advantage of the method may derived from the fact that in applications, the relative motion between any particle and the medium is very small, at the most being comparable to the particle size. It may thus be suited, within limits, to the study of dispersions in polymer gels, without the additional limitation of conventional methods to transparent media (matching refractive index of polymer and liquid). The present work seeks to probe experimentally the limits of the technique and its current theory for the determination of particle size distributions in gel media. Experiments measuring acoustic attenuation have been conducted on dispersions of silica particles of varying size in aqueous hydroxylpropyl cellulose (HPC) gels of varying cross-link density. The particle size distribution (PSD) was successfully measured by acoustic attenuation theory for dispersions in Newtonian media provided that the hydrodynamic particle diameter was less than the hydrodynamic mesh size of the gel, as given by simple rubber elasticity theory (mesh size/particle size ?1.5). The same results were obtained at particle loadings of up to 15 wt %. If the particles are larger than the mesh size, then a viscoelastic response from the gel matrix is observed that cannot be interpreted to yield the particle size using the existing theoretical framework. PMID- 20722459 TI - Artificial exocytotic system that secretes intravesicular contents upon Ca2+ influx. AB - Exocytosis is a crucial process of secreting various signaling molecules such as neurotransmitters, hormones, and other chemical mediators into the extracellular space. Exocytotic release is caused by membrane fusion of intracellular vesicles with the plasma membrane triggered by an increase in intracellular Ca(2+). In the present study, we developed an artificial system of exocytosis that secretes intravesicular contents upon Ca(2+) influx. We prepared artificial secretory cells using cell-sized giant unilamellar liposomal vesicles (GUVs) that contain small liposomes (SUVs) that correspond to secretory vesicles. To observe exocytosis-like secretion in an artificial system, we labeled both an intra-SUV solution and an SUV membrane with a soluble fluorescent dye and a rhodamine labeled phospholipid, respectively. To induce membrane fusion between SUVs and a GUV as observed in exocytosis, the Ca(2+) concentration of intra-GUV was elevated by incorporating ionomycin (a Ca(2+) ionophore) into the GUV membrane. We succeeded in inducing exocytosis-like secretion by Ca(2+) elevation in a GUV together with the osmolarity difference between the intra-GUV and extra-GUV solutions. PMID- 20722460 TI - Polymerization-like multilevel hierarchical self-assembly of polymer vesicles into macroscopic superstructures with controlled complexity. AB - We demonstrate a high-leveled hierarchical self-assembly process into fractal structures. Two hyperbranched multiarm copolymers are first coassembled into binary isotropic vesicles in the primary self-assembly. Then, these primary vesicles are in situ endowed with anisotropic hydrophobic "binding sites" through a pH-induced lateral microphase separation, undergoing an isotropic-anisotropic transition. Subsequently, the anisotropic vesicles further assemble together through the specific self-recognition between the binding sites into linear, branched, cyclization, and network-like vesicle chains. Furthermore, the obtained vesicle chains can transform into linear, branched, ring-like, and network tubes through successive vesicle fusion. Such a hierarchical process is pH-triggered and well-controlled by adjusting the vesicle compositions and is coined as "polymerization-like" self-assembly due to the striking analogy between the vesicle association model and polymerization process. PMID- 20722461 TI - Film thickness dependence of phase separation and dewetting behaviors in PMMA/SAN blend films. AB - Film thickness dependence of complex behaviors coupled by phase separation and dewetting in blend [poly(methyl methacrylate) (PMMA) and poly(styrene-ran acrylonitrile) (SAN)] films on silicon oxide substrate at 175 degrees C was investigated by grazing incidence ultrasmall-angle X-ray scattering (GIUSAX) and in situ atomic force microscopy (AFM). It was found that the dewetting pathway was under the control of the parameter U(q0)/E, which described the initial amplitude of the surface undulation and original thickness of film, respectively. Furthermore, our results showed that interplay between phase separation and dewetting depended crucially on film thickness. Three mechanisms including dewetting-phase separation/wetting, dewetting/wetting-phase separation, and phase separation/wetting-pseudodewetting were discussed in detail. In conclusion, it is relative rates of phase separation and dewetting that dominate the interplay between them. PMID- 20722462 TI - GP Proceduralists: 'the hidden heart' of rural and regional health in Australia. AB - INTRODUCTION: General practitioner proceduralists are a distinct and highly trained cohort of doctors who provide procedural services in hospitals and emergency rooms throughout Australia. However, their value is not well recognised in the wider system of primary health care. Consequently, an understanding of the landscape of GP procedural practice is an essential element of health service planning now and in the future. Therefore, empirical data from a 2008 study of GP procedural medicine in the Bogong region of north-east Victoria and southern New South Wales is presented. The implications of shifting trends in the demand for and supply of the GP procedural workforce on future health services is examined. A comprehensive literature review established past and future trends in procedural medicine and provided a context for three research questions: (1) What procedures are being performed by GP proceduralists in the Bogong region? (2) What procedures are no longer performed and why? (3) What is the likely future of GP procedural practice in the next 5 to 10 years? METHOD: A qualitative case study methodology was chosen to explore the factors that influence the nature of GP procedural medicine. A population of 70 GPs were initially identified as practising obstetric, surgical or anaesthetic procedures. Of these, 38 participated in structured interviews, 21 were electronically surveyed and 11 were excluded from the study. Combined interview and survey responses gave a response rate of 81%. Five health service executives and a senior Department of Human Services manager were interviewed to gather their perspectives about the research questions. Content and thematic analysis revealed key issues of importance. Data-sets were examined to analyse themes associated with trends in GP procedural medicine over time. RESULTS: General practitioner proceduralists are attracted by diversity, challenge and passion for procedural work. However, there has been a gradual but sustained decline in the volume and complexity of procedural work due, in part, to shifts in community demography, changing medical practices, the rise of specialisation, the centralisation of services, infrastructure and other costs, and fear of litigation. Moreover, an ageing workforce and a shift in the demographic profile of GPs and the pressures of procedural life have contributed to a decline in GP proceduralist numbers. Nevertheless, there remains a substantial demand for GP procedural medicine in rural communities. CONCLUSIONS: Rural towns are dependent upon GP proceduralists to ensure the continuing health and sustainability of local communities. However, the existence of a viable and robust workforce of GP proceduralists is at a 'breaking point'. Until GP proceduralists are recognised and counted as a distinct cohort of valued and highly trained medical practitioners they will remain the 'hidden heart' of primary care in rural and regional Australia. An holistic approach must be adopted to attract, train, maintain and recognise the GP proceduralists' unique place in rural health. With the Australian health system under government review, there are opportunities to revitalise GP procedural practice as a long term, viable and challenging career choice and ensure on-going support for rural in-patient and emergency department services. PMID- 20722463 TI - Intelligent thermoresponsive substrate from modified overhead projection sheet as a tool for construction and support of cell sheets in vitro. AB - Cell sheet engineering using thermoresponsive culture dishes allows harvesting of intact in vitro cell sheet. In this study, commercially available polyethylene terephthalate-based overhead projection transparency sheet (OHPS) was identified as a substrate for coating thermoresponsive poly(N-isopropylacrylamide-co glycidylmethacrylate) (NGMA) copolymer having lower critical solution temperature of 28 degrees C. Since OHPS is highly hydrophobic and rigid, the surface was modified by alkali treatment (OHPS-M) to functionalize the surface with carboxyl and hydroxyl groups so as to make it more suitable for efficient coating of NGMA copolymer and cell culture. To impart thermoresponsiveness, OHPS-M was coated with NGMA (OHPS-MC). Surface morphology, surface chemistry, and thermoresponsive coating were analyzed by profilometry, scanning electron microscopy, water contact angle, and Fourier transform infrared spectroscopy. The cytotoxicity, cell adhesion, and proliferation on OHPS-M and OHPS-MC were analyzed using L929 cells. Specific cytocompatibility analysis was done using SIRC (Rabbit corneal) cells. Data revealed cytocompatible nature of OHPS-M and OHPS-MC. Suitability of OHPS-MC for cell sheet harvest and transfer efficiency was assessed using primary corneal cells. Corneal cell sheet constructs retrieved by temperature variation was characterized by reverse transcriptase polymerase chain reaction for markers specific to differentiated corneal cells (keratin 3 and keratin 12) and proliferating cell nuclear antigen, and assessed for viability using fluorescein diacetate staining, tissue architecture by scanning electron microscopy, and cell cell contacts by connexin-43 staining. The retrieved cell sheets retained corneal epithelial characteristics such as keratin 3/12, viability, and tissue architecture with intact cell-cell contacts as in native tissue. The results proved that surface modification and coating with NGMA on OHPS offer a novel biocompatible thermosensitive cell culture substrate for generating cell sheet constructs. In addition, OHPS-M can also serve as an efficient carrier tool for retrieved cell sheet. PMID- 20722465 TI - Not your grandfather's genetic testing oversight. PMID- 20722464 TI - Detection of HIV gp120 in plasma during early HIV infection is associated with increased proinflammatory and immunoregulatory cytokines. AB - Events that occur during acute HIV infection likely contribute to the immune dysfunction common in HIV-infected individuals. During this early stage, there is high-level viral replication, loss in CD4(+) T cell number and function, and an up-regulation of proinflammatory and immunoregulatory cytokines. The mechanisms responsible for this are not completely understood. We hypothesize that the HIV envelope glycoprotein, gp120, contributes to immune dysfunction during early HIV infection. Using a cohort of subjects enrolled during acute and early HIV infection, we determined the amount of gp120, TNF-alpha, IL-6, IL-10, IFN-alpha, and IFN-gamma in plasma at baseline and 6 months. At matched time points, we also measured CD4(+) T cell proliferation, T cell activation, and apoptosis. Plasma from 109 subjects was screened for gp120. Thirty-six subjects (33%) had detectable gp120 (0.5-15.6 ng/ml). Subjects with greater than 1 ng/ml of gp120 at baseline had similar levels at all time points tested, even when viral replication was undetectable due to therapy. Subjects with detectable gp120 had higher levels of plasma IL-6, IL-10, and TNF-alpha. There was no difference in the level of T cell activation, proliferation, or apoptosis in subjects with gp120 compared to those without. We conclude that persistent expression of gp120 occurs in a subset of individuals. Furthermore, the presence of gp120 is associated with higher levels of plasma IL-6, IL-10, and TNF-alpha, which may contribute to immune dysfunction during early HIV infection. PMID- 20722466 TI - Diagnosis of Down syndrome and detection of origin of nondisjunction by short tandem repeat analysis. AB - CONTEXT: Conventional karyotyping for antenatal diagnosis is time consuming and hence there has been a growing interest in more rapid techniques for detection of chromosomal aneuploidies. Around 95% of Down syndrome cases are due to free trisomy 21. AIMS: The aims of this study were to demonstrate sensitivity of DNA diagnosis of Down syndrome using polymerase chain reaction (PCR) and short tandem repeat (STR) markers, and to determine the parental origin of the nondisjoined chromosome. METHODS: DNA polymorphism was studied using two tetranucleotide STR markers, D21S2055 situated at 21q22.2 and D21S11 situated at 21q21.1. PCR conditions for both markers were standardized. PCR products were analyzed in 15% poly-acrylamide gels. The results obtained by STR analysis were verified with the chromosomal analysis and quantitative fluorescent (QF)-PCR. RESULTS: These two STR markers were able to detect 86.7% cases of trisomy 21. Parental origin of extra chromosome was assigned to 77% of detected cases. CONCLUSION: The PCR-based DNA diagnostic method was found to be sensitive, reproducible, and efficient, not only for diagnosis of trisomy 21, but also for tracing allelic transmission from parents to the offspring. PMID- 20722467 TI - Evaluation of the contribution of the three breast cancer susceptibility genes CHEK2, STK11, and PALB2 in non-BRCA1/2 French Canadian families with high risk of breast cancer. AB - Inactivating mutations of the CHEK2 and STK11 genes are responsible for Li Fraumeni and Peutz-Jeghers syndrome, respectively, both autosomal dominant syndromes associated with an increased risk of breast cancer. The PALB2/FANCN gene encodes a nuclear partner of BRCA2 and acts as a linker between BRCA1 and BRCA2. Monoallelic PALB2 truncating mutations were shown to confer higher risk of breast cancer. To evaluate the proportion of French Canadian non-BRCA1/BRCA2 families with high risk of breast cancer potentially harboring alterations in these three breast cancer susceptibility genes, the whole coding and flanking intronic sequences were analyzed in a series of 96 high-risk breast cancer individuals. Despite no PALB2 deleterious truncating mutations being identified, the c.1100delC breast-cancer-associated CHEK2 mutation and a STK11 mutation reported to be the causative mutation in a Peutz-Jeghers family were identified. This extensive analysis also led to the identification of several variants in these genes. Ascertainment of allele frequency of these variants in a cohort of 96 healthy unrelated women suggests a difference in allele frequency for two STK11 intronic variants. In addition, large genomic rearrangements in both STK11 and PALB2 were also examined. Our analysis led to the conclusion that CHEK2, STK11, and PALB2 mutations or large genomic rearrangements of either STK11 or PALB2 are rare, and do not contribute to a substantial fraction of breast cancer susceptibility in high-risk French Canadian breast cancer families. PMID- 20722469 TI - Neonatal screening for hemoglobinopathies: results of a public health system in South Brazil. AB - AIM: The aim of this study was to estimate the prevalence of hemoglobinopathies in South Brazil. METHODS: Samples of dried blood spots collected by heel prick in neonates were evaluated by isoeletric focusing and/or high-performance liquid chromatography techniques. All variants were characterized at the molecular level. RESULTS: A total of 437,787 samples were evaluated. Among these, 6391 showed an abnormal hemoglobin pattern. These included 48 cases (0.01%) of sickle cell disorders (33 hemoglobin SS [Hb SS], 7 Hb SC, 7 Hb S/beta thalassemia, 1 Hb SD), 1 neonate who was homozygous for beta thalassemia, 6272 (1.4%) newborns who were heterozygous for Hb S, C, or D, and 71 (0.02%) neonates who were carriers for rare hemoglobin variants. Most of these rare variants were identified for the first time in Brazil. CONCLUSIONS: Comparing these results with those obtained in other Brazilian regions, we observe a highly heterogeneous distribution. This knowledge is useful in healthcare planning and allocation of resources, as well as identifying at-risk couples, which will assist with disease prevention. PMID- 20722468 TI - Analysis of human CD36 gene sequence alterations in the oxidized low-density lipoprotein-binding region using denaturing high-performance liquid chromatography. AB - Denaturing high-performance liquid chromatography (DHPLC) has been employed as a prescreening tool to reduce the amount of DNA sequencing. It could be a simple and cost-effective screening method for mutations and polymorphisms in exons 4, 5, and 6 of the CD36 gene, which encode the protein region responsible for the removal of oxidized low-density lipoprotein. Genomic DNA was isolated from 306 Caucasian infants of Polish origin. Six single-nucleotide substitutions were detected by DHPLC and confirmed by direct sequencing. The A591T, G550A, and C572T alterations have not been described so far. Each of two nonsynonymous substitutions (Asp184Asn, Pro191Leu) was found in one subject (0.2% minor allele frequency). The results suggest that nonsynonymous alterations in the analyzed CD36 region are rare in Caucasians. DHPLC is a specific and cost-effective technique that may prove to be particularly useful for the identification of polymorphisms and mutations in the CD36 gene. PMID- 20722470 TI - Cystic fibrosis conductance regulator, tumor necrosis factor, interferon alpha 10, interferon alpha-17, and interferon gamma genotyping as potential risk markers in pulmonary sarcoidosis pathogenesis in Greek patients. AB - Sarcoidosis is a complex disease with autoimmune basis and still unknown etiology. We have screened for mutations in the cystic fibrosis conductance regulator (CFTR) gene and genotyped single-nucleotide polymorphisms in the tumor necrosis factor (TNF), interferon alpha-10 (IFNA10), IFNA17, and interferon gamma (IFNG) genes in 89 Greek patients with sarcoidosis and 212 control subjects to detect possible association between them and the risk for developing sarcoidosis. We have found a statistically significant increase (p = 6.1 x 10(-8)) of CFTR mutation carriers in the population of patients with sarcoidosis versus the control population. A difference was also noted within the group of patients with sarcoidosis where the ones with CFTR mutations suffered more frequently from dyspnea than those without (p = 5 x 10(-6)). Our study did not reproduce the associations previously noted with the TNF, IFNA10, IFNA17, and IFNG genes, which highlights the genetic complexity of the disorder and is in agreement with previous studies showing that CFTR might be an important factor in the clinical course of the disease. PMID- 20722471 TI - Effects of yoga versus walking on mood, anxiety, and brain GABA levels: a randomized controlled MRS study. AB - OBJECTIVES: Yoga and exercise have beneficial effects on mood and anxiety. gamma Aminobutyric acid (GABA)-ergic activity is reduced in mood and anxiety disorders. The practice of yoga postures is associated with increased brain GABA levels. This study addresses the question of whether changes in mood, anxiety, and GABA levels are specific to yoga or related to physical activity. METHODS: Healthy subjects with no significant medical/psychiatric disorders were randomized to yoga or a metabolically matched walking intervention for 60 minutes 3 times a week for 12 weeks. Mood and anxiety scales were taken at weeks 0, 4, 8, 12, and before each magnetic resonance spectroscopy scan. Scan 1 was at baseline. Scan 2, obtained after the 12-week intervention, was followed by a 60-minute yoga or walking intervention, which was immediately followed by Scan 3. RESULTS: The yoga subjects (n = 19) reported greater improvement in mood and greater decreases in anxiety than the walking group (n = 15). There were positive correlations between improved mood and decreased anxiety and thalamic GABA levels. The yoga group had positive correlations between changes in mood scales and changes in GABA levels. CONCLUSIONS: The 12-week yoga intervention was associated with greater improvements in mood and anxiety than a metabolically matched walking exercise. This is the first study to demonstrate that increased thalamic GABA levels are associated with improved mood and decreased anxiety. It is also the first time that a behavioral intervention (i.e., yoga postures) has been associated with a positive correlation between acute increases in thalamic GABA levels and improvements in mood and anxiety scales. Given that pharmacologic agents that increase the activity of the GABA system are prescribed to improve mood and decrease anxiety, the reported correlations are in the expected direction. The possible role of GABA in mediating the beneficial effects of yoga on mood and anxiety warrants further study. PMID- 20722472 TI - Metabolism and excretion of [14C]taranabant, a cannabinoid-1 inverse agonist, in humans. AB - Taranabant (N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2 methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 MUCi [14C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (~92%), with the majority of the dose (~87%) excreted into faeces and a much smaller fraction (~5%) into urine. Taranabant was absorbed rapidly, with C(max) of radioactivity attained at 1-2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised ~12-24% and 33-42%, respectively, of the plasma radioactivity for up to 48 h. A second monohydroxylated metabolite, designated as M1a, represented ~10-12% of the radioactivity in the 2- and 8-h postdose plasma profiles. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route. PMID- 20722473 TI - Socio-demographic disparities in distribution shifts over time in various adiposity measures among American children and adolescents: What changes in prevalence rates could not reveal. AB - Background. While obesity prevalence in the US has been increasing, adiposity shifts may vary across socio-demographic groups, and various adiposity measures may reveal different patterns. Methods. To study changes over time in adiposity measures, distributional shifts in body mass index (BMI, kg/m(2)), BMI percentile, waist circumference (WC) and triceps skinfold thickness (TST), and compare between-group differences, National Health and Nutrition Examination Surveys (NHANES) III 1988-94 and 1999-2004 from children aged 2-19 years old data were analyzed. Annual shift in adiposity measures across percentiles were shown as Tukey's mean-difference plots, with percentile-specific mean differences being divided by 10.5 years. Overall and quintile-specific adjusted shifts were estimated from multivariate ordinary least square (OLS) regression models. Results. Mean 10.5-year increases in adiposity were statistically significant, higher in older groups, more pronounced in some sex-ethnic groups (e.g., black girls) and at upper percentiles (more obese groups) for most measures and sex-age ethnic groups. Adjusted increase in mean BMI was 0.60 in girls and 0.64 in boys; BMI percentile, 3.02 and 3.15 units; WC, 2.85 and 2.42 cm; and TST, 0.81 and 1.18 mm, for girls and boys, respectively. Ethnic, age and sex disparities in mean BMI became wider over time. Several significant ethnic differences in adjusted adiposity shifts within the lowest (Q1) and uppermost (Q5) quintiles of adiposity measure distributions were noted. Conclusions. The increase in adiposity among American children was unequally distributed across groups and varied across the spectrum of various adiposity measures. Overweight groups gained more adiposity over time, especially WC. Solely examining prevalence shifts masks pattern complexity. PMID- 20722474 TI - Targeting sigma-1 receptor with fluvoxamine ameliorates pressure-overload-induced hypertrophy and dysfunctions. AB - OBJECTIVE: We here investigated the effect of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy, cardiac functional recovery and defined mechanisms underlying its cardioprotective action. METHODS: Wistar rats subjected to bilateral ovariectomy (OVX) were treated with abdominal aortic banding between the right and left renal arteries. To confirm the cardioprotective role of Sig-1R stimulation, we treated the rats with Sig-1R agonist (fluvoxamine, 0.5 and 1 mg/kg) orally once a day for 4 weeks after the onset of aortic banding. RESULTS: Interestingly, the expression of Sig-1R in the left ventricle (LV) decreased significantly 4 weeks after pressure overload (PO) induced hypertrophy in OVX rats. The fluvoxamine administration significantly attenuated PO-induced myocardial hypertrophy with concomitant increase in the expression of Sig-1R in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV functions. The cardioprotective effect of fluvoxamine was nullified by treatment with Sig-1R antagonist (NE-100; 1 mg/kg). Fluvoxamine treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV. CONCLUSION: We here found, for the first time, the potential role of Sig-1R expression in the heart in attenuating PO-induced hypertrophy in OVX rats. Fluvoxamine treatment protects PO-induced cardiac injury via upregulation of Sig 1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in ovariectomized rats. PMID- 20722475 TI - "It's our job": qualitative study of family responses to ableism. AB - Forty-five parents of children with autism, cerebral palsy, Down syndrome, and sickle cell disease participated in 8 focus groups. Parents discussed how they, the child with the disability, and the siblings addressed community perceptions about the child's disability. Themes evolving from the interviews included (a) support and lack of support, (b) inclusion and exclusion, and (c) the family members' roles during their interactions with the community. Parents viewed their roles in the community as (a) advocating, (b) educating, (c) informing, (d) ignoring, and (e) hiding. The relationship between themes is presented, and the relationship between themes and parent empowerment is discussed as well as the ways in which the themes reflect underlying ableism. PMID- 20722476 TI - Extended child and caregiver benefits of behavior-based child contingency learning games. AB - Findings from 2 studies of the relationship between response-contingent child behavior and child, caregiver-child, and caregiver behavior not directly associated with child contingency learning are described. The participants were 19 children with significant developmental delays and their mothers in 1 study and 22 children with significant developmental delays and their teachers in the second study. Caregivers engaged the children in learning games characterized by behavior-based contingencies for 15 weeks. Research staff observed the children and their caregivers in everyday routines and activities and rated child and caregiver behavior while the children and caregivers were not playing the games. Results from both studies showed that the degree of response-contingent responding during the games was related to child and caregiver behavior, not the focus of the contingency learning opportunities afforded the children. Implications for practice are described. PMID- 20722477 TI - Nursing perspectives on cancer screening in adults with intellectual and other developmental disabilities. AB - Health care disparities have been documented in cancer screenings of adults with intellectual and other developmental disabilities. Developmental disabilities nurses were surveyed to better understand and improve this deficiency. Two thirds of respondents believed that adults with intellectual and developmental disabilities received fewer cancer screenings compared with the general population. The most frequently cited barriers to cancer screenings were as follows: patient need for sedation, unsuccessful attempts at screening, and failure of the primary care clinician to order cancer screening tests. Nurses observed that health care providers frequently did not tailor cancer screening recommendations to individuals' family histories, life expectancies, or their disability-specific cancer risks. The authors suggest interventions to improve cancer screening centered around education and training, accessibility, financing insurance, modification of procedures, and patient tracking. PMID- 20722478 TI - Public attitudes toward people with intellectual disabilities: a cross-cultural study. AB - This study investigated attitudes toward people with intellectual disabilities among the general Hong Kong Chinese population and compared these to a White British sample, using the Community Living Attitudes Scale-Mental Retardation form (CLAS-MR; D. Henry, C. Keys, F. Balcazar, & D. Jopp, 1996 ). As predicted, attitudes among the Hong Kong Chinese public (n = 149) were less favorable than the British sample (n = 135). The former were less opposed to the exclusion of people with intellectual disabilities, less likely to view them as similar to themselves and more in favor of sheltering such individuals. Of all demographic variables examined, ethnicity was the strongest predictor of attitudes, although it only accounted for a small part of the variance in attitudes. The results are discussed in terms of policy implementation and additional research. PMID- 20722479 TI - The editor's perspective. PMID- 20722480 TI - Doreen Croser: introduction from the president. PMID- 20722481 TI - Croser to retire as Executive Director of AAIDD. AB - Washington, DC-Doreen Croser retired as Executive Director of the American Association on Intellectual and Developmental Disabilities (AAIDD) in June, 2010, following a distinguished 22-year tenure in the position. Past presidents of AAIDD have issued statements in Doreen's honor. PMID- 20722482 TI - Letter to the membership. PMID- 20722483 TI - Spirituality and disabilities: implications for special education. PMID- 20722488 TI - The role of exposure reconstruction in occupational human health risk assessment: current methods and a recommended framework. AB - Exposure reconstruction for substances of interest to human health is a process that has been used, with various levels of sophistication, as far back as the 1930s. The importance of robust and high-quality exposure reconstruction has been recognized by many researchers. It has been noted that misclassification of reconstructed exposures is relatively common and can result in potentially significant effects on the conclusions of a human health risk assessment or epidemiology study. In this analysis, a review of the key exposure reconstruction approaches described in over 400 papers in the peer-reviewed literature is presented. These approaches have been critically evaluated and classified according to quantitative, semiquantitative, and qualitative approaches. Our analysis indicates that much can still be done to improve the overall quality and consistency of exposure reconstructions and that a systematic framework would help to standardize the exposure reconstruction process in the future. The seven recommended steps in the exposure reconstruction process include identifying the goals of the reconstruction, organizing and ranking the available data, identifying key data gaps, selecting the best information sources and methodology for the reconstruction, incorporating probabilistic methods into the reconstruction, conducting an uncertainty analysis, and validating the results of the reconstruction. Influential emerging techniques, such as Bayesian data analysis, are highlighted. Important issues that will likely influence the conduct of exposure reconstruction into the future include improving statistical analysis methods, addressing the issue of chemical mixtures, evaluating aggregate exposures, and ensuring transparency with respect to variability and uncertainty in the reconstruction effort. PMID- 20722489 TI - KTO-7924, a Beta3-adrenergic receptor agonist, reduces hyperglycemia, and protects beta-cells in the islets of langerhans of db/db mice. AB - INTRODUCTION: The effect of beta3-adrenergic receptor agonists on beta cells in the islets of Langerhans is not yet clear. This study examined the beta3 adrenergic receptor agonist on beta cells in the islets of Langerhans. METHODS: Obese diabetic C57BL/KsJ-db/db mice were treated with KTO-7924, a newly-developed beta3-adrenergic receptor agonist for 28-day. We analyzed plasma parameters, insulin resistance, and insulin-positive areas among beta-cells in the islets of Langerhans. RESULTS AND CONCLUSION: After a 28-day oral administration period, plasma levels of hemoglobin (Hb) A1c, glucose, triglyceride (TG), and free fatty acid (FFA) were all significantly reduced in KTO-7924 treatment groups compared with controls. Plasma adiponectin levels decreased with age in the control group, but were significantly higher in a treatment group throughout the study period. Furthermore, sequential administration of KTO-7924 led to an improvement in insulin resistance in the OGTT (Oral glucose tolerance test (OGTT)), and an increase in the percentage of insulin-positive areas among beta-cells in the islets of Langerhans compared with controls. This is the first study to show islet histology after treatment of a beta3-adrenergic receptor agonist, and reveals that KTO-7924 reduces hyperglycemia, and protects beta-cells in the islets of Langerhans of db/db mice. PMID- 20722490 TI - Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development. AB - IMPORTANCE OF THE FIELD: Despite the beneficial effect of imatinib treatment in chronic myeloid leukemia patients, some patients develop resistance and/or intolerance and need a switch to second-generation tyrosine kinase inhibitors. Dasatinib is indicated for chronic myeloid leukemia patients with resistance or intolerance to imatinib; it has 325-fold increase potency compared to imatinib and is active in mutated and unmutated resistant patients. Pleural/pericardic effusions are frequent complications during treatment with dasatinib, and usually are reported to require dose reduction or drug discontinuation. Changing the dasatinib regimen from 70 mg twice daily to 100 mg once daily reduces the risk of pleural effusions. AREA COVERED IN THIS REVIEW: In this article, we review the incidence of the phenomenon observed in different dasatinib trials (Phase I - III) and the currently suggested management. We also describe the identified pathogenetic mechanisms related to the development and discuss the associated risk factors. WHAT THE READER WILL GAIN: The aim of this paper is to provide healthcare professionals with clear guidance on the management of pleural effusions associated with dasatinib treatment. Recommendations are based on the published data and clinical experience from a number of different centers. TAKE HOME MESSAGE: Literature evidences support the fact that with adequate management and monitoring of patients with predisposing factors, pleural effusions can be easily managed. PMID- 20722491 TI - Safety of capecitabine: a review. AB - IMPORTANCE OF THE FIELD: Fluoropyrimidines, in particular 5-fluorouracil (5-FU), have been the mainstay of treatment for several solid tumors, including colorectal, breast and head and neck cancers, for > 40 years. AREAS COVERED IN THIS REVIEW: This article reviews the pharmacology and efficacy of capecitabine with a special emphasis on its safety. WHAT THE READER WILL GAIN: The reader will gain better insight into the safety of capecitabine in special populations such as patients with advanced age, renal and kidney disease. We also explore different dosing and schedules of capecitabine administration. TAKE HOME MESSAGE: Capecitabine is an oral prodrug of 5-FU and was developed to fulfill the need for a more convenient therapy and provide an improved safety/efficacy profile. It has shown promising results alone or in combination with other chemotherapeutic agents in colorectal, breast, pancreaticobiliary, gastric, renal cell and head and neck cancers. The most commonly reported toxic effects of capecitabine are diarrhea, nausea, vomiting, stomatitis and hand-foot syndrome. Capecitabine has a well-established safety profile and can be given safely to patients with advanced age, hepatic and renal dysfunctions. PMID- 20722492 TI - Whisking in air: encoding of kinematics by VPM neurons in awake rats. AB - Rodent whisking behavior generates two types of neural signals: one produced by whisker contact with objects; the other by movements in air. While kinematic signals generated by contact reliably activate neurons at all levels of the trigeminal neuraxis, the extent to which the kinematics of whisking in air are reliably encoded at each level remains unclear. Previously, we showed that the responses of trigeminal ganglion (TG) neurons in awake, head-fixed rats are correlated with whisking kinematic parameters, but that individual neurons may differ substantially in the reliability of their kinematic encoding. Here, we extend that analysis to neurons in the ventral posterior medial (VPM) nucleus. Three possible coding strategies were examined: (1) firing rate across an entire movement; (2) the probability of individual spikes as a function of the instantaneous movement trajectory; and (3) the coherence between spikes and whisking. While VPM neurons were clearly responsive to variations in whisker kinematics during whisking in air, the encoding of whisker kinematics by VPM neurons was less consistent than that of TG neurons. Furthermore, we found that, in VPM as in TG, movement direction is an important determinant of unit responsiveness during whisking in air. PMID- 20722493 TI - Personal factors associated with reported benefits of Huntington disease family history or genetic testing. AB - AIMS: A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. METHODS: Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spirituality were significantly associated with benefits in both groups. CONCLUSIONS: Perceptions of benefit may not be as likely until later years in people with prodromal HD. A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD. Associations among spirituality, perceived benefits, and other indicators of personal and family well-being may be useful in genetic counseling and health care of people with prodromal HD. PMID- 20722494 TI - Absence of commonly reported leucine-rich repeat kinase 2 mutations in Eastern Indian Parkinson's disease patients. AB - BACKGROUND: Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2; PARK8) encoding dardarin, implicated in patients with autosomal dominant and sporadic Parkinson's disease (PD) among different ethnic groups (Ashkenazi Jews, North African Arabs, Basques) might be of some help in diagnostic screening and genetic counseling. AIM OF THE STUDY: We investigated the seven common mutations spanning exons 31, 35, and 41 reported in the LRRK2 gene among Eastern Indian patients with PD. METHODS: Mutations R1441G, R1441C, R1441H, G2019S, Y1699C, I2020T, and I2012T were screened in 320 individuals (PD, 150 and controls, 170) by direct sequencing. RESULTS: We did not observe any of these abovementioned mutations in our studied individuals. CONCLUSION: We conclude that these mutations are rare causes of PD in the Eastern Indian population and, therefore, of little help for genetic counseling and diagnostic purposes. PMID- 20722495 TI - Role of the mitochondrial mutations, m.827A>G and the novel m.7462C>T, in the origin of hearing loss. AB - Samples from 30 deaf probands exhibiting features suggestive of syndromic mitochondrial deafness or from families with maternal transmission of deafness were selected for investigation of mutations in the mitochondrial genes MT-RNR1 and MT-TS1. Patients with mutation m.1555A>G had been previously excluded from this sample. In the MT-RNR1 gene, five probands presented the m.827A>G sequence variant, of uncertain pathogenicity. This change was also detected in 66 subjects of an unaffected control sample of 306 Brazilian individuals from various ethnic backgrounds. Given its high frequency, we consider it unlikely to have a pathogenic role on hereditary deafness. As to the MT-TS1 gene, one proband presented the previously known pathogenic m.7472insC mutation and three probands presented a novel variant, m.7462C>T, which was absent from the same control sample of 306 individuals. Because of its absence in control samples and association with a family history of hearing impairment, we suggest it might be a novel pathogenic mutation. PMID- 20722496 TI - Knowledge about hereditary colorectal cancer among colorectal cancer survivors. AB - AIM: Little is known about colorectal cancer (CRC) patients' knowledge regarding hereditary CRC (HCRC). The primary aim of this study was to evaluate CRC survivors' level of knowledge about HCRC and determine if this knowledge varies by demographic or clinical characteristics. METHODS: Data were obtained using a cross-sectional survey of CRC patients at low, moderate, and high risk for HCRC seen at a comprehensive cancer center over a 5-year period (n = 93). Seven items (with potential responses of yes/no/don't know) assessed patients' knowledge. A t test was conducted to compare composite knowledge among individuals at increased risk for CRC to those who were not at increased risk. RESULTS: For all but one of seven questions, most individuals reported that they did not know the answer to the question. Knowledge among participants at increased risk for HCRC (mean = 2.46, standard deviation = 1.93) was greater than those who were not at increased risk (mean = 1.51, standard deviation = 1.84). There was a statistically significant difference in knowledge between the groups, t(90) = 2.40, p = 0.018. CONCLUSIONS: Results suggest an overall deficit of knowledge among CRC patients. More efforts should focus on increasing knowledge about HCRC prevention among patients and family members. With a better understanding of knowledge gaps, researchers and health-care providers can reevaluate how to better inform CRC patients about HCRC risks. PMID- 20722497 TI - Time perspective in hereditary cancer: psychometric properties of a short form of the Zimbardo Time Perspective Inventory in a community and clinical sample. AB - AIMS: We aimed to assess the psychometric properties of a 25-item short form of the Zimbardo Time Perspective Inventory in a community sample (N = 276) and in individuals with a strong family history of cancer, considering genetic testing for cancer risk (N = 338). RESULTS: In the community sample, individuals with high past-negative or present-fatalistic scores had higher levels of distress, as measured by depression, anxiety, and aggression. Similarly, in the patient sample, past-negative time perspective was positively correlated with distress, uncertainty, and postdecision regret when making a decision about genetic testing. Past-negative-oriented individuals were also more likely to be undecided about, or against, genetic testing. Hedonism was associated with being less likely to read the educational materials they received at their clinic, and fatalism was associated with having lower knowledge levels about genetic testing. CONCLUSIONS: The assessment of time perspective in individuals at increased risk of cancer can provide valuable clinical insights. However, further investigation of the psychometric properties of the short form of this scale is warranted, as it did not meet the currently accepted criteria for psychometric validation studies. PMID- 20722498 TI - Formulation, characterization and in vitro evaluation of theophylline-loaded Eudragit RS 100 microspheres prepared by an emulsion-solvent diffusion/evaporation technique. AB - The aim was to prepare theophylline-loaded Eudragit RS 100 microsphere to achieve sustained release pattern with relatively high production yield. To this end, microspheres were prepared by oil/oil solvent evaporation method using an acetone methanol mixture and liquid paraffin system containing aluminum tristearate. Drug release profiles were determined at pH 1.2 and 7.4. Morphology and solid state of microspheres were examined using SEM, DSC, X-ray powder diffraction (XRPD), and FT-IR. As the ratio of acetone/methanol increased during the preparation of microspheres the size of microsphere was reduced. The highest drug loading efficiency (87.21%) was obtained for the microsphere containing a high ratio of polymer to drug (6:1) and high volume of acetone. SEM studies showed that the microspheres are almost spherical with a few pores and cracks at surfaces. The FT IR, XRPD and DSC results ruled out any chemical interaction between theophylline and Eudragit. The microspheres prepared with low ratio of polymer to drug (1:2) showed faster dissolution rate than those with high polymer to drug ratio. The ratio of polymer to drug and the volume of polymer solvent were found to be the key factors affecting the release profile which could lead to microspheres with desired release behavior. PMID- 20722499 TI - Differential heat of adsorption of water vapor on silicified microcrystalline cellulose (SMCC): an investigation using isothermal microcalorimetry. AB - A novel dual-shaft configuration in isothermal microcalorimetry was developed to study the interaction of water vapor with pharmaceutical excipients. An instrument performance test is suggested to validate the experimental data. Reliable experimental results can be collected using a single perfusion shaft; however, there was limitation of the dual-shaft configuration, which resulted deviation in the experimental results. A periodic performance test is recommended. Silicified microcrystalline cellulose (SMCC) was used as a model system to study the interaction using the dual-shaft method. Enthalpy of water vapor adsorption on SMCC was determined and compared to literature data. The data collected using the dual-shaft configuration did not reflect the actual physical system. The deviation was most likely due to the lack of flow control caused by viscous resistance. The enthalpy of adsorption was then calculated using isothermal microcalorimetry coupled with a dynamic vapor sorption apparatus. The results, -55 kJ/mol at low relative humidity (RH) to -22 kJ/mol at high RH, were consistent with the physical phenomenon of water vapor adsorption. Enthalpy of adsorption showed surface heterogeneity of SMCC and suggested multilayer condensation of water at approximately 60% RH. However, at high RH, the results showed the moisture-excipient interaction can be more complex than the proposed mechanism. PMID- 20722500 TI - Analysis of CD14 expression levels in putative mesenchymal progenitor cells isolated from equine bone marrow. AB - A long-term goal of mesenchymal progenitor cell (MPC) research is to identify cell-surface markers to facilitate MPC isolation. One reported MPC feature in humans and other species is lack of CD14 (lipopolysaccharide receptor) expression. The aim of this study was to evaluate CD14 as an MPC sorting marker. Our hypothesis was that cells negatively selected by CD14 expression would enrich MPC colony formation compared with unsorted and CD14-positive fractions. After validation of reagents, bone marrow aspirate was obtained from 12 horses. Fresh and cultured cells were analyzed by flow cytometry and reverse transcription and quantitative polymerase chain reaction to assess dynamic changes in phenotype. In fresh samples, cells did not consistently express protein markers used for lineage classification. Short-term (2-day) culture allowed distinction between hematopoietic and nonhematopoietic populations. Magnetic activated cell sorting was performed on cells from 6 horses to separate adherent CD14(+) from CD14(-) cells. MPC colony formation was assessed at 7 days. Cells positively selected for CD14 expression were significantly more likely to form MPC colonies than both unsorted and negatively selected cells (P <= 0.005). MPCs from all fractions maintained low levels of CD14 expression long term, and upregulated CD14 gene and protein expression when stimulated with lipopolysaccharide. The equine CD14 molecule was trypsin-labile, offering a plausible explanation for the discrepancy with MPC phenotypes reported in other species. By definition, MPCs are considered nonhematopoietic because they lack expression of molecules such as CD14. Our results challenge this assumption, as equine MPCs appear to represent a descendant of a CD14-positive cell. PMID- 20722502 TI - Where angels fear to tread: proxy consent and novel technologies. AB - BACKGROUND: Individuals suffering from severe disorders of consciousness (DOC) face a bleak prognosis and are susceptible to therapeutic neglect according to Fins. Because of the increasing occurrence of severe brain injury, some physicians and researchers take the study of DOC to be a moral imperative and perceive novel technologies, such as Deep Brain Stimulation (DBS), as offering potential therapeutic benefit. METHOD: This article examines the decisional process faced by proxy decision-makers for patients with severe DOC when confronted by novel treatments such as DBS. RESULTS: If there is awareness in the literature that surrogate consent is complicated by the contingencies of severe brain injury such as disability and the possibility of long-term care, surrogate consent is often equated with substituted judgement and taking the best interests of the patient into account. However, for surrogates of patients with severe DOC, advocacy becomes a central component of the surrogate's role as there is no established standard of care for these patients in the post-acute phase. If participation in research is offered, the surrogate may perceive research participation as a way of providing benefits such as stimulation and some rehabilitation services for the patient. CONCLUSION: Researchers need to be aware how the absence of a standard of care can shape surrogate choice. PMID- 20722501 TI - Quality of life after traumatic brain injury: the clinical use of the QOLIBRI, a novel disease-specific instrument. AB - OBJECTIVE: To report the clinical use of the QOLIBRI, a disease-specific measure of health-related quality-of-life (HRQoL) after traumatic brain injury (TBI). METHODS: The QOLIBRI, with 37 items in six scales (cognition, self, daily life and autonomy, social relationships, emotions and physical problems) was completed by 795 patients in six languages (Finnish, German, Italian, French, English and Dutch). QOLIBRI scores were examined by variables likely to be influenced by rehabilitation interventions and included socio-demographic, functional outcome, health status and mental health variables. RESULTS: The QOLIBRI was self completed by 73% of participants and 27% completed it in interview. It was sensitive to areas of life amenable to intervention, such as accommodation, work participation, health status (including mental health) and functional outcome. CONCLUSION: The QOLIBRI provides information about patient's subjective perception of his/her HRQoL which supplements clinical measures and measures of functional outcome. It can be applied across different populations and cultures. It allows the identification of personal needs, the prioritization of therapeutic goals and the evaluation of individual progress. It may also be useful in clinical trials and in longitudinal studies of TBI recovery. PMID- 20722503 TI - Anoxic brain injury: Clinical patterns and functional outcomes. A study of 93 cases. AB - BACKGROUND: Anoxic brain injury (ABI) is a syndrome of diverse aetiology, most case series published to date being confined to ABI of a single aetiology or to a limited numbers of patients. METHODS: This study performed a retrospective analysis on all patients admitted for rehabilitation following ABI over a 14-year period. It identified 93 cases and presents a summary of their clinical patterns and functional and psychometric outcome measures. In addition a database involving 584 patients admitted for rehabilitation following traumatic brain injury (TBI) during the same time interval was used to compare demographic, functional and cognitive patterns. CONCLUSIONS: Relative to TBI, there was a peak frequency of ABI in males aged 60 years and in females in their late 20s. ABI patients were referred later for rehabilitation, had similar lengths of stay, but made slower progress, with poorer outcomes and were more likely to be transferred to residential care. Those with ABI had more severe impairments on cognitive assessment relative to those with TBI, being particularly susceptible to impairments in memory, especially visual memory or short-term memory. Neurological impairments of speech and language were present in 72 patients; visual field loss in eight and cortical blindness in 10; six suffered myoclonus and 10 late epilepsy. PMID- 20722504 TI - Use of brain electrical activity to quantify traumatic brain injury in the emergency department. AB - PRIMARY OBJECTIVE: To validate a QEEG algorithm on traumatic brain injury in an Emergency Department (ED) setting. METHODS AND PROCEDURES: EEG data were collected from 105 patients with head injury (53 CT+ and 52 CT-) and 50 ED controls. Ten minutes of eyes closed resting EEG was collected from five frontal locations. A discriminant index of the probability of belonging to the TBI CT+ group was computed. Analysis of variance was computed comparing this index across the three patient groups. Using ROC curves, the p < 0.05 confidence level was determined to compute sensitivity and specificity for the TBI CT+ population. RESULTS: CT+ patients had a mean TBI discriminant index of 80.4, CT- patients 38.9 and controls 24.5; F = 70.2, p < 0.0001. Sensitivity was 92.45% for the CT+ group and specificity was 90.00% for the control group. CONCLUSIONS: The TBI discriminant index appears to be a sensitive index of brain function. It may be used to suggest whether or not a patient presenting with altered mental status requires a CT scan. This index may aid in the triage of such patients in the ED. Such an easy to use, automated system may greatly enhance the clinical utility of EEG in the ED. PMID- 20722505 TI - Cathepsin D messenger RNA is downregulated in human lung cancer. AB - OBJECTIVES: Lysosomal proteases cathepsins B and D (CB and CD) play a significant part in cancer progression. For many oncological diseases protein expression levels of CB and CD have been investigated and correlations with tumour characteristics revealed. Meanwhile, there is very little information concerning mRNA expression level. METHODS: In the present work, data about mRNA levels of CB and CD in human lung cancer was obtained using reverse transcription followed by real-time polymerase chain reaction. RESULTS: For the first time CD and CB mRNA in human lung cancer tumours was quantified. It was shown that CB and CD mRNA levels do not correlate with any tumour characteristics. However, in most analysed tumours, expression of CD mRNA was downregulated compared with adjacent normal tissue (p <0.0003). CONCLUSIONS: The data obtained indicate CD mRNA as a potential lung cancer marker. PMID- 20722506 TI - Redox stimulation of cardiomyogenesis versus inhibition of vasculogenesis upon treatment of mouse embryonic stem cells with thalidomide. AB - Thalidomide [alpha-(N-phthalimido)-glutarimide] exerts antiangiogenic properties and causes cardiac malformations in embryos. Herein the effects of thalidomide on cardiovascular differentiation were investigated in mouse embryonic stem (ES) cell-derived embryoid bodies. Thalidomide inhibited the formation of capillary like blood vessels and decreased tumor-induced angiogenesis in confrontation cultures of embryoid bodies and multicellular prostate tumor spheroids, but stimulated cardiomyogenesis of ES cells. The number of CD31- and CD144-positive endothelial cells was not impaired, suggesting that thalidomide acted on vascular tube formation and cell migration rather than endothelial differentiation. Thalidomide increased reactive oxygen species generation, which was abolished by the NADPH oxidase inhibitor VAS2870 and the complex I respiratory chain inhibitor rotenone. Conversely, thalidomide decreased nitric oxide (NO) generation and endothelial NO synthase activity. VAS2870 abrogated thalidomide stimulation of cardiomyogenesis, whereas inhibition of vasculogenesis persisted. In NOX-1 and NOX-4 shRNA gene-inactivated ES cells, cardiomyogenesis was severely impaired and thalidomide failed to stimulate cardiac cell commitment. The NO donor S nitrosopenicillamine reversed the antiangiogenic effect of thalidomide and increased capillary structure formation, whereas scavenging NO by 2-(4 carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and inhibition of endothelial NO synthase by N(G)-nitro-l-arginine methyl ester decreased cardiovascular differentiation. Our data demonstrate that thalidomide causes an imbalance of reactive oxygen species/NO generation, thus stimulating cardiomyogenesis and impairing vascular sprout formation. PMID- 20722507 TI - A functional variation in pre-microRNA-196a is associated with susceptibility of esophageal squamous cell carcinoma risk in Chinese Han. AB - MicroRNAs (miRNAs) are small, non-protein-coding RNAs that function as tumour suppressors or oncogenes. A single nucleotide change in the sequence of pre-miRNA can affect miRNA expression, so single-nucleotide polymorphisms (SNPs) in pre miRNA may be biomarkers for biomedical applications. In this study, we performed a genetic association study between the SNP (rs11614913) in pre-miRNA-196a and esophageal squamous cell carcinoma (ESCC) susceptibility in a case-control study. We found that the homozygote CC of this SNP increased the risk of ESCC compared with the homozygote TT and the risk was more evident among smokers than non smokers. Therefore, this functional SNP may be a biomarker for ESCC outcome. PMID- 20722529 TI - Salivary stress markers, stress, and periodontitis: a pilot study. AB - BACKGROUND: Some cross-sectional and longitudinal studies attempted to link periodontitis with stress. To our knowledge, only one small study was published on the mechanism by which stress may influence periodontal diseases, suggesting behavioral and physiologic mechanisms and investigating the role of inflammation as a potential mediator. The present study is planned to explore the associations among periodontal disease, psychologic factors, and salivary markers of stress, psychoneuroimmunologic variables, and health behaviors. METHODS: One hundred periodontitis patients were selected, and participants provided information on general health, chronic stress, and demographics. Stress markers (choromogranin A, cortisol, alpha-amylase, and beta-endorphin) were measured from saliva. A dentist assessed the presence of dental plaque on lingual and buccal surfaces, the gingival index, and the number of remaining teeth with periodontal disease. RESULTS: Stress and salivary stress markers were significantly correlated with clinical parameters of periodontal disease (ranging from 0.19 to 0.59; P <0.001). Neglecting to brush teeth during stress was associated with missing teeth. After adjusting for stress variables, salivary cortisol and beta-endorphin were significantly associated with tooth loss and periodontal clinical parameters (P <0.001; R(2) = 0.59). CONCLUSIONS: This study suggests that stress might be associated with periodontal disease through physiologic and behavioral mechanisms. In making diagnoses of psychiatric patients, the association between salivary stress markers and periodontal disease needs to be included. Further exploration of relationships between periodontitis and stress is warranted. PMID- 20722530 TI - Gingival overgrowth among patients medicated with cyclosporin A and tacrolimus undergoing renal transplantation: a prospective study. AB - BACKGROUND: The aim of this study is to make a longitudinal evaluation of the incidence and severity of gingival overgrowth (GO) induced by immunosuppressive agents, such as tacrolimus (Tcr) and cyclosporin A (CsA), in the absence of calcium channel blockers in patients undergoing renal transplantation (RT). METHODS: This longitudinal study is conducted in 49 patients with RT who were divided into a CsA group (n = 25) and Tcr group (n = 24). The individuals were assessed at four time intervals: before transplant and 30, 90, and 180 days after RTs. Demographic data and periodontal clinical parameters (plaque index, cemento enamel junction to the gingival margin, probing depth, clinical attachment level, bleeding on probing [BOP], and GO) were collected at all time intervals. RESULTS: The mean GO index was significantly lower in the Tcr group compared to the CsA group after 30 (P = 0.03), 90 (P = 0.004), and 180 (P = 0.01) days of immunosuppressive therapy. One hundred eighty days after RTs, a clinically significant GO was observed in 20.0% of individuals in the CsA group and 8.3% of individuals in the Tcr group. However, this difference was not statistically significant (P = 0.41). There was a reduction in periodontal clinical parameters regarding the time of immunosuppressive therapy for PI and BOP (P <0.001) in both groups. CONCLUSION: Although there was no statistical difference in the incidences of clinically significant GO after 180 days of immunosuppressive therapy, it was observed that GO occurred later in the Tcr group, and the severity of GO in this group was lower than in patients who used CsA. PMID- 20722531 TI - Ridge preservation with acellular dermal matrix and anorganic bone matrix cell binding peptide P-15 after tooth extraction in humans. AB - BACKGROUND: Preventing ridge collapse with the extraction of maxillary anterior teeth is vital to an esthetic restorative result. Several regenerative techniques are available and are used for socket preservation. The aim of this study is to analyze by clinical parameters the use of acellular dermal matrix (ADM) and anorganic bovine bone matrix (ABM) with synthetic cell-binding peptide P-15 to preserve alveolar bone after tooth extraction. METHODS: Eighteen patients in need of extraction of maxillary anterior teeth were selected and randomly assigned to the test group (ADM plus ABM/P-15) or the control group (ADM only). Clinical measurements were recorded initially and at 6 months after ridge-preservation procedures. RESULTS: In the clinical measurements (external vertical palatal measurement [EVPM], external vertical buccal measurement [EVBM], and alveolar horizontal measurement [AHM]) the statistical analysis showed no difference between test and control groups initially and at 6 months. The intragroup analysis, after 6 months, showed a statistically significant reduction in the measurements for both groups. In the comparison between the two groups, the differences in the test group were as follows: EVPM = 0.83 +/- 1.53 mm; EVBM = 1.20 +/- 2.02 mm; and AHM = 2.53 +/- 1.81 mm. The differences in the control group were as follows: EVPM = 0.87 +/- 1.13 mm; EVBM = 1.50 +/- 1.15 mm; and AHM = 3.40 +/- 1.39 mm. The differences in EVPM and EVBM were not statistically significant; however, in horizontal measurement (AHM), there was a statistically significant difference (P<0.05). CONCLUSION: The results of this study show that ADM used as membrane associated with ABM/P-15 can be used to reduce buccal palatal dimensions compared to ADM alone for preservation of the alveolar ridge after extraction of anterior maxillary teeth. PMID- 20722532 TI - Cleaning efficacy and soft tissue trauma after use of manual toothbrushes with different bristle stiffness. AB - BACKGROUND: The purpose of this study is to evaluate the efficacy of manual toothbrushes of the same type with different bristle stiffness concerning plaque removal, gingivitis development, and soft tissue trauma. METHODS: In a randomized controlled trial, three groups with 40 subjects each used manual toothbrushes with either hard-, medium-, or soft-bristle stiffness. The at-home brushing time was set for 2 minutes, twice a day. Four and 8 weeks after the baseline examination, clinical parameters for plaque removal, gingivitis, and soft tissue damage were recorded again. Recruitment and examinations of the subjects were performed at the Department of Operative and Preventive Dentistry and Endodontics, Heinrich Heine University. A total of 120 volunteers (age range: 18 to 62 years) were recruited and stratified according to sex and age. Primary outcome measures were differences in the Quigley and Hein index (QHI) and papillary bleeding index (PBI) compared to baseline; secondary outcome measures were differences in the modified approximal plaque index (MAPI) and Danser gingival abrasion index. RESULTS: The QHI and MAPI showed lower index scores in subjects who used hard-bristled toothbrushes after 8 weeks (P <0.05 and P <0.001, respectively). In contrast, subjects who used toothbrushes with hard bristles demonstrated more gingival lesions (P <0.01) and higher PBI scores after 4 and 8 weeks (P <0.001) compared to subjects who used soft- or medium-bristled toothbrushes. CONCLUSION: Manual toothbrushes with hard bristles may better remove plaque, but may also cause more soft tissue trauma compared to brushes with softer bristles. PMID- 20722534 TI - Mucosal coronally positioned flap for the management of excessive gingival display in the presence of hypermobility of the upper lip and vertical maxillary excess: a case report. AB - BACKGROUND: Excessive gingival display is a frequent finding that can occur because of various intraoral or extraoral etiologies. This report describes the use of a mucosal coronally positioned flap for the management of a gummy smile associated with vertical maxillary excess and hypermobility of the upper lip. METHODS: A 24-year-old female presented for consultation regarding a gummy smile. At full smile the average gingival display ranged from 2 to 4 mm. A clinical examination revealed hypermobility of the upper lip and absence of generalized altered passive eruption. A cephalometric analysis pointed to the presence of vertical maxillary excess. The surgical procedure consisted of an elliptical mucosal excision followed by coronal advancement of the flap. This procedure aimed to limit the activity of the elevator muscles and reestablish the depth of the vestibule. RESULTS: Rapid surgical healing with minimal postoperative sequelae was observed. The patient reported significant reduction of gingival display at 1 week, which was maintained at the 1-year postoperative visit. Reduction in the amount of gingival display at the 1-year follow-up visit was stable. CONCLUSIONS: For patients desiring a less invasive alternative to orthognathic surgery, the mucosal coronally positioned flap is a viable alternative. We demonstrate short-term successful use of this technique for the management of excessive gingival display in the presence of slight vertical maxillary excess and hypermobility of the upper lip. Long-term follow-up studies are needed to determine stability of the results. PMID- 20722535 TI - Modulation of matrix metalloproteinase and cytokine production by licorice isolates licoricidin and licorisoflavan A: potential therapeutic approach for periodontitis. AB - BACKGROUND: Inflammatory cytokines and matrix metalloproteinases (MMPs) produced by resident and inflammatory cells in response to periodontopathogens play a major role in the tissue destruction observed in periodontitis, which is a disease that affects tooth-supporting structures. In the present study, we investigate the effects of licorice-derived licoricidin (LC) and licorisoflavan A (LIA) on the secretion of various cytokines and MMPs by human monocyte-derived macrophages stimulated with Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) lipopolysaccharide (LPS). METHODS: Macrophages were treated with non-toxic concentrations of LC or LIA before being stimulated with A. actinomycetemcomitans LPS. The secretion of cytokines and MMPs and the activation of nuclear factor-kappa B (NF-kappaB) p65 and activator protein (AP)-1 were assessed by enzyme-linked immunosorbent assays. RESULTS: LC and LIA inhibited the secretion of interleukin (IL)-6 and chemokine (C-C motif) ligand 5 in a concentration-dependent manner but did not affect the secretion of IL-8 by LPS-stimulated macrophages. LC and LIA also inhibited the secretion of MMP-7, -8, and -9 by macrophages. The suppression of cytokine and MMP secretion by LC and LIA was associated with the reduced activation of NF-kappaB p65 but not that of AP-1. CONCLUSION: The present study suggests that LC and LIA have potential for the development of novel host-modulating strategies for the treatment of cytokine and/or MMP-mediated disorders such as periodontitis. PMID- 20722551 TI - Immunohistochemical expression of procaspase-3 and its clinical significance in childhood non-Hodgkin lymphomas. AB - Previous studies have shown differences in expression levels of apoptosis regulatory proteins in non-Hodgkin lymphomas (NHLs) and indicated the correlation of procaspase-3 (proC-3) and caspase-3 activation to the response of chemotherapy. We investigated whether proC-3 expression in tumor biopsies of childhood NHLs is related to clinical outcome. Formalin-fixed paraffin-embedded tissues from 58 children with NHL were evaluated for proC-3 expression by immunochemistry analysis. The study included 20 cases of Burkitt lymphoma, 7 cases of diffuse large B-cell lymphoma, 18 cases of anaplastic large cell lymphoma (ALCL), and 13 cases of precursor lymphoblastic lymphoma. The highest expression level of proC-3 was observed in ALCL. In the multivariate analysis the higher clinical stage of disease and higher expression level of proC-3 were independent and appear to be significant prognostic factors of treatment failure. Our results suggest that the high expression level of proC-3 may be a powerful independent predictor of response to chemotherapy and progression-free survival in childhood NHLs. PMID- 20722533 TI - Association between chronic periodontal disease and obesity: a systematic review and meta-analysis. AB - BACKGROUND: Obesity is increasing in prevalence and is a major contributor to worldwide morbidity. One consequence of obesity might be an increased risk for periodontal disease, although periodontal inflammation might, in turn, exacerbate the metabolic syndrome, of which obesity is one component. This review aims to systematically compile the evidence of an obesity-periodontal disease relationship from epidemiologic studies and to derive a quantitative summary of the association between these disease states. METHODS: Systematic searches of the MEDLINE, SCOPUS, BIOSIS, LILACS, Cochrane Library, and Brazilian Bibliography of Dentistry databases were conducted with the results and characteristics of relevant studies abstracted to standardized forms. A meta-analysis was performed to obtain a summary measure of association. RESULTS: The electronic search identified 554 unique citations, and 70 studies met a priori inclusion criteria, representing 57 independent populations. Nearly all studies matching inclusion criteria were cross-sectional in design with the results of 41 studies suggesting a positive association. The fixed-effects summary odds ratio was 1.35 (Shore corrected 95% confidence interval: 1.23 to 1.47), with some evidence of a stronger association found among younger adults, women, and non-smokers. Additional summary estimates suggested a greater mean clinical attachment loss among obese individuals, a higher mean body mass index (BMI) among periodontal patients, and a trend of increasing odds of prevalent periodontal disease with increasing BMI. Although these results are highly unlikely to be chance findings, unmeasured confounding had a credible but unknown influence on these estimates. CONCLUSIONS: This positive association was consistent and coherent with a biologically plausible role for obesity in the development of periodontal disease. However, with few quality longitudinal studies, there is an inability to distinguish the temporal ordering of events, thus limiting the evidence that obesity is a risk factor for periodontal disease or that periodontitis might increase the risk of weight gain. In clinical practice, a higher prevalence of periodontal disease should be expected among obese adults. PMID- 20722553 TI - Identification of bacteria in paraffin-embedded tissues using 16S rDNA sequencing from a neonate with necrotizing enterocolitis. AB - The conventional approach to bacterial identification in paraffin-embedded tissue relies mainly on morphology, with the aid of Gram stain. This approach is only able to provide some clues; it does not offer the capability of accurate identification. Bacterial identification based on sequencing of 16S ribosomal DNA (rDNA) is able to identify bacteria to the species level. Here we demonstrate the application of this technique in the postmortem examination, for which we had obtained different results from premortem and postmortem blood cultures. In the postmortem examination, abundant gram-negative rods were present in gastrointestinal tract lumen and lymphatic space. DNA was extracted from paraffin embedded tissue of the above sections and subjected to 16S rDNA polymerase chain reaction for the first 500 base pairs, followed by sequencing. The results of sequencing correlated well with the postmortem culture result. In this review, the newly emerging field of bacterial identification with molecular techniques employing both broad-range and targeted approaches and their clinical applications and limitations are discussed. PMID- 20722554 TI - Evolution of cryptic coloration in ectoparasites. AB - Cryptic coloration is a classic example of evolution by natural selection. However, it has been studied almost exclusively in predator-prey systems, despite the fact that it may evolve in other groups, such as ectoparasites. The principle defense of hosts against ectoparasites is grooming behavior, which has a visual component. Host-imposed selection should lead to the evolution of background matching if it helps ectoparasites escape from grooming. Here we use sister taxa comparisons to show that avian feather lice (Phthiraptera: Ischnocera) have evolved coloration that matches the host's plumage, except in the case of head lice, which are protected from grooming. We also show covariation of parasite and host color within a single species of louse. Thus, cryptic coloration has evolved both within and between species of feather lice. Other examples of the evolution of crypsis presumably exist among the 70,000 known species of ectoparasites that collectively represent five animal phyla. PMID- 20722555 TI - Impact of amlodipine or ramipril treatment on left ventricular mass and carotid intima-media thickness in nondiabetic hemodialysis patients. AB - OBJECTIVE: Left ventricular hypertrophy (LVH) and atherosclerosis are frequently observed in uremic patients and they have appeared as an independent predictor of cardiovascular morbidity and mortality. The aim of this study was to compare the effects of ramipril and amlodipine on left ventricular mass index (LVMI) and carotid intima-media thickness (CIMT) in nondiabetic hypertensive hemodialysis patients. METHODS: A total of 112 hemodialysis (HD) patients were included in this study. Patients were randomly allocated to receive ramipril or amlodipine for 1 year. Blood pressure (BP) measurements, LVMI, and CIMT were assessed at baseline and 6-month intervals. Biochemical parameters and inflammatory markers were also determined at the initiation and during the study period. RESULTS: Similar BP decrease was observed in treatment groups. During follow-up, LVMI and CIMT progressed likewise in both treatment groups despite BP control. However, subgrouping analyses due to the pattern of left ventricular geometry showed that LVMI in patients with eccentric LVH increased, whereas LVMI decreased in subjects with concentric LVH under antihypertensive treatment. DISCUSSION: BP control with ramipril or amlodipine could not provide adequate protection for development or progression of atherosclerosis and eccentric type of LVH in nondiabetic HD patients. PMID- 20722556 TI - A comparison of the effects of ramipril and losartan on blood pressure control and left ventricle hypertrophy in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: Hypertension is frequently seen in autosomal dominant polycystic kidney disease (ADPKD), and it has a negative effect on renal progression. Hypertension and left ventricle hypertrophy (LVH) are related in terms of pathogenesis and their effects on renal progression. In this study, we aimed to compare the effects of losartan and ramipril on blood pressure (BP) control, LVH, and renal progression in patients with hypertensive ADPKD. METHODS: Thirty-two ADPKD patients with ages ranging between 18 and 70 years who were stage 1-2 hypertensive were included in this study. Routine biochemical tests and echocardiography were obtained at first examination of the patients. Following these, the patients were randomized. One group was given losartan and the other ramipril. They were followed up for 1 year, and their echocardiographies and routine biochemical tests were repeated at the end of the year. RESULTS: BP values decreased in both the groups at the end of the first year (p < 0.001). There was a statistically significant difference in LVH in both the groups at the end of the first year than at the beginning (losartan, p = 0.007; ramipril, p < 0.001). CONCLUSIONS: In this study, effective BP control was obtained with losartan and ramipril and LVH was found to be regressed significantly in the hypertensive patients with ADPKD. These two groups of antihypertensive drugs may also have beneficial effects on the retardation of renal progression and in reducing cardiovascular mortality in hypertensive patients with ADPKD. PMID- 20722557 TI - Renal glomerular alterations in patients with cancer: a clinical and immunohistochemical autopsy study. AB - BACKGROUND: Membranous glomerulonephritis (MGN) can be found in patients with cancer as a paraneoplastic syndrome or it could be manifested clinically before tumor detection. The aim of this study was to evaluate the frequency and type of renal histopathological alterations in patients with malignancy that died without cancer treatment and were submitted to necropsy. METHODS: Patient's demographical and clinical data collection and laboratory tests (serum creatinine and urine sample) were evaluated. RESULTS: Kidney fragments from 21 patients were obtained and studied by light microscopy after habitual staining. Immunohistochemistry studies were performed with monoclonal immunoglobulin and tumor markers. Patients' mean age was 71 years and 62% were male. The most frequent tumor was gastric cancer (five cases), followed by colon and oral cavity (three cases each). In 67% of the cases, malignancy was the main cause of death. Serum creatinine was increased in 10 cases, proteinuria in 15, and hematuria was present in 8 cases. The most usual glomerular lesion found was thickening of basement membrane (BM) of the capillary loops. There were two cases of IgA nephropathy, three cases of focal segmental glomerulosclerosis, and one case of MGN. Only in the patient with MGN and metastatic melanoma specific tumor markers were identified in the kidney. CONCLUSIONS: We observed a wide range of glomerular pathological changes and abnormal urinary sediments in almost all patients, but we found tumor marker deposits only in the patient with MGN. PMID- 20722558 TI - Factors affecting outcome of intracerebral hemorrhage in patients undergoing chronic hemodialysis. AB - To date, despite a markedly high incidence of intracerebral hemorrhage (ICH) in patients with end-stage renal disease, only few studies have focused on factors that affect patient's prognosis. To elucidate these factors, we retrospectively investigated 22 consecutive patients who had chronic renal failure, were maintained by hemodialysis (HD), had suffered from ICH, and were hospitalized and treated in our institute from 2006 to 2008. Hematoma volume, blood pressure on admission, blood pressure 3 days after ICH onset, and neurological deterioration significantly affected patient mortality. Progression of neurological symptoms during HD was observed often in patients with hematoma of more than 60 mL or in patients with pontine hemorrhages. Age, gender, duration of HD, anti-platelet or anticoagulant therapies, or maximal dose of nicardipine did not affect patient's prognosis. Based on this study we conclude that controlling blood pressure on admission and within 3 days after onset of ICH may be the most important factor that would improve patient's prognosis. Further, special care might be required for patients with large hematomas (more than 60 mL) or those with brainstem hemorrhages, because progression of neurological symptoms occurs often in such patients. PMID- 20722559 TI - Contrast-induced nephropathy: current practices among cardiologists. AB - OBJECTIVE: Contrast-induced nephropathy (CIN) is a serious complication of diagnostic and therapeutic coronary angiography. There are an increasing number of guidelines in the literature to help lessen this complication. Practice patterns in the cardiology community remain relatively unknown. This survey is an effort to better understand such practices. METHODS: Questions were written based on the American College of Cardiology (ACC), the American Heart Association (AHA), and the Society of Cardiovascular Angiography and Intervention (SCAI) guidelines to identify cardiologist background and experience. The survey was emailed to 5000 randomly chosen cardiologists in December 2009. RESULTS: A total of 291 responses were received. Among these, 97% reported checking renal function in all patients prior to angiography, 45% checked both estimated glomerular filtration rate (eGFR) and serum creatinine (SCr), 31% checked SCr alone, 19% checked eGFR alone, and 2% checked albumin-to-creatinine (A-C) ratio. Among responding cardiologists, 70% considered eGFR level less than 60 mL/min/1.73 m(2) a high risk for CIN whereas 25% considered a level less than 30 mL/min/1.73 m(2) a high risk. Thirty percent used only isosmolar media in high-risk patients, 33% used only low osmolar media, and 37% used either one. CONCLUSIONS: There is significant diversity in the measures taken by cardiologists to prevent CIN. More studies and clearer guidelines are needed to unify the practices. PMID- 20722560 TI - The differences of asymmetric dimethylarginine removal by different dialysis treatments. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA) as a uremia toxin is accumulated in end-stage renal disease (ESRD) patients. Elevated ADMA level has been shown to be predictive of cardiovascular diseases (CVDs) and all-cause mortality in ESRD. Therefore, we investigated the removal of ADMA by different dialysis treatments. METHODS: There were 30 each of hemodialysis (HD), hemodiafiltration (HDF), peritoneal dialysis (PD) patients, and healthy volunteers enrolled. The ADMA concentrations in serum, urine, and spent dialysate samples were determined. The urine and spent dialysate volumes were recorded. The ADMA removals by urine and spent dialysate in 1 week were calculated and compared among four groups. It was also analyzed for the correlations between the total removal of ADMA in 1 week and the parameters of age, durance of dialysis, glomerular filtration rate, urine volume, urinal ADMA level, spent dialysate volume, and spent dialysate ADMA level. RESULTS: The serum levels of ADMA in dialysis patients were much higher than in healthy subjects (0.32 +/- 0.09 micromol/L), and their 1-week total removals of ADMA were much lower than healthy controls (249.21 +/- 57.04 micromol/week) (p-values all were less than 0.01). Among dialysis groups, serum ADMA levels decreased significantly in PD patients compared with HD or HDF patients (1.38 +/- 0.30 micromol/L vs. 1.82 +/- 0.38 micromol/L and 1.63 +/- 0.32 micromol/L, p < 0.01), and the total removal of ADMA diminished remarkably by turns of PD, HDF, and HD groups (47.79 +/- 8.20 micromol/week, 31.79 +/- 8.92 micromol/week, 14.63 +/- 6.53 micromol/week, respectively, p < 0.01). The total removal of ADMA in 1 week was related directly with the spent dialysate concentrations of ADMA, the spent dialysate volume, and the urine volume. CONCLUSIONS: ADMA was mainly removed by dialysate in dialysis patients. Different dialysis models have different clearance capability on plasma ADMA. PD might be more effective on ADMA removal than HD and HDF, with HDF being more effective than HD. PMID- 20722561 TI - Evaluation of role of doxycycline (a matrix metalloproteinase inhibitor) on renal functions in patients of diabetic nephropathy. AB - This study was conducted to see the effect of doxycycline on renal functions, especially proteinuria, in patients of diabetic nephropathy (DN). The study included 40 clinically proven adult patients of DN. All patients were on stable doses of angiotensin-converting enzyme inhibitors (ACEIs) and or angiotensin receptor blockers (ARBs) for 2 months before the study. The patients were divided into two groups of 20 patients each. Group A patients were maintained on stable dose of ACEIs and/or ARBs, whereas Group B patients received doxycycline (100 mg/day) for a period of 3 months in addition to ACEIs and or ARBs. Adequate glycemic control was achieved with insulin or oral hypoglycemic agents in all the patients. Renal parameters were assessed at the beginning of the study, at 1, 3, and 6 months (after a washout period of 3 months). All renal parameters remained unaltered during the study in both groups. However, proteinuria showed improvement in Group B (doxcycycline group).The mean basal value of proteinuria was 1.74 + 1.70 for Group A and 2.17 + 2.95 for Group B. At the end of 3 months, proteinuria was 1.22 + 2.11 in Group B whereas it was 1.50 + 1.50 in Group A (p < 0.05). However, the decrease in proteinuria at 6 months in the two groups did not show any statistically significant difference. No significant side effects of doxycycline were observed. The study showed that doxycycline was effective in reducing proteinuria in patients of DN when used for the short duration of 3 months. PMID- 20722562 TI - The impact of dialysis modality on arterial stiffness in patients with end-stage renal disease. AB - BACKGROUND: Arterial stiffness determined by brachial-ankle pulse wave velocity (baPWV) has been established as a powerful predictor of cardiovascular mortality in hemodialysis (HD) patients. There are, however, few studies regarding the comparative impact of different renal replacement therapies (RRTs) on PWV. Therefore, we conducted a cross-sectional study to compare arterial wall properties and cardiac function between patients treated with continuous ambulatory peritoneal dialysis (CAPD) and those with HD who were matched for age, dialysis duration, and blood pressure. METHODS: baPWV and transthoracic echocardiography (TTE) were performed in HD patients (n = 23) after 1 h of midweek dialysis session and CAPD patients (n = 26) with empty abdomen after drainage of dialysate. The baseline data were retrospectively reviewed. RESULTS: baPWV was significantly higher in HD patients than in CAPD patients (18.1 +/- 2.8 vs. 16.1 +/- 2.7 m/s, p = 0.015). TTE revealed significantly increased E/E', left atrial volume index (LAVI), and inferior vena cava (IVC) diameter index in HD patients compared with CAPD patients (p < 0.05). In a multivariate regression analysis adjusted for dialysis modality, age, systolic BP, residual glomerular filtration rate, diabetes, and echocardiographic parameters, HD was independently associated with increased baPWV. CONCLUSION: This study showed that HD patients had significantly increased arterial stiffness and severe diastolic dysfunction compared with CAPD patients. PMID- 20722563 TI - Syndrome of rapid-onset end-stage renal disease: a new unrecognized pattern of CKD progression to ESRD. AB - By most estimates, we have an increasing worldwide end-stage renal disease (ESRD) epidemic. This is despite at least two decades of intensified reno-protection strategies, including attempts at optimal hypertension management, optimization of diabetic control, smoking cessation efforts, and the extensive application of renin-angiotensin-aldosterone system (RAAS) blockade in both diabetic and nondiabetic chronic nephropathies. The current consensus is that chronic kidney disease (CKD) progression to ESRD is a continuous, progressive, and predictable loss of estimated glomerular filtration rate (eGFR) in CKD patients, inexorably leading to ESRD. Our recent experience in a Mayo Health System Hypertension Clinic, as well as new reports associating ESRD development in CKD patients with episodes of acute kidney injury (AKI), led us to hypothesize that CKD to ESRD progression may not be that predictable, after all. Among a 100 high-risk CKD patient cohort that we have followed up prospectively since 2002, we demonstrated that in 15 of 17 (88%) patients who progressed to ESRD, progression from CKD to ESRD was unpredictable, nonlinear, abrupt, and rapid, and this followed AKI secondary to medical and surgical events. We have coined a new term, the syndrome of rapid-onset end-stage renal disease (SORO-ESRD), to represent this unrecognized syndrome. Larger studies are warranted to confirm our single-center findings. If confirmed to represent a significant proportion of the ESRD population, at least here in the United States, this finding will demand major paradigm shifts in the current concepts of reno-protection and "A-V Fistula first" programs. PMID- 20722564 TI - Protective effect of trapidil and l-arginine against renal and hepatic toxicity induced by cyclosporine in rats. AB - RATIONALE: Cyclosporine A (CsA) leads to renal and liver injury, production of free radicals and nitric oxide (NO) deficiency. This study investigates the possible protective effects of trapidil and L-arginine against CsA-induced tissue injury. OBJECTIVES: Forty adult male Wistar rats (180 +/- 20 g) were divided into five groups, eight animals in each. The first group served as control, second group served as CsA group, third group served as CsA + trapidil group, fourth group served as CsA + L-arginine group, and fifth group served as CsA + trapidil + L-arginine group. Kidney and liver functions, inflammatory mediators, cytokines, oxidant and antioxidant parameters as well as histopathological studies of renal and liver tissue were assessed in all groups. MAIN FINDINGS: CsA induced renal and hepatic dysfunction, which was confirmed by laboratory and histopathological examination. Administration of trapidil diminished the renal and liver injury and significantly attenuated the levels of serum creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and oxidative stress, while it significantly elevated the level of serum nitric oxide and the activity of antioxidative stress. L-Arginine gave the same trend as trapidil, but trapidil effect was more pronounced. Coadministration of trapidil + L-arginine significantly ameliorated the toxic effect of CsA, but did not differ significantly from the effect of trapidil alone. CONCLUSIONS: Treatment with trapidil or L-arginine diminished the renal and hepatic CsA-induced toxicity. However, the effect of trapidil was more pronounced. Therefore, treatment with trapidil alone may be the most economic and effective as a potential therapeutic agent in CsA injury. PMID- 20722565 TI - Vitamin D receptor genetic variants among patients with end-stage renal disease. AB - BACK GROUND AND OBJECTIVES: Vitamin D receptor (VDR) gene polymorphism is reported to be associated with end-stage renal disease (ESRD). We have investigated the potential role of VDR gene polymorphisms among ESRD. DESIGN AND METHODS: The influence of VDR gene polymorphism in 258 ESRD patients comprising of 226 (87.5%) male and 32 (12.5%) females was investigated in this study. We compared ESRD patients with 569 healthy controls. The distribution of male and female among controls was 485 (85.3%) males and 84 (14.7%) females. This polymorphism was studied by using polymerase chain reaction (PCR). The product was digested by using restriction enzymes Apa1, Taq1, Fok1, and Bsm1. RESULTS: We observed a significant difference in the genotype frequencies of the Apa1-aa (p = 0.0001, OR = 2.1, 95% CI = 1.45-3.08), Fok1-ff (p = 0.001, OR = 3.44, 95% CI = 1.76-6.76), and Bsm1-BB (p = 0.0004, OR = 6.8, 95% CI = 2.2-21.58). At allelic level B allele of Bsm1 was significantly different among ESRD patients as compared to controls (p = 0.0001). The combined analysis revealed that ESRD patients with Fok1 and Bsm1 polymorphism were at increased risk of 4.33-fold. The haplotype analysis revealed individuals with a/t/F/b haplotype were at greater risk of 11.0-fold (95% CI = 1.38-87.69). The serum calcium levels were significantly higher (p = 0.001) in Bsm1 "BB" genotype. INTERPRETATIONS AND CONCLUSIONS: Bsm1 and Fok1 gene polymorphism of VDR gene were associated with ESRD among north Indians. PMID- 20722566 TI - Methylguanidine cytotoxicity on HK-2 cells and protective effect of antioxidants against MG-induced apoptosis in renal proximal tubular cells in vitro. AB - Methylguanidine (MG), a small molecule among guanidine compounds, is a product of protein catabolism. The concentration of MG in the serum of uremic patients is nearly 80 times of that in the serum of normal people. The present study was designed to explore the toxic effect of MG on renal proximal tubular cells as well as the protective effect of antioxidants PGE1 and probucol against MG induced apoptosis in renal proximal tubular cells. HK-2 cells were used as the subject. The cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. N-Acetyl-3-D-glucosaminidase (NAG) activity, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity were determined. Cell apoptosis was determined by flow cytometry (light scatter and propidium iodide/annexin V-FTC fluorescence) and by nuclear staining with Hoechst 33258. Cells were exposed to MG (0.25, 0.5, or 1 mmol/L), MG (0.5 mmol/L) + PGE1 (2 microg/L), and MG (0.5 mmol/L) + probucol (20 micromol/L) respectively for 24 h. MG induced a significant dose-dependent loss of cell viability. Both PGE1 and probucol improved the viability of MG-treated HK-2 cells. Cells showed apoptotic morphology (deepened stain, karyopyknosis, and apoptotic body) when exposed to 0.5 mmol/L MG for 24 h, and the apoptosis ratio was increased compared with the control. The presence of PGE1 or probucol significantly lowered the apoptotic ratio. Moreover, PGE1 or probucol notably decreased the MDA content and increased the SOD activity compared with when the cells were treated with MG only. The results of the present study clearly demonstrate that MG could promote apoptosis of renal proximal tubular cells in vitro. Both PGE1 and probucol could protect renal proximal tubular cells from MG-induced apoptosis. PMID- 20722567 TI - Ang II enhances tubular cell Ets-1 expression and associated down stream signaling is mediated through AT1 receptors. AB - Angiotensin II (Ang II) has been reported to play an important role in both the development and progression of renal injury. Many of the downstream effects of Ang II are mediated through the activation of nuclear factor-kappaB (NF-kappaB). In the present study, we evaluated the effect of Ang II on the activation of Ets 1 (a transcription factor) in tubular cells. In addition, we studied the expression of pro-inflammatory molecules transcribed by Ets-1 in response to Ang II. Mice receiving Ang II infusion showed enhanced renal cortical mRNA expression of Ets-1. Immunolabeling studies localized the expression of Ets-1 in distal tubular cells of mice receiving Ang II. However, this effect of Ang II was mitigated by telmisartan, an AT1-receptor blocker. Mice receiving Ang II infusion also showed increased tubular cell expression of macrophage chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and p21 when compared with control mice; nevertheless, this effect of Ang II was attenuated by telmisartan. In in vitro studies, Ang II enhanced mRNA expression of Ets-1 by MDCK cells. However, this effect of Ang II was inhibited by losartan, an AT1 receptor blocker. Losartan also inhibited Ang II-induced PAI-1 and p21 expression by MDCK cells. These findings indicate that Ang II-induced tubular cell expression Ets-1 and associated downstream signaling is mediated through AT1 receptors. PMID- 20722568 TI - Effect of sodium bicarbonate in an experimental model of radiocontrast nephropathy. AB - AIM: The aim of this study is to investigate the efficacy and mechanism of action of intravenous (IV) bicarbonate in preventing radiocontrast nephropathy (RCN). MATERIALS AND METHODS: Twenty-eight Wistar rats were randomized into four groups including control (group 1), radiocontrast (group 2), bicarbonate (group 3), and radiocontrast plus bicarbonate (group 4). Once blood chemistry and arterial blood gases were examined and 24 h urine samples were collected, all rats were administered furosemide (2 mg/kg subcutaneous) and deprived of water for 24 h. Iothalamate sodium (6 mL/kg) was administered to group 2 and group 4. IV bicarbonate (8.4%) was administered to group 3 and group 4 (3 h before the administration of iothalamate). On the fourth day, 24 h urine was collected, and at the end of the day rats were sacrificed and blood chemistry and arterial blood gases were reexamined. Myeloperoxidase (MPO), nitric oxide (NO), total glutathione, and malondialdehyde were quantified on the renal tissue. H&E slides were examined. RESULTS: Basal creatinine and creatinine clearance were similar between groups. There was no significant difference between creatinine and creatinine clearance by the end of the experiment. Glutathione level in group 2 was lower than in group 4. Histopathologically, there was no injury in the control group (group 1) whereas there was an intermediate-severe injury (71.4%) in the radiocontrast group (group 2). The percentage of intermediate-severe injury was significantly lower (71.4% vs. 28.6%, p = 0.02) in the radiocontrast plus bicarbonate group (group 4). CONCLUSIONS: Sodium bicarbonate attenuates the development of radiocontrast-induced tubular necrosis. PMID- 20722569 TI - Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed. AB - We present a case of interstitial nephritis and nephrogenic diabetes insipidus (NDI) in a patient treated with pemetrexed (500 mg/m(2)) for non-small cell lung cancer. Renal impairment and diabetes insipidus appeared after the first treatment cycle while he totally received four cycles of chemotherapy. There was not any significant myelosuppression and the patient was on regular supplementation with folic acid and vitamin B(12). He was not on any other medications and he did not receive any nephrotoxic agents. Kidney biopsy showed acute tubular necrosis together with interstitial inflammatory infiltrate of mononuclear cells and interstitial fibrosis occupying 25% of the cortex. There was not any improvement of renal function after a 2-week trial of oral prednisone. In the present case report, we review the literature for pemetrexed induced renal toxicity and the possible mechanisms involved. PMID- 20722570 TI - Challenges in clinical-pathologic correlations: acute tubular necrosis in a patient with collapsing focal and segmental glomerulosclerosis mimicking rapidly progressive glomerulonephritis. AB - Herein, we report a case of acute kidney injury (AKI) due to diarrhea-induced acute tubular necrosis (ATN) in a patient with nephrotic syndrome secondary to biopsy-proven collapsing focal and segmental glomerulosclerosis (FSGS). The clinical picture mimicked rapidly progressive glomerulonephritis (RPGN) and motivated pulse therapy with methylprednisolone and cyclophosphamide. The case presentation is followed by a brief overview of the epidemiology of AKI in nephrotic syndrome as well as a discussion of its risk factors and potential mechanisms involved. PMID- 20722571 TI - An exceptional case of acute renal failure: is there a renal toxicity of Artemisia herba-alba? AB - A 59-year-old diabetic man was admitted for severe acute renal failure. Clinical signs were compatible with an acute tubular necrosis but no etiology was found. Kidney biopsy showed an osmotic nephrosis. Resumption of interrogatoire reveals consumption of Artemisia herba-alba accused in very few experimental studies to cause a lesion indicative of osmotic nephrosis. PMID- 20722572 TI - Malignant pleural mesothelioma with associated minimal change disease and acute renal failure. AB - Paraneoplastic manifestations in malignant pleural mesothelioma are rare. We report a case of malignant pleural mesothelioma associated with minimal change disease (MCD). A 58-year-old man with occupational exposure to asbestos presented with severe peripheral edema, heavy proteinuria, and acute renal failure shortly after the diagnosis of mesothelioma had been confirmed. The renal biopsy demonstrated MCD. The underlying pathogenesis of this association remains unknown. PMID- 20722573 TI - An occult cause of hemodialysis vascular access dysfunction. AB - Although hemodialysis vascular access dysfunction is often caused by venous stenosis, stenosis can occur anywhere in the circuit. Herein, we report a 75-year old woman who received repeated percutaneous angioplasty due to insufficient flow. Finally, a culprit stenosis at the subclavian artery was found and treated. Subclavian artery stenosis is often atherosclerotic in origin and is usually delayed to be diagnosed because of caveats in the care of vascular access. This case highlights important clues that can assist in the early discovery of inflow problems and reminds the physician that inflow stenosis may be hidden at a site far from the anastomosis. PMID- 20722574 TI - Orlistat and calcium oxalate crystalluria: an association that needs consideration. AB - Obesity is currently an epidemic across the globe. Obese patients unable to achieve significant weight loss with lifestyle changes alone may require drug therapy. Clinical trials have shown that orlistat administration may not only lead to weight loss but also protect against type 2 diabetes in around 37% of cases. Orlistat can induce and maintain weight loss, even in patients with comorbid conditions such as hypertension or type 2 diabetes. Recently, orlistat can induce marked weight loss in individuals with chronic kidney disease (CKD). In small numbers of individuals especially those with CKD, orlistat administration may precipitate oxalate nephropathy and renal stone disease. The focus of this article is to review current studies showing impact of orlistat on renal function and outcomes. PMID- 20722575 TI - Which is the best way for estimating transferrin saturation? PMID- 20722576 TI - The role of bariatric surgery in the management of female fertility. AB - Obesity is associated with significant affects on reproductive health. Strategies to achieve weight reduction include bariatric surgery. Here we describe guidance for the use of bariatric surgery in women wishing to conceive. PMID- 20722577 TI - Polymorphisms of the angiotensin converting enzyme gene in Iranian Azeri Turkish women with unexplained recurrent pregnancy loss. AB - Several factors which influence the balance between fibrinolysis and coagulation pathways play role in the outcome of conception. A large body of studies demonstrate that gene variations are associated with recurrent pregnancy loss (RPL) by different mechanisms. We aimed to determine the allele and genotype frequencies of the angiotensin converting enzyme (ACE) gene in Iranian Azeri Turkish women with unexplained RPL. Fifty patients with RPL and 63 fertile healthy women as controls were entered in the study. A standard method was used for DNA isolation. All genotypes were determined using PCR. Our analysis showed that patient (chi(2) = 0.347, p = 0.84) and control (chi(2) = 0.77, p = 0.68) groups fitted the Hardy-Weinberg equilibrium strongly. No significant differences were found regarding the frequencies of ACE genotypes [deletion/deletion (D/D), insertion/deletion (I/D) and insertion/insertion (I/I)] and alleles between cases and controls. Based on these findings, we could not find any association between ACE (D/D, I/D and I/I) gene polymorphisms and RPL. PMID- 20722578 TI - A decade of the sperm-washing programme: where are we now? AB - Since 1999, we have treated HIV-positive men with sperm washing as part of a risk reduction programme with a year-on-year increase in total infectious cycles performed to over 200 in 2008. Four hundred and thirty nine cycles of IUI, 114 cycles of IVF and 117 cycles of ICSI have been performed in HIV positive men over the decade and of the 259 couples treated, a pregnancy rate and ongoing pregnancy rate per couple of 45.4% and 36.3% have been achieved with over 100 children born with no seroconversions. We outline the continued importance of such risk reduction measures with 9.7% of samples from men with 'stable' disease on anti retroviral treatment and undetectable viral load demonstrating detectable viral particles in seminal fluid and discuss measures to improve outcome in this patient group. PMID- 20722579 TI - A descriptive study of selected oocyte, blood and organ/tissue donation features among fertility patients in Ireland. AB - OBJECTIVE: Anonymous oocyte donation and participation in organ and blood/tissue donation programmes were studied specifically among Irish fertility patients. METHODS: An anonymous questionnaire measured patient perceptions of, and participation in, blood/organ/tissue donor programmes, and to record opinion on anonymous donor oocyte compensation. RESULTS: A total of 337 patents were sampled; 56.7% had no children. None had participated in a donor oocyte programme either as donor or recipient. At baseline, 19.6% had previous in vitro fertilisation experience, more than one-third (35.9%) had donated blood anonymously, 19.9% were organ/tissue donors and 52.2% indicated that anonymous oocyte donors should receive some compensation. We found patients with infertility for extended periods were more likely to view oocyte donation favourably, compared to those with infertility of shorter durations (p = 0.022, by Krusksal-Wallis Rank Sum test). Average recommended compensation for anonymous oocyte donor was euro 2177 (range euro 200-euro 9500), and most (77.2%) favoured confidential protections for recipient and donor identity. CONCLUSION: This is the first investigation of blood and organ/tissue donation features among fertility patients in Ireland; the rate of blood donation in this group was more than 10 times higher than in the general Irish population. Protection of anonymity for both donors and recipients was supported by most patients, even opponents of compensated anonymous donation. Further studies should clarify patient perceptions about oocyte donation as a function of involvement in organ/tissue procurement programmes and blood banks. PMID- 20722580 TI - A rare case of rupture of ovary causing haemorrhagic shock following uncomplicated oocyte retrieval--a case report. AB - Oocyte retrieval is a common procedure for in vitro fertilisation. Usually it is safe, but sometimes serious complications such as major intra-peritoneal bleeding, can occur. For units without rapid access to blood transfusion and theatre facilities, this can be potentially life threatening. We are presenting a case report of a woman who required emergency surgery for management of intra peritoneal haemorrhage due to an extremely rare complication of ovarian rupture after routine uncomplicated transvaginal oocyte retrieval. PMID- 20722583 TI - Hypothesis-based weight of evidence: a tool for evaluating and communicating uncertainties and inconsistencies in the large body of evidence in proposing a carcinogenic mode of action--naphthalene as an example. AB - Human health risk assessment consists of bringing to bear a large body of in vitro, animal, and epidemiologic studies on the question of whether environmental exposures to a substance are a potential risk to humans. The body of scientific information is typically less than definitive and often contains apparent contradictions. Often various possible conclusions about potential human risks may be drawn from the data and these may vary from very strong to tenuous. The task, therefore, is to communicate the uncertainties in the inferences from the data effectively, giving proper consideration to contrary data and alternative scientifically plausible interpretations. We propose an approach, Hypothesis Based Weight of Evidence (HBWoE), to organize, evaluate, and communicate the large body of available relevant data on a given chemical, using naphthalene as an example. The goal for our use of the term "weight of evidence" (WoE) is broad in that we express the relative degrees of credence that should be placed in alternative possible interpretations of the naphthalene data and hypothesized carcinogenic modes of action (MoAs), expressed in a way that shows how such credence is tied to specific scientific interpretations, considering consistencies, inconsistencies, and contradictions within the data set. PMID- 20722584 TI - Tertiary-Butanol: a toxicological review. AB - Tert-Butanol is an important intermediate in industrial chemical synthesis, particularly of fuel oxygenates. Human exposure to tert-butanol may occur following fuel oxygenate metabolism or biodegradation. It is poorly absorbed through skin, but is rapidly absorbed upon inhalation or ingestion and distributed to tissues throughout the body. Elimination from blood is slower and the half-life increases with dose. It is largely metabolised by oxidation via 2 methyl-1,2-propanediol to 2-hydroxyisobutyrate, the dominant urinary metabolites. Conjugations also occur and acetone may be found in urine at high doses. The single-dose systemic toxicity of tert-butanol is low, but it is irritant to skin and eyes; high oral doses produce ataxia and hypoactivity and repeated exposure can induce dependence. Tert-Butanol is not definable as a genotoxin and has no effects specific for reproduction or development; developmental delay occurred only with marked maternal toxicity. Target organs for toxicity clearly identified are kidney in male rats and urinary bladder, particularly in males, of both rats and mice. Increased tumour incidences observed were renal tubule cell adenomas in male rats and thyroid follicular cell adenomas in female mice and, non significantly, at an intermediate dose in male mice. The renal adenomas were associated with alpha(2u)-globulin nephropathy and, to a lesser extent, exacerbation of chronic progressive nephropathy. Neither of these modes of action can function in humans. The thyroid tumour response could be strain-specific. No thyroid toxicity was observed and a study of hepatic gene expression and enzyme induction and thyroid hormone status has suggested a possible mode of action. PMID- 20722585 TI - A review of the electrophilic reaction chemistry involved in covalent DNA binding. AB - The need to assess the ability of a chemical to act as a mutagen or a genotoxic carcinogen (collectively termed genotoxicity) is one of the primary requirements in regulatory toxicology. Several pieces of legislation have led to an increased interest in the use of in silico methods, specifically the formation of chemical categories for the assessment of toxicological endpoints. A key step in the development of chemical categories for genotoxicity is defining the organic chemistry associated with the formation of a covalent bond between DNA and an exogenous chemical. This organic chemistry is typically defined as structural alerts. To this end, this article has reviewed the literature defining the structural alerts associated with covalent DNA binding. Importantly, this review article also details the mechanistic organic chemistry associated with each of the structural alerts. This information is extremely important in terms of meeting regulatory requirements for the acceptance of the chemical category approach. The structural alerts and associated mechanistic chemistry have been incorporated into the Organisation for Economic Co-operation and Development (OECD) (Q)SAR Application Toolbox. PMID- 20722586 TI - Letter to the editor: "Comparing milled fiber, Quebec ore, and textile factory dust: has another piece of the asbestos puzzle fallen into place?" by D. Wayne Berman. PMID- 20722590 TI - Current treatments for radiation retinopathy. AB - BACKGROUND: to review the currently available therapeutic modalities for radiation retinopathy (RR), including newer investigational interventions directed towards specific aspects of the pathophysiology of this refractory complication. METHODS: a review of the literature encompassing the pathogenesis of RR and the current therapeutic modalities available was performed. RESULTS: RR is a chronic and progressive condition that results from exposure to any source of radiation. It might be secondary to radiation treatment of intraocular tumors such as choroidal melanomas, retinoblastomas, and choroidal metastasis, or from unavoidable exposure to excessive radiation from the treatment of extraocular tumors like cephalic, nasopharyngeal, orbital, and paranasal malignancies. After the results of the Collaborative Ocular Melanoma Study, most of the choroidal melanomas are being treated with plaque brachytherapy increasing by that the incidence of this radiation complication. RR has been reported to occur in as many as 60% of eyes treated with plaque radiation, with higher rates associated with larger tumors. Initially, the condition manifests as a radiation vasculopathy clinically seen as microaneurysms and telangiectases, with posterior development of retinal hard exudates and hemorrhages, macular edema, neovascularization and tractional retinal detachment. Regrettably, the management of these eyes remains limited. Photodynamic therapy, laser photocoagulation, oral pentoxyphylline and hyperbaric oxygen have been attempted as treatment modalities with inconclusive results. Intravitreal injections of anti-vascular endothelial growth factor such as bevacizumab, ranibizumab and pegaptanib sodium have been recently used, also with variable results. DISCUSSION: RR is a common vision threatening complication following radiation therapy. The available therapeutic options are limited and show unsatisfactory results. Further large investigative studies are required for developing better therapeutic as well as preventive treatment strategies. PMID- 20722591 TI - Host tissue as a niche for biomaterial-associated infection. PMID- 20722592 TI - Clostridium difficile infection: an emerging epidemic with more questions than answers. PMID- 20722593 TI - Malaria: what can apes teach humans? PMID- 20722595 TI - Carbapenems in the treatment of intra-abdominal infection. Report from the 20th European Congress of Clinical Microbiology and Infectious Diseases. Vienna, Austria, 10-13 April 2010. AB - The changing pattern of resistance to antibacterial agents was a major theme at the 20th European Congress of Clinical Microbiology and Infectious Diseases. This article highlights presentations on the increasing threat from multidrug resistant Gram-negative pathogens, particularly extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae, which are limiting the choice of drug therapy for serious infections. Surveillance data suggest that carbapenem antibiotics are appropriate choices for the empiric treatment of intra abdominal infection. PMID- 20722596 TI - How do malaria parasites activate dendritic cells? AB - Evaluation of: Wu X, Gowda NM, Kumar S, Gowda S: Protein-DNA complex is the exclusive malaria parasite component that activates dendritic cells and triggers innate immune responses. J. Immunol. 184(8), 4338-4348 (2010). Malaria parasites induce strong proinflammatory immune responses upon infection. These responses, driven largely by CD4+ Th1 cells, help the body to control malaria parasitemia. When excessive, inflammatory responses contribute to the pathology observed in malaria infection. Dendritic cells (DCs) are innate immune cells that activate Th1 cells in malaria infection via the secretion of the cytokine IL-12. It remains unclear precisely which components of malaria-infected red blood cells are responsible for activating DCs. In this study, Wu et al. set out to deconstruct malaria-infected red blood cells to determine the immunogenic components that induce production of the proinflammatory cytokines IL-12 and TNF alpha from DCs. The authors suggest that parasite DNA complexed with protein is the main trigger for activation of DCs in malaria-infected red blood cells. PMID- 20722597 TI - The Rcs phosphorelay: more than just a two-component pathway. AB - The Rcs phosphorelay is a complex signaling pathway found in many, but not all, members of the Enterobacteriaceae. The complexity of this pathway is due to the direct involvement of three proteins (RcsC, RcsD and RcsB) in the phosphorelay and the presence of multiple accessory proteins with important roles in modulating the inputs and outputs associated with this signaling pathway. This article will discuss the various inputs and outputs associated with the Rcs phosphorelay and also present a model suggesting an important role for this signaling pathway in the temporal control of virulence in Salmonella enterica and biofilm formation in Escherichia coli. PMID- 20722599 TI - Architecture of the type II secretion and type IV pilus machineries. AB - Motility and protein secretion are key processes contributing to bacterial virulence. A wealth of phylogenetic, biochemical and structural evidence support the hypothesis that the widely distributed type IV pilus (T4P) system, involved in twitching motility, and the type II secretion (T2S) system, involved in exoprotein release, are descended from a common progenitor. Both are composed of dedicated but dynamic assemblages, which have been proposed to function through alternate polymerization and depolymerization or degradation of pilin-like subunits. While ongoing studies aimed at understanding the details of assembly and function of these systems are leading to new insights, there are still large knowledge gaps with respect to several fundamental aspects of their biology, including the localization and stoichiometry of critical assembly components, and the nature of their interactions. This article highlights recent advances in understanding the architectures of the T4P and T2S systems, and the organization of their inner and outer membrane components. As structural data accumulates, it is becoming increasingly apparent that even components with little-to-no sequence similarity have similar folds, further supporting the idea that both systems function by a similar mechanism. PMID- 20722600 TI - Uncivil engineers: Chlamydia, Salmonella and Shigella alter cytoskeleton architecture to invade epithelial cells. AB - The obligate intracellular bacterial pathogen Chlamydia trachomatis is a major cause of blindness and sexually transmitted diseases. Like the enteric pathogens Salmonella and Shigella, Chlamydia injects effector proteins into epithelial cells to initiate extensive remodeling of the actin cytoskeleton at the bacterial attachment site, which culminates in the engulfment of the bacterium by plasma membrane extensions. Numerous Salmonella and Shigella effectors promote this remodeling by activating Rho GTPases and tyrosine kinase signaling cascades and by directly manipulating actin dynamics. Recent studies indicate that similar host-cell alterations occur during Chlamydia invasion, but few effectors are known. The identification of additional Chlamydia effectors and the elucidation of their modes of function are critical steps towards an understanding of how this clinically important pathogen breaches epithelial surfaces and causes infection. PMID- 20722601 TI - Role of virulence factors and host cell signaling in the recognition of Helicobacter pylori and the generation of immune responses. AB - Helicobacter pylori colonizes a large proportion of the world's population, with infection invariably leading to chronic, lifelong gastritis. While the infection often persists undiagnosed and without causing severe pathology, there are a number of host, bacterial and environmental factors that can influence whether infection provokes a mild inflammatory response or results in significant morbidity. Intriguingly, the most virulent H. pylori strains appear to deliberately induce the epithelial signaling cascades responsible for activating the innate immune system. While the reason for this remains unclear, the resulting adaptive immune responses are largely ineffective in clearing the bacterium once infection has become established and, as a result, inflammation likely causes more damage to the host itself. PMID- 20722598 TI - Recent insights into Pasteurella multocida toxin and other G-protein-modulating bacterial toxins. AB - Over the past few decades, our understanding of the bacterial protein toxins that modulate G proteins has advanced tremendously through extensive biochemical and structural analyses. This article provides an updated survey of the various toxins that target G proteins, ending with a focus on recent mechanistic insights in our understanding of the deamidating toxin family. The dermonecrotic toxin from Pasteurella multocida (PMT) was recently added to the list of toxins that disrupt G-protein signal transduction through selective deamidation of their targets. The C3 deamidase domain of PMT has no sequence similarity to the deamidase domains of the dermonecrotic toxins from Escherichia coli (cytotoxic necrotizing factor [CNF]1-3), Yersinia (CNFY) and Bordetella (dermonecrotic toxin). The structure of PMT-C3 belongs to a family of transglutaminase-like proteins, with active site Cys-His-Asp catalytic triads distinct from E. coli CNF1. PMID- 20722602 TI - Pneumocystis jirovecii multilocus gene sequencing: findings and implications. AB - Pneumocystis jirovecii pneumonia (PcP) remains a major cause of respiratory illness among immunocompromised patients, especially patients infected with HIV, but it has also been isolated from immunocompetent persons. This article discusses the application of multilocus genotyping analysis to the study of the genetic diversity of P. jirovecii and its epidemiological and clinical parameters, and the important concepts achieved to date with these approaches. The multilocus typing studies performed until now have shown that there is an important genetic diversity of stable and ubiquitous P. jirovecii genotypes; infection with P. jirovecii is not necessarily clonal, recombination between some P. jirovecii multilocus genotypes has been suggested. P. jirovecii-specific multilocus genotypes can be associated with severity of PcP. Patients infected with P. jirovecii, regardless of the form of infection they present with, are part of a common human reservoir for future infections. The CYB, DHFR, DHPS, mtLSU rRNA, SOD and the ITS loci are suitable genetic targets to be used in further epidemiological studies focused on the identification and characterization of P. jirovecii haplotypes correlated with drug resistance and PcP outcome. PMID- 20722603 TI - Mechanisms of cryptococcal virulence and persistence. AB - Cryptococcus neoformans is an environmental yeast that is a leading cause of fatal mycosis in AIDS patients and a major cause of meningoencephalitis and CNS related mortality around the globe. Although C. neoformans infection is mostly a manifestation of immune deficiency, up to 25% of cases reported in the USA occur in patients without recognizable immune defects, indicating that C. neoformans can develop mechanisms that allow it to evade immune defenses and persist in noncompromised hosts. This article discusses mechanisms and routes of infection and the most important elements of host response as well as the mechanisms that promote cryptococcal survival within the host. Metabolic adaptation to physiological host conditions and the mechanisms limiting immune recognition, interfering with phagocytosis and extending intracellular survival of C. neoformans are highlighted. We describe the mechanisms by which C. neoformans can alter adaptive host responses, especially cell-mediated immunity, which is required for clearance of this microbe. We also review cryptococcal strategies of survival in the CNS and briefly discuss adaptations developing in response to medical treatment. PMID- 20722604 TI - Targeted expression of anthrax protective antigen by Lactobacillus gasseri as an anthrax vaccine. AB - AIM: Induction of protective immunity against pathogenic microbes, including Bacillus anthracis, requires efficient vaccines that potentiate antibody avidity and increase T-cell longevity. We recently reported that the delivery of targeted B. anthracis protective antigen (PA) genetically fused to a DC-binding peptide (DCpep) by Lactobacillus acidophilus induced mucosal and systemic immunity against B. anthracis challenge in mice. MATERIALS & METHODS: Improvement of this oral vaccine strategy was attempted by use of the high copy and genetically stable q-replicating vector, pTRKH2, for expression of the targeted PA fusion protein in Lactobacillus gasseri, a common human commensal microbe, to vaccinate animals against anthrax Sterne infection. RESULTS: Oral application of L. gasseri expressing the PA-DCpep fusion proteins elicited robust PA-neutralizing antibody and T-cell mediated immune responses against anthrax Sterne challenge, resulting in complete animal survival. Collectively, this improved expression vaccine strategy reduced the number of inoculations and length of the boosting period, leading to animal protection via efficacious bacterial adjuvanticity and safe oral delivery of this vaccine to mucosal immune cells, including dendritic cells. CONCLUSION: Lactobacillus-based delivery offers tremendous practical advantages. Recombinant antigens such as PA would not require chemical coupling agents, and the recombinant bacteria can be administered orally where upon both mucosal and systemic immune responses are elicited. PMID- 20722608 TI - Image-guided frameless stereotactic needle biopsy in awake patients without the use of rigid head fixation. AB - OBJECT: Image-guided frameless stereotactic techniques provide an alternative to traditional head-frame fixation in the performance of fine-needle biopsies. However, these techniques still require rigid head fixation, usually in the form of a head holder. The authors report on a series of fine-needle biopsies and brain abscess aspirations in which a frameless technique was used with a patient's head supported on a horseshoe headholder. To validate this technique, they performed an in vitro accuracy study. METHODS: Forty-eight patients underwent fine-needle biopsy of intracranial lesions that ranged in size from 0.9 to more than 107.7 ml; a fiducial-less, frameless, image-guided technique was used without rigid head fixation. In 1 of the 48 patients a cerebral abscess was drained. The accuracy study was performed with a skull phantom that was imaged with a CT scanner and tracked with a registration mask containing light-emitting diodes. The objective was a skin fiducial marker with a 4-mm circular target to accommodate the 2.5-mm biopsy needle. A series of 50 trials was conducted. RESULTS: Diagnostic tissue was obtained on the first attempt in 47 of 48 brain biopsy cases. In 2 cases small hemorrhages at the biopsy site were noted as a complication on the postoperative CT scan. One of these hemorrhages resulted in hand and arm weakness. The accuracy study demonstrated a 98% success rate of the biopsy needle passing through the 4-mm circular target using the registration mask as the registration and tracking device. This demonstrates a +/- 0.75-mm tolerance on the targeting method. CONCLUSIONS: The accuracy study demonstrated the ability of the mask to actively track the target and allow navigation to a 4 mm-diameter circular target with a 98% success rate. The frameless, pinless, fiducial-less technique described herein will likely be another safe, fast alternative to frame-based stereotactic techniques for fine-needle biopsy that avoids the potential morbidity of rigid head-pin fixation. Furthermore, it should lend itself to other image-guided applications such as the placement of ventricular catheters for shunting or Ommaya reservoirs. PMID- 20722609 TI - The use of diffusion tensor tractography to measure the distance between the anterior tip of the Meyer loop and the temporal pole in a cohort from Southern China. AB - OBJECT: Anterior temporal lobe resection plus amygdalohippocampectomy can cause damage to the anterior portion of the optic radiation, also known as the Meyer loop, resulting in homonymous superior quadrantanopia. Magnetic resonance diffusion tensor tractography (DTT) of the Meyer loop can help in surgical planning. In this study, the distance of the anterior tip of the Meyer loop to the temporal lobe pole (ML-TP) in the Southern Chinese population was assessed. METHODS: The authors studied 16 Southern Chinese individuals (8 men and 8 women; mean age 45.6 years, range 21-60 years). Diffusion tensor images were obtained with a 3-T MR imaging system using a single-shot spin echo echo planar imaging sequence. Two trained operators, one neurosurgeon (Operator A) and one radiologist (Operator B), carried out the DTT analysis with software iPlan (BrainLAB) and FiberTrak (Philips). RESULTS: For the 32 temporal lobes, the intraclass correlation coefficient (ICC) of the 2 operators' results using iPlan was 0.96, while that of Operator A using iPlan and Operator B using FiberTrak was 0.75. The ICC of Operator B using iPlan and FiberTrak was 0.81. The ML-TP distance of normal lobes (30 lobes [2 lobes that previously underwent surgery were excluded]) was 36.3+/-5.5 mm (range 26.6-48.9 mm), 36.3+/-5.3 mm (range 26.8 48.2 mm), and 35.9+/-6.4 mm (range 20.8-48.4 mm) for Operator A using iPlan, Operator B using iPlan, and Operator B using FiberTrak, respectively (p>0.05). CONCLUSIONS: The 2 operators reached good agreement on ML-TP distance measurement using DTT. The DDT results can be more software dependent than operator dependent. The measurement with FiberTrak demonstrated larger range and standard deviation than measurement with iPlan. PMID- 20722610 TI - Premorbid oral antithrombotic therapy and risk for reaccumulation, reoperation, and mortality in acute subdural hematomas. AB - OBJECT: Acute subdural hematomas (SDHs) impart serious morbidity and mortality on the elderly population, with only 5% of those older than 65 years of age attaining functional independence. Despite its widespread use, oral antithrombotic therapy (OAT) in the context of acute SDH has not been extensively studied. The authors sought to evaluate the impact of premorbid OAT on recurrence of SDH, radiographic outcome, and mortality in patients undergoing surgical evacuation of an acute SDH. METHODS: The authors conducted a retrospective comparative cohort study reviewing all surgically treated cases of acute SDH at their institution between September 2005 and December 2008. They assessed baseline demographics, coagulation parameters, surgical management, and clinical course. Study end points included additional craniotomy for SDH reaccumulation, follow-up Rotterdam score, recurrent SDH volumetric analysis, Glasgow Outcome Score, and death. RESULTS: A total of 300 patients with acute SDH treated by craniotomy were assessed. Of these patients, 49% (148 patients) were receiving OAT. Of those who were on a regimen of OAT, 49% were taking warfarin (mean international normalized ratio 3.1 +/- 1.8), 31% were receiving antiplatelet therapy, and 20% were on a regimen of a combination of agents. On presentation, 72% of those using OAT received reversal agents. Recurrence of SDH necessitating additional evacuation was not significantly different with respect to premorbid OAT status (13% vs 14%). Patients with a history of OAT did not demonstrate a significant difference in Rotterdam score (2 vs 2), recurrent SDH volume (24.1 vs 19.6 cm(3)), GOS score (4 vs 3), or mortality (21% vs 24%). These findings remained stable after controlling for age, injury mechanism, and injury severity. CONCLUSIONS: Premorbid OAT was not a significant risk factor for recurrence of SDH necessitating additional evacuation following acute SDH. Additionally, postoperative Rotterdam score, volume of SDH reaccumulation, and overall mortality were not predicted by antithrombotic history. While premorbid use may predispose the patient to an SDH, OAT does not increase the risk of morbidity or mortality following surgical intervention. PMID- 20722611 TI - Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: magnetic resonance imaging and histological study. AB - OBJECT: Longitudinal multiparametric MR imaging and histological studies were performed on simvastatin- or atorvastatin-treated rats to evaluate vascular repair mechanisms after experimental intracerebral hemorrhage (ICH). METHODS: Primary ICH was induced in adult Wistar rats by direct infusion of 100 MUl of autologous blood into the striatal region adjacent to the subventricular zone. Atorvastatin (2 mg/kg), simvastatin (2 mg/kg), or phosphate-buffered saline was given orally at 24 hours post-ICH and continued daily for 7 days. The temporal evolution of ICH in each group was assessed by MR imaging measurements of T2, T1(sat), and cerebral blood flow in brain areas corresponding to the bulk of the hemorrhage (core) and edematous border (rim). Rats were killed after the final MR imaging examination at 28 days, and histological studies were performed. A small group of sham-operated animals was also studied. Neurobehavioral testing was performed in all animals. Analysis of variance methods were used to compare results from the treatment and control groups, with significance inferred at p <= 0.05. RESULTS: Using histological indices, animals treated with simvastatin and atorvastatin had significantly increased angiogenesis and synaptogenesis in the hematoma rim compared with the control group (p <= 0.05). The statin-treated animals exhibited significantly increased cerebral blood flow in the hematoma rim at 4 weeks, while blood-brain barrier permeability (T1(sat)) and edema (T2) in the corresponding regions were reduced. Both statin-treated groups showed significant neurological improvement from 2 weeks post-ICH onward. CONCLUSIONS: The results of the present study demonstrate that simvastatin and atorvastatin significantly improve the recovery of rats from ICH, possibly via angiogenesis and synaptic plasticity. In addition, in vivo multiparametric MR imaging measurements over time can be effectively applied to the experimental ICH model for longitudinal assessment of the therapeutic intervention. PMID- 20722613 TI - Bisphosphonates and bone diseases: past, present and future. PMID- 20722614 TI - A comparison between bisphosphonates and other treatments for osteoporosis. AB - Since their development 30 years ago, bisphosphonates are now one of the standard therapy in the management of osteoporosis. Improvements in terms of anti resorptive potency have leaded to new molecules available either orally or intravenously, from weekly to yearly administration. Overall tolerance of bisphosphonates is good with regards to the risk of mandibular necrosis, not comparable with those observed in cancer treatment, and with no causal link yet established in osteoporotic patients. Compliance remains poor and should be improved by a better education of the patients about their treatment. Other treatments like teriparatide, raloxifene or strontium ranelate are now also available and give more therapeutic options but also more questions on the best molecule to choose for each patient. There is currently no valid basis for distinguishing in a formal and objective manner the different new-generation bisphosphonates, in terms of efficacy against either vertebral, peripheral or hip fractures. In a same way, comparison between bisphosphonates and the other treatments available for osteoporosis is hard in absence of proper randomised controlled study. This review gives an overview of the recent data on the efficacity and tolerance of bisphosphonates in the different forms of osteoporosis and compares them to the other treatments currently available. PMID- 20722615 TI - Molecular targets of the nitrogen containing bisphosphonates: the molecular pharmacology of prenyl synthase inhibition. AB - The nitrogen containing bisphosphonates (N-BP) are the drug of choice for treating disease characterised by resorption of bone such as osteoporosis and metastatic bone disease. The overall mechanism of action is achieved through a combination of precise targeting to the bone environment and an extremely potent inhibition of a vital enzyme in an essential metabolic pathway. This targeting to bone is achieved through the phosphate-carbon-phosphate backbone of the drug which gives a high affinity for bone mineral. Once bound to bone the N-BP can be internalised by osteoclasts as they resorb bone where the drug can then interact with its molecular target. The enzyme target of these drugs, FPP synthase, is at a branch point in the mevalonate pathway. This pathway is principally used for the manufacture of cholesterol but also many other biochemicals including farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These prenyl groups are used in the post-transcriptional modification of proteins such as small GTPases that require a lipid membrane anchor to function. The main cellular effect of the blockade of FPP synthase by N-BP is to prevent protein prenylation resulting in disruption to vital signalling pathways and loss of osteoclast function. This review will examine the biochemistry of FPP synthase, inhibition by the N-BP and and other potential uses of prenyl synthase inhibitors. PMID- 20722616 TI - Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. AB - Bisphosphonates are widely used in the treatment of diseases involving excessive bone resorption, such as osteoporosis, cancer-associated bone disease, and Paget's disease of bone. They target to the skeleton due to their calcium chelating properties, where they primarily act by inhibiting osteoclast-mediated bone resorption. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolised to cytotoxic ATP analogues, while the more potent, nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase, thereby preventing the prenylation of small GTPases that are necessary for the normal function and survival of osteoclasts. In recent years, these concepts have been refined, with an increased understanding of the exact mode of inhibition of FPP synthase and the consequences of inhibiting this enzyme. Recent studies further suggest that the R2 side chain, as well as determining the potency for inhibiting the target enzyme FPP synthase, also influences bone mineral binding, which may influence distribution within bone and duration of action. While bisphosphonates primarily affect the function of resorbing osteoclasts, it is becoming increasingly clear that bisphosphonates may also target the osteocyte network and prevent osteocyte apoptosis, which could contribute to their anti-fracture effects. Furthermore, increasing evidence implicates monocytes and macrophages as direct targets of bisphosphonate action, which may explain the acute phase response and the anti-tumour activity in certain animal models. Bone mineral affinity is likely to influence the extent of any such effects of these agents on non-osteoclast cells. While alternative anti resorptive therapeutics are becoming available for clinical use, bisphosphonates currently remain the principle drugs used to treat excessive bone resorption. PMID- 20722617 TI - Combined therapies of bone disease with bisphosphonates. AB - Bisphosphonates are standard treatment for cancer-induced bone disease, a common feature of many advanced malignancies. Traditionally used to inhibit bone turnover and reduce the risk of skeletal-related events, there is now increasing pre-clinical evidence that these agents may also affect tumour burden and disease progression. In particular, combining bisphosphonates with chemotherapeutic agents has been demonstrated to cause substantially increased anti-tumour effects compared to giving the single agents. Clinical studies are in progress to determine whether adding bisphosphonates to standard anti-cancer therapy results in improved outcome for patients. Here we give an overview of the key pre clinical studies of anti-tumour effects of bisphosphonates, alone and in combination with other agents, and introduce some of the ongoing clinical trials that aim to determine the clinical relevance of bisphosphonates in combination therapy. PMID- 20722618 TI - Assessment of bisphosphonate activity in vitro. AB - Bisphosphonates are a class of drugs developed over the past three decades for the treatment of metabolic bone diseases with high bone turnover, such as Paget's disease, tumor associated osteolysis and osteoporosis. The exceptional pharmacokinetic profile of bisphosphonates makes them very suitable and safe drugs for the treatment of bone diseases, because, by conventional administration, osseous tissue and bone resorbing osteoclasts are the targets for these drugs as a result of the very high affinity of bisphosphonates for bone mineral. Several recent studies have demonstrated, however, that bisphosphonates decrease tumor burden in bone in rodent models of myeloma and metastatic bone disease, with suggestions of antitumor effects also in patients. Although decreased tumor burden could be a consequence of inhibition of bone resorption, there is increasing evidence that bisphosphonates might also have direct effects on tumor cell in vivo, since effects on tumors outside of skeleton or at doses not inhibiting bone resorption have been reported. Recent studies also suggest that bisphosphonates have inhibitory effect also on endothelial cell function and angiogenesis in tumor tissue. These findings suggest that the target cells for bisphosphonates as well as their molecular mechanism of action may be more diverse and complex than realized so far. This review highlights the main methodologies used to monitor the action of BPs in vitro cell models, with a special emphasis on the detection of BP-induced ATP-analoques by mass spectrometry. In addition, cell death monitoring, immunomodulatory effects and inhibition of growth/proliferation are described. PMID- 20722619 TI - Bisphosphonate therapy in the treatment of multiple myeloma. AB - Multiple myeloma is an incurable B cell neoplasm caused by the monoclonal expansion of malignant plasma cells in the bone marrow, often resulting in devastating bone disease. For over 2 decades bisphosphonates have been successfully used to treat the tumour-induced bone disease associated with multiple myeloma. This review will focus on preclinical studies and investigations in patients with multiple myeloma that have led to our current understanding of the mechanisms of action of bisphosphonates in myeloma bone disease. Major advances in the use of bisphosphonates, including findings that they may have additional benefits such as anti-tumour effects and promoting patient survival will be discussed. PMID- 20722620 TI - Alternative use of bisphosphonate therapy for rheumatic disease. AB - Bisphosphonates are widely use for pathologies such as osteoporosis, Paget's disease or bone metastasis. However, their potent antiresorptive properties open new therapeutic opportunities for other conditions associated with an increased focal or systemic bone remodelling. Moreover, apart from their antiresorptive activity, bisphosphonates could also have others properties through a specific analgesic or anti-inflammatory effect. Thus, rheumatic diseases like rheumatoid arthritis, spondylarthritis or SAPHO syndrome (acronym for synovitis, acne, pustulosis, hyperostosis and osteitis) that are associated with systemic and sometimes focal bone loss could be good candidates for bisphosphonate therapy. Other non-inflammatory rheumatic diseases like bone osteonecrosis, algodystrophy, fibrous dysplasia or neuropathic osteoarthropathy are also associated with pain and an increase of focal bone remodelling. Several studies have shown that bisphosphonate could have promising therapeutic potential in these inflammatory or non-inflammatory diseases where therapeutic options are usually few. This review will focus on the new potential alternative indications for bisphosphonate in rheumatic diseases. PMID- 20722621 TI - Targeted therapy options for treatment of bone metastases; beyond bisphosphonates. AB - Cancer is a major leading cause of death in the western world (following heart diseases). It poses an enormous burden on patients and society with a major impact on healthcare and economy. Once cancers have spread to the skeleton, treatment options are predominantly limited to palliation, treatment of hypercalcemia and prevention of pathological fractures. Despite the elaborate efforts of modern medicine to improve treatment, novel therapies for the treatment of solid tumors in patients with advanced disease, including metastatic bone disease, have generally failed to improve patient overall survival. Despite initial beneficial responses on metastatic tumor burden this is frequently followed by re-growth of therapy resistant, malignant metastatic bone lesions. Cancer relapse in bone coincides with devastating consequences and causes considerable morbidity. Bisphosphonates represent the current gold standard in bone metastasis therapies. Because of the progress made in our understanding of the pathogenesis of skeletal metastasis using preclinical models, newer and more efficacious compounds and therapies have been developed that are being evaluated (or will soon be) in clinical trails. In this chapter, we discuss novel therapeutic targets and strategies for the treatment of metastatic bone disease. Future, successful treatment of skeletal metastasis will rely on targeting critical molecular mediators/processes in both metastasis-initiating subpopulations of osteotropic cancers ("the seed") together with their supportive, cellular and extra-cellular surrounding bone/bone marrow stroma ("the soil"). PMID- 20722622 TI - Therapeutic approach of primary bone tumours by bisphosphonates. AB - Bone tumours can be dissociated in two main categories: i) primary bone tumours (benign or malignant) including mainly osteosarcoma and other sarcomas.ii)and giant cell tumour and bone metastases originate from others cancer (Breast, prostate, kidney cancer, etc). These tumours are able to destroy or/and induce a new calcified matrix. However, the first step of bone tumour development is associated with an induction of bone resorption and the establishment of a vicious cycle between the osteoclasts and the tumour growth. Indeed, bone resorption contributes to the pathogenesis of bone tumour by the release of cytokines (IL6, TNFalpha) which govern the bone tumour's development and which are trapped into the bone matrix. Bisphosphonates (BPs) are chemical compounds of P-C-P structure with a high affinity for bone hydroxyapatite crystals. Thus, they have been used as a carrier for radio nucleotides to develop novel approaches of bone imaging. BPs exert also indirect anti-tumour activities in vivo. Indeed, BPs directly interfere with the bone microenvironment and target osteoclasts, endothelial cells and immune cells (tumour-associated macrophages, gamma9delta2 T cells). BPs induce tumour cell death in vitro and same activity is suspected in vivo. The present review summarizes the mechanisms of actions of BPs as well as their clinical interests in bone primary tumours. PMID- 20722624 TI - Prevention and treatment of bone metastases. AB - Certain primary tumours including breast and prostate cancers have a particular propensity for metastasis to bone. Metastatic bone disease can have significant impact on morbidity and mortality of cancer patients. Skeletal-morbidity (spinal cord compression, hypercalcaemia, fracture, need for radiotherapy and surgery to bone) can be effectively reduced by bisphosphonates, a class of anti-resorptive drugs. They are also effective in relieving pain from bone metastases, and may improve survival in patients with accelerated bone resorption. Additionally, there is an exciting body of evidence that suggest these drugs may have anti tumor effects that may be exploited to prevent or delay the development of bone metastases. Reported effects include inhibition of cancer cell migration, adhesion and invasion as well as anti-angiogenic and immunomodulating effects. The pre-clinical evidence is compelling, and some recently reported randomised clinical studies go part way to support their use in clinical practice at earlier stages of the disease to prevent bone metastases. However, further results are awaited before routine clinical use in the adjuvant setting can be recommended. PMID- 20722623 TI - Nitrogen-containing bisphosphonates and cancer immunotherapy. AB - Bisphosphonates, especially nitrogen-containing bisphosphonates (N-BPs), are widely used to block bone destruction in cancer patients with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. In addition to their antiresorptive effects, preclinical evidence strongly suggests that N-BPs have anticancer activity. Some of the activities associated with N-BPs are observed in human gammadeltaT cells that straddle the interface of innate and adaptive immunity and have potent anti-tumour activity. This review examines the molecular and cellular mechanisms through which N-BPs stimulate the expansion and cytotoxic activity of human gammadelta T cells. In addition, we discuss the emerging clinical evidence that N-BPs have a role in cancer immunotherapy. PMID- 20722625 TI - Co-expression of recombinant human CYP2C9 with human cytochrome P450 reductase in protease deficient S. cerevisiae strain at a higher scale yields an enzyme of higher specific activity. AB - Cytochrome P450 (CYP450) isozymes play an important role in the study of drug metabolism and drug discovery. A number of reports are available that describe recombinant expression of CYP450 isozymes. In this paper, human CYP2C9 and human cytochrome P450 reductase cDNAs were cloned and expressed in Premas proprietary yeast episomal and integrative vectors respectively under the influence of GAL1 promoter. Yeast cells were grown and induced at optimal parameters to make microsomal membranes. Isolated microsomal membranes were analyzed for CYP2C9 and cytochrome P450 reductase activity, CYP2C9 content and inhibition properties. We report heterologous expression of human CYP2C9 along with human cytochrome P450 reductase in protease deficient S. cerevisiae at a 5 litre scale resulting in high yields (8-10 nmols/litre) of enzyme with higher specific activity (2-3 fold higher). This yields a superior enzyme and makes it amenable to miniaturization of screening assays with concomitant lowering of costs. PMID- 20722626 TI - Current options in the treatment of mitochondrial diseases. AB - Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future. PMID- 20722627 TI - On the future development of optimally-sized lipid-insoluble systemic therapies for CNS solid tumors and other neuropathologies. AB - It remains a challenge to deliver effective concentrations of therapeutics into CNS pathologies, which is primarily due to the fact that current and investigational CNS therapeutics are suboptimally-sized to accumulate to effective concentrations in individual diseased CNS tissue cells. The blood-CNS barrier of blood capillary microvasculature within neuropathologic tissues is known to be permeable to lipid-insoluble macromolecules in a wide-spectrum of neuropathologies. In the case of CNS solid tumor tissue blood capillaries, the physiological upper limit of pore size to the transcapillary passage of spherical lipid-insoluble macromolecules is approximately 12 nanometers, and systemically administered imageable dendrimer nanoparticles within the 7 to 10 nanometer size range accumulate to therapeutic concentrations in solid tumors since this size range of particles maintain peak blood concentrations for several hours. In preliminary pre-clinical studies, it has recently been shown that one intravenous dose of small molecule chemotherapy-conjugated imageable dendrimer nanoparticles within the 7 to 10 nanometer size range, with doxorubicin bound to the particle exterior via acid-labile covalent linkages, is effective at regressing orthotopic rodent malignant gliomas. Although it is foreseeable that such drug-conjugated imageable nanoparticles within the 7 to 10 nanometer size range will be effective theranostic agents for the concurrent treatment (i.e. neutron capture therapy) and imaging (i.e. magnetic resonance) of solid tumor disease, the issue of maintaining a neutralized particle exterior following the attachment of cationic drugs will need to be addressed to eliminate cationic charge-mediated nanoparticle toxicity to blood capillary walls. In this review, the ultrastructural basis for blood capillary microvascular permeability to lipid insoluble macromolecules is discussed, and the importance of delineating the precise physiologic upper limits of pore size in the blood capillary microvasculature of other CNS pathologies, including neurodegenerative, inflammatory and ischemic CNS diseases, is emphasized. The discussion herein will serve as guide for the future development of optimally-sized, non-toxic and non immunogenic lipid-insoluble systemic therapies, which should be the focus of future patent applications and patents on CNS drug development. PMID- 20722628 TI - Glucose deficiency reduces collagen synthesis in breast cancer MCF7 cells. AB - We decided to study the effect of glucose deprivation on collagen metabolism in MCF7 cells. The incorporation of [3H]-proline into collagenase-sensitive and hydroxyproline-containing proteins was used as an index of collagen synthesis, whereas pulse-chase technique was employed to evaluate the degradation of newly synthesized proteins. The MCF7 cells incubated in high glucose medium synthesized detectable amounts of collagenous proteins. Most of them were found in the cell layer. The shortage of glucose resulted in about 30% reduction in collagen synthesis. The pulse-chase experiments demonstrated that proportionally less collagen was degraded in cultures incubated in low-glucose than in high-glucose media. PMID- 20722629 TI - Targeting P2X7 receptor inhibits the metastasis of murine P388D1 lymphoid neoplasm cells to lymph nodes. AB - The P2X7R (P2X7 receptor) is an ATP-gated cation channel expressed in normal cells that participates in both cell proliferation and apoptosis. Here, we have confirmed P2X7R expression on murine P388D1 lymphoid neoplasm cells. In addition, ATP-stimulated P2X7R expression was found to trigger increased intracellular calcium flux. Furthermore, silencing with short hairpin RNA and blocking with P2X7R antibody significantly reduced the metastasis of P388D1 cells to lymph nodes. These results indicate that inhibition of the expression and function of P2X7R attenuates the metastatic ability of murine lymphoid neoplasm cell line P388D1, which represents a new potential target for anti-metastatic therapy. PMID- 20722630 TI - Masking of the Fc region in human IgG4 by constrained X-ray scattering modelling: implications for antibody function and therapy. AB - Of the four human IgG antibody subclasses IgG1-IgG4, IgG4 is of interest in that it does not activate complement and exhibits atypical self-association, including the formation of bispecific antibodies. The solution structures of antibodies are critical to understand function and therapeutic applications. Thus IgG4 was studied by synchrotron X-ray scattering. The Guinier X-ray radius of gyration R(G) increased from 5.0 nm to 5.1 nm with an increase of concentration. The distance distribution function P(r) revealed a single peak at 0.3 mg/ml, which resolved into two peaks that shifted to smaller r values at 1.3 mg/ml, even though the maximum dimension of IgG4 was unchanged at 17 nm. This indicated a small concentration dependence of the IgG4 solution structure. By analytical ultracentrifugation, no concentration dependence in the sedimentation coefficient of 6.4 S was observed. Constrained scattering modelling resulted in solution structural determinations that showed that IgG4 has an asymmetric solution structure in which one Fab-Fc pair is closer together than the other pair, and the accessibility of one side of the Fc region is masked by the Fab regions. The averaged distances between the two Fab-Fc pairs change by 1-2 nm with the change in IgG4 concentration. The averaged conformation of the Fab regions appear able to hinder complement C1q binding to the Fc region and the self-association of IgG4 through the Fc region. The present results clarify IgG4 function and provide a starting point to investigate antibody stability. PMID- 20722631 TI - HDHD1, which is often deleted in X-linked ichthyosis, encodes a pseudouridine-5' phosphatase. AB - Pseudouridine, the fifth-most abundant nucleoside in RNA, is not metabolized in mammals, but is excreted intact in urine. The purpose of the present work was to search for an enzyme that would dephosphorylate pseudouridine 5'-phosphate, a potential intermediate in RNA degradation. We show that human erythrocytes contain a pseudouridine-5'-phosphatase displaying a Km <= 1 MUM for its substrate. The activity of the partially purified enzyme was dependent on Mg2+, and was inhibited by Ca2+ and vanadate, suggesting that it belonged to the 'haloacid dehalogenase' family of phosphatases. Its low molecular mass (26 kDa) suggested that this phosphatase could correspond to the protein encoded by the HDHD1 (haloacid dehalogenase-like hydrolase domain-containing 1) gene, present next to the STS (steroid sulfatase) gene on human chromosome Xp22. Purified human recombinant HDHD1 dephosphorylated pseudouridine 5'-phosphate with a kcat of 1.6 s-1, a Km of 0.3 MUM and a catalytic efficiency at least 1000-fold higher than that on which it acted on other phosphate esters, including 5'-UMP. The molecular identity of pseudouridine-5'-phosphatase was confirmed by the finding that its activity was negligible (<10% of controls) in extracts of B-cell lymphoblasts or erythrocytes from X-linked ichthyosis patients harbouring a combined deletion of the STS gene (the X-linked ichthyosis gene) and the HDHD1 gene. Furthermore, pseudouridine-5'-phosphatase activity was 1.5-fold higher in erythrocytes from women compared with men, in agreement with the HDHD1 gene undergoing only partial inactivation in females. In conclusion, HDHD1 is a phosphatase specifically involved in dephosphorylation of a modified nucleotide present in RNA. PMID- 20722632 TI - Early identification of non-remission in first-episode psychosis in a two-year outcome study. AB - OBJECTIVE: To identify predictors of non-remission in first-episode, non affective psychosis. METHOD: During 4 years, we recruited 301 patients consecutively. Information about first remission at 3 months was available for 299 and at 2 years for 293 cases. Symptomatic and social outcomes were assessed at 3 months, 1 and 2 years. RESULTS: One hundred and twenty-nine patients (43%) remained psychotic at 3 months and 48 patients (16.4%) remained psychotic over 2 years. When we compared premorbid and baseline data for the three groups, the non remitted (n = 48), remitted for <6 months (n = 38) and for more than 6 months (n = 207), duration of untreated psychosis (DUP) was the only variable that significantly differentiated the groups (median DUP: 25.5, 14.4 and 6.0 weeks, respectively). Three months univariate predictors of non-remission were being single, longer DUP, core schizophrenia, and less excitative and more negative symptoms at baseline. Two-year predictors were younger age, being single and male, deteriorating premorbid social functioning, longer DUP and core schizophrenia. In multivariate analyses DUP, negative and excitative symptoms predicted non-remission at 3 months, but only DUP predicted at 2 years. CONCLUSION: Long DUP predicted both 3 month and 2-year non-remission rates in first-episode psychosis. PMID- 20722633 TI - Changes in smoking prevalence in 16-17-year-old versus older adults following a rise in legal age of sale: findings from an English population study. AB - AIM: To assess smoking prevalence before and after the rise in legal age of sale of cigarettes in England and Wales from age 16 to age 18 in October 2007. DESIGN: A series of monthly cross-sectional household surveys: the 'Smoking Toolkit Study'. SETTING: England. PARTICIPANTS: A total of 53, 322 adults aged 16 and over interviewed between October 2006 and May 2009, 1136 of whom were aged 16 or 17 years. MEASUREMENTS: Change in smoking prevalence from pre- to post legislation, assessed by self-reported smoking status, among the 16-17-year-old group and older adults. FINDINGS: The prevalence change following the legislation among those aged 16 and 17 was 7.1 percentage points (denominator=1136) compared with 2.4 percentage points (denominator=52,186) for older adults (odds ratio 1.36, P=0.024, 95% confidence interval=1.04-1.77 for the interaction). There was no difference within older age categories. CONCLUSIONS: There was a greater fall in prevalence in 16-17-year-olds following an increase in age of sale than in older age groups. This provides some support to the view that raising the age of sale can, at least in some circumstances, reduce smoking prevalence in younger age groups. PMID- 20722634 TI - What is neonatal sepsis? PMID- 20722635 TI - Treatment decisions for extremely preterm newborns: beyond gestational age. PMID- 20722636 TI - Don't forget other causes of wheeze. ABPA in a boy with asthma. A case report and review of the literature. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a rare pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus. The prevalence is estimated to be about 1-2% in adult patients with asthma and 2-15% in patients with cystic fibrosis. In paediatric patients with asthma, only single case reports on ABPA exist. We report on a 13-year-old boy with allergic asthma complicated by ABPA. Despite the presentation of typical clinical symptoms, it took 6 years before he was diagnosed. The clinical course improved rapidly after ABPA therapy was started, and 12 months after diagnosis, the boy is still free of symptoms. Clinical symptoms of ABPA may be unspecific making a rapid diagnosis difficult in some cases. CONCLUSION: A delay in diagnosis and treatment increases the risk for irreversible lung damage. Once bronchiectasis has developed, the outcome is unfavourable. Thus, ABPA has to be considered in patients whose asthma remains uncontrolled despite adequate therapy. PMID- 20722637 TI - In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones. AB - BACKGROUND: Hypersensitivity IgE-mediated reactions to quinolones are not easy to diagnose, with skin testing inducing false positive results. The aim of the study was to evaluate the in vitro-specific IgE response in patients with immediate allergic reactions to quinolones. METHODS: We evaluated 38 patients with confirmed immediate allergic reactions to quinolones. Those with anaphylaxis were considered allergic by clinical history, once other possible causes were ruled out, and those with urticaria by drug provocation. Sepharose radioimmunoassay (RIA) and basophil activation test (BAT) with ciprofloxacin, moxifloxacin and levofloxacin were performed. RESULTS: The quinolones involved were moxifloxacin (N = 24), ciprofloxacin (N = 11) and levofloxacin (N = 3). Sepharose-RIA was positive in 12 cases (31.57%) and BAT in 27 (71.05%). With Sepharose-RIA, 8 (21%) were positive to ciprofloxacin, 7 (18.4%) to moxifloxacin and 7 (18.4%) to levofloxacin. With BAT, 23 (60.5%) were positive to ciprofloxacin, 12 (31.6%) to moxifloxacin and 8 (21%) to levofloxacin. The specificity of the Sepharose-RIA was demonstrated by inhibition tests. To confirm that the BAT results observed were IgE mediated, the PI3K inhibitor wortmannin was used, with this compound inhibiting the BAT when stimulated with anti-IgE and the different quinolones, but not when fMLP was used as the basophil stimulator. Sepharose-RIA and BAT were repeated in positive cases 1 year later, detecting a decrease in all cases, with four becoming negative. CONCLUSION: Immediate hypersensitivity reactions to quinolones do occur, with moxifloxacin being the drug most frequently involved. The BAT is a useful method for diagnosing patients. Specific IgE was demonstrated by Sepharose-RIA and inhibition assay. PMID- 20722639 TI - Inhaled 1,8-cineole reduces inflammatory parameters in airways of ovalbumin challenged Guinea pigs. AB - Eucalyptol, also known as 1,8-cineole, is a monoterpene traditionally used to treat respiratory disorders due to its secretolytic properties. In addition to its myorelaxant effects, it also has anti-inflammatory actions in vitro. In this study, we aimed to evaluate the efficacy of acute treatment with 1,8-cineole on reducing airway inflammatory parameters. Ovalbumin (OVA)-sensitized guinea pigs were submitted to antigenic challenge (OVA) with or without pre-treatment with a single dose of 1,8-cineole administered by inhalation. Airway inflammatory parameters were reduced or absent in 1,8-cineole-treated animals as compared with untreated guinea pigs. Acute treatment with 1,8-cineole impaired the development of airway hyperresponsiveness to carbachol in isolated tracheal rings. Levels of the pro-inflammatory cytokines TNFalpha and IL-1beta was lower in bronchoalveolar lavage fluid (BALF) of 1,8-cineol-treated guinea pigs than in untreated animals. 1,8-Cineole impaired the OVA-induced increase of the myeloperoxidase activity in BALF. 1,8-Cineole also prevented the reduction of the mucociliary clearance induced by the antigen presentation. The present investigation provides evidence that inhaled 1,8-cineole prevents hyperresponsiveness and inhibits inflammation in airways of ovalbumin-challenged guinea pigs. PMID- 20722638 TI - Role of PD-L1 and PD-L2 in allergic diseases and asthma. AB - Asthma is the result of chronic airway inflammation associated predominantly with CD4+ cells, eosinophils, mast cells, and basophils. Several T-cells subsets, including NKT cells, play a critical role in orchestrating the inflammation in the airways predominantly, by secreting interleukin-4 and interleukin-13. Recently, programmed death-1 (PD-1) with its ligands, programmed death ligand B7H1 (PD-L1) and B7DC (PD-L2), was shown to regulate T-cell activation and tolerance. PD-1 has been characterized as a negative regulator of conventional CD4+T cells. In addition, the relative roles of PD-L1 and PD-L2 in regulating the activation and function of T cells have recently been characterized. Recent studies have demonstrated that PD-L1 and PD-L2 have important but opposing roles in modulating and polarizing T-cell functions in airway hyperreactivity. Whereas the severity of asthma is greatly enhanced in absence of PD-L2, PD-L1 deficiency resulted in reduced airway hyperresponsiveness and only minimal inflammation. This observation is partially because of the polarization of NKT cells in PD-L1- and PD-L2-deficient mice. This review will discuss the recent literature regarding the role of PD-L1 and PD-L2 in allergic disease and asthma. Current understanding of the role of PD ligands in allergic asthma gives impetus to the development of novel therapeutic approaches. PMID- 20722640 TI - Possible involvement of oxidative stress in 5-fluorouracil-mediated myelosuppression in mice. AB - Certain chemotherapeutic agents subject cells to oxidative stress, thereby promoting adverse effects. However, the molecular machinery governing 5 fluorouracil (5-FU)-mediated myelotoxicity is obscure. The purpose of this study was to clarify whether 5-FU-induced myelotoxicity is a cause of oxidative stress. Treatment of mice with 5-FU (75 mg/kg, i.p.) caused a significant induction of haem oxygenase-1 and a decrease in glutathione contents in bone marrow cells, both of which are the indicators of oxidative stress. The 5-FU-mediated decrease in the myeloid colony formation was intensified in Nrf2(-/-) mice, in which antioxidant proteins were down-regulated. N-Acetylcysteine reversed the 5-FU induced decreases in the glutathione content, number of bone marrow cells per femur and myeloid colony formation. Results from the present study reveal that 5 FU induces oxidative stress in bone marrow, which is involved, at least in part, in myelotoxicity in mice. Therefore, Nrf2-dependent genes as well as glutathione levels in bone marrow could be therapeutic targets for decreasing such side effects in 5-FU-based chemotherapy. PMID- 20722642 TI - Recurrence risk of stillbirth in the second pregnancy. PMID- 20722643 TI - A randomised controlled trial of low-dose misoprostol and dinoprostone vaginal pessaries for cervical priming. AB - OBJECTIVE: We studied the efficacy of 25-microg misoprostol pessaries as either single or double dose compared with a 3-mg dinoprostone pessary for cervical priming. DESIGN AND SETTING: A randomised controlled trial in Singapore. POPULATION: One hundred and seventy-one women with term pregnancies and modified Bishop scores (mBS) < or =6 from 2003 to 2004. METHOD: Patients were randomised to single misoprostol dose, double misoprostol dose or the current dinoprostone regimen. MAIN OUTCOME MEASURES: Primary outcome was number of women who achieved favourable mBS >6 or active labour by day 2. Secondary outcomes were time interval from insertion to delivery, cardiotocographic abnormalities, delivery and neonatal outcome. RESULTS: More women in the misoprostol double-dose group (96.6%) and dinoprostone group (93%) achieved the primary outcome compared with the single-dose group (77.8%) (P = 0.003 and P = 0.03, respectively). There was no difference in secondary outcomes. More multiparous women achieve primary outcome compared with nulliparous women (odds ratio 0.21, 95% confidence interval 0.06-0.77). CONCLUSION: Double-dose misoprostol 25 microg is as effective as dinoprostone 3 mg inserts for cervical priming; both are more efficacious than a single-dose misoprostol pessary. Parity prognosticates the success of induction. PMID- 20722644 TI - Radiofrequency ablation for selective reduction in complex monochorionic pregnancies. AB - Monochorionic pregnancies present unique challenges for selective fetal reduction, as vaso-occlusive procedures are required to ablate blood flow, usually in the umbilical cord, to achieve asystole in the selected fetus. We describe a case series of 35 monochorionic pregnancies (27 twins and eight triplets) undergoing selective fetal reduction using radiofrequency ablation. All procedures were performed under local anaesthesia. The procedure was technically successful in all cases. The live born rate was 88.6%. One (2.9%) woman miscarried within 2 weeks of the procedure, and two (5.7%) babies were stillborn. The median gestation at delivery was 36 weeks of gestation (range 24-41 weeks). There were no maternal complications. The median gestational age at procedure was 17 + 3 weeks (range from 12 + 5 to 27 + 4 weeks). All women had antenatal magnetic resonance imaging (MRI) post procedure. There were two (5.7%) cases of abnormal brain imaging. Our experience suggests that radiofrequency ablation is a safe and effective procedure for fetal reduction in complicated monochorionic pregnancies. PMID- 20722645 TI - Surgical training in gastrointestinal procedures within a UK gynaecological oncology subspecialty programme. PMID- 20722650 TI - A community breast center report card determined by participation in the national quality measures for breast centers program. AB - Measurement of quality indicators and peer comparison has been demonstrated to improve quality of care. The goal of this study was to determine whether a community breast center, in collaboration with the National Consortium of Breast Centers (NCBC), could voluntarily audit the quality of breast cancer care, confidentially transmit quality information to the NCBC, and receive peer performance comparisons. Quality indicator metrics from consecutive breast cancer patients undergoing care at a community interdisciplinary breast center were entered into a prospective database of quality measures that were defined by the NCBC. Retrospective review of patients from 2004 to 2006 was performed and subsequent quality indicator data was submitted electronically to the NCBC National Quality Measures for Breast Centers (NQMBC(TM) ) program. The percentage of new cancer diagnoses made by needle biopsy techniques was 94%, 95% and 96% from 2004 to 2006. Sentinel lymph node utilization in eligible patients was 93%, 96% and 91% from 2004 to 2006 and the immediate intraoperative pathologic frozen section false negative rate of the sentinel lymph node was 6.5%, 4.7% and 4%. Chart documentation of "patient participation in shared decision making for breast conserving therapy versus mastectomy" improved from 74% to 99% (p<0.05) from 2004 to 2006. Adjuvant systemic treatment for stage 2 breast cancer occurred in 76%, 89% and 77% of patients from 2004 to 2006. Neutropenia requiring hospital admission occurred in no patients in 2004 but in 4.8% and 2.9% in 2005 and 2006. The re-excision lumpectomy rates for stage 0, 1, 2, and 3 breast cancer patients from 2004 to 2006 was 14.2%, 22% and 24.8%. Quality indicator data was submitted to the NQMBC(TM) with successful confidential receipt of peer performance comparisons. Voluntary interdisciplinary institutional audits of breast cancer quality can be successfully submitted to the NQMBC(TM) with confidential peer performance comparison. PMID- 20722651 TI - Is there a reliable method to assess the complete pathologic response on the tumor after neo-adjuvant chemotherapy in inflammatory breast cancer toward recommendations for the pathologic process? Experience in 56 patients treated in a single institution. AB - The aim of this study was to compare the complete pathologic response (CPR) rate in 56 nonmetastatic inflammatory breast cancer patients according to the classification used and to look for a correlation between the CPR and overall survival. Initial biopsies and mastectomy specimens were reviewed by the same pathologist. The clinical response rate was 75%. A CPR was observed in 11 cases according to Sataloff, three according to Chevallier and five according to the NSABP. There was no correlation between the clinical and pathologic responses and none of them was predictive of relapse free survival or overall survival. We propose a standardization of the pathologic process of the mastectomy specimens so that a CPR has a clear definition across the institutions, with a good reproducibility whatever the classification used. PMID- 20722652 TI - Breast calciphylaxis following coronary artery bypass grafting completely resolved with total parathyroidectomy. PMID- 20722653 TI - Multimodal single-step vitiligo surgery: a novel approach. PMID- 20722654 TI - Repair of dilated earlobe due to plug piercing. PMID- 20722655 TI - Retronychia: diagnosis and treatment. PMID- 20722656 TI - Multiple V-Y advancement and rotation flaps for a large cheek defect. PMID- 20722657 TI - Evaluation of hydrogen peroxide as an intraprocedural hemostatic agent in manual dermabrasion. PMID- 20722658 TI - Closure pearls for defects under tension. PMID- 20722659 TI - Optimal repair of the composite graft donor wound at the root of the helix. PMID- 20722660 TI - A phase IIa open-label dose-escalation pilot study using allogeneic human dermal fibroblasts for nasolabial folds. AB - BACKGROUND AND OBJECTIVE: The correction of soft tissue contour defects and dermal atrophy is a growing area driven by medical and aesthetic need. Deterioration of the skin's appearance occurs as a result of age and trauma, such as surgery, infections, and acne. Typically, imperfections are treated with volume-correcting fillers. This study evaluated allogeneic human dermal fibroblasts (HDFs) for the treatment of nasolabial folds as an alternative strategy to improve the structure, texture, and quality of the skin. METHODS AND MATERIALS: In this phase IIa study, a suspension of allogeneic HDF (2 * 10(6) cells/mL or 2 * 10(7) cells/mL) was injected intradermally along the nasolabial fold; line severity was assessed using a photographic scale. RESULTS: Mean investigator satisfaction was 7.4 (range 4.7-9.5) at 12 weeks and 7.6 (range 4.4 9.8) at 24 weeks. Subject satisfaction scores were 7.0 (range 0.1-10.0) at 12 weeks and 7.8 (range 1.5-10.0) at 24 weeks. All patients experienced adverse events, the majority of which were deemed treatment related. Most were mild to moderate in severity and resolved completely. CONCLUSION: This study demonstrated that allogeneic HDF can produce an improvement in aesthetic appearance with minimal adverse events and warrants further investigation and development. Intercytex provided financial support for this study. John Roberts is an employee of Intercytex. PMID- 20722661 TI - Reduction in osmidrosis using a suction-assisted cartilage shaver improves the quality of life. AB - BACKGROUND: Axillary osmidrosis is a benign disorder that causes functional and emotional problems in Asian patients. Surgical treatments have proven effective in treating this disease, but changes in quality of life after surgical procedures have not been investigated so far. OBJECTIVE: To evaluate quality of life in patients with osmidrosis before and after surgery with suction-assisted cartilage shaver using the Dermatology Life Quality Index (DLQI). METHODS: Seventy patients with axillary osmidrosis (aged 14-49, 8 men and 62 women) who were treated using a suction-assisted cartilage shaver at the Department of Dermatology, Chang Gung Memorial Hospital, from May 2006 to November 2008 were included. Patients completed the DLQI before and 6 to 35 (mean 18.3) months after treatment. Scores for patient satisfaction and improvement were also investigated. RESULTS: Mean DLQI score before treatment was 11.3 (range 5-27). After 6 to 35 (mean 18.3) months of postoperative follow-up, DLQI scores (mean 0.8, range 0-4) declined significantly (93% reduction). Fifty-nine patients (84.2%) reported odor reduction of 90% or more; 24 patients (34.3%) were greatly satisfied, and 41 were (58.6%) absolutely satisfied with this procedure. CONCLUSION: Our data demonstrate that the suction-assisted cartilage shaver can greatly improve functional and social disabilities in patients with axillary osmidrosis. The authors have indicated no significant interest with commercial supporters. PMID- 20722662 TI - Self-care and mobility skills in children with cerebral palsy, related to their manual ability and gross motor function classifications. AB - AIM: The aim of this study was to investigate the acquisition of self-care and mobility skills in children with cerebral palsy (CP) in relation to their manual ability and gross motor function. METHOD: Data from the Pediatric Evaluation of Disability Inventory (PEDI) self-care and mobility functional skill scales, the Manual Ability Classification System (MACS), and the Gross Motor Function Classification System (GMFCS) were collected from 195 children with CP (73 females, 122 males; mean age 8 y 1 mo; SD 3 y 11 mo; range 3-15 y); 51% had spastic bilateral CP, 36% spastic unilateral CP, 8% dyskinetic CP, and 3% ataxic CP. The percentage of children classified as MACS levels I to V was 28%, 34%, 17%, 7%, and 14% respectively, and classified as GMFCS levels I to V was 46%, 16%, 15%, 11%, and 12% respectively. RESULTS: Children classified as MACS and GMFCS levels I or II scored higher than children in MACS and GMFCS levels III to V on both the self-care and mobility domains of the PEDI, with significant differences between all classification levels (p<0.001). The stepwise multiple regression analysis verified that MACS was the strongest predictor of self-care skills (66%) and that GMFCS was the strongest predictor of mobility skills (76%). A strong correlation between age and self-care ability was found among children classified as MACS level I or II and between age and mobility among children classified as GMFCS level I. Many of these children achieved independence, but at a later age than typically developing children. Children at other MACS and GMFCS levels demonstrated minimal progress with age. INTERPRETATION: Knowledge of a child's MACS and GMFCS level can be useful when discussing expectations of, and goals for, the development of functional skills. PMID- 20722663 TI - A possible association of responsiveness to adrenocorticotropic hormone with specific GRIN1 haplotypes in infantile spasms. AB - AIM: Adrenocorticotropic hormone (ACTH) has been used as the major therapy for infantile spasms since 1958 because it effectively suppresses seizures; it also normalizes the electroencephalogram in the short-term treatment of infantile spasms. G protein-regulated inducer of neurite outgrowth 1 (GRIN1, also known as N-methyl-D-aspartate receptor 1, NMDAR1), a glutamate receptor, is the main component of functional N-methyl-D-aspartic acid receptors that are involved in the glucocorticoid-induced neuronal damage. Thus, it may be a candidate gene to be tested for responsiveness to ACTH in infantile spasms. In the present study, polymorphisms in the GRIN1 gene in infantile spasms were investigated using a case-control design. METHOD: Twelve single nucleotide polymorphisms in the GRIN1 gene were genotyped in a Chinese case-control set consisting of 97 unrelated patients with infantile spasms (60 males, 37 females; mean age 6.4 mo, SD 2.7) and 96 healthy individuals (63 males, 33 females; mean age 7.3 mo, SD 3.8). Association analysis was performed on the genotyped data. RESULTS: Five estimated haplotypes with a frequency of more than 3% were detected. Results of the study showed that responsiveness to treatment with ACTH in homozygous carriers of the CTA haplotype was higher than that in heterozygous carriers and non-carriers (p=0.022). Furthermore, CTG, a rare haplotype, was strongly associated with infantile spasms (p=0.013). INTERPRETATION: The results suggest that haplotypes of GRIN1 may influence responsiveness to ACTH. The findings necessitate further study for confirmation. PMID- 20722664 TI - Febrile seizures are a syndrome of secondarily generalized hippocampal epilepsy. AB - AIM: the objective of this study was to examine in detail the semiology of febrile seizures, particularly to look for features that might suggest focality. In prolonged febrile seizures there is acute evidence of hippocampal involvement. Retrospective data relates mesial temporal sclerosis to such early prolonged febrile seizures. Animal models of prolonged seizures causing hippocampal damage show limbic seizures at low dose of the precipitants. METHOD: a detailed history of the early ictal phase of 10 children with typical febrile seizures and of the behavioural components of 10 children with high fever was taken by two independent observers and a consensus reached. RESULTS: there were seven males and three females aged 1 year to 2y 8mo (mean age 1y 11mo). In seven of the 10 children with febrile seizures there was an early phase of the attack compatible with focal origin and in four of these there were clear mesial temporal features. No such features were seen in the children with fever alone. INTERPRETATION: we conclude that the majority of febrile seizures have evidence of focal origin and many appear to arise in the hippocampus. PMID- 20722665 TI - Doose syndrome (myoclonic-astatic epilepsy): 40 years of progress. AB - Doose syndrome, otherwise traditionally known as myoclonic-astatic epilepsy, was first described as a unique epilepsy syndrome by Dr Hermann Doose in 1970. In 1989, the International League Against Epilepsy classified it formally as a symptomatic generalized epilepsy, and 20 years later it was renamed 'epilepsy with myoclonic-atonic seizures'. In this review, we discuss the components of this unique disorder including its incidence, clinical features, and electroencephalographic findings. Recent evidence has suggested possible genetic links to the GEFS+ (generalized epilepsy with febrile seizures plus) family, and, additionally, some children with structural brain lesions can mimic the Doose syndrome phenotype. Treatment strategies such as corticosteroids, ethosuximide, and valproate have been described as only partially effective, but newer anticonvulsants, such as levetiracetam and zonisamide, may provide additional seizure control. The most effective treatment reported to date appears to be the ketogenic diet. Prognosis is quite varied in this disorder; however, many children can have a remarkably normal neurodevelopmental outcome. PMID- 20722666 TI - Do healthy preterm children need neuropsychological follow-up? Preschool outcomes compared with term peers. AB - AIM: the aim of this study was to determine neuropsychological performance (possibly predictive of academic difficulties) and its relationship with cognitive development and maternal education in healthy preterm children of preschool age and age-matched comparison children born at term. METHOD: a total of 35 infants who were born at less than 33 weeks' gestational age and who were free from major neurosensory disability (16 males, 19 females; mean gestational age 29.4wk, SD 2.2wk; mean birthweight 1257g, SD 327g) and 50 term-born comparison children (25 males, 25 females; mean birthweight 3459g, SD 585g) were assessed at 4 years of age. Cognition was measured using the Griffiths Mental Development scales while neuropsychological abilities (language, short-term memory, visual-motor and constructive spatial abilities, and visual processing) were assessed using standardized tests. Multivariable regression analysis was used to explore the effects of preterm birth and sociodemographic factors on cognition, and to adjust neuropsychological scores for cognitive level and maternal education. RESULTS: the mean total Griffiths score was significantly lower in preterm than in term children (97.4 vs 103.4; p<0.001). Factors associated with higher Griffiths score were maternal university education (beta=6.2; 95% confidence interval [CI] 0.7-11.7) and having older siblings or a twin (beta=4.0; 95% CI 0.5-7.6). At neuropsychological assessment, preterm children scored significantly lower than term comparison children in all tests except lexical production (Boston Naming Test) and visual-processing accuracy. After adjustment for cognitive level and maternal education, differences remained statistically significant for verbal fluency (p<0.05) and comprehension, short term memory, and spatial abilities (p<0.01). INTERPRETATION: neuropsychological follow-up is also recommended for healthy very preterm children to identify strengths and challenges before school entry, and to plan interventions aimed at maximizing academic success. PMID- 20722667 TI - A valuable non-invasive diagnostic investigation for paediatric idiopathic brachial neuritis. AB - Idiopathic brachial neuritis (idiopathic neuralgic amyotrophy) in children is a well-recognized but rare condition. Although the precise aetiology is unknown, its usual occurrence after an infection suggests an immunological process. There is no specific test for brachial neuritis, and the diagnosis is one of exclusion with supportive evidence from nerve conduction studies, electromyography (EMG), and, in adults, changes in affected muscles on magnetic resonance imaging. Young children are often unable to tolerate EMG. PMID- 20722668 TI - Diabetes: costs and cost-effectiveness. PMID- 20722669 TI - Diabetes in the UK: time for a reality check? PMID- 20722670 TI - Systematic review of the association between lung function and Type 2 diabetes mellitus. AB - AIMS: To describe the association between lung function and Type 2 diabetes mellitus. METHODS: We identified English language studies evaluating the association between lung function and diabetes mellitus in the MEDLINE database from 1 January 1975 to 31 December 2009. We evaluated study quality based on established criteria (54 studies were reviewed, 34 met the inclusion criteria). RESULTS: Cross-sectional studies showed that adults with diabetes mellitus have lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), with reductions in FVC more consistent than FEV1 and lower diffusion capacity (DLCO) compared with their non-diabetic counterparts. The reduced lung function in patients with diabetes is inversely related to blood glucose levels, duration of diabetes and its severity and is independent of smoking or obesity. Findings in cohort studies have been less consistent, with only a few studies identifying an increased rate of lung function decline in adults with diabetes. In addition, other cohort studies have reported an association between decreased lung function and incident insulin resistance and diabetes. Studies evaluating biological mechanisms to explain the association between lung impairment and diabetes identified microangiopathy of the alveolar capillaries and pulmonary arterioles, chronic inflammation, autonomic neuropathy involving the respiratory muscles, loss of elastic recoil secondary to collagen glycosylation of lung parenchyma, hypoxia-induced insulin resistance and low birthweight, as being associated with both insulin resistance and impaired lung function. CONCLUSIONS: There is an association between diabetes mellitus and decreased lung function, but the definitive direction as well as the exact pathophysiological mechanism to explain this association requires further investigation. PMID- 20722671 TI - Imbalance of the autonomic nervous system at night in women with gestational diabetes. AB - AIMS: Autonomic nervous system dysfunction is observed in Type 2 diabetes. As gestational diabetes is a potent risk factor of later Type 2 diabetes, we set out to determine whether autonomic nervous system imbalance could already be observed in women with this condition. Because activity of the sympathetic nervous system tends to be relatively stable in the nocturnal hours, we performed the study at night. RESEARCH DESIGN AND METHODS: We studied 41 women with gestational diabetes, 22 healthy pregnant controls and 14 non-pregnant controls. We assayed plasma noradrenaline at 24.00, 04.00 and 07.00 h and performed an overnight Holter recording for heart rate variability analysis. In addition, we assayed plasma adrenomedullin, a cardiovascular protective hormone. RESULTS: Compared with non-pregnant controls, plasma noradrenaline levels were increased at 04.00 and 07.00 h in the gestational diabetic (P = 0.003) and pregnant control (P = 0.002) groups, with no difference between them. Heart rate variability, very-low frequency and low-frequency power were lower in pregnant groups compared to the non-pregnant controls. Heart rate variability remained unchanged between specified sampling times in the gestational diabetic group, in contrast to fluctuation seen in the control groups. CONCLUSIONS: Gestational diabetes, compared with normal pregnancy, seems not to be a state of overall sympathetic nervous system activation. At the heart level, however, an inhibitory effect on autonomic nervous system modulation was seen. Plasma noradrenaline and heart rate variability correlated well, supporting the use of this function in future studies of overall sympathetic activity during pregnancy. PMID- 20722672 TI - Who attends a UK diabetes screening programme? Findings from the ADDITION Cambridge study. AB - AIMS: One of the factors influencing the cost-effectiveness of population screening for Type 2 diabetes may be uptake. We examined attendance and practice- and individual-level factors influencing uptake at each stage of a diabetes screening programme in general practice. METHODS: A stepwise screening programme was undertaken among 135, 825 people aged 40-69 years without known diabetes in 49 general practices in East England. The programme included a score based on routinely available data (age, sex, body mass index and prescribed medication) to identify those at high risk, who were offered random capillary blood glucose (RBG) and glycosylated haemoglobin tests. Those screening positive were offered fasting capillary blood glucose (FBG) and confirmatory oral glucose tolerance tests (OGTT). RESULTS: There were 33 539 high-risk individuals invited for a RBG screening test; 24 654 (74%) attended. Ninety-four per cent attended the follow up FBG test and 82% the diagnostic OGTT. Seventy per cent of individuals completed the screening programme. Practices with higher general practitioner staff complements and those located in more deprived areas had lower uptake for RBG and FBG tests. Male sex and a higher body mass index were associated with lower attendance for RBG testing. Older age, prescription of antihypertensive medication and a higher risk score were associated with higher attendance for FBG and RBG tests. CONCLUSIONS: High attendance rates can be achieved by targeted stepwise screening of individuals assessed as high risk by data routinely available in general practice. Different strategies may be required to increase initial attendance, ensure completion of the screening programme, and reduce the risk that screening increases health inequalities. PMID- 20722673 TI - Associations between leptin and the leptin / adiponectin ratio and incident Type 2 diabetes in middle-aged men and women: results from the MONICA / KORA Augsburg study 1984-2002. AB - AIMS: Adipocyte-derived hormones seem to be involved in the development of Type 2 diabetes. Therefore, we assessed the association between the proinflammatory adipokine leptin and incident Type 2 diabetes, taking into account interactions between leptin and the anti-inflammatory adipokine adiponectin. METHODS: Using a case-cohort design, serum levels of adipokines were measured in 460 cases with incident Type 2 diabetes and 1474 non-cases selected from a source population of 7936 middle-aged subjects participating in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) Augsburg cohort study between 1984 and 1995 and followed up until 2002 (mean follow-up 10.9+/-4.7 years). RESULTS: High leptin and low adiponectin levels were associated with an increased Type 2 diabetes risk. The multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing tertile extremes were 1.71 (1.12-2.63) for leptin (top vs. bottom tertile) and 2.65 (1.88-3.76) for adiponectin (bottom vs. top tertile), respectively. There was a significant interaction between leptin and adiponectin, with highest diabetes risk being observed in individuals with high leptin and low adiponectin levels (P = 0.029 for interaction).While the addition of adiponectin to a basic risk factor model improved model prediction (Delta area under the curve 0.011), the change in model prediction was only marginal after the addition of leptin (Delta area under the curve 0.002). CONCLUSIONS: Our findings indicate that the two adipokines leptin and adiponectin interact in modulating Type 2 diabetes risk, but adiponectin is more strongly associated with Type 2 diabetes risk than leptin. PMID- 20722674 TI - The impact of sickle cell trait on glycated haemoglobin in diabetes mellitus. AB - AIMS: To determine the effect of sickle cell trait on measurement of glycated haemoglobin (HbA(1c)) in African American patients with diabetes mellitus. METHODS: This is a retrospective study including 885 outpatients who underwent HbA(1c) testing. Medical record review and sickle cell trait determinations based on the HbA(1c) assay were performed in African American participants. The relationship between HbA(1c) and serum glucose measurements was analysed. RESULTS: Data were obtained from 385 AA (109 with SCT, 22 with haemoglobin C trait and 254 without haemoglobinopathy) and 500 European American patients. In a model created through multivariate repeated-effects regression, the relationship between HbA(1c) and simultaneous serum glucose did not differ between African American subjects with and without the sickle cell trait, but differed between African American subjects without the sickle cell trait and European Americans (P = 0.0002). CONCLUSIONS: Sickle cell trait does not impact the relationship between HbA(1c) and serum glucose concentration. In addition, it does not appear to account for ethnic difference in this relationship between African Americans and whites. PMID- 20722675 TI - Comparison of the prevalence of chronic kidney disease in Japanese patients with Type 1 and Type 2 diabetes. AB - AIMS: The relationship between type of diabetes and risk of chronic kidney disease has not been studied in detail. We conducted this study to determine the prevalence of chronic kidney disease in Japanese adults with diabetes, with a particular emphasis on the comparison of Type 1 and Type 2 diabetes. METHODS: We studied 3,575 Japanese patients with diabetes, 504 with Type 1 (mean +/- SD age 38 +/- 13 years; 350 women and 154 men) and 3071 with Type 2 diabetes (60 +/- 13 years; 1187 women and 1884 men). Prevalence rates of albuminuria [urinary albumin/creatinine ratio (> or = 30 mg/g], decreased estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m(2)) and chronic kidney disease (defined as albuminuria and/or decreased eGFR) were compared between the two diabetic groups. RESULTS: The prevalence of albuminuria was higher in Type 2 than Type 1 diabetic patients by both Fisher's exact test (36.1 vs. 15.9%, P < 0.001) and multivariate logistic regression analysis [adjusted odds ratio (OR) = 1.482, 95% confidence interval (CI) = 1.050-2.091, P = 0.025]. The prevalence of decreased eGFR was also higher in Type 2 diabetic patients (25.2 vs. 7.9%, P < 0.001); however, the statistical significance disappeared after adjusting for covariates, including age (OR = 0.656, 95% CI = 0.395-1.088, P = 0.102). The prevalence of chronic kidney disease was also higher in Type 2 diabetic patients (46.0 vs. 19.1%, P < 0.001); however, the statistical significance disappeared in the multivariate analysis. CONCLUSIONS Type 2 diabetic patients are more than twice as likely as Type 1 diabetic patients to have chronic kidney disease due to an age-independent higher prevalence of albuminuria and age-dependent decreased eGFR. PMID- 20722677 TI - Comparison of the efficacy and safety of tramadol/acetaminophen combination therapy and gabapentin in the treatment of painful diabetic neuropathy. AB - AIMS: This study compared the efficacy and safety of tramadol/acetaminophen (T/A) and gabapentin in the management of painful diabetic neuropathy. METHODS: An open, randomized, comparative study was conducted. Subjects with painful symmetric neuropathy in the lower limbs and mean pain-intensity score > or = 4 on a numeric rating scale were eligible. Subjects were randomized to receive either tramadol (37.5 mg)/acetaminophen (325 mg) or gabapentin (300 mg) for 6 weeks. After 2 weeks of the titration period (1200 mg/day for gabapentin and three tablets/day for T/A), the doses were maintained if the pain was relieved. The primary efficacy outcome was a reduction in pain intensity. Secondary measures evaluated a pain relief scale, a Brief Pain Inventory, a 36-item Short Form Health Survey, average pain intensity and sleep disturbance. RESULTS: One hundred and sixty-three subjects (T/A 79; gabapentin 84) were included. At the final visit, the mean doses were 1575 mg/day for gabapentin and 4.22 tablets/day for T/A. Both groups were similar in terms of baseline pain intensity (mean intensity: T/A 6.7 +/- 1.6; gabapentin 6.3 +/- 1.6, P = 0.168). At the final visit, the mean reductions in pain intensity were similar in both groups (T/A 3.1 +/- 2.0; gabapentin -2.7 +/- 2.1, P = 0.744). Both groups had similar improvements in every Short Form Health Survey category and Brief Pain Inventory subcategory, and in the mean pain relief scores. CONCLUSION: This study suggests that the T/A combination treatment is as effective as gabapentin in the treatment of painful diabetic neuropathy in patients with Type 2 diabetes. PMID- 20722678 TI - Four-year impact of a continuous quality improvement effort implemented by a network of diabetes outpatient clinics: the AMD-Annals initiative. AB - AIMS: We evaluated the impact of a continuous quality improvement effort implemented by a network of Italian diabetes clinics operating in the national healthcare system. METHODS: This was a controlled before-and-after study involving 95 centres, of which 67 joined the initiative since 2004 (group A) and 18 were first involved in 2007 (group B, control). All centres used electronic medical record systems. Information on quality indicators was extracted for the period 2004-2007. Data were centrally analysed anonymously and results were published annually. Each centre's performance was ranked against the 'best performers'. We compared quality indicators between the two groups of centres over 4 years. RESULTS: Over 100 000 Type 2 diabetes mellitus patients were evaluated annually. The proportion of patients with glycated haemoglobin levels < 7% increased by 6% in group A (2007-2004 difference) and by 1.3% in group B. The proportion of patients with low-density lipoprotein-cholesterol < 100 mg/dl improved by over 10% in both groups. The rate of patients with blood pressure values < or = 130/85 mmHg increased in group A (+6.4%), but not in group B ( 1.4%). The use of insulin increased in group A only (+5.2%), while the use of statins increased by over 20% in both groups. CONCLUSIONS: A physician-led quality improvement effort, based on the systematic evaluation of routine data, is effective in improving the performance of a large number of diabetes clinics. The small percentage increase in the number of patients at target, if applied to large numbers of patients, would translate into a significant impact on public health. PMID- 20722679 TI - The views of patients with diabetes about nurse prescribing. AB - AIMS: To explore the views of patients with diabetes about nurse prescribing and the perceived advantages and disadvantages. METHODS: Patients were recruited from the case-loads of seven nurse prescribers in six National Health Service sites in England. Sites reflected the key settings in which nurses typically prescribe for patients with diabetes within primary care. Forty-one interviews were undertaken by trained qualitative researchers. Interviews addressed opinions and experiences of nurse prescribing; audiotapes were transcribed, coded, and themes identified. RESULTS: Patients were confident in nurse prescribing. Distinctions were made between the role of the nurse and that of the doctor, and views varied with regard to the extent patients felt nurses should work autonomously. Confidence in nurse prescribing was inspired by nurses' specialist knowledge and experience, a mutual trusting relationship, a thorough consultation, and experience of the benefits of nurse prescribing. Communication between nurses and doctors about patient care, awareness by nurses of their area of competence, training and experience, specialist diabetes knowledge and access to training updates were considered important for safe prescribing. Patterns of attendance had changed in some cases, with patients tending to see doctors less often. Access to medicines was improved for patients during non-routine/emergency situations. CONCLUSIONS: Nurse prescribing is acceptable to patients and can increase the efficiency of diabetes service in primary care. Workforce planners need to include the services of nurse prescribers alongside those of doctors. PMID- 20722676 TI - Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. AB - AIMS: To evaluate the dose-response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes. METHODS: Randomized, double-blind, placebo-controlled, parallel-group, 13 week study of 542 patients with Type 2 diabetes inadequately controlled [glycated haemoglobin (HbA(1c)) > or = 7.0 and < 9.0% (> or = 53 and < 75 mmol/mol)] on metformin (> or = 1000 mg/day) treated with subcutaneous lixisenatide doses of 5, 10, 20 or 30 microg once daily or twice daily or placebo. The primary end-point was change in HbA(1c) from baseline to 13 weeks in the intent-to-treat population. RESULTS: Lixisenatide significantly improved mean HbA(1c) from a baseline of 7.55% (59.0 mmol/mol); respective mean reductions for 5, 10, 20 and 30 microg doses were 0.47, 0.50, 0.69 and 0.76% (5.1, 5.5, 7.5 and 8.3 mmol/mol), on once-daily and 0.65, 0.78, 0.75 and 0.87% (7.1, 8.5, 8.2 and 9.5 mmol/mol) on twice-daily administrations vs. 0.18% (2.0 mmol/mol) with placebo (all P < 0.01 vs. placebo). Target HbA(1c) < 7.0% (53 mmol/mol) at study end was achieved in 68% of patients receiving 20 and 30 microg once-daily lixisenatide vs. 32% receiving placebo (P < 0.0001). Dose-dependent improvements were observed for fasting, postprandial and average self-monitored seven-point blood glucose levels. Weight changes ranged from -2.0 to -3.9 kg with lixisenatide vs. -1.9 kg with placebo. The most frequent adverse event was mild to-moderate nausea. CONCLUSIONS: Lixisenatide significantly improved glycaemic control in mildly hyperglycaemic patients with Type 2 diabetes on metformin. Dose response relationships were seen for once- and twice-daily regimens, with similar efficacy levels, with a 20 microg once-daily dose of lixisenatide demonstrating the best efficacy-to-tolerability ratio. This new, once-daily GLP-1 receptor agonist shows promise in the management of Type 2 diabetes to be defined further by ongoing long-term studies. PMID- 20722680 TI - Caring for older adults with diabetes mellitus: characteristics of carers and their prime roles and responsibilities. AB - AIMS: Expanding prevalence of diabetes has a major health impact on older people and the burden experienced by their informal carers. We report research which aimed to examine the burden on carers and highlight their input into diabetes care. METHODS: Of 98 diabetes patients aged over 59 years, 89 regularly received help with day-to-day activities or looking after from someone else and, of these, 83 carers consented to interview. Patients and carers were administered questionnaires related to the management of diabetes and personal strain (including Diabetes Knowledge Questionnaire, EuroQol, Caregiver Strain Scale and General Health Questionnaire). RESULTS: A substantial unmet need of older people with diabetes mellitus, in relation to domestic activities and diabetes care, was highlighted. Patient and carer diabetes knowledge was low. Primary carers were generally female relatives from the same household, not in paid employment. Twenty-seven carers (33%) provided > or = 35 h of care work each week. Most carers experienced a moderate level of stress, but 11 (14%) regularly felt overwhelmed. Thirty-three carers (40%) said they had never received any information on diabetes from professionals. Help most frequently wanted was advice and support in relation to accessing community services and about finances, benefits and/or allowances. CONCLUSIONS: Both patient and carer diabetes education strategies are required. Instruction for carers in the basic care of patients with diabetes is also needed and should be targeted. As many as one in seven carers felt regularly overwhelmed and lacked adequate support. Finally, 26 carers (31%) were entitled to benefits which they did not claim. PMID- 20722681 TI - Psychosocial factors associated with use of continuous glucose monitoring. AB - AIMS: To identify psychosocial factors associated with the use of continuous glucose monitoring by adults with Type 1 diabetes. METHODS: Twenty adult patients (aged 45 +/- 15 years, diabetes duration 25 +/- 19 years, 50% female) followed at our site in the multi-centre Juvenile Diabetes Research Foundation continuous glucose monitoring trial were divided into three groups: Glycated haemoglobin (HbA(1c)) Responders who demonstrated an improvement in glycaemic control with continuous glucose monitoring (baseline HbA(1c)> or = 7.0%, HbA(1c) reduction greater than or equal to 0.5%), Hypoglycaemia Responders (baseline HbA(1c) < 7.0%) who demonstrated decreased time < 3.9 mmol/l while remaining within target HbA(1c), and HbA(1c) Non-Responders (baseline HbA(1c)> or = 7.0%, HbA(1c) reduction less than 0.5%). Subjects participated in semi-structured interviews focusing on their psychosocial experiences with continuous glucose monitoring. RESULTS: Three major themes were identified that differentiated Responders (including both the HbA(1c) and Hypoglycaemia groups) from Non-Responders: (i) coping with frustrations-Responders used self-controlled rather than emotions based coping when faced with continuous glucose monitoring frustrations; (ii) use of information-Responders used retrospective pattern analysis, not just minute-by minute data analysis, in glycaemic management; (iii) 'significant other'/spousal involvement-Responders endorsed interest, encouragement and participation by their loved ones. Both Responders and Non-Responders expressed body image concerns when wearing continuous glucose monitoring devices. CONCLUSIONS: This qualitative study points to the importance of coping skills, retrospective review of data, and 'significant other' involvement in the effective use of continuous glucose monitoring. These findings will inform clinical initiatives to improve patient selection and training in the use of this new technology and have served as the basis for development of quantitative surveys to be used in clinical practice. PMID- 20722682 TI - Estimated costs of acute hospital care for people with diabetes in the United Kingdom: a routine record linkage study in a large region. AB - AIMS: Diabetes represents a notable burden to health payers. The purpose of this study was to estimate acute hospital care costs of treating people with diabetes with reference to the costs of treating those without. METHODS: This was a retrospective study. Data from routine hospital practice were available from a large health region (439 000 people), with an estimated prevalence of diabetes of 3.4%. Common records were identified using probabilistic record linkage. Cost estimates were attributed to admissions using healthcare resource group software. Outpatient costs were attributed using published values. Data described are for 2004, and prices in pounds sterling for 2005. Standardised cost ratios were estimated to compare the costs observed in the diabetes population with those expected from the non-diabetic reference population. RESULTS: The total annual cost of admissions was pound28 944 811 per 100 000 people, of which pound3 650 869 per 100 000 (12.6%) was diabetes related. The standardised cost rate of inpatient treatment was 2.9. The total cost of outpatient attendances was pound6 589 971 per 100 000, of which pound711 431 per 100 000 (10.8%) was diabetes related. The standardised cost ratio for outpatient care was 4.1. The total cost of hospital care for patients with diabetes was pound11 206 986 per 100 000, or 12.3% of acute hospital expenditure. The combined standardised cost ratio was 3.1. Costs of care for inpatient treatment increased from 8.7% of revenue in 1994 to 12.3% in 2004. CONCLUSIONS: The costs of acute hospital care for treating people with diabetes increased markedly over a decade, and now exceed 12% of revenue. PMID- 20722684 TI - Safe and rapid resolution of severe hypertriglyceridaemia in two patients with intravenous insulin. AB - AIM: To rapidly reduce serum triglyceride to a safe serum level. Severe hypertriglyceridaemia is associated with uncontrolled diabetes, obesity and poor physical activity. Even moderate increases in triglyceride levels (> 5mmol/L) confer an increased risk of pancreatitis and coronary artery disease. We present two patients with diabetes and serum triglyceride levels of greater than 85mmol/L despite polypharmacy intervention. METHOD: 72-hour intravenous insulin infusion was administered. RESULTS: Serum triglyceride levels fell to 9.4 and 4.6 mmol/L respectively, without adverse events and sustained effect over several months. CONCLUSION: We suggest the use of intravenous insulin infusion where lifestyle and oral drug therapies have failed can impact on severe hypertriglyceridaemia. PMID- 20722683 TI - A common variant of NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes. AB - AIMS: Electrocardiographic ventricular repolarization QT parameters are independent risk factors for cardiovascular events and sudden cardiac death in diabetic patients. The aim of the study was to investigate the association of polymorphisms of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene with QT interval in Chinese subjects with or without Type 2 diabetes. METHODS: Three single nucleotide polymorphisms (SNPs) (rs10494366, rs12143842 and rs12029454) were genotyped in 1240 Type 2 diabetic patients (631 men and 609 women) and 1196 normal controls (433 men and 763 women). Individuals with overt diseases other than diabetes were excluded. Heart-rate corrected QT interval (QTc) was determined by standard 12-lead ECG and Bazett formula. Sex-pooled analysis and sex-specific analysis for genotype-phenotype association were both conducted. RESULTS: In the diabetic group, the rs12143842 T allele was associated with a 3.87-ms (P = 0.014, empirical P = 0.039) increase in QTc duration for each additional allele copy, while rs10494366 and rs12029454 exhibited no significant association with QTc. We found no evidence of association for the three SNPs in subjects with normal glucose regulation. No significant SNP-gender and -diabetes affection interaction was observed. CONCLUSIONS: The genetic variant rs12143842 in NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes. Future studies in different populations are needed to validate this finding and to evaluate the impact of NOS1AP variants on cardiovascular events and sudden cardiac death in diabetic patients. PMID- 20722685 TI - Psychological adjustment of well siblings of children with Type 1 diabetes. AB - AIMS: Studies of siblings of children with Type 1 diabetes (Type 1 DM) have shown either increased levels of maladjustment or, alternatively, increased levels of pro-social behaviour according to whether the sibling or parent was interviewed. The purpose of this study was to examine the psychological adjustment of Type 1 DM siblings using both parent and sibling report and to assess the concordance between child and parent reports. METHODS: Ninety-nine siblings aged 11-17 years and parents of children with Type 1 DM treated at the Royal Children's Hospital, Melbourne were recruited sequentially. The Strengths and Difficulties Questionnaire (SDQ) was used to assess well siblings' emotional and behavioural functioning using data collected within a semi-structured interview. SDQ data between the sibling cohort and normative data sample were compared using independent-samples t-tests. Sibling reports and parent reports were compared using a series of paired-sample t-tests and correlation analyses. RESULTS: Type 1 DM siblings did not report greater emotional or behavioural maladjustment or more pro-social behaviour than norms. Parents rated siblings' pro-social behaviour as being comparable with that of youth from the general community; however, parents rated healthy siblings as having lower levels of maladjustment; specifically, significantly fewer conduct problems, hyperactive behaviour and peer-related problems (all P < 0.01). There were no significant differences between parent ratings and sibling ratings on peer-related problems or pro-social behaviour. CONCLUSIONS: Type 1 DM siblings did not report increased behavioural or emotional dysfunction relative to children in the general population and, according to their parents, were even better adjusted than their peers. PMID- 20722686 TI - The effects of total energy expenditure from all levels of physical activity vs. physical activity energy expenditure from moderate-to-vigorous activity on visceral fat and insulin sensitivity in obese Type 2 diabetic women. AB - AIMS: We examined the effects of physical activity with or without dietary restriction for 3 months on regional fat and insulin sensitivity and compared the effect of total energy expenditure from all levels of physical activity with that of physical activity energy expenditure from moderate-to-vigorous exercise in obese women with Type 2 diabetes. METHODS: In this randomized, controlled trial, we assessed change of body weight, abdominal visceral fat area, subcutaneous fat area and insulin sensitivity, expressed as K(ITT), and monitored total energy expenditure and physical activity energy expenditure using an accelerometer during a 12-week intervention in four groups: control, diet, exercise and diet plus exercise. RESULTS: The mean body mass index was 28.0 +/- 2.7 kg/m(2) and the mean duration of diabetes was 8 +/- 6 years. Both the diet and diet plus exercise groups showed significant body weight loss compared with the control group (P < 0.05). However, the visceral fat area was reduced only in the diet and exercise group (P = 0.017) and the subcutaneous fat area was reduced only in the diet group (P = 0.009). Mean energy intake was an independent determinant of the change in subcutaneous fat area (P = 0.020) and mean total anergy expenditure was an independent determinant of visceral fat area (P = 0.002). Insulin sensitivity K(ITT) was associated with physical activity energy expenditure (P = 0.006), energy intake (P = 0.047) and the change in fructosamine level (P = 0.016) but not with changes in body weight, subcutaneous fat area, visceral fat area or adipokine level. CONCLUSIONS: Exercise had an additive effect to dietary restriction on visceral fat reduction. Visceral fat area was associated with total energy expenditure, but insulin sensitivity was associated with physical activity energy expenditure. PMID- 20722687 TI - Driving and insulin-treated diabetes: comparing practices in Scotland and New Zealand. PMID- 20722688 TI - Asteroid hyalosis and photographic diabetic retinopathy screening. PMID- 20722689 TI - Business closure and relocation: a comparative analysis of the Loma Prieta earthquake and Hurricane Andrew. AB - The occurrence of a number of large-scale disasters or catastrophes in recent years, including the Indian Ocean tsunami (2004), the Kashmir earthquake (2005), Hurricane Katrina (2005) and Hurricane Ike (2008), have raised our awareness regarding the devastating effects of disasters on human populations and the importance of developing mitigation and preparedness strategies to limit the consequences of such events. However, there is still a dearth of social science research focusing on the socio-economic impact of disasters on businesses in the United States. This paper contributes to this research literature by focusing on the impact of disasters on business closure and relocation through the use of multivariate logistic regression models, specifically focusing on the Loma Prieta earthquake (1989) and Hurricane Andrew (1992). Using a multivariate model, we examine how physical damage to the infrastructure, lifeline disruption and business characteristics, among others, impact business closure and relocation following major disasters. PMID- 20722690 TI - Revisiting sphere: new standards of service delivery for new trends in protracted displacement. AB - The proportion of people living in protracted displacement, as well as the duration of this displacement, is increasing. International humanitarian standards for services provided in protracted displacement are based on the Sphere Standards, which were formulated using evidence and experience from acute phase emergencies. However, the majority of protracted emergencies are in the post-emergency phase. This paper discusses trends in displacement, outlines reasons why using the Sphere Standards as minimum standards of service provision in protracted displacement does not adequately meet the needs of these populations, and analyses areas where greater standards of service provision are necessary. An expansion of the evidence base regarding determinants of morbidity and mortality in protracted emergencies is needed. This, followed by a joint approach to designing new, effective standards focused on proactive policies, will allow the humanitarian community more appropriately to serve and enable the millions of people currently living in protracted displacement. PMID- 20722691 TI - Pinning down vulnerability: from narratives to numbers. AB - Social vulnerability analyses have typically relied upon narratives to capture the nuances of the concept. While narratives have enhanced our understanding of the multiple drivers of vulnerability, they have had limited influence on hazards and climate adaptation policy. This is partially a function of the different needs and goals of the policy and research communities. The former prioritises generalised quantitative information, while the latter is more concerned with capturing complexity. A theoretically driven and empirically tested quantitative vulnerability and capacities index (VCI) for use at the local scale is presented to help connect vulnerability research and policy. There are four versions of the index for use in rural and urban contexts at the household and community levels. There can be an infinite number of drivers of vulnerability, but the VCI draws upon 12 indicators to represent material, institutional and attitudinal aspects of differential vulnerability and capacities. PMID- 20722692 TI - Information technology and emergency management: preparedness and planning in US states. AB - The purpose of this paper is to examine the impact of information technology (IT) on emergency preparedness and planning by analysing a survey of US state government departments of emergency management. The research results show that there has been a significant impact of IT on emergency planning. IT has proven to be effective for all phases of emergency management, but especially for the response phase. There are numerous technologies used in emergency management, ranging from the internet, Geographic Information Systems and wireless technologies to more advanced hazard analysis models. All were generally viewed as being effective. Lack of financial resources and support from elected officials is a perennial problem in public administration, and was found to be prevalent in this study of IT and emergency management. There was evidence that state governments rating high on a performance index were more likely to use IT for emergency management. PMID- 20722693 TI - The relationship between demographic/educational parameters and perceptions, knowledge and earthquake mitigation in Israel. AB - Perceptions, knowledge and mitigation are factors that might play a role in preventing injury and loss of life during a major earthquake.(2) Little is known about the relationships between different demographic and educational parameters and these factors. A national representative sample of 495 adults was investigated in order to determine the relationship between demographic and educational parameters in terms of the perceived threat, perceived coping, knowledge and mitigation of earthquakes in Israel. Compared to females, males perceived the threat of earthquakes to be lower (t = 3.183, p = 0.002), manifested higher levels of perceived coping (t = 2.55, p = 0.011), and had higher levels of earthquake related knowledge (t = 2.047, p = 0.041). We conclude that there are gender differences in perceptions and knowledge regarding earthquakes. PMID- 20722694 TI - A multiple additive regression tree analysis of three exposure measures during Hurricane Katrina. AB - This paper analyses structural and personal exposure to Hurricane Katrina. Structural exposure is measured by flood height and building damage; personal exposure is measured by the locations of 911 calls made during the response. Using these variables, this paper characterises the geography of exposure and also demonstrates the utility of a robust analytical approach in understanding health-related challenges to disadvantaged populations during recovery. Analysis is conducted using a contemporary statistical approach, a multiple additive regression tree (MART), which displays considerable improvement over traditional regression analysis. By using MART, the percentage of improvement in R-squares over standard multiple linear regression ranges from about 62 to more than 100 per cent. The most revealing finding is the modelled verification that African Americans experienced disproportionate exposure in both structural and personal contexts. Given the impact of exposure to health outcomes, this finding has implications for understanding the long-term health challenges facing this population. PMID- 20722695 TI - Disaster risk reduction and 'built-in' resilience: towards overarching principles for construction practice. AB - The emerging emphasis on disaster risk reduction has broadened the range of experts whose knowledge must be garnered to resolve complex socio-technical challenges. This paper examines the role and position of the construction sector for addressing these concerns. Specifically, it examines the recursive nature of practices within the built environment, which can be seen as deeply ingraining fragmented approaches to the development process. These, in turn, render the industry a difficult arena within which to enact structural and cultural change. Based on a wide body of literature on resiliency a set of overarching principles are proffered to help inform efforts to overcome some of the barriers to creating a more resilient built environment. It is argued that these principles offer a point of departure for embedding resilience considerations at both project and institutional levels, although real change would demand challenging some of the conventions that currently underpin construction development. PMID- 20722696 TI - Host migration impacts on the phylogeography of Lyme Borreliosis spirochaete species in Europe. AB - The geographic patterns of transmission opportunities of vector-borne zoonoses are determined by a complex interplay between the migration patterns of the host and the vector. Here we examine the impact of host migration on the spread of a tick-borne zoonotic disease, using Lyme Borreliosis (LB) spirochaetal species in Europe. We demonstrate that the migration of the LB species is dependent on and limited by the migration of their respective hosts. We note that populations of Borrelia spp. associated with birds (Borrelia garinii and B. valaisiana) show limited geographic structuring between countries compared with those associated with small mammals (Borrelia afzelii), and we argue that this can be explained by higher rates of migration in avian hosts. We also show the presence of B. afzelii strains in England and, through the use of the multi-locus sequence analysis scheme, reveal that the strains are highly structured. This pattern in English sites is very different from that observed at the continental sites, and we propose that these may be recent introductions. PMID- 20722697 TI - Heterogenic expression of genes encoding secreted proteins at the periphery of Aspergillus niger colonies. AB - Colonization of a substrate by fungi starts with the invasion of exploring hyphae. These hyphae secrete enzymes that degrade the organic material into small molecules that can be taken up by the fungus to serve as nutrients. We previously showed that only part of the exploring hyphae of Aspergillus niger highly express the glucoamylase gene glaA. This was an unexpected finding since all exploring hyphae are exposed to the same environmental conditions. Using GFP as a reporter, we here demonstrate that the acid amylase gene aamA, the alpha-glucuronidase gene aguA, and the feruloyl esterase gene faeA of A. niger are also subject to heterogenic expression within the exploring mycelium. Coexpression studies using GFP and dTomato as reporters showed that hyphae that highly express one of these genes also highly express the other genes encoding secreted proteins. Moreover, these hyphae also highly express the amylolytic regulatory gene amyR, and the glyceraldehyde-3-phosphate dehydrogenase gene gpdA. In situ hybridization demonstrated that the high expressers are characterized by a high 18S rRNA content. Taken together, it is concluded that two subpopulations of hyphae can be distinguished within the exploring mycelium of A. niger. The experimental data indicate that these subpopulations differ in their transcriptional and translational activity. PMID- 20722698 TI - Solenicola setigera is the first characterized member of the abundant and cosmopolitan uncultured marine stramenopile group MAST-3. AB - Culture-independent molecular methods based on the amplification, cloning and sequencing of small-subunit (SSU) rRNA genes are a powerful tool to study the diversity of prokaryotic and eukaryotic microorganisms for which morphological features are not conspicuous. In recent years, molecular data from environmental surveys have revealed several clades of protists lacking cultured and/or described members. Among them are various clades of marine stramenopiles (heterokonts), which are thought to play an essential ecological role as grazers, being abundant and distributed in oceans worldwide. In this work, we show that Solenicola setigera, a distinctive widespread colonial marine protist, is a member of the environmental clade MArine STramenopile 3 (MAST-3). Solenicola is generally considered as a parasite or an epiphyte of the diatom Leptocylindrus mediterraneus. So far, the ultrastructural, morphological and ecological data available were insufficient to elucidate its phylogenetic position, even at the division or class level. We determined SSU rRNA gene sequences of S. setigera specimens sampled from different locations and seasons in the type locality, the Gulf of Lions, France. They were closely related, though not identical, which, together with morphological differences under electron microscopy, suggest the occurrence of several species. Solenicola sequences were well nested within the MAST-3 clade in phylogenetic trees. Since Solenicola is the first identified member of this abundant marine clade, we propose the name Solenicolida for the MAST-3 phylogenetic group. PMID- 20722699 TI - A novel RUNX1 mutation in a kindred with familial platelet disorder with propensity to acute myeloid leukaemia: male predominance of affected individuals. PMID- 20722700 TI - SYTO9 and SYBR GREEN1 with a high-resolution melting analysis for prenatal diagnosis of beta0-thalassemia/hemoglobin-E. AB - The beta0-thalassemia/Hb-E causes a wide range of severe conditions. A high medical cost is incurred in severe cases. Thus, the prevention of new cases of beta0-thalassemia/Hb-E is required. The aim of this study is to use the SYTO9 and SYBR GREEN1 high-resolution melting (HRM) analysis for prenatal diagnosis of beta0-thalassemia/Hb-E. DNA samples were extracted from amniotic fluid or cord blood of 11 pregnancies whose fetuses were at risk for beta-thalassemia/Hb-E. PCR products from multiplex amplification refractory mutation system PCR for the detection of beta0-thalassemia mutations at codons 17(A>T), 41/42(-TCTT), and 71/72(+A) and from amplification refractory mutation system PCR for the detection of Hb-E were characterized by SYTO9 HRM analysis. Moreover, beta0-thalassemia 3.5 kb deletion was detected using real-time PCR with SYBR GREEN1 HRM analysis. Seven of 11 fetuses (64%) were diagnosed as beta0-thalassemia/Hb-E (4 fetuses with mutation at codon 17, 2 with mutation at codon 41/42, and 1 with 3.5- kb deletion). Results from HRM analysis were completely consistent with those from fetal blood samplings analyzed at the time of delivery or pregnancy termination using HPLC. Therefore, the HRM analysis is easy to use. It is simple, flexible, non-destructive and has superb sensitivity and specificity. This approach might facilitate the laboratory diagnosis and genetic counseling for regions with a high prevalence of beta0-thalassemia/Hb-E. PMID- 20722701 TI - Longer survival associated with HLA-A*03, B*14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA-A and -B typing and haplotyping. AB - BACKGROUND: Human leukocyte antigen (HLA) haplotypes may influence iron phenotypes in patients with HFE hemochromatosis and could affect survival. METHODS: We tabulated general characteristics of HLA-A and -B types and haplotypes of HFE C282Y/C282Y probands diagnosed in medical care and analyzed these data to identify HLA survival modifiers. RESULTS: There were 212 probands (130 men, 82 women). Mean follow-up was 12.0 +/- 6.4 yr (0.1-41.2 yr; 34 deaths). HLA-A*03 was more prevalent in men (76.9% vs. 61.0% women; P = 0.0129); 35.4% of men and 29.3% of women had A*03, B*07; and 7.7% of men and 8.5% of women had A*03, B*14. Twenty-three probands had cirrhosis; none had A*03, B*14. Positivity for A*03 or A*03, B*07 was not a significant predictor or modifier of survival. In multiple regression analyses, A*03, B*14 predicted longer survival (P = 0.0004). Kaplan-Meier analysis confirmed longer survival in probands with A*03, B*14 (P = 0.0199, log-rank test). After excluding the 23 non-A*03, B*14 probands with cirrhosis, survival of probands with A*03, B*14 was still greater than that of probands without A*03, B*14 (P = 0.0254; log-rank test). Twenty-four years after diagnosis, cumulative survival of probands with and without A*03, B*14 was 100% and 58%, respectively. The percentage of deaths due to iron overload was lower in probands with A*03, B*14 (0% vs. 21.9%; P = 0.0392). CONCLUSIONS: In hemochromatosis probands with HFE C282Y/C282Y, survival was longer in those with HLA-A*03, B*14. Earlier age at diagnosis and less severe iron overload in probands with A*03, B*14 could explain this difference. PMID- 20722702 TI - Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma. AB - Achievement of complete response (CR) is a new goal of therapy for multiple myeloma (MM). By sensitive methods, the depth of response can be measured even among the patients in CR. We used a sensitive real-time quantitative polymerase chain reaction by allele-specific primers (qASO-PCR) to assess the level of minimal residual disease (MRD) in bone marrow of 37 patients with myeloma who had achieved CR/near-to-CR after autologous or allogeneic stem cell transplantation (SCT). Allele-specific primers could be successfully designed for 86% of patients. Three to six months after autotransplantation, the PCR target was not detectable in 53% of patients (16/30 patients), and the respective figure after allotransplantation was 71% (5/7 patients); the median sensitivity of PCR assay was <0.002%. The proportion of patients without detectable PCR target was 22% of all autotransplanted patients. A threshold level of 0.01% in the qASO-PCR assay 3 6 months after SCT was found to be a useful cut-off limit to divide the patients into two prognostic groups: MRD low/negative vs. MRD high. Low/negative MRD after SCT was a significant predictive factor for the prolongation of progression free (70 vs. 19 months; P = 0.003) and suggestively also for overall survival. We conclude that not only CR but also its depth is important for the long-term outcome in MM. PMID- 20722703 TI - The incidence of traumatic brain injury in an adult population--how to classify mild cases? AB - BACKGROUND: The incidence of traumatic brain injury (TBI) varies considerably between reports mainly because of variable methods used in recruiting of cases and especially in defining mild TBI. This study was carried out to evaluate the incidence in a given population according to published criteria for mild TBIs. METHODS: All cases with symptoms of brain injury after a head trauma were collected from the health centres serving a defined population in South East Finland and from the one hospital taking care of all corresponding TBI cases. After reviewing the health records, the author classified the TBIs according to the guidelines of European Federation of Neurological Societies (EFNS). RESULTS: A total of 370 patients were enrolled. The total crude annual incidence rate was 221 per 100.000 (95% CI: 176-265). A mild TBI was defined in 71% of the patients. According to the EFNS criteria, one-third of them should be classified only with head traumas because of the lack of either loss consciousness (LOC) or post traumatic amnesia (PTA). This would reduce the total crude incidence rate to 137 per 100.000(95% CI: 101-172), an effect of the same magnitude as excluding mild TBIs treated out of hospital. CONCLUSIONS: The incidence rate falls within the wide range of previous published figures. Use of LOC or PTA as a criterion for mild TBI affects the incidence rate considerably as does the exclusion of mild cases treated out of hospital. PMID- 20722704 TI - The burden of headache in Russia: validation of the diagnostic questionnaire in a population-based sample. AB - BACKGROUND: We report validation of the Russian-language version of the Lifting The Burden headache screening and diagnostic questionnaire in a population-based sample of 501 individuals in four cities (Smolensk, Tchelyabinsk, Nishny Novgorod and Tver) and three rural areas (Tula, Tver and Gornyi) of Russia. METHODS: The structured questionnaire, based on ICHD-II criteria, was applied face to face by trained non-medical interviewers calling at randomly selected households. Response rates were about 73% in cities and 80% in rural areas. RESULTS: Of those responding, 301 reported headache in the previous year; of the total sample, 143 people with and 47 without headache according to the questionnaire were re interviewed by telephone by one of the two neurologists unaware of the questionnaire diagnoses. Migraine (MIG), either definite (dMIG) or probable (pMIG), was diagnosed by the questionnaire in 72 cases, and tension-type headache (TTH), either definite (dTTH) or probable (pTTH), in 66 cases; the five others with headache were unclassifiable by questionnaire. Physicians diagnosed dMIG or pMIG in 65 cases, dTTH or pTTH in 89 cases and no headache in 31 cases; in five cases, headache was unclassifiable. The questionnaire had sensitivities and specificities of 77% and 82% for MIG (kappa=0.58) and of 64% and 91% for TTH (kappa=0.56). CONCLUSIONS: We concluded that the questionnaire can be utilized in a population-based countrywide survey of the burden attributable to primary headache disorders in Russia. PMID- 20722705 TI - Brain immunohistopathological study in a patient with anti-NMDAR encephalitis. AB - BACKGROUND AND PURPOSE: Anti-N-methyl-D-asparate (NMDA) receptor encephalitis is thought to be antibody-mediated. To perform an immunohistopathological study of the inflammatory reaction in a brain biopsy performed before immunomodulatory treatments in a patient with anti-NMDA receptor encephalitis. METHODS: An immunohistochemical study was performed using CD3, CD68, CD20, CD138 and CD1a antibodies. RESULTS: Prominent B-cell cuffing was present around brain vessels accompanied by some plasma cells, while macrophages and T cells were scattered throughout the brain parenchyma. CONCLUSION: These findings suggest that the B cells interact with the T cells and are involved in antibody secretion by the plasma cells. PMID- 20722706 TI - Survival to akinetic mutism state in Japanese cases of MM1-type sporadic Creutzfeldt-Jakob disease is similar to Caucasians. AB - BACKGROUND: It is not known whether the clinical course of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases differs from that of Caucasian sCJD cases. PATIENTS AND METHODS: To investigate the clinical course of Japanese sCJD, clinical findings from 29 patients with Japanese MM1-type sCJD were retrospectively evaluated and compared to Caucasian sCJD findings. RESULTS: Survival of Japanese MM1-type sCJD up to the time of akinetic mutism state is similar to that of Caucasian subjects. However, the total disease duration of Japanese patients was approximately three times longer. CONCLUSIONS: The present observations indicate that Japanese sCJD cases generally show a longer disease duration because of the longer survival period after reaching the akinetic mutism state. PMID- 20722707 TI - Ischaemic stroke and essential thrombocythemia: a series of 14 cases. AB - BACKGROUND: Essential thrombocythemia (ET) is considered as a rare cause of stroke, partially because of difficulties to identify it when platelet count is not greatly elevated. However, early detection of ET is important because, without adapted treatment, recurrent thromboses are frequent. METHOD: We collected, retrospectively, data from 14 cases of stroke patients with ET. Clinical characteristics, ischaemic stroke, laboratory data (platelet and leucocyte count, haemoglobin, JAK2 V617F mutation, culture of haematopoietic progenitors) and treatment were reviewed. Every patient has been interviewed by phone to evaluate outcome. RESULTS: The population consisted of nine women and five men with ages ranging from 40 to 87 years. Most of the patients (12) had atherosclerotic risk factors and two presented a thrombus in the internal carotid. ET was diagnosed early after the onset of stroke except in two patients. The platelet count was under 600*10(9) /L for five patients. Mutation JAK2 V617F was found for eight patients. Thirteen patients were treated with an association between antiplatelet and cytoreductive treatment and did not present further thrombosis. Median follow-up is 2.8 years. CONCLUSION: These cases emphasize the problems of diagnosing ET at the onset of the stroke. Complete blood count has to be carefully read and ET can be suspected even if platelet count is not greatly increased. Diagnosis must be confirmed by haematologist to initiate appropriate treatment. PMID- 20722708 TI - Metabolic syndrome and impaired vasomotor reactivity: causal relationship or chance association? PMID- 20722710 TI - Natalizumab treatment in paediatric multiple sclerosis: a case of induction, de escalation and escalation. PMID- 20722711 TI - Allergy and risk of glioma: a meta-analysis. AB - We evaluated the association between allergic conditions and the risk of glioma in case-control and cohort studies published so far on this issue. A total of 12 studies (10 case-control and 2 cohort studies) were included in the analysis, involving 61 090 participants, of whom 6408 had glioma. When compared with non allergic conditions, the pooled odds ratio (OR) with any allergic conditions for glioma was 0.60 (95% CI: 0.52-0.69, P<0.001), suggesting a significant negative association (protective effect) between allergy and glioma. Subgroup analysis showed that the ORs were 0.70 (95% CI: 0.62-0.79, P<0.001), 0.69 (95% CI: 0.62 0.78, P<0.001), and 0.78 (95% CI: 0.70-0.87, P<0.001) for asthma, eczema, and hay fever, respectively. The significant association remained even after excluding the bias of proxy reporting (OR=0.61; 95% CI: 0.50-0.75, P<0.001). We conclude that allergic conditions may significantly reduce the risk of glioma. PMID- 20722712 TI - Post-hypoxic cortical myoclonus mimicking spinal myoclonus - electrophysiological and functional MRI manifestations. PMID- 20722713 TI - A magnetization transfer study of mild and advanced Parkinson's disease. AB - BACKGROUND AND PURPOSE: Magnetization transfer ratio (MTR) technique has identified brain changes in grey and white matter in Parkinson's disease (PD), even in the early phase. However, how these tissue changes differ along the course of the illness is still unclear. This study was aimed at investigating how MTR values change from mild PD (PD1) to patients with advanced PD (PD2). METHODS: We measured MTR values by region of interest, in 11 PD1, 11 PD2 and 10 healthy age-matched subjects. RESULTS: Compared with controls, patients with PD1 exhibited a significant MTR reduction in substantia nigra pars compacta, substantia nigra pars reticulata, putamen, periventricular white matter and parietal white matter. In addition to the changes observed in PD1, the PD2 group exhibited a significant MTR reduction in caudate, pons, frontal white matter and lateral thalamus. CONCLUSION: These results suggest that MTR might reflect morphological changes induced by the disease in distinct brain areas at different stages. PMID- 20722714 TI - Risk of incident depression in patients with Parkinson disease in the UK. AB - BACKGROUND: Non-motor symptoms are not widely recognized in patients with Parkinson disease (PD). We sought to assess the incidence rate as well as the risk of depression in newly diagnosed patients with PD and to compare it to PD free controls. METHODS: We conducted a population-based follow-up study with a nested case-control analysis based on data from the UK-based General Practice Research Database (GPRD). We included PD patients >= aged 40 years with a first PD diagnosis between 1994 and 2005, and a matched comparison group free of PD. We assessed incidence rates (IRs) and relative risk estimates (odds ratios [ORs] with 95% confidence intervals [CI]). RESULTS: The IR of depression in newly diagnosed PD in the UK community was 26.0 (95% CI 22.9-29.5) per 1000 person years. The risk of developing depression was increased almost twofold in patients with PD when compared to patients without PD (adj. OR 1.89; 95% CI 1.49-2.40). The increased relative risk was most pronounced in women and in individuals 40-69 years of age. Long-term users of levodopa had an increased depression risk when compared to short-term users. CONCLUSIONS: Patients with PD are at an approximately twofold increased risk of being diagnosed with depression compared to the PD-free population. PMID- 20722715 TI - Dissociating the role of the caudate nucleus and dorsolateral prefrontal cortex in the monitoring of events within human working memory. AB - There is evidence that the dorsolateral prefrontal cortex is involved in the monitoring of information held in memory whether it is self-ordered or externally triggered. However, the functional contribution of the caudate nucleus in the monitoring of events has not yet been studied. We have previously proposed that the striatum is involved when a novel self-initiated action needs to be generated. The present study aimed to test the hypothesis that the caudate nucleus is significantly more required when the monitoring is self-ordered as opposed to externally triggered. Self-ordered monitoring refers to keeping track of which items have been selected so far in order to perform the current selection. Externally triggered monitoring refers to keeping track of which items have been selected by an outside source. Thirteen healthy young adults were scanned using functional magnetic resonance imaging while performing a monitoring task with three conditions: self-ordered, externally triggered and recognition. As predicted, a significant increase of activity was found in the dorsolateral prefrontal cortex bilaterally when the self-ordered and externally triggered conditions were compared with the recognition condition. Most importantly, significantly increased activity was found in the right caudate nucleus when comparing the self-ordered with the recognition condition or with the externally triggered condition, but not when comparing the externally triggered with the recognition condition. We suggest that the caudate nucleus is involved in the planning of a self-initiated novel action, especially when no clear indication is given for the response choice, and that this may be the case across different domains of cognition. PMID- 20722716 TI - Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+. AB - Trophic deprivation-mediated neuronal death is important during development, after acute brain or nerve trauma, and in neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro, and an in vivo model is provided by neuronal death in the mouse dorsal lateral geniculate nucleus (LGNd) after ablation of the visual cortex (VCA). Oxidant-induced intracellular Zn(2+) release ([Zn(2+) ](i) ) from metallothionein-3 (MT-III), mitochondria or 'protein Zn(2+) ', was implicated in trophic deprivation neurotoxicity. We have previously shown that neurotoxicity of extracellular Zn(2+) required entry, increased [Zn(2+) ](i) , and reduction of NAD(+) and ATP levels causing inhibition of glycolysis and cellular metabolism. Exogenous NAD(+) and sirtuin inhibition attenuated Zn(2+) neurotoxicity. Here we show that: (1) Zn(2+) is released intracellularly after oxidant and SD injuries, and that sensitivity to these injuries is proportional to neuronal Zn(2+) content; (2) NAD(+) loss is involved - restoration of NAD(+) using exogenous NAD(+) , pyruvate or nicotinamide attenuated these injuries, and potentiation of NAD(+) loss potentiated injury; (3) neurons from genetically modified mouse strains which reduce intracellular Zn(2+) content (MT-III knockout), reduce NAD(+) catabolism (PARP-1 knockout) or increase expression of an NAD(+) synthetic enzyme (Wld(s) ) each had attenuated SD and oxidant neurotoxicities; (4) sirtuin inhibitors attenuated and sirtuin activators potentiated these neurotoxicities; (5) visual cortex ablation (VCA) induces Zn(2+) staining and death only in ipsilateral LGNd neurons, and a 1 mg/kg Zn(2+) diet attenuated injury; and finally (6) NAD(+) synthesis and levels are involved given that LGNd neuronal death after VCA was dramatically reduced in Wld(s) animals, and by intraperitoneal pyruvate or nicotinamide. Zn(2+) toxicity is involved in serum and trophic deprivation-induced neuronal death. PMID- 20722717 TI - Time course of allocation of spatial attention by acoustic cues in non-human primates. AB - Spatial attention mediates the selection of information from different parts of space. When a brief cue is presented shortly before a target [cue to target onset asynchrony (CTOA)] in the same location, behavioral responses are facilitated, a process called attention capture. At longer CTOAs, responses to targets presented in the same location are inhibited; this is called inhibition of return (IOR). In the visual modality, these processes have been demonstrated in both humans and non-human primates, the latter allowing for the study of the underlying neural mechanisms. In audition, the effects of attention have only been shown in humans when the experimental task requires sound localization. Studies in monkeys with the use of similar cues but without a sound localization requirement have produced negative results. We have studied the effects of predictive acoustic cues on the latency of gaze shifts to visual and auditory targets in monkeys experienced in localizing sound sources in the laboratory with the head unrestrained. Both attention capture and IOR were demonstrated with acoustic cues, although with a faster time course than with visual cues. Additionally, the effect was observed across sensory modalities (acoustic cue to visual target), suggesting that the underlying neural mechanisms of these effects may be mediated within the superior colliculus, a center where inputs from both vision and audition converge. PMID- 20722718 TI - Differential participation of temporal structures in the consolidation and reconsolidation of taste aversion extinction. AB - The extinction process has been described as the decline in the frequency or intensity of the conditioned response following the withdrawal of reinforcement. Hence, experimental extinction does not reflect loss of the original memory, but rather reflects new learning, which in turn requires consolidation in order to be maintained in the long term. During extinction of conditioned taste aversion (CTA), a taste previously associated with aversive consequences acquires a safe status through continuous presentations of the flavor with no aversive consequence. In addition, reconsolidation has been defined as the labile state of a consolidated memory after its reactivation by the presentation of relevant information. In this study, we analyzed structures from the temporal lobe that could be involved in consolidation and reconsolidation of extinction of CTA by means of new protein synthesis. Our results showed that protein synthesis in the hippocampus (HC), the perirhinal cortex (PR) and the insular cortex (IC) of rats participate in extinction consolidation, whereas the basolateral amygdala plays no part in this phenomenon. Furthermore, we found that inhibition of protein synthesis in the IC in a third extinction trial had an effect on reconsolidation of extinction. The participation of the HC in taste memory has been described as a downmodulator for CTA consolidation, and has been related to a context-taste association. Altogether, these data suggest that extinction of aversive taste memories are subserved by the IC, HC and PR, and that extinction can undergo reconsolidation, a process depending only on the IC. PMID- 20722719 TI - A paradox: after stroke, the non-lesioned lower limb motor cortex may be maladaptive. AB - What are the neuroplastic mechanisms that allow some stroke patients to regain high-quality control of their paretic leg, when others do not? One theory implicates ipsilateral corticospinal pathways projecting from the non-lesioned hemisphere. We devised a new transcranial magnetic stimulation protocol to identify ipsilateral corticospinal tract conductivity from the non-lesioned hemisphere to the paretic limb in chronic stroke patients. We also assessed corticospinal tract degeneration by diffusion tensor imaging, and used an ankle tracking task to assess lower limb motor control. We found greater tracking error during antiphase bilateral ankle movement for patients with strong conductivity from the non-lesioned hemisphere to the paretic ankle than for those with weak or no conductivity. These findings suggest that, instead of assisting motor control, contributions to lower limb motor control from the non-lesioned hemisphere of some stroke survivors may be maladaptive. PMID- 20722721 TI - Impairment of CaMKII activation and attenuation of neuropathic pain in mice lacking NR2B phosphorylated at Tyr1472. AB - Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is a key mediator of long term potentiation (LTP), which can be triggered by N-methyl-d-aspartate (NMDA) receptor-mediated Ca(2+) influx. We previously demonstrated that Fyn kinase mediated phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 in the dorsal horn was involved in a neuropathic pain state even 1 week after nerve injury. Here we show that Y1472F-KI mice with a knock-in mutation of the Tyr1472 site to phenylalanine did not exhibit neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses and induction of inflammatory pain. Phosphorylation of NR2B at Tyr1472 was only impaired in the spinal cord of Y1472F-KI mice among the major phosphorylation sites. There was no difference in the Ca(2+) response to glutamate and sensitivity to NMDA receptor antagonists between naive wild-type and Y1472F-KI mice, and the Ca(2+) response to glutamate was attenuated in the Y1472F-KI mice after nerve injury. Autophosphorylation of CaMKII at Thr286 was markedly impaired in Y1472F-KI mice after nerve injury, but there was no difference in phosphorylation of CaMKII at Thr305 or protein kinase Cgamma at Thr674, and activation of neuronal nitric oxide synthase and microglia in the superficial layer of spinal cord between wild type and Y1472F-KI mice after the operation. These results demonstrate that the attenuation of neuropathic pain is caused by the impaired NMDA receptor-mediated CaMKII signaling in Y1472F-KI mice, and suggest that autophosphorylation of CaMKII at Thr286 plays a central part not only in LTP, but also in persistent neuropathic pain. PMID- 20722720 TI - Functional subdivision of feline spinal interneurons in reflex pathways from group Ib and II muscle afferents; an update. AB - A first step towards understanding the operation of a neural network is identification of the populations of neurons that contribute to it. Our aim here is to reassess the basis for subdivision of adult mammalian spinal interneurons that mediate reflex actions from tendon organs (group Ib afferents) and muscle spindle secondary endings (group II afferents) into separate populations. Re examining the existing experimental data, we find no compelling reasons to consider intermediate zone interneurons with input from group Ib afferents to be distinct from those co-excited by group II afferents. Similar patterns of distributed input have been found in subpopulations that project ipsilaterally, contralaterally or bilaterally, and in both excitatory and inhibitory interneurons; differences in input from group I and II afferents to individual interneurons showed intra- rather than inter-population variation. Patterns of reflex actions evoked from group Ib and II afferents and task-dependent changes in these actions, e.g. during locomotion, may likewise be compatible with mediation by premotor interneurons integrating information from both group I and II afferents. Pathological changes after injuries of the central nervous system in humans and the lineage of different subclasses of embryonic interneurons may therefore be analyzed without need to consider subdivision of adult intermediate zone interneurons into subpopulations with group Ib or group II input. We propose renaming these neurons 'group I/II interneurons'. PMID- 20722722 TI - Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU induced ROR-alpha allele. AB - ROR-alpha is an orphan nuclear receptor, inactivation of which cell-autonomously blocks differentiation of cerebellar Purkinje cells with a secondary loss of granule neurons. As part of our ENU mutagenesis screen we isolated the recessive tmgc26 mouse mutant, characterized by early-onset progressive ataxia, cerebellar degeneration and juvenile lethality. Detailed analysis of the tmgc26-/- cerebella revealed Purkinje cell and granule cell abnormalities, and defects in molecular layer interneurons and radial glia. Chimera studies suggested a cell-autonomous effect of the tmgc26 mutation in Purkinje cells and molecular layer interneurons, and a non-cell-autonomous effect in granule cells. The mutation was mapped to a 13-Mb interval on chromosome 9, a region that contains the ROR-alpha gene. Sequencing of genomic DNA revealed a T-to-A transition in exon 5 of the ROR-alpha gene, resulting in a nonsense mutation C257X and severe truncation of the ROR alpha protein. Together, our data identify new roles for ROR-alpha in molecular layer interneurons and radial glia development and suggest tmgc26 as a novel ROR alpha allele that may be used to further delineate the molecular mechanisms of ROR-alpha action. PMID- 20722725 TI - On the paradigm of altruistic suicide in the unicellular world. AB - Altruistic suicide is best known in the context of programmed cell death (PCD) in multicellular individuals, which is understood as an adaptive process that contributes to the development and functionality of the organism. After the realization that PCD-like processes can also be induced in single-celled lineages, the paradigm of altruistic cell death has been extended to include these active cell death processes in unicellular organisms. Here, we critically evaluate the current conceptual framework and the experimental data used to support the notion of altruistic suicide in unicellular lineages, and propose new perspectives. We argue that importing the paradigm of altruistic cell death from multicellular organisms to explain active death in unicellular lineages has the potential to limit the types of questions we ask, thus biasing our understanding of the nature, origin, and maintenance of this trait. We also emphasize the need to distinguish between the benefits and the adaptive role of a trait. Lastly, we provide an alternative framework that allows for the possibility that active death in single-celled organisms is a maladaptive trait maintained as a byproduct of selection on pro-survival functions, but that could-under conditions in which kin/group selection can act-be co-opted into an altruistic trait. PMID- 20722723 TI - Heterogeneity of the supramammillary-hippocampal pathways: evidence for a unique GABAergic neurotransmitter phenotype and regional differences. AB - The supramammillary nucleus (SuM) provides substantial projections to the hippocampal formation. This hypothalamic structure is involved in the regulation of hippocampal theta rhythm and therefore the control of hippocampal-dependent cognitive functions as well as emotional behavior. A major goal of this study was to characterize the neurotransmitter identity of the SuM-hippocampal pathways. Our findings demonstrate two distinct neurochemical pathways in rat. The first pathway originates from neurons in the lateral region of the SuM and innervates the supragranular layer of the dorsal dentate gyrus and, to a much lesser extent, the ventral dentate gyrus. This pathway displays a unique dual phenotype for GABAergic and glutamatergic neurotransmission. Axon terminals contain markers of GABAergic neurotransmission, including the synthesizing enzyme of GABA, glutamate decarboxylase 65, and the vesicular GABA transporter and also a marker of glutamatergic neurotransmission, the vesicular glutamate transporter 2. The second pathway originates from neurons in the most posterior and medial part of the SuM and innervates exclusively the inner molecular layer of the ventral dentate gyrus and the CA2/CA3a pyramidal cell layer of the hippocampus. The axon terminals from the medial part of the SuM contain the vesicular glutamate transporter 2 only. These data demonstrate for the first time the heterogeneity of the SuM-hippocampal pathways, not only from an anatomical but also a neurochemical point of view. These pathways, implicated in different neuronal networks, could modulate different hippocampal activities. They are likely to be involved differently in the regulation of hippocampal theta rhythm and associated cognitive functions as well as emotional behavior. PMID- 20722726 TI - Directional cultural change by modification and replacement of memes. AB - Evolutionary approaches to culture remain contentious. A source of contention is that cultural mutation may be substantial and, if it drives cultural change, then current evolutionary models are not adequate. But we lack studies quantifying the contribution of mutations to directional cultural change. We estimated the contribution of one type of cultural mutations--modification of memes--to directional cultural change using an amenable study system: learned birdsongs in a species that recently entered an urban habitat. Many songbirds have higher minimum song frequency in cities, to alleviate masking by low-frequency noise. We estimated that the input of meme modifications in an urban songbird population explains about half the extent of the population divergence in song frequency. This contribution of cultural mutations is large, but insufficient to explain the entire population divergence. The remaining divergence is due to selection of memes or creation of new memes. We conclude that the input of cultural mutations can be quantitatively important, unlike in genetic evolution, and that it operates together with other mechanisms of cultural evolution. For this and other traits, in which the input of cultural mutations might be important, quantitative studies of cultural mutation are necessary to calibrate realistic models of cultural evolution. PMID- 20722727 TI - Reproductive patterns shape introgression dynamics and species succession within the European white oak species complex. AB - The reproductive system of hybrids is an important factor shaping introgression dynamics within species complexes. We combined paternity and parentage analyses with previous species characterization by genetic assignment, to directly identify reproductive events that occurred within a stand comprising four European white oak species. Comparing species status of parent pairs provided a precise quantification of hybridization rate, backcrosses, and intraspecific matings in two life stages. The detailed mating system analysis revealed new findings on the dynamics of interspecific gene flow. First, hybrids acted successfully as both male and female during reproduction. They produced acorns and seedlings that were as viable as those sired by purebreds. Second, species maintenance could be due to a relatively low level of interspecific mating contrasting with a large proportion of intraspecific crosses and backcrosses. Despite a high proportion of hybrids and extensive interspecific gene flow, partial species integrity is maintained by genetically controlled pollen discrimination, ensuring preferential matings within purebreds and high parental species fidelity in hybrid reproduction, which impedes complete collapse into a continuous hybrid swarm. Finally, we showed that pollen from the different species had unequal contributions to reproduction suggesting that introgression processes could ultimately lead to extirpation or expansion of some species. PMID- 20722728 TI - Fitness variation due to sexual antagonism and linkage disequilibrium. AB - Extensive fitness variation for sexually antagonistic characters has been detected in nature. However, current population genetic theory suggests that sexual antagonism is unlikely to play a major role in the maintenance of variation. We present a two-locus model of sexual antagonism that is capable of explaining greater fitness variance at equilibrium than previous single-locus models. The second genetic locus provides additional fitness variance in two complementary ways. First, linked loci can maintain gene variants that are lost in single-locus models of evolution, expanding the opportunity for polymorphism. Second, linkage disequilibrium results between any two sexually antagonistic genes, producing an excess of high- and low-fitness haplotypes. Our results uncover a unique contribution of conflicting selection pressures to the maintenance of variation, which simpler models that neglect genetic architecture overlook. PMID- 20722729 TI - Comparative evidence for the correlated evolution of polyploidy and self compatibility in Solanaceae. AB - Breakdown of self-incompatibility occurs repeatedly in flowering plants with important evolutionary consequences. In plant families in which self incompatibility is mediated by S-RNases, previous evidence suggests that polyploidy may often directly cause self-compatibility through the formation of diploid pollen grains. We use three approaches to examine relationships between self-incompatibility and ploidy. First, we test whether evolution of self compatibility and polyploidy is correlated in the nightshade family (Solanaceae), and find the expected close association between polyploidy and self compatibility. Second, we compare the rate of breakdown of self-incompatibility in the absence of polyploidy against the rate of breakdown that arises as a byproduct of polyploidization, and we find the former to be greater. Third, we apply a novel extension to these methods to show that the relative magnitudes of the macroevolutionary pathways leading to self-compatible polyploids are time dependent. Over small time intervals, the direct pathway from self-incompatible diploids is dominant, whereas the pathway through self-compatible diploids prevails over longer time scales. This pathway analysis is broadly applicable to models of character evolution in which sequential combinations of rates are compared. Finally, given the strong evidence for both irreversibility of the loss of self-incompatibility in the family and the significant association between self-compatibility and polyploidy, we argue that ancient polyploidy is highly unlikely to have occurred within the Solanaceae, contrary to previous claims based on genomic analyses. PMID- 20722730 TI - Temperature-dependent turnovers in sex-determination mechanisms: a quantitative model. AB - Sex determination is often seen as a dichotomous process: individual sex is assumed to be determined either by genetic (genotypic sex determination, GSD) or by environmental factors (environmental sex determination, ESD), most often temperature (temperature sex determination, TSD). We endorse an alternative view, which sees GSD and TSD as the ends of a continuum. Both effects interact a priori, because temperature can affect gene expression at any step along the sex determination cascade. We propose to define sex-determination systems at the population- (rather than individual) level, via the proportion of variance in phenotypic sex stemming from genetic versus environmental factors, and we formalize this concept in a quantitative-genetics framework. Sex is seen as a threshold trait underlain by a liability factor, and reaction norms allow modeling interactions between genotypic and temperature effects (seen as the necessary consequences of thermodynamic constraints on the underlying physiological processes). As this formalization shows, temperature changes (due to e.g., climatic changes or range expansions) are expected to provoke turnovers in sex-determination mechanisms, by inducing large-scale sex reversal and thereby sex-ratio selection for alternative sex-determining genes. The frequency of turnovers and prevalence of homomorphic sex chromosomes in cold-blooded vertebrates might thus directly relate to the temperature dependence in sex determination mechanisms. PMID- 20722731 TI - Parasite-mediated protection against osmotic stress for Paramecium caudatum infected by Holospora undulata is host genotype specific. AB - Under certain conditions, otherwise parasitic organisms may become beneficial to their host. Parasite-mediated heat and osmotic stress resistance have been demonstrated for Paramecium caudatum, infected by several species of parasitic bacteria of the genus Holospora. Here, using the micronucleus-specific bacterium Holospora undulata, we investigate how infection mediates the response of two genotypes (clones 'K8' and 'VEN') of P. caudatum to heat (35 degrees C) and osmotic (0.24% NaCl) stress. In contrast to previous findings, we find no evidence for heat stress protection in infected individuals. We do, however, show an effect of symbiont-mediated osmotic stress resistance for the K8 clone, with infected individuals having higher survival than their uninfected counterparts up to 24 h after the onset of salt exposure. Despite this, both infected and uninfected individuals of the VEN clone showed higher survival rates than clone K8 individuals under osmotic stress. Thus, it would seem that parasite-mediated stress protection is restricted to certain combinations of host genotypes and types of stress and does not represent a general phenomenon in this system. PMID- 20722732 TI - Plants as resource islands and storage units--adopting the mycocentric view of arbuscular mycorrhizal networks. AB - The majority of herbaceous plants are connected by arbuscular mycorrhizal (AM) fungi in complex networks, but how this affects carbon (C) and phosphorus (P) allocation among symbionts is poorly understood. We utilized a monoxenic AM system where hyphae from donor roots colonized two younger receiver roots of varying C status. AM fungal C allocation from donor to receiver compartments was followed by measuring the (13)C contents in fungal- and plant-specific lipids, and P movement from a hyphal compartment was traced using (33)P. Four times more (13)C was translocated from donor to C-limited receiver roots, but C remained in fungal tissue. Root C status did not influence the overall AM colonization, but arbuscule density was twice as high in non-C-limited roots, and they received 10 times more (33)P. The number of hyphal connections between compartments did not influence C and P allocation. Interestingly, there were more fungal storage lipids, but fewer structural lipids inside C-limited roots. Our results indicate that AM colonization may poorly reflect host quality as C can be supplied from neighboring roots. A mycocentric view of the symbiosis is proposed where C delivering hosts are resource islands for the exchange of P for C, and C-limited hosts are storage units. PMID- 20722733 TI - Influence of temperature, oxygen and bacterial strain identity on the association of Campylobacter jejuni with Acanthamoeba castellanii. AB - Campylobacteriosis is the most frequently reported foodborne disease in the industrialized world, mainly through consumption of contaminated chicken meat. To date, no information is available on the primary infection sources of poultry. In this study, the ability of five Campylobacter jejuni strains with different invasion potential towards Caco-2 cells to survive and replicate in the protozoan Acanthamoeba castellanii was tested under simulated in situ conditions (i.e. chicken broiler houses). Results indicate that environmental conditions play a crucial role in C. jejuni-A. castellanii interactions. Co-culture in general did not result in an increase of either bacteria or amoebae. However, co-culture with Acanthamoeba did result in a delayed decline and an increased long-term survival of Campylobacter. Bacterial strain-specific effects were observed, with higher survival rates for low-invasive strains. The presence of C. jejuni in general did not affect A. castellanii viability, except at 37 degrees C under microaerobic conditions, where the presence of the reference and low-invasive Campylobacter strains resulted in a significant decline in amoebal viability. Confocal laser scanning microscopy revealed that intra-amoebal campylobacters were not always colocated with acidic organelles, suggesting potential bacterial interference with digestive processes. As Acanthamoeba enhances the persistence of C. jejuni, the presence of the amoeba in broiler house environments may have important implications for the ecology and epidemiology of this food pathogen. PMID- 20722734 TI - Identification of putative two-component regulatory systems in the bovine pathogen Mannheimia haemolytica A1, and preliminary characterization of the NarQ/P system. AB - The complete genome sequence of the bovine pathogen Mannheimia haemolytica A1 was analyzed by blast searches for the presence of two-component regulatory system proteins. Five complete sets of putative two-component systems were identified, and the NarQ/P system was further investigated. in silico analysis of the NarQ and NarP proteins showed features that are typical of the sensor and response regulator proteins. A narP knock-out mutant was constructed. The narP mutant has lost its ability to respond to NaNO(3) in the media and fail to alter the expression of several proteins. One of the proteins that showed increased production in the parent strain in response to NaNO(3) was analyzed by matrix assisted laser desorption ionization time-of-flight MS. Unexpectedly, the protein was identified to be FbpA, a periplasmic component of the iron transporter system. Sequence analysis of the promoter region of fbpA identified motifs typical for NarP-regulated genes. The expression of the leukotoxin gene was also altered in the narP mutant as shown by Western immunoblot analysis and reverse transcription-PCR. PMID- 20722735 TI - RmtC introduces G1405 methylation in 16S rRNA and confers high-level aminoglycoside resistance on Gram-positive microorganisms. AB - Seven plasmid-mediated 16S rRNA methyltransferases (MTases), RmtA, RmtB, RmtC, RmtD, RmtE, ArmA, and NpmA, conferring aminoglycoside resistance have so far been found in Gram-negative pathogenic microorganisms. In the present study, by performing an RNase protection assay, primer extension, and HPLC, we confirmed that RmtC indeed methylates at the N7 position of nucleotide G1405 in 16S rRNA as found in ArmA and RmtB. RmtC has an MTase activity specific for the bacterial 30S ribosomal subunit consisting of 16S rRNA and several ribosomal proteins, but not for the naked 16S rRNA, as seen in ArmA, RmtB, and NpmA. All seven 16S rRNA MTases have been found exclusively in Gram-negative bacilli to date, and no plasmid-mediated 16S rRNA MTase has been reported in Gram-positive pathogenic microorganisms. Thus, we checked whether or not the RmtC could function in Gram positive bacilli, and found that RmtC could indeed confer high-level resistance to gentamicin and kanamycin in Bacillus subtilis and Staphylococcus aureus. 16S rRNA MTases seemed to be functional to some extent in any bacterial species, regardless of the provenance of the 16S rRNA MTase gene responsible for aminoglycoside resistance. PMID- 20722736 TI - Transcription of Vibrio parahaemolyticus T3SS1 genes is regulated by a dual regulation system consisting of the ExsACDE regulatory cascade and H-NS. AB - Vibrio parahaemolyticus, one of the human pathogenic vibrios, causes gastroenteritis, wound infections and septicemia. Genomic sequencing of this organism revealed that it has two distinct type III secretion systems (T3SS1 and T3SS2). T3SS1 plays a significant role in lethal activity in a murine infection model. It was reported that expression of the T3SS1 gene is controlled by a positive regulator, ExsA, and a negative regulator, ExsD, which share a degree of sequence similarity with Pseudomonas aeruginosa ExsA and ExsD, respectively. However, it is unknown whether T3SS1 is regulated by a mechanism similar to that demonstrated for P. aeruginosa, because functional analysis of VP1701, which is homologous to ExsC, is lacking and there is no ExsE homologue in the T3SS1 region. Here, we demonstrate that vp1701 and vp1702 are functional orthologues of exsC and exsE, respectively, of P. aeruginosa. VP1701 was required for the production of T3SS1-related proteins. VP1702 was a negative regulator for T3SS1 related protein production and was secreted by T3SS1. We also found that H-NS represses T3SS1-related gene expression by suppressing exsA gene expression. These findings indicate that the transcription of V. parahaemolyticus T3SS1 genes is regulated by a dual regulatory system consisting of the ExsACDE regulatory cascade and H-NS. PMID- 20722737 TI - Fewer essential genes in mycoplasmas than previous studies suggest. AB - Here, we describe mutants of Mycoplasma pulmonis that were obtained using a minitransposon, Tn4001TF1, which actively transposes but is then unable to undergo subsequent excision events. Using Tn4001TF1, we disrupted 39 genes previously thought to be essential for growth. Thus, the number of genes required for growth has been overestimated. This study also revealed evidence of gene duplications in M. pulmonis and identified chromosome segregation proteins that are dispensable in mycoplasmas but essential in Bacillus subtilis. PMID- 20722738 TI - Genetic dissection of Helicobacter pylori AddAB role in homologous recombination. AB - Helicobacter pylori infects the stomach of about half of the world's human population, frequently causing chronic inflammation at the origin of several gastric pathologies. One of the most remarkable characteristics of the species is its remarkable genomic plasticity in which homologous recombination (HR) plays a critical role. Here, we analyzed the role of the H. pylori homologue of the AddAB recombination protein. Bioinformatics analysis of the proteins unveils the similarities and differences of the H. pylori AddAB complex with respect to the RecBCD and AddAB complexes from Escherichia coli and Bacillus subtilis, respectively. Helicobacter pylori mutants lacking functional addB or/and addA show the same level of sensitivity to DNA-damaging agents such as UV or irradiation and of deficiency in intrachromosomal RecA-dependent HR. Epistasis analyses of both DNA repair and HR phenotypes, using double and triple recombination mutants, demonstrate that, in H. pylori, AddAB and RecOR complexes define two separate presynaptic pathways with little functional overlap. However, neither of these complexes participates in the RecA-dependent process of transformation of these naturally competent bacteria. PMID- 20722739 TI - Cloning, overexpression and characterization of Leishmania donovani squalene synthase. AB - Squalene synthase (SSN, EC 2.5.1.21), a major enzyme in the sterol biosynthetic pathway, catalyses an unusual head-to-head reductive dimerization of two molecules of farnesyl-pyrophosphate (FPP) in a two-step reaction to form squalene. FPP serves as a metabolic intermediate in the formation of sterols, dolichols, ubiquinones and farnesylated proteins. Here, we report cloning, expression and purification of a catalytically active recombinant squalene synthase of Leishmania donovani (LdSSN). The pH and temperature optima of LdSSN were 7.4 and 37 degrees C, respectively. Biochemical studies revealed that the K(m) and V(max) for the substrate FPP were 3.8 MUM and 0.59 nM min(-1) mg(-1) and for NADPH were 43.23 MUM and 0.56 nM min(-1) mg(-1). LdSSN was found to be sensitive towards denaturants as manifested by a loss of enzyme activity at the concentration of 1 M urea or 0.25 M guanidine hydrochloride. Zaragozic acid A, a potent inhibitor of mammalian SSN, was also a competitive inhibitor of recombinant LdSSN, with a K(i) of 74 nM. This is the first report on the purification and characterization of full-length recombinant SSN from L. donovani. Studies on recombinant LdSSN will help in evaluating this enzyme as a potential drug target for visceral leishmaniasis. PMID- 20722740 TI - Characterization of dextran-producing Weissella strains isolated from sourdoughs and evidence of constitutive dextransucrase expression. AB - The study of exopolysaccharide production by heterofermentative sourdough lactic acid bacteria has shown that Weissella strains isolated from sourdoughs produce linear dextrans containing alpha-(1->6) glucose residues with few alpha-(1->3) linkages from sucrose. In this study, several dextran-producing strains, Weissella cibaria and Weissella confusa, isolated from sourdough, were characterized according to carbohydrate fermentation, repetitive element-PCR fingerprinting using (GTG)(5) primers and glucansucrase activity (soluble or cell associated). This study reports, for the first time, the characterization of dextransucrase from Weissella strains using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and in situ polymer production (after incubation with sucrose) from enzymatic fractions harvested from both sucrose and glucose culture media. Results demonstrate that dextransucrase activity was mainly soluble and associated with a constitutive 180-kDa protein. In addition, microsequencing of the active dextransucrase from W. cibaria LBAE-K39 allowed the design of specific primers that could detect the presence of glucansucrase encoding genes similar to GTFKg3 of Lactobacillus fermentum Kg3 and to DSRWC of W. cibaria CMU. This study hence indicates that sourdough Weissella strains synthesize original dextransucrase. PMID- 20722741 TI - A comparative analysis of phenotypic and genotypic methods for the determination of the biofilm-forming abilities of Staphylococcus epidermidis. AB - The collection of 146 Staphylococcus epidermidis strains isolated from the nasopharynx of lung cancer patients has been studied for the ability of slime secretion and biofilm formation using the Congo red agar (CRA) test and the microtiter plate (MtP) method, respectively. The prevalence of the icaAD and the aap genes was also analyzed. Some isolates (35.6%) were biofilm positive by the MtP method, while 58.9% of isolates exhibited a slime-positive phenotype by the CRA test. The sensitivities of the CRA test evaluated using the MtP method as a gold standard of biofilm production were 73.1%, 97.3% and 13.3% for all the strains screened, ica-positive and ica-negative strains, respectively. The genotype ica(+)aap(+) was correlated with a strong biofilm-producer phenotype. Interestingly, some of the ica(-)aap(-) isolates could also form a biofilm. The correlation between the presence of icaAD genes and the biofilm-positive phenotype by the MtP method as well as slime production by the CRA test was statistically significant (P<0.0001). However, some S. epidermidis strains possess the potential ability of ica-independent biofilm formation; thus, further studies are needed to determine reliable, short-time criteria for an in vitro assessment of biofilm production by staphylococci. PMID- 20722742 TI - Secondary prophylaxis treatment versus on-demand treatment for patients with severe haemophilia A: comparisons of cost and outcomes in Taiwan. AB - This study compared secondary prophylaxis treatment with on-demand treatment for severe haemophilia A in Taiwan. Fifty patients from one medical centre were evaluated over a 5-year period. Differences in annual bleed rates and factor VIII (FVIII) utilization were assessed between patients receiving secondary prophylaxis and patients receiving FVIII concentrates on-demand. Results were then used as inputs in a pharmacoeconomic model to predict outcomes of future haemophilia therapy strategies in Taiwan. The median annual number of total bleeding episodes was significantly lower in the 13 (26%) patients who received secondary prophylaxis than in the 37 patients who received FVIII on-demand (7.76 vs. 31.91, P < 0.0001). The between-group difference in median annual factor VIII utilization was statistically significant (1824.41 IU kg(-1) for the prophylaxis group and 1324.81 IU kg(-1) for the on-demand group, P < 0.01). It was estimated that approximately $2 million (USD) per year would be added to the cost of treatment by having all severe haemophilia A patients in Taiwan receive secondary prophylaxis instead of on-demand therapy while 12,566 bleeding will be prevented. It is recommended that National Health Insurance officials utilize these data to evaluate the benefits of enhanced treatment strategies and before making substantial policy changes to haemophilia care in Taiwan. PMID- 20722743 TI - Does haemophilia influence cancer-related mortality in HIV-negative patients? AB - Clinical investigations and animal studies suggest haemophilia specific effects on cancer-related mortality aside from virus induced malignancies. Analysis of results in the literature proposes that coagulation factor deficiency might inhibit cancer metastasis through decreased activation of thrombin. On the other hand, substitution of coagulation factor might increase cancer rates. A review of epidemiological studies was conducted to survey the clinical data on cancer rates. Clinical investigations concerning cancer-related mortality in haemophilia always deal with virus-related malignancies caused by HIV and/or hepatitis C virus (HCV) infections. Therefore, analysis of cancer rates and standardized mortality ratios (SMR) of cancer in the literature was conducted under exclusion of HIV infection and concomitant malignancies like non-Hodgkin-lymphomas and under exclusion of HCV-related deaths caused by liver disease and hepatocellular carcinoma. The survey covers epidemiological studies which report causes of deaths of more than 8000 haemophilia patients, including more than 2700 HIV negative patients. Results show virus independent cancer rates of 8-16% of deaths. Analysis of corresponding SMRs supports the hypothesis that cancer rates, unaffected through HIV or hepatoma, are decreased in haemophilia when compared with the general population. Prospective data collection regarding factor consumption as well as severity of haemophilia in virus negative cancer patients is needed to investigate the interaction between haemophilia and cancer. PMID- 20722745 TI - Gene analysis and prenatal diagnosis for two families of congenital factor V deficiency. AB - We studied two families in which the probands had severe bleeding tendency and showed low plasma levels of coagulation factor V (FV) antigen and activity. Sequence analysis of the FV gene on proband 1 demonstrated a novel G16088C homozygous missense mutation in exon 3 resulting in an Asp 68 to His substitution and on proband 2, a C69969T homozygous missense mutation in exon 23 leading to Gly2079Val. The parents of both families were each heterozygous for the corresponding FV gene defect. During their second pregnancy, the two families requested prenatal diagnosis. Chorionic villi were analysed at 12 weeks of gestation and cord blood samples were tested at 22 weeks. Microsatellite analysis performed in family 1 showed that the foetus sample was not contaminated by maternal tissue. The foetus 1 was found to be heterozygous for the familiar G16088C mutation with lower FV activity in the cord blood; the foetus 2 was a normal one. The diagnosis was confirmed after the birth. This is the first report of prenatal diagnosis for FV deficiency. PMID- 20722746 TI - Haemophilia care in Europe: a survey of 19 countries. AB - In 2009, a questionnaire was circulated to 19 national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The responses received highlighted differences in the level of care despite the recent promulgation of consensus guidelines designed to standardize the care of haemophilia throughout the continent of Europe. There was a wide range in factor VIII consumption with usage ranging from 0.38 IU per capita in Romania to 8.7 IU per capita in Sweden (median: 3.6 IU per capita). Despite the specific inclusion of coagulation factor concentrate in the WHO list of essential medications, cryoprecipitate is still used in some eastern European countries. PMID- 20722744 TI - Impact of HIV on liver fibrosis in men with hepatitis C infection and haemophilia. AB - Hepatitis C virus (HCV) is the major cause of liver disease in haemophilia. Few data exist on the proportion with liver fibrosis in this group after long-term HCV and HIV co-infection. We conducted a cross-sectional multi-centre study to determine the impact of HIV on the prevalence and risk factors for fibrosis in haemophilic men with chronic hepatitis C. Biopsies were independently scored by Ishak, Metavir and Knodell systems. Variables were tested for associations with fibrosis using logistic regression and receiver operating curves (ROC). Of 220 biopsied HCV(+) men, 23.6% had Metavir >= F3 fibrosis, with higher mean Metavir fibrosis scores among HIV/HCV co-infected than HCV mono-infected, 1.6 vs. 1.3 (P = 0.044). Variables significantly associated with fibrosis included AST, ALT, APRI score (AST/ULN * 100/platelet * 10(9) /L), alpha-fetoprotein (all P < 0.0001), platelets (P = 0.0003) and ferritin (P = 0.0008). In multiple logistic regression of serum markers, alpha-fetoprotein, APRI and ALT were significantly associated with >= F3 fibrosis [AUROC = 0.77 (95% CI 0.69, 0.86)]. Alpha fetoprotein, APRI and ferritin were significant in HIV(-) [AUROC = 0.82 (95% CI 0.72, 0.92)], and alpha-fetoprotein and platelets in HIV(+) [AUROC = 0.77 (95% CI 0.65, 0.88]. In a multivariable model of demographic and clinical variables, transformed (natural logarithm) of alpha-fetoprotein (P = 0.0003), age (P = 0.006) and HCV treatment (P = 0.027) were significantly associated with fibrosis. Nearly one-fourth of haemophilic men have Metavir >= 3 fibrosis. The odds for developing fibrosis are increased in those with elevated alpha-fetoprotein, increasing age and past HCV treatment. PMID- 20722747 TI - Ranking hospitals on surgical mortality: the importance of reliability adjustment. AB - OBJECTIVE: We examined the implications of reliability adjustment on hospital mortality with surgery. DATA SOURCE: We used national Medicare data (2003-2006) for three surgical procedures: coronary artery bypass grafting (CABG), abdominal aortic aneurysm (AAA) repair, and pancreatic resection. STUDY DESIGN: We conducted an observational study to evaluate the impact of reliability adjustment on hospital mortality rankings. Using hierarchical modeling, we adjusted hospital mortality for reliability using empirical Bayes techniques. We assessed the implication of this adjustment on the apparent variation across hospitals and the ability of historical hospital mortality rates (2003-2004) to forecast future mortality (2005-2006). PRINCIPAL FINDINGS: The net effect of reliability adjustment was to greatly diminish apparent variation for all three operations. Reliability adjustment was also particularly important for identifying hospitals with the lowest future mortality. Without reliability adjustment, hospitals in the "best" quintile (2003-2004) with pancreatic resection had a mortality of 7.6 percent in 2005-2006; with reliability adjustment, the "best" hospital quintile had a mortality of 2.7 percent in 2005-2006. For AAA repair, reliability adjustment also improved the ability to identify hospitals with lower future mortality. For CABG, the benefits of reliability adjustment were limited to the lowest volume hospitals. CONCLUSION: Reliability adjustment results in more stable estimates of mortality that better forecast future performance. This statistical technique is crucial for helping patients select the best hospitals for specific procedures, particularly uncommon ones, and should be used for public reporting of hospital mortality. PMID- 20722748 TI - Receipt of care and reduction of lower extremity amputations in a nationally representative sample of U.S. Elderly. AB - OBJECTIVE: To determine effectiveness of receipt of care from podiatrist and lower extremity clinician specialists (LEC specialists) on diabetes mellitus (DM) related lower extremity amputation. DATA SOURCES: Medicare 5 percent sample claims, 1991-2007. STUDY DESIGN: Individuals with DM-related lower extremity complications (LECs) were followed 6 years. Visits with podiatrists, LEC specialists, and other health professionals were tracked to ascertain whether receipt of such care reduced the hazards of an LEC amputation. DATA COLLECTION: Individuals were stratified based on disease severity, Stage 1--neuropathy, paresthesia, pain in feet, diabetic amyotrophy; Stage 2--cellulitis, charcot foot; Stage 3--ulcer; Stage 4--osteomyelitis, gangrene. PRINCIPAL FINDINGS: Half the LEC sample died within 6 years. More severe lower extremity disease increased risk of death and amputation. Persons visiting a podiatrist and an LEC specialist within a year before developing all stage complications were between 31 percent (ulceration) and 77 percent (cellulitis and charcot foot) as likely to undergo amputation compared with individuals visiting other health professionals. CONCLUSIONS: Individuals with an LEC had high mortality. Visiting both a podiatrist and an LEC specialist in the year before LEC diagnosis was protective of undergoing lower extremity amputation, suggesting a benefit from multidisciplinary care. PMID- 20722749 TI - Performance characteristics of a methodology to quantify adverse events over time in hospitalized patients. AB - OBJECTIVE: To assess the performance characteristics of the Institute for Healthcare Improvement Global Trigger Tool (GTT) to determine its reliability for tracking local and national adverse event rates. DATA SOURCES: Primary data from 2008 chart reviews. STUDY DESIGN: A retrospective study in a stratified random sample of 10 North Carolina hospitals. Hospital-based (internal) and contract research organization-hired (external) reviewers used the GTT to identify adverse events in the same 10 randomly selected medical records per hospital in each quarter from January 2002 through December 2007. DATA COLLECTION/EXTRACTION: Interrater and intrarater reliability was assessed using kappa statistics on 10 percent and 5 percent, respectively, of selected medical records. Additionally, experienced GTT users reviewed 10 percent of records to calculate internal and external teams' sensitivity and specificity. PRINCIPAL FINDINGS: Eighty-eight to 98 percent of the targeted 2,400 medical records were reviewed. The reliability of the GTT to detect the presence, number, and severity of adverse events varied from kappa=0.40 to 0.60. When compared with a team of experienced reviewers, the internal teams' sensitivity (49 percent) and specificity (94 percent) exceeded the external teams' (34 and 93 percent), as did their performance on all other metrics. CONCLUSIONS: The high specificity, moderate sensitivity, and favorable interrater and intrarater reliability of the GTT make it appropriate for tracking local and national adverse event rates. The strong performance of hospital-based reviewers supports their use in future studies. PMID- 20722751 TI - Long-term follow-up of 11 protease inhibitor (PI)-naive and PI-treated HIV infected patients harbouring virus with insertions in the HIV-1 protease gene. AB - OBJECTIVES: Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long-term viro-immunological follow-up of HIV-infected patients harbouring virus with protease insertions. METHODS: Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected. RESULTS: Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI-naive patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI-naive patients were infected with an HIV-1 non-B subtype. Follow-up of these PI-naive patients showed that the insert containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI-experienced patients, 63% were infected with HIV-1 subtype B; one had been antiretroviral-free for 5 years and seven were heavily PI experienced (median duration of follow-up 24 months; range 10-62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI-resistance mutations, and following long-term exposure to PIs. The insert-containing virus persisted for a median of 32 months (range 12-62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity. CONCLUSION: Our data, obtained during long-term follow-up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI-based regimens, although further work is required to confirm it. PMID- 20722750 TI - The HIV protease inhibitor lopinavir/ritonavir (Kaletra) alters the growth, differentiation and proliferation of primary gingival epithelium. AB - OBJECTIVE: This study was designed to evaluate the effects of the HIV protease inhibitor lopinavir/ritonavir on gingival epithelium growth, integrity and differentiation. METHODS: Organotypic (raft) cultures of gingival keratinocytes were established and treated with a range of lopinavir/ritonavir concentrations. To examine the effect of lopinavir/ritonavir on gingival epithelium growth and stratification, haematoxylin and eosin staining was performed. To investigate the effect of this drug on tissue integrity, transmission electron microscopy (TEM) was performed on untreated and drug-treated tissues. Further, immunohistochemical analysis of raft cultures was performed to assess the effect of lopinavir/ritonavir on the expression of key differentiation and proliferation markers including cytokeratins, proliferating cell nuclear antigen (PCNA) and cyclin A. RESULTS: Lopinavir/ritonavir treatments drastically inhibited the growth of gingival epithelium when the drug was present throughout the growth period of the tissue. When the drug was added on day 8 of tissue growth, lopinavir/ritonavir treatments compromised tissue integrity over time and altered the proliferation and differentiation of gingival keratinocytes. Expression of cytokeratins 5, 14, 10 and 6, PCNA and cyclin A was induced, and their expression patterns were also altered over time in treated rafts. CONCLUSIONS: The findings of our studies suggest that lopinavir/ritonavir treatments compromised tissue integrity over time and deregulated the cell cycle/proliferation and differentiation pathways, resulting in abnormal epithelial repair and proliferation. Our study provides a model of potential utility in studying the effects of antiretroviral drugs in vitro. PMID- 20722752 TI - Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial. AB - OBJECTIVE: The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART). METHODS: Sixty-three HAART-naive patients were randomized to zidovudine/lamivudine+efavirenz or lopinavir/ritonavir+efavirenz. We performed dual energy X-ray absorptiometry (DEXA) at baseline and at weeks 24, 48, 96 and 144 to evaluate lumbar spine and femoral neck (hip) BMD. RESULTS: At baseline, 33 patients (55.9%) had low BMD (T score < -1.0) and of these eight had osteoporosis (T-score < -2.5). Spine BMD declined in both arms until week 24, before stabilizing. In the NRTI-sparing arm, the mean percentage change from baseline was -2.7% [95% confidence interval (CI) 3.9 to -1.4] at week 24 and -2.5% (95% CI -5.4 to 0.3) at week 144, compared with -3.2% (95% CI -4.4 to -2.1) and -1.9% (95% CI -3.5 to -0.3) in the protease inhibitor-sparing arm. Hip BMD declined until week 48 before stabilizing. In the NRTI-sparing arm, BMD had decreased by -5.1% (95% CI -7.1 to -3.1) at week 48 and -4.5% (95% CI -6.9 to -2.1) at week 144, compared with -6.1% (95% CI -8.2 to 4.0) and -5.0% (95% CI -6.8 to -3.1) in the protease inhibitor-sparing arm. There were no significant differences between arms. Low baseline CD4 cell count was independently associated with spine (P=0.007) and hip (P=0.04) BMD loss and low body mass index with hip BMD loss (P=0.03). CONCLUSION: Spine and hip BMD declined rapidly 24 to 48 weeks after initiating HAART, independent of the assigned drug class, but thereafter BMD values remained stable. PMID- 20722753 TI - Root canal debridement using manual dynamic agitation or the EndoVac for final irrigation in a closed system and an open system. AB - AIM: This study examined canal debridement efficacy by testing the null hypothesis that there is no difference between a 'Closed' and an 'Open' system design in smear layer and debris removal using either manual dynamic agitation or the EndoVac for irrigant delivery. METHODOLOGY: Forty teeth were divided into four groups and submitted to a standardized instrumentation protocol. Final irrigation was performed with either manual dynamic agitation or the EndoVac on groups of teeth with or without a sealed apical foramen. Smear and debris scores were evaluated using SEM and analysed using Cochran-Mantel-Haenszel statistic. RESULTS: The ability of manual dynamic agitation to remove smear layer and debris in a closed canal system was significantly less effective than in an open canal system and significantly less effective than the EndoVac (P<0.001). CONCLUSION: The null hypothesis was rejected; the presence of a sealed apical foramen adversely affected debridement efficacy when using manual dynamic agitation but not the EndoVac. Apical negative pressure irrigation is an effective method to overcome the fluid dynamics challenges inherent in closed canal systems. PMID- 20722754 TI - Ex vivo assessment of genotoxicity and cytotoxicity in murine fibroblasts exposed to white MTA or white Portland cement with 15% bismuth oxide. AB - AIMS: To evaluate whether white mineral trioxide aggregate (MTA) or white Portland cement with 15% bismuth oxide were able to induce genetic damage and cellular death ex vivo. METHODOLOGY: Aliquots of 1 * 10(4) murine fibroblasts were incubated at 37 degrees C for 3 h with MTA (white) or white Portland cement with 15% bismuth oxide, at final concentrations ranging from 10 to 1000 MUg mL( 1) individually. Data of three independent repeats from the comet assay and the trypan blue exclusion test were assessed by the one-way anova followed by Tukey's test. RESULTS: Mineral trioxide aggregate or Portland cement containing bismuth oxide did not produce genotoxic effects with respect to the single-cell gel (comet) assay data for all concentrations evaluated. Furthermore, no cytotoxicity was observed for MTA or Portland cement. CONCLUSION: White MTA or white Portland cement containing 15% bismuth oxide were not genotoxic and cytotoxic. PMID- 20722755 TI - Incidence of dentinal defects after root canal filling procedures. AB - AIM: To compare the incidence of dentinal defects (cracks and craze lines) after root canal preparation, lateral compaction and continuous wave compaction of gutta-percha and AH26 sealer. METHODOLOGY: Two hundred mandibular premolar teeth were divided into four groups with similar average canal diameters (n=50). One group was left untreated and served as the control. The other three groups were prepared with ProTaper rotary instruments up to size F4. After preparation, one group was left unfilled while two groups were filled with gutta-percha and AH26 using either lateral compaction or the continuous wave technique. Roots were then sectioned at 3, 6 and 9 mm from the apex and inspected under a microscope. The appearance of dentinal defects was noted as well as the minimum and mean remaining dentine thickness. Chi-square tests were performed to compare the incidence of dentinal defects between the groups (alpha=0.05), and Pearson correlation test was performed to check the correlation between defects and root level or remaining dentine thickness. RESULTS: The unprepared control group had no dentinal defects. The other groups exhibited significantly more defects than the unprepared group (P<0.05). There was no difference in the incidence of defects between the two filling techniques. There was no correlation between the appearance of defects and level of the root or remaining dentine thickness. CONCLUSIONS: In extracted teeth, dentinal defects were observed in roots filled with gutta-percha and AH26 using the lateral compaction and continuous wave techniques. PMID- 20722756 TI - Histological evaluation of the effectiveness of increased apical enlargement for cleaning the apical third of curved canals. AB - OBJECTIVE: To evaluate the influence of apical size on cleaning of the apical third of curved canals prepared with rotary instruments. METHODOLOGY: Forty-four mesiobuccal canals of maxillary molars teeth were instrumented to different apical sizes (30, 0.02; 35, 0.02; 40, 0.02; 45, 0.02) using a crown-down technique. After canal preparation, the apical thirds of the roots were submitted to histological processing and examination. The specimens were analysed at 40* magnification and the images were submitted to morphometric analysis with an integration grid to evaluate the percentage of debris and uninstrumented root canal walls. The action of the instruments on the root canal walls was assessed based on the surface regularity, abrupt change on the continuity of root canal walls, and partial or total pre-dentine removal. The results were statistically compared using one-way anova with post hoc Tukey test. Pearson's correlation was performed to identify potential correlations between values. RESULTS: The percentage of uninstrumented root canal dentine was higher when apical enlargement was performed with instruments 30, 0.02 taper (55.64 +/- 4.62%) and 35, 0.02 taper (49.03 +/- 5.70%) than with instruments 40, 0.02 taper (38.08 +/- 10.44%) and 45, 0.02 taper (32.65 +/- 8.51%) (P < 0.05). More debris were observed when apical enlargement was performed with instruments 30, 0.02 taper (34.62 +/- 9.49%) and 35, 0.02 taper (25.33 +/- 7.37%) (P < 0.05). There was a significant correlation between the amount of remaining debris and the perimeter of uninstrumented root canal dentine (r = 0.9130, P < 0.001). CONCLUSION: No apical enlargement size allowed the root canal walls to be prepared completely. Apical third cleanliness could be predicted by instrument diameter. PMID- 20722757 TI - Influence of bacterial growth modes on the susceptibility to light-activated disinfection. AB - AIM: To evaluate the efficacy of light-activated disinfection (LAD) using methylene blue (MB) and a non-coherent light source on gram-positive and gram negative bacteria in different growth modes. The influence of different photosensitizer (PS) formulations in the MB-mediated LAD of biofilms was also evaluated. METHODOLOGY: Light-activated disinfection using MB was tested on Enterococcus faecalis in a planktonic suspension, coaggregated suspension and mono-species biofilms and on Pseudomonas aeruginosa in a planktonic suspension and mono-species biofilms. Further, the difference in susceptibility of E. faecalis and P. aeruginosa biofilms to LAD with modified PS formulations was assessed by conventional culturing methods and confocal laser scanning microscopy (CLSM). RESULTS: Higher energy dose was required for LAD of bacteria in a coaggregated suspension and in biofilm compared to their planktonic counterparts. Biofilm mode of growth offered the greatest resistance to LAD in both the tested strains of pathogens (P<0.001). Gram-positive E. faecalis was more susceptible to LAD than the gram-negative P. aeruginosa, and the use of modified PS formulations was found to enhance the efficacy of LAD to destroy the biofilm (P<0.001). CONCLUSIONS: Bacterial growth modes play a vital role in influencing the susceptibility to LAD in a dose-dependent manner. The nature of the PS formulation influences the susceptibility of biofilms to LAD. PMID- 20722758 TI - Osteopontin is up-regulated and associated with neutrophil and macrophage infiltration in glioblastoma. AB - Osteopontin (OPN) is a glycophosphoprotein with multiple intracellular and extracellular functions. In vitro, OPN enhances migration of mouse neutrophils and macrophages. In cancer, extracellular OPN facilitates migration of cancer cells via its RGD sequence. The present study was designed to investigate whether osteopontin is responsible for neutrophil and macrophage infiltration in human cancer and in particular in glioblastoma. We found that in vitro mouse neutrophil migration was RGD-dependent. In silico, we found that the OPN gene was one of the 5% most highly expressed genes in 20 out of 35 cancer microarray data sets in comparison with normal tissue in at least 30% of cancer patients. In some types of cancer, such as ovarian cancer, lung cancer and melanoma, the OPN gene was one of those with the highest expression levels in at least 90% of cancer patients. In glioblastoma, the most invasive type of brain tumours/glioma, but not in lower grades of glioma it was one of the 5% highest expressed genes in 90% of patients. In situ, we found increased protein levels of OPN in human glioblastoma versus normal human brain confirming in silico results. OPN protein expression was co localized with neutrophils and macrophages. In conclusion, OPN in tumours not only induces migration of cancer cells but also of leucocytes. PMID- 20722759 TI - Novel role of regulatory T cells in limiting early neutrophil responses in skin. AB - It is clear that CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells inhibit chronic inflammatory responses as well as adaptive immune responses. Among the CD4(+) T-cell population in the skin, at least one-fifth express Foxp3. As the skin is constantly exposed to antigenic challenge and is a common site of vaccination, understanding the role of these skin-resident Treg cells is important. Although the suppressive effect of Treg cells on T cells is well documented, less is known about the types of innate immune cells influenced by Treg cells and whether the Treg cells suppress acute innate immune responses in vivo. To address this we used a mouse melanoma cell line expressing Fas ligand (B16FasL), which induces an inflammatory response following subcutaneous injection of mice. We demonstrate that Treg cells limit this response by inhibiting neutrophil accumulation and survival within hours of tumour cell inoculation. This effect, which was associated with decreased expression of the neutrophil chemoattractants CXCL1 and CXCL2, promoted survival of the inoculated tumour cells. Overall, these data imply that Treg cells in the skin are rapidly mobilized and that this activity serves to limit the amplification of inflammatory responses at this site. PMID- 20722760 TI - Histamine H(4) receptor activation on human slan-dendritic cells down-regulates their pro-inflammatory capacity. AB - 6-Sulpho LacNAc dendritic cells (slanDC) are a major population of human blood DC that are highly pro-inflammatory, as characterized by their outstanding capacity to produce tumour necrosis factor-alpha and interleukin-12 (IL-12) and to prime antigen-specific T-cell responses. SlanDC were found to be present in inflamed tissue such as atopic dermatitis, where high levels of histamine are also present. As histamine is an important regulator of allergic inflammation we investigated the role of histamine receptors, particularly the most recently identified histamine H(4) receptor (H(4) R), in modulating the pro-inflammatory function of slanDC. The expression of H(4) R was evaluated by real-time PCR and flow cytometry. Cytokine production in response to H(4) R stimulation was assessed by intracellular flow cytometric staining and enzyme-linked immunosorbent assay. We show that slanDC express the H(1) R, H(2) R and H(4) R on mRNA and the H(4) R on protein level. No differences were observed in basal H(4) R expression in patients with atopic dermatitis and psoriasis, but in atopic dermatitis patients the H(4) R was up-regulated by interferon-gamma. When stimulated with lipopolysaccharide in the presence of histamine, slanDC produced substantially lower levels of the pro-inflammatory cytokines tumour necrosis factor-alpha and IL-12, mediated solely via the H(4) R and via the combined action of H(2) R and H(4) R, respectively. In contrast, the production of IL-10 was not affected by histamine receptor activation on slanDC. The slanDC express the H(4) R and its stimulation leads to reduced pro-inflammatory capacity of slanDC. Hence, H(4) R agonists might have therapeutic potential to down-regulate immune reactions, e.g. in allergic inflammatory skin diseases. PMID- 20722761 TI - The roles of antigen-specificity, responsiveness to transforming growth factor beta and antigen-presenting cell subsets in tumour-induced expansion of regulatory T cells. AB - In this study we investigated the impact of several factors on the expansion of natural regulatory T (nTreg) cells by tumours, including antigen specificity, transforming growth factor-beta (TGF-beta) signalling and the antigen-presenting cell subsets responsible for expansion. We found that antigen non-specific expansion of nTreg cells is tumour cell line-dependent. Although both antigen specific and non-specific pathways can contribute to expansion, the migration of activated nTreg cells to tumour tissues is strictly antigen-dependent. Intact TGF beta signalling on nTreg cells is also essential for tumour-induced expansion. Finally, for stimulation of resting antigen-specific CD4 T cells, CD11c(+) cells purified from tumour-draining lymph nodes were more potent than CD11b(+) cells, suggesting that dendritic cells are the key antigen-presenting cell subset involved in cross-presentation of tumour antigens. This study not only provides an in vivo system in which cross-talk between nTreg cells and tumours can be explored but also reveals novel aspects of tumour immune evasion. PMID- 20722762 TI - Persistent viral infection in humans can drive high frequency low-affinity T-cell expansions. AB - CD8 T cells that recognize cytomegalovirus (CMV) -encoded peptides can be readily detected by staining with human leucocyte antigen (HLA) -peptide tetramers. These cells are invariably highly differentiated effector memory cells with high avidity T-cell receptors (TCR). In this report we demonstrate an HLA-A*0201 restricted CMV-specific CD8 T-cell response (designated YVL) that represents several percent of the CD8 T-cell subset, yet fails to bind tetrameric major histocompatibility complex (MHC) ligands. However, these tetramer-negative cells are both phenotypically and functionally similar to other CMV-specific CD8 T cells. YVL peptide-specific CD8 T-cell clones were generated and found to be of high avidity in both cytotoxicity and interferon-gamma (IFN-gamma) assays, and comparable with other CMV peptide-specific CD8 T-cell clones. However, under conditions of CD8 blockade, the response was almost nullified even at very high ligand concentrations. This was also the case in IFN-gamma experiments using peripheral blood mononuclear cells stimulated with peptide ex vivo. In contrast, all other CMV specificities (tetramer-positive) displayed minimal or only partial CD8 dependence. This suggests that YVL-specific responses depict a low-affinity TCR-MHC-peptide interaction, that is compensated by substantial CD8 involvement for functional purposes, yet cannot engage multivalent soluble ligands for ex vivo analysis. It is interesting that such a phenomenon is apparent in the face of a persistent virus infection such as CMV, where the responding cells represent an immunodominant response in that individual and may present a highly differentiated effector phenotype. PMID- 20722765 TI - Do androgens play any role in the physical frailty of ageing men? AB - The term frailty describes an age-related state of vulnerable health. The aetiology of this condition is not well understood. A number of mechanisms may contribute to frailty. Amongst these is the possible influence of age-related perturbations of sex hormones, particularly, the fall in testosterone in ageing men. This declining androgenic function has been thought to contribute to the loss of muscle mass (sarcopaenia) and strength that occurs with ageing and thereby underpin the development of frailty. Testosterone replacement has therefore been suggested as a possible intervention to treat frailty. This review summarizes evidence from observational and interventional studies on the effects of testosterone on frailty and its key components including body composition, muscle strength and physical function. Evidence from these studies is considered against study design, methodological issues and in the context of the current understanding of frailty. The role of androgens in the development of frailty and their utility in treating this condition are evaluated. Future research directions for the use of androgens in the treatment of frailty are suggested. The potential interaction between testosterone and other frailty mechanisms and the possibility that secondary components of the sex hormone system may be appropriate frailty biomarkers are also discussed. PMID- 20722764 TI - The tortoise and the hare: slowly evolving T-cell responses take hastily evolving KIR. AB - The killer cell immunoglobulin-like receptor (KIR) locus comprises a variable and rapidly evolving set of genes encoding multiple inhibitory and activating receptors. The activating receptors recently evolved from the inhibitory receptors and both bind HLA class I and probably also class I-like structures induced by viral infection. Although generally considered natural killer (NK) cell receptors, KIR are also expressed by a large fraction of effector memory T cells, which slowly accumulate during human life. These effector memory cells are functionally similar to NK cells, as they are immediate effector cells that are cytotoxic and produce IFN-gamma. However, different rules apply to NK and T cells with respect to KIR expression and function. For example, KIR tend to modulate signals driven by the T-cell receptor (TCR) rather than to act independently, and use different signal transduction pathways to modulate only a subset of effector functions. The most important difference may lie in the rules governing tolerance: while NK cells with activating KIR binding self-HLA are hyporesponsive, the same is unlikely to apply to T cells. We argue that the expression of activating KIR on virus-specific T cells carrying TCR that weakly cross-react with autoantigens can unleash the autoreactive potential of these cells. This may be the case in rheumatoid arthritis, where cytomegalovirus specific KIR2DS2(+) T cells might cause vasculitis. Thus, the rapid evolution of activating KIR may have allowed for efficient NK-cell control of viruses, but may also have increased the risk that slowly evolving T-cell responses to persistent pathogens derail into autoimmunity. PMID- 20722763 TI - Immunoinformatics: an integrated scenario. AB - Genome sequencing of humans and other organisms has led to the accumulation of huge amounts of data, which include immunologically relevant data. A large volume of clinical data has been deposited in several immunological databases and as a result immunoinformatics has emerged as an important field which acts as an intersection between experimental immunology and computational approaches. It not only helps in dealing with the huge amount of data but also plays a role in defining new hypotheses related to immune responses. This article reviews classical immunology, different databases and prediction tools. It also describes applications of immunoinformatics in designing in silico vaccination and immune system modelling. All these efforts save time and reduce cost. PMID- 20722767 TI - Linguistic validation of the N-QOL (ICIQ), OAB-q (ICIQ), PPBC, OAB-S and ICIQ MLUTSsex questionnaires in 16 languages. AB - OBJECTIVE: Overactive bladder (OAB) is a highly prevalent condition with a negative impact on both health-related quality of life and sexual functioning. We aimed to create and validate conceptually equivalent tools to assess OAB for use in diverse cultural and linguistic settings. RESEARCH DESIGN AND METHODS: To evaluate the linguistic validity of harmonised translations of the Nocturia Quality of Life (N-QOL) questionnaire, Overactive Bladder Questionnaire (OAB-q) family, Patient Perception of Bladder Condition (PPBC) questionnaire, Overactive Bladder Satisfaction Questionnaire (OAB-S) and International Consultation on Incontinence Questionnaire (ICIQ) Male Sexual Matters associated with Lower Urinary Tract Symptoms Questionnaire (ICIQ-MLUTSsex), bilingual (target language and English) interviewers cognitively debriefed subjects to assess their ability to paraphrase and understand the instructions, questions and responses within each questionnaire. RESULTS: Overall item comprehension rates were 96% for the N QOL, 98.9% for the OAB-q, 92% for the PPBC, 98.5% for the OAB-S and 94.3% for the ICIQ-MLUTSsex. DISCUSSION: We found that the translations were well-understood by subjects, although a number of minor changes were made to the N-QOL, OAB-q, OAB-S and ICIQ-MLUTSsex translations in an effort to improve clarity and cultural appropriateness. In a few instances, the majority of subjects in a language were unable to paraphrase a specific term or phrase prior to the revisions. In several cases, problems arose from the wording of the question in the source language. CONCLUSIONS: The translated instruments in this study demonstrated a high level of overall linguistic validity. PMID- 20722768 TI - Recombinant factor VIIa for unlicensed indications--a definite No or a cautious Maybe in selected patients? PMID- 20722769 TI - Two percent topical phenytoin sodium solution in treating pyoderma gangrenosum: a cohort study. AB - Oral phenytoin is an extensively used medicine for the treatment of convulsive disorders. Topical phenytoin has also been used for various types of ulcers. To determine the effectiveness of 2% topical phenytoin sodium solution in treating recalcitrant pyoderma gangrenosum. Six patients with treatment-resistant pyoderma gangrenosum who attended to Dermatology Unit/Ward were taken to the study and applied topical 2% phenytoin sodium solution to the wounds alone with other systemic therapy. Response to the treatment was assessed weekly. Three patients had idiopathic PG and other three had secondary diseases. At the end of the 4th week four patients showed complete resolution of the ulcers whereas other two patients showed the partial resolution. No adverse effects were noted. Phenytoin sodium 2% solution is beneficial for pyoderma gangrenosum (PG) with various etiologies. It enhanced the healing of the ulcer especially when the patient has treatment resistant disease. PMID- 20722770 TI - Primary pneumonic plague in the African Green monkey as a model for treatment efficacy evaluation. AB - BACKGROUND: Primary pneumonic plague is rare among humans, but treatment efficacy may be tested in appropriate animal models under the FDA 'Animal Rule'. METHODS: Ten African Green monkeys (AGMs) inhaled 44-255 LD(50) doses of aerosolized Yersinia pestis strain CO92. Continuous telemetry, arterial blood gases, chest radiography, blood culture, and clinical pathology monitored disease progression. RESULTS: Onset of fever, >39 degrees C detected by continuous telemetry, 52-80 hours post-exposure was the first sign of systemic disease and provides a distinct signal for treatment initiation. Secondary endpoints of disease severity include tachypnea measured by telemetry, bacteremia, extent of pneumonia imaged by chest x-ray, and serum lactate dehydrogenase enzyme levels. CONCLUSIONS: Inhaled Y. pestis in the AGM results in a rapidly progressive and uniformly fatal disease with fever and multifocal pneumonia, serving as a rigorous test model for antibiotic efficacy studies. PMID- 20722771 TI - A possible case of hantavirus infection in a Borneo orangutan and its conservation implication. AB - BACKGROUND: Natural infection of hantavirus in orangutans has never been reported. METHODS: Enzyme-linked immunosorbent assays (ELISA), Indirect immunofluorescence assay (IFA), and RT-PCR were used to diagnosis a suspected case in a pet orangutan in southern Taiwan. RESULTS: Although the RT-PCR result was negative, the high IgG titer in the beginning and its dramatic drop after treatments suggested a recent Seoul-type hantavirus infection. CONCLUSIONS: Hantavirus transmission and its potential damage to wild orangutans should not be overlooked. PMID- 20722772 TI - Dentine hypersensitivity in a private practice patient population in Australia. AB - Although dentine hypersensitivity (DH) has been widely investigated, studies based on randomly selected general practice populations are scarce. This study aimed to examine the intra-oral distribution of DH and its association with age, sex, symptoms, stimuli, pre-disposing factors and management strategies in a private practice patient population in Australia. A randomly selected sample of 800 Australian private dental practice dentists was invited to participate in a questionnaire-based survey. A log diary about the total number of patients seen during a typical week in practice and the details of patients with DH were recorded. The details included teeth and sites involved with DH and the age and sex of people affected, symptoms, stimuli, pre-disposing factors and management strategies. The prevalence of DH was 9.1% among patients seen over the typical week with 2.3 teeth/person and 1.2 surfaces/tooth affected. Women (60.7%) were more affected than men (39.3%) whilst 30- to 49 -year-olds (48.8%) were the most common among those affected. Premolars (36.5%) and buccal surfaces (54.8%), respectively, were the most commonly affected teeth and tooth sites. Although cold stimulation (80.1%) was the commonest stimulus, dietary acid was the only stimulus that was significantly associated with DH. Gingival recession and erosion emerged as significant pre-disposing factors, whereas using desensitising toothpastes was the most important management strategy. The findings suggested that dietary acid, gingival recession and erosion were significantly associated with DH, while desensitising toothpastes was the key management strategy used for DH in this patient population. PMID- 20722773 TI - Reliability of novel multidirectional lip-closing force measurement system. AB - This study aimed to quantify the directional specificity of multidirectional lip closing force (LCF) and evaluate the reliability of multidirectional LCF measurements made using a novel system. In fourteen healthy subjects (seven females, seven males, median age = 28 years), LCFs in eight directions and electromyograms (EMGs) from four parts of the orbicularis oris muscles (OOM) were recorded during voluntary pursing-like lip closure tasks. The quantitative reliability was assessed from repeated measurements of the LCFs in the eight directions and from summed values for all eight directions [total lip-closing force (TLCF)]. The intra- and inter-investigator reliabilities for TLCF were assessed by the interclass correlation of the measurements by the same investigator and two investigators, respectively. Lip-closing forces showed directional specificity in vertical, horizontal and oblique directions but those in oblique and horizontal directions were symmetrical bilaterally. The quantitative reliability of measurements was between 0.735 and 0.948 in the eight directions and that of TLCF was 0.934. Interclass correlations of intra- and inter-investigator reliabilities were 0.96 [lower limit of 95% confidence interval (95% LL), 0.87] and 0.96 (95% LL, 0.91), respectively. The intra- and inter-investigator differences of measurements were randomly distributed in the whole range of measurements. The 95% confidence intervals of these differences were significantly narrower than those of the limits of agreement (mean +/- 1.96 s.d.). In 13 subjects, Pearson's correlation coefficients between LCF and EMGs from OOM were above 0.95. We conclude that this system has a reasonable quality and reliability for quantitative measurements of multidirectional LCF for evaluating lip functions. PMID- 20722774 TI - Oral appliance treatment for obstructive sleep apnoea patients with severe dental condition. AB - This clinical report introduces and evaluates the use of a mandibular advancement oral appliance (OA) attached to a denture base for the treatment of obstructive sleep apnoea syndrome (OSAS) in a patient presenting severe dental problems and multiple missing teeth. It concerned a 58-year-old man with moderate OSAS (apnoea index (AI): 15.9 h(-1) ; apnoea hypopnea index (AHI): 21.7 h(-1) ), presenting ten remaining teeth (maxilla: 5, mandible: 5) and important dental and periodontal problems. A treatment OA comprising both maxillary and mandibular parts was fabricated with an acrylic resin base, simulating the structure of a conventional removable partial denture (RPD). The polysomnography examination performed after the use of the OA showed the treatment induced a significant decrease in OSAS symptoms (AI: 0.7 h(-1) , AHI: 8.2 h(-1) ). All the necessary dental and periodontal treatments were performed to assure the reestablishment of oral health. The treatment OA was modified after each treatment to adapt it to each new oral condition. After 18 months, once the oral health was reestablished with seven remaining teeth (maxilla: 5, mandible: 2), final RPDs and final OA were fabricated. Polysomnography with final OA showed a similar positive result with respect to OSAS symptoms. No side effects related to the OA treatment were detected during the 3-year follow-up. To keep a sound oral condition, periodical dental care was performed by specialists in both periodontal and prosthodontic clinics. This clinical report shows the feasibility of treating OSAS patients with OA even in the presence of severe oral conditions and multiple missing teeth. PMID- 20722775 TI - Evidence for dental and dental specialty treatment of obstructive sleep apnoea. Part 1: the adult OSA patient and Part 2: the paediatric and adolescent patient. AB - Until recently, obstructive sleep apnoea was a largely unknown condition. Because of the well-publicised death of some high-profile people resulting from untreated obstructive sleep apnoea, now mostly everyone has heard of the condition. Following diagnosis, several medical treatment modalities are available to patients. However, the role that dentistry and its various specialties can play in successful treatment for obstructive sleep apnoea should not be overlooked. The common causes for adult and paediatric obstructive sleep apnoea will be presented as well as a review of the more successful forms of dental treatment. Finally, a summary of the current evidence regarding obstructive sleep apnoea treatment will be presented. PMID- 20722776 TI - Penile sclerosing lipogranulomas and disfigurement from use of "1Super Extenze" among Laotian immigrants. AB - INTRODUCTION: Subcutaneous penile injection of various oils for penile augmentation has been described among men in Laos. We have now treated three Laotian immigrants with penile disfigurement secondary to sclerosing lipogranulomas, also known as paraffinoma, induced by injection of a mineral oil compound marketed as "1Super Extenze," which they purchased in the United States. AIM: This series describes the clinical course and management of complications associated with the use of "1Super Extenze" in three Laotian men. METHODS: Surgeons excised all grossly affected tissue and performed reconstruction using skin grafting, Z-plasty, and tissue advancement, respectively. Tissue from the penile shaft of each patient and a local lymph node in one patient was examined microscopically. Mass spectroscopy was performed on an aliquot of "1Super Extenze." MAIN OUTCOME MEASURES: Urinary function, sexual function, and cosmesis of the three reported cases, chemical composition of "1Super Extenze," and microscopic analysis of penile and regional lymphatic tissue. RESULTS: Short-term cosmetic and functional outcomes were acceptable after surgical intervention. Histologic findings consistent with sclerosing lipogranulomas were seen in specimens from affected subcutaneous and lymphatic tissue. "1Super Extenze" proved to be composed of mineral oil with tocopherol acetate (vitamin E). CONCLUSION: Injection of "1Super Extenze" into the penile shaft results in sclerosing lipogranulomas, which can cause severe sexual and urinary complications. Surgical resection of all grossly involved tissue with appropriate reconstruction can mitigate these problems. This series supports previous recommendations in the literature that men should avoid the use of non-medical foreign bodies and fillers as means of penile augmentation. PMID- 20722777 TI - Prostate-specific antigen levels are associated with arterial stiffness in essential hypertensive patients. AB - INTRODUCTION: Prostate-specific antigen (PSA) has been recently related to cardiovascular system in a multifactorial way. Arterial stiffness is a independent predictor of cardiovascular events and is involved in the pathogenesis of hypertension. The aim of the present study was to investigate whether PSA values, are associated with arterial stiffness indices in patients with essential arterial hypertension. METHODS: The study comprised 150 consecutive male patients (mean age 60 years) with uncomplicated never-treated essential hypertension. All patients underwent a complete clinical and laboratory evaluation, including measurement of PSA levels. Aortic stiffness and arterial wave reflection assessment was made by using carotid-femoral (PWVc-f) pulse wave velocity and aortic augmentation index corrected for heart rate (AIx75). Patients with prostate cancer or benign prostate hyperplasia (PSA > 4 ng/mL) were excluded from the study. RESULTS: PSA was positively associated with waist-to-hip ratio (r = 0.235, P = 0.04), PWVc-f (r = 0.426, P < 0.001), AIx75 (r = 0.264, P = 0.001), and high sensitivity C-reactive protein (hsCRP; r = 0.376, P < 0.001). In categorization to PSA quartiles, patients in the higher quartile presented with higher waist-to hip ratio (P = 0.009), PWVc-f (P < 0.00001), AIx75 (P < 0.001) and hsCRP (P < 0.001) values. In multivariate analysis after adjustment for various confounders PSA remained a significant determinant of PWVc-f values (beta [SE] = 0.477 [0.13], R(2) = 0.405, P < 0.001). CONCLUSION: The present study points towards an association between PSA levels and aortic stiffness in untreated essential hypertensive males. Potential causal relationships between PSA and arterial stiffness remain to be further explored. PMID- 20722778 TI - Measuring women's satisfaction with treatment for sexual dysfunction: development and initial validation of the Women's Inventory of Treatment Satisfaction (WITS 9). AB - AIM: To develop a brief, psychometrically sound, measure of satisfaction with treatment for female sexual arousal disorder. METHOD: In Phase 1, women in focus groups generated items measuring satisfaction with treatment for arousal disorder. In Phase 2, expert clinicians/researchers and women with self-reported female sexual arousal disorder (FSAD) assessed the content validity of the items. In Phase 3, women enrolled in a double-blind treatment trial for female sexual dysfunction completed the Women's Inventory of Treatment Satisfaction (WITS) and the Female Sexual Function Inventory (FSFI) to provide reliability and validity information. MAIN OUTCOME MEASURES: WITS and FSFI. RESULTS: In Phase 2, 36 items demonstrated adequate content validity. In Phase 3, 20 items correlated with symptom improvement on the FSFI arousal subscale. Factor analysis sorted these items into three dimensions: initiation/receptivity satisfaction, treatment satisfaction, and perceived partner satisfaction. The three items with the highest loadings on each factor formed the WITS-9. Internal consistency (alpha) reliability coefficients for the total WITS-9 score and the three subscale scores were 0.92, 0.93, 0.92, and 0.79, respectively. Correlations of WITS-9 scores with the FSFI change scores for subgroups with different sexual dysfunctions offer construct validity support that the WITS-9 measures treatment satisfaction for women with a variety of sexual dysfunctions. CONCLUSION: The WITS-9 is a brief, psychometrically sound scale that is useful for assessing treatment satisfaction in women with sexual dysfunctions. While the WITS-9 is promising, further work needs to be done to obtain reliability and validity information in additional samples. PMID- 20722779 TI - Evaluation of quality of life and sexual satisfaction in women suffering from chronic pelvic pain with or without endometriosis. AB - INTRODUCTION: Chronic pelvic pain (CPP) is one of the most frequent symptoms in women of reproductive age. This is an enigmatic clinical condition that results from the complex interactions of physiological and psychological factors with direct impact on the social, marital, and professional lives of women. AIM: To evaluate the quality of life and sexual satisfaction of women who suffer from CPP with or without endometriosis. METHOD: Forty-nine patients who had been diagnosed with endometriosis and 35 patients with CPP diagnosed with another gynecological condition, all 84 of whom were treated at the Chronic Pelvic Pain and Endometriosis Clinic at Universidade Federal de Sao Paulo (UNIFESP) from January to July of 2008. The controls were 50 healthy women from the Family Planning Clinic at UNIFESP. MAIN OUTCOME MEASURES: World Health Organization Quality of Life Assessment-Bref (WHOQOL-BREF) quality of life questionnaire and the Golombok Rust Inventory of Sexual Satisfaction (GRISS). RESULTS: No statistically significant differences were observed between the groups with CPP symptoms, in either the results from the WHOQOL-BREF or in the GRISS questionnaire. In both questionnaires, differences were observed when the two groups of symptomatic women were compared with the group of healthy women. CONCLUSION: CPP caused by endometriosis or other gynecological conditions leads to a significant reduction of quality of life and sexual satisfaction. PMID- 20722780 TI - Impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility. AB - INTRODUCTION: Previous reports linked varicocele in infertile males with Leydig cell dysfunction and hypogonadism. AIM: The aim of this study was to determine the impact of varicocelectomy on serum total testosterone (TT) level and erectile function in men with infertility and clinical varicocele. METHODS: This study included 141 heterosexual infertile men diagnosed to have clinical varicocele. They were divided into two groups: group 1 (103 men), who had microsurgical varicocelectomy, and group 2 (38 patients), who decided to pursue assisted reproduction procedures. All participants completed the International Index of Erectile Function (IIEF)-5 questionnaire and underwent semen analysis. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and TT were measured both at recruitment time and 6 months later. MAIN OUTCOME MEASURE: Changes in serum TT and IIEF-5 following varicocelectomy. RESULTS: In group 1, the mean TT level increased significantly post varicocelectomy (379.1 +/- 205.8 to 450.1 +/- 170.2 ng/dL, P < 0.0001). No similar change was found in group 2. Out of the 49 patients in group 1 with hypogonadism at baseline assessment (TT < 300 ng/dL), 37 (75.5%) exhibited a postoperative normalization of TT. However, only 3/15 hypogonadal men (20%) in group 2 had normal testosterone levels at the second visit. IIEF-5 scores improved significantly postoperatively in patients with hypogonadism (17.1 +/- 2.6 to 19.7 +/- 1.8, P < 0.001). Neither operating vein diameter 3.6 +/- 0.57 mm nor testicular size 10.46 +/- 3.3 mL correlated with the mean change in TT (71.1 +/- 101.2 ng/dL) (r = 0.162, P = 0.183 and r = -0.077, P = 0.536, respectively). CONCLUSIONS: Varicocele is associated with hypogonadism in some infertile patients. Varicocelectomy significantly improves serum testosterone in infertile men, especially those with hypogonadism. This improvement in TT level may be reflected in the IIEF score. PMID- 20722781 TI - Increased risk of stroke among men with erectile dysfunction: a nationwide population-based study. AB - INTRODUCTION: Previous cross-sectional studies have suggested that erectile dysfunction (ED) represents an independent risk factor for future cardiovascular events. However, very few studies have attempted to examine the association between ED and subsequent stroke. AIM: The aim of this study is to estimate the risk of stroke during a 5-year follow-up period after the first ambulatory care visit for the treatment of ED using nationwide, population-based data and a retrospective case-control cohort design in Taiwan. METHODS: This study used data sourced from the "Longitudinal Health Insurance Database." The study cohort comprised 1,501 patients who received a principal diagnosis of ED between 1997 and 2001 and 7,505 randomly selected subjects as the comparison cohort. Each patient (N = 9,006) was then individually tracked for 5 years from their index ambulatory care visit to identify those who had diagnosed episodes of stroke. MAIN OUTCOME MEASURE: Stratified Cox proportional hazard regressions were performed as a means of comparing the 5-year stroke-free survival rate for the two cohorts. RESULTS: Of the sampled patients, 918 (10.2%) developed stroke within the 5-year follow-up period, that is, 188 individuals (12.5% of the patients with ED) from the study cohort and 730 individuals (9.7% of patients in the comparison cohort) from the comparison cohort. The log-rank test indicated that patients with ED had significantly lower 5-year stroke-free survival rates than those in the comparison cohort (P < 0.001). After adjusting for the patient's monthly income, geographical location, hypertension, diabetes, coronary heart disease, peripheral vascular disease, atrial fibrillation, and hyperlipidemia, patients with ED were more likely to have a stroke during the 5 year follow-up period than patients in the comparison cohort (hazard ratio = 1.29, 95% confidence interval = 1.08 - 1.54, P < 0.01). CONCLUSIONS: These results suggest that ED is a surrogate marker for future stroke in men. PMID- 20722782 TI - Inflatable penile prosthesis placement in men with Peyronie's disease and drug resistant erectile dysfunction: A single-center study. AB - INTRODUCTION: Erectile dysfunction (ED) frequently accompanies Peyronie's disease (PD) and changes the therapeutic approach. AIM: To evaluate a single-center experience with inflatable penile prostheses (IPP) in men with medication refractory ED and PD. METHODS: Ninety men underwent placement of an IPP with straightening maneuvers as necessary to address their deformity and ED. MAIN OUTCOME MEASURES: Preoperative assessment included International Index of Erectile Function-erectile function domain (IIEF-EF) and duplex ultrasound to confirm ED and measure erect deformity. Postoperative assessment included a modified Erectile Dysfunction Index of Treatment Satisfaction (EDITS) questionnaire, as well as office visits at 1, 6, and every 12 months thereafter. RESULTS: Complete chart review was performed with mean follow-up of 49 months. Mean preoperative IIEF-EF score was 11. Full rigidity was not obtained in any patient during duplex ultrasound. Mean curvature at maximum erection was 53 degrees . There were seven mechanical failures requiring device replacement, two revision surgeries for pump or reservoir malposition, one infected device, and two corporoplasties for distal tunica erosion. Postoperative office assessment revealed a functionally straight (i.e., <20 degrees ) erect penis and a properly positioned as well as operational device in all patients. The modified EDITS questionnaire was returned by 56 (62%). Overall, 84% of patients were satisfied with their outcome, yet only 73% were satisfied with their straightness. Patient perceived postoperative curvature correction stabilized quickly and was complete by 3 months in 84% of patients. Satisfaction with ease of inflation, deflation, and concealability was 84%, 71%, and 91%, respectively. Coital activity was reported by 91% of men in this group. CONCLUSION: In men with PD and ED, IPP placement allowed reliable and satisfactory coitus for the great majority of men. Mechanical failure was 7%. Men with PD undergoing IPP placement should be counseled regarding potential penile length loss and residual curvature, neither of which appeared to interfere with coitus but may reduce satisfaction. PMID- 20722783 TI - Replication of psychometric properties of the FSFI and validation of a modified version (FSFI-LL) assessing lifelong sexual function in an unselected sample of females. AB - INTRODUCTION: The 19-item Female Sexual Function Index (FSFI) is an easy-to administer self-report questionnaire, allowing multidimensional assessment of female sexual function and female sexual dysfunction (FSD) over the past 4 weeks. However, studies aiming to dissect the underlying pathoetiology-especially biophysiological factors-often require assessment of sexual function over a broader time frame. AIM: The purpose of this study was to develop a modified version of the widely used FSFI which allows assessment of women's lifelong sexual function-the FSFI-LL-and to evaluate the psychometric properties and aptness of this new version. METHODS: A total of 1,589 unselected female twins from the TwinsUK registry completed both original and new versions of the FSFI. After applying exclusion criteria, 1,489 women were eligible for this study. MAIN OUTCOME MEASURE: Reliability was tested using Cronbach's alpha coefficient. Construct validity was evaluated by exploratory factor analysis and confirmatory factor analysis (CFA). Domain response differences between the original FSFI and the FSFI-LL were assessed using unpaired t-tests. RESULTS: The modified FSFI-LL showed adequate internal consistency reliabilities for all six dimensions and the total score (Cronbach's alpha = 0.79 - 0.92). Principal component analysis resulted in a best fitting five-factor solution. CFA confirmed the underlying domain structure to be same as for the FSFI, supporting the factorial validity of the modified questionnaire. In addition, successful replication of the psychometric properties of the original FSFI was demonstrated. CONCLUSIONS: The results provide evidence of good reliability and validity of the FSFI-LL. This modified version therefore represents a suitable tool for screening lifelong sexual function in women and can be applied in trials investigating etiological factors contributing to more enduring patterns of FSD. PMID- 20722784 TI - Time course of recovery of erectile function after radical retropubic prostatectomy: does anyone recover after 2 years? AB - INTRODUCTION: Given the paucity of literature on the time course of recovery of erectile function (EF) after radical prostatectomy (RP), many publications have led patients and clinicians to believe that erections are unlikely to recover beyond 2 years after RP. AIMS: We sought to determine the time course of recovery of EF beyond 2 years after bilateral nerve sparing (BNS) RP and to determine factors predictive of continued improved recovery beyond 2 years. METHODS: EF was assessed prospectively on a 5-point scale: (i) full erections; (ii) diminished erections routinely sufficient for intercourse; (iii) partial erections occasionally satisfactory for intercourse; (iv) partial erections unsatisfactory for intercourse; and (v) no erections. From 01/1999 to 01/2007, 136 preoperatively potent (levels 1-2) men who underwent BNS RP without prior treatment and who had not recovered consistently functional erections (levels 1 2) at 24 months had further follow-up regarding EF. Median follow-up after the 2 year visit was 36.0 months. MAIN OUTCOME MEASURES: Recovery of improved erections at a later date: recovery of EF level 1-2 in those with level 3 EF at 2 years and recovery of EF level 1-3 in those with level 4-5 EF at 2 years. RESULTS: The actuarial rates of further improved recovery of EF to level 1-2 in those with level 3 EF at 2 years and to level 1-3 in those with level 4-5 EF at 2 years were 8%, 20%, and 23% at 3, 4, and 5 years postoperatively, and 5%, 17%, and 21% at 3, 4, and 5 years postoperatively, respectively. Younger age was predictive of greater likelihood of recovery beyond 2 years. CONCLUSION: There is continued improvement in EF beyond 2 years after BNS RP. Discussion of this prolonged time course of recovery may allow patients to have a more realistic expectation. PMID- 20722785 TI - Endothelial nitric oxide synthase polymorphisms and erectile dysfunction: a meta analysis. AB - INTRODUCTION: Erectile dysfunction (ED) is a common disorder noted for affecting quality of life. Several studies have reported the influence of endothelial nitric oxide synthase (eNOS) polymorphisms on ED susceptibility. However, results of association studies with individually low statistical power are conflicting. AIM: Our study aimed to carry out a meta-analysis estimating the association between eNOS variants and the risk of ED. METHODS: Studies regarding the association between eNOS polymorphisms and ED were searched in Medline and Embase databases. The relevant studies that met the inclusion criteria were eligible for the analysis. MAIN OUTCOME MEASURES: Five genetic models and a generalized odds ratio (OR(G) ) were used to estimate the association between eNOS G894T and variable number of 27-bp tandem repeats in intron 4 (4 VNTR) and the risk of ED. RESULTS: Nine articles were included in our meta-analysis. Overall, significant association between the 894T variant and an increased risk of ED was derived for all genetic contrasts except for the recessive model (allele contrast: OR = 1.64, 95% confidence interval [CI]: 1.03-2.60). The meta-analysis based on the OR(G) also produced significant results: OR(G) = 1.64, 95% CI: 1.03-2.61. Significant heterogeneity and publication bias were detected. The cumulative meta-analysis showed the OR increased from 2003 to 2009 and then declined in 2010. Instability in the relative change of OR was observed. Regarding 4 VNTR and its association with ED, the overall analysis showed a lack of significant association (OR = 0.96, 95% CI: 0.72-1.28). No evidence for heterogeneity among studies was observed. Subgroup analysis by ethnicity and recruitment strategy also yielded nonsignificant results. CONCLUSION: The result supports that G894T variant is associated with an increase in the risk of ED. No evidence for a significant association between 4VNTR and ED is observed. The results of the present meta analysis should be interpreted with caution. Further confirmation in large and well-designed studies is needed. PMID- 20722786 TI - The job satisfaction of female sex workers working in licensed brothels in Victoria, Australia. AB - INTRODUCTION: Previous studies have examined sex workers' attitudes to work but not their levels of job satisfaction compared with other occupations. AIM: The job satisfaction levels and standards of living of sex workers in licensed brothels in Victoria were compared with Australian women. MAIN OUTCOME MEASURES: Responses to a questionnaire that included questions about sex work and their "most likely alternative job." Survey data was compared with identical questions from the Households, Income and Labour Dynamics in Australia Survey. METHODS: A structured survey was undertaken with sex workers in Victoria attending a a sexual health service. RESULTS: Of the 112 sex workers who agreed to participate in the study, 85 (76%) completed the survey. The median years women had been working as sex workers was three (range 0.1-18). The main reasons women started sex work was because "they needed the money" (69%), were attracted to the flexible hours (44%) or had a particular goal in mind (43%). The two biggest concerns women had about sex work were their safety (65%) and the risk of sexually transmitted infections (65%). When compared with the median job satisfaction scores of Australian women working in sex workers' "most likely alternative jobs," 50% of sex workers reported a higher median satisfaction score for sex work in relation to hours worked, 47% in relation to flexibility, 43% in relation to total pay, 26% in relation to job security, 19% in relation to the work itself, and 25% in relation to overall job satisfaction. CONCLUSIONS: Women reported that they primarily do sex work for financial gain although a significant minority prefer it to other work they would be likely to do. These results should be interpreted in the context that the presence of personality disorders that are common among sex workers were not measured in this study. PMID- 20722787 TI - Pulse pressure independently predicts major cardiovascular events in younger but not in older subjects with erectile dysfunction. AB - INTRODUCTION: Pulse pressure (PP; i.e., the arithmetic difference between systolic and diastolic blood pressure) has been suggested to be an independent cardiovascular risk (CV) factor in the general population. We previously also reported a negative association between PP and arteriogenic erectile dysfunction (ED). This finding has recently been questioned. AIM: To verify the association of PP with ED severity and to evaluate its role in predicting forthcoming CV events. METHODS: This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our Andrological Unit for ED. MAIN OUTCOME MEASURES: Several hormonal and biochemical parameters were studied, along with SIEDY structured interviews and penile Doppler ultrasound. RESULTS: Subjects with PP in the lowest quartile (I: 20-45; II: 46-55; III: 56-62; IV: 63-115 mm Hg) had a significant reduction in the risk of severe ED (RR = 0.60[0.47-0.76]; P < 0.0001). When the same analysis was repeated as a function of age quartile (I = 17-44, II = 45-55, III = 56-62, and IV = 63-88 years old), after adjusting for testosterone levels, mean blood pressure, Chronic Disease Score, and body mass index, PP was inversely related to ED only in the youngest age group. During a mean follow up of 4.4 +/- 2.6 years, 147 major cardiovascular events (MACE) were observed. In a Cox regression model, after adjusting for possible confounding factors, a lower PP was associated with a lower risk of MACE in the whole sample and in younger subjects, but not in the older ones. CONCLUSIONS: Checking for blood pressure in ED subjects and calculating PP should become a routine practice in sexual medicine. In younger individuals, low PP reflects not only sexual health (better erection) but also cardiovascular health (less prevalence of MACE). PMID- 20722788 TI - Recreational use of phosphodiesterase type 5 inhibitors by healthy young men. AB - INTRODUCTION: In recent years, PDE5 inhibitors (PDE5i) use has become more popular among men without ED to enhance sexual performance. However, reports in the literature are scarce. AIM: The aim of this study was to evaluate the recreational use of PDE5i in healthy young men. MAIN OUTCOME MEASURES: We evaluated the recreational use of PDE5i among young and healthy men, their main reasons for use, how they were obtained these drugs, and the combination with alcohol or other drugs. METHODS: Descriptive, transversal study consisting in 400 brief surveys with structured multiple choice and open questions. Nonprobability samples (quota samples) included young men between 18 and 30 years of age in a public area (high schools, universities, and gyms) between August and November 2009. Collecting the questionnaires in a sealed box enforced confidentiality. The survey included demographic and sexual health data and PDE5i use characteristics. For statistical analysis we used Fisher's exact and Mann-Whitney tests. RESULTS: A total of 321 questionnaires were appropriate for the purposes of evaluation. Mean age and standard deviation were 25.1+/-3.3 years old. Regarding PDE5i use, 69 men (21.5%) mentioned trying the pill (being sildenafil the most commonly used one) at least one time in their lives and 37 (53.4%) men combined it with alcohol or drugs. Referred sources of acquisition PDE5i were 75.4% (N=52) from a friend, 17.4% (N=15) from a pharmacy/drugstore without a medical prescription, 4.3% (N=3) prescribed by a physician and 2.9% (N=2) through Internet. There were several reasons for taking PDE5i related to sexual confidence, erection quality, and better sexual performance. CONCLUSION: According to our results, 21.5% of healthy men between 18 and 30 years old used PDE5i as a recreational drug, mostly associated with alcohol or other drugs without medical control. This could have led to misuse and a public health problem. Further studies are needed to evaluate not only PDE5i recreational use prevalence, but also psychosocial determinants, long term safety, misuse, and abuse related to it. PMID- 20722789 TI - Safety of physiological testosterone therapy in women: lessons from female-to male transsexuals (FMT) treated with pharmacological testosterone therapy. AB - INTRODUCTION: The safety of long-term physiological doses of testosterone (T) therapy in women with sexual dysfunction is a contentious issue, in part, because of fear of adverse effects, such as breast cancer, vascular disease, and excessive virilization. This unsubstantiated fear has hampered progress in treating women with sexual dysfunction using T therapy in physiological doses to achieve circulating levels in the normal range. AIM: To examine evidence derived from studies in female-to-male transsexuals (FMT) treated with supraphysiological (pharmacological) doses of T for long periods of time with no apparent major adverse effects. METHODS: A comprehensive literature search of relevant articles published between 1980 and 2010 pertaining to the topic of T in FMTs was performed using PubMed. The following key words were used: female-to-male transsexuals; testosterone; virilization; gender re-assignment; and androgen therapy in women. Relevant articles were retrieved, reviewed, and the information was analyzed and evaluated for study methodology and major findings. MAIN OUTCOME MEASURES: Data from peer-reviewed publications were critically analyzed and the information was summarized. RESULTS: The data from the studies reported in the literature to date strongly suggest that treatment of FMTs with supra physiological doses of T had minimal adverse effects. No increase in mortality, breast cancer, vascular disease, or other major health problems were reported. CONCLUSIONS: No significant serious adverse effects were reported in FMTs treated with pharmacological doses of T. In light of the findings with supraphysiological doses of T, we suggest that treatment with T at doses producing physiological levels in women with sexual dysfunction are expected to produce limited and minimal adverse effects. PMID- 20722790 TI - Sexual function in obese women with and without binge eating disorder. AB - INTRODUCTION: Binge eating disorder (BED) is highly prevalent among individuals seeking treatment for obesity. No controlled studies assessing the sexual functioning of these patients have been published so far. AIM: To investigate the sexual functioning of a clinical sample of obese women affected by BED, comparing them with obese non-BED patients (Ob), and with normal weight controls. METHODS: A consecutive series of 107 obese BED and 110 obese non-BED patients referring for the first time to the Clinic for Obesity of the University of Florence, together with a control group of 92 normal weight subjects, were studied. MAIN OUTCOME MEASURES: Patients were studied by means of the Structured Clinical Interview for DSM-IV and the Female Sexual Function Index (FSFI). Moreover, several self-reported questionnaires assessing the eating specific and general psychopathology were used. RESULTS: BED and obese non-BED probands reported a lower sexual activity compared to controls, in terms of absence of sexual intercourse rate, and sexual intercourse frequency. BED patients showed lower FSFI total and subscales scores compared to Ob, and Ob probands reported lower scores compared to controls. According to the multiple linear regression analysis, emotional eating was the main determinant of FSFI scores (FSFI total score, desire, arousal, lubrication, orgasm, satisfaction) for both BED and Ob patients, while impulsivity (inversely associated with FSFI total, orgasm, and pain) and shape concern (inversely associated with arousal, lubrication, orgasm) were main determinants for BED patients only. CONCLUSIONS: BED patients, compared to obese non-BED and controls, have worse sexual functioning, which is associated with high levels of emotional eating, impulsivity, and shape concerns. The relationship between sexual functioning and eating psychopathology should be carefully addressed in obese patients with and without BED. PMID- 20722791 TI - Parturition after vestibulectomy. AB - INTRODUCTION: Provoked vestibulodynia is the most common cause of sexual pain in premenopausal women. Vulvar vestibulectomy has been shown to be an effective treatment. AIM: To determine the optimum route of parturition in women who become pregnant after vulvar vestibulectomy. METHODS: All women who underwent a complete vulvar vestibulectomy by one of four surgeons were contacted between 12 and 72 months after surgery. For all women who had a term pregnancy and subsequent delivery, the research assistant abstracted data from the charts. Descriptive statistics were applied. MAIN OUTCOME MEASURES: The number of women who underwent a delivery after a vestibulectomy, mode of delivery, and rate of perineal lacerations. RESULTS: Of 109 women, 44 (40%) had undergone at least one term pregnancy and delivery; 23 (52%) were vaginal, and 21 (48%) were cesarean deliveries. Of the vaginal deliveries, 11 (48%) were over an intact perineum. Three (13%) women had a midline episiotomy, none of which extended into third or fourth degree lacerations and one woman (4.4%) sustained a spontaneous fourth degree perineal laceration. CONCLUSIONS: Vaginal delivery after vulvar vestibulectomy appears to be a safe option, with no increased perineal morbidity above the general population. Furthermore, it is not an indication for a cesarean delivery. PMID- 20722792 TI - Simple strategies for vaginal health promotion in cancer survivors. AB - INTRODUCTION: With the population of cancer survivors nearing 12 million, an ever increasing number of women will face vaginal health issues related to their disease and/or treatment. Abrupt menopause triggered by cancer treatment, for example, can cause intense and prolonged estrogen deprivation symptoms, including vaginal dryness and discomfort. Simple strategies to promote vaginal health are available. AIMS: To provide a comprehensive overview of vaginal health issues caused by estrogen deprivation in female cancer patients/survivors and provide recommendations to identify, treat, and promote vaginal health. METHODS: We describe a treatment algorithm, based on scientific literature and supported by clinical experience, found to be effective in treating these patients at two major cancer centers. We also provide examples of handouts for patient education on vaginal health promotion. MAIN OUTCOME MEASURES: Evidence-based medicine and psychosocial literature, in addition to clinical experience at two major cancer centers. RESULTS: Simple, non-hormonal interventions for sexual dysfunction are often overlooked. Several studies show that education on vaginal lubricants, moisturizers, and dilator use (as needed) can decrease the morbidity of vaginal atrophy. These studies also provide support for our clinical treatment recommendations. Our goal in this article is to increase awareness of these strategies and to provide assistance to general gynecologists and oncologists caring for cancer patients and survivors. CONCLUSIONS: Dedicating a small amount of time to educate female cancer survivors about methods to promote vaginal health can result in the reduction or elimination of vaginal discomfort. Non hormonal vaginal health strategies often appear sufficient to remedy these issues. However, large randomized trials are needed, varying the format and components of the treatment program and exploring efficacy in various groups of female cancer survivors. PMID- 20722793 TI - Medicinal plants as alternative treatments for female sexual dysfunction: utopian vision or possible treatment in climacteric women? AB - INTRODUCTION: Female sexual dysfunction (FSD) is a complex and multifactorial condition. An increased incidence of FSD is especially associated with the decline of estrogen. Thus, menopause is a critical phase for FSD complaints. In this context, medicinal plants may be a therapeutic option. AIM: To identify and describe the popular and clinical uses of medicinal plants for FSD treatment in climacteric women. We highlighted the majority of the plants commonly involved with the female reproductive system including: Angelica sinensis, Cimicifuga racemosa, Ferula hermonis, Ginkgo biloba, Humulus lupulus, Lepidium meyenii, Tribulus terrestris, Trifolium pratense, and Vitex agnus-castus. METHODS: This study is a narrative review of studies of plants that are possible alternative treatments for FSD. The species described have clinical and popular uses in different cultures as well as medical indications for female reproductive disturbances, mainly in climacteric women. We have also analyzed the evidence level of clinical studies. MAIN OUTCOME MEASURES: The main outcome assessed is the efficacy of plants in improving the symptoms of FSD. RESULTS: There is little evidence from the literature to recommend the use of medicinal plants when treating FSD. The majority of studies with a strong level of evidence are associated with the treatment of the vasomotor symptoms of menopause. Ferula hermonis, Angelica sinensis, and Gingko biloba may be suggested for arousal disorder studies. Cimicifuga racemosa, Trifolium pratense, and Vitex agnus-castus may be recommended for several FSD. Humulus lupulus and Tribulus terrestris may help with desire disorder studies. Lepidium meyenii should be studied further. CONCLUSIONS: Studies of these plants indicate that they may be useful as a possible alternative and/or complementary approach for studies aimed at the treatment of FSD. At this time, however, this review cannot recommend a plant that has a strong enough level of evidence for treatment of FSD. Thus, there is a need for clinical (double-blinded and randomized) studies to evaluate the efficacy and safety of several plants that can exert a positive effect on the management of FSD. PMID- 20722795 TI - Chinese version of the Pain Assessment in Advanced Dementia Scale: initial psychometric evaluation. AB - AIM: This paper is a report of the validity and reliability testing of the Chinese version of the Pain Assessment in Advanced Dementia Scale (PAINAD-C). BACKGROUND: Pain is under-reported and under-treated for people with dementia, largely due to impairment of communication. An adequate instrument for assessment of pain in this population is essential to improving their quality of life and decreasing disability and behavioural disturbances, but none were found that were appropriate for these purposes. METHOD: The PAINAD-C was developed in three phases in 2006. First, back-translation was used to create the Chinese version, where five medical and nursing experts assessed content validity. Inter-rater reliability, internal consistency reliability and test-retest reliability were then examined. Finally, principal component analysis and known-group comparisons were used to test construct validity. Participants with dementia were selected from five licensed long-term care facilities in Taiwan. Direct observation was used to collect data. RESULTS: Inter-rater reliability showed an intra-class correlation coefficient of 0.80-0.86, and a test-retest reliability intra-class correlation coefficient of 0.71. The internal consistency reliability was 0.55 0.66. Factor analysis of the PAINAD-C showed two factors that explained 62.48% of variance. The PAINAD-C scores showed statistically significant differences between the non-dementia group and the advanced dementia group as well as significant differences between activities and rest groups. CONCLUSION: The PAINAD-C is useful in a clinical setting for people with advanced dementia for both research and practice. It is easy to use and is a comprehensive instrument. PMID- 20722796 TI - What informs parents' decision-making about childhood vaccinations? AB - AIM: This paper is a report of a study conducted to identify parents' decision making processes in relation to childhood vaccinations, including barriers and facilitators to searching for information. BACKGROUND: Decision-making about childhood vaccinations is complex. Access to the best available evidence and the ability to obtain and understand such information are necessary for effective participation in decision-making. METHODS: A grounded theory approach was used, with semi-structured interviews and focus groups with parents (n = 10) and public health nurses (n = 16) conducted in 2008. Data were derived through incident-to incident and axial coding. FINDINGS: Being positive towards vaccination and being decided were found to be main barriers to participation and obtaining information; other factors were perceptions about own abilities and capacity. Public health nurses were the parents' most important source of information, but tended to inform to facilitate vaccinations. Issues related to this and being inadequately informed were that some parents expressed low confidence about the decision they had made and uncertainty about their rights and responsibilities in decision-making. CONCLUSION: Information delivered by public health nurses should not facilitate a specific choice but rather be balanced, explaining the benefits and harms, and accompanied by a qualified recommendation. Useful tools to improve practice may include checklists for shared decision-making and guidelines about trustworthy websites. PMID- 20722794 TI - Nitric oxide-induced vasorelaxation in response to PnTx2-6 toxin from Phoneutria nigriventer spider in rat cavernosal tissue. AB - INTRODUCTION: Priapism is one of several symptoms observed in accidental bites by the spider Phoneutria nigriventer. The venom of this spider is comprised of many toxins, and the majority has been shown to affect excitable ion channels, mainly sodium (Na(+) ) channels. It has been demonstrated that PnTx2-6, a peptide extracted from the venom of P. nigriventer, causes erection in anesthetized rats and mice. AIM: We investigated the mechanism by which PnTx2-6 evokes relaxation in rat corpus cavernosum. MAIN OUTCOME MEASURES: PnTx2-6 toxin potentiates nitric oxide (NO)-dependent cavernosal relaxation. METHODS: Rat cavernosal strips were incubated with bretylium (3 * 10(-5) M) and contracted with phenylephrine (PE; 10(-5) M). Relaxation responses were evoked by electrical field stimulation (EFS) or sodium nitroprusside (SNP) before and after 4 minutes of incubation with PnTx2 6 (10(-8) M). The effect of PnTx2-6 on relaxation induced by EFS was also tested in the presence of atropine (10(-6) M), a muscarinic receptor antagonist, N-type Ca(2+) channel blockers (omega-conotoxin GVIA, 10(-6) M) and sildenafil (3 * 10( 8) M). Technetium99m radiolabeled PnTx2-6 subcutaneous injection was administrated in the penis. RESULTS: Whereas relaxation induced by SNP was not affected by PnTx2-6, EFS-induced relaxation was significantly potentiated by this toxin as well as PnTx2-6 plus SNP. This potentiating effect was further increased by sildenafil, not altered by atropine, however was completely blocked by the N type Ca(2+) channels. High concentrated levels of radiolabeled PnTx2-6 was specifically found in the cavernosum tissue, suggesting PnTx2-6 is an important toxin responsible for P. nigriventer spider accident-induced priapism. CONCLUSION: We show that PnTx2-6 slows Na(+) channels inactivation in nitrergic neurons, allowing Ca(2+) influx to facilitate NO/cGMP signalling, which promotes increased NO production. In addition, this relaxation effect is independent of phosphodiesterase enzyme type 5 inhibition. Our data displays PnTx2-6 as possible pharmacological tool to study alternative treatments for erectile dysfunction. PMID- 20722797 TI - Nurses' use of non-pharmacological methods in children's postoperative pain management: educational intervention study. AB - AIM: This paper is a report of study of the impact of an educational intervention in pain management on nurses' self-reported use of non-pharmacological methods for children's postoperative pain relief and their perceptions of barriers that limited their use of these methods. BACKGROUND: Non-pharmacological methods have been shown to be effective in relieving pain; however, many barriers, including lack of knowledge, limit nurses' use of these methods. Pain education is a promising strategy for changing nursing practice, but only a few authors have examined the effectiveness of educational interventions for nurses to help relieve children's postoperative pain. METHODS: A quasi-experimental one-group pre- and post-test design was used. Questionnaire surveys were conducted with a convenience sample of 108 Registered Nurses in two public hospitals in Singapore in 2008. RESULTS: Statistically significant increases were found in nurses' self reported use of imagery, positive reinforcement, thermal regulation, massage and positioning in the postintervention survey. Before the intervention, these methods were less frequently used compared to other methods. Heavy workload/lack of time and the child's inability to cooperate were the most commonly reported barriers at pre- and post-test. CONCLUSION: The educational intervention had a positive effect on nurses' use of several non-pharmacological methods. Regular dissemination of updated information to nurses on these pain management methods is recommended to maintain the positive changes. Nevertheless, education alone was not sufficient to optimize nurses' use of these methods, as various barriers limited their practice. PMID- 20722798 TI - Nursing care for patients requesting euthanasia in general hospitals in Flanders, Belgium. AB - AIM: This paper is a report of a study exploring nurses' involvement in the care process for mentally competent, terminally ill patients requesting euthanasia in general hospitals in Flanders, Belgium. BACKGROUND: International literature shows that nurses are involved in the care process surrounding euthanasia, regardless of the legal status of euthanasia in the country being studied. However, their actual involvement remains unclear. METHODS: A grounded theory approach was used. Data were collected over a 20-month period in 2005 and 2006, using individual in-depth interviews. The sample included 18 Registered Nurses employed in nine general hospitals geographically spread over the five provinces of Flanders, Belgium. RESULTS: The care process for patients requesting euthanasia is complex and dynamic, consisting of several stages. Major themes characterized nurses' involvement: being on the alert for a euthanasia request; open and active listening; multidisciplinary team cooperation and analysis of the group dynamics; continuously providing maximum palliative care; multi-tasking; organizing and directing the euthanasia; and finally, providing support for the family, colleagues and oneself. CONCLUSION: Nurses make a unique and indispensable contribution to making the euthanasia care process a good care process. This has to do with their specific form of knowledge, expertise and responsibilities, and their willingness to personally, continually and fully care for the patients requesting euthanasia and for their relatives. PMID- 20722799 TI - The HIV Medication Taking Self-efficacy Scale: psychometric evaluation. AB - AIM: This paper is a report of an examination of the psychometric properties of the HIV Medication Taking Self-efficacy Scale. BACKGROUND: Self-efficacy is a critically important component of strategies to improve HIV medication-taking; however, valid and reliable tools for assessing HIV medication-taking self efficacy are limited. METHOD: We used a cross-sectional, correlational design. Between 2003 and 2007, 326 participants were recruited from sites in Pennsylvania and Ohio in the United States of America. Six self-report questionnaires administered at baseline and 12 weeks later during 'Improving Adherence to Antiretroviral Therapy' were used to examine the variables of interest. Means and variances, reliability, criterion, and construct validity of the HIV Medication Taking Self-efficacy Scale were assessed. FINDINGS: Participants reported high self-confidence in their ability to carry out specific medication-related tasks (mean = 8.31) and in the medication's ability to effect good outcomes (mean = 8.56). The HIV Medication Taking Self-efficacy Scale and subscales showed excellent reliability (alpha = 0.93~0.94). Criterion validity was well established by examining the relationships between the HIV Medication Taking Self efficacy Scale and selected physiological and psychological factors, and self reported medication adherence (r = -0.20~0.58). A two-factor model with a correlation between self-efficacy belief and outcome expectancy fitted the data well (model chi(2) = 3871.95, d.f. = 325, P < 001; CFA = 0.96; RMSEA = 0.046). CONCLUSION: The HIV Medication Taking Self-efficacy Scale is a psychometrically sound measure of medication-taking self-efficacy for use by researchers and clinicians with people with HIV. The findings offer insight into the development of interventions to promote self-efficacy and medication adherence in persons with HIV. PMID- 20722800 TI - Factors predicting blood pressure control in older Chinese immigrants to the United States of America. AB - AIM: This paper is a report of a study of the extent to which demographic characteristics, medication-related factors, hypertension-related knowledge and medication adherence predict systolic and diastolic blood pressure. BACKGROUND: Little is known about predictors of hypertension control in Chinese elders. METHODS: A longitudinal study with a 3-month follow-up was conducted with 90 Chinese immigrants to the United States of America aged >=65 years and recruited from 2006 to 2007. The independent variables were measured at baseline. Blood pressure was measured at 3 months. Multiple linear regression analysis was used to evaluate the independent effects of seven variables on change in blood pressure at 3 months. RESULTS: Participants ranged in age from 66 to 92 years (Mean 76.7, sd 6.6). The overall regression model for systolic blood pressure was statistically significant (R2 = 0.32, F = 4.37, P < 0.01). A higher number of prescribed oral medications (sr2 = 0.06, t = 2.42, P = 0.02) and lower medication adherence (sr2 = 0.07, t = -2.60, P = 0.01) were statistically significant determinants of an increased systolic blood pressure. The overall regression model for diastolic blood pressure was statistically significant (R2 = 0.21, F = 2.39, P = 0.03). Male gender (sr2 = 0.06, t = 2.26, P = 0.03) and lower medication adherence (sr2 = 0.11, t = -3.03, P < 0.01) were statistically significant determinants of an increased diastolic blood pressure. CONCLUSION: A greater number of prescribed medications and lower adherence predicted higher level of systolic blood pressure. Male gender and lower adherence were significantly associated with higher level of diastolic blood pressure. These predictors should be considered when designing interventions to help Chinese elders achieve better hypertension management. PMID- 20722801 TI - Terms used for isolation practices by nurses at an academic medical center. AB - AIM: This paper is a report of a study to determine if the terms used by nurses to describe isolation precautions are associated with correct identification of required personal protective equipment. BACKGROUND: Isolation measures are important in the prevention of healthcare-associated infections. The terms used to describe categories of isolation have changed in response to new pathogens and with advances in infection prevention. METHODS: For 3 months in 2009, nurses from an academic medical center on the East Coast of the United States of America completed a survey consisting of ten clinical scenarios which asked about recommended personal protective equipment and for the name of the recommended isolation type. Correct identification of required personal protective equipment was compared to use of an approved isolation category term, controlling for infection knowledge and demographic variables. RESULTS: Three hundred and seventeen nurses gave responses to 2215 clinical scenarios. Use of non-approved category terms was associated with statistically significantly lower rates of correct personal protective equipment identification compared to use of an approved term (62.2% vs. 77.8%; P < 0.001). Specific PPE was also selected for use when not indicated - including gowns (42%), N-95 respirators (13%), fluid shield masks (13%) and sterile gloves (6%). CONCLUSION: Inconsistent terminology for isolation precautions may contribute to variations in practice. Adoption of internationally accepted and standardized category terms may improve adherence to these precautions. PMID- 20722802 TI - Patients with colorectal cancer: relationship between demographic and disease characteristics and acceptance of disability. AB - AIM: This article is a report of a study conducted to examine acceptance of disability among patients with colorectal cancer and its relationships to other disease-related factors. BACKGROUND: Colorectal cancer had become the third leading cause of cancer death worldwide. Recently, the topic of acceptance of disability in patients with chronic disease, especially cancer, has attracted enormous attention because the higher acceptance, the better coping with disease and the better quality of life after therapy. METHOD: A cross-sectional study was carried out with 110 patients with colorectal cancer recruited from a medical centre in northern Taiwan in 2008. Data were collected using the Acceptance of Disability Scale. Descriptive statistics, Pearson correlations and multiple linear regression analysis were used for analysis. FINDINGS: Participants reported moderate levels of acceptance of disability. The regression model showed that those with shorter disease duration, stoma, lower educational level (below 9th grade), or in Duke C1 stage or above reported lower levels of acceptance, and these variables accounted for 25% of the total variance. CONCLUSION: The results suggest that acceptance of disability (i) is a useful construct to examine in future studies on psychosocial adaptation to cancer, and (ii) can be integrated into a clinical intervention programme of providing holistic care to patients with colorectal cancer. PMID- 20722803 TI - Insomnia Severity Index: psychometric properties with Chinese community-dwelling older people. AB - AIM: This paper is a report of a study to evaluate the psychometric properties of the Chinese version of the Insomnia Severity Index. BACKGROUND: Despite the high prevalence of insomnia in older people and its detrimental impact on well-being and healthcare costs, this problem is almost always undetected and consequently under-treated. The Insomnia Severity Index is psychometrically sound in measuring perceived insomnia severity. However, it has had very limited application in non White populations. METHODS: An instrument validation study was carried out between October 2008 and April 2009. The Insomnia Severity Index was translated into Chinese using Brislin's model and administered to a convenience sample of 585 older Chinese people recruited from three community centres for elders. Other instruments were also administered, including the Chinese version of the Pittsburgh Sleep Quality Index and the Geriatric Depression Scale. RESULTS: Cronbach's alpha of the Chinese version of the Insomnia Severity Index was 0.81, with item-to-total correlations in the range of 0.34-0.67. Construct validity was supported by its moderate relationship with the Chinese Pittsburgh Sleep Quality Index and sleep efficiency. The Chinese version of the Insomnia Severity Index also indicated more severe level of insomnia in older people who reported depressed mood on the Geriatric Depression Scale. Discriminant validity was supported as the Chinese version of the Insomnia Severity Index could discriminate poorer sleepers from normal sleepers. Exploratory factor analysis identified a two-factor structure for the Chinese version of the Insomnia Severity Index in measuring the severity and impacts of insomnia on the Chinese older people. CONCLUSION: The Chinese version of the Insomnia Severity Index is a culturally-relevant and psychometrically-sound instrument for assessing severity and impact of insomnia in Chinese community-dwelling older people. Nurses can use this tool to assess older people's perceptions of insomnia. PMID- 20722804 TI - Cigarette dependence questionnaire: development and psychometric testing with male smokers. AB - AIM: This paper is a report of a study conducted to develop and test a theoretically derived Cigarette Dependence Questionnaire for adult male smokers. BACKGROUND: Fagerstrom questionnaires have been used worldwide to assess cigarette dependence. However, these assessments lack any theoretical perspective. A theory-based approach is needed to ensure valid assessment. METHODS: In 2007, an initial pool of 103 Cigarette Dependence Questionnaire items was distributed to 109 adult smokers in Taiwan. Item analysis was conducted to select items for inclusion in the refined scale. The psychometric properties of the Cigarette Dependence Questionnaire were further evaluated 2007-08, when it was administered to 256 respondents and their saliva was collected and analysed for cotinine levels. Criterion validity was established through the Pearson correlation between the scale and saliva cotinine levels. Exploratory factor analysis was used to test construct validity. Reliability was determined with Cronbach's alpha coefficient and a 2-week test-retest coefficient. RESULTS: The selection of 30 items for seven perspectives was based on item analysis. One factor accounting for 44.9% of the variance emerged from the factor analysis. The factor was named as cigarette dependence. Cigarette Dependence Questionnaire scores were statistically significantly correlated with saliva cotinine levels (r = 0.21, P = 0.01). Cronbach's alpha was 0.95 and test-retest reliability using an intra-class correlation was 0.92. CONCLUSION: The Cigarette Dependence Questionnaire showed sound reliability and validity and could be used by nurses to set up smoking cessation interventions based on assessment of cigarette dependence. PMID- 20722805 TI - The novice objective structured clinical evaluation tool: psychometric testing. AB - AIM: This paper is a report of a study of the psychometric properties of the Novice Objective Structured Clinical Evaluation Tool. BACKGROUND: A collaborative undergraduate nursing programme is currently using an objective structured clinical evaluation at the conclusion of the first nursing clinical course to determine student competence as a component of quality and safety education. However, the reliability and validity of the assessment tool has not been established. METHODS: Psychometric testing was conducted with a convenience sample of 565 nursing students. Data were collected during three consecutive years from 2002 to 2004. Exploratory factor analysis and reliability testing were conducted on this 25-item tool. RESULTS: Principal axis factoring method identified two factors through the orthogonal, oblimin and promax rotations: Factor 1 Safety and Factor 2, Anticipation. Spearman-Brown's result for Factor 1 was 0.93 and for Factor 2 was 0.77. Cronbach's alpha was.94 for Factor 1 and 0.71 for Factor 2. CONCLUSION: The tool was found to have adequate construct validity and reliability. Its stability should be tested by conducting test-retest analysis. Equivalency dimensions of reliability should be evaluated by looking at interrater reliability. This tool shows merit for assessing elements of quality and safety education. PMID- 20722806 TI - New graduate nurses' experiences of bullying and burnout in hospital settings. AB - AIM: This paper is a report of a study conducted to test a model linking new graduate nurses' perceptions of structural empowerment to their experiences of workplace bullying and burnout in Canadian hospital work settings using Kanter's work empowerment theory. BACKGROUND: There are numerous anecdotal reports of bullying of new graduates in healthcare settings, which is linked to serious health effects and negative organizational effects. METHODS: We tested the model using data from the first wave of a 2009 longitudinal study of 415 newly graduated nurses (<3 years of experience) in acute care hospitals across Ontario, Canada. Variables were measured using the Conditions of Work Effectiveness Questionnaire, Negative Acts Questionnaire-Revised and Maslach Burnout Inventory General Survey. RESULTS: The final model fit statistics revealed a reasonably adequate fit (chi2 = 14.9, d.f. = 37, IFI = 0.98, CFI = 0.98, RMSEA = 0.09). Structural empowerment was statistically significantly and negatively related to workplace bullying exposure (beta = -0.37), which in turn, was statistically significantly related to all three components of burnout (Emotional exhaustion: beta = 0.41, Cynicism: beta = 0.28, EFFICACY: beta = -0.17). Emotional exhaustion had a direct effect on cynicism (beta = 0.51), which in turn, had a direct effect on efficacy (beta = -0.34). Conclusion. The results suggest that new graduate nurses' exposure to bullying may be less when their work environments provide access to empowering work structures, and that these conditions promote nurses' health and wellbeing. PMID- 20722807 TI - Smoking among young children in Hong Kong: influence of parental smoking. AB - AIMS: This paper is a report of a study comparing children with smoking parents and those with non-smoking parents, in terms of knowledge and attitude towards smoking and the influence of parents and peers on smoking initiation. BACKGROUND: Adolescence is a developmental stage when smoking habits are likely to start. Adolescents are most influenced by the smoking habits of their parents and friends. METHOD: A cross-section study was conducted with students aged 13-15 years in two schools in 2008, using a questionnaire that collected information on the smoking habits of their parents and peers, knowledge and attitude towards smoking, initiation and inclination towards smoking. Chi-square tests and binary logistic regression were used to analyse the data. RESULTS: A total of 257 of 575 (44.7%) students had smoking parent(s), and 25.4% reported having peers who smoked. Children with non-smoking parents were more likely than those with smoking parents to consider 'smoking as disgusting' (67.3% vs. 45.9%), and to know that 'smoking is addictive' (80.5% vs. 70.4%) and 'harmful to health' (81.8% vs. 67.7%). More of those with smoking parents had tried smoking than those with non-smoking parents (13.2% vs. 3.8%). CONCLUSION: Preventive programmes should involve smoking parents to increase their awareness of the impact their smoking has on their children. Interventions should include problem-solving skills for children to deal with daily stresses and thus eradicate the potential risk of smoking initiation. PMID- 20722808 TI - Family caregivers' needs predict functional recovery of older care recipients after hip fracture. AB - AIM: This paper is a report of a study of the effect of family caregivers' needs on the functional recovery of elders with a hip fracture during the first 6 months after discharge. BACKGROUND: Family members are closely involved in the postdischarge care of older Chinese patients. However, the influence of family caregiving-related variables, such as caregiver's needs, on recovery after hip fracture has not been explored. METHODS: Data were collected between 2002 and 2005 with elders with hip fracture and their family caregivers at a medical centre in Taiwan. Data were collected at 1, 3 and 6 months after discharge, and 120 people completed all follow-ups. The effect of caregiver needs on elders' recovery was analysed using the generalized estimating equations approach. FINDINGS: Elders whose caregivers reported a need for information on caregiving and related health care were more likely (odds ratio = 1.93, confidence interval = 1.08-3.46) to recover their walking ability than those whose caregivers did not report such need. However, elders whose caregivers reported a need for social services were less likely to recover their walking ability (odds ratio = 0.38, confidence interval = 0.18-0.78), and activities of daily living (odds ratio = 0.40, confidence interval = 0.17-0.94) than those whose caregivers did not report such need. CONCLUSION: Healthcare providers should include caregivers' needs in their clinical assessment of Chinese elders after surgery for hip fracture. Given the rapidly increasing population of Asian elders in Western countries, the results of this study may be applicable to other countries with Chinese populations. PMID- 20722809 TI - Conducting critical ethnography in long-term residential care: experiences of a novice researcher in the field. AB - AIM: In this paper, I describe my experiences as a novice researcher doing a critical ethnography in long-term residential care. I reflect upon the challenges and lessons learned in navigating trust and power relations in this complex sociopolitical field. BACKGROUND: Critical ethnography is an important method of inquiry that can lead to disruptions in the status quo and empowerment of disenfranchised groups. In nursing scholarship, there is a body of literature about this method of inquiry. This paper further contributes to this scholarship by describing my experiences in the field, with particular attention to the linkages between the study's theoretical perspective, method of inquiry, and criteria for trustworthiness, and how these elements guided my actions in the field. DATA SOURCES: The study that provides the context for this paper was a critical ethnography that examined the organization of long-term residential care in British Columbia, Canada. The method of inquiry was underpinned by a theoretical perspective that wove together a postcolonial feminist approach with Foucauldian epistemology. The study's criteria for trustworthiness were: credibility, reflexivity, reciprocity, voice and praxis. DISCUSSION: Throughout the study, I found myself navigating issues related to building trust in the researcher/participant relationship and navigating power relations. Using examples, I describe how I approached these issues using the criteria for trustworthiness and theoretical perspective as guides. CONCLUSION: Critical ethnography is a method of inquiry that can enrich nursing research and educational scholarship by generating greater understanding about the complex fields in which nurses practise. PMID- 20722810 TI - 'Mutual intacting': a grounded theory study of clinical judgement practice issues. AB - AIM: This paper reports a study conducted to explore how nurses working at advanced practice level in chronic and acute care outpatient contexts responded to decision-making concerns in clinical practice. BACKGROUND: Current theoretical explanations of clinical judgement offer insight into how healthcare professionals process information; however, they are incomplete as they do not consider psychosocial issues. Research evidence informing clinical judgement practice is based largely on acute care hospital settings. Consequently, little is known about how practitioners make clinical judgements in outpatient contexts where patients can participate in their own care. METHOD: A grounded theory approach was used to analyse interview data about clinical judgements made in actual clinical practice. Twenty-one nurses working at advanced practice level in mental healthcare clinics and accident and emergency in the Republic of Ireland were recruited. Concurrent data collection and analysis, constant comparative analysis and theoretical sampling were conducted in 2002-2005. FINDINGS: The core category to emerge from the data was 'mutual intacting'. This refers to the main strategies that practitioners used to resolve concerns about eliciting patient information and selecting treatments that were acceptable to patients. It highlights the clinical judgement practices that practitioners find useful to engage patients to facilitate effective decision-making. CONCLUSION: Practitioners could draw from the various strategies identified in this research to develop their clinical judgement practice further in ways that include the development of an effective relationship with their patients. Negotiation and compromise are particularly useful strategies that should be used to facilitate effective treatment delivery that takes account of patients' circumstances. PMID- 20722811 TI - Usability evaluation of a web-based patient information system for individuals with severe mental health problems. AB - AIM: This paper is a report of a study conducted to compare service users', nursing students' and Registered Nurses' evaluations of the usability of a patient education website intended for individuals with severe mental health problems. BACKGROUND: There is an obvious need for reliable mental health information on the Internet. When evaluating the usability of Internet-based patient education methods, the opinions of all parties need to be ascertained. METHODS: An explorative descriptive design was used. Twenty-one service users, 20 nursing students and 35 Registered Nurses were recruited for the study in 2003 and 2004. Data were collected using a self-developed questionnaire on the content, structure and visual appearance of the website. RESULTS: Service users had positive attitudes towards computer and Internet use but they needed support when using the computer and Internet. According to the evaluations, the content, structure and visual appearance of the website were good and it could be adopted for clinical practise after minor revisions. There were some differences in the evaluations between participant groups. Nurses were the most critical group, and the service user group was the most satisfied, although they were less experienced with using both computers and the Internet. CONCLUSION: It is especially important to include service users' evaluations at the early stages of the development process of Web-based patient education systems. It is possible to produce an information technology-based patient education system for individuals with severe mental health problems. Nurses working in psychiatric services need to pay more attention to supporting service users in computer and Internet use. PMID- 20722813 TI - Health index, sense of coherence scale, brief religious coping scale and spiritual perspective scale: psychometric properties. AB - AIM: This paper is a report of a study to translate one Swedish and three English instruments into the Persian language, and to estimate their validity and reliability. BACKGROUND: The Sense of Coherence Scale, Health Index, Brief Religious Coping Scale and Spiritual Perspective Scale are all well tested instruments for use in nursing research. Since there was no Persian translation of these instruments, they had to be translated and cross-culturally adapted for nursing research in the Iranian culture. METHOD: After the translation process, sampling for psychometric tests was done. A sample of healthy Iranian people (n = 375) was selected to response to the instruments in 2006, at baseline and 1 month later. FINDINGS: Cronbach's alpha values and intra-class correlations were high (>0.70). Tests of criterion-related validity showed that six of the ten hypotheses were confirmed, and the four rejected hypotheses did not imply a threat to validity. Hierarchical multiple regression analysis showed that sense of coherence was the strongest predictor of well-being (Health Index scores) both at baseline (= 0.52, P < 0.001) and 1 month later (= 0.58, P < 0.001). CONCLUSION: There is a sound psychometric basis for using the Iranian versions of these instruments in nursing research with the Iranian population. The Sense of Coherence Scale proved to be as valid and reliable as in Western countries, which supports its cross-cultural applicability. PMID- 20722812 TI - Effect of patient coping preferences on quality of life following renal transplantation. AB - AIM: This paper is a report of a study investigating the relationships between quality of life, patient coping preferences, and desire to be actively involved in care following renal transplantation. BACKGROUND: While the general consensus is that quality of life is improved greatly by kidney transplantation, it is apparent that it is not uniformly a positive experience in this regard. There is a need to identify individual difference factors that influence quality of life following renal transplantation. METHOD: A correlational study was conducted in the national referral centre for renal transplantation in the Republic of Ireland in 2006 with a sample of 172 transplant recipients. Data were collected using a questionnaire composed of standardized instruments to measure the key concepts. RESULTS: Participants perceived that they had good quality of life, and used more problem-solving than avoidance coping strategies. Avoidance coping strategies were associated with statistically significantly lower quality of life following transplantation. Being younger, attaining a higher education level, being in employment and being married were associated with higher quality of life following transplantation. CONCLUSION: Assessment of coping strategies among the transplant population should be further explored in clinical practice, and steps employed to promote the use of positive coping strategies in order to maximize quality of life after transplant. PMID- 20722814 TI - Pain management interventions with parents in the emergency department: a randomized trial. AB - AIM: This paper is a report of the efficacy of a parental educational intervention on children's pain intensity and experience of pain-related unpleasantness at 24 hours post-discharge from the emergency department, and on parents' beliefs about pain. BACKGROUND: Parents' misbeliefs about pain management may inhibit them from managing their child's pain appropriately. Educating parents about pain management may increase their knowledge, dispel myths and help decrease children's pain intensity and unpleasantness related to pain following a visit to an emergency department. METHOD: A randomized design was adopted with samples of parent/child dyads. The experimental group received a bookmark, booklet on pain management and pain scale. The control group only received a pain scale. Pain intensity and unpleasantness were measured at triage and 24 hours after discharge from the emergency department. Parents' beliefs were measured with the Pain Belief Questionnaire. Data were collected from November 2005 to May 2006. RESULTS: Samples of 98 (experimental) and 97 (control) children/parents were recruited. No statistically significant differences were found between both groups regarding pain intensity and unpleasantness, at triage and 24 hours post-discharge. Results for the Pain Belief Questionnaire were similar between the groups (t = 1.751, P = 0.082). CONCLUSION: The interventions were not effective to reduce pain and unpleasantness related to pain, as well as to improve pain beliefs of parents. Other interventions, such as having parents participate actively in their child's pain management, might be more effective than a passive educational intervention. PMID- 20722815 TI - Influenza vaccine preference and uptake among older people in nine countries. AB - AIM: This paper is a report of a study delineating factors that influence older people's preferences and uptake of the influenza vaccine in nine countries. BACKGROUND: Vaccination uptake for the aging population in many countries still remains below the World Health Organization recommended rate. Older people who perceive higher susceptibility to and severity of influenza, and more benefits from vaccination and action cues prompting vaccination, tend to accept the vaccine, but those with more perceived barriers to vaccination are less likely to accept it. METHOD: A total of 208 older people from China, Indonesia, Turkey, Korea, Greece, Canada, the United Kingdom, Brazil and Nigeria were recruited to 14 vaccinated and 12 unvaccinated focus groups. They shared their experiences of influenza, and influenza vaccination, and promotion of influenza vaccination in focus groups. The data were collected in 2007. FINDINGS: We identified five themes and generated a hypothetical framework for in-depth understanding of vaccination behaviour among older people. Participants' vaccine preferences were determined by their behavioural beliefs in vaccination, which were based on their probability calculation of susceptibility to and severity of influenza and vaccine effectiveness, and their utility calculation of vaccine, healthcare and social costs. Action cues prompting vaccination and vaccine access further affected the vaccine uptake of participants with vaccine preferences. Vaccination coverage was likely to be higher in the countries where normative beliefs in favour of vaccination had formed. CONCLUSION: The hypothetical framework can be used to guide healthcare providers in developing strategies to foster normative beliefs of older people in vaccination, provide effective action cues and promote vaccine access. PMID- 20722816 TI - Linda Hiddemen Barondess, who put American Geriatrics Society on map, to step down. PMID- 20722817 TI - The American Geriatrics Society transitions staff leadership: collaborating for future growth and influence. PMID- 20722818 TI - The American Geriatrics Society transitions to new leadership. PMID- 20722819 TI - Sleep quality in residents of assisted living facilities: effect on quality of life, functional status, and depression. AB - OBJECTIVES: To describe sleep patterns in older adults living in assisted living facilities (ALFs) and to explore the relationship between sleep disturbance and quality of life, functional status, and depression over 6 months of follow-up. DESIGN: Prospective, observational cohort study. SETTING: Eighteen ALFs in the Los Angeles area. PARTICIPANTS: One hundred twenty-one ALF residents aged 65 and older (mean age 85.3, 86% female, 88% non-Hispanic white). MEASUREMENTS: Data were collected at baseline and 3 and 6 months after enrollment. Data collected were demographics, physical and cognitive functioning, depression, quality of life, comorbidities, medications, and subjective (i.e., questionnaires) and objective (i.e., 3 days and nights of wrist actigraphy) measures of sleep. RESULTS: Sixty-five percent of participants reported clinically significant sleep disturbance on the Pittsburgh Sleep Quality Index, and objective wrist actigraphy confirmed poor sleep quality. In regression analyses including sleep variables and other predictors, more self-reported sleep disturbance at baseline was associated with worse health-related quality of life (Medical Outcomes Study 12 item Short Form Survey Mental Component Summary score) and worse depressive symptoms five-item Geriatric Depression Scale at follow-up. Worse nighttime sleep (according to actigraphy) at baseline was associated with worse activities of daily living functioning and more depressive symptoms at follow-up. CONCLUSIONS: Sleep disturbance is common in older ALF residents, and poor sleep is associated with declining functional status and quality of life and greater depression over 6 months of follow-up. Studies are needed to determine whether improving sleep in ALF residents will result in improvements in these outcomes. Well-established treatments should be adapted for use in ALFs and systematically evaluated in future research. PMID- 20722820 TI - Greater risk of dementia when spouse has dementia? The Cache County study. AB - OBJECTIVES: To examine the effects of caring for a spouse with dementia on the caregiver's risk for incident dementia. DESIGN: Population-based study of incident dementia in spouses of persons with dementia. SETTING: Rural county in northern Utah. PARTICIPANTS: Two thousand four hundred forty-two subjects (1,221 married couples) aged 65 and older. MEASUREMENTS: Incident dementia was diagnosed in 255 subjects, with onset defined as age when subject met Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria for dementia. Cox proportional hazards regression tested the effect of time-dependent exposure to dementia in one's spouse, adjusted for potential confounders. RESULTS: A subject whose spouse experienced incident dementia onset had a six times greater risk for incident dementia as subjects whose spouses were dementia free (hazard rate ratio (HRR)=6.0, 95% confidence interval (CI)=2.2-16.2, P<.001). In sex-specific analyses, husbands had higher risks (HRR=11.9, 95% CI=1.7-85.5, P=.01) than wives (HRR=3.7, 95% CI=1.2-11.6, P=.03). CONCLUSION: The chronic and often severe stress associated with dementia caregiving may exert substantial risk for the development of dementia in spouse caregivers. Additional (not mutually exclusive) explanations for findings are discussed. PMID- 20722823 TI - Cost consideration by Medicare Part D plans may promote the use of potentially inappropriate medications. PMID- 20722821 TI - Bedside-to-Bench conference: research agenda for idiopathic fatigue and aging. AB - The American Geriatrics Society, with support from the National Institute on Aging and the John A. Hartford Foundation, held its fifth Bedside-to-Bench research conference, "Idiopathic Fatigue and Aging," to provide participants with opportunities to learn about cutting-edge research developments, draft recommendations for future research, and network with colleagues and leaders in the field. Fatigue is a symptom that older persons, especially by those with chronic diseases, frequently experience. Definitions and prevalence of fatigue may vary across studies, across diseases, and even between investigators and patients. The focus of this review is on physical fatigue, recognizing that there are other related domains of fatigue (such as cognitive fatigue). Many definitions of fatigue involve a sensation of "low" energy, suggesting that fatigue could be a disorder of energy balance. Poor energy utilization efficiency has not been considered in previous studies but is likely to be one of the most important determinants of fatigue in older individuals. Relationships between activity level, capacity for activity, a tolerable rate of activity, and a tolerable fatigue threshold or ceiling underlie a notion of fatiguability. Mechanisms probably contributing to fatigue in older adults include decline in mitochondrial function, alterations in brain neurotransmitters, oxidative stress, and inflammation. The relationships between muscle function and fatigue are complex. A number of diseases (such as cancer) are known to cause fatigue and may serve as models for how underlying impaired physiological processes contribute to fatigue, particularly those in which energy utilization may be an important factor. A further understanding of fatigue will require two key strategies: to develop and refine fatigue definitions and measurement tools and to explore underlying mechanisms using animal and human models. PMID- 20722824 TI - Dynamic lighting as a tool to influence the day-night rhythm of clients with psychogeriatric disorders: a pilot study in a Dutch nursing home. PMID- 20722822 TI - An ironic tragedy: are spouses of persons with dementia at higher risk for dementia than spouses of persons without dementia? PMID- 20722825 TI - Parkinson's disease in older adults: a new scenario for this old actor? PMID- 20722826 TI - Changes in the serum bone metabolism markers of elderly alcoholics during abstinence. PMID- 20722828 TI - Leiomyosarcoma of the spermatic cord: an unusual tumor misdiagnosed as inguinal hernia in a geriatric patient. PMID- 20722827 TI - Metronomic cyclophosphamide in elderly patients with advanced, castration resistant prostate cancer. PMID- 20722829 TI - Prognosis of upper gastrointestinal bleeding in the oldest-old patients: a post hoc analysis of a prospective study. PMID- 20722830 TI - Aspirin use, depression, and cognitive impairment in later life: the health in men study. PMID- 20722831 TI - Simplifying detection of mild cognitive impairment subtypes. PMID- 20722832 TI - Treating anemia to improve cognition. PMID- 20722834 TI - The overlap syndrome of depression and delirium in elderly patients: a comment. PMID- 20722835 TI - Depression and outcome of delirium. PMID- 20722836 TI - No shortcuts for delirium prevention. PMID- 20722838 TI - The role of tumor necrosis factor-alpha in cognitive improvement after peroxisome proliferator-activator receptor gamma agonist pioglitazone treatment in Alzheimer's disease. PMID- 20722839 TI - Emergence of rifampicin resistance during rifampicin-containing treatment in elderly patients with persistent methicillin-resistant Staphylococcus aureus bacteremia. PMID- 20722840 TI - Comparison of three tools predicting functional decline after hospitalization of older patients. PMID- 20722841 TI - Effect of clinical decision support on psychotropic medication prescribing in the long-term care setting. PMID- 20722842 TI - Factors associated with nonadherence to medication in community-dwelling disabled older adults in Japan. PMID- 20722845 TI - Two-year effects of interdisciplinary intervention for hip fracture in older Taiwanese. AB - OBJECTIVES: To explore the 2-year outcomes of an interdisciplinary intervention for elderly patients with hip fracture. DESIGN: Randomized experimental design. SETTING: A 3,000-bed medical center in northern Taiwan. PARTICIPANTS: Patients with hip fracture (N=162): 80 in the intervention group and 82 in the usual care control group. INTERVENTION: An interdisciplinary program of geriatric consultation, continuous rehabilitation, and discharge planning. MEASUREMENTS: Outcomes (clinical outcomes, self-care ability, health-related quality of life (HRQoL), service utilization, and depressive symptoms) were assessed 1, 3, 6, 12, 18, and 24 months after discharge. Self-care ability (ability to perform activities of daily living (ADLs)) was measured using the Chinese Barthel Index. HRQoL was measured using the Medical Outcomes Study 36-item Short Form Survey, Taiwan version (SF-36). Depressive symptoms were measured using the Chinese Geriatric Depression Scale, short form. RESULTS: Subjects in the intervention group had significantly better ratios of hip flexion (beta=5.43, P<.001), better performance on ADLs (beta=9.22, P<.001), better recovery of walking ability (odds ratio (OR)=2.23, P<.001), fewer falls (OR=0.56, P=.03), fewer depressive symptoms (beta=-1.31, P=.005), and better SF-36 physical summary scores (beta=6.08, P<.001) than the control group during the first 24 months after discharge. The intervention did not affect the peak force of the fractured limb's quadriceps, mortality, service utilization, or SF-36 mental summary score. CONCLUSION: The interdisciplinary intervention for hip fracture benefited elderly persons with hip fracture by improving clinical outcomes, self-care ability, and physical health-related outcomes and by decreasing depressive symptoms during the first 24 months after hospital discharge. PMID- 20722844 TI - Renin angiotensin system gene polymorphisms modify angiotensin-converting enzyme inhibitors' effect on cognitive function: the health, aging and body composition study. AB - OBJECTIVES: To investigate the effect of polymorphisms in renin angiotensin system genes on the association between angiotensin-converting enzyme inhibitor (ACEI) exposure and global and executive cognitive function in the Health, Aging and Body Composition study. DESIGN: Cohort study. SETTING: Community. PARTICIPANTS: Three thousand seventy-five participants: mean age 73.6, 58% Caucasian, 52% female, 15% taking ACE-Is, 8 years of follow-up. MEASUREMENTS: The outcomes were longitudinal change in Executive Clock Drawing Test-1 (CLOX1), the Digit Symbol Substitution test, and the Modified Mini-Mental State Examination. The genetic polymorphisms included angiotensin-converting enzyme insertion deletion (ACEID) in the ACE gene and the M235T and 6AG polymorphisms in the angiotensinogen (AGT) gene. RESULTS: For the CLOX1 outcome, there was significant interaction between 6AG and M235T polymorphisms in the AGT gene and angiotensin converting enzyme inhibitors (ACE-Is) in Caucasian participants (P=.01 for both polymorphisms) independent of blood pressure levels. Specifically, ACE-I exposure was protective against CLOX1 score decline in carriers of the AA genotype of the 6AG and the CC genotype of the M235T (for the ACE-I vs non-ACE-I groups, P=.01 for 6AG and P=.005 for M235T) but not the other genotypes. These associations were not significant with other cognitive tests, with ACEID, or in African Americans. CONCLUSION: ACE-Is may provide a protective effect on executive function in Caucasians with AGT gene polymorphisms known to be associated with greater renin angiotensin system activity. If confirmed in a pharmacogenetic trial, ACE-Is may be found to have additional cognitive protection in a select group of elderly individuals. PMID- 20722846 TI - Linking glycemic control and executive function in rural older adults with diabetes mellitus. AB - OBJECTIVES: To examine the association between glycemic control and the executive functioning domain of cognition and to identify risk factors for inadequate glycemic control that may explain this relationship. DESIGN: Cross-sectional study. SETTING: In-person interviews conducted in participants' homes. PARTICIPANTS: Ninety-five rural older African Americans, American Indians, and whites with diabetes mellitus (DM) from three counties in south-central North Carolina. MEASUREMENTS: Participants underwent uniform evaluations. Glycemic control was measured using a validated method, and executive function was assessed using a previously established set of measures and scoring procedure. Information pertaining to medication for treatment of DM, knowledge of DM, and DM self-care behaviors were obtained. RESULTS: In linear regression models adjusting for sex, age, education, ethnicity, duration of DM, and depressive symptoms, executive function was significantly associated with glycemic control. A 1-point higher executive function score was associated with a 0.47 lower glycosylated hemoglobin value (P=.01). The association between glycemic control and executive function became nonsignificant (P=.08) when controlling for several glycemic control risk factors, including use of DM medication and DM knowledge. CONCLUSION: These results suggest that poor glycemic control is associated with impairments in performance on composite measures of executive function and that modifiable risk factors for glycemic control such as use of DM medication and DM knowledge may explain this relationship. PMID- 20722848 TI - Web-based training in geriatrics for medical residents: a randomized controlled trial using standardized patients to assess outcomes. AB - Although Web-based instruction offers an advantageous approach to medical education, few studies have addressed the use of Web-based education to teach clinical content at the postgraduate level. Even fewer studies have addressed clinical outcomes after the Web-based instruction, yet postgraduate training requirements now focus on outcomes of training. A randomized trial was conducted to compare knowledge of postgraduate year (PGY) 1 residents after Web-based with that after paper-based instruction and to compare residents' clinical application of their instruction using unannounced standardized patients (SPs) and unannounced activated standardized patients (ASPs). PGY 1 residents were assigned to a month-long ambulatory rotation during which they were randomized as a block to Web- or paper-based instruction covering the same four geriatric syndromes (dementia, depression, falls, and urinary incontinence). Outcome measures were mean change scores for before and after testing and scores from SP and ASP clinical encounter forms (checklist, chart abstraction, and electronic order entry). Residents who completed the Web-based instruction showed significantly greater improvement on the knowledge tests than those who received paper-based instruction. There were no significant differences in the scores from the SP and ASP clinical encounters except that the chart abstraction score was better for Web-based group than the paper-based group for dementia. Web-based instruction is an educational tool that medical residents readily accept and can be used to improve knowledge of core geriatrics content as measured using immediate posttesting. More-intensive educational interventions are needed to improve clinical performance by trainees in the care of older patients. PMID- 20722847 TI - Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. AB - OBJECTIVES: To investigate the effects of testosterone supplementation on bone, body composition, muscle, physical function, and safety in older men. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: A major medical institution. PARTICIPANTS: One hundred thirty-one men (mean age 77.1 +/- 7.6) with low testosterone, history of fracture, or bone mineral density (BMD) T-score less than -2.0 and frailty. INTERVENTION: Participants received 5 mg/d of testosterone or placebo for 12 to 24 months; all received calcium (1500 mg/d diet and supplement) and cholecalciferol (1,000 IU/d). MEASUREMENTS: BMD of hip, lumbar spine, and mid-radius; body composition; sex hormones, calcium-regulating hormones; bone turnover markers; strength; physical performance; and safety parameters. RESULTS: Ninety-nine men (75.6%) completed 12 months, and 62 (47.3%) completed end therapy (mean 23 months; range 16-24 months for 62 who completed therapy). Study adherence was 54%, with 40% of subjects maintaining 70% or greater adherence. Testosterone and bioavailable testosterone levels at 12 months were 583 ng/dL and 157 ng/dL, respectively, in the treatment group. BMD on testosterone increased 1.4% at the femoral neck and 3.2% at the lumbar spine (P=.005) and decreased 1.3% at the mid-radius (P<.001). There was an increase in lean mass and a decrease in fat mass in the testosterone group but no differences in strength or physical performance. There were no differences in safety parameters. CONCLUSION: Older, frail men receiving testosterone replacement increased testosterone levels and had favorable changes in body composition, modest changes in axial BMD, and no substantial changes in physical function. PMID- 20722849 TI - Keep on track: a volunteer-run community-based intervention to lower blood pressure in older adults. AB - Uncontrolled hypertension in older adults is a common yet preventable threat to healthy aging. Improvements in blood pressure (BP) control and related health outcomes require innovative approaches that reach beyond the clinical environment. Keep on Track (KOT), a volunteer-run, community-based BP-monitoring program that aims to lower BP of community-dwelling older adults through senior center programming, is described and evaluated. KOT is based on a New York City (NYC) Department for the Aging program that has been in existence for more than 20 years and is evaluated in six senior centers in low- to middle-income neighborhoods in NYC. Program design includes monitoring sessions every other week to measure and record participant BP. BP education is provided using low literacy materials, and medication adherence is encouraged. Over 6 months of observation, 244 participants enrolled (mean age 73). Of the 181 (74%) with hypertension at baseline, 92% were previously aware of their condition, 78% were treated, and 31% were controlled. BP control among the treated was 42%. Forty three percent of enrollees (n=105) were multiple-visit participants who experienced on average a 3.9-mmHg reduction in systolic BP (SBP) between the first and last program visit (95% confidence interval (CI)=-7.6 to -0.1, P=.04). Participants with an initial SBP greater than 160 mmHg (n=20) experienced on average a 20.9-mmHg reduction in SBP (95% CI=-32.4 to -9.4, P<.001). Areas for program improvement include greater attention to peer counseling and timely communication with participants' healthcare providers. Volunteer-run, community based BP monitoring in senior centers may provide an effective, replicable model for reducing BP in older adults. PMID- 20722850 TI - Paper geriatrics. PMID- 20722851 TI - Diabetes mellitus and hypertension in elderly highlanders in Asia. PMID- 20722852 TI - Pain management to promote independence in older adults. PMID- 20722853 TI - Improving fall prevention programs using evidence-based practice. PMID- 20722854 TI - Obese nursing home residents: a call to research action. PMID- 20722855 TI - Association between early and late catheter removal and outcome of elderly patients with catheter-related bloodstream infection and persistent bacteremia caused by methicillin-resistant Staphylococcus aureus. PMID- 20722856 TI - The Takeda Three Colors Combination Test: an easy and quick screening for Alzheimer's disease. PMID- 20722857 TI - Joint effect of C-reactive protein and high-density lipoprotein cholesterol in predicting short-term mortality in older community-dwelling korean population. PMID- 20722858 TI - Comprehensive care for older adults: case management approach. PMID- 20722859 TI - Outcome of ischemic stroke in older adults. PMID- 20722860 TI - Diazepam conversion in older adults. PMID- 20722861 TI - Reluctance of older people to discontinue long-term benzodiazepines and related hypnotics. PMID- 20722862 TI - Effect of psychoactive medication on gait variability in community-dwelling older adults: a cross-sectional study. PMID- 20722863 TI - The mediating effect of physical activity and smoking on the relationship between coffee drinking and body weight in elderly individuals: the Mediterranean Islands study. PMID- 20722864 TI - Aging population and health inequalities in the rural areas of China. PMID- 20722865 TI - Diagnostic yield of water enema computed tomography in first-line investigation of lower gastrointestinal bleeding in elderly patients. PMID- 20722867 TI - Comments on article on older drivers in Australia. PMID- 20722868 TI - Statins: a case for drug withdrawal in patients with dementia. PMID- 20722869 TI - Pyogenic liver abscess in older patients: comparison with younger patients. PMID- 20722870 TI - Acupuncture for pain and sleep in knee osteoarthritis. PMID- 20722871 TI - Do-not-hospitalize order: is it absolute? PMID- 20722873 TI - Direct and indirect effects of temperature on the population dynamics and ecosystem functioning of aquatic microbial ecosystems. AB - 1. While much is known about the direct effect that temperature can have on aquatic communities, less is known about its indirect effect via the temperature dependence of viscosity and temperature-dependent trophic interactions. 2. We manipulated the temperature (5-20 degrees C) and the viscosity (equivalent to 5 20 degrees C) of water in laboratory-based bacteria-protist communities. Communities contained food chains with one, two or three trophic levels. Responses measured were population dynamics (consumer carrying capacity and growth rate, average species population density, and the coefficient of variation of population density through time) and ecosystem function (decomposition). 3. Temperature, viscosity and food chain length produced significant responses in population dynamics. Temperature-dependent viscosity had a significant effect on the carrying capacity and growth rates of consumers, as well as the average density of the top predator. Overall, indirect effects of temperature via changes in viscosity were subtle in comparison to the indirect effect of temperature via trophic interactions. 4. Our results highlight the importance of direct and indirect effects of temperature, mediated through trophic interactions and physical changes in the environment, both for population dynamics and ecosystem processes. Future mechanistic modelling of effects of environmental change on species will benefit from distinguishing the different mechanisms of the overall effect of temperature. PMID- 20722874 TI - Fine-scale spatial variability in anatoxin-a and homoanatoxin-a concentrations in benthic cyanobacterial mats: implication for monitoring and management. AB - AIMS: The purpose of this study was to determine the variability in anatoxin-a (ATX) and homoanatoxin-a (HTX) concentrations in benthic cyanobacterial mats within sampling sites and to assess the applicability of using a PCR-based approach to determine ATX- and HTX-production potential. METHODS AND RESULTS: ATX and HTX variability was investigated by collecting 15 samples from 10 * 10 m grids in seven rivers. ATX and HTX concentrations were determined using liquid chromatography-mass spectrometry (LC-MS). Samples from two sites contained no ATX or HTX and at one site ATX and HTX were detected in all samples. At four sites, both toxic and nontoxic samples co-occurred and these samples were sometimes spaced less than 1 m apart. PCR amplification of a region of a polyketide synthase (ks2, putatively involved in the biosynthetic pathway of ATX and HTX) successfully distinguished ATX-and-HTX- and non-ATX-and-HTX-producing cultured Phormidium strains. Results from environmental samples were more variable, and the results were in congruence with the LC-MS data in only 58% of samples. CONCLUSIONS: Fine-scale spatial variability in ATX and HTX concentrations occurs among benthic cyanobacterial mats. SIGNIFICANCE AND IMPACT OF THE STUDY: Multiple benthic cyanobacterial mat samples must be collected at a sampling site to provide an accurate assessment of ATX and HTX concentrations at that location. The PCR-based technique offers the potential to be a useful early warning technique. PMID- 20722875 TI - Influence of the maize silage to grass silage ratio and feed particle size of rations for ruminants on the community structure of ruminal Firmicutes in vitro. AB - AIMS: To investigate the effect of the forage source and feed particle size (FPS) in ruminant rations on the composition of the ruminal Firmicutes community in vitro. METHODS AND RESULTS: Three diets, varying in maize silage to grass silage ratio and FPS, were incubated in a rumen simulation system. Microbial samples were taken from the liquid fermenter effluents. Microbial community analysis was performed by 16S rRNA-based techniques. Clostridia-specific single-strand conformation polymorphism profiles revealed changes of the community structure in dependence on both factors tested. The coarse grass silage-containing diets seemed to enhance the occurrence of different Roseburia species. As detected by real-time quantitative PCR, Ruminococcus albus showed a higher abundance with decreasing FPS. A slightly lower proportion of Bacilli was found with increasing grass silage to maize silage ratio by fluorescence in situ hybridization (FISH). In contrast, a slightly higher proportion of bacterial species belonging to the Clostridium-clusters XIV a and b was detected by FISH with increasing grass silage contents in the diet. CONCLUSIONS: The ruminal Firmicutes community is affected by the choice of the forage source and FPS. SIGNIFICANCE AND IMPACT OF THE STUDY: This study supplies fundamental knowledge about the response of ruminal microbial communities to changing diets. Moreover, the data suggest a standardization of grinding of feeds for in vitro studies to facilitate the comparison of results of different laboratories. PMID- 20722876 TI - Salmonella enterica isolates from pasture-raised poultry exhibit antimicrobial resistance and class I integrons. AB - AIMS: While considerable foodborne pathogen research has been conducted on conventionally produced broilers and turkeys, few studies have focused on free range (organic) or pastured poultry. The current surveillance study was designed to isolate, identify and genetically characterize Salmonella from pastured poultry farm environment and from retail samples. METHODS AND RESULTS: In this study, 59 isolates were collected from two pastured poultry farms (n = 164; pens, feed, water and insect traps) and retail carcasses (n = 36) from a local natural foods store and a local processing plant. All isolates were serotyped and analysed phenotypically (antimicrobial resistance profiles) and genotypically (DNA fingerprints, plasmid profiles and integron analysis). Salmonella enterica was detected using standard microbiological methods. Salmonella Kentucky was the most prevalent serotype detected from the sampled sources (53%), followed by Salmonella Enteritidis (24%), Bareilly (10%), Mbandaka (7%), Montevideo (5%) or Newport (2%). All isolates were resistant to sulfisoxazole and novobiocin, and the majority (40/59) possessed class I integrons shown by PCR detection. Each Salmonella serotype elicited a distinct pulsed-field gel electrophoresis fingerprint profile, and unique differences were observed among the serotypes. CONCLUSIONS: The findings of this study show that Salmonella serotypes isolated from pasture-raised poultry exhibit antimicrobial resistance and class I integrons. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that despite the cessation of antibiotic usage in poultry production, antibiotic resistant Salmonella may still be recovered from the environment and poultry products. PMID- 20722877 TI - Feasibility of methods based on nucleic acid amplification techniques to fulfil the requirements for microbiological analysis of water quality. AB - Molecular methods based on nucleic acid recognition and amplification are valuable tools to complement and support water management decisions. At present, these decisions are mostly supported by the principle of end-point monitoring for indicators and a small number of selected measured by traditional methods. Nucleic acid methods show enormous potential for identifying isolates from conventional culture methods, providing data on cultivable and noncultivable micro-organisms, informing on the presence of pathogens in waters, determining the causes of waterborne outbreaks, and, in some cases, detecting emerging pathogens. However, some features of water microbiology affect the performance of nucleic acid-based molecular techniques and thus challenge their suitability for routine water quality control. These features include the variable composition of target water samples, the generally low numbers of target micro-organisms, the variable water quality required for different uses and the physiological status or condition of such micro-organisms. The standardization of these molecular techniques is also an important challenge for its routine use in terms of accuracy (trueness and precision) and robustness (reproducibility and reliability during normal usage). Most of national and international water regulations recommend the application of standard methods, and any new technique must be validated respect to established methods and procedures. Moreover, molecular methods show a high cost-effectiveness value that limits its practicability on some microbial water analyses. However, new molecular techniques could contribute with new information or at least to supplement the limitation of traditional culture-based methods. Undoubtedly, challenges for these nucleic acid-based methods need to be identified and solved to improve their feasibility for routine microbial water monitoring. PMID- 20722878 TI - Use of bioluminescence imaging to monitor Campylobacter survival in chicken litter. AB - AIM: The aim of this study was to develop a novel approach for characterizing the growth and persistence of Campylobacter in different poultry-rearing environments. Specifically, we constructed bioluminescent Campylobacter strains and used them to monitor the survival of these pathogens in litter (bedding) material. METHODS AND RESULTS: We inserted shuttle plasmids carrying the luminescence genes (luxCDABE) into C. jejuni and C. coli to construct bioluminescent strains of these pathogens. The strains were spiked into microcosms containing samples of litter-washings and dry litter collected from different enclosures that housed broiler chickens. Our results show that C. jejuni and C. coli survived for at least 20 days in reused (old) litter while the growth of these pathogens was inhibited in clean (new) litter. Furthermore, our results suggest that the availability of nutrients and the condition of the litter (reused vs new) are important factors in the persistence of these pathogens. CONCLUSIONS: Reused litter can potentially predispose chickens to Campylobacter contamination and maintaining clean litter might reduce the incidences of colonization with these pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: Bioluminescence provided a simple, sensitive, and rapid approach for analysing the growth dynamics of Campylobacter. Using this technology, we highlighted the potential role of litter material in maintaining these pathogens in the chicken environment. PMID- 20722872 TI - Unravelling the development of the visual cortex: implications for plasticity and repair. AB - The visual cortex comprises over 50 areas in the human, each with a specified role and distinct physiology, connectivity and cellular morphology. How these individual areas emerge during development still remains something of a mystery and, although much attention has been paid to the initial stages of the development of the visual cortex, especially its lamination, very little is known about the mechanisms responsible for the arealization and functional organization of this region of the brain. In recent years we have started to discover that it is the interplay of intrinsic (molecular) and extrinsic (afferent connections) cues that are responsible for the maturation of individual areas, and that there is a spatiotemporal sequence in the maturation of the primary visual cortex (striate cortex, V1) and the multiple extrastriate/association areas. Studies in both humans and non-human primates have started to highlight the specific neural underpinnings responsible for the maturation of the visual cortex, and how experience-dependent plasticity and perturbations to the visual system can impact upon its normal development. Furthermore, damage to specific nuclei of the visual cortex, such as the primary visual cortex (V1), is a common occurrence as a result of a stroke, neurotrauma, disease or hypoxia in both neonates and adults alike. However, the consequences of a focal injury differ between the immature and adult brain, with the immature brain demonstrating a higher level of functional resilience. With better techniques for examining specific molecular and connectional changes, we are now starting to uncover the mechanisms responsible for the increased neural plasticity that leads to significant recovery following injury during this early phase of life. Further advances in our understanding of postnatal development/maturation and plasticity observed during early life could offer new strategies to improve outcomes by recapitulating aspects of the developmental program in the adult brain. PMID- 20722879 TI - Population mean scores predict child mental disorder rates: validating SDQ prevalence estimators in Britain. AB - BACKGROUND: For adult physical and mental health, the population mean predicts the proportion of individuals with 'high' scores. This has not previously been investigated for child mental health. It is also unclear how far symptom scores on brief questionnaires provide an unbiased method of comparing children with different individual, family or social characteristics. METHODS: Subjects were 18,415 British children aged 5-16 years. Parents, teachers, and children aged 11 16 completed Strengths and Difficulties Questionnaires (SDQs) and diagnostic interviews; the latter were used to assign multi-informant clinician-rated diagnoses. We examined how closely the prevalence of child mental disorder was predicted by SDQ mean total difficulty scores, and how these mean scores compared to alternative SDQ-based summary statistics. We did this for populations defined in terms of a wide range of risk factors using one randomly selected half of the study sample. Using these results we generated SDQ prevalence estimator equations, and validated these on the second half of the study sample. RESULTS: Mean symptom scores closely predicted the prevalence of clinician-rated child mental disorder (R(2) = .89-.95) and performed better than alternative summary statistics based on binary SDQ outcomes. The predictions of the SDQ prevalence estimators were on average only 1-2% different from the true prevalence, with no systematic tendency towards under- or overestimation. There were only a few outlier subpopulations, all relating to children with learning difficulties. CONCLUSION: The proportion of children with a disorder is closely predicted by mean symptom scores, highlighting the potential importance of population-wide interventions to improve child mental health. In Britain, SDQ mean total difficulty scores generally provide an accurate and unbiased method of assessing the mental health of different subgroups. SDQ prevalence estimators may facilitate presenting these research findings as proportions that are more easily interpreted by policymakers and service providers. PMID- 20722880 TI - Evaluation of a health service delivery intervention to promote falls prevention in older people across the care continuum. AB - RATIONALE, AIMS AND OBJECTIVES: The incidence of falls and fall-related injuries in older age is predicted to increase concomitantly with global population ageing, representing a serious challenge to health care systems. In spite of the availability of policy and practice guidelines for the prevention of falls and fall-related injuries, a considerable gap remains between best practice and current health service delivery. This paper describes the method and results of the implementation and evaluation of a state-wide workforce enhancement strategy to promote the uptake of evidence-based falls prevention activities for older people. METHODS: The project was undertaken in Queensland, Australia in 2008 across the community, acute and residential aged care sectors. Six Falls Safety Officers (FSOs) were appointed to implement a 1-year pilot of strategies aimed at enhancing workforce capacity to deliver a coordinated approach to falls prevention across the care continuum. The project was independently evaluated for process, impact and outcome. Both quantitative and qualitative data were extracted from records maintained by the FSOs for the evaluation and additional data were obtained from interviews with key stakeholders. RESULTS: Considerable progress was achieved towards the project's objectives, including the wide dissemination of information and resources, as well as the establishment of working groups to continue falls prevention planning and implementation. Barriers and facilitators to the project's implementation were identified. CONCLUSION: The formal evaluation provides evidence for the development of a cross-continuum service delivery model for implementing coordinated state-wide falls prevention strategies for the prevention of falls in older people. PMID- 20722881 TI - Are interventions recommended by pharmacists during Home Medicines Review evidence-based? AB - INTRODUCTION: Over the past decade medication review services have been implemented in many countries, including Australia, UK and USA. Although, the attitudes and barriers to the implementation of evidence-based medicine have been investigated, the extent to which medication review recommendations are evidence based is not known. OBJECTIVE: To determine (1) the extent to which pharmacist's recommendations during medication review services were consistent with the evidence-based guides at the time of the review; and (2) the nature and extent of drug-related problems (DRPs) and the actions recommended by pharmacists to resolve DRPs. METHOD: A retrospective review of Home Medicines Review cases performed on 224 community-dwelling older people (65 years or older). The chi squared test for categorical variables was used to compare the proportion of recommendations that were evidence-based and recommendations for which no evidence could be identified in the most common Australian information sources. DRPs and the actions recommended to resolve the DRPs were classified according to previously employed criteria. RESULTS: Pharmacists made a total of 1114 therapeutic recommendations to general practitioners, of which 964 required supporting pharmacotherapeutic evidence. The majority (94%) of the pharmacists' recommendations were in accordance with the evidence-based guides, as compared with the recommendations for which no evidence could be identified (P < 0.001). Pharmacists reported that 98% of the patients had at least one problem with use of their medication detected. CONCLUSION: The majority of the actions recommended by pharmacists during the medication review process were consistent with the literature embedded in key Australian information sources. Medication management in older people is complex and challenging, as highlighted by the DRPs identified in 98% of our patients. A suitably trained pharmacist, with full access to the patient, medical record and supporting resources, can help to improve the quality use of medicines in this at-risk population. PMID- 20722882 TI - Evaluation of email alerts in practice: Part 2. Validation of the information assessment method. AB - RATIONALE AND OBJECTIVE: The information assessment method (IAM) permits health professionals to systematically document the relevance, cognitive impact, use and health outcomes of information objects delivered by or retrieved from electronic knowledge resources. The companion review paper (Part 1) critically examined the literature, and proposed a 'Push-Pull-Acquisition-Cognition-Application' evaluation framework, which is operationalized by IAM. The purpose of the present paper (Part 2) is to examine the content validity of the IAM cognitive checklist when linked to email alerts. METHODS: A qualitative component of a mixed methods study was conducted with 46 doctors reading and rating research-based synopses sent on email. The unit of analysis was a doctor's explanation of a rating of one item regarding one synopsis. Interviews with participants provided 253 units that were analysed to assess concordance with item definitions. RESULTS AND CONCLUSION: The content relevance of seven items was supported. For three items, revisions were needed. Interviews suggested one new item. This study has yielded a 2008 version of IAM. PMID- 20722883 TI - The identification of risk factors for infectious patients with acute fever and formulation of activation criteria to alert outpatient clinic doctors. AB - RATIONALE, AIMS AND OBJECTIVES: Acute fever is the most common clinical symptom for infectious diseases. It is necessary to identify risk factors for infectious patients with acute fever and formulate activation criteria of early warning infectiosity score system (EWIS) to alert outpatient clinic doctors. METHODS: Logistic regression analysis was used to determine risk factors for infectious diseases from the clinical data of 758 patients with acute fever. Risk factors were weighted and an EWIS was formulated. A receiver operator characteristic (ROC) analysis of weighted cumulative scores was performed to evaluate the diagnostic accuracy of EWIS, and the Kappa test used to confirm diagnostic reliability. A chi(2) -test for trend was applied to determine the relevance between EWIS and incidence of infectious diseases. RESULTS: Risk factors for infections included conjunctival hyperaemia, rash, diarrhoea, increased alanine aminotransferase, splenomegaly and abnormal percentage of peripheral neutrophils (NE%). Risk factors were weighted and tabulated. The areas under the ROC curves of the EWIS was 0.929 and >= 4 points predicted infectious diseases, and the Kappa values were 0.750. As the score increased, the incidence of infectious diseases increased. The areas under the ROC curves of the EWIS predicting on single viral and bacterial infectious diseases were 0.961 and 0.896, and the Kappa values were 0.807 and 0.701, respectively. CONCLUSIONS: Risk factors for infections have been identified, quantified and formulated into a table of EWIS that have high diagnostic accuracy and reliability for the early identification of contagious diseases. PMID- 20722884 TI - Predictors of doctor-rated and patient-rated gout severity: gout impact scales improve assessment. AB - RATIONALE, AIMS AND OBJECTIVES: Our objective was to describe the factors associated with doctor-rated and patient-rated gout severity to explain how doctor assessment involving patient-reported outcomes can improve the clinical management of gout. METHODS: Patients completed a newly validated gout-specific health-related quality of life instrument, the Gout Impact Scale (GIS) and other questions regarding their gout. Both patients and their doctors gave an overall gout severity assessment. We conducted correlation analyses between each predictor of interest and the two different severity ratings (doctor-rated severity and patient-rated severity). Stepwise multiple regressions were performed to determine the best predictors for doctor-rated and patient-rated severity, respectively. RESULTS: Doctor-rated severity more closely correlated with objective clinical and laboratory findings, particularly the presence of tophi, which was not a leading factor in patient-rated severity assessments. Patient-rated severity more closely correlated with the domains of the GIS, which expressed the impact of gout on health-related quality of life. CONCLUSION: Doctors might have a better understanding of their patients' level of disease impact if they incorporate an instrument such as the GIS in their evaluation of gout severity and their decisions regarding aggressiveness of treatment. The increased use of patient-reported outcomes measures has the potential to improve quality of care and patient satisfaction, as well as reduce costs of health care utilization. PMID- 20722885 TI - Evaluation of email alerts in practice: Part 1. Review of the literature on clinical emailing channels. AB - RATIONALE: Methods to systematically assess electronic knowledge resources by health professionals may enhance evaluation of these resources, knowledge exchange between information users and providers, and continuing professional development. We developed the Information Assessment Method (IAM) to document health professional perspectives on the relevance, cognitive impact, potential use and expected health outcomes of information delivered by (push) or retrieved from (pull) electronic knowledge resources. However, little is known about push communication in health sciences, and what we propose to call clinical emailing channels (CECs). CECs can be understood as a communication infrastructure that channels clinically relevant research knowledge, email alerts, from information providers to the inboxes of individual practitioners. AIMS: In two companion papers, our objectives are to (part 1) explore CEC evaluation in routine practice, and (part 2) examine the content validity of the cognitive component of IAM. METHODS: The present paper (part 1) critically reviews the literature in health sciences and four disciplines: communication, information studies, education and knowledge translation. Our review addresses the following questions. What are CECs? How are they assessed? RESULTS: The review contributes to better define CECs, and proposes a 'push-pull-acquisition-cognition application' evaluation framework, which is operationalized by IAM. CONCLUSION: Compared with existing evaluation tools, our review suggests IAM is comprehensive, generic and systematic. PMID- 20722886 TI - Doctor characteristics and prescribing antibiotics for urinary tract infections: the experience of an Asian country. AB - RATIONALE, AIMS AND OBJECTIVES: This study aims to explore the relationship between doctor characteristics and prescribing behaviour for patients with urinary tract infections (UTIs) using a 2-year population-based data set in Taiwan. METHODS: This study used data from the Taiwan National Health Insurance Research Database. Our study sample consists of first-time ambulatory care visits for treatment of UTIs among female patients between 2005 and 2006 (n=45,934). The primary outcome studied was 'whether a broad-spectrum antibiotic was prescribed', and the key independent variables were 'doctor characteristics'. Doctor characteristics included gender, age (<41, 41-50, >50), specialty, type (hospital based vs. office-based) and practice location. Multivariate logistic regression analysis using generalized estimated equations was performed to assess the adjusted odds ratio of the doctors using broad-spectrum antibiotics. RESULTS: Among the sampled patients, 13.5% were prescribed broad-spectrum antibiotics at their first visit for treatment of UTIs. The adjusted odds of prescribing second line antibiotics for doctors aged between 41-50 years and >50 years were 0.80 (P<0.001) and 0.90 (P=0.007) times, respectively, that of doctors aged <41 years. Doctors specializing in family medicine were 1.10 (P=0.006) times more likely than doctors specializing in obstetrics and gynaecology to prescribe broad spectrum, and office-based doctors were 1.41 (P<0.001) times more likely than hospital-based doctors to do so. CONCLUSIONS: We conclude that there is variation in doctor prescribing behaviour of antimicrobial therapy for UTIs, after adjusting for possible confounding factors. Continuing medical education and intervention should be designed for doctor groups with undesirable performance in prescribing antibiotics. PMID- 20722887 TI - Allied health clinicians' beliefs and attitudes about medication adherence in depressive disorders. PMID- 20722888 TI - Use of a clinical decision support system to increase osteoporosis screening. AB - BACKGROUND: In 2002, the US Preventive Services Task Force recommended routine osteoporosis screening for women aged 65 years or older. However, studies have indicated that osteoporosis remains underdiagnosed, and various methods such as the use of health information technology have been tried to increase screening rates. We investigated whether we could boost the low rates of bone mineral density testing with implementation of a point-of-care clinical decision support system in our primary care practice. METHODS: We retrospectively reviewed the medical records of female patients eligible for osteoporosis screening who had no prior bone mineral density test who were seen at our primary care practice sites in 2007 or 2008 (before and after implementation of a point-of-care clinical decision support system). RESULTS: Overall, screening rates were 80.1% in 2007 and 84.1% in 2008 (P < 0.001). Of patients who did not have osteoporosis screening before the visit, 5.87% completed the screening after the visit in 2007, compared with 9.79% in 2008 (when the clinical support system was implemented), a 66.7% improvement (P = 0.025). CONCLUSION: Clinical decision support for primary care doctors significantly improved osteoporosis screening rates among eligible women. Carefully designed clinical decision support systems can optimize care delivery, ensuring that important preventive services such as osteoporosis screening for patients at risk for fracture are performed while unnecessary testing is avoided. PMID- 20722889 TI - Exploratory cross-sectional study of factors associated with pre-hospital management of pain. AB - RATIONALE, AIMS AND OBJECTIVES: Improving pain management is important in pre hospital settings. We aimed to investigate how pain was managed in pre-hospital suspected acute myocardial infarction (AMI) or fracture and how this could be improved. METHOD: We conducted a cross-sectional study in Lincolnshire using recorded suspected AMI and fracture between April 2005 and March 2006. Outcomes included pain assessment, improvement in pain scores and administration of Entonox, opiates or GTN (in AMI). RESULTS: We accessed 3654 patients with suspected AMI or fracture. Pain was assessed in over three quarters of patients but analgesics administered in under two-fifths. Assessment was more likely in patients with suspected AMI (OR 2.05, 95% CI [1.70, 2.47]), and who were alert (OR 3.55, 95% CI [2.32, 5.43]). Entonox was less likely to be administered for suspected AMI (OR 0.11, 95% CI [0.087, 0.15]) or by paramedic crews (OR 0.56, 95% CI [0.45, 0.68]) but more likely to be given when pain had been assessed (OR 3.54, 95% CI [2.77, 4.52]). Opiates were more likely to be prescribed for suspected AMI (OR 1.30, 95% CI [1.07, 1.57]), in alert patients (OR 1.35, 95% CI [0.71, 2.56]) assessed for pain (OR 2.20, 95% CI [1.73, 2.80]) by paramedic crews. CONCLUSIONS: This exploratory study showed shortfalls in assessment and treatment of pain, but also demonstrated that assessment of pain was associated with more effective treatment. Further research is needed to understand barriers to pre-hospital pain management and investigate mechanisms to overcome these. PMID- 20722890 TI - Using VLAD scores to have a look insight ICU performance: towards a modelling of the errors. AB - RATIONALE, AIMS AND OBJECTIVES: Mortality prediction models using logistic regression analysis play a pivotal role in intensive care quality evaluation, allowing a hospital's performance to be compared with a standard. However, when a difference between predicted and observed mortality exists, that is, the numerator of the Variable Life Adjusted Display (VLAD) score, the investigation for a possible explanation could be arduous. In this article we tested the ability of Bayesian Network (BN) to identify factors determining the negative discrepancy between expected and actual outcomes recorded in four Italian intensive care units (ICUs). METHODS: A BN was implemented to predict the extent of the expected-observed distance quantified by the VLAD score. BN performance was compared with those of a set of tools including Linear Model, Random Forest Regression Tree analysis, Artificial Neural Networks and Support Vector Machine. RESULTS: BN allows the identification of critical areas responsible for bad performance. Compared with other techniques, BN always explains a higher variance percentage and it shows similar or superior discrimination ability. CONCLUSIONS: BN, being able to guide interpretation of covariates role by means of a graphic representation of relationships, confirms its utility particularly where many interactions between predictors exist and when a coherent set of theories regarding which variables are related and how is not available. PMID- 20722891 TI - The role of genotype-by-environment interactions in sexual selection. AB - Genotype-by-environment interactions (GxEs) in naturally selected traits have been extensively studied, but the impact of GxEs on sexual selection has only recently begun to receive attention. Here, we review recent models and consider how GxEs might affect the evolution of sexual traits through influencing sexual signal reliability and also how GxEs may influence variation in sexually selected traits and the process of reproductive isolation. We then assess the current empirical literature on GxEs in sexual selection and conclude by highlighting areas that need additional work. Research on GxEs and sexual selection is an important new area of study for the discipline, which has largely focused on relatively simple mate choice/competition scenarios to date. Investigators now need to apply this knowledge to more complex, but realistic, situations, to more fully explore the evolution of sexual traits, and in this review we suggest potentially useful directions for future research. PMID- 20722892 TI - Combining capture-recapture data and pedigree information to assess heritability of demographic parameters in the wild. AB - Quantitative genetic analyses have been increasingly used to estimate the genetic basis of life-history traits in natural populations. Imperfect detection of individuals is inherent to studies that monitor populations in the wild, yet it is seldom accounted for by quantitative genetic studies, perhaps leading to flawed inference. To facilitate the inclusion of imperfect detection of individuals in such studies, we develop a method to estimate additive genetic variance and assess heritability for binary traits such as survival, using capture-recapture (CR) data. Our approach combines mixed-effects CR models with a threshold model to incorporate discrete data in a standard 'animal model' approach. We employ Markov chain Monte Carlo sampling in a Bayesian framework to estimate model parameters. We illustrate our approach using data from a wild population of blue tits (Cyanistes caeruleus) and present the first estimate of heritability of adult survival in the wild. In agreement with the prediction that selection should deplete additive genetic variance in fitness, we found that survival had low heritability. Because the detection process is incorporated, capture-recapture animal models (CRAM) provide unbiased quantitative genetics analyses of longitudinal data collected in the wild. PMID- 20722893 TI - The diversity and radiation of the largest monophyletic animal group on New Caledonia (Trichoptera: Ecnomidae: Agmina). AB - In area, New Caledonia is the smallest of the world's 25 official biodiversity hotspots, but in many taxonomic groups, the island has the highest concentration of species on earth, particularly so in the freshwater insect order Trichoptera. This study aims at applying molecular data and morphology for estimating the real species diversity of the genus Agmina on New Caledonia and investigating potential effects of ultramafic rock substrate on diversification. A dated molecular phylogeny was applied to study diversity and diversification related to geological substrate using the dispersal-extinction-cladogenesis model, diva and Bayesian ancestral character reconstruction. More than 47 species (>63%) were unknown to science. Initial radiation occurred on ultramafic substrate followed by several independent dispersal events to nonultramafic substrate. The rate of shift from ultramafic to nonultramafic substrate was significantly higher than the rate of shift in the opposite direction, indicating a possible cost associated with living on ultramafic substrate. PMID- 20722894 TI - Geographic variation in phenotypic plasticity in response to dissolved oxygen in an African cichlid fish. AB - Genetic adaptation and phenotypic plasticity are two ways in which organisms can adapt to local environmental conditions. We examined genetic and plastic variation in gill and brain size among swamp (low oxygen; hypoxic) and river (normal oxygen; normoxic) populations of an African cichlid fish, Pseudocrenilabrus multicolor victoriae. Larger gills and smaller brains should be advantageous when oxygen is low, and we hypothesized that the relative contribution of local genetic adaptation vs. phenotypic plasticity should be related to potential for dispersal between environments (because of gene flow's constraint on local genetic adaptation). We conducted a laboratory-rearing experiment, with broods from multiple populations raised under high-oxygen and low-oxygen conditions. We found that most of the variation in gill size was because of plasticity. However, both plastic and genetic effects on brain mass were detected, as were genetic effects on brain mass plasticity. F(1) offspring from populations with the highest potential for dispersal between environments had characteristically smaller and more plastic brains. This phenotypic pattern might be adaptive in the face of gene flow, if smaller brains and increased plasticity confer higher average fitness across environment types. PMID- 20722895 TI - Sex-related variation in migration phenology in relation to sexual dimorphism: a test of competing hypotheses for the evolution of protandry. AB - Timing of arrival/emergence to the breeding grounds is under contrasting natural and sexual selection pressures. Because of differences in sex roles and physiology, the balance between these pressures on either sex may differ, leading to earlier male (protandry) or female (protogyny) arrival. We test several competing hypotheses for the evolution of protandry using migration data for 22 bird species, including for the first time several monochromatic ones where sexual selection is supposedly less intense. Across species, protandry positively covaried with sexual size dimorphism but not with dichromatism. Within species, there was weak evidence that males migrate earlier because, being larger, they are less susceptible to adverse conditions. Our results do not support the 'rank advantage' and the 'differential susceptibility' hypotheses, nor the 'mate opportunity' hypothesis, which predicts covariation of protandry with dichromatism. Conversely, they are compatible with 'mate choice' arguments, whereby females use condition-dependent arrival date to assess mate quality. PMID- 20722896 TI - Male-induced costs of mating for females compensated by offspring viability benefits in an insect. AB - Sexual conflict facilitates the evolution of traits that increase the reproductive success of males at the expense of components of female fitness. Theory suggests that indirect benefits are unlikely to offset the direct costs to females from antagonistic male adaptations, but empirical studies examining the net fitness pay-offs of the interaction between the sexes are scarce. Here, we investigate whether matings with males that invest intrinsically more into accessory gland tissue undermine female lifetime reproductive success (LRS) in the cricket Teleogryllus oceanicus. We found that females incur a longevity cost of mating that is proportional to the partner's absolute investment into the production of accessory gland products. However, male accessory gland weight positively influences embryo survival, and harmful ejaculate-induced effects are cancelled out when these are put in the context of female LRS. The direct costs of mating with males that sire offspring with higher viability are thus compensated by direct and possibly indirect genetic benefits in this species. PMID- 20722897 TI - Historical mutation rates predict susceptibility to radiation in Chernobyl birds. AB - Extreme environmental perturbations are rare, but may have important evolutionary consequences. Responses to current perturbations may provide important information about the ability of living organisms to cope with similar conditions in the evolutionary past. Radioactive contamination from Chernobyl constitutes one such extreme perturbation, with significant but highly variable impact on local population density and mutation rates of different species of animals and plants. We explicitly tested the hypothesis that species with strong impacts of radiation on abundance were those with high rates of historical mutation accumulation as reflected by cytochrome b mitochondrial DNA base-pair substitution rates during past environmental perturbations. Using a dataset of 32 species of birds, we show higher historical mitochondrial substitution rates in species with the strongest negative impact of local levels of radiation on local population density. These effects were robust to different estimates of impact of radiation on abundance, weighting of estimates of abundance by sample size, statistical control for similarity in the response among species because of common phylogenetic descent, and effects of population size and longevity. Therefore, species that respond strongly to the impact of radiation from Chernobyl are also the species that in the past have been most susceptible to factors that have caused high substitution rates in mitochondrial DNA. PMID- 20722898 TI - Chemical composition and anticancer and antioxidant activities of Schinus molle L. and Schinus terebinthifolius Raddi berries essential oils. AB - Essential oils were obtained by steam distillation from berries of Schinus molle L. and Schinus terebinthifolius Raddi originating from southern of Tunisia and analyzed by GC-FID and GC-MS. Among 57 and 62 compounds (%[mg/100 g dry matter]) identified in these oils, the main were alpha-phellandrene (46.52%[1256.15] and 34.38%[859.60]), beta-phellandrene (20.81%[561.74] and 10.61%[265.15]), alpha terpineol (8.38%[226.26] and 5.60%[140.03]), alpha-pinene (4.34%[117.29] and 6.49%[162.25]), beta-pinene (4.96%[133.81] and 3.09%[77.30]) and p-cymene (2.49%[67.28] and 7.34%[183.40]), respectively. A marked quantity of gamma cadinene (18.04%[451.05]) was also identified in the S. terebinthifolius essential oil whereas only traces (0.07%[1.81]) were detected in the essential oil of S. molle. The in vitro antioxidant and antiradical scavenging properties of the investigated essential oils were evaluated by using 1,1-diphenyl-2 picrylhydrazyl (DPPH) and 2,2'-Azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. Essential oil of S. terebinthifolius expressed stronger antioxidant activity in the ABTS assay, with an IC(50) of 24 +/- 0.8 mg/L, compared to S. molle (IC(50)= 257 +/- 10.3 mg/L). Essential oils were also evaluated for their anticancer activities against human breast cancer cells (MCF 7). S. terebinthifolius essential oil was more effective against tested cell lines (IC(50)= 47 +/- 9 mg/L) than that from S. molle (IC(50)= 54 +/- 10 mg/L). Suggestions on relationships between chemical composition and biological activities are outlined. PMID- 20722899 TI - Two endogenous substrates for polyphenoloxidase in pericarp tissues of postharvest rambutan fruit. AB - The catalytic oxidation of phenolic substrates by polyphenoloxidase (PPO) causes pericarp browning of postharvest rambutan fruit. In the present study, PPO and its endogenous substrates were extracted from rambutan pericarp tissues (RPT). The substrate extracts were sequentially partitioned with ethyl acetate and n butanol. The analysis of total phenolic content showed that the most phenolic compounds were distributed in ethyl acetate fraction. By high-performance liquid chromatography (HPLC), (-)-epicatechin (EC) and proanthocyanidin A2 (PA2) were identified from this fraction. After reacting with rambutan PPO, EC turned brown rapidly within 10 min, indicating that it was a significant endogenous substrate. Although PA2 could also be oxidized by the PPO, it turned brown very slowly. In addition, because EC and PA2 were continually catalyzed into browning products by PPO during storage of the fruit at 4 and 25 degrees C, their contents in RPT gradually declined with the extended storage time. It was further observed that both substrate contents in rambutan fruit storing at 25 degrees C decreased more rapidly than that storing at 4 degrees C, suggesting that low temperature inhibited the catalytic oxidation of substrates so as to slow down pericarp browning. Practical Application: Pericarp browning is a serious problem to storage and transport of harvested rambutan fruit. A generally accepted opinion on the browning mechanism is the oxidation of phenolic substrates by PPO. Ascertaining PPO substrates will effectively help us to control enzymatic reaction by chemical methods so as to delay or even prevent pericarp browning of harvested rambutan fruit. PMID- 20722900 TI - Addition of soluble soybean polysaccharides to dairy products as a source of dietary fiber. AB - Increasing consumption of dietary fiber in food leads to many important health benefits: for example, reduction in blood cholesterol, reduced risk of diabetes, and improved laxation. Water soluble soybean polysaccharide (SSPS) is a dietary fiber extracted and refined from okara, a byproduct of soy manufacturing. It was incorporated into 3 categories of dairy-based products, thickened milkshake-style beverages, puddings, and low-fat ice cream, to the maximum amount without over texturing the food. Rheological measurements and sensory tests were used to develop desirable SSPS-fortified products. From the rheological data, 4% SSPS fortified dairy beverages and 4% SSPS -fortified puddings were in the range of commercial products. From sensory analyses, 4% SSPS-fortified dairy beverage with 0.015%kappa-carrageenan, 4% SSPS-fortified pudding with 0.1%kappa-carrageenan, and 2% SSPS-fortified low-fat ice cream gained the highest scores in consumer hedonic rating. Panelists also indicated their willingness to consume those products if they were available commercially. Practical Application: Since the dietary fiber intake of many people is below their suggested adequate intake values, strategies to successfully fortify foods with fiber may help alleviate this gap. We have developed 3 dairy products, a beverage, a pudding, and a low fat ice cream, that have been fortified with soluble soybean polysaccharide at levels of 4%, 4%, and 2%, respectively. These products were within acceptable ranges of rheological parameters and other physical stability measurements and were judged to be acceptable by sensory analyses. PMID- 20722901 TI - Physicochemical, nutritional, and functional characterization of fruits xoconostle (Opuntia matudae) pears from Central-Mexico Region. AB - Xoconostle cv. Cuaresmeno (Opuntia matudae) has attracted domestic and international industry attention; however, variations of composition from xoconostle structures have not been evaluated. Industries discard the pulp (endocarp) and peel (pericarp) as wastes and utilize the skin (mesocarp), which is the edible portion. The physicochemical, nutritional, and functional characterization of structures from xoconostle pear from 3 major sites of production in Mexico were assessed. Skin yield ranged from 58% to 64% and was higher to that of peel (22% to 24%) and pulp (12% to 18%) yields. pH, degrees Brix, and acidity were similar among xoconostle structures. Total fiber showed by peel (18.23% to 20.37%) was 2-fold higher than that of skin. Protein and ether extract were higher in xoconostle pulp compared to that showed by peel and skin. Iron content of xoconostle peel (6 to 9.6 mg/100 g, DWB) was higher to that of skin and pulp and prickly pear pulp. Soluble phenols of peel (840 to 863 mg GAE/100 g, DWB) were almost similar to that of skin (919 to 986 mg GAE/100 g, dry weigh basis); meanwhile, ascorbic acid concentration of skin was 2-fold higher compared to that of peel. The phenolic fraction of xoconostle structures consisted of gallic, vanillic, and 4-hydroxybenzoic acids; catechin, epicatechin, and vanillin were also identified by high-performance liquid chromatography-didoe array detection (HPLC-DAD). Xoconostle peel showed higher antioxidant activity (TEAC) compared to that of skin (2-fold) and pulp (6-fold) of commonly consumed fruits and vegetables. The potential of xoconostle peel and pulp for the production of feed or food is promissory. Practical Application: Outstanding nutritional and functional properties of xoconostle cv. Cuaresmeno fruits are demonstrated. Increased consumption could contribute positively to improve the diet of rural and urban consumers. The high fiber, mineral, and antioxidant components of xoconostle peel and pulp suggest that these fruit structures, which are currently discarded as waste, have promissory use as feed or food by industry. PMID- 20722902 TI - Development of soybean protein-isolate edible films incorporated with beeswax, Span 20, and glycerol. AB - The effect of the beeswax, Span 20, and glycerol content on qualities of soybean protein-isolate edible films was evaluated. Beeswax and Span 20 were selected to improve qualities of soybean-protein-isolate films from 11 emulsifiers. The content of beeswax, Span 20, and glycerol was further optimized by response surface analysis. The optimal composite emulsifier was beeswax (1.87% of soybean protein-isolate), Span 20 (10.25% of soybean protein-isolate), and glycerol (29.12% of soybean protein-isolate) with tensile strength of 908 MPa, percentage elongation at break of 25.8%, water vapor permeability of 19.2 g/m.d.MPa, and oxygen permeability of 0 cm(3)/m.d.MPa. The quality of soybean-protein-isolate films incorporated with the optimal composite emulsifier was 2.34 times higher than that of the control. Furthermore, the disulfide bond content of soybean protein-isolate films showed a positive correlation with their quality, which provided a simple and rapid way to rank quality of soybean-protein-isolate films. Therefore, our result will not only give an instruction to soybean-protein isolate-film production, but also give a simple and rapid way to rank film qualities. Practical Application: Our results give the optimal composite emulsifiers for the soybean-protein-isolate-film production. The soybean-protein isolate films based on the optimal composite emulsifiers show their tensile strength of 908 MPa, percentage elongation at break of 25.8%, water vapor permeability of 19.2 g/m.d.MPa, and oxygen permeability of 0 cm(3)/m.d.MPa, being stronger than the control. Moreover, our results give a simple and rapid way to rank film qualities, because the disulfide bond content of soybean-protein isolate films showed a positive correlation with their quality. Hence, the disulfide bond content was an indicator to rank qualities of soybean-protein isolate films. PMID- 20722903 TI - Temperature dependence of autoxidation of perilla oil and tocopherol degradation. AB - Temperature dependence of the autoxidation of perilla oil and tocopherol degradation was studied with corn oil as a reference. The oils were oxidized in the dark at 20, 40, 60, and 80 degrees C. Oil oxidation was determined by peroxide and conjugated dienoic acid values. Tocopherols in the oils were quantified by HPLC. The oxidation of both oils increased with oxidation time and temperature. Induction periods for oil autoxidation decreased with temperature, and were longer in corn oil than in perilla oil, indicating higher sensitivity of perilla oil to oxidation. However, time lag for tocopherol degradation was longer in perilla oil, indicating higher stability of tocopherols in perilla oil than in corn oil. Activation energies for oil autoxidation and tocopherol degradation were higher in perilla oil (23.9 to 24.2, 9.8 kcal/mol, respectively) than in corn oil (12.5 to 15.8, 8.8 kcal/mol, respectively) indicating higher temperature dependence in perilla oil. Higher stability of tocopherols in perilla oil was highly related with polyphenols. The study suggests that more careful temperature control is required to decrease the autoxidation of perilla oil than that of corn oil, and polyphenols contributed to the oxidative stability of perilla oil by protecting tocopherols from degradation, especially at the early stage of oil autoxidation. PMID- 20722904 TI - Direct spectroscopic observation of singlet oxygen quenching and kinetic studies of physical and chemical singlet oxygen quenching rate constants of synthetic antioxidants (BHA, BHT, and TBHQ) in methanol. AB - Singlet oxygen quenching by synthetic antioxidants (BHA, BHT, and TBHQ) was directly observed by spectroscopic monitoring of luminescence at 1268 nm. The luminescence data showed unambiguous evidence of singlet oxygen quenching by synthetic phenolic antioxidants with the highest activity for TBHQ, followed by BHA and BHT. The protective activities of these synthetic antioxidants on alpha terpinene oxidation with chemically-induced singlet oxygen under dark further confirmed their singlet oxygen quenching abilities. Total singlet oxygen quenching rate constants (k(r) + k(q)) of BHA, BHT, and TBHQ were determined in a system containing alpha-terpinene (as a singlet oxygen trap) and methylene blue (as a sensitizer) during light irradiation, and the values were 5.14 x 10(7), 3.41 x 10(6), and 1.99 x 10(8) M(-1)s(-1), respectively. After the k(r) value of alpha-terpinene was first determined, the k(r) values of the synthetic antioxidants were calculated by measuring their relative reaction rates with singlet oxygen to that of alpha-terpinene under the identical conditions. The k(r) values of the BHA, BHT, and TBHQ were 3.90 x 10(5), 1.23 x 10(5), and 2.93 x 10(6), M(-1)s(-1). The percent partition of chemical quenching over total singlet oxygen quenching (k(r) x 100)/(k(r) + k(q)) for BHA, BHT, and TBHQ were 0.76%, 3.61%, and 1.47%, respectively. The results showed that the synthetic antioxidants quench singlet oxygen almost exclusively through the mechanism of physical quenching. This represents the first report on the singlet oxygen quenching mechanism of these synthetic antioxidants. Practical Application: The synthetic antioxidants, especially TBHQ, have been found to have a strong singlet oxygen quenching ability. This article also clearly showed that singlet oxygen quenching by synthetic antioxidants was mainly by the physical quenching mechanism. The results suggested that these synthetic antioxidants, especially TBHQ, could be used practically for the protection of the food components such as edible oils and vitamins against singlet oxygen induced oxidations without significant losses of antioxidant activity during storage under light. PMID- 20722905 TI - Biochemical traits of Ciauscolo, a spreadable typical Italian dry-cured sausage. AB - Ciauscolo is a short-ripened fermented sausage manufactured in the Marche region (central Italy) that has recently received a protected geographical indication product classification (PGI). The aim of this study was the exploration of the biochemical traits of this traditional Italian salami, with a special focus on protein and lipid composition. Ciauscolo salami was characterized by pH of 5.1 and 0.91 water activity. A prevalence of lactic acid bacteria in the microbiota was found. The free amino acids and biogenic amines average content was 2657 and 255 mg/kg, respectively. With regards to lipids composition unsaturated fatty acids represented 63% and 72% of total and free fatty acids. Despite these results had wide statistical variability, attributable to differences in the processing parameters and raw matter used, some peculiar traits were found: (1) structural muscular proteins underwent to less proteolysis than sarcoplasmic ones; (2) glycogen phosphorylase, enolase, and aldolase were the most proteolyzed among the sacoplasmic proteins; (3) there was inverse correlation between histamine content and yeasts population, and a direct correlation between the gly pro content and lactic acid bacteria counts; (4) the content of aspartic acid and methyonine seem to be a possible molecular marker able to distinguish between double and single milling. PMID- 20722906 TI - Effect of partial substitution of NaCl with KCl on Halloumi cheese during storage: chemical composition, lactic bacterial count, and organic acids production. AB - The effect of partial substitution of NaCl with KCl on chemical composition, lactic bacterial count, and organic acids profile of Halloumi cheese was investigated. Halloumi cheeses were made and kept in 4 different brine solutions at 18% including NaCl only (HA), 3NaCl : 1KCl (HB), 1NaCl : 1KCl (HC), and 1NaCl : 3KCl (HD) and then stored at 4 degrees C for 56 d. No significant effect was observed between control and experimental cheeses in terms of moisture, fat, protein, lactic bacterial count, and pH values at the same storage period. There was a significant difference in ash, sodium, and potassium contents among experimental cheeses at the same storage period. Ash, sodium, and potassium contents increased significantly during storage at same salt treatment. There was no significant difference in lactic and citric acid contents among experimental cheeses and that of the control. In contrary, there was a significant difference in acetic acid among experimental cheeses. A strong positive correlation was observed between ash, Na, and K contents. An inverse correlation between organic acids and both Na and K contents was also observed. PMID- 20722907 TI - Isolation and identification of antioxidant compounds from Ligularia fischeri. AB - The plant Ligularia fischeri var. spiciformis Nakai, a well-known edible medicinal herb in Korea, has been used to treat maladies such as jaundice, scarlet fever, rheumatoid arthritis, and hepatic function failure. In this research, 4 major antioxidant compounds were detected from this plant's leaves using an on-line high-performance liquid chromatography (HPLC)-ABTS screening system, which can determine the antioxidant activity based on a decrease in absorbance at 734 nm after postcolumn reaction of HPLC-separated antioxidants with the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radicals (ABTS(*)). In order to isolate these active compounds, a preparative HPLC was applied and their chemical structures were identified as 5-O-caffeoylquinic acid (5-CQA), 3,4-di-O-caffeoylquinic acid (3,4-DCQA), 3,5-di-O-caffeoylquinic acid (3,5-DCQA), and 4,5-di-O-caffeoylquinic acid (4,5-DCQA) by ESI/MS(n) and (1)H NMR. These 4 isomers comprised over 10% of the dried leaves, with 3,5-DCQA being the most abundant compound. The radical scavenging activity of each isomer was also evaluated simultaneously through the on-line HPLC-ABTS method, which showed 94% antioxidant activity of the ethanol extract derived from caffeoylquinic acids. Among these isomers, 3,4-DCQA contained the most strong antioxidant activity while 3,5-DCQA accounted for the highest radical scavenging capacity due to having the highest content. PMID- 20722908 TI - Influence of droplet charge on the chemical stability of citral in oil-in-water emulsions. AB - The chemical stability of citral, a flavor component widely used in beverage, food, and fragrance products, in oil-in-water emulsions stabilized by surfactants with different charge characteristics was investigated. Emulsions were prepared using cationic (lauryl alginate, LAE), non-ionic (polyoxyethylene (23) lauryl ether, Brij 35), and anionic (sodium dodecyl sulfate, SDS) surfactants at pH 3.5. The citral concentration decreased over time in all the emulsions, but the rate of decrease depended on surfactant type. After 7 d storage, the citral concentrations remaining in the emulsions were around 60% for LAE- or Brij 35 stabilized emulsions and 10% for SDS-stabilized emulsions. An increase in the local proton (H(+)) concentration around negatively charged droplet surfaces may account for the more rapid citral degradation observed in SDS-stabilized emulsions. A strong metal ion chelator (EDTA), which has previously been shown to be effective at increasing the oxidative stability of labile components, had no effect on citral stability in LAE- or Brij 35-stabilized emulsions, but it slightly decreased the initial rate of citral degradation in SDS-stabilized emulsions. These results suggest the surfactant type used to prepare emulsions should be controlled to improve the chemical stability of citral in emulsion systems. PMID- 20722909 TI - White and green teas (Camellia sinensis var. sinensis): variation in phenolic, methylxanthine, and antioxidant profiles. AB - Recent investigations have associated white teas with anti-carcinogenic, immune boosting, and antioxidative properties that may impact human health in a manner comparable to green teas. An in-depth chemical analysis of white tea types was conducted to quantify polyphenols and antioxidant potential of 8 commercially available white teas, and compare them to green tea. Extraction and HPLC protocols were optimized and validated for the quantification of 9 phenolic and 3 methylxanthine compounds to examine inter- and intra-variation in white and green tea types and subtypes. A sampling strategy was devised to assess various subtypes procured from different commercial sources. Variation in antioxidant activity and total phenolic content (TPC) of both tea types was further assessed by the 1-1-diphenyl-2-picrylhydrazyl (DPPH) and Folin-Ciocalteau (F-C) assays, respectively. Total catechin content (TCC) for white teas ranged widely from 14.40 to 369.60 mg/g of dry plant material for water extracts and 47.16 to 163.94 mg/g for methanol extracts. TCC for green teas also ranged more than 10-fold, from 21.38 to 228.20 mg/g of dry plant material for water extracts and 32.23 to 141.24 mg/g for methanol extracts. These findings indicate that statements suggesting a hierarchical order of catechin content among tea types are inconclusive and should be made with attention to a sampling strategy that specifies the tea subtype and its source. Certain white teas have comparable quantities of total catechins to some green teas, but lesser antioxidant capacity, suggesting that white teas have fewer non-catechin antioxidants present. Practical Application: In this investigation white and green teas were extracted in ways that mimic common tea preparation practices, and their chemical profiles were determined using validated analytical chemistry methods. The results suggest certain green and white tea types have comparable levels of catechins with potential health promoting qualities. Specifically, the polyphenolic content of green teas was found to be similar to certain white tea varieties, which makes the latter tea type a potential substitute for people interested in consuming polyphenols for health reasons. Moreover, this study is among the first to demonstrate the effect subtype sampling, source of procurement, cultivation, and processing practices have on the final white tea product, as such analysis has previously been mostly carried out on green teas. PMID- 20722910 TI - Effect of milk on the deodorization of malodorous breath after garlic ingestion. AB - The effect of milk and milk components on the deodorization of diallyl disulfide (DADS), allyl methyl disulfide (AMDS), allyl mercaptan (AM), allyl methyl sulfide (AMS), and methyl mercaptan (MM) in the headspace of garlic as well as in the mouth- and nose-space after garlic ingestion was investigated using selected ion flow tube-mass spectrometry (SIFT-MS). Fat-free and whole milk significantly reduced the head-, mouth-, and nose-space concentrations of all volatiles. Water was the major component in milk responsible for the deodorization of volatiles. Due to its higher fat content, whole milk was more effective than fat-free milk in the deodorization of the more hydrophobic volatiles diallyl disulfide and allyl methyl disulfide. Milk was more effective than water and 10% sodium caseinate in the deodorization of allyl methyl sulfide, a persistent garlic odor, in the mouth after garlic ingestion. Addition of milk to garlic before ingestion had a higher deodorizing effect on the volatiles in the mouth than drinking milk after consuming garlic. Practical Application: Ingesting beverages or foods with high water and/or fat content such as milk may help reduce the malodorous odor in breath after garlic ingestion and mask the garlic flavor during eating. To enhance the deodorizing effect, deodorant foods should be mixed with garlic before ingestion. PMID- 20722911 TI - The impact of antioxidant addition on flavor of cheddar and mozzarella whey and cheddar whey protein concentrate. AB - Lipid oxidation products are primary contributors to whey ingredient off-flavors. The objectives of this study were to evaluate the impact of antioxidant addition in prevention of flavor deterioration of fluid whey and spray-dried whey protein. Cheddar and Mozzarella cheeses were manufactured in triplicate. Fresh whey was collected, pasteurized, and defatted by centrifugal separation. Subsequently, 0.05% (w/w) ascorbic acid or 0.5% (w/w) whey protein hydrolysate (WPH) were added to the pasteurized whey. A control with no antioxidant addition was also evaluated. Wheys were stored at 3 degrees C and evaluated after 0, 2, 4, 6, and 8 d. In a subsequent experiment, selected treatments were then incorporated into liquid Cheddar whey and processed into whey protein concentrate (WPC). Whey and WPC flavors were documented by descriptive sensory analysis, and volatile components were evaluated by solid phase micro-extraction with gas chromatography mass spectrometry. Cardboard flavors increased in fluid wheys with storage. Liquid wheys with ascorbic acid or WPH had lower cardboard flavor across storage compared to control whey. Lipid oxidation products, hexanal, heptanal, octanal, and nonanal increased in liquid whey during storage, but liquid whey with added ascorbic acid or WPH had lower concentrations of these products compared to untreated controls. Mozzarella liquid whey had lower flavor intensities than Cheddar whey initially and after refrigerated storage. WPC with added ascorbic acid or WPH had lower cardboard flavor and lower concentrations of pentanal, heptanal, and nonanal compared to control WPC. These results suggest that addition of an antioxidant to liquid whey prior to further processing may be beneficial to flavor of spray-dried whey protein. Practical Application: Lipid oxidation products are primary contributors to whey ingredient off-flavors. Flavor plays a critical and limiting role in widespread use of dried whey ingredients, and enhanced understanding of flavor and flavor formation as well as methods to control or minimize flavor formation during processing are industrially relevant. The results from this study suggest that addition of an antioxidant to liquid whey prior to further processing may be beneficial to minimize flavor of spray-dried whey protein. PMID- 20722912 TI - Synergistic and antagonistic interactions of phenolic compounds found in navel oranges. AB - Phenolic compounds are known to have antioxidant and antimicrobial properties. These properties may be useful in the preservation of foods or beverages. The interactive antioxidant capacity of phenolic compounds within foods has not been well explored. Interactions of individual phenolic compounds (chlorogenic acid, hesperidin, luteolin, myricetin, naringenin, p-coumaric acid, and quercetin) at the concentrations found in navel oranges (Citrus sinensis) were analyzed for their antioxidant capacity to observe potential antagonistic, additive, or synergistic interactions. Mixtures of 2, 3, and 4 phenolic compounds were prepared. The Oxygen Radical Absorbance Capacity (ORAC) assay was used to quantify the antioxidant capacities of these combinations. Three different combinations of 2 compounds and 5 combinations of 3 compounds were found to be synergistic. One antagonistic combination of 2 was also found. No additional synergism occurred with the addition of a 4th compound. A model was developed to explain our results. Reduction potentials, relative concentration, and the presence or absence of catechol (o-dihydroxy benzene) groups were factors in the model. Practical Application: Understanding how combinations of fruit antioxidants work together will support their future use in preservation of foods and/or beverages. PMID- 20722913 TI - (1)H-NMR-based discrimination of thermal and vinegar treated ginseng roots. AB - To investigate the changes in nonvolatile metabolites of thermal and/or vinegar treated ginseng (TVG), samples prepared using various treatment conditions were analyzed using an (1)H-NMR-based metabolomics technique. The processing conditions of the ginseng in this study were 100, 140, and 180 degrees C with and without vinegar and the duration of exposure to each temperature was 10, 30, and 50 min, respectively. There was a clear separation in the score plots among various treatment conditions. Major compounds contributing to the separation of 50% methanol extracts of TVG with various process conditions were valine, lactate, alanine, arginine, glucose, fructose, and sucrose. As temperature increased, valine, arginine, glucose, fructose, and sucrose concentrations decreased, whereas lactate, glucose, and fructose increased in the vinegar treated samples compared to non-vinegar-treated samples. The present study suggests the usefulness of an (1)H-NMR-based metabolomics approach to discriminate TVG samples, subjected to different processing conditions. PMID- 20722914 TI - Optimization of hydrolysis conditions for the production of antioxidant peptides from fish gelatin using response surface methodology. AB - Fish skin gelatin was hydrolyzed with papain to produce antioxidant peptides. Response surface methodology (RSM) was applied to optimize the hydrolysis conditions (including enzyme to substrate ratio [E/S], hydrolysis time, and temperature). The highest degree of hydrolysis (DH) (50.1 +/- 1.1%) was obtained at an E/S of 2% at 56.8 degrees C, 2.11 h, and was not significantly different from the predicted values within a 95% confidence interval. The highest 1,1 diphenyl-2-picrylhydrazyl (DPPH) (96.8 +/- 0.9%) and 2,2'-azinobis (3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS(*+)) (9.80 +/- 0.11 mM Trolox [6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid]) radical scavenging activities of fish gelatin hydrolyzates were obtained at an E/S of 3% at 52.1 degrees C, 2.65 h, and both DPPH and ABTS(*+) radical-scavenging activities were not significantly different from the predicted values 97.3% and 9.86 mM Trolox within the 95% confidence interval. Therefore, RSM is an efficient way to optimize fish gelatin hydrolysation and the resultant hydrolyzates show promise as antioxidant peptides. Practical Application: There is a growing interest in the use of fish gelatin as an alternative to mammalian gelatin. One potential use is as a source of widely acceptable functional compounds. In this study, a search for antioxidant peptides from fish gelatin prepared by an enzymatic method has been successfully done. This suggests that this is a practical way to obtain bioactive peptides. PMID- 20722915 TI - A novel method for simultaneous and continuous determination of thermal properties during phase transition applied to Calanus finmarchicus. AB - The thermal properties of a product are the most important parameters for practical engineering purposes and models in food science. Calanus finmarchicus is currently being examined as a marine resource for uncommon aquatic lipids and proteins. Thermal conductivity, specific heat, enthalpy and density were measured over the temperature range from -40 to +20 degrees C. The initial freezing point was determined to be -2.3 degrees C. The thermal properties were recorded continuously on 4 samples using a new method, and the results were compared with predictive models. The accuracy of the new method is demonstrated by different calibration runs. Significant differences in the thermal conductivity of the frozen material were found between the parallel-series model and the data, whereas the model of Pham and Willix (1989) or the Maxwell-Euken adaption showed better agreement. The measured data for specific heat, enthalpy, and density agreed well with the model. Practical Application: The thermal data obtained can be used directly in food engineering and technology applications, for example, in a thin layer model for freezing food for which precise thermal data for each layer are now available, enabling the more accurate prediction of freezing times and temperature profiles. Dimensionless numbers (such as the Biot number) can also be based on measured data with minor deviations compared to more general modeled thermal properties. Future activities will include the generation of a comprehensive database for different products. PMID- 20722916 TI - Enhanced anthocyanin extraction from red cabbage using pulsed electric field processing. AB - This study was conducted to evaluate the effect of pulsed electric field (PEF) treatment on anthocyanin extraction from red cabbage using water as a solvent. Mashed cabbage was placed in a batch treatment chamber and subjected to PEF (2.5 kV/cm electric field strength; 15 micros pulse width and 50 pulses, specific energy 15.63 J/g). Extracted anthocyanin concentrations (16 to 889 microg/mL) were determined using HPLC. Heat and light stabilities of the control and PEF treated samples, having approximately the same initial concentrations, were studied. PEF treatments enhanced total anthocyanin extraction in water from red cabbage by 2.15 times with a higher proportion of nonacylated forms than the control (P < 0.05). The heat and light stabilities of the PEF-treated samples and control samples were not significantly different (P > 0.05). Practical Application: An innovative pretreatment technology, pulsed electric field processing, enhanced total anthocyanin extraction in water from red cabbage by 2.15 times. Manufacturers of natural colors can use this technology to extract anthocyanins from red cabbage efficiently. PMID- 20722917 TI - Viscosity and non-Newtonian features of thickened fluids used for dysphagia therapy. AB - Thickening agents based primarily on granulated maize starch are widely used in the care of patients with swallowing difficulties, increasing viscosity of consumed fluids. This slows bolus flow during swallowing, allowing airway protection to be more properly engaged. Thickened fluids have been shown to exhibit time-varying behavior and are non-Newtonian, complicating assessment of fluid thickness, potentially compromising efficacy of therapy. This work aimed to quantify the flow properties of fluids produced with commercial thickeners at shear rates representative of slow tipping in a beaker to fast swallowing. Results were presented as indices calculated using a power-law model representing apparent viscosity (consistency index) and non-Newtonian nature of flow (flow behavior index). Immediately following mixing, 3 fluid thicknesses showed distinct consistency indices and decreasing flow behavior index with increasing thickener concentration. An increase in consistency index over 30 min was observed, but only for samples that were repeatedly sheared during acquisition. Three-hour measurements showed changes in consistency index across fluids with the largest being a 25% rise from initial value. This may have implications for efficacy of treatment, as fluids are not always consumed immediately upon mixing. Flow behavior indices were comparable across thickeners exhibiting similar rises over time. The indices were a more complete method of quantifying flow properties compared with single viscosity measurements, allowing an increased depth of analysis. The non-Newtonian nature of fluids perhaps renders them particularly suitable for use as dysphagia therapies, and such analysis may allow the possibility of altering these properties to optimize therapeutic efficacy to be explored. Practical Application: Effective treatment of swallowing disorders relies upon the appropriate choice and subsequent reproduction of drinks thickened to one of a number of predetermined levels. Currently there are no agreed methods of measuring the thickness of these drinks in use and the specifications are subjective, relying on descriptions such as "syrup" thick. This research aims to further understanding of the flow properties of thickened drinks and bring a quantified measure of thickness closer to being a practical reality. PMID- 20722918 TI - Mass transfer and nutrient absorption in a simulated model of small intestine. AB - There is an increasing need to understand how food formulations behave in vivo from both food and pharma industries. A number of models have been proposed for the stomach, but few are available for the other parts of the gastrointestinal tract. An experimental rig that simulates the segmentation motion occurring in the small intestine has been developed. The objective of developing such an experimental apparatus was to study mass transport phenomena occurring in the lumen and their potential effect on the concentration of species available for absorption. When segmentation motion was applied the mass transfer coefficient in the lumen side was increased up to a factor of 7. The viscosity of the lumen, as influenced by guar gum concentration, had a profound effect on the mass transfer coefficient. The experimental model was also used to demonstrate that glucose available for absorption, resulting from starch hydrolysis, can be significantly reduced by altering the lumen viscosity. Results suggest that absorption of nutrients could be controlled by mass transfer. Practical Application: To address health-related diseases such as obesity, novel foods that provide advanced functions are required. To achieve the full potential offered by the latest developments in the field of food material science, a fundamental understanding of the behavior of food structures in vivo is required. Using the developed gut model we have demonstrated that absorption of nutrients can be controlled by mass transfer limitations. PMID- 20722919 TI - Development and characterization of edible films based on mucilage of Opuntia ficus-indica (L.). AB - Mucilage of Opuntia ficus-indica (OFI) was extracted and characterized by its composition and molecular weight distribution. Mucilage film-forming dispersions were prepared under different pHs (3, 4, 5.6, 7, and 8) and calcium concentration (0% and 30% of CaCl(2), with respect to mucilage's weight), and their particle size determined. Mucilage films with and without calcium (MFCa and MF, respectively) were prepared. The effect of calcium and pH on mucilage films was evaluated determining thickness, color, water vapor permeability (WVP), tensile strength (TS), and percentage of elongation (%E). The average molecular weight of the different fractions of mucilage was: 3.4 x 10(6) (0.73%), 1 x 10(5) (1.46%), 1.1 x 10(3) (45.79%), and 2.4 x 10(2) Da (52.03%). Aqueous mucilage dispersions with no calcium presented particles with an average size d(0.5) of 15.4 microm, greater than the dispersions with calcium, 13.2 microm. MFCa films showed more thickness (0.13 mm) than the MF films (0.10 mm). The addition of calcium increased the WVP of the films from 109.94 to 130.45 gmm/m(2)dkPa. Calcium and pH affected the mechanical properties of the films; the largest TS was observed on MF films, whereas the highest %E was observed on MFCa films. The highest differences among MF and MFCa films were observed at pHs 5.6 and 7 for TS and at pHs 4 and 8 for %E. No effect of pH and calcium was observed on luminosity and hue angle. Chroma values were higher for MF when compared with MFCa, and increased as pH of the films increased. Practical Application: In this study mucilage from nopal was extracted and characterized by its ability to form edible films under different pHs, and with or without the addition of calcium. Opuntia ficus-indica mucilage had the ability to form edible films. In general, it can be considered that mucilage films without modification of pH and without the addition of calcium have the best water vapor barrier properties and tensile strength. Mucilage from nopal could represent a good option for the development of edible films in countries where nopal is highly produced at low cost, constituting a processing alternative for nopal. PMID- 20722920 TI - A novel approach to study biscuits and breadsticks using X-ray computed tomography. AB - In this study X-ray microtomography (muCT) was used for analysis of the microstructure of 6 different types of Italian biscuits and 3 types of Italian breadsticks. Appropriate quantitative 3-D parameters describing the microstructure were calculated, such as the structure thickness (ST), the object structure volume ratio (OSVR), the degree of anisotropy (DA), and the percentage object volume (POV). Sensory analysis was also performed to discriminate samples on the basis of texture characteristics. A correlation between microstructural data (OSVR for biscuits and OSVR, POV, and DA for breadsticks) and sample crunchiness was also found. Results obtained from the current study showed that analysis at a microscopic level could be useful to the food industry, as the accurate calculation of number, dimension, and distribution of pores in the products could be used to improve the sensorial properties of food. Further study by muCT could be carried out to correlate microstructure to specific ingredients and process conditions to allow obtaining more tailored food. PMID- 20722921 TI - Microencapsulation of fish oil by spray granulation and fluid bed film coating. AB - The stability of microencapsulated fish oil prepared with 2 production processes, spray granulation (SG) and SG followed by film coating (SG-FC) using a fluid bed equipment, was investigated. In the 1st process, 3 types of fish oil used were based on the ratios of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (10/50, 33/22, and 18/12). Each type was emulsified with soluble soybean polysaccharide (SSPS) and maltodextrin to produce 25% oil powders. In the 2nd process, 15% film coating of hydroxypropyl betacyclodextrin (HPBCD) was applied to the granules from the 1st process. The powder stability against oxidation was examined by measurement of peroxide values (PV) and headspace propanal after storage at room temperature and at 3 to 4 degrees C for 6 wk. Uncoated powder containing the lowest concentration of PUFA (18/12) was found to be stable during storage at room temperature with maximum PV of 3.98 +/- 0.001 meq/kg oil. The PV increased sharply for uncoated powder with higher concentration of omega-3 (in 33/22 and 10/50 fish oils) after 3 wk storage. The PVs were in agreement with the concentration of propanal, and these 2 parameters remained constant for most of the uncoated powders stored at low temperature. Unexpectedly, the outcomes showed that the coated powders had lower stability than uncoated powders as indicated by higher initial PVs; more hydroperoxides were detected as well as increasing propanal concentration. The investigation suggests that the film-coating by HPBCD ineffectively protected fish oil as the coating process might have induced further oxidation; however, SG is a good method for producing fish oil powder and to protect it from oxidation because of the "onion skin" structure of granules produced in this process. PMID- 20722922 TI - Development and evaluation of a fluidized bed system for wheat grain disinfection. AB - Durum wheat grain from the field is naturally contaminated with bacteria, yeast, and mold. The reduction in aerobic plate count (APC) and yeast and mold count (YMC) is often necessary before processing wheat. Gaseous ozone, ozonated water, and acetic acid solution are nontraditional antimicrobial agents for grains and are safe for humans and the environment. Better disinfection may be possible by applying antimicrobial agents to grain in a fluidized state. Fluidization increases the exposure of grain surfaces, resulting in uniform and quick contact of grain with antimicrobial agents. Therefore, a fluidized bed was developed with automated spraying system (to spray treatment waters), and a port for gaseous ozone injection. The pressures and velocities within the fluidized bed system were measured to characterize the system. The treatments used on fluidized grain were: distilled water (control), gaseous ozone (6 ppm), ozonated water (23 mg/L), gaseous ozone + ozonated water (6 ppm, 23 mg/L), acetic acid solution (0.5%), acetic acid + ozonated water (0.5%, 26 mg/L), and gaseous ozone + acetic acid + ozonated water (6 ppm, 0.5%, 26 mg/L). The last of these treatments was most effective with 1.7 and 3.3 log reduction in APC and YMC, respectively. This combined treatment can be used to replace the chlorinated water that industry uses during tempering of grain. Ozonated water alone resulted in a 0.3 log reduction in both APC and YMC. Gaseous ozone alone did not cause a significant reduction in APC and YMC. PMID- 20722924 TI - Impact of mechanical shear on the survival of Listeria monocytogenes on surfaces. AB - The impact of mechanical surface shear on microbial viability is rarely a subject for exploration in food processing. The objective of this research was to investigate the impact of mechanical shear on the survival of Listeria monocytogenes on surfaces. Mechanical shear created by slicing a model food was explored to investigate the viability of L. monocytogenes. Cell injury/death was readily demonstrated in fluorescence images by confocal microscopy in which the live and dead cells were fluorescently stained green and red, respectively, with a viability dye kit. Images showed that a large percentage of dead cells appeared after slicing, and they were readily transferred from the slicer blade onto the surfaces of sliced agar, indicating that surface shear may cause the lethal effect on L. monocytogenes. Surface transfer results also showed that viable cell counts on agar slices (in a slicing series) followed a consistently decreasing pattern. The cell counts initially at 5 to 6.5 log CFU/slice (slices 1 to 6), decreased to 3 to 4 log CFU/slice (slices 8 to 30), then to 2 to 3 log CFU/slice (slices 31 to 40), and counts would be expected to further decrease if slicing continued. The overall cell recovery (survival) ratio was about 2% to 3% compared to the initial 8.4 log CFU/blade on a 10 cm(2) edge area. The impact of shear on microbial viability during slicing may contribute 99% of viable cell count reduction. This study provides clear evidence that surface shear can kill foodborne pathogens and reduce cross-contamination. The lethal effects of surface shear may further enhance food safety. PMID- 20722923 TI - High pressure inactivation kinetics of a Thermomyces lanuginosus xylanase evaluated as a process indicator. AB - The potential use of Thermomyces lanuginosus xylanase to develop a pressure temperature-time integrator (PTTI) for high pressure processing was investigated. The combined effect of pressure and temperature on the inactivation of xylanase was studied in the pressure range of 100 to 600 MPa and temperature range of 50 to 70 degrees C. A synergistic effect of pressure and temperature was observed. Xylanase inactivation at the studied processing conditions followed first-order kinetics and was found to be very sensitive to changes in pressure and temperature. The values of activation energy and activation volume were estimated as 92.8 kJ/mol and -23.3 mL/mol at a reference pressure of 450 MPa and a reference temperature of 60 degrees C, respectively. A mathematical model of xylanase inactivation, having as variables time, pressure, and temperature allows the calculation of remaining enzyme activity at any combination of processing conditions within the studied domain. Practical Application: To ensure the optimization and control of high pressure processing, evaluation of the process impact on both safety and quality attributes of foods is essential. Enzymes can serve as effective tools in evaluating the impact of high pressure processes of foods. PMID- 20722925 TI - Effect of spray nozzle design on fish oil-whey protein microcapsule properties. AB - Microencapsulation improves oxidative stability and shelf life of fish oil. Spray and freeze drying are widely used to produce microcapsules. Newer spray-nozzles utilize multiple fluid channels allowing for mixing of wall and core materials at the point of atomization. Sonic energy has also been employed as a means of atomization. The objective of this study was to examine the effect of nozzle type and design on fish oil encapsulation efficiency and microcapsule properties. A total of 3 nozzle types, a pressure nozzle with 1 liquid channel, a pressure nozzle with 2 liquid channels, and a sonic atomizer with 2 liquid channels were examined for their suitability to encapsulate fish oil in whey protein isolate. Physical and chemical properties of freeze dried microcapsules were compared to those of microcapsules produced by spray drying. The 2-fluid pressure and ultrasonic nozzles had the highest (91.6%) and the lowest microencapsulation efficiencies (76%), respectively. There was no significant difference in bulk density of microcapsules produced by ultrasonic and 3-fluid pressure nozzles. The ultrasonic nozzle showed a significantly narrower particle size distribution than the other nozzles. This study demonstrated that new nozzle designs that eliminate emulsion preparation prior to spray drying can be beneficial for microencapsulation applications. However, there is still a need for research to improve microencapsulation efficiency of multiple channel spray nozzles. Practical Application: Since this research evaluates new spray nozzle designs for oil microencapsulation, the information presented in this article could be an interest to fish oil producers and food industry. PMID- 20722926 TI - Separation of curcuminoids enriched fraction from spent turmeric oleoresin and its antioxidant potential. AB - The rhizomes of turmeric are processed to obtain oleoresin and subsequently curcuminoids are isolated. The mother liquor, after partial isolation of curcuminoids, known as spent turmeric oleoresin (STO), is considered as industrial waste. Curcuminoids enriched spent turmeric oleoresin (CSTO) is prepared by removal of nonantioxidant constituents, and investigated for its antioxidant potential using in vitro methods, and also the total curcuminoids and phenolic contents were determined. CSTO has a total phenolic content of 267.27 +/ 5.75 mg GAE/g that is almost double the amount present in STO (118.3 +/- 3.0 mg GAE/g). The total amount of curcuminoids in CSTO is found to be 39 +/- 1.2%, whereas STO had 15 +/- 2.0%. CSTO possessed radical scavenging activity of 84% at 50 microg/mL, antioxidant activity of 74% at 25 microg/mL, high antioxidant capacity, and moderate total reducing power. These results provide scope for utilization of CSTO/STO as natural antioxidant/preservative as well as colorant in various foods. PMID- 20722927 TI - Induction of heme oxygenase-1 by whisky congeners in human endothelial cells. AB - It is expected that the production of the cytoprotective heme oxygenase-1 (HO-1) protein in endothelial cells would reduce severity of vascular injuries, while phenolic compounds are known to induce HO-1 mRNA and protein in various cells. We investigated the activation of HO-1 by whisky, which contains various phenolic substances. The congeners of whisky stored from 4 to 18 y in oak barrels were shown to induce an increase of HO-1 protein in human umbilical vein endothelial cells, while those of freshly distilled whisky spirit exhibited no activity. To determine the compounds with potent HO-1-inducing activity among the whisky congeners, several chemicals that had been reported to exist in whisky or oak barrels were screened, and coniferyl aldehyde and sinapyl aldehyde showed the activity. Thus, compounds that emerged in whisky during barrel storage induced cytoprotective protein, HO-1, in human endothelial cells. PMID- 20722928 TI - Methylglyoxal content in drinking coffee as a cytotoxic factor. AB - A causal relationship between metabolic syndrome and methylglyoxal (MG) has been suggested. Consumption of coffee and other types of beverages has been known to produce MG, thus resulting in both nutritional and health concerns. The purpose of this study was to determine the ideal combination of coffee, cream, and sugar in order to minimize MG consumption. Four types of black coffee were tested: espresso, bold, mild, and a decaffeinated mild roast. Sugar and/or cream were added to the coffee samples to test whether MG levels were altered. Using high performance liquid chromatography, the concentration of MG in various coffee samples was determined. The espresso coffee sample was found to contain the highest level of MG at 230.9 microM. The bold coffee roast had the 2nd highest amount of MG, followed by the mild and decaffeinated varieties. Adding cream to bold coffee significantly reduced its MG level in comparison to the coffee sample without cream. On the other hand, the addition of sugar to the bold coffee did not further increase the MG level in the samples. The cellular damaging effect of MG was shown as there were decreased numbers of cultured HEK-293 cells after 24 h of MG treatment (100 and 300 microM), which is consistent with an increased cell apoptosis induced by MG treatment (100 and 300 microM). Due to the overconsumption of exogenous MG, drinking an excess of any type of coffee poses health risks. PMID- 20722930 TI - Effects of theabrownin from pu-erh tea on the metabolism of serum lipids in rats: mechanism of action. AB - Theabrownin (TB), one of the main bioactive components in pu-erh tea, has a significant blood lipid-lowering effect in hyperlipidemic rats. Therefore, it was hypothesized that TB would regulate the activity of key enzymes involved in lipid metabolism and accelerate the catabolism of exogenous cholesterol in rats fed a high fat diet. A total of 90 Sprague-Dawley rats were randomly divided into a normal control group (Group I), a high fat diet group (Group II), and high-fat diet plus TB group (Group III). A total of 10 rats were selected from each group and killed at 15, 30, or 45 d after starting the study for analysis. After feeding 45 d, the contents of TC, TG, and LDL-C levels in Group II were increased by 54.9%, 93.1%, and 134.3% compared with those in Group III, respectively, and the content of HDL-C in Group II was decreased by 55.7%. These effects were inhibited in the rats in Group III, which exhibited no significant differences in these levels compared with Group I, indicating that TB can prevent hyperlipidemia in rats fed a high fat diet. TB enhanced the activity of hepatic lipase and hormone-sensitive triglyceride lipase (HSL) and increased the HSL mRNA expression in liver tissue and epididymis tissue. The HL activity in serum of Group III was increased by 147.6% compared with that in Group II. The content of cholesterol and bile acid in the feces of rats was increased by 21.11- and 4.08-fold by TB. It suggested that TB could promote the transformation and excretion of dietary cholesterol of rats in vivo. PMID- 20722929 TI - Development of an ingredient containing apple peel, as a source of polyphenols and dietary fiber. AB - Apple peel is a waste product from dried apple manufacture. The content of phenolic compounds, dietary fiber, and mineral are higher in apple peel, compared to other edible parts of this fruits. The objective of this study was to develop an ingredient from Granny Smith apple peel, using a pilot scale double drum dryer, as drying technology. The control of all steps to maximize the retention of phenolic compounds and dietary fiber was considered. Operational conditions, such as drying temperature and time were determined, as well as important preprocessing steps like grinding and PPO inhibition. In addition, the physical chemical characteristics, mineral and sugar content, and technological functional properties such as water retention capacity, solubility index, and dispersability among others, were analyzed. A simple, economical, and suitable pilot scale process, to produce a powder ingredient from apple peel by-product, was obtained. The drying process includes the application of ascorbic acid at 0.5% in the fresh apple peel slurry, drum-dryer operational conditions were 110 degrees C, 0.15 rpm and 0.2 mm drum clearance. The ingredient developed could be considered as a source of phenolic compounds (38.6 mg gallic acid equivalent/g dry base) and dietary fiber (39.7% dry base) in the formulation of foods. Practical Application: A method to develop an ingredient from Granny Smith apple peel using a pilot scale double drum-dryer as drying technology was developed. The method is simple, economical, feasible, and suitable and maximizes the retention of phenolic compounds and dietary fiber present in the raw matter. The ingredient could be used in the formulation of foods. PMID- 20722931 TI - Induction of detoxification enzymes by feeding unblanched Brussels sprouts containing active myrosinase to mice for 2 wk. AB - In cruciferous vegetables, myrosinase metabolizes the relatively inactive glucosinolates into isothiocyanates and other products that have the ability to increase detoxification enzyme expression. Thus, maintaining myrosinase activity during food preparation may be critical to receiving the maximum benefit of consumption of Brussels sprouts or other cruciferous vegetables. To test the importance of maintaining myrosinase activity for maximizing bioactivity, experimental diets containing 20% unblanched (active myrosinase) or 20% blanched (inactivated myrosinase) freeze-dried Brussels sprouts and a nutrient-matched control diet were evaluated in vitro and in vivo for their ability to induce detoxification enzymes. Treatment of immortalized HepG2 human hepatoma cells with the unblanched Brussels sprout diet caused a greater increase quinone activity compared to the blanched Brussels sprout diet. C3H/HeJ mice fed the unblanched Brussels sprout diets for 2 wk had significantly higher plasma sulforaphane concentrations. Liver expression of CYP1A1 and epoxide hydrolase, measured using real-time PCR, was correlated with the plasma concentration of sulforaphane. In the lung, expression of epoxide hydrolase, thioredoxin reductase, UDP glucuronosyltransferase, quinone reductase, heme oxygenase, CYP1A1, CYP1A2, and CYP1B1 were also correlated with the plasma concentration of sulforaphane. Together these data demonstrate that, as predicted by the in vitro experiment, in vivo exposure to Brussels sprouts with active myrosinase resulted in greater induction of both phase I and phase II detoxification enzymes in the liver and the lungs that correlated with plasma sulforaphane concentrations. PMID- 20722932 TI - Effects of vitamin D3 on expression of tumor necrosis factor-alpha and chemokines by monocytes. AB - The association between vitamin D deficiency and asthma epidemic has been recognized. Tumor necrosis factor (TNF)-alpha and chemokines play important roles in pathogenesis of asthma. However, whether vitamin D has immunoregulatory function on TNF-alpha and chemokines expression in human monocytes is still unknown. The human monocytic cell line, THP-1 cells and human primary monocytes were pretreated with various concentration of 1alpha,25-(OH)(2)D(3) for 2 h before stimulation with lipopolysaccharide (LPS). Supernatants were collected 24 or 48 h after LPS stimulation. The levels of TNF-alpha, interferon-inducible protein 10 (IP-10)/CXCL10 (the Th1-related chemokine), macrophage-derived chemokine (MDC)/ CCL22 (the Th2-related chemokine), and interleukin 8 (IL 8)/CXCL8 (the neutrophil chemoattractant) were measured by ELISA. 1alpha,25 (OH)(2)D(3) could significantly suppress TNF-alpha and IP-10 expression in LPS stimulated THP-1 and human primary monocytes. However, 1alpha,25-(OH)(2)D(3), especially in higher concentration, could significantly enhance MDC expression. 1alpha,25-(OH)(2)D(3) had no significant effects on IL-8 expression. We found 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and Th1-related chemokine IP-10, which both play important roles in pathogenesis of severe refractory asthma and autoimmune diseases. However, 1alpha,25-(OH)(2)D(3) enhanced Th2-related chemokine MDC, which may result in Th2 inflammatory cell recruitment and thus adversely affect asthmatic patients. Although vitamin D has potential utility in the treatment of asthma and autoimmune diseases, excessive use of vitamin D may not be suitable in patients with Th2 allergic diseases. PMID- 20722933 TI - Hypolipidemic effect of bamboo shoot oil (P. pubescens) in Sprague-Dawley rats. AB - Atherosclerosis and its related complications are the leading causes of death in the West and in many developed countries. This study aims to investigate the hypolipidemic effect of bamboo shoot oil (BSO) in Sprague-Dawley rats. A group of rats had induced hyperlipidemia, hypercholesterolemia, and fatty liver by being fed with a high-fat, high-cholesterol diet for 4 wk. The control group was administered 10 mL distilled water per kg body weight, while the other groups were, respectively, administered 250 mg beta-sitosterol, 250 mg BSO, 500 mg BSO, and 1000 mg BSO per kg body weight by oral gavage. The results demonstrated that BSO could significantly decrease the levels of total cholesterol, triacylglycerol, low-density lipoprotein-cholesterol, phytosterol, lipoprotein lipase, hepatic lipase, and atherogenic index in serum, and increase the levels of cholesterol in feces. It could also significantly decrease the level of relative liver weight and liver lipids. The pronounced hypolipidemic effects of BSO might be attributed to its ability to inhibit cholesterol absorption and increase cholesterol excretion. These results suggest that consuming BSO may provide benefits in managing hypercholesterolemia. Therefore, BSO may be a good candidate for development as a functional food and nutraceutical. PMID- 20722934 TI - Detection of E. coli O157:H7 from ground beef using Fourier transform infrared (FT-IR) spectroscopy and chemometrics. AB - FT-IR spectroscopy methods for detection, differentiation, and quantification of E. coli O157:H7 strains separated from ground beef were developed. Filtration and immunomagnetic separation (IMS) were used to extract live and dead E. coli O157:H7 cells from contaminated ground beef prior to spectral acquisition. Spectra were analyzed using chemometric techniques in OPUS, TQ Analyst, and WinDAS software programs. Standard plate counts were used for development and validation of spectral analyses. The detection limit based on a selectivity value using the OPUS ident test was 10(5) CFU/g for both Filtration-FT-IR and IMS-FT-IR methods. Experiments using ground beef inoculated with fewer cells (10(1) to 10(2) CFU/g) reached the detection limit at 6 h incubation. Partial least squares (PLS) models with cross validation were used to establish relationships between plate counts and FT-IR spectra. Better PLS predictions were obtained for quantifying live E. coli O157:H7 strains (R(2)> or = 0.9955, RMSEE < or = 0.17, RPD > or = 14) and different ratios of live and dead E. coli O157:H7 cells (R(2)= 0.9945, RMSEE = 2.75, RPD = 13.43) from ground beef using Filtration-FT-IR than IMS-FT-IR methods. Discriminant analysis and canonical variate analysis (CVA) of the spectra differentiated various strains of E. coli O157:H7 from an apathogenic control strain. CVA also separated spectra of 100% dead cells separated from ground beef from spectra of 0.5% live cells in the presence of 99.5% dead cells of E. coli O157:H7. These combined separation and FT-IR methods could be useful for rapid detection and differentiation of pathogens in complex foods. PMID- 20722935 TI - Optimization of nisin production by Lactococcus lactis UQ2 using supplemented whey as alternative culture medium. AB - Lactococcus lactis UQ2 is a nisin A-producing native strain. In the present study, the production of nisin by L. lactis UQ2 in a bioreactor using supplemented sweet whey (SW) was optimized by a statistical design of experiments and response surface methodology (RSM). In a 1st approach, a fractional factorial design (FFD) of the order 2(5-1) with 3 central points was used. The effect on nisin production of air flow, SW, soybean peptone (SP), MgSO(4)/MnSO(4) mixture, and Tween 80 was evaluated. From FFD, the most significant factors affecting nisin production were SP (P = 0.011), and SW (P = 0.037). To find optimum conditions, a central composite design (CCD) with 2 central points was used. Three factors were considered, SW (7 to 10 g/L), SP (7 to10 g/L), and small amounts of added nisin as self-inducer (NI 34.4 to 74.4 IU/L). Nisin production was expressed as international units (IU). From RSM, an optimum nisin activity of 180 IU/mL was predicted at 74.4 IU/L NI, 13.8 g/L SP, and 14.9 or 5.11 g/L SW, while confirmatory experiments showed a maximum activity of 178 +/- 5.2 IU/mL, verifying the validity of the model. The 2nd-order model showed a coefficient of determination (R(2)) of 0.828. Optimized conditions were used for constant pH fermentations, where a maximum activity of 575 +/- 17 IU/mL was achieved at pH 6.5 after 12 h. The adsorption-desorption technique was used to partially purify nisin, followed by drying. The resulting powder showed an activity of 102150 IU/g. Practical Application: Nisin production was optimized using supplemented whey as alternative culture medium, using a native L. lactis UQ2 strain. Soybean peptone, SW, and subinhibitory amounts of nisin were successfully employed to optimize nisin production by L. lactis UQ2. Dried semipurified nisin showed an activity of 102150 IU/g. PMID- 20722936 TI - Inhibition of citrus fungal pathogens by using lactic acid bacteria. AB - The effect of lactic acid bacteria (LAB) on pathogenic fungi was evaluated and the metabolites involved in the antifungal effect were characterized. Penicillium digitatum (INTA 1 to INTA 7) and Geotrichum citri-aurantii (INTA 8) isolated from decayed lemon from commercial packinghouses were treated with imazalil and guazatine to obtain strains resistant to these fungicides. The most resistant strains (4 fungal strains) were selected for evaluating the antifungal activity of 33 LAB strains, among which only 8 strains gave positive results. The antifungal activity of these LAB strains was related to the production of lactic acid, acetic acid, and phenyllactic acid (PLA). A central composite design and the response surface methodology were used to evaluate the inhibitory effect of the organic acids produced by the LAB cultures. The antifungal activity of lactic acid was directly related to its concentration; however, acetic acid and PLA showed a peak of activity at 52.5 and 0.8 mM, respectively, with inhibition rates similar to those obtained with Serenade((R)) (3.0 ppm) imazalil (50 ppm) and guazatine (50 ppm). Beyond the peak of activity, a reduction in effectiveness of both acetic acid and PLA was observed. Comparing the inhibition rate of the organic acids, PLA was about 66- and 600-fold more effective than acetic acid and lactic acid, respectively. This study presents evidences on the antifungal effect of selected LAB strains and their end products. Studies are currently being undertaken to evaluate the effectiveness in preventing postharvest diseases on citrus fruits. PMID- 20722937 TI - Characterization by volatile compounds of microbial deep spoilage in Iberian dry cured ham. AB - In the present study, volatile compounds of spoiled dry-cured Iberian ham with deep spoilage or "bone taint" were analyzed and correlated with level of spoilage and the microorganisms detected. Volatile compounds extracted by a solid phase micro-extraction technique were assayed by gas chromatography/mass spectrometry. The spoiled hams were evaluated sensorially, and the correlations among volatile compounds, spoilage level, and microbial counts were studied. The spoiled hams had higher concentrations of hydrocarbons, alcohols, acids, esters, pyrazines, sulfur compounds, and other minor volatile compounds than unspoiled hams. The sensorial analysis showed that the spoilage level of hams correlated with several volatile compounds, most of them associated with Gram-positive catalase positive cocci and Enterobacteriaceae counts. Cyclic compounds such as cyclohexanone, some ethers, and pyrazines should be considered as indicators to monitor incipient microbial deep spoilage in the elaboration of this meat product. PMID- 20722938 TI - Characterization of biogenic amines and factors influencing their formation in traditional Chinese sausages. AB - Biogenic amines in 42 traditional Chinese sausage samples obtained from different regions were determined by HPLC. The result showed that cadaverine was the major amine, followed by tyramine and putrescine. A total of 4 groups of samples were identified on the basis of total amines by cluster analysis. Group A included samples showing low amine contents (76.5 to 220 mg/kg) and accounted for 28.5% of the sausages examined. Group B included samples with moderate amine contents (220 to 600 mg/kg) and accounted for 45.2%. Group C included 11.9% of the samples showing high total biogenic amines contents (600 to 1000 mg/kg) and group D contained 14.28% of the samples showing very high levels of biogenic amines (higher than 1000 mg/kg). High correlation coefficients were found between the total counts of Enterobacteria and concentrations of total biogenic amines (r = 0.73). Sanitary quality of raw materials and the specific flora are import factors influencing biogenic amines formation in traditional Chinese sausages. Practical Application: Biogenic amines are considered potentially harmful substances to human health worldwide and are usually found in fermented sausage.Traditional Chinese sausage is one form of spontaneously fermented sausage and manufactured in small-scale plants following spontaneous fermentation. Little information, however, exists on the traditional Chinese sausage. PMID- 20722939 TI - Phytase activity from Lactobacillus spp. in calcium-fortified soymilk. AB - The presence of phytate in calcium-fortified soymilk may interfere with mineral absorption. Certain lactic acid bacteria (LAB) produce the enzyme phytase that degrades phytates and therefore may potentially improve mineral bioavailability and absorption. This study investigates the phytase activity and phytate degradation potential of 7 strains of LAB including: Lactobacillus acidophilus ATCC4962, ATCC33200, ATCC4356, ATCC4161, L. casei ASCC290, L. plantarum ASCC276, and L. fermentum VRI-003. Activity of these bacteria was examined both in screening media and in calcium-fortified soymilk supplemented with potassium phytate. Most strains produced phytase under both conditions with L. acidophilus ATCC4161 showing the highest activity. Phytase activity in fortified soymilk fermented with L. acidophilus ATCC4962 and L. acidophilus ATCC4161 increased by 85% and 91%, respectively, between 12 h and 24 h of fermentation. All strains expressed peak phytase activity at approximately pH 5. However, no phytate degradation could be observed. PMID- 20722940 TI - Localization, growth, and inactivation of Salmonella Saintpaul on jalapeno peppers. AB - Consumption of Salmonella-contaminated jalapeno peppers has been implicated in one of the largest foodborne illness outbreaks in the summer of 2008. The objective of this study was to investigate representative groups of native microflora and the distribution, growth, and inactivation of experimentally inoculated Salmonella Saintpaul on jalapeno peppers. Two genetically modified strains of Salm. Saintpaul producing either green- or red-fluorescent protein were constructed and used in the study. Microbiological analyses showed that jalapeno peppers contained an average of 5.6 log units of total aerobic count and 3.5, 1.8, and 1.9 log units, respectively, of enterobacteriaceae, lactic acid bacteria, and yeast/mold per gram of tissue. Strains typical of Pseudomonas accounted for 8.3% of total aerobic count, and 0.2% of which exhibited pectolytic activity. On inoculated peppers, a vast majority (>90%) of Salm. Saintpaul was recovered from stem/calyx and only a small proportion recovered from fleshy pods. Growth of Salm. Saintpaul on peppers was indicated by an increase in the population of 3 log units after incubation of samples at 20 degrees C for 48 h. Fluorescent Salm. Saintpaul aggregates could be readily detected on stem/calyx using stereofluorescence imaging microscopy and scanning electron microscopy. Data presented showed that Salm. Saintpaul could survive for at least 8 wk on peppers stored at 4 degrees C. Immersion of inoculated peppers in 200 ppm of sodium hypochlorite, acidified sodium chlorite, or peroxy acetic acid for 10 min could reduce the number of Salm. Saintpaul on stem/calyx by 1.5 to 1.7 and that on flesh by 2.1 to 2.4 log units. Practical Application: Consumption of Salmonella-contaminated jalapeno peppers has been implicated in foodborne illness outbreaks. The vast majority of Salmonella Saintpaul recovered from inoculated jalapeno peppers (>90%) was from stem/calyx. Salmonella increased by 3 log units during storage at 68 degrees F (20 degrees C) for 48 h. Salmonella could survive for at least 8 wk on peppers stored at 4 degrees C. Immersion of inoculated peppers in 200 ppm of sodium hypochlorite, acidified sodium chlorite, or peroxyacetic acid for 10 min reduced Salmonella on stem/calyx by 1.5 to 1.7 log units, compared with reductions of 2.1 to 2.4 log units on flesh. These results highlight the need to consider the stem/calyx as the most likely area for contamination of jalapeno peppers, and to process this commodity accordingly to minimize exposure and cross-contaminations. PMID- 20722941 TI - Effect of extracted housefly pupae peptide mixture on chilled pork preservation. AB - The peptide mixture from housefly pupae has broad spectrum antimicrobial activity but has not previously been reported as a food preservative. In this study, the preservation effects of a housefly pupae peptide mixture, nisin, and sodium dehydroacetate (DHA-S) on the number of mesophilic aerobic bacteria (MAB), total volatile basic nitrogen (TVB-N), and pH value of chilled pork were compared. All results showed that a good preservation effect was observed among 3 treatments with the peptide mixture of housefly pupae, nisin, and DHA-S and that there was no significant difference among them. These results indicate that housefly peptide mixture has a great potential as a food preservative. The results of scanning electron microscope and transmission electron microscopy suggest that the primary mechanism of housefly pupae peptide mixture may be bacterial cytoplasmic membrane lysis and pores induced in the membranes. Practical Applications: Peptide mixture extracted from housefly pupae using low-cost and simple method has broad spectrum antimicrobial activity. According to the effect on chilled pork preservation, extracted housefly peptide mixture has a great potential as a food preservative. PMID- 20722942 TI - Characterization and stability analysis of zinc oxide nanoencapsulated conjugated linoleic acid. AB - Nanoencapsulation technology has a diverse range of applications, including drug delivery systems (DDS) and cosmetic and chemical carriers, because it can deliver various bio- and organic-molecules and improve their stabilities. Conjugated linoleic acid (CLA) has health benefits, including being an anticancer agent, but it decreases flavor due to volatiles from oxidation. To improve the stability of CLA for food applications, nanoencapsulated CLA was synthesized for use in zinc basic salt (ZBS) and characterized by powder X-ray diffractometry, thermogravimetric analysis (TGA), elemental CHN analysis, inductively coupled plasma (ICP) analysis, UV/VIS spectroscopy, and FTIR spectroscopy. The thermal stability of nanoencapsulated CLA at 180 degrees C, a temperature similar to that used in cooking, was analyzed by gas chromatography. The gallery height of nanoencapsulated CLA was determined to be approximately 26 A through powder X-ray diffractometry; therefore, the CLA molecules were closely packed with zig-zag form between the intracrystalline spaces of nano particles. Elemental CHN analysis and ICP data determined the chemical composition of nanoencapsulated CLA to be Zn(4.86)(OH)(8.78)(CLA)(0.94). By TGA, it was determined about 45% (wt/wt) of weight loss corresponded to CLA, which is good agreement with the 42.13% (wt/wt) determined from high-performance liquid chromatography (HPLC) and elemental CHN analysis. UV/VIS spectroscopy and Fourier-transformed infrared (FTIR) spectroscopy showed encapsulated CLA maintained a conjugated diene structure, supporting the presence of CLA. Nanoencapsulation improved the thermal stability of CLA by about 25%, compared to pristine CLA. Practical Application: This system can be used for protection of encapsulated negatively-charged food ingredients from thermal processing. PMID- 20722943 TI - Stabilization of a nutraceutical omega-3 fatty acid by encapsulation in ultrathin electrosprayed zein prolamine. AB - Docosahexaenoic acid (DHA) is a long chain polyunsaturated fatty acid of the omega-3 series (omega-3), which exerts strong positive influences on human health. The target of this study was the stabilization by encapsulation of this bioactive ingredient in zein ultrathin capsules produced by electrospraying. The zein ultrathin DHA encapsulation was observed by ATR-FTIR spectroscopy to be more efficient against degradation under both ambient conditions and in a confined space (so-called headspace experiment). In the latter case, that more closely simulates a sealed food packaging situation, the bioactive DHA was considerably more stable. By fitting the degradation data to a specific auto-decomposition food lipids kinetic model, it was seen that the encapsulated omega-3 fatty acid showed a 2.5-fold reduction in the degradation rate constant and also had much higher degradation induction time. Moreover, the ultrathin zein-DHA capsules resulted to be more stable across relative humidity and temperature. Finally, headspace analysis by gas chromatography coupled with mass spectrometry showed that the presence of 3 main flavor-influencing aldehydes in the headspace was much lower in the zein encapsulated DHA, suggesting that the encapsulated bioactive also releases much less off-flavors. Electrosprayed ultrathin capsules of zein are shown to exhibit potential in the design of novel functional foods or bioactive packaging strategies to enhance the stability of functional ingredients. Practical Application: This article presents a novel methodology for the stabilization by encapsulation of omega 3 nutraceuticals via electrospraying and has potential application in the development of functional foods. PMID- 20722944 TI - Electrospinning of poly(vinyl alcohol) nanofibers loaded with hexadecane nanodroplets. AB - The feasibility of producing poly(vinyl alcohol) (PVA) nanofibers containing fine disperse hexadecane droplets by electrospinning a blend of hexadecane-in-water emulsions and PVA was investigated. Hexadecane oil-in-water nanoemulsions (d(10)= 181.2 +/- 0.1 nm) were mixed with PVA at pH 4.5 to yield polymer-emulsion blends containing 0.5 to 1.5 wt% oil droplets and 8-wt% PVA. The solution properties of emulsions and emulsion-PVA blends (viscosity, conductivity, surface tension) were determined. Solutions were electrospun and the morphology and thermal properties of deposited fiber mats characterized by scanning electron microscopy and differential scanning calorimetry. Fiber mats were dissolved in buffer to liberate incorporated hexadecane droplets and the buffer solutions analyzed by optical microscopy, UV-spectroscopy, and light scattering. Analysis of dry fiber mats and their solutions showed that emulsion droplets were indeed part of the electrospun fiber structures. Depending on the concentration of hexadecane in the initial emulsion-polymer blends, droplets were dispersed in the fibers as individual droplets or in form of aggregated flocs of hexadecane droplets. Nanofibers with spindle-like perturbations or nanofibers containing bead-like structures with approximately 5 times larger than the size of droplets in the original nanoemulsion were obtained. Remarkably, incorporation of hexadecane droplets in fibers did not alter size of individual droplets, that is, no coalescence occurred. The manufacture of solid matrix containing nanodroplets could be of substantial interest for manufacturers wishing to develop encapsulation system for lipophilic functional compounds such as lipid-soluble flavors, antimicrobials, antioxidants, and bioactives with tailored release kinetics. Practical Applications: The paper describes the formation of electrospun nanofibers from hydrophilic polymers that contain fine-disperse emulsion droplets. By incorporating emulsion droplets, a large variety of lipophilic ingredients can be easily loaded into the fibers' hydrophilic polymer matrix. This is of practical importance as to date the only way to include a lipophilic ingredient in a nanofibers is by dissolving the lipophilic ingredient and polymer in an organic solvent followed by electrospinning. However, use of an organic solvent is (a) not feasible if one wants to electrospin hydrophilic polymers, and (b) use of organic solvents is generally highly undesirable in the food industry. Our results should be of interest to a number of industries such as the food, pharmaceutical, chemical, and personal care industries that are generally in need of novel matrices that can serve as carrier vehicles and release functional components such as flavors, antimicrobials, antioxidants, drugs, and bioactives. PMID- 20722945 TI - Evaluation of the genotoxicity of chitosan nanoparticles for use in food packaging films. AB - The use of nanoparticles in food packaging has been proposed on the basis that it could improve protection of foods by, for example, reducing permeation of gases, minimizing odor loss, and increasing mechanical strength and thermal stability. Consequently, the impacts of such nanoparticles on organisms and on the environment need to be investigated to ensure their safe use. In an earlier study, Moura and others (2008a) described the effect of addition of chitosan (CS) and poly(methacrylic acid) (PMAA) nanoparticles on the mechanical properties, water vapor, and oxygen permeability of hydroxypropyl methylcellulose films used in food packaging. Here, the genotoxicity of different polymeric CS/PMAA nanoparticles (size 60, 82, and 111 nm) was evaluated at different concentration levels, using the Allium cepa chromosome damage test as well as cytogenetic tests employing human lymphocyte cultures. Test substrates were exposed to solutions containing nanoparticles at polymer mass concentrations of 1.8, 18, and 180 mg/L. Results showed no evidence of DNA damage caused by the nanoparticles (no significant numerical or structural changes were observed), however the 82 and 111 nm nanoparticles reduced mitotic index values at the highest concentration tested (180 mg/L), indicating that the nanoparticles were toxic to the cells used at this concentration. In the case of the 60 nm CS/PMAA nanoparticles, no significant changes in the mitotic index were observed at the concentration levels tested, indicating that these particles were not toxic. The techniques used show promising potential for application in tests of nanoparticle safety envisaging the future use of these materials in food packaging. PMID- 20722946 TI - Development of associations and kinetic models for microbiological data to be used in comprehensive food safety prediction software. AB - The objective of this study was to use an existing database of food products and their associated processes, link it with a list of the foodborne pathogenic microorganisms associated with those products and finally identify growth and inactivation kinetic parameters associated with those pathogens. The database was to be used as a part of the development of comprehensive software which could predict food safety and quality for any food product. The main issues in building such a predictive system included selection of predictive models, associations of different food types with pathogens (as determined from outbreak histories), and variability in data from different experiments. More than 1000 data sets from published literature were analyzed and grouped according to microorganisms and food types. Final grouping of data consisted of the 8 most prevalent pathogens for 14 different food groups, covering all of the foods (>7000) listed in the USDA Natl. Nutrient Database. Data for each group were analyzed in terms of 1st order inactivation, 1st-order growth, and sigmoidal growth models, and their kinetic response for growth and inactivation as a function of temperature were reported. Means and 95% confidence intervals were calculated for prediction equations. The primary advantage in obtaining group-specific kinetic data is the ability to extend microbiological growth and death simulation to a large array of product and process possibilities, while still being reasonably accurate. Such simulation capability could provide vital ''what if'' scenarios for industry, Extension, and academia in food safety. PMID- 20722947 TI - Biochemical changes during the storage of high hydrostatic pressure processed avocado paste. AB - High hydrostatic pressure (HHP) processing improves the shelf life of avocado paste without a significant impact on flavor; however, scarce information is available on biochemical modifications during its extended storage period. The present study focused on the changes in oxidative enzyme activities of pressurized avocado paste (600 MPa for 3 min) during refrigerated storage (45 d at 4 degrees C). Aerobic plate counts (APC), lactic acid bacteria counts (LAB), pH, and instrumental color were also evaluated during storage. Processing with HHP caused a decrease in polyphenol oxidase (PPO) and lipoxygenase (LOX) activities, resulting in residual enzyme levels of 50.72% and 55.16%, respectively. Although instrumental color values didn't change significantly during the evaluated storage period, both enzymes (PPO and LOX) recuperated their activities at 10 to 15 d of storage, reached the original values observed in the fresh paste, and then started a declining phase until the end of the storage period. Pulp pH presented a consistent decline during the first 20 d of storage. LAB counts were very low during storage, discarding lactic acid production as responsible for the observed pH decline. Enzyme reactivation, cell disruption, and a gradual migration of intracellular components such as organic acids are herein proposed as the main mechanisms for the deterioration of HHP treated avocado paste during its refrigerated storage. Practical Application: At the present, HHP is the most effective commercial nonthermal technology to process avocado paste when compared to thermal and chemical alternatives. Although it has proven to be an excellent product-technology match, little information is known on the biochemical changes that take place in the product during its refrigerated shelf life. Biochemical reactions during storage are important, since they can influence avocado paste nutritional and flavor qualities at the time of product consumption. The present study reports for the first time the re-activation of PPO and LOX during storage of avocado paste under commercial and economically feasible processing conditions (600 MPa and 3 min). The reactivation of oxidative enzymes observed in the present study is relevant for future studies on the HHP stability of food systems in general, and it is considered an important finding for the food industry and researchers seeking to deliver products with superior nutritional and flavor characteristics. PMID- 20722948 TI - Sensory profile of a model energy drink with varying levels of functional ingredients-caffeine, ginseng, and taurine. AB - Energy drinks have increased in popularity in recent years due to the claimed energy boost provided by functional ingredients. A multitude of functional ingredients have been utilized; however, there is limited research on their sensory effects in energy drink formulations. A 13-member descriptive analysis panel was conducted to investigate the effects on the sensory and rheological properties of 3 common functional ingredients-caffeine, ginseng, and taurine-in a noncarbonated model energy drink solution. Combinations of these functional ingredients at 3 levels (low, medium, high) were added to create a total of 27 different solutions (3 x 3 x 3 factorial design). Analysis of variance was performed to evaluate the sensory effects of the varying concentrations of functional ingredients in solution. Principal component analysis (PCA) was performed to summarize the relationship among the attributes and solutions. In general, high levels of caffeine in solution resulted in low ratings of fruity attributes and high ratings of bitter tea and fruit bitter attributes. The high level of ginseng in solution was characterized by high ratings of bitter attributes. A horns effect was observed as the sweet, artificial lemon-lime, pear, mango, and pineapple attributes were rated lower in intensity with increased ginseng levels. Taurine levels of up to 416 mg/100 mL had no significant effect on the sensory attribute ratings of the model energy drink solutions. These findings can be utilized to predict the changes in sensory characteristics when formulating energy drinks containing these popular functional ingredients. PMID- 20722949 TI - Effect of salmon type and presence/absence of bone on color, sensory characteristics, and consumer acceptability of pureed and chunked infant food products. AB - Salmon-based infant food (puree) and toddler food (puree plus chunks) were manufactured from pink salmon, with and without bone, and from Sockeye salmon, with and without bone, to contain 45% salmon, 55% water, and 5% starch. Products were retort processed at 118 to 121 degrees C for 55 min in a steam-jacketed still retort. A trained descriptive panel (n = 7) evaluated infant and toddler foods separately. Instrumental color, pH, and water activity were also determined. Infant and toddler foods were also evaluated by a consumer panel (n = 104) of parents for product acceptability. During the manufacturing process (cooking, homogenization, retort processing), salmon infant food from pink salmon lost much of its characteristic pink color while that from sockeye salmon retained a greater amount. Bitterness was more evident in samples with bones. In the toddler food formulation containing chunks, the odor and flavor characteristics were influenced primarily by the type of salmon. The presence of bone affected visual pink color and lightness, and salmon odor only. Consumers scored products made with sockeye salmon as more acceptable despite the fact that they had more off-flavor than products from pink salmon. The appearance and thickness of the pureed infant food was more acceptable than the toddler food with chunks despite the chunky toddler product having more acceptable salmon flavor. This indicates that the color and appearance of the prototypes were the main drivers for liking. Of the total number of parents surveyed, 73% would feed this salmon product to their children. PMID- 20722950 TI - Survival analysis applied to the sensory shelf-life dating of high hydrostatic pressure processed avocado and mango pulps. AB - High hydrostatic pressure (HHP) pasteurized and refrigerated avocado and mango pulps contain lower microbial counts and thus are safer and acceptable for human consumption for a longer period of time, when compared to fresh unprocessed pulps. However, during their commercial shelf life, changes in their sensory characteristics take place and eventually produce the rejection of these products by consumers. Therefore, in the present study, the use of sensory evaluation was proposed for the shelf-life determinations of HHP-processed avocado and mango pulps. The study focused on evaluating the feasibility of applying survival analysis methodology to the data generated by consumers in order to determine the sensory shelf lives of both HHP-treated pulps of avocado and mango. Survival analysis proved to be an effective methodology for the estimation of the sensory shelf life of avocado and mango pulps processed with HHP, with potential application for other pressurized products. Practical Application: At present, HHP processing is one of the most effective alternatives for the commercial nonthermal pasteurization of fresh tropical fruits. HHP processing improves the microbial stability of the fruit pulps significantly; however, the products continue to deteriorate during their refrigerated storage mainly due to the action of residual detrimental enzymes. This article proposes the application of survival analysis methodology for the determination of the sensory shelf life of HHP-treated avocado and mango pulps. Results demonstrated that the procedure appears to be simple and practical for the sensory shelf-life determination of HHP-treated foods when their main mode of failure is not caused by increases in microbiological counts that can affect human health. PMID- 20722951 TI - Drivers of liking for soy-based Indian-style extruded snack foods determined by U.S. and Indian consumers. AB - Although many researchers have studied potential ways to deliver soy in novel forms, little is known about specific sensory attributes associated with soy snacks, or how those attributes drive liking for consumers. The first objective of this study was to use sensory descriptive analysis to characterize 9 extruded soy snacks with varying soy levels and soy grits contents. A total of 12 trained panelists used a descriptive analysis method to evaluate the snacks and found 14 attributes to be significantly different across the samples. Furthermore, it is not known how preferences of Indian snack consumers living in the United States and India may vary for sensory attributes of soy snacks. The 2nd objective was to correlate descriptive profiling data and previously collected consumer data to construct preference maps illustrating consumers' attitudes toward the snacks. Results indicate that consumers generally accept samples characterized by attributes such as crunchy, cumin, curry, salty, and umami, but dislike samples with wheat, rough, or porous attributes. Indian consumers differed from the U.S. consumers in that their preferences were more varied, and they tended to be more tolerant of wheat and porous attributes. Therefore, different strategies should be utilized when developing products for these groups to cater to their specific inclinations. PMID- 20722952 TI - Ghanaian cocoa bean fermentation characterized by spectroscopic and chromatographic methods and chemometrics. AB - Export of cocoa beans is of great economic importance in Ghana and several other tropical countries. Raw cocoa has an astringent, unpleasant taste, and flavor, and has to be fermented, dried, and roasted to obtain the characteristic cocoa flavor and taste. In an attempt to obtain a deeper understanding of the changes in the cocoa beans during fermentation and investigate the possibility of future development of objective methods for assessing the degree of fermentation, a novel combination of methods including cut test, colorimetry, fluorescence spectroscopy, NIR spectroscopy, and GC-MS evaluated by chemometric methods was used to examine cocoa beans sampled at different durations of fermentation and samples representing fully fermented and dried beans from all cocoa growing regions of Ghana. Using colorimetry it was found that samples moved towards higher a* and b* values as fermentation progressed. Furthermore, the degree of fermentation could, in general, be well described by the spectroscopic methods used. In addition, it was possible to link analysis of volatile compounds with predictions of fermentation time. Fermented and dried cocoa beans from the Volta and the Western regions clustered separately in the score plots based on colorimetric, fluorescence, NIR, and GC-MS indicating regional differences in the composition of Ghanaian cocoa beans. The study demonstrates the potential of colorimetry and spectroscopic methods as valuable tools for determining the fermentation degree of cocoa beans. Using GC-MS it was possible to demonstrate the formation of several important aroma compounds such 2-phenylethyl acetate, propionic acid, and acetoin and the breakdown of others like diacetyl during fermentation. Practical Application: The present study demonstrates the potential of using colorimetry and spectroscopic methods as objective methods for determining cocoa bean quality along the processing chain. Development of objective methods for determining cocoa bean quality will be of great importance for quality insurance within the fields of cocoa processing and raw material control in chocolate producing companies. PMID- 20722953 TI - Sensory quality of functional beverages: bitterness perception and bitter masking of olive leaf extract fortified fruit smoothies. AB - Olive leaf extract (OLE) contains high amounts of oleuropein and hydroxytyrosol. The antioxidant capacity of these polyphenols makes OLE a promising ingredient for functional food. OLE causes very strong bitterness perception and can therefore only be formulated in low concentrations. In this research, bitter detection and recognition thresholds of OLE-fortified fruit smoothies were determined by a trained sensory panel (n = 11). Masking of the OLE's bitter taste was investigated with addition of sodium cyclamate, sodium chloride, and sucrose by means of a standardized ranking method and a scale test. Detection (5.78 mg/100 g) and recognition thresholds (8.05 mg/100 g) of OLE polyphenols confirmed the low formulation limits when bitterness was not masked by other substances. At higher polyphenol levels of 20 mg/100 g, sodium cyclamate and sucrose were able to reduce bitter taste perception by 39.9% and 24.9%, respectively, whereas sodium chloride could not effectively mask bitterness. Practical Application: Development of functional food poses new challenges for the food industry. A major problem in this field is the high bitterness of natural polyphenol containing extracts with potential health benefits. This research was conducted to understand the sensory impact of olive leaf extract (OLE), a novel food ingredient with very bitter taste. In product development, the data of this research can be considered for formulation limits and the general sensory quality of OLE-fortified food and beverages. PMID- 20722954 TI - Germination conditions affect selected quality of composite wheat-germinated brown rice flour and bread formulations. AB - Brown rice has been reported to be more nutritious after germination. Germinated brown rice flours (GBRFs) from different steeping conditions (in distilled water [DI, pH 6.8] or in a buffer solution [pH 3] for either 24 or 48 h at 35 degrees C) were evaluated in this study. GBRF obtained from brown rice steeped at pH 3 for 48 h contained the highest amount of free gamma aminobutyric acid (GABA; 67 mg/100 g flour). The composite flour (wheat-GBRF) at a ratio of 70 : 30 exhibited significantly lower peak viscosity (PV) (56.99 - 132.45 RVU) with higher alpha amylase activity (SN = 696 - 1826) compared with those of wheat flour (control) (PV = 136.46 RVU and SN = 1976). Bread formulations, containing 30% GBRF, had lower loaf volume and greater hardness (P < 0.05) than the wheat bread. However, the hardness of bread containing 30% GBRF (except at pH 6.8 and 24 h) was significantly lower than that of bread containing 30% nongerminated brown rice flour (BRF). Acceptability scores for aroma, taste, and flavor of breads prepared with or without GBRFs (30% substitution) were not significantly different, with the mean score ranging from 6.1 (like slightly) to 7 (like moderately). Among the bread formulations containing GBRF, the one with GBRF prepared after 24 h steeping at pH 3 had a slightly higher (though not significant) overall liking score (6.8). This study demonstrated that it is feasible to substitute wheat flour with up to 30% GBRF in bread formulation without negatively affecting sensory acceptance. Practical Application: Our previous study revealed that flours from germinated brown rice have better nutritional properties, particularly gamma-aminobutyric acid (GABA), than the nongerminated one. This study demonstrated feasibility of incorporating up to 30% germinated brown rice flour in a wheat bread formulation without negatively affecting sensory acceptance. In the current United States market, this type of bread may be sold as frozen bread which would have a longer shelf life. Further study is thus needed. PMID- 20722955 TI - Shelf life and sensory characteristics of baby spinach subjected to electron beam irradiation. AB - The use of ionizing radiation for the control of foodborne pathogens and extending the shelf life of fresh iceberg lettuce and fresh spinach has recently been approved by the U.S. Food and Drug Administration. The efficacy of electron beam irradiation for controlling foodborne pathogens has been reported. For this experiment, the effectiveness of electron beam irradiation on the microbiological and sensory characteristics of fresh spinach was studied. Total aerobic plate counts were reduced by 2.6 and 3.2 log CFU/g at 0.7 and 1.4 kGy, respectively. Lactic acid bacteria were reduced at both doses of e-beam but grew slowly over the 35 d of the experiment. Yeasts and molds were not reduced in samples exposed to 0.7 kGy whereas 1.4 kGy significantly reduced microbial counts. Gas compositions (O(2) and CO(2)) were significantly different than controls. Oxygen levels inside the spinach sample bags decreased over time; however, O(2) levels did not drop below 1% that can induce anaerobic fermentation. CO(2) levels for all treatments increased through day 4; yet 7 d after irradiation, CO(2) level differences were not significant in both control and irradiated samples. Irradiation dose did not affect the basic tastes, aromatics, or mouth feels of fresh spinach, however; hardness attributes decreased as irradiated dose increased and slimy attributes of fresh spinach were higher in control samples compared to irradiated samples. PMID- 20722956 TI - Quality characterization of celery (Apium graveolens L.) by plant zones and two harvest dates. AB - The aim of this study was to characterize the quality of celery petioles (Apium graveolens L. cv Golden Clause) from the external, middle, and internal zones of each plant. Harvest dates were 93 (HD1) and 124 (HD2) days after transplantation. Total weight (TW), total length (TL), total leaves number (LN), and petiole length of leaves (PL) for the 3 zones were measured. Physicochemical (color, b* and h; texture; total soluble solids, TSS; titratable acidity, TA; water content, WC), nutraceutical (ascorbic acid, AA; total quinones, TQ; browning potential, BP), and sensorial analysis (flavor, fibrosity, crunchiness) were done at harvest on petioles of each zone. No differences between harvesting dates were found in TW, TL, LN, and PL. Middle leaves had the highest PL. Harvest dates were not different in b*, h, TA, AA, and WC. Texture, TSS, BP, and TQ resulted higher in petioles of HD2 than in HD1. Similar TSS and TA were found in leaves of different plant zones. The yellow color of both external and internal zones was significantly higher than in the middle zone. The texture and BP was similar between the external and middle zones but the WC was lower in the external zone. Similarly, the AA content as well as the TQ was also lower than in the middle zone. Harvest delay improved the nutraceutical value in terms of BP and TQ, even though it also resulted in pithiness and fibrosity of the leaves. This study therefore suggests that the petioles of the middle zone when harvested at HD1 are the most suitable for consumption. Practical Application: Celery is a vegetable reduced in calories, has a high nutritional value and its fresh petioles are mainly consumed in salads. The texture and flavor are the most important attributes that define consumers' acceptability. As nutritional value, texture, and flavor may change with plant age and different zones of the plant, harvest date plays an important role on quality. Results indicate that harvest delay improved the nutraceutical value even though it also resulted in pithiness and fibrosity of the stalks. Petioles of the middle zone, when harvested at 93 d after transplanting, are the most suitable for consumers' consumption. PMID- 20722957 TI - Physicochemical properties and consumer acceptance of wheat-germinated brown rice bread during storage time. AB - Selected physicochemical properties and consumer acceptance of bread prepared from composite flour (wheat:germinated brown rice:germinated glutinous brown rice flours at 60:30:10 ratio) were evaluated during storage for 0, 3, and 5 d, and compared with wheat bread (0 d, control). During storage, color profiles and water activity (from 0.947 to 0.932) of crumbs of composite flour breads slightly changed, but moisture content drastically decreased along with increasing crumb hardness (from 4.16 N to 10.37 N). Higher retrogradation in bread crumb was observed particularly for 5-d stored bread (DeltaH = 2.24 J/g) compared to that of the fresh composite bread and the control (DeltaH = 0.70 and 0.51 J/g, respectively). Mean (n = 116) overall liking score of the fresh composite flour bread (0 d) was slightly lower than that of the control (7.1 compared with 7.6 based on a 9-point hedonic scale). At least 76% of consumers would purchase the fresh composite flour bread if commercially available. Breads were differentiated by textural (moistness, smoothness, and softness) acceptability with canonical correlation of 0.84 to 0.87. The signal-to-noise ratio values of the 5-d stored breads were lower than the control, due mainly to the non-JAR (not-enough) intensity responses for moistness, smoothness, and softness; the mean drop of liking scores for these attributes ranged from 2.42 to 2.98. Flavor acceptability and overall liking were factors influencing consumers' purchase intent of composite flour breads based on logistic regression analysis. This study demonstrated feasibility of incorporating up to 40% germinated brown rice flour in a wheat bread formulation. Practical Application: Our previous study revealed that flours from germinated brown rice have better nutritional properties, particularly gamma-aminobutyric acid (GABA), than the nongerminated one. This study demonstrated feasibility of incorporating up to 40% germinated brown rice flour in a wheat bread formulation. In the current U.S. market, this type of bread may be sold as frozen bread that would have a longer shelf life, or may be supplied as a food-service product that would be made-to-order or made fresh daily as currently practiced in some major grocery stores. PMID- 20722958 TI - Toxicity study of ethanolic extract of Chrysanthemum morifolium in rats. AB - Chrysanthemum morifolium extract (CME) has many pharmacological effects, and the effective components of CME are luteolin and apigenin which have been reported with cytotoxicity in vitro. The purpose of this study was to evaluate the safety of CME in Sprague-Dawley (S-D) rats. In the acute toxicity study, a single oral dose of 15 g/kg body weight (bw) CME was administered to rats, then the rats were observed for 14 d. No treatment-related death was observed, and the maximal tolerance dose estimated was greater than 15 g/kg bw in rats. In the long-term toxicity study, the rats were administered daily by gavage at dose levels of 320, 640, and 1280 mg/kg bw/d for consecutive 26 wk followed by 4 wk recovery period. The results showed that no toxicological changes in body weight, food, and water consumption, hematologic examination, blood biochemical examination, organ weight, and microscopic histopathologic examination were found in any treatment group. Therefore, CME is considered to be safe in general in rats at the limited dose level. PMID- 20722959 TI - Development of a sandwich enzyme-linked immunosorbent assay (ELISA) for detection of buckwheat residues in food. AB - Buckwheat is a pseudocereal (an eudicot with seed qualities and uses similar to those of monocot cereals, family Poaceae) that is consumed in some Asian countries as a staple, and in some western countries as a health food. Allergic reactions to buckwheat are common in some countries. The objective was to develop a specific and sensitive sandwich enzyme-linked immunosorbent assay (ELISA) to detect traces of buckwheat that might inadvertently contaminate other foods in order to assure accurate labeling and consumer protection. Buckwheat-specific antibodies produced in 3 species of animals were tested for specificity and titer by direct ELISA and immunoblot. A sandwich ELISA was developed utilizing pooled rabbit antibuckwheat sera to capture buckwheat proteins and pooled goat antibuckwheat sera, followed by enzyme-labeled rabbit antigoat immunoglobulin G (IgG), to detect bound buckwheat proteins. The lower limit of quantification (LOQ) of the sandwich ELISA was 2 parts per million (ppm) of buckwheat in the presence of complex food matrices. The ELISA is highly specific with no cross reactivity to any of 80 food ingredients and matrices tested. Validation studies conducted with buckwheat processed into noodles and muffins showed greater than 90% and 60% recovery, respectively. The percent recovery of buckwheat from noodles was similar to that achieved with a commercial buckwheat ELISA kit (ELISA Systems Pty. Ltd., Windsor, Queensland, Australia) at high buckwheat concentrations. However, the sensitivity of this ELISA was greater than the commercial ELISA. This newly developed ELISA is sufficiently specific and sensitive to detect buckwheat residues in processed foods to protect buckwheat allergic subjects from potential harm. Practical Application: Buckwheat is becoming a common food ingredient in a number of processed foods due to potentially beneficial nutritional properties, without the celiac disease inducing glutenin proteins of wheat and related cereals. However, buckwheat causes allergy in some individuals and must be labeled and tested accurately to protect those with allergy to buckwheat. We describe the development of a new test assay to help food producers ensure that buckwheat is not present in foods that are not intended to contain buckwheat. PMID- 20722960 TI - A rapid direct solvent extraction method for the extraction of 2 dodecylcyclobutanone from irradiated ground beef patties using acetonitrile. AB - The amount of irradiated beef in the U.S. market is growing, and a reliable, rapid method is needed to detect irradiated beef and quantify the irradiation dose. The official analytical method (BS EN 1785 2003) that has been adopted by the European Union is time consuming. The objective of this study was to develop a rapid method for the analysis of 2-dodecylcyclobutanone (2-DCB) in irradiated beef. A 5 g sample of commercially irradiated ground beef patty (90/10) was extracted with n-hexane using a Soxhlet apparatus or with acetonitrile via direct solvent extraction. The Soxhlet hexane extract was evaporated to dryness, and the sample was dissolved in a mixture of ethyl acetate and acetonitrile (1:1). The defatted extract was purified with a 1 g silica cartridge. Another 5 g aliquot of the same patty was mixed with 50 mL acetonitrile and either blended for 1 min with a hand blender or crushed for 10 min with a glass rod. The extraction procedure was repeated 3 times, and the acetonitrile was collected and evaporated to dryness. Eluants from both methods were concentrated under nitrogen and injected into a gas chromatography-mass spectrometry. The 2-DCB concentration in the commercial samples was 0.031 +/- 0.0026 ppm (n = 5) for the Soxhlet method and 0.031 +/- 0.0025 ppm (n = 10) for direct solvent extraction. Recovery of 2 DCB from spiked beef samples in the direct solvent extraction method was 93.2 +/- 9.0% (n = 7). This study showed that the direct solvent extraction method is simple and as efficient and reproducible as the Soxhlet method. PMID- 20722961 TI - Antiangiogenetic effects of 4 varieties of grapes in vitro. AB - The purpose of this study was to investigate the inhibitory effects of grapes on the human umbilical vein endothelial (HUVE) cells' capillary tube formation and matrix metalloproteinase-2 (MMP-2) expression secreted into the medium. Four different grape varieties (Concord, Niagara, Chardonnay, and Pinot Noir) were extracted using 80% acetone and the extracts were stored at -80 degrees C. The total amount of phenolics and flavonoids for each of the 4 grape varieties were determined by spectrophotometry. Grape extracts were co-cultured with HUVE cells on Matrigel and inhibitory effects on tube formation were observed under a microscope. The inhibitory effects of grape extracts on MMP-2 expression were examined by zymogram. All 4 grape varieties inhibited the tube formation of HUVE cells in a dose-dependent manner on Matrigel. Except for Chardonnay, the other 3 grape varieties completely inhibited secretion of MMP-2 at 20 mg/mL. There was a significant positive relationship between the total phenolics and flavonoids and antiangiogenetic activities. The grapes tested have the potential to inhibit angiogenesis mainly by their phenolics and flavonoids contents, which partly contribute to their cancer chemopreventive efficacy. PMID- 20722962 TI - Possible role of caffeine in autism spectrum disorders, a new testable hypothesis. PMID- 20722964 TI - Plagiarism: the plague of publishing. PMID- 20722965 TI - Unique clockwork in photoreceptor of rat. AB - In mammals, the retina contains a clock system that oscillates independently of the master clock in the suprachiasmatic nucleus and allows the retina to anticipate and to adapt to the sustained daily changes in ambient illumination. Using a combination of laser capture micro-dissection and quantitative PCR in the present study, the clockwork of mammalian photoreceptors has been recorded. The transcript amounts of the core clock genes Clock, Bmal1, Period1 (Per1), Per3, Cryptochrome2, and Casein kinase Iepsilon in photoreceptors of rat retina have been found to undergo daily changes. Clock and Bmal1 peak with Per1 and Per3 around dark onset, whereas Casein kinase Iepsilon and Cryptochrome2 peak at night. As shown for Clock, Per1, and Casein kinase Iepsilon, the oscillation of transcript amounts results in daily changes of the protein products. The in-phase oscillation of Clock/Bmal1 with Pers and the rhythmic expression of Casein kinase Iepsilon do not occur in molecular clocks of other tissues including the suprachiasmatic nucleus. Therefore, the findings presented suggest that the photoreceptor clock is unique not only in its position outside the clock hierarchy mastered by the suprachiasmatic nucleus, but also with regard to the intrinsic rhythmic properties of its molecular components. PMID- 20722966 TI - Inhibition of CCAAT/enhancer binding protein delta expression by chrysin in microglial cells results in anti-inflammatory and neuroprotective effects. AB - The control of neuroinflammation is a potential target to be considered in the treatment of neurodegenerative diseases. It is therefore important to find anti inflammatory drugs and study new targets that inhibit neuroinflammation. We designed an experimental model of neuroinflammation in vitro to study the anti inflammatory and neuroprotective effects of the flavonoid chrysin and the involvement of nuclear factor-kappaB p65 and CCAAT/enhancer binding proteins (C/EBPs) beta and delta transcription factors in its mechanism of action. We used primary cultures of mouse embryonic cortical neurons and cultures of BV2 (murine microglial cell line) or mouse primary microglia. We induced neuronal death in neuronal-BV2/microglial co-cultures using lipopolysaccharide of Escherichia coli and interferon-gamma. Chrysin pre-treatment inhibited nitric oxide and tumor necrosis factor-alpha production, as well as inducible nitric oxide synthase expression in lipopolysaccharide E. coli and interferon-gamma-treated microglial cells, but did not affect cyclooxygenase-2 expression. Chrysin pre-treatment also protected neurons against the neurotoxicity induced by reactive microglial cells. These effects were associated to a decrease in C/EBPdelta protein level, mRNA expression, and DNA-binding activity, with no effect on C/EBPbeta and p65 nuclear protein levels or DNA-binding activity, pointing out C/EBPdelta as a possible mediator of chrysin effects. Consequently, C/EBPdelta is a possible target to act against neuroinflammation in neurodegenerative processes. PMID- 20722967 TI - Critical role of lipid rafts in virus entry and activation of phosphoinositide 3' kinase/Akt signaling during early stages of Japanese encephalitis virus infection in neural stem/progenitor cells. AB - Japanese encephalitis virus (JEV), the leading cause of acute encephalitis in South-East Asia is a neurotropic virus infecting various CNS cell types. Most Flaviviruses including JEV get internalised into cells by receptor-mediated endocytosis, which involve clathrin and membrane cholesterol. The cholesterol enriched membrane microdomains referred to as lipid rafts act as portals for virus entry in a number of enveloped viruses, including Flavivirus. However, the precise role played by membrane lipid rafts in JEV internalisation into neural stem cells is still unknown. We have established neural stem/progenitor cells and C17.2 cell line as models of productive JEV infection. Increase in membrane fluidity and clustering of viral envelope proteins in lipid rafts was observed in early time points of infection. Localisation of non-structural proteins to rafts at later infection stages was also observed. Co-localisation of JEV glycoprotein with Cholera toxin B confirmed that JEV internalisation occurs in a lipid-raft dependent manner. Though JEV entry is raft dependent, however, there is requirement of functional clathrin during endocytosis inside the cells. Besides virus entry, the lipid rafts act as signalling platforms for Src tyrosine kinases and result in activation of phosphoinositide 3'-kinase/Akt signalling during early JEV infection. Disruption of lipid raft formation by cholesterol depletion using Methyl beta-cyclodextrin, reduced JEV RNA levels and production of infectious virus particles as well as impaired phosphoinositide 3'-kinase/Akt signalling during initial infection. Overall, our results implicate the importance of host membrane lipid rafts in JEV entry and life cycle, besides maintaining survival of neural stem/progenitor cells during early infection. PMID- 20722969 TI - Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrity. AB - Since the advent of HAART, there have been substantial improvements in HIV patient survival; however, the prevalence of HIV associated dementia has increased. Importantly, HIV positive individuals who smoke progress to HIV associated neurological conditions faster than those who do not. Recent in vitro data have shown that pharmacological levels of saquinavir causes endothelial oxidative stress and significantly decreases Notch-4 expression, a primary protein involved in maintaining stability of blood-brain barrier (BBB) endothelium. This is concerning as nicotine can also generate reactive oxygen species in endothelium. It is largely unknown if pharmacological doses of these drugs can cause a similar in vivo down-regulation of Notch-4 and if there is a concurrent destabilization of the integrity of the BBB. The data herein show: (i) nicotine and protease inhibitors cause an additive oxidative stress burden in endothelium; (ii) that the integrity of the BBB is disrupted after concurrent chronic nicotine and protease inhibitor administration; and (iii) that BBB endothelial dysfunction is correlated with a decrease in Notch-4 and ZO-1 expression. Considering the high prevalence of smoking in the HIV infected population (3- to 4-fold higher than in the general population) this data must be followed up to determine if all protease inhibitors cause a similar BBB disruption or if there is a safer alternative. In addition, this data may suggest that the induced BBB disruption may allow foreign molecules to gain access to brain and be a contributing factor to the slow progression of HIV associated dementia. PMID- 20722968 TI - The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum. AB - Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum. PMID- 20722970 TI - Neuropeptide S stimulates dopaminergic neurotransmission in the medial prefrontal cortex. AB - Neuropeptide S (NPS) is known to produce anxiolytic-like effects and facilitate extinction of conditioned fear. Catecholaminergic neurotransmission in the medial prefrontal cortex (mPFC) has been suggested to be crucially involved in these brain functions. In the current study, we investigated the effect of NPS on the release of dopamine and serotonin in the mPFC by in vivo microdialysis in rats. Central administration of NPS dose-dependently enhanced extracellular levels of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid, with maximal effects lasting up to 120 min. In contrast, no effect on serotonergic neurotransmission was detected. Dopamine release in the mPFC has been previously linked to modulation of anxiety states and fear extinction. The present results may thus provide a physiological and anatomical basis for the reported effects of NPS on these behaviors. PMID- 20722972 TI - Microglial activation mediates de novo lysophosphatidic acid production in a model of neuropathic pain. AB - We recently demonstrated that de novo lysophosphatidic acid (LPA) production in the spinal cord occurs in the early phase after nerve injury or LPA injection, and underlies the peripheral mechanisms of neuropathic pain. In this study, we examined the possible involvement of spinal cord microglia in such LPA-mediated functions. Intrathecal LPA injection rapidly increased the gene expression of CD11b and protein expression of phosphor-p38, accompanied by a morphological change of microglia from a ramified to amoeboid shape. Although early treatment with minocycline significantly inhibited LPA-induced neuropathic pain-like behavior and microglial activation, late treatment did not. Early treatment with minocycline also blocked LPA-evoked de novo LPA production and the increased activation of cytosolic phospholipase A(2), an LPA synthesis-related enzyme. Similar results were observed when the sciatic nerve was partially injured: early, but not late, treatment with minocycline significantly inhibited the injury-induced neuropathic pain, microglial activation, de novo LPA production and the underlying increased activation of cytosolic phospholipase A(2) as well as calcium-independent phospholipase A(2), another LPA synthesis-related enzyme. These findings suggest that the early phase of microglial activation is involved in de novo LPA production, and that this underlies the initial mechanisms of nerve injury-induced neuropathic pain. PMID- 20722971 TI - Light touch induces ERK activation in superficial dorsal horn neurons after inflammation: involvement of spinal astrocytes and JNK signaling in touch-evoked central sensitization and mechanical allodynia. AB - Activation of extracellular signal-regulated kinase (ERK) in spinal cord neurons could serve as a marker for sensitization of dorsal horn neurons in persistent pain. ERK is normally activated by high-threshold noxious stimuli. We investigated how low-threshold mechanical stimuli could activate ERK after complete Freund's adjuvant (CFA)-induced inflammation. Unilateral injection of CFA induced ipsilateral heat hyperalgesia and bilateral mechanical allodynia. CFA induced ERK activation in ipsilateral dorsal horn neurons declined after 2 days. Interestingly, low-threshold mechanical stimulation given by light touch either on the inflamed paw or the contralateral non-inflamed paw dramatically increased ERK phosphorylation in the dorsal horn ipsilateral to touch stimulation. Notably, light touch induced ERK phosphorylation mainly in superficial neurons in laminae I-IIo. Intrathecal administration of the astroglial toxin L-alpha-aminoadipate on post-CFA day 2 reversed CFA-induced bilateral mechanical allodynia but not heat hyperalgesia. Furthermore, L-alpha-aminoadipate, the glial inhibitor fluorocitrate, and a peptide inhibitor of c-Jun N-terminal Kinase all reduced light touch-evoked ERK activation ipsilateral to touch. Collectively, these data suggest that (i) ERK can be activated in superficial dorsal horn neurons by low threshold mechanical stimulation under pathological condition and (ii) ERK activation by light touch is associated with mechanical allodynia and requires an astrocyte network. PMID- 20722974 TI - Activity of hypothalamic dopaminergic neurones during the day of oestrus: involvement in prolactin secretion. AB - A secretory surge of prolactin occurs on the afternoon of oestrus in cycling rats. Pituitary prolactin is inhibited by dopamine. We evaluated the activity of the neuroendocrine dopaminergic neurones during oestrus and dioestrus, as determined by dopaminergic activity in the median eminence and neurointermediate lobe of the pituitary, as well as Fos-related antigen expression in tyrosine hydroxylase (TH)-immunoreactive (ir) neurones of the arcuate nucleus (ARC) and periventricular nucleus (Pe). During oestrus, the 4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence decreased at 16.00 h, coinciding with the increase in plasma prolactin levels. Similarly, the expression of Fos-related antigen in TH-ir neurones of Pe and rostral-, dorsomedial- and caudal-ARC also decreased at 16.00 h. On dioestrus, 4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence and Fos-related antigen expression in TH-ir neurones of Pe and rostral-ARC decreased at 18.00 h, whereas prolactin levels were unaltered. No variation in dopaminergic activity was found in the neurointermediate lobe of the pituitary on either oestrus or dioestrus. The number of TH-ir neurones in the ARC and parameters of dopaminergic activity were found to be generally lower on oestrus compared to dioestrus. The transitory decrease in the activity of neuroendocrine dopaminergic neurones temporally associated with the prolactin surge on the afternoon of oestrus suggests a role for dopamine in the generation of the oestrous prolactin surge. PMID- 20722973 TI - 3beta-HSD in songbird brain: subcellular localization and rapid regulation by estradiol. AB - The enzyme 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) catalyzes the conversion of dehydroepiandrosterone to androstenedione, thereby playing a key role in sex steroid synthesis. In peripheral tissues, 3beta-HSD is membrane-bound, is present in both mitochondria and microsomes, and is regulated differentially in these two subcellular compartments. In the brain, 3beta-HSD is present, but its subcellular compartmentalization is unknown. Here, in Study 1, we examined the subcellular localization of 3beta-HSD in the brain of a songbird, the zebra finch. In Study 2, in males and females, we determined whether 3beta HSD activity in different subcellular compartments is rapidly regulated by in vitro treatment with estradiol (E(2) ), which has many rapid effects on the brain. Brain 3beta-HSD was enriched primarily in microsomes and secondarily in mitochondria and synaptosomes. In both males and females, E(2) treatment rapidly (within 5 min) inhibited 3beta-HSD activity in both mitochondria/synaptosomes and microsomes, with greater inhibition in microsomes. We also assessed the activity of 5beta-reductase, which acts on androstenedione. E(2) rapidly inhibited 5beta reductase activity in microsomes only. This is the first study to examine the subcellular localization of 3beta-HSD in the brain, and the data demonstrate the importance of subcellular localization for the regulation of steroidogenic enzymes in the brain. PMID- 20722976 TI - Expression and translocation of aquaporin-2 in the endolymphatic sac in patients with Meniere's disease. AB - Meniere's disease, characterised by episodic vertigo, fluctuating hearing loss and tinnitus, can occur under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although its pathogenesis has been proposed to be a disorder of water transport in the inner ear, subsequently, it remains unsolved, until now. A recent study revealed that both plasma stress hormone, vasopressin (pAVP) and its receptor, V2 (V2R) expression in the inner ear endolymphatic sac were significantly higher in Meniere's patients. In the present study, to link V2R-related molecules and inner ear hydrops, we examined V2R-linked water channel molecule, aquaporin-2 (AQP2) expression and translocation in human endolymphatic sac. AQP2 mRNA expression in the endolymphatic sac was significantly higher in Meniere's patients by using real-time polymerase chain reaction, as further confirmed by western blotting. AQP2-like immunoreactivity (-LIR) was translocated from luminal to basolateral side with endosomal trapping in the endolymphatic sac at the time of AVP exposure in human endolymphatic sac tissue culture. The similar AQP2-LIR translocation was also demonstrated by forskolin and blocked by vasopressin/V2R specific antagonist, OPC31260 and protein kinase A (PKA) specific antagonists, H-89 and KT 5720. We concluded that in the pathogenesis of inner ear hydrops resulting in Meniere's attacks, pAVP elevation as a result of stress and subsequent V2R-cAMP PKA-AQP2 activation and endosomal trapping of AQP2 in the endolymphatic sac, might be important as a basis of this disease. Further experimental and clinical studies are needed to better clarify the neuroscientific relationship between stress and Meniere's disease. PMID- 20722975 TI - Involvement of brain-derived neurotrophic factor and neurogenesis in oestradiol neuroprotection of the hippocampus of hypertensive rats. AB - The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17beta-oestradiol (E(2) ) for 2 weeks. The present work investigated whether E(2) treatment of SHR and of hypertensive DOCA-salt male rats modulated the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E(2) was simultaneously determined by counting the number of doublecortin immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)-positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E(2) pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA-salt-treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA-salt hypertensive rats and (ii) E(2) was able to normalise these biologically important functions in the hippocampus of hypertensive animals. PMID- 20722977 TI - A novel developmental role for kisspeptin in the growth of gonadotrophin releasing hormone neurites to the median eminence in the mouse. AB - The puberty- and fertility-regulating neuropeptide kisspeptin (KISS1) exerts dramatic effects on the physiology of adult gonadotrophin-releasing hormone (GnRH) neurones as a master regulator of mammalian reproduction. Given the action of KISS1 directly on adult GnRH neurones, and that KISS1 activates a signal transduction cascade involved in neurite growth in other neurones, we investigated whether KISS1 may play a role in the normal growth of GnRH neurites to the median eminence. A reverse transcription-polymerase chain reaction demonstrated the expression of Kiss1 mRNA in the embryonic mediobasal hypothalamus, the target region for GnRH neurite termination, as early as embryonic day 13.5 (E13.5), a time when the first GnRH neurites are arriving. Complementary expression of the mRNA encoding the KISS1 receptor, Kiss1r, in the preoptic area (POA) at E13.5 was also observed, suggesting that POA-resident GnRH neurones can respond to KISS1 from an early age. To examine the effects of KISS1 on GnRH neurite growth in isolation, E15.5 POA explants, containing GnRH neurones actively extending neurites, were grown in three-dimensional collagen gels. In the presence of KISS1 (1 MUm), both the number and length of GnRH neurites were increased significantly compared to controls without KISS1. The effects of KISS1 on GnRH neurite growth could be inhibited by pretreatment with the phospholipase C inhibitor U73122 (50 MUm), indicating that embryonic and adult GnRH neurones respond to KISS1 with the same intracellular signalling pathway. KISS1 provided in a concentration gradient from a fixed source had no effect on GnRH neurite growth, indicating that KISS1 does not function as a long-range chemoattractant. Taken together, these results identify KISS1 as a stimulator of GnRH neurite growth, and suggest that it influences GnRH neurites at close-range to innervate the median eminence. These data add a novel developmental role to the repertoire of the functions of KISS1 in mammalian reproduction. PMID- 20722978 TI - Insulin secretory granules enter a highly calcium-sensitive state following palmitate-induced dissociation from calcium channels: a theoretical study. AB - Impaired insulin secretion is a major contributor to diabetes. Obesity is a known risk factor for the development of diabetes, and prolonged exposure of pancreatic islets to lipids results in impaired insulin secretion. Insulin is released from pancreatic beta-cells as a result of Ca(2+) -induced exocytosis. Recent experiments have shown that chronic palmitate exposure results in the loss of localised Ca(2+) -influx and impaired exocytosis of insulin secretory granules in beta-cells. In the present study, the roles of Ca(2+) -channel clustering disruption, and dissociation of granules from Ca(2+) -channels, in the impaired exocytotic and secretory responses from palmitate-treated beta-cells, are investigated using mathematical models of Ca(2+) dynamics, granule pools, exocytosis and secretion. It is shown that either disruption of Ca(2+) -channel clusters or dissociation of granules from Ca(2+) -channels with a shift to a highly calcium-sensitive pool can explain the recent experimental findings of palmitate-induced defects of exocytosis and insulin secretion. On the basis of imaging results, it is argued that a shift to a highly calcium-sensitive state after dissociation of granules from Ca(2+) -channels is the most likely explanation for the experimental findings from beta-cells exposed chronically to palmitate. PMID- 20722979 TI - A dynamical model for the control of the gonadotrophin-releasing hormone neurosecretory system. AB - The gonadotrophin-releasing hormone (GnRH) neurosecretory system involves both endocrine neurones and associated brain cells responsible for the control of GnRH release into the pituitary portal blood. Alternation between a pulsatile regime and the pre-ovulatory surge is the hallmark of GnRH secretion in ovarian cycles of female mammals. In previous studies, we have introduced a mathematical model of the pulse and surge GnRH generator and derived appropriate dynamics-based constraints on the model parameters, both to reproduce the right sequence of secretion events and to fulfil quantitative specifications on GnRH release. In the present study, we explain how these constraints amount to embedding time- and dose-dependent steroid control within the model. We further examine under which conditions the oestradiol-driven surge may be withdrawn by pre-surge progesterone administration and simulate both oestradiol and progesterone challenges in the pulsatile regime. PMID- 20722980 TI - Preterm labour: tsunami waves? AB - Preterm labour and birth can be delayed but are generally unstoppable, threatening the health of the mother-baby duo. This may be a result of peripheral signals prematurely recruiting the oxytocin neurones that co-ordinate the timing of birth and, via specialised activity and secretion patterns, drive uterine contractions. Once sensitised, these neurones respond with waves of activity, even to weak stimuli, resulting in a positive-feedback loop that escalates towards inevitable birth. PMID- 20722981 TI - Transvaginal color Doppler study of uterine artery: is there a role in chronic pelvic pain? AB - AIM: To determine the value of transvaginal color Doppler study of uterine artery and investigate the differences in blood flow of uterine artery among women with chronic pelvic pain (CPP). MATERIAL & METHODS: A total of 50 female patients were recruited. The study group consisted of 25 women with CPP of possible gynecological origin. Twenty-five women without CPP made a control group. All women were examined using transvaginal color Doppler ultrasonogram after negative finding of pelvic examination. The mean pulsality index (PI) and resistant index (RI) of the uterine arteries were recorded and compared. RESULTS: The mean ages were 36.6 +/- 10.6 and 32.0 +/- 6.7 years in the study group and control group, respectively. The duration of pain ranges from 6-48 months (mean, 14.8). The mean PI and RI values of the uterine arteries in patients with CPP were significantly lower than in the control group; PI = 2.12 +/- 0.78, 2.76 +/- 0.84 and RI = 0.79 +/- 0.19, 0.89 +/- 0.05, respectively (P < 0.05). CONCLUSIONS: Doppler flow indices demonstrated significant increase of uterine arteries vascularization in CPP women related to pelvic causes. Transvaginal ultrasound with noninvasive Doppler study could be a useful primary investigation for CPP women, especially when financial resource is an issue. PMID- 20722982 TI - Cesarean section and hernia repair: simultaneous approach. AB - AIM: Hernias of the abdominal wall occurring during pregnancy are usually treated a few weeks after delivery. The aim of this study was to retrospectively evaluate the clinical outcome of inguinal or umbilical hernioplasty performed at the time of the cesarean section, and to compare the outcome of this group with a control population, who received a cesarean section alone. MATERIAL & METHODS: We reviewed 28 women who developed an inguinal or umbilical hernia during pregnancy from January 1, 2000 to December 31, 2007 and who received a combined cesarean section and hernia repair, and we compared this group with 100 women (controls) who only received a cesarean section. RESULTS: In the group of women who received a combined cesarean section and inguinal or umbilical hernia repair, median age was 23.8 years and hospital stay ranged from 3 to 5 days (versus 3-4 days for cesarean sections alone). The time employed for the combined surgical procedure was of 50 +/- 7 min and 70 +/- 4 min, respectively, for umbilical and inguinal hernia (versus 37.4 +/- 12.6 min for cesarean sections alone). No complication was recorded during the perinatal and follow-up periods, and no recurrences were observed. CONCLUSION: Our analysis suggests that cesarean section and hernia repair, performed in one session, avoids need for readmission to hospital, is safe, effective, and well accepted. It neither increases the complication rate nor prolongs the hospital stay, with clear advantages for both the patients and the hospital budget. PMID- 20722983 TI - The Portuguese version of the Postpartum Depression Screening Scale-Short Form. AB - AIMS: The aim of this study was to demonstrate the validity and reliability of the short form of the Postpartum Depression Screening Scale in Southern Brazil. MATERIAL & METHODS: Research volunteers completed the Postpartum Depression Screening Scale-Short Form (PDSS-SF) and a Structured Clinical Interview for Mental Disorders (SCID). Evaluation parameters included reliability and correlational investigations analyses. RESULTS: The proposed Portuguese version of the PDSS-SF attained significant Cronbach's alphas (0.71 or superior). The best cut-off score (>=17) accounted for 89% of sensitivity and 77% of specificity. In addition, nonparametric correlation procedures revealed a significant correlation between the screening results of the PDSS-SF and the assessment based on the SCID. CONCLUSIONS: The Portuguese version of the PDSS-SF demonstrated sound psychometric properties. The results of the correlation analyses between the PDSS-SF and the SCID assessment also indicate a significant concurrent validity. The Portuguese version of the PDSS was adequately translated and adapted to Portuguese. PMID- 20722984 TI - Microsurgical training in a rat model: an approach and concept for gynecological surgeons. AB - AIMS: This study aims to introduce a training program for microvascular anastomosis that includes an in vivo model which is elegant and effective. MATERIAL & METHODS: The infrarenal abdominal aorta or inferior vena cava of anesthetized live Sprague-Dawley rats were dissected, clamped and divided. Two trainees each created 12 microsurgical anastomoses in six animals. The training effect was measured by comparing the time taken to perform the initial anastomoses with the final attempts for each trainee. Afterwards, each anastomosis was probed to check whether the procedure was successful. RESULTS: The training model was practical and easy to set up. The average diameter of the aorta measured 1.5 mm and the vein measured 2.1 mm, which reflects the situation in human gynecological reconstructive surgery. The achieved training effect over the course of the training was highly significant. Arterial anastomosis time improved by an average of 8.5 min (P < 0.01) and venous anastomosis time improved by an average of 13.2 min (P < 0.01). The success rate for arterial anastomoses was 67%. In contrast, venous anastomosis was a more difficult exercise, with a success rate of 36% (P < 0.05). CONCLUSION: The study establishes a practicable in vivo model of microvascular anastomotic training for gynecologists. PMID- 20722985 TI - The electronically-controlled axis-traction handle: preliminary report. AB - AIM: The scope of this preliminary report is to illustrate the performance characteristics of an electronically-controlled axis-traction handle. MATERIAL & METHOD: Preclinical testing was conducted with a prototype of the innovative device, using a childbirth simulator. RESULTS: The simulated forceps deliveries demonstrated that the innovative device allows the obstetrician to measure (unencumbered by dials, scales and cable connections) the traction applied, to be alerted when the preset 50 lbs (22.68 kg) safety limit is approached, and to generate a hard copy print-out of the traction data. CONCLUSION: The electronically-controlled axis-traction handle represents a major technologic advance, that could help improve the training and safe practice of forceps deliveries. PMID- 20722986 TI - Association of maternal serum high sensitive C-reactive protein level with body mass index and severity of pre-eclampsia at third trimester. AB - AIM: To assess a maternal serum level of high sensitive C-reactive protein (hs CRP) as a useful clinical parameter in prediction of pre-eclampsia severity and, to evaluate the correlation between hs-CRP and body mass index (BMI). MATERIAL & METHODS: Using cross-sectional study design, CRP was measured by a high sensitive immunoturbidimetric method between 24 and 40 weeks of gestation in normotensive controls (n = 115), in mild (n = 63) and severe (n = 34) pre-eclamptic patients. The receiver operating characteristic analysis was used to estimate the optimal threshold score of hs-CRP. RESULTS: For disease severity evaluation, a hs-CRP concentration of 9.66 mg/L was determined as cut-off point with 88% sensitivity, 81% specificity, 71% positive predictive value and 92% negative predictive value. When all three groups of patients were adjusted for gestational age [24( degrees /7) -27,(6/7) 28( degrees /7) -33,(6/7) 34( degrees /7) -40(6/7) ] and BMI, hs CRP levels of severe pre-eclamptic patients were significantly higher than mild ones and controls in the study group with BMI < 25 kg/m(2) (P < 0.001). In the study group with BMI >= 25 kg/m(2), only severe pre-eclamptic patients between 28( degrees /7) and 33(6/7) weeks of gestation had significantly higher hs-CRP levels when compared with control and mild pre-eclamptic group (P < 0.001). When the patients were subgrouped as high (>= 9.66 mg/L) and low hs-CRP group (< 9.66 mg/L), adverse outcomes for hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and intrauterine growth-restricted baby were statistically significant higher in high hs-CRP group (P = 0.004 and P < 0.001, respectively). CONCLUSION: Elevated level of hs-CRP is a useful parameter in the severity of clinical risk of pre-eclampsia in patients with BMI < 25 kg/m(2) at third trimester. PMID- 20722987 TI - Prenatal diagnosis and postnatal follow-up of a child with mosaic trisomy 22 with several levels of mosaicism in different tissues. AB - We report on the case of a patient with mosaic trisomy 22, who was diagnosed prenatally by amniocentesis during the 16(th) week of pregnancy. In the foetus, three trisomic clones were found out of the nine that were analyzed (the other six clones had a 46,XY karyotype). Cytogenetic analysis of cord blood during the 20(th) week of pregnancy showed a normal male karyotype; however, a placental biopsy that was performed at the same time showed 100% and 95% trisomic cells in the chromosomal analysis of direct and long-term cultures, respectively. A follow up ultrasonographic examination excluded major congenital malformations and the abdominal and cranial circumferences were normal until the 24(th) week of pregnancy. At this point, a deflection of the growth curve occurred and the values were persistently below the 3(rd) centile until birth. After birth, karyotypic and fluorescent in situ hybridisation analyses performed on the fibroblasts of the neonate showed that 3-4% of the cell lines were trisomic, and studies using microsatellite markers showed normal allelic segregation, which excluded uniparental disomy. The period of postnatal follow-up was characterised by a significant growth deficit (height and head circumference were less than the 3(rd) centile) and by mental retardation. The present case is compatible with other earlier reports that showed that the levels of trisomy 22 are tissue specific and are of little help in establishing the prognosis of the chromosomal abnormality. PMID- 20722988 TI - Postoperative concurrent chemoradiotherapy for the high-risk uterine cervical cancer. AB - AIM: To determine whether concurrent chemoradiotherapy (CCRT) can improve the survival rate of high-risk uterine cervical cancer. MATERIAL & METHODS: We analyzed 16 cases of uterine cervical cancer that had undergone radical hysterectomy and pelvic lymphadenectomy from 2003 to 2008. The patients were eligible if they had histologically confirmed positive parametrial involvement, positive pelvic lymph nodes or non-squamous cell carcinoma. They received 50 Gy of external beam radiotherapy (RT) for the pelvis which was combined with chemotherapy. Cisplatin was administered intravenously every 3 weeks at a dose of 70 mg/m(2) during the RT. For renal function complication case, carboplatin was administered weekly. For control purposes, there were 14 cases treated in our hospital from 1995 to 2003 who had received only RT. RESULTS: We did not find any statistically significant difference in the disease-free survival rate between the CCRT group and the RT group. However, the overall survival rate was significantly higher for patients in the CCRT group compared with the RT group in positive lymph node cases and non-squamous cell carcinoma cases. Adverse effects were more frequent in the CCRT group. Over grade 3 toxicities were manifested as leukopenia, diarrhea and anemia. There was no local recurrence in CCRT group patients. CONCLUSION: CCRT seems to be beneficial for improving the survival rate of either positive lymph node or non-squamous cell carcinoma cases in high-risk uterine cervical cancer patients. PMID- 20722989 TI - Changes in heart rate patterns by lipopolysaccharide and intermittent hypoxia ischemia in 7-day-old rats. AB - AIM: We previously reported that lipopolysaccharide (LPS) and hypoxia-ischemia (HI) act additively to induce brain damage in the developing rat model. The present study was undertaken to determine whether LPS-HI-induced brain damage is associated with changes in heart rate (HR) patterns. MATERIAL & METHODS: Seven day-old Wistar rats were administered LPS (1 mg/kg, n = 17) or saline (n = 15) intraperitoneally. After 4 h, the left common carotid artery was ligated and electrocardiogram electrodes were placed on the chest under ether anesthesia, followed by intermittent HI (8% oxygen for 6 min) at 10-min intervals for a total of 10 times. Seven days later, rats were sacrificed and brains removed for histological examination. Neuronal damage for a single section was categorized as mild (<= 25% of the surface area), moderate (25-50%) or severe (>= 50%). RESULTS: Brain damage was induced only in the LPS/HI group, which was statistically significant when compared to the saline/HI group. Baseline HR increased significantly due to LPS administration (P < 0.05). In the LPS/HI group, the amplitude of hypoxia-driven tachycardia decreased significantly in the last 5 hypoxic episodes in brain-damaged rats compared to rats with no visible damage (28 +/- 1 vs 16 +/- 2 bpm). Baseline HR variability was also suppressed significantly during the last five hypoxic episodes in brain-damaged rats compared to rats with no visible damage. CONCLUSIONS: LPS administration caused a gradual decrease in baseline HR variability and blunted tachycardia in response to repetitive HI, suggesting these signs are indicative of future neonatal brain damage. PMID- 20722990 TI - Retroperitoneal ectopic pregnancy: is there any place for non-surgical treatment with methotrexate? AB - Cases of retroperitoneal ectopic pregnancy are very rare. To date, few published and unpublished reports are available and no clear or specific management guidelines have been defined. Despite concern for the risk of surgical resection of the gestational tissue and associated hemorrhage when these lesions are in close proximity to the large retroperitoneal blood vessels, conservative treatment with methotrexate has so far failed to obviate the ultimate need for surgical management. A case of retroperitoneal ectopic pregnancy located very close to large retroperitoneal blood vessels and treated with methotrexate is presented. Two other varying cases of failed methotrexate treatment for similar diagnosis are discussed. The presented patient failed methotrexate treatment and eventually underwent surgical excision. PMID- 20722991 TI - Polypropylene mesh used for adjuvant reconstructive surgical treatment of advanced pelvic organ prolapse. AB - AIM: To elucidate the outcome of transvaginal pelvic reconstructive surgery using polypropylene mesh (Gynemesh; Ethicon, Somerville, NJ, USA) for patients with pelvic organ prolapse (POP) stage III or IV. METHODS: Thirty-nine patients who underwent transvaginal pelvic reconstructive surgery from September 2004 through December 2005 were collected and analyzed. All patients underwent pelvic reconstructive surgery with anterior and posterior colporrhaphy with Gynemesh reinforcement. RESULTS: The average age of the patients was 64.1 years and average parity was 3.9. Thirty-four patients had Pelvic Organ Prolapse Quantification (POP-Q) stage 0, four patients had stage I, and one patient had stage II at a median follow-up time of 18 months postoperatively. The success rate was 97.4%. Only one patient (2.6%) had recurrent genital prolapse (stage II) postoperatively. Quality of life was evaluated before and after the operations. The mean scores on the Urinary Distress Inventory-6 (UDI-6) and Incontinence Impact Questionnaire-7 (IIQ-7) were 5.0 +/- 4.6 and 8.7 +/- 6.2 before the operation and 3.0 +/- 4.7 and 3.2 +/- 5.6 after the operation, respectively (P = 0.03 and 0.01). The complication rate was 10.3 %, including one vaginal mesh erosion (2.6%), one dyspareunia (2.6%) and two prolonged bladder drainage (longer than 14 days, 5.1%). The mean duration of postoperative bladder drainage was 2.4 days and mean postoperative hospital stay was 5.1 days. Neither long-term nor major complication was identified. CONCLUSION: Transvaginal pelvic reconstructive surgery with polypropylene mesh reinforcement is a safe and effective procedure for POP on 1.5 years' follow- up. It also has positive influence on quality of life. PMID- 20722992 TI - Brain infarction localized on left inferior temporal gyrus of presumed fetal onset. AB - Idiopathic perinatal cerebral infarction is recognized to be more common in the preterm infant than previously realized. However, the pathogenic mechanisms and the onset time remain unclear. We encountered an extremely low birth weight female infant with severe intrauterine growth retardation and brain infarction localized on the left inferior temporal gyrus. The onset of the infarction and the precise sequential changes were evaluated with blood data, cranial ultrasound imaging, computed tomography, magnetic resonance imaging and magnetic resonance angiography. This is the first published fetal case with brain infarction specifically localized on the left inferior temporal gyrus. Careful observation with serial brain imaging is indispensable for high-risk infarction groups, such as preterm infants with severe intrauterine growth retardation, to detect neurological abnormality earlier and precisely. PMID- 20722993 TI - 'I enjoy teaching but...': Paediatricians' attitudes to teaching medical students and junior doctors. AB - AIM: To explore consultant paediatricians' attitudes, motivations, and barriers to training medical students and junior doctors. METHODS: Qualitative research involving 24 paediatricians (with a diversity of specialties, experience, age, gender, teaching activity and employment status) from a tertiary paediatric hospital and clinical school in Sydney, Australia. Participants were engaged in semi-structured focus group discussions which explored their attitudes to teaching medical students and junior doctors, their role and experience of teaching, their training in medical education, perceived barriers to teaching, and possible solutions to these barriers. Data from the transcriptions of the focus group discussions were coded using the constant comparative method and analysed for themes using NVivo 7 software. Differences in responses between participants were explored. RESULTS: All participants reported enjoying teaching. However, a number of factors which occurred at the consultant, learner and institution level affected the enjoyment or challenge of teaching. Consultant factors included time commitments, knowledge of and confidence in the learner's course, and comfort with teaching. Learner factors included level of knowledge, attendance, interest and enthusiasm, and cultural changes. Institution factors included acknowledgement of teaching contribution, communication, teaching support and resources, and attitude to teaching. These factors and the consultant's relationship with the learner and institution impacted on their ownership, involvement, and commitment to teaching. CONCLUSIONS: Consultant paediatricians identified challenges to their involvement and commitment to teaching. Actions to address these challenges and improve the relationship between the consultant and the learner and the consultant and the institution may enhance the consultant's commitment to teaching. PMID- 20722994 TI - 'Halving the heel pricks': evaluation of a neonatal jaundice protocol incorporating the use of a transcutaneous bilirubinometer. AB - AIM: This study aimed to assess the impact of implementing a new jaundice protocol incorporating the use of the Konica Minolta/Air Shields JM 103 Jaundice Meter (JM103) (Konica Minolta Sensing Inc., Osaka, Japan) in the setting of an Australian post-natal ward. METHODS: A before-and-after study was completed following the introduction of a protocol integrating the use of the JM103 monitor on to the post-natal ward. Eligible infants were >= 36 weeks gestation, > 24 h and < 8 days of age. The number of Total Serum Bilirubin tests (TSBRs) were compared for the 12 months prior (T1) with a 6-month period and 6 months after protocol introduction (T2). Transcutaneous bilirubin (TcBR) results were also collected in T2. Rates of phototherapy and peak TSBRs at commencement were also compared as measures of safety. RESULTS: Four hundred and twenty-six of the 2197 live births in T1 required one or more TSBRs compared with 119 of the 1169 live births in T2. This represents an odds ratio of 0.47 (95% confidence interval 0.38 0.58) for infants in T2 having >= 1 TSBR compared with T1. There was no difference between the groups for rates of phototherapy (3.8% vs. 3.0%; P= 0.2) nor any difference between the groups for peak SBR during phototherapy (301.9 umol/L (standard deviation, SD 58) for T1 vs. 303.2 umol/L (SD 54) for T2; P= 0.45). The estimated cost saving per year is $6966.00. CONCLUSION: TcBR measurement in conjunction with our protocol significantly reduces painful procedures and costs without increasing the risk of delaying treatment with phototherapy. PMID- 20722995 TI - Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus. AB - OBJECTIVES: In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of metabolites, AUC(metabolite)/AUC(parent drug) ratios, or the time-averaged nonrenal and total body clearances (CL(NR) and CL, respectively) of parent drugs as reported in the literature have been compared. KEY FINDINGS: After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CL(int)) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. SUMMARY: Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans. PMID- 20722996 TI - Ketorolac trometamol topical formulations: release behaviour, physical characterization, skin permeation, efficacy and gastric safety. AB - OBJECTIVES: The objective of this study was to improve systemic delivery of the highly analgesic ketorolac trometamol (ketorolac tromethamine) via the transdermal route, through cost-effective topical formulations, to avoid most of the problems associated with ketorolac trometamol therapy. METHODS: In-vitro release behaviour of the drug from different microemulsion and emulgel formulations was evaluated. E2 emulgel (based on isopropyl myristate as penetration enhancer) and E7 emulgel (based on Brij 92 as penetration enhancer) were evaluated for their physical properties, rat skin permeation, in-vivo analgesic effect (hot-plate test and the paw pressure test), acute and chronic anti-inflammatory activity and gastric safety. KEY FINDINGS: Isopropyl myristate and the synergistic effect of the two known penetration enhancers (propylene glycol and Brij 92) significantly modulated drug permeation and may be a promising approach for the transdermal delivery of ketorolac trometamol and other drugs. Selected in-vivo tested formulae (E2 and E7) caused significantly less ulcer score and less gastric erosion compared with oral ketorolac trometamol. E7 showed significantly higher analgesic and anti-inflammatory activity compared with E2 with no significant difference compared with oral ketorolac trometamol. CONCLUSIONS: The developed ketorolac trometamol E7 emulgel appeared promising for dermal and transdermal delivery of ketorolac trometamol, which would circumvent most of the problems associated with drug therapy. PMID- 20722997 TI - Development of an original method to study drug release from polymeric nanocapsules in the skin. AB - OBJECTIVES: This study aimed to investigate the distribution and release profile in the skin of a lipophilic model molecule, octylmethoxycinnamate (OMC), loaded in poly(epsilon-caprolactone) nanocapsules (NC) by the Franz cell method. METHODS: Nanocapsules were formulated in a hydroxyethylcellulose gel and compared to the same gel containing 5% of free OMC as control. A new extraction method was used to discriminate the OMC still entrapped in the NC from free OMC released in the skin strata. The OMC extraction from the skin was performed using acetonitrile, which broke the NC, or isopropyl myristate, which kept the NC intact. KEY FINDINGS: When isopropylmyristate was used to determine the OMC released from NC, the results showed that more than 80% of the OMC was released from the NC at the skin surface after 6 h, whereas only 30% was released in the stratum corneum and epidermis. CONCLUSIONS: It is suggested that the mechanism of release is different at the surface and in viable skin, probably due to the different local environments surrounding the NC. The small amount of OMC that reached the dermis was no longer encapsulated, suggesting that the NC did not reach the dermis. The viable epidermis seemed to be the limiting barrier against NC diffusion into the skin. PMID- 20722998 TI - Glucuronidation of piceatannol by human liver microsomes: major role of UGT1A1, UGT1A8 and UGT1A10. AB - OBJECTIVES: Piceatannol, a dietary polyphenol present in grapes and wine, is known for its promising anticancer and anti-inflammatory activity. The aim of this study was to analyse the concentration-dependent glucuronidation of piceatannol in vitro. METHODS: To determine the glucuronidation of piceatannol, experiments were conducted with human liver microsomes as well as using a panel of 12 recombinant UDP-glucuronosyltransferase isoforms. Furthermore, the chemical structures of novel glucuronides were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). KEY FINDINGS: Along with piceatannol it was possible to identify three metabolites whose structures were identified by LC MS/MS as piceatannol monoglucuronides (M1-M3). Formation of M1 and M3 exhibited a pattern of substrate inhibition, with apparent K(i) and V(max)/K(m) values of 103 +/- 26.6 microm and 3.8 +/- 1.3 microl/mg protein per min, respectively, for M1 and 233 +/- 61.4 microm and 19.8 +/- 9.5 microl/mg protein per min, respectively, for M3. In contrast, formation of metabolite M2 followed classical Michaelis Menten kinetics, with a K(m) of 18.9 +/- 8.1 microm and a V(max) of 0.21 +/- 0.02 nmol/mg protein per min. Incubation in the presence of human recombinant UDP glucuronosyltransferases (UGTs) demonstrated that M1 was formed nearly equally by UGT1A1 and UGT1A8. M2 was preferentially catalysed by UGT1A10 and to a lesser extent by UGT1A1 and UGT1A8. The formation of M3, however, was mainly catalysed by UGT1A1 and UGT1A8. CONCLUSIONS: Our results elucidate the importance of piceatannol glucuronidation in the human liver, which must be taken into account in humans after dietary intake of piceatannol. PMID- 20722999 TI - Assessment of the in-vivo drug release from pellets film-coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery. AB - OBJECTIVES: The aim of this study was to test the ability of a colon targeting system comprising pellets film-coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5 aminosalicylic acid; 5-ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control. METHODS: Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5-ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre-determined times and the plasma analysed by a validated HPLC method with fluorescence detection. RESULTS: Analysis of the 5-ASA plasma levels following administration of the uncoated pellets showed a C(max) of 2.38 +/- 0.49 microg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (C(max) 0.22 +/- 0.19 microg/ml and t(max) of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24-h study. They had a drug content of < 40%, suggesting that the film-coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits. CONCLUSIONS: Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon. PMID- 20723000 TI - Effects of polysorbate 80 on the in-vitro precipitation and oral bioavailability of halofantrine from polyethylene glycol 400 formulations in rats. AB - OBJECTIVES: The aim of this study was to examine the effects of formulations of polysorbate 80 (PS 80) and polyethylene glycol 400 (PEG 400) on the precipitation and oral bioavailability of the hydrophobic drug halofantrine. METHODS: The in vitro dilution profile of the formulations was evaluated in phosphate buffer and in simulated intestinal fluids using a standard dissolution apparatus. The pharmacokinetic profile of the formulations was investigated in fasted rats at two dose levels, 5 and 17.5 mg/kg, with blood sampling by vein puncture in the tail. KEY FINDINGS: The solubility of halofantrine was found to be highest in PS 80, and in co-mixtures there was a correlation with the content of PS 80. The in vitro dilution profile revealed precipitation of halofantrine when dissolved in pure PEG 400, although the precipitation was smaller in the simulated intestinal fluid. Addition of 25% PS 80 to the PEG 400 significantly decreased precipitation. The animals dosed with the PEG 400 formulation had significant lower bioavailability than the PS 80-PEG 400 co-mixtures, possibly due to halofantrine precipitation in the gastrointestinal tract. CONCLUSIONS: Addition of PS80 to the formulation increased the bioavailability of halofantrine and the more compound, the more PS80 was needed to prevent precipitation. PMID- 20723001 TI - Intracellular pharmacokinetics of telithromycin, a ketolide antibiotic, in alveolar macrophages. AB - OBJECTIVES: Telithromycin, a ketolide antibiotic, has an antibacterial range that covers intracellular parasitic pathogens that survive or multiply intracellularly in alveolar macrophages. The intracellular pharmacokinetics of TEL in alveolar macrophages was evaluated in vitro. METHODS: Telithromycin (50 microm) was applied to NR8383 as cultured alveolar macrophages, followed by incubation at 37 degrees C or 4 degrees C. After incubation, the amount of telithromycin in cells was determined. KEY FINDINGS: Telithromycin exhibited high accumulation in NR8383 and its intracellular accumulation was temperature dependent. Also, telithromycin distributed to the organelles and cytosol in NR8383 and, in particular, it accumulated in the acidic organelle compartments. CONCLUSIONS: This study suggests that the high accumulation of telithromycin in NR8383 is due to its high influx via active transport systems and trapping in acidic organelles, such as lysosomes. Moreover, this study provides important information for optimizing the treatment of respiratory intracellular parasitic infections based on the intracellular pharmacokinetics of antibiotics and parasitic sites. PMID- 20723002 TI - CPU228, a derivative of dofetilide, relieves cardiac dysfunction by normalizing FKBP12.6, NADPH oxidase and protein kinase C epsilon in the myocardium. AB - OBJECTIVES: The aim of this study was to determine if CPU228, a derivative of dofetilide, is more effective than dofetilide in attenuating isoproterenol induced heart failure by recovering downregulated FK506 binding protein (FKBP12.6), and suppressing oxidative stress, upregulated NADPH oxidase and protein kinase C epsilon (PKC epsilon) hyperphosphorylation in the myocardium. METHODS: Heart failure was induced by isoproterenol (1 mg/kg s.c. for 5 days) in male Sprague-Dawley rats. Intervention with either CPU228 or dofetilide (2 mg/kg on Days 3-5) was then conducted in vivo and in vitro. KEY FINDINGS: Isoproterenol produced compromised left ventricular systolic pressure, left ventricular pressure rise (dp/dt(max)) and fall (dp/dt(min)), and left ventricular end diastolic pressure, associated with oxidative stress, abnormal FKBP12.6, NADPH oxidase p67phox and PKC epsilon in the myocardium. CPU228 was more effective in attenuating these changes than dofetilide in vivo. Dofetilide produced a prolonged QTc to replace a shortened one. In primary neonatal cardiomyocytes, cultured with isoproterenol and treated with either CPU228 or dofetilide at 10( 8), 10(-7) and 10(-6) mol/l, isoproterenol produced a hyperadrenergic state characterized by downregulated FKBP12.6, upregulated NADPH oxidase p67phox and PKC epsilon in vitro. CPU228 was more effective than dofetilide in recovering these changes in a dose-dependent manner without a prolonged QTc. CONCLUSIONS: CPU228 was more effective than dofetilide in attenuating heart failure by normalizing isoproterenol-induced changes, including downregulation of FKBP12.6, upregulation of NADPH oxidase and PKC epsilon hyperphosphorylation in vivo and in vitro. PMID- 20723003 TI - The role of erythropoietin in the protection of gastric mucosa from indometacin induced gastric injury and its relationship with oxidant and antioxidant parameters in rats. AB - OBJECTIVES: Erythropoietin has anti-oxidative and anti-inflammatory activity. We wanted to evaluate its activity in preventing damage to the gastric mucosa. METHODS: We examined the protective effect of erythropoietin on indometacin induced gastric mucosa damage in the rat stomach and compared its potency with that of famotidine. We also measured effects on oxidant and antioxidant parameters in the rat stomach. KEY FINDINGS: Famotidine and erythropoietin 2500 and 5000 IU/kg reduced the ulcer area by 98%, 31% and 58%, respectively, compared with the indometacin group. Superoxide dismutase activity and glutathione level were decreased and myeloperoxidase activity increased in the indometacin group compared with healthy rats. Famotidine and erythropoietin at all doses increased superoxide dismutase and glutathione levels significantly compared with the indometacin group. Myeloperoxidase activity was decreased by erythropoietin and famotidine. CONCLUSIONS: These results support the view that erythropoietin counteracts the effects of indometacin in inducing gastric ulcer and could be used as a an antiulcer compound. Its antiulcer effect is less potent than that of famotidine. The antiulcerogenic effects of erythropoietin may be related to its intrinsic ability to sustain the activities of free-radical scavenging enzymes and the bioavailability of glutathione. PMID- 20723004 TI - A bioassay for mosquito repellency against Aedes aegypti: method validation and bioactivities of DEET analogues. AB - OBJECTIVES: Vector-borne diseases are still a major mortality factor in Africa and South-east Asia and effective mosquito repellents are therefore needed. An efficient and safe in-vitro assay system using artificial blood and skin substitute could facilitate the development of novel repellents, as most assays currently rely on human subjects or vertebrate whole blood. Moreover, examining the skin permeation profiles could provide safer mosquito repellents. The new assay system could serve as an initial system for testing new repellent candidates upon validation with DEET and its analogues. METHODS: N,N-Diethyl-meta toluamide (DEET) and five analogues were synthesised and used to validate a novel in-vitro bioassay using artificial blood and collagen membrane. Repellency against Aedes aegypti was correlated with lipophilicity and skin permeation. KEY FINDINGS: The new in-vitro assay showed good reproducibility (interday relative standard deviation <10% at high concentrations). Four of the five DEET analogues showed repellency similar or superior to that of DEET. Repellency correlated linearly with lipophilicity but stronger repellents tended to permeate skin better. CONCLUSIONS: The new in-vitro assay using blood substitute and collagen membrane significantly simplifies screening of possible mosquito repellents. Lipophilicity as well as skin permeation profiles should be considered before testing of compounds that are candidates for mosquito repellents. PMID- 20723005 TI - Geranylgeranylacetone preconditioning may attenuate heat-induced inflammation and multiorgan dysfunction in rats. AB - OBJECTIVES: Geranylgeranylacetone, an acyclic isoprenoid, is a non-toxic inducer of heat shock protein (HSP)70. HSP70 overproduction is associated with heat tolerance in rats. This study aimed to investigate whether geranylgeranylacetone preconditioning of rats reduced heat-induced inflammation and multiple organ dysfunction. METHODS: Anaesthetised rats were given vehicle or geranylgeranylacetone (800 mg/kg) orally. After 48 h they were exposed to ambient temperature of 43 degrees C for 70 min to induce heatstroke. Another group of rats kept at room temperature were used as normothermic controls. KEY FINDINGS: Vehicle-treated rats all succumbed to heat stress; their survival time was 25 +/- 4 min. Pretreatment with geranylgeranylacetone significantly increased survival time to 92 +/- 15 min. Compared with normothermic controls, all vehicle-treated heatstroke rats displayed hepatic and renal dysfunction (e.g. increased plasma levels of serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and active inflammation (e.g. increased plasma and brain levels of interleukin-1 beta, tumour necrosis factor alpha and interleukin-6). These heat-stress response indicators were all significantly suppressed by geranylgeranylacetone pretreatment. In addition, the plasma and brain levels of interleukin-10 (an anti-inflammatory cytokine) and brain levels of HSP70 were significantly increased after geranylgeranylacetone preconditioning during heatstroke. CONCLUSIONS: Geranylgeranylacetone preconditioning attenuates heat-induced inflammation and multiorgan dysfunction in rats. PMID- 20723006 TI - Anti-ischaemic activity of an antioxidant aldose reductase inhibitor on diabetic and non-diabetic rat hearts. AB - OBJECTIVES: Many observations report the cardioprotective effects of inhibitors of aldose reductase in different models of ischaemia-reperfusion injury in diabetic myocardium. In this paper, the inhibitory effects of the new pyrido[1,2 a]-pyrimidin-4-one derivative PPO, whose aldose reductase-inhibitory and antioxidant effects were shown in a previous study, were evaluated. METHODS: The effect of PPO was evaluated on aldose reductase from hearts of diabetic and non diabetic rats, and compared with that of the reference drug epalrestat. Moreover, the two drugs were tested on isolated and Langendorff-perfused diabetic and non diabetic hearts submitted to ischaemia-reperfusion cycle. KEY FINDINGS: Epalrestat showed equivalent levels of potency in inhibiting the activity of the enzyme in the diabetic and in the non-diabetic hearts. On the contrary, the inhibitory potency of PPO was decreased in the diabetic organs. In the diabetic hearts submitted to ischaemia-reperfusion, an increased level of heart aldose reductase activity was recorded, and both PPO and epalrestat produced cardioprotective effects, suggesting that aldose reductase is deeply involved in the process of ischaemia-reperfusion injury in diabetic myocardium. In non diabetic hearts, where aldose reductase has a lower activity, epalrestat failed to produce significant protection, while PPO still maintained cardioprotective effects, which may be reasonably attributed to useful 'ancillary' effects - such as antioxidant activity - independent from the aldose reductase inhibition. CONCLUSIONS: Therefore PPO, a new molecule endowed with both aldose reductase inhibitory effects and antioxidant activity, may represent the prototype of a new class of multitarget drugs, focused on two different steps deeply involved in the pathogenesis of ischaemic injury of diabetic hearts. PMID- 20723007 TI - Aloe vera gel alleviates cardiotoxicity in streptozocin-induced diabetes in rats. AB - OBJECTIVES: Persistent hyperglycaemia results in oxidative stress along with the generation of oxygen free radicals and appears to be an important factor in the production of secondary complications in diabetes. The aim of this work was to evaluate markers of oxidative stress in heart tissue along with the protective, antioxidant and antidiabetic activity of 30%Aloe vera gel in diabetic rats. METHODS: Streptozocin was given as a single intravenous injection and 30%Aloe vera gel was given in two doses for 20 days, orally. Blood glucose, glycosylated haemoglobin, blood reduced glutathione, serum lactate dehydrogenase and serum creatine kinase levels were measured on day 21 after drug treatment. Heart rate and mean blood pressure were recorded at the end of the study. Different biochemical variables were evaluated in the heart tissue, including thiobarbituric acid reactive substance (TBARS), reduced glutathione, superoxide dismutase and catalase in diabetic and in Aloe vera-treated diabetic rats. KEY FINDINGS: In streptozocin diabetic rats, the TBARS level was increased significantly, superoxide dismutase and reduced glutathione significantly decreased, and the catalase level was significantly increased. Aloe vera 30% gel (200 mg/kg) treatment in diabetic rats reduced the increased TBARS and maintained the superoxide dismutase and catalase activity up to the normal level. Aloe vera gel increased reduced glutathione by four times in diabetic rats. CONCLUSIONS: Aloe vera gel at 200 mg/kg had significant antidiabetic and cardioprotective activity. PMID- 20723008 TI - Application of hanging drop technique to optimize human IgG formulations. AB - OBJECTIVES: The purpose of this work is to assess the hanging drop technique in screening excipients to develop optimal formulations for human immunoglobulin G (IgG). METHODS: A microdrop of human IgG and test solution hanging from a cover slide and undergoing vapour diffusion was monitored by a stereomicroscope. Aqueous solutions of IgG in the presence of different pH, salt concentrations and excipients were prepared and characterized. KEY FINDINGS: Low concentration of either sodium/potassium phosphate or McIlvaine buffer favoured the solubility of IgG. Addition of sucrose favoured the stability of this antibody while addition of NaCl caused more aggregation. Antimicrobial preservatives were also screened and a complex effect at different buffer conditions was observed. Dynamic light scattering, differential scanning calorimetry and size exclusion chromatography studies were performed to further validate the results. CONCLUSIONS: In conclusion, hanging drop is a very easy and effective approach to screen protein formulations in the early stage of formulation development. PMID- 20723009 TI - Inhibitory effects of uraemic toxins 3-indoxyl sulfate and p-cresol on losartan metabolism in vitro. AB - OBJECTIVES: The purpose of this study was to clarify the cause of decreased metabolic clearance of losartan in patients with end-stage renal failure. The influence of serum from haemodialysis patients (uraemic serum) and uraemic toxins on the metabolism of losartan to EXP-3174 was investigated in vitro. METHODS: The formation of EXP-3174 was estimated using pooled human liver microsomes. 3 Carboxy-4-methyl-5-propyl-2-furanpropanoic acid, hippuric acid, indole-3-acetic acid, 3-indoxyl sulfate and p-cresol were used as uraemic toxins. KEY FINDINGS: Uraemic serum potently decreased the formation of EXP-3174 in pooled human liver microsomes. In addition, 3-indoxyl sulfate and p-cresol significantly decreased the formation of EXP-3174 in a concentration-dependent manner. Furthermore, normal serum (10% v/v) with both 3-indoxyl sulfate and p-cresol (both 20 micromol/l) significantly decreased the formation of EXP-3174 by 46%, which was similar to the level of inhibition with uraemic serum (10% v/v). CONCLUSIONS: These results suggest that decreased the metabolic clearance of losartan in patients with end-stage renal failure is partly due to high concentrations of 3 indoxyl sulfate and p-cresol. PMID- 20723010 TI - Preparation, characterisation and anti-tumour activity of Ganoderma lucidum polysaccharide nanoparticles. AB - OBJECTIVES: The aim was to prepare novel Ganoderma lucidum polysaccharide nanoparticles and to evaluate the physicochemical properties and anti-tumour activity in in-vitro cytotoxicity studies using HepG2, HeLa and A549 cancer cell lines, and growth promotion effects on mouse spleen cells. METHODS: Chitosan nanoparticles loaded with G. lucidum polysaccharide were prepared using the ion revulsion method. The diameter distribution of the particles and the surface charge were measured using a zetasizer analyser. The entrapment efficiency and drug loading capacity were examined by the diethylaminoethanol weak anion exchange method. The cytotoxic effects of nanoparticles on tumour cells and the growth promotion effects on mouse spleen cells were tested using the MTT assay. KEY FINDINGS: Nanoparticles loaded with G. lucidum polysaccharide at 6 microg/ml and chitosan/sodium tripolyphosphate (mass) ratio of 5.5 had significantly greater cytotoxic effects on tumour cells and growth promotion effects on mouse spleen cells than empty nanoparticles. CONCLUSIONS: G. lucidum polysaccharide nanoparticles showed significant anti-tumour efficacy, having both cytotoxic effects on tumour cells and growth promotion effects on spleen cells, making it a promising candidate in the clinical setting. PMID- 20723011 TI - JS-K has potent anti-angiogenic activity in vitro and inhibits tumour angiogenesis in a multiple myeloma model in vivo. AB - OBJECTIVES: Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O(2)-(2,4-Dinitrophenyl) 1 [(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity. METHODS: We studied the effect of JS-K on angiogenesis in human umbilical vein endothelial cells (HUVECs), OPM1 multiple myeloma cells, chick aortic rings and in mice. KEY FINDINGS: JS-K inhibited the proliferation of HUVECs with a 50% inhibitory concentration (IC50) of 0.432, 0.466 and 0.505 microm at 24, 48 and 72 h, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 microm, respectively. JS-K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 microm. In the chick aortic ring assay using VEGF or FGF-2 for vessel growth stimulation, 0.5 microm JS-K completely inhibited vessel growth. JS-K inhibited tumour angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells. CONCLUSIONS: JS-K is a potent inhibitor of angiogenesis in vitro and tumour vessel growth in vivo. As such, it establishes a new class of antineoplastic agent that targets the malignant cells directly as well as their microenvironment. PMID- 20723012 TI - Influence of preliminary damage on the load-bearing capacity of zirconia fixed dental prostheses. AB - PURPOSE: The objective of this investigation was to evaluate the influence of differently shaped preliminary cuts in combination with artificial aging on the load-bearing capacity of four-unit zirconia fixed dental prostheses (FDPs). MATERIALS AND METHODS: Forty frameworks were fabricated from white-stage zirconia blanks (InCeram YZ, Vita) by means of a computer-aided design/computer-aided manufacturing system (Cerec inLab, Sirona). Frameworks were divided into four homogeneous groups with ten specimens each. Prior to veneering, frameworks of two groups were "damaged" by defined saw cuts of different dimensions, to simulate accidental flaws generated during shape cutting. After the veneering process, FDPs, with the exception of a control group without preliminary damage, were subjected to thermal and mechanical cycling (TMC) during 200 days storage in distilled water at 36 degrees C. Following the aging procedure, all specimens were loaded until fracture, and forces at fracture were recorded. The statistical analysis of force at fracture data was performed using two-way ANOVA, with the level of significance chosen at 0.05. RESULTS: Neither type of preliminary mechanical damage significantly affected the load-bearing capacity of FDPs. In contrast, artificial aging by TMC proved to have a significant influence on the load-bearing capacity of both the undamaged and the predamaged zirconia restorations (p < 0.001); however, even though load-bearing capacity decreased by about 20% due to simulated aging, the FDPs still showed mean load-bearing capacities of about 1600 N. CONCLUSIONS: The results of this study reveal that zirconia restorations have a high tolerance regarding mechanical damages. Irrespective of these findings, damage to zirconia ceramics during production or finishing should be avoided, as this may nevertheless lead to subcritical crack growth and, eventually, catastrophic failure. Furthermore, to ensure long-term clinical success, the design of zirconia restorations has to accommodate the decrease in load-bearing capacity due to TMC in the oral environment. PMID- 20723013 TI - Prospective observation of CAD/CAM titanium-ceramic-fixed partial dentures: 3 year follow-up. AB - PURPOSE: There is lack of knowledge about the clinical performance of computer aided design/computer-aided manufacturing (CAD/CAM) titanium-ceramic-fixed partial dentures (FPDs). The purpose of this study was to evaluate CAD/CAM titanium-ceramic FPDs after 3 years in function. MATERIALS AND METHODS: Thirty one FPDs were fabricated for 23 patients. The Ti frameworks were completely fabricated using CAD/CAM technology, and the low-fusing porcelain was veneered. After confirming there were no mechanical or biological complications, the FPDs were cemented using zinc phosphate cement. The patients were recalled at 12, 24, and 36 months after cementation to examine for the presence of any mechanical complications, such as fractures of the veneering porcelain or the supportive framework, or biological complications, including caries, gingivitis, or periodontitis. The periodontal condition was measured using probing depth (PD), bleeding on probing (BOP), and plaque index (PI). Success and survival rates were estimated using the Kaplan-Meier analysis. RESULTS: There were four cohesive and three adhesive porcelain fractures, but no framework fractured. The Kaplan-Meier cumulative success rate of the CAD/CAM titanium-ceramic crown with regard to mechanical complications was 76.4%, and the cumulative survival rate was 96.8% after 3 years of use. One patient developed caries, but the condition was not associated with marginal discrepancy. No other biological complications were reported. The periodontal parameters demonstrated a tendency that slightly increased up to 24 months and was maintained by 36 months. At the end of the follow-up, PD was 2.86 mm, percentile of surface with BOP was 23.5, and PI was 0.45. CONCLUSION: The CAD/CAM titanium-ceramic FPDs survived in the mouths of patients without major complications for 3 years, although the risk of porcelain fracture appeared to be relatively high. PMID- 20723014 TI - Microleakage of porcelain and composite machined crowns cemented with self adhesive or conventional resin cement. AB - PURPOSE: Resistance of machined crowns to microleakage when cemented with new self-adhesive cements has not been fully investigated. This study evaluated microleakage of machined crowns milled from porcelain and composite blocks and bonded to teeth with self-adhesive and conventional resin cement. MATERIALS AND METHODS: Thirty-two freshly extracted premolars of similar shape and size were sterilized and mounted in resin blocks. Teeth received standard crown preparations with 1-mm circumferential shoulder finish line, flat occlusal surface reduced by 2 mm, and ideal angle of convergence. Prepared teeth were divided into two equal groups and assigned to either porcelain (Vita Mark II, Vident) or composite (Paradigm MZ100, 3M ESPE) blocks for crown fabrication. Optical impressions were captured for each tooth with the intraoral camera of a CEREC 3D machine. Crowns were designed and milled from both materials. Each group was then subdivided into two subgroups (n = 8) according to cement used (self adhesive resin cement, RelyX Unicem, 3M ESPE or resin cement with self-etching adhesive, Panavia F 2.0, Kuraray). Following seating, a 5-kg weight was applied on the occlusal surface of the crown for 5 minutes. Specimens were then stored in water at 37 degrees C for 24 hours. Specimens were thermocycled for 3000 cycles between 5 degrees C and 55 degrees C, then coated with nail varnish and immersed in a 2.0% basic red fuchsine dye solution for 24 hours. Teeth were then rinsed and sectioned mesiodistally and assessed under magnification for microleakage. A five-point scale was used to score degree of microleakage. Data were statistically analyzed with 2-way ANOVA and Kruskal-Wallis nonparametric test. RESULTS: Crown material had no significant effect on microleakage (p= 0.67); however, cement type had a significant effect (p < 0.0001), with Panavia F 2.0 resulting in lower microleakage scores than RelyX Unicem. CONCLUSIONS: Compared to the self-adhesive cement, the resin cement with separate primer/bonding agent resulted in significantly lower microleakage scores, irrespective of crown material. PMID- 20723016 TI - Residents' perceptions of implant surgical training in advanced education in prosthodontic programs. AB - PURPOSE: The purpose of this study was to assess residents' perspectives on their implant surgical training in Advanced Education in Prosthodontic programs in the United States. MATERIALS AND METHODS: Questionnaires were distributed to all prosthodontic residents (N = 442). The 27 questions assessed the subjective and objective aspects of implant surgical training from the view of prosthodontic residents. The data were compiled and reported as frequencies. Descriptive statistics were used to analyze the data. RESULTS: One hundred and ninety-eight responses (44.8%) were received and analyzed. Forty-seven percent (94) of the respondents felt that the philosophy of their programs regarding implant placement in prosthodontics was "optional but encouraged," whereas 30% (60) felt that it was "mandatory." The majority of the respondents (73%, 144) stated that their programs allowed them to place implants for their own patients. For those respondents who placed their own implants, 40% (58) of them indicated that the level of their clinical training was "competent." Almost half of the respondents expressed that they would like to have a proficient level of clinical training in implant surgery by the completion of their residency programs. Forty-four percent (87) of the respondents felt their residency training adequately prepared them for implant surgery, whereas the other 37% (73) did not. For those who did not, 74% (55) felt their residency programs should have prepared them for implant surgical training. CONCLUSION: The current generation of prosthodontic residents has an opportunity to place implants in their programs and would like to be trained in surgical aspects of implant dentistry at the level of competency or higher. PMID- 20723015 TI - Effect of obturating systems, dowel materials, and adhesive luting techniques on the resistance to fracture of endodontically treated teeth. AB - PURPOSE: The aim of this study was to assess the role of obturating systems, dowel materials, and adhesive techniques on the resistance to fracture of endodontically treated teeth. MATERIAL AND METHODS: Eighty maxillary central incisors were selected and randomly divided into two groups according to the obturating system (n = 40); group I: gutta-percha and Roeko sealer; group II: RealSeal. Both groups were further subdivided into two subgroups; subgroup A: using ceramic dowels (Cosmopost); subgroup B using fiber dowels (Easy Post). Each subgroup was assigned to two divisions according to the adhesive luting technique; division V (total-etch) Variolink II resin cement; division U (self adhesive) RelyX Unicem. Composite core build-up was made using a core former. Each specimen was loaded 2 mm from its incisal edge on the palatal side at a 135 degrees angle with the long axis of the tooth using a universal testing machine with a load cell of 5 KN at a crosshead speed of 0.5 mm/min until fracture. Failure loads were recorded in N. Scanning electron microscopic examination at the dentin/resin interface (1000x) was performed. Three-way ANOVA was used to test the effect of obturating system, dowel material, adhesive technique, and their interactions (obturating system * dowel material, obturating system * adhesive, dowel material * adhesive, obturating system * dowel material * adhesive). Duncan's test was used for pairwise comparison. The significance level was set at p<= 0.05. Statistical analysis was performed with SPSS 16.0. RESULTS: The mean resistance to fracture (617.4 N) was statistically significantly higher in the ceramic dowel with gutta-percha and Variolink (GP/C/V) group than in the other groups. The RealSeal and RelyX fiber dowel group's mean resistance was the lowest and was significantly lower than the other groups. CONCLUSIONS: In this study, three factors played a part in enhancing the resistance to fracture of endodontically treated teeth. High resistance to fracture was achieved when ceramic dowels were luted with total-etch technique in gutta-percha-obturated teeth. PMID- 20723017 TI - Stabilized record base for implant treatment. AB - It is important to obtain an accurate interocclusal record for the restoration of patients undergoing implant treatment. Atrophic alveolar bone in the mandible not only limits the placement of implants, but also contributes to deficient ridge morphology resulting in unstable record bases. Securing the record base to the implants is a useful way to obtain an accurate registration. The technique presented in this article uses two widely spaced implants as the optimal number of implants to stabilize record bases. PMID- 20723018 TI - The effect of coating patterns with spinel-based investment on the castability and porosity of titanium cast into three phosphate-bonded investments. AB - PURPOSE: This study evaluated the effect of pattern coating with spinel-based investment Rematitan Ultra (RU) on the castability and internal porosity of commercially pure (CP) titanium invested into phosphate-bonded investments. The apparent porosity of the investment was also measured. MATERIALS AND METHODS: Square patterns (15 * 15 * 0.3 mm(3)) were either coated with RU, or not and invested into the phosphate-bonded investments: Rematitan Plus (RP), Rema Exakt (RE), Castorit Super C (CA), and RU (control group). The castings were made in an Ar-arc vacuum-pressure machine. The castability area (mm(2) ) was measured by an image-analysis system (n = 10). For internal porosity, the casting (12 * 12 * 2 mm(3) ) was studied by the X-ray method, and the projected porous area percentage was measured by an image-analysis system (n = 10). The apparent porosity of the investment (n = 10) was measured in accordance with the ASTM C373-88 standard. RESULTS: Analysis of variance (One-way ANOVA) of castability was significant, and the Tukey test indicated that RU had the highest mean but the investing technique with coating increased the castability for all phosphate-bonded investments. The analysis of the internal porosity of the cast by the nonparametric test demonstrated that the RP, RE, and CA with coating and RP without coating did not differ from the control group (RU), while the CA and RE casts without coating were more porous. The one-way ANOVA of apparent porosity of the investment was significant, and the Tukey test showed that the means of RU (36.10%) and CA (37.22%) were higher than those of RP (25.91%) and RE (26.02%). CONCLUSION: Pattern coating with spinel-based material prior to phosphate-bonded investments can influence the castability and the internal porosity of CP Ti. PMID- 20723019 TI - Efficient resource use in simplified complete denture fabrication. AB - PURPOSE: Conventional dentures will remain the only treatment available to most edentulous people for the foreseeable future. In this study, we compared the efficiency of two methods of making complete conventional dentures-the traditional academic standard (T) and a simplified technique (S) used in private practice. We have previously shown that they produce similar levels of patient satisfaction and denture quality. MATERIALS AND METHODS: Data were gathered during a randomized controlled clinical trial of 122 subjects from initial examination until 6-month follow-up. For this report, the direct costs of providing one set of conventional complete dentures by T or S techniques were estimated. All materials used were recorded and their cost was calculated in Canadian dollars (CAN$). The costs of fabrication in an outside laboratory were added. Clinician's labor time was recorded for every procedure. Between-group comparisons for each clinical procedure were carried out with independent t tests. The number of patients in each group who needed postdelivery treatment was compared with Chi-square tests. The effect of group assignment and of treatment difficulty on outcomes was analyzed with multiple regression analysis. RESULTS: The mean total cost of the T method was significantly greater than S (CAN$166.3; p < 0.001), and clinicians spent 90 minutes longer (p < 0.001) on clinical care. The difficulty of the case had no significant influence on outcomes. CONCLUSIONS: The results indicate that the S method is the more cost-efficient method and that there are no negative consequences that detract from the cost savings. PMID- 20723020 TI - Effect of extraoral aging conditions on color stability of maxillofacial silicone elastomer. AB - PURPOSE: Maxillofacial prostheses require enhancement or replacement due to deterioration in their color during service. The purpose of this study was to investigate color stability of pigmented and nonpigmented maxillofacial silicone elastomer exposed to different human and environmental aging conditions. MATERIAL AND METHODS: One hundred and twelve disk-shaped silicone (TechSil S25, Technovent, Leeds, UK) specimens were prepared and equally divided into pigmented (using intrinsic rose-pink skin shade, P409, Principality Medical, Newport, UK) and nonpigmented categories of seven groups (n = 16; 8 pigmented and 8 nonpigmented): dark storage (control) (group 1), sebum solution storage (group 2), acidic perspiration storage (group 3), light aging (group 4), natural outdoor weathering (group 5), silicone-cleaning solution (group 6), and mixed conditioning of sebum storage and light aging (group 7). Conditioning periods (groups) were 6 months (groups 1, 2, 3, 5), 360 hours (groups 4, 7), and 30 hours (group 6). Color change (DeltaE) was measured at the start and end of conditioning. In addition, for groups 1, 2, and 4, DeltaE was measured at fixed intervals of 30 days, 15 days, and 30 hours, respectively. Data were analyzed with one-way analysis of variance (ANOVA), Dunnett's-T3 post hoc, and independent t-tests (p < 0.05). Linear regression was implemented to investigate DeltaE with time for groups 1, 2, and 4. RESULTS: Six of the seven treatment conditions induced perceivable color change (DeltaE > 3). Within the nonpigmented category, specimens stored in the dark for 6 months (group 1) exhibited high DeltaE (6.17), which was greater (p < 0.05) than that produced by silicone-cleaning solution for 30 hours (group 6) (DeltaE = 2.08). Within the pigmented category, light aging (group 4), outdoor (group 5), and mixed (group 7) conditionings induced greatest color changes (DeltaE = 8.26, 8.30, 9.89, respectively) (p < 0.05); however, there was a strong positive linear function of log-time after dark storage (group 1) and light aging (group 4). CONCLUSIONS: There is inherent color instability of nonpigmented silicone elastomer, which adds to the overall color change of silicone prostheses. Storing silicone elastomer in simulated sebum under light aging induced the greatest color changes. Overall, the color stability of TechSil S25 maxillofacial heat-temperature-vulcanizing (HTV) silicone elastomer was unacceptable (DeltaE > 3.0, range from 3.48 to 9.89 for pigmented and 3.89 to 10.78 for nonpigmented) when subjected to six of the seven extraoral aging conditionings used in this study. Inherent color instability of nonpigmented facial silicone elastomers primarily contributes to the color degradation of extraoral facial prostheses. Sebaceous skin secretions along with daylight radiation cause the greatest perceivable color change to the silicone and pigment used in this study. PMID- 20723021 TI - Sleep's role in the processing of unwanted memories. AB - The concept of 'repression' dates back to Freud, assuming that undesirable memories can become suppressed and that dreams ease repression by permitting these memories to be reinstated. Here, we followed this idea adopting the 'directed forgetting' approach of experimental psychology. The voluntary suppression of unwanted memories results in impaired later retrieval. Because sleep is known to benefit consolidation of newly learned materials, including cognitive skills, we hypothesized that memory suppression would be enhanced by sleep, and perhaps particularly by rapid eye movement (REM) sleep, which is associated more often with dream reports. Subjects (n=42) learned a list of word pairs and, subsequently, the first (cue) words of the pairs were presented again; for half these words subjects had to recall respective second words (response pairs) and for the other half they had to keep respective second words out of mind (suppression pairs). Retrieval of both response and suppression pairs was tested after 8h of sleep or wakefulness (main experiment) or after 3-h periods of early slow wave sleep (SWS)-rich or late REM-rich sleep (supplementary experiment). Response pairs were generally recalled better after sleep than wakefulness (P<0.05). Recall of suppression pairs was, as expected, worse than of response pairs. Contrary to our hypothesis, memory for suppression pairs was not affected differentially by sleep. In the supplementary experiment, compared to SWS-rich sleep, REM-rich sleep even improved recall of suppression pairs (P<0.05). Thus, sleep does not benefit the forgetting of unwanted memories but, on the contrary, REM sleep might even counteract the voluntary suppression of memories making them more accessible for retrieval. PMID- 20723022 TI - The impact of bright artificial white and 'blue-enriched' light on sleep and circadian phase during the polar winter. AB - Delayed sleep phase (and sometimes free-run) is common in the Antarctic winter (no natural sunlight) and optimizing the artificial light conditions is desirable. This project evaluated sleep when using 17,000 K blue-enriched lamps compared with standard white lamps (5000 K) for personal and communal illumination. Base personnel, 10 males, five females, 32.5+/-8 years took part in the study. From 24 March to 21 September 2006 light exposure alternated between 4 5-week periods of standard white (5000 K) and blue-enriched lamps (17,000 K), with a 3-week control before and after extra light. Sleep and light exposure were assessed by actigraphy and sleep diaries. General health (RAND 36-item questionnaire) and circadian phase (urinary 6-sulphatoxymelatonin rhythm) were evaluated at the end of each light condition. Direct comparison (rmanova) of blue enriched light with white light showed that sleep onset was earlier by 19 min (P=0.022), and sleep latency tended to be shorter by 4 min (P=0.065) with blue enriched light. Analysing all light conditions, control, blue and white, again provided evidence for greater efficiency of blue-enriched light compared with white (P<0.05), but with the best sleep timing, duration, efficiency and quality in control natural light conditions. Circadian phase was earlier on average in midwinter blue compared with midwinter white light by 45 min (P<0.05). Light condition had no influence on general health. We conclude that the use of blue enriched light had some beneficial effects, notably earlier sleep, compared with standard white light during the polar winter. PMID- 20723023 TI - The value of a native milieu: mutated non-muscle myosin IIA does lead to thrombocytopenia. PMID- 20723024 TI - Cytoplasmic stabilities of 3'UTR-polymorphic prothrombin mRNAs. PMID- 20723026 TI - Secretion and antifibrinolytic function of thrombin-activatable fibrinolysis inhibitor from human platelets. AB - BACKGROUND: The thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen first characterized in human plasma that is activated through proteolytic cleavage by thrombin, thrombin in complex with thrombomodulin, or plasmin. Active TAFI attenuates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin, thereby inhibiting a potent positive feedback loop in the fibrinolytic cascade. The existence of a separate pool of TAFI within platelets has been described. OBJECTIVES AND METHODS: We aimed to confirm the presence of TAFI in the medium of washed, thrombin-stimulated platelets and to evaluate the characteristics of platelet TAFI by western blot analysis and with a quantitative assay for activated TAFI. We also assessed the ability of platelet TAFI to inhibit fibrinolysis in vitro, using a platelet-rich thrombus lysis assay. RESULTS: Our data are consistent with the presence of TAFI in the alpha granules of resting platelets. In contrast to previous reports, platelet TAFI is very similar in electrophoretic mobility to plasma-derived TAFI. We also show, for the first time, that platelet-derived TAFI is capable of attenuating platelet rich thrombus lysis in vitro independently of plasma TAFI. Moreover, we demonstrate additive effects on thrombolysis of platelet-derived TAFI and TAFI present in plasma. CONCLUSIONS: Taken together, these observations indicate that the secretion of platelet-derived TAFI can augment the concentrations of TAFI already present in plasma to enhance attenuation of the fibrinolytic cascade. This could be significant in regions of vascular damage or pathologic thrombosis, where activated platelets are known to accumulate. PMID- 20723025 TI - Platelet endothelial cell adhesion molecule-1 regulates collagen-stimulated platelet function by modulating the association of phosphatidylinositol 3-kinase with Grb-2-associated binding protein-1 and linker for activation of T cells. AB - BACKGROUND: Platelet activation by collagen depends on signals transduced by the glycoprotein (GP)VI-Fc receptor (FcR)gamma-chain collagen receptor complex, which involves recruitment of phosphatidylinositol 3-kinase (PI3K) to phosphorylated tyrosines in the linker for activation of T cells (LAT). An interaction between the p85 regulatory subunit of PI3K and the scaffolding molecule Grb-2-associated binding protein-1 (Gab1), which is regulated by binding of the Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) to Gab1, has been shown in other cell types to sustain PI3K activity to elicit cellular responses. Platelet endothelial cell adhesion molecule-1 (PECAM-1) functions as a negative regulator of platelet reactivity and thrombosis, at least in part by inhibiting GPVI-FcRgamma-chain signaling via recruitment of SHP-2 to phosphorylated immunoreceptor tyrosine-based inhibitory motifs in PECAM-1. OBJECTIVE: To investigate the possibility that PECAM-1 regulates the formation of the Gab1-p85 signaling complexes, and the potential effect of such interactions on GPVI mediated platelet activation in platelets. METHODS: The ability of PECAM-1 signaling to modulate the LAT signalosome was investigated with immunoblotting assays on human platelets and knockout mouse platelets. RESULTS: PECAM-1 associated SHP-2 in collagen-stimulated platelets binds to p85, which results in diminished levels of association with both Gab1 and LAT and reduced collagen stimulated PI3K signaling. We therefore propose that PECAM-1-mediated inhibition of GPVI-dependent platelet responses result, at least in part, from recruitment of SHP-2-p85 complexes to tyrosine-phosphorylated PECAM-1, which diminishes the association of PI3K with activatory signaling molecules, such as Gab1 and LAT. PMID- 20723027 TI - Cilostazol augments the inhibition of platelet aggregation in clopidogrel low responders. PMID- 20723028 TI - The minor allele of GP6 T13254C is associated with decreased platelet activation and a reduced risk of recurrent cardiovascular events and mortality: results from the SMILE-Platelets project. AB - BACKGROUND: Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein VI, on platelet function and the risk of cardiovascular disease. METHODS: We performed a population-based case-control study, the Study of Myocardial Infarctions in Leiden, among 547 male patients with a first myocardial infarction (MI) and 646 control subjects, as well as a prospective cohort study in which the same MI patients were followed for recurrent events (fatal and non-fatal MI and unstable angina) and mortality (median follow-up of 12 years). P-selectin expression by platelets induced by crosslinked collagen-related peptide (CRP-XL) was measured by whole blood flow cytometry in 274 MI patients. RESULTS: T13254C was not associated with a first MI, but seemed to be associated with a reduced incidence of recurrent events [per allele hazard ratio 0.77, 95% confidence interval (CI) 0.56-1.06] and mortality (hazard ratio 0.57, 95% CI 0.37-0.89). Pooling with the Heart and Estrogen/Progestin Replacement Study revealed hazard ratios of 0.81 (95% CI 0.66 0.99) and 0.73 (95% CI 0.55-0.96). The minor C-allele was also strongly associated with a reduced percentage of P-selectin-expressing platelets. The reduction per C-allele was 23% (95% CI 18-28%). In an independent study of 219 healthy volunteers, the per-allele reduction of CRP-XL-induced aggregation was 10% (95% CI 2-18%). CONCLUSION: The minor allele of GP6 T13254C that reduced platelet activation and aggregation also seemed to be associated with a reduced incidence of recurrent cardiovascular events and mortality, but was not associated with first MI. PMID- 20723029 TI - High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events. AB - BACKGROUND: High on-aspirin platelet reactivity (HAPR) is associated with atherothrombotic events following percutaneous coronary intervention (PCI). The aim of the present study was to identify the platelet function test sensitive for platelet cyclooxygenase-1 inhibition that best predicts atherothrombotic events. METHODS AND RESULTS: Nine hundred and fifty-one consecutive patients on dual antiplatelet therapy undergoing elective PCI were enrolled. On-aspirin platelet reactivity was measured in parallel by arachidonic acid (AA)-induced light transmittance aggregometry (AA-induced LTA), the VerifyNow(r) Aspirin Assay (VerifyNow(r) Aspirin Assay), the arachidonic acid prestimulated IMPACT-R (IMPACT R AA) and the PFA-100 collagen/epinephrine cartridge (PFA COL/EPI). Cut-offs for HAPR were established by receiver-operator characteristic curve analysis. At 1 year follow-up, the composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischemic stroke occurred more frequently in patients with HAPR when assessed by LTA [10.1% vs. 6.0%, P=0.020 (n=925)] and VerifyNow((r)) [13.3% vs. 5.9%, P=0.015 (n=422)]. The VerifyNow((r)) ASA assay (AUC=0.78) and, to a lesser extent, AA-induced LTA (AUC=0.73) added significantly to a model consisting of clinical and procedural risk factors in predicting atherothrombotic events. In contrast, the IMPACT-R (n=791) and the PFA Collagen/Epinephrine (n=719) were unable to discriminate between patients with and without primary endpoint at 1-year follow-up. None of the platelet function tests was able to identify patients at risk for bleeding. CONCLUSIONS: AA induced LTA and the VerifyNow((r)) ASA test were able to identify aspirin-treated patients undergoing PCI with stenting at risk for atherothrombotic events. The VerifyNow((r)) Aspirin Assay had the highest predictive accuracy. None of the tests was able to identify patients at higher risk of bleeding. PMID- 20723030 TI - Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. AB - BACKGROUND: Rate of major bleeding is generally accepted as a good measure of the risks associated with anticoagulant therapy, but this may not be true if the proportion of major bleeds with the most serious consequences differs according to the indication for anticoagulant therapy. OBJECTIVE: To determine whether the indication for long-term oral anticoagulant therapy influences the proportion of major bleeds that are intracranial and fatal. PATIENTS/METHODS: Two authors abstracted intracranial and fatal bleeds from randomized trials of patients who received anticoagulant therapy for a minimum of 6months for atrial fibrillation, ischemic heart disease, venous thromboembolism, prosthetic heart valves and ischemic stroke. RESULTS: There were 877 major bleeds among 23,518 patients in 39 studies. The proportion of bleeds that were intracranial was significantly higher in patients with ischemic stroke (36%; 95% CI, 22-52%; P=0.02) compared with patients with venous thromboembolism (10%; 95% CI, 5-20%). The difference in the proportion of bleeds that were intracranial among atrial fibrillation, ischemic heart disease, venous thromboembolism and prosthetic heart valves was not statistically significant; however, the estimates varied from 10% to 27%. The proportion of bleeds that were fatal did not differ significantly according to indication, but varied from 8% to 20%. For all indications for anticoagulation, intracranial bleeds were much more likely to be fatal than extracranial major bleeds (44% vs. 4% overall). CONCLUSIONS: In current practise, the indication for oral anticoagulant therapy has limited influence on the proportion of major bleeds that are intracranial or fatal. PMID- 20723031 TI - High incidence of tumors in diabetic thrombin activatable fibrinolysis inhibitor and apolipoprotein E double-deficient mice. AB - BACKGROUND: Activation of the complement system has been implicated in tumor growth. The antifibrinolytic protein, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), can modulate the activation of the complement system by inactivating the anaphylatoxins C3a and C5a. The apolipoprotein-E (ApoE) genotype has been associated with carcinogenesis. OBJECTIVE: The aim of this study was to evaluate whether TAFIa can affect the development of cancer in the ApoE-deficient mouse model. METHODS: TAFI and ApoE double-knockout mice were generated. A group of mice was treated with the diabetogenic and carcinogenic compound streptozotocin (stz). Mice treated with saline, single knockout mice and wild type (wt) mice served as controls. RESULTS: Six months after treatment with stz, mice were sacrificed. Hepatic tumors were found in male double-knockout mice treated with stz but none was found in control animals that were not treated with stz or in single knockout of ApoE or wt animals. There was no significant difference in coagulation system activation between the groups of mice. The plasma concentrations of C5a, factor D and transforming growth factor-beta1 were increased in TAFI/ApoE double-deficient mice treated with stz compared with the mice of the same genotype treated with saline. CONCLUSION: Apo-E deficiency alone was not associated with tumors but the lack of TAFI appears to make the mice permissive for tumor formation in ApoE mice. PMID- 20723032 TI - Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. AB - AIM: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. METHODS: We carried out a patient-level meta-analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan-Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. RESULTS: The 5-year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5-year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5-year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1-fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9-5.1). Patients with proximal DVT had a 4.8-fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1-11.0). CONCLUSION: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE. PMID- 20723033 TI - A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. AB - BACKGROUND: Edoxaban (the free base of DU-176b) is an oral, direct factor (F)Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. OBJECTIVES: The aim of the present study was to evaluate the efficacy and safety of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA). PATIENTS/METHODS: This was a randomized, double-blind, placebo-controlled, multicenter study conducted in Japan. A total of 523 Japanese patients were assigned to receive edoxaban 5, 15, 30 or 60 mg once daily or placebo for 11-14 days. A placebo control was used as neither low-molecular-weight heparin (LMWH) nor fondaparinux had been approved for thromboprophylaxis at the time of the study in Japan. The primary efficacy outcome was the incidence of VTE (lower-extremity deep vein thrombosis, symptomatic pulmonary embolism or symptomatic deep vein thrombosis). The primary safety outcome was the incidence of major and clinically relevant non major bleeding. RESULTS: Edoxaban produced a significant dose-related reduction in VTE: the incidence of VTE was 29.5%, 26.1%, 12.5% and 9.1% in the edoxaban 5-, 15-, 30- and 60-mg treatment groups vs. 48.3% in the placebo group. The incidence of major and clinically relevant non-major bleeding was similar across all groups without any significant differences among edoxaban doses or between edoxaban and placebo. CONCLUSIONS: Edoxaban demonstrated significant dose-dependent reductions in VTE in patients undergoing TKA with a bleeding incidence similar to placebo. [This trial is registered with JAPIC, JapicCTI-060283 (ja).]. PMID- 20723035 TI - The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C. AB - The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 MUm; P=0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 MUm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P=0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P=0.002) but marginal in HCV-1 (38.7%vs 27.8%; P=0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P=0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1. PMID- 20723036 TI - Natural history and treatment of chronic delta hepatitis. AB - Chronic delta hepatitis (CDH) represents a severe form of chronic viral hepatitis, induced by the hepatitis delta virus (HDV) in conjunction with the hepatitis B virus (HBV). Delta hepatitis may lead to disease in humans through co infection. The former leads to acute hepatitis which clinically can range from mild hepatitis to fulminant hepatitis and death. Severe or fulminant hepatitis is more often observed with HBV-HDV co-infection compared to HBV mono-infection. Chronic infection after acute hepatitis B + D co-infection is infrequent and similar to the rate in mono-infected patients. CDH develops in 70-90% of patients with superinfection. CDH runs a more progressive course than chronic hepatitis B and may lead to cirrhosis within 2 years in 10-15% of patients. However, as with any immune-mediated disease, different patterns of progression, ranging from mild to severe progressive disease, are observed. Active replication of both HBV and HDV may be associated with a more progressive disease pattern. Further, different HDV and HBV genotypes may contribute to various disease outcomes. CDH may be frequently associated with hepatocellular carcinoma development although recent studies provided conflicting results. The only established therapy for CDH is treatment with interferons for a duration of at least 1 year. On treatment, 6 month HDV RNA assessment may give clues as to whether to stop treatment at 1 year or continue beyond 1 year. New approaches to treatment of CDH are an urgent need of which the use of prenylation inhibitors appears the most promising. PMID- 20723037 TI - Distinct geographical and demographic distribution of hepatitis B virus genotypes in the Canadian Arctic as revealed through an extensive molecular epidemiological survey. AB - Very little is known of hepatitis B virus (HBV) in Canadian Arctic indigenous populations, where HBV was considered endemic prior to the introduction of HBV vaccine. This study expands upon an HBV seroepidemiological survey conducted between 1983 and 1985 throughout the Canadian Arctic, to characterize HBV in this population. Archived hepatitis B surface antigen (HBsAg)-positive sera (n = 401) were processed for HBV DNA, followed by sequencing and phylogenetic analysis of the HBsAg- and HBcAg-coding regions. Sixty-nine per cent of samples (277/401) were DNA positive, with most having low viral load (median 3.4 log 10 IU/mL). The predominant HBV genotype observed was genotype B (HBV/B, 75%), followed by HBV/D (24%) and HBV/A (1%). All HBV/B strains clustered within subgenotype B6, a newly recognized HBV genotype among western circumpolar Inuit and Alaska Native people. HBV/D strains included both D3 (88%) and D4 (12%) subgenotypes, while all HBV/A strains were subgenotype A2. An association of HBV genotype B with Inuit living in the eastern Arctic and an association of genotype D with First Nation (Dene) living in the western Arctic was observed. This study establishes the high prevalence of HBV/B6 and HBV/D genotypes in Arctic populations and reveals their marked distribution within the Canadian Arctic based on geographical and demographic attributes. PMID- 20723034 TI - Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study. AB - BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 +/- 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 MUm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated. PMID- 20723039 TI - Tobacco and other factors have a negative impact on quality of life in hepatitis C patients. AB - Hepatitis C virus (HCV) is known to adversely affect general, social, emotional and mental health domains. This study was designed to identify variables that may be associated with these measurable outcomes. We conducted a cross-sectional retrospective review of demographic and clinical data from 800 patients with HCV evaluated between January 1998 and November 2007. Data were collected using a standardized questionnaire filled out by the patients at the first encounter. Variables evaluated included fibrosis stages (i.e. FS0/1/2 vs FS3/4), demographics, comorbid health conditions, tobacco and alcohol use, high-risk social behaviours and laboratory data. Variables assessed were depression, fatigue, problems sleeping and loss of interest in sex. Statistical analysis was performed using univariate and multivariate logistic regression. Depression (29.3%) in our HCV study population was associated with female gender, tobacco use, hyperlipidemia, history of heavy alcohol use and intravenous drug use. Fatigue (44.6%) was associated with end-stage renal disease, past and current tobacco use and current alcohol use. Difficulty sleeping (13.8%) was associated with past and current tobacco use, current alcohol use and diabetes. Loss of interest in sex (7.7%) was associated with current tobacco use, multiple risk factors for HCV and age at time of evaluation. Fibrosis stage (FS) also had a significant positive association with alcohol use (OR 2.61; P = 0.003) and tobacco use (OR 2.00; P = 0.002). Smoking and alcohol use have a significant negative impact on the presence of depression, fatigue, difficulty sleeping and loss of interest in sex in HCV patients. Practitioners should be aware of these associations, particularly tobacco use, which significantly and negatively impacted every variable evaluated. PMID- 20723038 TI - A perspective on modelling hepatitis C virus infection. AB - By mathematically describing early hepatitis C virus (HCV) RNA decay after initiation of interferon (IFN)-based antiviral therapy, crucial parameters of the in vivo viral kinetics have been estimated, such as the rate of production and clearance of free virus, and the rate of loss of infected cells. Furthermore, by suggesting mechanisms of action for IFN and ribavirin mathematical modelling has provided a means for evaluating and optimizing treatment strategies. Here, we review recent modelling developments for understanding complex viral kinetics patterns, such as triphasic HCV RNA declines and viral rebounds observed in patients treated with pegylated interferon and ribavirin. Moreover, we discuss new modelling approaches developed to interpret the viral kinetics observed in clinical trials with direct-acting antiviral agents, which induce a rapid decline of wild-type virus but also engender a higher risk for emergence of drug resistant variants. Lastly, as in vitro systems have allowed a better characterization of the virus lifecycle, we discuss new modelling approaches that combine the intracellular and the extracellular viral dynamics. PMID- 20723042 TI - Effect of agitation and aeration on the production of nitrile hydratase by Rhodococcus erythropolis MTCC 1526 in a stirred tank reactor. AB - AIMS: To evaluate the effect of different physicochemical parameters such as agitation, aeration and pH on the growth and nitrile hydratase production by Rhodococcus erythropolis MTCC 1526 in a stirred tank reactor. METHODS AND RESULTS: Rhodococcus erythropolis MTCC 1526 was grown in 7-l reactor at different agitation, aeration and controlled pH. The optimum conditions for batch cultivation in the reactor were an agitation rate of 200 rev min(-1) , aeration 0.5 v/v/m at controlled pH 8. In this condition, the increase in nitrile hydratase activity was almost threefold compared to that in the shake flask. CONCLUSION: Agitation and aeration rate affected the dissolved-oxygen concentration in the reactor which in turn affected the growth and enzyme production. SIGNIFICANCE AND IMPACT OF THE STUDY: Cultivation of R. erythropolis MTCC 1526 in the reactor was found to have significant effect on the growth and nitrile hydratase production when compared to the shake flask. PMID- 20723040 TI - Hepatocyte apoptotic bodies encasing nonstructural HCV proteins amplify hepatic stellate cell activation: implications for chronic hepatitis C. AB - Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from hepatitis C virus (HCV)-negative vs HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human HSC line (LX2). Uptake of Huh7(Con1+) ABs by LX2 cells dose dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV(+) ABs exhibited a more pronounced effect than HCV(-) ABs. In contrast, neither noningested ABs nor nucleic acids obtained from Huh7, Huh7(Con1+) or HepG2 cells triggered those AB-dependent effects. Both the engulfment of Huh7(Con1+) ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation. PMID- 20723041 TI - Isolation of clinically relevant fungal species from solid waste and environment of dental health services. AB - AIMS: This study was undertaken to detect, identify and determine antifungal susceptibility of yeast strains isolated from dental solid waste and to evaluate airborne fungi in the Brazilian dental health care environment and in the waste storage room. METHODS AND RESULTS: A group of 17 yeast strains were identified by macroscopic and microscopic characteristics, API 20C Aux system and Multiplex PCR. All 104 airborne fungal colonies were identified by macroscopic and microscopic morphology. The CLSI broth microdilution method was utilized as the susceptibility test. Candida parapsilosis was the prevailing yeast species recovered from waste, followed by Rhodotorula glutinis. Three strains of Candida guilliermondii presented minimal inhibitory concentration values considered to be susceptible dose dependent (2 MUg ml(-1)) to voriconazole. Of all airborne fungal species, 69% were recovered from the waste storage room and 31% were recovered from the clinical/surgical environment. Most of them were identified as Cladosporium spp. CONCLUSIONS: These findings reinforce the potential risk of waste handling and point out the need for safe management to minimize the spread of these agents to the environment. Filamentous fungi isolation in almost all sampled environments indicates that a periodic monitoring of airborne microbiota in the dental health care service environment is required. SIGNIFICANCE AND IMPACT OF THE STUDY: The survival of yeast strains for 48 h suggests that dental waste should be carefully controlled and monitored. PMID- 20723043 TI - Reactivation of Giardia lamblia cysts after exposure to polychromatic UV light. AB - AIMS: In this study, we determined the ability of a promising alternative UV technology--a polychromatic emission from a medium-pressure UV (MP UV) technology -to inhibit the reactivation of UV-irradiated Giardia lamblia cysts. METHODS AND RESULTS: A UV-collimated beam apparatus was used to expose shallow suspensions of purified G. lamblia cysts in PBS (pH 7.2) or filtered drinking water to a low dose (1 mJ cm(-2)) of MP UV irradiation. After UV irradiation, samples were exposed to two repair conditions (light or dark) and two temperature conditions (25 degrees C or 37 degrees C for 2-4 h). The inactivation of G. lamblia cysts by MP UV was very extensive, and c. 3 log(10) inactivation was achieved with a dose of 1 mJ cm(-2) . Meanwhile, there was no apparent reactivation (neither in vivo nor in vitro) of UV-irradiated G. lamblia under the conditions tested. CONCLUSION: The results of this study indicated that, unlike the traditional low pressure (LP) UV technology, an alternative UV technology (MP UV) could inhibit the reactivation of UV-irradiated G. lamblia cysts even when the cysts were exposed to low UV doses. SIGNIFICANCE AND IMPACT OF THE STUDY: It appears that alternative UV technology has some advantages over the traditional LP UV technology in drinking water disinfection because of their high level of inactivation against G. lamblia cysts and also effective inhibition of reactivation in UV-irradiated G. lamblia cysts. PMID- 20723044 TI - Efficient secretion of a modified E7 protein from human papilloma virus type-16 by Lactococcus lactis. AB - AIMS: To create and provide a strain of the food-grade bacterium Lactococcus lactis able to efficiently secrete a modified form of the E7 protein from the human papilloma virus (HPV) type-16. METHODS AND RESULTS: We cloned the coding sequence of a modified E7 (E7m) from the HPV-16 in a plasmid regulated by the strong expression promoter p59. Secretion of the E7m was made by the signal peptide of the usp45 gene. The E7m was detected by Western blot in the cell-free medium fraction, showing no degradation or aberrant forms. CONCLUSIONS: We constructed a strain of L. lactis able to secrete efficiently a HPV-16 E7 modified protein with diminished transforming activity. SIGNIFICANCE AND IMPACT OF THE STUDY: Human papilloma virus infection is associated with more than 99% of cervical cancers. Immunotherapy targeting E7 to treat HPV-associated cervical malignancies has been demonstrated to be highly efficient. However, native E7 maintains transforming activity. We present this new strain of a food-grade bacterium able to efficiently secrete a HPV-16 E7-modified protein with diminished transforming activity. This new strain could be used as a live vaccine to deliver E7 at a mucosal level and generate antitumour immune responses against HPV-associated tumours. PMID- 20723045 TI - Genetic diversity and differentiation at MHC genes in island populations of tuatara (Sphenodon spp.). AB - Neutral genetic markers are commonly used to understand the effects of fragmentation and population bottlenecks on genetic variation in threatened species. Although neutral markers are useful for inferring population history, the analysis of functional genes is required to determine the significance of any observed geographical differences in variation. The genes of the major histocompatibility complex (MHC) are well-known examples of genes of adaptive significance and are particularly relevant to conservation because of their role in pathogen resistance. In this study, we survey diversity at MHC class I loci across a range of tuatara populations. We compare the levels of MHC variation with that observed at neutral microsatellite markers to determine the relative roles of balancing selection, diversifying selection and genetic drift in shaping patterns of MHC variation in isolated populations. In general, levels of MHC variation within tuatara populations are concordant with microsatellite variation. Tuatara populations are highly differentiated at MHC genes, particularly between the northern and Cook Strait regions, and a trend towards diversifying selection across populations was observed. However, overall our results indicate that population bottlenecks and isolation have a larger influence on patterns of MHC variation in tuatara populations than selection. PMID- 20723046 TI - Seascape genetics along a steep cline: using genetic patterns to test predictions of marine larval dispersal. AB - Coupled biological and physical oceanographic models are powerful tools for studying connectivity among marine populations because they simulate the movement of larvae based on ocean currents and larval characteristics. However, while the models themselves have been parameterized and verified with physical empirical data, the simulated patterns of connectivity have rarely been compared to field observations. We demonstrate a framework for testing biological-physical oceanographic models by using them to generate simulated spatial genetic patterns through a simple population genetic model, and then testing these predictions with empirical genetic data. Both agreement and mismatches between predicted and observed genetic patterns can provide insights into mechanisms influencing larval connectivity in the coastal ocean. We use a high-resolution ROMS-CoSINE biological-physical model for Monterey Bay, California specifically modified to simulate dispersal of the acorn barnacle, Balanus glandula. Predicted spatial genetic patterns generated from both seasonal and annual connectivity matrices did not match an observed genetic cline in this species at either a mitochondrial or nuclear gene. However, information from this mismatch generated hypotheses testable with our modelling framework that including natural selection, larval input from a southern direction and/or increased nearshore larval retention might provide a better fit between predicted and observed patterns. Indeed, moderate selection and a range of combined larval retention and southern input values dramatically improve the fit between simulated and observed spatial genetic patterns. Our results suggest that integrating population genetic models with coupled biological-physical oceanographic models can provide new insights and a new means of verifying model predictions. PMID- 20723047 TI - Was it an explosion? Using population genetics to explore the dynamics of a recent radiation within Protea (Proteaceae L.). AB - Adaptive radiations likely underlie much of the world's diversity, especially that of hyper-diverse regions. They are usually characterized by a burst of speciation early in their evolutionary history, a pattern which can be detected using population genetic tools. The Cape Floristic Region (CFR) of southwestern South Africa is home to many spectacular plant radiations. Here, we investigate the white proteas (Protea section Exsertae), a typical CFR radiation, to determine if it demonstrates the burst of speciation associated with adaptive radiations in recent models. Inferences from individual assignment, tree-based population relationships, and pairwise F-statistics based on 10 microsatellite loci reveal that while the white proteas radiated recently they did not radiate explosively. In addition, we found evidence that there is little gene flow between sampled populations of most species. Taken together, these results demonstrate that within a small clade, the processes underlying the radiation are different from those envisioned by current models of adaptive radiation and suggest that geographical isolation could have played a role in the diversification of the group. Our study implicates both adaptive and non-adaptive processes in the evolution of botanical diversity of the CFR. PMID- 20723048 TI - Reconstructing routes of invasion using genetic data: why, how and so what? AB - Detailed knowledge about the geographical pathways followed by propagules from their source to the invading populations--referred to here as routes of invasion provides information about the history of the invasion process and the origin and genetic composition of the invading populations. The reconstruction of invasion routes is required for defining and testing different hypotheses concerning the environmental and evolutionary factors responsible for biological invasions. In practical terms, it facilitates the design of strategies for controlling or preventing invasions. Most of our knowledge about the introduction routes of invasive species is derived from historical and observational data, which are often sparse, incomplete and, sometimes, misleading. In this context, population genetics has proved a useful approach for reconstructing routes of introduction, highlighting the complexity and the often counterintuitive nature of the true story. This approach has proved particularly useful since the recent development of new model-based methods, such as approximate Bayesian computation, making it possible to make quantitative inferences in the complex evolutionary scenarios typically encountered in invasive species. In this review, we summarize some of the fundamental aspects of routes of invasion, explain why the reconstruction of these routes is useful for addressing both practical and theoretical questions, and comment on the various reconstruction methods available. Finally, we consider the main insights obtained to date from studies of invasion routes. PMID- 20723049 TI - Major histocompatibility complex variation and age-specific endoparasite load in subadult European rabbits. AB - Genes of the major histocompatibility complex (MHC) play a fundamental role in the vertebrate immune response and are amongst the most polymorphic genes in vertebrate genomes. It is generally agreed that the highly polymorphic nature of the MHC is maintained through host-parasite co-evolution. Two nonexclusive mechanisms of selection are supposed to act on MHC genes: superiority of MHC heterozygous individuals (overdominance) and an advantage for rare MHC alleles. However, the precise mechanisms and their relative importance are still unknown. Here, we examined MHC dependent parasite load in European rabbits (Oryctolagus cuniculus) from a distinct population with low MHC diversity (three alleles, six genotypes). Using a multivariate approach, we tested for associations of individual MHC class II DRB constitution and the rabbits' intestinal burden with nematodes and coccidia. Rabbits having a particular allele showed lower infestations with hepatic coccidia (E. stiedai). However, a comparison of all six genotypes in the population revealed that carriers of this allele only benefit when they are heterozygous, and furthermore, MHC heterozygosity in general did not affect individual parasite load. In conclusion, this study suggests an immunogenetic basis of European rabbit resistance to hepatic coccidiosis, which can strongly limit survival to maturity in this species. Our study gives a complex picture of MHC-parasite correlations, unveiling the limits of the classical hypotheses of how MHC polymorphism is maintained in natural systems. PMID- 20723050 TI - Contributions of landscape genetics - approaches, insights, and future potential. PMID- 20723051 TI - Considering spatial and temporal scale in landscape-genetic studies of gene flow. AB - Landscape features exist at multiple spatial and temporal scales, and these naturally affect spatial genetic structure and our ability to make inferences about gene flow. This article discusses how decisions about sampling of genotypes (including choices about analytical methods and genetic markers) should be driven by the scale of spatial genetic structure, the time frame that landscape features have existed in their current state, and all aspects of a species' life history. Researchers should use caution when making inferences about gene flow, especially when the spatial extent of the study area is limited. The scale of sampling of the landscape introduces different features that may affect gene flow. Sampling grain should be smaller than the average home-range size or dispersal distance of the study organism and, for raster data, existing research suggests that simplifying the thematic resolution into discrete classes may result in low power to detect effects on gene flow. Therefore, the methods used to characterize the landscape between sampling sites may be a primary determinant for the spatial scale at which analytical results are applicable, and the use of only one sampling scale for a particular statistical method may lead researchers to overlook important factors affecting gene flow. The particular analytical technique used to correlate landscape data and genetic data may also influence results; common landscape-genetic methods may not be suitable for all study systems, particularly when the rate of landscape change is faster than can be resolved by common molecular markers. PMID- 20723052 TI - Landscape modelling of gene flow: improved power using conditional genetic distance derived from the topology of population networks. AB - Landscape genetics is a burgeoning field of interest that focuses on how site specific factors influence the distribution of genetic variation and the genetic connectivity of individuals and populations. In this manuscript, we focus on two methodological extensions for landscape genetic analyses: the use of conditional genetic distance (cGD) derived from population networks and the utility of extracting potentially confounding effects caused by correlations between phylogeographic history and contemporary ecological factors. Individual-based simulations show that when describing the spatial distribution of genetic variation, cGD consistently outperforms the traditional genetic distance measure of linearized F(ST) under both 1- and 2-dimensional stepping stone models and Cavalli-Sforza and Edward's chord distance D(c) in 1-dimensional landscapes. To show how to identify and extract the effects of phylogeographic history prior to embarking on landscape genetic analyses, we use nuclear genotypic data from the Sonoran desert succulent Euphorbia lomelii (Euphrobiaceae), for which a detailed phylogeographic history has previously been determined. For E. lomelii, removing the effect of phylogeographic history significantly influences our ability to infer both the identity and the relative importance of spatial and bio-climatic variables in subsequent landscape genetic analyses. We close by discussing the utility of cGD in landscape genetic analyses. PMID- 20723053 TI - Spatial modelling and landscape-level approaches for visualizing intra-specific variation. AB - Spatial analytical methods have been used by biologists for decades, but with new modelling approaches and data availability their application is accelerating. While early approaches were purely spatial in nature, it is now possible to explore the underlying causes of spatial heterogeneity of biological variation using a wealth of environmental data, especially from satellite remote sensing. Recent methods can not only make inferences regarding spatial relationships and the causes of spatial heterogeneity, but also create predictive maps of patterns of biological variation under changing environmental conditions. Here, we review the methods involved in making continuous spatial predictions from biological variation using spatial and environmental predictor variables, provide examples of their use and critically evaluate the advantages and limitations. In the final section, we discuss some of the key challenges and opportunities for future work. PMID- 20723054 TI - Gene movement and genetic association with regional climate gradients in California valley oak (Quercus lobata Nee) in the face of climate change. AB - Rapid climate change jeopardizes tree populations by shifting current climate zones. To avoid extinction, tree populations must tolerate, adapt, or migrate. Here we investigate geographic patterns of genetic variation in valley oak, Quercus lobata Nee, to assess how underlying genetic structure of populations might influence this species' ability to survive climate change. First, to understand how genetic lineages shape spatial genetic patterns, we examine historical patterns of colonization. Second, we examine the correlation between multivariate nuclear genetic variation and climatic variation. Third, to illustrate how geographic genetic variation could interact with regional patterns of 21st Century climate change, we produce region-specific bioclimatic distributions of valley oak using Maximum Entropy (MAXENT) models based on downscaled historical (1971-2000) and future (2070-2100) climate grids. Future climatologies are based on a moderate-high (A2) carbon emission scenario and two different global climate models. Chloroplast markers indicate historical range wide connectivity via colonization, especially in the north. Multivariate nuclear genotypes show a strong association with climate variation that provides opportunity for local adaptation to the conditions within their climatic envelope. Comparison of regional current and projected patterns of climate suitability indicates that valley oaks grow in distinctly different climate conditions in different parts of their range. Our models predict widely different regional outcomes from local displacement of a few kilometres to hundreds of kilometres. We conclude that the relative importance of migration, adaptation, and tolerance are likely to vary widely for populations among regions, and that late 21st Century conditions could lead to regional extinctions. PMID- 20723055 TI - Landscape genetics of high mountain frog metapopulations. AB - Explaining functional connectivity among occupied habitats is crucial for understanding metapopulation dynamics and species ecology. Landscape genetics has primarily focused on elucidating how ecological features between observations influence gene flow. Functional connectivity, however, may be the result of both these between-site (landscape resistance) landscape characteristics and at-site (patch quality) landscape processes that can be captured using network based models. We test hypotheses of functional connectivity that include both between site and at-site landscape processes in metapopulations of Columbia spotted frogs (Rana luteiventris) by employing a novel justification of gravity models for landscape genetics (eight microsatellite loci, 37 sites, n = 441). Primarily used in transportation and economic geography, gravity models are a unique approach as flow (e.g. gene flow) is explained as a function of three basic components: distance between sites, production/attraction (e.g. at-site landscape process) and resistance (e.g. between-site landscape process). The study system contains a network of nutrient poor high mountain lakes where we hypothesized a short growing season and complex topography between sites limit R. luteiventris gene flow. In addition, we hypothesized production of offspring is limited by breeding site characteristics such as the introduction of predatory fish and inherent site productivity. We found that R. luteiventris connectivity was negatively correlated with distance between sites, presence of predatory fish (at-site) and topographic complexity (between-site). Conversely, site productivity (as measured by heat load index, at-site) and growing season (as measured by frost-free period between-sites) were positively correlated with gene flow. The negative effect of predation and positive effect of site productivity, in concert with bottleneck tests, support the presence of source-sink dynamics. In conclusion, gravity models provide a powerful new modelling approach for examining a wide range of both basic and applied questions in landscape genetics. PMID- 20723056 TI - Perspectives on the use of landscape genetics to detect genetic adaptive variation in the field. AB - Understanding the genetic basis of species adaptation in the context of global change poses one of the greatest challenges of this century. Although we have begun to understand the molecular basis of adaptation in those species for which whole genome sequences are available, the molecular basis of adaptation is still poorly understood for most non-model species. In this paper, we outline major challenges and future research directions for correlating environmental factors with molecular markers to identify adaptive genetic variation, and point to research gaps in the application of landscape genetics to real-world problems arising from global change, such as the ability of organisms to adapt over rapid time scales. High throughput sequencing generates vast quantities of molecular data to address the challenge of studying adaptive genetic variation in non-model species. Here, we suggest that improvements in the sampling design should consider spatial dependence among sampled individuals. Then, we describe available statistical approaches for integrating spatial dependence into landscape analyses of adaptive genetic variation. PMID- 20723057 TI - Common factors drive adaptive genetic variation at different spatial scales in Arabis alpina. AB - A major challenges facing landscape geneticists studying adaptive variation is to include all the environmental variables that might be correlated with allele frequencies across the genome. One way of identifying loci that are possibly under selection is to see which ones are associated with environmental gradient or heterogeneity. Since it is difficult to measure all environmental variables, one may take advantage of the spatial nature of environmental filters to incorporate the effect of unaccounted environmental variables in the analysis. Assuming that the spatial signature of these variables is broad-scaled, broad scale Moran's eigenvector maps (MEM) can be included as explanatory variables in the analysis as proxies for unmeasured environmental variables. We applied this approach to two data sets of the alpine plant Arabis alpina. The first consisted of 140 AFLP loci sampled at 130 sites across the European Alps (large scale). The second one consisted of 712 AFLP loci sampled at 93 sites (regional scale) in three mountain massifs (local scale) of the French Alps. For each scale, we regressed the frequencies of each AFLP allele on a set of eco-climatic and MEM variables as predictors. Twelve (large scale) and 11% (regional scale) of all loci were detected as significantly correlated to at least one of the predictors ( > 0.5), and, except for one massif, 17% at the local scale. After accounting for spatial effects, temperature and precipitation were the two major determinants of allele distributions. Our study shows how MEM models can account for unmeasured environmental variation in landscape genetics models. PMID- 20723058 TI - Modelling functional landscape connectivity from genetic population structure: a new spatially explicit approach. AB - Functional connectivity between spatially disjoint habitat patches is a key factor for the persistence of species in fragmented landscapes. Modelling landscape connectivity to identify potential dispersal corridors requires information about those landscape features affecting dispersal. Here we present a new approach using spatial and genetic data of a highly fragmented population of capercaillie (Tetrao urogallus) in the Black Forest, Germany, to investigate effects of landscape structure on gene flow and to parameterize a spatially explicit corridor model for conservation purposes. Mantel tests and multiple regressions on distance matrices were employed to detect and quantify the effect of different landscape features on relatedness among individuals, while controlling for the effect of geographic distance. We extrapolated the results to an area-wide landscape permeability map and developed a new corridor model that incorporates stochasticity in simulating animal movement. The model was evaluated using both a partition of the data previously set apart and independent observation data of dispersing birds. Most land cover variables (such as coniferous forest, forest edges, agricultural land, roads, settlements) and one topographic variable (topographic exposure) were significantly correlated with gene flow. Although inter-individual relatedness inherently varies greatly and the variance explained by geographic distance and landscape structure was low, the permeability map and the corridor model significantly explained relatedness in the validation data and the spatial distribution of dispersing birds. Thus, landscape structure measurably affected within-population gene flow in the study area. By converting these effects into spatially explicit information our model enables localizing priority areas for the preservation or restoration of metapopulation connectivity. PMID- 20723059 TI - Exploring the population genetic consequences of the colonization process with spatio-temporally explicit models: insights from coupled ecological, demographic and genetic models in montane grasshoppers. AB - Understanding the genetic consequences of shifting species distributions is critical for evaluating the impact of climate-induced distributional changes. However, the demographic expansion associated with the colonization process typically takes place across a heterogeneous environment, with population sizes and migration rates varying across the landscape. Here we describe an approach for coupling ecological-niche models (ENMs) with demographic and genetic models to explore the genetic consequences of distributional shifts across a heterogeneous landscape. Analyses of a flightless grasshopper from the sky islands of the Rocky Mountains of North America are used to show how biologically informed predictions can be generated about the genetic consequences of a colonization process across a spatially and temporally heterogeneous landscape (i.e. the suitability of habitats for the montane species differs across the landscape and is itself not static, with the displacement of contemporary populations into glacial refugia). By using (i) ENMs for current climatic conditions and the last glacial maximum to (ii) parameterize a demographic model of the colonization process, which then (iii) informs coalescent simulations, a set of models can be generated that capture different processes associated with distributional shifts. We discuss how the proposed approach for model generation can be integrated into a statistical framework for estimating key demographic parameters and testing hypotheses about the conditions for which distributional shifts may (or may not) enhance species divergence, including the importance of habitat stability, past gene-flow among currently isolated populations, and maintenance of refugial populations in multiple geographic regions. PMID- 20723060 TI - Back to nature: ecological genomics of loblolly pine (Pinus taeda, Pinaceae). AB - Genetic variation is often arrayed in latitudinal or altitudinal clines, reflecting either adaptation along environmental gradients, migratory routes, or both. For forest trees, climate is one of the most important drivers of adaptive phenotypic traits. Correlations of single and multilocus genotypes with environmental gradients have been identified for a variety of forest trees. These correlations are interpreted normally as evidence of natural selection. Here, we use a genome-wide dataset of single nucleotide polymorphisms (SNPs) typed from 1730 loci in 682 loblolly pine (Pinus taeda L.) trees sampled from 54 local populations covering the full-range of the species to examine allelic correlations to five multivariate measures of climate. Applications of a Bayesian generalized linear mixed model, where the climate variable was a fixed effect and an estimated variance-covariance matrix controlled random effects due to shared population history, identified several well-supported SNPs associating to principal components corresponding to geography, temperature, growing degree days, precipitation and aridity. Functional annotation of those genes with putative orthologs in Arabidopsis revealed a diverse set of abiotic stress response genes ranging from transmembrane proteins to proteins involved in sugar metabolism. Many of these SNPs also had large allele frequency differences among populations (F(ST) = 0.10-0.35). These results illustrate a first step towards a ecosystem perspective of population genomics for non-model organisms, but also highlight the need for further integration of the methodologies employed in spatial statistics, population genetics and climate modeling during scans for signatures of natural selection from genomic data. PMID- 20723061 TI - Landscape genetics: where are we now? AB - Landscape genetics has seen rapid growth in number of publications since the term was coined in 2003. An extensive literature search from 1998 to 2008 using keywords associated with landscape genetics yielded 655 articles encompassing a vast array of study organisms, study designs and methodology. These publications were screened to identify 174 studies that explicitly incorporated at least one landscape variable with genetic data. We systematically reviewed this set of papers to assess taxonomic and temporal trends in: (i) geographic regions studied; (ii) types of questions addressed; (iii) molecular markers used; (iv) statistical analyses used; and (v) types and nature of spatial data used. Overall, studies have occurred in geographic regions proximal to developed countries and more commonly in terrestrial vs. aquatic habitats. Questions most often focused on effects of barriers and/or landscape variables on gene flow. The most commonly used molecular markers were microsatellites and amplified fragment length polymorphism (AFLPs), with AFLPs used more frequently in plants than animals. Analysis methods were dominated by Mantel and assignment tests. We also assessed differences among journals to evaluate the uniformity of reporting and publication standards. Few studies presented an explicit study design or explicit descriptions of spatial extent. While some landscape variables such as topographic relief affected most species studied, effects were not universal, and some species appeared unaffected by the landscape. Effects of habitat fragmentation were mixed, with some species altering movement paths and others unaffected. Taken together, although some generalities emerged regarding effects of specific landscape variables, results varied, thereby reinforcing the need for species-specific work. We conclude by: highlighting gaps in knowledge and methodology, providing guidelines to authors and reviewers of landscape genetics studies, and suggesting promising future directions of inquiry. PMID- 20723062 TI - Comparative landscape genetics of two pond-breeding amphibian species in a highly modified agricultural landscape. AB - Evaluating fine-scale population structure of multiple species in the same landscape increases our ability to identify common patterns as well as discern ecological differences among species' landscape genetic relationships. In the Palouse bioregion of northern Idaho, USA, 99% of the native prairie has been converted to nonirrigated agriculture and exotic grasslands. Columbia spotted frogs (Rana luteiventris) and long-toed salamanders (Ambystoma macrodactylum) in this area breed almost entirely in artificial ponds on private land. We used genetic distances (F(ST) and D(c)) derived from eight microsatellite loci in 783 samples to evaluate the relationships among sympatric breeding populations (N = 20 and 26) of these species in a 213-km(2) landscape. Both species showed a pattern of isolation by distance that was not improved when distance was measured along drainages instead of topographically corrected straight lines (P < 0.01). After testing for autocorrelation among genetic distances, we used an information theoretic approach to model landscape resistance based on slope, soil type, solar insolation, and land cover, and multi-model inference to rank the resistance of landscape surfaces to dispersal (represented by genetic distance). For both species, urban and rural developed land cover provided the highest landscape resistances. Resistance values for long-toed salamanders followed a moisture gradient where forest provided the least resistance, while agriculture and shrub/clearcut provided the least resistance for Columbia spotted frogs. Comparative landscape genetics can be a powerful tool for detecting similarities and differences between codistributed species, and resulting models can be used to predict species-specific responses to landscape change. PMID- 20723063 TI - Taking the chaos out of genetic patchiness: seascape genetics reveals ecological and oceanographic drivers of genetic patterns in three temperate reef species. AB - Marine species frequently show weak and/or complex genetic structuring that is commonly dismissed as 'chaotic' genetic patchiness and ecologically uninformative. Here, using three datasets that individually feature weak chaotic patchiness, we demonstrate that combining inferences across species and incorporating environmental data can greatly improve the predictive value of marine population genetics studies on small spatial scales. Significant correlations in genetic patterns of microsatellite markers among three species, kelp bass Paralabrax clathratus, Kellet's whelk Kelletia kelletii and California spiny lobster Panulirus interruptus, in the Southern California Bight suggest that slight differences in diversity and pairwise differentiation across sampling sites are not simply noise or chaotic patchiness, but are ecologically meaningful. To test whether interspecies correlations potentially result from shared environmental drivers of genetic patterns, we assembled data on kelp bed size, sea surface temperature and estimates of site-to-site migration probability derived from a high resolution multi-year ocean circulation model. These data served as predictor variables in linear models of genetic diversity and linear mixed models of genetic differentiation that were assessed with information theoretic model selection. Kelp was the most informative predictor of genetics for all three species, but ocean circulation also played a minor role for kelp bass. The shared patterns suggest a single spatial marine management strategy may effectively protect genetic diversity of multiple species. This study demonstrates the power of environmental and ecological data to shed light on weak genetic patterns and highlights the need for future focus on a mechanistic understanding of the links between oceanography, ecology and genetic structure. PMID- 20723064 TI - Use of resistance surfaces for landscape genetic studies: considerations for parameterization and analysis. AB - Measures of genetic structure among individuals or populations collected at different spatial locations across a landscape are commonly used as surrogate measures of functional (i.e. demographic or genetic) connectivity. In order to understand how landscape characteristics influence functional connectivity, resistance surfaces are typically created in a raster GIS environment. These resistance surfaces represent hypothesized relationships between landscape features and gene flow, and are based on underlying biological functions such as relative abundance or movement probabilities in different land cover types. The biggest challenge for calculating resistance surfaces is assignment of resistance values to different landscape features. Here, we first identify study objectives that are consistent with the use of resistance surfaces and critically review the various approaches that have been used to parameterize resistance surfaces and select optimal models in landscape genetics. We then discuss the biological assumptions and considerations that influence analyses using resistance surfaces, such as the relationship between gene flow and dispersal, how habitat suitability may influence animal movement, and how resistance surfaces can be translated into estimates of functional landscape connectivity. Finally, we outline novel approaches for creating optimal resistance surfaces using either simulation or computational methods, as well as alternatives to resistance surfaces (e.g. network and buffered paths). These approaches have the potential to improve landscape genetic analyses, but they also create new challenges. We conclude that no single way of using resistance surfaces is appropriate for every situation. We suggest that researchers carefully consider objectives, important biological assumptions and available parameterization and validation techniques when planning landscape genetic studies. PMID- 20723065 TI - Landscape influences on genetic differentiation among bull trout populations in a stream-lake network. AB - This study examined the influence of landscape heterogeneity on genetic differentiation between migratory bull trout (Salvelinus confluentus) populations in Glacier National Park, Montana. An information-theoretic approach was used to compare different conceptual models of dispersal associated with barriers, different models of isolation by distance, and the combined effects of barriers, waterway distance, patch size, and intra- and inter-drainage distribution of populations on genetic differentiation between bull trout populations. The effect of distance between populations on genetic differentiation was best explained by partitioning the effects of mainstem and tributary stream sections. Models that categorized barriers as having a one-way effect (i.e. allowed downstream dispersal) or a two-way effect were best supported. Additionally, patch size and the distribution of populations among drainages influenced genetic differentiation. Genetic differentiation between bull trout populations in Glacier National Park is linked to landscape features that restrict dispersal. However, this analysis illustrates that modelling variability within landscape features, such as dispersal corridors, will benefit landscape genetic analyses. Additionally, the framework used for evaluating the effects of barriers must consider not just barrier presence, but also potential asymmetries in barrier effects with respect to the organism under investigation. PMID- 20723066 TI - Inferring landscape effects on gene flow: a new model selection framework. AB - Populations in fragmented landscapes experience reduced gene flow, lose genetic diversity over time and ultimately face greater extinction risk. Improving connectivity in fragmented landscapes is now a major focus of conservation biology. Designing effective wildlife corridors for this purpose, however, requires an accurate understanding of how landscapes shape gene flow. The preponderance of landscape resistance models generated to date, however, is subjectively parameterized based on expert opinion or proxy measures of gene flow. While the relatively few studies that use genetic data are more rigorous, frameworks they employ frequently yield models only weakly related to the observed patterns of genetic isolation. Here, we describe a new framework that uses expert opinion as a starting point. By systematically varying each model parameter, we sought to either validate the assumptions of expert opinion, or identify a peak of support for a new model more highly related to genetic isolation. This approach also accounts for interactions between variables, allows for nonlinear responses and excludes variables that reduce model performance. We demonstrate its utility on a population of mountain goats inhabiting a fragmented landscape in the Cascade Range, Washington. PMID- 20723067 TI - Genetic discontinuities and disequilibria in recently established populations of the plant pathogenic fungus Mycosphaerella fijiensis. AB - Dispersal processes of fungal plant pathogens can be inferred from analysis of spatial genetic structures resulting from recent range expansion. The relative importance of long-distance dispersal (LDD) events vs. gradual dispersal in shaping population structures depends on the geographical scale considered. The fungus Mycosphaerella fijiensis, pathogenic on banana, is an example of a recent worldwide epidemic. Founder effects in this species were detected at both global and continental scale, suggesting stochastic spread of the disease through LDD events. In this study, we analysed the structure of M. fijiensis populations in two recently (~1979-1980) colonized areas in Costa Rica and Cameroon. Isolates collected in 10-15 sites distributed along a ~250- to 300- km-long transect in each country were analysed using 19 microsatellite markers. We detected low-to moderate genetic differentiation among populations in both countries and isolation by distance in Cameroon. Combined with historical data, these observations suggest continuous range expansion at the scale of banana-production area through gradual dispersal of spores. However, both countries displayed specific additional signatures of colonization: a sharp discontinuity in gene frequencies was observed along the Cameroon transect, while the Costa Rican populations seemed not yet to have reached genetic equilibrium. These differences in the genetic characteristics of M. fijiensis populations in two recently colonized areas are discussed in the light of historical data on disease spread and ecological data on landscape features. PMID- 20723068 TI - A novel assessment of population structure and gene flow in grey wolf populations of the Northern Rocky Mountains of the United States. AB - The successful re-introduction of grey wolves to the western United States is an impressive accomplishment for conservation science. However, the degree to which subpopulations are genetically structured and connected, along with the preservation of genetic variation, is an important concern for the continued viability of the metapopulation. We analysed DNA samples from 555 Northern Rocky Mountain wolves from the three recovery areas (Greater Yellowstone Area, Montana, and Idaho), including all 66 re-introduced founders, for variation in 26 microsatellite loci over the initial 10-year recovery period (1995-2004). The population maintained high levels of variation (H(O) = 0.64-0.72; allelic diversity k=7.0-10.3) with low levels of inbreeding (F(IS) < 0.03) and throughout this period, the population expanded rapidly (n(1995) =101; n(2004) =846). Individual-based Bayesian analyses revealed significant population genetic structure and identified three subpopulations coinciding with designated recovery areas. Population assignment and migrant detection were difficult because of the presence of related founders among different recovery areas and required a novel approach to determine genetically effective migration and admixture. However, by combining assignment tests, private alleles, sibship reconstruction, and field observations, we detected genetically effective dispersal among the three recovery areas. Successful conservation of Northern Rocky Mountain wolves will rely on management decisions that promote natural dispersal dynamics and minimize anthropogenic factors that reduce genetic connectivity. PMID- 20723069 TI - Endosymbiont metacommunities, mtDNA diversity and the evolution of the Bemisia tabaci (Hemiptera: Aleyrodidae) species complex. AB - Bemisia tabaci, an invasive pest that causes crop damage worldwide, is a highly differentiated species complex, divided into biotypes that have mainly been defined based on mitochondrial DNA sequences. Although endosymbionts can potentially induce population differentiation, specialization and indirect selection on mtDNA, studies have largely ignored these influential passengers in B. tabaci, despite as many as seven bacterial endosymbionts have been identified. Here, we investigate the composition of the whole bacterial community in worldwide populations of B. tabaci, together with host genetic differentiation, focusing on the invasive B and Q biotypes. Among 653 individuals studied, more than 95% of them harbour at least one secondary endosymbiont, and multiple infections are very common. In addition, sequence analyses reveal a very high diversity of facultative endosymbionts in B. tabaci, with some bacterial genus being represented by more than one strain. In the B and Q biotypes, nine different strains of bacteria have been identified. The mtDNA-based phylogeny of B. tabaci also reveals a very high nucleotide diversity that partitions the two ITS clades (B and Q) into six CO1 genetic groups. Each genetic group is in linkage disequilibrium with a specific combination of endosymbionts. All together, our results demonstrate the rapid dynamics of the bacterial endosymbiont-host associations at a small evolutionary scale, questioning the role of endosymbiotic communities in the evolution of the Bemisia tabaci species complex and strengthening the need to develop a metacommunity theory of inherited endosymbionts. PMID- 20723070 TI - Luminal serotonin time-dependently modulates vagal afferent driven antinociception in response to colorectal distention in rats. AB - BACKGROUND: Compelling evidence shows that vagal afferents mediate antinociception in response to visceral insults. Our recent findings implied that luminal serotonin (5-hydroxytryptamine, 5-HT) might mediate chronic food allergen sensitized visceral hyperalgesia, in which vagal afferents might be implicated. Here, to test this hypothesis, we investigated the effects of luminal infused 5 HT on visceral nociception and the involvement of vagal antinociceptive pathway. METHODS: The vagus-intact or vagotomized rats were given acute intraluminally or intraperitoneally administered 5-HT, or chronic luminal infusion of 5-HT. The visceromotor response (VMR) to colorectal distension (CRD) was electrophysiologically recorded. KEY RESULTS: Acute intraluminal infusion of 5-HT (10 or 100 nmol) significantly attenuated VMR to CRD, while systemic administered 5-HT at similar doses resulted in markedly augmented nociception. Pretreatment with luminal application of granisetron or lidocaine, or pharmacological depletion of endogenous 5-HT with injection of p-chlorophenylalanine, a 5-HT synthesis inhibitor, and subdiaphragmatic vagotomy or functional deafferentation with capsaicin abolished the effect of luminal (but not systemic) 5-HT. Chronic infusion of 5-HT (10 nmol d(-1) for 5 days) produced gradual augmentation of baseline VMR. And, the VMR to CRD after 5-HT infusion decreased on day 1 and 2, then gradually increased from day 3. Surgical vagotomy or daily preperfusion with granisetron canceled these time-dependent patterns. CONCLUSIONS & INFERENCES: Luminal 5-HT time-dependently modulates vagal afferent driven antinociception. Acute infusion of 5-HT attenuates visceral nociception via activation of vagal afferent 5-HT type 3 receptors (5-HT(3)Rs)within intestinal mucosa; while chronic luminal 5-HT caused gradually developed visceral hyperalgesia, which may also involve vagal 5-HT(3)Rs. PMID- 20723071 TI - Spectrum of gastric emptying patterns in adult patients with cyclic vomiting syndrome. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) in adults is a disorder characterized by recurrent and stereotypic episodes of severe nausea, vomiting and abdominal pain separated by symptom-free intervals. Both rapid and delayed gastric emptying (GE) have been observed but the reports involved small numbers of CVS patients. METHODS: We performed a retrospective study of 92 adult patients who met Rome SH diagnostic criteria for CVS between 2003 and 2009 at the Kansas University Medical Center. Gastric emptying was measured by a standardized scintigraphic method involving a low fat (2%) isotope labeled egg white meal of 250 Kcal, with anterior and posterior gastric imaging in the standing position obtained at 0, 1, 2, 4 h after meal ingestion. Rapid GE was defined as <50% isotope retention at 1st h and/or <30% at 2nd h and delayed GE as >10% at 4 h. KEY RESULTS: Ninety two patients were analyzed: 47 males and 45 females mean of age 37 +/- 12 years (range: 20-68 years). There were 27 patients with a personal history of migraine headache, 30 with history of marijuana use, 12 had diabetes mellitus (DM) and 10 had irritable bowel syndrome (IBS) as an accompanying diagnosis. Fifty four patients (59%) met criteria for rapid GE, 25 (27%) had normal GE and 13 (14%) had slow GE. Eighty percent of patients with co-existing IBS symptoms were identified as rapid. The subset with delayed emptying was often associated with narcotics use, DM and marijuana use (P < 0.05). CONCLUSIONS & INFERENCES: (i) In adult CVS patients, GE is generally either rapid or normal. (ii) Cyclic vomiting syndrome is an important new etiology to explain the finding of rapid GE on a radionuclide test. (iii) The small subset of CVS patients (14%) whose GE was slow were explained by the role of narcotics and/or marijuana. PMID- 20723072 TI - Effects and mechanisms of electroacupuncture on glucagon-induced small intestinal hypomotility in dogs. AB - BACKGROUND: Little is known on the effect of electroacupuncture (EA) (Br Med J, 2, 1976, 1225) on intestinal motility. The aim of this study was to investigate effects and mechanisms of EA on small intestinal contractions, transit, and slow waves in dogs. METHODS: Six dogs were equipped with two intestinal cannulas for the measurement of small intestinal contractions and transit. Glucagon was used to induce postprandial intestinal hypomotility. Each dog was studied in five randomized sessions: Control, glucagon, glucagon + EA, glucagon + EA + naloxone, and glucagon + EA + atropine. KEY RESULTS: 1 In the fasting state, EA induced intestinal contractions during motor quiescence (contractile index or CI: 4.4 +/- 0.8 VS 8.3 +/- 0.7, P < 0.05). 2 In the fed state, EA improved glucagon-induced intestinal hypomotility (CI: 3.8 +/- 0.4 VS 6.1 +/- 0.6, P < 0.05). 3 Electroacupuncture accelerated intestinal transit delayed by glucagon (67.9 +/- 4.3 VS 40.2 +/- 5.0 min, P < 0.05). 4 There was a negative correlation between the CI and the total transit time (R(2) = 0.59, P < 0.05). 5 The excitatory effect of EA was blocked by naloxone and partially blocked by atropine. 6 The percentage of normal slow waves was reduced with glucagon (70 +/- 2%VS 98 +/- 1% at baseline, P = 0.0015). Electroacupuncture normalized impaired slow waves and the effect was blocked by naloxone. CONCLUSIONS & INFERENCES: Electroacupuncture enhances intestinal contractions during Phase I of the migrating motor complex and glucagon-induced hypomotility in the fed state, and accelerates intestinal transit via the opioid and cholinergic pathways in dogs. Electroacupuncture may have a therapeutic potential for intestinal hypomotility. PMID- 20723074 TI - Methyl jasmonate elicits rapid changes in carbon and nitrogen dynamics in tomato. AB - * Evidence is emerging to support the notion that in response to herbivory, plants undergo changes in their primary metabolism and are able to fine-tune the allocation of new and existing resources and temporarily direct them to storage organs. * We hypothesized that simulated herbivory increases the export of resources out of the affected tissues and increases allocation to roots. We used short-lived radioisotopes to study in vivo the dynamics of newly incorporated (11)CO(2) and (13)NH(3). Methyl jasmonate (MeJA), a known defense elicitor, was applied to the foliage of tomato plants and 4 h later we monitored leaf uptake, export and whole-plant allocation of [(11)C]photosynthate and [(13)N]amino acids. * There was a marginally significant decrease in the fixation of (11)CO(2), and an increase in the export of newly acquired carbon and nitrogen out of MeJA treated leaves. The proportion of nitrogen allocated to roots increased, whereas the proportion of carbon did not change. * These results are in agreement with our hypotheses, showing a change in the allocation of resources after treatment with MeJA; this may reduce the chance of resources being lost to herbivores and act as a buffer to biotic stress by increasing the potential for plant regrowth and survival after the attack. PMID- 20723073 TI - Changes in interstitial cells of cajal with age in the human stomach and colon. AB - BACKGROUND: Aging produces inevitable changes in the function of most organs including the gastrointestinal tract. Together with enteric nerves and smooth muscle cells, interstitial cells of Cajal (ICC) play a key role in the control of gastrointestinal motility, yet little is known about the effect of aging on ICC. The aim of this study was to determine the effect of aging on ICC number and volume in the human stomach and colon. METHODS: Gastric and colonic tissues from patients aged 25-70 and 36-92 years old, respectively, and with no co-existent motility disorders were immunolabeled with an anti-Kit antibody and ICC were counted in the circular muscle and myenteric regions. Network volumes were measured using 3D reconstructions of confocal stacks. The effects of aging were determined by testing for linear trends using regression analysis. KEY RESULTS: In both stomach and colon, the number of ICC bodies and volume significantly decreased with age at a rate of 13% per decade. ICC size was only affected in the myenteric plexus in the colon. The changes associated with age were not differentially affected by sex or colonic region. CONCLUSIONS & INFERENCES: The number and volume of ICC networks in the normal human stomach and colon decline with age. This decrease in ICC likely reduces the functional capacity of the gastrointestinal motor apparatus, may contribute to changes in gastrointestinal motility with aging and may influence intestinal responses to insults such as disease, operative interventions and medications in older patients. Tissue specimens must be carefully age-matched when studying ICC in disease. PMID- 20723075 TI - Determination of the silicon concentration in plant material using Tiron extraction. AB - * The quantification of silicon (Si) in plants generally requires a digestion procedure before the determination of the dissolved Si concentration by spectrometric analysis. Recent procedures produce rapid and accurate measurements, but are based on either hazardous chemicals or sophisticated instrumentation. * Here, we describe a simpler procedure using Tiron. Tiron [4,5 dihydroxy-1,3-benzene-disulfonic acid disodium salt, (HO)(2)C(6)H(2)(SO(3)Na)(2)] is currently used as a selective extractant for amorphous silica in soils. Because Si in the shoots is mostly composed of amorphous opaline silica particles (i.e. phytoliths), we tested the Tiron extraction procedure for plants. * Our results are critically discussed in relation to two other standard procedures: electrothermal vaporization determination and high-temperature lithium-metaborate digestion. * We demonstrate that Tiron extraction is an alternative method which allows the rapid, safe and accurate quantification of Si in shoots of various plants covering a wide range of Si concentrations. PMID- 20723076 TI - Pollinators exert natural selection on flower size and floral display in Penstemon digitalis. AB - * A major gap in our understanding of floral evolution, especially micro evolutionary processes, is the role of pollinators in generating patterns of natural selection on floral traits. Here we explicitly tested the role of pollinators in selecting floral traits in a herbaceous perennial, Penstemon digitalis. * We manipulated the effect of pollinators on fitness through hand pollinations and compared phenotypic selection in open- and hand-pollinated plants. * Despite the lack of pollen limitation in our population, pollinators mediated selection on floral size and floral display. Hand pollinations removed directional selection for larger flowers and stabilizing selection on flower number, suggesting that pollinators were the agents of selection on both of these traits. * We reviewed studies that measured natural selection on floral traits by biotic agents and generally found stronger signatures of selection imposed by pollinators than by herbivores and co-flowering plant species. PMID- 20723078 TI - Performance of the lumenless 4.1-Fr diameter pacing lead implanted at alternative pacing sites in congenital heart: a chronic 5-year comparison. AB - PURPOSE: United States approval of the Model 3830, 4.1-French (Fr) diameter, lumenless, pacing lead (Medtronic Inc., Minneapolis, MN, USA) in patients under 17 years of age, and those with congenital heart disease (CHD), was in 2005. To date, long-term performance at alternative pacing sites (APS) is limited and chronic efficacy comparisons with more established leads is lacking. The purpose of this study was to evaluate these factors. METHODS: Implant and follow-up data on leads were compared: group 1 (non-3830 leads) and group 2 (Model 3830 leads). These included acute and chronic sensing and pacing, impedances, implant sites, and complications. Groups were compared using Fischer's exact test, paired, and nonpaired t-tests, with significance defined at P < 0.05. RESULTS: A total of 119 patients (ages 5-48 years) received 171 leads: group 1 (n = 80) and group 2 (n = 91). At implant, there were no differences in patient age, CHD, sensing, or pacing thresholds between groups. Implant lead impedances differed between groups but all were within normal values for each lead design. Chronic data showed no difference in sensing, pacing thresholds, or impedances. There were five (6%) early lead dislodgements in group 1 and one (1%) in group 2. APS were achieved in group 2 with mean 1.6 +/- 1.3 minutes fluoroscopy time. CONCLUSION: The new 4.1 Fr lumenless lead shows similar performance indices to established leads even at APS, yet is thinner and achieves APS with technical ease, permitting more efficient chronic pacing in children and all patients with CHD. PMID- 20723077 TI - Nuclear and chloroplast DNA phylogeography reveal two refuge areas with asymmetrical gene flow in a temperate walnut tree from East Asia. AB - * Recently, there has been a debate about whether the temperate forests of East Asia merged or fragmented during glacial periods in the Pleistocene. Here, we tested these two opposing views through phylogeographical studies of the temperate-deciduous walnut tree, Juglans mandshurica (Juglandaceae) in northern and northeastern China, as well as Japan and Korea. * We assessed the genetic structure of 33 natural populations using 10 nuclear microsatellite loci and seven chloroplast DNA (cpDNA) fragments. * The cpDNA data showed the complete fixation of two different haplotype lineages in northeastern vs northern populations. This pronounced phylogeographic break was also indicated by nuclear microsatellite data, but there were disparities regarding individual populations. Among those populations fixed for haplotype A (the northeastern group), three were clustered in the northern group and four showed evidence of mixed ancestry based on microsatellite data. * Our results support the hypothesis that two independent refugia were maintained across the range of J. mandshurica in the north of China during the last glacial maximum, contrary to the inference that all temperate forests migrated to the south (25-30 degrees N). The discordance between the patterns revealed by cpDNA and microsatellite data indicate that asymmetrical gene flow has occurred between the two refugia. PMID- 20723079 TI - Pacing the right ventricular septum: time to abandon apical pacing. PMID- 20723080 TI - An acute myocardial infarction case that survived an out-of-hospital cardiac arrest in which prominent ischemic J waves were documented. AB - We describe a case of a myocardial infarction, in which prominent ischemic J waves were documented during recurrent ventricular fibrillation attacks. The patient was referred to our hospital to treat an out-of hospital cardiac arrest. Although the 12-lead electrocardiogram obtained just after the first cardioversion did not show any apparent J waves, a J wave-like steep downsloping type ST-segment elevation associated with q waves in the inferior leads was documented during multiple episodes of ventricular fibrillation. Our report revealed the appearance of J waves as an important marker for lethal arrhythmias in acute ischemia. PMID- 20723081 TI - Limitations of the DF-4 defibrillator connector necessitating device removal. AB - The DF-4 implantable defibrillator connector was recently released for clinical practice. This connector facilitates lead to device connection, reduces bulk in the device pocket, and eliminates the risk of incorrect device connection. Unfortunately, new technology often introduces new challenges. We report the case of a 63-year-old male with chronic systolic heart failure referred for cardiac resynchronization therapy-defibrillator implant. Limitations implicit to the current iteration of this technology include a lack of additional connectivity. In the present case, these limitations ultimately warranted device removal and reimplant with a traditional trifurcating IS-1/DF-1 connector. PMID- 20723082 TI - Submammary pacemakers and ICDs in women: long-term follow-up and patient satisfaction. AB - BACKGROUND: Device placement in women has unique considerations not addressed with standard implant techniques. These may include irritation and discomfort from purse and/or bra straps, changes in body image, and cosmetic issues with visible scars. Submammary device placement (SMI) addresses these problems and may be associated with greater patient comfort, cosmesis, and device acceptance. METHODS AND RESULTS: Over a 9-year period, 51 women, mean age 47 years (range 13 70 years), underwent submammary device implantation at our institution. These included seven cardiac resynchronization therapy devices, 26 implantable cardioverter defibrillators, and 18 pacemakers. Devices had been implanted for a mean of 57 months (range 2-118 months) when, in 2009, patient satisfaction was assessed via a telephone survey. Questions related to the initial decision, the preprocedure education, implant experience, recovery, complications, and long term satisfaction. Seventy-three percent of women listed cosmesis as their main reason for SMI, 76% had a mammogram since implant, and 89% reported no issues with mammography. Ninety-seven percent felt that SMI was the right choice and 95% stated they would do SMI again. Ninety-five percent also said they would recommend the procedure to others. CONCLUSION: Complications were rare (three lead dislodgements and one pneumothorax). SMI has high patient acceptance and long-term satisfaction with few complications. This procedure should be considered in women requiring device implantation. PMID- 20723083 TI - Incidence and predictors of permanent pacemaker requirement after transcatheter aortic valve implantation with a self-expanding bioprosthesis. AB - BACKGROUND: Previous reports have suggested the occurrence of cardiac conduction disorders and permanent pacemaker (PPM) requirement after transcatheter aortic valve implantation (TAVI). Based on a single-center experience, we aim to assess the incidence of postprocedural conduction disorders, need for PPM, and its determinants after TAVI with a self-expanding bioprosthesis. METHODS: From August 2007 to October 2009, 32 consecutive patients underwent TAVI with the Medtronic CoreValve (MCV) System (Medtronic Inc., Minneapolis, MN, USA). Three patients paced at baseline and two cases of procedure-related mortality were excluded. We analyzed the 12-lead electrocardiogram at baseline, immediately after procedure and at discharge. Requirements for PPM were documented and potential clinical, electrophysiological, echocardiographic, and procedural predictors of PPM requirement were studied. RESULTS: After TAVI, eight patients (29.6%) required PPM implantation due to high-grade atrioventricular (AV) block. The prevalence of left bundle branch block increased from 13.8% to 57.7% directly after implantation (P = 0.001). Need for PPM was correlated to the depth of prosthesis implantation (r = 0.590; P = 0.001). At a cutoff point of 10.1 mm, the likelihood of pacemaker could be predicted with 87.5% sensitivity and 74% specificity and a receiver operator characteristic curve area of 0.86 +/- 0.07 (P = 0.003). Of the seven patients with preexisting right bundle branch block (RBBB), four (57.1%) required PPM implantation after TAVI. CONCLUSIONS: High-grade AV block requiring PPM implantation is a common complication following TAVI and could be predicted by a deeper implantation of the prosthesis. Patients with preexisting RBBB also seem to be at risk for the development of high-grade AV block and subsequent pacemaker implantation. PMID- 20723084 TI - Linking as the cause of unnecessary right ventricular pacing. AB - BACKGROUND: The current report describes a manifestation of linking phenomenon in DDD pacemaker recipients: impairment of atrioventricular (AV) conduction and ensuing unnecessary right ventricular (RV) pacing. METHODS: Three patients with second-degree AV block and sudden impairment of native AV conduction following pacemaker implantation are presented. Loss of native AV conduction was considered functional and related to repetitive retrograde invasion of ventricular depolarization to the AV junction that was "linked" to ventricular pacing triggered by nonconducted P-waves. CONCLUSION: This case series demonstrates that linking phenomenon should be considered in analysis of pacemaker behavior, and that retrograde concealment can be responsible for unnecessary RV pacing. PMID- 20723085 TI - Re: Use of an angioplasty wire to perforate the interatrial septum for a difficult transseptal puncture. PMID- 20723086 TI - Unusual marker annotation: something shifty is going on. PMID- 20723087 TI - Pacemaker-mediated bigeminy: what is the mechanism? PMID- 20723088 TI - Implantation of a fully subcutaneous ICD in children. AB - The subcutaneous implantable cardioverter defibrillator (S-ICD) from Cameron Health (San Clemente, CA, USA) does not require a lead to be placed on or in the heart. Such a device, being subcutaneous, has potential benefits in children who require ICDs where problems largely relate to transvenous or epicardial leads and inappropriate shocks. The S-ICD was approved for use in Europe in June 2009 and recently a study commenced to acquire data in 330 patients in order to submit to the FDA. We shall describe the implantation of the S-ICD in two children aged 10 and 12 years at our institution. PMID- 20723089 TI - Epicardial macroreentrant ventricular tachycardia associated with a left ventricular aneurysm. AB - A 62-year-old man with severe coronary artery disease and a left ventricular aneurysm underwent catheter ablation of ventricular tachycardia (VT) with right bundle branch block QRS morphology. Endocardial bipolar voltage mapping with standard threshold settings demonstrated no low-voltage areas within the aneurysm. Catheter ablation of the epicardial surface of the aneurysm eliminated the VT. Endocardial bipolar voltage mapping with any other settings could not predict the site of the epicardial arrhythmogenic substrate whereas endocardial unipolar voltage mapping could. Endocardial unipolar voltage mapping may be helpful for predicting epicardial arrhythmogenic substrates. PMID- 20723090 TI - Hemiazygous coil placement for high-defibrillation thresholds in a patient with a right-sided implantable cardioverter defibrillator. AB - A 41-year-old man underwent implantation of a right-sided implantable cardioverter defibrillator after removal of an infected left-sided system. Defibrillation threshold (DFT) testing on the right-sided system failed to convert ventricular fibrillation at maximum device output (35 J) compared with a DFT of less than 15 J on the previous left-sided system. A single-coil lead was selectively placed into the hemiazygous vein, which courses leftward of the spine in a posterior-anterior projection, resulting in an improved shocking vector and reduction in DFTs to less than 25 J. PMID- 20723091 TI - Recurrence of RVOT PVCs with a marked shift of its exit point. Gradual elimination of arrhythmogenic focus by multisite approach. AB - We present a case of recurrent outflow tract arrhythmia despite repeated ablations. Premature ventricular contractions (PVCs) morphology suggested a right sided focus. However, electrograms preceding PVCs were recorded from the right and left outflow tracts, distal coronary sinus, and right sinus of Valsalva. Arrhythmia was eliminated after radiofrequency (RF) applications delivered from different sites. We conclude that, in patients with recurrent outflow tract PVCs, mapping all the sites mentioned above may be necessary to find the earliest activation site and carry out successful ablation. In some patients, RF applications from multiple sites may be necessary to completely eliminate arrhythmia. PMID- 20723092 TI - Catheter ablation of scar-related ventricular tachycardia in patients with electrical storm using remote magnetic catheter navigation. AB - BACKGROUND: A remote magnetic navigation system (MNS) has been used for ablation of ventricular arrhythmias. However, irrigated tip catheter has not been evaluated in large series of patients. OBJECTIVE: To evaluate acute and long-term efficiency of the newly available irrigated tip magnetic catheter for radiofrequency (RF) ablation of scar-related ventricular tachycardia (VT) in patients with ischemic heart disease. METHODS: Between January 2008 and October 2009, a total of 30 consecutive patients with ischemic heart disease (26 men, age 70.1 +/- 8.7 years, left ventricular ejection fraction: 30 +/- 9%) and electrical storm due to monomorphic VT underwent RF ablation using a remote MNS and a magnetic irrigated tip catheter. RESULTS: Acute success was defined as noninducibility of any monomorphic VT during programmed right and left ventricular stimulation, and obtained in 24 (80%) patients. A total of 1-6 VTs (mean 2.3 +/- 1.2, 394 +/- 108 ms, 210-660 ms) were inducible during each procedure. The duration of RF energy application was 41.2 +/- 23.3 minutes, with total procedure and fluoroscopy times of 158 +/- 47 minutes and 9.8 +/- 5.3 minutes, respectively. No acute complications were observed during the procedures. During mean follow-up of 7.8 months, 21 patients (70%) had no recurrence of VT and received no implantable cardioverter defibrillator therapy. Among patients who were noninducible during programmed right ventricular stimulation (n = 25), >=1 monomorphic VT was inducible during programmed left ventricular stimulation in four (16%) that was ablated successfully in three of them. CONCLUSIONS: Irrigated ablation of scar-related VT using remote MNS is an effective modality for management of the monomorphic VT in patients with ischemic cardiomyopathy with minimal radiation exposure. Programmed left (in addition to right) ventricular stimulation might be necessary to assess acute outcome of the ablation procedure. PMID- 20723093 TI - Risk in pediatric anesthesia. AB - Risk in pediatric anesthesia can be conveniently classified as minor or major. Major morbidity includes cardiac arrest, brain damage and death. Minor morbidity can be assessed by clinical audits with small patient samples. Major morbidity is rare. It is best assessed by very large clinical studies and by review of closed malpractice claims. Both minor and major morbidity occur most commonly in infants and children under three, especially those with severe co-morbidities. Knowledge of risk profiles in pediatric anesthesia is a starting point for the reduction of risk. PMID- 20723094 TI - Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. AB - AIMS AND OBJECTIVES: To illustrate the complex interaction between ontogeny, i.e., age-dependent maturation, genetic polymorphisms and renal elimination clearance during infancy, based on developmental disposition of intravenous tramadol during infancy. BACKGROUND: Tramadol (M) is metabolized by O demethylation (cytochrome P450 [CYP] 2D6) to the pharmacodynamic active metabolite O-demethyl tramadol (M1). This metabolite is subsequently eliminated by renal route while M1 formation will in part depend on ontogeny, i.e., age dependent activity and CYP2D6 polymorphisms. However, these pathways do not mature simultaneously. METHODS: A pooled pharmacokinetic analysis of earlier reported time-concentration profiles in neonates and infants was performed with subsequent simulation of the impact of ontogeny, polymorphisms and renal elimination clearance during infancy. RESULTS: Tramadol plasma time-concentration profile changes with postmenstrual age. The highest metabolite concentrations occur in the 52-week infant, where M1 formation clearance (hepatic, CYP2D6) is already mature but metabolite elimination clearance (through glomerular filtration rate) is immature. DISCUSSION: The phenotypic observations might in part explain unanticipated (side-)effects of tramadol. In addition to the compound-specific clinical implications, it is important to stress that the maturational trends in the elimination processes described can be considered for other compounds (e.g., codeine) that undergo similar elimination routes. PMID- 20723095 TI - Anesthetic management of congenital tracheoesophageal fistula. AB - This article reviews (a) risk factors and preoperative considerations of the patient with tracheoesophageal fistula, (b) anesthetic management, including (i) airway management, (ii) induction of anesthesia and monitoring and (iii) postoperative disposition, (c) considerations for concomitant congenital heart disease, (d) considerations for thoracoscopic repair and (e) long-term outcomes and considerations of the patient with repaired esophageal atresia/tracheoesophageal fistula. PMID- 20723096 TI - Retrospective evaluation of clinical characteristics, pharmacotherapy and healthcare resource use among patients prescribed pregabalin or duloxetine for diabetic peripheral neuropathy in usual care. AB - OBJECTIVE: To evaluate treatment patterns and costs among patients with painful diabetic peripheral neuropathy (pDPN) newly prescribed pregabalin or duloxetine in usual care settings. METHODS: Using the PharMetrics(r) Database, patients with pDPN (ICD-9-CM codes 357.2 or 250.6x) newly prescribed pregabalin or duloxetine were identified. Patients initiated on duloxetine (n=713; mean age 55.4 +/- 9.5 years) were propensity score-matched with patients initiated on pregabalin (n=713; mean age 56.3 +/- 9.3 years). Prevalence of comorbidities, pain-related pharmacotherapy and healthcare resource use/costs (pharmacy, outpatient, inpatient, total) were examined during the 12 months preceding (pre-index) and following (follow-up) the date of the first pregabalin or duloxetine prescription. RESULTS: Both cohorts had multiple comorbidities and a substantial pain medication burden. Among pregabalin patients, use of other anticonvulsants (35.6% vs. 24.7%) and tricyclic antidepressants significantly decreased (18.2% vs. 13.7%) and serotonin-norepinephrine reuptake inhibitors (SNRIs) increased (7.9 % vs. 12.9%) in the follow-up period; all P values <0.05. Among duloxetine patients, use of other SNRIs (8.7% vs. 5.2%) and selective serotonin reuptake inhibitors decreased significantly (32.1% vs. 18.9%) in the follow-up period, but there were increases for anticonvulsants (42.1% vs. 48.4%), benzodiazepines (25.5% vs. 32%), and sedative/hypnotics (22.6% vs. 25.8%); all P values <0.05. Among pregabalin and duloxetine patients there were increases (P<0.05) in pharmacy, outpatient, and total healthcare costs from the pre-index to the follow up period. Total medication costs in the follow-up period were significantly higher for duloxetine (median $6,763 [IQR $3,970-$10,914]) relative to pregabalin (median $6,059 [IQR $3,277-$9,865]); P=0.0017. CONCLUSIONS: Patients with pDPN prescribed pregabalin and duloxetine were characterized by a substantial comorbidity and pain medication burden. Although there were no differences in total healthcare costs, medication costs were significantly higher in the duloxetine cohort relative to the pregabalin cohort. PMID- 20723097 TI - Factors associated with increased risk of insulin pump discontinuation in pediatric patients with type 1 diabetes. AB - BACKGROUND: There are few reports on rates and predictors for pump discontinuation in the pediatric population. OBJECTIVE: To study the rate of and predictors for insulin pump discontinuation among pediatric patients with type 1 diabetes. METHODS: Medical chart review of 530 patients with type 1 diabetes who had started pump therapy between 2000 and 2008 in our center revealed that 11.3% had discontinued pump use after 3 d to 5 yr; of these, 9.1% discontinued pump use at least 3 months after initiation. Relevant data were retrieved from the files of these patients and from those of 100 randomly assigned pump-treated patients. RESULTS: The pump discontinuation group had a significantly higher proportion of female patients (75 vs. 46%, p = 0.001) and patients above 10 yr of age (93.8 vs. 80%, p = 0.03) than the reference group. Comparable findings were noted for age at diagnosis, pubertal stage, anthropometric data and duration of diabetes at pump initiation, rate of severe hypoglycemic and diabetic ketoacidosis episodes. There were no between-group differences in number of daily insulin injections and blood glucose measurements before pump treatment. At pump initiation, HbA(1c) was significantly higher in patients discontinuing pump therapy than in the controls (8.6 +/- 1.4 vs. 8.1 +/- 1.0, p = 0.02). This difference was maintained at the last follow-up visit recorded. CONCLUSIONS: Almost 90% of our cohort maintained pump therapy. Female gender, age older than 10 years in girls and poor metabolic control at pump initiation were associated with higher risk for pump discontinuation - for such patients intensified individual and family support may serve to maximize persistent pump therapy. PMID- 20723098 TI - GADA positivity at onset of type 1 diabetes is a risk factor for the development of autoimmune thyroiditis. AB - AIM: To evaluate whether the presence of diabetes-specific autoantibodies may predict the development of autoimmune thyroiditis (AIT) in children with type 1 diabetes (T1D). METHODS: Glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase IA2 antibodies (IA2A), and insulin autoantibodies (IAA) were determined at T1D onset in 341 children and adolescents. Thyroid antibodies (anti TG, anti-TPO), thyroid stimulating hormone (TSH), T(3) and T(4) were measured in 335 patients at T1D onset and thereafter annually with a follow-up time of 1-15 yr. In case of thyroid antibody positivity and/or TSH elevation, thyroid gland sonography was performed. Treatment with l-thyroxine was started if persistent elevation of TSH and/or thyroid volume was present. RESULTS: The majority of patients (92.1%) had at least one T1D antibody (71.6% GADA, 73.0% IA2A, and 44.9% IAA). GADA positive patients were older than those without GADA (p < 0.001). Thyroid autoimmunity was found in 15 of 335 patients (4.5%) at T1D onset with female preponderance (p = 0.013). At the end of follow-up, 70 patients (20.9%) had developed thyroid autoantibodies [cumulative incidence (CI) 0.36 +/- 0.06 at 10 yr of T1D]. In 30 patients (9.0%), AIT was diagnosed up to 9.4 yr after T1D onset (CI 0.24 +/- 0.06 at 10 yr). AIT incidence was not influenced by IAA or IA2A positivity. In multivariate analysis, GADA positive patients were estimated to have a 3.5-fold increased risk of AIT (CI 0.31 +/- 0.11 at 10 yr) compared to those without GADA (p = 0.024). CONCLUSION: Based on the present results, a special focus should be given to GADA positive patients concerning screening for AIT as they are at increased risk to develop autoimmune thyroiditis. PMID- 20723099 TI - The effect of home visits on the quality of life of children and adolescents with type 1 diabetes mellitus. AB - OBJECTIVE: The aim of the study was to analyze the impact of home and school visits and to strengthen the knowledge on diabetes education on the quality of care and life of children and adolescents with diabetes. METHODOLOGY AND RESULTS: This was a descriptive cross-sectional study of all children and adolescents (n = 16, seven males and nine females), attending a pediatric diabetes center (mean age: 11.25 yr +/- 4.82, range: 5-17 yr), mean duration of diabetes being 4.6 +/- 3.9 yr, range 0.5-8.4 yr. Ten patients were visited by the medical social worker at home and school, their knowledge ondiabetes education was strengthened, and intervention effect was evaluated 4 months later. Positive effects observed were that clinic visits became regular, there was notification by school of clinical status, a reduction in number of hypoglycemic episodes at school, increased acquisition of glucometers, and daily and regular (100%) self home blood glucose (BG) monitoring. The mean center HbA1c was reduced from 12.86 +/- 2.5% to 9.41 +/ 1.56%, the change from previsit was 3.45%. The mean center morning BG dropped from 181.60 +/- 71.96 to 127.54 +/- 27.54 mg/dL reflecting change from previsit BG of 54.19 mg/dL. However, these visitations had little effect on checking of BG at school. CONCLUSION: This study stressed the importance of home and school visits and diabetes education on the quality of care and life of the children and adolescents with diabetes in our region. PMID- 20723100 TI - A 5-yr follow-up nerve conduction study for the detection of subclinical diabetic neuropathy in children with newly diagnosed insulin-dependent diabetes mellitus. AB - OBJECTIVE: To investigate the changes of peripheral nerve conduction in children with insulin-dependent diabetes mellitus (IDDM) prospectively from diagnosis and to know how those results were related to clinical risk factors. METHODS: A total of 37 patients (14 males and 23 females) aged 3-19 yr (mean 12.0 +/- 3.7) with newly diagnosed IDDM underwent bilateral nerve conduction studies (NCS) of median, ulnar, posterior tibial, peroneal, and sural nerves annually for 5 yr. RESULTS: In all, 12 patients (32.4%) showed electrophysiological evidence of polyneuropathy in at least two different nerves including the sural nerve at the diagnosis of IDDM; 20 patients (54%) had multiple (>=2) abnormalities in parameters of NCS. The most common abnormal parameters at the diagnosis were conduction velocities of peroneal motor and sural nerves. In sequential NCS over 5 yr, the percentage of abnormal nerve conduction velocities rose except within the sural nerve. Poor metabolic control, height, duration of diabetes, and older age of onset were related to the changes of parameters of NCS over 5 yr. Among those risk factors, the duration of diabetes and sustained hyperglycemia affected the parameters of NCS more frequently than others. CONCLUSIONS: Children with IDDM frequently have nerve conduction abnormalities without clinical neuropathy at initial diagnosis. The frequency of abnormalities of any attribute of nerve conduction increased over the 5 yr follow-up. The duration of diabetes and poor glycemic control proved to be more important risk factors over 5 yr as related to the development of subclinical neuropathy. PMID- 20723101 TI - The relationship between the age of onset of type 1 diabetes and the subsequent development of a severe eating disorder by female patients. AB - OBJECTIVES: To determine the age of onset of type 1 diabetes that is most closely related to the subsequent development of a severe eating disorder such as anorexia nervosa (AN) or bulimia nervosa (BN). METHODS: Participants were 53 female type 1 diabetes patients with AN or BN referred to our outpatient clinic from the Diabetes Center of Tokyo Women's Medical University. Forty-nine female type 1 diabetes patients who regularly visited the Diabetes Center and had no eating disorder-related problems constituted the 'direct control' group, whereas 941 female patients who for the first time visited the Diabetes Center constituted the 'historical control' group. The kernel function method was used to generate a density estimation of the onset age of each group and the chi square test was used to compare the distribution. RESULTS: The control groups had similar density shapes for the onset age of type 1 diabetes, but both differed from the 'eating disorder' group. For onset age 7-18 yr, the density of the 'eating disorder' group was higher than those of the control groups, but for the younger and older onset ages the densities were lower. The 'eating disorder' group developed type 1 diabetes significantly more frequently than the 'historical control' group between 7 and 18 yr of age (chi2 = 9.066, p < 0.011). CONCLUSION: The development of type 1 diabetes in preadolescence or adolescence seems to place girls at risk for the subsequent development of AN or BN. Careful attention should be paid to these high-risk patients. PMID- 20723102 TI - Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population-based study. AB - OBJECTIVE: Hypoglycemia remains a central problem in the management of type 1 diabetes mellitus (T1DM) and limits the achievement of good or normal glycemic control. The Diabetes Control and Complication Trial showed that intensive treatment of T1DM increased the risk of severe hypoglycemia (SH) when compared to conventional therapy. The aim of our study was to determine the incidence of SH and associated variables in a population of children and adolescents with T1DM. RESEARCH DESIGN AND METHODS: We performed a 7.5-yr prospective study enrolling 195 patients aged 13.9 +/- 6.6 yr. The study was carried out by referring to the T1DM population-based register in the Abruzzo region of Italy. The incidence of SH, defined as blood glucose levels <50 mg/dL (<2.77 mmol/L) associated with altered states of consciousness (including confusional state, seizures, and coma) was recorded. Glycated hemoglobin (HbA1c) percentage, insulin dose, insulin regimen, time since diagnosis, and age at onset were also recorded. RESULTS: One hundred and thirty-three severe hypoglycemic events occurred during the study period; the overall incidence was 9.4 episodes per 100 patient-years. Significant predictors of hypoglycemia were diabetes duration >10 yr (p = 0.01), basal/bolus insulin ratio (ratio of daily basal insulin units to daily bolus insulin units) >0.8 (p = 0.01). No relationship was found between hypoglycemic episodes and HbA1c levels, daily insulin requirements, or insulin regimen. CONCLUSIONS: In these patients, a relatively low incidence of SH was recorded, without pronounced association with lower HbA1c or multiple daily injection insulin therapy. SH seems to be mainly related to management of diabetes. We believe that the main path to SH prevention is through patient and family education in the management of T1DM. PMID- 20723103 TI - Evaluation of growth and neurodevelopment in children with congenital heart disease. AB - BACKGROUND: Children with congenital heart disease are under risk of delayed growth and development. We evaluated physical growth parameters and neurodevelopment in these patients in comparison with normal children and examined the effect of hemodynamic status. METHODS: Patients with congenital heart disease (n= 76) and healthy children (n= 51) aged 1-72 months applied to Mersin University Hospital, Mersin, Turkey were included. Patients with heart failure and those requiring intervention or surgery were classified as hemodynamically impaired (HI group, n= 30), and the others, hemodynamically normal (HN group, n= 46). Growth parameters including weight, height, body mass index (BMI), mid-arm circumference (MAC), and triceps skin fold thickness (TSF) were measured and standard deviations (SD) were determined. Functional development was assessed by Denver Developmental Screening Test-II (DDST II). RESULTS: MAC and BMI values of the group with impaired hemodynamic status were significantly lower than the hemodynamically normal and control groups (MAC P < 0.05 and BMI P < 0.01). In the DDST II, the group with hemodynamic abnormality had more failures in gross motor and fine motor skills than HN group and controls (gross motor P= 0.011, P < 0.001 and fine motor P= 0.028, P= 0.001, respectively) and more failures in language development than the control group (P= 0.001). CONCLUSION: The results showed the importance of hemodynamic status in growth and neurodevelopment of children with congenital heart disease. Besides routine growth parameters, more detailed examinations such as BMI, MAC, TSF, and developmental screening tests appear useful in identifying children with cardiac disease who are under risk for delayed growth and development. PMID- 20723104 TI - Reading skills of Japanese second-graders. AB - BACKGROUND: A few studies have explored the prevalence of dyslexia among children who speak Japanese as their native language by evaluating them individually by means of reading-based tasks. The present study was designed to clarify the frequency of suspected dyslexia among second-graders attending ordinary classes. METHODS: The subjects were 40 children (22 males, 18 females; 7 years 4 months-8 years 4 months; mean age, 7 years 11 months) out of 182 second-graders at a public elementary school situated in a local city. Each subject underwent a monomoraic syllable reading task, a word reading task, a non-word reading task, and a short sentence reading task. RESULTS: The scores on the four tests were not normally distributed; rather, they were strongly skewed to shorter reading time or fewer reading errors. In addition, they were significantly extended toward either longer reading time or more reading errors. Except in the non-word reading task, most subjects only made a few reading errors. Seven subjects (17.5%) showed at least one score that was more than 1.5 IQR (interquartile range) higher than the third quartile of that subject's eight scores on the four tasks. Assuming that those seven children are potentially dyslexic, at least 3.8% of second graders (seven out of 182) are suspected to be suffering from dyslexia. CONCLUSION: It is likely that the prevalence of dyslexia in Japan is comparable to that in Europe and the US. To confirm this, a more comprehensive study on a larger scale should be implemented in the future. PMID- 20723105 TI - Two types of orthostatic dysregulation assessed by diameter of inferior vena cava. AB - AIMS: Orthostatic dysregulation (OD) is common in adolescents. This study was conducted to evaluate the usefulness of the measurement of the diameter of the inferior vena cava (IVC) for objective assessment of patients with OD. METHODS: Twenty children with OD (median 14 years, range 9-15 years) and 23 age-matched healthy children (median 12 years, range 10-15 years) were enrolled. A diameter of IVC was measured by an abdominal echogram before and after a head-up tilt table testing (HUT). Changes in IVC was assessed by an arbitrary parameter, collapse index (CI) as the following equation: [(maximal IVC diameter in the supine position - maximal IVC diameter in the standing position)/(maximal IVC diameter in the supine position)]* 100. CI was evaluated 4 weeks after treatment with an adrenergic agent. RESULTS: Children with OD demonstrated either higher CI or lower CI compared to that in control children: CI was more than 50 (range 50 71) in 12 patients with OD while that was equal to or less than 0 (range -225 to 0) in eight out of 20 patients. In contrast, CI was between 0 and 50 (range 1-26) in 23 healthy children. Pharmacological treatment induced the normalization in the CI in both higher and lower CI group. CONCLUSION: OD can be classified into two subtypes: by HUT, one is characterized by an increase of IVC diameter while another is characterized by its decrease. Measurement of IVC diameter by HUT is useful to understand the pathophysiology and to assess the efficacy of treatment. PMID- 20723107 TI - Continuous hydrocortisone infusion in severe pediatric community-acquired pneumonia (CAP). PMID- 20723106 TI - Antimicrobial susceptibility of Staphylococcus aureus in children with atopic dermatitis. AB - BACKGROUND: Skin infection and/or nasal carriage of Staphylococcus aureus in children with atopic dermatitis (AD) is a risk factor for exacerbating disease or subsequent recurrent S. aureus infection. The purpose of the study is to evaluate the antibiotic susceptibilities of S. aureus strains from AD children and determine the most appropriate choice of antibiotics. METHODS: Nasal swabs from 168 healthy children with AD and 20 AD children with concurrent skin and soft tissue infections (SSTI) were collected in 2005-2008. S. aureus strains were further analyzed for and compared with antibiotic susceptibilities. RESULTS: There were 78 (46.4%) healthy children with AD colonized with S. aureus, and 24 (30.8%) were methicillin-resistant S. aureus (MRSA). Among the 20 SSTI-infecting strains, 12 (60%) were MRSA. Antimicrobial susceptibility testing showed that, after penicillin, colonizing and SSTI-infecting strains had the highest rates of resistance to erythromycin (50% and 70%, respectively). All isolated strains were susceptible to vancomycin, rifampin, and mupirocin. Multi-drug resistance was found in 70% of the colonizing and 50% of the SSTI-infecting strains. D-test assay revealed inducible clindamycin resistance in 75% of the colonizing strains. The most prevalent resistance gene was ermB which was present in 94.9% and 92.9% of colonizing and SSTI-infecting strains, respectively. CONCLUSIONS: This study found that colonizing and SSTI-infecting strains of S. aureus from AD children had a high prevalence of MRSA and multi-drug resistance. Trimethoprim sulfamethoxazole, rifampin, fusidic acid and mupirocin appear to be more suitable for treatment and decolonization of S. aureus in AD children. PMID- 20723108 TI - Twenty-four-year-old male patient with infantile onset of Schimke immuno-osseous dysplasia. PMID- 20723109 TI - Congenital atresia of left main coronary artery followed up for ages as a sequela of Kawasaki disease. PMID- 20723110 TI - Incomplete Kawasaki disease in a patient with chronic granulomatous disease. PMID- 20723111 TI - Protracted febrile myalgia in two children with familial Mediterranean fever. PMID- 20723112 TI - Somatostatin for the treatment of chylothorax in a premature baby with Down syndrome. PMID- 20723114 TI - Ph+ALL in a pediatric patient with neuroblastoma in infancy. PMID- 20723113 TI - Trisomy 12p syndrome secondary to a balanced familial translocation. PMID- 20723115 TI - Case of glycogen storage disease type VI (phosphorylase deficiency) complicated by focal nodular hyperplasia. PMID- 20723116 TI - Two preterm infants with late onset circulatory collapse induced by levothyroxine sodium. PMID- 20723117 TI - Transcarotid balloon valvuloplasty for critical aortic stenosis in a premature neonate weighing 1100 g. PMID- 20723118 TI - Treatment of disfiguring chronic graft versus host disease in a child with topical pimecrolimus. PMID- 20723119 TI - Mycophenolate mofetil therapy in a child with Churg-Strauss syndrome. PMID- 20723120 TI - Protein-losing gastropathy in a child and Guillain-Barre syndrome in a father caused by intrafamilial infection. PMID- 20723121 TI - Gastrointestinal presentation of late acute lymphoblastic leukemia relapse. PMID- 20723122 TI - Improvement of migraine symptoms after coil embolotherapy of pulmonary arteriovenous fistulae. PMID- 20723123 TI - Forty-two-day-old boy with acute idiopathic thrombocytopenic purpura. PMID- 20723124 TI - Naloxone use in a newborn with apnea due to tetrahydrozoline intoxication. PMID- 20723125 TI - Morganella morganii pericarditis in a child with X-linked agammaglobulinemia. PMID- 20723126 TI - Paternal mosaic inv(20) resulting in a recombinant chromosome 20 in two siblings. PMID- 20723127 TI - Self-limited septic arthritis caused by Staphylococcus aureus. PMID- 20723128 TI - Sepsis-like cerebrovascular event in a newborn with MTHFR homozygous mutation. PMID- 20723129 TI - Congenital myotonic dystrophy associated with Moebius syndrome and double-outlet right ventricle. PMID- 20723130 TI - Prader-Willi syndrome associated with dilated cardiomyopathy. PMID- 20723131 TI - Amniotic band syndrome associated with sacral meningocele and anal atresia. PMID- 20723132 TI - Infantile spontaneous spinal epidural hematoma. PMID- 20723133 TI - Use of doubled haploid technology for development of stable drought tolerant bread wheat (Triticum aestivum L.) transgenics. AB - Anther culture-derived haploid embryos were used as explants for Agrobacterium mediated genetic transformation of bread wheat (Triticum aestivum L. cv CPAN1676) using barley HVA1 gene for drought tolerance. Regenerated plantlets were checked for transgene integration in T0 generation, and positive transgenic haploid plants were doubled by colchicine treatment. Stable transgenic doubled haploid plants were obtained, and transgene expression was monitored till T4 generation, and no transgene silencing was observed over the generations. Doubled haploid transgenic plants have faster seed germination and seedling establishment and show better drought tolerance in comparison with nontransgenic, doubled haploid plants, as measured by per cent germination, seedling growth and biomass accumulation. Physiological evaluation for abiotic stress by assessing nitrate reductase enzyme activity and plant yield under post-anthesis water limitation revealed a better tolerance of the transgenics over the wild type. This is the first report on the production of double haploid transgenic wheat through anther culture technique in a commercial cultivar for a desirable trait. This method would also be useful in functional genomics of wheat and other allopolyploids of agronomic importance. PMID- 20723134 TI - Production of biologically active recombinant human factor H in Physcomitrella. AB - The human complement regulatory serum protein factor H (FH) is a promising future biopharmaceutical. Defects in the gene encoding FH are associated with human diseases like severe kidney and retinal disorders in the form of atypical haemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis II (MPGN II) or age-related macular degeneration (AMD). There is a current need to apply intact full-length FH for the therapy of patients with congenital or acquired defects of this protein. Application of purified or recombinant FH (rFH) to these patients is an important and promising approach for the treatment of these diseases. However, neither protein purified from plasma of healthy individuals nor recombinant protein is currently available on the market. Here, we report the first stable expression of the full-length human FH cDNA and the subsequent production of this glycoprotein in a plant system. The moss Physcomitrella patens perfectly suits the requirements for the production of complex biopharmaceuticals as this eukaryotic system not only offers an outstanding genetical accessibility, but moreover, proteins can be produced safely in scalable photobioreactors without the need for animal-derived medium compounds. Transgenic moss lines were created, which express the human FH cDNA and target the recombinant protein to the culture supernatant via a moss-derived secretion signal. Correct processing of the signal peptide and integrity of the moss-produced rFH were verified via peptide mapping by mass spectrometry. Ultimately, we show that the rFH displays complement regulatory activity comparable to FH purified from plasma. PMID- 20723135 TI - The production of artemisinin precursors in tobacco. AB - Artemisinin, in the form of artemisinin-based combination therapies (ACTs), is currently the most important compound in the treatment of malaria. The current commercial source of artemisinin is Artemisia annua, but this represents a relatively expensive source for supplying the developing world. In this study, the possibility of producing artemisinin in genetically modified plants is investigated, using tobacco as a model. Heterologous expression of A. annua amorphadiene synthase and CYP71AV1 in tobacco led to the accumulation of amorphadiene and artemisinic alcohol, but not artemisinic acid. Additional expression of artemisinic aldehyde Delta11(13) double-bond reductase (DBR2) with or without aldehyde dehydrogenase 1 (ALDH1) led to the additional accumulation dihydroartemisinic alcohol. The above-mentioned results and in vivo metabolic experiments suggest that amorphane sesquiterpenoid aldehydes are formed, but conditions in the transgenic tobacco cells favour reduction to alcohols rather than oxidation to acids. The biochemical and biotechnological significance of these results are discussed. PMID- 20723136 TI - Formation of an antral follicle-like structure of bovine cumulus-oocyte complexes embedded individually or in groups in collagen gels. AB - Culture techniques of antral follicle-like structure (AFLS) derived from cumulus oocyte complexes (COCs) might provide important insights into follicular development and oocyte maturation. This study was undertaken to investigate the effects of embedding bovine COCs individually (one COC) or in groups (4-5 COCs) in collagen gels on the formation of AFLS and the meiotic status of oocytes. The observations of AFLS formation were performed every second day for 14 days. The AFLS was formed at Day 2 or 4 after the start of culture (Day=0), irrespective of the culture methods. The mean diameters of AFLS during Days 4-14 using the individual culture method were significantly higher (p<0.05) than those using the group culture method. However, the AFLS formation rate in the individual culture method was significantly lower compared to that in the group culture method (26.1% vs 62.7%, p<0.01). Almost all oocytes had undergone the germinal vesicle breakdown stage, irrespective of the culture method or AFLS formation. In conclusion, comparison with the individual culture method revealed that the mean diameters of AFLS in the group culture method were smaller, but more COCs formed AFLS. The group culture method might be useful for evaluating the various hypotheses of follicular formation and interfollicular communication. However, improvement of the group culture system is necessary to prevent the meiotic resumption of oocytes, because the AFLS formation is dependent on the cumulus/granulosa cells surrounding oocytes. PMID- 20723137 TI - Improvement of 2D-PAGE resolution of human, porcine and equine follicular fluid by means of hexapeptide ligand library. AB - The major challenge of follicular fluid proteomic analysis is the presence of high-abundance proteins that originate from plasma. These proteins can prevent the detection of lower abundant ones, produced locally by follicle cells and that may have important roles in follicular activity. In this study, the novel technology called hexapeptide ligand library was evaluated to enrich the low abundance proteins in follicular fluid of human (HFF), porcine (PFF) and equine (EFF) prior 2D-PAGE. Our results showed that the new strategy enabled detection of many new protein spots, increased resolution and highly improved the intensity of low-abundance proteins by 2D-PAGE. PMID- 20723138 TI - Endoscopic lung volume reduction effectively treats acute respiratory failure secondary to bullous emphysema. AB - Emphysema often affects the lungs in a heterogeneous fashion, and collapse or removal of severely hyperinflated portions of lung can improve overall lung function and symptoms. The role of lung volume reduction (LVR) surgery in selected patients is well established, but that of non-surgical LVR is still being defined. In particular, use of endobronchial LVR is still under development. This case report describes a 48-year-old non-smoker with severe bullous emphysema complicated by acute hypercapnic respiratory failure, who was successfully treated by endobronchial valve placement while intubated in an intensive care unit. PMID- 20723139 TI - Targeted therapy: an evolving world of lung cancer. AB - Lung cancer remains one of the most fatal illnesses. Recent development in cancer genomics and molecular targeted therapy leads to a paradigm shift in management of advanced-stage non-small cell lung cancer. Patients with activated mutation of epidermal growth factor receptor (EGFR) responded dramatically to EGFR tyrosine kinase inhibitor such as gefitinib or erlotinib. Multiple randomized studies have showed EGFR tyrosine kinase inhibitor to be superior to standard first-line chemotherapy in this biomarker-selected population. As the vasculature is considered to be the 'Achillus heel' of the tumour, anti-angiogenic treatment is considered to be a suitable target. Inhibition of vascular endothelial growth factor may improve the efficacy of chemotherapy, although a practical biomarker has not been identified. We have entered an era of personalized therapy for lung cancer and this evolvement holds great promises for better treatment in future. PMID- 20723140 TI - Pseudomonas aeruginosa: host defence in lung diseases. AB - Lung infections caused by the opportunistic pathogen Pseudomonas aeruginosa can present as a spectrum of clinical entities from a rapidly fatal pneumonia in a neutropenic patient to a multi-decade bronchitis in patients with cystic fibrosis. P. aeruginosa is ubiquitous in our environment, and one of the most versatile pathogens studied, capable of infecting a number of diverse life forms and surviving harsh environmental factors. It is also able to quickly adapt to new environments, including the lung, where it orchestrates virulence factors to acquire necessary nutrients, and if necessary, turn them off to prevent immune recognition. Despite these capabilities, P. aeruginosa rarely infects healthy human lungs. This is secondary to a highly evolved host defence mechanism that efficiently removes inhaled or aspirated pseudomonads. Many arms of the respiratory host defence have been elucidated using P. aeruginosa as a model pathogen. Human infections with P. aeruginosa have demonstrated the importance of the mechanical barrier functions including mucus clearance, and the innate immune system, including the critical role of the neutrophilic response. As more models of persistent or biofilm P. aeruginosa infections are developed, the role of the adaptive immune response will likely become more evident. Understanding the pathogenesis of P. aeruginosa, and the respiratory host defence response to it has, and will continue to, lead to novel therapeutic strategies to help patients. PMID- 20723141 TI - Obstructive sleep apnoea is associated with risk factors comprising the metabolic syndrome. AB - BACKGROUND AND OBJECTIVE: Several features of OSA syndrome suggest that it is a manifestation of the metabolic syndrome (MS). In this study, we investigated the prevalence of the MS among male Japanese patients with OSA, as well as the relationship between OSA in non-obese patients and components of the MS other than obesity (hypertension, dyslipidaemia and glucose intolerance). METHODS: The study included 416 Japanese men who were diagnosed as having OSA by polysomnography. Among these, 101 non-obese patients were selected and the severity of OSA, as well as the prevalence of hypertension, dyslipidaemia and glucose intolerance, was assessed. RESULTS: The MS was associated with OSA in 218/416 patients (52.4%). A significant increase in the prevalence of the MS was associated with increased severity of OSA, as categorized according to AHI. In the non-obese patients with OSA (mean age 57.6 years, BMI 22.7 kg/m(2), AHI 34.3 events/h), hypertension, dyslipidaemia and glucose intolerance were identified in 70 (69.3%), 43 (42.6%) and 20 patients (19.8%), respectively. At least two of these factors were identified in 40 patients (39.6%). Non-obese patients with severe OSA had a significantly higher prevalence of two or more of these factors (33/59 patients, 55.9%). CONCLUSIONS: Although Asians are generally less obese than Caucasians, the prevalence of the MS was high among Japanese patients with OSA, and even among non-obese patients, OSA was associated with risk factors for the MS. PMID- 20723142 TI - Chronic obstructive pulmonary disease in the absence of chronic bronchitis in China. AB - BACKGROUND AND OBJECTIVE: COPD has a variable natural history and not all individuals follow the same course. The aim of this study was to assess the prevalence of COPD in the absence of chronic bronchitis (CB) based on a population survey in China, and to identify the determinants of CB in patients with COPD. METHODS: A multi-stage cluster sampling strategy was used to survey a population from seven different provinces/cities of China. All residents over 40 years of age were interviewed using a standardized questionnaire and spirometry was measured. A post-bronchodilator FEV(1)/FVC < 70% was defined as the diagnostic criterion for COPD. All COPD patients who were screened were divided into two groups according to the presence or absence of CB. RESULTS: Of the population of 20,245 that was surveyed, 70% of the 1668 patients who were diagnosed with COPD reported no history of CB. The ages, BMI and comorbidities of COPD patients with or without CB were similar. Male gender, residence in a rural area, having a lower level of education, exposure to tobacco smoke or biomass fuels, poor ventilation in the kitchen and a family history of respiratory disease were all associated with a higher risk of COPD with CB. Patients without CB had less difficulty in walking and higher FEV(1)/FVC values than patients with CB, but were more likely to be underdiagnosed. The strongest predictors of CB were male gender, current smoking and severity of dyspnoea. CONCLUSIONS: This survey confirmed that there is a high prevalence of COPD in the absence of CB in China. It appears that CB is not essential to the diagnosis of COPD. PMID- 20723143 TI - Risk governance for mobile phones, power lines, and other EMF technologies. AB - Power-frequency electric and magnetic fields (EMFs) have been present in industrialized countries since the late 19th century and a considerable amount of knowledge has been accumulated as to potential health effects. The mainstream scientific view is that even if there is a risk, it is unlikely to be of major public-health significance. EMFs from cellular communications and other radio frequency technologies have increased rapidly in the last decade. This technology is constantly changing, which makes continued research both more urgent and more challenging. While there are no persuasive data suggesting a health risk, research and particularly exposure assessment is still immature. The principal risk-governance issue with power frequencies is how to respond to weak and uncertain scientific evidence that nonetheless causes public concern. For radio frequency electromagnetic fields, the issue is how to respond to large potential consequences and large public concern where only limited scientific evidence exists. We survey these issues and identify deficits in risk governance. Deficits in problem framing include both overstatement and understatement of the scientific evidence and of the consequences of taking protective measures, limited ability to detect early warnings of risk, and attempted reassurance that has sometimes been counterproductive. Other deficits relate to the limited public involvement mechanisms, and flaws in the identification and evaluation of tradeoffs in the selection of appropriate management strategies. We conclude that risk management of EMFs has certainly not been perfect, but for power frequencies it has evolved and now displays many successful features. Lessons from the power frequency experience can benefit risk governance of the radio-frequency EMFs and other emerging technologies. PMID- 20723144 TI - Prioritizing environmental health risks in the UAE. AB - This article presents the results of a comparative environmental risk-ranking exercise that was conducted in the United Arab Emirates (UAE) to inform a strategic planning process led by the Environment Agency-Abu Dhabi (EAD). It represents the first national-level application of a deliberative method for comparative risk ranking first published in this journal. The deliberative method involves a five-stage process that includes quantitative risk assessment by experts and deliberations by groups of stakeholders. The project reported in this article considered 14 categories of environmental risks to health identified through discussions with EAD staff: ambient and indoor air pollution; drinking water contamination; coastal water pollution; soil and groundwater contamination; contamination of fruits, vegetables, and seafood; ambient noise; stratospheric ozone depletion; electromagnetic fields from power lines; health impacts from climate change; and exposure to hazardous substances in industrial, construction, and agricultural work environments. Results from workshops involving 73 stakeholders who met in five separate groups to rank these risks individually and collaboratively indicated strong consensus that outdoor and indoor air pollution are the highest priorities in the UAE. Each of the five groups rated these as being among the highest risks. All groups rated soil and groundwater contamination as being among the lowest risks. In surveys administered after the ranking exercises, participants indicated that the results of the process represented their concerns and approved of using the ranking results to inform policy decisions. The results ultimately shaped a strategic plan that is now being implemented. PMID- 20723145 TI - Risk perception among smokers: a qualitative study. AB - The aim of this qualitative study is to identify the dimensions people used to assess the risk of smoking and then compare them with those used by health professionals in primary healthcare. Five discussion groups were conducted. The field work was carried out in Barcelona (Spain), from February 2005 to January 2006. Data were analyzed following a semantic-thematic categorical content analysis (ACC-ts). Results showed that people tend to employ stereotypical discourses when evaluating the risk of smoking. Similarly, they reassess the risk in the context of their life experience and incorporate new nuances to the arguments sustaining their behavior. Once this reassessment takes place, the decision to continue smoking emerges, and smokers come up with additional arguments justifying their habit (i.e., age, benefits related to costs). Professionals are aware of this process and its multidimensional nature. Nevertheless, their discourse loses this multidimensional feature when discussing the strategies they use at smoking cessation interventions. This qualitative study increases the understanding of various meanings that people attribute to their life experience. These assumptions may be useful for developing health practices that are closer to people. As a practical utility of these results, it would be interesting to apply a preliminary assessment of the different meanings that people attribute to smoking from their life context in risk communication. PMID- 20723146 TI - The effectiveness of risk management: an analysis of project risk planning across industries and countries. AB - This article examines the effectiveness of current risk management practices to reduce project risk using a multinational, multi-industry study across different scenarios and cultures. A survey was administered to 701 project managers, and their supervisors, in seven industries and three diverse countries (New Zealand, Israel, and Japan), in multiple languages during the 2002-2007 period. Results of this study show that project context--industry and country where a project is executed--significantly impacts perceived levels of project risk, and the intensity of risk management processes. Our findings also suggest that risk management moderates the relationship between risk level and project success. Specifically, we found that even moderate levels of risk management planning are sufficient to reduce the negative effect risk levels have on project success. PMID- 20723147 TI - Dose-response model of Coxiella burnetii (Q fever). AB - Q fever is a zoonotic disease caused by the intracellular gram-negative bacterium Coxiella burnetii (C. burnetii), which only multiplies within the phagolysosomal vacuoles. Q fever may manifest as acute or chronic disease. The acute form is generally not fatal and manifestes as self-controlled febrile illness. Chronic Q fever is usually characterized by endocarditis. Many animal models, including humans, have been studied for Q fever infection through various exposure routes. The studies considered different endpoints including death for animal models and clinical signs for human infection. In this article, animal experimental data available in the open literature were fit to suitable dose-response models using maximum likelihood estimation. Research results for tests of severe combined immunodeficient mice inoculated intraperitoneally (i.p.) with C. burnetii were best estimated with the Beta-Poisson dose-response model. Similar inoculation (i.p.) trial outcomes conducted on C57BL/6J mice were best fit by an exponential model, whereas those tests run on C57BL/10ScN mice were optimally represented by a Beta-Poisson dose-response model. PMID- 20723148 TI - A quality risk management model approach for cell therapy manufacturing. AB - International regulatory authorities view risk management as an essential production need for the development of innovative, somatic cell-based therapies in regenerative medicine. The available risk management guidelines, however, provide little guidance on specific risk analysis approaches and procedures applicable in clinical cell therapy manufacturing. This raises a number of problems. Cell manufacturing is a poorly automated process, prone to operator introduced variations, and affected by heterogeneity of the processed organs/tissues and lot-dependent variability of reagent (e.g., collagenase) efficiency. In this study, the principal challenges faced in a cell-based product manufacturing context (i.e., high dependence on human intervention and absence of reference standards for acceptable risk levels) are identified and addressed, and a risk management model approach applicable to manufacturing of cells for clinical use is described for the first time. The use of the heuristic and pseudo quantitative failure mode and effect analysis/failure mode and critical effect analysis risk analysis technique associated with direct estimation of severity, occurrence, and detection is, in this specific context, as effective as, but more efficient than, the analytic hierarchy process. Moreover, a severity/occurrence matrix and Pareto analysis can be successfully adopted to identify priority failure modes on which to act to mitigate risks. The application of this approach to clinical cell therapy manufacturing in regenerative medicine is also discussed. PMID- 20723149 TI - Variability and uncertainty in Swedish exposure factors for use in quantitative exposure assessments. AB - Information of exposure factors used in quantitative risk assessments has previously been compiled and reported for U.S. and European populations. However, due to the advancement of science and knowledge, these reports are in continuous need of updating with new data. Equally important is the change over time of many exposure factors related to both physiological characteristics and human behavior. Body weight, skin surface, time use, and dietary habits are some of the most obvious examples covered here. A wealth of data is available from literature not primarily gathered for the purpose of risk assessment. Here we review a number of key exposure factors and compare these factors between northern Europe- here represented by Sweden--and the United States. Many previous compilations of exposure factor data focus on interindividual variability and variability between sexes and age groups, while uncertainty is mainly dealt with in a qualitative way. In this article variability is assessed along with uncertainty. As estimates of central tendency and interindividual variability, mean, standard deviation, skewness, kurtosis, and multiple percentiles were calculated, while uncertainty was characterized using 95% confidence intervals for these parameters. The presented statistics are appropriate for use in deterministic analyses using point estimates for each input parameter as well as in probabilistic assessments. PMID- 20723150 TI - Incorporating equity in regulatory and benefit-cost analysis using risk-based preferences. AB - The analysis of federal regulations focuses on the analysis of economic efficiency through standard benefit-cost analysis in which reductions in risk tend to represent benefits and variability may be investigated through sensitivity or simulation methods. Such analyses typically ignore distributional consequences that can affect decisions. Although analytical guidance from the Office of Management and Budget (OMB) mentions distributional consequences, there is little specificity regarding how it might be analyzed. Specificity might be improved by OMB: (1) communicating and enforcing distributional impacts as more central to the process, (2) identifying default types of descriptive distributional statistics, (3) identifying whether legislation has created a constraint to not harm a subgroup, and (4) requesting a distributional sensitivity test of the net benefits along with a standard benefit-cost analysis. Although such actions have a data collection and analysis cost, they may make the results of regulatory analysis more relevant by investigating both efficiency and equity measures. PMID- 20723151 TI - Behavioral channels in the cross-market diffusion of major terrorism shocks. AB - The diffusion mechanism of terrorist shocks to third countries' stock market responses is explored by employing a Heckit model. Stock market response is broken down to (i) the direction of reaction and (ii) conditional on negative reaction, its magnitude. The analysis puts forward two behavioral factors (memory based utility/availability heuristic, social amplification of risk), proxied by past terrorism record and terrorism risk concern as the shocks' diffusion channels. The findings are that the likelihood and the size of negative stock market reaction increase with terrorism record and risk concern. Additionally, weak evidence is uncovered for a mitigation of risk concern's impact by favorable macroeconomic stance. Furthermore, the impact of behavioral factors, especially over the magnitude of reaction, is robust when controlling for economic linkages. The latter are also significant predictors of the direction of stock market reaction, but not of its magnitude. PMID- 20723152 TI - Nanotechnology, risk, and oversight: learning lessons from related emerging technologies. AB - Emerging technologies are defined by their novelty and thus are accompanied by significant uncertainty in determining appropriate ways to manage risks associated with them. Yet, there is a body of prior knowledge about risk management and oversight policy for other technologies that have already permeated society. Here, we describe two ways in which prospective oversight policy analysis for emerging technologies can draw upon these past experiences. One involves comparing specific products that have already been marketed to similar products of the emerging technology (cognate-product approach). The other treats the emerging technology as a body of products and methods and relates it to another technological field that has already emerged and penetrated markets (whole-technology approach). In this article, we describe our work using these approaches to inform risk and oversight policy for nanotechnology and its products. We draw parallels between biotechnology and nanotechnology as whole fields of development and also between genetically engineered organisms in the food supply and agricultural products of nanotechnology. Through these comparisons, we find that both approaches to historical learning have value and present lessons that could be applied to nanotechnology. PMID- 20723153 TI - Parents' experience of living with a baby with infantile colic--a phenomenological hermeneutic study. AB - BACKGROUND: About 10% of newborn babies have infantile colic which means that they cry more than 3 hours per day. The baby's crying risks disturbing the early parent-child interaction. OBJECTIVE: This study aimed to illuminate the meaning of being a parent of a baby with infantile colic. DESIGN: An inductive qualitative interview study. PARTICIPANTS AND SETTINGS: Twenty-three parents (12 mothers and 11 fathers) seeking help for infantile colic at a Child Health Clinic in south Sweden, having verified in a diary their babies' crying to more than 3 hours/day, were individually interviewed between March 2006 and April 2007. Parents were selected to ensure variation in age and gender and if they were first-time parents. METHOD: Parent's narratives were analysed using a phenomenological hermeneutic method. FINDINGS: The main theme found was 'Colic overshadows everything'. Tired and worried parents experienced living in an inferno. Both fathers and mothers suffered with their babies, felt powerless and overwhelmed by strong feelings and neglected their other needs. To get through this period, parents used various strategies to ease their baby's pain. Parents forced themselves not to lose control, to keep a stiff upper lip and generally to bear up. Sharing the burden was important. In spite of the suffering, they also felt hope, happiness and gratitude that they had a healthy baby. The results were reflected upon in relation to systems theory, attachment theory and a theory of interpersonal aspects of nursing. CONCLUSION: It is an important task for professionals to empower parents and help them to endure the colic period and to gain higher self-esteem as parents. By listening to the parents' stories they can better understand their situation, offer support and increase self-efficacy. PMID- 20723154 TI - Seeking a balance between employment and the care of an ageing parent. AB - RATIONALE: A growing number of middle-aged people are engaged in informal care of their parents while employed. To provide support as employers, co-workers or staff, health care professionals need insight into the experiences of people managing these responsibilities. AIM: To elucidate the experience of providing informal care to an ageing parent while managing the responsibilities of a working life. METHODS: Narrative interviews were performed with 11 persons with experience of the phenomenon. Transcribed interviews were analysed with phenomenological hermeneutics. ETHICS: Informed consent was given prior to the interviews. The study was approved by a research ethics committee. FINDINGS: Providing informal care to an ageing parent while also pursuing a working life implies seeking balance: a balance between providing support to the parent's needs and one's responsibilities at work. Being employed supports this balance as it provides both fulfilment and refuge. Being capable of managing both roles grants a sense of satisfaction, supporting one's sense of balance in life. The balance can be supported by sharing the responsibility of caring for the ageing parent with others. STUDY LIMITATIONS: Despite perceived saturation and an effort to provide for the possibility to consider internal consistency, the findings should be considered as a contribution to the understanding of the phenomenon, as experienced by individuals in their life world. CONCLUSIONS: It is essential to recognise the impact that providing care for an ageing parent may have on the lives of a growing number of people, particularly if they have employment responsibilities. Acknowledgement by others supports one's ability to attain balance; as co-workers and managers, we can acknowledge the efforts of an informal caregiver and as health care staff recognise the valuable contribution made by people in mid-life who provide informal care for their ageing parents. PMID- 20723155 TI - Psychosocial child adjustment and family functioning in families reached with an assertive outreach intervention. AB - Families who experience a chronic complex of socio-economic and psychosocial problems are hard to reach with mainstream care. Evidence exists that the core of this problem is a problematic interaction between this type of family and current systems of care and services. To improve access to problem families, an assertive outreach intervention was implemented into the field of preventive child health care, The Netherlands. The study aimed to provide a more detailed insight into characteristics of the target group. Although there is consensus about some general features of hard to reach problem families, little is known about their specific characteristics because empirical studies among this group are rarely conducted. Especially, the problems of the children is shed insufficient light on. The studied population consisted of families included in the assertive outreach intervention delivered during one year (N=116). To assess psychosocial adjustment of the children, the Strengths and Difficulties Questionnaire was filled in by the parents. Furthermore, a Dutch questionnaire on family functioning was completed by professional carers. Descriptive data were calculated. The findings show that by using the assertive outreach intervention, programme staff came into contact with families characterised by a considerably higher than average proportion of single parents and unemployed households receiving social benefits. The families faced a high level of risk and a wide range of severe and multiple difficulties, including a lack of basic child care, an inadequate social network and poor parenting. Children in these families were also facing a number of risks. The proportion of psychosocial problems was well above the (inter)national average. The findings reveal the problem areas of unreached families and a need to improve the access to care for these families. PMID- 20723156 TI - Retrograde occlusive arteriography of hemodialysis access: failure to detect inflow lesions? AB - Once thought to be a minor player in hemodialysis (HD) access dysfunction relative to outflow stenosis, inflow stenosis has recently come to be viewed as a major cause of access failure. Indeed, recent literature has shown that up to 40% of all accesses referred for dysfunction have an inflow lesion. Imaging of the inflow segment has been traditionally performed by interventional nephrologists via retrograde occlusive arteriography (ROA). Recent advances in our understanding of ROA have cast the technique in a negative light, with the possibility of vascular complications and poor diagnostic yield coming to the fore. Using a prospectively collected, vascular access database, we identified 18 consecutive patients who received imaging of inflow lesions by ROA and direct arteriogram (DA). The mean percent luminal stenoses were found to be 59.89 +/- 24 and 79.06 +/- 17.8 (p = 0.009) for the ROA vs. DA groups, respectively. Using multiple regression analysis, DA was found to be associated with detecting higher degree of luminal stenosis (beta = 19.17, 95% CI 6.28-32.05, p = 0.006). This small case series provides evidence on the theoretical concern that ROA does not adequately evaluate inflow lesions. We may conclude that by relying solely on ROA, interventional nephrologists may be failing to detect a subset of hemodynamically significant inflow lesions. PMID- 20723157 TI - Comparison of radiocephalic fistulas placed in the proximal forearm and in the wrist. AB - Non-maturation is a common problem in patients receiving an arteriovenous fistula. The first vascular access choice is a distal radiocephalic fistula (dRCF) at the wrist. Patients with a failed dRCF or with vessels unsuitable for dRCF, the recommendation is to place a brachiocephalic fistula in the upper arm. Proximal forearm radiocephalic fistulas (pRCF) are created infrequently, but may permit a second forearm fistula before proceeding to the upper arm. The goal of the present study was to compare the outcomes of them. We retrospectively analyzed a computerized access database to compare the outcomes of 19 RCF and 39 dRCF placed during a 6-month period. The baseline characteristics were similar, except those with a pRCF were more likely to have previous access and be male. Primary failure (non-maturation) was lower for pRCF than dRCF (32 vs. 59%, p = 0.05); and excluding secondary failures, cumulative fistula survival was similar (92 vs. 86% at 1 year and 74 vs. 76% at 2 years, p = 0.56). pRCF may be an attractive alternative to a brachiocephalic fistula in patients who cannot receive a dRCF. pRCF has a lower non-maturation rate than that of a dRCF, and a comparable cumulative survival once it is used successfully for dialysis. PMID- 20723158 TI - Predictive factors associated with left ventricular hypertrophy at baseline and in the follow-up period in non-diabetic hemodialysis patients. AB - Hemodialysis (HD) patients frequently have an elevated left ventricular mass index (LVMI). Currently, left ventricular (LV) hypertrophy and dysfunction are considered to be the strongest predictors of cardiovascular mortality in dialysis patients. The objectives of the present study are to investigate the factors associated with elevated LVMI and to discuss therapeutic implications for the treatment strategy for pre-dialysis and HD patients. The correlation among biochemical values, physical specimens, and LVMI using echocardiography was prospectively analyzed in 30 non-diabetic HD patients in the Juntendo University Hospital. Measurement of these parameters was performed at 0, 12, and 24 months after initiation of HD. Systolic blood pressure (SP), human atrial natriuretic peptide (hANP), and hemoglobin (Hb) levels were significantly correlated with LVMI. SBP, residual glomerular filtration rate (rGFR), and serum albumin levels were identified as independent risk factors for LVMI in multivariate regression analysis at initiation of HD. SBP, hANP, and Hb levels were identified as independent risk factors for LVMI in multivariate regression analysis after 24 months. SBP, rGFR, and serum albumin levels were predictive factors for LVMI at initiation of HD. SBP, hANP, and Hb levels were also predictive factors for LVMI after initiation of HD. PMID- 20723159 TI - Stent graft infection and protrusion through the skin: clinical considerations and potential medico-legal ramifications. AB - Stent grafts have been used for a variety of arteriovenous access associated issues. This article presents three cases of stent graft infection and a case of protruded metal piece of the stent graft through the skin. All four required surgical treatment and three cases required a tunneled dialysis catheter to provide long-term dialysis therapy. This report highlights that stent graft problems can occur that may result in loss of the access. Additionally, strut protrusion can pose a medical hazard to those performing preparation and cannulation of the arteriovenous access. PMID- 20723160 TI - Automated intravascular access pressure surveillance reduces thrombosis rates. AB - Although monitoring of vascular accesses by physical examination is nearly as sensitive as surveillance measurements by vascular access pressure when performed by examiners, the frequency of examinations is limited by time. We developed intravascular access pressure surveillance as a surrogate to physical examination. Using real-time data from hemodialysis machines, we derived intravascular access pressure ratios for each dialytic procedure. An automated, noninvasive surveillance algorithm that generated a "warning" list of patients at risk for thrombosis was formulated. We hypothesized that this algorithm would reduce access thrombosis frequency. We designed a study comparing thrombosis rates during a baseline 6-month interval to three subsequent 6-month periods of active surveillance. Referrals for interventions during this 18-month period were based on persistently abnormal elevated vascular access pressure ratio tests (VAPRT) >0.55. Thrombosis rates declined progressively for arteriovenous grafts (AVG) during the intervention period compared with the baseline period. Arteriovenous fistula (AVF) thrombosis rates decreased during postintervention months 13-18 during employment of the VAPRT. We conclude that use of VAPRT can reduce thrombosis rates in vascular accesses, and the magnitude of the effect is larger and more consistent in arteriovenous grafts (AVGs) than autologous AVFs. PMID- 20723162 TI - Coxiella burnetii Infections in domestic ruminants in Canary Islands (Spain). PMID- 20723161 TI - Serological evidence of foot-and-mouth disease virus infection in randomly surveyed goat population of Orissa, India. AB - India is endemic for foot-and-mouth disease (FMD), and goats constitute the second largest susceptible population of domestic livestock. FMD surveillance and control strategies in the country largely ignore small ruminants, known to be critical in the epidemiology of the disease. Here, serological investigations were carried out to generate estimates of antibody prevalence in goats of Orissa state to both non-structural (NSP-Ab) and structural proteins (SP-Ab) of FMD. The apparent overall NSP-Ab and SP-Ab seroprevalences were 38% and 20.7%, respectively, which signifies a very high level of FMD virus circulation in the goat population despite the lack of clinical signs in this species. The apparent prevalence of NSP-Ab and SP-Ab was positively correlated in the sampling areas. Interestingly, the values found for NSP-Ab prevalence were almost consistently higher than those found for SP-Ab prevalence. This could have been attributable to either issues related to sensitivity and specificity of the test systems employed or differences in the post-infection kinetics of NSP- and SP-Ab. The pattern that emerged from SP-Ab analysis indicated goats being infected with all three prevalent serotypes (O, A and Asia 1) and reinforces the concept that non vaccinated goats can be exploited as tracer animals for detecting serotypes involved in outbreaks. The results underscore the requirement to bring caprine species under comprehensive surveillance and vaccination campaigns to check silent amplification, excretion and transmission of the virus. PMID- 20723163 TI - Application of semi-quantitative M gene-based hydrolysis probe (TaqMan) real-time RT-PCR assay for the detection of peste des petits ruminants virus in the clinical samples for investigation into clinical prevalence of disease. AB - Peste des petits ruminants (PPR) is a contagious, notifiable and economically important transboundary viral disease of small ruminants. In this study, a hydrolysis probe-based real-time reverse transcription-polymerase chain reaction (rt RT-PCR) assay for the detection and semi-quantification of PPR virus (PPRV) nucleic acid was developed using the virus RNA and matrix (M) gene-specific primers with Hex-labelled fluorescent probe and applied for the detection of PPRV in clinical samples to identify outbreaks and to monitor the prevalence of disease. The assay was found specific with a sensitivity detection limit of 0.5 pg of total PPRV RNA. Based on a serial dilution of the live-attenuated PPR vaccine virus, the detection limits were approximately 0.1 and 1 TCID50 for the hydrolysis probe and conventional RT-PCR assays, respectively. The assay was linear within a range of 50 ng to 0.5 pg total virus RNA with an intra-assay coefficient of variation (CV) in the range of 0.91-2.86% and an inter-assay CV ranging between 0.59% and 2.37%. The standardized rt RT-PCR was easily employed for the detection of PPRV nucleic acid directly in the experimental/field clinical samples. This assay detected the PPRV in pre-clinical swab materials as early as the 4th day post-infection (dpi) and up to 17th dpi in nasal, ocular and oral swabs collected from experimentally infected animals. The rt RT-PCR was rapid, specific and 10 times more sensitive than conventional RT-PCR. It is an alternative test to the existing diagnostic assays and could be useful with enhanced applicability in field clinical diagnosis by avoiding the use of expensive commercial real-time PCR reagents. This assay was adopted directly in the detection of PPRV nucleic acid in clinical samples collected from sheep and goats suspected of PPR to monitor outbreak situations and the clinical prevalence of PPR in India. PMID- 20723164 TI - An epidemiological analysis of the foot-and-mouth disease epidemic in Miyazaki, Japan, 2010. AB - An epidemic of foot-and-mouth disease occurred in Miyazaki, Japan, beginning in late March 2010. Here, we document the descriptive epidemiological features and investigate the between-farm transmission dynamics. As of 10 July 2010, a total of 292 infected premises have been confirmed with a cumulative incidence for cattle and pig herds of 8.5% and 36.4%, respectively, for the whole of Miyazaki prefecture. Pig herds were more likely to be infected than cattle herds (odds ratio = 4.3 [95% confidence interval (CI): 3.2, 5.7]). Modelling analysis suggested that the relative susceptibility of a cattle herd is 4.2 times greater than a typical pig herd (95% CI: 3.9, 4.5), while the relative infectiousness of a pig herd is estimated to be 8.0 times higher than a cattle herd (95% CI: 5.0, 13.6). The epidemic peak occurred around mid-May, after which the incidence started to decline and the effective reproduction numbers from late May were mostly less than unity, although a vaccination programme in late May could have masked symptoms in infected animals. The infected premises were geographically confined to limited areas in Miyazaki, but sporadic long-distance transmissions were seen within the prefecture. Given that multiple outbreaks in Far East Asian countries have occurred since early 2010, continued monitoring and surveillance is deemed essential. PMID- 20723165 TI - Weak D and DEL alleles detected by routine SNaPshot genotyping: identification of four novel RHD alleles. AB - BACKGROUND: Molecular RHD blood group typing is very efficient for managing donors and patients carrying any of the various molecular types of weak D and DEL. The purpose of the work was to develop a multiplex polymerase chain reaction (PCR) SNaPshot assay for simultaneous detection of weak D and DEL alleles that are prevalent in Europeans, Africans, and Asians. STUDY DESIGN AND METHODS: Preliminary profiling was carried out on single-nucleotide polymorphisms (SNPs) associated with 13 prevalent RHD alleles, that is, weak D Types 1, 2, 3, 4.0, 4.0.1, 4.1, 4.2, 5, 11, 15, and 17; RHD(IVS3+1g>a); and RHD(K409K). Multiplex PCR was used to amplify six RHD regions encompassing 14 SNPs. Identification was obtained by incorporation of the complementary dye single base at the 3'-end of each probe-primer. A prospective analysis was then carried out on 152 blood samples from patients (n = 53) and donors (n = 88) with equivocal RhD serology and pregnant women (n = 11). RESULTS: After validation, our SNaPshot assay allowed direct genotyping of 82.9% of samples overall and 100% of samples harboring weak D Types 1, 2, 3, and 4.1 alleles. In the remaining 17.1% of samples overall, sequence investigation allowed accurate genotyping. In addition, four novel RHD alleles were identified, that is, RHD(S256P), RHD(L390L), RHD(F410V), and RHD(IVS4-2a>g). CONCLUSION: The SNaPshot assay described herein is a helpful supplementary tool for resolving doubtful RhD serology. By allowing accurate identification of weak D and DEL alleles this assay should allow better management of the donors and the patients genotyped weak D Types 1, 2, 3, and 4.1 who can receive D+ blood units. PMID- 20723166 TI - Postponing or eliminating red blood cell transfusions of very low birth weight neonates by obtaining all baseline laboratory blood tests from otherwise discarded fetal blood in the placenta. AB - BACKGROUND: Safely reducing the proportion of very low birth weight neonates (<1500 g) that receive a red blood cell (RBC) transfusion would be an advance in transfusion practice. STUDY DESIGN AND METHODS: We performed a prospective, single-centered, case-control, feasibility analysis, preparatory to designing a definitive trial. Specifically, we sought to determine whether we could obtain all baseline neonatal intensive care unit blood tests from the placenta, after placental delivery, thereby initially drawing no blood from the neonate. RESULTS: Ten cases where all baseline blood tests were drawn from the placenta, and 10 controls where all tests were drawn from the neonate, were closely matched for birth weight, gestational age, sex, and race. Early cord clamping was used for all 20. Over the first 18 hours the hemoglobin increased in nine cases versus two controls (p = 0.005). During the first 72 hours one case versus five controls qualified for and received an RBC transfusion. In the first week the cases received four transfusions and the controls received 16 (p = 0.02). None of the cases had an intraventricular hemorrhage (IVH) but four of the controls had a Grade 1 and two had a Grade 3 (p = 0.01). CONCLUSION: We speculate that this method is feasible and generally postpones the first RBC transfusion until beyond the period of peak vulnerability to IVH. PMID- 20723167 TI - Factors affecting banking quality of umbilical cord blood for transplantation. AB - BACKGROUND: The most important objective for cord blood banks is to store cord blood units of high quality, which is determined by total nucleated cells (TNCs) and CD34+ cells. Determining the factors affecting the stored life-saving cells would be beneficial to the field. STUDY DESIGN AND METHODS: A total of 4930 cord blood units were collected between January 2007 and October 2009 and processed using a double extraction technique to sediment red blood cells with variable centrifugation time determined by the formula CT = KL - M, where CT is centrifuge time, K is 7.7227, M is 29.742, and L is ln (volume of cord blood with anticoagulant). The recovery rate of TNCs and other relevant factors affecting banking quality were analyzed. RESULTS: The mean recovery rate of TNCs was 97.7 +/- 2.5% with 0.04% (2/4930) units below 80% and 10.8% (532/4930) units below 95%. The TNCs per unit was affected by gestation duration (p < 0.01), sex of infant (p < 0.01), mode of delivery (p < 0.01), collection method (p < 0.01), and ethnicity (p < 0.001). The number of postprocessing CD34+ cells was affected only by sex of the infant (p < 0.05). The viability of nucleated cells after processing was 94.8 +/- 4.8% and was affected by the number of hours between collection and processing (p < 0.01). In contrast, the viability of CD34+ cells was 99.5 +/- 1.0% (n = 30) when samples with low viability of TNCs were assessed. The results did not reveal a significant correlation (r = 0.07, p = 0.38). CONCLUSION: The double extraction technique provides a high and consistent recovery of TNCs, which ensures that more life-saving cells will be banked for transplants. PMID- 20723168 TI - Implementing a program to improve compliance with neonatal intensive care unit transfusion guidelines was accompanied by a reduction in transfusion rate: a pre post analysis within a multihospital health care system. AB - BACKGROUND: We previously reported that in the year 2006, approximately 35% of the transfusions administered in the Intermountain Healthcare neonatal intensive care units (NICU) were noncompliant with our transfusion guidelines. In January 2009 we instituted an electronic NICU transfusion ordering and monitoring system as part of a new program to improve compliance with transfusion guidelines. STUDY DESIGN AND METHODS: In the four largest NICUs of Intermountain Healthcare, we performed a pre-post analysis of compliance with transfusion guidelines and transfusion usage. RESULTS: After beginning the new transfusion compliance program all four NICUs had an increase in compliance from 65% to 90%. Accompanying the improved compliance, all four NICUs had a reduction in transfusions administered. Specifically, compared with 2007 and 2008, there were 984 fewer NICU transfusions given in 2009. This included 554 fewer red blood cell (RBC) transfusions, 174 fewer platelet transfusions, and 256 fewer frozen plasma infusions. We calculate that in 2009, a total of 200 NICU patients who in previous years would have received one or more transfusions instead received none. Applying specific Intermountain Healthcare billing data to the observed transfusion reductions, this new program resulted in an annual decrease of $780,074 in blood bank charges (blood administration charges were not included). During the 3-year period, January 2007 through December 2009, we detected no change in NICU demographics, major morbidities, length of hospital stay, or mortality rate. CONCLUSION: Implementing a systemwide NICU program to improve compliance with already-established transfusion guidelines increased compliance from 65% to 90%. Improved compliance with transfusion guidelines was accompanied by a significant reduction in transfusions given, with no increase in NICU length of stay or mortality rate. PMID- 20723169 TI - Hemostatic function of buffy coat platelets in additive solution treated with pathogen reduction technology. AB - BACKGROUND: Pathogen reduction technologies (PRTs) may influence the hemostatic potential of stored platelet (PLT) concentrates. To investigate this, buffy coat PLTs (BCPs) stored in PLT additive solution (SSP+) with or without Mirasol PRT treatment (CaridianBCT Biotechnologies) were compared by functional hemostatic assays. STUDY DESIGN AND METHODS: We performed in vitro comparison of PRT (PRT BCP) and control pooled-and-split BCPs (CON-BCP) after 2, 3, 6, 7, and 8 days' storage. Hemostatic function was evaluated with thrombelastography (TEG) and impedance aggregometry (Multiplate), the latter also in a sample matrix (Day 2) with or without addition of red blood cells (RBCs), control plasma, and/or PRT treated plasma. RESULTS: PRT treatment of 8-day-stored BCPs influenced clot formation (TEG) minimally, with reductions in maximum clot strength (maximum amplitude, p = 0.014) but unchanged initial fibrin formation (R), clot growth rate (alpha), and fibrinolysis resistance. In the absence of RBCs and plasma, PRT impaired aggregation (Multiplate) in stored BCPs, with reduced aggregation against thrombin receptor activating peptide-6 (p < 0.001), collagen (p = 0.014), adenosine 5'-diphosphate (p = 0.007), and arachidonic acid (p = 0.070). Addition of RBCs and PRT-treated or untreated plasma to PRT-BCP and CON-BCP, respectively, enhanced aggregation in both groups. CONCLUSIONS: Mirasol PRT treatment of BCPs had a minimal influence on clot formation, whereas aggregation in the absence of RBCs and plasma was significantly reduced. Addition of RBCs and plasma increased agonist-induced responses resulting in comparable aggregation between PRT-BCP and CON-BCP. The clinical relevance for PLT function in vivo of these findings will be investigated in a clinical trial. PMID- 20723171 TI - Novel test for microparticles in platelet-rich plasma and platelet concentrates using dynamic light scattering. AB - BACKGROUND: The level and clinical importance of platelet (PLT)-derived microparticles (PMPs) in PLT-rich plasma (PRP) and PLT transfusions is largely unknown due to the lack of technology to routinely determine the number and size of PMP in PLT samples. Dynamic light scattering (DLS) is ideally suited to measure particles of submicron size but has previously been limited to the analysis of PLT-free samples. STUDY DESIGN AND METHODS: PMPs were enumerated in 81 PRP and 79 apheresis PLT concentrate (APC) samples from the same donors using ThromboLUX (LightIntegra Technology, Inc.), a new DLS PLT quality test. The ThromboLUX results were compared with flow cytometry. Phase contrast and differential interference contrast (DIC) microscopy were used to qualitatively determine PMP levels. RESULTS: The relative counts of PMPs measured by flow cytometry strongly correlated with the relative light scattering intensities of the PMP determined by ThromboLUX in both PRP (R = 0.7596, p < 0.0001) and APC (R = 0.6572, p < 0.0001) samples. High or low PMP levels in PLT samples were confirmed by phase contrast and DIC microscopy. The mean PMP radius measured with ThromboLUX, an absolute sizing technology, was 117.1 +/- 77.6 nm as determined from the distribution of PMP content in all PLT samples investigated in this study. CONCLUSIONS: Correlation with flow cytometry and microscopy showed that ThromboLUX is well suited to measure PMP concentration and size distribution in PLT concentrate samples. In combination with noninvasive sampling, ThromboLUX could provide routine microparticle enumeration of PLT-containing samples. PMID- 20723170 TI - Granulocyte-colony-stimulatory factor: a strong inhibitor of natural killer cell function. AB - BACKGROUND: The human cytokine granulocyte-colony stimulatory factor (G-CSF) has found widespread application in the medical treatment of neutropenia and to mobilize hematopoietic stem cells used for transplantation. So far, the effect of G-CSF on natural killer (NK) cells has not been fully investigated. STUDY DESIGN AND METHODS: The effect of G-CSF on the phenotype, cytokine secretion profile, and cytotoxicity of NK cells was assessed. NK cells incubated in vitro in presence of G-CSF for 48 hours as well as NK cells isolated from peripheral blood of G-CSF-mobilized stem cell donors (in vivo) were used. RESULTS: In vitro, G-CSF caused a strongly altered phenotype in NK cells with 49% down regulation of NKp44 frequency. Furthermore, the expression of the activating receptors NKp46 and NKG2D decreased 40 and 64%, respectively. The expression of KIR2DL1 and KIR2DL2 decreased by 46% each. In cytotoxicity assays, the lytic capacity of G-CSF exposed NK cells is reduced by up to 68% in vitro and up to 83% in vivo. Accordingly, granzyme B levels of in vivo G-CSF-exposed NK cells were reduced by up to 87% in comparison to nonstimulated NK cells. Cytokine production of in vitro and in vivo incubated NK cells was strongly decreased for interferon-gamma, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor as well as interleukin (IL)-6 and IL-8. Furthermore, we observed a reduction in proliferation and a positive feedback loop that increased the expression of the G CSF receptor. CONCLUSION: G-CSF was demonstrated to be a strong inhibitor of NK cells activity and may prevent their graft-versus-leukemia effect after transplantation. PMID- 20723172 TI - Falsification or paradigm shift? Toward a revision of the common sense of transfusion. PMID- 20723173 TI - Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients. AB - BACKGROUND: Transfusion-associated circulatory overload (TACO) is a frequent complication of blood transfusion. Investigations identifying risk factors for TACO in critically ill patients are lacking. STUDY DESIGN AND METHODS: We performed a 2-year prospective cohort study of consecutive patients receiving blood product transfusion in the medical intensive care unit (ICU) of the tertiary care institution. Patients were followed for development of transfusion related complications. TACO was defined as acute hydrostatic pulmonary edema occurring within 6 hours of transfusion. In a nested case-control design, transfusion characteristics were compared between cases (TACO) and controls after matching by age, sex, and ICU admission diagnostic category. In a secondary analysis, patient characteristics before transfusion were compared between cases (TACO) and randomly selected controls. RESULTS: Fifty-one of 901 (6%) transfused patients developed TACO. Compared with matched controls, TACO cases had a more positive fluid balance (1.4 L vs. 0.8 L, p = 0.003), larger amount of plasma transfused (0.4 L vs. 0.07 L, p = 0.007), and faster rate of blood component transfusion (225 mL/hr vs. 168 mL/hr, p = 0.031). In a secondary analysis comparing TACO cases and random controls, left ventricular dysfunction before transfusion (odds ratio [OR], 8.23; 95% confidence interval [CI], 3.36-21.97) and plasma ordered for the reversal of anticoagulant (OR, 4.31; 95% CI, 1.45-14.30) were significantly related to the development of TACO. CONCLUSION: Volume of transfused plasma and the rate of transfusion were identified as transfusion specific risk factors for TACO. Left ventricular dysfunction and fresh-frozen plasma ordered for the reversal of anticoagulant were strong predictors of TACO before the onset of transfusion. PMID- 20723174 TI - A new Ser472Asn (Cab2(a+)) polymorphism localized within the alphaIIb "thigh" domain is involved in neonatal thrombocytopenia. AB - BACKGROUND: A new platelet antigen, Cab2(a+), was identified in a case of severe neonatal alloimmune thrombocytopenia (<8 * 10(9)/L) in twins. STUDY DESIGN AND METHODS: Coding sequences of alphaIIb and beta3 genes from parents were amplified and sequenced. CHO cell lines expressing wild-type or mutated forms of the complex were established to study the role of the mutation in alloimmunization and in alphaIIbbeta3 functions. RESULTS: The father and twins were heterozygous for a single alphaIIb c.1508G>A mutation leading to a Ser472Asn substitution. Immunologic assays with transfected CHO cells revealed the Asn472 form of alphaIIbbeta3 responsible for the Cab2(a+) epitope but not an Ala472 form. Using these cells lines we demonstrated that both Ser472Asn and Ser472Ala substitutions produced limited structural alteration as revealed by the reactivity of a panel of anti-alphaIIbbeta3 monoclonal antibodies (MoAbs). Activated Asn472 and Ala472 forms of alphaIIbbeta3 supported 1) binding of soluble fibrinogen and of the ligand mimetic MoAb PAC-1, 2) ligand-induced binding site epitopes exposure (MoAbs AP-5 and D3GP3), and 3) cell aggregation. Adhesion onto adsorbed fibrinogen was conserved and was specifically inhibited by MoAb AP-2 or peptide RGDS. Finally outside-in signaling was not affected. CONCLUSION: We have characterized a new low-frequency alloantigen (<1%) resulting from the Ser472Asn substitution in alphaIIb and shown this polymorphism to have a limited effect, if any, on the alphaIIbbeta3 complex functions. PMID- 20723175 TI - Initiation of a screening protocol for polyoma virus results in a decreased rate of opportunistic non-BK viral disease after renal transplantation. AB - BACKGROUND: Polyoma BK virus nephropathy (PVN) is a leading cause of renal allograft injury and loss. The mainstay of treatment, as there are no target therapies approved by the US Food & Drug Administration, is reduction in immunosuppression. However, current approaches are shifting to screening for viremia as an indicator of oncoming nephropathy, with subsequent reduction in immunotherapy. We attempted not only to replicate these data but also to evaluate the utility of polyoma viremia as a surrogate marker for overimmunosuppression in general, thus allowing prevention not only of PVN but also of other viral opportunistic infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) disease. PATIENTS AND METHODS: We conducted a retrospective cohort analysis of renal transplant recipients at our center. The historical controls (2003-2005, n = 134) had received their allograft before the institution of a monthly serum polymerase chain reaction (PCR) polyoma screening protocol. The screened cohort received their allograft afterwards (2006-2008, n=134). Screening was performed using PCR techniques with prompt reduction in immunosuppression for viremic patients. The patients were followed for the development of PVN, acute rejection, renal allograft function, and survival. RESULTS: Polyoma viremia was noted in 16% of the screened population, with none developing PVN after prompt reduction of immunosuppression. Clearance of the viremia occurred by 6 months in 95% of the patients after reduction of immunotherapy. No patient in the screened group developed CMV or EBV disease. Of the controls, 7 (5%) developed PVN and 12 (9%) developed CMV or EBV disease, compared with none of the screened patients (P<0.05). The incidence of acute rejection was comparable between the groups (4% controls, 5% screened). No deleterious effects were noted on patient or allograft survival, allograft function (measured by serum creatinine), rates of fungal infection, or the rate of post-transplant lymphoproliferative disorder in the screened patients. CONCLUSIONS: Monthly PCR monitoring for BK viremia, together with a modest decrease in immunotherapy, is not only safe but also effectively prevents PVN and is associated with a significantly decreased rate of CMV and EBV disease in renal transplant patients. BK viremia may also serve as a surrogate marker for overimmunosuppression. PMID- 20723176 TI - Surfactant alterations following donation after cardiac death donor lungs. AB - The use of lungs from donation after cardiac death (DCD) donors is one of the strategies to increase the donor pool. The aim of this study was to assess the surfactant alterations in DCD donor lungs. Pigs were sacrificed and left untouched for 1 (DCD1), 2 (DCD2) and 3 (DCD3) h. Lungs were then topically cooled with saline for 1, 2 or 3 h to reach a total ischemic time of 4 h. Heart-beating donors (HBD) served as control group. Bronchoalveolar lavage (BAL) samples were assessed for protein levels and surfactant function. Left lungs were prepared for ex-vivo evaluation. Pulmonary vascular resistance (PVR), oxygenation, airway pressure (AWP) and wet-to-dry weight ratio were significantly different between HBD and DCD3 groups (P < 0.05). BAL protein levels were statistically higher in DCD3 compared with HBD group (P < 0.05). Surface tension and surface tension measured at minimal bubble diameter (adsorption) were lower in HBD compared with DCD groups (P < 0.05). Adsorption was also lower in DCD1 compared with DCD2 (P < 0.05). Adsorption and surface tension were correlated with oxygenation and AWP (P < 0.05). This study has shown that lung function deteriorates with increasing warm ischemic time intervals. BAL protein, surface tension, adsorption, peak AWP and PVR increase significantly after 2 h of warm ischemia together with a significant reduction of the ratio PaO(2)/FiO(2). PMID- 20723177 TI - Ventricular arrhythmia in incident kidney transplant recipients: prevalence and associated factors. AB - Cardiovascular mortality in kidney transplant recipients has shown to be substantially elevated particularly in the first year of transplantation. Complex ventricular arrhythmia (VA) has been pointed as one of the etiologies of sudden death. The aim of this study was to evaluate the prevalence of VA and to investigate the factors associated with their occurrence in incident kidney transplant recipients. A total of 100 incident kidney transplant recipients were included in the study (39.7 +/- 10.1 years, 55% male, 43.6 +/- 10.1 days of transplantation, 66% living donors). All the patients underwent 24 h electrocardiogram, echocardiogram and multi-slice computed tomography. Thirty percent of the patients had VA. Left ventricular hypertrophy was observed in 57% of the patients while heart failure was found in 5%. Coronary artery calcification (CAC) was observed in 26 patients, from which 31% had severe calcification. The group of patients with VA was predominantly male, had been on dialysis therapy for a longer time and had more coronary calcification. In the multiple logistic regression analysis, male gender and CAC score were independently associated with the presence of VA. In conclusion, kidney transplant recipients exhibited a high prevalence of VA and the factors associated with its occurrence were the male gender and the presence of CAC. PMID- 20723178 TI - Comparison of surgical methods in liver transplantation: retrohepatic caval resection with venovenous bypass (VVB) versus piggyback (PB) with VVB versus PB without VVB. AB - Use of piggyback technique (PB) and elimination of venovenous bypass (VVB) have been advocated in adult liver transplantation (LT). However, individual contribution of these two modifications on clinical outcomes has not been fully investigated. We performed a retrospective review of 426 LTs within a 3-year period, when three different surgical techniques were employed per the surgeons' preference: retrohepatic caval resection with VVB (RCR+VVB) in 104 patients, PB with VVB (PB+VVB) in 148, and PB without VVB (PB-Only) in 174. The primary outcomes were intraoperative blood transfusion and the patient and graft survivals. Demographic profiles were similar, except younger recipient age in RCR+VVB and fewer number of grafts with cold ischemic time over 16 h in PB-Only. PB-Only required lesser intraoperative red blood cells (P=0.006), fresh frozen plasma (P=0.005), and cell saver return (P=0.007); had less incidence of acute renal failure (P=0.001), better patient survival (P=0.039), and graft survival (P=0.003). The benefits of PB+VVB were only found in shortened total surgical time (P=0.0001) and warm ischemic time (P=0.0001), and less incidence of acute renal failure (P=0.001) than RCR+VVB. PB-Only method seemed to provide the best clinical outcome. The benefit of PB was not fully achieved when it was used with VVB. PMID- 20723179 TI - Current views on rejection pathology in liver transplantation. AB - Histological assessments continue to play an important role in the diagnosis and management of liver allograft rejection. The changes occurring in acute and chronic rejection are well recognized and liver biopsy remains the 'gold standard' for diagnosing these two conditions. Recent interest has focused on the diagnosis of late cellular rejection, which may have different histological appearances to early acute rejection and instead has features that overlap with so-called 'de novo autoimmune hepatitis' and 'idiopathic post-transplant chronic hepatitis'. There is increasing evidence to suggest that 'central perivenulitis' may be an important manifestation of late rejection, although other causes of centrilobular necro-inflammation need to be considered in the differential diagnosis. There are also important areas of overlap between rejection and recurrent hepatitis C infection and the distinction between these two conditions continues to be a problem in the assessment of liver allograft biopsies. Studies using immunohistochemical staining for C4d as a marker for antibody-mediated damage have found evidence of C4d deposition in liver allograft rejection, but the functional significance of these observations is currently uncertain. This review will focus on these difficult and controversial areas in the pathology of rejection, documenting what is currently known and identifying areas where further clarification is required. PMID- 20723180 TI - One- and five-year follow-ups on blood pressure and renal function in kidney donors. AB - It is considered safe to donate a kidney if internationally accepted medical criteria are fulfilled. However, some donors have encountered hypertension, proteinuria and impaired renal function after donation. The study was based on retrospective data on 908 donors, donating in the period 1997-2007. Preoperative and follow-up data were collected from patient files and the Norwegian Living Donor Registry. Follow-up data were available for 665 donors at 1 year after donation, and 256 donors at 5 years after donation. We calculated the estimated glomerular filtration rate (eGFR) using the four variable Modification of Diet in Renal Disease equation. At 1 and 5 years after donation, the prevalence of hypertension was 11.7% and 27.1% respectively compared to 2.6% before donation. Proteinuria was present in 3.3% and 1.6% at 1 and 5 years. Mean eGFR was 56.1 +/- 10.8 ml/min/1.73 m2 at 1 year and 61.0 +/- 11.8 ml/min/1.73 m2 at 5 years. Mean blood pressure was 122.5 +/- 10.6/76.2 +/- 7.5 mmHg at donation (n = 908), 124.3 +/- 14.2/77.9 +/- 8.2 mmHg at 1-year (n = 649) and 127.2 +/- 15.4/78.8 +/- 8.3 mmHg at 5-year follow-ups (n = 247). We found no evidence of further decline in renal function beyond the initial decrement following nephrectomy. PMID- 20723181 TI - Reducing the joint burden of disease from diabetes mellitus and tuberculosis: missing research priorities. PMID- 20723182 TI - Malaria, mummies, mutations: Tutankhamun's archaeological autopsy. AB - The cause of death of the Egyptian pharoah Tutankhamun has now for decades been matter of speculation and various hypotheses. A recent article in the Journal of the American Medical Association (JAMA) provided new evidence and suggested malaria, together with Kohler's disease, as the most probable cause of death of the boy king. We are sceptical towards this elucidation of the cause of death of King Tut and discuss alternative and differential diagnoses, among them, in particular, sickle cell disease and Gauche's disease. PMID- 20723183 TI - Challenges in HIV and visceral Leishmania co-infection: future research directions. PMID- 20723184 TI - First attempt to validate the gSG6-P1 salivary peptide as an immuno epidemiological tool for evaluating human exposure to Anopheles funestus bites. AB - SUMMARY OBJECTIVE: The development of a biomarker of exposure based on the evaluation of the human antibody response specific to Anopheles salivary proteins seems promising in improving malaria control. The IgG response specific to the gSG6-P1 peptide has already been validated as a biomarker of An. gambiae exposure. This study represents a first attempt to validate the gSG6-P1 peptide as an epidemiological tool evaluating exposure to An. funestus bites, the second main malaria vector in sub-Saharan Africa. METHODS: A multi-disciplinary survey was performed in a Senegalese village where An. funestus represents the principal anopheline species. The IgG antibody level specific to gSG6-P1 was evaluated and compared in the same children before, at the peak and after the rainy season. RESULTS: Two-thirds of the children developed a specific IgG response to gSG6-P1 during the study period and--more interestingly--before the rainy season, when An. funestus was the only anopheline species reported. The specific IgG response increased during the An. funestus exposure season, and a positive association between the IgG level and the level of exposure to An. funestus bites was observed. CONCLUSIONS: The results suggest that the evaluation of the IgG response specific to gSG6-P1 in children could also represent a biomarker of exposure to An. funestus bites. The availability of such a biomarker evaluating the exposure to both main Plasmodium falciparum vectors in Africa could be particularly relevant as a direct criterion for the evaluation of the efficacy of vector control strategies. PMID- 20723185 TI - 'I never thought that this baby would survive; I thought that it would die any time': perceptions and care for preterm babies in eastern Uganda. AB - SUMMARY OBJECTIVE: To explore the current care for and perceptions about preterm babies among community members in eastern Uganda. METHODS: A neonatal midwife observed care of preterm babies in one general hospital and 15 health centres using a checklist and a field diary. In-depth interviews were conducted with 11 community health workers (CHWs) and also with 10 mothers, six fathers and three grandmothers of preterm babies. Three focus group discussions were conducted with midwives and women and men in the community. Content analysis of data was performed. RESULTS: Community members mentioned many features which may correctly be used to identify preterm babies. Care practices for preterm babies at health facilities and community level were inadequate and potentially harmful. Health facilities lacked capacity for care of preterm babies in terms of protocols, health workers' skills, basic equipment, drugs and other supplies. However, community members and CHWs stated that they accepted the introduction of preterm care practices such as skin-to-skin and kangaroo mother care. CONCLUSION: In this setting, care for preterm babies is inadequate at both health facility and community level. However, acceptance of the recommended newborn care practices indicated by the community is a window of opportunity for introducing programmes for preterm babies. In doing so, consideration needs to be given to the care provided at health facilities as well as to the gaps in community care that are largely influenced by beliefs, perceptions and lack of awareness. PMID- 20723187 TI - Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. AB - OBJECTIVES: To determine whether (i) supplementation of oral 100,000 iu of vitamin D(3) (cholecalciferol) along with antibiotics will reduce the duration of illness in children with pneumonia; (ii) supplementation will reduce the risk of repeat episodes. METHODS: Double-blind individually randomised placebo-controlled trial in an inner-city hospital in Kabul, of 453 children aged 1-36 months, diagnosed with non-severe or severe pneumonia at the outpatient clinic. Children with rickets, other concurrent severe diseases, very severe pneumonia or wheeze, were excluded. Children were given vitamin D(3) or placebo drops additional to routine pneumonia treatment. RESULTS: Two hundred and twenty-four children received vitamin D(3;) and 229 received placebo. There was no significant difference in the mean number of days to recovery between the vitamin D(3) (4.74 days; SD 2.22) and placebo arms (4.98 days; SD 2.89; P = 0.17). The risk of a repeat episode of pneumonia within 90 days of supplementation was lower in the intervention (92/204; 45%) than the placebo group [122/211; (58%; relative risk 0.78; 95% CI 0.64, 0.94; P = 0.01]. Children in the vitamin D(3) group survived longer without experiencing a repeat episode (72 days vs. 59 days; HR 0.71; 95% CI 0.53-0.95; P = 0.02). CONCLUSION: A single high-dose oral vitamin D(3) supplementation to young children along with antibiotic treatment for pneumonia could reduce the occurrence of repeat episodes of pneumonia. PMID- 20723189 TI - Multiple progressive piloleiomyomas in a ferret (Mustela putorius furo): a case report. AB - A 2.5-year-old ovariectomized female ferret developed multiple progressive linear and raised nodules on the skin. The first lesions occurred on the tail, which was then amputated. Over the following 3 years, additional lesions appeared in the vicinity of the scar and then further rostrally on the flanks and thorax. Histological and immunohistochemical investigation led to a diagnosis of multiple piloleiomyomas. The unique characteristics of this ferret disease are described and compared with those of multiple piloleiomyomas in humans and with those of other cutaneous smooth muscle cell tumours reported in the veterinary literature. PMID- 20723188 TI - Oxidative stress in the pathogenesis of canine zinc-responsive dermatosis. AB - Zinc deficiency causes skin diseases both in humans and in animals. The underlying pathogenic mechanisms remain unclear, but a growing body of evidence indicates a role for zinc in skin protection against free radical-induced oxidative damage. The immunohistochemical expression of heat shock proteins (HSPs; Hsp27, Hsp72, Hsp73 and Hsp90), Cu/Zn superoxide dismutase (SOD), metallothionein (MT), Ki-67 antigen and active caspase-3 were evaluated in normal canine skin and in samples from eight dogs with zinc-responsive dermatosis. All investigated HSPs showed intense cytoplasmic immunostaining in the affected epidermis. Focal nuclear positivity of Hsp72 was also detected in keratinocytes. Although Cu/Zn SOD expression was similar to that observed in normal skin, MT immunoreactivity occurred in both the cytoplasm and the nucleus of basal cells in normal skin but was absent from the affected epidermis. Caspase-3 activation was also absent in the involved epidermis, which revealed a high Ki-67 index (a 3.5- to 9-fold increase compared with normal skin). These results support the hypothesis that cellular response to stress, particularly oxidative stress, is involved in the pathogenesis of skin lesions in canine zinc-responsive dermatosis. The lack of MT immunoreactivity in the affected epidermis may be indicative of low zinc levels, thus resulting in vulnerability to oxidative damage. In contrast, high expression levels of HSPs in skin during zinc deficiency may confer protection against a variety of dangerous stimuli, contributing to inhibition of apoptosis and to cell cycle regulation of proliferating keratinocytes. PMID- 20723190 TI - Laser vaporization of the dorsal turbinate as an alternative method of accessing and evaluating the paranasal sinuses. AB - OBJECTIVE: To report a technique for stoma creation into the conchofrontal sinus (CFS) through the dorsal turbinate and to evaluate stoma as a site for sinoscopy. STUDY DESIGN: Prospective experimental study. ANIMALS: Cadaveric equine heads (n=2) and normal adult horses (5). METHODS: Technique feasibility was established on 2 cadaver heads. A diode laser fiber with a contact probe was passed into the nasal passage through a custom built, laser introducer rod (LIR). A videoendoscope was passed ventral to the LIR. A site on the caudal, medial aspect of the turbinate overlying the dorsal conchal sinus (DCS) was identified. A stoma to facilitate endoscope passage was created through the turbinate and sinoscopy performed to identify structures within the CFS and caudal maxillary sinus (CMS) and to evaluate the quality of the approach. The procedure was then performed in standing, sedated horses. Time required, laser energy used and complications were recorded. Endoscopy was performed >=5 weeks postoperatively to assess stoma size and long-term effects of the procedure. RESULTS: A stoma was successfully created through the turbinate in both cadaveric skulls and in 4 horses; the stoma persisted for >=5 weeks. The location of the stoma in 1 horse precluded sinoscopy. CONCLUSIONS: Laser vaporization of the dorsal turbinate through the nasal passage creates a stoma that lasts for at least 5 weeks providing a portal to the paranasal sinuses. Based on experience in 1 horse stoma location is critical to ensure adequate endoscope manipulation and sinoscopy. CLINICAL RELEVANCE: Standing endoscopic sinusotomy within the nasal cavity through the DCS is an alternative to more invasive sinusotomy techniques with fewer potential complications and a cosmetic result. PMID- 20723191 TI - Radiographic evaluation of the anconeal process in skeletally immature dogs. AB - OBJECTIVE: To determine if a secondary center of ossification (SCO) of the anconeal process is present in skeletally immature dogs that do not develop an ununited anconeal process (UAP). STUDY DESIGN: Case series. ANIMALS: Dogs 77-154 days of age with conditions other than developmental disease of the elbow (n=78 dogs; total elbows=100). METHODS: Mediolateral radiographic projections of the elbow were reviewed for presence or absence of a SCO of the anconeal process. RESULTS: A SCO was radiographically evident in 16% of elbows from breeds that have been reported to be affected by UAP. The appearance of the SCO was different to an UAP fragment. None of the elbows with SCO of the anconeal process developed UAP. A SCO was not present in any small breed dogs. CONCLUSIONS: A SCO of the anconeal process is uncommon in medium and large breed dogs and the presence of a SCO does not indicate that UAP will develop. CLINICAL RELEVANCE: Because radiographic diagnosis of a SCO of the anconeal process and UAP lesions have distinct appearances, an earlier diagnosis of UAP is possible. PMID- 20723192 TI - Biomechanical evaluation of acetabular cup implantation in cementless total hip arthroplasty. AB - OBJECTIVE: To report biomechanical properties of the Biologic Fixation System (BFX) acetabular cup impacted into a normal canine pelvis and to compare the effect of implant positioned to and beyond the medial acetabular wall. STUDY DESIGN: In vitro cadaveric study. ANIMALS: Hemipelves of mature, large-breed dogs (n=6). METHODS: For each dog, 1 hemipelvis was reamed to the depth of the acetabular wall (group A) and 1 was reamed an additional 6 mm after penetration of the medial cortex of the acetabulum (group B). The hemipelves were implanted with acetabular cups and loaded in compression through a matching femoral prosthetic component until failure. Specimen stiffness, and failure displacement, load, and energy were determined from load and displacement data and results between groups compared with a paired t-test. RESULTS: Mean failure load was greater in group A (3812 +/- 391 N) than group B (2924 +/- 316 N; P<.014). No other differences (P>.05) were observed between groups. Bone fracture (n=5) and cup displacement (1) occurred in group A whereas in group B there were 3 fractures and 3 cup displacements. CONCLUSIONS: Although medial placement of the BFX cup affected compressive failure loads, failure loads for both groups exceeded normal physiologic loads. CLINICAL RELEVANCE: Medial positioning of the acetabular cup does not appear to compromise acetabular implant-pelvic stability under normal physiologic loads. Because arthroplasty candidates often have abnormal acetabular architecture, mechanical properties of the cup placed in acetabula without a dorsal rim should be investigated. PMID- 20723193 TI - Micro total hip replacement for dogs and cats: surgical technique and outcomes. AB - OBJECTIVE: To describe the surgical technique for the micro total hip replacement (Micro THR) system and report clinical outcomes. STUDY DESIGN: Prospective study. ANIMALS: Dogs (n=49) and cats (n=8) with coxofemoral arthropathy. METHODS: Small breed dogs and cats with coxofemoral arthritis were enrolled for Micro THR. Patient data were recorded. Implant positioning and cement mantle quality were evaluated radiographically. Orthopedic examinations and client interviews were used to assess outcome. RESULTS: Micro THR was performed unilaterally (40 dogs, 8 cats) and staged bilaterally (9 dogs) to resolve pain associated with osteoarthritis or trauma. Mean body weight was 7.2 kg. Postoperative complications included prosthesis luxation (9), cup aseptic loosening (1), and sciatic neurapraxia (1). Mean radiographic follow up was 96.1 weeks; 10 joints were followed for >=3.0 years. Sixty of the 66 (91%) Micro THRs had excellent outcomes. Two dogs (<2.75 kg) were too small for the prosthesis and 4 dogs with unmanageable luxation had explantation. CONCLUSIONS: Micro THR is considered a satisfactory procedure for management of small breed dogs and cats with coxofemoral disease unresponsive to medical management. CLINICAL RELEVANCE: Micro THR is a viable option to treat disabling disorders of the hip. More than 170 cat and small dog breeds, and many mixed breeds, could benefit from Micro THR surgery. PMID- 20723194 TI - Removal of 11 incompletely erupted, impacted cheek teeth in 10 horses using a dental alveolar transcortical osteotomy and buccotomy approach. AB - OBJECTIVE: To describe surgical technique and outcome in 10 horses with impacted cheek teeth that were removed by a transcortical osteotomy and buccotomy technique. STUDY DESIGN: Case series. ANIMALS: Horses (n=10) with impacted cheek teeth. METHODS: Medical records (2002-2008) of horses with impacted cheek teeth requiring removal were reviewed; surgical technique and outcome were determined. RESULTS: Exodontia of 11 cheek teeth was performed surgically in 10 horses; 3 horses had complications (residual swelling of the mandible) that resolved and all horses returned to their previous use. CONCLUSIONS: Transcortical buccotomy technique is effective for removal of incompletely erupted impacted cheek teeth in horses and has a good long-term prognosis for remission of clinical signs. CLINICAL RELEVANCE: Transcortical buccotomy approach is an effective technique for removal of unerupted impacted equine cheek teeth. PMID- 20723195 TI - Evaluation of a transvaginal laparoscopic natural orifice transluminal endoscopic surgery approach to the abdomen of mares. AB - OBJECTIVE: To report natural orifice transluminal endoscopic surgery (NOTES) using laparoscopic and endoscopic instrumentation transvaginally into the mare's abdomen and identify structures visible using this approach. DESIGN: Descriptive experimental study. ANIMALS: Mares (n=8). METHODS: A standing, transvaginal approach was made in the cranial vaginal vault at either the 1 (right; 4 mares) or 11 (left; 4 mares) o'clock position relative to the cervix. The abdomen was visually explored and the viscera evaluated using a 2 m flexible endoscope followed by a 62 cm laparoscope. Incisional healing was monitored by vaginoscopy at days 3 and 7. RESULTS: Abdominal exploration was adequate through either a left or a right transvaginal approach. Endoscopically, the left kidney, spleen, nephrosplenic space, stomach, cecum, duodenum, left and right ovaries, diaphragm, and caudal peritoneal reflection were consistently observed and the liver inconsistently. Similar views of the caudal abdomen were obtained with the laparoscope; however, we were unable to view cranially beyond the nephrosplenic space or base of the cecum and lateral mobility of the laparoscope was limited. Incisional closure was evident at 3 days. Complications in 1 mare included mild colic behavior that resolved with conservative treatment. CONCLUSIONS: The NOTES transvaginal approach is seemingly well tolerated and safe and provides adequate observation of most structures within the dorsal caudal region of the abdomen on the side of endoscope or laparoscope insertion. CLINICAL RELEVANCE: NOTES transvaginal approach may be a useful tool in the diagnosis of intraabdominal disorders in mares. PMID- 20723196 TI - Laparoscopic splenectomy for treatment of splenic hemangiosarcoma in a dog. AB - OBJECTIVE: To report laparoscopic splenectomy in a dog. STUDY DESIGN: Clinical report. ANIMALS: Mixed breed dog (n=1). METHODS: Hemangiosarcoma was diagnosed by ultrasound-guided fine-needle aspiration of a splenic mass in an 11-year-old, 30 kg, mixed breed dog. No metastatic disease was identified during complete staging (chest radiographs, echocardiogram, and abdominal ultrasonography); however, cystic calculi were identified. Laparoscopic splenectomy using Ligasure V was performed through 3 portals and the calculi were removed by laparoscopic-assisted cystoscopy. RESULTS: Total surgical time was 2 hours and for laparoscopic splenectomy, 65 minutes. The celiotomy incision for splenic removal was 7 cm. The dog recovered uneventfully and was ambulatory 2 hours postoperatively. CONCLUSION: Laparoscopy with Ligasure V facilitated successful removal of a spleen with a 3 cm mass. CLINICAL RELEVANCE: Laparoscopic splenectomy in dogs is feasible for removal of a normal-sized spleen with a moderate-sized mass. PMID- 20723198 TI - Pig islet xenotransplantation acceptance in a Latin-American diabetic population. AB - Progress in porcine islet xenotransplantation has been accompanied by studies on acceptance of this new procedure by patients, health professionals or the general public. Such studies have not been done in the Latin-American population. We conducted a questionnaire in 108 diabetes patients (insulin-dependent, n = 53; insulin-independent, n = 55) in a public hospital in Argentina. The questions addressed the general perception of the xenotransplant procedure and specific items related to the outcome (achieving insulin independence, improvement in metabolic control, delay in emergence of diabetic complications, need for repeat procedures, potential of transfer of infectious viruses, association with psychological problems, and anticipated success in relation to achieving a cure). Eighty-six (79%) of the patients accepted islet xenotransplantation; this incidence was not different for insulin-dependent or insulin-independent patients, patients with or without complications, or patients with good or poor metabolic control. Also, over 75% of patients accepted the procedure if this is only associated with a reduction in insulin requirement, if the procedure just delays but not prevents the onset of complications, or if the procedure needs to be performed every 6 months. Fifty-seven percent of patients indicated acceptance even if the potential transmission of a virus infection cannot be completely ruled out: this outcome was not affected by the outbreak of the H1N1 flu epidemic during the conduct of this study. Forty percent of patients indicated that living with porcine cells in their body could give psychological problems. We conclude that this population of Latin-American diabetic patients shows a high acceptance rate of a porcine islet xenotransplantation product. PMID- 20723200 TI - Efficiency of porcine endothelial cell infection with human cytomegalovirus depends on both virus tropism and endothelial cell vascular origin. AB - BACKGROUND: Human cytomegalovirus (HCMV) infection or reactivation has been linked to allograft rejection resulting from endothelial injury and immune activation. In pig-to-human xenotransplantation, currently investigated to circumvent the shortage of human organs in transplantation medicine, the porcine endothelium will inevitably be exposed to human pathogens such as HCMV. We investigated the susceptibility of porcine endothelial cells (pEC) to HCMV infection. METHODS: Immortalized porcine aortic (PEDSV15) and porcine microvascular bone-marrow derived EC (2A2) as well as a panel of primary pEC originated from different vascular beds were inoculated with the endotheliotropic (TB40/E) and the fibroblast propagated (TB40/F) HCMV strains at multiplicity of infection (MOI) ranging from 0.1 to 5. Viral replication kinetics, development of cytopathology and release of viral progeny were analyzed. RESULTS: All viral strains infected pEC with differences in both infection efficiency and kinetics of cytopathology. Moreover, differences in susceptibility of pEC derived from distinct vascular beds were observed. HCMV underwent a complete replication cycle in about 5% of the infected pEC. Comparing the permissiveness of pEC to human aortic EC (HAEC) revealed differences in strain susceptibility and lower rates of late antigen expression in pEC. Finally, HCMV-infected pEC released viral particles but with a lower efficiency than infected HAEC. CONCLUSIONS: Our data demonstrate that HCMV productively infects pEC, therefore finding strategies to render pEC resistant to HCMV infection will be of interest to reduce the potential risk carried by HCMV reactivation in xenotransplantation. PMID- 20723199 TI - CD47 in xenograft rejection and tolerance induction. AB - Robust immune responses to xenografts remain a major obstacle to clinical translation of xenotransplantation, which could otherwise be a potential solution to the worldwide shortage of organ donors. The more vigorous xenograft rejection relative to allograft rejection is largely accounted for by the extensive genetic disparities between the donor and recipient. Xenografts activate host immunity not only by expressing immunogenic xenoantigens that provide the targets for immune recognition and rejection, but also by lacking ligands for the host immune inhibitory receptors. This review is focused on recent findings regarding the role of CD47, a ligand of an immune inhibitory receptor SIRPalpha, in xenograft rejection and induction of xenotolerance. PMID- 20723201 TI - Characterization of baboon NK cells and their xenogeneic activity. AB - BACKGROUND: Baboons are commonly used as models for transplantation and preclinical testing of various types of therapeutic agents. For proper assessment of information gathered from these models, differences between the baboon and human immune systems need to be characterized. Natural killer (NK) cells are the first line of defense against many infectious agents and cancer and are important mediators of transplantation rejection reactions, particularly during xenotransplantation. In this study, we examined baboon NK cell function and developed methods for purifying and expanding these cells. METHODS: Baboon NK cells were analyzed using a combination of extracellular and intracellular cell staining, cell sorting, interleukin (IL)-2 mediated stimulation and expansion, and 4 h cytotoxicity assays with human and pig target cell lines. RESULTS: Baboon peripheral blood mononuclear cell (PBMC) exert very low but detectable cytolytic activity against both human (K562) and pig (PAEC, J2) target cells, and this activity is enhanced within 4 h of treatment with IL-2. Like human NK cells, many baboon PBMC express the lytic enzymes granzyme A, granzyme B, and perforin. Based on these markers, we identified a subpopulation of CD3(-) baboon lymphocytes that are CD8(dim) and CD16(bright) that likely represents the baboon NK cells. These cells also are characterized by expression of the natural cytotoxicity receptor NKp46. Baboon CD3(-)NKp46(+) cells purified by flow cytometric cell sorting have high cytolytic capacity that can be further enhanced by IL-2 stimulation. These baboon NK cells can be expanded in vitro and retain extremely high cytolytic capacity. While fresh baboon lymphocytes express very little CD56, the expanded baboon NK cells are predominantly CD56(+); approximately 10% of the expanded NK cells are CD56(dim), and the remainder are CD56(bright). CONCLUSIONS: Baboon NK cells that are IL-2 responsive can be identified on the basis of a CD3( )NKp46(+)CD8(dim)CD16(+/-) or CD3(-)CD8(dim)CD16(bright) phenotype and can be isolated and expanded in culture. These results may allow for a more accurate representation of the human innate immune system in baboon models and more accurate analyses of the role of the baboon innate immune system cells in preclinical models. PMID- 20723203 TI - CD4+ CD25+ regulatory T cells suppressed the indirect xenogeneic immune response mediated by porcine epithelial cell pulsed dendritic cells. AB - BACKGROUND: CD4(+) CD25(+) regulatory T cells have been reported to suppress T cell-mediated xenogeneic immune responses. Although the direct T cell response to xenogeneic cells is important, the indirect xenogeneic immune response mediated by dendritic cells (DCs) is also likely involved in rejection. We have generated an in vitro indirect immune reaction model and evaluated the effect of CD4(+) CD25(+) regulatory T cells on this system. METHODS: Human DCs were generated from peripheral blood and cultured with X-ray-irradiated porcine kidney epithelial cells. Porcine cell-pulsed DCs were mixed with autologous CD4(+) T cells, CD4(+) CD25(-) T cells and/or CD4(+) CD25(+) T cells. After 7 days of culture, T cell proliferation was measured. RESULTS: The co-culture of human DCs and X-ray irradiated porcine epithelial cells resulted in observable DC phagocytic activity within 2 days. These porcine cell-pulsed DCs stimulated CD4(+) T cell proliferation much more potently than unpulsed DCs or porcine cells. This proliferation was blocked by CTLA4-Ig or an anti-HLA-DR antibody. CD4(+) CD25(+) regulatory T cells also suppressed CD4(+) CD25(-) T cell proliferation in response to porcine cell-pulsed DCs. CONCLUSIONS: An in vitro model of the indirect xenogeneic immune response was established. Porcine cell-pulsed DCs stimulated CD4(+) T cells, and CD4(+) CD25(+) regulatory T cells suppressed this response. PMID- 20723202 TI - Occurrence of specific humoral non-responsiveness to swine antigens following administration of GalT-KO bone marrow to baboons. AB - BACKGROUND: Hematopoietic chimerism induces transplantation tolerance across allogeneic and xenogeneic barriers, but has been difficult to achieve in the pig to-primate model. We have now utilized swine with knockout of the gene coding for alpha-1,3-galactosyltransferase (GalT-KO pigs) as bone marrow donors in an attempt to achieve chimerism and tolerance by avoiding the effects of natural antibodies to Gal determinants on pig hematopoietic cells. METHODS: Baboons (n = 4; Baboons 1 to 4 = B156, B158, B167, and B175, respectively) were splenectomized and conditioned with TBI (150 cGy), thymic irradiation (700 cGy), T cell depletion with rabbit anti-thymocyte globulin (rATG) and rat anti-primate CD2 (LoCD2b), and received FK506 and supportive therapy for 28 days. All animals received GalT-KO bone marrow (1 to 2 x 10(9) cells/kg) in two fractions on days 0 and 2, and were thereafter monitored for the presence of pig cells by flow cytometry, for porcine progenitor cells by PCR of BM colony-forming units, and for cellular reactivity to pig cells by mixed lymphocyte reaction (MLR). In vitro antibody formation to LoCD2b and rATG was tested by ELISA; antibody reactivity to GalT-KO pig cells was tested by flow cytometry and cytotoxicity assays. Additionally, Baboons 3 and 4 received orthotopic kidney transplants on days 17 and 2, respectively, to test the potential impact of the protocol on renal transplantation. RESULTS: None of the animals showed detectable pig cells by flow cytometry for more than 12 h post-BM infusion. However, porcine progenitor cell engraftment, as evidenced by pig-derived colony forming units in the BM, as well as peripheral microchimerism in the thymus, lymph node, and peripheral blood was detected by PCR in baboons 1 and 2 for at least 28 days post-transplant. ELISA results confirmed humoral immunocompetence at time of transplantation as antibody titers to rat (LoCD2b) and rabbit (ATG) increased within 2 weeks. However, no induced antibodies to GalT-KO pig cells or increased donor specific cytotoxicity was detectable by flow cytometry. In contrast, baboons 3 and 4 developed serum antibodies to pig cells as well as to rat and rabbit immunoglobulin by day 14. Retrospective analysis revealed that although all four baboons possessed low levels of antibody-mediated cytotoxicity to GalT-KO cells prior to transplantation, the two baboons (3 and 4) that became sensitized to pig cells (and rejected pig kidneys) had relatively high pre-transplantation titers of anti non-Gal IgG detectable by flow cytometry, whereas baboons 1 and 2 had undetectable titers. CONCLUSIONS: Engraftment and specific non-responsiveness to pig cells has been achieved in two of four baboons following GalT-KO pig-to baboon BMT. Engraftment correlated with absence of preformed anti-non-Gal IgG serum antibodies. These results are encouraging with regard to the possibility of achieving transplantation tolerance across this xenogeneic barrier. PMID- 20723204 TI - Xenotransplantation literature update: April-May, 2010. PMID- 20723205 TI - RAD51C germline mutations in breast and ovarian cancer patients. PMID- 20723206 TI - Efficacy assessed in follow-ups of clinical trials: methodological conundrum. AB - Increasingly, we see papers describing the long-term follow-up results of randomised clinical trials. Sometimes, like the article by Rantalaiho and colleagues in the previous issue of Arthritis Research & Therapy, the follow-up extends to more than 10 years. It is not uncommon that authors of such articles describe their results as a comparison of the original treatment groups in the original randomised clinical trial. Methodologically, such a comparison is fallible for several reasons. In this editorial, two important sources of bias that may jeopardise the results of such follow-up studies are discussed: confounding by indication and confounding by trial completion. PMID- 20723207 TI - Can serum hyaluronic acid replace simple non-invasive indexes to predict liver fibrosis in HIV/Hepatitis C coinfected patients? AB - BACKGROUND: Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4). METHODS: We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy. Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by area under the receiver operating characteristic curves (AUROCs). RESULTS: The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F>=2), 31.8% with advanced fibrosis (F>=3), and 11.4% with cirrhosis (F4). Values for the AUROC of HA levels corresponding to significant fibrosis (F>=2), advanced fibrosis (F>=3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes. The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients. CONCLUSIONS: The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage. However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis. PMID- 20723208 TI - Axon fasciculation in the developing olfactory nerve. AB - Olfactory sensory neuron (OSN) axons exit the olfactory epithelium (OE) and extend toward the olfactory bulb (OB) where they coalesce into glomeruli. Each OSN expresses only 1 of approximately 1,200 odor receptors (ORs). OSNs expressing the same OR are distributed in restricted zones of the OE. However, within a zone, the OSNs expressing a specific OR are not contiguous - distribution appears stochastic. Upon reaching the OB the OSN axons expressing the same OR reproducibly coalesce into two to three glomeruli. While ORs appear necessary for appropriate convergence of axons, a variety of adhesion associated molecules and activity-dependent mechanisms are also implicated. Recent data suggest pre-target OSN axon sorting may influence glomerular convergence. Here, using regional and OR-specific markers, we addressed the spatio-temporal properties associated with the onset of homotypic fasciculation in embryonic mice and assessed the degree to which subpopulations of axons remain segregated as they extend toward the nascent OB. We show that immediately upon crossing the basal lamina, axons uniformly turn sharply, usually at an approximately 90 degrees angle toward the OB. Molecularly defined subpopulations of axons show evidence of spatial segregation within the nascent nerve by embryonic day 12, within 48 hours of the first OSN axons crossing the basal lamina, but at least 72 hours before synapse formation in the developing OB. Homotypic fasciculation of OSN axons expressing the same OR appears to be a hierarchical process. While regional segregation occurs in the mesenchyme, the final convergence of OR-specific subpopulations does not occur until the axons reach the inner nerve layer of the OB. PMID- 20723209 TI - Transfer RNA gene arrangement and codon usage in vertebrate mitochondrial genomes: a new insight into gene order conservation. AB - BACKGROUND: Mitochondrial (mt) gene arrangement has been highly conserved among vertebrates from jawless fishes to mammals for more than 500 million years. It remains unclear, however, whether such long-term persistence is a consequence of some constraints on the gene order. RESULTS: Based on the analysis of codon usage and tRNA gene positions, we suggest that tRNA gene order of the typical vertebrate mt-genomes may be important for their translational efficiency. The vertebrate mt-genome encodes 2 rRNA, 22 tRNA, and 13 transmembrane proteins consisting mainly of hydrophobic domains. We found that the tRNA genes specifying the hydrophobic residues were positioned close to the control region (CR), where the transcription efficiency is estimated to be relatively high. Using 47 vertebrate mt-genome sequences representing jawless fishes to mammals, we further found a correlation between codon usage and tRNA gene positions, implying that highly-used tRNA genes are located close to the CR. In addition, an analysis considering the asymmetric nature of mtDNA replication suggested that the tRNA loci that remain in single-strand for a longer time tend to have more guanine and thymine not suffering deamination mutations in their anticodon sites. CONCLUSIONS: Our analyses imply the existence of translational constraint acting on the vertebrate mt-gene arrangement. Such translational constraint, together with the deamination-related constraint, may have contributed to long-term maintenance of gene order. PMID- 20723210 TI - In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells. AB - BACKGROUND: Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules. METHODS: The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed. RESULTS: Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect. CONCLUSIONS: Results from our in vitro model suggest that the sequence 24 h MTA --> 1 h dFdC - > RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic. PMID- 20723211 TI - Fertility disorders and pregnancy complications in hairdressers - a systematic review. AB - BACKGROUND: Hairdressers often come into contact with various chemical substances which can be found in hair care products for washing, dyeing, bleaching, styling, spraying and perming. This exposure can impair health and may be present as skin and respiratory diseases. Effects on reproduction have long been discussed in the literature. METHOD: A systematic review has been prepared in which publications from 1990 to 2010 were considered in order to specifically investigate the effects on fertility and pregnancy. The results of the studies were summarised separately in accordance with the type of study and the examined events. RESULTS: A total of 2 reviews and 26 original studies on fertility disorders and pregnancy complications in hairdressers were found in the relevant databases, as well as through hand searches of reference lists. Nineteen different outcomes concerning fertility and pregnancy are analysed in the 26 original studies. Most studies looked into malformation (n = 7), particularly orofacial cleft. Two of them found statistically significant increased risks compared to five that did not. Small for gestational age (SGA), low birth weight (LBW) and spontaneous abortions were frequently investigated but found different results. Taken together the studies are inconsistent, so that no clear statements on an association between the exposure as a hairdresser and the effect on reproduction are possible. The different authors describe increased risks of infertility, congenital malformations, SGA, LBW, cancer in childhood, as well as effects from single substances. CONCLUSION: On the basis of the identified epidemiological studies, fertility disorders and pregnancy complications in hairdressers cannot be excluded. Although the evidence for these risks is low, further studies on reproductive risks in hairdressers should be performed as there is a high public health interest. PMID- 20723212 TI - Hodgkin lymphoma treatment with ABVD in the US and the EU: neutropenia occurrence and impaired chemotherapy delivery. AB - BACKGROUND: In newly diagnosed patients with Hodgkin lymphoma (HL) the effect of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)-related neutropenia on chemotherapy delivery is poorly documented. The aim of this analysis was to assess the impact of chemotherapy-induced neutropenia (CIN) on ABVD chemotherapy delivery in HL patients. STUDY DESIGN: Data from two similarly designed, prospective, observational studies conducted in the US and the EU were analysed. One hundred and fifteen HL patients who started a new course of ABVD during 2002 2005 were included. The primary objective was to document the effect of neutropenic complications on delivery of ABVD chemotherapy in HL patients. Secondary objectives were to investigate the incidence of CIN and febrile neutropenia (FN) and to compare US and EU practice with ABVD therapy in HL. Pooled data were analysed to explore univariate associations with neutropenic events. RESULTS: Chemotherapy delivery was suboptimal (with a relative dose intensity < or = 85%) in 18-22% of patients. The incidence of grade 4 CIN in cycles 1-4 was lower in US patients (US 24% vs. EU 32%). Patients in both the US and the EU experienced similar rates of FN across cycles 1-4 (US 12% vs. EU 11%). Use of primary colony-stimulating factor (CSF) prophylaxis and of any CSF was more common in the US than the EU (37% vs. 4% and 78% vs. 38%, respectively). The relative risk (RR) of dose delays was 1.54 (95% confidence interval [CI] 1.08 2.23, p = 0.036) for patients with vs. without grade 4 CIN and the RR of grade 4 CIN was 0.35 (95% CI 0.12-1.06, p = 0.046) for patients with vs. without primary CSF prophylaxis. CONCLUSIONS: In this population of HL patients, CIN was frequent and FN occurrence clinically relevant. Chemotherapy delivery was suboptimal. CSF prophylaxis appeared to reduce CIN rates. PMID- 20723213 TI - Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase. AB - BACKGROUND: Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT), a known mediator of cellular immortalization. METHODS: We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3) and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. RESULTS: We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs) in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC. CONCLUSIONS: We propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis. PMID- 20723214 TI - Specific eradication of HIV-1 from infected cultured cells. AB - A correlation between increase in the integration of Human Immunodeficiency virus-1 (HIV-1) cDNA and cell death was previously established. Here we show that combination of peptides that stimulate integration together with the protease inhibitor Ro 31-8959 caused apoptotic cell death of HIV infected cells with total extermination of the virus. This combination did not have any effect on non infected cells. Thus it appears that cell death is promoted only in the infected cells. It is our view that the results described in this work suggest a novel approach to specifically promote death of HIV-1 infected cells and thus may eventually be developed into a new and general anti-viral therapy. PMID- 20723215 TI - Strictosidine activation in Apocynaceae: towards a "nuclear time bomb"? AB - BACKGROUND: The first two enzymatic steps of monoterpene indole alkaloid (MIA) biosynthetic pathway are catalysed by strictosidine synthase (STR) that condensates tryptamine and secologanin to form strictosidine and by strictosidine beta-D-glucosidase (SGD) that subsequently hydrolyses the glucose moiety of strictosidine. The resulting unstable aglycon is rapidly converted into a highly reactive dialdehyde, from which more than 2,000 MIAs are derived. Many studies were conducted to elucidate the biosynthesis and regulation of pharmacologically valuable MIAs such as vinblastine and vincristine in Catharanthus roseus or ajmaline in Rauvolfia serpentina. However, very few reports focused on the MIA physiological functions. RESULTS: In this study we showed that a strictosidine pool existed in planta and that the strictosidine deglucosylation product(s) was (were) specifically responsible for in vitro protein cross-linking and precipitation suggesting a potential role for strictosidine activation in plant defence. The spatial feasibility of such an activation process was evaluated in planta. On the one hand, in situ hybridisation studies showed that CrSTR and CrSGD were coexpressed in the epidermal first barrier of C. roseus aerial organs. However, a combination of GFP-imaging, bimolecular fluorescence complementation and electromobility shift-zymogram experiments revealed that STR from both C. roseus and R. serpentina were localised to the vacuole whereas SGD from both species were shown to accumulate as highly stable supramolecular aggregates within the nucleus. Deletion and fusion studies allowed us to identify and to demonstrate the functionality of CrSTR and CrSGD targeting sequences. CONCLUSIONS: A spatial model was drawn to explain the role of the subcellular sequestration of STR and SGD to control the MIA metabolic flux under normal physiological conditions. The model also illustrates the possible mechanism of massive activation of the strictosidine vacuolar pool upon enzyme-substrate reunion occurring during potential herbivore feeding constituting a so-called "nuclear time bomb" in reference to the "mustard oil bomb" commonly used to describe the myrosinase-glucosinolate defence system in Brassicaceae. PMID- 20723216 TI - Codon usage bias and the evolution of influenza A viruses. Codon Usage Biases of Influenza Virus. AB - BACKGROUND: The influenza A virus is an important infectious cause of morbidity and mortality in humans and was responsible for 3 pandemics in the 20th century. As the replication of the influenza virus is based on its host's machinery, codon usage of its viral genes might be subject to host selection pressures, especially after interspecies transmission. A better understanding of viral evolution and host adaptive responses might help control this disease. RESULTS: Relative Synonymous Codon Usage (RSCU) values of the genes from segment 1 to segment 6 of avian and human influenza viruses, including pandemic H1N1, were studied via Correspondence Analysis (CA). The codon usage patterns of seasonal human influenza viruses were distinct among their subtypes and different from those of avian viruses. Newly isolated viruses could be added to the CA results, creating a tool to investigate the host origin and evolution of viral genes. It was found that the 1918 pandemic H1N1 virus contained genes with mammalian-like viral codon usage patterns, indicating that the introduction of this virus to humans was not through in toto transfer of an avian influenza virus.Many human viral genes had directional changes in codon usage over time of viral isolation, indicating the effect of host selection pressures. These changes reduced the overall GC content and the usage of G at the third codon position in the viral genome. Limited evidence of translational selection pressure was found in a few viral genes. CONCLUSIONS: Codon usage patterns from CA allowed identification of host origin and evolutionary trends in influenza viruses, providing an alternative method and a tool to understand the evolution of influenza viruses. Human influenza viruses are subject to selection pressure on codon usage which might assist in understanding the characteristics of newly emerging viruses. PMID- 20723217 TI - Varicella vaccination coverage of children under two years of age in Germany. AB - BACKGROUND: Since July 2004, routine varicella vaccination is recommended by the German Standing Vaccination Committee in Germany. Health Insurance Funds started to cover vaccination costs at different time points between 2004 and 2006 in the Federal States. Nationwide representative data on vaccination coverage against varicella of children under two years of age are not available. We aimed to determine varicella vaccination coverage in statutory health insured children under two years of age in twelve German Federal States using data from associations of statutory health insurance physicians (ASHIPs), in order to investigate the acceptance of the recommended routine varicella vaccination programme. METHODS: We analysed data on varicella vaccination from 13 of 17 ASHIPs of the years 2004 to 2007. The study population consisted of all statutory health insured children under two years of age born in 2004 (cohort 2004) or 2005 (cohort 2005) in one of the studied regions. Vaccination coverage was determined by the number of children vaccinated under 2 years of age within the study population. RESULTS: Varicella vaccination coverage of children under two years of age with either one dose of the monovalent varicella vaccine or two doses of the measles, mumps, rubella, and varicella vaccine increased from 34% (cohort 2004) to 51% (cohort 2005) in the studied regions (p < 0.001). More than half of the vaccinated children of cohort 2004 and two third of cohort 2005 were immunised at the recommended age 11 to 14 months. The level of vaccination coverage of cohort 2004 was significantly associated with the delay in introduction of cost coverage since the recommendation of varicella vaccination (p < 0.001). CONCLUSIONS: Our study shows increasing varicella vaccination coverage of young children, indicating a growing acceptance of the routine varicella vaccination programme by the parents and physicians. We recommend further monitoring of vaccination coverage using data from ASHIPs to investigate acceptance of the routine vaccination programmes over time. PMID- 20723218 TI - Determining the interviewer effect on CQ Index outcomes: a multilevel approach. AB - BACKGROUND: The CQ Index for the elderly, a quality-of-care questionnaire administered by conducting interviews, is used to assess clients' experiences in Dutch nursing homes and homes for the elderly. This article describes whether inter-interviewer differences influence the perceived quality of healthcare services reported by residents, the size of this interviewer effect and the influence of the interviewer characteristics on CQ Index dimensions for public reporting. METHODS: Data from 4345 questionnaires was used. Correlations were calculated, reliability analyses were performed, and a multilevel analysis was used to calculate the degree of correlation between two interviewers within one health care institution. Five models were constructed and the Intra Class Correlation (ICC) was calculated. Healthcare institutions were given 1-5 stars on every quality dimensions (1 = worst and 5 = best), adjusted for resident and interviewer characteristics. The effect of these characteristics on the assignment of the stars was investigated. RESULTS: In a multilevel approach, the ICC showed a significant amount of variance on five quality dimensions. Of the interviewer characteristics, only previous interviewing experience, the reason of interviewing and general knowledge of health care had a significant effect on the quality dimensions. Adjusting for interviewer characteristics did not affect the overall star assignment to the institutions regarding 7 of 12 quality dimensions. For the other five dimensions (Shared decision-making, Meals, Professional competency, Autonomy, and Availability of personnel) a minor effect was found. CONCLUSIONS: We have shown that training, the use of experienced interviewers, written instructions, supervision and educational meetings do not automatically prevent interviewer effects. While the results of this study can be used to improve the quality of services provided by these institutions, several CQ index dimensions should be interpreted with caution for external purposes (accountability and transparency). PMID- 20723219 TI - A randomised controlled trial of the efficacy of the ABCD Parenting Young Adolescents Program: rationale and methodology. AB - BACKGROUND: The transition to adolescence is a time of increased vulnerability for risk taking and poor health, social and academic outcomes. Parents have an important role in protecting their children from these potential harms. While the effectiveness of parenting programs in reducing problem behavior has been demonstrated, it is not known if parenting programs that target families prior to the onset of significant behavioral difficulties in early adolescence (9-14 years) improve the wellbeing of adolescents and their parents. This paper describes the rationale and methodology of a randomised controlled trial testing the efficacy of a parenting program for the promotion of factors known to be associated with positive adolescent outcomes, such as positive parenting practices, parent-adolescent relationships and adolescent behavior. METHODS/DESIGN: One hundred and eighty parents were randomly allocated to an intervention or wait list control group. Parents in the intervention group participated in the ABCD Parenting Young Adolescents Program, a 6-session behavioral family intervention program which also incorporates acceptance-based strategies. Participants in the Wait List control group did not receive the intervention during a six month waiting period. The study was designed to comply with recommendations of the CONSORT statement. The primary outcome measures were reduction in parent-adolescent conflict and improvements in parent-adolescent relationships. Secondary outcomes included improvements in parent psychosocial wellbeing, parenting self-efficacy and perceived effectiveness, parent-adolescent communication and adolescent behavior. CONCLUSIONS: Despite the effectiveness of parenting programs in reducing child behavioral difficulties, very few parenting programs for preventing problems in adolescents have been described in the peer reviewed literature. This study will provide data which can be used to examine the efficacy of a universal parenting interventions for the promotion of protective factors associated with adolescent wellbeing and will add to the literature regarding the relationships between parent, parenting and adolescent factors. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000194268. PMID- 20723220 TI - Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis. AB - BACKGROUND: In the present work, we describe a group of anomalous dose-response (DR) profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol) against two microorganisms (Carnobacterium piscicola and Leuconostoc mesenteroides). RESULTS: Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between sensu stricto hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents. CONCLUSIONS: The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena. PMID- 20723221 TI - Design and baseline characteristics of the ParkFit study, a randomized controlled trial evaluating the effectiveness of a multifaceted behavioral program to increase physical activity in Parkinson patients. AB - BACKGROUND: Many patients with Parkinson's disease (PD) lead a sedentary lifestyle. Promotion of physical activities may beneficially affect the clinical presentation of PD, and perhaps even modify the course of PD. However, because of physical and cognitive impairments, patients with PD require specific support to increase their level of physical activity. METHODS: We developed the ParkFit Program: a PD-specific and multifaceted behavioral program to promote physical activity. The emphasis is on creating a behavioral change, using a combination of accepted behavioral motivation techniques. In addition, we designed a multicentre randomized clinical trial to investigate whether this ParkFit Program increases physical activity levels over two years in sedentary PD patients. We intended to include 700 sedentary patients. Primary endpoint is the time spent on physical activities per week, which will be measured every six months using an interview based 7-day recall. RESULTS: In total 3453 PD patients were invited to participate. Ultimately, 586 patients--with a mean (SD) age of 64.1 (7.6) years and disease duration of 5.3 (4.5) years--entered the study. Study participants were younger, had a shorter disease duration and were less sedentary compared with eligible PD patients not willing to participate. DISCUSSION: The ParkFit trial is expected to yield important new evidence about behavioral interventions to promote physical activity in sedentary patients with PD. The results of the trial are expected in 2012. TRIAL REGISTRATION: http://clinicaltrials.gov (nr NCT00748488). PMID- 20723222 TI - Unique health care utilization patterns in a homeless population in Ghent. AB - BACKGROUND: Existing studies concerning the health care use of homeless people describe higher utilisation rates for hospital-based care and emergency care, and lower rates for primary care by homeless people compared to the general population. Homeless people are importantly hindered and/or steered in their health care use by barriers directly related to the organisation of care. Our goal is to describe the accessibility of primary health care services, secondary care and emergency care for homeless people living in an area with a universal primary health care system and active guidance towards this unique system. METHODS: Observational, cross-sectional study design. Data from the Belgian National health survey were merged with comparable data collected by means of a face-to-face interview from homeless people in Ghent. 122 homeless people who made use of homeless centres and shelters in Ghent were interviewed using a reduced version of the Belgian National Health survey over a period of 5 months. 2-dimensional crosstabs were built in order to study the bivariate relationship between health care use (primary health care, secondary and emergency care) and being homeless. To determine the independent association, a logistic model was constructed adjusting for age and sex. RESULTS AND DISCUSSION: Homeless people have a higher likelihood to consult a GP than the non-homeless people in Ghent, even after adjusting for age and sex. The same trend is demonstrated for secondary and emergency care. CONCLUSIONS: Homeless people in Ghent do find the way to primary health care and make use of it. It seems that the universal primary health care system in Ghent with an active guidance by social workers contributes to easier GP access. PMID- 20723223 TI - Application of mobile-technology for disease and treatment monitoring of malaria in the "Better Border Healthcare Programme". AB - BACKGROUND: The main objective of this study was to assess the effectiveness of integrating the use of cell-phones into a routine malaria prevention and control programme, to improve the management of malaria cases among an under-served population in a border area. The module for disease and treatment monitoring of malaria (DTMM) consisted of case investigation and case follow-up for treatment compliance and patients' symptoms. METHODS: The module combining web-based and mobile technologies was developed as a proof of concept, in an attempt to replace the existing manual, paper-based activities that malaria staff used in treating and caring for malaria patients in the villages for which they were responsible. After a patient was detected and registered onto the system, case-investigation and treatment details were recorded into the malaria database. A follow-up schedule was generated, and the patient's status was updated when the malaria staff conducted their routine home visits, using mobile phones loaded with the follow-up application module. The module also generated text and graph messages for a summary of malaria cases and basic statistics, and automatically fed to predetermined malaria personnel for situation analysis. Following standard public health practices, access to the patient database was strictly limited to authorized personnel in charge of patient case management. RESULTS: The DTMM module was developed and implemented at the trial site in late November 2008, and was fully functioning in 2009. The system captured 534 malaria patients in 2009. Compared to paper-based data in 2004-2008, the mobile-phone-based case follow-up rates by malaria staff improved significantly. The follow-up rates for both Thai and migrant patients were about 94-99% on Day 7 (Plasmodium falciparum) and Day 14 (Plasmodium vivax) and maintained at 84-93% on Day 90. Adherence to anti malarial drug therapy, based on self-reporting, showed high completion rate for P. falciparum-infected cases, but lower rate for P. vivax cases. Patients' symptoms were captured onto the mobile phone during each follow-up visit, either during the home visit or at Malaria Clinic; most patients had headache, muscle pain, and fatigue, and some had fever within the first follow-up day (day 7/14) after the first anti-malarial drug dose. CONCLUSIONS: The module was successfully integrated and functioned as part of the malaria prevention and control programme. Despite the bias inherent in sensitizing malaria workers to perform active case follow-up using the mobile device, the study proved for its feasibility and the extent to which community healthcare personnel in the low resource settings could potentially utilize it efficiently to perform routine duties, even in remote areas. The DTMM has been modified and is currently functioning in seven provinces in a project supported by the WHO and the Bill & Melinda Gates Foundation, to contain multi-drug resistant malaria on the Thai Cambodian border. PMID- 20723224 TI - Augmented inhibition of angiogenesis by combination of HER2 antibody chA21 and trastuzumab in human ovarian carcinoma xenograft. AB - BACKGROUND: chA21 is a novel tumor-inhibitory antibody which recognized subdomain I of HER2 extracellular domain with an epitope distinct from other HER2 antibodies. Previously, we demonstrated that chA21 inhibits human ovarian carcinoma cell line SKOV-3 growth in vitro and in vivo study. In this study, we further investigated the anti-angiogenic efficacy combination of chA21 with trastuzumab in SKOV-3 xenograft model. METHODS: Nude mice were s.c. challenged with SKOV-3 cells and received treatment of chA21 alone, trastuzumab alone or both antibodies together twice a week for 21 days. Tumor volume and microvessel density (MVD) were evaluated. The effect of chA21 plus trastuzumab treament on vascular endothelial growth factor (VEGF) secretion, endothelial cells proliferation and migration, and the status of HER2 downstream pathway AKT/phosphorylated AKT (pAKT) were evaluated in vitro. RESULTS: In vivo study combination of chA21 with trastuzumab resulted in reduce tumor growth and angiogenesis than each monotherapy. In vitro study, the combination of chA21 with trastuzumab inhibits VEGF secretion, endothelial cells proliferation and migration. Furthermore, the combination treatment inhibits pAKT expression. CONCLUSION: Our findings suggested that the combination of chA21 with trastuzumab can cause augmented inhibition of angiogenesis in SKOV-3 xenograft model. Inhibition of agniogenesis may through suppression of AKT pathway. The therapeutic benefits of combination chA21 with trastuzumab warrant further study in an attempt to make the translation into the clinic. PMID- 20723225 TI - Medicago truncatula contains a second gene encoding a plastid located glutamine synthetase exclusively expressed in developing seeds. AB - BACKGROUND: Nitrogen is a crucial nutrient that is both essential and rate limiting for plant growth and seed production. Glutamine synthetase (GS), occupies a central position in nitrogen assimilation and recycling, justifying the extensive number of studies that have been dedicated to this enzyme from several plant sources. All plants species studied to date have been reported as containing a single, nuclear gene encoding a plastid located GS isoenzyme per haploid genome. This study reports the existence of a second nuclear gene encoding a plastid located GS in Medicago truncatula. RESULTS: This study characterizes a new, second gene encoding a plastid located glutamine synthetase (GS2) in M. truncatula. The gene encodes a functional GS isoenzyme with unique kinetic properties, which is exclusively expressed in developing seeds. Based on molecular data and the assumption of a molecular clock, it is estimated that the gene arose from a duplication event that occurred about 10 My ago, after legume speciation and that duplicated sequences are also present in closely related species of the Vicioide subclade. Expression analysis by RT-PCR and western blot indicate that the gene is exclusively expressed in developing seeds and its expression is related to seed filling, suggesting a specific function of the enzyme associated to legume seed metabolism. Interestingly, the gene was found to be subjected to alternative splicing over the first intron, leading to the formation of two transcripts with similar open reading frames but varying 5' UTR lengths, due to retention of the first intron. To our knowledge, this is the first report of alternative splicing on a plant GS gene. CONCLUSIONS: This study shows that Medicago truncatula contains an additional GS gene encoding a plastid located isoenzyme, which is functional and exclusively expressed during seed development. Legumes produce protein-rich seeds requiring high amounts of nitrogen, we postulate that this gene duplication represents a functional innovation of plastid located GS related to storage protein accumulation exclusive to legume seed metabolism. PMID- 20723226 TI - The activation of Proteinase-Activated Receptor-1 (PAR1) mediates gastric cancer cell proliferation and invasion. AB - BACKGROUND: In addition to regulating platelet function, the G protein-coupled sub-family member Proteinase-activated receptor-1 (PAR1) has a proposed role in the development of various cancers, but its exact role and mechanism of action in the invasion, metastasis, and proliferation process in gastric cancer have yet to be completely elucidated. Here, we analyzed the relationship between PAR1 activation, proliferation, invasion, and the signaling pathways downstream of PAR1 activation in gastric cancer. METHODS: We established a PAR1 stably transfected MKN45 human gastric cancer cell line (MKN45/PAR1) and performed cell proliferation and invasion assays employing this cell line and MKN28 cell line exposed to PAR1 agonists (alpha-thrombin and TFLLR-NH2). We also quantified NF kappaB activation by electrophoretic mobility shift assay (EMSA) and the level of Tenascin-C (TN-C) expression in conditioned medium by ELISA of MKN45/PAR1 following administration of alpha-thrombin. A high molecular weight concentrate was derived from the resultant conditioned medium and subsequent cultures of MKN45/PAR1 and MKN28 were exposed to the resultant concentrate either in the presence or absence of TN-C-neutralizing antibody. Lysates of these subsequent cells were probed to quantify levels of phospholyrated Epidermal Growth Factor Receptor (EGFR). RESULT: PAR1 in both PAR1/MKN45 and MKN28 was activated by PAR1 agonists, resulting in cell proliferation and matrigel invasion. We have shown that activation of NF-kappaB and EGFR phosphorylation initially were triggered by the activation of PAR1 with alpha-thrombin. Quantitative PCR and Western blot assay revealed up-regulation of mRNA and protein expression of NF-kappaB target genes, especially TN-C, a potential EGFR activator. The suppressed level of phosphorylated EGFR, observed in cells exposed to concentrate of conditioned medium in the presence of TN-C-neutralizing antibody, identifies TN-C as a putative autocrine stimulatory factor of EGFR possibly involved in the sustained PAR1 activation responses observed. CONCLUSION: Our data indicate that in gastric carcinoma cells, PAR1 activation can trigger an array of responses that would promote tumor cell growth and invasion. Over expression of NF-kappaB, EGFR, and TN-C, are among the effects of PAR1 activation and TN-C induces EGFR activation in an autocrine manner. Thus, PAR1 is a potentially important therapeutic target for the treatment of gastric cancer. PMID- 20723227 TI - Symptomatic cerebral oedema during treatment of diabetic ketoacidosis: effect of adjuvant octreotide infusion. AB - INTRODUCTION: A potentially lethal complication of diabetic ketoacidosis (DKA) in children is brain oedema, whether caused by DKA itself or by the therapeutic infusion of insulin and fluids. CASE PRESENTATION: A 10-year old previously healthy boy with DKA became unconscious and apnoeic due to cerebral oedema (confirmed by abnormal EEG and CT-scan) during treatment with intravenous fluids (36 ml/h) and insulin (0.1 units/kg/h). He was intubated and artificially ventilated, without impact on EEG and CT-scan. Subsequently, adjuvant infusion of octreotide was applied (3.5 MUg/kg/h), suppressing growth hormone (GH) and IGF-1 production and necessitating the insulin dose to be reduced to 0.05 - 0.025 units/kg/h. The brain oedema improved and the boy made a full recovery. CONCLUSION: Co-therapy with octreotide was associated with a favourable outcome in the present patient with DKA and cerebral oedema. Whether this could be ascribed to the effects of octreotide on the insulin requirement or on the GH/IGF axis remains to be elucidated. PMID- 20723228 TI - Clinical and parasitological response to oral chloroquine and primaquine in uncomplicated human Plasmodium knowlesi infections. AB - BACKGROUND: Plasmodium knowlesi is a cause of symptomatic and potentially fatal infections in humans. There are no studies assessing the detailed parasitological response to treatment of knowlesi malaria infections in man and whether antimalarial resistance occurs. METHODS: A prospective observational study of oral chloroquine and primaquine therapy was conducted in consecutive patients admitted to Kapit Hospital, Sarawak, Malaysian Borneo with PCR-confirmed single P. knowlesi infections. These patients were given oral chloroquine for three days, and at 24 hours oral primaquine was administered for two consecutive days, primarily as a gametocidal agent. Clinical and parasitological responses were recorded at 6-hourly intervals during the first 24 hours, daily until discharge and then weekly to day 28. Vivax malaria patients were studied as a comparator group. RESULTS: Of 96 knowlesi malaria patients who met the study criteria, 73 were recruited to an assessment of the acute response to treatment and 60 completed follow-up over 28 days. On admission, the mean parasite stage distributions were 49.5%, 41.5%, 4.0% and 5.6% for early trophozoites, late trophozoites, schizonts and gametocytes respectively. The median fever clearance time was 26.5 [inter-quartile range 16-34] hours. The mean times to 50% (PCT50) and 90% (PCT90) parasite clearance were 3.1 (95% confidence intervals [CI] 2.8 3.4) hours and 10.3 (9.4-11.4) hours. These were more rapid than in a group of 23 patients with vivax malaria 6.3 (5.3-7.8) hours and 20.9 (17.6-25.9) hours; P = 0.02). It was difficult to assess the effect of primaquine on P. knowlesi parasites, due to the rapid anti-malarial properties of chloroquine and since primaquine was administered 24 hours after chloroquine. No P. knowlesi recrudescences or re-infections were detected by PCR. CONCLUSIONS: Chloroquine plus primaqine is an inexpensive and highly effective treatment for uncomplicated knowlesi malaria infections in humans and there is no evidence of drug resistance. Further studies using alternative anti-malarial drugs, including artemisinin derivatives, would be desirable to define optimal management strategies for P. knowlesi. PMID- 20723229 TI - Association of hypoglycemic symptoms with patients' rating of their health related quality of life state: a cross sectional study. AB - BACKGROUND: To evaluate the association between patient-reported hypoglycemic symptoms with ratings of their health-related quality of life state and patient reported adverse events in patients with type 2 diabetes mellitus (T2DM). METHODS: This observational, multicenter, cross sectional study was based on a sample of patients with T2DM from seven European countries who added sulfonylurea or thiazolidinedione to metformin monotherapy between January 2001 and January 2006. Included patients were required to have at least one hemoglobin A1c (HbA1c) measurement in the 12 months before enrollment and to not be receiving insulin. Demographic and clinical data from medical records were collected using case report forms. Questionnaires measured patient-reported hypoglycemic symptoms, health-related quality of life (EuroQol visual analogue scale, EQ-5D VAS), and treatment-related adverse events. RESULTS: A total of 1,709 patients were included in the study. Mean patient age was 63 years, 45% were female, mean HbA1c was 7.06%, and 28% were at HbA1c goal (HbA1c < 6.5%). Hypoglycemic symptoms during the 12 months before enrollment were reported by 38% of patients; among whom 68% reported their most severe symptoms were mild, 27% moderate, and 5% severe. Adjusted linear regression analyses revealed that patients reporting hypoglycemic symptoms had significantly lower EQ-5D VAS scores indicating worse patient-reported quality of life (mean difference -4.33, p < 0.0001). Relative to those not reporting symptoms, the adjusted decrement to quality of life increased with greater hypoglycemic symptom severity (mild: -2.68, p = 0.0039; moderate: 6.42, p < 0.0001; severe: -16.09, p < 0.0001). Patients with hypoglycemia reported significantly higher rates of shakiness, sweating, excessive fatigue, drowsiness, inability to concentrate, dizziness, hunger, asthenia, and headache (p < 0.0001 for each comparison). CONCLUSIONS: Hypoglycemic symptoms and symptom severity have an adverse effect on patients' rating of their health related quality of life state. Hypoglycemic symptoms are correlated with treatment related adverse effects. Minimizing the risk and severity of hypoglycemia may improve patients' quality of life and clinical outcomes. Results are subject to limitations associated with observational studies including the potential biases due to unobserved patient heterogeneity and the use of a convenience sample of patients. PMID- 20723230 TI - Family structure, parent-child conversation time and substance use among Chinese adolescents. AB - BACKGROUND: The family plays a vital role in shaping adolescent behaviours. The present study investigated the associations between family structure and substance use among Hong Kong Chinese adolescents. METHODS: A total of 32,961 Form 1 to 5 (grade 7-12 in the US) Hong Kong students participated in the Youth Smoking Survey in 2003-4. An anonymous questionnaire was used to obtain information about family structure, daily duration of parent-child conversation, smoking, alcohol drinking and drug use. Logistic regression was used to calculate the adjusted odds ratios (OR) for each substance use by family structure. RESULTS: Adjusting for sex, age, type of housing, parental smoking and school, adolescents from non-intact families were significantly more likely to be current smokers (OR = 1.62), weekly drinkers (OR = 1.72) and ever drug users (OR = 1.72), with significant linear increases in ORs from maternal, paternal to no-parent families compared with intact families. Furthermore, current smoking (OR = 1.41) and weekly drinking (OR = 1.46) were significantly more common among adolescents from paternal than maternal families. After adjusting for parent-child conversation time, the ORs for non-intact families remained significant compared with intact families, but the paternal-maternal differences were no longer significant. CONCLUSIONS: Non-intact families were associated with substance use among Hong Kong Chinese adolescents. The apparently stronger associations with substance use in paternal than maternal families were probably mediated by the poorer communication with the father. PMID- 20723231 TI - Characterization and genomic analysis of chromate resistant and reducing Bacillus cereus strain SJ1. AB - BACKGROUND: Chromium is a toxic heavy metal, which primarily exists in two inorganic forms, Cr(VI) and Cr(III). Chromate [Cr(VI)] is carcinogenic, mutational, and teratogenic due to its strong oxidizing nature. Biotransformation of Cr(VI) to less-toxic Cr(III) by chromate-resistant and reducing bacteria has offered an ecological and economical option for chromate detoxification and bioremediation. However, knowledge of the genetic determinants for chromate resistance and reduction has been limited so far. Our main aim was to investigate chromate resistance and reduction by Bacillus cereus SJ1, and to further study the underlying mechanisms at the molecular level using the obtained genome sequence. RESULTS: Bacillus cereus SJ1 isolated from chromium-contaminated wastewater of a metal electroplating factory displayed high Cr(VI) resistance with a minimal inhibitory concentration (MIC) of 30 mM when induced with Cr(VI). A complete bacterial reduction of 1 mM Cr(VI) was achieved within 57 h. By genome sequence analysis, a putative chromate transport operon, chrIA1, and two additional chrA genes encoding putative chromate transporters that likely confer chromate resistance were identified. Furthermore, we also found an azoreductase gene azoR and four nitroreductase genes nitR possibly involved in chromate reduction. Using reverse transcription PCR (RT-PCR) technology, it was shown that expression of adjacent genes chrA1 and chrI was induced in response to Cr(VI) but expression of the other two chromate transporter genes chrA2 and chrA3 was constitutive. In contrast, chromate reduction was constitutive in both phenotypic and gene expression analyses. The presence of a resolvase gene upstream of chrIA1, an arsenic resistance operon and a gene encoding Tn7-like transposition proteins ABBCCCD downstream of chrIA1 in B. cereus SJ1 implied the possibility of recent horizontal gene transfer. CONCLUSION: Our results indicate that expression of the chromate transporter gene chrA1 was inducible by Cr(VI) and most likely regulated by the putative transcriptional regulator ChrI. The bacterial Cr(VI) resistant level was also inducible. The presence of an adjacent arsenic resistance gene cluster nearby the chrIA1 suggested that strong selective pressure by chromium and arsenic could cause bacterial horizontal gene transfer. Such events may favor the survival and increase the resistance level of B. cereus SJ1. PMID- 20723232 TI - Sleep stage and obstructive apneaic epoch classification using single-lead ECG. AB - BACKGROUND: Polysomnography (PSG) is used to define physiological sleep and different physiological sleep stages, to assess sleep quality and diagnose many types of sleep disorders such as obstructive sleep apnea. However, PSG requires not only the connection of various sensors and electrodes to the subject but also spending the night in a bed that is different from the subject's own bed. This study is designed to investigate the feasibility of automatic classification of sleep stages and obstructive apneaic epochs using only the features derived from a single-lead electrocardiography (ECG) signal. METHODS: For this purpose, PSG recordings (ECG included) were obtained during the night's sleep (mean duration 7 hours) of 17 subjects (5 men) with ages between 26 and 67. Based on these recordings, sleep experts performed sleep scoring for each subject. This study consisted of the following steps: (1) Visual inspection of ECG data corresponding to each 30-second epoch, and selection of epochs with relatively clean signals, (2) beat-to-beat interval (RR interval) computation using an R-peak detection algorithm, (3) feature extraction from RR interval values, and (4) classification of sleep stages (or obstructive apneaic periods) using one-versus-rest approach. The features used in the study were the median value, the difference between the 75 and 25 percentile values, and mean absolute deviations of the RR intervals computed for each epoch. The k-nearest-neighbor (kNN), quadratic discriminant analysis (QDA), and support vector machines (SVM) methods were used as the classification tools. In the testing procedure 10-fold cross-validation was employed. RESULTS: QDA and SVM performed similarly well and significantly better than kNN for both sleep stage and apneaic epoch classification studies. The classification accuracy rates were between 80 and 90% for the stages other than non-rapid-eye-movement stage 2. The accuracies were 60 or 70% for that specific stage. In five obstructive sleep apnea (OSA) patients, the accurate apneaic epoch detection rates were over 89% for QDA and SVM. CONCLUSION: This study, in general, showed that RR-interval based classification, which requires only single lead ECG, is feasible for sleep stage and apneaic epoch determination and can pave the road for a simple automatic classification system suitable for home-use. PMID- 20723233 TI - Transcriptional profiling of root-knot nematode induced feeding sites in cowpea (Vigna unguiculata L. Walp.) using a soybean genome array. AB - BACKGROUND: The locus Rk confers resistance against several species of root-knot nematodes (Meloidogyne spp., RKN) in cowpea (Vigna unguiculata). Based on histological and reactive oxygen species (ROS) profiles, Rk confers a delayed but strong resistance mechanism without a hypersensitive reaction-mediated cell death process, which allows nematode development but blocks reproduction. RESULTS: Responses to M. incognita infection in roots of resistant genotype CB46 and a susceptible near-isogenic line (null-Rk) were investigated using a soybean Affymetrix GeneChip expression array at 3 and 9 days post-inoculation (dpi). At 9 dpi 552 genes were differentially expressed in incompatible interactions (infected resistant tissue compared with non-infected resistant tissue) and 1,060 genes were differentially expressed in compatible interactions (infected susceptible tissue compared with non-infected susceptible tissue). At 3 dpi the differentially expressed genes were 746 for the incompatible and 623 for the compatible interactions. When expression between infected resistant and susceptible genotypes was compared, 638 and 197 genes were differentially expressed at 9 and 3 dpi, respectively. CONCLUSIONS: In comparing the differentially expressed genes in response to nematode infection, a greater number and proportion of genes were down-regulated in the resistant than in the susceptible genotype, whereas more genes were up-regulated in the susceptible than in the resistant genotype. Gene ontology based functional categorization revealed that the typical defense response was partially suppressed in resistant roots, even at 9 dpi, allowing nematode juvenile development. Differences in ROS concentrations, induction of toxins and other defense related genes seem to play a role in this unique resistance mechanism. PMID- 20723235 TI - Role of positron emission tomography-computed tomography in bronchial mucoepidermoid carcinomas: a case series and review of the literature. AB - INTRODUCTION: Mucoepidermoid carcinoma of the tracheobronchial tree is rare. Such tumors usually present with signs and symptoms of bronchial obstruction. Histologically, they can be classified as high-grade or low-grade tumors. Experience of imaging these tumors with 18fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) is limited. We present three cases of this rare tumor, describe the functional imaging results, and review the available literature. CASE PRESENTATION: Three Caucasian patients, two men (21 and 24 years of age) and one woman (14 years of age), with bronchial masses were evaluated by us. All three patients were symptomatic, and underwent a thorough clinical examination, bronchoscopy and biopsy, plain computed tomography, 18F-FDG PET-CT and 68Gallium 1,4,7,10-Tetraazacyclododecane-NI,NII,NIII,NIIII,- tetra acetic acid (D) - Phel1-Tyr3-octreotide positron emission tomography-computed tomography (68Ga-DOTATOC PET-CT). 18F-FDG PET-CT revealed mild uptake in all three patients, whereas 68Ga-DOTATOC PET-CT revealed no significant uptake in any patient, making carcinoid tumor unlikely. Results of histopathological examination were consistent with low-grade mucoepidermoid carcinoma in all patients. CONCLUSION: Our study reveals that functional imaging may be helpful in the initial investigation of patients with mucoepidermoid carcinoma. 18F-FDG PET CT may have a prognostic relevance by predicting the histopathologic differentiation of the tumor. PMID- 20723234 TI - Detection and quantitation of HPV in genital and oral tissues and fluids by real time PCR. AB - BACKGROUND: Human papillomaviruses (HPVs) remain a serious world health problem due to their association with anogenital/oral cancers and warts. While over 100 HPV types have been identified, a subset is associated with malignancy. HPV16 and 18 are the most prevalent oncogenic types, while HPV6 and 11 are most commonly responsible for anogenital warts. While other quantitative PCR (qPCR) assays detect oncogenic HPV, there is no single tube assay distinguishing the most frequent oncogenic types and the most common types found in warts. RESULTS: A Sybr Green-based qPCR assay was developed utilizing degenerate primers to the highly conserved HPV E1 theoretically detecting any HPV type. A single tube multiplex qPCR assay was also developed using type-specific primer pairs and TaqMan probes that allowed for detection and quantitation of HPV6,11,16,18. Each HPV type was detected over a range from 2 x 10(1) to 2 x 10(6)copies/reaction providing a reliable method of quantitating type-specific HPV in 140 anogenital/cutaneous/oral benign and malignant specimens. 35 oncogenic and low risk alpha genus HPV types were detected. Concordance was detected in previously typed specimens. Comparisons to the gold standard detected an overall sensitivity of 89% (95% CI: 77% - 96%) and specificity of 90% (95%CI: 52% - 98%). CONCLUSION: There was good agreement between the ability of the qPCR assays described here to identify HPV types in malignancies previously typed using standard methods. These novel qPCR assays will allow rapid detection and quantitation of HPVs to assess their role in viral pathogenesis. PMID- 20723236 TI - Oncogenic role of the chromobox protein CBX7 in gastric cancer. AB - BACKGROUND: Chromobox 7 (CBX7) is a Polycomb family protein that extends the lifespan of normal human cells via downregulating the expression of INK4a/ARF tumor suppressor locus. It was found that CBX7 expression was upregulated in lymphoma, but downregulated in some other human malignancies. The role of CBX7 in most types of cancer is still not clear. The purpose of this study is to investigate the role of CBX7 in gastric cancer. METHODS: The expression of CBX7 and its potential target protein p16(INK4a) in gastric cancer cell lines and gastric tumors was assayed by Western blot analysis and immunohistochemistry(IHC). The correlations between CBX7 expression and p16(INK4a), clinicopathological characteristics, and prognosis were analyzed. Gastric cancer cell line SGC-7901 was transfected with CBX7 siRNA expressing plasmids, and the expression of various proteins was analyzed by Western blot analysis. Cellular senescence, anchorage independent growth, and cell migration assays were performed to determine the functional role of CBX7 in gastric cancer cells. RESULTS: CBX7 was found to be overexpressed in gastric cancer cell lines and gastric tumors. Overexpression of CBX7 in gastric cancer tissues correlated with patients' age, clinical stage and lymph node metastasis. Knockdown of CBX7 expression in gastric cancer cells led to increased cellular senescence, decreased cellular proliferation and migration ability, accompanied by upregulation of p16(INK4a). CONCLUSIONS: CBX7 acts as an oncogene in the carcinogenesis and progression of gastric cancer, and it may regulate tumorigenesis, cell migration and cancer metastasis partially via p16(INK4a) regulatory pathway. PMID- 20723238 TI - A model building exercise of mortality risk for Taiwanese women with breast cancer. AB - BACKGROUND: The accurate estimation of outcome in patients with malignant disease is an essential component of the optimal treatment, decision-making and patient counseling processes. The prognosis and disease outcome of breast cancer patients can differ according to geographic and ethnic factors. To our knowledge, to date these factors have never been validated in a homogenous loco-regional patient population, with the aim of achieving accurate predictions of outcome for individual patients. To clarify this topic, we created a new comprehensive prognostic and predictive model for Taiwanese breast cancer patients based on a range of patient-related and various clinical and pathological-related variables. METHODS: Demographic, clinical, and pathological data were analyzed from 1 137 patients with breast cancer who underwent surgical intervention. A survival prediction model was used to allow analysis of the optimal combination of variables. RESULTS: The area under the receiver operating characteristic (ROC) curve, as applied to an independent validation data set, was used as the measure of accuracy. Results were compared by comparing the area under the ROC curve. CONCLUSIONS: our model building exercise of mortality risk was able to predict disease outcome for individual patients with breast cancer. This model could represent a highly accurate prognostic tool for Taiwanese breast cancer patients. PMID- 20723237 TI - Growth status and menarcheal age among adolescent school girls in Wannune, Benue State, Nigeria. AB - BACKGROUND: Menarcheal age is a sensitive indicator of environmental conditions during childhood. The aim of study is to determine the age at menarche and growth status in adolescents in a rural area of Tarka, Wannune, Nigeria. METHODS: Data on 722 female students (aged 12-18 years) were collected in February 2009. Height and weight were measured. Body mass index (BMI; kg m-2) was used as an index of relative weight. RESULTS: Mean and median menarcheal age calculated by probit analysis were 13.02 (SD 3.0) (95% CI: 13.02-13.07), and age 13.00 (SD 2.8) (95% CI: 12.98-13.04), respectively. Girls who reach menarche are significantly heavier and taller with higher BMIs than those of their pre-menarcheal peers. CONCLUSION: The age of menarche is probably still declining in Nigeria. Although BMI is an important factor in the onset of menstruation, some other unmeasured environmental variables may be implicated in this population. PMID- 20723239 TI - Evaluation of health outcomes in osteoarthritis patients after total knee replacement: a two-year follow-up. AB - OBJECTIVES: To quantify the improvement in health outcomes in patients after total knee replacement (TKR). METHODS: This was a two-year non-randomized prospective observational study in knee osteoarthritis (OA) patients undergone TKR. Patients were interviewed one week before, six months after, and two years after surgery using a standardized questionnaire including the SF-36, the Oxford Knee Score (OKS), and the Knee Society Clinical Rating Scale (KSS). A generalized estimating equation (GEE) model was used to estimate the magnitudes of the changes with and without the adjustment of age, ethnicity, BMI, and years with OA. RESULTS: A total of 298 (at baseline), 176 (at six-months), and 111 (at two years) eligible patients were included in the analyses. All the scores changed significantly over time, with the exception of SF-36 social functioning, vitality, and mental health. With the adjustment of covariates, the magnitude of changes in these scores was similar to those without the adjustment. CONCLUSIONS: Both general and knee-specific physical functioning had been significantly improved after TKR, while other health domains have not been substantially improved after the surgery. PMID- 20723240 TI - Selecting HIV infection prevention interventions in the mature HIV epidemic in Malawi using the mode of transmission model. AB - BACKGROUND: Malawi is reassessing its HIV prevention strategy in the light of a limited reduction in the epidemic. No community based incidence studies have been carried out in Malawi, so estimates of where new infections are occurring require the use of mathematical models and knowledge of the size and sexual behaviour of different groups. The results can help to choose where HIV prevention interventions are most needed. METHODS: The UNAIDS Mode of Transmission model was populated with Malawi data and estimates of incident cases calculated for each exposure group. Scenarios of single and multiple interventions of varying success were used to identify those interventions most likely to reduce incident cases. RESULTS: The groups accounting for most new infections were the low-risk heterosexual group - the discordant couples (37%) and those who had casual sex and their partners (a further 16% and 27% respectively) of new cases.Circumcision, condoms with casual sex and bar girls and improved STI treatment had limited effect in reducing incident cases, while condom use with discordant couples, abstinence and a zero-grazing campaign had major effects. The combination of a successful strategy to eliminate multiple concurrent partners and a successful strategy to eliminate all infections between discordant couples would reduce incident cases by 99%. CONCLUSIONS: A revitalised HIV prevention strategy will need to include interventions which tackle the two modes of transmission now found to be so important in Malawi - concurrency and discordancy. PMID- 20723241 TI - Influence of hydrological conditions on the Escherichia coli population structure in the water of a creek on a rural watershed. AB - BACKGROUND: Escherichia coli is a commensal bacterium of the gastro-intestinal tract of human and vertebrate animals, although the aquatic environment could be a secondary habitat. The aim of this study was to investigate the effect of hydrological conditions on the structure of the E. coli population in the water of a creek on a small rural watershed in France composed of pasture and with human occupation. RESULTS: It became apparent, after studying the distribution in the four main E. coli phylo-groups (A, B1, B2, D), the presence of the hly (hemolysin) gene and the antibiotic resistance pattern, that the E. coli population structure was modified not only by the hydrological conditions (dry versus wet periods, rainfall events), but also by how the watershed was used (presence or absence of cattle). Isolates of the B1 phylo-group devoid of hly and sensitive to antibiotics were particularly abundant during the dry period. During the wet period and the rainfall events, contamination from human sources was predominantly characterized by strains of the A phylo-group, whereas contamination by cattle mainly involved B1 phylo-group strains resistant to antibiotics and exhibiting hly. As E. coli B1 was the main phylo-group isolated in water, the diversity of 112 E. coli B1 isolates was further investigated by studying uidA alleles (beta-D-glucuronidase), the presence of hly, the O-type, and antibiotic resistance. Among the forty epidemiolgical types (ETs) identified, five E. coli B1 ETs were more abundant in slightly contaminated water. CONCLUSIONS: The structure of an E. coli population in water is not stable, but depends on the hydrological conditions and on current use of the land on the watershed. In our study it was the ratio of A to B1 phylo-groups that changed. However, a set of B1 phylo-group isolates seems to be persistent in water, strengthening the hypothesis that they may correspond to specifically adapted strains. PMID- 20723242 TI - Human mammary fibroblasts stimulate invasion of breast cancer cells in a three dimensional culture and increase stroma development in mouse xenografts. AB - INTRODUCTION: Tumour phenotype is regulated in a complex fashion as a result of interactions between malignant cells and the tumour stroma. Fibroblasts are the most abundant and perhaps most active part of the tumour stroma. A better understanding of the changes that occur in fibroblasts in response to the presence of malignant cells may lead to the development of new strategies for cancer treatment. We explored the effects of fibroblasts on the growth and invasion of mammary carcinoma tumour cells in vitro and in vivo. METHODS: In order to analyse secreted factors that affect invasive abilities of breast cancer cells we co-cultured human mammary fibroblasts (HMF3s) and cancer cells (MCF7S1) in three-dimensional (3D) growth conditions devoid of heterogeneous cell-cell contact. To study the possible influence of fibroblasts on MCF7S1 cancer cell growth in vivo we co-injected HMF3s and MCF7S1 cells in Balb/c nu/nu mice. RESULTS: In 3D co-culture both HMF3s and MCF7S1 cells demonstrated enhanced invasion into a Matrigel matrix. This was correlated with enhanced expression of the metastasis promoting S100A4 protein in fibroblasts, stimulation of the matrix metalloproteinase (MMP)-2 activity, and enhanced secretion of a range of different cytokines. Orthotopic injection of oestrogen-dependent MCF7S1 cancer cells together with fibroblasts showed stimulation of tumour growth in mice without an external oestrogen supply. The resulting tumours were characterized by increased development of extracellular matrix, as well as an increase of murine S100A4 concentration and activity of MMP-2 in the tumour interstitial fluid. CONCLUSION: Stimulation of the invasive phenotype of tumour cells in 3D co cultures with fibroblasts could be correlated with increased production of S100A4 and MMP-2. We propose that enhanced development of mouse host-derived tumour stroma in a MCF7S1 co-injection xenograft model leads to oestrogen independency and is triggered by the initial presence of human fibroblasts. PMID- 20723243 TI - Optimization of odour-baited resting boxes for sampling malaria vector, Anopheles arabiensis Patton, in arid and highland areas of Africa. AB - BACKGROUND: Odour baited resting boxes are simple, reliable and important tools for sampling malaria vector mosquitoes in surveillance and control programmes in different parts of Africa. To optimize the use of cow urine baited resting boxes for sampling An. arabiensis, a community-based study was conducted in Mabogini hamlet in the Lower Moshi irrigation scheme area. METHOD: Experimental designs using 3 by 3 Latin square were conducted for twenty days to evaluate the following: i) the effect of different parameters in the sampling of mosquitoes using odour baited resting boxes; ii) the performance of odour baited traps under indoor and outdoor conditions and the effect of people sleeping indoors on mosquito density; iii) the effect of position in the placement of traps on collection of mosquitoes; and, iv) the efficiency of the trap outdoors at three different distances from the house wall. One extra house served as the sentinel house to monitor species abundance using a CDC-miniature light trap. RESULTS: 8581 mosquitoes were sampled by odour baited resting boxes of which, 8051 (93.82%) were An. arabiensis and 530 (6.18%) Cx. quinquefasciatus. The light trap collected 12,420 mosquitoes, of which 9442 (76.02%) were An. arabiensis, 126 (1.01%) An. funestus group, 230 (1.85%) An. rufipes and 2622 (21.11%) Cx. quinquefasciatus. The best height for outdoor mosquitoes sampling was 15 cm and 220 cm while indoors was 105 cm. The difference in mosquito collection between different outdoor and indoor heights was statistically significant (p < 0.0001). The optimal outdoor location of odour baited resting boxes from the wall of the house was 3 m. CONCLUSIONS: The results of these studies demonstrate an optimal method for sampling during surveillance and control programmes in rural villages of highlands and arid areas of Africa using inexpensive baits and boxes. PMID- 20723244 TI - How do existing HIV-specific instruments measure up? Evaluating the ability of instruments to describe disability experienced by adults living with HIV. AB - BACKGROUND: Despite the multitude of health challenges faced by adults living with HIV, we know of no HIV-specific instrument developed for the purpose of describing the health-related consequences of HIV, a concept known as disability. In a previous phase of research, adults living with HIV conceptualized disability as symptoms/impairments, difficulties carrying out day-to-day activities, challenges to social inclusion, and uncertainty that may fluctuate on a daily basis and over the course of living with HIV. In this paper, we describe the extent to which existing HIV-specific health-status instruments capture the experience of disability for adults living with HIV. METHODS: We searched databases from 1980 to 2006 for English language, HIV-specific, self-reported questionnaires consisting of at least two items that were tested for reliability and validity. We then conducted a content analysis to assess how well existing questionnaires describe disability as defined by the Episodic Disability Framework, a framework that conceptualizes this experience from the perspective of adults living with HIV. We matched items of the instruments with categories of the framework to evaluate the extent to which the instruments capture major dimensions of disability in the framework. RESULTS: We reviewed 4274 abstracts, of which 30 instruments met the inclusion criteria and were retrieved. Of the four major dimensions of disability, symptoms/impairments were included in all 30 instruments, difficulties with day-to-day activities in 16, challenges to social inclusion in 16, and uncertainty in 9. Seven instruments contained at least 1 item from all 4 dimensions of disability (breadth) however, the comprehensiveness with which the dimensions were represented (depth) varied among the instruments. CONCLUSIONS: In general, symptoms/impairments and difficulties carrying out day to-day activities were the disability dimensions characterized in greatest depth while uncertainty and challenges to social inclusion were less well represented. Although none of the instruments described the full breadth and depth of disability as conceptualized by the Episodic Disability Framework, they provide a foundation from which to build a measure of disability for adults living with HIV. PMID- 20723245 TI - Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism. AB - BACKGROUND: Autism is a behaviourally defined neurodevelopmental disorder with unknown etiology. Recent studies in autistic children consistently point to neuropathological and functional abnormalities in the temporal association cortex (TeA) and its associated structures. It has been proposed that the trajectory of postnatal development in these regions may undergo accelerated maturational alterations that predominantly affect sensory recognition and social interaction. Indeed, the temporal association regions that are important for sensory recognition and social interaction are one of the last regions to mature suggesting a potential vulnerability to early maturation. However, direct evaluation of the emerging hypothesis that an altered time course of early postnatal development can lead to an ASD phenotype remains lacking. RESULTS: We used electrophysiological, histological, and behavioural techniques to investigate if the known neuronal maturational promoter valproate, similar to that in culture systems, can influence the normal developmental trajectory of TeA in vivo. Brain sections obtained from postnatal rat pups treated with VPA in vivo revealed that almost 40% of cortical cells in TeA prematurely exhibited adult like intrinsic electrophysiological properties and that this was often associated with gross cortical hypertrophy and a reduced predisposition for social play behaviour. CONCLUSIONS: The co-manifestation of these functional, structural and behavioural features suggests that alteration of the developmental time course in certain high-order cortical networks may play an important role in the neurophysiological basis of autism. PMID- 20723246 TI - Prevalence and predictors of HIV-related stigma among institutional- and community-based caregivers of orphans and vulnerable children living in five less wealthy countries. AB - BACKGROUND: In the face of the HIV/AIDS epidemic that has contributed to the dramatic increase in orphans and abandoned children (OAC) worldwide, caregiver attitudes about HIV, and HIV-related stigma, are two attributes that may affect caregiving. Little research has considered the relationship between caregiver attributes and caregiver-reported HIV-related stigma. In light of the paucity of this literature, this paper will describe HIV-related stigma among caregivers of OAC in five less wealthy nations. METHODS: Baseline data were collected between May 2006 through February 2008. The sample included 1,480 community-based and 192 institution-based caregivers. Characteristics of the community-based and institution-based caregivers are described using means and standard deviations for continuous variables or counts and percentages for categorical variables. We fit logistic regression models, both for the full sample and separately for community-based and institution-based caregivers, to explore predictors of acceptance of HIV. RESULTS: Approximately 80% of both community-based and institution-based caregivers were female; and 84% of institution-based caregivers, compared to 66% of community-based caregivers, said that they would be willing to care for a relative with HIV. Similar proportions were reported when caregivers were asked if they were willing to let their child play with an HIV-infected child. In a multivariable model predicting willingness to care for an HIV-infected relative, adjusted for site fixed effects, being an institution based caregiver was associated with greater willingness (less stigma) than community-based caregivers. Decreased willingness was reported by older respondents, while willingness increased with greater formal education. In the adjusted models predicting willingness to allow one's child to play with an HIV infected child, female gender and older age was associated with less willingness. However, willingness was positively associated with years of formal education. CONCLUSIONS: The caregiver-child relationship is central to a child's development. OAC already face stigma as a result of their orphaned or abandoned status; the addition of HIV-related stigma represents a double burden for these children. Further research on the prevalence of HIV-related acceptance and stigma among caregivers and implications of such stigma for child development will be critical as the policy community responds to the global HIV/AIDS orphan crisis. PMID- 20723247 TI - Antiproliferative effect of D-glucuronyl C5-epimerase in human breast cancer cells. AB - BACKGROUND: D-glucuronyl C5-epimerase (GLCE) is one of the key enzymes in the biosynthesis of heparansulfate proteoglycans. Down-regulation of GLCE expression in human breast tumours suggests a possible involvement of the gene in carcinogenesis. In this study, an effect of GLCE ectopic expression on cell proliferation and viability of breast carcinoma cells MCF7 in vitro and its potential molecular mechanisms were investigated. RESULTS: D-glucuronyl C5 epimerase expression was significantly decreased in MCF7 cells compared to normal human breast tissue. Re-expression of GLCE inhibited proliferative activity of MCF7 cells according to CyQUANT NF Cell Proliferation Assay, while it did not affect their viability in Colony Formation Test. According to Cancer PathFinder RT Profiler PCR Array, antiproliferative effect of GLCE in vitro could be related to the enhanced expression of tumour suppressor genes r53 (+3.3 fold), E2F1 (+3.00 fold), BRCA1 (+3.5 fold), SYK (+8.1 fold) and apoptosis-related genes BCL2 (+4.2 fold) and NFKB1 (+2.6 fold). Also, GLCE re-expression in MCF7 cells considerably changed the expression of some genes involved in angiogenesis (IL8, +4.6 fold; IFNB1, +3.9 fold; TNF, +4.6 fold and TGFB1, -5.7 fold) and invasion/metastasis (SYK, +8.1 fold; NME1, +3.96 fold; S100A4, -4.6 fold). CONCLUSIONS: The ability of D-glucuronyl S5-epimerase to suppress proliferation of breast cancer cells MCF7 through the attenuated expression of different key genes involved in cell cycle regulation, angiogenesis and metastasis molecular pathways supports the idea on the involvement of the gene in regulation of breast cancer cell proliferation. PMID- 20723249 TI - The effect of Aloe ferox Mill. in the treatment of loperamide-induced constipation in Wistar rats. AB - BACKGROUND: Constipation is the most common gastrointestinal complaint all over the world and it is a risk factor of colorectal cancer. In this study, the efficacy of aqueous leaf extract of Aloe ferox Mill. was studied against loperamide-induced constipation in Wistar rats. METHODS: Constipation was induced by oral administration of loperamide (3 mg/kg body weight) while the control rats received normal saline. The constipated rats were treated with 50, 100 and 200 mg/kg body weight/day of the extract for 7 days during which the feeding characteristics, body weight, fecal properties and gastrointestinal transit ratio were monitored. RESULTS: The extract improved intestinal motility, increased fecal volume and normalized body weight in the constipated rats, which are indications of laxative property of the herb with the 200 mg/kg body weight of the extract showing the best efficacy. CONCLUSION: The effect of the extract compares favourably well with senokot, a standard laxative drug. These findings have therefore, lent scientific credence to the folkloric use of the herb as a laxative agent by the people of the Eastern Cape of South Africa. PMID- 20723248 TI - Serotonin synthesis, release and reuptake in terminals: a mathematical model. AB - BACKGROUND: Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. METHODS: We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. RESULTS: We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine. CONCLUSIONS: Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions. PMID- 20723251 TI - Acute left main coronary artery thrombosis due to cocaine use. AB - It is common knowledge that cocaine has been linked to the development of various acute and chronic cardiovascular complications including acute coronary syndromes. We present a young, male patient, drug abuser who underwent CABG due to anterolateral myocardial infarction. Our presentation is one of the very rare cases reported in literature regarding acute thrombosis of left main coronary artery related to cocaine use, in a patient with normal coronary arteries, successfully operated. Drug-abusers seem to have increased mortality and morbidity after surgery and high possibility for stent thrombosis after percutaneous coronary interventions, because of their usually terrible medical compliance and coexistent several problems of general health. There are no specific guidelines about treatment of thrombus formation in coronary arteries, as a consequence of cocaine use. So, any decision making concerning the final treatment of these patient is a unique and individualized approach. We strongly recommend that all these patients should be treated surgically, especially patients with thrombus into the left main artery. PMID- 20723252 TI - Calcified amorphous tumor of the heart in an adult female: a case report. AB - INTRODUCTION: Cardiac calcified amorphous tumor is a rare, non-neoplastic intra cavity cardiac mass composed of calcium deposits in a background of amorphous degenerating fibrinous material. Only a few cases of this rare lesion have been reported in the available literature. Clinico-pathological differentiation of this lesion from calcified atrial myxoma, calcified thrombi or other cardiac neoplasms is extremely difficult; hence pathologic examination is the mainstay of diagnosis. To the best of our knowledge this entity has not been reported in the Indian literature. CASE PRESENTATION: A 40-year-old woman of Indian origin presented with progressive dyspnea, fatigue and cough. She was diagnosed as having a calcified right atrial mass. The mass was excised. Histologic examination revealed the mass to be composed of amorphous eosinophilic fibrin with dense calcification. No myxomatous tissue was seen and a final diagnosis of calcified amorphous tumor of the heart was rendered. CONCLUSIONS: Calcified amorphous tumor is a rare cardiac lesion with an excellent outcome following complete surgical removal. Since clinico-radiologic differentiation from other cardiac masses is not possible in most cases, histopathological examination is the only modality for diagnosis. Hence, histopathologists should be aware of this rare entity in the differential diagnoses of cardiac mass. PMID- 20723250 TI - Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma. AB - BACKGROUND: Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene PON1, located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous PON1 polymorphisms and the risk of developing astrocytoma and meningioma. METHODS: Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous PON1 genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain. RESULTS: The frequencies of the PON1 genotypes and allelic variants of the polymorphisms PON1 L55M and PON1 Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: PON1 55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; PON1 192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the p values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma. CONCLUSIONS: Common nonsynonymous PON1 polymorphisms are not related with the risk of developing astrocytoma and meningioma. PMID- 20723253 TI - Pulmonary hemodynamic responses to in utero ventilation in very immature fetal sheep. AB - BACKGROUND: The onset of ventilation at birth decreases pulmonary vascular resistance (PVR) resulting in a large increase in pulmonary blood flow (PBF). As the large cross sectional area of the pulmonary vascular bed develops late in gestation, we have investigated whether the ventilation-induced increase in PBF is reduced in immature lungs. METHODS: Surgery was performed in fetal sheep at 105 d GA (n = 7; term ~147 d) to insert an endotracheal tube, which was connected to a neonatal ventilation circuit, and a transonic flow probe was placed around the left pulmonary artery. At 110 d GA, fetuses (n = 7) were ventilated in utero (IUV) for 12 hrs while continuous measurements of PBF were made, fetuses were allowed to develop in utero for a further 7 days following ventilation. RESULTS: PBF changes were highly variable between animals, increasing from 12.2 +/- 6.6 mL/min to a maximum of 78.1 +/- 23.1 mL/min in four fetuses after 10 minutes of ventilation. In the remaining three fetuses, little change in PBF was measured in response to IUV. The increases in PBF measured in responding fetuses were not sustained throughout the ventilation period and by 2 hrs of IUV had returned to pre-IUV control values. DISCUSSION AND CONCLUSION: Ventilation of very immature fetal sheep in utero increased PBF in 57% of fetuses but this increase was not sustained for more than 2 hrs, despite continuing ventilation. Immature lungs can increase PBF during ventilation, however, the present studies show these changes are transient and highly variable. PMID- 20723254 TI - Prospective study of urinary tract infection surveillance after kidney transplantation. AB - BACKGROUND: Urinary tract infection (UTI) remains one of the main complications after kidney transplantation and it has serious consequences. METHODS: Fifty-two patients with kidney transplantation were evaluated for UTI at 3-145 days (mean 40.0 days) after surgery.. Forty-two received a graft from a live donor and 10 from a deceased donor. There were 22 female and 30 male patients, aged 11-47 years. Microscopic examinations, leukocyte esterase stick, and urinary culture were performed every third day and weekly after hospitalization. A positive culture was consider when patients presented bacterial counts up to 105 counts. RESULTS: UTI developed in 19/52 (37%) patients at 3-75 days (mean 19.5 days after transplantation. Recurrent infection was observed in 7/52 (13.4%) patients at days 17-65. UTI was more frequent in patients who received deceased grafts compared with live grafts (7/10, 70% vs. 12/42, 28%; p < 0.007). Female patients were more susceptible than male (11/22, 50% vs. 8/22, 36.35%; p < 0.042). Five year survival rate was 94.5% (49/52 patients). Kidney Graft exit update is 47/52 (90.2%), and there were no significant differences between graft rejection and UTI (p = 0.2518). Isolated bacteria were Escherichia coli (31.5%), Candida albicans (21.0%) and Enterococcus spp. (10.5%), followed by Pseudomonas aeruginosa, Klebsiella pneumoniae, Morganella morganii, Enterobacter cloacae and Micrococcus spp. Secondary infections were produced by (7/19, 36.8%). Enterococcus spp. (57%), E. coli (28%) and Micrococcus spp. (14.2%). Antibiotic resistance was 22% for ciprofloxacin and 33% for ampicillin. Therapeutic alternatives were aztreonam, trimethoprim-sulfamethoxazole, netilmicin and fosfomycin. CONCLUSIONS: Surveillance of UTI for the first 3 months is a good option for improving quality of life of kidney transplantation patients and the exit of graft function especially for female patients and those receiving deceased grafts. Antibiograms provided a good therapeutic alternative to patients who presented with UTIs after receiving a kidney allograft. PMID- 20723255 TI - Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients. AB - INTRODUCTION: Purpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels. METHODS: In Germany, patients receiving protein C concentrate (Ceprotin, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study. RESULTS: Complete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03). CONCLUSIONS: This retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial. PMID- 20723256 TI - DNA methylation status of nuclear-encoded mitochondrial genes underlies the tissue-dependent mitochondrial functions. AB - BACKGROUND: Mitochondria are semi-autonomous, semi-self-replicating organelles harboring their own DNA (mitochondrial DNA, mtDNA), and their dysregulation is involved in the development of various diseases. While mtDNA does not generally undergo epigenetic modifications, almost all mitochondrial proteins are encoded by nuclear DNA. However, the epigenetic regulation of nuclear-encoded mitochondrial genes (nuclear mt genes) has not been comprehensively analyzed. RESULTS: We analyzed the DNA methylation status of 899 nuclear mt genes in the liver, brain, and heart tissues of mouse, and identified 636 nuclear mt genes carrying tissue-dependent and differentially methylated regions (T-DMRs). These nuclear mt genes are involved in various mitochondrial functions and they also include genes related to human diseases. T-DMRs regulate the expression of nuclear mt genes. Nuclear mt genes with tissue-specific hypomethylated T-DMRs were characterized by enrichment of the target genes of specific transcription factors such as FOXA2 in the liver, and CEBPA and STAT1 in the brain. CONCLUSIONS: A substantial proportion of nuclear mt genes contained T-DMRs, and the DNA methylation status of numerous T-DMRs should underlie tissue-dependent mitochondrial functions. PMID- 20723257 TI - Cardiac and vascular changes in elderly atherosclerotic mice: the influence of gender. AB - BACKGROUND: Although advanced age is considered a risk factor for several diseases, the impact of gender on age-associated cardiovascular diseases, such as atherosclerotic processes and valvular diseases, remains not completely clarified. The present study was designed to assess aortic valve morphology and function and vascular damage in elderly using the apolipoprotein E knockout (ApoE KO) mouse. Our hypothesis was that advanced age-related cardiovascular changes are aggravated in atherosclerotic male mice. METHODS: The grade (0 to 4) of aortic regurgitation was evaluated through angiography. In addition, vascular lipid deposition and senescence were evaluated through histochemical analyses in aged male and female ApoE KO mice, and the results were compared to wild-type C57BL/6J (C57) mice. RESULTS: Aortic regurgitation was observed in 92% of the male ApoE KO mice and 100% of the male C57 mice. Comparatively, in age-matched female ApoE KO and C57 mice, aortic regurgitation was observed in a proportion of 58% and 53%, respectively. Histological analysis of the aorta showed an outward (positive) remodeling in ApoE KO mice (female: 1.86 +/- 0.15; male: 1.89 +/- 0.68) using C57 groups as reference values. Histochemical evaluation of the aorta showed lipid deposition and vascular senescence only in the ApoE KO group, which were more pronounced in male mice. CONCLUSION: The data show that male gender contributes to the progression of aortic regurgitation and that hypercholesterolemia and male gender additively contribute to the occurrence of lipid deposition and vascular senescence in elderly mice. PMID- 20723258 TI - Unilateral sectioning of the superior ovarian nerve of rats with polycystic ovarian syndrome restores ovulation in the innervated ovary. AB - The present study tested the hypothesis that if polycystic ovary syndrome (PCOS) results from activating the noradrenergic outflow to the ovary, unilaterally sectioning the superior ovarian nerve (SON) will result in ovulation by the denervated ovary, and the restoration of progesterone (P4), testosterone (T) and estradiol (E2) normal serum level. A single 2 mg dose of estradiol valerate (EV) to adult rats results in the development of a syndrome similar to the human PCOS. Ten-day old rats were injected with EV or vehicle solution (Vh) and were submitted to sham surgery, unilateral or bilateral sectioning of the SON at 24 days of age. The animals were sacrificed at 90 to 92 days of age, when they presented vaginal estrus preceded by a pro-estrus smear. In EV-treated animals, unilateral sectioning of the SON restored ovulation by the innervated ovary and unilateral or bilateral sectioning of the SON normalized testosterone and estradiol levels. These results suggest that aside from an increase in ovarian noradrenergic tone in the ovaries, in the pathogenesis of the PCOS participate other neural influences arriving to the ovaries via the SON, regulating spontaneous ovulation. Changes in P4, T and E2 serum levels induced by EV treatment seem to be controlled by neural signals arising from the abdominal wall and other signals arriving to the ovaries through the SON, and presents asymmetry. PMID- 20723259 TI - Ethnic and sex differences in the incidence of hospitalized acute myocardial infarction: British Columbia, Canada 1995-2002. AB - BACKGROUND: As populations in Western countries continue to change in their ethnic composition, there is a need for regular surveillance of diseases that have previously shown some health disparities. Earlier data have already demonstrated high rates of cardiovascular mortality among South Asians and relatively lower rates among people of Chinese descent. The aim of this study was to describe the differences in the incidence of hospitalized acute myocardial infarction (AMI) among the three largest ethnic groups in British Columbia (BC), Canada. METHODS: Using hospital administrative data, we identified all patients with incident AMI in BC between April 1, 1995, and March 31, 2002. Census data from 2001 provided the denominator for the entire BC population. Ethnicity was determined using validated surname analysis and applied to the census and hospital administrative datasets. Direct age standardization was used to compare incidence rates. RESULTS: A total of 34,848 AMI cases were identified. Among men, South Asians had the highest age standardized rate of AMI hospitalization at 4.97/1000 population/year, followed by Whites at 3.29, and then Chinese at 0.98. Young South Asian men, in particular, showed incidence rates that were double that of young Whites and ten times that of young Chinese men. South Asian women also had the highest age-standardized rate of AMI hospitalization at 2.35/1000 population/year, followed by White women (1.53) and Chinese women (0.49). CONCLUSIONS: South Asians continue to have a higher incidence of hospitalized AMI while incidence rates among Chinese remain low. Ethnic differences are most notable among younger men. PMID- 20723260 TI - Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder. AB - BACKGROUND: Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine. METHODS: Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models. RESULTS: The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively. CONCLUSIONS: A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials. TRIAL REGISTRATION: The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723). PMID- 20723261 TI - Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV infected patients. AB - BACKGROUND: The 516G > T polymorphism in exon 4 of the CYP2B6 gene has been associated with increased plasma Efavirenz (EFV) concentrations. EFV concentrations greater than the recommended therapeutic range have been associated with the increased likelihood of developing adverse CNS effects. The aims of this study were to a) determine the presence of the 516G > T and other CYP2B6 exon 4 polymorphisms in a South African group of HIV-infected individuals b) investigate the relationship between the EFV plasma concentrations, the CYP2B6 516G > T polymorphism and the occurrence of CNS related side effects in this group of patients and c) develop and validate a rapid method for determination of EFV in plasma. METHOD: Data from 80 patients is presented. Genetic polymorphisms in exon 4 of the CYP2B6 gene were identified using PCR amplification of this region followed by sequencing of the amplification products. EFV concentrations were analysed by UPLC-MS/MS. Assessment of the presence of CNS related side effects following EFV initiation were elicited with the use of a questionnaire together with physical examination. RESULTS: Plasma EFV concentrations displayed high inter-individual variability amongst subjects with concentrations ranging from 94 mug/l to 23227 mug/l at 2 weeks post initiation of treatment. For the 516G > T polymorphism the following frequencies were observed 23% of patients were TT homozygous, 36% GG and 41% GT. The TT homozygous patients had significantly higher EFV concentrations vs. those with the wild (GG) genotype (p < 0.05). Patients who experienced no side effects had significantly lower EFV plasma concentrations vs. the group of patients which experienced the most severe side effects (p < 0.05). CONCLUSION: The significant association between the 516G > T polymorphism and plasma EFV concentrations has been demonstrated in this study. A rapid and sensitive method for the measurement of plasma EFV concentration was developed and validated. PMID- 20723262 TI - Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis. AB - BACKGROUND: Young women diagnosed with breast cancer are known to have a higher mortality rate from the disease than older patients. Specific risk factors leading to this poorer outcome have not been identified. In the present study, we hypothesized that iron deficiency, a common ailment in young women, contributes to the poor outcome by promoting the hypoxia inducible factor-1alpha (HIF-1alpha and vascular endothelial growth factor (VEGF) formation. This hypothesis was tested in an in vitro cell culture model system. RESULTS: Human breast cancer MDA MB-231 cells were transfected with transferrin receptor-1 (TfR1) shRNA to constitutively impair iron uptake. Cellular iron status was determined by a set of iron proteins and angiogenesis was evaluated by levels of VEGF in cells as well as by a mouse xenograft model. Significant decreases in ferritin with concomitant increases in VEGF were observed in TfR1 knockdown MDA-MB-231 cells when compared to the parental cells. TfR1 shRNA transfectants also evoked a stronger angiogenic response after the cells were injected subcutaneously into nude mice. The molecular mechanism appears that cellular iron deficiency elevates VEGF formation by stabilizing HIF-1alpha. This mechanism is also true in human breast cancer MCF-7 and liver cancer HepG2 cells. CONCLUSIONS: Cellular iron deficiency increased HIF-1alpha, VEGF, and angiogenesis, suggesting that systemic iron deficiency might play an important part in the tumor angiogenesis and recurrence in this young age group of breast cancer patients. PMID- 20723263 TI - Acute morbidity and complications of thigh compartment syndrome: A report of 26 cases. AB - BACKGROUND: To describe the patient population, etiology, and complications associated with thigh compartment syndrome (TCS). TCS is a rare condition, affecting less than 0.3% of trauma patients, caused by elevated pressure within a constrained fascial space which can result in tissue necrosis, fibrosis, and physical impairment in addition to other complications. Compartment releases performed after irreversible tissue ischemia has developed can lead to severe infection, amputation, and systemic complications including renal insufficiency and death. METHODS: This study examines the course of treatment of 23 consecutive patients with 26 thigh compartment syndromes sustained during an eight-year period at two Level 1 trauma centers, each admitting more than 2,000 trauma patients yearly. RESULTS: Patients developing TCS were young (average 35.4 years) and likely to have a vascular injury on presentation (57.7%). A tense and edematous thigh was the most consistent clinical exam finding leading to compartment release (69.5%). Average time from admission to the operating room was 18 +/- 4.3 hours and 8/23 (34.8%) were noted to have ischemic muscle changes at the time of release. Half of those patients (4/8) developed local complications requiring limb amputations. CONCLUSION: TCS is often associated with high energy trauma and is difficult to diagnose in uncooperative, obtunded and multiply injured patients. Vascular injuries are a common underlying cause and require prompt recognition and a multidisciplinary approach including the trauma and orthopaedic surgeons, intensive care team, vascular surgery and interventional radiology. Prompt recognition and treatment of TCS are paramount to avoid the catastrophic acute and long term morbidities. PMID- 20723264 TI - Young pregnant women's views on the acceptability of screening for chlamydia as part of routine antenatal care. AB - BACKGROUND: In pregnancy, untreated chlamydia infection has been associated with adverse outcomes for both mother and infant. Like most women, pregnant women infected with chlamydia do not report genital symptoms, and are therefore unlikely to be aware of their infection. The aim of this study was to determine the acceptability of screening pregnant women aged 16-25 years for chlamydia as part of routine antenatal care. METHODS: As part of a larger prospective, cross sectional study of pregnant women aged 16-25 years attending antenatal services across Melbourne, Australia, 100 women were invited to participate in a face-to face, semi structured interview on the acceptability of screening for chlamydia during pregnancy. Women infected with chlamydia were oversampled (n = 31). RESULTS: Women had low levels of awareness of chlamydia before the test, retained relatively little knowledge after the test and commonly had misconceptions around chlamydia transmission, testing and sequelae. Women indicated a high level of acceptance and support for chlamydia screening, expressing their willingness to undertake whatever care was necessary to ensure the health of their baby. There was a strong preference for urine testing over other methods of specimen collection. Women questioned why testing was not already conducted alongside other antenatal STI screening tests, particularly in view of the risks chlamydia poses to the baby. Women who tested positive for chlamydia had mixed reactions, however, most felt relief and gratitude at having had chlamydia detected and reported high levels of partner support. CONCLUSIONS: Chlamydia screening as part of routine antenatal care was considered highly acceptable among young pregnant women who recognized the benefits of screening and strongly supported its implementation as part of routine antenatal care. The acceptability of screening is important to the uptake of chlamydia screening in future antenatal screening strategies. PMID- 20723266 TI - The arcuate uterine anomaly: a critical appraisal of its diagnostic and clinical relevance. AB - The diagnostic criteria and clinical relevance of the arcuate uterine anomaly have long been debated. Our review critically examines the contemporary and past literature regarding the definition, prevalence, and clinical impact of the arcuate uterine anomaly on reproductive outcomes. To bring a novel perspective to the debate, we examined studies evaluating the clinical significance of the presence of a residual septal stump following surgical resection, which has morphology comparable to that of the arcuate anomaly. The balance of the existing literature does not support an association of the arcuate anomaly to adverse reproductive outcomes. Hysteroscopic resection of arcuate anomaly does not appear to be universally indicated. Treatment decisions should be individualized at clinician discretion for symptomatic patients without otherwise identifiable etiology. TARGET AUDIENCE: General Obstetricians & gynecologists, Reproductive Endocrinology & Infertility Specialists and Radiologists. LEARNING OBJECTIVES: After completion of this article, the reader should be able to distinguish the arcuate uterine anomaly and its diagnosis, demonstrate its clinical significance, and what impact, if any, it may have on reproductive potential. Furthermore, the reader should be able to assess which patient population, if any, might benefit from surgical management of the arcuate anomaly. PMID- 20723265 TI - Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response. AB - BACKGROUND: Resveratrol (RES), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. However, the underlying molecular mechanisms are at present only partially understood. METHOD: The effects of RES on activation of unfolded protein responses (UPR) were evaluated using Western blotting, semi quantitative and real-time RT-PCR. Cell death was evaluated using Annexin V/PI staining and subsequent FACS. RESULTS: Similar as tunicamycin, treatment with RES lead to the activation of all 3 branches of the UPR, with early splicing of XBP-1 indicative of IRE1 activation, phosphorylation of eIF2alpha consistent with ER resident kinase (PERK) activation, activating transcription factor 6 (ATF6) splicing, and increase in expression levels of the downstream molecules GRP78/BiP, GRP94 and CHOP/GADD153 in human Burkitt's lymphoma Raji and Daudi cell lines. RES was shown to induce cell death, which could be attenuated by thwarting upregulation of CHOP. CONCLUSIONS: Our data suggest that activation of the apoptotic arm of the UPR and its downstream effector CHOP/GADD153 is involved, at least in part, in RES-induced apoptosis in Burkitt's lymphoma cells. PMID- 20723267 TI - Paraneoplastic dermatoses associated with gynecologic and breast malignancies. AB - Paraneoplastic dermatoses are a heterogeneous group of skin disorders that manifest an underlying internal malignancy. Early recognition of these cutaneous hallmarks offers an opportunity for early diagnosis, treatment of the internal malignancy and monitoring for tumor recurrence. The 9 most common paraneoplastic and metastatic cutaneous manifestations of malignancies found in women with gynecologic or breast disease are reviewed including a review of multicentric reticulohistiocytosis, dermatomyositis, malignant acanthosis nigricans, erythema gyratum repens, hypertrichosis lanuginosa acquisita, Sweet syndrome, Paget disease, extramammary Paget disease, and Sister Mary Joseph nodule. TARGET AUDIENCE: General obstetricians & gynecologists, reproductive endocrinology & infertility specialists, radiologists. LEARNING OBJECTIVES: After completion of this educational activity, the participant should be better able to identify cutaneous manifestations of gynecologic malignancies, evaluate patients with a thorough workup to screen those who have dermatoses suggestive of malignancy and assess patients with malignancy for the opportunity of early diagnosis and appropriate treatment. PMID- 20723268 TI - Diagnosis and management of bacterial vaginosis and other types of abnormal vaginal bacterial flora: a review. AB - Bacterial vaginosis (BV) is a common cause of abnormal vaginal discharge. It is characterised by an overgrowth of predominantly anaerobic organisms (Gardnerella vaginalis, Prevotella spp., Peptostreptocci, Mobiluncus spp.) in the vagina leading to a replacement of lactobacilli and an increase in vaginal pH. BV can arise and remit spontaneously, but often presents as a chronic or recurrent disease. BV is found most often in women of childbearing age, but may also be encountered in menopausal women, and is rather rare in children. The clinical and microscopic features and diagnosis of BV are herein reviewed, and antibiotic and non-antibiotic treatment approaches discussed. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the participant should be better able to analyze bacterial vaginosis clinically, formulate an oral antibiotic treatment regimen for bacterial vaginosis and use vaginal treatments for bacterial vaginosis. PMID- 20723269 TI - Ventricular tachycardia in infants with structurally normal heart: a benign disorder. AB - We evaluated the presentation, treatment, and outcome of infants who present with ventricular tachycardia in the first year of life. Seventy-six infants were admitted to our institution with a diagnosis of ventricular tachycardia between January, 1987 and May, 2006. Forty-five infants were excluded from the study because of additional confounding diagnoses including accelerated idioventricular rhythm, Wolff-Parkinson-White syndrome, supraventricular tachycardia with aberrancy, long QT syndrome, cardiac rhabdomyoma, myocarditis, congenital lesions, or incomplete data. The remaining 31 included infants who had a median age at presentation of 1 day, with a range from 1 to 255 days, and a mean ventricular tachycardia rate of 213 beats per minute, with a range from 171 to 280, at presentation. The infants were treated chronically with propranolol (38.7%), amiodarone (12.9%), mexiletine (3.2%), propranolol and mexiletine (9.7%), or propranolol and procainamide (6.5%). The median duration of treatment was 13 months, with a range from 3 to 105 months. Ventricular tachycardia resolved spontaneously in all infants. No patient died, or received catheter ablation or device therapy. Median age at last ventricular tachycardia was 59 days, with a range from 1 to 836 days. Mean follow-up was 45 months, with a range from 5 to 164 months, with a mean ventricular tachycardia-free period of 40 months. Infants with asymptomatic ventricular tachycardia, a structurally normal heart, and no additional electrophysiological diagnosis all had spontaneous resolution of tachycardia. Furthermore, log-rank analysis of the time to ventricular tachycardia resolution showed no difference between children who received chronic outpatient anti-arrhythmic treatment and those who had no such therapy. While indications for therapy cannot be determined from this study, lack of symptoms or myocardial dysfunction suggests that therapy may not be necessary. PMID- 20723270 TI - Anomalous origin of the pulmonary artery from the aorta: early diagnosis and repair leading to immediate physiological correction. AB - INTRODUCTION: Anomalous origin of one pulmonary artery from the ascending aorta is a rare cardiac anomaly in which the pulmonary artery abnormally arises from the ascending aorta. Physiologically, most patients develop signs of cardiac failure due to high flow to both lungs, with systemic or supra-systemic pressures in the normally connected lung. The purpose of this study is to present our experience with this rare anomaly, in which early anatomic repair lead to rapid physiologic correction. MATERIALS AND METHODS: Retrospective case review of all patients with anomalous origin of one pulmonary artery from the ascending aorta at Schneider Children's Medical center of Israel between 1986 and 2007. All clinical operative and echocardiographic charts were analysed. RESULTS: Twelve patients were diagnosed as anomalous origin of one pulmonary artery from the ascending aorta. In 10 patients, the right pulmonary artery rose from the ascending aorta, while in two an anomalous origin of the left pulmonary artery was associated with a right aortic arch. Initial diagnoses was made with two dimensional echocardiography in all patients. In six patients, diagnostic cardiac catheterisation was performed in order to confirm the diagnosis. Age at diagnosis ranged from 5 to 180 days with a median of 15 days, and patient weight ranged from 780 grams to 5 kilograms, with a median of 3 kilograms. Initial echocardiographic evaluation showed systemic (four patients) or supra-systemic (seven patients) pressures in the right ventricle and normally connected lung. All underwent surgical repair. There was no operative mortality. All reconstructed patients achieved normal right ventricular pressures within days after surgery. The flow pattern in both pulmonary arteries was normalised. CONCLUSIONS: Early surgical repair of anomalous origin of one pulmonary artery from the ascending aorta is feasible and safe even in newborn and premature babies with complete resolution of the pulmonary hypertension and normalisation of pulmonary vascular resistance. PMID- 20723271 TI - Morbidity after paediatric cardiac surgery assessed with usage of medicines: a population-based registry study. AB - OBJECTIVE: To examine the overall morbidity of patients who underwent surgery for congenital cardiac defect during childhood. BACKGROUND: A congenital cardiac defect treated with surgery is seldom totally cured. The incidence of residua, sequelae, and comorbidity is quite high. The morbidity has not been thoroughly examined. METHODS AND PATIENTS: Medication was used as an indicator of morbidity. Data from the Finnish Research Registry of Paediatric Cardiac Surgery were linked to data from the medication registry of Finland's Social Insurance Institution. This study includes 5116 patients with a mean age of 33.5 (ranged from 14.7 to 64.8) years, who had undergone surgery for congenital cardiac defect between 1953 and 1989. The use of medicines among patients in 2004 was compared with 10232 age and sex-matched control subjects. RESULTS: The overall use of medicines was frequent; 62% of patients and 53% of controls had purchased at least one prescribed medicine (risk ratio: 1.2, 95% confidence interval: 1.1-1.2). The number of patients using cardiovascular medicines (17%) and anti-thrombotic agents (5%) was higher than that of control subjects (risk ratio: 2.2 and 8.4). In addition, the patients needed medicinal care for epilepsy (3%), asthma (7%), and psychiatric diseases (10%) more often than did controls (risk ratio: 2.2, 1.5, and 1.3, respectively). CONCLUSION: Patients operated on for congenital cardiac defect had more chronic diseases and used more medicines than did controls. PMID- 20723272 TI - Transient complete atrioventricular block after percutaneous pulmonary valve implantation. AB - Percutaneous pulmonary valve implantation for conduit dysfunction in the right ventricular outflow tract is a safe and efficient treatment in selected patients. We report on a patient with stenosis and regurgitation of a homograft in the right ventricular outflow tract who developed complete atrioventricular block during percutaneous implantation of a MelodyTM valve. This complete atrioventricular block spontaneously reverted to a stable sinus rhythm after 3 weeks. PMID- 20723273 TI - Bovine colostrum is superior to enriched formulas in stimulating intestinal function and necrotising enterocolitis resistance in preterm pigs. AB - Milk contains immunomodulatory compounds that may be important to protect the immature intestine in preterm neonates from harmful inflammatory reactions involved in disorders like necrotising enterocolitis (NEC). We hypothesised that bovine colostrum and milk formulas enriched with sialic acids (SL), gangliosides (Gang) or osteopontin (OPN) would improve gastrointestinal function and NEC resistance in preterm neonates. Forty-seven caesarean-delivered preterm pigs were given total parenteral nutrition for 2 d followed by 1.5 d of enteral feeding. In Expt 1, a control formula was compared with an OPN-enriched formula (n 13), while Expt 2 compared a control formula with bovine colostrum or formulas enriched with Gang or SL (n 4-6). OPN enrichment decreased NEC severity relative to control formula (P < 0.01), without any significant effects on NEC incidence, digestive enzyme activities and hexose absorption. Neither SL- nor Gang-enriched formulas improved NEC resistance or digestive functions, while all the intestinal functional parameters were significantly improved in pigs fed bovine colostrum, relative to formula. The effects in vivo were supported in vitro by bacteria- and dose-dependent modulation by colostrum whey of the cytokine response from bacteria-stimulated murine bone marrow-derived dendritic cells (DC). In conclusion, OPN had only moderate NEC-protective effects, while formulas enriched with Gang or SL were ineffective. The observed modulation of DC cytokine response by bovine colostrum whey in vitro may be due to a synergistic action of various milk bioactives, and it may explain its beneficial effects on NEC development and intestinal function in a piglet model of preterm infants. PMID- 20723274 TI - Investigating children at high risk for bipolar and psychotic disorders: findings and implications. PMID- 20723275 TI - The early natural history of bipolar disorder: what we have learned from longitudinal high-risk research. AB - Longitudinal high-risk research has provided convergent evidence that major mood and psychotic disorders often develop from nonspecific antecedents in predisposed people over time and development. For example, bipolar disorder (BD) appears to evolve from nonspecific childhood antecedents, including anxiety and sleep problems, followed by adjustment and minor mood disturbances through early adolescence, culminating in major mood episodes in later adolescence and early adulthood. Therefore, the current cross-sectional symptom-based diagnostic approach requires rethinking: it considers neither the familial risk nor the longitudinal clinical course, with the consequence that the early stages of illness are not recognized as belonging to the end-stage disorder. Emerging evidence of identifiable clinical stages in the development of BD has tremendous potential for early identification, development of stage-specific treatments, and advancing our understanding of the pathophysiology associated with illness onset and progression. The clinical staging model also has direct implications for the optimal organization of clinical services for high-risk youth. Specifically, specialty psychiatric programs are needed that break down traditional institutional barriers to provide surveillance and timely comprehensive psychiatric assessment during the entire risk period, from childhood through to early adulthood. In this regard, the development of specialty psychiatric programs aiming to identify youth in the early stages of evolving psychosis are substantially ahead of services for youth in the early stages of evolving major mood disorders. PMID- 20723276 TI - Clinical staging: a heuristic and practical strategy for new research and better health and social outcomes for psychotic and related mood disorders. AB - Most mental illnesses emerge during adolescence and early adulthood, with considerable associated distress and functional decline appearing during this critical developmental phase. Our current diagnostic system lacks therapeutic validity, particularly for the early stages of mental disorders when symptoms are still emerging and intensifying and have not yet stabilized sufficiently to fit the existing syndromal criteria. While this is, in part, due to the difficulty of distinguishing transient developmental or normative changes from the early symptoms of persistent and disabling mental illness, these factors have contributed to a growing movement for the reform of our current diagnostic system to more adequately inform the choice of therapeutic strategy, particularly in the early stages of a mental illness. The clinical staging model, which defines not only the extent of progression of a disorder at a particular point in time but also where a person lies currently along the continuum of the course of an illness, is particularly useful as it differentiates early, milder clinical phenomena from those that accompany illness progression and chronicity. This will not only enable clinicians to select treatments relevant to earlier stages of an illness, where such interventions are likely to be more effective and less harmful than treatments delivered later in the course of illness, but also allow a more efficient integration of our rapidly expanding knowledge of the biological, social, and psychological vulnerability factors involved in the development of mental illness into a useful diagnostic framework. PMID- 20723277 TI - Subtyping study of a pathological gamblers sample. AB - OBJECTIVE: To classify into subgroups a sample of pathological gambling (PG) patients according to personality variables and to describe the subgroups at a clinical level. METHOD: PG patients (n = 1171) were assessed with the South Oaks Gambling Screen; the Temperament and Character Inventory-Revised; the Symptom Checklist-90-Revised; Eysenck's Impulsivity Scales, a diagnostic questionnaire for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) PG criteria; and the Structured Clinical Interview for the DSM-IV, Axis I disorders, substance use module. Clinical measures were collected through a semi-structured interview. We performed a 2-step cluster analysis based on the above-mentioned personality variables. Clinical data were compared across clusters. RESULTS: Four clusters were generated. Type I (disorganized and emotionally unstable) showed schizotypic traits, high impulsiveness, substance and alcohol abuse, and early age of onset, as well as psychopathological disturbances. Type II (schizoid) showed high harm avoidance, social aloofness, and alcohol abuse. Type III (reward sensitive) showed high sensation seeking and impulsiveness but no psychopathological impairments. Type IV (high-functioning) showed a globally adaptive personality profile, low level of substance and alcohol abuse or smoking, and no psychopathological disturbances. CONCLUSIONS: At least 4 types of PG patients may be identified. Two types showed a response modulation deficit, but only one of them had severe psychopathological disturbances. Two other types showed no impulsiveness or sensation seeking and one of them even exhibited good general functioning. The different personality and clinical configuration of these clusters might be linked to different therapeutic approaches. PMID- 20723278 TI - Does early emotional distress predict later child involvement in gambling? AB - OBJECTIVE: Younger people are engaging in gambling, with some showing excessive involvement. Although a consequence of gambling could be anxiety and depression, emotional distress could be a precursor to gambling involvement. This could reflect developmental proneness toward problem behaviour. We assessed whether early emotional distress directly influences later gambling or if it operates through an indirect pathway. METHODS: Using a prospective longitudinal design, an intentional subsample of children from the 1999 kindergarten cohort of the Montreal Longitudinal Preschool Study (Quebec) from intact families were retraced in 2005 for follow-up in Grade 6. Consenting parents and children were separately interviewed. Key child variables and sources included kindergarten teacher ratings of emotional distress and impulsivity and self-reported parent and child gambling. RESULTS: Higher levels of teacher-rated emotional distress in kindergarten significantly predicted a higher propensity toward later gambling behaviour. Impulsivity, a factor often comorbidly present with emotional distress, completely explained this predictive relation above and beyond potential child- and family-related confounds, including parental gambling. CONCLUSIONS: Children with higher levels of emotional distress at kindergarten were more inclined toward child gambling behaviour in Grade 6. The influence of early emotional distress completely vanished when behaviours reflecting impulsivity were considered when predicting later child gambling behaviour. The relation between emotional distress and child gambling involvement in children was thus explained by its comorbidity with early impulsivity. This study does not rule out the possibility that emotional distress could become a correlate or consequence of excessive involvement in gambling activities at a later developmental period. PMID- 20723280 TI - [French adaptation and validation of the scale to assess unawareness of mental disorder]. AB - OBJECTIVES: To validate the French version of the Scale to Assess Unawareness of Mental Disorder (SUMD) in patients with schizophrenia. METHOD: One hundred patients with schizophrenic disorders were included. Our statistical analyses evaluated interrater reliability, theoretical validity, and convergent or divergent validity. Finally, an exploratory factor analysis was conducted. RESULTS: The results revealed good psychometric properties for the French version of the SUMD. Both interrater reliability (ICC ranged from 0.68 to 1.00) and internal consistency (Cronbach 0.70) were satisfactory. Criterion validity was confirmed by high correlation values between SUMD scores and scores on the Positive and Negative Syndrome Scale G12 item evaluating insight. Moreover, as hypothesized, there were few associations between SUMD scores and clinical variables. Finally, Principal Component Analyses confirmed the hypothesis of 2 distinct insight dimensions (consciousness and attribution) for both present and past aspects. CONCLUSIONS: This French version of the SUMD is a reliable and valid measure of insight in schizophrenia. The clinical relevance of its measure and the development of psychosocial interventions to improve insight into illness in patients with schizophrenia are discussed. PMID- 20723279 TI - Persistence and remission of psychiatric disorders in the quebec older adult population. AB - OBJECTIVE: To document the remission and persistence of psychiatric disorders in Quebec's older adult population. METHOD: Data came from the Enquete sur la sante des aines (ESA) study conducted in 2005-2008 using a representative sample (n = 2784) of community-dwelling older adults. RESULTS: The ESA study results indicate that 12% of respondents met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression, mania, anxiety disorders, or benzodiazepine drug dependency at the baseline interview. The results also indicate that the 12-month rate of patients with a persistent psychiatric condition was 19.4%. Sixty-seven percent of the patients in remission experienced a total recovery of their symptoms during the following year. The probability of presenting a persistent psychiatric condition or a partial remission after 1 year of follow-up, compared with those in total remission, did not vary according to sociodemographic characteristics. The results also showed that social support and the number of chronic health problems did not influence mental health at follow-up. However, results indicated that the use of health services (OR 7.4; 95% CI 3.72 to 14.55) and the change in the number of chronic health problems reported between baseline and the second interview (OR 1.2; 95% CI 1.06 to 1.34) increased the probability of patients with prevalent disorders at Time 1 having persistent disorders at Time 2. CONCLUSION: Results suggest that a deterioration of physical health status was associated with the persistence of DSM-IV disorders in the elderly. These results also suggest that the use of mental health services is associated with severity of the mental illness. PMID- 20723281 TI - Frequency of antidepressant use in relation to recent and past major depressive episodes. AB - OBJECTIVE: There has been a trend toward increasing antidepressant (AD) use in recent decades. We used data from the National Population Health Survey (NPHS) to determine whether this trend is continuing and to provide updated estimates of the frequency of use. METHODS: The NPHS is a longitudinal general health survey that began collecting data in 1994. The NPHS evaluates past-year major depressive episodes (MDEs) using a brief diagnostic instrument. At each biannual interview (from 1994 to 2006) current medication use is recorded. We estimated the frequency with which ADs were taken by respondents (aged 12 years and older) with and without past-year MDEs. These frequencies were cross-tabulated by sex, year of interview, and the reported duration of symptoms. RESULTS: ADs are taken by about 5.4% of the household population at any point in time. Most respondents taking ADs did not report past-year MDEs but 63.9% of respondents taking ADs in the absence of past-year episodes reported previous episodes or being diagnosed by a health professional with depression. This pattern is consistent with long term treatment for relapse prevention. The overall frequency of use of ADs is increasing only in respondents without past-year episodes. CONCLUSIONS: AD use among community residents with past-year MDEs is no longer increasing. The continued increase in the overall frequency of use may point toward broadening indications for AD treatment and may indicate that people are taking these medications for longer periods of time. PMID- 20723282 TI - [Leukocyte synapse: structure, function and significance]. AB - Neuronal synapse is the critical structure of neuronal network. Immune system is mainly consisted of invisible network. Recently, evidence showed that leukocyte synapses between immune cells named as immunological synapses (IS), were formed under some functional conditions to form temporal local network. In fact, they are dynamic structures, which can be classified into synapse and kinase. Different leukocytes have different synapses. Inflammatory and leukemic cells showed special patterns of IS. Similar structure is also observed in some viral infected lymphocytes, which is called virological synapse (VS). This is one of the mechanisms for viral transmission, not only enhancing the transmission efficiency but also mediating the escape from antibody neutralization, leading persistent infection. Recently the flower-like poly synapses was reported by French scientists. This is a multi-tunneling nanotube flower-like structure on cell surface. We had observed this kind of structure in EB virus infected human leukemic cell line J6-2. In this paper, the structure and function of leukocyte synapses are reviewed combined with authors' own work. Their significance is discussed. PMID- 20723283 TI - [Expression of growth-factor independence 1 in patients with leukemia and its significance]. AB - This study was purposed to investigate the expression of the growth-factor independence 1 (GFI1) in patients with leukemia and its clinical significance. Bone marrow mononuclear cells were obtained from 65 newly diagnosed leukemia patients including 24 acute myeloid leukemia (AML), 18 chronic myelogenous leukemia (CML), 6 acute lymphoblastic leukemia (ALL), 17 blast crisis of chronic myelogenous leukemia and 13 patients with iron deficiency anemia (IDA) were used as controls. The relative expression of gene gfi1 was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and taqman quantitative real time reverse transcription polymerase chain reaction (QRT-PCR). The results showed that gene expression of gene gfi1 in leukemia patients was obviously higher than that in controls and the difference was statistically significant (p < 0.01), in which the expression of gene gfi1 in newly diagnosed CML patients was higher than that in newly diagnosed AML, newly diagnosed ALL, CML-BCP patients and the difference was significant (p < 0.01). Expression of gene gfi1 in lymphocytic blast crisis of CML was higher than that in nonlymphocytic blast crisis of CML, and the difference was significant. It is concluded that gene gfi1 may play an important role in leukemia, especially in CML incidence and progression. The high level expression of gene gfi1 may be participate in the development of lymphoma. PMID- 20723284 TI - [Bag3 gene expression in chronic lymphocytic leukemia and its association with patients' prognosis]. AB - The aim of this study was to investigate bag3 gene expression in chronic lymphocytic leukemia (CLL)patients and its association with clinical prognosis. A total of 46 blood samples from untreated CLL patients were collected, SYBR Green based real-time PCR was used to detect the bag3 mRNA expression, and its association with prognostic index was analyzed by statistical software. The results showed that the median values of bag3 level detected by real-time PCR in 46 CLL patients and normal controls were 0.021 (0.0007 - 1.124) and 0.0025 (0.0005 - 0.014) respectively, the former was significantly higher than the latter. The bag3 level in drug-resistant group was obviously higher as compared with the drug-responsive group. No association was found between bag3 expression and patient clinical baseline information (gender and age) as well as established prognostic factors (lymphocyte count, disease stage, IgVH mutation status, cytogenetics analysis and CD38, ZAP 70 expression). It is concluded that the bag3 expression in CLL patients is markedly higher than that in normal controls, while the high bag3 level in CML patients is probably related with drug resistance, but is not related with clinically established prognostic factors. PMID- 20723285 TI - [Detection of puma mRNA levels by real-time quantitative RT-PCR in chronic lymphocytic leukemia and its clinical significance]. AB - This study was aimed to investigate the expression level of puma (p53 up regulated modulator of apoptosis) mRNA in chronic lymphocytic leukemia (CLL) and its significance in evaluation of CLL prognosis. The puma mRNA expressions in 100 CLL patients and 11 normal controls were measured by relative quantification RT PCR with fluorescent dye SYBR Green I, the beta-actin was used as internal reference. The difference of puma expression rate between groups with different prognostic factors was described using the Mann-Whitney U test. The relative quantitative value of puma expression was calculated by means of 2 (-DeltaCt). The results indicated that the correlation coefficients of the standard curves in qRT-PCR were >= 0.99. The coefficients of variations (CV) within group or between groups were < 5%, and the sensitivity reached 102 copies/microg RNA. The median puma mRNA expression level was 1.038 x 10-3 (4.106 x 10-4 - 2.806 x 10-3) in CLL patients, which was 1.220 x 10-3 (7.233 x 10-4 - 1.405 x 10-3) in normal controls. There was no difference of puma mRNA expression between CLL patients and normal controls (U = 544.5, p = 0.957). Puma expression was significantly correlated with Binet stages (p < 0.001), expression of CD38 (p = 0.002), ZAP-70 protein (p = 0.012), LDH levels (p = 0.009) and beta2-MG (p = 0.046). The puma expression level in patients with earlier Binet stage (Binet stage A) was obviously higher than that in patients with later Binet stage (Binet stage B, C). The puma expression levels in patients with positive expression of CD38 and ZAP 70 protein, elevating levels of LDH and beta2-MG were sharply lower than those in patients without above-mentioned unfavorable factors. The puma expression was also correlated with molecular cytogenetic abnormalities, the puma expression levels in patients with trisomy 12 (p = 0.003) and 14q32 translocation (p = 0.045) detected by FISH were significantly lower than those in patients without above-mentioned molecular cytogenetic abnormalities. It is concluded that the qRT PCR assay is reliable and sensitive. Puma mRNA expression is significantly correlated with a great deal of prognostic factors, and may be a prognostic marker of CLL. PMID- 20723286 TI - [Gfi-1 expression in leukemia patients and inhibitory effects of lentiviral vector mediated silence of Gfi-1 gene on proliferation in K562 cells]. AB - This study was aimed to quantitatively detect the expression levels of gfi-1 gene in leukemia patients, and to investigate the effect of gfi-1 gene silenced by short hairpin RNA (shRNA) on proliferation of leukemia cell line K562. Quantitative real-time PCR and Western blot were used to detect the mRNA and protein expression levels of GFI-1 in newly diagnosed patients with leukemia. One pair of oligonucleotide sequences targeted at human gfi-1 mRNA were designed and synthesized. The annealed oligonucleotide fragments were subcloned into pLVTHM vector. Virus particles were collected when the control and shRNA vectors had been co-transfected with the psPAX2 packaging plasmid and the envelope plasmid pMD2 G into HEK-293T cells using Lipofectamine 2000. The K562 cells were transfused with 1 x 106 recombinant lentivirus-transfusing units plus 6 microg/ml of polybrene. Rea-time PCR and Western blot were used to detect the expressions of gfi-1 and bax mRNA after lentivirus transfusion. CCK-8 assays was used to evaluate the proliferation potential of cells. The results showed that the gfi-1 expression level in all leukemia patients was significantly higher than that in normal group (p < 0.05); the gfi-1 mRNA expression in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) patients was significantly higher than that in normal group (p < 0.05); but the difference of gfi-1 mRNA expression between AL and CML or ALL and AML was not significant. Notably, the gfi-1 mRNA expression level had a positive correlation with high white blood cell count of > 20.0 x 109/L (p < 0.05). As was expected, the mRNA and protein level of gfi-1 was reduced significantly in K562 cells after lentivirus transfusion, whereas the mRNA and protein level of bax was upregulated. And CCK-8 assay showed that gfi-1 gene silencing can inhibit K562 proliferation. It is concluded that gfi-1 expression is upregulated in leukemia patients and may contribute to leukemogenesis. The gfi-1 specific shRNA mediated by lentivirus can effectively down-regulate the expression of gfi-1 and inhibit the proliferation of K562 cells, which lay a basis for further research on gene therapy in leukemia. PMID- 20723287 TI - [Quantification of prame gene transcript in chronic myeloid leukemia]. AB - This study was purposed to analyze the expression level of preferentially expressed antigen of melanoma (prame) transcript in the patients with chronic myeloid leukemia (CML) and explore its clinical significance. Real-time quantitative PCR (RQ-PCR) assay was used to detect the level of prame gene transcript in the bone marrow samples from 30 patients with CML and 15 patients with iron deficiency anemia (IDA). The results showed that CML patients had significantly higher prame mRNA level (0% - 772.25%, median 8.28%) than IDA cases (0% - 1.46%, median 0.19%) (p < 0.001). The level of prame gene transcript was significantly correlated with that of bcr-abl fusion gene transcript (r = 0.708, p < 0.001) in CML patients. Furthermore, 6 patients in blastic crisis (BC) and accelerated phase (AP) had significantly higher prame gene transcript than that of 24 cases in chronic phase (CP) (p = 0.007). In 2 CML patients with sequential samples, prame gene transcript increased in AP and BC, compared with in CP, and was consistent with the altering tendency of bcr-abl transcript. It is concluded that the level of prame gene transcript increases in CML which associates with the progression of the disease, prame gene transcript level can be used for monitoring the disease state. PMID- 20723288 TI - [Analysis of CEBPA mutation in acute myeloid leukemia]. AB - In order to evaluate the incidence of CCAAT/enhancer binding protein alpha (cebpa) gene mutation in patients with acute myeloid leukemia (AML), 22 AML patients with normal karyotype (NK-AML) were enrolled in this study, including de novo AML and relapsed AML. The cebpa gene was amplified by 2 stages using genomic DNA as template, the cebpa gene mutation amplified product was detected by direct sequencing or clone sequencing. The results showed that the cebpa mutations including deletion and insertion were found in 4 out of 22 AML patients (18.2%) and all of these 4 patients were M(2). Two patients had N-terminal nonsense mutation and the other two had C-terminal in-frame mutation. It is concluded that PCR combined with direct sequencing and clone sequencing can be used to detect cebpa mutations. cebpa mutations are mainly identified in M(2) subtype of NK-AML patients, its significance for prognosis needs to further investigate. PMID- 20723289 TI - [Methylation status of zo-1 gene promoter in acute leukemia]. AB - This study was purposed to investigate the difference of zo-1 gene promoter methylation between healthy individuals and acute leukemia patients. BS-PCR method was used to detect the status of zo-1 gene methylation in healthy individuals, acute leukemia patients and leukemic cell line NB4 cells. The results showed that zo-1 gene was hypomethylated in bone marrow samples from healthy individuals (1.9%). In newly diagnosed AL and relapsed patients, the rate of zo-1 gene methylation was 93.2% and 66.9% respectively, while it was 16.4% in AL patients in complete remission, which was much higher than that in healthy individuals. There was significant difference between them. It is concluded that as compared with healthy individuals, zo-1 gene in acute leukemia patients is hypermethylated and with different degrees in various phases of leukemia. Analysis of zo-1 gene methylation status may be useful to monitor the development of acute leukemia. PMID- 20723290 TI - [Effect of triptolide on reversing hypermethylation of apc gene in Jurkat cells and its possible mechanisms]. AB - This study was aimed to investigate the effect of traditional Chinese medicine, Triptolide (TPL) on reversing hypermethylation of antioncogene (apc gene) in acute lymphoblastic leukemia cell line Jurkat in vitro and to explore its mechanisms. The effects of TPL on cell growth, proliferation and cell cycle were detected by growth curve, MTT assay, colony formation test and flow cytometry, respectively. The effect of TPL on apc gene methylation of Jurkat cells was analyzed by nested methylation specific PCR; the expressions of apc gene, dnnt3a, dnmt3b mRNA were measured by RT-PCR; the protein expression of apc gene was detected by Western blot. The results showed that as compared with untreated control cells, the TPL of different concentrations could significantly inhibit growth and proliferation of Jurkat cells in dose-and time-dependent manners with IC50 19.7 ng/ml at 48 hours. All cytosines in CpG dinucleotides in untreated Jurkat cells had no changed, while all cytosines in Jurkat cells treated with TPL had been converted to thymidine suggesting the methylation of apc gene in Jurkat cells. The TPL could reverse hypermethylation of apc gene and induced the mRNA and protein expression of apc gene in dose-dependent manner. It is concluded that the small dose of TPL can obviously suppress the proliferation of Jurkat cells, activate and up-regulate the expression of apc gene through demethylation of apc gene resulting from DNMT and/or direct action, thereby inhibit the proliferation rate of Jurkat cells. PMID- 20723291 TI - [Rituximab-mediated sensitization of B-NHL cell lines to apoptosis induced by gemcitabine and Navelbine in vitro]. AB - This study was purposed to explore the Rituximab (RTX)-mediated sensitization of B-NHL cell lines to apoptosis induced by Gemcitabine or Navelbine and its possible mechanism. The inhibitory rate of B-NHL cell proliferation was detected by XTT method, the IC50 from Gemcitabine or Navelbine and combination of Gemcitabine or Navelbine with RTX was compared. The expression level of antiapoptotic protein BCL-2 in Daudi, Ramos, Raji and Namalwa cells treated with RTX of 20 MUg/ml for 24 hours was detected by Western blot. The results showed that the RTX as a single agent could weakly induce the apoptosis of Daudi, Namalwa, Raji and Ramos lymphoma cell lines, the inhibiting rate of cell proliferation ranged from 3% to 10%; RTX could sensitize significantly the cytotoxity of Gemcitabine or Navelbine in Daudi, Namalwa and Raji cell lines; The expression of BCL-2 in Raji and Namalwa cell lines treated with RTX of 20 microg/ml for 24 hours was down-regulated. It is concluded that RTX can sensitize the cytotoxicity of Gemcitabine or Navelbine to the human lymphoma cell lines which displayed the synergistic effect on Daudi, Namalwa and Raji cell lines. The BCL-2 expression level in Raji and Namalwa cell lines treated by RTX is down regulated which may be one of the mechanisms sensitizing the cytotoxicity of Gemcitabine or Navelbine. PMID- 20723292 TI - [Enhancement of all-trans retinoic acid induced HL-60 leukemia cell differentiation by human umbilical cord mesenchymal stem cells]. AB - This study was aimed to investigate the enhancement of all-trans retinoic acid induced HL-60 leukemia cell differentiation by human umbilical cord mesenchymal stem cells (hucMSC). The HL-60 cells were divided into 4 groups: control group (HL-60 cells treated without ATRA), hucMSC group (HL-60 cells co-cultured with hucMSCs), ATRA group (HL-60 cells treated with ATRA) and ATRA + hucMSC group (HL 60 cells treated with ATRA and co-cultured with hucMSCs). The proliferations of control group and hucMSC group were compared by Cell Counting Kit-8 (CCK8). The morphology of HL-60 cells and NBT positive rate in 4 groups were observed and compared by means of microscopy, the c-myc expression of HL-60 cells in different groups was evaluated by real-time PCR, and the CD11b expression on HL-60 cells in different groups were detected by flow cytometry. The results showed that in the co-culturing system, hucMSCs could inhibit the proliferation of HL-60 (hucMSC:HL 60 is 1:1, 48 hours p < 0.05, 72 hours p < 0.01; hucMSC:HL-60 is 1:5, 72 hours p < 0.05). In condition of stimulation with 2 micromol/L ATRA, the neutrophil like HL-60 cells and NBT positive rate in ATRA + hucMSC group were higher than those in ATRA group (p < 0.05). The c-myc expression of HL-60 cells in ATRA + hucMSC group was lower than that in ATRA group (p < 0.05). Furthermore, HL-60 cells in ATRA + hucMSC group had stronger CD11b expression than ATRA group (48 hours p < 0.05, 72 hours p < 0.01). It is concluded that hucMSC not only can inhibit the proliferation of HL-60 cells, but also can enhance the differentiation effect of HL-60 cells induced by ATRA. PMID- 20723293 TI - [Effects of STI571 combined with As2O3 on proliferation, apoptosis and caspase 3, Bcl-xL expression of K562 cells]. AB - This study was aimed to explore the effects of STI571 alone or with As2O3 on proliferation, apoptosis and caspase 3, bcl-xL mRNA expression of K562 cells, and the molecular mechanism of As2O3 enhancing the anti-leukemia effect of STI571 so as to provide the scientific basis for clinical treatment of chronic myeloid leukemia. The effect of drugs on proliferation of K562 cells was assayed by MTT method, the apoptosis rate of K562 cells was detected by flow cytometry with Annexin V/PI double staining, the caspase 3, bcl-xL mRNA expressions of K562 cells were determined by real time quantitative PCR. The results showed that STI571 alone or with As2O3 both could inhibit the proliferation of K562 cells. OD value in test groups reduced along with prolonging of action times, the OD values between different time points were significantly different (p < 0.05), furthermore the OD values at 72 hours in test groups were lowest, while as compared with control group, OD values at same time points in test groups all gradually decreased, among which decrease of OD value in test 5 group was most significant. The flow cytometric detection indicated that along with time prolonging, the apoptotic rate in control group not obviously changed, but the apoptotic rate in test groups gradually increased, the difference between time points was significant (p < 0.05), moreover apoptotic rate increased most obviously at 72 hours, while as compared with control group, apoptotic rate at same time points in test groups was gradually enhanced (p < 0.05), among which the apoptotic rate in test 5 group was highest. The real time qPCR assay revealed that as compared with control group, the bcl-xL mRNA expression in test groups reduced with decrease of 2-DeltaDeltaCT value, furthermore the decrease of expression level in test 3 group was higher than that in test 2 group (p < 0.05), while the caspase 3 mRNA expression in test groups was enhanced with increase of 2-DeltaDeltaCT value, moreover the increase of expression level in test 3 group was higher than that in test 2 group (p < 0.05). It is concluded that the STI571 can inhibit the proliferation of K562 cells, accelerate the apoptosis of K562 cells. The STI571 combined with As2O3 can enhance these two effects, increase the expression of caspase-3 mRNA and decrease the expression of bcl-xL mRNA. Therefore, the effect of STI571 combined with As2O3 on expression of caspase 3 and bcl-xL mRNA may be one of molecular mechanisms underlying their synergic antileukemia efficacy. PMID- 20723294 TI - [Proliferative inhibition and apoptotic induction effects of crocin on human leukemia HL-60 cells and their mechanisms]. AB - This study was to investigate the proliferative inhibition and apoptosis of human leukemia HL-60 cells induced by crocin and their possible mechanisms. The cell viability was tested by cell counting. The morphology of HL-60 cells was observed by fluorescence microscopy. The MTT assay was used to evaluate the inhibitory effect of crocin on the growth of HL-60 cells. Flow cytometry was used to measure the cell cycle. RT-PCR was used to detect bcl-2 and bax expression. The results indicated that the growth of HL-60 cells was inhibited remarkably in the dose and time dependent way. When the crocin concentration was higher than 5 mg/ml, the percentage of apoptotic HL-60 cells was not increased, on the contrary this percentage decreased, the cells manifested necrosis. Flow cytometry profiles revealed that cells were blocked in G0/G1 phase, the cell proliferation was inhibited obviously at 5 mg/ml. RT-PCR detection revealed that the expression of bcl-2 was down-regulated strikingly and bax was up-regulated. It is concluded that the crocin can inhibit the proliferation of HL-60 cells effectively, and block cells in G0/G1 phase. The mechanisms by which crocin induced apoptosis in HL-60 cells may be related to the inhibition of bcl-2 and activation of bax. PMID- 20723295 TI - [Levels of P27Kip1 expression and apoptosis in HL-60 cells after treatment with TGF-beta1 and/or arsenic trioxide]. AB - This study was purposed to investigate the effects of TGF-beta1 and arsenic trioxide (As2O3) on cell apoptosis, cell cycle and changes of P27(Kip1), endogenous TGF-beta1, cyclin E and BCL-2 in HL-60 cells, and to explore the relationship between expression of P27(Kip1) and apoptosis induced by As2O3 and/or TGFbeta1. Cell apoptosis and cell cycle changes of HL-60 cells treated with As2O3 and/or TGFbeta1 were detected by cytomorphologic observation and flow cytometry, the protein expressions of P27(Kip1), TGF-beta1, cyclin E and BCL-2 were measured by immunohistochemistry. The results showed the effect of 5 MUmol/L of As2O3 was the most strong among the different concentration of As2O3 ,and the effect on apoptosis at 48 hour was more strong than that at 24 hours (p < 0.05). The TGF-beta1 (5 ng/ml) induced arrest of cells in G1 phase (p < 0.05) compared with As2O3 alone and As2O3 combined with TGF-beta1, while there was no difference with control. P27(Kip1) expression was up regulated (p < 0.05), cyclin E and BCL 2 expression was down-regulated (p < 0.05) in TGFbeta1-treated group. BCl-2 expression was down regulated, endogenesis TGFbeta1 expression was up regulated (p < 0.05), and the level of P27(kip1) and cyclin E were not changed in As2O3 treated group (p > 0.05). The down-regulating effect of TGF-beta1 combined with As2O3 on BCL-2 protein was more strong than that in single factor treated group (p < 0.05). It is concluded that TGFbeta1 induces cell cycle arrest and apoptosis in HL-60 cells, while the P27(kip1) expression is up regulated. P27 protein is the key effector of TGFbeta-induced cell cycle arrest. The effect of TGF-beta1 combined with As2O3 on apoptosis as well as the down-regulation of BCL-2 protein in HL-60 cells is more strong than that in single factor-treated groups, that indicates the passages linking up each other. PMID- 20723296 TI - [Celastrol down-regulates expression of P-Akt and cyclin D1 in HL-60 cells and induces apoptosis]. AB - The aim of this study was to investigate the effect of Celastrol on induction of HL-60 cell apoptosis and its possible mechanism. The proliferative activity of HL 60 cells treated with 0.25 - 8.0 MUmol/L of Celastrol for 24 - 72 hours was assayed by MTT method, the effects of Celastrol on apoptosis and cell cycle of HL 60 were detected by TUNEL staining and flow cytometry with Annexin V-FITC/PI double labeling, the expression of pAkt and cyclin D1 at protein and gene level in HL-60 cells treated with Celastrol were measured by Western blot and RT-PCR. The results showed that the Celastrol could obviously inhibit the proliferation of HL-60 cells in concentration-and time-dependent manners, the IC50 value of Celastrol for 24 hours was 6.21 +/- 0.242 MUmol/L. The Celastrol concentration dependently induced the apoptosis of HL-60 cells, accompanying with morphological changes of apoptotic cells, which may be related with arrest of cells in G0/G1 phase. The Celastrol suppressed the expression of pAkt and Cyclin D1 in HL-60 cells to a varying degree which showed obvious concentration-and time-dependent manners. It is concluded that the Celastrol inhibits the proliferation and induced the apoptosis of HL-60 cells. Its mechanism may be related with down regulation of p-Act and cyclin D1 expressions. PMID- 20723297 TI - [Reversal effect of nuclear factor-kappaB protease inhibitor PDTC on multidrug resistance of K562/AO2 cells and its mechanism]. AB - This study was purposed to investigate the relationship between activation of nuclear factor-kappaB (NF-kappaB) and multidrug resistance in K562/AO2 cells and its mechanism. Human erythroleukemic cell line K562 and its adriamycin-resistant counterpart K562/AO2 cells were used in the study. After inhibiting the activation of NF-kappaB with noncytotoxic concentration of antioxidant pyrrolidine dithiocarbamate (PDTC) in vitro, the multiple of drug resistance of K562/AO2 cells was assessed by MTT assay. RT-PCR and flow cytometry method were used to detect the relative expression of mdr-1 mRNA and P-gp, respectively. The results showed that (1) multidrug resistance of K562/AO2 cells to ADM was 59 times higher than that of K562 cells. When being pretreated with 0.2 MUmol/L PDTC which is noncytotoxic to cells, the IC50 of ADM in K562/AO2 cells was sharply decreased with relative reverse efficiency of 93.03%, which was more higher than that of classic modifying agents Verapamil (Ver); (2) NF-kappaB activity of K562/AO2 cells was significantly higher than that of K562 cells (p < 0.01). When being treated with PDTC, the activation of NF-kappaB was sharply decreased in K562/AO2 cells; with 0.2 MUmol/L PDTC for 24 hours it decreased to the lowest, nearly to the K562 cell level (p > 0.05); (3) the relative expression of both mdr 1 mRNA and P-gp in K562/AO2 cells was more higher; the expressions of mdr-1 mRNA and P-gp both were inhibited in K562/AO2 cell group treated with PDTC for 48 hours. It is concluded that the PDTC used as an inhibitor of NF-kappaB activity can partially reverse the multidrug resistance of K562/AO2 cells, which mechanism can be associated with the down-regulation of mdr-1 mRNA and P-gp. PMID- 20723298 TI - [Effect of arsenic trioxide on induction of apoptosis in MCL cell line and its possible mechanisms]. AB - This study was aimed to explore the effect of arsenic trioxide (ATO) on proliferation and apoptosis of mantle cell lymphoma (MCL) cell lines and the underlying mechanisms of the apoptosis. MCL cell lines (jeko-1, mino, JVM-2) were treated with different concentrations of ATO, then growth profile of these cells were detected by MTT. Apoptosis of ATO-treated jeko-1 cells were detected by flow cytometry with Annexin V-FITC/PI double staining. The loss of mitochondrial membrane potential of ATO-treated jeko-1 cells were detected by FCM with DiOC6(3) staining. The expressions of cyclin D1 and apoptosis related proteins MCL-1, BCL 2, PUMA, NOXA, cCaspase-3 (cleaved caspase-3), cCaspase-9 (cleaved caspase-9), cPARP (cleaved PARP) were detected by Western blot. The results indicated that ATO inhibited cell growth, induced apoptosis of MCL cells and disrupted mitochondrial membrane potential. ATO could decrease expressions of MCL-1, PUMA and cyclin D1, increase expressions of cPARP, cCaspase-3, cCaspase-9 and the expressions of BLC-2 and NOXA were not changed. It is concluded that ATO can induce cell growth arrest and apoptosis of MCL cells. The mitochondrial pathway plays a very important role in cell apoptosis. PMID- 20723299 TI - [Improvement of mouse model for thymic lymphoma induced by N-methyl-N nitrosourea]. AB - The objective of this study was to elevate the tumorigenic rate of animal model with thymic lymphoma induced by N-methyl-N-nitrosourea (MNU) and to reduce the mortality of this mouse model. The injection regimen and experimental cycle were improved on the basis of previous experiments. The male and female C57BL/6 mice were injected by the intraperitoneal route with MNU solution at different dosages in the first week and the 4th week respectively. Following injection of MNU, the general features of the mice were observed. All mice were sacrificed for autopsy before the 24th experimental week. Complete gross examination was performed for detection of tumor masses. The pathologic and immunohistochemical methods were used to identify the origin and subtype classification of the neoplasm. The results showed that at the 25th week the incidence of thymic lymphoma in mice injected with MNU was 83.3% (55/66), the mortality was 7.6%. In conclusion, improving the program and changing the experimental cycle can increase the tumorigenic rate in the mouse model induced by MNU from 67.5% to 83.3% and reduce the mortality from 10% to 7.6%. PMID- 20723300 TI - [Effect of bortezomib on lymphoma cell line CA46 and its relative mechanisms]. AB - The objective of this study was to explore the effect of bortezomib (BZM) on lymphoma cell line CA46 and its relative mechanisms in vitro. The effects of BZM on the proliferation and apoptosis of CA46 cells were assayed by MTT method and flow cytometry respectively. The effect of BZM on the expression levels of procaspase-3 and BCL-2 protein were detected by Western blot. The results indicated that the BZM could inhibit the growth of CA46 cells significantly and the concentration of 50% growth inhibition (IC50) at 24 and 48 hours were 53.19 and 19.68 nmol/L respectively. After treatment with 20, 40, 80 nmol/L BZM for 24, 48 and 72 hours, a dose- and time-dependent apoptosis of CA46 cells could be observed. After treatment with 20 nmol/L BZM at different time point, a time dependent reduction of procaspase-3 and BCL-2 protein expression in CA46 cells was found. It is concluded that the BZM can inhibit the proliferation and induce the apoptosis of CA46 cells, which relative mechanism may involve the reduction of BCL-2 and the activation of caspase 3. PMID- 20723301 TI - [Influence of dipyridamole on expression of PAC-1 and CD62p in patients with malignant lymphoma]. AB - This study was purposed to explore the expressions of platelet-activated markers PAC-1 and CD62p in peripheral blood of malignant lymphoma patients and the influence of dipyridamole on their expression. 32 lymphoma patients were divided into simple chemotherapy group (simple group) and chemotherapy plus dipyridamole group (combined group) randomly, and 15 healthy peoples were selected as control group. The dipyridamole of 100 mg/day was given to the patients in combined group. The expression levels of PAC-1, CD62p and fibrinogen (Fib) were detected by flow cytometry and magnetic bead method on day 0, 3, 7 and 14 of chemotherapy respectively. The results showed that the levels of PAC-1, CD62p and Fib in lymphoma patients were significantly higher than those in control group (p < 0.01, 0.05), moreover there was positive correlation between levels of PAC-1 and Fib (r = 0.549, p < 0.01). PAC-1 expression on day 0 and 3 of chemotherapy in simple group was higher than that on day 14 (p < 0.05, 0.01) and CD62p expression on day 3 of chemotherapy was higher than that on day 0, 7 and 14 (p < 0.05, 0.01). PAC-1 expression in combined group on day 14 of chemotherapy was lower than than on day 0 and 3 (p < 0.05, 0.01), and CD62p on day 14 was lower than that on day 3 of chemotherapy (p < 0.05); PAC-1 and CD62p expressions in combined group on day 3, 7 and 14 of chemotherapy were decreased than those in simple group, but Fib level was not changed significantly. It is concluded that the patients with malignant lymphoma usually accompany with platelet activation and hyperfibrinogenemia in peripheral blood. Applying dipyridamole routine dosage in chemotherapy can efficiently restrain platelet activation. PMID- 20723302 TI - [Expression of human Jagged-1 protein on eukaryotic cells and establishment of stable transfectant cell line]. AB - Jagged-1 protein is one of the ligands belonging to Notch signaling pathway. Notch signaling pathway is one of the major signaling pathways mediated by contact between cells and plays an important role to regulate the process of proliferation and differentiation of hematopoietic cells in the hematopoietic microenvironment. To study the biological effect after the combination of receptor and ligand in Notch signaling pathway and the mechanism of Notch signaling pathway in bone marrow stromal cells mediated-drug resistance, a NIH 3T3 cell line over-expressing Jagged-1 protein was constructed for further research purposes. A full coding region of Jagged-1 gene was cloned and inserted into eukaryotic expression plasmid to construct pEGFP-IRES2-Jagged-1 eukaryotic expression vector, then transfected into NIH-3T3 cell line, a mammalian cells. As a result Western blot analysis confirmed that the transfectant NIH-3T3 cells highly expressed Jagged-1 protein and flow cytometry analysis confirmed that the NIH-3T3-pEGFP-IRES2-Jagged-1 cell line over-expressed Jagged-1 protein was monoclonal after screened by selective medium and limiting dilution analysis. It is concluded that the pEGFP-IRES2-Jagged-1 eukaryotic expression vector and a stable transfectant monoclonal NIH-3T3 cell line are successfully established. The construction of the stable transfectant monoclonal NIH-3T3 cell line which overexpressed Jagged-1 protein, provides the conditions to further study the mechanism of the bone marrow stromal cell-mediated drug resistance and to discover the new drug targets. PMID- 20723303 TI - Platelets inhibit antigen presentation by dendritic cells and tumor cells. AB - This study was aimed to investigate the effects of intact platelets on antigen presentation by either tumor cells or bone-marrow derived dendritic cells (BMDCs). The antigen presentation assay models included BMDC stimulated mixed allogenic lymphocyte reaction and antigen presentation by OVA-harboring EG7 cells to OVA-specific TCR transgenic OT-I T lymphocytes. Fresh platelets prepared from hemogenic murine bloods were added to the culture systems to different levels. Lymphocyte proliferation, level of secreted cytokines in the culture and phenotype of BMDCs were measured by isotope incorporation, ELISA and flow cytometry respectively. The results indicated that when platelets at certain concentrations were added in co-culture system containing both OVA-harboring EG7 cells and OVA-specific TCR transgenic OT-I T lymphocytes, both lymphocyte proliferation and IFNgamma production were inhibited. The addition of platelets to the BMDC culture followed by LPS or CpG ODN treatment blocked B7-2 upregulation, cytokine production of the BMDCs, and stimulation potency of such BMDCs for allogenic lymphocytes. Furthermore, platelets inhibited the ability of BMDCs to present both soluble and cellular antigens to clonal specific T lymphocytes, which reflected by decreased lymphocyte proliferation and cytokine production. All these platelet-dependent effects were related to the concentrations of platelets in culture. FACS analysis also revealed that platelets bound to BMDCs induced slightly higher cell death rate of BMDCs. It is concluded that under certain conditions, platelets may affect antigen presentation and the overall outcome of immune responses in a negative way, providing new evidence for the hypothesis that platelets play much more complicated roles in the regulation of immune compartments than originally believed. PMID- 20723304 TI - [Change of expression pattern of CD3 genes in peripheral blood T-cells from CML patients]. AB - Our previous finding showed that down-regulation of CD3zeta gene was detected in patients with chronic myeloid leukemia (CML). In order to further elucidate the feature of T cell immune status in the signal transduction in CML patients, the expression patterns of all 4 CD3 genes were characterized in peripheral blood of patients, the expression levels of CD3gamma, delta, epsilon and zeta chain genes were detected by real time qPCR with SYBR Green I staining in peripheral blood mononuclear cells (PBMNCs) from 17 cases of de novo CML patients in chronic phase and 17 cases of healthy individuals, the beta2-microglobulin gene was used as an internal reference, and the mRNA expression level of each CD3 gene was evaluated by the 2(-DeltaCt) x 100% method. The results showed that the median expression levels of CD3gamma, delta and epsilon genes (2.344%, 0.515% and 3.516%) in CML patients were not significantly different from healthy individuals (p = 0.072, p = 0.190, p = 0.615, respectively), while the expression level of CD3zeta gene in PBMNCs from CML patients (0.395%) was lower than that from healthy individuals (1.538%) (p < 0.001). The expression patterns of 4 CD3 genes in proper order were CD3epsilon > CD3gamma > CD3delta > CD3zeta in CML group, in contrast, the expression patterns were presented as CD3gamma > CD3epsilon > CD3zeta > CD3delta in healthy group. It is concluded that the present study characterized the expression pattern of CD3gamma, delta, epsilon and zeta chain genes in CML patients, lower expression of CD3zeta is the feature of TCR signal transduction immunodeficiency and the expression patterns of 4 CD3 genes are changed in CML patients. PMID- 20723305 TI - [Immunophenotyping characteristics of adult patients with acute lymphoblastic leukemia in different ages]. AB - The purpose of this study was to investigate the immunophenotyping characteristics of adult acute lymphoblastic leukemia (ALL) patients in groups of different ages. Immunophenotyping was performed in 260 ALL patients by flow cytometry using a panel of monoclonal antibodies and CD45/SSC gating. The results indicated that (1) all the 82 cases of T-cell acute lymphoblastic leukemia (T ALL) expressed CD7 (100%) while the positive rate of CD2 remarkably decreased with aging. The positive rate of CD2 in patients aged 14 to 18 years (adolescents) was 91.67%, which is significantly higher than that in cases aged 19 to 35 years (young adults) and > 35 years (older adults) (65.71% and 43.48% respectively, p < 0.05); the positive rate of CD34 and HLA-DR increased with aging, there was significant difference of the HLA-DR expression between the older adults group (39.13%) and the other two groups (4.17% in adolescents and 11.43% in young adults respectively (p < 0.05). Moreover, there were significant differences of the myeloid antigen (MyAg) and CD13 expression between the older adults and younger adults (p < 0.05). (2) As to adult B-cell acute lymphoblastic leukemia (B-ALL), the positive rates of CD19 and HLA-DR in 178 cases were 100%; the positive rate of CD33 in young adults was significant higher than that in adolescents (p < 0.05), the differences of the other marker expressions failed to reach statistical significance in adult B-ALL patients. It is concluded that the immunophenotypes of adult T-ALL are evidently heterogeneous in different ages, and expression with more aberrant phenotypes indicates poor prognostic significance in patients older than 35 years. There is no significant association of immunophenotypes with ages among different age groups of adult B-ALL. PMID- 20723306 TI - Influence of dendritic cells on biological activity of the homologous CIK cells and its anti-leukemia effect in vitro. AB - This study was aimed to investigate the effect of cord blood dendritic cells (DCs) on the in vitro proliferation capability, immunophenotype changes, level of secreted cytokines and activity against leukemia cells of the homologous cytokine induced killer (CIK) cells. DCs and CIK cells were induced from cord blood mononuclear cells. They were co-cultured at the ratio of 1:5, and CIK cells from cord blood or DC-CIK cells from peripheral blood were cultured as controls. Immunophenotypic changes were analyzed by flow cytometry, increased number of cells were counted by trypan-blue staining, the killing activity to leukemia cells was assayed by MTT, the levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) in the cultured supernatant were detected by ELISA. The results showed that the proliferation capability of cord blood DC-CIK cells was significantly higher than that of cord blood CIK cells and peripheral blood DC-CIK cells (p < 0.05 and p < 0.05). Under the same condition, the rate of double positive cells with CD3(+)CD8(+) and CD3(+)CD56(+) in CIK cells was significantly enhanced by co-culture with cord blood DCs (p < 0.05). The level of IL-12, IFN-gamma, and TNF-alpha in cultured supernatants of cord blood DC-CIK cells increased noticeably on day 3 as compared with CIK cells cultured alone (p < 0.01, p < 0.05, p < 0.05). Within the effector target ratio range between 2.5:1 to 20:1, the activity of cord blood DC-CIK cells against all subtypes of acute leukemia cells was much higher than that of CIK cells (p < 0.05), and there was no significant difference among all subtypes of acute leukemia cells, which was the same with the killing effect of peripheral blood DC-CIK cells against leukemia cells. It is concluded that the proliferation capability and anti-leukemia effect of the homologous CIK cells can be enhanced by cord blood DCs. The proliferation capability of cord blood DC-CIK cells is stronger than that of peripheral blood DC-CIK cells, but there is no significant differences of cytotoxicity between DCs and CIK cells. As the cord blood is easily gained and does not easily cause a serious graft rejection, the DC-CIK cells should be clinically applied more extensively as novel immune therapy. PMID- 20723307 TI - [Determination of leukemia stem cells in childhood acute myeloid leukemia and its clinical significance]. AB - The aim of this study was to detect the presence of human AML leukemia stem cells (LSC) in childhood patients with acute leukemia (AL) and analyze the correlation between LSC concentrations and minimal residual disease (MRD) levels in AML cases after remission. The multi-parameter flow cytometry (FCM) and a panel of monoclonal antibody combination were used to detect the AML LSC or AML LSC immunophenotype-identical cell (AML LSC-IPIC) concentrations in childhood AML or ALL leukemia both at new diagnosis and at remission and correlated AML LSC to the MRD levels at different time points after remission. The results indicated that the AML LSC or AML LSC-IPIC concentrations [in average 166 (range 14 - 1459)/100 000 mononuclear cells (MNCs)] in AML at initial diagnosis were significantly higher than those in ALL [7 (range 0 - 560)/100 000 MNCs, p < 0.017] and control [0 (range 0 - 6)/100 000 MNCs, p < 0.017], respectively. The AML LSC concentrations in AML at non-CR were in average 36 (range 5 - 224)/100 000 MNCs. No statistical difference (p > 0.05) was found between the AML LSC or AML LSC IPIC concentrations in AML (in average 6 (range 0 - 41)/100, 000 MNCs) and ALL [10 (range 0 - 105)/100, 000 MNCs] after CR. The significantly negative correlation was noticed between AML LSC concentrations and MRD levels. It is concluded that the AML LSCs exist in newly diagnosed AML, which are significantly reduced when complete remission has achieved, but the low levels of these populations still remain. The phenotypically similar (CD34(+)CD38-CD123(+)) AML LSC populations have also been found in the bone marrow from ALL patients, but their concentrations are not significantly different when CR has achieved. The significantly negative correlation between AML LSC concentrations and MRD levels is observed in AML patients after remission. PMID- 20723308 TI - [Fcgamma receptorIIIa polymorphism in healthy children and those with hematological malignancies]. AB - Fcgamma receptorIIIa (FcgammaRIIIa) polymorphism was considered to influence clinical response to therapeutic monoclonal antibody (MAb) against cancer, which is suggested to affect MAb binding and MAb-dependent NK cell-mediated cytotoxicity. The purpose of this study was to examine the FcgammaRIIIa gene polymorphisms in healthy children and in children with hematological malignancy, and to explore its possible effect on MAb in children with hematological malignancies. 43 healthy children (H) and 20 pediatric patients with hematological malignancies (HM) were enrolled in this study. DNA was isolated from peripheral blood, and then nest-polymerase chain reaction-restriction fragment length polymorphism (nest-PCR and PCR-RFLP) was used to determine the FcgammaRIIIa-158 genotypes in each groups of subject, digested fragments were subjected to electrophoresis on 15% PAGE. The results showed that there were a higher frequencies of FcgammaRIIIa-158V/F in H and HM group (72.1% and 75.0% respectively), the frequencies of FcgammaRIIIa-158V/V were 27.9% and 25.0% in H and HM group respectively, but there was no FcgammaRIIIa-158F/F in the two groups. No significant difference in distribution of the FcgammaRIIIa-158 genotype was found between HM and H groups (p > 0.05). It is concluded that FcgammaRIIIa-158V/F is more frequent, while FcgammaRIIIa-158V/V is less, but FcgammaRIIIa-158F/F is very rare in both groups. No significant difference of FcgammaRIIIa polymorphism distribution is found between healthy and hematological malignancy groups. PMID- 20723309 TI - [Effect of muramyl dipeptide on proliferation of dendritic cells derived from children acute leukemia bone marrow in vitro]. AB - The aim of this study was to explore the effect of muramyl dipeptide (MDP) on proliferation of dendritic cells (DCs) from bone marrow of children with acute leukemia in vitro. The mononuclear cells were isolated from bone marrow of children with acute leukemia to induce dendritic cells. The experiment was divided into 4 groups. The control group: MNC + RPMI 1640 medium; test group 1: MNC + MDP; test group 2: MNC + rhGM-CSF + IL-4 + rhTNFalpha; test group 3: MNC + rhGM-CSF + IL-4 + rhTNFalpha + MDP. The growth of DCs was observed by inverted microscope every day; the number of DCs in different groups were counted, the immunophenotypes of DCs were detected by flow cytometry on day 8 of culture. The results indicated that a certain number of typical DCs could be detected in all experimental groups. The DC number in control and 3 test groups were (0.85 +/- 0.23) x 105/L, (2.31 +/- 0.24) x 105/L, (3.26 +/- 0.37) x 105/L and (4.16 +/- 0.34) x 105/L, respectively, among which DC number is in all 3 test groups were higher than that in control group (p < 0.01), the DC number in test group 1 was lower than that in test groups 2 and 3 (p < 0.01), while it in test group 3 was higher than that in test group 2 (p < 0.01). The percentages of HLA-DR in control, test group 1, 2 and 3 were 19.98 +/- 3.74, 37.24 +/- 4.32, 58.81 +/- 2.08 and 77.48 +/- 5.57 respectively; the percentages of CD1a and CD83 in control, test group 1, 2 and 3 were 11.46 +/- 2.43, 28.71 +/- 6.64, 46.92 +/- 4.78 and 57.03 +/- 3.07, as well as 13.05 +/- 5.70, 36.32 +/- 5.61, 54.95 +/- 7.83 and 75.70 +/- 6.67 respectively. The comparison of HLA-DR, CD1a and CD83 levels in control and test group 1, 2 showed that their results were consistent with results of DC numbers. It is concluded that MDP not only promotes the proliferation of DCs derived from bone marrow of children with acute leukemia in vitro, cooperates with rhGM-CSF, rhIL-4 and rhTNFalpha in promoting of the proliferation and maturation of DCs, while the promotive effect of MDP alone on the proliferation of DCs is not as good as its combination with cytokines. PMID- 20723310 TI - [Impact of vWF gene A1381T polymorphism and ABO blood group on von Willebrand factor level in plasma]. AB - This study was aimed to investigate the impact of vWF A1381T polymorphism (rs216311) and ABO blood group on von Willebrand factor level in plasma. 120 healthy volunteers, aging from 19 to 33 years (average 24) were recruited. The vWF:Ag level in plasma was determined by ELISA. vWF gene A1381T polymorphisms were analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequenced when necessary. The data were grouped by gender, blood group and/or genotype. The difference of plasma vWF level between male and female were analyzed by independent sample t test. One way ANOVA were used to analyze the difference of vWF level in each blood group of genotype while factorial design ANOVA were used to test the difference of vWF level in plasma between A1381T genotype and/or ABO blood groups. The results showed that analysis of plasma vWF level in 120 volunteers of both male (60) and female (60) demonstrated no statistical difference (t = 1.039, p = 0.301). The vWF level was lower in blood type O group than that in non-O group (p < 0.001); the plasma vWF level in AA mutant of vWF A1381T gene polymorphism was lower than that in AG and GG mutant (p = 0.003 and 0.019, respectively). In blood type O group, the vWF plasma level in AG mutant of vWF A1381T gene polymorphism resulted in non difference (p = 0.070) compared with AA or AG mutant, while there was significant difference in vWF of plasma level when contrast tests were applied (t = 2.321 and p = 0.028, respectively). In non-O group, the plasma vWF level in AG mutant of vWF A1381T gene polymorphism were significantly different from AA mutant (p = 0.032). It is concluded that plasma vWF level unrelated with gender but interrelates with ABO blood groups. Plasma vWF level in vWF gene A1381T polymorphism with AA mutant is significantly lower than that with AG and GG mutant. In blood type O group, plasma vWF level in vWF gene A1381T polymorphism with AG mutant is higher than that with AA and GG mutant. In non-O group, the vWF plasma level in A1381T gene polymorphism with AG mutant is significantly higher than that with AA mutant. This change may be beneficial to understand some diseases, especially cardio-cerebral vascular diseases. PMID- 20723311 TI - [Significance of platelet parameters and lactate dehydrogenase level in differential diagnosis for thrombocytosis]. AB - This study was purposed to explore the clinical application of mean platelet volume (MPV), platelet distribution width (PDW), platelet-large cell ratio (P LCR), lactate dehydrogenase (LDH) level in the differential diagnosis of thrombocytosis. The clinical applications of 3 platelet routine laboratory parameters (MPV, PDW, P-LCR) and LDH were examined in 1048 patients with thrombocytosis-related diseases: reactive thrombocytosis (RT), chronic myeloproliferative disease (CMPD) including chronic myeloid leukemia (CML), essential thrombocythemia (ET) and polycythemia vera (PV). Receiver operating characteristic (ROC) curve was used to predict the cause of thrombocytosis. The results indicated that there were significant differences in MCV, PDW, P-LCR and LDH level between RT and CMPD groups (p < 0.05). The area under ROC curve of PDW and P-LCR for prediction of CMPD were 0.96 (95% CI: 0.93 - 0.99) and 0.89 (95% CI: 0.84 - 0.95) respectively, and whose optimal cut-off value was 11.95%and 23.05% respectively. Three types of CMPD were characterized as follows: high P LCR and high LDH level in chronic myeloid leukemia, whose optimal cut-off value was 424 U/L and 26.10% respectively; slightly high LDH level and high Plt count in ET, the optimal cut-off value of Plt was 939 x 109/L. In conclusion, these characteristics of MPV, PDW, P-LCR and LDH levels may be useful for simple and primary differential diagnosis of the thrombocytosis-related disease mentioned above. PMID- 20723312 TI - [Erythropoietin gene-modified conditioned medium of human mesenchymal cells promotes hematopoietic development from human embryonic stem cells]. AB - The study was aimed to investigate the effect of deriving hematopoietic cells from human embryonic stem cells (hESCs) by the erythropoietin gene-modified conditioned medium of human mesenchymal cells. The mesenchymal stem cells (MSCs) steadily expressing EPO were established by lentiviral system. The expression of exogenous EPO was detected by RT-PCR and Western blot. After suspension culture, hESCs developed into embryonic bodies (EBs). Then the EB cells were cultured in conditional medium. The hESCs-derived hematopoietic cells were analyzed by immunofluorescence, CFU assay and RT-PCR. The results indicated that the exogenous EPO successfully expressed in the EPO transfected MSCs (EPO/MSCs). The supernatant from EPO/MSCs increased CD34(+) cell population and the expression of globin, and enhanced colony forming unit incidence. These effects were obviously higher than that of control. It is concluded that the EPO gene-modified conditioned medium of human mesenchymal cells can induce the hESCs to differentiate into hematopoietic cells. PMID- 20723313 TI - [Involvement of MAPK pathway in the osteoblastic differentiation of mouse mesenchymal stem cells]. AB - This study was purposed to investigate the effect of mitogen-activated protein kinase (MAPK) pathway on the osteoblast differentiation of mouse mesenchymal stem cells (MSCs), MSCs were isolated from mouse compact bone and serially passaged. After being cultured in osteogenic induction medium, the phosphorylation levels of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 were detected by Western blot. The effects of corresponding pathway inhibitors including PD98059, JNK II and SB203580 on alkaline phosphatase (ALP) and calcium accumulation in the osteoblastic differentiation of MSCs were determined by ALP staining and von kossa staining respectively. The results showed that MAPK pathway including ERK, JNK and p38 was activated in differentiation of MSCs into osteoblasts. ALP activity of MSCs increased in the early phase by addition of PD98059 treatment, whereas ALP activity and calcium accumulation were not observed via JNK II treatment. However, SB203580 strongly inhibited the ALP expression and the calcium accumulation. It is concluded that p38 plays a positive role in the osteogenic differentiation of MSCs, and ERK is probably a negative factor at the early phase of differentiation, but the effect of JNK is not essential. PMID- 20723314 TI - [Effects of peptidoglycan on proliferation and cell cycle of human bone marrow derived mesenchymal stem cells]. AB - This study was aimed to explore the effects of peptidoglycan (PGN) on proliferation and cell cycle of human bone marrow mesenchymal stem cells (MSCs). MSCs were isolated from human bone marrow by density gradient centrifugation. The purity of MSCs with the spindle fibroblastic morphology was identified by microphotography and the phenotypes were detected by flow cytometry (FCM). MSCs incubated with different doses of PGN (1, 10, 20 MUg/ml) were used as test groups, and those incubated without PGN were regarded as control group. The isolated and cultured MSCs were inoculated into 96-well plates according to a certain concentration. Cell cycle was measured by flow cytometry after incubated with PGN for 72 hours. The results showed that the cell proliferation index was significantly increased in dose and time dependent manners after MSCs was incubated with PGN. Its effects on the proliferation of MSCs were highest in 10 MUg/ml group. Compared with the control group, PGN could significantly decrease proportion of MSCs in G0/G1 phase and increase them in S and G2/M phases (p < 0.05). It is concluded that PGN can promote more MSCs to enter the DNA synthesis phase and proliferate many much MSCs in dose and time dependent manners. PMID- 20723315 TI - [Effect of cisplatin, topotecan, daunorubicin and hydroxyurea on human mesenchymal stem cells]. AB - Mesenchymal stem cells (MSC) are important cellular component of the bone marrow microenvironment in supporting hemopoiesis. Li J et al reported previously that MSCs are resistant to chemotherapy commonly used in hematologic malignancies but are relatively sensitive to anti-microtubule agents. However, the response of MSCs to other chemotherapeutic agents commonly used in solid tumour settings remains unknown. This study was purposed to evaluate the acute direct effects of 4 individual chemotherapeutic agents on human MSCs (hMSC), including cisplatin, topotecan, daunorubicin and hydroxyurea. Using an in vitro culture system, the chemosensitivity of hMSC was determined by XTT assay and compared with NB-4 cells and normal peripheral blood mononuclear cells (PBMNC). The recovery of cell numbers following exposure to chemotherapeutic agents and apoptosis induced by chemotherapy in hMSC were evaluated. The results showed that although hMSCs were more resistant to the 4 agents above mentioned than NB-4 cells, they were sensitive to topotecan, cisplatin and daunorubicin than PBMNCs. The IC50 values of hMSCs for topotecan, cisplatin, hydroxyurea and daunorubicin were 636, 24.8, > 20 and 2.4 times of those of NB-4 cells respectively. The IC50 values of human PBMNCs for topotecan, cisplatin and daunorubicin were > 27, 1.9 and 1.4 times of those of hMSCs respectively. Reduction of cell number was observed in hMSCs treated with the 4 drugs in clinically relative concentrations. Sustained suppression in hMSCs was observed following 3 days exposure to the 4 agents. It is concluded that the cisplatin, topotecan, daunorubicin and hydroxyurea alone can induce apoptosis of hMSCs and exert persistent suppressive effect on the proliferation of hMSCs even with short term exposure. PMID- 20723316 TI - [Effect of various oxygen concentrations on biological function of human bone marrow hematopoietic stem/progenitor cells]. AB - Hypoxia in bone marrow is suitable for the perfect preservation of biological functions of bone marrow hematopoietic stem cells (BM HSC). It is deserved to study whether the biological functions of BM HSC are influenced when being exposed to environment of oxygen at various concentration during amplification of BM HSCs in normal oxygen condition in vitro and process of peripheral blood hematopoietic stem cell transplantation (PBSCT). This study was purposed to investigate the effects of various oxygen concentrations on biological functions of human BM HSCs. The BM HSCs were amplified in vitro, the amplification level of CD34(+) HSCs and CD34(+)AC133(+) HSCs were detected by flow cytometry, the apoptosis and cell cycle distribution of CD34(+) HSCs amplified in various oxygen concentrations were assayed by flow cytometry with Annexin V/PI double staining as well as PI and Ki-67 antibody, respectively, the differentiation of amplified CD34(+) HSCs in vitro was determined by direction differentiation assay, the migration ability of amplified CD34(+)AC133(+) HSCs was measured by migration test. The results indicated that the oxygen environment below normal oxygen, especially hypoxia, could amplify more primitive CD34(+)AC133(+) HSCs and CD34(+) HSCs with activity, arrest more HSCs in G0/G1 phase, promote the generation of BFU-E, CFU-GM, CFU-GEMM, and better preserve the migration ability of HSCs. While the above functional indicators of BM HSCs were poor when HSCs exposed to normoxia, oxygen-unstable and oxygen-severe changeable environments. It is concluded that the biological functions of BM HSCs in PBSCT are related with oxygen concentration and its stability, the culture of BM HSCs in lower oxygen environment may be more beneficial for PBSCT. PMID- 20723317 TI - [Establishment and evaluation of quantitative analysis method for donor chimerism of mice]. AB - This study was aimed to explore the effectiveness of sequential and quantitative detection method for analysing donor chimerism (DC). In order to simulate a mouse model of haploidentical stem cell transplantation, C57BL/6 male mice were used as donors, while CB6F1 female mice were used as recipients and were divided into 2 groups. The two groups of recipients were irradiated with 2 Gy and 6 Gy from (60CO gamma-ray source respectively, and then were inoculated intravenously with bone marrow cells (BMCs) and spleen mononuclear cells (SPMNCs). Quantitative analyses of DC were performed with real-time PCR or flow cytometry (FCM) on different days after transplantation. The results showed that real-time PCR and FCM both have advantages and disadvantages in the detection of DC. When DC amount in group of 6 Gy was > 90% with stable macrochimerism for more than 3 months, the efficacy of detection by FCM was well; while the DC amount in group of 2 Gy was below 10% and gradually transformed to different forms of microchimerism until disappeared, in which condition the use of real time-PCR was more appropriate. It is concluded that FCM can detect macrochimerism with high accuracy but would fail when DC amount is less than 1% due to sensitivity limitation, while the real time PCR is more sensitive for detecting microchimerism but lack of accuracy for detecting macrochimerism. Combination of the two methods can afford sensitive and accurate tool for quantitative analysis of chimerism in mouse model of transplantation and adoptive immunotherapy. PMID- 20723318 TI - [Incidence and risk factors of hemorrhagic cystitis after hematopoietic stem cell transplantation]. AB - The aim of this study was to analyze the risk factors of hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT). The data of 188 transplant patients treated from July 2003 to August 2009 in Peking University First Hospital were studied. The patients were followed up to 180 days after HSCT. Clinical records of the total 188 cases and the 150 cases underwent allogeneic HSCT out of 188 cases were analyzed by using a Cox regression model respectively. The results indicated as follows: (1) 51 of 188 patients developed HC (27.12%). Univariate analysis showed that sex (male RR = 1.673, p = 0.076), allogeneic HSCT (RR = 1.848, p = 0.061) were related to HC, and allogeneic HSCT (RR = 4.508, p = 0.037) was the independent risk factor for HC by multivariate analysis. (2) HC occurred in 32.67% (49/150) patients who underwent allogeneic HSCT, with 42 cases of grade II-IV HC (28.00%). For the incidence of grade II-IV HC, univariate analysis revealed mismatched related donor/matched unrelated donor (RR 2.444, p = 0.018), CMV viruria (RR 2.059, p = 0.021) and CMV positive in serum and urine at the same time (RR 2.497, p = 0.003) were risk factors. The following factors, as conditioning with Fludarabine (Flu) (RR 0.504, p = 0.059) and TBI (RR 0.185, p = 0.095), were associated with a decreased tendency of II-IV HC at age of 26 - 40 (compared with age <= 25 or >= 41, RR 0.454, p = 0.056). Some others, as conditioning with CTX (RR2.015, p = 0.063), the application of ATG (RR 2.343, p = 0.054) and CMV viremia (RR 2.123, p = 0.088), were associated with an increased tendency of II-IV HC by univariate analysis. Multivariate analysis demonstrated that CMV positive in serum and urine at the same time (RR 2.269, p = 0.008), conditioning without Flu (RR = 2.106, p = 0.040) were the independent risk factor for grade II-IV HC. And the application of ATG (RR = 2.154, p = 0.083) was related to the tendency of higher incidence of grade II-IV HC. It is concluded that the incidence of HC is high in patients underwent allogeneic HSCT. CMV positive in serum and urine at the same time, while conditioning without Flu are the independent risk factors of grade II-IV HC. Application of ATG is related to the increased trend of grade II-IV HC. PMID- 20723319 TI - [Kinetic study of splenocytes after allogeneic murine bone marrow transplantation]. AB - The study was purposed to understand immunological reconstitution of peripheral immune organs after transplantation, through establishing allogeneic murine bone marrow transplantation model and detecting the kinetic change of splenocytes after transplantation. C57BL/6 mice were donors, BALB/c mice were recipients. Recipient mice were divided into irradiation group (R), irradiation plus inoculating bone marrow mononuclear cells (MNC) group (B), and irradiation plus inoculating bone marrow mononuclear cells and spleno-MNC group (S). After transplantation, the mice were examined daily for the symptoms such as weight, hunched posture, activity, ruffled fur, diarrhea, and survival. Blood routine test was done once a week, splenocyte was counted and CD3, CD4, CD8, B220, CD11c positive cell relative count was detected by FACS on day 2, 7, 14, 27, 60 after transplantation, Liver, skin and intestine were biopsied for histopathological examination before dying. The results indicated that 89% mice in S group died of acute graft-versus-host disease (aGVHD) during day 6 to 78. The spleno mononuclear cell count quickly decreased and reached to lowest level on day 2, then gradually recovered to level of pretransplantation on day 14; CD8 and B220 positive cells decreased to lowest level on day 12, in which CD8(+) cells quickly recovered and reached to level of pretransplantation, but the B220(+) recovered most slowly and sustained to be with low level, then gradually recovered to level of pretransplantation on day 60; CD3 and CD4 positive cells decreased relatively slowly, and reached to lowest level on day 14, then both gradually recovered to level of pretransplantation on day 60; CD11c positive cell count changed unstrikingly except day 14. It is concluded that when C57BL/6 mice are donors, and BALB/c mice are recipients treated with irradiation of 7.5 Gy and inoculated with 1 x 107 bone marrow MNC and 1 x 107 spleno-MNC, allogeneic murine bone marrow transplantation model can be thus set up. The spleno-mononuclear cells show obviously kinetic changes after transplantation, that CD8 positive cells recover ahead of all, then followed by CD3 and CD4 positive cells, and the reconstitution of B220 positive cells is the slowest. PMID- 20723320 TI - [Safety comparison of mobilization and collection of hematopoietic stem cells between related and unrelated donors]. AB - The study was aimed to compare the safety of hematopoietic stem cell mobilization and collection in related donors providing bone marrow and peripheral blood stem cells and in unrelated donors providing peripheral blood stem cells only. 100 related donors from September 2005 to August 2006 at Institute of Hematology & People Hospital, Peking University, and 71 unrelated donors from November 2003 to December 2007 in Data Bank of Chinese Hematopoietic Stem Cell Donor Beijing Management Center, were observed in process of bone marrow and peripheral blood stem cell mobilization, collection, and follow-up. The change of hematologic parameters (white blood cell count, platelet count and hemoglobin level) and the side effects were recorded and evaluated on months 1, 3 and 6 as well as annually after PBSC donation. During follow-up, long-term side effects and life quality were investigated by questionnaires. The results showed that the total MNC count of bone marrow and PBSC from related donors was 6.70 (4.11 - 12.23) x 108/kg, and the total CD34(+) cell count was 3.40 (1.61 - 13.57) x 106/kg; the total MNC count of PBSC from unrelated donors was 6.69 (3.35 - 11.48) x 108/kg, and the total CD34(+) cell count was 3.50 (1.15 - 11.60) x 106/kg. The main side effect of mobilization was bone pain, reported in 47.0% of the related donors and in 43.7% of unrelated ones, the main side effect of collection was paresthesia, reported in 25.0% of the related donors and in 29.6% of unrelated ones, there was no significant difference on side effects between related and unrelated donors during mobilization and collection of hematopoietic stem cells, all donors could endure these side effects, and no donor discontinued G-CSF administration because of side effects. After collection, the hemoglobin level of related donors was lower than that of unrelated donors [(125.8 +/- 20.2) g/L vs (143.2 +/- 20.1) g/L] (p < 0.05) because of bone marrow and peripheral blood collection, and the platelet count of unrelated donors were lower than that of related donors [(126.2 +/- 57.2) x 109/L vs (162.4 +/- 72.9) x 109/L] (p < 0.05) because of more than two times of collection. There was no significant difference on hematologic parameters between two groups during long-term follow-up, and the majority of the donors reported were in good or very good health. It is concluded that the donation proved from related and unrelated donors is safe to mobilize hematopoietic stem cells for allogeneic transplantation. Long-term monitoring of healthy PBSC donors remains important to guarantee the safety standards of bone marrow and peripheral blood stem cell mobilization and collection, including comprehensive medical examination before mobilization and collection, careful manipulation during collection, long term follow up after collection and so on. PMID- 20723321 TI - [Application of SPECT/PET in patients with lymphoma and its significance in monitoring relapse]. AB - The aim of this study was to evaluate the application value of SPECT/PET (18)F FDG imaging in patients with lymphoma and its significance in monitoring relapse of this disease. A retrospective analysis of 71 SPECT/PET examinations was performed in patients with lymphoma diagnosed by pathologic and immunohistochemistry means from 1998 to 2008 in Peking university first hospital. The results showed that 28 patients underwent SPECT/PET before initial therapy, the accuracy of SPECT/PET and CT were 100% and 81.7% respectively. The diagnostic sensitivity of SPECT/PET and CT for foci were 85.7% and 53.5% respectively, and there was significant difference between them (p = 0.003). The diagnostic sensitivity of SPECT/PET and CT for extranodal foci were 91.3% and 56.5% respectively, there was significant difference also between them (p = 0.007). 32 patients underwent 43 SPECT/PET for monitoring relapse during follow up. The positive predictive value and negative predictive value of SPECT/PET for relapse were 100% and 92.9% respectively. The relapse were found by SPECT/PET in 6 patients more early than appearance of clinical symptoms and physical signs as well as laboratory examination, imaging examination. In conclusion, SPECT/PET has significant value in diagnosing and monitoring relapse for patients with lymphoma. PMID- 20723322 TI - [Adverse effects of PAD and VAD regimens in multiple myeloma patients]. AB - The study was aimed to evaluate the adverse effects of PAD (bortezomib + adriamycin + dexamethasone) and VAD (vincristine + adriamycin + dexamethasone) as chemotherapy regimens in multiple myeloma patients. 27 and 30 patients with multiple myeloma (MM) were enrolled in PAD and VAD groups respectively. MM patients accepted 3 - 5 cycles of VAD or PAD regimens. The type, degree and occurrence time of adverse reactions during the treatment were observed. The results showed that the rash was found in two patients only in PAD group, leucocytopenia, thrombocytopenia, peripheral neuropathy, infection, fatigue, nausea, constipation, and adverse effects of cortex hormone (hypertension, glycemia, hypokalemia, hyponatremia and acne) were found in the both two groups. The thrombosis was not observed in both two groups during treatment. Although statistical analysis indicated that only the incidence of thrombocytopenia was higher in PAD group than in VAD group with statistical difference but the incidence of leucocytopenia, peripheral neuropathy and infection in PAD group were higher than those in VAD group. Rash, constipation, peripheral neuropathy could be found in the first course of chemotherapy, while the others mostly emerged after 3 courses of treatment. The main reasons for the patients who's treatment was stopped include infection and intolerable peripheral neuropathy. Although peripheral neuropathy could be found in the two groups, but the chemotherapy was stopped only in 2 patients of PAD group after 3 cycles of treatment. It is concluded that compared with conventional VAD chemotherapy, PAD may improve therapeutic effect, but it may bring more severe toxicities to the patients with multiple myeloma. PMID- 20723323 TI - [Changes of pathogens for nosocomial infection of patients with hematological diseases]. AB - In order to investigate the distribution of nosocomial infection in patients with hematological diseases in our hospital, and to explore the changes of the pathogens isolated. The method of retrospective investigation and analysis was employed. 1164 strain pathogens were isolated from the patients with hematological diseases during the period of 1997-2009. The results showed that the Gram-positive cocci infection increased gradually during the 13 years, but has been stable in the last 4 years. The Gram-negative bacteria showed a trend decrease. The fungi increased during these years. The rates of infection with gram-positive cocci, gram-negative bacteria and fungus were 28.2%, 59.8% and 12.0% respectively. For the details, Escherichia coli infection rate was the highest: 12.1%, followed by Pseudomonas aeruginosa (9.1%), Enterobacter (8.4%), Klebsiella pneumoniae (7.4%), Staphylococcus epidermidis (6.3%) and Enterococci (6.6%). The distribution of G(+)- and G- pathogens showed obvious change on end of 1990's and beginning of this century, but it was tending towards stability on recent years; the incidence of fungus was tending towards increase, which was related to wide application of strong broad-spectrum antibiotics. In conclusion, the patients with hematological diseases, as the high-risk group of nosocomial infection, should be monitored strictly. Infection is related to many factors, and the main factor is dysfunction of autoimmunity. The strategies should be explored to strengthen the immune protection and set up a reasonable scheme of antibiotics. PMID- 20723324 TI - [Clinical and biological features in refractory anemia with ringed sideroblasts with fluctuant platelet counts]. AB - The objective of this study was to explore the differences between refractory anemia with ringed sideroblast (RARS) and RARS associated with marked thrombocytosis (RARS-T) in the clinical, biological features and prognosis. The morphological changes of cells were observed by bone marrow smear and biopsy. Immunologic phenotype was analyzed by flow cytometry, and chromosome was examined by conventional chromosomal analysis. JAK2 V617F and MPL W515L mutations were screened by allele-specific polymerase chain reaction (AS-PCR) and sequence analysis. The results showed that this case was clinically diagnosed as RARS with thrombophilia, the level of serum potassium was positively related with platelet counts. When platelets increased, the clusters of atypical giant platelets and megakaryocytes were observed in peripheral blood and bone marrow examined by bone marrow smear and bone marrow biopsy respectively, JAK2 V617F and MPL W515L mutations were negative. It is concluded that RARS may transform into RARS-T accompanied with megakaryocyte proliferation, large atypical platelets and negative JAK2 V617F. Preventing thrombophilia and monitoring relative gene mutations are necessary when atypical giant platelets and fluctuant platelet counts occurred in process of RARS with tendency to RARS-T. PMID- 20723325 TI - [Clinical analysis of 22 cases of POEMS syndrome]. AB - This study was purposed to investigate the clinical characteristics of POEMS syndrome in China, the clinical data of 22 patients with POEMS syndrome admitted in Chinese PLA general hospital from April 1993 to April 2008 were analyzed retrospectively. The results showed that the average age of patients was 47.7 years old, and the male:female ratio was 2.67. Weakness was the most frequent initial symptom. Nervous system lesions were found in all cases, weakness and numbness were predominant. Electromyogram showed neurogenic damage. Cerebrospinal fluid pressure and protein level were often elevated. Monoclonal band could be seen in electrophoresis of cerebrospinal fluid. Enlargement of liver, spleen and lymph nodes were common. Endocrine diseases accounted for 95.5%, in which gonadal dysfunction was most common. The sensitive test in M protein examination was immunofixation electrophoresis with positive rate 92.9%. IgA level was higher than IgG, and lambda-type light chain was the majority, but kappa-type light chain appeared in a small number of patients. Changes in skin included hyperpigmentation, hirsutism and sweating. In conclusion, clinical characteristics of patients in this group were basically similar to that reported in home, but were some different from that reported in abroad including following indicators: cerebrospinal fluid protein level, incidence of hepatomegaly and splenomegaly, serum protein level, light chain kappa and lambda level, incidence of peripheral edema, ascites, pleural effusion and platelet count. PMID- 20723326 TI - [Mode and size of HPA-typed platelet apheresis donor bank in Chinese Han population]. AB - This study was purposed to determine the mode and size of human platelet antigens (HPA) typed platelet apheresis donor bank. The published data of HPA distribution collected from Chinese Han population of 16 provinces were analyzed. The combined data were tested with the Hardy-Weinberg equilibrium. The results showed that the bb homozygote was not detected in HPA-1, -4, -6, -10, and b gene was not found in HPA-7-9, 11-14, -16. There were 648 combined HPA 1-16 genotypes in Chinese Han population, and the cumulative frequency of 42 combinations higher than 0.001 were 0.9763. The highest frequency (0.2012) in combination was HPA-(7-8-9-11-12 13-14-16) aa - (1-4-5-6-10) aa-2aa-3ab-15ab. The probability of HPA dual antigen mismatch in HPA-15, -3 and -2 was higher than the 0.1, and the probability in the HPA-1, -5, and -6 was between 0.01 - 0.1. The probability of full-match in HPA1 16 antigens was 0.3195 in Chinese Han population after the random blood transfusion. According to the curve drawn by donor number (N) versus frequency (F), the regression equation LogN = -0.4394 x Ln (F) +0.4324 was derived at P = 95%. If the derived frequency (product of HPA frequency and ABO frequency) is 0.005, then the N should be 576.07 at least in Chinese Han population. It is concluded that the mode of regional, multi-center database of HPA-typed platelet apheresis donor bank may be acceptable in Chinese Han population, and the suitable number of HPA-typed platelet donor in one bank may be 600. Therefore, the bank can be used to treat the platelet transfusion refractoriness (PTR) caused by HPA-15, 3 and 2 mismatch mainly, and can be expanded effectively in similar genetic background to deal with the low-frequency HPA antigens mismatch. The number of HPA-typed platelet apheresis donor influences not only on the frequency of HPA, but also on the frequency of ABO group. PMID- 20723327 TI - [Molecular basis for real RhD negative and RhDel phenotypes in Yiwu population of Zhejiang Province in China]. AB - This study was purposed to investigate the molecular basis for RhD negative phenotype in Yiwu population in Zhejiang Province of China. The RhD negative samples were screened by saline agglutination test in blood donors. Some real RhD negative and RhDel phenotypes were identified using anti-human globulin test and absorbtion elution test. Ten exons of RHD gene in these samples were amplified by PCR-SSP, and positive exons were DNA sequenced. The results indicated that 30 real RhD negative and 8 RhDel phenotypes were identified in 38 initial RhD negative samples. Ten exons were complete negative in 28 real RhD negative samples and only exon 1, 2 and 10 were positive in 2 real RhD negative samples amplified by PCR. All 10 exons in 8 RbDel samples were positive and a DNA variant (1227G > A) was found in 8 RhDel samples. It is concluded that all exons are absence in most real RhD negative phenotypes, and the partial exons absence is also found in some real negative phenotypes among Yiwu population in Zhejiang province of China. The G to A mutation at position 1227 is found in all RhDel phenotypes. PMID- 20723328 TI - [Associations of human leukocyte antigen-A, B, DRB1 genes with leukemia patients in Anhui province of China]. AB - This study was aimed to investigate the relation of human leukocyte antigen-A, B, DRB1 genes with the susceptibility of population to leukemia in Anhui province of China. The HLA genotypes were analyzed by PCR-SSP in 140 patients with chronic myelocytic leukemia (CML), 84 patients with acute lymphoblastic leukemia (ALL), 90 patients with acute nonlymphocytic leukemia (ANLL) and 916 healthy unrelated donors of hematopoietic stem cell as normal control admitted to Anhui provincial hospital. The gene frequencies of HLA-A, B, DRB1 between patients and normal controls were compared, chi2 test was used for statistical analysis. The results showed that as compared with normal controls, the gene frequencies of A2, A11, B58 and DR9 in CML patients all obviously increased, and gene frequency of DR7 decreased; the gene frequencies of All and B13 in ALL patients were significantly higher than that in normal controls; the gene frequencies of A24, B58 and DR9 in ANLL patients were significantly higher than that in normal controls. It is concluded that HLA-A2, A11, B58 and DR9 are predisposing genes of CML patients, DR7 is an antagonistic gene, HLA-A11 and B13 are predisposing genes of ALL patients, HLA-A24, B58 and DR9 are predisposing genes of ANLL patients. PMID- 20723330 TI - [Advances of study on prognostic factors of molecular biology in acute myeloid leukemia with normal cytogenetics]. AB - Acute myeloid leukemia (AML) is a group of diseases with a conspicuous heterogeneity. Following the development of cytogenetics, multiple reproducible chromosome aberrations have been discovered in AML, many of which not only are diagnostic markers for specific AML subtypes but also significant prognostic factors for determining complete remission (CR), relapse risk, and overall survival (OS). However, with the foundation of available chromosome analysis, a large group of acute myeloid leukemia (AML) patients, 40% to 49% of adults and 25% of children had not been found abnormality of chromosome karyotype under microscope. These so-called cytogenetically normal acute myeloid leukemia (CN AML) patients have usually been classified in an intermediate-risk prognostic category. Nevertheless, the outcome of the CN-AML patients are varied in clinical studies, likely because there exist diverse gene mutations in these patients according to recent researches. Those mutations at the molecular level, on basis of which AML could be further classified, are significantly associated with CN AML patients and offer potential targets for specific therapeutic studies. The review focuses on research advances abroad in this field including gene mutations suggesting bad prognosis such as FMS-related tyrosine kinase 3 gene mutation, Baalc gene and ETS-related gene hyperexpression, Wilms' tumor gene mutation and other gene mutations as well as gene mutations suggesting good prognosis such as nucleophosmin gene mutation, mixed lineage leukemia-partial tandem duplication, CCAAT/enhancer-binding protein alpha gene mutation. PMID- 20723329 TI - [Effects of riboflavin combined with photosensitization on reduction of Gram positive and Gram-negative indicating germs in plasma and P-selectin expression of apheresis platelet concentrates]. AB - This study was purposed to confirm the practical efficacy of reducing indicating germs suspended in plasma by riboflavin and photosensitized inactivation and to evaluate its influence on activation of apheresis platelet concentrates. The synergistic effects of riboflavin combined with ultraviolet irradiation on inactivation of germs were investigated by using Escherichia Coli (E. coli) and Staphylococcus Aureus (S. aureus) as Gram- and Gram(+) indicating germs, respectively. The activation status of apheresis-platelet concentrates treated with riboflavin combined with ultraviolet irradiation was detected by flow cytometry. The results showed that when 50 MUmol/L of riboflavin was combined with 6.2 J/ml of ultraviolet irradiation, the T/E ratios reached 1.42 for E. coli and 1.68 for S. Aureus, and reduction of E. Coli and S. Aureus were 3.87 Logs and 3.82 Logs respectively; the CD62p expression level on germ-inactivated platelets stored at 22 degrees C for 0 and 5 days were 4.92% and 36.18% respectively, which slightly increased as compared with controls (3.94% and 32.03)% (p < 0.05). It is concluded that combination of riboflavin with ultraviolet irradiation displays well synergistic effects which can reduce E. Coli and S. Aureus counts, but no significantly influence on platelets. The partial activation of liquid platelets mainly presents metabolism damage during storage, which is found at an acceptable level. PMID- 20723331 TI - [Noncanonical NF-kappaB pathway and hematological malignancies]. AB - Nuclear factor kappaB (NF-kappaB), including RelA, RelB, c-Rel, NF-kappaB1, and NF-kappaB2, plays a crucial role in immune response, inflammatory reaction, tumorigenesis, and development of peripheral lymphoid organs and lymphocytes. There are two NF-kappaB activation pathways: canonical pathway (classical pathway) and noncanonical pathway (alternative pathway). Previous studies focused on the effects of the canonical NF-kappaB pathway (mainly p50-RelA) in hematological malignancies. Recently, the noncanonical NF-kappaB pathway (mainly p52-RelB) is gradually taken importance in pathogenesis of hematological malignancies. Understanding the relations of the noncanonical pathway with hematological malignancies would provide a new therapeutic approach for these diseases. This review focuses on the noncanonical NF-kappaB signaling transduction pathway and its relation to hematologic malignancies. PMID- 20723332 TI - [Progress in biology of dendritic cells]. AB - As the most potent antigen-presenting cells (APC), dendritic cells are important in launching both humoral and cellular immune responses against tumor. Although the high evaluation of DC in immunotherapy for cancer by means of DC vaccines, more studies have indicated DC is a heterogeneous population and proved that DC subsets are prominent determinants for the effectiveness of immune responses. Different DC subsets display different receptors and surface molecules, and express different sets of cytokines/chemokines, which result in distinct immunological outcomes. Clinical trials with ex vivo generated DC vaccines also manifest unexpected immunological tolerance as well as allergic response. It is essential to study the biological aspects of human DC subsets, which may be a key to the generation of novel DC-based vaccines. In this article, the progress of studies on biology of dendritic cells including their origins, differentiation, function and application of DC subsets is reviewed. PMID- 20723333 TI - [Recent research advance in immunomodulatory function of mesenchymal stem cells on immune cells]. AB - Mesenchymal stem cells (MSCs) can inhibit T cell proliferation, the effects of MSCs on various T cell subsets have showed different immune regulatory reactions, and their mechanisms mainly include cell-cell contact and mediation by cytokines secreted from MSCs. Encouragingly, recent studies have showed that the effects of MSCs on T-cell response to pathogens is not significant, but can obviously suppress T cell response to allogeneic antigens. In addition, MSCs can regulate the proliferation, survival, antibody secretion and differentiation of B cells, inhibit the production, proliferation, migration and antigen-presentation of DCs, and modulate the differentiation and maturation of DCs, and regulate the proliferation, cell toxicity and cytokine secretion of NK cells. In this review, the research advances on immunomodulatory effects of MSCs on various immune cells including T-lymphocytes, B-lymphocytes, NK cells and DCs are summarized with emphasis on the immunoregulatory effects of MSCs on T-lymphocytes. PMID- 20723334 TI - [Role of mesenchymal stem cells in angiogenesis and clinical applications]. AB - Mesenchymal stem cells (MSC) are multipotent cells able to differentiate into multiple lineages including cardiomyocytes and vascular endothelial cells under in vitro culture conditions. In vivo studies have shown that MSC can facilitate angiogenesis, and they localize to the site of ischemic injury which block or reverse the pathologic process. All the data suggest that MSC may be a promising strategy in the treatment of ischemic heart diseases. In recent years, more and more reports demonstrated that researchers have made enormous advances in this field. This review focuses on the angiogenesis and therapeutic applications of MSC derived from human bone marrow, including basic biological features of MSC, role of MSC in angiogenesis, preclinical study of MSC therapy in ischemic heart disease and prospect of MSC application in this disease. PMID- 20723335 TI - [CD47 and leukemia stem cells]. AB - CD47, also known as integrin-associated protein (IAP), is an immunoglobulin-like protein. It can inhibit the phagocytosis of macrophages through binding with signal-regulatory protein alpha chain of inhibitory receptor on macrophage (SIRPalpha). The expression of CD47 on normal hematopoietic stem cells (HSCs) is useful for maintaining the stability of HSCs in body, but the high expression of CD47 existed on leukemia stem cell (LSCs) of AML patients which can reduce the macrophage-induced phagocytosis to LSCs and decrease the clearance of innate immune system of organism to LSCs. In this article, the expression and function of CD47 on HSCs and LSCs as well as the role of CD47 in the prognosis and target therapy of AML are reviewed. PMID- 20723336 TI - [Research advance on clinical blood transfusion and tumor therapy]. AB - Clinical blood transfusion is one of the most important supportive therapy for patients with tumor. The blood transfusion has dual effects for patients with tumor. First, blood transfusion can rectify anemia and improve oxygen saturation, accelerate oxidation and necrosis for tumor cells; the second, blood transfusion can induce immunosuppression, tumor recurrence and postoperative infection for tumor patients. Filtering white blood cells (WBC) before blood transfusion can decrease the incidence of the adverse reactions. The rational perioperative autotransfusion for patients with tumors is focus to which the world medical sciences pay close attention. In this article, the support effect of blood transfusion for treatment of tumor patients, blood transfusion and immunosuppression, blood transfusion and postoperative infection and relapse of tumor patients, depleted leukocyte blood transfusion and autologous transfusion of tumor patients are reviewed. PMID- 20723337 TI - [Mutation of tet2 gene and malignant blood disease]. AB - Tet2 (the 2nd member of tet oncogene family) is a newly discovered antioncogene on the chromosome 4q24 of the patient with malignant myeloma, which has a potential for functional deletion. Recent studies demonstrated that tet2 mutation was found in polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis, systematic mastocytosis (SM), and myelodysplastic syndrome (MDS). However, a great number of perspective researches are still needed for exploring the role of tet2 in the pathogenesis of malignant blood diseases. In this review, the relation of tet2 mutation with myeloproliferative neoplasm, systemic mastocytosis, myelodysplastic syndrome, acute myeloid leukemia and other malignant blood diseases are summarized. PMID- 20723338 TI - [Research advances on relationship between suppressor of cytokine signaling 3 and myeloproliferative neoplasms]. AB - Suppressor of cytokine signaling (SOCS) is a protein family negatively regulating signal transduction pathway of a certain class of cytokines and growth factors. More than 20 members have been found in SOCS family, SOCS3 is one of them and has been studied hottest and most clearly. Recent studies demonstrated that SOCS3 abnormalities were found in patients with myeloproliferative neoplasms (MPN), suggesting that SOCS3 plays a significant role in the pathogenesis, development and metastasis in MPN. In this review, the advances of research on relationship between SOCS3 and MPN were summarized, including general profile of SOCS family; structure, function and regulation of SOCS3, relation of SOCS3 to MPN and so on. PMID- 20723342 TI - [Establishment and Characterization of a Novel Chinese Human Lung Adenocarcinoma Cell Line CPA-Yang2 in Immunodeficient Mice.]. AB - BACKGROUND: The recurrence, metastasis and multidrug resistance (MDR) in lung cancer are the tough problems worldwide. This study was to establish a novel chinese lung adenocarcinoma cell line with high metastasis potential for exploring the mechanism of reccurrence, development and MDR in lung cancer. METHODS: The cell came from the abdominal dropsy of a fifty-six years old female patient with lung adenocarcinoma and the tumor markers CA125, CYFRA21-1, CEA, NSE were detected to be higher secretion by radioimmunoassay in the abdominal dropsy. Tumorigenicity of immunodeficient mice was confirmed in 8th passage. The cell growth curve was mapped. Analysis of chromosome karyotype was tested. The gene expression was measured by real-time quantitative PCR. RESULTS: The tumorigenesis rate started at 8th passage in 3/10 immunodeficient mice via subcutaneously and the fully tumorigenicity was at 11th passage as well as later passages. Under the microscope, the cell showed oval-shap and adherence. The chromosome karyotype analysis of the cells was sub-triploid. Approximately 1*10(6) and 1.5*10(6) cancerous cells were injected into left cardiac ventricle and tail vein of immunodeficient mice respectively. The results showed multiorgan metastasis in the mice after three-four weeks, including mandible, scapula, humerus, vertebral column, femur, rib and brain, liver, adrenal gland, pulmonary in the mice after inoculation. The bone metastasis rate was 100% in the tumor bearing mice by bone scintigraphy and pathology. Quantitative real-time PCR was used to examined and compared with SPC-A-1 lung adenocarcinoma, ESM1, VEGF-C, IL-6, IL-8, AR genes were overexpressed. The novel cell was named CPA-Yang2 CONCLUSIONS: The characteristics of novel strain CPA-Yang2 is a highly metastasis cell line of Chinese lung adenocarcinoma. It has stable traits, highly metastasis ability and maybe is a MDR lung cancerous cell line. Of course, it's a good experimental model for lung cancer research. PMID- 20723343 TI - [Screening the Drug Sensitivity Genes Related to GEM and CDDP in the Lung Cancer Cell-lines.]. AB - BACKGROUND: Background and objective Screening of small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines with gemcitabine hydrochloride (GEM) and cisplatin (CDDP) related to drug sensitivity gene might clarify the action mechanism of anti-cancer drugs and provide a new clue for overcoming drug resistance and the development of new anti-cancer drugs, and also provide theoretical basis for the clinical treatment of individual. METHODS: The drug sensitivity of CDDP and GEM in 4 SCLC cell lines and 6 NSCLC cell lines was determined using MTT colorimetric assay, while the cDNA macroarray was applied to detect the gene expression state related to drug sensitivity of 10 lung cancer cell line in 1 291, and the correlation between the two was analysized. RESULTS: There were 6 genes showing significant positive correlation (r>=0.632, P<0.05) with GEM sensitivity; 45 genes positively related to CDDP; another 41 genes related to both GEM and CDDP (r>=+/- 0.4). Lung cancer with GEM and CDDP sensitivity of two types of drugs significantly related genes were Metallothinein (Signal transduction molecules), Cathepsin B (Organization protease B) and TIMP1 (Growth factor); the GEM, CDDP sensitivity associated genes of lung cancer cell lines mainly distributed in Metallothinein, Cathepsin B, growth factor TIMP1 categories. CONCLUSIONS: There existed drug-related sensitive genes of GEM, CDDP in SCLC and NSCLC cell lines; of these genes, Metallothinein, Cathepsin B and TIMP1 genes presented a significant positive correlation with GEM drug sensitivity, a significant negative correlation with CDDP drug sensitivity. PMID- 20723344 TI - [hsa-miR-125a-5p Enhances Invasion in Non-small Cell Lung Carcinoma Cell Lines by Upregulating Rock-1.]. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous, non-coding small RNA in eukaryotes. They recognize their target sites by incomplete base pairing and posttranscriptionally regulate gene expression, and function on a lot of complex vital processes of organisms. The objective of this work is to study how hsa-miR 125a-5p enhances the invasive ability of lung cancer cells. METHODS: The target gene and its target sites of hsa-miR-125a-5p were predicted by microRNA.org. We investigated Rock-1 mRNA and protein expressions by RT-PCR and Western blot according to the result of prediction further. The invasive ability of A549 cells, which were transfected with sense hsa-miR-125a-5p 2'-O-methyl oligonucleotide after being blocked by anti-Rock-1, was observed by Transwell. RESULTS: With RT-PCR and Western blot, Rock-1 mRNA and protein were both increased in A549 cells transfected with sense hsa-miR-125a-5p 2'-O-methyl oligonucleotide and were both decreased in the cells which transfected with antisense vs control groups. The invasive ability of A549 cells transfected with sense hsa-miR-125a-5p 2'-O-methyl oligonucleotide were weakened after being blocked by anti-Rock-1, vs non-blocking group by Transwell test. CONCLUSIONS: hsa miR-125a-5p could up-regulate Rock-1 and enhance invasion in lung cancer cells. PMID- 20723345 TI - [Expression and Significance of Clusterin in Anip973/CDDP Cell Lines.]. AB - BACKGROUND: Clusterin (CLU) is a multifunctional protein which attracts much attentions in recent years due to its function and variation in tumor formation and development. So far, there have no reports on its variation in lung cancer and its relationship with sensitivity of anti-cancer drugs. This study was to compare the expression of clusterin in wild Anip973 and Anip973/CDDP, thus to investigate the correlation of clusterin expression to tumorigenesis, tumor development and drug resistance in non-small cell lung cancer (NSCLC). METHODS: Western blot and RT-PCR were used to compare the clusterin expression at protein level and mRNA level in Anip973/CDDP with that in wild Anip973. Flow cytometry was employed to detect and analyze the relationship between clusterin and cell cycle, p53 or Bax. RESULTS: Clusterin protein expression levels were significantly higher in those Anip973/CDDP than those in wild Anip973. The p53 expression levels were higher in Anip973/CDDP than in Anip973 (P<0.01). The expression of Bax showed no significant difference between Anip973 and Anip973/CDDP (P>0.05). As to drug resistant lung cancer cell lines, Anip973/CDDP had more cells in G0-G1 stage while less cells in S stage or G2-M stage than non resistant cell line. CONCLUSIONS: Clusterin is associated with resistance to CDDP in NSCLC. The abnormal expression of clusterin and p53 in Anip973/CDDP indicated that both clusterin and p53 might be involved in drug resistance in NSCLC. PMID- 20723346 TI - [The Association between Polymorphisms of XPD and Susceptibility of Lung Cancer: A meta Analysis.]. AB - BACKGROUND: Many studies concluded that the polymorphisms of XPD were involved in the risk of lung cancer. However, several other studies suggested no association. To explore whether the polymorphisms of XPD contribute to the genetic susceptibility to lung cancer, we carried a meta-analysis based on the published works. METHODS: All works related to XPD and lung cancer risk were searched and carefully selected. The genotype frequencies of XPD and related variables were abstracted and the pooled ORs were calculated after the heterogeneity test with the software Stata 10. Publication bias and sensitivity were evaluated at the same time. RESULTS: Twenty-two studies were included according to the selection criteria, of which fifteen investigated the codon 312 of XPD and twenty studied the codon 751. The pooled OR of susceptibility to lung cancer with XPD312 Asn/Asn genotype compared to the wild Asp/Asp were 1.18 (95%CI: 1.03-1.34, P=0.018). And the polymorphisms of XPD codon 751 were also associated with increased lung cancer risk (Lys/Gln OR=1.09, 95%CI: 1.02-1.18; Gln/Gln OR=1.24, 95%CI: 1.10 1.41). However, subgroup analysis indicated that the association between XPD751 and lung cancer could only be found in Europeans and Americans. The publication bias analysis had no statistically significant results. CONCLUSIONS: Polymorphisms of XPD codons 312 and 751 seem to be involved in elevated risk of lung cancer. PMID- 20723347 TI - [The Clinical Application of Video Mediastinoscopy and CT in the N Staging of Preoperative Lung Cancer.]. AB - BACKGROUND: Preoperative lung cancer with mediastinal lymph nodes metastasis can be diagnosed by vedio mediastinoscopy (VM) and CT. This study was to explore the value of VM and CT in the diagnosis of N staging of preoperative lung cancer, and to discuss the difference between the two methods. METHODS: Forty-eight cases diagnosed of lung cancer by CT or PET-CT were examined by VM. The sensitivity, specificity, validity, positive predictive value and negative predictive value of VM and CT were speculated according to the postoperative pathological reports, and the difference between VM and CT in the diagnosis of lung cancer with mediastinal lymph nodes metastasis was discussed. RESULTS: (1)Under the examination of VM, 31 patients with the negative outcome received the direct operation; 14 patients with N2 received 2 courses of neoadjuvant chemotherapy before operation; 3 patients with N3 received chemotherapy and/or radiotherapy. (2)Forty-one cases with final diagnosis of lung cancer were used as samples to speculate the sensitivity, specificity, validity, positive predictive value and negative predictive value of VM. They were 93.3%, 100%, 97.6%, 100%, 96.3%, which of CT were 66.7%, 53.8%, 58.5%, 45.5%, 73.7% (Chi-square=4.083, P=0.039), the difference between VM and CT was statistically significant. (3)In this group, the complications of VM incidence rate was 2.08% (1/48), and the case was pneumothorax. CONCLUSIONS: VM is superior to CT in the diagnosis of N staging of preoperative lung cancer; Due to its safety and effectiveness, VM will be wildly used in the field of thoracic surgery. PMID- 20723348 TI - [Expression and Significance of bag-1, bcl-2 in Non-small Cell Lung Cancer and the Correlation with Multi-drug Resistance.]. AB - BACKGROUND: bag-1, bcl-2 and bax are all apoptosis-related proteins. They play a role in the diagnosis, progress, metastasis and prognosis of tumor. The aim of the study was to investigate the expression of bag-1, bcl-2 and bax in non-small cell lung cancer, and to study the relationship between their expression levels and the clinical pathological characteristics, furthermore, to evaluate their correlation with multi-drug resistance. METHODS: The expressions of bag-1, bcl-2 and bax in 140 non-small cell lung cancer tissues (40 of 140 were processed neoadjuvant chemotherapy) and 15 lung benign lesion tissues were examined with SP immuno-histochemical stain. RESULTS: The positive expression rates of bag-1 and bcl-2 protein in non-small cell lung cancer were significantly higher than those in pulmonary benign lesion tissues (P<0.05), but the positive expression rate of bax in non-small cell lung cancer was significantly lower than that in pulmonary benign lesion tissues (P<0.05). The expressions of bag-1, bcl-2 and bax protein were not related to the age and sex of patients, histological classification, P TNM stage and lymph node involvement of the cancer (P>0.05), but bag-1 was related to the differentiation degree of the tumor. The lower the differentiation was, the higher the levels of expression of bag-1 were. bcl-2 protein expression was highly positive correlated with the bag-1 protein expression in non-small cell lung cancer (r =0.371, P<0.01), and bcl-2 protein was highly negative correlated with bax protein expression (r=-0.225, P<0.01). The positive expression rates of bag-1 and bcl-2 showed increasing trends from the patients without neoadjuvant therapy to those with neoadjuvant therapy, but the difference had no statistic significance (P>0.05). CONCLUSIONS: The high expression of bag 1, bcl-2 protein and the low expression of bax protein exist in nonsmall cell lung cancer. The expression level of bag-1 protein is closely related to the differentiation degree of non-small cell lung cancer. A highly positive correlation exists between bag-1 and bcl-2 expression, and a highly negative correlation is observed between bcl-2 and bax expression. The study doesn't provide the evidence that there is a close correlation between the expression levels of bag-1, bcl-2, bax and the multi-drug resistance in non-small cell lung cancer. PMID- 20723349 TI - [Research on Postoperative Radiotherapy for Non-small Cell Lung Cancer of Stage IIIA (N2) according to the Failure Patterns after Pulmonary Resection.]. AB - BACKGROUND: Postoperative radiotherapy (PORT) after complete resection of non small cell lung cancer (NSCLC) has been introduced in order to reduce locoregional recurrence, but it remains controversy whether PORT can improve survival. Therefore, we want to investigate the effect of PORT and the relationship between failure patterns and primarily location of stage IIIA (N2) in NSCLC. METHODS: This retrospective analysis included 233 patients who underwent resection of NSCLC, first recurrence involving a local-regional site. It illustrated the factors affecting local recurrence and the sites of failure on the basis of lobe of primary tumor. RESULTS: Multivariable analysis demonstrated the number of positive lymph nodes (P=0.003), T stage (P<0.001), histological type (P=0.038), modus operandi (P=0.013) and the number of mediastinal lymph node stations involved (P=0.018) were the independent factors. For all patients, the most common site of failure was the bronchial stump/staple line, which was present more often in those who had a wedge resection than in those who had a more radical procedure (P<0.001). The local-region frequency of squamous was higher than adenocarcinoma carcinoma (P=0.025). The recurrence frequency of mediastinal lymph node among T1 and T2-3 were 36.4%, 62.0% (P=0.009) respectively. The localregion recurrence among primarily tumor location were different. CONCLUSIONS: The number of positive lymph nodes, T stage, histological type, modus operations and the number of mediastinal lymph node stations involved were the independent factors in IIIA (N2) NSCLC. PMID- 20723350 TI - [Weekly Paclitaxel and Cisplatin in the Treatment of Elderly Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: Lung cancer is one of the most common cancers in the world. The number of elderly lung cancer patients is expected to rapidly increase. Therefore, the management of elderly lung cancer patients is becoming a major challenge in the field of oncology. This study was to evaluate the efficacy and safety of weekly paclitaxel (PTX) and cisplatin (DDP) as the first-line chemotherapy on advanced NSCLC patients of more than 70 years old. METHODS: Fifty chemotherapy-naive patients with advanced NSCLC more than 70 years old were administrated weekly paclitaxel and pisplatin regiment: PTX 80 mg/m(2) intravenous infusion for 1 h, d1, d8 (given routine premedications before PTX), DDP 20 mg/m(2) intravenous infusion, d1, d8, every 21 days. RESULTS: Total 50 patients were enrolled, and 48 patients were evaluable for response. The ORR (overall response rate) was 39.6%; median survival time (MST) was 14.8 months; One year survival rate was 58.3%. Most common adverse events were leucopenia (60%), anemia (62%), nausea and vomiting (30%), alopecia (100%). There were no chemotherapy-related deaths. CONCLUSIONS: The patients of advanced NSCLC more than 70 years old can tolerate weekly paclitaxel and cisplatin and can get benefit from this regiment. PMID- 20723351 TI - [Advance on Chemokines in Organ-specific Metastasis of Non-small Cell Lung Cancer.]. PMID- 20723352 TI - [Advances of EGFR and HER-2 Autoantibodies in Serum of Lung Cancer Patients.]. PMID- 20723353 TI - [Current treatment of brain metastases from lung cancer.]. PMID- 20723354 TI - [The application of nuclear medicine imaging in bronchioloalveolar carcinoma.]. PMID- 20723355 TI - [Analysis of lymphocyte count in 300 lung cancer patients.]. PMID- 20723356 TI - [A large of liquid continuous effluence in local lung after resection of lung cancer: a case report.]. PMID- 20723357 TI - [Pulmonary tuberculosis accompanied by lung cancer treatment-2 cases reports.]. PMID- 20723358 TI - [The Relationship between Nano-quartz Oxidative Damage and the High Expression of Nuclear Factor NF-kappaB of Lung Cancer in Xuanwei, Yunnan.]. PMID- 20723359 TI - [Lobectomy with Bronchoplasty and Reconstruction of Pulmonary Artery by Minitrauma-technique for Lung Cancer.]. AB - BACKGROUND: To research the effect and practicalbility of lobectomy with bronchoplasty and reconstruction of pulmonary artery by minitrauma-technique for lung cancer. METHODS: We retrospectibely reviewed our experience on 61 cases being lobectomy with bronchoplasty and bronchoplasty with or without video assisted thoracic small incision surgery for lung cancer from July 2005 to June 2009 from Shandong Provincal Hospital and 46 cases simultaneously by routine posterolateral incision. All patients whose bronchus and/or pulmonary artery were involved underwent the operation and experienced the bronchial sleeve/wedge resection or reconstruction of the pulmonary artery. RESULTS: All patients were done operation successfully and there were no operative mortality and no occurrence of anastomosis stenosis as well as fistula. The small incisions' length was from 8 cm-15 cm while the routine posterolateral incision's length was 25 cm-35 cm. The patients done the operation of small incision had less postoperative shoulder joint dysfunction and had better quality of life compaired to the patients done the routine posterolateral incision. CONCLUSIONS: Lobectomy with bronchoplasty and reconstruction of pulmonary artery by minitrauma-technique for lung cancer could finished the same work with the traditional thoracic lateral incision and had less trauma, less pain, less recovery time. PMID- 20723360 TI - [Trichostatin A Induced Bcl-2 Protein Level Decrease Mediated A549/CDDP Cells Apoptosis by Mitochondria Pathway.]. AB - BACKGROUND: The use of platinum-based combination chemotherpy remains the standard treatment for non-small cell lung cancer. However, the resistance to platinum limits further treatment clinically. Trichostatin A (TSA) is one of histone deacetylase (HDAC) inhibitors. It inhibits tumor cell proliferation and acts as a chemosensitizer. The aim of this study is to investigate the action mechanism of TSA on cisplatin-resistant human lung adenocarcinoma cell line A549/CDDP. METHODS: Cytotoxicity and cell viability was assayed by Neutral Red method. Morphologic assessment of apoptosis was determined by fluorescence microscope; cell cycle and mitochondrial membrane potential were detected by flow cytometry. In addition, A549/CDDP cells were transfected with Bcl-2 expression Vector and siRNA-bcl-2. RESULTS: A549/CDDP cells treated with TSA showed apparently cytotoxicity, IC50 of TSA was (446.59+/-27.32) nmol/L. The growth curve showed the ratio of growth decreased with the increase of concentration of TSA. The apoptosis appeared 24 hours after treated by (125-500) nmol/L TSA, morphologic changes including nuclear chromatin condensation. Fluorescence strength was observed with fluorescence microscope. Treated by TSA, mitochondrial membrane potential was decreased and cells were arrested at S phase. Western blotting analyses showed that the levels of Bcl-2 decreased, while expression of Bax increased. Simultaneously caspase-3 was activated. Over expression of Bcl-2 can inhibit TSA-induced A549/CDDP cell apoptosis, while the decrease of Bcl-2 enhanced the sensitivity of A549/CDDP cell to TSA. CONCLUSIONS: TSA induce A549/CDDP cell apoptosis by mitochondria pathway. PMID- 20723361 TI - [Expression and significance of nrf2 and its target genes in pulmonary adenocarcinoma a549 cells resistant to Cisplatin.]. AB - BACKGROUND: Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor in oxidation-reduction reaction. It has been proved that Nrf2 is relevant to cisplatin-resistance in ovarian cancer cells. Up to now, little is know whether Nrf2 and it's signal patheways play an important role in cisplatin-resistance in pulmonary adenocarcinoma cells or not. The aim of this study is to explore the expression levels of transcription factor Nrf2 and its target genes in A549 cells which are resistance to cisplatin and reveal the mechanism behind it. METHODS: A549/DDP and A549 were cultured in vitro. MTT was used to detect the drug resistance index of A549/DDP cells. Real-time PCR was used to evaluate the expression of transcription factor Nrf2 and its target genes mRNA. RESULTS: The drug resistance index of A549/DDP was 12.12, and its Keap1, Nrf2, NQO1, GSTP1, GCL, HO-1, MRP4 mRNA expressions were all significantly increased compared with A549 (P<0.01). On the other hand, MRP1, MRP2, MRP3 showd the crosscurrent (P<0.01). CONCLUSIONS: It proves that the transcription factor Nrf2 and it's signal pathways are closely related with drug resistance of tumors. Moreover, this provides a new direction to reverse drug resistance and have significance to avoid and overcome drug resistance of tumor. PMID- 20723362 TI - [Comparative Proteomic Analysis of Human Lung Adenocarcinoma Cisplatin-resistant Cell Strain A549/CDDP.]. AB - BACKGROUND: Chemotherapy plays an important role in the comprehensive therapy of lung cancer. However, the drug-resistance often causes the failure of the chemotherapy. The aim of this study is to identify differently expressed protein before and after cisplatin resistance of human lung adenocarcinoma cell A549 by proteomic analysis. METHODS: Cisplatin-resistant cell strain A549/CDDP was established by combining gradually increasing concentration of cisplatin with large dosage impact. Comparative proteomic analysis of A549 and A549/CDDP were carried out by means of two-dimensional gel electrophoresis. The differentially expressed proteins were detected and identified by MALDI-TOF mass spectrometry. RESULTS: Eighty-two differentially expressed proteins were screened by analysis the electrophoretic maps of A549 and A549/CDDP. Six differential proteins were analyzed by peptide mass fingerprinting. Glucose regulating protein 75, ribosomal protein S4, mitochondrial ATP synthase F1 complex beta subunit and immunoglobulin heavy chain variable region were identified. All four differentially expressed proteins were over-expressed in A549/CDDP, whereas low-expressed or no-expressed in A549. CONCLUSIONS: These differentially expressed proteins give some clues to elucidate the mechanism of lung cancer cell resistant of cisplatin, providing the basis of searching for potential target of chemotherapy of lung cancer. PMID- 20723363 TI - [Down-regulation of GRP78 Enhances Chemotherapy Sensitivity to VP-16 in Lung Adenocarcinoma.]. AB - BACKGROUND: GRP78, a member of GRPs, plays a critical role in chemotherapy resistance in some cancers. To investigate the relationship between the expression of GRP78 and resistance to anti-cancer drug VP-16 in vitro in lung adenocarcinoma SPCA-1 cell line. METHODS: SPCA-1 cells were divided into three groups: BAPTA-AM-treated group, A23187-treated group and the control group. RT PCR and immunofluorescence were used to analyze the expression of GRP78 at both mRNA and protein levels, respectively. Cell apoptosis was analyzed by flow cytometry in order to evaluate the therapeutic sensitivity to VP-16. RESULTS: The expression of GRP78 at both protein and mRNA levels in the BAPTA-AM-treated cells dramatically decreased as compared to that of both A23187-treated and control groups. After treatment by VP-16, the percentages of apoptotic cells were 10.84+/ 0.86, 6.85+/-0.20, 4.95+/-0.19 in BAPTA-M-treated group, the control group and A23187-treated group, respectively. CONCLUSIONS: BAPTA-AM is highly effective in the inhibition of GRP78, down-regulation of GRP78 can significantly increase the sensitivity of adenocacinoma lung cancer to VP-16. All these suggest that inhibition of the expression of GRP78 by chemicals such as BAPTA-AM or anti-sense RNA may be a new therapeutic strategies to lung cancer. PMID- 20723364 TI - [The Role of Postoperative Radiotherapy on Stage N2 Non-small Cell Lung Cancer.]. AB - BACKGROUND: The clinical value of postoperative radiotherapy (PORT) in stage N2 nonsmall-cell lung cancer (NSCLC) is controversy. The aim of this study is to analyze the efficacy of PORT in subgroup of stage N2 NSCLC, which can help clinicians to choose proper patients for PORT. METHODS: Clinical data of 359 patients with stage N2 NSCLC treated with radical surgery between Mar. 2000 and Jul. 2005 were retrospectively reviewed. Two hundred and seven patients received adjuvant chemotherapy and one hundred and four patients received adjuvant radiotherapy. First, the group of patients were analyzed to evaluate the factors affecting the overall survival. The all patients were divided based on tumor size and the number of lymph node metastasis station (single station or multiple station) so as to evaluate the role of PORT. The endpoint was overall survival (OS) and local recurrence-free survival (LRFS). Kaplan-Meier method was used to calculate the OS, LRFS and Log-rank was used to compare the difference in OS and LRFS between different groups. RESULTS: The median duration of follow-up was 2.3 years. 224 patients died. The median survival was 1.5 years and 1, 3, 5-year survival were 78%, 38% and 26%. Univariate analysis showed tumor size, the number of lymph node metastasis station and PORT were correlated with OS. Among patients, 5-year survival rates in PORT and non-PORT were 29% and 24% (P=0.047) respectively. In subgroups, PORT was related with high survival in patients with multiple station N2 compared to non-PORT: 36% vs 20% (P=0.013) and 33% vs 15% (P=0.002) in patients in patients with tumor size>3 cm. Also, it was related with low local recurrence compared to non-PORT: 65% vs 48% (P=0.006) and 62% vs 48% (P=0.033). CONCLUSIONS: PORT can improve overall survival for N2 NSCLC, especially the patients with the factors as follows: tumor size>3 cm and multiple station N2 can benefit from PORT more or less. PMID- 20723365 TI - [The Clinical Analysis of 21 Patients with Lymphoepithelioma-like Carcinoma after Operation.]. AB - BACKGROUND: Lung lymphoepithelioma-like carcinoma is a rare subtype of large cell carcinomas of the lung. The aim of this study is to retrospectively analyze the clinical characteristics, surgical methods, laboratory inspection, chemotherapy, radiotherapy and prognosis of LELC. METHODS: From 2004 to 2008, clinical data were collected from 21 patients who were treated in Shanghai Chest Hospital. The correlation between clinicopathological characteristics and prognosis was evaluated. RESULTS: Of the 21 patients, 15 patients had lobectomy; 4 patients had wedge resection; 1 patient had pneumonectomy and 1 patient had sleeve resection. 12 patients received chemotherapy and 3 patients received radiotherapy after operation. Until 2009-4-31, 4 patients died, and the median survival time (MST) was 49 months. CONCLUSIONS: Lymphoepitheliomalike carcinoma of the lung is a very rare and unique subtype of large cell carcinomas of the lung, which has a better prognosis with surgical, chemotherapy and radiotherapy. PMID- 20723366 TI - [Detection of Chemerin and It's Clinical Significance in Peripheral Blood of Patients with Lung Cancer.]. AB - BACKGROUND: Chemerin was recently found a chemoattractant just like a chemotatic factor. It can induce immune chemotaxis to dendritic cells and macrophages by binding to its receptor ChemR23. It has been known that the activation of Chemerin could enhance the phagocytosis and antigen presentation of APC. Along with this observation, the contribution of Chemerin in the genesis and development of a tumor attracts more attention. We explored the relation between Chemerin and lung cancer through detecting the expression of Chemerin in peripheral blood of patients. METHODS: The experiment selected samples of lung cancer patients and normal people. The concentration of Chemerin in peripheral blood was detected by ELISA method. T test was used to compare the statistic difference. We compared the concentration of Chemerin in peripheral blood with age, sex, pathological type, degree of differentiation, metastasis of lymphonode, UICC staging and other clinicopathological index, and analyzed by t test and one way ANOVA. RESULTS: The concentration of Chemerin in peripheral blood of 42 patients with lung cancer (1 965.81 pg/mL+/-374.03 pg/mL) were significantly higher than the concentration of 31 healthy examination (1 111.44 pg/mL+/-250.72 pg/mL)(P<0.001). The concentration of Chemerin in peripheral blood of patients with lung cancer had no relationship with clinicopathological factors. CONCLUSIONS: Chemerin has the potential to lung cancer diagnosis as a marker. PMID- 20723367 TI - [Comparison of the Clinical Effects of Paclitaxel and Paclitaxel plus Oxaliplatin as the Second-line Treatment of Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: Second-line chemotherapy with taxanes for the patients with non-small cell lung cancer (NSCLC), who had disease recurrence or failure in previously treated with platinum-based chemotherapy, has been shown to be effective. Besides docetaxel, paclitaxel, the other available taxane, has also demonstrated potential activity in the same indication in a few studies. The aim of this study is to compare the treatment efficacy and safety between paclitaxel and paclitaxel plus oxaliplatin as the second-line treatment of advanced NSCLC. METHODS: Sixty six patients from Sep 2000 to Sep 2007 whose disease progressed after first-line chemotherapy were enrolled and randomized into 2 groups: one group was administered with only paclitaxel (44 patients), the other was given paclitaxel plus oxaliplatin (22 patients), ECOG 0-2. The regiments were: single agent paclitaxel (175 mg/m(2), d1) or paclitaxel (175 mg/m(2), d1) plus oxaliplatin(130 mg/m(2), d1), 3-4 weeks/cycle. RESULTS: The overall response rate of single paclitaxel and paclitaxel plus oxaliplatin were 13.6% and 18.2%, respectively. The median time to progression were 3.2 months vs 4.5 months. Median survival time were 6.9 months vs 8.2 months. There were no statistical differences. The haematological toxicities of paclitaxel plus oxaliplatin group were more severe than single agent group: grade 3/4 leukopenia (P=0.039). The rate of nausea, vomiting and acroaesthesia in paclitaxel plus oxaliplatin group was higher than that of single-paclitaxel group, but there were no statistical differences. Other adverse effects were mild. CONCLUSIONS: Singlepaclitaxel administration as the second-lined treatment of advanced NSCLC is tolerable and has the response effect no worse than the combined chemotherapy. PMID- 20723368 TI - [The Comparison of Clinical Effect of Rh-endostar on Retreated Non-Small Cell Lung Cancer and Colorectal Cancer.]. AB - BACKGROUND: Antiangiogenesis has become the fourth module of cancer therapy nowadays. However, its clinical effect varies from cancer to cancer. The aim of this study is to compare the clinical efficacy of rh-endostatin (YH-16, Endostar) on retreated non-small cell lung cancer and colorectal cancer. METHODS: The patients including 17 cases of retreated non-small cell lung cancer (NSCLC) and 15 cases of retreated colorectal cancer were confirmed by histopathology or cytopathology. All the cases were administrated with rh-endostatin combining chemotherapy and radiotherapy. 7.5 mg/m(2) rhendostatin solved in 500 mL of normal saline was slow intravenously dropped from day 1 to day 14. The efficacy was evaluated strictly according to RECIST criteria and the quality of life (QOL) was based on the Karnofsky performance (KPS). RESULTS: The response rate (RR) of 17 cases of retreated NSCLC was 11.8% (2/17), and the disease control rate (DCR) was 41.2% (7/17). However, the RR and DCR of the 15 cases of retreated colorectal cancer were up to 40% (6/15) and 86.6% (13/15). There was significant difference between these two tumors (P<0.05). Moreover, significant difference was also found on the QOL of these two tumors [The improving and stable QOL was 41.2% (7/17) and 86.6% (13/15), respectively (P<0.05)]. CONCLUSIONS: The clinical efficacy of rh-endostatin on retreated colorectal cancer was better than on retreated non-small cell lung cancer, which suggested that it was necessary to perform more clinical observations on the digestive tumors. PMID- 20723369 TI - [Pathogenesis of Molecular Signaling Pathways Changes in Smoking-induced Lung Cancer.]. PMID- 20723370 TI - [Dll4/Notch signaling pathway and tumor angiogenesis.]. PMID- 20723371 TI - [Roles of Volume-sensitive Cl- Channel on Apoptosis and Drug Resistance in Cancer Cells.]. PMID- 20723372 TI - [Expression of PTEN, p53 and P-glycoprotein in Non-small cell Lung Cancer and Their Predictive Values.]. AB - BACKGROUND: Multiple drug resisting (MDR) phenotype is the sign of intrinsic or acquired resistance and is the key factor which leads to chemotherapy failure. It has been proven that PTEN, p53, P-gp expressions were related to drug resistance and prognosis of the patients with lung cancer. The aim of this study is to analyze the association of the expression of PTEN, p53, P-gp with postoperative survival in patients with non-small cell lung cancer (NSCLC), and to explore the relationship between the characteristics and drug resistance of NSCLC patients. METHODS: A total of 61 patients with NSCLC were followed up. Immunohistochemical staining using polyclonal PTEN, p53 and P-gp antibody were performed on paraffinimbedded specimens from 61 patients with NSCLC and 20 specimens of tumor surrounding normal lung tissue were used as control. RESULTS: The PTEN expression was significantly lower in NSCLC than in tumor-surrounding normal lung tissue and the expression of p53 and P-gp were in the opposite aspects (P<0.05). Expression of PTEN was positively related with histology, clinical stage, lymphatic metastasis, p53 expression was positively related with gender, lymphatic metastasis and the three kinds of protein expression were related with prognosis (P<0.05). The expression of PTEN was related with p53 expression (r=-0.282, P<0.05), but the expression of PTEN and p53 were not related with P-gp in NSCLC (P>0.05). CONCLUSIONS: To some extent, the expression level of PTEN, p53 and P-gp may predict the effect of radiotherapy, chemotherapy and prognosis of NSCLC. PMID- 20723373 TI - [A case report of tongue metastasis from lung carcinoma.]. PMID- 20723374 TI - [Detection and Its Clinical Significance of EGFR Gene Mutation and Gene Amplification in 187 Patients with Non-small Cell Lung Cancer.]. AB - BACKGROUND: It has been demonstrated that epidermal growth factor receptor (EGFR) signal pathway had an important role in the oncogenesis and development of non small cell lung cancer (NSCLC). Small-molecule tyrosine kinase inhibitors (TKIs) that target at the kinase domain of EGFR are recently developed target therapy reagents for treatment of NSCLC patients. Previous studies revealed that different patient groups response differently to EGFR-TKI, which is based on the EGFR gene status. The aim of this research was to define the clinicopathologic features associated with the gene amplification and mutation status of the EGFR gene in NSCLC patients and determine the most likely population to benefit from TKI treatment. METHODS: 187 of NSCLC cases were collected. The mutation status of EGFR exon 19 and 21 were determined by Real-time PCR, as well as the gene amplification status of EGFR gene by FISH. The relationship between EGFR mutation and gene amplification and the clinical pathologic features were analyzed with Chi-Square test. RESULTS: EGFR gene amplifications were identified in 89 of 187 samples (47.6%). EGFR gene amplification was not associated with age, gender, pathological type, smoking status and metestasis status (P>0.05). 20.3% (38/187) of NSCLC patients had EGFR gene mutation. EGFR gene mutation rates were significantly higher in the female (32.3% vs 14.4% male), non-smoker (38.2% vs 10.1% smoker) and patients with adenocarinoma (35.5% vs 9.9% non-adenocarcinoma) (P<0.05). There was a correlation between EGFR gene mutation and gene amplification (P=0.012), especially in the early stage, adenocarcinoma and never smoking female patients. The patients with EGFR gene mutation and/or gene amplification had longer overall survival than those without, but had no significant difference (P>0.05). The patients with EGFR gene mutation had a better response to TKIs therapy than those without. CONCLUSIONS: The EGFR gene mutation rate is different in the patients with different lung cancers. EGFR gene mutation occurs more frequently in female, non-smoker and patients with adenocarcinoma. Although there wasn't a significant relationship between EGFR gene amplication and the clinicopathologic features, EGFR gene amplication may correlate with the prognosis of lung cancer patients. PMID- 20723375 TI - [Erlotinib in the trentment of Advanced Non-small-cell Lung Cancer: A Systematic Review.]. AB - BACKGROUND: Erlotinib is a new and efficient anti-tumor targeted therapy drug, and it has been used in China for non-small cell lung cancer since 2006. The aim of this study is to review the effectiveness and safety of erlotinib for treating advanced non-small cell lung cancer. METHODS: Authors searched the Cochrane Library, Pubmed, Embase, CBM, CNKI and Wanfang Date. The randomized controlled trials (RCTs) were analyzed by RevMan 4.2 software. Authors also included retrospective case report published in Chinese journals. RESULTS: Four RCTs and 8 uncontrolled case reports were analyzed. The results of the RCTs showed that erlotinib was significantly better than placebo on progression-free survival, median survival time, response rate (OR=10.21, 95%CI: 2.44-42.73) and 1-yr survival rate (OR=1.67, 95%CI: 1.13-2.46); Erlotinib was superior than paclitaxel+carboplatin on median survival time (HR=1.73, 95%CI: 1.09-2.73; P=0.018), the other efficacy were similar; The efficacy of erlotinib combined chemotherapy was close to chemotherapy alone. The main side effects caused by erlotinib were rash and diarrhea, and the tolerance was well. The overall uncontrolled clinical studies showed that the response rate was 27.27%, and the 1 yr survival rate was 56.1%. CONCLUSIONS: Erlotinib is effect for non-small cell lung cancer, and maybe better for never smokers, female, Asia and adenocarcima. The clinical favor from erlotinib combined chemotherapy remains uncertain. But the effect of erlotinib being used in clinical settings needs to be confirmed by further large and multicenter. PMID- 20723376 TI - [Pooled Analysis of the Trials of Erlotinib Monotherapy for Epidermal Growth Factor Receptor (EGFR)-mutant Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: Erlotinib has been approved worldwide for second- and third-line treatment of advanced NSCLC. Clinical trials showed that patients with EGFR mutations treated with erlotinib has better clinical outcomes. The aim of this study is to evaluate the effects of erlotinib monotherapy in EGFR-mutated advanced NSCLC. METHODS: Search the published trials involving EGFR-mutant patients and erlotinib in following database: MEDLINE (2004-2009), CBMdic (2004 2008), CNKI (2004-2008). Search the references cited by the included studies. Identify the included trials. Extract and pooled data from the included trials. RESULTS: Seven studies were identified including 463 advanced NSCLC patients. Based on the available evidence, erlotinib monotherapy showed active effect in EGFR-mutated advanced NSCLC. The response rate reached 66%. 1-year survival and 2 year survival were approximately 73% and 53%. Median survival was more than 23 months while the progression free survival was more than 8.6 months. CONCLUSIONS: Based on the available evidence, erlotinib monotherapy leads to objective response and prolongs survival in most advanced NSCLC patients with EGFR mutations. Small molecule TKI, erlotinib, should be recommended as the first-line treatment of EGFR-mutant NSCLC. PMID- 20723377 TI - [Clinical Observation of Erlotnib in the Treatment of Non-small Cell Lung Cancer with Multimetastases in Elderly Patients.]. AB - BACKGROUND: Erlotnib is the inhibitor of epidemic growth factor receptor and mainly used to treat non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the antitumor efficacy and toxicity of erlotnib in the treatment of Chinese elderly NSCLC patients with multimetastases. METHODS: Tirty-three Chinese elderly NSCLC patients with multimetastases received 150 mg of erlotnib orally once daily until disease progressing or intolerable toxic developing. RESULTS: Tirty patients were evaluable for therpeutic effect. Without complete regression being observed, 6 patients got partial resonse (PR, 20%), 16 stable disease (SD, 53.33%) and 8 progressive disease (PD, 26.68%). The total response rate was 20.0% and disease control rate including both tumor response and stable disease was 73.3%. On the pathology, compared with the patients with squamous cell carcinoma, those with adenocarcinoma had not significant longer median overall (13.592+/ 1.914 months vs 9.846+/-1.598 months, P=0.301) and progression-free survival times (7.367+/-0.923 months vs 6.615+/-1.366 months, P=0.488), The median survival was sigificantly related with meningeal metastasis, metastasis of liver, pleural efusion using survival analysis. The main toxicities of erlotnib were skin toxicity (rash) and diarrhea with no need of further treatment. CONCLUSIONS: Erlotnib demonstrates significant antitumor activity and a favorable tolerability profile in Chinese elderly advanced NSCLC patients with multimetastases. PMID- 20723378 TI - [The Association between EGFR Gene Amplification and the Prognosis in Non-small Cell Lung Cancer: A meta-analysis.]. AB - BACKGROUND: Many studies concluded that epidermal growth factor receptor (EGFR) gene amplification might be related with the prognosis in non-small cell lung cancer. However, the results were not consistent. To identify whether EGFR gene amplification could affect the prognosis, a meta-analysis was conducted based on the published works. METHODS: According to inclusion and exclusion criteria, articles were selected from medical electronic databases searching, including PubMed, Cochrane library and CNKI. The qualities of included articles were scored based on the European Lung Cancer Working Party scale, and the hazard ratio (HR) and the 95% confidence interval (CI) were also collected. Meta-analysis was completed using software Review Manager 4.2. RESULTS: Forest plot from 12 studies in which 1 221 included patients were all treated with EGFR-TKI showed that the prognosis of patients harboring EGFR gene amplification were superior to negative ones (HR=0.82, 95%CI: 0.68-0.99, P=0.04), and for Caucasian patients who received EGFR-TKI, the survivals were longer in EGFR gene amplification positive cases than those without amplification (HR=0.42, 95%CI: 0.31-0.57, P<0.001). Meta results from 8 studies in which 658 included patients did not receive EGFR-TKI indicated that the casualty hazard of amplification positive patients was comparable with negative ones. However, for Asia patients who failed to receive EGFR-TKI, the prognosis of patients with EGFR gene amplification were inferior to negative ones (HR=1.88, 95%CI: 1.21-2.93, P=0.005). CONCLUSIONS: EGFR gene amplification may be a positive predictive factor in terms of survival for Caucasian patients receiving EGFR-TKI rather than Asia patients. However, the prognosis was inferior in Asia patients with EGFR amplification to those without the amplification, if they failed to receive EGFR-TKI. PMID- 20723379 TI - [EGFR Mutations Detection in Non-small Cell Lung Cancer Tissues by Real-time PCR and DNA Sequencing.]. AB - BACKGROUND: Small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib that target the kinase domain of epidermal growth factor receptor (EGFR) are making successful progression for advanced non-small cell lung cancer patients treatment. The growing evidences revealed that EGFR exon 19 and 21 mutation status in NSCLC patients was correlated with the outcome for EGFR-TKI treatment. In this study, two methods of Real-time PCR and DNA sequencing were compared to detected EGFR exon 19 and 21 mutations. METHODS: EGFR exon19 mutation del-E746-A750 and exon 21mutation L858R were detected by Real-time PCR and DNA sequencing in 103 NSCLC patients. Chi-square test was used to analyze the consistance. RESULTS: There was no significant difference between the two methods. However, Real-time PCR was more convenient and sensitive compared to DNA sequencing. CONCLUSIONS: Real-time PCR was more suitable for clinical testing than DNA sequencing. PMID- 20723380 TI - [A Systematic Review of Erlotinib for Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: It was unclear whether advanced non-small cell lung cancer (NSCLC) patients could benefit from erlotinib therapy. This study was aimed to evaluate the efficacy and safety of NSCLC patients treated with erlotinib. METHODS: The relevant randomized controlled trials (RCT) were searched from VIP, CMB, CNKI, PubMed, EMBASE and The Cochrane Library. The related references and experts in this field were traced, and other authors were communicated with to obtain the information that has not been found. Quality assessment of qualified RCTs assessed by the exclusion and inclusion criteria and RevMan 5.0 provided by the Cochrane Collaboration was used to perform meta-analysis. RESULTS: Three RCTs involving 2 969 patients were included. Meta analysis results suggested that erlotinib was superior to placebo for one year survival rate (OR=1.18, 95%CI: 1.01-1.38), tumor response rate (OR=1.24, 95%CI: 1.03-1.49), median overall survival, median progression-free survival and tumor responses duration. At the same time, the incidence of grade 3-4 skin rash (OR=16.33, 95%CI: 7.01-38.02) and diarrhea (OR=5.02, 95%CI: 2.93-8.60) of the adverse reactions was increased. CONCLUSIONS: Advanced non-small cell lung cancer patients could benefit from Erlotinib therapy, but the incidence of skin rash and diarrhea was significantly increased, and in the absence of damage to the blood system, serious liver and kidney damage, cardiac toxicity, etc, there were no difference with placebo. PMID- 20723381 TI - [The Impact of Smoking Status on the Efficacy of Erlotinib in Patients with Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: Erlotinib is a targeted treatment for advanced non-small cell lung cancer. Smoking status may be one of influencing factors of the efficacy of erlotinib. The aim of this study is to explore the impact of smoking status on the efficacy of erlotinib in patients with advanced non-small cell lung cancer. METHODS: Patients with nonsmall cell lung cancer who had been previously treated with at least one course of platinum based chemotherapy received 150 mg oral doses of erlotinib once daily until disease progression. Response rate, progression-free survival, overall survival were analyzed in the different smoking status groups. Kaplan-Meier method was used to analyze the survival rate. RESULTS: Fortyeight patients were enrolled into the study from December 2005 to September 2006. We followed up these patients until 28th December, 2008. Median follow up time was 30 months. The compliance rate was 100%. The response rate was 32.1% in the smoking group and 35% in the never smoking group (P=0.836); The median progression-free survival was 3 months and 9 months, respectively (P=0.033). The median overall survival was 5 months and 17 months, respectively (P=0.162). CONCLUSIONS: Erlotinib is an effective drug for advanced non-small cell lung cancer patients with different smoking status. Progressionfree survival is better in the never smoking patients than the smoking patients. PMID- 20723382 TI - [The Analysis of Erlotinib on Brain Metastases in Patients with Non-small-cell Lung Cancer.]. AB - BACKGROUND: Brain metastases are common in non-small-cell lung cancer (NSCLC) and the prognosis is poor. Erlotinib is a specific inhibitor of the epidermal growth factor receptor-associated tyrosine kinase (EGFRTKI), which has been gradually used in the treatment for advanced NSCLC. The aim of this study is to evaluate the antitumor efficacy and its relevant factors of erlotinib in NSCLC patients with brain metastases. METHODS: The clinical data of 30 NSCLC patients with brain metastases were reviewed retrospectively. All of them were treated with erlotinib, given orally 150mg daily. These patients discontinued administration of erlotinib until disease progression, death or intolerable side effects. RESULTS: In terms of intracranial lesions, partial response (PR) was observed in 2 patients (6.7%), with stable disease (SD) in 17 patients (56.7%), for overall disease control rate (DCR) of 63.4%. As for systemic disease, PR was observed in 2 patients (6.7%), with SD in 5 patients (16.7%), for overall DCR of 23.4%. There was no statistical difference in DCR among different subtypes of age, gender, smoking history, histology, PS score, the number of brain metastases, the onset of brain metastases, chemotherapy, brain radiotherapy and side effects. The median time to disease progression (MTTP) and median survival time (MST) was 2.4 months and 7.7 months respectively. The 1 and 2 year survival rate was 38.4% and 15.2%. The univariate analysis showed that the survival time was related to the patients' PS score, smoking history, brain radiotherapy and chemotherapy. The multivariate analysis indicated that brain radiotherapy was the independent prognostic factor and the relationship between the survival time and smoking history was near to statistical significance. CONCLUSIONS: The patients receiving brain radiotherapy may have better survival benefit. Non-smokers have a trend to survive longer than smokers. Erlotinib may be effective on brain metastases in NSCLC patients and appears to be a possible new treatment option. PMID- 20723383 TI - [Clinical Observation of Erlotinib in the Treatment of Advanced and Previously Treated Non-small Cell Lung Cancer.]. AB - BACKGROUND: Erlotinib is a small molecular inhibitor of tyrosine kinase. One study has confirmed that it can prolong the median progression-free survival time (PFS), and can improve the one-year survival rate of patients with advanced non small cell lung cancer. The aim of this trial is to evaluate the response and adverse reaction of agent erlotinib in advanced and previously treated non-small cell lung cancer. METHODS: The study was one part of the EAP (Expanded Access Programme) study. Forty-five patients with advanced non-small cell lung cancer, which had been treated with 1-2 regimens containing platinum previously, were treated with erlotinib from Dec 2005. Erlotinib was prescribed at a dose of 150 mg daily. RESULTS: Forty-three patients were evaluated response and all patients were evaluated toxicity. Among these patients, CR 0 case, PR 19 cases (44.2%), RR (CR+PR) 44.2% and SD 13 cases as their best response, disease control rate (DCR=CR+PR+SD) 74.4%, PD 11cases (25.6%). The median progression-free survival time was 4.8 months; the median survival time was 15.0 months; the one-year survival rate was 68.8% (31/45). The median PFS of patients with adenocarcinoma and with non-adenocarcinoma was 7.6 months vs 2.6 months (P=0.018). The drug related adverse reactions were skin rash (41 cases, 91.1%), billirubine increased (15 cases, 33.3%), ALT increased (9 cases, 20%) and diarrhea (4 cases, 8.9%). For patients with and without skin rash, the median PFS was 7.5 months vs 1.1 months (P=0.001), and the median survival time was 15.6 months vs 5.2 months (P=0.002). CONCLUSIONS: Erlotinib is effective in advanced and previously treated non-small cell lung cancer, and it is much more effective in adenocarcinoma and patients with skin rash. It is well tolerated, only with some minimal adverse reactions. PMID- 20723384 TI - [Clinical Observation of Erlotinib as the First-line Treatment for Patients with Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: To evaluate the efficacy and toxicity of erlotinib as the first-line therapy for advanced non-small cell lung cancer (NSCLC). METHODS: A total of 28 pathologically-confirmed NSCLC patients who could not receive willingly or tolerate traditional cytotoxic drugs chemotherapy were enrolled. Erlotinib was orally administered 150 mg daily until disease progression or the occurrence of intolerable toxicity. RESULTS: Among a total of 28 patients, the objective response rate (ORR) of erlotinib was 28.6%. The disease control rate (DCR) was 60.7%. The rate of symptom relief was 53.6%. The median progression free survival (PFS) was 3.2 (95%CI: 0.851-5.585) months. The median overall survival (OS) was 9.6 (95%CI: 7.179-12.021) months. One-year survival rate was 32.1%. The therapeutic effect was better in patients with rash. Most of the toxicities were grade I and grade II toxicity. The most common adverse events were rash (46.4%), diarrhea (32.1%), skin dry (25.0%), anorexia(17.9%), fatigue (10.7%) and increased transaminase (7.1%). CONCLUSIONS: Erlotinib provided another choice for the patients who could not willingly receive or tolerate chemotherapy. PMID- 20723385 TI - [Clinical Study of Erlotinib in the Treatment of Patients with Advanced Stage Non small Cell Lung Cancer.]. AB - BACKGROUND: Erlotinib has been used widely in non-small cell lung cancer (NSCLC), and a portion of patients can gain remarkable benefit. This aim of the study is to evaluate the response and the side effects of Erlotinib as the treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Total 14 NSCLC(IIIb or IV stage)patients, treated from June 2007 to July 2008, were enrolled in our study. Erlotinib was prescribed on the oral dose of 150 mg daily. The treatment response and side-effects were recorded. Patients were followed up. Kaplan-Meier method was used to perform survival analysis. RESULTS: Forty-two NSCLC patients were enrolled into the study and followed up until July 10, 2009. The median follow-up period was 16 months and the follow-up ratio was 100%. CR, PR, SD, PD were achieved 2.4% (1/42), 35.8% (15/42), 47.6% (20/42) and 14.3% (6/42), respectively. Disease control rate (DCR) was reported by 85.7%. Median time to progression and median overall survival period were 7 and 12.2 months, respectively. One year progression-free survival rate and 1-year overall survival rate were 29% and 55%, respectively. Adverse events included acneiform rash 78.6% (33/42), diarrhea 35.7% (15/42), hepatic dysfunction 7.1% (3/42) and acute interstitial lung disease 2.4% (1/42). CONCLUSIONS: Erlotinib is an effective therapy for patients with advanced non-small cell lung cancer with acceptable side effects. PMID- 20723386 TI - [A Clinical Observation of Concomitant Therapy of Erlotinib and Whole Brain Radiotherapy in Patients of NSCLC Combined with Brain Metastases.]. AB - BACKGROUND: Treatments to brain metastases in patients of NSCLC include operation, chemotherapy and radiotherapy, while the disease control rate of brain lesions is not so good, the media survival time is 4-6 months. Tyrosine kinase inhibitor erlotinib can get into blood-brain barrier as reported, and it is used as a effetive method to control brain metastases. The aim of this clinical observation was to evaluate the efficacy and adverse reactions after concomitant therapy of erlotinib and whole brain radiotherapy (WBRT) in patients of NSCLC with brain metastasis. METHODS: This was a retrospective study. From 2006 to 2009, There were 12 cases of NSCLC with brain metastases. They were accepted the concomitant therapy of erlotinib and WBRT. The dose of erlotinib was 150 mg/d and the radiotherapy dose was (3 000-3 600) cGy/(10-12) F. After 2 months of radiotherapy the early efficacy was evaluabed. RESULTS: The control rate of brain metastases was 91.7% with PR 66.7%, SD 25%. The major adverse reactions were skin rash (75%) and fatigue (91.7%). CONCLUSIONS: The effect of the concomitant of erlotinib and WBRT in patients of NSCLC with brain metastases is better than WBRT alone, and the concomitant therapy is well tolerated. PMID- 20723387 TI - [Observation of Erlotinib in the Treatment of Elderly Patients with Advanced Non small Cell Lung Cancer and COPD.]. AB - BACKGROUND: To evaluate the clinical efficacy and the security of erlotinib in the treatment of elderly patients with advanced non-small cell lung cancer and COPD. METHODS: Fifteen patients with advanced non-small cell lung cancer and COPD were treated with erlotinib 150 mg/d, and then the adverse reactions and clinical effects were recorded. RESULTS: The effective rate was 20%. We analyzed the effective rate of stage III and IV, and there were no significant difference between the two (P=0.569). KPS was increased in 40% patients. Mild or moderate rash, diarrhea, nausea and vomiting were the main adverse reactions. CONCLUSIONS: For elderly patients with advanced non-small cell lung cancer and COPD, the use of erlotinib might achieve better security and effectiveness. PMID- 20723388 TI - [Erlotinib as the Second-line Treatment for NSCLC Patients of Stage IIIb/IV.]. AB - BACKGROUND: Erlotinib has begun to show its unique advantage in the past several years. The aim of this study was to evaluate the efficacy and adverse reactions of erlotinib on patients with advanced non-small cell lung cancer (NSCLC) of stage IIIb/IV. METHODS: Patients with advanced NSCLC ( IIIb/IV stage) were recruited in this study. They had recurrence after receiving at least one or two regimens of platinum-based chemotherapy from March 2007 to January 2009. Erlotinib was given orally to the patients at dose of 150 mg/d, once daily until disease progression. The clinical outcomes and adverse reactions were observed. Patients were followed up. Kaplan-Meier method was used to perform survival analysis. RESULTS: Among the 16 patients, 0 patients got complete response (0%); 2 patients got partial response (12.5%); 5 stable disease (31.2%) and 9 progressive disease (56.2%). The total response rate (CR+PR) was 12.5% and the disease control rate (including tumor response and stable disease) was 43.7%. All patients were followed up for 1-22 months; 2 cases are still alive until January 2009; the follow-up ratio was 100%. The average survival time could reach 10.25 (3-22) months. The median overall survival period were 9 months and one year progression free survival rate were 13.3%. The main toxicities were rash (93.7%), diarrhea (68.7%), reduced appetite (43.7%) and liver dysfunction (18.7%). CONCLUSIONS: Erlotnib demonstrated significant anti-tumor activity and a favorable tolerability profile in this series of NSCLC patients. PMID- 20723389 TI - [A Retrospective Analysis of Erlotinib and TP/GP Regimen in the Treatment of Advanced Non-small Cell Lung Cancer.]. AB - BACKGROUND: About 80% lung cancers belong to non-small cell lung cancer (NSCLC) and more than 70% are in advanced stage. The aim of this study was to evaluate the clinical efficacy and toxicity of erlotinib and GP/TP regimen on advanced non small cell lung cancer. METHODS: Ninety-one advanced NSCLC patients with different treatments from January 2007 to April 2009 in our hospital were retrospectively analyzed. Ninety-one patients were divided into the erlotinib and TP/GP group. Erlotinib group: received erlotinib 150 mg/dl TP/GP group: the original chemotherapy for advanced non-small cell lung cancer. The cycles were repeated for 21 days. The patients were given docetaxel (80 mg/m(2), d1) or gemcitabine (1 000 mg/m(2), d1, 8) +cisplatin (70 mg/m(2), d2); then the adverse reaction and clinical efficacy were recorded during 3 months. RESULTS: Total 91 patients were evaluated for efficacy. The total rate of effect was 23.33% in erlotinib group. The side effects were erythra, diarrhea and vomiting. Pulmonary fibrosis was found in one patient after 21 days. TP/GP group: the total rate of effect was 27.78% and 28% and the side effects were bone marrow depression and reaction of gastrointestinal tract. There were no significantly difference between the two groups in the total rate of effect (P>0.05). But the side effects were less in erlotinib group, and there were significantly difference between the two groups. CONCLUSIONS: Erlotinib on advanced non-small cell lung cancer shows more effectiveness and adverse reactions are tolerable. The further clinical study should be warranted. PMID- 20723390 TI - [Clinical Observation of Erlotinib in the Treatment of Advanced Non-small Cell Lung Cancer: A Report of 92 Eases.]. AB - BACKGROUND: Erlotinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase, has been approved effective in local advanced or metastatic non small cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy and safety of erlotinib for the treatment of advanced NSCLC. METHODS: Ninety-two patients with advanced NSCLC who had failed or not tolerated or refused chemotherapy received 150 mg oral doses of erlotinib once daily until the disease progression or intolerable toxicity. RESULTS: Among the 92 NSCLC patients, 2 patient got complete response (2.2%), 22 partial response (23.9%), 48 stable disease (52.2%) and 20 progressive disease (21.7%). The overall response rate and the disease controlled rate of erlotinib was 26.1% (24/92) and 78.3% (72/92), respectively. The response rate of erlotinib were significantly higher in rash and ECOG 0-1 than no rash and ECOG >= 2. The disease controlled rate of erlotinib was significantly higher in female and non-smokers than male and smokers (P<0.05). The response rate of erlotinib did not show significant differences within pathological type or previous treatment. The most common side effects were rash and diarrhea with 84.8% and 31.5%, respectively, but usually were mild. CONCLUSIONS: Erlotinib is effective and safe in the treatment of advanced NSCLC patients. PMID- 20723391 TI - [A Retrospective Study of Erlotinib in the Treatment of 70 Patients with Non small Cell Lung Cancer.]. AB - BACKGROUND: Erlotinib is a small molecular inhibitor of tyrosine kinase. Multiple foreign and demestic studies have confirmed that it can prolong the median progression-free survival time (PFS) and the overall survival (OS), which could be more significant in the selected population. In this study we retrospectively oberserved the response, the survival and adverse reaction of erlotinib in non selected non-small cell lung cancer. METHODS: The retrospective study included seventy non-small-cell lung cancer patients, who were treated with erlotinib from July 2005 to July 2009. Erlotinib was prescribed at a dose of 150 mg daily. RESULTS: Sixty-eight patients were evaluated response. Among these patients, CR 0 case, PR 26 cases, RR (CR+PR) 38.2% and SD 24 cases as their best response, disease control rate (DCR=CR+PR+SD) 73.5%, PD 18 cases (26.5%). Sixty-three patients were evaluated PFS. The median PFS was 3.0 months. The median PFS of adenocarcinoma and non-adenocarcinoma was 3.0 months vs 2.6 months. The drug related adverse reactions were skin rash, diarrhea and interstitial lung disease (ILD)(4.3%). CONCLUSIONS: Erlotinib is active in non-small cell lung cancer, and it is much more effective in adenocarcinoma and non-smoking patients. There is no difference in response or suvival concerning the sexuality. It is well tolerated in most patients. PMID- 20723392 TI - [Combined Inhibition of Vascular Endothelial Growth Factor and Epidermal Growth Factor Signaling Pathways in Non-small Cell Lung Cancer Therapy.]. PMID- 20723393 TI - [The Mechanism of Resistance to EGFR-TKI in NSCLC and Exploration to Overcome the Resistance.]. PMID- 20723394 TI - [Erlotinib-induced Skin Rash in Patients with Non-small Cell Lung Cancer: Pathogenesis, Clinical Significance and Treatment.]. PMID- 20723395 TI - [Erlotinib in Patients with Brain Metastases for Non-small Cell Lung Cancer.]. PMID- 20723396 TI - [Advanced Research on the Response of EGFR Tyrosine Kinase Inhibitors for Non small Cell Lung Cancer Therapy.]. PMID- 20723397 TI - [Mechanisms of Acquired Resisitance to EGFR Tyrosine Kinase Inhibitors in Non small Cell Lung Cancer.]. PMID- 20723398 TI - [Progression in Therapy of Erlotinib for Patients with Non-small Cell Lung Cancer.]. PMID- 20723399 TI - [Biomarkers of Patients with Non-small Cell Lung Cancer who Benefited from Erlotinib Treatment.]. PMID- 20723400 TI - [Advances of Targeted therapies in Non-small Cell Lung Cancer.]. PMID- 20723401 TI - [Molecular Predictor to Response and Toxicity of EGFR-targeted Medicines in Lung Cancer.]. PMID- 20723402 TI - [Advances of KRAS Mutation in Non-small Cell Lung Cancer.]. PMID- 20723403 TI - [A Case Report of Erlotinib as First-line Therapy in Extensive Metastatic Patient with Advanced Non-small Cell Lung Cancer.]. PMID- 20723404 TI - [Neuroendocrine dysfunction in sepsis and its therapeutic strategy]. AB - Severe sepsis provokes significant abnormalities in host neuroendocrine system, and they are hallmarked by the glucocorticoid and growth hormone resistance, vasopressin deficiency, and compromised vagal activity. As a consequence, the increased stress hormones result in a hyperdynamic circulation, hypermetabolic state, and the hyperglycemia/insulin resistance in sepsis. The cardiac autonomic dysfunction also occurs as a consequence of depressed vagal activity. Current therapeutic strategies include insulin therapy to control hyperglycemia, physiologic doses of corticosteroids to improve immunity, growth hormone to reverse negative nitrogen balance, and vasopressin to raise blood pressure. Non specific beta-adrenergic blockade has also been attempted to either attenuate the hypermetabolism or to reduce the inflammatory response. Future therapy may be directed at both central and peripheral immune system so as to alleviate the hyperdynamic inflammatory state and possibly encephalopathy in severe sepsis. PMID- 20723405 TI - [Effect of sirolimus on capacity of splenic dendritic cells from traumatized mice in inducing T cell responses ex vivo]. AB - OBJECTIVE: To study the ex vivo effect of sirolimus on capacity of splenic dendritic cells (DC) from traumatized mice in inducing T cell responses. METHODS: Twenty-four BALB/c mice were divided into control group and trauma group according to the random number table, with 12 mice in each group. Mice in trauma group were bled followed by closed femur fracture after anaesthesia, while mice in control group were only anaesthetized without injury. Twenty-four hours later DC were isolated from spleens and divided into 4 subgroups: sirolimus devoid control (trauma) groups [consisted of cells from control (trauma) groups, without sirolimus treatment] and sirolimus treated control (trauma) groups [consisted of cells from control (trauma) groups, treated with 10 microg/L sirolimus for 6 hours]. Then their autophagic activity, DC-induced mixed lymphocyte reaction (MLR) were measured and recorded as fluorescence intensity (FI) value and absorbance value respectively. The expression of major histocompatibility complex class (MHC) II and costimulatory molecules CD40, CD80, and CD86 on DC surface were measured with flow cytometry. IL-12p40, IL-12p70 and IL-10 levels in lipopolysaccharide-stimulated DC supernatants were determined by ELISA. Data were processed with one-way analysis of variance. RESULTS: (1) Compared with those of sirolimus devoid control group (FI value = 22 +/- 6), DC autophagic activity (FI value = 13 +/- 2) and DC-induced MLR in mice from sirolimus devoid trauma group were significantly weakened (F = 212.836, P < 0.05). Compared with those of sirolimus devoid control (trauma) groups, DC autophagic activity in mice from sirolimus treated control (trauma) groups (FI = 45 +/- 8, 44 +/- 8 respectively) were significantly strengthened (F = 212.836, P < 0.05 or P < 0.01). MLR in mice from sirolimus treated trauma group was stronger than that from sirolimus devoid trauma group (with F value respectively 101.426, 86.533, P values all below 0.05). (2) Compared with those of sirolimus devoid control group [MHC II (85 +/- 6)%, CD40 (8 +/- 1)%], the expressions of MHCII [(60 +/- 9)%] and CD40 [(4 +/- 1)%] on DC surface from sirolimus devoid trauma group were significantly reduced (with F value respectively 37.918, 40.426, P values all below 0.05). The expression of MHCII from sirolimus treated trauma group [(78 +/- 7)%] was higher than that from sirolimus devoid trauma group (F = 37.918, P < 0.05). (3) IL 12p40, IL-12p70 secretion by DC from sirolimus devoid trauma group [(120 +/- 13), (10 +/- 3) pg/mL] were significantly reduced as compared with those from sirolimus devoid control group [(200 +/- 25), (20 +/- 6) pg/mL, with F value respectively 218.646, 310.253, P values all below 0.05]. Compared with those from sirolimus devoid control (trauma) groups, IL-12p40 [(560 +/- 34), (540 +/- 29) pg/mL], IL-12p70 [(55 +/- 8), (60 +/- 11) pg/mL] secretion by DC from sirolimus treated control (trauma) groups were obviously enhanced (with F value respectively 218.646, 310.253, P values all below 0.01), while IL-10 secretion levels were significantly decreased (F = 246.108, P < 0.01). CONCLUSIONS: Sirolimus can partially ameliorate DC functions ex vivo in traumatized mice, and further enhance the capacity of DC in inducing T cell responses. PMID- 20723406 TI - [Formation of bacterial biofilm on deep vein catheters in burn patients and its significance]. AB - OBJECTIVE: To observe the biofilm (BF) formation of Staphylococcus aureus (SA), Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) on the surface of deep vein catheters in burn patients after infection. METHODS: The bacteria from deep vein catheters in 20 patients hospitalized from November 2008 to August 2009 were isolated, and were compared with their respective standard stains. Catheters tips were examined with scanning electron microscope (SEM). The semi-quantitative adhesion assay of bacterial BF was performed with modified microtiter-plate test, and the thickness of BF was scanned and measured by confocal laser scanning microscopy (CLSM) after double fluorescence staining, after being cultured in vitro for 12, 24, 48, 72 hours and 5 days, respectively. Data were processed with grouped t test. RESULTS: Six strains of SA, 8 strains of AB, and 6 strains of PA, all drug resistant, were isolated from the deep vein catheters. SEM showed that the BF structures on the inner surfaces of catheters were in diverse in their shape and degree, characterized by adherence and flake formation, and embedded in polysaccharide matrix. BF gathered in clusters, forming three-dimensional structure, in which small amount of red blood cells were found. A small number of bacteria were incompletely embedded, with some bacteria adhered to them. The absorbance values for SA after 24, 48 and 72 hours of culture (PCH) were above the cut-off value, the same for AB at PCH 12, 24, 48 and 72, and PA after PCH 48. Except for PA standard strain, CLSM showed scattered green fluorescence, mainly close to the bottom of plate, while the red fluorescence was observed in full scope at PCH 24 for each strain. At PCH 48 green fluorescence increased obviously and extended upward from the bottom, overlapping partly with red fluorescence, forming yellow fluorescence, and among the bacteria it was most obvious in AB culture, with SA the next. Compared with those of the standard stains, the intensity and quantity of fluorescence from the clinical strains were stronger; at PCH 72 the green fluorescence increased obviously especially for PA and its standard strain, while the yellow fluorescence was full of the scope for other strains. On in vitro culture day 5, the green fluorescence was dispersed and was obvious on the bottom of the plate. BF mature time for AB and SA was PCH 48, and for PA was PCH 72. The BF thickness of AB was (18.2 +/- 3.6) microm at PCH 72, which was thicker than that [(9.4 +/- 2.6) microm] of its standard strain (t = 5.42, P < 0.05), and was also the thickest among the three clinically found strains. CONCLUSIONS: SA, AB and PA, which are commonly found bacteria in burn patients, can form BF in deep vein catheters. Their ability to form BF seems to be stronger than other usually pathogenic strains, especially AB, which is the important pathogen leading to catheter related infection. PMID- 20723407 TI - [Inhibitive effect of exogenous carbon monoxide-releasing molecules 2 on the activation of Janus kinase/signal transducer and activator of transcription pathway in sepsis]. AB - OBJECTIVE: To study the inhibitive effect of exogenous carbon monoxide-releasing molecules 2 (CORM-2) on the activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in sepsis. METHODS: RAW264.7 cells were divided into normal control group, LPS group (10 mg/mL LPS, the same concentration below), LPS + inactive CORM-2 (iCORM-2) group, LPS + 50 mmol/L CORM 2 group, and LPS + 100 mmol/L CORM-2 group. TNF-alpha level in the supernatant was determined with ELISA, and the phosphorylation levels of JAK1 and JAK3 were determined with Western blot. Thirty-five male BALB/c mice were divided into normal control group, cecal ligation and puncture (CLP) group, CLP + iCORM-2 (8.0 mg/kg) group and CLP + CORM-2 group (8.0 mg/kg) according to the random number table. Mice in CLP + CORM-2 group were treated the same as mice in CLP group except for administration of CORM-2 after CLP. The plasma levels of TNF-alpha, IL 1beta, and the phosphorylation levels of JAK1, JAK3 in liver tissue were determined with ELISA 24 hours post CLP. Data were processed with t test. RESULTS: Compared with that of normal control group [(1.9 +/- 0.3) pg/mL], the TNF-alpha level [(8.2 +/- 2.7) pg/mL, t = 2.844, P < 0.01] and phosphorylation levels of JAK1, JAK3 in LPS group increased significantly; while TNF-alpha levels in LPS + 50 mmol/L CORM-2 and LPS + 100 mmol/L CORM-2 groups decreased obviously as compared with that of LPS group [(5.7 +/- 1.4), (3.2 +/- 0.9) pg/mL, with t value respectively 2.104 and 2.363, P values all below 0.05], and it was the same with phosphorylation levels of JAK1, JAK3 in a dose-dependent manner. Compared with those of normal control group, plasma levels of TNF-alpha and IL-1beta and phosphorylation levels of JAK1, JAK3 in liver tissue significantly increased in CLP group (with t value respectively 2.916 and 2.796, and P values all below 0.05); while plasma levels of TNF-alpha and IL-1beta and the phosphorylation levels of JAK1, JAK3 in liver tissue decreased significantly in CLP + CORM-2 group (with t value respectively 2.115 and 2.398, and P values all below 0.05). CONCLUSIONS: Exogenous CORM-2 can obviously inhibit the phosphorylation of JAKs molecules and then inhibit the activation of JAK/STAT signal pathway in sepsis, and decrease the expression of downstream cytokines to effectively prevent cascade reaction in the inflammatory response after severe infection. PMID- 20723408 TI - [Influence of splenic high mobility group box-1 protein on immune function of regulatory T lymphocytes in scald rats]. AB - OBJECTIVE: To observe the influence of high mobility group box-1 protein (HMGB1) derived from spleen on the phenotype of regulatory T lymphocytes (Treg) and HMGB1 mediated immune function in severely scalded rats after delayed resuscitation. METHODS: One hundred and four Wistar rats were divided into normal control group (NC, n = 8), sham scald group (SS, n = 32), scald group (S, n = 32), and ethyl pyruvate (EP) treatment group (EPT, n = 32) according to the random comparison table. Rats in the latter 2 groups were subjected to 30%TBSA full-thickness scald, which were intraperitoneally injected with Ringer solution or EP solution at post scald hour (PSH) 6 (delayed antishock treatment) and administered with 4 mL Ringer solution or EP solution per 12 hours after PSH 12 till PSH 48. Rats in SS group were treated the same as that of S group except for sham scald with 37 degrees C water. Injured rats were sacrificed at post scald day (PSD) 1, 3, 5, 7 (rats in NC group were also sacrificed), and CD4(+)CD25(+)Treg were isolated from spleen with magnetic-activated cell sorting method. The content of HMGB1 in spleen and IL-2 level in supernatant were determined with ELISA. The expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on Treg was determined with flow cytometry, and the proliferation activity of T lymphocytes was also detected (recorded as absorbance value). Data were processed with analysis of variance among groups and independent samples t test. RESULTS: (1) Compared with that of rats in SS group and EPT group, the expression of splenic HMGB1 in S group increased significantly on PSD 1 through PSD 7 [peaked on PSD 1: (46.7 +/- 8.3) ng/mg protein]. (2) Compared with that in SS group, the expression of CTLA-4 in S group was enhanced significantly on PSD 1 through PSD 5 (with t value respectively 10.459, 12.051, 4.029, P < 0.05 or P < 0.01); while that in EPT group decreased significantly on PSD 1 through PSD 7 as compared with that from S group (with t value respectively 2.796, 9.913, 9.581, 10.022, P < 0.05 or P < 0.01). (3) Compared with that of rats in SS group, the proliferation activity of T lymphocytes in S group was markedly suppressed on PSD 1 through PSD 7 (nadir on PSD1: 0.167 +/- 0.059), and release of IL-2 was decreased significantly [nadir on PSD 5: (44 +/- 24) pg/mL]. T lymphocytes proliferation activity was restored and excretion of IL-2 increased in EPT group as compared respectively with that of S group at each time point. CONCLUSIONS: The release of HMGB1 may stimulate splenic Treg to mature, thereby induce suppression of proliferation activity of T lymphocytes and immune function. EP can ameliorate immune dysfunction in animals with delayed resuscitation through inhibiting the synthesis and release of HMGB1. PMID- 20723409 TI - [Influence of CD14 gene polymorphism on the expression of high mobility group box 1 protein in patients with severe burn]. AB - OBJECTIVE: To investigate the influence of the lipopolysaccharide receptor CD14 159C/T gene polymorphism on the synthesis and release of high mobility group box 1 protein (HMGB1), and its relation to sepsis in patients with severe burn. METHODS: Venous blood from 35 patients with burn area equal to or larger than 30% TBSA was obtained on post burn day (PBD) 1, 3, 5, 7, 14, 21, and 28 respectively. Eleven volunteers were enrolled as healthy control group (HC).CD14-159C/T gene polymorphism was detected with polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. Plasma level of HMGB1 was determined with ELISA. Leukocyte HMGB1 mRNA expression was determined with RT-PCR. Data were processed with chi(2) test, analysis of variance, and t test. RESULTS: Among the C-159T genotype of CD14 gene in the 35 patients, the distribution frequency of the T and the C allele was respectively 57.2% and 42.8%. Seven cases (20.0%) were homozygous for the C allele (CC), 16 cases (45.7%) were heterozygous (TC), and 12 cases (34.3%) were homozygous for the T allele (TT). Allele and genotype frequencies in cases were testified as reaching the Hard-Weinberg equilibrium. The incidence of sepsis was markedly lower in CC homozygous patients than in TC heterozygous and TT homozygous patients. Only one of the 3 septic patients in CC homozygous type died; 4 of 9 septic cases in TC heterozygous type and 4 of 7 septic cases in TT homozygous type died. Plasma levels of HMGB1 of patients were significantly elevated early on PBD 1 as compared with HC group, and higher values were found in TC heterozygous and TT homozygous patients than that in CC homozygous patients on PBD 14, 21, 28 (with F value respectively 3.5671, 4.2035, 3.8529, P < 0.05 or P < 0.01). Higher HMGB1 mRNA expression was found in septic patients as compared with non-sepsis patients on PBD 14 (1.5 +/- 0.5 vs. 1.2 +/- 0.4, t = -2.205, P < 0.05). Plasma level of HMGB1 was also respectively higher in septic patients than in non-sepsis patients on PBD 7, 21 [(44 +/- 29) ng/mL vs. (26 +/- 12) ng/mL, t = -2.355, P < 0.05; (25 +/- 15) ng/mL vs. (10 +/- 6) ng/mL, t = -3.872, P < 0.01)]. CONCLUSIONS: CD14C-159T gene polymorphism might markedly influence the synthesis and release of HMGB1, and it is associated with increase in susceptibility of sepsis in patients with severe burn. PMID- 20723410 TI - [Role of angiotensin II type 1 receptor in activation of nuclear factor-kappaB and activator protein-1 in lung of mice with acute lung injury]. AB - OBJECTIVE: To explore the role of angiotensin II type 1 (AT1) receptor in activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in lung of mice with LPS-induced acute lung injury (ALI). METHODS: Eighty-eight BABL/c mice were divided into control group (n = 8), LPS group (n = 40), and LPS + AT1 receptor antagonist ZD7155 group (n = 40) according to the random number table. Puncture of trachea was done in all mice. Mice in LPS + ZD7155 group were intraperitoneally injected with 10 mg/kg ZD7155. Mice in LPS and control groups were intraperitoneally injected with normal saline in the same volume as that of ZD7155. Thirty minutes later, 1 mg/mL LPS was dripped into trachea of mice in LPS and LPS + ZD7155 groups (2 mg/kg). Normal saline in the same volume as that of LPS was dripped into trachea of mice in control group. Lung tissue samples of mice in LPS and LPS + ZD7155 groups were harvested at post dripping hour (PDH) 1, 3, 6, 12, and 24. Lung tissue sample of mice in control group was harvested at PDH 24. Expression of AT1 receptor was determined with Western blot. AP-1 and NF kappaB activity in lung tissue was detected with electrophoretic mobility shift assay. Data were processed with one-way analysis of variance. RESULTS: The relative expression amount of AT1 receptor protein in lung tissue of mice in LPS group at each time point was increased obviously as compared with that of mice in control group (0.69 +/- 0.28, F = 9.356, with P values all below 0.01), and it peaked at PDH 6 (3.44 +/- 0.90), while that of mice in LPS + ZD7155 group was less than that in LPS group at each time point (F = 9.356, with P values all below 0.01). NF-kappaB activity in mice lung was markedly increased in LPS group at each time point as compared with mice in control group (5.47 +/- 0.08, F = 26.443, with P values all below 0.05), and its peak value in LPS group was found at PDH 3 (52.33 +/- 3.25). While NF-kappaB activity in mice of LPS + ZD7155 group was obviously lower than that in LPS group at each time point (F = 26.443, with P values all below 0.05). AP-1 activity in lung was enhanced significantly in LPS group at each time point as compared with that in control group (2.5 +/- 0.4, F = 34.685, with P values all below 0.05), and the activity peaked at PDH 6 (73.3 +/- 9.5) in LPS group. The activity was obviously weaker in mice in LPS + ZD7155 group as compared with that in LPS group at each time point (F = 34.685, with P values all below 0.05). CONCLUSIONS: AT1 receptor contributes to LPS-induced ALI through activating NF-kappaB and AP-1 in lung tissue. PMID- 20723411 TI - [Effect of survivin antisense oligodeoxynucleotide on proliferation and apoptosis of human malignant melanoma cells]. AB - OBJECTIVE: To investigate the effect of survivin antisense oligodeoxynucleotide (ASODN) on proliferation and apoptosis of human malignant melanoma cells. METHODS: hMMC A375 colonies in log growth phase were collected and divided into control group (C, without transfection), sense chain group [SC, transfected with 600 nmol/L survivin sense oligodeoxynucleotide (ODN)], mismatch chain group (MC, transfected with 600 nmol/L survivin mismatch sense ODN), liposome group (L, treated with liposome), antisense chain group (AC, transfected with survivin ASODN, and subdivided into AC 200, 400, 600 nmol/L subgroups) according to the random number table. Transfection result was observed under inverted fluorescence microscope. Inhibition rate of cell proliferation was calculated after determination of cell viability with MTT method. Cell cycle and apoptosis rate were detected with bi-variable flow cytometry. Expression of survivin protein was determined with Western blot. Activity of caspase-3 was assessed with kinase method. Data were processed with analysis of variance. RESULTS: (1) Cell transfection rates in SC, MC, AC 600 nmol/L groups were all above 80%. (2) Compared with those in SC group [(5.23 +/- 0.25)%], MC group [(5.09 +/- 0.13)%] and L group [(4.70 +/- 0.45)%], inhibition rates of cell proliferation in AC 200, 400, 600 nmol/L groups 24 hours after transfection [(10.30 +/- 0.56)%, (16.69 +/- 0.58)%, (24.67 +/- 0.67)%] were significantly increased (F = 746.91, and P values all below 0.05). As time after transfection went on, proliferation inhibition rate was increased obviously. (3) Apoptosis rate in AC 200, 400, 600 nmol/L groups 24 hours after transfection was respectively (13.5 +/- 1.9)%, (20.1 +/- 1.5)%, (32.1 +/- 2.9)%, which were significantly higher than those in C, SC, MC, and L groups [(6.5 +/- 0.6)%, (5.6 +/- 0.7)%, (6.4 +/- 1.0)%, (6.5 +/- 1.3)%, F = 139.9, P values all below 0.05]. Cells in AC group were blocked in G2/M stage. (4) Compared with those in C group, expression amount of survivin protein decreased, and caspase-3 activity obviously increased (F = 63.1, P values all below 0.05) in AC group. No significant difference in caspase-3 activity between SC, MC, L groups and C group was observed (F = 0.512, P values all above 0.05). CONCLUSIONS: Survivin ASODN can inhibit the proliferation of hMMC A375 in a concentration-time dependent manner, and it induces G2/M stage block and promotes its apoptosis. PMID- 20723412 TI - [Effect of heat injured keratinocytes supernatant on biological behavior of fibroblasts]. AB - OBJECTIVE: To observe the effect of the supernatant of heat injured keratinocytes (KC) on biological behavior of the dermal fibroblasts (Fb). METHODS: Human dermal Fb were isolated and cultured. A model of heat injured KC (HaCaT) was reproduced in vitro. Supernatant of normal KC and the supernatant of KC culture 12 hours after heat injury were collected and diluted with non-serum DMEM in 1:1 volume ratio to make normal KC conditioned medium (NKCM) and heat injury KC conditioned medium (HKCM) respectively. Fb was respectively treated with non-serum DMEM and 2 kinds of conditioned medium. (1) The proliferation of Fb was detected with MTT method at post culture hour (PCH) 12, 24, 36, 48. (2) The apoptosis of Fb was determined by flow cytometry at PCH 12 (Fb were heat injured in advance; Fb without heat treatment was used as control). (3) At PCH 24, expression of a-SMA in Fb cytoplasm was determined with immunofluorescence method; expression of a SMA mRNA in Fb was determined with real-time quantified PCR. Data were processed with one-way analysis of variance, and pairwise comparison among groups with LSD t test. RESULTS: (1) The proliferation of Fb: the absorbance value of Fb cultured with HKCM at PCH 12, 24, 36, 48 was respectively higher than that of Fb cultured with non-serum DMEM (with t value respectively 1.89, 2.35, 2.02, 1.94, and P values all below 0.01). There were significant statistical differences between the absorbance values of Fb cultured with HKCM and those of Fb cultured with NKCM at PCH 12, 24, and 48 (at PCH 12, t = 1.83, P < 0.01; at PCH 24, t = 2.91, P < 0.05; at PCH 48, t = 1.83, P < 0.05). (2) Apoptosis of Fb cultured with HKCM was diminished as compared with that of Fb cultured with NKCM and of Fb without treatment (t = 3.31, P < 0.05; t = 1.47, P < 0.01). (3) The expression of alpha SMA (red fluorescence) in Fb cultured with non-serum DMEM or NKCM was less as seen under fluorescence scope, and it was obviously increased in Fb cultured with HKCM. (4) The relative expression amount of alpha-SMA mRNA in Fb cultured with HKCM was 1.32 +/- 0.06, which was higher than that both in Fb cultured with NKCM (1.14 +/- 0.07, t = 2.51, P < 0.05) and in Fb cultured with non-serum DMEM (1.00 +/- 0.09, t = 1.77, P < 0.05). CONCLUSIONS: The supernatant of KC 12 hours after heat injury can obviously promote the proliferation of Fb, inhibit its apoptosis and accelerate transdifferentiation of Fb to myofibroblasts. PMID- 20723413 TI - [Effect of hypoxia-inducible factor-1alpha inhibition caused by RNA interference on permeability of hypoxic endothelial cells]. AB - OBJECTIVE: To study the effect of hypoxia-inducible factor-1alpha (HIF-1alpha) inhibition caused by RNA interference on permeability of hypoxic vascular endothelial (VE) cells. METHODS: Plasmid pcDNA6.2-GW/EmGFP-miR was applied to construct the RNA interference expression vector targeted to human HIF-1alpha gene. VE cells were divided into normal control group (NC), hypoxia group (H, cells were treated for hypoxia in mixed gas with 1% O(2) for 6 hours), transfection group (T), and transfection hypoxia group (TH, transfected with vector and treated with hypoxia). Expression of HIF-1alpha mRNA in NC and T groups were determined with RT-PCR. Expression of HIF-1alpha protein in each group was determined with Western blot. The permeability of VE cell monolayer was detected by fluorospectrophotometer. Another sample of VE cells were divided into dimethyloxallyl glycine (DMOG) group, transfected with DMOG group (TD), normal control group (NC), and transfection group (T), with 1 mmol/L DMOG (HIF-1alpha specific derivant) replacing hypoxia treatment. The expression of HIF-1alpha protein in each group was determined with Western blot. All data were recorded as density value ratio except for permeability data, which was recorded as fluorescence intensity value. Data were processed with t test (pairwise comparison among groups). RESULTS: The relative content of HIF-1alpha mRNA of cells in NC group (0.765 +/- 0.069) was significantly higher than that of cells in T group (0.093 +/- 0.007, t = 16.696, P < 0.05). Content of HIF-1alpha protein of cells in TH group (0.591 +/- 0.029) was significantly lower than that of cells in H group (2.612 +/- 0.259, t = 13.415, P < 0.05). Content of HIF-1alpha protein of cells in TD group (0.566 +/- 0.008) was significantly lower than that of cells in DMOG group (3.243 +/- 0.551, t = 6.975, P < 0.05). The permeability of cell monolayer in H group (41.6 +/- 11.1) was significantly higher than that of cell monolayer in NC group (9.4 +/- 1.5, t = 6.238, P < 0.05). The permeability of cell monolayer in TH group (13.3 +/- 4.5) was markedly lower than that of cell monolayer in H group (t = 5.430, P < 0.05). CONCLUSIONS: The expression of HIF 1alpha gene in vascular endothelial cells is effectively inhibited by specific RNA interference, which significantly prevents the hypoxia-induced increase in vascular endothelial cell permeability. PMID- 20723414 TI - [Treatment of cicatricial stricture subsequent to esophageal chemical burns with transverse colon replacing esophagus in children]. AB - OBJECTIVE: To study the validity of transplanting transverse colon to replace esophagus in treating cicatricial stricture resulting from severe esophageal chemical burns in children. METHODS: A retrospective study was carried out on the clinical data of 46 patients with severe chemical esophageal burns who were treated from November 1972 to September 2008. The transverse colon with the ascending branch of the left colic artery was brought through a retrosternal tunnel to replace strictured esophagus. Thirty-two patients underwent colon esophageal anastomosis and 14 patients underwent colon-pharyngeal anastomosis. RESULTS: All patients survived after surgery, but complications occurred in 7 cases, including leakage of anastomosis in cervical region in 4 cases, stenosis of anastomosis in 2 cases, and dyspnea in 1 case, and they were cured after due treatment. Follow-up study (1 - 26 years) in 39 patients revealed that there was no difference in growth, development and diet between the patients and the normal children of the same age. CONCLUSIONS: Esophageal reconstruction with transverse colon together with the ascending branch of the left colic artery through a retrosternal tunnel is a valuable method for treating cicatricial stricture of the esophagus secondary to severe chemical burns of the esophagus in children. PMID- 20723415 TI - [Effect of nitric oxide on HaCaT cell migration]. AB - OBJECTIVE: To investigate the effect of exogenous nitric oxide (NO) on the migration of HaCaT cell and its possible mechanism. METHODS: Sodium nitroprusside (SNP) was used as the donor of NO. Different concentrations of SNP (0.1, 1.0, 10.0, 100.0, 1000.0 micromol/L) were added into nutrient culture medium of HaCaT cells. Cell migration rate was observed and calculated at post scratching hour (PSH) 0 (immediately after scratching), 6, 12, 24, 48. The most suitable concentration of SNP and culture duration were selected as stimulation condition. Cytoskeletons of HaCaT cells were observed under confocal laser scanning microscope. The expressions of integrin beta 1, RhoA, Rac1 and Cdc42 of cells in experiment group (cultured with 10.0 micromol/L SNP for 24 hours) and negative control group were determined at mRNA and protein levels with RT-PCR and Western blot respectively. Data were processed with one-way analysis of variance (ANOVA) and repeated measure ANOVA. RESULTS: Migration rate of HaCaT cells in each group increased gradually as time after scratching went on. There were significant differences between PSH 6-48 and PSH 0 in cells cultured with 10.0 micromol/L SNP (F = 31.002, P values all below 0.05). Pili were rarely observed in negative control group with slender stress fibers in cells. In comparison, the amount of pili amount increased obviously in experiment group with thickened stress fibers. Compared with those of cells in control group (RhoA protein expression = 0.64 +/- 0.04), integrin beta 1 expression decreased obviously (F = 8.25, P = 0.015), RhoA (0.92 +/- 0.04), Cdc42 and Rac1 were up-regulated at both protein (with F value respectively 7.25, 14.10, 6.50, P values all below 0.05) and mRNA levels (with F value respectively 23.67, 10.39, 9.52, P values all below 0.05). CONCLUSIONS: Exogenous NO in suitable concentration can promote the proliferation and migration of HaCaT cell, suggesting it exerts significant effect in wound repair. The changed cytoskeletons and the down-regulated integrin beta 1 expression may be involved in this process. PMID- 20723416 TI - [Strengthen researches on translational medicine and regenerative medicine in burns]. AB - Translational medicine and regenerative medicine are presently the hottest areas in medical research. Translational medicine is regarded as a two-way model of medical research, i.e. bench to bedside and bedside to bench. The purpose of translational research is to test novel therapeutic strategies developed through experimentation in human beings, and to facilitate the transformation of findings resulting from basic research to clinical practice. Regenerative medicine is to search for effective biotherapy methods to promote self repair and regeneration; or to construct new tissues and organs to improve or restore the function of the injured tissues and organs. To strengthen researches on translational medicine and regenerative medicine in burns may promote the application of new clinical therapeutic strategies, and supply effective therapeutic measures for treatment of severe burns. PMID- 20723417 TI - [Evaluation of the clinical curative effect of applying vacuum sealing drainage therapy in treating deep partial-thickness burn wound at the initial stage]. AB - OBJECTIVE: To evaluate the clinical curative effect of applying vacuum sealing drainage (VSD) therapy in treating deep partial-thickness burn wound at the initial stage prospectively, and to provide the basis for its clinical application. METHODS: Twenty-two patients with about 10% TBSA burn of the lower limbs, and in which partial-thickness wound exceeded 1% TBSA in each limb, were admitted to our hospital within 3 hours after burn from May 2009 to March 2010. Wounds in each patient were divided into VSD treatment group (treated with VSD therapy) and control group (treated with 10 g/L silver sulfadiazine cream) based on the principles of symmetry of location, identical deepness, and similarity in size etc. The amount of water evaporation, the swelling intensity, the status of bacterial colonization, the degree of pain, the healing time, and the quality of healing of wounds in 2 groups were observed and compared. Data were processed with t test and rank-sum test. RESULTS: The observation was completed in 21 patients. All of the wounds were treated within 4 hours post burn (PBH). The amount of water evaporation of the normal skin and burn wounds before dressing coverage in VSD treatment group was respectively close to that in control group (with t value respectively 1.310, -0.911, P values all above 0.05); the amount of water evaporation on the surface of dressing in VSD treatment group [(44.3+/-3.9) mLxh(-1)xm(-2)] was less than that in control group [(66.1+/-6.4) mLxh(-1)xm(-2), t=-11.39, P<0.01]. In VSD treatment group, the circumference of proximal thigh increased (3.48+/-0.35) and (2.51+/-0.21) cm on post burn day (PBD) 3, 7 as compared with that on PBH 5, which was respectively smaller than that [(8.02+/ 0.41), (3.99+/-0.32) cm] in control group (with t value respectively 4.110, 3.569, P values all below 0.01). Positive bacteria' culture rate on PBD 10 of each group was respectively lower than that at admission (with Z value respectively -3.220, -3.870, P values all below 0.01), and there was no significant statistical difference between 2 groups at admission or on PBD 10 (with Z value respectively -0.894, 0.000, P values all above 0.05). The wound surface in VSD treatment group was weak acidic (pH value 7.12+/-0.06) on PBD 10, and it was neutral (pH value 7.41+/-0.13) in control group. The wound pain degree in control group on PBD 1, 3, 7 was respectively higher than that in VSD treatment group (with t value respectively -16.132, -21.230, -16.453, P values all below 0.01). There was no significant statistical difference between 2 groups in healing time of wounds (t=1.186, P>0.05). The healing quality of wounds in VSD treatment group (100.00%, 100.00%) 2 or 3 months after burn was better than that in control group (19.05%, 85.71%) (with Z value respectively -11.638, -3.870, P values all below 0.01). CONCLUSIONS: Early application of VSD therapy cannot expedite the healing process of deep partial-thickness burn wounds, but it can improve the healing quality. It is one of the effective methods to deal with deep partial-thickness burn wounds, which is worthy of clinical attention and further research. PMID- 20723418 TI - [Inhibitory effect of insulin on nuclear factor-kappa B nuclear translocation of vascular endothelial cells induced by burn serum]. AB - OBJECTIVE: To study the inhibitory effects of insulin on nuclear factor-kappa B (NF-kappaB) nuclear translocation of vascular endothelial cells induced by burn serum and its correlative mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and divided into 5 groups: blank control group (BC, ordinary culture without any stimulation), normal serum control group (NS, cultured with nutrient solution containing 20% healthy human serum), burn serum stimulation group (BS, cultured with nutrient solution containing 20% burn human serum), burn serum+insulin treatment group (BI, cultured with nutrient solution containing 20% burn human serum and 1x10(-7) mol/L insulin), inhibitor pretreatment group [IP, pretreated with 50 micromol/L protein kinase B (Akt) specific inhibitor LY-294002, then cultured with the same medium as used in BI group 30 minutes later] according to the random number table. Six hours later, the injury and apoptosis of HUVECs was respectively observed by the scanning electron microscope and determined by the flow cytometry. Meanwhile, the phosphorylation of inhibitor kappa B-alpha (p-IkappaB-alpha) and Akt (p-Akt) in cytoplasm, and the content of NF-kappaB-p65 in nucleus were determined with Western blot. RESULTS: (1) Compared with those in BC group, HUVECs in BS group shrank obviously with irregular nuclear structure, and intercellular links jagged or vanished. Slight change was observed in HUVECs structure in NS and BI groups, with the cell ductility and nuclear structure much better than those in BS group. (2) The apoptosis rates of HUVECs in BS group [(28.5+/-2.3)%], BI group [(22.3+/ 1.8)%], and IP group [(29.7+/-2.4)%] were all obviously higher than that in BC group [(15.7+/-2.2)%, F=14.288, P<0.05 or P<0.01]. There was no significant statistical difference between NS group [(17.0+/-2.5)%] and BC group in apoptosis rate (F=14.288, P>0.05). The apoptosis rate of HUVECs in BI group was obviously lower than that in BS group (F=14.288, P<0.05). (3) Compared with those in BC group, the protein expressions of p-IkappaB-alpha in cytoplasm and NF-kappaB-p65 in nucleus were up-regulated, and the protein expression of p-Akt in cytoplasm was down-regulated in BS and IP groups. The expression levels of the three proteins in NS and BI groups were close to those in BC group. CONCLUSIONS: Insulin could inhibit the IkappaB phosphorylation, and then restrict NF-kappaB nuclear translocation and improve the vascular endothelial cells function accordingly through regulating phosphatidylinositol 3 kinase/Akt pathway. PMID- 20723419 TI - [Protective effect of early application of lytic cocktail on small intestine of severely scalded rats]. AB - OBJECTIVE: To study the protective effect of early application of lytic cocktail on small intestine of severely scalded rats. METHODS: Sixty-six male SD rats were divided into sham injury group (SI, n=6), scald group (S, n=30) and scald+lytic cocktail group (SL, n=30) according to the random number table. After anesthesia, rats in the latter 2 groups were inflicted with 30% full-thickness scald, while rats in S group were sham scalded with 37 degrees C water. Resuscitation was carried out by intraperitoneal injection with 2 mLxkg(-1)x%TBSA(-1) lactated Ringer's solution in all rats; meanwhile 12 mL/kg lytic cocktail [1 mL pethidine (50 mg/mL)+1 mL chlorpromazine (25 mg/mL)+1 mL promethazine (25 mg/mL)+125 mL saline] was hypodermically injected to rats in SL group, while 12 mL/kg saline was injected into rats in the other 2 groups. Samples of blood and small intestine were harvested from S and SL groups at post scald hour (PSH) 3, 6, 12, 24, 48 and from SI group at PSH 3, with 6 rats in each group at each time point. Pathological changes in intestine were observed, and the expression of intercellular adhesion molecule 1 (ICAM-1) and CD68 were determined with immunohistochemistry at PSH 24 for S and SL groups and at PSH 3 for SI group. Plasma levels of D-lactate, diamine oxidase (DAO), IL-1beta, TNF-alpha, IL-10 were determined with ELISA. Data were processed with one-way analysis of variance. RESULTS: (1) At PSH 24, mild hemorrhage, inflammatory cell infiltration and epithelial cell shedding were observed in small intestinal mucosa of rats in S group. Compared with S group, the intestinal villi of SL group were arranged regularly without obvious hyperemia and edema. (2) Expression levels of ICAM-1 and CD68 [(1.69+/-0.27)%, (0.80+/-0.09)%] in S group were significantly higher than those in SI group [(0.77+/-0.10)%, (0.30+/-0.05)%, with F value respectively 77.303 and 66.933, P<0.05 or P < 0.01] and SL group [(0.53+/-0.09)%, (0.32+/ 0.06)%, with F value respectively 77.303 and 66.933, P values all below 0.01]. (3) D-lactate levels of rats in SL group were significantly lower than those of rats in S group at PSH 12, 24 (with F value respectively 20.936 and 19.854, P values all below 0.01), while DAO levels of rats in SL group were significantly lower than those of rats in S group at PSH 3, 12 (with F value respectively 21.930 and 11.342, P values all below 0.05). (4) The levels of IL-1beta and TNF alpha in S group were significantly higher than those of SI group at each time point (P values all below 0.01). The levels of IL-1beta and TNF-alpha in SL group were significantly higher than those of S group at PSH 6, 12 and 24 (with F value respectively 96.517, 17.365, 79.715 and 21.328, 17.682, 28.424, P<0.05 or P<0.01). IL-10 level in SL group was higher than that in S group at each time point, and the differences were statistically significant at PSH 6 and 24 (with F value respectively 8.668, 19.634, P < 0.05 or P<0.01). CONCLUSIONS: Early administration of lytic cocktail can attenuate edema and injury of intestinal mucosa in severely scalded rats. The mechanism may lie in that it can reduce the expression of ICAM-1 in intestinal mucosa, decrease the number of intestinal inflammatory cells and regulate the levels of inflammatory cytokines. PMID- 20723420 TI - [Alteration in bulbar conjunctiva microcirculation and interventional effect of Pentoxifylline after high-voltage electrical burn in rabbits]. AB - OBJECTIVE: To study the changes in bulbar conjunctiva microcirculation (BCM) and the therapeutic effect of Pentoxifylline on BCM disturbance after high-voltage electrical burn (HEB) in rabbits. METHODS: Forty-five rabbits were divided into control group (C), electrical burn group (EB), and Pentoxifylline treatment group (PT) according to random number table, with 15 rabbits in each group. Model of HEB was reproduced in rabbits from EB and PT groups with voltage regulator and experimental transformer. Rabbits in C group were sham injured with the same devices without electrification. Changes in BCM were observed with microcirculation microscope at 15 minutes before HEB and 5 minutes, 1, 2, 4, 8 hour(s) post HEB (PHM or PHH), including: (1) morphology of microvessels, such as the discernible, diameters of arterioles, venules, and capillaries, the unevenness in caliber, and ischemic area; (2) dynamic changes in microvascular blood flow, such as blood flow speed in arterioles, venules, and capillaries, erythrocyte aggregation, and microthrombi formation; (3) condition of tissues surrounding microvessel, such as bleeding and exudation. Measurement data were processed with t test; enumeration data were processed with Fisher's exact test. RESULTS: (1) Morphology of microvessel: discernible of microvessels in EB and PT groups was decreased, but that of PT group was better than that of EB group. At PHM 5, diameter of arterioles, venules and capillaries was respectively (7.3+/ 2.5), (12.3+/-2.4), (3.5+/-0.7) microm in EB group, all narrower than those of the control group [(14.6+/-3.1), (27.2+/-3.5), (9.0+/-1.4) microm, with t value respectively 5.23, 13.66, 14.04, P values all below 0.05]. Diameters of the microvessels in PT group [(10.2+/-3.8), (21.5+/-3.1), (7.1+/-1.2) microm] were larger than those in EB group (with t value respectively 2.21, 8.99, 10.18, P values all below 0.05). Diameters of arterioles, venules and capillaries in EB and PT groups recovered to the before HEB size at PHH 1. From PHH 2 to 8, arterioles and capillaries decreased gradually in caliber, venules dilated gradually in EB and PT groups, but the changes in PT group were not obvious. Thickness of microvessel was observed uneven in EB group at PHM 5, which lasted until PHH 8. Ischemia of the tissue was observed in EB group at PHM 5, which improved at PHH 2. Situation in PT group was better. (2) Dynamic changes in microvascular blood flow: at PHM 5, blood flow speed in arterioles, venules and capillaries was respectively (202+/-53), (198+/-44), (46+/-12) microm/s in EB group, all slower than those of the control group [(544+/-37), (359+/-32), (220+/ 19) microm/s, with t value respectively 20.47, 11.51, 30.02, P values all below 0.05], and those of PT group [(335+/-42), (260+/-35), (119+/-23) microm/s] were faster than those of EB group (with t value respectively 7.55, 4.26, 14.85, P values all below 0.05). Blood flow speed in EB and PT groups recovered to the before HEB level at PHH 1. From PHH 2 to 8, blood flow speed decreased gradually in EB and PT groups, but that of PT group was faster than that of EB group. Erythrocyte aggregation in venules and capillaries was observed in EB group at PHM 5, which eased up at PHH 1, but aggregated at PHH 2, lasting until PHH 8. Obvious microthrombi were observed in EB group at PHH 2, which increased gradually. These changes were less obvious in PT group. (3) Condition of surrounding tissues of microvessel: in EB group, exudation was observed around microvessels at PHH 1, bleeding at PHH 2, with a worsening tendency. Changes in those in PT group were less obvious. CONCLUSIONS: HEB causes disturbance in BCM, but it can be ameliorated by Pentoxifylline. PMID- 20723421 TI - [Analysis of drug resistance and risk factors of Enterobacteriaceae in burn units]. AB - OBJECTIVE: To study the risk factors of infection of extended-spectrum beta lactamases (ESBL)-producing strains and drug resistance of Enterobacteriaceae that infected burn patients. METHODS: A retrospective study was performed on clinical information of 92 patients with Enterobacteriaceae infection in our burn unit from January 2001 to December 2008. The distribution and drug resistance of Enterobacteriaceae, and the detection rate, drug resistance of ESBL-producing strains, and its risk factors of nosocomial infection were analyzed. Data were processed with Chi-square test. RESULTS: One hundred and nine strains of Enterobacteriaceae were isolated, with 38 (34.9%) strains of Enterobacter cloacae, 25 (22.9%) strains of Escherichia coli, 22 (20.2%) strains of Klebsiella pneumoniae, 13 (11.9%) strains of Proteus mirabilis, and 11 (10.1%) other strains of Enterobacteriaceae. Enterobacteriaceae were moderately or highly resistant to antibiotics except imipenem, resistance rate of which was less than 8.0%. ESBL producing strains accounted for 44.0% in Escherichia coli, and 77.3% in Klebsiella pneumoniae. Drug-resistance rate of ESBL-producing strains to antibiotics was obviously higher than that of non ESBL-producing strains. Length of hospital stay longer than 20 days, and use of the third-generation cephalosporin longer than 5 days, quinolone antibiotics longer than 7 days, and topical antibiotics longer than 5 days were the risk factors of nosocomial infection caused by ESBL-producing strains, comparing with non ESBL-producing strains, the difference was statistically significant (with chi2 value respectively 5.491, 4.441, 15.186, 4.938, P values all below 0.05). CONCLUSIONS: Enterobacteriaceae strains in burn unit of our hospital are highly drug resistant, with high lactamase-producing rates, calling for intense monitor to control the risk factors that predispose the infection of ESBL-producing strains in order to lower the infection rate. PMID- 20723422 TI - [Study on cotransfection of genes of insulin-like growth factor I and herpes simplex virus thymidine kinase for optimization of wound healing]. AB - OBJECTIVE: To study the effect of cotransfection of genes of insulin-like growth factor I (IGF-I) and herpes simplex virus thymidine kinase (HSV-tk) on wound healing. METHODS: Thirty male Wistar rats were inflicted with 30% TBSA full thickness scald. They were then divided into A group (4.6 microg pcDNA3.1/IGF I+Lipofectamine 2000+saline), B group (3.6 microg pcDNA3.1/HSV-tk+Lipofectamine 2000+saline), C1 group and C2 group (2.3 microg pcDNA3.1/IGF-I+1.8 microg pcDNA3.1/HSV-tk+Lipofectamine 2000+saline), and D group (3.0 microg pcDNA3.1+Lipofectamine 2000+saline) according to the random number table, with 6 rats in each group. The above-mentioned mixtures were subcutaneously injected into left back of each rat the moment after injury and on post scald day (PSD) 7, 14, 21, and 28. Gancyclovir (2.5 mg/100 g) was hypodermically injected into rats in C2 group on PSD 29, 30, 31, 32. Changes in body weight of rats were measured. Wound healing rates were calculated. On PSD 35, the expressions of IGF-I gene in local wound and liver tissue were determined with immunohistochemical staining. The serum expression of IGF-I was determined with radioimmunoassay. Expression of HSV-tk gene in local wound was determined with RT-PCR. Apoptosis of fibroblast in C1 and C2 groups was observed under transmission electron microscope. Data were processed with one-way analysis of variance and Turkey method. RESULTS: Body weight of rats in A, C1, and C2 groups increased from PSD 7 through 35, and the difference between former three groups and B, D groups was statistically significant (with F value respectively 2.764, 4.519, 5.009, 13.449, 5.877, P values all below 0.05). Wound healing rates of rats in A, C1, and C2 groups were higher than those in B, D groups (with F value respectively 5.286, 100.880, 152.380, 127.850, 147.750, P values all below 0.05). IGF-I gene was positively expressed in wound fibroblast in A, C1 and C2 groups, but negatively in liver tissues of all the rats. There was no significant statistical difference among groups in serum content of IGF-I [from (1185+/-170) to (1270+/-130) ng/mL, F=0.355, P=0.838]. HSV-tk gene was positively expressed in rat skin tissue in B, C1 and C2 groups. Fibroblast apoptosis was observed under transmission electron microscope in C2 group, but it was not observed in C1 group. CONCLUSIONS: Cotransfection of pcDNA3.1/IGF-I and pcDNA3.1/HSV-tk mediated by liposome can promote wound healing, and inhibit the scar proliferation to some extent. PMID- 20723423 TI - [Effect of calcium on the activity and expression of integrin beta1 promoter in HaCaT cells and cell migration]. AB - OBJECTIVE: To study the effect of calcium on the activity and protein expression of integrin beta1 promoter in human immortal keratinocyte colony HaCaT cell and cell migration. METHODS: (1) HaCaT cells were cultured in vitro (12-slot plate) and divided into 5 groups according to the random number table, with 18 slots in each group: reporter plasmid pGL3 promoter (positive control group, PC), pGL3 empty vector (negative control group, NC), pGL3-1756 bp (total length promoter group, TL), pGL3-1442 bp (distal promoter group, D), and pGL3-261 bp (proximal promoter group, P) was respectively used to transfect HaCaT cells in non-serum RPMI 1640 culture medium with 0.00, 0.03, 0.09, 0.30, 0.80, or 1.20 mmol/L calcium (3 slots in each group with each concentration). Luciferase activity was detected with dual-luciferase reporter assay system 24 hours after transfection. (2) HaCaT cells steadily transfected with small interfering RNA-integrin beta1 vector (steadily transfected in brief) constructed in our laboratory were normally cultured and divided into 6 parts according to the random number table. And then they were treated with former 6 different concentrations of calcium, with 3 samples for each concentration. Expression level of integrin beta1 protein was determined with Western blot. (3) Normal and steadily transfected HaCaT cells were cultured in 6-slot plate, 18 slots for each kind of cells. They were cultured with former 6 kinds of calcium culture media (divided according to the random number table, with 3 slots of cells for each concentration) for 12 hours after scratch test. Cell migration rate was observed and determined. (4) Data were processed with one-way analysis of variance and independent samples t test. RESULTS: (1) The luciferase activity of cells in TL group increased from 0.16+/ 0.09 to 0.39+/-0.09 and 0.35+/-0.05 (with t value respectively 3.143, 3.140, P values all below 0.05) as calcium concentration increasing from 0.00 mmol/L to 0.09 and 0.30 mmol/L, and it decreased as calcium concentration increased to 0.80 and 1.20 mmol/L. The change pattern of luciferase activity of cells along with calcium concentration in D group was similar to that in TL group, but its activity (0.56+/-0.32, 0.64+/-0.06) at the concentration of 0.09, 0.30 mmol/L was respectively higher than that in TL group (with t value respectively 0.887, 6.122, P values all below 0.05). There was no obvious influence of calcium in either concentration on the luciferase activity of cells in P group. (2) The expression amount of integrin beta1 of steadily transfected HaCaT cells cultured with 0.03, 0.09, 0.30, 0.80, 1.20 mmol/L calcium (0.58+/-0.09, 1.40+/-0.29, 1.41+/-0.09, 0.99+/-0.10, 1.16+/-0.15) were all increased as compared with that cultured with 0.00 mmol/L calcium (0.53+/-0.10, with t value respectively 0.687, 4.880, 11.210, 5.578, 6.199, P values all below 0.05). (3) Migration speed of normal HaCaT cells cultured with 0.09, 0.30 mmol/L calcium increased obviously as compared with that cultured with 0.00 mmol/L calcium, and it slowed down when cultured with 0.80, 1.20 mmol/L calcium. There was no obvious difference of migration rate among steadily transfected HaCaT cells treated with different concentration of calcium. CONCLUSIONS: Distal promoter region of integrin beta1 plays a vital role in regulating integrin beta1 transcription in human epidermal cells. And calcium regulates activity, protein expression of integrin beta1 promoter and cell migration. PMID- 20723424 TI - [Promotion effect of stromal cell-derived factor 1 on the migration of epidermal stem cells in the healing process of frostbite-wound model ex vivo]. AB - OBJECTIVE: To study the promotion effect of stromal cell-derived factor 1 (SDF-1) on the migration of epidermal stem cells (ESC) in the healing process of frostbite-wound model ex vivo. METHODS: A three-dimensional model of full thickness frostbite of skin was constructed (with slot-like wound) out of skin equivalent. The expression of SDF-1 in wound stroma was observed with immunohistochemistry staining on post injury days (PID) 3 and 7. The model frostbite wounds were divided into control group (treated with PBS 50 microL per wound), SDF-1 group (treated with 100 ng/mL SDF-1, 50 microL per wound), and AMD3100 group [treated with 100 ng/mL AMD3100 (50 microL per wound) for 30 minutes, and then SDF-1 50 microL was added per wound]. The redistribution of ESC around wound was observed. RESULTS: The expression of SDF-1 in wound stroma increased gradually on PID 3 and 7. Compared with those in control and AMD3100 groups, there were more ESC and epithelial cell layers, and more integrin beta(1) positive cells appeared at the basal layer of wound in SDF-1 group, and some of the positive cells migrated upward to epidermis. CONCLUSIONS: SDF-1 contributes to wound repair through promoting ESC to migrate toward and gather around wound edge. This may be one of the mechanisms of ESC participating in wound repair. PMID- 20723425 TI - [Analysis of articles published in Chinese Journal of Burns winning high citation rate during 2000-2009]. AB - OBJECTIVE: To analyze the inherent quality of articles published in our journal enjoying high citation rate, and to explore strategies on improving impact of papers. METHODS: Scientific papers published in Chinese Journal of Burns from February 2000 to December 2009, with citation rate equal to or higher than 20 times were collected for classification according to their publication year, publication form, subject distribution, regional and institutional distribution, frequency of authors appeared in those published papers, frequency of winning prizes, and sources of fund (national, ministerial, or provincial). Data were processed by Microsoft Excel software. RESULTS: Altogether 64 scientific papers with high citation rate were published from 2000 to 2006. Original articles and expert forum accounted for 55 (86.0%). Twenty-one articles of clinical study were cited frequently, among them one was cited for 79 times. Articles dealing with subjects with popular interest or cutting-edge problems were cited frequently. Most articles winning high citation rate were originated from institutions located in Chongqing, Beijing, Shanghai, and Xi'an, etc. Those scientific papers which were instructed by specialists, with high level foundation and won prizes were cited with high frequency. The top 20 articles were mainly cited by excellent doctoral dissertations and master theses originated from 11 institutions for higher education, and source journals of Chinese Scientific and Technical Papers and Citations Database. CONCLUSIONS: Authors should emphasize subject planning in order to compose papers with high quality. The editorial board should make arrangements with influential specialists with related skills for their contributions based on subjects of popular interest concerning the cutting-edge problems of the specific specialty, and pay close attention to papers on clinical study and those with funding from high levels, to improve impact of the articles. PMID- 20723426 TI - [Difference of colon cancer and rectal cancer-from the view of an oncological physician]. PMID- 20723427 TI - [Functional Bax polymorphism associated with lung cancer susceptibility]. AB - OBJECTIVE: The Bcl-2 associated X protein (Bax), belonging to the Bcl-2 family, plays a pivotal role in mitochondria-dependent apoptosis. The aims of this study are to revalidate the functional significance of Bax G(-248)A polymorphism, and investigate its association with lung cancer risk in Chinese population. METHODS: The biological function of Bax G(-248)A was tested by luciferase assays, and its effects on lung cancer risk was determined by case-control analysis of 989 patients with lung cancer and 990 controls. RESULTS: Bax -248A allele exhibited significantly higher transcriptional activity compared with G allele. The Bax 248A allele carriers yielded a significantly decreased risk of lung cancer, compared with -248G allele carriers (OR = 0.68, 95% CI = 0.48 approximately 0.90, P = 0.01). Furthermore, a significant gene-smoking interaction between Bax G( 248)A polymorphism and smoking existed among the light smokers. CONCLUSION: Bax G(-248)A polymorphism is associated with lung cancer susceptibility in Chinese population. PMID- 20723428 TI - [Correlation of the methylation status of CpG islands in the promoter region of 10 genes with the 5-Fu chemosensitivity in 3 breast cancer cell lines]. AB - OBJECTIVE: To explore the relationship between the methylation status of CpG islands in the promoter region of 10 genes in breast cancer cells and their sensitivity to 5-fluouracil (5-Fu), and to identify the genes responsible for the 5-Fu resistance in breast cancer. METHODS: Three cell lines (differently resistant to chemotherapy) were used in this study: Bcap-37 (IC(50): 289.77 microg/ml), T47D (IC(50): 134.16 microg/ml) and ZR-75-30 (IC(50): 4.20 microg/ml). The methylation profile of 10 genes (BAG1, C11ORF31, CBR1, CBR4, GJA1, FOXL2, IGFBP6, P4HA1, SRI and TYMS) in the 3 breast cancer cell lines was determined by methylation specific PCR. The steady-state mRNAs of ABCC8, CHFR and IGFBP6 genes were quantified by real-time RT PCR analysis. RESULTS: Among the 10 genes, only genes IGFBP6 and FOXL2 displayed differential DNA methylation pattern between the 5-Fu-resistant and 5-Fu-sensitive cell lines. The mRNA expression level of genes PRSS21, LOX, IGFBP6, ABCC8 and CHFR was quantified by real-time RT PCR analysis. Except for CHFR, the expression level of the other 4 genes was correlated with the methylation status of CpG islands, namely, a lower expression level with methylation status and a higher level with demethylation status. CONCLUSION: The results of the present study have demonstrated that there are 8 genes with differential methylation status in chemosensitive and chemoresistant breast cancer cell lines, i.e. two genes more than the six genes we reported previously. Our findings provide both mechanistic insights for the drug resistance of breast cancer and the basis for further studies on potential application of the DNA methylation in this set of genes for prediction of chemosensitivity of breast cancer. PMID- 20723429 TI - [Killing effect of dendritic cell vaccine transfected by recombinant adeno associated virus with hAFP gene fragment on hepatocellular carcinoma cells in vitro]. AB - OBJECTIVE: Dendritic cell vaccines are one of the important active immunotherapies for neoplasms. The aim of this study was to observe the killing effect of specific cytotoxic T lymphocytes (CTL) on liver carcinoma HepG2 and SMMC-7721 cells in vitro. The CTL was induced by human peripheral blood mononuclear cells-originated dendritic cells (DC) transfected by recombinant adeno-associated virus (rAAV) with hAFP gene fragment (137-145). METHODS: Immature DCs were generated from peripheral blood mononuclear cells of healthy volunteers and then transfected by rAAV with AFP gene fragment. The CTL was thereafter induced. The activities of DC and CTL were measured and the killing effect of the CTL on HepG2 cells was detected using M1Tr assay. RESULTS: The mature DC, transfected or not, highly expressed CD40, CD86 and IL-12. IFN-gamma was highly expressed in the CTL. The DC-induced CTL could effectively recognize and destroy the HepG2 and SMMC-7721 cells. CONCLUSION: DC transfected by rAAV can stimulate the proliferation and differentiation of lymphocytes and also induce the proliferation of CTL, and their own phenotypes are not significantly altered. The DC vaccine can be effectively used as an adjuvant immunotherapy for patients with hepatocellular carcinoma. PMID- 20723430 TI - [Preparation of renal cancer vaccine of IL-12-anchored exosomes and its antitumor effect in vitro]. AB - OBJECTIVE: To prepare a vaccine of IL-12-anchored exosomes derived from renal cancer cells and to evaluate its antitumor effect in vitro. METHODS: A mammalian co-expression plasmid of glycolipid-anchor-IL-12 (GPI-IL-12) was constructed by subcloning IL-12A chain gene (P35 subunit) and a fusion gene containing GPI anchor signal sequence and IL-12B chain gene (P40 subunit) in pBudCE4.1. Confocal laser scanning microscopy and flow cytometry were used to analyze the expression of the fusion proteins. Transmission electron microscopy and Western blot were used to identify the morphology and characteristic molecules of exosomes separated by ultrafiltration and sucrose gradient centrifugation. The function of IL-12-anchored exosomes was determined by IFN-gamma release assay. RESULTS: Mammalian co-expression plasmids were successfully constructed. Confocal laser scanning microscopy and flow cytometric analysis of the RC-2-GPI-IL-12 transfectants showed the expression of IL-12 on the cell surface. Exosomes were purified by ultrafiltration and sucrose gradient centrifugation, which were 30-80 nm in diameter, typically saucer-shaped, and expressing HSP70, ICAM-1, G250 and GPI-IL-12. (80.0 +/- 9.6) pg/ml of IL-12 was detected in 10 microg/ml exosomes and it significantly induced the release of IFN-gamma. Stimulation with EXO-IL-12 could efficiently induce antigen-specific cytotoxic T lymphocytes (CTL), resulting in more significant cytotoxic effects in vitro. CONCLUSION: A vaccine of exosomes-GPI-IL-12 can be obtained from the culture supernatant of renal cancer cells modified to express anchored IL-12. This vaccine expressing IL-12 and tumor associated antigen G250 may become a new strategy for the treatment of renal cancer. PMID- 20723431 TI - [Nuclear accumulation of CXCR4 and overexpressions of VEGF-C and CK19 are associated with a higher risk of lymph node metastasis in hepatocellular carcinoma]. AB - OBJECTIVE: The aim of this study was to evaluate the correlation of protein expressions of CXC chemokine receptor 4 (CXCR4), vascular endothelial growth factor-C (VEGF-C) and cytokeratin 19 (CK-19) with lymph node metastasis (LNM) in patients with hepatocellular carcinoma (HCC), and their survival. METHODS: The expressions of CXCR4, VEGF-C and CK-19 in HCC patients with (n = 123) or without (n = 145) LNM were determined using tissue microarray and immunohistochemical staining. The relationship between clinicopathological features and CXCR4, VEGF-C and CK-19 were analyzed. Evaluation of immunostaining was performed semiquantitatively by visual assessment. RESULTS: The UICC T stage, and expressions of nuclear CXCR4, VEGF-C and CK-19 were independent risk factors for LNM. Nuclear CXCR4, VEGF-C and CK-19 expression were predictive factors for LNM in HCC patients. In patients with LNM, the median survival time was 15.1 months for patients with high nuclear CXCR4 expression and 24.5 months for those with low nuclear CXCR4 expression. The median survival time was 15.1 months for patients with high tumor VEGF-C expression and 31.1 months for those with low tumor VEGF-C expression. The median survival time was 12.0 months for patients with positive CK-19 expression and 19.2 months for patients with negative CK-19 expression. Patients with high nuclear CXCR4, VEGF-C or CK-19 expression had significantly poorer prognosis than those with low expression (all P < 0.05). PVT, UICC T stage and expressions of nuclear CXCR4, VEGF-C, and CK-19 were independent prognostic factors. CONCLUSION: Increased protein expressions of nuclear CXCR4, VEGF-C, and CK-19 are independent risk factors for developing lymph node metastasis, and they are significantly correlated with LNM and poor outcome in HCC patients. PMID- 20723432 TI - [Primary subcutaneous panniculitis-like T-cell cutaneous lymphoma: clinical presentation, treatment and prognosis]. AB - OBJECTIVE: To explore the clinical presentation, treatment and prognosis study of primary subcutaneous panniculitis-like T-cell cutaneous lymphoma (SCPTCL). METHODS: Ten cases of SCPTCL, treated in our hospital from January 1999 to January 2009, were included in this study. Their clinicopathological data were reviewed and analyzed retrospectively. RESULTS: the median age was 50.5 years (range: 10 - 58), 4 males and 6 females. There were seven CD56 positive, two negative cases and 1 unclear case. Four cases had repeatedly nodules regressed spontaneously without treatment before diagnosis and new nodules appeared at different sites. Seven patients presented with multiple subcutaneous nodules or deeply seated plaques, most commonly on the extremities and trunk. Ulceration of nodules occurred in 3 cases, and the lesions were painful in five cases. The lesions appeared nodules at the beginning, and then gradually grew into tumors. Four patients had abnormal liver function and one patient had hemophagocytic syndrome (HPS), four patients had lymphadenopathy or visceral involvement. Three cases with single lesion underwent surgical excision in combination with chemotherapy or chemotherapy/radiotherapy. One case lost follow up, and two cases live without disease. Among the seven patients with multiple lesions, lymphadenopathy or visceral involvement, one underwent local surgical excision and is alive without disease, six of them received chemotherapy or multi-modality treatment mainly with chemotherapy. Three of these 6 cases are alive without progression, one used histone deacetylase inhibitors after progression and obtained partial regression, and 2 died. The median follow-up for all the 10 patients was 44 months (range: 14 - 99). The progression free survival was 66.7% (6/9), and overall survival was 77.8% (7/9). CONCLUSION: SPTCL has an indolent course, some lesions can regress spontaneously and relapse again. Patients with single lesion may live long-term without disease after multimodality therapy. Patients with multiple lesions or extracutaneous involvement are sensitive to CHOP-like regimen, but the duration of remission is short. Histone deacetylase inhibitors may be a promising drug in the treatment for SCPTCL relapse. PMID- 20723433 TI - [Clinicopathologic analysis of papillary renal cell carcinoma]. AB - OBJECTIVE: To analyze the clinicopathologic and immunohistochemical features and prognosis of papillary renal cell carcinoma (PRCC) in 19 cases. METHODS: A retrospective study was performed including reviewing the clinical documents and pathological sections of 19 cases of PRCC. Immunohistochemical staining were performed and follow-up was made in 16 cases. RESULTS: There were 11 men and 8 women included in this study. The mean age was 52 years (range, 33 to 82 years old). Clinically, most tumors were found incidentally by physical examination because the majority of patients were asymptomatic. Histologically, the PRCC were characterized by varying proportions of papillary and tubular architecture covered by single- or multiple-layer of tumor cells with scanty or voluminous basophilic or eosinophilic cytoplasm. Foam cells and psammoma bodies were seen in some papillary cores and stroma, and the cytoplasm of some tumor cells contained hemosiderin. Of these 19 patients, 12 (63.2%) and 7 (36.8%) were diagnosed as type I and type II PRCC, respectively. The Fuhrman nuclear grade in all the type I PRCC was grade 1 - 2, significantly lower than that in the type II PRCC. Immunohistochemically, the PRCC often showed positive immunostaining for vimentin, EMA, CKpan, CK7, CD10 and p504s. Among the 19 patients, 16 were followed-up from 2 to 67 months. The distant metastasis, including lung, liver and bone metastases were detected in 3 patients at 3, 8, and 9 months after surgery, which were all of type II PRCC. Two patients died of other diseases. The other 11 patients were alive without recurrence or metastasis. CONCLUSION: Two subtypes of PRCC show different features of morphology, immunohistochemistry and prognosis. The type II PRCC tends to have unfavorable prognosis in comparison with type I PRCC. The presence of higher nuclear grade, sarcomatoid elements or clear cell carcinoma structure may indicate an aggressive behavior and poor prognosis. PMID- 20723434 TI - [CT features of ovarian Brenner tumor and a report of 9 cases]. AB - OBJECTIVE: In order to improve the preoperative diagnostic accuracy, the computed tomographic (CT) features of ovarian Brenner tumor were described and analyzed. METHODS: CT image and clinical data of nine patients with pathologically confirmed Brenner tumor were collected and analyzed retrospectively. There were 8 benign lesions and 1 borderline lesion. RESULTS: All lesions in the nine cases were unilateral, round, lobulated or irregular in shape and well defined, in a mean diameter of 7.8 cm. Among the nine cases, 5 were benign tumors with uniform structure, 3 were benign tumors accompanied with other pathological components, and 1 was borderline tumor. On the CT images, the 5 uniform benign lesions showed to be solid tumor of low density (lower than that of muscle) or with small cyst inside, two of the 5 lesions had calcification, and other 2 lesions showed slightly heterogeneous enhancement after enhanced scanning. The 3 benign Brenner tumors accompanied with other pathological structures were solid-cystic or cystic, with a clear demarcation of solid and cystic components. The density of solid parts was lower than that of muscle, and slight enhancement, and one of them had calcification. The one borderline tumor was a heterogeneous solid one and its density was higher than that of muscle, with a large proportion of low density and large calcification, and moderately enhanced after enhancing. None of the 9 cases had metastasis or effusion. CONCLUSION: Ovarian Brenner tumors are usually unilateral and often accompanied with other type of tumor components. When a tumor is of uniform component, the CT imaging often shows a homogeneous solid tumor with homogeneous or heterogeneous density. When a tumor is accompanied with other tumor components, it may be solid-cystic or cystic and has partial calcification. After enhancing, a benign Brenner tumor is slightly enhanced, while the borderline one is moderately/highly enhanced. PMID- 20723435 TI - [Imaging features and clinicopathological manifestations of solitary fibrous tumors]. AB - OBJECTIVE: To investigate the imaging features, clinical manifestations and pathological characteristics of solitary fibrous tumors (SFT). METHODS: The clinicopathological manifestations and medical imaging findings were analyzed retrospectively in 27 patients with surgically confirmed SFT. RESULTS: The SFTs originated from different parts of the body, including 18 in the chest, 4 in the abdomen, 1 in the lumboscral area, 3 in the pelvis, and 1 in the left shoulder. Twenty-three cases were found by CT scan, among which there were 16 benign diseases, presented with well-defined round or elliptic margins, with homogeneous attenuation and clearly surrounding; 6 malignant cases with unclear demarcations, invasive surrounding, heterogeneous attenuation due to calcification and/or irregular necrosis, and 1 junctional case with well-defined margins, which was enlarged during follow-up. There were 4 SFTs scanned by MRI with clear margin and homogeneous or heterogeneous signal intensity. All of the 4 cases were isointense or hyperintense to muscle on T1-weighted images, and were hyperintense on the T2 weighted images. All tumors showed heterogeneously intense enhancement with geographic pattern. Immunohistochemical staining showed that CD34-positive was 81.5%, vimentin (100.0%), CD99 (100.0%) and bcl-2 (96.3%), as well as negative CK (100.0%) and S-100 (96.3%). CONCLUSION: The location of SFT is varying. Though its clinical manifestations vary, the diagnosis is depended on pathology and immunohistochemistry. There are certain specific features related to SFTs on CT or MRI. These imaging techniques may serve to provide helpful information as to the location and vicinal anatomic structure of the tumor, which is of substantial importance for planning surgery. PMID- 20723436 TI - [Application of ATP-tumor chemosensitivity assay in primary epithelial ovarian cancer]. AB - OBJECTIVE: To evaluate the predictive value of the adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA) in the chemotherapy applied in primary epithelial ovarian cancer (PEOC), and to analyze if the neoadjuvant chemotherapy have any influence on the postoperative chemosensitivity. METHODS: ATP-TCA results from 61 PEOC specimens were analyzed retrospectively. Patients were divided into sensitive group and resistant group according to the ATP-TCA results. Sensitive index (SI) was applied to analyze the ATP-TCA results. The correlation between in vitro results and clinical outcome was assessed by univariate and multivariate analysis. RESULTS: SI set at > 250 had the highest test sensitivity, specificity, positive and negative predictive value of 91.6%, 73.9%, 84.6% and 85.0%, respectively. The ATP-TCA results had significant correlation with clinical outcome (chi(2) = 26.9, P < 0.001). Patients with tumors shown to be resistant had a higher risk of recurrence in comparison with those who were tested as sensitive (P = 0.030, OR = 0.033, 95%CI 0.002 approximately 0.724). The median progression-free survival (PFS) and overall survival (OS) of in vitro-sensitive patients were 26 months and 39 months, respectively, significantly longer than those in the in vitro drug-resistant group of patients (PFS 10 months and OS 25 months) (both P < 0.01). Neoadjuvant chemotherapy had a significant correlation with the clinical chemoresistance (chi(2) = 15.214, P < 0.001). CONCLUSION: ATP-TCA assay may effectively predict the chemosensitivity of primary ovarian cancer, and predict the early recurrence of the tumor. PMID- 20723437 TI - [A preliminary clinical study on the treatment of primary hepatic carcinoma by transcatheter arterial perfusion of batroxobin combined with TACE]. AB - OBJECTIVE: To explore the therapeutic efficacy and safety of batroxobin in patients with primary hepatic carcinoma (PHC) and the advantages of transcatheter arterial perfusion of batroxobin combined with transcatheter arterial chemoembolization (TACE). METHODS: 40 patients with PHC were randomized into experimental group (transcatheter arterial perfusion of batroxobin combined with TACE treatment, 20 patients) and control group (TACE alone group, 20 patients). The patients were followed up and the data were recorded, compared and analyzed. RESULTS: (1) Compared with the control group, the FIB level in the experimental group was significantly decreased at the first month after treatment (P < 0.05). (2) The baseline of the tumor was shortened in both groups after the treatment. There was a significant difference between the two groups at different time intervals (P < 0.05). (3) After the treatment, there was a significant difference of PFS levels between the two groups (t = 2.877, P < 0.05).(4) The incidence of metastasis were 5.0% (1/20) in both groups at 6 months after treatment, and that after one year was 10.0% (2/20) in the experimental group and 25.0% (5/20) in the control group. However, the difference was not significant (chi(2) = 0.693, P > 0.05). CONCLUSION: Batroxobin can rapidly and effectively decrease the FIB level. Therefore it may be used as an effective and safe adjuvant drug for the the treatment of primary hepatic carcinoma. Transcatheter arterial perfusion of batroxobin combined with TACE therapy has advantages in comparison with TACE alone. It could be taken as a new therapeutic regimen in the PHC treatment. PMID- 20723438 TI - [Value of diffusion weighted imaging (DWI) in evaluating early response to neoadjuvant chemotherapy in locally advanced breast cancer]. AB - OBJECTIVE: To evaluate the role and the performance of diffusion weighted imaging (DWI) for predicting the early response to neoadjuvant chemotherapy (NAC) in local advanced breast cancer (LABC) and to assess the accuracy of DWI in evaluating residual lesion after NAC. METHODS: 88 women with LABC (89 lesions) underwent DWI before and after the first and final cycle of NAC. For each patient, the apparent diffusion coefficient (ADC) values were compared between the baseline and follow-up to predict the early response to NAC. The residual tumor volumes were obtained using 3D maximum intensity projections (MIP) of DWI map, and were compared with pathological findings to assess the accuracy of DWI in detecting and measuring residual tumor. All results were proved or analyzed comparing with the data from histopathology. RESULTS: There were 68 lesions responding to NAC, while 21 non-responders. The baseline ADC values of responders and non-responders were (1.049 +/- 0.135) x 10(-3) mm(2)/s and (1.171 +/- 0.134) x 10(-3)mm(2)/s, respectively, with a significant difference (t = -2.731, P = 0.009 < 0.01). The ADC value measured prior to treatment was (1.087 +/- 0.146) x 10(-3)mm(2)/s, and the degree of the changes in tumor volume after NAC was (70.4% +/- 55.1)%. A negative correlation was observed (r = -0.430, P = 0.025 < 0.05). In the response group, there was a significant difference in ADC value between prior to NAC and 1st cycle of NAC, the final cycle of NAC, respectively (P < 0.001). While no significant differences were found in non-responders during NAC (P > 0.05). The tumor volume correlation coefficient between DWI and pathology measurements was very high (r = 0.749, P < 0.01). CONCLUSION: DWI appears to provide functional information regarding changes in ADC value of tumors due to NAC. DWI may be useful in monitoring the early pathological response of tumor after the initiation of treatment and in evaluating the residual tumor after NAC. PMID- 20723439 TI - [(99m)Tc-MDP wholebody bone imaging in evaluation of the characteristics of bone metastasis of primary lung cancer]. AB - OBJECTIVE: To explore the image characteristics of bone metastasis of primary lung carcinoma. METHODS: Whole-body bone imaging ((99)Tc(m)-MDP) was performed in 258 patients with pathologically proven lung carcinoma. The rate of bone metastasis, distribution of the metastatic lesions and their characteristics were analyzed. RESULTS: Among the 258 cases, 142 patients developed bone metastasis. The overall rate of bone metastasis was 55.0%. The metastases located in axial skeleton were 49.6%, appendicular skeleton 36.0%, trunk bones of the axial skeleton 48.4%, and appendicular girdle skeleton 31.4%. Ribs, thoracic vertebrae, ilium and lumbar vertebrae had a higher rate of bone metastasis, higher than 20%, respectively. 1252 lesions were detected including 406 at the left side of the body, 387 in the axial skeleton and 459 at the right side of the body. There was no significant difference in terms of number of lesions between left side and right side (chi(2) = 3.3, P = 0.072). 1224 bone metastatic foci (97.8%) were presented as strong radioactive, 26 (2.1%) mixed lesion, and 2 (0.2%) low radioactive. According to the shape of the lesions, there were 810 punctate lesions (71.5%), 159 (14.0%) lump form, 108 (9.5%) strip form and 56 (4.9%) lamellar form. The accumulative bone metastasis rate was 28.7% for the patients with one to three lesions. The metastasis rate decreased gradually with the increasing number of metastatic lesions. CONCLUSION: Bone metastasis is very common in patients with lung cancer. Most bone metastases are characterized by strong radioactive and earlier punctate form, often occurs in the trunk bones of axial skeleton or appendicular girdles. The distribution of earlier metastases has not obvious regularity, and advanced bone metastases are often concurrent, multiple and multiform, widely and randomly distributed in the body. PMID- 20723440 TI - [Related factors of right recurrent nerve nodal involvement in esophageal cancer]. AB - OBJECTIVE: To study the related factors of right recurrent nerve nodal involvement in esophageal cancer. METHODS: 280 patients with thoracic esophageal cancer received esophagectomy and right recurrent nerve node dissection. The clinicopathological data were analyzed retrospectively. Univariate data were analyzed by chi-square test, and multivariate data were analyzed by logistic regression. RESULTS: The right recurrent nerve nodal metastasis was found in 76 cases (27.1%, 76/280). In the 979 excised right recurrent nerve nodes, metastases were found in 118 nodes (12.1%). The tumor staging, the total number of involved lymph nodes, vascular invasion, the number of lymph node metastases in the thorax, the number of lymph node metastasis in the abdomen, subcarinal node metastasis, and peri-esophageal lymph node metastasis were independent risk factors of right recurrent nerve node metastasis in esophageal carcinoma. CONCLUSION: Right recurrent nerve lymph nodes should be dissected in those patients with high risk factors of lymph node metastasis in thoracic esophageal carcinoma. PMID- 20723441 TI - [Characteristics of the lymph node metastases and influencing factors and their value in target region delineation in postoperative radiotherapy for thoracic esophageal carcinoma]. AB - OBJECTIVE: To explore the distribution of lymph node metastases, to analyze the cliniopathologic factors of thoracic esophageal carcinoma after curative resection, and to provide the criteria of irradiated region delineation in radiotherapy for esophageal carcinoma. METHODS: The clinicopathological data of 763 patients who underwent esophagecotomy from Jun 2002 to Jun 2006 were retrospectively analyzed. The regularity of lymph node metastases of thoracic esophageal cancer and clinicopathological factors were stratified and analyzed with SPSS13.0 software. RESULTS: Of the 763 patients, a total of 5846 lymph nodes were dissected with an average of 7.7 lymph nodes in each case. Metastatic lymph nodes were 711, the ratio of metastatic lymph node was 12.2%, and 297 patients had lymph node involved, the lymph node metastasis rate was 38.9%. The metastatic lymph nodes of upper-thoracic esophagus were mainly observed in the supraclavicular and paratracheal regions (P < 0.05), the metastatic lymph nodes of middle-third thoracic esophagus were bidirectional, and those of the lower third thoracic esophagus mainly metastasized to the regions adjacent to the esophagus, gastric cardia and gastric artery (P < 0.05). Both the metastasis ratio and rate of lymph nodes adjacent to the gastric artery in the lower thoracic esophageal cancer were significantly higher than those in the middle third and upper-third thoracic esophageal cancers (P = 0.007, P = 0.001). The multiple factors logistic regression analysis showed that tumor length, depth of tumor invasion, vascular tumor emboli and distant metastasis were major factors for lymphatic metastasis (P < 0.01). For the whole group of patients the lymph node metastatic rate was 28.5% in upper-thoracic esophageal cancer, significantly lower than 38.8% of the lower-thoracic esophageal cancer (P = 0.039) and 43.4% in the middle-thoracic esophageal cancer (P = 0.010). However, the lymph node metastatic rates were 37.0%, 37.9% and 41.4% in the upper-, middle- and lower thoracic esophageal cancers of the 592 cases receiving left chest notches, with a non-significant difference among them (P = 0.715). CONCLUSION: The lesion length, depth of tumor invasion, vascular tumor embolus and distant metastasis are the most important parameters for lymph node metastases. Operative modes have obvious influence on the distribution of regional lymph node metastases. Therefore, in the clinical management, a postoperative prophylactic radiotherapy may be selected according to the tumor length, depth of tumor invasion, vascular tumor embolus and distant lymph node metastasis. PMID- 20723442 TI - [Expert consensus for the diagnosis and treatment of bone metastasis from prostate cancer]. PMID- 20723445 TI - What about placebos? "Trick or treatment?". PMID- 20723529 TI - The AOA's Healthy Eyes Healthy People program 6-year evaluation report (2004 2009). PMID- 20723530 TI - The AOA Commission on Paraoptometric Certification (CPC) 2009 year-in-review report. PMID- 20723531 TI - The 2009 Eyeglasses and Eye Care Services Index. PMID- 20723532 TI - Working without a script. PMID- 20723533 TI - Common questions on electronic health records incentives. PMID- 20723534 TI - Influence of microwave exposure on fertility of male rats. AB - The present study investigates the effect of 10-GHz microwave radiation on the fertility pattern of 70-day-old male rats (sham exposed and exposed), which were exposed for 2 h/d for 45 days continuously at a specific absorption rate of 0.014 W/kg and a power density of 0.21 mW/cm(2). Results show a significant change in the level of reactive oxygen species, histone kinase, apoptotic cells, and percentage of G(2)/M transition phase of cell cycle in the exposed group compared with the sham-exposed group. The study concludes that there is a significant effect of microwave radiations on the reproductive pattern in male rats, which is a causative factor of male infertility. PMID- 20723535 TI - The status of oocyte cryopreservation in the United States. AB - OBJECTIVE: To determine the current status of oocyte cryopreservation across the United States, and the perceived indications for its use. DESIGN: Cross-sectional survey of all IVF Centers in the United States. SETTING: Telephone and fax based survey of all IVF practice or laboratory directors, conducted March to June of 2009. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of oocyte cryopreservation, acceptable indications and age groups, number of oocyte cryopreservation cycles performed and thawed, fertilization and pregnancy rates, number of live births. RESULT(S): Of 442 centers contacted, 282 (64%) responded in 49 states. In these centers 143 (51%) programs currently offer oocyte cryopreservation, with a geographic trend toward the western-located clinics. Of all programs, 36% offer oocyte cryopreservation only for cancer patients or as an alternative to embryo cryopreservation after IVF, whereas 64% of programs offer it electively in women of advancing maternal age. For elective indications, 87% of programs accept patients aged 35-37 years, 49% consider age 38-40 years as acceptable, whereas only 26% of programs cryopreserve oocytes beyond age 40 years. Three hundred thirty-seven live births resulting from 857 thawed cycles (39.3% pregnancy rate [PR]) were reported across all centers. CONCLUSION(S): Oocyte cryopreservation is offered in more than 50% of ART clinics in the United States. Most programs that perform oocyte cryopreservation for cancer indications offer it for elective delay of childbearing as well. These data suggest a growing acceptance for this technology within our field. PMID- 20723536 TI - Targeted messenger RNA profiling of transfected breast cancer gene in a living cell. AB - Selective messenger RNA (mRNA) profiling of transfected breast cancer gene expression in a living cell is demonstrated. Atomic force microscope (AFM) probe tips are structurally modified to create a dielectrophoretic force that attracts mRNA molecules within the cell nucleus. The tip end is chemically modified to hybridize only to the target mRNA from a pool of molecules within the nucleus. We successfully combined this scheme with standard assay techniques to develop an assay technology that can be used for early disease detection and basic studies in cell biology. PMID- 20723537 TI - Effect of glucocorticoid on the biosynthesis of growth hormone-containing secretory granules in pituitary cells. AB - Recent studies have suggested that treatment of glucocorticoid to immature growth hormone (GH)-producing cell line, MtT/S cells, dramatically induced the accumulation of GH-containing secretory granules in the cytosol and differentiated into mature GH-producing cells. However, the molecular mechanism of glucocorticoid-induced GH-containing secretory granule biogenesis in the MtT/S cells remains unknown. In the present study, we found that GH mRNA expression was facilitated by application of glucocorticoid. We artificially increased GH synthesis by transfection of green fluorescent protein-tagged GH (GH-GFP) gene. We found that the artificial elevation of GH expression in the cells did not accumulate the secretory granules in the cytosol, whereas glucocorticoid-induced the biogenesis of granules in GH-GFP-expressing MtT/S cells. We next performed DNA microarray and real-time RT-PCR analysis and found that glucocorticoid significantly altered the expression of membrane trafficking-related protein, syntaxin11 (Syx11). Immunocytochemical analysis further demonstrated that Syx11 positive structures were well colocalized with GH-containing granules in both MtT/S cells and rat anterior pituitary gland. Our findings indicate that glucocorticoid regulate the expression of Syx11 and facilitate the biogenesis and the trafficking of GH-containing granules in the MtT/S cells. PMID- 20723538 TI - Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling. AB - Secreted Frizzled-related proteins (sFRP) are involved in embryonic development as well as pathological conditions including bone and myocardial disorders and cancer. Because of their sequence homology with the Wnt-binding domain of Frizzled, they have generally been considered antagonists of canonical Wnt signaling. However, additional activities of various sFRPs including both synergism and mimicry of Wnt signaling as well as functions other than modulation of Wnt signaling have been reported. Using human embryonic kidney cells (HEK293A), we found that sFRP2 enhanced Wnt3a-dependent phosphorylation of LRP6 as well as both cytosolic beta-catenin levels and its nuclear translocation. While addition of recombinant sFRP2 had no activity by itself, Top/Fop luciferase reporter assays showed a dose-dependent increase of Wnt3a-mediated transcriptional activity. sFRP2 enhancement of Wnt3a signaling was abolished by treatment with the Wnt antagonist, Dickkopf-1 (DKK1). Wnt-signaling pathway qPCR arrays showed that sFRP2 enhanced the Wnt3a-mediated transcriptional up regulation of several genes regulated by Wnt3a including its antagonists, DKK1, and Naked cuticle-1 homolog (NKD1). These results support sFRP2's role as an enhancer of Wnt/beta-catenin signaling, a result with biological impact for both normal development and diverse pathologies such as tumorigenesis. PMID- 20723539 TI - IL-4-mediated transcriptional regulation of human CYP2E1 by two independent signaling pathways. AB - Cytochrome P450 2E1 (CYP2E1), the alcohol-inducible member of the cytochrome P450 super family, plays an important role in both physiological and pathophysiological processes. The present study focused on the induction of human CYP2E1 transcription by the anti-inflammatory cytokine interleukin-4 (IL-4) in human hepatoma B16A2 cells and revealed that this regulation is mediated by two independent pathways. RNA interference and overexpression of STAT6, indicated that the JAK-STAT signaling pathway is involved in IL-4-dependent induction and mutagenesis revealed the presence of a STAT6 binding site in CYP2E1 proximal promoter region (-583/-574-bp). However, inhibition of the JAK-STAT6 pathway using JAK1 siRNA constructs could only partially inhibit the induction of CYP2E1 promoter constructs indicating the presence of a second IL-4 responsive element. Indeed by using a series of truncated CYP2E1 promoter constructs a second more distal IL-4 responsive element (-1604/-1428-bp) was identified, which was further shown to involve the activation of IRS1/2. This induction was dependent on the transcription factor NFATc1 as IL-4-induced CYP2E1 expression was altered by silencing or overexpressing NFATc1. A NFATc1 binding site was identified in the second distal IL-4 responsive element (-1551/-1545-bp) by chromatin immunoprecipitation (ChIP) analysis. Finally simultaneous siRNA-mediated down regulation of both STAT6 and NFATc1 or mutation of both STAT6 and NFATc1 binding sites abolished the IL-4-dependent transcriptional induction of CYP2E1, demonstrating that both pathways are required for maximal activation. In conclusion, the present study indicates that the induction of CYP2E1 transcription by IL-4 is mediated through two independent parallel pathways, involving JAK-STAT6 and IRS1/2 and NFATc1. PMID- 20723540 TI - Induction of thymidine kinase 1 after 5-fluorouracil as a mechanism for 3'-deoxy 3'-[18F]fluorothymidine flare. AB - Imaging the pharmacodynamics of anti-cancer drugs may allow early assessment of anti-cancer effects. Increases in 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake early after thymidylate synthase inhibition (TS) inhibition, the so-called flare response, is considered to be largely due to an increase in binding sites for type-1 equilibrative nucleoside transporter. We investigated the induction of thymidine kinase 1 (TK1) after 5-fluorouracil (5-FU) treatment as one of mechanisms for [(18)F]FLT flare. Exposure of nine cancer cell lines to 5-FU for 24h induced a 2.5- to 3.5-fold increase in [(18)F]FLT uptake, significantly higher than the 1.5-fold increase observed 2h after treatment. The increase of [(18)F]FLT uptake 24h after 5-FU exposure accompanied TK1 induction in most cell lines. In representative cell lines (A431 and HT29), 5-FU time-dependently increased [(18)F]FLT uptake, kinase activity and the levels of protein and mRNA for TK1, sequential cyclin E and A induction, and G(1)-S phase transition. Cycloheximide treatment and knockdown of TK1 completely inhibited 5-FU-induced [(18)F]FLT flare. On the other hand, HCT8 cells showed a biphasic [(18)F]FLT flare with lacked TK1 induction in response to the dosage of 5-FU. Cycloheximide did not inhibit 5-FU-induced [(18)F]FLT flare in this cells. In vivo dynamic [(18)F]FLT-PET and ex vivo analysis in HT29 tumor-bearing mice showed significantly increased [(18)F]FLT flux and TK1 activity of tumor tissue 24h after 5-FU administration (P<0.05). Conclusively, 5-FU induced TK1 and TK1 mediated high [(18)F]FLT flare in most of cell lines. [(18)F]FLT-PET may be used to assess pharmacodynamics of TS inhibitor by a mechanism involving TK1 induction. PMID- 20723542 TI - Kinetics of polymorphonuclear leukocytes in an experimental hypopyon model. AB - Regarding the process of uveitis development, many past studies have used the experimental autoimmune uveoretinitis (EAU) and other animal models to observe histologically the infiltration of inflammatory cells and the process of lesion progression. However, no detailed study of the process of clearance of infiltrated inflammatory cells from the eye has been reported. The purpose of this study was to investigate the process of clearance of polymorphonuclear leukocytes (PMNs) using an experimental hypopyon model. PMNs obtained from ascites of SD rat were injected into the anterior chamber of SD rats. The process of PMNs clearance was evaluated by serial photography and 3D optical coherence tomography (3D-OCT), and histological changes were observed simultaneously. The hypopyon heights regressed from 1.04+/-0.06 mm at 1h (day 0) to 0.45+/-0.07 mm at day 1, and 0 mm at day 3 after PMNs injection. When the hypopyon heights at the three time points were compared, significant differences were found between groups (P<0.05). The hypopyon volumes also decreased from 1.46+/-0.07 mm(3) at 1h to 1.16+/-0.09 mm(3) at 2h, and 0.83+/-0.04 mm(3) at 3h after PMN injection. When the hypopyon volumes at the three time points were compared, significant differences were found between groups (P<0.05). Light micrographs of inferior segment of the eyeball revealed dense PMNs in the chamber angle at 1h after PMNs injection and many PMNs in the iris stroma and vessels, as well as at the episcleral and subconjunctival tissues around limbus at 3h and day 1 after PMNs injection. Light micrographs of superior segment of the eyeball at 3h after injection revealed PMNs in the episcleral and subconjunctival vessels. Electron micrographs of inferior segment of the eyeball at 3h after PMNs injection revealed dense PMNs with slightly condensed nuclei in the anterior chamber, as well as in the iris stroma and vessels. In conclusion, in the experimental hypopyon model, PMNs injected into the anterior chamber were cleared from the eye mainly through the iris stroma and vessels, as well as the episcleral and subconjunctival tissues around limbus. PMID- 20723541 TI - Transduction of the inner mouse retina using AAVrh8 and AAVrh10 via intravitreal injection. AB - Adeno-associated virus (AAV) is a proven, safe and effective vector for gene delivery in the retina. There are over 100 serotypes of AAV, and AAV2 through AAV9 have been evaluated in the retina. Each AAV serotype has different cell tropism and transduction efficiency. Intravitreal injections of AAV into the eye tend to transduce cells in the ganglion cell layer (GCL), while subretinal injections tend to transduce retinal pigment epithelium and photoreceptors. Efficient transduction of the inner retina beyond the GCL is not well established with the current methodologies and serotypes used to date. In this study, we compared the cellular tropism of AAVrh8 and AAVrh10 vectors encoding enhanced green fluorescent protein (EGFP) using intravitreal injections. We found that AAVrh8 largely transduced cells in the GCL and also amacrine cells in the inner nuclear layer (INL), as well as Muller and horizontal cells. Inner retinal transduction with AAVrh10 was similar to AAVrh8, but AAVrh10 appeared to also transduce bipolar cells. The transduction efficiency as measured by the intensity of EGFP signal was 3.5 fold higher in horizontal cells transduced with AAVrh10 than AAVrh8. Glial fibrillary accessory protein (GFAP) levels were increased in Muller cells in transduced areas for both serotypes. The results of this study suggest that AAVrh8 and AAVrh10 may be excellent vector candidates to deliver genetic material to the INL, particularly for amacrine and horizontal cells, however they may also cause cellular stress as shown by increased glial GFAP expression. PMID- 20723543 TI - Protective effects of Aloe vera-based diets in Eimeria maxima-infected broiler chickens. AB - Aloes have been widely used for a broad range of pharmacological activities, including parasitic problems. Avian coccidiosis is the most costly and wide spread parasitic disease in the poultry industry, and has been mainly controlled by the use of chemotherapeutic agents. Due to the emergence of drug-resistant strains, alternative control strategies are needed. In this study, the protective effects of Aloe vera-based diets were assessed in broiler chickens following oral infection with Eimeria maxima. Chickens were fed a regular diet supplemented with ground Aloe vera throughout the duration of the experiment beginning 2 days prior to infection with 1 * 10(4) sporulated oocysts of E. maxima. No significant differences were found in body weight gain or loss between the Aloe vera supplemented and unsupplemented groups with or without E. maxima infections. Fecal oocyst shedding decreased significantly (p < 0.05) in all of the treatment groups that were supplemented with Aloe vera as compared to the unsupplemented group. Furthermore, the Aloe vera-supplemented group showed significantly fewer intestinal lesions (p < 0.05) than the unsupplemented group following infection. The findings of this study suggest that Aloe vera could be used an alternative treatment for controlling avian coccidiosis. PMID- 20723544 TI - Interval fecal immunochemical testing in a colonoscopic surveillance program speeds detection of colorectal neoplasia. AB - BACKGROUND & AIMS: Rapidly progressing or missed lesions can reduce the effectiveness of colonoscopy-based colorectal cancer surveillance programs. We investigated whether giving fecal immunochemical tests (FITs) for hemoglobin between surveillance colonoscopies resulted in earlier detection of neoplasia. METHODS: The study included 1736 patients with a family history or past neoplasia; they received at least 2 colonoscopy examinations and were followed for a total of 8863 years. Patients were excluded from the study if they had genetic syndromes, colorectal surgery, or inflammatory bowel disease. An FIT was offered yearly, in the interval between colonoscopies; if results were positive, the colonoscopy was performed earlier than scheduled. RESULTS: Among the 1071 asymptomatic subjects (61%) who received at least 1 FIT, the test detected 12 of 14 cancers (86% sensitivity) and 60 of 96 (63%) advanced adenomas. In patients with positive results from the FIT, the diagnosis of cancer was made 25 months (median) earlier and diagnosis of advanced adenoma 24 months earlier. Patients who had repeated negative results from FIT had an almost 2-fold decrease in risk for cancer and advanced adenoma compared with patients who were not tested (5.5% vs 10.1%, respectively, P = .0004). The most advanced stages of neoplasia, observed across the continuum from nonadvanced adenoma to late-stage cancer, were associated with age (increased with age), sex (increased in males), and FIT result. The probability of most advanced neoplastic stage was lowest among those with a negative result from the FIT (odds ratio, 0.68; P < .001). CONCLUSIONS: Interval examinations using the FIT detected neoplasias sooner than scheduled surveillances. Subjects with negative results from the FIT had the lowest risk for the most advanced stage of neoplasia. Interval FIT analyses can be used to detect missed or rapidly developing lesions in surveillance programs. PMID- 20723546 TI - Increasing hybridoma viability and antibody repertoire after the cell fusion by the use of human plasma as an alternative supplement. AB - Prion diseases such as Bovine Spongiform Encephalopathy (BSE) and new variant Creutzfeldt-Jakob disease (nvCJD) have caused a major safety concern in cell cultures using fetal calf serum (FCS). In this study, we found that screened and tested human plasma (HP) obtained from blood centers may be an ideal alternate nutrient substitute to FCS for culturing hybridoma. In addition to the inherent safety, a ten-fold increase in the fusion efficiency has been observed if the HP was used as the nutrient supplement instead of FCS. Subsequently, a broader antibody repertoire may be recovered. The HP supplement was found to promote the growth of hybridoma cells but no impact on antibody secretion. Interestingly, this effect of enrichment was only observed for HP, but not plasma from other animals. Unidentified murine hybridoma cloning factors other than IL-6 may specifically reside in human blood. PMID- 20723547 TI - Stochastic amplification in an epidemic model with seasonal forcing. AB - We study the stochastic susceptible-infected-recovered (SIR) model with time dependent forcing using analytic techniques which allow us to disentangle the interaction of stochasticity and external forcing. The model is formulated as a continuous time Markov process, which is decomposed into a deterministic dynamics together with stochastic corrections, by using an expansion in inverse system size. The forcing induces a limit cycle in the deterministic dynamics, and a complete analysis of the fluctuations about this time-dependent solution is given. This analysis is applied when the limit cycle is annual, and after a period doubling when it is biennial. The comprehensive nature of our approach allows us to give a coherent picture of the dynamics which unifies past work, but which also provides a systematic method for predicting the periods of oscillations seen in whooping cough and measles epidemics. PMID- 20723548 TI - Semantic and layered protein function prediction from PPI networks. AB - BACKGROUND: The past few years have seen a rapid development in novel high throughput technologies that have created large-scale data on protein-protein interactions (PPI) across human and most model species. This data is commonly represented as networks, with nodes representing proteins and edges representing the PPIs. A fundamental challenge to bioinformatics is how to interpret this wealth of data to elucidate the interaction of patterns and the biological characteristics of the proteins. One significant purpose of this interpretation is to predict unknown protein functions. Although many approaches have been proposed in recent years, the challenge still remains how to reasonably and precisely measure the functional similarities between proteins to improve the prediction effectiveness. RESULTS: We used a Semantic and Layered Protein Function Prediction (SLPFP) framework to more effectively predict unknown protein functions at different functional levels. The framework relies on a new protein similarity measurement and a clustering-based protein function prediction algorithm. The new protein similarity measurement incorporates the topological structure of the PPI network, as well as the protein's semantic information in terms of known protein functions at different functional layers. Experiments on real PPI datasets were conducted to evaluate the effectiveness of the proposed framework in predicting unknown protein functions. CONCLUSION: The proposed framework has a higher prediction accuracy compared with other similar approaches. The prediction results are stable even for a large number of proteins. Furthermore, the framework is able to predict unknown functions at different functional layers within the Munich Information Center for Protein Sequence (MIPS) hierarchical functional scheme. The experimental results demonstrated that the new protein similarity measurement reflects more reasonably and precisely relationships between proteins. PMID- 20723545 TI - Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) treatment is frequently complicated by anemia from ribavirin (RBV)-related hemolysis and peginterferon-alfa (PEG-IFN) related bone marrow suppression. We investigated the relationships among treatment outcomes, anemia, and their management with RBV dose reduction and/or erythropoiesis-stimulating agents (ESAs). METHODS: We analyzed data from a trial conducted at 118 United States academic and community centers in treatment-naive patients with HCV genotype 1. Patients were treated for as many as 48 weeks with 1 of 3 PEG-IFN/RBV regimens. ESAs were permitted for anemic patients (hemoglobin [Hb] <10 g/dL) after RBV dose reduction. Sustained virologic responses (SVR) were assessed based on decreases in Hb, anemia, and ESA use. RESULTS: While patients received treatment, 3023 had their Hb levels measured at least once. An SVR was associated with the magnitude of Hb decrease: >3 g/dL, 43.7%; <=3 g/dL, 29.9% (P < .001). Anemia occurred in 865 patients (28.6%); 449 of these (51.9%) used ESAs. In patients with early-onset anemia (<= 8 weeks of treatment), ESAs were associated with higher SVR rate (45.0% vs 25.9%; P < .001) and reduced discontinuation of treatment because of adverse events (12.6% vs 30.1%, P < .001). ESAs did not affect SVR or discontinuation rates among patients with late stage anemia. CONCLUSIONS: Among HCV genotype 1-infected patients treated with PEG-IFN/RBV, anemia was associated with higher rates of SVR. The effect of ESAs varied by time to anemia; patients with early-onset anemia had higher rates of SVR with ESA use, whereas no effect was observed in those with late-onset anemia. Prospective trials are needed to assess the role of ESAs in HCV treatment. PMID- 20723549 TI - Differential modulatory effects of rosiglitazone and pioglitazone on white adipose tissue in db/db mice. AB - AIMS: this study was performed to clarify the different action mechanisms through which rosiglitazone and pioglitazone regulate lipogenesis in white adipose tissues of db/db mice, an animal model of diabetes. MAIN METHODS: male C57BLKS/J Lepr(db/db) (db/db) mice were used for all experiments. Rosiglitazone or pioglitazone were administered once daily by oral gavage for 4 weeks at concentrations of 20mg/kg and 75 mg/kg, respectively. At 0, 3, 6, 9, 12, 15, 21, and 28 days of administration, body weights and blood glucose were determined. At the end of experiment, adiposity and gene expression were confirmed by perilipin A immunostaining and real-time PCR. KEY FINDINGS: pioglitazone treatment increased fat mass and the surface area of adipocytes more than rosiglitazone at dosages with equivalent effects on plasma glucose. Lipid parameters including plasma total cholesterol and triglycerides were decreased more in rosiglitazone treated mice. Relative mRNA expression levels for lipid synthesis and transport including diacylglycerol acyltransferase (DGAT1/2), fatty acid translocase (CD36/FAT), fatty acid transport protein (FATP) were increased in pioglitazone treated group compared to rosiglitazone-treated mice, but mRNA expression levels of beta-oxidation-related genes acyl-Coenzyme A dehydrogenase, very long chain (Acadvl), acyl-Coenzyme A dehydrogenase, medium chain (Acadm), and the energy expenditure-related genes triosephosphate isomerase 1 (Tpi1) and carnitine palmitoyltransferase 1b (Cpt1b) were decreased. SIGNIFICANCE: these results suggest that pioglitazone activates lipid deposition by increasing lipid synthesis and transport, but rosiglitazone stimulates beta-oxidation and energy expenditure in adipocytes of db/db mice. PMID- 20723550 TI - The effect of chromium on rat insulinoma cells in high glucose conditions. AB - AIMS: it has been suggested that Chromium (Cr), one of the essential minerals, can be beneficial to type 2 diabetic patients because it lowers blood glucose levels by improving various steps in insulin action. A few studies reported that Cr might also have some beneficial effects in people with type 1 diabetes mellitus and in streptozotocin-treated rats, but direct beneficial effects of Cr on pancreatic beta cells have not been proven. We performed this study to determine whether Cr could have direct protective effects on INS-1 cells in high glucose conditions that mimic the actual diabetic state. MAIN METHODS: INS-1 cells were cultured for 48h in RPMI medium with 33mM glucose as the stress condition and 11mM glucose as a control. CrCl(3) was used to verify whether Cr could protect INS-1 cells from glucotoxic stress. Cell viability and apoptosis were evaluated by MTT assay and FACS. The level of insulin mRNA, by semi quantitative RT-PCR, was significantly reduced at 33mM glucose concentration after 48h of incubation. KEY FINDINGS: cell viability was reduced by 50%, and 35% of the cells underwent apoptosis at the same culture condition. Addition of various concentrations of CrCl(3) to INS-1 cells in 33mM glucose for different durations of time did not reveal any beneficial effects on cell viability, degree of apoptosis, insulin mRNA levels, and glucose stimulated insulin secretion. SIGNIFICANCE: we could not find any evidence that Cr had direct beneficial effects on INS-1 cells in high glucose induced stress conditions. PMID- 20723551 TI - Effects of sleep restriction on adiponectin levels in healthy men and women. AB - OBJECTIVE: Population studies have consistently found that shorter sleep durations are associated with obesity and cardiovascular disease, particularly among women. Adiponectin is an adipocyte-derived, anti-inflammatory hormone that is related to cardiovascular disease risk. We hypothesized that sleep restriction would reduce adiponectin levels in healthy young adults. METHODS: 74 healthy adults (57% men, 63% African American, mean age 29.9years) completed 2 nights of baseline sleep at 10h time in bed (TIB) per night followed by 5 nights of sleep restricted to 4h TIB per night. An additional 8 participants were randomized to a control group that received 10h TIB per night throughout the study. Plasma adiponectin levels were measured following the second night of baseline sleep and the fifth night of sleep restriction or control sleep. RESULTS: Sleep restriction resulted in a decrease in plasma adiponectin levels among Caucasian women (Z= 2.19, p=0.028), but an increase among African American women (Z=-2.73, p=0.006). No significant effects of sleep restriction on adiponectin levels were found among men. A 2*2 between-group analysis of covariance on adiponectin change scores controlling for BMI confirmed significant interactions between sleep restriction and race/ethnicity [F(1,66)=13.73, p<0.001], as well as among sleep restriction, race/ethnicity and sex [F(1,66)=4.27, p=0.043)]. CONCLUSIONS: Inflammatory responses to sleep loss appear to be moderated by sex and race/ethnicity; observed decreases in adiponectin following sleep restriction may be one avenue by which reduced sleep duration promotes cardiovascular risk in Caucasian women. PMID- 20723552 TI - Blocking oxytocin receptors inhibits vaginal marking to male odors in female Syrian hamsters. AB - In Syrian hamsters (Mesocricetus auratus), precopulatory behaviors such as vaginal scent marking are essential for attracting a suitable mate. Vaginal marking is dependent on forebrain areas implicated in the neural regulation of reproductive behaviors in rodents, including the medial preoptic/anterior hypothalamus (MPOA-AH). Within MPOA-AH, the neuropeptide oxytocin (OT) acts to facilitate copulation (lordosis), as well as ultrasonic vocalizations towards males. It is not known, however, if OT in this area also facilitates vaginal marking. In the present study, a specific oxytocin receptor antagonist (OTA) was injected into MPOA-AH of intact female Syrian hamsters to determine if oxytocin receptor-dependent signaling is critical for the normal expression of vaginal marking elicited by male, female, and clean odors. OTA injections significantly inhibited vaginal marking in response to male odors compared with vehicle injections. There was no effect of OTA on marking in response to either female or clean odors. When injected into the bed nucleus of the stria terminalis (BNST), a nearby region to MPOA-AH, OTA was equally effective in decreasing marking. Finally, the effects of OTA appear to be specific to vaginal marking, as OTA injections in MPOA-AH or BNST did not alter general locomotor activity, flank marking, or social odor investigation. Considered together, these results suggest that OT in MPOA-AH and/or BNST normally facilitates male odor-induced vaginal marking, providing further evidence that OT generally supports prosocial interactions among conspecifics. PMID- 20723553 TI - Oxytocin, cortisol, and triadic family interactions. AB - The neuropeptide oxytocin (OT) supports the development of parenting in mammals primarily through its impact on parent-infant proximity and touch behaviors; however, much less is known about the links between OT and parental touch and contact in humans. In this study, we examined the relations between maternal and paternal OT and patterns of touch and contact in the family unit during triadic interactions. Thirty-seven parents and their firstborn child were seen twice: during the 2nd and 6th postpartum month. Plasma OT and salivary cortisol (CT) were assessed with ELISA methods. At six months, triadic mother-father-infant interactions were videotaped and micro-coded for patterns of proximity, touch, and gaze behavior. Triadic synchrony, defined as moments of coordination between physical proximity and affectionate touch between the parents as well as between parent and infant while both parent and child are synchronizing their social gaze, was predicted by both maternal and paternal OT. Among mothers, triadic synchrony was also independently related to lower levels of CT. Results highlight the role of OT in the early formation of the family unit at the transition to parenthood. PMID- 20723554 TI - Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter controlled luciferase as a tool for the study of endocrine disrupting chemicals. AB - Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA(r))CD-1-Tg(Cyp19-luc) Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n=14; p=0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30 mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p<0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for environmental contaminants. PMID- 20723556 TI - Visuomotor robustness is based on integration not segregation. AB - How can we explain, that DF - a patient with a damaged ventral stream - can act normally in many everyday tasks despite her profound perceptual disability. The classical answer is that perception and action are based on separate visual streams. Here, I will explain why this view is problematic and offer an alternative answer. Specifically, I will argue that the preserved performance of DF should be seen as evidence of the redundancy of visuomotor control and not as evidence of a segregation between vision for perception and action. PMID- 20723555 TI - A novel approach for in vivo screening of toxins using the Drosophila Giant Fiber circuit. AB - Finding compounds that affect neuronal or muscular function is of great interest as potential therapeutic agents for a variety of neurological disorders. Alternative applications for these compounds include their use as molecular probes as well as insecticides. We have developed a bioassay that requires small amounts of compounds and allows for unbiased screening of biological activity in vivo. For this, we paired administering compounds in a non-invasive manner with simultaneous electrophysiological recordings from a well-characterized neuronal circuit, the Giant Fiber System of Drosophila melanogaster, which mediates the escape response of the fly. The circuit encompasses a variety of neurons with cholinergic, glutamatergic, and electrical synapses as well as neuromuscular junctions. Electrophysiological recordings from this system allow for the detection of compound-related effects against any molecular target on these components. Here, we provide evidence that this novel bioassay works with small molecules such as the cholinergic receptor blocker mecamylamine hydrochloride and the potassium channel blocker tetraethylammonium hydroxide, as well as with venom from Conus brunneus and isolated conopeptides. Conopeptides have been developed into powerful drugs, such as the painkillers PrialtTM and Xen2174. However, most conopeptides have yet to be characterized, revealing the need for a rapid and straightforward screening method. Our findings show that mecamylamine hydrochloride, as well as the alpha-conotoxin ImI, which is known to be an antagonist of the human alpha7 nicotinic acetylcholine receptor, efficiently disrupted the synaptic transmission of a Drosophila alpha7 nicotinic acetylcholine receptor-dependent pathway in our circuit but did not affect the function of neurons with other types of synapses. This demonstrates that our bioassay is a valid tool for screening for compounds relevant to human health. PMID- 20723557 TI - Time course of the integration of spatial frequency-based information in natural scenes. AB - It is known that visual information is processed separately and based on multiple spatial frequencies. Therefore, integration of information is important for categorization of natural scenes. To clarify the time course of visual integration, we examined categorization accuracies for spatially filtered images as a function of image exposure duration. Results indicated that, with image durations of 100-ms, accuracy was superior with spatially integrable images when compared with accuracy levels based upon the probability summation model estimated from accuracies of separately presented low- and high-frequency images. This finding suggests that spatial frequency integration begins earlier than 100 ms after the image onset. PMID- 20723558 TI - Treatment of addiction and anxiety using extinction approaches: neural mechanisms and their treatment implications. AB - Clinical interventions which produce cue and contextual extinction learning can reduce craving and relapse in substance abuse and inhibit conditioned fear responses in anxiety disorders. In both types of disorders, classical conditioning links unconditioned drug or fear responses to associated contextual cues and result in enduring pathological responses to multiple stimuli. Extinction therapy countermeasures seek to reduce conditioned responses using a set of techniques in which patients are repeatedly exposed to conditioned appetitive or aversive stimuli using imaginal imagery, in vivo exposure, or written scripts. Such interventions allow patients to rehearse more adaptive responses to conditioned stimuli. The ultimate goal of these interventions, extinction of the original conditioned response, is a new learning process that results in a decrease in frequency or intensity of conditioned responses to drug or fear cues. This review explores extinction approaches in conditioned drug reward and fear responses. The behavioral, neuroanatomical and neurochemical mechanisms of conditioned reward and fear responses and their extinction are derived from our understanding of the animal literature. Extensive neuroscience research shows that even though many mechanisms differ in conditioned fear and reward, converging prefrontal cortical glutamatergic pathways underlie extinction learning. Efficacy of pharmacological and behavioral treatment approaches in addiction and anxiety disorders may be optimized by enhancing extinction and weakening the bond between the original conditioned stimuli and conditioned responses. Adjunctive pharmacotherapy approaches using agents which alter glutamate or gamma-aminobutyric acid signaling or epigenetic mechanisms in prefrontal cortical pathways can enhance extinction learning. A comparative study of extinction processes and its neural mechanisms can be translated into more effective behavioral and pharmacological treatment approaches in substance abuse and anxiety. PMID- 20723559 TI - Use of patient-delivered coupons as a vehicle for HIV partner notification: results of a pilot study in Guatemala. PMID- 20723560 TI - Molecular cloning of a small heat shock protein (sHSPII) from the cattle tick Rhipicephalus (Boophilus) annulatus salivary gland. AB - Immunoscreening of a cDNA expression library of the Rhipicephalus (Boophilus) annulatus tick with purified rabbit anti-R annulatus salivary glands antigens polyclonal antibodies led to the identification of a 661bp sequence. The sequence includes an open reading frame of 543bp encoding a protein of 180 amino acids with calculated molecular weight of 20.51kDa, isoelectric point of 9.071 and with no signal sequence. Comparison of the deduced amino acids with protein data bank showed that the identified polypeptide belongs to the alpha crystallin small heat shock proteins superfamily and shows sequence similarity of 62% and 55% to Ixodes scapularis fed tick salivary gland protein and Ornithodoros parkeri alpha crystallin protein, respectively. Accordingly, this protein was called Ra-sHSPII. The Ra-sHSPII protein was expressed in E. coli under T7 promotor of the pET-30b vector, purified under denaturation conditions and the immunogenicity and cross reactivity of the recombinant Ra-sHSPII were evaluated. Direct ELISA showed that the Ra-sHSPII is a strong immunogen. In immunoblotting assay the anti-rRa-sHSPII antisera reacted specifically with purified rRa-sHSPII, with several proteins in R. annulatus whole tick, larval and gut protein extracts in addition to Hyalomma dromedarii and Ornithodoros moubata whole tick protein extracts, as examples of hard and soft tick species, respectively. The rRa-sHSPII protein confers thermal protection to other proteins in vitro as found in other sHSPs. E. coli cell extracts containing the protein were protected from heat-denatured precipitation when heated up to 100 degrees C, whereas extracts from cells not expressing the protein were heat-sensitive at 60 degrees C. PMID- 20723561 TI - Synthesis and characterization of hemoglobin conjugates with antioxidant enzymes via poly(ethylene glycol) cross-linker (Hb-SOD-CAT) for protection from free radical stress. AB - Hemoglobin (Hb) conjugated with the antioxidant enzymes (SOD and CAT), by employing dicarboxymethylated poly(ethylene glycol), was designed for protection of hemoglobin against free radicals. In this study, the conjugation process was confirmed by employing SDS-PAGE and SEC techniques. The average molecular weight of the conjugates was estimated to be around 1000 kDa. The enzymatic activities of the SOD and CAT in the conjugates (Hb-SOD-CAT) after conjugation were found to retain greater than 70% and 90% of the original bioactivity. Results show that antioxidant enzymes helped minimize methemoglobin (non-carrier of oxygen) formation during the conjugation process and also during storage at 4 degrees C over a period of 1 month. In summary, the optimized (1:10 Hb/PEG) crosslinked conjugates with antioxidant enzymes showed protective properties from severe free radical stresses when incubated with hydrogen peroxide (0.1 and 1 mM) and xanthine (1 mM)/xanthine oxidase (10 and 20 mU/ml) system. PMID- 20723562 TI - Performance evaluation of the ADVIA Centaur((r)) HIV Ag/Ab Combo assay. AB - Early diagnosis of HIV infection and appropriate care reduces morbidity and mortality. As a result, recent guidelines recommend that HIV screening be routinely included in patient care. Routine screening will likely result in more patients being tested prior to seroconversion; fourth-generation assays can facilitate diagnosis in these patients. This study evaluated the performance of the automated fourth-generation ADVIA Centaur((r)) HIV Ag/Ab Combo assay. Samples from three sites were tested using the HIV Ag/Ab Combo assay and a CE-marked predicate assay. The HIV Ag/Ab Combo assay's relative sensitivity was 98.36% (599/609; 95% confidence interval: 97.00-99.21%), and the relative specificity was 99.74% (7743/7763; 95% confidence interval: 99.60-99.84%). The HIV Ag/Ab Combo assay detected seroconversion at the same bleed or at least one bleed earlier in 34/37 panels compared to the CE-marked predicate assay. Compared to the final result, the HIV Ag/Ab Combo assay's sensitivity was 100% (598/598; 95% confidence interval: 99.39-100.00%), and the specificity was 99.74% (7753/7773; 95% confidence interval: 99.60-99.84%). Sensitivity was 100% for the HIV genotypes tested. The HIV Ag/Ab Combo assay is a sensitive and specific assay that can assist clinicians in the early diagnosis of HIV infection. PMID- 20723563 TI - Development and evaluation of a sensitive and quantitative assay for hirame rhabdovirus based on quantitative RT-PCR. AB - The aim of the present work was to develop a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay using a TaqMan probe to detect and quantify hirame rhabdovirus (HRV). The results demonstrated that the assay had a detection limit of 100 copies of RNA per reaction and a log-linear range up to 10(8) copies of HRV RNA. Regression analysis demonstrated a significant correlation with an R(2) value of 0.9963 and a slope of -3.18 between the mean C(t) values and HRV cRNA. This assay was 100 times more sensitive than the conventional one-step RT-PCR assay. The qRT-PCR assay was found to be highly reproducible with intra- and inter-assay coefficients of variation of 0.37-1.72% and 1.37-3.79%, respectively. The primers and TaqMan probe were specific for HRV and did not react with either the spring viraemia of carp virus (SVCV), infectious pancreatic necrosis virus (IPNV), infectious haematopoietic necrosis virus (IHNV), marine birnavirus (MABV), viral hemorrhagic septicemia virus (VHSV), or viral nervous necrosis virus (VNNV). This assay was evaluated using 40 fish samples, indicating that such method offers considerable advantages over the classical virus isolation method currently used for HRV surveillance. In conclusion, the developed qRT-PCR assay was a reliable, specific and sensitive tool for the quantitative diagnosis of HRV in fish samples. PMID- 20723564 TI - Multiplex semi-nested RT-PCR with exogenous internal control for simultaneous detection of bovine coronavirus and group A rotavirus. AB - Neonatal calf diarrhea is a multi-etiology syndrome of cattle and direct detection of the two major agents of the syndrome, group A rotavirus and Bovine coronavirus (BCoV) is hampered by their fastidious growth in cell culture. This study aimed at developing a multiplex semi-nested RT-PCR for simultaneous detection of BCoV (N gene) and group A rotavirus (VP1 gene) with the addition of an internal control (mRNA ND5). The assay was tested in 75 bovine feces samples tested previously for rotavirus using PAGE and for BCoV using nested RT-PCR targeted to RdRp gene. Agreement with reference tests was optimal for BCoV (kappa=0.833) and substantial for rotavirus detection (kappa=0.648). the internal control, ND5 mRNA, was detected successfully in all reactions. Results demonstrated that this multiplex semi-nested RT-PCR was effective in the detection of BCoV and rotavirus, with high sensitivity and specificity for simultaneous detection of both viruses at a lower cost, providing an important tool for studies on the etiology of diarrhea in cattle. PMID- 20723565 TI - Targeting highly conserved 3'-untranslated region of pecluviruses for sensitive broad-spectrum detection and quantitation by RT-PCR and assessment of phylogenetic relationships. AB - The 3'-end region of many virus isolates has been shown to possess conserved sequences in addition to the presence of numerous genomic and subgenomic RNAs. Utilizing these sequences, a broad-spectrum reverse transcription-polymerase chain reaction protocol has been developed to detect all the known Indian peanut clump virus and Peanut clump virus isolates, that cause peanut clump diseases in West Africa and India. The primers were targeted at the highly conserved 3' untranslated regions of the PCV RNA-1 and RNA-2. The conservation was confirmed by sequencing these untranslated regions of RNA-1 for six isolates and RNA-2 for one isolate. The conserved structure of the RNA-1 and RNA-2 was observed and the importance of this region for the virus survival was confirmed. The primers were also designed for virus quantitation using a Taqman((r))-based real-time RT-PCR. The use of RT-PCR and real-time quantitative RT-PCR improved the sensitivity of PCV detection compared to ELISA. RT-PCR also led to the detection of IPCV and PCV on two new natural hosts: Oldenlandia aspera and Vigna subterranea. Real-time RT PCR is considered to be an ideal tool for identifying resistant sources to both IPCV and PCV. PMID- 20723566 TI - Facilitated acquisition of the classically conditioned eyeblink response in females is augmented in those taking oral contraceptives. AB - Sex differences in attentional processing and new motor learning remain controversial, and are complicated by the influence of endogenous and exogenous gonadal hormones. Facilitated acquisition of a classically conditioned eyeblink response in oral contraceptive-using women has been reported, as have menstrual cycle-dependent changes in pre-pulse inhibition (PPI). The current study sought to replicate and extend these findings by comparing acquisition of the conditioned eyeblink response and PPI in women currently taking oral contraceptives (OCs), women not taking OCs, as well as men. Women were assigned to participate either during their follicular or luteal menstrual cycle phase. Acquisition was assessed in a two-tone discrimination delay paradigm (500-ms conditional stimulus (CS); 100-ms airpuff unconditional stimulus (US)). PPI was lower in males and OC-users depending on stimulus intensity. Consistent with early classical conditioning research, females acquired an eyeblink conditioned response faster than males. Faster acquisition was associated with larger unconditional responses. Women taking OCs demonstrated accelerated conditioned response acquisition compared to women not taking OCs and males although unconditional responses were comparable to males. Facilitated acquisition of new motor learning in OC-users was replicated in a college-aged population of women and was not secondary to enhanced reactivity to sensory stimuli. PMID- 20723567 TI - Anxiolytic and anxiogenic drug effects on male and female gerbils in the black white box. AB - Neurokinin-1, (NK1) receptor antagonists offer strong potential as anxiolytic drugs with few side effects. The use of the Mongolian gerbil for anxiety research offers advantages because gerbil NK1 receptors share a greater homology with human NK1 receptors than those of other rodents. Studies are needed to validate existing tests of anxiety for use with this species. This study examined the effects of two anxiolytics (buspirone and diazepam) and two anxiogenics (caffeine and FG142) on male and female gerbil behaviour in the black-white box (BWB). Diazepam was anxiolytic in males but not females. The anxiolytic effects of buspirone were apparent at the lower doses in both males and females. Higher doses resulted in sedative effects in both sexes. Caffeine produced mild anxiogenesis in females at the lowest dose, and in males at the highest dose. FG7142 was mildly anxiogenic in males and not at all in females. Findings are discussed in light of previous research. The gerbil BWB should not be used as a valid test of anxiety in its current form. PMID- 20723568 TI - Reviewing the impact of problem structure on planning: a software tool for analyzing tower tasks. AB - Cognitive, clinical, and neuroimaging studies on planning abilities most frequently implement the Tower of London task or one of its variants. Yet, cumulating evidence from a series of experiments suggests that the commonly used approximation of problem difficulty in terms of the minimum number of moves for goal attainment is too coarse a measure for the underlying cognitive operations, and in some cases may be even misleading. Rather, problem difficulty can be more specifically characterized by a set of structural task parameters such as the number and nature of optimal and suboptimal solution paths, the required search depths, the patterns of intermediate and goal moves, goal hierarchies and the associated degree of ambiguity in the sequential ordering of goal moves. First applications in developmental and patient studies have proven fruitful in targeting fundamental alterations of planning abilities in healthy and clinical conditions. In addition, recent evidence from neuroimaging shows that manipulations of problem structure relate to separate cognitive and neural processes and are accompanied by dissociable brain activation patterns. Here, we briefly review these structural problem parameters and the concepts behind. As controlling for task parameters and selecting a balanced problem set is a complex and error-prone endeavor, we further present TowerTool, a software solution that allows easy access to in-depth analysis of the problem structure of widely used planning tasks like the Tower of London, the Tower of Hanoi, and their variants. Thereby, we hope to encourage and facilitate the implementation of structurally balanced task sets in future studies on planning and to promote transfer between the cognitive, developmental, and clinical neurosciences. PMID- 20723569 TI - Disturbance of contralateral unipedal postural control after stimulated and voluntary contractions of the ipsilateral limb. AB - One session of sustained unilateral voluntary muscular contractions increases central fatigue and induces a cross-over of fatigue of homologous contralateral muscles. It is not known, however, how this cross-transfer affects contralateral unipedal postural control. Moreover, contralateral neurophysiological effects differ between voluntary muscular contractions and electrically stimulated contractions. The aims of this study were thus to examine the effects of muscle fatigue on contralateral unipedal postural control and to compare the effects of stimulated and voluntary contractions. Fifteen subjects took part in the protocol. Fatigue of the ipsilateral quadriceps femoris was generated either by neuromuscular electrical stimulation (NMES) or by isometric voluntary muscular contraction (VOL). Postural control on the contralateral limb was measured before (PRE condition) and after the completion of the two fatiguing exercises (POST condition) using a force platform. We analyzed body sway area and the spectral power density given by the wavelet transform. In POST condition, postural control recorded in the unipedal stance on the contralateral limb was disturbed after NMES and VOL fatiguing exercises. In addition, postural control was similarly disturbed for both exercises. These results suggest that cross-over fatigue is able to disturb postural control after both stimulated and voluntary contractions. PMID- 20723570 TI - Proteomic analysis of the host response in the bursa of Fabricius of chickens infected with Marek's disease virus. AB - Marek's disease virus (MDV) is an oncogenic herpesvirus that causes a disease in chickens characterized by tumor formation and immunosuppression. In this paper, we identified differentially expressed proteins in the bursa of Fabricius of chickens infected with the highly virulent MDV strain RB1B, using two-dimensional gel electrophoresis on samples from time points coinciding with MDV life-cycle phases. By MALDI-TOF/TOF mass spectrometer, 26 proteins were identified, including 8 persistently up-regulated, four persistently down-regulated, 12 with fluctuating regulation, and 2 with significant differential expression but with no match in the published fowl databases. Database queries confirmed that these proteins were mainly associated with tumor biology, protein folding, signal transduction, immunology, cell proliferation and apoptosis. Interestingly, most stress and immune-associated proteins, such as apolipoprotein A-1, were significantly down-regulated, but tumor-associated proteins were significantly increased at 14 days post-infection (d.p.i), and at 21 d.p.i. These findings provide a basis for further studies to elucidate the role of these proteins in MDV-host interaction. This could lead to a better understanding of MDV infection mechanisms that cause immune suppression, and trigger tumor formation. PMID- 20723571 TI - Structural and functional insights into nuclear receptor signaling. AB - Nuclear receptors are important transcriptional factors that share high sequence identity and conserved domains, including a DNA-binding domain (DBD) and a ligand binding domain (LBD). The LBD plays a crucial role in ligand-mediated nuclear receptor activity. Hundreds of different crystal structures of nuclear receptors have revealed a general mechanism for the molecular basis of ligand binding and ligand-mediated regulation of nuclear receptors. Despite the conserved fold of nuclear receptor LBDs, the ligand-binding pocket is the least conserved region among different nuclear receptor LBDs. Structural comparison and analysis show that several features of the pocket, like the size and also the shape, have contributed to the ligand binding affinity and specificity. In addition, the plastic nature of the ligand-binding pockets in many nuclear receptors provides greater flexibility to further accommodate specific ligands with a variety of conformations. Nuclear receptor coactivators usually contain multiple LXXLL motifs that are used to interact with nuclear receptors. The nuclear receptors respond differently to distinct ligands and readily exchange their ligands in different environments. The conformational flexibility of the AF-2 helix allows the nuclear receptor to sense the presence of the bound ligands, either an agonist or an antagonist, and to recruit the coactivators or corepressors that ultimately determine the transcriptional activation or repression of nuclear receptors. PMID- 20723572 TI - Urotensin II alters vascular reactivity in animals subjected to volume overload. AB - Congestive heart failure (CHF) alters vascular reactivity and up regulates in urotensin II (UTII), a potent vasoactive peptide. The aim of this study was to investigate the interaction between CHF and UTII in altering vascular reactivity in a rat model of volume overload heart failure. Animals were divided into 4 groups: control, UTII infused (UTII), volume overload only (VO) or volume overload+UTII (VO+UTII). Volume overload was established by the formation of an aortocaval fistula. Following fistula formation animals were administered UTII at a rate of 300 pmol/kg/h for 4 weeks subcutaneously with mini-osmotic pumps. Thoracic aorta rings, with/without endothelium, were subjected to cumulative dose responses to phenylephrine, sodium nitroprusside (SNP), acetylcholine (ACH), UTII, and the Rho-kinase inhibitor HA-1077. Aortas from VO animals exhibited increased sensitivity to phenylephrine and UTII with a decreased relaxation response to ACH and HA-1077. Aortas from animals subjected to chronic UTII with volume overload (VO + UTII) retained their sensitivity to phenylephrine and UTII while they improved their relaxation to HA-1077 but not ACH. The constrictive response to UTII was dose-dependent and augmented at concentrations <0.01 MUM in VO animals. The changes in vascular reactivity paralleled an elevation of both the UTII and alpha(1A)-adrenergic receptor while the Rho and Rho-kinase signalling proteins were diminished. We found that volume overload increased sensitivity to the vasoconstrictor agents that was inversely related to changes in the Rho-kinase expression. The addition of UTII with VO reversed the constrictive vascular response through alterations in the Rho-kinase signalling pathway. PMID- 20723573 TI - Clarifying carcinogenicity of ethylbenzene. AB - Ethylbenzene has been evaluated for carcinogenic activity in Fischer rats and B6C3F1 mice exposed by inhalation (Chan et al., 1998; Chan, 1999) and in Sprague Dawley rats after oral exposure (Maltoni et al., 1985,1997). Bioassay findings are summarized below to expand on those not stated clearly or completely in Saghir et al. (2010). Overall in these three studies animals exposed to ethylbenzene had increased tumors in rats for kidneys, testes, head (including rare neuroesthesioepitheliomas), and total malignant tumors, whilst in mice tumor incidences were increased in the lung and liver (Huff, 2002). Thus ethylbenzene was carcinogenic by two exposure routes to both sexes of two species of rodents, two strains of rats, and one strain of mice, causing collectively tumors in five different target organs and a composite of "total malignant" tumors. PMID- 20723574 TI - Identification and characterization of a phospholipase A2 from the venom of the Saw-scaled viper: Novel bactericidal and membrane damaging activities. AB - Phospholipase A(2) (PLA(2)), a common toxic component of snake venom, has been implicated in various pharmacological effects. In this study, a basic myotoxic PLA(2), named EcTx-I was isolated from Echis carinatus snake venom by using gel filtration on Superdex G-75, and reverse phase HPLC on C18 and C8 Sepharose columns. PLA(2), EcTx-I was 13,861.72 molecular weight as estimated by MALDI-TOF (15 kD by SDS-PAGE), and consisted of 121 amino acid residues cross-linked by seven disulfide bonds. The N-terminal sequences revealed significant homology with basic myotoxic PLA(2)s from other snake venoms. The purified PLA(2) EcTx-I was evaluated (250 MUg/ml) for bactericidal activity of a wide variety of human pathogens against Burkholderia pseudomallei (KHW&TES), Enterobacter aerogenes, Escherichia coli, Proteus vulgaris, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus. EcTx-I showed strong antibacterial activity against B. pseudomallei (KHW) and E. aerogenes among the tested bacteria. Other Gram negative and Gram-positive bacteria showed only a moderate effect. However, the Gram-positive bacterium E. aerogenes failed to show any effect on EcTx-I protein at tested doses. The most significant bacteriostatic and bactericidal effect of EcTx-I was observed at MICs of >15 MUg/ml against (B. pseudomallei, KHW) and MICs >30 MUg/ml against E. aerogenes. Mechanisms of bactericidal and membrane damaging effects were proved by ultra-structural analysis. EcTx-I was able to induce cytotoxicity on THP-1 cells in vitro as well as lethality in BALB/c mice. EcTx-I also induced mild myotoxic effects on mouse skin, but was devoid of hemolytic effects on human erythrocytes up to 500 MUg/ml. It is shown that the toxic effect induced by E. carinatus venom is due to the presence of myotoxic PLA(2) (EcTx-I). The result also corroborates the hypothesis of an association between toxic and enzymatic domains. In conclusion, EcTx-I displays a heparin binding C-terminal region, which is probably responsible for the cytotoxic and bactericidal effects. PMID- 20723575 TI - The psychology of potential threat: properties of the security motivation system. AB - Results of three experiments support hypothesized properties of the security motivation system, a special motivational system for handling potential threats, as proposed by Szechtman and Woody (2004). First, mild stimuli suggesting potential harm produced a marked state of activation (evident in both objective and subjective measures), consistent with the hypothesis that the security motivation system is finely tuned for the detection of potential threat. Second, in the absence of corrective behavior, this evoked activation is persistent, supporting the hypothesis that once stimulated, the security motivation system produces an enduring motivational state involving the urge to engage in threat reducing behavior. Third, engagement in corrective behavior was effective in returning activation levels to baseline, whereas cognitive reappraisal was not. These findings are consistent with the hypothesis that deactivation of the security motivation system depends on performance of security-related behaviors, rather than non-behavioral events such as cognitive re-evaluation of threat. PMID- 20723576 TI - ERPs on a continuous performance task and self-reported psychopathic traits: P3 and CNV augmentation are associated with Fearless Dominance. AB - Both augmented and reduced P3 amplitude have been associated with psychopathic personality. The Two Process Theory (TPT) suggests that there are two etiologically distinct traits underling psychopathy. One of these traits appears to be related to enhanced attention engagement and reduced anxiety. The other is related to impulsivity, social deviance and poor executive function. P3 is a multi-determined component indexing attention and working memory processes related to executive function. As such, we hypothesized that dissociable relationships would exist between these two dimensions and P3. We recorded P3 and the Contingent Negative Variation (CNV), an ERP response shown to be augmented in psychopaths, during an expectancy AX-continuous performance task from 60 undergraduates. We administered the Psychopathic Personality Inventory (PPI). One factor of the PPI, Fearless Dominance, was related to the dimension of the TPT predicted to reflect relatively better executive function. We found that Fearless Dominance was uniquely associated with P3 augmentation. More negative CNV and faster reaction time were also specifically related to Fearless Dominance. These results illustrate the need to examine the differential relationships between psychopathic traits and P3 amplitude. PMID- 20723577 TI - Information processing in cells and tissues (IPCAT'2009): from small scale dynamics to understanding systems behavior. PMID- 20723578 TI - Inflammatory pathways in endometrial disorders. AB - Complex interactions between the endocrine and immune systems govern the key endometrial events of implantation and menstruation. In contrast to other tissue sites, cyclical endometrial inflammation is physiological. However, dysregulation of this inflammatory response can lead to endometrial disorders. This review examines the inflammatory processes occurring in the normal endometrium during menstruation and implantation, highlighting recent advances in our understanding and gaps in current knowledge. Subsequently, the role of inflammatory pathways in the pathology of various common endometrial conditions is discussed, including heavy menstrual bleeding, dysmenorrhoea (painful periods), uterine fibroids, endometriosis and recurrent miscarriage. PMID- 20723580 TI - Bioengineered glial strands for nerve regeneration. AB - Nerve guide implants approved for human application in the peripheral nervous system generally fail to bridge lesion gaps longer than 2 cm and cannot match the clinical performance of autologous nerve transplants. Since current synthetic implants are simply hollow tubes, we aim to recreate the native microarchitecture of nerves inside the tubular implants. Most importantly, in the regenerating nerve, dedifferentiated Schwann cells align to form thousands of long glial strands, which act as guiding structures for the regrowing axons. In order to artificially induce the formation of Schwann cell strands, 28 MUm thick, endless poly-p-dioxanone filaments (PDO) were synthesized with longitudinal grooves. A polycationic coating on the PDO filaments rendered the polymer surface cell permissive and induced the growth of highly oriented Schwann cells with polarized expression of N-cadherin at cell-cell contact sites. In vitro cell proliferation on three-dimensional PDO filaments was significantly increased in comparison to planar PDO substrates. Time lapse video recordings revealed high Schwann cell motility, which is advantageous for the repopulation of cell-free implants after implantation. In a pilot study we employed a novel microsurgical technique in vivo. All axon fascicles were selectively dissected from sciatic rat nerves, and the remaining epineural tube was filled with hundreds of PDO filaments. Histological analysis 6 weeks postoperatively showed no fibrosis or encapsulation but instead longitudinal cell alignment and axonal regrowth. The data suggest that the addition of microstructured PDO filaments to the lumen of synthetic tubular implants might significantly improve performance. PMID- 20723579 TI - Adenosine regulates Sertoli cell function by activating AMPK. AB - This work evaluates adenosine effects on Sertoli cell functions, which are different to those resulting from occupancy of purinergic receptors. The effects of adenosine and N(6)-cyclohexyladenosine (CHA) - an A(1) receptor agonist resistant to cellular uptake - on Sertoli cell physiology were compared. Adenosine but not CHA increased lactate production, glucose uptake, GLUT1, LDHA and MCT4 mRNA levels, and stabilized ZO-1 protein at the cell membrane. These differential effects suggested a mechanism of action of adenosine that cannot be solely explained by occupancy of type A(1) purinergic receptors. Activation by adenosine but not by CHA of AMPK was observed. AMPK participation in lactate production and ZO-1 stabilization was confirmed by utilizing specific inhibitors. Altogether, these results suggest that activation of AMPK by adenosine promotes lactate offer to germ cells and cooperates in the maintenance of junctional complex integrity, thus contributing to the preservation of an optimum microenvironment for a successful spermatogenesis. PMID- 20723581 TI - Brief naturalistic stress induces an alternative splice variant of SMG-1 lacking exon 63 in peripheral leukocytes. AB - Alternative splicing (AS) not only regulates the gene expression program in response to surrounding environment, but also produces protein isoforms with unique properties under stressful conditions. However, acute psychological stress initiated AS events have not been documented in human studies. After assessments of changes in salivary cortisol levels and anxiety among 28 fourth-grade medical students 7 weeks prior to, 1 day before, immediately after, and 1 week after an examination for promotion, we selected 5 male students, who showed a typical stress response, and screened AS events in their circulating leukocytes using the GeneChip human exon 1.0 ST array. AS events of 27 genes with splicing indices >1.0 could be detected between immediately after and either 7 weeks before, 1 day before, or 1 week after the examination. The examination stress preferentially caused skipping rather than inclusion: 21 out of the 27 pre-mRNAs underwent skipping of exons, and skipping in 3'UTR was observed in 8 genes. Among the candidate genes, real-time reverse transcription PCR validated the stress initiated skipping of exon 63 of SMG-1 that encodes a phosphatidylinositol 3 kinase-related protein kinase crucial for activations of p53-dependent pathways and nonsense-mediated mRNA decay. Our results indicate a significant impact of brief naturalistic stressors on AS-mediated regulation of gene expression in peripheral leukocytes, and suggest the SMG-1 splice variant as a potential biomarker for acute psychological stress. PMID- 20723582 TI - Increased alphaB-crystallin in hypothalamic paraventricular nucleus of rats with myocardial infarction. AB - The hypothalamus plays an important role in maintaining a homeostasis of the body against stress response. In particular, the paraventricular nucleus of the hypothalamus is a critical region for disorders related to the autonomic nervous system, such as congestive heart failure and hypertension. alphaB-crystallin is a family of heat shock proteins that are widely expressed in the brain, including in glial cells, astrocytes, oligodendrocytes, and neurons. Many studies have demonstrated that expression level of alphaB-crystallin is up-regulated and involved in protecting cells from pathological conditions. In the present study, we examined the expression and potential role of alphaB-crystallin in the paraventricular nucleus (PVN) regions of rats with myocardial infarction (MI). Our results demonstrate that mRNA encoding alphaB-crystallin and protein for both native and phosphorylate forms (Ser-59) of alphaB-crystallin was significantly increased in the PVN during MI. PMID- 20723583 TI - Side of symptom onset affects motor dysfunction in Parkinson's disease. AB - The healthy brain appears to have an asymmetric dopamine distribution, with higher levels of dopamine in the left than in the right striatum. Here, we test the hypothesis that this neurochemical asymmetry renders the right striatum relatively more vulnerable to the effects of dopaminergic denervation in Parkinson's disease (PD). Using the pegboard dexterity test, we compared motor performance of both hands between healthy subjects (n=48), PD patients with predominantly right-hemispheric dopamine depletion (PD-RIGHT; n=83) and PD patients with more severe left-hemispheric dopamine depletion (PD-LEFT; n=103). All subjects were right-handed. After adjusting for hand-dominance effects, we found that PD-RIGHT patients exhibited a 55% larger difference between right and left dexterity scores than PD-LEFT patients. This effect could be attributed to greater motor dysfunction of the more-affected hand in PD-RIGHT patients, while the less-affected hand performed similarly in both groups. We conclude that the side of symptom onset affects motor dysfunction in PD, and suggest that the non dominant right hemisphere may be more susceptible to dopaminergic denervation than the dominant left hemisphere. PMID- 20723584 TI - SCAR markers: a potential tool for authentication of herbal drugs. AB - Randomly Amplified Polymorphic DNA (RAPD) is easy to develop and simple molecular marker, but lack of reproducibility makes it less reliable for authentication of herbal drugs. Besides RAPD, other popular PCR and non-PCR based markers like AFLP, ISSR, SSR and RFLP are also used for authentication. However, these also have disadvantages like use of radioactive isotopes, high cost and absolute requirement of sequence information. Therefore, it is a better option to improve the reproducibility of RAPD by converting RAPD amplicons into Sequence Characterized Amplified Region (SCAR) markers. SCAR markers are easy, reliable and reproducible thus, have an advantage over RAPD markers for authentication of medicinal herbs used in the preparation of traditional medicines. These markers however, have been developed for only a few medicinal herbs. This review is an attempt to evaluate critically the role of SCAR markers in authentication of medicinal herbs used in traditional formulations. PMID- 20723585 TI - Two new chamigrane metabolites from fermentation broth of Steccherinum ochraceum. AB - Two new chamigrane-type metabolites named steperoxides C (1) and D (2) were isolated from the basidiomycetes Steccherinum ochraceum. The structures of 1 and 2 were established on the basis of spectral methods (MS, IR, ID and 2D NMR experiments). Compounds 2 showed significant antimicrobial activity against Staphylococcus aureus at 10 and 5 MUg/disk. PMID- 20723586 TI - Introduction to the special issue of behavioral processes in honor of Donald A. Riley. PMID- 20723587 TI - Oxidative damage to biological macromolecules in Prague bus drivers and garagemen: impact of air pollution and genetic polymorphisms. AB - DNA integrity was investigated in the lymphocytes of 50 bus drivers, 20 garagemen and 50 controls using the comet assay with excision repair enzymes. In parallel, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 15-F(2t)-isoprostane levels in the urine and protein carbonyl levels in the plasma were assessed as markers of oxidative damage to DNA, lipids and proteins. Exposure to carcinogenic polycyclic aromatic hydrocarbons (cPAHs) and volatile compounds was measured by personal samplers for 48 and 24h, respectively, before the collection of biological specimens. Both exposed groups exhibited a higher levels of DNA instability and oxidative damage to biological macromolecules than the controls. The incidence of oxidized lesions in lymphocyte DNA, but not the urinary levels of 8-oxodG, correlated with exposure to benzene and triglycerides increased this damage. Oxidative damage to lipids and proteins was associated with exposure to cPAHs and the lipid peroxidation levels positively correlated with age and LDL cholesterol, and negatively with vitamin C. The carriers of at least one variant hOGG1 (Cys) allele tended to higher oxidative damage to lymphocyte DNA than those with the wild genotype, while XPD23 (Gln/Gln) homozygotes were more susceptible to the induction of DNA strand breaks. In contrast, GSTM1 null variant seemed to protect DNA integrity. PMID- 20723588 TI - The protective effect of tetramethylpyrazine on cartilage explants and chondrocytes. AB - AIMS OF STUDY: Ligusticum wallichi Franchat (chuanxiong) is a very common traditional Chinese herbal medicine in China. Tetramethylpyrazine (TMP) is a major active ingredient extracted from Ligusticum wallichi Franchat. We investigated the protective effect of TMP on interleukin-1beta (IL-1beta) induced proteoglycan (PG) degradation and apoptosis in rabbit articular cartilage and chondrocytes. MATERIALS AND METHODS: Rabbit articular cartilage explants and chondrocytes were cultured with 10 ng/ml IL-1beta for 72 h in the absence or presence of various concentrations of TMP (50, 100 or 200 MUM). Cartilage and chondroprotective effects of TMP were determined by evaluating (1) the degree of PG degradation by measuring the amount of glycosaminoglycan (GAG) released into the culture media with 1,9-dimethylmethylene blue (DMMB) assay in cartilage explants; (2) gene expression of MMP-3 and TIMP-1 by real-time quantitative reverse transcription-polymerase chain reaction analysis in cartilage explants; (3) chondrocytes viability with MTT assay; (4) the production of intracellular reactive oxygen species (ROS) with laser scanning confocal microscopy (LSCM). Anti-apoptotic effects of TMP were determined by measuring (1) apoptosis with flow cytometric analysis; (2) mitochondrial membrane potential assay with LSCM; (3) caspase-3 activity with special assay kit. RESULTS: IL-1beta treatment increased the level of GAG released into the culture media, and induced the gene expression of MMP-3 and inhibited the gene expression of TIMP-1 in cartilage explants. Moreover, IL-1beta treatment decreased the cell viability and mitochondrial membrane potential, and enhanced the level of intracellular ROS, apoptosis rate, and caspase-3 activity in chondrocytes. However, simultaneous treatment with TMP attenuated the IL-1beta-induced cartilage and chondrocyte destruction in a dose-dependent manner. TMP showed the decrease of GAG degradation and MMP-3 mRNA production, and the enhancement of TIMP-1 mRNA production in cartilage explants. TMP also increased the cell viability in chondrocytes. Furthermore, TMP inhibited the chondrocytes apoptosis through suppression of ROS production, maintaining of mitochondrial membrane potential and downregulation of caspase-3 activity. CONCLUSION: These results demonstrate that TMP has the cartilage and chondroprotective effect, which suggest that TMP could act as an agent for pharmacological intervention in the progress of OA. PMID- 20723589 TI - The effect of Tulbaghia violacea extracts on testosterone secretion by testicular cell cultures. AB - AIM OF THE STUDY: This study aimed to determine the effect of Tulbaghia violacea Harv. on the male reproductive system in vitro by using testicular cell cultures. Tulbaghia violacea is a plant species indigenous to southern Africa and is used locally as a herbal remedy/medicine to treat several ailments. MATERIALS AND METHODS: A 50% ethanol extract of Tulbaghia violacea was prepared. Three-month old male Balb/C mice were sacrificed and testicular cell cultures were prepared. Cells were then treated with varying concentrations of the Tulbaghia violacea ethanol extract (with/without Luteinizing hormone (LH)-treatment) and incubated for 4 h. Hormone production and cell viability were evaluated. RESULTS: Treatment of cells with Tulbaghia violacea (312.5-5000 MUg ml(-1)) significantly increased (P<0.05) LH-induced testosterone production as compared to vehicle-treated control (DMSO) whereas cells without LH-treatment showed no significant change in testosterone concentrations. No significant effect on cell viability was observed at all concentrations tested. CONCLUSIONS: The data presented shows that Tulbaghia violacea has androgenic properties. Further studies are warranted to determine and clarify the exact mechanisms involved. PMID- 20723590 TI - Inhibitory effects of 1-O-methyl-fructofuranose from Schisandra chinensis fruit on melanogenesis in B16F0 melanoma cells. AB - AIM OF THE STUDY: 1-O-methyl-fructofuranose (1-O-MFF) from the fruit of Schisandra chinensis is a traditional Korean medicinal herb that has a variety of beneficial properties. The effect of purified 1-O-MFF on melanogenesis including the activation of related signaling pathways was investigated. MATERIALS AND METHODS: The inhibitory activities of 1-O-MFF were examined by melanin synthesis, tyrosinase activity assay, Western blot and flow cytometric analyses in B16F0 mouse melanoma cells. RESULTS: 1-O-MFF significantly inhibited both melanin synthesis and tyrosinase activity in a concentration-dependent manner, and reduced the expression of melanogenic proteins including microphthalmia associated transcription factor (MITF), tyrosinase and tyrosinase-related protein 1. 1-O-MFF phosphorylated and activated melanogenesis inhibitory proteins such as mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and Akt. Flow cytometry confirmed that 1-O-MFF phosphorylated ERK and Akt proteins and recovered partially phosphorylated forms in cells treated with the MEK/ERK inhibitor compound PD98059 and the phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor compound LY294002. CONCLUSIONS: The suppressive effects of 1 O-MFF on melanogenesis may involve down-regulation of MITF and its downstream signal pathway via the activation of MEK/ERK or PI3K/Akt. PMID- 20723591 TI - The expression of erythropoietin triggered by danggui buxue tang, a Chinese herbal decoction prepared from radix Astragali and radix Angelicae Sinensis, is mediated by the hypoxia-inducible factor in cultured HEK293T cells. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Danggui buxue tang (DBT), a Chinese medicinal decoction that is being commonly used as hematopoietic medicine to treating woman menopausal irregularity, contains two herbs: radix Astragali and radix Angelicae Sinensis. Pharmacological results indicate that DBT can stimulate the production of erythropoietin (EPO), a specific hematopoietic growth factor, in cultured cells. AIM OF THE STUDY: In order to reveal the mechanism of DBT's hematopoietic function, this study investigated the activity of the DBT-induced EPO expression and the upstream regulatory cascade of EPO via hypoxia-induced signaling in cultured kidney fibroblasts (HEK293T). MATERIALS AND METHODS: DBT-induced mRNA expressions were revealed by real-time PCR, while the change of protein expressions were analyzed by Western blotting. For the analysis of hypoxia dependent signaling, a luciferase reporter was used to report the transcriptional activity of hypoxia response element (HRE). RESULTS: The plasmid containing HRE, being transfected into HEK293T, was highly responsive to the challenge of DBT application. To account for the transcriptional activation of HRE, DBT treatment was shown to increase the mRNA and protein expressions of hypoxia-inducible factor-1alpha (HIF-1alpha). In addition, the activation of Raf/MEK/ERK signaling pathway by DBT could also enhance the translation of HIF-1alpha, suggesting the dual actions of DBT in stimulating the EPO expression in kidney cells. CONCLUSION: Our study indicates that HIF pathway plays an essential role in directing DBT-induced EPO expression in kidney. These results provide one of the molecular mechanisms of this ancient herbal decoction for its hematopoietic function. PMID- 20723592 TI - Anti-angiogenic effects of the fruit of Alpinia oxyphylla. AB - AIM OF STUDY: The fruit of Alpinia oxyphylla, an herb commonly used in East Asian medicine, is variously used for the treatment of cancer and inflammatory conditions, which may possibly be mediated through anti-angiogenesis. This study aims to check for anti-angiogenic functions in the herb. MATERIALS AND METHODS: The 95% ethanol extract and four subsequent fractions (n-hexane, ethyl acetate, n butanol and aqueous fractions) of the fruit of A. oxyphylla were tested on zebrafish model by quantitative endogenous alkaline phosphatase assay; then the active fractions were further tested on wild type and Tg(fli1a:EGFP)y1 zebrafish embryos and human umbilical vein endothelial cells and tumor cell lines for the anti-angiogenic effects. RESULTS: The n-hexane and ethyl acetate fractions showed anti-angiogenic potentials in both in vivo and in vitro models. CONCLUSIONS: The use of A. oxyphylla for cancer and inflammation diseases may be partly due to its effects against vessel formation. PMID- 20723593 TI - Liu wei di huang wan, a well-known traditional Chinese medicine, induces CYP1A2 while suppressing CYP2A6 and N-acetyltransferase 2 activities in man. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Liu wei di huang wan (LDW), a well-known traditional Chinese medicine, is frequently combined with other prescription or non-prescription drugs in China. AIM OF THE STUDY: This study was designed to investigate the effects of LDW on the activities of CYP1A2, CYP2A6, N acetyltransferase 2 (NAT2) and xanthine oxidase (XO) in healthy subjects, using caffeine as a probe drug. MATERIALS AND METHODS: Twelve unrelated healthy males were enrolled in a single-blind, randomized, placebo-controlled, two-phase crossover study. Placebo or LDW (12 pills, 0.2 g/pill, twice daily) was given to each participant for 14 continuous days with a wash-out period of 2 weeks. A dose of 100 mg caffeine was given afterwards to test the activities of drug metabolizing enzymes of interest. RESULTS: Compared to placebo, LDW significantly induced the CYP1A2 activity, as determined by an increase in the ratio of (AFMU+1U+1X)/17U and the formation of 17X and 1X after taking caffeine. Interestingly, LDW significantly decreased the ratio of 17U/(17U+17X+1X+1U+AFMU) and the formation of 17U (CYP2A6-mediated) (by 39.2%; 95%CI: 23.1-55.3%; P=0.026), and decreased the ratio of AFMU/(AFMU+1U+1X) and the formation of AFMU (NAT2-catalyzed) (by 26.2%; 95%CI: 9.2-61.6%; P=0.038), suggesting a marked inhibition of CYP2A6 and NAT2, respectively. CONCLUSIONS: LDW can induce CYP1A2 and suppress CYP2A6 and NAT2 activities, and affect caffeine metabolism in vivo. PMID- 20723594 TI - Mechanisms of the relaxant effect of a danshen and gegen formulation on rat isolated cerebral basilar artery. AB - AIM OF THE STUDY: Danshen (root of Salvia miltiorrhiza) and gegen (root of Pueraria lobata) are two herbs used in traditional Chinese medicine, most commonly for their putative cardioprotective and anti-atherosclerotic effects. In this study, the actions of a danshen and gegen formulation (DG; ratio 7:3) were investigated on rat-isolated cerebral basilar artery. MATERIALS AND METHODS: Rat basilar artery rings were precontracted with 100 nM U46619. Involvement of endothelium-dependent mechanisms was investigated by mechanical removal of the endothelium; K(+) channels were investigated by pretreatment of the artery rings with various K(+) channel inhibitors, and Ca(2+) channels were investigated in artery rings incubated with Ca(2+)-free buffer and primed with 100 nM U46619 for 5 min prior to adding CaCl(2) to elicit contraction. RESULTS: DG produced concentration-dependent relaxation of the artery rings with an IC(50) of 895+/ 121 MUg/ml. Mechanical removal of the endothelium or pretreatment with the BK(Ca) channel inhibitor iberiotoxin (100 nM), the K(V) channel inhibitor 4 aminopyridine (1 mM), or the K(IR) channel inhibitor barium chloride (100 MUM), all had no effect on the DG-induced response (P>0.05 for all). However, pretreatment with the K(ATP) channel inhibitor glibenclamide (1 MUM), the non selective K(+) channel inhibitor tetraethylammonium (TEA, 100 mM), or a combination of all the K(+) channel inhibitors (iberiotoxin+4 aminopyrindine+barium chloride+glibenclamide+TEA) produced significant inhibition on the DG-induced response (P<0.01 for all); its maximum vasorelaxant effect (Imax) was reduced by 37, 24, and 30%, respectively. Preincubation of the artery rings with DG for 10 min produced concentration-dependent (1, 3 and 7 mg/ml) and total inhibition on the CaCl(2)-induced vasoconstriction. CONCLUSIONS: These findings suggest the vasorelaxant effect of DG on rat basilar artery is independent of endothelium-derived mediators, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important, and a minor component is mediated by the opening of K(ATP) channels. DG could be a useful cerebroprotective agent in some patients with occlusive cerebrovascular disease. PMID- 20723595 TI - Effects of dahuangzhechong pills on cytokines and mitogen activated protein kinase activation in rats with hepatic fibrosis. AB - RELEVANCE TO ETHNOPHARMACOLOGY: Dahuangzhechong pill (DHZCP), a well-known and canonical Chinese medicine formula from "The Synopsis of Prescriptions of the Golden Chamber", is officially approved and recommended by Chinese association of integrative medicine for the prevention and treatment of hepatic fibrosis in China. AIM OF THE STUDY: To test the hypothesis that therapeutic effects of DHZCP on hepatic fibrosis are conferred by regulating cytokine profile through a mitogen activated protein kinase (MAPK) pathway. MATERIALS AND METHODS: Hepatic fibrosis is inducted by carbon tetrachloride (CCl(4)) in rats which then were randomly divided into six groups: hepatic fibrosis model group, high dose DHZCP group, low dose DHZCP group, Fufang Biejia Ruangan Pian (FBRP) group, Colchicine group and control group. Pathological, immunohistochemical, multiplex immunoassay and protein expression studies (Western blotting) are performed. RESULTS: DHZCP significantly decreases the levels of alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, laminin, type IV collagen and procollagen III, and reverses hepatic fibrosis in rat model. DHZCP also could reduce the expression of alpha-smooth muscle actin, and lower the serum level of tumor necrosis factor alpha (TNF-alpha) and interleukin 13 (IL-13). The expressions of phosphorylated p38 MAPK and extracellular signal-regulated kinase (ERK) are down regulated, while no significant changes are found in phosphorylation of c-Jun N terminal kinase (JNK). CONCLUSIONS: DHZCP can alleviate hepatic fibrosis induced by CCl(4). The anti-fibrotic effects of DHZCP are conferred by decreasing the secretion of TNF-alpha and IL-13 through down-regulating p38 and ERK phosphorylation. PMID- 20723596 TI - Ethnobotanical study on some Malaysian anti-malarial plants: a community based survey. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Various plants species are used in the traditional medicine for the treatment of malaria. This is the first community based ethnobotanical study in Peninsular Malaysia. AIM OF THE STUDY: To investigate the plants traditionally used in the treatment of malaria in Malaysia. MATERIALS AND METHODS: An ethnobotanical survey was carried out among 233 Aboriginal and rural households, and traditional healers in malaria endemic areas in Peninsular Malaysia. Data were collected using a pre-tested questionnaire. RESULTS: Nineteen species belonging to 17 families were identified. Twelve plant species have not previously been documented for the treatment of malaria in Malaysia. CONCLUSIONS: Findings of this study can be used as an ethnopharmacological basis for selecting plants for further anti-malarial phytochemical and pharmaceutical studies. PMID- 20723597 TI - Application of a combined sulphorhodamine B and melanin assay to the evaluation of Chinese medicines and their constituent compounds for hyperpigmentation treatment. AB - AIM OF THE STUDY: To investigate the efficacy of traditional Chinese medicine (TCM) in the treatment of hyperpigmentation problems, extracts of herbs selected based on traditional Chinese medical literature were screened. MATERIALS AND METHODS: Forty extracts were extracted from 10 selected herbs using hexane, dichloromethane, methanol and water. They were then screened using melan-a cells, an immortalized non-tumorigenic mouse melanocyte cell line. Sulphorhodamine B (SRB) assay and measurement of melanin production were performed to examine the effects of the extracts as well as some natural compounds from these herbs on melanogenesis in the melan-a cells. RESULTS: The hexane and dichloromethane extracts of Angelica sinensis exhibited strong hypopigmentary effects. CONCLUSIONS: Natural compounds occurring in this herb were also investigated. Among them 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol demonstrated positive effects in attenuating melanin synthesis in the cultured cells. PMID- 20723598 TI - Hydrophobic constituents and their potential anticancer activities from Devil's Club (Oplopanax horridus Miq.). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Devil's Club (Oplopanax horridus) is one of the most important spiritual and medicinal plants to many indigenous peoples of Alaska and the Pacific Northwest. It is widely used for external and internal infections as well as arthritis, respiratory ailments, digestive tract ailments, broken bones, fever, headaches, and cancer. AIM OF THE STUDY: To investigate hydrophobic constituents and their potential anticancer activity from Devil's Club, Oplopanax horridus. MATERIALS AND METHODS: The root bark extract of Oplopanax horridus was isolated by chromatographic techniques. Structures of isolated compounds were identified by spectroscopic methods and comparison with published data. The anti-proliferation of isolated hydrophobic constituents in human breast cancer MCF-7 cells, human colon cancer SW-480 and HCT-116 cells were tested. The potential mechanism of anti-proliferation was also investigated using cell cycle and apoptosis assays. RESULTS AND DISCUSSION: Six compounds were isolated and structurally identified as 9,17-octadecadiene-12,14-diyne-1,11,16 triol, 1-acetate (1), oplopandiol acetate (2), falcarindiol (3), oplopandiol (4), trans-nerolidol (5) and t-cadinol (6). These compounds showed potential anticancer activities on human breast cancer and colon cancer cells, of which compound 3 possesses the strongest activity. Further cell cycle and apoptosis tests by flow cytometry showed the polyacetylenes 1-4 induced HCT-116 cell arresting in G2/M phase and inhibited proliferation by the induction of apoptosis at both earlier and later stages. CONCLUSION: These results provide promising baseline information for the potential use of Oplopanax horridus, as well as some of the isolated compounds in the treatment of cancer. PMID- 20723600 TI - New hypotheses on the pathways of formation of malondialdehyde and isofurans. AB - Malondialdehyde (MDA) is a mutagenic compound that has been widely used as a biomarker of oxidative stress. However, the nonenzymatic mechanisms of its formation are not well understood. Some lipid oxidation products were previously suggested to be MDA precursors and found to afford MDA heterolytically under acidic conditions. We predict that some of these compounds are not important MDA sources under the autoxidative conditions under which the bulk of MDA should be formed in vivo and that others require further oxidative modifications to generate MDA homolytically. Thus, we outline the likely important pathways of MDA formation in vivo. All these pathways are intense aldehyde producers, generating two other aldehydic products for every MDA molecule formed. Some of the predicted aldehydes are new and may merit further analytical and biological studies. Peracids derived from the aldehydes are proposed to participate in the formation of isofurans (which at high oxygen tensions are excellent markers of oxidative stress) as well as important bioactive epoxides such as leukotoxins. This generates interest in the biological relevance of lipid aldehyde-derived peracids. The suitability of tissue MDA determination methods is discussed based on their likelihood of involving acid-catalyzed artifactual MDA formation. PMID- 20723599 TI - IL-10 within the CNS is necessary for CD4+ T cells to mediate neuroprotection. AB - We have previously shown that immunodeficient mice exhibit significant facial motoneuron (FMN) loss compared to wild-type (WT) mice after a facial nerve axotomy. Interleukin-10 (IL-10) is known as a regulatory cytokine that plays an important role in maintaining the anti-inflammatory environment within the central nervous system (CNS). IL-10 is produced by a number of different cells, including Th2 cells, and may exert an anti-apoptotic action on neurons directly. In the present study, the role of IL-10 in mediating neuroprotection following facial nerve axotomy in Rag-2- and IL-10-deficient mice was investigated. Results indicate that IL-10 is neuroprotective, but CD4+ T cells are not the requisite source of IL-10. In addition, using real-time PCR analysis of laser microdissected brainstem sections, results show that IL-10 mRNA is constitutively expressed in the facial nucleus and that a transient, significant reduction of IL 10 mRNA occurs following axotomy under immunodeficient conditions. Dual labeling immunofluorescence data show, unexpectedly, that the IL-10 receptor (IL-10R) is constitutively expressed by facial motoneurons, but is selectively induced in astrocytes within the facial nucleus after axotomy. Thus, a non-CD4+ T cell source of IL-10 is necessary for modulating both glial and neuronal events that mediate neuroprotection of injured motoneurons, but only with the cooperation of CD4+ T cells, providing an avenue of novel investigation into therapeutic approaches to prevent or reverse motoneuron diseases, such as amyotrophic lateral sclerosis (ALS). PMID- 20723601 TI - Vitamin D(3) metabolites induce osteogenic differentiation in human dental pulp and human dental follicle cells. AB - Vitamin D(3) metabolites regulate the bone metabolism and 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to play an important role in teeth mineralization. However, little is known about the potential of vitamin D as an osteogenic inducer in human dental pulp (hDPCs) and dental follicle cells (hDFCs) in vitro. Therefore, we investigated the effects of vitamin D(3) metabolites 1alpha,25(OH)(2)D(3) and 25-hydroxyvitamin D(3) (25OHD(3)) on proliferation and osteogenic differentiation of hDPCs and hDFCs in vitro. We also examined whether vitamin D(3) metabolic enzymes were regulated in hDFCs and hDPCs. Cell proliferation was decreased by both metabolites in hDPCs and hDFCs. Vitamin D(3) metabolites increased ALP activity and induced mineralization when osteogenic supplements (OS; l-ascorbic acid-2-phosphate+beta-glycerophosphate) were added, though the expression of osteocalcin (OC) and osteopontin (OPN) were regulated without the addition of OS. CYP24 and CYP27B1 expressions were upregulated by vitamin D(3) metabolites and 25OHD(3) was converted into 1alpha,25(OH)(2)D(3) in the culture medium. These results confirm that 1alpha,25(OH)(2)D(3) (10 and 100 nM) and 25OHD(3) (500 nM) can be used as osteogenic inducers synergistically with osteogenic supplements for differentiation of hDPCs and hDFCs. Furthermore, our findings strengthen our knowledge about the role of hDPCs and hDFCs as vitamin D(3) target cells. PMID- 20723602 TI - In situ detection of microRNAs in paraffin embedded, formalin fixed tissues and the co-localization of their putative targets. AB - This manuscript details a protocol for the co-localization of a microRNA and its putative protein target in paraffin embedded formalin fixed tissues. The key variables for the first step, microRNA in situ hybridization, includes probe concentration (1-2 pmol/MUl), locked nucleic acid (LNA) modified probes, protease digestion (pepsin 1.3mg/ml), and a low stringency wash. Key variables for the subsequent immunohistochemical step are the concentration of the primary antibody, proper pretreatment (none, proteinase K, or antigen retrieval), and use of a highly sensitive detection system. A computer based system can convert the colorimetric signals (blue chromogen (NBT/BCIP) for the microRNA, and either a red (fast red) or brown (DAB) chromogen for the protein) to distinct fluorescent based colors, and then mix them to determine if a given cell has the microRNA and protein of interest. Co-expression of a microRNA and its putative target in tissue sections offers physiologic corroboration of solution-based methods that a given microRNA may be regulating a specific protein. PMID- 20723603 TI - Reprint of: Atmospheric scanning electron microscope observes cells and tissues in open medium through silicon nitride film. AB - Direct observation of subcellular structures and their characterization is essential for understanding their physiological functions. To observe them in open environment, we have developed an inverted scanning electron microscope with a detachable, open-culture dish, capable of 8 nm resolution, and combined with a fluorescence microscope quasi-simultaneously observing the same area from the top. For scanning electron microscopy from the bottom, a silicon nitride film window in the base of the dish maintains a vacuum between electron gun and open sample dish while allowing electrons to pass through. Electrons are backscattered from the sample and captured by a detector under the dish. Cells cultured on the open dish can be externally manipulated under optical microscopy, fixed, and observed using scanning electron microscopy. Once fine structures have been revealed by scanning electron microscopy, their component proteins may be identified by comparison with separately prepared fluorescence-labeled optical microscopic images of the candidate proteins, with their heavy-metal-labeled or stained ASEM images. Furthermore, cell nuclei in a tissue block stained with platinum-blue were successfully observed without thin-sectioning, which suggests the applicability of this inverted scanning electron microscope to cancer diagnosis. This microscope visualizes mesoscopic-scale structures, and is also applicable to non-bioscience fields including polymer chemistry. PMID- 20723604 TI - Diversity of teleost leukocyte molecules: role of alternative splicing. AB - Alternative splicing is an important mechanism of gene expression control that also produces a large proteome from a limited number of genes. In the immune system of mammals, numerous relevant genes have been found to undergo alternative splicing that contributes to the complexity of immune response. An increasing number of reports have recently indicated that alternative splicing also occurs in other vertebrates, such as fish. In this review we summarize the general features of such molecular events in cytokines and leukocyte co-receptors and their contribution to diversity and regulation of fish leukocytes. PMID- 20723605 TI - Similarities and differences in perceiving threat from dynamic faces and bodies. An fMRI study. AB - Neuroscientific research on the perception of emotional signals has mainly focused on how the brain processes threat signals from photographs of facial expressions. Much less is known about body postures or about the processing of dynamic images. We undertook a systematic comparison of the neurofunctional network dedicated to processing facial and bodily expressions. Two functional magnetic resonance imaging (fMRI) experiments investigated whether areas involved in processing social signals are activated differently by threatening signals (fear and anger) from facial or bodily expressions. The amygdala (AMG) was more active for facial than for bodily expressions. Body stimuli triggered higher activation than face stimuli in a number of areas. These were the cuneus, fusiform gyrus (FG), extrastriate body area (EBA), temporoparietal junction (TPJ), superior parietal lobule (SPL), primary somatosensory cortex (SI), as well as the thalamus. Emotion-specific effects were found in TPJ and FG for bodies and faces alike. EBA and superior temporal sulcus (STS) were more activated by threatening bodies. PMID- 20723606 TI - Elucidating the evolutionary history of the Southeast Asian, holoparasitic, giant flowered Rafflesiaceae: pliocene vicariance, morphological convergence and character displacement. AB - The aim of the present study is to elucidate the evolutionary history of the enigmatic holoparasitic Rafflesiaceae. More specifically, floral morphological evolution is interpreted in a molecular phylogenetic context, the biogeographic history of the family is investigated, and the possibility of character displacement to have been operating in this family is assessed. Parsimony and Bayesian methods are used to estimate phylogeny and divergence times among Rafflesiaceae species based on nuclear and mitochondrial DNA sequence data from Barkman et al. (2008) as well as new sequence data from additional samples and an additional genetic marker, the plastid 16S. Ancestral areas are inferred using dispersal-vicariance analysis (DIVA) as well a more recently developed parametric likelihood method (LAGRANGE), now including an update that allows for estimation over the posterior distribution of dated trees. Our extended molecular phylogeny of Rafflesiaceae implies a general lack of morphological synapomorphies as well as a high level of morphological homoplasy. In particular, a high level of floral morphological homoplasy is detected among Rafflesia species suggestive of similar patterns of pollinator-based selection in different geographic areas, and multiple instances of divergent floral size evolution is consistent with a model of character displacement. Initial diversification of Rafflesiaceae during the Late Cretaceous was followed by a long period of no-net diversification, likely due to extinctions caused by a Late Eocene to Miocene dramatic reduction in rainforest cover. A Late Miocene to Early Pliocene rise in sea-level probably caused the vicariant diversification observed between areas of endemism. The most recent species divergences are concordant with Pleistocene changes in climate and sea-levels, but apparently with no successful inter-area migrations, supportive of savannah, rather than rainforest, covered landbridges. An explosive increase in net diversification rate, most pronounced in Rafflesia, may be explained by Mid-Miocene to Pliocene rainforest-favorable conditions as well as natural selection promoting character displacement for Rafflesia flower size. PMID- 20723607 TI - Inferring the demographic history of the Adriatic Flexopecten complex. AB - Phylogenetic analysis of DNA sequences can be a useful tool in taxonomical studies, which has important implications in terms of species traceability. The aim of our study is to solve the controversy regarding the taxonomical status of the Flexopecten group, which includes two putative sister species (F. glaber and F. proteus) that co-occur in the Adriatic Sea and are clearly distinguishable on the basis of morphometric characters. Our molecular analysis using three mitochondrial genes (COI, 12S rRNA and 16S rRNA) and one nuclear gene (Histone H3) suggest that F. glaber and F. proteus are the same species, as evidenced by both putative species appearing mixed in all genetic trees with no clustering according to species. Using a Bayesian approach, we inferred the demographic history of the Flexopecten group, which suggests that first F. glaber occurred in the Mediterranean, then F. glaber colonized the Adriatic sometime in the last 18,000 years, and finally the F. proteus morph appeared only recently in the Adriatic Sea. We propose F. proteus to be synonymized with F. glaber, which should have priority and be used in the future. PMID- 20723608 TI - Domestication of olive fly through a multi-regional host shift to cultivated olives: comparative dating using complete mitochondrial genomes. AB - The evolutionary history of the olive fly, Bactrocera oleae, was reconstructed in a phylogenetic and coalescent framework using full mitochondrial genome data from 21 individuals covering the entire worldwide distribution of the species. Special attention was given to reconstructing the timing of the processes under study. The early subdivision of the olive fly reflects the Quaternary differentiation between Olea europea subsp. europea in the Mediterranean area and the two lineages of Olea europea subsp. cuspidata in Africa and Asia, pointing to an early and close association between the olive fly and its host. The geographic structure and timing of olive fly differentiation in the Mediterranean indicates a clear connection with the post-glacial recolonization of wild olives in the area, and is irreconcilable with the early historical process of domestication and spread of the cultivated olive from its Levantine origin. Therefore, we suggest an early co-history of the olive fly with its wild host during the Quaternary and post-glacial periods and a multi-regional shift of olive flies to cultivated olives as these cultivars gradually replaced wild olives in historical times. PMID- 20723609 TI - Diversification in species complexes: tests of species origin and delimitation in the Bursera simaruba clade of tropical trees (Burseraceae). AB - Molecular phylogenies are invaluable for testing morphology-based species delimitation in species complexes, as well as for examining hypotheses regarding the origination of species in these groups. Using five nucleotide markers, we reconstructed the phylogeny of the Bursera simaruba species complex of neotropical trees to test the notion that four "satellite" species originated from populations of the most widely distributed member of the genus, B. simaruba, which the satellites strongly resemble. In addition to molecular phylogenetic reconstruction, we tested species delimitation of B. simaruba and the satellites using multivariate analyses of morphological and ecological characters. The analyses evaluated the taxonomic value of these traditional characters and pinpointed those in need of further study, such as the expression of pubescence. Phylogenetic data rejected the origin of three satellite species from their purported ancestor, B. simaruba, and we ascribe their morphological similarity to convergence or parallelism. The fourth satellite species likely represents one end of a spectrum of inflorescence length variation within B. simaruba and is conspecific. Despite its marked morphological variability, we recovered B. simaruba as a single valid species, which implies that it maintains genetic cohesion among distant populations throughout its vast range. PMID- 20723610 TI - Geographic and phylogenetic patterns in Silene section Melandrium (Caryophyllaceae) as inferred from chloroplast and nuclear DNA sequences. AB - The phylogenetic relationships between the five dioecious species in Silene section Melandrium (Caryophyllaceae) and their putative hermaphrodite relatives are investigated based on an extensive geographic and taxonomic sample, using DNA sequence data from the chloroplast genome and the nuclear ribosomal ITS region. The hermaphrodite S. noctiflora (the type species of section Elisanthe) is distantly related to the dioecious species. With the exception of chloroplast sequences in one S. latifolia population from Turkey, the dioecious taxa form a strongly supported monophyletic group (Silene section Melandrium). The phylogenetic structure within section Melandrium differs between chloroplast and nuclear sequences. While there is extensive sharing of chloroplast haplotypes among all the dioecious species (the observed patterns reflect geographic structure), the nuclear ITS phylogeny shows a higher degree of taxonomic structure. Chloroplast-sharing by the section Melandrium species is most plausibly explained by a history of hybridization and extensive backcrossing. PMID- 20723611 TI - Molecular phylogenetic analysis of an endangered Mexican sparrow: Spizella wortheni. AB - The Worthen's Sparrow (Spizella wortheni) is an endemic bird species of the Mexican Plateau that is protected by Mexican law. Considering its limited range (25 km(2)), small population size (100-120 individuals), and declining population, it is one of the most endangered avian species in North America. Although it has been assumed to be the sister taxon of the Field Sparrow (Spizella pusilla), the systematic and evolutionary relationships of Worthen's Sparrow have never been tested using modern molecular phylogenetic methods. We addressed the molecular phylogeny of S. wortheni analyzing six mitochondrial genes (3571 bp) from all of the natural members of the genus Spizella. Our maximum likelihood and Bayeasian analysis indicate that despite the superficial similarity, S. wortheni is not the sister taxon of S. pusilla, but is instead most closely related to the Brewer's Sparrow (Spizella breweri). Also new insights about the phylogenetics relationships of the Spizella genera are presented. PMID- 20723612 TI - Hypertrophic differentiation and calcification during intervertebral disc degeneration. AB - BACKGROUND: In degenerative intervertebral discs (IVDs) collagen type X expression and calcifications have been demonstrated, resembling advanced osteoarthritis (OA), which is associated with hypertrophic differentiation, characterized by the production of collagen type X, Runt-related transcription factor 2 (Runx2), osteoprotegerin (OPG), alkaline phosphatase (ALP) and calcifications. OBJECTIVE: The aim of this study was to determine if hypertrophic differentiation occurs during IVD degeneration. METHODS: IVDs from all Thompson degeneration grades were prepared for histology, extraction of nucleus pulposus (NP) and annulus fibrosis (AF) tissue (N=50) and micro-CT (N=27). The presence of collagen type X, OPG and Runx2 was determined by immunohistochemistry, with OPG levels also determined by Enzyme-linked immunosorbent assay (ELISA). The presence of calcification was determined by micro-CT, von Kossa and Alizarin Red staining. RESULTS: Immunohistochemical staining for collagen type X, OPG, Runx2 appeared more intense in the NP of degenerative compared to healthy IVD samples. OPG levels correlated significantly with degeneration grade (NP: P<0.000; AF: P=0.002) and the number of microscopic calcifications (NP: P=0.002; AF: P=0.008). The extent of calcifications on micro-CT also correlated with degeneration grade (NP: P<0.001, AF: P=0.001) as did von Kossa staining (NP: P=0.015, AF: P=0.016). ALP staining was only incidentally seen in the transition zone of grades IV and V degenerated IVDs. CONCLUSION: This study for the first time demonstrates that hypertrophic differentiation occurs during IVD degeneration, as shown by an increase in OPG levels, the presence of ALP activity, increased immunopositivity of Runx2 and collagen type X. PMID- 20723613 TI - Anaerobic meningitis after missed penetrating trauma in a 6-year old child. AB - Anaerobic meningitis may occur alone, but is usually encountered as a complication of a brain abscess. In either case it is rare in a normal host. We present a 6-year old boy with anaerobic meningitis after missed penetrating trauma, stressing the need for a thorough investigation after head trauma. PMID- 20723614 TI - Evaluation of a modified CD71 MicroFlow method for the flow cytometric analysis of micronuclei in rat bone marrow erythrocytes. AB - The aim of this study was to evaluate a modified flow cytometric method for the quantification of micronuclei in rat bone marrow reticulocytes. The method identified uses the erythrocyte pure fraction from cellulose filtered bone marrow with slight modifications to the widely published MicroFlow((r)) method developed by Litron Laboratories, Rochester, NY for the detection of micronuclei in peripheral blood. A number of experiments were conducted to compare the micronucleus induction measured by flow cytometry with traditional microscopic analysis in male rats treated daily for 2 days with appropriate vehicle controls or various doses of cyclophosphamide (CP), mitomycin C (MMC), vinblastine sulfate (VBS), 1,2-dimethylhydrazine (DMH), etoposide (ETO), colchicine (COL), or 4 nitroquinoline-1-oxide (4NQO). In addition, for a subset of chemical we compared the induction of micronuclei in bone marrow and peripheral blood. The results from this study showed a very good correlation of micronucleus frequencies in bone marrow between microscopic analysis and the flow cytometry as well as between blood and bone marrow. In general, micronucleus frequencies of test compound treated animals and inter-animal variability were slightly lower by flow cytometric analysis compared to manual slide analysis. The data presented in this study support the use of the CD71 flow method for the analysis of micronuclei in rat bone marrow and also suggest that peripheral blood may be equally as sensitive as bone marrow in detecting a micronucleus response in short term studies. PMID- 20723615 TI - Using text to build semantic networks for pharmacogenomics. AB - Most pharmacogenomics knowledge is contained in the text of published studies, and is thus not available for automated computation. Natural Language Processing (NLP) techniques for extracting relationships in specific domains often rely on hand-built rules and domain-specific ontologies to achieve good performance. In a new and evolving field such as pharmacogenomics (PGx), rules and ontologies may not be available. Recent progress in syntactic NLP parsing in the context of a large corpus of pharmacogenomics text provides new opportunities for automated relationship extraction. We describe an ontology of PGx relationships built starting from a lexicon of key pharmacogenomic entities and a syntactic parse of more than 87 million sentences from 17 million MEDLINE abstracts. We used the syntactic structure of PGx statements to systematically extract commonly occurring relationships and to map them to a common schema. Our extracted relationships have a 70-87.7% precision and involve not only key PGx entities such as genes, drugs, and phenotypes (e.g., VKORC1, warfarin, clotting disorder), but also critical entities that are frequently modified by these key entities (e.g., VKORC1 polymorphism, warfarin response, clotting disorder treatment). The result of our analysis is a network of 40,000 relationships between more than 200 entity types with clear semantics. This network is used to guide the curation of PGx knowledge and provide a computable resource for knowledge discovery. PMID- 20723616 TI - A quality improvement model for healthcare terminologies. AB - A number of controlled healthcare terminologies and classification systems have been developed for specific purposes, resulting in variations in content, structure, process management, and quality. A terminology quality improvement (TQI) model or framework would be useful for various stakeholders to guide terminology selection, to assess the quality of healthcare terminologies and to make improvements according to an agreed standard. A TQI model, thus, was formulated based on a review of the literature and existing international standards developed for healthcare terminologies. The TQI model, adapted from Donabedian's approach, encompasses structure, process, and outcome components in relation to a terminology life cycle--change request, editing, and publication. Multi-dimensional quality outcome measures also were identified in the areas of terminology content, modeling structure, mapping, and process management. A case study was developed to validate the TQI model using the International Classification for Nursing Practice (ICNP). The TQI model represented the complexity of activities involved in terminology quality management. The ICNP case study demonstrated both the applicability of the TQI model and the appropriateness of the criteria identified in the TQI model: openness and responsiveness, clarity and reproducibility, understandability, accessibility and usability, interoperability, and quality of documentation. The applicability of the TQI model was validated using ICNP. While ICNP exhibits many of the desirable characteristics of contemporary terminologies, the case study identified a need for further work on ICNP policy and on documentation. PMID- 20723617 TI - Patients with typical laboratory features of autoimmune hepatitis rarely need a liver biopsy for diagnosis. AB - BACKGROUND & AIMS: The importance of histologic analysis of biopsy samples in the diagnosis and management of patients with autoimmune hepatitis (AIH) is unclear. METHODS: Patients with AIH were identified from a 10-year database. Individuals with overlap syndromes and decompensated liver disease were excluded. The proportion of patients who fulfilled the new simplified criteria for AIH was calculated. RESULTS: A total of 257 patients (203 female) with a median age of 52 years (interquartile range, 39-63 y) were diagnosed with AIH. Overall, 183 of 257 (71%) were positive for antinuclear antibodies, 116 (45%) had positive smooth muscle antibodies, and 29 of 257 (11%) were seronegative. A total of 250 (97%) patients had increased levels of autoantibodies and/or gamma-globulins. In 95% (243 of 257 cases), the histology was compatible with AIH whereas 5% (14 cases) had atypical histology. Overall, 77% had a score of at least 6, indicating probable or definite AIH according to most recent criteria; 22% were diagnosed with AIH with less than 6 points and 1 patient had nonalcoholic steatohepatitis based on biopsy analysis. Immunosuppression occurred in 93% of patients. Patients with atypical versus compatible histology were similar in terms of seronegativity or gamma-globulins; 86% (12 of 14) received immunosuppressive therapy despite atypical histology. CONCLUSIONS: Most patients with features of AIH, based on laboratory analyses, are likely to have a compatible liver histology. Few patients have atypical histology and these findings have little impact on patient management. These findings indicate biopsy samples might not need to be collected from patients who meet other clinical criteria for AIH. PMID- 20723618 TI - Increased mortality and length of stay among patients with inflammatory bowel disease and hospital-acquired infections. AB - BACKGROUND & AIMS: Hospitalized patients with inflammatory bowel disease (IBD) could be at increased risk for hospital-acquired infections (HAIs). By using HAI outcome data from Pennsylvania, we examined the influence of HAIs on in-patient mortality and length of stay (LOS) in the hospital among patients with IBD. METHODS: Data were generated by linking the Clinical Research Databases from CareFusion (formerly MediQual), which includes all acute care hospitals in Pennsylvania, with publicly reported HAI data from Pennsylvania. The study population included all patients discharged in 2004 with International Classification of Diseases, 9th Clinical Modification codes of 555.x or 556.x (2324 IBD cases from 161 hospitals). Controls were selected using risk-score matching with a 5:1 ratio. Mortality and LOS end points were estimated and corroborated with regression methods. RESULTS: Among the IBD patients studied, there were 20 deaths and 22 reported cases of HAI. The mortality from HAI among patients with IBD was 13.6%, compared with 0.9% among controls (P = .0146, Fisher exact test). The odds ratio for mortality was 17.2 (95% confidence interval, 1.7 174.3). The median LOS for patients with IBD and HAI was 22 days, versus 6 days for controls (P < .001, Wilcoxon). Of the 22 cases with HAIs, 15 were urinary tract infections, 5 were blood stream infections, and 2 were from multiple sources. CONCLUSIONS: Results from a population-based data set indicate that mortality and LOS are increased among IBD patients who develop HAIs. A majority of the HAIs were from urinary sources. Although HAIs are low-frequency events, increased vigilance to avoid HAI among patients with IBD could improve outcomes. PMID- 20723619 TI - Accelerometer use in a physical activity intervention trial. AB - This paper describes the application of best practice recommendations for using accelerometers in a physical activity (PA) intervention trial, and the concordance of different methods for measuring PA. A subsample (n = 63; 26%) of the 239 healthy, sedentary adults participating in a PA trial (mean age = 47.5; 82% women) wore the ActiGraph monitor at all 3 assessment time points. ActiGraph data were compared with self-report (i.e., PA weekly recall and monthly log) and fitness variables. Correlations between the PA recall and ActiGraph for moderate intensity activity ranged from 0.16-0.48 and from 0.28-0.42 for vigorous intensity activity. ActiGraph and fitness [estimated VO(2)(ml/kg/min)] had correlations of 0.15-0.45. The ActiGraph and weekly self-report were significantly correlated at all time points (correlations ranged from 0.23 to 0.44). In terms of detecting intervention effects, intervention groups recorded more minutes of at least moderate-intensity PA on the ActiGraph than the control group at 6 months (min = 46.47, 95% CI = 14.36-78.58), but not at 12 months. Limitations of the study include a small sample size and only 3 days of ActiGraph monitoring. To obtain optimal results with accelerometers in clinical trials, the authors recommend following best practice recommendations: detailed protocols for monitor use, calibration of monitors and validation of data quality, and use of validated equations for analysis. The ActiGraph has modest concordance with other assessment tools and is sensitive to change over time. However, until more information validating the use of accelerometry in clinical trials becomes available, properly administered self-report measures of PA should remain part of the assessment battery. PMID- 20723620 TI - Expression of two type II cadherins, Cdh12 and Cdh22 in the developing and adult mouse brain. AB - The expression of type II classic cadherins described so far displays a wide range of partially overlapping patterns during mammalian central nervous system development indicating their potential role during migratory and lamination processes as well as axon guidance. Expression of a few members of this family however, has not been characterized in detail. Here, we describe the spatio temporal mRNA distribution pattern of two such neglected members of this family Cdh12 (also known as Br-cadherin) and Cdh22 (PB-cadherin) during mammalian CNS development using RT-PCR and in situ hybridization. In addition, we demonstrate the presence of Cdh12 and Cdh22 mRNA in specific and partially overlapping groups of both excitatory and inhibitory neurons in various areas of the adult mouse CNS including the cerebellum, neocortex, hippocampus and in different subcortical nuclei. Neocortical layer-specificity during development is further characterized using double in situ hybridization with the layer-specific markers cux2 and ctip2. The specific and partially overlapping expression patterns described here strongly suggest that these cadherins are likely to play a significant and quite possibly a partially redundant role during development and in the adult function of the mouse CNS. PMID- 20723621 TI - Expression patterns of the mouse Spir-2 actin nucleator. AB - Spir proteins are the founding members of the novel class of WH2 domain containing actin nucleation factors. They initiate actin polymerization by binding of actin monomers to four WH2 domains in the central part of the proteins. Despite their ability to nucleate actin polymerization in vitro by themselves, Spir proteins form a regulatory complex with the distinct actin nucleators of the formin subgroup of formins. The mammalian genome encodes two spir genes, spir-1 and spir-2. The corresponding proteins have an identical structural array and share a high degree of homology. Here, we have addressed the yet unknown expression of the mouse spir-2 gene. Northern blot analysis revealed that the spir-2 gene is expressed as a single mRNA. During embryogenesis in situ hybridizations show spir-2 to be expressed in the developing nervous system and intestine. In adult mouse tissues highest expression of spir-2 was detected in the epithelial cells of the digestive tract and in neuronal cells of the nervous system. High expression was also detected in testical spermatocytes. In contrast to the restricted expression of the mouse spir-1 gene, which is mainly found in the nervous system, our data presented here show a distinct and broader expression pattern of the spir-2 gene and by this support a more general cell biological function of the novel actin nucleators. PMID- 20723622 TI - Isolation, molecular characterization and phylogenetic analysis of canine parvovirus. AB - Canine parvovirus type 2 (CPV-2) causes acute haemorrhagic enteritis in dogs. Canine parvovirus is prone to genetic evolution and has undergone several mutations that produced different strains like CPV-2a, CPV-2b, New CPV-2a, New CPV-2b and CPV-2c in the past three decades. Mutations affecting the VP2 gene of CPV have been responsible for evolution of different antigenic variants. Sequence analysis of VP2 gene of the virus and subsequent characterization is important for molecular epidemiology. The present study was conducted to isolate and to characterize the virus by amplifying partial VP2 gene and further sequence analysis and also to estimate phylogenetic relationship of field virus with the reference strains. Out of 77 samples, 51 samples were found to be positive by PCR and all the 51 samples were subjected for virus isolation in CRFK cell line. Sixteen viruses could be isolated and 10 randomly selected isolates were subjected to sequence analysis along with four random clinical samples. All the 10 isolates and 4 clinical samples were characterized as New CPV-2a (CPV2a with 297-Ser->Ala). One of the field isolates was found to be phylogenetically closely related to New CPV-2a strains of Japan and India; another field isolates was found to share ancestral origins with New CPV-2a strains of Korea, USA, Italy, Brazil, Germany, Taiwan and Vietnam; rest other sequences had distinct lineage but shared molecular relationship with New CPV-2a reference strains. PMID- 20723623 TI - Transgenic crops coping with water scarcity. AB - Water scarcity is a serious problem that will be exacerbated by global climate change. Massive quantities of water are used in agriculture, and abiotic stresses, especially drought and increased salinity, are primary causes of crop loss worldwide. Various approaches may be adopted to consume less water in agriculture, one of them being the development of plants that use less water yet maintain high yields in conditions of water scarcity. In recent years several molecular networks concerned with stress perception, signal transduction and stress responses in plants have been elucidated. Consequently, engineering some of the genes involved in these mechanisms promises to enhance plant tolerance to stresses and in particular increase their water use efficiency. Here we review the various approaches used so far to produce transgenic plants having improved tolerance to abiotic stresses, and discuss criteria for choosing which genes to work on (functional and regulatory genes) and which gene expression promoters (constitutive, inducible, and cell-specific) have been used to obtain successful results. PMID- 20723624 TI - Poly(A) tail affects equilibrium and thermodynamic behavior of tobacco etch virus mRNA with translation initiation factors eIF4F, eIF4B and PABP. AB - We have investigated the effects of poly(A)-tail on binding of eIF4F, eIF4B and PABP with tobacco etch virus (TEV) IRES RNA. The fluorescence anisotropy data showed that the addition of poly(A)(20) increases the binding affinity of eIF4F.4B and eIF4F.PABP complexes to IRES RNA ~2- and 4-fold, respectively. However, the binding affinity of eIF4F with PK1 was enhanced ~11-fold with the addition of PABP, eIF4B, and poly(A)(20) together. Whereas, poly(A)(20) alone increases the binding affinity of eIF4F.4B.PABP with PK1 RNA about 3-fold, showing an additive effect rather than the large increase in affinity as shown for cap binding. Thermodynamic data showed that PK1 RNA binding to protein complexes in the presence of poly(A)(20) was enthalpy-driven and entropy favorable. Poly(A)(20) decreased the entropic contribution 75% for binding of PK1 RNA to eIF4F.4B.PABP as compared to eIF4F alone, suggesting reduced hydrophobic interactions for complex formation and an overall conformational change. Overall, these results demonstrate the first direct effect of poly(A) on the equilibrium and thermodynamics of eIF4F and eIF4F.4B.PABP with IRES-RNA. PMID- 20723625 TI - The proteasome and its regulatory roles in gene expression. AB - Cumulative evidence indicates that the proteasome, which is mainly known as a protein-degrading machine, is very essential for gene expression. Destructive functions of the proteasome, i.e., ubiquitin-dependent proteolytic activity, are significant for activator localization, activator destruction, co activator/repressor destruction and PIC disassembly. Non-proteolytic functions of the proteasome are important for recruitment of activators and co-activators to promoters, ubiquitin-dependent histone modification, transcription elongation and possibly maturation of mRNA via the facilitation of mRNA export from the nucleus to the cytoplasm. In this review, we discuss how the proteasome regulates transcription at numerous stages during gene expression. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough! PMID- 20723626 TI - Inactivated trivalent seasonal influenza vaccine induces limited cross-reactive neutralizing antibody responses against 2009 pandemic and 1934 PR8 H1N1 strains. AB - BACKGROUND: In June 2009, we conducted a prospective study in Singapore on 51 individuals to determine their serologic responses before and following receipt of the 2009 Southern Hemisphere seasonal influenza vaccine. MATERIALS AND METHODS: Paired serum samples were obtained before and 3-4 weeks after vaccination. Virus microneutralization assays were performed to quantify antibodies against A/Brisbane/59/2007 vaccine, pandemic H1N1-2009 and A/Puerto Rico/08/34 H1N1 strains. RESULTS: Post-vaccination, 43%, 12% and 24% of subjects displayed a 4-fold or greater rise in neutralizing antibody titers against the three strains, respectively. There was a positive correlation among individuals who showed increased titers to both pandemic H1N1-2009 and A/Puerto Rico/08/34 (p<0.001). However, this correlation was not observed for A/Brisbane/59/2007 with either strain. The relative conservation and accessibility of predicted B-cell epitopes may explain the limited cross-reactivity of the antibodies directed against common H1N1 epitopes. CONCLUSIONS: These results suggest that seasonal influenza vaccination confers a certain degree of cross-protection to other H1N1 strains. The correlation in cross-reactive antibody titers to A/Puerto Rico/08/34 and pandemic H1N1-2009 implies that previous exposure to pre-1957 H1N1 strains may confer some protection against the 2009 pandemic strain. PMID- 20723627 TI - Multiple tandem copies of conserved gp41 epitopes incorporated in gag virus-like particles elicit systemic and mucosal antibodies in an optimized heterologous vector delivery regimen. AB - Induction of neutralizing antibodies to prevent HIV infection, especially at the mucosa, is a critical goal of future vaccines. In this study, we have designed chimeric HIV-gag virus-like particles (VLPs) that contain multiple copies of the two highly conserved gp41 membrane-proximal external region (MPER) epitopes, ELDKWA and NWFDIT, with the objective of generating high titers of MPER-specific antibodies. We have shown that the implementation of optimized vector design, delivery regimens and appropriate delivery methods is critical to significantly increase epitope-specific antibody titers. One goal of the methods that were tested and employed was to generate high levels of mucosal MPER-specific antibodies, as mucosal immune induction could play a key role in preventing HIV infection. We also tested a design strategy that incorporated multiple repeats of the MPER epitopes within gag, which significantly increased specific antibody titers, systemically and mucosally. This alternative design strategy and the implementation of optimized heterologous immunization regimens can serve to 'immuno-focus' and significantly increase epitope-specific titers. PMID- 20723628 TI - Socioeconomic status is a critical risk factor for human rabies post-exposure prophylaxis. AB - The socioeconomic status of the patients is the important factor for post exposure prophylaxis (PEP). However, few investigations were designed to study the correlation between the socioeconomic status and PEP. This study set out to determine the importance of socioeconomic status for PEP. All of the 11,670 at risk populations of rabies in the public health centre of San Sheng County in Chengdu from January 2002 to December 2009 were reviewed retrospectively. We identified 11,350 patients on vaccination and 550 patients with rabies immunoglobulin. RIG was administered to 4.85% bite victims attending the rabies prevention clinics, while 61.36% had a category III exposure. The incidence of receiving RIG in the population of the high level of income (49.38%) was much higher than the groups of the medium level (8.08%) and the low level of income (1.46%) (P<0.05). The incidence of receiving RIG with above high school (23.08%) was much higher than the groups of the primary school (3.01%), the junior school (12.56%) and the illiteracy (2.08%) (P<0.05). In the logistic regression analysis by stepwise approach, the socioeconomic status was the most important factor for PEP (95% CI 1.20-2.04). Vaccination and immunoglobulin proved to be the most prominent two factors for PEP but whether receiving Vaccination and immunoglobulin treatment or not is determined by the socioeconomic status. So, the socioeconomic status was the most important factor for PEP. PMID- 20723630 TI - Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. AB - OBJECTIVE: To estimate current age-specific rates of immunity to hepatitis A virus (HAV) in world regions by conducting a systematic review and meta-analysis of published data. The estimation of the global burden of hepatitis A and policies for public health control are dependent on an understanding of the changing epidemiology of this viral infection. METHODS: Age-specific IgG anti-HAV seroprevalence data from more than 500 published articles were pooled and used to fit estimated age-seroprevalence curves in 1990 and 2005 for each of 21 world regions (as defined by the Global Burden of Disease 2010 Study). FINDINGS: High income regions (Western Europe, Australia, New Zealand, Canada, the United States, Japan, the Republic of Korea, and Singapore) have very low HAV endemicity levels and a high proportion of susceptible adults, low-income regions (sub Saharan Africa and parts of South Asia) have high endemicity levels and almost no susceptible adolescents and adults, and most middle-income regions have a mix of intermediate and low endemicity levels. CONCLUSION: Anti-HAV prevalence estimates in this analysis suggest that middle-income regions in Asia, Latin America, Eastern Europe, and the Middle East currently have an intermediate or low level of endemicity. The countries in these regions may have an increasing burden of disease from hepatitis A, and may benefit from new or expanded vaccination programs. PMID- 20723631 TI - Effectiveness of pneumococcal polysaccharide vaccine against pneumonia and cost analysis for the elderly who receive seasonal influenza vaccine in Japan. AB - To determine the clinical efficacy and cost-saving effect of pneumococcal polysaccharide vaccine (PPV) against community-acquired pneumonia (CAP), an open label, randomized clinical trial was conducted involving 786 Japanese subjects older than 65 years of age receiving a routine influenza vaccine during the 2 year period. Study subjects were randomly assigned to either a PPV group (n=394) or to a non-PPV group (n=392). The incidence, admission and the medical cost for all-cause pneumonia were compared between these two groups. PPV vaccination significantly reduced the incidence of admission for all-cause pneumonia for subjects older than 75 years of age (41.5%, P=0.039) and for those who had difficulty walking (62.7%, P=0.005), but not for all study subjects older than 65 years of age (P=0.183), for the 2-year period. The Kaplan-Meier survival curves for subjects who had difficulty walking free from all-cause pneumonia demonstrated a significant difference (P=0.0146) between the two groups. PPV vaccination significantly reduced medical costs for all study subjects during the first year period (P=0.027). Our present data demonstrated that PPV was effective for all-cause pneumonia for study subjects older than 75 years of age, although the effect was not significant for all study subjects older than 65 years of age. PMID- 20723629 TI - Effective induction of protective systemic immunity with nasally administered vaccines adjuvanted with IL-1. AB - IL-1alpha and IL-1beta were evaluated for their ability to provide adjuvant activity for the induction of serum antibody responses when nasally administered with protein antigens in mice and rabbits. In mice, intranasal (i.n.) immunization with pneumococcal surface protein A (PspA) or tetanus toxoid (TT) combined with IL-1beta induced protective immunity that was equivalent to that induced by parenteral immunization. Nasal immunization of awake (i.e., not anesthetized) rabbits with IL-1-adjuvanted vaccines induced highly variable serum antibody responses and was not as effective as parenteral immunization for the induction of antigen-specific serum IgG. However, i.n. immunization of deeply anesthetized rabbits with rPA+IL-1alpha consistently induced rPA-specific serum IgG ELISA titers that were not significantly different than those induced by intramuscular (IM) immunization with rPA+alum although lethal toxin-neutralizing titers induced by nasal immunization were lower than those induced by IM immunization. Gamma scintigraphy demonstrated that the enhanced immunogenicity of nasal immunization in anesthetized rabbits correlated with an increased nasal retention of i.n. delivered non-permeable radio-labeled colloidal particles. Our results demonstrate that, in mice, IL-1 is an effective adjuvant for nasally administered vaccines for the induction of protective systemic immunity and that in non-rodent species, effective induction of systemic immunity with nasally administered vaccines may require formulations that ensure adequate retention of the vaccine within the nasal cavity. PMID- 20723632 TI - Effect of coronary collaterals on long-term prognosis in patients undergoing primary angioplasty for acute ST-elevation myocardial infarction. AB - The aim of this study was to examine the effect of coronary collateral flow before reperfusion on long-term clinical prognosis in patients with acute ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. We studied 235 patients with STEMI within 12 hours after symptom onset. All patients had Thrombolysis In Myocardial Infarction grade < or =1 flow before percutaneous coronary intervention. Collateral flow was graded according to the Rentrop classification. Patients were categorized as having absent or poor collateral flow to the infarct-related artery (group A) or significant flow (group B). In 166 patients there was absent or weak collateral flow (group A), whereas 69 had significant flow (group B). Long-term follow-up was available in 227 patients (97%) at a median of 797 days. Overall, 25 patients died during the follow-up period, 22 patients (13.8%) in group A and 3 patients (4.4%) in group B (p = 0.04). A total of 12 (7.5%) nonfatal recurrent myocardial infarctions occurred in group A compared to 2 (2.9%) in group B (p = 0.18). The combined major adverse cardiovascular event end point (death or nonfatal reinfarction) showed a significantly lower event rate in group B (p = 0.02). Extensive collateral flow at baseline was a significant predictor for a favorable long-term clinical outcome on multivariable analysis after adjustment for established prognostic markers. In conclusion, the presence of a well-developed collateral network before mechanical reperfusion in patients with STEMI is associated with improved long-term survival and lower major adverse cardiovascular event rates. PMID- 20723633 TI - Long-term outcomes of intravascular ultrasound-guided stenting in coronary bifurcation lesions. AB - Stenting for bifurcation lesions is still challenging, and the effect of intravascular ultrasound (IVUS) guidance on long-term outcomes has not been evaluated. We assessed the long-term outcomes of IVUS-guided stenting in bifurcation lesions. We evaluated 758 patients with de novo nonleft main coronary bifurcation lesions who underwent stent implantation from January 1998 to February 2006. We compared the adverse outcomes (i.e., death, stent thrombosis, and target lesion revascularization) within 4 years, after adjustment using a multivariate Cox proportional hazard model and propensity scoring. IVUS-guided stenting significantly reduced the long-term all-cause mortality (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.13 to 0.74, p = 0.008) in the total population and in the patients receiving drug-eluting stents (DESs) (HR 0.24, 95% CI 0.06 to 0.86, p = 0.03), but not in the patients receiving bare metal stents (HR 0.41, 95% CI 0.13 to 1.26, p = 0.12). IVUS-guided stenting had no effect on the rate of stent thrombosis (HR 0.48, 95% CI 0.16 to 1.43, p = 0.19) or target lesion revascularization (HR 1.47, 95% CI 0.79 to 2.71, p = 0.21). In patients receiving DESs, however, IVUS guidance reduced the development of very late stent thrombosis (0.4% vs 2.8%, p = 0.03, log-rank test). In conclusion, in patients receiving DESs, IVUS-guided stenting for treatment of bifurcation lesions significantly reduced the 4-year mortality compared to conventional angiographically guided stenting. In addition, IVUS guidance reduced the development of very late stent thrombosis in patients receiving DESs. PMID- 20723634 TI - Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. AB - The effect of periprocedural platelet reactivity and clinical outcomes in diabetic patients taking clopidogrel and undergoing percutaneous coronary intervention (PCI) is unclear. The aim of the present study was to prospectively evaluate the influence of diabetes mellitus (DM) on platelet reactivity measured by the VerifyNow P2Y12 assay and on periprocedural outcomes in patients receiving clopidogrel and undergoing PCI. A total of 285 consecutive clopidogrel-treated patients undergoing elective PCI were included. Platelet function analysis was performed using the VerifyNow P2Y12 assay. High platelet reactivity (HPR) after clopidogrel was defined as a platelet reaction unit value > or =240. Cardiac biomarkers were measured before and 8 and 24 hours after intervention. Patients with DM had significantly higher platelet reactivity before PCI compared to nondiabetics (214 +/- 83 vs 193 +/- 68 platelet reaction units, p = 0.02). HPR was more frequently observed in diabetics (36% vs 22%, p = 0.01) before PCI. Patients with DM had an increased incidence of periprocedural myocardial infarction (MI; 11% vs 4%, p = 0.04). When the entire population was divided by the presence or absence of DM and HPR, patients with DM and HPR presented the highest incidence of periprocedural MI (p for trend = 0.0008). HPR was an independent predictor of periprocedural MI (odds ratio 8.34, 95% confidence interval 2.60 to 26.76, p = 0.0003). In conclusion, patients with DM undergoing PCI have higher platelet reactivity at the time of PCI despite adequate clopidogrel pretreatment and subsequently worse periprocedural outcomes. Point-of care platelet function testing may help to identify patients at higher risk of periprocedural MI. PMID- 20723635 TI - Impact of thrombectomy with EXPort Catheter in Infarct-Related Artery during Primary Percutaneous Coronary Intervention (EXPIRA Trial) on cardiac death. AB - In ST-segment elevation myocardial infarction (STEMI) impairment of microcirculatory function is a negative independent predictor of myocardial function recovery. In the Impact of Thrombectomy with EXPort Catheter in Infarct Related Artery during Primary Percutaneous Coronary Intervention (PCI; EXPIRA) trial we found that manual thrombectomy resulted in a better myocardial reperfusion expressed by an improved procedural outcome and a decrease of infarct size compared to conventional PCI. The aim of the present study was to investigate whether the early efficacy of thrombus aspiration translates into very long-term clinical benefit. We randomized 175 patients with STEMI with occlusive thrombus at baseline undergoing primary PCI to thromboaspiration with a manual device (Export Medtronic, n = 88) or standard PCI (n = 87). No differences in baseline, clinical, and angiographic preprocedural findings were observed between the 2 groups except for incidence of hypertension and cholesterol levels. After 24 months major adverse cardiac events were 13.7% versus 4.5% (p = 0.038, log-rank test) and cardiac death was 6.8% versus 0% (p = 0.012, log-rank test). A strict correlation was observed between cardiac death incidence and tissue reperfusion parameters (postprocedural myocardial blush grade and ST-segment resolution). In conclusion, manual thrombus aspiration before stenting of the infarct-related artery in selected patients with STEMI improving myocardial reperfusion significantly decrease cardiac death and major adverse cardiac events at 2 years. PMID- 20723636 TI - Usefulness of the QRS score as a strong prognostic marker in patients discharged after undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - The prognostic value of myocardial infarct size estimation by QRS scoring in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI) is unclear. The standard 32 point Selvester QRS score on the discharge electrocardiogram (each point approximately 3% left ventricular mass) was calculated in 4,113 patients with STEMI who underwent primary PCI and survived to hospital discharge in the APEX AMI trial. QRS scores were divided into tertiles, i.e., < or =3 (<10% myocardium), 4 to 7 (10% to 21% myocardium), and > or =8 (>21% myocardium). Adjusted associations between QRS score and 90-day outcomes (death and composite of death/congestive heart failure (CHF)/shock) were examined. Higher QRS scores were associated with male gender, higher heart rate, worse Killip class, noninferior infarct location, greater ST-segment deviation, and longer times to reperfusion. Higher QRS scores were also associated with impaired culprit artery flow before and after PCI and more frequent multivessel disease. Adverse outcomes occurred more often in patients with higher QRS scores (90-day death: 1.9%, QRS score 0 to 3; 3.4%, 4 to 7; 4.9%, > or =8; 90-day death/shock/CHF: 4.5%, 0-3; 7.8%, 4 to 7; 12.1%, > or =8). After multivariable adjustment, patients with higher QRS scores remained more likely to develop an adverse outcome versus those with QRS scores < or =3 (score 4 to 7, hazard ratios [HR] for death 2.08, 95% confidence interval [CI] 1.26 to 3.41; HR for death/CHF/shock 2.00, 95% CI 1.26 to 3.17; score > or =8, HR for death 2.57, 95% CI 1.56 to 4.24, HR for death/CHF/shock 2.93, 95% CI 1.84 to 4.67). In conclusion, infarct size as estimated by QRS scoring at hospital discharge is an independent and prognostically relevant metric in patients with STEMI undergoing primary PCI. PMID- 20723637 TI - Relation between infarct size in ST-segment elevation myocardial infarction treated successfully by percutaneous coronary intervention and left ventricular ejection fraction three months after the infarct. AB - The goal of this analysis was to determine the relation between myocardial infarct size and left ventricular (LV) ejection fraction (EF) in patients with ST segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI) using cardiovascular magnetic resonance imaging (CMR). After STEMI, LVEF and infarct size correlate with prognosis, but the relation between infarct size and LVEF is incompletely known. Consecutive subjects presenting to a single center with STEMI treated with pPCI were enrolled, and cine functional and late gadolinium enhancement CMR was performed 3 months after presentation. From cine images, LVEF was calculated using volumetric summation of disks method. Infarct size was measured as percent LV myocardial volume with late gadolinium enhancement. In the 78 patients enrolled (mean age 54.5 years, range 42 to 82), median LVEF was 56% (interquartile range 49 to 62) and median infarct size was 11% (interquartile range 5 to 18). Of the 53 patients with infarct size <15%, all had LVEF >40%, and there was no significant relation between infarct size and LVEF (slope -0.43, R(2) = 0.045, p = 0.13). In patients with infarct size > or =15%, there was a significant negative linear association between infarct size and LVEF (slope -1.21, R(2) = 0.66, p <0.001), such that for every 5% increase in infarct size, there was a 6.1% decrease in LVEF. In conclusion, there is a negative linear relation between infarct size and LVEF for moderate to large infarcts. For small infarcts there is no significant relation between infarct size and LVEF. Up to 15% of LV myocardial volume may be infarcted before there is any appreciable decrease in LVEF. PMID- 20723639 TI - Relation of pre-event use of inhibitors of the renin-angiotensin system with myocardial infarct size in patients presenting with a first ST-segment elevation myocardial infarction. AB - Agents that block the renin-angiotensin system (RAS), including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are of proven benefit in patients after ST-segment elevation myocardial infarction (STEMI). However, no studies have evaluated the benefit of pre-event use of RAS inhibitors before STEMI. A retrospective review was performed of patients admitted to a single hospital with the diagnosis of STEMI and without a history of coronary disease or the equivalent, including diabetes mellitus, peripheral vascular disease, or stroke. Patients were stratified according to the use of RAS inhibitors before STEMI. Compared to patients not taking RAS inhibitors, patients who were taking RAS inhibitors had a lower peak troponin I level (79 vs 120 ng/dl, p = 0.016). Of the patients who had medically treated hypertension, those receiving RAS inhibitors had a significantly lower peak troponin I compared to those receiving non-RAS agents (79 vs 130 ng/dl, p = 0.015), despite equivalent blood pressure across the 2 groups. The beneficial effect of RAS inhibitor pretreatment remained when concomitant aspirin and statin use were controlled for. In conclusion, in patients presenting with a first STEMI, pretreatment with RAS inhibitors conferred a cardioprotective effect. The mechanism of this benefit appears to be independent of an effect on blood pressure control and was not wholly due to the effect of concomitant use of other medicines known to be protective in patients with STEMI. PMID- 20723638 TI - A novel percutaneous coronary intervention risk score to predict one-year mortality. AB - Clinical and angiographic risk factors associated with adverse outcomes after percutaneous coronary intervention (PCI) have been included in previous validated risk scores. Complications after PCI are known to increase mortality and morbidity but have not been included in any model. Records of 6,932 consecutive patients who underwent PCI from 2000 to 2005 were reviewed. Patients presenting with cardiogenic shock were excluded. Logistic regression and bootstrap methods were used to build an integer risk score for estimating risk of death at 1 year after PCI using baseline, angiographic, and procedural characteristics and postprocedural complications. This risk score was validated in a set of consecutive patients who underwent PCI from 2006 to 2007. The following 8 variables were significantly correlated with outcome: older age, history of diabetes mellitus, chronic renal failure, heart failure, left main coronary artery disease, lower baseline hematocrit, greater hematocrit decrease after PCI, and Thrombolysis In Myocardial Infarction grade <3 flow after PCI. In the validation population (n = 973), average receiver operating characteristic curve area was 0.836. In conclusion, we developed and validated a simple integer risk score, including postprocedural variables that closely predict long-term mortality after PCI. This model emphasizes the significant impact of complications occurring after PCI on long-term outcomes. PMID- 20723640 TI - Usefulness of biomarker strategy to improve GRACE score's prediction performance in patients with non-ST-segment elevation acute coronary syndrome and low event rates. AB - We sought to assess whether multiple biomarkers would correlate with the outcome and could improve event prediction in non-ST-segment elevation acute coronary syndrome populations with low event rates. Nine inflammatory, ischemic, or neurohormonal biomarkers were measured within 48 hours after symptom onset in 440 patients with non-ST-segment elevation acute coronary syndrome from the ARCHIPELAGO (Irbesartan in Patients With Acute Coronary Syndrome Without ST Segment Elevation) trial. We assessed the relation between biomarkers and ischemic or heart failure composite end points at 2 months of follow-up. We also evaluated whether biomarkers could improve the predictive performance of the validated and well-performing Global Registry of Acute Coronary Events risk score. Among all biomarkers measured at baseline, only interleukin-6 correlated with the ischemic end point (adjusted odds ratio 1.69, 95% confidence interval [CI] 1.23 to 2.31). The independent correlates of the heart failure end point were B-type natriuretic peptide (adjusted odds ratio 3.16, 95% CI 1.99 to 5.03), aldosterone (adjusted odds ratio 1.57, 95% CI 1.14 to 2.16) and matrix metalloproteinase-9 (adjusted odds ratio 0.64, 95% CI 0.46 to 0.88). The Global Registry of Acute Coronary Events score predicted poorly the ischemic end point (area under the curve [AUC] 0.591) and fairly (AUC 0.775) the heart failure end point. The performance of the models was significantly improved by the introduction of interleukin-6 (AUC 0.685) for the ischemic end point and of the 3 biomarkers (AUC 0.874) for the heart failure end point. In conclusion, the interleukin-6 level only, and B-type natriuretic peptide, aldosterone, and matrix metalloproteinase-9 together, independently correlated with the ischemic and heart failure end points, respectively. The Global Registry of Acute Coronary Events risk score's performance was significantly improved with a biomarker strategy. In low-risk populations, a strategy using these biomarkers might help in identifying patients at greater risk of additional events. PMID- 20723641 TI - Effect of healthy lifestyle behaviors on the association between leukocyte telomere length and coronary artery calcium. AB - The telomere length is an indicator of biologic aging, and shorter telomeres have been associated with coronary artery calcium (CAC), a validated indicator of coronary atherosclerosis. It is unclear, however, whether healthy lifestyle behaviors affect the relation between telomere length and CAC. In a sample of subjects aged 40 to 64 years with no previous diagnosis of coronary heart disease, stroke, diabetes mellitus, or cancer (n = 318), healthy lifestyle behaviors of greater fruit and vegetable consumption, lower meat consumption, exercise, being at a healthy weight, and the presence of social support were examined to determine whether they attenuated the association between a shorter telomere length and the presence of CAC. Logistic regression analyses controlling for age, gender, race/ethnicity, and Framingham risk score revealed that the relation between having shorter telomeres and the presence of CAC was attenuated in the presence of high social support, low meat consumption, and high fruit and vegetable consumption. Those with shorter telomeres and these characteristics were not significantly different from those with longer telomeres. Conversely, the subjects with shorter telomeres and less healthy lifestyles had a significantly increased risk of the presence of CAC: low fruit and vegetable consumption (odds ratio 3.30, 95% confidence interval 1.61 to 6.75), high meat consumption (odds ratio 3.33, 95% confidence interval 1.54 to 7.20), and low social support (odds ratio 2.58, 95% confidence interval 1.24 to 5.37). Stratification by gender yielded similar results for men; however, among women, only fruit and vegetable consumption attenuated the shorter telomere length and CAC relation. In conclusion, the results of the present study suggest that being involved in healthy lifestyle behaviors might attenuate the association between shorter telomere length and coronary atherosclerosis, as identified using CAC. PMID- 20723642 TI - Comparison of cardiovascular and metabolic risk factors in professional baseball players versus professional football players. AB - In 2006, a newspaper report indicated an increased prevalence of cardiovascular disease and early mortality in retired professional football players compared to professional baseball players. This study included 69 professional football players from a 2008 National Football League training camp and 155 professional baseball players from an American League 2009 spring training site who volunteered to participate in a study of cardiovascular and metabolic risk factors. The prevalence of body mass index > or =30 kg/m(2), waist circumference > or =100 cm, waist/height ratio >0.5, blood pressure > or =130/85 mm Hg, triglycerides > or =150 mg/dl, triglycerides/high-density lipoprotein cholesterol ratio >3.5, high-density lipoprotein cholesterol < or =40 mg/dl, and alanine aminotransferase > or =40 IU/L was determined in baseball players and compared to measurements obtained in a matched cohort from the National Health and Nutrition Examination Survey (NHANES), professional football players, and linemen and nonlinemen subsets. In conclusion, professional baseball players had favorable cardiovascular parameters, with the exception of an increased prevalence of hypertension, compared to the reference population, and professional baseball players had decreased measures of obesity, hyperglycemia, and the cardiometabolic syndrome compared to professional football lineman. PMID- 20723643 TI - Relation of QRS width in healthy persons to risk of future permanent pacemaker implantation. AB - In the setting of acute myocardial infarction, prolongation of the QRS interval on electrocardiography identifies patients at risk for needing permanent pacemaker implantation. However, the implications of prolonged QRS intervals in healthy subjects are unclear, especially given that the QRS prolongation encountered in this setting is typically mild. The aim of this study was to assess the relation between QRS duration and incident pacemaker implantation in a community-based cohort of 8,311 subjects (mean age 54 years, 55% women) who attended 17,731 routine examinations with resting 12-lead electrocardiography. QRS duration was analyzed as a continuous and a categorical variable (<100, 100 to <120, and > or =120 ms). During up to 35 years of follow-up, 157 participants (56 women) developed need for permanent pacemakers. In multivariable Cox regression models adjusting for cardiovascular risk factors and previous myocardial infarction or heart failure, mild QRS prolongation was associated with a threefold risk for pacemaker implantation (adjusted hazard ratio 2.90, 95% confidence interval 1.81 to 4.66, p <0.0001), and bundle branch block was associated with a fourfold risk for pacemaker implantation (hazard ratio 4.43, 95% confidence interval 2.94 to 6.68, p <0.0001). Each standard deviation increment in QRS duration (11 ms) was associated with an adjusted hazard ratio of 1.14 (95% confidence interval 1.11 to 1.18, p <0.0001) for pacemaker placement. This association remained significant after excluding subjects with QRS durations > or =120 ms. In conclusion, subjects with prolonged QRS durations, even without bundle branch block, are at increased risk for future pacemaker implantation. Such individuals may warrant monitoring for progressive conduction disease. PMID- 20723644 TI - Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. AB - Ibutilide is a class III antiarrhythmic agent indicated for cardioversion of atrial fibrillation and atrial flutter to sinus rhythm (SR). The most serious complication of ibutilide is torsades de pointes (TdP). Magnesium has been successfully used for the treatment of TdP, but its use as a prophylactic agent for this arrhythmia has not yet been established. The present study investigated whether high dose of magnesium would increase the safety and efficacy of ibutilide administration. A total of 476 patients with atrial fibrillation or atrial flutter who were candidates for conversion to SR were divided into 2 groups. Group A consisted of 229 patients who received ibutilide to convert atrial fibrillation or atrial flutter to SR. Group B consisted of 247 patients who received an intravenous infusion of 5 g of magnesium sulfate for 1 hour followed by the administration of ibutilide. Then, another 5 g of magnesium were infused for 2 additional hours. Of the patients in groups A and B, 154 (67.3%) and 189 (76.5%), respectively, were converted to SR (p = 0.033). Ventricular arrhythmias (sustained, nonsustained ventricular tachycardia, and TdP) occurred significantly more often in group A than in group B (7.4% vs 1.2%, respectively, p = 0.002). TdP developed in 8 patients (3.5%) in group A and in none (0%) in group B (p = 0.009). The administration of magnesium (despite the high doses used) was well tolerated. In conclusion, the administration of high doses of magnesium probably makes ibutilide a much safer agent, and magnesium increased the conversion efficacy of ibutilide. PMID- 20723645 TI - Comparison of detection of arrhythmias in patients with chronic heart failure secondary to non-ischemic versus ischemic cardiomyopathy by 1 versus 7-day holter monitoring. AB - The purpose of this study was to compare the diagnostic sensitivity of 1-day Holter monitoring versus 7-day Holter monitoring (7DH) to detect atrial and ventricular arrhythmias in a population of stable patients with chronic heart failure and left ventricular dysfunction. Sixty-three consecutive stable patients with chronic heart failure with left ventricular ejection fractions < or =50% were included. Blood samples were obtained, the Minnesota Living With Heart Failure Questionnaire was administered, and echocardiography, 6-minute walk tests, and 7DH were performed at enrollment. The mean ejection fraction was 35.8 +/- 9.8%, and the mean age was 55.5 +/- 13.9 years. Seven-day Holter monitoring did not significantly increase the detection of nonsustained atrial tachycardia or atrial fibrillation. In contrast, the incidence of nonsustained ventricular tachycardia increased in nonischemic patients from 35.1% on day 1 to 54.1% on day 7 (p = 0.01). In ischemic patients, the sensitivity increased from 11.5% to 46.2% (p = 0.004). Two patients without nonsustained ventricular tachycardia on day 1 had episodes of 13 and 16 beats on days 3 and 6 of monitoring. In patients with left ventricular ejection fractions >35% and N-terminal-pro-brain natriuretic peptide levels <1,000 pg/ml, no episodes of nonsustained ventricular tachycardia were detected on day 1 in nonischemic and ischemic patients, but 7DH detected 3 new patients in each group. In conclusion, 7DH clearly improves the detection and allows a better characterization of ventricular arrhythmic episodes but seems to be less useful for supraventricular events. PMID- 20723646 TI - Effect of cardiac resynchronization therapy on subendo- and subepicardial left ventricular twist mechanics and relation to favorable outcome. AB - The analysis of left ventricular (LV) mechanics provides novel insights into the effects of cardiac resynchronization therapy (CRT) on LV performance. Currently, advances in speckle-tracking echocardiographic analysis have permitted the characterization of subendocardial and subepicardial LV twist. The aim of this study was to investigate the role of the acute changes in subendocardial and subepicardial LV twist for the prediction of midterm beneficial effects of CRT. A total of 84 patients with heart failure scheduled for CRT were recruited. All patients underwent echocardiography before and <48 hours after CRT implantation and at 6-month follow-up. The assessment of LV volumes, ejection fractions, and mechanical dyssynchrony (systolic dyssynchrony index) was performed with real time 3-dimensional echocardiography. The assessment of subendocardial and subepicardial LV twist was performed with 2-dimensional speckle-tracking echocardiography. A favorable outcome was defined as the occurrence of a reduction > or =15% in LV end-systolic volume associated with an improvement of > or =1 New York Heart Association functional class at 6-month follow-up. At 6 month follow-up, 53% of the patients showed favorable outcomes. Ischemic cause of heart failure, baseline systolic dyssynchrony index, immediate improvement in the LV ejection fraction, immediate improvement in systolic dyssynchrony index, and immediate improvement in subendocardial and subepicardial LV twist were significantly related to favorable outcomes. However, in multivariate logistic regression analysis, only the immediate improvement of subepicardial LV twist was independently related to favorable outcomes (odds ratio 2.31, 95% confidence interval 1.29 to 4.15, p = 0.005). Furthermore, the immediate improvement of subepicardial LV twist had incremental value over established parameters. In conclusion, the immediate improvement of subepicardial LV twist (but not subendocardial LV twist) is independently related to favorable outcomes after CRT. PMID- 20723648 TI - Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure. AB - The nonosmotic release of arginine vasopressin, concurrent with the activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, is thought to represent the maladaptive response that is central to the pathophysiology of heart failure (HF). The degree of neurohormonal activation correlates with the severity of the disease and can predict the outcomes. However, quantification of components of neurohormonal axis (e.g., serum arginine vasopressin level) is mainly reserved for research purposes rather than routine practice. The results of several recent HF trials have shed light on the differential role of blood urea nitrogen (BUN) and creatinine in predicting the outcomes in this setting. These studies suggest that BUN could indeed represent a surrogate marker for "renal response" to neurohormonal activation in this setting, above and beyond its role in the estimation of renal function. In this report, the relevant physiologic mechanisms underlying urea and water transport in the kidney are first reviewed. Then, the activation of the neurohormonal axis and the impact of its components on renal urea transport, independent of changes in renal function, are explained. Finally, the unique role of BUN as a biomarker of neurohormonal activation in the setting of HF is discussed, and the potential clinical implication of this novel concept is emphasized. In conclusion, this review explains the pathophysiologic basis for the emerging role of BUN as a biomarker in HF. PMID- 20723647 TI - Frequency of atrial tachyarrhythmias in patients treated by cardiac resynchronization (from the Prospective, Multicenter Mona Lisa Study). AB - The continuous measurement of sustained atrial tachyarrhythmia (AT) is now possible with some permanently implanted devices. Data on this subject remain controversial. The aim of this study was to evaluate the incidence of sustained AT in patients treated with cardiac resynchronization therapy using pacemakers without backup defibrillators (CRT-P), within the first year after implantation, using strict definition criteria for sustained AT and a systematic review of all high-quality electrographically recorded episodes. The Mona Lisa study was a prospective, multicenter, cohort study carried out from February 2004 to February 2006, with a 12-month follow-up period. Sustained AT was defined as an episode lasting > or =5 minutes; episodes were confirmed by a systematic review of electrograms in the whole study population. Of the 198 patients who underwent CRT P device implantation and were enrolled in the study, 173 were in stable sinus rhythm at baseline and were included in the analysis (mean age 70 +/- 9 years, 66% men, 91% in New York Heart Association class III, mean QRS duration 164 +/- 26 ms, mean left ventricular ejection fraction 25 +/- 7%). During a mean follow up period of 9.9 +/- 3.6 months, 34 patients experienced > or =1 episode of sustained AT, for an incidence rate of 27.5% (95% confidence interval 18.2 to 36.7). Only a history of AT was independently associated with the occurrence of sustained AT within the 12 months after CRT-P device implantation (hazard ratio 2.3, 95% confidence interval 1.2 to 4.4, p = 0.02). In conclusion, this first prospective electrogram-based evaluation of AT incidence demonstrated that 27% of patients developed > or =1 episode of sustained AT lasting > or =5 minutes in the 12 months after CRT-P device implantation. PMID- 20723649 TI - Echocardiographic predictors for persistent functional mitral regurgitation after aortic valve replacement in patients with aortic valve stenosis. AB - Moderate functional mitral regurgitation (MR) in patients with aortic valve stenosis (AS) is often left unaddressed at the time of aortic valve replacement (AVR) because it is expected to decrease after AVR. However, some patients have persistent moderate MR after AVR. We sought to determine the preoperative echocardiographic predictor for persistent functional MR after AVR in patients with AS. Pre- and postoperative echocardiograms were reviewed in 110 patients with severe AS and functional MR who underwent AVR without mitral valve (MV) surgery. Fifty-eight patients received concomitant coronary artery bypass graft surgery. In patients with MV tenting, defined as apical displacement of mitral leaflets in the apical 4-chamber view, MV tenting area and tenting height were measured at midsystole. Eighty patients had MV tenting (mean MV tenting area 1.4 +/- 0.5 cm(2), mean MV tenting height 0.8 +/- 0.2 cm) and 30 did not have it before AVR. MR severity decreased in 51 of 80 patients (64%) with MV tenting after AVR and in 25 of 30 patients (83%) without MV tenting (p <0.05). In patients with MV tenting, multivariate analysis revealed that presence of long term atrial fibrillation and MV tenting area were independent predictors of postoperative MR severity (all p values <0.05). The sensitivity and specificity in predicting persistent moderate MR after AVR were 72% and 82% for MV tenting area >1.4 cm(2). In conclusion, preoperative MV tenting predicts persistent functional MR after AVR in patients with severe AS. PMID- 20723650 TI - Frequency of conduction disturbances after transcatheter implantation of an Edwards Sapien aortic valve prosthesis. AB - We evaluated the incidence of conduction abnormalities and requirement for permanent pacemaker in patients undergoing transcatheter aortic valve implantation (TAVI) with the Edwards Sapien prosthesis. In 2009, >8,000 patients were treated with TAVI using 1 of the 2 commercialized models of bioprosthesis (Edwards Sapien, Edwards Lifesciences, Irvine, California; and CoreValve, Medtronic, Irvine, California). Occurrence of conduction abnormalities including complete atrioventricular block requiring permanent pacemaker has been reported after TAVI with the 2 models of valve, more frequently with the CoreValve. We analyzed standard 12-lead electrocardiograms of 69 consecutive patients in whom an Edwards Sapien prosthesis was successfully implanted. Electrocardiograms were examined before treatment, at day 1, and at 1-month follow-up. Heart rate, PR and QT intervals and QRS duration were measured and the presence of a first-, second , or third-degree atrioventricular block was documented. There was a slight increase in heart rate and a discrete decrease in QT interval at day 1. These values had returned to baseline values at 1 month. There was no change in PR interval but a transitory increase in QRS duration was noted. Frequency of left bundle branch block increased from 14.5% at baseline to 27.5% at day 1 with a decreased incidence at day 30 (21.3%). Permanent pacemaker was required in only 3 patients (4.3%). In conclusion, in our experience, conductive disorders and requirement of a definitive pacemaker after implantation of an Edwards Sapien aortic bioprosthesis are infrequent. The physical properties of this prosthesis may explain this observation. PMID- 20723651 TI - Effect of candesartan treatment on left ventricular remodeling after aortic valve replacement for aortic stenosis. AB - In hypertension, angiotensin receptor blockers can augment regression of left ventricular (LV) hypertrophy. It is not known whether this also is the case after aortic valve replacement (AVR) for severe aortic stenosis (AS). To test the hypothesis that treatment with candesartan in addition to conventional treatment is able to augment LV and left atrial (LA) reverse remodeling in patients with AS undergoing AVR, we studied 114 patients scheduled for AVR. Patients were randomized to treatment with candesartan 32 mg 1 time/day or conventional therapy immediately after AVR. Patients were followed with echocardiographic evaluations 3, 6, and 12 months after surgery. Primary end point was change in LV mass index. At baseline and during follow-up no differences in systolic, diastolic, and pulse pressures were seen between groups. Baseline LV mass index was 134 +/- 41 g/m(2) with no difference between groups. Mean decrease in LV mass index in the control group was 12 +/- 28 g/m(2) compared to 30 +/- 40 g/m(2) in the candesartan group (p = 0.015) during follow-up. After 12 months LV mass index was significantly lower in the candesartan group (103 +/- 29 vs 119 +/- 31 g/m(2), p = 0.01). In addition, the candesartan group had greater improvement in longitudinal LV systolic function assessed by tissue Doppler S' wave (0.6 +/- 0.1-cm/s increase in control group vs 1.4 +/- 0.1 cm/s in candesartan group, p = 0.01, p for trend = 0.02) and a decrease in LA volume (p for trend = 0.01). Treatment had no effect on diastolic E/e' ratio or B-type natriuretic peptide. In conclusion, angiotensin receptor blockade with candesartan after AVR in patients with AS is associated with augmented reverse LV and LA remodeling compared to conventional management. PMID- 20723652 TI - Atrial arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and ventricular tachycardia. AB - Information on atrial arrhythmia associated with right ventricular cardiomyopathy/dysplasia (ARVC/D) is limited. In 36 patients with task force criteria for ARVC/D and history of ventricular tachycardia (VT), we confirmed the incidence and type of atrial arrhythmia, onset related to referral for VT ablation, fastest documented ventricular rate, management, and clinical and hemodynamic factors associated with their development. Thirty-six patients (28 men) had a mean age of 47 years (range 17 to 80) and mean follow-up of 56 +/- 44 months. Thirty-five patients (97%) had implantable cardioverter-defibrillator (ICD) devices, 15 with atrial leads. Fifteen of 36 patients (42%) had documented atrial arrhythmias, with atrial flutter (aFL) in 11, atrial fibrillation (AF) in 11 patients, and aFL and AF in 7 patients. Maximum heart rate noted with atrial arrhythmia was 62 to 150 beats/min. In 9 patients, initial atrial arrhythmia preceded or was concurrent with presentation for VT ablation. In the remaining 6 patients, atrial arrhythmia (symptomatic in 4 patients) followed VT presentation. Three of these patients received ICD shock therapy for atrial arrhythmias. Seven of 11 patients with recurrent aFL required aFL ablation, 1 patient underwent His bundle ablation for AF with rapid rate, and 8 patients required long-term drug therapy for AF control. Atrial arrhythmias were more common in patients with RV enlargement and moderate/severe tricuspid regurgitation. In conclusion, in patients with ARVC/D and VT, atrial arrhythmias are common, frequently necessitate ablative or pharmacologic treatment, and are more common in patients with moderate/severe tricuspid regurgitation and markedly enlarged right ventricle. PMID- 20723653 TI - Relation of left ventricular twist and global strain with right ventricular dysfunction in patients after operative "correction" of tetralogy of fallot. AB - In patients with corrected tetralogy of Fallot (cToF), left ventricular (LV) dysfunction is closely related to right ventricular (RV) dysfunction, indicating adverse ventricular-ventricular interactions. However, the mechanism that links RV dysfunction to LV dysfunction remains unclear. In this prospective study, 32 patients with cToF and 19 controls were enrolled. With cardiac magnetic resonance imaging, biventricular ejection fractions were assessed. Using 2-dimensional speckle tracking, global and regional RV and LV strains and LV twist were assessed. To detect and characterize ventricular-ventricular interaction, the relation between global and regional RV mechanics and global and regional LV mechanics was assessed. Global RV strain, global LV strain, and LV twist were decreased in patients with cToF. Global RV strain correlated with global LV strain (r = 0.66, p <0.001) and LV twist (r = -0.72, p <0.001), indicating the presence of adverse ventricular-ventricular interaction. Furthermore, close relations were observed between apical RV strain and apical LV strain (r = 0.62, p <0.001) and apical LV rotation (r = -0.67, p <0.001). In conclusion, RV strain was significantly related to LV strain and LV twist in patients with cToF and controls. Furthermore, apical RV strain correlated with apical LV strain and apical LV rotation, indicating adverse apical ventricular-ventricular interactions. PMID- 20723654 TI - Rate of inducible ventricular arrhythmia in adults with congenital heart disease. AB - Patients with adult congenital heart disease are at increased risk of ventricular arrhythmia (VA) and sudden cardiac death, although no clear predictors have been found. Ventricular programmed stimulation has been shown to predict clinical ventricular tachycardia and sudden death events, but the role of screening electrophysiology studies (S-EPSs) in this population remains poorly defined. Therefore, we sought to determine the prevalence of inducible VA and to evaluate the clinical predictors in a heterogeneous group of patients with adult congenital heart disease (> or =18 years old) undergoing S-EPSs at preoperative or interventional cardiac catheterization. Studies for the primary evaluation of clinical VA were excluded. The demographic, clinical, and diagnostic findings were compared between the patients with positive and negative findings. From 2005 to 2009, 80 patients (mean age 30 +/- 9 years) underwent S-EPSs, and 23 had inducible VA. The diagnoses for those with studies positive for VA included tetralogy of Fallot (n = 12), d-transposition of the great arteries (n = 6), pulmonary stenosis (n = 2), double outlet right ventricle (n = 1), double inlet left ventricle (n = 1), and Ebstein's anomaly (n = 1). Men were significantly more likely to have a S-EPS positive for VA (p = 0.015). Increasing QRS duration, decreasing peak oxygen uptake (percentage of predicted), and ventricular fibrosis with cardiovascular magnetic resonance imaging were significantly associated with studies positive for VA (p <0.05). Combined fibrosis and a peak oxygen uptake <80% of predicted had 100% sensitivity for positive VA findings. In conclusion, almost 30% of those with adult congenital heart disease undergoing S-EPSs had inducible VA. A prolonged QRS duration, diminished exercise capacity, and the presence of ventricular fibrosis were significantly associated with findings positive for VA and might improve patient selection for screening evaluations. PMID- 20723655 TI - Incidence, risk factors, and clinical outcomes of atrial fibrillation and atrial flutter after heart transplantation. AB - Atrial fibrillation (AF) and atrial flutter (AFL) after heart transplantation (HT) has been associated with increased mortality. Diverse incidence rates have been reported to date, with no clear classification according to the time of onset of such arrhythmias. We determined the incidence of AF/AFL using the time of onset after HT and analyzed the associated risk factors and outcomes. We performed a retrospective study of 228 HT recipients (March 1996 to July 2007), including donor and recipient demographics, gender mismatch, ischemia time, surgical anastomosis, time of onset of AF/AFL, acute cellular rejection, left ventricular systolic function, and all-cause mortality. The mean age of the donors (81% men) was 30 +/- 12 years and of the recipients (78% men) was 53 +/- 11 years. AF/AFL occurred in 45 patients (20%): 24 (11%) in the first 30 days, 10 (4%) within the 31 days to 1 year, and 11 (5%) after 1 year. When the patients with AF/AFL were compared to those with sinus rhythm, the significant difference was the older mean age of the donors (p = 0.001) and the recipients (p = 0.02). The all-cause mortality rate was 43% for those with AF/AFL compared to 23% for those with sinus rhythm (hazard ratio 2.45; 95% confidence interval 1.2 to 4.8), mostly driven by the greater mortality in the later-onset AF/AFL group (>30 days after HT). In conclusion, AF and AFL have an incidence of 20% after HT and are associated with increased overall mortality compared to that in patients in sinus rhythm. AF/AFL is more common within the first 30 days of HT, with an overall incidence of 20%. Older donor and recipient age is a risk factor associated with AF/AFL. PMID- 20723656 TI - Meta-analysis of adverse cardiovascular events associated with echocardiographic contrast agents. AB - In October 2007, the Federal Drug Agency issued a black box warning for contrast agents used in patients undergoing echocardiography and restricted their use in patients with acute coronary syndrome, a decompensated heart, and respiratory failure. We performed a systemic review and meta-analysis to study the adverse effects of contrast agents used with respect to myocardial infarction and all cause mortality. MEDLINE, EMBASE, BIOSIS, and Cochrane databases from inception to October 2009 were searched for studies that reported myocardial infarction and all-cause mortality after the use of contrast agents for echocardiography. A total of 8 studies were included in the present meta-analysis. A random-effect model was used, and between-studies heterogeneity was estimated with I(2). A total of 8 studies reported death as an outcome and only 4 reported myocardial infarction. The incidence of death in the contrast group was 0.34% (726 of 211,162 patients) compared to 0.9% (45,970 of 5,078,666 patients) in the noncontrast group. The pooled odds ratio was 0.57 (95% confidence interval 0.32 to 1.01, p = 0.05). The reported incidence of myocardial infarction in the contrast group was 0.15% (86 of 57,264 patients) compared to 0.2% (92 of 44,503 patients) in the noncontrast group. The pooled odds ratio was 0.85 (95% confidence interval 0.35 to 2.05, p = 0.72). Significant heterogeneity was seen among the studies. In conclusion, the cumulative evidence has suggested that the use of contrast agents for echocardiography is safe and not associated with a greater incidence of myocardial infarction or and mortality. PMID- 20723657 TI - Novel hypertrophic cardiomyopathy phenotype: segmental hypertrophy isolated to the posterobasal left ventricular free wall. AB - Few other diseases show the degree of phenotypic heterogeneity expressed by HC. The two novel patients reported here with isolated posterobasal LV free wall hypertrophy (and mitral valve prolapse) extend this morphologic diversity even farther, now 3 decades after the introduction of contemporary 2-dimensional imaging. PMID- 20723658 TI - A meta-analysis of association between serum lipoproteins and abdominal aortic aneurysm. PMID- 20723659 TI - The difficult challenge of assessing the clinical status of octogenarians with severe aortic stenosis. PMID- 20723660 TI - Diabetes mellitus is not a coronary heart disease equivalent. PMID- 20723662 TI - Invited review: Annatto usage and bleaching in dairy foods. AB - Annatto is a yellow/orange colorant that is widely used in the food industry, particularly in the dairy industry. Annatto, consisting of the carotenoids bixin and norbixin, is most commonly added to produce orange cheese, such as Cheddar, to achieve a consistent color over seasonal changes. This colorant is not all retained in the cheese, and thus a percentage remains in the whey, which is highly undesirable. As a result, whey is often bleached. Hydrogen peroxide and benzoyl peroxide are the 2 bleaching agents currently approved for bleaching whey in the United States. Recent studies have highlighted the negative effect of bleaching on whey flavor while concurrently there is a dearth of current studies on bleaching conditions and efficacy. Recent international mandates have placed additional concern on the use of benzoyl peroxide as a bleaching agent. This review discusses the advantages, disadvantages, regulatory concerns, flavor implications, and optimal usage conditions of 2 widely used bleaching agents, hydrogen peroxide and benzoyl peroxide, as well as a few alternative methods including lipoxygenase, peroxidase, and lactoperoxidase systems. PMID- 20723663 TI - Effects of seasonal changes in feeding management under part-time grazing on the evolution of the composition and coagulation properties of raw milk from ewes. AB - Ewe raw milk composition, rennet coagulation parameters, and curd texture were monitored throughout the milk production season in 11 commercial flocks reared under a part-time grazing system. Milking season lasted from February to July. During that period, the diet of the animals shifted from indoor feeding, consisting of concentrate and forage, to an outdoor grazing diet. Lean dry matter, fat, protein, calcium, and magnesium contents increased throughout the milking season, as did rennet coagulation time, curd firmness, and curd resistance to compression. However, lean dry matter, protein content, and curd resistance to compression stabilized when sheep started to graze. Principal component analysis correlated curd resistance to compression and proteins, whereas curd firmness was highly correlated with fat content and minerals. Discriminant analysis distributed milk samples according to the feeding management. Curd firmness, fat, and magnesium turned out to be discriminant variables. Those variables reflected the evolution of the composition and coagulation parameters when fresh pasture prevailed over other feeds in the diet of the flocks. The present study shows that seasonal changes associated with feeding management influence milk technological quality and that milk of good processing quality can be obtained under part-time grazing. PMID- 20723664 TI - A methodology for monitoring globular milk protein changes induced by ultrafiltration: a dual structural and functional approach. AB - Understanding filtration mechanisms at a molecular level is important for predicting structural and functional properties of globular milk proteins after membrane operations. This stage is thus highly decisive for the further development of membrane separations as an efficient alternative to chromatographic processes for the fractionation of milk proteins. In this study, we proposed an original and complete analytical package for the examination of the putative effect of filtration at both macroscopic and molecular levels. We then investigated the pertinence of this analytical package during ultrafiltration (UF) of globular milk proteins in both dead-end and crossflow modes. Reverse-phase HPLC combined with statistical computing was shown to be relevant for the assessment of even slight physically induced modifications. Adaptations of circular dichroism and solubility measurements, regarding their respective dependence on temperature and pH, were also useful for an accurate evaluation of functional modifications. At last, immunochemistry was proven to be a pertinent tool for the specific detection of modifications affecting a targeted protein, even in mixed solutions. Moreover, results obtained by such methods were shown to be coherent with data obtained from classical techniques such as fluorescence. For beta-lactoglobulin, some physically induced modifications were noticed in the permeate because of shear stress inside membrane pores. In the case of alpha-lactalbumin dead-end UF, permeation was shown to affect protein characteristics because of an increase in the relative calcium content responsible for a conformational transition from the apo-form to the holo-form of the protein. Finally, during crossflow UF with limited transmission of BSA, observations were coherent with a partial aggregation because of the circulation of proteins in the filtration pilot. Such a hypothesis corroborates results previously mentioned in the literature. PMID- 20723665 TI - Effect of bovine lactoferricin on DNA methyltransferase 1 levels in Jurkat T leukemia cells. AB - Abnormal methylation of the promoter of several genes is common in patients with acute lymphoblastic leukemia. Methylation of DNA is brought about by DNA methyltransferases (DNMT). Bovine lactoferricin (Lfcin B) is a cationic peptide that possesses potent in vitro and in vivo anticancer activity and might affect the expression of DNMT1. In the current study, we determined the mRNA and protein expression of DNMT1 in Jurkat T-leukemia cells, after incubation with Lfcin B, by real-time quantitative reverse transcription PCR and Western blot analysis. The results of real-time quantitative reverse transcription PCR showed that DNMT1 expression in Jurkat T-leukemia cells was reduced after treatment with Lfcin B, and Lfcin B reduced the half-life of DNMT1 mRNA from approximately 8 to 2h. The results of Western blot analysis showed that the expression of DNMT1 protein was down-modulated by Lfcin B in Jurkat T-leukemia cells. Moreover, we found that protein biosynthesis in Jurkat T-leukemia cells was essential for Lfcin B to down modulate the expression of DNMT1. PMID- 20723666 TI - Self-assembled beta-lactoglobulin-conjugated linoleic acid complex for colon cancer-targeted substance. AB - Beta-lactoglobulin (beta-LG) is a member of the lipocalin protein family and can bind a variety of hydrophobic molecules, such as fatty acids, in vitro. In this study, a potential colon-targeted antitumor drug was developed using bovine beta LG as a carrier loaded with cis-9, trans-11 conjugated linoleic acid (CLA). The intrinsic tryptophan fluorescence intensity of beta-LG monitored by spectrofluorometer showed that 2.46 mol of CLA can be bound per mole of beta-LG. Dynamic light scattering showed the formation of a beta-LG-CLA self-assembled complex with particle size of 170+/-0.08 nm. After treatment with gastrointestinal pH and digestive enzymes, beta-LG-CLA complex showed very good stability in gastrointestinal conditions in vitro, measured by zeta potential analyzer and sodium dodecyl sulfate PAGE, respectively. In an intestinal model in vitro, the concentration of CLA in Caco-2 cells was detected by reverse-phase HPLC, and the level of CLA in cells after treatment with beta-LG-CLA complex was significantly greater than after treatment with CLA, which means beta-LG served as a capsular vehicle of CLA for intracellular transport. According to cell proliferation assay, beta-LG-CLA complex can inhibit the viability of Caco-2 cells, and the inhibition rate is significantly greater than with the same concentration of CLA (100 microM). The study revealed that bovine beta-LG as a carrier binding with CLA can potentially be used for colon cancer therapy. PMID- 20723667 TI - Neutral and acidic oligosaccharides in Holstein-Friesian colostrum during the first 3 days of lactation measured by high performance liquid chromatography on a microfluidic chip and time-of-flight mass spectrometry. AB - Oligosaccharides (OS) from bovine milk are a class of bioactive molecules that are receiving increasing commercial attention for their potential health benefits. In the present work we measured, comprehensively and systematically, free milk OS in the colostrum of 7 Holstein-Friesian cows during the first 3 d of lactation in 12-h intervals by HPLC-chip/time-of-flight mass spectrometry to determine the biological variation of free milk OS in early lactation. The high sensitivity and resolution of the analytical technique made it possible to monitor all OS species, thus providing a comprehensive and quantitative analysis of OS variations during colostrum production. This study confirmed that although sialyllactose is the major OS in bovine colostrum, several neutral OS species are present in significant abundance even at the third day of lactation. Furthermore, variation in terms of OS species and relative abundances of OS between cows suggest individual animal variation. These variations are likely due to genetic factors because environmental factors such as nutrition, lactation number, and accommodation were the same for all cows. This investigation revealed that colostrum milk from Holstein-Friesian cows is a rich source of neutral and acidic OS for the food and pharmaceutical industries. PMID- 20723669 TI - Short communication: Correlation of on-site inspection and laboratory milk testing results for Wisconsin grade A dairy farms in 2007 and 2008. AB - This study examined whether regulatory on-site dairy farm inspection results correlated with reported laboratory somatic cell count (SCC), standard plate count (SPC), and beta-lactam drug residue (DR) results for individual farms. Results were obtained for Wisconsin grade A dairy farms in 2007 and 2008 (>11,000 farms, >1.4 million data points). The proportion of farms failing an on-site inspection ranged from 12% for farms that had never failed an SCC test (>750,000 cells/mL), an SPC test (>100,000 cfu/mL), or a DR test (drug detected) to 55% for farms that had failed at least 1 of each type of test. Conditional probability analysis showed that the probability of a farm failing an on-site farm inspection was higher if the farm had failed a DR test and increased as the proportion of samples failing SCC or SPC or both increased. However, the statistical correlations were weak (R0.33 ng/mL) were predictive of a positive d 32 pregnancy diagnosis (sensitivity=100%; specificity=90.6%). In conclusion, Resynch and control protocols had comparable pregnancy per AI for first and second TAI services, but pregnancy occurred 3.2 d earlier in the Resynch group because inseminations in the Resynch treatment began 7 d before those in the control treatment. Administration of an intravaginal progesterone insert, or GnRH, or both increased progesterone during pregnancy. Dynamics of pregnancy-associated glycoproteins were indicative of pregnancy status and pregnancy loss. PMID- 20723676 TI - Relationship between udder health and hygiene on farms with an automatic milking system. AB - Poor hygiene is an important risk factor for reduced udder health. Because the teat cleaning process is done automatically on farms with an automatic milking system (AMS), hygiene management might differ. The aim of this study was to determine the relationship between hygiene and udder health on farms with an AMS at the farm level as well as at the cow level. Information on hygiene and udder health was collected on 151 Dutch dairy farms with an AMS. Teams of 2 veterinary students collected data with the use of a partially open-ended questionnaire and scoring protocols for hygiene of the cows, cleanliness of the AMS, and functioning of the AMS. Milk production records from the Dutch dairy herd information association were also collected. Stepwise general linear models were used to analyze the relation between hygiene and udder health at farm level. Dependent variables were average herd somatic cell count (SCC), the average percentage of new cows with a high SCC, and the incidence rate of clinical mastitis, all in the year preceding the farm visit. The annual average herd SCC was positively related to the proportion of cows with dirty teats before milking and the proportion of cows with dirty thighs. The annual average percentage of new cows with a high SCC was positively related to the proportion of cows with dirty teats before milking and the proportion of milkings where teats were not covered with teat disinfecting spray by the AMS. The annual incidence rate of clinical mastitis was positively related to the frequency of replacing the milking filters. At the cow level, hygiene scores of the udder, thighs, and legs (range 1 to 4, where 1 is clean and 4 is very dirty) were related with cow SCC from the milk production test day closest to the farm visit using a general linear mixed model. The relationship between cow SCC and the hygiene score of the udder was positive. PMID- 20723677 TI - Bioeconomic modeling of lactational antimicrobial treatment of new bovine subclinical intramammary infections caused by contagious pathogens. AB - This study determined the direct and indirect epidemiologic and economic effects of lactational treatment of new bovine subclinical intramammary infections (IMI) caused by contagious pathogens using an existing bioeconomic model. The dynamic and stochastic model simulated the dynamics of Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, and Escherichia coli during lactation and the dry period in a 100-cow dairy herd during 1 quota year. Input parameters on cure were obtained from recent Dutch field data. The costs of clinical IMI, subclinical IMI, and intervention were calculated into the combined total annual net costs of IMI per herd. The cost effectiveness of 4 scenarios with lactational intervention was determined; scenarios included no intervention, treatment after 1 mo of infection, treatment after 2 mo of infection, and treatment after 1 mo of infection and culling of uncured cows after 2 mo of infection. Model behavior was observed for variation in parameter input values. Compared with no lactational intervention, lactational intervention of new subclinical IMI resulted in fewer clinical flare ups, less transmission within the herd, and much lower combined total annual net costs of IMI in dairy herds. Antimicrobial treatment of IMI after 1 mo of infection and culling of uncured cows after 2 mo of infection resulted in the lowest costs, whereas treatment after 2 mo of infection was associated with the highest costs between the scenarios with intervention. Changing the probability of cure resulted in a nonlinear change in the cumulative incidence of IMI cases and associated costs. Lactational treatment was able to prevent IMI epidemics in dairy herds at high transmission rates of Strep. uberis, Strep. dysgalactiae, and E. coli. Lactational treatment did not limit the spread of Staph. aureus at high transmission rates, although the associated costs were lower compared with no intervention. To improve udder health in a dairy herd, lactational treatment of contagious subclinical IMI must therefore be preceded by management measures that lower the transmission rate. Lactational treatment of environmental subclinical IMI seemed less cost effective. Detection of subclinical IMI needs improvement to be able to most effectively treat subclinical IMI caused by contagious pathogens during lactation. PMID- 20723678 TI - Association between milk yield and serial locomotion score assessments in UK dairy cows. AB - This study investigated the effect of lameness, measured by serial locomotion scoring over a 12-mo period, on the milk yield of UK dairy cows. The data set consisted of 11,735 records of test-day yield and locomotion scores collected monthly from 1,400 cows kept on 7 farms. The data were analyzed in a multilevel linear regression model to account for the correlation of repeated measures of milk yield within cow. Factors affecting milk yield included farm of origin, stage of lactation, parity, season, and whether cows were ever lame or ever severely lame during the study period. Cows that had been severely lame 4, 6, and 8 mo previously gave 0.51 kg/d, 0.66 kg/d, and 1.55 kg/d less milk, respectively. A severe case of lameness in the first month of lactation reduced 305-d milk yield by 350 kg; this loss may be avoidable by prompt, effective treatment. Larger reductions can be expected when cases persist or recur. Evidence-based control plans are needed to reduce the incidence and prevalence of lameness in high yielding cows to improve welfare and productivity. PMID- 20723679 TI - Effects of 6 times daily milking during early versus full lactation of Holstein cows on milk production and blood metabolites. AB - An experiment was conducted to determine the effects of different milking frequencies on entire lactation production performance in Holstein cows. One hundred twenty Holstein cows were assigned to 3 milking treatments (35 multiparous and 5 primiparous cows in each): 1) milking 6 times daily for the entire lactation (6x); 2) milking 6 times daily for the first 90 d in milk (DIM) and switching to 3 times daily milking afterward (6x-3x); and 3) milking 3 times daily for the entire lactation (3x). Milk yield was recorded every other day during the first 60 DIM and on 2 consecutive days per week subsequently. Cows were weighed and scored for their body condition immediately after parturition and monthly afterward. Blood and milk samples were taken from each cow on 30, 60, 90, 120, 150, 210, and 270 DIM, with an additional blood sampling on 15 DIM. Milk and fat corrected milk yield was greater for 6x and 6x-3x cows than for 3x cows (36.82, 37.32, and 36.1, 36.75 versus 34.56, 35.33 kg/d, respectively) during the experimental period. Milk fat and lactose percentage were not different among treatments, but milk protein was lower in 6x cows than in 6x-3x and 3x cows. Blood glucose concentration was higher and blood nonesterified fatty acids and beta-hydroxybutyrate concentration were lower in 3x cows than in 6x and 6x-3x cows during early lactation. Dry matter intake was greater in 6x cows than in 6x 3x and 3x cows (23.05, 22.58, and 22.45 kg/d, respectively). The 3x cows began to gain weight earlier than the 6x and 6x-3x cows, but there was no difference among groups for BW change regarding the entire experimental period. These results indicate that increasing milking frequency to 6 times daily increases milk yield only during early lactation and that there are no advantages of milking 6 times daily compared with 3 times daily during the mid and late lactation periods. Given the results of this study and the economical aspects of production, milking 6 times daily until 90 DIM and subsequently switching to milking 3 times daily is preferred. PMID- 20723681 TI - The effect of claw horn disruption lesions and body condition score at dry-off on survivability, reproductive performance, and milk production in the subsequent lactation. AB - The objective of this study was to evaluate the effects of claw horn disruption lesions (CHDL; sole ulcers and white line disease) and body condition score (BCS) at dry-off on survivability, milk production, and reproductive performance during the subsequent lactation. An observational prospective cohort study was conducted on a large commercial dairy in Cayuga County, New York, from September 2008 until January 2009. A total of 573 cows enrolled at dry-off were scored for body condition and hoof trimmed; digits were visually inspected for the presence of CHDL. The BCS data were recategorized into a 3-level variable BCS group (BCSG), with cows with BCS<3 placed in BCSG 1 (n=113), cows with BCS=3 placed in BCSG 2 (n=254), and cows with BCS>3 placed in BCSG 3 (n=206). Cows in BCSG 2 were 1.35 and 1.02 times more likely to conceive than cows in BCSG 1 and 3, respectively. The cull/death hazard for BCSG 1 cows was 1.55 and 1.47 times higher than for cows in BCSG 2 and BCSG 3, respectively. Milk yield for cows in BCSG 2 (44.6 kg/d, 95% CI 43.4-45.8) was significantly greater than that for cows in BCSG 1 (41.5 kg/d, 95% CI 39.8-43.3). Cows with previous lactation days open14,054 kg had a similar 1.6 times higher odds of being classified into BCSG 1. Claw horn disruption lesions were found in 24.4% of the cows (n=140) at dry-off. Cows without CHDL were 1.4 times more likely to conceive than cows with CHDL. Additionally, lesion cows were 1.7 times more likely to die or be culled than nonlesion cows. Absence of CHDL did not have a significant effect on milk yield. These findings highlight the importance of claw health and BCS at the end of lactation on future survival and performance. PMID- 20723680 TI - The effects of milk removal or four-times-daily milking on mammary expression of genes involved in the insulin-like growth factor-I axis. AB - Frequent milking of dairy cows during early lactation elicits both an immediate increase in milk yield and a partial carryover effect that persists to the end of lactation. We hypothesized that the immediate response would be associated with a local increase in insulin-like growth factor (IGF)-I signaling and a consequent increase in mammary growth. Four multiparous cows were assigned at parturition to unilateral frequent milking [UFM; milking of the left udder half twice daily (2x; 0230 and 1430 h); milking of the right udder half 4 times daily (4x; 0230, 0530, 1430, and 1730 h)]. Mammary biopsies were obtained from both udder halves at 5 d in milk at 0530 h (immediately after 4x glands were milked). Incorporation of [3H]-thymidine into DNA and mammary cell apoptosis were not affected by UFM. Because biopsies were obtained when udder halves were at different postmilking intervals, our results reflected both the acute, transient mammary response to milking and the sustained mammary response to frequent milking treatment. We further hypothesized that the acute, transient response involves mechanisms distinct from those regulating the sustained response to frequent milking. To test that hypothesis, mammary biopsies were obtained from UFM cows (n=5) at 0500 h, when time postmilking was the same for both udder halves. Mammary cell apoptosis was not affected by UFM. Expression of genes involved in the IGF-I axis was analyzed to identify acute responses associated with milking, per se, versus sustained responses to frequent milking treatment. Removal of milk from 4x glands was associated with an acute increase in expression of IGF binding protein-1, -3, and -4 mRNA in 2x glands, whereas IGF-I expression was increased by frequent milking treatment. These effects, however, were significant only for expression of IGF binding protein-3. Expression of IGF-I receptor did not differ because of milking frequency but was higher in both udder halves immediately postmilking, indicating a systemic effect. We conclude that several genes of the IGF-I axis respond to milking, per se, or frequent milking treatment, via at least 3 distinct patterns. Increased milking frequency does not alter mammary cell proliferation or apoptosis at 5 d in milk; however, it may increase the bioavailability of IGF-I in the mammary gland. Moreover, the increase in local expression of IGF-I in 4x udder halves indicates a role for this gene in the immediate milk yield response to frequent milking during early lactation. PMID- 20723682 TI - Effects of 2.1 and 3.5x10(6) sex-sorted sperm dosages on conception rates of Holstein cows and heifers. AB - The objective was to compare conceptions rates of Holstein cows and heifers after artificial insemination (AI) with 2.1 or 3.5x10(6) sex-sorted sperm or 15x10(6) conventional sperm. Ejaculates collected from 7 Holstein sires were cryopreserved conventionally at 15x10(6) sperm per dose or sorted to 90% purity for X chromosome-bearing spermatozoa using flow cytometry and cryopreserved at either 2.1 or 3.5x10(6) sperm per dose. All treatments were processed in an egg-yolk (20%), Tris, glycerol (7%) extender and packaged in color-coded 0.25-mL French straws. Straws (n=700 straws/dosage per sire) were packaged and distributed in aliquots of 12 (4 straws/sperm dosage) to 69 Holstein herds with an across-herd goal of achieving approximately 50% use in heifers and cows. Straw color was recorded in the on-farm recordkeeping system at the time of AI and retrieved by electronic download. Data for cows and heifers were analyzed separately. Among heifers, 6,268 services were retrieved from 45 herds (298+/-4.2 services/sperm dose per sire; range: 244 to 344). Conception rate of heifers was influenced by the sire by treatment interaction. Conception rate of the 2.1 and 3.5x10(6) sex sorted sperm dosages were comparable in 6 of 7 sires. Conception rate of both sex sorted dosages were less than those of conventional semen for 6 of 7 sires. Across sires, heifer conception rates for 2.1 and 3.5x10(6) sex-sorted sperm dosages and 15x10(6) conventional dosages were 44, 46, and 61%, respectively. Among cows, 5,466 services were retrieved from 52 herds (260+/-3.3 services/sperm dose per sire; range: 236 to 289). Conception rates of cows were influenced by herd, sire, and sperm dosage. Conception rates of the 2.1 and 3.5x10(6) sex sorted sperm dosage were comparable for all 7 sires. Conception rates of 2.1x10(6) sex-sorted sperm dosage were less than those of conventional semen for 4 of 7 sires and conception rates of the 3.5x10(6) sex-sorted sperm dosage were less than those of conventional semen for 2 of 7 sires. Across sires, conception rates for 2.1 and 3.5x10(6) sex-sorted sperm dosages and 15x10(6) conventional dosages in cows were 23, 25, and 32%, respectively. In conclusion, these data could not confirm that a meaningful improvement in conception rates should be expected in cows or heifers from increasing sex-sorted sperm dosage from 2.1 to 3.5x10(6) sperm per dose. PMID- 20723684 TI - Evaluation of a biological risk management tool on large western United States dairies. AB - Critical to changing biosecurity practices on the farm is an individual assessment of those practices contributing to disease transmission. The purpose of this project was to assess, implement, and refine a biological risk management survey for use on large western United States dairy farms. Assessment tools developed by Iowa State University Center for Food Security and Public Health (Ames, IA) were refined using a focus group process and by testing them on 40 dairy herds in California. Each question was evaluated using standard criteria and producer responses. Some survey questions required refinement for clarity and others were considered unnecessary. New questions were added based on a biosecurity literature review, resulting in a new set of questions that can be used by extension educators and food animal veterinarians to help identify disease risk areas and educate dairy producers. PMID- 20723683 TI - Resynchronization strategies to improve fertility in lactating dairy cows utilizing a presynchronization injection of GnRH or supplemental progesterone: I. Pregnancy rates and ovarian responses. AB - Objectives were to evaluate 3 resynchronization protocols for lactating dairy cows. At 32+/-3 d after pre-enrollment artificial insemination (AI; study d -7), 1 wk before pregnancy diagnosis, cows from 2 farms were enrolled and randomly assigned to 1 of 3 resynchronization protocols after balancing for parity, days in milk, and number of previous AI. All cows were examined for pregnancy at 39+/ 3 d after pre-enrollment AI (study d 0). Cows enrolled as controls (n=386) diagnosed not pregnant were submitted to a resynchronization protocol (d 0-GnRH, d 7-PGF2alpha, and d 10-GnRH and AI) on the same day. Cows enrolled in the GGPG (GnRH-GnRH-PGF2alpha-GnRH) treatment (n=357) received a GnRH injection at enrollment (d -7) and if diagnosed not pregnant were submitted to the resynchronization protocol for control cows on d 0. Cows enrolled in CIDR treatment (n=316) diagnosed not pregnant received the resynchronization protocol described for control cows with addition of a controlled internal drug release (CIDR) insert containing progesterone (P4) from d 0 to 7. In a subgroup of cows, ovaries were scanned and blood was sampled for P4 concentration on d 0 and 7. After resynchronized AI, cows were diagnosed for pregnancy at 39+/-3 and 67+/-3 d (California herds) or 120+/-3 d (Arizona herds). Cows in the GGPG treatment had more corpora lutea than CIDR and control cows on d 0 (1.30+/-0.11, 1.05+/-0.11, and 1.05+/-0.11, respectively) and d 7 (1.41+/-0.14, 0.97+/-0.13, and 1.03+/ 0.14, respectively). A greater percentage of GGPG cows ovulated to GnRH given on d 0 compared with CIDR and control cows (48.4, 29.6, and 36.6%, respectively), but CIDR and control did not differ. At 39+/-3 d after resynchronized AI, pregnancy per AI (P/AI) was increased in GGPG (33.6%) and CIDR (31.3%) cows compared with control (24.6%) cows. At 67 or 120+/-3 d after resynchronized AI, P/AI of GGPG and CIDR cows was increased compared with control cows (31.2, 29.5, and 22.1%, respectively). Presynchronizing the estrous cycle of lactating dairy cows with a GnRH 7 d before the start of the resynchronization protocol or use of a CIDR insert within the resynchronization protocol resulted in greater P/AI after resynchronized AI compared with control cows. PMID- 20723685 TI - Cefoperazone sodium preparation behavior after intramammary administration in healthy and infected cows. AB - Selection of the antimicrobial agent and maintenance of adequate drug concentrations at the site of infection are the most relevant problems in mastitis antibiotic therapy. Intramammary drug efficacy can be maximized by keeping drug concentrations at the site of infection above the minimum inhibitory concentration (MIC) as long as possible; the most important pharmacokinetic and pharmacodynamic (PK/PD) measure for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). To evaluate this measure, the PK profile of cefoperazone (CFP) after single intramammary administration in healthy and subclinical infected Staphylococcus aureus cows and the MIC of Staph. aureus field strains were assessed. In addition, the degree of drug passage from udder to bloodstream was investigated by measuring systemic drug absorption in healthy and infected animals. Cefoperazone concentrations were quantified by HPLC in quarter milk samples and blood serum samples. Systemic drug absorption was negligible in healthy animals (0.020+/-0.006 microg/mL serum at 4 h), whereas it was higher in infected animals (0.102+/-0.079 microg/mL at 4h and 0.025 microg/mL at 24 h), probably due to the damage of epithelial cell junctions caused by subclinical infections. The MIC90 value for CFP in Staph. aureus field strains (n=24) was 0.64 microg/mL. The PK/PD evaluation, determined by t>MIC, showed a longer persistence of CFP in infected quarters than in healthy ones (mean residence time was 8.37+/-1.51 vs. 11.42+/-5.74 h in September and 2.07+/-0.43 vs. 3.31+/-0.91 h in October), with a t>MIC of 45+/-6 h for infected quarters versus 38+/-5 h for healthy quarters different only in October. This could mean a prolonged time in which microorganisms are exposed to drug activity and thus, a greater efficacy of the drug. PMID- 20723686 TI - Physiological calf responses to increased chromium supply in summer. AB - The primary objective was to determine pre- and postweaning calf physiological responses to increased Cr supply under high ambient temperatures. In a randomized complete block design, 24 neonate Holstein calves (BW=41.5+/-1.9 kg) were grouped based on sex and randomly assigned to 3 treatments within each group. Treatments included either no supplemental Cr (control), 0.02 mg of supplemental Cr/kg of BW0.75, or 0.04 mg of supplemental Cr/kg of BW0.75. The average temperature humidity index was 77 during the study. Chromium was provided as a commercial product in whole milk for preweaning calves and in a starter concentrate for postweaning calves. Calves were weaned at 1 kg of daily calf starter intake lasting for 6 consecutive days. A glucose tolerance test was conducted on d 25 postweaning. Treatments had no effects on preweaning dry matter intake, feed conversion ratio, average daily gain, and weaning age. Chromium decreased dry matter intake in postweaning calves; however, it did not affect growth and feed conversion ratio. Chromium lowered respiration rate at wk 5 without affecting fecal score and rectal temperature. Preweaning serum cortisol concentrations were altered by a 3-way interaction of Cr dose with calf sex and age. Preweaning serum glucose showed week-dependent increases by Cr. Serum insulin, urea, albumin, total protein, triiodothyronine, and thyroxin concentrations through weaning were not affected. The increasing Cr doses caused quadratic declines in serum thyroxin on d 21 postweaning, whereas blood triiodothyronine declined only with the higher Cr dose. Serum NEFA remained unchanged, but BHBA decreased by Cr in male calves on d 21 postweaning. The glucose tolerance test revealed linear reductions in area under insulin curve between 0 to 90 and 0 to 120 min after glucose infusion, suggesting improvements in peripheral insulin efficiency. Sex-dependent responses to Cr were observed for serum total protein and albumin concentrations at 21 d postweaning. Overall, results indicate that in summer, increased dietary Cr supply can benefit postweaning insulin metabolism, alter preweaning blood cortisol and glucose levels, and reduce respiration rate and may have only minor effects on calf growth. PMID- 20723687 TI - Effect of saturated fatty acid supplementation on production and metabolism indices in heat-stressed mid-lactation dairy cows. AB - Experimental objectives were to determine the effects of supplemental saturated fatty acids on production, body temperature indices, and some aspects of metabolism in mid-lactation dairy cows experiencing heat stress. Forty-eight heat stressed Holstein cows were allocated into 3 groups (n=16/group) according to a completely randomized block design. Three treatment diets consisted of supplemental saturated fatty acids (SFA) at 0 (SFA0), 1.5 (SFA1.5), or 3.0% (SFA3) of dry matter (DM) for 10 wk. Diets were isonitrogenous (crude protein=16.8%) and contained 1.42, 1.46, and 1.49 Mcal of net energy for lactation/kg of DM for the SFA0, SFA1.5 and SFA3 diets, respectively. The average temperature-humidity index at 0700, 1400 and 2200 h was 72.2, 84.3, and 76.6, respectively. Rectal temperatures at 1400 h were decreased with fat supplementation. Treatment did not affect dry matter intake (20.1+/-0.02 kg/d), body condition score (2.72+/-0.04), body weight (627+/-16.1 kg), or calculated energy balance (1.32+/-0.83 Mcal/d). Saturated fatty acid supplementation increased milk yield, milk fat content, and total milk solids. Increasing fat supplementation decreased plasma nonesterified fatty acids (8%) but had no effect on other energetic metabolites or hormones. In summary, supplemental SFA improved milk yield and milk fat content and yield and reduced peak rectal temperatures in mid-lactation heat-stressed dairy cows. This demonstrates the remarkable amount of metabolic heat that is "saved" by energetically replacing fermentable carbohydrates with supplemental SFA. PMID- 20723688 TI - Predicting energy x protein interaction on milk yield and milk composition in dairy cows. AB - Feed management is one of the principal levers by which the production and composition of milk by dairy cows can be modulated in the short term. The response of milk yield and milk composition to variations in either energy or protein supplies is well known. However, in practice, dietary supplies of energy and protein vary simultaneously, and their interaction is still not well understood. The objective of this trial was to determine whether energy and protein interacted in their effects on milk production and milk composition and whether the response to changes in the diets depended on the parity and potential production of cows. From the results, a model was built to predict the response of milk yield and milk composition to simultaneous variations in energy and protein supplies relative to requirements of cows. Nine treatments, defined by their energy and protein supplies, were applied to 48 cows divided into 4 homogeneous groups (primiparous or multiparous x high or low milk potential) over three 4-wk periods. The control treatment was calculated to cover the predicted requirements of the group of cows in the middle of the trial and was applied to each cow. The other 8 treatments corresponded to fixed supplies of energy and protein, higher or lower than those of the control treatment. The results highlighted a significant energy x protein interaction not only on milk yield but also on protein content and yield. The response of milk yield to energy supply was zero with a negative protein balance and increased with protein supply equal to or higher than requirements. The response of milk yield to changes in the diet was greater for cows with high production potential than for those with low production potential, and the response of milk protein content was higher for primiparous cows than for multiparous cows. The model for the response of milk yield, protein yield, and protein content obtained in this trial made it possible to predict more accurately the variations in production and composition of milk relative to the potential of the cow because of changes in diet composition. In addition, the interaction obtained was in line with a response corresponding to the more limiting of 2 factors: energy or protein. PMID- 20723689 TI - Ruminal degradability and intestinal digestibility of protein and amino acids in soybean and corn distillers grains products. AB - New fractionation and fermentation technologies in the ethanol industry have resulted in the production of different forms of distillers grains (DG). Such products are reduced-fat, high-protein, and "modified" wet feeds. Characterization of protein fractions of these co-products and other commonly used feedstuffs is important for the formulation of dairy cattle diets. In situ and in vitro techniques were conducted to compare crude protein (CP) availability in 4 DG products with commonly used soybean proteins. Soybean protein products included solvent-extracted soybean meal (SBM; 44% CP), expeller soybean meal (ESBM), and extruded soybeans (ES). The DG products were conventional distillers dried grains with solubles, reduced-fat distillers dried grains with solubles (RFDGS), high-protein distillers dried grains, and modified wet distillers grains with solubles (MWDGS). Nylon bags containing 5 g of each feed were incubated in the rumen of 3 cannulated lactating cows for 2, 4, 8, 16, 24, and 48 h. The rapidly degradable CP fraction varied from 8.1 to 37.2% for SBM and MWDGS, respectively. The slowly degradable CP fraction was greatest for SBM, ES, and high-protein distillers dried grains (88.0%+/-3.7), followed by ESBM, distillers dried grains with solubles, and RFDGS (76.8+/-4.1%). The MWDGS had the lowest slowly degradable CP fraction (61.1%). The rate of degradation of the slowly degradable CP fraction ranged from 11.8 for SBM to 2.7%/h for RFDGS. Rumen undegradable protein varied widely (32.3 to 60.4%), with RFDGS having the greatest and SBM the lowest concentrations. Intestinal digestibility of rumen undegradable protein (IDP) was estimated by pepsin-pancreatin digestion of ruminally preincubated (16 h) samples. The IDP was greatest for SBM, ESBM, and ES (97.7%+/-0.75), whereas IDP of DG products was 92.4%+/-0.87. Similarly, total digestible protein was greatest (99.0%) for soybean products, whereas DG products had a total digestible protein of 96.0%. Intestinal digestibility of most AA in DG products exceeded 92% and was slightly lower than for soybean products, except for Lys, where the digestibility was 84.6% for DG compared with 97.3% for soybean products. Absorbable Lys was lower for DG (7.0 g/kg of CP) compared with ESBM and ES (average of 23.8 g/kg of CP). Dried DG, ESBM, and ES provided more absorbable AA compared with SBM and MWDGS. These results suggest that the AA availability from DG products is comparable with that from soybean products. PMID- 20723690 TI - Effect of multiple intravenous injections of butaphosphan and cyanocobalamin on the metabolism of periparturient dairy cows. AB - Numerous adjunct therapeutic agents have been investigated for the treatment or control of fat mobilization syndrome in periparturient dairy cows. The aim of this study was to determine the effects of multiple i.v. injections of 10% butaphosphan and 0.005% cyanocobalamin combination (Catosal, Bayer Animal Health, Leverkusen, Germany) between 1 and 2 wk antepartum (a.p.) on the metabolism and health of dairy cows. Forty-five late-gestation Holstein-Friesian cows (second pregnancy) were allocated randomly to 1 of 3 groups with 15 cows/group: group C6 (6 daily i.v. injections of butaphosphan at 10 mg/kg of body weight (BW) and cyanocobalamin at 5 microg/kg of BW in the last 2 wk of gestation); group C3 (3 daily i.v. injections of butaphosphan at 10 mg/kg of BW and cyanocobalamin at 5 microg/kg of BW in the last week of gestation); and group C0 (equivolume daily i.v. injections of 0.9% NaCl solution). Serum biochemical analysis was performed on jugular venous blood samples that were periodically obtained a.p. and postpartum (p.p.). Health status and milk production were monitored p.p. Serum cyanocobalamin concentration increased in groups C6 and C3 p.p. Multiple daily i.v. injections of Catosal before parturition increased p.p. glucose availability, as evaluated by p.p. serum glucose concentration, and decreased peripheral fat mobilization and ketone body formation, as evaluated by p.p. serum nonesterified fatty acid and beta-OH butyrate concentrations. The number of puerperal infections in the first 5 d after calving was decreased in group C6, relative to group C0. We conclude that multiple injections of Catosal during the close-up period have a beneficial effect on the metabolism of periparturient dairy cows. Our results are consistent with the hypothesis that high-producing dairy cows in early lactation may have a relative or actual deficiency of cyanocobalamin. PMID- 20723691 TI - Morphology, proliferation, and ribonucleic acid and fractional protein syntheses in the small intestinal mucosa of young goats fed soy protein-based diets with or without amino acid supplementation. AB - The study was designed to examine whether feeding soy protein isolate as partial replacement of casein (CN) affects jejunal protein synthesis and whether effects may be ameliorated by supplementation of those AA known to be at lower concentrations in soy protein isolate than in CN. Goat kids (14 d) were fed comparable milk protein diets, in which 50% of the crude protein was CN (CAS), soy protein isolate (SPI), or soy protein isolate supplemented with AA (SPIA) for 43 d (n=8 per group). On d 42, plasma concentrations of protein, urea, and AA were measured before and after morning feeding. In the morning of d 43, [15N]RNA from yeast [13 mg/kg of body weight (BW)] was given with the diet to measure the reutilization of dietary RNA precursors for mucosal RNA biosynthesis. Four hours later, an oral dose of l-[1-(13)C]leucine (180 mg/kg of BW) was administered and blood samples were collected between -15 and +45 min relative to tracer administration for analysis of plasma 13C alpha-ketoisocaproic acid and 13C recovery in blood CO2. Kids were killed 60 min after the tracer application, and jejunal tissue was collected to determine mucosal morphology, cell proliferation, enzyme activities, RNA synthesis, and fractional protein synthesis rate. Plasma protein concentrations were higher in CAS than in SPI and SPIA. Plasma concentrations of Thr were higher in CAS than in SPI and SPIA, and those of Met were lower in SPI than in CAS and SPIA. In mid-jejunum, villus circumferences were higher in CAS than in SPI and SPIA, and villus height and villus height:crypt depth ratio were higher in CAS than in SPI. In mid-jejunum, mucosal protein concentrations were higher in CAS than in SPI and SPIA and mucosal activities of aminopeptidase N tended to be higher in CAS than in SPI, whereas activities of dipeptidyl peptidase IV tended to be lower in SPI than in SPIA. Activities of 5' nucleotidase and xanthine oxidase were lower in CAS than in SPI. The 13C recovery in blood CO2 tended to be higher in SPI than in CAS. In mid jejunum, 15N enrichment of RNA tended to be higher in CAS than in SPI, and 13C enrichment of protein-bound Leu was higher in SPI than in CAS. In mid-jejunum, the fractional protein synthesis rate tended to be higher in SPI than in CAS. Our results revealed changes in intestinal growth after soy protein feeding that were associated with effects on intestinal RNA and protein synthesis but that were not ameliorated by AA supplementation. PMID- 20723692 TI - Particle size distribution and chemical composition of total mixed rations for dairy cattle: water addition and feed sampling effects. AB - Four dairy farms were used to determine the effects of water addition to diets and sample collection location on the particle size distribution and chemical composition of total mixed rations (TMR). Samples were collected weekly from the mixing wagon and from 3 locations in the feed bunk (top, middle, and bottom) for 5 mo (April, May, July, August, and October). Samples were partially dried to determine the effect of moisture on particle size distribution. Particle size distribution was measured using the Penn State Particle Size Separator. Crude protein, neutral detergent fiber, and acid detergent fiber contents were also analyzed. Particle fractions 19 to 8, 8 to 1.18, and <1.18 mm were judged adequate in all TMR for rumen function and milk yield; however, the percentage of material>19 mm was greater than recommended for TMR, according to the guidelines of Cooperative Extension of Pennsylvania State University. The particle size distribution in April differed from that in October, but intermediate months (May, July, and August) had similar particle size distributions. Samples from the bottom of the feed bunk had the highest percentage of particles retained on the 19-mm sieve. Samples from the top and middle of the feed bunk were similar to that from the mixing wagon. Higher percentages of particles were retained on >19, 19 to 8, and 8 to 1.18 mm sieves for wet than dried samples. The reverse was found for particles passing the 1.18-mm sieve. Mean particle size was higher for wet than dried samples. The crude protein, neutral detergent fiber, and acid detergent fiber contents of TMR varied with month of sampling (18-21, 40-57, and 21-34%, respectively) but were within recommended ranges for high-yielding dairy cows. Analyses of TMR particle size distributions are useful for proper feed bunk management and formulation of diets that maintain rumen function and maximize milk production and quality. Water addition may help reduce dust associated with feeding TMR. PMID- 20723693 TI - Supplementation of the diet of dairy cows with trehalose results in milk with low lipid peroxide and high antioxidant content. AB - The objective of this study was to investigate the effect of dietary supplementation with the disaccharides trehalose and cellobiose on antioxidant activity in rumen fluid, blood, and milk of dairy cows. Nine Holstein dairy cows housed in a free-stall barn were divided into 3 groups, with each group receiving a different dietary treatment (a control diet, a 1% trehalose-supplemented diet, or a 1% cellobiose-supplemented diet) following a 3x3 Latin square design. Feed intake and milk production increased in cows receiving the trehalose-supplemented diet compared with those receiving the control and cellobiose-supplemented diets. The total protozoa numbers in the rumen fluid of cows fed trehalose- or cellobiose-supplemented diets were greater than those of the control group. The C18:0 and C18:1 fatty acid content was increased in the milk of cows fed the trehalose-supplemented diet compared with that of the control group, and the C18:3n-3 fatty acid content in the milk of cows fed the cellobiose-supplemented diet was less than that of the control group. Plasma biochemical parameters were unchanged among the different treatments. In rumen fluid, 1,1-diphenyl-2 picrylhydrazyl radical scavenging activity and superoxide dismutase activity were increased 2h after feeding in cows receiving the cellobiose-supplemented diet compared with the control group, and the concentration of thiobarbituric acid reactive substances in the rumen fluid of cows fed the cellobiose-supplemented diet was decreased. In contrast, the values of these parameters measured in the milk of cows fed the cellobiose-supplemented diet were no different from those of control cows. Dietary supplementation with trehalose did, however, bring about an improvement of the oxidative status of milk and blood in these animals compared with controls. These results provide the first evidence supporting the use of dietary disaccharides to decrease lipid peroxide levels and increase the antioxidant content of dairy cow milk. The findings suggest that disaccharides, particularly trehalose, might be useful as supplements for reducing oxidative stress and improving the quality of milk for human consumption, as well as possibly impairing the processes that give rise to lipid oxidation odor in dairy cow milk. PMID- 20723694 TI - Effects of dietary cation-anion difference on ruminal metabolism and blood acid base regulation in dairy cows receiving 2 contrasting levels of concentrate in diets. AB - Dietary cation-anion difference [DCAD=Na+K-Cl in mEq/kg of dry matter (DM)] increases DM intake (DMI) in cows fed diets containing rapidly degraded starch. Increased DMI of diets containing rapidly degraded starch could potentially exacerbate subacute acidosis. The objective of this study was to determine metabolic effects of increasing DCAD in low and high starch diets. Six cannulated Holstein cows were blocked into 2 groups of 3 cows and assigned to two 3 x 3 Latin squares in a split-plot design. Each group received a level of concentrate at either 20 or 40% on a DM basis. The diet containing 20% concentrate supplied 4% rapidly degraded starch, whereas the diet containing 40% concentrate supplied 22% rapidly degraded starch. Diets in each square were formulated to provide a DCAD of 0, 150, or 300 mEq/kg of DM. The 3 values were obtained by manipulating Na and Cl contents. Increasing the proportion of rapidly degraded starch decreased rumen pH and the acetate to propionate ratio but did not affect digestibility, blood acid-base status, pH of urine, and strong ion excretion. Increasing DCAD increased DMI, the effect being higher when the cows were fed the 40% concentrate diet. Increasing DCAD did not affect mean ruminal pH, molar proportion of VFA, and fiber digestibility; reduced the range of rumen pH decrease during the meal in cows fed the 40% concentrate diet; and strongly increased blood pH and blood HCO3 concentration. Increasing DCAD increased urine pH and modified the urinary excretion of minerals. With low DCAD, 70% of Cl and only 16% of Na were excreted in urine whereas with high DCAD, 33% of Cl and 53% of Na were excreted. These results suggest that DMI of cows fed diets rich in rapidly degraded starch and low DCAD was limited to maintain the blood pH in a physiological range. Increasing DCAD allowed the cows to increase DMI because of the ability of positive DCAD to maintain blood acid-base status. A localized rumen buffering effect could not be excluded and could be linked with a higher amount of HCO3 recycled into the rumen. Main mechanisms involved in regulating blood pH might be renal excretion of protons and strong ions and renal HCO3 reabsorption. PMID- 20723695 TI - Effect of dietary concentrate on rumen fermentation, digestibility, and nitrogen losses in dairy cows. AB - The objective of this experiment was to investigate the effect of level of dietary concentrate on rumen fermentation, digestibility, and N losses in lactating dairy cows. The experiment was a replicated 3x3 Latin square design with 6 cows and 16-d adaptation periods. Ruminal contents were exchanged between cows at the beginning of each adaptation period. Data for 2 of the diets tested in this experiment are presented here. The diets contained (dry matter basis): 52% (LowC; control) and 72% (HighC) concentrate feeds. Crude protein contents of the diets were 16.5 and 16.4%, respectively. The HighC diet decreased ruminal pH and ammonia concentration and increased propionate concentration compared with LowC. Acetate:propionate ratio was greater for LowC than for HighC. Rumen methane production and microbial protein synthesis were unaffected by diet. Dry matter intake was similar among diets, but milk yield was increased by HighC compared with LowC (36.0 and 33.2 kg/d, respectively). Milk fat percentage and yield and total-tract apparent NDF digestibility were decreased by HighC compared with LowC. More ruminal ammonia N was transferred into milk protein with HighC than with LowC. Urinary N excretion, plasma urea N, and milk urea N concentration were not affected by diet. The ammonia emitting potential of manure was similar between LowC and HighC diets. Increased concentrate proportion in the diet of dairy cows resulted in reduced ruminal ammonia concentration and enhanced ammonia utilization for milk protein synthesis. These effects, however, did not result in reduced urinary N losses and only marginally improved milk N efficiency. Increasing dietary concentrate was not a successful strategy to mitigate enteric methane production and ammonia emissions from manure. PMID- 20723696 TI - Effects of particle size and dry matter content of a total mixed ration on intraruminal equilibration and net portal flux of volatile fatty acids in lactating dairy cows. AB - Effects of physical changes in consistency of ruminal contents on intraruminal equilibration and net portal fluxes of volatile fatty acids (VFA) in dairy cows were studied. Four Danish Holstein cows (121+/-17 d in milk, 591+/-24 kg of body weight, mean+/-SD) surgically fitted with a ruminal cannula and permanent indwelling catheters in the major splanchnic blood vessels were used. The experimental design was a 4x4 Latin square with a 2x2 factorial design of treatments. Treatments differed in forage (grass hay) particle size (FPS; 3.0 and 30 mm) and feed dry matter (DM) content of the total mixed ration (44.3 and 53.8%). The feed DM did not affect chewing time, ruminal variables, or net portal flux of VFA. However, decreasing the FPS decreased the overall chewing and rumination times by 151+/-55 and 135+/-29 min/d, respectively. No effect of the reduced chewing time was observed on ruminal pH or milk fat percentage. Cows maintained average ventral ruminal pH of 6.65+/-0.02, medial ruminal pH of 5.95+/ 0.04, and milk fat of 4.42+/-0.12% with chewing time of 28.0+/-2.1 min/kg of DM when fed short particles. The medial ruminal pool of wet particulate matter was decreased by 10.53+/-2.29 kg with decreasing FPS, thereby decreasing the medial pool of total VFA, acetate, propionate, butyrate, isobutyrate, and isovalerate by 1,143+/-333, 720+/-205, 228+/-69, 140+/-51, 8.0+/-2.3, and 25.2+/-5.6 mmol, respectively. Ventral pool variables were not affected by treatments. Relatively large intraruminal differences of VFA concentrations and pH between the ventral and medial pools were observed, VFA concentrations being largest and pH being the lowest medially. This indicates that the ruminal mat acts as a barrier retaining VFA. The effects of reduced FPS were limited to the VFA pool sizes of the mat, leaving ruminal pH, ruminal VFA concentrations, and net portal flux of VFA unaffected. Consequently reduced FPS affected the intraruminal equilibration of VFA between mat and ventral rumen with an estimated turnover rate of isobutyrate increasing from 66+/-3%/h with long particles to 81+/-3%/h [corrected] with short particles. The estimated ruminal fluid flow and therefore intraruminal VFA transport between medial and ventral phase was not affected by the FPS. In conclusion, the ruminal mat pool of VFA was proportional to the size of the mat and the only detected effects of decreasing FPS were decreasing the mat size and an increasing turnover of the mat pool of VFA. PMID- 20723697 TI - Effects of feeding organic trace minerals on milk production and reproductive performance in lactating dairy cows: a meta-analysis. AB - The objectives of this meta-analysis were to evaluate the effectiveness of supplementation with the organic trace minerals (OTM; Availa-4 and 4-Plex, Zinpro Corp., Eden Prairie, MN) on milk yield, composition, and component yields and reproductive performance in dairy cows. Twenty research papers and reports on the effects of OTM were considered in this meta-analysis. Criteria for inclusion in the study were information on the form of OTM, an adequate description of randomization, production and reproduction data, and associated measures of variance (SE or SD) and P-values. The OTM increased milk production by 0.93 kg [95% confidence interval (CI)=0.61 to 1.25], milk fat by 0.04 kg (95% CI=0.02 to 0.05), and milk protein by 0.03 kg (95% CI=0.02 to 0.04) per day. Milk SCC was not different in cows supplemented with OTM. All production outcomes except milk solids (yield) and milk SCC were heterogeneous. Meta-regression analysis showed that feeding before calving, feeding for a full lactation after calving, and the use of other supplements increased responses over feeding after calving only, feeding for part of lactation, or not using other supplements, respectively. Supplementation of cows with OTM reduced days open (weighted mean difference=13.5 d) and number of services per conception (weighted mean difference=0.27) in lactating dairy cows. The risk of pregnancy on d 150 of lactation was greater in cows fed OTM (risk ratio=1.07), but OTM had no significant effect on the interval from calving to first service and 21-d pregnancy rate. There was no evidence of heterogeneity for any of the reproductive outcomes evaluated. The results of this meta-analysis showed that organic trace mineral supplementation could improve production and reproduction in lactating dairy cows. PMID- 20723698 TI - Effect of method of conservation of timothy on endogenous nitrogen flows in lactating dairy cows. AB - The effect of the method of conservation of forage on endogenous N (EN) secretion was studied using a 15N isotope dilution technique in 4 lactating Holstein cows selected from a replicated 3x3 Latin square. Cows were equipped with ruminal, duodenal (n=4), and ileal (n=2) cannulas. Diets comprised 44% concentrate plus first-cut timothy conserved either as hay or as restrictively (formic) or extensively (inoc) fermented silage. Crude protein contents of hay, formic, and inoc averaged 10.4, 13.6, and 14.8%, respectively. Total EN flow and free EN at the duodenum were increased with hay compared with silages but were similar when expressed as proportion of duodenal N flow, with total EN flow averaging 25.8, 23.9, and 23.9% for hay, formic, and inoc, respectively, and free EN at the duodenum averaging 11.5, 9.8, and 9.7% for hay, formic, and inoc, respectively. Flow of bacterial N at the duodenum originating from an endogenous source tended to be higher with inoc compared with formic. Overall, the proportion of bacterial N derived from endogenous sources and urea was similar between treatments, averaging 23 and 15%, respectively. In the feces, flow of EN was similar across treatments and averaged 31% of total fecal N. More than 70% of fecal EN originated from undigested secretions into the forestomach. Absorption of N from the forestomach tended to increase for silages compared with hay. In conclusion, EN represented an important fraction of N flowing at the duodenum and in the feces. The free EN and the total EN at the duodenum were altered by the different methods of forage conservation studied. Estimation of true dietary N supply and requirements of the dairy cow should allow for endogenous N flows and losses. PMID- 20723699 TI - The effects of feeding medium-chain triglycerides on the growth, insulin responsiveness, and body composition of Holstein calves from birth to 85 kg of body weight. AB - The objective of this study was to determine the effects of feeding calves isocaloric, isonitrogenous diets that varied in the amount and type of fatty acids on growth, response to an insulin challenge, and body composition. Thirty six calves were assigned to a randomized block design with 3 dietary treatments, 10 calves per treatment, and a baseline group of 6 calves. Three different milk replacer-based diets were designed to deliver less than 2% of the lipid as medium chain triglycerides (control; diet contained no added medium-chain triglycerides), 32% medium-chain triglycerides primarily as caprylate (CAP oil), and 32% of fatty acids primarily as laurate from coconut oil (CCO). Calves were offered 0.28 Mcal of intake energy/kg of body weight (BW)0.75 from d 1 to 7 and 0.32 Mcal of intake energy/kg of BW0.75 adjusted weekly for BW from d 8 to harvest. Dry matter, intake energy, crude protein, and fat intakes were 53.7 kg, 281.8 Mcal, 14.6 kg, and 13.0 kg; 56.6 kg, 297.2 Mcal, 15.8 kg, and 14.2 kg; and 53.8 kg, 280.4 Mcal, 15.4 kg, and 13.3 kg for the control, CAP oil, and CCO treatments, respectively. Dry matter, energy, protein, and fat intakes did not differ among treatments. At approximately 65 kg of BW, 5 calves per treatment were given an insulin challenge. After the challenge the decrease in plasma glucose concentration was greater for the calves fed the CAP oil diet compared with those fed the control and CCO diets. Calves were harvested at approximately 88 kg of BW. Empty body gains were 0.92, 0.79, and 0.87 kg/d for control-, CAP oil-, and CCO-fed calves, respectively, and the gains of the CAP oil-fed calves were less than those of the control-fed calves. Empty body crude protein, ash, and water were not different among treatments. Empty body retained energy and fat tended to be 5.6 and 8.7% greater for calves consuming the CCO diet than for those fed the control diet. The livers of calves consuming the CCO diet were 330 g heavier and contained 15% more fat than the livers of the control and CAP oil calves. The results of this study demonstrate that the energy demand of the calf to maintain body temperature resulted in increased oxidation of intake energy; thus, overall body composition differences could not be detected. However, the intake of CCO increased the accumulation of lipid in the liver and carcass despite the apparent cold stress conditions. PMID- 20723700 TI - The effect of group composition and age on social behavior and competition in groups of weaned dairy calves. AB - The objective of the present study was to investigate how group composition affects behavior and weight gain of newly weaned dairy calves and how age within heterogeneous groups affects behavior and competition. Seventy-two calves were introduced into 6 groups of 12 calves, of which 3 groups were homogeneous and 3 groups were heterogeneous (including 6 young and 6 old calves). The 9.8 mx9.5 m large experimental pen had 4 separate lying areas as well as a feeding area. Behavior and subgrouping were recorded on d 1, 7, and 14 after grouping, and calves were weighed before and after the experimental period of 14 d. Analysis of the effect of group composition on behavior and weight gain included young calves in heterogeneous groups and calves in homogeneous groups within the same age range at grouping (30 to 42 d). Irrespective of group composition, time spent feeding and lying increased, whereas time spent active decreased from d 1 to 7. In homogeneous groups, calves were more explorative on d 1 after grouping. Finally, calves in homogeneous groups had a higher average daily weight gain than calves in heterogeneous groups. Analysis of the effect of age included young and old calves of heterogeneous groups. Young calves were less explorative than old calves. Young calves were more active than old calves on d 1 but less active on d 7. Time spent lying and lying alone increased over time. More displacements from the feed manger were performed by old calves than by young calves. An analysis including all calves in both homogeneous and heterogeneous groups showed that when lying, calves were evenly distributed on the 4 lying areas and formed subgroups of on average 3 calves. In conclusion, age heterogeneity leads to increased competition, which may have a negative influence on the young calves' performance. PMID- 20723701 TI - Effects of feeding polyphenols from pomegranate extract on health, growth, nutrient digestion, and immunocompetence of calves. AB - Objectives were to determine effects of feeding pomegranate extract (POMx) rich in polyphenols on performance, health, nutrient digestion, and immunocompetence of calves in the first 70 d of age. Holstein calves (n=67), at 2+/-1 d of age (d 0=birth day) were randomly assigned to 0 (control), 5 (POMx5), or 10 g/d (POMx10) of pomegranate extract containing 16.9% gallic acid equivalent (GAE) to result in intakes of 0, 850 and 1,700 mg of GAE/d or an average of approximately 0, 15, and 30 mg of GAE/kg of body weight (BW) per day. All calves received colostrum during the first 24 h, pasteurized milk thereafter until 61 d of age, and grain was fed ad libitum for the first 70 d of age. Calves were housed in individual hutches, and grain intake, attitude and fecal scores, incidence and duration of health disorders, and treatments for health problems were evaluated daily. Body weight was measured on 2 consecutive days at 2, 30, and 70 d of age and averaged for each measurement. Concentrations of glucose and 3-hydroxybutyrate were measured in plasma. Nutrient digestion was measured using total fecal collection during a 3-d period. Neutrophil phagocytic and killing activities and antibody response to immunization with ovalbumin were measured. Peripheral blood mononuclear cells were cultured and cytokine production measured. Feeding POMx had no effect on intake or BW gain in the first 30 d of age, but after 30 d of age, both grain dry matter intake and BW gain decreased with increasing addition of POMx, which resulted in calves that were 1.8 and 4.3 kg lighter at 70 d of age for POMx5 and POMx10, respectively, compared with controls. Feeding POMx did not influence dry matter, organic matter, or starch digestibility, but it reduced crude protein and fat digestion. Plasma concentrations of glucose and 3-hydroxybutyrate were similar among treatments throughout the first 70 d of age. Measures of calf health such as fecal and attitude scores, risk of fever, and rectal temperature were not altered by treatments. Similarly, neutrophil phagocytic and killing activities did not differ among treatments. On the contrary, feeding POMx increased synthesis of interferon-gamma and interleukin-4 by peripheral blood mononuclear cells and improved total immunoglobulin G responses to ovalbumin vaccination. These results suggest that feeding POMx top-dressed onto the grain suppresses intake of grain and digestibility of fat and protein, likely because of the high tannin content. Nevertheless, polyphenols from POMx enhanced mitogen induced cytokine production and response to vaccination, which might benefit immune competence of calves and potentially health. Additional studies are warranted to minimize the effect of POMx on intake and digestibility and to better understand the mechanisms by which polyphenols improve immune response of calves. PMID- 20723702 TI - Short communication: Effects of dietary nonstructural carbohydrates pre- and postpartum on reproduction of grazing dairy cows. AB - The working hypothesis was that postpartum anovulatory intervals (PPAI) of grazing dairy cows are shortened by inclusion of concentrates that increase the nonstructural carbohydrate content of the transition diet. Dietary treatments were arranged as a 2x2 factorial, with 68 multiparous cows assigned to isoenergetic diets (114 MJ of metabolizable energy/cow per day) of pasture and pasture silage (PreP) or pasture and pasture silage supplemented with 3 kg of dry matter/cow per day a corn- and barley-based concentrate for 36 d prepartum (PreC). After calving, cows within each prepartum diet group were managed on isoenergetic diets (179 MJ of metabolizable energy/cow per day) of either pasture and pasture silage (PostP) or pasture and pasture silage supplemented with 5 kg of dry matter/cow per day a corn- and barley-based concentrate (PostC) for at least 35 d and until reestablishment of ovulatory cycles. Relative to day of calving (d 0), blood samples were collected at least weekly from d -28 to 35 and milk samples were collected twice weekly for progesterone determination to diagnose ovulatory status. The main variable of interest was PPAI, defined as the interval between calving and the first detected increase in milk progesterone (>3 ng/mL), followed by a pattern of progesterone concentrations consistent with onset of an ovulatory cycle. Subsequent mating records, pregnancy testing, and recalving data were also examined. Prepartum diet did not affect reproduction. The PPAI was 8 d shorter and the 6-wk pregnancy rate was 17% greater in PostC cows compared with PostP cows. Measured indicators of metabolic state and energy balance were poorly related to PPAI. The results support the existence of nutritional signals associated with nonstructural carbohydrates in the postpartum diet, independent of energy balance; these signals benefit the physiological mechanisms underlying the timing of first ovulation and possibly subsequent breeding performance. PMID- 20723703 TI - Short communication: Effects of dietary fat supplements and forage:concentrate ratio on feed intake, feeding, and chewing behavior of Holstein dairy cows. AB - Feed intake and feeding behavior of dairy cows fed diets that varied in fat supplementation and forage:concentrate (F:C) ratio were investigated. Eight multiparous Holstein dairy cows were used in a replicated 4x4 Latin square experiment with 21-d periods. Treatments were 1) no supplemental fat and 34:66 F:C ratio; 2) 2% hydrogenated palm oil and 34:66 F:C ratio; 3) 2% yellow grease and 34:66 F:C ratio; and 4) 2% yellow grease and 45:55 F:C ratio. Cows were fed ad libitum twice daily as total mixed ration with free access to water. Dry matter intake (DMI) was not affected by fat supplementation regardless of fat source, whereas increased F:C ratio (from 34:66 to 45:55) lowered DMI by 7.5%. Meal interval, eating rate, and meal size were lower for cows fed yellow grease, and eating rate was less for cows fed the 45:55 F:C ratio diet. Chewing activity was not affected by fat supplementation, but was greater for cows fed the 45:55 F:C ratio diet. Results suggest that supplementation of 2% hydrogenated palm oil or 2% yellow grease had little effect on DMI and chewing behavior of Holstein dairy cows fed a 34:66 F:C ratio diet. The 2 fat sources can replace each other, depending on the availability or cost. Results also showed that DMI and chewing activity can be effectively manipulated by changing the F:C ratio of diet. PMID- 20723704 TI - Increasing milk solids production across lactation through genetic selection and intensive pasture-based feed system. AB - The objective of the study was to quantify the effect of genetic improvement using the Irish total merit index, the Economic Breeding Index (EBI), on overall performance and lactation profiles for milk, milk solids, body weight (BW), and body condition score (BCS) within 2 pasture-based systems of milk production likely to be used in the future, following abolition of the European Union's milk quota system. Three genotypes of Holstein-Friesian dairy cattle were established from within the Moorepark dairy research herd: LowNA, indicative of animals with North American origin and average or lower genetic merit at the time of the study; HighNA, North American Holstein-Friesians of high genetic merit; and HighNZ, New Zealand Holstein-Friesians of high genetic merit. Animals from within each genotype were randomly allocated to 1 of 2 possible pasture-based feeding systems (FS): 1) The Moorepark pasture (MP) system (2.64 cows/ha and 344 kg of concentrate supplement per cow per lactation) and 2) a high output per hectare (HC) system (2.85 cows/ha and 1,056 kg of concentrate supplement per cow per lactation). Pasture was allocated to achieve similar postgrazing residual sward heights for both treatments. A total of 126, 128, and 140 spring-calving dairy cows were used during the years 2006, 2007, and 2008, respectively. Each group had an individual farmlet of 17 paddocks and all groups were managed similarly throughout the study. The effects of genotype, FS, and the interaction between genotype and FS on milk production, BW, and BCS across lactation were studied using mixed models with factorial arrangements of genotype and FS accounting for the repeated cow records across years. No significant genotype by FS interaction was observed for any of the variables measured. Results show that milk solids production of the national average dairy cow can be increased across lactation through increased EBI. High EBI genotypes (HighNA and HighNZ) produced more milk solids per cow and per hectare than the LowNA genotype (2.7 and 4.1%, respectively). The results also suggest that when concentrate supplementation is used to facilitate increased stocking rates, increased herbage utilization and decreased substitution of concentrate for herbage can be achieved. When implemented, the HC FS could increase the overall productivity of pasture-fed dairy farming systems where land availability is the primary limiting factor of production. PMID- 20723705 TI - Dry matter intake and feed efficiency profiles of 3 genotypes of Holstein Friesian within pasture-based systems of milk production. AB - The primary objective of the study was to quantify the effect of genetic improvement using the Irish total merit index (Economic Breeding Index) on dry matter intake and feed efficiency across lactation and to quantify the variation in performance among alternative definitions of feed efficiency. Three genotypes of Holstein-Friesian dairy cattle were established from within the Moorepark dairy research herd: 1) low Economic Breeding Index North American Holstein Friesian representative of the Irish national average dairy cow, 2) high genetic merit North American Holstein-Friesian, and 3) high genetic merit New Zealand Holstein-Friesian. Animals from within each genotype were randomly allocated to 1 of 2 possible intensive pasture-based feed systems: 1) the Moorepark pasture system (2.64 cows/ha and 500 kg of concentrate supplement per cow per lactation) and 2) a high output per hectare pasture system (2.85 cows/ha and 1,200 kg of concentrate supplement per cow per lactation). A total of 128 and 140 spring calving dairy cows were used during the years 2007 and 2008, respectively. Each group had an individual farmlet of 17 paddocks, and all groups were managed similarly throughout the study. The effects of genotype, feed system, and the interaction between genotype and feed system on dry matter intake, milk production, body weight, body condition score, and different definitions of feed efficiency were studied using mixed models with factorial arrangements of genotypes and feed systems accounting for the repeated cow records across years. No significant genotype-by-feed-system interactions were observed for any of the variables measured. Results showed that aggressive selection using the Irish Economic Breeding Index had no effect on dry matter intake across lactation when managed on intensive pasture-based systems of milk production, although the ranking of genotypes for feed efficiency differed depending on the definition of feed efficiency used. Performance of animals grouped on alternative definitions of feed efficiency showed that conventional definitions such as feed conversion efficiency or residual feed intake may be inappropriate measures of efficiency for lactating dairy cows. An alternative definition, residual solids production, is proposed. This definition of feed efficiency identifies animals that produce greater volumes of milk solids at similar levels of feed intake without excessive body tissue mobilization and with improved fertility performance. The results also suggest that although there are differences in feed efficiency between strains of Holstein-Friesian, there is also variation within genotypes so that improvements in feed efficiency can be realized if the appropriate definition of feed efficiency is incorporated into breeding programs. PMID- 20723706 TI - Association between the polymorphism of the goat stearoyl-CoA desaturase 1 (SCD1) gene and milk fatty acid composition in Murciano-Granadina goats. AB - Genetic variability of the caprine stearoyl-CoA desaturase 1 (SCD1) gene has been investigated by sequencing a 4.7-kb cDNA in 6 goats from the Murciano-Granadina and Malaguena breeds. Sequence alignment revealed the existence of one synonymous polymorphism at exon 5 (c.732C>T) and one nucleotide substitution (c.*3504G>A) at exon 6 that encodes the 3' untranslated region (UTR). Moreover, the existence of a previously reported 3'UTR polymorphism involving a 3-bp indel (c.*1902_1904delTGT) was confirmed. Single nucleotide polymorphism and haplotype based association analyses revealed suggestive associations between genetic variability of the SCD1 locus and lactose, stearic, polyunsaturated, and conjugated linoleic fatty acid contents. Associations with milk fatty acid composition might be explained by the global effects that SCD1 exerts on mammary gland lipid metabolism through the down-modulation of key transcription factors. Interestingly, the performance of an in silico analysis revealed that the c.*1902_1904delTGT polymorphism involves a considerable change in the secondary structure of the SCD1 mRNA. Gene reporter assays and quantitative PCR analysis would be needed to assess if this mutation has a causal effect on milk polyunsaturated and conjugated linoleic fatty acid levels by altering the amount of SCD1 transcripts in mammary epithelial cells. PMID- 20723707 TI - Caprine CSN1S1 haplotype effect on gene expression and milk composition measured by Fourier transform infrared spectroscopy. AB - The Norwegian dairy goat population has a high frequency of a CSN1S1 (alphaS1 casein) haplotype with negative effects on protein and fat content. It is characterized by a single point deletion in exon 12 of CSN1S1, leading to a truncated protein and hence a low content of alphaS1-casein in the milk. This haplotype together with another haplotype with a deletion in exon 9 are called "weak" haplotypes. "Strong" haplotypes, on the other hand, have positive effects on important milk production traits. We show that expression of CSN1S1 in the mammary gland of lactating goats is significantly lower in animals with 2 weak haplotypes. Moreover, the effects of defective alleles were not detected in animals having 1 strong and 1 weak haplotype. Expression levels of other genes in the casein cluster were not affected by the CSN1S1 haplotypes investigated. Milk samples from goats with 2 weak haplotypes could be distinguished from the other milk samples using Fourier transform infrared (FTIR) spectroscopy and partial least squares discriminant analysis (PLS-DA). The PLS-DA components were related to spectra of pure caseins and whey proteins, hence FTIR has a potential for identifying milk samples with low alphaS1-casein content and different protein composition. The results indicate that FTIR-based measurements can be incorporated into breeding plans, or for selection of milk samples with high casein content, which in turn may improve cheese-making properties of the milk. PMID- 20723708 TI - Comparison of different models for genetic analysis of clinical mastitis in Austrian Fleckvieh dual-purpose cows. AB - The performance of different models for genetic analyses of clinical mastitis in Austrian Fleckvieh dual-purpose cows was evaluated. The main objective was to compare threshold sire models (probit and logit) with linear sire and linear animal models using REML algorithm. For comparison, data were also analyzed using a Bayesian threshold sire model. The models were evaluated with respect to ranking of sires and their predictive ability in cross-validation. Only minor differences were observed in estimated variance components and heritability from Bayesian and REML probit models. Heritabilities for probit and logit models were 0.06 and 0.08, respectively, whereas heritabilities for linear sire and linear animal models were lower (0.02). Correlations among ranking of sires from threshold and linear sire models were high (>0.99), whereas correlations between any sire model (threshold or linear) and the linear animal model were slightly lower (0.96). The worst sires were ranked very similar across all models, whereas for the best sires some reranking occurred. Further, models were evaluated based on their ability to predict future data, which is one of the main concerns of animal breeders. The predictive ability of each model was determined by using 2 criteria: mean squared error and Pearson correlation between predicted and observed value. Overall, the 5 models did not differ in predictive ability. In contrast to expectations, sire models had the same predictive ability as animal models. Linear models were found to be robust toward departures from normality and performed equally well as threshold models. PMID- 20723709 TI - Analysis of the relationship between workability traits and functional longevity in Canadian dairy breeds. AB - The aim of this study was to assess the effect of workability traits like milking speed and temperament on functional longevity of Canadian dairy cattle using a Weibull proportional hazards model. First-lactation data consisted of the following: 1,728,289 and 2,426,123 Holstein cows for milking temperament and milking speed, respectively, from 18,401 herds and sired by 8,248 sires; 39,618 and 60,121 Jersey cows for milking temperament and milking speed, respectively, from 1,845 herds and sired by 2,413 sires; and 54,391 and 94,847 Ayrshire cows for milking temperament and milking speed, respectively, from 1,316 herds and sired by 2,779 sires. Functional longevity was defined as the number of days from the first calving to culling, death, or censoring adjusted for production. Milking temperament and milking speed were recorded on a 1- to 5-point scale from very nervous to very calm and from very slow to very fast, respectively. The statistical model included the effects of stage of lactation; season of production; the annual change in herd size; type of milk recording supervision; age at first calving; effects of milk, fat, and protein yields calculated as within herd-year-parity deviations; herd-year-season of calving; sire; and milking temperament or milking speed class. The relative culling rate was calculated for animals in each milking temperament or milking speed class after accounting for the above-mentioned effects. The study showed that there was a statistically significant association between workability traits and functional longevity. Very nervous cows were 26, 23, and 46% more likely to be culled than very calm cows in Holstein, Ayrshire, and Jersey breeds, respectively. Similarly, very slow milkers were 36, 33, and 28% more likely to be culled than average milkers in Holstein, Ayrshire, and Jersey breeds, respectively. Additionally, very fast milkers were 11, 13, and 15% more likely to be culled than average milkers in Holstein, Ayrshire, and Jersey breeds, respectively. Producers might want to avoid consequences associated with the fast milkers such as udder health problems. PMID- 20723710 TI - Impact of genetic progress on the profits of dairy farmers. AB - This paper analyzes the role that genetic progress may play in improving profits of dairy farms. A novel data set of Spanish commercial dairy farms including management data and cow indices of genetic merit for production and nonproduction traits was used. In the empirical section, a frontier production function that included a farm genetic index for milk yield was estimated. To evaluate the full effect of genetics on farm profit it was necessary to consider the fact that feed intake increases with cows' genetic improvement. Results show that the increase in profits corresponding to the average genetic progress during the sample period is equivalent to a 5% increase in income from milk sales. Managerial ability plays an important role in exploiting genetics. Optimal management increases the return of genetics by 22% compared with farms with average management in the sample. PMID- 20723711 TI - Energy balance in first-lactation Holstein, Jersey, and reciprocal F1 crossbred cows in a planned crossbreeding experiment. AB - The Virginia Tech crossbreeding project began in the fall of 2002 by mating Holstein (H) and Jersey (J) foundation females to Holstein and Jersey bulls to create HH, HJ, JH, and JJ genetic groups, where the sire breed is listed first followed by dam breed. Collection of individual daily feed intakes began in September 2005 and continued through November 2008, resulting in observations on 43, 34, 41, and 22 HH, HJ, JH, and JJ cows, respectively. Intakes were measured for 2 wk out of every 6-wk period for first-lactation cows less than 310 d in milk. The ration was analyzed for dry matter and nutrient content, which was used to calculate net energy of lactation (NEL, Mcal/kg). Body and milk weights were collected daily with milk components measured monthly. The NEL requirements for maintenance, growth (in the form of retained energy), pregnancy, and production were calculated using National Research Council (2001) equations. Random regression models were used to predict consumed NEL and NEL required for production, maintenance, and body weight at every week in lactation. Energy required for growth was calculated for each cow at each stage of lactation using five 2-mo stages. Energy balance was estimated by subtracting the predicted energy required for production, maintenance, growth, and pregnancy from the predicted NEL consumed. A linear model with fixed effects of genetic group, year season of calving group, and a linear and quadratic effect of age at calving was used to analyze the energy terms. The HJ and JH groups were not different in any of the analyses for energy terms. The HH cows consumed more energy than did HJ and JJ cows. There were no genetic group differences for total energy for pregnancy. The HH, HJ, and JH groups were not different from each other for energy required for production but required more energy for production than the JJ. The JH allocated a lower percentage of their energy intake to maintenance than the HH (25.7 to 27.4%) and the JJ allocated less energy to growth than the HH and HJ. Genetic group explained significant variation for percentage of energy partitioned to production with the JJ allocating more energy to production than the HH (66.3 vs. 60.9%). Genetic group differences in characterization of energy balance warrant further study. PMID- 20723712 TI - Short communication: Born to be a loser cow? AB - Over the last few years, an increasing awareness has arisen in Denmark of the existence of cows with a generally lowered health and production status, referred to as "loser cows." A previous study has estimated that the overall prevalence of loser cows in Danish Holstein herds is 3.2%. The aim of this study was to estimate genetic and phenotypic parameters for the loser cow state and the underlying traits: lameness, hock lesions, other cutaneous lesions, and condition of hair coat. Records on 6,098 cows were analyzed with an animal model including fixed effects of herd, season of scoring and location of scoring, age at first calving, lactation stage, and parity in addition to additive genetic effects and permanent environmental effects. The heritability of the loser cow score was 0.08 and for the underlying traits the heritability ranged from 0.05 to 0.12. The genetic correlations between various pairs of traits included in the loser cow score ranged from 0.04 to 0.68 and the phenotypic correlations ranged from 0.09 to 0.21. The genetic and phenotypic correlations between the loser cow score and the underlying traits ranged from 0.25 to 0.89 and 0.20 to 0.85, respectively, supporting the concept of the loser cow score. The traits included in the loser cow score are easy to assess and all showed genetic variation. They are therefore suitable for inclusion in a total merit index aimed at breeding for more robust cows. PMID- 20723713 TI - Short communication: Genetic variation of saturated fatty acids in Holsteins in the Walloon region of Belgium. AB - Random regression test-day models using Legendre polynomials are commonly used for the estimation of genetic parameters and genetic evaluation for test-day milk production traits. However, some researchers have reported that these models present some undesirable properties such as the overestimation of variances at the edges of lactation. Describing genetic variation of saturated fatty acids expressed in milk fat might require the testing of different models. Therefore, 3 different functions were used and compared to take into account the lactation curve: (1) Legendre polynomials with the same order as currently applied for genetic model for production traits; 2) linear splines with 10 knots; and 3) linear splines with the same 10 knots reduced to 3 parameters. The criteria used were Akaike's information and Bayesian information criteria, percentage square biases, and log-likelihood function. These criteria indentified Legendre polynomials and linear splines with 10 knots reduced to 3 parameters models as the most useful. Reducing more complex models using eigenvalues seemed appealing because the resulting models are less time demanding and can reduce convergence difficulties, because convergence properties also seemed to be improved. Finally, the results showed that the reduced spline model was very similar to the Legendre polynomials model. PMID- 20723714 TI - Short communication: Genetic relationship between calving traits and body condition score before and after calving in Canadian Ayrshire second-parity cows. AB - The objective of this study was to investigate the genetic relationship between body condition score (BCS) and calving traits (including calving ease and calf survival) for Ayrshire second-parity cows in Canada. The use of random regression models allowed assessment of the change of genetic correlation from 100 d before calving to 335 d after calving. Therefore, the influence of BCS in the dry period on subsequent calving could be studied. Body condition scores were collected by field staff several times over the lactation in 101 herds from Quebec and calving records were extracted from the official database used for Canadian genetic evaluation of calving ease. Daily heritability of BCS increased from 0.07 on d 100 before calving to 0.25 at 335 d in milk. Genetic correlations between BCS at different stages ranged between 0.59 and 0.99 and indicated that genetic components for BCS did not change much over lactation. With the exception of the genetic correlation between BCS and direct calving ease, which was low and negative, genetic correlations between BCS and calving traits were positive and moderate to high. Correlations were the highest before calving and decreased toward the end of the ensuing lactation. The correlation between BCS 10 d before calving and maternal calving ease was 0.32 and emphasized the relationship between fat cows before calving with dystocia. Standards errors of the genetic correlations estimates were low. Genetic correlations between BCS and calf survival were moderate to high and favorable. This indicates that cows with a genetically high BCS across lactation would have a greater chance of producing a calf that survived (maternal calf survival) and that they would transmit genes that allow the calf to survive (direct calf survival). PMID- 20723715 TI - Economic comparison of natural service and timed artificial insemination breeding programs in dairy cattle. AB - The objective was to compare the costs of natural service (NS) and timed artificial insemination (TAI) as breeding programs for dairy cows. Both programs were directly compared in a field study from November 2006 to March 2008. Reproductive results in that study were similar and served as inputs for this study. A herd budget accounting for all costs and revenues was created. Net cost during the field study for the NS program was $100.49/cow per year and for the TAI program was $67.80/cow per year, unadjusted for differences in voluntary waiting period for first insemination (VWP) and pregnancy rates (PR). After inclusion of the differences in VWP and PR, the economic advantage of the TAI program was $9.73/cow per year. Costs per day a cow was eligible for insemination were estimated at $1.45 for the NS program and $1.06 for the TAI program. Sensitivity analysis revealed that if the marginal feed cost increased to $5/hundredweight (cwt; 1 cwt=45.36kg), the advantage of TAI increased to $48.32/cow per year. In addition, higher milk prices and greater genetic progress increased the advantage of TAI. When semen price increased from $6 to $22, the NS program had an economic advantage of $33.29/cow per year. If each NS bull was replaced by an additional cow, the advantage of the TAI program was $60.81/cow per year. Setting the PR for both programs at 18% and the VWP at 80 d resulted in an advantage of $37.87/cow per year for the TAI program. In conclusion, any advantage of TAI depended greatly on cost to feed bulls, semen price, and genetic merit of semen. PMID- 20723716 TI - An advisory tool to improve management practices affecting calf and heifer welfare on dairy farms. AB - We developed an advisory tool addressing 10 critical areas of calf and heifer management, including calving management, care to newborn calves and painful procedures, colostrum management, cow-calf separation, calf feeding, weaning, calf housing, heifer feeding, heifer housing, and general monitoring. Targets and indicators for each critical area were validated by a panel of experts and maximum scores were assigned based on experts' opinions and reviews of scientific literature. The tool was tested on 28 Quebec dairy farms for feasibility and repeatability between 2 observers. Farmers were asked to test colostrum quality, measure blood IgG concentrations, and record health events. The on-farm evaluation included an interview on management practices and an evaluation of conditions in the barn. Scorings and recommendations were discussed with producers. The usefulness of our on-farm welfare tool was evaluated by the producers themselves during a final debriefing. We reached the main goals of a successful advisory tool of calf and heifer management to improve welfare on dairy farms. We respected the targeted time limit of a 3-h visit covering all aspects of our tool including data collection on management and environment, scoring, practical demonstration with producers, and debriefing. We had no problems collecting management- and environment-based data and had high repeatability of qualitative environment-based measures (kappa value>0.6). Our tool helped to detect problems and to discuss these problems with the producers; producers scored below 50% for some targets in calving management, care to newborn calves and painful procedures, colostrum management, and calf feeding. The targets were realistic so producers were not discouraged. All producers were convinced of the usefulness of our tool for identifying areas of calf and heifer management in need of improvement. They were also convinced of the usefulness of our tool as an advisory tool for technical advisors and veterinarians. Six months after the on-farm visit, recommended practices were implemented in many of these areas. Voluntary improvements in animal welfare can be facilitated by using appropriate tools to educate producers and help them change their attitudes toward calf management and animal welfare. PMID- 20723717 TI - Relationship between female fertility and production traits in Canadian Holsteins. AB - The objectives of this study were a) to estimate the genetic correlation between milk production and some female fertility traits such as 56-d nonreturn rate in cows (NRRC), calving to first service (CTFS), and first service to conception (FSTC); b) to assess the influence of including milk production as a correlated trait on the genetic evaluation of these traits in Canadian Holsteins; and c) to determine if using heifer nonreturn rate (NRRH) had a similar effect as using milk production on cow NRRC evaluation. The data included fertility and production records of first-parity Holstein cows. Genetic parameters were estimated using uni- and bivariate analyses in which milk production at around 90 DIM (TD90M) was included as a correlated trait to NRRC, CTFS, and FTSC. A bivariate analysis was also carried out in which NRRH was included as a correlated trait to NRRC. The models were compared by genetic trend (NRRC, CTFS, and FSTC) and cross-validation and predictability (NRRC). The heritability estimates for NRRC from the uni- and bivariate analyses were 0.017 and 0.020, respectively. The corresponding figures for CTFS were 0.07 and 0.08 and for FSTC were 0.049 and 0.05. The genetic trends for NRRC of the 2 models (NRRC+TD90M and NRRC+NRRH) gave very similar results. However, when milk production was included in the genetic evaluation of CTFS and FSTC, the genetic trends of the 2 fertility traits were higher compared with the univariate analysis. In NRRC evaluation by cross-validation and predictability, the bivariate analyses were more consistent and gave a better predictability than the univariate analysis. However, there was no major difference between the 2 models. Consequently, it might be worth including milk production or heifer fertility as correlated traits in the genetic evaluation of female fertility traits. PMID- 20723718 TI - Novel use of plasmapheresis in a patient with heparin-induced thrombocytopenia requiring urgent insertion of a left ventricular assist device under cardiopulmonary bypass. PMID- 20723719 TI - Non solus--a leadership challenge. PMID- 20723720 TI - "Back to the future": recruiting the best and brightest into cardiothoracic surgery. PMID- 20723721 TI - Epithelial to mesenchymal transition: the doorway to metastasis in human lung cancers. PMID- 20723722 TI - A contemporary comparison of the effect of shunt type in hypoplastic left heart syndrome on the hemodynamics and outcome at Fontan completion. AB - OBJECTIVE: We previously reported no difference in morbidity or mortality in a cohort of infants undergoing stage 1 and 2 reconstructions for hypoplastic left heart syndrome with either a modified Blalock-Taussig shunt or a right ventricular to pulmonary artery conduit. This article compares the hemodynamics and perioperative course at the time of the Fontan completion and reports longer term survival for this cohort. METHODS: We retrospectively reviewed the hospital records of all patients who underwent stage 1 reconstruction between January 2002 and May 2005 and subsequent surgical procedures, as well as cross-sectional analysis of hospital survivors. RESULTS: A total of 176 patients with hypoplastic left heart syndrome or a variant underwent stage 1 reconstruction with either modified Blalock-Taussig shunt (n = 114) or right ventricular to pulmonary artery conduit (n = 62). Shunt selection was at the discretion of the surgeon. The median duration of follow-up was 58 months (range 1-87 months). By Kaplan-Meier analysis, shunt type did not influence survival or freedom from transplant at 5 years (right ventricular to pulmonary artery conduit 61%; 95% confidence limit, 47-72 vs modified Blalock-Taussig shunt 70%; 95% confidence limit, 60-77; P = .55). A total of 107 patients underwent Fontan (69 modified Blalock-Taussig shunts and 38 right ventricular to pulmonary artery conduits) with 98% (105/107) early survival. Patients with a right ventricular to pulmonary artery conduit shunt pre-Fontan had higher pulmonary artery (13 +/- 8 mm Hg vs 11 +/- 3 mm Hg, P = .026) and common atrial (8 +/- 2.3 mm Hg vs 6.8 +/- 2.7 mm Hg, P = .039) pressures. By echocardiography evaluation, there was more qualitative moderate to severe ventricular dysfunction (right ventricular to pulmonary artery conduit 31% [12/36] vs modified Blalock-Taussig shunt 17% [11/67], P = .05) and moderate to severe atrioventricular valve regurgitation (right ventricular to pulmonary artery conduit 40% [14/35] vs modified Blalock-Taussig shunt 16% [11/67], P = .01) in the right ventricular to pulmonary artery conduit group. Use of diuretic therapy, angiotensin-converting enzyme inhibition, reflux medications, and tube feedings were not different between groups. Overall, 5 patients underwent heart transplantation (right ventricular to pulmonary artery conduit 4 vs modified Blalock-Taussig shunt 1, P = .1) before Fontan. There was no difference in age or weight at Fontan, bypass time, intensive care unit or hospital length of stay, postoperative pleural effusions, or need for reoperation between groups. CONCLUSIONS: Interim analyses continue to suggest there is no survival advantage of one shunt type compared with the other. Longer-term follow-up of a randomized patient population remains of utmost importance. PMID- 20723724 TI - Reintervention for arch obstruction after stage 1 reconstruction does not adversely affect survival or outcome at Fontan completion. AB - OBJECTIVE: To determine the effect of reintervention for coarctation after stage 1 reconstruction for hypoplastic left heart syndrome and variants on survival, suitability for Fontan, and morbidity at Fontan. METHODS: A retrospective review of echocardiograms, catheterizations, hospital records of patients who underwent stage 1 reconstruction from January 2002 to May 2005, with a cross-sectional analysis of hospital survivors, was performed. Kaplan-Meier curves were derived for patients alive more than 30 days after stage 1 reconstruction. RESULTS: A total of 176 patients underwent stage 1 reconstruction. Forty-three patients (23%) underwent balloon angioplasty (n = 43) or surgical intervention (n = 4) for re-coarctation. Median time to intervention was 123 (1-316) days. Seven of 43 patients (16%) underwent more than 1 balloon angioplasty. Thirty-nine patients underwent intervention before stage 2 reconstruction, and 4 patients had intervention between stage 2 reconstruction and Fontan. Kaplan-Meier curves showed no difference in freedom from death or transplant between patients who did and did not undergo intervention for re-coarctation. Fontan completion was performed in 107 patients. By echocardiogram, the prevalence of moderate to severe ventricular dysfunction between groups was similar at Fontan; however, significant atrioventricular valve regurgitation was more common in patients who required intervention (28/33 vs 40/65, P = .02). Overall Fontan mortality was 2% and not different between groups. Length of stay was not different between patients with and without re-coarctation. CONCLUSIONS: Reintervention for coarctation after stage 1 reconstruction is common. Hemodynamic differences between groups did not affect Fontan completion, mortality, or hospital length of stay. Follow-up is necessary to determine the impact of re-coarctation on longer term mortality and morbidity. PMID- 20723725 TI - Single double-lumen venous-venous pump-driven extracorporeal lung membrane support. AB - OBJECTIVE: We sought to investigate the safety and feasibility of obtaining total respiratory support during 72 hours using a pump-driven (Levitronix CentriMag; Levitronix LLC, Waltham, Mass) venous-venous extracorporeal lung membrane (Novalung; Novalung GmbH, Hechingen, Germany) attached through a single double lumen cannula (Novalung) into the femoral or jugular vein in pigs. METHODS: Twelve pigs were initially mechanically ventilated for 2 hours (respiratory rate, 20-25 breaths/min; tidal volume, 10-12 mL/kg; fraction of inspired oxygen, 1.0; positive end-expiratory pressure, 5 cm H(2)O). Thereafter, the extracorporeal lung membrane was attached to the right femoral (n = 6, 26F) or jugular (n = 6, 22F) vein by using a single double-lumen cannula placed transcutaneously. Ventilatory settings were then reduced to near-apneic ventilation (respiratory rate, 4 breaths/min; tidal volume, 1-2 mL/kg; fraction of inspired oxygen, 0.21; positive end-expiratory pressure, 10 cm H(2)O), and pump flow was increased hourly until maximal efficacy. Blood gases and hemodynamics were measured hourly, and lung and plasma cytokine levels were measured every 4 hours. RESULTS: The device's mean blood flow was 2.16 +/- 0.43 L/min, permitting an oxygen transfer and carbon dioxide removal of 203.6 +/- 54.6 and 590.3 +/- 23.3 mL/min, respectively. Despite static ventilation, all pigs showed optimal respiratory support, with a PaO(2), PaCO(2), and mixed venous oxygen saturation of 226.2 +/- 56.4, 59.7 +/- 8.8, and 85.6 +/- 5.3 mm Hg, respectively. There were no significant inflammatory, cellular, or coagulatory responses; lung cytokine levels remained in the normal range. Route (femoral vs jugular) or size (22F vs 26F) of the cannula did not change hemodynamic or respiratory parameters significantly. CONCLUSIONS: This circuit provides total respiratory support over 72 hours without inducing significant hemodynamic, coagulatory, cellular, or inflammatory responses. PMID- 20723727 TI - National Emphysema Treatment Trial redux: accentuating the positive. AB - OBJECTIVE: Under the Freedom of Information Act, we obtained the follow-up data of the National Emphysema Treatment Trial (NETT) to determine the long-term outcome for "a heterogeneous distribution of emphysema with upper lobe predominance," postulated by the NETT hypothesis to be optimal candidates for lung volume reduction surgery. METHODS: Using the NETT database, we identified patients with heterogeneous distribution of emphysema with upper lobe predominance and analyzed for the first time follow-up data for those receiving lung volume reduction surgery and those receiving medical management. Furthermore, we compared the results of the NETT reduction surgery group with a previously reported consecutive case series of 250 patients undergoing bilateral lung volume reduction surgery using similar selection criteria. RESULTS: Of the 1218 patients enrolled, 511 (42%) conformed to the NETT hypothesis selection criteria and received the randomly assigned surgical or medical treatment (surgical = 261; medical = 250). Lung volume reduction surgery resulted in a 5 year survival benefit (70% vs 60%; P = .02). Results at 3 years compared with baseline data favored surgical reduction in terms of residual volume reduction (25% vs 2%; P < .001), University of California San Diego dyspnea score (16 vs 0 points; P < .001), and improved St George Respiratory Questionnaire quality of life score (12 points vs 0 points; P < .001). For the 513 patients with a homogeneous pattern of emphysema randomized to surgical or medical treatment, lung volume reduction surgery produced no survival advantage and very limited functional benefit. CONCLUSIONS: Patients most likely to benefit from lung volume reduction surgery have heterogeneously distributed emphysema involving the upper lung zones predominantly. Such patients in the NETT trial had results nearly identical to those previously reported in a nonrandomized series of similar patients undergoing lung volume reduction surgery. PMID- 20723729 TI - Have hybrid procedures replaced open aortic arch reconstruction in high-risk patients? A comparative study of elective open arch debranching with endovascular stent graft placement and conventional elective open total and distal aortic arch reconstruction. AB - OBJECTIVE: Open total arch procedures have been associated with significant morbidity and mortality in patients with multiple comorbidities. Aortic arch debranching with endovascular graft placement, the hybrid arch procedure, has emerged as a surgical option in this patient population. This study evaluates the outcomes of a contemporary comparative series from one institution of open total arch and hybrid arch procedures for extensive aortic arch pathology. METHODS: From July 2000 to March 2009, 1196 open arch procedures were performed, including 45 elective and 7 emergency open total arch procedures. From 2005 to 2009, 64 hybrid arch procedures were performed: 37 emergency type A dissections and 27 elective open arch debranchings. Hemiarch procedures were excluded. RESULTS: The hybrid arch cohort was significantly older (P = .008) and had greater predominance of atherosclerotic pathophysiology (P < .001). The incidence of permanent cerebral neurologic deficit was similar at 4% (1/27) for the hybrid arch cohort and 9% (4/45) for the open aortic arch cohort. In-hospital mortality was similar at 11% (3/27) for the hybrid arch cohort and 16% (7/45) for the open aortic arch cohort. However, in the open arch group, there was a significant difference in mortality between patients aged less than 75 years at 9% (3/34) and patients aged more than 75 years at 36% (4/11) (P = .05). CONCLUSIONS: Hybrid arch procedures provide a safe alternative to open repair. This study suggests the hybrid arch approach has a lower mortality for high-risk patients aged more than 75 years. This extends the indication for the hybrid arch approach in patients with complex aortic arch pathology previously considered prohibitively high risk for conventional open total arch repair. PMID- 20723731 TI - Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets. AB - OBJECTIVES: In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions. METHODS: Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5). RESULTS: High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05). CONCLUSIONS: Anti-ETA therapy accelerated the reversal of flow induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy. PMID- 20723732 TI - Sewing needles embedded in the cardiac interventricular septum and chest wall. PMID- 20723733 TI - Experimental design for optimal flow rate of antegrade cerebral perfusion. PMID- 20723734 TI - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa. PMID- 20723735 TI - The trap for researchers: misrepresentation of data from articles. PMID- 20723737 TI - The future of cardiac surgery. PMID- 20723738 TI - Treatment of subglottic stricture. PMID- 20723742 TI - Reporting of mortality associated with pediatric and congenital cardiac surgery. PMID- 20723739 TI - Is early antithrombotic therapy necessary in bioprosthetic valves? PMID- 20723743 TI - Comparable patencies of the radial artery and right internal thoracic artery or saphenous vein beyond 5 years: results from the Radial Artery Patency and Clinical Outcomes trial. PMID- 20723745 TI - Delayed paraplegia in transition countries: are we missing something? PMID- 20723747 TI - In situ right internal thoracic artery is usually long enough for grafting the circumflex artery through the transverse sinus. PMID- 20723748 TI - Stroke prevention by means of left atrial appendage strangulation? PMID- 20723749 TI - Induced domain formation in endocytic invagination, lipid sorting, and scission. AB - Lipid segregation occurs in biological membranes, but how this plays into cellular processes like endocytosis has been unclear. Here, we discuss how the active or passive induction of lipid-protein domain formation in membranes can alter membrane mechanics and thus affect processes such as the generation of curvature, the scission of buds and tubules, and lipid sorting. PMID- 20723750 TI - Reversing cachexia. AB - Muscle atrophy (cachexia) in cancer patients is a life-threatening condition for which therapeutic options are limited. Zhou et al. (2010) now identify a new target for treating cachexia, the activin type-2 receptor (ActRIIB). In several mouse models of cachexia, the authors reversed wasting of skeletal and cardiac muscle and increased life span by blocking ActRIIB with a decoy receptor. PMID- 20723751 TI - The ins and outs of EGFR asymmetry. AB - The epidermal growth factor receptor (EGFR) regulates cell proliferation in many tissues. A new structure of the Drosophila EGFR presented by Alvarado et al. (2010) reveals an asymmetric dimer with the ligand bound to only one subunit. The structure provides a rationale for the receptor's negative cooperativity and necessitates a reconsideration of models for activation of human EGFR. PMID- 20723752 TI - Up a hydrophobic creek with a short paddle. AB - The mechanism by which voltage-dependent ion channels sense membrane potentials has been the most intensively studied and debated topic in modern ion channel research. In this issue, Xu et al. (2010) provide new insights into the minimal topological and physicochemical features required for voltage sensing. PMID- 20723753 TI - The Immunoproteasome Cleans up after Inflammation. AB - Immune cells and cells activated by the inflammatory cytokine interferon express variant proteasomes called immunoproteasomes that are characterized by unique catalytic subunits. Seifert et al. (2010) now show in mouse models of inflammatory disease that immunoproteasomes help prevent the accumulation of harmful protein aggregates. PMID- 20723754 TI - Cellular strategies for regulating DNA supercoiling: a single-molecule perspective. AB - Entangling and twisting of cellular DNA (i.e., supercoiling) are problems inherent to the helical structure of double-stranded DNA. Supercoiling affects transcription, DNA replication, and chromosomal segregation. Consequently the cell must fine-tune supercoiling to optimize these key processes. Here, we summarize how supercoiling is generated and review experimental and theoretical insights into supercoil relaxation. We distinguish between the passive dissipation of supercoils by diffusion and the active removal of supercoils by topoisomerase enzymes. We also review single-molecule studies that elucidate the timescales and mechanisms of supercoil removal. PMID- 20723755 TI - Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. AB - Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival. PMID- 20723756 TI - PcrA helicase dismantles RecA filaments by reeling in DNA in uniform steps. AB - Translocation of helicase-like proteins on nucleic acids underlies key cellular functions. However, it is still unclear how translocation can drive removal of DNA-bound proteins, and basic properties like the elementary step size remain controversial. Using single-molecule fluorescence analysis on a prototypical superfamily 1 helicase, Bacillus stearothermophilus PcrA, we discovered that PcrA preferentially translocates on the DNA lagging strand instead of unwinding the template duplex. PcrA anchors itself to the template duplex using the 2B subdomain and reels in the lagging strand, extruding a single-stranded loop. Static disorder limited previous ensemble studies of a PcrA stepping mechanism. Here, highly repetitive looping revealed that PcrA translocates in uniform steps of 1 nt. This reeling-in activity requires the open conformation of PcrA and can rapidly dismantle a preformed RecA filament even at low PcrA concentrations, suggesting a mode of action for eliminating potentially deleterious recombination intermediates. PMID- 20723757 TI - The monopolin complex crosslinks kinetochore components to regulate chromosome microtubule attachments. AB - The monopolin complex regulates different types of kinetochore-microtubule attachments in fungi, ensuring sister chromatid co-orientation in Saccharomyces cerevisiae meiosis I and inhibiting merotelic attachment in Schizosaccharomyces pombe mitosis. In addition, the monopolin complex maintains the integrity and silencing of ribosomal DNA (rDNA) repeats in the nucleolus. We show here that the S. cerevisiae Csm1/Lrs4 monopolin subcomplex has a distinctive V-shaped structure, with two pairs of protein-protein interaction domains positioned approximately 10 nm apart. Csm1 presents a conserved hydrophobic surface patch that binds two kinetochore proteins: Dsn1, a subunit of the outer-kinetochore MIND/Mis12 complex, and Mif2/CENP-C. Csm1 point-mutations that disrupt kinetochore-subunit binding also disrupt sister chromatid co-orientation in S. cerevisiae meiosis I. We further show that the same Csm1 point-mutations affect rDNA silencing, probably by disrupting binding to the rDNA-associated protein Tof2. We propose that Csm1/Lrs4 functions as a molecular clamp, crosslinking kinetochore components to enforce sister chromatid co-orientation in S. cerevisiae meiosis I and to suppress merotelic attachment in S. pombe mitosis, and crosslinking rDNA repeats to aid rDNA silencing. PMID- 20723758 TI - Structural basis for negative cooperativity in growth factor binding to an EGF receptor. AB - Transmembrane signaling by the epidermal growth factor receptor (EGFR) involves ligand-induced dimerization and allosteric regulation of the intracellular tyrosine kinase domain. Crystallographic studies have shown how ligand binding induces dimerization of the EGFR extracellular region but cannot explain the "high-affinity" and "low-affinity" classes of cell-surface EGF-binding sites inferred from curved Scatchard plots. From a series of crystal structures of the Drosophila EGFR extracellular region, we show here how Scatchard plot curvature arises from negatively cooperative ligand binding. The first ligand-binding event induces formation of an asymmetric dimer with only one bound ligand. The unoccupied site in this dimer is structurally restrained, leading to reduced affinity for binding of the second ligand, and thus negative cooperativity. Our results explain the cell-surface binding characteristics of EGF receptors and suggest how individual EGFR ligands might stabilize distinct dimeric species with different signaling properties. PMID- 20723759 TI - ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. AB - ATG12, an ubiquitin-like modifier required for macroautophagy, has a single known conjugation target, another autophagy regulator called ATG5. Here, we identify ATG3 as a substrate for ATG12 conjugation. ATG3 is the E2-like enzyme necessary for ATG8/LC3 lipidation during autophagy. ATG12-ATG3 complex formation requires ATG7 as the E1 enzyme and ATG3 autocatalytic activity as the E2, resulting in the covalent linkage of ATG12 onto a single lysine on ATG3. Surprisingly, disrupting ATG12 conjugation to ATG3 does not affect starvation-induced autophagy. Rather, the lack of ATG12-ATG3 complex formation produces an expansion in mitochondrial mass and inhibits cell death mediated by mitochondrial pathways. Overall, these results unveil a role for ATG12-ATG3 in mitochondrial homeostasis and implicate the ATG12 conjugation system in cellular functions distinct from the early steps of autophagosome formation. PMID- 20723760 TI - Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity. AB - Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG 4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases. PMID- 20723761 TI - Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. AB - Interferon (IFN)-induced immunoproteasomes (i-proteasomes) have been associated with improved processing of major histocompatibility complex (MHC) class I antigens. Here, we show that i-proteasomes function to protect cell viability under conditions of IFN-induced oxidative stress. IFNs trigger the production of reactive oxygen species, which induce protein oxidation and the formation of nascent, oxidant-damaged proteins. We find that the ubiquitylation machinery is concomitantly upregulated in response to IFNs, functioning to target defective ribosomal products (DRiPs) for degradation by i-proteasomes. i-proteasome deficiency in cells and in murine inflammation models results in the formation of aggresome-like induced structures and increased sensitivity to apoptosis. Efficient clearance of these aggregates by the enhanced proteolytic activity of the i-proteasome is important for the preservation of cell viability upon IFN induced oxidative stress. Our findings suggest that rather than having a specific role in the production of class I antigens, i-proteasomes increase the peptide supply for antigen presentation as part of a more general role in the maintenance of protein homeostasis. PMID- 20723763 TI - SnapShot: Homologous recombination in DNA double-strand break repair. PMID- 20723762 TI - Activation of specific apoptotic caspases with an engineered small-molecule activated protease. AB - Apoptosis is a conserved cellular pathway that results in the activation of cysteine-aspartyl proteases, or caspases. To dissect the nonredundant roles of the executioner caspase-3, -6, and -7 in orchestrating apoptosis, we have developed an orthogonal protease to selectively activate each isoform in human cells. Our approach uses a split-tobacco etch virus (TEV) protease under small molecule control, which we call the SNIPer, with caspase alleles containing genetically encoded TEV cleavage sites. These studies reveal that all three caspases are transiently activated but only activation of caspase-3 or -7 is sufficient to induce apoptosis. Proteomic analysis shown here and from others reveals that 20 of the 33 subunits of the 26S proteasome can be cut by caspases, and we demonstrate synergy between proteasome inhibition and dose-dependent caspase activation. We propose a model of proteolytic reciprocal negative regulation with mechanistic implications for the combined clinical use of proteasome inhibitors and proapoptotic drugs. PMID- 20723764 TI - Art. PMID- 20723765 TI - A physician's personal experience as a cancer of the neck patient. AB - The author presents his personal experiences as a physician who had several surgical procedures to remove pyriform sinus squamous cell carcinoma, which included laryngectomy. He recently published a book that captures the three years of his life that followed his throat cancer diagnosis and tells his story of facing and dealing with medical and surgical treatments and adjusting to life afterwards. The editorial highlights some of the book's features that relate to the important role of head and neck surgeons in the care of patients with cancer. PMID- 20723766 TI - Improving the letter of recommendation. AB - The selection of applicants to otolaryngology training programs is a challenging task. Applicants and their evaluators rely on objective and subjective data to facilitate the selection process. Unfortunately, data are often less helpful than either side assumes, suffering from poor validity and reliability in predicting future performance. The traditional resume-based letter of recommendation bears some responsibility in this. It is often a lengthy reiteration of already available objective data and contains nonstandardized, superlative evaluations of personal attributes. As a result, many letters are similar, describing "excellent" candidates who have done well on previous examinations and clerkships. Research has indicated improved reliability and satisfaction as well as decreased time expenditure using standardized letters of recommendation. These letters demonstrate how basic, easy-to-implement improvements can create letters that provide accurate information, separate applicants, and improve the selection process. Consideration should be given to adopting these improvements at the program director and/or educational committee level. PMID- 20723767 TI - A practical guide to understanding Kaplan-Meier curves. AB - In 1958, Edward L. Kaplan and Paul Meier collaborated to publish a seminal paper on how to deal with incomplete observations. Subsequently, the Kaplan-Meier curves and estimates of survival data have become a familiar way of dealing with differing survival times (times-to-event), especially when not all the subjects continue in the study. "Survival" times need not relate to actual survival with death being the event; the "event" may be any event of interest. Kaplan-Meier analyses are also used in nonmedical disciplines. The purpose of this article is to explain how Kaplan-Meier curves are generated and analyzed. Throughout this article, we will discuss Kaplan-Meier estimates in the context of "survival" before the event of interest. Two small groups of hypothetical data are used as examples in order for the reader to clearly see how the process works. These examples also illustrate the crucially important point that comparative analysis depends upon the whole curve and not upon isolated points. PMID- 20723768 TI - Primary care perceptions of otolaryngology. AB - OBJECTIVE: To identify diseases of the head and neck for which primary care physicians may underappreciate the role of the otolaryngologist. STUDY DESIGN: Cross-sectional analysis. SETTING: With increasing subspecialization in the world of medicine, there is the potential for confusion about the scope of practice for different specialties by primary care physicians. These clinicians are often faced with patients who have disease processes in which otolaryngologist are trained but may end up referring patients to other specialists. SUBJECTS AND METHODS: A brief, web-based survey was administered via e-mail to resident physicians of family medicine, pediatrics, and internal medicine programs in the United States. The survey asked responders which specialist they believed was an expert for particular clinical entities: allergies, oral cancer, restoring a youthful face, sleep apnea, thyroid surgery, and tracheostomy. Respondents could choose from a dermatologist, general surgeon, ophthalmologist, oral maxillofacial surgeon, orthopedic surgeon, otolaryngologist, and plastic surgeon. The responder was able to choose more than one specialist for each question. RESULTS: A total of 1064 completed surveys were analyzed. The percentage of primary care residents who picked otolaryngologists as experts was 13.8 percent for allergies, 73.6 percent for oral cancer, 2.7 percent for restoring a youthful face, 32.4 percent for sleep apnea, 47.2 percent for thyroid surgery, and 72.5 percent for tracheostomy. CONCLUSION: This study demonstrates that many primary care residents are not aware of the scope of expertise that an otolaryngologist may offer. Increased exposure to otolaryngology during primary care residency training may increase understanding of the specialty among primary care physicians. PMID- 20723769 TI - Clinical value of office-based endoscopic incisional biopsy in diagnosis of nasal cavity masses. AB - OBJECTIVE: To evaluate clinical features and the diagnostic accuracy of office based endoscopic incisional biopsy in patients with nasal cavity masses. STUDY DESIGN: Diagnostic test assessment with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: From January 1997 to August 2006, preoperative diagnosis was achieved using endoscopic incisional biopsy in 521 patients. Cytopathologic and histologic findings were categorized as malignancy, benign neoplasm, or non-neoplastic lesion. Preoperative imaging was done in 462 patients (computed tomography: 438 cases; magnetic resonance imaging: 24 cases). We investigated the accuracy of endoscopic incisional biopsy and preoperative imaging by comparing it with pathologic results from tumor resection as the "gold standard." RESULTS: Most of the patients had unilateral nasal symptoms (e.g., nasal obstruction, unilateral epistaxis, unilateral facial pain), and the clinical symptoms were of little diagnostic value in the differentiation of tumor and inflammatory lesion. The sensitivity and specificity of endoscopic incisional biopsy were 43.7 and 98.9 percent, respectively, for the diagnosis of nasal cavity malignancies, and 78.2 and 96.2 percent, respectively, for the diagnosis of benign neoplasms. The sensitivity and specificity of preoperative imaging were 78.3 and 97.5 percent, respectively, for the diagnosis of nasal cavity malignancies and 66.4 and 86.3 percent, respectively, for the diagnosis of benign neoplasms. Combining the two modalities increased diagnostic accuracy in nasal cavity masses. CONCLUSION: Endoscopic incisional biopsy alone did not ensure accurate diagnosis of nasal cavity tumors, but in combination with preoperative imaging it was helpful for the diagnosis of nasal cavity malignancies. PMID- 20723770 TI - Radiofrequency inferior turbinate reduction: an evaluation of olfactory and respiratory function. AB - OBJECTIVE: The aim of this study was to assess the outcomes after radiofrequency inferior turbinate reduction (RITR) on objective and subjective nasal function in patients with nasal obstruction caused by turbinate hypertrophy and to evaluate the possible effect on olfactory function. STUDY DESIGN: Case series with planned data collection. SETTING: ENT division, university hospital. SUBJECTS AND METHODS: Forty consecutive patients who underwent RITR for allergic or nonallergic chronic rhinitis with inferior turbinate hypertrophy were tested before and two months after the surgical procedure, using the Sniffin' Sticks test battery, anterior rhinomanometry, and the nasal obstruction symptom evaluation (NOSE) scale. RESULTS: The total basal nasal resistance at 150 Pa diminished significantly two months after surgery. Preoperative olfactory tests showed anosmia in five percent (n = 2) of the patients, hyposmia in 82 percent (n = 33), and normosmia in 12 percent (n = 5). At two months from the intervention, two percent (n = 1) were diagnosed as anosmic, 12 percent (n = 5) as hyposmic, and 85 percent (n = 34) as normosmic. The means of preoperative odor threshold (T), discrimination (D), identification (I), and the overall TDI score improved significantly postoperatively (P < 0.001). The NOSE score in the two-month follow up improved in 97.5 percent (n = 39) of patients, with a mean difference in pre- vs. postintervention score of 40.12 (95% confidence interval 35.75-44.25; P < 0.001). CONCLUSION: RITR may provide excellent outcomes in terms of improvement in olfactory function and nasal flow in patients affected by turbinate hypertrophy refractory to medical therapy. PMID- 20723771 TI - Demographics and efficacy of head and neck cancer screening. AB - OBJECTIVE: This study was designed to 1) describe the demographics and 2) determine the efficacy of a head and neck cancer screening program to optimize future programs. STUDY DESIGN: Database analysis plus chart review. SETTING: Tertiary care academic medical center. SUBJECTS AND METHODS: After Institutional Review Board approval, we reviewed our 14-year experience (1996-2009) conducting a free annual head and neck cancer screening clinic. Available demographic and clinical data, as well as clinical outcomes, were analyzed for all participants (n = 761). The primary outcome was the presence of a finding suspicious for head and neck cancer on screening evaluation. RESULTS: Five percent of participants had findings suspicious for head and neck cancer on screening evaluation, and malignant or premalignant lesions were confirmed in one percent of participants. Lack of insurance (P = 0.05), tobacco use (P < 0.001), male gender (P = 0.03), separated marital status (P = 0.03), and younger age (P = 0.04) were the significant demographic predictors of a lesion suspicious for malignancy. Patients complaining of a neck mass (P < 0.001) or oral pain (P < 0.001) were significantly more likely to have findings suspicious of malignancy. A high percentage (40%) was diagnosed with benign otolaryngologic pathologies on screening evaluation. CONCLUSION: A minority of patients presenting to a head and neck cancer screening clinic will have a suspicious lesion identified. Given these findings, to achieve maximal potential benefit, future head and neck cancer screening clinics should target patients with identifiable risk factors and take full advantage of opportunities for education and prevention. PMID- 20723772 TI - Development and preliminary validation of the lip reanimation outcomes questionnaire. AB - OBJECTIVE: Lip paralysis is associated with eating, speaking, and appearance impairments. The lip reanimation outcome questionnaire is designed to assess these functional impairments after lip reanimation. STUDY DESIGN: Cross-sectional validation study. SETTING: Tertiary care academic center. SUBJECTS AND METHODS: Patients who underwent lip reanimation and control subjects. A disease-specific instrument was created by systematic literature review and expert opinion. The 15 item patient completed subscale was administered to 20 lip reanimation patients. Photographs of 19 patients and three control subjects were taken in four poses and rated by six raters (2 surgeons, 2 residents, and 2 novices) by the use of a external rater subscale, and reliability was determined by the use of intraclass correlation coefficients (ICC). Content and construct validity were assessed. RESULTS: Internal consistency (ICC range 0.813-0.915 for each domain), test retest reliability (ICC range 0.616-0.981 for each item) for the patient completed subscale, and interrater (ICC = 0.852) and interlevel reliability (ICC = 0.929) for the external rater subscale were substantial to excellent. The content validity index was 0.87. Construct validity was demonstrated by poorer scores in patients with transected nerves versus intact nerves for appearance (P = 0.04) and oral competence (P = 0.011). Photographs of control patients had lower asymmetry scores (P < 0.001), and the instrument detected greater asymmetry in patients with progressively more exaggerated smile (P < 0.001). CONCLUSION: The lip reanimation outcome questionnaire has promising reliability and validity in this preliminary study, but additional psychometric testing with larger samples is required before the survey can be recommended for clinical use. PMID- 20723773 TI - Utilizing computed tomography as a road map for designing selective and superselective neck dissection after chemoradiotherapy. AB - OBJECTIVE: To determine whether computed tomography can distinguish low risk neck levels that can be omitted when neck dissection is undertaken after chemoradiotherapy. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: Head and neck squamous cell carcinoma patients undergoing neck dissection after chemoradiotherapy between January 1998 and June 2008. We compared computed tomography findings after chemoradiotherapy with neck dissection pathology results; used primary location and computed tomography findings to design selective or superselective neck dissection; and determined whether these surgeries would have contained all metastatic disease. RESULTS: A total of 104 patients were identified, providing 110 heminecks, 531 neck levels, and 3009 lymph nodes for analysis. Neck dissections were positive in 20 (19%) of 104 patients, corresponding to 20 hemineck dissections, 31 neck levels, and 53 lymph nodes. The negative predictive value for computed tomography was 95 percent. The negative predictive value for computed tomography per neck level was as follows: I, 100 percent; II, 96 percent; III, 96 percent; IV, 97 percent; and V, 96 percent. A selective neck dissection or a superselective neck dissection, guided by level specific computed tomography findings and limited to necks with post treatment partial response in one level, would have captured all disease in 52 (95%) of 55 and 51 (93%) of 55 heminecks. CONCLUSION: Negative computed tomography accurately predicts pathologic complete response at neck dissection. Neck dissection can be avoided in these patients. Additionally, computed tomography reliably identifies low risk neck levels that do not require dissection, permitting selective neck dissection or superselective neck dissection in partial response patients with limited residual disease. PMID- 20723774 TI - Esophageal pathology in patients after treatment for head and neck cancer. AB - OBJECTIVE: To determine the prevalence of esophageal pathology following treatment for primary head and neck cancer (HNCA). STUDY DESIGN: Case series with planned data collection. SETTING: Academic medical practice. SUBJECTS AND METHODS: Subjects comprised HNCA survivors. Esophagoscopy was prospectively performed on 100 patients at least three months after treatment for HNCA. Patient demographics including cancer stage, cancer treatment, use of reflux medications, symptoms surveys, and esophageal findings were prospectively determined. RESULTS: The mean age of the cohort was 64 (+/- 10) years; 75 percent were male. The mean time between the end of treatment and endoscopy was 40 (+/- 51) months. Eighty one percent of HNCA was advanced stage (3 or 4). The distribution of site of the primary HNCA was as follows: oropharynx (38%), larynx (33%), oral cavity (17%), unknown primary (10%), hypopharynx (1%), and nasopharynx (1%). Treatment modalities included surgery alone (15%), surgery with radiation (34%), radiation alone (6%), chemoradiation alone (24%), and chemoradiation with surgery (20%). The findings on esophagoscopy included peptic esophagitis (63%), stricture (23%), candidiasis (9%), Barrett metaplasia (8%), gastritis (4%), and carcinoma (4%). Only 13 percent had a normal esophagoscopy. CONCLUSION: Esophageal pathology is extremely common in patients treated for HNCA. These findings support routine esophageal screening after HNCA treatment. PMID- 20723775 TI - Immunoglobulin E-mediated food allergies among adults with allergic rhinitis. AB - OBJECTIVE: To compare the prevalence of food allergy for peanut, shrimp, and milk in adults with allergic rhinitis and to determine predictive values of these allergens and total immunoglobulin E (IgE) to detect food allergies. STUDY DESIGN: Cross-sectional study. SETTING: University of Chicago Medical Center, Chicago, Illinois. SUBJECTS AND METHODS: We retrospectively analyzed in vitro enzyme-linked immunosorbent assays of adults with rhinitis. Subjects were tested for nine inhalants and three foods (peanut, shrimp, milk) and total IgE. Subjects with food allergy history were tested with additional foods. The sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of the allergens and total IgE to detect food allergies were calculated. RESULTS: A total of 283 subjects received in vitro tests. Forty-one percent tested negative and 59 percent tested positive for inhalants. The prevalence of subjects with a positive peanut or shrimp allergy in the inhalant positive population was significantly greater than subjects with milk allergy (23.4% peanut [P = 0.008], 22.2% shrimp [P = 0.001], and 13.2% milk [P = 0.008], P = 0.001). For subjects with food allergy history, peanut had the best SP (100.0%), SE (28.1%), PPV (100.0%), and NPV (64.6%) in detecting allergies to other foods. In patients positive for the initial panel (inhalants and peanut), the SP, SE, PPV, and NPV of elevated total IgE was 71.4, 72.4, 77.8, and 65.2 percent, respectively. CONCLUSION: Peanut and shrimp were the most common foods encountered in adults with allergic rhinitis. Peanut was best in predicting other food allergies. Total IgE levels with inhalants plus peanut provided the optimal combination of SE, SP, PPV, and NPV. In vitro testing may be important to identify and prevent anaphylaxis to foods in adults. PMID- 20723776 TI - Released intranasal eosinophilic major basic protein as a diagnostic marker for polypoid chronic rhinosinusitis. AB - OBJECTIVE: To investigate the hypothesis that eosinophil major basic protein is released in high concentrations in the nasal mucus of patients with polypoid chronic rhinosinusitis. STUDY DESIGN: Single center, open, prospective trial. SETTING: Medical University of Graz, Austria. SUBJECTS AND METHODS: Patients with polypoid chronic rhinosinusitis (n = 23) were compared to three different control groups: patients with chronic rhinosinusitis-like symptoms but without general mucosal thickening, patients who underwent functional endoscopic sinus surgery for reasons other than chronic rhinosinusitis, and patients without sinus disease (total n = 21). Mucus was harvested from each patient using a standardized technique and analyzed for eosinophil major basic protein with an enzyme-linked immunosorbent assay. RESULTS: In the patient group with polypoid chronic rhinosinusitis, 20 of 23 (87%) were positive for eosinophil major basic protein. In contrast, only one control patient was positive, whereas the remainder had no detectable amount of eosinophil major basic protein in the mucus (P < 0.001 vs chronic rhinosinusitis). CONCLUSION: Toxic eosinophil major basic protein levels are elevated in polypoid chronic rhinosinusitis patients compared to control groups that have similar clinical presentations but upon closer examination turn out not to have chronic rhinosinusitis. In the future, the detection of eosinophil major basic protein in nasal mucus may become a sensitive and specific marker for chronic rhinosinusitis and a helpful diagnostic tool. PMID- 20723777 TI - Sinogenic orbital and subperiosteal abscesses: microbiology and methicillin resistant Staphylococcus aureus incidence. AB - OBJECTIVE: To assess the current bacteriology and the incidence of methicillin resistant Staphylococcus aureus in orbital and subperiosteal abscesses of paranasal sinus disease origin. STUDY DESIGN: Case series with chart review. SETTING: An otolaryngology and ophthalmology specialty hospital. SUBJECTS AND METHODS: Fifty-three patients were treated between 1994 and 2008 for orbital or subperiosteal abscess and paranasal sinusitis, confirmed by imaging and surgical intervention; 46 had operative culture specimens and comprise the study cohort. RESULTS: The mean patient age was 28 years; one third were younger than 18. Nearly twice as many patients had subperiosteal (n = 30) as had orbital abscesses (n = 16). In 12 patients (26%), cultures were negative or grew only skin flora contaminants (coagulase-negative staphylococci, diphtheroids, and Propionibacterium acnes). Fifteen patients (33%) grew more than one pathogen. Streptococci were isolated in 17 of the 46 cases (37%), S. aureus in 13 (28.3%), gram-negative bacilli in eight (17.4%), and anaerobes in nine (19.6%). Methicillin-resistant S. aureus accounted for three (23.1%) of the S. aureus isolates and 6.5 percent of the total cases. CONCLUSION: Abscess cultures grew a mixture of bacteria, including gram-positive cocci, gram-negative bacilli, and anaerobes. Although streptococci were the most common genus of bacteria isolated, S. aureus was the single most common pathogen recovered and one fourth of these cases were methicillin-resistant S. aureus. Given the significant morbidity that may result from inadequate treatment, an antibiotic active against methicillin resistant S. aureus should be included in the initial broad-spectrum antimicrobial treatment regimen of orbital and subperiosteal abscesses of sinusitis origin until culture results are available. PMID- 20723779 TI - Canalith repositioning variations for benign paroxysmal positional vertigo. AB - OBJECTIVE: To determine if variations in common treatments for benign paroxysmal positional vertigo (BPPV) affected efficacy. STUDY DESIGN: Prospective, pseudo randomized study. SETTING: Outpatient practice in a tertiary care facility. SUBJECTS AND METHODS: Patients (n = 118) with unilateral BPPV of the posterior canal, including 13 patients with BPPV of the lateral canal, were tested at a tertiary care center on one of five interventions: canalith repositioning maneuver (CRP), CRP plus home exercise, modified CRP, CRP for patients with involvement of two semicircular canals, and self-CRP home exercise. Self-CRP was also compared to previously published data on efficacy of the Brandt Daroff exercise. Main outcome measures were vertigo intensity and frequency, presence/absence of Dix-Hallpike responses, Vestibular Disorders Activities of Daily Living Scale (VADL), and computerized dynamic posturography. RESULTS: Vertigo intensity and frequency and Dix-Hallpike responses decreased significantly, and posturography and VADL improved significantly from pre- to post tests. No other significant changes were found. The groups did not differ significantly. Vertigo intensity and frequency were not strongly related at pretest but were related at post-test. Length of illness and age did not influence the results. CONCLUSION: However the head is moved, as long as it is moved rapidly enough and through the correct planes in space, repositioning treatments are likely to be effective. Therefore, clinicians have a range of choices in selecting the treatment best suited for each patient's unique needs. PMID- 20723778 TI - Hesperidin stimulates cystic fibrosis transmembrane conductance regulator mediated chloride secretion and ciliary beat frequency in sinonasal epithelium. AB - OBJECTIVE: Pharmacologic agents designed to promote mucociliary clearance (MCC) in chronic rhinosinusitis (CRS) represent a novel therapeutic strategy. The objectives of the present study were to investigate whether the natural bioflavonoid hesperidin 1) increases transepithelial chloride (Cl(-)) secretion in vitro and in vivo, 2) enhances ciliary beat frequency (CBF), and 3) exerts its mechanistic effects through cAMP/PKA-dependent pathways. STUDY DESIGN: In vitro and in vivo study. SETTING: Laboratory. SUBJECTS AND METHODS: Transepithelial Cl( ) transport (Ussing chamber) and CBF were investigated in primary murine nasal septal (MNSE) and human sinonasal epithelial (HSNE) cultures. In vivo activity was measured using the murine nasal potential difference (NPD) assay, cystic fibrosis transmembrane conductance regulator (CFTR) R-domain phosphorylation, and cAMP levels were investigated to rule out a cAMP/PKA-dependent mechanism of activation. RESULTS: Hesperidin significantly increased CFTR-mediated Cl(-) transport (change in short-circuit current, DeltaI(SC)) in both MNSE (13.51 +/- 0.77 vs 4.4 +/- 0.66 [control]; P < 0.05) and HSNE (12.28 +/- 1.08 vs 0.69 +/- 0.32 [control]; P < 0.05). Cl(-) transport across in vivo murine nasal epithelium was also significantly enhanced with hesperidin (-2.3 +/- 1.0 vs -0.8 +/- 0.8 mV [control], P < 0.05). There was no increase in cellular cAMP or phosphorylation of the CFTR R-domain. Hesperidin significantly increased CBF (ratio of pretreatment to post-treatment) with both basal (1.31 +/- 0.07 vs 0.93 +/- 0.06 [control]; P < 0.05), apical (1.72 +/- 0.09 vs 1.40 +/- 0.07 [control]; P < 0.05), and basal + apical delivery (2.26 +/- 0.18 vs 1.60 +/- 0.21, respectively; P < 0.05). CONCLUSION: Our in vitro and in vivo investigations provide strong support for future testing of this robust Cl(-) secretagogue and CBF activator in human clinical trials for CRS. PMID- 20723780 TI - Benign paroxysmal positional vertigo secondary to inner ear disease. AB - OBJECTIVES: To contrast clinical characteristics of secondary benign paroxysmal positional vertigo (s-BPPV) with idiopathic BPPV (i-BPPV). STUDY DESIGN: Case series with chart review. SETTING: University hospital. SUBJECTS AND METHODS: A total of 718 patients whose medical records were reviewed had BPPV. Sixty-nine patients had existing inner ear diseases and thus were considered to have s-BPPV. We reviewed demographics, concurrent causative disorders, involved area, and response to particle repositioning maneuvers for these s-BPPV patients in comparison with i-BPPV subjects. RESULTS: Female subjects with i-BPPV outnumbered male subjects by a ratio of 1.9:1, but there was no significant sex difference for s-BPPV patients. The diseases associated with s-BPPV were idiopathic sudden sensory hearing loss (ISSHL, 50.7%), Meniere's disease (MD, 28.9%) and unilateral vestibulopathy such as acute vestibular neuronitis and herpes zoster oticus (20.2%). The posterior canal was most commonly involved in both i-BPPV and s BPPV. The horizontal canal was the second most common, followed by multi-canal involvement. However, MD-associated BPPV most commonly involved the lateral canal. The mean durations of treatment for i-BPPV and s-BPPV were 2.28 and 4.87 days, respectively. The mean duration of treatment was 6.28 days for ISSHL with BPPV, 5.07 days for BPPV with unilateral vestibulopathy, and 2.28 days for BPPV with MD. CONCLUSION: The mean duration of treatment for BPPV with ISSHL or unilateral vestibulopathy was longer than for other groups. The different pathophysiologies of s-BPPV associated with different inner ear diseases may explain its diverse clinical features and courses. PMID- 20723781 TI - Aging effect on galvanic vestibular-evoked myogenic potentials. AB - OBJECTIVE: This study compared the characteristic parameters of vestibular-evoked myogenic potentials (VEMPs) via galvanic vestibular stimulation (GVS) in healthy subjects of various ages to measure the effect of aging on GVS-VEMPs. STUDY DESIGN: Prospective study. SETTING: University hospital. SUBJECTS AND METHODS: Fifty-two healthy subjects were divided into five groups by age. Each group consisted of 10 subjects in one decade (except 12 subjects in the group of 60 to 69 years). All subjects underwent VEMP testing via GVS with an intensity of 5 mA for 1 ms. RESULTS: All 10 subjects (20 ears) in each group aged 20 to 29, 30 to 39, 40 to 49, and 50 to 59 years exhibited clear GVS-VEMPs, whereas 20 (83%) of 24 ears in the group aged 60 to 69 years had clear GVS-VEMPs, exhibiting nonsignificant differences in terms of prevalence between the groups of subjects younger and older than 60 years. The mean p13 and n23 latencies and p13-n23 amplitude of the subjects in the groups aged 20 to 29, 30 to 39, 40 to 49, 50 to 59, and 60 to 69 years differed significantly among the five groups: the p13 and n23 latencies of the group aged older than 60 years was significantly longer than those of subjects younger than 60 years and their p13-n23 amplitude was lower. CONCLUSION: The decline of the amplitude and prolongation of the latencies in GVS VEMPs after the age of 60 may, at least in part, be caused by the decrease in the number of vestibular afferents and their caliber. PMID- 20723782 TI - Long-term results with the Rion E-type semi-implantable hearing aid. AB - OBJECTIVE: The Rion implantable hearing aid (IHA) Ehime (E)-type was developed for ears with middle ear diseases. This study focused on the current status of the patients, device problems, postoperative difficulties, and preventive measures against them. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral hospital. SUBJECTS AND METHODS: Subjects were 30 patients who were implanted with the IHA E-type between 1984 and 1997 and followed up for more than 10 years. Current status of IHA implantees, incidents of device problems, and postoperative troubles and hearing outcomes were reviewed. RESULTS: Eleven patients (36.7%) still use the original device. The average period of use was 16.6 +/- 3.3 years (21 years at most). The incidence of problems was lower with the second version of the device compared to the first version. Frequencies of the troubles were related to the types of original ear diseases: seven of 17 cases with chronic otitis media (41.2%), two of seven cases with cholesteatoma (28.6%), and two of six cases with tympanosclerosis (33.3%). No cholesteatoma occurred after surgical procedures (i.e., external ear canal closure and tympanic membrane lateralized) (P = 0.06). The device was exposed through a retroauricular skin fistula where the internal coil had been implanted. Significantly fewer infections were observed when the two-stage operation was used (P < 0.01). CONCLUSION: For long-term success in implantation of the IHA, careful control of middle ear inflammation and measures against eustachian tube dysfunction are required in addition to technological advancements. PMID- 20723783 TI - A combination antioxidant therapy prevents age-related hearing loss in C57BL/6 mice. AB - OBJECTIVE: Age-related hearing loss (ARHL) is characterized by gradual, progressive sensorineural hearing loss, which impairs communication, lending to clinical depression and social withdrawal. There are currently no effective treatments for ARHL. The purpose of this study is to evaluate the potential of a combination antioxidant therapy in preventing ARHL. STUDY DESIGN: Randomized controlled trial. SETTING: Animal study. SUBJECTS AND METHODS: C57BL/6 mice, a recognized animal model of ARHL, were assigned to one of three groups: early treatment (n = 12), late treatment (n = 9), or control group (n = 9). Treatment groups of mice were fed with a combination agent comprising six antioxidant agents that target four sites within the oxidative pathway: L-cysteine glutathione mixed disulfide, ribose-cysteine, NW-nitro-L-arginine methyl ester, vitamin B12, folate, and ascorbic acid. Auditory brainstem response (ABR) thresholds were recorded at baseline and every three months following initiation of treatment. RESULTS: Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies (P < 0.001). The ABR threshold shift at 12 months of age for the control group was 34.7 dB with a 95% confidence interval (CI) of +/-1.6. The mean threshold shifts for the early and late treatment groups were 7.5 dB (+/-0.87, 95% CI) and 9.2 dB (+/-1.6, 95% CI). CONCLUSION: Combination antioxidant therapy effectively decreased threshold shifts on ABR within an animal model of ARHL. Combination antioxidant therapy, with further research and investigation, may provide a safe and cost-effective method of preventing presbycusis in the growing elderly population. PMID- 20723784 TI - Acellular porcine intestinal submucosa as fascial graft in an animal model: applications for revision tympanoplasty. AB - OBJECTIVE: To demonstrate regeneration of muscle fascia appropriate for future harvest with the use of acellular porcine intestinal submucosa in a rat model. STUDY DESIGN: Animal cohort study. SETTING: Tertiary care academic medical center. SUBJECTS AND METHODS: Sixteen male Sprague-Dawley rats underwent excision of rectus abdominis muscle fascia. A sheet of acellular porcine intestinal submucosa was placed in the fascia harvest defect. Graft and underlying muscle were harvested at three-, six-, and nine-week intervals. Histologic examination, including immunohistology for anti-von Willebrand factor, was performed at each timepoint. Additional selected specimens were subjected to latex vascular perfusion casts to examine vessel growth patterns within the graft. RESULTS: Gross examination revealed a new tissue plane, indistinguishable from surrounding native fascia. Histology revealed an initial inflammatory response within the graft. Progressive influx of native tissue was noted over successive timepoints. Via collagen-specific staining, we noted progressive reorganization and maturation of the graft collagen matrix. At the final nine-week time point, a new loose connective tissue plane was reestablished between the graft and underlying muscle. Immunohistochemistry and latex perfusion both demonstrate an initial development of small capillaries that progresses over time to greater organization and arteriole formation. CONCLUSION: Fascia regeneration may be possible with use of an acellular porcine intestinal submucosa graft in an animal model. Future studies may prove beneficial in restoring fascia in humans. Implications for potential advantages in tympanoplasty are discussed. PMID- 20723785 TI - Obstructive sleep apnea surgery practice patterns in the United States: 2000 to 2006. AB - OBJECTIVE: To determine obstructive sleep apnea (OSA) surgical volume, types, costs, and trends. To explore whether specific patient and hospital characteristics are associated with the performance of isolated palate versus hypopharyngeal surgery and with costs. STUDY DESIGN: Cross-sectional study. SETTING: Inpatient and outpatient medical facilities in the United States. SUBJECTS AND METHODS: OSA procedures were identified in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for 2000, 2004, and 2006 and from State Ambulatory Surgery Databases and State Inpatient Databases for 2006 from four representative states (California, New York, North Carolina, and Wisconsin). National combined inpatient and outpatient surgery estimates for 2006 were generated using a combination of databases. Chi-square and regression analysis examined procedure volume and type and inpatient procedure costs. RESULTS: In 2006, an estimated 35,263 surgeries were performed in inpatient and outpatient settings, including 33,087 palate, 6561 hypopharyngeal, and 1378 maxillomandibular advancement procedures. The odds of undergoing isolated palate surgery were higher for younger (18-39 yrs) and black patients. Outpatient procedures were more common than inpatient procedures. Inpatient surgical volume declined from 2000 to 2006, but it was not possible to evaluate trends in total volumes. In 2006, mean costs were approximately $6000 per admission. For inpatient procedures in 2004 and 2006, costs were higher for hypopharyngeal (vs isolated palate) surgery, in rural hospitals, and for patients who were younger, with greater medical comorbidity, and with primary Medicaid coverage. CONCLUSION: Surgical treatment is performed in 0.2 percent of all adults with OSA annually. Validation of the exploratory findings concerning procedure type and cost requires additional studies, ideally including adjustment for clinical factors. PMID- 20723786 TI - Coblation lesion formation in a porcine tongue model. AB - OBJECTIVE: To investigate, in a porcine tongue model, the lesions created by coblation to define the optimal application of this method in treating the enlarged tongue base in patients with obstructive sleep apnea syndrome. STUDY DESIGN: A prospective, experimental animal study. SETTING: Military medical center. SUBJECTS AND METHODS: Fifteen fresh porcine tongue specimens were injected with normal saline, and a single coblation probe was applied to the tongue specimens to create multiple submucosal lesions at specific energy settings. Control lesions were created without the use of saline injections. After creating the lesions, the porcine tongue specimens were sectioned and examined grossly. Size and character of lesions were recorded for each of the specimens and were compared across energy settings. RESULTS: The energy applied at each setting was calculated on the basis of watts multiplied by treatment time. Coblation with saline injection created visible lesions with an average lesion area of 1.20 to 2.87 cm(2). The average lesion area increased as setting increased. Without saline injection, the average lesion area was 0.15 to 0.8 cm(2). CONCLUSION: The porcine tongue model describes the relationship between lesion size and cold ablation device settings. Setting, but not time, significantly affects lesion size. The coblation setting and treatment time directly impact the amount of energy delivered. Additionally, submucosal normal saline injection significantly increases lesion size at all settings and application times. Given the average lesion diameter described in this study, placing lesions 1 cm apart will optimize the area affected by coblation while minimizing lesion overlap. PMID- 20723787 TI - Reducing risk of fire in the operating room using coblation technology. AB - Operating room fires are rare, but when they occur, they have potentially devastating and deadly consequences. Coblation (ArthroCare ENT, Austin, TX) technology has become popular for many otolaryngology procedures and seems to have the advantage of reducing fire risk. Our objective was to test the Coblator II on various flammable materials commonly found and used in the operating room. We placed the active Coblator II at the highest settings, in direct contact with flammable operating room equipment and materials, and made the environment even more volatile by introducing oxygen into the testing environment. We found that the Coblator II did not produce fire when in contact with any of the materials. This finding is very important in otolaryngology because airway procedures often take place in environments with high concentrations of oxygen. Our testing shows that the Coblator II is safe to use in these types of environments. PMID- 20723788 TI - Endoscopic sphenoid nasalization for the treatment of advanced sphenoid disease. PMID- 20723789 TI - Adenoma of the ceruminous gland. PMID- 20723790 TI - Nasal natural killer/T-cell lymphoma. PMID- 20723791 TI - Cochlear implantations in patients with Cochlear fistulae. PMID- 20723792 TI - Gingival leukemic infiltration as the first manifestation of acute myeloid leukemia. PMID- 20723793 TI - Transnasal endoscopic approach for drainage of pediatric parapharyngeal space abscess. PMID- 20723794 TI - Ethical conduct of human research: some controversies. PMID- 20723796 TI - Pediatric otogenic intracranial abscesses. PMID- 20723797 TI - Images in cardiology. Pseudoatrioventricular block manifesting as a 2:1 atrioventricular block and advanced atrioventricular block because of concealed junctional ectopic impulses. PMID- 20723798 TI - Stroke prevention and treatment. AB - The decline in stroke incidence and mortality in the U.S. over the past 20 years is reaching a plateau, and the number of strokes may actually start to increase as the population ages. However, recent clinical trials have demonstrated that there are numerous opportunities to improve stroke prevention strategies and also opportunities to effectively intervene in and treat acute strokes. For patients with diabetes and for those with prior strokes or transient ischemic attacks, it has become evident that aggressive low-density lipoprotein lowering with statin medications will decrease the risk for total and fatal strokes. Optimal anticoagulation and antiplatelet therapy for primary and secondary stroke prevention in atrial fibrillation is being carefully defined. With numerous novel factor Xa and direct thrombin inhibitor drugs completing phase III clinical trials, it is likely that additional oral anticoagulant drugs will be clinically available for stroke prevention soon. Additionally, a major clinical trial is nearing completion that may resolve the role of carotid stenting and carotid endarterectomy in primary and secondary stroke prevention. There are recent notable advances in the acute treatment of stroke. It is likely that the time window for thrombolysis for appropriate patients with strokes will be increased from 3 to 4.5 h, permitting the inclusion of more patients in this treatment approach. There is ongoing investigation of intra-arterial thrombolysis and of acute intra-arterial thrombus extraction for treatment of selected patients with strokes. Unlike the progress in treatment of ischemic strokes, treatment of hemorrhagic stroke is progressing more slowly. PMID- 20723800 TI - Sadness in heart failure: what is a clinician to do? PMID- 20723799 TI - Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. AB - OBJECTIVES: The objective was to test the hypothesis that heart failure (HF) patients treated with sertraline will have lower depression scores and fewer cardiovascular events compared with placebo. BACKGROUND: Depression is common among HF patients. It is associated with increased hospitalization and mortality. METHODS: The SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial was a randomized, double-blind, placebo-controlled trial of sertraline 50 to 200 mg/day versus matching placebo for 12 weeks. All participants also received nurse-facilitated support. Eligible patients were age 45 years or older with HF (left ventricular ejection fraction < or =45%, New York Heart Association functional class II to IV) and clinical depression (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for current major depressive disorder). Those with significant cognitive impairment, psychosis, recent alcohol or drug dependence, bipolar or severe personality disorder, active suicidal ideation, and current antipsychotic or antidepressant medications were excluded. Primary end points were change in depression severity (Hamilton Depression Rating Scale total score) and composite cardiovascular status at 12 weeks. RESULTS: A total of 469 patients were randomized (n = 234 sertraline, n = 235 placebo). The mean +/- SE change from baseline to 12 weeks in the Hamilton Depression Rating Scale total score was -7.1 +/- 0.5 (sertraline) and -6.8 +/- 0.5 (placebo) (p < 0.001 from baseline, p = 0.89 between groups, mean change between groups -0.4; 95% confidence interval: -1.7 to 0.92). The proportions whose composite cardiovascular score worsened, improved, or was unchanged were 29.9%, 40.6%, and 29.5%, respectively, in the sertraline group and 31.1%, 43.8%, and 25.1%, respectively, in the placebo group (p = 0.78). CONCLUSIONS: Sertraline was safe in patients with significant HF. However, treatment with sertraline compared with placebo did not provide greater reduction in depression or improved cardiovascular status among patients with HF and depression. (Antidepressant Medication Treatment for Depression in Individuals With Chronic Heart Failure [SADHART-CHF]; NCT00078286). PMID- 20723801 TI - Survival in schistosomiasis-associated pulmonary arterial hypertension. AB - OBJECTIVES: The objective of this study was to evaluate the natural history of untreated schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) patients as compared to idiopathic pulmonary arterial hypertension (IPAH) with respect to hemodynamics recorded at presentation and 36 months survival. BACKGROUND: Schistosomiasis (Sch) is one of the most prevalent chronic infectious diseases in the world. Nevertheless data regarding one of its most severe clinical complications, pulmonary arterial hypertension (PAH), is scarce. METHODS: We retrospectively analyzed case notes of all consecutive patients diagnosed of Sch-PAH and IPAH referred to the Heart Institute in Sao Paulo, Brazil, between 2004 and 2008. None of the Sch-PAH received PAH specific treatment whereas all IPAH patients did. RESULTS: Sch-PH patients (n = 54) had less severe pulmonary hypertension as evidenced by lower levels of pulmonary vascular resistance (11.3 +/- 11.3 W vs. 16.7 +/- 10.6 W; p = 0.002) and mean pulmonary artery pressure (56.7 +/- 18.7 mm Hg vs. 64.6 +/- 17.4 mm Hg; p = 0.01) and higher cardiac output (4.62 +/- 1.5 l/min vs. 3.87 +/- 1.5 l/min; p = 0.009) at presentation than IPAH patients (n = 95). None of the Sch-PAH patients demonstrated a positive response to acute vasodilator testing, whereas 16.2% of IPAH patients did (p = 0.015). Survival rates at 1, 2, and 3 years were 95.1%, 95.1%, and 85.9% and 95%, 86%, and 82%, for Sch-PAH and IPAH, respectively (p = 0.49). Both groups had a higher survival rate when compared to IPAH survival as estimated by the NIH equation (71%, 61%, and 52%, respectively). CONCLUSIONS: Sch PAH has a more benign clinical course than IPAH despite a lack of demonstrable acute vasoreactivity at hemodynamic evaluation. PMID- 20723803 TI - Boot camp for mesenchymal stem cells. PMID- 20723802 TI - Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. AB - OBJECTIVES: The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction. BACKGROUND: Adult stem cells, delivered in their naive state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome. METHODS: hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor beta(1), bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points. RESULTS: Although the majority of patient derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix-loop-helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. CONCLUSIONS: Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy. PMID- 20723804 TI - INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support): a new paradigm for translating registry data into clinical practice. PMID- 20723805 TI - Images in cardiology. A previously undescribed variant of isolated left ventricular noncompaction. PMID- 20723806 TI - Under-diagnosis of sleep apnea in patients after acute myocardial infarction. PMID- 20723808 TI - Discordance of individual risk estimates. PMID- 20723810 TI - Pulse pressure amplification as a predictor of cardiovascular risk. PMID- 20723811 TI - Are all distal protection devices created equal? PMID- 20723813 TI - Type I diabetes. Foreword. PMID- 20723814 TI - Type I diabetes. Preface. PMID- 20723816 TI - Economics of type 1 diabetes. AB - This article reviews economic methodologies developed for estimating cost of illness, examines the current literature on diabetes costs, and presents the latest estimates of the economic impact of type 1 diabetes in terms of direct medical costs (ie, treatment costs) and indirect costs (eg, lost wages). PMID- 20723815 TI - Epidemiology of type 1 diabetes. AB - This article describes the epidemiology of type 1 diabetes mellitus (T1D) around the world and across the lifespan. Epidemiologic patterns of T1D by demographic, geographic, biologic, cultural, and other factors in populations are presented to gain insight about the causes, natural history, risks, and complications of T1D. Data from large epidemiologic studies worldwide indicate that the incidence of T1D has been increasing by 2% to 5% worldwide and that the prevalence of T1D is approximately 1 in 300 in the United States by 18 years of age. Research on risk factors for T1D is an active area of research to identify genetic and environmental triggers that could potentially be targeted for intervention. Although significant advances have been made in the clinical care of T1D with resultant improvements in quality of life and clinical outcomes, much more needs to be done to improve care of, and ultimately find a cure for, T1D. Epidemiologic studies have an important ongoing role to investigate the complex causes, clinical care, prevention, and cure of T1D. PMID- 20723817 TI - Advances in the prediction and natural history of type 1 diabetes. AB - Type 1 diabetes (T1D) has the hallmark characteristics of autoimmunity superimposed on genetic susceptibility. Both genes (HLA) and immune markers (autoantibodies) have been validated as predictive markers of the subsequent development of the disease in higher-risk relatives and the lower-risk general population. Over the last three decades, using a combination of genes, immune, and metabolic markers, clinicians are now able to quantify an individual's disease risk from 1 in 100,000 to more than 1 in 2. This article reviews these biomarkers and T1D prediction strategies, and discusses potential implications of prediction and natural history for the pathogenesis of T1D. PMID- 20723818 TI - Efforts to prevent and halt autoimmune beta cell destruction. AB - Despite improvements in understanding of the natural history of type 1 diabetes (T1D), an intervention capable of consistently and safely preventing or reversing the disease has not been developed. The inability to cure this disorder is largely because of the complex pathophysiology of T1D, continued struggles to identify its precise etiologic triggers, and voids in understanding of the immunologic mechanisms that specifically target pancreatic beta cells. Rapidly improving technologies for managing T1D require critical discussions about equipoise, especially when considering interventions deemed high risk in terms of their safety. This article reviews the conceptual basis for prevention versus intervention trials in settings of T1D, past experiences of clinical trials studying these purposes, and controversial issues regarding disease interdiction, and seeks to provide a roadmap for future efforts to cure this disorder. PMID- 20723820 TI - The intestinal microbiome: relationship to type 1 diabetes. AB - This article discusses recent evidence that associates the developing intestinal microbiome to the pathogenesis of autoimmune T1D. It attempts to identify avenues that should be pursued that relate this new evidence to interventions that eventually could result in prevention. PMID- 20723821 TI - Contemporary management of patients with type 1 diabetes. AB - The current standard of care for patients with type 1 diabetes (T1D) employs a system of intensive diabetes management aimed at near-normal glycemia, which reduces the risk of micro- and macrovascular complications. Optimal management is an ongoing process based on a patient-centered collaboration with a primary care clinician and a multidisciplinary diabetes team that provides diabetes management, including education and psychosocial support. Intensive diabetes therapy attempts to mimic physiologic insulin replacement. Over the past 15 years, there has been widespread use of multiple-dose insulin regimens using a variety of insulin analogs, administered either by injection or insulin pump therapy, together with medical nutrition therapy, frequent self-monitoring of blood glucose and, more recently, continuous logo glucose monitoring. It is now possible to achieve previously unattainable levels of glycemic control with less risk of severe hypoglycemia, and yet only a minority of patients achieves target hemoglobin A1c values. This review discusses contemporary management of T1D with a focus on health outcomes. PMID- 20723819 TI - Use of nonobese diabetic mice to understand human type 1 diabetes. AB - In 1922, Leonard Thompson received the first injections of insulin prepared from the pancreas of canine test subjects. From pancreatectomized dogs to the more recent development of animal models that spontaneously develop autoimmune syndromes, animal models have played a meaningful role in furthering diabetes research. Of these animals, the nonobese diabetic (NOD) mouse is the most widely used for research in type 1 diabetes (T1D) because the NOD shares several genetic and immunologic traits with the human form of the disease. In this article, the authors discuss the similarities and differences in NOD and human T1D and the potential role of NOD mice in future preclinical studies, aiming to provide a better understanding of the genetic and immune defects that lead to T1D. PMID- 20723822 TI - Inpatient management of adults and children with type 1 diabetes. AB - Type 1 diabetes poses unique inpatient challenges because of the risks of diabetic ketoacidosis, uncontrolled hyperglycemia, and hypoglycemia. Although newer insulin analogs and insulin pumps provide means for improved glycemic control, they can be daunting for nonexperts. This article focuses on inpatient and perioperative insulin management of stable, nonketotic, nonpregnant adults and children with type 1 diabetes. These principles can also be applied to patients with steroid-induced hyperglycemia. PMID- 20723824 TI - Complications of type 1 diabetes. AB - The prevalence of diabetes is increasing worldwide and the concern regarding the number of new cases of diabetes relates to the development of chronic complications. It has been recognized for years that the complications are a cause of considerable morbidity and mortality worldwide and as such, negatively affect the quality of life in individuals with diabetes with an increase in disability and death. Specifically, the complications of diabetes have been classified as either microvascular (ie, retinopathy, nephropathy, and neuropathy) or macrovascular (ie, cardiovascular disease, cerebrovascular accidents, and peripheral vascular disease). For purposes of this article, the authors focus on a brief review of the major complications. PMID- 20723823 TI - Toward closing the loop: an update on insulin pumps and continuous glucose monitoring systems. AB - This article reviews current pump and continuous glucose monitoring therapy and what will be required to integrate these systems into closed-loop control. Issues with sensor accuracy, lag time, and calibration are discussed as well as issues with insulin pharmacodynamics, which result in a delayed onset of insulin action in a closed-loop system. A stepwise approach to closed-loop therapy is anticipated, where the first systems will suspend insulin delivery based on actual or predicted hypoglycemia. Subsequent systems may control to range, limiting the time spent in hyperglycemia by mitigating the effects of a missed food bolus or underestimate of consumed carbohydrates, while minimizing the risk of hypoglycemia. PMID- 20723826 TI - Update on transplanting beta cells for reversing type 1 diabetes. AB - Whole pancreas has been used successfully for transplantation for more than 30 years, and islets have been used reproducibly with success for 10 years; both procedures require drugs for immunosuppression. Success is judged by discontinuation of exogenous insulin-based treatment and maintenance of normal or nearly normal hemoglobin A1c. Successful pancreas transplantation has beneficial effects on retinopathy, nephropathy, neuropathy, macrovascular disease, and quality of life. Such findings are suggested for islet transplantation, but insufficient information is available to draw firm conclusions. Because of the paucity of annual pancreas donations, research for human beta cell surrogates is essential to provide a transplantation approach to therapy for a greater number of recipients. PMID- 20723827 TI - Introduction. PMID- 20723825 TI - Hypoglycemia in type 1 diabetes mellitus. AB - Iatrogenic hypoglycemia, typically the result of the interplay of therapeutic hyperinsulinemia and compromised defenses resulting in hypoglycemia-associated autonomic failure (HAAF) in diabetes, is a problem for people with type 1 diabetes mellitus (T1DM). It causes recurrent morbidity is sometimes fatal, leads to recurrent hypoglycemia, and precludes euglycemia over a lifetime of T1DM. Risk factors include those that result in relative or absolute insulin excess and those indicative of HAAF in diabetes. Elimination of hypoglycemia from the lives of people with T1DM will likely be accomplished by new treatment methods that provide plasma glucose-regulated insulin replacement or secretion. PMID- 20723828 TI - Radiation exposure and uterine artery embolization: current risks and risk reduction. AB - Uterine embolization has become accepted into the mainstream of fibroid therapies and now is among the most common interventions for the condition. Because the procedure is based on angiographic techniques, it requires fluoroscopic and angiographic imaging, both dependent on exposure to ionizing radiation. Given the increasing popularity of this procedure, it is important to understand the potential impacts of this exposure on both individual patients and also the population as a whole. This review is intended to summarize the our current knowledge of the potential risks associated with the radiation exposure from procedure and how those risks might be controlled and reduced by adjusting techniques used during the procedure. PMID- 20723829 TI - Interventional radiology: management of the pregnant patient. AB - This article reviews a practical approach to managing the dose of ionizing radiation during IR procedures where the patient is, or might be pregnant. PMID- 20723830 TI - Radiation safety in pediatric interventional radiology. AB - Pediatric interventional radiology procedures are becoming increasingly common in the medical community, in part due to the significant medical benefit derived from these studies. At the same time, the medical radiation used for these studies contributes to the radiation dose to this unique population of patients. As children are more sensitive to radiation than adults and have a longer lifetime to manifest those changes, a concerted effort should be made toward radiation protection in this setting. Pediatric interventional procedures may differ from adult examinations in several ways, including the small size of the patient, the proximity of the operator's body and hands to the beam, and small body spaces resulting in precarious wire purchase. We describe specific strategies to improve patient and staff safety. These include staff education, safety checklists, a team approach, and formalized review and quality assurance programs. Practical steps to reduce patient dose are reviewed, and tools to assist in achieving the goal of optimizing radiation safety in children undergoing interventional procedures are provided. PMID- 20723831 TI - Operator shielding: how and why. AB - Staff are exposed to potentially high levels of radiation exposure during interventional radiology procedures. Radiation protection shielding devices should be used to help maintain personnel exposures as low as reasonably achievable. Body protection tools include lead aprons, thyroid shields, radiation protection cabins, and floor- and table-mounted shields. Eye protection tools include leaded glasses, ceiling-mounted shields, and protective patient drapes. Hand protection tools include leaded surgical gloves and protective patient drapes. For the most part, these radiation protection tools provide substantial dose reduction for personnel, with several notable exceptions. Leaded glasses without lateral protection do not provide adequate protection to operators because they are typically exposed to scatter radiation from the side. Leaded surgical gloves are not useful for hand protection when hands are placed in the primary x-ray beam. Although other radiation protection tools are effective, they come with drawbacks, including staff physical discomfort and reduced procedure efficiency. As a result, further development of new protection devices is encouraged. PMID- 20723832 TI - Optimizing dose in computed tomographic guided procedures. AB - In the recent past, computed tomography (CT) use has grown by approximately 10% per year, with 62 million examinations performed in the USA in 2006. While these studies make up only 15% of the total number of radiologic examinations, they contribute approximately half of the public exposure due to medical radiation. CT guided procedures comprise a small, but important minority of the total number of CT scans performed each year, as a significant dose can be delivered in this setting. This article reviews techniques to optimize patient exposure during CT guided interventions. PMID- 20723833 TI - Patient radiation management and preprocedure planning and consent. AB - Protection of patients from excessive medical radiation has become a high priority in health care. As clinical physicians, interventional radiologists must remain cognizant of the radiation we use in daily practice. Radiation reduction begins before the procedure itself, as with appropriate preprocedural planning the amount of fluoroscopy and angiography used can then be reduced. Patients should be counseled regarding the potential for use of significant amounts of radiation when procedures associated with such doses are planned, as part of the process of obtaining informed consent. If significant radiation is used, patients should be alerted to have appropriate follow-up. The amount of radiation used can be reduced by careful attention to imaging technique. PMID- 20723834 TI - Managing image quality and patient dose in the angiography suite: do you really need that image quality? AB - Angiographic equipment used for intervention has evolved dramatically over the last 20 years. As a result, attainable image quality has improved significantly. Since image quality and radiation dose are intricately related, the potential patient dose has risen as well. Image quality must therefore be managed in a manner that meets the needs of the procedure with the most beneficial limitation of radiation delivery. This article reviews the basic tenets of minimizing patient dose in the angiography suite. In addition, it investigates technical parameters that can be manipulated, allowing the operator to achieve the image quality needed to successfully complete the task with the least dose delivered to the patient. While a detailed description of each manufacturer's operating instructions is beyond the scope of this article, general principles are reviewed so that operators can understand the questions and issues involved. The hope is that this will facilitate the adaptation of these principles, which can then be applied to any machine. The responsibility is then on the operators to become facile with their own technical environment, so the maximum benefit/risk ratio can be afforded patients. PMID- 20723835 TI - Measuring and monitoring radiation dose during fluoroscopically guided procedures. AB - The principal problem in measuring patient radiation dose during fluoroscopically guided procedures is that dose is not administered uniformly throughout the patient's body. Four dose metrics have been developed to quantify patient radiation dose for fluoroscopically guided procedures: fluoroscopy time, peak skin dose, reference dose, and kerma-area-product. Each metric must be understood to be used appropriately. Fluoroscopy time correlates poorly with other dose metrics. It should not be used as the sole method to estimate, monitor, or record patient radiation dose unless no alternative is available. Kerma-area-product is a good metric for estimating stochastic risk. Reference dose is a conservative method to estimate peak skin dose and deterministic risk and is recommended for this purpose. Every fluoroscope sold in the USA since mid 2006 is able to measure, display, and record reference dose. Radiation dose should be monitored during fluoroscopically guided procedures, either by the operator or by a designated individual in the procedure room, such as a technologist or nurse. Patient radiation dose should be recorded appropriately in the medical record. Patients who have received a sufficiently large radiation dose should have follow up at 10-14 days and at 1 month after the procedure for possible deterministic effects. PMID- 20723836 TI - How to create a quality assurance program for radiation safety in interventional radiology. AB - The practice of medicine is becoming increasingly complex with regard to its economic and academic aspects. In a climate of increasing cutbacks and reduced reimbursements, health care providers are being held more accountable for proving that the services they render are top quality and worthy of the cost of the care provided. Furthermore, patient safety is currently in the public eye and a driving force behind the Pay for Performance initiative. Therefore, quality assurance programs and practice quality improvement systems have been developed to promote patient safety, improve current practice patterns, and help practitioners maintain their board certification. This article very briefly describes one simple example of a radiation safety quality assurance program. PMID- 20723837 TI - Mandatory radiation safety training for interventionalists: the European perspective. AB - Radiation protection (RP) knowledge is of paramount importance for interventionalists. All international bodies acknowledge the importance of education and training in reducing patient doses while maintaining the desired level of quality in medical exposures. The basic recommendations of the International Commission on Radiological Protection (ICRP) on RP training for Interventional Radiology (IR) are summarized as follows: a second, specific level of training in RP; specific additional training whenever new X-ray systems or techniques are implemented, and quality assurance programs, including RP training. The European perspective is discussed in the framework of the Directive on Medical Exposures: Competence in RP must be certified. The Member States of the European Union shall ensure that appropriate curricula are established and shall recognize the corresponding diplomas, certificates, or formal qualifications. Some examples of the accredited training courses on RP organized by national IR Societies are described (content, training strategy, training material available, and results obtained). The work carried out in this area and the training material produced by the International Atomic Energy Agency are also quoted, together with a new set of recommendations on RP training and the certification produced by the ICRP that will be published in 2010. PMID- 20723838 TI - Time is brain for carotid endarterectomy. PMID- 20723839 TI - Public health strategies could reduce the global stroke epidemic. PMID- 20723842 TI - Preventing Alzheimer's disease: could a new kind of trial be the key? PMID- 20723843 TI - Francisco Cardoso: a Brazilian journey in movement disorders. PMID- 20723845 TI - Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. AB - Cerebellar ataxias with autosomal dominant transmission are rare, but identification of the associated genes has provided insight into the mechanisms that could underlie other forms of genetic or non-genetic ataxias. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multisystemic neurological deficits. The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum. 11 of 18 known genes are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions, including glutamate signalling (SCA5/SPTBN2) and calcium signalling (SCA15/16/ITPR1), channel function (SCA13/KCNC3, SCA14/PRKCG, SCA27/FGF14), tau regulation (SCA11/TTBK2), and mitochondrial activity (SCA28/AFG3L2) or RNA alteration (SCA31/BEAN-TK2). The diversity of underlying mechanisms that give rise to the dominant cerebellar ataxias need to be taken into account to identify therapeutic targets. PMID- 20723847 TI - Optical coherence tomography in multiple sclerosis: a systematic review and meta analysis. AB - Optical coherence tomography (OCT) is a new method that could aid analysis of neurodegeneration in multiple sclerosis (MS) by capturing thinning of the retinal nerve fibre layer (RNFL). Meta-analyses of data for time domain OCT show RNFL thinning of 20.38 microm (95% CI 17.91-22.86, n=2063, p<0.0001) after optic neuritis in MS, and of 7.08 microm (5.52-8.65, n=3154, p<0.0001) in MS without optic neuritis. The estimated RNFL thinning in patients with MS is greater than the extent expected in normal ageing, probably because of retrograde trans synaptic degeneration and progressive loss of retinal ganglion cells, in addition to the more pronounced thinning caused by optic neuritis if present. RNFL thickness correlates with visual and neurological functioning as well as with paraclinical data. Developments that could improve understanding of the relation between structure and function in MS pathophysiology include spectral or Fourier domain OCT technology, polarisation-sensitive OCT, fluorescence labelling, structural assessment of action-potential propagation, and segmentation algorithms allowing quantitative assessment of retinal layers. PMID- 20723846 TI - Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke. AB - Stroke remains a primary cause of morbidity throughout the world mainly because of its effect on cognition. Individuals can recover from physical disability resulting from stroke, but might be unable to return to their previous occupations or independent life because of cognitive impairments. Cognitive dysfunction ranges from focal deficits, resulting directly from an area of infarction or from hypoperfusion in adjacent tissue, to more global cognitive dysfunction. Global dysfunction is likely to be related to other underlying subclinical cerebrovascular disease, such as white-matter disease or subclinical infarcts. Study of cognitive dysfunction after stroke is complicated by varying definitions and lack of measurement of cognition before stroke. Additionally, stroke can affect white-matter connectivity, so newer imaging techniques, such as diffusion-tensor imaging and magnetisation transfer imaging, that can be used to assess this subclinical injury are important tools in the assessment of cognitive dysfunction after stroke. As research is increasingly focused on the role of preventable risk factors in the development of dementia, the role of stroke in the development of cognitive impairment and dementia could be another target for prevention. PMID- 20723848 TI - Unprotected left main coronary disease and ST-segment elevation myocardial infarction: a contemporary review and argument for percutaneous coronary intervention. AB - Acute occlusion involving the unprotected left main coronary artery (ULMCA) is a clinically catastrophic event, often leading to abrupt and severe circulatory failure, lethal arrhythmias, and sudden cardiac death. Although coronary artery bypass grafting (CABG) is the standard of care for ULMCA disease in patients with stable ischemic heart disease, uncertainty surrounds the optimal revascularization strategy for patients with ST-elevation myocardial infarction (MI) and ULMCA occlusion who survive to hospitalization, and treatment guidelines in this setting are vague. Percutaneous coronary intervention (PCI) is technically feasible in most patients, has the advantage of providing more rapid reperfusion compared with CABG with acceptable short- and long-term outcomes, and is associated with a lower risk of stroke. PCI of the ULMCA should be considered as a viable alternative to CABG for selected patients with MI, including those with ULMCA occlusion and less than Thrombolysis In Myocardial Infarction flow grade 3, cardiogenic shock, persistent ventricular arrhythmias, and significant comorbidities. The higher risk of target vessel revascularization associated with ULMCA PCI compared with CABG is an acceptable tradeoff given the primary need for rapid reperfusion to enhance survival. PMID- 20723849 TI - Impact of bivalirudin therapy in high-risk patients with acute myocardial infarction: 1-year results from the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial. AB - OBJECTIVES: This study sought to assess the relationship between 1-year mortality and baseline patient risk in the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial. BACKGROUND: The HORIZONS-AMI trial showed that bivalirudin compared with unfractionated heparin (UFH) plus glycoprotein IIb/IIIa inhibitors (GPI) decreased major bleeding and 30-day and 1-year mortality in patients undergoing primary percutaneous intervention for acute myocardial infarction. METHODS: Patients in the HORIZONS-AMI trial were classified as low, intermediate, and high risk according to the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) risk score based on 7 clinical variables. RESULTS: Among 2,530 CADILLAC-score evaluable HORIZONS-AMI trial patients, 1,522 (60%) were classified as low risk, 531 (21%) as intermediate risk, and 477 (19%) as high risk. The mortality rates in the bivalirudin and UFH plus GPI arms, respectively, were 0.4% and 1.2% (p = 0.09) in the low-risk group, 4.2% and 4.1% (p = 0.99) in the intermediate-risk group, and 8.4% and 15.9% (p = 0.01) in the high-risk group. Among high-risk patients, there was also a decreased rate of recurrent myocardial infarction in patients randomized to bivalirudin as compared to UFH plus GPI (3.6% vs. 7.9%, p = 0.04). CONCLUSIONS: In high-risk patients undergoing primary percutaneous coronary intervention for acute myocardial infarction, bivalirudin compared with UFH plus GPI reduces 1-year mortality and recurrent myocardial infarction. (HORIZONS-AMI trial; NCT00433966). PMID- 20723850 TI - Bivalirudin in acute myocardial infarction: "primum non nocere": the eternal dilemma: balancing risks and benefits in high-risk patients. PMID- 20723851 TI - Angiographic and clinical outcomes among patients with acute coronary syndromes presenting with isolated anterior ST-segment depression: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) substudy. AB - OBJECTIVES: This study sought to determine angiographic and clinical outcomes among patients with acute coronary syndrome (ACS) presenting with isolated anterior ST-segment depression on 12-lead electrocardiogram (ECG). BACKGROUND: In patients with ACS, anterior ST-segment depression on 12-lead ECG may represent plaque rupture with: 1) acute thrombotic occlusion with elevation of cardiac biomarkers (+Tn); 2) a patent artery with +Tn; or 3) a patent artery with -Tn. METHODS: The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) enrolled 13,608 ACS patients. Those with isolated anterior (leads V(1) to V(4)) ST-segment depression were analyzed. Angiograms and ECGs were interpreted by local investigators. RESULTS: There were 1,198 (8.8%) patients with isolated anterior ST-segment depression. Of those, 314 (26.2%) had an occluded culprit artery (TIMI flow grade 0/1) and +Tn, 641 (53.5%) had a patent culprit artery (TIMI flow grade 2/3) and +Tn, and 243 (20.3%) had TIMI flow grade 2/3 and -Tn. Among patients with an occluded artery, the culprit artery was most often the left circumflex artery (48.4%). The 30-day incidence of the composite of death and MI was significantly higher among patients with an occluded artery (8.6%) than among those with a patent culprit artery and either +Tn (6.3%) or -Tn (2.9%) (3-way p = 0.006). Among patients with an occluded artery, the median time from ECG to percutaneous coronary intervention was 29.4 h (interquartile range 26.1 to 44.1 h). CONCLUSIONS: Among ACS patients presenting with isolated anterior ST-segment depression, over one-quarter had an occluded culprit artery and elevated cardiac biomarkers. These patients had significantly worse clinical outcomes, and few underwent urgent angiography. PMID- 20723853 TI - If you want to stent ... do intravascular ultrasound! PMID- 20723852 TI - Outcomes of percutaneous coronary intervention in intermediate coronary artery disease: fractional flow reserve-guided versus intravascular ultrasound-guided. AB - OBJECTIVES: This study sought to evaluate the long-term clinical outcomes of a fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) strategy compared with intravascular ultrasound (IVUS)-guided PCI for intermediate coronary lesions. BACKGROUND: Both FFR- and IVUS-guided PCI strategies have been reported to be safe and effective in intermediate coronary lesions. METHODS: The study included 167 consecutive patients, with intermediate coronary lesions evaluated by FFR or IVUS (FFR-guided, 83 lesions vs. IVUS guided, 94 lesions). Cutoff value of FFR in FFR-guided PCI was 0.80, whereas that for minimal lumen cross sectional area in IVUS-guided PCI was 4.0 mm(2). The primary outcome was defined as a composite of major adverse cardiac events including death, myocardial infarction, and ischemia-driven target vessel revascularization at 1 year after the index procedure. RESULTS: Baseline percent diameter stenosis and lesion length were similar in both groups (51 +/- 8% and 24 +/- 12 mm in the FFR group vs. 52 +/- 8% and 24 +/- 13 mm in the IVUS group, respectively). However, the IVUS-guided group underwent revascularization therapy significantly more often (91.5% vs. 33.7%, p < 0.001). No significant difference was found in major adverse cardiac event rates between the 2 groups (3.6% in FFR guided PCI vs. 3.2% in IVUS-guided PCI). Independent predictors for performing intervention were guiding device: FFR versus IVUS (relative risk [RR]: 0.02); left anterior descending coronary artery versus non-left anterior descending coronary artery disease (RR: 5.60); and multi- versus single-vessel disease (RR: 3.28). CONCLUSIONS: Both FFR- and IVUS-guided PCI strategy for intermediate coronary artery disease were associated with favorable outcomes. The FFR-guided PCI reduces the need for revascularization of many of these lesions. PMID- 20723854 TI - Effective radiation dose, time, and contrast medium to measure fractional flow reserve. AB - OBJECTIVES: This study sought to define the additional effective radiation dose, procedural time, and contrast medium needed to obtain fractional flow reserve (FFR) measurements after a diagnostic coronary angiogram. BACKGROUND: The FFR measurements performed at the end of a diagnostic angiogram allow the obtaining of functional information that complements the anatomic findings. METHODS: In 200 patients (mean age 66 +/- 10 years) undergoing diagnostic coronary angiography, FFR was measured in at least 1 intermediate coronary artery stenosis. Hyperemia was achieved by intracoronary (n = 180) or intravenous (n = 20) adenosine. The radiation dose (mSv), procedural time (min), and contrast medium (ml) needed for diagnostic angiography and FFR were recorded. RESULTS: A total of 296 stenoses (1.5 +/- 0.7 stenoses per patient) were assessed. The additional mean radiation dose, procedural time, and contrast medium needed to obtain FFR expressed as a percentage of the entire procedure were 30 +/- 16% (median 4 mSv, range 2.4 to 6.7 mSv), 26 +/- 13% (median 9 min, range 7 to 13 min), and 31 +/- 16% (median 50 ml, range 30 to 90 ml), respectively. The radiation dose and contrast medium during FFR were similar after intravenous and intracoronary adenosine, though the procedural time was slightly longer with intravenous adenosine (median 11 min, range 10 to 17 min, p = 0.04) than with intracoronary adenosine (median 9 min, range 7 to 13 min). When FFR was measured in 3 or more lesions, radiation dose, procedural time, and contrast medium increased. CONCLUSIONS: The additional radiation dose, procedural time, and contrast medium to obtain FFR measurement are low as compared to other cardiovascular imaging modalities. Therefore, the combination of diagnostic angiography and FFR measurements is warranted to provide simultaneously anatomic and functional information in patients with coronary artery disease. PMID- 20723855 TI - Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. AB - OBJECTIVES: This study sought to evaluate the platelet response to aspirin and the immature platelet fraction in patients with previous stent thrombosis (ST). BACKGROUND: ST is a potentially fatal complication of coronary stenting. A reduced platelet response to aspirin increases the risk of cardiovascular events. METHODS: We included 117 patients previously undergoing percutaneous coronary intervention. A total of 39 patients had suffered ST and 78 patients served as controls matched at a 1:2 ratio with respect to age, sex, stent type, and percutaneous coronary intervention indication. All patients were treated with aspirin 75 mg once daily. Platelet function was assessed by multiple electrode aggregometry in citrated and hirudinized blood and by VerifyNow Aspirin Assay (Accumetrics, San Diego, California). Flow cytometric determination of the immature platelet fraction was performed to evaluate platelet turnover. Platelet activation was evaluated by soluble serum P-selectin. Compliance was confirmed by serum thromboxane B(2). RESULTS: All patients were fully compliant, which was confirmed by suppressed levels of serum thromboxane B(2). Platelet aggregation was increased in patients with previous ST when assessed by multiple electrode aggregometry induced by collagen (p(citrated blood) = 0.003; p(hirudinized blood) < 0.0001) and by arachidonic acid (p(citrated blood) = 0.16; p(hirudinized blood) = 0.04), respectively. Similarly, platelet aggregation assessed by VerifyNow was higher in ST cases (p = 0.12). A trend toward an increased immature platelet fraction among cases was seen (p = 0.13), whereas P-selectin levels (p = 0.56) did not differ between groups. CONCLUSIONS: Overall, patients with previous ST had a reduced antiplatelet effect of aspirin, which might be explained by an increased platelet turnover. PMID- 20723856 TI - 3-Dimensional optical coherence tomography assessment of jailed side branches by bioresorbable vascular scaffolds: a proposal for classification. AB - OBJECTIVES: The purpose of this study is to assess jailing of side branches (SB) by the everolimus-eluting, bioresorbable vascular scaffold (BVS) with 3 dimensional (3D) optical coherence tomography (OCT) reconstruction. BACKGROUND: Because BVS struts at the SB orifice are suspected of being bioresorbed and/or forming a neointimal bridge, OCT has been used to evaluate the struts in detail at that particular site. Our understanding of the 3D relationship of the strut and the SB orifice is limited by the use of 2-dimensional OCT images. Fourier domain OCT enables reliable 3D reconstruction of coronary vessels. METHODS: The ABSORB Cohort B (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions) trial is a multicenter single-arm trial to assess the safety and performance of the BVS. Fourier-domain OCT pullbacks (C7-XR system, LightLab Imaging Inc., Westford, Massachusetts) are obtained at pullback speed of 20 mm/s and 3D renderings are performed. The orifices of the SB are assessed visually. The area of SB orifice and the number of strut-free compartments delineated by the BVS struts are evaluated. RESULTS: Fifty-one OCT pullbacks were acquired: 33 pullbacks were imaged with Fourier-domain OCT and 27 treated segments had 46 side branches. Three-dimensional assessment was feasible in 87% (40 of 46) of pullbacks. The mean area of the SB orifice was 1.16 +/- 1.02 mm(2). The mean number of strut-free compartments was 2.0 +/- 1.1. The classification of the overhanging struts is proposed. CONCLUSIONS: This study demonstrates that 3D OCT reconstruction is feasible to evaluate the orifices of SB jailed with BVS. (ABSORB Clinical Investigation, Cohort B; NCT00856856). PMID- 20723857 TI - Retroperitoneal hematoma after percutaneous coronary intervention: prevalence, risk factors, management, outcomes, and predictors of mortality: a report from the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry. AB - OBJECTIVES: This study sought to evaluate the prevalence, risk factors, outcomes, and predictors of mortality of retroperitoneal hematoma (RPH) following percutaneous coronary intervention. BACKGROUND: Retroperitoneal hematoma is a serious complication of invasive cardiovascular procedures. METHODS: The study sample included 112,340 consecutive patients undergoing percutaneous coronary intervention in a large, multicenter registry between October 2002 and December 2007. End points evaluated included the development of RPH and mortality. RESULTS: Retroperitoneal hematoma occurred in 482 (0.4%) patients. Of these, 92.3% were treated medically and 7.7% underwent surgical repair. Female sex, body surface area <1.8 m(2), emergency procedure, history of chronic obstructive pulmonary disease, cardiogenic shock, pre-procedural IV heparin, pre-procedural glycoprotein IIb/IIIa inhibitors, adoption of sheath size >or=8-F, and use of vascular closure devices were independent predictors of RPH, whereas the use of bivalirudin was associated with a lower risk. The development of RPH was associated with a higher frequency of post-procedure myocardial infarction (5.81% vs. 1.67%, p < 0.0001), infection and/or sepsis (17.43% vs. 3.00%, p < 0.0001), and heart failure (8.00% vs. 1.63%, p < 0.0001). In-hospital mortality was significantly higher in patients who developed RPH than in patients who did not (6.64% vs. 1.07%, p < 0.0001). Among patients with RPH, independent predictors of death were history of myocardial infarction, cardiogenic shock, pre-procedural creatinine >or=1.5 mg/dl, and left ventricular ejection fraction <50%. CONCLUSIONS: Retroperitoneal hematoma is an uncommon complication of contemporary percutaneous coronary intervention associated with high morbidity and mortality. The identification of risk factors for the development of RPH could lead to modification of procedure strategies aimed toward reducing its incidence. PMID- 20723858 TI - Outcomes of patients discharged the same day following percutaneous coronary intervention. AB - OBJECTIVES: This study evaluated the outcomes of patients discharged the day of percutaneous coronary intervention (PCI) by analyzing the data from a single center, large, multioperator registry of interventions. BACKGROUND: Although same day discharge is likely safe after interventions on low-risk stable patients, there is limited data to guide selection of a broader population of patients. Due to numerous patient variables and physician preferences, standardization of the length of stay after PCI has been a challenge. Most of the reported studies on same-day discharge have strict inclusion criteria and hence do not truly reflect a real-world population. METHODS: We analyzed the outcomes of consecutive same day discharge in 2,400 of 16,585 patients who underwent elective PCI without any procedural or hospital complication. Composite end point included 30-day major adverse cardiac cerebral events and bleeding/vascular complications. RESULTS: The mean age of the study population was 57.0 +/- 23.7 years with 12% aged over 65 years. Twenty-eight percent received glycoprotein IIb/IIIa inhibitor with closure devices in 90.5%. Clinical and angiographic success was noted in 97% of all PCIs. The average length-of-stay following PCI was 8.2 +/- 2.5 h. The composite end point was reached in 23 patients (0.96%). Major adverse cardiac cerebral events occurred in 8 patients (0.33%) and vascular/bleeding complications in the form of Thrombolysis In Myocardial Infarction minor bleeding in 14 patients (0.58%) and pseudoaneurysm in 1 patient (0.04%). CONCLUSIONS: When appropriately selected, with strict adherence to the set protocol, same-day discharge after uncomplicated elective PCI is safe despite using femoral access in a wide spectrum of patients. PMID- 20723859 TI - Anatomic suitability for present and next generation transcatheter aortic valve prostheses: evidence for a complementary multidevice approach to treatment. AB - OBJECTIVES: This study sought to assess the proportion of patients anatomically suitable for transcatheter aortic valve implantation by multiple access approaches. BACKGROUND: The devices currently in mainstream use for transcatheter treatment of severe aortic stenosis are those of Edwards (Edwards Lifesciences, Nyon, Switzerland) and Medtronic CoreValve (M-C) (Luxembourg City, Luxembourg). The range of patients that these can presently treat requires elucidation to guide the necessary evolution of these technologies and increase their scope of therapy. METHODS: A consecutive series of patients were assessed with transthoracic or transesophageal echocardiography and invasive angiography to assess anatomical suitability by different approaches. The transfemoral access requirements for Edwards and M-C (Edwards currently 22- and 24-F, soon to be 18- and 19-F; M-C 18-F) as well as the aortic valve annular criteria (18 to 25 mm and 20 to 27 mm, respectively) were incorporated in this assessment. Patients unsuitable for the transfemoral approach were considered for Edwards transapical and M-C transaxillary and direct ascending aortic access. Patients suitable for these devices and access approaches were identified. RESULTS: Data were analyzed for 100 consecutive patients. Edwards suitability was 28% for Edwards-Sapien transfemoral, 78% for Edwards Novaflex transfemoral, and 88% for Edwards-Sapien transapical. Medtronic CoreValve suitability was 84% for transfemoral and 89% using additional transaxillary and direct aortic approaches. Of the 12 patients unsuitable for Edwards-based procedures, 8 were suitable for M-C. Of the 11 patients unsuitable for M-C-based techniques, 8 were suitable for Edwards. Only 3% were anatomically unsuitable for all approaches. CONCLUSIONS: In this series, 97% of patients were anatomically suitable for a complementary approach to treatment. PMID- 20723860 TI - Anatomical suitability for transcatheter aortic valve implantation with complementary roles for 2 rivals. PMID- 20723861 TI - Left atrial appendage obliteration: mechanisms of healing and intracardiac integration. AB - OBJECTIVES: The objectives of this study were: 1) to delineate the temporal course of histopathologic healing as the left atrial appendage (LAA) is obliterated by a mechanical device; and 2) to compare this process with other intravascular and intracardiac implanted technologies. BACKGROUND: Intracardiac device healing is incompletely understood. We thus studied the histopathology of device-based LAA obliteration. METHODS: Nine dog hearts were examined over time after LAA device placement and results were compared with human hearts with prior LAA obliteration using the same device. RESULTS: At 3 days in dogs, atrial surfaces were covered by fibrin, which sealed gaps between the LA wall and the device and filled the LA appendage cavity. At 45 days, endothelial cells covered the endocardial surface with underlying smooth muscle cells that sealed the device-LA interface. Regions with prior thrombus were replaced by endocardium surrounding the device membrane. Disorganized thrombus remained in the LAA body and at the periphery near the appendage walls. Mild inflammation was observed as thrombus resorbed. By 90 days, a complete endocardial lining covered the former LAA ostium. Organizing thrombus had become connective tissue, with no residual inflammation. The human necropsy hearts had similar findings. In these 4 hearts (139, 200, 480, and 852 days after implant), the ostial fabric membrane was covered with endocardium. The appendage surface contained organizing thrombus with minimal inflammation. Organizing fibrous tissue was inside the LAA cavity, prominent near the atrial wall. The LAA interior contained organizing thrombus. CONCLUSIONS: This intracardiac device integration study delineated healing stages of early thrombus deposition, thrombus organization, inflammation and granulation tissue, final healing by connective tissue, and endocardialization without inflammation. These observations may yield insight into cellular healing processes in other cardiac devices. PMID- 20723863 TI - Arteria lusoria diagnosed by transradial coronary catheterization. PMID- 20723862 TI - Contained aortic rupture as a late complication of transcutaneous aortic valve implantation. PMID- 20723864 TI - Society for Cardiovascular Angiography and Interventions 2010 and EuroPCR 2010: an update in interventional cardiology. PMID- 20723865 TI - Spasm and occlusion in contemporary radial practice. PMID- 20723866 TI - Major differences between hydrophilic-coated radial sheaths in regards to skin infection and reaction. PMID- 20723868 TI - The best and the brightest. PMID- 20723869 TI - Is guilt 'likely' or 'not certain'? Contrast with previous probabilities determines choice of verbal terms. AB - This research focuses on what determines speakers' choice of positive and negative probability phrases (e.g., "a chance" vs. "not certain") in a legal context. We argue that choice of phrase to describe an event's probability of occurrence can be determined by the contrast between its current p value and an earlier p value, and not by that current value alone. Three experiments were conducted describing scenarios where profilers communicated a suspect's probability of guilt to the police. In the first study, a probability estimate is revised upwards or downwards. In the second one, the probability estimate of a speaker is higher or lower than that given by a previous speaker. In both cases, participants expected upward trends to lead to positive phrases, whereas downward trends were associated with negative phrases. In a third study, participants had to select probability phrases to characterize two different suspects. No contrast effects were found. We conclude that verbal probability directionality has primarily an argumentative function, where positive phrases are selected when probabilities are contrasted with smaller p values, and negative when contrasted with higher p values. PMID- 20723870 TI - Long-term physical and neurologic development in newborn infants with isolated single umbilical artery. AB - OBJECTIVE: This study compared birth parameters and the longitudinal course in physical and neurologic development between children with 2 and 3 vessel umbilical cords. STUDY DESIGN: Our study of the Collaborative Perinatal Project included singletons of at least 24 weeks' gestation with single umbilical artery at birth and no identifiable congenital anomalies. Demographics that were collected included maternal age, race, smoking status, and socioeconomic index. Delivery data included gestational age, birthweight, Apgar scores, placental weight, and umbilical cord insertion and length. Growth and neurodevelopmental parameters were collected at various intervals from birth to 7 years. RESULTS: There were 263 infants with isolated single umbilical artery and 41,415 infants with 3 vessel cords. A random effect model that controlled for potential confounders did not show clinically significant differences in the physical and neurodevelopment measures between these groups. CONCLUSION: Our study shows no evidence of differential longitudinal physical growth or neurologic outcomes between infants with 2 or 3 vessel cords. PMID- 20723873 TI - A randomized study comparing the use of the Ligaclip with bipolar energy to prevent lymphocele during laparoscopic pelvic lymphadenectomy for gynecologic cancer. AB - OBJECTIVE: This prospective randomized pilot study compared the use of the Ligaclip (Ethicon Endo-Surgery, Cincinnati, OH) with bipolar coagulation in preventing lymphoceles after laparoscopic pelvic lymphadenectomy for gynecologic cancer. STUDY DESIGN: Thirty patients with gynecologic malignancy, who had laparoscopic pelvic lymphadenectomy were randomly assigned for lymphadenectomy in 1 side of the pelvis using the Ligaclip, whereas, in the other side, the bipolar coagulation to seal lymphatic vessels was used. RESULTS: At ultrasound examination, we detected lymphocele in 10 patients (33%). Lymphocele developed in 9 (30%) patients on the side where laparoscopic pelvic lymphadenectomy was perfomed using bipolar coagulation, and in 1 (3.3%) patient on the side where laparoscopic pelvic lymphadenectomy was performed using the Ligaclip. Univariate analysis revealed that the Ligaclip's use compared with electrocoagulation in the laparoscopic pelvic lymphadenectomy is an independent predictive factor for development of lymphocele (P = .006). CONCLUSION: This study demonstrates that the use of the Ligaclip to close lymphatic vessels may reduce the incidence of lymphoceles in patients undergoing laparoscopic pelvic lymphadenectomy. PMID- 20723871 TI - Neurogenic characteristics of placental stem cells in preeclampsia. AB - OBJECTIVE: Preeclampsia is associated with perinatal brain injury. Autologous placenta stem cell transplantation represents a promising future treatment option for neuroregeneration. The aim of this study was to compare the neuroregenerative capacity of preeclampsia-placenta stem cells to previously characterized placentas from uncomplicated pregnancies. STUDY DESIGN: Placenta stem cells from amnion (epithelium, mesenchyme) and chorion were assessed for cell surface markers and the formation of neuronal-like cells, oligodendrocytes and their progenitors in culture. RESULTS: Markers of preeclampsia-placenta stem cells were different from uncomplicated pregnancies-placenta stem cells in amnion epithelium and chorion, but not in amnion mesenchyme. Similarly to uncomplicated pregnancies placenta stem cells, preeclampsia-placenta stem cells derived from amnion and chorion differentiated preferably into nestin-positive stem/progenitor cells and Tuj-1-positive neurons. However, other important markers were varying after neurogenic differentiation of uncomplicated pregnancies- and preeclampsia placenta stem cells. CONCLUSION: Surface marker expression patterns of preeclampsia-placenta stem cell's and uncomplicated pregnancies-placenta stem cell's differ. In vitro differentiation assays, however, provide evidence that both preeclampsia-placenta stem cells and uncomplicated pregnancies-placenta stem cells are comparably suitable for neuroregeneration purposes. PMID- 20723874 TI - Preeclampsia is associated with increased cytotoxic T-cell capacity to paternal antigens. AB - OBJECTIVE: During an uncomplicated pregnancy the conceptus is a semiallogeneic entity in which rejection is prevented by suppression of the maternal immune system. We hypothesized that this suppression is disturbed in patients with preeclampsia and that a maternal immune response to fetal (foreign/paternal) antigens in the fetal-maternal interface may be responsible for local inflammation, with subsequent endothelial dysfunction and systemic disease. STUDY DESIGN: Blood samples were obtained from 14 women with preeclampsia (cases), 14 gestational-age and parity-matched women with uncomplicated pregnancies (controls), and their partners. We determined the partner-specific cytotoxic T lymphocyte precursor frequency (CTLpf) and the CTLpf directed to unrelated partners with uncomplicated pregnancies. We measured the CTLpf in peripheral blood mononuclear cells (PBMCs) from cases and controls using limited-dilution assays. In addition, proliferation was tested in a mixed-lymphocyte culture (MLR). RESULTS: The partner-specific CTLpf was significantly higher in cases compared with controls (median, 183 [15-338] vs 67 [9-232] per million PBMCs, P = .02). In contrast, in women with uncomplicated pregnancies, the partner-specific CTLpf was down-regulated compared with the CTLpf directed to an unrelated partner who fathered uncomplicated pregnancies (P = .02). No difference was found in partner-specific MLR response between cases and controls. CONCLUSION: These results suggest that women with preeclampsia have a higher cytotoxic T-cell response to paternal antigens compared with pregnant controls. This insufficiently suppressed immune response may eventually lead to the development of preeclampsia. PMID- 20723875 TI - The myth of vitamins C and E for the prevention of preeclampsia: just when will the penny drop? PMID- 20723876 TI - Ultrasound prediction of birthweight and growth restriction in fetal gastroschisis. AB - OBJECTIVE: Most ultrasound estimated fetal weight (EFW) formulas incorporate abdominal circumference, which may overstimate growth restriction in fetal gastroschisis. The aim of this study was to determine the optimal ultrasound formula for prediction of birthweight and fetal growth restriction (FGR) in gastroschisis. STUDY DESIGN: We conducted a retrospective cohort analysis of singleton fetuses with gastroschisis. Percentage of error between ultrasound EFW (performed within 2 weeks of delivery) and birthweight was calculated. Agreement between EFW by ultrasound formulas and birthweight was determined by Bland-Altman limits of agreement; concordance between ultrasound and birthweight diagnosis of FGR was evaluated with McNemar's test. RESULTS: Birthweight was best predicted by the formulas of Shepard et al and Siemer et al. Only these formulas demonstrated significant agreement with birthweight for prediction of FGR at the 5th and 10th percentiles. CONCLUSION: The formulas of Shepard et al and Siemer et al best estimate birthweight, and their use has the potential to reduce rates of overdiagnosis of FGR. PMID- 20723877 TI - Improved recipient survival with maternal nifedipine in twin-twin transfusion syndrome complicated by TTTS cardiomyopathy undergoing selective fetoscopic laser photocoagulation. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of maternal nifedipine on fetal survival when started 24-48 hours before selective fetoscopic laser photocoagulation (SFLP). STUDY DESIGN: We conducted a case control study of consecutive cases of twin-twin transfusion syndrome (TTTS) in which TTTS cardiomyopathy was treated with maternal nifedipine 24-48 hours before SFLP, compared with gestational age and stage-matched control cases. The primary outcome was recipient and donor survival. RESULTS: One hundred forty-one cases of TTTS were treated with nifedipine, and 152 gestational age- and stage-matched control cases were analyzed. There was a significant increase in overall fetal survival in nifedipine-treated cases compared with control cases (237/284 [83%] vs 232/308 [75%]; P = .015). There is an increase in survival of recipients who were treated with nifedipine in stage IIIA (100% vs 81%; P = .021) and IIIB (93% vs 71%; P = .014); however, there was no difference in donor survival. CONCLUSION: Maternal nifedipine is associated with improved recipient survival in TTTS that undergoes SFLP. This is the first study to suggest a benefit of adjunctive maternal medical therapy in patients with TTTS who undergo SFLP. PMID- 20723878 TI - [Postpartum group B streptococcal endocarditis of the tricuspid valve]. AB - The B streptococcal endocarditis are very rare. They primarily affect the left heart valves, the achievement of the tricuspid valve is exceptional. We report a young patient aged of 36 years who presented in postpartum a tricuspid endocarditis with streptococcus B. She was treated by third-generation cephalosporin and aminoglycoside. The evolution after 5 days of antibiotic therapy was marked by a rapid valvular destruction with worsening tricuspid insufficiency leading to death of the patient. This is the 23rd case of tricuspid endocarditis streptococcal B reported in the literature. The mortality of this disease reached 36% in the absence of surgical treatment. The medico-surgical approach is the treatment of choice for these patients. PMID- 20723879 TI - [Impact of the angles and the age of the thrombus on efficacity of thromboaspiration device. A bench study]. AB - INTRODUCTION: Coronary thrombectomy is usually used to treat acute coronary syndrome. Many studies evaluated its benefit in this context however, it is still unknown if coronary characteristics are predictive of success or failure. The aim of our laboratory bench study was to evaluate the impact of angiographic characteristics on the thromboaspiration efficiency. METHODS: Glass tubes of 150 mm in the length were used, with five diameters: 2; 2.6; 3; 3.6 and 4 mm; and for each diameter, three angulations: no angulation; 90 degrees and 120 degrees . Blood sample were taken from healthy subject and thrombi of 3 and 6 hours old were performed, with a constant volume for each test. Thromboaspirations were performed with an Export((r)) catheter (Medtronic). The primary endpoint was total thrombectomy. A total of 240 thromboaspirations were performed. RESULTS: A total thrombectomy was obtained for 71.2% of the tests. It was achieved more frequently with the smaller diameter, respectively: 100% for 2 mm, 81.3% for 2.6 mm, 89.6% for 3 mm vs 54.2% for 3.6 mm and 31.3% for 4 mm (P<0.001). No differences were observed between the 2 thrombi ages (73.3% for the 3 hours old thrombi and 69.2% for the 6 hours old thrombi, P = 0.476), nor between the three tube's angulations (77.5% for no angle, 66.3% for 90 degrees and 70.0% for 120 degrees , P = 0.278). RESULTS AND CONCLUSION: This study shows an impact of the coronary diameters on the rate of thromboaspiration success with an Export((r)) catheter. Beyond 3 mm of diameter, the rate of success is divided by 2: for diameters less or equal to 3 mm, 90.3% of success vs 42.7% for diameters greater than 3 mm (P<0.001). There is no difference of efficiency between the 3 and 6 hours old thrombi, neither between the tube's angulations. However, this is a preliminary and further works are needed to clarify how to optimize the aspiration and the impact of other catheters. PMID- 20723880 TI - [Thyroid ectopic tumour in the right ventricle of the heart]. AB - The intracardiac ectopic thyroid tumour is rare. We report the case of a woman who was admitted for exertional dyspnea. The echocardiography revealed an obstructive tumor in the right ventricular outflow tract. Histological examination of the removed tumour showed the ectopic follicular thyroid tissue. PMID- 20723881 TI - [Ischemic strokes as a presenting feature of marantic endocarditis despite heparin treatment]. AB - We report on two patients hospitalized in intensive care unit for ischemic strokes presenting the feature of marantic endocarditis complicating lung's adenocarcinoma. These two cases turned out to be very interesting because of the occurrence of ischemic strokes even though the patients were receiving the recommended treatment, namely anticoagulation with heparin, in well-adjusted doses. The management of nonbacterial thrombotic endocarditis remains a challenge and its mortality is still high. PMID- 20723882 TI - [Intramural hematoma of the thoracic aorta: Medical treatment or surgery?]. AB - Intramural hematoma (IMH) of the aorta is an uncommon entity. This disease shares many characteristics with acute aortic dissection. Treatment of IMH remains controversial. We report the case of a 58 years old man with hypertension disease who was admitted in emergency department with suspicion of acute aortic dissection. Transoesophageal echocardiography showed IMH involving the descending aorta which spread afterwards to the ascending aorta. Patient was treated medically and echocardiographic follow-up showed that aortic hematoma remains stable. Two years later, patient is alive and the last TEE reveals disappearance of hematoma in ascending aorta and decrease of it in descending aorta. PMID- 20723883 TI - Development of a method for evaluating accessibility of medical equipment for patients with disabilities. AB - OBJECTIVE: The purpose of this study was to develop a method for evaluating accessibility of medical equipment for patients with disabilities. METHODS: The researchers reviewed videotapes of patient-participants with various physical and sensory disabilities using different types of medical equipment. For each of 11 videotapes, four observers independently identified and documented access and safety barriers, such as physical, sensory, cognitive, and environmental barriers. Inter-observer variability for identifying barrier presence was assessed with kappa statistics for pairs of observers. RESULTS: A list of 10 access and safety barriers was developed through an iterative consensus process, which identified design features of medical equipment that presented difficulties for participants with disabilities. The list is useful for identifying and categorizing accessibility problems found in equipment. While reliability of barrier identification was substantial or moderate for some barriers, reconciliation of barrier events identified by multiple video observers is recommended for optimal results. PMID- 20723884 TI - The effects of knee angles on subjective discomfort ratings, heart rates, and muscle fatigue of lower extremities in static-sustaining tasks. AB - The purpose of this study was to investigate the effects of knee-flexion angles on subjective discomfort ratings, heart rates, and muscle fatigue using median frequency (MDF) in a static-sustaining task. Thirty healthy participants maintained 13 postures including standing, squatting, sitting, and kneeling postures and then MDFs from the erector spinae, biceps femoris, vastus medialis, gastrocnemius, and tibialis anterior muscles, subjective discomfort, and heart rates were collected every 3 min during a sustained 15 min task. Results showed that the discomfort, heart rate and muscle fatigue were significantly influenced by the body postures. In general, standing and sitting postures showed less discomfort as well as lower heart rates, whereas squatting postures (KF120, KF90, KF60) had higher discomfort and heart rates. Three MDF change trends were reported associated with postures in this study. First, there were less changes of MDFs for standing and sitting postures; second, all patterns of MDFs for KF 150 and KF120 decreased, and lastly some MDFs had increasing trends and others showed decreasing trends for KF30, KF30T, and kneeling postures. PMID- 20723885 TI - One-year follow-up results of unsupported online computerized cognitive behavioural therapy for depression in primary care: A randomized trial. AB - OBJECTIVE: To report the one-year follow-up results of computerized cognitive behavioural therapy (CCBT), offered online without professional support, for depression compared with usual GP care and a combination of both treatments. To explore potential relapse prevention effects of CCBT. METHODS: 303 depressed patients were randomly allocated to (a) unsupported online CCBT (b) treatment as usual (TAU), or (c) CCBT and TAU combined. We had a 12-month follow-up period. Primary outcome measure was the Beck Depression Inventory II. Self-reported health care use was also measured. KEY FINDINGS: At 12 months, no statistically significant differences between the three interventions are found in the intention-to-treat population for depressive severity, reliable improvement, remission, and relapse. In the first quarter, differences in health care consumption between the three interventions are significant (i.e. less GP contacts, less antidepressant medication, and less specialist mental health care in the CCBT group), but these differences disappear over time. CONCLUSIONS: Unsupported online CCBT is not superior to TAU by a GP for depression. With equal effects, CCBT alone leads to less health care consumption than TAU and CCBT&TAU. Overall effects are modest in all interventions, which can be explained by the finding that the use of health care services decreases despite the lack of substantial improvements. PMID- 20723886 TI - Does habituation matter? Emotional processing theory and exposure therapy for acrophobia. AB - Clinically, there is wide subscription to emotional processing theory (EPT; Foa & Kozak, 1986) as a model of therapeutic effectiveness of exposure therapy: EPT purports that exposure is maximal when (1) fear is activated (IFA), (2) fear subsides within sessions (WSH), and (3) fear subsides between sessions (BSH). This study examined these assumptions, using in vivo exposure therapy for 44 students scoring high on acrophobia measures. Results indicated that no EPT variables were consistently predictive of treatment outcome. No support was found for IFA or WSH; measures of BSH were predictive of short-term change, but these effects were attenuated at follow-up. Furthermore, EPT variables were not predictive of each other as previously hypothesized, indicating the variables are not functionally related. PMID- 20723888 TI - The synthesis of the rough set model for the better applicability of sagittal abdominal diameter in identifying high risk patients. AB - This paper aims to investigate possible application of the rough set approach to table-organized data in the medical domain, which reveals some relationships among sagittal abdominal diameter, anthropometric parameters and cardiovascular risk factors. When applied to table-organized data, the methodology based on the rough set theory is capable of producing decision rules in the form of If-Then rules. Such rules are suitable for inspection, examination and further analysis. By examination of the selected 30 decision rules, sagittal abdominal diameter could point out a group of obese and preobese patients with high content of visceral fat with different combination and composition of cardiovascular risk factors. These results suggest that sagittal abdominal diameter could be a clinically useful marker for identification of risk factors, combination and structure of total cardiovascular risk by applying different rules in obese and preobese persons. PMID- 20723889 TI - Levonorgestrel-releasing intrauterine system (LNG-IUS) as an effective treatment option for endometrial hyperplasia: a 15-year follow-up study. AB - The levonorgestrel-releasing intrauterine system may represent an effective treatment option in >85% of endometrial hyperplasia cases, but histologic regression during and/or at the end of treatment does not assure stable recovery. We recommend periodic endometrial samplings for at least the first 2 years of follow-up and long-term clinical surveillance thereafter. PMID- 20723890 TI - Clinical relevance of sperm DNA assessment: an update. AB - For sperm DNA assessments to be widespread effective clinical tools, key objectives need to be urgently achieved. These include robust standardized methods, systems for training staff and ongoing quality control; and rigorous examination of the clinical outcomes. We discuss the significance of these objectives and conclude that, if achieved, the clinical utility of DNA damage assessment will be fully realized. PMID- 20723887 TI - Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. AB - BACKGROUND: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis. METHODS: The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene * sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). RESULTS: In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 * 10-4, 2.1 * 10-4; p(corrected) = .03, .04) and were consistent across two large datasets. CONCLUSIONS: Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype. PMID- 20723891 TI - In combined first-trimester Down syndrome screening, the false-positive rate is not higher in pregnancies conceived after assisted reproduction compared with spontaneous pregnancies. AB - The maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) were reduced in hormonally stimulated pregnancies in the in vitro fertilization and intracytoplasmic sperm injection groups (N=176; PAPP-A: 0.82) and in the entire assisted reproduction group (N=282; PAPP-A: 0.83) as compared with controls (N=24,783; PAPP-A: 0.94). However, the false-positive rate of first-trimester combined screenings was not statistically significantly increased in assisted reproduction pregnancies after adjustment for maternal age. PMID- 20723892 TI - Fetal growth restriction in Latvia. PMID- 20723893 TI - Cilostazol enhances macrophage reverse cholesterol transport in vitro and in vivo. AB - OBJECTIVE: Recent failure of an HDL-cholesterol raising strategy using a cholesteryl ester transfer protein inhibitor highlights the importance of the anti-atherogenic function rather than plasma concentration of HDL. Cilostazol, a selective inhibitor of phosphodiesterase 3, has been widely used in patients with atherosclerotic diseases and is known to increase HDL-cholesterol. However, it remains unclear whether cilostazol enhances anti-atherogenic properties by promoting reverse cholesterol transport (RCT), a major anti-atherogenic function of HDL. METHODS AND RESULTS: We observed that treatment of THP-1 macrophages, human monocyte-derived macrophages, and RAW264.7 cells with cilostazol increased ABCA1 and ABCG1 expression in a concentration-dependent manner, translating into enhanced apoA-I- and HDL-mediated cholesterol efflux from the macrophages. However, other cyclic AMP (cAMP)-elevating agents did not increase ABCA1 gene expression in THP-1 macrophages. Cilostazol did not change intracellular cAMP levels in THP-1 macrophages and RAW264.7 cells, and a protein kinase A (PKA) inhibitor did not affect cilostazol-induced ABCA1 and ABCG1 expression. To further investigate RCT in vivo, (3)H-cholesterol-labeled and acetyl LDL-loaded RAW264.7 cells were intraperitoneally injected into mice and the appearance of the (3)H-tracer was monitored in plasma, liver, and feces. Supporting the in vitro data, cilostazol was found to significantly increase (3)H-tracer levels in both plasma and feces. CONCLUSIONS: These findings indicate that cilostazol might provide anti-atherosclerotic effects by promoting RCT through increased ABCA1/G1 expression in macrophages. PMID- 20723894 TI - Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: roles of PPARgamma and Th2 cytokines. AB - OBJECTIVE: Pharmacological activation of the nuclear receptor PPARgamma is linked to numerous beneficial effects in the contexts of inflammation, lipid homeostasis, Type-2 Diabetes (T2D) and atherosclerosis. These beneficial effects include priming of circulating monocytes for differentiation towards an 'alternative' anti-inflammatory M2 macrophage phenotype. As we have recently shown that participation in low-intensity exercise increases PPARgamma expression and activity in leukocytes from previously sedentary individuals, we aimed to elucidate whether low-intensity exercise elicited a pattern of gene expression similar to that reported for M2 monocyte-macrophage differentiation. METHODS: 17 sedentary individuals undertook an 8-week low-intensity exercise programme (walking 10,000steps/day, three times/week). Changes in expression of PPARs and the PPARgamma co-activators PGC-1alpha and PGC-1beta; Th2 (IL-4; IL-10) and Th1 (IL-6) cytokines; and markers for the M2 (AMAC1, CD14, MR, IL-4) and the 'classical' pro-inflammatory M1 (MCP-1, TNFalpha, IL-6) phenotypes, were determined using RT-PCR (to assess leukocyte mRNA expression) and ELISA (to assess plasma cytokine levels). RESULTS: Exercise was associated with upregulation of M2 markers, PGC-1alpha and PGC-1beta, and with downregulation of M1 markers. Moreover, plasma levels of Th2 cytokines increased after exercise, while those of Th1 cytokines decreased. However, other PPARs (PPARalpha; PPARbeta/delta) did not undergo marked exercise-induced activation or upregulation. Thus, participation in low-intensity exercise may prime monocytes for differentiation towards an M2 macrophage phenotype via PPARgamma/PGC 1alpha/beta. CONCLUSION: Given the similarities between these effects and pharmacologically induced M2 polarisation, we propose that exercise-induced PPARgamma/PGC-1alpha/beta-mediated M2 polarisation may constitute a novel anti inflammatory benefit of low-intensity exercise. PMID- 20723895 TI - Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E knockout mice. AB - OBJECTIVE: Donepezil, a reversible acetylcholinesterase inhibitor, improves cognitive function of Alzheimer's disease. Stimulation of cholinergic system was reported to improve long-term survival of rats with chronic heart failure and to attenuate inflammatory response in mice with lipopolysaccharide-induced sepsis. We sought to determine whether the pharmacological stimulation of cholinergic system by donepezil reduces atherogenesis in apolipoprotein (Apo) E-knockout (KO) mice. METHODS AND RESULTS: Male ApoE-KO mice (10-week-old) were fed a high-fat diet and received infusion of angiotensin (Ang) II (490 ng/kg/day). Donepezil or physostigmine was administered for 4 weeks. Oral administration of donepezil (5 mg/kg/day) or infusion of physostigmine (2 mg/kg/day) significantly attenuated atherogenesis (Oil Red O-positive area) without significant changes in heart rate, blood pressure and total cholesterol levels. Administration of donepezil suppressed expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha, NADPH oxidase activity and production of reactive oxygen species in the aorta. CONCLUSION: The present study revealed novel anti-oxidative and anti atherosclerotic effects of pharmacological stimulation of cholinergic system by donepezil. Donepezil may be used as a novel therapeutics for the atherosclerotic cardiovascular diseases. PMID- 20723896 TI - Fatty acid-binding protein 4 is associated with endothelial dysfunction in patients with type 2 diabetes. AB - OBJECTIVE: Adipocyte fatty acid-binding protein (FABP4) plasma levels are higher in type 2 diabetes (T2D). Endothelial dysfunction is also common in T2D. We have investigated the relationship between circulating FABP4 levels and endothelial function in diabetic patients. METHODS: In 257 patients (105 diabetic and 152 non diabetic) at increased risk of cardiovascular disease, we measured circulating FABP4, reactive hyperemia index (RHI) by peripheral artery tonometry, intima media thickness, and biomarkers of inflammation, oxidation and endothelial function. RESULTS: In T2D subjects, FABP4 was negatively associated with endothelial function, as measured by RHI (r=-0.226, P=0.05). In a stepwise multivariate linear regression model, FABP4 was a predictor of RHI in T2D patients (P=0.04). CONCLUSION: Circulating levels of FABP4 are inversely associated with endothelial function in T2D patients, as measured by RHI. We suggest a direct effect of plasma FABP4 on the vascular endothelium in those with T2D. PMID- 20723897 TI - Can a consensus be reached on waist circumference cutoffs by optimising sensitivity and specificity? PMID- 20723898 TI - The role of mineral content in determining the micromechanical properties of discrete trabecular bone remodeling packets. AB - In trabecular bone, each remodeling event results in the resorption and/or formation of discrete structural units called 'packets'. These remodeling packets represent a fundamental level of bone's structural hierarchy at which to investigate composition and mechanical behaviors. The objective of this study was to apply the complementary techniques of quantitative backscattered electron microscopy (qBSEM) and nanoindentation to investigate inter-relationships between packet mineralization, elastic modulus, contact hardness and plastic deformation resistance. Indentation arrays were performed across nine trabecular spicules from 3 human donors; these spicules were then imaged using qBSEM, and discretized into their composite remodeling packets (127 in total). Packets were classified spatially as peripheral or central, and mean contact hardness, plastic deformation resistance, elastic modulus and calcium content calculated for each. Inter-relationships between measured parameters were analysed using linear regression analyses, and dependence on location assessed using Student's t-tests. Significant positive correlations were found between all mechanical parameters and calcium content. Elastic modulus and contact hardness were significantly correlated, however elastic modulus and plastic deformation resistance were not. Calcium content, contact hardness and elastic modulus were all significantly higher for central packets than for peripheral, confirming that packet mineral content contributes to micromechanical heterogeneity within individual trabecular spicules. Plastic deformation resistance, however, showed no such regional dependence, indicating that the plastic deformation properties in particular, are determined not only by mineral content, but also by the organic matrix and interactions between these two components. PMID- 20723899 TI - Epidermal differentiation governs engineered skin biomechanics. AB - Engineered skin must be mechanically strong to facilitate surgical application and prevent damage during the early stages of engraftment. However, the evolution of structural properties during culture, the relative contributions of the epidermis and dermis, and any correlation with tissue morphogenesis are not well known. These aspects are investigated by assessing the mechanical properties of engineered skin (ES) and engineered dermis (ED) during a 21-day culture period, including correlations with cellular metabolism, cellular organization and epidermal differentiation. During culture, the epidermis differentiates and begins to cornify, as evidenced by immunostaining and surface electrical capacitance. Tensile testing reveals that the ultimate tensile strength and linear stiffness increase linearly with time for ES, but are relatively unchanged for ED. ES strength correlates significantly with epidermal differentiation (p < 0.001) and a composite strength model indicates that strength is largely determined by the epidermis. These data suggest that strategies to improve ES biomechanics should target the dermis. Additionally, time-dependant changes in average ES strength and percent elongation can be used to set upper bound limits on mechanical stimulation profiles to avoid tissue damage. PMID- 20723900 TI - The mechanics of atherosclerotic plaque rupture by inclusion/matrix interfacial decohesion. AB - Histological investigation along with finite element analysis of arterial wall/atherosclerotic plaque geometries indicates the paradoxical result that ruptures often occur at sites with predicted stresses of half the plaque cap strength. Recent experiments have revealed calcified cells within the cap suggesting that these inclusions, situated close to the cap/luminal blood surface, precipitate rupture at low nominal loads by concentrating stress. In this paper, we investigate the proposition that rupture at low nominal loads occurs by (possibly brittle) decohesion of the calcification/cap interface followed by tearing of cap tissue. A novel boundary value problem is analyzed consisting of a remotely loaded linear elastic layer (extracellular matrix cap) containing a rigid spherical inclusion (calcified cell) that interacts with it through a nonlinear structural interface which models the binding of the calcified cell to the extracellular matrix via integrin receptor proteins. Equilibrium solutions are obtained from equations derived from the Boussinesq potentials for spherical domains. Results indicate a brittle character to the rupture process with the size of the domains between the inclusion center and the matrix surfaces determining the concentration of stress. For an inclusion close to a surface the abrupt unloading of the interface during brittle decohesion produces a sharp spike in circumferential stress. We conjecture that when this dynamic stress exceeds the cap strength, tearing occurs followed by thrombus formation and possibly infarction. PMID- 20723901 TI - Ambulatory estimation of foot placement during walking using inertial sensors. AB - This study proposes a method to assess foot placement during walking using an ambulatory measurement system consisting of orthopaedic sandals equipped with force/moment sensors and inertial sensors (accelerometers and gyroscopes). Two parameters, lateral foot placement (LFP) and stride length (SL), were estimated for each foot separately during walking with eyes open (EO), and with eyes closed (EC) to analyze if the ambulatory system was able to discriminate between different walking conditions. For validation, the ambulatory measurement system was compared to a reference optical position measurement system (Optotrak). LFP and SL were obtained by integration of inertial sensor signals. To reduce the drift caused by integration, LFP and SL were defined with respect to an average walking path using a predefined number of strides. By varying this number of strides, it was shown that LFP and SL could be best estimated using three consecutive strides. LFP and SL estimated from the instrumented shoe signals and with the reference system showed good correspondence as indicated by the RMS difference between both measurement systems being 6.5 +/- 1.0 mm (mean +/- standard deviation) for LFP, and 34.1 +/- 2.7 mm for SL. Additionally, a statistical analysis revealed that the ambulatory system was able to discriminate between the EO and EC condition, like the reference system. It is concluded that the ambulatory measurement system was able to reliably estimate foot placement during walking. PMID- 20723902 TI - Evaluation of ternary mobile phases for reversed-phase liquid chromatography: effect of composition on retention mechanism. AB - The effect of varying mobile phase composition across a ternary space between two binary compositions is examined, on four different reversed-phase stationary phases. Examined stationary phases included endcapped C8 and C18, as well as a phenyl phase and a C18 phase with an embedded polar group (EPG). Mobile phases consisting of 50% water and various fractions of methanol and acetonitrile were evaluated. Retention thermodynamics are assessed via use of the van't Hoff relationship, and retention mechanism is characterized via LSER analysis, as mobile phase composition was varied from 50/50/0 water/methanol/acetonitrile to 50/0/50 water/methanol acetonitrile. As expected, as the fraction of acetonitrile increases in the mobile phase, retention decreases. In most cases, the driving force for this decrease in retention is a reduction of the enthalpic contribution to retention. The entropic contribution to retention actually increases with acetonitrile content, but not enough to overcome the reduction in the enthalpic contribution. In a similar fashion, as methanol is replaced with acetonitrile, the v, e, and a LSER system constants change to favor elution, while the s and c constants change to favor retention. The b system constant did not show a monotonic change with mobile phase composition. Overall changes in retention across the mobile phase composition range varied, based on the identity of the stationary phase and the composition of the mobile phase. PMID- 20723903 TI - Preparation of thermo-responsive polymer brushes on hydrophilic polymeric beads by surface-initiated atom transfer radical polymerization for a highly resolutive separation of peptides. AB - Poly(N-isopropylacrylamide-co-N-tert-butylacrylamide) [P(IPAAm-co-tBAAm)] brushes were prepared on poly(hydroxy methacrylate) (PHMA) [hydrolyzed poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate)] beads having large pores by surface-initiated atom transfer radical polymerization (ATRP) and applied to the stationary phases of thermo-responsive chromatography. Optimized amount of copolymer brushes grafted PHMA beads were able to separate peptides and proteins with narrow peaks and a high resolution. The beads were found to have a specific surface area of 43.0 m(2)/g by nitrogen gas adsorption method. Copolymer brush of P(IPAAm-co-tBAAm) grafted PHMA beads improved the stationary phase of thermo responsive chromatography for the all-aqueous separation of peptides and proteins. PMID- 20723904 TI - Creation of regenerated cellulose microspheres with diameter ranging from micron to millimeter for chromatography applications. AB - Regenerated cellulose microspheres (RCM) with different diameters were prepared from cellulose solution using 7 wt% NaOH/12 wt% urea aqueous solvent pre-cooled to -12 degrees C by the sol-gel transition method via a "green" process. By varying the hydrophile-lipophile balance, the amount of the surfactants, the proportion of the water to the oil phase and the stirring speed, the mean diameter of the cellulose microsphere with nanoscale pore size could be controlled easily from 5 microm to 1mm. The structure and physicochemical properties of the microspheres were characterized by FT-IR spectroscopy, scanning electron microscopy, X-ray diffraction, mercury intrusion-porosimetry and particle size analyzer. The RCM microspheres exhibited spherical shape with the cellulose II structure. A preparative size-exclusion chromatography (SEC) column packed with the cellulose microspheres was used for the fractionation of a polyethylene oxide (PEO) in water, which indicated high efficiency for the fractionations and a large daily throughput of 4 g. Moreover, they had good adsorption capacity to dye particles through physical interaction. The cellulose microspheres would have potential applications in the fields of purification, separation and fractionation of polymers as chromatography packing and adsorbent both at laboratory and industrial scale. PMID- 20723905 TI - In vivo solid-phase microextraction for single rodent pharmacokinetics studies of carbamazepine and carbamazepine-10,11-epoxide in mice. AB - The use of solid-phase microextraction (SPME) for in vivo sampling of drugs and metabolites in the bloodstream of freely moving animals eliminates the need for blood withdrawal in order to generate pharmacokinetics (PK) profiles in support of pharmaceutical drug discovery studies. In this study, SPME was applied for in vivo sampling in mice for the first time and enables the use of a single animal to construct the entire PK profile. In vivo SPME sampling procedure used commercial prototype single-use in vivo SPME probes with a biocompatible extractive coating and a polyurethane sampling interface designed to facilitate repeated sampling from the same animal. Pre-equilibrium in vivo SPME sampling, kinetic on-fibre standardization calibration and liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) were used to determine unbound and total circulating concentrations of carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZEP) in mice (n=7) after 2mg/kg intravenous dosing. The method was linear in the range of 1-2000ng/mL CBZ in whole blood with acceptable accuracy (93-97%) and precision (<17% RSD). The single dose PK results obtained using in vivo SPME sampling compare well to results obtained by serial automated blood sampling as well as by the more conventional method of terminal blood collection from multiple animals/time point. In vivo SPME offers the advantages of serial and repeated sampling from the same animal, speed, improved sample clean-up, decreased animal use and the ability to obtain both free and total drug concentrations from the same experiment. PMID- 20723906 TI - Change in the microstructure at W/Si interface and surface by swift heavy ions. AB - Metal/Si thin film interfaces and surfaces can be modified by swift heavy ions (SHI) in a controlled manner. The mixing induced by 120 MeV Au(+9) ions at W/Si interface are presented in the manuscript. Grazing Incident X-ray Diffraction (GIXRD) result shows the formation of two type of tungsten silicides t-W(5)Si(3) along with t-WSi(2) by atomic mixing at the interface on increasing the ion fluence. The diffusivity value calculated from the Rutherford Backscattering Spectroscopy (RBS) measurements, suggest a transient molten phase at the interface causing the atomic mixing following by Thermal spike model. Atomic Force Microscopy (AFM) results revealed increase in surface roughness and grain size formation, which increases with ion fluence showing the irradiation effect at the surface also. PMID- 20723907 TI - Water-soluble ZnO-Au nanocomposite-based probe for enhanced protein detection in a SPR biosensor system. AB - A surface plasmon resonance biosensor based on ZnO-Au nanocomposites was developed for the detection of rabbit IgG. The ZnO-Au nanocomposites can bind protein by covalent attachment to construct a probe for target analyte. The probe with unique optical properties and good biocompatibility could enhance the sensitivity of SPR biosensor. Under the optimized conditions, the biosensor based on ZnO-Au nanocomposites exhibits a satisfactory response to rabbit IgG in the concentration range of 0.15-20.00 MUg ml(-1). For comparison, the biosensor based on Au film and the biosensor based on Au nanoparticles were also studied for the detection of rabbit IgG. The biosensor based on Au film shows a response to rabbit IgG in the concentration range of 2.50-20.00 MUg ml(-1). The biosensor based on Au nanoparticles shows a response in the concentration range of 0.30 20.00 MUg ml(-1). The biosensor based on ZnO-Au nanocomposites was therefore found to be the most sensitive of the three types of biosensors. The lowest concentration of rabbit IgG that can be determined by the proposed biosensor is about 16-fold lower than that of the biosensor based on Au film alone. PMID- 20723908 TI - Pickering emulsions stabilized by self-assembled colloidal particles of copolymers of P(St-alt-MAn)-co-P(VM-alt-MAn). AB - A new type of copolymer containing two alternating segments, poly-(styrene-alt maleic anhydride)-co-poly (7-(4-vinylbenzyloxyl)-4-methylcoumarin-alt-maleic anhydride) P(St-alt-MAn)-co-P(VM-alt-MAn)(PSMVM), was prepared. The copolymer self-assembled into nanoparticles with internal microphase structures in water because the hydrophilicity of segment P(VM-alt-MAn) is higher than that of P(St alt-MAn). The particle size, morphology, zeta potential and surface properties and their dependence on the pH and slat concentrations were studied with a combination of techniques. The nanoparticles of PSMVM showed surface activity and pH sensitivity for producing Pickering oil-in-water emulsions. The emulsion volume increased and the size of oil/water droplet decreased with increasing salt concentration. Furthermore, cross-linked nanoparticles (CLPs) were obtained by photo-dimerization of the pendent coumarin groups in PSMVM under UV irradiation. The emulsions produced by using the CLPs as emulsifiers showed even better stability upon standing. Solid oil-phase droplets were obtained by preparation of CLPs-stabilized Pickering emulsions with an oil phase of styrene containing the initiator AIBN followed by the polymerization of styrene. Thus, the enrichment and aggregation of the CLPs on the emulsion droplets was visible because the solid droplets remained unchanged during the SEM sample preparation. PMID- 20723909 TI - Assessment and intervention of bilingual children with language impairment. PMID- 20723910 TI - Sucking pads in a full-term newborn. PMID- 20723911 TI - Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome. AB - OBJECTIVE: To investigate the frequency of various nonorthostatic complaints in children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN: We used our autonomic laboratory database to identify all pediatric patients with traditionally defined POTS who had completed the Ohio Dysautonomia Survey (ODYSA). The responses of the patients to questions targeting various autonomic complaints, including syncope, gastrointestinal symptoms, sleep disturbances, headaches, urinary symptoms, chronic pain, and Raynaud-like symptoms, were collected and analyzed. RESULTS: A total of 53 pediatric patients completed the ODYSA questionnaire. The participants reported high frequencies of sleep abnormalities, chronic pain, Raynaud-like symptoms, and gastrointestinal abnormalities, with lower rates of headaches, syncope, and urinary complaints. CONCLUSIONS: Our findings demonstrate the occurrence of various nonorthostatic symptoms in pediatric patients with POTS. These findings suggest the need for an interdisciplinary approach to the treatment and management of POTS, as well as for further investigation into the mechanisms that lead to the concurrent presentation of both orthostatic and nonorthostatic symptoms in these patients. PMID- 20723912 TI - Susac's syndrome, a rare, potentially severe or lethal neurological disease. AB - Susac's syndrome (SS) is a rare, immune-mediated endotheliopathy affecting the microvasculature of the brain, the inner ear and the retina. Clinical presentation is characterised by a triad: encephalopathy, hearing loss and branch retinal artery occlusion (BRAO). Given the rarity of this disease, its natural history still remains partially unknown, but lethal cases appear to be extremely rare since there has never been, to our knowledge, a report of SS leading to death. We report 2 cases of SS illustrating the multiplicity of neurological symptomatology and its unpredictable course. One case is particularly unusual due to its severe neurological evolution, leading to death despite treatments. This report presents clinical and paraclinical findings contributory to SS diagnosis and offers an innovative perspective on disease management. These cases represent the potential severity of this disease. Early, aggressive treatment strategies may be warranted for SS in order to avoid neurological deterioration and lethal evolution. PMID- 20723913 TI - Periodontitis affects neurological deficit in acute stroke. AB - BACKGROUND AND PURPOSE: Periodontitis is an independent risk factor for ischaemic stroke, but its influence on stroke severity has not been investigated yet. We studied the association of advanced periodontitis or edentulousness with neurological deficit on admission and short-term outcome of stroke patients. METHODS: The study included 169 patients with ischaemic stroke. The neurological deficit on admission was evaluated using the NIH stroke scale (NIHSS). The outcome at discharge was assessed using the modified Rankin scale (mRS) and the Barthel Index (BI). The clinical attachement level (CAL), the distance between cemento-enamel junction and the probed base of periodontal pocket, was recorded for each tooth at six sites. Advanced periodontitis was defined as CAL>=6mm in at least one measured site. RESULTS: Patients with advanced periodontitis or edentulousness were older than those with no or mild periodontitis (71.4years vs. 60.1; p<0.001), had greater neurological deficit on admission (8.9 vs. 5.7; p=0.01) and worse outcome at hospital discharge measured in the mRS (2.2 vs. 1.4; p=0.009). The presence of advanced periodontitis or edentulousness was independent risk factor for greater NIHSS on admission (p=0.025), after adjusting for age, gender and the studied risk factors. The logistic regression model, however, showed that stroke severity on admission but not advanced periodontitis or edentulousness, affected the outcome of stroke patients. CONCLUSIONS: Advanced periodontitis or edentulousness in patients with ischaemic stroke is associated with greater neurological deficit on admission. PMID- 20723914 TI - Correlates of bother following treatment for clinically localized prostate cancer. AB - PURPOSE: We determined factors associated with bother, the distress patients experience as a result of functional detriments after treatment for localized prostate cancer. MATERIALS AND METHODS: A prospective cohort of men treated for clinically localized prostate cancer completed a questionnaire comprising the UCLA-PCI, Medical Outcomes Study Short Form-36, American Urological Association Symptom Index and Memorial Anxiety Scale for Prostate Cancer fear of recurrence subscale. We used nonlinear mixed models to identify factors associated with severe urinary, sexual and bowel bother. RESULTS: Worse function scores were associated with severe urinary, sexual and bowel bother following treatment (OR 0.88-0.94, p <0.001). Worse American Urological Association Symptom Index score was associated with severe urinary bother (OR 1.22, 95% CI 1.16-1.28). Time since treatment was inversely associated with urinary (OR 0.68, 95% CI 0.54-0.83) and bowel bother (OR 0.63, 95% CI 0.47-0.80) early after treatment but not for the entire 48-month study period. Receipt of concomitant androgen deprivation therapy was not associated with bother 48 months after radiation. CONCLUSIONS: Addressing functional detriment may confer improvement in urinary, sexual and bowel bother. Patient distress related to dysfunction improves with time. Measuring health related quality of life after prostate cancer treatment should incorporate functional and bother assessments. PMID- 20723915 TI - VEGF polymorphisms are associated with an increasing risk of developing renal cell carcinoma. AB - PURPOSE: Vascular endothelial cell growth factor is studied in different malignant tumors as a key endothelial cell mitogen. Many single nucleotide polymorphisms in the VEGF gene have been described. We compared VEGF gene polymorphisms between a control group and a renal cancer group. MATERIALS AND METHODS: This study was performed in 202 control, white, healthy blood donors (control group) and in 51 consecutive patients with renal cell carcinoma. We studied VEGF genotype polymorphisms at positions -2549, -460, -1154, +405 and +936 using polymerase chain restriction fragment length polymorphism, and looked for correlations with clinical data. RESULTS: No association was found between VEGF gene polymorphism and renal cell carcinoma prognostic parameters. However, in contrast as observed for controls and other polymorphisms the patient group displayed a heterozygote excess (p = 0.0179, 35.9% more than that expected) at the -460 polymorphism. Comparing the control group and the renal cell carcinoma group we detected a significantly increased risk of renal cell carcinoma in subjects with the C-460T polymorphism. T carrier genotypes and the T allele increased the risk of renal cell carcinoma with an OR of 14.15 (95% CI 1.900 105.41, p = 0.0017) and 2.14 (95% CI 1.34-3.419, p = 0.0018), respectively. The genotype at the -2549 polymorphism exhibited a nonsignificant trend for increased risk but the D allele was significantly associated with increased risk (p = 0.0305). CONCLUSIONS: Our results suggest that the -460 polymorphism is a risk factor for renal cancer. An individual screening test could be proposed for high risk populations. PMID- 20723916 TI - Editorial comment. PMID- 20723917 TI - The evolution of renal surgery for malignancy. PMID- 20723918 TI - Should hypogonadal men with prostate cancer receive testosterone? PMID- 20723919 TI - Chronic pelvic pain syndrome: a role for aberrant cytokine function. PMID- 20723920 TI - Tubeless percutaneous nephrolithotomy--the new standard of care? AB - PURPOSE: Traditionally the placement of a nephrostomy tube at the conclusion of percutaneous nephrolithotomy is considered the standard of care. However, the need for nephrostomy tube placement has been questioned by numerous authors. We evaluated the literature regarding tubeless percutaneous nephrolithotomy, and determined potential candidates for tubeless percutaneous nephrolithotomy and whether this procedure can be considered the new standard of care for complex stone removal. MATERIALS AND METHODS: A MEDLINE search was conducted between May 1997 and January 2010 to detect studies reporting tubeless percutaneous nephrolithotomy. "Nephrolithiasis," "percutaneous nephrolithotomy," "tubeless" and "lithotripsy" were used as medical subject headings (MeSH) key words. Additional citations were identified by reviewing the reference lists of the included articles. All relevant articles were reviewed for indications, outcomes and complications. RESULTS: The data obtained from 50 reports document comparable complication rates between tubeless and standard percutaneous nephrolithotomy. Tubeless percutaneous nephrolithotomy demonstrated advantages such as less pain, less debilitation, less costs and a shorter hospital stay. Mean stone-free rates for tubeless percutaneous nephrolithotomy were as high as 89%. CONCLUSIONS: Tubeless percutaneous nephrolithotomy appears to be safe and efficacious in uneventful procedures, in children, in obese patients, in simultaneous bilateral procedures, in supracostal access and in renal units with coexisting anatomical anomalies. Nephrostomy tube placement should still be considered in certain cases such as those with more than 2 nephrostomy access tracts, those necessitating a second look and those with intraoperative complications such as significant bleeding or collecting system perforation. PMID- 20723921 TI - Intraductal carcinoma of the prostate without invasive carcinoma on needle biopsy: emphasis on radical prostatectomy findings. AB - PURPOSE: Limited information is available on radical prostatectomy findings in men with intraductal carcinoma of the prostate on needle core biopsy in the absence of invasive prostate cancer. MATERIALS AND METHODS: From the consulting files of one of us we identified 83 men in whom biopsy showed only intraductal prostate cancer. Followup was available in 66 cases. We reviewed slides in 21 radical prostatectomy cases. RESULTS: Treatment was radical prostatectomy in 23 men, radiation therapy in 15, hormone therapy in 8 and radiation plus hormone therapy in 15 while 5 underwent no treatment or repeat biopsy. Of the 21 radical prostatectomies available for review findings revealed pathological stage pT3a in 8 (38%), pT3b in 3 (13%), pT2 in 8 (38%) and intraductal carcinoma without identifiable invasive cancer in 2 (10%). One patient with pT3a had a positive lymph node at surgery. Average Gleason score was 7.9. Three patients (14%) experienced post-prostatectomy biochemical failure and another (5%) had bone metastases 2.5 years after prostatectomy. In 15 prostatectomies (71%) there was extensive intraductal carcinoma, defined as greater than 10% of tumor being intraductal, including the 2 cases of intraductal carcinoma only. Of the 19 prostatectomies with invasive adenocarcinoma 16 (84%) were conventional acinar adenocarcinoma, 2 (11%) ductal adenocarcinoma, and 1 (5%) mixed ductal and acinar adenocarcinoma. CONCLUSIONS: At radical prostatectomy men in whom prior biopsies showed only intraductal carcinoma of the prostate typically have high grade (Gleason score 7 or greater) invasive adenocarcinoma and most have advanced stage disease (pT3). Definitive therapy is recommended in men with intraductal carcinoma of the prostate on needle biopsy even in the absence of pathologically documented invasive prostate cancer. PMID- 20723922 TI - Enhancing detection of bladder carcinoma in situ by 3-dimensional optical coherence tomography. AB - PURPOSE: We examined the usefulness of 3-dimensional optical coherence tomography to enhance the diagnosis of urothelial carcinoma in situ. MATERIALS AND METHODS: By expressing SV40T antigen with uroplakin II promoter, carcinoma in situ readily develops in SV40T transgenic mice at about ages 8 to 20 weeks and then frank high grade papillary carcinoma develops in bladder epithelium. We examined 10 control and 40 SV40T mice during weeks 8 to 20 after birth by parallel en face white light imaging and 3-dimensional optical coherence tomography, and compared results with histology findings. We applied quantitative analysis of computer aided detection to 3-dimensional tomography images to enhance the diagnosis of carcinoma in situ, including 3-dimensional segmentation, speckle reduction, fast Fourier transform analysis, and standard deviation and histogram evaluation. RESULTS: We identified carcinoma in situ in 23 SV40T mice by histology. Most carcinoma could not be detected by en face imaging and 2-dimensional optical coherence tomography but was well differentiated by 3-dimensional optical coherence tomography. The 56.5% sensitivity and 61.5% specificity of 2 dimensional optical coherence tomography for carcinoma in situ diagnosis were significantly enhanced by 3-dimensional optical coherence tomography to 95.7% and 92.3%, respectively (p <=0.031). CONCLUSIONS: On quantitative analysis of increased urothelial heterogeneity induced by carcinogenesis we noted that 3 dimensional optical coherence tomography enabled accurate differentiation of carcinoma in situ from normal bladder and benign lesions. Results reveal the potential of cystoscopic 3-dimensional optical coherence tomography to significantly enhance the clinical diagnosis of nonmuscle invasive bladder cancer, particularly carcinoma in situ. PMID- 20723923 TI - Relief of stent related symptoms: review of engineering and pharmacological solutions. AB - PURPOSE: We review the recent publications on developing engineering and pharmaceutical agents to alleviate stent related symptoms, and examine basic science studies that may support a particular approach. MATERIALS AND METHODS: Data on randomized controlled trials for relief of stent related symptoms were analyzed. Studies involving engineering and pharmacological agents to resolve stent related morbidity were assessed separately. RESULTS: A variety of physical characteristics of stents, including materials, diameter, length and shape, have been modified to reduce stent related symptoms. Numerous studies have been conducted to engineer the ideal stent without clear and definite conclusions. There are mixed results with materials and negative results with shape. Appropriate stent length appears to be important but decreased diameter has not been shown to help. A recent study using a ketorolac eluting stent showed no significant benefit. Even with the best material and length it appears that patients still have significant stent related symptoms. To relieve stent related symptoms several classes of oral medications have been proposed for off-label use based on intuition or experience. Recently prospective, randomized, placebo controlled trials have been performed, along with basic science studies regarding the pharmacology of the ureter. They showed a clear and consistent beneficial effect of alpha1-blockers in patients with indwelling ureteral stents. CONCLUSIONS: Although there have been many advances in stent composition, construction geometry and design, the ideal stent has yet to be engineered. By contrast, the oral administration of alpha-blockers has shown the greatest reduction in stent morbidity. PMID- 20723924 TI - Sodium restriction as initial conservative treatment for urinary stone disease. AB - PURPOSE: Sodium restriction is widely recommended to prevent urinary stone recurrence. However, the effect of urinary sodium excretion has not been fully evaluated. We investigated the relationship between urinary sodium, urinary metabolite excretion and the risk of recurrence in urinary stone formers. MATERIALS AND METHODS: Selected for study were 798 stone formers with no evidence of metabolic disorders as the cause of abnormal urinary solutes. We analyzed the relationship between urinary sodium and other metabolic parameters by gender. Values were adjusted by covariates according to correlation status. Patients were divided into stone formers with hypernatriuresis or normal natriuresis (less than 220 mEq daily) and urinary parameters were compared. Kaplan-Meier analysis was done to determine the cumulative incidence of recurrent stones by urinary sodium. Patients were considered recurrence-free at a minimum followup of 3 years without incidence. RESULTS: In the 492 men and 306 women mean +/- SD age was 40.0 +/- 11.4 and 45.4 +/- 12.7 years, and mean body mass index was 23.9 +/- 3.1 and 23.0 +/- 3.0 kg/m(2), respectively. Using covariate adjusted partial correlation coefficients urinary sodium was noted to influence volume, pH, calcium, uric acid, oxalate and citrate in men, and volume, pH, calcium, uric acid and citrate in women (each p <0.05). At a median followup of 56.1 months 46 of 98 stone formers (46.9%) with normal natriuresis experienced stone recurrence vs 60 of 93 (64.5%) with hypernatriuresis. Patients with hypernatriuresis also had significantly decreased time to recurrence than those with normal natriuresis (log rank test p = 0.043). CONCLUSIONS: Results show that urinary sodium is an important determinant of other stone forming parameters and of the risk of recurrent stones. These findings suggest that a sodium restricted diet should be the initial step when treating stone formers. PMID- 20723925 TI - Biochemical recurrence after radical prostatectomy: multiplicative interaction between surgical margin status and pathological stage. AB - PURPOSE: A positive surgical margin after radical prostatectomy is considered an adverse prognostic feature. However, few groups have explored the potential interaction between surgical margin status and other cancer characteristics, specifically pathological stage. We addressed the first degree of interaction between positive surgical margins and other established adverse predictors of biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: We used univariate and multivariate analysis to test the effect of surgical margin status on biochemical recurrence in 4,490 patients treated at a single institution between 1992 and 2008. We systematically tested all first-degree interactions between surgical margin status, and pretreatment prostate specific antigen, pT and pN stage, and radical prostatectomy Gleason sum. If interactions were significant, we quantified the effect on the biochemical recurrence rate. RESULTS: Overall 850 patients (18.9%) had positive surgical margins. In those with negative vs positive surgical margins the 5-year biochemical recurrence-free survival rate was 95% vs 83%, 74% vs 62% and 47% vs 29% for pT2, pT3a and pT3b disease, respectively. In multivariate models only the pT stage-surgical margin status interaction achieved independent predictor status (p = 0.003). Negative vs positive surgical margin multivariate HRs were 1 vs 2.9, 2.3 vs 4.3 and 4.1 vs 5.6 in pT2, pT3a and pT3b cases, respectively. CONCLUSIONS: Compared to negative surgical margins, positive surgical margins increase the absolute biochemical recurrence 5-year rate by 12% to 18%. More importantly, positive surgical margins may substantially worsen the prognosis beyond that of the original pathological disease stage. PMID- 20723926 TI - Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. AB - PURPOSE: Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. MATERIALS AND METHODS: In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. RESULTS: The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. CONCLUSIONS: Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles. PMID- 20723927 TI - Opioid blockade and inflammation reveal estrous cycle effects on visceromotor reflexes evoked by bladder distention. AB - PURPOSE: Painful bladder disorders vary in intensity with the menstrual cycle in women. We evaluated the influence of the correlate in rats (the estrous cycle) on the nociceptive visceromotor reflex to bladder distention in the presence/absence of inflammation and of spinal opioid blockade. MATERIALS AND METHODS: We recorded visceromotor reflexes as electromyogram responses of the abdominal musculature to graded (10 to 60 mm Hg) bladder distention in anesthetized female rats in the presence of intrathecal saline or naloxone (10 MUg) 1 day after receiving intravesical zymosan or anesthesia alone. RESULTS: In saline treated rats visceromotor reflexes to bladder distention were significantly greater in those with an inflamed vs a noninflamed bladder when examined together. When separated into phases, rats with bladder inflammation showed complex estrous cycle effects with significantly greater visceromotor reflexes to bladder distention during metestrus and proestrus than diestrus. In naloxone treated rats visceromotor reflexes to bladder distention were significantly greater in those with an inflamed vs a noninflamed bladder when examined together. Naloxone enhanced the overall magnitude of visceromotor reflexes to bladder distention in the inflamed and noninflamed conditions. The magnitude of visceromotor reflexes to bladder distention in noninflamed and inflamed conditions in the presence of naloxone was estrous phase dependent in the order, estrus >metestrus >diestrus >proestrus. Similar findings were apparent on analysis of data on responses at threshold intensity (30 mm Hg). CONCLUSIONS: Data suggest that circulating hormones present during the estrous cycle alter bladder reactivity and opioid modulatory systems to maintain constancy of input from the bladder to the central nervous system. PMID- 20723928 TI - Prostate secretions from men with chronic pelvic pain syndrome inhibit proinflammatory mediators. AB - PURPOSE: In the past numerous chemokines have been noted in the expressed prostatic secretions of patients with chronic prostatitis/chronic pelvic pain syndrome. We examined the functional effects of chemokines in expressed prostatic secretions of patients with chronic pelvic pain syndrome. MATERIALS AND METHODS: We studied the functional effects of expressed prostatic secretions on human monocytes by examining monocyte chemotaxis in response to monocyte chemoattractant protein-1, a major chemoattractant previously identified in chronic prostatitis/chronic pelvic pain syndrome cases. We determined effects on cellular signaling by quantifying intracellular calcium increase in monocytes and nuclear factor-kappaB activation in normal prostate epithelial cells. RESULTS: Results show that the monocyte chemoattractant protein-1 in expressed prostatic secretions is nonfunctional with an inability to mediate human monocyte chemotaxis, or mediate signaling in monocytes or prostate epithelial cells. This lack of functionality could be extended to other proinflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, when incubated with expressed prostatic secretions from patients with chronic pelvic pain syndrome. The mechanism underlying this apparent ability to modulate proinflammatory cytokines involves heat labile extracellular proteases that mediate the inhibition of immune and prostate epithelial cell function. CONCLUSIONS: These results may have implications for the design of specific diagnostic and therapeutic methods targeted toward the complete resolution of prostate inflammatory insults. PMID- 20723929 TI - Myopodin methylation is associated with clinical outcome in patients with T1G3 bladder cancer. AB - PURPOSE: Bacillus Calmette-Guerin is standard treatment to decrease tumor recurrence and delay progression of high risk, nonmuscle invasive bladder tumors. However, it is not yet clear which T1G3 cases are more prone to more aggressive clinical behavior or susceptible to respond to bacillus Calmette-Guerin. We evaluated the role of myopodin methylation as a clinical outcome prognosticator and predictive biomarker for the bacillus Calmette-Guerin response in patients with T1G3 bladder tumors. MATERIALS AND METHODS: We analyzed the methylation status of myopodin in tumor specimens from 170 patients with T1G3 bladder cancer, including a subset of 108 who underwent bacillus Calmette-Guerin treatment. Myopodin methylation was assessed by methylation specific polymerase chain reactions. Recurrence, progression to muscle invasive tumors and disease specific overall survival were analyzed using competing risks regression analysis. RESULTS: Of the 170 cases analyzed 72 recurred (42.4%) and 36 progressed (21.2%). A total of 24 patients (14.1%) died of the disease. Univariate and multivariate survival analysis revealed that myopodin methylation was significantly associated with an increased recurrence rate (p = 0.004), progression (p = 0.002) and shorter disease specific overall survival (p = 0.020). In a subset treated with bacillus Calmette-Guerin myopodin methylation was also related to an increased recurrence rate (p = 0.011), progression (p = 0.030) and shorter disease specific overall survival (p = 0.028). CONCLUSIONS: Epigenetic analysis revealed that myopodin methylation was associated with tumor aggressiveness and clinical outcome in patients with T1G3 disease. Myopodin methylation distinguished patients responding to bacillus Calmette-Guerin from those who may require a more aggressive therapeutic approach. PMID- 20723930 TI - Gene based prediction of clinically localized prostate cancer progression after radical prostatectomy. AB - PURPOSE: Accurate estimates of recurrence risk are needed for optimal treatment of patients with clinically localized prostate cancer. We combined an established nomogram and what to our knowledge are novel molecular predictors into a new prognostic model of prostate specific antigen recurrence. MATERIALS AND METHODS: We analyzed gene expression profiles from formalin fixed, paraffin embedded, localized prostate cancer tissues to identify genes associated with prostate specific antigen recurrence. Profiles of the identified markers were reproduced by reverse transcriptase-polymerase chain reaction. We used the profiles of 3 of these genes along with output from the Kattan postoperative nomogram to produce a predictive model of prostate specific antigen recurrence. RESULTS: After variable selection we built a model of prostate specific antigen recurrence combining expression values of 3 genes and the postoperative nomogram. The 3-gene plus nomogram model predicted 5-year prostate specific antigen recurrence with a concordance index of 0.77 in a validation set compared to a concordance index of 0.67 for the nomogram. This model identified a subgroup of patients at high risk for recurrence that was not identified by the nomogram. CONCLUSIONS: This new gene based classifier has superior predictive power compared to that of the 5 year nomogram to assess the risk of prostate specific antigen recurrence in patients with organ confined prostate cancer. Our classifier should provide more accurate stratification of patients into high and low risk groups for treatment decisions and adjuvant clinical trials. PMID- 20723931 TI - Editorial comment. PMID- 20723932 TI - Comparative analysis of whole mount processing and systematic sampling of radical prostatectomy specimens: pathological outcomes and risk of biochemical recurrence. AB - PURPOSE: Whole mount processing is more resource intensive than routine systematic sampling of radical retropubic prostatectomy specimens. We compared whole mount and systematic sampling for detecting pathological outcomes, and compared the prognostic value of pathological findings across pathological methods. MATERIALS AND METHODS: We included men (608 whole mount and 525 systematic sampling samples) with no prior treatment who underwent radical retropubic prostatectomy at Vanderbilt University Medical Center between January 2000 and June 2008. We used univariate and multivariate analysis to compare the pathological outcome detection rate between pathological methods. Kaplan-Meier curves and the log rank test were used to compare the prognostic value of pathological findings across pathological methods. RESULTS: There were no significant differences between the whole mount and the systematic sampling groups in detecting extraprostatic extension (25% vs 30%), positive surgical margins (31% vs 31%), pathological Gleason score less than 7 (49% vs 43%), 7 (39% vs 43%) or greater than 7 (12% vs 13%), seminal vesicle invasion (8% vs 10%) or lymph node involvement (3% vs 5%). Tumor volume was higher in the systematic sampling group and whole mount detected more multiple surgical margins (each p <0.01). There were no significant differences in the likelihood of biochemical recurrence between the pathological methods when patients were stratified by pathological outcome. CONCLUSIONS: Except for estimated tumor volume and multiple margins whole mount and systematic sampling yield similar pathological information. Each method stratifies patients into comparable risk groups for biochemical recurrence. Thus, while whole mount is more resource intensive, it does not appear to result in improved detection of clinically important pathological outcomes or prognostication. PMID- 20723933 TI - Citizenship in our profession. PMID- 20723934 TI - Prognostic significance of extranodal extension in patients with pathological node positive penile carcinoma. AB - PURPOSE: We assessed the prognostic significance of extranodal extension, defined as tumor extension through the lymph node capsule into the perinodal fibrous adipose tissue, as well as several other risk factors in node positive penile cancer cases. MATERIALS AND METHODS: We analyzed prospectively collected data on a consecutive series of 156 chemotherapy naive patients with proven lymph node involvement who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was indicated when histopathological analysis revealed more tumor than 1 intranodal metastasis. We estimated cancer specific survival using the Kaplan-Meier method. Multivariate analysis was done according to the Cox proportional hazards model of factors statistically significant on univariate analysis. RESULTS: Adjuvant radiotherapy was done in 70 patients (45%). Median followup was 57.8 months. Overall 5-year cancer specific survival was 61%. Men with extranodal extension had significantly decreased 5-year cancer specific survival compared with men without it (42% vs 80%). Other prognostic variables on univariate analysis were bilateral metastatic involvement vs unilateral, 3 or greater unilateral metastatic inguinal nodes vs 2 or fewer, inguinal lymphadenectomy positive margin status vs negative status and pelvic lymph node involvement. Pathological T stage or differentiation grade were not significant predictors of outcome. On multivariate analysis extranodal extension and pelvic lymph node involvement remained associated with decreased cancer specific survival (HR 2.37 and 2.20, respectively). CONCLUSIONS: Metastatic inguinal lymph node extranodal extension and pelvic lymph node involvement are independent predictive parameters of cancer specific survival in patients with pathologically node positive penile carcinoma despite surgery with postoperative radiotherapy. PMID- 20723935 TI - Hypospadias reporting--how good is the literature? PMID- 20723936 TI - Renal functional outcomes after partial nephrectomy with extended ischemic intervals are better than after radical nephrectomy. AB - PURPOSE: Partial nephrectomy is now a standard of care for clinical stage T1 renal cancers amenable to a nephron sparing approach. Based on tumor size and location, some partial nephrectomies can be more challenging and necessitate longer ischemic intervals, and radical nephrectomy is considered an alternative standard of care for these tumors. We evaluate whether partial nephrectomy with extended ischemia provides improved renal functional outcomes compared with radical nephrectomy. MATERIALS AND METHODS: Renal functional outcomes were analyzed in 2,402 consecutive patients with serum creatinine 1.4 mg/dl or less and 2 functioning kidneys treated for cT1 renal cancer at Cleveland Clinic with partial (1,833, 76%) or radical nephrectomy (569, 24%). Patients treated with partial nephrectomy were grouped according to duration of ischemia using the categories of limited (less than 30 minutes), unknown or extended (greater than 30 minutes). RESULTS: Patients in all 4 groups had similar preoperative creatinine (median 0.9 mg/dl) and estimated glomerular filtration rate (median 82 to 84 ml/minute/1.73 m(2)). Patients undergoing radical nephrectomy on average were older, and had more comorbidities and larger tumors (p <0.001). Regardless of type of surgery, this cohort as a whole was at low risk (less than 1%) for renal failure (estimated glomerular filtration rate less than 15 ml/minute/1.73 m(2)). However, patients in the radical nephrectomy cohort were far more likely (p <0.001) to have an estimated glomerular filtration rate less than 45 ml/minute/1.73 m(2) (35%) than any of the partial nephrectomy groups (limited 11%, unknown 15%, extended ischemia 19%). CONCLUSIONS: Even when performed with extended ischemia, partial nephrectomy is associated with renal functional outcomes superior to those of radical nephrectomy for clinical stage T1 renal cancers. Partial nephrectomy should be considered even for tumors in which anticipated ischemia may exceed 30 minutes. PMID- 20723937 TI - Visual enhancement of laparoscopic partial nephrectomy with 3-charge coupled device camera: assessing intraoperative tissue perfusion and vascular anatomy by visible hemoglobin spectral response. AB - PURPOSE: We report the novel use of 3-charge coupled device camera technology to infer tissue oxygenation. The technique can aid surgeons to reliably differentiate vascular structures and noninvasively assess laparoscopic intraoperative changes in renal tissue perfusion during and after warm ischemia. MATERIALS AND METHODS: We analyzed select digital video images from 10 laparoscopic partial nephrectomies for their individual 3-charge coupled device response. We enhanced surgical images by subtracting the red charge coupled device response from the blue response and overlaying the calculated image on the original image. Mean intensity values for regions of interest were compared and used to differentiate arterial and venous vasculature, and ischemic and nonischemic renal parenchyma. RESULTS: The 3-charge coupled device enhanced images clearly delineated the vessels in all cases. Arteries were indicated by an intense red color while veins were shown in blue. Differences in mean region of interest intensity values for arteries and veins were statistically significant (p >0.0001). Three-charge coupled device analysis of pre-clamp and post-clamp renal images revealed visible, dramatic color enhancement for ischemic vs nonischemic kidneys. Differences in the mean region of interest intensity values were also significant (p <0.05). CONCLUSIONS: We present a simple use of conventional 3-charge coupled device camera technology in a way that may provide urological surgeons with the ability to reliably distinguish vascular structures during hilar dissection, and detect and monitor changes in renal tissue perfusion during and after warm ischemia. PMID- 20723938 TI - Editorial comment. PMID- 20723939 TI - Early and late perioperative outcomes following radical cystectomy: 90-day readmissions, morbidity and mortality in a contemporary series. AB - PURPOSE: Radical cystectomy remains associated with significant morbidity. Most series report outcomes with relatively short-term followup that may underestimate the true magnitude of the procedure and many report length of hospital stay but ignore readmission rates. We analyzed the predictors of early (30 days or less), late (31 to 90 days) and cumulative 90-day hospital readmissions, as well as morbidity and mortality rates. MATERIALS AND METHODS: We reviewed our prospectively collected database of 753 patients who underwent radical cystectomy for urothelial cancer between January 2001 and December 2007. We examined the relationship between clinical variables and readmission rates during the early, late and 90-day postoperative period, and reviewed mortality and perioperative morbidity rates. RESULTS: There were 200 (26.6%) patients readmitted in the first 90 days following radical cystectomy. Of these patients 148 (19.7%) were readmitted early, 81 (10.8%) were readmitted late, and 29 (3.9%) had an early and late readmission. Logistical regression revealed gender (OR 1.50, 95% CI 1.00 2.27, p = 0.05), age adjusted Charlson comorbidity index (OR 1.19, 95% CI 1.06 1.34, p = 0.003) and any postoperative complications before discharge home (OR 1.84, 95% CI 1.19-2.83, p = 0.006) as independent predictors of 90-day readmission. The 30 and 90-day mortality rates were 2.1% (16) and 6.9% (52), respectively. CONCLUSIONS: Readmission rates after radical cystectomy are significant, approaching 27% within the first 90 days. Gender and age adjusted Charlson comorbidity index were independent predictors providing preoperative information identifying patients more likely to require readmission or possibly to benefit from a longer initial hospital stay. PMID- 20723940 TI - Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden Follow-Up Study. AB - PURPOSE: We assessed outcomes in terms of adverse pathology and prostate cancer specific mortality in men who underwent primary or deferred radical prostatectomy. MATERIALS AND METHODS: In the National Prostate Cancer Register of Sweden Follow-Up Study men 70 years old or younger at diagnosis with localized low to intermediate risk prostate cancer diagnosed from 1997 to 2002 were identified. Outcome in terms of adverse pathology, namely upgrading of Gleason score, positive surgical margins and extraprostatic extension, as well as prostate cancer specific mortality, was assessed in 2,344 men who underwent primary radical prostatectomy and 222 who underwent deferred radical prostatectomy after an initial period of surveillance. RESULTS: Upgrading of Gleason score in surgical specimens vs core biopsies was less frequent after primary (25%) vs deferred radical prostatectomy (38%), p <0.001. There was no significant difference in the percentage of men who underwent primary vs deferred radical prostatectomy for positive surgical margins (33% vs 24%) or extraprostatic extension (27% vs 25%), and there was no difference in any 1 or more of the 3 adverse pathology features (55% vs 56%). After a median followup of 8 years 0.7% of men in the primary radical prostatectomy group and 0.9% in the deferred radical prostatectomy group had died of prostate cancer. CONCLUSIONS: There was no significant difference in the presence of any 1 or more adverse pathology features or in prostate cancer specific mortality after primary compared to deferred radical prostatectomy. However, longer followup is needed to conclusively evaluate the role of deferred radical prostatectomy. PMID- 20723941 TI - Source and distribution of lead in the surface sediments from the South China Sea as derived from Pb isotopes. AB - Rapid economic development in East Asian countries has inevitably resulted in environmental degradation in the surrounding seas, and concern for the environment and its protection against pollutants is increasing. Identification of sources of contaminants and evaluation of current environmental status are essential to environmental pollution management, but relatively little has been done in the South China Sea (SCS). In order to investigate the abundance, distribution, and sources of Pb within the SCS, stable Pb isotopes and their ratios were employed to assess the contamination status and to differentiate between natural and anthropogenic origins of Pb in the surface sediments. The total Pb concentrations in sediments varied from 4.18 to 58.7 mg kg(-1), with an average concentration of 23.6 +/- 8.9 mg kg(-1). The observed Pb isotope ratios varied from 18.039 to 19.211 for (206)Pb/(204)Pb, 15.228 to 16.080 for (207)Pb/(204)Pb, 37.786 to 39.951 for (208)Pb/(204)Pb, 1.176 to 1.235 for (206)Pb/(207)Pb, and 2.468 to 2.521 for (208)Pb/(207)Pb. The majority of these ratios are similar to those reported for natural detrital materials. Combined with Pb enrichment factor values, our results show that Pb found within most of the SCS sediments was mainly derived from natural sources, and that there was not significant Pb pollution from anthropogenic sources before 1998. Further studies are needed to reconstruct deposition history and for trend analysis. PMID- 20723942 TI - Biogeochemical typology and temporal variability of lagoon waters in a coral reef ecosystem subject to terrigeneous and anthropogenic inputs (New Caledonia). AB - Considering the growing concern about the impact of anthropogenic inputs on coral reefs and coral reef lagoons, surprisingly little attention has been given to the relationship between those inputs and the trophic status of lagoon waters. The present paper describes the distribution of biogeochemical parameters in the coral reef lagoon of New Caledonia where environmental conditions allegedly range from pristine oligotrophic to anthropogenically influenced. The study objectives were to: (i) identify terrigeneous and anthropogenic inputs and propose a typology of lagoon waters, (ii) determine temporal variability of water biogeochemical parameters at time-scales ranging from hours to seasons. Combined ACP-cluster analyses revealed that over the 2000 km(2) lagoon area around the city of Noumea, "natural" terrigeneous versus oceanic influences affecting all stations only accounted for less than 20% of the spatial variability whereas 60% of that spatial variability could be attributed to significant eutrophication of a limited number of inshore stations. ACP analysis allowed to unambiguously discriminating between the natural trophic enrichment along the offshore-inshore gradient and anthropogenically induced eutrophication. High temporal variability in dissolved inorganic nutrients concentrations strongly hindered their use as indicators of environmental status. Due to longer turn over time, particulate organic material and more specifically chlorophyll a appeared as more reliable nonconservative tracer of trophic status. Results further provided evidence that ENSO occurrences might temporarily lower the trophic status of the New Caledonia lagoon. It is concluded that, due to such high frequency temporal variability, the use of biogeochemical parameters in environmental surveys require adapted sampling strategies, data management and environmental alert methods. PMID- 20723943 TI - Oil viscosity limitation on dispersibility of crude oil under simulated at-sea conditions in a large wave tank. AB - This study determined the limiting oil viscosity for chemical dispersion of oil spills under simulated sea conditions in the large outdoor wave tank at the US National Oil Spill Response Test Facility in New Jersey. Dispersant effectiveness tests were completed using crude oils with viscosities ranging from 67 to 40,100 cP at test temperature. Tests produced an effectiveness-viscosity curve with three phases when oil was treated with Corexit 9500 at a dispersant-to-oil ratio of 1:20. The oil viscosity that limited chemical dispersion under simulated at sea conditions was in the range of 18,690 cP to 33,400 cP. Visual observations and measurements of oil concentrations and droplet size distributions in the water under treated and control slicks correlated well with direct measurements of effectiveness. The dispersant effectiveness versus oil viscosity relationship under simulated at sea conditions at Ohmsett was most similar to those from similar tests made using the Institut Francais du Petrole and Exxon Dispersant Effectiveness (EXDET) test methods. PMID- 20723944 TI - Observed impact of upwelling events on water properties and biological activity off the southwest coast of New Caledonia. AB - The upwelling events that follow strong trade wind episodes have been described in terms of their remarkable signature in the sea surface temperature southwest off New Caledonia. Upwelling brings deeper, and colder waters to the surface, causing 2-4 degrees C drops in temperature in a few hours, followed by a slower relaxation over several days. Upwelling may sporadically bring nutrients to the surface under certain conditions, and increase the biological productivity. Two multidisciplinary hydrographic cruises allow the impact of upwelling on the chemical and biological properties of the water to be documented. Both cruises took place in austral summer (December 2004 and December 2005), but the first cruise occurred during a strong upwelling event, while the second cruise occurred in calm conditions. The water properties and planktonic composition show important contrasts, with a strong southeastward current (the "ALIS current of New Caledonia") competing with the upwelling system. Our analysis suggests that, while observed productivities are far less than those of typical upwelling systems, some wind events in New Caledonia may contribute to biological activity. A currentmeter mooring, deployed during the second cruise, documents the ocean response to a changing wind field and the local impact of upwelling on currents and temperatures on the water column. The results are discussed, with the help of climatology, Argo float profiler data, satellite data and of a high-resolution numerical simulation. PMID- 20723945 TI - The APOE -219G/T and +113G/C polymorphisms affect insulin resistance among Turks. AB - The -219G/T (rs405509) and +113G/C (rs440446) polymorphisms within the regulatory region of the apolipoprotein E (APOE) gene have been related to the transcriptional activity of the gene. We examined the effect of the stated polymorphisms and their construct haplotypes with the APOE E2/E3/E4 polymorphism on lipid levels and insulin resistance in the Turkish Adult Risk Factor Study. Randomly selected 1774 adults (mean age, 55.0 +/- 11.7 years; 51.2% women) participating in the population-based Turkish Adult Risk Factor Study were cross sectionally analyzed for the -219G/T, +113G/C, and E2/E3/E4 polymorphisms as well as their haplotypes. Insulin resistance was defined as the 70th percentile in the sample (>2.51) of the homeostatic model assessment (HOMA). The frequencies of the -219T and +113C alleles were 0.477 and 0.423, respectively; and those of haplotype 1 (GGE3) and haplotype 2 (TCE3) were 44.1% and 41.9%, respectively. The -219G/T and +113G/C genotypes (both P < .04) and diplotypes of haplotype 2 (TCE3) (P < .014) were inversely related to serum fasting insulin and the HOMA index, even after controlling for 8 relevant covariates, but not to serum lipids. Within the APOE3 group, haplotype 2 (TC-/TC+) heterozygotes had an odds ratio of 0.66 (95% confidence interval, 0.42-0.99) for HOMA of insulin resistance after adjusting for 8 covariates. APOE promoter polymorphisms and their diplotypes are independently related with serum fasting insulin levels and HOMA index among Turks. PMID- 20723946 TI - Functional variability in corticosteroid receptors is a major component of strain differences in fat deposition and metabolic consequences of enriched diets in rat. AB - We aimed to distinguish mineralocorticoid (MR) from glucocorticoid receptor (GR) actions in the nutritional differences between the Fischer 344 (F344) and LOU/C (LOU) rat strains. The decrease of urinary Na+/K+ ratio induced via MR activation by aldosterone and decrease of circulating lymphocyte counts exerted via GR activation by dexamethasone revealed a higher efficiency of corticosteroid receptor in LOU than in F344 rats. Afterward, we submitted F344 and LOU male rats to adrenalectomy and to substitution treatments with agonists of MR or GR under 3 successive diets--standard, free choice between chow and pork lard, and an imposed high-fat/high-sugar diet--to explore the involvement of the interactions between activation of corticosteroid receptors and diet on food intake, body composition, and metabolic blood parameters in these rats. Lastly, we measured energy expenditure and substrate oxidization in various experimental conditions in LOU and F344 rats by indirect calorimetry. In LOU rats, we showed greater basal and MR-induced energy expenditure, diet-induced thermogenesis, and lipid oxidization. We showed that the F344 rat strain constitutes a relevant model of the unfavorable effects exerted by glucocorticoids via GR on food preference for high-calorie diets, abdominal fat deposition, diabetes, and other deleterious consequences of visceral obesity. Contrary to F344 rats, the LOU rats did not exhibit the expected visceral fat deposition linked to GR activation. This strain is therefore a relevant model of resistance to diet-induced obesity and to the deleterious effects exerted by glucocorticoids on metabolism. PMID- 20723947 TI - Metabolic syndrome and ALA54THR polymorphism of fatty acid-binding protein 2 in obese patients. AB - The prevalence of metabolic syndrome (MS) has been estimated to be approximately 25% of the population at large. A transition G to A at codon 54 of fatty acid binding protein 2 (FABP2) results in an amino acid substitution (ala54 to Thr54), and this polymorphism was associated with some cardiovascular risk factors. The aim of our study was to investigate the relationship between MS and Thr54 polymorphism in the FABP2 gene in obese patients. A population of 750 (body mass index >30) obese patients was analyzed in cross-sectional survey. Bioimpedance, blood pressure, and serial assessment of nutritional intake with 3-day written food records and biochemical analysis were performed. The statistical analysis was performed for the combined Ala54/Thr54 and Thr54/Thr54 as a mutant group and wild-type Ala54/Ala54 as second group. Prevalence of MS with Adult Treatment Panel III definition was 49.7% (373 patients; 24.9% male and 75.1% female), and 50.3% of the patients had no MS (n = 377; 34.2% male and 65.8% female). Prevalence of FABP genotypes was similar in patients with MS (55.5% wild genotype and 44.5% mutant genotype) and without MS (54.6% wild genotype and 45.4% mutant genotype). Prevalence of each criteria of MS was calculated in wild- and mutant type genotypes, without statistical differences. No differences in anthropometric and biochemical parameters were detected between genotypes in the same group of MS. The finding of our study is the lack of association of the Thr54/Ala54 and Thr54/Thr54 FABP2 genotypes with MS. PMID- 20723948 TI - Insufficient sensitivity of hemoglobin A(1C) determination in diagnosis or screening of early diabetic states. AB - An International Expert Committee made recommendations for using the hemoglobin A(1C) (A1C) assay as the preferred method for the diagnosis of diabetes in nonpregnant individuals. A concentration of at least 6.5% was considered as diagnostic. It is the aim of this study to compare the sensitivity of A1C with that of plasma glucose concentrations in subjects with early diabetes or impaired glucose tolerance (IGT). We chose 2 groups of subjects who had A1C not exceeding 6.4%. The first group of 89 subjects had family histories of diabetes (MODY or type 2 diabetes mellitus) and had oral glucose tolerance test (OGTT) and A1C determinations. They included 36 subjects with diabetes or IGT and 53 with normal OGTT. The second group of 58 subjects was screened for diabetes in our Diabetes Clinic by fasting plasma glucose, 2-hour plasma glucose, or OGTT and A1C; and similar comparisons were made. Subjects with diabetes or IGT, including those with fasting hyperglycemia, had A1C ranging from 5.0% to 6.4% (mean, 5.8%). The subjects with normal OGTT had A1C of 4.2% to 6.3% (mean, 5.4%), or 5.5% for the 2 groups. The A1C may be in the normal range in subjects with diabetes or IGT, including those with fasting hyperglycemia. Approximately one third of subjects with early diabetes and IGT have A1C less than 5.7%, the cut point that the American Diabetes Association recommends as indicating the onset of risk of developing diabetes in the future. The results of our study are similar to those obtained by a large Dutch epidemiologic study. If our aim is to recognize early diabetic states to apply effective prophylactic procedures to prevent or delay progression to more severe diabetes, A1C is not sufficiently sensitive or reliable for diagnosis of diabetes or IGT. A combination of A1C and plasma glucose determinations, where necessary, is recommended for diagnosis or screening of diabetes or IGT. PMID- 20723949 TI - Gender differences in adolescent health-related behaviour diminished between 1998 and 2006. AB - OBJECTIVES: Male teenagers used to smoke more than females, but this male:female ratio has reversed in several European countries over recent decades. The aim of this study was to assess whether a similar shift in gender differences in smoking and other health-related behaviours has occurred in Slovak adolescents over the last decade. STUDY DESIGN: Cross-sectional study. METHODS: Data were collected in 1998 (n=2616, 52.4% male, mean age 14.9+/-0.6 years, response rate 96.3%) and 2006 (n=1081, 47.0% male, mean age 14.3+/-0.6 years, response rate 93.0%). Changes in gender-specific prevalence rates for smoking, alcohol consumption and lack of physical activity were assessed for both cohorts overall and by socio economic group using the highest educational level of the parents. RESULTS: Statistically significant changes occurred in the male:female ratios for smoking and lack of physical activity but not for alcohol consumption. The prevalence of smoking in males dropped below that in females, and the physical activity of females increased substantially. However, changes in gender ratios varied strongly by socio-economic group. The greatest shift in the gender ratio for smoking occurred in the middle socio-economic group, showing an increase in the entire sample. Changes in gender ratios over time among adolescents from the highest socio-economic group were much smaller. CONCLUSIONS: The behaviour of Slovak female adolescents has become similar to that of their male peers in terms of smoking and physical activity. This shift in the gender ratio in Slovakia over the last decade mimics the shift in Western Europe from approximately two decades ago. PMID- 20723950 TI - Association of availability of tobacco products with socio-economic and racial/ethnic characteristics of neighbourhoods. AB - OBJECTIVE: To examine the association of neighbourhood median income and racial/ethnic composition with the availability of tobacco products in Omaha Metropolitan Area, Nebraska, USA. METHODS: A total of 94 census tracts were selected at random. The outcome measures were the percentage of stores that sold tobacco and the number of stores that sold tobacco per square mile in each census tract. RESULTS: Median household income was negatively associated (P<0.001), and percentage African American population (P<0.001) and percentage Hispanic population (P=0.049) were positively associated with the percentage of stores that sold tobacco. Median household income was negatively associated (P<0.001) and percentage Hispanic population (P=0.012) was positively associated with the number of stores that sold tobacco per square mile. CONCLUSION: Policies that reduce the number of tobacco outlets might reduce social disparities in tobacco use. PMID- 20723951 TI - Transmission of Cyprinid herpesvirus-3 (CyHV-3) from goldfish to naive common carp by cohabitation. AB - Cyprinid herpesvirus-3 (CyHV-3) has spread worldwide and has had a major impact on koi and common carp production. Previous studies on the host range of the CyHV 3 found that fish species other than koi and common carp are fully resistant to natural virus exposure. Recently, CyHV-3 was detected in goldfish (Carassius auratus auratus) that were in contact with CyHV-3 infected koi. In the present study, a specific RT-PCR product was amplified from the viral thymidine kinase gene in gills, intestine and brain tissues of CyHV-3 infected goldfish. This implied that CyHV-3 replicated in these goldfish. Also, in the presence of a stress factor such as temperature fluctuation, the CyHV-3 infected goldfish transmitted the virus to cohabitated naive SPF common carp. CyHV-3 DNA was detected in the cohabitated naive carp tissues by PCR. The results of this study demonstrate that goldfish is a carrier for CyHV-3, permit virus propagation, and disseminate the virus to susceptible carp causing the disease. PMID- 20723952 TI - In growing pigs, chlortetracycline induces a reversible green bone discoloration and a persistent increase of bone mineral density dependent of dosing regimen. AB - We studied in growing pigs the effects of exposure to dietary chlortetracycline on bone mineral density (BMD) and bone color. Pigs were randomly allocated to a drug-free diet (n=48) or a diet fortified with 800 ppm of chlortetracycline, starting either at 28- or 84-d of age, and for either a 28- or 56-d duration (n=16 pigs/group). The lumbar vertebral discoloration and BMD of randomly chosen pigs were evaluated at 28-d intervals up to 168-d of age. The odds of bone discoloration increased with dosing duration and age at treatment onset, and decreased with the withdrawal time and age at treatment onset interaction (p < or = 0.001). The measured trabecular BMD linearly increased with age and squared treatment duration (p < or = 0.005). Therefore, TC-induced bone discoloration is reversible, and may be prevented with proper dosing regimen design. Moreover, TC induces a persistent increase on BMD that could be detected with quantitative computed tomography. PMID- 20723953 TI - Identification, characterization and expression analysis of hepcidin gene in sheep. AB - Hepcidin is part of the innate immune system, and it plays a central role in the regulation of iron homeostasis. This peptide has been previously characterized in man, non-human primates, rat, mouse, dog, swine, cattle, horse, fishes, reptiles and birds but until now not in sheep. The aim of this study was to sequence, characterize and perform hepcidin expression analysis in different tissues collected from healthy sheep. The resulting open reading frame consisted of 249 bp predicted to encode an 82 aa peptide with a putative 23 aa signal peptide, a 34 aa pro-region and the 25 aa mature hepcidin. The deduced sequence of the sheep hepcidin precursor was most homologous to Bos taurus and Bubalus bubalis. Hepcidin was predominantly expressed in liver, although high expression was present in abomasum and lower level expression occurred in other tissues. These findings extend our comparative knowledge showing the relationship of sheep hepcidin to other mammalian hepcidins and will be helpful for additional studies on iron metabolism and inflammatory processes in sheep. PMID- 20723954 TI - First isolation and molecular characterization of Ehrlichia canis in Costa Rica, Central America. AB - The present study investigated Ehrlichia species in blood samples from dogs suspected of clinical ehrlichiosis, using molecular and isolation techniques in cell culture. From a total of 310 canine blood samples analyzed by 16S rRNA nested PCR, 148 (47.7%) were positive for Ehrlichia canis. DNA from Ehrlichia chaffeensis or Ehrlichia ewingii was not detected in any sample using species specific primers in separated reactions. Leukocytes from five PCR-positive dogs were inoculated into DH82 cells; successful isolation of E. canis was obtained in four samples. Partial sequence of the dsb gene of eight canine blood samples (including the five samples for in vitro isolation) was obtained by PCR and their analyses through BLAST showed 100% of identity with the corresponding sequence of E. canis in GenBank. This study represents the first molecular diagnosis, isolation, and molecular characterization of E. canis in dogs from Costa Rica. PMID- 20723955 TI - The effect of selected microbial strains on internal milieu of broiler chickens after peroral administration. AB - The aim of this work was to investigate the effect of probiotic preparation with multi-strains composition (Lactobacillus delbrueckii ssp. bulgaricus LAT 187, Lactobacillus acidophilus LAT 180, Lactobacillus helveticus LAT 179, Lactobacillus delbrueckii ssp. lactis LAT 182, Streptococcus thermophilus LAT 205 and Enterococcus faecium E 253) on internal milieu, antioxidant status and body weight of broiler chickens. Chickens were divided into three groups (C, control; E1 and E2, experimental groups). Experimental chickens received the probiotic preparation in drinking water. Probiotic preparation caused a significant increase of serum calcium and potassium content. In the group with higher dose of probiotic strains serum triglycerides level decreased. Total antioxidant status in groups with addition of probiotic strains showed higher values in comparison to control group. Serum albumin level was found to increase after consumption of probiotic preparation in group with higher dose of probiotic strains. Probiotic strains improved body weight in last observed weeks of feeding. PMID- 20723956 TI - Postoperative parathyroid hormone testing decreases symptomatic hypocalcemia and associated emergency room visits after total thyroidectomy. AB - BACKGROUND: Symptomatic hypocalcemia, the most common complication of total thyroidectomy, can lead to postoperative emergency room visits for laboratory testing and intravenous calcium infusion. A method to identify patients reliably at risk for postoperative hypocalcemia could allow prophylactic treatment to avoid this. We hypothesized that quick parathyroid hormone testing within 4 hours of thyroidectomy and a protocol to treat parathyroid-hormone-deficient patients would reduce symptomatic hypocalcemia, eliminating the need for emergency room visits. METHODS: After January 1, 2006, 271 consecutive patients underwent total thyroidectomy with postoperative parathyroid hormone testing (group 1). Patients with parathyroid hormone levels <10 pg/mL were treated according to a newly instituted protocol with 0.25-ug calcitriol twice daily and 2-6 g of calcium carbonate daily for 1 week. Patients with parathyroid hormone levels >=10 pg/mL were treated with calcium only. Group 2 consisted of 100 consecutive patients who underwent total thyroidectomy prior to 2006 without parathyroid hormone testing and were treated according to surgeon preference and serum calcium levels. RESULTS: Patients in the 2 groups were similar with regard to age, sex, and thyroiditis. However, patients in group 1, who had parathyroid hormone testing, had greater postoperative calcium levels (P < .005). Also, patients in group 2 had a higher incidence of malignancy (P = .04). Importantly, patients in group 1 had a lesser incidence of symptomatic hypocalcemia (7% vs 17%; P = .005). Furthermore, the number of patients who made visits to the emergency room was less in patients who had parathyroid hormone testing compared with those who did not (1.8% vs 8.0%; P = .008). CONCLUSION: Postoperative parathyroid hormone testing reliably identifies patients at risk for hypocalcemia after thyroid surgery. Moreover, parathyroid hormone testing and calcitriol administration to patients at risk decreases the incidence of hypocalcemia and associated emergency room visits after total thyroidectomy. Therefore, patients with postoperative serum parathyroid hormone levels <10 pg/mL after thyroid surgery should be treated with calcitriol and calcium to prevent symptomatic hypocalcemia. PMID- 20723957 TI - Exogenous high-mobility group box 1 improves myocardial recovery after acute global ischemia/reperfusion injury. AB - BACKGROUND: High-mobility group box 1 (HMGB1) is a mediator of inflammation with dose-dependent effects. In the setting of regional myocardial infarction, a high dose HMGB1 treatment decreases myocardial function, whereas low-dose HMGB1 improves function; however, it is unknown what role HMGB1 has in the setting of global ischemia/reperfusion (I/R) injury. We hypothesized that a low-dose HMGB1 treatment would improve myocardial functional recovery and decrease infarct size after global I/R injury in association with increased levels of cardioprotective paracrine factors and decreased inflammation. METHODS: Adult rat hearts were isolated and perfused using the Langendorff method and were subjected to global I/R and treatment with either the vehicle, 200-ng HMGB1, or 1-MUg HMGB1. The treatment was administered during 1 min at the start of reperfusion, and myocardial function was measured for 60 min of reperfusion. At the end of reperfusion, the hearts were sectioned and incubated in triphenyltetrazolium chloride to assess myocardial infarct size or homogenized to measure levels of inflammatory cytokines and growth factors. RESULTS: Postischemic treatment with 200-ng HMGB1 significantly improved myocardial functional recovery after global I/R in association with decreased infarct size and decreased interleukin-1 (IL 1), IL-6, IL-10, and vascular endothelial growth factor (VEGF) levels. In addition, 1-MUg HMGB1 decreased myocardial inflammation but did not result in subsequent improvement in functional recovery. CONCLUSION: In the setting of global I/R, 200-ng postischemic HMGB1 treatment improves myocardial function and decreases infarct size in association with suppressed myocardial inflammation. These results suggest a potential role for exogenous HMGB1therapy in the acute postischemic period. PMID- 20723958 TI - Two-stage brachial-basilic transposition fistula provides superior patency rates for dialysis access in a safety-net population. AB - BACKGROUND: Guidelines of the National Kidney Foundation recommending aggressive pursuit of autogenous fistulae for dialysis access in lieu of prosthetic arteriovenous grafts have stimulated a renewed interest in transposed brachial basilic fistulae as an alternative technique for upper arm access in patients who may not be candidates for a lower arm radial-cephalic or forearm brachial cephalic fistula. We hypothesized that in our safety-net population, where radial cephalic and brachial-cephalic often are not possible, brachial-basilic would provide patency rates superior to arteriovenous grafts and equivalent to radial cephalic and brachial-cephalic fistulae. METHODS: We analyzed retrospectively our most recent 2.5-year experience with dialysis access procedures at our metropolitan safety-net hospital. Procedures were grouped as follows: radial cephalic, brachial-cephalic, brachial-basilic, and arteriovenous grafts. The access outcomes measured were primary failure, time to use, need for intervention, and primary as well as secondary patency. Differences in age, sex, race, renal function (Modification of Diet in Renal Disease), baseline diagnoses (diabetes mellitus, hypertension, coronary artery disease, and peripheral vascular disease), as well as the number of previous accesses, were adjusted in the analysis. Logistic regression was used to identify independent predictors of primary failure, and Kaplan-Meier plots assessed differences in primary patency rates. A log of the time variables was used to approximate normal distribution. RESULTS: In all, 193 patients were included in this study as follows: radial cephalic, 75 (39%) patients; brachial-cephalic, 35 (18%) patients; brachial basilic, 33 (17%) patients; and arteriovenous grafts, 50 (26%) patients. Primary patency means differed marginally between groups (P = .08), and when grafts were excluded from the analysis, no difference was found between primary patency in all autogenous fistula techniques (P = .88). Kaplan-Meier plots showed that when analyzing the first 35 weeks, a significantly lower primary patency among graft recipients early after the procedure was noted, and a higher performance of BB after 20 weeks was noted (log-rank P = .05, Wilcoxon P = .004). Furthermore, secondary patency did not vary significantly between groups (P = .62). Radial cephalic were more likely to fail primarily when compared with the other access groups (P = .03), and in a univariate analysis, underlying hypertension was associated with a lower risk of primary failure (P = .01) compared with other diagnoses. A logistic regression stepwise selection showed that the underlying diagnoses of peripheral vascular disease, diabetes mellitus, or coronary artery disease were associated with a greater risk of primary failure compared with those with HTN (P = .001; odds ratio, 4.05; 95% confidence interval, 1.71-9.59), as well as the presence of a previously failed access (P = .04; odds ratio, 2.39; 95% confidence interval, 1.08-5.67). CONCLUSION: In a safety-net population, our results suggest that 2-stage brachial-basilic transposition fistulae provide patency rates equivalent to brachial-cephalic and radial-cephalic fistulae and superior to grafts. Although 2 procedures are required, brachial-basilic fistulae provide a reliable access and should be considered the next choice when radial cephalic and/or brachial-cephalic are not possible. PMID- 20723959 TI - Prevalence and stability of antibodies to 37 human papillomavirus types--a population-based longitudinal study. AB - Information about serostability of cutaneous HPV types over time is very limited. We investigated seroprevalence and serostability of 37 different HPV types over 41/2 years in an Australian population-based study. Sera and data were analyzed for 390 people who had never been diagnosed with SCC and had blood collected in 1992, 1993 and 1996. Eighty-six percent of participants were seropositive to at least one of the 37 HPV types at baseline. HPV-4 was the type with the highest seroprevalence (41%), followed by HPV-38 and HPV-8 (both 33%). Over 90% of people retained their baseline serostatus during the 41/2 year follow-up. Highest serostability was observed for HPV-88 (99.7% stayed seropositive or seronegative), while HPV-65 was least stable with 17% altering their serostatus during follow-up. Seroprevalence to cutaneous HPV types are relatively stable over time, and a single measure can be used as a reasonable marker of long-term antibody status. PMID- 20723960 TI - The effect of high speed mixing and polymer dosing rates on the geometric and rheological characteristics of conditioned anaerobic digested sludge (ADS). AB - Wastewater sludges are non-Newtonian fluids because their shear rates change with shear stress and no linear relationship is observed between their shear stress and shear rate. Therefore, it is necessary to condition sludges with polyelectrolytes prior to dewatering to increase in the dewaterability. Since 1978, researchers have observed that the yield strength of conditioned sludge increased with the addition of polymer up to the optimum dose. Then sludge rheogram was used as a control parameter to optimize the addition of polymers, and the peak height in the shear stress vs. shear rate curve was an indication of sludge conditionablity, where the optimum polymer conditioning corresponding to the highest peak was obtained. However, few studies have addressed the effects of distinct conditioning factors on the appearance of peaks in such rheograms. In this study, the impact of factors such as high speed mixing and polymer dosing rates on the geometric and rheological characteristics of conditioned anaerobic digested sludge (ADS) with the polymer zetag7557 were investigated through the jar test method. The results showed that both the high speed mixing time and polymer dosing time had important effects on the emergence of the initial peak in test curves obtained using the Haake RV20 and Flokky rheometers for evaluation of conditioned ADS. A high speed mixing time within 60 s or a polymer dosing time of 5 s was sufficient for observation of the initial peak in flow curves, and both peak height and area decreased as the high speed mixing times were prolonged in most cases in this study. As same as the high speed mixing time, the extension of zetag7557 dosing time can also lead to the gradual decrease in the initial peak size of test curves, and form small aggregates with a decrease in two-dimensional fractal dimensions (D(2)). Although the initial peak in the test curves was observed when high speed mixing intensities increased up to 300 rpm, there were several differences in the peak height and area observed on the Haake RV20 test rheograms and Floccky test curves. In addition, a high speed mixing intensity of 300 rpm was found to lead to the formation of smaller and less compact aggregates than other mixing intensities. All of the rheological and geometric parameters were somewhat correlated with fractal dimension-D(2P) (based on regression analysis of the logarithmics of area and perimeter). However, D(2L)(based on regression analysis of the logarithmics of area and maximum diameter) did not show good correlation with any other parameters. The median diameters of the aggregates were well correlated with one-dimensional fractal dimensions (D(1)). PMID- 20723961 TI - A conceptual ecosystem model of microbial communities in enhanced biological phosphorus removal plants. AB - The microbial populations in 25 full-scale activated sludge wastewater treatment plants with enhanced biological phosphorus removal (EBPR plants) have been intensively studied over several years. Most of the important bacterial groups involved in nitrification, denitrification, biological P removal, fermentation, and hydrolysis have been identified and quantified using quantitative culture independent molecular methods. Surprisingly, a limited number of core species was present in all plants, constituting on average approx. 80% of the entire communities in the plants, showing that the microbial populations in EBPR plants are rather similar and not very diverse, as sometimes suggested. By focusing on these organisms it is possible to make a comprehensive ecosystem model, where many important aspects in relation to microbial ecosystems and wastewater treatment can be investigated. We have reviewed the current knowledge about these microorganisms with focus on key ecophysiological factors and combined this into a conceptual ecosystem model for EBPR plants. It includes the major pathways of carbon flow with specific organic substances, the dominant populations involved in the transformations, interspecies interactions, and the key factors controlling their presence and activity. We believe that the EBPR process is a perfect model system for studies of microbial ecology in water engineering systems and that this conceptual model can be used for proposing and testing theories based on microbial ecosystem theories, for the development of new and improved quantitative ecosystem models and is beneficial for future design and management of wastewater treatment systems. PMID- 20723962 TI - Elimination and fate of selected micro-organic pollutants in a full-scale anaerobic/anoxic/aerobic process combined with membrane bioreactor for municipal wastewater reclamation. AB - The occurrence and elimination of 19 micro-organic pollutants including endocrine disrupting chemicals (EDCs) and pharmaceuticals and personal care products (PPCPs) in a full-scale anaerobic/anoxic/aerobic-membrane bioreactor process was investigated. The investigated process achieved over 70% removal of the target EDCs and 50%-100% removal of most of the PPCPs, with influent concentration ranging from ng/L to MUg/L. Three PPCPs, carbamazepine, diclofenac and sulpiride were not well removed, with the removal efficiency below 20%. A rough mass balance suggests that the targets were eliminated through sludge-adsorption and/or biodegradation, the former of which was particularly significant for the removal of hydrophobic compounds. The two-phase fate model was employed to describe the kinetics of sludge-adsorption and biodegradation. It was found that the fast sludge adsorption (indicated by mass-transfer rates greater than 10 for most compounds) is responsible for the rapid decline of the aqueous concentration of the targets in the first compartment of the treatment process (i.e. in the anaerobic tank). In contrast, the slow biodegradation proved to be the rate determining step for the entire degradation process, and the rates are generally positively related to the dissolved oxygen level. On the other hand, this study showed that the removal rates of most targets can reach a quasi-plateau in 5 h under aerobic conditions, indicating that hydraulic retention time of ca. 5 h in aerobic tanks should be sufficient for the elimination of most targets. PMID- 20723963 TI - Characterization of Enterococcus faecalis-infecting phages (enterophages) as markers of human fecal pollution in recreational waters. AB - Enterophages are a novel group of phages that specifically infect Enterococcus faecalis and have been recently isolated from environmental water samples. Although enterophages have not been conclusively linked to human fecal pollution, we are currently characterizing enterophages to propose them as viral indicators and possible surrogates of enteric viruses in recreational waters. Little is known about the morphological or genetic diversity which will have an impact on their potential as markers of human fecal contamination. In the present study we are determining if enterophages can be grouped by their ability to replicate at different temperatures, and if different groups are present in the feces of different animals. As one of the main objectives is to determine if these phages can be used as indicators of the presence of enteric viruses, the survival rate under different conditions was also determined as was their prevalence in sewage and a large watershed. Coliphages were used as a means of comparison in the prevalence and survival studies. Results indicated that the isolates are mainly DNA viruses. Their morphology as well as their ability to form viral plaques at different temperatures indicates that several groups of enterophages are present in the environment. Coliphage and enterophage concentrations throughout the watershed were lower than those of thermotolerant coliforms and enterococci. Enterophage concentrations were lower than coliphages at all sampling points. Enterophages showed diverse inactivation rates and T(90) values across different incubation temperatures in both fresh and marine waters and sand. Further molecular characterization of enterophages may allow us to develop probes for the real-time detection of these alternative indicators of human fecal pollution. PMID- 20723964 TI - Bacterial activity in plant (Schoenoplectus validus) biofilms of constructed wetlands. AB - Biofilm-bacterial communities have been exploited in the treatment of wastewater in 'fixed-film' processes. Our understanding of biofilm dynamics requires a quantitative knowledge of bacterial growth-kinetics in these microenvironments. The aim of this paper was to apply the thymidine assay to quantify bacterial growth without disturbing the biofilm on the surfaces of emergent macrophytes (Schoenoplectus validus) of a constructed wetland. The isotope was rapidly and efficiently taken-up and incorporated into dividing biofilm-bacteria. Isotope diffusion into the biofilm did not limit the growth rate measurement. Isotope dilution was inhibited at >12 MUM thymidine. Biofilm-bacterial biomass and growth rates were not correlated to the plant surface area (r(2) < 0.02). The measurements of in situ biofilm-bacterial growth rates both displayed, and accommodated, the inherent heterogeneity of the complex wetland ecosystem. Biofilm-bacterial respiratory activities, measured using the redox dye CTC, and growth rates were measured simultaneously. The dye did not interfere with bacterial growth. Biofilm-bacterial specific growth rates ranged from 1.4 +/- 0.6 d(-1) to 3.3 +/- 1.3 d(-1). In the constructed wetlands of this study biofilm bacterial specific growth rates, compared to those of natural ecosystems, could be markedly improved through changes in wetland design that increased bacterial respiration while minimising biofilm growth. PMID- 20723965 TI - Association of gastrointestinal illness and recreational water exposure at an inland U.S. beach. AB - Recent epidemiology studies examining U.S. recreational water exposure and illness relationships have focused primarily on coastal and Great Lakes beaches. Human-made lakes in the U.S. have received little attention in epidemiology studies despite contributing to more waterborne disease epidemics annually than coastal U.S. waters. In a comprehensive beach cohort study, we examined relationships between water quality indicators and reported adverse health outcomes among users of a beach at an inland U.S. lake. Human health data was collected over 26 swimming days during the 2009 swimming season in conjunction with water quality measurements. Adverse health outcomes were reported 8-9 days post-exposure via a phone survey. Wading, playing or swimming in the water was observed to be a significant risk factor for GI illness (adjusted odds ratio (AOR) of 3.2; CI 1.1, 9.0). Among water users, Escherichia coli density was significantly associated with elevated GI illness risk where the highest E. coli quartile was associated with an AOR of 7.0 (CI 1.5, 32). GI illness associations are consistent with previous freshwater epidemiology studies. Our findings are unique in that our observations of positive associations with GI illness risk are based upon a single daily E. coli measurement. Lastly, this study focused on an understudied issue, illness risk at inland reservoirs. Our results support the usefulness of E. coli as a health-relevant indicator of water quality for this inland U.S. beach. PMID- 20723966 TI - Simulation of the long-term transfer and fate of DDT in Lanzhou, China. AB - A level IV fugacity model is used to simulate the fate and transfer of DDT in the Lanzhou area over a 67-year period from their introduction into agricultural field until 2019. The established model is successfully applied to simulate the transfer processes and the concentration distribution of DDT in four environmental compartments: air, water, soil, and sediment in Lanzhou area under non-steady state assumptions. Furthermore, the calculated results agree well with monitoring data from the literature in same period of time. We assume 20% of the total usage of DDT enters into air and 80% enters the soils. The results indicate that the main source of DDT in the area is agricultural application, the biggest bulk sink is soil (accounting for 99.8% of total amount in the environment). Among all the transfer processes, the deposition from air to soil, deposition from air to water, soil erosion, and sedimentation from water to sediment are the primary processes, and the degradation in soil and air are the key process of DDT disappearance. PMID- 20723967 TI - Degradation of PCE, TCE and 1,1,1-TCA by nanosized FePd bimetallic particles under various experimental conditions. AB - The degradation of chlorinated organic compounds, such as PCE (tetrachloroethene), TCE (trichloroethene) and 1,1,1-TCA (1,1,1-trichloroethane), was conducted using nanosized FePd bimetallic particles. In order to enhance the reactivity of ZVI (zero valent iron) nanoparticles, surface modification of ZVI nanoparticles was performed using Pd and CMC (carboxymethyl cellulose). The surface modification was found to form CMC-stabilized FePd bimetallic nanoparticles (CMC-FePd). The average TCE removal efficiency by the CMC-FePd was significantly increased by ~85% compared to employing conventional ZVI nanoparticles (~15%). This increase in the TCE removal efficiency was most likely due to the increased amount of atomic hydrogen produced by the formation of CMC FePd. For PCE and 1,1,1-TCA, the removal efficiencies by CMC-FePd were approximately 80% and 56%, respectively. For all three chlorinated organic compounds, the amount of Cl- ions in the aqueous phase during the degradation increased with increasing reaction time. This result suggests that the main degradation mechanism of the chlorinated compounds by CMC-FePd was reductive dechlorination. PMID- 20723968 TI - Use of activated carbon as a reactive support to produce highly active regenerable Fe-based reduction system for environmental remediation. AB - Composites based on iron supported on high surface area activated carbon were prepared and characterized with (57)Fe Mossbauer spectroscopy, X-ray diffraction, saturation magnetization measurements and temperature-programmed reduction. Upon thermal treatment, the supported iron oxides react with carbon to yield reduced chemical species, i.e. Fe(3)O(4) and Fe(0). This so produced composite was found to be highly efficient in two environmental applications: (i) degradation of textile dye and (ii) reduction of Cr(VI) in aqueous medium. Sequential reuses evidenced a progressive chemical deactivation of the composites due to a corresponding oxidation of the reactive species. Even after being virtually deactivated, the initial chemical reducing ability of the composites can be regenerated by heating at 800 degrees C under N(2) atmosphere, and then reused for several consecutive times. PMID- 20723969 TI - Effect of preparation methods on toxicity of fullerene water suspensions to Japanese medaka embryos. AB - The physicochemical properties of fullerene water suspensions (nC(60)) and their subsequent toxicity were influenced by different preparation methods. The nC(60) suspensions were produced by three methods: toluene exchange (Tol/nC(60)), DMSO dissolving (DMSO/nC(60)), and stirring overtime (Aqu/nC(60)). The particle size, zeta potential, and nC(60) structure were strongly dependent on both the type of aggregates formed and the test medium addition. Specifically, Tol/nC(60) exhibited small and spherical closed aggregates, whereas DMSO/nC(60) and Aqu/nC(60) presented mesoscale aggregates of smaller spherical aggregates. These differences in the physicochemical properties of nC(60) determined the embryonic toxicity and oxidative stress of Japanese medaka (Oryzias latipes). The mortality and glutathione (GSH) induction of embryos were ranked in the order of Tol/nC(60)>DMSO/nC(60)>Aqu/nC(60), and the morphological malformations were in the order of DMSO/nC(60)>Tol/nC(60)>Aqu/nC(60). The mortality of Tol/nC(60) was attributed to its closely packed fullerene structure, which remained as largely underivatized C(60). The malformations of DMSO/nC(60) might have originated from the co-effect of organic solvent remaining in the fullerene colloid. To summarize, these findings clearly illustrated the need to consider the effect of preparation method on the physicochemical properties when assessing nC(60) toxicity. PMID- 20723970 TI - The role of TFPI in regulation of TF-induced thrombogenicity on the surface of human monocytes. AB - INTRODUCTION: Although the procoagulant reactivity of monocytes largely depends on expression and cell surface presentation of tissue factor (TF), little is known about the impact of tissue factor pathway inhibitor (TFPI) on regulation of TF function on the monocyte surface. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy subjects and cryopreserved. We investigated TF and TFPI mRNA expression by reverse transcription-quantitative real-time PCR (RT-qPCR), surface presentation by flow cytometry and confocal microscopy, and TFPI-mediated regulation of TF functional activity on the surface of resting and LPS-stimulated PBMCs by TF activity assay and Calibrated Automated Thrombogram (CAT) assay. RESULTS: Unstimulated PBMCs contained nearly no TF, but detectable TFPI protein levels. TFPI mRNA levels were 2-fold higher than TF, and the TFPIalpha mRNA isoform expression was higher than TFPIbeta. LPS stimulation caused a parallel and sustained upregulation of both TFPI isoforms, concomitant with increased surface presentation of TFPI antigen. Stronger, but transient upregulation of TF mRNA and surface antigen was observed at 6hrs of LPS stimulation. After LPS stimulation TF and TFPI were co-localized in the same areas of the monocyte membrane. Pre-incubation of PBMCs with anti TFPI IgG significantly enhanced TF activity, shortened Lag-time, and increased thrombin generation. TFPI-dependent inhibition of TF was more prominent in resting than in LPS-stimulated cells. CONCLUSIONS: Our results support the concept that surface TFPI is an important regulator of procoagulant reactivity of human monocytes. PMID- 20723971 TI - The quantitative detection of total HER2 load by quantum dots and the identification of a new subtype of breast cancer with different 5-year prognosis. AB - Accurate classification is fundamental for breast cancer (BC) personalized care. Current BC classification based on the either traditional morphological staging or molecular signatures seems inefficient to reveal the"true"behaviors of invasive BC evolution. An appropriate approach combining the macro- and micro pathologic information might be more useful academically as well as clinically. Here we explore a holistic approach by integrating a key molecular prognostic indicator of BC, HER2, with quantitative determination using quantum dots (QDs)- based nanotechnology and spectral analysis, and a key macropathologic indicator, tumor size, resulting a new indicator, total HER2 load. This indicator might better reveal BC heterogeneity and new subtypes of BC with different 5-year disease-free survival compared with current methods, which could be helpful in formulating a more personalized targeted therapy for BC. Furthermore, this mode integrating macro- and micro-pathological indicators might help gain new insights into invasive BC biological behaviors. PMID- 20723972 TI - PEG-interspersed nitrilotriacetic acid-functionalized quantum dots for site specific labeling of prion proteins expressed on cell surfaces. AB - A strategy has been put forward to fabricate PEG-interspersed nitrilotriacetic acid (NTA)-functionalized QDs by one-step self-assembly using a mixture of self synthesized NTA-terminated amphiphilic polymer and 1,2-Distearoyl-sn-Glycero-3 Phosphoethanolamine-N-[Carboxy(Polyethylene Glycol)2000] (DSPE-PEG-COOH). The process was highly reproducible for facile functionalization of QDs via simultaneous self-assembly of biocompatible PEG molecules onto their surface. An optimized molar ratio of NTA-terminated amphiphilic polymer to DSPE-PEG-COOH was used to obtain NTA-functionalized QDs for site-specific labeling of prion proteins (PrP(C)) expressed on cell surfaces. Fabricated NTA-functionalized QDs can be a good candidate used for real-time visualization of PrP(C) in single live cells so as to clarify the nosogenesis of pathogenic scrapie prion protein (PrP(Sc)). PMID- 20723973 TI - Biodegradable shape-memory block co-polymers for fast self-expandable stents. AB - Block co-polymers PCTBVs (M(n) of 36,300-65,300 g/mol, T(m) of 39-40 and 142 degrees C) containing hyperbranched three-arm poly(epsilon-caprolactone) (PCL) as switching segment and microbial polyester PHBV as crystallizable hard segment were designed as biodegradable shape-memory polymer (SMP) for fast self expandable stent and synthesized in 96% yield by the reaction of three-arm PCL triol (M(n) of 4200 g/mol, T(m) of 47 degrees C) with methylene diphenyl 4,4' diisocyanate isocynate (MDI) to form the hyperbrached MDI-linked PCL (PTCM; M(n) of 25,400 g/mol and a T(m) of 38 degrees C), followed by further polymerization with PHBV-diol (M(n) of 2200 g/mol, T(m) of 137 and 148 degrees C). The polymers were characterized by (1)H NMR, GPC, DSC, tensile test, and cyclic thermomechanical tensile test. PCTBVs showed desired thermal properties, mechanical properties, and ductile nature. PCTBV containing 25 wt% PHBV (PCTBV 25) demonstrated excellent shape-memory property at 40 degrees C, with R(f) of 94%, R(r) of 98%, and shape recovery within 25s. PCTBV-25 was also shown as a safe material with good biocompatibility by cytotoxicity tests and cell growth experiments. The stent made from PCTBV-25 film showed nearly complete self expansion at 37 degrees C within only 25 s, which is much better and faster than the best known self-expandable stents. PMID- 20723974 TI - Are SRC family kinases responsible for imatinib- and dasatinib-resistant chronic myeloid leukemias? PMID- 20723975 TI - Renewed interest in myeloma tumor growth, or just one more method to assess proliferation? PMID- 20723976 TI - More on the determination of Ki-67 as a novel potential prognostic marker in B cell chronic lymphocytic leukemia. PMID- 20723977 TI - PAX5-AUTS2 fusion resulting from t(7;9)(q11.2;p13.2) can now be classified as recurrent in B cell acute lymphoblastic leukemia. PMID- 20723978 TI - Agranulocytosis occurring in a patient with chronic lymphocytic leukemia in complete remission; treatment by rituximab and cyclosporin. PMID- 20723980 TI - Effect of chiral differences of metolachlor and its (S)-isomer on their toxicity to earthworms. AB - The effects of (Rac)-metolachlor and (S)-metolachlor on the avoidance behavior, bodyweight change and in vivo enzyme activity of earthworms (Eisenia foetida) were determined and compared in this study. The effects of (Rac)-metolachlor on the enzyme activities of E. foetida and bodyweight were more significant than those of (S)-metolachlor at the same concentrations. In the short term (2 d, 7 d), (S)-metolachlor had faster effects on cellulase and catalase activities of E. foetida. However, in the relatively long term (14 d, 28 d), (Rac)-metolachlor had higher toxic effects on cellulase and catalase activities. The inter-group difference between (Rac)-metolachlor and (S)-metolachlor on E. foetida enzyme activities was the most significant for catalase, and the least significant for cellulase. The test of avoidance behavior shows that earthworms are more sensitive to the stimulation of (Rac)-metolachlor than to that of (S) metolachlor. The results will help to develop an understanding of the biologically mediated environmental processes of these two herbicides. PMID- 20723979 TI - Effects of dietary cadmium contamination on bird Anas platyrhynchos--comparison with species Cairina moschata. AB - This study aimed to assess the effect of two dietary cadmium (Cd) levels (C1: 1 mgkg(-1); C10: 10 mgkg(-1)) on bird Anas platyrhynchos exposed for 10, 20 and 40 days (5 animals per experimental condition). Ducks were able to accumulate high amounts of Cd, especially in kidneys (after 40 days: C1 8.1 +/- 1 mgkg(-1), C10 37.7 +/- 4.3 mgkg(-1)). After 40 days, the lowest Cd level triggered oxidative stress and stimulated mitochondrial metabolism. At the same time, highest amounts of Cd (C10 group) only triggered repression of genes encoding for catalase and acetyl-CoA carboxylase, with repression factors of 1/50 and 1/5, respectively. High dose exposures were then associated with the repression of genes encoding for antioxidant, whereas low dose exposure triggered their induction. In contrast, the onset of MT gene expression appeared quickly for the C10 group even if a time delay was observed between gene expression and protein accumulation. Through the comparison of A. platyrhynchos and Cairina moschata, the response to Cd toxicity appeared species-dependent. Discrepancies between species could be explained by differential utilization of MT. This pathway of detoxification seemed sufficient to counter Cd toxicity. PMID- 20723981 TI - Assessment of respiratory mechanics by impulse oscillometry in orthopneic patients with acute left ventricular failure. AB - BACKGROUND: This study investigated the respiratory function and mechanics of patients with orthopnea caused by acute left ventricular failure (ALVF). METHODS: The study comprised 40 patients with ALVF and 15 control subjects. All patients underwent lung function tests and impulse oscillometry in both sitting and supine positions. In a subgroup of 22 patients, isosorbide dinitrate was administered and impulse oscillometry was performed 15 minutes later in the supine position. RESULTS: No patient reported dyspnea while seated, and the orthopnea score was 2.9 +/- 1.4. Left ventricular ejection fraction was 43% +/- 10%. Patients demonstrated restrictive spirometric pattern in the sitting position, whereas functional residual capacity was comparable to that of the control group. In the supine position, all pulmonary volumes decreased, except inspiratory capacity which increased. Respiratory reactance (Xrs5) was higher in patients in both sitting (421.8 +/- 630.6%pred vs 147.2 +/- 72.8%pred, P = .01) and supine (699.8 +/- 699.9%pred vs 251.2 +/- 151.6%pred, P <= .001) positions. Respiratory resistance (Rrs5) (10.6% +/- 17.8% mean decrease) and Xrs5 (17.2% +/- 39.4% mean decrease) improved after nitrates administration. Orthopnea was better correlated with Xrs5%pred in the supine position (r = .42, P = .007). Ejection fraction was positively correlated with inspiratory capacity %pred (r = .42, P = .007) in the sitting position. CONCLUSION: Patients with ALVF demonstrated increased respiratory reactance that correlated with orthopnea severity and improved after nitrates administration. PMID- 20723982 TI - Deleterious impact of mild anemia on survival of young adult patients (age 45 +/- 14 years) with idiopathic dilated cardiomyopathy: data from the Trieste Cardiomyopathies Registry. AB - OBJECTIVE: The study objective was to evaluate the impact of anemia on a large population of young patients with idiopathic dilated cardiomyopathy (DCM) who were receiving optimal medical treatment. METHODS: The data of 491 patients with DCM who were enlisted in the Trieste Heart Muscle Disease Registry were analyzed. Anemia was defined as hemoglobin less than 13 g/dL for male patients and less than 12 g/dL for female patients. RESULTS: At baseline, 13% of our patients were anemic. During the follow-up of 134 +/- 56 months, 144 patients died or underwent heart transplantation: 36.5% anemic patients and 28% non-anemic patients (P = .05). Anemia present at baseline was an independent predictor of outcome (hazard ratio = 1.85, P = .014). Serial hemoglobin determinations during the entire follow-up were available in 122 of 428 patients without anemia at baseline. The impact of new-onset anemia was analyzed in this cohort of patients. Forty-seven patients (39%) developed anemia during follow-up. The new onset of anemia was an independent predictor of poor outcome (hazard ratio = 2.85, P = .02). CONCLUSION: The presence or development of mild anemia in young patients with optimally treated idiopathic DCM is frequent and associated with a worse outcome. PMID- 20723983 TI - Long-term prognosis of transient left ventricular ballooning syndrome and cancer. PMID- 20723984 TI - Actigraphy: analyzing patient movement. AB - BACKGROUND: Actigraphic data during simulated participant movements were evaluated to differentiate among patient behavior states. METHODS: Arm and leg actigraphic data were collected on 30 volunteers who simulated 3 behavioral states (calm, restless, agitated) for 10 minutes; counts of observed participant movements (head, torso, extremities) were documented. RESULTS: The mean age of participants was 34.7 years, and 60% were female. Average movement was significantly different among the states (P < .0001; calm [mean = .48], restless [mean = 2.16], agitated [mean = 3.75]). Mean actigraphic measures were significantly different among states for both arm (P < .0001; calm [mean = 6.8], restless [mean = 28.5], agitated [mean = 52.6]) and leg (P < .0001; calm [mean = 3.5], restless [mean = 18.7], agitated [mean = 37.7]). CONCLUSION: Distinct levels of behavioral states were successfully simulated. Actigraphic data can provide an objective indicator of patient activity over a variety of behavioral states, and these data may offer a standard for comparison among these states. PMID- 20723985 TI - Pregnancy-associated plasma protein predicts outcomes of percutaneous coronary intervention in patients with non-ST-elevation acute coronary syndrome. AB - OBJECTIVE: Pregnancy-associated plasma protein A (PAPP-A) may play an important role in the development of acute coronary syndrome. This study aimed to investigate the relationship between the levels of circulating PAPP-A and the mid term outcomes of percutaneous coronary intervention (PCI) in patients with non-ST elevation acute coronary syndrome. METHODS: The circulating PAPP-A levels and high-sensitivity C-reactive protein before PCI were measured in 129 patients with single coronary artery stenosis. The end point of clinical follow-up was cardiac death, nonfatal myocardial infarction, target vessel revascularization, and rehospitalization for angina. RESULTS: During the follow-up of an average of 20.3 +/- 5.2 months, a cardiac event was recorded in 25 patients (19.4%). The levels of PAPP-A (29.85 +/- 19.51 mIu/L vs 20.47 +/- 14.33 mIu/L, P = .007) and high sensitivity C-reactive protein (5.63 +/- 2.13 mg/L vs 4.11 +/- 1.28 mg/L, P = .014) in patients with cardiac events were higher than in those without cardiac events. PAPP-A >= 11.33 mIu/L has a strong predictive value for a combined end point (risk ratio = 4.1; 95% confidence interval, 1.0-16.2; P = .037). Patients with lower PAPP-A levels (<11.33 mIu/L) had higher event-free survivals than patients with higher PAPP-A levels (log rank = 9.334, P = .025). CONCLUSION: Circulating PAPP-A levels predict the mid-term outcomes of PCI in patients with non-ST-elevation acute coronary syndrome and single-vessel stenosis. PMID- 20723986 TI - Anxiety in patients undergoing percutaneous coronary interventions. AB - OBJECTIVE: Many patients undergoing percutaneous coronary intervention (PCI) experience symptoms of anxiety; however, it is unclear whether anxiety is an issue in the early recovery period and the types of factors and patient concerns that are associated. This study set out to determine the patterns of anxiety and concerns experienced by patients undergoing PCI and the contributing factors in the time period surrounding PCI. METHODS: A convenience sample of patients undergoing PCI (n = 100) were recruited, and anxiety was measured using the Spielberger State Anxiety Inventory immediately before the PCI, the first day postprocedure, and 1 week postdischarge. Patients were also asked to identify their most important concern at each time. Independent predictors of anxiety at each time were determined by multiple regression analysis. RESULTS: Anxiety scores were highest pre-procedure (35.72, standard deviation [SD] 11.75), decreasing significantly by the postprocedure time (31.8, SD 10.20) and further still by the postdischarge time (28.79, SD 9.78) (repeated-measures analysis of variance: F = 39.72, P < .001). The concerns patients identified most frequently as most important were the outcome of the PCI and the possibility of surgery pre procedure (37%) and postdischarge (31%), and the limitations and discomfort arising from the access site wound and immobility postprocedure (25%). The predictor of anxiety at the pre-procedure time was taking medication for anxiety and depression (b = 7.12). The predictors of anxiety at the postprocedure time were undergoing first-time PCI (b = 4.44), experiencing chest pain (b = 7.63), and experiencing pre-procedural anxiety (b = .49). The predictors of anxiety at the postdischarge time were reporting their most important concern as the future progression of CAD (b = 7.51) and pre-procedural anxiety (b = .37). CONCLUSION: Symptoms of anxiety were common, particularly before PCI. These symptoms are important to detect and treat because pre-procedural anxiety is predictive of anxiety on subsequent occasions. Patients who have had chest pain or their first PCI should be targeted for intervention during the early recovery period after PCI, and information on CAD should be provided postdischarge. PMID- 20723987 TI - Effects of five parent-and-child risk factors on salivary cortisol levels and symptoms of posttraumatic stress disorder in school-age, critically ill children: pilot study. AB - OBJECTIVE: We examined the contributions of risk factors to the psychological and neuroendocrine status of children admitted to a pediatric intensive care unit (PICU), and explored the feasibility of a full-scale study of these risk factors. METHODS: A prospective, correlational design was used. Risk factors included parental stress, parental anxiety, child anxiety, severity of the child's illness, and invasive procedures administered to the child. Outcomes variables were pediatric posttraumatic stress disorder (PTSD) symptoms and salivary cortisol levels. Measures were taken at 3 time points over 3 months. RESULTS: The mothers' state anxiety significantly increased over time, whereas the children's PTSD symptoms decreased. Most children with average or high anxiety demonstrated varying degrees of PTSD symptomatology, whereas children with low anxiety exhibited doubtful or mild symptoms of PTSD. As the severity of PTSD symptoms increased over time, the level of salivary cortisol decreased at two weeks and three months after hospital discharge. CONCLUSIONS: Predicted trends in data were found and warrant further investigation, using a similar methodology in a full scale study with an emphasis on recruiting the most seriously ill children. PMID- 20723988 TI - Polychlorinated biphenyls (PCB-153) and (PCB-77) absorption in human liver (HepG2) and kidney (HK2) cells in vitro: PCB levels and cell death. AB - An understanding of congener specific cellular absorption of PCBs is important to the study of the organ specific body burden of an individual and to their toxic effects. We have previously demonstrated that single PCB congeners induce cytotoxicity, as evidenced by decreased cellular viability and accelerated apoptotic death. There is very little, if any, information available on the differences in toxicity due to the nature of absorption of PCBs in different cells. To obtain such information human liver (HepG2) cells (in medium with 10% FBS) were exposed to 70 MUM of both PCB-153 (non-coplanar hexachlorobiphenyl) and PCB-77 (coplanar tetrachlorobiphenyl), and human kidney (HK2) cells in serum free medium were exposed to 80 and 40 MUM of PCB-153 and PCB-77 respectively, according to their LC(50) values in these cells. Medium and cells were collected separately at each time interval from 30 min to 48 h, and PCB concentrations were analyzed in both by GC-MS using biphenyl as an internal standard following hexane:acetone (50:50) extraction. We also performed trypan blue exclusion, DNA fragmentation and fluorescence microscopic studies in assessing cell viability and apoptotic cell death. About 40% of PCB-153 (35 MUM, 50% of the maximum value) was detected in HepG2 cells within 30 min, and it reached its highest concentration at 6h (60 MUM), concomitant with the PCB depletion in the medium (5 MUM). For PCB-77, the highest concentrations within the cells were reached at 3h. However, the absorption levels of PCB-153 and PCB-77 in HK2 cells reached their peaks at 3 and 6h respectively. Exposure of human liver and kidney cells to PCB 153 and PCB-77 caused accelerated apoptotic cell death in a time-dependent manner. The studies demonstrated that (1) liver cells initiate the absorption of PCBs much faster than kidney cells; however, the concentration reaches its maximum level much earlier in kidney cells; (2) both PCB-153 and PCB-77 induced enhanced apoptotic death in liver and kidney cells; and (3) kidney cells are more vulnerable to PCBs based on the results of apoptosis and cellular viability, even with almost similar absorption or tissue burden of PCBs. PMID- 20723989 TI - A physicist at Woods Hole: introducing the image intensifier and image processing to cell biology. AB - In 1963, by invitation, particle physicist George Reynolds (Princeton University) brought an image intensifier to Woods Hole Marine Biological Laboratory. Together, he and a group of biologists began experimenting with the device as a way to create images of cells in low-light level situations, especially in the study of bioluminescence. In this paper I am interested in how the scientists, a physicist and biologists in collaboration, assessed, interpreted and presented the pictures that they created with the aid of image intensification. In particular, I consider the problem of 'noise' in the image. The paper ends with an example of how Reynolds and a biologist at Woods Hole contended with the presence of noise in images used for publication. Here is an example of how data is modified, that is, enhanced, to serve as scientific evidence. By presenting an early and simple case of the altered image I reveal one way scientists addressed the potentiality of presenting inappropriately modified data - a concern that has garnered much attention in the current age of digital imaging technologies. PMID- 20723990 TI - Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. AB - PURPOSE: To evaluate prognostic factors based on origin of conjunctival melanoma. DESIGN: Interventional case series. PARTICIPANTS: Three hundred eighty-two consecutive patients. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Melanoma-related metastasis and death. RESULTS: The melanoma arose from primary acquired melanosis (PAM; n = 284; 74%), from pre-existing nevus (n = 26; 7%), and de novo (n = 72; 19%). The mean tumor base was 11 mm for melanoma arising from PAM, 6 mm for melanoma arising from nevus, and 10 mm for those arising de novo. At 5 years (10 years), melanoma metastasis occurred in 19% (25%) in melanoma arising from PAM (P = 0.003), 10% (26%) in melanoma from nevus (P = 0.193), and 35% (49%) in those de novo. Factors predictive of metastasis by multivariable analysis included tumor origin de novo (P = 0.001), palpebral location (P<0.001), nodular tumor (P = 0.005), and orbital invasion (P = 0.022). At 5 years (10 years), melanoma-related death occurred in 5% (9%) in melanoma arising from PAM (P<0.001), 0% (9%) in melanoma arising from nevus (P<0.057), and 17% (35%) in those arising de novo. Factors predictive of death by multivariable analysis included tumor origin de novo (P<0.001), fornix location (P = 0.04), and nodular tumor (P = 0.001). CONCLUSIONS: Melanoma arising de novo carries a higher risk of melanoma-related metastasis and death compared with those cases arising from PAM or nevus. PMID- 20723991 TI - Natural history of visual outcome in central retinal vein occlusion. AB - OBJECTIVE: To investigate systematically the natural history of visual outcome in central retinal vein occlusion (CRVO). DESIGN: Cohort study. PARTICIPANTS: Six hundred sixty-seven consecutive patients (30 patients had both eyes involved resulting in 697 eyes) with CRVO first seen in the authors' clinic from 1973 through 2000. METHODS: At the first visit, all patients underwent a detailed ophthalmic and medical history and a comprehensive ophthalmic evaluation. Visual evaluation was carried out by recording visual acuity, using the Snellen visual acuity chart, and assessing visual fields with a Goldmann perimeter. The same ophthalmic evaluation was performed at each follow-up visit. Central retinal vein occlusion was classified into nonischemic (588 eyes) and ischemic (109 eyes) types at the initial visit based on functional and morphologic criteria. MAIN OUTCOME MEASURES: Visual acuity and visual fields. RESULTS: Of the eyes first seen within 3 months, visual acuity was 20/100 or better in 78% with nonischemic CRVO and in only 1% with ischemic CRVO (P < 0.0001), and visual field defects were minimal or mild in 91% and 8%, respectively (P < 0.0001). Final visual acuity, on resolution of macular edema, was 20/100 or better in 83% with nonischemic CRVO and in only 12% with ischemic CRVO (P < 0.0001), and visual field defects were minimal or mild in 95% and 18%, respectively (P < 0.0001). On resolution of macular edema, in eyes with initial visual acuity of 20/70 or worse, visual acuity improved in 59% with nonischemic CRVO, with no significant (P = 0.55) improvement in ischemic CRVO. Similarly, on resolution of macular edema, in eyes with moderate to severe initial visual field defect, improvement was seen in 86% of nonischemic CRVO eyes, but no significant (P = 0.83) improvement was seen in eyes with ischemic CRVO. In nonischemic CRVO, development of foveal pigmentary degeneration, epiretinal membrane, or both, was the main cause of poor final visual acuity. This shows that initial presentation and the final visual outcome in the 2 types of CRVO are entirely different. CONCLUSIONS: A clear differentiation of CRVO into nonischemic and ischemic types, based primarily on functional criteria, is crucial and fundamental in determining visual outcome. Visual outcome is good in nonischemic CRVO and poor in ischemic CRVO. PMID- 20723992 TI - Interobserver agreement and intraobserver reproducibility of the subjective determination of glaucomatous visual field progression. AB - PURPOSE: To determine the extent of interobserver agreement and intraobserver reproducibility of the subjective determination of visual field progression with achromatic automated static perimetry in eyes with glaucoma, and to determine the impact of access to Glaucoma Progression Analysis (GPA) data on interobserver agreement. DESIGN: Retrospective, observational case series. PARTICIPANTS: Five glaucoma subspecialists from 5 different academic medical centers. METHODS: Five visual field tests from each of 100 eyes of 83 patients being monitored for glaucoma were retrospectively identified and subjectively and independently evaluated by the 5 glaucoma subspecialists. Each set of visual fields was classified regarding progression as "none," "questionable," "probable," or "definite." More than 1 month later, the same expert observers reevaluated the same sets of visual field tests to allow determination of intraobserver reproducibility. A final subjective evaluation regarding progression was performed 3 months later, at which time the expert observers had access to the GPA printout. MAIN OUTCOME MEASURES: The level of interobserver agreement and intraobserver reproducibility was estimated using kappa statistics on the raw classification data and also on dichotomized data in which "none" and "questionable" progression were reclassified together as nonprogressed and " probable" and "definite" were reclassified as progressed. RESULTS: Intraobserver reproducibility was good to excellent (kappa = 0.62-0.78) for the raw data and moderate to good (kappa = 0.58-0.71) for the dichotomized data. Interobserver agreement was moderate (kappa = 0.45; 95% confidence interval [CI], 0.35-0.55) for the raw classification data and also for dichotomized data (kappa = 0.55; 95% CI, 0.46-0.64). Access to the GPA printout did not significantly change the level of interobserver agreement. CONCLUSIONS: Five glaucoma experts had good to excellent reproducibility of the determination of visual field progression compared with earlier evaluation of the same field sets. Agreement among the experts with each other was only moderate, and did not improve when each had access to GPA results. . PMID- 20723993 TI - Optical coherence tomographic evaluation of foveal hard exudates in patients with diabetic maculopathy accompanying macular detachment. AB - OBJECTIVE: To study morphologic changes of serous retinal detachment (SRD) and hyperreflective dots, which have been reported to be precursors of hard exudates, detectable in SRD using optical coherence tomography (OCT) to assess whether or not the OCT findings are correlated with the subfoveal deposition of hard exudates in patients with diabetic macular edema (DME) accompanied by SRD. DESIGN: Retrospective chart review. PARTICIPANTS: Twenty-eight eyes of 19 patients with DME accompanied by SRD. METHODS: We imaged SRD and the hyperreflective dots in SRD using spectral domain OCT (SD-OCT). The number and distribution of the hyperreflective dots in SRD were evaluated before the initial treatment at our hospital for DME accompanied by SRD. Based on a difference in the SD-OCT findings, the study eyes were divided into 2 groups: eyes with a few dots and those with many dots. We studied the clinical course of these 2 groups to assess whether or not the findings of SRD and hyperreflective dots on the SD OCT images were correlated with deposition of hard exudates in the subfoveal space during follow-up. MAIN OUTCOME MEASURES: Correlation of the SD-OCT findings of SRD and hyperreflective dots with deposition of hard exudates in the subfovea of patients with DME accompanied by SRD. RESULTS: Subfoveal deposition of hard exudates was seen in 11 of the 28 eyes at the final examination. Before initial treatment at our hospital, 14 eyes had a few hyperreflective dots SRD and 14 eyes had many hyperreflective dots. Whereas no deposition of hard exudates in the subfoveal space was seen in the former eyes, it was seen in 11 of the latter 14 eyes (P < 0.0001). In addition, using SD-OCT, we found discontinuity of the outer border of detached neurosensory retina in 9 of the 28 eyes. Of these 9 eyes, 1 was in the group with few hyperreflective dots and eight were in the group with many hyperreflective dots (P = .0046). CONCLUSIONS: In patients with DME accompanied by SRD, SD-OCT revealed that hyperreflective dots may be associated with the subfoveal deposition of hard exudates during follow-up. PMID- 20723994 TI - Development and validation of clinical scores for visual outcomes after cataract surgery. AB - PURPOSE: To develop and validate a clinical score to predict visual acuity (VA) and functional changes after phacoemulsification on the basis of readily obtainable preoperative history data and patient assessment. DESIGN: Prospective follow-up study. PARTICIPANTS: A sample of 5512 patients on waiting lists for phacoemulsification at 17 hospitals in Spain. METHODS: Data were obtained at the baseline examination from the 5512 patients. The patients were divided randomly into 2 subgroups: derivation (n = 3285; 60%) and validation (n = 2227; 40%). The preoperative predictors of postoperative gains in VA and visual function index 14 (VF-14) were determined by multivariate logistic regression analysis and implemented using a prediction score. MAIN OUTCOME MEASURES: Probability of postoperative improvement in VA and VF-14 scores. The cutoff points were established for each outcome on the basis of the minimal clinically important difference values. RESULTS: The predictive variables for VA gain were the baseline VA, patient age, ocular comorbidity, and surgical complexity. Regarding the VF-14, the predictive factors were the preoperative VF-14, the eye with the better VA, and the surgical complexity. In the multivariate logistic model in the derivation sample, the final VA and VF-14 scores ranged from 0 to 44 and from 0 and 24, respectively. Receiver operating characteristic curves were developed in the derivation and validation samples, and no statistical significance was found when their areas under the curve were compared. Areas under the curve ranged from 65% to 80%. Both scores had a positive predictive value from 74% to 85%. CONCLUSIONS: Newly developed and validated clinical prediction scores may assist physicians and patients in decision making about the expected outcomes and benefits of cataract surgery. PMID- 20723995 TI - Endothelial keratoplasty: the relationship between donor tissue storage time and donor endothelial survival. AB - PURPOSE: To evaluate the relationship between storage time in Optisol GS (Bausch & Lomb, St. Louis, MO) and postoperative cell loss after Descemet's stripping automated endothelial keratoplasty (DSAEK) surgery. DESIGN: Retrospective analysis of a noncomparative, interventional case series. PARTICIPANTS: Three hundred sixty-two eyes of 265 patients undergoing DSAEK surgery for Fuchs' endothelial dystrophy. METHODS: Storage times (death to surgery) of donor tissue were recorded for 362 eyes undergoing DSAEK surgery. Donor cell loss at 6, 12, and 24 months was recorded. Analysis of storage times with endothelial cell loss was performed using a Pearson correlation coefficient and an independent samples Student t test. MAIN OUTCOME MEASURES: Percentage of donor endothelial cell loss as measured by specular microscopy of central endothelial cell density (ECD). RESULTS: The mean storage time was 98.95 +/- 33 hours (range, 20.65-186.02 hours). The mean percent endothelial cell loss from before to after surgery was 29 +/- 16% at 6 months (n = 362), 31 +/- 16% at 12 months (n = 263), and 32 +/- 20% at 24 months (n = 98). Storage time did not correlate significantly with endothelial cell loss at any postoperative time point (6 months: r = -0.047, P = 0.373; 12 months: r = -0.023, P = 0.709; 24 months: r = -0.14, P = 0.169). The mean cell loss for corneas stored 0 to 4 days (n = 55) was 32 +/- 17% at 2 years and the mean cell loss for corneas stored for more than 4 days (n = 43) was 30 +/ 18% at 2 years (P = 0.57). At the extremes of storage time, 10 corneas stored for the shortest time (1.5 days) had a 1-year cell loss of 33% and 10 corneas stored for the longest time (7 days) had a 1-year cell loss of 30% (P = 0.45). CONCLUSIONS: No correlation was found between the characteristic of storage time and the decline of ECD. Surgeons should not make special requests to the eye bank for short storage times with the hope of improving donor endothelial survival. The upper limit of donor storage time as it relates to acceptable postoperative endothelial cell loss is not known. PMID- 20723996 TI - Split cornea transplantation for 2 recipients: a new strategy to reduce corneal tissue cost and shortage. AB - PURPOSE: To evaluate the feasibility of using a single donor cornea for 2 recipients by combining deep anterior lamellar keratoplasty (DALK) and Descemet's membrane endothelial keratoplasty (DMEK) surgeries on the same day. DESIGN: Single-center, nonrandomized, prospective, interventional case series. PARTICIPANTS: Twelve consecutive donor corneas were scheduled for split cornea transplantation combining DALK for a keratoconus patient and DMEK for a Fuchs' endothelial dystrophy patient on the same surgery day. METHODS: First, a big bubble DALK procedure was performed for the keratoconus eye. When bare Descemet's membrane was prepared successfully requiring no conversion to penetrating keratoplasty (PK), then during surgery the donor, endothelium-Descemet's membrane layer was removed and stored for subsequent DMEK in a second patient, and the remaining anterior lamella of the donor cornea was used to complete the DALK surgery. Afterward, a DMEK procedure was performed on the second patient with Fuchs' endothelial dystrophy, grafting the stored endothelium-Descemet's membrane layer of the original donor button. MAIN OUTCOME MEASURES: Success of using a single donor cornea for 2 recipient eyes, best spectacle-corrected visual acuity (BSCVA), and complication rates within 6 months follow-up. RESULTS: A single donor cornea could be used for 2 recipients in 10 of 12 donor buttons (83%). In 2 cases (17%), the DALK procedure had to be converted to PK requiring a full thickness corneal graft. Therefore, 10 donor corneas (45%) could be saved. Six months after surgery, mean BSCVA was 20/35 (range, 20/50-20/25) in 10 eyes that underwent successful DALK, 20/50 (range, 20/63-20/40) in 2 eyes that underwent conversion from DALK to PK, and 20/31 (range, 20/50-20/16) in 10 eyes that underwent DMEK. Postoperative complications after DALK included Descemet's folds in 3 eyes (30%) and epitheliopathy in 2 eyes (20%). After DMEK, partial graft detachment occurred in 5 eyes (50%) and was managed successfully with intracameral air reinjection. All corneas remained clear up to 6 months after surgery. CONCLUSIONS: Split use of donor corneal tissue for combined DALK and DMEK procedures in 2 recipients on the same surgery day is a promising strategy to reduce donor shortage and cost in corneal transplantation surgery in the future. PMID- 20723997 TI - Infants' social withdrawal symptoms assessed with a direct infant observation method in primary health care. AB - Distressed infants may withdraw from social interaction, but recognising infants' social withdrawal is difficult. The aims of the study were to see whether an infant observation method can be reliably used by front line workers, and to examine the prevalence of infants' social withdrawal symptoms. A random sample of 363 families with four, eight or 18-month-old infants participated in the study. The infants were examined by general practitioners (GPs) in well-baby clinics with the Alarm Distress BaBy Scale (ADBB), an observation method developed for clinical settings. A score of five or more on the ADBB Scale in two subsequent assessments at a two-week interval was regarded as a sign of clinically significant infant social withdrawal. Kappas were calculated for the GPs' correct rating of withdrawn/not withdrawn against a set of videotapes rated by developer of the method, Professor Guedeney and his research group. The kappas for their ratings ranged from 0.5 to 1. The frequency of infants scoring above the cut off in two subsequent assessments was 3%. The ADBB Scale is a promising method for detecting infant social withdrawal in front line services. Three percents of infants were showing sustained social withdrawal as a sign of distress in this normal population sample. PMID- 20723998 TI - Maternal sleep and depressive symptoms: links with infant Negative Affectivity. AB - This study assessed whether elevated severities of maternal depression and disturbed maternal sleep would be associated with maternal perceptions of higher Negative Affectivity of her infant. Sixty-nine mothers participated in this study. The study was part of a larger randomized controlled study testing the efficacy of acupuncture as a treatment for depression during pregnancy. The present study focused on data collected at 6 months postpartum in a naturalistic follow-up design, using the Hamilton Rating Scale for Depression (HRSD), maternal sleep diaries (completed daily for 1 week), and the Infant Behavior Questionnaire Revised (IBQ-R). Regression analyses revealed that (a) maternal depression severity was a significant predictor of the IBQ-R Distress and Falling Reactivity scales and (b) poor maternal sleep was a significant predictor of the IBQ-R Sadness scale. Our findings support previous findings of significant links between maternal emotional distress and perceived Negative Affectivity of her infant's temperament and provide a novel insight linking maternal poor sleep with perceived sadness of the infant. PMID- 20723999 TI - Maternal and child correlates of anxiety in 21/2-year-old children. AB - The goal of this study was to predict the development of anxiety in 21/2 year olds as a function of maternal anxiety and child inhibited temperament, and to test the mediating, moderating, and curvilinear effects of maternal sensitivity. Participants were 83 mothers and their 21/2-year-old children (32 females). Maternal anxiety, child inhibition, and child anxiety were assessed by maternal report. Maternal sensitivity was rated based on the appropriateness and timeliness of mothers' responses to children's fear observed during their exposure to novel events in the laboratory and from mothers' diaries documenting their responses to children's fear in everyday situations. Gender predicted child anxiety, with mothers reporting girls as more anxious, as did child inhibition, with more inhibited children exhibiting more anxiety. Maternal sensitivity predicted child anxiety as a main effect and, in addition, inhibition moderated the curvilinear association of maternal sensitivity and child anxiety. For highly inhibited children, maternal sensitivity predicted anxiety in both a negative linear and a curvilinear fashion; anxiety decreased as maternal sensitivity increased up to a moderately high level, then increased at very high levels of maternal sensitivity. For less inhibited children, maternal sensitivity showed only a significant negative linear association with child anxiety. PMID- 20724000 TI - Childhood physical abuse, aggression, and suicide attempts among criminal offenders. AB - Childhood physical abuse (CPA) has numerous short and long-term negative effects. One of the most serious consequences of CPA is an increased risk for suicide attempts. Clarifying the mechanisms by which CPA increases risk for suicidal behavior may enhance preventive interventions. One potential mechanism is a tendency toward aggression. In a sample of 266 criminal offenders, ages 18-62, we examined the relationships among CPA, lifetime aggression, and suicide attempts and tested lifetime history of aggression as a mediator of the relationship between CPA and suicide attempts. Results indicated that CPA and aggression were associated with suicide attempts. Consistent with our hypothesis, lifetime aggression mediated the CPA and suicide attempts relationship. Findings suggest that aggression may be an important mediator of the relationship between CPA and suicide attempts among criminal offenders, and are consistent with the possibility that treating aggression may reduce risk for suicide attempts. PMID- 20724001 TI - Assessing relational schemas in parents of children with externalizing behavior disorders: reliability and validity of the Family Affective Attitude Rating Scale. AB - Direct observational assessment of parent-child interaction is important in clinical intervention with conduct-problem children, but is costly and resource intensive. We examined the reliability and validity of a brief measure of parents' relational schemas (RSs) regarding their child. Children (aged 4 to 11years) and their families receiving treatment at a clinic for externalizing behavior problems (n=150) or mood/developmental disorders (n=28) were assessed using a multi-method, multi-informant procedure. RSs were coded from Five-Minute Speech Samples (FMSS) using the Family Affective Attitude Rating Scale (FAARS), and were compared with directly observed parent-child interaction and questionnaire measures of family and parental dysfunction and conduct problems. Mothers' and fathers' RS scales were internally consistent and could be reliably coded in under 10min. Less positive RSs and more negative RSs were associated with higher rates of child conduct problems, and were more characteristic of the speech samples of parents of children with externalizing disorders, compared with clinic control parents. RSs demonstrated some associations with parenting behavior and measures of family functioning and symptoms of parental psychopathology, and predicted conduct problems independently of observed parental criticism. The results demonstrate the reliability and validity of the FAARS assessment of parental RSs in clinic-referred families. This brief measure of parent-child dynamics appears well-suited to 'real-world' (i.e., community) clinical settings in which intensive methods of observation are often not feasible. PMID- 20724002 TI - Mental illness, gender and homicide: a population-based descriptive study. AB - In England and Wales, a lifetime history of mental disorder is recorded in almost a third of homicides but mental illness as a defence in homicide cases has recently come under review. In this study, we aimed to compare the social, criminological and clinical characteristics of women and men convicted of homicide and secondly, to understand how pathways through the judicial system differ by gender of the perpetrator, characteristics of the offence and mental illness. A cross sectional study of 4572 convicted homicide perpetrators in England and Wales 1997-2004 was performed. Significantly more women who had committed homicide had a lifetime history of mental illness and were more likely to be mentally ill at the time of offence compared to men. Women more often received non-custodial sentences, whether or not they had mental illness. If the victim were a child or other relative, the courts were more lenient with women. Gender and the presence of mental illness both influence the characteristics of homicide and outcome of the legal process in the UK. Our findings suggest that all perpetrators of homicide should have a psychiatric assessment pre-trial. Psychiatrists need to rate risk objectively in a gender blind way when providing psychiatric reports to be used as evidence in court. PMID- 20724003 TI - Decreased self-reported arousal in schizophrenia during aversive picture viewing compared to bipolar disorder and healthy controls. AB - Both schizophrenia (SCZ) and bipolar disorder (BD) are associated with disturbances in emotion processing. Previous studies suggest that patients with SCZ assess unpleasant pictures as less arousing than healthy controls (HC), while patients with BD assess neutral pictures as more arousing than HC. No previous studies have investigated whether there is a difference in emotional response across all three groups. Our aim was to explore whether there was a difference in the evaluation of valence and in arousal between SCZ, BD and HC for aversive and neutral pictures. We showed 72 pictures (neutral, non-socially aversive and socially aversive) from the International Affective Picture System (IAPS) to 347 subjects. There was a clear interaction effect between the diagnostic group and increasing picture aversiveness for both valence and arousal. There were no significant differences in valence ratings between the different groups or in arousal ratings on any type of stimuli between BD patients and HC. However, SCZ patients reported significantly lower arousal for aversive stimuli, particularly with a social content, when compared to BD patients and HC. This was more pronounced in females. The presence of lifetime psychotic symptoms did not influence emotional responses. PMID- 20724004 TI - Prevalence, correlates, and comorbidities of adult ADHD symptoms in Korea: results of the Korean epidemiologic catchment area study. AB - We examined the prevalence, correlates, and comorbidities of adult attention deficit hypersensitivity disorder (ADHD) symptoms in a Korean community using data from the National Epidemiological Survey of Psychiatric Disorders in Korea conducted in 2006. A total of 6081 subjects aged 18 to 59 years participated in this study. Diagnostic assessments were based on the Adult ADHD Self-Report Scale Screener and Composite International Diagnostic Interview administered by lay interviewers. The frequencies of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) disorders, sleep disturbances, and suicidal tendency were compared in the ADHD and non-ADHD groups. Odds ratios and significance levels were calculated. The 6 month prevalence of adult ADHD symptoms was 1.1%. Associations between ADHD symptoms and alcohol abuse/dependence, nicotine dependence, mood disorders, major depressive disorder, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, post traumatic stress disorder, social phobia, specific phobia, somatoform disorder, sleep disturbances, and suicidality were overwhelmingly positive and significant (P<0.05), after controlling for gender and age. Adult ADHD symptoms are highly associated with substance abuse, mood and anxiety disorders, somatoform disorders, sleep disturbances and suicidality, suggesting that clinicians should carefully evaluate and treat such psychiatric disorders in adults with ADHD symptoms. PMID- 20724005 TI - Allelic diversity at MHC class II DQ loci in buffalo (Bubalus bubalis): evidence for duplication. AB - The genetic diversity of MHC class II DQ genes was investigated in riverine buffalo (Bubalus bubalis) by PCR-RFLP and sequencing. Highly variable regions (exons 2-3) of DQ genes were amplified from 152 buffaloes and genotyped by PCR RFLP. Alleles identified by differential restriction patterns were sequenced for the characterization. PCR-RFLP was a rapid method to discriminate between DQA1 and duplicated DQA2 genes in buffalo, however, the method appeared to be inadequate for determining the more complicated DQB genotypes. A total of 7 and 10 alleles were identified for DQA and DQB loci, respectively. Nucleotide as well as amino acid variations among DQ alleles particularly at peptide binding regions were high. Such variations were as expected higher in DQB than DQA alleles. The phylogenetic analysis for both genes revealed the grouping of alleles into two major sub-groups with higher genetic divergence. High divergence among DQ allelic families and the isolation of two diverse DQA and DQB sequences from individual samples indicated duplication of DQ loci was similar in buffalo to other ruminants. PMID- 20724006 TI - In vitro and in vivo induction and activation of nNOS by LPS in oligodendrocytes. AB - There are currently four known isoforms of nitric oxide synthase (NOS). Of these, neuronal NOS (nNOS) is known to be present exclusively in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. The fourth isoform, mitochondrial NOS (mtNOS), represents a post-translational modification of nNOS. Using western blotting and real time-PCR, we show induction and activation of nNOS following culture of oligodendrocyte progenitor cells (OPC) with lipopolysaccharide (LPS). Activation of nNOS results in accumulation of peroxynitrite and tyrosine nitration of proteins in oligodendrocytes resulting in reduced cell viability. Injection of LPS in vivo into the corpus callosum of rats leads to the development of extensive demyelination of the white matter tracts. Immunostaining of regions close to the injection site shows the presence of nNOS, but not iNOS, in oligodendrocytes. Neither iNOS nor nNOS was seen in astrocytes in areas of demyelination. These studies suggest that activation of nNOS in oligodendrocytes leads to oligodendrocyte injury resulting in demyelination. PMID- 20724007 TI - The role of measurement of serum autoantibodies in prediction of pediatric neuropsychiatric systemic lupus erythematosus. AB - Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most difficult manifestations of lupus to diagnose. Measurement of serum brain antibodies has contributed to early diagnosis and management of NPSLE before development of a debilitating disease. We aimed to assess the value of serum anti ganglioside M1 antibodies in prediction of NPSLE, in comparison to other antibodies used in routine laboratory diagnosis of NPSLE. In addition, we are the first to study the relationship between these antibodies and cognitive function in lupus patients. Serum anti-ganglioside M1, anti-ribosomal P protein and anti cardiolipin antibodies were measured in 30 lupus patients without clinical evidence of NPSLE, aged 8-16 years, and 30 healthy matched-subjects. Patients were followed-up clinically by monthly neuropsychiatric evaluation and assessment of cognitive function for 12 months. Twelve patients developed neuropsychiatric manifestations during follow-up. Of those patients, 83.3%, 50% and 16.7% were seropositive for anti-ganglioside M1, anti-ribosomal P and anti-cardiolipin antibodies, respectively at the time of initial evaluation before clinical presentation of NPSLE. There was a significant positive association between anti ganglioside seropositivity and cognitive dysfunction (P<0.001). In addition, anti ganglioside seropositivity had a significant risk for association with cognitive dysfunction (odds ratio: 36; 95% CI: 4.3-302.8). CONCLUSIONS: Serum anti ganglioside M1 antibodies had a higher predictive value for NPSLE than other antibodies used in routine laboratory diagnosis of this disease. Thus, they may be reliable parameters for early diagnosis and management of NPSLE before clinical manifestations ensue. In addition, anti-ganglioside M1 antibodies may play a role in cognitive dysfunction found in some lupus patients. PMID- 20724008 TI - Intracerebroventricular injection of an agonist-like monoclonal antibody to adenosine A(2A) receptor has antinociceptive effects in mice. AB - Adenosine is a modulator of nociceptive pathways, both at the spinal and supraspinal levels. Adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R) are expressed in the basal ganglia where they are the target of caffeine, the most widely use psychoactive drug which acts as an antagonist to both types of receptors. Given the controversial role of A(2A)R versus A(1)R in modulating pain in brain areas, mice received intracerebroventricular injection of Adonis, an agonist-like monoclonal antibody with high specificity for the A(2A)R and were subjected to behavioral tests investigating nociceptive thresholds. We report that Adonis led to a significant dose-dependent increase in hot-plate and tail flick latencies in mice and that such increase was prevented by caffeine and ZM 241385, a specific A(2A)R antagonist. The Adonis antinociceptive effects were also inhibited by naloxone, a non selective antagonist for opioid receptors, suggesting that Adonis acts, at least in part, through the stimulation of the endogenous opioid system. These results confirm the A(2A)R as a target for pain control and Adonis as a potential drug with therapeutic interest. PMID- 20724009 TI - Evolutionary inspirations for drug discovery. AB - Conceptual innovations are needed to address the challenge of 'more investments, fewer drugs' in the pharmaceutical industry. Since the publication of The Origin of Species by Charles Darwin 150 years ago, evolution has been a central concept in biology. In this article, we show that evolutionary concepts are also helpful to streamline the drug-discovery pipeline through facilitating the discovery of targets and drug candidates. Furthermore, the antioxidant paradox can be addressed by an evolutionary methodology. Through examining the evolved biological roles of natural polyphenols (which dominate current antioxidant drug discovery), we reveal that polyphenols (particularly flavonoids) are not evolved for scavenging free radicals. This finding provides new clues to understanding why the strong in vitro antioxidant activities of polyphenols cannot be translated into in vivo effects. Polyphenols have evolved a superior ability to bind various proteins, so we also argue that they are good starting points for multi-target drugs. PMID- 20724010 TI - Nanosilver as a new generation of nanoproduct in biomedical applications. AB - Nanosilver (NS), comprising silver nanoparticles, is attracting interest for a range of biomedical applications owing to its potent antibacterial activity. It has recently been demonstrated that NS has useful anti-inflammatory effects and improves wound healing, which could be exploited in developing better dressings for wounds and burns. The key to its broad-acting and potent antibacterial activity is the multifaceted mechanism by which NS acts on microbes. This is utilized in antibacterial coatings on medical devices to reduce nosocomial infection rates. Many new synthesis methods have emerged and are being evaluated for NS production for medical applications. NS toxicity is also critically discussed to reflect on potential concerns before widespread application in the medical field. PMID- 20724011 TI - Detection of radiation-induced lung injury in non-small cell lung cancer patients using hyperpolarized helium-3 magnetic resonance imaging. AB - PURPOSE: To compare hyperpolarized helium-3 magnetic resonance imaging ((3)He MRI) acquired from non-small cell lung cancer (NSCLC) patients before and after external beam radiotherapy (EBRT). METHODS AND MATERIALS: In an Ethics Committee approved prospective study, five patients with histologically confirmed NSCLC gave written informed consent to undergo computed tomography (CT) and (3)He-MR ventilation imaging 1 week prior to and 3 months after radiotherapy. Images were registered to pre-treatment CT using anatomical landmark-based rigid registration to enable comparison. Emphysema was graded from examination of the CT. MRI defined ventilation was calculated as the intersection of (3)He-MRI and CT lung volume as a percentage of the CT lung volume for the whole lung and regions of CT defined pneumonitis. RESULTS: On pre-treatment images, there was a significant correlation between the degree of CT-defined emphysema and (3)He-MRI whole lung ventilation (Spearman's rho=0.90, p=0.04). After radiation therapy, pneumonitis was evident on CT for 3/5 patients. For these cases, (3)He-MRI ventilation was significantly reduced within the regions of pneumonitis (pre: 94.1+/-2.2%, post: 73.7+/-4.7%; matched pairs Student's t-test, p=0.02, mean difference=20.4%, 95% confidence interval 6.3-34.6%). CONCLUSIONS: This work demonstrates the feasibility of detecting ventilation changes between pre- and post-treatment using hyperpolarized helium-3 MRI for patients with NSCLC. Pre-treatment, the degree of emphysema and (3)He-MRI ventilation were correlated. For three cases of radiation pneumonitis, (3)He-MRI ventilation changes between pre- and post treatment imaging were consistent with CT evidence of radiation-induced lung injury. PMID- 20724012 TI - Which alpha/beta ratio and half-time of repair are useful for predicting outcomes in prostate cancer? AB - PURPOSE: To calculate the alpha/beta of prostate adenocarcinoma. MATERIALS AND METHODS: From January 1997 to December 2005, 328 patients were treated consecutively with external beam radiotherapy and brachytherapy boost. The patients with at least one of the following adverse prognostic factors were included: PSA>10 ng/ml, Gleason score >=7, T>=2B. A total EQD2 of 80 Gy was delivered uniformly within the same timeframe. Prior to August 2002, the patients were treated to low-dose-rate brachytherapy using (192)Ir (n=201), and those treated thereafter received a high-dose-rate brachytherapy boost (n=127). The equivalency of dose was established using the incomplete repair model, with generally accepted alpha/beta ratio of 3 Gy, and half-time for repair of sublethal damage (HTR) of 1.5h. RESULTS: In a Cox proportional hazards model, the two groups displayed no difference (HR: 0.99, 95% CI: 0.87-1.1, p=0.98) in biochemical control. Analyzing using the linear quadratic model, the data fit well an alpha/beta ratio of 3.41 Gy (95% CI: 2.56-4.26) and the recently published HTR of 1.9 h (95% CI: 1.4-2.4), but also an alpha/beta of 5.87 Gy (95% CI: 4.67-7.07) and the more widely established HTR of 1.5 h. CONCLUSIONS: Unlike the previously published data, calculation of the alpha/beta ratio from consecutive patients and using a uniform treatment duration points to higher values than 2.5 Gy. PMID- 20724013 TI - PET radiopharmaceuticals in radiation treatment planning - synthesis and biological characteristics. AB - During the last decade several different PET radiopharmaceuticals entered into the clinic and positron emission tomography (PET) became an important tool for staging of cancer patients and assessing response to therapy. Meanwhile FDG-PET has also found application in radiation treatment planning. Potential radiopharmaceuticals for radiation treatment planning may also include tracers allowing monitoring of proliferation, amino acid metabolism, hypoxia, lipid metabolism and receptor expression. Here the syntheses of a selection of clinically tested promising tracers are summarized and the different molecular mechanisms for accumulation are discussed which may help to choose the appropriate tracer for planning radiation treatment strategies. PMID- 20724014 TI - Exploring children's movement characteristics during virtual reality video game play. AB - There is increasing interest in the use of commercially-available virtual reality video gaming systems within pediatric rehabilitation, yet little is known about the movement characteristics of game play. This study describes quantity and quality of movement during Nintendo Wii and Wii Fit game play, explores differences in these movement characteristics between games and between novice and experienced players, and investigates whether motivation to succeed at the game impacts movement characteristics. Thirty-eight children (aged 7-12) with and without previous game experience played Wii (boxing and tennis) and Wii Fit (ski slalom and soccer heading) games. Force plate data provided center of pressure displacement (quantity) and processed pelvis motion indicated smoothness of pelvic movement (quality). Children rated their motivation to succeed at each game. Movement quantity and quality differed between games (p<.001). Children with previous experience playing Wii Fit games demonstrated greater movement quantity during Wii Fit game play (p<.001); quality of movement did not differ between groups. Motivation to succeed did not influence the relationship between experience and outcomes. Findings enhance clinical understanding of this technology and inform the development of research questions to explore its potential to improve movement skills in children with motor impairments. PMID- 20724015 TI - Collaborative validation of a rapid method for efficient virus concentration in bottled water. AB - Enteric viruses, including norovirus (NoV) and hepatitis A virus (HAV), have emerged as a major cause of waterborne outbreaks worldwide. Due to their low infectious doses and low concentrations in water samples, an efficient and rapid virus concentration method is required for routine control. Three newly developed methods, A, B and C, for virus concentration in bottled water were compared against the reference method D: (A) Convective Interaction Media (CIM) monolithic chromatography; filtration of viruses followed by (B) direct lysis of viruses on membrane; (C) concentration of viruses by ultracentrifugation; and (D) concentration of viruses by ultrafiltration, for each methods' (A, B and C) efficacy to recover 10-fold dilutions of HAV and feline calicivirus (FCV) spiked in bottles of 1.5L of mineral water. Within the tested characteristics, all the new methods showed better performance than method D. Methods A, B and C shared a limit of detection (LOD(50)) of nine 50%-tissue culture infectious dose (TCID(50)) of FCV/1.5L, but differed with regard to the LOD(50)'s of HAV with 45, 361 and 3607 TCID(50)/1.5L, respectively, and the percentage of recoveries of HAV/FCV with 34/6, 32/25 and 0.3/0.5, respectively. Method B resulted in significantly (p<0.0001) lower C(t)-values for both HAV and FCV relative to the reference method D than any of the other methods. The most efficient method (B) was evaluated through a collaborative trial by five laboratories for the detection of HAV, FCV and NoV genogroup I and II (GI and GII), which resulted in the corresponding average LOD(50)'s and percentage of recoveries: 211 TCID(50)/1.5L and 51% for HAV; 66 TCID(50)/1.5L and 34% for FCV; 9 reverse transcriptase-PCR Units (RT-PCR U)/1.5L and 61% for NoV GI and 286 RT-PCR U/1.5L and 35% for NoV GII. The results indicate that method B could be considered robust enough for routine control and useful for harmonized data generation. PMID- 20724016 TI - Factors influencing the accuracy of the plating method used to enumerate low numbers of viable micro-organisms in food. AB - This study aims to assess several factors that influence the accuracy of the plate count technique to estimate low numbers of micro-organisms in liquid and solid food. Concentrations around 10CFU/mL or 100CFU/g in the original sample, which can still be enumerated with the plate count technique, are considered as low numbers. The impact of low plate counts, technical errors, heterogeneity of contamination and singular versus duplicate plating were studied. Batches of liquid and powdered milk were artificially contaminated with various amounts of Cronobacter sakazakii strain ATCC 29544 to create batches with accurately known levels of contamination. After thoroughly mixing, these batches were extensively sampled and plated in duplicate. The coefficient of variation (CV) was calculated for samples from both batches of liquid and powdered product as a measure of the dispersion within the samples. The impact of technical errors and low plate counts were determined theoretically, experimentally, as well as with Monte Carlo simulations. CV-values for samples of liquid milk batches were found to be similar to their theoretical CV-values established by assuming Poisson distribution of the plate counts. However, CV-values of samples of powdered milk batches were approximately five times higher than their theoretical CV-values. In particular, powdered milk samples with low numbers of Cronobacter spp. showed much more dispersion than expected which was likely due to heterogeneity. The impact of technical errors was found to be less prominent than that of low plate counts or of heterogeneity. Considering the impact of low plate counts on accuracy, it would be advisable to keep to a lower limit for plate counts of 25 colonies/plate rather than to the currently advocated 10 colonies/plate. For a powdered product with a heterogeneous contamination, it is more accurate to use 10 plates for 10 individual samples than to use the same 10 plates for 5 samples plated in duplicate. PMID- 20724017 TI - Clinical approach to the patient with diabetes mellitus and very high insulin requirements. AB - A number of patients with diabetes require very high (> 2 Ukg-1 day-1), or extremely high (> 3 Ukg-1 day-1), insulin doses for the management of their hyperglycemia. Unfortunately, many of the physicians who treat these patients limit themselves to prescribing ever higher doses of insulin, without questioning why. Furthermore, when the insulin requirements get to be extreme, demanding an explanation, clinicians are frequently lost in a sea of literature where there is not a single paper dealing with this problem systematically. A systematic approach to the evaluation of these patients is necessary to facilitate an appropriate diagnosis, select the most reasonable therapy, and hopefully improve the long-term outcome of these patients. This manuscript intends to provide the clinician with a review of the literature pertinent for the differential diagnosis, work-up, and management of these patients. We will review the definitions of insulin sensitivity during normality, the various degrees or categories of insulin resistance, and the expected insulin requirements during each of these states. Subsequently, we propose a simple alphabetic mnemonic approach to help remember the differential diagnosis, and a clinical algorithm to help guide the work-up of these patients. Lastly, we briefly discuss general management considerations in these conditions. PMID- 20724018 TI - Diabetes prevalence and income: Results of the Canadian Community Health Survey. AB - This paper contributes to a growing body of literature indicating the importance of income as a key socioeconomic status marker in accounting for the increased prevalence of type 2 diabetes (T2DM). METHODS: We analyzed data from the Canadian Community Health Survey cycle 3.1 conducted by Statistics Canada. Descriptive statistics on the prevalence of self-reported diabetes were computed. Multiple logistic regression was used to examine the association between income and prevalence of T2DM. RESULTS: In 2005 an estimated 1.3 million Canadians (4.9%) reported having diabetes. The prevalence of T2DM in the lowest income group is 4.14 times higher than in the highest income group. Prevalence of diabetes decreases steadily as income goes up. The likelihood of diabetes was significantly higher for low-income groups even after adjusting for socio demographic status, housing, BMI and physical activity. There is a graded association between income and diabetes with odds ratios almost double for men (OR 1.94, 95% CI 1.57-2.39) and almost triple for women (OR 2.75 95% CI 2.24 3.37) in the lowest income compared to those in highest income. CONCLUSION: These findings suggest that strategies for diabetes prevention should combine person centered approaches generally recommended in the diabetes literature research with public policy approaches that acknowledge the role of socioeconomic position in shaping T2DM prevalence/incidence. PMID- 20724019 TI - Health reform and cesarean sections in the private sector: The experience of Peru. AB - OBJECTIVES: To test the hypothesis that the health reform enacted in Peru in 1997 increased the rate of cesarean sections in the private sector due to non-clinical factors. METHODS: Different rounds of the Demographic and Health Survey are used to estimate determinants of c-section rates in private and public facilities before and after the healthcare reform. Estimations are based on a pooled linear regression controlling by obstetric and socioeconomic characteristics. RESULTS: C section rates in the private sector grew from 28 to 53% after the health reform. Compared to the Ministry of Health (MOH), giving birth in a private hospital in the post-reform period adds 19% to the probability of c-section. CONCLUSIONS: The health reform implemented in the private sector increased physician incentives to over-utilize c-sections. The reform consolidated and raised the market power of private health insurers, but at the same time did not provide mechanisms to enlarge, regulate and disclose information of private providers. All these factors created the conditions for fee-for-service paid providers to perform more c-sections. Comparable trends in c-section rates have been observed in Latin American countries who implemented similar reforms in their private sector, suggesting a need to rethink the role of private health providers in developing countries. PMID- 20724020 TI - SAS macros for estimation of direct adjusted cumulative incidence curves under proportional subdistribution hazards models. AB - The cumulative incidence function is commonly reported in studies with competing risks. The aim of this paper is to compute the treatment-specific cumulative incidence functions, adjusting for potentially imbalanced prognostic factors among treatment groups. The underlying regression model considered in this study is the proportional hazards model for a subdistribution function [1]. We propose estimating the direct adjusted cumulative incidences for each treatment using the pooled samples as the reference population. We develop two SAS macros for estimating the direct adjusted cumulative incidence function for each treatment based on two regression models. One model assumes the constant subdistribution hazard ratios between the treatments and the alternative model allows each treatment to have its own baseline subdistribution hazard function. The macros compute the standard errors for the direct adjusted cumulative incidence estimates, as well as the standard errors for the differences of adjusted cumulative incidence functions between any two treatments. Based on the macros' output, one can assess treatment effects at predetermined time points. A real bone marrow transplant data example illustrates the practical utility of the SAS macros. PMID- 20724021 TI - Establishment and phenotypic characterization of the first human pulmonary blastoma cell line. AB - BACKGROUND: Sarcomatoid carcinomas are a group of poorly differentiated carcinomas containing a sarcomatoid component with the presence of epithelial mesenchymal transition. MATERIALS AND METHODS: To obtain a stabilized cell line, three mediums were used: IMDM, BEBM and IMDM/BEBM. CD44, CD29, CD90, CD133, CD326 antigens, cytokeratins and vimentin were tested by flow cytometry and immunofluorescence assay. Side population, spheres formation, tumorigenicity in vitro and in vivo and cell cycle analysis were analyzed. RESULTS: At day of surgery, cytometric analysis revealed that CD133, CD90 and CD326 levels were very low, CD29 and CD44 were about 80%. After 30 days of culture, CD133 levels increased up to 30%, all cells expressed CD90 and vimentin markers and CD326 was lost. The cells grew only in IMDM/BEBM medium. The cell population was heterogeneous with epithelial and mesenchymal cells. After about 15-30 days, only fibroblast-like cells were observed. LC114 cells were not able to grow as spheres and they did not show a side-population phenotype. The cell cycle analysis confirmed an aneuploid population in the tissue and normal diploid population in cell line. CONCLUSIONS: We selected, characterized and stabilized a primary cell line of human pulmonary blastoma by the expression both of stemness and differentiation markers and confirmed the presence of the marker CD133. PMID- 20724022 TI - Phycobiliproteins in Prochlorococcus marinus: biosynthesis of pigments and their assembly into proteins. AB - Prochlorococcus sp. is a very unique and highly abundant class of organisms within the cyanobacteria. Found in the world's oceans Prochlorococcus is very small in size and possesses the smallest genome of a photosynthetic autotroph. Prochlorococcus is characterized by a special chlorophyll antenna for light harvesting and the absence of classical cyanobacterial phycobilisomes. Despite the lack of phycobilisomes Prochlorococcus possesses remnants thereof which is the phycobiliprotein phycoerythrin (PE) encoded in a PE operon as well as genes encoding enzymes of phycobilin biosynthesis. The size of this PE operon varies depending on the light-adapted ecotype. While high-light strains only possess a beta-subunit of PE, low-light adapted strains possess both, an alpha- and a beta subunit. alpha-/beta-subunits are also present in functional phycobilisomes. Consistent with the number of subunits is also the varying number of putative lyase genes, involved in the transfer and attachment of phycobilins (open-chain tetrapyrroles) to the PE subunits. This minireview summarizes the only sparely available data on the biosynthesis and assembly of Prochlorococcus PE. On one hand the quite well understood biosynthesis of pigments will be reviewed but also new data on the phycobiliprotein lyase-mediated transfer of the phycobilins to the PE subunits will be discussed. PMID- 20724023 TI - AtFer4 ferritin is a determinant of iron homeostasis in Arabidopsis thaliana heterotrophic cells. AB - In plants, the iron storage protein ferritin can be targeted to both chloroplasts and mitochondria. To investigate the role of Arabidopsis ATFER4 ferritin in mitochondrial iron trafficking, atfer4-1 and atfer4-2 mutant knock-outs for the AtFer4 gene were grown in heterotrophic suspension cultures. Both mutants showed altered cell size and morphology, reduced viability, higher H2O2 content and reduced O2 consumption rates when compared to wt. Although no reduction in total ferritin or in mitochondrial ferritin was observed in atfer4 mutants, total iron content increased in atfer4 cells and in atfer4 mitochondria. Transcript correlation analysis highlighted a partial inverse relationship between the transcript levels of the mitochondrial ferric reductase oxidase FRO3, putatively involved in mitochondrial iron import/export, and AtFer4. Consistent with this, FRO3 transcript levels were higher in atfer4 cells. We propose that the complex molecular network maintaining Fe cellular homeostasis requires, in Arabidopsis heterotrophic cells, a proper balance of the different ferritin isoforms, and that alteration of this equilibrium, such as that occurring in atfer4 mutants, is responsible for an altered Fe homeostasis resulting in a change of intraorganellar Fe trafficking. PMID- 20724024 TI - [Retinal vasculitis. Epidemiological, clinical and etiological features]. AB - PURPOSE: To study the epidemiological and clinical features of noninfectious retinal vasculitis (NIRV). METHODS: We analyzed 128 consecutive patients with NIRV, collected over 15 years (1993-2007) in an ophthalmological reference university hospital in Tunis, Tunisia. Data were analyzed regarding associated systemic disease, ocular syndromes, anatomic features (type and topography of vessel and type of capillaropathy), age and sex. The results of the etiologic work-up were based on the Levy-Clarke and Perez classification. RESULTS: A total of 240 cases of NIRV (128 patients) were collected (mean age: 32; sex ratio: 2.6). It was bilateral in 93.7% of cases. The mean visual acuity (VA) was 20/50 (range: 20/800-20/20). NIRV was mainly venous (84.1%), diffuse (57%), with a mixed capillaropathy (40.2%). There were complications in 56.25% of the cases, mainly macular edema (48.1%), vascular occlusion (25.9%), optic atrophy (22.2%) and cataract (19.2%). NIRV was idiopathic in 15.6% of the cases, characterized by a predominance of young subjects (mean: 38 years old), males (sex ratio: 4), VA at 20/25, and edematous periphlebitis in 100% of cases. There were ocular disorders in 12.5% of the cases and systemic disease in 72% of the cases, with a predominance of Behcet disease (BD): 53.9% of all patients and 81% of systemic disease with predominant venous features. In 48.3% of cases, VA was less than 20/200, due to BD in 48% of the cases. CONCLUSION: In NIRV, the etiologic work-up is oriented on anatomic presentation, based on fluorescein retinal angiography, and requires an interdisciplinary approach. In young adults with retinal phlebitis, BD is suggested first. PMID- 20724025 TI - [Serious fireworks-related eye injuries in Alsace (France)]. AB - AIM: The purpose of the study was to review cases of serious fireworks-related eye injuries presented in the Strasbourg (France) University Hospital ophthalmology emergency department and to analyze epidemiological and clinical data such as visual outcomes and risk factors. METHOD: A 13-year retrospective study (1994-2007) including fireworks-related ocular and adnexal injuries requiring hospitalization was conducted. RESULTS: Thirty-nine patients were reported; 95% were male. The mean age was 19.38 years old. There was 61.5% contusions, 33.3% eye and adnexal burns, and 15.4% of the patients suffered from a penetrating injury. More than half of the patients required emergency ophthalmic surgical procedures. Twenty-six percent of the patients had final visual acuity of 20/400 or less. CONCLUSIONS: Fireworks are a cause of severe eye injury in France. These injuries are potentially preventable, especially in young males. PMID- 20724026 TI - [Adenoviral keratoconjunctivitis]. AB - Adenovirus keratoconjunctivitis is caused by numerous types of adenovirus with different clinical presentations. The most frequent is epidemic keratoconjunctivitis (EKC), but follicular conjunctivitis and pharyngoconjunctival fever are also possible. The virus is very resistant to desiccation and it is transmitted by direct contact. On the conjunctiva, the symptoms will be those of any conjunctivitis. On the cornea, remnants of viral proteins will remain on the surface of the Bowman layer. Immune reaction against these remnants will lead to the formation of subepithelial infiltrates. The diagnosis is mainly clinical, with laboratory tests only rarely contributing information rapidly. There is no other treatment than symptomatic eyedrops. The major sequelae are subepithelial infiltrates, which are difficult to treat. The use of topical steroids is discussed at all stages of the disease. Prevention is the most important action of the ophthalmologist in this viral infection. PMID- 20724027 TI - [Cicatricial conjunctivitis]. AB - Cicatricial conjunctivitis is chronic conjunctivitis with conjunctival fibrosis and may lead to alterations of conjunctival architecture, which are potentially sight-threatening. The patient's medical history, physical exam, and laboratory tests often provide the diagnosis of the underlying disease. Causes of conjunctival cicatrization are autoimmune diseases such as ocular cicatricial pemphigoid, thermal and chemical burns, postinfectious conjunctivitis, Stevens Johnson syndrome, etc. Medical management varies according to specific causes and may lead to severe side effects. Furthermore, strategies may be necessary to restore corneal transparency and normal palpebral architecture. PMID- 20724028 TI - Silver sulfadiazine for the treatment of partial-thickness burns and venous stasis ulcers. AB - BACKGROUND: For decades silver-containing antibiotics such as silver sulfadiazine (SSD) have been applied as standard topical therapy for patients with partial thickness burns and venous stasis ulcers. This evidence-based review intends to answer the following research question: in ambulatory patients with partial thickness burns or stasis dermatitis ulcers, does the use of topical SSD compared with nonantibiotic dressings improve mortality, wound healing, re epithelialization, or infection rates? METHODS: MEDLINE, EMBASE, Cochrane Library, and other databases were searched. We considered trials that enrolled patients of any age with partial-thickness burns or venous stasis ulcers and randomized them to either topical SSD or placebo, saline-soaked gauze, paraffin gauze, sterile dry dressing, or nonantibiotic moist dressing. Outcomes included mortality, wound healing, speed of re-epithelialization, and infection rates. RESULTS: For burns, our search revealed 400 potential articles. No human studies met the inclusion criteria. Only 7 animal studies (1 mouse, 4 rat, and 2 pig) were relevant to the proposed question. These animal studies provided conflicting results. Whereas some support the use of SSD for treatment of partial-thickness burns, others question its effectiveness. For stasis dermatitis ulcer, the search identified 50 articles for review, of which 20 abstracts were reviewed, and one article met the inclusion criteria. This study did not show any significant improvement in the rate of complete healing in SSD group compared with placebo either at 4 weeks (relative risk 6.2, 95% confidence interval 0.8-48) or at 1 year (relative risk 5.2, 95% confidence interval 0.6-41.6) of follow-up. CONCLUSION: There is insufficient evidence to either support or refute the routine use of SSD for ambulatory patients with either partial-thickness burns or stasis dermatitis ulcers to decrease mortality, prevent infection, or augment wound healing in human beings. PMID- 20724029 TI - Onychoheterotopia: pathogenesis, presentation, and management of ectopic nail. AB - BACKGROUND: Onychoheterotopia is an extremely rare condition in which the nail tissue grows outside the classic nail unit of the dorsal fingers and toes. It presents as either small outgrowths of a deviant nail or a complete double fingernail malformation. The histology of the onychoheterotopia matrix is oftentimes very similar to the normal nail matrix, although it plays a central role in diagnosis. OBJECTIVE: We sought to review the current literature on the clinical and histologic aspects of onychoheterotopia. METHODS: A literature search was performed to evaluate peer-reviewed articles on the topic. RESULTS: Detailed reports have characterized many features of onychoheterotopia. The various etiology and treatment options are reviewed. LIMITATIONS: The study was limited to those articles in the English-language literature. CONCLUSIONS: In this article, we provide a review of the literature based on the current understanding of onychoheterotopia, its diagnosis, and its management. PMID- 20724030 TI - Diagnosis and treatment of primary immunodeficiency disease: the role of the otolaryngologist. AB - OBJECTIVE: The objective of the study was to review the diagnosis and treatment of primary immunodeficiency disease (PID) and the role of otolaryngologists in the management of PID. METHODS: A search was conducted of PubMed and the Web sites of organizations for PID patients for literature pertaining to the diagnosis and treatment of PID, with an emphasis on the role of otolaryngologists. The reference lists of selected articles were reviewed for additional articles. RESULTS: Patients with PID commonly present with respiratory tract infections (eg, recurrent ear, nose, or throat infections) and chest disease. Diagnostic delays or inadequate treatment of PID may lead to significant morbidity and premature mortality. Immunoglobulin (Ig) replacement is the cornerstone of therapy for most patients with PID. Although intravenous Ig is the most popular route of administration in the United States, subcutaneous Ig administration may be appropriate for patients with poor venous access, those who are unable to tolerate intravenous Ig, or those who prefer the independence and flexibility of self-administration. CONCLUSIONS: Recognition and diagnosis of PID by otolaryngologists are critical to optimizing patient outcomes. Several therapeutic regimens for Ig replacement are now available that offer patients increased flexibility and independence. PMID- 20724031 TI - Changing topological patterns in normal aging using large-scale structural networks. AB - We examine normal aging from the perspective of topological patterns of structural brain networks constructed from two healthy age cohorts 20 years apart. Based on graph theory, we constructed structural brain networks using 90 cortical and subcortical regions as a set of nodes and the interregional correlations of grey matter volumes across individual brains as edges between nodes, and further analyzed the topological properties of the age-specific networks. We found that the brain structural networks of both cohorts had small world architecture, and the older cohort (N = 374; mean age = 66.6 years, range 64-68) had lower global efficiency but higher local clustering in the brain structural networks compared with the younger cohort (N = 428; mean age = 46.7, range 44-48). The older cohort had reduced hemispheric asymmetry and lower centrality of certain brain regions, such as the bilateral hippocampus, bilateral insula, left posterior cingulated, and right Heschl gyrus, but that of the prefrontal cortex (PFC) was not different. These structural network differences may provide the basis for changes in functional connectivity and indeed cognitive function as we grow older. PMID- 20724032 TI - White matter hyperintensities alter functional organization of the motor system. AB - Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 +/- 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits. PMID- 20724033 TI - Early onset of aging-like changes is restricted to cognitive abilities and skin structure in Cnr1-/- mice. AB - Genetic deletion of the cannabinoid 1 (CB1) receptor leads to an early onset of learning and memory impairment. In the present study we asked whether the lack of CB1 receptors accelerates aging in general or is selective for cognitive functions. We therefore compared the onset and dynamics of age-dependent changes in social memory, locomotor activity, hearing ability, and in the histopathology of peripheral organs between wild-type and Cnr1 knockout (Cnr1(-/-)) mice. We observed deficits in social memory already in 3-month-old Cnr1(-/-) mice. In contrast, wild-type animals showed such deficits at the age of 6 months. Sensory and motor functions were similar between the genotypes. Thus, hearing loss for higher frequencies and the development of hypomotility showed a similar age dependent course. In the periphery we detected an early onset of aging-like histological changes in the skin, but not in other organs. We conclude that the lack of CB1 receptor does not induce accelerated aging in general, but induces changes in cognitive function and in skin structure that resemble those associated with aging. PMID- 20724034 TI - Pro-oxidant diet enhances beta/gamma secretase-mediated APP processing in APP/PS1 transgenic mice. AB - The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Abeta) levels and Abeta plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Abeta-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Abeta in the cortex of TASTPM but did not alter Abeta plaque load, presenilin 1, or beta-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro oxidant conditions resulting in increased levels of APP and Abeta likely as a result of enhanced beta/gamma secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD. PMID- 20724035 TI - A complementary diffusion tensor imaging (DTI)-histological study in a model of Huntington's disease. AB - In vivo diffusion tensor imaging (DTI) was performed on the quinolinic acid (QUIN) rat model of Huntington's disease, together with behavioral assessment of motor deficits and histopathological characterization. DTI and histology revealed the presence of a cortical lesion in 53% of the QUIN animals (QUIN(+ctx)). Histologically, QUIN(+ctx) were distinguished from QUIN(-ctx) animals by increased astroglial reaction within a subregion of the caudate putamen and loss of white matter in the external capsula. Although both techniques are complementary, the quantitative character of DTI makes it possible to pick up subtle differences in tissue microstructure that are not identified with histology. DTI demonstrated differential changes of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) in the internal and external capsula, and within a subregion of the caudate putamen. It was suggested that FA increased due to a selective loss of the subcortical connections targeted by degenerative processes at the early stage of the disease, which might turn the striatum into a seemingly more organized structure. When tissue degeneration becomes more severe, FA decreased while AD, RD and MD increased. PMID- 20724037 TI - Normal aging reduces motor synergies in manual pointing. AB - Depending upon its organization, movement variability may reflect poor or flexible control of a motor task. We studied adult age-related differences in the structure of postural variability in manual pointing using the uncontrolled manifold (UCM) method. Participants from 2 age groups (younger: 20-30 years; older: 70-80 years; 12 subjects per group) completed a total of 120 pointing trials to 2 different targets presented according to 3 schedules: blocked, alternating, and random. The age groups were similar with respect to basic kinematic variables, end point precision, as well as the accuracy of the biomechanical forward model of the arm. Following the uncontrolled manifold approach, goal-equivalent and nongoal-equivalent components of postural variability (goal-equivalent variability [GEV] and nongoal-equivalent variability [NGEV]) were determined for 5 time points of the movements (start, 10%, 50%, 90%, and end) and used to define a synergy index reflecting the flexibility/stability aspect of motor synergies. Toward the end of the movement, younger adults showed higher synergy indexes than older adults. Effects of target schedule were not reliable. We conclude that normal aging alters the organization of common multidegree-of-freedom movements, with older adults making less flexible use of motor abundance than younger adults. PMID- 20724036 TI - Association between variants in IDE-KIF11-HHEX and plasma amyloid beta levels. AB - Genetic linkage and association studies in late-onset Alzheimer's disease (LOAD) or its endophenotypes have pointed to several regions on chromosome 10q, among these the ~ 250 kb linkage disequilibrium (LD) block harboring the genes IDE, KIF1, and HHEX. We explored the association between variants in the genomic region harboring the IDE-KIF11-HHEX complex with plasma Abeta40 and Abeta42 levels in a case-control cohort of Caribbean Hispanics. First, we performed single marker linear regression analysis relating the individual single nucleotide polymorphisms (SNPs) with plasma Abeta40 and Abeta42 levels. Then we performed 3-SNP sliding window haplotype analyses, correcting all analyses for multiple testing. Out of 32 SNPs in this region, 3 SNPs in IDE (rs2421943, rs12264682, rs11187060) were associated with plasma Abeta40 or Abeta42 levels in single marker and haplotype analyses after correction for multiple testing. All these SNPs lie within the same LD block, and are in LD with the previously reported haplotypes. Our findings provide support for an association in the IDE region on chromosome 10q with Abeta40 and 42 levels. PMID- 20724038 TI - Synthesis, characterization and antiglaucoma activity of some novel pyrazole derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide. AB - Pyrazole carboxylic acid derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide (inhibitor 1) were synthesized from ethyl 3-(chlorocarbonyl)-1-(3-nitrophenyl)-5 phenyl-1H-pyrazole-4-carboxylate compound. The inhibitory effects of inhibitor 1, acetazolamide (AAZ) and of 11 newly synthesized amides (5a-b, 6, 7a-g, and 8) on hydratase and esterase activities of carbonic anhydrase isoenzymes (hCA-I and hCA II) have been studied in vitro. The comparison of newly synthesized amides to inhibitor 1 and to AAZ indicated that the new derivatives inhibit CA isoenzymes and they are more potent inhibitors than the parent inhibitor 1 and AAZ. PMID- 20724039 TI - Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones. AB - A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus. PMID- 20724040 TI - Recent methodologies toward the synthesis of valdecoxib: a potential 3,4 diarylisoxazolyl COX-II inhibitor. AB - Non-steroidal anti-inflammatory drugs are widely used therapeutic agents in the treatment of inflammation, pain and fever. Cyclooxygenase catalyzes the initial step of biotransformation of arachidonic acid to prostanoids, and exist as three distinct isozymes; COX-I, COX-II and COX-III. Selective COX-II inhibitors are a class of potential anti-inflammatory, analgesic, and antipyretic drugs with reduced gastrointestinal (GI) side effects compared to nonselective inhibitors. 3,4-Diarylisoxazole scaffold is recurrently found in a wide variety of NSAIDs, protein kinase inhibitors, hypertensive agents, and estrogen receptor (ER) modulators. In the present review, we document on the recent synthetic strategies of 3,4-diarylisoxazolyl scaffolds of valdecoxib and its relevant structural analogues. PMID- 20724041 TI - Antimycobacterial and antitumor activities of palladium(II) complexes containing isonicotinamide (isn): X-ray structure of trans-[Pd(N3)2(isn)(2)]. AB - Complexes of the type trans-[PdX(2)(isn)(2)] {X = Cl (1), N(3) (2), SCN (3), NCO (4); isn = isonicotinamide} were synthesized and evaluated for in vitro antimycobacterial and antitumor activities. The coordination mode of the isonicotinamide and the pseudohalide ligands was inferred by IR spectroscopy. Single crystal X-ray diffraction determination on 2 showed that coordination geometry around Pd(II) is nearly square planar, with the ligands in a trans configuration. All the compounds demonstrated better in vitro activity against Mycobacterium tuberculosis than isonicotinamide and pyrazinamide. Among the complexes, compound 2 was found to be the most active with MIC of 35.89 MUM. Complexes 1-4 were also screened for their in vitro antitumor activity towards LM3 and LP07 murine cancer cell lines. PMID- 20724042 TI - Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors. AB - Inhibition of the 5-hydroxytryptamine receptor (5-HT(3)R), a member of the Cys loop superfamily of Ligand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. With respect to the many other drugs already in use, such as the first generation 5-HT(3)R antagonist granisetron, palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potency towards the 5-HT(3)Rs. Five different receptor monomers, the 5 HT(3)R A-E, have been identified although the A and B subunits are the only known to build functional receptors, the homopentameric 5-HT(3A)R and the heteropentameric 5-HT(3B-A)R (with BBABA subunit arrangement). At present, however, no three-dimensional structure has been reported for any of the 5-HT(3)R subunits. To understand the binding properties of agonists and antagonists, models of the extracellular portion of the 5-HT(3)R A and B subunits are built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of the known three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results of docking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron into the modelled homomeric and heteromeric 5-HT(3)R binding interfaces, provide a possible rationalization both of the higher potency of palonosetron with respect to other antagonists, and of its previously reported allosteric binding and positive cooperativity properties. PMID- 20724043 TI - The effect of voluntariness on the acceptance of e-learning by nursing students. AB - Although e-learning is an innovation that is worth making generally available, it is not always accepted by nursing students. Many researchers state that voluntariness is closely related to the individual level of adoption of innovations. Hence, we hypothesized that voluntariness moderates the effect of perceived attributes of innovations (e.g. relative advantage, compatibility, complexity, trialability, and observability), which determines the acceptance of e-learning. To test the hypothesis a survey involving two groups of nursing students was carried out. For the first group the usage of e-learning was mandatory, for the second group it was optional. The results confirm our hypothesis. Institutions, interested in e-learning initiatives, should consider the effect of voluntariness when implementing e-learning. This paper provides a useful reference that can help e-learning providers to develop guidelines that can improve the acceptance of e-learning. PMID- 20724044 TI - Age-related differences in lower-limb force-time relation during the push-off in rapid voluntary stepping. AB - BACKGROUND: This study investigated the force-time relationship during the push off stage of a rapid voluntary step in young and older healthy adults, to study the assumption that when balance is lost a quick step may preserve stability. The ability to achieve peak propulsive force within a short time is critical for the performance of such a quick powerful step. We hypothesized that older adults would achieve peak force and power in significantly longer times compared to young people, particularly during the push-off preparatory phase. METHODS: Fifteen young and 15 older volunteers performed rapid forward steps while standing on a force platform. Absolute anteroposterior and body weight normalized vertical forces during the push-off in the preparation and swing phases were used to determine time to peak and peak force, and step power. Two-way analyses of variance ('Group' [young-older] by 'Phase' [preparation-swing]) were used to assess our hypothesis (P <= 0.05). FINDINGS: Older people exerted lower peak forces (anteroposterior and vertical) than young adults, but not necessarily lower peak power. More significantly, they showed a longer time to peak force, particularly in the vertical direction during the preparation phase. INTERPRETATIONS: Older adults generate propulsive forces slowly and reach lower magnitudes, mainly during step preparation. The time to achieve a peak force and power, rather than its actual magnitude, may account for failures in quickly performing a preventive action. Such delay may be associated with the inability to react and recruit muscles quickly. Thus, training elderly to step fast in response to relevant cues may be beneficial in the prevention of falls. PMID- 20724045 TI - Long-term Hg pollution-induced structural shifts of bacterial community in the terrestrial isopod (Porcellio scaber) gut. AB - In previous studies we detected lower species richness and lower Hg sensitivity of the bacteria present in egested guts of Porcellio scaber (Crustacea, Isopoda) from chronically Hg polluted than from unpolluted environment. Basis for such results were further investigated by sequencing of 16S rRNA genes of mercury resistant (Hgr) isolates and clone libraries. We observed up to 385 times higher numbers of Hgr bacteria in guts of animals from polluted than from unpolluted environment. The majority of Hgr strains contained merA genes. Sequencing of 16S rRNA clones from egested guts of animals from Hg-polluted environments showed elevated number of bacteria from Pseudomonas, Listeria and Bacteroidetes relatives groups. In animals from pristine environment number of bacteria from Achromobacter relatives, Alcaligenes, Paracoccus, Ochrobactrum relatives, Rhizobium/Agrobacterium, Bacillus and Microbacterium groups were elevated. Such bacterial community shifts in guts of animals from Hg-polluted environment could significantly contribute to P. scaber Hg tolerance. PMID- 20724046 TI - Correlations between in situ denitrification activity and nir-gene abundances in pristine and impacted prairie streams. AB - Denitrification is a process that reduces nitrogen levels in headwaters and other streams. We compared nirS and nirK abundances with the absolute rate of denitrification, the longitudinal coefficient of denitrification (i.e., Kden, which represents optimal denitrification rates at given environmental conditions), and water quality in seven prairie streams to determine if nir-gene abundances explain denitrification activity. Previous work showed that absolute rates of denitrification correlate with nitrate levels; however, no correlation has been found for denitrification efficiency, which we hypothesise might be related to gene abundances. Water-column nitrate and soluble-reactive phosphorus levels significantly correlated with absolute rates of denitrification, but nir gene abundances did not. However, nirS and nirK abundances significantly correlated with Kden, as well as phosphorus, although no correlation was found between Kden and nitrate. These data confirm that absolute denitrification rates are controlled by nitrate load, but intrinsic denitrification efficiency is linked to nirS and nirK gene abundances. PMID- 20724047 TI - Occurrence of monoethylmercury in the Florida Everglades: identification and verification. AB - A few studies have reported the occurrence of monoethylmercury (CH(3)CH(2)Hg(+)) in the natural environment, but further verification is needed due to the lack of direct evidence and/or uncertainty in analytical procedures. Various analytical techniques were employed to verify the occurrence of CH(3)CH(2)Hg(+) in soil of the Florida Everglades. The identity of CH(3)CH(2)Hg(+) in Everglades soil was clarified, for the first time, by GC/MS. The employment of the recently developed aqueous phenylation-purge-and-trap-GC coupled with ICPMS confirmed that the detected CH(3)CH(2)Hg(+) was not a misidentification of CH(3)SHg(+). Stable isotope-tracer experiments further indicated that the detected CH(3)CH(2)Hg(+) indeed originated from Everglades soil and was not an analytical artifact. All these evidence clearly confirmed the occurrence of CH(3)CH(2)Hg(+) in Everglades soil, presumably as a consequence of ethylation occurring in this wetland. The prevalence of CH(3)CH(2)Hg(+) in Everglades soil suggests that ethylation could play an important role in the biogeochemical cycling of Hg. PMID- 20724048 TI - Metal fractionation in a contaminated soil after reforestation: temporal changes versus spatial variability. AB - In a lysimeter experiment, topsoils were polluted with filter dust from a non ferrous metal smelter and then planted with trees. Sequential extractions were used to follow the changes in metal fractionation of Cu, Zn, Cd, and Pb over 42 months. Plant-free and uncontaminated soils served as reference. In the contaminated and planted soils, the largest changes in speciation occurred within the first 6 months. The relative amounts of certain metal fractions were linearly related to each other, indicating systematic redistribution between fractions. The results indicate that under natural conditions with high heterogeneity in total metal contents spatial differences are more important than temporal variations in determining the fractionation and solubility of metals in contaminated soils. In the absence of plants soils exhibited a completely different fractionation 30 months after pollution, with much higher proportions in the more refractory phases. This suggests that plant activity kept the metals in a more soluble form. PMID- 20724049 TI - Assessment of the physico-chemical behavior of titanium dioxide nanoparticles in aquatic environments using multi-dimensional parameter testing. AB - Assessment of the behavior and fate of engineered nanoparticles (ENPs) in natural aquatic media is crucial for the identification of environmentally critical properties of the ENPs. Here we present a methodology for testing the dispersion stability, zeta-potential and particle size of engineered nanoparticles as a function of pH and water composition. The results obtained from already widely used titanium dioxide nanoparticles (Evonik P25 and Hombikat UV-100) serve as a proof-of-concept for the proposed testing scheme. In most cases the behavior of the particles in the tested settings follows the expectations derived from classical DLVO theory for metal oxide particles with variable charge and an isoelectric point at around pH 5, but deviations also occur. Regardless of a 5 fold difference in BET specific surface area particles composed of the same core material behave in an overall comparable manner. The presented methodology can act as a basis for the development of standardised methods for comparing the behavior of different nanoparticles within aquatic systems. PMID- 20724050 TI - Moral landscapes and everyday life in families with Huntington's disease: aligning ethnographic description and bioethics. AB - This article is concerned with understanding moral aspects of everyday life in families with Huntington's Disease (HD). It draws on findings from an empirical research project in Denmark in 1998-2002 involving multi-sited ethnography to argue that medical genetics provides a particular framework for conducting life in an HD family. A framework that implies that being informed and making use of genetic services expresses greater moral responsibility than conducting life without drawing on these resources. The moral imperative of engagement in medical genetics is challenged here by two pieces of ethnographic analysis. The first concerns a person who, as described by a family member, does not engage with medical genetics but who brings to the fore other culturally legitimate concerns, priorities and areas of responsibility. The second figures a genetic counselling session where neither the knowledge nor the imagined solutions of medical genetics are as unproblematic and straightforward as might be thought. To assist our understanding of the moral aspects of living with severe familial disease, the ethnographic analysis is aligned with bioethical reflections that place the concrete concerns of those personally involved centre stage in the development of theoretical stances that aim to assist reflections in practice. PMID- 20724052 TI - Structural forces and the production of TB-related stigma among Haitians in two contexts. AB - In recent years renewed interest in health-related stigma has underscored the importance of better understanding the structural underpinnings of stigma processes. This study investigated the influence of sociocultural context on perceived components of tuberculosis-related stigma in non-affected persons by comparing Haitians living in South Florida, USA, with Haitians residing in Leogane Commune, Haiti. Using the methods of cultural epidemiology, a two-phase study based on fieldwork between 2004 and 2007 collected ethnographic data on the cultural context and components of tuberculosis (TB) stigma, and administered a stigma scale developed specifically for these populations. Thematic analysis of stigma components expressed in interviews, focus groups and observation revealed commonalities as well as distinctive emphases of TB stigma in the two comparison groups. Factor analyses of stigma scale scores confirmed the thematic differences revealed in ethnographic findings and highlight the influence of political and economic factors in shaping the meaning and experience of illness. Perceived components of TB stigma among Haitians in South Florida incorporated aspects of Haitian identity as a negatively stereotyped minority community within the larger society, while in Haiti, stigma was associated primarily with poverty, malnutrition, and HIV co-infection. Discussion of findings focuses on the social production of perceived and anticipated stigma as it is influenced by structural forces including the influences of politics, economics, institutional policies, and health service delivery structures. The findings also demonstrate the value of a transnational framework encompassing both sending and receiving countries for understanding TB-related stigma in immigrant communities. PMID- 20724053 TI - [Role of the plastic surgeon in the management of ecthyma gangrenosum in children: clinical example]. AB - Ecthyma gangrenosum is a cutaneous infection, which result from a Pseudomonas aeruginosa septicemia, encountered in most of the case in immunocompromised people. Authors demonstrate the important role of the plastic surgeon in the diagnosis and therapeutic management of the disease in children. An eight-month old infant has been hospitalized for acute leukaemia. She developed an extensive painful macule in the buttocks and perineal area in a septic context. A multidisciplinary management allowed to set up an adapted antibiotherapy, an early escharrotomy, a protection of the wound by digestive and urine derivation and a reconstruction with wound healing by second intention and split thickness skin graft, which lead to a good quality cure and wound healing at the end of 37 days of evolution. This case demonstrates the importance of the surgical management in the treatment of ecthyma gangrenosum. The wound healing associated with a split thickness skin graft seems to be the less invasive solution in a frail patient and the fastest to re-start the chemotherapy. PMID- 20724054 TI - [Surgical treatment of sequelae of deep breast burns: a 25-year experience]. AB - INTRODUCTION: Deep chest burns in prepubescent girl prevent the development of the mammary gland, because scar contracture becomes an inextensible envelope. In adults, scar contracture can deform the breast shape. The aim of this work is to define the interest of tissue expansion in breast reconstruction of prepubescent's and adult's post-burns scars. PATIENTS AND METHODS: We conducted a 25-year retrospective study including patients treated surgically for deep thoracomammary burns. We studied following parameters: surgical techniques step by step, average time between each intervention, and morphologic and aesthetic results achieved. RESULTS: Twenty-eight patients have been operated between 1983 and 2008. Each patient has been operated on average 4.5 times (two to 12 times) during 6.3 years on average (1-19 years). Adult patients have showed a higher number of response (5.5 on average) than prepubescent girls (2.4 on average). Number of skin expansion has been 1.2 (0 to three) per patient. Sixty-two expanders have been placed (one to eight), 390cm(3) volume on average (180-1200). Delay of skin expansion has been about 7 months (4-10). Twenty-five breast implants have been raised on average 11 months (6-17) after debridement. Three changes of breast implant have occurred on average 5.3 years after insertion (3 8). Reconstruction of the areolonipple complex and controlateral symetrisation were conducted generally in the same time, 1 year after the last intervention. All patients will receive the possible additional volume (breast implant). Alternatives in breast volume reconstruction are lipomodelling and musculocutaneous expanded flaps. They are also discussed. Breast reconstruction in post-burns scars give clever cosmetic and morphologic despite of breast shape imperfections and apparent scars persistence satisfied cosmetic and morphologic results. These results, analyzed over a period of 25 years, show a qualitative change and decreased postoperative complications. DISCUSSION: Locoregional tissue expansion provide very clever results. In pre-pubescent grils, skin expanded flaps allow a near-normal mammary gland development. In adult women, they make the envelope that will receive the possible additional volume (breast implant). Alternatives in breast volume reconstruction are lipomodelling and musculo cutaneous expanded flaps. They are also discussed. Breast reconstruction in post burns scars give clever cosmetic and morphologic despite of breast shape imperfections and apparent scars persistence. PMID- 20724055 TI - [Salvage of infected prosthesis in breast reconstruction: About seven consecutive cases]. AB - In breast reconstruction, periprosthetic infection is one of the most feared complications. Treatment is not clearly defined. The classical recommendation mandates implant removal and antibiotic treatment before a 3- to 6-month delayed reimplantation. This approach may compromise the final result. PATIENTS AND METHOD: The authors present a series of seven consecutive infected implants early "salvages" in six patients over 304 implants during a period ranging from February 2008 to October 2009, All patients were operated using the same protocol: implant removal, irrigation with 6l of saline, implant replacement, antibiotic treatment for staphylococcus during 3 weeks. RESULTS: The seven infections were treated successfully. No recurrent infection was found with a mean follow-up of 16 months. One case of Baker III capsular contracture is noticed. Cosmetic results were moderate in one case, and satisfying or very satisfying in six cases. CONCLUSIONS: In case of periprosthetic infection without sign of severity or skin necrosis, abundant irrigation and implant salvage is an effective alternative to implant removal. PMID- 20724056 TI - [Donor site preserved skin grafts. A clinical study of 10 cases]. AB - INTRODUCTION: In spite of a rigorous technique, a graft will not necessarily completely take on a burned area. We propose to preserve on the donor site the excess skin graft harvested during the excision-graft procedure. PATIENTS AND METHODS: A clinical study was carried out in nine patients who had their excess skin graft preserved at the time of excision-graft for deep burn. The unused fragments of skin graft were preserved on the donor site. In the event of a small skin graft failure, the preserved skin graft was separated from its donor site and used as a new skin graft during wound dressing. RESULTS: Nine patients required the use of 10 preserved skin grafts. The average age was 54years and the average burned third degree surface was 17% total body surface area. In seven procedures for six patients, the preserved skin graft was taken off without pain and was used with a complete take. In three cases, the preserved skin graft was not used because in two cases, the take of the initial skin graft was complete and in one case, a definitely insufficient take required reoperation. CONCLUSION: The preservation and use of the skin graft as a complement was simple and useful and made it possible to easily complete a skin graft when the initial take was incomplete. It would appear to be efficient in burn surgery since it accelerates cicatrisation and avoids the need for a new graft harvesting procedure. PMID- 20724057 TI - Assessing the impact of immersive simulation on clinical performance during actual in-hospital cardiac arrest with CPR-sensing technology: A randomized feasibility study. AB - AIM: Advanced simulation tools are increasingly being incorporated into cardiopulmonary resuscitation (CPR) training. These educational methods have been shown to improve trainee performance in simulated settings, but translation into clinical practice remains unknown for many aspects of CPR quality. This study attempts to measure the impact of simulation-based training for resuscitation team leaders on some measures of CPR quality during actual in-hospital resuscitation attempts. METHODS: In this prospective, randomized interventional cluster trial, internal medicine resident physicians (post-graduate year 2) were randomized using a random number generator to participate in a 4-h, immersive simulation course in cardiopulmonary resuscitation leadership using a high fidelity simulator with video debriefing prior to serving as resuscitation team leaders at an academic medical center. Objective metrics of actual resuscitation performance were obtained from a CPR-sensing monitor/defibrillator. RESULTS: Thirty-two residents were randomized to receive simulation training or no additional training between April and July 2007 and data were collected following 98 actual resuscitations between July 2007 and June 2008. CPR quality from resuscitations led by 14 simulation-trained and 16 control group residents was similar in terms of mean compression depth (48 vs 49 mm; p = 0.53); compression rate (107 vs 104 min-1; p = 0.30); ventilation rate (12 vs 12 min-1; p = 0.45) and no-flow fraction (0.08 vs 0.07; p = 0.34). CONCLUSIONS: Although we failed to detect any significant differences in objective measures of CPR quality, we have demonstrated that CPR-sensing technology has the potential for use in assessing the impact of a simulation curriculum on some aspects of actual resuscitation performance. A larger study, performed in a setting with lower baseline performance, would be required to assess the specific simulation curriculum. PMID- 20724058 TI - Assessing protein-surface interactions with a series of multi-labeled BSA using fluorescence lifetime microscopy and Forster Energy Resonance Transfer. AB - Reliably measuring the physicochemical properties of protein thin layers deposited on surfaces is critical to understanding the surface chemistry, biocompatibility, and performance of implanted biomaterials. Here we apply a series of multi-fluorophore labeled Bovine Serum Albumin (BSA) proteins as model probes to investigate surface-induced conformational changes of BSA by the use of a confocal Fluorescence Lifetime Imaging Microscopy and Forster Resonance Energy Transfer (FLIM-FRET) method. In this FLIM-FRET approach we study six different constructs where the BSA is covalently linked to one (BSA-F1) or five (BSA-F5) fluorescein molecules, one (BSA-T1) or seven (BSA-T7) rhodamine molecules, and hetero labeled with both (BSA-F4-T2 and BSA-F6-T1). The fluorescence intensity and decays were simultaneously measured at two different emission regions (green and red channels) of the labeled BSA deposited on substrates of different hydrophilicity and hydrophobicity. To generate reliable data, several different regions (10(4)MUm(2) in each case) of the surfaces were scanned for each measurement. The amplitude-weighted lifetimes, obtained from the fluorescence decay parameters, are discussed based on the average distance between the conjugated fluorophores acting as a donor and acceptor pair in the Energy Transfer framework. The number of probes conjugated has significant effects on the fluorescence emission intensity and lifetimes in solution and on surfaces. The BSA-F4-T2 constructs showed a significant ability to differentiate using lifetime the hydrophilicity and hydrophobicity of the surfaces, by detecting local expansion and contraction of protein structure in the deposited layers. Using these multiple labeled BSA probes in conjunction with FLIM-FRET can provide a way to assess structural changes in proteins induced by variations in surface chemistry of biomaterials. PMID- 20724059 TI - Multivalent ions control the transport through lysenin channels. AB - We report the effect of different ions on the conducting properties of lysenin channels inserted into planar lipid bilayer membranes. Our observations indicated that multivalent ions inhibited the lysenin channels conductance in a concentration dependent manner. The analysis performed on single channels revealed that multivalent ions induced reversible sub-conducting or closed states depending on the ionic charge and size. Good agreement is reported between experimental results and a theoretical model that is proposed to describe the interaction between divalent ions and lysenin channels as a simple isothermal absorption process. PMID- 20724060 TI - Influence of xenobiotic contaminants on landfill soil microbial activity and diversity. AB - Landfills are often the final recipient of a range of environmentally important contaminants such as hydrocarbons, polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs). In this study the influence of these contaminants on microbial activity and diversity was assessed in a municipal solid waste (MSW) landfill placed in Torrejon de Ardoz (Madrid, Spain). Soil samples were collected from four selected areas (T2, T2B, T8 and T9) in which the amount of total hydrocarbons, PAHs and PCBs were measured. Soil biomass, substrate induced respiration (SIR) and physiological profiles of soil samples were also determined and used as indicators of total microbial activity. Highest concentration of total hydrocarbons was detected in T2 and T9 samples, with both PCBs and benzopyrene being detected in T9 sample. Results corresponding to microbial estimation (viable bacteria and fungi, and SIR) and microbiological enzyme activities showed that highest values corresponded to areas with the lowest concentration of hydrocarbons (T2B and T8). It is noticeable that in such areas was detected the lowest concentration of the pollutants PAHs and PCBs. A negative significant correlation between soil hydrocarbons concentration and SIR, total bacteria and fungi counts and most of the enzyme activities determined was established. DGGE analysis was also carried out to determine the microbial communities' structure in the soil samples, establishing different profiles of Bacteria and Archaea communities in each analysed area. Through the statistical analysis a significant negative correlation was only found for Bacteria domain when Shannon index and hydrocarbon concentration were correlated. In addition, a bacterial 16S rRNA gene based clone library was prepared from each soil. From the clones analysed in the samples, the majority corresponded to Proteobacteria, followed by Acidobacteria and Actinobacteria. It is important to remark that the most polluted sample (T9) showed the lowest microbial diversity only formed by six phyla being Proteobacteria and Acidobacteria the most representative. PMID- 20724061 TI - Economic assessment of flash co-pyrolysis of short rotation coppice and biopolymer waste streams. AB - The disposal problem associated with phytoextraction of farmland polluted with heavy metals by means of willow requires a biomass conversion technique which meets both ecological and economical needs. Combustion and gasification of willow require special and costly flue gas treatment to avoid re-emission of the metals in the atmosphere, whereas flash pyrolysis mainly results in the production of (almost) metal free bio-oil with a relatively high water content. Flash co pyrolysis of biomass and waste of biopolymers synergistically improves the characteristics of the pyrolysis process: e.g. reduction of the water content of the bio-oil, more bio-oil and less char production and an increase of the HHV of the oil. This research paper investigates the economic consequences of the synergistic effects of flash co-pyrolysis of 1:1 w/w ratio blends of willow and different biopolymer waste streams via cost-benefit analysis and Monte Carlo simulations taking into account uncertainties. In all cases economic opportunities of flash co-pyrolysis of biomass with biopolymer waste are improved compared to flash pyrolysis of pure willow. Of all the biopolymers under investigation, polyhydroxybutyrate (PHB) is the most promising, followed by Eastar, Biopearls, potato starch, polylactic acid (PLA), corn starch and Solanyl in order of decreasing profits. Taking into account uncertainties, flash co pyrolysis is expected to be cheaper than composting biopolymer waste streams, except for corn starch. If uncertainty increases, composting also becomes more interesting than flash co-pyrolysis for waste of Solanyl. If the investment expenditure is 15% higher in practice than estimated, the preference for flash co pyrolysis compared to composting biopolymer waste becomes less clear. Only when the system of green current certificates is dismissed, composting clearly is a much cheaper processing technique for disposing of biopolymer waste. PMID- 20724062 TI - Biosorption of Reactive Black 5 from aqueous solutions by chitosan: column studies. AB - Fixed-bed column studies were carried out to investigate the dynamic sorption of Reactive Black 5 (RB5) onto chitosan. The effect of operating parameters such as initial dye concentration, superficial flow velocity, bed height and particle size on the sorption of RB5 onto chitosan was studied. Column regeneration, dye recovery and the possibility of reusing the regenerated chitosan were also investigated. The results show that both the breakthrough curves and the adsorption parameters of the column were strongly affected by the operating parameters studied. An analysis of the breakthrough curves indicated that adsorption was affected by mass transfer limitations, probably due to intraparticle diffusion. An empirical model was applied to describe the breakthrough curves, while the Bohart-Adams and BDST models were used to determine the operating parameters useful in the process design. Elution of the column with 0.01 mol L(-1) NaOH allowed the chitosan to be regenerated and the dye to be recovered and concentrated. The concentration factor was 10. Several cycles of adsorption-elution showed that the regenerated chitosan retained good adsorption efficiency and the elution efficiency was always higher than 80%. PMID- 20724063 TI - Trade-offs between development, culture and conservation--willingness to pay for tropical river management among urban Australians. AB - Australia's system of tropical rivers constitutes one of the largest and least changed drainage networks in the world. However increasing demand for water in parts of Australia, along with ongoing drought, is driving pressure to develop these rivers. This paper reports the results of a choice experiment (CE) to assess the benefits of different management strategies for three tropical rivers in northern Australia: the Daly, Mitchell and Fitzroy Rivers. The CE was carried out using a survey mailed to Australian urban populations. The results showed that 90% of Australians were willing to pay a once-off payment for the management of tropical rivers. Respondents who had visited or lived near the rivers were willing to pay more for cultural, recreational and environmental services than those who had not. Respondents classed as 'developers', who made up only 4% of the 684 respondents, considered a substantial income from irrigated agriculture as important. Unlike 'environmentalists' and 'neutrals', 'developers' were unwilling to pay for high quality recreational fishing or for having floodplains in good environmental condition. All groups, however, were willing to pay for high cultural values. PMID- 20724064 TI - Liver transplantation techniques for the surgical management of renal cell carcinoma with tumor thrombus in the inferior vena cava: step-by-step description. AB - BACKGROUND: Renal cell carcinoma (RCC) with tumor thrombus in the inferior vena cava (IVC) poses a challenge to the surgeon given the operative difficulty, potential for massive hemorrhage, and possibility of tumor thromboemboli. OBJECTIVE: To determine the applicability of a self-developed technique based on orthotopic liver transplantation procedures for safe resection of these tumors. DESIGN, SETTING, AND PARTICIPANTS: From August 1997 to February 2008, 68 consecutive patients underwent resection of RCC with suprahepatic and/or retrohepatic (level 3 and 4) tumor thrombus in a single referral institution. SURGICAL PROCEDURE: A triradiate incision over the upper abdomen permits the placement of a Rochard retractor. Early vascular control of the renal artery is achieved by creating a posterior plane of dissection. Venous collateral decompression permits development of a bloodless anterior plane by mobilizing the liver in a "piggy-back" fashion and the spleen-pancreas en bloc to the midline. Thrombus extraction requires circumferential control at the renal veins, hepatic hilum, and IVC before cavotomy. The central tendon of the diaphragm may be opened for cranial control and gentle traction over the right atrium performed. Repositioning of the proximal clamp and Pringle release avoid veno-venous bypass and cardiopulmonary bypass (CPB) in most cases. MEASUREMENTS: The extent of the tumor thrombus was retrohepatic in 56 patients and suprahepatic/intra-atrial in 12 patients. RESULTS AND LIMITATIONS: Mean operative time was 5 h 32 min. Mean estimated blood loss (EBL) was 2112+/-3834 ml (range: 100-25 000), with a mean transfusion being 4.2+/-4.1 U (range: 0-30). Five patients (7.3%) required CPB. Three patients (4.4%) died in the immediate postoperative period. All had complete tumor resection. No patient developed intraoperative thromboembolism. CONCLUSIONS: This surgical approach provides excellent exposure and control of the IVC in cases with level 3 and 4 tumor thrombus, avoiding CPB except in rare circumstances. PMID- 20724065 TI - Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of patients: are recurrence and disease-specific survival associated with surgical technique? AB - BACKGROUND: Open radical nephroureterectomy (ORN) is the current standard of care for upper tract urothelial carcinoma (UTUC), but laparoscopic radical nephroureterectomy (LRN) is emerging as a minimally invasive alternative. Questions remain regarding the oncologic safety of LRN and its relative equivalence to ORN. OBJECTIVE: Our aim was to compare recurrence-free and disease specific survival between ORN and LRN. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed data from 324 consecutive patients treated with radical nephroureterectomy (RN) between 1995 and 2008 at a major cancer center. Patients with previous invasive bladder cancer or contralateral UTUC were excluded. Descriptive data are provided for 112 patients who underwent ORN from 1995 to 2001 (pre-LRN era). Comparative analyses were restricted to patients who underwent ORN (n=109) or LRN (n=53) from 2002 to 2008. Median follow-up for patients without disease recurrence was 23 mo. INTERVENTION: All patients underwent RN. MEASUREMENTS: Recurrence was categorized as bladder-only recurrence or any recurrence (bladder, contralateral kidney, operative site, regional lymph nodes, or distant metastasis). Recurrence-free probabilities were estimated using Kaplan-Meier methods. A multivariable Cox model was used to evaluate the association between surgical approach and disease recurrence. The probability of disease-specific death was estimated using the cumulative incidence function. RESULTS AND LIMITATIONS: Clinical and pathologic characteristics were similar for all patients. The recurrence-free probabilities were similar between ORN and LRN (2-yr estimates: 38% and 42%, respectively; p=0.9 by log-rank test). On multivariable analysis, the surgical approach was not significantly associated with disease recurrence (hazard ratio [HR]: 0.88 for LRN vs ORN; 95% confidence interval [CI], 0.57-1.38; p=0.6). There was no significant difference in bladder only recurrence (HR: 0.78 for LRN vs ORN; 95% CI, 0.46-1.34; p=0.4) or disease specific mortality (p=0.9). This study is limited by its retrospective nature. CONCLUSIONS: Based on the results of this retrospective study, no evidence indicates that oncologic control is compromised for patients treated with LRN in comparison with ORN. PMID- 20724066 TI - Does reduced [(123)I]-FP-CIT binding in Huntington's disease suggest pre-synaptic dopaminergic involvement? AB - OBJECTIVE: To evaluate the usefulness of SPECT in assessing damage to the pre synaptic dopaminergic system in Huntington's disease (HD) using [(123)I]-FP-CIT (DaTSCAN), a selective radioligand with regulatory approval as the diagnostic test for investigating functional dopaminergic neuron loss in the striatum in Parkinson's disease. METHODS: We studied twelve symptomatic HD patients using DaTSCAN/SPECT imaging. [(123)I]-FP-CIT caudate and putamen uptake levels were qualitatively and semi-quantitatively analyzed to assess pre-synaptic damage in the striatal dopamine system. Possible correlations were analyzed between HD severity on the Unified Huntington's Disease Rating Scale (UHDRS), duration of clinical symptoms, and [(123)I]-FP-CIT/SPECT striatal uptake. RESULTS: DaTSCAN/SPECT qualitative analysis showed reduced striatal uptake in eight patients. Semi-quantitative analysis revealed a significant reduction in four. Of these four, uptake reduction was at putamen level in all, and also at caudate level in one. Although we observed no linear correlation between HD severity and reduced striatal [(123)I]-FP-CIT uptake, the patients with the worst UHDRS scores had more severe reductions in radioligand uptake. CONCLUSION: This is the first study to use in vivo [(123)I]-FP-CIT/SPECT imaging to confirm prior descriptions using PET of a pre-synaptic dopaminergic system defect in HD. PMID- 20724067 TI - Hepatocyte apoptosis and its molecular mechanisms in mice caused by titanium dioxide nanoparticles. AB - While the hepatocyte apoptosis induced by TiO(2) nanoparticles (NPs) has been demonstrated, very little is known about the molecular mechanisms underlying this mouse liver apoptosis. In order to understand the hepatocyte apoptosis induced by intragastric administration of TiO(2) NPs for consecutive 60 days, the hepatocyte apoptosis, various oxidative stress parameters and the stress-related gene expression levels were assayed for the mouse liver. 60 days of TiO(2) NPs exposure, hepatocyte apoptosis in the liver could be observed, which was followed by increased reactive oxygen species accumulation, and decreased the stress related gene expression levels of superoxide dismutase, catalase, glutathione peroxidase, metallothionein, heat shock protein 70, glutathione S transferase, P53, and transferrin; and the significant enhancement of the cytochrome p450 1A expression level. It implied that hepatocyte apoptosis, oxidative stresses, and alteration of expression levels of the genes related with TiO(2) NPs detoxification/metabolism regulation and radical scavenging action. Therefore, the application of TiO(2) NPs and exposure effects especially on human liver for long-term and low-dose treatment should be cautious. PMID- 20724068 TI - Contamination status and accumulation features of PCDDs, PCDFs and dioxin-like PCBs in finless porpoises (Neophocaena phocaenoides) from Korean coastal waters. AB - Data on the concentrations and accumulation profiles of polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL PCBs) in cetaceans are scarce. In this study, concentrations and accumulation profiles of PCDD/Fs and DL-PCBs were measured in the blubber of finless porpoises (Neophocaena phocaenoides) collected from Korean coastal waters. Total dioxin like toxic equivalent (TEQ) concentrations (6.5-31 pg/g lipid weight) in finless porpoises were lower than those reported for cetaceans and pinnipeds from other countries. Significant gender-specific differences were found in the concentrations and accumulation profiles of PCDD/Fs and DL-PCBs and this difference was associated with maternal and lactation transfer of contaminants from mature females to their fetus. All of the PCDD/F homologue groups were detected in all of the samples and the proportions of PCDFs were higher than those of PCDDs. The dominant congeners found in finless porpoise blubber were 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF and OCDD for PCDD/Fs and PCB 118 for DL-PCBs. The accumulation profiles of PCDD/Fs in finless porpoise in our study were different from those found for cetaceans from other countries. Total TEQ levels in finless porpoises in Korea were below the suggested threshold values for adverse health effects in marine mammals. PMID- 20724069 TI - A comparative investigation on absorption performances of three expanded graphite based complex materials for toluene. AB - Three kinds of expanded graphite-based complex materials were prepared to absorb toluene by dispersing plant oil, animal oil and mineral oil on the surface of expanded graphite, respectively. These complex materials were characterized by scanning electronic micrograph, contact angle meter and Brunauer-Emmett-Teller surface area. And their absorption capacities for toluene were comparatively investigated. The results showed that the surfaces of the three types of sorbents were very hydrophobic and nonporous, but they all had excellent absorption capacities for toluene. And their absorption capacities were proportional to the toluene concentration in streams and decreased differently with increasing the absorption temperature. It was noteworthy that the absorption capacities varied with the unsaturated degree of the complex materials and kept unchanged under different relative humidities of streams. Moreover, the regeneration experiments showed that after 15-run regeneration the absorption capacities of expanded graphite modified by mineral oil almost kept unchanged, while that of expanded graphite loaded plant oil and animal oil dropped by 157 and 93.6 mg g(-1), respectively. The losses of their absorption capacities were ascribed to the destruction of their unsaturated carbon bounds. PMID- 20724070 TI - Determination of alkylphenol polyethoxylates, bisphenol-A, 17alpha ethynylestradiol and 17beta-estradiol and its metabolites in sewage samples by SPE and LC/MS/MS. AB - Recently, many chemicals released into the environment have been shown to mimic endogenous hormones such as estradiol. It has been demonstrated that these compounds cause several adverse effects on wildlife and humans, such as the feminization of animal species, development of physical abnormalities and birth defects, and reproductive failure. In an effort to model the behaviour of some endocrine-disrupting chemicals (EDCs) and to establish the level of contamination in sewage samples, a quantitative method for the simultaneous determination of nonylphenol, octylphenol and corresponding ethoxylates (1-12), 17alpha ethynylestradiol, bisphenol-A, and 17beta-estradiol and two of its metabolites have been developed. Identification and quantification were achieved by high performance liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS). Satisfactory detection limits (between 0.5-6 ng L(-1) in the dissolved phase and 1.4-12.7 ng g(-1) in the particulate phase) and analyte recoveries (between 60% and 108%) were achieved for target compounds. The optimised method was applied to the determination of EDCs in liquid sewage samples collected from a wastewater treatment plant (WWTP) in Las Palmas de Gran Canaria (Spain). Concentrations of EDCs ranged from <10 ng L(-1) to nearly 1200 ng L(-1) in the dissolved phase, and from 0.005 MUg g(-1) to 2.8 MUg g(-1) in the suspended particulate matter. PMID- 20724071 TI - Comparative uptake study of toxic elements from aqueous media by the different particle-size-fractions of fly ash. AB - The purpose of the study described in this paper was to determine the removal of Cr (total), Cr (VI), Cu, Ni, Pb, Zn and Cd from wastewater using different particle-size-fractions of highly calcareous and highly siliceous fly ashes (FAs). Three different Hellenic FAs (two calcareous and one siliceous) were tested for their capability of precipitating heavy metals from aqueous solutions. Each FA sample was separated into six different size-fractions with a grain diameter range of: [(0-25) (25-40) (40-90) (90-150) (150-400) and (>400)] MUm. The different FA grain-fractions were evaluated in terms of their chemical composition, pH, Loss on Ignition (LOI) and CaO(f) (%). Batch adsorption experiments were then carried out, indicating that the various grain-fractions of the highly siliceous FA were more efficient in precipitating Cr (VI) but less capable of retaining Cd, Cu, Ni, Pb and Zn. On the other hand, the high-Ca fly ashes were proven to be more efficient in uptaking Cd, Cu, Ni, Pb and Zn, but less in hexavalent chromium. This particular tendency was also confirmed in the case of the different particle-size-fractions of same fly ashes. It was actually verified that FAs can be more effective in the field of industrial wastewater remediation when separated into their size-fractions. PMID- 20724072 TI - High temperature CO2 capture using calcium oxide sorbent in a fixed-bed reactor. AB - The gas-solid reaction and breakthrough curve of CO(2) capture using calcium oxide sorbent at high temperature in a fixed-bed reactor are of great importance, and being influenced by a number of factors makes the characterization and prediction of these a difficult problem. In this study, the operating parameters on reaction between solid sorbent and CO(2) gas at high temperature were investigated. The results of the breakthrough curves showed that calcium oxide sorbent in the fixed-bed reactor was capable of reducing the CO(2) level to near zero level with the steam of 10 vol%, and the sorbent in CaO mixed with MgO of 40 wt% had extremely low capacity for CO(2) capture at 550 degrees C. Calcium oxide sorbent after reaction can be easily regenerated at 900 degrees C by pure N(2) flow. The experimental data were analyzed by shrinking core model, and the results showed reaction rates of both fresh and regeneration sorbents with CO(2) were controlled by a combination of the surface chemical reaction and diffusion of product layer. PMID- 20724073 TI - Isolation of polycyclic aromatic hydrocarbons (PAHs)-degrading Mycobacterium spp. and the degradation in soil. AB - The goal of this study was to isolate PAHs degraders that can utilize PAHs associated with soil particulates and investigate the biodegradation of PAHs on agar plate, in liquid culture and soil. Two Mycobacterium strains (NJS-1 and NJS P) were isolated from PAHs-contaminated farmland soil using enrichment based on soil slurry. The isolates could degrade five test PAHs including pyrene, phenanthrene, fluoranthene, anthracene and benzo[a]pyrene on plate, but showed different effects in liquid culture, especially for fluoranthene. Isolate NJS-1 was capable of utilizing benzo[a]pyrene as a sole carbon and energy source, and an enhanced degradation was observed when pyrene was supplied as cometabolic substrate. Reintroduction of the isolates into sterile contaminated soil resulted in a significant removal of aged pyrene and fluoranthene (over 40%) in 2-months incubation. In pyrene-spiked soil, the degradation of pyrene and fluoranthene increased to 90% and 50%, respectively. Comparing PAHs degradation on plate, in liquid culture and soil, we can conclude that there was corresponding degradation in different test systems. In addition, the degradation of aged PAHs in soil suggested the potential application of two isolates in further bioremediation. PMID- 20724074 TI - Promoted biodegradation and microbiological effects of petroleum hydrocarbons by Impatiens balsamina L. with strong endurance. AB - Phytoremediation is a promising green technology for cleanup of petroleum hydrocarbons (PHCs) in contaminated environment. Based on the objective of identifying special ornamental plants for the effective biodegradation of PHCs, the efficacy of Impatiens balsamina L. to phytoremedy petroleum contaminated soil from the Shengli Oil Field in Dongying City, Shandong Province, China, was further examined in a field plot-culture experiment under greenhouse conditions. After a 4-month culture period, the average degradation rate of total petroleum hydrocarbons (TPHs) by the plant was up to 18.13-65.03%, greatly higher than that (only 10.20-35.61%) in their corresponding controls by natural degradation. Among petroleum compositions saturated hydrocarbons had the highest degradation. The release of polar metabolic byproducts during phytoremediation of contaminated soils with >=20,000 mg/kg of PHCs by I. balsamina may occur. Some growth indexes of I. balsamina indicated that the plant had a good tolerance to contaminated soils with <=10,000 mg/kg of PHCs. Moreover rhizosphere bacteria and fungi became the dominant microbial population in soils with 5000 and 10,000 mg/kg of PHCs and were probably responsible for TPH degradation. Thus, I. balsamina L. could be a potential ornamental plant for effective phytoremediation of contaminated soils with <=10,000 mg/kg of PHCs. PMID- 20724075 TI - Rice husk ash sorbent doped with copper for simultaneous removal of SO2 and NO: optimization study. AB - In order to reduce the negative impact of coal utilization for energy generation, the pollutants present in the flue gas of coal combustion such as sulfur dioxide (SO(2)) and nitrogen oxide (NO) must be effectively removed before releasing to the atmosphere. Thus in this study, sorbent prepared from rice husk ash that is impregnated with copper is tested for simultaneous removal of SO(2) and NO from simulated flue gas. The effect of various sorbent preparation parameters; copper loading, RHA/CaO ratio, hydration period and NaOH concentration on the sorbent desulfurization/denitrification capacity was studied using Design-Expert Version 6.0.6 software. Specifically, Central Composite Design (CCD) coupled with Response Surface Method (RSM) was used. Significant individual parameters that affect the sorbent capacity are copper loading and NaOH concentration. Apart from that, interaction between the following parameters was also found to have significant effect; copper loading, RHA/CaO ratio and NaOH concentration. The optimum sorbent preparation condition for this study was found to be 3.06% CuO loading, RHA/CaO ratio of 1.41, 8.05 h of hydration period and NaOH concentration of 0.80 M. Sorbent characterization using SEM, XRD and surface area analysis were used to describe the effect of sorbent preparation parameters on the desulfurization/denitrification activity. PMID- 20724076 TI - A serological and molecular survey of cattle hypodermosis in east-Turkey. AB - The aim of this study was to determine the seroprevalence of hypodermosis in cattle in East-Turkey and to identify Hypoderma species using morphological and molecular methods. For this purpose, a total of 778 serum samples of cattle were collected from Erzurum provinces of east-Turkey from December 2008 to February 2009. The sera were analyzed using a Hypodermin C antigen by means of indirect ELISA. In addition, 10 Hypoderma spp. larvae were collected from slaughtered animals in the abattoir for morphological identification and molecular characterization on the basis of mitochondrial CO1 gene sequence analysis and PCR RFLP. Two hundred and twenty three (28.6%) out of 778 cattle were seropositive for hypoderma antibodies. All positive cattle were female of a local breed. Seven out of 10 Hypoderma larvae were morphologically classified as third instar larvae (L3) of H. bovis and 3 were classified as L3 of H. lineatum. The TaqI restriction enzyme was used to differentiate the Hypoderma species on the basis of the 438 and 250 bp bands for H. bovis and the 488 and 200 bp bands for H. lineatum resulting from PCR-RFLP. According to the alignment of the mitochondrial CO1 sequences of the Hypoderma species and the PCR-RFLP results, all examined larva samples were classified as H. bovis. PMID- 20724077 TI - Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. AB - Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate stage HCC includes a heterogeneous population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options. Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE. Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients. PMID- 20724078 TI - Luteinising hormone releasing hormone agonists (LH-RHa) in premenopausal early breast cancer patients: current role and future perspectives. AB - Luteinising hormone releasing hormone agonists (LH-RHa) induce ovarian suppression in premenopausal women that is usually reversible on cessation of therapy. They act by binding to pituitary LH-RH receptors, resulting in down regulation of receptors and subsequent suppression of luteinising hormone and estradiol. LH-RHa are effective in the treatment of advanced breast cancer in premenopausal women but their role as adjuvant treatment of early breast cancer is still controversial. Approximately 60% of tumors in premenopausal women are hormone sensitive and these patients are candidates for hormonal treatment. Tamoxifen for 5 years is considered the standard endocrine therapy for all premenopausal women with hormone sensitive breast cancer. There is no definitive evidence of additional benefit associated with the use of LH-RHa administered as an alternative or in addition to tamoxifen. In this review we discuss available data on the role of LH-RHa alone or in combination with tamoxifen; on the role of LH-RHa in combination with aromatase inhibitors; and on the potential role of LH RHa as a strategy to preserve ovarian function during adjuvant chemotherapy. PMID- 20724080 TI - Psychological traits and the cortisol awakening response: results from the Netherlands Study of Depression and Anxiety. AB - BACKGROUND: Hypothalamus-Pituitary-Adrenal (HPA) axis dysregulation is often seen in major depression, and is thought to represent a trait vulnerability - rather than merely an illness marker - for depressive disorder and possibly anxiety disorder. Vulnerability traits associated with stress-related disorders might reflect increased sensitivity for the development of psychopathology through an association with HPA axis activity. Few studies have examined the association between psychological trait factors and the cortisol awakening response, with inconsistent results. The present study examined the relationship between multiple psychological trait factors and the cortisol awakening curve, including both the dynamic of the CAR and overall cortisol awakening levels, in a sample of persons without psychopathology, hypothesizing that persons scoring high on vulnerability traits demonstrate an elevated cortisol awakening curve. METHODS: From 2981 participants of the Netherlands Study of Depression and Anxiety (NESDA), baseline data from 381 controls (aged 18-65) without previous, current and parental depression and anxiety disorders were analyzed. Psychological measures included the Big Five personality traits (neuroticism, extraversion, openness to experience, conscientiousness, and agreeableness) measured using the NEO-FFI, anxiety sensitivity assessed by the Anxiety Sensitivity Index, cognitive reactivity to sadness (hopelessness, acceptance/coping, aggression, control/perfectionism, risk aversion, and rumination) as measured by the LEIDS-R questionnaire, and mastery, assessed using the Pearlin and Schooler Mastery scale. Salivary cortisol levels were measured at awakening, and 30, 45, and 60 min afterwards. RESULTS: In adjusted analyses, high scores of hopelessness reactivity (beta=.13, p=.02) were consistently associated with a higher cortisol awakening response. In addition, although inconsistent across analyses, persons scoring higher on extraversion, control/perfectionism reactivity, and mastery tended to show a slightly flatter CAR. No significant associations were found for neuroticism, openness to experience, agreeableness, conscientiousness, anxiety sensitivity, and acceptance/coping, aggression, or risk aversion reactivity. CONCLUSION: Of various psychological traits, only hopelessness reactivity, a trait that has been associated with depression and suicidality, is consistently associated with HPA axis dysregulation. Hopelessness reactivity may represent a predisposing vulnerability for the development of a depressive or anxiety disorder, possibly in part mediated by HPA axis activity. PMID- 20724079 TI - Interleukin-15 affects serotonin system and exerts antidepressive effects through IL15Ralpha receptor. AB - Contrary to the reduction of depressive-like behavior observed in several strains of cytokine receptor knockout mice, mice lacking the specific receptor for interleukin (IL)-15 showed increased immobility in tail suspension and modified forced swimming tests. There was also a reduction in social interactions. The hippocampus of the IL15Ralpha knockout mice had decreased mRNA for 5-HT(1A), increased mRNA for 5-HT(2C), and region-specific changes of serotonin reuptake transporter (SERT) immunoreactivity. Fluoxetine (the classic antidepressant Prozac, which inhibits 5-HT(2C) and SERT) reduced the immobility of the IL15Ralpha knockout mice in comparison with their pretreatment baseline. Together with the unchanged performance of the IL15Ralpha knockout mice on the rotarod, this response to fluoxetine indicates that the immobility reflects depression. Wildtype mice responded to IL15 treatment with improvement of immobility induced by forced swimming, whereas the knockout mice failed to respond. Thus, the cognate IL15 receptor is necessary for the antidepressive activity of IL15. In ex vivo studies, IL15 decreased synaptosomal uptake of 5-HT, and modulated the expression of 5-HT(2C) and SERT in cultured neurons in a dose- and time-dependent manner. Thus, the effect of IL15 on serotonin transmission may underlie the depressive-like behavior of IL15Ralpha knockout mice. We speculate that IL15 is essential to maintain neurochemical homeostasis and thereby plays a role in preventing neuropsychiatric symptoms. PMID- 20724081 TI - Revenue implications to the Vietnamese government of using taxes to curb cigarette smoking. AB - This study explores the impact on government taxation revenue from increasing excise on cigarettes in Vietnam. A dynamic population model is used to estimate future patterns (both prevalence and consumption) of tobacco use in Vietnam, with and without changes to tobacco excise for the period 2006-2016. Three increases in the base case excise tax rate of 55% are modelled: 65%, 75% and 90%. Various price elasticities are used to examine variations in cigarette consumption while cross price elasticities are used to explore shifts from cigarette to other forms of tobacco. Revenue implications for the period 2006-2016 are reported as discounted net present values (NPV) in 2006 values. The model predicts that smoking rates in 2016, for both males and females, are marginally lower than base case estimates for all taxation excise options with higher price elasticities generating greater reductions in prevalence. In all cases, compared to base case estimates, the results indicate a fall in number of smokers, a reduction in amount of tobacco consumed and an increase in overall taxation revenue. The additional gain in government revenue, expressed in NPV terms, ranges from a low of VND 69,579 billion (or USD $4.35 billion) to a high of VND 108,492 billion (or USD $6.79 billion). Increases in tobacco excise provide an opportunity for the Vietnamese government to increase revenue at the same time as reducing tobacco consumption. Further research into the wider social and economic consequences of increasing tobacco excise in Vietnam is warranted. PMID- 20724082 TI - Floating distal interphalangeal joint injury: case report. AB - A 37-year-old man sustained a floating distal interphalangeal (DIP) joint injury to the left index finger. The diagnosis was not confirmed until 3 months after the injury because of minimal deformity of the injured finger. Open reduction and internal fixation of the dorsally displaced floating DIP joint was carried out. Bone union was achieved but radiographs revealed osteoarthritis of the DIP joint. PMID- 20724083 TI - The effects of priming restrained versus disinhibited behaviour on alcohol seeking in social drinkers. AB - BACKGROUND: Deficient response inhibition (disinhibition) may play a causal role in alcohol abuse, with impaired inhibition occurring prior to, and acting as a risk factor for, subsequent alcohol problems. We experimentally primed either disinhibited or restrained behaviour while participants completed a Stop-Signal task, before examining the effects on alcohol-seeking behaviour. METHODS: Fifty three social drinkers completed a Stop-Signal task following instructions that either emphasised rapid responding at the expense of successful inhibition (Disinhibition group) or vice versa (Restrained group). Subsequent ad lib alcohol seeking was measured with a bogus taste test. RESULTS: As predicted, participants in the Disinhibition group consumed more beer during the taste test compared to participants in the Restrained group. Furthermore, within the Restrained group only, correlations indicated that those participants who responded more cautiously during the Stop-Signal task subsequently consumed less beer. CONCLUSIONS: An experimental manipulation of response set during a response inhibition task, emphasising either restrained or disinhibited responding, has a causal influence on alcohol-seeking behaviour in social drinkers. PMID- 20724084 TI - Postmortem mRNA profiling II: Practical considerations. AB - Using human postmortem tissues for gene expression studies is particularly challenging. Besides the problem of impaired RNA one has to face a very high degree of biological variance within a sample set. Variations of individual parameters like age, body mass, health, but also the cause and circumstances of death and the postmortem interval lead to a rather inhomogeneous collection of samples. To meet these problems it is necessary to consider certain precautions before starting a gene expression project. These precautions include the sample collection and the determination of the RNA integrity, the number of replicates needed and the methods used for reverse transcription and quantitative polymerase chain reaction, but also the strategy for data normalisation and data interpretation. In this article practical issues are discussed to address some of the problems occurring in the work with postmortem human samples obtained during medico-legal autopsy. PMID- 20724085 TI - mRNA profiling in forensic genetics I: Possibilities and limitations. AB - Molecular investigations gain increasing interest in forensic medicine. Examination of gene expression levels at the time point of death might have the power to become a complementing tool to the current methods for the determination of cause and circumstances of death. This includes pathophysiological conditions of disease and injury as well as the duration of agony or other premortem factors. Additionally, recent developments in forensic genetics revealed that tissue specific mRNAs can be used to determine the type of body fluid present in a crime scene stain. Although RNA is known to be rather instable, RNA could be extracted in adequate quality from tissue samples collected during medico-legal autopsy. Nevertheless, working with human postmortem tissue means to deal with highly variable RNA integrities. This review aims to give a brief overview of the possible advantages of postmortem mRNA profiling and to shed further light into the limitations of this method arising from reduced RNA integrities. PMID- 20724086 TI - Canine pulp ratios in estimating pensionable age in subjects with questionable documents of identification. AB - One of the most interesting reasons for needing to estimate age in adult subjects is to ascertain the age of a person of questionable pensionable age. This problem is becoming increasingly important in Europe, owing to the high number of immigrants without valid birth certificates. The aim of this paper is to evaluate the application of the apposition of secondary dentine of canines by the method of Cameriere et al. [10], in order to estimate the pensionable age of subjects without proper birth certificates. Periapical X-rays of 180 canines from 90 subjects aged between 50 and 79, 46 men and 44 women, were analysed. Estimated ages were used to test the medico-legal question as to whether an individual was older or younger than 65 years of age. In subjects under 65, age was correctly evaluated in 91% and 89% of individuals using maxillary and mandibular canines, respectively. In subjects over 65, of pensionable age, estimates were correct in 85% and 88% of cases, respectively. The proportion of individuals with correct classifications was 89% for both maxillary and mandibular canines taken together. In only four subjects, the results of maxillary and mandibular canines were discordant; in the other 86 subjects, the test of maxillary and mandibular canines yielded concordant results. Among the latter, the proportion of individuals who were really aged 65 years or older, and who were correctly estimated as such, was 94%, and the proportion of individuals younger than 65 years of age who were correctly estimated as such was 96%. PMID- 20724087 TI - Two types of direction-changing positional nystagmus with neutral points. AB - OBJECTIVES: We encountered patients who had static direction-changing positional nystagmus (DCPN) canceled at about 20-30 degrees yaw head rotation from the supine position. This nystagmus was also canceled when the head was rotated 180 degrees from this position. We termed these head positions neutral points. The positional nystagmus observed (except at the neutral points) was thought to occur due to a "heavy cupula" or "light cupula". The purpose of this study was to examine DCPN with neutral points as well as the pathomechanism of this condition. METHODS: Retrospective case review of patients attending two hospitals. Sixteen patients who exhibited DCPN with neutral points were examined using an infrared camera (installed in goggles). Using this system, the vestibulo-ocular reflex (VOR) was recorded, and VOR gain was obtained. Vestibular function and the affected side were determined. In addition, the angle between the supine position and neutral point was measured in each patient. We also examined other positional nystagmus occurring at other times. RESULTS: In the heavy cupula type group, we noted positional nystagmus for which repositioning maneuvers were successful, whereas, in the light cupula type group, repositioning maneuvers were not effective. The angle between supine position and neutral point was 26.5 +/- 11.6 degrees . CONCLUSIONS: Heavy cupula type may occur as a result of otoconia while light cupula type may be due to the specific gravity of the endolymph. The VOR gain and side of the benign paroxysmal positional vertigo (BPPV) observed suggested that the affected side was that to which the neutral point was deviated. PMID- 20724088 TI - Effectiveness and safety of non-intravenous high-dose phenobarbital therapy for intractable epilepsy during childhood. AB - High-dose phenobarbital (PB) therapy is effective for refractory status epilepticus. We reviewed medical records of patients with intractable partial epilepsies on whom performed non-intravenous high-dose PB therapy. Thirteen patients received PB rectally or orally at a dosage of 20-30mg/kg/day initially, and the PB dosage was gradually reduced to a maintenance dosage of 5-10mg/kg/day orally. We evaluated the effectiveness and safety of this procedure after 14days at the maintenance dosage level. Twelve patients had partial seizures and one had secondary generalized seizures. In six of 13 patients (46%), seizure frequencies decreased more than 50%, and two of 13 patients (15%) became seizure free. In five of seven patients who were treated by continuous midazolam infusion therapy, we were able to discontinue the midazolam therapy. Adverse effects were found in seven of 13 patients. We were able to continue high-dose PB therapy in six patients because their adverse effects were transient and improved after a decrease in PB concentration, but we discontinued this therapy in the patient who developed Stevens-Johnson syndrome. Respiratory depression and hypotension were not found in our study. We conclude that high-dose PB therapy is effective and may be considered as an additional treatment for intractable partial epilepsy in childhood. PMID- 20724089 TI - [A case of Salmonella enterica serovar typhi with decreased susceptibility to ciprofloxacin]. AB - The use of fluoroquinolone (FQ) as first line therapy for typhoid fever should be reconsidered because of the emergence of Salmonella Typhi and Paratyphi A strains with decreased susceptibility to FQ, mainly from Asia. Relapse can occur when ciprofloxacin MIC is over 0.12 mg/l, as illustrated by our case report. Azithromycin can be used successfully for patients infected with reduced ciprofloxacin susceptibility isolates. Literature review led us to suggest a new therapeutic strategy for uncomplicated typhoid fever, the antibiotic was chosen according to nalidixic acid susceptibility and ciprofloxacin MIC of the strain. High-dose intravenous ceftriaxone (4 g per day) is always efficient in first line therapy. Depending on FQ susceptibility testing results, it is relayed by oral therapy with a FQ (ciprofloxacin 500 mg bid for 7 days) if the isolate has maintained susceptibility, or azithromycin (1 g first day and 500 mg per day, 7 days) if the isolate is resistant to nalidixic acid or has a ciprofloxacin MIC superior to 0.12 mg/l. PMID- 20724090 TI - Evaluation of the early enhancement of coronary atherosclerotic plaque by contrast-enhanced MR angiography. AB - PURPOSE: To evaluate the early enhancement of coronary atherosclerotic plaque using contrast-enhanced MR angiography (CE-MRA) and investigate the association between unstable angina pectoris (UAP) and early enhancement of the plaque. METHODS: Forty-one patients presenting with angina pectoris and demonstrating single-vessel disease with non-calcified plaque and significant coronary stenosis (>=50%) on CTA were consecutively recruited for coronary CE-MRA. Contrast-to noise ratio of the culprit plaque guided by CTA was measured on a cross-sectional multi-planar reconstruction image of the plaque on both pre- and post-CE-MRA. A 50% increasing of CNR was defined as plaque enhancement. The association between early enhancement of the plaques and UAP was analyzed. RESULTS: Thirty-seven non calcified plaques with significant coronary stenosis were detected in the 37 patients on MRA. 4 subjects were excluded because coronary atherosclerotic plaques were inadequate for identification on MRA. Of the 37 patients, 18 patients had UAP and other 19 patients presented stable angina pectoris (SAP). Of the 37 plaques on CE-MRA, 13 and 24 plaques presented early enhancement and no enhancement, respectively. Of the 13 early-enhanced plaques, 11 (85%) and 2 (15%) were found in the patients with UAP and SAP, respectively (p<0.01). Of the 37 patients, 11 (61%) with UAP and 2 (11%) with SAP had early-enhanced plaques, respectively (p<0.01). CONCLUSION: CE-MRA allows detection of early enhancement of coronary atherosclerotic plaque. The early enhancement is common in unstable angina and could be a sign of vulnerability. PMID- 20724091 TI - Vibrio celticus sp. nov., a new Vibrio species belonging to the Splendidus clade with pathogenic potential for clams. AB - A group of four motile facultative anaerobic marine isolates (Rd 8.15(T) [=CECT 7224(T), =LMG 23850(T)], Rd 16.13, Rd 6.8 [=LMG 25696] and Rd2L5) were obtained from cultured clams (Ruditapes philippinarum and Venerupis pullastra) in Galicia, north-western Spain. They formed a tight phylogenetic group based on sequences of the 16S rRNA gene and the four housekeeping genes rpoA (encoding the alpha-chain of RNA polymerase), rpoD (encoding the sigma factor of RNA polymerase), recA (encoding RecA protein), and atpA (encoding the alpha-subunit of bacterial ATP synthase). The phylogenies based on these sequences indicated that the four isolates represented a novel species in the genus Vibrio, and more precisely in the Splendidus clade. DNA-DNA hybridizations with the type strains of species showing more than 98.6% 16S rRNA gene sequence similarity, revealed a DNA-DNA relatedness below 70%. The isolates could be differentiated from the phylogenetically related Vibrio species on the basis of several phenotypic features. In addition, strain Rd 8.15(T) showed potential pathogenic activity for adult clams in virulence assays. The name Vibrio celticus sp. nov. is proposed for this new taxon, with the type strain being Rd 8.15(T) (=CECT 7224(T), =LMG 23850(T)). PMID- 20724092 TI - Quantitation of irbesartan and major proteins in human plasma by mass spectrometry with time-of-flight analyzer. AB - A simple matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method was developed to analyze irbesartan in human plasma. Irbesartan is a kind of angiotensin II receptor blocker (ARB) and is used as an antihypertensive drug. MALDI-TOF MS is a rare application for clinical drug analysis in human plasma. After simple micro-liquid-liquid extraction, irbesartan containing supernatant was spotted on a target plate, mixed with matrix and then detected by MALDI-TOF MS within the clinically therapeutic range. Furthermore, we used cheaper chemical analogues to label the major proteins in human plasma for protein quantitation. After enzyme digestion, peptide mixtures were injected into nanoliquid chromatography (nanoLC) coupled with tandem mass spectrometry (MS-MS). Protein identification could be carried out simultaneously by peptide sequencing and database searching. Chemical analogue labeling method is an alternative way for expensive isotope reagents. Quantity change of proteins before and after administration of irbesartan could be detected by this method. Application of these methods in human plasma demonstrated that these two micro-scale MS methods used for clinical drug monitoring, protein quantitation and identification are successful. PMID- 20724093 TI - Separation of vinca alkaloid enantiomers by capillary electrophoresis applying cyclodextrin derivatives and characterization of cyclodextrin complexes by nuclear magnetic resonance spectroscopy. AB - In this work, the enantiomeric separation of three vinca alkaloid enantiomers (vincamine, vinpocetine and vincadifformine) has been investigated in an aqueous capillary electrophoresis (CE) system using cyclodextrins (CDs). The investigated CDs were the native alpha-, beta-, and gamma-CDs and their hydroxypropylated, randomly methylated, carboxymethylated and sulfobutylated derivatives. The first part of this study consisted of the determination of the apparent averaged complex stability constants with the selected CDs. Several parameters, such as the nature and the concentration of the CD, were studied and were found to have a significant effect on the enantiomeric resolution for all studied compounds. All three vinca alkaloids were successfully enantioseparated with CDs where different migration orders were observed in case of several CDs depending on the cavity size or substituent of the host. Chiral separation and determination of the stability constants were also performed with NMR spectroscopy which confirmed the CE results. Averaged stoichiometries of the complexes were determined using the Job plot method resulting in a 1:1 complex irrespective of the alkaloid enantiomers or cyclodextrin derivative. The structures of the inclusion complexes were elucidated using 2D ROESY NMR spectroscopy. On the basis of NMR results reversal of enantiomer migration order was clarified in various cases. PMID- 20724094 TI - Development and validation of rapid ion-chromatographic method with conductivity detection for trace level determination of allylamine in sevelamer drug substances. AB - A sensitive and rapid ion chromatography (IC) method was developed for the low level determination of allylamine (AAM) in sevelamer (SVM) drug substances, i.e., sevelamer hydrochloride (SVH) and sevelamer carbonate (SVC). This method utilized a Dionex Ion Pack CS14 IC column, a mobile phase of 10mM methane sulfonic acid with conductivity detection. The total chromatographic run time was as short as 8 min. The various factors involved in the sample preparation such as, extraction solvent, extraction time and stirrer speed were evaluated. This method was validated as per United States Pharmacopoeia (USP) and International Conference on Harmonization (ICH) guidelines in terms of detection limit, quantitation limit, linearity, precision, accuracy, specificity and robustness. Linearity of the method was very good over the concentration range of 9-750 MUg/mL with the coefficient of determination (r(2)) 0.999. The detection and quantitation limit of AAM were 2.7 and 9.0 MUg/mL, respectively. The recovery data obtained for AAM were between 97% and 109%. Also, the specificity of the method was proved through IC coupled with mass spectrometer (IC-MS). The developed method was found to be robust and applied successfully to determine the content of AAM in Sevelamer bulk drugs. PMID- 20724096 TI - Open techniques for arch vessel reconstruction during thoracic endovascular aneurysm repair (TEVAR). PMID- 20724095 TI - HIV patients' willingness to share personal health information electronically. AB - OBJECTIVE: To assess the attitudes of persons living with HIV/AIDS (PLWH) towards having their personal health information (PHI) stored and shared electronically. METHODS: PLWH (n = 93) in New York City completed surveys using audio computer assisted self-interview (ACASI) that assessed willingness to share their PHI with various people and entities via a secure electronic network. The survey also included questions on satisfaction with and trust of health care providers, current health, HIV-associated stigma, and frequency of internet access. Data were analyzed with descriptive and multivariate statistical methods. RESULTS: The majority (84%) of individuals were willing to share their PHI with clinicians involved in their care. Fewer individuals (39%) were as willing to share with non clinical staff. Willingness to share PHI was positively associated with trust and respect of clinicians. CONCLUSION: PLWH accepted clinicians' need for access to accurate information. Patients' trust in their primary care providers highlights the importance of the clinician-patient relationship which can be used to engage patients support for health information exchange initiatives. PRACTICE IMPLICATIONS: As electronic storage and sharing of PHI is increasing, clinicians and PLWH should discuss patients' attitudes towards sharing PHI electronically. PMID- 20724097 TI - Endoleak management and postoperative surveillance following endovascular repair of thoracic aortic aneurysms. PMID- 20724098 TI - Endovascular techniques for arch vessel reconstruction. PMID- 20724099 TI - Long-term outcomes of secondary procedures after endovascular aneurysm repair. AB - PURPOSE: This study evaluated the outcomes of secondary procedures after endovascular aneurysm repair (EVAR). METHODS: From 2002 to 2009, 1768 patients underwent EVAR for treatment of 1662 elective (94%) and 106 emergent (6%) infrarenal abdominal aortic aneurysm (AAA) with a variety of Food and Drug Administration-approved and commercially available stent grafts. Postoperative follow-up included clinical examination, pulse volume recording, duplex ultrasound imaging, and computed tomography and magnetic resonance angiography at 1, 6, and 12 months, and yearly thereafter. Patients with type I and III endoleaks, unexplained endotension, limb occlusion, stent graft migration, with and without type I endoleak, and aneurysm rupture underwent secondary interventions. Type II endoleak at >6 months without a decrease in the aneurysm sac underwent translumbar embolization. Data were prospectively collected. RESULTS: EVAR was performed in 1768 patients. During a mean follow-up of 34 (SD, 30.03) months, 339 patients (19.2%) required additional secondary procedures for aneurysm-related complications, including type I (n = 51, 15.0%), type II (n = 136, 40.1%), and type III (n = 5, 1.5%) endoleaks; endotension (n = 8, 2.4%), stent graft migration proximal fixation site (n = 46, 13.6%), stent graft iliac limb thrombosis or stenosis (n = 25, 7.4%), subsequent iliac aneurysm formation (n = 39, 11.5%), or aneurysm rupture after EVAR (n = 29, 8.6%). The mean age was 74 (SD, 9.15) years. Mean AAA size was 5.7 (SD 3.24) cm. Compared with secondary procedures for AAA rupture, the nonrupture patients had a significantly lower mortality (1.6% vs 17.2%, P < .05) and a higher likelihood of being managed by endovascular means (98.8% vs 44.8%, P < .05). When nonruptured EVAR patients required urgent secondary procedures for type I endoleaks and stent graft migration or limb thrombosis, the mortality was 6.0% vs 0.5% for elective procedures (P < .05). CONCLUSIONS: Our long-term EVAR experience indicates that 18% of patients require additional secondary procedures, and most of these patients can be managed by endovascular means with an acceptable overall mortality of 2.9%. Most type I and II endoleaks can be successfully treated by transluminal embolization, and most patients with delayed aneurysm rupture after EVAR can be successfully managed by endovascular or open surgical repair. PMID- 20724100 TI - Discussion. Long-term outcomes of secondary procedures after endovascular aneurysm repair. PMID- 20724101 TI - Endovascular aneurysm repair for ruptured abdominal aortic aneurysm: the Albany Vascular Group approach. AB - Improvements in endovascular technology and techniques have allowed us to treat patients in ways we never thought possible. Today, endovascular treatment of ruptured abdominal aortic aneurysms is associated with markedly decreased morbidity and mortality compared with the open surgical approach, yet there are several fundamental obstacles in our ability to offer these endovascular techniques to most patients with ruptured aneurysms. This article will focus on the technical aspects of endovascular aneurysm repair for rupture, with particular attention to developing a standardized multidisciplinary approach that will help vascular surgeons deal with not just the technical aspects of these procedures but also address some of the challenges, including the availability of preoperative computed tomography, the choice of anesthesia, the percutaneous vs femoral cutdown approach, use of aortic occlusion balloons, need for bifurcated vs aortouniiliac stent grafts, need for adjunctive procedures, diagnosis and treatment of abdominal compartment syndrome, and conversion to open surgical repair. PMID- 20724102 TI - Establishment of steady-state metabolism of ethanol in perfused rat liver: the quantitative analysis using kinetic mechanism-based rate equations of alcohol dehydrogenase. AB - Alcohol dehydrogenase (ADH) catalyzes oxidation of ingested ethanol to acetaldehyde, the first step in hepatic metabolism. The purpose of this study was to establish an ex vivo rat liver perfusion system under defined and verified steady states with respect to the metabolites and the metabolic rates, and to quantitatively correlate the observed rates with simulations based on the kinetic mechanism-based rate equations of rat liver ADH. Class I ADH1 was isolated from male Sprague-Dawley rats and characterized by steady-state kinetics in the Krebs Ringer perfusion buffer with supplements. Nonrecirculating liver perfusion with constant input of ethanol at near physiological hepatic blood flow rate was performed in situ. Ethanol and the related metabolites acetaldehyde, acetate, lactate, and pyruvate in perfusates were determined. Results of the initial velocity, product, and dead-end inhibition studies showed that rat ADH1 conformed to the Theorell-Chance Ordered Bi Bi mechanism. Steady-state metabolism of ethanol in the perfused liver maintained up to 3h as evidenced by the steady state levels of ethanol and metabolites in the effluent, and the steady-state ethanol disappearance rates and acetate production rates. The changes of the metabolic rates were qualitatively and in general quantitatively correlated to the results from simulations with the kinetic rate equations of ADH1 under a wide range of ethanol, in the presence of competitive inhibitor 4-methylpyrazole and of uncompetitive inhibitor isobutyramide. Preliminary flux control analysis estimated that apparent C(ADH)(J) in the perfused liver may approximate 0.7 at constant infusion with 1-2 mM ethanol, suggesting that ADH plays a major but not the exclusive role in governing hepatic ethanol metabolism. The reported steady state rat liver perfusion system may potentially be applicable to other drug or drug-ethanol interaction studies. PMID- 20724103 TI - The impact of publication of Australian treatment recommendations for DCIS on clinical practice: A population-based, "before-after" study. AB - BACKGROUND: Clinical practice guidelines/recommendations have been promoted as a mechanism for ensuring evidence-based medicine. We examine the impact of the publication of Australian treatment recommendations (ATR) for ductal carcinoma in situ (DCIS) on clinical practice and surgeons' attitudes to the ATR. METHODS: All new cases of DCIS diagnosed in the 12-months immediately before the ATR release (pre-ATR: September 2002 to August 2003) and three years later (post-ATR: September 2006 to August 2007) were identified from the state of Victoria's population cancer registry. Treatment information, extracted for each case by treating surgeon or study manager, was available for 342 of 353 (97%) tumours pre ATR and 371 of 378 (98%) tumours post-ATR. Sixty-three surgeons (58% response) completed a survey on awareness and attitudes to the ATR. RESULTS: The proportion of cases undergoing image-guided biopsy, or breast conservation surgery (BCS) did not change between surveys nor did extent of surgical margins. Compared to the pre-ATR period, more BCS cases were referred to a radiation oncologist (67% versus 58%) and more received radiotherapy (53% versus 44%) post-ATR. Tumours greater than 20 mm, of intermediate grade and moderate necrosis were more likely to receive radiotherapy post-ATR. While surgeons agreed with most recommendations, items reflecting radiotherapy recommendations generated most disagreement. CONCLUSION: With the possible exception of adjuvant radiotherapy, most DCIS cases were treated according to treatment recommendations before the ATR's release. The lack of change in radiotherapy for low grade, smaller tumours may reflect surgeon's uncertainty regarding this therapy for all BCS treated cases. PMID- 20724104 TI - [A simple technique to retrieve a guidewire forgotten within a central venous catheter]. PMID- 20724105 TI - [Uterine embolization in the operating theater in severe post-partum haemorrhage]. AB - Uterine embolization is indicated in severe post-partum hemorrhage. Bearing in mind the potential transfer risks, it is usually done in an angiography room when the patient's circulatory condition is stable. If no angiography room is available, an alternative care strategy could consist of performing embolizations in operating theater with suitable equipment. Over a 3-year period, in our center, 10 uterine embolizations have been done in operating theater. This approach proved feasible in satisfactory conditions. Embolization was efficient for eight patients. For the remaining two patients, an hysterectomy was performed immediately without any transfer constraint. PMID- 20724106 TI - [Chlorobutanol poisoning: about a case]. PMID- 20724107 TI - [Sciatic block nerve by emergency physicians]. PMID- 20724108 TI - Evaluation of the clinical application of the ACCF/ASE appropriateness criteria for stress echocardiography. AB - BACKGROUND: The aim of this study was to evaluate the clinical application of the American College of Cardiology Foundation and American Society of Echocardiography appropriateness criteria for stress echocardiography (SE) in a single-center university hospital. METHODS: Indications were determined for consecutive studies by two reviewers and categorized as appropriate, uncertain, or inappropriate. RESULTS: Of 477 studies for which primary indications could be determined, 188 specifically related to university transplantation programs were excluded. Of the remaining 289 studies, 88% were addressed in the appropriateness criteria for SE. Of these, 71% were appropriate, 9% were uncertain, and 20% were inappropriate. Inappropriate studies were more likely to be ordered on younger patients and women and were less likely to be ordered by cardiologists. Abnormal results on SE were more frequent among appropriate than inappropriate studies. CONCLUSIONS: The appropriateness criteria for SE encompass and effectively characterize the majority of studies ordered in a single-center university hospital and appear to reasonably stratify the likelihood of abnormal results on SE. However, revisions will be required to fully capture and stratify appropriate clinical practice of SE. PMID- 20724109 TI - A novel method for detection of pigment network in dermoscopic images using graphs. AB - We describe a novel approach to detect and visualize pigment network structures in dermoscopic images, based on the fact that the edges of pigment network structures form cyclic graphs which can be automatically detected and analyzed. First we perform a pre-processing step of image enhancement and edge detection. The resulting binary edge image is converted to a graph and the defined feature patterns are extracted by finding cyclic subgraphs corresponding to skin texture structures. We filtered these cyclic subgraphs to remove other round structures such as globules, dots, and oil bubbles, based on their size and color. Another high-level graph is created from each correctly extracted subgraph, with a node corresponding to a hole in the pigment network. Nodes are connected by edges according to their distances. Finally the image is classified according to the density ratio of the graph. Our results over a set of 500 images from a well known atlas of dermoscopy show an accuracy of 94.3% on classification of the images as pigment network Present or Absent. PMID- 20724110 TI - Patient-specific bivariate-synchrony-based seizure prediction for short prediction horizons. AB - This paper evaluates the patient-specific seizure prediction performance of pre ictal changes in bivariate-synchrony between pairs of intracranial electroencephalographic (iEEG) signals within 15min of a seizure in patients with pharmacoresistant focal epilepsy. Prediction horizons under 15min reduce the durations of warning times and should provide adequate time for a seizure control device to intervene. Long-term continuous iEEG was obtained from 6 patients. The seizure prediction performance was evaluated for all possible channel pairs and for different prediction methods to find the best performing channel pairs and methods for both pre-ictal decreases and increases in synchrony. The different prediction methods involved changes in window duration, signal filtering, thresholding approach, and prediction horizon durations. Performance for each patient, for all seizures, was first compared with an analytical-Poisson-based random predictor. The performance of the top 5% of channel pairs for each patient closely matched the top 5% of analytical-Poisson-based random predictor performance indicating that patient-specific, bivariate-synchrony-based seizure prediction could be random in general (under the assumption that channel-pair prediction times are statistically independent). Analysis of the spatial patterns of performance showed no clear relationship to the seizure onset zone. For each patient the best channel pair showed better performance than Poisson-based random prediction for a selected subset of prediction thresholds. Given the caveats of comparing with this form of random prediction, alarm time surrogates were employed to assess statistical significance of a four-fold out-of-sample cross validation analysis applied to the best channel-pairs. The cross-validation analysis obtained reasonable testing performance for most patients when performance was compared to random prediction based on alarm time surrogates. The most significant case was a patient whose testing set sensitivity and false positive rate were 0.67+/-0.09 and 3.04+/-0.29h(-1), respectively, for decreases in synchrony, an intervention time of 15min and a seizure onset period of 5min. For each testing set for this patient, performance was better than that obtained by random prediction at the significance level of 0.05 (average sensitivity of 0.47+/-0.05). Moreover, there were 9 seizures in each testing set which gives greater power to this cross-validation result, although the cross-validation was performed on the best channel pair selected by within-sample optimization for all seizures of the patient. Further validation with larger datasets from individual patients is needed. Improvements in prediction performance should be achievable through investigations of multivariate synchrony combined with non-linear classification methods. PMID- 20724111 TI - Psychophysiological prodromal signs of schizophrenic relapse: a pilot study. AB - Do physiological changes occur shortly prior to psychotic relapse in schizophrenia outpatients? We addressed this question in a group of schizophrenia outpatients by measuring changes in symptoms and changes in activation of the sympathetic nervous system, as indexed by changes in skin conductance level (SCL), on a biweekly basis for between one and two years. All six outpatients exhibited heightened SCL within two weeks prior to relapse or exacerbation, compared to SCL proceeding continued remission. These results shed light on the psychotic relapse process and are consistent with neural diathesis-stress models of schizophrenia. PMID- 20724112 TI - Duration of untreated psychosis and ethnicity. PMID- 20724113 TI - Left dorsolateral prefrontal cortex dysfunction in medication-naive schizophrenia. AB - Abnormalities in the frontal lobe are considered to be central to the pathology of schizophrenia. Neuroimaging studies indeed report abnormal function of the frontal lobe in schizophrenia patients. However, the nature of these functional abnormalities is unclear, in particular whether they are affected by medication. We therefore investigated whether frontal functioning is already abnormal in first-episode medication-naive schizophrenia, and if so, if this dysfunction is related to symptomatology. Thirty medication-naive male patients with first episode schizophrenia and 36 matched healthy controls performed a modified working memory task while fMRI data were acquired. During the task, subjects were presented with novel task (NT) and practiced task (PT) memory sets. Compared to controls, patients showed reduced performance during NT and PT. However, both groups performed better during PT, indicating that practice improved performance. Importantly, practice reduced brain activation in both patients and controls, but this effect of practice was significantly smaller in patients compared to controls, specifically in the left dorsolateral prefrontal cortex (DLPFC; p=0.01). The reduced effect of practice on brain activation was related to the severity of negative symptoms and disorganization. These results suggest that DLPFC function is deficient in the early phases of schizophrenia and cannot be attributed to the use of antipsychotics. PMID- 20724114 TI - Aberrant salience network (bilateral insula and anterior cingulate cortex) connectivity during information processing in schizophrenia. AB - A salience network, comprising bilateral insula and anterior cingulate cortex (ACC), is thought to play a role in recruiting relevant brain regions for the processing of sensory information. Here, we present a functional network connectivity (FNC) analysis of spatial networks identified during somatosensation, performed to test the hypothesis that salience network connectivity is disturbed during information processing in schizophrenia. 19 medicated individuals with schizophrenia and 19 matched healthy controls participated in a functional magnetic resonance imaging study. 100 Hz vibrotactile stimuli were presented to the right index fingertip while whole-head blood oxygenation level-dependent contrast gradient-echo echo-planar images were acquired. Six spatial components of interest were identified using group independent component analysis: (1) bilateral insula, superior temporal and precentral gyrus (INS); (2) dorsal ACC; (3) left dorsolateral frontal and parietal cortex (left central executive network (LCEN)); (4) right dorsolateral frontal and parietal cortex (RCEN); (5) ventromedial frontal cortex (FDMN); and (6) precuneus, posterior cingulate and angular gyrus (PDMN). Maximal-lagged correlation was examined between all pairwise combinations of components. Significantly reduced FNC was observed in schizophrenia compared to controls between: INS and ACC; INS and FDMN; and LCEN and PDMN. There was no evidence of increased FNC in schizophrenia. Reduced salience network connectivity during information processing in schizophrenia suggests disturbance to the system which effects changes between contextually-relevant functional brain states. This aberrance may provide a mechanistic explanation of several clinical features of the disorder. PMID- 20724115 TI - Hypomethylation and overexpression of CD70 (TNFSF7) in CD4+ T cells of patients with primary Sjogren's syndrome. AB - BACKGROUND: Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration and the production of autoantibodies, leading to the destruction of lacrimal and salivary glands. However, very little is known about the pathogenesis of the disorder. CD70 (TNFSF7), a B cell costimulatory molecule, is overexpressed in CD4(+) T cells from patients with systemic erythematosus lupus (SLE) due to the hypomethylation of its promoter. OBJECTIVE: In this study we asked whether the epigenetic regulation of CD70 expression is abnormal in pSS. METHODS: CD70 levels in CD4(+) T cells from pSS patients, tinea pedis and healthy controls were measured by real-time RT-PCR and flow cytometry. Bisulphite sequencing was performed to determine the methylation status of the TNFSF7 promoter region. RESULTS: CD70 expression was significantly elevated and correlated with a decrease in TNFSF7 promoter methylation in pSS CD4(+) T cells compared to controls. CONCLUSIONS: Demethylation of the CD70 promoter regulatory elements contributes to CD70 overexpression in pSS CD4(+) T cells, and may contribute to autoreactivity. PMID- 20724116 TI - Homoisoflavanone inhibits UVB-induced skin inflammation through reduced cyclooxygenase-2 expression and NF-kappaB nuclear localization. AB - BACKGROUND: Since the generation of reactive oxygen species (ROS) and release of inflammatory mediators play a major role in UVB-induced inflammation, vigorous attempts have been made for the pharmacological management of these molecules as well as for uncovering the molecular signaling pathways. Homoisoflavanone (5,7 dihydroxy-3-(3-hydroxy-4-methoxybenzyl)-chroman-4-one, HIF) extracted from Cremastra appendiculata has anti-angiogenic activities, but its effect on inflammation was unknown. OBJECTIVE: To investigate the anti-inflammatory effects of HIF on the skin and the underlying molecular mechanisms. METHODS: HaCaT cells were irradiated by UVB (10 mJ/cm(2)) with or without HIF. Prostaglandin E(2) (PGE(2)) level was measured by enzyme immunoassay. Activation of MAPK and production of cyclooxygenase-2 (COX-2) were determined by Western blot analysis. Localization of nuclear factor kappa B (NF-kappaB) was assessed by immunofluorescence microscopy. Hairless mice were stimulated with UVB or chemical stimulants to induce inflammatory responses in skin. RESULTS: Pretreatment with HIF inhibited the production of intracellular ROS induced by UVB irradiation in HaCaT cells. Further analysis revealed a decrease in the level of MAPK activation and down-regulation of COX-2 expression. In addition, HIF attenuated the nuclear localization of NF-kappaB, resulting in the suppression of inflammatory molecules such as IL-6, IL-8, and TNF-alpha. Finally, topical treatment with HIF inhibited ear edema induced by UVB, 12-O-tetradecanoylphorbol-13-acetate (TPA), arachidonic acid (AA), or croton oil. CONCLUSION: HIF has a strong protective effect against proinflammatory responses, implying the possibility of preventive application for inflammatory skin diseases. PMID- 20724117 TI - Isolation of a VIM-1 metallo-beta-lactamase-producing Klebsiella pneumoniae isolate in Denmark. PMID- 20724118 TI - The post-antibiotic effect of manuka honey on gastrointestinal pathogens. PMID- 20724119 TI - Antimicrobial treatment of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) pneumonia: current and future options. AB - Meticillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of nosocomial pneumonia. Inadequate or inappropriate antimicrobial therapy, often caused by antimicrobial resistance, is associated with increased mortality for these infections. Agents currently recommended for the treatment of MRSA pneumonia include vancomycin and linezolid in the USA, and vancomycin, linezolid, teicoplanin and quinupristin/dalfopristin in Europe. Antimicrobials such as tigecycline and daptomycin, although approved for the treatment of some MRSA infections, have not demonstrated efficacy equivalent to the approved agents for MRSA pneumonia. Further agents lack data from randomised controlled trials (e.g. fosfomycin, fusidic acid or rifampicin in combination with vancomycin). Antimicrobial agents that have recently been approved or are being investigated as treatments for MRSA infections include the lipoglycopeptides telavancin (approved for the treatment of complicated skin and skin-structure infections in the USA and Canada), dalbavancin and oritavancin, the cephalosporins ceftobiprole and ceftaroline, and the dihydrofolate reductase inhibitor iclaprim. To be an effective treatment for MRSA pneumonia, antimicrobial agents must have activity against antimicrobial-resistant S. aureus, penetrate well into the lung, have a low potential for resistance development and have a good safety profile. Here, the available data for current and potential future MRSA pneumonia antimicrobials are reviewed and discussed. PMID- 20724120 TI - Evaluation of various isotherm models, and metal sorption potential of cyanobacterial mats in single and multi-metal systems. AB - Isotherm curves for the biosorption of Cu(II), Cd(II) and Pb(II) by the biomass of five different cyanobacterial mats (Mat # 1-5) showed concave shape and plateau. Suitability of ten different isotherm models was evaluated for the equilibrium modeling of these isotherm curves, however, only the Toth model was found appropriate. Mat # 2, dominated by Phormidium sp., was identified as an excellent metal biosorbent because: (i) the Toth estimated maximum biosorption capacity (mmol g(-1)) of Mat # 2 for Pb(II) (1.028), Cu(II) (0.696) and Cd(II) (0.549) was the highest among the tested mats and compares favourably with Langmuir estimated metal sorption capacity of many seaweeds, regarded as the best metal biosorbents, (ii) Na+, K+ and Ca2+ did not substantially inhibit the biosorption of the test metals, (iii) and total metal sorption ability of Mat # 2 increased or remained unaffected in binary and ternary metal systems. PMID- 20724121 TI - [Infant botulism in France, 1991-2009]. AB - Infant botulism is caused by the ingestion of spores of Clostridium botulinum and affects newborns and infants under 12 months of age. Ingested spores multiply and produce botulinum toxin in the digestive tract, which then induces clinical symptoms. A single French case was described in the literature prior to 1991. We describe the cases of infant botulism identified in France between 1991 and 2009. All clinical suspicions of botulism must be declared in France. Biological confirmation of the disease is provided by the National reference laboratory for anaerobic bacteria and botulism at the Pasteur Institute. During this period, 7 cases of infant botulism were identified, 1 per year from 2004 to 2008 and 2 in 2009. The median age of affected infants was 119 days and all were female. All infants presented with constipation and oculomotor symptoms. All were hospitalized and required mechanical ventilation. The infants recovered from their botulism. The diagnosis of infant botulism was biologically confirmed for all patients. One 4-month-old infant was treated with a single dose of the human derived botulism antitoxin specific for infant botulism types A and B (BabyBIG(r)). The infants all had different feeding habits ranging from exclusive breast feeding to a mix of formula feeding and solid food consumption. The consumption of honey, the only documented risk food for this disease, was reported for 3 of the infants. The honey had been placed on the pacifier of 2 infants and directly in the mouth of the 3rd by the mother. Infant botulism, a form of botulism that was previously rarely recognized in France, has been reported more frequently during the last 6 years. This disease remains rare but nonetheless severe. In light of recent epidemiological data, efforts to raise awareness among parents of infants and health professionals on the danger of infant botulism and particularly, its association with honey consumption seems necessary. PMID- 20724122 TI - [Perinatal care in France: is the Swedish model possible?]. PMID- 20724123 TI - International recommendations for training future toxicologic pathologists participating in regulatory-type, nonclinical toxicity studies. AB - The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type - nonclinical toxicology studies. Trainees optimally should undertake a scientific curriculum of at least 5 years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more years of intensive pathology practice during a residency and/or on-the-job "apprenticeship," at least 2 years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A nonclinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one's understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID- 20724124 TI - Total ginsenosides increase coronary perfusion flow in isolated rat hearts through activation of PI3K/Akt-eNOS signaling. AB - BACKGROUND: Ginseng is the most popular herb used for treatment of ischemic heart diseases in Chinese community; ginsenosides are considered to be the major active ingredients. However, whether ginsenosides can enhance the coronary artery flow of ischemic heart and, if so, by what mechanisms they do this, remains unclear. METHODS: Isolated rat hearts with ischemia/reperfusion injury in Langendorff system were employed for examining the effect of total ginsenosides (TGS) on coronary perfusion flow (CPF). In addition, human aortic endothelial cells (HAECs) were used for mechanistic study. Levels of various vasodilative molecules, intracellular calcium concentration ([Ca2+](i)), and expressions and activation of proteins involving regulation of nitric oxide (NO) signaling pathways in heart tissues and HAECs were determined. RESULTS: TGS dose dependently and significantly increased CPF and improved systolic and diastolic function of the ischemia/reperfused rat heart, while inhibitors of NO synthase (NOS), soluble guanylate cyclase (sGC), heme oxygenase (HO), cyclooxygenase (COX), and potassium channel abolished the vasodilation effect of TGS. Positive control verapamil was effective only in increasing CPF. TGS elevated levels of NO and 6-keto-prostaglandin F1alpha, a stable hydrolytic product of prostacyclin I2 (PGI2), in both coronary effluents and supernatants of HAECs culturing medium, and augmented [Ca2+](i) in HAECs. TGS significantly up-regulated expression of phosphoinositide 3-kinase (PI3K) and phosphorylations of Akt and endothelial NOS (eNOS) as well. CONCLUSIONS: TGS significantly increased CPF of ischemia/reperfused rat hearts through elevation of NO production via activation of PI3K/Akt-eNOS signaling. In addition, PGI2, EDHF and CO pathways also partially participated in vasodilation induced by TGS. PMID- 20724125 TI - Interaction of phytochemicals with hypoglycemic drugs on glucose uptake in L6 myotubes. AB - The present study analyses the effect of eugenol, arecoline and vanillic acid alone and in combination with two oral hypoglycemic drugs (OHD), namely, metformin and 2,4-thiazolodinedione (THZ), on 2-deoxyglucose (2DG) uptake in L6 myotubes. 2DG uptake in L6 myotubes was determined using an enzymatic assay developed by Yamamoto et al. (2006). Lipid content inside the cells has been estimated with oil red O assay. The absorption, distribution, metabolism, and excretion (ADME) and drug likeness properties of these phytochemicals are estimated using software QikProp((r)). All the three phytochemicals enhance 2DG uptake both in time- and dose-dependent manner. Eugenol and arecoline enhances 2DG uptake synergistically with both the OHD; whereas vanillic acid showing partly synergy with THZ and antagonistic activity with metformin on 2DG uptake. Eugenol and arecoline significantly increase the expressions of the glucose transporter type 4 (GLUT4) and phosphoinositide 3-kinase (PI3K) genes, but not the peroxisome proliferator-activated receptor (PPAR) gamma. Whereas vanillic acid does not has any significant effect on the expressions of these genes, the ADME results indicate that these phytochemicals are satisfying all the conditions to have a good oral bioavailability. These findings suggest that these phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects caused by the later as well as reduce the secondary complications. PMID- 20724126 TI - Stimulation of IFN-gamma production by garlic lectin in mouse spleen cells: involvement of IL-12 via activation of p38 MAPK and ERK in macrophages. AB - Several lectins, present in beans and edible plant products, have immuno potentiating and anti-tumor activities. We here report the effects of garlic lectin purified from garlic bulbs on the production of cytokines such as interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) in the mouse. Garlic lectin induced IFN-gamma production in spleen cells in a bell-shaped time (24-60 h)- and concentration (0.25-2.0 mg/ml)-dependent manner. The maximal enhancement was observed at 36 h with 0.5 mg/ml of garlic lectin. The stimulatory effect of garlic lectin on IFN-gamma production was completely inhibited by both actinomycin D and cycloheximide, an inhibitor of ribosomal protein synthesis and DNA-dependent RNA polymerase, respectively, and was associated with an increase in IFN-gamma mRNA level. Garlic lectin also induced IL-12 production in mouse peritoneal macrophages in a concentration (0.25-1.0 mg/ml)- and bell-shaped time (3-24 h)-dependent manner. The lectin increased the phosphorylation of extracellular signal-regulated kinases (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) in macrophages. Furthermore, specific pharmacological inhibitors of ERK kinase (U0126) and p38 MAPK (SB203580) also suppressed the production of IL-12 induced by garlic lectin. The present findings suggest that garlic lectin induces IL-12 production via activation of p38 MAPK and ERK in mouse macrophages, which, in turn, stimulates IFN-gamma production through an increase in IFN-gamma mRNA in the spleen cells. PMID- 20724127 TI - Anti-hypoxia activity and related components of Rhodobryum giganteum par. AB - Different extracts of Rhodobryum giganteum Par. were screened with mice model of acute myocardial hypoxia induced by isoproterenol and pituitrin, eight compounds, i.e. p-hydroxycinnamic acid, caffeic acid-4-O-beta-d-glucopyranoside, salicin, 7,8-dihydroxy coumarin, menthol, allantoin, palmitic acid, palmitamide were isolated and identified from the active fraction, among which p-hydroxycinnamic acid and 7,8-dihydroxy coumarin were confirmed having protective effects on myocardial hypoxia-reoxygenation injury, suggesting that these two components were major active ingredients of R. giganteum for cardiovascular disease. PMID- 20724128 TI - Proteomic identification of proteins involved in the anticancer activities of oridonin in HepG2 cells. AB - Oridonin is the main bioactive constituent of the Chinese medicinal herb Isodon rubescens and has been shown to have anti-neoplastic effects against a number of cancers in vitro and in vivo. Here we report the proteomic identification of proteins involved in the anticancer properties of oridonin in hepatocarcinoma HepG2 cells. Cell viability assay showed that oridonin dose-dependently inhibited cell growth with an IC(50) of 41.77MUM. Treatment with oridonin at 44MUM for 24h induced apoptosis and G2/M cell cycle arrest, which were associated with nine differentially expressed proteins identified by proteomic analysis. The proteomic expression patterns of Hsp70.1, Sti1 and hnRNP-E1 were confirmed by quantitative real-time PCR and/or immunoblotting. Eight of the nine identified proteins are shown, for the first time, to be involved in the anticancer activities of oridonin. Up-regulation of Hsp70.1, STRAP, TCTP, Sti1 and PPase, as well as the down-regulation of hnRNP-E1 could be responsible for the apoptotic and G2/M arresting effects of oridonin observed in this study. Up-regulation of HP1 beta and GlyRS might contribute to inhibitory effects of oridonin on telomerase and tyrosine kinase, respectively. These findings shed new insights into the molecular mechanisms underlying the anticancer properties of oridonin in liver cancer cells. PMID- 20724129 TI - Quality of life in breast cancer patients during chemotherapy and concurrent therapy with a mistletoe extract. AB - BACKGROUND: The effects of standardized aqueous mistletoe extracts on Health Related Quality of Life (HRQoL) of tumor patients needs further evaluation. METHODS: in this non-interventional, prospective clinical investigation the longitudinal course of Quality of Life of 270 breast cancer patients during adjuvant chemotherapy and mistletoe therapy with abnobaVISCUM((r)) Mali was investigated. HRQoL was measured 4 times by self-assessment with the QLQ-C30 and QLQ-BR23 questionnaire of the European Organization for Research and Treatment of Cancer (EORTC): at the beginning of mistletoe- and chemotherapy, 4 weeks later, at the end of the chemotherapy and 4 weeks after finishing chemotherapy. Secondary objectives were the tolerability and safety of mistletoe therapy in combination with chemotherapy under conditions of daily practice. RESULTS: after an initial deterioration the average range of all obtained QLQ-C30 function scales (n=262, 48.9-71.5) remained stable even at the last chemotherapy cycle and improved significantly (p<0.0001) to 66.9-80.7 4 weeks later, compared to the initial visit. Also the QLQ-BR23 function scales significantly improved (p<0.0001) 4 weeks later. The symptom scales of the QLQ-C30 remained stable under chemotherapy even at the final chemotherapy cycle and decreased from 16.2 to 44.1 at the initial visit to 11.2-29.9 (p<0.001) at the final visit. These results were comparable to the subgroup with initial visit before chemotherapy (n=114) in which rather stable function scales during chemotherapy (difference of the mean values: 9.6 to -3.7) and only little increase of symptoms (difference: 13.2 to 4.9) was measured. The tolerability of the therapy was judged by the physicians as good or very good for 91% of the patients and the efficacy was rated as good or very good for 94%. 89% of the patients reported about a good or very good benefit. CONCLUSION: the overall results point to a relevant stabilisation of Health Related Quality of Life during various chemotherapy regimes, possibly due to a reduction of chemotherapy caused side effects with an excellent tolerability of the mistletoe therapy. PMID- 20724130 TI - The cyclooxygenase-2-765C promoter polymorphism protects against the development of chronic obstructive pulmonary disease. AB - BACKGROUND: Susceptibility to Chronic Obstructive Pulmonary Disease (COPD) has a genetic component. We undertook a study to determine if a genetic variant of the gene encoding the cyclooxygenase-2 gene influences the likelihood of developing COPD. METHODS: In a case control study the frequency of a single nucleotide polymorphism in the promoter region of the cyclooxygenase-2 gene (-765 G -> C) was determined in 205 subjects with COPD, 171 chronic smokers with normal lung function (resistant smokers) and 95 healthy blood donors using the polymerase chain reaction and restriction enzyme fragment length polymorphism. RESULTS: The frequency of the C allele of the -765 cyclooxygenase-2 polymorphism was higher in resistant smokers (24.6%) compared with subjects with COPD (14.4%, OR = 1.98, 95% CI = 1.28-3.06, p = 0.003) and blood donors (14.7%, OR = 1.97, 95% CI = 1.14 3.41, p = 0.03). CONCLUSIONS: The -765C allele, which has been shown to be associated with decreased promoter activity of the cyclooxygenase-2 gene, is more common in resistant smokers. This raises the possibility that decreased activity of cyclooxygenase-2 may protect smokers against the development of COPD. PMID- 20724131 TI - COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). AB - Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease (COPD), relatively little is known about the effect in younger patients. We report a pre-specified post-hoc analysis of 356 patients with COPD <= 50 years old from the four year randomised, double blind placebo controlled Understanding Potential Long Term Impact on Function with Tiotropium (UPLIFT) trial. Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s (FEV(1)) of <=70%, FEV(1)/FVC < 0.70, age >=40 years, and smoking history of >=10 pack years. Younger patients had a mean FEV(1) of 1.24 L (39% predicted) and an impaired health-related quality of life (St. George's Respiratory Questionnaire (SGRQ)) compared to the entire UPLIFT population. There were 40.2% women and 51.1% current smokers in the younger age group. Tiotropium was associated with a sustained improvement in spirometry and SGRQ. Mean decline in post-bronchodilator FEV(1) was 58 ml/year (placebo) vs. 38 ml/year (tiotropium) (p = 0.01). Corresponding values for pre-bronchodilator FEV(1) were 41 ml/year (placebo) compared with 34 ml/year (tiotropium) (p = 0.34). The hazard ratio (95%CI) for an exacerbation in the younger age group was 0.87(0.68, 1.13)). The rate of exacerbations was reduced by tiotropium (rate ratio (95%CI) = 0.73(0.56, 0.95)). Tiotropium resulted in sustained bronchodilation, improved quality of life, and a decreased exacerbation rate in younger patients. Tiotropium also resulted in a significant reduction in the decline in post-bronchodilator FEV(1), suggesting possible disease modification by tiotropium in younger patients with COPD. PMID- 20724132 TI - Cell adhesion in regulation of asymmetric stem cell division. AB - Adult stem cells inevitably communicate with their cellular neighbors within the tissues they sustain. Indeed, such communication, particularly with components of the stem cell niche, is essential for many aspects of stem cell behavior, including the maintenance of stem cell identity and asymmetric cell division. Cell adhesion mediates this communication by placing stem cells in proximity to the signaling source and by providing a polarity cue that orients stem cells. Here, I review the recent discovery that cell adhesion molecules govern the behavior of stem cells. PMID- 20724133 TI - Biomethanation under psychrophilic conditions. AB - The biomethanation of organic matter represents a long-standing, well-established technology. Although at mesophilic and thermophilic temperatures the process is well understood, current knowledge on psychrophilic biomethanation is somewhat scarce. Methanogenesis is particularly sensitive to temperature, which not only affects the activity and structure of the microbial community, but also results in a change in the degradation pathway of organic matter. There is evidence of psychrophilic methanogenesis in natural environments, and a number of methanogenic archaea have been isolated with optimum growth temperatures of 15-25 degrees C. At psychrophilic temperatures, large amounts of heat are needed to operate reactors, thus resulting in a marginal or negative overall energy yield. Biomethanation at ambient temperature can alleviate this requirement, but for stable biogas production, a microbial consortium adapted to low temperatures or a psychrophilic consortium is required. Single-step or two-step high rate anaerobic reactors [expanded granular sludge bed (EGSB) and up flow anaerobic sludge bed (UASB)] have been used for the treatment of low strength wastewater. Simplified versions of these reactors, such as anaerobic sequencing batch reactors (ASBR) and anaerobic migrating blanket reactor (AMBR) have also been developed with the aim of reducing volume and cost. This technology has been further simplified and extended for the disposal of night soil in high altitude, low temperature areas of the Himalayas, where the hilly terrain, non-availability of conventional energy, harsh climate and space constraints limit the application of complicated reactors. Biomethanation at psychrophilic temperatures and the contribution made to night-soil degradation in the Himalayas are reviewed in this article. PMID- 20724134 TI - Substitution of peat, fertiliser and manure by compost in hobby gardening: user surveys and case studies. AB - Four user surveys were performed at recycle centres (RCs) in the Municipalities of Aarhus and Copenhagen, Denmark, to get general information on compost use and to examine the substitution of peat, fertiliser and manure by compost in hobby gardening. The average driving distance between the users' households and the RCs was found to be 4.3 km and the average amount of compost picked up was estimated at 800 kg per compost user per year. The application layer of the compost varied (between 1 and 50 cm) depending on the type of use. The estimated substitution (given as a fraction of the compost users that substitute peat, fertiliser and manure with compost) was 22% for peat, 12% for fertiliser and 7% for manure (41% in total) from the survey in Aarhus (n=74). The estimate from the survey in Copenhagen (n=1832) was 19% for peat, 24% for fertiliser and 15% for manure (58% in total). This is the first time, to the authors' knowledge, that the substitution of peat, fertiliser and manure with compost has been assessed for application in hobby gardening. Six case studies were performed as home visits in addition to the Aarhus surveys. From the user surveys and the case studies it was obvious that the total substitution of peat, fertiliser and manure was not 100%, as is often assumed when assigning environmental credits to compost. It was more likely around 50% and thus there is great potential for improvement. It was indicated that compost was used for a lot of purposes in hobby gardening. Apart from substitution of peat, fertiliser and manure, compost was used to improve soil quality and as a filling material (as a substitute for soil). Benefits from these types of application are, however, difficult to assess and thereby quantify. PMID- 20724135 TI - Gold nanoparticle-based electrochemical magnetoimmunosensor for rapid detection of anti-hepatitis B virus antibodies in human serum. AB - A sandwich immunoassay using magnetic beads as bioreaction platforms and AuNPs as electroactive labels for the electrochemical detection of human IgG antibodies anti-Hepatitis B surface antigen (HBsAg), is here presented as an alternative to the standard methods used in hospitals for the detection of human antibodies directed against HBsAg (such as ELISA or MEIA). The electrochemical detection of AuNPs is carried out approaching their catalytic properties towards the hydrogen evolution in an acidic medium, without previous nanoparticle dissolution. The obtained results are a good promise toward the development of a fully integrated biosensing set-up. The developed technology based on this detection mode would be simple to use, low cost and integrated into a portable instrumentation that may allow its application even at doctor-office. The sample volumes required can be lower than those used in the traditional methods. This may lead to several other applications with interest for clinical control. PMID- 20724136 TI - Characterisation and analytical potential of a photo-responsive polymeric material based on spiropyran. AB - In this paper we consider the critical issues inhibiting the widespread deployment of bio/chemo-sensors in wireless sensor networks. Primary among these is the problem of performing calibration at remote locations, and the consequent need for integrated fluidic systems for performing tasks like sampling, calibration and detection. Our conclusion is that low-cost, bio/chemo-sensing platforms that provide reliable information over long periods of use will only be realised through the use of microfluidic platforms that are much more biomimetic in nature than technologies employed in current devices. Central to driving down costs will be the development of fluidic platforms with integrated soft polymer actuators that will replace existing pumps and valves. A particularly attractive approach is to employ photo-controlled polymer actuators, wherein the status of the material can be effectively switched using light, as this allows physical separation of the control layer from the fluidic platform layer in a planar system. This, in principle, should greatly simplify manufacturing and therefore drive down costs. In this paper, we describe a polymeric gel and a linear polymer modified with a photochromic moiety and show that it is possible to utilize photochromic molecules for performing sensing and actuating functions. PMID- 20724137 TI - Application of fluorescent protein-tagged trans factors and immobilized cis elements to monitoring of toxic metals based on in vitro protein-DNA interactions. AB - Environmental toxic metals cause serious global public health problems. On-site monitoring protects people from exposure to such harmful elements. In this study, the bacterial transcriptional switches were applied to monitoring of toxic metals. ArsR and CadC, trans factors of Escherichia coli and Staphylococcus aureus, were fused to GFP. The fusion proteins, ArsR-GFP and CadC-GFP, associated with cis elements, P(ars)-O(ars) and P(cad)-O(cad), respectively and dissociated from those upon recognition of As(III) or Pb/Cd. Cell lysates containing ArsR-GFP were pre-incubated with As(III) standard solutions for 15 min and loaded into P(ars)-O(ars)-immobilized microplate wells. Cell lysates containing CadC-GFP were pre-incubated with Pb or Cd solutions and loaded into P(cad)-O(cad)-immobilized wells. The cell lysates were incubated for 15 min and removed from the wells. Fluorescence intensity in the wells dose-dependently decreased in response to As(III) up to 200 MUg/l or Pb/Cd up to 100 MUg/l. Detection limits were 10 MUg/l for As(III) 10 MUg/l for Cd, and 20 MUg/l for Pb with a microplate fluororeader, whereas 5.0 MUg/l for As(III), 1.0 MUg/l for Cd, and 10 MUg/l for Pb with a handheld fluorometer. This method was available to detect Pb/Cd or As(III) in water containing soil extracts. This is the first demonstration of a simple and rapid fluorometry to detect analytes based on in vitro interaction between a cis element and a trans factor. PMID- 20724138 TI - Functional polarity in neurons: what can we learn from studying an exception? AB - Dendrites and axons typically handle very different aspects of neuronal signaling. However, many of the functional distinctions between these two types of processes are absent in neurons with release-competent dendrites. This raises fundamental questions about the molecular mechanisms that promote and permit functional specialization, and suggests that the 'exceptional' case of presynaptic dendrites may provide important clues on how neuronal polarity is established. To help stimulate thinking on this new front, we summarize some key aspects of the physiology of dendritic neurotransmitter release, together with recent work on the molecular basis of neuronal polarity. PMID- 20724139 TI - Further tales of the midline. AB - In the vertebrate central nervous system (CNS), specialized glial and neuronal cells positioned at the dorsal and ventral midline act as intermediate targets for commissural axons by secreting a variety of attractants and repellents. Despite the diversity of commissural projections, recent findings suggest that the same basic set of molecules controls midline crossing at all level of the CNS. Midline crossing is associated with an important switch of the combinatorial expression of several axon guidance receptors on the growth cone of commissural axons. I will review here novel studies that reveal how the expression of these receptors and the activity of their ligands are modulated by transcriptional, translational, and post-translational modifications. This also uncovers extensive cross talks between axon guidance pathways. PMID- 20724140 TI - Time until definitive quality of life score deterioration as a means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma. AB - BACKGROUND: The Federation Francophone de Cancerologie Digestive phase III trial in patients with metastatic pancreatic adenocarcinoma comparing 5FU, folinic acid and cisplatin combination followed by gemcitabine (Arm A) versus the opposite sequence (Arm B) failed to demonstrate a benefit in overall survival. To longitudinally compare the quality of life (QoL) we explored different definitions of time until definitive deterioration (TUDD) of QoL scores according to minimal clinically important difference (MCID) cut-offs. METHODS: QoL was evaluated using the EORTC QLQ-C30 every 8 weeks until death. The following scores were analysed: global health, emotional functioning, physical functioning, fatigue and pain. TUDD was defined as the time interval between randomisation and the first occurrence of a decrease in QLQ-C30 score >=5 points without any further improvement in QoL score >=5 points or any further available QoL data. Analyses were repeated using a 10 point MCID and/or including death as event. RESULTS: From 08/2003 to 05/2006, 102 patients in Arm A and 100 in Arm B were included. Using a 5 and a 10 point MCID, TUDD curves of the 5 scores did not differ according to treatment arm., The median TUDD of global health was 5.2 months (4.3-6.2) in Arm A and 6.1 months (5.1-8.5) in Arm B (log-rank p=0.50) including death as an event for a 5 point MCID. Multivariate Cox model showed that tumour localisation and progression were independently associated with TUDD (p<0.05). CONCLUSIONS: The strategy of chemotherapy did not influence the deterioration of QoL. The TUDD approach seems to provide meaningful clinical results that are adapted to metastatic pancreatic adenocarcinoma trials. PMID- 20724141 TI - Differential expression and prognostic value of HMGA1 in pancreatic head and periampullary cancer. AB - The high mortality rate and minimal progress made in the treatment of pancreatic cancer over the last few decades, warrant an alternative approach. Treatment protocols should be individualised to the patient guided by prognostic markers. A particularly interesting target would be the architectural transcription factor high mobility group A1 (HMGA1), that is low or undetectable in normal tissue, induced during neoplastic transformation and consequently often exceptionally high in cancer. The aim of the current study was therefore to determine the differential expression of HMGA1 in pancreatic head and periampullary cancer and investigate its relation with outcome. HMGA1 expression was determined by immunohistochemistry on original paraffin embedded tissue from 99 pancreatic head and 112 periampullary cancers (with R0). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS) and conventional prognostic factors. HMGA1 was expressed in 47% and 26% of pancreatic head- and periampullary cancer, respectively and associated with poor RFS, CSS and OS in periampullary cancer. CSS 5years following surgery was 25% and 44% for patients with tumours which were positive or negative for HMGA1 protein, respectively. HMGA1 expression was not associated with survival in pancreatic head cancer. In conclusion HMGA1 was identified as an independent prognostic marker predicting poor outcome in periampullary cancer. Although expressed to a higher extent as compared to periampullary cancer, HMGA1 was not associated with survival in pancreatic head cancer. PMID- 20724142 TI - Elevated expression of HMGB1 in squamous-cell carcinoma of the head and neck and its clinical significance. AB - PURPOSE: HMGB1 overexpression has been reported in a variety of human cancers. However, the role of HMGB1 in squamous-cell carcinoma of the head and neck (SCCHN) remains unclear. The aim of the present investigation was to analyse HMGB1 protein expression in both SCCHN tissue and cell levels and to assess its prognostic significance in SCCHN. METHODS: HMGB1 protein expression in 103 primary SCCHN tissue specimens was analysed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, HMGB1 protein expression was evaluated in cell level by Western blotting. RESULTS: By Western blotting analysis, all the 5 SCCHN cell lines overexpressed HMGB1 protein, whereas the non-transformed immortalised cell line NP-69 had relatively weak HMGB1 protein expression. Immunohistochemical staining revealed that HMGB1 protein was detected in 91 (91/103, 88.3%) primary tumour samples, but only in 7 (7/16, 43.75%) adjacent non-carcinoma samples (p<0.001); moreover, HMGB1 overexpression was significantly associated with T classification (p=0.001), clinical stage (p<0.001), recurrence (p<0.001) and lymph node metastasis (p<0.001). Survival analysis demonstrated that high HMGB1 expression was significantly associated with shorter disease-free and overall survival (both p<0.001), especially in late patients with SCCHN. When HMGB1 expression and lymph node status were combined, patients with HMGB1 overexpression/lymph node (+) had both poorer disease-free and overall survival than others (both p<0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with SCCHN. CONCLUSIONS: HMGB1 protein may contribute to the malignant progression of SCCHN, and present as a novel prognostic marker and a potential therapeutic target for patients with SCCHN. PMID- 20724143 TI - A lethal combination for cancer cells: synthetic lethality screenings for drug discovery. AB - In recent years, cancer drug discovery has faced the challenging task of integrating the huge amount of information coming from the genomic studies with the need of developing highly selective target-based strategies within the context of tumour cells that experience massive genome instability. The combination between genetic and genomic technologies has been extremely useful and has contributed to efficiently transfer certain approaches typical of basic science to drug discover projects. An example comes from the synthetic lethal approaches, very powerful procedures that employ the rational used by geneticists working on model organisms. Applying the synthetic lethality (SL) screenings to anticancer therapy allows exploiting the typical features of tumour cells, such as genome instability, without changing them, as opposed to the conventional anticancer strategies that aim at counteracting the oncogenic signalling pathways. Recent and very encouraging clinical studies clearly show that certain promising anticancer compounds work through a synthetic lethal mechanism by targeting pathways that are specifically essential for the viability of cancer cells but not of normal cells. Herein we describe the rationale of the synthetic lethality approaches and the potential applications for anticancer therapy. PMID- 20724144 TI - Virtual reality in radiation therapy training. AB - Integration of virtual reality (VR) in clinical training programs is a novel tool in radiotherapy. This paper presents a review of the experience with VR and Immersive visualization in 3D perspective for planning and delivery of external radiotherapy. Planning and delivering radiation therapy is a complex process involving physicians, physicists, radiographers and radiation therapists/nurses (RTT's). The specialists must be able to understand spatial relationships in the patient anatomy. Although still in its infancy, VR tools have become available for radiotherapy training, enabling students to simulate and train clinical situations without interfering with the clinical workflow, and without the risk of making errors. Immersive tools like a 3D linear accelerator and 3D display of dose distributions have been integrated into training, together with IT-labs with clinical software. Training in a VR environment seems to be cost-effective for the clinic. Initial reports suggest that 3D display of dose distributions may improve treatment planning and decision making. Whether VR training qualifies the students better than conventional training is still unsettled, but the first results are encouraging. PMID- 20724145 TI - Methane yield from switchgrass harvested at different stages of development in Eastern Canada. AB - Mesophilic methane yield of ensiled switchgrass grown in Eastern Canada was assessed. Switchgrass was harvested at three stages of development, corresponding to mid-summer, late summer and early fall in 2007. The regrowth of plots harvested in mid-summer was also harvested in early fall as a two-cut strategy. Specific methane yields decreased significantly with crop maturity from 0.266 to 0.309 (N)L CH(4)g(-1) VS in mid-summer to 0.191-0.250 (N)L CH(4)g(-1) VS in early fall; values were similar for the first harvest in late July and the second harvest (regrowth) in October. Approximately 25% more methane was produced by hectare for the two-cut strategy (2.90-3.44 x 10(6)(N)L CH(4)ha(-1)) compared to the one-cut strategy with a harvest in late summer (2.28-2.77 x 10(6)(N)L CH(4)ha(-1)). Methane yields from switchgrass grown under the cool humid climate of Eastern Canada suggest that this crop remains an interesting renewable alternative energy source. PMID- 20724146 TI - Enhanced H2 gas production from bagasse using adhE inactivated Klebsiella oxytoca HP1 by sequential dark-photo fermentations. AB - Sequential dark-photo fermentations (SDPF) was used for hydrogen production from bagasse, an acetaldehyde dehydrogenase (adhE) gene inactivated Klebsiella oxytoca HP1 (DeltaadhE HP1) mutant was used to reduce the alcohol content in dark fermentation (DF) broths and to further enhance the hydrogen yield during the photo fermentation (PF) stage. Compared with that of the wild strain, the ethanol concentration in DF broths of DeltaadhE HP1 decreased 69.4%, which resulted in a hydrogen yield in the PF stage and the total hydrogen yield over the two steps increased by 54.7% and 23.5%, respectively. The culture conditions for hydrogen production from acid pretreated bagasse by SDPF were optimized as culture temperature 37.5 degrees C, initial pH 7.0, and cellulase loading 20 FPA/g in the DF stage, with initial pH 6.5, temperature 30 degrees C and photo intensity 5,000 lux in the PF stage. Under optimum conditions, by using DeltaadhE HP1 and wild type strain, the H(2) yields were 107.8+/-5.3 mL H(2)/g-bagasse, 96.2+/-4.4 mL H(2)/g-bagasse in DF and 54.3+/-2.2 mL H(2)/g-bagasse, 35.1+/-2.0 mL H(2)/g bagasse in PF, respectively. The special hydrogen production rate (SHPR) were 5.51+/-0.34 mL H(2)/g-bagasseh, 4.95+/-0.22 mL H(2)/g-bagasseh in DF and 0.93+/ 0.12 mL H(2)/g-bagasseh, 0.59+/-0.07 mL H(2)/g-bagasseh in PF, respectively. The total hydrogen yield from bagasse over two steps was 162.1+/-7.5 mL H(2)/g bagasse by using DeltaadhE HP1, which was 50.4% higher than that from dark fermentation only. These results indicate that reducing ethanol content during dark fermentation by using an adhE inactivated strain can significantly enhance hydrogen production from bagasse in the SDPF system. This work also proved that SDPF was an effective way to improve hydrogen production from bagasse. PMID- 20724147 TI - Increase in complexation ability of humic acids with the addition of ligneous bulking agents during sewage sludge composting. AB - Wood sawdust and maize straw were selected to co-compost sewage sludge to investigate the effects of organic bulking agents on the formation and molecular transformation of humic substances. The results showed that composting process increased humic acids (HA) while decreased fulvic acids (FA), and the wood sawdust and maize straw promoted the formation of HA by 25.6% and 16.1%, respectively. Results from fluorescence titration demonstrated that organic bulking agents also increased the binding ability of HA with the heavy metal ions, Cu(II) and Cd(II), but had little influence on that of FA. These findings indicate that organic materials especially wood sawdust may be used as bulking agents to reduce the mobility and bioavailability of toxic metals in solid waste composts. PMID- 20724148 TI - Comparison of sulfidogenic up-flow and down-flow fluidized-bed reactors for the biotreatment of acidic metal-containing wastewater. AB - Biotreatment of Cu- and Zn-containing synthetic wastewater was studied in sulfate reducing up-flow (UFBR) and down-flow fluidized-bed reactors (DFBR) at 35 degrees C. The robustness of the systems was studied by stepwise increasing feed metal concentrations (total metal concentrations 25-300 mg/L) and decreasing feed pH (down to 2.0). Lactate was used as a carbon and energy source for sulfate reducing bacteria. After start-up, sulfate reduction and COD oxidation efficiencies were 60-86% and 87-95% in UFBR and, 40-88 and 55-95% in DFBR, respectively. Optimum COD/sulfate ratio for sulfate reduction was 0.85 and 1.25 for UFBR and DFBR, respectively. Approximately 70% and 55% of the electrons produced from lactate oxidation were used for sulfate reduction in UFBR and DFBR, respectively. Sulfide production and metal precipitation capacity of UFBR were higher than those of DFBR, although down-flow regime gave the possibility of metal recovery. Metals were precipitated more than 99% in both reactors. XRF analyses showed that metals were precipitated as metal-sulfides. PMID- 20724149 TI - N,O-diacyl-4-benzoyl-N-phenylhydroxylamines as photoinduced DNA cleaving agents. AB - Photoinduced homolytic fission of nitrogen-oxygen bond in N,O-diacyl-4-benzoyl-N phenylhydroxylamines using 310 nm UV light for 10 min produced acylaminyl and acyloxy radicals, which resulted in single strand cleavage of DNA at pH 7.0. Further the DNA cleaving ability of N,O-diacyl-4-benzoyl-N-phenylhydroxylamines found to depend both on its concentration and acyl substituents. PMID- 20724150 TI - Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity. AB - Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization. PMID- 20724151 TI - Synthesis and antimicrobial activity of novel fluorine containing 4-(substituted 2-hydroxybenzoyl)-1H-pyrazoles and pyrazolyl benzo[d]oxazoles. AB - A series of fluorine containing 4-(substituted-2-hydroxybenzoyl) pyrazoles and pyrazolyl benzo[d]oxazoles were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis and antifungal activity against Candida albicans. The antibacterial activities were expressed as the minimum inhibitory concentration (MIC50) in microg/ml. The compounds 1-(3,4-difluorophenyl)-4-(5-fluoro-2 hydroxybenzoyl)-1H-pyrazole (4b), oxime derivatives such as 1-(3,4 difluorophenyl)-1H-pyrazol-4-yl)(2-hydroxy-4-methylphenyl)methanone oxime (5b) and (5-chloro-2-hydroxyphenyl)(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)methanone oxime (5e) exhibited promising activities against tested bacterial strains. Except compound 1-(3,4-difluorophenyl)-4-(2-hydroxybenzoyl)-1H-pyrazole (4d), none of the other compounds showed promising antifungal activity. PMID- 20724152 TI - Iminoheterocycles as gamma-secretase modulators. AB - The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models. PMID- 20724153 TI - Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors. AB - A series of 3-aryl-3-azolylpropan-1-amines was prepared and screened for its capability of inhibiting monoamine reuptake. Analogs with nanomolar potency, good human in vitro microsomal stability, and low drug-drug interaction potential were described. In vivo models were used to evaluate the compound 19r for antidepressive, anxiolytic, and analgesic activity. PMID- 20724154 TI - RGD-cyclam conjugate: synthesis and potential application for positron emission tomography. AB - Cyclam and DOTA-containing positron emission tomography radiotracers were prepared by using a modular chemical strategy based on peptide synthesis and chemoselective ligations. These molecules encompass two functional domains, one a tumour 'homing' domain and the other a chelating ligand for copper allowing nuclear imaging of tumours. PMID- 20724155 TI - Prenylflavonoids from Glycyrrhiza uralensis and their protein tyrosine phosphatase-1B inhibitory activities. AB - Two new 2-arylbenzofurans, glycybenzofuran (1) and cyclolicocoumarone (2), together with 10 known flavonoids including licocoumarone (3), glycyrrhisoflavone (4), glisoflavone (5), cycloglycyrrhisoflavone (6), isoliquiritigenin (7), licoflavone A (8), apigenin (9), isokaempferide (10), glycycoumarin (11), and isoglycycoumarin (12), were isolated from the roots of Glycyrrhiza uralensis and their structures were determined by extensive spectroscopic analyses. Compounds 1 and 5 showed significant protein tyrosine phosphatase-1B (PTP1B) inhibitory activity in vitro with the IC50 values of 25.5 and 27.9 microM, respectively. The structure-activity relationship indicated that the presence of prenyl group and ortho-hydroxy group is important for exhibiting the activity. Kinetic analysis indicated that compound 1 inhibits PTP1B by a competitive mode, whereas compound 5 by a mixed mode. PMID- 20724156 TI - Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists. AB - Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. PMID- 20724157 TI - 170th ENMC International Workshop: bone protection for corticosteroid treated Duchenne muscular dystrophy. 27-29 November 2009, Naarden, The Netherlands. PMID- 20724158 TI - Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. AB - BACKGROUND: Recent epidemiologic and laboratory studies have suggested that non steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of cyclooxygenase-2 (COX-2). METHODS: We conducted a case control study to measure the association between selective cox-2 inhibitors, particularly celecoxib, rofecoxib, valdecoxib and non-specific NSAID subgroups, and breast cancer risk. Between 2003 and 2006, a total of 18,368 incident breast cancer cases were identified in the Ingenix/Lab Rx insurance database, which contains clinical encounter and drug prescription data. Four controls per case were randomly selected, matched on age and time in database. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Breast cancer risk was inversely associated with both non specific NSAID and selective COX-2 inhibitor use. Greater than 12 months' duration of use of Celecoxib at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97). We observed the greatest risk reduction in association with >2 years of rofecoxib exposure (OR=0.54, 95% CI=0.37, 0.80). Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer. CONCLUSION: Consistent with animal models and laboratory investigations, higher doses of selective COX-2 inhibitors were more protective against breast cancer than non-specific NSAIDs. With exposure to rofecoxib, a selective COX-2 inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective COX-2 inhibitors in breast cancer prophylaxis. PMID- 20724159 TI - The segmentation clock mechanism moves up a notch. AB - The vertebrate segmentation clock is a molecular oscillator that regulates the periodicity of somite formation. Three signalling pathways have been proposed to underlie the molecular mechanism of the oscillator, namely the Notch, Wnt and Fgf pathways. Characterizing the roles and hierarchy of these three pathways in the oscillator mechanism is currently the focus of intense research. Recent publications report the first identification of a molecular mechanism involved in the regulation of the pace of this oscillator. We review these and other recent findings regarding the interaction between the three pathways in the oscillator mechanism that have significantly expanded our understanding of the segmentation clock. PMID- 20724161 TI - Epigenetic reprogramming of host genes in viral and microbial pathogenesis. AB - One of the key questions in the study of mammalian gene regulation is how epigenetic methylation patterns on histones and DNA are initiated and established. These stable, heritable, covalent modifications are largely associated with the repression or silencing of gene transcription, and when deregulated can be involved in the development of human diseases such as cancer. This article reviews examples of viruses and bacteria known or thought to induce epigenetic changes in host cells, and how this might contribute to disease. The heritable nature of these processes in gene regulation suggests that they could play important roles in chronic diseases associated with microbial persistence; they might also explain so-called 'hit-and-run' phenomena in infectious disease pathogenesis. PMID- 20724163 TI - Computer assisted knee arthrodesis in a primary case of septic arthritis: a case report. AB - We report a case of a 78 year old patient with primary septic arthritis who was treated with knee arthrodesis using computer navigation. Use of computer navigation avoided violating the medullary canal and its associated risks. Also, it offered the advantage of making precise bone cuts in all the three planes, thus minimizing the risk of malalignment. At 3 months, our patient showed good appositional contact of the bone ends, stable fusion, with no sign of infection and was mobilized with a simple brace. At 6 months review, the patient was walking painlessly without support. We achieved a mechanical axis alignment of 0 degrees and 11 degrees flexion as planned. PMID- 20724164 TI - A case of anterior cruciate ligament tear accompanied by avulsion fractures of tibial tuberosity and Gerdy's tubercle. AB - A 54-year-old man visited our clinic due to a painful swelling of his right knee. He had attempted a forceful kick by his right leg during a Sepak Takraw-like sports activity, only to fail to hit the ball. He felt a popping sense on the knee and collapsed, even without direct trauma. Imaging studies revealed a disruption of the anterior cruciate ligament (ACL), and separate avulsion fractures of the tibial tuberosity and Gerdy's tubercle. The fractures were stabilized by two cancellous screws, respectively. The intra-operative fluoroscopy demonstrated a manifest ACL insufficiency. A simultaneous reconstruction of the ligament was not performed. At 6 months after surgery, he had no difficulty in his activities of daily living. The involved knee joint was believed to have undergone a forceful pivot shift mechanism. Injuries to the ACL can be suspected from indirect signs on the radiologic images by a careful reconstitution of the injury mechanism and the associated lesions. Manifest osseous lesions on the plain radiographs can herald a major ligamentous injury and may be interpreted as an indirect sign of the ACL injury, which helps to establish a relevant management plan. PMID- 20724162 TI - Influence of solubilizing environments on membrane protein structures. AB - Membrane protein structures are stabilized by weak interactions and are influenced by additional interactions with the solubilizing environment. Structures of influenza virus A M2 protein, a proven drug target, have been determined in three different environments, thus providing a unique opportunity to assess environmental influences. Structures determined in detergents and detergent micelles can have notable differences from those determined in lipid bilayers. These differences make it imperative to validate membrane protein structures. PMID- 20724165 TI - An electromyographic exploratory study comparing the difference in the onset of hamstring and quadriceps contraction in patients with anterior knee pain. AB - Idiopathic anterior knee pain in teenagers and young adults is a common condition. Patellar maltracking has been considered as a causative factor. The aim of our study was to investigate whether there was a difference in the timing of electromyographic (EMG) activity in the medial and lateral hamstring and quadriceps muscles of patients with anterior knee pain compared to asymptomatic control participants. This was a cross sectional observational study measuring EMG activation patterns. Two groups of participants were tested, one patient (mean age 15 years, n = 20) and one asymptomatic control (mean age 16 years, n = 17). Surface EMG (sampling rate 1000 Hz) was recorded from vastus medialis obliqus, vastus lateralis, and the medial and lateral hamstrings during three repetitions of maximal voluntary isometric contractions. The relative timing of the medial and lateral quadriceps and hamstrings was evaluated. The mean (95% confidence interval) difference between the groups in the lateral-medial hamstring onset timing was 53.8(1.9 to 105.6)ms during the maximal contraction. An independent t test showed that this difference was statistically significant (p = 0.043). The differences between the groups in the relative VMO to VL onset did not reach statistical significance. The results of this study suggest that the lateral hamstrings contract significantly earlier in patients with AKP compared to healthy controls for this small cohort. This altered activation pattern could produce external rotation of the tibia on the femur and cause lateral patella tracking. PMID- 20724166 TI - Studies on ligand binding to histidine triad nucleotide binding protein 1. AB - Histidine triad nucleotide binding protein (HINT1) is an intracellular protein that binds purine mononucleotides. Strong sequence conservation suggests that these proteins play a fundamental role in cell biology, however its exact cellular function continues to remain elusive. nuclear magnetic resonance (NMR) studies using STD and HSQC were conducted to observe ligand binding to HINT1. These studies were confirmed using fluorescence spectroscopy titrations. We found that AICAR, the first non-phosphate containing ligand, binds to mouse histidine triad nucleotide binding protein 1 (HINT1). Chemical shift perturbations are mapped onto the X-ray structure showing AICAR binds at the same site as GMP. The NMR results demonstrated that this method will be valuable for the future screening of small molecules that can be used to modulate the function of HINT1. PMID- 20724167 TI - Insights into MAPK p38alpha DFG flip mechanism by accelerated molecular dynamics. AB - The DFG motif at the beginning of the activation loop of the MAPK p38alpha undergoes a local structural reorganization upon binding of allosteric type-II and type-III inhibitors, which causes the residue F169 to move from a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out). Although both experimental and computer simulation studies had been performed with the aim of unveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from being unequivocally depicted. Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loop flexibility of p38alpha and sample special protein conformations which can be accessible only in some conditions or time periods. Starting from the assumption of an experimentally known initial and final state of the protein, the study allowed the description of the interaction network and the structural intermediates which lead the protein to change its loop conformation and active site accessibility. Besides a few important hydrogen bond interactions, a primary role seems to be played by cation-pi interactions, involving the DFG-loop residue F(169), which participate in the stabilization of an intermediate conformation and in its consequent transition to the DFG-out conformation. From this study, insights which may prove useful for inhibitor design and/or site directed mutagenesis studies are derived. PMID- 20724168 TI - Collagen targeting using multivalent protein-functionalized dendrimers. AB - Collagen is an attractive marker for tissue remodeling in a variety of common disease processes. Here we report the preparation of protein dendrimers as multivalent collagen targeting ligands by native chemical ligation of the collagen binding protein CNA35 to cysteine-functionalized dendritic divalent (AB(2)) and tetravalent (AB(4)) wedges. The binding of these multivalent protein constructs was studied on collagen-immobilized chip surfaces as well as to native collagen in rat intestinal tissues. To understand the importance of target density we also created collagen-mimicking surfaces by immobilizing synthetic collagen triple helical peptides at various densities on a chip surface. Multivalent display of a weak-binding variant (CNA35-Y175K) resulted in a large increase in collagen affinity, effectively restoring the collagen imaging capacities for the AB(4) system. In addition, dissociation of these multivalent CNA35 dendrimers from collagen surfaces was found to be strongly attenuated. PMID- 20724169 TI - Fluorescent schweinfurthin B and F analogs with anti-proliferative activity. AB - The natural tetracyclic schweinfurthins are potent and selective inhibitors of cell growth in the National Cancer Institute's 60 cell-line screen. At this time, the mechanism or cellular target that underlies this activity has not yet been identified, and efforts to illuminate the schweinfurthins' mode of action would benefit from development of potent fluorescent analogs that could be readily visualized within cells. This report describes the synthesis of fluorescent analogs of schweinfurthins B and F, and demonstrates that these compounds retain the potent and differentially toxic activities against select human cancer cells that are characteristic of the natural schweinfurthins. In addition, the synthesis of control compounds that maintain parallel fluorescent properties, but lack the potent activity of the natural schweinfurthin is described. Use of fluorescence microscopy shows differences between the localization of the active and relatively inactive schweinfurthin analogs. The active compounds localize in peripheral puncta which may identify the site(s) of activity. PMID- 20724170 TI - Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity. AB - P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine 123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells. PMID- 20724171 TI - Medium to large scale radioisotope production for targeted radiotherapy using a small PET cyclotron. AB - In recent years the use of radionuclides in targeted cancer therapy has increased. In this study we have developed a high-current solid target system and demonstrated that by the use of a typical low-energy medical cyclotron, it is possible to produce tens of GBq's of many unconventional radionuclides relevant for cancer therapy such as (64)Cu and (119)Sb locally at the hospitals. PMID- 20724172 TI - Calculation of generalized Hubbell rectangular source integral. AB - A simple formula for computing the generalized Hubbell radiation rectangular source integral [formula in text] is introduced. Tables are given to compare the numerical values derived from our approximation formula with those given earlier in the literature. PMID- 20724173 TI - Evaluation of excitation functions of 3He- and alpha-particle induced reactions on antimony isotopes with special relevance to the production of iodine-124. AB - Cross section data were evaluated for the production of the medically important positron emitter (124)I (T(1/2)=4.18d) via (3)He- and alpha-particle induced reactions on Sb isotopes. The consistency in the measured data available in the literature was checked against the cross section calculations of three nuclear model codes (i.e. STAPRE, EMPIRE and TALYS). The recommended excitation functions obtained by a statistical procedure were used to derive the integral yields. An assessment of the (124)I yields and associated radioisotopic impurities suggests that the (123)Sb(alpha,3n)(124)I process over the energy range of E(alpha)=45 -> 32 MeV could be of potential interest for the production of (124)I. PMID- 20724174 TI - Training and assessment of technical skills and competency in cardiac surgery. AB - The assessment of surgical competency has become a priority for both surgical educators and licensing boards. Surgical educators must incorporate rigorous, reliable, and valid means of assessment into residency programs. Objective evaluation of technical skills has been extensively explored in various surgical specialties, but its role in cardiac surgery has not been well studied and there is limited experience with integration into the educational curricula. Several cardiac and vascular surgery simulation models have been designed and evaluated, ranging from simple low-fidelity models using inert materials to a complex, computer-controlled, high-fidelity simulator using biological tissues to practice entire surgical cases. Most of the available models have not been well validated or integrated into educational curricula. The cardiac surgery simulation tools in development need validation and incorporation into structured, competency-based training curricula. The ongoing development of surgical simulators and educational curricula will enable a transition from the century-old graded responsibility training program to a competency-based program, where trainees must demonstrate technical competence to progress to the next level of training and gain certification and re-certification--ultimately ensuring better and faster technical skill acquisition as well as improved quality of care and patient safety. PMID- 20724176 TI - The role of nitric oxide in the treatment of tumours with aminolaevulinic acid induced photodynamic therapy. AB - Photodynamic therapy (PDT) is a local cancer treatment which induces cell death by the interaction of light with a photosensitizing drug. Previous studies indicate that nitric oxide (NO) plays a role in Photofrin-PDT, but this has not been investigated in aminolaevulinic acid (ALA)-PDT. The current study determines whether inhibition of nitric oxide synthase (NOS) activity modulates treatment responses to ALA-PDT, in tumours displaying differential levels of NO. Murine tumours with low (EMT6) or high (RIF-1) NO levels were implanted into the cremaster muscle of BALB/c or C3H/HeN mice respectively. Animals were prepared for in vivo microscopy 7-14days later. Mice received oral ALA (200mg/kg) 4h before PDT. l-NAME, l-NNA or 1400W (10mg/kg) were administered via the jugular vein 5min before PDT. NOS inhibition (l-NAME or l-NNA) combined with ALA-PDT in RIF-1 tumours demonstrated enhanced damage to both the tumour and normal microvasculature, with increased macromolecular leak and reduction in vessel diameter, whereas ALA-PDT alone had no effect. In contrast, EMT6 tumours responded to ALA-PDT alone but sensitivity was not enhanced in the presence of NOS inhibition. 1400 W combined with ALA-PDT induced similar microvascular effects to l-NAME in both tumours, but were less pronounced. The data demonstrates that NO has an important role in events likely to be critical for treatment response, sensitivity and therapeutic outcome of ALA-PDT. PMID- 20724175 TI - The malondialdehyde-derived fluorophore DHP-lysine is a potent sensitizer of UVA induced photooxidative stress in human skin cells. AB - Light-driven electron and energy transfer involving non-DNA skin chromophores as endogenous photosensitizers induces oxidative stress in UVA-exposed human skin, a process relevant to photoaging and photocarcinogenesis. Malondialdehyde is an electrophilic dicarbonyl-species derived from membrane lipid peroxidation. Here, we present experimental evidence suggesting that the malondialdehyde-derived protein epitope dihydropyridine (DHP)-lysine is a potent endogenous UVA photosensitizer of human skin cells. Immunohistochemical analysis revealed the abundant occurrence of malondialdehyde-derived and DHP-lysine epitopes in human skin. Using the chemically protected dihydropyridine-derivative (2S)-Boc-2-amino 6-(3,5-diformyl-4-methyl-4H-pyridin-1-yl)-hexanoic acid-t-butylester as a model of peptide-bound DHP-lysine, photodynamic inhibition of proliferation and induction of cell death were observed in human skin Hs27 fibroblasts as well as primary and HaCaT keratinocytes exposed to the combined action of UVA and DHP lysine. DHP-lysine photosensitization induced intracellular oxidative stress, p38 MAPkinase activation, and upregulation of heme oxygenase-1 expression. Consistent with UVA-driven ROS formation from DHP-lysine, formation of superoxide, hydrogen peroxide, and singlet oxygen was detected in chemical assays, but little protection was achieved using SOD or catalase during cellular photosensitization. In contrast, inclusion of NaN(3) completely abolished DHP-photosensitization. Taken together, these data demonstrate photodynamic activity of DHP-lysine and support the hypothesis that malondialdehyde-derived protein-epitopes may function as endogenous sensitizers of UVA-induced oxidative stress in human skin. PMID- 20724177 TI - Is VEGF a predictive biomarker to anti-angiogenic therapy? AB - Tumor growth and metastasis are dependent on angiogenesis. Inhibiting angiogenesis has therapeutic potentials for treating cancer. Researchers have identified many of the pathways involved in angiogenesis and proposed selective targeted strategies. A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to anti-angiogenic agents are inconclusive for predicting benefit from these drugs. This paper reviews the most important biomarker of angiogenesis, namely VEGF, in relation to its expression in cancer and the treatment of these cancers through targeting VEGF and its pathways. PMID- 20724179 TI - Inactivation and removal of influenza A virus H1N1 during the manufacture of plasma derivatives. AB - Although transmission of pandemic influenza A virus H1N1 2009 is still occurring globally, little has been reported about how this outbreak has affected the safety of plasma derivatives. To evaluate the safety of plasma derivatives, dedicated virus clearance processes used during their production were investigated for their effectiveness in eliminating this virus of recent concern. In this study, influenza A virus H1N1 strain A/NWS/33 (H1N1) was chosen as a surrogate. H1N1 was completely inactivated by fraction IV fractionation as well as pasteurization during the manufacture of albumin. H1N1 was also effectively removed into the precipitate by fraction III fractionation and completely inactivated by low pH incubation as well as pasteurization during the manufacture of intravenous immunoglobulin. H1N1 was completely inactivated within 1 min of solvent/detergent treatment using 0.3% tri (n-butyl) phosphate and 1.0% Triton X 100 and also completely inactivated within 10 min of dry-heat treatment at 98 degrees C during the manufacture of factor VIII. H1N1 was completely removed by virus filtration process using Viresolve NFP filter and also completely inactivated by pasteurization during the manufacture of anti-thrombin III. These results indicate that all the virus clearance processes commonly used have sufficient H1N1 reducing capacity to achieve a high margin of safety. PMID- 20724180 TI - Application of the Three Rs to challenge assays used in vaccine testing: tenth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement. AB - This report aims to facilitate the implementation of the Three Rs (reduction, refinement and replacement) in the testing of vaccines for regulatory and other purposes. The focus is predominantly on identification of reduction and refinement opportunities in batch potency testing but the principles described are widely applicable to other situations that involve experimental infections of animals. The report should also help to interpret the requirements of the European Pharmacopoeia with regard to the use of alternative tests, humane endpoints and other refinements. Two specific worked examples, for batch potency testing of Clostridium chauvoei and canine leptospira, with recommendations for harmonisation of international test requirements for these and other vaccines, are provided as appendices online. PMID- 20724178 TI - Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. AB - Type 1B diabetes (typically with early onset and without islet autoantibodies) has been described in patients bearing small coding sequence mutations in the INS gene. Not all mutations in the INS gene cause the autosomal dominant Mutant INS gene Induced Diabetes of Youth (MIDY) syndrome, but most missense mutations affecting proinsulin folding produce MIDY. MIDY patients are heterozygotes, with the expressed mutant proinsulins exerting dominant-negative (toxic gain of function) behavior in pancreatic beta cells. Here we focus primarily on proinsulin folding in the endoplasmic reticulum, providing insight into perturbations of this folding pathway in MIDY. Accumulated evidence indicates that, in the molecular pathogenesis of the disease, misfolded proinsulin exerts dominant effects that initially inhibit insulin production, progressing to beta cell demise with diabetes. PMID- 20724181 TI - Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events--a longitudinal in vivo magnetic resonance imaging-based finite element study. AB - BACKGROUND: High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. METHODS: A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. RESULTS: During a median follow-up duration of 514 days, 20% of patients (n = 12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, p = 0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61-33.82), p = 0.009) and PH (HR: 5.85 (95% CI: 1.27-26.77), p = 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229-494) vs. 254 kPa (166-290), p = 0.04). CONCLUSIONS: High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events. PMID- 20724182 TI - Functional electrical stimulation of the left recurrent laryngeal nerve using a vagus nerve stimulator in a normal horse. AB - The aim of this study was to assess the feasibility of implanting an existing vagus nerve stimulating (VNS) electrode around the recurrent laryngeal nerve. The stimulus response characteristics required to achieve abduction of the ipsilateral arytenoid by the VNS electrode in the normal horse could then be determined. The electrode was wound around the left recurrent laryngeal nerve at the cervical level and connected to a pulse generator. Stimulus response characteristics were obtained by measuring stimulated arytenoid displacement endoscopically in the standing, non-sedated horse. A full and sustained abduction of the arytenoid was obtained with a stimulation frequency of 25 Hz and intensity of 1 mA with a pulse width of 250 MUs. PMID- 20724183 TI - Myokymia and neuromyotonia in 37 Jack Russell terriers. AB - The clinical and clinicopathological characteristics, treatment and outcome of vermicular muscle contractions (myokymia) and generalized muscle stiffness (neuromyotonia) in 37 Jack Russell terriers were evaluated retrospectively. Thirty dogs were affected by both disorders, whereas seven were presented with myokymia and never developed neuromyotonia. Clinical signs started at the mean age of 8 months. Except for signs of myokymia and neuromyotonia, clinical and neurological examination was normal in all dogs. Thirty dogs demonstrated typical signs of hereditary ataxia. Changes in serum chemistry included increased creatine kinase, aspartate aminotransferase and alanine aminotransferase concentrations. Electromyographic abnormalities, especially in muscles showing macroscopically visible myokymia, consisted of semirhythmic bursts of doublet, triplet, or multiplet discharges of a single motor unit. The amplitudes varied between 80 MUV and 1 mV and occurred with an interburst frequency between 10 and 40 Hz and an intraburst frequency between 150 and 280 Hz. Most dogs were treated with a sodium channel blocker with variable results. Seven dogs died (most likely because of hyperthermia) or were euthanased during a neuromyotonic attack; 15 dogs were euthanased due to worsening of clinical signs, or lack of or no long lasting effect of medication, and three were euthanased for unknown or unrelated reasons. Nine dogs were lost to follow-up and three were still alive 5-10.5 years after the start of clinical signs. In conclusion, young Jack Russell terriers with myokymia and neuromyotonia should undergo a complete blood and electrophysiological examination. Long-term prognosis is not favourable. PMID- 20724184 TI - A coarse-grained molecular model for actin-myosin simulation. AB - We describe a very coarse-grained molecular model for the simulation of myosin V on an actin filament. The molecular representation is hierarchical with the finest level representing secondary structure elements (end-points) which are grouped into domains which are then grouped into molecules. Each level moves with a Brownian-like motion both in translation and rotation. Molecular integrity is maintained by steric exclusion and inter-domain restraints. A molecular description is developed for a myosin dimer on a actin filament with binding interactions also specified between domains to simulate both loose and tight binding. The stability of the model was tested in the pre- and post-power-stroke conformations with simulations in both states being used to test the preferred binding site of the myosin on the filament. The effects of the myosin twofold symmetry and the restriction of an attached cargo were also tested. These results provide the basis for the development of a dynamic model of processive motion. PMID- 20724186 TI - Use of gadolinium diethylene triamine penta-acetic acid, as measured by ELISA, in the determination of glomerular filtration rates in cats. AB - The goal of this study was to evaluate a commercially available assay for gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) for use in estimating glomerular filtration rate (GFR) in cats (Gd-DTPA GFR) with a wide range of GFRs. Eighteen adult cats (11 healthy and seven with chronic kidney disease) were included. Plasma concentrations of Gd-DTPA following intravenous injection were measured with an ELISA kit (FIT-GFR). Results for Gd-DTPA GFR were compared with simultaneously obtained values for plasma clearance of iohexol (iohexol GFR), plasma blood urea nitrogen (BUN) and creatinine concentrations. A negative correlation existed between iohexol GFR and plasma concentrations of BUN and creatinine. A positive correlation existed between Gd-DTPA GFR and iohexol GFR. There was no correlation between Gd-DTPA GFR and plasma concentrations of BUN and creatinine. In this study plasma clearance of Gd-DTPA assayed by FIT-GFR did not appear to provide a sufficiently accurate estimation of GFR in cats when compared with plasma clearance of iohexol, and plasma concentrations of BUN and creatinine. PMID- 20724185 TI - Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle. AB - OBJECTIVES: To investigate the effects of combined hormone replacement therapy (HRT) and its effective agents on the IGF-1 signaling pathway. DESIGN AND METHODS: To examine the effects of HRT on skeletal muscle in vivo, we utilized pre- and post-intervention samples from a randomized double blinded trial with 50 57-year-old women. The intervention included the year-long use of either HRT preparation (2 mg 17beta-estradiol, E2; 1mg norethisterone acetate, NETA, n=10) or placebo (CO, n=9). Microarray technology and quantitative PCR (qPCR) were used to study the expression of insulin-like growth factor I (IGF-1) and its splice variants as well as IGF-1 receptor, Akt1, mTOR, FOXO1, FOXO3, atrogin, estrogen receptors and androgen receptor in muscle samples. Serum concentrations of IGF-1, E(2) and testosterone were measured. C2C12 myotubes were fed with E2 or NETA followed by analyzing the expression of essentially the same gene transcripts as in human samples by qPCR and phosphorylation of Akt and mTOR by Western blotting. RESULTS: The gene expression of IGF-1 and its splice variant, IGF-1Ec (also known as the mechano growth factor or MGF), mTOR, FOXO3, and AR was up-regulated among the HRT users compared to the CO (P<0.05), while Akt1 was down-regulated (P<0.05). The change in the level of IGF-1Ec transcript correlated positively with muscle size at post-intervention (r=0.5, P<0.05). In C2C12 myotubes, no statistically significant effects of either E2 or NETA at the level of gene transcripts studied were identified. The amount of phosphorylated Akt appeared to respond to NETA, albeit the response was not statistically significant. Phosphorylation of mTOR did not respond to either of the treatments. CONCLUSION: Year-long postmenopausal HRT was found to affect the expression of the genes along the IGF-1 signaling cascade reflecting the higher muscle mass compared to the CO women. By using cell culture model we were, however, unable to confirm the possible differential role of E2 and NETA. It appears that the synchronous presence of both effective agents of the HRT or the presence of yet unidentified microenvironmental factors providing proper paracrine signals naturally existing in the intact muscle tissue is critical for appropriate signaling via sex steroid IGF-1 axis to occur. PMID- 20724187 TI - Suspected choledochal cyst in a domestic shorthair cat. AB - A 9-year-old female neutered domestic shorthair cat was presented with a history of polyphagia, weight loss and inappropriate urination. Clinical examination revealed jaundice and a mid-cranial abdominal mass. Further investigations revealed a large extra-hepatic cyst originating from the biliary tract (choledochal cyst). Concurrent chronic, active neutrophilic cholangitis and chronic lymphoplasmacytic pancreatitis were also noted. Surgical drainage, subtotal resection and omentalisation of the cyst, along with supportive medical management, were successful in relieving the clinical signs. PMID- 20724188 TI - [Reirradiation of spine and lung tumor with CyberKnife]. AB - We present the results of two retrospective studies, one regarding reirradiation of spinal tumours and the second, concerning lung tumours. In the first case, primary or secondary tumours were located in or in contact with the vertebrae and spinal cord. The first irradiation has given a full dose to the spinal cord. In the second case, primary or secondary lung tumours have already been treated by irradiation alone or by radiochemotherapy. No grade 3 or 4 early toxicity has been found. Preliminary clinical results are encouraging. The use of CyberKnife represents a major therapeutic advance in the management of irradiated spinal or lung lesions. The possibility of sparing organs at risk and increasing the dose in the tumour target volume are the main advantages. PMID- 20724189 TI - [Which intensity modulated radiation therapy? From "step and shoot" to volumetric modulated arc therapy, point of view of the radiation oncologist]. AB - Intensity modulated radiation therapy (IMRT) offers optimal dosimetric and clinical results in terms of acute toxicity, allows augmenting the dose to the target volumes and therefore, appears promising for local control and disease free survival. However, several pitfalls to this treatment are to be considered, namely a long treatment time and a high number of monitor unit (MU) required. The dosimetric results of the volumetric modulated arctherapy gives at least similar target coverage and preservation of organs at risk, while significantly reducing the number of required MUs and the overall treatment time. This has a potential impact on the treatment quality and the potential risk of secondary cancers. Volumetric modulated arctherapy allows implementation of stereotactic radiation therapy and complex treatments previously considered not feasible with IMRT. The future will involve this technology of high precision to determine the dose and to the target in real time using the image-guided radiotherapy. Tools combining these two methods are in development. PMID- 20724190 TI - [Which modality for prostate brachytherapy?]. AB - Brachytherapy techniques by permanent implant of radioactive sources or by temporary high-dose-rate (HDR) fractions are nowadays extensively used for the treatment of prostatic carcinoma. Long-term results (at 20 years) concerning large amount of patients have been published by major centers confirming both in terms of efficacy and toxicities that permanent implant of radioactive iodine-125 seeds yields at least the same good results of surgery and of external beam irradiation when proposed to patients affected by low-risk disease. For intermediate to high-risk tumors, HDR temporary implants are proposed as a boost for dose escalation. For both techniques, several topics still need to be clarified dealing with a recent enlargement of indications (HDR alone for low risk, iodine-125 seeds boost for intermediate-high-risk cancers), or with technical aspects (loose seeds versus linked ones, number of fractions and dose for HDR protocols), while dosimetric issues have only recently been addressed by cooperatives groups. Last but not least, there is a real need to address and clearly characterize the correct definition of biochemical disease control both for iodine permanent implant and for HDR implant. New challenges are facing the prostate-brachytherapy community in the near future: local relapse after external beam radiotherapy are currently managed by several salvage treatments (prostatectomy, cryo, high intensity focused ultrasounds [HIFU]) but the role of reirradiation by brachytherapy is also actively investigated. Focal therapy has gained considerable interest in the last 5 years aiming at treating only the area of cancer foci inside the prostate and preserving nearby healthy tissues. Encouraging results have been obtained with the so-called "minimally invasive" approaches and both permanent seed implantation and HDR brachytherapy techniques may be worthwhile testing in this setting because of their capability of exactly sculpting the dose inside the prostatic gland. PMID- 20724192 TI - [Quality of life for patients treated for head and neck carcinoma]. AB - A large consensus admits that quality of life is a multifactorial concept including at least physical, psychical and social dimensions of the disease as well as symptoms related to the disease and to the requested treatments. Quality of life is actually considered as one of the major assessment criteria for taking care of patients with cancer and to evaluate results of clinical trials. Self evaluation by the patient is considered as the gold standard to evaluate the clinical symptoms. This evaluation is not unambiguous. Medical doctors underestimate patients' symptoms. In the field of surgery, development of organ preservation strategies should be considered as one of the major improvement observed in the modern era of head and neck oncology. The role of xerostomia, the most frequent complication reported after head and neck radiation therapy, is major in this field. However, odynophagia is considered as the most detrimental component of quality of life. Radiation oncologists should realize the role of these parameters in order to include these concepts as relevant in the global evaluation of treatments. PMID- 20724193 TI - [Systematic review of stereotactic radiotherapy for high-grade gliomas]. AB - The purpose of this literature systematic review was the use of stereotactic radiotherapy in glioma. Research was performed in Medline/PubMed and associated references found in published articles without publication date limit. The quality of series is variable and many biases can be evidenced. Only two randomized trials have been published using stereotactic radiotherapy for up front treatment. There is a lack of evidence of survival advantages to use this treatment at the time of diagnosis or relapse. There is also insufficient evidence regarding the benefice/harms in the use of stereotactic fractionated radiation therapy for patients with glioma. No recommendations can be enounced. Stereotactic irradiation as boost in primary diagnosed glioma or relapsed tumour is not associated with survival improvement. For relapsed patients, treatment needs to be discussed according to the other treatment options. PMID- 20724194 TI - Looking for microRNA polymorphisms as new rheumatoid arthritis risk loci? PMID- 20724195 TI - [Glomus tumors in the extremities of children--a rare cause of chronic pain. Two clinical cases]. AB - Glomus tumor (GT) of limb extremities (finger, toe) is a rare tumor, especially in children. It is formed by hyperplasia of the neuro-myoarterial elements. Chronic pain is often associated. The diagnosis is made by the history and several clinical tests (Hildreth's and Love's tests). This diagnosis must be suspected in a child with chronic extremity pain. Magnetic resonance imaging (MRI) is the most sensitive imaging test. Complete surgical excision of the lesion is curative. We report two clinical cases of glomus tumor of limb extremities (finger and toe) in two children - aged 7 and 12 - causing severe chronic pain; the diagnosis of this condition remains a challenge. PMID- 20724196 TI - [Infection of a tophaceous nodule of the middle finger]. AB - Gouty involvement of the hand is uncommon and the complications the most described are bony destruction, digital joint instability, tenosynovitis and double ipsilateral tunnel syndrome of the median and ulnar nerves at the wrist. Septic complications, such as infection of a tophaceous nodule, are a rare entity. The authors report a case of an infection of a tophaceous nodule of the middle finger in a 67-year-old man. The diagnosis was suspected on physical examination and radiological findings but final diagnosis is provided by bacteriological examination. This case is presented to heighten awareness of this rare entity and to provide a setting for a discussion of management. PMID- 20724197 TI - [Juxta articular myxoma of the wrist: a case report]. AB - Juxta articular myxomas are rare tumors. The treatment is surgical with a high recurrence rate. A location proximal to the wrist joint is exceptional. We report a case of juxta articular myxoma of the wrist in a 30-year-old patient, with no recurrence four months after surgical excision. PMID- 20724198 TI - Limits of reconstruction in mangled hands. PMID- 20724199 TI - [Hammer hypothenar syndrome: review of the literature and case report]. AB - Hypothenar hammer syndrome is a rare disease first described by Conn et al. in 1970. It groups together symptoms of chronic microtraumatism to the ulnar artery or its superficial palmar branch against the hamate. Manual workers using vibrating tools are the most affected by this. Diagnosis is made by echodoppler, while arteriography is the gold standard for establishing the treatment plan. Hypothenar hammer syndrome may lead to severe complications secondary to ischemia and to embolic events resulting from delayed diagnosis or maltreatment. There is no real consensus as to the place of medical or surgical treatments. Medical treatment consists of eliminating favorizing factors and long-term antiplatelet aggregation treatment. Surgical treatment depends on the vascular lesions: simple arterial ligation, resection of the thrombosed arterial segment and end-to-end anastomosis, or revascularization using a pontage venous or arterial graft. Some authors suggested an associated thoracic sympathectomy. The diagnosis must be made early; the choice of treatment must be targeted at preventing serious embolic complications. PMID- 20724200 TI - Osteoid osteoma of the pisiform: a case report. AB - Osteoid osteoma of the pisiform is exceptional, and has been reported previously only once, in 1985, by Kernohan. This report presents a clinical case of osteoid osteoma of the pisisform assessed by CT-scanning, 3D reconstruction CT-scan images, MRI imaging and per-operative pictures. PMID- 20724201 TI - [Intra-articular sub-periosteal osteoid osteoma of the triquetrum. Case report]. AB - We report a case of subperiosteal osteoid osteoma of the triquetrum located into the piso-triquetral joint space. Such a variant at this particular location is very rare. The diagnosis was delayed for six years. A bloc resection of the tumour was followed by complete recovery. PMID- 20724202 TI - [Fractures of the distal radius in patients over 70 years old: Volar plates or K wires?]. AB - In a growing elderly osteoporotic population, the management of distal radius fractures remains without consensus as to volar distal plate versus K-wires. The goal of this retrospective study was to evaluate these treatments in elderly people. In a series of 38 patients over 70 years, 21 were treated by a volar plate and 17 by percutaneous K-wire fixation. Follow-up was at least 6 months. Results were analyzed using the disabilities of the arm, shoulder and hand (DASH), patient-rated wrist evaluation (PRWE) and Herzberg score by an independent operator. Radiological parameters were radio-ulnar variance, radial inclination and palmar or dorsal tilt. Radio-ulnar variance was better for the plate group (-0.7mm versus -0.1mm in K-wires). Mean functional outcomes were good but there were more satisfied patients in the plate group (67% versus 39% for the K-wire group). Secondary displacements were frequent in both groups but more with K-wires (50% versus 37% in case of plates). Six articles about surgical treatment of elderly radius distal fractures were published up to 2009 showing similar results. However, they analyze only global mean scores. Volar plates give more stability and a higher rate of satisfaction, with similar results of wrist mobility and grasp strength. The main advantage of the plates is earlier return to daily activities. PMID- 20724203 TI - [Surf and Seymour's fractures]. AB - The authors present four cases of Seymour-like juxtaepiphyseal fractures related to surf accidents. All four patients were novices at the sport, had the same fractures in identical circumstances. In all cases, reduction was achieved using an 'in-and-out' 1.2 K-wire serving as a 'joystick' which was then also used for fixation. The nail was fixed at the end. PMID- 20724204 TI - [Rare localization of an aggressive epithelioid sarcoma in an adolescent]. AB - Epithelioid sarcoma is a rare soft-tissue sarcoma affecting mostly young adult males. It is exceptional under the age of 20. Diagnosis is by histiochemistry. Treatment is mainly wide surgical excision. The normal evolution is local spread followed by generalized metastasis. We report a case of epithelioid sarcoma of the left arm in a 16-year old adolescent of 8 months duration. PMID- 20724205 TI - [Conventional IVF versus ICSI in sibling oocytes: a French experience analysis for BLEFCO]. AB - Assisted Reproductive Techniques (ART) separating oocytes in sibling oocytes treated either by conventional IVF or ICSI is called mid-IVF/ICSI. We sum up here 487 attempts of this kind from six French ART centers. The mid-IVF/ICSI technique was performed in 5.6% of cases. The fertilization rate by micro-injected oocytes was significantly higher (P<0.01) than oocytes inseminated conventionally, 72.6% versus 53.4%. A failure of fertilization was observed only in mid-IVF in 21.6% of cases, which prevented a complete fertilization failure when we decided to propose to the couples concerned the mid-IVF/ICSI technique. Conversely, in 75.2% of cases, fertilization was found for the two batches of oocytes. The overall pregnancy rate has improved since the use of the mid-IVF/ICSI technique (33.1% versus 28.9%, P=0.013) and the fertilization failures decreased (10.4% versus 14.3%, P=0. 019). The pregnancy rate in only mid-IVF/ICSI cases is very high at 39.8% but for a selected population. The indications for mid-IVF/ICSI remain to be clarified especially with regard to male and idiopathic indications. PMID- 20724206 TI - Efficient sonochemical synthesis of thiazolidinones from piperonilamine. AB - An efficient multicomponent reaction of arenealdehydes, mercaptoacetic acid and piperonilamine under ultrasound irradiation to afford 2-aryl-3-(piperonylmethyl) 1,3-thiazolidin-4-ones is reported. Applying this methodology, eleven heterocycles were synthesized and isolated in good yields after short reaction times. PMID- 20724207 TI - Making the narrative walk-in-real-time methodology relevant for public health intervention: towards an integrative approach. AB - The purpose of this article is to describe a novel approach for understanding the subjective experience of being a pedestrian in urban settings. In so doing, we take into account the "experience of the body in movement" as described in different theories and according to different methods, and develop a tool to allow citizens and urban planners to exchange ideas about how to make cities more walkable. Finally, we present the adaptation of the approach for use in public health and provide a rationale for its more widespread use in place and health research. PMID- 20724208 TI - Geographic issues in cardiac rehabilitation utilization: a narrative review. AB - OBJECTIVE: The purpose of this study was to review the current evidence regarding the relationship between geographic indicators and cardiac rehabilitation (CR) utilization among coronary heart disease (CHD) patients. RESULTS: Seventeen articles were identified for inclusion, where nine studies assessed rurality, 10 studies assessed travel time/distance, and two of these studies assessed both. Nine of the 17 studies (52.9%) showed a significant negative relationship between geographic barrier and CR use. Four of the 17 studies (23.5%) showed a null relationship, while four studies (23.5%) showed mixed findings. Inconsistent findings identified appeared to be related to restricted geographic range, regional density, and socioeconomic status. CONCLUSIONS: Overall, 52.9% of the identified studies reported a significant negative relationship between geographic indicators and CR utilization. This relationship appeared to be particularly consistent in North American and Australian settings, but somewhat less so in the United Kingdom where there is greater population density and availability of public transport. PMID- 20724209 TI - Episode of fainting and tetany after an evaluation technique of the upper cervical region: a case report. PMID- 20724210 TI - Sex-related variation in human behavior and the brain. AB - Male and female fetuses differ in testosterone concentrations beginning as early as week 8 of gestation. This early hormone difference exerts permanent influences on brain development and behavior. Contemporary research shows that hormones are particularly important for the development of sex-typical childhood behavior, including toy choices, which until recently were thought to result solely from sociocultural influences. Prenatal testosterone exposure also appears to influence sexual orientation and gender identity, as well as some, but not all, sex-related cognitive, motor and personality characteristics. Neural mechanisms responsible for these hormone-induced behavioral outcomes are beginning to be identified, and current evidence suggests involvement of the hypothalamus and amygdala, as well as interhemispheric connectivity, and cortical areas involved in visual processing. PMID- 20724211 TI - A neurophysiological approach to the complex organisation of the spine: F-wave duration and the cutaneous silent period in restless legs syndrome. AB - OBJECTIVE: It is generally accepted that F-wave duration (FWD) and the cutaneous silent period (CSP) are influenced by diminished central inhibition. The aim of this study was to diagnose patients of restless legs syndrome (RLS) with the help of FWD and/or CSP parameters. METHODS: In all, 24 patients with primary RLS were compared with 31 age- and sex-matched controls. The participants were evaluated based on nerve conduction study (NCS), F-wave parameters (minimum, maximum and mean latency; chronodispersion, persistence and duration; and the ratio of the mean FWD to compound muscle action potential (CMAP) duration), CSP (latency, duration and the ratio of lower-extremity (LE) to upper-extremity (UE) duration that is, silent period ratio (SPR)), the expiration to inspiration ratio (E/I) and sympathetic skin response (SSR). RESULTS: There were not any significant differences in NCS, E/I or SSR between the patients and controls. However, FWD was prolonged (P<0.0001 for UE and LE) and FWD/CMAP duration was increased in upper and lower extremities (P<0.001 for UE and P<0.0001 for LE). Further, CSP latencies in UE (P=0.030) and LE (P<0.001) were prolonged, and CSP duration and SPR were significantly reduced in the patient group (P<0.0001). CONCLUSIONS: As both NCS and autonomic test results were in the normal range, abnormalities in FWD and CSP parameters were attributed to the dysfunction of different interneuron groups in the spine. SIGNIFICANCE: The use of FWD and CSP could aid in the diagnosis of RLS patients in whom conventional electrophysiological procedures are ineffective. PMID- 20724212 TI - The development of the perception of facial emotional change examined using ERPs. AB - OBJECTIVE: The development of the perception of changes in facial emotion was investigated using event-related potentials (ERPs) in children and adults. METHODS: Four different conditions were presented: (1) N-H: a neutral face that suddenly changed to a happy face. (2) H-N: reverse of N-H. (3) N-A: a neutral face that suddenly changed to an angry face. (4) A-N: reverse of N-A. RESULTS: In the bilateral posterior temporal areas, a negative component was evoked by all conditions in younger children (7-10 years old), older children (11-14 years old), and adults (23-33 years old) within 150-300 ms. Peak latency was significantly shorter and amplitude was significantly smaller in adults than younger and older children. Moreover, maximum amplitude was significantly larger for N-H and N-A than H-N and A-N in younger children and for N-H than the other three conditions in adults. CONCLUSION: The areas of the brain involved in perceiving changes in facial emotion have not matured by 14 years of age. SIGNIFICANCE: Our study is the first to clarify a difference between children and adults in the perception of facial emotional change. PMID- 20724213 TI - Bioprocess strategies for enhanced production of xylanase by Melanocarpus albomyces IITD3A on agro-residual extract. AB - The production of high titer xylanase without cellulase is required for prebleaching of pulps in pulp and paper industry. The mutant IITD3A of Melanocarpus albomyces developed from the spores of the wild type organism was used in this study. The statistical optimization of the process parameters by response surface methodology revealed that the production of xylanase was most affected by changes in the pH of the production medium which contained a soluble extract of wheat straw as the sole carbon source. When the pH of the production medium in a 14 L bioreactor was controlled on-line at 7.8, xylanase activity of 415 IU mL-1 was obtained after 36 h fermentation. On cycling the pH between 7.8 and 8.2, the same activity could be attained in 24 h with an overall productivity of 16,670 IU L-1 h-1. The production of xylanase was also influenced by the fungus morphology; the activity being maximum when it exhibited pellet form at an agitation speed of 600 rpm. On optimization of aeration rate to 0.25 vvm, the xylanase activity further increased to 550 IU mL-1 with a very high overall volumetric productivity of 22,000 IU L-1 h-1. Thus, a 5.2-fold enhancement in overall volumetric productivity of xylanase could be obtained by the mutant in comparison to that obtained on insoluble wheat straw. PMID- 20724214 TI - An epidemiologic study of sleep problems among adolescents in North Taiwan. AB - BACKGROUND AND PURPOSE: To investigate the prevalence of sleep problems and their association with daytime sleepiness among Taiwanese adolescents by use of a validated questionnaire. PATIENTS AND METHODS: This is a cross-sectional, community based study with self-reported sleep questionnaires. Completed questionnaires from 1939 adolescent subjects from schools in Lin-Kou district (Taipei, Taiwan) (96.7% responded); 1906 valid questionnaires (62.3% girls) were analyzed. The randomly selected classes included elementary grade 6 (age range: 12-13 years), junior high school (age range: 14-16 years) and senior high school students (age range: 17-18 years). RESULT: The mean sleep duration on weekdays was 7.35+/-1.23 h and on weekends 9.38+/-1.62 h. Weeknight sleep decreased significantly with increasing school grade (6.87+/-1.14 h for high school seniors). There was a trend towards increased daytime sleepiness for students in higher school grade levels. Daytime sleepiness directly correlated with shorter total sleep time (TST) on weekdays, longer TST on weekends, snoring, insomnia and nightmares. Coffee intake, smoking, periodic leg movement/restless legs syndrome, body mass index (BMI), mouth breathing and breathing problems were indirect factors that induced daytime sleepiness. Pearson correlation showed no significant correlation between the TST during the weekday and BMI (-0.047, p=0.079) or body weight (BW) (-0.048, p=0.072). But it showed significant negative correlation (-0.103, p=0.0001) for increasing total sleep time on the weekend and decreasing BMI. CONCLUSIONS: Daytime sleepiness correlated with the shorter TST on weekdays, longer TST on weekends, snoring, insomnia and nightmares. There is no significant correlation between the weekday TST and BMI or BW. Meals and food intake of children are still traditional and have not changed as much in Taiwan as in some other western countries, and compared to a similar survey performed 12 years ago in Taiwan among junior high school students, sleep duration was not significantly different but reduced due to school demands. PMID- 20724215 TI - A biomechanical, histological and biochemical study in an experimental rabbit hypospadias repair model using scanning acoustic microscopy. AB - OBJECTIVE: To investigate the biomechanical, histological and biochemical properties of rabbit urethra at long-term follow up after hypospadias simulation and acute repair. MATERIALS AND METHODS: Thirty-eight white New Zealand male rabbits underwent experimental creation of a hypospadias-like defect and acute repair (mobilization and advancement, tubularized incised posterior urethral plate (TIP), modified TIP) and sham operation. After 23 weeks all groups + controls underwent biomechanical, histological and biochemical assessments. RESULTS: The mobilization and advancement group showed a higher stiffness compared to the TIP groups (P < 0.05) in the posterior urethra, whereas the TIP group was stiffer compared to the other two operative groups (P < 0.001) in the ventral urethra. In the dorsal urethra, the mobilization and advancement group and the modified TIP group had a higher collagen content compared to shams (P < 0.05). No differences in collagen content were found between groups in the ventral urethra. A correlation between acoustic and histological layers was found, partially related to collagen content. CONCLUSION: The urethras had different microelastic properties in different layers of the dorsal and ventral urethra, with higher stiffness in the connective tissue layers surrounding and within the urethra. The repaired urethras had partially recovered their elasticity at micrometer resolution at long-term follow up. Scanning acoustic microscopy elucidated structure-function relationships at microscopic level in normal and operated urethra. PMID- 20724216 TI - Commentary to "Safety and efficacy of spica casts for immobilization following initial bladder closure in classic bladder exstrophy". PMID- 20724217 TI - The development of a new speciality training programme in obstetrics and gynaecology in the UK. AB - In 2004, the Royal College of Obstetricians and Gynaecologists (RCOG) established a working group of experienced Fellows, Members, trainees and educationalists, who were responsible for writing and coordinating the development of a new curriculum in obstetrics and gynaecology. The curriculum would underpin the new 7 year speciality training programme. In December 2006, the UK Postgraduate Medical Education and Training Board approved the curriculum. In August 2007, the new Speciality Training and Education programme in Obstetrics and Gynaecology was launched. The curriculum forms the backbone of the 7-year speciality training programme in obstetrics and gynaecology. The programme is divided into three levels of training: basic, intermediate and advanced. The programme is competency based rather than being focussed on time periods or the number of hours or number of procedures required to progress through the programme. Successful progress is achieved by meeting the requirements at designated waypoints defined within the programme. The curriculum outlines not only the knowledge and technical clinical skill requirements, but also the professional skills and attitudes that must consistently be adopted by health-care professionals in a modern health service. The curriculum was originally benchmarked against the General Medical Council's Good Medical Practice criteria: (1) Good clinical care; (2) Good medical practice; (3) Successful relationships with patients; (4) Working with colleagues; (5) Teaching and training; (6) Probity; (7) Health. PMID- 20724218 TI - Vagus nerve stimulation and the postictal state. AB - Vagus nerve stimulation (VNS) is an established neurostimulation therapy used to treat refractory epilepsy. The effect of acute or chronic VNS on the postictal state as a separate entity is seldom reported in clinical or experimental studies. Apart from its antiseizure effects, VNS has several other beneficial effects. These effects may be of particular benefit for patients with postictal neuropsychiatric symptoms. The hypothesized mechanisms underlying the initiation and sustainment of the postictal phase, to some extent, overlap with mechanisms involved in the seizure-suppressing effects of VNS as well as other neurological and psychotropic effects of VNS. Both the clinical symptoms and the basic research hypotheses of the postictal state show similarities with clinical effects induced by VNS and its underlying mechanisms of action. PMID- 20724219 TI - The postictal EEG. PMID- 20724221 TI - Nonepileptic psychogenic status: markedly prolonged psychogenic nonepileptic seizures. AB - Little is known about markedly prolonged psychogenic nonepileptic seizures (PNES) though they are reported in up to 78% of PNES. Entry to the tertiary referral epilepsy monitoring unit (EMU) is often urgent and the stay usually brief, resulting thus far in almost no data regarding outcomes. The American Epilepsy Society (AES) Nonepileptic Seizure Task Force was asked to gather evidence for consensus of practice and treatment for PNES and its spectrum. As part of the subcommittee focusing on "pseudostatus epilepticus," we sent questionnaires to AES membership inquiring about markedly prolonged events, which we call nonepileptic psychogenic status (NEPS). Ninety U.S. and international neurologists from at least 19 states in the United States responded, with approximately 45% reporting that they do not distinguish NEPS from PNES. Eighty percent of responders considered a period of 20 minutes or longer as "prolonged." Lack of consensus between responders on how to manage these patients was uncovered. The NES Task Force subcommittee on "pseudostatus" recommends that the duration of PNES is tracked and those events lasting 20 minutes or longer, with or without change in level of consciousness, are considered NEPS. Future research needs are discussed. PMID- 20724220 TI - The postictal state: effects of age and underlying brain dysfunction. AB - There is relatively little information on the underlying parameters that affect clinical features of the postictal period. Age-related physiological changes, including alterations in cerebral blood flow and metabolism, neurotransmitter function, and responses of the brain to seizure activity may affect postictal clinical phenomena. Some conclusions can be drawn. Elderly adults and children, particularly in the presence of diffuse cerebral dysfunction, may have more prolonged postictal confusion. Postictal dysphasia strongly suggests a dominant hemisphere focus, more often temporal, and Todd's paralysis is always contralateral to the epileptogenic zone. Much additional information could be derived from the vast amount of video/EEG monitoring data available. PMID- 20724222 TI - Epileptic seizures and spirit possession in Haitian culture: report of four cases and review of the literature. AB - Epileptic seizures have historically been associated with religious beliefs in spirit possession. These attitudes and misconceptions about epilepsy still flourish in developing countries as byproducts of specific sociocultural environments. This article presents a case series of four Haitian patients with epilepsy whose seizures were initially attributed to Voodoo spirit possession. All patients reported ictal experiential phenomena (epigastric aura, ictal fear, depersonalization, and derealization symptoms) followed by complete loss of consciousness. Electroclinical investigations revealed a temporal lobe focus. We review the existing literature on attitudes toward seizures within the Haitian culture and discuss the link between religion and epilepsy, highlighting the possible detrimental influence of specific traditional belief systems on the appropriate diagnosis and treatment of patients with epilepsy. PMID- 20724224 TI - Autonomic control of gut motility: a comparative view. AB - Gut motility is regulated to optimize food transport and processing. The autonomic innervation of the gut generally includes extrinsic cranial and spinal autonomic nerves. It also comprises the nerves contained entirely within the gut wall, i.e. the enteric nervous system. The extrinsic and enteric nervous control follows a similar pattern throughout the vertebrate groups. However, differences are common and may occur between groups and families as well as between closely related species. In this review, we give an overview of the distribution and effects of common neurotransmitters in the vertebrate gut. While the focus is on birds, reptiles, amphibians and fish, mammalian data are included to form the background for comparisons. While some transmitters, like acetylcholine and nitric oxide, show similar distribution patterns and effects in most species investigated, the role of others is more varying. The significance for these differences is not yet fully understood, emphasizing the need for continued comparative studies of autonomic control. PMID- 20724223 TI - Prostatic length predicts functional outcomes after iodine-125 prostate brachytherapy. AB - PURPOSE: To determine the value of prostatic length as a predictor of urinary morbidity after brachytherapy for prostate cancer. METHODS AND MATERIALS: Between May 2002 and September 2008, 214 consecutive patients received brachytherapy for localized prostate cancer at our institution. A prospective analysis of factors predicting urinary toxicity was carried out for these patients. To evaluate urinary morbidity, the posttreatment International Prostate Symptom Score (IPSS) at 3, 9, and 18 months together with rates of urinary retention was recorded. RESULTS: The mean patient age was 62 years, and the mean followup period was 24.4 months. The median IPSS before treatment was 5 (range, 0-20). This increased to 15 (0-33) at 3 months, before subsequently falling to 8 (0-31) and 6 (0-35) at 9 and 18 months, respectively. Twenty-six of 214 (12%) patients experienced urinary retention. Both prostatic length (p-value=0.001, <0.001) and volume (p value=0.002, <0.001) correlated with a higher posttreatment IPSS at 3 and 9 months. In addition, prostate length and volume predicted those patients developing urinary retention requiring catheterization (p-value <0.001, <0.001). Pretreatment IPSS predicted IPSS at 3, 9, and 18 months (p-value <0.001, <0.001, and 0.011) but did not significantly correlate with retention rates. Other factors predicting IPSS at 3 months included radiation dose (D(90)) (p value=0.01) and number of needles used (p-value=0.01). CONCLUSION: Prostatic length is a useful tool for determining urinary toxicity after brachytherapy for prostate cancer and should be included in the pretreatment assessment. PMID- 20724225 TI - Sensitive lactate determination based on acclimated mixed bacteria and palygorskite co-modified oxygen electrode. AB - A sensitive bacteria biosensor was prepared for the detection of trace lactate. The sensitive bioelement, Lactobacillus bulgaricus and Streptococcus thermophilus mixed culture, and palygorskite, a perfect matrix for bacteria, was co immobilized on the surface of oxygen electrode. The biosensor possesses fine selective specificity, good sensitivity and longer operational life time, which were due to the mutual help relationship of symbiotic bacteria and 240 days acclimation with lactate as the carbon source. Hydrodynamic amperometry, an advanced electrochemical method, is suitable for on-line monitoring the concentration change of dissolved oxygen that is closely accompanied with the metabolism of lactate. Electrochemical data show that the current is very sensitive to the changes of the concentration of lactate. The response current was linear with lactic acid concentration in the range from 0 to 300MUmol L(-1), where the response time is no more than 240 s (R=0.9952), and the sensitivity was 1.87mA mol(-1)L. Experiments show the biosensor is also very useful for long time on-line monitoring of lactate, such as fermentation progress. PMID- 20724226 TI - Interplay of DNA repair, homologous recombination, and DNA polymerases in resistance to the DNA damaging agent 4-nitroquinoline-1-oxide in Escherichia coli. AB - Escherichia coli has three DNA damage-inducible DNA polymerases: DNA polymerase II (Pol II), DNA polymerase IV (Pol IV), and DNA polymerase V (Pol V). While the in vivo function of Pol V is well understood, the precise roles of Pol IV and Pol II in DNA replication and repair are not as clear. Study of these polymerases has largely focused on their participation in the recovery of failed replication forks, translesion DNA synthesis, and origin-independent DNA replication. However, their roles in other repair and recombination pathways in E. coli have not been extensively examined. This study investigated how E. coli's inducible DNA polymerases and various DNA repair and recombination pathways function together to convey resistance to 4-nitroquinoline-1-oxide (NQO), a DNA damaging agent that produces replication blocking DNA base adducts. The data suggest that full resistance to this compound depends upon an intricate interplay among the activities of the inducible DNA polymerases and recombination. The data also suggest new relationships between the different pathways that process recombination intermediates. PMID- 20724228 TI - The interplay between BRCA1 and 53BP1 influences death, aging, senescence and cancer. AB - In proliferating cells DNA double strand breaks (DSBs) are a common occurrence during DNA replication. DSB repair using homologous recombination is essential for the error-free repair of such breaks and proliferating cells require some level of HR activity for their viability. The BRCA1 tumour suppressor has an important role in this process and is believed to channel the DSBs into the HR pathway. The related 53BP1 gene is known to positively regulate repair of DSBs outside of S phase, but via the NHEJ pathway. Two new studies suggest a new role for 53BP1 as an inhibitor of HR [1,2]. These genetic studies establish that 53BP1, but not other components of the NHEJ machinery, can inhibit the early resection step of HR. In cells defective for BRCA1, which is required for efficient HR, the balance between promoting and inhibiting HR is thrown towards inhibition. Simultaneous loss of 53BP1 can rescue the HR defect of BRCA1 defective cells and restore cellular viability. Here, I provide an overview of these studies and discuss their implications for tumourigenesis. PMID- 20724227 TI - Ser 524 is a phosphorylation site in MUTYH and Ser 524 mutations alter 8 oxoguanine (OG): a mismatch recognition. AB - MUTYH-associated polyposis (MAP) is a colorectal cancer predisposition syndrome that is caused by inherited biallelic mutations in the base excision repair (BER) gene, MUTYH. MUTYH is a DNA glycosylase that removes adenine (A) misinserted opposite 8-oxo-7,8-dihydro-2'-deoxyguanosine (OG). In this work, wild type (WT) MUTYH overexpressed using a baculovirus-driven insect cell expression system (BEVS) provided significantly higher levels of enzyme compared to bacterial overexpression. The isolated MUTYH enzyme was analyzed for potential post translational modifications using mass spectrometry. An in vivo phosphorylation site was validated at Serine 524, which is located in the C-terminal OG recognition domain within the proliferating cell nuclear antigen (PCNA) binding region. Characterization of the phosphomimetic (S524D) and phosphoablating (S524A) mutants together with the observation that Ser 524 can be phosphorylated suggest that this residue may play an important regulatory role in vivo by altering stability and OG:A mismatch affinity. PMID- 20724229 TI - A sensitive and specific liquid chromatography-tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients. AB - A novel, sensitive and reliable liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of belinostat (PXD101) in human plasma. Oxamflatin was used as the internal standard. Liquid liquid extraction of the plasma sample was performed using tert-butyl methyl ether as the organic solvent. Chromatographic separation was achieved on a BDS Hypersil C18 column (2.1 mm x1 00 mm, 5 microm) using gradient elution mode using 0.05% formic acid in water and 0.05% formic acid in acetonitrile as solvents A and B, respectively, 60/40. The run time was 6 min. The mass spectrometer was operated under a positive electrospray ionization condition and a multiple reaction monitoring mode. An excellent linear calibration was achieved in the range of 0.5-1000 ng/mL. An average recovery of belinostat for four quality controls was 72.6% and the recovery of the internal standard at 1000 ng/mL was 67.8%. The intra-day and inter-day precisions for belinostat were 5G to 4G>5G or 4G>4G alleles are associated with overexpression of PAI-1. In this study patients with residual venous thrombi were observed to have increased PAI-1 levels and more frequent shifts to 4G alleles. Of the 26, 20 (76.9%) patients with unresolved thrombus had elevated PAI-1 values. 4G genomic shifts were found in 92.9% patients studied. Normal PAI-1 levels were found in 5 patients with 4G polymorphisms. Thus, PAI-1 is often elevated among patients with residual thrombus, with an unexpectedly high prevalence of the 4G polymorphism of the promoter genome. Patients with persistent thrombus should be considered at risk of having constituently increased PAI-1 due to genomic changes in the PAI-1 promoter genome. Hypotheses are proposed to explain those with normal PAI-1, despite having 4G polymorphisms. PMID- 20724305 TI - Radon concentrations in water in the region of Tokat city in Turkey. AB - The aim of this study is to measure the radon ((222)Rn) concentrations in drinking water and river water in the region of Tokat city in Turkey. The measurements were performed by analysing the water samples collected from tap water, spring water and Yesilirmak river water flowing through the centre of the city of Tokat. The obtained radon concentrations ranged from 0.48 +/- 0.22 to 1.30 +/- 0.27 Bq l(-1) in tap water, from 0.13 +/- 0.17 to 1.20 +/- 0.29 Bq l(-1) in spring water and from 0.09 +/- 0.12 to 0.83 +/- 0.17 Bq l(-1) in the Yesilirmak river water. The results are presented and compared with other studies. From these data, the average effective dose equivalent from radon in tap water and in spring water has been estimated as 5.0 and 3.0 uSv y(-1), respectively. PMID- 20724306 TI - Evolutionary lineages of nickel hyperaccumulation and systematics in European Alysseae (Brassicaceae): evidence from nrDNA sequence data. AB - BACKGROUND AND AIMS: Nickel (Ni) hyperaccumulation is a rare form of physiological specialization shared by a small number of angiosperms growing on ultramafic soils. The evolutionary patterns of this feature among European members of tribe Alysseae (Brassicaceae) are investigated using a phylogenetic approach to assess relationships among Ni hyperaccumulators at the genus, species and below-species level. METHODS: Internal transcribed spacer (ITS) sequences were generated for multiple accessions of Alysseae. Phylogenetic trees were obtained for the genera of the tribe and Alyssum sect. Odontarrhena. All accessions and additional herbarium material were tested for Ni hyperaccumulation with the dimethylglyoxime colorimetric method. KEY RESULTS: Molecular data strongly support the poorly known hyperaccumulator endemic Leptoplax (Peltaria) emarginata as sister to hyperaccumulator species of Bornmuellera within Alysseae. This is contrary to current assumptions of affinity between L. emarginata and the non-hyperaccumulator Peltaria in Thlaspideae. The lineage Bornmuellera-Leptoplax is, in turn, sister to the two non-hyperaccumulator Mediterranean endemics Ptilotrichum rupestre and P. cyclocarpum. Low ITS sequence variation was found within the monophyletic Alyssum sect. Odontarrhena and especially in A. murale sensu lato. Nickel hyperaccumulation was not monophyletic in any of three main clades retrieved, each consisting of hyperaccumulators and non-hyperaccumulators of different geographical origin. CONCLUSIONS: Nickel hyperaccumulation in Alysseae has a double origin, but it did not evolve in Thlaspideae. In Bornmuellera-Leptoplax it represents an early synapomorphy inherited from an ancestor shared with the calcicolous, sister clade of Mediterranean Ptilotrichum. In Alyssum sect. Odontarrhena it has multiple origins even within the three European clades recognized. Lack of geographical cohesion suggests that accumulation ability has been lost or gained over the different serpentine areas of south Europe through independent events of microevolutionary adaptation and selection. Genetic continuity and strong phenotypic plasticity in the A. murale complex call for a reduction of the number of Ni hyperaccumulator taxa formally recognized. PMID- 20724307 TI - Oestrogen prevents cardiomyocyte apoptosis by suppressing p38alpha-mediated activation of p53 and by down-regulating p53 inhibition on p38beta. AB - AIMS: we have previously shown that 17-beta-estradiol (E2) protects cardiomyocytes exposed to simulated ischaemia-reperfusion (I/R) by differentially regulating pro-apoptotic p38alpha mitogen-activated protein kinase (p38alpha MAPK) and pro-survival p38beta. However, little is known about how E2 modulation of these kinases alters apoptotic signalling. An attractive downstream target is p53, a well-known mediator of apoptosis and a substrate of p38alpha MAPK. The aim of this study was to determine whether the cytoprotective actions of oestrogen involve regulation of p53 via cardiac p38 MAPKs. METHODS AND RESULTS: cultured rat cardiomyocytes underwent hypoxia followed by reoxygenation (H/R) to simulate I/R. We found that inhibiting p53 significantly reduced apoptosis. Phosphorylation of p53 at serine 15 [p-p53(S15)] increased after H/R in a p38alpha MAPK- and reactive oxygen species (ROS)-dependent manner. E2 at 10 nM effectively inhibited p-p53(S15) and mitochondrial translocation of p53. Blocking p53 led to augmented p38beta activity and attenuated ROS, suggesting suppression of this antioxidant kinase by p53. The use of a specific agonist for each oestrogen receptor (ER) isoform, ERalpha and ERbeta, demonstrated that both isoforms participate in preventing cell death by inhibiting p53 in the mitochondria-centred apoptotic processes. CONCLUSION: our results demonstrate that during H/R stress, cardiomyocytes undergo p53-dependent apoptosis following phosphorylation of p53 by p38alpha MAPK, leading to p38beta suppression. E2 protects cardiomyocytes by inhibiting p38alpha-p53 signalling in apoptosis. PMID- 20724308 TI - Cardioprotection induced by Na(+)/K(+)-ATPase activation involves extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/Akt pathway. AB - AIMS: Na(+)/K(+)-ATPase (NKA) has recently been found to relay extracellular signals to intracellular compartments. Activation of NKA with polyclonal antibody produces positive inotropic effects. The present study was designed to examine whether DRRSAb, a NKA DR region-specific antibody, also produces cardioprotective effects. METHODS AND RESULTS: contractile function was examined in both isolated cardiomyocytes and hearts subjected to ischaemic injury. We found that DRRSAb (0.125-2.0 uM) concentration-dependently stimulated the activity of NKA in rat or mouse kidney tissues. Moreover, DRRSAb increased the amplitudes of cell shortening and electrically induced [Ca(2+)](i) transients in rat or mouse cardiac myocytes. These effects were significantly attenuated by blockade of either extracellular signal regulated kinase 1/2 (ERK1/2) with PD98059 or Src with herbimycin A, suggesting a role of ERK1/2 and Src kinases in the positive inotropic effect of DRRSAb. More importantly, DRRSAb significantly increased cell survival rates for at least 24 h after isolating from the heart. Activation of NKA also protected hearts against ischaemic injury in both cardiomyocytes and isolated hearts. The protective effect was reversed by blockade of ERK1/2 or phosphoinositide 3-kinase (PI3K)/Akt but not by inhibition of protein kinase C. The involvement of ERK1/2 and PI3K/Akt was further confirmed by examining the phosphorylation of these kinases with western blot analysis. CONCLUSION: activation of NKA with DRRSAb induces both positive inotropic and cardioprotective effects via stimulation of Src/PI3K/Akt/ERK1/2 pathways. The unique properties of DRRSAb may make NKA antibody a promising drug to treat heart failure. PMID- 20724309 TI - EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. AB - OBJECTIVES: To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. METHODS: The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. RESULTS: Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence > 5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1-5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. CONCLUSIONS: Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly. PMID- 20724310 TI - Validation of ultrasound imaging for Achilles entheseal fibrocartilage in bovines and description of changes in humans with spondyloarthritis. AB - BACKGROUND: Entheseal fibrocartilage (EF) derangement is hypothesised to be pivotal to the pathogenesis of spondyloarthritis. Ultrasound is useful for visualisation of the enthesis but its role in EF visualisation is uncertain. This work aimed to demonstrate face and content validity of ultrasound for EF visualisation both by bovine histological evaluation and EF imaging in spondyloarthritis. METHODS: Achilles enthesis of 18 bovine hindfeet was visualised using a MyLab 70 ultrasound machine. The presence of tissue with EF characteristics was documented and histological confirmation was performed on five randomly selected sections using Masson trichrome staining. Ultrasound of the Achilles tendon (AT) was performed in 19 patients with spondyloarthritis and 21 healthy controls (HC). RESULTS: The bovine EF could be visualised in all cases and seen as a thin, uncompressible, well-defined, anechoic layer between the hyperechoic bone and the hyperechoic fibrils of the enthesis both in longitudinal and transverse scans. This region corresponded to EF on histological examination. The same pattern of low signal corresponding to EF location was seen in 17/19 patients and all HC. Discontinuities of the anechoic layer around the erosions and enthesophytes were observed in the spondyloarthritis group. The thickness of the anechoic layer was not significantly different in spondyloarthritis and HC (0.5 +/- 0.1 vs 0.5 +/- 0.2 mm, p=0.9) whereas the thickness of the EF was greater in men (0.6 +/- 0.2 vs 0.5 +/- 0.1 mm; p=0.009) compared with women. CONCLUSION: Ultrasound can visualise EF of the AT insertion, which can be abnormal in cases of spondyloarthritis. This has implications for a better understanding of enthesopathy. PMID- 20724313 TI - Seamless phase II/III designs. AB - In recent years, there has been a drive to save development costs and shorten time-to-market of new therapies. Research into novel trial designs to facilitate this goal has led to, amongst other approaches, the development of methodology for seamless phase II/III designs. Such designs allow treatment or dose selection at an interim analysis and comparative evaluation of efficacy with control, in the same study. Methods have gained much attention because of their potential advantages compared to conventional drug development programmes with separate trials for individual phases. In this article, we review the various approaches to seamless phase II/III designs based upon the group-sequential approach, the combination test approach and the adaptive Dunnett method. The objective of this article is to describe the approaches in a unified framework and highlight their similarities and differences to allow choice of an appropriate methodology by a trialist considering conducting such a trial. PMID- 20724312 TI - Meta-analyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility. AB - OBJECTIVE: To study whether common genetic variants of the genes involved in the complex regulatory mechanism determining the intracellular bio-availability of T3 influence osteoarthritis onset. METHODS: In total 17 genetic variants within the genes encoding WD40-repeat/SOCS-box protein 1, ubiquitin specific protease 33, thyroid hormone receptor alpha, deiodinase, iodothyronine, type III (DIO3) and Indian hedgehog were measured and associated with osteoarthritis in a meta analyses in European populations from the UK, The Netherlands, Greece and Spain containing a total of 3252 osteoarthritis cases and 2132 controls. RESULTS: The minor allele of the DIO3 variant rs945006 showed suggestive evidence for protective association in the overall meta-analyses, which was supported by individual osteoarthritis studies and osteoarthritis subtypes. The association appeared most significant in cases with knee and/or hip with an allelic OR of 0.81 (95% CI 0.70 to 0.930) with a nominal p value of 0.004 and a permutation based corrected p value for multiple testing of 0.039. CONCLUSION: The findings suggest that the DIO3 gene modulates osteoarthritis disease risk; however, additional studies are necessary to replicate our findings. To elucidate the molecular mechanisms focus should be on the local adaptation to T3 availability either during the endochondral ossification process or during ageing of the articular cartilage. PMID- 20724314 TI - Increased occupational coal dust toxicity in blood of central heating system workers. AB - Coal dust causes lung diseases in occupational exposure. Reactive oxygen species have been implicated in the pathogenesis of its toxicity. In this study, serum enzymes, lipid profile and other biochemical values with oxidant/antioxidant status in whole blood and serum of central heating system workers (CHSW; the persons responsible for heating the apartment with coal) were determined to reflect the cell injury. Blood samples were obtained from CHSW (n = 25) and healthy individuals (n = 25). All values were measured in whole blood and serum. ANOVA was used for the estimation of statistical data. In the group of CHSW, creatinine, ferritin, alanin aminotransferase, aspartate aminotransferase, creatine phosphokinase, gamma glutamyl transferase, lactate dehydrogenase and glutathione reductase activities as well as triglyceride, very low density lipoprotein, protein carbonyl and malondialdehide were significantly higher, while transferrin, high density lipoprotein and catalase (CAT) activities were lower than the group of healthy individuals. This result is consistent with hypothesis that respirable coal dust generates lipid and protein oxidation and induces leakage of serum enzymes by cell damage. It also leads to imbalance in antioxidant defense system, lipid profile and other biochemical parameters. PMID- 20724311 TI - Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. AB - OBJECTIVE: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). METHODS: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. CONCLUSIONS: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use. PMID- 20724315 TI - Extreme hyperglycemia and hyperosmolar state in new onset type 1 diabetes: are sugar- and salt-containing beverages at fault? PMID- 20724316 TI - Pediatrician-psychiatrist collaboration to care for children with attention deficit hyperactivity disorder, depression, and anxiety. AB - OBJECTIVE: To describe pediatrician experiences collaborating with psychiatrists when caring for children with attention deficit hyperactivity disorder (ADHD), depression, and anxiety. METHOD: A random sample of Massachusetts primary care pediatricians completed a mailed self-report survey. RESULTS: Response rate was 50% (100/198). Most pediatricians preferred psychiatrists to initiate medications for anxiety (87%) or depression (85%), but not ADHD (22%). Only 14% of respondents usually received information about a psychiatry consultation. For most (88%), the family was the primary conduit of information from psychiatrists, although few (14%) believed the family to be a dependable informant. Despite this lack of direct communication, most pediatricians reported refilling psychiatry initiated prescriptions for ADHD (88%), depression (76%), and anxiety (72%). CONCLUSIONS: Pediatricians preferred closer collaboration with psychiatrists for managing children with anxiety and depression, but not ADHD. The communication gap between psychiatrists and pediatricians raises concerns about quality of care for children with psychiatric conditions. PMID- 20724317 TI - Bacterial conjunctivitis in children: antibacterial treatment options in an era of increasing drug resistance. PMID- 20724318 TI - A female neonate presenting with fever and rash. PMID- 20724319 TI - More than meets the eye: a presentation of extramedullary infiltration (AML-M7). PMID- 20724320 TI - Review of Duchenne muscular dystrophy (DMD) for the pediatricians in the community. PMID- 20724321 TI - A teenager with sore throat and neck pain. PMID- 20724322 TI - Posterior reversible encephalopathy syndrome in a 13-year-old female with mild systemic lupus erythematosus. PMID- 20724323 TI - A teenager with neck pain. PMID- 20724324 TI - Pediatric patients seen in Port-au-Prince, Haiti. PMID- 20724325 TI - Younger asthmatics are less likely to receive inhaled corticosteroids and asthma education after admission for exacerbation. AB - BACKGROUND: Recommended care prior to discharge from an asthma hospitalization includes prescribing controller medications, providing asthma education, and scheduling a follow-up appointment. OBJECTIVE: To identify factors associated with receipt of recommended preventive care among children hospitalized for asthma. METHODS: Retrospective chart review of patients 2-18 years with primary diagnosis of asthma admitted to MUSC Children's Hospital in 2005. Gender, race, age (2-6 yrs v. 7-18 yrs), primary payer, and season of admission were recorded. Outcome variables were: prescription for inhaled corticosteroids (ICS), asthma education, and scheduling a follow-up appointment. RESULTS: Of the 146 subjects analyzed, 59% were male, 69% non-white, 64% 2-6 years old, 73% Medicaid/other, and 66% were admitted between Oct-March. 73% were prescribed ICS, 71% got asthma education, and 66% had a follow-up appointment scheduled. Bivariate analyses showed that 2-6 year olds were less likely to get ICS (65% v. 88% p < .01) and asthma education (64% v. 84% p < .05). Multivariable analyses demonstrated that younger children were less likely to get ICS (OR= 0.27 95% CI 0.10 - 0.70), younger children were less likely to get asthma education (OR 0.29 95% CI 0.11- 0.74), and commercial payer patients were less likely to get follow-up appointments scheduled (OR 0.39 95% CI 0.18 -0.87) (all models, p < .05). CONCLUSIONS: Among children hospitalized for asthma at our institution, younger patients are significantly less likely to receive inhaled steroids and asthma education. Targeting younger asthmatics may be a way to efficiently and effectively improve delivery of recommended preventive care in the hospital. PMID- 20724326 TI - The utility of alkaline phosphatase measurement as a screening test for rickets in breast-fed infants and toddlers: a study from the puget sound pediatric research network. AB - To determine if alkaline phosphatase (AP) levels are a useful screening test for rickets, the authors measured serum AP levels in children 6 to 15 months old who were predominantly breast-fed for > 6 months without vitamin D supplementation. Radiographs were obtained on children with elevated AP levels to determine the presence of rickets. AP levels were obtained on 246 children; levels were elevated in 33 (13.4%). Rickets was present in 4 of 18 children with elevated levels on whom radiographs were obtained. The sensitivity and specificity of AP levels as a test for rickets was maximal at a cutoff value of 552 U/L. Using this cutoff value, the specificity of AP levels as a test for rickets was 97.4%, and the positive predictive value (PPV) was 40.0%. These results suggest that AP levels may be a useful screening test for rickets in children who are breast-fed for prolonged periods without vitamin D supplementation. PMID- 20724327 TI - Activity and dietary habits of mothers and children: close ties. AB - OBJECTIVE: To examine associations between activity and dietary habits reported by mothers for themselves and their children aged 2 to 11 years. DESIGN/METHODS: Cross-sectional, consecutive samples of parents at 13 primary care practices were surveyed on health behaviors. Survey questions were used to define 5 "healthy" habits: low-fat milk choice; low fast food use; low weekend screen time; low juice/sweet drinks intake; and high-frequency physical activity. Mixed-effects logistic regression models were applied. RESULTS: Responses from a socioeconomically diverse group of 2115 mothers were analyzed. For each healthy behavior self-reported by the mother, the odds of the healthy behavior being reported for the child were significantly higher (range: odds ratio [OR] = 3.2 for high-frequency physical activity to OR = 19.7 for low-fat milk choice). CONCLUSIONS: Mothers and children often have similar health habits. The impact of clinician counseling for children may be strengthened by promotion of healthy habits for their mothers. PMID- 20724328 TI - Morbidity and discharge timing of late preterm newborns. AB - Late preterm newborns (LPNs), those with gestational ages (GAs) between 34 weeks and 36 weeks 6 days, account for 70% of preterm births. Because they have a mature appearance and are often cared for in a well baby nursery (WBN), parents may anticipate that the nursery course will be similar to that of a term infant and that their newborn will be discharged with his/her mother. How frequently their hospitalizations are prolonged beyond that of their mothers and the morbidities associated with prolonged hospitalization (PH) have not been well described. The objectives of the study were to (1) determine the proportion of LPNs with a PH and (2) describe the most common morbidities in LPNs and identify those associated with PH. The authors conducted retrospective chart reviews of the neonatal courses of LPNs born between December 2002 and April 2007 at the University of Utah Hospital. They compared maternal and newborn discharge dates to determine the proportion of LPNs with a PH and calculated frequencies of conditions and interventions indicating morbidity and identified associations between each of the conditions/interventions and PH. Of 235 LPNs, 94 (40%) had a PH; 75% of 34-week LPNs had a PH compared with 50% of those with GAs of 35 weeks and 25% of those with GAs of 36 weeks. The most common conditions/interventions were an oxygen need, phototherapy for jaundice, and hypothermia requiring an isolette. A need for nasogastric feeding and antibiotic administration for >3 days was consistently associated with a PH. LPNs whose only intervention was phototherapy for jaundice or IV antibiotics for <3 days did not have a PH. As a group, two thirds of LPNs experienced one or more conditions/interventions indicating morbidity, and 40% had a PH. Both were much more common in LPNs with GAs of 34 weeks compared with LPNs with GAs of 36 weeks. Nursery clinicians should counsel parents of LPNs regarding the likely possibility of morbidity and PH. PMID- 20724330 TI - Evaluation of a 2-question screening tool for detecting depression in adolescents in primary care. AB - Eighty-five adolescents (ages 13 to 17), recruited from various metropolitan pediatric outpatient clinics, were administered the Patient Health Questionnaire (PHQ)-2, a two-item depression screener, along with two other well-established measures of depression, the Children's Depression Inventory (CDI) and the Beck Depression Inventory (BDI). Results indicated a significant relationship between the second question of the PHQ-2 and the two established measures of depression. Discriminant function analysis revealed that classification of adolescents as depressed or not depressed on the basis of their responses to this second question resulted in correct classification of 73% of adolescents with a sensitivity of 0.48 and specificity of 0.60. The use of both questions resulted in lower classification accuracy (67%) but a higher sensitivity of 0.85 and a slightly lower specificity of 0.51 than either question alone. These results support the use of this measure as a brief screener for adolescent depression in primary care. PMID- 20724329 TI - Asthma in 10- to 13-year-olds: challenges at a time of transition. AB - In 10- to 13-year-old children with asthma, we know less than is desirable about the nature of the disease management tasks they face as youngsters approaching adolescence. This article reviews aspects of asthma management in youngsters at a time of significant transition. They experience puberty and growth spurts. Their cognitive abilities enable more abstract thinking. They seek individuation from their parents and socialization with peers. These factors influence asthma outcomes, including symptom control, health care use, and school attendance and performance. Furthermore, significant sex- and gender-related differences in outcome exist. Those with asthma who are 10 to 13 years of age contend not only with the particular management demands their chronic condition imposes on them but also the challenges associated with maturation. Most asthma management interventions do not account for the challenges faced at this transitional phase, and developmentally appropriate programs are needed. PMID- 20724331 TI - Some infants with Down syndrome spontaneously outgrow their obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is commonly seen in children with Down syndrome (DS). Though some infants with DS spontaneously outgrow their OSA, it is not clear how often this occurs or how this should affect the choice between surgical and nonsurgical treatment. METHODS: Retrospective chart review of all infants with DS younger than 2 years referred over a 66-month period to Children's Hospital Boston for sleep study because of suspected OSA. RESULTS: A total of 16 of 29 children studied were diagnosed with OSA; 6 were treated with continuous positive airway pressure (CPAP), 3 of whom were found 5, 5, and 10 months later on repeat sleep study to have no further evidence of OSA. CONCLUSION: A significant number of infants with DS and OSA may outgrow it within several months. This has implications for treatment choice, especially between CPAP and tracheostomy, because it may only be needed for a short time. PMID- 20724332 TI - Abdominal pain and vomiting in a boy with nephrotic syndrome. PMID- 20724333 TI - A teenager with sore throat and neck pain. PMID- 20724334 TI - Comparison of the Inverness Medical Acceava Strep A test with the Genzyme OSOM and Quidel QuickVue Strep A tests. AB - Previous studies of the accuracy of rapid in-office tests for group A Streptococcus had disparate results, ranging from sensitivity of 70% to more than 90%. The sensitivity and specificity of 3 commercially available Strep A tests were determined in 2 private pediatric office settings. Acceava Strep A, Genzyme OSOM Strep A, and the Quidel QuickVue Strep A tests were the representative rapid tests for detection of Streptococcus pyogenes. Overnight culture on standard 5% sheep blood agar was the reference standard for this study. All 3 CLIA (Clinical Laboratory Improvement Amendments)-waived tests had sensitivities and specificities that exceeded 95%. PMID- 20724335 TI - Traumatic brain injury in children and adolescents: surveillance for pituitary dysfunction. AB - BACKGROUND: Children who sustain traumatic brain injury (TBI) are at risk for developing hypopituitarism, of which growth hormone deficiency (GHD) is the most common manifestation. OBJECTIVE: To determine the prevalence of GHD and associated features following TBI among children and adolescents. STUDY DESIGN: A total of 32 children and adolescents were recruited from a pediatric TBI clinic. Participants were diagnosed with GHD based on insufficient growth hormone release during both spontaneous overnight testing and following arginine/glucagon administration. RESULTS: GHD was diagnosed in 5/32 participants (16%). Those with GHD exhibited more rapid weight gain following injury than those without GHD and had lower levels of free thyroxine and follicle-stimulating hormone. Males with GHD had lower testosterone levels. CONCLUSIONS: GHD following TBI is common in children and adolescents, underscoring the importance of assessing for GHD, including evaluating height and weight velocities after TBI. Children and adolescents with GHD may further exhibit absence or intermediate function for other pituitary hormones. PMID- 20724336 TI - A treatment trial of vitamin D supplementation in breast-fed infants: universal supplementation is not necessary for rickets prevention in Southern Louisiana. AB - This study was conducted to determine if vitamin D supplementation is required to prevent rickets in breast-fed infants. Breast-feeding rates are increasing, and there are concerns about whether the vitamin D content of breast milk is sufficient. There are a few treatment trials of vitamin D supplementation in breast-fed infants; these were conducted in northern climates. The authors therefore performed a prospective clinical trial comparing vitamin D supplementation with placebo as control in southern Louisiana. Blood samples and questionnaires were collected at birth, 2, 4, and 6 months of age. There were no cases of rickets observed, and no differences in alkaline phosphatase levels between groups. Thus, there was no evidence that vitamin D supplementation reduced rickets risk in the authors' study population. This suggests that the current recommendations for universal vitamin D supplementation of breast-fed infants throughout the United States may need to be revised. PMID- 20724337 TI - Racial differences in obese youth's perception of health care and weight loss. AB - Within the United States, minority youth are at greater risk of becoming overweight/obese and are less likely to receive preventive health care. The authors examined several domains of preventive health care perceptions among persistently overweight/obese white and black adolescents. A total of 55 youth (29 white, 26 black) who had previously sought weight management treatment participated in a follow-up study 4 years later (M (years) = 4.2 +/- 0.8). All participants remained overweight (5% at the 85th- 94th BMI percentiles) or obese (95% >= 95th BMI percentile), with no significant difference in weight by race. Relative to whites, blacks perceived greater physician concern about and counseling regarding weight (P (concern) < .01; P (counsel) < .01), eating habits(P (concern) < .001; P (counsel) < .01), and physical activity (P (concern) < .001; P (counsel) < .05). Although whites reported knowing more weight-related comorbidities than blacks, there were no group differences in number of weight loss methods attempted (M (methods) = 7.5 +/- 2.7). Overall, there were no group differences in perceptions of risk. Physicians may be appropriately focusing efforts on educating black youth, but knowledge and behavior gaps persist. PMID- 20724338 TI - Toddlers with respiratory distress and seizures. PMID- 20724339 TI - Content analysis of online pediatric drowning prevention handouts. PMID- 20724340 TI - Bullous Henoch-Schonlein purpura in children: a report of 6 cases and review of the literature. AB - Henoch-Schonlein purpura (HSP) is the most common vasculitis occurring in childhood. Clinical presentation involves the classic tetrad of abdominal pain, nonthrombocytopenic purpura, arthritis, and renal involvement. Dermatological manifestations of HSP are characteristic of the condition and consist of palpable purpura and edema of the lower extremities and buttocks. The clinical spectrum of HSP is highly variable; however, vesicles and bullae have rarely been reported as the presenting feature. To date, there are 14 case reports of bullous HSP in the literature in English. The authors report 6 additional cases of bullous HSP, including a recurrent case, presenting to the Hospital for Sick Children in Toronto, Canada. PMID- 20724341 TI - Asthma in pediatric patients: unmet need and therapeutic options. PMID- 20724342 TI - Safety, efficacy, and pharmacokinetics of telmisartan in pediatric patients with hypertension. AB - OBJECTIVE: To assess the safety, pharmacokinetics (PKs), and blood pressure (BP) lowering efficacy of telmisartan in pediatric (6 to <18 years) patients with hypertension. STUDY DESIGN: Patients with diagnosed hypertension were randomized to 4 weeks of treatment with placebo, or with 1 of 2 nominal telmisartan dose levels (1 mg/kg/d or 2 mg/kg/d). The primary end point was change in seated systolic BP (SBP) from baseline to study end. RESULTS: A total of 77 patients were randomized and received at least 1 dose of study medication (placebo, n = 16; low-dose telmisartan, n = 30; high-dose telmisartan, n = 31). Adjusted mean changes (standard errors) in SBP from baseline to study end were -6 (2.4), -14 (1.7), and -9.7 (1.7) mm Hg, respectively, in the placebo, high-dose telmisartan, and low-dose telmisartan groups. CONCLUSIONS: Telmisartan may be an appropriate therapy for treatment of pediatric hypertension, although more extensive studies are required in patients younger than age 12. PMID- 20724343 TI - Maternal knowledge and attitudes toward influenza vaccination: a focus group study in metropolitan Atlanta. AB - OBJECTIVE: To explore the knowledge and attitudes of mothers of school-aged children toward influenza vaccination and assess what methods of communication about vaccination and its delivery work best among this audience. METHODS: The authors conducted focus groups with mothers of school-aged children. Prior to the focus groups, investigators agreed on key themes and discussion points. They independently reviewed transcripts using systematic content analysis and came to an agreement on outcome themes. RESULTS: Many study participants had misunderstandings about influenza vaccines and the definition of influenza. A common perception was that flu is a catch-all term for a variety of undefined illnesses, ranging from a severe cold to stomach upset. Few participants saw a societal benefit in vaccinating children to protect other populations (eg, the elderly). CONCLUSIONS: This study represents a first step in understanding how mothers perceive influenza vaccination and for crafting effective communication to increase vaccination among school-aged children. PMID- 20724344 TI - Cocooning: influenza vaccine for parents and caregivers in an urban, pediatric medical home. AB - OBJECTIVE: To determine the acceptance of influenza vaccination by caregivers of children at risk for complications of influenza, if their annual vaccination could be administered by their child's pediatric caregivers during their child's office visit. RESULTS: During the 2008-2009 influenza season, 474 caregivers were approached, and 336 (70.9%) agreed to participate; 44 were excluded because they had already received their seasonal influenza vaccination, leaving 292 participants. Most were female (80.8%), the child's mother (68.5%), and African American (58.6%). In all, 250 of the 292 participants agreed to receive the influenza vaccine in the pediatrician's office. There were no clinically relevant demographic differences between those who received the vaccine and those who did not. The change in vaccination rate for the group of participants from the previous year was significant (23.7% to 85.6%; P < .001). CONCLUSION: Caregivers of at-risk pediatric patients are accepting of influenza vaccination from pediatric practitioners while attending their child's pediatric clinic visit. PMID- 20724345 TI - A child with a hive-like rash and bilateral sixth nerve palsies. PMID- 20724346 TI - Complications associated with outpatient parenteral antibiotic therapy in children. AB - BACKGROUND: The authors sought to determine the prevalence, risk factors, and clinical impact of complications associated with outpatient parenteral antimicrobial therapy (OPAT) in children. METHODS: A cohort of patients <=18 years old with infections, who received OPAT were evaluated retrospectively. Antibiotic-associated complications (AACs), catheter-associated complications (CACs), and unplanned medical care visits were the main outcome measures. RESULTS: Overall, 36 complications (25 CACs and 11 AACs) occurred in 32 of 98 patients. Mean age of patients, race, gender, and infecting organism did not differ between study groups. The use of OPAT for osteomyelitis was associated with complications (odds ratio = 2.69; 95% confidence interval = 0.99-7.35; P = .05). All patients, except for 4 who had complications, clinically improved by the end of OPAT. Unplanned medical visits occurred in 17 patients, 15 of which were because of CACs. CONCLUSION: Complications occurred commonly in children receiving OPAT and resulted in unplanned medical visits. PMID- 20724347 TI - Infant with failure to thrive. PMID- 20724349 TI - Fulminant mulch pneumonitis in undiagnosed chronic granulomatous disease: a medical emergency. PMID- 20724348 TI - Impact of a computerized template on antibiotic prescribing for acute respiratory infections in children and adolescents. AB - BACKGROUND: Computerized decision support (CDS) can potentially improve patient safety and guideline adherence. The authors developed an acute respiratory illness interactive template (ARI-IT) within an electronic health record (EHR) to manage pediatric ARIs and assessed the impact on antibiotic prescribing. METHODS: They randomized 12 practices either to receive the ARI-IT or to the control group. Antibiotic rates among all eligible ARI diagnoses were compared among control and intervention ARI visits, controlling for clustering by clinician. RESULTS: There was no difference in total antibiotic prescriptions between control and intervention clinics. Use of the ARI-IT significantly reduced antibiotic prescriptions (31.7% vs 39.9%; P = .02) and use of macrolides (6.2% vs 9.5%; P = .02) among visits compared with those eligible visits where it was not used. CONCLUSION: Use of the CDS reduced antibiotic prescribing and macrolide prescriptions among children with an ARI. Nonetheless, the low overall use resulted in an ineffective intervention. PMID- 20724350 TI - Vitamin D deficiency in a cohort of patients with systemic lupus erythematous from the South of Spain. PMID- 20724351 TI - Elevated levels of human beta-defensin 2 and human neutrophil peptides in systemic lupus erythematosus. AB - OBJECTIVE: Defensins are immunomodulatory peptides and components of the innate immune response. They have been shown to be modulated in various disease states and in response to inflammatory stimuli. Recently, alpha-defensins have been implicated in the pathogenesis of autoimmune diseases. In order to explore whether these defensins may have a role in the pathogenesis of systemic lupus erythematosus (SLE), we sought to determine whether altered expression can be found in SLE patients. MATERIAL AND METHODS: Serum and EDTA-blood of 50 SLE patients who fulfilled the American College of Rheumatology (ACR) criteria (aged 41.4 +/- 13.3 years) and 28 age- and sex-matched healthy controls were collected. Real-time polymerase chain reaction with gene-specific primers for human neutrophil peptides (HNPs), human beta-defensin 2 and 3 (hBD2, 3) in isolated polymorphonuclear cells and enzyme-linked immunosorbent assay (ELISA) in serum samples were performed. Results of SLE patients were compared with the control group and correlated to routine laboratory parameters, clinical data and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: SLE patients were predominantly female (90%) with a mean SLEDAI of 5.7 +/- 6.1. In sera, patients displayed higher amounts of hBD2 and HNPs when compared with healthy controls. Furthermore, hBD2 correlated with levels of anti-dsDNA antibodies, erythrocyte count and the SLEDAI. Elevated values were observed in patients with myositis (n = 4). Serum HNPs on the other hand correlated with the neutrophil count and was elevated in patients with a rash (n = 7). Lupus patients suffering from transverse myelitis (n = 3) had raised serum-values of both HNPs and hBD2. While no mRNA of hBD2 or hBD3 was detected in polymorphonuclear cells, HNP mRNA was found in both healthy controls and patients without significant difference. Lupus nephritis and rash were associated with higher amounts of HNP mRNA, and the relative amount of copies correlated positively with the SLEDAI and negatively with C3 measurements. CONCLUSIONS: Serum levels of hBD2 and HNPs are elevated in SLE. The correlations of hBD2 and HNPs to established disease activity parameters and distinct clinical situations suggest that innate immune mechanisms are activated. Defensins may be involved in SLE pathogenesis. PMID- 20724352 TI - Primary biliary cirrhosis/autoimmune hepatitis overlap syndrome developing in a patient with systemic lupus erythematosus: a case report and review of the literature. PMID- 20724353 TI - Hearing for the masses. PMID- 20724354 TI - Designing of a digital behind-the-ear hearing aid to meet the World Health Organization requirements. AB - Hearing loss is a common health issue that affects nearly 10% of the world population as indicated by many international studies. The hearing impaired typically experience more frustration, anxiety, irritability, depression, and disorientation than those with normal hearing levels. The standard rehabilitation tool for hearing impairment is an electronic hearing aid whose main components are transducers (microphone and receiver) and a digital signal processor. These electronic components are manufactured by supply chain rather than by hearing aid manufacturers. Manufacturers can use custom-designed components or generic off the-shelf components. These electronic components are available as application specific or off-the-shelf products, with the former designed for a specific manufacturer and the latter for a generic approach. The choice of custom or generic components will affect the product specifications, pricing, manufacturing, life cycle, and marketing strategies of the product. The World Health Organization is interested in making available to developing countries hearing aids that are inexpensive to purchase and maintain. The hearing aid presented in this article was developed with these specifications in mind together with additional contemporary features such as four channels with wide dynamic range compression, an adjustable compression rate for each channel, four comfort programs, an adaptive feedback manager, and full volume control. This digital hearing aid is fitted using a personal computer with minimal hardware requirements in intuitive three-step fitting software. A trimmer-adjusted version can be developed where human and material resources are scarce. PMID- 20724355 TI - Objective neural indices of speech-in-noise perception. AB - Numerous factors contribute to understanding speech in noisy listening environments. There is a clinical need for objective biological assessment of auditory factors that contribute to the ability to hear speech in noise, factors that are free from the demands of attention and memory. Subcortical processing of complex sounds such as speech (auditory brainstem responses to speech and other complex stimuli [cABRs]) reflects the integrity of auditory function. Because cABRs physically resemble the evoking acoustic stimulus, they can provide objective indices of the neural transcription of specific acoustic elements (e.g., temporal, spectral) important for hearing speech. As with brainstem responses to clicks and tones, cABRs are clinically viable in individual subjects. Subcortical transcription of complex sounds is also clinically viable because of its known experience-dependence and role in auditory learning. Together with other clinical measures, cABRs can inform the underlying biological nature of listening and language disorders, inform treatment strategies, and provide an objective index of therapeutic outcomes. In this article, the authors review recent studies demonstrating the role of subcortical speech encoding in successful speech-in-noise perception. PMID- 20724356 TI - Probing the electrode-neuron interface with focused cochlear implant stimulation. AB - Cochlear implants are highly successful neural prostheses for persons with severe or profound hearing loss who gain little benefit from hearing aid amplification. Although implants are capable of providing important spectral and temporal cues for speech perception, performance on speech tests is variable across listeners. Psychophysical measures obtained from individual implant subjects can also be highly variable across implant channels. This review discusses evidence that such variability reflects deviations in the electrode-neuron interface, which refers to an implant channel's ability to effectively stimulate the auditory nerve. It is proposed that focused electrical stimulation is ideally suited to assess channel-to-channel irregularities in the electrode-neuron interface. In implant listeners, it is demonstrated that channels with relatively high thresholds, as measured with the tripolar configuration, exhibit broader psychophysical tuning curves and smaller dynamic ranges than channels with relatively low thresholds. Broader tuning implies that frequency-specific information intended for one population of neurons in the cochlea may activate more distant neurons, and a compressed dynamic range could make it more difficult to resolve intensity-based information, particularly in the presence of competing noise. Degradation of both types of cues would negatively affect speech perception. PMID- 20724357 TI - Cued speech for enhancing speech perception and first language development of children with cochlear implants. AB - Nearly 300 million people worldwide have moderate to profound hearing loss. Hearing impairment, if not adequately managed, has strong socioeconomic and affective impact on individuals. Cochlear implants have become the most effective vehicle for helping profoundly deaf children and adults to understand spoken language, to be sensitive to environmental sounds, and, to some extent, to listen to music. The auditory information delivered by the cochlear implant remains non optimal for speech perception because it delivers a spectrally degraded signal and lacks some of the fine temporal acoustic structure. In this article, we discuss research revealing the multimodal nature of speech perception in normally hearing individuals, with important inter-subject variability in the weighting of auditory or visual information. We also discuss how audio-visual training, via Cued Speech, can improve speech perception in cochlear implantees, particularly in noisy contexts. Cued Speech is a system that makes use of visual information from speechreading combined with hand shapes positioned in different places around the face in order to deliver completely unambiguous information about the syllables and the phonemes of spoken language. We support our view that exposure to Cued Speech before or after the implantation could be important in the aural rehabilitation process of cochlear implantees. We describe five lines of research that are converging to support the view that Cued Speech can enhance speech perception in individuals with cochlear implants. PMID- 20724358 TI - Standard audiograms for the IEC 60118-15 measurement procedure. AB - For the characterization of hearing aids, a new test method has been defined in the new International Electrotechnical Commission (IEC) standard 60118-15. For this characterization, the hearing aid will be set to actual user settings as programmed by standard fitting software from the hearing aid manufacturer. To limit the variation of programming outcomes, 10 standard audiograms, which cover the entire range of audiograms met in clinical practice, have been defined. This article describes how the set of standard audiograms has been developed. This set of standard audiogram has been derived by a vector quantization analysis method on a database of 28,244 audiograms. Using this analysis method, sets of typical audiograms have been obtained of sizes 12 and 60. It turned out that the smaller set could not be used for selecting audiograms as sloping audiograms were absent. Therefore, the larger set has been analyzed to provide seven standard audiograms for flat and moderately sloping hearing loss and three standard audiograms for steep hearing loss. PMID- 20724359 TI - Adaptation of the vestibulo-ocular reflex for forward-eyed foveate vision. AB - To maintain visual fixation on a distant target during head rotation, the angular vestibulo-ocular reflex (aVOR) should rotate the eyes at the same speed as the head and in exactly the opposite direction. However, in primates for which the 3 dimensional (3D) aVOR has been extensively characterised (humans and squirrel monkeys (Saimiri sciureus)), the aVOR response to roll head rotation about the naso-occipital axis is lower than that elicited by yaw and pitch, causing errors in aVOR magnitude and direction that vary with the axis of head rotation. In other words, primates keep the central part of the retinal image on the fovea (where photoreceptor density and visual acuity are greatest) but fail to keep that image from twisting about the eyes' resting optic axes. We tested the hypothesis that aVOR direction dependence is an adaptation related to primates' frontal-eyed, foveate status through comparison with the aVOR of a lateral-eyed, afoveate mammal (Chinchilla lanigera). As chinchillas' eyes are afoveate and never align with each other, we predicted that the chinchilla aVOR would be relatively low in gain and isotropic (equal in gain for every head rotation axis). In 11 normal chinchillas, we recorded binocular 3D eye movements in darkness during static tilts, 20-100 deg s(1) whole-body sinusoidal rotations (0.5-15 Hz), and 3000 deg s(2) acceleration steps. Although the chinchilla 3D aVOR gain changed with both frequency and peak velocity over the range we examined, we consistently found that it was more nearly isotropic than the primate aVOR. Our results suggest that primates' anisotropic aVOR represents an adaptation to their forward-eyed, foveate status. In primates, yaw and pitch aVOR must be compensatory to stabilise images on both foveae, whereas roll aVOR can be under-compensatory because the brain tolerates torsion of binocular images that remain on the foveae. In contrast, the lateral-eyed chinchilla faces different adaptive demands and thus enlists a different aVOR strategy. PMID- 20724360 TI - Chronic heart failure decreases cross-bridge kinetics in single skeletal muscle fibres from humans. AB - Skeletal muscle function is impaired in heart failure patients due, in part, to loss of myofibrillar protein content, in particular myosin. In the present study, we utilized small-amplitude sinusoidal analysis for the first time in single human skeletal muscle fibres to measure muscle mechanics, including cross-bridge kinetics, to determine if heart failure further impairs contractile performance by altering myofibrillar protein function. Patients with chronic heart failure (n = 9) and controls (n = 6) were recruited of similar age and physical activity to diminish the potentially confounding effects of ageing and muscle disuse. Patients showed decreased cross-bridge kinetics in myosin heavy chain (MHC) I and IIA fibres, partially due to increased myosin attachment time (t(on)). The increased t(on) compensated for myosin protein loss previously found in heart failure patients by increasing the fraction of the total cycle time myosin is bound to actin, resulting in a similar number of strongly bound cross-bridges in patients and controls. Accordingly, isometric tension did not differ between patients and controls in MHC I or IIA fibres. Patients also had decreased calcium sensitivity in MHC IIA fibres and alterations in the viscoelastic properties of the lattice structure of MHC I and IIA fibres. Collectively, these results show that heart failure alters skeletal muscle contraction at the level of the myosin actin cross-bridge, leading to changes in muscle mechanics which could contribute to impaired muscle function. Additionally, we uncovered a unique kinetic property of MHC I fibres, a potential indication of two distinct populations of cross bridges, which may have important physiological consequences. PMID- 20724361 TI - Corticogeniculate feedback and visual processing in the primate. AB - Corticogeniculate neurones make more synapses in the lateral geniculate nucleus (LGN) than retinal ganglion cells, yet we know relatively little about the functions of corticogeniculate feedback for visual processing. In primates, feedforward projections from the retina to the LGN and from the LGN to primary visual cortex are organized into anatomically and physiologically distinct parallel pathways. Recent work demonstrates a close relationship between these parallel streams of feedforward projections and the corticogeniculate feedback pathway. Here, we review the evidence for stream-specific feedback in the primate and consider the implications of parallel streams of feedback for vision. PMID- 20724362 TI - Histamine regulates activities of neurons in the ventrolateral preoptic nucleus. AB - The neurons responsible for the onset of sleep are thought to be located in the ventrolateral preoptic nucleus (VLPO), which receives a dense histaminergic innervation from the tuberomammillary nucleus (TMN). Yet, the role of histamine in the VLPO remains unclear. Here we report that microinjection of histamine into the VLPO increases the motor activity of rats. Moreover, a bath application of histamine to acute brain slices inhibits the majority of VLPO neurons, which are also inhibited by noradrenaline. Histamine hyperpolarizes the membrane potential and lowers the firing rate. These effects are associated with an increase in the frequency but not in the amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents, and are blocked by gabazine or tetrodotoxin, indicating an indirect action. Conversely, on the noradrenaline-excited VLPO neurons, histamine depolarizes the membrane potential and increases the firing rate via activation of H(1) and H(2) subtype histamine receptors. Moreover, histamine-induced depolarization persists in the presence of gabazine or tetrodotoxin, indicating a direct action. Based on these findings, we propose that in the VLPO, noradrenaline-inhibited neurons may normally be under the inhibitory control of noradrenaline-excited neurons. By facilitating the inhibitory control of the noradrenaline-excited neurons, histamine may inhibit the noradrenaline-inhibited neurons, resulting in excitation of histamine releasing neurons in the TMN through disinhibition. This effect of histamine in the VLPO may contribute to the maintenance of wakefulness. PMID- 20724364 TI - Visual pathways and psychophysical channels in the primate. AB - The main cell systems of the retina that provide input to the striate cortex are now well described, although certain aspects of their anatomy and physiology remain contentious. Under simple stimulus conditions and in a threshold context psychophysical performance can often be assigned to one or other of these systems, and an identification of psychophysical channels with afferent pathways is justifiable. However, results from psychophysical studies using more complex stimulus conditions are more difficult to relate to 'front end' channels, and it is more difficult to separate the physiological contributions of afferent pathways from those of cortical mechanisms, in particular the separation of dorsal and ventral streams. PMID- 20724363 TI - MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. AB - Maintaining skeletal muscle function throughout the lifespan is a prerequisite for good health and independent living. For skeletal muscle to consistently function at optimal levels, the efficient activation of processes that regulate muscle development, growth, regeneration and metabolism is required. Numerous conditions including neuromuscular disorders, physical inactivity, chronic disease and ageing are associated with perturbations in skeletal muscle function. A loss or reduction in skeletal muscle function often leads to increased morbidity and mortality either directly, or indirectly, via the development of secondary diseases such as diabetes, obesity, cardiovascular and respiratory disease. Identifying mechanisms which influence the processes regulating skeletal muscle function is a key priority. The discovery of microRNAs (miRNAs) provides a new avenue that will extend our knowledge of factors controlling skeletal muscle function. miRNAs may also improve our understanding and application of current therapeutic approaches as well as enable the identification of new therapeutic strategies and targets aimed at maintaining and/or improving skeletal muscle health. This review brings together the latest developments in skeletal muscle miRNA biology and focuses on their role and regulation under physiological and patho-physiological conditions with an emphasis on: myogenesis, hypertrophy, atrophy and regeneration; exercise and nutrition; muscle disease, ageing, diabetes and obesity. PMID- 20724365 TI - Encoding of whisker input by cerebellar Purkinje cells. AB - The cerebellar cortex is crucial for sensorimotor integration. Sensorimotor inputs converge on cerebellar Purkinje cells via two afferent pathways: the climbing fibre pathway triggering complex spikes, and the mossy fibre-parallel fibre pathway, modulating the simple spike activities of Purkinje cells. We used, for the first time, the mouse whisker system as a model system to study the encoding of somatosensory input by Purkinje cells.We show that most Purkinje cells in ipsilateral crus 1 and crus 2 of awake mice respond to whisker stimulation with complex spike and/or simple spike responses. Single-whisker stimulation in anaesthetised mice revealed that the receptive fields of complex spike and simple spike responses were strikingly different. Complex spike responses, which proved to be sensitive to the amplitude, speed and direction of whisker movement, were evoked by only one or a few whiskers. Simple spike responses, which were not affected by the direction of movement, could be evoked by many individual whiskers. The receptive fields of Purkinje cells were largely intermingled, and we suggest that this facilitates the rapid integration of sensory inputs from different sources. Furthermore, we describe that individual Purkinje cells, at least under anaesthesia, may be bound in two functional ensembles based on the receptive fields and the synchrony of the complex spike and simple spike responses. The 'complex spike ensembles' were oriented in the sagittal plane, following the anatomical organization of the climbing fibres, while the 'simple spike ensembles' were oriented in the transversal plane, as are the beams of parallel fibres. PMID- 20724366 TI - Developmental change in the electrophysiological and pharmacological properties of acid-sensing ion channels in CNS neurons. AB - Acid-sensing ion channels (ASICs) are proton-gated cation channels that play important roles in the CNS including synaptic plasticity and acidosis-mediated neuronal injury. ASIC1a and ASIC2a subunits are predominant in CNS neurons, where homomultimeric and heteromultimeric channel configurations co-exist. Since ASIC1a and ASIC2a have dramatic differences in pH sensitivity, Ca(2+) permeability and channel kinetics, any change in the level of individual subunits may have significant effects on the properties and functions of ASICs. Using patch-clamp recording, fluorescent Ca(2+) imaging and molecular biological techniques, we show dramatic developmental changes in the properties of ASICs in mouse cortical neurons. For example, the amplitude of ASIC currents increases whereas desensitization decreases with neuronal maturation. Decreased H(+) affinity and acid-evoked [Ca(2+)](i) but increased Zn(2+) potentiation were also recorded in mature neurons. RT-PCR revealed significant increases in the ratio of ASIC2/ASIC1 mRNA with neuronal maturation. Thus, contributions of ASIC1a and ASIC2a to overall ASIC-mediated responses undergo distinct developmental changes. These findings may help in understanding the precise role of ASICs in physiological and pathological conditions at different developmental stages. PMID- 20724367 TI - Flufenamic acid decreases neuronal excitability through modulation of voltage gated sodium channel gating. AB - The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC(50) = 189 MUm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug. PMID- 20724368 TI - Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle. AB - Muscle specific miRNAs, myomiRs, have been shown to control muscle development in vitro and are differentially expressed at rest in diabetic skeletal muscle. Therefore, we investigated the expression of these myomiRs, including miR-1, miR 133a, miR-133b and miR-206 in muscle biopsies from vastus lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemic-euglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training. The subjects increased their endurance capacity, VO2max (l min-1) by 17.4% (P < 0.001), and improved insulin sensitivity by 19% (P < 0.01). While myomiR expression remained stable during a hyperinsulinaemic-euglycaemic clamp, an acute bout of exercise increased mir-1 (P < 0.05) and mir-133a (P < 0.05) expression before, but not after, training. In resting biopsies, endurance training for 12 weeks decreased basal expression of all four myomiRs (P < 0.05). Interestingly, all myomiRs reverted to their pre-training expression levels 14 days after ceasing the training programme. Components of major pathways involved in endurance adaptation such as MAPK and TGF-beta were predicted to be targeted by the myomiRs examined. Tested predicted target proteins included Cdc42 and ERK 1/2. Although these proteins were downregulated between post-training period and 2 weeks of cessation, an inverse correlation between myomiR and target proteins was not found. In conclusion, our data suggest myomiRs respond to physiological stimuli, but their role in regulating human skeletal muscle adaptation remains unknown. PMID- 20724369 TI - Tissue contribution to the mechanical features of diaphragmatic initial lymphatics. AB - The role of the mechanical properties of the initial lymphatic wall and of the surrounding tissue in supporting lymph formation and/or progression was studied in six anaesthetized, neuromuscularly blocked and mechanically ventilated rats. After mid-sternal thoracotomy, submesothelial initial lymphatics were identified on the pleural diaphragmatic surface through stereomicroscopy. An 'in vivo' lymphatic segment was prepared by securing two surgical threads around the vessel at a distance of ~2.5 mm leaving the vessel in place. Two glass micropipettes were inserted into the lumen, one for intraluminar injections of 4.6 nl saline boluses and one for hydraulic pressure (Plymph) recording. The compliance of the vessel wall (Clymph) was calculated as the slope of the plot describing the change in segment volume as a function of the post-injection Plymph changes. Two superficial lymphatic vessel populations with a significantly different Clymph (6.7 +/- 1.6 and 1.5 +/- 0.4 nl mmHg-1 (mean +/- S.E.M.), P < 0.001) were identified. In seven additional rats, the average elastic modulus of diaphragmatic tissue strips was determined by uniaxial tension tests to be 1.7 +/ 0.3 MPa. Clymph calculated for an initial lymphatic completely surrounded by isotropic tissue was 0.068 nl mmHg-1, i.e. two orders of magnitude lower than in submesothelial lymphatics. Modelling of stress distribution in the lymphatic wall suggests that compliant vessels may act as reservoirs accommodating large absorbed fluid volumes, while lymphatics with stiffer walls serve to propel fluid through the lumen of the lymphatic vessel by taking advantage of the more efficient mechanical transmission of tissue stresses to the lymphatic lumen. PMID- 20724370 TI - Erythropoietin down-regulates proximal renal tubular reabsorption and causes a fall in glomerular filtration rate in humans. AB - Recombinant human erythropoietin (rHuEPO) elevates haemoglobin concentration both by increasing red blood cell volume and by a decrease in plasma volume. This study delineates the association of rHuEPO-induced changes in blood volumes with changes in the renin-aldosterone system and renal function. Sixteen healthy males were given rHuEPO for 28 days in doses raising the haematocrit to 48.3+/ 4.1%.Renal clearance studieswith urine collections (N = 8) were done at baseline and at days 4, 11, 29 and 42. Glomerular filtration rate (GFR) was measured by 51Cr-EDTA.Renal clearance of lithium (CLi)was used as an index of proximal tubular outflow and to assess segmental renal tubular handling of sodium and water. rHuEPO-induced increases in haematocrit occurred from day 10 onwards and was caused by both an increase in red cell volume and a fall in plasma volume. Well before that (from day 2 and throughout the treatment time), rHuEPO decreased plasma levels of renin and aldosterone (N = 8) by 21-33% (P < 0.05) and 15-36% (P < 0.05), respectively. After cessation of rHuEPO, values returned to baseline. On days 11 and 29, CLi increased (P < 0.02) indicating a significant 10-16% decrease in absolute proximal reabsorption of sodium and water (APR = GFR - CLi, P < 0.05). GFR decreased slightly, albeit significantly, on day 4 (P < 0.05). In conclusion, rHuEPO promptly, and before any changes in blood volumes and haematocrit can be detected, causes a down-regulation of the renin-aldosterone system. The results are compatible with a rHuEPO-induced reduction in proximal reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in GFR. Therefore, treatment with rHuEPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intrarenal oxygen consumption. PMID- 20724371 TI - Orbitofrontal contributions to human working memory. AB - Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in human memory, the necessity of the orbitofrontal cortex for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether the orbitofrontal cortex is necessary for working memory function, administering subtests of the Wechsler memory scale, the Wechsler adult intelligence scale, and the n-back task to 3 participant groups: orbitofrontal lesions (n = 24), prefrontal lesions not involving orbitofrontal cortex (n = 40), and no brain lesions (n = 54). Orbitofrontal damage was reliably associated with deficits on neuropsychological tests involving the coordination of working memory maintenance, manipulation, and monitoring processes (n-back task) but not on pure tests of working memory maintenance (digit/spatial span forward) or manipulation (digit/spatial span backward and letter-number sequencing). Our findings elucidate a central component of the neural architecture of working memory, providing key neuropsychological evidence for the necessity of the orbitofrontal cortex in executive control functions underlying the joint maintenance, manipulation, and monitoring of information in working memory. PMID- 20724372 TI - Neglected children, shame-proneness, and depressive symptoms. AB - Neglected children may be at increased risk for depressive symptoms. This study examines shame-proneness as an outcome of child neglect and as a potential explanatory variable in the relation between neglect and depressive symptoms. Participants were 111 children (52 with a Child Protective Services [CPS] allegation of neglect) seen at age 7. Neglected children reported more shame proneness and more depressive symptoms than comparison children. Guilt-proneness, in contrast, was unrelated to neglect and depressive symptoms, indicating specificity for shame-proneness. The potential role of shame as a process variable that can help explain how some neglected children exhibit depressive symptoms is discussed. PMID- 20724373 TI - Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells. AB - We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of human breast cancer cells in culture and in vivo in association with apoptosis induction. The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies including breast cancer. The WA treatment (2 and 4 MUM) decreased constitutive (MDA-MB-231) and/or IL-6-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr(705)) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr(1007/1008)) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (i) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (ii) dimerization of STAT3 (MDA-MB-231) and (iii) nuclear translocation of Tyr(705)-phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred a modest protection against WA mediated suppression of MDA-MB-231 cell invasion. General implication of these findings is that WA can trigger apoptosis and largely inhibit cell migration/invasion of breast cancer cells even after IL-6-induced activation of STAT3, which should be viewed as a therapeutic advantage for this agent. PMID- 20724374 TI - Influence of polyvascular disease on cardiovascular event rates. Insights from the REACH Registry. AB - Cardiovascular event rates have been shown to increase substantially with the number of symptomatic disease locations. We sought to assess the risk profile, management and subsequent event rates of polyvascular disease patients. Consecutive outpatients were assessed for atherosclerotic risk factors and medications in the REACH Registry. A total of 19,117 symptomatic patients in Europe completed a 2-year follow-up: 77.2% with single arterial bed disease (coronary artery or cerebrovascular or peripheral arterial disease) and 22.8% with polyvascular disease (>/= 1 disease location). Polyvascular disease patients were older (68.5 +/- 9.4 vs 66.3 +/- 9.9 years, p < 0.0001), more often current or former smokers (64.9% vs 58.7%, p < 0.0001), and more often suffered from hypertension (59.5% vs 46.6%, p < 0.0001) and diabetes (34.5% vs 25.9%, p < 0.0001) than single arterial bed disease patients. Despite more intense medical therapy, risk factors (smoking, hypertension, low fasting glucose, and low fasting total cholesterol) were less often controlled in polyvascular disease patients. This was associated with substantially more events over 2 years compared with single arterial bed disease patients (cMACCE [cardiovascular death/non-fatal stroke/non-fatal MI] odds ratio, 1.63 [95% CI, 1.45-1.83], p < 0.0001). In conclusion, polyvascular disease patients have more cardiovascular risk factors, and the prognosis for these patients is significantly worse than for patients with single arterial bed disease. This suggests a need to improve detection and consequent medical treatment of polyvascular disease. PMID- 20724375 TI - Pulse pressure is a predictor of vascular endothelial function in middle-aged subjects with no apparent heart disease. AB - Elevated pulse pressure (PP) is increasingly being recognized as a cardiovascular risk factor. To investigate whether PP is associated with endothelial function in subjects with no apparent heart disease we prospectively assessed brachial flow mediated dilation (FMD) in 525 consecutive subjects with no apparent heart disease [323 (61%) men, mean age 52 +/- 11 years, mean body mass index (BMI) 26 +/- 4 kg/m(2)]. Following an overnight fast and discontinuation of all medications for >/= 12 hours, the FMD and endothelium-independent, nitroglycerin mediated vasodilation (NTG) were assessed using high-resolution linear array ultrasound. Univariate linear analysis revealed a significant inverse association between FMD and PP (r = -0.65, p < 0.01), systolic blood pressure (r = -0.52, p < 0.01) and age (r = -0.21, p < 0.05). Multivariate analysis showed that PP was the strongest independent predictor of FMD. We therefore divided the study population into two groups: group A (n = 290) the median PP of 50 mmHg. Male sex, hypertension, diabetes, BMI, heart rate, and the use of aspirin, long-acting nitrates, calcium channel blockers, angiotensin converting enzyme inhibitors and beta blockers were significantly more common in Group B compared with Group A. FMD but not NTG was significantly greater in patients with PP the median PP (14.9 +/- 7.9% vs 10.8 +/- 8.8%, p < 0.001 and 16.1 +/- 9.6% vs 14.8 +/- 8.4%, p = 0.38; respectively). Thus, PP is inversely associated with brachial FMD in middle-aged subjects with no apparent heart disease, suggesting a potential mechanism whereby elevated PP contributes to cardiovascular disease. Long-term follow-up is warranted to elucidate the incidence of coronary artery disease in both study groups. PMID- 20724376 TI - Delivery of negatively charged liposomes into the atheromas of Watanabe heritable hyperlipidemic rabbits. AB - Liposomes have been used as imaging and therapeutic agents in various tissues but only infrequently in the cardiovascular system. We prepared a liposome to target atheromas in a Watanabe heritable hyperlipidemic (WHHL) rabbit model. Liposomes labeled with rhodamine and nanogold were injected intra-arterially into the descending thoracic aortas of WHHL rabbits. The arterial segments of interest were perfusion-fixed and evaluated with immunohistochemistry, light microscopy, and electron microscopy. Deconvolution microscopy showed that rhodamine label was concentrated in the plaque shoulder regions of advanced-stage atheromas; however, rhodamine label was not found in adjacent, non-atherosclerotic aorta. Transmission electron microscopy revealed liposome remnants and the highest concentration of nanogold label in lipid-laden areas of atheromas. Liposomes were concentrated in areas of lipoprotein-associated phospholipase A(2) expression. We conclude that modified liposomes can be delivered to the shoulder regions of advanced atheromas in WHHL rabbits and may be useful therapeutically for targeting metabolically active plaque. PMID- 20724377 TI - Spontaneous regression of an abdominal aortic aneurysm in an immunocompromised patient. AB - Spontaneous aneurysmal regression is a rare event, having been observed only in association with arteritides or immunosuppression following solid-organ transplantation. In particular, the spontaneous regression of an aortic aneurysm, to our knowledge, has never been documented. We report a case of a 46-year-old, HIV-positive, African-American man who developed an asymptomatic juxtarenal abdominal aortic aneurysm, which significantly regressed over a 6-month period in the absence of arteritides or systemic immunosuppressive therapy. This case describes the spontaneous regression of an inflammatory AAA in an HIV-positive patient. Further studies will be required to determine if this was an isolated occurrence or if it occurs with any frequency in specific patient populations. PMID- 20724378 TI - To be a good food provider: an exploratory study among spouses of persons with Alzheimer's disease. AB - Large proportions of people with dementia live at home and need help from a relative. The aim of the current study was to examine how people living with persons with Alzheimer's disease (AD) perceived everyday life aspects of food choices, cooking, and food-related work. The analyses are based on focus group interviews including women and men acting as caregivers to people with AD and living in Sweden. The main results identified from the data, were how cohabitants to persons with AD struggle with either taking on a new role as a food provider or extending it, but also how they tried to cope as carer, which entailed food being an important part of the treatment of the disease. Those expressing greatest concern were those perceiving themselves as inexperienced food providers and carers, which in this study were all men. PMID- 20724379 TI - Phylogenetic substitution models for detecting heterotachy during plastid evolution. AB - There is widespread evidence of lineage-specific rate variation, known as heterotachy, during protein evolution. Changes in the structural and functional constraints acting on a protein can lead to heterotachy, and it is plausible that such changes, known as covarion shifts, may affect many amino acids at once. Several previous attempts to model heterotachy have used covarion models, where the sequence undergoes covarion drift, whereby each site may switch independently among a set of discrete classes having different substitution rates. However, such independent switching may not capture biologically important events where the selective forces acting on a protein affect many sites at once. We describe a new class of models that allow the rates of substitution and switching to vary among branches of a phylogenetic tree. Such models are better able to handle covarion shifts. We apply these models to a set of genes occurring in nonphotosynthetic bacteria, cyanobacteria, and the plastids of green and red algae. We find that 4/5 genes show evidence of some form of rate switching and that 3/5 genes show evidence that the relative switching rate differs among taxonomic groups. We conclude that covarion shifts may be frequent during the deep evolution of plastid genes and that our methodology may provide a powerful new tool for investigating such shifts in other systems. PMID- 20724380 TI - Conservation and evolution in and among SRF- and MEF2-type MADS domains and their binding sites. AB - Serum response factor (SRF) and myocyte enhancer factor 2 (MEF2) represent two types of members of the MCM1, AGAMOUS, DEFICIENS, and SRF (MADS)-box transcription factor family present in animals and fungi. Each type has distinct biological functions, which are reflected by the distinct specificities of the proteins bound to their cognate DNA-binding sites and activated by their respective cofactors. However, little is known about the evolution of MADS domains and their DNA-binding sites. Here, we report on the conservation and evolution of the two types of MADS domains with their cognate DNA-binding sites by using phylogenetic analyses. First, there are great similarities between the two types of proteins with amino acid positions highly conserved, which are critical for binding to the DNA sequence and for the maintenance of the 3D structure. Second, in contrast to MEF2-type MADS domains, distinct conserved residues are present at some positions in SRF-type MADS domains, determining specificity and the configuration of the MADS domain bound to DNA sequences. Furthermore, the ancestor sequence of SRF- and MEF2-type MADS domains is more similar to MEF2-type MADS domains than to SRF-type MADS domains. In the case of DNA-binding sites, the MEF2 site has a T-rich core in one DNA sequence and an A rich core in the reverse sequence as compared with the SRF site, no matter whether where either A or T is present in the two complementary sequences. In addition, comparing SRF sites in the human and the mouse genomes reveals that the evolution rate of CArG-boxes is faster in mouse than in human. Moreover, interestingly, a CArG-like sequence, which is probably functionless, could potentially mutate to a functional CArG-box that can be bound by SRF and vice versa. Together, these results significantly improve our knowledge on the conservation and evolution of the MADS domains and their binding sites to date and provide new insights to investigate the MADS family, which is not only on evolution of MADS factors but also on evolution of their binding sites and even on coevolution of MADS factors with their binding sites. PMID- 20724381 TI - Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases. AB - Collagen type I alpha 1 (COL1a1), which encodes the primary subunit of type I collagen, the main structural and most abundant protein in vertebrates, harbors hundreds of mutations linked to human diseases like osteoporosis and osteogenesis imperfecta. Previous studies have attempted to predict the phenotypic severity associated with type I collagen mutations, yet an evolutionary analysis that compares historical and recent selective pressures, including across noncoding regions, has never been conducted. Here, we use a comparative genomic and species evolutionary analysis representing ~450 My of vertebrate history to investigate functional constraints associated with both exons and introns of the >17-kb COL1a1 gene. We find that although the COL1a1 amino acid sequence is highly conserved, there are both spatial and temporal signatures of varying selective constraint across protein domains. Furthermore, sites of high evolutionary constraint significantly correlate with the location of disease-associated mutations, the latter of which also cluster with respect to specific severity classes typically categorized in clinical studies. Finally, we find that COL1a1 introns are significantly short in length with high GC content, patterns that are shared across highly diverged vertebrates, and which may be a signature of strong stabilizing selection for high COL1a1 gene expression. In conclusion, although previous studies focused on COL1a1 coding regions, the current results implicate introns as areas of high selective constraint and targets of bone-related phenotypic variation. From a broader perspective, our comparative evolutionary approach provides further resolution to models predicting mutations associated with bone-related function and disease severity. PMID- 20724383 TI - HrcA and DnaK are important for static and continuous-flow biofilm formation and disinfectant resistance in Listeria monocytogenes. AB - The food-borne pathogen Listeria monocytogenes is able to form biofilms in food processing environments. Since biofilms are generally difficult to eradicate during clean-up procedures, they pose a major risk for the food industry. Stress resistance mechanisms involved in L. monocytogenes biofilm formation and disinfectant resistance have, to our knowledge, not been identified thus far. In this study, we investigated the role of hrcA, which encodes the transcriptional regulator of the class I heat-shock response, and dnaK, which encodes a class I heat-shock response chaperone protein, in static and continuous-flow biofilm formation and resistance against benzalkonium chloride and peracetic acid. Induction of both hrcA and dnaK during continuous-flow biofilm formation was observed using quantitative real-time PCR and promoter reporters. Furthermore, in frame deletion and complementation mutants of hrcA and dnaK revealed that HrcA and DnaK are required to reach wild-type levels of both static and continuous flow biofilms. Finally, disinfection treatments of planktonic-grown cells and suspended static and continuous-flow biofilm cells of wild-type and mutants showed that HrcA and DnaK are important for resistance against benzalkonium chloride and peracetic acid. In conclusion, our study revealed that HrcA and DnaK are important for L. monocytogenes biofilm formation and disinfectant resistance. PMID- 20724382 TI - A pilot study to assess smokeless tobacco use reduction with varenicline. AB - INTRODUCTION: Long-term smokeless tobacco (ST) use is known to increase the risk for oropharyngeal cancer, heart attack, and stroke. Extant literature on cigarette smokers suggests that smoking reduction increases smoking abstinence among smokers not interested in quitting. Similarly, a reduction strategy may reduce ST exposure and increase ST abstinence rates among ST users not interested in quitting. METHODS: We conducted a pilot study to obtain preliminary data on the use of 12 weeks of varenicline as a tobacco reduction strategy among ST users not interested in quitting. RESULTS: We enrolled 20 male ST users with a mean age of 42.8 +/- 11.7 years who used an average of 3.9 +/- 1.7 cans/pouches per week for 18.6 +/- 8.6 years. At end of treatment (12 weeks), 60% (12/20) of subjects reduced their ST use by >= 50% and 15% (3/20) were biochemically confirmed abstinent from tobacco. At end of study (6 months), 50% (10/20) reduced by >= 50% of baseline use and 10% (2/20) were biochemically confirmed abstinent from tobacco. Varenicline reduced ST satisfaction, reward, and craving. Among subjects able to reduce ST, all subjects reported that reduction increased motivation and confidence in being able to maintain reduction and quit. The most common side effects were sleep disturbance (25%) and nausea (15%). DISCUSSION: Varenicline may be effective in reducing ST use and achieving ST abstinence among ST users with no plans to quit but who are interested in reducing their ST use. PMID- 20724384 TI - Novel approaches for analysing gut microbes and dietary polyphenols: challenges and opportunities. AB - Polyphenols, ubiquitously present in the food we consume, may modify the gut microbial composition and/or activity, and moreover, may be converted by the colonic microbiota to bioactive compounds that influence host health. The polyphenol content of fruit and vegetables and derived products is implicated in some of the health benefits bestowed on eating fruit and vegetables. Elucidating the mechanisms behind polyphenol metabolism is an important step in understanding their health effects. Yet, this is no trivial assignment due to the diversity encountered in both polyphenols and the gut microbial composition, which is further confounded by the interactions with the host. Only a limited number of studies have investigated the impact of dietary polyphenols on the complex human gut microbiota and these were mainly focused on single polyphenol molecules and selected bacterial populations. Our knowledge of gut microbial genes and pathways for polyphenol bioconversion and interactions is poor. Application of specific in vitro or in vivo models mimicking the human gut environment is required to analyse these diverse interactions. A particular benefit can now be gained from next-generation analytical tools such as metagenomics and metatranscriptomics allowing a wider, more holistic approach to the analysis of polyphenol metabolism. Understanding the polyphenol-gut microbiota interactions and gut microbial bioconversion capacity will facilitate studies on bioavailability of polyphenols in the host, provide more insight into the health effects of polyphenols and potentially open avenues for modulation of polyphenol bioactivity for host health. PMID- 20724385 TI - A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. AB - Clostridium difficile infection (CDI) is the most common identifiable cause of diarrhoea in hospitalized patients. Current therapies rely on the administration of metronidazole or vancomycin, which reduce vegetative populations of C. difficile in the bowel. Recurrence of the disease when treatment with these antibiotics ceases indicates that metronidazole and vancomycin affect not only C. difficile but also commensal populations that normally mediate competitive exclusion. Fidaxomicin is a new antibiotic that inhibits C. difficile. Our study shows that fidaxomicin had little effect on the composition of the faecal microbiota in terms of its major phylogenetic clusters. Notably, clostridial clusters XIVa and IV, and Bifidobacterium, were much less affected by fidaxomicin compared to vancomycin treatment. These findings help to explain the substantially reduced rates of relapse following treatment of CDI with fidaxomicin in recent clinical trials. PMID- 20724386 TI - Glutamine synthetase encoded by glnA-1 is necessary for cell wall resistance and pathogenicity of Mycobacterium bovis. AB - Pathogenic strains of mycobacteria produce copious amounts of glutamine synthetase (GS) in the culture medium. The enzyme activity is linked to synthesis of poly-alpha-l-glutamine (PLG) in the cell walls. This study describes a glnA-1 mutant of Mycobacterium bovis that produces reduced levels of GS. The mutant was able to grow in enriched 7H9 medium without glutamine supplementation. The glnA-1 strain contained no detectable PLG in the cell walls and showed marked sensitivity to different chemical and physical stresses such as lysozyme, SDS and sonication. The sensitivity of the mutant to two antitubercular drugs, rifampicin and d-cycloserine, was also increased. The glnA-1 strain infected THP-1 cells with reduced efficiency and was also attenuated for growth in macrophages. A Mycobacterium smegmatis strain containing the M. bovis glnA-1 gene survived longer in THP-1 cells than the wild-type strain and also produced cell wall associated PLG. The M. bovis mutant was not able to replicate in the organs of BALB/c mice and was cleared within 4-6 weeks of infection. Disruption of the glnA 1 gene adversely affected biofilm formation on polystyrene surfaces. The results of this study demonstrate that the absence of glnA-1 not only attenuates the pathogen but also affects cell surface properties by altering the cell wall chemistry of the organism via the synthesis of PLG; this may be a target for drug development. PMID- 20724387 TI - Transcriptional autoregulation of the RcsCDB phosphorelay system in Salmonella enterica serovar Typhimurium. AB - The RcsCDB (Rcs) phosphorelay system is involved in the regulation of many envelope genes, such as those responsible for capsule synthesis, flagella production and O-antigen chain length, as well as in other cellular activities of several enteric bacteria. The system is composed of three proteins: the sensor RcsC, the response regulator RcsB, and the phospho-transfer intermediary protein RcsD. Previously, we reported two important aspects of this system: (a) rcsB gene expression is under the control of P(rcsDB) and P(rcsB) promoters, and (b) rcsD gene transcription decreases when the bacteria reach high levels of the RcsB regulator. In the present work, we demonstrate that the RcsB protein represses rcsD gene expression by binding directly to the P(rcsDB) promoter, negatively autoregulating the Rcs system. Furthermore, we report the physiological role of the RcsB regulator, which is able to modify bacterial swarming behaviour when expressed under the control of the P(rcsB) promoter. PMID- 20724389 TI - Small subunits of RNA polymerase: localization, levels and implications for core enzyme composition. AB - Bacterial RNA polymerases (RNAPs) contain several small auxiliary subunits known to co-purify with the core alpha, beta and beta' subunits. The omega subunit is conserved between Gram-positive and Gram-negative bacteria, while the delta subunit is conserved within, but restricted to, Gram-positive bacteria. Although various functions have been assigned to these subunits via in vitro assays, very little is known about their in vivo roles. In this work we constructed a pair of vectors to investigate the subcellular localization of the delta and omega subunits in Bacillus subtilis with respect to the core RNAP. We found these subunits to be closely associated with RNAP involved in transcribing both mRNA and rRNA operons. Quantification of these subunits revealed delta to be present at equimolar levels with RNAP and omega to be present at around half the level of core RNAP. For comparison, the localization and quantification of RNAP beta' and omega subunits in Escherichia coli was also investigated. Similar to B. subtilis, beta' and omega closely associated with the nucleoid and formed subnucleoid regions of high green fluorescent protein intensity, but, unlike omega in B. subtilis, omega levels in E. coli were close to parity with those of beta'. These results indicate that delta is likely to be an integral RNAP subunit in Gram positives, whereas omega levels differ substantially between Gram-positives and negatives. The omega subunit may be required for RNAP assembly and subsequently be turned over at different rates or it may play roles in Gram-negative bacteria that are performed by other factors in Gram-positives. PMID- 20724388 TI - Telomere position effect is regulated by heterochromatin-associated proteins and NkuA in Aspergillus nidulans. AB - Gene-silencing mechanisms are being shown to be associated with an increasing number of fungal developmental processes. Telomere position effect (TPE) is a eukaryotic phenomenon resulting in gene repression in areas immediately adjacent to telomere caps. Here, TPE is shown to regulate expression of transgenes on the left arm of chromosome III and the right arm of chromosome VI in Aspergillus nidulans. Phenotypes found to be associated with transgene repression included reduction in radial growth and the absence of sexual spores; however, these pleiotropic phenotypes were remedied when cultures were grown on media with appropriate supplementation. Simple radial growth and ascosporogenesis assays provided insights into the mechanism of TPE, including a means to determine its extent. These experiments revealed that the KU70 homologue (NkuA) and the heterochromatin-associated proteins HepA, ClrD and HdaA were partially required for transgene silencing. This study indicates that TPE extends at least 30 kb on chromosome III, suggesting that this phenomenon may be important for gene regulation in subtelomeric regions of A. nidulans. PMID- 20724390 TI - Patient safety culture: factors that influence clinician involvement in patient safety behaviours. AB - OBJECTIVES: To develop an understanding of the factors that influence patient safety-related behaviours by nurses, doctors and allied health staff employed by Queensland Health, using a theory-driven behavioural model. DESIGN: Cross sectional survey analysed with multiple logistic regression. SETTING: Metropolitan, regional and rural public hospitals in Queensland, Australia. PARTICIPANTS: 5294 clinical and managerial staff. MAIN OUTCOME MEASURES: The Theory of Planned Behaviour was used to develop behavioural models for high-level Patient Safety Behavioural Intent (PSBI) of senior and junior doctors, senior and junior nurses, and allied health professionals. Multiple logistic regression analysis was used to identify factors that significantly influenced PSBI between the five professional groups. RESULTS: The factors that influence high-level PSBI give rise to unique predictive models for each professional group. Two factors stand out as influencing high-level PSBI for all healthcare workers (HCWs): (1) Preventive Action Beliefs (adjusted OR 2.38), HCWs' belief that engaging in the target behaviours will lead to improved patient safety; and (2) Professional Peer Behaviour (adjusted OR 1.79), perceptions about the patient safety-related behaviours of one's professional colleagues. CONCLUSIONS: Professional peer modelling behaviours and individuals' beliefs about the value of those behaviours in improving patient safety are important predictors of HCWs' patient safety behaviour. These findings may help explain the limitations of current knowledge based educational approaches to patient safety reform. Use of the behavioural models developed in this study when designing future patient safety improvement initiatives may prove more effective in driving the behavioural change necessary for improved patient safety. PMID- 20724391 TI - Detecting breaches in defensive barriers using in situ simulation for obstetric emergencies. AB - BACKGROUND: In Reason's safety model, high-reliability healthcare organisations are characterised by multiple layers of defensive barriers in depth associated with increased levels of safety in the care delivery system. However, there is very little empirical evidence describing and defining defensive barriers in healthcare settings or systematic analysis documenting the nature of breaches in these barriers. This study uses in situ simulation to identify defensive barriers and classify the nature of active and latent breaches in these barriers. METHODS: An in situ simulation methodology was used to study team performance during obstetrics emergencies. The authors conducted 46 trials of in situ simulated obstetrics emergencies in two phases at six different hospitals involving 823 physicians, nurses and support staff from January 2006 to February 2008. These six hospitals included a university teaching hospital, two suburban community hospitals and three rural hospitals. The authors created a high-fidelity simulation by developing scenarios based on actual sentinel events. RESULTS: A total of 965 breaches were identified by participants in 46 simulation trials. Of the 965 breaches, 461 (47.8%) were classified as latent conditions, and 494 (51.2%) were classified as active failures. CONCLUSIONS: In Reason's model, all sentinel events involve a breached protective layer. Understanding how protective layers breakdown is the first step to ensure patient safety and establish a high reliability. These findings suggest where to invest resources to help achieve a high reliability. In situ simulation helps recognise and remedy both active failures and latent conditions before they combine to cause bad outcomes. PMID- 20724392 TI - Automated categorisation of clinical incident reports using statistical text classification. AB - OBJECTIVES: To explore the feasibility of using statistical text classification techniques to automatically categorise clinical incident reports. METHODS: Statistical text classifiers based on Naive Bayes and Support Vector Machine algorithms were trained and tested on incident reports submitted by public hospitals to identify two classes of clinical incidents: inadequate clinical handover and incorrect patient identification. Each classifier was trained on 600 reports (300 positives, 300 negatives), and tested on 372 reports (248 positives, 124 negatives). The results were evaluated using standard measures of accuracy, precision, recall, F-measure and area under curve (AUC) of receiver operating characteristics (ROC). Classifier learning rates were also evaluated, using classifier accuracy against training set size. RESULTS: All classifiers performed well in categorising clinical handover and patient identification incidents. Naive Bayes attained the best performance on handover incidents, correctly identifying 86.29% of reporter-classified incidents (precision = 0.84, recall = .90, F-measure = 0.87, AUC = 0.93) and 91.53% of expert-classified incidents (precision = 0.87, recall = 0.98, F-measure = 0.92, AUC = 0.97). For patient identification incidents, the best results were obtained when Support Vector Machine with radial-basis function kernel was used to classify reporter classified reports (accuracy = 97.98%, precision = 0.98, recall = 0.98, F-measure = 0.98, AUC = 1.00); and when Naive Bayes was used on expert-classified reports (accuracy = 95.97%, precision = 0.95, recall = 0.98, F-measure = 0.96, AUC = 0.99). A relatively small training set was found to be adequate, with most classifiers achieving an accuracy above 80% when the training set size was as small as 100 samples. CONCLUSIONS: This study demonstrates the feasibility of using text classification techniques to automatically categorise clinical incident reports. PMID- 20724393 TI - Incidence and types of non-ideal care events in an emergency department. AB - AIM: To identify and characterise hazardous conditions in an Emergency Department (ED) using active surveillance. METHODS: This study was conducted in an urban, academic, tertiary care medical centre ED with over 45,000 annual adult visits. Trained research assistants interviewed care givers at the discharge of a systematically sampled group of patient visits across all shifts and days of the week. Care givers were asked to describe any part of the patient's care that they considered to be 'not ideal.' Reports were categorised by the segment of emergency care in which the event occurred and by a broad event category and specific event type. The occurrence of harm was also determined. RESULTS: Surveillance was conducted for 656 h with 487 visits sampled, representing 15% of total visits. A total of 1180 care giver interviews were completed (29 declines), generating 210 non-duplicative event reports for 153 visits. Thirty-two per cent of the visits had at least one non-ideal care event. Segments of care with the highest percentage of events were: Diagnostic Testing (29%), Disposition (21%), Evaluation (18%) and Treatment (14%). Process-related delays were the most frequently reported events within the categories of medication delivery (53%), laboratory testing (88%) and radiology testing (79%). Fourteen (7%) of the reported events were associated with patient harm. CONCLUSIONS: A significant number of non-ideal care events occurred during ED visits and involved failures in medication delivery, radiology testing and laboratory testing processes, and resulted in delays and patient harm. PMID- 20724394 TI - Real-time operational feedback: daily discharge rate as a novel hospital efficiency metric. AB - BACKGROUND: Part of delivering quality care means providing it in a timely, efficient manner. Improving the efficiency of care requires measurement. The selection of appropriate indicators that are valid and responsive is crucial to focus improvement initiatives. Indicators of operational efficiency should be conceptually simple, generated in real time, calculated using readily available hospital administrative data, sufficiently granular to reveal detail needed to focus improvement, and correlate with other valid indicators of operational efficiency. DISCUSSION: In this paper, the authors propose daily discharge rate as a novel real-time metric of hospital operational discharge efficiency and compare it with average length of stay. The authors also suggest the use of control charts as an effective way to present daily discharge rate data to clinicians and managers in real time to prompt actionable improvements in discharge efficiency. CONCLUSION: The authors conclude that daily discharge rate has the potential to drive timely improvements in the discharge process and warrants consideration and further study by others interested in improving hospital operational efficiency and the delivery of quality care. PMID- 20724395 TI - Electronic health records and adverse drug events after patient transfer. AB - BACKGROUND: Our objective was to examine the frequencies of medication error and adverse drug events (ADEs) at the time of patient transfer in a system with an electronic health record (EHR) as compared with a system without an EHR. It was hypothesised that the frequencies of these events would be lower in the EHR system because of better information exchange across sites of care. METHODS: 469 patients transferred between seven nursing homes and three hospitals in New York and Connecticut between 1999 and 2005 were followed retrospectively. Two groups of patients were compared: US Veterans Affairs (VA) patients, with an EHR, and non-VA patients, without an EHR, on the following measures: (1) medication prescribing discrepancies at nursing home/hospital transfer, (2) high-risk medication discrepancies and (3) ADEs caused by medication discrepancies according to structured medical record review by pairs of physician and pharmacist raters. RESULTS: The overall incidence of ADE caused by medication discrepancies was 0.20 per hospitalisation episode. After controlling for demographic and clinical covariates, there were no significant differences between VA and non-VA groups in medication discrepancies (mean difference 0.02; 95% CI -0.81 to 0.85), high-risk medication discrepancies (-0.18; 95%CI -0.22 to 0.58) or occurrence of an ADE caused by a medication discrepancy (OR 0.96; 95% CI 0.18 to 5.01). CONCLUSIONS: There was no difference, with and without an EHR, in the occurrence of medication discrepancies or ADEs caused by medication discrepancies at the time of transfer between sites of care. Reducing such problems may require specialised computer tools to facilitate medication review. PMID- 20724396 TI - Multilayered approach to patient safety culture. AB - BACKGROUND: The concept of patient safety culture (PSC) has increasingly been used in the development of patient safety. However, no theoretical framework on the nature of the underlying phenomenon has been created. Multiple characterisations of the key dimensions of PSC exist, but they yield little theory on patient safety culture or its relation to patient safety. The authors propose a dynamic and multilayered construct of patient safety culture and illustrate the critical dimensions at each layer. CONCLUSIONS: PSC can be defined as the willingness and ability of an organisation to understand safety as well as the willingness and ability to act on safety. Patient safety requires controlling and steering the organisation, and being mindful of the social processes and psychological phenomena. PMID- 20724397 TI - Lean thinking in healthcare: a realist review of the literature. AB - OBJECTIVE: To understand how lean thinking has been put into practice in healthcare and how it has worked. DESIGN: A realist literature review. Data sources The authors systematically searched for articles in PubMed, Web of Science and Business Source Premier (January 1998 to February 2008) and then added articles through a snowball approach. REVIEW METHODS: The authors included empirical studies of lean thinking applications in healthcare and excluded those articles that did not influence patient care, or reported hybrid approaches. The authors conducted a thematic analysis based on data collected using an original abstraction form. Based on this, they articulated interactions between context, lean interventions, mechanisms and outcomes. RESULTS: The authors reviewed 33 articles and found a wide range of lean applications. The articles describe initial implementation stages and emphasise technical aspects. All articles report positive results. The authors found common contextual aspects which interact with different components of the lean interventions and trigger four different change mechanisms: understand processes to generate shared understanding; organise and design for effectiveness and efficiency; improve error detection to increase awareness and process reliability; and collaborate to systematically solve problems to enhance continual improvement. CONCLUSIONS: Lean thinking has been applied successfully in a wide variety of healthcare settings. While lean theory emphasises a holistic view, most cases report narrower technical applications with limited organisational reach. To better realise the potential benefits, healthcare organisations need to directly involve senior management, work across functional divides, pursue value creation for patients and other customers, and nurture a long-term view of continual improvement. PMID- 20724398 TI - Checking it twice: an evaluation of checklists for detecting medication errors at the bedside using a chemotherapy model. AB - OBJECTIVE: To determine what components of a checklist contribute to effective detection of medication errors at the bedside. DESIGN: High-fidelity simulation study of outpatient chemotherapy administration. SETTING: Usability laboratory. PARTICIPANTS: Nurses from an outpatient chemotherapy unit, who used two different checklists to identify four categories of medication administration errors. MAIN OUTCOME MEASURES: Rates of specified types of errors related to medication administration. RESULTS: As few as 0% and as many as 90% of each type of error were detected. Error detection varied as a function of error type and checklist used. Specific step-by-step instructions were more effective than abstract general reminders in helping nurses to detect errors. Adding a specific instruction to check the patient's identification improved error detection in this category by 65 percentage points. Matching the sequence of items on the checklist with nurses' workflow had a positive impact on the ease of use and efficiency of the checklist. CONCLUSIONS: Checklists designed with explicit step by-step instructions are useful for detecting specific errors when a care provider is required to perform a long series of mechanistic tasks under a high cognitive load. Further research is needed to determine how best to assist clinicians in switching between mechanistic tasks and abstract clinical problem solving. PMID- 20724399 TI - Determinants of disparities between perceived and physiological risk of falling among elderly people: cohort study. AB - OBJECTIVES: To gain an understanding of elderly people's fear of falling by exploring the prevalence and determinants of perceived and physiological fall risk and to understand the role of disparities in perceived and physiological risk in the cause of falls. DESIGN: Prospective cohort study. SETTING: Community sample drawn from eastern Sydney, Australia. PARTICIPANTS: 500 men and women aged 70-90 years. MAIN OUTCOME MEASURES: Baseline assessment of medical, physiological, and neuropsychological measures, with physiological fall risk estimated with the physiological profile assessment, and perceived fall risk estimated with the falls efficacy scale international. Participants were followed up monthly for falls over one year. RESULTS: Multivariate logistic regression analyses showed that perceived and physiological fall risk were both independent predictors of future falls. Classification tree analysis was used to split the sample into four groups (vigorous, anxious, stoic, and aware) based on the disparity between physiological and perceived risk of falling. Perceived fall risk was congruent with physiological fall risk in the vigorous (144 (29%)) and aware (202 (40%)) groups. The anxious group (54 (11%)) had a low physiological risk but high perceived fall risk, which was related to depressive symptoms (P=0.029), neurotic personality traits (P=0.026), and decreased executive functioning (P=0.010). The stoic group (100 (20%)) had a high physiological risk but low perceived fall risk, which was protective for falling and mediated through a positive outlook on life (P=0.001) and maintained physical activity and community participation (P=0.048). CONCLUSION: Many elderly people underestimated or overestimated their risk of falling. Such disparities between perceived and physiological fall risk were primarily associated with psychological measures and strongly influenced the probability of falling. Measures of both physiological and perceived fall risk should be included in fall risk assessments to allow tailoring of interventions for preventing falls in elderly people. PMID- 20724401 TI - Can specific fruits and vegetables prevent diabetes? PMID- 20724400 TI - Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis. AB - OBJECTIVE: To investigate the independent effects of intake of fruit and vegetables on incidence of type 2 diabetes. DESIGN: Systematic review and meta analysis. DATA SOURCES: Medline, Embase, CINAHL, British Nursing Index (BNI), and the Cochrane library were searched for medical subject headings and keywords on diabetes, prediabetes, fruit, and vegetables. Expert opinions were sought and reference lists of relevant articles checked. STUDY SELECTION: Prospective cohort studies with an independent measure of intake of fruit, vegetables, or fruit and vegetables and data on incidence of type 2 diabetes. RESULTS: Six studies met the inclusion criteria; four of these studies also provided separate information on the consumption of green leafy vegetables. Summary estimates showed that greater intake of green leafy vegetables was associated with a 14% (hazard ratio 0.86, 95% confidence interval 0.77 to 0.97) reduction in risk of type 2 diabetes (P=0.01). The summary estimates showed no significant benefits of increasing the consumption of vegetables, fruit, or fruit and vegetables combined. CONCLUSION: Increasing daily intake of green leafy vegetables could significantly reduce the risk of type 2 diabetes and should be investigated further. PMID- 20724403 TI - How long should treatments be continued? PMID- 20724404 TI - Importance of accurately identifying disease in studies using electronic health records. PMID- 20724402 TI - Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. AB - OBJECTIVE: To study rates of relapse in remitted patients with first episode psychosis who either continued or discontinued antipsychotic drugs after at least one year of maintenance treatment. DESIGN: 12 month randomised, double blind, placebo controlled trial. SETTING: Early psychosis outpatient clinics in Hong Kong. PARTICIPANTS: 178 patients with first episode psychosis who had received at least one year of antipsychotic drug treatment between September 2003 and July 2006 and had no positive symptoms of psychosis. INTERVENTIONS: Patients received either maintenance treatment with quetiapine (400 mg/day) or placebo and were followed up for the next 12 months or until a relapse occurred. MAIN OUTCOME MEASURE: Relapse assessed monthly and defined as re-emergence of psychotic symptoms (delusions, conceptual disorganisation, hallucinations, suspiciousness, and unusual thought content) according to predefined thresholds. RESULTS: 178 patients were randomised (89 to quetiapine and 89 to placebo). The Kaplan-Meier estimate of the risk of relapse at 12 months was 41% (95% confidence interval 29% to 53%) for the quetiapine group and 79% (68% to 90%) for the placebo group (P<0.001). Although quetiapine was generally well tolerated, the rate of discontinuation due to adverse or serious adverse events was greater in the quetiapine group (18%; 16/89) than in the placebo group (8%; 7/89) (relative risk 2.29, 95% confidence interval 0.99 to 5.28; chi(2)=3.20, df=1; P=0.07). CONCLUSION: In a group of asymptomatic patients with first episode psychosis and at least one year of previous antipsychotic drug treatment, maintenance treatment with quetiapine compared with placebo resulted in a substantially lower rate of relapse during the following year. Trial registration Clinical trials NCT00334035. PMID- 20724405 TI - What do we want to die from? How should we define "ageism"? PMID- 20724406 TI - Umbilical cord pH and outcomes. Might measuring cord pH in itself affect outcome? PMID- 20724407 TI - Nutrition in type 2 diabetes. Individual dietary intervention is cost effective. PMID- 20724408 TI - Bad medicine: medicated minors. Is psychiatry thinking adequately about behaviour? PMID- 20724409 TI - Nutrition in type 2 diabetes. Metabolic surgery may be more effective. PMID- 20724410 TI - Barriers to suicide. Strategies at Bloor Viaduct. PMID- 20724411 TI - GPs and the white paper. See the opportunities, not the problems. PMID- 20724412 TI - Screening for breast cancer. Always something missing in this debate. PMID- 20724413 TI - Screening for breast cancer. "Mega-trial" needed. PMID- 20724414 TI - Quadrivalent HPV vaccine. Wider cost benefits of vaccine. PMID- 20724415 TI - Ban on multidose vials. The proposal is misguided. PMID- 20724416 TI - Community acquired pneumonia. Management in primary care. PMID- 20724418 TI - The Move & PLAY study: an example of comprehensive rehabilitation outcomes research. AB - This perspective article provides an example of a study planned using guidelines for comprehensive rehabilitation outcomes research, an approach that is believed to give service providers meaningful evidence to support practice. This line of investigation has been guided by the World Health Organization's International Classification of Functioning, Disability and Health. The short title of a study under way is Move & PLAY (Movement and Participation in Life Activities of Young Children). The article briefly describes the conceptual model, provides guidelines on how indicators and measures are selected, alludes to the details of selected measures, and describes processes of preparing for data collection, including obtaining ethics approval, preparing data collection booklets, training assessors and interviewers, and sampling. The aim of this investigation is to gain a better understanding of the multiple child, family, and service factors associated with changes in mobility, self-care, and play of preschool children with cerebral palsy as a result of using this research method. Comprehensive rehabilitation outcomes research holds promise in providing evidence that supports the complexities of planning rehabilitation services with clients with chronic conditions, such as children with cerebral palsy. PMID- 20724419 TI - Measurement of femoral torsion by ultrasound and magnetic resonance imaging: concurrent validity. AB - BACKGROUND: Abnormal femoral torsion has been linked to osteoarthritis in the knee as well as to patellofemoral pain. Inexpensive, valid, and reliable methods for assessing femoral torsion are needed. Ultrasound (US) is a noninvasive and clinically accessible method that can be used for the assessment of bone morphology, such as femoral torsion. OBJECTIVE: The objective of this study was to determine the concurrent validity of US for the measurement of femoral torsion with a reference method, magnetic resonance imaging (MRI). DESIGN: Repeated measurements of femoral torsion were obtained with US and MRI in a laboratory setting. METHODS: Twenty-eight people (4 men, 24 women; mean age=26.8 years [SD=4.0 years], mean body height=170.3 cm [SD=8.0 cm], mean body weight=64.7 kg [SD=9.8 kg]) participated in this study. T1-weighted axial oblique images of the femoral neck and epicondylar axis were acquired with a 1.5-T magnetic resonance system. Ultrasonographic measurements then were obtained by a tilting technique with a linear transducer that was 4.5 cm long and operated at a frequency of 10 MHz and a depth of 5 cm. RESULTS: The average angles of anteversion measured by US and by MRI were 20.7 degrees (SD=11.0) and 19 degrees (SD=11.3), respectively. The reliability, reported as the intraclass correlation coefficient [ICC (2,1)], of repeated measurements of in vivo femoral torsion by US was .98. The reliability [ICC (2,1)] of magnetic resonance image analysis was .96. The standard error of the measurement for US was 2.2 degrees, and that for MRI was 1.9 degrees. The concurrent validity of US with MRI (R(2)) was .93 (r=.96). LIMITATIONS: Obtaining measurements by US requires appropriate training before data collection. CONCLUSIONS: Ultrasound measurement of femoral torsion has high concurrent validity with in vivo MRI and may be used when an assessment of bony morphology is needed but MRI is not available. PMID- 20724420 TI - Core journals that publish clinical trials of physical therapy interventions. AB - OBJECTIVE: The objective of this study was to identify core journals in physical therapy by identifying those that publish the most randomized controlled trials of physical therapy interventions, provide the highest-quality reports of randomized controlled trials, and have the highest journal impact factors. DESIGN: This study was an audit of a bibliographic database. METHODS: All trials indexed in the Physiotherapy Evidence Database (PEDro) were analyzed. Journals that had published at least 80 trials were selected. The journals were ranked in 4 ways: number of trials published; mean total PEDro score of the trials published in the journal, regardless of publication year; mean total PEDro score of the trials published in the journal from 2000 to 2009; and 2008 journal impact factor. RESULTS: The top 5 core journals in physical therapy, ranked by the total number of trials published, were Archives of Physical Medicine and Rehabilitation, Clinical Rehabilitation, Spine, British Medical Journal (BMJ), and Chest. When the mean total PEDro score was used as the ranking criterion, the top 5 journals were Journal of Physiotherapy, Journal of the American Medical Association (JAMA), Stroke, Spine, and Clinical Rehabilitation. When the mean total PEDro score of the trials published from 2000 to 2009 was used as the ranking criterion, the top 5 journals were Journal of Physiotherapy, JAMA, Lancet, BMJ, and Pain. The most highly ranked physical therapy-specific journals were Physical Therapy (ranked eighth on the basis of the number of trials published) and Journal of Physiotherapy (ranked first on the basis of the quality of trials). Finally, when the 2008 impact factor was used for ranking, the top 5 journals were JAMA, Lancet, BMJ, American Journal of Respiratory and Critical Care Medicine, and Thorax. There were no significant relationships among the rankings on the basis of trial quality, number of trials, or journal impact factor. CONCLUSIONS: Physical therapists who are trying to keep up-to-date by reading the best available evidence on the effects of physical therapy interventions have to read more broadly than just physical therapy-specific journals. Readers of articles on physical therapy trials should be aware that high-quality trials are not necessarily published in journals with high impact factors. PMID- 20724421 TI - Long-term results of chest wall reconstruction with DualMesh. AB - The aim of this study was to evaluate the clinical outcomes of chest wall reconstruction using a new, expanded polytetrafluoroethylene prosthesis, 'DualMesh'. Between December 2005 and March 2010, chest wall reconstruction using 2-mm DualMesh was performed in 11 patients. The indication for resection was primary lung cancer in six patients, malignant mesothelioma in one patient, recurrent lung cancer in one patient, recurrent invasive thymoma in one patient, postirradiated osteomyelitis in one patient, and chondro-hamartoma in one patient. The mean observation period was 23 months, and four cases were observed for more than three years. There were no operative deaths and no wound infections. There were two postoperative complications: prolonged air leakage occurred in a patient with pulmonary emphysema who underwent right lower lobectomy, and slight paradoxical respiration occurred in the patient who underwent resection of the entire sternal body for osteomyelitis. Follow-up chest computed tomography was performed routinely. No dehiscence occurred in any cases. Chest wall reconstruction using DualMesh demonstrated acceptable durability and biocompatibility, even after long-term follow-up. DualMesh has the potential to become an ideal prosthesis for the bony chest wall as an alternative to conventional polytetrafluoroethylene or polypropylene grafts. PMID- 20724422 TI - Aortic pseudoaneurysm detected on external jugular venous distention following a Bentall procedure 10 years previously. AB - An asymptomatic 49-year-old woman was admitted for the purpose of surgery for aortic pseudoaneurysm. She had Marfan syndrome and had undergone an emergent Bentall procedure 10 years previously. About six months previously, she could palpate distended bilateral external jugular veins, which became distended only in a supine position and without any other symptoms. Enhanced computed tomography revealed an aortic pseudoaneurysm originating from a previous distal anastomosis site. During induction of general anesthesia in a supine position, bilateral external jugular venous distention was remarkable. Immediately after a successful operation, distention completely resolved. The present case emphasizes the importance of physical examination leading to a diagnosis of asymptomatic life threatening diseases in patients with a history of previous aortic surgery. PMID- 20724423 TI - Death in low-risk cardiac surgery: Stockholm experience. AB - In cardiac surgery, perioperative death in low-risk patients is uncommon, but does occur. Reports on the incidence, cause and circumstances of death in this population are rare. We analyzed the early mortality and cause of death in patients with an additive EuroSCORE<=3 who underwent cardiac surgery between 2001 and August 2009 in Stockholm. We also investigated if death could be considered preventable, and in that case, if it was due to a technical or a system error. Among 3924 low-risk patients, 15 died within 30 days of surgery, and early mortality was 0.38%. Cause of death was mostly cardiac related (11 of 15). Death occurred after hospital discharge in three patients, and was classified as non preventable in 13 patients. In the remaining two patients, the circumstances leading to death were categorized as due to a system error. A systematic and structured analysis of the circumstances resulting in death in low-risk patients, in addition to traditional morbidity and mortality conferences, have the potential to identify problems and offer improvements in the quality of care. PMID- 20724424 TI - Ciliated muconodular papillary tumour of the lung: a newly defined low-grade malignant tumour. AB - We present two cases of ciliated muconodular papillary tumour (CMPT) in this report. CMPT is a newly defined low-grade malignant tumour with ciliated columnar epithelial cells, occurring in the peripheral lung. Both patients underwent pulmonary resection due to an enlarged solitary pulmonary nodule. Pathological findings in both cases confirmed a papillary tumour with a mixture of ciliated columnar and goblet cells. The tumours were rich in mucous and had spread along the alveolar walls, as observed in bronchioloalveolar carcinoma. Nuclear atypia was mild, and no mitotic activity was observed. Immunohistochemically, tumour cells stained positive for carcinoembryonic antigen, thyroid transcription factor 1 and cytokeratin 7 but not for cytokeratin 20. The immunohistochemical staining patterns were almost identical to those of pulmonary adenocarcinoma. We definitively diagnosed as CMPT. Both patients remained relapse-free. PMID- 20724425 TI - Flap valved closure of ventricular septal defects with increased pulmonary vascular resistance. AB - Closure of ventricular septal defect (VSD) in children with elevated pulmonary vascular resistance (PVR) is associated with significant morbidity and mortality with pulmonary hypertensive (PH) episodes being a major postoperative problem. Flap valved closure of VSD is reported to decrease morbidity and mortality. We report our experience of closure of a VSDs in patients with severe PH, using a valved patch in an effort to reduce the risk of operation. Eighteen consecutive patients with a large VSD with severe PH (mean PVR>8 Wood units) underwent flap valved closure (as described by Novick et al.) of VSD during a one-year study period. The mean age at surgery was 8.3+/-3.9 years (range: 3-13 years). Mean PVRI was 13.02+/-4.05 Wood units. In-hospital 30-day mortality was 5.6% (1/18). Mechanical ventilation time averaged 11.6+/-8.1 hours. Postoperative pulmonary artery pressures were significantly reduced. Four patients had PH crisis postoperatively. Obvious opening and closing of the flap valve was detected by echocardiography in eight patients. There were no late deaths due to cardiac causes. Closure of a large VSD in patients with severe pulmonary hypertension could be performed with low morbidity and mortality when a flap valve patch was used. PMID- 20724426 TI - Preoperative neutrophil response as a predictive marker of clinical outcome following open heart surgery and the impact of leukocyte filtration. AB - OBJECTIVES: Open heart surgery is associated with a massive systemic inflammatory response. Neutrophils, are the main mediator of this response. We hypothesised that the degree of neutrophil activation and inflammatory response to open heart surgery varies individually and correlates with clinical outcome. The aim of this study was to determine if individual clinical outcome can be predicted preoperatively through assessment of in-vitro stimulated neutrophil responses. Following that, the effects of neutrophil depletion through leukocyte filters are examined. METHODS: Neutrophil responses were assessed preoperatively (n=40) through change in neutrophil adhesion molecule [CD11b, CD62L and P Selectin Glycoprotein-1 (PSGL-1)] expression before and after in-vitro stimulation with Phorbol 12-myristate 13-acetate, PMA (1 ng/ml), lipopolysaccharide, LPS (1 MUg/ml) and N-Formyl-Met-Leu-Phe, fMLP (1 ng/ml). Stimulated neutrophil responses were then correlated with postoperative clinical outcome. Patients were then randomised to leukocyte filtration (n=20) and a control group (n=20) and the effect of leukocyte filtration on neutrophil response and clinical outcome were investigated. RESULTS: An individual variation in in-vitro stimulated neutrophil responses was demonstrated. Significant correlations were shown between neutrophil responses and maximum serum creatinine change, CKMB-fraction, adrenaline requirement, noradrenaline requirement, duration of adrenaline required and time to extubation. White cell count and percentage neutrophils were lower in the LD group (P=0.05). CD11b expression (P=0.005) and PSGL-1 expression (P=0.043) across leukocyte filters were also increased. However, no significant difference was detected in clinical outcome between the LD and control groups. CONCLUSION: Preoperative neutrophil responses to in-vitro stimuli can predict clinical outcome following open heart surgery. However, leukocyte filtration did not offer significant benefit in clinical outcome in our study. PMID- 20724427 TI - Favorable outcome using a maze procedure for left pneumonectomy combined with resection of the left atrium in stage IIIB lung cancer. AB - We report a case of a 67-year-old woman with stage IIIB locally advanced non small cell lung cancer who had also suffered from hyperthyroidism with persistent atrial fibrillation (AF). Thiamazole provided euthyroid status, but medication failed to resolve AF. A computed tomography (CT)-scan revealed a 5*5-cm mass in the left hilar region that involved the left atrium (LA) and bifurcation of the pulmonary artery. Left pneumonectomy, LA partial resection and reconstruction of the bifurcation of the pulmonary artery were performed. In addition, a maze procedure was performed using cardiopulmonary bypass and cardiac arrest. We present the first case report of advanced lung cancer surgery with a maze procedure. Follow-up by CT-scan 34 months later did not show any recurrence and attacks of AF (no medication after surgery) were completely resolved after the operation. PMID- 20724428 TI - A rare cause of graft dysfunction after a heart transplant. AB - A 39-year-old man with a dilated cardiomyopathy was treated for recurrent life threatening ventricular arrhythmias with an automatic defibrillator and multiple antiarrhythmic agents. After transplant, the donor heart was asystolic probably secondary to these agents. A biventricular paracorporeal device supported the patient for four days and the heart recovered. He remains NYHA class I seven years later. PMID- 20724429 TI - Is a sleeve lobectomy significantly better than a pneumonectomy? AB - A best evidence topic was written according to a structured protocol. The question addressed was 'whether a sleeve lobectomy results in a better survival rate than a pneumonectomy in suitable patients?' Altogether, more than 327 papers were found using the reported search, of which 15 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude in the biggest meta-analysis of nearly 3000 patients, the five-year survival was 50% for sleeve lobectomy compared to 30% for pneumonectomy. Operative mortality was 3% vs. 6% for pneumonectomy, and locoregional recurrence was 17% vs. 30%. These results are broadly consistent across all the 13 cohort studies presented here many of which document a 20-year single centre experience or more. There are significant issues in all cohort studies on this subject as, due to their non-randomized nature, the reason for not performing a sleeve resection may well have been more advanced disease, which would necessarily mean that the pneumonectomy patients would have a lower expected survival and higher local recurrence. In addition, there have been many large cohort studies to date and thus no more are required, as future studies are unlikely to resolve this issue. Thus, the only study that would adequately correct for this issue would be a randomized trial, but to prove a 10% increase in five-year survival a 300 patient study would be needed. This is bigger than any study ever done in this area and as some centres took 30 years to collect these numbers of potential sleeve patients an RCT is not a realistic possibility. Therefore, we conclude that no more cohort studies should be performed, as the results will be consistent with the meta-analyses and an RCT to eliminate their bias is unattainable, and thus no more research should be done on this topic and surgeons should use the figures presented above and in more detail in this best evidence topic to govern their management in the future. PMID- 20724430 TI - A tip for controlling the main pulmonary artery during video-assisted thoracic major pulmonary resection: the outside-field vascular clamping technique. AB - Cross-clamping the main pulmonary artery (PA) is a risky, stressful procedure for the general thoracic surgeon performing video-assisted thoracic major pulmonary resection (VATS). However, converting VATS to thoracotomy each time PA clamping is planned is a poor tactic. We present a simpler technique for VATS than the traditional method involving a thoracotomy. In VATS, DeBakey vascular clamps with double angle jaws are inserted through 1-cm access incisions. We clamped the main PA so as to maintain the limited visual field through the working port. Thus, we modified the position of these vascular clamps, which we call 'the outside-field vascular clamping technique'. Our technique should be used for VATS lobectomy to prevent conversion to open thoracotomy when one requires scheduled control of the PA during VATS. PMID- 20724431 TI - Mobilization of endothelial progenitor cells by intravenous cyclophosphamide in patients with systemic sclerosis. AB - OBJECTIVE: To evaluate the effects of i.v. CYC on the number of circulating endothelial progenitor cells (EPCs) in patients with SSc, and the potential association of the EPC response with CYC's effect for treating interstitial lung disease (ILD). METHODS: This open-label, prospective study involved 12 patients with SSc and alveolitis (CYC group). All patients received six courses of i.v. CYC (0.5 g/m2) at 4-week intervals in combination with low-dose prednisolone. Ten patients were followed for 24 months. Seven SSc patients treated with low-dose prednisolone alone were used as a control for the EPC measurement (control group). Five patients with non-SSc CTD who received i.v. CYC and prednisolone also served as disease controls. EPCs were quantified by the partial enrichment of CD34+ cells followed by three-colour flow cytometry. The circulating levels of vascular injury markers were measured by immunoassay. RESULTS: The EPC count was significantly increased at 2 weeks after treatment in the CYC group (P=0.02), but not in the control group, while CYC increased EPC count in all disease controls. The SSc patients in the CYC group were divided into five EPC responders and seven EPC non-responders. Circulating vascular injury markers were reduced in the responders, but not in the non-responders. During the 24-month follow-up, 3 of 10 patients developed end-stage lung disease, and all of them were EPC non responders. CONCLUSION: A low-dose i.v. CYC induces EPC mobilization, which may contribute to the efficacy for treating SSc-associated ILD. PMID- 20724432 TI - Arthritis in leprosy. AB - Leprosy, a chronic granulomatous infection caused by Mycobacterium leprae, classically presents with cutaneous and neurological manifestations. Musculoskeletal involvement though third most common is underdiagnosed and underreported. It may manifest in the form of Charcot's arthropathy, acute symmetrical polyarthritis or swollen hands and feet syndrome during lepra reactions, insidious-onset chronic symmetrical polyarthritis mimicking RA or as isolated tenosynovitis or tenosynovitis associated with arthritis or neuropathy. At times, articular involvement may be the sole presenting manifestation even without cutaneous lesions. Other rheumatological manifestations occasionally reported are enthesitis, sacroiliitis, cryoglobulinaemic vasculitis and DM. With increasing travel of population between tropical and temperate zones, it is likely that rheumatology clinics in countries free of leprosy may come across cases of leprosy with rheumatological manifestations. Delay in diagnosis and management may be detrimental and may result in deformities and loss of function. Not only this, but recent reports of leprosy being diagnosed in native white populations following anti-TNF-alpha therapy should alert rheumatologists across the globe to be more familiar with this disease. This review is aimed at presenting a comprehensive clinical scenario of various rheumatological manifestations of leprosy to sensitize rheumatologists and physicians across the continents. PMID- 20724433 TI - Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration associated chemokine receptor expression. AB - OBJECTIVES: The contribution of IL-17-producing Th17 cells to the pathogenesis of T-cell-mediated inflammatory disorders such as RA and atopic dermatitis (AD) has to be viewed in relation to the role of Th1/Th2 cells and long-recognized key cytokines like TNF. We aimed to study the frequency and migration-associated phenotype of peripheral Th17, Th1 and Th2 cells in healthy individuals, RA and AD patients, and to study the influence of anti-TNF therapy in RA. METHODS: Intracellular IL-17, IFN-gamma and IL-4 production and CC-chemokine receptor CCR4 and CCR6 expression were analysed flow cytometrically in peripheral memory Th cells from healthy individuals, AD and RA patients. The latter were grouped by disease activity and presence or absence of adalimumab therapy. In RA patients initiating anti-TNF therapy, cytokine production by in vitro-stimulated peripheral mononuclear cells was measured by cytometric bead array. RESULTS: The peripheral Th17 cell frequency is elevated in AD but not in RA. In RA, Th17 cells and IL-17 production increase after anti-TNF therapy, irrespective of disease activity. Th1 cells and IFN-gamma production are elevated in remission and under anti-TNF therapy. CCR6 expression is up-regulated in Th17 cells, but RA patients in remission under anti-TNF therapy have significantly lower expression than those with active disease. CONCLUSIONS: The increase in peripheral Th17 cells in RA patients after anti-TNF therapy is accompanied by a decrease in Th17-specific CCR6 expression, which might prevent homing of these potentially pro-inflammatory cells to the synovium. PMID- 20724434 TI - Diagnostic performance and validation of autoantibody testing in myositis by a commercial line blot assay. AB - OBJECTIVE: Serological testing for myositis-specific or associated autoantibodies [myositis-specific antibody (MSA) and myositis-associated antibody (MAA)] is useful for the diagnosis of idiopathic inflammatory myopathies (IIMs). However, available assays are neither standardized nor validated. The objective is to evaluate the accuracy of a commercial line blot assay for myositis diagnosis. METHODS: IgG antibodies against Jo-1, PL-7, PL-12, PM/Scl, Ku, Mi-2 and Ro52 antigens were detected by a line blot and in-house RNA immunoprecipitation or immunoblot. We tested sera from 208 IIM patients, 50 healthy subjects and 180 control patients (11 non-autoimmune myopathy, 23 muscular dystrophy, 11 UCTD, 68 SLE, 36 SSc, 22 SS and 9 arthropathy). RESULTS: MSAs or MAAs were detected in 98 (47%) out of the 208 IIM patients by line blot: anti-Jo-1 in 43 (21%), anti-PL-7 or anti-PL-12 in 8 (4%), anti-Mi-2 in 9 (4%), anti-PM/Scl in 9 (4%), anti-Ku in 10 (5%) and anti-Ro52 in 49 (24%). Overall specificity was: 100% for anti-Jo-1, anti-PL-7 or PL-12 and anti-PM/Scl; 96% for anti-Ku; 98% for anti-Mi-2; and 76% for anti-Ro52. In-house testing confirmed line blot results regarding anti-Jo-1, anti-PM/Scl and anti-Ku, while it was more accurate than line blot in detecting anti-Mi-2 (7 vs 4% sensitivity, 100 vs 98% specificity), and anti-aminoacyl-tRNA synthetase (anti-ARS) non-Jo-1 antibodies (11 vs 4% sensitivity, 97 vs 99% specificity). CONCLUSIONS: Line blot could be a suitable serological test in the diagnostic workup for myositis, and it represents a reliable alternative to more time-consuming procedures. Continuous effort is recommended in order to improve its accuracy. PMID- 20724435 TI - Identification, subcellular localization, biochemical properties, and high resolution crystal structure of Trypanosoma brucei UDP-glucose pyrophosphorylase. AB - The protozoan parasite Trypanosoma brucei is the causative agent of the cattle disease Nagana and human African sleeping sickness. Glycoproteins play key roles in the parasite's survival and infectivity, and the de novo biosyntheses of the sugar nucleotides UDP-galactose (UDP-Gal), UDP-N-acetylglucosamine, and GDP fucose have been shown to be essential for their growth. The only route to UDP Gal in T. brucei is through the epimerization of UDP-glucose (UDP-Glc) by UDP-Glc 4'-epimerase. UDP-Glc is also the glucosyl donor for the unfolded glycoprotein glucosyltransferase (UGGT) involved in glycoprotein quality control in the endoplasmic reticulum and is the presumed donor for the synthesis of base J (beta D-glucosylhydroxymethyluracil), a rare deoxynucleotide found in telomere-proximal DNA in the bloodstream form of T. brucei. Considering that UDP-Glc plays such a central role in carbohydrate metabolism, we decided to characterize UDP-Glc biosynthesis in T. brucei. We identified and characterized the parasite UDP glucose pyrophosphorylase (TbUGP), responsible for the formation of UDP-Glc from glucose-1-phosphate and UTP, and localized the enzyme to the peroxisome-like glycosome organelles of the parasite. Recombinant TbUGP was shown to be enzymatically active and specific for glucose-1-phosphate. The high-resolution crystal structure was also solved, providing a framework for the design of potential inhibitors against the parasite enzyme. PMID- 20724436 TI - Pattern of injuries among children and adolescents in Riyadh, Saudi Arabia: a household survey. AB - OBJECTIVES: To determine the incidence and pattern of injuries among children and adolescents <18 years old in Riyadh city and to identify associated factors. MATERIAL AND METHODS: A cross sectional household survey included children and adolescents <18 years. A two-stage cluster sample was used to recruit the participants from thirty clusters each consisted OF 23 households. A questionnaire was used for data collection by interview. RESULTS: The study included 1650 children and adolescents. Of them, 22.2% reported having had injuries in the previous 12 months. The most common injuries were falls (40.4%), Road Traffic Accidents (RTA) (15%), food intoxication (8.8%). Males were more affected by injuries than females (26% vs. 18%). Males living near playgrounds or public gardens, playing in the street are independent risk factors for occurrence of both falls and RTA injuries. RECOMMENDATIONS: school safety education and environmental modification should be applied in Riyadh. PMID- 20724437 TI - Emphysematous pancreatitis: a severe complication of acute pancreatitis. PMID- 20724438 TI - Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1. AB - TopBP1 is a scaffold protein that coordinates activation of the DNA-damage checkpoint response by coupling binding of the 9-1-1 checkpoint clamp at sites of ssDNA, to activation of the ATR-ATRIP checkpoint kinase complex. We have now determined the crystal structure of the N-terminal region of human TopBP1, revealing an unexpected triple-BRCT domain structure. The arrangement of the BRCT domains differs significantly from previously described tandem BRCT domain structures, and presents two distinct sites for binding phosphopeptides in the second and third BRCT domains. We show that the site in the second but not third BRCT domain in the N-terminus of TopBP1, provides specific interaction with a phosphorylated motif at pSer387 in Rad9, which can be generated by CK2. PMID- 20724439 TI - Capturing, sharing and analysing biophysical data from protein engineering and protein characterization studies. AB - Large amounts of data are being generated annually on the connection between the sequence, structure and function of proteins using site-directed mutagenesis, protein design and directed evolution techniques. These data provide the fundamental building blocks for our understanding of protein function, molecular biology and living organisms in general. However, much experimental data are never deposited in databases and is thus 'lost' in journal publications or in PhD theses. At the same time theoretical scientists are in need of large amounts of experimental data for benchmarking and calibrating novel predictive algorithms, and theoretical progress is therefore often hampered by the lack of suitable data to validate or disprove a theoretical assumption. We present PEAT (Protein Engineering Analysis Tool), an application that integrates data deposition, storage and analysis for researchers carrying out protein engineering projects or biophysical characterization of proteins. PEAT contains modules for DNA sequence manipulation, primer design, fitting of biophysical characterization data (enzyme kinetics, circular dichroism spectroscopy, NMR titration data, etc.), and facilitates sharing of experimental data and analyses for a typical university based research group. PEAT is freely available to academic researchers at http://enzyme.ucd.ie/PEAT. PMID- 20724440 TI - Building promoter aware transcriptional regulatory networks using siRNA perturbation and deepCAGE. AB - Perturbation and time-course data sets, in combination with computational approaches, can be used to infer transcriptional regulatory networks which ultimately govern the developmental pathways and responses of cells. Here, we individually knocked down the four transcription factors PU.1, IRF8, MYB and SP1 in the human monocyte leukemia THP-1 cell line and profiled the genome-wide transcriptional response of individual transcription starting sites using deep sequencing based Cap Analysis of Gene Expression. From the proximal promoter regions of the responding transcription starting sites, we derived de novo binding-site motifs, characterized their biological function and constructed a network. We found a previously described composite motif for PU.1 and IRF8 that explains the overlapping set of transcriptional responses upon knockdown of either factor. PMID- 20724441 TI - Blank peak current-suppressed electrochemical aptameric sensing platform for highly sensitive signal-on detection of small molecule. AB - In this contribution, an electrochemical aptameric sensing scheme for the sensitive detection of small molecules is proposed using adenosine as a target model. A ferrocene (Fc)-functionalized thiolated aptamer probe is adapted and immobilized onto an electrode surface. Introducing a recognition site for EcoRI into the aptamer sequence not only suppresses the peak current corresponding to blank sample but also provides a signal-on response mechanism. In the absence of adenosine, the aptamer can fold into a hairpin structure and form a cleavable double-stranded region. Fc is capable of being removed from electrode surface by treatment with endonuclease, and almost no peak current is observed. The adenosine/aptamer binding induces the conformational transition of designed aptamer, dissociating the cleavable double-stranded segment. Therefore, the integrated aptamer sequence is maintained when exposing to endonuclease, generating a peak current of Fc. Utilizing the present sensing scheme, adenosine even at a low concentration can give a detectable current signal. Thus, a detection limit of 10(-10) M and a linear response range from 3.74*10(-9) to 3.74*10(-5) M are achieved. The proposed proof-of-principle of a novel electrochemical sensing is expected to extend to establish various aptameric platforms for the analysis of a broad range of target molecules of interest. PMID- 20724442 TI - Essential structural requirements for specific recognition of HIV TAR RNA by peptide mimetics of Tat protein. AB - The pharmacological disruption of the interaction between the HIV Tat protein and its cognate transactivation response RNA (TAR) would generate novel anti-viral drugs with a low susceptibility to drug resistance, but efforts to discover ligands with sufficient potency to warrant pharmaceutical development have been unsuccessful. We have previously described a family of structurally constrained beta-hairpin peptides that potently inhibits viral growth in HIV-infected cells. The nuclear magnetic resonance (NMR) structure of an inhibitory complex revealed that the peptide makes intimate contacts with the 3-nt bulge and the upper helix of the RNA hairpin, but that a single residue contacts the apical loop where recruitment of the essential cellular co-factor cyclin T1 occurs. Attempting to extend the peptide to form more interactions with the RNA loop, we examined a library of longer peptides and achieved > 6-fold improvement in affinity. The structure of TAR bound to one of the extended peptides reveals that the peptide slides down the major groove of the RNA, relative to our design, in order to maintain critical interactions with TAR. These conserved contacts involve three amino acid side chains and identify critical interaction points required for potent and specific binding to TAR RNA. They constitute a template of essential interactions required for inhibition of this RNA. PMID- 20724443 TI - Characterization of an interplay between a Mycobacterium tuberculosis MazF homolog, Rv1495 and its sole DNA topoisomerase I. AB - The MazEF systems are thought to contribute to the capacity for long-term dormancy observed in the human pathogen, Mycobacterium tuberculosis. However, except for their functions as mRNA interferases, little is known regarding any additional cellular functions of these systems in the pathogen. In the present study, we observed a negative interplay between MazF protein Rv1495 and the sole M. tuberculosis DNA topoisomerase I (MtbTopA) with respect to protein functions. Through its C-terminal domain, MtbTopA physically interacted with and inhibited the mRNA cleavage activity of Rv1495. Rv1495, in turn, inhibited the DNA cleavage activity of MtbTopA as well as its function of relaxation of supercoiled DNA. An N-terminus fragment of Rv1495, designated Rv1495-N(29-56), lost mRNA cleavage activity, but retained a significant physical interaction and inhibitory effect on TopA proteins from both M. tuberculosis and M. smegmatis. This fragment, although less effective than the full-length protein, was able to inhibit mycobacterial growth when expressed through a recombinant plasmid in M. smegmatis. The Rv1495 physically interacted with the M. smegmatis TopA both in vitro and in vivo. Our findings imply that MazEF systems can affect bacterial survival by a novel mechanism that allows direct modulation of M. tuberculosis topoisomerase I. PMID- 20724444 TI - Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice. AB - Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles in nuclear genome maintenance. RNR is also essential for maintenance of mitochondrial DNA (mtDNA) in mammals. The mechanisms regulating mtDNA copy number in mammals are only being discovered. In budding yeast, RNR overexpression resulted in increased mtDNA levels, and rescued the disease phenotypes caused by a mutant mtDNA polymerase. This raised the question of whether mtDNA copy number increase by RNR induction could be a strategy for treating diseases with mtDNA mutations. We show here that high-level overexpression of RNR subunits (Rrm1, Rrm2 and p53R2; separately or in different combinations) in mice does not result in mtDNA copy number elevation. Instead, simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis. We also show that endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear mitochondrial crosstalk with regard to mtDNA copy number. Our results establish that RNR is not limiting for mtDNA copy number in mice, and provide new evidence for the importance of balanced dNTP pools in mtDNA maintenance in postmitotic tissues. PMID- 20724445 TI - Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. AB - PURPOSE: Aggressive fibromatoses (AF; desmoid tumors) are rare clonal neoplastic proliferations of connective tissues that can be locally aggressive despite wide surgical resection and/or radiation therapy. The Sarcoma Alliance for Research through Collaboration (SARC) initiated a prospective phase II trial to investigate the outcome of patients treated with imatinib, a multiple tyrosine kinase inhibitor, in patients with AF, or 1 of 10 sarcoma subtypes. Here, we report specifically on the outcome of patients with AF as well as evaluations undertaken to examine the mechanism of imatinib. EXPERIMENTAL DESIGN: Patients >=10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg twice daily [body surface area (BSA) >= 1.5 m(2)], 200 mg twice daily (BSA = 1.0-1.49 m(2)), or 100 mg twice daily (BSA < 1.0 m(2)). Response outcomes at 2 and 4 months were assessed. Tissue specimens were analyzed by immunohistochemistry for expression of cKIT, platelet derived growth factor receptor alpha (PDGFRalpha), PDGFRbeta, AKT, PTEN, FKHR, and beta-catenin. Tumor DNA was analyzed for PDGFRalpha exon 18 and APC mutations by allelic discrimination PCR. RESULTS: Fifty-one patients were enrolled. The median number of prior regimens was 1. Kaplan-Meier estimates of 2- and 4-month progression-free survival rates were 94% and 88%, respectively, and 1-year progression-free survival was 66%. Objective response rate was 6% (3 of 51). Expression and polymorphisms of target proteins were identified in tissue samples, but no significant correlation with outcome was observed using the samples available. CONCLUSION: Imatinib may have a role in the management of unresectable or difficult to resect desmoid tumors. PMID- 20724446 TI - Coordinated sequential action of EGFR and Notch signaling pathways regulates proneural wave progression in the Drosophila optic lobe. AB - During neurogenesis in the medulla of the Drosophila optic lobe, neuroepithelial cells are programmed to differentiate into neuroblasts at the medial edge of the developing optic lobe. The wave of differentiation progresses synchronously in a row of cells from medial to the lateral regions of the optic lobe, sweeping across the entire neuroepithelial sheet; it is preceded by the transient expression of the proneural gene lethal of scute [l(1)sc] and is thus called the proneural wave. We found that the epidermal growth factor receptor (EGFR) signaling pathway promotes proneural wave progression. EGFR signaling is activated in neuroepithelial cells and induces l(1)sc expression. EGFR activation is regulated by transient expression of Rhomboid (Rho), which is required for the maturation of the EGF ligand Spitz. Rho expression is also regulated by the EGFR signal. The transient and spatially restricted expression of Rho generates sequential activation of EGFR signaling and assures the directional progression of the differentiation wave. This study also provides new insights into the role of Notch signaling. Expression of the Notch ligand Delta is induced by EGFR, and Notch signaling prolongs the proneural state. Notch signaling activity is downregulated by its own feedback mechanism that permits cells at proneural states to subsequently develop into neuroblasts. Thus, coordinated sequential action of the EGFR and Notch signaling pathways causes the proneural wave to progress and induce neuroblast formation in a precisely ordered manner. PMID- 20724447 TI - Mouse Emi2 as a distinctive regulatory hub in second meiotic metaphase. AB - The oocytes of vertebrates are typically arrested at metaphase II (mII) by the cytostatic factor Emi2 until fertilization. Regulatory mechanisms in Xenopus Emi2 (xEmi2) are understood in detail but contrastingly little is known about the corresponding mechanisms in mammals. Here, we analyze Emi2 and its regulatory neighbours at the molecular level in intact mouse oocytes. Emi2, but not xEmi2, exhibited nuclear targeting. Unlike xEmi2, separable N- and C-terminal domains of mouse Emi2 modulated metaphase establishment and maintenance, respectively, through indirect and direct mechanisms. The C-terminal activity was mapped to the potential phosphorylation target Tx(5)SxS, a destruction box (D-box), a lattice of Zn(2+)-coordinating residues and an RL domain. The minimal region of Emi2 required for its cytostatic activity was mapped to a region containing these motifs, from residue 491 to the C terminus. The cytostatic factor Mos-MAPK promoted Emi2-dependent metaphase establishment, but Mos autonomously disappeared from meiotically competent mII oocytes. The N-terminal Plx1-interacting phosphodegron of xEmi2 was apparently shifted to within a minimal fragment (residues 51-300) of mouse Emi2 that also contained a calmodulin kinase II (CaMKII) phosphorylation motif and which was efficiently degraded during mII exit. Two equimolar CaMKII gamma isoform variants were present in mII oocytes, neither of which phosphorylated Emi2 in vitro, consistent with the involvement of additional factors. No evidence was found that calcineurin is required for mouse mII exit. These data support a model in which mammalian meiotic establishment, maintenance and exit converge upon a modular Emi2 hub via evolutionarily conserved and divergent mechanisms. PMID- 20724448 TI - The ubiquitin proteasome system is required for cell proliferation of the lens epithelium and for differentiation of lens fiber cells in zebrafish. AB - In the developing vertebrate lens, epithelial cells differentiate into fiber cells, which are elongated and flat in shape and form a multilayered lens fiber core. In this study, we identified the zebrafish volvox (vov) mutant, which shows defects in lens fiber differentiation. In the vov mutant, lens epithelial cells fail to proliferate properly. Furthermore, differentiating lens fiber cells do not fully elongate, and the shape and position of lens fiber nuclei are affected. We found that the vov mutant gene encodes Psmd6, the subunit of the 26S proteasome. The proteasome regulates diverse cellular functions by degrading polyubiquitylated proteins. Polyubiquitylated proteins accumulate in the vov mutant. Furthermore, polyubiquitylation is active in nuclei of differentiating lens fiber cells, suggesting roles of the proteasome in lens fiber differentiation. We found that an E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is involved in lens defects in the vov mutant. These data suggest that the ubiquitin proteasome system is required for cell proliferation of lens epithelium and for the differentiation of lens fiber cells in zebrafish. PMID- 20724449 TI - Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. AB - Mice carrying mutations in Wise (Sostdc1) display defects in many aspects of tooth development, including tooth number, size and cusp pattern. To understand the basis of these defects, we have investigated the pathways modulated by Wise in tooth development. We present evidence that, in tooth development, Wise suppresses survival of the diastema or incisor vestigial buds by serving as an inhibitor of Lrp5- and Lrp6-dependent Wnt signaling. Reducing the dosage of the Wnt co-receptor genes Lrp5 and Lrp6 rescues the Wise-null tooth phenotypes. Inactivation of Wise leads to elevated Wnt signaling and, as a consequence, vestigial tooth buds in the normally toothless diastema region display increased proliferation and continuous development to form supernumerary teeth. Conversely, gain-of-function studies show that ectopic Wise reduces Wnt signaling and tooth number. Our analyses demonstrate that the Fgf and Shh pathways are major downstream targets of Wise-regulated Wnt signaling. Furthermore, our experiments revealed that Shh acts as a negative-feedback regulator of Wnt signaling and thus determines the fate of the vestigial buds and later tooth patterning. These data provide insight into the mechanisms that control Wnt signaling in tooth development and into how crosstalk among signaling pathways controls tooth number and morphogenesis. PMID- 20724450 TI - Hand2 ensures an appropriate environment for cardiac fusion by limiting Fibronectin function. AB - Heart formation requires the fusion of bilateral cardiomyocyte populations as they move towards the embryonic midline. The bHLH transcription factor Hand2 is essential for cardiac fusion; however, the effector genes that execute this function of Hand2 are unknown. Here, we provide in zebrafish the first evidence for a downstream component of the Hand2 pathway that mediates cardiac morphogenesis. Although hand2 is expressed in cardiomyocytes, mosaic analysis demonstrates that it plays a non-autonomous role in regulating cardiomyocyte movement. Gene expression profiles reveal heightened expression of fibronectin 1 (fn1) in hand2 mutant embryos. Reciprocally, overexpression of hand2 leads to decreased Fibronectin levels. Furthermore, reduction of fn1 function enables rescue of cardiac fusion in hand2 mutants: bilateral cardiomyocyte populations merge and exhibit improved tissue architecture, albeit without major changes in apicobasal polarity. Together, our data provide a novel example of a tissue creating a favorable environment for its morphogenesis: the Hand2 pathway establishes an appropriate environment for cardiac fusion through negative modulation of Fn1 levels. PMID- 20724452 TI - miR-18, a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis. AB - miR-18 belongs to the Oncomir-1 or miR-17~92 cluster that is intimately associated with the occurrence and progression of different types of cancer. However, the physiological roles of the Oncomir-1 cluster and its individual miRNAs are largely unknown. Here, we describe a novel function for miR-18 in mouse. We show that miR-18 directly targets heat shock factor 2 (HSF2), a transcription factor that influences a wide range of developmental processes including embryogenesis and gametogenesis. Furthermore, we show that miR-18 is highly abundant in testis, displaying distinct cell-type-specific expression during the epithelial cycle that constitutes spermatogenesis. Expression of HSF2 and of miR-18 exhibit an inverse correlation during spermatogenesis, indicating that, in germ cells, HSF2 is downregulated by miR-18. To investigate the in vivo function of miR-18 we developed a novel method, T-GIST, and demonstrate that inhibition of miR-18 in intact seminiferous tubules leads to increased HSF2 protein levels and altered expression of HSF2 target genes. Our results reveal that miR-18 regulates HSF2 activity in spermatogenesis and link miR-18 to HSF2 mediated physiological processes such as male germ cell maturation. PMID- 20724451 TI - Drosophila ataxin 2-binding protein 1 marks an intermediate step in the molecular differentiation of female germline cysts. AB - In the Drosophila ovary, extrinsic signaling from the niche and intrinsic translational control machinery regulate the balance between germline stem cell maintenance and the differentiation of their daughters. However, the molecules that promote the continued stepwise development of ovarian germ cells after their exit from the niche remain largely unknown. Here, we report that the early development of germline cysts depends on the Drosophila homolog of the human ataxin 2-binding protein 1 (A2BP1) gene. Drosophila A2BP1 protein expression is first observed in the cytoplasm of 4-, 8- and 16-cell cysts, bridging the expression of the early differentiation factor Bam with late markers such as Orb, Rbp9 and Bruno encoded by arrest. The expression of A2BP1 is lost in bam, sans fille (snf) and mei-P26 mutants, but is still present in other mutants such as rbp9 and arrest. A2BP1 alleles of varying strength produce mutant phenotypes that include germline counting defects and cystic tumors. Phenotypic analysis reveals that strong A2BP1 alleles disrupt the transition from mitosis to meiosis. These mutant cells continue to express high levels of mitotic cyclins and fail to express markers of terminal differentiation. Biochemical analysis reveals that A2BP1 isoforms bind to each other and associate with Bruno, a known translational repressor protein. These data show that A2BP1 promotes the molecular differentiation of ovarian germline cysts. PMID- 20724453 TI - Recognition of pre- and postsynaptic neurons via nephrin/NEPH1 homologs is a basis for the formation of the Drosophila retinotopic map. AB - Topographic maps, which maintain the spatial order of neurons in the order of their axonal connections, are found in many parts of the nervous system. Here, we focus on the communication between retinal axons and their postsynaptic partners, lamina neurons, in the first ganglion of the Drosophila visual system, as a model for the formation of topographic maps. Post-mitotic lamina precursor cells differentiate upon receiving Hedgehog signals delivered through newly arriving retinal axons and, before maturing to extend neurites, extend short processes toward retinal axons to create the lamina column. The lamina column provides the cellular basis for establishing stereotypic synapses between retinal axons and lamina neurons. In this study, we identified two cell-adhesion molecules: Hibris, which is expressed in post-mitotic lamina precursor cells; and Roughest, which is expressed on retinal axons. Both proteins belong to the nephrin/NEPH1 family. We provide evidence that recognition between post-mitotic lamina precursor cells and retinal axons is mediated by interactions between Hibris and Roughest. These findings revealed mechanisms by which axons of presynaptic neurons deliver signals to induce the development of postsynaptic partners at the target area. Postsynaptic partners then recognize the presynaptic axons to make ensembles, thus establishing a topographic map along the anterior/posterior axis. PMID- 20724454 TI - Commentary: postpartum vitamin A supplementation and infant mortality. PMID- 20724455 TI - War-related stress exposure and mortality: a meta-analysis. AB - BACKGROUND: Domestic and international wars continue to be pervasive in the 21st century. This study summarizes the effects of war-related stress on all-cause mortality using meta-analyses and meta-regressions. METHODS: A keyword search was performed, supplemented by extensive iterative hand-searches for observational studies of war-related stress and mortality. Two hundred and twenty mortality risk estimates from 30 studies were extracted, providing data on more than 9 million persons. RESULTS: The mean hazard ratio (HR) was 1.05 [95% confidence interval (CI) 0.98-1.13] among HRs adjusted for age and additional covariates. The mean effect for men was 1.14 (CI 1.00-1.31), and for women it was 0.92 (CI 0.66-1.28). No differences were found for various follow-up durations or for various types of war stress. Neither civilians nor military personnel had an elevated mortality risk. Those exposed to a combat zone during the Vietnam War had a slightly higher chance of death (HR 1.11; 95% CI 1.00-1.23). CONCLUSIONS: The results show that, over all, exposure to war-stress did not increase the risk of death when studies were well controlled. Effects were small when found. This lack of substantial effect may be the result of selection processes, developed resiliency and/or institutional support. PMID- 20724457 TI - Perspectives on presentation and pedagogy in aid of bioinformatics education. AB - Using live presentation to communicate the interdisciplinary and abstract content of bioinformatics to its educationally diverse studentship is a sizeable challenge. This review collects a number of perspectives on multimedia presentation, visual communication and pedagogy. The aim is to encourage educators to reflect on the great potential of live presentation in facilitating bioinformatics education. PMID- 20724456 TI - Kinetic basis for global loss of fidelity arising from mismatches in the P-site codon:anticodon helix. AB - Faithful decoding of the genetic information by the ribosome relies on kinetically driven mechanisms that promote selection of cognate substrates during elongation. Recently, we have shown that in addition to these kinetically driven mechanisms, the ribosome possesses a post peptidyl transfer quality control system that retrospectively monitors the codon-anticodon interaction in the P site, triggering substantial losses in the specificity of the A site during subsequent tRNA and RF selection when a mistake has occurred. Here, we report a detailed kinetic analysis of tRNA selection in the context of a mismatched P-site codon:anticodon interaction. We observe pleiotropic effects of a P-site mismatch on tRNA selection, such that near-cognate tRNA is processed by the ribosome almost as efficiently as cognate. In particular, after a miscoding event, near cognate codon-anticodon complexes are stabilized on the ribosome to an extent similar to that observed for cognate ones. Moreover, the two observed forward rates of GTPase activation and accommodation are greatly accelerated (~10-fold) for near-cognate tRNAs. Because the ensemble of effects of a mismatched P site on substrate selection were found to be different from those reported for other ribosomal perturbations and miscoding agents, we propose that the structural integrity of the mRNA-tRNA helix in the P site provides a distinct molecular switch that dictates the specificity of the A site. PMID- 20724458 TI - De novo assembly of short sequence reads. AB - A new generation of sequencing technologies is revolutionizing molecular biology. Illumina's Solexa and Applied Biosystems' SOLiD generate gigabases of nucleotide sequence per week. However, a perceived limitation of these ultra-high-throughput technologies is their short read-lengths. De novo assembly of sequence reads generated by classical Sanger capillary sequencing is a mature field of research. Unfortunately, the existing sequence assembly programs were not effective for short sequence reads generated by Illumina and SOLiD platforms. Early studies suggested that, in principle, sequence reads as short as 20-30 nucleotides could be used to generate useful assemblies of both prokaryotic and eukaryotic genome sequences, albeit containing many gaps. The early feasibility studies and proofs of principle inspired several bioinformatics research groups to implement new algorithms as freely available software tools specifically aimed at assembling reads of 30-50 nucleotides in length. This has led to the generation of several draft genome sequences based exclusively on short sequence Illumina sequence reads, recently culminating in the assembly of the 2.25-Gb genome of the giant panda from Illumina sequence reads with an average length of just 52 nucleotides. As well as reviewing recent developments in the field, we discuss some practical aspects such as data filtering and submission of assembly data to public repositories. PMID- 20724459 TI - Cumulus cell gene expression following the LH surge in bovine preovulatory follicles: potential early markers of oocyte competence. AB - Cumulus cells (CCs) are essential for oocytes to reach full development competency and become fertilized. Many major functional properties of CCs are triggered by gonadotropins and governed by the oocyte. Consequently, cumulus may reflect oocyte quality and is often used for oocyte selection. The most visible function of CCs is their ability for rapid extracellular matrix expansion after the LH surge. Although unexplained, LH induces the final maturation and improves oocyte quality. To study the LH signaling and gene expression cascade patterns close to the germinal vesicle breakdown, bovine CCs collected at 2 h before and 6 h after the LH surge were hybridized to a custom-made microarray to better understand the LH genomic action and find differentially expressed genes associated with the LH-induced oocyte final maturation. Functional genomic analysis of the 141 overexpressed and 161 underexpressed clones was performed according to their molecular functions, gene networks, and cell compartments. Following real-time PCR validation of our gene lists, some interesting pathways associated with the LH genomic action on CCs and their possible roles in oocyte final maturation, ovulation, and fertilization are discussed. A list of early potential markers of oocyte competency in vivo and in vitro is thereafter suggested. These early biomarkers are a preamble to understand the LH molecular pathways that trigger the final oocyte competence acquisition process in bovine. PMID- 20724460 TI - Rapid extravasation and establishment of breast cancer micrometastases in the liver microenvironment. AB - To examine the interplay between tumor cells and the microenvironment during early breast cancer metastasis, we developed a technique for ex vivo imaging of murine tissue explants using two-photon microscopy. Cancer cells in the liver and the lung were compared by imaging both organs at specific time points after the injection of the same polyomavirus middle T-initiated murine mammary tumor cell line. Extravasation was greatly reduced in the lung compared with the liver, with 56% of tumor cells in the liver having extravasated by 24 hours, compared with only 22% of tumor cells in the lung that have extravasated. In the liver, imaged cells continually transitioned from an intravascular location to an extravascular site, whereas in the lung, extravasation rates slowed after 6 hours. Within the liver microenvironment, the average size of the imaged micrometastatic lesions increased 4-fold between days 5 and 12. Histologic analysis of these lesions determined that by day 12, the micrometastases were heterogeneous, consisting of both tumor cells and von Willebrand factor-positive endothelial cells. Further analysis with intravenously administered lectin indicated that vessels within the micrometastatic tumor foci were patent by day 12. These data present the use of two-photon microscopy to directly compare extravasation times in metastatic sites using the same tumor cell line and highlight the differences in early events and metastatic patterns between two important secondary sites of breast cancer progression with implications for future therapy. PMID- 20724461 TI - Estrogen and progesterone receptor status affect genome-wide DNA methylation profile in breast cancer. AB - DNA methylation is the main epigenetic modification that occurs at the early stages of carcinogenesis. We performed a genome-wide DNA methylation profiling to evaluate whether the DNA methylation state is different in the estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer. Twelve ER+/PR+ and 12 ER-/PR- breast cancer tissues were selected from the biorepository of the Seoul Breast Cancer Study for Infinium Methylation Assay. The difference of the DNA methylation state of 27 578 methylation sites in 14 000 genes between two groups was evaluated by Student's t-test. False discovery rate (FDR) was estimated to evaluate the probability of false positive associations. Of the 27 578 sites, 148 sites (0.54%) were significantly different between ER+/PR+ and ER /PR- breast cancers (P < 0.001); 93 hypermethylated and 55 hypomethylated. Five genes, FAM124B (P = 7.26 * 10(-7)), MANEAL (P = 3.38 * 10(-7)), ST6GALNAC1 (P = 2.85 * 10(-6)), NAV1 (P = 5.94 * 10(-6)) and PER1 (P = 6.45 * 10(-6)) remained significant after correction for multiple tests (FDR < 0.05). In a subsequent replication study for five genes, four of the five genes were validated; FAM124B and ST6GALNAC1 were significantly hypermethylated, and NAV1 and PER1 were significantly hypomethylated in ER+/PR+ breast cancers (P < 0.05). In the first genome-wide DNA methylation profiling according to the receptor status of breast cancer, we found that ER/PR status affects the DNA methylation state of FAM124B, ST6GALNAC1, NAV1 and PER1 in breast cancer. PMID- 20724462 TI - A nonthiazolidinedione peroxisome proliferator-activated receptor alpha/gamma dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice. AB - Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPARalpha agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPARgamma agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPARalpha/gamma dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPARalpha/gamma dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPARalpha/gamma dual agonist, (R)-1-(4-(2-(5-methyl-2-p tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPARalpha and PPARgamma and induced expression of their target genes in a PPARalpha- and PPARgamma-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPARalpha/gamma agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia. PMID- 20724463 TI - Evaluation of ThoraQuik: a new device for the treatment of pneumothorax and pleural effusion. AB - BACKGROUND: ThoraQuik is a device with a unique design incorporating an aspiration port and one-way valve controlled by a three-way tap, fit for purpose for the treatment of pneumothorax and pleural effusion. Its use, safety and efficacy were evaluated in a prospective observational trial. METHODS: Stage 1: The safety and ability of the device to penetrate the chest wall and the ease of use were evaluated in patients undergoing thoracoscopic procedures by introducing the device at a second port site under vision. Stage 2: The device was evaluated on patients with pneumothorax and pleural effusion. Clinical and radiological improvement were endpoints and operator feedback was evaluated. RESULTS: Phase 1: 10 patients (mean age: 48.5 years (18-76 years) six men) were studied between May 2005 and March 2007. Satisfactory penetration of the chest wall and safe entry in the pleural space was achieved. Phase 2: 20 patients (mean age: 59 years (24-81 years) 13 men) were recruited between May 2007 and May 2008. 10 patients presented with pneumothorax (tension pneumothorax, n=1) and 10 had pleural effusions. One patient withdrew consent and another patient was withdrawn as there was no fluid on trial aspiration. Of the 18 who completed the study, 10/18 had partial and 7/18 patients had complete resolution with no change in one. The qualitative assessments of the ThoraQuik in terms of ease of use and utility were positive. CONCLUSIONS: ThoraQuik achieves satisfactory penetration of the chest wall. It was safe and easy to use to manage pneumothoraces and pleural effusions. PMID- 20724464 TI - A pain in the foot. PMID- 20724465 TI - On-scene times and critical care interventions for an aeromedical retrieval service. AB - BACKGROUND: The Emergency Medical Retrieval Service (EMRS) provides an aeromedical retrieval service to remote and rural communities. Most of these facilities are unable to deliver Critical Care Interventions (CCI). CCI are delivered by the EMRS team prior to transfer of the patient to definitive care. This study addresses correlation between total on-scene times (TOST) and level of intervention delivered, and whether there is any variation in TOST between medical and trauma emergencies. METHODS: Prospective data were collected on EMRS secondary retrievals over a 5-year period from GP-led facilities. Data were collected on the CCI undertaken by EMRS during TOST prior to transfer of the patient. Interventions undertaken were scored using TISS-76. Correlation was analysed using Spearman's coefficient and differences between groups analysed using Mann-Whitney tests. Statistical significance was defined as p<0.01. RESULTS: EMRS retrieved 308 patients suitable for inclusion. Complete data were available for 97% of patients (n=300). Underlying diagnosis was trauma in 26% (n=72) and medical in 74% (n=228). There was a significant correlation between TOST and TISS-76 for all EMRS patients. Spearman's coefficient of rank correlation was (rho)=0.616 with p<0.0001. The median TOST for the medical group was 60 min and for the trauma group 60 min (point estimate for difference 0 min, 95% CI 10 to 10, p=0.951). CONCLUSION: This study demonstrates a significant relationship between TOST on-scene by the retrieval team and the level of intervention delivered to patients. The present data do not support the assertion that there is a difference in TOST for medical and trauma patients. PMID- 20724466 TI - Emergency department-focused thrombolysis for acute ischaemic stroke. AB - Acute ischaemic stroke (AIS) is a leading cause of death and disability. Until the 1990s early intervention in AIS was limited to prevention of secondary brain injury. Early thrombolysis has now become standard practice in many areas of the world. Despite the evidence of benefit, the lack of good alternative acute treatments and the recent shift in political focus to stroke management, a thrombolytic strategy for AIS has been very slow to develop in the UK. In this paper, the successful introduction of thrombolysis for AIS through the development of an emergency department-focused process is reported. Obstacles to service development and ways to overcome these are discussed and this therapeutic process is demonstrated to be both possible and self-sustaining in most UK hospitals. PMID- 20724467 TI - Variability in the 3,4-methylenedioxymethamphetamine content of 'ecstasy' tablets in the UK. AB - BACKGROUND: Toxicity, such as hyperpyrexia, associated with the use of 3,4 methylenedioxymethamphetamine (MDMA; 'ecstasy') appears to be related to serum MDMA concentrations. However, there does not appear to be a similar association with the number of tablets ingested, suggesting variation in the tablet content of MDMA. Although work has shown this variation in other areas of the world, no studies have reported on the variation of MDMA content in UK ecstasy tablets. METHODS: Ecstasy tablets seized from individuals attending nightclubs were analysed qualitatively to determine if they contained MDMA and quantitatively to determine the MDMA content per tablet. RESULTS: The mean amount of MDMA hydrochloride in 101 seized ecstasy tablets was 58.7+/-22.9 mg per tablet, with a range of 20 mg to 131 mg per tablet. The majority (96.0%) of tablets contained less than 100 mg MDMA per tablet. There appeared to be a bimodal distribution of MDMA content at approximately 20-40 mg per tablet and 60-80 mg per tablet. CONCLUSION: There is variability in the MDMA content of ecstasy tablets in the UK. This variability could potentially put users at increased risk of acute harm due to inadvertent excess ingestion of MDMA, as they are unaware of the differences in the MDMA content. Repeat sampling and quantification of MDMA content of ecstasy tablets in the UK will allow better education of users about the potential harms associated with the variability in the MDMA content. In addition, it will provide information to allow the monitoring of changes in not only the MDMA content, but also other adulterants, in ecstasy tablets. PMID- 20724468 TI - Characterization of HACD1 K64Q mutant found in arrhythmogenic right ventricular dysplasia patients. AB - Arrhythmogenic right ventricular dysplasia (ARVD) is an autosomal dominant heart disease. A K64Q mutation was found in ARVD-affected individuals in the HACD1 gene, which encodes an enzyme involved in very long-chain fatty acid (VLCFA) elongation, although any relationship between mutation and pathology remained unclear. Here, we demonstrate that HACD1 (K64Q) exhibits normal enzyme activity, intracellular localization and interaction with other VLCFA enzymes, with no dominant negative effect on VLCFA elongation. Thus, it appears unlikely that this mutation is ARVD-causative. Moreover, through these analyses we found that HACD1 interacts with KAR and TER, the reductase enzymes involved in the second and fourth VLCFA elongation cycle, respectively. This finding indicates that the enzymes responsible for the VLCFA elongation cycle form an elongase complex. PMID- 20724469 TI - Discovery and verification of osteopontin and Beta-2-microglobulin as promising markers for staging human African trypanosomiasis. AB - Human African trypanosomiasis, or sleeping sickness, is a parasitic disease endemic in sub-Saharan Africa, transmitted to humans through the bite of a tsetse fly. The first or hemolymphatic stage of the disease is associated with presence of parasites in the bloodstream, lymphatic system, and body tissues. If patients are left untreated, parasites cross the blood-brain barrier and invade the cerebrospinal fluid and the brain parenchyma, giving rise to the second or meningoencephalitic stage. Stage determination is a crucial step in guiding the choice of treatment, as drugs used for S2 are potentially dangerous. Current staging methods, based on counting white blood cells and demonstrating trypanosomes in cerebrospinal fluid, lack specificity and/or sensitivity. In the present study, we used several proteomic strategies to discover new markers with potential for staging human African trypanosomiasis. Cerebrospinal fluid (CSF) samples were collected from patients infected with Trypanosoma brucei gambiense in the Democratic Republic of Congo. The stage was determined following the guidelines of the national control program. The proteome of the samples was analyzed by two-dimensional gel electrophoresis (n = 9), and by sixplex tandem mass tag (TMT) isobaric labeling (n = 6) quantitative mass spectrometry. Overall, 73 proteins were overexpressed in patients presenting the second stage of the disease. Two of these, osteopontin and beta-2-microglobulin, were confirmed to be potential markers for staging human African trypanosomiasis (HAT) by Western blot and ELISA. The two proteins significantly discriminated between S1 and S2 patients with high sensitivity (68% and 78%, respectively) for 100% specificity, and a combination of both improved the sensitivity to 91%. The levels of osteopontin and beta-2-microglobulin in CSF of S2 patients (MUg/ml range), as well as the fold increased concentration in S2 compared with S1 (3.8 and 5.5 respectively) make the two markers good candidates for the development of a test for staging HAT patients. PMID- 20724470 TI - Reduction in Ki-67 in benign breast tissue of high-risk women with the lignan secoisolariciresinol diglycoside. AB - Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a >3-fold increase in 5-year risk, and baseline Ki-67 of >=2% in areas of hyperplasia in breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG (50 mg/d) was given for 12 months, followed by repeat RPFNA. The primary end point was change in Ki-67. Secondary end points included change in cytomorphology, mammographic breast density, serum bioavailable estradiol and testosterone insulin-like growth factor I and IGF-binding protein-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ~9-fold, and total lignans increased 16-fold. Thirty-six (80%) of the 45 evaluable subjects showed a decrease in Ki-67, from a median of 4% (range, 2-16.8%) to 2% (range, 0-15.2%; P < 0.001, Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (P = 0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG versus placebo in premenopausal women. PMID- 20724471 TI - Glycan analysis and influenza A virus infection of primary swine respiratory epithelial cells: the importance of NeuAc{alpha}2-6 glycans. AB - To better understand influenza virus infection of pigs, we examined primary swine respiratory epithelial cells (SRECs, the primary target cells of influenza viruses in vivo), as a model system. Glycomic profiling of SRECs by mass spectrometry revealed a diverse range of glycans terminating in sialic acid or GalalphaGal. In terms of sialylation, alpha2-6 linkage was more abundant than alpha2-3, and NeuAc was more abundant than NeuGc. Virus binding and infection experiments were conducted to determine functionally important glycans for influenza virus infection, with a focus on recently emerged swine viruses. Infection of SRECs with swine and human viruses resulted in different infectivity levels. Glycan microarray analysis with a high infectivity "triple reassortant" virus ((A/Swine/MN/593/99 (H3N2)) that spread widely throughout the North American swine population and a lower infectivity human virus isolated from a single pig (A/Swine/ONT/00130/97 (H3N2)) showed that both viruses bound exclusively to glycans containing NeuAcalpha2-6, with strong binding to sialylated polylactosamine and sialylated N-glycans. Treatment with mannosamine precursors of sialic acid (to alter NeuAc/NeuGc abundances) and linkage-specific sialidases prior to infection indicated that the influenza viruses tested preferentially utilize NeuAcalpha2-6-sialylated glycans to infect SRECs. Our data indicate that NeuAcalpha2-6-terminated polylactosamine and sialylated N-glycans are important determinants for influenza viruses to infect SRECs. As NeuAcalpha2 6 polylactosamine glycans play major roles in human virus infection, the importance of these receptor components in virus infection of swine cells has implications for transmission of viruses between humans and pigs and for pigs as possible adaptation hosts of novel human influenza viruses. PMID- 20724472 TI - Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. AB - Organogenesis is a highly integrated process with a fundamental requirement for precise cell cycle control. Mechanistically, the cell cycle is composed of transitions and thresholds that are controlled by coordinated post-translational modifications. In this study, we describe a novel mechanism controlling the persistence of the transcription factor ATF4 by multisite phosphorylation. Proline-directed phosphorylation acted additively to regulate multiple aspects of ATF4 degradation. Stabilized ATF4 mutants exhibit decreased beta-TrCP degron phosphorylation, beta-TrCP interaction, and ubiquitination, as well as elicit early G(1) arrest. Expression of stabilized ATF4 also had significant consequences in the developing neocortex. Mutant ATF4 expressing cells exhibited positioning and differentiation defects that were attributed to early G(1) arrest, suggesting that neurogenesis is sensitive to ATF4 dosage. We propose that precise regulation of the ATF4 dosage impacts cell cycle control and impinges on neurogenesis. PMID- 20724473 TI - 2E8 binds to the high affinity I-domain in a metal ion-dependent manner: a second generation monoclonal antibody selectively targeting activated LFA-1. AB - The activation of leukocyte function-associated antigen-1 (LFA-1) plays a critical role in regulating immune responses. The metal ion-dependent adhesion site on the I-domain of LFA-1 alpha(L) subunit is the key recognition site for ligand binding. Upon activation, conformation changes in the I-domain can lead LFA-1 from the low affinity state to the high affinity (HA) state. Using the purified HA I-domain locked by disulfide bonds for immunization, we developed an mAb, 2E8, that specifically binds to cells expressing the HA LFA-1. The surface plasmon resonance analysis has shown that 2E8 only binds to the HA I-domain and that the dissociation constant (K(D)) for HA I-domain is 197 nm. The binding of 2E8 to the HA I-domain is metal ion-dependent, and the affinity decreased as Mn(2+) was replaced sequentially by Mg(2+) and Ca(2+). Surface plasmon resonance analysis demonstrates that 2E8 inhibits the interaction of HA I-domain and ICAM 1. Furthermore, we found that 2E8 can detect activated LFA-1 on both JY and Jurkat cells using flow cytometry and parallel plate adhesion assay. In addition, 2E8 inhibits JY cell adhesion to human umbilical vein endothelial cells and homotypic aggregation. 2E8 treatment reduces the proliferation of both human CD4(+) and CD8(+) T cells upon OKT3 stimulation without the impairment of their cytolytic function. Taken together, these data demonstrate that 2E8 is specific for the high affinity form of LFA-1 and that 2E8 inhibits LFA-1/ICAM-1 interactions. As a novel activation-specific monoclonal antibody, 2E8 is a potentially useful reagent for blocking high affinity LFA-1 and modulating T cell activation in research and therapeutics. PMID- 20724474 TI - The Sll0606 protein is required for photosystem II assembly/stability in the cyanobacterium Synechocystis sp. PCC 6803. AB - An insertional transposon mutation in the sll0606 gene was found to lead to a loss of photoautotrophy but not photoheterotrophy in the cyanobacterium Synechocystis sp. PCC 6803. Complementation analysis of this mutant (Tsll0606) indicated that an intact sll0606 gene could fully restore photoautotrophic growth. Gene organization in the vicinity of sll0606 indicates that it is not contained in an operon. No electron transport activity was detected in Tsll0606 using water as an electron donor and 2,6-dichlorobenzoquinone as an electron acceptor, indicating that Photosystem II (PS II) was defective. Electron transport activity using dichlorophenol indolephenol plus ascorbate as an electron donor to methyl viologen, however, was the same as observed in the control strain. This indicated that electron flow through Photosystem I was normal. Fluorescence induction and decay parameters verified that Photosystem II was highly compromised. The quantum yield for energy trapping by Photosystem II (F(V)/F(M)) in the mutant was less than 10% of that observed in the control strain. The small variable fluorescence yield observed after a single saturating flash exhibited aberrant Q(A)(-) reoxidation kinetics that were insensitive to dichloromethylurea. Immunological analysis indicated that whereas the D2 and CP47 proteins were modestly affected, the D1 and CP43 components were dramatically reduced. Analysis of two-dimensional blue native/lithium dodecyl sulfate polyacrylamide gels indicated that no intact PS II monomer or dimers were observed in the mutant. The CP43-less PS II monomer did accumulate to detectable levels. Our results indicate that the Sll0606 protein is required for the assembly/stability of a functionally competent Photosystem II. PMID- 20724475 TI - Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK. AB - EGF-induced activation of ERK has been extensively studied by both experimental and theoretical approaches. Here, we used a simulation model based mostly on experimentally determined parameters to study the ERK-mediated negative feedback regulation of the Ras guanine nucleotide exchange factor, son of sevenless (SOS). Because SOS1 is phosphorylated at multiple serine residues upon stimulation, we evaluated the role of the multiplicity by building two simulation models, which we termed the decisive and cooperative phosphorylation models. The two models were constrained by the duration of Ras activation and basal phosphorylation level of SOS1. Possible solutions were found only in the decisive model wherein at least three, and probably more than four, phosphorylation sites decisively suppress the SOS activity. Thus, the combination of experimental approaches and the model analysis has suggested an unexpected role of multiple phosphorylations of SOS1 in the negative regulation. PMID- 20724476 TI - p38 MAP kinase and MAPKAP kinases MK2/3 cooperatively phosphorylate epithelial keratins. AB - The MAPK-activated protein kinases (MAPKAP kinases) MK2 and MK3 are directly activated via p38 MAPK phosphorylation, stabilize p38 by complex formation, and contribute to the stress response. The list of substrates of MK2/3 is increasing steadily. We applied a phosphoproteomics approach to compare protein phosphorylation in MK2/3-deficient cells rescued or not by ectopic expression of MK2. In addition to differences in phosphorylation of the known substrates of MK2, HSPB1 and Bag-2, we identified strong differences in phosphorylation of keratin 8 (K8). The phosphorylation of K8-Ser(73) is catalyzed directly by p38, which in turn shows MK2-dependent expression. Notably, analysis of small molecule p38 inhibitors on K8-Ser(73) phosphorylation also demonstrated reduced phosphorylations of keratins K18-Ser(52) and K20-Ser(13) but not of K8-Ser(431) or K18-Ser(33). Interestingly, K18-Ser(52) and K20-Ser(13) are not directly phosphorylated by p38 in vitro, but by MK2. Furthermore, anisomycin-stimulated phosphorylations of K20-Ser(13) and K18-Ser(52) are inhibited by small molecule inhibitors of both p38 and MK2. MK2 knockdown in HT29 cells leads to reduced K20 Ser(13) phosphorylation, which further supports the notion that MK2 is responsible for K20 phosphorylation in vivo. Physiologic relevance of these findings was confirmed by differences of K20-Ser(13) phosphorylation between the ileum of wild-type and MK2/3-deficient mice and by demonstrating p38- and MK2 dependent mucin secretion of HT29 cells. Therefore, MK2 and p38 MAPK function in concert to phosphorylate K8, K18, and K20 in intestinal epithelia. PMID- 20724477 TI - Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF 1alpha protein. AB - Carbon monoxide (CO) plays a significant role in vascular functions. We here examined the molecular mechanism by which CO regulates HIF-1 (hypoxia-inducible transcription factor-1)-dependent expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. We found that astrocytes stimulated with CORM-2 (CO-releasing molecule) promoted angiogenesis by increasing VEGF expression and secretion. CORM-2 also induced HO-1 (hemeoxygenase 1) expression and increased nuclear HIF-1alpha protein level, without altering its promoter activity and mRNA level. VEGF expression was inhibited by treatment with HIF-1alpha siRNA and a hemeoxygenase inhibitor, indicating that CO stimulates VEGF expression via up-regulation of HIF-1alpha protein level, which is partially associated with HO-1 induction. CORM-2 activated the translational regulatory proteins p70(S6k) and eIF-4E as well as phosphorylating their upstream signal mediators Akt and ERK. These translational signal events and HIF-1alpha protein level were suppressed by inhibitors of phosphatidylinositol 3-kinase (PI3K), MEK, and mTOR, suggesting that the PI3K/Akt/mTOR and MEK/ERK pathways are involved in a translational increase in HIF-1alpha. In addition, CORM-2 also increased stability of the HIF-1alpha protein by suppressing its ubiquitination, without altering the proline hydroxylase-dependent HIF-1alpha degradation pathway. CORM-2 increased HIF-1alpha/HSP90alpha interaction, which is responsible for HIF-1alpha stabilization, and HSP90-specific inhibitors decreased this interaction, HIF-1alpha protein level, and VEGF expression. Furthermore, HSP90alpha knockdown suppressed CORM-2-induced increases in HIF-1alpha and VEGF protein levels. These results suggest that CO stimulates VEGF production by increasing HIF-1alpha protein level via two distinct mechanisms, translational stimulation and protein stabilization of HIF-1alpha. PMID- 20724478 TI - Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. AB - The NAD rescue pathway consists of two enzymatic steps operated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide mononucleotide adenylyltransferases. Recently, the potent Nampt inhibitor FK866 has been identified and evaluated in clinical trials against cancer. Yet, how Nampt inhibition affects NAD contents and bioenergetics is in part obscure. It is also unknown whether NAD rescue takes place in mitochondria, and FK866 alters NAD homeostasis within the organelle. Here, we show that FK866-dependent reduction of the NAD contents is paralleled by a concomitant increase of ATP in various cell types, in keeping with ATP utilization for NAD resynthesis. We also show that poly- and mono(ADP-ribose) transferases rather than Sirt-1 are responsible for NAD depletion in HeLa cells exposed to FK866. Mass spectrometry reveals that the drug distributes in the cytosolic and mitochondrial compartment. However, the cytoplasmic but not the mitochondrial NAD pool is reduced upon acute or chronic exposure to the drug. Accordingly, Nampt does not localize within the organelles and their bioenergetics is not affected by the drug. In the mouse, FK866 dependent reduction of NAD contents in various organs is prevented by inhibitors of poly(ADP-ribose) polymerases or the NAD precursor kynurenine. For the first time, our data indicate that mitochondria lack the canonical NAD rescue pathway, broadening current understanding of cellular bioenergetics. PMID- 20724479 TI - Structure of human stabilin-1 interacting chitinase-like protein (SI-CLP) reveals a saccharide-binding cleft with lower sugar-binding selectivity. AB - Human secreted protein stabilin-1 interacting chitinase-like protein (SI-CLP) has been identified as a novel member of Glyco_18 domain-containing proteins that is involved in host defense and inflammatory reactions. Efficient secretion of SI CLP is mediated by its interaction with the endocytic/sorting receptor stabilin 1. SI-CLP is expressed abundantly in macrophages and neutrophils and is up regulated by Th2 cytokine IL-4 and glucocorticoid, which suggest that SI-CLP could be a marker for adverse effects of glucocorticoid therapy. To gain insight into the biological function of SI-CLP, we determined the crystal structure of SI CLP at 2.7 A resolution by x-ray crystallography and found that it featured a typical triose-phosphate isomerase barrel fold with a putative saccharide-binding cleft. Comparison with other chitinase-like proteins showed the cleft to be atypically wide and open. The saccharide-binding capacity of SI-CLP was investigated, and its ligand-binding specificity was found to relate to the length of the oligosaccharides, with preference for chitotetraose. Further investigations reveal that SI-CLP could bind LPS in vitro and neutralize its endotoxin effect on macrophages. Our results demonstrate the saccharide-binding property of SI-CLP by structure and in vitro biochemical analyses and suggest the possible roles of SI-CLP in pathogen sensing and endotoxin neutralization. PMID- 20724480 TI - Regulation of NADPH oxidase activity in phagocytes: relationship between FAD/NADPH binding and oxidase complex assembly. AB - The X(+)-linked chronic granulomatous disease (X(+)-CGD) variants are natural mutants characterized by defective NADPH oxidase activity but with normal Nox2 expression. According to the three-dimensional model of the cytosolic Nox2 domain, most of the X(+)-CGD mutations are located in/or close to the FAD/NADPH binding regions. A structure/function study of this domain was conducted in X(+) CGD PLB-985 cells exactly mimicking 10 human variants: T341K, C369R, G408E, G408R, P415H, P415L, Delta507QKT509-HIWAinsert, C537R, L546P, and E568K. Diaphorase activity is defective in all these mutants. NADPH oxidase assembly is normal for P415H/P415L and T341K mutants where mutation occurs in the consensus sequences of NADPH- and FAD-binding sites, respectively. This is in accordance with their buried position in the three-dimensional model of the cytosolic Nox2 domain. FAD incorporation is abolished only in the T341K mutant explaining its absence of diaphorase activity. This demonstrates that NADPH oxidase assembly can occur without FAD incorporation. In addition, a defect of NADPH binding is a plausible explanation for the diaphorase activity inhibition in the P415H, P415L, and C537R mutants. In contrast, Cys-369, Gly-408, Leu-546, and Glu-568 are essential for NADPH oxidase complex assembly. However, according to their position in the three-dimensional model of the cytosolic domain of Nox2, only Cys 369 could be in direct contact with cytosolic factors during oxidase assembly. In addition, the defect in oxidase assembly observed in the C369R, G408E, G408R, and E568K mutants correlates with the lack of FAD incorporation. Thus, the NADPH oxidase assembly process and FAD incorporation are closely related events essential for the diaphorase activity of Nox2. PMID- 20724481 TI - ATP-dependent mechanism protects spectrin against glycation in human erythrocytes. AB - Human erythrocytes are continuously exposed to glucose, which reacts with the amino terminus of the beta-chain of hemoglobin (Hb) to form glycated Hb, HbA1c, levels of which increase with the age of the circulating cell. In contrast to extensive insights into glycation of hemoglobin, little is known about glycation of erythrocyte membrane proteins. In the present study, we explored the conditions under which glucose and ribose can glycate spectrin, both on the intact membrane and in solution and the functional consequences of spectrin glycation. Although purified spectrin could be readily glycated, membrane associated spectrin could be glycated only after ATP depletion and consequent translocation of phosphatidylserine (PS) from the inner to the outer lipid monolayer. Glycation of membrane-associated spectrin led to a marked decrease in membrane deformability. We further observed that only PS-binding spectrin repeats are glycated. We infer that the absence of glycation in situ is the consequence of the interaction of the target lysine and arginine residues with PS and thus is inaccessible for glycation. The reduced membrane deformability after glycation in the absence of ATP is likely the result of the inability of the glycated spectrin repeats to undergo the obligatory unfolding as a consequence of interhelix cross links. We thus postulate that through the use of an ATP-driven phospholipid translocase (flippase), erythrocytes have evolved a protective mechanism against spectrin glycation and thus maintain their optimal membrane function during their long circulatory life span. PMID- 20724482 TI - The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1. AB - Folates are essential vitamins that play a key role as one-carbon donors in a spectrum of biosynthetic pathways including RNA and DNA synthesis. The proton coupled folate transporter (PCFT/SLC46A1) mediates obligatory intestinal folate absorption. Loss-of-function mutations in PCFT result in hereditary folate malabsorption, an autosomal recessive disorder characterized by very low folate levels in the blood and cerebrospinal fluid. Hereditary folate malabsorption manifests within the first months after birth with anemia, immune deficiency, and neurological deficits. Here we studied the role of inducible trans-activators of PCFT gene expression. Bioinformatics identified three putative nuclear respiratory factor 1 (NRF-1) binding sites in the minimal promoter. The following evidence establish that PCFT is an NRF-1-responsive gene; electrophoretic mobility shift assay showed NRF-1 binding to native but not mutant NRF-1 sites, whereas antibody-mediated supershift analysis and chromatin immunoprecipitation revealed NRF-1 binding to its consensus sites within the PCFT promoter. Moreover, mutational inactivation of individual or all NRF-1 binding sites resulted in 40 60% decrease in luciferase reporter activity. Consistently, overexpression of NRF 1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. Conversely, introduction of a dominant-negative NRF-1 construct markedly repressed reporter activity and PCFT mRNA levels; likewise, introduction of NRF-1 siRNA duplexes to cells resulted in decreased PCFT transcript levels. Moreover, NRF-1 silencing down-regulated genes encoding for key folate transporters and enzymes in folate metabolism. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. The implications of this linkage between folate transport and metabolism with mitochondria biogenesis and respiration are discussed. PMID- 20724483 TI - The residual nonadrenergic contractile response to nerve stimulation of the mouse prostate is mediated by acetylcholine but not ATP in a comparison with the mouse vas deferens. AB - Neuronal release of noradrenaline is primarily responsible for the contraction of prostatic smooth muscle in all species, and this forms the basis for the use of alpha(1)-adrenoceptor antagonists as pharmacotherapies for benign prostatic hyperplasia. Previous studies in mice have demonstrated that a residual nonadrenergic component to nerve stimulation remains after alpha(1)-adrenoceptor antagonism. In the guinea pig and rat prostate and the vas deferens of guinea pigs, rats, and mice, ATP is the mediator of this residual contraction. This study investigates the mediator of residual contraction in the mouse prostate. Whole prostates from wild-type, alpha(1A)-adrenoceptor, and P2X1-purinoceptor knockout mice were mounted in organ baths, and the isometric force that tissues developed in response to electrical field stimulation or exogenously applied agonists was recorded. Deletion of the P2X1 purinoceptor did not affect nerve mediated contraction. Furthermore, the P2-purinoceptor antagonist suramin (30 MUM) failed to attenuate nerve-mediated contractions in wild-type, alpha(1A) adrenoceptor, or P2X1-purinoceptor knockout mice. Atropine (1 MUM) attenuated contraction in prostates taken from wild-type mice. In the presence of prazosin (0.3 MUM) or guanethidine (10 MUM), or in prostates taken from alpha(1A) adrenoceptor knockout mice, residual nerve-mediated contraction was abolished by atropine (1 MUM), but not suramin (30 MUM). Exogenously administered acetylcholine elicited reproducible concentration-dependent contractions of the mouse prostate that were atropine-sensitive (1 MUM), but not prazosin-sensitive (0.3 MUM). Acetylcholine, but not ATP, mediates the nonadrenergic component of contraction in the mouse prostate. This cholinergic component of prostatic contraction is mediated by activation of muscarinic receptors. PMID- 20724484 TI - The antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P mediated responses in vitro and in vivo. AB - Palonosetron is the only 5-HT(3) receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT(3) cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT(3) receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic. PMID- 20724485 TI - Double dissociation of the effects of haloperidol and the dopamine D3 receptor antagonist ABT-127 on acquisition vs. expression of cocaine-conditioned activity in rats. AB - Dopamine receptors play a critical role in reward-related learning, but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol [4-[4-(4 chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one] with the D3 receptor-preferring antagonist 2,3-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4] triazol-3-yisulfanyl)-propyl]-piperazin-1-y1}-pyrimidine hydrochloride (ABT-127), given at D3 receptor-selective doses [i.e., no displacement of [(3)H]3,5-dichloro N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide binding, no effects on gamma-butyrolactone-induced striatal l-3,4-dihydroxyphenylalanine; haloperidol accumulation; no attenuation of apomorphine-induced stereotypy]. We hypothesized that haloperidol and ABT-127 will produce a doubly dissociable effect on acquisition versus expression of cocaine-conditioned activity. Rats received three 1-h habituation sessions to activity monitors followed by three 1 h cocaine (10 mg/kg) conditioning sessions. The expression phase (no cocaine injections) took place 48 h later. Haloperidol (50 MU/kg) given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT 127 (1.0 mg/kg), when given during conditioning, failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are more critically involved in acquisition than initial expression and D3 receptors are more critically involved in expression than acquisition of conditioned activity based on cocaine. PMID- 20724486 TI - An alpha-linolenic acid-rich formula reduces oxidative stress and inflammation by regulating NF-kappaB in rats with TNBS-induced colitis. AB - We have previously shown that alpha-linolenic acid (ALA), a (n-3) PUFA exerts in vitro antiinflammatory effects in the intestine. In this study, we aimed to evaluate its effect on inflammatory and oxidative stress in a colitis model. Colitis was induced in 2 groups at d 0 by intrarectal injection of 2-4-6 trinitrobenzen sulfonic acid (TNBS), whereas the control group received the vehicle. Rats we fed 450 mg . kg(-1) . d(-1) of ALA (TNBS+ALA) while the other colitic group (TNBS) and the control group were fed an isocaloric corn oil formula for 14 d (from d -7 to d 7). RBC fatty acid composition was assessed. Oxidative stress was studied by measuring urinary 8-isoprostanes (8-IP) and colon glutathione (GSH) concentration and inducible nitric oxide synthase (iNOS) expression. Colitis was assessed histologically, by production of proinflammatory mediators, including cytokines, leukotrienes B(4) (LTB(4)), and cyclooxygenase-2 (COX-2) and by nuclear factor-kappaB (NF-kappaB) activation. The ALA-rich diet significantly increased the RBC levels of ALA, eicosapentaenoic acid, and docosapentaenoic acid (n-3) compared with the TNBS group (P < 0.01 for all). The beneficial effect of ALA supplementation on oxidative stress was reflected by lower urinary 8-IP levels (P < 0.05), a normalized colon GSH concentration (P < 0.01), and reduced colon iNOS expression (P < 0.05) compared with the TNBS group. ALA also protected against colon inflammation as assessed by lower tumor necrosis factor-alpha secretion and mRNA level (P < 0.05), reduced NF-kappaB activation (P = 0.01), and lower colon lipid mediator concentrations such as LTB(4) and COX-2 (P < 0.05) compared with the TNBS group. These findings show that an ALA-rich formula is beneficial to TNBS-induced colitic rats via inhibition of oxidative and inflammatory stress. PMID- 20724487 TI - Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. AB - Dietary supplementation with whole blueberries in a preclinical study resulted in a reduction in glucose concentrations over time. We sought to evaluate the effect of daily dietary supplementation with bioactives from blueberries on whole-body insulin sensitivity in men and women. A double-blinded, randomized, and placebo controlled clinical study design was used. After screening to resolve study eligibility, baseline (wk 0) insulin sensitivity was measured on 32 obese, nondiabetic, and insulin-resistant subjects using a high-dose hyperinsulinemic euglycemic clamp (insulin infusion of 120 mU(861 pmol)?m(-2)?min(-1)). Serum inflammatory biomarkers and adiposity were measured at baseline. At the end of the study, insulin sensitivity, inflammatory biomarkers, and adiposity were reassessed. Participants were randomized to consume either a smoothie containing 22.5 g blueberry bioactives (blueberry group, n = 15) or a smoothie of equal nutritional value without added blueberry bioactives (placebo group, n = 17) twice daily for 6 wk. Both groups were instructed to maintain their body weight by reducing ad libitum intake by an amount equal to the energy intake of the smoothies. Participants' body weights were evaluated weekly and 3-d food records were collected at baseline, the middle, and end of the study. The mean change in insulin sensitivity improved more in the blueberry group (1.7 +/- 0.5 mg?kg FFM( 1)?min(-1)) than in the placebo group (0.4 +/- 0.4 mg?kg FFM(-1)?min(-1)) (P = 0.04). Insulin sensitivity was enhanced in the blueberry group at the end of the study without significant changes in adiposity, energy intake, and inflammatory biomarkers. In conclusion, daily dietary supplementation with bioactives from whole blueberries improved insulin sensitivity in obese, nondiabetic, and insulin resistant participants. PMID- 20724488 TI - Functional characteristics of the human ortholog of riboflavin transporter 2 and riboflavin-responsive expression of its rat ortholog in the small intestine indicate its involvement in riboflavin absorption. AB - Riboflavin transporter (RFT) 2 has recently been identified as a transporter that may be, mainly based on the functional characteristics of its rat ortholog (rRFT2), involved in the intestinal absorption of riboflavin. The present study was conducted to further examine such a possible role of RFT2, focusing on the functional characteristics of its human ortholog (hRFT2) and the response of rRFT2 expression in the small intestine to deprivation of dietary riboflavin. When transiently expressed in human embryonic kidney 293 cells, hRFT2 could transport riboflavin efficiently in a pH-sensitive manner, favoring acidic pH and without requiring Na(+). Riboflavin transport by hRFT2 was saturable with a Michaelis constant of 0.77 MUmol/L at pH 6.0, and inhibited by some riboflavin derivatives, such as lumiflavin. It was also inhibited, to a lesser extent, by some cationic compounds, such as ethidium. Thus, hRFT2 was suggested to, together with a finding that its mRNA is highly expressed in the small intestine, have characteristics as an intestinal RFT. Furthermore, feeding rats a riboflavin deficient diet caused an upregulation of the expression of rRFT2 mRNA in the small intestine, presumably as an adaptive response to enhance riboflavin absorption, which would involve rRFT2, and its apically localized characteristic was suggested by the observation of rRFT2 tagged with green fluorescent protein stably expressed in polarized Madin-Darby canine kidney II cells. All these results combined indicate that RFT2 is a transporter involved in the epithelial uptake of riboflavin in the small intestine for its nutritional utilization. PMID- 20724489 TI - Dietary fluoride restriction does not alter femoral biomechanical strength in col1a2-deficient (oim) mice with type I collagen glomerulopathy. AB - Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease due primarily to mutations in the type I procollagen genes, COL1A1 and COL1A2, causing bone deformity and numerous lifetime fractures. OI murine (oim) model mice carry a mutation in the col1a2 gene causing aberrant production of homotrimeric type I collagen [alpha1(I)(3)], leading to bone fragility and glomerular accumulation of type I collagen. Previous studies demonstrated that heterozygous (+/oim) and homozygous (oim/oim) mice have elevated tibiae fluoride concentrations but reduced femoral biomechanics. However, it is unclear whether these 2 variables are causally related, because impaired renal function could reduce urinary fluoride excretion, thus elevating bone fluoride concentrations regardless of disease status. Our goal in this study was to determine whether dietary fluoride restriction would improve femoral biomechanics in oim mice. Wild type, +/oim, and oim/oim mice were fed a control (5 mg/kg fluoride) or fluoride restricted diet (0 mg/kg fluoride) for ~13 wk, at which time plasma and femora were analyzed for fluoride concentrations and bone biomechanical properties. In wild-type, +/oim, and oim/oim mice, dietary fluoride restriction reduced femoral fluoride burden by 54-74%, respectively (P < 0.05), without affecting glomerular collagen deposition. Oim/oim mice fed the fluoride-restricted diet had reduced material tensile strength (P < 0.05) compared with oim/oim mice fed the control diet. However, dietary fluoride restriction did not affect stiffness or whole bone femoral breaking strength, regardless of genotype. These data suggest that oim mice have reduced bone strength due to homotrimeric type I collagen, independent of bone fluoride content. PMID- 20724490 TI - Salt-induced cardiac hypertrophy and interstitial fibrosis are due to a blood pressure-independent mechanism in Wistar rats. AB - High salt intake is a known cardiovascular risk factor and is associated with cardiac alterations. To better understand this effect, male Wistar rats were fed a normal (NSD: 1.3% NaCl), high 4 (HSD4: 4%), or high 8 (HSD8: 8%) salt diet from weaning until 18 wk of age. The HSD8 group was subdivided into HSD8, HSD8+HZ (15 mg . kg(-1) . d(-1) hydralazine in the drinking water), and HSD8+LOS (20 mg . kg( 1) . d(-1) losartan in the drinking water) groups. The cardiomyocyte diameter was greater in the HSD4 and HSD8 groups than in the HSD8+LOS and NSD groups. Interstitial fibrosis was greater in the HSD4 and HSD8 groups than in the HSD8+HZ and NSD groups. Hydralazine prevented high blood pressure (BP) and fibrosis, but not cardiomyocyte hypertrophy. Losartan prevented high BP and cardiomyocyte hypertrophy, but not fibrosis. Angiotensin II type 1 receptor (AT(1)) protein expression in both ventricles was greater in the HSD8 group than in the NSD group. Losartan, but not hydralazine, prevented this effect. Compared with the NSD group, the binding of an AT(1) conformation-specific antibody that recognizes the activated form of the receptor was lower in both ventricles in all other groups. Losartan further lowered the binding of the anti-AT(1) antibody in both ventricles compared with all other experimental groups. Angiotensin II was greater in both ventricles in all groups compared with the NSD group. Myocardial structural alterations in response to HSD are independent of the effect on BP. Salt-induced cardiomyocyte hypertrophy and interstitial fibrosis possibly are due to different mechanisms. Evidence from the present study suggests that salt induced AT(1) receptor internalization is probably due to angiotensin II binding. PMID- 20724491 TI - Frank Chytil (1924-2010). PMID- 20724492 TI - Steatosis in mice is associated with gender, folate intake, and expression of genes of one-carbon metabolism. AB - Disrupted choline metabolism may affect hepatic lipid metabolism and lead to steatosis. Because folate and the choline metabolite betaine independently serve as methyl donors for homocysteine (Hcy) remethylation to methionine, we assessed the impact of folate deficiency on steatosis, choline metabolism, and expression of 9 genes involved in folate-mediated one-carbon metabolism. Liver histology, choline metabolites, and mRNA and protein expression were examined in mice fed control (CD; 2 mg/kg folic acid) or folate-deficient diets (FD; 0.3 mg/kg folic acid) for 12 mo. Females fed CD were not steatotic (0/6), whereas males were mildly to moderately steatotic (5/6). Steatosis was observed in FD-fed males and females; it was more severe and more frequent in males (7/7) than in females (4/10) (P = 0.005). Hepatic betaine was lower in males (P = 0.014) and FD-fed mice (P < 0.001) and negatively correlated with steatosis severity in mice fed CD (r = -0.87; P = 0.001). Gender differences in the expression of 6 enzymes may contribute to increased steatosis susceptibility in males. Males relied more on betaine-dependent (folate-independent) Hcy remethylation [72% more betaine-Hcy methyltransferase (P < 0.001) and 28% less folate-dependent methionine synthase (MTR) (P < 0.001)]. FD-fed mice of both genders appeared to shift to betaine dependent remethylation by reducing MTR expression 70% (P < 0.001) and increasing betaine demand; there was a correlation between MTR expression and betaine levels (r = 0.50; P = 0.031). Our work demonstrates that chronic folate insufficiency leads to steatosis in mice. Increased utilization of betaine for Hcy remethylation in males and in both genders during folate deficiency may lead to steatosis by disrupting choline metabolism. PMID- 20724493 TI - Price changes alone are not adequate to produce long-term dietary change. AB - Taxation has been proposed as a means to reduce consumption of unhealthy food items. However, it is unknown if taxation without regulations or other activities known to shift eating behaviors lead to long-term dietary change. This unexplored issue is examined using data from the Russia Longitudinal Monitoring Survey. Data were from adults aged 25-55 y who participated in the nationally representative Russian Longitudinal Monitoring Survey. Twenty-four-hour dietary recalls, detailed food expenditure data, and community-level food prices collected over 1994-2005 were used for these analyses. Longitudinal random effects models were used to test the relation of time on the structure of diet while controlling for total household expenditures. The proportion of total energy consumed from fat was higher in all other years combined compared with 1998 (P < 0.001). The proportion of dietary fat from high-fat meat and high-fat dairy items were lowest in 1998 and increased over subsequent years despite increasing costs. Percent fat from fats and oils continued to decline with rising costs. Price changes led to substantial shifts in the structure of food consumption. However, except for the most expensive items, consumption of items returned to levels consumed in the former Soviet Union following price stabilization. PMID- 20724498 TI - Impact of ignoring extraction ratio when predicting drug-drug interactions, fraction metabolized, and intestinal first-pass contribution. AB - Many mathematical models for in vitro to in vivo prediction of drug-drug interactions (DDIs) of orally administered victim drugs have been developed. However, to date, none of these models have been applicable to all intravenously administered victim drugs. We derived and conducted a sensitivity/error analysis of a modification to the existing multiple mode interaction prediction model such that it is applicable to all intravenously administered victim drugs. Using this model we showed that ignoring the hepatic extraction ratio (EH) (as low as 0.3) of intravenously administered victim drugs can result in 1) substantial underestimation of f(m, CYPi) (the fraction of hepatic clearance of the victim drug via a given enzymatic pathway) and 2) error in dissecting the contribution of intestinal and hepatic components of DDIs for orally administered drugs. Using this model we describe DDI boundaries (degree of inhibition or induction) at which ignoring the EH of commonly used victim drugs results in >=30% error in the predicted area under the concentration-time curve (AUC) ratio or contribution of intestinal interaction to a DDI (CYP3A probes only). For the most widely used victim drug midazolam, these boundaries for AUC ratio are net inhibition (I/K(i) or lambda/k(deg)) >=1.3 or fold induction >=2.1; for intestinal contribution the boundaries are 0.37 and 1.5, respectively. To accurately predict the intravenous AUC ratio, intestinal contribution, or f(m, CYPi) 1) for all induction DDIs irrespective of EH of the victim drug and 2) for modest to potent inhibition DDIs even when the EH is moderate (>=0.3), we propose that our model be used. PMID- 20724499 TI - Detection of phenolic metabolites of styrene in mouse liver and lung microsomal incubations. AB - Metabolic activation is considered to be a critical step for styrene-induced pulmonary toxicity. Styrene-7,8-oxide is a primary oxidative metabolite generated by vinyl epoxidation of styrene. In addition, urinary 4-vinylphenol (4-VP), a phenolic metabolite formed by aromatic hydroxylation, has been detected in workers and experimental animals after exposure to styrene. In the present study, new oxidative metabolites of styrene, including 2-vinylphenol (2-VP), 3 vinylphenol (3-VP), vinyl-1,4-hydroquinone, and 2-hydroxystyrene glycol were detected in mouse liver microsomal incubations. The production rates of 2-VP, 3 VP, 4-VP, and styrene glycol were 0.0527 +/- 0.0045, 0.0019 +/- 0.0006, 0.0053 +/ 0.0002, and 4.42 +/- 0.33 nmol/(min . mg protein) in mouse liver microsomes, respectively. Both disulfiram (100 MUM) and 5-phenyl-1-pentyne (5 MUM) significantly inhibited the formation of the VPs and styrene glycol. 2-VP, 3-VP, and 4-VP were metabolized in mouse liver microsomes at rates of 2.50 +/- 0.30, 2.63 +/- 0.13, and 3.45 +/- 0.11 nmol/(min . mg protein), respectively. The three VPs were further metabolized to vinylcatechols and/or vinyl-1,4-hydroquinone and the corresponding glycols. Pulmonary toxicity of 2-VP, 3-VP, and 4-VP was evaluated in CD-1 mice, and 4-VP was found to be more toxic than 2-VP and 3-VP. PMID- 20724503 TI - Evaluation of the specificity and effectiveness of selected oral hygiene actives in salivary biofilm microcosms. AB - The microbiological effects of biocidal products used for the enhancement of oral hygiene relate to the active compound(s) as well as other formulation components. Here, we test the specificities of selected actives in the absence of multiple excipients. Salivary ecosystems were maintained in tissue culture plate-based hydroxyapatite disc models (HDMs) and modified drip-flow biofilm reactors (MDFRs). Test compounds stannous fluoride (SF), SDS, triclosan (TCS), zinc lactate (ZL) and ZL with SF in combination (ZLSF) were delivered to the HDMs once and four times daily for 6 days to MDFRs. Plaques were characterized by differential viable counting and PCR-denaturing gradient gel electrophoresis (DGGE). TCS and SDS were the most effective compounds against HDM plaques, significantly reducing total viable counts (P<0.05), whilst SF, ZL and ZLSF were comparatively ineffective. TCS exhibited specificity for streptococci (P<0.01) and Gram-negative anaerobes (P<0.01) following a single dosing and also on repeated dosing in MDFRs. In contrast to single exposures, multiple dosing with ZLSF also significantly reduced all bacterial groups, whilst SF and ZL caused significant but transient reductions. According to PCR-DGGE analyses, significant (P<0.05) reductions in eubacterial diversity occurred following 6 day dosing with both TCS and ZLSF. Concordance of MDFR eubacterial profiles with salivary inocula ranged between 58 and 97%. TCS and ZL(SF) exhibited similar specificities to those reported for formulations. TCS was the most potent antibacterial, after single and multiple dosage regimens. PMID- 20724504 TI - Multilocus microsatellite typing for Rhizopus oryzae. AB - Rhizopus oryzae is the most frequent causative agent of zygomycosis. Although zygomycosis causes considerable morbidity and mortality in immunocompromised patients, the epidemiology of the disease is not well studied and no standard molecular typing method has been described for any of the causative agents. Here we describe a multilocus microsatellite typing (MLMT) method for R. oryzae. R. oryzae genome sequences were downloaded from the Fungal Genome Initiative database (Broad Institute). The intergenic regions and ORFs of approximately 5.7 Mb were screened for repeat regions with the help of the online repeat search tool Repeat Masker. Of the 30 microsatellite loci identified, 3 microsatellites [RO3, (CCT)(n); RO4, (TA)(n); and RO8, (GAA)(GGA)(n)] were selected after validation of the ability to amplify them and their size variation in 8 randomly selected clinical isolates of R. oryzae. Nucleotide sequence analysis of these loci demonstrated polymorphism in the microsatellite repeat number. The capabilities of these microsatellite loci were assessed for strain differentiation on 30 clinical isolates, based on fragment size determination in an automated capillary electrophoresis using fluorescent labelled primers. These three polymorphic microsatellite loci were found to have good discriminatory power (D) (RO3, D=0.846; RO4, D=0.747; RO8, D=0.742; with a combined D=0.986) and stability for seven subcultures. It was also confirmed that the MLMT method may be applied to both R. oryzae and Rhizopus delemar (a proposed new species), although MLMT analysis could not differentiate them into two clusters. The MLMT system, described here for what is believed to be the first time for a zygomycotic fungus, holds promise as a powerful tool for the strain typing of R. oryzae. PMID- 20724505 TI - Escherichia coli carrying the blaCTX-M-15 gene of ST648. PMID- 20724506 TI - Mapping the fitness of Mycobacterium tuberculosis strains: a complex picture. PMID- 20724507 TI - Determination of urinary D-/L-arabinitol ratios as a biomarker for invasive candidiasis in children with cardiac diseases. AB - A non-invasive, non-culture-based method of determining urinary D-/L-arabinitol (D-/L-ARA) ratios was investigated as a tool for the diagnosis of invasive candidiasis in nosocomial paediatric infection cases. The study encompassed 138 children aged 4 days to 16 years (mean +/- SD=1.6 +/- 4.2 years) with congenital heart defects (91.4%) or with rhythm disorders or circulatory failure (8.6%). ARA enantiomers were detected by GC using an electron capture detector. Positive D-/L ARA ratios were found for 11/11 patients with proven candidiasis and 17/19 patients with clinically suspected invasive candidiasis. Thirty children were undergoing antifungal chemotherapy. D-/L-ARA ratios (mean +/- SD) were 2.601 +/- 0.544 in hospitalized cardiac patients without fungal infection and 5.120 +/- 1.253 in those receiving antifungal therapy (P<0.001). The sensitivity of the method was 100%, the specificity 97.2%, the positive predictive value was 78.6% and the negative predictive value was 100%. PMID- 20724508 TI - Prepatellar bursitis due to Brucella abortus: case report and analysis of the local immune response. AB - A case of prepatellar bursitis in a man with chronic brucellosis is presented. Brucella abortus biotype 1 was isolated from the abundant yellowish fluid obtained from the bursa. Clinical and epidemiological data did not suggest a direct inoculation of the agent in the bursa. However, the patient mentioned occasional local trauma due to recreational sports, which may have constituted a predisposing factor. As determined by ELISA, there were higher levels of IgG against Brucella LPS and cytosolic proteins detected in the patient's bursal synovial fluid when compared with serum. Levels of proinflammatory cytokines (tumour necrosis factor alpha, interleukin 1 beta, gamma interferon, interleukin 8 and MCP-1) were higher than in synovial fluids obtained from patients with rheumatoid arthritis and a patient with septic arthritis, and a zymographic analysis revealed a gelatinase of about 92 kDa. These findings indicate that it may be possible to diagnose brucellar bursitis by measuring specific antibodies in the bursal synovial fluid. In addition, our findings suggest a role of increased local levels of proinflammatory cytokines and gelatinases in the inflammatory manifestations of brucellar bursitis. PMID- 20724509 TI - Characterization of the type III capsular polysaccharide produced by Burkholderia pseudomallei. AB - Burkholderia pseudomallei has been shown to produce more than one capsular polysaccharide (CPS). Analysis of the B. pseudomallei genome has revealed that the organism contains four CPS operons (I-IV). One of these operons (CPS III) was selected for further study. Comparative sequencing analysis revealed that the genes encoding CPS III are present in B. pseudomallei and Burkholderia thailandensis but not in Burkholderia mallei. In this study, CPS III was not found to contribute to the virulence of B. pseudomallei. Strains containing mutations in CPS III had the same LD(50) value as the wild-type when tested in an animal infection model. Production of CPS III was shown to be induced in water but inhibited in 30% normal human serum using a lux reporter fusion assay. Microarray analysis of capsule gene expression in infected hamsters revealed that the genes encoding CPS III were not significantly expressed in vivo compared with the genes encoding the previously characterized mannoheptose capsule (CPS I), which is an important virulence factor in B. pseudomallei. Glycosyl-composition analysis by combined GC/MS indicated that the CPS III genes are involved in the synthesis of a capsule composed of galactose, glucose, mannose and xylose. PMID- 20724510 TI - Recurrent infective endocarditis due to Aggregatibacter actinomycetemcomitans: reinfection or relapse? AB - Aggregatibacter actinomycetemcomitans is commonly part of the normal microflora of the human upper respiratory tract. It has been implicated in periodontal disease and various infections, particularly endocarditis. We report here what we believe to be the first case of recurrent infective endocarditis due to A. actinomycetemcomitans in a 44-year-old woman occurring 5 years after the initial episode. Genomic analysis proved that the strains were closely related. Despite efficient antibiotic treatment, surgery was necessary for recovery. PMID- 20724511 TI - Invasive pulmonary aspergillosis due to Aspergillus terreus: value of DNA, galactomannan and (1->3)-beta-D-glucan detection in serum samples as an adjunct to diagnosis. AB - A case of invasive pulmonary aspergillosis caused by Aspergillus terreus is described. The diagnosis was based on demonstration of branched septate hyphae in a sputum specimen and isolation of the fungus in culture. The diagnosis was further supported by detection of A. terreus-specific DNA, galactomannan (GM) and (1->3)-beta-D-glucan (BDG) in consecutive serum specimens. The patient was treated for about 10 weeks with voriconazole. The decreasing levels of GM and BDG in serum samples were accompanied by symptomatic and radiological improvement. The report highlights the value of surrogate markers in the diagnosis and for monitoring the course of invasive aspergillosis during therapy. PMID- 20724513 TI - Synergistic interaction of phenylpropanoids with antibiotics against bacteria. AB - Phenylpropanoids constitute a large part of our daily diet and there is a possibility that they might interact with synthetic drugs. The present work was aimed at studying the interaction of seven phenylpropanoids (cinnamic, p coumaric, caffeic, chlorogenic, ferulic, 3,4-dimethoxycinnamic and 2,4,5 trimethoxycinnamic acid) with five antibiotics (amikacin, ampicillin, ciprofloxacin, erythromycin and vancomycin) against Gram-negative (Escherichia coli, Enterobacter aerogenes and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. The interaction studies were performed by chequerboard and time-kill curve assays. Both assays revealed that cinnamic, p coumaric and ferulic acids were the most active. They combined synergistically with the majority of the antibiotics and exhibited enhanced activity against all the micro-organisms. The time-kill curve parameters were better (P<0.05) for the combinations of amikacin with ferulic, cinnamic or p-coumaric acid than for the individual treatments. Amikacin was the most favourable antibiotic and S. aureus was the most sensitive microbe to most of the combinations. These phenylpropanoids damaged the bacterial membrane as assessed by the LIVE/DEAD BacLight kit, and structure-activity relationship studies indicated that hydrophilic groups enhanced this activity. PMID- 20724512 TI - Serological diagnosis of Chlamydia pneumoniae infection: limitations and perspectives. AB - Chlamydia pneumoniae is an obligate intracellular human pathogen responsible for a wide range of acute and chronic human diseases, including pneumonia and other respiratory diseases. Serological methods for the diagnosis of C. pneumoniae infection vary widely, and several authors have reported significant inter- and intra-laboratory variability in diagnostic methods and criteria. Over the past 10 years, numerous studies have focused on the identification of specific antigens for application in serodiagnosis, including the diagnosis of persistent infections. The use of proteomics may enable the development of serological diagnosis kits that offer reliable sensitivity and specificity and might even differentiate between the various stages of infection with this pathogen. PMID- 20724514 TI - Immunological efficacy of glycoconjugates derived from Vibrio cholerae O1 serotype Ogawa detoxified LPS in mice. AB - This study focused on changes in selected parameters of humoral and cellular immunity following vaccination of mice with unique Vibrio cholerae LPS-protein complexed conjugates. The V. cholerae detoxified LPS (dLPS)-derived antigenic structures O-specific polysaccharide (O-SP) and de-O-acylated LPS (DeOAc-LPS) were used to prepare glycoconjugates by linking both dLPSs to glucan, the immunomodulating matrix, and then to BSA carrier. Animals were given a primary vaccination and boosted at 2-week intervals with a dose of 4.5 MUg saccharide antigen. The last boost was given either subcutaneously or intraperitoneally (i.p.) to compare the boosting effect and to optimize the effective immunization route. Both conjugates (O-SP-BSA and DeOAc-LPS-BSA) induced significant levels of antigen-specific Ig isotypes, especially IgG and IgM. The i.p. booster route was more effective. A T helper 1 response was achieved only by immunization with O-SP BSA conjugate administered i.p. Significant acceleration of phagocytic capacity and respiratory burst of neutrophils was demonstrated by both immunogenic formulations. Activation of T- and B-cell adaptive immunities was exhibited as specific changes in CD3 : CD19 and CD4 : CD8 ratios, B-cell low-affinity Fcgamma II and III receptor expression and induction of CD45R antigen. PMID- 20724515 TI - Increased vancomycin minimum inhibitory concentration among Staphylococcus aureus isolates in Malaysia. PMID- 20724516 TI - Neoplasia and granulomas surrounding microchip transponders in Damaraland mole rats (Cryptomys damarensis). AB - Damaraland mole rats (Cryptomys damarensis) are among the longest-living rodents, with a maximum longevity of approximately 16 years. As one of the few mammals termed eusocial, these animals have been used in behavioral, genetic, metabolic, and physiologic research at the University of Connecticut since 1997. For individual identification at 3 to 4 months of age, mole rats were subcutaneously implanted with microchip transponders (11 mm in length) in the dorsal cervical region. In 2007, 2 of the 90 implanted adults, 10-year-old and 9-year-old females, developed subcutaneous masses at the site of the implant. Histopathological and immunohistochemical examinations revealed amelanotic melanoma and fibrosarcoma, respectively, with metastasis of the amelanotic melanoma. In 2008, a total of 3 adult males were castrated as part of a sex behavior study; 3 months later, all 3 castrated males developed subcutaneous masses around their implants, whereas none of the noncastrated males had masses. After an additional 9 months, these masses were found to be granulomas. To the authors' knowledge, this is the first report of neoplasia in this species. Both the tumors and the granulomas surrounded the microchip transponder. PMID- 20724517 TI - Multiple sclerosis and risk of cancer: a meta-analysis. PMID- 20724518 TI - Current status of the measurement of blood hepcidin levels in chronic kidney disease. AB - Hepcidin is a small defensin-like peptide produced in the liver in response to anemia, hypoxia, or inflammation. In addition to its anti-microbial properties, it has also been found to be a key regulator of iron utilization, providing increased understanding of why chronic kidney disease patients absorb iron poorly from the gut and also why many hemodialysis patients develop functional iron deficiency in the presence of inflammation. Hepcidin synthesis is upregulated in uremia, as in other inflammatory states. The ability to measure hepcidin in biologic fluids has stimulated interest in the potential applicability of this measurement as a more informative marker of iron status than the traditional iron indices such as serum ferritin and transferrin saturation. Until recently, however, the assays for measuring hepcidin have lacked precision, accuracy, and internal validation. Over the last few years, however, several assays have become available that address these limitations. Broadly speaking, these can be divided into radioimmunoassays, ELISAs, and mass spectrometry methods. The purpose of this review is to outline the various assays available at the present time, to critique their advantages and limitations, and to report comparative data in patients with chronic kidney disease. A concern with the immunoassays is that they detect more than biologically active hepcidin-25. Mass spectrometric assays are specific for hepcidin-25 but are labor intensive and require more costly and sophisticated instrumentation. Thus, although mass spectrometry is more accurate, it is less practical for routine clinical use at the present time. PMID- 20724519 TI - Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. AB - BACKGROUND AND OBJECTIVES: We assessed whether nonalcoholic steatohepatitis (NASH) diagnosed by liver biopsy is associated with decreased kidney function and whether such association is independent of insulin resistance and features of the metabolic syndrome. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: We enrolled 80 consecutive overweight patients with biopsy-proven NASH and 80 nonsteatotic control subjects who were matched for age, gender, and body mass index. Chronic kidney disease (CKD) was defined as the presence of estimated GFR (eGFR) of <=60 ml/min per 1.73 m(2) and/or abnormal albuminuria (i.e., urinary albumin/creatinine ratio >=30 mg/g). RESULTS: NASH patients had significantly (P < 0.001) lower eGFR (75.3 +/- 12 versus 87.5 +/- 6 ml/min per 1.73 m(2)) and a greater frequency of abnormal albuminuria (14 versus 2.5%) and CKD (25 versus 3.7%) than control subjects. The significant differences in eGFR, albuminuria, and CKD that were observed between the two groups were only slightly weakened after adjustment for age, gender, body mass index, smoking status, insulin resistance (by homeostasis model assessment), and components of the metabolic syndrome. Notably, histologic severity of NASH (i.e., fibrosis stage) was strongly associated with either decreasing eGFR or increasing albuminuria (P < 0.01 or less), independently of potential confounding factors. CONCLUSIONS: Our findings suggest that patients with biopsy-proven NASH have moderately decreased eGFR and a higher frequency of abnormal albuminuria and CKD than matched control subjects and that the severity of NASH histology is associated with decreased kidney function, independently of traditional risk factors, insulin resistance, and components of the metabolic syndrome. PMID- 20724520 TI - Peritonitis and exit site infections in First Nations patients on peritoneal dialysis. AB - BACKGROUND AND OBJECTIVES: First Nations (FN) patients on peritoneal dialysis experience poor outcomes. Whether discrepancies exist regarding the microbiology, rate of infections, and outcomes between FN and non-FN peoples remains unknown. Design, setting, participants, & measures: All adult peritoneal dialysis patients (n = 727) from 1997 to 2007 residing in Manitoba, Canada, were included. Parametric and nonparametric tests were used as necessary. Negative binomial regression was used to determine the relationship of rates of exit site infections (ESIs) and peritonitis between FN and non-FN peoples. RESULTS: A total of 161 FN and 566 non-FN subjects were included in the analyses. The unadjusted relative rates of peritonitis and ESIs in FN subjects were 132.7 and 86.0/100 patient-years compared with 87.8 and 78.2/100 patient-years in non-FN populations, respectively. FN subjects were more likely to have culture-negative peritonitis (36.5 versus 20.8%, P < 0.0001) and Staphylococcus ESIs (54.1 versus 32.9%, P < 0.0001). The crude and adjusted rates of peritonitis were higher in FN subjects for total episodes and culture-negative and gram-negative peritonitis. Catheter removal because of peritonitis was similar in both groups (42.9 versus 38.1% for FN and non-FN subjects, respectively; P = 0.261). CONCLUSIONS: FN patients experience higher rates of peritonitis and similar rates of ESIs compared with non-FN patients. Interventions to improve outcomes and prevent infections should specifically be targeted to the FN population. PMID- 20724521 TI - Genotype-phenotype correlations: filling the void. PMID- 20724522 TI - Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. AB - This phase I trial examined the safety, pharmacokinetics, and pharmacodynamics of MLN8054, an oral, selective, small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received increasing doses of MLN8054 in 28 day cycles until dose-limiting toxicity (DLT) was seen in >=2 of 3-6 patients in a cohort. For the 10-mg and 20-mg cohorts, treatment was administered once daily on days 1 to 5 and 8 to 12. Patients in later cohorts (25, 35, 45, 55, 60, 70, and 80 mg/day) were treated four times daily on days 1 to 14, with the largest dose at bedtime (QID-14D) to mitigate benzodiazepine-like effects possibly associated with peak plasma concentrations. Patients (n = 43) received a median of 1 cycle (range, 1-10). DLT of somnolence was first noted in the 20-mg cohort. Two DLTs of somnolence (n = 1) and transaminitis (n = 1) were seen at QID-14D 80 mg. Grade 2 oral mucositis (n = 1), predicted to be a mechanistic effect, was observed only at QID-14D 80 mg. MLN8054 exposure levels were roughly linear with dose; terminal half-life was 30 to 40 hours. Pharmacodynamic analyses of skin and tumor mitotic indices, mitotic cell chromosome alignment, and spindle bipolarity provided evidence of Aurora A inhibition. MLN8054 dosing for 10 to 14 days in 28 day cycles was feasible. Somnolence and transaminitis were DLTs. Pharmacodynamic analyses in mitotic cells of both skin and tumor provided proof of mechanism for Aurora A kinase inhibition. A more potent, selective, second-generation Aurora A kinase inhibitor, MLN8237, is in clinical development. PMID- 20724523 TI - The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells. AB - Mammalian AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status. It is activated by phosphorylation of the catalytic subunit on Thr172. The main objective of this study was the identification of a phosphatase involved in the regulation of AMPK activity. Mouse MIN6 beta cells were used to study the glucose-induced regulation of the phosphorylation of AMPK. Small interfering RNA (siRNA) technology was used to deplete putative phosphatase candidate genes that could affect AMPK regulation. The effect of the siRNAs used in the study was compared with the effect observed using a negative control siRNA. A protein phosphatase complex composed of the catalytic subunit of protein phosphatase-1 (PP1) and the regulatory subunit R6 participates in the glucose-induced dephosphorylation of AMPK. R6 interacts physically with the beta-subunit of the AMPK complex and recruits PP1 to dephosphorylate the catalytic alpha-subunit on Thr172. siRNA depletion of R6 decreases glucose-induced insulin secretion due to the presence of a constitutively active AMPK complex. The characterization of the PP1-R6 complex identifies this holoenzyme as a possible target for therapeutic intervention with the aim of regulating the activity of AMPK in pancreatic beta cells. PMID- 20724524 TI - Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. AB - Recent studies showed that germ-free (GF) mice are resistant to obesity when consuming a high-fat, high-carbohydrate Western diet. However, it remains unclear what mechanisms are involved in the antiobesity phenotype and whether GF mice develop insulin resistance and dyslipidemia with high-fat (HF) feeding. In the present study, we compared the metabolic consequences of HF feeding on GF and conventional (conv) C57BL/6J mice. GF mice consumed fewer calories, excreted more fecal lipids, and weighed significantly less than conv mice. GF/HF animals also showed enhanced insulin sensitivity with improved glucose tolerance, reduced fasting and nonfasting insulinemia, and increased phospho-Akt((Ser-473)) in adipose tissue. In association with enhanced insulin sensitivity, GF/HF mice had reduced plasma TNF-alpha and total serum amyloid A concentrations. Reduced hypercholesterolemia, a moderate accretion of hepatic cholesterol, and an increase in fecal cholesterol excretion suggest an altered cholesterol metabolism in GF/HF mice. Pronounced nucleus SREBP2 proteins and up-regulation of cholesterol biosynthesis genes indicate that enhanced cholesterol biosynthesis contributed to the cholesterol homeostasis in GF/HF mice. Our results demonstrate that fewer calorie consumption and increased lipid excretion contributed to the obesity-resistant phenotype of GF/HF mice and reveal that insulin sensitivity and cholesterol metabolism are metabolic targets influenced by the gut microbiota. PMID- 20724525 TI - Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor. AB - Growing evidence indicates a critical role of ubiquitin-proteosome system in apoptosis regulation. A cardioprotective effect of ubiquitin (Ub) ligase of the C terminus of Hsc70-interacting protein (CHIP) on myocytes has been reported. In the current study, we found that the cardioprotective effect of insulin growth factor-1 (IGF-1) was mediated by ERK5-CHIP signal module via inducible cAMP early repressor (ICER) destabilization. In vitro runoff assay and Ub assay showed ICER as a substrate of CHIP Ub ligase. Both disruption of ERK5-CHIP binding with inhibitory helical linker domain fragment (aa 101-200) of CHIP and the depletion of ERK5 by siRNA inhibited CHIP Ub ligase activity, which suggests an obligatory role of ERK5 on CHIP activation. Depletion of CHIP, using siRNA, inhibited IGF-1 mediated reduction of isoproterenol-mediated ICER induction and apoptosis. In diabetic mice subjected to myocardial infarction, the CHIP Ub ligase activity was decreased, with an increase in ICER expression. These changes were attenuated significantly in a cardiac-specific constitutively active form of MEK5alpha transgenic mice (CA-MEK5alpha-Tg) previously shown to have greater functional recovery. Furthermore, pressure overload-mediated ICER induction was enhanced in heterozygous CHIP(+/-) mice. We identified ICER as a novel CHIP substrate and that the ERK5-CHIP complex plays an obligatory role in inhibition of ICER expression, cardiomyocyte apoptosis, and cardiac dysfunction. PMID- 20724526 TI - Incomplete reprogramming after fusion of human multipotent stromal cells and bronchial epithelial cells. AB - Bone marrow-derived progenitor cells can fuse with cells of several different tissues, including lung, especially following injury. Despite many reports of cell fusion, few studies have examined the function of the resulting hybrid cells. We cocultured human multipotent stromal cells (hMSCs) and normal human bronchial epithelial cells (NHBEs) and observed the formation of hMSC/NHBE heterokaryons. The heterokaryons expressed several proteins characteristic of epithelial cells, such as keratin and occludin. Hybrid cells also expressed the mRNAs and proteins for 2 important ion channels that maintain bronchial and alveolar fluid balance: the cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial Na(+) channel (ENaC). By immunocytochemistry, CFTR was expressed in many hybrid cells but was absent or low in others. Whole-cell patch-clamp recordings demonstrated a glibenclamide sensitive current in the presence of barium chloride, consistent with functional CFTR channels, in control NHBEs and hMSC/NHBE heterokaryons. Total cell capacitance measurements showed that the membrane surface area of heterokaryons was similar to that of NHBEs. Heterokaryons expressed the alpha- and gamma-ENaC subunits but did not express the beta-ENaC subunit, indicating the inability to form a complete ENaC channel. In addition, hybrid cells formed by the fusion of hMSCs with immortalized bronchial cells that expressed CFTR DeltaF508 did not lead to reprogramming of the hMSC nucleus and expression of wild-type CFTR mRNA. Our data show that reprogramming can be incomplete following fusion of adult progenitor cells and somatic cells and may lead to altered cell function. PMID- 20724527 TI - Multiple mechanisms limit the accumulation of unesterified cholesterol in the small intestine of mice deficient in both ACAT2 and ABCA1. AB - Cholesterol homeostasis in the enterocyte is regulated by the interplay of multiple genes that ultimately determines the net amount of cholesterol reaching the circulation from the small intestine. The effect of deleting these genes, particularly acyl CoA:cholesterol acyl transferase 2 (ACAT2), on cholesterol absorption and fecal sterol excretion is well documented. We also know that the intestinal mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1) increases in Acat2(-/-) mice. However, none of these studies has specifically addressed how ACAT2 deficiency impacts the relative proportions of esterified and unesterified cholesterol (UC) in the enterocyte and whether the concurrent loss of ABCA1 might result in a marked buildup of UC. Therefore, the present studies measured the expression of numerous genes and related metabolic parameters in the intestine and liver of ACAT2-deficient mice fed diets containing either added cholesterol or ezetimibe, a selective sterol absorption inhibitor. Cholesterol feeding raised the concentration of UC in the small intestine, and this was accompanied by a significant reduction in the relative mRNA level for Niemann-Pick C1-like 1 (NPC1L1) and an increase in the mRNA level for both ABCA1 and ABCG5/8. All these changes were reversed by ezetimibe. When mice deficient in both ACAT2 and ABCA1 were fed a high-cholesterol diet, the increase in intestinal UC levels was no greater than it was in mice lacking only ACAT2. This resulted from a combination of compensatory mechanisms including diminished NPC1L1-mediated cholesterol uptake, increased cholesterol efflux via ABCG5/8, and possibly rapid cell turnover. PMID- 20724528 TI - Effect of aging on gastric mucosal defense mechanisms: ROS, apoptosis, angiogenesis, and sensory neurons. AB - Aging changes in the stomach lead to a decreased capacity for tissue repair in response to gastric acid. The aim of this study was to determine the mechanism associated with the increased susceptibility to injury of aging mucosa including reactive oxygen species (5), apoptosis, angiogenesis, and sensory neuron activity. Fischer 344 rats at four different ages (6, 31, 74 wk, and 2 yr of age) were studied. The connective tissue indicators [salt-soluble collagen and sulfated glycosaminoglycan (sGAG)], lipid hydroperoxide (LPO), myeloperoxidase (MPO), and hexosamine were assessed. We also evaluated the expression of early growth response-1 (Egr-1), phosphatase and tension homologue deleted on chromosome 10 (PTEN), caspase-9 (index of apoptosis), VEGF (index of angiogenesis), calcitonin gene-related peptide (CGRP, index of sensory neurons), and neuronal nitric oxide synthase (nNOS). The histological connective tissue area in the lower part of rat gastric mucosa increased with aging, with increase of salt-soluble collagen and sGAG. LPO and MPO in old rats were significantly greater than in the young rats, whereas hexosamine was significantly reduced. The old gastric mucosa had increased expression of Egr-1, PTEN, and caspase-9, whereas the VEGF, CGRP, and nNOS expression were significantly reduced. These results indicate that the lower part of rat gastric mucosa was found to be replaced by connective tissue with accumulation of oxidative products with aging. In addition, impairment of apoptosis, angiogenesis, and sensory neuron activity via the activation of Egr-1 and PTEN might increase the susceptibility of gastric mucosa to injury during aging. PMID- 20724529 TI - Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine. AB - Nonalcoholic fatty liver (NAFL) is a common liver disease, associated with insulin resistance. Betaine has been tested as a treatment for NAFL in animal models and in small clinical trials, with mixed results. The present study aims to determine whether betaine treatment would prevent or treat NAFL in mice and to understand how betaine reverses hepatic insulin resistance. Male mice were fed a moderate high-fat diet (mHF) containing 20% of calories from fat for 7 (mHF) or 8 (mHF8) mo without betaine, with betaine (mHFB), or with betaine for the last 6 wk (mHF8B). Control mice were fed standard chow containing 9% of calories from fat for 7 mo (SF) or 8 mo (SF8). HepG2 cells were made insulin resistant and then studied with or without betaine. mHF mice had higher body weight, fasting glucose, insulin, and triglycerides and greater hepatic fat than SF mice. Betaine reduced fasting glucose, insulin, triglycerides, and hepatic fat. In the mHF8B group, betaine treatment significantly improved insulin resistance and hepatic steatosis. Hepatic betaine content significantly decreased in mHF and increased significantly in mHFB. Betaine treatment reversed the inhibition of hepatic insulin signaling in mHF and in insulin-resistant HepG2 cells, including normalization of insulin receptor substrate 1 (IRS1) phosphorylation and of downstream signaling pathways for gluconeogenesis and glycogen synthesis. Betaine treatment prevents and treats fatty liver in a moderate high-dietary-fat model of NAFL in mice. Betaine also reverses hepatic insulin resistance in part by increasing the activation of IRS1, with resultant improvement in downstream signaling pathways. PMID- 20724531 TI - Advances in pharmacologic stress agents: focus on regadenoson. AB - Myocardial perfusion imaging using radionuclides is a well-established protocol for determining the diagnosis, prognosis, and management of coronary artery disease. Pharmacologic stress agents are used to induce cardiac hyperemia in patients unable to achieve the target workload by physical exercise alone. The vasodilators adenosine and dipyridamole are most commonly used, with dobutamine used only when these agents are contraindicated. However, because of frequent and intense side effects, as well as complex procedures both for patients and the nuclear medicine staff, there is room for improvement in these traditional stress agents. An ideal stress agent would be effective, safe, and well tolerated; have a simple protocol; be suitable for use in patients with reactive airway disease; and have few restrictions for the patient to adhere to before the procedure. Neither adenosine nor dipyridamole are receptor-specific, and act on A(1), A(2A), A(2B), and A(3) adenosine receptors. As it is the A(2A) receptor that mediates the desired coronary vasodilation, the A(1), A(2B), and A(3) adenosine receptors are deemed responsible for most side effects associated with adenosine and dipyridamole. A(2A)-selective pharmacologic stress agents should mediate the required hyperemic response while reducing the frequency of adverse events. The only selective A(2A) adenosine receptor agonist currently approved for clinical use as a pharmacologic stress agent for myocardial perfusion imaging is regadenoson. Regadenoson has demonstrated non-inferiority to adenosine for detecting reversible myocardial perfusion defects in phase 3 trials, and patients were more comfortable during the regadenoson stress procedure than during an adenosine infusion. As regadenoson dosing is not dependent on patient weight or renal impairment and can be administered by rapid injection, it has the potential to simplify the stress procedure, reduce costs, and streamline the working day for the staff of the nuclear medicine department. In this review, the need to improve on older pharmacologic stress agents will be considered, along with an assessment of how A(2A) receptor agonists fulfill that potential. Practical aspects of regadenoson are reviewed, and the impact that A(2A) receptor agonist use may have on the nuclear medicine department is evaluated. PMID- 20724530 TI - The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine. AB - Lysophosphatidic acid (LPA) is a lipid mediator that mediates several effects that promote cancer progress. The LPA receptor type 2 (LPA(2)) expression is often elevated in several types of cancers, including colorectal cancer (CRC). In this study, we investigated the role of LPA(2) in the development of intestinal adenomas by comparing Apc(Min/+) mice with Apc(Min/+)/Lpar2(-/-) mice. There were 50% fewer intestinal adenomas in Apc(Min/+)/Lpar2(-/-) mice than Apc(Min/+) mice. Smaller-size adenomas (<1 mm) were found at higher frequencies in Apc(Min/+)/Lpar2(-/-) mice compared with Apc(Min/+) mice at the two age groups examined. The expression level of LPA(2) correlated with increased size of intestinal adenomas. Reduced tumor multiplicity and size in Apc(Min/+)/Lpar2(-/-) mice correlated with decreased proliferation of intestinal epithelial cells. Apc(Min/+)/Lpar2(-/-) mice showed an increased level of apoptosis, suggesting that LPA(2)-mediated signaling stimulates intestinal tumor development and progress by regulating both cell proliferation and survival. In addition, the expression levels of Krupple-like factor 5 (KLF5), beta-catenin, cyclin D1, c Myc, and hypoxia-inducible factor-1alpha (HIF-1alpha) were significantly altered in Apc(Min/+)/Lpar2(-/-) mice compared with Apc(Min/+) mice. In vitro studies using HCT116 cells showed that LPA induced cyclin D1, c-Myc, and HIF-1alpha expression, which was attenuated by knockdown of LPA(2). In summary, intestinal tumor initiated by Apc mutations is altered by LPA(2)-mediated signaling, which regulates tumor growth and survival by altering multiple targets. PMID- 20724532 TI - The association of dipyridamole side effects with hemodynamic parameters, ECG findings, and scintigraphy outcomes. AB - Dipyridamole has extensively been administered as a substitute for physical activity in cardiovascular assessment. The aim of this study was to evaluate the association of dipyridamole side effects with hemodynamic oscillations, scanning results, and electrocardiography (ECG) findings. METHODS: Overall, 590 patients referred to the nuclear medicine center for myocardial perfusion imaging were evaluated for adverse dipyridamole effects concurrent with a low level of exercise. Before and during dipyridamole infusion, the patients' vital signs, electrocardiogram, heart rate, systolic blood pressure, and diastolic blood pressure were monitored; all patients underwent stress-rest (99m)Tc-sestamibi gated SPECT using a 2-d protocol. RESULTS: Eighty-eight patients (14.9%) experienced at least one side effect during dipyridamole infusion, and abnormal ECG and scan results were observed in 32.4% and 48.6% of patients, respectively. We observed a positive correlation between a higher incidence of chest discomfort, headache, and dyspnea and abnormalities on ECG and myocardial perfusion imaging. In addition, these 3 side effects were also associated with a higher postinfusion heart rate, lower preinfusion systolic blood pressure, and lower postinfusion diastolic blood pressure. There were significant differences between pre- and postinfusion heart rate, preinfusion systolic blood pressure, and postinfusion diastolic blood pressure among patients with or without side effects, whereas no significant difference was observed in any of the hemodynamic parameters between patients with normal and abnormal ECG results or myocardial perfusion imaging results. CONCLUSION: This study demonstrated a correlation between hemodynamic variables and side effects but not with imaging findings or ECG findings. PMID- 20724533 TI - Whole-body 18F-FDG PET/CT: the need for a standardized field of view--a referring physician aid. AB - PET/CT fusion of anatomic and functional imaging modalities is in evolution, with rapid clinical dissemination. The imaged field of view (FOV) selected for whole body PET/CT protocols is not standardized and varies by institution. Misuse of the term whole body, as well as the pressure to increase the number of daily studies by reducing scanning time, contributes to the lack of standardization. The purpose of this study was to evaluate variations in the FOV and arm positioning selected for whole-body PET/CT protocols at private, as well as academic, PET centers. METHODS: Two hundred consecutive whole-body (18)F-FDG PET/CT studies were retrospectively reviewed for FOV: 50 studies from a private stationary site, 50 studies from 2 separate private mobile sites (25 consecutive studies from each), and 100 studies from a stationary university site: 50 before and 50 after implementation of a true whole-body protocol covering the top of the head through the bottom of the feet. Data were categorized into 5 different anatomic scan lengths: base of skull to upper thigh, base of skull to mid thigh, top of head to upper thigh, top of head to mid thigh, and true whole-body. Studies were further categorized into 2 patient arm positions: up and down. RESULTS: The private stationary and mobile sites had only 2 categories of anatomic scan lengths identified: base of skull to mid thigh, and top of head to upper thigh. At the university site, before implementation of a true whole-body protocol, the 5 different anatomic scan lengths were identified; after implementation, only the true whole-body scan length was identified. Patients' arms in the private stationary sites were down 100% of the time. At the private mobile sites, patients' arms were up 72% of the time and down 28% of the time. At the university site, patients' arms were up 54% of the time and down 46% of the time. The same site, after implementation of a true whole-body protocol, had patients' arms up 58% of the time and down 42% of the time. Overall, patients' arms were up 46% of the time and down 54% of the time. CONCLUSION: The continued use of the term whole body is misleading because frequently it may not include the brain, skull, or significant portions of the upper and lower extremities. PET/CT anatomic scan length varied not only from one site to the next but also within individual sites. The Centers for Medicare and Medicaid Services have different current procedural terminology codes distinguishing between base of skull to upper thigh and true whole-body covering the top of the skull to the bottom of the feet, thus underscoring the need to standardize the terminology used in describing PET/CT scan length. PMID- 20724534 TI - Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway. AB - High-density lipoprotein (HDL) is known as an important factor in vascular wall remodeling that also affects gene expression in cell proliferation and differentiation. In this article, the role of HDL on endothelial progenitor cell (EPC) proliferation, angiogenesis and the signal pathway involved was studied, particularly the influence of HDL in strengthening the promoting effect of EPCs on wound healing of the arterial wall in hypercholesterolemic rats. Mononuclear cells isolated from rat bone marrow displayed characteristics of EPCs after cultivation. The role of HDL on EPC function and the signal pathway involved were studied by Western blotting, in vitro migration and 'tube' formation. Re endothelialization and the number of circulating EPCs were compared between normal rats, hypercholesterolemic rats and hypercholesterolemic rats with HDL treatment. Results showed that HDL participated in the healing process by promoting EPC proliferation, migration and 'tube' formation. HDL activates cyclin D1 via phosphatidylinositol 3-kinase (PI3K)/Akt stimulation. Inhibition of PI3K/Akt via pharmacological or small interfering RNA approaches significantly attenuated HDL-induced EPC migration, proliferation and 'tube' formation. Results of experiments in vivo showed that HDL increased the number of circulating EPCs and promoted re-endothelialization in wound healing. These findings demonstrate for the first time that PI3K/Akt-dependent cyclin D1 activation plays an essential role in HDL-induced EPC proliferation, migration and angiogenesis. PMID- 20724535 TI - Molecular biomarker panels for assessment of selenium status in rats. AB - Molecular biomarkers are mRNA transcripts that indicate the (nutrient) status of an organism or tissue. Molecular biomarker panels have the potential to readily and more accurately determine nutrient status than individual traditional biomarkers. To study the efficacy of molecular biomarker panels for predicting selenium (Se) status, we examined 30 biomarkers from rats fed graded levels of Se from deficient to eight times the minimum Se requirement, including four liver and four kidney traditional biomarkers, and 13 liver and nine kidney selenoprotein mRNA levels. Multiple regression analysis against liver and kidney Se and glutathione peroxidase-1 (Gpx1) activity, with stepwise single elimination of biomarkers that did not significantly contribute, was used to identify biomarker panels with significant (P < 0.05) regression coefficients. Resulting regression equations were then used to predict Se status, and compared with traditional Se biomarkers panels. Over the full spectrum of Se status from 0 to 0.8 microg Se/g diet, the resulting 4-selenoprotein mRNA biomarker panel predicted liver Se concentration with a correlation of 0.948, which was nominally higher and statistically the same as the correlation of 0.909 for the panel based on Gpx1 activity. The molecular biomarker panels for predicting kidney Se and liver and kidney Gpx1 activity were all comparable to predictions based on traditional biomarkers. These analyses show that molecular biomarker panels can be used to predict accurately two traditional biomarkers of Se status. The resulting analyses also illustrate that additional orthogonal biomarkers reflecting higher Se intakes are needed to better predict supernutritional Se status and further strengthen this approach. PMID- 20724536 TI - Reciprocal regulation of aquaporin-2 abundance and degradation by protein kinase A and p38-MAP kinase. AB - Arginine-vasopressin (AVP) modulates the water channel aquaporin-2 (AQP2) in the renal collecting duct to maintain homeostasis of body water. AVP binds to vasopressin V2 receptors (V2R), increasing cAMP, which promotes the redistribution of AQP2 from intracellular vesicles into the plasma membrane. cAMP also increases AQP2 transcription, but whether altered degradation also modulates AQP2 protein levels is not well understood. Here, elevation of cAMP increased AQP2 protein levels within 30 minutes in primary inner medullary collecting duct (IMCD) cells, in human embryonic kidney (HEK) 293 cells ectopically expressing AQP2, and in mouse kidneys. Accelerated transcription or translation did not explain this increase in AQP2 abundance. In IMCD cells, cAMP inhibited p38 mitogen-activated protein kinase (p38-MAPK) via activation of protein kinase A (PKA). Inhibition of p38-MAPK associated with decreased phosphorylation (serine 261) and polyubiquitination of AQP2, preventing proteasomal degradation. Our results demonstrate that AVP enhances AQP2 protein abundance by altering its proteasomal degradation through a PKA- and p38-MAPK-dependent pathway. PMID- 20724537 TI - Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. AB - New treatment options are required for primary systemic amyloid light chain (AL) amyloidosis. This phase 1/2 dose-escalation study aimed to determine the maximum tolerated dose (MTD) of lenalidomide in combination with melphalan and dexamethasone (M-dex), and assess the efficacy and tolerability of this therapy for patients with de novo AL amyloidosis. Twenty-six patients were enrolled across 4 cohorts: M-dex + lenalidomide 5, 10, 15, and 20 mg once daily on days 1 to 21 in a 28-day cycle. No dose limiting toxicity (DLT) was observed in cohorts 1, 2, and 3. 4. Seven patients in cohort 4, M-dex + lenalidomide 20 mg/day, experienced DLT. MTD was defined as 15 mg of lenalidomide. A complete hematologic response was achieved in 42% at the dose of 15 mg of lenalidomide per day. After a median follow-up of 19 months, estimated 2-year overall survival (OS) and event free survival (EFS) were 80.8% and 53.8%, respectively. Hematologic and organ responses were both associated with superior EFS rates (P = .0001). A higher EFS was also observed in patients whose free light chains decreased by more than 50% during therapy (P = .019). Lenalidomide 15 mg/d + M-dex is a new effective combination therapy in patients with newly diagnosed AL amyloidosis. This study is registered at www.clinicaltrials.gov as NCT00621400. PMID- 20724538 TI - Olfactomedin 4 is a novel target gene of retinoic acids and 5-aza-2' deoxycytidine involved in human myeloid leukemia cell growth, differentiation, and apoptosis. AB - Clinical application of retinoic acids (RAs) and demethylation agents has proven to be effective in treating certain myeloid leukemia patients. However, the target genes that mediate these antileukemia activities are still poorly understood. In this study, we identified olfactomedin 4 (OLFM4), a myeloid lineage-specific gene from the olfactomedin family, as a novel target gene for RAs and the demethylation agent, 5-aza-2'-deoxycytidine. We demonstrated that the retinoic acid receptor alpha/retinoic X receptor alpha heterodimer binds to a retinoic acid response-element (DR5) site in the OLFM4 promoter and mediates all trans-retinoic acid (ATRA)-induced transactivation of the OLFM4 gene. OLFM4 overexpression in HL-60 cells led to growth inhibition, differentiation, and apoptosis, and potentiated ATRA induction of these effects. Conversely, down regulation of endogenous OLFM4 in acute myeloid leukemia-193 cells compromised ATRA-induced growth inhibition, differentiation, and apoptosis. Overexpression of OLFM4 in HL-60 cells inhibited constitutive and ATRA-induced phosphorylation of the eukaryote initiation factor 4E-binding protein 1 (4E-BP1), whereas down regulation of OLFM4 protein in acute myeloid leukemia-193 cells increased 4E-BP1 phosphorylation, suggesting that OLFM4 is a potent upstream inhibitor of 4E-BP1 phosphorylation/deactivation. Thus, our study demonstrates that OLFM4 plays an important role in myeloid leukemia cellular functions and induction of OLFM4 mediated effects may contribute to the therapeutic value of ATRA. PMID- 20724539 TI - Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function. AB - Mutations in bone morphogenetic protein receptor II (BMPR-II) underlie most heritable cases of pulmonary arterial hypertension (PAH). However, less than half the individuals who harbor mutations develop the disease. Interestingly, heterozygous null BMPR-II mice fail to develop PAH unless an additional inflammatory insult is applied, suggesting that BMPR-II plays a fundamental role in dampening inflammatory signals in the pulmonary vasculature. Using static- and flow-based in vitro systems, we demonstrate that BMPR-II maintains the barrier function of the pulmonary artery endothelial monolayer suppressing leukocyte transmigration. Similar findings were also observed in vivo using a murine model with loss of endothelial BMPR-II expression. In vitro, the enhanced transmigration of leukocytes after tumor necrosis factor alpha or transforming growth factor beta1 stimulation was CXCR2 dependent. Our data define how loss of BMPR-II in the endothelial layer of the pulmonary vasculature could lead to a heightened susceptibility to inflammation by promoting the extravasation of leukocytes into the pulmonary artery wall. We speculate that this may be a key mechanism involved in the initiation of the disease in heritable PAH that results from defects in BMPR-II expression. PMID- 20724540 TI - Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease. AB - Erdheim-Chester disease (ECD) pathophysiology remains largely unknown. Its treatment is not codified and usually disappointing. Interferon (IFN)-alpha therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile. Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-alpha, we hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD. We treated 2 patients who had poor tolerance or contraindication to IFN-alpha with anakinra as a rescue therapy and measured their serum C-reactive protein, IL-1beta, IL-6, and monocytic membranous IL-1alpha (mIL-1alpha) levels before, under, and after therapy. Another untreated ECD patient and 5 healthy subjects were enrolled as controls. After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in one patient. In addition, retroperitoneal fibrosis completely or partially regressed, and C-reactive protein, IL-6, and mIL-1alpha levels decreased to within the normal and control range. Beside injection-site reactions, no adverse event was reported. Therefore, our results support a central role of the IL-1 network, which seemed to be overstimulated in ECD. Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD. PMID- 20724541 TI - BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. AB - The major limitation for the development of curative cancer therapies has been an incomplete understanding of the molecular mechanisms driving cancer progression. Human models to study the development and progression of chronic myeloid leukemia (CML) have not been established. Here, we show that BMI1 collaborates with BCR ABL in inducing a fatal leukemia in nonobese diabetic/severe combined immunodeficiency mice transplanted with transduced human CD34(+) cells within 4-5 months. The leukemias were transplantable into secondary recipients with a shortened latency of 8-12 weeks. Clonal analysis revealed that similar clones initiated leukemia in primary and secondary mice. In vivo, transformation was biased toward a lymphoid blast crisis, and in vitro, myeloid as well as lymphoid long-term, self-renewing cultures could be established. Retroviral introduction of BMI1 in primary chronic-phase CD34(+) cells from CML patients elevated their proliferative capacity and self-renewal properties. Thus, our data identify BMI1 as a potential therapeutic target in CML. PMID- 20724543 TI - Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation. PMID- 20724544 TI - Thalamic damage and long-term progression of disability in multiple sclerosis. AB - PURPOSE: To estimate the relative contributions of baseline thalamic atrophy and abnormalities shown at magnetization transfer (MT) magnetic resonance (MR) imaging, as well as their 12-month changes, in predicting accumulation of disability in a relatively large sample of patients with relapse-onset multiple sclerosis (MS) during an 8-year period. MATERIALS AND METHODS: The study was conducted with approval of the institutional review board. Written informed consent was obtained from each participant. Conventional and MT MR imaging of the brain was performed at baseline and at 12-month follow-up in 13 healthy control subjects and 73 patients with relapse-onset MS; participants were monitored with clinical visits for 8 years. The following parameters were evaluated at baseline and at 12-month follow-up: volume of lesions with high signal intensity at T2 weighted imaging, volume of lesions with low signal intensity at T1-weighted imaging, mean lesion MT ratio, thalamic fraction, and thalamic MT ratio. A multivariate analysis was used to evaluate the predictors of long-term neurologic deterioration. RESULTS: At 8-year follow-up, 44 patients showed worsening disability. During follow-up, reduction in thalamic fraction was more pronounced in patients with relapsing-remitting MS than in those with secondary progressive MS (P = .001); thalamic MT ratio decreased only in patients with secondary progressive MS (P = .007). In the multivariable model, baseline thalamic fraction (odds ratio = 0.62, P = .01) and mean percentage change in lesion MT ratio after 12 months (odds ratio = 0.90, P = .04) were independent predictors of worsening disability at 8 years. At baseline, thalamic fraction was correlated with lesion volumes at T2-weighted imaging (r = -0.75, P < .001) and T1-weighted imaging (r = -0.60, P < .001). CONCLUSION: Thalamic atrophy is correlated with long-term accumulation of disability in patients with MS. White matter lesions are likely to contribute to the loss of tissue seen in the thalamus of patients with MS. PMID- 20724542 TI - FLIP: a novel regulator of macrophage differentiation and granulocyte homeostasis. AB - FLIP is a well-established suppressor of death receptor-mediated apoptosis. To define its essential in vivo role in myeloid cells, we generated and characterized mice with Flip conditionally deleted in the myeloid lineage. Myeloid specific Flip-deficient mice exhibited growth retardation, premature death, and splenomegaly with altered architecture and extramedullary hematopoiesis. They also displayed a dramatic increase of circulating neutrophils and multiorgan neutrophil infiltration. In contrast, although circulating inflammatory monocytes were also significantly increased, macrophages in the spleen, lymph nodes, and the peritoneal cavity were reduced. In ex vivo cultures, bone marrow progenitor cells failed to differentiate into macrophages when Flip was deleted. Mixed bone marrow chimera experiments using cells from Flip deficient and wild-type mice did not demonstrate an inflammatory phenotype. These observations demonstrate that FLIP is necessary for macrophage differentiation and the homeostatic regulation of granulopoiesis. PMID- 20724545 TI - Similar yet different. PMID- 20724546 TI - The White House crusade against ... MGUS? PMID- 20724547 TI - "Micro"-managing the MiRNome in SzS. PMID- 20724548 TI - S100A10: a complex inflammatory role. PMID- 20724549 TI - Evidence against a protein in plasma that is a product of a factor XI mRNA splice variant missing exons 6 and 7. PMID- 20724551 TI - The alpha4beta1 integrin in localization of Mycobacterium tuberculosis-specific T helper type 1 cells to the human lung. AB - Rapid mobilization of antigen-specific T helper (Th) type 1-like CD4(+) T cells to the lung appears to be critically important for control of the respiratory pathogen Mycobacterium tuberculosis (M. tb), and for protection against pulmonary tuberculosis, the most contagious form of the disease. Accordingly, the preferential circulation of memory lymphocytes back to the tissues in which they first encountered antigen (i.e., "homing") may underlie the limited efficacy of current intradermal vaccination with the M. bovis strain bacillus Calmette Guerrin. We previously developed a method of bronchoscopic antigen challenge with purified protein derivative of M. tb (PPD) to model local recall responses of healthy PPD-positive individuals who were infected via respiratory exposure to M. tb. Bronchoscopic challenge with PPD results in recruitment of additional antigen specific Th1-like cells into challenged lung segments of healthy M. tb-infected individuals but not those of PPD-negative control subjects. In this study, we assessed the role of homing molecule expression in localization of M. tb-specific recall responses to the lung. Compared with peripheral blood, baseline bronchoalveolar lavage is significantly enriched for CD4(+) T cells expressing the alpha4beta1 integrin homing molecule. This skewing is continued after PPD induced recruitment of CD4(+) T cells, and is even more pronounced for recruited CD4(+) cells that display PPD-specific production of IFN-gamma, of which over 83% express alpha4beta1. Expression of the alpha4beta1 integrin, therefore, appears likely to optimize localization of M. tb-specific Th1-like recall responses to the human lung. PMID- 20724552 TI - Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. AB - Cystic fibrosis (CF), the most common fatal monogenic disease in the United States, results from mutations in CF transmembrane conductance regulator (CFTR), a chloride channel. The mechanisms by which CFTR mutations cause lung disease in CF are not fully defined but may include altered ion and water transport across the airway epithelium and aberrant inflammatory and immune responses to pathogens within the airways. We have shown that Cftr(-/-) mice mount an exaggerated IgE response toward Aspergillus fumigatus, with higher levels of IL-13 and IL-4, mimicking both the T helper cell type 2-biased immune responses seen in patients with CF. Herein, we demonstrate that these aberrations are primarily due to Cftr deficiency in lymphocytes rather than in the epithelium. Adoptive transfer experiments with CF splenocytes confer a higher IgE response to Aspergillus fumigatus compared with hosts receiving wild-type splenocytes. The predilection of Cftr-deficient lymphocytes to mount T helper cell type 2 responses with high IL-13 and IL-4 was confirmed by in vitro antigen recall experiments. Conclusive data on this phenomenon were obtained with conditional Cftr knockout mice, where mice lacking Cftr in T cell lineages developed higher IgE than their wild-type control littermates. Further analysis of Cftr-deficient lymphocytes revealed an enhanced intracellular Ca(2+) flux in response to T cell receptor activation. This was accompanied by an increase in nuclear localization of the calcium sensitive transcription factor, nuclear factor of activated T cell, which could drive the IL-13 response. In summary, our data identified that CFTR dysfunction in T cells can lead directly to aberrant immune responses. These findings implicate the lymphocyte population as a potentially important target for CF therapeutics. PMID- 20724553 TI - Epigenetic regulation of thy-1 by histone deacetylase inhibitor in rat lung fibroblasts. AB - Thy-1 is a cell surface glycoprotein present on normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis. Thy-1 correlates inversely with fibrogenic phenotypic characteristics and functions as a "fibrosis suppressor." Promoter region hypermethylation can silence Thy-1 expression in fibroblastic foci, suggesting that epigenetic regulation is important in programming the fibrotic phenotype. We examined whether histone modifications are important in regulating Thy-1 expression in lung fibroblasts. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) restored Thy-1 expression in Thy-1(-) cells in a time-dependent and concentration dependent fashion and was associated with enrichment of histone acetylation. Chromatin immunoprecipitation demonstrated Thy-1 depletion of trimethylated H3K27 after 24 hours of TSA treatment, concurrent with enrichment of trimethylated H3K4 and acetylated H4. Bisulfite sequencing of the Thy-1 promoter region revealed demethylation of the previously hypermethylated CpG sites after treatment with TSA. Although Thy-1 was hypermethylated in Thy-1(-) lung fibroblasts, we observed that Thy-1(-) cells have lower global DNA methylation compared with Thy-1(+) lung fibroblasts, which was partially reversed by TSA treatment. TSA treatment up regulates total methyltransferase activity in these cells. Our data indicate that Thy-1 silencing is regulated by histone modifications in addition to promoter hypermethylation in lung fibroblasts. Additionally, our findings indicate that alteration of histone modifications alters DNA methylation. Understanding the molecular hierarchy of events with respect to reactivation of transcription and reversal of histone modification will be critical to understand and modify the regulated expression of Thy-1, a tumor-supressor and fibrosis-suppressor gene. PMID- 20724554 TI - Modeling asthma in mice: what have we learned about the airway epithelium? AB - Clinical reports of areas of damaged airway epithelium associated with shed epithelial cells in bronchoalveolar lavage fluid, aberrant epithelial repair processes, and altered cytokine and growth factor release have highlighted some fundamental differences between the airway epithelium in individuals with and without asthma. However, the consequences of these epithelial changes are not clearly defined, and may be difficult to assess in the clinic. In this Review, we answer the two questions. (1) What in vivo models and methods have been used to inform us about airway epithelium damage, repair, and immune responses? Our response focuses on genetic influences as well as allergen exposure, environmental/chemical, and mechanical models. (2) How can we improve on existing mouse models to understand changes in airway epithelium biology in asthma? In answering the second question, we include exciting recent studies that have combined multiple exposure methods and/or epithelium-centric outcome measurements. By addressing these two questions, we propose that future interrogation of epithelial responses of both existing and nascent mouse models may provide greater understanding of the mechanisms underlying airway inflammation and remodeling in asthma with hope of generating novel therapeutic targets. PMID- 20724555 TI - Human bronchial epithelial cells differentiate to 3D glandular acini on basement membrane matrix. AB - To create a model system that investigates mechanisms resulting in hyperplasia and hypertrophy of respiratory tract submucosal glands, we developed an in vitro three-dimensional (3D) system wherein normal human bronchial epithelial (HBE) cells differentiated into glandular acini when grown on a basement membrane matrix. The differentiation of primary HBE cells into glandular acini was monitored temporally by light microscopy. Apoptosis-induced lumen formation was observed by immunofluorescence analysis. The acinar cells expressed and secreted MUC5B mucin (marker for glandular mucous cells) and lysozyme, lactoferrin, and zinc-alpha2-glycoprotein (markers for glandular serous cells) at Day 22. beta Tubulin IV, a marker for ciliated cells, was not detected. Expression of mucous and serous cell markers in HBE glandular acini demonstrated that HBE cells grown on a basement membrane matrix differentiated into acini that exhibit molecular characteristics of respiratory tract glandular acinar cells. Inhibition studies with neutralizing antibodies resulted in a marked decrease in size of the spheroids at Day 7, demonstrating that laminin (a major component of the basement membrane matrix), the cell surface receptor integrin alpha6, and the cell junction marker E-cadherin have functional roles in HBE acinar morphogenesis. No significant variability was detected in the average size of glandular acini formed by HBE cells from two normal individuals. These results demonstrated that this in vitro model system is reproducible, stable, and potentially useful for studies of glandular differentiation and hyperplasia. PMID- 20724556 TI - A comprehensive review of arsenic levels in the semiconductor manufacturing industry. AB - This paper presents a summary of arsenic level statistics from air and wipe samples taken from studies conducted in fabrication operations. The main objectives of this study were not only to describe arsenic measurement data but also, through a literature review, to categorize fabrication workers in accordance with observed arsenic levels. All airborne arsenic measurements reported were included in the summary statistics for analysis of the measurement data. The arithmetic mean was estimated assuming a lognormal distribution from the geometric mean and the geometric standard deviation or the range. In addition, weighted arithmetic means (WAMs) were calculated based on the number of measurements reported for each mean. Analysis of variance (ANOVA) was employed to compare arsenic levels classified according to several categories such as the year, sampling type, location sampled, operation type, and cleaning technique. Nine papers were found reporting airborne arsenic measurement data from maintenance workers or maintenance areas in semiconductor chip-making plants. A total of 40 statistical summaries from seven articles were identified that represented a total of 423 airborne arsenic measurements. Arsenic exposure levels taken during normal operating activities in implantation operations (WAM = 1.6 MUg m-3, no. of samples = 77, no. of statistical summaries = 2) were found to be lower than exposure levels of engineers who were involved in maintenance works (7.7 MUg m-3, no. of samples = 181, no. of statistical summaries = 19). The highest level (WAM = 218.6 MUg m-3) was associated with various maintenance works performed inside an ion implantation chamber. ANOVA revealed no significant differences in the WAM arsenic levels among the categorizations based on operation and sampling characteristics. Arsenic levels (56.4 MUg m-3) recorded during maintenance works performed in dry conditions were found to be much higher than those from maintenance works in wet conditions (0.6 MUg m-3). Arsenic levels from wipe samples in process areas after maintenance activities ranged from non detectable to 146 MUg cm-2, indicating the potential for dispersion into the air and hence inhalation. We conclude that workers who are regularly or occasionally involved in maintenance work have higher potential for occupational exposure than other employees who are in charge of routine production work. In addition, fabrication workers can be classified into two groups based on the reviewed arsenic exposure levels: operators with potential for low levels of exposure and maintenance engineers with high levels of exposure. These classifications could be used as a basis for a qualitative ordinal ranking of exposure in an epidemiological study. PMID- 20724557 TI - Prevalence of mandibular asymmetries in growing patients. AB - The aim of the present study was to determine the prevalence of mandibular asymmetries during the mixed dentition in growing children. For this purpose, a retrospective study was designed where various measurements were performed on the right and left sides of the mandible of panoramic radiographs of 327 children (males: 169; females: 158), 8-12 years old. Four linear measurements, mandibular ramus height, ramus width, corpus height, and corpus length, and two angles, mandibular gonial (Go) and mandibular condyle (Co), and the developmental stage of the permanent lower second molar were analysed. All measurements were adjusted for the magnification factor. The final data were then processed for the asymmetry index (AI) to determine the severity of the asymmetries and statistically analysed by Wilcoxon paired tests at the 95 per cent level of confidence. A moderate-to-severe mandibular asymmetry for the linear dimensions when both sides of the mandible were contrasted was found in more than a half of the sample. There was also a high prevalence of moderate and severe asymmetries when comparing Go and Co angles on both sides of the mandible. No differences were observed in the developmental stage of the lower permanent second molar between either side. There was a high prevalence of both dimensional and angular mandibular asymmetries in the studied population. PMID- 20724558 TI - Phenol increases intracellular [Ca2+] during twitch contractions in intact Xenopus skeletal myofibers. AB - Phenol is a neurolytic agent used for management of spasticity in patients with either motoneuron lesions or stroke. In addition, compounds that enhance muscle contractility (i.e., polyphenols, etc.) may affect muscle function through the phenol group. However, the effects of phenol on muscle function are unknown, and it was, therefore, the purpose of the present investigation to examine the effects of phenol on tension development and Ca(2+) release in intact skeletal muscle fibers. Dissected intact muscle fibers from Xenopus laevis were electrically stimulated, and cytosolic Ca(2+) concentration ([Ca(2+)](c)) and tension development were recorded. During single twitches and unfused tetani, phenol significantly increased [Ca(2+)](c) and tension without affecting myofilament Ca(2+) sensitivity. To investigate the phenol effects on Ca(2+) channel/ryanodine receptors, single fibers were treated with different concentrations of caffeine in the presence and absence of phenol. Low concentrations of phenol significantly increased the caffeine sensitivity (P < 0.01) and reduced the caffeine concentrations necessary to produce nonstimulated contraction (contracture). However, at high phenol concentrations, caffeine did not increase tension or Ca(2+) release. These results suggest that phenol affects the ability of caffeine to release Ca(2+) through an effect on the ryanodine receptors, or on the sarcoplasmic reticulum Ca(2+) pump. During tetanic contractions inducing fatigue, phenol application decreased the time to fatigue. In summary, phenol increases intracellular [Ca(2+)] during twitch contractions in muscle fibers without altering myofilament Ca(2+) sensitivity and may be used as a new agent to study skeletal muscle Ca(2+) handling. PMID- 20724559 TI - Sustained hyperoxia stabilizes breathing in healthy individuals during NREM sleep. AB - The present study was designed to determine whether hyperoxia would lower the hypocapnic apneic threshold (AT) during non-rapid eye movement (NREM) sleep. Nasal noninvasive mechanical ventilation was used to induce hypocapnia and subsequent central apnea in healthy subjects during stable NREM sleep. Mechanical ventilation trials were conducted under normoxic (room air) and hyperoxic conditions (inspired PO(2) > 250 Torr) in a random order. The CO(2) reserve was defined as the minimal change in end-tidal PCO(2) (PET(CO(2))) between eupnea and hypocapnic central apnea. The PET(CO(2)) of the apnea closest to eupnea was designated as the AT. The hypocapnic ventilatory response was calculated as the change in ventilation below eupnea for a given change in PET(CO(2)). In nine participants, compared with room air, exposure to hyperoxia was associated with a significant decrease in eupneic PET(CO(2)) (37.5 +/- 0.6 vs. 41.1 +/- 0.6 Torr, P = 0.001), widening of the CO(2) reserve (-3.8 +/- 0.8 vs. -2.0 +/- 0.3 Torr, P = 0.03), and a subsequent decline in AT (33.3 +/- 1.2 vs. 39.0 +/- 0.7 Torr; P = 001). The hypocapnic ventilatory response was also decreased with hyperoxia. In conclusion, 1) hyperoxia was associated with a decreased AT and an increase in the magnitude of hypocapnia required for the development of central apnea. 2) Thus hyperoxia may mitigate the effects of hypocapnia on ventilatory motor output by lowering the hypocapnic ventilatory response and lowering the resting eupneic PET(CO(2)), thereby decreasing plant gain. PMID- 20724560 TI - Heat acclimation improves exercise performance. AB - This study examined the impact of heat acclimation on improving exercise performance in cool and hot environments. Twelve trained cyclists performed tests of maximal aerobic power (VO2max), time-trial performance, and lactate threshold, in both cool [13 degrees C, 30% relative humidity (RH)] and hot (38 degrees C, 30% RH) environments before and after a 10-day heat acclimation (~50% VO2max in 40 degrees C) program. The hot and cool condition VO2max and lactate threshold tests were both preceded by either warm (41 degrees C) water or thermoneutral (34 degrees C) water immersion to induce hyperthermia (0.8-1.0 degrees C) or sustain normothermia, respectively. Eight matched control subjects completed the same exercise tests in the same environments before and after 10 days of identical exercise in a cool (13 degrees C) environment. Heat acclimation increased VO2max by 5% in cool (66.8 +/- 2.1 vs. 70.2 +/- 2.3 ml.kg(-1).min(-1), P = 0.004) and by 8% in hot (55.1 +/- 2.5 vs. 59.6 +/- 2.0 ml.kg(-1).min(-1), P = 0.007) conditions. Heat acclimation improved time-trial performance by 6% in cool (879.8 +/- 48.5 vs. 934.7 +/- 50.9 kJ, P = 0.005) and by 8% in hot (718.7 +/- 42.3 vs. 776.2 +/- 50.9 kJ, P = 0.014) conditions. Heat acclimation increased power output at lactate threshold by 5% in cool (3.88 +/- 0.82 vs. 4.09 +/- 0.76 W/kg, P = 0.002) and by 5% in hot (3.45 +/- 0.80 vs. 3.60 +/- 0.79 W/kg, P < 0.001) conditions. Heat acclimation increased plasma volume (6.5 +/- 1.5%) and maximal cardiac output in cool and hot conditions (9.1 +/- 3.4% and 4.5 +/- 4.6%, respectively). The control group had no changes in VO2max, time-trial performance, lactate threshold, or any physiological parameters. These data demonstrate that heat acclimation improves aerobic exercise performance in temperate-cool conditions and provide the scientific basis for employing heat acclimation to augment physical training programs. PMID- 20724561 TI - Voluntary activation failure contributes more to plantar flexor weakness than antagonist coactivation and muscle atrophy in chronic stroke survivors. AB - The contributions of nervous system muscle activation and muscle atrophy to poststroke weakness have not been evaluated together in the same subject. Maximal voluntary contraction (MVC) torque, voluntary activation (twitch interpolation), and electromyographic (EMG) amplitude were determined bilaterally in the plantar flexors of seven chronic stroke survivors (40-63 yr, 24-51 mo poststroke). Volumes of the plantar flexor muscles were determined bilaterally with magnetic resonance imaging (MRI). The mean (+/-SD) contralesional (paretic) MVC torque was less than one-half of the ipsilesional leg: 56.7 +/- 57.4 vs. 147 +/- 35.7 Nm (P = 0.006). Contralesional voluntary activation was only 48 +/- 36.9%, but was near complete in the ipsilesional leg, 97 +/- 1.9% (P = 0.01). The contralesional MVC EMG amplitude (normalized to the maximum M-wave peak-to-peak amplitude) of the gastrocnemii and soleus were 36.0 +/- 28.5 and 36.0 +/- 31.0% of the ipsilesional leg. Tibialis anterior (TA) EMG coactivation was not different between the contralesional (23.2 +/- 24.0% of TA MVC EMG) and ipsilesional side (12.3 +/- 5.7%) (P = 0.24). However, TA EMG coactivation was excessive (71%) in one subject and accounted for ~8% of her weakness based on the estimated antagonist torque. Relative (%ipsilesional leg) plantar flexor and gastrocnemii volumes were 88 +/- 6% (P = 0.004) and 76 +/- 15% (P = 0.01), respectively. Interlimb volume differences of the soleus, deep plantar flexors, and peronei were not significant. Preferred walking speed (0.83 +/- 0.33 m/s) was related to the contralesional MVC torque (r(2) = 0.57, P = 0.05, N = 7), but the two subjects with the greatest weakness walked faster than three others. Our findings suggest that plantar flexor weakness in mobile chronic stroke survivors reflects mostly voluntary activation failure, with smaller contributions from antagonist activity and atrophy. PMID- 20724562 TI - Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance. AB - It has recently been reported that dietary nitrate (NO(3)(-)) supplementation, which increases plasma nitrite (NO(2)(-)) concentration, a biomarker of nitric oxide (NO) availability, improves exercise efficiency and exercise tolerance in healthy humans. We hypothesized that dietary supplementation with L-arginine, the substrate for NO synthase (NOS), would elicit similar responses. In a double blind, crossover study, nine healthy men (aged 19-38 yr) consumed 500 ml of a beverage containing 6 g of l-arginine (Arg) or a placebo beverage (PL) and completed a series of "step" moderate- and severe-intensity exercise bouts 1 h after ingestion of the beverage. Plasma NO(2)(-) concentration was significantly greater in the Arg than the PL group (331 +/- 198 vs. 159 +/- 102 nM, P < 0.05) and systolic blood pressure was significantly reduced (123 +/- 3 vs. 131 +/- 5 mmHg, P < 0.01). The steady-state O(2) uptake (VO(2)) during moderate-intensity exercise was reduced by 7% in the Arg group (1.48 +/- 0.12 vs. 1.59 +/- 0.14 l/min, P < 0.05). During severe-intensity exercise, the Vo(2) slow component amplitude was reduced (0.58 +/- 0.23 and 0.76 +/- 0.29 l/min in Arg and PL, respectively, P < 0.05) and the time to exhaustion was extended (707 +/- 232 and 562 +/- 145 s in Arg and PL, respectively, P < 0.05) following consumption of Arg. In conclusion, similar to the effects of increased dietary NO(3)(-) intake, elevating NO bioavailability through dietary L-Arg supplementation reduced the O(2) cost of moderate-intensity exercise and blunted the VO(2) slow component and extended the time to exhaustion during severe-intensity exercise. PMID- 20724563 TI - Aerobic fitness does not influence the biventricular response to whole body passive heat stress. AB - We examined biventricular function during passive heat stress in endurance trained (ET) and untrained (UT) men to evaluate whether aerobic fitness alters the volumetric response. Body temperature was elevated ~0.8 degrees C above baseline in 20 healthy men (10 ET, 64.4 +/- 3.0 ml.kg(-1).min(-1); and 10 UT, 46.3 +/- 6.2 ml.kg(-1).min(-1)) by circulating warm water (50 degrees C) throughout a tube-lined suit. Cardiac magnetic resonance imaging was used to measure biventricular volumes, function, filling velocities, volumetric flow rates, and left ventricular (LV) twist and circumferential strain at baseline (BL) and after 45 min of heat stress. In both groups, passive heat stress reduced biventricular end-diastolic (ET, -19.5 +/- 24.0 ml; UT, -25.1 +/- 23.8 ml) and end-systolic (ET, -15.9 +/- 8.8 ml; UT, -17.6 +/- 7.9 ml) volumes and left atrial volume (ET, -19.2 +/- 11.6 ml; UT, -15.0 +/- 12.7 ml) and significantly increased heart rate (ET, 29.3 +/- 9.0 beats/min; UT, 31.7 +/- 10.4 beats/min) and cardiac output (ET, 3.8 +/- 2.2 l/min; UT, 3.2 +/- 1.4 l/min) similarly, while biventricular stroke volume was unchanged. There were no between-group differences in any parameter. Heat stress increased (P < 0.05), as a percentage of baseline values, biventricular ejection fraction (ET, 3.4 +/- 5.3%; UT, 4.4 +/ 3.7%), annular systolic tissue velocities (ET, 32.5 +/- 34.9%; UT, 44.0 +/- 38.1%), and peak LV twist (ET, 51.6 +/- 59.7%; UT, 59.7 +/- 54.2%) and untwisting rates (ET, 45.5 +/- 42.3%; UT, 51.8 +/- 55.0%) similarly in both groups. Early LV diastolic tissue and blood velocities, volumetric flow rates, and strain rates (diastole) were unchanged with heat stress in both groups. The present findings indicate that aerobic fitness does not influence the biventricular response to passive heat stress. PMID- 20724564 TI - Elevated baseline VO2 per se does not slow O2 uptake kinetics during work-to-work exercise transitions. AB - We investigated whether the characteristic slowing of pulmonary oxygen uptake (VO2) kinetics during "work-to-work" exercise is attributable to elevations in baseline metabolic rate (VO2) as opposed to the elevated baseline work rate, per se. We hypothesized that a step transition to a higher work rate from "unloaded" cycling, but with elevations in VO2 [and heart rate (HR)] reflective of a work-to work transition, would result in a lengthened phase II time constant (tau(p)). Seven male subjects (mean +/- SD age 27 +/- 10 yr) completed 1) transitions to a high-intensity work rate from a moderate-intensity work rate (M->H) and 2) two consecutive bouts of high-intensity exercise (U->H and E->H, respectively) initiated from unloaded cycling, with the time separating the exercise bouts chosen such that the baseline VO2 for the second transition was similar to the baseline VO2 for the M->H transition. The tau(p) for M->H (48 +/- 16 s) was significantly greater (P < 0.05) than the tau(p) for U->H (28 +/- 8 s) and E->H (27 +/- 6 s), which did not differ significantly. These findings suggest that the altered VO2 dynamics that are observed during work-to-work exercise are not related to the elevated baseline VO2 (or HR) per se; rather, these effects appear to be linked to the elevated baseline work rate, which would be expected to dictate the subsequent muscle fiber recruitment profile. PMID- 20724565 TI - Alpha-adrenergic control of blood flow during exercise: effect of sex and menstrual phase. AB - Sex differences exist in autonomic control of the cardiovascular system. This study was designed to directly test sex or female menstrual phase-related differences in alpha-adrenergic control of blood flow during exercise. We hypothesized that women would exhibit reduced alpha-adrenergic vasoconstriction compared with men during exercise; in addition, women would constrict less during the early luteal than the early follicular phase of the female menses. Young men (n = 10) were studied once and women (n = 9) studied twice, once during the early follicular phase and once during the early luteal phase of female menses. We measured forearm blood flow (FBF; Doppler ultrasound of the brachial artery) during rest and steady-state dynamic exercise (15 and 30% of maximal voluntary contraction, 20 contractions/min). A brachial artery catheter was inserted for the local administration of alpha-adrenergic agonists [phenylephrine (PE; alpha(1)) or clonidine (CL; alpha(2))]. Blood flow responses to exercise [forearm vascular conductance (FVC)] were similar between all groups. At rest, infusion of PE or CL decreased FVC in all groups (40-60% reduction). Vasoconstriction to PE was abolished in all groups at 15 and 30% exercise intensity. Vasoconstriction to CL was reduced at 15% and abolished at 30% intensity in all groups; women had less CL-induced constriction during the early luteal than early follicular phase (P < 0.017, 15% intensity). These results indicate that vasodilator responses to forearm exercise are comparable between men and women and are achieved through similar paths of alpha-adrenergic vascular control at moderate intensities; this control may differ at low intensities specific to the female menstrual phase. PMID- 20724566 TI - The effect of tissue elastic properties and surfactant on alveolar stability. AB - This paper presents a novel mathematical model of alveoli, which simulates the effects of tissue elasticity and surfactant on the stability of human alveoli. The model incorporates a spherical approximation to the alveolar geometry, the hysteretic behavior of pulmonary surfactant and tissue elasticity. The model shows that the alveolus without surfactant and the elastic properties of the lung tissue are always at an unstable equilibrium, with the capability both to collapse irreversibly and to open with infinite volume when the alveolus has small opening radii. During normal tidal breathing, the alveolus can becomes stable, if surfactant is added. Including the passive effect of tissue elasticity stabilizes the alveolus, further allowing the alveoli to be stable, even for lung volumes below residual volume. The model is the first to describe the combined effects of tissue elasticity and surfactant on alveolar stability. The model may be used as an integrated part of a more comprehensive model of the respiratory system, since it can predict opening pressures of alveoli. PMID- 20724567 TI - Pulmonary transit of agitated contrast is associated with enhanced pulmonary vascular reserve and right ventricular function during exercise. AB - Pulmonary transit of agitated contrast (PTAC) occurs to variable extents during exercise. We tested the hypothesis that the onset of PTAC signifies flow through larger-caliber vessels, resulting in improved pulmonary vascular reserve during exercise. Forty athletes and fifteen nonathletes performed maximal exercise with continuous echocardiographic Doppler measures [cardiac output (CO), pulmonary artery systolic pressure (PASP), and myocardial velocities] and invasive blood pressure (BP). Arterial gases and B-type natriuretic peptide (BNP) were measured at baseline and peak exercise. Pulmonary vascular resistance (PVR) was determined as the regression of PASP/CO and was compared according to athletic and PTAC status. At peak exercise, athletes had greater CO (16.0 +/- 2.9 vs. 12.4 +/- 3.2 l/min, P < 0.001) and higher PASP (60.8 +/- 12.6 vs. 47.0 +/- 6.5 mmHg, P < 0.001), but PVR was similar to nonathletes (P = 0.71). High PTAC (defined by contrast filling of the left ventricle) occurred in a similar proportion of athletes and nonathletes (18/40 vs. 10/15, P = 0.35) and was associated with higher peak-exercise CO (16.1 +/- 3.4 vs. 13.9 +/- 2.9 l/min, P = 0.010), lower PASP (52.3 +/- 9.8 vs. 62.6 +/- 13.7 mmHg, P = 0.003), and 37% lower PVR (P < 0.0001) relative to low PTAC. Right ventricular (RV) myocardial velocities increased more and BNP increased less in high vs. low PTAC subjects. On multivariate analysis, maximal oxygen consumption (VO(2max)) (P = 0.009) and maximal exercise output (P = 0.049) were greater in high PTAC subjects. An exercise-induced decrease in arterial oxygen saturation (98.0 +/- 0.4 vs. 96.7 +/ 1.4%, P < 0.0001) was not influenced by PTAC status (P = 0.96). Increased PTAC during exercise is a marker of pulmonary vascular reserve reflected by greater flow, reduced PVR, and enhanced RV function. PMID- 20724568 TI - Sympathetic nerve-dependent regulation of mucosal vascular tone modifies airway smooth muscle reactivity. AB - The airways contain a dense subepithelial microvascular plexus that is involved in the supply and clearance of substances to and from the airway wall. We set out to test the hypothesis that airway smooth muscle reactivity to bronchoconstricting agents may be dependent on airway mucosal blood flow. Immunohistochemical staining identified vasoconstrictor and vasodilator nerve fibers associated with subepithelial blood vessels in the guinea pig airways. Intravital microscopy of the tracheal mucosal microvasculature in anesthetized guinea pigs revealed that blockade of alpha-adrenergic receptors increased baseline arteriole diameter by ~40%, whereas the alpha-adrenergic receptor agonist phenylephrine produced a modest (5%) vasoconstriction in excess of the baseline tone. In subsequent in vivo experiments, tracheal contractions evoked by topically applied histamine were significantly reduced (P < 0.05) and enhanced by alpha-adrenergic receptor blockade and activation, respectively. alpha-Adrenergic ligands produced similar significant (P < 0.05) effects on airway smooth muscle contractions evoked by topically administered capsaicin, intravenously administered neurokinin A, inhaled histamine, and topically administered antigen in sensitized animals. These responses were independent of any direct effect of alpha-adrenergic ligands on the airway smooth muscle tone. The data suggest that changes in blood flow in the vessels supplying the airways regulate the reactivity of the underlying airway smooth muscle to locally released and exogenously administered agents by regulating their clearance. We speculate that changes in mucosal vascular function or changes in neuronal regulation of the airway vasculature may contribute to airways responsiveness in disease. PMID- 20724569 TI - Changes in lung volume and diaphragm muscle activity at sleep onset in obese obstructive sleep apnea patients vs. healthy-weight controls. AB - Obese obstructive sleep apnea (OSA) patients potentially defend end-expiratory lung volume (EELV) during wakefulness via increased expiratory diaphragmatic activity (eEMG(dia)). A reduction in eEMG(dia) and EELV at sleep onset could, therefore, increase upper airway collapsibility via reduced tracheal traction. The aim of this study was to establish if eEMG(dia) is greater in obese OSA patients vs. healthy-weight controls during wakefulness, and to compare eEMG(dia) and EELV changes at sleep onset between groups as a function of stable breathing, hypopnea vs. apnea events developing within the first few breaths after sleep onset. Eight obese men with OSA and eight healthy-weight men without OSA were studied in the supine position while instrumented with an intraesophageal catheter to measure eEMG(dia) and magnetometer coils to assess changes in EELV. While eEMG(dia) expressed as %maximal activity was not significantly different between groups during wakefulness, OSA patients experienced a greater fall in eEMG(dia) following sleep onset (group * breath, P < 0.001) and a greater decrease when respiratory events accompanied sleep onsets (category * breath, P < 0.001). The decrease in EELV by the third postsleep onset breath was small (OSA, 61.4 +/- 8.0 ml, P < 0.001; controls, 34.0 +/- 4.2 ml, P < 0.001), with the decrease significantly greater in OSA patients over time (group * breath, P = 0.007). There was a greater decrease with more severe events (category * breath, P < 0.001), with EELV decreasing by 89.6 +/- 14.2 ml (P < 0.001) at the onset of apneas in the OSA group. These data support that diaphragm tone and EELV frequently decrease following sleep onset, with greater falls at transitions accompanied by respiratory events. In addition to decrements in upper airway dilator muscle activity, decreasing lung volume potentially contributes to an increased propensity for upper airway collapse in OSA patients at sleep onset. PMID- 20724570 TI - The abundance and activation of mTORC1 regulators in skeletal muscle of neonatal pigs are modulated by insulin, amino acids, and age. AB - Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for the regulation of protein synthesis. Most of known mTORC1 regulators have been isolated and characterized using cell culture systems, and the physiological roles of these regulators have not been fully tested in vivo. Previously we demonstrated that the insulin (INS) and amino acid (AA)-induced activation of mTORC1 is developmentally regulated in skeletal muscle (Suryawan A et al. Am J Physiol Endocrinol Metab 293: E1597-E1605, 2007). The present study aimed to characterize in more detail the effects of the postprandial rise in INS and AA on the activation and abundance of mTORC1 regulators in muscle and how this is modified by development. Overnight fasted 6- and 26-day-old pigs were studied during 1) euinsulinemic-euglycemic-euaminoacidemic conditions (control), 2) euinsulinemic-euglycemic-hyperaminoacidemic clamps (AA), and 3) hyperinsulinemic euglycemic-euaminoacidemic clamps (INS). INS, but not AA, enhanced the PRAS40 phosphorylation, and this effect was greater in 6- than in 26-day old pigs. Phospholipase D1 (PLD1) abundance and phosphorylation, and the association of PLD1 with Ras homolog enriched in brain (Rheb), were greater in the younger pigs. Neither INS, AA, nor age altered the abundance of Rheb, vacuolar protein sorting 34 (Vps34), or FK506-binding protein 38 (FKBP38). Although INS and AA had no effect, the abundance of ras-related GTP binding B (RagB) and the association of RagB with Raptor were greater in 6- than in 26-day-old pigs. Neither INS, AA, nor age altered AMPK-induced phosphorylation of Raptor. Our results suggest that the enhanced activation of mTORC1 in muscle of neonatal pigs is in part due to regulation by PRAS40, PLD1, and the Rag GTPases. PMID- 20724571 TI - The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. AB - This study examined whether time of day and repeated exposure to intermittent hypoxia have an impact on the hypoxic ventilatory response (HVR) and ventilatory long-term facilitation (vLTF). Thirteen participants with sleep apnea were exposed to twelve 4-min episodes of isocapnic hypoxia followed by a 30-min recovery period each day for 10 days. On days 1 (initial day) and 10 (final day) participants completed the protocol in the evening (PM); on the remaining days the protocol was completed in the morning (AM). The HVR was increased in the morning compared with evening on the initial (AM 0.83 +/- 0.08 vs. PM 0.64 +/- 0.11 l.min-1.%SaO2-1; P <= 0.01) and final days (AM 1.0 +/- 0.08 vs. PM 0.81 +/- 0.09 l.min-1.%SaO2-1; P <= 0.01, where %SaO2 refers to percent arterial oxygen saturation). Moreover, the magnitude of the HVR was enhanced following daily exposure to intermittent hypoxia in the morning (initial day 0.83 +/- 0.08 vs. final day 1.0 +/- 0.08 l.min-1.%SaO2-1; P <= 0.03) and evening (initial day 0.64 +/- 0.11 vs. final day 0.81 +/- 0.09 l.min-1.%SaO2-1; P <= 0.03). vLTF was reduced in the morning compared with the evening on the initial (AM 19.03 +/- 0.35 vs. PM 22.30 +/- 0.49 l/min; P <= 0.001) and final (AM 20.54 +/- 0.32 vs. PM 23.11 +/- 0.54 l/min; P <= 0.01) days. Following daily exposure to intermittent hypoxia, vLTF was enhanced in the morning (initial day 19.03 +/- 0.35 vs. final day 20.54 +/- 0.32 l/min; P <= 0.01). We conclude that the HVR is increased while vLTF is decreased in the morning compared with the evening in individuals with sleep apnea and that the magnitudes of these phenomena are enhanced following daily exposure to intermittent hypoxia. PMID- 20724572 TI - Should we be on the fence or can we open the gate? Evidence that QRS gating in FMD analysis is not essential. PMID- 20724573 TI - Mechanisms and modulators of temperature regulation. PMID- 20724574 TI - A prospective multicenter phase II study of oral and i.v. vinorelbine plus trastuzumab as first-line therapy in HER2-overexpressing metastatic breast cancer. AB - BACKGROUND: To evaluate the efficacy and safety of oral and i.v. vinorelbine plus trastuzumab as first-line regimen in a patient-convenient application for human epidermal growth factor receptor 2 (HER2)-overexpressing patients with metastatic breast cancer. PATIENTS AND METHODS: Forty-two women were enrolled in a multicenter study. The patients received i.v. vinorelbine at a dose of 25 mg/m(2) on day 1 followed by oral vinorelbine at a dose of 60 mg/m(2) on days 8 and 15 in a 3-week cycle. Standard dose trastuzumab was given at 3-week intervals. RESULTS: Complete response was observed in 7 patients (18.9%) and partial response in 19 patients (51.4%), for an overall response rate of 70.3% [95% confidence interval (CI) 53.0-84.1]. The disease control rate reached 91.9% (95% CI 78.1-98.3). The median time to progression was 9.3 months, while median overall survival reached 35.6 months. Hematological and non-hematological toxic effects were acceptable with grade 3-4 leukopenia of 14% and neutropenia of 38%; cardiac toxicity did not reach the level of clinical relevance. CONCLUSION: The combination of i.v. and oral vinorelbine plus trastuzumab demonstrates high activity and good tolerability in first-line treatment of HER2-overexpressing metastatic breast cancer. In addition, it offers convenience for the patients with only one i.v. treatment every 3 weeks. PMID- 20724575 TI - Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. AB - BACKGROUND: In the present study, we investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC). METHODS: Of 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine. RESULTS: Median age was 45 years (range 24-75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4-6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01). CONCLUSIONS: LC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression. PMID- 20724576 TI - Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. AB - BACKGROUND: The aim of this subgroup analysis of the Mabthera International Trial Group study was to evaluate the impact of chemotherapy and rituximab in primary mediastinal B-cell lymphoma (PMBCL) in comparison to other diffuse large B-cell lymphoma (DLBCL). METHODS: Patients were randomly assigned to six cycles of CHOP like regimens with or without rituximab. RESULTS: Of 824 patients enrolled, 87 had PMBCL and 627 other types of DLBCL. Rituximab increased the rates of complete remission (unconfirmed) in both PMBCL (from 54% to 80%, P = 0.015) and DLBCL (from 72% to 87%, P < 0.001). In PMBCL, rituximab virtually eliminated progressive disease (PD) (2.5% versus 24%, P < 0.001), whereas without rituximab, PD was more frequent in PMBCL than in DLBCL (24% versus 10%, P = 0.010). With a median observation time of 34 months, 3-year event-free survival (EFS) was improved by rituximab for PMBCL (78% versus 52%, P = 0.012) and for DLBCL (81% versus 61%, P < 0.001). Overall survival benefit was similar for DLBCL (93% versus 85%, P < 0.001) and PMBCL (89% versus 78%, P = 0.158). CONCLUSION: In young patients with PMBCL (age-adjusted International Prognostic Index 0-1), rituximab added to six cycles of CHOP-like chemotherapy increases response rate and EFS to the same extent as other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment in PMBCL with good prognosis features. PMID- 20724577 TI - Characterisation of MutaTMMouse lambdagt10-lacZ transgene: evidence for in vivo rearrangements. AB - The multicopy lambdagt10-lacZ transgene shuttle vector of MutaTMMouse serves as an important tool for genotoxicity studies. Here, we describe a model for lambdagt10-lacZ transgene molecular structure, based on characterisation of transgenes recovered from animals of our intramural breeding colony. Unique nucleotide sequences of the 47 513 bp monomer are reported with GenBank(r) assigned accession numbers. Besides defining ancestral mutations of the lambdagt10 used to construct the transgene and the MutaTMMouse precursor (strain 40.6), we validated the sequence integrity of key lambda genes needed for the Escherichia coli host-based mutation reporting assay. Using three polymerase chain reaction (PCR)-based chromosome scanning and cloning strategies, we found five distinct in vivo transgene rearrangements, which were common to both sexes, and involved copy fusions generating ~10 defective copies per haplotype. The transgene haplotype was estimated by Southern hybridisation and real-time polymerase chain reaction, which yielded 29.0 +/- 4.0 copies based on spleen DNA of MutaTMMouse, and a reconstructed CD2F(1) genome with variable lambdagt10-lacZ copies. Similar analysis of commercially prepared spleen DNA from Big Blue(r) mouse yielded a haplotype of 23.5 +/- 3.1 copies. The latter DNA is used in calibrating a commercial in vitro packaging kit for E.coli host-based mutation assays of both transgenic systems. The model for lambdagt10-lacZ transgene organisation, and the PCR-based methods for assessing copy number, integrity and rearrangements, potentially extends the use of MutaTMMouse construct for direct, genomic-type assays that detect the effects of clastogens and aneugens, without depending on an E.coli host, for reporting effects. PMID- 20724578 TI - Evaluation of A2BP1 as an obesity gene. AB - OBJECTIVE: A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. RESEARCH DESIGN AND METHODS: Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157 159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. RESULTS: No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 * 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 * 10(-10)) and children (rs8054147, P = 9.2 * 10(-6)) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. CONCLUSIONS: Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway. PMID- 20724579 TI - Pparg-P465L mutation worsens hyperglycemia in Ins2-Akita female mice via adipose specific insulin resistance and storage dysfunction. AB - OBJECTIVE: The dominant-negative P467L mutation in peroxisome proliferator activated receptor-gamma (PPARgamma) was identified in insulin-resistant patients with hyperglycemia and lipodystrophy. In contrast, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. We hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, which is masked by hyperinsulinemia and increased pancreatic islet mass, to retain normal plasma glucose. RESEARCH DESIGN AND METHODS: We introduced in Pparg(P465L/+) mice an Ins2-Akita mutation that causes improper protein folding and islet apoptosis to lower plasma insulin. RESULTS: Unlike Ins2(Akita/+) littermates, male Pparg(P465L/+)Ins2(Akita/+) mice have drastically reduced life span with enhanced type 1 diabetes. Hyperglycemia in Ins2(Akita/+) females is mild. However, Pparg(P465L/+)Ins2(Akita/+) females have aggravated hyperglycemia, smaller islets, and reduced plasma insulin. In an insulin tolerance test, they showed smaller reduction in plasma glucose, indicating impaired insulin sensitivity. Although gluconeogenesis is enhanced in Pparg(P465L/+)Ins2(Akita/+) mice compared with Ins2(Akita/+), exogenous insulin equally suppressed gluconeogenesis in hepatocytes, suggesting that Pparg(P465L/+)Ins2(Akita/+) livers are insulin sensitive. Expression of genes regulating insulin sensitivity and glycogen and triglyceride contents suggest that skeletal muscles are equally insulin sensitive. In contrast, adipose tissue and isolated adipocytes from Pparg(P465L/+)Ins2(Akita/+) mice have impaired glucose uptake in response to exogenous insulin. Pparg(P465L/+)Ins2(Akita/+) mice have smaller fat depots composed of larger adipocytes, suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia. CONCLUSIONS: PPARg P465L mutation worsens hyperglycemia in Ins2(Akita/+) mice primarily because of adipose-specific insulin resistance and altered storage function. This underscores the important interplay between insulin and PPARgamma in adipose tissues in diabetes. PMID- 20724580 TI - Pharmacological vasodilation improves insulin-stimulated muscle protein anabolism but not glucose utilization in older adults. AB - OBJECTIVE: Skeletal muscle protein metabolism is resistant to the anabolic action of insulin in healthy, nondiabetic older adults. This defect is associated with impaired insulin-induced vasodilation and mTORC1 signaling. We hypothesized that, in older subjects, pharmacological restoration of insulin-induced capillary recruitment would improve the response of muscle protein synthesis and anabolism to insulin. RESEARCH DESIGN AND METHODS: Twelve healthy, nondiabetic older subjects (71 +/- 2 years) were randomized to two groups. Subjects were studied at baseline and during local infusion in one leg of insulin alone (Control) or insulin plus sodium nitroprusside (SNP) at variable rate to double leg blood flow. We measured leg blood flow by dye dilution; muscle microvascular perfusion with contrast enhanced ultrasound; Akt/mTORC1 signaling by Western blotting; and muscle protein synthesis, amino acid, and glucose kinetics using stable isotope methodologies. RESULTS: There were no baseline differences between groups. Blood flow, muscle perfusion, phenylalanine delivery to the leg, and intracellular availability of phenylalanine increased significantly (P < 0.05) in SNP only. Akt phosphorylation increased in both groups but increased more in SNP (P < 0.05). Muscle protein synthesis and net balance (nmol . min(-1) . 100 ml . leg(-1)) increased significantly (P < 0.05) in SNP (synthesis, 43 +/- 6 to 129 +/- 25; net balance, -16 +/- 3 to 26 +/- 12) but not in Control (synthesis, 41 +/- 10 to 53 +/- 8; net balance, -17 +/- 3 to -2 +/- 3). CONCLUSIONS: Pharmacological enhancement of muscle perfusion and amino acid availability during hyperinsulinemia improves the muscle protein anabolic effect of insulin in older adults. PMID- 20724581 TI - Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies. AB - OBJECTIVE: Large-scale genome-wide association (GWA) studies have thus far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children and adolescents. RESEARCH DESIGN AND METHODS: Seventeen variants representing 16 obesity susceptibility loci were genotyped in 1,252 children (mean +/- SD age 9.7 +/- 0.4 years) and 790 adolescents (15.5 +/- 0.5 years) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analyzed with previously reported data (N(total) = 13,071 children and adolescents). RESULTS: In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta analysis showed directionally consistent associations with BMI for all 13 variants, of which 9 were significant (0.033-0.098 SD/allele; P < 0.05). The near TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 * 10(-11)). Effect sizes for BMI tended to be more pronounced in children and adolescents than reported earlier in adults for variants in or near SEC16B, TMEM18, and KCTD15, (0.028-0.035 SD/allele higher) and less pronounced for rs925946 in BDNF (0.028 SD/allele lower). Each additional effect allele in the GPS-17 was associated with an increase of 0.034 SD in BMI (P = 3.6 * 10(-5)), 0.039 SD, in sum of skinfolds (P = 1.7 * 10(-7)), and 0.022 SD in waist circumference (P = 1.7 * 10(-4)), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference). CONCLUSIONS: Most obesity susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. Whereas the association of some variants may differ with age, the cumulative effect size is similar. PMID- 20724582 TI - Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet. AB - OBJECTIVE: Chemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo. RESEARCH DESIGN AND METHODS: We used recombinant adeno associated virus to express human chemerin in LDL receptor knockout mice on high fat diet. RESULTS: Expression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5'AMP activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue. CONCLUSIONS: Chemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle. PMID- 20724583 TI - A unifying genetic model for facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. PMID- 20724584 TI - Tracking hydrocarbon plume transport and biodegradation at Deepwater Horizon. AB - The Deepwater Horizon blowout is the largest offshore oil spill in history. We present results from a subsurface hydrocarbon survey using an autonomous underwater vehicle and a ship-cabled sampler. Our findings indicate the presence of a continuous plume of oil, more than 35 kilometers in length, at approximately 1100 meters depth that persisted for months without substantial biodegradation. Samples collected from within the plume reveal monoaromatic petroleum hydrocarbon concentrations in excess of 50 micrograms per liter. These data indicate that monoaromatic input to this plume was at least 5500 kilograms per day, which is more than double the total source rate of all natural seeps of the monoaromatic petroleum hydrocarbons in the northern Gulf of Mexico. Dissolved oxygen concentrations suggest that microbial respiration rates within the plume were not appreciably more than 1 micromolar oxygen per day. PMID- 20724585 TI - A red-shifted chlorophyll. AB - Chlorophylls are essential for light-harvesting and energy transduction in photosynthesis. Four chemically distinct varieties have been known for the past 60 years. Here we report isolation of a fifth, which we designate chlorophyll f. Its in vitro absorption (706 nanometers) and fluorescence (722 nanometers) maxima are red-shifted compared to all other chlorophylls from oxygenic phototrophs. On the basis of the optical, mass, and nuclear magnetic resonance spectra, we propose that chlorophyll f is [2-formyl]-chlorophyll a (C55H70O6N4Mg). This finding suggests that oxygenic photosynthesis can be extended further into the infrared region and may open associated bioenergy applications. PMID- 20724586 TI - Plastic accumulation in the North Atlantic subtropical gyre. AB - Plastic marine pollution is a major environmental concern, yet a quantitative description of the scope of this problem in the open ocean is lacking. Here, we present a time series of plastic content at the surface of the western North Atlantic Ocean and Caribbean Sea from 1986 to 2008. More than 60% of 6136 surface plankton net tows collected buoyant plastic pieces, typically millimeters in size. The highest concentration of plastic debris was observed in subtropical latitudes and associated with the observed large-scale convergence in surface currents predicted by Ekman dynamics. Despite a rapid increase in plastic production and disposal during this time period, no trend in plastic concentration was observed in the region of highest accumulation. PMID- 20724587 TI - A Vibrio effector protein is an inositol phosphatase and disrupts host cell membrane integrity. AB - The marine bacterium Vibrio parahaemolyticus causes gastroenteritis in humans and encodes the type III effector protein VPA0450, which contributes to host cell death caused by autophagy, cell rounding, and cell lysis. We found that VPA0450 is an inositol polyphosphate 5-phosphatase that hydrolyzed the D5 phosphate from the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate. VPA0450 disrupted cytoskeletal binding sites on the inner surface of membranes of human cells and caused plasma membrane blebbing, which compromised membrane integrity and probably contributed to cell death by facilitating lysis. Thus, bacterial pathogens can disrupt adaptor protein-binding sites required for proper membrane and cytoskeleton dynamics by altering the homeostasis of membrane-bound inositol signaling molecules. PMID- 20724588 TI - Phosphorylation of focal adhesion kinase at Tyr397 in gastric carcinomas and its clinical significance. AB - Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various cancers; however, it remains unclear how FAK participates in tumor malignancy in vivo. This study seeks to understand the role of FAK activation in gastric cancer progression. Using immunohistochemical staining and Western blotting, we found that pY397 FAK, an autophosphorylation site on FAK activation, was abundant in the cancerous tissues of 21 of 59 patients with gastric carcinomas. We attempted to correlate clinicopathological parameters, including histological types, TNM staging, and cancer recurrence, with the expression of FAK and pY397 FAK in cancerous tissues. Intriguingly, patients with higher levels of pY397 FAK displayed higher incidences of gastric cancer recurrence after surgery and poor 5 year recurrence-free survival. Furthermore, multivariate analyses showed that pY397 FAK was an independent predictor of gastric cancer recurrence. As a result, expression of pY397 FAK is a significant prognostic factor for the recurrence of gastric cancer. Additionally, in vitro studies showed that overexpression of Y397F, a dominant-negative mutant of FAK, in AGS human gastric carcinoma cells impaired cell migration, invasion, and proliferation compared with cells overexpressing wild-type FAK. Thus, activation of FAK through autophosphorylation at Tyr397 leads to the progression of gastric carcinomas by promoting cell migration, invasion, and proliferation. Collectively, our results have provided valuable insights for the development of novel diagnoses and therapeutic targets for gastric cancer treatments. PMID- 20724589 TI - Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes. AB - Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases. PMID- 20724590 TI - Evaluation of bone marrow- and brain-derived neural stem cells in therapy of central nervous system autoimmunity. AB - Adult subventricular zone (SVZ)-derived neural stem cells (NSCs) have therapeutic effects in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, SVZ precursor cells as a source of NSCs are not readily accessible for clinical application. In the present study, we demonstrate that NSCs derived from bone marrow (BM) cells exhibit comparable morphological properties as those derived from SVZ cells and possess a similar ability to differentiate into neurons, astrocytes, and oligodendrocytes both in vitro and in vivo. Importantly, both types of NSCs suppressed chronic experimental autoimmune encephalomyelitis to a comparable extent on transplantation. Mechanisms underlying the therapeutic effects of NSCs include immunomodulation in the periphery and the central nervous system (CNS), neuron/oligodendrocyte repopulation by transplanted cells, and enhanced endogenous remyelination and axonal recovery. Furthermore, we provide evidence for the trans-differentiation of transplanted BM-NSCs into neural cells in the CNS, while no fusion of these cells with host neural cells was detected. This is the first study that directly compares SVZ- versus BM-NSCs with regard to in vivo neural differentiation and anti-inflammatory and therapeutic effects on CNS inflammatory demyelination. Their virtually identical therapeutic potential, greater accessibility, and autologous properties make BM-NSCs a novel and highly applicable substitute for SVZ-NSCs in cell-based multiple sclerosis therapies. PMID- 20724591 TI - Proteomic analysis identification of a pattern of shared alterations in the secretome of dermal fibroblasts from systemic sclerosis and nephrogenic systemic fibrosis. AB - A proteomic analysis of the secretome of cultured dermal fibroblasts from patients with systemic sclerosis (SSc) and nephrogenic systemic fibrosis (NSF) was performed to identify proteins that reflect the fibrotic process. Confluent culture supernatants from three cell strains each of normal, SSc, and NSF dermal fibroblasts were pooled separately, and each pool was labeled with a specific fluorochrome. The three pools were electrophoresed together on two-dimension SDS gels, and protein differential expression was evaluated by quantitative fluorescence analysis. The secretome analysis identified 1694 spots per sample, among which 890 spots (52%) were differentially increased or decreased (more than twofold) in SSc fibroblasts, and 985 spots (58%) were differentially increased or decreased in NSF fibroblasts compared with normal fibroblasts. Mass spectrometry analysis was then used to identify the proteins that had increased by the greatest extent in both NSF and SSc secretomes. Three reticulocalbin family members were among the 10 most up-regulated proteins. Confocal microscopy results validated the differential increase of reticulocalbin-1 in affected SSc and NSF skin, and Western blot findings demonstrated its presence in SSc sera. The secretomes of both SSc and NSF fibroblasts display a pattern of shared changes compared with the normal fibroblast secretome. The differentially increased proteins reflect an activated fibroblast phenotype and may represent a specific "fibrosis signature" that can be used as a biomarker for fibrotic diseases. PMID- 20724592 TI - Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically. AB - Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that sensitizes cells to apoptosis; therefore, Par-4 modulation has therapeutic potential. No data currently exist on Par-4 expression in cholangiocarcinoma (CCA). We evaluated the expression of Par-4 in normal and neoplastic cholangiocytes and the effects of its pharmacological or genetic modulation. The study was performed in human and rat liver, CCA patient biopsies, and two CCA cell lines. PAR-4 was expressed in normal rat and human cholangiocytes, but its expression levels decreased in both human CCA and CCA cell lines. In both intrahepatic and extrahepatic CCA, Par-4 expression (as shown by immunohistochemistry) was inversely correlated with markers of proliferation (eg, proliferating cellular nuclear antigen) and directly correlated with apoptotic markers (eg, Bax and Bax/BCL2 ratio). Par-4 expression was decreased during CCA cell proliferation but was enhanced after apoptosis induction. Pharmacological induction of Par-4 expression in CCA cell lines by diindolymethane or withaferin A promoted activation of apoptosis and inhibition of proliferation. In contrast, specific Par-4 silencing by small-interfering RNA determined activation of CCA cell line proliferation. Par-4 is expressed in rat and human cholangiocytes and is down-regulated in both human CCA and CCA cell lines. Par-4 protein levels decrease during cell proliferation but increase during apoptosis. Pharmacological or genetic induction of Par-4 determines apoptosis of CCA cells, suggesting Par-4 targeting as a CCA treatment strategy. PMID- 20724593 TI - tPA activates LDL receptor-related protein 1-mediated mitogenic signaling involving the p90RSK and GSK3beta pathway. AB - In renal fibrosis, interstitial fibroblasts have an increased proliferative phenotype, and the numbers of interstitial fibroblasts closely correlate with the extent of kidney damage. The mechanisms underlying proliferation and resulting expansion of the interstitium remain largely unknown. Here we define the intracellular signaling events by which tissue plasminogen activator (tPA) promotes renal interstitial fibroblast proliferation. tPA promoted the proliferation of renal interstitial fibroblasts independent of its protease activity. The mitogenic effect of tPA required Tyr(4507) phosphorylation of the cytoplasmic tail of its receptor LDL receptor-related protein 1. tPA triggered sequential proliferative signaling events involving Erk1/2, p90RSK, GSK3beta phosphorylation, and cyclin D1 induction. Blockade of Erk1/2 activation or knockdown of p90RSK suppressed tPA-induced GSK3beta phosphorylation, cyclin D1 expression, and fibroblast proliferation. In contrast, expression of constitutively active Mek1 mimicked tPA in inducing GSK3beta phosphorylation and cyclin D1 expression. Ectopic overexpression of an uninhibitable GSK3beta mutant eliminated tPA-induced cyclin D1 expression. In the murine obstruction model, tPA deficiency reduced renal GSK3beta phosphorylation and induction of PCNA and FSP 1. These findings show that tPA induces Tyr(4507) phosphorylation of LDL receptor related protein 1, which in turn leads to the downstream phosphorylation of Erk1/2, p90RSK, and GSK3beta, followed by the induction of cyclin D1 in murine interstitial fibroblasts. This study implicates tPA as a mitogen that promotes interstitial fibroblast proliferation, leading to expansion of these cells. PMID- 20724594 TI - Stem cells derived from human amniotic fluid contribute to acute kidney injury recovery. AB - Stem cells isolated from human amniotic fluid are gaining attention with regard to their therapeutic potential. In this work, we investigated whether these cells contribute to tubular regeneration after experimental acute kidney injury. Cells expressing stem cell markers with multidifferentiative potential were isolated from human amniotic fluid. The regenerative potential of human amniotic fluid stem cells was compared with that of bone marrow-derived human mesenchymal stem cells. We found that the intravenous injection of 3.5 * 10(5) human amniotic fluid stem cells into nonimmune-competent mice with glycerol-induced acute kidney injury was followed by rapid normalization of renal function compared with injection of mesenchymal stem cells. Both stem cell types showed enhanced tubular cell proliferation and reduced apoptosis. Mesenchymal stem cells were more efficient in inducing proliferation than amniotic fluid-derived stem cells, which, in contrast, were more antiapoptotic. Both cell types were found to accumulate within the peritubular capillaries and the interstitium, but amniotic fluid stem cells were more persistent than mesenchymal stem cells. In vitro experiments demonstrated that the two cell types produced different cytokines and growth factors, suggesting that a combination of different mediators is involved in their biological actions. These results suggest that the amniotic fluid derived stem cells may improve renal regeneration in acute kidney injury, but they are not more effective than mesenchymal stem cells. PMID- 20724595 TI - Assessing pulmonary pathology by detailed examination of respiratory function. AB - Pulmonary inflammation causes multiple alterations within the lung, including mucus production, recruitment of inflammatory cells, and airway hyperreactivity (AHR). Measurement of AHR by direct, invasive means (eg, mechanical ventilation) or noninvasive techniques, like whole body plethysmography (WBP), assesses the severity of pulmonary inflammation in animal models of inflammatory lung disease. Direct measurement of AHR is acknowledged as the most accurate method for assessing airway mechanics, but analysis of all data obtained from WBP may offer insights into which inflammatory aspects of the lung are altered along with AHR. Using WBP, we compared the respiratory parameters of two groups of mice sensitized with cockroach allergen. One group was treated with dexamethasone (Dex) before final challenge (Dex-Asthma), while the other group received vehicle treatment (Asthma). Respiratory parameters from plethysmography revealed that Dex Asthma mice compensated to maintain high minute ventilation, whereas Asthma mice showed significant impairment in minute ventilation despite increased peak expiratory flow (103 +/- 5 ml/min vs. 69 +/- 70 ml/min). The WBP data suggest that enhanced air exchange in the Dex-Asthma mice results from significant decreases in airway mucus production. Additional studies with quantitative morphometry of histological sections confirmed that Dex reduced airway mucus. In conclusion, a detailed examination of WBP parameters can accurately assess the respiratory health of mice and will help direct additional studies. PMID- 20724596 TI - Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development. AB - Akt-mediated signaling plays an important role in blood vascular development. In this study, we investigated the role of Akt in lymphatic growth using Akt deficient mice. First, we found that lymphangiogenesis occurred in Akt1(-/-), Akt2(-/-), and Akt3(-/-) mice. However, both the diameter and endothelial cell number of lymphatic capillaries were significantly less in Akt1(-/-) mice than in wild-type control mice, whereas there was only a slight change in Akt2(-/-) and Akt3(-/-) mice. Second, valves present in the small collecting lymphatics in the superficial dermal layer of the ear skin were rarely observed in Akt1(-/-) mice, although these valves could be detected in the large collecting lymphatics in the deep layer of the skin tissues. A fluorescence microlymphangiography assay showed that the skin lymphatic network in Akt1(-/-) mice was functional but abnormal as shown by fluorescein isothiocyanate-dextran draining. There was an uncharacteristic enlargement of collecting lymphatic vessels, and further analysis showed that smooth muscle cell coverage of collecting lymphatic vessels became much more sparse in Akt1-deficient mice than in wild-type control animals. Finally, we showed that lymphatic vessels were detected in compound Akt-null mice and that lymphangiogenesis could be induced by vascular endothelial growth factor C delivered via adenoviral vectors in adult mice lacking Akt1. These results indicate that despite the compensatory roles of other Akt isoforms, Akt1 is more critically required during lymphatic development. PMID- 20724597 TI - Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53 mutant breast cancers. AB - Treatment options for triple-receptor negative (ER-/PR-/Her2-) and Her2 overexpressing (ER-/PR-/Her2+) breast cancers with acquired or de novo resistance are limited, and metastatic disease remains incurable. Targeting of growth signaling networks is often constrained by pathway redundancy or growth independent cancer cell cycles. The cell-cycle protein Cdc7 regulates S phase by promoting DNA replication. This essential kinase acts as a convergence point for upstream growth signaling pathways and is therefore an attractive therapeutic target. We show that increased Cdc7 expression during mammary tumorigenesis is linked to Her2-overexpressing and triple-negative subtypes, accelerated cell cycle progression (P < 0.001), arrested tumor differentiation (P < 0.001), genomic instability (P = 0.019), increasing NPI score (P < 0.001), and reduced disease-free survival (HR = 1.98 [95% CI: 1.27-3.10]; P = 0.003), thus implicating its deregulation in the development of aggressive disease. Targeting Cdc7 with RNAi, we demonstrate that p53-mutant Her2-overexpressing and triple negative breast cancer cell lines undergo an abortive S phase and apoptotic cell death due to loss of a p53-dependent Cdc7-inhibition checkpoint. In contrast, untransformed breast epithelial cells arrest in G1, remain viable, and are able to resume cell proliferation on recovery of Cdc7 kinase activity. Thus, Cdc7 appears to represent a potent and highly specific anticancer target in Her2 overexpressing and triple-negative breast cancers. Emerging Cdc7 kinase inhibitors may therefore significantly broaden the therapeutic armamentarium for treatment of the aggressive p53-mutant breast cancer subtypes identified in this study. PMID- 20724598 TI - Different roles of 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies. AB - Up-regulation of 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, causes impaired cell signaling, oxidative-nitrosative stress, and inflammation. This study evaluated the role for 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies. Control and streptozotocin-diabetic wild-type and 12/15 lipoxygenase-deficient mice were maintained for 14 to 16 weeks. 12/15 lipoxygenase gene deficiency did not affect weight gain or blood glucose concentrations. Diabetic wild-type mice displayed increased sciatic nerve 12/15 lipoxygenase and 12(S)-hydroxyeicosatetraenoic acid levels. 12/15-lipoxygenase deficiency prevented or alleviated diabetes-induced thermal hypoalgesia, tactile allodynia, motor and sensory nerve conduction velocity deficits, and reduction in tibial nerve myelinated fiber diameter, but not intraepidermal nerve fiber loss. The frequencies of superior mesenteric-celiac ganglion neuritic dystrophy, the hallmark of diabetic autonomic neuropathy in mouse prevertebral sympathetic ganglia, were increased 14.8-fold and 17.2-fold in diabetic wild-type and 12/15 lipoxygenase-deficient mice, respectively. In addition, both diabetic groups displayed small (<1%) numbers of degenerating sympathetic neurons. In conclusion, whereas 12/15-lipoxygenase up-regulation provides an important contribution to functional changes characteristic for both large and small fiber peripheral diabetic neuropathies and axonal atrophy of large myelinated fibers, its role in small sensory nerve fiber degeneration and neuritic dystrophy and neuronal degeneration characteristic for diabetic autonomic neuropathy is minor. This should be considered in the selection of endpoints for future clinical trials of 12/15-lipoxygenase inhibitors. PMID- 20724599 TI - Alveolar macrophages stimulate enhanced cytokine production by pulmonary CD4+ T lymphocytes in an exacerbation of murine chronic asthma. AB - The mechanisms underlying the exaggerated distal airway inflammation and hyperresponsiveness that characterize acute exacerbations of asthma are largely unknown. Using BALB/c mouse experimental models, we demonstrated a potentially important role for alveolar macrophages (AM) in the development of an allergen induced exacerbation of asthma. To induce features of airway inflammation and remodeling characteristic of mild chronic asthma, animals were systemically sensitized and exposed to low mass concentrations (~3 mg/m(3)) of aerosolized ovalbumin for 30 minutes per day, 3 days per week, for 4 weeks. A subsequent single moderate-level challenge (~30 mg/m(3)) was used to trigger an acute exacerbation. In chronically challenged animals, cytokine expression by AM was not increased, whereas after an acute exacerbation, AM exhibited significantly enhanced expression of proinflammatory cytokines, including interleukin (IL) 1beta, IL-6, CXCL-1, and tumor necrosis factor alpha. In parallel, there was a marked increase in the expression of several cytokines by CD4(+) T-lymphocytes, notably the Th2 cytokines IL-4 and IL-13. Importantly, AM from an acute exacerbation stimulated the expression of Th2 cytokines when cocultured with CD4(+) cells from chronically challenged animals, and their ability to do so was significantly greater than AM from either chronically challenged or naive controls. Stimulation was partly dependent on interactions involving CD80/86. We conclude that in an acute exacerbation of asthma, enhanced cytokine expression by AM may play a critical role in triggering increased expression of cytokines by pulmonary CD4(+) T-lymphocytes. PMID- 20724600 TI - Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice. AB - Impairment in the regeneration process is a critical determinant for skeletal muscle wasting in chronic diseases and degenerative muscle disorders. Inflammatory cytokines are known to cause significant muscle wasting, however, their role in myofiber regeneration is less clear. In this study we have investigated the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in skeletal muscle regeneration in vivo. Our results show that expression levels of TWEAK and its receptor Fn14 are significantly increased in skeletal muscles of mice after injury. Genetic deletion of TWEAK increased the fiber cross sectional area and levels of embryonic isoform of myosin heavy chain in regenerating tibial anterior muscle. Conversely, muscle-specific transgenic overexpression of TWEAK reduced the fiber cross-sectional area and levels of the embryonic myosin heavy chain in regenerating muscle. TWEAK induced the expression of several inflammatory molecules and increased interstitial fibrosis in regenerating muscle. Genetic ablation of TWEAK suppressed, whereas overexpression of TWEAK increased, the activation of nuclear factor-kappa B without affecting the activation of Akt or p38 kinase in regenerating myofibers. Primary myoblasts from TWEAK-null mice showed enhanced differentiation in vitro, whereas myoblasts from TWEAK-Tg mice showed reduced differentiation compared with wild-type mice. Collectively, our study suggests that TWEAK negatively regulates muscle regeneration and that TWEAK is a potential therapeutic target to enhance skeletal muscle regeneration in vivo. PMID- 20724601 TI - PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation. AB - Of the 33 million people infected with the human immunodeficiency virus (HIV) worldwide, 40-60% of individuals will eventually develop neurocognitive sequelae that can be attributed to the presence of HIV-1 in the central nervous system (CNS) and its associated neuroinflammation despite antiretroviral therapy. PrP(C) (protease resistant protein, cellular isoform) is the nonpathological cellular isoform of the human prion protein that participates in many physiological processes that are disrupted during HIV-1 infection. However, its role in HIV-1 CNS disease is unknown. We demonstrate that PrP(C) is significantly increased in both the CNS of HIV-1-infected individuals with neurocognitive impairment and in SIV-infected macaques with encephalitis. PrP(C) is released into the cerebrospinal fluid, and its levels correlate with CNS compromise, suggesting it is a biomarker of HIV-associated neurocognitive impairment. We show that the chemokine (c-c Motif) Ligand-2 (CCL2) increases PrP(C) release from CNS cells, while HIV-1 infection alters PrP(C) release from peripheral blood mononuclear cells. Soluble PrP(C) mediates neuroinflammation by inducing astrocyte production of both CCL2 and interleukin 6. This report presents the first evidence that PrP(C) dysregulation occurs in cognitively impaired HIV-1-infected individuals and that PrP(C) participates in the pathogenesis of HIV-1-associated CNS disease. PMID- 20724602 TI - Regulation of interleukin-6 expression in human decidual cells and its potential role in chorioamnionitis. AB - Chorioamnionitis frequently precedes both genital tract and placental inflammation and is both a primary cause of maternal morbidity and a major antecedent of preterm premature rupture of the membranes (PPROM) as well as preterm delivery (PTD). In most cases of chorioamnionitis, neutrophils dominate the decidua. In a subset of these cases, a predominance of monocytes is uniquely associated with both neonatal intraventricular hemorrhage and death. The multifunctional cytokine, interleukin-6, promotes local monocyte dominance via several mechanisms. In this study, immunostaining of placental sections revealed significantly higher interleukin-6 HSCOREs in decidual cells (DCs) but not in interstitial trophoblasts, in chorioamnionitis versus gestational age-matched control placentas (P < 0.05). In confluent leukocyte-free term DCs, secreted interleukin-6 levels in incubations with estradiol-17beta were increased 2500 fold by IL-1beta (P < 0.05). This up-regulation was inhibited by more than 50% in parallel incubations that included medroxyprogesterone acetate (n = 12, P < 0.05). Western blotting data confirmed these enzyme-linked immunosorbent assay results; quantitative RT-PCR findings demonstrated corresponding changes in interleukin-6 mRNA levels. Specific inhibitors of signaling for both nuclear factor-kappaB activation and p38-mitogen-activated protein kinase, but not for protein kinase C, significantly decreased IL-1beta-enhanced interleukin-6 expression levels in cultured DCs. In conclusion, in situ and in vitro results indicate that significantly enhanced interleukin-6 expression levels in DCs during chorioamnionitis could be pivotal in skewing decidual monocyte differentiation to macrophages. PMID- 20724604 TI - Nurturing young scientists. PMID- 20724605 TI - Gulf oil spill. The case of the missing $470 million in BP's promised research fund. PMID- 20724603 TI - The calreticulin-binding sequence of thrombospondin 1 regulates collagen expression and organization during tissue remodeling. AB - Amino acids 17-35 of the thrombospondin1 (TSP1) N-terminal domain (NTD) bind cell surface calreticulin to signal focal adhesion disassembly, cell migration, and anoikis resistance in vitro. However, the in vivo relevance of this signaling pathway has not been previously determined. We engineered local in vivo expression of the TSP1 calreticulin-binding sequence to determine the role of TSP1 in tissue remodeling. Surgical sponges impregnated with a plasmid encoding the secreted calreticulin-binding sequence [NTD (1-35)-EGFP] or a control sequence [mod NTD (1-35)-EGFP] tagged with enhanced green fluorescent protein were implanted subcutaneously in mice. Sponges expressing NTD (1-35)-EFGP formed a highly organized capsule despite no differences in cellular composition, suggesting stimulation of collagen deposition by the calreticulin-binding sequence of TSP1. TSP1, recombinant NTD, or a peptide of the TSP1 calreticulin binding sequence (hep I) increased both collagen expression and matrix deposition by fibroblasts in vitro. TSP1 stimulation of collagen was inhibited by a peptide that blocks TSP1 binding to calreticulin, demonstrating the requirement for cell surface calreticulin. Collagen stimulation was independent of TGF-beta activity and Smad phosphorylation but was blocked by an Akt inhibitor, suggesting that signaling through the Akt pathway is important for regulation of collagen through TSP1 binding to calreticulin. These studies identify a novel function for the NTD of TSP1 as a mediator of collagen expression and deposition during tissue remodeling. PMID- 20724606 TI - Gulf oil spill. After outcry, oil data inches into the open. PMID- 20724607 TI - Cognition research. Investigation leaves field in the dark about a colleague's work. PMID- 20724611 TI - U.S. science budget. Senator builds his legacy with University of Alabama earmarks. PMID- 20724612 TI - Astronomy. U.S. astronomers unveil stripped-down 'short list'. PMID- 20724610 TI - Molecular genetics. One-two punch elevates rats to the knockout ranks. PMID- 20724613 TI - Free journals grow amid ongoing debate. PMID- 20724614 TI - Plant science. Pavlovsk's hopes hang on a tweet. PMID- 20724616 TI - National indicators show biodiversity progress. PMID- 20724618 TI - Life in science. Up a creek in Indonesia. PMID- 20724617 TI - Local programs take a bite out of malaria. PMID- 20724619 TI - Putting census data to work. PMID- 20724620 TI - Comment on "The silicate-mediated formose reaction: bottom-up synthesis of sugar silicates". AB - Lambert et al. (Reports, 19 February 2010, p. 984) reported that silicate ions catalyze the formation and stabilization of four- and six-carbon sugars from simple sugars, suggesting a possible prebiotic pathway for the synthesis of biologically important sugars. Here, we show that silicate has minimal impact in these respects, especially when compared to borate minerals. PMID- 20724621 TI - Science education. Partnerships for STEM education. PMID- 20724622 TI - Astronomy. A tale of two jets. PMID- 20724623 TI - Cell biology. Nuclei get TAN lines. PMID- 20724624 TI - Physics. Directing light emission from quantum dots. PMID- 20724625 TI - Genetics. Replication error amplified. PMID- 20724626 TI - Neuroscience. A glutamate pathway to faster-acting antidepressants? PMID- 20724627 TI - Immunology. Double TIP-ping. PMID- 20724628 TI - Cosmological constraints from strong gravitational lensing in clusters of galaxies. AB - Current efforts in observational cosmology are focused on characterizing the mass energy content of the universe. We present results from a geometric test based on strong lensing in galaxy clusters. Based on Hubble Space Telescope images and extensive ground-based spectroscopic follow-up of the massive galaxy cluster Abell 1689, we used a parametric model to simultaneously constrain the cluster mass distribution and dark energy equation of state. Combining our cosmological constraints with those from x-ray clusters and the Wilkinson Microwave Anisotropy Probe 5-year data gives Omega(m) = 0.25 +/- 0.05 and w(x) = -0.97 +/- 0.07, which are consistent with results from other methods. Inclusion of our method with all other available techniques brings down the current 2sigma contours on the dark energy equation-of-state parameter w(x) by approximately 30%. PMID- 20724629 TI - Dual jets from binary black holes. AB - The coalescence of supermassive black holes--a natural outcome when galaxies merge--should produce gravitational waves and would likely be associated with energetic electromagnetic events. We have studied the coalescence of such binary black holes within an external magnetic field produced by the expected circumbinary disk surrounding them. Solving the Einstein equations to describe black holes interacting with surrounding plasma, we present numerical evidence for possible jets driven by these systems. Extending the process described by Blandford and Znajek for a single, spinning black hole, the picture that emerges suggests that the electromagnetic field extracts energy from the orbiting black holes, which ultimately merge and settle into the standard Blandford-Znajek scenario. Emissions along these jets could potentially be observable at large distances. PMID- 20724630 TI - Unidirectional emission of a quantum dot coupled to a nanoantenna. AB - Nanoscale quantum emitters are key elements in quantum optics and sensing. However, efficient optical excitation and detection of such emitters involves large solid angles because their interaction with freely propagating light is omnidirectional. Here, we present unidirectional emission of a single emitter by coupling to a nanofabricated Yagi-Uda antenna. A quantum dot is placed in the near field of the antenna so that it drives the resonant feed element of the antenna. The resulting quantum-dot luminescence is strongly polarized and highly directed into a narrow forward angular cone. The directionality of the quantum dot can be controlled by tuning the antenna dimensions. Our results show the potential of optical antennas to communicate energy to, from, and between nano emitters. PMID- 20724631 TI - Ceria maintains smaller metal catalyst particles by strong metal-support bonding. AB - The energies of silver (Ag) atoms in Ag nanoparticles supported on different cerium and magnesium oxide surfaces, determined from previous calorimetric measurements of metal adsorption energies, were analyzed with respect to particle size. Their stability was found to increase with particle size below 5000 atoms per particle. Silver nanoparticles of any given size below 1000 atoms had much higher stability (30 to 70 kilojoules per mole of silver atoms) on reduced CeO2(111) than on MgO(100). This effect is the result of the very large adhesion energy (approximately 2.3 joules per square meter) of Ag nanoparticles to reduced CeO2(111), which we found to be a result of strong bonding to both defects and CeO2(111) terraces, apparently localized by lattice strain. These results explain the unusual sinter resistance of late transition metal catalysts when supported on ceria. PMID- 20724632 TI - Evidence of recent thrust faulting on the Moon revealed by the Lunar Reconnaissance Orbiter Camera. AB - Lunar Reconnaissance Orbiter Camera images reveal previously undetected lobate thrust-fault scarps and associated meter-scale secondary tectonic landforms that include narrow extensional troughs or graben, splay faults, and multiple low relief terraces. Lobate scarps are among the youngest landforms on the Moon, based on their generally crisp appearance, lack of superposed large-diameter impact craters, and the existence of crosscut small-diameter impact craters. Identification of previously known scarps was limited to high-resolution Apollo Panoramic Camera images confined to the equatorial zone. Fourteen lobate scarps were identified, seven of which are at latitudes greater than +/-60 degrees, indicating that the thrust faults are globally distributed. This detection, coupled with the very young apparent age of the faults, suggests global late stage contraction of the Moon. PMID- 20724633 TI - Drought-induced reduction in global terrestrial net primary production from 2000 through 2009. AB - Terrestrial net primary production (NPP) quantifies the amount of atmospheric carbon fixed by plants and accumulated as biomass. Previous studies have shown that climate constraints were relaxing with increasing temperature and solar radiation, allowing an upward trend in NPP from 1982 through 1999. The past decade (2000 to 2009) has been the warmest since instrumental measurements began, which could imply continued increases in NPP; however, our estimates suggest a reduction in the global NPP of 0.55 petagrams of carbon. Large-scale droughts have reduced regional NPP, and a drying trend in the Southern Hemisphere has decreased NPP in that area, counteracting the increased NPP over the Northern Hemisphere. A continued decline in NPP would not only weaken the terrestrial carbon sink, but it would also intensify future competition between food demand and proposed biofuel production. PMID- 20724634 TI - Loss of DNA replication control is a potent inducer of gene amplification. AB - Eukaryotic cells use numerous mechanisms to ensure that no segment of their DNA is inappropriately re-replicated, but the importance of this stringent control on genome stability has not been tested. Here we show that re-replication in Saccharomyces cerevisiae can strongly induce the initial step of gene amplification, increasing gene copy number from one to two or more. The resulting amplicons consist of large internal chromosomal segments that are bounded by Ty repetitive elements and are intrachromosomally arrayed at their endogenous locus in direct head-to-tail orientation. These re-replication-induced gene amplifications are mediated by nonallelic homologous recombination between the repetitive elements. We suggest that re-replication may be a contributor to gene copy number changes, which are important in fields such as cancer biology, evolution, and human genetics. PMID- 20724635 TI - Chloroplasts divide by contraction of a bundle of nanofilaments consisting of polyglucan. AB - In chloroplast division, the plastid-dividing (PD) ring is a main structure of the PD machinery and is a universal structure in the plant kingdom. However, the components and formation of the PD ring have been enigmatic. By proteomic analysis of PD machineries isolated from Cyanidioschyzon merolae, we identified the glycosyltransferase protein plastid-dividing ring 1 (PDR1), which constructs the PD ring and is widely conserved from red alga to land plants. Electron microscopy showed that the PDR1 protein forms a ring with carbohydrates at the chloroplast-division site. Fluorometric saccharide ingredient analysis of purified PD ring filaments showed that only glucose was included, and down regulation of PDR1 impaired chloroplast division. Thus, the chloroplasts are divided by the PD ring, which is a bundle of PDR1-mediated polyglucan filaments. PMID- 20724636 TI - Conserved fungal LysM effector Ecp6 prevents chitin-triggered immunity in plants. AB - Multicellular organisms activate immunity upon recognition of pathogen-associated molecular patterns (PAMPs). Chitin is the major component of fungal cell walls, and chitin oligosaccharides act as PAMPs in plant and mammalian cells. Microbial pathogens deliver effector proteins to suppress PAMP-triggered host immunity and to establish infection. Here, we show that the LysM domain-containing effector protein Ecp6 of the fungal plant pathogen Cladosporium fulvum mediates virulence through perturbation of chitin-triggered host immunity. During infection, Ecp6 sequesters chitin oligosaccharides that are released from the cell walls of invading hyphae to prevent elicitation of host immunity. This may represent a common strategy of host immune suppression by fungal pathogens, because LysM effectors are widely conserved in the fungal kingdom. PMID- 20724637 TI - Linear arrays of nuclear envelope proteins harness retrograde actin flow for nuclear movement. AB - Nuclei move to specific locations to polarize migrating and differentiating cells. Many nuclear movements are microtubule-dependent. However, nuclear movement to reorient the centrosome in migrating fibroblasts occurs through an unknown actin-dependent mechanism. We found that linear arrays of outer (nesprin2G) and inner (SUN2) nuclear membrane proteins assembled on and moved with retrogradely moving dorsal actin cables during nuclear movement in polarizing fibroblasts. Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. The coupling of actin cables to the nuclear membrane for nuclear movement via specific membrane proteins indicates that, like plasma membrane integrins, nuclear membrane proteins assemble into actin-dependent arrays for force transduction. PMID- 20724638 TI - mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. AB - The rapid antidepressant response after ketamine administration in treatment resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine. PMID- 20724639 TI - Females use multiple mating and genetically loaded sperm competition to target compatible genes. AB - Individuals in socially monogamous species may participate in copulations outside of the pair bond, resulting in extra-pair offspring. Although males benefit from such extra-pair behavior if they produce more offspring, the adaptive function of infidelity to females remains elusive. Here we show that female participation in extra-pair copulations, combined with a genetically loaded process of sperm competition, enables female finches to target genes that are optimally compatible with their own to ensure fertility and optimize offspring viability. Such female behavior, along with the postcopulatory processes demonstrated here, may provide an adaptive function of female infidelity in socially monogamous animals. PMID- 20724640 TI - Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy. AB - Quantifying cell behaviors in animal early embryogenesis remains a challenging issue requiring in toto imaging and automated image analysis. We designed a framework for imaging and reconstructing unstained whole zebrafish embryos for their first 10 cell division cycles and report measurements along the cell lineage with micrometer spatial resolution and minute temporal accuracy. Point scanning multiphoton excitation optimized to preferentially probe the innermost regions of the embryo provided intrinsic signals highlighting all mitotic spindles and cell boundaries. Automated image analysis revealed the phenomenology of cell proliferation. Blastomeres continuously drift out of synchrony. After the 32-cell stage, the cell cycle lengthens according to cell radial position, leading to apparent division waves. Progressive amplification of this process is the rule, contrasting with classical descriptions of abrupt changes in the system dynamics. PMID- 20724642 TI - Arthroscopically assisted meniscal allograft transplantation in the knee: a medium-term subjective, clinical, and radiographical outcome evaluation. AB - BACKGROUND: Allograft meniscal transplantation is known as a possible procedure to solve pain and loss of function in the knee of patients with a history of subtotal or total meniscectomy. PURPOSE: This work was undertaken to evaluate, using subjective questionnaires and clinical and radiographical scores, patients who underwent an arthroscopically assisted meniscal allograft transplantation with a minimum follow-up between 5 and 15 years (range, 62-169 months). STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Demographic data of 49 patients (50 meniscal allograft transplantations) were collected. At the latest follow-up visit, the authors collected preoperative and follow-up Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, Tegner, and Short Form 36 (SF-36) scores, and visual analog scale (VAS) scores for pain for comparison. Patients were also evaluated with a standardized clinical examination of the knee to objectively evaluate knee-related symptoms. Standard weightbearing radiographs and a full-leg standing radiograph were performed to evaluate the progression of osteoarthritis and malalignment. RESULTS: Five patients underwent total knee replacement and were considered failures, 8 patients could only be contacted by phone, and 2 patients were lost to follow-up, so 34 patients underwent the complete study protocol (except for 1 patient who did not have a radiographical evaluation because of pregnancy). The study group consisted of 18 men and 16 women, with a mean age of 33 years at the moment of transplantation and with an average follow-up of 8 years and 9 months. There were only a few concomitant procedures. There was a significant (P < .001) and clinically relevant decrease in the VAS (7 to 3.4) and increase in KOOS (35.8 to 60.2), Lysholm (39.7 to 71.8), and total SF-36 (51.5 to 75.2) from preoperative mean score to postoperative mean score. This improvement stayed consistent during the follow-up period. Despite this improvement, there was no increase in Tegner activity level (P = .604). The more severe the osteoarthritis, the less the improvement. There was a significant (P < .001) increase in osteoarthritis in 42% of the patients (14 of 33), as scored following the Kellgren-Lawrence classification. When strictly respecting the indications, there was no significant correlation between preoperative cartilage damage, preoperative osteoarthritis, alignment deviation, gender, and body mass index and the outcome scores or improvement. In this series, with few concomitant procedures, there was no difference in outcome between medial and lateral transplants. CONCLUSION: Meniscal allograft transplantation may result in important pain relief and functional improvement in patients with a history of (sub)total meniscectomy and pain localized in the affected compartment. Strictly following the indications, meniscal transplantation can give good and predictable results. In 58% of patients, there was no increase in osteoarthritis according to the Kellgren-Lawrence classification. In 42%, there was a slight or moderate increase in osteoarthritis. No severe increase was noted. PMID- 20724643 TI - Cartilage intermediate layer protein gene is associated with lumbar disc degeneration in male, but not female, collegiate athletes. AB - BACKGROUND: The authors previously identified a significant association between lumbar disc degeneration (LDDG) and cartilage intermediate layer protein (CILP) single nucleotide polymorphism (SNP) in collegiate male judokas. HYPOTHESIS: A significant association between LDDG and the CILP SNP is observed in Japanese collegiate athletes. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The participants were 601 trained collegiate athletes (male, 403; female, 198) from 7 different sports. Lumbar disc degeneration was evaluated using T2-weighted magnetic resonance imaging. Genotyping of the CILP gene (1184T/C) was performed by using DNA sequencing. RESULTS: Among the 601 collegiate athletes, the odds ratio (OR) for the occurrence of LDDG with the CILP C allele was 1.4 (95% confidence interval [CI], 1.05-1.86). By using logistic regression analysis concomitant with the interaction term and the Wald test, the authors found that weight (OR, 1.04; 95% CI, 1.02-1.06), CILP genotype (CT: OR, 2.0; 95% CI, 1.24-3.15; CC: OR, 2.9; 95% CI, 1.09-7.74), and gender (OR, 2.1; 95% CI, 1.21-3.67) were significant risk factors for LDDG. These analyses also indicated that there was no effect of the CILP genotype on LDDG in female athletes. CONCLUSION: The CILP SNP 1184T/C is a risk factor for male collegiate athletes. Information regarding the CILP gene polymorphism may be important for preventing and managing lumbar disc diseases, especially in male athletes. PMID- 20724644 TI - Nonreductive iron uptake mechanism in the marine alveolate Chromera velia. AB - Chromera velia is a newly cultured photosynthetic marine alveolate. This microalga has a high iron requirement for respiration and photosynthesis, although its natural environment contains less than 1 nm of this metal. We found that this organism uses a novel mechanism of iron uptake, differing from the classic reductive and siderophore-mediated iron uptake systems characterized in the model yeast Saccharomyces cerevisiae and present in most yeasts and terrestrial plants. C. velia has no trans-plasma membrane electron transfer system, and thus cannot reduce extracellular ferric chelates. It is also unable to use hydroxamate siderophores as iron sources. Iron uptake from ferric citrate by C. velia is not inhibited by a ferrous chelator, but the rate of uptake is strongly decreased by increasing the ferric ligand (citrate) concentration. The cell wall contains a large number of iron binding sites, allowing the cells to concentrate iron in the vicinity of the transport sites. We describe a model of iron uptake in which aqueous ferric ions are first concentrated in the cell wall before being taken up by the cells without prior reduction. We discuss our results in relation to the strategies used by the phytoplankton to take up iron in the oceans. PMID- 20724645 TI - Reproductive development modulates gene expression and metabolite levels with possible feedback inhibition of artemisinin in Artemisia annua. AB - The relationship between the transition to budding and flowering in Artemisia annua and the production of the antimalarial sesquiterpene, artemisinin (AN), the dynamics of artemisinic metabolite changes, AN-related transcriptional changes, and plant and trichome developmental changes were measured. Maximum production of AN occurs during full flower stage within floral tissues, but that changes in the leafy bracts and nonbolt leaves as the plant shifts from budding to full flower. Expression levels of early pathway genes known to be involved in isopentenyl diphosphate and farnesyl diphosphate biosynthesis leading to AN were not immediately positively correlated with either AN or its precursors. However, we found that the later AN pathway genes, amorpha-4,11-diene synthase (ADS) and the cytochrome P450, CYP71AV1 (CYP), were more highly correlated with AN's immediate precursor, dihydroartemisinic acid, within all leaf tissues tested. In addition, leaf trichome formation throughout the developmental phases of the plant also appears to be more complex than originally thought. Trichome changes correlated closely with the levels of AN but not its precursors. Differences were observed in trichome densities that are dependent both on developmental stage (vegetative, budding, and flowering) and on position (upper and lower leaf tissue). AN levels declined significantly as plants matured, as did ADS and CYP transcripts. Spraying leaves with AN or artemisinic acid inhibited CYP transcription; artemisinic acid also inhibited ADS transcription. These data allow us to present a novel model for the differential control of AN biosynthesis as it relates to developmental stage and trichome maturation and collapse. PMID- 20724646 TI - Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations. AB - OBJECTIVE: Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY). RESEARCH DESIGN AND METHODS: Serum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded approximately 11% of subjects in whom the single available hs-CRP measurement was >10 mg/l. RESULTS: Geometric mean (SD range) hs-CRP levels were significantly lower (P 18 years of age) without a history of myocardial infarction was assessed to determine the proportion of adults who met the criteria for IFG/IGT, and the proportion of IFG/IGT subjects who: 1) reported receiving a diagnosis from their physicians; 2) were prescribed lifestyle modification or an antihyperglycemic agent; and 3) were currently on therapy. We used multivariable regression analysis to identify predictors of diagnosis and treatment. RESULTS: Of the 1,547 subjects, 34.6% (CI 30.3-38.9%) had pre-diabetes; 19.4% had IFG only; 5.4% had IGT only, and 9.8% had both IFG and IGT. Only 4.8% of those with pre-diabetes reported having received a formal diagnosis from their physicians. No subjects with pre-diabetes received oral antihyperglycemics, and the rates of recommendation for exercise or diet were 31.7% and 33.5%, respectively. Among the 47.7% pre-diabetic subjects who exercised, 49.4% reported exercising for at least 30 min daily. CONCLUSIONS: Three years after a major clinical trial demonstrated that interventions could greatly reduce progression from IFG/IGT to type 2 diabetes, the majority of the U.S. population with IFG/IGT was undiagnosed and untreated with interventions. Whether this is due to physicians being unaware of the evidence, unconvinced by the evidence, or clinical inertia is unclear. PMID- 20724650 TI - Neck circumference positively related with central obesity, overweight, and metabolic syndrome in Chinese subjects with type 2 diabetes: Beijing Community Diabetes Study 4. AB - OBJECTIVE: To investigate the association between neck circumference and central obesity, overweight, and metabolic syndrome in Chinese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 3,182 diabetic subjects (aged 20-80 years) were recruited from 15 community health centers in Beijing using a multistage random sampling approach. RESULTS: Receiver operating characteristic analysis showed that the area under the curve for neck circumference and central obesity was 0.77 for men and 0.75 for women (P<0.001). Furthermore, a neck circumference of >=38 cm for men and >=35 cm for women was the best cutoff point for determining overweight subjects. A neck circumference of >=39 cm for men and >=35 cm for women was the best cutoff point to determine subjects with metabolic syndrome. CONCLUSIONS: In the present study, neck circumference is positively related with BMI, waist circumference, and metabolic syndrome in Chinese individuals with type 2 diabetes. PMID- 20724651 TI - Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. AB - OBJECTIVE: To verify whether the leptin gene epigenetic (DNA methylation) profile is altered in the offspring of mothers with gestational impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Placental tissues and maternal and cord blood samples were obtained from 48 women at term including 23 subjects with gestational IGT. Leptin DNA methylation, gene expression levels, and circulating concentration were measured using the Sequenom EpiTYPER system, quantitative real time RT-PCR, and enzyme-linked immunosorbent assay, respectively. IGT was assessed after a 75-g oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. RESULTS: We have shown that placental leptin gene DNA methylation levels were correlated with glucose levels (2-h post-OGTT) in women with IGT (fetal side: rho=-0.44, P<=0.05; maternal side: rho=0.53, P<=0.01) and with decreased leptin gene expression (n=48; rho>=-0.30, P<=0.05) in the whole cohort. Placental leptin mRNA levels accounted for 16% of the variance in maternal circulating leptin concentration (P<0.05). CONCLUSIONS: IGT during pregnancy was associated with leptin gene DNA methylation adaptations with potential functional impacts. These epigenetic changes provide novel mechanisms that could contribute to explaining the detrimental health effects associated with fetal programming, such as long-term increased risk of developing obesity and type 2 diabetes. PMID- 20724652 TI - Prothrombotic state, cardiovascular, and metabolic syndrome risk factors in prepubertal children born large for gestational age. AB - OBJECTIVE: To evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age (LGA) to nondiabetic, nonobese mothers. RESEARCH DESIGN AND METHODS: At 6-7 years of age, the comparison of various factors was made between 31 LGA and 34 appropriate-for gestational-age (AGA) children: fibrinogen, antithrombin III, protein C and S, fasting insulin, glucose, homeostasis assessment model of insulin resistance (HOMA-IR) index, adiponectin, leptin, visfatin, IGF-1, IGF-binding protein (IGFBP)-1, IGFBP-3, lipids, and the genetic factors V Leiden G1691A mutation, prothrombin 20210A/G polymorphism, and mutation in the enzyme 5,10 methylenetetrahydrofolate-reductase gene (MTHFR-C677T). RESULTS: LGA children had higher levels of leptin (P<0.01), fasting insulin (P<0.01), and HOMA-IR (P<0.01), but lower IGFBP-3 (P=0.0001), fibrinogen (P=0.0001), and lipoprotein(a) (P<0.001) than AGA children. Significantly more LGA children were homozygous for the MTHFR C677T mutation (P=0.0016). CONCLUSIONS: Being born LGA to nondiabetic, nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty. PMID- 20724653 TI - Prognostic value of gated myocardial perfusion imaging for asymptomatic patients with type 2 diabetes: the J-ACCESS 2 investigation. AB - OBJECTIVE: Individuals with type 2 diabetes are at high risk for cardiovascular events. We evaluated the prognostic value of gated myocardial perfusion single photon computed tomography (SPECT) for asymptomatic diabetic patients in a Japanese population. RESEARCH DESIGN AND METHODS: Asymptomatic patients (n=485) aged>=50 years with either a maximal carotid artery intima-media thickness of >=1.1 mm, or a urinary albumin >=30 mg/g creatinine or who had at least two of the following, abdominal obesity, low HDL cholesterol, high triglyceride levels, and hypertension, were enrolled at 50 institutions. The patients were evaluated using gated SPECT with the stress-rest protocol and followed up for 3 years. RESULTS: During the follow-up period, 62 (13%) events occurred, including 5 cardiac deaths and 57 cardiovascular events. Patients with summed stress scores (SSS) of >=9 had a significantly higher incidence (of either death or cardiovascular events) than those with SSS scores of <9 (23 vs. 12%; P=0.009). Multivariate Cox regression analysis showed that significant variables were SSS>=9, a low estimated glomerular filtration rate, and being a current smoker. Univariate Cox regression analysis showed that ticlopidine and insulin use are potent medical modulators of cardiovascular events. CONCLUSIONS: The incidences of cardiovascular events and death were significantly high in a select population of type 2 diabetic patients with SPECT abnormalities. A targeted treatment strategy is required for asymptomatic but potentially high-risk patients with type 2 diabetes. PMID- 20724654 TI - Interaction of phospholipid transfer protein with human tear fluid mucins. AB - In addition to circulation, where it transfers phospholipids between lipoprotein particles, phospholipid transfer protein (PLTP) was also identified as a component of normal tear fluid. The purpose of this study was to clarify the secretion route of tear fluid PLTP and elucidate possible interactions between PLTP and other tear fluid proteins. Human lacrimal gland samples were stained with monoclonal antibodies against PLTP. Heparin-Sepharose (H-S) affinity chromatography was used for specific PLTP binding, and coeluted proteins were identified with MALDI-TOF mass spectrometry or Western blot analysis. Immunoprecipitation assay and blotting with specific antibodies helped to identify and characterize PLTP-mucin interaction in tear fluid. Human tear fluid PLTP is secreted from the lacrimal gland. MALDI-TOF analysis of H-S fractions identified several candidate proteins, but protein-protein interaction assays revealed only ocular mucins as PLTP interaction partners. We suggest a dual role for PLTP in human tear fluid: (1) to scavenge lipophilic substances from ocular mucins and (2) to maintain the stability of the anterior tear lipid film. PLTP may also play a role in the development of ocular surface disease. PMID- 20724656 TI - Grandmothers and caregiving to grandchildren: continuity, change, and outcomes over 24 months. AB - PURPOSE: Transitions in caregiving, such as becoming a primary caregiver to grandchildren or having adult children and grandchildren move in or out, may affect the well-being of the grandmother. DESIGN AND METHODS: This report describes caregiving patterns at 3 time points over 24 months in a sample of 485 Ohio grandmothers and examines the effects of stability and change in grandmother caregiving roles (raising a grandchild, living in a multigenerational home, or not caregiving to grandchildren). Drawing on the Resiliency Model of Family Stress, the study examined caregiving stress and reward, intrafamily strain, social support, resourcefulness, depressive symptoms, mental and physical health, and perceived family functioning. Caregiver group, time of measurement, switching between caregiver groups, and baseline age, race, education, work status, and marital status were considered as independent variables within the context of a one-way treatment structure in a mixed-model multivariate analysis. RESULTS: There were significant caregiver group effects for all variables, except mental health and resourcefulness. Grandmothers raising grandchildren reported the most stress, intrafamily strain, and perceived problems in family functioning, the worst physical health and more depressive symptoms, and the least reward and subjective support. Across groups, there were significant time effects, with worsening physical health and increased stress over time. Switching to higher levels of caregiving was associated with worsening physical health and increases in stress, intrafamily strain, and perceived problems in family functioning. IMPLICATIONS: Recommendations for research and for practice, especially during times of caregiving transition or for grandmothers raising grandchildren, are discussed. PMID- 20724655 TI - Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study. AB - Hypertriglyceridemia, defined as a triglyceride measurement > 150 mg/dl, occurs in up to 34% of adults. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential core of triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in triglyceride (TG) response to fenofibrate treatment. Participants (N = 958) from the Genetics of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate 160 mg/day. Associations of four APOB gene single nucleotide polymorphisms (SNP) (rs934197, rs693, rs676210, and rs1042031) were tested for association with the TG response to fenofibrate using a mixed growth curve model where the familial structure was modeled as a random effect and cardiovascular risk factors were included as covariates. Three of these four SNPs changed the amino acid sequence of APOB, and the fourth was in the promoter region. TG response to fenofibrate treatment was associated with one APOB SNP, rs676210 (Pro2739Leu), such that participants with the TT genotype of rs676210 had greater TG lowering than those with the CC genotype (additive model, P = 0.0017). We conclude the rs676210 variant may identify individuals who respond best to fenofibrate for TG reduction. PMID- 20724657 TI - Threat to valued elements of life: the experience of dementia across three ethnic groups. AB - PURPOSE: There is a fundamental knowledge gap regarding the experience of dementia within minority ethnic groups in the United Kingdom and elsewhere. The present study examined the subjective reality of living with dementia from the perspective of people with dementia within the 3 largest ethnic groups in the United Kingdom. DESIGN AND METHODS: This was a qualitative study in which in depth individual interviews were conducted with 11 Black Caribbean, 9 south Asian, and 10 White British older people with dementia. The lack of information in this area prompted the use of a grounded theory approach. RESULTS: The main theme to emerge from the interviews with the people with dementia was "threat to valued elements of life." Participants engaged in a process of appraisal in which they assessed the degree to which their condition and support needs interfered with valued elements of life. The analysis revealed that each element of this process was culturally informed. IMPLICATIONS: There is potential for modifying beliefs to reduce the perceived threat of dementia and for family and professional carers to promote the roles, relationships, and activities that each person with dementia values. The findings outlined in this paper can inform the development of a culturally sensitive approach. PMID- 20724658 TI - Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling. AB - Hydrogen peroxide (H(2)O(2)) produced by cell-surface NADPH Oxidase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H(2)O(2) to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H(2)O(2) into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl Ester (PY1-ME), a new chemoselective fluorescent indicator for H(2)O(2), directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H(2)O(2) specifically through membranes in mammalian cells. Moreover, we show that intracellular H(2)O(2) accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Nox-derived H(2)O(2) signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H(2)O(2) can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions. PMID- 20724659 TI - Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid. AB - It is difficult to overestimate the importance of nucleoside triphosphates in cellular chemistry: They are the building blocks for DNA and RNA and important sources of energy. Modifications of biologically important organic molecules with fluorine are of great interest to chemists and biologists because the size and electronegativity of the fluorine atom can be used to make defined structural alterations to biologically important molecules. Although the concept of nonhydrolyzable nucleotides has been around for some time, the progress in the area of modified triphosphates was limited by the lack of synthetic methods allowing to access bisCF(2)-substituted nucleotide analogs-one of the most interesting classes of nonhydrolyzable nucleotides. These compounds have "correct" polarity and the smallest possible steric perturbation compared to natural nucleotides. No other known nucleotides have these advantages, making bisCF(2)-substituted analogs unique. Herein, we report a concise route for the preparation of hitherto unknown highly acidic and polybasic bis(difluoromethylene)triphosphoric acid 1 using a phosphorous(III)/phosphorous(V) interconversion approach. The analog 1 compared to triphosphoric acid is enzymatically nonhydrolyzable due to substitution of two bridging oxygen atoms with CF(2) groups, maintaining minimal perturbations in steric bulkiness and overall polarity of the triphosphate polyanion. The fluorinated triphosphoric acid 1 was used for the preparation of the corresponding fluorinated deoxynucleotides (dNTPs). One of these dNTP analogs (dT) was demonstrated to fit into DNA polymerase beta (DNA pol beta) binding pocket by obtaining a 2.5 A resolution crystal structure of a ternary complex with the enzyme. Unexpected dominating effect of triphosphate/Mg(2+) interaction over Watson-Crick hydrogen bonding was found and discussed. PMID- 20724660 TI - Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense. AB - The rapid induction of type I IFN is a central event of the innate defense against viral infections and is tightly regulated by a number of cellular molecules. Viral components induce strong type I IFN responses through the activation of toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as an RNA helicase RIG-I and/or MDA5. According to recent studies, the NF kappaB essential modulator (NEMO, also called IKKgamma) is crucial for this virus induced antiviral response. However, the precise roles of signal activation by NEMO adaptor have not been elucidated. Here, we show that virus-induced IRF3 and NF-kappaB activation depends on the K(lys)-27-linked polyubiquitination to NEMO by the novel ubiquitin E3 ligase triparite motif protein 23 (TRIM23). Virus induced IRF3 and NF-kappaB activation, as well as K27-linked NEMO polyubiquitination, were abrogated in TRIM23 knockdown cells, whereas TRIM23 knockdown had no effect on TNFalpha-mediated NF-kappaB activation. Furthermore, in NEMO-deficient mouse embryo fibroblast cells, IFN-stimulated response element driven reporter activity was restored by ectopic expression of WT NEMO, as expected, but only partial recovery by NEMO K165/309/325/326/344R multipoints mutant on which TRIM23-mediated ubiquitin conjugation was substantially reduced. Thus, we conclude that TRIM23-mediated ubiquitin conjugation to NEMO is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses. PMID- 20724661 TI - Insights into the mechanism of polysaccharide dephosphorylation by a glucan phosphatase. PMID- 20724662 TI - Culture, distress, and oxytocin receptor polymorphism (OXTR) interact to influence emotional support seeking. AB - Research has demonstrated that certain genotypes are expressed in different forms, depending on input from the social environment. To examine sensitivity to cultural norms regarding emotional support seeking as a type of social environment, we explored the behavioral expression of oxytocin receptor polymorphism (OXTR) rs53576, a gene previously related to socio-emotional sensitivity. Seeking emotional support in times of distress is normative in American culture but not in Korean culture. Consequently, we predicted a three way interaction of culture, distress, and OXTR genotype on emotional support seeking. Korean and American participants (n = 274) completed assessments of psychological distress and emotional support seeking and were genotyped for OXTR. We found the predicted three-way interaction: among distressed American participants, those with the GG/AG genotypes reported seeking more emotional social support, compared with those with the AA genotype, whereas Korean participants did not differ significantly by genotype; under conditions of low distress, OXTR groups did not differ significantly in either cultural group. These findings suggest that OXTR rs53576 is sensitive to input from the social environment, specifically cultural norms regarding emotional social support seeking. These findings also indicate that psychological distress and culture are important moderators that shape behavioral outcomes associated with OXTR genotypes. PMID- 20724663 TI - A general basis for quarter-power scaling in animals. AB - It has been known for decades that the metabolic rate of animals scales with body mass with an exponent that is almost always <1, >2/3, and often very close to 3/4. The 3/4 exponent emerges naturally from two models of resource distribution networks, radial explosion and hierarchically branched, which incorporate a minimum of specific details. Both models show that the exponent is 2/3 if velocity of flow remains constant, but can attain a maximum value of 3/4 if velocity scales with its maximum exponent, 1/12. Quarter-power scaling can arise even when there is no underlying fractality. The canonical "fourth dimension" in biological scaling relations can result from matching the velocity of flow through the network to the linear dimension of the terminal "service volume" where resources are consumed. These models have broad applicability for the optimal design of biological and engineered systems where energy, materials, or information are distributed from a single source. PMID- 20724664 TI - Mas-related G-protein-coupled receptors inhibit pathological pain in mice. AB - An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein-coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8-22 (BAM 8-22), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8-22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets. PMID- 20724666 TI - Expression of C-type lectin, SIGNR3, on subsets of dendritic cells, macrophages, and monocytes. AB - The C-type lectin SIGNR3 is a mouse homologue of human DC-SIGN, which shares carbohydrate-binding specificity with human DC-SIGN. However, the expression profile of SIGNR3 is largely unknown. To examine the expression of SIGNR3 in immune cells, we generated SIGNR3-specific mAb and investigated SIGNR3 expression in vivo. SIGNR3 was expressed on a fraction of MHC II(+) DCs and Mphis in the dermis and CD115(+)Ly6C(int-low) monocytes in the blood and BM. In the LNs, SIGNR3(+) cells localized adjacent to PNAd(+) HEV-like vessels. They were also found in interfollicular regions in sLNs but not mLNs. Those SIGNR3(+) cells expressed CD11b and variable levels of CD11c and MHC II. As in LNs, SIGNR3 was expressed on a large proportion of the CD11b(+)CD11c(int-high) cells in the spleen. In the lung, SIGNR3(+) cells belonged to the CD11b(+)CD11c(int) population, and Mphis in the airway and lung faintly expressed SIGNR3. When PKH67 labeled CD115(+)Ly6C(high) BM monocytes were transferred into normal recipients, they up-regulated SIGNR3 expression along with the decrease in Ly6C expression during the circulation and upon arrival at the peripheral LNs through HEV. In addition, CD11b(high)Ly6C(high) monocytes that entered sLNs differentiated into CD11b(+) DCs in a couple of days, whereas those in the spleen, mLNs, and lung differentiated into CD11c(int) monocytic cells. These results suggest that SIGNR3 is a new differentiation marker for myeloid mononuclear cells and indicate that some DCs, especially in the sLNs, are possibly replenished by Ly6C(high) monocytes. PMID- 20724665 TI - Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-delta (delta-PKC). AB - Inflammation and proinflammatory mediators are activators of delta-PKC. In vitro, delta-PKC regulates proinflammatory signaling in neutrophils and endothelial and epithelial cells, cells that can contribute to lung tissue damage associated with inflammation. In this study, a specific delta-PKC TAT peptide inhibitor was used to test the hypothesis that inhibition of delta-PKC would attenuate lung injury in an animal model of ARDS. Experimental ARDS was induced in rats via 2CLP, a model of polymicrobial sepsis. Following 2CLP surgery, the delta-PKC TAT inhibitory peptide (2CLP+delta-PKC TAT in PBS) or PBS (2CLP+PBS) was administered intratracheally. Controls consisted of SO, where animals underwent a laparotomy without 2CLP. Twenty-four hours after SO or 2CLP, blood, BALF, and lung tissue were collected. 2CLP induced delta-PKC phosphorylation in the lung within 24 h. Treatment with the delta-PKC TAT inhibitory peptide significantly decreased pulmonary delta-PKC phosphorylation, indicating effective inhibition of delta-PKC activation. Plasma and BALF levels of the chemokines CINC-1 and MIP-2 were elevated in 2CLP + PBS rats as compared with SO rats. Treatment with delta-PKC TAT reduced 2CLP-induced elevations in chemokine levels in BALF and plasma, suggesting that delta-PKC modulated chemokine expression. Most importantly, intratracheal administration of delta-PKC TAT peptide significantly attenuated inflammatory cell infiltration, disruption of lung architecture, and pulmonary edema associated with 2CLP. Thus, delta-PKC is an important regulator of proinflammatory events in the lung. Targeted inhibition of delta-PKC exerted a lung-protective effect 24 h after 2CLP. PMID- 20724667 TI - Adult health. PMID- 20724668 TI - Evidence hierarchies versus synergistic interventions. PMID- 20724669 TI - Recent trends in maternal, newborn, and child health in Brazil: progress toward Millennium Development Goals 4 and 5. AB - We analyzed Brazil's efforts in reducing child mortality, improving maternal and child health, and reducing socioeconomic and regional inequalities from 1990 through 2007. We compiled and reanalyzed data from several sources, including vital statistics and population-based surveys. We also explored the roles of broad socioeconomic and demographic changes and the introduction of health sector and other reform measures in explaining the improvements observed. Our findings provide compelling evidence that proactive measures to reduce health disparities accompanied by socioeconomic progress can result in measurable improvements in the health of children and mothers in a relatively short interval. Our analysis of Brazil's successes and remaining challenges to reach and surpass Millennium Development Goals 4 and 5 can provide important lessons for other low- and middle income countries. PMID- 20724670 TI - Concepts of capability and overlooked applications. PMID- 20724671 TI - HPV vaccination's second act: promotion, competition, and compulsion. AB - Developments regarding human papillomavirus (HPV) vaccines will transform HPV vaccination in the United States while simultaneously raising several new policy and ethical concerns. Policymakers, vaccine manufacturers, and the public health community must now respond to the presence of competing vaccines that are similar but distinct, particularly with respect to genital wart prevention and the benefits of vaccinating males. This work arises in the shadow of the contentious introduction of the HPV vaccine Gardasil (Merck & Co, Inc, Whitehouse Station, NJ) in 2006, particularly the opposition to efforts in many states to require the vaccine for school attendance. I review the current status of HPV vaccine policy in the United States and examine issues of public health ethics and policy central to ongoing and future HPV vaccination programs. PMID- 20724672 TI - Gun shows and gun violence: fatally flawed study yields misleading results. AB - A widely publicized but unpublished study of the relationship between gun shows and gun violence is being cited in debates about the regulation of gun shows and gun commerce. We believe the study is fatally flawed. A working paper entitled "The Effect of Gun Shows on Gun-Related Deaths: Evidence from California and Texas" outlined this study, which found no association between gun shows and gun related deaths. We believe the study reflects a limited understanding of gun shows and gun markets and is not statistically powered to detect even an implausibly large effect of gun shows on gun violence. In addition, the research contains serious ascertainment and classification errors, produces results that are sensitive to minor specification changes in key variables and in some cases have no face validity, and is contradicted by 1 of its own authors' prior research. The study should not be used as evidence in formulating gun policy. PMID- 20724673 TI - Evaluation of a cervical cancer control intervention using lay health workers for Vietnamese American women. AB - OBJECTIVES: We conducted a trial to evaluate the effectiveness of a cervical cancer control intervention for Vietnamese American women that used lay health workers. METHODS: The study group included 234 women who had not received a Papanicolaou (Pap) test in the last 3 years. Experimental group participants received a lay health worker home visit. Our trial endpoint was Pap test receipt within 6 months of randomization. Pap testing completion was ascertained through women's self-reports and medical record reviews. We examined intervention effects among women who had ever received a Pap test (prior to randomization) and women who had never received a Pap test. RESULTS: Three quarters of the women in the experimental group completed a home visit. Ever-screened experimental group women were significantly more likely to report Pap testing (P < .02) and to have records verifying Pap testing (P < .04) than were ever-screened control group women. There were no significant differences between the trial arms for women who had never been screened. CONCLUSIONS: Our findings indicate that lay health worker-based interventions for Vietnamese American women are feasible to implement and can increase levels of Pap testing use among ever-screened women but not among never-screened women. PMID- 20724674 TI - The association between community water fluoridation and adult tooth loss. AB - OBJECTIVES: We sought to estimate the association between community water fluoridation (CWF) exposure at various stages of life and adult tooth loss. METHODS: We used data from the 1995 through 1999 Behavioral Risk Factor Surveillance System, merged with data from the 1992 Water Fluoridation Census, to estimate interval regression models that relate CWF exposure with tooth loss. RESULTS: Our results indicate that CWF levels in the county of residence at the time of the respondent's birth are significantly related to tooth loss but current CWF levels are not. In addition, the impact of CWF exposure is larger for individuals of lower socioeconomic status. CONCLUSIONS: This study suggests that the benefits of CWF may be larger than previously believed and that CWF has a lasting improvement in racial/ethnic and economic disparities in oral health. PMID- 20724675 TI - Walking and cycling to health: a comparative analysis of city, state, and international data. AB - OBJECTIVES: We sought to determine the magnitude, direction, and statistical significance of the relationship between active travel and rates of physical activity, obesity, and diabetes. METHODS: We examined aggregate cross-sectional health and travel data for 14 countries, all 50 US states, and 47 of the 50 largest US cities through graphical, correlation, and bivariate regression analysis on the country, state, and city levels. RESULTS: At all 3 geographic levels, we found statistically significant negative relationships between active travel and self-reported obesity. At the state and city levels, we found statistically significant positive relationships between active travel and physical activity and statistically significant negative relationships between active travel and diabetes. CONCLUSIONS: Together with many other studies, our analysis provides evidence of the population-level health benefits of active travel. Policies on transport, land-use, and urban development should be designed to encourage walking and cycling for daily travel. PMID- 20724676 TI - Godfrey H. Hochbaum (1916-1999): from social psychology to health behavior and health education. PMID- 20724678 TI - A soldier's hero: Edith Cavell (1865-1915). PMID- 20724677 TI - Smoking-related health risks among persons with HIV in the Strategies for Management of Antiretroviral Therapy clinical trial. AB - OBJECTIVES: We sought to determine smoking-related hazard ratios (HRs) and population-attributable risk percentage (PAR%) for serious clinical events and death among HIV-positive persons, whose smoking prevalence is higher than in the general population. METHODS: For 5472 HIV-infected persons enrolled from 33 countries in the Strategies for Management of Antiretroviral Therapy clinical trial, we evaluated the relationship between baseline smoking status and development of AIDS-related or serious non-AIDS events and overall mortality. RESULTS: Among all participants, 40.5% were current smokers and 24.8% were former smokers. Adjusted HRs were higher for current than for never smokers for overall mortality (2.4; P < .001), major cardiovascular disease (2.0; P = .002), non-AIDS cancer (1.8; P = .008), and bacterial pneumonia (2.3; P < .001). Adjusted HRs also were significantly higher for these outcomes among current than among former smokers. The PAR% for current versus former and never smokers combined was 24.3% for overall mortality, 25.3% for major cardiovascular disease, 30.6% for non-AIDS cancer, and 25.4% for bacterial pneumonia. CONCLUSIONS: Smoking contributes to substantial morbidity and mortality in this HIV-infected population. Providers should routinely integrate smoking cessation programs into HIV health care. PMID- 20724679 TI - The myth of meritocracy and African American health. AB - Recent theoretical and empirical studies of the social determinants of health inequities have shown that economic deprivation, multiple levels of racism, and neighborhood context limit African American health chances and that African Americans' poor health status is predicated on unequal opportunity to achieve the American Dream. President Obama's election has been touted as a demonstration of American meritocracy-the belief that all may obtain the American Dream-and has instilled hope in African Americans. However, we argue that in the context of racism and other barriers to success, meritocratic ideology may act as a negative health determinant for African Americans. PMID- 20724680 TI - Workplace assaults on nursing assistants in US nursing homes: a multilevel analysis. AB - OBJECTIVES: We examined risk factors for injuries to nursing assistants from assaults by nursing home residents at both the individual and the organizational level. METHODS: We analyzed data from the 2004 National Nursing Assistant Survey that were linked to facility information from the 2004 National Nursing Home Survey by use of multilevel modeling that accounted for the complex survey design effect. RESULTS: Thirty-four percent of nursing assistants surveyed reported experiencing physical injuries from residents' aggression in the previous year. Mandatory overtime (odds ratio [OR] = 1.65; 95% confidence interval [CI] = 1.22, 2.24) and not having enough time to assist residents with their activities of daily living (OR = 1.49; 95% CI = 1.25, 1.78) were strongly associated with experiencing injuries from assaults. Nursing assistants employed in nursing homes with Alzheimer care units were more likely to experience such injuries, including being bitten by residents. CONCLUSIONS: Reducing mandatory overtime and having a less demanding workload may reduce the risk of workplace violence. In particular, prevention activities should be targeted at those nursing homes that care for cognitively impaired patients. PMID- 20724681 TI - Drinking rainwater: a double-blinded, randomized controlled study of water treatment filters and gastroenteritis incidence. AB - OBJECTIVES: We examined whether drinking untreated rainwater, a practice that is on the rise in developed countries because of water shortages, contributes to community gastroenteritis incidence. METHODS: We conducted a double-blinded, randomized controlled trial in Adelaide, Australia. Sham or active water treatment units were installed, and participants recorded incidences of illness in a health diary for 12 months. The primary outcome was highly credible gastroenteritis (HCG; characterized by a specified number of loose stools or vomiting alone or in combination with abdominal pain or nausea in a 24-hour period), and we used generalized estimating equations to account for correlations between numbers of HCG events for individuals in the same family. RESULTS: Participants reported 769 episodes during the study (0.77 episodes/person/year), with an HCG incidence rate ratio (active vs sham) of 1.05 (95% confidence interval [CI] = 0.82, 1.33). Blinding of the participants was effective (index = 0.65; 95% CI = 0.58, 0.72). CONCLUSIONS: Our results suggest that consumption of untreated rainwater does not contribute appreciably to community gastroenteritis. However, our findings may not be generalizable to susceptible and immunocompromised persons because these groups were specifically excluded from the study. PMID- 20724683 TI - The utilization of home care by the elderly in Brazil's primary health care system. AB - OBJECTIVES: We assessed the utilization of home care by the elderly in Brazil after implementation of the Family Health Strategy (FHS). METHODS: Data were derived from a cross-sectional study in a southern city in Brazil. Using the chi(2) test and a logistic regression with different levels of determination, we tested the hypothesis that the FHS increased the utilization of home care compared with utilization under the Traditional Primary Health Care (TPHC) system. RESULTS: We interviewed 1593 residents aged 60 years and older. Home care utilization under the FHS was 2.7 times the rate of utilization under the TPHC (95% confidence interval = 1.5, 4.7; P = .001), and utilization increased among the older group, the less educated, those with history of hospitalization, and those with functional limitations. CONCLUSIONS: Improvement in access to care resulted in greater utilization of home care. Our findings have policy implications that include expanding the coverage of the FHS throughout big cities where coverage is limited. These findings are important because the population is aging and the family strategy operates in poorer areas; thus, it can promote equity in access to home health care among the elderly. PMID- 20724682 TI - Antiretroviral therapy as HIV prevention: status and prospects. AB - As antiretroviral treatment of HIV infection has become increasingly accessible, attention has focused on whether these drugs can used for prevention because of increased tolerability of newer medications, decreased cost, and the limitations of other approaches. We review the status of antiretroviral HIV prevention, including chemoprophylaxis, as well as the effects of treatment of infected individuals on prevention. It is possible that the life-saving agents that have transformed the natural history of AIDS can be a critical component of HIV prevention efforts, but their ultimate role in affecting HIV transmission dynamics remains to be defined. PMID- 20724684 TI - Racial disparities in stage-specific colorectal cancer mortality: 1960-2005. AB - OBJECTIVES: We examined whether racial disparities in stage-specific colorectal cancer survival changed between 1960 and 2005. METHODS: We used US Mortality Multiple-Cause-of-Death Data Files and intercensal estimates to calculate standardized mortality rates by gender and race from 1960 to 2005. We used Surveillance, Epidemiology, and End Results (SEER) data to estimate stage specific colorectal cancer survival. To account for SEER sampling uncertainty, we used a bootstrap resampling procedure and fit a Cox proportional hazards model. RESULTS: Between 1960-2005, patterns of decline in mortality rate as a result of colorectal cancer differed greatly by gender and race: 54% reduction for White women, 14% reduction for Black women, 39% reduction for White men, and 28% increase for Black men. Blacks consistently experienced worse rates of stage specific survival and life expectancy than did Whites for both genders, across all age groups, and for localized, regional, and distant stages of the disease. CONCLUSIONS: The rates of stage-specific colorectal cancer survival differed among Blacks when compared with Whites during the 4-decade study period. Differences in stage-specific life expectancy were the result of differences in access to care or quality of care. More attention should be given to racial disparities in colorectal cancer management. PMID- 20724685 TI - Urban sprawl, smart growth, and deliberative democracy. AB - Urban sprawl is an increasingly common feature of the built environment in the United States and other industrialized nations. Although there is considerable evidence that urban sprawl has adverse affects on public health and the environment, policy frameworks designed to combat sprawl-such as smart growth have proven to be controversial, making implementation difficult. Smart growth has generated considerable controversy because stakeholders affected by urban planning policies have conflicting interests and divergent moral and political viewpoints. In some of these situations, deliberative democracy-an approach to resolving controversial public-policy questions that emphasizes open, deliberative debate among the affected parties as an alternative to voting-would be a fair and effective way to resolve urban-planning issues. PMID- 20724686 TI - Effectiveness of HIV prevention social marketing with injecting drug users. AB - Social marketing involves applying marketing principles to promote social goods. In the context of health behavior, it has been used successfully to reduce alcohol-related car crashes, smoking among youths, and malaria transmission, among other goals. Features of social marketing, such as audience segmentation and repeated exposure to prevention messages, distinguish it from traditional health promotion programs. A recent review found 8 of 10 rigorously evaluated social marketing interventions responsible for changes in HIV-related behavior or behavioral intentions. We studied 479 injection drug users to evaluate a community-based social marketing campaign to reduce injection risk behavior among drug users in Sacramento, California. Injecting drugs is associated with HIV infection in more than 130 countries worldwide. PMID- 20724687 TI - Socioeconomic and racial/ethnic disparities in the incidence of bacteremic pneumonia among US adults. AB - OBJECTIVES: We examined associations between the socioeconomic characteristics of census tracts and racial/ethnic disparities in the incidence of bacteremic community-acquired pneumonia among US adults. METHODS: We analyzed data on 4870 adults aged 18 years or older with community-acquired bacteremic pneumonia identified through active, population-based surveillance in 9 states and geocoded to census tract of residence. We used data from the 2000 US Census to calculate incidence by age, race/ethnicity, and census tract characteristics and Poisson regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs). RESULTS: During 2003 to 2004, the average annual incidence of bacteremic pneumonia was 24.2 episodes per 100 000 Black adults versus 10.1 per 100 000 White adults (RR = 2.40; 95% CI = 2.24, 2.57). Incidence among Black residents of census tracts with 20% or more of persons in poverty (most impoverished) was 4.4 times the incidence among White residents of census tracts with less than 5% of persons in poverty (least impoverished). Racial disparities in incidence were reduced but remained significant in models that controlled for age, census tract poverty level, and state. CONCLUSIONS: Adults living in impoverished census tracts are at increased risk of bacteremic pneumonia and should be targeted for prevention efforts. PMID- 20724689 TI - Innovative approaches to reducing financial barriers to obstetric care in low income countries. AB - Lack of access to quality care is the main obstacle to reducing maternal mortality in low-income countries. In many settings, women must pay out-of-pocket fees, resulting in delays, some of them fatal, and catastrophic expenditure that push households into poverty. Various innovative approaches have targeted the poor or exempted specific services, such as cesarean deliveries. We analyzed 8 case studies to better understand current experiments in reducing financial barriers to maternal care. Although service utilization increased in most of the settings, concerns remain about quality of care, equity between rich and poor patients and between urban and rural residents, and financial sustainability to support these new strategies. PMID- 20724688 TI - Age and gender trends in long-term opioid analgesic use for noncancer pain. AB - OBJECTIVES: We describe age and gender trends in long-term use of prescribed opioids for chronic noncancer pain in 2 large health plans. METHODS: Age- and gender-standardized incident (beginning in each year) and prevalent (ongoing) opioid use episodes were estimated with automated health care data from 1997 to 2005. Profiles of opioid use in 2005 by age and gender were also compared. RESULTS: From 1997 to 2005, age-gender groups exhibited a total percentage increase ranging from 16% to 87% for incident long-term opioid use and from 61% to 135% for prevalent long-term opioid use. Women had higher opioid use than did men. Older women had the highest prevalence of long-term opioid use (8%-9% in 2005). Concurrent use of sedative-hypnotic drugs and opioids was common, particularly among women. CONCLUSIONS: Risks and benefits of long-term opioid use are poorly understood, particularly among older adults. Increased surveillance of the safety of long-term opioid use is needed in community practice settings. PMID- 20724690 TI - Can medicaid reimbursement help give female condoms a second chance in the United States? AB - The female condom is the only other barrier contraception method besides the male condom, and it is the only "woman-initiated" device for prevention of sexually transmitted infections. Although studies demonstrate high acceptability and effectiveness for this device, overall use in the United States remains low. The female condom has been available through Medicaid in many states since 1994. We provide the first published summary of data on Medicaid reimbursement for the female condom. Our findings demonstrate low rates of claims for female condoms but high rates of reimbursement. In light of the 2009 approval of a new, cheaper female condom and the recent passage of comprehensive health care reform, we call for research examining how health care providers can best promote consumer use of Medicaid reimbursement to obtain this important infection-prevention device. PMID- 20724691 TI - Relationship between past food deprivation and current dietary practices and weight status among Cambodian refugee women in Lowell, MA. AB - OBJECTIVES: We investigated Cambodian refugee women's past food experiences and the relationship between those experiences and current food beliefs, dietary practices, and weight status. METHODS: Focus group participants (n = 11) described past food experiences and current health-related food beliefs and behaviors. We randomly selected survey participants (n = 133) from a comprehensive list of Cambodian households in Lowell, Massachusetts. We collected height, weight, 24-hour dietary recall, food beliefs, past food experience, and demographic information. We constructed a measure of past food deprivation from focus group and survey responses. We analyzed data with multivariate logistic and linear regression models. RESULTS: Participants experienced severe past food deprivation and insecurity. Those with higher past food-deprivation scores were more likely to currently report eating meat with fat (odds ratio [OR] = 1.14 for every point increase on the 9-to-27-point food-deprivation measure), and to be overweight or obese by Centers for Disease Control and Prevention (OR = 1.28) and World Health Organization (OR = 1.18) standards. CONCLUSIONS: Refugees who experienced extensive food deprivation or insecurity may be more likely to engage in unhealthful eating practices and to be overweight or obese than are those who experienced less-extreme food deprivation or insecurity. PMID- 20724692 TI - Household expenditures for medicines and the role of free medicines in the Brazilian public health system. AB - OBJECTIVES: We sought to investigate, across different socioeconomic groups, the proportion of household medicine expenses that were paid by households and the proportion paid by the Brazilian national health system. METHODS: We carried out a survey in Porto Alegre, Brazil, that included 2988 individuals of all ages. We defined 2 expenditure variables: "out-of-pocket medicines value" (the sum of retail prices of all medicines used by family members within the previous 15 days and paid for out of pocket) and "free medicines value" (a similar definition for medicines obtained without charge). RESULTS: In 2003, the Brazilian national health system provided, free of charge, 78% of the monetary value of medicines reported (79% in the bottom wealth quintile and 32% in the top 2 quintiles). The mean out-of-pocket expense for medicines was 6 times greater among the top wealth quintiles compared with those in lower quintiles, but free medicines constituted a 3-times-greater proportion of potential expenditures for medicines among the bottom quintile than among the top 2 quintiles. CONCLUSIONS: Free provision of medicines seems to be saving substantial amounts of medicine expenditures for poor people in Brazil. PMID- 20724693 TI - Consistency and change in club drug use by sexual minority men in New York City, 2002 to 2007. AB - We used repeated cross-sectional data from intercept surveys conducted annually at lesbian, gay, and bisexual community events to investigate trends in club drug use in sexual minority men (N = 6489) in New York City from 2002 to 2007. Recent use of ecstasy, ketamine, and gamma-hydroxybutyrate decreased significantly. Crystal methamphetamine use initially increased but then decreased. Use of cocaine and amyl nitrates remained consistent. A greater number of HIV-positive (vs HIV-negative) men reported recent drug use across years. Downward trends in drug use in this population mirror trends in other groups. PMID- 20724694 TI - Concurrent partnerships, nonmonogamous partners, and substance use among women in the United States. AB - OBJECTIVES: We determined the prevalence, distribution, and correlates of US women's involvement in concurrent sexual partnerships, a sexual-network pattern that speeds population-wide HIV dissemination. METHODS: We used sexual partnership dates reported by 7643 women in the 2002 National Survey of Family Growth to determine prevalence of concurrent sexual partnerships during the preceding 12 months. We examined associations between concurrency and sociodemographic characteristics and risk behaviors. RESULTS: Prevalence of concurrent partnerships was 5.7% based on reported partnerships and 8.3% after adjustment for possible underreporting. Concurrency was associated with younger age (22 to 24 years: prevalence odds ratio [POR] = 2.44) versus older age (40 to 44 years); marital status (formerly married: POR = 6.56; never married: POR = 3.81; vs married); Black race/ethnicity (POR = 1.78); younger age at first sexual intercourse (12 to 13 years: POR = 2.89) versus 18 years or older); having a nonmonogamous sexual partner (POR = 6.96); having intercourse while "high" on drugs or alcohol (POR = 1.61); binge drinking (POR = 1.70); and crack or cocaine use (POR = 2.72). CONCLUSIONS: The association of concurrency with nonmonogamous sexual partners and substance use suggests the existence of extensive sexual networks that link people at higher risk for HIV infection with increased opportunities for disseminating infection. PMID- 20724695 TI - Perceived discrimination and its association with psychological distress among newly arrived immigrants before and after September 11, 2001. AB - OBJECTIVES: We compared the evolution of perception of discrimination from 1998 to 2007 among recent Arab (Muslim and non-Muslim) and Haitian immigrants to Montreal; we also studied the association between perception of discrimination and psychological distress in 1998 and 2007. METHODS: We conducted this cross sectional comparative research with 2 samples: one recruited in 1998 (n = 784) and the other in 2007 (n = 432). The samples were randomly extracted from the registry of the Ministry of Immigration and Cultural Communities of Quebec. Psychological distress was measured with the Hopkins Symptom Checklist-25. RESULTS: The perception of discrimination increased from 1998 to 2007 among the Arab Muslim, Arab non-Muslim, and Haitian groups. Muslim Arabs experienced a significant increase in psychological distress associated with discrimination from 1998 to 2007. CONCLUSIONS: These results confirm an increase in perception of discrimination and psychological distress among Arab Muslim recent immigrant communities after September 11, 2001, and highlight the importance this context may have for other immigrant groups. PMID- 20724696 TI - Alcohol retail density and demographic predictors of health disparities: a geographic analysis. AB - OBJECTIVES: We examined whether the geographic density of alcohol retailers was greater in geographic areas with higher levels of demographic characteristics that predict health disparities. METHODS: We obtained the locations of all alcohol retailers in the continental United States and created a map depicting alcohol retail outlet density at the US Census tract level. US Census data provided tract-level measures of poverty, education, crowding, and race/ethnicity. We used multiple linear regression to assess relationships between these variables and retail alcohol density. RESULTS: In urban areas, retail alcohol density had significant nonlinear relationships with Black race, Latino ethnicity, poverty, and education, with slopes increasing substantially throughout the highest quartile for each predictor. In high-proportion Latino communities, retail alcohol density was twice as high as the median density. Retail alcohol density had little or no relationship with the demographic factors of interest in suburban, large town, or rural census tracts. CONCLUSIONS: Greater density of alcohol retailers was associated with higher levels of poverty and with higher proportions of Blacks and Latinos in urban census tracts. These disparities could contribute to higher morbidity in these geographic areas. PMID- 20724697 TI - Chlamydia trachomatis infection among women reporting sexual activity with women screened in Family Planning Clinics in the Pacific Northwest, 1997 to 2005. AB - OBJECTIVES: We sought to define Chlamydia trachomatis positivity among women who report sexual activity with women, a population for which sparse data on this infection are available and for whom health disparities including challenged access to comprehensive sexual and reproductive health services, have been reported. METHODS: We analyzed data from 9358 family planning clinic visits with C trachomatis tests among women aged 15 to 24 years who reported sexual activity within the past year exclusively with women (WSW) or with men and women (WSMW), in the Region X Infertility Prevention Project. Characteristics were compared with women who reported sexual activity exclusively with men (WSM). Results. C trachomatis positivity among both WSW and WSMW was 7.1%, compared with 5.3% among WSM. Behavioral risks were more commonly reported by WSW and WSMW, compared with reports by WSM. Risks for C trachomatis positivity were comparable across groups and included younger age, non-White race, behavioral risks, and clinical signs. CONCLUSIONS: Higher C trachomatis positivity among women reporting same-sex sexual behavior supports investigation into potential explanatory factors, including sexual behaviors, biological susceptibility, routine C trachomatis screening disparities, sexual identity disclosure, and sexual network assessment. PMID- 20724698 TI - American Indian/Alaska Native uninsurance disparities: a comparison of 3 surveys. AB - OBJECTIVES: We examined whether 3 nationally representative data sources produce consistent estimates of disparities and rates of uninsurance among the American Indian/Alaska Native (AIAN) population and to demonstrate how choice of data source impacts study conclusions. METHODS: We estimated all-year and point-in time uninsurance rates for AIANs and non-Hispanic Whites younger than 65 years using 3 surveys: Current Population Survey (CPS), National Health Interview Survey (NHIS), and Medical Expenditure Panel Survey (MEPS). RESULTS: Sociodemographic differences across surveys suggest that national samples produce differing estimates of the AIAN population. AIAN all-year uninsurance rates varied across surveys (3%-23% for children and 18%-35% for adults). Measures of disparity also differed by survey. For all-year uninsurance, the unadjusted rate for AIAN children was 2.9 times higher than the rate for White children with the CPS, but there were no significant disparities with the NHIS or MEPS. Compared with White adults, AIAN adults had unadjusted rate ratios of 2.5 with the CPS and 2.2 with the NHIS or MEPS. CONCLUSIONS: Different data sources produce substantially different estimates for the same population. Consequently, conclusions about health care disparities may be influenced by the data source used. PMID- 20724699 TI - Protease-activated receptor 2 deficiency reduces cardiac ischemia/reperfusion injury. AB - OBJECTIVE: To investigate the effect of protease-activated receptor (PAR) 2 deficiency on ischemia/reperfusion (I/R) injury-induced infarct size, inflammation, heart remodeling, and cardiac function. METHODS AND RESULTS: PAR-2 signaling enhances inflammation in different diseases. The effect of PAR-2 deficiency in cardiac I/R injury is unknown. PAR-2(-/-) mice and wild-type littermates were subjected to 30 minutes of ischemia and up to 4 weeks of reperfusion. Infarct size, oxidative/nitrative stress, phosphorylation of mitogen activated protein kinases, and inflammatory gene expression were assessed 2 hours after reperfusion. Changes in heart size and function were measured by echocardiography up to 4 weeks after reperfusion. Infarct size was significantly reduced in hearts of PAR-2(-/-) mice compared with wild-type littermates. In addition, oxidative/nitrative stress, phosphorylation of mitogen-activated protein kinase, and expression of proinflammatory genes were significantly attenuated in injured hearts of PAR-2(-/-) mice. Finally, PAR-2(-/-) mice were protected from postinfarction remodeling and showed less impairment in heart function compared with wild-type littermates up to 4 weeks after I/R injury. CONCLUSIONS: PAR-2 deficiency reduces myocardial infarction and heart remodeling after I/R injury. PMID- 20724700 TI - Essential role of copper-zinc superoxide dismutase for ischemia-induced neovascularization via modulation of bone marrow-derived endothelial progenitor cells. AB - OBJECTIVE: To investigate the effect of oxidative stress on ischemia-induced neovascularization in copper-zinc (CuZn) superoxide dismutase (SOD)-deficient mice. METHODS AND RESULTS: In the vascular wall, CuZnSOD is essential for protecting against excessive oxidative stress and maintaining endothelial function. However, its specific role for the development of new vessels in response to ischemia is unknown. After surgically induced hind limb ischemia, CuZnSOD-deficient mice showed impaired neovascularization, as assessed by blood flow recuperation (laser Doppler) and capillary density in the ischemic muscles. This was associated with increased levels of oxidative stress in ischemic tissues and peripheral blood, together with reduced plasmatic NO production. CuZnSOD deficient mice demonstrated an important reduction in the number of endothelial progenitor cells (EPCs) in the bone marrow and spleen. Moreover, EPCs isolated from CuZnSOD-deficient mice showed increased oxidative stress levels, decreased NO production, and a reduced ability to migrate and integrate into capillary-like networks. Importantly, the functional activities of CuZnSOD-deficient EPCs were rescued after treatment with the SOD-mimetic Tempol (a membrane-permeable radical scavenger) or the NO donor sodium nitroprusside (SNP). Moreover, the neovascularization defect in CuZnSOD-deficient mice could be rescued by wild-type (but not CuZnSOD-deficient) EPC supplementation. CONCLUSIONS: Protection against oxidative stress by CuZnSOD may be essential for EPC function and reparative neovascularization after ischemia. PMID- 20724701 TI - The scavenger receptor class B, type I is a primary determinant of paraoxonase-1 association with high-density lipoproteins. AB - OBJECTIVE: To examine the contribution of the scavenger receptor (SR) BI to the mechanism by which high-density lipoprotein (HDL) acquires paraoxonase-1 (PON1). METHODS AND RESULTS: Serum PON1 activity contributes to the antioxidant capacity of HDLs and is suggested to be an independent risk factor for atherosclerosis. The association of PON1 with HDL is a major determinant of its serum activity levels. PON1 secretion was studied in stably transfected Chinese hamster ovary and HepG2 models. Complementary analyses were performed in transgenic models. Modulation of SR-BI expression, by SR-BI small and interfering RNA knockdown and pharmacologically, correlated with significant changes (P<0.01) in PON1 secretion to HDLs and very-low-density lipoproteins. Block lipid transport-1 (BLT1), which increases the affinity of HDL for SR-BI without modulating its expression, was associated with significant increases in secretion. Downregulating postsynaptic density 95/disc-large/zona occludens kinase in HepG2 reduced cell SR-BI protein and lowered enzyme secretion. Serum PON1 activity was significantly reduced in postsynaptic density 95/disc-large/zona occludens kinase knockout mice. CONCLUSIONS: The present study identifies SR-BI as a major determinant of the capacity of HDL to acquire PON1. It reinforces the concept of the receptor as a docking molecule, allowing communication between HDL and the cell, and extends the importance of SR-BI to HDL metabolism and function. PMID- 20724702 TI - A new role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis. AB - OBJECTIVE: Ferlins are known to regulate plasma membrane repair in muscle cells and are linked to muscular dystrophy and cardiomyopathy. Recently, using proteomic analysis of caveolae/lipid rafts, we reported that endothelial cells (EC) express myoferlin and that it regulates membrane expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The goal of this study was to document the presence of other ferlins in EC. METHODS AND RESULTS: EC expressed another ferlin, dysferlin, and that in contrast to myoferlin, it did not regulate VEGFR-2 expression levels or downstream signaling (nitric oxide and Erk1/2 phosphorylation). Instead, loss of dysferlin in subconfluent EC resulted in deficient adhesion followed by growth arrest, an effect not observed in confluent EC. In vivo, dysferlin was also detected in intact and diseased blood vessels of rodent and human origin, and angiogenic challenge of dysferlin-null mice resulted in impaired angiogenic response compared with control mice. Mechanistically, loss of dysferlin in cultured EC caused polyubiquitination and proteasomal degradation of platelet endothelial cellular adhesion molecule-1 (PECAM-1/CD31), an adhesion molecule essential for angiogenesis. In addition, adenovirus-mediated gene transfer of PECAM-1 rescued the abnormal adhesion of EC caused by dysferlin gene silencing. CONCLUSIONS: Our data describe a novel pathway for PECAM-1 regulation and broaden the functional scope of ferlins in angiogenesis and specialized ferlin-selective protein cargo trafficking in vascular settings. PMID- 20724703 TI - Bone morphogenic protein-4 impairs endothelial function through oxidative stress dependent cyclooxygenase-2 upregulation: implications on hypertension. AB - RATIONALE: Bone morphogenic protein (BMP)4 can stimulate superoxide production and exert proinflammatory effects on the endothelium. The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain elusive. OBJECTIVE: To elucidate the cellular pathways by which BMP4-induced endothelial dysfunction is mediated through oxidative stress-dependent upregulation of cyclooxygenase (COX)-2. METHODS AND RESULTS: Impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4-treated mouse aortae, which were prevented by the BMP4 antagonist noggin. Pharmacological inhibition with thromboxane prostanoid receptor antagonist or COX-2 but not COX-1 inhibitor prevented BMP4-induced endothelial dysfunction, which was further confirmed with the use of COX-1(-/-) or COX-2(-/-) mice. Noggin and knockdown of BMP receptor 1A abolished endothelium-dependent contractions and COX-2 upregulation in BMP4 treated aortae. Apocynin and tempol treatment were effective in restoring endothelium-dependent relaxations, preventing endothelium-dependent contractions and eliminating ROS overproduction and COX-2 overexpression in BMP4-treated aortae. BMP4 increased p38 mitogen-activated protein kinase (MAPK) activity through a ROS-sensitive mechanism and p38 MAPK inhibitor prevented BMP4-induced endothelial dysfunction. COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS overproduction and COX-2 upregulation. Importantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction. CONCLUSIONS: We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 upregulation in endothelial cells, leading to endothelial dysfunction through ROS-dependent p38 MAPK activation. This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension. PMID- 20724704 TI - Upregulation of Nox4 by TGF{beta}1 oxidizes SERCA and inhibits NO in arterial smooth muscle of the prediabetic Zucker rat. AB - RATIONALE: Vascular smooth muscle cell (SMC) migration is an important pathological process in several vascular occlusive diseases, including atherosclerosis and restenosis, both of which are accelerated by diabetes mellitus. OBJECTIVE: To determine the mechanisms of abnormal vascular SMC migration in type 2 diabetes, the obese Zucker rat (ZO), a model of obesity and insulin resistance, was studied. METHODS AND RESULTS: In culture, ZO aortic SMCs showed a significant increase in Nox4 mRNA and protein levels compared with the control lean Zucker rat (ZL). The sarco-/endoplasmic reticulum Ca(2+) ATPase (SERCA) nitrotyrosine-294,295 and cysteine-674 (C674)-SO(3)H were increased in ZO SMCs, indicating oxidant stress. Unlike ZL SMC, nitric oxide (NO) failed to inhibit serum-induced SMC migration in ZO. Transfection of Nox4 small interference RNA or overexpression of SERCA2b wild type, but not C674S mutant SERCA, restored the response to NO. Knockdown of Nox4 also decreased SERCA oxidation in ZO SMCs. In addition, transforming growth factor-beta1 via Smad2 was necessary and sufficient to upregulate Nox4, oxidize SERCA, and block the antimigratory action of NO in ZO SMCs. Corresponding to the results in cultured SMCs, immunohistochemistry confirmed that Nox4 and SERCA C674-SO(3)H were significantly increased in ZO aorta. After common carotid artery injury, knockdown of Nox4 by adenoviral Nox4 short hairpin RNA decreased Nox4 and SERCA C674-SO(3)H staining and significantly decreased injury-induced neointima. CONCLUSION: These studies indicate that the upregulation of Nox4 by transforming growth factor-beta1 in ZO SMCs is responsible for the impaired response to NO by a mechanism involving the oxidation of SERCA C674. Knockdown of Nox4 inhibits oxidation of SERCA, as well as neointima formation, after ZO common carotid artery injury. PMID- 20724705 TI - Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel. AB - RATIONALE: Pyridine nucleotides regulate the cardiac Na(+) current (I(Na)) through generation of reactive oxygen species (ROS). OBJECTIVE: We investigated the source of ROS induced by elevated NADH. METHODS AND RESULTS: In human embryonic kidney (HEK) cells stably expressing the cardiac Na(+) channel, the decrease of I(Na) (52+/-9%; P<0.01) induced by cytosolic NADH application (100 MUmol/L) was reversed by mitoTEMPO, rotenone, malonate, DIDS (4,4' diisothiocyanatostilbene-2,2'-disulfonic acid), PK11195, and 4'-chlorodiazepam, a specific scavenger of mitochondrial superoxide and inhibitors of the mitochondrial complex I, complex II, voltage-dependent anion channels, and benzodiazepine receptor, respectively. Anti-mycin A (20 MUmol/L), a complex III inhibitor known to generate ROS, decreased I(Na) (51+/-4%, P<0.01). This effect was blocked by NAD(+), forskolin, or rotenone. Inhibitors of complex IV, nitric oxide synthase, the NAD(P)H oxidases, xanthine oxidases, the mitochondrial permeability transition pore, and the mitochondrial ATP-sensitive K(+) channel did not change the NADH effect on I(Na). Analogous results were observed in cardiomyocytes. Rotenone, mitoTEMPO, and 4'-chlorodiazepam also blocked the mutant A280V GPD1-L (glycerol-3-phosphate dehydrogenase 1-like) effect on reducing I(Na), indicating a role for mitochondria in the Brugada syndrome caused by this mutation. Fluorescent microscopy confirmed mitochondrial ROS generation with elevated NADH and ROS inhibition by NAD(+). CONCLUSIONS: Altering the oxidized to reduced NAD(H) balance can activate mitochondrial ROS production, leading to reduced I(Na). This signaling cascade may help explain the link between altered metabolism, conduction block, and arrhythmic risk. PMID- 20724707 TI - Platelet function testing for aspirin resistance is reasonable to do: yes! PMID- 20724706 TI - Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function. AB - RATIONALE: Vascular endothelial (VE)-cadherin localized at adherens junctions (AJs) regulates endothelial barrier function. Because WNT (wingless) signaling induced activation of the transcription factor Kruppel-like factor (KLF)4 may have an important role in mediating the expression of VE-cadherin and AJ integrity, we studied the function of KLF4 in regulating VE-cadherin expression and the control of endothelial barrier function. OBJECTIVE: The goal of this study was to determine the transcriptional role of KLF4 in regulating VE-cadherin expression and endothelial barrier function. METHODS AND RESULTS: Expression analysis, microscopy, chromatin immunoprecipitation, electrophoretic mobility shift assays, and VE-cadherin-luciferase reporter experiments demonstrated that KLF4 interacted with specific domains of VE-cadherin promoter and regulated the expression of VE-cadherin at AJs. KLF4 knockdown disrupted the endothelial barrier, indicating that KLF4 is required for normal barrier function. In vivo studies in mice showed augmented lipopolysaccharide-induced lung injury and pulmonary edema following Klf4 depletion. CONCLUSION: Our data show the key role of KLF4 in the regulation of VE-cadherin expression at the level of the AJs and in the acquisition of VE-cadherin-mediated endothelial barrier function. Thus, KLF4 maintains the integrity of AJs and prevents vascular leakage in response to inflammatory stimuli. PMID- 20724708 TI - The use of platelet function assays may help to determine appropriate antiplatelet treatment options in a patient with recurrent stroke on baby aspirin: against. PMID- 20724709 TI - Patterns and predictors of discharge statin prescription among hospitalized patients with intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Many patients hospitalized with intracerebral hemorrhage are at high future risk for ischemic events and may benefit from stain therapy. However, little is known about patterns of statin prescription among patients with intracerebral hemorrhage, especially after the finding of higher hemorrhagic stroke risk in the statin treatment arm of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. We evaluated recent nationwide trends in discharge statin treatment after intracerebral hemorrhage hospitalization. METHODS: Using data from 25 673 patients with hemorrhagic stroke admitted to Get With Guidelines-Stroke participating hospitals between January 1, 2005, and December 31, 2007, we assessed factors associated with discharge statin prescription, including treatment over time and in relation to dissemination of the SPARCL results. Piecewise logistic multivariable regression models were fit to track statin use in various periods. RESULTS: Mean age was 67.9+/-15 years, 48.1% female, and discharge statin treatment in 39.5%. Variables independently associated with lower discharge statin use included female sex (OR 0.87, 95% CI, 0.82 to 0.93), prior stroke/transient ischemic attack (OR 0.85, 95% CI, 0.78 to 0.92), academic center (OR 0.87, 95% CI, 0.82 to 0.93), and Midwest region (OR 0.65, 95% CI, 0.56 to 0.80). Statin prescription climbed over the study period from 66.9% to 74.5% (P<0.001) among eligible patients with a decrease during SPARCL reporting (P=0.03) and then a return to prior levels thereafter. CONCLUSIONS: Discharge statin prescription among hospitalized patients with intracerebral hemorrhage has modestly risen over time. The clinical implications of this care pattern among patients with intracerebral hemorrhage require further study. PMID- 20724710 TI - Platelet function assays in stroke management: more study is needed. PMID- 20724712 TI - J-shaped association between serum glucose and functional outcome in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Hyperglycemia after stroke is associated with larger infarct volume and poorer functional outcome. In an animal stroke model, the association between serum glucose and infarct volume is described by a U-shaped curve with a nadir ~7 mmol/L. However, a similar curve in human studies was never reported. The objective of the present study is to investigate the association between serum glucose levels and functional outcome in patients with acute ischemic stroke. METHODS: We analyzed 1446 consecutive patients with acute ischemic stroke. Serum glucose was measured on admission at the emergency department together with multiple other metabolic, clinical, and radiological parameters. National Institutes of Health Stroke Scale (NIHSS) score was recorded at 24 hours, and Rankin score was recorded at 3 and 12 months. The association between serum glucose and favorable outcome (Rankin score <=2) was explored in univariate and multivariate analysis. The model was further analyzed in a robust regression model based on fractional polynomial (-2-2) functions. RESULTS: Serum glucose is independently correlated with functional outcome at 12 months (OR, 1.15; P=0.01). Other predictors of outcome include admission NIHSS score (OR, 1.18; P<0001), age (OR, 1.06; P<0.001), prestroke Rankin score (OR, 20.8; P=0.004), and leukoaraiosis (OR, 2.21; P=0.016). Using these factors in multiple logistic regression analysis, the area under the receiver-operator characteristic curve is 0.869. The association between serum glucose and Rankin score at 12 months is described by a J-shaped curve with a nadir of 5 mmol/L. Glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome. A similar curve was generated for the association of glucose and 24-hour NIHSS score, for which glucose values between 4.0 and 7.2 mmol/L are associated with a NIHSS score <7. Discussion-Both hypoglycemia and hyperglycemia are dangerous in acute ischemic stroke as shown by a J-shaped association between serum glucose and 24-hour and 12-month outcome. Initial serum glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome. PMID- 20724711 TI - Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. AB - BACKGROUND AND PURPOSE: Induced hypothermia is a promising neuroprotective therapy. We studied the feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke. METHODS: Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) was a randomized, multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke. Enrollment was stratified to the treatment time windows 0 to 3 and 3 to 6 hours. Patients presenting within 3 hours of symptom onset received standard dose intravenous alteplase and were randomized to undergo 24 hours of endovascular cooling to 33 degrees C followed by 12 hours of controlled rewarming or normothermia treatment. Patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not. Results- In total, 59 patients were enrolled. One patient was enrolled but not treated when pneumonia was discovered just before treatment. All 44 patients enrolled within 3 hours and 4 of 14 patients enrolled between 3 to 6 hours received tissue plasminogen activator. Overall, 28 patients randomized to receive hypothermia (HY) and 30 to normothermia (NT). Baseline demographics and risk factors were similar between groups. Mean age was 65.5+/-12.1 years and baseline National Institutes of Health Stroke Scale score was 14.0+/-5.0; 32 (55%) were male. Cooling was achieved in all patients except 2 in whom there were technical difficulties. The median time to target temperature after catheter placement was 67 minutes (Quartile 1 57.3 to Quartile 3 99.4). At 3 months, 18% of patients treated with hypothermia had a modified Rankin Scale score of 0 or 1 versus 24% in the normothermia groups (nonsignificant). Symptomatic intracranial hemorrhage occurred in 4 patients (68); all were treated with tissue plasminogen activator <3 hours (1 received hypothermia). Six patients in the hypothermia and 5 in the normothermia groups died within 90 days (nonsignificant). Pneumonia occurred in 14 patients in the hypothermia and in 3 of the normothermia groups (P=0.001). The pneumonia rate did not significantly adversely affect 3 month modified Rankin Scale score (P=0.32). CONCLUSIONS: This study demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia, but further studies are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke. PMID- 20724713 TI - Persistent hyperglycemia >155 mg/dL in acute ischemic stroke patients: how well are we correcting it?: implications for outcome. AB - BACKGROUND AND PURPOSE: We aimed to analyze the frequency of persistent hyperglycemia (PH), its implications for outcome, and to document the inpatient management of hyperglycemia. METHODS: Post hoc analysis of the GLIAS (Glycemia in Acute Stroke) study, a multicenter, prospective, and observational cohort study of 476 acute ischemic stroke patients. Capillary finger-prick glucose was determined on admission and during the first 48 hours. We defined PH was defined as at least 2 values >=155 mg/dL. Outcome (modified Rankin Scale) was evaluated at 3 months. RESULTS: PH developed in 117 patients (24.7%). PH was associated with poorer outcome (modified Rankin Scale score >2: 56.2% vs 28.1%; P<0.01) and higher mortality (26.7% vs 5.9%; P<0.01) than those with glycemia <155 mg/dL. PH >=155 mg/dL was associated with a 4-fold increase in the odds of poor outcome at 3 months (odds ratio, 4.7; 95% confidence interval, 2.2-10.2) after adjustment for age, gender, hypertension, diabetes, stroke severity, admission glycemia, and infarct volume. Only 20% of patients with hyperglycemia >=155 mg/dL received insulin on admission, with a progressive increase in the use of insulin during the following 48 hours. However, 114 (39.1%) out of 291 patients who received corrective treatment for hyperglycemia still had levels >=155 mg/dL. CONCLUSIONS: PH >=155 mg/dL is a common observation in acute ischemic stroke patients that is associated with poorer outcome and higher mortality. Almost 40% of patients maintained levels >=155 mg/dL despite corrective treatment. PMID- 20724715 TI - Effect of weekend compared with weekday stroke admission on thrombolytic use, in hospital mortality, discharge disposition, hospital charges, and length of stay in the Nationwide Inpatient Sample Database, 2002 to 2007. AB - BACKGROUND AND PURPOSE: A stroke "weekend effect" on mortality has been demonstrated in other countries with a possible slight effect in the United States. We studied patients with stroke in the Nationwide Inpatient Sample database for a weekend effect on thrombolytic use, in-hospital mortality, discharge disposition, hospital charges, and length of stay. METHODS: The Nationwide Inpatient Sample 2002 to 2007 was searched for all emergency room admissions for International Classification of Diseases, 9th Revision codes corresponding to ischemic stroke. Generalized estimated equations for generalized linear models were performed, adjusting for gender, age, race, season, median income level, payer, comorbidity score, hospital region, hospital location, teaching status, bed size, and hospital annual stroke case volume to compare weekend versus weekday stroke admission incidence of thrombolytic use, in hospital mortality, discharge disposition, hospital charges, and length of stay. The same analysis was performed using the International Classification of Diseases, 9th Revision codes for ischemic stroke AND transient cerebral ischemia to check internal validity for coding irregularities that may occur in differentiating stroke from transient ischemic attack. RESULTS: There were 599 087 emergency room admissions for ischemic stroke: 159 906 weekend admissions and 439 181 weekday admissions. Generalized estimated equation for generalized linear model analysis was performed and demonstrated weekend compared with weekday patients with stroke were slightly more likely to receive thrombolytics (OR=1.114; 95% CI=1.039 to 1.194; P=0.003); incur slightly higher total hospital charges (effect ratio=1.011; 95% CI=1.006 to 1.017; P<0.001); and have slightly longer lengths of stay (effect ratio=1.021; 95% CI=1.015 to 1.027; P<0.001). There was no difference in in-hospital mortality or discharge disposition. CONCLUSIONS: There is a slight stroke weekend effect on thrombolytic use, total hospital charges, and length of stay, but no difference in in-hospital mortality or discharge disposition. PMID- 20724716 TI - Whole brain and regional hyperintense white matter volume and blood pressure: overlap of genetic loci produced by bivariate, whole-genome linkage analyses. AB - BACKGROUND AND PURPOSE: The volume of T2-hyperintense white matter (HWM) is an important neuroimaging marker of cerebral integrity with a demonstrated high heritability. Pathophysiology studies have shown that the regional, ependymal, and subcortical HWM lesions are associated with elevated arterial pulse pressure and arterial blood pressure (BP), respectively. We performed bivariate, whole genome linkage analyses for HWM volumes and BP measurements to identify chromosomal regions that contribute jointly to both traits in a population of healthy Mexican Americans. Our aims were to localize novel quantitative trait loci acting pleiotropically on these phenotypes and to replicate previous genetic findings on whole brain HWM volume and BP measurements. METHODS: BP measurements and volumes of whole-brain (WB), subcortical, and ependymal HWM lesions, measured from high-resolution (1 mm(3)) 3-dimensional fluid-attenuated inversion recovery images, served as focal quantitative phenotypes. Data were collected from 357 (218 females; mean age=47.9+/-13.2 years) members of large extended families who participated in the San Antonio Family Heart Study. RESULTS: Bivariate genomewide linkage analyses localized a significant quantitative trait locus influencing WB and regional (ependymal) HWM volumes and pulse pressure and systolic BP to chromosomal location 1q24 between markers D1S196 and D1S1619. Several other chromosomal regions (1q42, 10q24-q26, and 15q26) exhibited suggestive linkages. The results of the post hoc analyses that excluded 55 subjects taking antihypertensive medication showed no substantive differences from the results obtained in the full cohort. CONCLUSIONS: This study confirms several previously observed quantitative trait loci influencing BP and cerebral integrity and identifies a novel significant quantitative trait locus at chromosome 1q24. The genetic results strongly support a role for pleiotropically acting genes jointly influencing BP and cerebral white matter integrity. PMID- 20724717 TI - Cerebral emboli detected by transcranial Doppler during cardiopulmonary bypass are not correlated with postoperative cognitive deficits. AB - BACKGROUND AND PURPOSE: High-intensity transient signals (HITS) are the transcranial Doppler representation of both air and solid cerebral emboli. We studied the frequency of HITS associated with different surgical maneuvers during cardiopulmonary bypass for coronary artery bypass graft surgery and their association with postoperative cognitive dysfunction (POCD). METHODS: We combined 356 patients undergoing coronary artery bypass graft from 2 clinical trials who had both neuropsychological testing (before, 1 week and 3 months after surgery) and transcranial Doppler during cardiopulmonary bypass. HITS were grouped into periods that included: cannulation, cardiopulmonary bypass onset, aortic crossclamp-on, aortic crossclamp-off, side clamp-on, side clamp-off, and decannulation. POCD was defined by a decreased combined Z-score of at least 2.0 or reduction in Z-scores of at least 2.0 in 20% of the individual tests. RESULTS: Incidence of POCD was 47.3% and 6.3% at 1 week and 3 months after surgery. There was no association between cardiopulmonary bypass counts of HITS and POCD at 1 week (P=0.617) and 3 months (P=0.110). No differences in HITS counts were identified at any of the surgical periods between patients with and without POCD. Factors affecting HITS counts were surgical period (P<0.0001), blood flow velocity (P=0.012), cardiopulmonary bypass duration (P=0.040), and clinical study (P=0.048). CONCLUSIONS: Although cerebral microemboli have been implicated in the pathogenesis of POCD, in this study that included low-risk patients undergoing coronary artery bypass surgery, there was no demonstrable correlation between the counts of HITS and POCD. PMID- 20724718 TI - Magnesium sulfate for subarachnoid hemorrhage: a piece of the mosaic. PMID- 20724719 TI - Binge drinking and hypertension on cardiovascular disease mortality in Korean men and women: a Kangwha cohort study. AB - BACKGROUND AND PURPOSE: The purpose of this study was to examine combined effects of hypertension and binge drinking on the risk of mortality from cardiovascular disease in Koreans. METHODS: This study followed a cohort of 6100 residents in Kangwha County, aged >=55 years as of March 1985, for cardiovascular mortality for 20.8 years up to December 31, 2005. We calculated hazard ratios (HRs) for cardiovascular mortality by blood pressure and binge drinking habits using the Cox proportional hazard model. Binge drinkers and heavy binge drinkers were defined as having >=6 drinks on 1 occasion and >=12 drinks on 1 occasion. RESULTS: After adjusting for total alcohol consumption, male heavy binge drinkers with Grade 3 hypertension had a 12-fold increased risk of cardiovascular mortality (HR, 12.7; 95% CI, 3.47 to 46.5), whereas male binge drinkers with Grade 3 hypertension had a 4-fold increased risk of cardiovascular mortality (HR, 4.41; 95% CI, 1.38 to 14.1) when compared with nondrinkers with normal blood pressure. However, in considering separate effects of heavy binge drinking and hypertension on the risk of cardiovascular mortality, HRs were rather low (HR of heavy binge drinkers, 1.88, 1.10 to 3.20; HR of hypertensives, 2.00, 1.70 to 2.35) compared with nondrinkers with normal blood pressure. CONCLUSIONS: Binge drinkers and heavy binge drinkers with Grade 3 hypertension showed a marked increase in cardiovascular mortality risk. Even after adjusting for total alcohol consumption, the former revealed 4.41 and the latter indicated 12.7 of HR for the risk of cardiovascular mortality. PMID- 20724720 TI - Carotid bruits and cerebrovascular disease risk: a meta-analysis. AB - BACKGROUND AND PURPOSE: Current guidelines recommend against routine auscultation of carotid arteries, believing that carotid bruits are poor predictors of either underlying carotid stenosis or stroke risk in asymptomatic patients. We investigated whether the presence of a carotid bruit is associated with increased risk for transient ischemic attack, stroke, or death by stroke (stroke death). METHODS: We searched Medline (1966 to December 2009) and EMBASE (1974 to December 2009) with the terms "carotid" and "bruit." Bibliographies of all retrieved articles were also searched. Articles were included if they prospectively reported the incidence of transient ischemic attack, stroke, or stroke death in asymptomatic adults. Two authors independently reviewed and extracted data. RESULTS: We included 28 prospective cohort articles that followed a total of 17 913 patients for 67 708 patient-years. Among studies that directly compared patients with and without bruits, the rate ratio for transient ischemic attack was 4.00 (95% CI, 1.8 to 9.0, P<0.0005, n=5 studies), stroke was 2.5 (95% CI, 1.8 to 3.5, P<0.0005, n=6 studies), and stroke death was 2.7 (95% CI, 1.33 to 5.53, P=0.002, n=3 studies). Among the larger pool of studies that provided data on rates, transient ischemic attack rates were 2.6 per 100 patient-years (95% CI, 2.0 to 3.2, P<0.0005, n=24 studies) for those with bruits compared with 0.9 per 100 patient-years (95% CI, 0.2 to 1.6, P=0.02, n=5 studies) for those without carotid bruits. Stroke rates were 1.6 per 100 patient-years (95% CI, 1.3 to 1.9, P<0.0005, n=26 studies) for those with bruits compared with 1.3 per 100 patient years (95% CI, 0.8 to 1.7, P<0.0005, n=6) without carotid bruits, and death rates were 0.32 (95% CI, 0.20 to 0.44, P<0.005, n=13 studies) for those with bruits compared with 0.35 (95% CI, 0.00 to 0.81, P=0.17, n=3 studies) for those without carotid bruits. CONCLUSIONS: The presence of a carotid bruit may increase the risk of cerebrovascular disease. PMID- 20724722 TI - Venter's build-a-bug workshop. PMID- 20724723 TI - Novel phosphatase PHLPP-1 regulates mitochondrial Akt activity and cardiac cell survival. PMID- 20724724 TI - The fifteen years of discoveries that shaped molecular electrophysiology: time for appraisal. AB - This article serves as an introductory overview to a thematic review series that will present the latest advancements in the field of inherited arrhythmias. This area of cardiac electrophysiology started approximately 15 years ago thanks to the contribution of Mark Keating and coworkers, who discovered the molecular basis of long QT syndrome. The field rapidly expanded when clinicians, molecular biologists, geneticists, and cellular electrophysiologists, who undertook an impressive collaborative effort to clarify the genetic basis of "cardiac channelopathies." As a result of this hard work, the paradigms for diagnosis and management of patients with inherited arrhythmogenic diseases were substantially modified, demonstrating once more the value of "translational research." As more and more genes have been implicated in the genesis of inherited arrhythmias, we keep broadening our understanding of the complexity of ion channels and their multifaceted regulatory processes. Despite the fact that several discoveries have already been made, the field is facing new challenges that are attracting young investigators who share with the pioneers the ambitious goal of finding new therapies and even a cure for these conditions. PMID- 20724725 TI - Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins. AB - Over the past 15 years, gene mutations in cardiac ion channels have been linked to a host of potentially fatal human arrhythmias including long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. More recently, a new paradigm for human arrhythmia has emerged based on gene mutations that affect the activity of cardiac ion channel- and transporter- associated proteins. As part of the Circulation Research thematic series on inherited arrhythmias, this review focuses on the emerging field of human arrhythmias caused by dysfunction in cytosolic gene products (including ankyrins, yotiao, syntrophin, and caveolin-3) that regulate the activities of key membrane ion channels and transporters. PMID- 20724726 TI - Effects of prostate-specific antigen testing on familial prostate cancer risk estimates. AB - BACKGROUND: Family history is a strong risk factor for prostate cancer. The aim of this study was to investigate whether increased diagnostic activity is related to the incidence of prostate cancer among brothers of men with prostate cancer. METHODS: Data were from the nationwide population-based Prostate Cancer Database Sweden (PCBaSe Sweden), which includes data from the National Prostate Cancer Register, the Swedish Cancer Register, the Register of the Total Population, the Multi-Generation Register, and the Census database. We investigated the relationship of tumor characteristics, time from diagnosis of the index patient (i.e., prostate cancer patients in the National Prostate Cancer Register for whom at least one brother and their father could be identified), calendar period, geographic factors, and socioeconomic status to standardized incidence ratios (SIRs) for prostate cancer among 22 511 brothers of 13 975 index patients in PCBaSe Sweden. RESULTS: Brothers of index patients with prostate cancer were at increased risk for a diagnosis of prostate cancer (SIR = 3.1, 95% confidence interval [CI] = 2.9 to 3.3). Risk was higher for T1c tumors (SIR = 3.4, 95% CI = 3.2 to 3.8) than for metastatic tumors (SIR = 2.0, 95% CI = 1.5 to 2.6), and risk of T1c tumors was especially high during the first year after the diagnosis of the index patient (SIR = 4.3, 95% CI = 3.8 to 4.9), compared with the following years (SIR range = 2.8-3.3), and for brothers of index patients who had a higher socioeconomic status (SIR = 4.2, 95% CI = 3.7 to 4.7), compared with brothers of index patients with lower socioeconomic status (SIR = 2.8, 95% CI = 2.4 to 3.2). CONCLUSIONS: Increased diagnostic activity among men with a family history of prostate cancer appears to contribute to their increased risk of prostate cancer and to lead to detection bias in epidemiological and genetic studies of familial prostate cancer. PMID- 20724727 TI - Prostate-specific antigen, risk factors, and prostate cancer: confounders nestled in an enigma. PMID- 20724729 TI - Multiple roles of CD4 and CD8 in T cell activation. PMID- 20724730 TI - Pillars article: the CD4 receptor is complexed in detergent lysates to a protein tyrosine kinase (pp58) from human T lymphocytes. 1988. PMID- 20724731 TI - Pillars article: the CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. 1994. PMID- 20724732 TI - Complement-dependent transport of antigen into B cell follicles. AB - Since the original proposal by Fearon and Locksley (Fearon and Locksley. 1996. Science 272: 50-53) that the complement system linked innate and adaptive immunity, there has been a rapid expansion of studies on this topic. With the advance of intravital imaging, a number of recent papers revealed an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin opsonization of influenza and uptake by macrophages, and the capture of virus by dendritic cells residing in the medullary compartment of peripheral lymph nodes. PMID- 20724733 TI - Noninvasive diagnosis of pulmonary embolism. AB - BACKGROUND: We designed a simple and integrated diagnostic algorithm for acute pulmonary embolism (PE). Diagnosis was based on clinical probability assessment, plasma D-dimer testing, then sequential testing to include lower limb venous compression ultrasonography, ventilation perfusion lung scan, and chest multidetector CT (MDCT) imaging. METHODS: We included 321 consecutive patients presenting at Brest University Hospital in Brest, France, with clinically suspected PE and positive d-dimer or high clinical probability. Patients in whom VTE was deemed absent were not given anticoagulants and were followed up for 3 months. RESULTS: Detection of DVT by ultrasonography established the diagnosis of PE in 43 (13%). Lung scan associated with clinical probability was diagnostic in 243 (76%) of the remaining patients. MDCT scan was required in only 35 (11%) of the patients. The 3-month thromboembolic risk in patients not given anticoagulants, based on the results of the diagnostic protocol, was 0.53% (95% CI, 0.09-2.94). CONCLUSIONS: A diagnostic strategy combining clinical assessment, d-dimer, ultrasonography, and lung scan gave a noninvasive diagnosis in the majority of outpatients with suspected PE and appeared to be safe. PMID- 20724734 TI - Ultrasound-guided catheterization of the radial artery: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Ultrasound guidance commonly is used for the placement of central venous catheters (CVCs). The Agency for Healthcare Research and Quality recommends the use of ultrasound for CVC placement as one of its 11 practices to improve patient care. Despite increased access to portable ultrasound machines and comfort with ultrasound-guided CVC access, fewer clinicians are familiar with ultrasound-guided techniques of arterial catheterization. The goal of this systematic review and meta-analysis was to determine the utility of real-time two dimensional ultrasound guidance for radial artery catheterization. METHODS: A comprehensive literature search of Medline, Excerpta Medica Database, and the Cochrane Central Register of Controlled Trials by two independent reviewers identified prospective, randomized controlled trials comparing ultrasound guidance with traditional palpation techniques of radial artery catheterization. Data were extracted on study design, study size, operator and patient characteristics, and the rate of first-attempt success. A meta-analysis was constructed to analyze the data. RESULTS: Four trials with a total of 311 subjects were included in the review, with 152 subjects included in the palpation group and 159 in the ultrasound-guided group. Compared with the palpation method, ultrasound guidance for arterial catheterization was associated with a 71% improvement in the likelihood of first-attempt success (relative risk, 1.71; 95% CI, 1.25-2.32). CONCLUSIONS: The use of real-time two-dimensional ultrasound guidance for radial artery catheterization improved first-pass success rate. PMID- 20724735 TI - Airway hyperresponsiveness in children with sickle cell anemia. AB - BACKGROUND: The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained. METHODS: To determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS. RESULTS: Methacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV1<4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age (P<.001), IgE (P=.009), and lactate dehydrogenase (LDH) levels (P=.005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma (P=.986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airflow obstruction. CONCLUSIONS: In children with SCA, AHR to methacholine is prevalent. Younger age, serum IgE concentration, and LDH level, a marker of hemolysis, are associated with AHR. With the exception of serum IgE, no signs or symptoms of an allergic diathesis are associated with AHR. Although the relationship between methacholine responsiveness and LDH suggests that factors related to SCA may contribute to AHR, these results will need to be validated in future studies. PMID- 20724736 TI - Poor prognostic factors in patients with stage IB non-small cell lung cancer according to the seventh edition TNM classification. AB - BACKGROUND: This study investigated poor prognostic factors in patients with stage IB non-small cell lung cancer (NSCLC) according to the seventh edition of the TNM classification. METHODS: Between July 1992 and December 2004, 1,204 consecutive patients with stage I NSCLC diagnosed based on the sixth edition TNM classification underwent complete resection with systematic node dissection. Of these patients, 434 were reclassified as stage IB according to the seventh edition TNM classification. Univariate analyses were performed using the log-rank test to select prognostic factors. The Cox proportional hazards regression model was used for multivariate analyses to identify independent factors indicating an unfavorable prognosis. RESULTS: On multivariate analyses, two variables were independent significant factors indicating an unfavorable prognosis: presence of intratumoral vascular invasion and presence of visceral pleural invasion. According to subgroup analyses combining these two risk factors, 5-year disease specific survival probabilities were 93%, 83%, and 73% for patients with zero, one, or two risk factors, respectively. The 5-year disease-specific survival of patients without risk factors was not statistically different from that of patients with stage IA cancer. In addition, the 5-year disease-specific survival curve of patients with two risk factors lay beneath that of patients with T2b or T3N0M0, stage II cancer, and there were no statistically significant differences between them. CONCLUSIONS: We identified the presence of intratumoral vascular invasion and the presence of visceral pleural invasion as independent poor prognostic factors in patients with stage IB NSCLC. When these two factors are combined, higher- and lower-risk subgroups can be identified, which will help to personalize adjuvant chemotherapy. PMID- 20724737 TI - International Classification of Diseases coding changes lead to profound declines in reported idiopathic pulmonary arterial hypertension mortality and hospitalizations: implications for database studies. AB - BACKGROUND: Database studies have reported several associations between the diagnosis of idiopathic pulmonary arterial hypertension (IPAH) and mortality attributable to IPAH, including older age, black race, and diabetes. METHODS: We investigated reported deaths and hospital discharges coded as IPAH and compared these with other forms of pulmonary hypertension. Three databases were used: the US National Center for Health Statistics database (1979-2006), queried for mortality data; the Nationwide Inpatient Sample database (1993-2007), queried for hospital discharge data; and the University of Texas Southwestern Hospital-Zale Lipshy discharge database (1999, 2002). RESULTS: Marked increases in mortality attributable to IPAH and to pulmonary hypertension (all codes combined) generally were reported from 1979 until 2002 in the National Center for Health Statistics database. In 2003, reported IPAH mortality fell sharply while total pulmonary hypertension deaths increased. The Nationwide Inpatient Sample database showed a similar pattern of changes beginning approximately 2 years earlier. In both cases, the timing of these observations corresponded with changes made to the International Classification of Diseases (ICD) coding system in use for pulmonary hypertension in that particular database. Review of pulmonary hypertension discharge data from the University of Texas Southwestern Hospital-Zale Lipshy showed similar changes in diagnosis code use. CONCLUSIONS: Sudden shifts in reported IPAH mortality and hospital discharges were seen in all databases, likely related to coding changes. These findings raise questions about the accuracy of pulmonary hypertension diagnosis codes. Studies based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, 10th Revision codes may have inadvertently included patients with other forms of pulmonary hypertension and should be reevaluated in this context. Validation studies of the IPAH diagnosis code are needed, and changes to the ICD coding system should be considered. PMID- 20724738 TI - Ventilator-associated tracheobronchitis in a mixed surgical and medical ICU population. AB - BACKGROUND: Ventilator-associated tracheobronchitis (VAT) is considered an intermediate condition between bacterial airway colonization and ventilator associated pneumonia (VAP). The purpose of this prospective cohort study was to further characterize VAT in terms of incidence, etiology, and impact on patient outcomes. METHODS: Patients intubated for >48 h in the surgical and medical ICUs of Barnes-Jewish Hospital were screened daily for the development of VAT and VAP over 1 year. Patients were followed until hospital discharge or death, and patient demographics, causative pathogens, and clinical outcomes were recorded. RESULTS: A total of 28 patients with VAT and 83 with VAP were identified corresponding to frequencies of 1.4% and 4.0%, respectively. VAP was more common in surgical than medical ICU patients (5.3% vs 2.3%; P<.001), but the occurrence of VAT was similar between surgical and medical patients (1.3% vs 1.5%; P=.845). VAT progressed to VAP in nine patients (32.1%) despite antibiotic therapy. There was no significant difference in hospital mortality between patients with VAP and VAT (19.3% vs 21.4%; P=.789). VAT was caused by a multidrug-resistant (MDR) pathogen in nine cases (32.1%). CONCLUSION: VAT occurs less commonly than VAP but at a similar incidence in medical and surgical ICU patients. VAT frequently progressed to VAP, and patients diagnosed with VAT had similar outcomes to those diagnosed with VAP, suggesting that antimicrobial therapy is appropriate for VAT. VAT is also frequently caused by MDR organisms, and this should be taken into account when choosing antimicrobial therapy. PMID- 20724739 TI - Nonsteroidal antiinflammatory drugs may affect the presentation and course of community-acquired pneumonia. AB - BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used as antipyretics and analgesics and may affect the host response to acute infection. We investigated the potential influence of NSAIDs on the presentation and short term outcomes of nonimmunocompromised inpatients with community-acquired pneumonia (CAP) admitted to the ICU. METHODS: All consecutive patients with CAP admitted to the ICU or step-down unit of a university hospital during a 4-year period were prospectively included, except when receiving long-term NSAIDs or steroids. Drug exposures, presentation, and hospital course were recorded. RESULTS: Of the 90 patients included, 32 (36%) had taken NSAIDs prior to hospital referral. Compared with nonexposed patients, they were younger and had fewer comorbidities but similar severity of disease at presentation, despite a longer duration of symptoms before referral. However, they more often developed pleuropulmonary complications, such as pleural empyema and lung cavitation (37.5% vs 7%; P = .0009), and had a trend to more-invasive disease, with a higher frequency of pleural empyema (25% vs 5%, P = .014) and bacteremia, especially in those not having received concomitant antibiotics (69% vs 27%, P = .009). Nevertheless, the patients in the NSAID group had no more severe systemic inflammation or remote organ dysfunction. In multivariable analyses, NSAID exposure was independently associated with the occurrence of pleuropulmonary complications (OR, 8.1; 95% CI, 2.3-28). CONCLUSIONS: Our findings suggest that NSAID exposure at the early stage of CAP is associated with a more complicated course but a blunted systemic response, which may be associated with a delayed diagnosis and a protracted course. PMID- 20724740 TI - Resistance arm training in patients with COPD: A Randomized Controlled Trial. AB - BACKGROUND: The study aimed to evaluate the effect of upper extremity resistance training for patients with COPD on dyspnea during activity of daily living (ADL), arm function, arm exercise capacity, muscle strength, and health-related quality of life (HRQL). METHODS: Patients were randomly assigned to an intervention or control group. The intervention group underwent arm resistance training. The control group performed a sham. Both groups exercised three times a week for 6 weeks. Dyspnea during ADL and HRQL were measured using the Chronic Respiratory Disease Questionnaire (CRDQ). Arm function and exercise capacity were measured using the 6-min pegboard and ring test (6PBRT) and the unsupported upper limb exercise test (UULEX), respectively. Muscle strength for the biceps, triceps, and anterior and middle deltoids was obtained using an isometric dynamometer. RESULTS: Thirty-six patients with COPD (66 +/- 9 years) participated in the study. Compared with the control group, the magnitude of change in the intervention group was greater for the 6PBRT (P = .03), UULEX (P = .01), elbow flexion force (P = .01), elbow extension force (P = .02), shoulder flexion force (P = .029), and shoulder abduction force (P = .01). There was no between-group difference in dyspnea during ADL, HRQL, or symptoms during the 6PBRT or UULEX (all P values > .08). CONCLUSIONS: Resistance-based arm training improved arm function, arm exercise capacity, and muscle strength in patients with COPD. No improvement in dyspnea during ADL, HRQL, or symptoms was demonstrated. PMID- 20724741 TI - The nonspecific pulmonary function test: longitudinal follow-up and outcomes. AB - BACKGROUND: The nonspecific (NS) pulmonary function (PF) pattern refers to a PF test with a normal total lung capacity (TLC), normal FEV1/FVC ratio, and a low FEV1, a low FVC, or both. Currently, no information is available regarding the long-term stability of the NS pattern or variables that predict changes in subjects with an initial NS PF pattern. METHODS: From 1990 to 2005 we identified 1,284 subjects with an NS pattern on initial PF testing with one or more follow up PF tests 6 months or more after the initial NS test result. Lung volumes, diffusing capacity, and spirometry data were analyzed. A multivariate, multinomial logistic regression model was used to study the association between different variables and the final PF pattern. RESULTS: Overall, 3,674 PF tests were performed in 1,284 subjects over a median follow-up period of 3 years. At last follow-up, 818/1,284 (64%) subjects continued to show the NS pattern, whereas 208/1,284 (16%) showed a restrictive pattern, 191/1,284 (15%) an obstructive pattern, 42/1,284 (3%) a normal pattern, and 25/1,284 (2%) a mixed pattern. The multinomial logistic regression analysis showed that increasing values for specific airway resistance and the difference between TLC and alveolar volume were predictors of a change to an obstructive pattern on follow-up. CONCLUSIONS: The NS pattern is a distinct and stable PF test pattern with roughly two-thirds of patients continuing to show this pattern on follow-up testing. Current interpretation guidelines erroneously label the NS pattern as representing obstruction and need to be changed to reflect these data. PMID- 20724742 TI - Acute bronchodilator responsiveness in bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation. AB - BACKGROUND: The obstructive abnormality of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is deemed to be virtually insensitive to treatment with inhaled bronchodilators. We studied whether nonconventional assessment of bronchodilation may help to detect physiologically meaningful airway responses missed by traditional criteria. METHODS: Standard spirometry, partial and maximal expiratory flow-volume curves, and lung volumes were measured before and 90 min after inhalation of albuterol plus tiotropium in 17 patients who developed mild to very severe BOS following HSCT. RESULTS: After treatment with bronchodilators, the standard criteria of reversibility based on FEV1 and FVC were met in seven out of 17 patients. In eight patients, residual volume (RV) decreased beyond its within-session spontaneous variability, and functional residual capacity (FRC) was reduced in four of them. Partial forced expiratory flow (Vpart) increased beyond its within session spontaneous variability in nine patients. Out of 10 patients in whom neither FEV1 nor FVC met the standard criteria of reversibility, six had a positive increase in Vpart or a decrease of lung hyperinflation (ie, FRC) or RV. In six patients with limited expiratory flow during tidal breathing, the postbronchodilator increase in Vpart was correlated with a decrease in FRC (R2=0.83; P=.011). CONCLUSIONS: This study suggests that airway smooth muscle tone plays a significant role in BOS after HSCT and that the common knowledge of BOS as an irreversible obstructive disease may stem from the limitation of simple spirometry to detect changes in small airways. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01112241 (BOS-01); URL: www.clinicaltrials.gov. PMID- 20724743 TI - Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis. AB - BACKGROUND: Organizing pneumonia (OP) is a distinct clinical and pathologic entity. This condition can be cryptogenic (COP) or secondary to other known causes (secondary OP). In the present study, we reviewed the features associated with COP and secondary OP in patients from two teaching hospitals. METHODS: The medical records of 61 patients with biopsy-proven OP were retrospectively reviewed. Forty patients were diagnosed with COP and 21 patients with secondary OP. The clinical presentation, radiographic studies, pulmonary function tests (PFTs), laboratory data, BAL findings, treatment, and outcome were analyzed. RESULTS: The mean age at presentation was 60.46 +/- 13.57 years. Malaise, cough, fever, dyspnea, bilateral alveolar infiltrates, and a restrictive pattern were the most common symptoms and findings. BAL lymphocytosis was observed in 43.8% of patients with OP. The relapse rate and mortality rate after 1 year of follow-up were 37.8% and 9.4%, respectively. The in-hospital mortality was 5.7%. The clinical presentation and radiographic findings did not differ significantly between patients with COP and secondary OP. A mixed PFT pattern (obstructive and restrictive physiology) and lower blood levels of serum sodium, serum potassium, platelets, albumin, protein, and pH were observed among patients with secondary OP. Higher blood levels of creatinine, bilirubin, Paco2, and BAL lymphocytes were also more common among patients with secondary OP. There were no differences in the relapse rate or mortality between patients with COP and secondary OP. The 1 year mortality correlated with an elevated erythrocyte sedimentation rate, low albumin, and low hemoglobin levels. CONCLUSIONS: The clinical and radiographic findings in patients with COP and secondary OP are similar and nonspecific. Although certain laboratory abnormalities are more common in secondary OP and can be associated with worse prognosis, they are likely due to the underlying disease. COP and secondary OP have similar treatment response, relapse rates, and mortality. PMID- 20724749 TI - Array comparative genomic hybridization detects chromosomal abnormalities in hematological cancers that are not detected by conventional cytogenetics. AB - Application of array comparative genomic hybridization (aCGH) has allowed an unprecedented high-resolution analysis of cancer genomes. We developed a custom genome-wide oligonucleotide microarray interrogating 493 genes involved in hematological disorders. We analyzed 55 patients with hematological neoplasms by using this microarray. In 33 patients with apparent normal conventional cytogenetic analysis, aneuploidy or isochromosomes were detected in 12% (4 of 33) of the patients by aCGH. The chromosomal changes included trisomy of chromosomes 10, 14, and 15, tetrasomy 11, and isochromosome 17q. In 17 patients with chronic lymphocytic leukemia who were initially investigated by using a panel of standard fluorescence in situ hybridization probes, additional copy number changes that were not interrogated by the fluorescence in situ hybridization (FISH) panel were detected in 47% (8 of 17) of the patients by aCGH. Important copy number changes included gain on 2p16 involving REL and BCL11A genes, rearrangements of chromosomes 8 and 15, and trisomy of chromosomes 19 and 22. In five patients with known abnormal karyotypes, aCGH identified the origin of two marker chromosomes and detected microdeletions at five breakpoints involved in three apparent balanced translocations. Our results suggest that a subset of potentially significant genomic alterations is missed by the currently available cytogenetic techniques. This pilot study clearly demonstrates high sensitivity of oligonucleotide aCGH for potential use in diagnosis and follow-up in patients with hematological neoplasms. PMID- 20724750 TI - Incidental neuroimaging findings in nonacute headache. AB - We studied the frequency and consequences of incidental neuroimaging findings in 400 otherwise healthy, nonacute pediatric headache patients through a retrospective, cross-sectional analysis. We excluded patients with currently recommended clinical criteria to consider diagnostic neuroimaging. We categorized neuroimaging results as normal, remarkable without clinical action, remarkable with clinical follow-up action, and abnormal. One hundred eighty-five of 400 patients (46%) had neuroimaging. Of these, 78.4% of neuroimaging studies were normal, and none was considered abnormal. Also, 21.5% had remarkable findings in the neuroradiology report. The frequency and types of all incidental findings were generally comparable to previous studies. One third of these patients received further consultation or neuroimaging because of incidental findings. In the evaluation of nonacute pediatric headache, overuse of neuroimaging leads to frequent discovery of incidental findings and increased testing. Individualized health care calls for physician-consumer discussions about current indications for neuroimaging, the general frequency of incidental findings, and potential difficulties in their interpretation. PMID- 20724751 TI - Early cranial ultrasound lesions predict microcephaly at age 2 years in preterm infants. AB - To assess how well early ultrasound lesions in preterm newborns predict reduced head circumference at 2 years, the investigators followed 923 children born before the 28th week of gestation who were not microcephalic at birth. Six percent of children who had a normal ultrasound scan were microcephalic compared with 15% to 20% who had intraventricular hemorrhage, an echolucent lesion, or ventriculomegaly. The odds ratios (95% confidence intervals) for microcephaly associated with different ultrasound images were intraventricular hemorrhage, 1.5 (0.8-3.0); ventriculomegaly, 3.3 (1.8-6.0); an echodense lesion, 1.6 (0.7-3.5); and an echolucent lesion, 3.1 (1.5-6.2). Ventriculomegaly and an echolucent lesion had very similar low positive predictive values (24% and 27%, respectively) and high negative predictive values (91% and 90%, respectively) for microcephaly. Ventriculomegaly had a higher sensitivity for microcephaly than did an echolucent lesion (24% vs 16%, respectively). Focal white-matter lesion (echolucent lesion) and diffuse white-matter damage (ventriculomegaly) predict an increased risk of microcephaly. PMID- 20724752 TI - Irregular shape symmetry analysis: theory and application to quantitative galaxy classification. AB - This paper presents a set of imperfectly symmetric measures based on a series of geometric transformation operations for quantitatively measuring the "amount" of symmetry of arbitrary shapes. The definitions of both bilateral symmetricity and rotational symmetricity give new insight into analyzing the geometrical property of a shape and enable characterizing arbitrary shapes in a new way. We developed a set of criteria for quantitative galaxy classification using our proposed irregular shape symmetry measures. Our study has demonstrated the effectiveness of the proposed method for the characterization of the shape of the celestial bodies. The concepts described in the paper are applicable to many fields, such as mathematics, artificial intelligence, digital image processing, robotics, biomedicine, etc. PMID- 20724753 TI - Auto-context and its application to high-level vision tasks and 3D brain image segmentation. AB - The notion of using context information for solving high-level vision and medical image segmentation problems has been increasingly realized in the field. However, how to learn an effective and efficient context model, together with an image appearance model, remains mostly unknown. The current literature using Markov Random Fields (MRFs) and Conditional Random Fields (CRFs) often involves specific algorithm design in which the modeling and computing stages are studied in isolation. In this paper, we propose a learning algorithm, auto-context. Given a set of training images and their corresponding label maps, we first learn a classifier on local image patches. The discriminative probability (or classification confidence) maps created by the learned classifier are then used as context information, in addition to the original image patches, to train a new classifier. The algorithm then iterates until convergence. Auto-context integrates low-level and context information by fusing a large number of low level appearance features with context and implicit shape information. The resulting discriminative algorithm is general and easy to implement. Under nearly the same parameter settings in training, we apply the algorithm to three challenging vision applications: foreground/background segregation, human body configuration estimation, and scene region labeling. Moreover, context also plays a very important role in medical/brain images where the anatomical structures are mostly constrained to relatively fixed positions. With only some slight changes resulting from using 3D instead of 2D features, the auto-context algorithm applied to brain MRI image segmentation is shown to outperform state-of-the-art algorithms specifically designed for this domain. Furthermore, the scope of the proposed algorithm goes beyond image analysis and it has the potential to be used for a wide variety of problems for structured prediction problems. PMID- 20724754 TI - Cost-sensitive face recognition. AB - Most traditional face recognition systems attempt to achieve a low recognition error rate, implicitly assuming that the losses of all misclassifications are the same. In this paper, we argue that this is far from a reasonable setting because, in almost all application scenarios of face recognition, different kinds of mistakes will lead to different losses. For example, it would be troublesome if a door locker based on a face recognition system misclassified a family member as a stranger such that she/he was not allowed to enter the house, but it would be a much more serious disaster if a stranger was misclassified as a family member and allowed to enter the house. We propose a framework which formulates the face recognition problem as a multiclass cost-sensitive learning task, and develop two theoretically sound methods for this task. Experimental results demonstrate the effectiveness and efficiency of the proposed methods. PMID- 20724755 TI - Determining both surface position and orientation in structured-light-based sensing. AB - Position and orientation profiles are two principal descriptions of shape in space. We describe how a structured light system, coupled with the illumination of a pseudorandom pattern and a suitable choice of feature points, can allow not only the position but also the orientation of individual surface elements to be determined independently. Unlike traditional designs which use the centroids of the illuminated pattern elements as the feature points, the proposed design uses the grid points between the pattern elements instead. The grid points have the essences that their positions in the image data are inert to the effect of perspective distortion, their individual extractions are not directly dependent on one another, and the grid points possess strong symmetry that can be exploited for their precise localization in the image data. Most importantly, the grid lines of the illuminated pattern that form the grid points can aid in determining surface normals. In this paper, we describe how each of the grid points can be labeled with a unique color code, what symmetry they possess and how the symmetry can be exploited for their precise localization at subpixel accuracy in the image data, and how 3D orientation in addition to 3D position can be determined at each of them. Both the position and orientation profiles can be determined with only a single pattern illumination and a single image capture. PMID- 20724756 TI - Generative supervised classification using Dirichlet process priors. AB - Choosing the appropriate parameter prior distributions associated to a given bayesian model is a challenging problem. Conjugate priors can be selected for simplicity motivations. However, conjugate priors can be too restrictive to accurately model the available prior information. This paper studies a new generative supervised classifier which assumes that the parameter prior distributions conditioned on each class are mixtures of Dirichlet processes. The motivations for using mixtures of Dirichlet processes is their known ability to model accurately a large class of probability distributions. A Monte Carlo method allowing one to sample according to the resulting class-conditional posterior distributions is then studied. The parameters appearing in the class-conditional densities can then be estimated using these generated samples (following bayesian learning). The proposed supervised classifier is applied to the classification of altimetric waveforms backscattered from different surfaces (oceans, ices, forests, and deserts). This classification is a first step before developing tools allowing for the extraction of useful geophysical information from altimetric waveforms backscattered from nonoceanic surfaces. PMID- 20724757 TI - Keep it simple with time: a reexamination of probabilistic topic detection models. AB - Topic detection (TD) is a fundamental research issue in the Topic Detection and Tracking (TDT) community with practical implications; TD helps analysts to separate the wheat from the chaff among the thousands of incoming news streams. In this paper, we propose a simple and effective topic detection model called the temporal Discriminative Probabilistic Model (DPM), which is shown to be theoretically equivalent to the classic vector space model with feature selection and temporally discriminative weights. We compare DPM to its various probabilistic cousins, ranging from mixture models like von-Mises Fisher (vMF) to mixed membership models like Latent Dirichlet Allocation (LDA). Benchmark results on the TDT3 data set show that sophisticated models, such as vMF and LDA, do not necessarily lead to better results; in the case of LDA, notably worst performance was obtained under variational inference, which is likely due to the significantly large number of LDA model parameters involved for document-level topic detection. On the contrary, using a relatively simple time-aware probabilistic model such as DPM suffices for both offline and online topic detection tasks, making DPM a theoretically elegant and effective model for practical topic detection. PMID- 20724758 TI - Kernelized sorting. AB - Object matching is a fundamental operation in data analysis. It typically requires the definition of a similarity measure between the classes of objects to be matched. Instead, we develop an approach which is able to perform matching by requiring a similarity measure only within each of the classes. This is achieved by maximizing the dependency between matched pairs of observations by means of the Hilbert-Schmidt Independence Criterion. This problem can be cast as one of maximizing a quadratic assignment problem with special structure and we present a simple algorithm for finding a locally optimal solution. PMID- 20724759 TI - L2 kernel classification. AB - Nonparametric kernel methods are widely used and proven to be successful in many statistical learning problems. Well-known examples include the kernel density estimate (KDE) for density estimation and the support vector machine (SVM) for classification. We propose a kernel classifier that optimizes the L2 or integrated squared error (ISE) of a "difference of densities." We focus on the Gaussian kernel, although the method applies to other kernels suitable for density estimation. Like a support vector machine (SVM), the classifier is sparse and results from solving a quadratic program. We provide statistical performance guarantees for the proposed L2 kernel classifier in the form of a finite sample oracle inequality and strong consistency in the sense of both ISE and probability of error. A special case of our analysis applies to a previously introduced ISE based method for kernel density estimation. For dimensionality greater than 15, the basic L2 kernel classifier performs poorly in practice. Thus, we extend the method through the introduction of a natural regularization parameter, which allows it to remain competitive with the SVM in high dimensions. Simulation results for both synthetic and real-world data are presented. PMID- 20724760 TI - Motion segmentation in the presence of outlying, incomplete, or corrupted trajectories. AB - In this paper, we study the problem of segmenting tracked feature point trajectories of multiple moving objects in an image sequence. Using the affine camera model, this problem can be cast as the problem of segmenting samples drawn from multiple linear subspaces. In practice, due to limitations of the tracker, occlusions, and the presence of nonrigid objects in the scene, the obtained motion trajectories may contain grossly mistracked features, missing entries, or corrupted entries. In this paper, we develop a robust subspace separation scheme that deals with these practical issues in a unified mathematical framework. Our methods draw strong connections between lossy compression, rank minimization, and sparse representation. We test our methods extensively on the Hopkins155 motion segmentation database and other motion sequences with outliers and missing data. We compare the performance of our methods to state-of-the-art motion segmentation methods based on expectation-maximization and spectral clustering. For data without outliers or missing information, the results of our methods are on par with the state-of-the-art results and, in many cases, exceed them. In addition, our methods give surprisingly good performance in the presence of the three types of pathological trajectories mentioned above. All code and results are publicly available at http://perception.csl.uiuc.edu/coding/motion/. PMID- 20724761 TI - Dynamic hybrid algorithms for MAP inference in discrete MRFs. AB - In this paper, we present novel techniques that improve the computational and memory efficiency of algorithms for solving multilabel energy functions arising from discrete mrfs or crfs. These methods are motivated by the observations that the performance of minimization algorithms depends on: 1) the initialization used for the primal and dual variables and 2) the number of primal variables involved in the energy function. Our first method (dynamic alpha-expansion) works by "recycling" results from previous problem instances. The second method simplifies the energy function by "reducing" the number of unknown variables present in the problem. Further, we show that it can also be used to generate a good initialization for the dynamic alpha-expansion algorithm by "reusing" dual variables. We test the performance of our methods on energy functions encountered in the problems of stereo matching and color and object-based segmentation. Experimental results show that our methods achieve a substantial improvement in the performance of alpha-expansion, as well as other popular algorithms such as sequential tree-reweighted message passing and max-product belief propagation. We also demonstrate the applicability of our schemes for certain higher order energy functions, such as the one described in [1], for interactive texture-based image and video segmentation. In most cases, we achieve a 10-15 times speed-up in the computation time. Our modified alpha-expansion algorithm provides similar performance to Fast-PD, but is conceptually much simpler. Both alpha-expansion and Fast-PD can be made orders of magnitude faster when used in conjunction with the "reduce" scheme proposed in this paper. PMID- 20724762 TI - Robust 3D face recognition by local shape difference boosting. AB - This paper proposes a new 3D face recognition approach, Collective Shape Difference Classifier (CSDC), to meet practical application requirements, i.e., high recognition performance, high computational efficiency, and easy implementation. We first present a fast posture alignment method which is self dependent and avoids the registration between an input face against every face in the gallery. Then, a Signed Shape Difference Map (SSDM) is computed between two aligned 3D faces as a mediate representation for the shape comparison. Based on the SSDMs, three kinds of features are used to encode both the local similarity and the change characteristics between facial shapes. The most discriminative local features are selected optimally by boosting and trained as weak classifiers for assembling three collective strong classifiers, namely, CSDCs with respect to the three kinds of features. Different schemes are designed for verification and identification to pursue high performance in both recognition and computation. The experiments, carried out on FRGC v2 with the standard protocol, yield three verification rates all better than 97.9 percent with the FAR of 0.1 percent and rank-1 recognition rates above 98 percent. Each recognition against a gallery with 1,000 faces only takes about 3.6 seconds. These experimental results demonstrate that our algorithm is not only effective but also time efficient. PMID- 20724763 TI - Self-validated labeling of Markov random fields for image segmentation. AB - This paper addresses the problem of self-validated labeling of Markov random fields (MRFs), namely to optimize an MRF with unknown number of labels. We present graduated graph cuts (GGC), a new technique that extends the binary s-t graph cut for self-validated labeling. Specifically, we use the split-and-merge strategy to decompose the complex problem to a series of tractable subproblems. In terms of Gibbs energy minimization, a suboptimal labeling is gradually obtained based upon a set of cluster-level operations. By using different optimization structures, we propose three practical algorithms: tree-structured graph cuts (TSGC), net-structured graph cuts (NSGC), and hierarchical graph cuts (HGC). In contrast to previous methods, the proposed algorithms can automatically determine the number of labels, properly balance the labeling accuracy, spatial coherence, and the labeling cost (i.e., the number of labels), and are computationally efficient, independent to initialization, and able to converge to good local minima of the objective energy function. We apply the proposed algorithms to natural image segmentation. Experimental results show that our algorithms produce generally feasible segmentations for benchmark data sets, and outperform alternative methods in terms of robustness to noise, speed, and preservation of soft boundaries. PMID- 20724764 TI - Tuning support vector machines for minimax and Neyman-Pearson classification. AB - This paper studies the training of support vector machine (SVM) classifiers with respect to the minimax and Neyman-Pearson criteria. In principle, these criteria can be optimized in a straightforward way using a cost-sensitive SVM. In practice, however, because these criteria require especially accurate error estimation, standard techniques for tuning SVM parameters, such as cross validation, can lead to poor classifier performance. To address this issue, we first prove that the usual cost-sensitive SVM, here called the 2C-SVM, is equivalent to another formulation called the 2nu-SVM. We then exploit a characterization of the 2nu-SVM parameter space to develop a simple yet powerful approach to error estimation based on smoothing. In an extensive experimental study, we demonstrate that smoothing significantly improves the accuracy of cross validation error estimates, leading to dramatic performance gains. Furthermore, we propose coordinate descent strategies that offer significant gains in computational efficiency, with little to no loss in performance. PMID- 20724765 TI - The association between vitamin D deficiency and type 2 diabetes mellitus in elderly patients. AB - AIM: to identify the association between vitamin D deficiency and type-2 diabetes mellitus in elderly population. METHODS: a study was conducted at the geriatric clinic of Cipto Mangunkusumo Hospital in November 2007, with a cross-sectional design. The accessible population of our study were patients with type-2 diabetes mellitus and non-diabetes mellitus patients who visited the clinic for treatment. The subject criteria were: patients >60 years old with operational definition of type-2 diabetes mellitus, and willing to participate in the study. Data collected included characteristics, such as age, sex, education level, history of family illness, frequency of outdoor activity, duration of direct sun exposure in their outdoor activities, history of using sun protector; and the laboratory data such as 25(OH)D3 serum level, calcium and albumin serum level. Data analysis was done by Chi-Square test and multivariate analysis was performed by logistic regression technique to control some identified confounding factors. All data processing and statistical analyses were done with SPSS 11.5 for windows. RESULTS: we found a total number of 78 subjects. Of them, 40 subjects were with DM, and 38 subjects without DM. Most subjects were female (66.7%), and obese (44.9%). Direct sun exposure of most subjects was indicated by the frequency of outdoor activity of more than 3 times a week (74.4%). Duration of exposure in most subjects was less than 15 minutes (43.6%), with application of sun protector agent (56.4%). The prevalence of vitamin D deficiency was 78.2%, with a cut-off of <50 nmol/L. CONCLUSION: sex, BMI and the use of sun protectors proven as variables are associated with vitamin D deficiency. The association between vitamin D deficiency and type-2 diabetes mellitus cannot be proven statistically in our study (p=0.482; OR=0.8; CI=0.5-1.3). PMID- 20724766 TI - Efficacy of Nigella sativa on serum free testosterone and metabolic disturbances in central obese male. AB - AIM: to study the efficacy of Nigella sativa in central obese men on serum free testosterone, body weight, waist circumference, blood sugar, lipid, uric acid, adiponectin, hs-CRP, and side effects in the treatment group compare to control. METHODS: an experimental, clinical test, double blinded with placebo control, pre test and post-test design. Subjects are 30-45 years old, divided into the treatment and control groups, and evaluated weekly for 3 months. Data obtained were subjective complaints, body weight, waist circumference, and blood pressure, serum free testosterone, fasting blood sugar, triglyceride, HDL-Cholesterol, uric acid, creatinin, SGOT and SGPT, adiponectin, and hs-CRP. Data collected from March 2007 to June 2007 at Prof.Dr.RD Kandou General Hospital, Manado, North Sulawesi, Indonesia. Statistical analysis was performed using descriptive for subjects characteristic and drug's side effect, t independent to compare between two parametric independent variables, Mann-Whitney U to compare between two non parametric independent variables, and Wilcoxon Signed Ranks test to compare between two non-parametric dependent variables. RESULTS: in the treatment group, complaints related to central obesity disappear in first week, very significant reduction of body weight, waist circumference, and systolic blood pressure, insignificant reduction in serum free testosterone, diastolic blood pressure, fasting blood sugar, triglyceride and cholesterol-HDL, uric acid, hs-CRP, and insignificant increase of adiponectin. On comparison between both groups, we found a very significant reduction on body weight and waist circumference, but the insignificant reduction on serum free testosterone, systolic and diastolic blood pressure, and the unsignificant increase of adiponectin, meanwhile the reduction of serum free testosterone in the treatment group was smaller than the control group, that means Nigella sativa could inhibit the decreasing of serum free testosterone. No side effects were detected in the treatment group. CONCLUSION: although the other variables in the treatment group were not significantly different, we found them better than the control group, which can be a good sign for metabolic restoration in COM. It is suggested that larger dose and longer duration of NS consumption will give better results. PMID- 20724767 TI - Serum gastrin level and pepsinogen I/II ratio as biomarker of Helicobacter pylori chronic gastritis. AB - AIM: to find out biomarker as diagnostic tool of H. pylori chronic gastritis. METHODS: the design of present study was a diagnostic test and there were 104 subjects with H. pylori chronic gastritis who fulfilled the inclusion and exclusion criteria. The diagnosis of H. pylori chronic gastritis was based on histopathological examination and PCR with ureC primer of the gastric biopsy specimen. In addition, we also performed the examination of serum gastrin, pepsinogen (PG) I and PG (pepsinogen) II level. By using analysis of receiver operating characteristic (ROC), an optimal cut off point of serum gastrin, PGI and PGII level as well as PGI/PGII ratio was determined. Analysis of bivariate logistic regression was used to determine the involved independent variables and possibilities as biomarkers. Significance level was determined by p value <0.05. RESULTS: we found optimal cut off points on serum gastrin, PGI and PGII level as well as the PGI/PGII ratio at 5.89 pmol/L; 82.5 ug/L; 6.48 ug/L and 13.6 respectively. By using the analysis of bivariate logistic regression, we found gastrin level with p = 0.078 (OR 2.75;95%CI 0.89-8.45) and PGI/PGII ratio with p = 0.000 (OR 14.63;95%CI 3.55-60.63). The opportunity of gastrin level and PGI/PGII ratio as biomarkers was 0.8 with 47% sensitivity, 83% specificity, 74% PPV, 61% NPV, 65% accuracy, LR+ = 2.76 and LR- = 0.64. CONCLUSION: gastrin level of >5.89 pmol/L and PGI/PGII ratio <=13.6 can be utilized as biomarkers of H. pylori chronic gastritis. PMID- 20724768 TI - Influence of iron on plasma interleukin-2 and gamma interferon level in iron deficiency anemia. AB - AIM: to find out the the influence of iron on the levels of plasma IL-2 and IFNgamma in iron deficiency anemia patient. METHODS: the study subjects were patients with IDA (intended samples) selected from the accessible population that met the inclusion and exclusion criteria using consecutive sampling technique and by signing an informed consent. Blood samples were taken for measurement of IL-2 and IFNgamma concentrations as well as list of questionnaires for obtaining data on age, gender, body weight, infections suffered, use of immunosuppressive medicines, malnutrition, malignancy and genetic disorder, and IDA diagnosis. The levels of IL-2 and IFNgamma were measured before and after 8 weeks of iron tablet adminitration using immunoassay solid phase ELISA. Descriptive statistics was used to illustrate patient's characteristics and frequency distribution of various variables. The average difference of IL-2 and IFNgamma concentrations was also examined pre and post administration of iron tablets for 8 weeks using Wilkoxon sign rank test. RESULTS: in the study, 26 IDA patients were eligible, chosen from 64 IDA patients who were then given iron tablets for 8 weeks. By the end of the treatment, they were tested for complete blood analysis, serum ferritin, and cytokines of plasma. Sign rank test of Wilcoxon was used to find out direction and degree of difference between the two paired groups which showed a significant difference between pre and post iron tablet administration of hemoglobin (Z= -4.561; p<0.001), MCV (Z= -4.276; p<0.001), MCH (Z= -3.616; p<0.001) and feritin (Z= -3.556; p<0.001). After 8 weeks of iron tablets, the study also noted, increasing of plasma IL-2 and IFNgamma. Before treatment level of plasma IL-2 was 7.65 pg/l then became 29.3 pg/l after treatment (Z=- 3.508, p<0.001) and plasma IFNg before treatment was 10.15 pg/l became 46.7 pg/l after treatment (Z= -4.241, p<0.001). CONCLUSION: concentration of IL2 dan IFNgamma in plasma significantly increased after administration of iron tablets for 8 weeks as compared to that before iron treatment. PMID- 20724769 TI - Risk factors of obstructive sleep apnea syndrome in obese early adolescents: a prediction model using scoring system. AB - AIM: to obtain the OSAS prevalence and risk factors of OSAS in obese early adolescents and to create a scoring system based on risk factors for diagnosing OSAS. METHODS: an observational study in Jakarta, November 2007 until December 2008 on obese adolescents aged 10-12 years with snoring. Subjects underwent clinical examination, lung function test, paranasal sinus X-ray, and polisomnography. Measured outcomes were diagnosis of OSAS; sensitivity, specificity, predictive values, and likelihood ratios of a scoring system based on risk factors. RESULTS: the prevalence of OSAS in obese early adolescents is 38.2% using AHI cut-off point of >=3 on PSG. Tonsillar hypertrophy, adenoid hypertrophy, and neck circumference were the main risk factors. Scoring system was designed based on these results: OS= T + A + NC; OS= OSAS score; T= tonsil hypertrophy (>=T3 scored 1, =0.8 scored 1.5, <0.8 scored 0); NC = neck circumference (>=34 cm scored 1; <34 cm scored 0). Children were most likely to have OSAS if they had a total score of 3.5. This scoring system has a sensitivity of 62% (95%CI 47 to 77%), specificity 100% (95%CI 100 to 100%), positive predictive value 100% (95%CI 100 to 100%), negative predictive value 81% (95%CI 73 to 89%), unlimited LR(+), LR(-) of 0.38 (CI 95% 0.6 to 0.56). CONCLUSION: a scoring system based on tonsillar hypertrophy, adenoid hypertrophy, and neck circumference has sensitivity and specificity of 62% and 100% in diagnosing OSAS. PMID- 20724770 TI - Normal protein diet and L-ornithine-L-aspartate for hepatic encephalopathy. AB - Excessive protein intake can cause hepatic encephalopathy (HE). Restricting protein in HE is becoming a controversy, because it can worsen malnutrition. This article reports the case of an under nourishment HE which is treated with L ornithine-L-aspartate (LOLA) and given appropriate diet according to the nutrition status. A 62-year-old man came with chief complaint of having reduced consciousness since 6 hours before admission. He had been diagnosed as liver cirrhosis for 6 years. Several days prior to admission he took high protein diet. Physical examination revealed under nutrition and unconsciousness. Hepatic encephalopathy was confirmed with low critical flicker test (CFF), and high blood ammonia level. He was treated with adequate diet and LOLA to decrease blood ammonia and improve the CFF. During the treatment, consciousness improved to normal, CFF increased and ammonia level decreased. In this case, the HE was treated with LOLA without protein restriction. The HE improvement, in this circumstance may be caused of LOLA treatment that helps decrease the plasma ammonia level. Adequate diet, 35-40 kcal/kgBW/d and protein intake 1.5 g/kgBW/d, has been administered safely to this patient with stage II hepatic encephalopathy. LOLA seemed to be effectively reduced ammonia level and improved the encephalopathy. PMID- 20724771 TI - Albumin infusion in liver cirrhotic patients. AB - Albumin infusions have been used for many years in the management of patients with decompensated cirrhosis in an attempt to reduce the formation of ascites, to improve circulatory and renal function, or in SBP patients. While some of these indications for albumin infusions are supported by the results of randomised studies, others are based on clinical experience and have not been proved in prospective investigations. Therefore, the use of albumin infusions in patients with cirrhosis is still controversial. However, despite the controversies, the use of albumin at least has been proven to be safe. Some guidelines recommended the use of albumin infusion in decompensated cirrhosis with spontaneous bacterial peritonitis, hepatorenal syndrome, large volume parecentesis and decompensated cirrhosis with complications. PMID- 20724772 TI - Multiple lytic lesions in multiple myeloma. PMID- 20724773 TI - Testosterone replacement therapy in prostate cancer patients: is it safe? AB - The increasing population of elderly men means there is also an increase in those suffering from late-onset hypogonadism and testosterone deficiency, with all its attending consequences such as reduced libido, erectile dysfunction, metabolic disturbances, cardiovascular disease, decreased bone density and reduced quality of life. The use of testosterone replacement therapy may benefit such patients but remains controversial, especially with regard to the risk it may have on prostate cancer. However, there is no conclusive evidence that testosterone therapy increases the risk of developing prostate cancer nor is there any evidence to suggest that it can convert subclinical or indolent prostate cancer into a clinically significant one. In fact, a number of recent reports have shown that it is safe to give testosterone therapy in patients who have been successfully treated for early prostate cancer. Therefore, the purpose of this review is to discuss the role of testosterone replacement therapy, focusing on those with prostate cancer, as well as the risks and benefits that every physician must consider before commencing treatment. PMID- 20724774 TI - Voltage-controlled ferromagnetic order in MnGe quantum dots. AB - Here, we speculate that room temperature voltage-controlled ferromagnetic ordering may become a founding phenomenon for the next generation of low-power spintronics nanodevices and discuss the special role of dilute magnetic semiconductors as the most reliable material basis to date. Then, we report on our latest experimental achievements in the voltage manipulation of the ferromagnetism in MnGe quantum dots, experimentally demonstrating the capacity of pushing the Curie temperature further above room temperature for technological applications. PMID- 20724775 TI - Layer-by-layer assembled multilayers using catalase-encapsulated gold nanoparticles. AB - We introduce a novel and versatile approach for the preparation of multilayers, based on catalase-encapsulated gold nanoparticles (CAT-Au(NP)), allowing electrostatic charge reversal and structural transformation through pH adjustment. CAT-Au(NP), which are synthesized directly from CAT stabilizer, can be electrostatically assembled with anionic and cationic PEs as a result of the charge reversal of the catalase stabilizers through pH control. In particular, at pH 5.2, near the pI of catalase, dispersed CAT-Au(NP) are structurally transformed into colloidal or network CAT-Au(NP) nanocomposites. Furthermore, we demonstrate that the layer-by-layer assembled multilayers composed of PEs and CAT Au(NP) induce an effective electron transfer between CAT and the electrode as well as a high loading of CAT and Au(NP), and resultantly exhibit a highly catalytic activity toward H(2)O(2). PMID- 20724776 TI - Oxidative stress-mediated hemolytic activity of solvent exchange-prepared fullerene (C60) nanoparticles. AB - The present study investigated the hemolytic properties of fullerene (C(60)) nanoparticles prepared by solvent exchange using tetrahydrofuran (nC(60)THF), or by mechanochemically assisted complexation with macrocyclic oligosaccharide gamma cyclodextrin (nC(60)CDX) or the copolymer ethylene vinyl acetate-ethylene vinyl versatate (nC(60)EVA-EVV). The spectrophotometrical analysis of hemoglobin release revealed that only nC(60)THF, but not nC(60)CDX or nC(60)EVA-EVV, was able to cause lysis of human erythrocytes in a dose- and time-dependent manner. Atomic force microscopy revealed that nC(60)THF-mediated hemolysis was preceded by erythrocyte shrinkage and increase in cell surface roughness. A flow cytometric analysis confirmed a decrease in erythrocyte size and demonstrated a significant increase in reactive oxygen species production in red blood cells exposed to nC(60)THF. The nC(60)THF-triggered hemolytic activity was efficiently reduced by the antioxidants N-acetylcysteine and butylated hydroxyanisole, as well as by serum albumin, the most abundant protein in human blood plasma. These data indicate that nC(60)THF can cause serum albumin-preventable hemolysis through oxidative stress-mediated damage of the erythrocyte membrane. PMID- 20724777 TI - A single-step electron beam lithography of buried nanostructures using cathodoluminescence imaging and low temperature. AB - We report a new electron beam lithography process using the cathodoluminescence properties of semiconductors to visualize nanostructures buried underneath the resist and to subsequently write the pattern associated with these nanostructures. This single-step process could be used, for example, to make electrical contacts to nanowires (as illustrated in this work) or to design a photonic crystal resonator centered on a single quantum dot. Fabrication speed and positioning accuracy are significantly increased as compared to the standard process since no alignment marks and the mapping step of the nanostructures with respect to these marks are needed. We show also that low temperature (down to 5 K) could be used to improve the observation of the nanostructures through the resist while keeping very good spatial resolution. PMID- 20724778 TI - A novel epitaxially grown LSO-based thin-film scintillator for micro-imaging using hard synchrotron radiation. AB - The efficiency of high-resolution pixel detectors for hard X-rays is nowadays one of the major criteria which drives the feasibility of imaging experiments and in general the performance of an experimental station for synchrotron-based microtomography and radiography. Here the luminescent screen used for the indirect detection is focused on in order to increase the detective quantum efficiency: a novel scintillator based on doped Lu(2)SiO(5) (LSO), epitaxially grown as thin film via the liquid phase epitaxy technique. It is shown that, by using adapted growth and doping parameters as well as a dedicated substrate, the scintillation behaviour of a LSO-based thin crystal together with the high stopping power of the material allows for high-performance indirect X-ray detection. In detail, the conversion efficiency, the radioluminescence spectra, the optical absorption spectra under UV/visible-light and the afterglow are investigated. A set-up to study the effect of the thin-film scintillator's temperature on its conversion efficiency is described as well. It delivers knowledge which is important when working with higher photon flux densities and the corresponding high heat load on the material. Additionally, X-ray imaging systems based on different diffraction-limited visible-light optics and CCD cameras using among others LSO-based thin film are compared. Finally, the performance of the LSO thin film is illustrated by imaging a honey bee leg, demonstrating the value of efficient high-resolution computed tomography for life sciences. PMID- 20724779 TI - Local structure of vanadium in doped LiFePO4. AB - LiFePO(4) composites with 5 at.% vanadium doping are prepared by solid state reactions. X-ray absorption fine-structure spectroscopy is used as a novel technique to identify vanadium sites. Both experimental analyses and theoretical simulations show that vanadium does not enter into the LiFePO(4) crystal lattice. When the vanadium concentration is lower then 1 at.%, the dopant remains insoluble. Thus, a single-phase vanadium-doped LiFePO(4) cannot be formed and the improved electrochemical properties of vanadium-doped LiFePO(4) previously reported cannot be associated with crystal structure changes of the LiFePO(4) via vanadium doping. PMID- 20724780 TI - Radiation dose optimized lateral expansion of the field of view in synchrotron radiation X-ray tomographic microscopy. AB - Volumetric data at micrometer level resolution can be acquired within a few minutes using synchrotron-radiation-based tomographic microscopy. The field of view along the rotation axis of the sample can easily be increased by stacking several tomograms, allowing the investigation of long and thin objects at high resolution. On the contrary, an extension of the field of view in the perpendicular direction is non-trivial. This paper presents an acquisition protocol which increases the field of view of the tomographic dataset perpendicular to its rotation axis. The acquisition protocol can be tuned as a function of the reconstruction quality and scanning time. Since the scanning time is proportional to the radiation dose imparted to the sample, this method can be used to increase the field of view of tomographic microscopy instruments while optimizing the radiation dose for radiation-sensitive samples and keeping the quality of the tomographic dataset on the required level. This approach, dubbed wide-field synchrotron radiation tomographic microscopy, can increase the lateral field of view up to five times. The method has been successfully applied for the three-dimensional imaging of entire rat lung acini with a diameter of 4.1 mm at a voxel size of 1.48 microm. PMID- 20724781 TI - Investigation of annealing-induced oxygen vacancies in the Co-doped ZnO system by Co K-edge XANES spectroscopy. AB - To clarify the mechanism of the observed room-temperature ferromagnetism (RTF), many studies have been focused on dilute magnetic semiconductor systems. Several investigations have demonstrated that oxygen vacancies play a significant role in mediating the RTF behavior so that much effort has been devoted to confirm their presence. In this investigation, X-ray absorption spectroscopy was combined with ab initio calculations of the electronic structure of Co and Zn in the Zn(0.9)Co(0.1)O system before and after annealing, which has been recognized as an effective method of originating oxygen vacancies. A feature at about 20 eV after the rising edge of the Co K-edge XANES that disappears after annealing has been associated with the presence of an oxygen vacancy located in the second shell surrounding the Co atom. Moreover, Zn K-edge XANES spectra point out that this oxygen vacancy affects the electronic structure near the Fermi level, in agreement with density functional theory calculations. PMID- 20724782 TI - Synchrotron PEEM and ToF-SIMS study of oxidized heterogeneous pentlandite, pyrrhotite and chalcopyrite. AB - Synchrotron-based photoemission electron microscopy (PEEM; probing the surface region) and time-of-flight secondary ion mass spectrometry (ToF-SIMS; probing the uppermost surface layer) have been used to image naturally heterogeneous samples containing chalcopyrite (CuFeS(2)), pentlandite [(Ni,Fe)(9)S(8)] and monoclinic pyrrhotite (Fe(7)S(8)) both freshly polished and exposed to pH 9 KOH for 30 min. PEEM images constructed from the metal L(3) absorption edges were acquired for the freshly prepared and solution-exposed mineral samples. These images were also used to produce near-edge X-ray absorption fine-structure spectra from regions of the images, allowing the chemistry of the surface of each mineral to be interrogated, and the effect of solution exposure on the mineral surface chemistry to be determined. The PEEM results indicate that the iron in the monoclinic pyrrhotite oxidized preferentially and extensively, while the iron in the chalcopyrite and pentlandite underwent only mild oxidation. The ToF-SIMS data gave a clearer picture of the changes happening in the uppermost surface layer, with oxidation products being observed on all three minerals, and significant polysulfide formation and copper activation being detected for pyrrhotite. PMID- 20724783 TI - The role of single element errors in planar parabolic compound refractive lenses. AB - The propagation of X-rays through a compound refractive lens (CRL) with imperfect CRL elements is investigated. The trajectories of random rays within the geometrical optics regime are calculated in one plane using Monte Carlo methods. Three different lenses were simulated: Be, Al and Ni lenses designed for photon energies of 20 keV, 60 keV and 175 keV, respectively. The results show that while transverse displacements of single elements in a CRL do not influence imaging resolution, rotational errors can be important. Systematic calculations of aberrations owing to the deviation of the element's surface from a perfect parabolic shape are also presented. PMID- 20724784 TI - An asynchronous high-speed synchrotron shutter. AB - A high-repetition-rate mechanical shutter with asynchronous control and sub millisecond operation has been developed and tested for specialist X-ray systems in the field of medical diagnostics and radiation therapy. Capacitor-coupled linear voice coil actuators are utilized to achieve opening and closing speeds as fast as 700 micros for an aperture height of 4 mm. The design allows for asynchronous control, permitting slave operation of the shutter, a feature that is distinctly suitable for a number of applications including particle image velocimetry, where high-frame-rate operation must be accurately synchronized and triggered by the image acquisition sequence of the detector or timing device. The design and construction of the shutter also makes it ideal, with simple and limited modifications, for applications requiring larger apertures, in particular wide beams as found in many synchrotron beamlines. PMID- 20724785 TI - High-resolution soft X-ray beamline ADRESS at the Swiss Light Source for resonant inelastic X-ray scattering and angle-resolved photoelectron spectroscopies. AB - The concepts and technical realisation of the high-resolution soft X-ray beamline ADRESS operating in the energy range from 300 to 1600 eV and intended for resonant inelastic X-ray scattering (RIXS) and angle-resolved photoelectron spectroscopy (ARPES) are described. The photon source is an undulator of novel fixed-gap design where longitudinal movement of permanent magnetic arrays controls not only the light polarization (including circular and 0-180 degrees rotatable linear polarizations) but also the energy without changing the gap. The beamline optics is based on the well established scheme of plane-grating monochromator operating in collimated light. The ultimate resolving power E/DeltaE is above 33000 at 1 keV photon energy. The choice of blazed versus lamellar gratings and optimization of their profile parameters is described. Owing to glancing angles on the mirrors as well as optimized groove densities and profiles of the gratings, the beamline is capable of delivering high photon flux up to 1 x 10(13) photons s(-1) (0.01% BW)(-1) at 1 keV. Ellipsoidal refocusing optics used for the RIXS endstation demagnifies the vertical spot size down to 4 microm, which allows slitless operation and thus maximal transmission of the high resolution RIXS spectrometer delivering E/DeltaE > 11000 at 1 keV photon energy. Apart from the beamline optics, an overview of the control system is given, the diagnostics and software tools are described, and strategies used for the optical alignment are discussed. An introduction to the concepts and instrumental realisation of the ARPES and RIXS endstations is given. PMID- 20724786 TI - Phase-space analysis and experimental results for secondary focusing at X-ray beamlines. AB - Micro-focusing optical devices at synchrotron beamlines usually have a limited acceptance, but more flux can be intercepted if such optics are used to focus secondary sources created by the primary optics. Flux throughput can be maximized by placing the secondary focusing optics close to or exactly at the secondary source position. However, standard methods of beamline optics analysis, such as the lens equation or matching the mirror surface to an ellipse, work poorly when the source-to-optics distance is very short. In this paper the general characteristics of the focusing of beams with Gaussian profiles by a ;thin lens' are analysed under the paraxial approximation in phase space, concluding that the focusing of a beam with a short source-to-optics distance is distinct from imaging the source; slope errors are successfully included in all the formulas so that they can be used to calculate beamline focusing with good accuracy. A method is also introduced to use the thin-lens result to analyse the micro-focusing produced by an elliptically bent trapezoid-shaped Kirkpatrick-Baez mirror. The results of this analysis are in good agreement with ray-tracing simulations and are confirmed by the experimental results of the secondary focusing at the 18-ID Bio-CAT beamline (at the APS). The result of secondary focusing carried out at 18 ID using a single-bounce capillary can also be explained using this phase-space analysis. A discussion of the secondary focusing results is presented at the end of this paper. PMID- 20724787 TI - The MYTHEN detector for X-ray powder diffraction experiments at the Swiss Light Source. AB - The MYTHEN single-photon-counting silicon microstrip detector has been developed at the Swiss Light Source for time-resolved powder diffraction experiments. An upgraded version of the detector has been installed at the SLS powder diffraction station allowing the acquisition of diffraction patterns over 120 degrees in 2theta in fractions of seconds. Thanks to the outstanding performance of the detector and to the calibration procedures developed, the quality of the data obtained is now comparable with that of traditional high-resolution point detectors in terms of FWHM resolution and peak profile shape, with the additional advantage of fast and simultaneous acquisition of the full diffraction pattern. MYTHEN is therefore optimal for time-resolved or dose-critical measurements. The characteristics of the MYTHEN detector together with the calibration procedures implemented for the optimization of the data are described in detail. The refinements of two known standard powders are discussed together with a remarkable application of MYTHEN to organic compounds in relation to the problem of radiation damage. PMID- 20724788 TI - A confocal set-up for micro-XRF and XAFS experiments using diamond-anvil cells. AB - A confocal set-up is presented that improves micro-XRF and XAFS experiments with high-pressure diamond-anvil cells (DACs). In this experiment a probing volume is defined by the focus of the incoming synchrotron radiation beam and that of a polycapillary X-ray half-lens with a very long working distance, which is placed in front of the fluorescence detector. This set-up enhances the quality of the fluorescence and XAFS spectra, and thus the sensitivity for detecting elements at low concentrations. It efficiently suppresses signal from outside the sample chamber, which stems from elastic and inelastic scattering of the incoming beam by the diamond anvils as well as from excitation of fluorescence from the body of the DAC. PMID- 20724789 TI - Carbon K-edge spectra of carbonate minerals. AB - Carbon K-edge X-ray spectroscopy has been applied to the study of a wide range of organic samples, from polymers and coals to interstellar dust particles. Identification of carbonaceous materials within these samples is accomplished by the pattern of resonances in the 280-320 eV energy region. Carbonate minerals are often encountered in the study of natural samples, and have been identified by a distinctive resonance at 290.3 eV. Here C K-edge and Ca L-edge spectra from a range of carbonate minerals are presented. Although all carbonates exhibit a sharp 290 eV resonance, both the precise position of this resonance and the positions of other resonances vary among minerals. The relative strengths of the different carbonate resonances also vary with crystal orientation to the linearly polarized X-ray beam. Intriguingly, several carbonate minerals also exhibit a strong 288.6 eV resonance, consistent with the position of a carbonyl resonance rather than carbonate. Calcite and aragonite, although indistinguishable spectrally at the C K-edge, exhibited significantly different spectra at the Ca L edge. The distinctive spectral fingerprints of carbonates provide an identification tool, allowing for the examination of such processes as carbon sequestration in minerals, Mn substitution in marine calcium carbonates (dolomitization) and serpentinization of basalts. PMID- 20724790 TI - K-edge XANES analysis of sulfur compounds: an investigation of the relative intensities using internal calibration. AB - Sulfur K-edge XANES (X-ray absorption near-edge structure) spectroscopy is an excellent tool for determining the speciation of sulfur compounds in complex matrices. This paper presents a method to quantitatively determine the kinds of sulfur species in natural samples using internally calibrated reference spectra of model compounds. Owing to significant self-absorption of formed fluorescence radiation in the sample itself the fluorescence signal displays a non-linear correlation with the sulfur content over a wide concentration range. Self absorption is also a problem at low total absorption of the sample when the sulfur compounds are present as particles. The post-edge intensity patterns of the sulfur K-edge XANES spectra vary with the type of sulfur compound, with reducing sulfur compounds often having a higher post-edge intensity than the oxidized forms. In dilute solutions (less than 0.3-0.5%) it is possible to use sulfur K-edge XANES reference data for quantitative analysis of the contribution from different species. The results show that it is essential to use an internal calibration system when performing quantitative XANES analysis. Preparation of unknown samples must take both the total absorption and possible presence of self absorbing particles into consideration. PMID- 20724791 TI - Improved tomographic reconstructions using adaptive time-dependent intensity normalization. AB - The first processing step in synchrotron-based micro-tomography is the normalization of the projection images against the background, also referred to as a white field. Owing to time-dependent variations in illumination and defects in detection sensitivity, the white field is different from the projection background. In this case standard normalization methods introduce ring and wave artefacts into the resulting three-dimensional reconstruction. In this paper the authors propose a new adaptive technique accounting for these variations and allowing one to obtain cleaner normalized data and to suppress ring and wave artefacts. The background is modelled by the product of two time-dependent terms representing the illumination and detection stages. These terms are written as unknown functions, one scaled and shifted along a fixed direction (describing the illumination term) and one translated by an unknown two-dimensional vector (describing the detection term). The proposed method is applied to two sets (a stem Salix variegata and a zebrafish Danio rerio) acquired at the parallel beam of the micro-tomography station 2-BM at the Advanced Photon Source showing significant reductions in both ring and wave artefacts. In principle the method could be used to correct for time-dependent phenomena that affect other tomographic imaging geometries such as cone beam laboratory X-ray computed tomography. PMID- 20724792 TI - MxCuBE: a synchrotron beamline control environment customized for macromolecular crystallography experiments. AB - The design and features of a beamline control software system for macromolecular crystallography (MX) experiments developed at the European Synchrotron Radiation Facility (ESRF) are described. This system, MxCuBE, allows users to easily and simply interact with beamline hardware components and provides automated routines for common tasks in the operation of a synchrotron beamline dedicated to experiments in MX. Additional functionality is provided through intuitive interfaces that enable the assessment of the diffraction characteristics of samples, experiment planning, automatic data collection and the on-line collection and analysis of X-ray emission spectra. The software can be run in a tandem client-server mode that allows for remote control and relevant experimental parameters and results are automatically logged in a relational database, ISPyB. MxCuBE is modular, flexible and extensible and is currently deployed on eight macromolecular crystallography beamlines at the ESRF. Additionally, the software is installed at MAX-lab beamline I911-3 and at BESSY beamline BL14.1. PMID- 20724795 TI - ISAR--a story of trials with impact on practice. AB - Since its inception approximately 15 years ago, the ISAResearch group has completed more than 40 randomized controlled trials (RCT) in the field of interventional cardiology, including more than 40,000 patients. Three main principles have characterized the ISAR trials: first, simplicity: 1 question 1 answer; second, a focus on issues that are relevant for practice at the given moment and third, a strong spirit of performing industry-independent studies. The seamless integration of clinical trials into everyday practice and a stringent study discipline allowed inclusion of more than 90% of the patients in 1 of the device or drug trials, the prerequisite for fast recruitment and evaluation of an all-comers population. Moreover, the early setup and maintenance of a comprehensive database with routine follow-up of all patients undergoing percutaneous coronary intervention made it possible to build up a large registry to answer questions beyond clinical trials. Finally, the close collaboration with basic research working groups within the department has triggered new innovations and facilitated translational research from bench to bedside. PMID- 20724794 TI - Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008)--digest version. PMID- 20724796 TI - Clinical impact of glycated albumin as another glycemic control marker. AB - It is known that glycation among various proteins is increased in diabetic patients compared with non-diabetic subjects. Currently, among these glycated proteins, glycated hemoglobin (HbA(1C)) is used as the gold standard index of glycemic control in clinical practice for diabetes treatment. However, HbA(1C) does not accurately reflect the actual status of glycemic control in some conditions where plasma glucose changes during short term, and in patients who have diseases such as anemia and variant hemoglobin. In comparison, another index of glycemic control, glycated albumin (GA), more accurately reflects changes in plasma glucose during short term and also postprandial plasma glucose. Although GA is not influenced by disorders of hemoglobin metabolism, it is affected by disorders of albumin metabolism. This review summarizes diseases and pathological conditions where GA measurement is useful. These include the status of glycemic control changes during short term, diseases which cause postprandial hyperglycemia, iron deficiency anemia, pregnancy, chronic liver disease (liver cirrhosis), chronic renal failure (diabetic nephropathy), and variant hemoglobin. PMID- 20724797 TI - Plasma C-peptide level is inversely associated with family history of type 2 diabetes in Korean type 2 diabetic patients. AB - Type 2 diabetes is characterized by progressive beta-cell dysfunction. Family history of type 2 diabetes has been known to be associated with an increased risk for the development of the disease. However, few studies have evaluated the effects of family history of diabetes on residual beta-cell function in type 2 diabetic patients. We investigated associations among family histories, clinical characteristics and plasma C-peptide levels in type 2 diabetic patients. A total of 1,350 patients with type 2 diabetes were recruited. The patients with a family history of type 2 diabetes had younger age at onset of diabetes, longer diabetes duration, higher LDL-cholesterol, and lower fasting C-peptide levels than the patients without family history. When divided according to the tertiles of diabetes duration, patients with a family history of type 2 diabetes had more decreased concentrations of fasting C-peptide as duration of diabetes increased, but patients without a family history did not. Multiple regression models were used to determine the association between fasting plasma C-peptide levels and a family history of type 2 diabetes mellitus. With adjustments for age and sex, glycated hemoglobin (HbA(1C)), fasting plasma glucose, free fatty acids, body mass index and diabetes mellitus (DM) duration, there was a significant association (P < 0.01). Our results showed that a family history of diabetes was significantly associated with the progressive decline of fasting plasma C-peptide levels in Korean type 2 diabetes mellitus. PMID- 20724798 TI - Beneficial effect of berberine on hepatic insulin resistance in diabetic hamsters possibly involves in SREBPs, LXRalpha and PPARalpha transcriptional programs. AB - The "lipotoxicity" hypothesis holds that fat-induced hepatic insulin resistance (FIHIR) may play a major role in the pathogenesis of type 2 diabetes. Berberine has been reported to have antidiabetic properties. However, the molecular mechanisms for this action are not fully clarified. Therefore, we will investigate the gene expression alterations involved in the therapeutic effect of berberine on FIHIR in diabetic hamsters and possible mechanisms. In this study, type 2 diabetic hamsters were induced by high-fat diet with streptozotocin injection. After 9 weeks of berberine-treatment, the gene expression alterations involved in the therapeutic molecular mechanisms of berberine on FIHIR will be studied by microarray technology and real time RT-PCR. Our study demonstrates berberine significantly improved fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters. The alterations of certain metabolism related genes and their main regulators: Liver X receptor (LXR) alpha, Peroxisome proliferator-activated receptor (PPAR) alpha and Sterol regulatory element binding protein (SREBPs) are observed in the liver of treated and untreated diabetic hamsters. Compared with diabetic hamsters, the increased mRNA levels of LXRalpha and PPARalpha and the decreased mRNA levels of SREBPs are observed in berberine-treated diabetic hamster. The statistical significance of the expression of hepatic LXRalpha, SREBPs and PPARalpha and their certain target genes is found between treated and untreated diabetic hamsters. These results suggest that altered hepatic SREBPs, LXRalpha and PPARalpha transcriptional programs possibly involve in the therapeutic mechanisms of berberine on FIHIR in type 2 diabetic hamsters. PMID- 20724799 TI - Attenuation of cell cycle progression by 2,3,7,8-tetrachlorodibenzo-p-dioxin eliciting ovulatory blockade in gonadotropin-primed immature rats. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) reduces ovulation rate in rats. The present study was to investigate whether TCDD alters the progression of cell cycle, and thus resulting in the blockade of ovulation in gonadotropin-primed, immature rats. The ovulation rate and ovarian weight were reduced in intact rats given TCDD (32 ug/kg BW in corn oil) by gavage one day before pregnant mare's serum gonadotropin (PMSG; 5 IU/rat) injection. Flow cytometry demonstrated that the percentage of granulosa cells in S-phase was increased at 24 h following PMSG treatment, but declined at 8 h following hCG treatment in corn oil-treated rats. Interestingly, the number of S-phase cells in TCDD-treated rats was reduced 24 and 48 h following PMSG treatment. TCDD, however, increased the percentage of cells in G2/M-phase at 24 h following PMSG treatment. TCDD inhibited the mRNA levels of Cdk2 at 0 h and 24 h, and cyclin D2 at 24 h and 48 h following PMSG treatment. Protein levels of aryl hydrocarbon receptor in granulosa cells were elevated in TCDD-treated rats at 12 h and 24 h following PMSG treatment. The present study indicates that TCDD reduces S-phase cells and inhibits levels of Cdk2 and cyclin D2 at 24 h following PMSG treatment, implying the ovulation inhibiting action of TCDD may be exerted through the attenuation of cell cycle progression via AhR-mediated cascade. PMID- 20724800 TI - Serum high molecular weight adiponectin is associated with mild renal dysfunction in Japanese adults. AB - AIMS: Renal dysfunction is a major public health problem, but there have been few investigations of the relationship between serum high molecular weight (HMW) adiponectin and renal function in Japanese community-dwelling adults. METHODS: We randomly recruited a sample of 1,849 adult Japanese (793 men aged 60 +/- 14 (mean +/- standard deviation; range, 20-89) years and 1,056 women aged 62 +/- 12 (range, 21-88) years) during their annual health examination in a single community. Participants with an eGFR of >= 60 mL/min/1.73 m2 were divided into four groups based on quartiles of serum HMW adiponectin levels, and it was investigated whether serum HMW adiponectin is independently associated with eGFR. RESULTS: Mean eGFR was significantly higher in the highest quartile than the lowest quartile of serum HMW adiponectin levels. Stepwise multiple linear regression analysis using eGFR as an objective variable, adjusted for confounding factors as explanatory variables, showed that serum HMW adiponectin (beta=0.068) as well as age (beta=-0.361), prevalence of antihypertensive medication (beta= 0.115), triglycerides (beta=-0.063), low-density lipoprotein cholesterol (beta= 0.094), and fasting plasma glucose (beta=0.148) were independently associated with eGFR. The multivariate-adjusted odds ratio for mild renal dysfunction of an eGFR < 70 mL/min/1.73 m2 was 0.62 (95% CI, 0.42-0.91) for the highest quartile compared with participants with the lowest serum adiponectin quartile. CONCLUSIONS: We conclude that a higher serum HMW adiponectin level is associated with a reduced odds ratio of mild renal dysfunction in Japanese adults. PMID- 20724801 TI - Pre-procedural platelet reactivity after clopidogrel loading in korean patients undergoing scheduled percutaneous coronary intervention. AB - AIM: Pre-procedural platelet reactivity (PR) in Korean patients may be greater because the CYP2C19*2 and *3 variant alleles are more common in Korean patients than in Caucasians. We investigated the level of PR and the prevalence of high post-clopidogrel platelet reactivity (HPPR) after a routine loading dose (LD) of clopidogrel in Korean patients. METHODS: We assessed the PR level at 12 to 24 hours after a 300-mg LD of clopidogrel in 215 patients undergoing scheduled percutaneous coronary intervention (PCI) (available CYP2C19 genotyping: n =176). PR was measured by conventional aggregometry and VerifyNow. Based on a previous study, HPPR was defined as a 5 umol/L ADP-induced maximal PR >50%. RESULTS: With 5 and 20 umol/L ADP stimuli, maximal PR were 48.7 +/- 17.1% and 62.1 +/- 15.7%, respectively, and the prevalence of HPPR reached 52.1%. The highest quartile cut offs of 5 and 20 umol/L ADP-induced PR(max) were 64% and 75%, respectively. P2Y12 reaction unit (PRU) was 274 +/- 76, and 69.8% (n =150) showed PRU >=240. A carrier of at least one CYP2C19 variant allele showed higher PRs than non carriers. In multivariate regression analysis, carriage of the CYP2C19 variant allele (*2 or *3) was determined to be a significant predictor of HPPR (odds ratio 4.202, 95% confidence interval 1.996 to 8.850, p< 0.001). CONCLUSIONS: Korean patients undergoing scheduled PCI cannot achieve adequate pre-procedural platelet inhibition from a 300-mg LD of clopidogrel, which is related with a higher prevalence of the CYP2C19 mutant allele. PMID- 20724802 TI - Inhibition of P-glycoprotein-mediated efflux of digoxin and its metabolites by macrolide antibiotics. AB - This study was conducted to determine the rate of P-glycoprotein (P-gp)-mediated efflux of digoxin analogues and metabolites and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9). HPLC methods were employed to measure drug transport. All digoxin metabolites were P gp substrates, although digoxin had the greatest efflux ratio. Erythromycin had no effect on the transport of digoxin, maintaining a basolateral to apical efflux ratio of 14.8, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin by 34% and 43%, respectively. Azithromycin also had little effect on the transport of digoxin or any of its metabolites. In contrast, clarithromycin and roxithromycin almost eliminated basolateral targeted efflux. Using paclitaxel as a known P-gp substrate, erythromycin demonstrated only partial P-gp inhibitory capacity, maintaining an efflux ratio over 100. In contrast, clarithromycin and roxithromycin were 10-fold greater P-gp inhibitors. Clarithromycin and roxithromycin are likely to exhibit drug interactions with digoxin via inhibition of efflux mechanisms. Azithromycin appears to have little influence on P-gp mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin. PMID- 20724803 TI - Caulophine protects cardiomyocytes from oxidative and ischemic injury. AB - Caulophine is a new fluorenone alkaloid isolated from the radix of Caulophyllum robustum MAXIM and identified as 3-(2-(dimethylamino) ethyl)-4,5-dihydroxy-1,6 dimethoxy-9H-fluoren-9-one. Due to its new chemical structure, the pharmacological activities of caulophine are not well characterized. The present study evaluated the protective effect and the primary mechanisms of caulophine on cardiomyocyte injury. Viability of cardiomyocytes was assayed with the MTT method, and cell apoptosis was detected by flow cytometry. Myocardial infarction was produced by ligating the coronary artery, and myocardial ischemia was induced by isoproterenol in rats. Myocardial infarction size was estimated with p-nitro blue tetrazolium staining. Lactate dehydrogenase (LDH), creatine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA), and free fatty acid (FFA) were spectrophotometrically determined. Histopathological and ultrastructural changes of ischemic myocardium were observed. The results showed that pretreatment with caulophine increased the viability of H(2)O(2)- and adriamycin-injured cardiomyocytes; decreased CK, LDH, and MDA; increased SOD; and inhibited H(2)O(2) induced cellular apoptosis. Caulophine reduced myocardial infarct size and serum CK, LDH, FFA, and MDA; raised serum SOD; and improved histopathological and ultrastructural changes of ischemic myocardium. The results demonstrate that caulophine has the ability to protect cardiomyocytes from oxidative and ischemic injury through an antioxidative mechanism that provides a basis for further study and development of caulophine as a promising agent for treating coronary heart disease. PMID- 20724804 TI - Cordycepin prevents hyperlipidemia in hamsters fed a high-fat diet via activation of AMP-activated protein kinase. AB - Hyperlipidemia is a major risk factor for cardiovascular diseases. In this study, we investigated the potential effects of cordycepin (3'-deoxyadenosine), a bioactive component of the fungus Cordyceps militaris, on hyperlipidemia. We found that in male Syrian golden hamsters fed a high-fat diet (HFD), daily administration of cordycepin effectively reduced the accumulation of serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c) and suppressed HFD-associated increases in relative retroperitoneal fat. It also increased the levels of phospho-AMP-activated protein kinase (AMPK) and phospho-acetyl-CoA carboxylase (phospho-ACC) in liver and retroperitoneal adipose tissues. In HepG2 cells, cordycepin stimulated robust concentration- and time dependent AMPK activation that correlated with the activation of ACC and the suppression of lipid biosynthesis. However, pretreatment with compound C, a specific inhibitor of AMPK, substantially abolished the effects of cordycepin on AMPK activation and lipid biosynthesis inhibition. These results indicate that cordycepin prevents hyperlipidemia via activation of AMPK. Experiments on abnormal metabolic mice indicated that cordycepin can also improve insulin sensitivity effectively. PMID- 20724805 TI - Ruscogenin mainly inhibits nuclear factor-kappaB but not Akt and mitogen activated protein kinase signaling pathways in human umbilical vein endothelial cells. AB - Our previous results suggested that ruscogenin inhibited tumor necrosis factor alpha (TNF-alpha)-induced leukocyte adhesion, which correlated with its suppression of intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells. In the present studies, we further examined its effects on the main signaling pathways involved in upregulation of ICAM-1 induced by TNF-alpha in human umbilical vein endothelial cells (HUVECs). The results showed that ruscogenin significantly suppressed p65 phosphorylation, IkappaB-alpha phosphorylation and degradation, and inhibited IkappaB kinase alpha (IKKalpha) and IKKbeta activation induced by TNF-alpha. However, it exerted weak effects on TNF-alpha-induced phosphorylations of p38, JNK, ERK1/2, and Akt. Overall, our results indicated that downregulation of ICAM-1 expression by ruscogenin in HUVECs might be mediated by nuclear factor-kappaB (NF-kappaB), but not by mitogen activated protein kinase (MAPK) and Akt signaling pathways. PMID- 20724806 TI - [Early initiation of antiplatelet therapy after urological surgery : a prospective study]. AB - In recent times, the number of patients receiving antiplatelet drugs for the prevention of cardiovascular and cerebrovascular diseases has been increasing. We examined the possibility of early initiation of antiplatelet therapy after urological operations. Between April 2008 and February 2009, 62 patients who received antiplatelet drugs and underwent urological surgeries (open surgery, transurethral surgery and laparoscopic surgery) and prostate biopsies were examined. Of the 62 patients, 59 were randomized into 2 groups ; 32 patients receiving antiplatelet treatment initiation within 24 hours (early group) and 29 patients receiving this treatment more than 24 hours (late group) after the urological operation. The end point of this study was the re-cessation of antiplatelet therapy because of the development of postoperative complications (hematuria, blood loss, etc.) and cardiovascular and cerebrovascular events within 1 month. There was no significant difference in the urological events observed between these groups, including 2 of the 32 (6.3%) patients in the early group and 3 of the 27 (11.1%) in the late group. Cardiovascular and cerebrovascular diseases were not noted in any of the patients within 1 month. In conclusion, we think that it is possible to initiate antiplatelet therapy within 24 hours after urological operations and prostate biopsies in the absence of active blood loss. Early initiation may prevent the risk of cardiovascular and cerebrovascular disease in the future. PMID- 20724807 TI - [A clinical study for intravesical recurrence after surgical therapy of urotherial carcinoma of the upper urinary tract]. AB - To identify the risk factors for developing subsequent bladder carcinoma in patients undergoing surgical management of urothelial carcinoma (UC) of the upper urinary tract, we retrospectively studied 119 (median age 69, 81 males and 38 females) patients who underwent surgical resection at Yokohama Municipal Citizen's Hospital, Yokosuka Kyousai Hospital and Chigasaki Municipal Hospital from August 1980 to September 2006. After a median follow up of 37.7 months, 42 cases (35.3%) developed recurrent bladder cancer and the intravesical recurrence free survival rate at 5 years (Kaplan-Meier method) was 57.7%. Bladder cancer was significantly more common in patients who had smaller primary tumors (less than 3 cm: p0.0444) by univariate analysis. This factor was also identified as independent predictor for the intravesical recurrence by multivariated analysis (p0.0495, Hazard ratio 2.099). In 42 intravesical recurrence cases, invasive recurrence was seen in 9 cases (21.4%). Invasive recurrence appeared to occur in the patients who were older and had longer interval by intravesical recurrence. PMID- 20724808 TI - [Effect of the 5-HT3 receptor antagonist granisetron on estramustine phosphate sodium (Estracyt)-induced emesis in ferrets]. AB - Estracyt(R) is an antimitotic drug used for the treatment of prostate cancer, and its most common adverse effects are nausea and vomiting. In this study, we investigated the effect of a 5-HT3 receptor antagonist, granisetron, on emesis induced in ferrets by estramustine phosphate sodium (EMP), the active ingredient of Estracyt. To clarify the mechanism of action of EMP-induced emesis, we also investigated the effect of EMP on the release of serotonin (5-HT) in the isolated rat ileum. EMP (3 mg/kg, per os) induced 75.3+/-10.2 retching episodes and 7.5+/ 1.3 vomiting episodes during a 2-h observation period. The latency to the first emetic response was 58.0+/-13.5 min. Granisetron (0.1 mg/kg, per os) administered 1 h before the administration of EMP reduced the number of EMP-induced retching and vomiting episodes to 1.3+/-1.3 and 1.0+/-1.0, respectively, and prolonged the latency by a factor of almost two. EMP (10-5 and 10-4 M) increased 5-HT release from isolated rat ileum, and 10 -7 M granisetron almost completely inhibited the increase induced by 10-4 M EMP. These results suggest that EMP induces nausea and vomiting via 5-HT release from the ileum, and that 5-HT3 receptor antagonists may be useful to prevent gastrointestinal adverse effects that occur during treatment with Estracyt. PMID- 20724809 TI - [Initial results of transurethral enucleation with bipolar system for benign prostate hypertrophy patients]. AB - We have performed transurethral enucleation with bipolar system (TUEB) on 60 patients since April 2008. The patients were 61 to 81 years old (average 71.7 years old), and estimated prostate volumes were 25 cm3 to 80.43 cm3 (average 51.1 cm3). The weight of prostate removed was 8 g to 56 g (average 27.4 g) during the operations which lasted between 40 min to 200 min (average 117.5 min). The International Prostate Symptom Score (IPSS), quality of life index (QOL) maximum flow rate (Q max) and average flow rate (Qave) were recorded before operation, and at 1 and at 3 months after operation. The results indicated a high safety with TUEB compared to TUR-P even for beginners. In conclusion, TUEB may become the most common approach in the treatment of BPH. PMID- 20724810 TI - [A case report of retroperitoneal fibrosis associated with IgG4-related sclerosing disease]. AB - A 67-year-old man had undergone a right ureteronephrectomy because of a right ureter tumor, but the pathological diagnosis was inflammatory tissue with plasma cells, lymphocytes, and fibrosis. About 3 years later, abdominal computed tomography (CT) revealed a solid tumor at the left renal hilus. We resected the tumor and the pathological diagnosis was the same as before. More than 2 years later, because of elevated pancreatic enzymes, immunoglobulin G (IgG) and IgG4, more detailed examinations ware done, and he was diagnosed with IgG4-related autoimmune pancreatitis. We believe that the retroperitoneal tumor was retroperitoneal fibrosis associated with IgG4-related sclerosing disease. Now, he is being treated with steroid therapy. IgG4-related sclerosing disease is a systemic disease whose concept is now being established. Much more work is needed to understand this disease. PMID- 20724811 TI - [A case of giant retroperitoneal paraganglioma]. AB - Paraganglioma is a rare neuroendocrine tumor which arises from extra adrenal paraganglionic cells of the autonomic nervous system. We report a case of a giant retroperitoneal paraganglioma. A 43-year-old man referred to our hospital for further examination of a retroperitoneal mass. The patient had neither familial nor past medical history. The blood and urine test, laboratory examinations including cathecolamines, were unremarkable. Abdominal computed tomography showed an enhancing solid mass 13 cm in diameter on the left kidney. The invasion to the left kidney was suspected. Angiography showed the left renal, splenic, middle suprarenal and left inferior diaphragmatic artery feeding the tumor. The splenic and left inferior diaphragmatic artery were embolized before surgical treatment. The tumor, left kidney, adrenal gland and spleen were surgically resected. Histological examination revealed extra-adrenal paraganglioma, and there was no invasion of the tumor to the left kidney, adrenal gland and spleen. The patient has now survived more than 10 months following the surgery without tumor recurrence. PMID- 20724812 TI - [Synchronous multiple carcinosarcoma of the renal pelvis and ureter: a case report]. AB - Carcinosarcoma is a rare biphasic neoplasm, with distinct malignant epithelial and mesenchymal components. A case of carcinosarcoma arising from the upper urinary tract is very rare case. To our knowledge, only 7 cases have ever been reported in Japan. Herein we present a case of carcinosarcoma of the renal pelvis and ureter. A 64-year-old man visited our hospital with gross hematuria. Computed tomography and cystoscopy revealed multiple tumors in the right upper urinary tract and nonpapillary sessile tumor of urinary bladder. Right nephroureterocystectomy and orthotopic ileal neobladder formation were performed. The specimen showed carcinosarcoma in the renal pelvis and ureter, while only urothelial carcinoma component in the urinary bladder by immunohistochemical examination. The patient has remained without any evidence of recurrence for 18 months after operation. Carcinosarcoma has an aggressive malignant potential and poor prognosis. Effective treatment without operation has not been established so far. We recommend a radical operation as soon as possible. PMID- 20724813 TI - [ureterocele prolapse through the urethra: a case report]. AB - We report a case of prolapse of a simple ureterocele presenting as perineural tumor. A 60-year-old woman presented with perineum pain and bleeding. A physical examination revealed a hard mass, 30 mm in diameter protruding from the external meatus. The computerized tomography, magnetic resonance imaging and cystography showed an uncharacterized tumor. Endoscopic examination was performed. However, just before resection the mass collapsed spontaneously and turned out to be a prolapse of ureterocele. No transurethral incision was performed. Eleven months postoperatively, the patient has not developed vesicoureteral reflux or urinary tract infection. Physicians should consider prolapse of a simple ureterocele in the differential diagnosis of the female meatal tumor. PMID- 20724814 TI - [A case of urethrovaginal fistula caused by a foreign body in the vagina]. AB - A 25-year-old woman had a urethrovaginal fistula caused by a foreign body in her vagina. The patient had sought an appointment with a gynecologist for removal of the foreign body in her vagina. However, one day before the scheduled appointment, she developed acute urinary retention and visited the emergency room of our hospital. A urinary catheter inserted into the urethra was found to come out through the vagina. The foreign body, a bottle cap made of polypropylene and measuring 48 x 28 mm in size, was removed. A cystourethroscopic examination confirmed the presence of the urethrovaginal fistula. Repeat cystourethroscopy performed after one month of conservative management showed a persistent urethrovaginal fistula, which had, in fact, increased in size as compared with that at the initial examination. Surgery was undertaken for repair of the fistula ; fistula closure was successfully accomplished by suture in three layers : urethral wall, subcutaneous tissue, and the vaginal wall. This is the second report of a urethrovaginal fistula caused by a foreign body in the vagina. PMID- 20724815 TI - [A case of malignant lymphoma mimicking a seminal vesicle tumor]. AB - A 76-year-old man was admitted to our hospital with severe diarrhea and syncope. Abdominal computed tomography (CT) showed a mass 7 cm in diameter mimicking a seminal vesicle tumor and magnetic resonance imaging showed a heterogeneously enhanced mass with an unclear borderline to the rectum. The differential diagnosis of the lesion included a tumor arising from a seminal vesicle, a local recurrence of rectal cancer, a rectal GIST, and a mesenchymal tumor. Transrectal needle biopsy revealed non-Hodgkin's malignant lymphoma (diffuse large B cell lymphoma). Chest and abdominal CT showed no specific findings except the lesion for the seminal vesicle lesion, but positron emission tomography showed accumulations in the gastrointestinal tract, pleura, and lymph nodes. The patient was thus determined to have stage IV malignant lymphoma and was given two courses of combination chemotherapy including RCHOP. The tumor responded to one course, but the patient died of neutropenic sepsis during the second course. PMID- 20724816 TI - [A case of Down's syndrome associated with recurrent testicular tumor treated by chemotherapy successfully: review of 41 cases in Japanese literature]. AB - A 35-year-old male patient with Down' s syndrome received radical inguinal orchitectomy for left testicular tumor in 2006. Histological examination revealed a typical seminoma. 18 months after the operation, we found a metastasis in the right retroperitoneum lymph node. He received adjuvant chemotherapy (bleomycin, etoposide, and cisplatin : BEP). After 3 cycles of chemotherapy, the tumor disappeared. There is no obvious re-occurrence sign and general condition is good after chemotherapy. As we treated a relapse of seminoma in Down's syndrome successfully, we report this case and review 41 cases in Japanese literatures. PMID- 20724817 TI - Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. AB - A half century ago, the antagonistic pleiotropy (AP) theory had solved a mystery of aging, by postulating genes beneficial early in life at the cost of aging. Recently it was argued however that there are very few clear-cut examples of antagonistically pleiotropic (AP) genes other than p53. In contrast, here I discuss that p53 is not a clear-cut example of AP genes but is rather an aging suppressor (gerosuppressor). In contrast, clear-cut examples of AP genes are genes that encode the TOR (target of rapamycin) pathway. TOR itself is the ultimate example of AP gene because its deletion is lethal in embryogenesis. Early in life the TOR pathway drives developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases. PMID- 20724818 TI - Transgenerational response to stress in Arabidopsis thaliana. AB - Plants exposed to stress pass the memory of exposure to stress to the progeny. Previously, we showed that the phenomenon of transgenerational memory of stress is of epigenetic nature and depends on the function of Dicer-like (DCL) 2 and DCL3 proteins. Here, we discuss a possible role of DNA methylation and function of small RNAs in establishing and maintaining transgenerational responses to stress. Our new data report that memory of stress is passed to the progeny predominantly through the female rather than male gamete. Possible evolutionary advantages of this mechanism are also discussed. PMID- 20724820 TI - Autophagic degradation of an oncoprotein. AB - Acute promyelocytic leukemia (APL) is characterized by a chromosomal t(15;17) translocation that fuses the gene encoding the promyelocytic leukemia protein (PML) to that encoding retinoic acid receptor alpha (RARA). The product of this genetic aberration, the PML/RARA fusion protein, is highly oncogenic and supports malignant transformation and growth of hematopoietic precursor cells at the promyelocytic stage of differentiation. Successful treatment of APL by all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) depends on the ability of these drugs to induce proteolytic degradation of this chimeric protein. In a recently published study we demonstrate that PML/RARA is amenable for degradation by autophagy and that ATRA- and ATO-induced PML/RARA degradation is autophagy dependent. Consequently, autophagic degradation regulates basal turnover as well as therapy-induced elimination of this oncoprotein. In addition, our study reveals an important role of autophagy in promoting granulocytic differentiation of APL cells. PMID- 20724819 TI - The fate of metaphase kinetochores is weighed in the balance of SUMOylation during S phase. AB - Genetic evidence suggests that conjugation of Small Ubiquitin-like Modifier proteins (SUMOs) plays an important role in kinetochore function, although the mechanism underlying these observations are poorly defined. We found that depletion of the SUMO protease SENP6 from HeLa cells causes chromosome misalignment, prolonged mitotic arrest and chromosome missegregation. Many inner kinetochore proteins (IKPs) were mis-localized in SENP6-depleted cells. This gross mislocalization of IKPs is due to proteolytic degradation of CENP-I and CENP-H via the SUMO targeted Ubiquitin Ligase (STUbL) pathway. Our findings show that SENP6 is a key regulator of inner kinetochore assembly that antagonizes the cellular STUbL pathway to protect IKPs from degradation during S phase. Here, we will briefly review the implications of our findings and present new data on how SUMOylation during S phase can control chromosome alignment in the subsequent metaphase. PMID- 20724821 TI - Autophagy, proteases and the sense of balance. AB - The knowledge of the molecular mechanisms underlying autophagy has considerably improved after the isolation and characterization of autophagy-defective mutants in the yeast Saccharomyces cerevisiae. Two ubiquitin-like conjugation systems are required for yeast autophagy. One of them requires the participation of Atg8 synthesized as a precursor protein, which is cleaved after a Gly residue by a cysteine proteinase called Atg4. The new Gly-terminal residue from Atg8 is activated by Atg7 (an E1-like enzyme) then transferred to Atg3 (an E2-like enzyme) and finally conjugated with membrane-bound phosphatidylethanolamine (PE) through an amide bond. The complex Atg8-PE is also deconjugated by the protease Atg4, facilitating the release of Atg8 from membranes. This modification system, which is essential for the membrane rearrangement dynamics that accompany the initiation and execution of autophagy, is conserved in higher eukaryotes including mammals. We have previously identified and cloned the four human orthologues of the yeast proteinase Atg4, whereas parallel studies have revealed that there are at least six orthologues of yeast Atg8 in mammals (LC3A, LC3B, LC3C, GABARAP, ATG8L/GABARAPL1 and GATE-16/GABARAPL2). Thus, in mammals, the Atg4 Atg8 proteolytic system is composed of four proteinases (autophagins) that may target at least six distinct substrates, contrasting with the simplified yeast system in which one single protease cleaves a sole substrate. Currently, it is unclear why mammals have developed this array of closely related enzymes, as other essential autophagy genes such as Atg3, Atg5 or Atg7 are represented in mammalian cells by a single orthologue. It has been suggested that the multiplication of Atg4 orthologues may reflect a regulatory heterogeneity of functionally redundant proteins or, alternatively, derive from the acquisition of new functions that are not related to autophagy. Our first approach to elucidate this question was based on the generation of autophagin-3/Atg4C-deficient mice, which, however, presented a minor phenotype. With the generation of autophagin 1/Atg4B-deficient mice, recently reported, we have progressed in our attempt to identify the in vivo physiological and pathological roles of autophagins. PMID- 20724822 TI - A novel class of anti-IL-12p40 antibodies: potent neutralization via inhibition of IL-12-IL-12Rbeta2 and IL-23-IL-23R. AB - While current therapeutic antibodies bind to IL-12 and IL-23 and inhibit their binding to IL-12Rbeta1, we describe a novel antibody, termed 6F6, that binds to IL-12 and IL-23 and inhibits the interaction of IL-12 and IL-23 with their cognate signalling receptors IL-12Rbeta2 and IL23R. This antibody does not affect the natural inhibition of the IL-12/23 pathway by the antagonists monomeric IL 12p40 and IL-12p80, which suggests that a dual antagonist system is possible. We have mapped the epitope of 6F6 to domain 3 of the p40 chain common to IL-12 and IL-23 and demonstrate that an antibody bound to this epitope is sufficient to inhibit engagement of the signalling receptors. Antibodies with this unique mechanism of inhibition are potent inhibitors of IL-12 induced IFN-gamma production and IL-23 induced IL-17 production in vitro, and in an in vivo model of psoriasis, treatment with a humanized variant of this antibody, h6F6, reduced the inflammatory response, resulting in decreased epidermal hyperplasia. We believe that this new class of IL-12/23 neutralising antibodies has the potential to provide improved potency and efficacy as anti-inflammatory agents, particularly in diseases characterized by an overproduction of IL-12. PMID- 20724823 TI - Glutaminolysis yields a metabolic by-product that stimulates autophagy. AB - Autophagy is an intracellular degradative pathway that plays key roles in the homeostatic turnover of long-lived or damaged proteins and organelles, and in the survival of cells during starvation or other stressful conditions. We have uncovered an unexpected link between glutamine (Gln) metabolism and the regulation of autophagy. Our findings indicate that ammonia, generated from Gln deamination in mitochondria, functions as an autocrine- and/or paracrine-acting stimulator of autophagic flux. PMID- 20724824 TI - Comparisons of early transcriptome responses to low-oxygen environments in three dicotyledonous plant species. AB - Waterlogging is a serious impediment to crop productivity worldwide which acts to reduce oxygen levels in the rhizosphere due to the low diffusion rate of molecular oxygen in water. Plants respond to low oxygen through rapid and specific changes at both the transcriptional and translational levels. Transcriptional changes to low-oxygen (hypoxia) stress have been studied in a number of plant species using whole genome microarrays. Using transcriptome data from root tissue from early time points (4-5 h) from cotton (Gossypium hirsutum), Arabidopsis and gray poplar (Populus x canescens), we have identified a core set of orthologous genes that responded to hypoxia in similar ways between species, and others that showed species specific responses . Responses to hypoxia were most similar between Arabidopsis and cotton, while the waterlogging tolerant poplar species exhibited some significant differences. PMID- 20724825 TI - The dark side of the mycorrhiza. AB - Plant association with arbuscular mycorrhizal (AM) fungi is usually regarded as mutualistic. However, this positive effect could disappear if the benefit of the fungal-plant association changes with colonization density. In order to test the conditionality of this interaction, we evaluated plant performance and tolerance to defoliation across five levels of commercial AM fungal inoculum concentrations. Additionally, we evaluated if plant performance and tolerance were similarly affected by a whole soil community collected under a native congener. Along the gradient of inoculation, plant performance exhibited a peak at intermediate inoculum concentration, indicating the presence of an optimum level of AM fungal concentration that maximized AM fungal benefit. Root colonization by fungal hyphae increased linearly across the experimental inoculation gradient. Paralleling root colonization, plant tolerance to defoliation decreased linearly along the inoculum gradient. Plant performance was similar under the whole soil and commercial treatments. Our results show a negative correlation between tolerance to defoliation and AM fungal inoculum concentration, indicating that AM fungi colonization could constrain the evolution of plant tolerance to herbivory. PMID- 20724826 TI - Palmate-like pentafoliata1 encodes a novel Cys(2)His(2) zinc finger transcription factor essential for compound leaf morphogenesis in Medicago truncatula. AB - As the primary site for photosynthetic carbon fixation and the interface between plants and the environment, plant leaves play a key role in plant growth, biomass production and survival, and global carbon and oxygen cycles. Leaves can be simple with a single blade or compound with multiple units of blades known as leaflets. In a palmate-type compound leaf, leaflets are clustered at the tip of the leaf. In a pinnate-type compound leaf, on the other hand, leaflets are placed on a rachis in distance from each other. Higher orders of complexities such as bipinnate compound leaves of the "sensitive" plant, Mimosa pudica, also occur in nature. However, how different leaf morphologies are determined is still poorly understood. Medicago truncatula is a model legume closely related to alfalfa and soybean with trifoliate compound leaves. Recently, we have shown that Palmate like Pentafoliata1 (PALM1) encodes a putative Cys(2)His(2) zinc finger transcription factor essential for compound leaf morphogenesis in M. truncatula. Here, we present our phylogenetic relationship analysis of PALM1 homologs from different species and demonstrate that PALM1 has transcriptional activity in the transactivation assay in yeast. PMID- 20724829 TI - Lgl, the SWH pathway and tumorigenesis: It's a matter of context & competition! AB - Loss of function of the neoplastic tumors suppressors, lgl, scrib and dlg or overexpression of the apical polarity components, Crumbs and atypical protein kinase C (aPKC), are associated with polarity loss and tissue overgrowth, however, the mechanism behind these effects is poorly understood. In our recent study, we showed that Lgl, aPKC and Crumbs mediate their effects on proliferation and survival via the Salvador/Warts/Hippo (SWH) tumor suppressor pathway. Loss of lgl can lead to substantial overgrowth, however the lgl mutant phenotype can be quite variable and the amount of overgrowth of the mutant tissue, its survival and ultimate fate is strongly determined by context and competition. In this extra-view we present a more detailed description of the lgl mutant phenotype and highlight the phenotypic differences between lgl and SWH pathway mutant phenotypes. In addition, we explore the role for the Jun kinase (JNK) pathway in the development of the lgl mutant phenotype. PMID- 20724827 TI - Clusters, factories and domains: The complex structure of S-phase comes into focus. AB - During S-phase of the cell cycle, chromosomal DNA is replicated according to a complex replication timing program, with megabase-sized domains replicating at different times. DNA fibre analysis reveals that clusters of adjacent replication origins fire near-synchronously. Analysis of replicating cells by light microscopy shows that DNA synthesis occurs in discrete foci or factories. The relationship between timing domains, origin clusters and replication foci is currently unclear. Recent work, using a hybrid Xenopus/hamster replication system, has shown that when CDK levels are manipulated during S-phase the activation of replication factories can be uncoupled from progression through the replication timing program. Here, we use data from this hybrid system to investigate potential relationships between timing domains, origin clusters and replication foci. We suggest that each timing domain typically comprises several replicon clusters, which are usually processed sequentially by replication factories. We discuss how replication might be regulated at different levels to create this complex organisation and the potential involvement of CDKs in this process. PMID- 20724828 TI - Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis. AB - Interactions between RNA binding proteins (RBPs) and genes are not well understood, especially in regulation of angiogenesis. The RBP HuR binds to the AU rich (ARE) regions of labile mRNAs, facilitating their translation into protein and has been hypothesized to be a tumor-maintenance gene. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness and poor prognosis for many cancers, including those of the breast. HuR controls the expression of multiple genes involved in angiogenesis including VEGFalpha, HIF1alpha and thrombospondin 1 (TSP1). We investigated the role of HuR in estrogen receptor negative (ER(-)) breast cancer. MDA-MB-231 cells with higher levels of HuR have alterations in cell cycle kinetics and faster growth. Unexpectedly, HuR overexpression significantly interfered with tumor growth in orthotopic mouse models. The putative mechanism seems to be an anti-angiogenetic effect by increasing expression of TSP1 but also surprisingly, downregulating VEGF, a target which HuR normally increases. Our findings reveal that HuR may be regulating a cluster of genes involved in blood vessel formation which controls tumor angiogenesis. An approach of modulating HuR levels may overcome limitations associated with monotherapies targeting tumor vessel formation. PMID- 20724830 TI - Fluorescent Citrine-IgG fusion proteins produced in mammalian cells. AB - Genetically encoded fluorescent antibodies are desirable for many applications in biotechnology, proteomics, microscopy, cell biology and molecular diagnostics, although efficient production of fluorescent IgGs in mammalian cells has been hampered by different and mutually incompatible secretion- and folding requirements of antibodies and green fluorescent protein-derived fluorescent entities. Here, we show that this hurdle can be overcome by generating whole antibody fusions with Citrine, a modified yellow fluorescent protein that folds properly in the endoplasmic reticulum of mammalian cells. Applying optimized connector sequences, one or more Citrine molecules can be fused to different positions of IgGs without interfering with folding, secretion or function of the fusion proteins. These proteins can be transiently expressed and purified to similar yields as unmodified antibodies using standard technologies. IgG-Citrine fusions fully retain binding specificity and affinity, and can be applied to assays that require labeled IgG. A particularly interesting feature is the pH dependency of Citrine fluorescence. This makes IgG-Citrine fusion proteins a valuable tool to track antibody target binding, internalization and subsequent intracellular trafficking to acidic compartments. PMID- 20724832 TI - Cdk5: Links to DNA damage. PMID- 20724831 TI - Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. AB - Apoptotic defects endow tumor cells with survival advantages. Such defects allow the cellular stress response to take the path of cytoprotective autophagy, which either precedes or effectively blocks an apoptotic cascade. Inhibition of the cytoprotective autophagic response shifts the cells toward apoptosis, by interfering with an underlying molecular mechanism of cytoprotection. The current study has identified such a mechanism that is centered on the regulation of caspase-8 activity. The study took advantage of Bax(-/-) Hct116 cells that are TRAIL-resistant despite significant DISC processing of caspase-8, and of the availability of a caspase-8-specific antibody that exclusively detects the caspase-8 large subunit or its processed precursor. Utilizing these biological tools, we investigated the expression pattern and subcellular localization of active caspase-8 in TRAIL-mediated autophagy and in the autophagy-to-apoptosis shift upon autophagy inhibition. Our results suggest that the TRAIL-mediated autophagic response counter-balances the TRAIL-mediated apoptotic response by the continuous sequestration of the large caspase-8 subunit in autophagosomes and its subsequent elimination in lysosomes. The current findings are the first to provide evidence for regulation of caspase activity by autophagy and thus broaden the molecular basis for the observed polarization between autophagy and apoptosis. PMID- 20724833 TI - Epidermal growth factor receptor revisited: prognostic marker or target for therapy? PMID- 20724834 TI - Actin-based mechanisms for light-dependent intracellular positioning of nuclei and chloroplasts in Arabidopsis. AB - The plant organelles, chloroplast and nucleus, change their position in response to light. In Arabidopsis thaliana leaf cells, chloroplasts and nuclei are distributed along the inner periclinal wall in darkness. In strong blue light, they become positioned along the anticlinal wall, while in weak blue light, only chloroplasts are accumulated along the inner and outer periclinal walls. Blue light dependent positioning of both organelles is mediated by the blue-light receptor phototropin and controlled by the actin cytoskeleton. Interestingly, however, it seems that chloroplast movement requires short, fine actin filaments organized at the chloroplast edge, whereas nuclear movement does cytoplasmic, thick actin bundles intimately associated with the nucleus. Although there are many similarities between photo-relocation movements of chloroplasts and nuclei, plant cells appear to have evolved distinct mechanisms to regulate actin organization required for driving the movements of these organelles. PMID- 20724835 TI - p66(shc)'s role as an essential mitophagic molecule in controlling neuronal redox and energetic tone. AB - Stroke is the leading cause of adult disability in the U.S. and is now recognized as a global epidemic. There are currently no FDA-approved drugs to block the cell death that results from oxygen and glucose deprivation. This void in clinical medicine has sparked an intense interest in understanding endogenous cellular protective pathways that might be exploited for therapeutic development. The work highlighted here describes the critical role between redox tone and energetic stress signaling in mediating mitophagy and determining neuronal cell fate following acute oxygen glucose deprivation. PMID- 20724836 TI - UVRAG mutations associated with microsatellite unstable colon cancer do not affect autophagy. AB - Reduced levels of autophagy correlate with tumorigenesis, and several inducers of autophagy have been found to be tumor suppressors. One such autophagic inducer is the Beclin 1 binding protein UVRAG, a positive regulator of the class III PI3K/Vps34 complex. UVRAG has been implicated in the formation and maturation of autophagosomes, as well as in endocytic trafficking and suppression of proliferation and in vivo tumorigenicity. In this study we show that approximately one-third of a large series of colon carcinomas with microsatellite instability (MSI) (n = 102) carry a monoallelic UVRAG mutation, leading to expression of a truncated protein, indicating that this event is involved in tumorigenesis. In order to investigate whether the high incidence of UVRAG mutation in MSI colorectal carcinomas is associated with dysfunctional autophagy we analyzed autophagy levels in several colon cancer cell lines that express wild type or mutant UVRAG protein. No reduction in autophagy was detected in cell lines expressing mutant UVRAG. Consistent with this, depletion of UVRAG in HEK cells stably expressing GFP-LC3 did not inhibit autophagy, but did decrease epidermal growth factor receptor (EGFR) degradation. Overall our results show that there is no correlation between the presence of the monoallelic UVRAG mutation and inhibition of autophagy. Thus, our data indicate that mechanisms other than autophagy contribute to the tumorigenicity of microsatellite unstable colon carcinomas with monoallelic UVRAG mutation. PMID- 20724837 TI - Nanoimaging for prion related diseases. AB - Misfolding and aggregation of prion proteins is linked to a number of neurodegenerative disorders such as Creutzfeldt-Jacob disease (CJD) and its variants: Kuru, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. In prion diseases, infectious particles are proteins that propagate by transmitting a misfolded state of a protein, leading to the formation of aggregates and ultimately to neurodegeneration. Prion phenomenon is not restricted to humans. There are a number of prion-related diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle. All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. Prion proteins were also found in some fungi where they are responsible for heritable traits. Prion proteins in fungi are easily accessible and provide a powerful model for understanding the general principles of prion phenomenon and molecular mechanisms of mammalian prion diseases. Presently, several fundamental questions related to prions remain unanswered. For example, it is not clear how prions cause the disease. Other unknowns include the nature and structure of infectious agent and how prions replicate. Generally, the phenomenon of misfolding of the prion protein into infectious conformations that have the ability to propagate their properties via aggregation is of significant interest. Despite the crucial importance of misfolding and aggregation, very little is currently known about the molecular mechanisms of these processes. While there is an apparent critical need to study molecular mechanisms underlying misfolding and aggregation, the detailed characterization of these single molecule processes is hindered by the limitation of conventional methods. Although some issues remain unresolved, much progress has been recently made primarily due to the application of nanoimaging tools. The use of nanoimaging methods shows great promise for understanding the molecular mechanisms of prion phenomenon, possibly leading toward early diagnosis and effective treatment of these devastating diseases. This review article summarizes recent reports which advanced our understanding of the prion phenomenon through the use of nanoimaging methods. PMID- 20724838 TI - Roles of calcineurin B-like protein-interacting protein kinases in innate immunity in rice. AB - Cytosolic free Ca(2+) mobilization induced by microbe/pathogen-associated molecular patterns (MAMPs/PAMPs) play key roles in plant innate immunity. However, components involved in Ca(2+) signaling pathways still remain to be identified and possible involvement of the CBL (calcineurin B-like proteins)-CIPK (CBL-interacting protein kinases) system in biotic defense signaling has yet to be clarified. Recently we identified two CIPKs, OsCIPK14 and OsCIPK15, which are rapidly induced by MAMPs, involved in various MAMP-induced immune responses including defense-related gene expression, phytoalexin biosynthesis and hypersensitive cell death. MAMP-induced production of reactive oxygen species as well as cell browning were also suppressed in OsCIPK14/15-RNAi transgenic cell lines. Possible molecular mechanisms and physiological functions of the CIPKs in plant innate immunity are discussed. PMID- 20724839 TI - Alamethicin-induced electrical long distance signaling in plants. AB - Systemic signals induced by wounding and/or pathogen or herbivore attack may be realized by either chemical or mechanical signals. In plants a variety of electrical phenomena have been described and may be considered as signal transducing events; such as variation potentials (VPs) and action potentials (APs) which propagate over long distances and hence are able to carry information from organ to organ. In addition, we recently described a new type of electrical long-distance signal that propagates systemically, i.e. from leaf to leaf, the 'system potential' (SP). This was possible only by establishing a non-invasive method with micro-electrodes positioned in sub-stomatal cavities of open stomata and recording apoplastic responses. Using this technical approach, we investigated the function of the peptaibole alamethicin (ALA), a channel-forming peptide from Trichoderma viride, which is widely used as agent to induce various physiological and defence responses in eukaryotic cells including plants. Although the ability of ALA to initiate changes in membrane potentials in plants has always been postulated it has never been demonstrated. Here we show that both local and long-distance electrical signals, namely depolarization, can be induced by ALA treatment. PMID- 20724840 TI - NFkappaB anti-apoptotic or pro-apoptotic, maybe both. PMID- 20724841 TI - Uncovering the roles of PINK1 and parkin in mitophagy. AB - Parkinson disease (PD) is the second most prevalent neurodegenerative disorder, and thus elucidation of the pathogenic mechanism and establishment of a fundamental cure is essential in terms of public welfare. Fortunately, our understanding of the pathogenesis of two types of recessive familial PDs--early onset familial PD caused by dysfunction of the PTEN induced putative kinase 1 (PINK1) gene and autosomal recessive juvenile Parkinsonism (ARJP) caused by a mutation in the Parkin gene--has evolved and continues to expand. PMID- 20724842 TI - HdmX overexpression inhibits oncogene induced cellular senescence. AB - Cellular senescence is an irreversible state of terminal growth arrest that requires functional p53. Acting to block tumor formation, induction of senescence has also been demonstrated to contribute to tumor clearance via the immune system following p53 reactivation. The Hdm2-antagonist, Nutlin-3a, has been shown to reactivate p53 and induce a quiescent state in various cancer cell lines, similar to the G(1) arrest observed upon RNAi targeting of Hdm2 in MCF7 breast cancer. In the present study we show that HdmX, a negative regulator of p53, impacts the senescence pathway. Specifically, overexpression of HdmX blocks Ras mediated senescence in primary human fibroblasts. The interaction of HdmX with p53 and the re-localization of HdmX to the nucleus through Hdm2 association appear to be required for this activity. Furthermore, inhibiting HdmX in prostate adenocarcinoma cells expressing wild-type p53, mutant Ras and high levels of HdmX induced cellular senescence as measured by an increase in irreversible b galactosidase staining. Together these results suggest that HdmX overexpression may contribute to tumor formation by blocking senescence and that targeting HdmX may represent an attractive anti-cancer therapeutic approach. PMID- 20724843 TI - TRPM7 regulates quiescent/proliferative metabolic transitions in lymphocytes. AB - A unique property of lymphocytes among all body tissues is their capacity for rapid proliferation in the context of responding to infectious challenges. Lymphocyte proliferation involves a transition from a quiescent metabolic state adjusted to maintain cellular energy homeostasis, to a proliferative metabolic state in which aerobic glycolysis is used to generate energy and biosynthetic precursors necessary for the accumulation of cell mass. Here we show that modulation of TRPM7 channel function in tumor B-lymphocytes directly induces quiescent/proliferative metabolic transitions. As TRPM7 is widely expressed outside of the immune system, our results suggest that TRPM7 may play an active role in regulating metabolic transitions associated with rapid cellular proliferation and malignancy. PMID- 20724844 TI - NDR proteins: lessons learned from Arabidopsis and animal cells prompt a testable hypothesis. AB - N-myc Down Regulated (NDR) genes were discovered more than fifteen years ago. Indirect evidence support a role in tumor progression and cellular differentiation, but their biochemical function is still unknown. Our detailed analyses on Arabidopsis NDL proteins show their involvement in altering auxin transport, local auxin gradients and expression level of auxin transport proteins. Animal NDL proteins may be involved in membrane recycling of E-cadherin and effector for the small GTPase. In light of these findings, we hypothesize that NDL proteins regulate vesicular trafficking of auxin transport facilitator PIN proteins by biochemically alterating the local lipid environment of PIN proteins. PMID- 20724845 TI - Calcium/calmodulin-regulated receptor-like kinase CRLK1 interacts with MEKK1 in plants. AB - Recently we reported that CRLK1, a novel calcium/calmodulin-regulated receptor like kinase plays an important role in regulating plant cold tolerance. Calcium/calmodulin binds to CRLK1 and upregulates its activity. Gene knockout and complementation studies revealed that CRLK1 is a positive regulator of plant response to chilling and freezing temperatures. Here we show that MEKK1, a member of MAP kinase kinase kinase family, interacts with CRLK1 both in vitro and in planta. The cold triggered MAP kinase activation in wild-type plants was abolished in crlk1 knockout mutants. Similarly, the cold induced expression levels of genes involved in MAP kinase signaling are also altered in crlk1 mutants. These results suggest that calcium/calmodulin-regulated CRLK1 modulates cold acclimation through MAP kinase cascade in plants. PMID- 20724847 TI - Recurrent corneal erosions and epithelial basement membrane dystrophy. AB - Epithelial basement membrane dystrophy, the most common hereditary anterior corneal dystrophy and considered a "category 1" dystrophy in some cases, encompasses microcystic dystrophy and other conditions affecting the epithelial basement membrane. The management of symptomatic epithelial basement membrane dystrophy includes alleviating blurred vision, treating recurrent corneal erosion, or both. Treatment of distorted vision may be as simple as prescribing lubricating drops and/or ointment, and posttrauma corneal erosion is often a limited problem that disappears over time and does not require laser or surgical treatment. This article describes treatment for more severe cases of corneal erosion, which includes mechanical debridement of the loosened epithelium. PMID- 20724846 TI - Hydrogen sulfide stimulates beta-amylase activity during early stages of wheat grain germination. AB - We recently reported that H 2S could significantly promote the germination of wheat grains subjected to aluminum (Al(3+)) stress.1 In these experiments seeds were pretreated with the H 2S donor NaHS for 12 h prior to Al(3+) stress. During this pre-incubation period we observed that H2S increased the activity of grain amylase in the absence of Al(3+). Using embryoless half grains of wheat we now show that H2S preferentially affects the activity of endosperm beta-amylase and that alpha-amylase synthesis and activity is unaffected by this treatment. PMID- 20724848 TI - Translational research in corneal epithelial wound healing. AB - PURPOSE: To review both the roles of fibronectin and the sensory neurotransmitter substance P in corneal epithelial wound healing and the clinical application of these agents to treat persistent corneal epithelial defects. RESULTS: Fibronectin is expressed at the site of corneal epithelial defects, serves as a provisional matrix for the migration of epithelial cells, and stimulates epithelial wound healing in vitro and in animal models. Eyedrops containing autologous plasma fibronectin are also effective for the treatment of persistent epithelial defects of the cornea in patients. Substance P and insulin-like growth factor-1 synergistically stimulate corneal epithelial wound healing in vitro and in animal models. Furthermore, the administration of eyedrops containing both a substance P derived peptide (FGLM-amide) and insulin-like growth factor-1-derived peptide (SSSR) is effective for the treatment of persistent epithelial defects in individuals with neurotrophic keratopathy. CONCLUSIONS: Basic research on the mechanism of corneal epithelial wound healing has the potential to lead to the development of new modes of treatment for persistent corneal epithelial defects. Clinical experience with eyedrops containing fibronectin or both FGLM-amide and SSSR has highlighted the importance of the basement membrane and neural stimuli in maintenance of the integrity of the normal corneal epithelium. PMID- 20724849 TI - Postmarket surveillance of Menicon Z rigid gas-permeable contact lenses for up to 30 days continuous wear in the United States. AB - OBJECTIVES: To evaluate the incidence of microbial keratitis associated with the use of the Menicon Z rigid gas-permeable (RGP) contact lenses (CLs) for up to 30 days continuous wear (CW). For this study, CW was defined as wearing CLs in an extended-wear modality with an average wearing time of 22 days or more. Microbial keratitis was the sole endpoint of the study safety evaluation. METHODS: Subjects who were interested in RGP lens CW were recruited for the study through 33 investigational practices. To be eligible for the study, subjects must have worn the Menicon Z lens for CW for at least 1.5 months with an average CW time of 22 days or more. Eligible wearers were then contacted at 6-month intervals for up to 24 months after enrollment to determine their typical wearing schedules and continuance of wear and to detect any problems that would be indicative of microbial keratitis. Discontinuation from the study was defined as a discontinuation of contact with or CL wear by the study participants. Study volunteers could be discontinued from the study at 6, 12, 18, or 24 months if they could not be contacted (lost to follow-up); if they were not wearing their CL for CW; or at their own request. Wearing time data collected for individuals discontinued from the study was included in the wearing time analysis. RESULTS: The study population included 507 participants, of whom 173 had discontinued by the end of study at 24 months. Lack of 22 days or more of CW was the most frequently cited reason for discontinuation and accounted for 121 of the 173 subject discontinuations. Lost to follow-up, study participant choice, and other reasons accounted for the remaining 52 subject discontinuations. Of the reported wearing times over the duration of the study, 1,275 of the 1,527 contacts resulted in reported wearing times of 22 days or more of CW. There were no findings of microbial keratitis during the study. Overall, there was a low reported rate of complications for the enrolled study participants. CONCLUSIONS: On the basis of this study, CW of the Menicon Z hyper-Dk/t RGP lens provides a safe and full-time vision correction alternative for patients who can adapt to RGP lens wear. PMID- 20724850 TI - Corneal morphogenesis during development and diseases. AB - OBJECTIVE: To review the use of genetically modified mouse lines for elucidating corneal morphogenesis during embryonic development and diseases. METHODS: Transgenesis and gene-targeting techniques were used to create doxycycline inducible mouse models (tet-On) to express transgenes or ablation of LoxP modified genes or both in corneal cells, e.g., epithelial cells, and keratocytes and periocular mesenchymal cells of neural crest origin. RESULTS: Two driver mouse lines, i.e., Krt12-rtTA and Kera-rtTA, were created, which express reverse tetracycline transcription activator (rtTA) in corneal epithelial cells and keratocytes, respectively. Bitransgenic (Krt12-rtTA/tet-o-FGF7) and triple transgenic mice (Krt12rtTA/tet-o-Cre/Ctnnb1 and Kera-rtTA/tet-o-Cre/Ctnnb1) were obtained through cross-breeding tet-o-FGF7, tet-o-Cre, and Ctnnb1 mice. On doxycycline induction, overexpression of FGF7 by corneal epithelial cells of bitransgenic Krt12-rtTA/tet-o-FGF7 mice caused nuclear translocation of beta catenin and epithelium hyperplasia resembling human ocular surface squamous neoplasia; in triple transgenic mice (Krt12rtTA/tet-o-Cre/Ctnnb1), constitutive nuclear translocation of mutant beta-catenin (loss of exon 3) leads to hyper proliferation of corneal epithelial cells; in comparison of expression of beta catenin mutant protein by migrating, periocular mesenchymal cells of Kera rtTA/tet-o-Cre/Ctnnb1 caused eyelid malformation. CONCLUSIONS: Use of genetically modified mice is of great value to study the pathophysiology of ocular surface defects resulting from genetic mutations. PMID- 20724851 TI - Optical coherence tomography for corneal diseases. AB - Anterior segment optical coherence tomography (OCT) is currently used for investigating the distribution of the corneal thickness, shape of the stromal interface after lamellar corneal surgery, association between host and corneal graft in keratoplasty, dimension of the anterior chamber, and lesions of the corneal diseases. In addition, the advances of OCT technology has enabled three dimensional imaging, tissue imaging, cell imaging, and topographic analysis. In this review, examples of tissue imaging with 840-nm spectral-domain OCT, cell imaging with full-field OCT, and corneal topographic analysis with 1,310-nm swept source OCT were introduced. PMID- 20724852 TI - Clinical findings and treatments of granular corneal dystrophy type 2 (avellino corneal dystrophy): a review of the literature. AB - OBJECTIVES: To review the literature about clinical findings and treatments of granular corneal dystrophy type 2 (GCD2). METHODS: Various literatures on clinical findings, exacerbations after refractive corneal surgery, and treatment modalities of GCD2 were reviewed. RESULTS: GCD2 is an autosomal dominant disease. Mutation of transforming growth factor beta-induced gene, TGFBI, or keratoepithelin gene in human chromosome 5 (5q31) is the key pathogenic process in patient with GCD2. Corneal trauma activates TGFBI and then it overproduces transforming growth factor beta-induced gene protein (TGFBIp), which is main component of the corneal opacity. Refractive corneal surgery is a popular procedure to correct refractive error worldwide. However, several cases about exacerbation of GCD2 after corneal refractive surgery such as photorefractive keratectomy, laser in situ keratomileusis, and laser epithelial keratomileusis have been reported. The opacities deteriorate patient's best-corrected visual acuity. Recurrence-free interval varies many factors such as the type of procedure the patient had received and the genotype of the patient. To treat the opacities in GCD2, phototherapeutic keratectomy, lamellar keratoplasty, deep lamellar keratoplasty, and penetrating keratoplasty (PKP) were used. However, the recurrence is still an unsolved problem. CONCLUSIONS: Perfect treatment of exacerbation after corneal surface ablation does not exist until now. To prevent exacerbation, refractive surgeons must do a careful preoperative examination of candidates in refractive surgeries. PMID- 20724853 TI - Meibomian gland dysfunction: the past, present, and future. AB - OBJECTIVE: To recount the historic evaluation of meibomian gland dysfunction (MGD) and describe new techniques to monitor disease and therapy. METHODS: A review of the literature regarding the description of MGD and the role of abnormalities of meibomian gland secretion in health and disease. RESULTS: Meibomian gland dysfunction is a common clinical condition and is a major cause of evaporative dry eye with associated discomfort, visual disturbance, and contact lens intolerance. Despite the early description of the anatomy and physiology of the meibomian gland, recognition of the importance of the MGD and particularly therapeutic options to treat it has been limited. CONCLUSIONS: Improved methods of spectroscopic and chemical analysis of the meibomian gland secretion in health and disease are providing a better understanding of the physical and chemical abnormalities of the meibomian gland secretions and are allowing better evaluation of medical therapies. PMID- 20724854 TI - Repeatability of measuring corneal subbasal nerve fiber length in individuals with type 2 diabetes. AB - PURPOSE: To analyze the repeatability of measuring nerve fiber length (NFL) from images of the human corneal subbasal nerve plexus using semiautomated software. METHODS: Images were captured from the corneas of 50 subjects with type 2 diabetes mellitus who showed varying severity of neuropathy, using the Heidelberg Retina Tomograph 3 with Rostock Corneal Module. Semiautomated nerve analysis software was independently used by two observers to determine NFL from images of the subbasal nerve plexus. This procedure was undertaken on two occasions, 3 days apart. RESULTS: The intraclass correlation coefficient values were 0.95 (95% confidence intervals: 0.92-0.97) for individual subjects and 0.95 (95% confidence intervals: 0.74-1.00) for observer. Bland-Altman plots of the NFL values indicated a reduced spread of data with lower NFL values. The overall spread of data was less for (a) the observer who was more experienced at analyzing nerve fiber images and (b) the second measurement occasion. CONCLUSIONS: Semiautomated measurement of NFL in the subbasal nerve fiber layer is highly repeatable. Repeatability can be enhanced by using more experienced observers. It may be possible to markedly improve repeatability when measuring this anatomic structure using fully automated image analysis software. PMID- 20724855 TI - What a study of pterygia teaches us about the cornea? Molecular mechanisms of formation. AB - Experiments were carried out in the early 1990s to investigate the cell types involved in a pterygium and to determine a possible mechanism of formation. Our first experiments used monoclonal antibodies to keratins and an associated protein (vimentin), to look at the cells that compose a pterygium. These experiments demonstrated that a pterygium is the result of an abnormal limbal basal epithelial stem cell that moves onto Bowman's layer and brings about the dissolution of this layer. More importantly, these data showed that the clear corneal epithelial cells in front of the pterygium also contained these abnormal limbal cells, which we named the pterygium cell. This demonstrated that when a pterygium is removed, a wide area of what appears to be normal epithelium must be removed to inhibit reoccurrence of the growth. Later experiments using expressed sequence tag analysis of an un-normalized unamplified complementary DNA library from surgically removed pterygia were compared with normal cornea and confirmed the role of the epithelial cells in this growth. The gene expression studies also showed that genes involved in cellular migration are stimulated, and this led to studies on polyamine analogs as inhibitors of pterygial migration. Immunohistochemical studies with antibodies to matrix metalloproteinases (MMPs) showed that it is the pterygium cell that produces the MMPs that dissolve Bowman's layer resulting in the growth stimulation of stromal fibroblasts. This led to experiments on the use of MMP inhibitors to inhibit the growth of pterygia. PMID- 20724856 TI - Evaluating corneal collagen organization using high-resolution nonlinear optical macroscopy. AB - PURPOSE: Recent developments in nonlinear optical (NLO) imaging using femtosecond lasers provides a noninvasive method for detecting collagen fibers by imaging second harmonic-generated (SHG) signals. However, this technique is limited by the small field of view necessary to generate SHG signals. The purpose of this report is to review our efforts to greatly extend the field of view to assess the entire collagen structure using high-resolution macroscopic (HRMac) imaging. METHODS: Intact human eyes were fixed under pressure, and the whole cornea (13-mm diameter) was excised and embedded in low-melting point agar for vibratome sectioning (200-300 microm). Sections were then optically scanned using a Zeiss LSM 510 Meta and Chameleon femtosecond laser (Carl Zeiss Microimaging Inc., Thornwood, NY) to generate SHG images. For each vibratome section, an overlapping series of three-dimensional data sets (466 x 466 x 150 microm) were taken, covering the entire tissue (15 mm x 6 mm area) using a motorized, mechanical stage. The three-dimensional data sets were then concatenated to generate an NLO based tomograph. RESULTS: The HRMac of the cornea yielded large macroscopic (80 megapixels per plane), three-dimensional tomographs with high resolution (0.81 microm lateral, 2.0 microm axial) in which individual collagen fibers (stromal lamellae) could be traced, segmented, and extracted. Three-dimensional reconstructions suggested that the anterior cornea comprises highly intertwined lamellae that insert into the anterior limiting lamina (Bowman's layer). CONCLUSIONS: We conclude that HRMac using NLO-based tomography provides a powerful new tool to assess collagen structural organization within the cornea. PMID- 20724857 TI - Femtosecond applications for anterior segment surgery. AB - PURPOSE: To review the currently available femtosecond lasers that are used for anterior segment surgery and to compare those lasers with mechanical microkeratomes. METHODS: The author reviewed the literature and websites of the manufacturers of femtosecond lasers to compare the hardware and software features of each system. A further review of the mechanical microkeratome literature and how these instruments compare with femtosecond lasers was performed. RESULTS: The known and published outcomes and risks of using a mechanical microkeratome are compared in tabular format with femtosecond lasers. The many applications of femtosecond laser technology for anterior segment surgery are summarized. New risks and complications associated with femtosecond lasers not found with mechanical microkeratomes are discussed. CONCLUSIONS: Femtosecond laser technology has greatly improved on the ability to perform numerous anterior segment procedures that cannot be performed with mechanical microkeratomes. The increased predictability and safety of femtosecond laser in situ keratomileusis flap creation over mechanical microkeratomes are now well accepted. PMID- 20724858 TI - Corneal endothelium--past, present, and future. AB - OBJECTIVE: To review the history of the growth in knowledge about the corneal endothelium. METHODS: Publications concerning the corneal endothelium were reviewed. RESULTS: Highpoints in the growth of knowledge about the corneal endothelium include discovery of barrier and pump functions, specular microscopy, reduction in surgical trauma, corneal preservation, and future advances. CONCLUSIONS: The highpoints in the history of the growth in knowledge about the corneal endothelium were elucidated. PMID- 20724859 TI - Functional significance of fat surrounding the orbicularis oculi muscle. PMID- 20724860 TI - Ophthalmic considerations in the management of Tessier cleft 5/9. AB - PURPOSE: To describe a patient with Tessier cleft number 5 and 9 and review the literature on the ocular impairment and management of this extremely rare anomaly. METHODS: Interventional case report and literature review. RESULTS: The literature review showed that the present patient is the second case with clefts 5/9. The ophthalmic consequences of this rare association are virtually unreported. Our case demonstrates that the presence of cleft number 9 adds a cicatricial component on the upper eyelid that severely impairs the dynamics of this lid. The corneal status of the patient was successfully managed with simultaneous upper eyelid lengthening and facial reconstruction. CONCLUSION: In order to avoid corneal perforation, simultaneous upper and lower eyelid reconstruction is mandatory in cases of cleft 5/9. The affected patients should be continuously followed in order to prevent amblyopia. PMID- 20724861 TI - Abobotulinum toxin A (Dysport) and botulinum toxin type A (Botox) for purposeful induction of eyelid ptosis. AB - Chemodervation with abobotulinum toxin A (Dysport) and botulinum toxin type A (Botox) is finding an expanding role in functional and cosmetic cases. We describe the use of chemodenervation with abobotulinum toxin A for functional corneal protection in two cases and botulinum toxin type A for facial symmetry after Bell's palsy in one patient. The first case is a 75-year-old female with a nonhealing corneal erosion in her right eye secondary to epithelial basement membrane corneal dystrophy who underwent injection of 24 units of abobotulinum toxin A to the right Muller's muscle and levator palpebrae superioris to induce a protective ptosis. The second case is a 40-year-old male with corneal decompensation in the right eye after penetrating keratoplasty who underwent similar injection at both sites. The third case is a 46-year-old Asian female with history of Bell's palsty affecting her right side and causing mild left eyelid retraction who was injected 3 units of botulinum toxin type A to her Muller's muscle for lid positioning. Chemodenervation is used in these cases to purposefully induce ptosis by careful injection to Muller's muscle and the levator palpebrae superioris for functional and cosmetic purposes. PMID- 20724862 TI - Eyelid varix with phlebolith formation, thrombus recanalization, and early intravascular papillary endothelial hyperplasia. AB - An asymptomatic, bluish-gray, movable, raised, and firm left upper eyelid mass had been present for 8 months in an 82-year-old woman. Histopathologic examination revealed a lesion restricted to the dermis and composed in part of a calcific nodule that was circumscribed by an acellular fibrous capsule. An adjacent nodule exhibited proliferating endothelial cells invading a fresh thrombus. Immunohistochemical staining revealed positivity for CD31, CD34, and CD68; D2-40 was negative, ruling out a lymphatic origin. Masson trichrome and elastic staining of deeper sections revealed recanalization of an earlier thrombus; surviving elastic fibers were discovered in the outer wall, establishing a venous source. This is the first reported case of 3 microscopically discernible events (old phlebolith, fresh intravascular endothelial hyperplasia invading a thrombus, and labyrinthine recanalization of a temporally more remote thrombus) in an eyelid varix. The clinical differential diagnosis is reviewed. PMID- 20724864 TI - Watery epiphora following DCR: the role of the lacrimal sac. PMID- 20724863 TI - Carcinoid tumor metastatic to the tarsal conjunctivae. AB - A 64-year-old woman who had been diagnosed with carcinoid tumor of the large intestine over a decade earlier presented with an acute right periorbital inflammatory reaction. On examination, 2 disc-shaped, gelatinous masses were noted on the right upper and lower tarsal conjunctivae. Excisional biopsies of these masses revealed metastatic carcinoid tumor. Her total burden of metastatic carcinoid tumor continued to increase during 2 years of follow-up, with new metastatic foci in the right choroid, in the left upper and lower eyelids, and subcutaneously in the neck and chest. Despite a comprehensive treatment approach including radionuclide therapy with the somatostatin peptide analog, Y-DOTATOC, the patient succumbed to the disease and died. The authors report an unusual case of a gastrointestinal carcinoid tumor metastatic to the tarsal conjunctivae, eyelids, choroid, and orbit. PMID- 20724865 TI - Measurement of eyebrow position from inferior corneal limbus to brow: a new technique. AB - PURPOSE: To develop a standard measure of eyebrow position for evaluation of eyebrow ptosis and to provide normative measurements for eyebrow position using this easily reproducible measure. METHODS: A noncomparative interventional case series was performed. Measurements of eyebrow position were made on 213 subjects without cosmetic or functional complaints who presented to the eye clinic for routine eye examination during a 1-year period. Measurements were taken in the primary position of gaze. Central eyebrow height was measured as the distance from the central inferior corneal limbus to the first row of mature brow hairs (ILB) under loupe magnification. Additional measurements included the distance from the upper eyelid margin to brow, margin reflex distance-1, and palpebral fissure width. RESULTS: Of the 213 subjects, 56 (26.5%) were male and 157 (73.5%) were female. Ages ranged from 5 to 80 years. Mean ILB height was 19.4 mm for males and 19.7 mm for females. The ILB was not associated with measures of eyelid height such as palpebral fissure width. There was no statistically significant difference in ILB height between males and females. However, increased ILB height was associated with increased age. African Americans had statistically significant increased mean ILB measurements compared with whites. CONCLUSIONS: Measurement of ILB height provides an accurate and easily reproducible measure of eyebrow height that may be useful in the diagnosis and treatment of conditions affecting the middle and upper face. Race, but not sex, seems to be an important consideration in proper central eyebrow position. PMID- 20724866 TI - Risk of glaucoma among patients with benign essential blepharospasm. AB - PURPOSE: Debate exists whether intraocular pressure fluctuation is a risk factor for glaucoma. Patients with benign essential blepharospasm (BEB) experience intermittent, ultra-short-term intraocular pressure elevations from frequent blinking and spastic eyelid closure. This article explores the development of incident glaucoma after BEB diagnosis. METHODS: Medicare claims files were used to identify patients with a diagnosis of BEB from 1994 to 2000. An equal-sized control group consisting of patients without BEB was created using one-to-one propensity score matching. The patients with BEB and those in the control group were followed for the development of one of the following main outcome measures: primary open angle glaucoma (POAG), closed angle glaucoma (CAG), or other glaucoma (besides POAG and CAG) over the following 2,190 days. RESULTS: There were 1,350 persons in each group, consisting of 29% men, 94% of whom were white, with a mean age of 76 years. In the unadjusted model, BEB patients did not develop POAG (hazard ratio [HR], 1.159; 95% confidence interval [CI], 0.876 1.534), CAG (HR, 1.477; 95% CI, 0.711-3.066), or other glaucoma (HR, 1.306; 95% CI, 0.904-1.886) more often than controls. Adjusting for age, gender, race, number of visits to the ophthalmologist, and other eye disease, a diagnosis of BEB did not affect the risk of POAG (HR, 1.152; 95% CI, 0.870-1.525), CAG (HR, 1.448; 95% CI, 0.696-3.015), or other glaucoma (HR, 1.296; 95% CI, 0.896-1.873). CONCLUSIONS: BEB is not a risk indicator for POAG, CAG, or other forms of glaucoma. PMID- 20724867 TI - A caruncular choristoma presenting as an eyelid mass in an infant. AB - A 7-week-old patient presented for evaluation of a congenital eyelid mass. Following surgical excision of the lesion, histopathologic diagnosis of caruncular choristoma was made. To the authors' knowledge, this is the first report of caruncular tissue presenting as an external eyelid mass. PMID- 20724868 TI - Late failure of dacryocystorhinostomy. AB - PURPOSE: The authors describe a group of patients with initially successful dacryocystorhinostomy surgery with late recurrence of epiphora. The causes of late failure and its management are documented. METHODS: A retrospective chart review of primary dacryocystorhinostomy cases was undertaken. Inclusion criteria were an initially successful primary dacryocystorhinostomy and recurrence of symptoms at least 12 months after surgery, together with clinical evidence of impaired lacrimal drainage. Patients' subsequent procedures were detailed and outcomes determined. RESULTS: Thirteen cases of late failure of dacryocystorhinostomy were identified (8 of 1,158 surgeries by A.A.M., 4 of 378 by D.S., 1 patient whose initial dacryocystorhinostomy was done by another surgeon). Most patients were female (85%), and average age at initial surgery was 57.9 years. Most cases had nasolacrimal duct obstruction as the initial cause of epiphora (10 of 13 or 76.9%). The mean time to recurrence of symptoms after initial surgery was 46.9 months (range, 15-97 months). Pre- and intraoperative findings at second lacrimal surgery identified the cause of epiphora in late failure to be common canalicular obstruction in 11 of 13 patients (84.6%). Eleven of the 13 patients avoided repeat dacryocystorhinostomy, instead undergoing probing (with or without common canalicular membranotomy/membranectomy) and silicone intubation. Twelve of the 13 patients (92.3%) remained asymptomatic at final follow-up (range, 4-131 months). CONCLUSIONS: Although late failure after primary dacryocystorhinostomy is rare, this newly described group appears to be a distinct clinical entity, with lacrimal system obstruction often occurring at the common canaliculus. In the large majority of cases, a less invasive surgical solution than repeat dacryocystorhinostomy is effective in resolving symptoms. PMID- 20724869 TI - Obtaining arterial stiffness indices from simple arm cuff measurements: the holy grail? PMID- 20724870 TI - Retinal arteriolar narrowing as marker of renal dysfunction: potential value and limitations. PMID- 20724871 TI - Electronic monitors of drug adherence: tools to make rational therapeutic decisions. PMID- 20724873 TI - Acute care surgery in evolution. AB - At the center of the development of acute care surgery is the growing difficulty in caring for patients with acute surgical conditions. Care demands continue to grow in the face of an escalating crisis in emergency care access and the decreasing availability of surgeons to cover emergency calls. To compound this problem, there is an ever-growing shortage of general surgeons as technological advances have encouraged subspecialization. Developed by the leadership of the American Association for the Surgery of Trauma, the specialty of acute care surgery offers a training model that would produce a new breed of specialist with expertise in trauma surgery, surgical critical care, and elective and emergency general surgery. This article highlights the evolution of the specialty in hope that these acute care surgeons, along with practicing general surgeons, will bring us closer to providing superb and timely care for patients with acute surgical conditions. PMID- 20724874 TI - Changing paradigms in surgical resuscitation. AB - Patients undergoing emergency surgery typically require resuscitation, either because they are hemorrhaging or because they are experiencing significant internal fluid shifts. Intravascular hypovolemia is common at the time of anesthesia induction and can lead to hemodynamic collapse if not promptly treated. Central pressure monitoring is associated with technical complications and does not improve outcomes in this population. Newer modalities are in use, but they lack validation. Fluid resuscitation is different in bleeding and septic patients. In the former group, it is advisable to maintain a deliberately low blood pressure to facilitate clot formation and stabilization. If massive transfusion is anticipated, blood products should be administered from the outset to prevent the coagulopathy of trauma. Early use of plasma in a ratio approaching 1:1 with red blood cells (RBCs) has been associated with improved outcomes. In septic patients, early fluid loading is recommended. The concept of "goal directed resuscitation" is based on continuing resuscitation until venous oxygen saturation is normalized. In either bleeding or septic patients, however, the most important goal remains surgical control of the source of pathology, and nothing should be allowed to delay transfer to the operating room. We review the current literature and recommendations for the resuscitation of patients coming for emergency surgery procedures. PMID- 20724875 TI - Damage control in trauma and abdominal sepsis. AB - Damage control surgery, initially formalized <20 yrs ago, was developed to overcome the poor outcomes in exsanguinating abdominal trauma with traditional surgical approaches. The core concepts for damage control of hemorrhage and contamination control with abbreviated laparotomy followed by resuscitation before definitive repair, although simple in nature, have led to an alteration in which emergent surgery is handled among a multitude of problems, including abdominal sepsis and battlefield surgery. With the aggressive resuscitation associated with damage control surgery, understanding of abdominal compartment syndrome has expanded. It is probably through avoiding this clinical entity that the greatest improvement in surgical outcomes for various emergent surgical problems has occurred in the past two decades. However, with its success, new problems have emerged, including increases in enterocutaneous fistulas and open abdomens. But as with any crisis, innovative strategies are being developed. New approaches to control of the open abdomen and reconstruction of the abdominal wall are being developed from negative pressure dressing therapies to acellular allograft meshes. With further understanding of new resuscitative strategies, the need for damage control surgery may decline, along with its concomitant complications, at the same time retaining the success that damage control surgery has brought to the critically ill trauma and general surgery patient in the past few years. PMID- 20724876 TI - Current trends in neurotrauma care. AB - Severe traumatic brain injury remains a significant cause of mortality and morbidity worldwide. The use of therapeutic interventions such as hypertonic saline administration and decompressive craniectomy have solid foundations and can improve outcomes, although questions remain about patient selection, optimal timing, and comparisons to other treatments. Hypothermia, while having promise, has not definitively been shown to benefit patients with traumatic brain injury, although clinical trials are underway. The use of beta-blockers in traumatic brain injury has been proposed as a neuroprotective measure, but data are lacking to support widespread clinical use. Brain tissue oxygenation monitoring is gaining widespread acceptance as a safe tool to provide additional information both to guide therapeutic interventions and to further elucidate mechanisms of secondary brain injury. Evidence is also mounting that guided therapy using brain tissue oxygenation in addition to intracranial pressure and cerebral perfusion pressure monitoring leads to better outcomes after traumatic brain injury. PMID- 20724877 TI - Compartment syndromes from head to toe. AB - Compartment syndrome is defined as the dysfunction of organs/tissues within the compartment due to limited blood supply caused by increased pressure within the compartment. The aim of this article is to introduce and discuss acute compartment syndromes that are essential for critical care physicians to recognize and manage. Various pathophysiological mechanisms (ischemia-reperfusion syndrome, direct trauma, localized bleeding) could lead to increased compartmental pressure and decreased blood flow through the intracompartmental capillaries. Although compartment syndromes are described in virtually all body regions, the etiology, diagnosis, treatment, and prevention are best characterized for three key body regions (extremity, abdominal, and thoracic compartment syndromes). Compartment syndromes can be classified as either primary (pathology/injury is within the compartment) or secondary (no primary pathology or injury within the compartment), and based on the etiology (e.g., trauma, burn, sepsis). A recently described phenomenon is the "multiple" compartment syndrome or "poly"-compartment syndrome, which is usually a complication of a severe shock and massive resuscitation. The prevention of compartment syndromes is based on preemptive open management of compartments (primary syndromes) in high-risk patients and/or careful fluid resuscitation (both primary and secondary syndromes) to limit interstitial swelling. PMID- 20724878 TI - Geriatric care in the surgical intensive care unit. AB - We describe the physiology of aging and its effect on elderly, critically ill, surgical patients. Postoperative age-specific complications and their management will be reviewed. The number of elderly persons, defined as those >65 yrs of age, is the fastest growing segment of the U.S. population. As a result, the frequency of surgery, both elective and emergent, performed on elderly patients will increase. Aging is associated with a decrease in the physiologic reserve; thus, many elderly persons are unable to compensate for the increased metabolic demands that accompany acute illness or injury. This inability to compensate leads to increased rates of postoperative complications and death. Aggressive, goal directed management in the surgical intensive care unit is beneficial for the geriatric patient. The management of the elderly, surgical, critical care patient is extremely challenging. Understanding age-related physiologic changes will help guide treatment to maximize outcome and prevent complications. PMID- 20724879 TI - Necrotizing soft tissue infections in the intensive care unit. AB - Necrotizing soft tissue infection is a severe illness that is associated with significant morbidity and mortality. It is often caused by a wide spectrum of pathogens and is most frequently polymicrobial. Care for patients with necrotizing soft tissue infection requires a team approach with expertise from critical care, surgery, reconstructive surgery, and rehabilitation specialists. The early diagnosis of necrotizing soft tissue infection is challenging, but the keys to successful management of patients with necrotizing soft tissue infection are early recognition and complete surgical debridement. Early initiation of appropriate broad-spectrum antibiotic therapy must take into consideration the potential pathogens. Critical care management components such as the initial fluid resuscitation, end-organ support, pain management, nutrition support, and wound care are all important aspects of the care of patients with necrotizing soft tissue infection. Soft tissue reconstruction should take into account both functional and cosmetic outcome. PMID- 20724880 TI - Management of the crushed chest. AB - Thoracic injuries are very common among trauma victims. This article reviews the current literature on the management of multiple aspects of the care of the patient with severe chest injury. The mechanics of chest injury are complex and varied. Chest wall injuries are the most common and noticeable manifestation of thoracic trauma. Overall morbidity and mortality are primarily determined by associated injuries. New ventilatory strategies permit oxygenation of the severely hypoxic patient. Acute pain management modalities offer the potential of decreasing associated pulmonary complications. Surgical chest wall fixation is clearly indicated in extreme cases of pulmonary herniation and chest wall disruption. There are potential benefits of surgical fixation in other settings, although further trials are needed. PMID- 20724881 TI - Difficulties in managing the surgical patient who is morbidly obese. AB - Managing patients who are morbidly obese in the intensive care unit is associated with a variety of problems uncommonly experienced with the those who are not morbidly obese. Clinicians experience a myriad of unique problems and circumstances, from the need for special beds and lifts to unusual and unknown volumes of distribution resulting in unclear drug dosing. This review examines several issues including sedation, invasive monitoring, venous thromboembolism prophylaxis, surgical infections, nutritional support, and other complications that may be of particular importance to the critically ill patient who is morbidly obese. In many cases, care is altered based on the complicating issues surrounding morbid obesity. In other cases, the presence of obesity suggests no alterations in our routine critical care delivery. A comprehensive review of the literature is undertaken, data are critically considered, and overall opinion is rendered based on the available peer-reviewed literature. In many cases, data are not available that address the specific patient population in question, so related papers (like gastric bypass data) are considered. Many issues do not have definitive answers based on randomized controlled trials, and much is left to treating clinician opinion and local practice patterns. Where good data exist, however, one should consider carefully and individually deviation from the evidence-based approach. PMID- 20724882 TI - Common complications in the surgical intensive care unit. AB - Surgical and trauma intensive care units provide the facilities, resources, and personnel needed to care for patients who have been severely injured, present with acute surgical emergencies, require prolonged and complex elective surgical procedures, or have severe underlying medical conditions. Correcting the immediately evident physiologic derangement is only the first step in the care of these patients, because in many cases their prognosis and ultimate outcome will depend on whether additional insults accrued during their intensive care unit and hospital stay will prevent them from a full recovery. The nature, number, and complexity of the interventions used to provide advanced support requires a unique attention to the concept of patient safety, particularly when the population involved is that most vulnerable to injury and with the least amount of physiologic reserve to recover from it. The medical community, the public, and even regulatory agencies have focused on specific preventable complications that are common in surgical and injured patients, such as medical errors, healthcare associated infections, and venous thromboembolism. Enough scientific knowledge has been obtained through well-conducted clinical trials to generate detailed evidence-based guidelines for the prevention and management of some of these pathologies, but still there are outstanding questions in terms of the applicability of the recommendations to the critically ill. In addition to clinical and technical expertise, performance improvement and quality monitoring activities provide direction for system solutions required to properly address many complications that are not provider specific. PMID- 20724883 TI - Alcohol withdrawal syndromes in the intensive care unit. AB - This article reviews the pathophysiology, diagnosis, and treatment of alcohol withdrawal syndromes in the intensive care unit as well as the literature on the optimal pharmacologic strategies for treatment of alcohol withdrawal syndromes in the critically ill. Treatment of alcohol withdrawal in the intensive care unit mirrors that of the general acute care wards and detoxification centers. In addition to adequate supportive care, benzodiazepines administered in a symptom triggered fashion, guided by the Clinical Institute Withdrawal Assessment of Alcohol scale, revised (CIWA-Ar), still seem to be the optimal strategy in the intensive care unit. In cases of benzodiazepine resistance, numerous options are available, including high individual doses of benzodiazepines, barbiturates, and propofol. Intensivists should be familiar with the diagnosis and treatment strategies for alcohol withdrawal syndromes in the intensive care unit. PMID- 20724884 TI - Ethical controversies at end of life after traumatic brain injury: defining death and organ donation. AB - Death is more than a mere biological occurrence. It has important legal, medical, and social ramifications that make it imperative that those who are responsible for determination of death be accurate and above suspicion. The medical and legal definitions of death have evolved to include consideration of such concepts as loss of integration of the whole organism, loss of autonomy, and loss of personhood. Development of the concept of brain death coincided with advances in medical technology that facilitated artificial ventilation and organ transplantation. More recently, the process of "timed" death with subsequent organ donation (controlled donation after cardiac death transplantation) has raised controversial questions having to do with the limits of treatments that facilitate organ transplant but might hasten death, and the duration of cardiac arrest necessary for declaration of death and the commencement of organ procurement. In this review, we discuss the background and ethical ramifications of the concepts of brain death, and of controversies involved in controlled donation after cardiac death organ transplantation. PMID- 20724886 TI - Consultative or integrative, palliative care must be part of intensive care unit care. PMID- 20724887 TI - Combination versus monotherapy for septic shock patients. PMID- 20724889 TI - Right ventricular function evaluation in acute respiratory distress syndrome: back to the future. PMID- 20724888 TI - Can one plus one ever equal three in the antibiotic therapy of sepsis? PMID- 20724890 TI - Vancomycin, unbeatable for methicillin-resistant Staphylococcus aureus hospital acquired pneumonia? Really? PMID- 20724891 TI - Assessing fluid responsiveness with the passive leg raising maneuver in patients with increased intra-abdominal pressure: be aware that not all blood returns! PMID- 20724892 TI - The Hering-Breuer reflex, feedback control, and mechanical ventilation: the promise of neurally adjusted ventilatory assist. PMID- 20724893 TI - Learner-centered simulated training: just what the patient ordered. PMID- 20724894 TI - Time to play harmoniously with other specialties. PMID- 20724895 TI - Refrain from exclusionary training. PMID- 20724898 TI - Pregnant women are at increased risk for severe A influenza because they have low serum 25-hydroxyvitamin D levels. PMID- 20724900 TI - Parenteral feeding and intensive insulin therapy. PMID- 20724901 TI - Comment on: 'Hypocapnia and the injured brain: more harm than benefit'. PMID- 20724902 TI - Pararenal splenosis encountered during the evaluation of a suspected pheochromocytoma. AB - The authors describe a patient in whom pararenal splenosis nodules were initially interpreted as probable pheochromocytoma. A 22-year-old man with chronic glomerulonephritis, hypertension and a childhood history of splenectomy was hospitalized for a hypertensive emergency. He did not improve with aggressive antihypertensive therapy. A pheochromocytoma was suspected, and a renal ultrasound and a magnetic resonance imaging showed 2 left pararenal masses. Laboratory evaluation for pheochromocytoma and aldosteronoma were negative. Biopsies of the masses were planned, but the masses were subsequently shown to be splenic tissue by a (99m)technnetium heat-damaged red blood cell scan. Ectopic splenic masses, eg, splenosis or accessory spleens, should be considered in patients with undiagnosed abdominal or kidney masses and a history of splenectomy. PMID- 20724903 TI - Management of intractable hypoglycemia with Yttirum-90 radioembolization in a patient with malignant insulinoma. AB - Metastatic insulinomas may present with recurrent life-threatening hypoglycemia. Treatment of hypoglycemia in such patients is difficult and frequently fails to respond to numerous therapeutic agents, requiring continuous dextrose infusion. The authors present our experience with Yttirum-90 radioembolization in a patient with metastatic malignant insulinoma who failed to respond to distal pancreatectomy, systemic chemotherapy with capecitabine and everolimus and medical treatment with somatostatin analogues, diazoxide and corticosteroids. Treatment with repeated Y-90 radioembolization resulted in rapid resolution of hypoglycemic events, allowing discontinuation of dextrose infusion and hospital discharge. However, the effect of Y-90 administration seems to be transient and without evidence of tumor shrinkage in imaging studies. PMID- 20724904 TI - Coronary artery phenotypes in subjects with negative myocardial perfusion imaging and typical angina pectoris. AB - INTRODUCTION: Limited data are available on coronary lesion morphology for patients with false-negative radionuclide findings together with typical angina symptoms. METHODS: The study group consisted of 25 subjects with a negative pharmacological thallium (Tl)-201 single-photon emission computed tomography perfusion imaging study but typical angina symptoms and coronary artery disease (CAD) confirmed by coronary angiography. The control group included 690 subjects with a positive pharmacological Tl-201 single-photon emission computed tomography study and CAD. RESULTS: The study group showed a significantly older and higher female ratio than the control group. Significant differences were found between the 2 groups in the presence of current smoking status and hypertension. A noticeably higher percentage of positive metabolic syndrome ratio, number of metabolic syndrome components, high waist-to-hip ratio percentage and high waist circumference percentage in the study group. The study group was noticeably lower in mean numbers of culprit vessel involvement and mean lesion numbers than the control group. There were more individuals with type A classification and a lower proportion of complex stenoses--which contain type B2 and C lesions--in the study group than in the control group. The study group had significantly fewer calcified stenoses and complex morphology stenoses--the latter of which include lesion morphologies with chronic total occlusion, diffuse and calcification--than the control group. CONCLUSIONS: For the high probability of CAD lesions that requires interventional therapy, patients with negative myocardial scintigraphy but typical angina symptoms would be beneficial to intensive medical treatment and coronary study. PMID- 20724905 TI - Reversible choreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease. AB - Neurologic manifestations, such as myoclonus, asterixis, seizures and altered level of consciousness, may be induced in patients with impaired renal function receiving beta-lactam antibiotics, which stem in part from drug accumulation because of altered pharmacokinetics. Because of its long half-life and easy penetration into the cerebrospinal fluid, the third generation cephalosporin, ceftriaxone (CTRX), is often chosen to treat patients with end-stage renal disease (ESRD). Here, the authors describe 4 patients with ESRD complicated with bacterial infection and choreoathetosis after the administration of CTRX. Choreoathetosis disappeared without leaving sequelae after CTRX therapy was withdrawn, although the severity and symptom duration varied. To our knowledge, there are few reports on choreoathetosis associated with beta-lactam antibiotic administration in patients with kidney diseases. To prevent delayed diagnosis, one should bear in mind that choreoathetosis might occur in patients with ESRD treated with CTRX, when it is given in high or even regular doses. PMID- 20724906 TI - Enhanced urinary angiotensinogen excretion in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. AB - INTRODUCTION: Previous studies have demonstrated that the urinary excretion of angiotensinogen is significantly increased in ANG II-infused hypertensive rats, which is associated with an augmentation of intrarenal ANG II levels. These findings suggest that urinary angiotensinogen excretion rates provide an index of intrarenal ANG II levels in ANG II-dependent hypertensive states. However, little information is available regarding the urinary excretion of angiotensinogen in ANG II-dependent malignant hypertension. METHODS: This study was performed to determine if urinary angiotensinogen excretion is increased in Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1aRen2)] with inducible ANG II-dependent malignant hypertension. Adult male Cyp1a1-Ren2 rats (n = 6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II dependent malignant hypertension. RESULTS: Rats induced with I3C exhibited pronounced increases in systolic blood pressure (208 +/- 7 versus 127 +/- 3 mm Hg; P < 0.001), marked proteinuria (29.4 +/- 3.6 versus 5.9 +/- 0.3 mg/d; P < 0.001) and augmented urinary angiotensinogen excretion (996 +/- 186 versus 241 +/ 31 ng/d; P < 0.01). Chronic administration of the AT1 receptor antagonist, candesartan (25 mg/L in drinking water, n = 6), prevented the I3C-induced increases in systolic blood pressure (125 +/- 5 mm Hg; P < 0.001), proteinuria (7.3 +/- 1.0 mg/d; P < 0.001) and urinary angiotensinogen excretion (488 +/- 51 ng/d, P < 0.01). CONCLUSIONS: These data demonstrate that the urinary excretion of angiotensinogen is markedly augmented in ANG II-dependent malignant hypertension. Such increased urinary angiotensinogen excretion may contribute to augmented intrarenal ANG II levels and, thereby, to the increased blood pressure in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. PMID- 20724907 TI - Genetic polymorphisms in apolipoprotein E and glutathione peroxidase 1 genes in the Ecuadorian population affected with Alzheimer's disease. AB - INTRODUCTION: The main objective of this study is to determine the prevalence of apolipoprotein E (Apo E) and glutathione peroxidase 1 (GPX1) polymorphisms and their influence on the development of Alzheimer disease (AD) in the Ecuadorian population. METHODS: The authors performed an analytic transversal case-control study. The study group (n = 39) consisted of patients with AD and dementia. The control group (n = 39) comprised elderly adults who have not been diagnosed with dementia and have the same age and education as the study group. Their inclusion period was from 2007 to 2008. Later on, after obtaining informed consent and after finishing a structural interview; the next step forward was to collect blood and extract DNA by standardized protocols. Besides, the authors performed polymerase chain reaction-restriction fragment length polymorphism technique to determine the genotype of each individual. RESULTS: The authors found a positive association between epsilon4 and epsilon2 alleles of Apo E. The GPX1 gene shows an association of leu allele, whereas pro allele shows a negative association. The odds ratio test shows no significant relative risk. CONCLUSIONS: Apo E is not a risk factor, nor a protective one for AD, whereas the leu allele of GPX1 is a possible risk factor for the disease. PMID- 20724909 TI - Recurrent Lower Extremity Pseudocellulitis. AB - The term "Pseudocellulitis" can be used to describe an uncomplicated nonnecrotizing inflammation of the dermis and hypodermis from a noninfectious etiology. Chemotherapeutic agents have been associated with a variety of cutaneous reactions, including radiation recall dermatitis, hypersensitivity reactions, and erysipeloid reactions. Gemcitabine (2,2-difluorodeoxycytidine) is currently being used for treatment of a variety of solid malignancies, including carcinoma of the lung. The dermatitis involved with gemcitabine is typically a radiation recall reaction whereby an inflammatory reaction occurs in the area previously treated with radiotherapy. We describe here a case of Gemcitabine induced pseudocellulitis that was unrelated to radiation exposure and manifested in an area of lymphedema. The pseudocellulitis in such cases could be related to the drug's pharmacokinetics and may last until the drug is displaced from the subcutaneous tissue of the affected area. Antibiotics have no role in the treatment, and diphenhydramine with nonsteroidal anti-inflammatories may be used for symptomatic management. PMID- 20724908 TI - Diagnosis and treatment of pulmonary tuberculosis in hospitalized patients are affected by physician specialty and experience. AB - INTRODUCTION: Healthcare system delays in the diagnosis of tuberculosis can increase the risk of its nosocomial transmission. We aimed to determine whether different physicians' specialties and experience influenced this diagnostic delay. METHODS: We retrospectively reviewed the cases of 167 patients with smear positive pulmonary tuberculosis who were hospitalized from September, 2004, to August, 2006, for 5 components of healthcare system delays according to the World Health Organization definitions and analyzed the impact of physicians' specialties and their experience (annual number of patients treated for tuberculosis) on these delays. RESULTS: The median suspicion delay was significantly longer for patients in surgical departments than those in medical departments (4 days versus 1 day, P = 0.001) and for patients treated by nontuberculosis specialists than those treated by tuberculosis specialists (including pulmonologists, infectious diseases specialists and thoracic surgeons; 3 days versus 1 day, P < 0.001). Both were independent factors related to suspicion delay examined by multivariate analysis. The annual number of tuberculosis patients in each department had a significant negative correlation with suspicion delay (r = -0.303, P < 0.001). CONCLUSIONS: Patients treated by surgeons and nontuberculosis specialists who were inexperienced in treating tuberculosis experienced a longer suspicion delay. Enhancing knowledge about tuberculosis among all physicians in the hospital, encouraging staff to consult tuberculosis specialists to confirm a diagnosis and implementing early alarm systems are crucial to improving the correct diagnosis of tuberculosis and to reducing delays in treatment. PMID- 20724910 TI - Management of F/P+/- hypereosinophilic syndromes: case report and treatment review. AB - Eosinophilia in clinical practice can occur due to various pathologic processes. Causes of eosinophilia include idiopathic eosinophilia, reactive eosinophilia, idiopathic hypereosinophilic syndrome (HES), chronic eosinophilic leukemia, and other hematopoietic neoplasms (myeloid, lymphatic, or mast cell). We present a case of a 22-year-old man with HES with remarkable clinical manifestations and treatment challenges. PMID- 20724911 TI - Hydralazine-induced pulmonary-renal syndrome: a case report. AB - Drug-induced lupus erythematosus differs in its manifestation from drug-induced vasculitis. The former is associated with characteristic symptoms that improve following discontinuation, whereas the latter is predominantly an antineutrophil cytoplasmic antibody (ANCA) positive small vessel vasculitis involving the kidneys, skin, and lungs. We present a case of advanced disease in an elderly Caucasian woman requiring corticosteroids, and immunosuppressive therapy, who was on hydralazine for >2 years. PMID- 20724912 TI - Delayed onset of clozapine-induced leucopenia. AB - Clozapine has been reported to cause agranulocytosis, neutropenia, and leucopenia that usually occur within 18 weeks of initiation of treatment. We report a case of delayed onset leucopenia after 11 years of treatment with clozapine, which reversed within a few days after discontinuation of medication. PMID- 20724913 TI - Effect of cyclodextrin infusion in a rat model of verapamil toxicity. AB - Sulfobutylether-beta-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. After intravenous administration, clearance of SBE-CD approximates glomerular filtration rate. We hypothesized that SBE-CD would complex with verapamil in vivo, enhance renal elimination, and increase time to death in a rat model of verapamil toxicity. Ten Wistar rats were allocated to control or intervention groups. All received isoflurane anesthesia followed by verapamil infusion (32 mg/kg) over 1 hour. The control group received saline bolus 7.5 mL/kg at 5 minutes. The intervention group received SBE-CD infusion 7.5 mL/kg (2.25 g/kg) at 5 minutes. Heart rate, respiratory rate, oxygen saturation, and temperature were monitored. The primary endpoint was time to death measured separately as time to asystole and time to apnea. There was no benefit derived from cyclodextrin infusion. Average time to death was significantly longer in the control group as measured by time to apnea (P < 0.05). Control group survival was significantly better as measured by time to asystole and time to apnea (Breslow P < 0.05). SBE-CD infusion resulted in a shorter time to death measured by time to apnea and asystole. Preliminary work demonstrated no effect in isoflurane anesthetized rats receiving only SBE-CD bolus. Verapamil poisoned rats treated with 2.25 g/kg of SBE-CD showed increased toxicity. We propose that this effect was related to the large hyperosmolar CD infusion combined with verapamil-induced cardiogenic shock. Additional studies are warranted to clarify the mechanism of increased toxicity in our study and to assess for potential beneficial effects at lower SBE-CD concentrations. PMID- 20724914 TI - Effect of bicarbonate on neonatal serum ionized magnesium in vivo. AB - Sodium bicarbonate is used to treat metabolic acidosis or to induce metabolic alkalosis in sick neonates. The aim of this study was to quantify the decrease in serum concentration of ionized magnesium ([Mg(2+)]) when sodium bicarbonate is administered in vivo. We administered 1 mEq/kg body weight sodium bicarbonate 4.2% for correction of metabolic acidosis (n = 11) for management of persistent pulmonary hypertension (n = 3). After sodium bicarbonate treatment, serum pH increased by an average of 0.046 (P < 0.001), serum [Mg(2+)] decreased by an average of 0.07 mmol/L (P < 0.01), and serum [Ca(2+)] decreased by an average of 0.06 mmol/L (P = 0.04). There was a significant correlation between baseline [Mg(2+)] and baseline [Ca(2+)] (R(2) = 0.328, P = 0.032). Sodium bicarbonate therapy in infants causes a significant decrease in [Mg(2+)] and serum [Ca(2+)]. We suggest that infusion of sodium bicarbonate be effected while monitoring serum [Mg(2+)] and serum [Ca(2+)]. PMID- 20724915 TI - Clotrimazole induces a late G1 cell cycle arrest and sensitizes glioblastoma cells to radiation in vitro. AB - Tumor cells are characterized by their high rate of glycolysis and clotrimazole has been shown to disrupt the glycolysis pathway thereby arresting the cells in the G1 cell cycle phase. Herein, we present data to support our hypothesis that clotrimazole arrests tumor cells in a radiosensitizing, late G1 phase. The effects of clotrimazole were studied using the glioblastoma cell line, U-87 MG. Flow cytometry was used to analyze cell cycle redistribution and induction of apoptosis. Immunoblots were probed to characterize a late G1 cell cycle arrest. Nuclear and cytoplasmic fractions were collected to follow the clotrimazole induced translocation of hexokinase II. Clonogenic assays were designed to determine the radiosensitizing effect by clotrimazole. Our studies have shown a dose-dependent and time-dependent clotrimazole arrest in a late G1 cell cycle phase. Concurrent with the late G1 arrest, we observed an overexpression of p27 along with a decreased expression of p21, cyclin-dependent kinase 1, cyclin dependent kinase 4, and cyclin D. Clotrimazole induced the translocation of mitochondrial-bound hexokinase II to the cytoplasm and the release of cytochrome c into the cytoplasm. Clotrimazole-induced apoptosis was enhanced when combined with radiation. Clotrimazole was shown to sensitize tumor cells to radiation when the cells were irradiated for 18 h post-clotrimazole treatment. The disruption of the glycolysis pathway by clotrimazole leads to cell cycle arrest of U-87 MG cells in the radiosensitizing late G1 phase. The use of clotrimazole as a radiosensitizing agent for cancer treatment is novel and may have broad therapeutic applications. PMID- 20724916 TI - 3,3'-Diindolylmethane negatively regulates Cdc25A and induces a G2/M arrest by modulation of microRNA 21 in human breast cancer cells. AB - 3,3'-Diindolylmethane (DIM) is a potential chemopreventive phytochemical derived from Brassica vegetables. In this study, we assessed the effects of DIM on cell cycle regulation in both estrogen-dependent MCF-7 and estrogen receptor negative p53 mutant MDA-MB-468 human breast cancer cells. In-vitro culture studies showed that DIM dose dependently inhibited the proliferation of both cells. In addition, in-vivo xenograft model showed that DIM strongly inhibited the development of human breast tumors. Fluorescence activated cell sorter analysis showed a DIM mediated G2/M cell cycle arrest in MCF-7 and MDA-MB-468 cells. Western blot analysis showed that DIM downregulated the expression of cyclin-dependent kinases 2 and 4 and Cdc25A, which plays an important role in G2/M phase. Furthermore, treatment of MCF-7 cells with DIM, which increased microRNA 21 expression, caused a downregulation of Cdc25A, resulting in an inhibition of breast cancer cell proliferation. Taken together, our data show that DIM is able to stop the cell cycle progression of human breast cancer cells regardless of their estrogen dependence and p53 status, by differentially modulating cell cycle regulatory pathways. The modulation of microRNA 21 mediates the DIM cell cycle regulator effect in MCF-7 cells. PMID- 20724917 TI - Isoprenoid geranylgeranylacetone inhibits human colon cancer cells through induction of apoptosis and cell cycle arrest. AB - Geranylgeranylacetone (GGA), an isoprenoid compound, is a widely used antiulcer drug developed in Japan. GGA is structurally similar to plaunotol and geranylgeraniol, another isoprenoid reported to exert strong anticancer effects. In an earlier study, GGA was shown to inhibit ovarian cancer invasion by attenuating not only Rho activation, but also Ras-MAPK activation. In this study, we aimed to test whether GGA could have a therapeutic effect on colon cancer cells. As a result, we found that GGA induced a dose-dependent decrease in the proliferative activity through induction of cell apoptosis and cell cycle arrest in the G1 phase. The induction of apoptosis was mediated by the activation of both caspase-8 and caspase-9 pathways. The induction of G1 arrest was mediated by the increase of p21 and p27, and also the decrease of phosphorylated retinoblastoma protein levels. This study showed the potential anticancer activity of GGA. As this drug is already available in Japan for clinical use as an antiulcer/antigastritis agent, clinical trials will be designed to confirm its potential usefulness for cancer patients. PMID- 20724918 TI - Development and characterization of a JAK-2-specific antibody suitable for immunohistochemical investigative studies. AB - Janus kinases (JAKs) are tyrosine kinases called JAK-1, JAK-2, JAK-3, and Tyk-2, which have been shown to participate in the signaling pathways of several cytokines that are believed to play a key role in several autoimmune-mediated disorders including rheumatoid arthritis (RA). However, the availability of JAK specific antibodies to be used in investigative efficacy studies in RA models is very limited. Therefore, in this study we developed and characterized a JAK-2 specific antibody that was used to evaluate its immunohistochemical expression in the joints of a rat adjuvant-induced arthritis (rAIA) RA preclinical model. An immunogen peptide sequence design was used to generate JAK-2-specific mouse, rat, and human polyclonal antibodies. JAK-2 plasmid cDNA was then generated and HEK293 transfected cell lines, gel electrophoresis, immunoblotting, and immunohistochemistry were used to further characterize the generated JAK-2 antibodies. We show that the generated JAK-2 antibody exhibits specificity and lacks cross-reactivity to JAK-1 and JAK-3. In addition, marked JAK-2 expression is shown in the rAIA in mixed inflammatory cells (macrophages and neutrophils), mast cells, and bone marrow elements. In conclusion, we show the development and characterization of a JAK-2-specific antibody that can be used in investigative and mechanistic studies such as preclinical efficacy models. PMID- 20724919 TI - Nuclear survivin is associated with malignant potential in epithelial ovarian carcinoma. AB - Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family. As abnormal inhibition of apoptosis during homeostasis is considered a critical step in the initiation of cancer, we investigated prognostic value of survivin expression in epithelial ovarian carcinomas. We carried out immunohistochemical experiments using a polyclonal antisurvivin antibody to stain formalin-fixed paraffin-embedded sections from 91 patients with ovarian tumors, including 10 cystadenomas, 17 borderline tumors, and 64 epithelial ovarian carcinomas. Nuclear and cytoplasmic survivin staining was scored separately. Survivin expression was undetectable in ovarian cystadenomas and was weakly detected in 4 of 17 (23.53%) borderline tumors. In contrast, nuclear and cytoplasmic survivin staining was observed in 55 of 64 (85.94%) epithelial ovarian carcinomas. Scoring on the basis of the percentage of survivin nuclear-positive cells indicated that nuclear survivin expression was associated significantly with clinical stage, histologic grade, proliferating cell nuclear antigen (PCNA)-labeling index, and clinical outcome in ovarian epithelial carcinoma patients (P<0.01). Taken together, the results of this study provide evidence that nuclear survivin expression is a strong, independent prognostic marker for poor clinical outcomes in epithelial ovarian carcinoma. PMID- 20724920 TI - Expression of 6 common antigenic markers in invasive ductal breast carcinoma: potential clinical implications. AB - Expression of estrogen (ER) and progesterone receptors, c-erbB-2 oncogene, mutant p53 antioncogene (mp53), e-cadherin adhesion, and apoptotic caspase-8 antigens in tumor relative to matched normal tissue specimens from 102 unselected patients with primary ductal breast carcinoma of various tumor grades was assessed by immunohistochemistry and correlated with patient's biologic and clinical features, such as age, menstrual status, age of menarche, tumor grade and diameter, the presence or absence of metastases, and number of infiltrated lymph nodes. We observed association of e-cadherin adhesion, ER and progesterone antigen marker expression with low histologic grade tumors and limited number of lymph node metastases and of c-erbB-2, mp53, and casp-8 antigen marker expression with high histologic grade tumors and increased number of lymph node metastases. We also observed strong correlation (P<0.05) between 4 of the 6 biomarkers and 4 of the 7 patient/tumor parameters examined. Our findings support the hypothesis of independent expression of these 4 strong biomarkers and reveal that nearly 40% of all breast tumor cases studied express similar proportions of 2 major phenotypic combinations [ER/c-erbB-2/mp53/casp-8: +/+/-/+ (19.6%) & +/-/-/+ (17.8%)]. We conclude that, in agreement with earlier reports, our findings support the diagnostic and potential prognostic value of these markers in the clinical assessment of breast cancer. PMID- 20724921 TI - The ocular surface in thyroid diseases. AB - PURPOSE OF REVIEW: The purpose of the present review is to describe recent insights into the pathomechanism of ocular surface impairment in the course of thyroid dysfunctions. The review focuses in particular on Graves' ophthalmopathy as the majority of the literature is published on this topic. RECENT FINDINGS: Mechanical factors were thought, until now, to be the indirect causes of ocular surface function failure. In particular, eyeglobe bulging and upper eyelid retraction with consequent eyelid fissure width increase were mainly considered responsible for increased exposed area and ocular surface impairment. Recent evidence demonstrated that ocular surface tissues are direct targets for autoantibodies in either hypothyroid or hyperthyroid states. A set of tear protein biomarkers were identified and shown to have high diagnostic performance. SUMMARY: New horizons can be displayed on the basis of these new findings, in particular, as referred earlier, Graves' ophthalmopathy diagnosis. A detailed slit-lamp examination and a careful medical history by validated questionnaires in patients with ocular surface discomfort symptoms are now recommended to investigate early manifestations of an underlying thyroid dysfunction. Ocular surface signs should also be included in professional guidelines. Autoantibody assays in tears and proteomic analysis of tear protein expression could be important further steps in early diagnosis and posttherapy control of thyroid dysfunction. PMID- 20724923 TI - Unraveling the complex genetic underpinnings of asthma and allergic disorders. AB - PURPOSE OF REVIEW: Asthma and other allergic diseases are complex genetic disorders that result from interactions between multiple genes and environmental factors. In this review, we summarize findings from candidate gene analyses, discuss the recent success of genome-wide association (GWA) studies, and outline challenges facing the field. RECENT FINDINGS: In the past year, five GWA studies have been reported for asthma, one for atopic dermatitis, and four for intermediate phenotypes using quantitative trait loci. These results have in general been more robust to replication than prior candidate gene studies, and have allowed the identification of novel loci for both asthma (i.e. 1q31, 9q21.31) and atopic dermatitis (11q13). SUMMARY: The integration of results from recent GWA studies with careful analyses of candidate gene associations studies has confirmed the importance of immune detection and TH2-cell mediated immune responses in the pathogenesis of allergic disease, and has raised new interest in the role of epithelial barrier function and tissue-level responses. GWA studies appear to provide a robust way to identify novel gene loci contributing to disease susceptibility. Dissecting gene-gene and gene-environment interactions, and exploring the contribution of epigenetic phenomena to allergic disease susceptibility remain important challenges to understanding the complex nature of asthma and other allergic diseases. PMID- 20724924 TI - What is pediatric gynecology? PMID- 20724922 TI - Genomewide association studies in allergy and the influence of ethnicity. AB - PURPOSE OF REVIEW: Asthma and allergic diseases are common and disproportionately affect racial and ethnic minorities. Large-scale research efforts and the expense committed to multiple genomewide association studies (GWAS) have led to the identification of numerous susceptibility loci for the allergic diseases, but few successes have been reported in populations that are not of European ancestry. RECENT FINDINGS: Of the more than two dozen GWAS for asthma and allergic disease performed to date, very few have included racial/ethnic minorities. Lessons learned from the studies conducted so far suggest that the GWAS approach must include considerations unique to the ancestral populations represented in the sample, population stratification due to admixture, and recognition that the current coverage of common variants both in the public database and on commercially available single-nucleotide polymorphism chips is inadequate to detect true genetic associations among ethnic/racial groups. SUMMARY: Advancements in the GWAS technology for identifying genes relevant to asthma and allergic disease among under-represented ethnic and racial minorities who suffer most will facilitate the identification and confirmation of validated genetic risk factors that are both unique to minority groups as well as confirm risk factors that are generic to the population at large. PMID- 20724925 TI - Update in Mullerian anomalies: diagnosis, management, and outcomes. AB - PURPOSE OF REVIEW: Mullerian anomalies include a fascinating constellation of congenital malformations. There is significant diversity in anatomic variants and their respective long-term sexual and reproductive outcomes. We review the current controversies in classification and management of vaginal, uterine, and fallopian tube anomalies. RECENT FINDINGS: Comparative trials of preoperative magnetic resonance imaging (MRI) and laparoscopic intraoperative evaluation have demonstrated a moderately well correlated prediction of anatomic description. Three-dimensional ultrasound technology appears to be equivalent to MRI in detecting uterine anomalies; however MRI is a consistently superior method of evaluating the vaginal and cervical anatomy. Despite advances in both modalities, care at an experienced center is most highly associated with an accurate preoperative diagnosis and a decrease in the number of inappropriate surgical procedures.Large case series continue to be the main vehicle by which treatment and surgical management of these unique anomalies are described and recommended. Case reports continue to provide information on novel approaches to improve operative techniques. In the absence of prospective studies, these series provide the only emerging information on the long-term sexual and reproductive function of women with vaginal and uterine anomalies. SUMMARY: Recent developments in three-dimensional ultrasonography and MRI improve our ability to accurately describe and diagnose female reproductive tract anomalies. With the description of new complex malformations, which do not fall into the recognized American Society of Reproductive Medicine, formerly American Fertility Society (AFS) classification system, questions arise regarding embryologic development upon which this classification system is based and support attempts to devise a new, comprehensive classification. Advances in surgical correction have expanded the options for the reconstructive surgeon when approaching a patient with an anomaly of the reproductive tract. PMID- 20724926 TI - Hormone replacement therapy and the adolescent. AB - PURPOSE OF REVIEW: We present an update on hormonal replacement therapy (HRT) for adolescents and young women with deficiencies of pubertal hormones. RECENT FINDINGS: Although the optimal HRT regimen remains unclear and data in adolescents are limited, this review will update clinicians regarding the current issues facing them as they care for adolescents with an insufficiency of sex steroids. We suggest a stepwise approach to HRT, with a gradual increase in dosing. Recent evidence regarding transdermal versus oral preparations, the effects of HRT on skeletal health, and newer methods for providing HRT are reviewed. SUMMARY: HRT is needed by many adolescents for varied reasons, all with hypogonadism as a common endpoint. Despite the large numbers of patients for whom HRT is prescribed, little prospective data exist to aid clinicians in making evidence-based decisions as to the optimal treatment regimens. Research consortia should be established to allow investigation of these important questions, and to allow clinicians to make the best possible healthcare decisions as they care for these adolescents and young women. PMID- 20724927 TI - Sacral neuromodulations for female lower urinary tract, pelvic floor, and bowel disorders. AB - PURPOSE OF REVIEW: In recent years, sacral neuromodulation (SNM) has been investigated for the treatment of various types of lower urinary tract and bowel dysfunctions. This review discusses recently published data related to the therapeutic applications of SNM in female lower urinary tract, pelvic floor, and bowel disorders. RECENT FINDINGS: SNM has been employed initially in the treatment of refractory idiopathic overactive bladder, urge urinary incontinence, and chronic nonobstructive urinary retention. Since then, several studies, including randomized and controlled trials, have confirmed the therapeutic effects of SNM in these disorders. The applications of SNM are now extended to the treatment of other female pelvic problems, such as fecal incontinence, chronic constipation, interstitial cystitis/painful bladder syndrome, sexual dysfunction, and neurogenic disorders, with similar promising results. SUMMARY: SNM is approved by the Food and Drug Administration for the treatment of idiopathic overactive bladder, urge urinary incontinence, and chronic nonobstructive urinary retention. SNM is not yet an approved method for the treatment of other pelvic disorders, but data supporting its benefit are emerging. The major advantage of SNM lies in its potential to treat the bladder, urethral sphincter, anal sphincters, and pelvic floor muscles simultaneously, which might result in better therapeutic effects. PMID- 20724928 TI - Risk factors for recurrence of genital prolapse. AB - PURPOSE OF REVIEW: To review the available evidence regarding those risk factors potentially predicting a recurrence of pelvic organ prolapse (POP). RECENT FINDINGS: POP is a very common condition in parous women, requiring very often a surgical treatment which may need to be repeated in up to 29% of cases. In the past few years, researchers have focused their attention on the evaluation of risk factors involved in either POP development or recurrence. Recent papers have reported the importance of genetic factors that could be responsible for an inherited weakness of the pelvic floor, predisposing to POP occurrence and/or recurrence. Moreover, a history of genital prolapse at the time of an elective hysterectomy, as well as an inappropriate reconstructive surgical procedure, can predict and be associated with POP development. SUMMARY: POP recurrence can be associated with a combination of predisposing, inciting, and intervening factors. Based on actual knowledge, it is not possible to weight or score the importance of each single risk factor reported in literature for the development of POP recurrence. Larger series (collected with validated diagnostic and therapeutic tools) and longer follow-up are, therefore, needed to draw definitive conclusions on this issue. PMID- 20724929 TI - Insulin-sensitizing agents in the treatment of polycystic ovary syndrome: an update. AB - PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in reproductive-aged women, mainly characterized by oligoanovulation and hyperandrogenism. Insulin resistance represents a major pathophysiological feature of the syndrome and, therefore, insulin-sensitizing agents (metformin and thiazolidinediones) have been applied in PCOS women. However, the clinical use of insulin sensitizers in PCOS has been debated. The aim of the current review was to update the knowledge regarding the role of metformin and thiazolidinediones in PCOS treatment, focusing on recently published studies. RECENT FINDINGS: Several clinical trials examined metformin effectiveness on lipids, atherosclerosis and inflammatory markers, hormone levels, menstrual irregularities, ovulation induction, fertility, hirsutism, obesity parameters and quality of life in PCOS women. Metformin treatment was shown to improve these features, although conflicting results were also reported. Only one study investigated pioglitazone effect on PCOS, reporting an improved IVF outcome in clomiphene citrate-resistant PCOS patients. Finally, both metformin and pioglitazone, as a part of a low-dose polytherapy, exerted beneficial effects on lipids, androgen levels, hirsutism and markers of atherosclerosis in nonobese PCOS women. SUMMARY: Further research, including larger randomized controlled trials and meta-analyses, is needed to clarify the role of metformin and thiazolidinediones in the treatment of clinical and biochemical PCOS characteristics. PMID- 20724930 TI - Recent thoughts on management and prevention of recurrent early pregnancy loss. AB - PURPOSE OF REVIEW: To provide an overview of the latest views and evidence available to clinicians managing couples with recurrent early pregnancy loss (RPL). RECENT FINDINGS: RPL is a heterogeneous condition associated with many pathologies, none of which is found in more than 50% of couples after routine investigations. The recommended treatment of low-dose aspirin and heparin in women with antiphospholipid syndrome has a weak evidence base. Recent randomized controlled trials (RCTs) of low-dose aspirin and heparin have failed to find an improvement in live birth rates, even in the presence of thrombophilia. Although parental karyotypic abnormalities are associated with RPL, conservative management of such couples may be optimal. Observational studies of hysteroscopic metroplasty have promising results, but evidence from RCTs is awaited. Progestogen therapy may improve pregnancy outcomes, but further RCTs are needed. Immunological factors are thought to be important in idiopathic RPL. Research is focused on natural killer cells and cytokines in influencing implantation as potential therapeutic treatments. Currently, RCTs have not substantiated a benefit for immunotherapy. SUMMARY: Management of RPL remains challenging, with many controversial issues regarding the underlying pathophysiology. Improvements in live birth rates in subsequent pregnancies have not been found in RCTs of treatment for most of the associated conditions. All women can be offered supportive care in subsequent pregnancies. Empirical treatment is widely used in idiopathic RPL. A better option may be to encourage women to participate in high quality and methodologically sound studies to guide optimal management. PMID- 20724931 TI - The oxygen uptake efficiency slope: what do we know? AB - PURPOSE: To summarize what is currently known about the oxygen uptake efficiency slope (OUES) as an objective and independent submaximal measure of cardiorespiratory fitness in health and disease. METHODS: A literature search was performed within the following electronic databases--PubMed, Cochrane Library, Embase, Web of Science, CINAHL, PsycINFO, Scopus, and MEDLINE--using the search terms "OUES," "oxygen uptake efficiency slope," and "ventilatory efficiency." The search identified 51 articles. Selection, evaluation, and data extraction were accomplished independently by 2 authors. RESULTS: Twenty-four studies satisfied all inclusion criteria: 17 cross-sectional studies and 7 intervention studies. The results indicated that the OUES is relatively independent of exercise intensity, correlates highly with other exercise parameters, appears to have discriminative value, and is sensitive to the effects of physical training in patients with cardiac disease. Oxygen uptake efficiency slope values are considerably influenced by anthropometric variables and show large interindividual variation. CONCLUSION: Oxygen uptake efficiency slope is an independent and reproducible measure of cardiorespiratory function that does not require maximal exercise. It greatly reduces test variability because of motivational and subjective factors and is reliable and easily determinable in all subjects. Although OUES appears not interchangeable with maximal parameters of cardiopulmonary function, it seems to be a useful submaximal alternative in subjects unable to perform maximal exercise. PMID- 20724932 TI - Measurement of peripheral muscle strength in individuals with chronic obstructive pulmonary disease: a systematic review. AB - PURPOSE: Reduced maximal, peripheral muscle strength is associated with exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). Therefore, it is important to accurately evaluate muscle strength to identify patients with muscle weakness and to prescribe adequate loads for resistance training. The objective here was to systematically identify and summarize the literature on measurement of peripheral muscle strength in individuals with COPD and to make recommendations for strength testing in clinical and research settings. METHODS: A literature search was conducted of electronic databases between 1999 and 2009 of all English language articles utilizing muscle strength measurements. RESULTS: The search resulted in retrieval of 178 articles, of which 66 were reviewed. Isometric muscle strength was measured using handgrip (n = 30), strain gauge (n = 15), computerized dynamometer (n = 13), magnetic stimulation (n = 8), handheld dynamometer (n = 6), or manual testing (n = 3). Isotonic muscle strength was measured using a hydraulic system (n = 3) or 1-repetition maximum (n = 9), and isokinetic muscle strength was measured using computerized dynamometer (n = 16). Methodological issues such as limb position, number of trials, subject familiarization, test instructions, rest periods, and muscle group tested were all identified as important variables to consider when developing a strength testing protocol. CONCLUSION: Muscle strength has been measured in people with COPD using similar methods as in other clinical populations. Each method presents advantages and disadvantages that need to be considered when selecting the most relevant measure. Standardization of the test procedures is essential in both clinical and research settings to obtain valid and reliable measurements of muscle strength. PMID- 20724933 TI - Effects of pulmonary rehabilitation on activity levels in patients with chronic obstructive pulmonary disease. AB - PURPOSE: The purpose of this study was to determine whether patients with chronic obstructive pulmonary disease (COPD) increase physical activity immediately after a short course (8 weeks) of pulmonary rehabilitation (PR). Activity levels in patients with COPD were also compared with those in healthy controls. METHODS: Consecutive patients with COPD (n = 24, aged 71.9 +/- 7.7 years, forced expiratory ventilation in 1 second 44.1 +/- 17.9% predicted, who completed PR) and 8 aged-matched controls (aged 66.6 +/- 7.2 years) were studied. Activity was monitored with a triaxial accelerometer for 5 days before and after PR. Activity was expressed as vector magnitude units (VMU) per minute and time spent at VMU above 250 and 500, respectively. RESULTS: Overall activity was significantly less in patients with COPD compared with that in controls (117 +/- 63 compared with 242 +/- 103 VMU/min, P = .0003). Time spent at VMU above 250 and 500 was also less in patients with COPD (166 +/- 71 vs 227 +/- 37 min, P = .028 and 39 +/- 43 vs 124 +/- 26 min, P < .0001, respectively). After PR, overall VMU activity was not significantly increased (117 +/- 63 vs 120 +/- 63 VMU/min). Time spent at VMU above 250 and 500 was also not significantly increased after PR. Increases in activity levels after PR did not correlate with improvements in exercise performance, quality of life, or quadriceps strength. CONCLUSIONS: Despite significant improvements in exercise capacity and quality of life after PR, this did not translate into a significant increase in activity level. Improving function in patients with copd may not translate into behavioral change. PMID- 20724934 TI - Effects of exercise training in patients with abdominal aortic aneurysm: preliminary results from a randomized trial. AB - OBJECTIVE: No effective medical therapy exists for early abdominal aortic aneurysm (AAA) disease. Lower extremity exercise improves aortic hemodynamics and reduces inflammation, but the safety and efficacy of exercise training in AAA disease is unknown. As an interim analysis of our prospective, randomized, longitudinal trial of exercise for AAA suppression, we investigated whether subjects with early disease could safely achieve target metabolic and hemodynamic goals. METHODS: One hundred eight participants were randomized to exercise training (EX) or usual care (UC). EX subjects participated in a combination of in house and home exercise training, with efforts directed toward moderate daily exercise participation. Comparisons were made between EX and UC subjects who completed 1 year of follow-up (n = 26 and 31, respectively, mean age 72 +/- 8 years). EX and UC groups were compared for safety, cardiopulmonary exercise test responses, weekly energy expenditure, and biometric indices. RESULTS: No paradoxical increase in AAA growth rate or adverse clinical events occurred as a consequence of exercise training. EX participants expended an average of 2269 +/- 1207 kcal/wk and increased exercise capacity (42% increase in treadmill time, 24% increase in estimated metabolic equivalents, P = .01 and .08 between groups, respectively). EX participants demonstrated a significant reduction in C-reactive protein and tended to reduce waist circumference and waist-to-hip ratio (P = .06 and .07, respectively). CONCLUSIONS: Preliminary analyses suggest that exercise training is well tolerated and sustainable in small AAA subjects over 1 year. Despite age and comorbidities, exercising AAA subjects achieve meaningful exercise targets and significantly modify activity-dependent variables. PMID- 20724935 TI - The impact of anxiety disorders on assessment of myocardial ischemia and exercise stress test performance. AB - PURPOSE: To evaluate the sensitivity of electrocardiogram (ECG) versus single photon emission computed tomography (SPECT) assessments of ischemia in patients with anxiety disorders (AD) and the extent to which patients exhibit poorer exercise performance, compared with patients without AD. METHODS: Patients referred for nuclear exercise stress testing (N = 2271) underwent a structured psychiatric interview (PRIME-MD) to assess for AD. Exercise performance parameters were assessed during ECG treadmill testing, after which patients underwent SPECT imaging. RESULTS: Analyses revealed that patients with AD exhibited lower peak exercise systolic blood pressure and rate pressure product than patients without AD. When major depressive disorder was included as an additional covariate, the previous results became trends. Results also indicated a lower rate of electrically positive ecg tests and a higher rate of false negative diagnoses of myocardial ischemia according to ecg among patients with AD. Including major depressive disorder as a covariate rendered the effects of ad nonsignificant. There was no evidence of reduced exercise performance in patients with AD. CONCLUSIONS: Findings suggest that AD may be associated with mild impairments in cardiovascular exercise reactivity and may also alter the detection of myocardial ischemia using ecg assessments in patients referred for exercise stress testing. However, the influence of AD appears to be moderated by comorbid depression. Results suggest that exercise test performance and detection of ischemia may be influenced by mood and/or anxiety disorders and that greater efforts should be made to include routine mood and/or anxiety disorder screening as part of exercise stress testing protocols. PMID- 20724936 TI - Traditional and nontraditional risk factors as predictors of cerebrovascular events in patients with end stage renal disease. AB - OBJECTIVES AND METHODS: End stage renal disease (ESRD) patients exhibit a higher risk of cerebrovascular events as compared with the general population. In 283 ESRD patients followed up for 10 years, we investigated the long-term predictive value for stroke and transient ischemic attacks of traditional and nontraditional risk factors. Data analysis was performed by a modified Cox regression analysis for repeated events and by a competing risks analysis. RESULTS: During the follow up, 61 cerebrovascular events occurred in 47 patients. On univariate Cox analysis, the risk of cerebrovascular outcomes was directly related to age, smoking, diabetes, BMI, systolic and pulse pressures, triglycerides, hemoglobin, history of stroke/transient ischemic attacks, arrhythmia and left ventricular mass index. Nontraditional risk factors in ESRD such as norepinephrine, homocysteine, interleukin-6 and asymmetric dimethylarginine failed to predict these events. In a multivariate Cox model for repeated events only smoking [hazard ratio: 2.45, 95% confidence interval (CI): 1.29-4.65], age (hazard ratio: 1.05, 95% CI: 1.01-1.08), hemoglobin (hazard ratio: 1.28, 95% CI 1.06-1.54), triglycerides (hazard ratio: 1.04, 95% CI 1.01-1.08), pulse pressure (hazard ratio: 1.53, 95% CI 1.01-2.23) and left ventricular mass index (hazard ratio: 1.02, 95% CI 1.01-1.04) maintained an independent relationship with cerebrovascular events. The direct link between hemoglobin and cerebrovascular events was significantly stronger (P < 0.05) than that of the same variable and death. CONCLUSION: The risk of stroke in ESRD depends mainly on traditional risk factors, high hemoglobin and left ventricular hypertrophy. Multiple interventions aimed to reduce arterial stiffness, left ventricular mass and smoking as well as to maintain hemoglobin within the recommended therapeutic range may have beneficial effects on the risk of cerebrovascular events in ESRD patients. PMID- 20724937 TI - The combined influence of hypertension and common mental disorder on all-cause and cardiovascular disease mortality. AB - BACKGROUND: Common mental disorders, such as anxiety and depression, are risk factors for mortality among cardiac patients, although this topic has gained little attention in individuals with hypertension. We examined the combined effects of hypertension and common mental disorder on mortality in participants with both treated and untreated hypertension. METHODS: In a representative, prospective study of 31 495 adults (aged 52.5 +/- 12.5 years, 45.7% men) we measured baseline levels of common mental disorder using the 12-item General Health Questionnaire (GHQ-12) and collected data on blood pressure, history of hypertension diagnosis, and medication use. High blood pressure (systolic/diastolic >140/90 mmHg) in study members with an existing diagnosis of hypertension indicated uncontrolled hypertension and, in undiagnosed individuals, untreated hypertension. RESULTS: There were 3200 deaths from all causes [943 cardiovascular disease (CVD)] over 8.4 years follow-up. As expected, the risk of CVD was elevated in participants with controlled [multivariate hazard ratio = 1.63, 95% confidence interval (CI) 1.26-2.12] and uncontrolled (multivariate hazard ratio = 1.57, 95% CI 1.08-2.27) hypertension compared with normotensive participants. Common mental disorder (GHQ-12 score of >=4) was also associated with CVD death (multivariate hazard ratio = 1.60, 95% CI 1.35-1.90). The risk of CVD death was highest in participants with both diagnosed hypertension and common mental disorder, especially in study members with controlled (multivariate hazard ratio = 2.32, 95% CI 1.70-3.17) hypertension but also in uncontrolled hypertension (multivariate hazard ratio = 1.90, 95% CI 1.18-3.05). The combined effect of common mental disorder was also apparent in participants with undiagnosed (untreated) hypertension, especially for all-cause mortality. CONCLUSIONS: These findings suggest that the association of hypertension with total and CVD mortality is stronger when combined with common mental disorder. PMID- 20724938 TI - Maternal smoking and blood pressure in different trimesters of pregnancy: the Generation R study. AB - OBJECTIVE: Smoking during pregnancy is a risk factor for various adverse birth outcomes but lowers the risk of preeclampsia. Cardiovascular adaptations might underlie these associations. We examined the associations of smoking in different trimesters of pregnancy with repeatedly measured blood pressure and the risks of preeclampsia and pregnancy-induced hypertension in a low-risk population-based cohort of 7106 pregnant women. METHODS: This study was embedded in a population based prospective cohort study from early pregnancy onwards. Smoking and systolic and diastolic blood pressures were assessed by questionnaires and physical examinations in each trimester of pregnancy. Information about preeclampsia and pregnancy-induced hypertension was obtained from medical records. RESULTS: Compared to nonsmoking women, both first-trimester-only and continued smoking were associated with a steeper increase for systolic blood pressure and a lowest mid-pregnancy level and steeper increase thereafter for diastolic blood pressure throughout pregnancy. We did not find any significant associations in risk of preeclampsia for first-trimester-only smoking (odds ratio of 1.28, 95% confidence interval 0.74, 2.21) and continued smoking (odds ratio of 0.83, 95% confidence interval 0.50, 1.36), respectively. CONCLUSIONS: Our results suggest that both first-trimester-only and continued smoking are associated with persistent maternal cardiovascular adaptations during pregnancy. Strategies for prevention of smoking during pregnancy should be focused on the preconception period. The effects of early and late-pregnancy smoking on the risk of preeclampsia should be further explored. Our results should be carefully interpreted to the general population of pregnant women. PMID- 20724939 TI - Augmentation index and central aortic blood pressure in patients with abdominal aortic aneurysms. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is a life-threatening disease as rupture of the aneurysm is associated with high mortality. The likelihood that an AAA will rupture is particularly influenced by the diameter of the aneurysm and the rate of expansion; the reasons for fast expansion are largely unknown. Applanation tonometry (APT) can predict outcome in certain cardiovascular diseases by measuring arterial stiffness (augmentation index, AIx) and central aortic blood pressure (CABP). We tested the hypothesis that AIx and CABP would be higher in patients with fast-progressing AAA. METHODS: We performed APT and peripheral blood pressure measurements in 114 patients with AAA (11 women) with a mean +/- SD age of 67.4+/-6.1 years. Annual AAA progression rate was determined by ultrasound. Patients were grouped into fast progressors (progression >=2 mm/year) and slow progressors (progression <2 mm/year). RESULTS: Mean follow-up time after inclusion into the AAA surveillance programme was 22.1 +/- 16.3 months. AIx was similar in fast progressors (27.3 +/- 13.0%) and slow progressors (26.5 +/- 12.6%) (P = 0.73). Fast progressors had a significantly higher CABP during systole (116.0 +/- 16.0 mmHg) and diastole (95.7 +/- 12.6 mmHg) than slow progressors (109.5 +/- 16.3 and 90.0 +/- 13.2 mmHg) (P = 0.04 and P = 0.02, respectively). Mean peripheral blood pressure was significantly higher in fast progressors (102.7 +/- 12.8 mmHg) than in slow progressors (97.7 +/- 12.9 mmHg) (P = 0.04). CONCLUSION: Augmentation index did not differ in patients with fast and slow-progressing AAA. However, fast progressors had higher central aortic blood pressures suggesting that elevated aortic blood pressure is a risk factor for faster AAA progression, but this needs to be proven in controlled interventional studies. PMID- 20724940 TI - Alterations in capillary morphology are found in mild blood pressure elevation. AB - OBJECTIVES: Remodeling of small resistance arteries is an early sign of target organ damage in hypertension. Peripheral capillary morphology abnormalities in hypertension are not well studied. The study objective was to determine whether altered capillary morphology is associated with SBP, DBP, or both in individuals without and with mild blood pressure elevation (SBP = 130-160 mmHg). Another objective was to determine whether capillary morphology is associated with minimum forearm vascular resistance, a measure of altered resistance artery structure. METHODS: Participants included 115 nonpregnant, nondiabetic individuals 23-55 years of age. A five-component morphology score (distribution, tone, configuration, hypertrophy, and extravasates) was developed to describe fingernail bed capillaries visualized using venous congestion in digital photomicrographs. Multiple linear regression models adjusted for age, sex, race, tobacco use, hyperglycemia, dyslipidemia, and renal function were used to analyze the relationship between SBP, DBP, and minimum forearm vascular resistance with the morphology score. RESULTS: The total morphology score was significantly associated with SBP and DBP as well as minimum forearm vascular resistance (P < 0.005 for all). Among the five individual morphology score components, hypertrophy was significantly associated with SBP and DBP (P = 0.002 and 0.001, respectively), whereas extravasates were significantly associated with SBP only (P = 0.002). CONCLUSION: A five-component capillary morphology score is associated with SBP, DBP, and altered resistance artery structure in individuals with and without mild blood pressure elevation. These observations suggest that target organ damage at the level of the microcirculation can be detected using capillary morphology. PMID- 20724941 TI - Atorvastatin upregulates nitric oxide synthases with Rho-kinase inhibition and Akt activation in the kidney of spontaneously hypertensive rats. AB - OBJECTIVE: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins reduce blood pressure and have beneficial effects in cardiovascular and kidney diseases. The present study examined the effect of chronic treatment with atorvastatin (ATV) on the expression of nitric oxide synthase (NOS) and the activity of Rho-kinase and Akt in the kidney of spontaneously hypertensive rats (SHRs). METHODS: SHRs were treated with ATV for 8 weeks and the SBP was measured. The expressions of endothelial, neuronal and inducible NOS (eNOS, nNOS and iNOS, respectively) proteins in the kidney were examined by immunoblot analysis. The activity of eNOS, Rho-kinase and Akt in the kidney was examined by assessing the phosphorylation of eNOS, ezrin/radixin/moesin (ERM) and Akt, respectively. RESULTS: ATV reduced the SBP without changing the plasma cholesterol levels. ATV increased eNOS expression in the cortex and medulla and nNOS expression in the medulla, whereas it did not affect iNOS expression. Although it upregulated eNOS expression in the kidney, ATV decreased the levels of phosphorylated eNOS in the cortex and did not affect the ratio of phosphorylated eNOS to total eNOS in the medulla. ATV also inhibited Rho-kinase activity and enhanced Akt activity in the kidney of SHRs. CONCLUSION: ATV upregulates eNOS and nNOS expressions with Rho kinase inhibition and Akt activation in the kidney of SHRs. The renal nitric oxide system, Rho-kinase and Akt may contribute to the antihypertensive and renoprotective effects of statins. PMID- 20724942 TI - Epigenetic regulation of the endothelial nitric oxide synthase gene in persistent pulmonary hypertension of the newborn rat. AB - OBJECTIVE: Persistent pulmonary hypertension of the newborn (PPHN) is a major clinical problem. Nitric oxide produced by endothelial nitric oxide synthase (eNOS) in endothelial cells plays an important role in the pathogenesis of PPHN. The eNOS expression in endothelial cells is controlled by epigenetic regulation. The aim of this study was to investigate the epigenetic regulatory mechanisms of the eNOS gene in PPHN. METHODS: The rat model of PPHN was induced by hypoxia and indomethacin. Pulmonary vascular endothelial cells were isolated from the fetal rat lungs by magnetic-activated cell sorting. Chromatin immunoprecipitation and bisulfite sequencing methods were used to analyze epigenetic regulation. RESULTS: The levels of acetylated histone H3 and acetylated histone H4 at the proximal promoter of the eNOS gene in pulmonary vascular endothelial cells from PPHN were significantly higher than those from the control group (P < 0.01, respectively). Total methylation percentage of the eNOS gene promoter in PPHN rat was slightly lower than that of control, but there was no statistically significant difference between the two groups (24.7 +/- 2.0 vs. 27.3 +/- 2.3%, P = 0.408). These changes of epigenetic modifications at the eNOS gene promoter were consistent with increased levels of eNOS mRNA and protein in PPHN. CONCLUSION: The increased expression of eNOS in PPHN was associated with epigenetic regulation. PMID- 20724943 TI - Photo essay. Isolated fascicular third nerve palsy. AB - A 72-year-old hypertensive woman developed acute diplopia and right upper lid ptosis. Examination showed a partial right third nerve palsy with complete ptosis, moderately impaired adduction and supraduction, and sparing of infraduction and the pupil. There were no other neurologic deficits. Brain MRI with diffusion weighting demonstrated an infarct in the right paramedian midbrain tegmentum along the course of the third nerve fascicles. The clinical deficit and neuroimaging in this case provide further support for a previously suggested topographic organization of the fascicles of the third nerve within the brainstem. PMID- 20724944 TI - Cancer-associated retinopathy in neuroendocrine carcinoma of the fallopian tube. AB - A 70-year-old woman developed progressive visual loss with compromised visual acuity and visual fields, cells in the anterior chamber and vitreous, attenuated retinal arterioles, and macular edema. She had undergone right oophorectomy and partial salpingectomy nearly 50 years earlier. Full-field and multifocal electroretinography showed waveforms of markedly attenuated amplitudes, findings consistent with cancer-associated retinopathy (CAR). Positron emission tomography revealed a nodule in the anterior wall of a right hydrosalpinx. Total laparoscopic hysterectomy yielded a neuroendocrine fallopian tube malignancy. She underwent partial treatment with paclitaxel and carboplatin that was aborted because of the development of herpes zoster infection. At 15 months following diagnosis, her ophthalmic status was stable. This is the first report of CAR in neuroendocrine carcinoma of the fallopian tube. PMID- 20724945 TI - Abducens ocular neuromyotonia in a patient with nasopharyngeal carcinoma following concurrent chemoradiotherapy. AB - We describe a case of ocular neuromyotonia (ONM) following concurrent chemoradiotherapy for nasopharyngeal carcinoma (NPC). During an episode of neuromyotonia, the patient developed involuntary contraction of the left lateral rectus muscle and globe retraction with down-shoot movement in the left eye. In the quiescent period, ocular motor examination revealed a partial left sixth nerve palsy. While diplopic complaints in patients with NPC raise suspicion of tumor recurrence or radiation-related cranial neuropathy, ONM must also be kept in the differential diagnosis. PMID- 20724946 TI - Selective saccadic palsy after cardiac surgery. AB - We report a patient who showed a selective deficit of voluntary saccades and quick phases of nystagmus after cardiac surgery. Voluntary saccades in the horizontal plane were very slow, while vertical saccades, vestibular and optokinetic nystagmus, were absent. However, smooth pursuit, the vestibulo-ocular reflex, and the ability to hold steady eccentric gaze were preserved. PMID- 20724947 TI - Stroke in a young boy with beta-thalassemia intermedia secondary to moyamoya syndrome. AB - Moyamoya disease is a rare cerebrovascular disorder, characterized by stenosis or occlusion of cerebral arteries. Well described with sickle cell anemia, its association with other hemoglobinopathies is a rarity. We report a 5-year-old boy with beta-thalassemia intermedia, on hydroxyurea therapy, who presented with a stroke. Magnetic resonance angiography findings were consistent with bilateral moyamoya disease. The literature with regard to the pathogenesis and options of management is reviewed. PMID- 20724948 TI - Arginine metabolism and nitric oxide bioavailability in sickle cell disease. PMID- 20724949 TI - Effect of oral arginine supplementation on exhaled nitric oxide concentration in sickle cell anemia and acute chest syndrome. AB - INTRODUCTION: Decreased exhaled nitric oxide levels (FE(NO)) have been described in patients with sickle cell disease (SCD) and a history of acute chest syndrome (ACS) when compared with non-ACS controls. Oral arginine supplementation has been shown to increase FE(NO) in healthy participants, but its effect in SCD patients is not known. OBJECTIVE: To determine the effect of oral arginine intake on FENO in sickle cell patients with and without history of ACS, and in healthy controls. HYPOTHESIS: No differences in the FE(NO) increase were seen in SCD patients with a history of ACS (ACS+) compared with healthy controls (HC) and SCD patients without history of ACS (ACS-). MATERIALS AND METHODS: ACS+ (n=6), ACS- (n=9), and HC (n=7) patients were studied. At baseline, and after the administration of escalating doses of oral L-arginine (0.1, 0.2, and 0.4 g/kg), serial measurements were made of the following: FE(NO), plasma concentrations of arginine, ornithine, citrulline, aspartate, glutamate, arginine/ornithine ratio, nitrite, nitrate, heart rate (HR), respiratory rate (RR), blood pressure (BP), oxygen saturation (SpO2), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). MAIN RESULTS: At baseline, FE(NO) did not differ among the groups. ACS- and ACS+ groups were deficient in arginine, and had decreased FEV1, FVC, and SaO2 when compared with HC patients. After arginine supplementation, FE(NO), arginine, ornithine, citrulline, nitrite, and the arginine/ornithine ratio increased similarly in all groups. Changes from baseline for HR, BP, SpO2, RR, FEV1, and FVC were minimal and similar in all groups. CONCLUSIONS: In contrast to our earlier study, ACS+ patients had similar FE(NO) values when compared with ACS- and HC patients. All SCD patients were arginine deficient at baseline and showed impairment in respiratory physiology when compared with HC patients. After arginine supplementation, FE(NO) concentration increased in all groups to a similar degree, and lung function and physiologic parameters were minimally affected. The physiologic significance of alterations in FE(NO) in SCD patients and its relationship to ACS predilection requires further delineation. PMID- 20724950 TI - Isolated central nervous system relapse in an adolescent with acute myelomonocytic leukemia, Charcot Marie Tooth syndrome, and paraneoplastic autoantibody. AB - A 17-year-old boy, with acute myelomonocytic leukemia and inversion 16(p13q22) developed polyneuropathy and isolated central nervous system relapse. Scoliosis and high-arched feet suggested a diagnosis of Charcot Marie Tooth (CMT) syndrome and genetic testing confirmed duplication at the PMP22 locus at chromosome 17p11.12. No mutation was found in another CMT gene, the CMT C1 LITAF locus at 16p13.2, to suggest that this association is anything more than chance. Titres to VGKC, a paraneoplastic autoantibody, were elevated, suggesting an additional mechanism for the polyneuropathy. This case extends the clinical spectrum of cancer with CMT, and of paraneoplastic disorders. PMID- 20724951 TI - Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. AB - L-asparaginase (L-ASNase) has been an essential component of multiagent chemotherapy for acute lymphoblastic leukemia in childhood for over 3 decades. There are currently 2 Food and Drug Administration (FDA)-approved formulations of L-ASNase derived from Escherichia coli and 1 non-FDA approved formulation derived from Erwinia chrysanthemi. Modifications in L-ASNase have included pegylation, which decreases drug immunogenicity and increases the half-life, allowing less frequent administration. Although L-ASNase is well-tolerated in most patients and causes little myelosuppression, significant toxicities occur in up to 30% of patients. Hypersensitivity is the most common toxicity of L-ASNase therapy and limits the further use of the drug. Other significant toxicities relate to a reduction in protein synthesis and include pancreatitis, thrombosis, central nervous system complications, and liver dysfunction. The spectrum of common toxicities and the efficacy of different formulations of L-ASNase are presented in this review. PMID- 20724952 TI - The tie that binds: relationships in perinatal bereavement. AB - Relationship is a central concept to the delivery of quality perinatal bereavement care. This article explores relevant bereavement research and clinically based writings about relationship in the care of families experiencing perinatal loss. Focusing on relationship provides a framework to guide interventions that will be perceived as meaningful and helpful to grieving parents. From the moment parents learn the difficult news of their baby's poor prognosis or death, nurses must strive to establish trust while building an effective working relationship with the family. A nurse with an understanding of the relationship needs can guide parents in creating a context for supporting each family member dealing with this unexpected family tragedy. Through sensitive follow-up bereavement care, nurses provide a source of hope for grieving families over time. Ultimately, nurses must find meaningful ways of self-care as a way of reinvesting in future relationship with other grieving families. PMID- 20724953 TI - Acute disseminated fatal toxoplasmosis after haploidentical stem cell transplantation despite atovaquone prophylaxis in a young man. AB - We describe a case of fatal acute disseminated breakthrough toxoplasmosis in a 19 year-old adolescent after haploidentical hematopoietic stem cell transplantation for acute lymphoblastic leukemia despite continued atovaquone prophylaxis. Diagnosis was at necropsy, and confirmed by postmortem polymerase chain reaction analysis in plasma. This report illustrates the need for protozoal monitoring despite atovaquone prophylaxis, in severely immunocompromised patients with intolerance to standard treatment. PMID- 20724954 TI - Epidemiology of rotavirus infections in children less than 5 years of age: Germany, 2001-2008. AB - BACKGROUND: rotavirus (RV) infection is the leading cause of acute gastroenteritis in young children worldwide. In 2006, 2 live-attenuated RV vaccines became available for use in infants <= 6 months of age. In Germany, a statutory notification system for RV infection has been in place since 2001 to monitor RV epidemiology. Our objective was to assess RV disease burden in German children <5 years of age. METHODS: Detailed descriptive analysis of national RV surveillance data in children <5 years of age collected in Germany between January 2001 and December 2008. RESULTS: between 2001 and 2008, 72% of all notified RV patients were children <5 years of age. The highest annual incidence (approximately, 200/10,000) was in children <2 years of age. In the <5 years age group, approximately 50% of reported patients were hospitalized and of those, 9% acquired the infection nosocomially. Since 2004, a total of 8 children <5 years of age were reported as RV-associated deaths, and case fatality due to RV infection was <0.01/10,000. CONCLUSIONS: the high incidence of RV infection and RV-associated hospitalization in children <5 years of age results in a high disease burden. Routine childhood RV vaccination would be a measure to reduce the burden in this age-group. However, cost-effectiveness analyses specific to the German setting should be considered in the decision-making process. An RV surveillance system is in place in Germany that could potentially monitor the effect of an RV-vaccination program once implemented. PMID- 20724955 TI - A randomized, multicenter, open-label clinical trial to assess the anamnestic immune response 4 to 8 years after a primary hepatitis B vaccination series. AB - This open-label, randomized study challenged 4- to 8-year-old children from Spain (N = 1478) with a single dose of hepatitis B vaccine to estimate anamnestic responses. At the time of preimmunization, 15.9% to 51.2% of subjects had antibody values >=10 mIU/mL. One month postimmunization, 91.6% to 97.3% of subjects had antibody titers >=10 mIU/mL. There were no serious, vaccine-related, adverse experiences, and no discontinuations as a result of adverse experience. PMID- 20724956 TI - Cross-reactive neutralizing antibody against pandemic 2009 H1N1 influenza a virus in intravenous immunoglobulin preparations. AB - Prepandemic intravenous immunoglobulin (IVIG) and sera from Kawasaki disease patients treated with this IVIG were analyzed for 2009 H1N1-specific microneutralization and hemagglutination inhibition antibodies. All 6 different IVIG preparations tested had significant levels of cross-reactive-specific antibody at a concentration of 2.0 g/dL of immunoglobulin. Sera from 18 of 19 Kawasaki disease patients had significant increases of cross-reactive-specific antibody after 2.0 g/kg of prepandemic IVIG. These results suggest a role for adjunctive IVIG therapy for severe and/or drug-resistant 2009 H1N1 virus and other highly antigenically drifted influenza strains, particularly in the immunocompromised. PMID- 20724957 TI - N-3 long-chain polyunsaturated fatty acids prevent excessive fat deposition in adulthood in a mouse model of postnatal nutritional programming. AB - This study investigates whether improved quality of nutrients during early postnatal life has effects on adult metabolic profile and body composition in a murine model of nutritional programming. Male offspring of C57Bl/6j dams received a diet containing 21% energy (En%) as fat of either 100% vegetable oils [control (CTRL)] or 80% vegetable oils/20% tuna fish oil [rich in n-3 long-chain polyunsaturated fatty acids (n-3 LCP)] from postnatal day (PN) 2 to 42. Subsequently, mice of both experimental groups were switched to a western style diet (WSD; 21 En% fat, high saturated fatty acid [FA] content, and cholesterol) until dissection at PN98. Body composition was analyzed by dual x-ray absorptiometry during the WSD challenge. Results showed that a n-3 LCP-rich diet during postnatal life not only reduced fat accumulation by ~30% during the WSD challenge from PN42 to 98 (p < 0.001) but also led to a healthier plasma lipid profile, healthier plasma glucose homeostasis, and less hypertrophic adipocytes compared with CTRL. This study shows that postnatal nutrition has programming effects on adult body composition and metabolic homeostasis. In addition, it emphasizes that moderate alterations in fat quality during early postnatal life considerably affect adult metabolic health. PMID- 20724958 TI - Association of metabolic syndrome with development of new-onset diabetes after transplantation. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is a major posttransplant complication associated with lower allograft and recipient survival. Our objective was to determine whether metabolic syndrome pretransplant is independently associated with NODAT development. METHODS: We recruited 640 consecutive incident nondiabetic renal transplant recipients from three academic centers between 1999 and 2004. NODAT was defined as the use of hypoglycemic medication, a random plasma glucose level more than 200 mg/dL, or two fasting glucose levels more than or equal to 126 mg/dL beyond 30 days posttransplant. RESULTS: Metabolic syndrome was common pretransplant (57.2%). NODAT developed in 31.4% of recipients 1 year posttransplant. Participants with metabolic syndrome were more likely to develop NODAT compared with recipients without metabolic syndrome (34.4% vs. 27.4%, P=0.057). Recipients with increasing number of positive metabolic syndrome components were more likely to develop NODAT (metabolic syndrome score prevalence at 1 year: 0 components-0.0%, 1-24.2%, 2 29.3%, 3-31.0%, 4-34.8%, and 5-73.7%, P=0.001). After adjustment for demographics, age by decade (hazard ratio [HR] 1.34 [1.20-1.50], P<0.0001), African American race (HR 1.35 [1.01-1.82], P=0.043), cumulative prednisone dosage (HR 1.18 [1.07-1.30], P=0.001), and metabolic syndrome (HR 1.34 [1.00 1.79], P=0.047) were independent predictors of development of NODAT at 1 year posttransplant. In a multivariable analysis incorporating the individual metabolic syndrome components themselves as covariates, the only pretransplant metabolic syndrome component to remain an independent predictor of NODAT was low high-density lipoprotein (hazard ratio [HR] 1.37 [1.01-1.85], P=0.042). CONCLUSIONS: Metabolic syndrome is an independent predictor for NODAT and is a possible target for intervention to prevent NODAT. Future studies to evaluate whether modification of metabolic syndrome factors pretransplant reduces NODAT development are needed. PMID- 20724959 TI - Cytomegalovirus mismatch as major risk factor for delayed graft function after pancreas transplantation. AB - BACKGROUND: Risk factors for delayed graft function (DGF) in pancreas transplantation (PTx) and its implications on graft survival are poorly defined. METHODS: Eighty-seven consecutive first-time PTx for type I diabetes performed between January 2003 and December 2007 were retrospectively reviewed. DGF was defined as a reversible need for exogenous insulin beyond postoperative day 10 (DGF group [DGFG]). For statistical analysis, DGFG patients were compared with patients with immediate graft function (control group [CG]). RESULTS: DGF occurred in 16 patients (18.6%). C-peptide levels and DGF were inversely correlated (r=0.24, P=0.03). In univariate analysis, donor cytomegalovirus (CMV)+ antibody status, and D+/R- CMV mismatch were significantly associated with DGF (81.3% vs. CG 52.1%, P=0.029; and 62.5% vs. CG 21.1%, P=0.002, respectively). Compared with University of Wisconsin solution, histidine tryptophan ketoglutarate-preserved grafts displayed higher DGF rates (37.5% vs. CG 12.7%, P=0.030), similar to female recipients (DGFG 68.8% vs. CG 35.2%, P=0.015). On multivariate analysis, a significantly higher DGF incidence was noted in female recipients (DGFG 68.8% vs. CG 35.2%; P=0.03) and in recipients with D+/R- CMV mismatch (DGFG 62.5% vs. CG 21.1%; P=0.03). With a median follow-up of 40.4 months (range 0.7-74.2), graft survival at 5 years did not differ between both groups (94.4% CG vs. 93.8% DGFG; P=0.791). CONCLUSION: This is the first study that identifies CMV mismatch (D+/R-) as an additional risk factor for DGF occurrence in PTx. In this particular cohort, DGF does not seem to affect graft survival. PMID- 20724960 TI - Synthesis and application of a 2-[(4-fluorophenyl)-sulfonyl]ethoxy carbonyl(Fsec) protected glycosyl donor in carbohydrate chemistry. AB - The 2-[(4-fluorophenyl)sulfonyl]ethoxy carbonyl (Fsec) group for protection of hydroxyl groups has been designed, synthesized, and evaluated. Fsec-Cl was readily prepared in 91% yield over three steps and subsequently used to protect 4 fluorobenzyl alcohol in high yield. The Fsec group was cleaved from the resulting model compound under mild basic conditions e.g., 20% piperidine in DMF and was stable under acidic conditions, e.g., neat acetic acid. The Fsec group was used to protect the unreactive 4-OH in a galactose building block that was later used in the synthesis of 6-aminohexyl galabioside. PMID- 20724961 TI - Design, synthesis, and biological evaluation of benzylamino-methanone based cholesteryl ester transfer protein inhibitors. AB - Cholesteryl ester transfer protein (CETP) is a glycoprotein involved in transporting lipoprotein particles and neutral lipids between high-density lipoprotein (HDL) and low density lipoproteins (LDL) and therefore its a proper target for treating dyslipidemia and related disorders. Guided by our previously reported pharmacophore and QSAR models for CETP inhibition, we synthesized and bioassayed a series of benzylamino-methanones. The most potent illustrated 30% CETP inhibition at 10 microM. PMID- 20724962 TI - Chemical composition and larvicidal activity against Aedes aegypti larvae of essential oils from four Guarea species. AB - The essential oils of four Guarea species collected at Manaus (Amazonas, Brazil) were obtained by hydrodistillation and analyzed by GC-MS. Except for one diterpene detected, the compounds identified in the essential oils were hydrocarbons and oxygenated sesquiterpenes. The major sesquiterpenes were alpha santalene (26.26%) and alpha-copaene (14.61%) from G. convergens branches; caryophyllene epoxide (40.91%) and humulene epoxide II (14.43%) from G. humaitensis branches; cis-caryophyllene (33.37%) and alpha-trans-bergamotene (11.88%) from G. scabra leaves; caryophyllene epoxide (36.54%) in leaves and spathulenol (14.34%) in branches from G. silvatica. The diterpene kaurene (15.61%) was found in G. silvatica leaves. Larvicidal activity assay of essential oils against third-instar Aedes aegypti larvae revealed that at higher concentrations (500 and 250 microg/mL), all the essential oils caused 100% mortality after 24 h of exposure. The most active essential oils were those of G. humaitensis branches (LC(50) 48.6 microg/mL), G. scabra leaves (LC(50) 98.6 microg/mL) and G. silvatica (LC(50) 117.9 microg/mL). The differences in the toxicity of essential oils of Guarea species on A. aegypti are due to qualitative and quantitative variations of the components, therefore the larvicidal effect may be due to higher amount of the sesquiterpenes with caryophyllane skeleton. PMID- 20724963 TI - Bronchial thermoplasty for asthma. PMID- 20724964 TI - Three new drugs for hereditary angioedema. PMID- 20724965 TI - An expanded pneumococcal vaccine (prevnar 13) for infants and children. PMID- 20724966 TI - Heat illness among high school athletes --- United States, 2005-2009. AB - Heat illness during practice or competition is a leading cause of death and disability among U.S. high school athletes. An estimated 7.5 million students participate in high school sports annually. To examine the incidence and characteristics of heat illness among high school athletes, CDC analyzed data from the National High School Sports-Related Injury Surveillance Study for the period 2005-2009, which includes the 2005-06, 2006-07, 2007-08 and 2008-09 school years. During 2005-2009, the 100 schools sampled reported a total of 118 heat illnesses among high school athletes resulting in >or=1 days of time lost from athletic activity (i.e., time-loss heat illness), a rate of 1.6 per 100,000 athlete-exposures and an average of 29.5 time-loss heat illnesses per school year. The average corresponds to a weighted average annual estimate of 9,237 illnesses nationwide. The highest rate of time-loss heat illness was among football players, 4.5 per 100,000 athlete-exposures, a rate 10 times higher than the average rate (0.4) for the eight other sports. Time-loss heat illnesses occurred most frequently during August (66.3%) and while practicing or playing football (70.7%). No deaths were reported. Consistent with guidelines from the National Athletic Trainers' Association (NATA), to reduce the risk for heat illness, high school athletic programs should implement heat-acclimatization guidelines (e.g., set limits on summer practice duration and intensity). All athletes, coaches, athletic trainers, and parents/guardians should be aware of the risk factors for heat illness, follow recommended strategies, and be prepared to respond quickly to symptoms of illness. Coaches also should continue to stress to their athletes the importance of maintaining proper hydration before, during, and after sports activities. PMID- 20724967 TI - Smoking in top-grossing movies --- United States, 1991-2009. AB - Exposure to onscreen smoking in movies increases the probability that youths will start smoking. Youths who are heavily exposed to onscreen smoking are approximately two to three times more likely to begin smoking than youths who are lightly exposed; a similar, but smaller effect exists for young adults. To monitor the extent to which tobacco use is shown in popular movies, Thumbs Up! Thumbs Down! (TUTD), a project of Breathe California of Sacramento-Emigrant Trails, counted the occurrences of tobacco use (termed "incidents") shown in U.S. top-grossing movies during 1991-2009. This report summarizes the results of that study, which found that the number of tobacco incidents depicted in the movies during this period peaked in 2005 and then progressively declined. Top-grossing movies released in 2009 contained 49% of the number of onscreen smoking incidents as observed in 2005 (1,935 incidents in 2009 versus 3,967 incidents in 2005). Further reduction of tobacco use depicted in popular movies could lead to less initiation of smoking among adolescents. Effective methods to reduce the potential harmful influence of onscreen tobacco use should be implemented. PMID- 20724968 TI - National, state, and local area vaccination coverage among adolescents aged 13-17 years --- United States, 2009. AB - The Advisory Committee for Immunization Practices (ACIP) recommends that adolescents routinely receive the following vaccines: meningococcal conjugate (MenACWY, 1 dose); tetanus, diphtheria, acellular pertussis (Tdap, 1 dose); and (for females) human papillomavirus (HPV, 3 doses). Adolescents also should receive the following recommended vaccinations they missed during childhood: measles, mumps, rubella (MMR, 2 doses); hepatitis B (HepB, 3 doses); and varicella (VAR, 2 doses). Since 2006, CDC has conducted the National Immunization Survey--Teen (NIS-Teen) to estimate vaccination coverage among adolescents aged 13-17 years. This report summarizes results from 2009 NIS-Teen and updates data from 2008 NIS-Teen. Comparing 2009 with 2008, vaccination coverage among adolescents for the three routinely administered adolescent vaccines increased for Tdap (from 40.8% to 55.6%), MenACWY (from 41.8% to 53.6%), >or=1 dose of HPV (from 37.2% to 44.3%), and >or=3 doses of HPV (from 17.9% to 26.7%). Vaccination coverage varied widely among states; four states (Connecticut, Massachusetts, New Hampshire, and Rhode Island) had coverage of >60% for all three of the routinely administered adolescent vaccines (Tdap, MenACWY, and HPV). Nationally, Healthy People 2010 vaccination objectives of 90% coverage among adolescents aged 13-15 years were met for >or=3 doses of HepB and >or=1 dose of VAR. Coverage with routine adolescent vaccines is increasing; however, more effort, including identification and dissemination of successful state-based practices, is needed to continue to increase the number of adolescents vaccinated according to ACIP recommendations. PMID- 20724969 TI - Notes from the field: acute hemorrhagic conjunctivitis outbreaks caused by coxsackievirus A24v --- Uganda and southern Sudan, 2010. AB - CDC was contacted on June 22, 2010, by the Ugandan Ministry of Health (MoH)/Uganda Virus Research Institute and on July 11 by the Government of Southern Sudan (GOSS) via the CDC Global Disease Detection Regional Center in Kenya to perform diagnostic laboratory testing on conjunctival swabs from persons with "red eye syndrome." Widespread, ongoing outbreaks of acute hemorrhagic conjunctivitis (AHC) have been observed in Uganda and Southern Sudan since spring 2010. AHC becomes a reportable condition in outbreak settings. Case numbers were estimated in Uganda after MoH confirmation of reported cases from district health facilities and, in Southern Sudan, after a medical record review in six health facilities. To date, 6,818 cases from 26 districts in Uganda, and 428 cases in Juba, Southern Sudan, have been counted; however, because most cases are not reported, these totals are considered underestimates. PMID- 20724970 TI - [The role of multispiral computed tomographic coronarography]. AB - The aim of the study was to assess the use of multispiral computed tomographic coronarography (MSCT-CG) in comparison with conventional coronary angiography. Overall 62 patients aged 45-72 years were examined, the MSCT-CG was conducted in 38 patients. The sensitivity of MSCT-CG was 92%, the specificity - 91,2%, in comparison with the CAG. The prognostic value of negative test was 95,7%, the prognostic value of positive test was 84%, overall accuracy was counted up to 91,5%. Though, the MSCT-CG showed certain overestimation in calculating the stenosis degree and, thus, false positive results, in cases with calcined atherosclerotic plaques. Main advantages of MSCT-CG were: non-invasiveness, possibility of vessel lumen, arterial wall and structure of the plaque assessment. PMID- 20724971 TI - [The noncomplicated colon cancer treatment]. AB - 531 patients with non-complicated and non-metastatic colon cancer were operated on during 1995-2008 years. Surgery was radical in all cases. Various types of surgical treatment of the colon cancer, postoperative complications and lethality were analyzed. Open methods reported a 1,6% complications rate and lethality rate was 0,4%. Whereas, laparoscopically operated patients showed the complication rate of 3,6% and lethality was 1,2%. Overall 5-year survival was 91,7% for T1 3N0M0; 75,6% for T4N0M0 and 55,3% for T1-4N1-2M0 stages. PMID- 20724972 TI - [Complex approach to the complicated forms of colorectal cancer]. AB - The results of the colon cancer treatment with the use of laparoscopic surgery and different radiotherapy regimens were compared. 75 patients were observed. The main group consisted of 38 patients, who were operated on laparoscopically and had received neoadjuvant radiotherapy course. The control group consisted of 37 patients. The were operated on with the use of "open" techniques, had been colostomized before radical surgery and received adjuvant radiotherapy course. Laparoscopic technologies allowed to improve immediate results of the treatment and to decrease the complication rate from 17.2 to 8.2%. Neoadjuvant radiotherapy allowed to decrease the rate of local cancer recurrence from 28.8 to 12.55%. PMID- 20724973 TI - [Total mesorectumectomy in surgical treatment of rectal cancer]. AB - 561 patients with rectal cancer were included in the study. The main group consisted of 119 patients, operated on during 2006-2009 years. They received total mesorectumectomy with the following pathomorphological control of the radicality. The group of control consisted of 442 patients, who had the rectum mobilized in a "standard" blunt fashion, without using principles of interfascial separation. The operation of total mesorectumectomy proved to take more time, though, it allowed to decrease the intraoperative blood loss, frequency of postoperative urogenital complications and did not increase rates of colorectal anastomosis insufficiency. PMID- 20724974 TI - [Dolichocolon as a reason of chronic constipation]. AB - 53 patients with dolichocolon and chronic cologenic constipations were operated on. Results of comprehensive preoperative check-up, as well as results of surgical treatment were assessed. 88,7% of patients demonstrated good and satisfactory results. Active surgical tactics in respect of these patients, such as wider use of total colectomy and ileorectostomy is suggested. PMID- 20724975 TI - [Endobronchial surgery and photodynamic therapy for the treatment of multiple primary lung cancer]. AB - Endoluminal endoscopic surgery and fotodynamic therapy were used in treatment of 104 patients with multiple primary lung cancer (MPLC), or more exactly, of trachea and lobar and segmental bronchi. Diagnostic division included videobronchoscopy of high resolution in with light and NBI-regimen; autoflourescent and 5-ALA-induced fluorescent videobronchoscopy, endosonography, computed tompgraphy or magnetic resonance imaging of the thorax and epithelial mucine (MUC-1) immunohistochemical analysis of scarificates. Result of treatment strongly depended on the size of primary tumor. Complete regression of cancer was observed for all tumors less then 1 sm in diameter. Endoscopic treatment, including fotodynamic therapy and argon coagulation, proved to be a method of choice in treatment early synchronous or metachronous multiple primary lung cancer in incurable patients. PMID- 20724976 TI - [Long-term quality of life of patients with postoperative ventral hernia]. AB - 125 patients with postoperative ventral hernia were included in the study. First group included patients who were operated on with the use of polypropylene mesh, second group of patients were operated on, using non-mesh techniques. Quality of life was assessed with the use of standard SF-36 questionnarie. The obtained data demonstrated inexpediency of mesh implantation in small hernias, so far the quality of life tended to be the same in both groups, but complication rate was higher in patients of the first group. Mesh implantation was reasonable in treatment of medium and large ventral hernias. PMID- 20724977 TI - [Clinico-morphologic and immunohystochemical characteristics of the angiogenesis by malignant osseous lymphoma]. AB - Clinico-morphologic and immunohystochemical characteristics of the angiogenesis were analyzed in 24 patients with malignant osseous lymphoma. Maximal density of CD-31 positive cells was registered. Immunopositivity was shown for cytoplasm and cell wall. Authors consider the elevated rate of CD-31 positive cells in tumor stroma to be a negative prognostic factor after radical surgery for malignant osseous lymphoma. PMID- 20724978 TI - [Postinfusion complications by acute blood loss]. AB - Highs and lows of infusion therapy for the treatment of the acute blood loss were studied experimentally and in clinic. Colloid and crystalloid solutions, being hemodilutants, do not transport oxygen, causing, therefore, several complications in recipient's organism. Dilutional anemic and lead to heart insufficiency, which, by-turn, cause the so called dilutional circulatory hypoxia. PMID- 20724979 TI - [Surgical and combined treatment of patients with metastatic liver and lymph nodes invasion by colorectal cancer]. AB - 527 patients were operated on for liver colorectal cancer metastases. Of all cases of lymphadenectomy during liver resections, lymph nodes invasion was morphologically proved in 43 patients. 3- and 5-year survival rate in this group was 12,8+/-6.6% and 6.4+/-5.6%, respectively. No patients survived a ten-year interval. Maximal follow-up period was 62 months, median - 17 months. 3-year disease-free survival rate was 5.1+/-4.8%. No 5-year disease-free survival was registered. Inclusion of oxaliplatin in adjuvant chemotherapy regimen allowed the dramatical improvement of survival rates. PMID- 20724980 TI - [Minimally invasive surgery of cholelithiasis in patients with high operation risk]. AB - Results of cholecystectomy from minilaparotomic access in 556 patients with high operation risk were analyzed. Patients aged 18-89 years, average age was 67.3 +/ 4.5 years. Average surgery duration was 43.5 +/-4.4 min. 82 (14.7%) of patient received a two-stage treatment: endoscopic retrograde cholangiopancreaticography and papillosphincterotomy followed by cholecystectomy, the rest patients had only cholecystectomy with common bile duct surgery, if it was necessary. Intraoperative complications were registered in 19 (3,4%) patients. Lethality rate was 0.18%. PMID- 20724981 TI - [Thoracoscopic treatment of esophageal atresia in infants]. AB - Atresia of esophagus result in absolute lethality without surgical treatment. Posterolateral thoracotomy is a traditional access during such operations, however thoracoscopic methods esophageal atresia has come into practice. Since 2008 all infants (n=22) in our clinic with esophageal atresia have been operated on thoracoscopically. Conversion was performed in 3 observations, 2 children died. Anastomosis insufficiency was diagnosed in 3 patients. 11 children received gullet bougienage in different terms after the operation. Tracheoesophageal fistula recurrence was observed in 2 cases, both were successfully treated thoracoscopically. PMID- 20724982 TI - [Free radical processes at patients with pathologies of biliary ducts and methods of their correction]. AB - The main objective of a research in the early diagnostics of a functional condition of a liver, is to estimate the degree of the level of its expressiveness and timely pathogenetic correction on the basis of the free radical system processes of studying of patients with mechanical jaundice. Results were carried out among 61 patients with pathologies of bile tracts( biliary ducts) which proved the essential role of free radical processes with strengthening of peroxidation of membrane lipids against the absolute or relative insufficiency of endogenic antioxidants in the mechanism of development of hepatic insufficiency at the given category of patients with the highest degree expressed at the serious conditions of the patients with malignant diseases. It is revealed that the inclusion of energy corrector antioxidants of reamberin to the therapy as a part of standard schemes of treatment promoted positive regressing dynamics of parameters of free radical processes that are correlated with positive clinical symptoms and outcome of diseases. PMID- 20724983 TI - Rapid flow cytometric detection of aberrant cytoplasmic localization of nucleophosmin (NPMc) indicating mutant NPM1 gene in acute myeloid leukemia. PMID- 20724984 TI - Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. PMID- 20724985 TI - Effects of MSC co-injection on the reconstitution of aplastic anemia patient following hematopoietic stem cell transplantation. PMID- 20724986 TI - Efficacy of the association of lenalidomide to erythropoiesis-stimulating agents in del (5q) MDS patients refractory to single-agent lenalidomide. PMID- 20724987 TI - Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis. AB - The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (Mll(F)) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis. PMID- 20724989 TI - Effect of older maternal age on birth outcomes in twin pregnancies: a population based study. AB - OBJECTIVE: We compared perinatal mortality, preterm birth (<37, <33 and <28 weeks), small for gestational age (SGA), Apgar score (<4), mechanical ventilation (?1 days) and prolonged neonatal intensive care unit (NICU) hospitalization (?13 days) between twins of 25 to 34 and >35-year-old women. Further, we examined whether older maternal age effects were modified by parity or otherwise affected by chorionicity. STUDY DESIGN: We carried out a population-based retrospective cohort study including all twin births in British Columbia (BC), Canada, from 1999 to 2003. The BC perinatal database registry was used to obtain clinical, behavioral and demographic data. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated using generalized estimating equation models. RESULT: Overall, twins of older women were more likely to be born preterm (<37 weeks), but not very or extremely preterm (<33 weeks). These twins were not at increased risk of perinatal death, mechanical ventilation or were not SGA compared with twins of younger women. Twins of older primiparous women did not have an elevated risk of NICU hospitalization; twins born to older multiparous women had higher risk (OR=1.8; 95% CI: 1.2 to 2.6). Analyses restricted to opposite-sex (dichorionic) twins showed that perinatal death, mechanical ventilation and very preterm birth occur less likely among older women (OR=0.2 (95% CI: 0.0 to 0.8), OR=0.3 (95% CI: 0.1 to 0.7) and OR=0.4 (95% CI: 0.2 to 0.7), respectively). Further, the risk of late preterm birth was increased and NICU hospitalization was reduced among opposite-sex twins born to older compared with younger primiparous women (OR=1.9 (95% CI: 1.3 to 2.8) and OR=0.2 (95% CI: 0.1 to 0.5), respectively). CONCLUSION: Twins of older mothers did not have an elevated risk for most adverse birth outcomes, except for late preterm birth. Risks of neonatal care admission may be elevated among older multiparous women. PMID- 20724988 TI - LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic phase disease with TET2, IDH, JAK2 or MPL mutations. AB - LNK mutation analysis was performed in 61 patients with blast-phase myeloproliferative neoplasms (MPN); post-primary myelofibrosis (PMF) in 41, post polycythemia vera in 11 and post-essential thrombocythemia in 9 patients. Paired chronic-blast phase sample analysis was possible in 26 cases. Nine novel heterozygous LNK mutations were identified in eight (13%) patients: six exon 2 missense mutations involving codons 215, 220, 223, 229 and 234, a synonymous mutation involving codon 208, and two deletion mutations involving exon 2 (685 691_delGGCCCCG) or exon 5 (955_delA); eight affected the pleckstrin homology (PH) domain. Mutations were detected in six (9.8%) blast-phase samples; chronic-phase sample analysis in four of these revealed the same mutation in one. Mutant LNK was detected in chronic-phase only in two patients and in both chronic-blast phases in one. JAK2V617F was documented in three and IDH2R140Q in one LNK-mutated patients. LNK mutations were not detected in 78 additional patients with chronic phase MPN enriched for TET2, IDH, JAK2V617F, or MPL-mutated cases. We conclude that LNK mutations (i) target an exon 2 'hot spot' in the PH domain spanning residues E208-D234, (ii) might be more prevalent in blast-phase PMF and (iii) are not mutually exclusive of other MPN-associated mutations but rarely occur in their presence in chronic-phase disease. PMID- 20724990 TI - Chorioamnionitis, respiratory distress syndrome and bronchopulmonary dysplasia in extremely low birth weight infants. AB - OBJECTIVE: To determine if histologic chorioamnionitis (HC) in the presence of respiratory distress syndrome (RDS) augments adverse pulmonary outcomes in extremely low birth weight (ELBW) infants. STUDY DESIGN: We retrospectively identified 184 ELBW infants who were born at and admitted to the neonatal intensive care units between June 2005 and June 2009. RESULTS: The mean gestational age of the cases was 27 +/- 2 weeks, and the mean birth weight was 791 +/- 147 g. A total of 88% (161/184) of patients developed bronchopulmonary dysplasia (BPD). HC was observed in 71 of 238 infants (39%). When infants were divided on the basis of the presence or absence of HC and RDS, the incidence of moderate or severe BPD and duration of oxygen requirement were greater in the HC+RDS+ group than in the HC-RDS+ or HC+RDS- groups. The combination of prenatal (HC) and postnatal (RDS) injuries increased significantly the risk for BPD. In the multivariate analysis, the significant predictors of developing BPD were low gestational age (odds ratio (OR), 0.6; confidence interval (CI), 0.4 to 0.7) and exposure to both HC and RDS (OR, 4.7; CI, 1.1 to 20.2). CONCLUSION: The HC and RDS work synergistically to induce lung injury in ELBW infants. Chorioamnionitis may interact with RDS to further increase the risk of BPD, despite either HC or RDS could not show independent significant association with BPD. PMID- 20724993 TI - Inferring echolocation in ancient bats. AB - Laryngeal echolocation, used by most living bats to form images of their surroundings and to detect and capture flying prey, is considered to be a key innovation for the evolutionary success of bats, and palaeontologists have long sought osteological correlates of echolocation that can be used to infer the behaviour of fossil bats. Veselka et al. argued that the most reliable trait indicating echolocation capabilities in bats is an articulation between the stylohyal bone (part of the hyoid apparatus that supports the throat and larynx) and the tympanic bone, which forms the floor of the middle ear. They examined the oldest and most primitive known bat, Onychonycteris finneyi (early Eocene, USA), and argued that it showed evidence of this stylohyal-tympanic articulation, from which they concluded that O. finneyi may have been capable of echolocation. We disagree with their interpretation of key fossil data and instead argue that O. finneyi was probably not an echolocating bat. PMID- 20724995 TI - After the pandemic. PMID- 20724991 TI - Laryngeally echolocating bats. AB - Echolocation of bats is a fascinating topic with an ongoing controversy regarding the signal processing that bats perform on the echo. Veselka et al. found that bats that use the larynx for producing the echolocating ultrasound have a stylohyal bone that connects the larynx to the auditory bulla. I propose that the stylohyal bone is used for heterodyne detection of Doppler-shifted echoes. This would allow very precise frequency resolution and phase-sensitive analysis of the returning echoes for determining the velocity of echolocated objects like insects. PMID- 20724996 TI - Far-sighted vision. PMID- 20725003 TI - Journal club. A cancer biologist weighs up p53, metabolism and cancer. PMID- 20725008 TI - Harvard probe kept under wraps. PMID- 20725009 TI - FDA challenges stem-cell clinic. PMID- 20725010 TI - US survey sets cosmic priorities. PMID- 20725011 TI - Science panel gives hope in river-pollution dispute. PMID- 20725012 TI - Jet reveals atmosphere's secrets. PMID- 20725013 TI - E-mails spark ethics row. PMID- 20725014 TI - Physiology: The bones of contention. PMID- 20725015 TI - Biotechnology: Crossing the barrier. PMID- 20725016 TI - World view: Leaders wanted. PMID- 20725017 TI - Monitoring systems outdated and protectionist. PMID- 20725018 TI - Track social and economic impacts of food production. PMID- 20725019 TI - Mitigate food loss to feed more people right now. PMID- 20725020 TI - Reduce soil damage for more sustainable crop production. PMID- 20725025 TI - Atmospheric chemistry: A missing sink for radicals. PMID- 20725021 TI - Culturing practices can make roots more robust too. PMID- 20725026 TI - Gene expression: How plants avoid incest. PMID- 20725028 TI - Astrophysics: Waves on Orion's shores. PMID- 20725029 TI - DNA repair: Blocking ubiquitin transfer. PMID- 20725030 TI - Evolutionary biology: Oh sibling, who art thou? PMID- 20725031 TI - Earthquakes: Double trouble at Tonga. PMID- 20725032 TI - Obituary: Stephen Henry Schneider (1945-2010). PMID- 20725034 TI - Waves on the surface of the Orion molecular cloud. AB - Massive stars influence their parental molecular cloud, and it has long been suspected that the development of hydrodynamical instabilities can compress or fragment the cloud. Identifying such instabilities has proved difficult. It has been suggested that elongated structures (such as the 'pillars of creation') and other shapes arise because of instabilities, but alternative explanations are available. One key signature of an instability is a wave-like structure in the gas, which has hitherto not been seen. Here we report the presence of 'waves' at the surface of the Orion molecular cloud near where massive stars are forming. The waves seem to be a Kelvin-Helmholtz instability that arises during the expansion of the nebula as gas heated and ionized by massive stars is blown over pre-existing molecular gas. PMID- 20725033 TI - Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. AB - DNA double-strand breaks (DSBs) pose a potent threat to genome integrity. These lesions also contribute to the efficacy of radiotherapy and many cancer chemotherapeutics. DSBs elicit a signalling cascade that modifies the chromatin surrounding the break, first by ATM-dependent phosphorylation and then by RNF8-, RNF168- and BRCA1-dependent regulatory ubiquitination. Here we report that OTUB1, a deubiquitinating enzyme, is an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppresses RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 does so by binding to and inhibiting UBC13 (also known as UBE2N), the cognate E2 enzyme for RNF168. This unusual mode of regulation is unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response. PMID- 20725035 TI - Enhancement of superconductivity by pressure-driven competition in electronic order. AB - Finding ways to achieve higher values of the transition temperature, T(c), in superconductors remains a great challenge. The superconducting phase is often one of several competing types of electronic order, including antiferromagnetism and charge density waves. An emerging trend documented in heavy-fermion and organic conductors is that the maximum T(c) for superconductivity occurs under external conditions that cause the critical temperature for a competing order to go to zero. Recently, such competition has been found in multilayer copper oxide high temperature superconductors (HTSCs) that possess two crystallographically inequivalent CuO(2) planes in the unit cell. However, whether the competing electronic state can be suppressed to enhance T(c) in HTSCs remains an open question. Here we show that pressure-driven phase competition leads to an unusual two-step enhancement of T(c) in optimally doped trilayer Bi(2)Sr(2)Ca(2)Cu(3)O(10+delta) (Bi2223). We find that T(c) first increases with pressure and then decreases after passing through a maximum. Unexpectedly, T(c) increases again when the pressure is further raised above a critical value of around 24 GPa, surpassing the first maximum. The presence of this critical pressure is a manifestation of the crossover from the competing order to superconductivity in the inner of the three CuO(2) planes. We suggest that the increase at higher pressures occurs as a result of competition between pairing and phase ordering in different CuO(2) planes. PMID- 20725036 TI - A strong ferroelectric ferromagnet created by means of spin-lattice coupling. AB - Ferroelectric ferromagnets are exceedingly rare, fundamentally interesting multiferroic materials that could give rise to new technologies in which the low power and high speed of field-effect electronics are combined with the permanence and routability of voltage-controlled ferromagnetism. Furthermore, the properties of the few compounds that simultaneously exhibit these phenomena are insignificant in comparison with those of useful ferroelectrics or ferromagnets: their spontaneous polarizations or magnetizations are smaller by a factor of 1,000 or more. The same holds for magnetic- or electric-field-induced multiferroics. Owing to the weak properties of single-phase multiferroics, composite and multilayer approaches involving strain-coupled piezoelectric and magnetostrictive components are the closest to application today. Recently, however, a new route to ferroelectric ferromagnets was proposed by which magnetically ordered insulators that are neither ferroelectric nor ferromagnetic are transformed into ferroelectric ferromagnets using a single control parameter, strain. The system targeted, EuTiO(3), was predicted to exhibit strong ferromagnetism (spontaneous magnetization, approximately 7 Bohr magnetons per Eu) and strong ferroelectricity (spontaneous polarization, approximately 10 microC cm(-2)) simultaneously under large biaxial compressive strain. These values are orders of magnitude higher than those of any known ferroelectric ferromagnet and rival the best materials that are solely ferroelectric or ferromagnetic. Hindered by the absence of an appropriate substrate to provide the desired compression we turned to tensile strain. Here we show both experimentally and theoretically the emergence of a multiferroic state under biaxial tension with the unexpected benefit that even lower strains are required, thereby allowing thicker high quality crystalline films. This realization of a strong ferromagnetic ferroelectric points the way to high-temperature manifestations of this spin lattice coupling mechanism. Our work demonstrates that a single experimental parameter, strain, simultaneously controls multiple order parameters and is a viable alternative tuning parameter to composition for creating multiferroics. PMID- 20725037 TI - Near-simultaneous great earthquakes at Tongan megathrust and outer rise in September 2009. AB - The Earth's largest earthquakes and tsunamis are usually caused by thrust faulting earthquakes on the shallow part of the subduction interface between two tectonic plates, where stored elastic energy due to convergence between the plates is rapidly released. The tsunami that devastated the Samoan and northern Tongan islands on 29 September 2009 was preceded by a globally recorded magnitude 8 normal-faulting earthquake in the outer-rise region, where the Pacific plate bends before entering the subduction zone. Preliminary interpretation suggested that this earthquake was the source of the tsunami. Here we show that the outer rise earthquake was accompanied by a nearly simultaneous rupture of the shallow subduction interface, equivalent to a magnitude-8 earthquake, that also contributed significantly to the tsunami. The subduction interface event was probably a slow earthquake with a rise time of several minutes that triggered the outer-rise event several minutes later. However, we cannot rule out the possibility that the normal fault ruptured first and dynamically triggered the subduction interface event. Our evidence comes from displacements of Global Positioning System stations and modelling of tsunami waves recorded by ocean bottom pressure sensors, with support from seismic data and tsunami field observations. Evidence of the subduction earthquake in global seismic data is largely hidden because of the earthquake's slow rise time or because its ground motion is disguised by that of the normal-faulting event. Earthquake doublets where subduction interface events trigger large outer-rise earthquakes have been recorded previously, but this is the first well-documented example where the two events occur so closely in time and the triggering event might be a slow earthquake. As well as providing information on strain release mechanisms at subduction zones, earthquakes such as this provide a possible mechanism for the occasional large tsunamis generated at the Tonga subduction zone, where slip between the plates is predominantly aseismic. PMID- 20725038 TI - The 2009 Samoa-Tonga great earthquake triggered doublet. AB - Great earthquakes (having seismic magnitudes of at least 8) usually involve abrupt sliding of rock masses at a boundary between tectonic plates. Such interplate ruptures produce dynamic and static stress changes that can activate nearby intraplate aftershocks, as is commonly observed in the trench-slope region seaward of a great subduction zone thrust event. The earthquake sequence addressed here involves a rare instance in which a great trench-slope intraplate earthquake triggered extensive interplate faulting, reversing the typical pattern and broadly expanding the seismic and tsunami hazard. On 29 September 2009, within two minutes of the initiation of a normal faulting event with moment magnitude 8.1 in the outer trench-slope at the northern end of the Tonga subduction zone, two major interplate underthrusting subevents (both with moment magnitude 7.8), with total moment equal to a second great earthquake of moment magnitude 8.0, ruptured the nearby subduction zone megathrust. The collective faulting produced tsunami waves with localized regions of about 12 metres run-up that claimed 192 lives in Samoa, American Samoa and Tonga. Overlap of the seismic signals obscured the fact that distinct faults separated by more than 50 km had ruptured with different geometries, with the triggered thrust faulting only being revealed by detailed seismic wave analyses. Extensive interplate and intraplate aftershock activity was activated over a large region of the northern Tonga subduction zone. PMID- 20725039 TI - Promiscuity and the evolutionary transition to complex societies. AB - Theory predicts that the evolution of cooperative behaviour is favoured by low levels of promiscuity leading to high within-group relatedness. However, in vertebrates, cooperation often occurs between non-relatives and promiscuity rates are among the highest recorded. Here we resolve this apparent inconsistency with a phylogenetic analysis of 267 bird species, demonstrating that cooperative breeding is associated with low promiscuity; that in cooperative species, helping is more common when promiscuity is low; and that intermediate levels of promiscuity favour kin discrimination. Overall, these results suggest that promiscuity is a unifying feature across taxa in explaining transitions to and from cooperative societies. PMID- 20725040 TI - An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. AB - Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86 transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic. PMID- 20725041 TI - Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. AB - The thymus develops from the third pharyngeal pouch of the anterior gut and provides the necessary environment for thymopoiesis (the process by which thymocytes differentiate into mature T lymphocytes) and the establishment and maintenance of self-tolerance. It contains thymic epithelial cells (TECs) that form a complex three-dimensional network organized in cortical and medullary compartments, the organization of which is notably different from simple or stratified epithelia. TECs have an essential role in the generation of self tolerant thymocytes through expression of the autoimmune regulator Aire, but the mechanisms involved in the specification and maintenance of TECs remain unclear. Despite the different embryological origins of thymus and skin (endodermal and ectodermal, respectively), some cells of the thymic medulla express stratified epithelium markers, interpreted as promiscuous gene expression. Here we show that the thymus of the rat contains a population of clonogenic TECs that can be extensively cultured while conserving the capacity to integrate in a thymic epithelial network and to express major histocompatibility complex class II (MHC II) molecules and Aire. These cells can irreversibly adopt the fate of hair follicle multipotent stem cells when exposed to an inductive skin microenvironment; this change in fate is correlated with robust changes in gene expression. Hence, microenvironmental cues are sufficient here to re-direct epithelial cell fate, allowing crossing of primitive germ layer boundaries and an increase in potency. PMID- 20725042 TI - Trans-acting small RNA determines dominance relationships in Brassica self incompatibility. AB - A diploid organism has two copies of each gene, one inherited from each parent. The expression of two inherited alleles is sometimes biased by the effects known as dominant/recessive relationships, which determine the final phenotype of the organism. To explore the mechanisms underlying these relationships, we have examined the monoallelic expression of S-locus protein 11 genes (SP11), which encode the male determinants of self-incompatibility in Brassica. We previously reported that SP11 expression was monoallelic in some S heterozygotes, and that the promoter regions of recessive SP11 alleles were specifically methylated in the anther tapetum. Here we show that this methylation is controlled by trans acting small non-coding RNA (sRNA). We identified inverted genomic sequences that were similar to the recessive SP11 promoters in the flanking regions of dominant SP11 alleles. These sequences were specifically expressed in the anther tapetum and processed into 24-nucleotide sRNA, named SP11 methylation inducer (Smi). Introduction of the Smi genomic region into the recessive S homozygotes triggered the methylation of the promoter of recessive SP11 alleles and repressed their transcription. This is an example showing sRNA encoded in the flanking region of a dominant allele acts in trans to induce transcriptional silencing of the recessive allele. Our finding may provide new insights into the widespread monoallelic gene expression systems. PMID- 20725043 TI - A mechanically stabilized receptor-ligand flex-bond important in the vasculature. AB - Haemostasis in the arteriolar circulation mediated by von Willebrand factor (VWF) binding to platelets is an example of an adhesive interaction that must withstand strong hydrodynamic forces acting on cells. VWF is a concatenated, multifunctional protein that has binding sites for platelets as well as subendothelial collagen. Binding of the A1 domain in VWF to the glycoprotein Ib alpha subunit (GPIbalpha) on the surface of platelets mediates crosslinking of platelets to one another and the formation of a platelet plug for arterioles. The importance of VWF is illustrated by its mutation in von Willebrand disease, a bleeding diathesis. Here, we describe a novel mechanochemical specialization of the A1-GPIbalpha bond for force-resistance. We have developed a method that enables, for the first time, repeated measurements of the binding and unbinding of a receptor and ligand in a single molecule (ReaLiSM). We demonstrate two states of the receptor-ligand bond, that is, a flex-bond. One state is seen at low force; a second state begins to engage at 10 pN with a approximately 20-fold longer lifetime and greater force resistance. The lifetimes of the two states, how force exponentiates lifetime, and the kinetics of switching between the two states are all measured. For the first time, single-molecule measurements on this system are in agreement with bulk phase measurements. The results have important implications not only for how platelets bound to VWF are able to resist force to plug arterioles, but also how increased flow activates platelet plug formation. PMID- 20725044 TI - Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. AB - Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms. Deficiencies in PCC activity in humans are linked to the disease propionic acidaemia, an autosomal recessive disorder that can be fatal in infants. The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa. The alpha subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the beta-subunit supplies the carboxyltransferase (CT) activity. Here we report the crystal structure at 3.2-A resolution of a bacterial PCC alpha(6)beta(6) holoenzyme as well as cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution demonstrating a similar structure for human PCC. The structure defines the overall architecture of PCC and reveals unexpectedly that the alpha-subunits are arranged as monomers in the holoenzyme, decorating a central beta(6) hexamer. A hitherto unrecognized domain in the alpha subunit, formed by residues between the BC and BCCP domains, is crucial for interactions with the beta-subunit. We have named it the BT domain. The structure reveals for the first time the relative positions of the BC and CT active sites in the holoenzyme. They are separated by approximately 55 A, indicating that the entire BCCP domain must translocate during catalysis. The BCCP domain is located in the active site of the beta-subunit in the current structure, providing insight for its involvement in the CT reaction. The structural information establishes a molecular basis for understanding the large collection of disease causing mutations in PCC and is relevant for the holoenzymes of other biotin dependent carboxylases, including 3-methylcrotonyl-CoA carboxylase (MCC) and eukaryotic acetyl-CoA carboxylase (ACC). PMID- 20725050 TI - Pharmacodynamics of clonidine therapy in pregnancy: a heterogeneous maternal response impacts fetal growth. AB - BACKGROUND: Clonidine, a centrally acting antihypertensive agent, has been used successfully in pregnancy. We sought to describe the pharmacodynamic effects of clonidine in pregnancy and the associated impact on fetal growth. METHODS: A retrospective cohort study was performed. Maternal hemodynamics were measured before and after treatment. Responses to clonidine were categorized by the predominant hemodynamic effect: decreased vascular resistance, decreased cardiac output (CO), or mixed. Multinomial logistic regression was used to evaluate predictors of hemodynamic response to clonidine and association between response group and birth weight. RESULTS: Sixty-six pregnant women were studied. Treatment was associated with a reduction of mean arterial pressure (MAP) (-9.2 mm Hg, P < 0.001), a reduction in total peripheral resistance (TPR) (-194 dyne.cm.sec-5, P < 0.001), and an increase in CO (+0.5 l/min, P < 0.001). The hemodynamic response was characterized by decreased resistance in 34 women; decreased CO in 22; and mixed effect in 10. No maternal demographic characteristics were associated with a reduction in CO. Mean birth weight percentile was lower in the group that experienced a reduction in CO compared to the group with a reduction in vascular resistance (26.1 vs. 43.6, P = 0.02). The rate of birth weight <10th percentile was also higher in the group experiencing decreased CO (41 vs. 8.8%, P = 0.008). CONCLUSIONS: The hemodynamic effect of clonidine in pregnancy is heterogeneous. The category of effect, reduction in vascular resistance vs. reduction in CO, significantly impacts fetal growth. A reduction in heart rate (HR) after therapy identifies pregnancies at risk for reduced fetal growth. PMID- 20725051 TI - Evidence that prenatal programming of hypertension by dietary protein deprivation is mediated by fetal glucocorticoid exposure. AB - BACKGROUND: Prenatal programming by maternal dietary protein deprivation and prenatal dexamethasone result in a reduction in nephron number and hypertension when the offspring are studied as adults. METHODS: To determine whether prenatal dietary protein deprivation results in a reduction in nephron number and hypertension in offspring by exposure to maternal glucocorticoids, we administered metyrapone to rats fed either a 6% or 20% protein diet to inhibit glucocorticoid production and compared the offspring to rats that were the product of mothers fed either a 6% or 20% protein diet during the last half of pregnancy. RESULTS: Male offspring from the 6% group had elevated systolic blood pressure (149 +/- 2 vs. 130 +/- 5 mm Hg, P < 0.05) and a reduction in glomeruli compared to the 20% group (22,111 +/- 627 vs. 29,666 +/- 654 glomeruli/kidney, P < 0.001). Maternal metyrapone administration did not affect the blood pressure in the 20% group but ameliorated the increase in blood pressure in the 6% male group to values comparable to the 20% control group (138 +/- 6 vs. 130 +/- 5 mm Hg). Male offspring of the 6% group that received metyrapone had an increase in the number of glomeruli compared to the vehicle-treated 6% group (26,780 +/- 377 vs. 22,111 +/- 627 glomeruli/kidney, P < 0.001), but less glomeruli compared to the 20% protein control group (26,780 +/- 377 vs. 29,666 +/- 654 glomeruli/kidney, P = 0.01). CONCLUSIONS: The reduction in nephron number and hypertension induced by maternal protein deprivation in male offspring is ameliorated by inhibition of glucocorticoid production. PMID- 20725052 TI - Role of reactive oxygen species during hypertension in response to chronic antiangiogenic factor (sFlt-1) excess in pregnant rats. AB - BACKGROUND: Preeclampsia is associated with increased levels of reactive oxygen species (ROS) and the antiangiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1). Moreover, recent studies have indicated that chronic sFlt-1 excess causes hypertension in pregnant animals. The purpose of this study was to evaluate the role of ROS in mediating sFlt-1-induced hypertension in the pregnant rat. METHODS: Mean arterial pressure (MAP), and plasma sFlt-1 and tissue ROS levels were measured in the following groups: (i) pregnant controls; (ii) sFlt-1 treated pregnant rats; (iii) Tempol-treated pregnant rats; (iv) sFlt-1- and Tempol-treated pregnant rats. RESULTS: MAP increased from 104 +/- 2 mm Hg in pregnant control rats to 118 +/- 3 mm Hg (P = 0.002) in sFlt-1-infused rats. Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated levels of tissue ROS were increased in response to excess sFlt-1 during pregnancy. Pretreatment with Tempol attenuated oxidative stress and hypertension in response to sFlt-1. CONCLUSIONS: ROS play an important role in mediating hypertension in response to chronic sFlt-1 excess during pregnancy. PMID- 20725053 TI - Characteristics of antihypertensive medication and change of prescription over 1 year of follow up in Japan: Fukushima Research of Hypertension (FRESH). AB - BACKGROUND: The relationship between achieving target blood pressures and medication modification among hypertensive patients in Japan is relatively unknown. We examined the incidence of prescription changes and how the prescription changes influence success rates in achieving target blood pressures in a group of patients with uncontrolled hypertension. METHODS: This prospective observational cohort study (July 2006 to May 2007) examined the association between blood pressure control and antihypertensive medication among 2,735 Japanese hypertensive patients who completed four seasonal follow-ups and whose medications were verified. The primary outcome was "therapeutic failure" at the third follow-up survey. Logistic regression analyzed how prescription changes may influence therapeutic failure risk. Common medication changes were estimated using follow-up data. RESULTS: Median ages and proportion of males were 73 years and 43.8% vs. 69 years and 45.6% in those with controlled and those with uncontrolled hypertension at baseline, respectively. At baseline, 1,496 patients were uncontrolled, and 296 (18.0%) changed prescriptions during the follow-up period. Among patients with diabetes mellitus, renal disease, or organ damage and vascular complications, who were uncontrolled at baseline, prescription changes during the year significantly increased therapeutic failures at the third follow up after adjusting for related variables. About half of the changes at each follow-up visit remained in the same class or combination category. CONCLUSIONS: This study identified infrequent changes in prescription and minor modifications of medication even among uncontrolled hypertension. We highlight the importance of reviewing prescription content to maintain or improve blood pressure levels to achieve recommended treatment goals. PMID- 20725054 TI - Adult hypertension is associated with blood pressure variability in childhood in blacks and whites: the bogalusa heart study. AB - BACKGROUND: Blood pressure (BP) is a variable physiological parameter in health and disease. Increased BP variability over time in adults is associated with severity of end-organ damage and a higher rate of cardiovascular events, even after adjusting for the mean levels. This study tested the hypothesis that childhood BP variability, besides the mean levels, is also predictive of adulthood hypertension. METHODS: The study cohort consisted of 1,797 subjects (1,091 whites and 706 blacks; age = 21-48 years) enrolled in the Bogalusa Heart Study since childhood. BP variability was depicted as s.d. of 4-8 serial measurements in childhood. RESULTS: Blacks showed significantly greater childhood systolic BP (SBP) variability than whites. In multivariable logistic regression analyses, adjusting for race, sex, mean childhood age, s.d. of childhood body mass index (BMI), mean childhood BP levels, adulthood age and BMI, adult hypertension was significantly associated with s.d. of childhood SBP (odds ratio (OR) (95% confidence intervals) = 1.28 (1.09, 1.51), P = 0.002) and s.d. of childhood diastolic BP (DBP; 1.36 (1.16, 1.58), P < 0.001). When using adulthood BP levels as continuous dependent variables in linear regression models, adjusting for the same covariates, adulthood SBP and DBP levels were significantly associated with s.d. of childhood SBP (standardized regression coefficient beta = 0.086, P < 0.001) and s.d. of childhood DBP (beta = 0.105, P < 0.001), respectively. CONCLUSIONS: Increases in BP variations as well as levels in early life are predictive of adult hypertension, which underscore the childhood origin of the natural history of essential hypertension. PMID- 20725055 TI - Pressor responses to antihypertensive drug types. AB - BACKGROUND: Pressor responses to antihypertensive drugs are not addressed in treatment guidelines although they have been described in various clinical situations. We now report the incidence of pressor responses to initiation of monotherapy using four antihypertensive drug types, and the influence of plasma renin activity (PRA) status, among participants in a worksite-based antihypertensive treatment program. METHODS: Systolic blood pressure (SBP) response was evaluated among 945 participants with no prior treatment who were given either a diuretic or calcium-channel blocker (natriuretic antivolume V drugs, n = 537) or a beta-blocker or angiotensin-converting enzyme (ACE) inhibitor (antirenin R drugs n = 408). PRA was categorized by low, middle, and high tertiles (L, M, and H). SBP rise > or =10 mm Hg was considered pressor. RESULTS: More pressor responses occurred with R than V drugs (11% vs. 5%, P = 0.001). L, M, and H renin tertiles had similar frequencies with V drugs (6, 4, and 6%), but low and middle tertiles given R had greater pressor frequencies (17% P = 0.003 vs. V and 10% P = 0.02 vs. V). Treatment SBP > or =160 mm Hg occurred more frequently with R than V drugs (19% vs. 13%; P = 0.007); moreover, in the lowest renin tertile 35% R vs. 13% V (P = 0.001) had SBP > or =160 mm Hg. Treatment SBP <130 mm Hg was more frequent in V patients in the lowest tertile (18% vs. 5%; P = 0.003), and in R patients in the highest tertile (26% vs. 12%, P = 0.002). CONCLUSIONS: Pressor responses to antihypertensive monotherapy occur sufficiently frequently to be of concern, especially in lower renin patients given a beta-blocker or ACE inhibitor (ACEI). PMID- 20725056 TI - Ethnic differences in blood pressure response to first and second-line antihypertensive therapies in patients randomized in the ASCOT Trial. AB - BACKGROUND: Some studies suggest that blood pressure (BP)-lowering effects of commonly used antihypertensive drugs differ among ethnic groups. However, differences in the response to second-line therapy have not been studied extensively. METHODS: In the BP-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA), BP levels of European (n = 4,368), African (203), and South-Asian- (132) origin patients on unchanged monotherapy (atenolol or amlodipine) and/or on second-line therapy (added thiazide or perindopril) were compared. Interaction between ethnicity and BP responses (defined as end BP minus start of therapy BP) to both first- and second-line therapies were assessed in regression models after accounting for age, sex, and several other potential confounders. RESULTS: BP response to atenolol and amlodipine monotherapy differed among the three ethnic groups (interaction test P = 0.05). Among those allocated atenolol monotherapy, black patients were significantly less responsive (mean systolic BP (SBP) difference +1.7 (95% confidence interval: -1.1 to 4.6) mm Hg) compared to white patients (referent). In contrast, BP response to amlodipine monotherapy did not differ significantly by ethnic group. BP responses to the addition of second-line therapy also differed significantly by ethnic group (interaction test P = 0.004). On adding a diuretic to atenolol, BP lowering was similar among blacks and South-Asians as compared to whites (referent). However, on addition of perindopril to amlodipine, BP responses differed significantly: compared to whites (SBP difference -1.7 (-2.8 to -0.7) mm Hg), black patients had a lesser response (SBP difference 0.8 (-2.5 to 4.2) mm Hg) and South-Asians had a greater response (SBP difference -6.2 (-10.2 to -2.2) mm Hg). CONCLUSIONS: We found important differences in BP responses among ethnic groups to both first- and second-line antihypertensive therapies. PMID- 20725057 TI - Plasma renin activity predicts blood pressure responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy for hypertension. AB - BACKGROUND: Age and race categories or renin profiling have been recommended to predict blood pressure responses to monotherapy with a beta-blocker or thiazide diuretic. Whether these or other characteristics predict blood pressure responses when the drugs are administered as add-on therapy is uncertain. METHODS: We evaluated predictors of blood pressure response in 363 men and women < or =65 years of age with primary hypertension (152 blacks, 211 whites), 86 of whom (24%) were untreated and 277 of whom (76%) were withdrawn from previous antihypertensive drugs before randomization to either atenolol followed by addition of hydrochlorothiazide (N = 180) or hydrochlorothiazide followed by addition of atenolol (N = 183). Responses were determined by home blood pressure averages before and after each drug administration. Race, age, plasma renin activity, and other characteristics including pretreatment blood pressure levels were incorporated into linear regression models to quantify their contributions to prediction of blood pressure responses. RESULTS: Plasma renin activity and pretreatment blood pressure level consistently contributed to prediction of systolic and diastolic responses to each drug administered as mono- and as add-on therapy. Higher plasma renin activity was consistently associated with greater blood pressure responses to atenolol and lesser responses to hydrochlorothiazide. The predictive effects of plasma renin activity were statistically independent of race, age, and other characteristics. CONCLUSIONS: Plasma renin activity and pretreatment blood pressure level predict blood pressure responses to atenolol and hydrochlorothiazide administered as mono- and as add-on therapy in men and women < or =65 years of age. PMID- 20725059 TI - The influence of overweight and obesity on longitudinal trends in maternal serum leptin levels during pregnancy. AB - Maternal obesity influences a number of metabolic factors that can affect the course of pregnancy. Among these factors, leptin plays an important role in energy metabolism and fetal development during pregnancy. Our objective was to estimate the influence of maternal overweight/obesity on variation in the maternal serum leptin profile during pregnancy. In a prospective cohort of 143 adult gravidas with singleton pregnancies presenting for general prenatal care, we measured serum leptin levels at 6-10, 10-14, 16-20, 22-26, and 32-36 weeks' gestation. The longitudinal effects of maternal prepregnancy BMI, categorized as nonoverweight (<= 26.0 kg/m(2)) and overweight/obese (>26.0 kg/m(2)), on serum leptin concentration were analyzed using linear mixed models. Overweight/obese women had significantly higher serum leptin concentrations than their nonoverweight counterparts throughout pregnancy (P < 0.01). Although these concentrations increased significantly across gestation for both groups, the rate of increase was significantly smaller for overweight/obese women (P < 0.05). To investigate whether these differences merely reflected differences in weight-gain patterns between the two groups, we examined an index of leptin concentration per unit body weight (leptin (ng/ml)/weight (kg)). Overweight/obese women had a significantly higher index throughout pregnancy (P < 0.01). However, although this index increased significantly across pregnancy for nonoverweight women, it actually decreased significantly for overweight/obese women (P < 0.01). Our results suggest that factors other than fat mass alone influence leptin concentrations in overweight/obese women compared to normal-weight women during pregnancy. Such factors may contribute to differences in the intrauterine environment and its influence on pregnancy outcomes in the two groups. PMID- 20725058 TI - Preventing obesity during infancy: a pilot study. AB - More than 20% of US children between ages 2 and 5 years are overweight suggesting efforts to prevent obesity must begin earlier. This study tested the independent and combined effects of two behavioral interventions delivered to parents, designed to promote healthy infant growth in the first year. Mother-newborn dyads intending to breastfeed were recruited from a maternity ward. With a 2 * 2 design, 160 dyads were randomized into one of four treatment cells to receive both, one, or no interventions delivered at two nurse home visits. The first intervention ("Soothe/Sleep") instructed parents on discriminating between hunger and other sources of infant distress. Soothing strategies were taught to minimize feeding for non-hunger-related fussiness and to prolong sleep duration, particularly at night. The second intervention ("Introduction of Solids") taught parents about hunger and satiety cues, the timing for the introduction of solid foods, and how to overcome infants' initial rejection of healthy foods through repeated exposure. A total of 110 mother-infant dyads completed the year-long study. At 1 year, infants who received both interventions had lower weight-for length percentiles (P = 0.009). Participants receiving both interventions had a mean weight-for-length in the 33rd percentile; in contrast, those in other study groups were higher first intervention only--50th percentile; second intervention only--56th percentile; control group--50th percentile).This suggests that multicomponent behavioral interventions may have potential for long-term obesity prevention (ClinicalTrials.gov number, NCT00359242). PMID- 20725060 TI - Leptin modulated changes in adipose tissue protein expression in ob/ob mice. AB - Comparative proteomic analyses were performed in adipose tissue of leptin deficient ob/ob mice treated with leptin or control buffer in order to identify the protein expression changes as the potential targets of leptin. Mice were treated with either phosphate-buffered saline (control) or 10 ug/day leptin for 14 days via subcutaneous osmotic minipumps. Total protein from white adipose tissue was extracted and labeled with different fluorescent cyanine dyes for analysis by two-dimensional difference gel electrophoresis (DIGE). Spots that were differentially expressed and appeared to have sufficient material for mass spectrometry analysis were picked and digested with trypsin and subjected to MALDI-TOF MS for protein identification. Twelve functional protein groups were found differentially expressed in adipose tissue of leptin-treated vs. control ob/ob mice, including molecular chaperones and redox proteins such as calreticulin (CALR), protein disulfide isomerase-associated 3 (PDIA3), prohibitin (PHB), and peroxiredoxin-6 (PRDX6); cytoskeleton proteins such as beta actin, desmin, and alpha-tubulin; and some other proteins. The mRNA levels of CALR, PDIA3, and PHB were measured by real-time reverse transcription-PCR and found to be upregulated (P < 0.05), consistent with the fold change in protein expression level. Our findings suggest that leptin's effects on lipid metabolism and apoptosis may be mediated in part by alterations in expression of molecular chaperones and redox proteins for regulating endoplasmic reticulum stress and cytoskeleton proteins for regulating mitochondrial morphology. PMID- 20725061 TI - MC4R variant is associated with BMI but not response to resistance training in young females. AB - Recently, a genome-wide association study (GWAS) that identified eight single nucleotide polymorphisms (SNPs) associated with BMI highlighted a possible neuronal influence on the development of obesity. We hypothesized these SNPs would govern the response of BMI and subcutaneous fat to resistance training in young individuals (age = 24 years). We genotyped the eight GWAS-identified SNPs in the article by Willer et al. in a cohort (n = 796) that undertook a 12-week resistance-training program. Females with a copy of the rare allele (C) for rs17782313 (MC4R) had significantly higher BMIs ( CC/CT: n = 174; 24.70 +/- 0.33 kg/m2, TT: n = 278; 23.41 +/- 0.26 kg/m2, P = 0.002), and the SNP explained 1.9% of overall variation in BMI. Males with a copy of the rare allele (T) for rs6548238 (TMEM18) had lower amounts of subcutaneous fat pretraining (CT/TT: n = 65; 156,534 +/- 7,415 mm3, CC: n = 136; 177,825 +/- 5,139 mm3, P = 0.019) and males with a copy of the rare allele (A) for rs9939609 (FTO) lost a significant amount of subcutaneous fat with exercise ( AT/AA: n = 83; -798.35 +/- 2,624.30 mm3, TT: n = 47; 9,435.23 +/- 3,494.44 mm3, P = 0.021). Females with a copy of the G allele for a missense variant in the SH2B1 (rs7498665) was associated with less change of subcutaneous fat volume with exercise ( AG/GG: n = 191; 9,813 +/- 2,250 mm3 vs. AA: n = 126; 770 +/- 2,772 mm3; P = 0.011). These data support the original finding that there is an association between measures of obesity and a variant near the MC4R gene and extends these results to a younger population and implicates FTO, TMEM18, and SH2B1 polymorphisms in subcutaneous fat regulation. PMID- 20725062 TI - Influence of short-term consumption of the caffeine-free, epigallocatechin-3 gallate supplement, Teavigo, on resting metabolism and the thermic effect of feeding. AB - Green tea is purported to promote weight loss. Resting metabolic rate (RMR) and the thermic effect of feeding (TEF) are significant components of total daily energy expenditure and are partially determined by the sympathetic nervous system via catecholamine-mediated stimulation of beta-adrenergic receptors. Epigallocatechin-3-gallate (EGCG: the most bioactive catechin in green tea) inhibits catechol-O-methyltransferase, an enzyme contributing to the degradation of catecholamines. Accordingly, we hypothesized that short-term consumption of a commercially available EGCG supplement (Teavigo) augments RMR and TEF. On two separate occasions, seven placebo or seven EGCG capsules (135 mg/capsule) were administered to 16 adults (9 males, 7 females, age 25 +/- 2 years, BMI 24.6 +/- 1.2 kg/m(2) (mean +/- s.e.)). Capsules (three/day) were consumed over 48 h; the final capsule was consumed 2 h prior to visiting the laboratory. Energy expenditure (ventilated hood technique) was determined at rest and for 5 h following ingestion of a liquid meal (caloric content: 40% RMR). Contrary to our hypothesis, RMR was not greater (P = 0.10) following consumption of EGCG (6,740 +/- 373 kJ/day) compared with placebo (6,971 +/- 352). Similarly, the area under the TEF response curve (Delta energy expenditure) was also unaffected by EGCG (246,808 +/- 23,748 vs. 243,270 +/- 22,177 kJ; P = 0.88). EGCG had no effect on respiratory exchange ratio at rest (P = 0.29) or throughout the TEF measurement (P = 0.56). In summary, together RMR and TEF may account for up to 85% of total daily energy expenditure; we report that short-term consumption of a commercially available EGCG supplement did not increase RMR or TEF. PMID- 20725063 TI - Waist circumference is an independent correlate of errors in self-reported BMI. AB - Although there are issues of reporting bias surrounding the use of self-reported BMI, it is frequently the method employed to establish the prevalence of obesity. The goal of this study was to assess whether, independently of measured BMI, waist circumference (WC) was associated with the magnitude of the difference between self-reported and measured BMI within a large sample of European-American (EA) and African-American (AA) adults. Self-reported height and weight, and measured height, weight, and WC were collected on 12,809 adults (61% women, 66% EA) aged 18-65 years. Mean negative BMI differences (self-reported minus measured BMI) were identified in all race-by-sex groups (AA men: -0.55; EA men: -0.63; AA women: -0.91; EA women: -0.67). WC was negatively associated with the BMI difference such that a higher WC was associated with greater under-reporting of BMI. However, after adjusting for age and measured BMI, WC was positively associated with the BMI difference in all race-by-sex groups. These results suggest that WC could be useful in gaining an insight into people's awareness of their own body size and fatness. PMID- 20725064 TI - Cardiovascular disease risk of abdominal obesity vs. metabolic abnormalities. AB - It remains unclear whether abdominal obesity increases cardiovascular disease (CVD) risk independent of the metabolic abnormalities that often accompany it. Therefore, the objective of this study was to evaluate the independent effects of abdominal obesity vs. metabolic syndrome and diabetes on the risk for incident coronary heart disease (CHD) and stroke. The Framingham Offspring, Atherosclerosis Risk in Communities, and Cardiovascular Health studies were pooled to assess the independent effects of abdominal obesity (waist circumference >102 cm for men and >88 cm for women) vs. metabolic syndrome (excluding the waist circumference criterion) and diabetes on risk for incident CHD and stroke in 20,298 men and women aged >=45 years. The average follow-up was 8.3 (s.d. 1.9) years. There were 1,766 CVD events. After adjustment for demographic factors, smoking, alcohol intake, number of metabolic syndrome components, and diabetes, abdominal obesity was not significantly associated with an increased risk of CVD (hazard ratio (HR) (95% confidence interval): 1.09 (0.98, 1.20)). However, after adjustment for demographics, smoking, alcohol intake, and abdominal obesity, having 1-2 metabolic syndrome components, the metabolic syndrome and diabetes were each associated with a significantly increased risk of CVD (2.12 (1.80, 2.50), 2.82 (1.92, 4.12), and 5.33 (3.37, 8.41), respectively). Although abdominal obesity is an important clinical tool for identification of individuals likely to possess metabolic abnormalities, these data suggest that the metabolic syndrome and diabetes are considerably more important prognostic indicators of CVD risk. PMID- 20725065 TI - Generation of microglial cells from mouse embryonic stem cells. AB - Microglia, the resident immune cells of the brain, are difficult to obtain in high numbers and purity using currently available methods; to date, microglia for experimental research are mainly isolated from the brain or from mixed glial cultures. In this paper, we describe a basic protocol for the in vitro differentiation of mouse embryonic stem (ES) cells into microglial precursor cells. Microglia are obtained by a protocol consisting of five stages: (i) cultivation of ES cells, (ii) formation and differentiation of embryoid bodies, (iii) differentiation into neuroectodermal lineage and isolation of myeloid precursor cells, (iv) differentiation into microglial precursor cells and (v) cultivation of ES cell-derived microglial precursors (ESdMs). The protocol can be completed in 60 d and results in stably proliferating ESdM lines, which show inducible transcription of inflammatory genes and cell marker expression comparable with primary microglia. Furthermore, ESdMs are capable of chemokine directed migration and phagocytosis, which are major functional features of microglia. PMID- 20725066 TI - Visualization and genetic analysis of alternative splicing regulation in vivo using fluorescence reporters in transgenic Caenorhabditis elegans. AB - Transgenic multicolor fluorescence reporters enable the visualization of alternative splicing patterns at a single-cell resolution in living organisms and facilitate further genetic analyses to identify cis-elements and trans-acting factors involved in splicing regulation. In this paper, we describe a method of generating fluorescence alternative splicing reporters for the nematode Caenorhabditis elegans. We describe strategies for designing minigene reporters and methods for constructing them; DNA fragments ('modules', such as promoter/3' cassettes, a genomic fragment of interest and a fluorescent protein cassette) that exist in separate vectors are assembled using site-directed recombination. We also describe strategies and methods for mutant screening and single nucleotide polymorphism mapping using fluorescence reporters. This is the first detailed description of the design and construction of fluorescence alternative splicing reporters for C. elegans and their use in subsequent genetic analyses. It takes 2-4 months to construct minigenes and generate extrachromosomal lines for visualizing spatiotemporal distribution of alternative splicing events in vivo. Identification of regulators by integration of transgenes, mutant screening and mapping of the responsible genes takes a further 6-12 months. The fluorescence-reporter construction described here can also be applied to the vertebrate cell culture system. PMID- 20725067 TI - Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice. AB - The retina is a powerful experimental system for the analysis of angiogenic blood vessel growth in the postnatal organisms. The three-dimensional architecture of the vessel network and processes as diverse as endothelial cell (EC) proliferation, sprouting, perivascular cell recruitment, vessel remodeling or maturation can be investigated at high resolution. The characterization of physiological and pathological angiogenic processes in mice has been greatly facilitated by inducible and cell type-specific loss-of-function and gain-of function genetics. In this paper, we provide a detailed protocol for tamoxifen inducible gene deletion in neonatal mice, as well as for retina dissection, whole mount immunostaining and the quantitation of EC sprouting and proliferation. These methods have been optimized by our laboratory and yield reliable results. The entire protocol takes approximately 10 d to complete. PMID- 20725068 TI - An environmental enrichment model for mice. AB - Environmental enrichment for animals is a combination of complex inanimate and social stimulation and generally consists of housing conditions that facilitate enhanced sensory, cognitive, motor and social stimulation relative to standard housing conditions. One of the most robust effects of environmental enrichment is the reduction of anxiety levels. However, the extreme variability in enrichment protocols may account for some of the inconsistencies in its effects and the variance among results reported by different laboratories. In this protocol, we describe a simple environmental enrichment strategy for the induction of a robust and replicable anxiolytic-like effect in mice. We provide detailed instructions on how to build an enrichment cage that is specially designed for easy manipulation, cleaning and observation by the experimenter. In addition, we describe the different enrichment items, their order in the cage, the frequency of renewal and their cleaning and sterilization procedures. The total length of the protocol is 6 weeks. PMID- 20725069 TI - Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. AB - Precision-cut tissue slices (PCTS) are viable ex vivo explants of tissue with a reproducible, well defined thickness. They represent a mini-model of the organ under study and contain all cells of the tissue in their natural environment, leaving intercellular and cell-matrix interactions intact, and are therefore highly appropriate for studying multicellular processes. PCTS are mainly used to study the metabolism and toxicity of xenobiotics, but they are suitable for many other purposes. Here we describe the protocols to prepare and incubate rat and human liver and intestinal slices. Slices are prepared from fresh liver by making a cylindrical core using a drill with a hollow bit, from which slices are cut with a specially designed tissue slicer. Intestinal tissue is embedded in cylinders of agarose before slicing. Slices remain viable for 24 h (intestine) and up to 96 h (liver) when incubated in 6- or 12-well plates under 95% O(2)/5% CO(2) atmosphere. PMID- 20725070 TI - Fluid-percussion-induced traumatic brain injury model in rats. AB - Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Various attempts have been made to replicate clinical TBI using animal models. The fluid percussion model (FP) is one of the oldest and most commonly used models of experimentally induced TBI. Both central (CFP) and lateral (LFP) variations of the model have been used. Developed initially for use in larger species, the standard FP device was adapted more than 20 years ago to induce consistent degrees of brain injury in rodents. Recently, we developed a microprocessor controlled, pneumatically driven instrument, micro-FP (MFP), to address operational concerns associated with the use of the standard FP device in rodents. We have characterized the MFP model with regard to injury severity according to behavioral and histological outcomes. In this protocol, we review the FP models and detail surgical procedures for LFP. The surgery involves tracheal intubation, craniotomy and fixation of Luer fittings, and induction of injury. The surgical procedure can be performed within 45-50 min. PMID- 20725072 TI - Out of the medicine closet: time to talk straight about prescription drug abuse. PMID- 20725075 TI - The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds. PMID- 20725076 TI - Bundle up: it's painful out there--the case for opioid-acetaminophen combinations. PMID- 20725077 TI - Limitations of point-of-care testing in the ED or ICU: a role for regional centralized toxicology laboratories. AB - Although speed in reporting results of clinical laboratory testing for emergency department and intensive care unit patients is always desirable, for clinical toxicology purposes, tests using immunoassays from the central laboratory or point-of-care devices do not have adequate performance or cover the menu of drugs needed to meet clinical standards. Therefore, a regional toxicology laboratory using liquid chromatography-mass spectrometry is desirable for accurate and comprehensive coverage of drug testing. PMID- 20725078 TI - The specialty of medical toxicology: beyond poisonous arrows and activated charcoal. AB - Medical toxicology is a subspecialty focusing on the diagnosis, management and prevention of poisoning effects due to medications, occupational and environmental toxins and xenobiotics, radiological and biological agents. This subspecialty provides an array of opportunities for physicians to care for patients in different settings: medication overdoses, substance abuse management, adverse drug events, exposures to industrial chemical products, and envenomations. Many medical toxicologists work in the pharmaceutical industry and in many government agencies such as as the Centers for Disease Control and Prevention (CDC), the Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA), and the Department of Homeland Security. PMID- 20725079 TI - Are generic drugs really inferior medicines? AB - In this issue Gagne et al. report an elegant case-crossover study of seizures in patients on antiepileptic drugs. They found that a dispensation episode approximately triples the risk of having a seizure within 21 days, but the risk is not statistically different whether the dispensation was of the same brand name or generic drug as previously used or a switch from brand-name to a generic or from a generic to a brand name. The cause of the seizure might be a delay in taking medication or late redispensation, among others, but apparently the nature of the product dispensed is not relevant in this study; this may alleviate some of the concerns about generic drugs and epilepsy. PMID- 20725080 TI - CYP2D6, serotonin, and suicide--a relationship? PMID- 20725082 TI - The EuroGentest clinical utility gene cards. PMID- 20725087 TI - Kruppel-like factor KLF9 regulates PPARgamma transactivation at the middle stage of adipogenesis. AB - Kruppel-like factors (KLFs) as a family of zinc-finger transcription factors involve in the regulation of many physiological processes. In these studies, KLF9 was characterized for its role in adipogenesis. The expression of KLF9 was markedly upregulated during the middle stage of 3T3-L1 adipocyte differentiation, and inhibition of KLF9 by RNAi impaired adipogenesis. Using promoter deletion and mutation analysis, we identified two KLF9-binding sites within the 0.6-kb region of the PPARgamma2 proximal promoter, indicating that KLF9 interacts with the PPARgamma2 promoter. Furthermore, we found that KLF9 could synergistically activate PPARgamma2 promoter by directly interacting with C/EBPalpha. In addition, overexpression of PPARgamma2 rescued the impairment of adipocyte differentiation induced by KLF9 knockdown, which supports that PPARgamma2 is a downstream target of KLF9. Collectively, our results indicate KLF9 as a key pro adipogenic transcription factor through regulation of PPARgamma2 expression with C/EBPalpha at the middle stage of adipogenesis. PMID- 20725089 TI - An eruption of European B-cell biology. AB - Volcanic ash clouds disrupted the 2010 ESF/EMBO meeting on B cells and protection. Nevertheless, the delegates who did make it to Catalonia put together their own programme of talks covering a range of themes from mutualism to epigenetics. PMID- 20725088 TI - Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation. AB - Ret finger protein-like 1 (RFPL1) is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. However, its cellular activity remains elusive. In this article, we report that Pax6 elicited expression of the human (h)RFPL1 gene in HeLa cells can be enhanced by in vivo p53 binding to its promoter and therefore investigated the hypothesis that hRFPL1 regulates cell-cycle progression. Upon expression in these cells, hRFPL1 decreased cell number through a kinase-dependent mechanism as PKC activates and Cdc2 inhibits hRFPL1 activity. hRFPL1 antiproliferative activity led to an increased cell population in G(2)/M phase and specific cyclin B1 and Cdc2 downregulations, which were precluded by a proteasome inhibitor. Specifically, cytoplasm-localized hRFPL1 prevented cyclin B1 and Cdc2 accumulation during interphase. Consequently, cells showed a delayed entry into mitosis and cell-cycle lengthening resulting from a threefold increase in G(2) phase duration. Given previous reports that RFPL1 is expressed during cell differentiation, its impact on cell-cycle lengthening therefore provides novel insights into primate-specific development. PMID- 20725090 TI - Understanding human genetic variation in the era of high-throughput sequencing. AB - The EMBO/EMBL symposium 'Human Variation: Cause and Consequence' highlighted advances in understanding the molecular basis of human genetic variation and its myriad implications for biology, human origins and disease. As high-throughput sequencing allows us to define genetic variation and its functional consequences at genome-wide resolution for a large number of people, important questions need to be asked about how to use new technologies to maximize the translational relevance of genetic research for society and the individual patient. PMID- 20725091 TI - A voice for science in Europe. An interview with Helga Nowotny, President of the European Research Council. Interview by Holger Breithaupt. PMID- 20725092 TI - Mitochondrial shape changes: orchestrating cell pathophysiology. AB - Mitochondria are highly dynamic organelles, the location, size and distribution of which are controlled by a family of proteins that modulate mitochondrial fusion and fission. Recent evidence indicates that mitochondrial morphology is crucial for cell physiology, as changes in mitochondrial shape have been linked to neurodegeneration, calcium signalling, lifespan and cell death. Because immune cells contain few mitochondria, these organelles have been considered to have only a marginal role in this physiological context-which is conversely well characterized from the point of view of signalling. Nevertheless, accumulating evidence shows that mitochondrial dynamics have an impact on the migration and activation of immune cells and on the innate immune response. Here, we discuss the roles of mitochondrial dynamics in cell pathophysiology and consider how studying dynamics in the context of the immune system could increase our knowledge about the role of dynamics in key signalling cascades. PMID- 20725093 TI - The case for entrepreneurship in R&D in the pharmaceutical industry. AB - A lack of entrepreneurial behaviour has often been highlighted as a contributor to the decline in the research and development (R&D) productivity of the pharmaceutical industry. Here, we present an assessment of entrepreneurship in the industry, based on interviews with 26 former and current leaders of R&D departments at major pharmaceutical and biotechnology companies. Factors are highlighted that could be important in promoting entrepreneurial behaviour, which might serve as a catalyst for revitalizing R&D productivity. PMID- 20725094 TI - An insight into the antifungal pipeline: selected new molecules and beyond. AB - Invasive fungal infections are increasing in incidence and are associated with substantial mortality. Improved diagnostics and the availability of new antifungals have revolutionized the field of medical mycology in the past decades. This Review focuses on recent developments in the antifungal pipeline, concentrating on promising candidates such as new azoles, polyenes and echinocandins, as well as agents such as nikkomycin Z and the sordarins. Developments in vaccines and antibody-based immunotherapy are also discussed. Few therapeutic products are currently in active development, and progression of therapeutic agents with fungus-specific mechanisms of action is of key importance. PMID- 20725095 TI - Spiking activity propagation in neuronal networks: reconciling different perspectives on neural coding. AB - The brain is a highly modular structure. To exploit modularity, it is necessary that spiking activity can propagate from one module to another while preserving the information it carries. Therefore, reliable propagation is one of the key properties of a candidate neural code. Surprisingly, the conditions under which spiking activity can be propagated have received comparatively little attention in the experimental literature. By contrast, several computational studies in the last decade have addressed this issue. Using feedforward networks (FFNs) as a generic network model, they have identified two dynamical activity modes that support the propagation of either asynchronous (rate code) or synchronous (temporal code) spiking. Here, we review the dichotomy of asynchronous and synchronous propagation in FFNs, propose their integration into a single extended conceptual framework and suggest experimental strategies to test our hypothesis. PMID- 20725097 TI - Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA prime, peptide-boost vaccination. AB - Active immunotherapy of cancer has yet to yield effective therapies in the clinic. To evaluate the translatability of DNA-based vaccines we analyzed the profile of T-cell immunity by plasmid vaccination in a murine model, using transcriptome microarray analysis and flow cytometry. DNA vaccination resulted in specific T cells expressing low levels of co-inhibitory molecules (most notably PD-1), strikingly different from the expression profile elicited by peptide immunization. In addition, the T-cell response primed through this dual-antigen expressing plasmid (MART-1/Melan-A and tyrosinase) translated into a substantial proliferation capacity and functional conversion to antitumor effector cells after tyrosinase and MART-1/Melan-A peptide analog boost. Furthermore, peptide boost rescued the immune response against the subdominant tyrosinase epitope. This immunization approach could be adapted to elicit potent immunity against multiple tumor antigens, resulting in a broader immune response that was more effective in targeting human tumor cells. Finally, this study sheds light on a novel mechanism of immune homeostasis through synchronous regulation of co inhibitory molecules on T cells, highly relevant to heterologous prime boost approaches involving DNA vaccines as priming agents. PMID- 20725098 TI - Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of DeltaNp63. AB - DeltaNp63, the N-terminal truncated isoform of p63, has been found to be overexpressed in several human epithelial cancers, including nasopharyngeal carcinomas (NPCs), suggesting a function in carcinogenesis. Trans-resveratrol (RSV) has been shown to exert proapoptotic activities through a p53-dependent or p53-independent pathway in various cancer cells. However, the effects of RSV on NPC are still unexplored. In this study, we investigated the apoptotic effects of RSV on DeltaNp63-overexpressing NPC cell lines. We showed that RSV (12-100 MU) induced dose-dependent growth suppression, cell-cycle arrest in the S phase and caspase-dependent apoptosis in NPC-TW076 and NPC-TW039 cells. The RSV effect was accompanied by the downregulation of DeltaNp63 and the upregulation of p53 protein in a dose-dependent manner. By using small-interfering RNA (siRNA) technology, we found that the targeted silencing of DeltaNp63 induced apoptosis and sensitized the NPC cells to RSV-induced apoptosis through caspase-3 activation, whereas suppression of p53 by siRNA did not inhibit RSV-induced apoptosis. Furthermore, transfection with p53 siRNA or pretreatment with caspase inhibitors (Z-VAD-fmk or Z-DEVD-fmk) had no influence on the RSV downregulation of DeltaNp63. Interestingly, ecoptic expression of DeltaNp63 did not significantly block RSV-induced cell death and was also downregulated after RSV treatment. Downregulation of DeltaNp63 by RSV was shown to occur at the mRNA transcript and post-translational levels. Importantly, RSV enhanced chemotheraptic drug-induced apoptosis in NPC and two human carcinoma cell lines, HT1376 and Hep3B cells. These results suggested that DeltaNp63, but not p53, is a molecular target of RSV-induced apoptosis and the regulation of DeltaNp63 expression by RSV may provide a therapeutic effect of RSV in human NPC. PMID- 20725096 TI - Socioeconomic status and the brain: mechanistic insights from human and animal research. AB - Human brain development occurs within a socioeconomic context and childhood socioeconomic status (SES) influences neural development--particularly of the systems that subserve language and executive function. Research in humans and in animal models has implicated prenatal factors, parent-child interactions and cognitive stimulation in the home environment in the effects of SES on neural development. These findings provide a unique opportunity for understanding how environmental factors can lead to individual differences in brain development, and for improving the programmes and policies that are designed to alleviate SES related disparities in mental health and academic achievement. PMID- 20725099 TI - Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2/neu-overexpressing cancers in human. AB - A chimeric human Her2/neu gene (ChHer2) harboring most of the known major histocompatibility complex class I epitopes of the HER2/neu oncogene was expressed as a fusion protein to a non-hemolytic fragment of listeriolysin O (LLO), by the highly attenuated Listeria vector LmddA, which lacks antibiotic selection markers and the ability to spread from cell-to-cell. This construct (ADXS31-164) was tested for immunogenicity and anti-tumor effects in mice. Despite being highly attenuated, ADXS31-164 proved to be efficacious in breaking immune tolerance toward the HER2/neu self-antigen. ADXS31-164 elicited strong T cell immune responses in experimental animals. In tumors, ADXS31-164 caused a reduction in regulatory T cells (Treg) accompanied by an increase in the CD8(+)/Treg ratio. Comparison of this vaccine with the conventional antibiotic resistant Listeria vector (Lm-LLO-ChHer2) shows that ADXS31-164 is more efficacious in delaying tumor growth in Her2/neu transgenic animals. Because of its well-defined attenuation mechanism and independence from antibiotic selection markers, ADXS31-164 is potentially more suitable for human use. These results support the future clinical development of this vaccine for the treatment of HER2/neu-overexpressing malignancies, such as breast, colorectal and pancreatic cancers. PMID- 20725100 TI - Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors. AB - Endothelial cells and endothelial cell precursors encoding a therapeutic gene have induced antitumor responses in preclinical models. Culture of peripheral blood provides a rich supply of autologous, highly proliferative endothelial cells, also referred to as blood outgrowth endothelial cells (BOECs). The aim of this study was to evaluate a novel antiangiogenic strategy using BOECs expressing fms-like tyrosine kinase-1 (sFlt1) and/or angiostatin-endostatin (AE) fusion protein. Conditioned medium from BOECs expressing sFlt1 or AE suppressed in vitro growth of pulmonary vein endothelial cells by 70% compared with conditioned medium from non-transduced BOEC controls. Reverse transcriptase-PCR analysis indicated that systemically administered BOECs proliferated in tumor tissue relative to other organs in C3(1)SV40 TAG transgenic (C3TAG) mice with spontaneous mammary tumors. Tumor volume was reduced by half in C3TAG mice and in mice bearing established lung or pancreatic tumors in response to the treatment with sFlt1-BOECs, AE-BOECs or their combination. Studies of tumor vascular density confirmed that angiogenic inhibition contributed to slowed tumor growth. In an orthotopic model of glioma, the median survival of mice treated with sFlt1 BOECs was double that of mice receiving no BOEC treatment (P=0.0130). These results indicate that further research is warranted to develop BOECs for clinical application. PMID- 20725102 TI - Poor health literacy: a 'hidden' risk factor. PMID- 20725101 TI - Susceptibility of breast cancer cells to an oncolytic matrix (M) protein mutant of vesicular stomatitis virus. AB - Matrix (M) protein mutants of vesicular stomatitis virus (VSV), such as rM51R-M virus, are attractive candidates as oncolytic viruses for tumor therapies because of their capacity to selectively target cancer cells. The effectiveness of rM51R M virus as an antitumor agent for the treatment of breast cancer was assessed by determining the ability of rM51R-M virus to infect and kill breast cancer cells in vitro and in vivo. Several human- and mouse-derived breast cancer cell lines were susceptible to infection and killing by rM51R-M virus. Importantly, non tumorigenic cell lines from normal mammary tissues were also sensitive to VSV infection suggesting that oncogenic transformation does not alter the susceptibility of breast cancer cells to oncolytic VSV. In contrast to results obtained in vitro, rM51R-M virus was only partially effective at inducing regression of primary breast tumors in vivo. Furthermore, we were unable to induce complete regression of the primary and metastatic tumors when tumor bearing mice were treated with a vector expressing interleukin (IL)-12 or a combination of rM51R-M virus and IL-12. Our results indicate that although breast cancer cells may be susceptible to VSV in vitro, more aggressive treatment combinations are required to effectively treat both local and metastatic breast cancers in vivo. PMID- 20725103 TI - Prevention: Reducing the risk of CVD in patients with periodontitis. AB - The association between periodontitis and other chronic diseases, such as cardiovascular disease (CVD) and type 2 diabetes mellitus, could be related to systemic inflammation initiated by a local inflammatory challenge. Oliveira et al. have added lack of oral hygiene, and its link with systemic inflammation, to the spectrum of risk factors for CVD. PMID- 20725104 TI - Acute coronary syndromes: No-reflow--an ominous sign of cardiac dysfunction. AB - Mechanical reperfusion in acute myocardial infarction does not always result in desirable optimal microvascular perfusion. Failure to achieve a normal myocardial blush in the infarcted region by contrast injection immediately after percutaneous coronary intervention--the 'no-reflow' phenomenon--is an ominous sign whose prognostic importance may go beyond its intimate association with infarct size. PMID- 20725105 TI - Coronary artery disease: Percent stenosis in CAD--a flaw in current practice. AB - The optimum strategy to treat patients with coronary artery disease (CAD) has been under debate. New data show that revascularization guided by fractional flow measurements leads to better outcomes than revascularization guided by arteriography. we call for a paradigm shift in CAD care, with coronary flow measurements by PET as key to diagnosis and clinical decision-making. PMID- 20725106 TI - Stenting of complex lesions: an overview. AB - Contemporary management of coronary artery disease relies increasingly on percutaneous techniques combined with medical therapy. Although percutaneous coronary intervention (PCI) can be performed successfully in most lesions, several difficult lesion subsets continue to present unique technical challenges. These complex lesions may be classified according to anatomic criteria, including extensive calcification, thrombus, and chronic occlusions, or by location, such as bifurcations, saphenous vein grafts and unprotected left main. PCI of these lesions often requires novel devices, such as drug-eluting stents, hydrophilic guidewires, distal protection balloons or filters, thrombectomy catheters, rotational atherectomy, and cutting balloons. An integrated approach that combines these devices with specialized techniques and adjunctive pharmacologic agents has greatly improved PCI success rates for these complex lesions. PMID- 20725107 TI - Determining gammadelta versus alphabeta T cell development. AB - The thymus produces several types of functionally distinct T cell subsets. However, at a more fundamental level only two genetically distinct T cell lineages exist: the gammadelta and alphabeta T cell lineages. Precisely how these two T cell lineages are generated from common thymocyte progenitor cells remains to be fully elucidated and is under intense investigation. Here, we highlight recent findings that have helped to provide important clues to the mechanisms that underpin the generation of gammadelta T cells in the mouse thymus. PMID- 20725109 TI - Sex differences in linear and nonlinear heart rate variability during early recovery from supramaximal exercise. AB - Women demonstrate greater RR interval variability than men of similar age. Enhanced parasympathetic input into cardiac regulation appears to be not only greater in women, but also protective during periods of cardiac stress. Even though women may have a more favorable autonomic profile after exercise, little research has been conducted on this issue. This study was designed to examine the cardiac autonomic response, in both male and female participants, during the early recovery from supramaximal exercise. Twenty-five individuals, aged 20 to 33 years (13 males and 12 females), performed a 30-s Wingate test. Beat-to-beat RR series were recorded before and 5 min after exercise, with the participants in the supine position and under paced breathing. Linear (spectral analysis) and nonlinear analyses (detrended fluctuation analysis (DFA)) were performed on the same RR series. At rest, women presented lower raw low frequency (LF) power and higher normalized high frequency (HF) power. Under these conditions, the LF/HF ratio of women was also lower than that of men (p<0.05), but there were no differences in the short-term scaling exponent (alpha1). Even though both sexes showed a significant modification in linear and nonlinear measures of heart rate variability (HRV) (p<0.05), women had a greater change in LF/HF ratio and alpha1 than men from rest to recovery. This study demonstrates that the cardiac autonomic function of women is more affected by supramaximal exercise than that of men. Additionally, DFA did not provide additional information about sexual dimorphisms, compared with conventional spectral HRV techniques. PMID- 20725110 TI - Fat-1 gene modulates the fatty acid composition of femoral and vertebral phospholipids. AB - Dietary polyunsaturated fatty acid (PUFA) incorporation into bone may alter its metabolism through changes in the fatty acid composition of membrane phospholipids. Alteration of the membrane phospholipid fatty acid composition may influence bone cell signalling and, potentially, bone mineralization. The objective of this study was to use the fat-1 mouse, a transgenic model that synthesizes n-3 from n-6 PUFA, to determine if the fat-1 gene modulates the fatty acid composition of femoral and vertebral phospholipids, and if so, whether the fatty acid levels would correlate with bone mineral density (BMD) at both skeletal sites. Male and female wild-type and fat-1 mice were fed an AIN93-G diet, containing 10% safflower oil, from weaning to 12 weeks of age. The fatty acid composition of femoral and vertebral phospholipids was measured by gas liquid chromatography. At 12 weeks of age, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine fractions in the vertebrae of fat-1 mice had a significantly lower n-6/n-3 ratio than wild-type mice (p<0.05). In fat-1 femurs, these fractions, along with phosphatidylinositol, had a lower n 6/n-3 ratio than wild-type mice (p<0.001). Docosahexaenoic acid (DHA) was positively correlated with BMD in all fractions in the vertebrae, and in phosphatidylinositol and phosphatidylserine in the femur (p<0.05). Overall, the fat-1 gene resulted in changes in the fatty acid composition of both femoral and vertebral phospholipids. Significant correlations between DHA and BMD may indicate a positive effect on bone mineralization. PMID- 20725111 TI - Hypohydration and muscular fatigue of the thumb alter median nerve somatosensory evoked potentials. AB - The mechanisms by which dehydration impairs endurance performance remain unresolved but may involve alterations in afferent neural processing. The purpose of this study was to determine the effect of hypohydration on somatosensory evoked potentials (SEPs) at rest and during recovery from fatiguing exercise. Fourteen volunteers (12 men, 2 women) performed repetitive isometric thumb contractions (50% maximal voluntary contractions (MVC) and 100% MVC in a 5:1 ratio, each contraction separated by 5 s of rest) until exhaustion when euhydrated (EU) and when hypohydrated by 4% body mass (HY). SEPs were obtained from the median nerve. The results indicated that HY did not produce statistical differences in time to exhaustion (EU=754 (SD 255); HY=714 (SD 318) s; p=0.66) or rate of muscle fatigue. However, HY was associated with greater subjective feelings of fatigue and loss of vigor after exhaustive exercise (p<0.01). HY affected N20 latency with an interaction effect of hydration by fatigue state (EU Rest: 18.5 (SD 1.6) ms; EU-Fatigue: 19.0 (SD 1.6) ms; HY-Rest: 18.3 (SD 1.3) ms; HY-Fatigue: 18.4 (SD 1.5) ms; p=0.034), but N20 and N20-P22 amplitude responses were similar between HY and EU trials. We concluded that moderate water deficits appear to alter afferent signal processing within the cerebral cortex. PMID- 20725108 TI - NFAT, immunity and cancer: a transcription factor comes of age. AB - Nuclear factor of activated T cells (NFAT) was first identified more than two decades ago as a major stimulation-responsive DNA-binding factor and transcriptional regulator in T cells. It is now clear that NFAT proteins have important functions in other cells of the immune system and regulate numerous developmental programmes in vertebrates. Dysregulation of these programmes can lead to malignant growth and cancer. This Review focuses on recent advances in our understanding of the transcriptional functions of NFAT proteins in the immune system and provides new insights into their potential roles in cancer development. PMID- 20725112 TI - Peripheral expression of inflammatory markers in overweight female adolescents and eutrophic female adolescents with a high percentage of body fat. AB - The objective of this study was to evaluate the peripheral expression of inflammatory markers in adolescents with different nutritional status and its correlation with parameters of the metabolic syndrome. Seventy-two female postpubescent adolescents were divided into 3 groups: eutrophic (Co), eutrophic with a high body fat percentage (HBF), and overweight (OW). Data related to the parameters of the metabolic syndrome and the peripheral expression of tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were evaluated. Higher values of glycemia and insulin resistance were found in the HBF group than in the Co group. No differences related to the peripheral expression of the cytokines were found among the groups. In the HBF group, a positive correlation was observed between TNF-α and IL-6, IL-10 and the proinflammatory cytokines, and IL-6 and glycemia. In the OW group, a positive correlation was found between IL-6 and triglycerides. Adolescents with normal weight but body fat excess present a metabolic profile and body composition similar to those of overweight adolescents. This suggests that these adolescents have a risk of developing cardiovascular diseases similar to that of overweight adolescents. The positive correlation between IL-10 and TNF-α and IL-6 suggests an attempt to inhibit the production of these cytokines by IL-10. PMID- 20725113 TI - Do neuromuscular adaptations occur in endurance-trained boys and men? AB - Most research on the effects of endurance training has focused on endurance training's health-related benefits and metabolic effects in both children and adults. The purpose of this study was to examine the neuromuscular effects of endurance training and to investigate whether they differ in children (9.0-12.9 years) and adults (18.4-35.6 years). Maximal isometric torque, rate of torque development (RTD), rate of muscle activation (Q30), electromechanical delay (EMD), and time to peak torque and peak RTD were determined by isokinetic dynamometry and surface electromyography (EMG) in elbow and knee flexion and extension. The subjects were 12 endurance-trained and 16 untrained boys, and 15 endurance-trained and 20 untrained men. The adults displayed consistently higher peak torque, RTD, and Q30, in both absolute and normalized values, whereas the boys had longer EMD (64.7+/-17.1 vs. 56.6+/-15.4 ms) and time to peak RTD (98.5+/ 32.1 vs. 80.4+/-15.0 ms for boys and men, respectively). Q30, normalized for peak EMG amplitude, was the only observed training effect (1.95+/-1.16 vs. 1.10+/-0.67 ms for trained and untrained men, respectively). This effect could not be shown in the boys. The findings show normalized muscle strength and rate of activation to be lower in children compared with adults, regardless of training status. Because the observed higher Q30 values were not matched by corresponding higher performance measures in the trained men, the functional and discriminatory significance of Q30 remains unclear. Endurance training does not appear to affect muscle strength or rate of force development in either men or boys. PMID- 20725114 TI - Palm cooling does not reduce heat strain during exercise in a hot, dry environment. AB - To compare the effectiveness of the rapid thermal exchange device (RTX) in slowing the development of hyperthermia and associated symptoms among hand immersed in water bath (WB), water-perfused vest (WPV), and no cooling condition (NC). Ten subjects performed 4 heat stress trials. The protocol consisted of 2 bouts of treadmill walking, separated by a cooling-rehydration period. The times to reach the predetermined rectal temperature in the first (38.5 degrees C) and second bouts (39 degrees C) were not different among RTX, NC, and WB, but was longer for the WPV in both bouts (p<0.05). Heat storage was significantly lower for WPV only in the first bout vs. the other conditions (p<0.05). Heart rate (HR) was not different at 10, 20, and 30 min during the first bout among RTX, NC, and WB, but was lower for WPV (p<0.05). HR was not different among conditions during the second bout. The RTX was not effective in slowing the development of hyperthermia. PMID- 20725115 TI - Aerobic capacity of rats recovered from fetal malnutrition with a fructose-rich diet. AB - The objective of this study was to analyze the aerobic capacity, through the maximal lactate steady-state (MLSS) protocol, of rats subjected to fetal protein malnutrition and recovered with a fructose-rich diet. Pregnant adult Wistar rats that were fed a balanced (17% protein) diet or a low-protein (6% protein) diet were used. After birth, the offspring were distributed into groups according to diet until 60 days of age: balanced (B), balanced diet during the whole experimental period; balanced-fructose (BF), balanced diet until birth and fructose-rich diet (60% fructose) until 60 days; low protein-balanced (LB), low protein diet until birth and balanced diet until 60 days; and low protein fructose (LF), low protein diet until birth and fructose-rich diet until 60 days. It was verified that the fructose-rich diet reduced body growth, mainly in the BF group. There was no difference among the groups in the load corresponding to the MLSS (B, 7.5+/-0.5%; BF, 7.4+/-0.6%; LB, 7.7+/-0.4%; and LF, 7.7+/-0.6% relative to body weight). However, the BF group presented higher blood lactate concentrations (4.8+/-0.9 mmol.L(-1)) at 25 min in the load corresponding to the MLSS (B, 3.2+/-0.9 mmol.L(-1); LB, 3.4+/-0.9 mmol.L(-1); and LF, 3.2+/-1.0 mmol.L(-1)). Taken together, these results indicate that the ability of young rats to perform exercise was not altered by intrauterine malnutrition or a fructose-rich diet, although the high fructose intake after the balanced diet in utero increased blood lactate during swimming exercises in rats. PMID- 20725116 TI - Lifestyle factors and other health measures in a Canadian university community. AB - With the increasing prevalence of obesity, there is a continuous search for effective obesity-prevention and health-promotion interventions. These interventions should be based on factors that have the potential to influence body weight and health. This study describes various health-related factors in a Canadian university community with the aim of developing more specific obesity interventions. A total of 3143 individuals completed an online questionnaire made up of 3 sections--on physical activity (PA), food habits, and other relevant lifestyle factors. The sampling error was +/-3.3% with a 95% confidence interval. Results showed that 22.9% of students and 37.3% of staff members were either overweight or obese. Students had less desirable eating patterns than staff members in terms of fish, energy drink, and regular milk product intake, and both groups reported undesirable breakfast consumption and quality. Nevertheless, results also showed that a high percentage of individuals in both groups did not meet the recommendations for vegetable, fruit, and fish intake, or PA. Only a few gender differences were observed in eating habits. Soft drink and energy drink consumption was higher and breakfast consumption was lower in men, whereas a higher percentage of women did not meet the recommendations for vegetable, fruit, or fish consumption. Dieting behaviours, disinhibition susceptibility, and moderate-intensity (MIPA) were the 3 lifestyle factors most highly associated with overweight and obesity in both groups. Results also suggest that female students were highly preoccupied with their body weight. This study shows that overweight and obesity are problems in a university community, and that they are associated with many health-related lifestyle behaviours. Although most of the lifestyle factors and health measures examined are similar across groups and genders, some differences call for the development of health-promotion programs with specific targeting strategies. PMID- 20725117 TI - The effect of short-term creatine loading on active range of movement. AB - During high-intensity exercise, intracellular creatine phosphate (PCr) is rapidly broken down to maintain adenosine triphosphate turnover. This has lead to the widespread use of creatine monohydrate as a nutritional ergogenic aid. However, the increase in intracellular PCr and the concomitant increase in intracellular water have not been investigated with regard to their effect on active range of movement (ROM). Forty male subjects (age, 24+/-3.2 years) underwent restricted randomization into 2 equal groups, either an intervention group (CS) or a control group (C). The CS group ingested 25 g.day(-1) of creatine monohydrate for 5 days, followed by 5 g.day(-1) for a further 3 days. Before (24 h before starting supplementation (PRE) and after (on the 8th day of supplementation (POST)) this loading phase, both groups underwent goniometry measurement of the shoulder, elbow, hip, and ankle. Data indicated significant reductions in active ROM in 3 movements: shoulder extension (57+/-11.3 degrees PRE vs. 48+/-11.2 degrees POST, p<0.01), shoulder abduction (183.4+/-6.8 degrees PRE vs. 180.3+/-5.1 degrees POST, p<0.05), and ankle dorsiflexion (14.2+/-4.7 degrees PRE vs. 12.1+/-6.4 degrees POST, p<0.01). There was also a significant increase in body mass for the CS group (83.6+/-6.2 kg vs. 85.2+/-6.3 kg, p<0.05). The results suggest that short-term supplementation with creatine monohydrate reduces the active ROM of shoulder extension and abduction and of ankle dorsiflexion. Although the mechanism for this is not fully understood, it may be related to the asymmetrical distribution of muscle mass around those joints. PMID- 20725118 TI - Noninvasive measures of vascular health are reliable in preschool-aged children. AB - Measures of vascular health are known to be important predictors of cardiovascular disease in adulthood. The reliability of commonly used measures of vascular health has been demonstrated in school-aged children, adolescents, and adults; however, their reliability in preschool-aged children remains to be determined. Twenty 2- to 6-year-old children participated in 2 identical testing sessions on different days. Following 10 min of supine rest, carotid artery blood pressures and common carotid artery images were assessed simultaneously for 10 heart cycles, using applanation tonometry and B-mode ultrasound, respectively, while electrocardiogram (ECG) and infrared measures of arterial pressure waves at the dorsalis pedis were recorded continuously. Brachial artery blood pressures were determined using an automated oscillometric device. Carotid artery diameters and intima-media thickness (IMT) were analyzed using a semiautomated detection software program. Carotid compliance, distensibility, and stiffness index were calculated from carotid diameters and carotid blood pressures. Whole-body pulse wave velocity (PWV) was determined from the time delay between the R spike of the ECG and the foot of the dorsalis pedis arterial pressure wave. Reliability of all measures was assessed using the coefficient of variation (CV) and the intraclass correlation coefficient (ICC). The most reliable measures were carotid artery IMT and PWV with CVs of 2.6% and 3.5% and ICCs of 0.86 and 0.76, respectively. The lower reliability of carotid compliance and distensibility (ICC<=0.63) is likely attributable to the variability of blood pressure measurements. This study confirms that vascular measurements demonstrate substantial reliability in preschool-aged children as young as 2 years. PMID- 20725120 TI - Postprandial insulin sensitivity and thermogenesis in frail elderly women. AB - The frailty syndrome is associated with inflammation, hypercortisolemia, and cardiovascular diseases, all of which are linked with insulin resistance. But whether frailty is characterized by insulin resistance is unclear, especially in the postprandial state. The prevalence of underweight with frailty is high. We wondered whether hypermetabolism associated with inflammation and hypercortisolemia could increase the thermic effect of food (TEF) and contribute to the frailty-associated body weight loss. In this study, we determined whether insulin sensitivity and TEF responses differ between frail and healthy elderly persons following a meal. Ten healthy and 13 frail elderly women were recruited and studied during the 5 h following the ingestion of a standardized liquid mixed meal test. Areas under the curve (AUC) for glucose and insulin, and the product of AUC glucosexAUC insulinx10(-6) (PGI) were used as indices of insulin sensitivity. TEF was measured by indirect calorimetry. Following the meal, glucose and insulin AUCs and PGI were significantly higher in frail than in healthy elderly women and, except for the insulin AUC; these differences remained significant after adjustment for age, body weight, and physical activity. Physical activity, determined by questionnaire, was the single best predictor of PGI, explaining 27% of its variance. There was no difference in TEF between groups, and it did not correlate with any significant variable measured. Our results suggest that postprandial insulin resistance is higher in frail than in healthy elderly women, and TEF is similar, indicating that both processes do not contribute to the propensity for body weight loss. PMID- 20725119 TI - Plasma prekallikrein levels are positively associated with circulating lipid levels and the metabolic syndrome in children. AB - Plasma prekallikrein (PK) has been shown to be associated with cardiovascular disease (CVD) and its risk factors, but these associations have not been investigated in children. The present study examined PK activity in relation to well-established cardiovascular risk factors in a cohort of children aged 9-11 years (N=97). We found a significant and positive association between PK and fasting levels of total cholesterol (p<0.01), non-high-density lipoprotein cholesterol (p<0.01), and triglycerides (p<0.001). In addition, there was a significant association between PK activity and the metabolic syndrome, a clustering of risk factors considered to have an impact on atherosclerosis and CVD mortality. Finally, we found that children with a family history of CVD had significantly elevated PK activity. These novel findings warrant further investigations into the relationship between circulating PK levels and CVD risk factors because PK may be involved in the progression of the disease state. PMID- 20725121 TI - Effect of eccentric contraction velocity on muscle damage in repeated bouts of elbow flexor exercise. AB - Eccentric exercise induces muscle damage, but controversy exists concerning the effect of contraction velocity on the magnitude of muscle damage, and little is known about the effect of contraction velocity on the repeated-bout effect. This study examined slow (60 degrees.s(-1)) and fast (180 degrees.s(-1)) velocity eccentric exercises for changes in indirect markers of muscle damage following 3 exercise bouts that were performed every 2 weeks. Fifteen young men were divided into 2 groups based on the velocity of eccentric exercise: 7 in the Ecc60 (60 degrees.s(-1)) group, and 8 in the Ecc180 (180 degrees.s(-1)) group. The exercise consisted of 30 maximal eccentric contractions of the elbow flexors at each velocity, in which the elbow joint was forcibly extended from 60 degrees to 180 degrees (full extension) on an isokinetic dynamometer. Changes in maximal voluntary isometric contraction strength, range of motion, muscle soreness, and plasma creatine kinase activity before and for 4 days after the exercise were compared in the 2 groups using a mixed-model analysis (groupxboutxtime). No significant differences between groups were evident for changes in any variables following exercise bouts; however, the changes were significantly smaller (p<0.05) after the second and third bouts than after the first bout. These results indicate that the contraction velocity does not influence muscle damage or the repeated-bout effect. PMID- 20725122 TI - Influence of high- and low-carbohydrate diet following glycogen-depleting exercise on heart rate variability and plasma catecholamines. AB - The purpose of this study was to investigate the effects of a short-term low- or high-carbohydrate (CHO) diet consumed after exercise on sympathetic nervous system activity. Twelve healthy males underwent a progressive incremental test; a control measurement of plasma catecholamines and heart rate variability (HRV); an exercise protocol to reduce endogenous CHO stores; a low- or high-CHO diet (counterbalanced order) consumed for 2 days, beginning immediately after the exercise protocol; and a second resting plasma catecholamine and HRV measurement. The exercise and diet protocols and the second round of measurements were performed again after a 1-week washout period. The mean (+/-SD) values of the standard deviation of R-R intervals were similar between conditions (control, 899.0+/-146.1 ms; low-CHO diet, 876.8+/-115.8 ms; and high-CHO diet, 878.7+/ 127.7 ms). The absolute high- and low-frequency (HF and LF, respectively) densities of the HRV power spectrum were also not different between conditions. However, normalized HF and LF (i.e., relative to the total power spectrum) were lower and higher, respectively, in the low-CHO diet than in the control diet (mean+/-SD, 17+/-9 normalized units (NU) and 83+/-9 NU vs. 27+/-11 NU and 73+/-17 NU, respectively; p<0.05). The LF/HF ratio was higher with the low-CHO diet than with the control diet (mean+/-SD, 7.2+/-6.2 and 4.2+/-3.2, respectively; p<0.05). The mean values of plasma catecholamines were not different between diets. These results suggest that the autonomic control of the heart rate was modified after a short-term low-CHO diet, but plasma catecholamine levels were not altered. PMID- 20725123 TI - Effect of intermittent hypoxia on muscle and cerebral oxygenation during a 20-km time trial in elite athletes: a preliminary report. AB - The effects of intermittent hypoxic exposure (IHE) on cerebral and muscle oxygenation, arterial oxygen saturation (SaO2), and respiratory gas exchange during a 20-km cycle time trial (20TT) were examined (n=9) in a placebo controlled randomized design. IHE (7:3 min hypoxia to normoxia) involved 90-min sessions for 10 days, with SaO2 clamped at ~80%. Prior to, and 2 days after the intervention, a 20TT was performed. During the final minute of the 20TT, in the IHE group only, muscle oxyhemoglobin (oxy-Hb) was elevated (mean+/-95% confidence interval 1.3+/-1.2 DeltamicroM, p=0.04), whereas cerebral oxy-Hb was reduced ( 1.9%+/-1.0%, p<0.01) post intervention compared with baseline. The 20TT performance was unchanged between groups (p=0.7). In the IHE group, SaO2 was higher (1.0+/-0.7Delta%, p=0.006) and end-tidal PCO2 was lower (-1.2+/-0.1 mm Hg, p=0.01) during the final stage of the 20TT post intervention compared with baseline. In summary, reductions in muscle oxy-Hb and systemic SaO2 occurring at exercise intensities close to maximal at the end of a 20TT were offset by IHE, although this was not translated into improved performance. PMID- 20725124 TI - Individual exercise sessions alter circulating hormones and cytokines in HIV infected men. AB - Exercise has the potential to impact disease by altering circulating anabolic and catabolic factors. It was the goal of this study to determine how different regimens of low-intensity and moderate-intensity exercise affected circulating levels of these anabolic and catabolic factors in HIV-infected men. Exercise naive, HIV-infected men, medically cleared for study participation, were randomized into one of the following groups: a moderate-intensity group (MOD, who completed 30 min of moderate-intensity aerobic training followed by 30 min of moderate-intensity resistance training; a low-intensity group (LOW), who completed 60 min of treadmill walking; or a control group (CON), who attended the clinic but participated in no activity. Blood and saliva samples were collected at selected time points before, during, and after each of the 3 required sessions. Compared with baseline, the MOD group (n=14) had a 135% increase in growth hormone (GH) (p<0.05) and a 34% decrease in cortisol (CORT) (p<0.05) at the post time point, a 31% increase in interleukin-6 (IL-6) (p<0.05) at 30-min post exercise, and a 23% increase in IL-6 (p<0.05) and a 13% decrease in soluble tumor necrosis factor receptor 2 (sTNFrII) (p<0.05) at 60-min post exercise. The LOW (n=11) group had a 3.5% decrease in sTNFrII (<0.05) at 30-min post exercise compared with baseline and a 49% decrease (p<0.05) in GH at 60-min post exercise. The CON group (n=13) had a decrease in GH at 30-min (62%, p<0.05) and 60-min (61%, p<0.05) post exercise compared with baseline. The increase in GH from baseline to post was greater in the MOD group (p<0.05) and the decrease in CORT from pre to post was greater in the MOD group (p<0.05) than in the other groups. These data suggest that individual sessions of both low-intensity and moderate intensity exercise can alter circulating anabolic and catabolic factors in HIV infected men. The changes in the MOD group present potential mechanisms for the increases in lean tissue mass seen with resistance exercise training. PMID- 20725126 TI - [Microbiota and probiotics: effects on human health]. AB - All accessible mucous membranes of the human body are colonized by an abundant and diversified microbial flora called microbiota. Recent studies have shown that these microorganisms, long regarded as purely commensal, have essential beneficial effects on human health. Thus, numerous human ailments are linked to dysbiosis; that is, imbalances in the microflora composition. The administration of probiotic microorganisms could, in some situations, provide substantial relief from such disorders. These live microorganisms, which, according to the definition, confer a health benefit to the host when administered in adequate amounts, are often derived from human flora and belong mostly to lactic acid bacteria, in particular to the genus Lactobacillus. The constant improvement of knowledge of the role of human microbiota and the growing popularity of probiotics are now opening the door to new prophylactic and therapeutic strategies in human health. PMID- 20725127 TI - Characterization of enterohemorrhagic Escherichia coli O157:H7 00B015: a Shiga toxin producing but virulence-attenuated isolate. AB - Enterohemorrhagic Escherichia coli (EHEC) causes a wide range of systematic diseases in human and animals in 2 main ways: (1) production of Shiga toxin (Stx) and (2) induction of actin polymerization characterized by attaching and effacing (A/E) lesions. Stx is commonly targeted in the development of drugs and vaccines to control EHEC infection for its indispensible contribution to EHEC pathogenesis. In this study, we isolated a Stx-producing EHEC O157:H7 isolate 00B015 and found that its ability to induce actin polymerization was impaired. In addition, it reduces pathogenicity and decreases mortality in mice. Our results report a Stx-producing but virulence-attenuated EHEC isolate 00B015 and suggest that the formation of actin polymerization may help Stx-induced pathogenesis and have a more important contribution in EHEC infections. PMID- 20725128 TI - Phaseolus vulgaris is nodulated in northern Spain by Rhizobium leguminosarum strains harboring two nodC alleles present in American Rhizobium etli strains: biogeographical and evolutionary implications. AB - In this study a collection of rhizobial strains were isolated from effective nodules of Phaseolus vulgaris in a wide region of northern Spain, which is the major producer region of this legume in Spain. The analysis of their core genes, rrs, atpD, and recA, and the 16S-23S intergenic spacer showed that all isolates belong to the phylogenetic group of Rhizobium leguminosarum and some of them were identical to those of strains nodulating Vicia or Trifolium. None of the isolates was identified as Rhizobium etli; however, all of them carry the nodC alleles alpha and gamma harboured by American strains of this species. These alleles were also found in strains nodulating P. vulgaris in southern Spain identified as R. etli. These results suggest that R. etli was carried from America to Spain with common bean seeds, but that they could have found difficulties persisting in the soils of northern Spain, probably because of the climatic conditions. The symbiotic genes of this species could have been transferred, after the arrival of P. vulgaris, to strains of R. leguminosarum already present in northern Spanish soils. PMID- 20725129 TI - Factors influencing the persistence of Escherichia coli O157:H7 lineages in feces from cattle fed grain versus grass hay diets. AB - Escherichia coli O157:H7 is a pathogenic, gram-negative bacterium that causes diarrhea, hemorrhagic colitis, and can lead to fatal hemolytic uremic syndrome in humans. We examined the persistence of E. coli O157:H7 lineages I and II in feces held at 4, 12, and 25 degrees C, from animals fed either grain or hay diets. Three strains of each lineage I and II were inoculated into grain-fed or hay-fed feces, and their persistence was monitored over 28 days. No significant differences in E. coli O157:H7 survival between the 2 lineages in both fecal types was found at the examined temperatures. Volatile fatty acids were higher in grain-fed than in hay-fed feces, resulting in consistently lower pH in the grain fed feces at 4, 12 and 25 degrees C. Regardless of lineage type, E. coli O157:H7 CFUs were significantly higher in grain-fed than in hay-fed feces at 4 and 25 degrees C. Escherichia coli O157:H7 survival was highest in grain-fed feces at 25 degrees C up to 14 days. Our results indicate that the 2 lineages of E. coli O157:H7 do not differ in their persistence; however, it appears that temperature and feces type both affect the survival of the pathogen. PMID- 20725130 TI - Rapid identification of Listeria species and screening for variants by melting curve and high-resolution melting curve analyses of the intergenic spacer region of the rRNA gene. AB - The presence of any Listeria species in food may be an indicator of poor hygiene in food processing facilities. The biochemical identification of Listeria species is laborious and time consuming. Therefore, the development of novel identification methods that are rapid and simple to perform would be an asset. In this study, large intergenic spacer region amplicons of 343-374 bp were generated from 207 Listeria isolates. The melting curve analysis of these amplicons specifically classified all isolates into 6 Listeria species and generated 11 high-resolution melting (HRM) curve profiles. In this study, 3 HRM profiles were found in Listeria monocytogenes and Listeria innocua, and 2 were found in Listeria seeligeri. Sequencing of the amplicons representing these profiles revealed that each profile related to a unique sequence. The smallest difference recognized in this study was 1 nt. The results represented in this study show that HRM curve analysis of Listeria intergenic spacer sequences is a simple, quick, and reproducible method of simultaneously identifying 6 Listeria species and screening for variants. In particular, the completion of both reaction and analysis in a closed tube saves time by eliminating the separate steps and lowers the risk of contamination. PMID- 20725131 TI - Dynamics of antimicrobial resistance and virulence genes in Enterococcus faecalis during swine manure storage. AB - In this study we used 2 experimental approaches to evaluate the stability of antimicrobial resistance (AMR) phenotypes, selected AMR genes, and selected virulence genes in Enterococcus faecalis during manure storage on a commercial swine farm. Isolates of E. faecalis were obtained directly from fresh fecal material (n = 120) and from the manure storage facility (n = 85) and compared. Tetracycline resistance and the virulence genes cob, esp, eep, and ccf were detected at lower frequency in manure isolates than in fecal isolates. A second approach consisted of immersing in diffusion chambers pure cultures of E. faecalis that varied in their AMR phenotypes and virulence genotypes in the swine manure storage facility for 8 weeks, sampling periodically, and evaluating the recovered strains for changes in their genotypic or phenotypic characteristics. Enterococcus faecalis populations declined exponentially, with rate constants ranging from 0.011 to 0.022 h(-1). Among the AMR and virulence genes examined, 1 AMR gene (sat4) and 7 virulence genes (agrB(fs), cob, cpd, cylB, efaA(fs), enlA, and esp) were lost at low frequencies in the recovered strains. The AMR phenotypes were stable during the incubation, with minimal loss (P > 0.05) of the streptomycin-resistance phenotype. Overall, these results suggest that some attributes of public health significance in populations of E. faecalis decrease in frequency during manure storage. PMID- 20725132 TI - Streptococcus salivarius mutants defective in mannose phosphotransferase systems show reduced sensitivity to mutacins I-T9 and R-3B. AB - Twenty-four mutacin-producing Streptococcus mutans strains were screened for their propensity to produce class II one-peptide bacteriocin using a deferred antagonism assay. Streptococcus salivarius and 3 mutants defective in their mannose phosphotransferase systems (mannose-PTS) were used as sensitive strains to identify which mannose-PTS could act as the docking site for class II one peptide bacteriocin activity. We observed that only 2 strains of S. mutans, T9 and 3B, potentially produce class II one-peptide bacteriocin, namely mutacins I T9 and R-3B, but with no preference for any mannose-PTS complex as a target. PMID- 20725133 TI - Identification of transcripts up-regulated in asexual and sexual fruiting bodies of the Dutch elm disease pathogen Ophiostoma novo-ulmi. AB - Suppression subtractive hybridization cDNA libraries were prepared from asexual synnemata (S-lib) and sexual perithecia (P-lib) fruiting bodies of the Dutch elm disease pathogen Ophiostoma novo-ulmi subsp. novo-ulmi isolate H327 (mating-type MAT1-1) consisting of 630 and 401 cDNA clones, respectively. Both libraries were differentially screened in duplicate with forward and reverse subtracted probes. Up-regulated S-lib transcripts included those with homologies to phosphoenolpyruvate carboxykinase and aquaporin. Up-regulated P-lib transcripts included those with homologies to aspartyl proteinase, DNA lyase 2, and part of a mating-type (MAT) protein containing a DNA-binding domain of the high-mobility group (HMG) type. Phylogenetic analyses of HMG domains present within the putative O. novo-ulmi MAT protein and within MAT1-1-3 and MAT1-2-1 proteins of other ascomycete fungi identified the O. novo-ulmi protein as a homologue of the MAT1-1-3 protein, which represents part of the so far uncharacterized O. novo ulmi MAT1-1 idiomorph. Reverse transcription - quantitative real-time PCR indicated up-regulation of the MAT1-1-3 homologue in O. novo-ulmi perithecia and synnemata. The present work identifies, for the first time, proteins involved in the formation of asexual and sexual fruiting bodies in O. novo-ulmi and should be of interest to researchers concerned with reproduction, mating type, and sexuality of filamentous ascomycete fungi. PMID- 20725134 TI - Short sleep duration is associated with enhanced endothelin-1 vasoconstrictor tone. AB - Short sleep duration is associated with increased cardiovascular disease (CVD) morbidity. Endothelial vasomotor dysfunction represents a potential mechanism contributing to the increased CVD risk associated with habitual short sleep duration. Endothelin (ET)-1 is a potent vasoconstrictor peptide that is associated with endothelial vasomotor dysfunction and increased CVD risk. Currently, there is no information regarding the influence of short sleep duration on ET-1 vasoconstrictor activity in adults. We tested the hypothesis that ET-1-mediated vasoconstrictor activity is greater in adults who sleep less than 7 h/night (short sleep duration) compared with those who sleep 7-9 h/night (normal sleep duration). Forearm blood flow (FBF) responses to intra-arterial infusion of BQ-123 (100 nmol/min for 60 min), a selective ETA receptor antagonist, were determined in 80 adults: 50 with normal sleep duration (32 males and 18 females; age: 56.6 +/- 1.2 years; sleep: 7.6 +/- 0.1 h/night) and 30 with short sleep duration (17 males and 13 females; age: 56.5 +/- 1.2 years; sleep: 6.1 +/- 0.1 h/night). In response to BQ-123, adults reporting short sleep duration had a greater increase in resting FBF compared with adults reporting normal sleep duration (approximately 20% vs. approximately 8%; P < 0.05). There was an inverse relation between mean nightly sleep duration and the FBF response to BQ-123 at 60 min (r = -0.29, P < 0.05). These findings indicate that habitual short sleep duration is associated with greater ET-1-mediated vasoconstrictor tone. Increased ET-1 vasoconstrictor activity may contribute to the elevated CVD risk associated with chronic reductions in sleep duration. PMID- 20725135 TI - Endothelin axis induces metalloproteinase activation and invasiveness in human lymphatic endothelial cells. AB - The molecular mechanisms involved in lymphangiogenesis were unknown until recently. We previously demonstrated that the endothelin-1 (ET-1) axis stimulates lymphatic endothelial cells (LEC) and lymphatic vessels to grow and invade. Here we further investigated the effect of ET-1 on lymphatic vessels and evaluated whether ET-1 actions result in the functional activation of lymphangiogenesis. Using highly purified human LEC, characterized for the expression of ET-1 axis members by quantitative real-time PCR, we found that the endothelin B receptor (ETB), upon activation by ET-1, induced matrix-metalloproteinase activation, demonstrating that ET-1 influenced the activity of the proteolytic enzymes required for LEC invasion. Functional assays performed by using intradermal lymphangiography demonstrated that ET-1 promoted the formation of lymphatic vessels and that these vessels were capable of lymphatic flow. ETB blockade with the specific antagonist BQ788 inhibited matrix-metalloproteinase activation and dye transport within the lymphatic vessels, demonstrating that ETB is involved in the regulation of the growth of and in the formation of functional vessels upon activation by ET-1. Our results suggest that ET-1 is a lymphangiogenic mediator and that targeting pharmacologically ETB may be therapeutically exploited in a variety of diseases, including cancer. PMID- 20725136 TI - Endothelin-1-mediated cerebrovascular remodeling is not associated with increased ischemic brain injury in diabetes. AB - Diabetes increases the risk of as well as poor outcome after stroke. Matrix metalloprotease (MMP) activation disrupts blood-brain barrier integrity after cerebral ischemia. We have previously shown that type 2 diabetes promotes remodeling of middle cerebral arteries (MCA) characterized by increased media/lumen (M/L) ratio and MMP activity in an endothelin (ET)-1-dependent manner in the Goto-Kakizaki (GK) rat model. In the present study, we examined the effects of ET-1-mediated vascular remodeling on neurovascular damage following cerebral ischemic injury in GK rats 5 and 12 weeks after the onset of diabetes. The MCA structure, cerebral perfusion as well as infarct size, and hemorrhage were measured in control and diabetic rats subjected to transient MCA occlusion. M/L ratio was increased after 12 but not 5 weeks of diabetes. The baseline cerebral perfusion was lower and the infarct volume smaller in diabetic rats in both age groups. The incidence of hemorrhagic transformation was higher after 5 weeks of diabetes as compared to that after 12 weeks or in the control groups. These findings provide evidence that ET-1-mediated cerebrovascular remodeling does not worsen the neurovascular damage of ischemic brain injury in diabetes. It is possible that this early remodeling response is compensatory in nature to regulate vascular tone and integrity, especially when ischemia is layered on diabetic vascular disease. PMID- 20725137 TI - Beta-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin linked kinase. AB - The contribution of the endothelin-1 (ET-1)/ET A receptor (ETAR) axis in tumor growth and progression is investigated in many tumor types, including ovarian carcinoma. In ovarian cancer cells, ET-1 acts as an autocrine growth factor selectively through the ETAR triggering the concomitant activation of multiple pathways. In these cells, the involvement of beta-arrestin-1 as signal transducer in ET-1-dependent signalling pathways has been recently highlighted. Because several G protein-coupled receptors have been shown to activate signalling pathways in a beta-arrestin-dependent manner, in this study we explored whether beta-arrestin-1 is involved in a distinct signalling mechanism linking the ETAR to phosphoinositide 3-kinase (PI3K)/integrin-linked kinase (ILK)/Akt in HEY ovarian cancer cells. The inhibitory effects of ZD4054 (zibotentan), a specific ETAR antagonist, in ET-1-dependent phosphorylation of ILK, Akt, and glycogen synthase kinase (GSK-3beta) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that beta-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3beta phosphorylation. These results reveal that beta-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3beta in response to ET-1 and further support the role of beta-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer. PMID- 20725139 TI - Endothelin signaling via guanine exchange factor C3G in renal glomerular mesangial cells. AB - The guanine nucleotide exchange factor C3G is one of the mediators of endothelin 1 (ET-1) intracellular signaling cascades and is vital for kidney development and homeostasis. The aim of the current study was to analyze the specificity of ET-1 induced signaling via C3G in rat glomerular mesangial cells (GMC) and to investigate the biological significance of C3G during mesangioproliferative glomerulonephritis. In GMC, C3G expression was increased (1) in vivo after induction of the anti-Thy1 model of glomerulonephritis and (2) in cell culture experiments after fetal bovine serum incubation. To examine the consequences of C3G up-regulation, adenovirus-mediated gene transfer of C3G into cultured glomerular cells was done, and the GTP loading of the small G proteins Rap1 and R Ras was analyzed. Overexpression of C3G in mesangial cells resulted in enhanced activation of Rap1, but failed to affect the GTP-bound status of R-Ras in ET-1 stimulated cells. C3G overexpression led to significant changes in GMC spreading and migration patterns in response to ET-1 stimulation and increased stress fiber formation, which was mimicked by Rap1A overexpression. Together, these findings suggest (1) the existence of regulatory mechanisms resulting in disease-related up-regulation of C3G in GMC and (2) that an increase in the C3G protein level may contribute to the resolution stage of mesangioproliferative glomerulonephritis by reducing GMC sensitivity to ET-1, modulating cellular motility, and actin dynamics. PMID- 20725138 TI - Contrasting effects of intervention with ETA and ETB receptor antagonists in hypertension induced by angiotensin II and high-salt diet. AB - Endothelin (ET) receptor antagonists are antihypertensive and renoprotective in angiotensin II (AngII)-induced hypertension if administered when AngII infusion commences, but their effects on established hypertension are poorly understood. We therefore tested the effects of intervening with an ETA (ABT-627) or ETB (A 192621) receptor antagonist after establishing hypertension with AngII (65 ng/min s.c.) plus 8% NaCl diet (AngII-HS) in rats. Prior to administration of ABT-627, AngII-HS and AngII-HS plus ABT-627 groups displayed robust hypertension (mean arterial pressure (MAP), 170 +/- 5 and 165 +/- 5 mm Hg versus 110 +/- 3 mm Hg in normal salt control rats at day 7, P < 0.05). Administering ABT-627 from day 8 of AngII-HS treatment prevented further rises in MAP (168 +/- 5 and 191 +/- 3 mm Hg at day 13 in AngII-HS plus ABT-627 and AngII-HS, P < 0.001), without blunting the significant increases in urinary protein (19-fold), albumin (25-fold), or MCP-1 excretion (6- to 8-fold) or the reduction in creatinine clearance. Administering A-192621 from day 8 mildly exacerbated AngII-HS induced hypertension (P < 0.05 for AngII-HS versus AngII-HS plus A-192621 on days 11 and 12 only) and reduced plasma nitrite/nitrate concentration (P < 0.05), without affecting proteinuria, albuminuria, or creatinine clearance. These results confirm the importance of ETA receptor signaling in maintaining AngII-HS hypertension and suggest that including ETB receptor blockade in therapeutic approaches to treating hypertension would be ineffective or even counterproductive. PMID- 20725140 TI - ETA receptors are present in human aortic vascular endothelial cells and modulate intracellular calcium. AB - Using immunofluorescence and real 3-D confocal microscopy, our results showed the presence of ET-1, ETA, and ETB receptors in isolated human aortic vascular endothelial cells (hVECs). The level of the peptide and its receptors was significantly higher in the nucleus (including the nuclear envelope membranes) than in the cytosol (including the cell membrane). Furthermore, using the Western blot technique we demonstrated the presence of both ETA and ETB receptors. Using intact and isolated human hVECs and the Fura-2 calcium (Ca2+) measurement technique, we showed that ET-1 induced a dose-dependent increase of total intracellular free Ca2+, with an EC50 of 1.3 x 10-10 mol/L. The specific ETA receptor antagonist ABT-627 (10-7 mol/L), but not the ETB receptor antagonist A 192621 (10-7 mol/L), prevented the ET-1 (10-9 mol/L) induced increase of total intracellular Ca2+. In conclusion, these results clearly show that similar to ETB receptors, ETA receptors are also present in human aortic vascular endothelial cells and their levels are higher than ETB in the nucleus when compared with the cytosol. Furthermore, we suggest that ETA, but not ETB, receptors mediate the effect of ET-1 on total intracellular Ca2+ of human aortic vascular endothelial cells. PMID- 20725141 TI - Endothelin-1 induces pulmonary but not aortic smooth muscle cell migration by activating ERK1/2 MAP kinase. AB - Endothelin 1 (ET-1) is an endogenous peptide that promotes vasoconstriction, endothelial and smooth muscle cell (SMC) proliferation, and fibrosis. ET-1 receptor antagonists are an important treatment strategy for pulmonary arterial hypertension, but less effective in systemic vascular disease. This observation suggests a special role for ET-1 in the pulmonary circulation. We hypothesized that ET-1 contributes to the pathogenesis of pulmonary arterial hypertension, in part, by promoting pulmonary vascular SMC migration. ET-1 treatment promoted migration in 3 distinct types of cultured pulmonary SMC. Pulmonary SMC migration was blocked by an ETA receptor selective agonist and a combined ETA-ETB antagonist, but not by a selective ETB antagonist. In contrast to the effect on pulmonary SMCs, ET-1 had no effect on migration of aortic SMCs. Flow cytometry showed that the ETA receptor was expressed at comparable levels on pulmonary and aortic SMCs, excluding receptor density as an explanation for the divergent effect. ET-1-induced pulmonary SMC migration was blocked by the structurally distinct MEK inhibitors PD98059 and U0126, consistent with a role for ERK1/2 MAP kinase. By Western blot in cultured cells and immunohistochemistry in ex vivo vessels, ET-1 stimulated phosphorylation of ERK1/2 as efficaciously as platelet derived growth factor in pulmonary, but not aortic, SMCs. In conclusion, ET-1 induces SMC migration, with the ETA receptor tightly coupled to ERK1/2 phosphorylation only in the pulmonary circulation. This finding may help explain the striking difference in the efficacy of endothelin receptor blockers for pulmonary hypertension as compared to that for systemic cardiovascular disease. PMID- 20725142 TI - Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries. AB - Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S) Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 +/- 0.14 (n = 4 animals; mean +/- SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S) darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries. PMID- 20725143 TI - ECE-1 influences prostate cancer cell invasion via ET-1-mediated FAK phosphorylation and ET-1-independent mechanisms. AB - Plasma concentrations of the mitogenic peptide endothelin-1 (ET-1) are significantly elevated in men with metastatic prostate cancer (PC). ET-1 also contributes to the transition of hormonally regulated androgen-dependent PC to androgen-independent disease. ET-1 is generated from big-ET-1 by endothelin converting enzyme (ECE-1). ECE-1 is present in PC cell lines and primary tissue and is elevated in primary malignant stromal cells compared with benign. siRNA or shRNA-mediated knockdown of endogenous ECE-1 in either the epithelial or stromal compartment significantly reduced PC cell (PC-3) invasion and migration. The re addition of ET-1 only partially recovered the effect, suggesting ET-1-dependent and -independent functions for ECE-1 in pPC. The ET-1-independent effect of ECE-1 on PC invasion may be due to modulation of downstream signalling events. Addition of an ECE-1 specific inhibitor to PC-3 cells reduced phosphorylation of focal adhesion kinase (FAK), a signalling molecule known to play a role in PC. siRNA mediated knockdown of ECE-1 resulted in a significant reduction in FAK phosphorylation. Accordingly, transient ECE-1 overexpression in PNT1-a cells increased FAK phosphorylation. In conclusion, ECE-1 influences PC cell invasion via both ET-1-mediated FAK phosphorylation and ET-1 independent mechanisms. PMID- 20725144 TI - Reexamining the DNA target selectivity of Scalloped. AB - Selector proteins are transcription factors that coordinate the formation and identity of organs and appendages. The proper formation of these tissues requires the selector proteins to regulate the expression of a large set of genes. Many selector proteins are involved in regulating multiple developmental processes, yet it is not completely clear how they are able to activate different sets of genes in a tissue-specific manner. An association with cofactors is thought to be one method by which enhancer selectivity is achieved. During wing development the selector protein Scalloped (SD) interacts with the cofactor Vestigial (VG). This interaction leads to the activation of a specific set of downstream wing genes. Herein, data are presented indicating that the switch in binding selectivity is likely achieved by VG altering the general affinity that the SD protein has for DNA. The decreased affinity for DNA is compensated for by the fact that the VG protein forms a complex containing two SD proteins. These two properties ensure that the SD-VG complex is able to bind only to enhancers that have two consecutive binding sites. Furthermore, data are presented that indicate that the function of the two terminal domains of the VG protein is not restricted to activating transcription and promoting the recruitment of two SD proteins. PMID- 20725145 TI - Recent transposition of yabusame, a novel piggyBac-like transposable element in the genome of the silkworm, Bombyx mori. AB - On the W chromosome of the silkworm, Bombyx mori, we found a novel piggyBac-like DNA transposon that potentially encodes an intact transposase (610 amino acid residues), which is flanked by 16-bp perfect inverted terminal repeats and a duplicated TTAA target site. Interestingly, we also identified another intact copy of this transposon on an autosome (chromosome 21), which showed 99.6% identity in the DNA sequence of the transposase (99.3% amino acid identity). These features raised the possibility that this novel piggyBac-like DNA transposon, designated as yabusame, may retain transposition activity. Here we report the identification and characterization of yabusame transposons from the silkworm. We cloned the full length of the yabusame transposon on the W chromosome (yabusame-W) and its autosomal copy (yabusame-1). Southern blot analysis showed that there are interstrain polymorphisms in yabusame elements for their insertion sites and copy number. We also found strong evidence for the recent transposition of yabusame elements in the silkworm genome. Although our in vitro excision assays suggested that the transposition activity of yabusame-1 and yabusame-W has been lost almost entirely, our data will lead to a greater understanding of the characteristics of piggyBac superfamily elements. PMID- 20725146 TI - Genomic affinities in Turnera (subseries Turnera, Turneraceae) inferred by in situ hybridization techniques. AB - Subseries Turnera comprises a polyploid complex with ploidy levels ranging from diploid (2n = 2x = 10) to octoploid (2n = 8x = 40). The use of fluorescent in situ hybridization greatly improved the knowledge of the karyotypes of Turnera species by detecting and mapping rDNA sites. Interspecific variability in the number of sites was detected, but not in correlation with the ploidy level. A chromosome pair with a strong hybridization signal was always visible and this signal corresponded to the secondary constriction detectable by conventional techniques. Genomic in situ hybridization experiments combined with information on meiotic pairing in species and interspecific hybrids revealed that homologies detected by molecular analysis are greater than those detected by chromosome pairing. This suggests that the formation of the allopolyploids could involve species more closely related than previously assumed. Despite the molecular affinity among the genomes, the meiotic pairing is probably controlled by specific genes that restrict homeologous pairing in polyploids. PMID- 20725147 TI - The history and disposition of transposable elements in polyploid Gossypium. AB - Transposable elements (TEs) are a major component of plant genomes. It is of particular interest to explore the potential activation of TE proliferation, especially in hybrids and polyploids, which often are associated with rapid genomic and epigenetic restructuring. Here we explore the consequences of genomic merger and doubling on copia and gypsy-like Gorge3 long terminal repeat (LTR) retrotransposons as well as on non-LTR long interspersed nuclear elements (LINEs) in allotetraploid cotton, Gossypium hirsutum. Using phylogenetic and quantitative methods, we describe the composition and genomic origin of TEs in polyploid Gossypium. In addition, we present information on ancient and recent transposition activities of the three TE types and demonstrate the absence of an impressive proliferation of TEs following polyploidization in Gossypium. Further, we provide evidence for present-day transcription of LINEs, a relatively minor component of Gossypium genomes, whereas the more abundant LTR retrotransposons display limited expression and only under stressed conditions. PMID- 20725148 TI - Comparative analysis of expression profiles of chemokines, chemokine receptors, and components of signaling pathways mediated by chemokines in eight cell types during rat liver regeneration. AB - It has been documented that chemokines can positively regulate liver regeneration at the tissue level after partial hepatectomy. However, the precise mechanism of the effects of chemokines on regeneration at the cellular level remains poorly defined. In this study, 8 cell types from rat regenerating liver at 8 recovery time points after 2/3 hepatectomy were isolated and purified using Percoll density gradient centrifugation and immunomagnetic bead methods. The expression profiles of each cell type were monitored using a microarray. RT-PCR analysis was performed to validate the reliability of the microarray results. The results showed that, on the whole, the expression profiles of chemokine and receptor genes varied among different cell types; most genes involved in chemokine signaling pathways showed an increase in expression across the 8 liver cell types during liver regeneration. The implication of these genes in regeneration was analyzed by bioinformatics and systems biology methods. According to the microarray results and gene synergy, activation of chemokine signaling pathways at 24 h in biliary epithelial cells and at 2-12 h in dendritic cells may be triggered by CCL2-CCR2 and CCL7-CCR3, respectively; activation of Plc/Pkc and Pi3k/Akt pathways at 2-12 h in sinusoidal endothelial cells might be caused by CCL7-CCR1; and activation of the Src/Ptk, Src/Vav, and Plc/Pkc pathways at the priming stage may be related to the inductive effect of CCL7. These data suggest the potential relevance of the pro-inflammatory chemokines for liver regeneration at the cellular level. PMID- 20725149 TI - Introgression of B-genome chromosomes in a doubled haploid population of Brassica napus x B. carinata. AB - The Brassica B-genome species possess many valuable agronomic and disease resistance traits. To transfer traits from the B genome of B. carinata into B. napus, an interspecific cross between B. napus and B. carinata was performed and a doubled haploid (DH) population was generated from the BC2S3 generation. Successful production of interspecific DH lines as identified using B-genome microsatellite markers is reported. Five percent of DH lines carry either intact B-genome chromosomes or chromosomes that have deletions. All of the DH lines have linkage group J13/B7 in common. This was further confirmed using B. nigra genomic DNA in a fluorescent in situ hybridization assay where the B-genome chromosomes were visualized and distinguished from the A- and C-genome chromosomes. The 60 DH lines were also evaluated for morphological traits in the field for two seasons and were tested for resistance to blackleg, caused by Leptosphaeria maculans, under greenhouse conditions. Variation in the DH population followed a normal distribution for several agronomic traits and response to blackleg. The lines with B-genome chromosomes were significantly different (p < 0.01) from the lines without B-genome chromosomes for both morphological and seed quality traits such as days to flowering, days to maturity, and erucic acid content. PMID- 20725150 TI - A novel QTL for Septoria speckled leaf blotch resistance in barley (Hordeum vulgare L.) accession PI 643302 by whole-genome QTL mapping. AB - Septoria speckled leaf blotch (SSLB), caused by Septoria passerinii, is one of the most important foliar diseases of barley (Hordeum vulgare L.) in North America. The primary problem caused by this disease is substantial yield loss. The objective of this study was to determine the chromosomal location of SSLB resistance genes in the barley accession PI 643302. A recombinant inbred line population was developed from the cross Zhenongda 7/PI 643302. PI 643302 is resistant while Zhenongda 7 is susceptible to SSLB. The population was phenotyped for SSLB resistance in five experiments in the greenhouse. A linkage map comprising 113 molecular markers was constructed and simplified composite interval mapping was performed. Two QTLs, designated QrSp-1H and QrSP-2H, were found. QrSp-1H was found on the short arm of chromosome 1H (1HS) in all five experiments and showed a large effect against SSLB. Based on the location of QrSp 1H, it is likely the SSLB resistance gene Rsp2. The QTL QrSp-2H mapped to the distal region on the long arm of chromosome 2H (2HL), had a smaller effect than QrSp-1H, and was also detected consistently in all five experiments. A QTL for SSLB resistance in the same region on chromosome 2H has not been reported previously in either cultivated or wild barley; thus, QrSp-2H is a new QTL for SSLB resistance in barley. PMID- 20725151 TI - LEM-PCR: a method for determining relative transcript isoform proportions using real-time PCR without a standard curve. AB - Many genes express multiple transcript isoforms generated by alternative splicing of mRNA. Using real-time PCR, it is straightforward to determine the relative expression level of each isoform independently. However, it is less trivial to determine the relative proportions of different isoforms in a cDNA sample. The relative proportions of different isoforms can be important, as a small change in a highly abundant transcript may be more relevant than a large change in a minimally expressed transcript. Currently, determining the relative proportions of isoforms requires the construction of a standard curve using recombinant plasmid DNA or genomic DNA. As recombinant or genomic DNA standards often amplify with different efficiencies to cDNA samples, they may give under- or overestimations of isoform abundances. The method described in this article uses a titration curve generated from the same cDNA samples measured in the experiment. By using samples with different levels of separate isoforms, it is possible to derive linear equations which, when solved, allow the determination of the proportion of each isoform within the samples under study. PMID- 20725152 TI - Development of genome-specific 5S rDNA markers in Brassica and related species for hybrid testing. AB - The Brassicaceae are targets for DNA manipulation to modify oil content and composition. However, any strategy for creating novel products using genetic modification or traditional breeding must take into account the potential for hybridization with other Brassica species, many of which are important sources of edible oils. In this study we have tested Brassica carinata, a possible target for oil modification, to establish whether it can cross with other Brassica species and related genera, and we have developed molecular DNA assays to confirm hybridization. PMID- 20725153 TI - Toxicology and carcinogenesis studies of dibromoacetonitrile (CAS No. 3252-43-5) in F344/N rats and B6C3F1 mice (drinking water studies). AB - BACKGROUND: Dibromoacetonitrile occurs in chlorinated drinking water that contains bromine and interacts with organic matter.We studied the effects of dibromoacetonitrile in drinking water on male and female rats and mice to identify potential toxic or cancer-related hazards. METHODS: We gave drinking water containing 50, 100, or 200 milligrams of dibromoacetonitrile per liter of water to groups of 50 male and female rats and mice for two years. Control animals received the same tap water with no chemical added. At the end of the study, tissues from more than 40 sites were examined for every animal. RESULTS: Survival was similar for animals receiving dibromoacetonitrile and the controls. Male and female rats receiving dibromoacetonitrile had increased rates of squamous cell adenomas or carcinomas of the mouth (oral mucosa or tongue). Two male rats receiving 200 mg/L had rare adenomas of the glandular stomach. There were a few instances of skin tumors in female rats receiving 100 or 200 mg/L. Male and female mice exposed to dibromoacetonitrile had increased rates of squamous cell papillomas of the forestomach. There were also slight increases in the occurrence of liver tumors in male mice. CONCLUSIONS: We conclude that dibromoacetonitrile in the drinking water caused cancer of the oral cavity in male and female rats and of the glandular stomach in male rats. We conclude that dibromoacetonitrile caused cancer of the forestomach in male and female mice. Tumors of the skin in female rats and of the liver in male mice may also have been related to exposure to dibromoacetonitrile. PMID- 20725154 TI - NTP toxicology and carcinogenesis studies of 5-(Hydroxymethyl)-2-furfural (CAS No. 67-47-0) in F344/N rats and B6C3F1 mice (gavage studies). AB - 5-(Hydroxymethyl)-2-furfural is formed when reducing sugars such as fructose and sucrose are heated in the presence of amino acids. 5-(Hydroxymethyl)-2-furfural is ubiquitous in the human diet and occurs at concentrations greater than 1 g/kg in dried fruits, caramel products, certain types of fruit juices, and up to 6.2 g/kg in instant coffee. 5-(Hydroxymethyl)-2-furfural also occurs naturally and has been identified in honey, apple juice, citrus juices, beer, brandy, milk, breakfast cereal, baked foods, tomato products, and home cooking of sugar and carbohydrates. Industrially, 5-(hydroxymethyl)-2-furfural is used in the synthesis of dialdehydes, glycols, ethers, aminoalcohols, acetals, and phenol/furfural novolak-type resins. 5-(Hydroxymethyl)-2-furfural was nominated by the National Institute of Environmental Health Sciences for study because of extensive human exposure and the lack of adequate data characterizing its toxicity and carcinogenicity. Male and female F344/N rats and B6C3F1 mice were administered 5-(hydroxymethyl)-2-furfural (at least 99% pure) by gavage in deionized water for 3 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. 3-WEEK STUDY IN RATS: core study groups of five male and five female rats were administered 0, 94, 188, 375, 750, or 1,500 mg 5 (hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for a total of 13 doses over a 22-day period. Special study groups of five male and five female rats designated for neuropathology were administered 0 or 1,500 mg/kg on the same schedule. Except for one 1,500 mg/kg core study male rat, all rats survived to the end of the study. The final mean body weight of 1,500 mg/kg males was significantly less than that of the vehicle control group. No chemical related histopathologic lesions were observed in core or special study animals. 3 WEEK STUDY IN MICE: groups of five male and five female mice were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for a total of 13 doses over a 22-day period. Three male and three female mice administered 1,500 mg/kg died before the end of the study. Mean body weights of 1,500 mg/kg males were significantly less than those of the vehicle control group. Heart weights of 1,500 mg/kg females were significantly greater than those of the vehicle controls. No chemical-related lesions were observed. 3-MONTH STUDY IN RATS: core groups and special study groups (for clinical pathology and neuropathological evaluation) of 10 male and 10 female rats were administered 0, 94, 188, 375, 750, or 1,500 mg 5 (hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 3 months. One male and three female rats administered 1,500 mg/kg died before the end of the study; the male died as a result of gavage trauma. Mean body weights of 750 and 1,500 mg/kg males were significantly less than those of the vehicle control group. Female rats had elongated estrous cycles; fewer 750 and 1,500 mg/kg females had regular cycles, and 375, 750, and 1,500 mg/kg females had a significantly increased probability of extended diestrus. No chemical-related lesions were observed in core or special study animals. 3-MONTH STUDY IN MICE: groups of 10 male and 10 female mice were administered 0, 47, 94, 188, 375, or 750 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 3 months. One 750 mg/kg male and one 375 mg/kg female died before the end of the study; the death of the female was attributed to ovarian teratoma. The final mean body weight of 750 mg/kg males and body weight gains of 750 mg/kg males and females were significantly less than those of the vehicle controls. The incidences of minimal to mild cytoplasmic alteration of the kidney were significantly increased in males administered 188 mg/kg or greater. 2-YEAR STUDY IN RATS: groups of 50 male and 50 female rats were administered 0, 188, 375, or 750 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 104 weeks. Survival of 188 and 750 mg/kg males was greater than that of the vehicle control group. Mean body weights of dosed groups of males and females were generally similar to those of the vehicle controls throughout the study. Incidences of olfactory epithelium degeneration were significantly increased in 750 mg/kg males and 188 and 375 mg/kg females. Incidences of olfactory epithelium respiratory metaplasia and respiratory epithelium squamous metaplasia were significantly increased in 750 mg/kg males and females. Incidences of suppurative inflammation of the nose and chronic active inflammation of the nasolacrimal duct were significantly increased in 750 mg/kg females. 2-YEAR STUDY IN MICE: groups of 50 male and 50 female mice were administered 0, 188, 375, or 750 mg 5 (hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 104 weeks. Survival of 750 mg/kg males and females was significantly less than that of the vehicle control groups. Mean body weights of 750 mg/kg males were 14% less than those of the vehicle controls after week 26. Mean body weights of 375 and 750 mg/kg females were 9% and 30% less, respectively, than those of the vehicle controls after week 36. Beginning in month 8 and continuing until the end of the study, 750 mg/kg males and females exhibited clinical signs indicative of neurological effects of 5-(hydroxymethyl)-2-furfural administration. These signs included decreased exploratory behavior, piloerection, salivation, Straub tail, catatonia, excitation, dyspnea, clonic-tonic seizures, and unconsciousness. Because of the reduced survival of this group and the presence of the treatment related clinical signs, groups of mice that received 750 mg/kg were not included in the evaluation of carcinogenic potential. The incidences of hepatocellular adenoma were significantly increased in 188 and 375 mg/kg females. In the nose, the incidences of olfactory epithelium metaplasia, degeneration, and hyaline droplet accumulation; chronic active inflammation; respiratory epithelium hyaline droplet accumulation; and hyperplasia, dilatation, and chronic active inflammation of the glands were significantly increased in 375 and 750 mg/kg males and females. Incidences of olfactory epithelium hyperplasia were significantly increased in 375 and 750 mg/kg females. GENETIC TOXICOLOGY 5 (Hydroxymethyl)-2-furfural was tested in two independent bacterial mutagenicity assays. In the first study, the chemical was weakly mutagenic in Salmonella typhimurium strain TA100 in the absence of exogenous metabolic activation; no mutagenic activity was detected in TA100 with activation or in strains TA97, TA98, TA102, or TA1535, with or without activation. In the second study, no mutagenicity was detected, with or without activation, in TA98 or TA100 or Escherichia coli WP2 uvrA/pKM101. No increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood of male or female mice administered 5-(hydroxymethyl)-2-furfural by gavage for 3 months. CONCLUSIONS: under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 5-(hydroxymethyl)-2-furfural in male or female F344/N rats administered 188, 375, or 750 mg/kg. There was no evidence of carcinogenic activity of 5-(hydroxymethyl)-2-furfural in male B6C3F1 mice administered 188 or 375 mg/kg. There was some evidence of carcinogenic activity of 5-(hydroxymethyl)-2-furfural in female B6C3F1 mice based on increased incidences of hepatocellular adenoma in the 188 and 375 mg/kg groups. Administration of 5-(hydroxymethyl)-2-furfural was associated with increased incidences of lesions of the olfactory and respiratory epithelium of the nose in male and female rats and mice. PMID- 20725155 TI - NTP technical report on the toxicology and carcinogenesis studies of 1,2-dibromo 2,4-dicyanobutane (CAS No. 35691-65-7) in F344/N rats and B6C3F1 mice (dermal studies). AB - 1,2-Dibromo-2,4-dicyanobutane is used in cosmetics and other household products. 1,2-Dibromo-2,4-dicyanobutane was nominated for study by the National Institute of Environmental Health Sciences because of its widespread use as a component of numerous over-the-counter health care products. Male and female F344/N rats and B6C3F1 mice received 1,2-dibromo-2,4-dicyanobutane (greater than 99% pure) in acetone (2-week and 3-month studies) or 95% ethanol (2-year studies) by dermal administration for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were dermally administered 0, 37.5, 75, 150, 300, or 600 mg 1,2-dibromo-2,4 dicyanobutane/kg body weight in acetone, 5 days per week for 16 days. All male and female rats survived to the end of the study. Mean body weights of dosed male and female rats were similar to those of the vehicle controls. Irritation, thickened skin, and ulcers were observed at the site of application in most dosed males and females. The thyroid gland weights of males administered 600 mg/kg were significantly less than those of the vehicle controls. The liver and kidney weights of 300 and 600 mg/kg females were significantly increased. A spectrum of nonneoplastic lesions including epidermal hyperplasia and hyperkeratosis, sebaceous gland hyperplasia, and dermal chronic active inflammation occurred at the site of application in all dosed groups of rats. Necrosis, ulcer, and parakeratosis of the epidermis occurred in most dosed groups of rats. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were dermally administered 0, 75, 150, 300, 600, or 1,200 mg/kg 1,2-dibromo-2,4-dicyanobutane in acetone, 5 days per week for 16 days. All male and female mice survived to the end of the study. The final mean body weight of 300 mg/kg males was significantly less than that of the vehicle controls. Hyperactivity was observed in all dosed groups of mice. Irritation, thickened skin, and ulcers were observed at the site of application in dosed mice. The liver weights of 600 and 1,200 mg/kg males and 1,200 mg/kg females were significantly increased relative to those of the vehicle control groups. The heart weights of 600 and 1,200 mg/kg males and the kidney weights of 150 and 600 mg/kg males were significantly increased. The thymus weights of males administered 300 mg/kg or greater and those of all dosed groups of females were significantly decreased. Skin lesions at the site of application including epidermal hyperplasia, hyperkeratosis, parakeratosis, necrosis, and ulcers; dermal chronic active inflammation; and sebaceous gland hyperplasia occurred in all dosed groups of mice. Necrosis of the dermis occurred in most dosed groups of mice. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were dermally administered 0, 0.2, 0.6, 2, 6, or 18 mg/kg 1,2-dibromo-2,4 dicyanobutane in acetone, 5 days per week for 14 weeks. All male rats survived to the end of the study. One 2 mg/kg female rat died on day 91. Mean body weights of dosed male and female rats were similar to those of the vehicle controls. Clinical findings of toxicity included thin hair coat in male and female rats and irritation at the site of application in males. At the site of application, the incidences of epidermal hyperplasia in males administered 0.6 mg/kg or greater and females administered 2 mg/kg or greater and the incidences of epidermal hyperkeratosis in all dosed groups of rats were significantly increased. In the dermis at the site of application, the incidences of chronic active inflammation in 6 and 18 mg/kg males and females administered 2 mg/kg or greater and sebaceous gland hyperplasia in males administered 6 or 18 mg/kg were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were dermally administered 0, 0.2, 0.6, 2, 6, or 18 mg/kg 1,2-dibromo-2,4 dicyanobutane in acetone, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of dosed male and female mice were similar to those of the vehicle controls. Irritation at the site of application was increased in male mice administered 18 mg/kg. The liver and lung weights of dosed females were generally significantly less than those of the vehicle control group. The incidences of minimal to mild epidermal hyperplasia and hyperkeratosis at the site of application were significantly increased in male and female mice administered 2 mg/kg or greater. The incidence of epidermal necrosis in 18 mg/kg males and the incidences of epidermal parakeratosis in 6 and 18 mg/kg males were significantly increased. In the dermis, the incidences of minimal to mild chronic active inflammation in 18 mg/kg males and in females administered 2 mg/kg or greater and fibrosis in 18 mg/kg males and females were significantly increased. The incidences of sebaceous gland hyperplasia at the site of application were significantly increased in males and females administered 6 or 18 mg/kg. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 2, 6, or 18 mg/kg 1,2-dibromo-2,4-dicyanobutane in 95% ethanol, 5 days a week for 104 to 105 weeks. Survival of males administered 18 mg/kg was significantly greater than that of the vehicle controls. Body weights of 18 mg/kg males and females were 7% less than those of the vehicle control groups after 1 year. Irritation at the site of application was reported in most males and females administered 6 or 18 mg/kg. There were no increases in the incidences of neoplasms in dosed rats. At the site of application, the incidences of epidermal hyperplasia in males and females administered 6 or 18 mg/kg and the incidences of hyperkeratosis of the epidermis in all dosed groups were significantly increased. The incidences of minimal to mild inflammation in the dermis at the site of application were significantly increased in males administered 6 or 18 mg/kg and in all dosed groups of females. The incidence of epidermal necrosis at the site of application in 18 mg/kg females was significantly increased. The incidences of inflammation of the nose were significantly increased in all dosed groups of male rats. The combined incidence of mammary gland fibroadenoma, adenoma, or adenocarcinoma occurred with a negative trend, and the incidence was significantly decreased in 6 mg/kg female rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were dermally administered 0, 0.6, 2, or 6 mg/kg 1,2 dibromo-2,4-dicyanobutane in 95% ethanol, 5 days a week for 105 weeks. Survival of male and female mice was similar to that of the vehicle controls. Body weights of male and female dosed groups were similar to those of the vehicle control groups. No clinical findings were attributed to administration of 1,2-dibromo-2,4 dicyanobutane. There were no increases in the incidences of neoplasms in dosed mice. At the site of application, the incidences of minimal to mild hyperplasia of the epidermis were significantly increased in 2 and 6 mg/kg males and in all dosed groups of females. The incidences of minimal to mild chronic active inflammation in the dermis were significantly increased in all dosed groups of females. GENETIC TOXICOLOGY: 1,2-Dibromo-2,4-dicyanobutane was not mutagenic in any of several strains of Salmonella typhimurium or Escherichia coli when tested with and without hamster and/or rat liver metabolic activation enzymes (S9). In addition, no increase in the frequency of micronucleated erythrocytes was observed in male or female mice treated for 3 months with 1,2-dibromo-2,4 dicyanobutane by dermal application in acetone, indicating no potential for inducing chromosomal alterations in dividing cells in this test system. CONCLUSIONS: Under the conditions of these 2-year dermal studies there was no evidence of carcinogenic activity of 1,2-dibromo-2,4-dicyanobutane in male or female F344/N rats administered 2, 6, or 18 mg/kg. There was no evidence of carcinogenic activity of 1,2-dibromo-2,4-dicyanobutane in male or female B6C3F1 mice administered 0.6, 2, or 6 mg/kg. 1,2-dibromo-2,4-dicyanobutane administration induced nonneoplastic lesions at the site of application in male and female rats and mice. PMID- 20725157 TI - Patents. AB - 5011244; 5013107; 5024508; 5028102; 5031190; 5032010; 5039222; 5050993. PMID- 20725156 TI - NTP toxicology and carcinogenesis studies of chromium picolinate monohydrate (CAS No. 27882-76-4) in F344/N rats and B6C3F1 mice (feed studies). AB - Chromium picolinate monohydrate is the commercially available form of chromium picolinate. Chromium picolinate is one of a number of compounds that contain chromium in the trivalent state (Cr III), which is the predominant form of chromium in nature. Humans ingest Cr III in food and dietary supplements. The major uses of Cr III in the chemical and manufacturing industries include production of chromium pigments and leather tanning. Chromium picolinate was nominated by the National Cancer Institute and a private individual for testing based on the potential for widespread consumer exposure from use as a dietary supplement. Male and female F344/N rats and B6C3F1 mice were exposed to chromium picolinate monohydrate (95% to 96% pure) in feed for 3 months or 2 years. Genetic toxicology studies with chromium picolinate monohydrate were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. Genetic toxicology studies with chromium picolinate were conducted in S. typhimurium and rat bone marrow cells. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 80, 240, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 7, 20, 160, 800, and 4,240 mg chromium picolinate monohydrate/kg body weight to males and 6, 20, 160, 780, and 4,250 mg/kg to females) for 14 weeks. All rats survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. No exposure-related lesions occurred in males or females. 3 MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 80, 240, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 17, 50, 450, 2,300, and 11,900 mg chromium picolinate monohydrate/kg body weight to males and 14, 40, 370, 1,775, and 9,140 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups were similar to those of the control groups throughout the study. No exposure-related lesions occurred in male or female mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 90, 460, and 2,400 mg/kg to males and 100, 510, and 2,630 mg/kg to females) for 105 weeks. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights and feed consumption of exposed groups of males and females were generally similar to those of the controls throughout the study. The incidence of preputial gland adenoma was significantly increased in males exposed to 10,000 ppm and exceeded the historical control ranges. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 250, 1,200, and 6,565 mg/kg to males and 240, 1,200, and 6,100 mg/kg to females) for 105 weeks. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of exposed groups of males were generally similar to those of the controls throughout the study; mean body weights of 50,000 ppm females was 10% less than the control group at 1 year. Feed consumption by exposed groups of males and females was similar to that by the controls throughout the study. No neoplasms or nonneoplastic lesions were attributed to exposure to chromium picolinate monohydrate. GENETIC TOXICOLOGY: In the standard screening assays conducted by the NTP, chromium picolinate monohydrate showed no clear evidence of genotoxicity. It was not mutagenic in Salmonella typhimurium strains TA98 or TA100 or Escherichia coli strain WP2 uvrA/pKM101 when tested with or without exogenous metabolic activation (S9). No increase in the frequency of micronucleated normochromatic erythrocytes was observed in male B6C3F1 mice administered chromium picolinate monohydrate in feed for 3 months. A small increase in micronucleated normochromatic erythrocytes was seen in female mice at the highest exposure concentration tested, and the results in female mice were considered equivocal. Additional genotoxicity testing was conducted with chromium picolinate (not the monohydrate form of the compound), and results were also negative. No induction of gene mutations was observed in two independent studies conducted in several strains of S. typhimurium with and without S9. No induction of micronucleated polychromatic erythrocytes was observed in bone marrow of male F344/N rats treated with chromium picolinate by oral gavage three times at 24-hour intervals. CONCLUSIONS: Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity* of chromium picolinate monohydrate in male F344/N rats based on an increase in the incidence of preputial gland adenoma. There was no evidence of carcinogenic activity of chromium picolinate monohydrate in female F344/N rats or in male or female B6C3F1 mice. PMID- 20725159 TI - Visualization of in-plane displacement fields by using phase-shifting holographic moire: application to crack detection and propagation. AB - Phase-shifted holographic moire is shown to provide highly improved visualization of the phase fields corresponding to in-plane displacements. Outstanding capabilities in the study of crack process are demonstrated. PMID- 20725160 TI - Phase-stepping holographic moire: simultaneous in-plane and out-of-plane displacement measurement. AB - A new use for the phase-stepping technique in holographic moire is demonstrated. The method has the advantage of providing instantaneous determination of in-plane and out-of-plane displacements without the necessity for auxiliary carrier fringes. PMID- 20725161 TI - Volume influence on intermodulation noise of dielectric diffuse-object holograms. AB - The influence of recording material thickness on intermodulation noise is analyzed in phase holograms of diffuse objects; an increase in the signal-to noise ratio is observed. However the intermodulation noise is independent of the thickness when there is high density before bleaching. PMID- 20725163 TI - Speckle interferometry: noise reduction by correlation fringe averaging. AB - A method for noise reduction in double-exposure speckle interferometry is proposed, based on averaging independent spatially filtered correlation fringe patterns. PMID- 20725162 TI - Temperature sensitivity of acoustic velocity and frequency registration in acousto-optic spectrum analyzers. AB - An upper bound DeltaT is derived for the temperature variation over which frequency registration is maintained. DeltaT is determined for a TeO(2) slow shear-mode Bragg cell. PMID- 20725164 TI - Fast learning in a backpropagation algorithm with a sine-type thresholding function. AB - A new approach to learning in a multilayer neural network based on a backpropagation algorithm is presented. With a sine-type thresholding function the model is more efficient and able to learn nonnegative interconnections that are suitable for optical implementations. PMID- 20725165 TI - Compact joint transform correlator with a thick photorefractive crystal. AB - A compact joint transform correlator with a thick photorefractive crystal is presented. We demonstrate that Bragg diffraction severely limits the correlation performance in a thick crystal. To relax the Bragg limitation of the crystal a Galilean telescopic beam compression technique is used in the joint transform correlator. PMID- 20725166 TI - Digital optical processing based on higher-order modified signed-digit symbolic substitution. AB - An efficient higher-order modified signed-digit optical symbolic substitution technique for addition and subtraction has been derived. This two-step symbolic substitution technique, which is independent of the number of bits to be processed, saves a tremendous amount of computation time. Two separate approaches for optical implementation that use content-addressable memory and the joint transform correlator are also suggested. PMID- 20725167 TI - Spatial mixed binary multiplication by photon echoes. AB - We demonstrate mixed binary multiplication of two or three numbers represented as spatial bit patterns by using a backward stimulated photon echo in a low temperature solid activated by rare-earth ions. The photon-echo output image is the convolution-correlation of input images in a holographic arrangement, which can be interpreted as multiplication in a mixed binary format. The computation is extremely fast (~ 50 ns) and may be combined with temporal data processing for a versatile vector and matrix processor. PMID- 20725168 TI - Delay synchronization in time-of-flight optical systems. AB - Time-of-flight optical computer designs must implicitly or explicitly allow for the synchronization of all signals at all interaction points. This paper details algorithms for calculating delays required for synchronization of optical systems, as well as the sensitivity of these systems to variations in delays from their nominal values. These algorithms, which are applied to graph models of systems, form the basis for an optical systems design methodology in which the designer develops architectures with lumped delays and idealized zero-delay devices. When applied to the system designs, the algorithms provide estimates of actual delay distributions and sensitivities. PMID- 20725169 TI - Simulation of board-level free-space optical interconnects for electronic processing. PMID- 20725170 TI - Implementation of an optical crossbar network based on directional switches. AB - We have implemented an all-optical digital switching network based on ferroelectric liquid crystal arrays used as directional switches. It connects eight input to eight output channels simultaneously and randomly. The reconfiguration rate of the system can reach 100 kHz by using a parallel-driven 6 x 6 ferroelectric liquid crystal array. The modulation bandwidth in each channel depends only on the transmitters and receivers, not on the system itself. PMID- 20725171 TI - Laser radar cross-section estimation from high-resolution image data. AB - A methodology for the estimation of ladar cross sections from high-resolution image data of geometrically complex targets is presented. Coherent CO(2) laser radar was used to generate high-resolution amplitude imagery of a UC-8 Buffalo test aircraft at a range of 1.3 km at nine different aspect angles. The average target ladar cross section was synthesized from these data and calculated to be sigma(T) = 15.4 dBsm, which is similar to the expected microwave radar cross sections. The aspect angle dependence of the cross section shows pronounced peaks at nose on and broadside, which are also in agreement with radar results. Strong variations in both the mean amplitude and the statistical distributions of amplitude with the aspect angle have also been observed. The relative mix of diffuse and specular returns causes significant deviations from a simple Lambertian or Swerling II target, especially at broadside where large normal surfaces are present. PMID- 20725172 TI - Transfer function for image formation of objects reconstructed from volume holograms with different wavelengths. AB - The imaging properties of coherent optical systems where images are formed as reconstructions from volume holograms are investigated. The apparent modulation transfer functions for a given optical system are determined for various imaging and reconstruction conditions, theoretically and experimentally. A model describes the formation of the image from the coherent superposition of three amplitudes. It is shown that a thin rectangular absorption grating is a suitable object for deducing the modulation transfer of the equivalent three-amplitude object from the measured intensity distribution of the grating image. These real modulation transfer functions are compared with the calculated ideal ones; this comparison represents a measure for image quality. PMID- 20725173 TI - Multiplexed holographic Fabry-Perot etalons. AB - We discuss a multiplexed holographic Fabry-Perot etalon that includes a multiplexed hologram in a novel holographic Fabry-Perot etalon. Two unique advantages can be achieved by using the multiplexed holographic Fabry-Perot etalon: coherently coupled fabrication of holographic Fabry-Perot mirrors significantly reduces the need to have the nearly flat surfaces typically required in conventional Fabry-Perot etalons, and the angular-wavelength multiplexing capability of a multiplexed hologram can be added to the tunable narrow-band filtering capability of Fabry-Perot etalons. Several types of multiplexed holographic Fabry-Perot etalon are experimentally demonstrated. PMID- 20725174 TI - Three-dimensional representation of ventriculography using contour-line holography. PMID- 20725175 TI - Photodoped chalcogenides as potential infrared holographic media. AB - The extension of holographic techniques from the visible to the infrared is important. Potentially, holographic diffractive elements have a large range of uses in this wave band. Examples include mirrors, lenses, filters, and beam combiners. All these elements would have similar advantages to those enjoyed by their visible band diffractive analogs. The metal photodissolution effect in chalcogenides shows promise as one of the few techniques for producing low-loss holographic materials for use at any given wavelength from 0.6 to beyond 16 microm. To date, the work has concentrated on the photodissolution of silver into arsenic sulfide glasses. Both bulk and surface relief gratings can be fabricated simply by holographic or mask exposure. In principle, kinoforms (e.g., blazed zone plates) and Fresnel lenses can also be made. The results of material studies show that phase gratings with high modulation and low absorption can be produced. A coupled-wave analysis is used to calculate the likely grating performance, and some initial grating characterization results are presented. The limitations of the medium are discussed and possible solutions are considered. PMID- 20725176 TI - Improvements of a spatial frequency analyzer for automated characterization of holographic recording materials. AB - A spatial frequency analyzer was designed to simplify characterization studies for new holographic recording materials. Mechanical movements were automated and a complete informational system gave rapid characterization results. A good fringe stabilization unit was improved by adding simple holographic optical beam combiners. Experimental characterization of two different recording materials shows the versatility of this automated apparatus. Also we present modulation transfer-function curves of dichromated gelatin between 500 and 3500 cycles/mm obtained with polarization volume transmission holograms. PMID- 20725178 TI - Error diffusion procedure: theory and applications in optical signal processing. AB - An analysis of the error diffusion procedure is presented that is based on the terminology of filter theory. It is demonstrated that the error diffusion procedure is a powerful means to avoid signal error caused by a nonlinear system. An appropriate filter design method is described. The theoretical results are applied to treat picture binarization as well as quantization and coding in diffractive optics-digital holography. PMID- 20725177 TI - Demonstration of acousto-optic bistability and chaos by direct nonlinear circuit modeling. AB - A novel technique involving nonlinear dependent sources expressed as convergent power series expansions of one or more variables representing the output fields of a Bragg-domain hybrid acousto-optic device with feedback is presented. Using some straightforward modifications of a basic circuit prototype, we show how optical bistability, possible multistability, and chaos may be generated for three fundamental types of tuning effects, i.e., feedback gain, bias voltage, and input amplitude. The results obtained are shown to compare favorably with the existing theory and experiments. PMID- 20725179 TI - Binarization of diffractive elements with nonperiodic structures. AB - An error diffusion and an iterative concept that is based on the Fourier transform algorithm are applied to binarize nonperiodic diffractive elements that generate speckle-free diffraction patterns. These methods are used successfully to calculate periodic elements and are adapted to specific constraints in the case of nonperiodic elements. Techniques to avoid stagnation are described, and optical experiments are presented. PMID- 20725180 TI - Effects of defocus and primary spherical aberration on three-dimensional coherent transfer functions in confocal microscopes. AB - For both reflection- and transmission-mode confocal scanning microscope systems, three-dimensional coherent transfer functions are investigated by considering the effects of defocus and primary spherical aberration. We numerically calculate the three-dimensional coherent transfer functions for various amounts of aberration and show that three-dimensional confocal imaging is strongly degraded if the amount of aberration is larger than a quarter wavelength. The compensation of the primary spherical aberration by introducing defocus is also discussed. PMID- 20725181 TI - Three-dimensional image realization in interference microscopy. AB - We describe an efficient algorithm based on the Hilbert transform for reconstructing cross-sectional or three-dimensional images from the input images acquired by an interference microscope. First the design of this filter is presented, and cross-sectional images of an integrated circuit constructed with this algorithm are demonstrated. It is shown that this Hilbert transform algorithm can be easily implemented with a low-cost frame grabber so that the computation time required for image reconstruction is drastically reduced. PMID- 20725182 TI - Error-free image compression algorithm using classifying-sequencing techniques. AB - The development of a new error-free digital image compression algorithm is discussed. Without the help of any statistics information of the images being processed, this algorithm achieves average bits-per-word ratios near the entropy of the neighboring pixel differences. Because this algorithm does not involve statistical modeling, generation of a code book, or long integer-floating point arithmetics, it is simpler and, therefore, faster than the studied statistics codes, such as the Huffman code or the arithmetic code. PMID- 20725183 TI - Different strategies in optical recognition of polychromatic images. AB - We treat two different problems in the recognition of polychromatic images: (1) recognition of an object with a given shape and color combination; (2) recognition of an object regardless of its color combination. To solve each problem we propose different strategies. The number of filters and the objects to which the filters are matched vary with the strategy. Phase-only filters have been used to achieve recognition of both problems. Computer results are given for different targets and scenes to show the behavior of the proposed strategies. PMID- 20725184 TI - Self-amplified optical pattern-recognition technique. AB - A self-amplified optical pattern-recognition technique that utilizes a photorefractive crystal as a real-time volume holographic filter with recording accomplished by means of laser beams of proper polarization and geometric configuration is described. After the holographic filter is recorded, it can be addressed with extremely weak object beams and an even weaker reference beam to obtain a pattern-recognition signal. Because of beam-coupling energy transfer from the input object beam to the diffracted beam, the recognition signal is greatly amplified. Experimental results of this technique using BaTiO(3) crystal show that 5 orders of magnitude of amplification of a recognition signal can be obtained. PMID- 20725185 TI - Design and analysis of a bidirectional free-space photonic switch based on the ALOHA scheme. AB - A bidirectional multichannel photonic switching architecture based on the ALOHA multiuser scheme is presented and analyzed. An implementation of the broadcasting hardware, which uses free-space digital optics and fiber-bundle arrays, is described. The advantages and disadvantages of such an implementation are outlined, and the throughput and delay performance of it are analyzed and compared to other architectures. Our investigation shows that the switching capacity of such an architecture grows at least linearly in the number of channels. PMID- 20725186 TI - Analysis of control subsystems for free-space photonic switching architectures. AB - Four different methods of injecting control signals into photonic switches are compared. A control injection model based on time-division-multiplexed switching is developed, and the analysis studies the effects of the different control injection schemes on network performance, system complexity, and system packaging. Serious system-level limitations are identified for all the control injection schemes in switching networks with high reconfiguration rates. PMID- 20725187 TI - Highly parallel architecture for optical disk database correlation with compensation for database errors. AB - Architectural prototypes and algorithms for performing many simultaneous complex correlations between external data and data stored on optical disks are presented. External data are modulated onto an addressing light beam acoustooptically. Analog correlation outputs are obtained at low bandwidth. Data may be encoded on the disk either digitally, and correlated by using a digital multiplication by analog convolution scheme, or by analog area modulation. Bipolar correlations are shown possible without data biasing when two auxilliary diode lasers are used in a sign determination scheme. Error issues include variations in reflectances of encoded bits and raw disk errors. PMID- 20725188 TI - Refraction in interferometric tomography. AB - Solutions to the tomographic problem of strongly refracting phase objects with not-too-large asymmetry and of objects with not-too-strong refraction, based on the perturbation approach, are proposed. The validity of the results is tested by numerical simulation of tomographic experiments. PMID- 20725189 TI - Propagation of the mutual coherence function in inhomogeneous turbulent media. AB - An inhomogeneous turbulent medium is characterized by a refractive index spectrum that varies from point to point. The mutual coherence function (MCF) is used to analyze the distortion that electromagnetic waves suffer when they propagate through such a medium. In this paper, we analyze the MCF in two dimensions for an incoherent line source. We show that the MCF consists of delta and non-delta components and derive the differential equations that each component must satisfy. Finally, we present results obtained by a numerical solution of these differential equations. PMID- 20725191 TI - Nasa patter. PMID- 20725190 TI - Compact optical pulse train generator. AB - A device that is capable of creating a series of equally spaced,i denticalp ulses from a inglep ulse is presented. It is useful for studying the time development of transient phenomena. PMID- 20725192 TI - Photoacoustic spectroscopy of C(2)H(4) with a tunable waveguide CO(2) laser. AB - A photoacoustic gas spectrometer using a wave-guide CO(2), laser, tunable over 500-MHz windows in 70 lines, is described. The spectrometer is used for mapping Doppler-limited spectral signatures of ethylene and for measuring pressure broadening rates for collisions with N(2), Ar, and He. A total of 41 observed transitions are assigned to the nu(7), nu(10), and nu(4) bands of normal ethylene and to the nu(7) band of the (13)C(12)CH(4) isotopomer. PMID- 20725193 TI - Cavity-enhanced photothermal spectroscopy: dynamics, sensitivity, and spatial resolution. AB - The spectrally resolved low-level absorption of thin films and of solid and liquid surfaces was measured by cavity-enhanced photothermal spectroscopy. The technique is ultrasensitive and can determine surfacespecific absorbances alpha(omega) ~ 10(-6) at a power density of 10(4)W/cm(2). Both cases of continuous wave and modulated laser light absorption were studied experimentally and are interpreted theoretically. It is shown that it is possible to achieve a spatial resolution of absorbance variations in the few-micrometer range. The thermal diffusivity can also be simultaneously measured by observing the time evolution of the surface temperature during laser irradiation. PMID- 20725194 TI - Long-time behavior of photon diffusion in an absorbing medium: application to time-resolved spectroscopy. AB - We have investigated the motion of photons after the injection of a light pulse into a highly scattering, inhomogeneous absorbing medium. We show that the terminal slope of the logarithm of the transmittance curve does not depend on the positions of the source or of the detector. We use numerical calculations to follow the motion of photons in a model system to further understand the physical process that gives rise to this result. PMID- 20725195 TI - Picosecond time-resolved vibrational spectroscopy using a regenerative amplifier. AB - We demonstrate and characterize an apparatus for transient infrared spectroscopy with a 5-ps resolution. A visible pump and narrow-band mid-infrared probe are both derived from a source that is based on a pulsed Nd:YAG regenerative amplifier that operates at 540 Hz. We measure transient spectra in the range 1770 2250 cm(-1) with a 1-cm(-1) resolution and sensitivity to absorbance changes less than or equal to 1 x 10(-3). As an example, we present results from experiments to study ligand photodissociation from carboxymyoglobin in D(2)0. PMID- 20725196 TI - y? Diagram, a powerful optical design method for laser systems. AB - We present a new method for synthesizing and analyzing laser systems based on the use of the y? diagram. The diagram is commonly used to represent two rays, the marginal and the chief rays, as they propagate through an optical system. Since a Gaussian beam can be represented by two rays, it is possible to use the y? diagram to represent these rays. This results in a representation of the beam as a single ray line on the y? diagram with simple graphic interpretations for the beam parameters. An equivalent representation of the Gaussian beam on the uu diagram is also presented and discussed. Complex design problems may be reduced to simple graphic problems, which often lead directly to algebraic solutions. Examples of y? diagrams are given for beam transfer through simple optical systems, including gradient optics. Diagram transformations are discussed and design examples are given of a three-element afocal system and a three-element collimator. PMID- 20725197 TI - Experimental investigation of Bessel beam characteristics. AB - We report on an experimental characterization of Bessel beams with finite apertures. We show that real Bessel beams can be generated with intensity profiles that closely resemble the ideal J(0)(2) transverseintensity distribution of Bessel beams. We also show interferometrically that these beams have planar phase fronts with pi-phase shifts from one Bessel ring to the next. We report tolerance conditions for Bessel beam generation and give an example of this generation that uses an unstable resonator as the light source. PMID- 20725198 TI - Vector formalism for circularly symmetric laser beams. AB - We present a finite dimensional vector formalism that describes the propagation of circularly symmetric beams in a simple and effective way. A propagation matrix operator is explicitly given that determines the amplitude as a function of the radius at any plane. Power transported to a circular or annular target is discussed in some detail. In particular, the problem of choosing a beam shape at the aperture that maximizes the power transported to a target has a simple solution in the new formalism. PMID- 20725199 TI - Mode-locking operation of a pulsed Nd:YAG laser with F(2) BF:LiF color-center crystal in a dual configuration. AB - Passive stable mode locking of a pulsed Nd:YAG laser was achieved with a long decay-time saturable absorber in a coupled-cavity longitudinal scheme. In this configuration the saturable absorber (LiF:F(2) ) also behaves as an active medium in intracavity pumping and is the load for the Nd laser. This arrangement provides proper lasing conditions for the F(2) color centers so that the cavity photon lifetime of the color centers is much shorter than the cavity round-trip time of the Nd laser. In this way the Nd pulses are simultaneously Q switched and mode locked. The pulses show a stable temporal profile, with an envelope of 160 ns and a train of mode-locked pulses of less than 200-ps duration. PMID- 20725200 TI - Characterization of the transverse modes in a laser beam: analysis and application to a Q-switched Nd:YAG laser. AB - We have developed a numerical code that, starting from far-field intensity measurements, is able to evaluate the excitation coefficients of the transverse modes in a laser system.Both the coherent and incoherent mode cases are addressed, and, while the incoherent case is shown to be equivalent to a linear problem, the coherent case is discussed through its equivalence to the phase retrieval problem. Problems arising from both ill posedness and the nonlinearity are discussed in detail.The validity of our approach is confirmed by several numerical simulations and some experimental results on the characterization of a Q-switched Nd:YAG laser. PMID- 20725201 TI - Method for pumping a Ti:sapphire laser with a stable resonator copper vapor laser. AB - An average laser power of > 3W and a slope efficiency of 20% have been obtained with a Ti:sapphire laser oscillator pumped by a copper vapor laser (CVL). A center-hole reflector inside a near-concentric resonator, instead of a dichroic mirror, has made it possible to utilize the stable resonator CVL as a pump source. PMID- 20725202 TI - Laser power beams obtained by the dynamic selection of emitting elements in an array. AB - A method for partially correcting the spatial coherence of an array of laser beams is described. The method trades far-field intensity for simplistic implementation and array lifetime extension, resulting in a quasicoherent array with features of adaptive optics. An algorithm for implementing the method is described and feasible options for improvement are presented. A computer experiment used the algorithm and fast Fourier transforms to calculate typical far-field intensity distributions of such arrays. The far-field distributions illustrate beam power concentration, beam steering, and (indirectly) extended lifetime of the array. PMID- 20725203 TI - Method for obtaining a collimated near-unity aspect ratio output beam from a DFB GSE laser with good beam quality. AB - A simple method for obtaining a collimated near-unity aspect ratio output beam from laser sources with extremely large (> 100:1) aspect ratios is demonstrated by using a distributed-feedback grating-surfaceemitting laser. Far-field power-in the-bucket measurements of the laser indicate good beam quality with a high Strehl ratio. PMID- 20725204 TI - Efficient second harmonic generation in beta-barium borate by a diffraction limited copper vapor laser. AB - The diffraction-limited beam of a copper vapor laser employing a self-filtering unstable resonator was used to induce second harmonic generation in a nonlinear crystal of beta-barium borate. Despite the moderate emission characteristics of our small-scale laser device (1.5-W average power, 25-kW peak power at 511 nm), we obtained average and peak power conversion efficiencies of approximately 20 and 30%, respectively, which improved on the previously reported results by a factor of 2. PMID- 20725205 TI - Nonlinear total internal reflection through the thermoplastic effect. AB - We report on the observation of strong nonlinear optical behavior of SF59 Schott glass. An unfocused Ar' laser beam undergoing total internal reflection in this glass shows extremely strong selffocusing. This effect is ~ 1 order of magnitude higher than the usual thermal lensing, and, by means of an interferometric technique, we demonstrate that this effect is due to the thermoplastic effect. Focal lengths that are shorter than 10 cm are observed for the beam intensity I asymptotically equal to 30 W/cm(2). The use of this glass as a self-limiter is shown experimentally. PMID- 20725206 TI - Laser-induced bubble trapping in liquids and its effect on light thermal blooming. AB - Bubble formation in a weak absorbing liquid and its subsequent trapping under the action of a cw laser beam of relatively low power are reported. The effect of the bubble trapping on the light thermal blooming is also presented. A new phenomenon of hysteresis of the thermal blooming is described. The physical origin of the observed effects is discussed. PMID- 20725207 TI - Analysis of lens and zone plate combinations for achromatic focusing of ultrashort laser pulses. AB - Analysis of a combination zone plate and lens system is presented for the design of optical systems to focus ultrashort laser pulses. A system design that is free of propagation-time delay distortion and chromatic aberration is presented. PMID- 20725208 TI - Dual focal point electro-optic lens with a Fresnel-zone plate on a PLZT ceramic. AB - A new dual focal point electro-optic lens that is switchable to focusing and unfocusing is proposed and successfully demonstrated. This electro-optic lens is constructed by coating transparent fine electrodes in the Fresnel-zone plate onto a PLZT ceramic plate. Its focal length changes from 1.25 m to infinity binary at 515 nm with the external voltage of 210 V. PMID- 20725209 TI - Triangularly phase-modulated optical fiber ring resonator sensor. AB - An optical fiber ring resonatory sensor system has been demonstrated by applying a triangular phase modulation signal to a fiber loop. The dynamic range for detection of optical phase change is 2pi. The sensor is linear within this range. The minimum detectable optical phase change is 1.5 x10(-4) rad/Hz((1/2)). PMID- 20725210 TI - Application of the coupled-mode theory to a specialized graded-index optical fiber coupler. AB - A specialized coupler formed by two identical multimode graded-index slab fibers is described. This special coupler can be used to examine the tilt or the roughness of a surface through the reflected beam. It may also find applications as a mode filter, an alignment sensor, or a feed component of an optical monopulse tracking radar. Coupled-mode theory is generalized for this application. The coupling length for maximum power transfer of the higher-order modes from the excited to the coupled fiber, leaving as much power of the lowest mode as possible to continue in the excited fiber, is computed. The fields are computed at the output of the system for incident optical beams with different axial displacements and beams launched on axis with tilted wavefronts. This desired coupling length is shown to be substantially independent of characteristics of the incident light beam. To compute the fields propagated through the tapered section introduced to separate the slab fibers, the stairwise approximation is used, and mode matching is used to connect the fields at the junctions between the successive segments. An optimum taper to separate the coupled fibers, with minimal perturbation of the fields, is present at the right hand end of the coupling section. PMID- 20725211 TI - Aging of plastic scintillating fibers. AB - We have measured the rate of natural aging on a sample of plastic scintillating fibers that were not exposed to any adverse environment. The measurements were performed with a radioactive source that bombarded the fibers only during the period of measurement and with a readout that consisted of photomultipliers connected to scalars. We normalized the output rate by using a Cerenkov radiationinduced monitor. PMID- 20725212 TI - Optical waveguides fabricated by ion exchange in high-index commercial glasses. AB - We present the fabrication process and the optical characterization of waveguides made by an ion-exchange technique in high-index D0035 and D0042C Corning glasses. We fabricate monomode channel waveguides in both kinds of glasses by exchange through a metallic mask. PMID- 20725213 TI - Analysis and fabrication of overlapping-electrode designs for poling and modulating channels in polymer thin films. AB - A design for overlapping electrodes for use with thin-film nonlinear optical polymer waveguides is analyzed. The suggested electrode structure serves both to pole birefringent waveguides in a polymer thin film and to apply rf modulation to the waveguide thus defined. This structure is also designed to minimize capacitance, to maximize electro-optic overlap, and to not require a conducting substrate or surface coating of the substrate. A figure-of-merit is developed to optimize both the longitudinal and the transverse geometry of this electrode structure. A fabrication approach to this general design is presented. Optical characterization data are presented for prototype optical phase modulators fabricated by this design. Fiber coupling losses, propagation losses, and dependence of propagation losses upon cladding thicknesses, composition, and electrode composition are presented. PMID- 20725214 TI - Simple measurement technique for the coupling coefficient of integrated optical directional couplers. AB - A simple technique for measuring the coupling coefficient and the power transfer efficiency of the optical directional coupler is presented. This technique consists of measuring Fraunhofer diffraction patterns emerging from the output prism coupler that is placed on the parallel waveguides. The measured values for the K(+)-diffused glass waveguide couplers that are fabricated at different diffusion times are demonstrated. A measurement error of <4% for the coupling coefficient is estimated for the 4-6 mm range of the coupling length. PMID- 20725215 TI - Techniques for measuring small changes in the intensity of a pulsed laser. AB - Several techniques are described that compensate for the pulse-to-pulse laser fluctuations that occur when small absorption or gain measurements are taken with pulsed lasers. The best approach tested used two matched diodes that were mounted in a bridge circuit with their bias batteries. One diode was illuminated by a single beam, and a second was illuminated by a reference beam. The bridge circuit output forms the difference in the two laser intensities. Using pulsed lasers with 8-ns widths, we observed that the error in subtraction was 0.01% of the pulse area. This was only 1.5 times the shot noise of the pulses. The technique is examined for application to Raman-induced Kerr-effect spectroscopy, in which difficulties arise because of the use of polarization-sensitive detection. PMID- 20725216 TI - Stray-light suppression with high-collection efficiency in laser light-scattering experiments. AB - We describe an optical system that we constructed to collect a large fraction of fluorescent light emitted isotropically from a cylindrical interaction region. While maintaining an overall detection efficiency of 9%, the system rejects, by more than 12 orders of magnitude, incident laser light along a single axis that intersects the interaction region. Such a system is useful for a wide variety of light-scattering experiments in which high-collection efficiency is desirable, but in which light from an incident laser beam must be rejected without resorting to spectral filters. PMID- 20725217 TI - Infrared multiple-photon dissociation by an unfocused beam in an optically thick medium: an analytical method for reaction yields. AB - Mathematical solutions are derived that, based on the power-law fluence dependence of dissociation probability, describe the reaction yields in infrared multiple-photon dissociation by an unfocused beam in an optically thick medium. Assuming linear absorption (Lambert-Beer's law), we present solutions for both a transversely uniform and a Gaussian beam geometry. An exact solution under a nonlinear absorption condition is also presented for the uniform beam geometry. The critical fluence (?(c)), a characteristic parameter for the dissociation probability, is determined from reaction yields using the solutions. It is found that the value of ?(c) can be fairly accurately determined over a wide range of optical absorption (up to 90% absorption), even when the Lambert-Beer law of absorption is approximately used for analysis instead of the exact treatment of nonlinear absorption. PMID- 20725218 TI - Measurements of OH concentration in flames at high pressure by two-optical path laser-induced fluorescence. AB - The two-optical path laser-induced fluorescence (TOPLIF) method was used to measure OH concentration profiles in flat, stoichiometric, premixed, methane-air flames burning at pressures ranging from 1 to 9 bars. The TOPLIF method does not require knowledge of the collisional quenching rates, which is a major advantage especially at these pressures. The population of a single rovibronic level is measured in a manner similar to many spectroscopic methods. TOPLIF measures this population at any location in flames at any pressure relative to this level's population in an arbitrary reference flame (here the 1-bar flame at 5 mm above the burner). Absolute values can therefore be obtained from the known value in the reference flame. In addition, the TOPLIF method is proposed as a technique to process standard laser-saturated fluorescence measurements. Using our approach, we can properly correct variations in the effective probe volume with pressure. PMID- 20725219 TI - Rayleigh-Brillouin scattering to determine one-dimensional temperature and number density profiles of a gas flow field. AB - Rayleigh-Brillouin spectra for heated nitrogen gas were measured by imaging the output of a Fabry-Perot interferometer onto a CCD array. The spectra were compared with the theoretical 6-moment model of Rayleigh-Brillouin scattering convolved with the Fabry-Perot instrument function. Estimates of the temperature and a dimensionless parameter proportional to the number density of the gas as functions of position in the laser beam were calculated by least-squares deviation fits between theory and experiment. PMID- 20725220 TI - Measurements of atomic sodium in flames by asynchronous optical sampling: theory and experiment. AB - Asynchronous optical sampling (ASOPS) is a pump-probe method for the measurement of species concentrations in turbulent high-pressure flames. We show that rapid measurement of species number density can be achieved in a highly quenched environment by maintaining a constant beat frequency between the mode-locking frequencies of the pump and the probe lasers. A model for the ASOPS method based on rate equation theory for three- and four-level atoms is presented. A number of improvements are made to the basic ASOPS instrument, which result in a greatly enhanced signal-to-noise ratio. Atomic sodium is aspirated into an atmospheric pressure C(2)H(4)/O(2)/N(2) flame and detected with the ASOPS instrument. When excited-state lifetimes are fitted by using the ASOPS theory, a 3P((1/2),3/2) ? 3S((1/2)) quenching-rate coefficient of 1.72 x 10(9) s(-1) and a 3P(3/2) ? 3P((1/2)) doublet-mixing rate coefficient of 3.66 x 109 s(-1) are obtained, in excellent agreement with literature values. ASOPS signals obtained over a wide range of pump and probe beam powers validate the rate equation theory. Improvements are suggested to improve the signal-to-noise ratio, since the present results are limited to laminar flows. PMID- 20725221 TI - Branch cuts in the phase function. AB - It is shown that, when the scalar field associated with the propagation of a distorted wave function has nulls in its intensity pattern, the phase function that goes with that scalar field has branch points at the location of these nulls and that there are unavoidable 2pi discontinuities across the associated branch cuts in the phase function. An analytic proof of this supposition is provided. Sample computer-wave optics propagation results are presented that manifest such unavoidable discontinuities. Among other things, the numerical results are organized in a way that demonstrates that for those cases the branch points are unavoidable. It is found in the sample numerical results that the branch cuts can be positioned so that the 2pidiscontinuities are located along lines of minimum intensity. This location tends to minimize the physical significance or importance of the discontinuities, a significant consideration for deformablemirroradaptive optics, for which there is an unavoidable correction error in the vicinity of the branch cut. An algorithm is briefly described that allows the branch cuts to be located automatically and a phase function to be calculated that has discontinuities equal only to 2pidiscontinuities that are located at the branch cuts. PMID- 20725222 TI - Terrain segmentation using laser radar range data. AB - A novel approach to segmentation of laser radar range images is presented. The approach is based on modeling horizontal and vertical scans of the terrain as piecewise-constant or piecewise-linear functions. The approach uses adaptive estimation based on Kalman filtering techniques. The performance of the segmentation algorithm is evaluated by application to laser range measurements. We also discuss how the output from the segmentation algorithm can be used for, e.g., object detection. PMID- 20725223 TI - Optimal truncation and optical efficiency of an apertured coherent lidar focused on an incoherent backscatter target. AB - Two earlier computations of the optimal truncation of Gaussian beams for a simple, focused, coherent lidar that used an incoherent backscatter target with identical circular transmitter and receiver apertures differ because they refer to different receiver geometries. The definitions of heterodyne and systemantenna efficiencies are reviewed in light of the discrepancy and are used to compare the optical performance of systems with apertures illuminated by beam profiles that are not Gaussian. The heterodyne efficiency is less than 0.5 for all cases considered here. PMID- 20725224 TI - Remote biodetection performance of a pulsed monostatic lidar system. AB - A monostatic pulsed lidar system called the laser cloud mapper was operated at the lidar range facility at the Defence Research Establishment Valcartier for 2 weeks during the autumn of 1990 to determine and assess its sensitivity for the remote detection of airborne biological organisms. The methodology called for the measurement of the depolarization of the lidar return signals that were backscattered from a biological aerosol cloud introduced into a large outdoor aerosol chamber. The test aerosol was produced by aerosolization of bacterial spores suspended in tap water; the relative concentration (by volume) of the bacterial material in tap water was varied from 1.0 to 0.001%. The detection performance of the laser cloud mapper is characterized through the ordered statistics of the depolarization ratio (e.g., sample distribution functions, quantile-quantile plots, and shift functions). In addition, a robust detection statistic based on the a-trimmed mean has been considered and the bootstrap resampling method has been utilized to estimate uncertainties or confidence limits for this statistic. The receiver-operating characteristic curves of the laser cloud mapper (i.e., the probability of detection,

P

(D), versus the probability of false alarm, P(FA)) for both the empirical distribution function and the linearly thresholded, trimmed mean-level detectors are presented as a function of the source concentration of the test aerosol. PMID- 20725225 TI - Simulated polarization diversity lidar returns from water and precipitating mixed phase clouds. AB - The dependence of polarization lidar returns on basic microphysical and thermodynamic variables is assessed by using a cloud model to simulate the growth of water and mixed (water and ice) phase clouds. Cloud contents that evolve with height in updrafts are converted, by using Mie theory, into cloud droplet single and double backscattering and attenuation coefficients. The lidar equation includes forward multiple scattering attenuation corrections based on diffraction theory for droplets and ice crystals, whose relative scattering contributions are treated empirically. Lidar depolarization is computed from droplet and crystal single scattering and an analytical treatment of droplet double scattering. Water cloud results reveal the expected increases in linear depolarization ratios (delta) with increasing lidar field of view and distance to cloud but also show that depolarization is a function of cloud liquid water content, which depends primarily on temperature. Ice crystals modulate mixed phase cloud liquid water contents through water vapor competition effects, thereby affecting multiple scattering delta values as functions of updraft velocity, temperature, and crystal size and concentration. Although the minimum delta at cloud base increases with increasing ice content, the peak measurable delta in the cloud decreases. Comparison with field data demonstrate that this modeling approach is a valuable supplement to cloud measurements. PMID- 20725226 TI - Light scattering by Prorocentrum micans: a new method and results. AB - Striking light-scattering behavior was observed from a marine dinoflagellate, Prorocentrum micans. Measurements of the angular dependence of the 16 Mueller matrix elements were performed on single cells with a polarization-modulation nephelometer by using a new method for cell immobilization. First the dinoflagellate cells were immobilized in a transparent silica gel containing alcohol, and then a second liquid was diffused into the gel to match the index of refraction of the gel network, thereby producing a transparent support medium that scatters less than one tenth the amount of light scattered by a single cell at 90 degrees . Measurements of scattering by a single cell revealed that all 16 matrix elements were significantly nonzero and different from each other. All matrix elements have an extremely rich, reproducible structure that is highly dependent on cell orientation. The matrix elements symmetrically across the diagonal were not equivalent. Striking features of the measurements are the large peak values of S(13), S(14), and other off-diagonal block elements. We believe that this is the first report of such scattering signals by single, suspended marine microorganisms. PMID- 20725227 TI - Reliability of the polar nephelometer for the measurement of visibility in fog. AB - The relation between the extinction coefficient of light at lambda = 0.55 microm and the scattered intensity was studied as a function of the scattering angle and the wavelength, in connection with its use in the measurement of visibility with the polar nephelometer. Computations used 239 spectra of natural fogs; they considered 181 scattering angles, 22 wavelengths from 0.25 to 5 microm, three cases of polarization, and four classes of visibility. Results show that for each wavelength within the interval micro = 0.25-1.06 microm and for each polarization and visibility class, there exists a corresponding well-defined angular interval in which the above relation is linear and quite reliable. The center and the width of the angular intervals, as well as the relative standard deviation concerning the relation at hand, depend strictly on the wavelength and the class of visibility considered; they range between 26 and 56 deg, 6 and 23 deg, and 0.5 and 3.5%, respectively, so that by a proper choice of avelength and related angular interval, visibility can be determined within 0.5%. PMID- 20725228 TI - Optical levitation experiments to assess the validity of the generalized Lorenz Mie theory. AB - Experimental near-forward-scattering diagrams obtained with one particle in optical levitation are recorded and compared with scattering diagrams computed by using the generalized Lorenz-Mie theory. Comparisons concern the particular case of an off-axis location of the particle. Agreement between experimental and computed diagrams is found to be satisfactory. PMID- 20725229 TI - Temperature dependence of refractive index and absorption of NaCl, MgCl(2), and Na(2)SO(4) solutions as major components in natural seawater. PMID- 20725230 TI - Fiber-optic two-beam interferometer fringe amplitude recovery using laser frequency control. PMID- 20725231 TI - Simple relations for a triple-layer antireflection coating. PMID- 20725232 TI - Birefringence measurement by the self-compensation method. PMID- 20725233 TI - Optical sensing for pressure in a medium vacuum region by using the drum effect. PMID- 20725234 TI - Linear Gaussian intensity distributions synthesized by reflection on elliptic cylinders: a proposal. PMID- 20725235 TI - Proposed method for fabricating 50-nm-period gratings by achromatic holographic lithography. PMID- 20725236 TI - Inductive high-pass filters for the visible. PMID- 20725237 TI - Flux modulation conversion factors for infrared detector responsivity measurements. PMID- 20725238 TI - Cutting optical fibers to equal lengths for broadband stellar interferometry. PMID- 20725239 TI - Simple, low-contrast thermal-resolution test target. PMID- 20725240 TI - Modulation transfer function degradation in segmented windows. PMID- 20725241 TI - Talbot effect and the array illuminators that are based on it. AB - A general method is described that permits demonstration that only three different array illuminators based on the Talbot effect can be produced. PMID- 20725242 TI - Simultaneous interferometric and polarimetric strain measurements on composites using a fiber-optic strain gauge. AB - A fiber-optic Michelson interferometer is used for remote sensing of the bending induced surface strain (up to 2500 microepsilon) of plates made from carbon-fiber composites. The double-polarization method is used for eliminating the ambiguity of fringe counting. Simultaneous measurement of the birefringencedependent phase offset yields an additional analog (polarimetric) signal, which allows for initialization of the incremental readout. The measured dependence of surface strain on plate bending agrees with the theoretically expected linear relationship, and it agrees with the gauge sensitivity published by Valis et al. [Proc. Soc. Photo-Opt. Instrum. Eng. 1170, 495 (1989)]. The observed hysteresis and temperature sensitivity are significantly smaller than the same effects in an electrical strain gauge. PMID- 20725243 TI - Localized dual-wavelength fiber-optic polarimeter for the measurement of structural strain and orientation. AB - A single-ended, all-fiber polarimetric strain sensor with wide dynamic range and linearized response is described. Linear response is achieved by using a dual wavelength technique, with modified pseudoheterodyne signal recovery. Single valued, multiple-fringe phase tracking is obtained by using a binary signal division technique. An average strain sensitivity of 0.050 +/- 0.02 deg microepsilon(-1) cm(-1) is found for sensors that are surface adhered to cantilever beams. The sensor system is applied successfully to the measurement of the local orientation of a 1-m structural beam, with an accuracy of +/-0.02 deg of beam slope. Limitations on the applicability of this sensing technique are discussed. PMID- 20725244 TI - Effect of twist in 3 x 3 fused tapered couplers. AB - Equilateral 3 x 3 tapered couplers made from single-mode fiber are found to behave in a less-than-ideal manner. This behavior is due to twist and can be corrected by twisting the coupler after its fabrication. A small amount of twist causes only a redistribution of output power between the two nonlaunch fibers, whereas a larger twist can restore the original response but with a cyclic change of fiber identity. An analysis of local mode coupling between the two degenerate LP(11) modes in the waist of the coupler leads to equations that successfully account for the twist-tuning effect. PMID- 20725245 TI - Holographic Fourier diffraction gratings with a high diffraction efficiency optimized for optical communication systems. AB - Novel diffraction gratings in a near-infrared region that is specially optimized for optical communication systems are studied and demonstrated by using a simple holographic exposure process. These gratings have a unique groove profile. The gratings of 770 lines/mm have a very high efficiency of 95% at a wavelength of 1.31 microm and more than 85% at a wavelength of 1.52 microm for nonpolarized light in the Littrow mounting. They also show a very low dependence (less than 2%) of the efficiency on the polarization. PMID- 20725246 TI - Evaluation of blood flow at ocular fundus by using laser speckle. AB - We report a method for noninvasively evaluating blood flow at the ocular fundus by using laser speckle phenomena. The intensity fluctuation of speckles scattered from a 1-mm-diameter illuminated area at the fundus is detected and analyzed by the photon-correlation technique, which gives us the relative degree of total blood flows within the probe area. The method is used to evaluate blood flows at the ocular fundus of a rabbit and normal human volunteers. The experimental results show that the present laser speckle method is useful for the relative evaluation of blood flows in the ocular fundus tissue. PMID- 20725247 TI - Fiber-optic confocal microscope: FOCON. AB - A new design for a reflecting fiber-optic confocal microscope, FOCON, is presented in which the beam splitter of a conventional confocal microscope is replaced by a fiber-optic splitter, and the core of a single-mode fiber takes the place of both the source and detector pinholes. It is shown that FOCON has the same resolution characteristics as a conventional confocal microscope, and requires fewer optical components and only rough alignment. The microscope is robust and can be rapidly scanned in the x, y, and z directions through the simple movement of the end of an optical fiber. PMID- 20725248 TI - Superresolution of near-field optical microscopy defined from properties of confined electromagnetic waves. AB - The experimental resolution that is obtained with a near-field microscope by optical tunneling detection is far beyond the Rayleigh criterion. We discuss the principal physical characteristics of this superresolution. Three different examples are presented. They show that the resolution increases as the collector width and collector-to-object distance decrease. It is interesting to note that, in the near-field microscope, as in all local probe microscopes, the resolution cannot be defined from the characteristics of the microscope only. In all tunnel devices the detector cannot be separated from the object. The superresolution that can be obtained results from this fact. This paper also points out the importance ofevanescent waves in near-field optics and makes the connection between resolving power and evanescent fields. PMID- 20725249 TI - Active-fiber star coupler that uses arrays of microlenses and liquid-crystal modulators. AB - An active-fiber star coupler that uses arrays of N x N microlenses and liquid crystal modulators is presented. A simplified implementation of this device uses an 8 x 8 array of Fresnel microlenses fan out an incident beam into 64 focused spots (an 18 dB fan-out loss); on-off capability (270:1 extinction ratio) at each element is provided by liquid-crystal spatial light modulators. A row of focused spots is coupled into an array of 1 x 8 multimode fibers with a measured excess loss of 12 dB along each path (with an estimated overall loss of 30 dB in an 8 x 8 device). A modification of this device that is capable of wavelength selection at individual output fibers is proposed for wavelength division multiplexing applications. PMID- 20725250 TI - New method of design of nonimaging concentrators. AB - A new method of designing nonimaging concentrators is presented and two new types of concentrators are developed. The first is an aspheric lens, and the second is a lens-mirror combination. A ray tracing of three-dimensional concentrators (with rotational symmetry) is also done, showing that the lens-mirror combination has a total transmission as high as that of the full compound parabolic concentrators, while their depth is much smaller than the classical parabolic mirror-nonimaging concentrator combinations. Another important feature of this concentrator is that the optically active surfaces are not in contact with the receiver, as occurs in other nonimaging concentrators in which the rim of the mirror coincides with the rim of the receiver. PMID- 20725251 TI - Analytical calculations and Monte Carlo simulations of laser Doppler flowmetry using a cubic lattice model. AB - In addition to the static cubic lattice model for photon migration in turbid biological media by Bonner et al. [J. Opt. Soc. Am. A 4, 423-432 (1987)], a dynamic method is presented to calculate the average absolute Doppler shift as a function of the distance between the point of injection of photons into the medium and the point of detection. At every lattice point a moving particle is assumed with a constant velocity in random directions. The velocity direction fluctuates randomly in time. When a photon is scattered at a lattice point it has a finite probability to be Dopper shifted, since in reality not every scattering event occurs with a moving particle. Calculated average absolute Doppler shifts are verified with Monte Carlo simulations. We verified the applicability of the derived formulas for continuous isotropic and continuous anisotropic media. Good agreement is found between the calculated and simulated average absolute Doppler shifts. Small differences between calculated and simulated average abso ute Doppler shifts can be explained by the assumptions made in the theory. Furthermore the calculations of the average absolute Doppler shift confirm the theory of Bonner et al. that the first moment ?omega? of a spectrum S(omega) measured with a blood perfusion meter is linearly proportional to the average number m of scattering events with a moving particle in case of m < 1 and linearly proportional to the square root of m in the case of m > 1. It is confirmed that the average absolute Doppler shift depends on the average number of scattering events at the position of the detection. This effect is, apart from the size and position of the probe volume, essential for the interpretation of the signal measured with a laser Doppler perfusion meter. PMID- 20725252 TI - Raman lidar system for the measurement of water vapor and aerosols in the Earth's atmosphere. AB - A nighttime operating Raman lidar system that is designed for the measurement of high vertical and temporal resolution profiles of the water vapor mixing ratio and the aerosol backscattering ratio is described. The theory of the measurements is presented. Particular attention is given to operational problems that have been solved during the development of the system. Data are presented from Sept. 1987 and described in their meteorological context. PMID- 20725253 TI - Panchromatic spectrograph with supporting monochromatic imagers. AB - The Arizona Imager/Spectrograph is a set of imaging spectrographs and two dimensional imagers for space flight. Nine nearly identical spectrographs record wavelengths from 114 to 1090 nm with a resolution of 0.5-1.3 nm. The spatial resolution along the slit is electronically selectable and can reach 192 elements. Twelve passband imagers cover wavelengths in the 160-900-nm range and have fields of view from 2 degrees to 21 degrees . The spectrographs and imagers rely on intensified CCD detectors to achieve substantial capability in an instrument of minimum mass and size. By use of innovative coupling techniques only two CCD's are required to record images from 12 imagers, and single CCD's record spectra from pairs of spectrographs. The fields of view of the spectrographs and imagers are coaligned, and all spectra and images can be exposed simultaneously. A scan platform can rotate the sensor head about two orthogonal axes. The Arizona imager/spectrograph is designed for investigations of the interaction between the Space Shttle and its environment. It is scheduled for flight on a Shuttle subsatellite. PMID- 20725254 TI - Application of the intensified ccd to airglow and auroral measurements. AB - New detector technology exemplified by advanced CCD and intensified CCD (ICCD) systems have important advantages for both spectrographic and imaging research. However, to realize the full potential of this new technology, we must consider the detector and the optical system as a whole. It is frequently not enough to simply substitute an ICCD for an earlier detector; rather, to achieve optimum results, the optics must be adapted to the specific detector. Properly designed airglow spectrographs based on the ICCD detector offer the advantages of high throughput over a broad spectral range, precise wavelength stability, low noise, and compactness. Imagers having the wide field and the high sensitivity needed for airglow research are practical as well. PMID- 20725255 TI - SNOP: a method for skeletonization of a fringe pattern along the fringe direction. AB - A new algorithm for fringe-pattern processing is proposed. It consists of tracing fringes along the fringe direction by searching the local extreme values of brightness distribution in the image. A detailed explanation of this method is given, the parameters and criteria for computerized processing are discussed, and some experimental results for testing the method are presented. PMID- 20725256 TI - Light-confining cavities for photovoltaic applications based on the angular spatial limitation of the escaping beam. AB - Integrating spheres are proposed as light-confining cavities for enhancing the absorption of light by devices such as solar cells, and also for making photovoltaic converters with cells of several band gaps. A new concept for achieving this light confinement by angular restriction of the escaping of rays, which avoids the requirement of having a small entry aperture and therefore concentrations on it that are much higher than those required on the solar cells, is proposed here. PMID- 20725257 TI - Electrical substitution radiometry with feedback control: optimization of measurement time and resolution for repeated observations. AB - The minimum measurement time needed to obtain a given variance in the mean power measurement is determined for feedback-controlled electrical substitution radiometers by combining previous results for response time and noise power gain with the variance in the mean of a sequence of N partially correlated observations. For large N and high sampling frequencies it is asymptotic to Lambda/2 in units of the detector time constant, where Lambda is the ratio of the square of the detector noise equivalent power to the desired variance in the mean power measurement. For a second-order system the optimum measurement time for repeated observations is typically 1.4-1.7 times smaller than that for a single observation. PMID- 20725258 TI - Holographic grating with two spatial frequencies for the simultaneous study of two spectral profiles. AB - A dispersive device that permits us to analyze two arbitrary spectral profiles simultaneously with the same detector like an optical multichannel analyzer has been designed. The device consists of a holographic grating with two different spatial frequencies, which are not recorded simultaneously, and that are calculated specifically for two spectral lines under study. PMID- 20725259 TI - Role of interface correlation in light scattering by a multilayer. AB - Four industries prepared optical coatings with a common design that permits an easy determination of cross-correlation laws between the rough interfaces in the stack. Different pairs of materials and deposition processes were used. After clarifying the differences between scalar and vector theories of light scattering caused by rough interfaces in optical multilayers, we compare the experimental values with both theories. Factors such as variations of correlation with spatial frequency, residual roughness, and slight errors in the design are taken into account for comparison with the vector theory of angular scattering. Correlation of the interface roughnesses is found to be high for practically all coatings. However, at low scatter-loss levels, scattering by localized defects in the coatings appears to dominate over the scattering caused by rough interfaces. PMID- 20725260 TI - Physically reasonable analytic expression for the single-scattering phase function. AB - An analytic phase function that reduces to the Rayleigh phase function for the scattering of unpolarized light is presented and compared with the traditional Henyey-Greenstein phase function. Comparisons between the proposed phase function and the phase function for three of Deirmendjian's polydispersions are shown and applications to radiative transfer are demonstrated. PMID- 20725261 TI - Solar imaging with a segmented adaptive mirror. AB - A 19-segment adaptive-mirror system is currently being used on the Sacramento Peak 76-cm Tower Telescope to remove wave-front distortions resulting from atmospheric turbulence. The system has proven to be capable of substantially improving the quality of an image, at times achieving 0.33-arcsec resolution in visible wavelengths under 1-3-arcsec seeing conditions. An improvement in resolution seems to occur across a large field of view that is, at times, 30 arcsec in diameter. PMID- 20725262 TI - Detection of nonradiative fields in light of the Heisenberg uncertainty principle and the Rayleigh criterion. AB - The new concept of superresolution microscopy involving nonradiative field detection by optical tunneling is analyzed in light of the Heisenberg principle and the Rayleigh criterion. A connection is demonstrated between the evanescent field components and the system's resolving power. This work is quite general and can be applied to scanning electronic tunneling microscopy. PMID- 20725263 TI - Optically efficient interferometric acousto-optic architecture for spectrum analysis. AB - An efficient in-line additive acousto-optic architecture that can provide a high dynamic-range spectrum analysis and is suitable for an integrated optic design is introduced. PMID- 20725264 TI - Simple real-time noise removal in intensified low-light-level television images. AB - A simple and novel real-time interframe operator substantially reduces short lived noisy scintillations in low-lightlevel video imaging systems that use image intensifiers. PMID- 20725265 TI - Multilevel computer-generated holograms with separable phase functions for beam shaping. AB - The Gaussian profile of a laser beam may be converted to a rectangular one of uniform intensity by using an on-axis pair of multilevel computer-generated holograms. PMID- 20725266 TI - Analysis of the holographic reciprocity law for dichromated gelatin. AB - The holographic reciprocity law for dichromated gelatin is investigated experimentally. The results obtained show that this law does not hold true for this material. PMID- 20725267 TI - Phase shifting of whole-field fringes in dual-plate speckle photography. AB - New developments of a phase-shifting readout system for the analysis of whole field fringes in dual-plate speckle photography are presented. PMID- 20725269 TI - Recoded signed-digit binary addition-subtraction using opto-electronic symbolic substitution. AB - Two opto-electronic implementations of carry-free addition and borrow-free subtraction of recoded signed-digit binary numbers that use optical symbolic substitution are proposed. PMID- 20725268 TI - Influence of R-10 bleaching on latent image formation in silver halide-sensitized gelatin. AB - The optimization of the silver halide-sensitized gelatin process is analyzed by considering the bleaching action, the influences of the developer, and the hardening modulation process. PMID- 20725270 TI - Cylindrical optical backplane. AB - A cylindrical optical backplane using Plexiglas stacked disks, light-emitting diodes, and p-i-n photodiodes is described. The main advantage of the design is its simplicity and lack of both precision optics and critical alignment requirements. PMID- 20725271 TI - Automatic low-frequency spatial filter that uses light-induced scattering in LiNbO(3):Fe crystal. AB - We propose and demonstrate a novel low-frequency spatial filter that uses light induced scattering in LiNbO3:Fe crystal, which can operate automatically. The self-diffraction effect and the size effect of the light-induced scattering are responsible for the mechanism of this filter. PMID- 20725272 TI - Bit-serial architecture for optical computing. AB - The design of a complete, stored-program digital optical computer is described. A fully functional, proof-of-principle prototype can be achieved by using LiNbO(3) directional couplers as logic elements and fiber-optic delay lines as memory elements. The key design issues are computation in a realm where propagation delays are much greater than logic delays and implementation of circuits without fip-flops. The techniques developed to address these issues yield architectures that do not change as their clocking speed is scaled upward and the size is scaled downward proportionally; these are called speed-scalable architectures. Signal amplitude restoration and resynchronization are accomplished by the novel technique of switching in a fresh copy of the system clock. Device characteristics that are important to the proof-of-principle demonstration are discussed, including the special properties and limitations that are important when designing with them. Design principles are exemplified by the design of an n bit counter. Following this, the design for a stored-program bit-serial computer is described. We estimate that the described prototype architecture can be operated in the 100-MHz region with off-the-shelf components, and in the O. 1-1 THz region with foreseeable future components. PMID- 20725273 TI - Design of digital-optical processors by using both intensity and polarization encoding schemes. AB - Here we propose two encoding schemes that utilize both light intensity and polarization to code input data in digital-optical computing. This approach results in a more efficient information carrying and processing technique when compared with the traditional intensity-only or polarization-only encoding schemes. Optical logic units that are based on the proposed encoding schemes are designed. A recursive parallel adder and a carry look-ahead adder that use these logic units as building blocks are also described. PMID- 20725274 TI - Implementation of a fiber-optic delay-line memory. AB - The construction and operation of a 50-MHz 64 x 16 bit fiber-optic bit-serial delay-line memory is described. It consists of LiNbO(3) directional coupler switches, fused-fiber couplers, and a 4.17-km fiber loop. It is a subsystem of a bit-serial optical computer under construction by our group. We discuss delay and clock source stability requirements for the long delay line in the face of a limited phase error tolerance. The reliability testing of the memory subsystem is described. The degradation of data in the memory loop as the phase error tolerance is exceeded by a small amount is studied through the temperature dependence of the memory loop. Data are presented for the memory-loop stability with respect to temperature variations. The memory subsystem design and construction is presented. The results of these experiments support the feasibility of a 100-MHz 128 x 16 bit memory. PMID- 20725275 TI - Optical content-addressable parallel processor: architecture, algorithms, and design concepts. AB - Associative processing based on content-addressable memories has been argued to be the natural solution for nonnumerical information processing applications. Unfortunately, the implementation requirements of these architectures when one uses conventional electronic technology have been cost prohibitive; therefore associative processors have not been realized. Instead, software methods that emulate the behavior of associative processing have been promoted and mapped onto conventional locationaddressable systems. However, this does not bring about the natural parallelism of associative processing, namely, the ability to access many data words simultaneously. Optics has the advantage over electronics of directly supporting associative processing by providing economic and efficient interconnects, massive parallelism, and high-speed processing. The principles of designing an optical content-addressable parallel processor (OCAPP) for the efficient support of parallel symbolic computing are presented. The architectu re is designed to exploit optics advantages fully in interconnects and high-speed operations. Several parallel search-and-retrieval algorithms are mapped onto an OCAPP to illustrate its capability of supporting parallel symbolic computing. A theoretical performance analysis of these algorithms is presented. This analysis reveals that the execution times of the parallel algorithms presented are independent of the problem size, which makes the OCAPP suitable for applications in which the number of data sets to be operated on is high (e.g., massive parallel processing). A preliminary optical implementation of the architecture with currently available optical components is also presented. PMID- 20725276 TI - Detection of a general ellipse by an optical Hough transform. AB - A method to detect five parameters of an ellipse with an optical Hough transform is described. The method employs the Hough transform for detection of a straight line and for the one-dimensional analysis of the resultant parameter domain. This technique is also applied for detection of four parameters of a straight line segment (the two coordinates of the center, the length, and the orientation) by representing it as a particular case of an ellipse with one axis of zero length. PMID- 20725277 TI - Wavelet analysis of short light pulses. AB - We demonstrate the possible use of the Wigner-Ville transformation for describing ultrashort light pulses in both time and frequency and give support to the intuitive pictures used by experimentalists in the field. Two cases are considered: the effect of linear dispersion and self phase modulation. Various characteristics can be extracted from the Wigner-Ville distribution, e.g., time broadening, power spectrum broadening and reshaping, instantaneous frequency time variation. PMID- 20725278 TI - Wavelet transform as a bank of the matched filters. AB - The wavelet transform is a powerful tool for the analysis of short transient signals. We detail the advantages of the wavelet transform over the Fourier transform and the windowed Fourier transform and consider the wavelet as a bank of the VanderLugt matched filters. This methodology is particularly useful in those cases in which the shape of the mother wavelet is approximately known a priori. A two-dimensional optical correlator with a bank of the wavelet filters is implemented to yield the time-frequency joint representation of the wavelet transform of one-dimensional signals. PMID- 20725279 TI - Acousto-optic architecture for two-dimensional beam scanning in phased-array antennas. AB - An in-line additive acousto-optic architecture for very high speed ( asymptotically equal to0.4 s) two-dimensional, phasedarray antenna beam scanning is introduced that uses only two independent analog scan control signals. Features include up to K(u) band operation, intrapulse beam forming, and multiband, wide (2-GHz) tunable bandwidth capability. PMID- 20725280 TI - Local learning algorithm for optical neural networks. AB - An anti-Hebbian local learning algorithm for two-layer optical neural networks is introduced. With this learning rule, the weight update for a certain connection depends only on the input and output of that connection and a global, scalar error signal. Therefore the backpropagation of error signals through the network, as required by the commonly used back error propagation algorithm, is avoided. It still guarantees, however, that the synaptic weights are updated in the error descent direction. With the apparent advantage of simpler optical implementation this learning rule is also shown by simulations to be computationally effective. PMID- 20725281 TI - Neural network model for unequally distributed neuron states. AB - A modified neural network model suitable for patterns with unequally distributed neuron states is proposed. The storage capacity and content addressability are greatly improved by adding a linear modification term to the interconnection weights of the Hopfield model. Computer simulations were performed to demonstrate the robustness of the modified model compared to the original. A gratingmodulated holographic hybrid system was employed for an optical demonstration. Experimental results are shown. PMID- 20725282 TI - Incoherent optical associative memory by using synthetic discriminant function filters. AB - A new associative memory system applying incoherent correlators is presented. With this system, which is composed of a nonlinear processor and optical electronic feedback loop, memorized patterns can be recalled without cross talk. To realize a high association ability and stable operation, a synthetic discriminant function filter is applied. Results of the computer simulation and actual experiments by using the system that is constructed here are demonstrated. PMID- 20725283 TI - Broadband reflection holograms in dichromated gelatin. AB - The spectral response of broadband reflection holograms in dichromated gelatin is studied; conditions for obtaining 100-nm bandwidth and 80% diffraction efficiency holograms are given. The structure of these holograms is discussed, and the scanning electron microscope is used to investigate fringe-spacing variations. PMID- 20725284 TI - Slit-aperture synthesis in holography of diffuse objects. AB - The conditions for slit-aperture synthesis by the holographic recording of an optical field distribution are presented. It is shown that only the movement of an element in the optical setup that can be described by a transmittance function, e.g., the illuminated object or the imaging lens, can realize the slit synthesis. The synthesis of multislits for application in rainbow and dispersive multichannel white-light holograms is discussed. PMID- 20725285 TI - Holographic system for copying holograms by using partially coherent light. AB - A method for copying holographic optical elements with partially coherent light by using a holographic system is presented. The system includes two holographic lenses that are made as thick-phase holograms on silver halide-sensitized gelatin. The geometric conditions during reconstruction of the holographic system with white light are studied and the performance of the system is analyzed by a ray-tracing technique. The spatial and temporal coherence factors for the system are > 0.9, and this indicates that it is possible to obtain good holographic elements with this holographic system. Copies of diffraction gratings and holographic lenses obtained with dichromated gelatin and photoresist as the recording material present good optical quality. PMID- 20725286 TI - Binary surface-relief gratings for array illumination in digital optics. AB - Separable binary-phase array illuminators for fan-out up to 1024 x 1024 and ~65% two-dimensional efficiency are designed by simulated annealing with constraints for maximizing the minimum feature size. A new nonseparable trapezoidal coding technique is introduced and applied to design high-efficiency (~75%-80%) array generators for fan-out up to 16 x 16. A rigorous electromagnetic diffraction theory is used to evaluate the range of validity of the scalar designs (both grating period and input angle are considered), to analyze fabrication errors (slanted groove walls and undercutting), and to design binary resonance-domain one-dimensional array generators with 90%-100% efficiency. Trapezoidal gratings for low fan-out (8 x 8), separable gratings for high fan-out (up to 128 x 128), and a 1 x 5 resonance domain (100% efficient) reflection grating are demonstrated experimentally. PMID- 20725287 TI - Pattern recognition with quantized computer-generated filters. AB - The influence of the quantization levels used in the computer-generated filter on the correlation is studied. Two types of objects, binary characters and gray-tone objects, are used in the scene and in the test. The filters are codified by the method proposed by Burckhardt. Three different filters (a classical matched filter, a high-frequency-enhanced filter, and an amplitude-encoded phase-only filter) are generated, and the influence of the quantization levels in such cases is studied. Numerical and experimental results are obtained. PMID- 20725288 TI - Flexible optical disk system with a sample servo format. AB - A high-capacity 90-mm flexible optical disk system with a phase-change rewritable disk is studied, aiming at low-cost recording media and small drives. The flexible disk rotates stably and is supported by two thrust air bearings fabricated in a plastic cartridge with a disk tilt of less than 5 mrad. A radial tracking-control precision of 0.2 microm is attained with a sample servo system by using photographically replicated square servo marks on the disk. The feasibility of this system is confirmed by write-erase operations in a 2-microm track pitch. PMID- 20725289 TI - Diffraction efficiency dependence of holographic subtraction interferometry in Fe:LiNbO(3). AB - Experimental results on holographic subtraction interferometry in photorefractive lithium niobate crystals are presented. The dependence of the subtraction operation on the hologram diffraction efficiency has been measured for both single holograms and angularly multiplexed holograms. Example results from heat transfer and acoustics are presented. PMID- 20725290 TI - Patterned wafer inspection using spatial filtering for the cluster environment. AB - Automated-process tool clusters are becoming increasingly prevalent in advanced semiconductor manufacturing plants, necessitating integrated inspection of patterned semiconductor wafers for defects and particulates. Integrated inspection tools must be small, sensitive, inexpensive, and fast in order to be compatible with the cluster environment. We show that intensity spatial filtering, with some refinements, can provide the required sensitivity and speed in a small, inexpensive package. By using dark-field illumination and a nonrectangular azimuthal orientation (e.g., 45 degrees ) to the primarily rectangular pattern, we show that the strongest diffraction from the pattern can be made to bypass the optical system entirely. This technique alleviates stringent scatter and antireflection requirements on the optics, and it permits the use of off-the-shelf components. PMID- 20725291 TI - Beam transmission characteristics of a collinear polarization rotator. AB - Beam transmission characteristics of a collinear prismatic polarization rotator are given. It is found that a TMoo laser beam is transmitted with good fidelity at an efficiency of 94.7%. PMID- 20725292 TI - Calculation of the bistability in detuned nonlinear prism coupling. AB - With the help of the Laplace and its inverse transformations, the bistable characteristics in detuned coupling to a diffusive nonlinear guide were numerically evaluated. PMID- 20725293 TI - Ion-exchanged Mach-Zehnder interferometers in glass. AB - Ion-exchanged Mach-Zehnder interferometers are produced in glass. The effect of fabrication parameters on their optical response in relation to their constituent components is investigated. PMID- 20725294 TI - Spectral modulation of two coherently separated femtosecond laser pulses. AB - A train of 150-fs 76-MHz pulses is directed into a Michelson interferometer with a path difference larger than the pulse spatial length. A modulated spectrum with a modulation frequency that increases with the path difference is observed. The consequence is discussed. PMID- 20725295 TI - Frequency stabilization of a GaAIAs semiconductor laser by voltage control. AB - A single-mode GaAlAs laser is frequency stabilized by keeping the injection current and the voltage across the laser constant. A long-term frequency stability of 7 x 10(-8) and a reproducibility of 3 x 10(-7) were obtained. PMID- 20725297 TI - Temperature dependence of beam scattering in young sea ice. AB - Laboratory measurements of the upward intensity distribution in young thin sea ice illustrate the variation of this distribution and peak intensity with growth temperature and ice thickness. PMID- 20725296 TI - Maximum gain in optical amplifier-based systems as determined from reflections and backscattering effects. AB - A simple method for stability investigations of systems with optical amplifiers is presented. Uppergain limits arepredicted for specified reflections and Rayleigh backscattering. PMID- 20725298 TI - Guided blue and green upconversion fluorescence in an erbium-ytterbium-containing silicate glass. AB - We observe guided blue and green upconversion fluorescence in an ion-exchanged waveguide that is fabricated in an erbium-ytterbium-codoped silicate laser glass. The guides are optically pumped at room temperature by using a Ti:sapphire laser with lambda = 880-980 nm; the observed fluorescence is in two bands, 480-490 and 520-560 nm, and results from multiphoton excitation. PMID- 20725299 TI - Focusing of diode laser beams: a simple mathematical model: comment. AB - The simple Gaussian and the Lorentzian-Gaussian models for the elliptical beams generated by laser diodes are compared experimentally by examining how well they match the measured irradiance patterns formed by actual devices. PMID- 20725300 TI - Focusing of diode laser beams: a simple mathematical model: reply to comment. AB - Gaussian and Lorentzian-Gaussian models for the elliptical cross-section beams of GaAs diode lasers are reexamined, emphasizing that the simplicity of the Gaussian model vanishes in many practical applications where laser beams are truncated by the collimating lens. The Lorentzian model is advantageous because the width of the distribution may be estimated from the composition of the semiconductorjunction. PMID- 20725301 TI - Applications of the CuBr vapor laser as an image-brightness amplifier in high speed photography and photomicrography. AB - A CuBr vapor laser with an output power of ~1 W has been used as a brightness amplifier, for the first time to our knowledge, in high-speed photography and photomicrography. PMID- 20725302 TI - Uniform performance of high-efficiency room-temperature GaInAsSb/GaSb photodiodes for 1.75 < lambda < 2.2 mum. AB - A group of 126 experimental, packaged, backilluminated, 1.75-2.2-microm wavelength, GaInAsSb mesa (~85-microm diameter) photodetectors have been assembled and evaluated. Average room-temperature properties were peak quantum efficiency, 86%; zero-bias capacitance, 3.9 pF; dark current at -0.5-V bias, 7.4 microA. PMID- 20725303 TI - Laser Doppler velocimeter based on the self-mixing effect in a fiber-coupled semiconductor laser: theory. AB - A laser Doppler velocimeter that consists of a semiconductor laser coupled to a fiber and that uses the self-mixing effect is presented. The velocimeter can be used for solids and fluids. A theoretical model is developed to describe the self mixing signals as a function of the amount of feedback into the laser and the distance from the laser to the moving object. Good agreement is found between this theory and measurements. PMID- 20725304 TI - Measurement of molecular concentrations and line parameters using line-locked second harmonic spectroscopy with an AlGaAs diode laser. AB - The technique of line-locked wavelength modulation with 2f detection is applied to the measurement of water vapor concentration and absorption line parameters by using an 820-nm AlGaAs communications diode laser. Measurements of the 2f signal as a function of the modulation amplitude yield accurate concentrations and line parameters over a pressure range of an order of magnitude and half-widths from 0.02 to 0.15 cm(-1). Usingtwo different spectral lines, we determined concentrations and line parameters with 1% precision, and the absolute accuracy of the line parameters is 3% or better. The results have been used to calculate calibration curves for a diode laser humidity monitor. PMID- 20725305 TI - Absorbing filter to flatten gaussian beams. AB - An absorbing filter that flattens the Gaussian intensity profile of a laser beam has been developed. The filter was fabricated by dc magnetron sputtering a thin tantalum film, by using a combination of substrate masking and motion. A model of the filter production has been developed that successfully predicts the film profile and performance. A typical filter produced by using these techniques results in a flat output to within +/-3% over a 2.2 mm with a transmission of 60% of the peak intensity of the Gaussian beam. PMID- 20725306 TI - Mode-index waveguide lens with novel gradient boundaries developed for application to optical recording. AB - A new type of mode-index waveguide lens is presented that has acircular gradient index boundaries. These lenses have relatively large apertures and are fabricated by physical vapor deposition by using organic materials. A deposition mask that is accurately defined by using lithographic processing techniques was used to shape the lens boundaries during the addition of the lens to the waveguide. A comprehensive analysis of the lens system is presented. After adjusting the model to have aberrations that are comparable with those of the fabricated lens, spot size and sidelobe intensity values were nearly identical for the theoretical and experimental systems. The application of these lenses to optical recording technology is demonstrated by the generation of focus and tracking error signals. PMID- 20725307 TI - Frequency-modulation spectroscopy with a multimode dye laser. AB - A multimode laser in frequency-modulation spectroscopy gives a signal that is broader than the absorption line by an amount that is determined by how sharp the edges of the laser profile are, not by the total bandwidth of the laser. We have experimentally demonstrated that one can therefore obtain frequency-modulation signals that are narrower than the total bandwidth of the laser. PMID- 20725308 TI - Method of concentration of power in materials for x-ray amplification. AB - Recent experimental and theoretical results indicate that a new technique for the controlled concentration of power in materials may be feasible. The power levels that are potentially achievable are sufficient for the generation of amplification of x-ray wavelengths in the kilovolt range. The method of power concentration involves the combination of (1) a new ultrahigh brightness subpicosecond laser technology, (2) multiphoton coupling to atoms and molecules, and (3) a new channeled mode of electromagnetic propagation. The energy scaling of this approach is the most important consideration, and it is shown that the control of the propagation is the key factor that enables high levels of amplification in the kilovolt regime to be achieved with a total excitation energy of ~1 J. PMID- 20725309 TI - Side-polished fibers. AB - We report a reproducible technique of making side-polished fibers by embedding fibers in silicon V grooves and by polishing them mechanically. Details of V grooves and polishing techniques are described. The attenuation characteristics of polished fibers were measured by a liquid-drop method; the results are in excellent agreement with existing theoretical predictions. To facilitate comparisons, we cast expressions for the attenuation constant in terms of three generalized parameters: the V and b parameters for the fiber and a new generalized parameter V(ex) for the external medium. By using these generalized parameters, we can study the effects of the external medium on the attenuation constant of side-polished fibers in great detail, including in particular the region where the attenuation changes precipitously. PMID- 20725310 TI - Correlation among the laser-induced breakdown thresholds in solids, liquids, and gases. AB - A simple expression is developed that permits a correlation among laser-induced breakdown thresholds in solids, liquids, and gases. It is shown that the breakdown thresholds for the bulk of solid dielectrics, linear liquids, and gases all follow a linear fit to the expression N(2/3)/(n(2) - 1), where N is the atomic number density and n is the refractive index. The gas breakdown threshold versus pressure is compared with the predicted dependence. PMID- 20725311 TI - Laser-induced diffraction patterns in germanium diselenide amorphous films. AB - We report the characterization of changes produced on germanium diselenide amorphous semiconductor thin films by a focused He-Ne laser beam. The diffraction pattern produced by the laser spot on the sample is studied as a function of the intensity and the irradiation time. At low intensities the state of polarization of the incident beam generates an asymmetry in the induced diffraction pattern. Moreover, if the polarization of the incident beam is rotated, the corresponding asymmetry rotates as well. These results show the difference between thermal and electromagnetic effects on the material. This system may be used as a high density recording medium. PMID- 20725312 TI - Laser-induced gas breakdown and its application to switching. AB - The effect of laser-produced plasma from a biased metal target in a background gas (argon) is studied. We report that switching of an argon gas discharge is controlled by metal plasma or by polarity of the target. PMID- 20725313 TI - Wide-angle high-resolution line-imager prototype flight test results. AB - A single-channel prototype pushbroom imager has been developed to the specifications required for forestry remote-sensing applications and for mapping. It is based on a commercially available 6000-element linear array for which a special wide-angle, high modulation transfer function lens was designed and fabricated. The test was flown aboard a twin-engine jet aircraft. The sensor has produced high-quality imagery with pixel sizes down to 25 cm. PMID- 20725314 TI - Accounting for the multiple-scattering effect in radiation intensities at the top of the atmosphere. AB - For obtaining aerosol optical depths over the ocean by using satellite measured radiances computations of backscattered solar radiation fields are necessary. Since a detailed multiple-scattering algorithm is time consuming a simple approach that allows parametrization of multiple-scattering processes is desired. Here the differences between multiple-scattered radiances, which are calculated by the successive order of scattering method, and single-scattered radiances, which use a simple single-scattering equation, and are obtained for different aerosol models defined as a correction term. It is shown that all correction terms could be linearly fitted with aerosol optical depths if they are scaled by the single-scattering albedo and 1 minus the asymmetry factor of the aerosol models considered. An analytic expression for the correction factor is obtained. Thus it is shown that multiple-scattered radiances at the top of the atmosphere can be estimated directly from the single-scattered radiances and with the co rection term for all Sun-satellite geometries that are usually used for remote sensing of aerosol turbidities over ocean surfaces with an uncertainty of less than 10% for aerosol optical depths up to 0.5 in the visible region. PMID- 20725315 TI - Unwrapped-phase distribution model for speckle and turbulence. AB - A model for the unwrapped phase of a speckle field that propagates through clear air turbulence is proposed, and a formulation for the probability density function of the unwrapped phase is developed. A method is given to obtain the parameters of the unwrapped density function from parameters of the diffuse target, the laser source, and the atmosphere. Unwrapped-phase measurements at an atmospheric test site with a CO(2) laser show agreement with the model. PMID- 20725316 TI - Light-scattering Mueller matrix for a rough fiber. AB - The light-scattering Mueller matrix for an r approximately 2.0 microm radius, rough quartz fiber contains phase information different from that of a perfectly cylindrical fiber of the same optical constants and radius. The rough surface creates higher-frequency, smaller-amplitude oscillations that mask the lowerfrequency oscillations indicative of a perfect cylinder. Roughness also causes scatter outside the plane of incidence. PMID- 20725317 TI - Local velocity and size measurements of particles in dense suspensions: theory and design of endoscopic grating velocimeter-granulometers. AB - Grating velocimeter-granulometers are devoted to size-velocity measurements of bubbles, droplets, or solid particles carried in flows. Principles that are already used by a phase Doppler particle analyzer are applied to dense suspensions by the use of grating-based endoscopic probes. For these the distance from the sensor to probe volume may be comparable to the particle size and the classical frequency-velocity and phase-radius relationships must be corrected. These corrections are quantified by using a simulation based on ray optics. Finally a probe devoted to mist flows is presented. The dispersion that is due to random parameters, such as particle trajectory; is +/-3% for velocity and less than +/-8% for size. PMID- 20725318 TI - Depolarization criterion for incoherent scattering. AB - We consider the problem of establishing conditions on a given Mueller matrix that ensure that the scattered light is purely polarized independently of the incident light polarization. It is shown that physically realizable Mueller matrices can be decomposed into a nondepolarizing part and an inputindependent additive depolarizing part. The nondepolarizing part, however, is not always derivable from a Jones matrix. Applications to polarimetric optimal transmission and reception are also discussed. PMID- 20725319 TI - Experimental tests of a simple diffusion model for the estimation of scattering and absorption coefficients of turbid media from time-resolved diffuse reflectance measurements. AB - When a picosecond light pulse is incident upon a turbid medium such as tissue, the temporal distribution of diffusely reflected and transmitted photons depends on the optical absorption and scattering properties of the medium. From diffusion theory it is possible to derive analytic expressions for the pulse shape in terms of the optical interaction coefficients of a homogeneous semi-infinite medium. Experimental tests of this simple model in tissue-simulating liquid phantoms of different geometries are presented here. The results of these tests show that, in a semi-infinite phantom, the application of the diffusion model provides estimates of the absorption and transport-scattering coefficients that are accurate to better than 10%. Comparable accuracy was also obtained with this simple model for finite slab, cylindrical, and spherical volumes as long as the objects were of sufficient size. For smaller volumes the absorption coefficient was overestimated because of the significant loss of photons at the bounda ries of the object. PMID- 20725320 TI - Energy-density distribution inside large nonabsorbing spheres by using Mie theory and geometrical optics. AB - Mie theory and geometrical-optics ray tracing are used to obtain the distribution of electric energy density inside a nonabsorbing micrometer-sized sphere illuminated by a polarized plane wave. The Mie solution shows the multiply reflected geometrical-optics rays inside a sphere having a diameter of ~ 150 free space wavelengths (size parameter = circumference/wavelength = 500). The geometrical-optics result shows the major features of the Mie solution and provides a physical interpretation of the electromagnetic interactions that result in the observed energy-density distributions. Both solutions show internal on-axis energy-density maxima inside the shadow surface of the sphere. The region of greatest enhanced energy density is approximately one internal wavelength in diameter and approximately twenty internal wavelengths in length. PMID- 20725321 TI - Multiple scattering by a planar array of parallel dielectric cylinders. AB - The solution of the multiple-scattering problem for N parallel dielectric cylinders is considered for plane-wave illumination perpendicular to the cylinder axes. We describe a nonlinear programming approach to solve the multiple scattering matrix for an arbitrary planar array of N parallel dielectric cylinders. To our knowledge, no calculations have been made previously for multiple scattering by more than two parallel dielectric cylinders. Numerical results for four abutting cylinders with end-on illumination demonstrate damping of internal resonance features similar to previously published results for two cylinders. Furthermore, we present numerical examples of scattering from eight unequally spaced, parallel dielectric cylinders with broadside illumination. Because of coupling between the cylinders, the incident energy is spread evenly between the intensity peaks behind the array of cylinders. PMID- 20725322 TI - Light-scattering investigations of thermochromic gels. AB - We investigate the optical switching behavior of thermochromic layers, i.e., their spectral directionalhemispherical transmission and reflection as a function of temperature. On switching, thermochromic materials in layers of 1 mm provide a reduction of transmission in the optical region from 90% to 50%. We also performed directional-directional transmission and differential-scattering measurements and optical microscopy to derive structural information: a dramatic growth in the number and the size of particles is observed when the switching temperature is surpassed. These particles are formed by expulsion of water during the agglomeration of polymeric chains, which occurs when a characteristic switching temperature is surpassed. A multiflux-model permits predictions of the dependence of the directional-hemispherical transmission on the sample thickness and the angle of incidence. PMID- 20725323 TI - Spectroscopic measurements of electron densities and gas temperatures in deuterium lamps. AB - Plasma diagnostics results of electron densities and gas temperatures in commercial low-pressure deuterium lamps at current densities from 38 A/cm(-2) to 306 A/cm(-2) are presented. These plasma parameters are obtained by comparing measured and calculated Balmer line profiles, taking into account Stark broadening, Doppler broadening, and the influence of fine structure and the apparatus profile. Results for the plasma spot show a steady increase of electron density from 1.6 x 10(13) cm(-3) to 5.0 x 10(13) cm(-3) and of gas temperature from 1800 to 6800 K. PMID- 20725324 TI - Two-dimensional imaging of sprays with fluorescence, lasing, and stimulated Raman scattering. AB - Two-dimensional fluorescence, lasing, and stimulated Raman scattering images of a hollow-cone nozzle spray are observed. The various constituents of the spray, such as vapor, liquid ligaments, small droplets, and large droplets, are distinguished by selectively imaging different colors associated with the inelastic light-scattering processes. PMID- 20725325 TI - Patents. AB - 5,039,219; 5,040,871; 5,040,876; 5,040,877; 5,042,912; 5,042,922; 5,042,928; 5,042,930; 5,044,706; 5,045,704; 5,046,794; 5,048,904; 5,050,961; 5,050,962; 5,052,763; 5,052,766; 5,053,619; PMID- 20725326 TI - Division-of-amplitude photopolarimeter based on conical diffraction from a metallic grating. PMID- 20725327 TI - Noninvasive assessment of the visual system and ophthalmic and visual optics: an introduction to the joint vision features. AB - This is an introduction to the joint feature on noninvasive assessment of the visual system and ophthalmic and visual optics. PMID- 20725328 TI - Spectacle lens design: a review. AB - This review considers the present state of the design of spectacle lenses with respect to minimizing the side effects that are associated with their wear. Topics include spherical lens design, aspheric lens design, progressive addition lenses, spectacle lens materials, assumptions of conventional lens design, and practical assessment of spectacle lens design. Future possibilities in the manufacture of spectacle lenses are discussed briefly. PMID- 20725329 TI - Traps in displaying optical performances of a progressive-addition lens. AB - Typical traps when displaying the partial optical performances of a progressive addition lens (PAL) are presented. The PAL is briefly described first. Then the ray-tracing software is described in detail. It permits the computation of the optical performance of the PAL in typical cases. For a reference PAL optical partial performances, which are computed in different cases, are displayed. The plots show that the performance depends on the computation conditions, that displaying only some areas of the partial performance may lead to traps for the characterization of the PAL, and that coma must be taken into account to obtain a precise measurement. PMID- 20725330 TI - The chromatic eye: a new reduced-eye model of ocular chromatic aberration in humans. AB - New measurements of the chromatic difference of focus of the human eye were obtained with a two-color, vernier-alignment technique. The results were used to redefine the variation of refractive index of the reduced eye over the visible spectrum. The reduced eye was further modified by changing the refracting surface to an aspherical shape to reduce the amount of spherical aberration. The resulting chromatic-eye model provides an improved account of both the longitudinal and transverse forms of ocular chromatic aberration. PMID- 20725331 TI - Coaxial photorefractive methods: an optical analysis. AB - We provide a novel geometrical optical analysis of two coaxial photorefractive methods (isotropic and orthogonal). The size of the photorefractive pattern is defined in terms of the critical optical parameters without reference to specific camera parameters. A set of equations is derived that defines the following: a working range where the photorefractive pattern increases linearly with refractive error and pupil size, a dead zone where changes in refractive error do not influence pattern size, and critical values where vignetting by the camera lens becomes important. From this analysis optical parameters can be systematically adjusted to vary a photorefractor's working range. Small discrepancies found between measurements taken with model eyes indicated threshold and blooming effects that require calibration. PMID- 20725332 TI - Optical performance of the bovine lens before and after cold cataract. AB - Cold cataracts were induced in ten bovine lenses and then removed by warming. Cataracts first appeared at an average temperature of 11.7 degrees C. The cataracts appeared to be densest at an average temperature of 1.2 degrees C, while warming caused them to disappear completely at an average temperature of 16.4 degrees C. A computer-operated scanning laser system was used to measure the equivalent focal length and changes in relative transmittance before, during, and after the cataract was induced. In general the focal length profile (spherical aberration) that existed before cooling was recaptured on warming. Scatter values indicate that transmittance is not affected by the temporary cold cataract. Thus the optical performance of the bovine lens appears to be identical before and after cold cataracts are induced. We believe that these results indicate that the cataract has a supramolecular origin. PMID- 20725333 TI - Diffractive multifocal intraocular lens image quality. AB - The diffractive multifocal intraocular lens is implanted in the eye to replace a cataractous crystalline lens. Axially separated images from two diffraction orders provide near and distance vision. Overall image quality is affected by both the quality of the in-focus component and the energy distribution between images. Modulation transfer function and energy distribution data are presented. Measurement accuracy is limited by the diameter of the point spread function and by the difficulty in separating the focused and defocused components. PMID- 20725334 TI - Corneal topography and the hirschberg test. AB - A simple trigonometric analysis of the Hirschberg test with the assumption that the corneal surface is spherical predicts a sinusoidal dependence of the corneal reflex displacement on the angle of ocular rotation. A comparison with corneal reflex photographs demonstrates that at angles larger than 50 prism diopters (26 deg) the reflex displacements are larger than predicted by the spherical model. This discrepancy may be accounted for by incorporating a more general description of the corneal topography into the geometric analysis. The linear Hirschberg relation that is seen in typical data is accounted for by a relative flattening of the peripheral cornea by ~ 20% of the apical curvature. This geometric analysis of the functional dependence of the Hirschberg relation on the corneal topography can be expressed as an integral equation. Differentiation yields a second-order differential equation for the corneal topography in terms of the Hirschberg data. If the Hirschberg relation is assumed to be linear, a quadratic dependence is found for the corneal curvature. A similar differential approach can be formulated for the Placido disk. In this sense the corneal topography problem given in terms of Placido disk data is shown to be wellformulated. The relative simplicity of the Hirschberg geometry is seen to stem from the alignment of the light source with the eye of the observer. PMID- 20725335 TI - Low-vision aid using a high-minus intraocular lens. AB - The theoretical performance and some results from the clinical investigation of a new low-vision aid system are analyzed. This device is composed of a spectacle lens and an intraocular lens. The aberrations of this system have been computed and then reduced by optimal aspherization of the optical surfaces. A specialized sophisticated system for controlling the aspheric surfaces is described briefly. Finally the results of the clinical investigation are presented. PMID- 20725336 TI - Modulation transfer functions of low-vision AIDS: comparison with spatial frequency requirements in low vision. AB - Modulation transfer functions (MTF's) of 26 low-vision aids (LVA's) were measured by using the EROS solid-state system. The object and image distances of the LVA's were as in normal usage by a patient. The contrast thresholds of patients who use LVA's were also measured. All LVA's measured have more than adequate contrast transmission at the low frequencies that are important for these subjects, but many have wasted transmission at medium and high frequencies. LVA's with poorer high-frequency MTF can be used successfully by low-vision patients. It is suggested that in future design high resolution should be sacrificed for a greater lens diameter while maintaining a high MTF at low spatial frequencies. PMID- 20725337 TI - Simultaneous measurement of two-point-spread functions at different locations across the human fovea. AB - An experimental system for measuring simultaneously the retinal images of two point tests has been developed. In particular we present one experiment in which one of the points is located at the center of the fovea and the other one is at 1 deg of eccentricity. At these two foveal locations the optical image quality is expected to be approximately the same, while the structure of the retina is known to be quite different. Our results of aerial images show small but systematic differences between the two-pointspread functions that are measured at 0 and 1 deg of eccentricity. The image quality is always slightly better in the center of the fovea with the differences more marked in the nasal and inferior orientations. That could be explained by a small but noticeable contribution of the retinal thickness to the optical aberrations of the eye. The possible increment of scattering caused by the increase in retinal thickness at 1 deg was barely measurable in our experiment. An indirect consequence is that retinal reflection has little practical influence on our particular double-pass measurements of the eye's image quality. PMID- 20725338 TI - Failures of isoluminance caused by ocular chromatic aberrations. AB -

Using a simple model eye with a wavelength-dependent diffraction, a wavelength dependent refractive error (chromatic difference in refractive error), and a wavelength-dependent displacement of the foveal images (transverse chromatic aberration), we have evaluated the luminance modulations in retinal images of isoluminant color gratings. In cases where the chromatic difference in refractive error has been corrected, the retinal image suffers from chromatic parallax, which creates wavelength-dependent displacements of the retinal image that are similar to those caused by transverse chromatic aberration.

Our calculations show that all three chromatic aberrations can introduce luminance modulations in the retinal images of isoluminant gratings. These luminance artifacts generally, but not always, increase with increasing spatial frequency. The contrast in the luminance artifact depends critically on the exact refractive error in the uncorrected eye and the precise position of the eye in the corrected case.

Wavelength-dependent diffraction has little effect for large pupils (e.g., 5 mm) but can become a significant factor with small pupils. Luminance artifacts created by chromatic aberrations can be more detectable than the original color contrasts at spatial frequencies above 3 cycles/deg.

PMID- 20725339 TI - Artificial pupils and Maxwellian view. AB - When control of the pupil size is required, the simplest method is to use a physical artificial pupil or aperture that is placed in the spectacle plane. In some clinical applications (e.g., the potential acuity meter) an optical artificial pupil is imaged in the plane of the natural pupil by a Maxwellian view optical system. We compared visual performance with physical and Maxwellian artificial pupils by measuring the effects of the pupil diameter (0.5-5 mm in range) and defocus (5-D myopia to 4-D hyperopia) on minimum angles of resolution (MAR's) and on angular blur disk diameters. For pupil diameters down to ~ 2.0 mm there were no meaningful differences between the visual resolution that is obtained with the physical and the Maxwellian pupils. At the smallest diameter (0.5 mm) the physical artificial pupils caused the MAR to increase because of the diffraction limitation on resolution, and defocus no longer affected MAR. With the small Maxwellian pupils vision did not become diffraction-limited so that maximum resolution could still be obtained. MAR was still affected by defocus. The angular blur disk diameters measured with the smaller Maxwellian pupils were slightly but significantly larger than those found with physical artificial pupils. For physical artificial pupils, field-of-view restrictions may result from vignetting with the eye pupil. Thus small physical artificial pupils can act as pinholes causing resolution to become impaired but insensitive to defocus. Also vignetting by the eye pupil can restrict the field of view. Small optical artificial pupils from Maxwellian viewing do not impair resolution, and the resolution may remain sensitive to defocus. The eye pupil does not cause any field restriction, although, if small, it may filter higher spatial frequencies out of the retinal image. PMID- 20725340 TI - Measurement of ocular local wavefront distortion with a spatially resolved refractometer. AB - Local wavefront distortion by the total refractive system of the eye is measured by a variant of the Scheiner principle at some thirty loci of 1 mm diameter. At each locus we find the normal to the wavefront that could form a point focus. A simple visual display is used to review the data, and a steepest descents fit of the wavefronts with a power series enables comparison with more traditional measures of refractive error. PMID- 20725341 TI - Sources of intraocular light scatter from inversion of an empirical glare function. AB - Many questions remain concerning the sources of intraocular light scatter. One approach, inversion of the empirical disability glare function, implies that refractive-index fluctuations extend over distances of tens of micrometers. Randomly placed inhomogeneities of these sizes, such as protein aggregates, are ruled out. It is argued that refractive-index fluctuations associated with the lens fiber lattice are capable of contributing significantly to intraocular scatter and that they provide the necessary large spatial extent. PMID- 20725342 TI - Clinical assessment of intraocular stray light. AB - A device that measures intraocular stray light for clinical use in, e.g., cataract evaluation by using the psychophysical direct compensation approach is described and evaluated. PMID- 20725343 TI - Reflectometry with a scanning laser ophthalmoscope. AB - We describe noninvasive techniques to optimize reflectometry measurements, particularly retinal densitometry, which measures the photopigment density difference. With these techniques unwanted scattered light is greatly reduced, and the retina is visualized during measurements. Thus results may be compared for each retinal location, and visible artifacts are minimized. The density difference measurements of the cone photopigment depend on the optical configuration of the apparatus. The cone photopigment density difference is greatest near the fovea and for most observers decreases rapidly with eccentricity. A research version for reflectometry and psychophysics of the scanning laser ophthalmoscope is described. PMID- 20725344 TI - Oxygen distribution in the retinal and choroidal vessels of the cat as measured by a new phosphorescence imaging method. AB - The oxygen tension in the vessels of the retina and optic nerve head has been measured noninvasively with a new phosphorescence imaging method. A phosphorescent oxygen-dependent probe, injected into the bloodstream of cats, was excited with a flash of light and the phosphorescence lifetime of the probe was measured. A simple Stern-Volmer relationship was used to convert lifetime to oxygen tension, and two-dimensional maps of intravascular oxygen tension were produced. We describe the equipment and the methodology for obtaining oxygen maps. PMID- 20725345 TI - Intensified charge-coupled-device-based eyetracker and image stabilizer. AB - An electro-optical eyetracker measures eye movement to stabilize a laser beam on the fundus in one dimension. Motion is detected by laser illumination of a fundus feature. The illuminated area is imaged on an intensified linear CCD. Electronics determine the intensity centroid of this image. Centroid motion on the CCD corresponds to eye movement in one dimension. Galvanometer-controlled mirrors reposition (at a 1-kHz rate) the illuminating beam on the fundus. The same mirrors reposition the centroid at the CCD center. Additional beams are also stabilized on the fundus. For typical fixational eye movement amplitudes and frequencies the beams follow the fundus feature within +/-10 microm. PMID- 20725346 TI - Spatially resolved birefringence of the retinal nerve fiber layer assessed with a retinal laser ellipsometer. AB - A retinal laser ellipsometer has been developed by coupling a Fourier ellipsometer to a laser scanning system. The instrument has been used to assess the origin and the amount of change in the state of polarization of a laser beam that has double passed the retina around the optic nerve head of postmortemhuman eyes. Eight eyes with no history of glaucoma were studied. At 200 points around the optic nerve head of each eye the Mueller matrices of the retina were examined for the amount of retardation, the orientation of the optic axis, and the amount of dichroism. The degree of polarization preservation of the detected light varied between 50% and 87%. Little dichroism was found, and there was no obvious correlation to the physical arrangement of any retinal structure. However, there was a substantial amount of linear uniaxial birefringence with the optic axis perpendicular to the incident laser beam. Furthermore the calculated optic axis direction showed a strong correlation with the physical orientation of the radial symmetrically arranged retinal nerve fiber axons around the optic nerve head. The local distribution of the corresponding retardation values showed two maxima that coincided with the areas of the thickest retinal nerve fiber layer. These results support the hypothesis that the thickness of the form birefringent retinal nerve fiber layer can be assessed by ellipsometric methods. PMID- 20725347 TI - Interferometric control of fiber lengths for a coherent telescope array. AB - Single-mode fibers have been proposed for connecting telescopes to mixing stations in coherent telescope arrays intended for image synthesis. We describe a laser-controlled servosystem that keeps the fiber-optical length differences stable and permits passage of wide-bandwidth astronomical beams from an unlimited number of telescopes. Initial laboratory results are presented. PMID- 20725348 TI - Aberration-reduced holographic spherical gratings for Rowland circle spectrographs. AB - We used a numerical minimization method to design a Rowland holographic spherical grating that is recorded with two stigmatic laser sources. The method aims at simultaneously reducing all aberrations up to fourth order over a significant spectral range. In the context of a high spectral resolution, far-ultraviolet spectrograph, an original solution is found that implies a nonclassical recording geometry with one virtual source. This solution satisfies the requirement of a resolving power of ~ 30 000 with the unquestionable advantage of manufacturing and testing simplicity. Finally, another example, which is obtained in a different context, shows that the properties of this recording geometry probably have a general applicability. PMID- 20725349 TI - Practical design of a bifocal hologram contact lens or intraocular lens. AB - When designing diffractive lenses, a high-diffraction efficiency at a particular design wavelength is often the most important criterion. Recently it has become of interest to consider lens designs that split incident light predominantly into two orders for use as bifocal contact lenses or intraocular lenses. Surface- relief profiles on contact and intraocular lenses are subject to many practical constraints in addition to requiring high efficiencies at the two focal points. A new lens design combining a binary-amplitude absorption profile with a unique nonparabolic surface-relief profile is proposed to satisfy these constraints. PMID- 20725350 TI - Projection moire system simulation. AB - A method to simulate arbitrary projection moire systems is presented. Based on the laws of geometric optics and the basic formulas for describing the projection moire system, subjects such as lens systems, object forms, free-formed gratings, and system alignment are treated. Some simulation results obtained by using the method presented are shown. PMID- 20725351 TI - High-aspect-ratio line focus and plasma production using a random phase plate. AB - The use of rectangular-element random phase plates to generate a line focus is described. Photographic records of the resultant focus are presented and compared with theoretical calculations made by using an interference code. Good agreement is found. The code is used to investigate possible design modifications to produce a more square-topped line focus. A 12-ps Raman-shifted KrF (lambda = 0.268 microm) laser pulse is used in combination with such plates to produce a laser plasma. The plasma conditions are extensively characterized by using time resolved extreme UV spectroscopy and a pinhole camera, and their suitability for x-ray laser applications is discussed. PMID- 20725352 TI - Absolute flatness testing by the rotation method with optimal measuring-error compensation. AB - The rotation method for the absolute testing of three flats by the evaluation of four interference patterns of pairs of these flats is developed further. Least squares methods for determining and minimizing the effect of random measuring errors are fully applied. This application makes an optimal resolution in depth and an enhanced lateral resolution possible. The computational effort mainly consists of a repeated solution of a linear equation system with 3N unknowns if N diameters of each flat are to be evaluated. The rms error of determining a flatness deviation is calculated as a function of the rms measuring error, the desired lateral resolution, and the position on the surface. The algorithm is extended to the case of using square-grid detector arrays by a special interpolation method. PMID- 20725353 TI - Photothermal radiometry probing of scars in the internal surface of a thin metal tube. AB - The principle and equipment of photothermal radiometry probing of scars in the internal surface of a thin metal tube are described. By measuring the amplitude frequency characteristics of the photothermal signal, we calculated the depth of the scars in the internal surface of a sample. PMID- 20725354 TI - Practical magnetron sputtering system for the deposition of optical multilayer coatings. AB - A magnetron sputtering system is described in which, at any one time, as many as four different 15-cm x 46-cm rectangular planar magnetron targets can be mounted vertically in the deposition chamber. These can be attached to either dc or rf power supplies for direct or reactive deposition of metal, metal oxide, or nitride films. Typical target materials include Ag, Al, C, Mo, Nb, Ni, Si, W, and Zr. Good uniformity can be obtained on stationary substrates, although better results are possible with oscillating substrates. The refractive indices are given for several useful oxide materials. The materials and thicknesses of the individual layers that comprise an optical multilayer system are entered into a computer that subsequently controls the deposition parameters, the substrate motion, and the deposition time. After a relatively simple calibration process, coatings that consist of between 20 and 60 layers can be produced to within an accuracy of 1% or 2%. A wideband optical monitor is available for checking the performance of the multilayer system during its deposition. Several examples of multilayer coatings that were prepared on this equipment are given. PMID- 20725355 TI - Computation speeds of different optical thin-film synthesis methods. AB - Several different thin-film design problems were solved by the comprehensive search, gradual-evolution, minus-filter, flip-flop, and inverse-Fourier transform, thin-film synthesis methods. In order to compare the relative effectiveness of each method, the results obtained and computation times required by these techniques for primary, intermediate, and final solutions are given. PMID- 20725356 TI - High performance optical wavelength multiplexer-demultiplexer. AB - The principle of an optical wavelength multiplexer-demultiplexer is described in which the signals undergo repeated reflections from special filter elements that can be designed for a wide range of cross-talk ratios. The insertion losses of these units can be quite small and they can be implemented to provide simultaneous multichannel two-way transmission. In a preliminary investigation of an experimental prototype an insertion loss of 0.5 dB and a cross talk of -35 dB were demonstrated. The multiplexer-demultiplexer is expected to have a long life and high reliability. PMID- 20725357 TI - Flip-flop thin-film design program with enhanced capabilities. AB - A flip-flop thin-film design program has been written that makes possible the incorporation of metallic films in the resulting multilayer coatings. This is done by allowing the selection process to choose from three different dispersive materials, one of which may be absorbing. Provision is also made to apply the flip-flop procedure to only part of the layer system. A more elaborate specification of the desired performance is now possible. These changes greatly increase the types of problem that may be solved by using this technique. The method is demonstrated on a number of different problems. PMID- 20725358 TI - Neutral and color-selective beam splitting assemblies with polarization independent intensities. AB - Arrangements consisting of at least three beam splitting surfaces are described that give rise to at least four different beams, of which at least two have polarization-independent spectral intensities. They can act over a wide spectral region and can be designed to be either achromatic or color selective. The performance of an experimentally produced device is described. PMID- 20725359 TI - Deposition error compensation for optical multilayer coatings. I. Theoretical description. AB - The manufacture of complicated optical coatings consisting of many layers of different thicknesses can be a challenge, especially if the deposition technique does not produce dense layers. Deposition errors in a layer can affect not only the desired performance of a multilayer, but can also lead to a complete breakdown of the monitoring and control of subsequent layers. The best chance to achieve the desired optical performance of a multilayer involves deposition error compensation. In this process, the construction parameters of a completed layer are evaluated to determine if any deposition errors have occurred and then the remaining layers of the multilayer system are reoptimized to compensate for any errors made. This paper describes a versatile deposition error compensation program developed at the National Research Council of Canada for the simulation and real-time control of the manufacture of multilayers composed of dielectric or absorbing films. To model porous layers, an effective medium theory approach is used to relate the optical constants of the layer in vacuum and air to the microstructure of the layer. In the simulation mode, random errors are applied to the thickness and porosity of the layers and measurement errors are also included. The best monitoring strategy for the manufacture of a given multilayer is established on the basis of statistical information obtained from a number of these simulations. In this paper the results of calculations on the effectiveness of various monitoring strategies are presented for a sharp edge filter produced by three different physical vapor deposition methods. An extensive list of references to previous papers dealing with sources of errors during deposition is also provided. PMID- 20725360 TI - Fourier-transform method for the design of wideband antireflection coatings. AB - An iterative correction process, recently incorporated into the National Research Council of Canada Fourier-transform thin-film synthesis program, is applied to the design of wideband antireflection coatings. This type of problem is different from those solved in the past by this method. It cannot be handled in a practical way without a correction process. We consider in detail the effects-critical for this application-of constraints on the refractive indices and overall thicknesses of the solutions. Our graded-index and multilayer designs have a remarkable resemblance in performance and refractive-index structure to results obtained by more conventional techniques. The Fourier-transform method is of interest because of its speed and versatility. PMID- 20725361 TI - Identification of contaminant coatings over rough surfaces using polarized infrared scattering. AB - An optical technique to identify the presence of chemical coatings over rough surfaces is described. It is based on the selective use of elements of the 4 x 4 Mueller matrix. The full-wave theory of electromagnetic scattering is used to predict six independent Mueller elements from randomly rough uncoated (dry) and coated (wet) surface materials as functions of the media complex dielectric coefficients, backscattering angle, and midinfrared wavelengths of laser-beam excitations that are polarization modulated. The set of independent elements at beam wavelengths and backscattering angles [M(mn) (lambda(i), lambda(i))] most sensitive to i optically thick contaminant coatings are statistically obtained from the full-wave database, and detection-parameter sets [lambda(i), lambda(i)] are inputs to another algorithm designed to identify the contaminant coating (when present and interacted by the irradiating beams). These algorithms facilitate the operation of a multi-CO(2) laser-ellipsometer facility now under development at the U.S. Army Chemical Research, Development, and Engineering Center for the remote detection of chemical or biological surface contaminants. PMID- 20725362 TI - Effects of quadratic phase distortion on correlator performance. AB - The deformable mirror spatial light modulator (SLM) has an inherent distortion characteristic that can be approximated as a square-law transfer function. We examine the result of this distortion when this SLM is used in an optical correlator. PMID- 20725363 TI - Spatial light modulators and their applications: introduction by the guest editors. AB - The feature in this issue of Applied Optics includes a collection of papers originally presented at the 1990 Lake Tahoe topical meeting on Spatial Light modulators. These papers emphasize materials and devices for spatial light modulation, smart pixels, and applications. PMID- 20725364 TI - Surface-plasmon spatial light modulators based on liquid crystal. AB - The development of a new class of spatial light modulator (SLM), which uses modulation of lossy guided waves generated by surface-plasmon resonance, is described. The potential advantages of this technique are explained, including increased response uniformity and enhanced sensitivity and speed. An optically addressed SLM that is based on a nematic liquid crystal with a spatial resolution better than 10 line pairs/mm (at 50% modulation transfer function) is demonstrated. For the design of devices that are based on newer smectic liquid crystals the use of anisotropy-induced polarization mixing and the so-called pseudoplasmon modes are described. Such modes offer controllable sensitivity spatial resolution characteristics in simple liquid-crystal SLM structures. Within a typical SLM resolution requirement of 10 line pairs/mm, for example, the sensitivity can be optimized to obtain a theoretical reflectivity modulation from 0 to 0.7 for a liquid-crystal director modulation of 5 degrees . PMID- 20725365 TI - Operating modes of a charge-transfer-plate liquid-crystal phase modulator. AB - New results for an electron-beam-addressed liquid-crystal phase modulator are presented. Local, as well as global, control of liquid-crystal molecular reorientation is demonstrated, and the results of five different operating modes are discussed. Linear phase modulation with depths up to 30pi are demonstrated with this device, as are two-dimensional arrays of computer-generated spherical lenses with actively variable focal lengths. The spherical lenses were written without the use of specialized transfer functions to compensate for device nonlinearities. Applications are discussed in the context of adaptive optics in spaceborne systems. PMID- 20725366 TI - Hydrogenated amorphous silicon photodiodes for optical addressing of spatial light modulators. AB - We discuss the use of hydrogenated amorphous silicon (a-Si:H) photodiodes as photosensors in high-performance optically addressed spatial light modulators (OASLM's). To find the performance limitations that result from the photodiode exclusively, a pseudo-OASLM is constructed; it is composed of an a-Si:H photodiode in series with a discrete capacitor and resistor to simulate an electrically ideal liquid-crystal modulator. The a-Si:H photodiode conduction regimes are identified, and the maximum and minimum frame rates that may be attained with an a-Si:H photodiode-driven OASLM are determined to be ~ 100 kHz and ~ 0 Hz, respectively. Optimum performance is obtained when the photodiode capacitance is equal to the light modulator capacitance. PMID- 20725367 TI - Applications of binary and analog hydrogenated amorphous silicon/ferroelectric liquid-crystal optically addressed spatial light modulators. AB - Analytical and experimental results that show novelty filtering, optical phase conjugation, and real-time edge enhancement by using optically addressed spatial light modulators that comprise amorphous silicon photodiodes and analog and binary ferroelectric liquid-crystal modulators are presented. The advantages of these devices for the above applications include high-speed, low-power operation and high spatial resolution. PMID- 20725368 TI - Quantized complex ferroelectric liquid crystal spatial light modulators. AB - A spatial light modulator design consisting of cascaded or sandwiched layers of ferroelectric liquid crystals (FLC's) is investigated. The interrelation between the FLC material, the polarization of the incident illumination, and the achievable modulation states is characterized. Magnitude modulation is accomplished by standard methods by addressing the FLC layer with linearly polarized light and following it with a properly oriented analyzer. When the FLC is addressed with circularly polarized light, lossless phase modulation results with the phase states separated by twice the angle of rotation of the optical axes. A continuum of elliptical polarization states ties together the lossless phase states achievable by using circular polarization with the more well-known 0 degrees -180 degrees phase states obtainable with linearly polarized light. Layers of various bistable FLC materials can be cascaded, possibly with polarization control layers between some of the layers, to yield a spatial light modulator that produces multip e quantized bits of complex-valued modulation and with independent control of magnitude and phase states. Four-state phase modulation, ternary amplitude-phase modulation, and four-state magnitude modulation are demonstrated experimentally by using two layers of FLC. PMID- 20725369 TI - Bistability and nonlinearity in optically addressed ferroelectric liquid-crystal spatial light modulators: applications to neurocomputing. AB - We report the characteristics of a truly bistable optically addressed ferroelectric liquid-crystal spatial light modulator that is capable of storing binary images. We show that, in addition to this bistability, a nonlinear response and gray scales can be observed under certain operating conditions. We then report on how these capabilities can be used in implementing optical neurocomputing architectures. PMID- 20725370 TI - Gray scale response from optically addressed spatial light modulators incorporating surface-stabilized ferroelectric liquid crystals. AB - We demonstrate the capability of optically addressed spatial light modulators that incorporate surfacestabilized ferroelectric liquid crystals to reproduce gray scale. This capability is based on temporal averaging and is observed in an operating mode in which the applied voltage repeatedly cycles the device between writing and erasing at operating frequencies between 100 and 2000 Hz. A gray scale response is observed for write-light intensities below a saturation level that increases from 100 microW/cm(2) at 100 Hz to 2 mW/cm(2) at 2 kHz. We develop a procedure to determine the modulation transfer function from measurements of the diffraction efficiency as a function of spatial frequency and write-light intensity in a device with a nonlinear transfer characteristic. At an operating frequency of 500 Hz, the modulation transfer function is greater than or equal to 0.50 at a spatial frequency of 40 line pairs/mm. PMID- 20725371 TI - Liquid-crystal integrated silicon spatial light modulator. AB - The integration issues regarding liquid crystals and silicon-chip technology are discussed. A 12 x 12 active-matrix array is fabricated in silicon and addresses a ferroelectric liquid crystal. The structure and performance of the resulting electronically addressed spatial light modulator are reported. PMID- 20725372 TI - Design issues and development of monolithic silicon/lead lanthanum zirconate titanate integration technologies for smart spatial light modulators. AB - System, device, and material issues for the design and realization of smart spatial light modulators are discussed. Silicon and lead lanthanum zirconate titanate (PLZT) are two promising materials that meet the system requirements. Two different technologies for the integration of Si and PLZT are described. Results show that large-scale smart spatial light modulators can be realized with Si/PLZT technologies. PMID- 20725373 TI - Bi(12)SiO(20) thin-film spatial light modulator. AB - A thin-film spatial light modulator that uses an epitaxial film of Bi(12)SiO(20) has been developed. By using a thin epitaxial film as a sensing, storing, and modulating layer, we can attain high resolution of 27 line pairs/mm at 50% modulation. In addition, a novel device structure that adopts a low resistivity substrate enables this device to be erased quickly only by bias voltage switching. PMID- 20725374 TI - Charge-transfer-plate spatial light modulators. AB - Charge-transfer-plate spatial light modulators (CTPSLM's) are a class of devices that employ chargetransfer plates as the interface between the charge-generation element and the light-modulation element. Both optically addressed and electrically addressed devices have been built. Chargegenerating elements for the optically addressed devices include photoconductors, photodiode and phototransistor arrays, optoelectronic integrated circuit chips, and photocathode microchannel-plate assemblies. For electrically addressed devices, electron guns, very large-scale integrated circuits, thin-film transistors, and matrix electrodes are among the possible charge-generation elements. Lightmodulation elements used in CTPSLM's include liquid crystals, electro-optic organic and inorganic crystals, polymers, deformable membrane mirrors, oil films, multilayer dielectric films, and electroluminescent films. In principle, all combinations of charge-generation elements and light-modulating elements are possible. This paper explores the fundamental performance limitations of CTP technology, and describes the design, operation, and applications of five different CTPSLM's (three based on membrane-mirror technology and two on liquid-crystal technology). PMID- 20725375 TI - Electron-beam-addressed membrane mirror light modulator for projection display. AB - The performance of a prototype, reflection-mode projection display based on an electron-beam-addressed membrane mirror light modulator (e-MLM) is described. The e-MLM converts electronic video information into a two-dimensional phase object, that is then schlieren imaged onto a screen. High-contrast dynamic projection of images is demonstrated over a broad range of wavelengths, from the visible to the midinfrared. As such this device is expected to find applications in large-screen visible displays and dynamic infrared scene projectors. PMID- 20725376 TI - Programmable coherent source arrays generated by spatial light modulators. AB - Programmable coherent source arrays are generated by using addressable liquid crystal spatial light modulators and two-dimensional arrays of Fresnel lenses. The modulators used are an optically addressed liquid-crystal light valve, a matrix-addressed pixelated display, and two devices that have individually addressable elements with specially designed patterned electrodes. One such device has a transparent electrode patterned as a Fresnel zone plate array; the other is a gate array used in a hybrid implementation with a Fresnel lens array etched on a glass substrate. The operation of devices that use binary-amplitude and binary-phase Fresnel lenses is described, identifying programmable features, resolution limits, and applications. PMID- 20725377 TI - Optical implementation of the Hamming net. AB - We present an optical implementation of the Hamming net that can be used as an optimum image classifier or an associative memory. We introduce a modified Hamming net, in which the dynamic range requirement of the spatial light modulator can be relaxed and the number of iteration cycles in the second layer (or maxnet) can be reduced. Experimental demonstrations of the optical implementation of the Hamming net are also given. PMID- 20725378 TI - Optical image subtraction in fluorescein-doped boric acid glass. AB - The interference of two coherent images with a controlled phase difference between them is shown by using four-wave mixing in fluorescein-dye-doped boric acid glass and a liquid-crystal television spatial light modulator. We present results showing the digital optical exclusive OR operation with milliwatt optical power and an output that is compatible with CCD camera sensitivities. PMID- 20725379 TI - Spatial light modulation techniques for system application to multipath delay estimation. AB - Three electronically addressed spatial light modulators (SLM's) are tested for their utility in forming optical taps onto an acousto-optic delay line. The SLM's are characterized as devices within a specific optical signal-processing application rather than as independent components. The signal-processing architecture described here uses a programmable tapped delay line for estimating multipath delays. Overall system performance specifications necessitate the SLM requirements. These requirements are compared with the measured performance characteristics of a magneto-optic SLM, a liquid-crystal display, and an acousto optic deflector used as an SLM. The magneto-optic SLM and the liquid-crystal display are found to provide insufficient contrast and system light efficiency. The acousto-optic-based SLM is found to provide the best overall SLM performance for this particular optical signal processing application. PMID- 20725380 TI - Sensitivity of the nonlinear joint transform correlator: experimental investigations. AB - Experiments are provided to investigate nonlinear joint transform correlator sensitivity to scaling and rotation changes of input objects for various degrees of nonlinearity applied to the joint power spectrum. The experimental results for the images used here show that a severe nonlinear transformation of the joint power spectrum increases the sensitivity of the correlation peak intensity to scaling and rotation changes of input objects. However, the correlation peak-to sidelobe ratio of the nonlinear joint transform correlator remains higher than the linear joint transform correlator. These experiments indicate that, in the presence of input signal rotation or scale changes, the performance of the nonlinear joint transform correlator may be better than the linear joint transform correlator. The effect of the modulation transfer function of the spatial light modulator on the nonlinear joint transform correlator performance in the presence of multiple input targets is discussed. PMID- 20725381 TI - Effects of spatial light modulator opaque dead zones on optical correlation. AB - Each pixel of a spatial light modulator (SLM) consists of a phase- or amplitude modulating area (the active zone) within an inactive area (the dead zone). Here we study optical correlators that contain input and filter SLM's whose dead zones are opaque. Computer simulations and analytical calculations are carried out for these correlators when a phase-only, a binary phase-only, or a classical matched filter is written on the filter SLM. The correlation signal-to-noise ratio for a particular filter is independent of a dead zone since its energy throughput is proportional to its peak correlation intensity. PMID- 20725382 TI - Binary encoding of gray-scale nonlinearly transformed filters for optical pattern recognition. AB - A binary-encoded nonlinear matched filter for optical correlation is described. The gray-scale matchedfilter function, transformed by a general type of nonlinearity, is represented in a binary format by a threshold function that changes as a function of the spatial frequency. The output correlation term of the binary-encoded filter is equivalent to the output correlation term of the gray-scale nonlinear matched filter. PMID- 20725383 TI - Optical multiscale morphological processor using a complex-valued kernel. AB - Morphological transformations are typically performed on binary images by convolution with a binary kernel, which is followed by a threshold. We present an alternate approach that uses a complex-valued kernel with odd symmetry to perform these morphological operations. The complex-valued kernel increases the information-processing ability of the processor with no increase in system complexity. One advantage is that the processor operates on all constant regions of a gray-level image in parallel. A scale-space representation of this processor is obtained by varying the size of the kernel continuously through a range of scales. By using redundant information in the scale representation, this system is found to be robust in the presence of noise and spatial nonuniformities in the image. An optical system to perform morphological filtering based on this system is presented. PMID- 20725384 TI - Narrow-band ten-channel optical multiplexer and demultiplexer using a Fourier diffraction grating. AB - A narrow-band ten-channel optical multiplexer and demultiplexer for densely spaced wavelength division multiplexing in multimode fiber communication systems are discussed. These devices consist of a Fourier diffraction grating having very high diffraction efficiency (85%), a telecentric lens system with low aberration, and a unique fiber array. The devices had a very narrow channel spacing of 1.9 nm and low dependence on polarizations in the range from 831.6 to 848.5 nm. The multiplexer had a bandwidth of 0.7 nm and the demultiplexer had a bandwidth of 1.1 nm. PMID- 20725385 TI - Design relationships for acousto-optic scanning systems. AB - We develop the general scanning relationships of an acousto-optic system by using both a purely geometric-optics and a physical-optics approach; each approach provides useful insights into the scanning relationships. The diffraction approach reveals that there are four basic scanning configurations: a long or short chirp scanner, either aperture or repetition-rate limited. The throughput rate for a scanner is always maximized if we use the short-chirp-scanning, repetition-rate-limited mode of operation. The maximum rate may be achieved with other configurations, but at the expense of a decrease in some of the other performance parameters. Examples are given of how these design relationships are used. PMID- 20725386 TI - Frequency-derived distributed optical-fiber sensing: Rayleigh backscatter analysis. AB - Frequency-derived distributed optical-fiber sensing is a powerful and convenient method for measuring the spatial distribution of birefringence in a high birefringence fiber. The method relies on the special statistical characteristics of Rayleigh backscatter for its action, and these are analyzed in the context of the sensing arrangement, with an emphasis on the physical mechanisms. Implications for system design are also discussed. PMID- 20725387 TI - Mobile fiber-optic laser Doppler anemometer. AB - A laser Doppler anemometer (LDA) has been developed that combines the compactness and low power consumption of laser diodes and avalanche photodiodes with the flexibility and possibility of miniaturization by using fiber-optic probes. The system has been named DFLDA for laser diode fiber LDA and is especially suited for mobile applications, for example, in trains, airplanes, or automobiles. Optimization considerations of fiber-optic probes are put forward and several probe examples are described in detail. Measurement results from three typical applications are given to illustrate the use of the DFLDA. Finally, a number of future configurations of the DFLDA concept are discussed. PMID- 20725388 TI - Stationary Fourier-transform spectrometer. AB - The performance and the characteristics of an interferometric double-mirror spectrometer with uncollimated light are studied by measuring spectra of different radiation sources. The stationary interferometer is fabricated without a beam splitter or moving components. The measured interferogram visibilities, which are limited by the size of the source aperture, agree with the theoretical predictions for a slit and a circular source aperture. By background subtraction the effect of detection nonuniformity can be radically reduced to increase the dynamics and the resolving power of the spectrometer. We used a mercury pencil lamp for measurement and found that the dynamic range was ~80 dBm. When isolated spectral lines are measured, the resolving power can be improved by squeezing more than half of a spatial interference cycle onto one pixel. The maximum resolving power reached in measuring the spectra of a diode laser was 1600. The instrument is applicable to a wide range of measurements, such as the recording of temporally variant, wideband radiation sources and the monitoring of laser wavelength. PMID- 20725389 TI - Efficiency and equivalence of homogeneously broadened lossy lasers. AB - A one-dimensional model of a laser with homogeneously broadened saturable gain and distributed loss is used to calculate the recirculating power and extraction efficiency for the case in which the mirrors are lossless. Accurate numerical results show that optimized single-ended lasers, equivalent symmetric lasers, and optimized symmetric lasers have the same extraction efficiency when the gain is small, but not when it is large. The peak efficiency of the single-ended laser is known to decrease with increasing length of the gain cell at high gain. The efficiency of the symmetric laser is found to decrease much less, so the output power nearly scales linearly with length over the range investigated. Thus past assumptions about equivalences between lasers must be reexamined. An approximate analytic solution of the laser equation is shown to be useful from threshold to closed cavity over a wide range of values of the small signal gain, the distributed loss coefficient, and the length of the gain cell. PMID- 20725390 TI - High-isolation optical isolator using a BiCalnVIG single crystal. AB - To the best of our knowledge this is the first time a new optical isolator has been developed that uses BiCaInVIG, a non-rare-earth iron garnet. The device has high isolation > 40 dB with an insertion loss of 1.0 dB at 1.3-microm wavelength and > 43 dB with 1.1 dB at 1.52-microm wavelength, including Fresnel reflection losses of ~0.8 dB for two polarizers. In addition, the device is inexpensive. In order to adjust maximum isolation when the isolator is assembled, a theoretical basis is presented, and the calculated values are in good agreement with the experimental results. PMID- 20725391 TI - Compact in-line laser radial shear interferometer. AB - A compact in-line radial shearing interferometer using laser as a light source is presented. The interferometer is made out of a cube-type beam splitter so that the two opposite surfaces are generated with different curvatures while the normal to the entrance and exit surfaces are in the same line. The interferometer is simple to make and easy to align. Aberration analysis of the interferometer is also presented. Some applications of the interferometer for testing lenses and infrared optical systems and for accessing the quality of an emerging wave front from the exit slit of a monochromator are suggested. PMID- 20725392 TI - Active dielectric film laser. AB - A laser configuration of an optical amplifier that consists of an active dielectric thin film is described. Both the spatial and the temporal mode structure are studied. Analytical and numerical formulations are used to describe the effects of this laser configuration, and experiments are performed to verify the predicted results. It is predicted and observed that the resonator beam width is dominated by the active region width of the film, not by the resonator-mirror curvature. PMID- 20725393 TI - Onset threshold analysis of defect-driven surface and bulk laser damage. AB - Surface and bulk laser damage probability distribution functions are derived for a Gaussian laser beam and a power-law defect damage ensemble. Closed-form solutions are derived and plotted for six and three values of the defect ensemble parameter p in the surface and bulk damage distribution functions, respectively. The derived degenerate (p = 1) and nondegenerate (p = 0) bulk damage equations are least-squares fitted to measured laser damage statistics in polymethyl methacrylate. The results show that the power-law defect ensemble is a reasonable description of the laser-damageable defects in the damage-tested polymethyl methacrylate and that the ensemble is more degenerate in character than uniform. PMID- 20725394 TI - Phase control of a Zeeman-split He-Ne gas laser by variation of the gaseous discharge voltage. AB - Zeeman-split lasers are useful for precise positioning or motion control. In applications that employ such a laser to control closely the position of a moving system, phase noise in the Zeeman frequency is a serious problem. Control of low frequency phase noise can be obtained through variation of the external magnetic field by way of a solenoid wound around the laser tube. It is the finding in this work that control of the residual higher-frequency noise of a He-Ne laser can be obtained through small variations of the high voltage that is used to effect the gaseous discharge in the laser tube. The application of the present system is to the control of the path difference in a Fourier-transform interferometric spectrometer. PMID- 20725395 TI - Spectroscopy and stimulated emission of Nd(3+) in an acentric CsY(2)F(7) host. AB - The results of preliminary spectroscopic studies of new fluoride single-crystal CsY(2)F(7) that is activated by Nd(3+) ions are given. Direct evidence for the possibility of application of this ordered material as a laser host is given for the first time to our knowledge. Stimulated emission of Nd(3+) ions on the main intermultiplet transition is obtained under both nonselective flash-lamp pumping conditions and continuous Ar ion laser pumping conditions. PMID- 20725396 TI - Stability analysis for grating-tuned strong-external-feedback semiconductor lasers. AB - We give a simple stability analysis within the scope of steady-state solution for the grating-tuned strong-external-feedback semiconductor lasers. In our model, a fluctuation in the refractive index of an active medium through the coupling of carrier density will cause another fluctuation in the refractive index. If the latter is always smaller than the former, the fluctuation will be damped, and therefore the corresponding operating point of the laser is stable. Our analysis indicates that there are various stable and unstable operating-frequency ranges for various reflectivities of the internal facet of the laser diode. In addition, it agrees well with the experimental results and explains the bistability of threshold gain versus operating frequency. PMID- 20725397 TI - Precise measurement of the rotational Raman gain coefficient in para-hydrogen by the large-signal method. AB - The plane-wave gain coefficient of stimulated rotational Raman scattering in para H(2) was determined for CO(2) laser-pumping pulses. Difficulties caused by lowered substantial gain for stimulated scattering in the infrared region were overcome by measuring converted energies instead of powers in the large-signal region. The measured gain coefficients showed excellent agreement with theoretical values. PMID- 20725398 TI - Third-harmonic generation in barium borate. AB - The cubic nonlinear susceptibility of barium metaborate was employed for the generation of phase-matched third-harmonic generation (THG) of 1.053-microm pump radiation. The various processes that are responsible for THG in this crystal are discussed and experimental results for types I and II phase matching are presented. THG power of 50 microW is recorded with an average pump power of 800 mW of 1-kHz repetition rate picosecond pulses. PMID- 20725399 TI - Determination of effective optical constants of infrared CO(2) waveguide laser materials. AB - We report a simple method for the determination of optical constants in the lambda = 10-microm region. The method is based on the measurement of reflectance over a wide range of angles of incidence by using a CO(2) laser as the source. Effective values of the refractive index and extinction coefficient at different CO(2) laser emission wavelengths are determined for alumina, fused silica, and beryllia, materials that are widely used for CO(2) waveguide lasers and for CO(2) laser beam transmission. PMID- 20725400 TI - Optical fiber geometry by gray-scale analysis with robust regression. AB - We have used least-median-of-squares (LMS) regression to analyze gray-scale images of optical fiber ends. This regression is a form of robust regression that ignores outlying data points. We fitted ellipses to the images of each of two fiber ends by using LMS and least-sum-of-squares regression. The two methods yielded nearly identical results on a pristine fiber end, but the LMS method was far superior on a damaged fiber end, even though we made no effort to filter the outlying data points. PMID- 20725401 TI - Integration Of SiON waveguides and photodiodes on silicon substrates. AB - Two methods of coupling integrated optical waveguides to photodetectors are investigated. As waveguides, SiON layers were deposited by low-pressure chemical vapor deposition on a thick isolation layer of thermally grown SiO(2) on silicon substrates. Lateral p-i-n diode photodetectors were fabricated by standard processing in the silicon substrates. Structures for end-fire and leaky-wave coupling were fabricated. Coupling efficiencies of up to 84% for end-fire and 88% for leaky-wave coupling were obtained. The fabrication steps are described, and the resulting optoelectrical behavior is discussed. PMID- 20725402 TI - Polarization properties of planar dielectric waveguide gratings. AB - An experimental and theoretical study of polarization properties of planar dielectric waveguide gratings operating at general (oblique) inicidence is reported. The radiation modes coupled out by a surface-relief waveguide grating, when the incident light is not normal to the grating rulings, are linearly polarized for TE excitation and are elliptically polarized for TM excitation. The polarization states of the radiation modes are determined primarily by the polarization state of the principal guided wave in the grating region and by the propagation directions of the radiation modes with respect to the plane of the principal guided wave. Experimental data and numerical results based on three physical models are presented. PMID- 20725403 TI - Characterization of multilayer nonlinear optical waveguides. AB - A polymeric waveguide material with nonlinear optical properties is studied: crosslinked poly(methyl) methacrylate (PMMA) doped with N,N'-dihexyl-amino nitrostilbene (DHANS). The fabrication and characterization of thin-film waveguides (2-4 microm) are demonstrated. The anisotropy of the refractive index and the damping of the films have been investigated by m-line spectroscopy and loss measurements. Thin polymeric multilayer structures, including a nonlinear optical core, sandwiched between buffer layers and electrodes have been produced. For these samples, the anisotropy of the refractive index in poled films are measured. Finally, two systems are compared: PMMA/DHANS and a side-chain polymer with the same nonlinear optical group. PMID- 20725404 TI - Edge technique: theory and application to the lidar measurement of atmospheric wind. AB - The edge technique is a new and powerful method for measuring small frequency shifts. With the edge technique a laser is located on the steep slope of a high resolution spectral filter, which produces large changes in transmission for small frequency shifts. A differential technique renders the frequency shift measurement insensitive to both laser and filter frequency jitter and drift. The measurement is shown to be insensitive to the laser width and shape for widths that are less than the half-width of the edge filter. The theory of the measurement is given with application to the lidar measurement of wind. The edge technique can be used to measure wind with a lidar by using either the aerosol or molecular backscattered signal. Examples of both measurements are presented. Simulations for a ground-based lidar at 1.06 microm using reasonable instrumental parameters are used to show an accuracy for the vector components of the wind that is better than 0.5 m/s from the ground to an altitude of 20 km for a 100-m vertical resolution and a 100-shot average. For a 20-m vertical resolution and a 10-shot average, simulations show an accuracy of better than 0.2 m/s in the first 2 km and better than 0.5 m/s to 5 km. PMID- 20725405 TI - Fluorescence lidar detection with shot noise and sky radiance. AB - Rank annihilation-factor analysis is potentially the best method of analyzing fluorescence lidar returns because of the following capability. Rank annihilation can recognize a fluorescence signal of a component that is hidden by a large fluorescence background without a spectrum of that background. Theoretical models were developed to analyze the effectiveness of rank annihilation-factor analysis in the interpretation of lidar returns. Interferents such as background fluorescence, photon-counting noise, sky radiance, and atmospheric extinction degraded the lidar-return spectra in numerical simulations. The rank annihilation factor analysis detection algorithm was most severely biased by the combination of photon-counting noise and sky radiance. Rank annihilation calculations were also compared with calculations done by two other detection algorithms: finding peak wavelengths and the least-squares technique. Rank annihilation is better than both techniques. PMID- 20725406 TI - High pulse repetition frequency, multiple wavelength, pulsed CO(2) lidar system for atmospheric transmission and target reflectance measurements. AB - A multiple wavelength, pulsed CO(2) lidar system operating at a pulse repetition frequency of 200 Hz and permitting the random selection of CO(2) laser wavelengths for each laser pulse is presented. This system was employed to measure target reflectance and atmospheric transmission by using laser pulse bursts consisting of groups with as many as 16 different wavelengths at a repetition rate of 12 Hz. The wavelength tuning mechanism of the transversely excited atmospheric laser consists of a stationary grating and a flat mirror controlled by a galvanometer. Multiple wavelength, differential absorption lidar (DIAL) measurements reduce the effects of differential target reflectance and molecular absorption interference. Examples of multiwavelength DIAL detection for ammonia and water vapor show the dynamic interaction between these two trace gases. Target reflectance measurements for maple trees in winter and autumn are presented. PMID- 20725407 TI - Optimizing coherent lidar performance with graded-reflectance laser resonator optics. AB - We demonstrate how the design of graded-reflectance output coupler unstable laser cavities may be tailored to significantly enhance the overall power transmission efficiency of a given laser system relative to that of a conventional diffractively coupled unstable resonator. The importance of these findings in coherent lidar applications is explained with particular emphasis on projected space-based systems. PMID- 20725408 TI - Signal-to-noise-ratio equations for a heterodyne laser radar. AB - We analyze the signal-to-noise-ratio equations for a heterodyne laser radar with identical transmit and receive optics. We defines the beam-profile efficiency, a quantity that must be maximized to optimize a system design. This calculation can be used to evaluate a system in both near and far fields for focused and nonfocused systems. The beam-profile efficiency can be evaluated in many ways, and we describe one possible solution. Using this solution, we present the results of an actual system evaluation. PMID- 20725409 TI - Surface-roughness considerations for atmospheric correction of ocean color sensors. I: The Rayleigh-scattering component. AB - The first step in the coastal zone color scanner (CZCS) atmospheric-correction algorithm is the computation of the Rayleigh-scattering contribution, Lr(r), to the radiance leaving the top of the atmosphere over the ocean. In the present algorithm Lr(r), is computed by assuming that the ocean surface is flat. Computations of the radiance leaving a Rayleigh-scattering atmosphere overlying a rough Fresnel-reflecting ocean are presented to assess the radiance error caused by the flat-ocean assumption. The surface-roughness model is described in detail for both scalar and vector (including polarization) radiative transfer theory. The computations utilizing the vector theory show that the magnitude of the error significantly depends on the assumptions made in regard to the shadowing of one wave by another. In the case of the coastal zone color scanner bands, we show that for moderate solar zenith angles the error is generally below the 1 digital count level, except near the edge of the scan for high wind speeds. For larger solar zenith angles, the error is generally larger and can exceed 1 digital count at some wavelengths over the entire scan, even for light winds. The error in Lr(r) caused by ignoring surface roughness is shown to be the same order of magnitude as that caused by uncertainties of +/- 15 mb in the surface atmospheric pressure or of +/- 50 Dobson units in the ozone concentration. For future sensors, which will have greater radiometric sensitivity, the error caused by the flat-ocean assumption in the computation of Lr(r) could be as much as an order of magnitude larger than the noise-equivalent spectral radiance in certain situations. PMID- 20725410 TI - Surface-roughness considerations for atmospheric correction of ocean color sensors. II: Error in the retrieved water-leaving radiance. AB - In the algorithm for the atmospheric correction of coastal zone color scanner (CZCS) imagery, it is assumed that the sea surface is flat. Simulations are carried out to assess the error incurred when the CZCS-type algorithm is applied to a realistic ocean in which the surface is roughened by the wind. In situations where there is no direct Sun glitter (either a large solar zenith angle or the sensor tilted away from the specular image of the Sun), the following conclusions appear justified: (1) the error induced by ignoring the surface roughness is less, similar1 CZCS digital count for wind speeds up to approximately 17 m/s, and therefore can be ignored for this sensor; (2) the roughness-induced error is much more strongly dependent on the wind speed than on the wave shadowing, suggesting that surface effects can be adequately dealt with without precise knowledge of the shadowing; and (3) the error induced by ignoring the Rayleigh-aerosol interaction is usually larger than that caused by ignoring the surface roughness, suggesting that in refining algorithms for future sensors more effort should be placed on dealing with the Rayleigh-aerosol interaction than on the roughness of the sea surface. PMID- 20725411 TI - Undersea compound radiometer. AB - We have built a simple, undersea radiometer that measures ten integral moments of the radiance as functions of depth in natural waters. From these data it is possible to calculate nine spherical moments of the scattering function, provided that this function varies slowly in the horizontal planes (i.e., the water is fairly stratified). This technique inverts the equations of radiative transfer, which avoids some of the limitations of conventional instruments. We took the instrument on a voyage in the coastal waters of San Diego and were able to measure the absorption coefficient in real time and in situ; we have been able to recover scattering functions with the help of nearly concurrent attenuation measurements. PMID- 20725412 TI - Delta-k-lidar sensing of the ocean surface. AB - A new lidar technique for detecting ocean surface waves is analyzed theoretically. The method is based on the Deltak-radar technique and detects the modulation of the low-frequency product of two frequency-separated backscattered laser fields. It is shown that this Deltak-lidar technique can have a much larger signal-to-noise ratio than Deltak-radar, primarily because of its ability to aperture average the speckle noise in the backscattered fields. PMID- 20725413 TI - Wave-front tilt power spectral density from the image motion of solar pores. AB - We have constructed an image-stabilization system that measures wave-front tilt over a telescope aperture that is due to atmospheric turbulence. This system uses small features on the Sun as point sources. The wave-front tilt power spectral density has been measured with this system out to more than 500 Hz. The spectra show three distinct asymptotic slopes that do not, in general, agree with theoretical predictions based on the Kolmogorov model. PMID- 20725414 TI - Two-color correlation of atmospheric scintillation. AB - We present the results of measurements of the correlation of scintillations of two colors of light made in the turbulent atmosphere. In strong path-integrated turbulence the correlation is below that predicted by the weak-turbulence theory. A phenomological theoretical approach is used to account for saturation effects. This simple theory provides a reasonable approximation to the correlation data. Thus, we conclude that saturation effects reduce the two-color correlation of atmospheric scintillation. PMID- 20725415 TI - Rotational coherent anti-stokes Raman spectroscopy measurements in a rotating cavity with axial throughflow of cooling air: oxygen concentration measurements. AB - In a rotating cavity rig, which models cooling air flow in the spaces between disks of a gas turbine compressor, the buildup of oxygen concentration after the cooling gas was changed from nitrogen to air was monitored using rotational coherent anti-Stokes Raman spectroscopy (CARS). From this information an estimate of the fraction of the throughflow entering the rotating cavity was obtained. This demonstrates that rotational CARS can be applied as a nonintrusive concentration-measurement technique in a rotating engineering test rig. PMID- 20725416 TI - Spectral characteristics of a short-pulse red-green-blue dye mixture laser. AB - Three-primary-color laser emissions of blue, green, and red were simultaneously obtained by using a Coumarin 460 (C460)/Disodium Fluorescein (DF)/Cresyl Violet (CV) mixture and a C460/DF/LD690 (LD) dye mixture excited by a nitrogen laser. The center wavelengths were 455 nm (C460; 4.8 x 10(-3) mol/L), 526 nm (DF; 2.4 x 10(-4) mol/L), and 630 nm (CV; 2.2 x 10(-4) mol/L) in the C460/DF/CV dye mixture laser, and 466 nm (C460; 4.8 x 10(-3) mol/L), 521 nm (DF; 2.4 x 10(-4) mol/L), and 650 nm (LD; 1.2 x 10(-3) mol/L) in the C460/DF/LD dye mixture laser. The pulse widths of the dye mixture lasers were several nanoseconds. The differences in oscillation wavelength (wavelength shift caused by mixing) and threshold concentration among the three dye mixtures, two dye mixtures, and the individual dyes that were used for the mix are experimentally described. A theoretical discussion of the selection of suitable dyes and the calculated results that were obtained by using the rate equations and the laser gain equations for the estimation of suitable concentrations for the dye mixture laser are also described. PMID- 20725417 TI - Space-exposure effects on optical-baffle coatings at far-infrared wavelengths. AB - Reflectance of six optical-black coatings was remeasured over the near-infrared to the far-infrared region after nearly 6 years in space aboard the Long Duration Exposure Facility satellite. Measurements were made at room temperature and at cryogenic temperatures. The most notable effect was a general decrease in reflectance for typical samples at all wavelengths. Analysis indicates that this decrease is caused by an increase in absorption resulting from an increase in the imaginary part of the index of refraction, and not by a change in thickness, or increased surface roughness giving rise to increased scattering. These results suggest that such optical-baffle materials will provide enhanced performance as a result of aging in the space environment. PMID- 20725418 TI - Beam quality changes of Gaussian Schell-model fields propagating through Gaussian apertures. PMID- 20725419 TI - New behavior in nonideal couplers. PMID- 20725420 TI - Real-time measurement of surface roughness through Young's fringes modulated speckle. PMID- 20725421 TI - Ultranarrow filters with good performance when tilted and cooled. PMID- 20725423 TI - Polarization-preserving totally reflecting prisms. PMID- 20725422 TI - Self-aligning optical measurement systems. PMID- 20725424 TI - Infrared optical characteristics of type 2A diamonds: erratum. PMID- 20725425 TI - Extending the caustic test to general aspheric surfaces. AB - The caustic test is capable of a high degree of accuracy in the measurement of aspheric surfaces. The essence of the test is to measure the locations of the centers of curvature for off-axis zones of an aspheric surface with a modified Foucault test apparatus. We present equations that extend the usefulness of the caustic test to general aspheric surfaces. Equations are also given for calculating derivatives for several caustic test parameters that are useful for tolerancing optical systems or in derivative increment calculations for computer lens design applications. Guidelines are given for the correct use of the caustic test in actual testing setups. PMID- 20725426 TI - Testing spherical surfaces: a fast, quasi-absolute technique. AB - A technique for measuring the quality of spherical surfaces that provides a quasi absolute result is presented. It requires only two measurement positions rather than the traditional method of absolute sphere measurement that requires three measurement positions. A measurement is taken with a mirror at the focus of the interferometer diverger lens and is subtracted from a measurement of the sphere tested at its center of curvature. This test assumes that the test sphere does not contain any aberrations with odd symmetry so that these aberrations can be subtracted to provide a fast, quasi-absolute measurement. We describe the new technique and compare measurement results from testing a lambda/12 peak-to-valley sphere (numerical aperture = 0.4) by using a phase-measuring Fizeau interferometer with results from the three-position absolute sphere measurement technique. The repeatability of this measurement technique is +/-0.01 waves peak to valley. PMID- 20725427 TI - Direct contact superpolishing of sapphire. AB - We show that sapphire can be superpolished in direct contact with a tin lap by using colloidal silica in water as the polishing liquid. The residual roughness is <0.05 nm rms. No damage to the layer remains. The typical polishing time is 15 30 min. The flatness is determined by prepolishing mainly. Curved surfaces can also be polished by using this method. The least roughness was observed when removal rates were low, i.e., ~ 10 nm/min, which corresponds to approximately half of an atomic layer per second. PMID- 20725428 TI - Improved wedge-plate shearing interferometric technique for a collimation test. AB - An improved wedge-plate shearing interferometric technique for collimation testing is presented. With two mirrors, the technique provides a twofold increase in sensitivity and has its own reference. PMID- 20725429 TI - Self-directioning with the revolving retroreflection technique. AB - We have developed a method for giving direction and/or position information in an optical guidance system based on the pulse position modulation property of a reflected light pulse train from a revolving retroreflector. The principle and theoretical analysis are described. Experimental verification of the one-axis, closed-loop tracking system is presented, which resulted in a static angular resolution as low as 22 microrad. This method suggests some potential applications to coordinate determinations or line-of-sight guidance systems. PMID- 20725430 TI - Antireflection surfaces in silicon using binary optics technology. AB - Binary optics processing methods were applied to a silicon substrate to generate an array of small pillars in order to enhance transmission. The volume fraction of the silicon in the pillars was chosen to simulate a single homogeneous antireflection layer, and the pillar height was targeted to be a quarter-wave thickness. A mask was generated, using a graphics computer-aided design system; reactive-ion etching was used to generate the pillars. An improvement in long wavelength infrared transmission is observed, with diffraction and scattering dominating at shorter wavelengths. PMID- 20725431 TI - Two-mirror unobscured optical system for reshaping the irradiance distribution of a laser beam. AB - The design of a two-mirror optical system for reshaping the irradiance distribution of a laser beam is presented. The second mirror is decentered relative to the first to eliminate the obscuration inherent in an axially symmetric design. A geometric-optics approach is used to derive a set of equations that describe the surface figures of each of the mirrors. (In general, the mirror surfaces are not rotationally symmetric.) The special case of a system to convert a Gaussian input beam into a uniform output distribution is considered. The expressions for the surface figures are evaluated numerically for several specific systems to provide illustrative examples. It is observed that in some cases rotationally symmetric aspheres may be used to construct the beam shaping system. PMID- 20725432 TI - Prime focus correctors for the spherical mirror. AB - The aberrations of a spherical mirror of moderate aperture ( approximately f/5) can be corrected by a lens system near the focal plane. A four-element lens system is necessary to provide a satisfactory state of correction over a full field of 0.5 deg. The design of such a lens system is described with emphasis on the intrinsic properties of each component and the logic behind the choice of layout. PMID- 20725433 TI - Effects of diffraction efficiency on the modulation transfer function of diffractive lenses. AB - Diffractive lenses differ from conventional optical elements in that they can produce more than one image because of the presence of more than one diffraction order. These spurious, defocused images serve to lower the contrast of the desired image. We show that a quantity that we define as the integrated efficiency serves as a useful figure of merit to describe diffractive lenses. The integrated efficiency is shown to be the limiting value for the optical transfer function; in most cases it serves as an overall scale factor for the transfer function. We discuss both monochromatic and polychromatic applications of the integrated efficiency and provide examples to demonstrate its utility. PMID- 20725434 TI - Fused-silica focusing lens for deep UV laser processing. AB - A simple four-element fused-silica lens is presented that has a focal length of 31.2 mm and a relative aperture of f/1 for use as a focusing lens for deep UV laser processing. The curvature of the lens is designed with a practical design method to match the curvature of existing optical tools. By applying an 8.5-mm beam diameter Nd:YAG laser at a wavelength of 266 nm through the lens, we can easily achieve the percussion drilled into samples of 25-microm-thick tantalum foil with a hole diameter of <6 microm. When the lens and/or the sample is tilted, the shape of the drilled hole is in agreement with the Gaussian beam spot simulation. PMID- 20725435 TI - High-resolution ground-based coronagraphy using image-motion compensation. AB - The first results of a new approach to ground-based stellar coronagraphy are reported. A coronagraph has been equipped with an image-motion compensation system for the stabilization of the telescope field, permitting both improved image resolution and contrast at optical wavelengths. By stopping the telescope aperture D to ~ 4 r(0), where r(0) is Fried's parameter, the maximum attainable resolution gain factor of 2.2 was achieved. Gains measured for D/r(0) > 14 were below the theoretical value of 1.3 theory and were indicative of centroid anisoplanatism, a small spatial coherence outer scale, or both. These effects are also evidenced by diminished power at low frequencies in the power spectrum of image motion over the full telescope aperture. A comparison of stabilized and unstabilized images shows that this coronagraph may detect circumstellar objects 2 magnitudes fainter than those detectable with a conventional coronagraph. PMID- 20725436 TI - Polarization-interference measurement of phase-inhomogeneous objects. AB - Phase-inhomogeneous optical crystals, slightly rough surfaces, and turbulence in a liquid are studied by measuring the transverse-coherence function. A new polarization interferometer for measuring the coherence function is suggested that ensures high accuracy of the measurement. PMID- 20725437 TI - Sensitivity of the reflection technique: optimum angles of incidence to determine the optical properties of materials. AB - The purpose of this study is to develop a technique that will provide the maximum sensitivity of the reflection technique for the determination of the optical properties of materials. Analytical relations are presented that yield the maximum sensitivity of the technique for a given range of angles of incidence and refractive indices. The methods of the reflectance ratio at one and two angles of incidence are compared. The angular range of 75 degrees to 80 degrees was found to be suitable for the maximum sensitivity for the reflectance ratio at one angle of incidence, whereas for the two angles of incidence the ranges 45 degrees to 60 degrees and 75 degrees to 85 degrees are suitable. Furthermore, angular reflectance measurements on a specular carbon-rod surface at the wavelength of 3.5 microm were used to demonstrate the advantages of inverting full-angularrange data as opposed to one or two angle measurements. The limitations of the measurements at normal incidence and 45 degrees are also assessed. PMID- 20725438 TI - Coherent gradient sensing: a Fourier optics analysis and applications to fracture. AB - A Fourier optics analysis for a recently developed lateral shearing interferometry-coherent gradient sensing-is presented. The governing equations for the method are explicitly derived. The method of coherent gradient sensing is particularly suitable for investigating the mechanics of fracture of transparent and opaque solids. Several examples demonstrating the applicability of the method to quasistatic and dynamic crack-growth problems is presented. PMID- 20725439 TI - Beam-jitter measurements of turbulent aero-optical path differences. AB - We have developed new a technique for measuring aero-optical aberrations in flowing turbulent fluids. The rms optical path difference power spectral density is obtained from angular beam-jitter measurements. We tested the technique in an airflow in which there was a temperature discontinuity at a turbulent interface. It was validated by comparison with the data from a pulsed interferometer. PMID- 20725440 TI - Intensity and resolution at the diffraction focus of optical systems with rotationally symmetric aberration functions. AB - The intensities and resolutions at the diffraction focus of optical systems with rotationally symmetric minimum-variance aberration functions as well as functions with slight variations from this shape and a prescribed fixed maximum deviation value at the edge of the exit pupil are calculated for circular and annular exit pupils. The results for the intensity at the diffraction focus obtained either by numerical integration of the diffraction integral or by using the Marechal formula show that the maxima of these intensities are achieved for optical systems with wave aberration functions of minimum variance, thus verifying the Marechal criterion. The resolutions (first zeros of the intensities in the radial direction) at this diffraction focus are also presented. PMID- 20725441 TI - Binary gratings with increased efficiency. AB - Coupled-wave analysis is used to design binary gratings with high efficiencies (70-80%). The binary designs have grating periods greater than one wavelength but use subwavelength structures within each period in order to achieve high efficiency. PMID- 20725442 TI - High-spatial-frequency binary and multilevel stairstep gratings: polarization selective mirrors and broadband antireflection surfaces. AB - High-spatial-frequency, surface-relief binary gratings have been shown to have diffraction properties that are similar to homogeneous layers of equivalent refractive indices, which depend on the grating characteristics, angle of incidence, and polarization. Thus these gratings in the long-wavelength limit could be used as equivalent thin-film coatings. Because of their polarization discrimination these gratings can function as polarization-selective mirrors. A procedure for designing these gratings to be antireflective for one polarization (TE or TM) and to maximize their reflectivity for the orthogonal polarization (TM or TE) is presented. Multilevel stairstep gratings can similarly exhibit characteristics that resemble those of multilayer antireflection coatings (quarter-wave impedance transformers), thus permitting a broader wavelength bandpass. A systematic procedure for designing multilevel stairstepgratings to operate as multilayer thin-film antireflection surfaces is presented. These design methods are valid for both TE and TM polarizations and for any angle of incidence. Example designs are presented, and the rigorous coupled-wave diffraction analysis is used to evaluate the performance of these gratings as functions of the ratio of their period to the incident wavelength. Comparisons are included with homogeneous layers that are equivalent to the gratings in the long-wavelength limit. PMID- 20725443 TI - Jones matrix for round-trip wave propagation in nonreciprocal media. AB - Using a communication channel model, we prove the known theorem that the Jones matrix of a system for backward propagation is the transpose of that for forward propagation. This result, together with the transformation of a coordinate system for opposite propagation directions, is shown to be useful for analyzing the round-trip wave propagation in nonreciprocal media. PMID- 20725444 TI - Method for the determination of optical constants of thin films: dependence on experimental uncertainties. AB - The analytical dependence of sigma(n) and sigma(k) on related experimental uncertainties when conventional reflectance-transmittance methods for the determination of optical constants of thin films are used has been found. Two kinds of singularity appear. These are responsible for the loss of solution in these methods. From the properties of the derivatives of n and k with respect to the measured thickness, a new method has been developed without loss of solution. Different derivative behaviors for physical and nonphysical solutions were found. The film thickness is also determined by this method with an accuracy better than 0.2%. The method has been applied to thin films of amorphous germanium. PMID- 20725445 TI - Simultaneous measurement of the refractive index and thickness of thin films by S polarized reflectances. AB - We have developed an innovation of the polarized reflectances measurement technique for thickness and index (PRETTI) method, PRETTI-S, which is a simple and accurate technique to obtain the refractive index n and thickness d of a thin film by using S-polarized and P-polarized reflectances measured at oblique angles of incidence. In the PRETTI-S method, the n and d are determined by using only S polarized reflectances. Therefore, the measurement and numerical procedure to extract the n and d are simpler than the conventional PRETTI method. As an example, measurement of a single-layer film (SiO(2)/Si) is carried out and excellent confirmation is obtained. PMID- 20725446 TI - Infrared radiation and reflection in an inhomogeneous coating layer on a substrate. AB - By taking into account all kinds of radiation source for the inhomogeneous coating layer on a substrate, that is, transmitted radiation from the radiative substrate, self-radiation of the coating layer and reflection of the coating layer to incident radiation, the radiative transfer equations are built and derived. The definitions of apparent emittance and reflectance for such an inhomogeneous coating system are given. The influence of various factors, such as layer thickness, the optical constants of components in the layer, and emittance of the substrate, on radiation and reflection properties of the coating is discussed in detail. PMID- 20725447 TI - Numerical inverse method of determining film parameters of uniaxial anisotropic film with an ellipsometer. AB - A numerical inversion method of ellipsometry has been developed for determining optical constants and the thickness of uniaxial anisotropic film, of which the optical axis is perpendicular to the film surface. The method of changing film thickness has been proposed to obtain multiple independent ellipsometric equations that can separate the calculation of optical constants and the thickness of the film and reduce the three-parameter problem to a two-parameter problem. A flow chart of the numerical inverse program is given, and an example that applies to Langmuir-Blodgett films is also illustrated. PMID- 20725448 TI - Comparison of theoretical performances for different single-wavelength thin-film polarizers. AB - Theoretical performances of single-wavelength thin-film polarizing cubes, Brewster polarizers, and polarizing plates at a 45 degrees angle of incidence are comparatively analyzed both numerically and analytically. PMID- 20725449 TI - Transmitted and tuning characteristics of birefringent filters. AB - Transmission formulas and transmission curves of birefringent filters when the optic axis is not in the plane of the filter plates are given and discussed in detail. The optimum parameters of birefringent filters, such as the most suitable ratio of thicknesses, tuning angles, and plate thicknesses, are obtained. As far as we know this is the first design of birefringent filters used in a tunable laser pumped by a quasi-cw source. PMID- 20725450 TI - Observations of winds with an incoherent lidar detector. AB - We have developed a Fabry-Perot interferometer and image-plane detector system to be used as a receiver for a Doppler lidar. This system incorporates the latest technology in multichannel detectors, and it is an important step toward the development of operational wind profiler systems for the atmosphere (troposphere, stratosphere, and lower mesosphere). The instrumentation includes a stable highresolution optically contacted plane talon and a multiring anode detector to scan the image plane of the Fabry-Perot interferometer spatially. The high wavelength resolution provided by the interferometer permits the aerosol and molecular components of the backscattered signal to be distinguished, and the Doppler shift of either component can then be used to determine the wind altitude profile. The receiverperformance has been tested by measuring the wind profile in the boundary layer. The Fabry-Perot interferometer and image-plane detector characteristics are described and sample measurements are presented. The potential of the system as a wind profiler in the troposphere, the stratosphere, and the mesosphere is also considered. PMID- 20725451 TI - Scanning Wiener-fringe microscope with an optical fiber tip. AB - A scanning probe optical microscope using the Wiener fringe is presented. The Wiener fringe is formed by a standing wave between the incident and reflected waves on an optically reflective surface and is detected by inserting an optical fiber tip into the fringe-field region. The detected signal is used to maintain the tip-sample distance constant so that a topographic image of a sample can be obtained by a computer-assisted instrument. A spatial resolution of 200 nm has been achieved by observing a sample of known geometry. PMID- 20725452 TI - Two-wavelength electronic speckle-pattern interferometry for the analysis of discontinuous deformation fields. AB - Ambiguity in the conversion of phase measurements to deformation values restricts the applicability of electronic speckle-pattern interferometry. The use of two wavelengths greatly relaxes this restriction. PMID- 20725453 TI - Measurement of the changes in air refractive index and distance by means of a two color interferometer. AB -

We discuss the measurements of the changes in air refractive indices and geometrical distances by means of a two-color phase-modulated fringe-counting interferometer. We analytically classified the optical path lengths for IR and visible light into the changes in the air refractive index and the distance by using a dispersion formula for air. The interferometer was tested over a 235-m path in the testing tunnel of the National Research Laboratory of Metrology, which has a sensor system for measuring air conditions.

The refractive index change by the two-color interferometer agreed with the value calculated by the air conditions within an accuracy of 0.15 ppm.

PMID- 20725454 TI - Calibration of a Fourier transform spectrometer using three blackbody sources. AB - A procedure to calibrate a Fourier transform spectrometer is presented. Blackbody sources of three different temperatures are used to eliminate errors in the calibration that result from the limited accuracy of the temperature measurement of the calibration sources. With three spectra of blackbodies it is possible to assume that the temperatures are unknown variables as are the parameters of the functions that describe the spectrometer. A nonlinear Gaussian balancing calculation is used to determine these unknown variables and to minimize the influence of noise. A comparison between the results obtained with this method and a conventional calibration procedure is presented. PMID- 20725455 TI - Distribution of zero crossings for the profile of random rough surfaces. AB - The distribution of zero crossings for the profile of a statistically rough surface of a silver thin film is determined and compared with a Poisson distribution. It is shown that the density of zero crossings may be related to the autocorrelation length and might be a useful parameter for characterizing spatial information of statistically rough surfaces. PMID- 20725456 TI - Achromatic holographic configuration for 100-nm-period lithography. AB - For the fabrication of large-area, spatially coherent gratings with periods of 100 nm or less, a grating interferometer is preferred over a conventional holographic configuration because of the limited coherence of available sources. Using a configuration that employs two matched fused silica phase gratings and an ArF excimer laser, we obtain high-quality 100-nm gratings in polymethyl methacrylate. We analyze the conditions for achieving high-contrast fringes with such an achromatic holographic configuration and show that the depth of focus depends only on the spatial coherence of the source. We also describe a highly accurate method for calculating the diffraction efficiency of the phase gratings as a function of polarization, incidence angle, and grating structure. PMID- 20725457 TI - Principal optical constants measurement of uniaxial crystal CdSe in the wavelength region between 380 and 950 nm. AB - The principal optical constants n(o), k(o), n(e), and k(e) of the hexagonal crystal CdSe are determined in the wavelength region between 380 and 950 nm at room temperature. The minimum reflectivities and the corresponding Brewster angles of parallel polarized light are measured for ordinary and extraordinary rays in the wavelength region between 380 and 728 nm. At longer wavelengths (k(o) < 10(-3)) Brewsterangle measurements and transmission measurements were applied. A plot of the absorption coefficients alpha(o) and alpha(e) versus wavelength indicates deviations from a direct band-gap parabolic absorption dependence. PMID- 20725458 TI - Refractive index of crystals from transmission and reflection measurements: MgO in the far-infrared region. AB - In principle, the real n and imaginary k parts of the complex refractive index of a crystal can be determined by measuring, when possible, its transmission and reflection spectra. We show that it is possible to derive the frequency dependence of n and k in a simple way by using exact expressions for the interference-free transmittance and reflectance to describe low-resolution data. We also derive n and k data starting from one high-resolution spectrum. As an example, we have measured the roomtemperature transmittance and reflectance of MgO in the far-infrared region. Reliable n and k data are then obtained in the frequency region 50-250 cm(-1). PMID- 20725459 TI - Estimating the thermal conductivity of magneto-optical recording media. AB - A method is presented for estimating the thermal conductivity of magneto-optical recording media by using the temperature dependence of their Kerr effect. The temperature distribution of a recording layer observed as the distribution of polarized light intensity is used to estimate the thermal conductivity of the recording media. The thermal conductivity of a TbFeCo film is between 0.08 and 0.18 W/cm degrees C, and the conductivity of an SiN film is <0.04 W/cm degrees C. Although these values are lower than the previously reported values, the performance parameters that we estimated by using them agree closely with the experimentally measured parameters. The proposed method thus seems valuable for quantitatively analyzing the thermal properties of magneto-optical recording media. PMID- 20725460 TI - Polarization contrast in near-field scanning optical microscopy. AB - Recent advances in probe design have led to enhanced resolution (currently as significant as ~ 12 nm) in optical microscopes based on near-field imaging. We demonstrate that the polarization of emitted and detected light in such microscopes can be manipulated sensitively to generate contrast. We show that the contrast on certain patterns is consistent with a simple interpretation of the requisite boundary conditions, whereas in other cases a more complicated interaction between the probe and the sample is involved. Finally application of the technique to near-filed magneto-optic imaging is demonstrated. PMID- 20725461 TI - Surface profiling with scanning optical microscopes using two-mode optical fibers. AB - A scanning optical microscope system is proposed that uses a slightly laterally offset optical fiber. The fiber is capable of supporting two modes, and it is shown that by detecting the interference between these modes the response to surface height is linear in the focal region. This linearity permits noncontacting surface profilometry to be readily obtained for specimens of uniform reflectivity. For other specimens, a simple feedback system is introduced to obtain surface profiles as well as intensity-coded height images. PMID- 20725462 TI - Edge-setting criterion in confocal microscopy. AB - The intensity that locates the image of an edge in a confocal microscope is calculated as a function of detector size. Both pinhole and slit detectors are considered. Knowledge of this edge-setting criterion permits accurate determination of the edge position, as is necessary for confocal metrology. PMID- 20725463 TI - Effect of phasing-sector angular extent in FM reticles. AB - A technique is presented for increasing the useful power of the FM modulation signal from a spinning FM reticle with a phasing sector. Spinning FM reticles often determine a target location by using a combination of a phasing sector to establish the angular target location and a radial frequency variation to establish the radial target location. Typically, the phasing sector of this reticle type consists of a semicircular transmissive sector with the other semicircular sector which provides FM modulation. The power of the FM modulation signal is increased by matching the phased-sector geometry to the size that corresponds to the period of the modulation frequency. This type of reticle is compared and contrasted with the more typical semicircular phasing-sector reticle in both the time and frequency domains. PMID- 20725464 TI - Reflection and transmission measurements with an integrating sphere and Fourier transform infrared spectrometer. AB - A method of measuring the total reflection and transmission spectra of scattering materials with an integrating sphere and a Fourier-transform infrared spectrometer is studied. The reflectance measurement system is considered in a specific case where the incident beam overfills the back side port of the sphere, and the correction functions for measured spectra are derived for this case. Correction formulas are based on the energy balance between incident radiation and absorbed or escaped radiation in the system. The absorption spectrum of the material is calculated from the corrected spectra. The optical properties of paper samples and radiating surfaces of infrared dryers in the 0.4-20-microm wavelength range are determined. The correction formulas are compared with previous work presented in the literature. PMID- 20725465 TI - CO(2) lidar backscatter profiles over Hawaii during fall 1988. AB - Aerosol and cloud backscatter data, obtained over a 24-day period in fall 1988 with the National Oceanic & Atmospheric Administration's Doppler lidar at 10.59 microm wavelength, are analyzed by using a new technique to lessen biases that are due to dropouts. Typical backscatter cross sections were significantly lower than those routinely observed over the continental United States, although episodic backscatter enhancements caused by cirrus and mineral dust also occurred. Implications of these data on the proposed Laser Atmospheric Wind Sounder wind profiling satellite sensor are discussed. PMID- 20725466 TI - Zero axial irradiance by annular screens with angular variation. AB - For optical alignment, it may be convenient to use a three-dimensional diffraction pattern with zero irradiance along the optical axis. This pattern is created here by using annular screens in the form of a phase daisy, a daisy flower, or a pie, with an even number of slices of an equal central angle and with every other slice with a phase retardation of 180 degrees . We recognize this form of angular variation as a particular solution of a wider set of functions that are able to produce zero axial irradiance. PMID- 20725467 TI - Binary optical data subtraction by using a ternary dibit representation technique in optical arithmetic problems. PMID- 20725468 TI - Low-impedance complementary metal-oxide-semiconductor optical receivers for optical interconnects. PMID- 20725469 TI - Optimized spatial frequency response in silver halide sensitized gelatin. PMID- 20725470 TI - Nonlinear refractive index of IV-IV compound semiconductors. PMID- 20725471 TI - Clarification of Horner efficiency. PMID- 20725472 TI - Image logic algebra and its optical implementations: errata. PMID- 20725473 TI - Optical implementation of terminal-attractor-based associative memory. AB - For the purpose of reducing the spurious states in a Hopfield neural net for associative memory, we invoke terminal attractors. In achieving the optical implementation of the terminal-attractor-based associative memory (TABAM) as described in this paper, we first prove the existence of the terminal-attractor model with binary neuron representation. We then present several one- and two dimensional optical architectures for the TABAM. Finally, as an example, we experimentally demonstrate an inner-product optical neural model using liquid crystal spatial light modulators with engineering approximations and discuss how to apply the inner-product model to build a two-dimensional parallel processing TABAM. PMID- 20725474 TI - Applications of image-logic algebra: wire routing and numerical data processings. AB - Image logic algebra (ILA) is a comprehensive language for single-instruction stream multidata stream-type parallel processing, particularly for processing that is based on pattern matching. To demonstrate the usefulness of ILA for application to the computer-aided design of very-large-scale-integrated circuits, we describe a mostly parallel wire-routing algorithm based on Lee's maze algorithm by using ILA; our computer simulation verifies its validity. Another application to numerical data processing algorithms (including addition and multiplication) that is based on Booth's algorithm is also described by using ILA. Furthermore, the computational complexity of the proposed algorithms is evaluated. PMID- 20725475 TI - Designing digitial optical computing systems: power distribution and cross talk. AB - Complex optical computer designs must implicitly or explicitly allow for power budgeting to compensate for cross talk and loss both in devices and in interconnections. We develop algorithms for calculating the system cross talk and power loss in optical systems by using a graph-theoretic model. Devices are modeled as directed graphs with nodes that represent inputs and outputs, and edges are weighted with the power relationships between nodes. Systems are modeled by interconnecting the individual device graphs in a manner that reflects the connectivity of the system. A system's power budget is efficiently computed by a depth-first search of its graph. The algorithms have been incorporated in an optical computer-aided design system that is presently being used to design a bit serial optical computer that contains hundreds of components. PMID- 20725476 TI - Generation and evaluation of d-dimensional (d >/= 3) optical shuffle patterns. AB - We use d-dimensional shuffle patterns to describe optical frequency division multiplexing. A complexity measure is derived from the geometry of common shuffle patterns and is extended to evaluate d-dimensional shuffle patterns. The least complexity of the generated patterns is determined with respect to the size and the dimension of the data sets. Trade-offs between the dimension of the data sets and the frequency-conversion-based processing of the pattern generation are discussed. A comparison of multiplexing on vectors and arrays is presented. The relation of the complexity analysis to the design of optical frequency division multiplexing systems is briefly discussed. PMID- 20725477 TI - Free-space optical bus using cascaded vertical-to-surface transmission electrophotonic devices. AB - A free-space optical bus, which consists of cascaded optical switch devices, is proposed. The switch devices have multiple functions, such as data transmission, data detection, and data repetition. Basic interconnection characteristics were measured with vertical-to-surface transmission electrophotonic devices. Optical switching energy as low as 150 FJ and up to 4 MHz and a relatively high datatransmission rate, i.e., more than 20 MHz, were obtained. Connection cascadability and extendibility were confirmed. PMID- 20725478 TI - White-light Fourier transformer with low chromatic aberration. AB - A simple Fourier transformation system working with broadband parallel illumination is presented. The proposed setup, consisting of two on-axis zone plates and an achromatic objective, allows us to obtain the achromatic Fourier transform representation of the input at a finite distance with a low chromatic aberration. The discussion of the system, using the Fresnel diffraction theory, leads to an analytical expression to evaluate the transversal and longitudinal chromatic aberrations. It is shown that the resulting chromatic aberrations for typical values of the involved parameters are less than 1% over the entire visible spectrum. PMID- 20725479 TI - White-light optical Fourier transform device. AB - The construction and operation of a new optical phase plate assembly is described that takes the Fourier transform of an intensity image in white light. It consists of symmetrical wedges of birefringent crystals that induce an angle between the wave fronts of the polarized components of the output beam. The wave front angle is shown to be linearly proportional to the angle of incidence. This is sufficient to generate the necessary phase factor for a Fourier transform. PMID- 20725480 TI - Arithmetic processing with a joint-transform correlator. AB - A technique for realizing arithmetic operations that uses a joint-transform correlator is presented. Optical implementations of the technique using a single and a multichannel joint-transform correlator are suggested. The performance of the proposed systems is verified by computer simulation. PMID- 20725481 TI - Design and performance analysis of fiber-optic infinite-impulse response filters. AB - Design of direct forms of infinite-impulse response digital filters using radiatively tapped fiber-optic delay lines is discussed. Infinite-impulse response filters are attractive because they can provide better magnitude characteristics and sharp transition bands in their frequency response for a smaller number of taps than finite-impulse response filters can. The designs described here use spatial-light modulators and thus can be incorporated into optical adaptive filters for processing light-wave signals. Models of error sources in the fiber-optical realization and their effects on both time- and frequency-response characteristics are explained. Cascading of lower-order subsystems to obtain higher-order filters is discussed. A possible way of reducing the insertion loss using erbium-doped fiber-optic amplifiers is derived. PMID- 20725482 TI - Optical neural network with bipolar neural states. AB - A method to achieve bipolar performance in a single-channel optical associative memory is presented. By coding the biased interconnection weights, a distributed background, and an input-dependent dynamic threshold on a single mask, we construct an optical network with both bipolar neural states and bipolar interconnections. Content addressability and other properties are improved by the introduction of a distributed background, as compared with the case in which this background is not used. Computer simulations and optical experiments are performed based on the Hopfield algorithm. PMID- 20725483 TI - Hologram record by means of film anisotropy photoinduction. AB - The diffraction efficiency of a hologram in crossed polarizers, recorded by means of photoinduction of the optical anisotropy in a film with a different orientation of the polarization planes of interfering plane waves, is studied. The dependence between the diffraction efficiency of the hologram and the angle of orientation against the optical axis of the analyzer is determined both theoretically and experimentally. The theoretical calculations are based on the assumption that the photoinduction of anisotropy is due to the formation of anisotropic grains following exposure to light and only the concentration of grains is a function of exposure. The experimental results, referring to azo-dye colored films, are in good agreement with the theoretical results of the given work. PMID- 20725484 TI - Measure of the diffraction efficiency of a holographic grating created by two Gaussian beams. AB - We present a methodology for analyzing the characteristics of a photosensitive material for holography. When two Gaussian beams of equal intensities are exactly superimposed on the recording material, the modulation of the interference pattern is equal to unity. When they are no longer exactly superimposed, this modulation varies from one to zero depending on the analyzed point. On the other hand, the modulation is constant in a direction that is perpendicular to the incident plane. Therefore it is possible to consider a complete analysis (point by point) of only one holographic grating to measure the diffraction efficiency eta at a given modulation versus exposure or for varying modulation (or beam ratio K) for a given exposure. We present the results that are obtained with an experimental setup that was devised for that purpose. From these measurements it was possible to extract various parameters such as refractive-index modulation of the photosensitive support. The tested recording materials consist of film of dichromated gelatin and films of dichromate polyvinyl alcohol. PMID- 20725485 TI - Method for reconstructing a hologram using a compact device. AB - A compact method for reconstructing a hologram is proposed in which the visible laser diode is used as a light source and the diffractive element is used to generate a collimated beam. The dependence of diffraction efficiency on the polarization of the beam is analyzed and the experiments with hologram reconstruction are reported. PMID- 20725486 TI - Compact holographic camera without vibration insulation using a 670-nm semiconductor laser. AB - A compact camera for holography and holographic interferometry is presented. Owing to its simple and rigid construction, vibration insulation is not necessary. The use of a semiconductor laser with a wavelength of 670 nm permits the use of common holographic recording materials. The only optical components of this camera are a beam splitter and a deflection mirror. As an example of the application of this camera, holographic surface contouring is demonstrated. PMID- 20725487 TI - Design of a modified uniform redundant-array mask for portable gamma cameras. AB - Uniform redundant-array masks have been reported as good lenses to form the image of gamma sources, with the correlation between the mask-aperture matrix and the shadows projected on a static position-sensitive detector. We present a modified uniform redundant-array configuration suitable for portable and small-size gamma cameras; its ability to reconstruct the image of several sources is analyzed. We have carried out a Montecarlo simulation of the gamma interactions in the mask, defining the expected response of the correlation process and comparing it with that achieved with the usual uniform redundant-array configurations. PMID- 20725488 TI - Imaging thermal objects with photon-counting detectors. AB - A photon-counting camera is used to generate images of thermal (blackbody) objects. Analytical estimates of the count rates that can be obtained for thermal objects in the 300-800-K temperature range are given for several different photocathode materials. Images generated with a photon-counting camera are compared with those obtained with infrared cameras that operate in the 3-5 and 8 12-microm ranges. It is found that high-resolution images of thermal objects can be generated with the photon-counting camera. The noise-equivalent differential temperature that can be obtained with a photon-counting camera is given as a function of the number of detected photoevents. Patternrecognition experiments that use low-light-level (quantum-limited) images of thermal objects are reported. In the experiments, photon-limited images of thermal objects are correlated with a reference function that is stored in computer memory. The number of detected photoevents required to reliablydistinguish between two thermal objects is determined and compared to the noise-equivalent differential temperature figure of merit. PMID- 20725489 TI - Spatial and temporal analysis of solid-state imaging systems. AB - Temporal and spatial properties of the image that is stored in the digital memory of a frame grabber through a solid-state image sensor, which employs the X-Y addressing method for scanning the image, are analyzed in the space-time domain by using the mathematical expression that we have obtained. This expression includes not only the static effects of the finite picture-cell size of the sensor and the image sampling in both the sensor and the grabber but also the dynamic effects of the temporal response of photoelectric conversion in the sensor, a one-dimensional electrical filter of the camera controller, and the asynchronous sampling with regard to time in both the sensor and the grabber. Results of the experiment and the numerical simulations based on the mathematical expression are presented for a time-varying one-dimensional object with good agreement. PMID- 20725490 TI - Real-time image processing using selective erasure in photorefractive two-wave mixing. AB - We describe a real-time image-processing scheme that uses selective erasure of spatial frequencies at the Fourier transform plane in an arrangement employing photorefractive two-beam coupling. The versatility of the device results from the use of the Fourier transform of the erasure beam, which counterpropagates to the image-bearing beam. The technique can perform spatial-filtering operations such as edge enhancement, bandpass filtering, and pattern recognition by controlling the information available at the erasure-beam Fourier plane. An experimental demonstration has been made on edge enhancement, bandpass filtering, and character recognition. PMID- 20725491 TI - Tutorial survey of composite filter designs for optical correlators. AB - A tutorial survey is presented of the many composite filter designs proposed for distortion-invariant optical pattern recognition. Remarks are made throughout regarding areas for further investigation. PMID- 20725492 TI - Analysis of DNA sequences by an optical time-integrating correlator. AB - The analysis of the molecular structure called DNA is of particular interest for the understanding of the basic processes governing life. Correlation techniques implemented on digital computers are currently used to do this analysis, but the process is so slow that the mapping and sequencing of the entire human genome requires a computational breakthrough. This paper presents a new method of performing the analysis of DNA sequences with an optical time-integrating correlator. The method is characterized by short processing times that make the analysis of the entire human genome a tractable enterprise. A processing strategy and the resultant processing times are presented. Experimental proofs of concept for the two types of analysis specified by the strategy are also included. PMID- 20725493 TI - Effects of thresholding in joint-transform correlation. AB - The joint-transform power spectrum of two identical objects can be represented as a one-dimensional sinusoidal grating modulated by a Fourier transform, and the correlation peaks can be regarded as the first-order diffraction of the grating. The peak intensity and the width are then determined by the aperture and the modulation of the grating. Based on this analysis, it is shown that dc blocking, hard clipping, or binarization of the power spectrum results in higher correlation peak intensity and a narrower peak width. Direct-current blocking is also found to be preferable if the input pattern to the correlator is corrupted by noise. PMID- 20725494 TI - Shift-and-scale-invariant pattern recognition using an elliptic coordinate transformed phase-only filter. AB - A shift-and-scale-invariant elliptic coordinate-transformed phase-only filter in proposed. The filter is built in three steps: the complex conjugate of a basic size target spectrum is calculated, its phase-only part is taken, and then the elliptic coordinate transformation is made. In the extreme case the scale ratio of recognizable objects equals 1:1.5, permitting good recognition of object sizes S within the range 0.83 10) for higher-order correlations typically require vast sample sizes. While multiple single-cell recordings become increasingly available, experimental approaches to investigate the role of higher-order correlations suffer from the limitations of available analysis techniques. We have recently presented a novel method for cumulant-based inference of higher order correlations (CuBIC) that detects correlations of higher order even from relatively short data stretches of length T = 10-100 s. CuBIC employs the compound Poisson process (CPP) as a statistical model for the population spike counts, and assumes spike trains to be stationary in the analyzed data stretch. In the present study, we describe a non-stationary version of the CPP by decoupling the correlation structure from the spiking intensity of the population. This allows us to adapt CuBIC to time-varying firing rates. Numerical simulations reveal that the adaptation corrects for false positive inference of correlations in data with pure rate co-variation, while allowing for temporal variations of the firing rates has a surprisingly small effect on CuBICs sensitivity for correlations. PMID- 20725511 TI - A personal view of the early development of computational neuroscience in the USA. AB - In the half-century since the seminal Hodgkin-Huxley papers were published, computational neuroscience has become an established discipline, evolving from computer modeling of neurons to attempts to understand the computational functions of the brain. Here, I narrate my experience of the early steps and sense of excitement in this field, with its promise of rapid development, paralleling that of computers. PMID- 20725512 TI - Design principles of sensory receptors. PMID- 20725513 TI - Do different neurons age differently? Direct genome-wide analysis of aging in single identified cholinergic neurons. AB - Aplysia californica is a powerful experimental system to study the entire scope of genomic and epigenomic regulation at the resolution of single functionally characterized neurons and is an emerging model in the neurobiology of aging. First, we have identified and cloned a number of evolutionarily conserved genes that are age-related, including components of apoptosis and chromatin remodeling. Second, we performed gene expression profiling of different identified cholinergic neurons between young and aged animals. Our initial analysis indicates that two cholinergic neurons (R2 and LPl1) revealed highly differential genome-wide changes following aging suggesting that on the molecular scale different neurons indeed age differently. Each of the neurons tested has a unique subset of genes differentially expressed in older animals, and the majority of differently expressed genes (including those related to apoptosis and Alzheimer's disease) are found in aging neurons of one but not another type. The performed analysis allows us to implicate (i) cell specific changes in histones, (ii) DNA methylation and (iii) regional relocation of RNAs as key processes underlying age related changes in neuronal functions and synaptic plasticity. These mechanisms can fine-tune the dynamics of long-term chromatin remodeling, or control weakening and the loss of synaptic connections in aging. At the same time our genomic tests revealed evolutionarily conserved gene clusters associated with aging (e.g., apoptosis-, telomere- and redox-dependent processes, insulin and estrogen signaling and water channels). PMID- 20725514 TI - The Nuclear Receptor PPARgamma as a Therapeutic Target for Cerebrovascular and Brain Dysfunction in Alzheimer's Disease. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (alpha, gamma, beta/delta), and synthetic ligands for PPARalpha (fibrates) and PPARgamma (Thiazolidinediones, TZDs) are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARgamma, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARgamma ligands in the treatment of brain disorders such as Alzheimer's disease (AD), leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARgamma agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials. PMID- 20725515 TI - Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. AB - Because regional blood flow increases in association with the increased metabolic demand generated by localized increases in neural activity, functional imaging researchers often assume that changes in blood flow are an accurate read-out of changes in underlying neural activity. An understanding of the mechanisms that link changes in neural activity to changes in blood flow is crucial for assessing the validity of this assumption, and for understanding the processes that can go wrong during disease states such as ischaemic stroke. Many studies have investigated the mechanisms of neurovascular regulation in arterioles but other evidence suggests that blood flow regulation can also occur in capillaries, because of the presence of contractile cells, pericytes, on the capillary wall. Here we review the evidence that pericytes can modulate capillary diameter in response to neuronal activity and assess the likely importance of neurovascular regulation at the capillary level for functional imaging experiments. We also discuss evidence suggesting that pericytes are particularly sensitive to damage during pathological insults such as ischaemia, Alzheimer's disease and diabetic retinopathy, and consider the potential impact that pericyte dysfunction might have on the development of therapeutic interventions and on the interpretation of functional imaging data in these disorders. PMID- 20725516 TI - From acoustic segmentation to language processing: evidence from optical imaging. AB - During language acquisition in infancy and when learning a foreign language, the segmentation of the auditory stream into words and phrases is a complex process. Intuitively, learners use "anchors" to segment the acoustic speech stream into meaningful units like words and phrases. Regularities on a segmental (e.g., phonological) or suprasegmental (e.g., prosodic) level can provide such anchors. Regarding the neuronal processing of these two kinds of linguistic cues a left hemispheric dominance for segmental and a right-hemispheric bias for suprasegmental information has been reported in adults. Though lateralization is common in a number of higher cognitive functions, its prominence in language may also be a key to understanding the rapid emergence of the language network in infants and the ease at which we master our language in adulthood. One question here is whether the hemispheric lateralization is driven by linguistic input per se or whether non-linguistic, especially acoustic factors, "guide" the lateralization process. Methodologically, functional magnetic resonance imaging provides unsurpassed anatomical detail for such an enquiry. However, instrumental noise, experimental constraints and interference with EEG assessment limit its applicability, pointedly in infants and also when investigating the link between auditory and linguistic processing. Optical methods have the potential to fill this gap. Here we review a number of recent studies using optical imaging to investigate hemispheric differences during segmentation and basic auditory feature analysis in language development. PMID- 20725517 TI - Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment? AB - Several epidemiological studies suggest that long-term use of non-steroidal anti inflammatory drugs (NSAIDs) may protect subjects carrying one or more epsilon4 allele of the apolipoprotein E (APOE epsilon4) against the onset of Alzheimer's disease (AD). The biological mechanism of this protection is not completely understood and may involve the anti-inflammatory properties of NSAIDs or their ability of interfering with the beta-amyloid (Abeta) cascade. Unfortunately, long term, placebo-controlled clinical trials with both non-selective and cyclooxygenase-2 (COX-2) selective inhibitors in mild-to-moderate AD patients produced negative results. A secondary prevention study with rofecoxib, a COX-2 selective inhibitor, in patients with mild cognitive impairment was also negative. A primary prevention study (ADAPT trial) of naproxen (a non-selective COX inhibitor) and celecoxib (a COX-2 selective inhibitor) in cognitively normal elderly subjects with a family history of AD was prematurely interrupted for safety reasons after a median period of treatment of 2 years. Although both drugs did not reduce the incidence of dementia after 2 years of treatment, a 4-year follow-up assessment surprisingly revealed that subjects previously exposed to naproxen were protected from the onset of AD by 67% compared to placebo. Thus, it could be hypothesized that the chronic use of NSAIDs may be beneficial only in the very early stages of the AD process in coincidence of initial Abeta deposition, microglia activation and consequent release of pro-inflammatory mediators. When the Abeta deposition process is already started, NSAIDs are no longer effective and may even be detrimental because of their inhibitory activity on chronically activated microglia that on long-term may mediate Abeta clearance. The research community should conduct long-term trials with NSAIDs in cognitively normal APOE epsilon4 carriers. PMID- 20725518 TI - Synapses, synaptic activity and intraneuronal abeta in Alzheimer's disease. AB - beta-Amyloid peptide accumulation plays a central role in the pathogenesis of Alzheimer's disease. Aberrant beta-amyloid buildup in the brain has been shown to be present both in the extracellular space and within neurons. Synapses are important targets of beta-amyloid, and alterations in synapses better correlate with cognitive impairment than amyloid plaques or neurofibrillary tangles. The link between beta-amyloid and synapses became even tighter when it was discovered that beta-amyloid accumulates within synapses and that synaptic activity modulates beta-amyloid secretion. Currently, a central question in Alzheimer's disease research is what role synaptic activity plays in the disease process, and how specifically beta-amyloid is involved in the synaptic dysfunction that characterizes the disease. PMID- 20725519 TI - Neurovascular Uncoupling: Much Ado about Nothing. PMID- 20725520 TI - On the evolution of calculation abilities. AB - Some numerical knowledge, such as the immediate recognition of small quantities, is observed in animals. The development of arithmetical abilities found in man's evolution as well as in child's development represents a long process following different stages. Arithmetical abilities are relatively recent in human history and are clearly related with counting, i.e., saying aloud a series of number words that correspond to a collection of objects. Counting probably began with finger sequencing, and that may explain the 10-base found in most numerical systems. From a neuropsychological perspective, there is a strong relationship between numerical knowledge and finger recognition, and both are impaired in cases of left posterior parietal damage (angular or Gerstmann's syndrome). Writing numbers appeared earlier in human history than written language. Positional digit value is clearly evident in Babylonians, and around 1,000 BC the zero was introduced. Contemporary neuroimaging techniques, specifically fMRI, have demonstrated that the left parietal lobe, particularly the intraparietal sulcus, is systematically activated during a diversity of tasks; other areas, particularly the frontal lobe, are also involved in processing numerical information and solving arithmetical problems. It can be conjectured that numerical abilities continue evolving due to advances in mathematical knowledge and the introduction of new technologies. PMID- 20725521 TI - Application of neuroanatomical ontologies for neuroimaging data annotation. AB - The annotation of functional neuroimaging results for data sharing and re-use is particularly challenging, due to the diversity of terminologies of neuroanatomical structures and cortical parcellation schemes. To address this challenge, we extended the Foundational Model of Anatomy Ontology (FMA) to include cytoarchitectural, Brodmann area labels, and a morphological cortical labeling scheme (e.g., the part of Brodmann area 6 in the left precentral gyrus). This representation was also used to augment the neuroanatomical axis of RadLex, the ontology for clinical imaging. The resulting neuroanatomical ontology contains explicit relationships indicating which brain regions are "part of" which other regions, across cytoarchitectural and morphological labeling schemas. We annotated a large functional neuroimaging dataset with terms from the ontology and applied a reasoning engine to analyze this dataset in conjunction with the ontology, and achieved successful inferences from the most specific level (e.g., how many subjects showed activation in a subpart of the middle frontal gyrus) to more general (how many activations were found in areas connected via a known white matter tract?). In summary, we have produced a neuroanatomical ontology that harmonizes several different terminologies of neuroanatomical structures and cortical parcellation schemes. This neuroanatomical ontology is publicly available as a view of FMA at the Bioportal website. The ontological encoding of anatomic knowledge can be exploited by computer reasoning engines to make inferences about neuroanatomical relationships described in imaging datasets using different terminologies. This approach could ultimately enable knowledge discovery from large, distributed fMRI studies or medical record mining. PMID- 20725522 TI - Spike timing-dependent plasticity as the origin of the formation of clustered synaptic efficacy engrams. AB - Synapse location, dendritic active properties and synaptic plasticity are all known to play some role in shaping the different input streams impinging onto a neuron. It remains unclear however, how the magnitude and spatial distribution of synaptic efficacies emerge from this interplay. Here, we investigate this interplay using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and spike timing-dependent plasticity (STDP). Specifically, we focus on the issue of how the efficacy of synapses contributed by different input streams are spatially represented in dendrites after STDP learning. We construct a simple feed forward network where a detailed model neuron receives synaptic inputs independently from multiple yet equally sized groups of afferent fibers with correlated activity, mimicking the spike activity from different neuronal populations encoding, for example, different sensory modalities. Interestingly, ensuing STDP learning, we observe that for all afferent groups, STDP leads to synaptic efficacies arranged into spatially segregated clusters effectively partitioning the dendritic tree. These segregated clusters possess a characteristic global organization in space, where they form a tessellation in which each group dominates mutually exclusive regions of the dendrite. Put simply, the dendritic imprint from different input streams left after STDP learning effectively forms what we term a "dendritic efficacy mosaic." Furthermore, we show how variations of the inputs and STDP rule affect such an organization. Our model suggests that STDP may be an important mechanism for creating a clustered plasticity engram, which shapes how different input streams are spatially represented in dendrite. PMID- 20725523 TI - Extending stability through hierarchical clusters in echo state networks. AB - Echo State Networks (ESN) are reservoir networks that satisfy well-established criteria for stability when constructed as feedforward networks. Recent evidence suggests that stability criteria are altered in the presence of reservoir substructures, such as clusters. Understanding how the reservoir architecture affects stability is thus important for the appropriate design of any ESN. To quantitatively determine the influence of the most relevant network parameters, we analyzed the impact of reservoir substructures on stability in hierarchically clustered ESNs, as they allow a smooth transition from highly structured to increasingly homogeneous reservoirs. Previous studies used the largest eigenvalue of the reservoir connectivity matrix (spectral radius) as a predictor for stable network dynamics. Here, we evaluate the impact of clusters, hierarchy and intercluster connectivity on the predictive power of the spectral radius for stability. Both hierarchy and low relative cluster sizes extend the range of spectral radius values, leading to stable networks, while increasing intercluster connectivity decreased maximal spectral radius. PMID- 20725524 TI - Brain specificity of diffuse optical imaging: improvements from superficial signal regression and tomography. AB - Functional near infrared spectroscopy (fNIRS) is a portable monitor of cerebral hemodynamics with wide clinical potential. However, in fNIRS, the vascular signal from the brain is often obscured by vascular signals present in the scalp and skull. In this paper, we evaluate two methods for improving in vivo data from adult human subjects through the use of high-density diffuse optical tomography (DOT). First, we test whether we can extend superficial regression methods (which utilize the multiple source-detector pair separations) from sparse optode arrays to application with DOT imaging arrays. In order to accomplish this goal, we modify the method to remove physiological artifacts from deeper sampling channels using an average of shallow measurements. Second, DOT provides three-dimensional image reconstructions and should explicitly separate different tissue layers. We test whether DOT's depth-sectioning can completely remove superficial physiological artifacts. Herein, we assess improvements in signal quality and reproducibility due to these methods using a well-characterized visual paradigm and our high-density DOT system. Both approaches remove noise from the data, resulting in cleaner imaging and more consistent hemodynamic responses. Additionally, the two methods act synergistically, with greater improvements when the approaches are used together. PMID- 20725525 TI - Temporal coding at the immature depolarizing GABAergic synapse. AB - In the developing hippocampus, GABA exerts depolarizing and excitatory actions and contributes to the generation of neuronal network driven giant depolarizing potentials (GDPs). Here, we studied spike time coding at immature GABAergic synapses and its impact on synchronization of the neuronal network during GDPs in the neonatal (postnatal days P2-6) rat hippocampal slices. Using extracellular recordings, we found that the delays of action potentials (APs) evoked by synaptic activation of GABA(A) receptors are long (mean, 65 ms) and variable (within a time window of 10-200 ms). During patch-clamp recordings, depolarizing GABAergic responses were mainly subthreshold and their amplification by persistent sodium conductance was required to trigger APs. AP delays at GABAergic synapses shortened and their variability reduced with an increase in intracellular chloride concentration during whole-cell recordings. Negative shift of the GABA reversal potential (E(GABA)) with low concentrations of bumetanide, or potentiation of GABA(A) receptors with diazepam reduced GDPs amplitude, desynchronized neuronal firing during GDPs and slowed down GDPs propagation. Partial blockade of GABA(A) receptors with bicuculline increased neuronal synchronization and accelerated GDPs propagation. We propose that spike timing at depolarizing GABA synapses is determined by intracellular chloride concentration. At physiological levels of intracellular chloride GABAergic depolarization does not reach the action potential threshold and amplification of GABAergic responses by non-inactivating sodium conductance is required for postsynaptic AP initiation. Slow and variable excitation at GABAergic synapse determines the level of neuronal synchrony and the rate of GDPs propagation in the developing hippocampus. PMID- 20725526 TI - Hundred Days of Cognitive Training Enhance Broad Cognitive Abilities in Adulthood: Findings from the COGITO Study. AB - We examined whether positive transfer of cognitive training, which so far has been observed for individual tests only, also generalizes to cognitive abilities, thereby carrying greater promise for improving everyday intellectual competence in adulthood and old age. In the COGITO Study, 101 younger and 103 older adults practiced six tests of perceptual speed (PS), three tests of working memory (WM), and three tests of episodic memory (EM) for over 100 daily 1-h sessions. Transfer assessment included multiple tests of PS, WM, EM, and reasoning. In both age groups, reliable positive transfer was found not only for individual tests but also for cognitive abilities, represented as latent factors. Furthermore, the pattern of correlations between latent change factors of practiced and latent change factors of transfer tasks indicates systematic relations at the level of broad abilities, making the interpretation of effects as resulting from unspecific increases in motivation or self-concept less likely. PMID- 20725528 TI - Electrophoretic Behavior of Anionic Triazine and PAMAM Dendrimers: Methods for Improving Resolution and Assessing Purity Using Capillary Electrophoresis. AB - The synthesis and characterization of second- and third-generation triazine dendrimers bearing carboxylic acid groups on the periphery are reported. These materials were synthesized by exhaustive succinylation of amine-terminated dendrimers. (1)H and (13)C NMR spectra are consistent with the desired products, but these techniques are limited by degeneracy in signals. MALDI-TOF mass spectrometry confirms the presence of the desired material. These materials display pH-dependent solubility in water. Capillary electrophoresis proves to be valuable in multiple elements of this work, and general protocols emerge that appear to be useful for the characterization of lower-generation anionic dendrimers. Specifically, capillary electrophoresis provides a convenient method for monitoring the removal of excess succinic anhydride/succinic acid and offers additional clues to the chemical nature of the impurities in these samples. Optimization of the background electrolyte and instrumental parameters allows for the assessment of the purity of these triazine targets as well as comparison with two sets of commercially available anionic poly(amidoamine) (PAMAM) dendrimers. Corroborative information from the different orthogonal analytical techniques employed supports the hypothesis that triazine dendrimers exist as very narrowly disperse mixtures of macromolecules approaching, in some cases, single chemical entities. PMID- 20725527 TI - Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults. AB - Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 +/- 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline. PMID- 20725529 TI - A deep-sea hydrothermal vent isolate, Pseudomonas aeruginosa CW961, requires thiosulfate for Cd tolerance and precipitation. AB - Pseudomonas aeruginosa CW961, an isolate from the vicinity of a deep-sea hydrothermal vent, grew in the presence of 5 mM Cd(2+) and removed Cd(2+) from solution. Sulfate was sufficient for growth when Cd(2+) was not present in the culture medium; however, thiosulfate was necessary for Cd(2+) precipitation and cell survival in the presence of Cd(2+). PMID- 20725531 TI - Simulations of Interacting Membranes in the Soft Confinement Regime. AB - The liquid crystalline model biomembrane system consisting of a stack of interacting membranes is studied in the realistic soft confinement regime by the newly developed Fourier Monte Carlo simulation technique. In this regime experiment and simulations show that the functional form of the fluctuation pressure is more nearly exponential rather than the power law valid for the hard confinement regime. The simulations provide quantitative improvement over perturbation theory. It is shown that the harmonic theory that is routinely used to interpret x-ray scattering line shapes is valid. PMID- 20725530 TI - Microfluidic Multicompartment Device for Neuroscience Research. AB - This paper describes and characterizes a novel microfabricated neuronal culture device. This device combines microfabrication, microfluidic, and surface micropatterning techniques to create a multicompartment neuronal culturing device that can be used in a number of neuroscience research applications. The device is fabricated in poly(dimethylsiloxane), PDMS, using soft lithography techniques. The PDMS device is placed on a tissue culture dish (polystyrene) or glass substrate, forming two compartments with volumes of less than 2 MUL each. These two compartments are separated by a physical barrier in which a number of micron size grooves are embedded to allow growth of neurites across the compartments while maintaining fluidic isolation. Cells are plated into the somal (cell body) compartment, and after 3-4 days, neurites extend into the neuritic compartment via the grooves. Viability of the neurons in the devices is between 50 and 70% after 7 days in culture; this is slightly lower than but comparable to values for a control grown on tissue culture dishes. Healthy neuron morphology is evident in both the devices and controls. We demonstrate the ability to use hydrostatic pressure to isolate insults to one compartment and, thus, expose localized areas of neurons to insults applied in soluble form. Due to the high resistance of the microgrooves for fluid transport, insults are contained in the neuritic compartment without appreciable leakage into the somal compartment for over 15 h. Finally, we demonstrate the use of polylysine patterning in combination with the microfabricated device to facilitate identification and visualization of neurons. The ability to direct sites of neuronal attachment and orientation of neurite outgrowth by micropatterning techniques, combined with fluidically isolated compartments within the culture area, offers significant advantages over standard open culture methods and other conventional methods for manipulating distinct neuronal microenvironments. PMID- 20725532 TI - Highly Articulated Robotic Probe for Minimally Invasive Surgery. AB - We have developed a novel highly articulated robotic probe (HARP) that can thread through tightly packed volumes without disturbing the surrounding tissues and organs. We use cardiac surgery as the focal application of this work. As such, we have designed the HARP to enter the pericardial cavity through a subxiphoid port. The surgeon can effectively reach remote intrapericardial locations on the epicardium and deliver therapeutic interventions under direct control. Our device differs from others in that we use conventional actuation and still have great maneuverability. We have performed proof-of-concept clinical experiments to give us preliminary validation of the ideas presented here. PMID- 20725533 TI - Distribution of Gb(3) Immunoreactivity in the Mouse Central Nervous System. AB - We have shown previously that neurons in the mouse spinal cord express Gb(3). We show in this article that distribution of anti-Gb(3)-Ab reactivity occurs in many different types of neurons of different areas of the central nervous system (CNS). The immunoreactive neurons are in olfactory bulbs, cerebral cortex, hippocampus, striatum, amygdala, thalamus, hypothalamus, cerebellum, and medulla oblongata. In several different circumventricular organs where vessels do not have the blood-brain-barrier (BBB) structure, anti-Gb(3)-Ab is not positive for vessel structures, while neurons at these regions are positive. Also, within the ventricular area, ependymal cells in the third ventricle express Gb(3), as revealed by anti-Gb(3)-Ab staining and intensity analysis. PMID- 20725534 TI - Resting-state functional connectivity differences in premature children. AB - We examine the coherence in the spontaneous brain activity of sleeping children as measured by the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals. The results are described in terms of resting state networks (RSN) and their properties. More specifically, in this study we examine the effect of severe prematurity on the spatial location of the visual, temporal, motor, basal ganglia, and the default mode networks, the temporal response properties of each of these networks, and the functional connectivity between them. Our results suggest that the anatomical locations of the RSNs are well developed by 18 months of age and their spatial locations are not distinguishable between premature and term born infants at 18 months or at 36 months, with the exception of small spatial differences noted in the basal ganglia area and the visual cortex. The two major differences between term and pre-term children were present at 36 but not 18 months and include: (1) increased spectral energy in the low frequency range (0.01-0.06 Hz) for pre-term children in the basal ganglia component, and (2) stronger connectivity between RSNs in term children. We speculate that children born very prematurely are vulnerable to injury resulting in weaker connectivity between resting-state networks by 36 months of age. Further work is required to determine whether this could be a clinically useful tool to identify children at risk of developmental delay related to premature birth. PMID- 20725537 TI - Treatment of large bulla formation after tattoo removal with a q-switched laser. AB - Widely considered the gold standard treatment option for tattoo removal, the use of Q-switched lasers may very rarely result in the formation of large bulla. While very disconcerting to patients, these lesions are easily managed and, with proper care, heal quickly with no long-term consequences. The authors present three cases of patients who had bullous reactions shortly after receiving Q switched laser treatment of tattoo ink. Bullous formation in all three patients was treated successfully. PMID- 20725535 TI - The role of airborne proteins in atopic dermatitis. AB - Atopic dermatitis is a common, chronic skin condition. A subpopulation of patients may have cutaneous exposure to common airborne proteins exacerbating their disease through direct proteolytic activity, direct activation of proteinase-activated receptor-2 itch receptors, and immunoglobulin E binding. The most common airborne proteins significant in atopic dermatitis include house dust mites, cockroach, pet dander, and multiple pollens. The literature on atopy patch testing, skin-prick testing, and specific IgE is mixed, with greater support for the use of atopy patch test. Patients with airborne proteins contributing to their disease typically have lesions predominately on air-exposed skin surfaces including the face, neck, and arms; a history of exacerbations after exposure to airborne proteins; severe disease resistant to conventional therapies; and concurrent asthma. Treatment strategies include airborne protein avoidance, removal of airborne proteins from the skin, and barrier repair. Further research is needed to establish the benefit of allergen-specific immunotherapy. PMID- 20725536 TI - Drug-provoked psoriasis: is it drug induced or drug aggravated?: understanding pathophysiology and clinical relevance. AB - Psoriasis is a commonly encountered dermatosis with a variety of internal and external paradoxical factors contributing to the clinical course of the disease. There are several drugs described in the literature that have been associated with the initiation, exacerbation, and aggravation of psoriasis. Understanding the pathophysiology can provide clues to treatment and management of drug-induced and drug-aggravated psoriasis, which may be indistinguishable from idiopathic psoriasis. The clinical manifestations of drug-associated psoriasis can range from plaque-type psoriasis to severe erythroderma, thus warranting astute and sustained clinical observation. PMID- 20725538 TI - Update on fractional laser technology. PMID- 20725539 TI - How Clinically Relevant is Dapsone-related Peripheral Neuropathy?: An Overview of Available Data with Emphasis on Clinical Recognition. PMID- 20725540 TI - Pregnancy is Not Detrimental to the Melanoma Patient with Clinically Localized Disease. AB - OBJECTIVE: There exists a strong belief among physicians and the lay public that pregnancy adversely affects survival in patients with melanoma. The authors asked if there was any evidence to support this in patients with clinically localized disease. METHODS: The authors reviewed the published literature on MEDLINE. RESULTS: The authors found no compelling evidence in the literature that pregnancy has a negative impact on survival in patients with clinically localized cutaneous melanoma. Two recent population-based studies reported no negative impact of pregnancy on survival when pregnant melanoma patients were compared to nonpregnant gender-matched controls. A small increased risk of cause-specific death was noted in a recent population-based study, though this effect was small (HR, 1.52, p=0.47) and pregnant patients were more likely to have axial primary sites, which are associated with a poorer outcome. CONCLUSION: There is no compelling evidence that pregnancy adversely affects outcome in melanoma patients who have clinically localized disease. Continuing to recommend a delay in childbearing for these patients is not supported by the published medical literature. PMID- 20725541 TI - The use of a contact cooling device to reduce pain and ecchymosis associated with dermal filler injections. AB - Objectives. Consensus guidelines developed for the use of hyaluronic acid dermal fillers describe the use of cooling the skin to reduce patient discomfort during injection. The vasoconstrictive effects of cold may provide reduced ecchymosis and swelling at the site. However, the effect of applying ice or cooled air is unpredictable because these modalities do not deliver precise temperature, which may result in cold burn or insufficient effect to targeted areas. This open label, randomized, single-blinded, split-face trial was conducted to measure the extent to which applying a spot cooling device reduces patient discomfort and ecchymoses in the clinical setting in patients undergoing a dermal filler procedure. Subjects. Twenty male and female subjects of any race, ages 35 to 65 years, with moderate and severe nasolabial folds were included in this study. Seven (35%) subjects had received previous small gel particle hyaluronic acid injections. Methods. Prior to injection, the topical cooling system was set at 35 degrees F and a cooled applicator was applied for 20 seconds on one nasolabial fold. A control using a noncooled applicator was applied for 20 seconds on the other nasolabial fold. Postprocedure ice packs were prohibited so as not to confound the subject's perception of procedure-related pain. Subjects (using visual analog pain scales) and blinded investigators rated pain and ecchymosis using predetermined scales and satisfaction surveys. Results. Use of the cooling system was associated with mean pain reduction of 61, 70, and 42 percent compared to control, as measured by visual analog pain scales, immediately following and one hour and three hours post small gel particle hyaluronic acid injection. Additionally, use of the cooling system was associated with mean ecchymosis reduction of 88, 89, 80, and 66 percent compared to control immediately following injection, one hour, three hours, and next-day postinjection. Conclusion. The cooling system provided adequate pain management (both subjectively and objectively through blinded evaluations) during and after small gel particle hyaluronic acid dermal filler injections for the correction of moderate nasolabial folds. Furthermore, results demonstrate that the cooling system is associated with decreased ecchymosis. Future studies are needed comparing the use of topical anesthetics to a cooling system for the reduction of pain and ecchymosis associated with the use of dermal filler injections. PMID- 20725542 TI - Topical botulinum toxin. AB - Nanotechnology is a rapidly growing discipline that capitalizes on the unique properties of matter engineered on the nanoscale. Vehicles incorporating nanotechnology have led to great strides in drug delivery, allowing for increased active ingredient stability, bioavailability, and site-specific targeting. Botulinum toxin has historically been used for the correction of neurological and neuromuscular disorders, such as torticollis, blepharospasm, and strabismus. Recent dermatological indications have been for the management of axillary hyperhydrosis and facial rhytides. Traditional methods of botulinum toxin delivery have been needle-based. These have been associated with increased pain and cost. Newer methods of botulinum toxin formulation have yielded topical preparations that are bioactive in small pilot clinical studies. While there are some risks associated with topical delivery, the refinement and standardization of delivery systems and techniques for the topical administration of botulinum toxin using nanotechnology is anticipated in the near future. PMID- 20725543 TI - 5-Aminolevulinic Acid-based Photodynamic Intense Pulsed Light Therapy Shows Better Effects in the Treatment of Skin Photoaging in Asian Skin: A Prospective, Single-blinded, Controlled Trial. AB - OBJECTIVE: To investigate the effects of photodynamic intense pulsed light therapy on skin photoaging in Asian skin. METHODS: This was a prospective, single blinded, controlled, clinical trial with 40 patients enrolled. The enrolled patients applied 5% 5-aminolevulinic acid on the left side of the face while a placebo was applied on the right side of the face. After a one-hour incubation, the patients received intense pulsed light therapy. After four treatment cycles, the pH values, transepidermal water loss of the dermis of the forehead and canthus skin, as well as the moisture capacity of stratum corneum and the global score of photoaging were assessed. RESULTS: The pH value of forehead and canthus skin, moisture capacity of stratum corneum, and the dermis of forehead and canthus skin of the photodynamic intense pulsed light therapy treated sides were significantly higher than those of the control sides in all of the patients. The photoaging score decreased after the therapy on both sides, with the photodynamic intense pulsed light therapy treated sides decreasing more than the control sides (P<0.01). CONCLUSION: 5-aminolevulinic acid photodynamic intense pulsed light therapy showed better effects in the treatment of skin photoaging compared to intense pulsed light therapy alone. PMID- 20725544 TI - Changes in skin cancer management : a personal perspective. PMID- 20725545 TI - A review of acne in ethnic skin: pathogenesis, clinical manifestations, and management strategies. AB - Acne vulgaris is one of the most common conditions for which all patients, including those with skin of color (Fitzpatrick skin types IV-VI), seek dermatological care. The multifactorial pathogenesis of acne appears to be the same in ethnic patients as in Caucasians. However, there is controversy over whether certain skin biology characteristics, such as sebum production, differ in ethnic patients. Clinically, acne lesions can appear the same as those seen in Caucasians; however, histologically, all types of acne lesions in African Americans can be associated with intense inflammation including comedones, which can also have some degree of inflammation. It is the sequelae of the disease that are the distinguishing characteristics of acne in skin of color, namely postinflammatory hyperpigmentation and keloidal or hypertrophic scarring. Although the medical and surgical treatment options are the same, it is these features that should be kept in mind when designing a treatment regimen for acne in skin of color. PMID- 20725546 TI - Management of high-risk cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma is an increasing public health concern, representing the second most common cancer in the United States. High-risk cutaneous squamous cell carcinoma represents a subgroup of this disease, where patients are at higher risk of metastasis and death. To date, there are no accepted criteria for defining or managing these patients. This review discusses the current state of knowledge of high-risk cutaneous squamous cell carcinoma and outlines reasonable management strategies based on available data. PMID- 20725547 TI - The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know? PMID- 20725549 TI - Three-dimensional, Full-sized, Silicone-based, Facial Replicas for Teaching Outcome Measures in Acne. AB - BACKGROUND: The scientific integrity of outcome measurements is dependent upon reproducibility and accuracy. In acne assessments, there is no current gold standard for accuracy in lesion counting and global grading. PURPOSE: The purpose of this study was to create facial acne replicas for use in acne training and for evaluation of rater accuracy. METHODS: Two full-sized, three-dimensional, silicone-based, facial replicas with predetermined acne lesion type and number were created. Their teaching value was evaluated by dermatologists and clinical coordinators undergoing training in acne evaluations. A questionnaire after the training session addressed realism, preferences, and ease of assessments with the facial replicas compared to live subjects. RESULTS: Of 55 potential respondents, 32 questionnaires were completed and analyzable. Of these, 23 were from dermatologists and nine were from clinical research coordinators performing acne assessments. The facial replicas were considered sufficiently realistic for acne lesion counting by 91 percent (29/32) and for global grading by 94 percent (30/32). Of these, 66 percent preferred to have both real subjects and replicas for training (21/32), 31 percent preferred real subjects only (9/32), and one preferred replicas only. Replicas were considered easier to evaluate for noninflammatory and inflammatory lesions (p=0.002 and p=0.013, respectively) and equivalent to live models for global grading (p=0.001). LIMITATIONS: Shortcomings include the limited spectrum of acne that could be represented due to production of only two prototypes, the relative paucity of secondary lesions, and production time and cost. CONCLUSION: These facial replicas provide a realistic and practical method for teaching and evaluating raters in acne outcome measures as they provide a gold standard for acne lesion counts. Furthermore, their use may obviate some of the shortcomings inherent in recruitment of human acne volunteers for acne training sessions. PMID- 20725550 TI - Actinic keratosis treatment as a key component of preventive strategies for nonmelanoma skin cancer. AB - Actinic keratosis is responsible for more than eight million visits to dermatologists and primary care physicians annually. Actinic keratosis, the result of chronic sun damage to the skin, is closely linked to nonmelanoma skin cancer, both histologically and pathophysiologically. Clinical evidence shows that not only does actinic keratosis have the potential to progress and transform into nonmelanoma skin cancer, but it also may in fact be an early stage of cancer. The treatment of actinic keratosis is evolving from a "treat-as-you-go" strategy to a more preventive approach to curtail the potential emergence of nonmelanoma skin cancer. As the interrelationship between actinic keratosis and nonmelanoma skin cancer, squamous cell carcinoma, and basal cell carcinoma continues to strengthen, treating actinic keratosis as part of a preventive strategy to reduce nonmelanoma skin cancer is coming to the forefront. The following review of the relationship between actinic keratosis and nonmelanoma skin cancer discusses the rationale for early actinic keratosis treatment to prevent or reduce nonmelanoma skin cancer occurrence. PMID- 20725551 TI - Nitric oxide nanoparticle technology: a novel antimicrobial agent in the context of current treatment of skin and soft tissue infection. AB - Staphylococcus aureus infections account for the majority of skin and soft tissue infections in the United States. Staphylococcus aureus is rapidly evolving resistance to contemporary topical as well as systemic antibiotics. Alternatives to current treatment options for skin and soft tissue infections are needed for more effective treatment now and in the future. Nitric oxide's proven roles in both wound repair and as an antimicrobial agent make it an excellent candidate for the treatment of skin infections. Recent attempts at novel nitric oxide therapies, in the form of nitric oxide donors, have shown limited potential in treating cutaneous infection. However, more recent developments in nitric oxide delivery, using nitric oxide nanoparticle technology, demonstrate substantial promise in the promotion of wound repair and eradication of skin and soft tissue infections. PMID- 20725552 TI - Inverse papular acrokeratosis of oswaldo costa: a case report. AB - Acrokeratoelastoidosis of Oswaldo Costa, or inverse papular acrokeratosis, is a rare genodermatosis first described in 1952 by Oswaldo Costa, a Brazilian dermatologist. It is characterized by flesh-colored papules on the lateral aspects of the palms and soles and dorsum of hands. The histological features are hyperkeratosis, hyalinized and homogenous collagen, and a decrease in and fragmentation of the elastic fibers (elastorrhexis). In the absence of elastic fiber fragmentation, a similar clinical presentation is diagnosed as focal acral hyperkeratosis. Many cases of inverse papular acrokeratosis of Oswaldo Costa may have been considered focal acral hyperkeratosis since it can be difficult to find the elastorrhexis. The authors report a case of a 51-year-old woman with inverse papular acrokeratosis of Oswaldo Costa with poor response to topical treatments. PMID- 20725548 TI - Nonsurgical innovations in the treatment of nonmelanoma skin cancer. AB - Basal cell carcinoma and squamous cell carcinoma are the most frequent types of cancer in the United States and represent 75 percent and 20 percent, respectively, of all nonmelanoma skin cancers. Since ultraviolet radiation is implicated in their development, photoprotection is fundamental in their prevention. Additional preventive measures include identifying high-risk individuals for early detection along with using agents, such as retinoids, that are effective in decreasing the risk of premalignant cells further developing into carcinomas. Newer agents achieving this goal include perillyl alcohol, T4 endonuclease 5, DL-alpha-tocopherol, and alpha-difluoromethylornithine. Procedural modalities are currently the standard of treatment, but recent evidence has consistently shown that newer (nonsurgical) therapies, such as interferon, imiquimod, retinoids, and 5-fluorouracil, can be used effectively either as monotherapies or as adjuvants to those surgical modalities for the treatment of superficial nonmelanoma skin cancers and premalignant lesions. These newer therapies have achieved significant reductions in morbidity and mortality. Procedural modalities that have been evolving into important tools for the treatment of actinic keratosis and nonmelanoma skin cancers include photodynamic therapy and lasers. Nonsurgical therapies currently proving to be effective in clinical trials include ingenol mebutate and cyclooxygenase-2 inhibitors. Agents that are showing promising results in early phases of clinical trials include betulinic acid; hedgehog signaling pathway inhibitors, such as cyclopamine and GDC-0449; alpha-melanocyte-stimulating hormone analogs, such as afamelanotide; epidermal growth factor receptor inhibitors, such as gefitinib and erlotinib; anti-epidermal growth factor receptor monoclonal antibodies, such as cetuximab and panitumumab; and the 5-fluorouracil prodrug capecitabine. PMID- 20725553 TI - Paraffin Granulomata, "Witch's Chin," and Nasal Deformities: Excision and Reconstruction with Reduction Chinplasty and Open Rhinotomy Resection. AB - A 57-year-old Filipino woman had paraffin materials placed in her nose, chin, and cheeks approximately 15 years prior to consultation. Progressive enlargement of the chin had occurred, simulating a witch's chin deformity, with a lesser degree of the distal nose and columellar area. Restoration of a relatively normal chin contour was accomplished by using tumescent bi-level anesthesia, mobilizing the protuberant tissues, hemi-ressecting the excess skin, and sculpting the subjacent tissue to an appropriate degree. The nose was then entered at the columellar junction with the upper lip, an open rhinotomy was accomplished, the supra cartilaginous fibrous tissue was serially ressected to reform the profile, the cartilage was replaced to narrow the nasal configuration, and the nose structure was then replaced. Cosmetic improvement was significant. PMID- 20725554 TI - Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. AB - Postinflammatory hyperpigmentation is a common sequelae of inflammatory dermatoses that tends to affect darker skinned patients with greater frequency and severity. Epidemiological studies show that dyschromias, including postinflammatory hyperpigmentation, are among the most common reasons darker racial/ethnic groups seek the care of a dermatologist. The treatment of postinflammatory hyperpigmentation should be started early to help hasten its resolution and begins with management of the initial inflammatory condition. First-line therapy typically consists of topical depigmenting agents in addition to photoprotection including a sunscreen. Topical tyrosinase inhibitors, such as hydroquinone, azelaic acid, kojic acid, arbutin, and certain licorice extracts, can effectively lighten areas of hypermelanosis. Other depigmenting agents include retinoids, mequinol, ascorbic acid, niacinamide, N-acetyl glucosamine, and soy with a number of emerging therapies on the horizon. Topical therapy is typically effective for epidermal postinflammatory hyperpigmentation; however, certain procedures, such as chemical peeling and laser therapy, may help treat recalcitrant hyperpigmentation. It is also important to use caution with all of the above treatments to prevent irritation and worsening of postinflammatory hyperpigmentation. PMID- 20725555 TI - Evidence and considerations in the application of chemical peels in skin disorders and aesthetic resurfacing. AB - Chemical peeling is a popular, relatively inexpensive, and generally safe method for treatment of some skin disorders and to refresh and rejuvenate skin. This article focuses on chemical peels and their use in routine clinical practice. Chemical peels are classified by the depth of action into superficial, medium, and deep peels. The depth of the peel is correlated with clinical changes, with the greatest change achieved by deep peels. However, the depth is also associated with longer healing times and the potential for complications. A wide variety of peels are available, utilizing various topical agents and concentrations, including a recent salicylic acid derivative, beta-lipohydroxy acid, which has properties that may expand the clinical use of peels. Superficial peels, penetrating only the epidermis, can be used to enhance treatment for a variety of conditions, including acne, melasma, dyschromias, photodamage, and actinic keratoses. Medium-depth peels, penetrating to the papillary dermis, may be used for dyschromia, multiple solar keratoses, superficial scars, and pigmentary disorders. Deep peels, affecting reticular dermis, may be used for severe photoaging, deep wrinkles, or scars. Peels can be combined with other in-office facial resurfacing techniques to optimize outcomes and enhance patient satisfaction and allow clinicians to tailor the treatment to individual patient needs. Successful outcomes are based on a careful patient selection as well as appropriate use of specific peeling agents. Used properly, the chemical peel has the potential to fill an important therapeutic need in the dermatologist's and plastic surgeon's armamentarium. PMID- 20725556 TI - Erythropoietic protoporphyria: a case report and literature review. AB - Erythropoietic protoporphyria is considered a rare disease overall, but in children is the most common form of porphyria, and certainly the most common type of erythropoietic porphyria. Despite this fact, erythropoietic protoporphyria is a disease that has been known to evade or at least delay diagnosis, leading to unnecessary suffering by the patient. Given the distress it may cause a patient and his or her family as well as the potential complications of this disease, the importance of maintaining a heightened awareness when presented with a child complaining of photosensitivity cannot be overstated. This case report will review the important clinical indicators, pathogenesis, histology, diagnosis, management, and treatment of this disease, so that affected children will no longer have to play "hide and seek" when diagnosed with this sun-sensitive disease. PMID- 20725557 TI - Overcoming the Barrier Treatment of Ichthyosis: A Combination-therapy Approach. AB - Ichthyosis vulgaris is an inherited disorder of keratinization that results in asteatotic scales on extensor surfaces of the arm, legs, and trunk. A combination therapy approach with a physiological lipid-based barrier repair topical emulsion and ammonium lactate 12% lotion applied topically was shown to be effective at four-week follow up without any untoward side effects. This combination therapy addresses the importance of caring for both the corneocytes ("bricks") and the intercellular lipid bilayer ("mortar") for optimal benefit. PMID- 20725558 TI - Multiple eruptive keratoacanthomas arising in a tattoo. AB - Keratoacanthomas are rapidly growing, keratinizing, epithelial neoplasms that tend to spontaneously involute and are rarely multiple or eruptive. There is still disagreement on whether or not this condition is a malignancy or a benign epidermal neoplasm; nevertheless, its appearance on tattoos has been reported in rare instances. When waiting for spontaneous involution is not an option, surgery is the preferred treatment. Other therapeutic modalities used for the treatment of this condition include radiotherapy; cryotherapy; laser therapy; and multiple intralesional, topical, and systemic agents. The authors report a patient who developed multiple, eruptive keratoacanthomas in the red ink portions of a tattoo and was successfully treated with acitretin. PMID- 20725559 TI - Gougerot-Carteaud Syndrome Treated with 13-cis-retinoic Acid. AB - A 15-year-old Caucasian boy with a diagnosis of confluent and reticulated papillomatosis who had received numerous treatments with minimal responses cleared with a 20-week course of 13-cis-retinoic acid and has remained in remission. It is important to consider the use of oral retinoids in the treatment of this stubborn, unsightly, and psychologically upsetting disease. PMID- 20725561 TI - Clinical performance of a dermal filler containing natural glycolic Acid and a polylactic Acid polymer: results of a clinical trial in human immunodeficiency virus subjects with facial lipoatrophy. AB - Lipoatrophy is a condition that affects certain individuals, most commonly those who are infected with the human immunodeficiency virus.(1-3) Injectable fillers are used for the treatment of these dermal contour deformities to smooth dermal depressions formed by the loss of volume. These dermal fillers (also known as soft tissue augmentation devices) can correct contour deformities caused by lipoatrophy in patients who are human immunodeficiency virus positive or negative. The product used in this study is a patented, second-generation, injectable, dermal collagen stimulator that combines glycolic acid and polylactic acid. The glycolic acid used is not a polymer, but rather an acid derived from sugar cane. Its chemical structure corresponds to that of an alpha-hydroxy acid. Glycolic acid is a well-characterized agent that is present in a number of cosmetic products. Polylactic acid is a synthetic, biocompatible, biodegradable, inert, synthetic polymer from the poly a-hydroxy-acid family that is believed to stimulate fibroblasts to produce more collagen, thus increasing facial volume. Together, polylactic acid and glycolic acid act in concert to 1) stimulate collagen production and 2) hydrate the outer layers of the skin. A multicenter, clinical investigation authorized by the Mexican Secretariat of Health was conducted between September 20, 2002, and September 19, 2004. This clinical study was conducted in male patients between 32 and 60 years of age with lipoatrophy as a result of highly active antiretroviral therapy for human immunodeficiency virus infection. The study objective was to measure the improvement of contour deformities after the injection of a dermal collagen stimulator containing glycolic acid and polylactic acid. In addition to safety, this dermal filler was assessed when used to correct volume deformities caused by lipoatrophy in subjects who are human immunodeficiency virus positive. Thirty male subjects participated and were treated as follows: seven in two sessions, eight in three sessions, 14 in four sessions, and one in five sessions. Each treatment session was separated by approximately 20 days as per the manufacturer's instructions. The follow-up phase consisted of four observation periods over two years from the last injection. The primary efficacy endpoint was measurement of correction of human immunodeficiency virus highly active antiretroviral therapy induced facial lipoatrophy. Using a multipoint scale of facial divergence, correction was measured as a percentage of correction (diversion correction percentage) from baseline. A secondary endpoint was safety based upon the incidence and type of adverse events experienced. All 30 patients completed the active treatment phase with 100 percent (N=30) undergoing at least two treatments at Days 1 and 20 after entry into study. Seventy-four percent (n=23) underwent a third treatment at Day 60, and 50 percent (n=15) received a fourth treatment at Day 80. A single subject received a fifth treatment at Day 100. There were no serious adverse events and no adverse events noted during the study period. Histology through skin biopsy (2mm punch) was performed on 10 subjects, and all subjects had dermal skin thickness measured with ultrasound. Histology demonstrated a foreign body reaction with multinucleated giant cells with phagocytized lactate crystals. New collagen formation was demonstrated. United States measurements of dermal skin thickness increase ranged from 0.22cm to 0.37cm. All subjects were rated for expected injection events to include erythema, edema, ecchymosis, and hematoma. This dermal collagen stimulator containing glycolic acid and polylactic acid represents a tangible alternative in therapeutic and aesthetic medicine. More than four years of clinical trials have demonstrated that this dermal collagen stimulator helps to improve the exterior quality of the skin while restoring lost facial volumes. Patient satisfaction was high due to its effectiveness and long lasting results, which in some cases have lasted more than two years. PMID- 20725562 TI - Low-energy intense pulsed light for hair removal at home. AB - Low-energy intense pulsed light for hair removal at home was evaluated in this clinical trial. Twenty-two female patients were enrolled into an institutional review board-approved clinical trial. Patients received six biweekly treatments with the device, and clinical results with hair counts and pictures were performed at four weeks and three months following the last treatment. Ninety five percent of the patients noted hair count reduction at the end of this clinical trial. Overall hair reduction was 78 percent at the one-month follow up and 72 percent at the three-month follow up. No serious adverse events were noted. This clinical trial confirmed the safety and efficacy of this device for hair removal at home. PMID- 20725560 TI - How much do we really know about our favorite cosmeceutical ingredients? AB - To date, we are unaware of a review that has investigated common cosmeceutical ingredients in order to answer the three specific questions proposed by the father of cosmeceuticals, Dr. Albert Kligman. It is the goal of this review to gather all the published scientific data on five common cosmeceutical ingredients, answer the three major questions about the scientific rationale for their use, and ascertain how much we really know about consumers' favorite cosmeceutical ingredients.Most of the research concerning cosmeceutical retinoid ingredients is based upon the effects of retinoic acid on the skin. Clinical trials concerning retinol and retinaldehyde are scant and lacking in statistical evaluation for significance. There is research substantiating the effects of kinetin in plants and also in-vitro antioxidant effects. However, proof of anti aging activity remains elusive, and the clinical efficacy of kinetin is based on limited data. Niacinamide is the ingredient investigated that most closely upholds the "Kligman standards" of cosmeceutical-ingredient analysis. With the available scientific evidence on topical niacinamide, clinicians are able to adequately answer questions about permeability, mechanism, and clinical effect. Both green tea and soy have been popularized commercially based on their antioxidant effects, yet there is a paucity of clinical studies concerning their efficacy as topical anti-aging agents. It may be that soy and green tea are better at preventing the signs and symptoms of skin aging than actually reversing them. Since cosmeceutical products are claiming to therapeutically affect the structure and function of the skin, it is rational and necessary to hold them to specified scientific standards that substantiate efficacy claims. PMID- 20725563 TI - Allergy to a hot tub water treatment chemical: an unexpectedly common cause of generalized dermatitis in men. PMID- 20725564 TI - Laser safety guidelines. PMID- 20725566 TI - Physician and Patient Assessment of Triamcinolone Acetonide Spray for Steroid responsive Dermatoses. AB - OBJECTIVE: To assess the clinical outcomes of triamcinolone acetonide spray for steroid-responsive dermatoses using investigator and patient global assessment scores and evaluate patient satisfaction. DESIGN: This open-label, single-center, noncomparator study enrolled 42 patients (aged 18 years or older) with dermatoses. Patients were instructed to use triamcinolone acetonide spray 1 to 4 times daily, depending on investigator instructions, for up to 28 days. MEASUREMENTS: Investigators and patients scored the overall severity of dermatoses based on a global assessment scale. Investigators also rated signs and symptoms of dermatoses and evaluated clinical outcomes based on an improvement assessment scale. Patient satisfaction with treatment was assessed at the end of treatment or at Day 28 using a questionnaire. Patients were evaluated on Days 7, 14, 21, and 28. Complete clearing of dermatoses warranted early discontinuation from the study. RESULTS: Triamcinolone acetonide spray effectively improved dermatoses scores, clinical outcomes, and signs and symptoms of dermatoses. More than 80 percent of patients entered the study with moderate or severe dermatoses. Within 14 days, none had severe dermatoses, and by 28 days, 64 percent of patients were completely clear or almost clear. From the patient perspective, 51.3 percent experienced improvement in only three days, and 84.6 percent experienced improvement in seven days. An overwhelming number of patients (95%) preferred triamcinolone acetonide spray over creams and ointments, and more than half experienced a cooling effect upon contact with the spray. CONCLUSION: Triamcinolone acetonide spray is an effective topical corticosteroid that should be considered for patients with steroid-responsive dermatoses of all ranges of severity. PMID- 20725567 TI - Severe Acute Local Reactions to a Hyaluronic Acid-derived Dermal Filler. AB - Injectable fillers are normally well tolerated by patients with little or no adverse effects. The most common side effects include swelling, redness, bruising, and pain at the injection site. This report describes three cases in which patients injected with a hyaluronic acid-derived injectable filler that is premixed with lidocaine developed adverse reactions including persistent swelling, pain, and nodule formation. Two of the three patients' abscesses were cultured for aerobic and anaerobic bacteria and mycobacterium. All three cultures were negative. Abscess persistence in all cases necessitated physical removal and/or enzymatic degradation with hyaluronidase. The effects subsided only after the product had been removed. Two of these patients were subsequently treated with other hyaluronic acid-derived dermal fillers without adverse events. PMID- 20725565 TI - Innovative therapies in the treatment of keloids and hypertrophic scars. AB - Keloids and hypertrophic scars are benign fibrous overgrowths of scar tissue, which results from an abnormal response to trauma. Several therapeutic modalities have been described for the treatment and prevention of these conditions, but the optimal management approach has not yet been defined. This article reviews the most recent, innovative, therapeutic strategies for the management of hypertrophic scars and keloids, including mitomycin-C, tamoxifen citrate, methotrexate, imidazolaquinolines, retinoids, calcineurin inhibitors, phenylakylamine calcium channel blockers, botulinum toxin, vascular endothelial growth factor inhibitors, hepatocyte growth factor, basic fibroblast growth factor, interleukin-10, manosa-6-phosphate, transforming growth factor beta, antihistamines, and prostaglandin E2. No consensus in treatment regimens has been reached due to the limited evidence-based information found in the literature. Most therapeutic options have potential effectiveness as both monotherapy and as combination therapy. However, recent reports offer novel modalities that may approach scarring from different angles. PMID- 20725568 TI - Update on tissue tightening. AB - A variety of medical devices are described under the heading of tissue tightening devices. This article reviews the tissue tightening devices currently available in the United States and some that may receive clearance in the upcoming year. These include the various radiofrequency devices as well as the pulsed light devices that achieve similar end results. The one noticeable factor seen with this group of devices is the paucity of large, clinical, controlled trials that appear in the medical literature for this group of medical devices as a whole. PMID- 20725569 TI - Toothpaste allergy diagnosis and management. PMID- 20725570 TI - Cutaneous tuberculosis: a practical case report and review for the dermatologist. AB - Cutaneous tuberculosis occurs rarely, despite a high and increasing prevalence of tuberculosis worldwide. Mycobacterium tuberculosis, Mycobacterrium bovis, and the Bacille Calmette-Guerin vaccine can cause tuberculosis involving the skin. Cutaneous tuberculosis can be acquired exogenously or endogenously and present as a multitude of differing clinical morphologies. Diagnosis of these lesions can be difficult, as they resemble many other dermatological conditions that are often primarily considered. Further, microbiological confirmation is poor, despite scientific advances, such as the more frequent use of polymerase chain reaction. The authors report a case that illustrates the challenges faced by dermatologists when considering a diagnosis of cutaneous tuberculosis. PMID- 20725571 TI - Epidermoid cyst mimicry: report of seven cases and review of the literature. AB - Cysts are entities encountered frequently in dermatological clinics. Various types of cysts have been described and include trichilemmal cysts, epidermoid cysts, steatocystomas, and the myriad of developmental cysts (branchial cleft cyst, thyroglossal duct cysts, bronchogenic cysts). Moreover, not all lesions that appear clinically as cystic structures are, in fact, cysts. Increased awareness of these mimickers and a systematic approach to the evaluation of these cases is essential. The authors report seven cases, over the course of six years, presenting to their dermatology department, all of which were originally clinically diagnosed as "cysts" and referred to the authors for management. In this article, the authors review seven cyst mimickers and describe important aspects of these diagnoses to increase awareness of the importance of a preoperative biopsy and evaluation. It is important to have a thorough understanding of the wide differential diagnosis of cutaneous nodules and to consider other causes of lesions that appear to be cysts, particularly in the anatomical locations described. PMID- 20725572 TI - Skin cancer in asians: part 2: melanoma. AB - The Asian population in the United States is expected to increase in the next 50 years. Concurrently, there is an overall rise in the incidence of melanoma. It is therefore crucial to obtain a better understanding of this deadly skin cancer in this minority population, as little information is currently available and prognosis remains poor. Through a review of the literature, this paper explores melanoma in the Asian population, including the most common subtype encountered, prognosis, theories on pathogenesis, and molecular biology. PMID- 20725573 TI - Diphenhydramine as an alternative local anesthetic agent. AB - Patients who present with a history of "allergy" to local anesthetics are common in clinical practice. Injectable 1% diphenhydramine is a safe, inexpensive, and effective local anesthetic for simple dermatological procedures in patients who report "caine" allergies. Utilizing this agent permits the dermatologist to operate at the time of the initial visit and schedule a referral to the allergist for definitive sensitivity testing at the patient's convenience. PMID- 20725574 TI - A case of hermansky-pudlak syndrome with pulmonary sarcoidosis. AB - Hermansky-Pudlak syndrome is an autosomal recessive disorder of lysosomal storage characterized by the triad of occulocutaneous albinism, bleeding diathesis, and pulmonary fibrosis. Sarcoidosis is a disease characterized by the development of noncaseating granulomas, most commonly affecting the lungs. The pathophysiology, histological findings, clinical symptoms, and treatment of the pulmonary manifestations of Hermansky-Pudlak syndrome are distinct from those of sarcoidosis. As patients with occulocutaneous and bleeding manifestations of Hermansky-Pudlak syndrome may also develop pulmonary fibrosis, the authors present this case to illustrate that pulmonary symptoms must be carefully evaluated in those with this syndrome because in this case, the patient developed underlying pulmonary sarcoidosis. To the authors' knowledge, this is the first documented case of Hermansky-Pudlak syndrome with concomitant pulmonary sarcoidosis. PMID- 20725575 TI - Seborrheic Dermatitis and Malassezia species: How Are They Related? PMID- 20725576 TI - A Three-Step Acne System Containing Solubilized Benzoyl Peroxide versus Benzoyl Peroxide/Clindamycin in Pediatric Patients with Acne. AB - Objective. To evaluate the clinical benefit in adolescents of a three-step acne system containing solubilized benzoyl peroxide. Design. Patients in this multicenter, investigator-blind trial were randomly assigned to receive 10 weeks of treatment with either the three-step acne system for normal-to-oily skin (proprietary 2% salicylic acid cleanser twice daily + proprietary 2% salicylic acid toner once daily + solubilized 5% benzoyl peroxide gel twice daily) or with control cleanser + 5% benzoyl peroxide/1% clindamycin gel twice daily. Setting. Patients seeking acne treatment from a dermatologist. Pediatric subgroup analysis from a larger trial. Participants. Eighty-two adolescents with mild-to-moderate facial acne vulgaris. Measurements. Noninflammatory and inflammatory lesion counts, erythema, dryness, peeling, burning/stinging, and itching. Results. The three-step acne system was significantly more effective than benzoyl peroxide/clindamycin in reducing the noninflammatory lesion count at Weeks 2 and 4. The antibiotic-free acne system was also comparably effective to benzoyl peroxide/clindamycin in reducing the inflammatory lesion count at all timepoints. Both regimens were generally well tolerated with mean levels of erythema, dryness, peeling, burning/stinging, and itching less than mild in both groups at all timepoints. Conclusions. The three-step acne system is an effective antibiotic-free acne treatment. Relative to benzoyl peroxide/clindamycin, its ability to achieve comparable reductions in inflammatory lesions, and significantly greater reductions in noninflammatory lesions in the early weeks of treatment is likely attributable to the solubilization of the benzoyl peroxide enhancing the bioavailability and intrafollicular penetration of the benzoyl peroxide. PMID- 20725577 TI - Neurological complications of biologic therapy in psoriasis: a review. AB - Biologic agents have been a significant advancement in the management of psoriasis. Along with significant clinical improvement, there have been concerns for emerging side effects with the use of biologics. Reports have emerged showing the association between efalizumab and the development of progressive multifocal leukoencephalopathy and other demyelinating disorders. Tumor necrosis factor alpha inhibitors have been associated with various demyelinating disorders. As such, it is imperative for dermatologists to be well informed regarding how to notify patients about the risks of biologic treatment. Dermatologists must be able to identify the signs and symptoms of neurological complications and recognize when to refer patients to neurologists for diagnostic workup, disease confirmation, and any necessary treatment. This review is a compilation of evidence showing the association between biologic therapy and neurological complications, as well as an overview of the clinical presentation and diagnosis of such diseases. PMID- 20725578 TI - Knowledge of Surgery-Related Allergic Contact Dermatitis among Florida Dermatological Surgeons: A Pilot Study. AB - Objective. To assess knowledge base and practice habits of dermatological surgeons regarding surgery-related allergic contact dermatitis. Design. Cross sectional study. Setting. The Florida Society of Dermatologic Surgery served as the study group. Participants. Cohort of dermatological surgeons. Measurements. An anonymous, close-ended survey instrument eliciting common surgical practices as well as allergic contact dermatitis knowledge. Results. Among the 45 respondents, 87 percent reported performing surgery more than 10 times per week and only 14 percent of respondents reported using latex-free gloves in their practice. Nearly two-thirds (66%) of respondents reported diagnosing allergic contact dermatitis either among themselves, their surgical staff, and/or patients. Surgeons were noted to use the TRUE Test((R)) to screen for adhesive allergy. While colophony can be found both in adhesive products and on the TRUE Test, the main adhesives found in perisurgical products, acrylates, cannot. Similarly, the TRUE Test does not screen for antiseptics, yet this group of respondents suspected antiseptics nearly one-fourth of the time and used the TRUE Test to screen for them. Lastly, six dermatological surgeons used the TRUE Test to screen for suture allergy. While only two used chromated cat gut (the TRUE Test screens for chromium), the other surgical components are not screened. Conclusion. Education among dermatological surgeons is needed regarding exposure to a potential allergen in the surgical setting and risk of developing allergic contact dermatitis. PMID- 20725579 TI - The botulinum toxin experience: results of a patient self-report questionnaire. AB - There are several words in our current vernacular that reliably elicit powerful cognitive, visual, and emotional reactions in the populace. Undoubtedly, "Botox()" is one of them. Beyond issues regarding the safety of the molecule, there are controversies surrounding the overall legitimacy of the cosmetic use of botulinum toxin type A-1. Many people question whether the cosmetic use of botulinum toxin type A-1 is a "legitimate" medical procedure versus a cosmetic indulgence. The authors report data obtained from a patient self-report questionnaire designed to assess positive or negative changes in feelings and functional status after botulinum toxin type A-1 treatment of the forehead and glabellar region. The authors developed concrete, succinct, and pointed questions pertaining to spheres of function (i.e., work, social, family, intrapsychic, and intimate functioning). Results of this pilot study serve as a persuasive preliminary database to argue that botulinum toxin therapy is more than simply an indulgence therapy. PMID- 20725580 TI - Hormonal treatment of acne in women. AB - Acne vulgaris is a common and chronic disorder of the pilosebaceous unit. Standard treatment protocols include topical retinoids, topical and oral antimicrobials, and isotretinoin. Hormonal therapies can be added to the regimen in some patients. This article will review the hormonal pathogenesis of acne, discuss the basics of an endocrine evaluation, and provide an overview of the current hormonal treatment options in women. PMID- 20725581 TI - Patient education strategies in dermatology: part 1: benefits and challenges. AB - Patient education is an important aspect of patient care in dermatology. Successful education increases patient satisfaction and results in improved outcomes and adherence. This article discusses the role of patient education in dermatology. Specifically, Part I of the review examines evidence demonstrating the benefits of patient education and recognizes the challenges that limit effective patient education. These challenges can be summarized as barriers to understanding, poor patient recall, conflicting information, and barriers to physician delivery. Further descriptions and an assessment of these limitations along with methods to combat them are included in the review. PMID- 20725582 TI - Patient education strategies in dermatology: part 2: methods. AB - Patient education is an important aspect of patient care in dermatology. Successful education increases patient satisfaction and results in improved outcomes and adherence. This article individually evaluates several patient education strategies: verbal education, written information, group-based learning, audiotapes, videotapes, computer-assisted education, and the internet. The review presents the strengths and limitations of each strategy based on recognized barriers to effective patient education that were discussed in Part 1. Additionally, a summary of recommendations for effective patient education is provided. PMID- 20725583 TI - Avoiding the legal "blemish": medicolegal pitfalls in dermatology. AB - In today's legal environment, it is unlikely that a physician will complete a medical career without being introduced to the legal system in some way. Despite this, medical education often does not incorporate a basic teaching of general legal principles, and many physicians are left unaware of some of the important legal aspects of practicing medicine. The purpose of this article is to provide a background of the essential legal principles of a malpractice action as well as review the fundamentals of the legal process, provide published caselaw of prior dermatological pitfalls, and ultimately, provide suggestions to better prepare the dermatologist to practice medicine. PMID- 20725584 TI - Clinical assessment of a combination lip treatment to restore moisturization and fullness. AB - Objective. To evaluate the efficacy and tolerance of a topical lip-care treatment. Step one of the two-step treatment is a lip-renewal formulation containing human growth factors, hyaluronic acid and marine filling spheres, emollients, and a tripeptide palmitoyl-glycyl-histidyl-lysine complex. Step two is a lip-plumper formulation containing niacin, emollients, and essential fatty acids. Design. Four-week, single-center, open-label, clinical study with clinical assessments at Baseline, Week 2, and Week 4. Treatment. Subjects wore the lip products at least eight hours every day with a minimum of three applications per day. Participants. Thirty-two women ages 22 to 40 years with mild-to-moderate lip dryness and average size lips completed the study. Measurements. Visual grading of the condition of the lips, rating of subjective irritation, corneometry, digital caliper measurements of lower lip, and digital photography. A self assessment questionnaire was also employed to assess patient satisfaction. Results. Clinical assessments showed statistically significant improvements (P<0.001) in key lip condition parameters after both two and four weeks of use. Key parameters included lip scaling, cupping, cracking/fissuring, fine lines due to dryness, lip texture/visual roughness, lip color/rosiness, lip definition/contour, and overall lip condition. Significant increases (P<0.001) were observed in both corneometer measurements, which confirm the moisturizing benefits, and in digital caliper measurements, which confirm the lip-plumping benefits. Self-assessment questionnaires showed a 97-percent overall satisfaction rating. No adverse events were reported during the course of the study. Conclusion. The results from this clinical study demonstrate that this two-part lip-care treatment product was well tolerated and effective in restoring moisture and fullness to the lips of female subjects with mild-to-moderate lip dryness. PMID- 20725586 TI - The MicroRNAs and Stroke: No Need to be Coded to be Counted. PMID- 20725585 TI - Prevention of rotavirus infections in vitro with aqueous extracts of Quillaja Saponaria Molina. AB - BACKGROUND: Rotavirus is the leading cause of severe diarrhea disease in newborns and young children worldwide, estimated to be responsible for over 300,000 childhood deaths every year, mostly in developing countries. Rotavirus-related deaths represent approximately 5% of all deaths in children younger than 5 years of age worldwide. Saponins are readily soluble in water and are approved by the US FDA for inclusion in beverages intended for human consumption. The addition of saponins to existing water supplies offers a new form of intervention into the cycle of rotavirus infection. We believe that saponins will 'coat' the epithelium of the host's small intestine and prevent attachment of rotavirus. DISCUSSION: This experiment provides in vitro data for the possibility of including saponin in drinking water to prevent infections of rotavirus. We demonstrate that microgram amounts of extract, while exhibiting no cell cytotoxicity or direct virucidal activity, prevent rotavirus from infecting its host cells. In addition, the presence of residual amounts of extract continue to block viral infection and render cells resistant to infection for at least 16 h after the removal of the extract from the cell culture media. CONCLUSION: We demonstrate that two Quillaja extracts possess strong antiviral activity at concentrations more than 1000-fold lower than concentrations exhibiting cell cytotoxicity. Extract concentrations as high as 1000 MUg/ml are not cytotoxic, but concentrations as low as 1.0 MUg/ml are able to block rotavirus and reovirus attachment and infection. PMID- 20725587 TI - Diagnosis and laparoscopic treatment of cornual ectopic pregnancy. AB - Cornual (interstitial) ectopic pregnancy is an uncommon variant of ectopic pregnancy which often poses a diagnostic and therapeutic challenge with a significant risk of rupturing and bleeding. We present a ruptured right cornual pregnancy and explain how to deal with such a case laparoscopically. PMID- 20725588 TI - Cost comparison of insulin glargine with insulin detemir in a basal-bolus regime with mealtime insulin aspart in type 2 diabetes in Germany. AB - OBJECTIVE: To compare the treatment costs of insulin glargine (IG; Lantus) to detemir (ID; Levemir), both combined with bolus insulin aspart (NovoRapid) in type 2 diabetes (T2D) in Germany. METHODS: Cost comparison was based on data of a 1-year randomised controlled trial. IG was administered once daily and ID once (57% of patients) or twice daily (43%) according to treatment response. At the end of the trial, mean daily basal insulin doses were 0.59 U/kg (IG) and 0.82 U/kg (ID). Aspart doses were 0.32 U/kg (IG) and 0.36 U/kg (ID). Costs were calculated from the German statutory health insurance (SHI) perspective using official 2008 prices. Sensitivity analyses were performed to test robustness of the results. RESULTS: Annual basal and bolus insulin costs per patient were euro 1,473 (IG) and euro 1,940 (ID). The cost of lancets and blood glucose test strips were euro 1,125 (IG) and euro 1,286 (ID). Annual costs for needles were euro 393 (IG) and euro 449 (ID). The total annual cost per patient of administering IG was euro 2,991 compared with euro 3,675 for ID, translating into a 19% annual cost difference of euro 684/patient. Base case results were robust to varying assumptions for insulin dose, insulin price, change in weight and proportion of ID once daily administrations. CONCLUSION: IG and ID basal-bolus regimes have comparative safety and efficacy, based on the Hollander study, IG however may represent a significantly more cost saving option for T2D patients in Germany requiring basal-bolus insulin analogue therapy with potential annual cost savings of euro 684/patient compared to ID. PMID- 20725589 TI - How to avoid liability litigation in courts--suggestions from a German example. AB - The medical art is difficult, its results can not always be predicted. After looking at TV, patients know more or think they know more about medicine. They tend to assume faulty diagnostics or treatment by their physician, if the good result promised by the news-media or by the doctor himself has not been obtained. The resulting litigation in court is time-consuming, causes a lot of paperwork and frequently leads to negative publicity for the doctor in the local news media. Therefore, in 1975, the German Medical Associations in the different federal areas have founded expert committees to help solve this problem. These avoid negative publicity, heavy expenses and law-suits. Presidents of these committees are high-level judges - mostly retired - with experience in the field. They are masters of the procedure, choose the experts and formulate the final draft. This structure invalidates the understandable suspicion that physicians will protect each other or - as we say in Germany: "A crow will not hurt the eye of another one". The system is now well accepted by liability insurances, lawyers and patients. PMID- 20725590 TI - Babbling and Chewing: Jaw Kinematics from 8 to 22 months. AB - Empirical gaps remain regarding infant mandibular kinematics observed during naturally occurring episodes of chewing and pre-linguistic vocalizations during the first 2-years of life. Vertical jaw displacement was measured from a typically developing infant from 8 to 22 months. Infant jaw kinematics was measured for vowel babble, non-variegated and variegated babble, and chewing. Results indicated that measures of kinematic variability were significantly less for chewing than all babble categories. These measures changed across age for chewing: (a) peak vertical jaw elevation decreased in variability, while (b) jaw displacement and (c) speed of movement increased in variability. Kinematics for vowel babble were characterized as exhibiting less jaw displacement with higher average vertical jaw position than other babble types and chewing. Developmentally, jaw kinematics for babble changed for jaw displacement and average vertical jaw position. These changes were related to decreased episodes for vowel babble productions and increased episodes for variegated babble and reduplicative syllables. These results suggest that developmental processes such as non-overlapping task-demands likely differentiate trajectories of jaw movement for infant chewing and babble. Infant jaw kinematics for babble cannot be predicted from observations of adult speakers or from non-speech behaviors observed for infants or adults. PMID- 20725591 TI - A picoampere A/D converter for biosensor applications. AB - Detection and analysis of biological and biochemical signals via compact sensor systems require low-power and compact analog-to-digital converter (ADC) systems. Here we present a highly sensitive flash current-mode ADC (IADC) design with resolution down to 15pA. The IADC's small-size and low-power capabilities allow integration for stand-alone biological or chemical microsensor applications. PMID- 20725592 TI - Towards the Total Synthesis of 3-Hydroxyvibsanin E. PMID- 20725593 TI - Synthesis and Reactivity Studies of alpha,alpha-Difluoromethylphosphinates. AB - The preparation and reactivity of some alpha,alpha-difluorophosphinates is investigated. Alkylation of H-phosphinates with LiHMDS and ClCF(2)H gives the corresponding alpha,alpha-difluorophosphinates in good yield. Deprotonation of these reagents with alkyllithium or LDA is then studied. Subtle electronic effects translate into significant differences in the deprotonation/alkylation of the two "Ciba-Geigy reagents" (EtO)(2)CRP(O)(OEt)H (R = H, Me). On the other hand, attempted methylation of difluoromethyl-octyl-phosphinic acid butyl ester resulted in the exclusive alkylation of the octyl chain. Finally, reaction with carbonyl compounds results in the formation of 1,1-difluoro-2-phosphinoyl compounds. PMID- 20725594 TI - Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H. AB - The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids as (+) (2R,5S) and (-)-(5S,2R). PMID- 20725595 TI - Peptide-Like Molecules (PLMs): A Journey from Peptide Bond Isosteres to Gramicidin S Mimetics and Mitochondrial Targeting Agents. AB - Peptides are natural ligands and substrates for receptors and enzymes and exhibit broad physiological effects. However, their use as therapeutic agents often suffers from poor bioavailability and insufficient membrane permeability. The success of peptide mimicry hinges on the ability of bioisosteres, in particular peptide bond replacements, to adopt suitable secondary structures relevant to peptide strands and position functional groups in equivalent space. This perspective highlights past and ongoing studies in our group that involve new methods development as well as specific synthetic library preparations and applications in chemical biology, with the goal to enhance the use of alkene and cyclopropane peptide bond isosteres. PMID- 20725596 TI - Update on biological therapeutics for asthma. AB - Asthma poses a significant burden on patients, families, health care providers, and the medical system. While efforts to standardize care through guidelines have expanded, difficulty in managing severe asthma has encouraged research about its pathobiology and treatment options. Novel biologic therapeutics are being developed for the treatment of asthma and are of potential use for severe refractory asthma, especially where the increased cost of such agents is more likely justified. This review will summarize currently approved (omalizumab) and investigational biological agents for asthma, such as antibodies, soluble receptors, and other protein-based antagonists, and highlight recent published data on efficacy and safety of these therapies in humans. As these newer agents with highly targeted pharmacology are tested in asthma, we are also poised to learn more about the role of cytokines and other molecules in the pathophysiology of asthma. PMID- 20725597 TI - Role Markers of Adulthood and Young Adults' Ties to Grandparents. AB - This study investigates the implications of residential independence, enrollment in postsecondary education, employment, marital status, and parenthood for contact with, and closeness to, grandparents. Data come from 1,507 young adults interviewed in Wave 3 of the National Survey of Families and Households. Findings suggest that adult roles can be either negatively or positively associated with grandparent-grandchild ties, depending on specific configurations among such factors as the adult role in question, a particular dimension of intergenerational solidarity, lineage, and grandchild's and grandparent's gender. Young adults' ties to parents can mediate the adverse consequences of residential independence for contact with grandparents. PMID- 20725598 TI - Sex-specific odorant receptors of the tobacco hornworm manduca sexta. AB - As odor information plays a vital role in the life of moths, their olfactory sense has evolved into a highly specific and sensitive apparatus relevant to reproduction and survival. The key players in the detection of odorants are olfactory receptor (OR) proteins. Here we identify four OR-encoding genes differentially expressed in the antennae of males and females of the sphingid moth Manduca sexta. Two male-specific receptors (the previously reported MsexOR-1 and the newly identified MsexOR-4) show great resemblance to other male moth pheromone ORs. The putative pheromone receptors are co-expressed with the co receptor involved in general odorant signal transduction, the DmelOr83b homolog MsexOR-2. One female-specific receptor (MsexOR-5) displays similarities to BmorOR 19, a receptor in Bombyx mori tuned to the detection of the plant odor linalool. PMID- 20725599 TI - Spike timing dependent plasticity: a consequence of more fundamental learning rules. AB - Spike timing dependent plasticity (STDP) is a phenomenon in which the precise timing of spikes affects the sign and magnitude of changes in synaptic strength. STDP is often interpreted as the comprehensive learning rule for a synapse - the "first law" of synaptic plasticity. This interpretation is made explicit in theoretical models in which the total plasticity produced by complex spike patterns results from a superposition of the effects of all spike pairs. Although such models are appealing for their simplicity, they can fail dramatically. For example, the measured single-spike learning rule between hippocampal CA3 and CA1 pyramidal neurons does not predict the existence of long-term potentiation one of the best-known forms of synaptic plasticity. Layers of complexity have been added to the basic STDP model to repair predictive failures, but they have been outstripped by experimental data. We propose an alternate first law: neural activity triggers changes in key biochemical intermediates, which act as a more direct trigger of plasticity mechanisms. One particularly successful model uses intracellular calcium as the intermediate and can account for many observed properties of bidirectional plasticity. In this formulation, STDP is not itself the basis for explaining other forms of plasticity, but is instead a consequence of changes in the biochemical intermediate, calcium. Eventually a mechanism-based framework for learning rules should include other messengers, discrete change at individual synapses, spread of plasticity among neighboring synapses, and priming of hidden processes that change a synapse's susceptibility to future change. Mechanism-based models provide a rich framework for the computational representation of synaptic plasticity. PMID- 20725600 TI - A BOLD Assumption. PMID- 20725601 TI - The biological effect of contralateral forepaw stimulation in rat focal cerebral ischemia: a multispectral optical imaging study. AB - Our group has already published the possible neuroprotective effect of contralateral forepaw stimulation in temporary focal ischemia in a study. However, the background is still unclear. In the present study we investigated the possible mechanism by monitoring focal ischemia with multispectral [laser speckle, imaging of intrinsic signals (OIS)] imaging. Sprague-Dawley rats were prepared using 1.2% isoflurane anesthesia. The middle cerebral artery was occluded by photothrombosis (4 mW) and the common carotid artery was ligated permanently. Physiological variables were constantly monitored during the experiment. A 6 x 6 mm area centered 3 mm posterior and 4 mm lateral to Bregma was thinned for laser speckle and OIS imaging. Nine circular regions of interests (0.3 mm in diameter) were evenly spaced on the speckle contrast image for the analysis of peri-infarct flow transients, blood flow, and metabolic changes. Both the sham (n = 7) and forepaw-stimulated animals (n = 7) underwent neurological examinations 24 h after ischemia at which point all animals were sacrificed and the infarct size was determined by triphenyltetrazolium chloride. The physiological variables were in normal range and the experimental protocol did not cause significant differences between groups. Both the neurological scores (sham: 3.6 +/- 1.7, stimulated: 4.3 +/- 1.4) and the infarct volume (sham: 124 +/ 39 mm(3), stimulated: 147 +/- 47 mm(3)) did not show significant differences between groups. The forepaw stimulation did not increase the intra-ischemic flow neither over the penumbral or the peri-ischemic area. However, the hemoglobin transients related metabolic load (CMRO(2)) was significantly lower (p < 0.001) while the averaged number of hyperemic flow transients were significantly (p = 0.013) higher in the forepaw (sham: 3.5 +/- 2.2, stimulated: 7.0 +/- 2.3) stimulated animals. PMID- 20725602 TI - Multi-photon nanosurgery in live brain. AB - In the last few years two-photon microscopy has been used to perform in vivo high spatial resolution imaging of neurons, glial cells and vascular structures in the intact neocortex. Recently, in parallel to its applications in imaging, multi photon absorption has been used as a tool for the selective disruption of neural processes and blood vessels in living animals. In this review we present some basic features of multi-photon nanosurgery and we illustrate the advantages offered by this novel methodology in neuroscience research. We show how the spatial localization of multi-photon excitation can be exploited to perform selective lesions on cortical neurons in living mice expressing fluorescent proteins. This methodology is applied to disrupt a single neuron without causing any visible collateral damage to the surrounding structures. The spatial precision of this method allows to dissect single processes as well as individual dendritic spines, preserving the structural integrity of the main neuronal arbor. The same approach can be used to breach the blood-brain barrier through a targeted photo-disruption of blood vessels walls. We show how the vascular system can be perturbed through laser ablation leading toward two different models of stroke: intravascular clot and extravasation. Following the temporal evolution of the injured system (either a neuron or a blood vessel) through time lapse in vivo imaging, the physiological response of the target structure and the rearrangement of the surrounding area can be characterized. Multi-photon nanosurgery in live brain represents a useful tool to produce different models of neurodegenerative disease. PMID- 20725603 TI - BIOLOGICAL PROPERTIES (IN VITRO) EXHIBITED BY FREE-LIVING AND SYMBIOTIC VIBRIO ISOLATES. AB - Adhesion and biofilm forming ability of symbiotic bacteria play a crucial role in host colonization and tissue infection. Bacteria benefit by adhering to their host in a manner that allows them to successfully maintain contact for the exchange of nutrients, hormones, or other necessary products. This study examined pili morphology, motility, and biofilm formation exhibited by Vibrio fischeri strains (free-living and symbiotic). Since these symbiotic factors contribute in some fashion to the interaction between V. fischeri and their squid host, variation between strains may be a contributing factor that leads to specificity among different hosts. V. fischeri strains examined in this study demonstrated considerable variation in their biological properties when observed in vitro. In addition to differences observed between strains isolated from several different host species, we observed variation between strains isolated from the same host species from diverse geographical locations. This study suggests that subtle differences in the biological properties of closely related V. fischeri strains may influence the nature of the interaction among V. fischeri and their sepiolid hosts. PMID- 20725604 TI - The Importance of Sound for Cognitive Sequencing Abilities: The Auditory Scaffolding Hypothesis. AB - Sound is inherently a temporal and sequential signal. Experience with sound therefore may help bootstrap - i.e., provide a kind of "scaffolding" for - the development of general cognitive abilities related to representing temporal or sequential patterns. Accordingly, the absence of sound early in development may result in disturbances to these sequencing skills. In support of this hypothesis we present two types of findings. First, normal-hearing adults do best on sequencing tasks when the sense of hearing, rather than vision, can be used. Second, recent findings suggest that deaf children have disturbances on exactly these same kinds of tasks that involve learning and manipulation of serial order information. We suggest that sound provides an "auditory scaffolding" for time and serial order behavior, possibly mediated through neural connections between the temporal and frontal lobes of the brain. Under conditions of auditory deprivation, auditory scaffolding is absent, resulting in neural reorganization and a disturbance to cognitive sequencing abilities. PMID- 20725605 TI - Disparities in health care among Vietnamese New Orleanians and the impacts of Hurricane Katrina. AB - This paper examines the use of routine health care and disparities by socio economic status among Vietnamese New Orleanians. It also assesses how these differences may have changed as the result of Hurricane Katrina, which struck the Gulf Coast in late summer 2005, devastating the infrastructure of the health care system of New Orleans. Data for this study come from a panel of Vietnamese New Orleanians who were interviewed in 2005, just weeks before the hurricane, and followed up twice near the disaster's anniversary in 2006 and 2007. Findings show a steep declining trend in routine health care after the hurricane, compared to 2005. Marked differences in health care were already apparent in 2005 (before Katrina) between education levels, home ownership, and health insurance coverage. These differences were significantly reduced one year after the hurricane. We argue, however, that the reduction in disparities was not due to improved health care services or improved health care practice. Instead, it was likely due to the influx of free health care services that were provided to meet urgent needs of hurricane survivors while the area's infrastructure was devastated. By 2007, these free health care services were no longer widely available. Routine health visits dropped further and the temporary reduction in disparities disappeared. The paper also underlines ongoing shortages of essential health care services for Vietnamese New Orleanians. Efforts need to ensure that all members of this community receive the full array of comprehensive and culturally-appropriate health care as they continue to rebuild from the Katrina disaster. PMID- 20725606 TI - Inducing Disorders in Pitch Perception and Production: a Reverse-Engineering Approach. AB - To perceive and produce music accurately, the brain must represent, categorize, plan, and execute pitched information in response to environmental stimuli. Convergent methods from psychophysics, voxel-based morphometry, and diffusion tensor imaging with normal and tone-deaf (TD) subjects have shown that neural networks controlling pitch perception and production systems include bilateral frontotemporal networks. Although psychophysical and neuroimaging results are suggestive of a superior temporal and inferior frontal network responsible for pitch perception and production, active intervention of these areas is necessary to establish a causal connection between superior temporal and inferior frontal areas and pitch production ability. We sought to reverse-engineer the pitch perception-production network by noninvasive brain stimulation. Transcranial direct current stimulation (tDCS), a noninvasive brain-stimulation technique that is optimal for auditory research, was applied over superior temporal and inferior frontal regions. Pitch matching ability was assessed using an individually optimized pitch matching task administered after each stimulation session. Results showed diminished accuracy in pitch matching after cathodal stimulation over inferior frontal and superior temporal areas compared to sham control. Results demonstrate that intact function and connectivity of a distributed cortical network, centered around bilateral superior temporal and inferior frontal regions, are required for efficient neural interactions with musical sounds. PMID- 20725607 TI - CCL3 genotype and current depression increase risk of HIV-associated dementia. AB - BACKGROUND: The prevalence of Human immunodeficiency virus (HIV)-associated dementia (HAD) has continued to rise even as incidence has fallen. Several host genetic variants have been identified that modify risk for HAD. However, the findings have not been replicated consistently and most studies did not consider the multitude of factors that might themselves confer risk for HAD. In the current study, we sought to replicate the findings of previous studies in a neurologically and behaviorally well-characterized cohort. METHODS: The sample consisted of 143 HIV+ individuals enrolled in the National NeuroAIDS Tissue Consortium (NNTC). Based on consensus diagnosis, 117 were considered neurologically normal upon study entry, and 26 had HAD. Seven single-nucleotide polymorphisms (SNPs) were genotyped within seven genes (CCL2, CCL3, CCL5, interleukin-1alpha [IL-1alpha], IL-10, stromal cell-derived factor 1, and tumor necrosis factor-alpha). Logistic regression analysis was used to predict group membership (normal vs HAD), with predictor variables including length of infection, age, current drug dependence, current depression, and genotype. RESULTS: The two groups were statistically similar with regards to demographic characteristics, current drug use, and disease factors. The HAD group had significantly greater number of individuals with current depression. Only one SNP, rs1130371 within the gene for CCL3, was entered into the analysis as the others showed symmetric distribution between groups. Logistic regression indicated that current depression and CCL3 genotype were significant predictors of HAD. Depression conferred a fivefold greater risk of HAD, while the TT genotype for CCL3 SNP (rs1130371) was associated with twofold risk for HAD. CONCLUSION: Depression and CCL3 genotype predicted HAD. The fact that SNPs previously found to be associated with HAD were not in our analysis, and that rs1130371 is in high linkage disequilibrium with neighboring genes indicates that more dense genotyping in significantly larger cohorts is required to further characterize the relationship between genotype and risk for HAD. PMID- 20725608 TI - Electrochemical and Laser Deposition of Silver for Use in Metal-Enhanced Fluorescence. AB - We describe two reagentless methods of silver deposition for metal-enhanced fluorescence. Silver was deposited on glass positioned between two silver electrodes with a constant current in pure water. Illumination of the glass between the electrodes resulted in localized silver deposition. Alternatively, silver was deposited on an Indium Tin Oxide cathode, with a silver electrode as the anode. Both types of deposited silver produced a 5-18-fold increase in the fluorescence intensity of a nearby fluorophore, indocyanine green (ICG). Additionally, the photostability of ICG was dramatically increased by proximity to the deposited silver. These results suggest the use of silver deposited from pure water for surface-enhanced fluorescence, with potential applications in surface assays and lab-on-a-chip-based technologies, which ideally require highly fluorescent photostable systems. PMID- 20725609 TI - Photoelectron anticorrelations and sub-Poisson statistics in scintillation detectors. AB - The performance of scintillation detectors for x rays and gamma rays is limited fundamentally by the statistics of the scintillation light and the resulting photoelectrons. This paper presents a new experimental approach to studying these statistics by observing correlations in the signals from two photodetectors. It is shown that the Fano factors (ratios of variance to mean), both for the number the photoelectrons produced on the photocathode of the photomultiplier and for the underlying number of scintillation photons, can be deduced from these correlations. For LaBr(3)(Ce) and 662 keV gamma rays, the photopeak signals obtained by photomultipliers on opposite faces of a thin sample are negatively correlated, and the Fano factor for the photoelectrons is significantly less than one. The inferred Fano factor for the optical photons is very small, indistinguishable from zero within experimental error. PMID- 20725610 TI - Specificity of the Acute Tryptophan and Tyrosine Plus Phenylalanine Depletion and Loading Tests Part II: Normalisation of the Tryptophan and the Tyrosine Plus Phenylalanine to Competing Amino Acid Ratios in a New Control Formulation. AB - Current formulations for acute tryptophan (Trp) or tyrosine (Tyr) plus phenylalanine (Phe) depletion and loading cause undesirable decreases in ratios of Trp or Tyr + Phe to competing amino acids (CAA), thus undermining the specificities of these tests. Branched-chain amino acids (BCAA) cause these unintended decreases, and lowering their content in a new balanced control formulation in the present study led to normalization of all ratios. Four groups (n = 12 each) of adults each received one of four 50 g control formulations, with 0% (traditional), 20%, 30%, or 40% less of the BCAA. The free and total [Trp]/[CAA] and [Phe + Tyr]/[BCAA + Trp] ratios all decreased significantly during the first 5 h following the traditional formulation, but were fully normalized by the formulation containing 40% less of the BCAA. We recommend the latter as a balanced control formulation and propose adjustments in the depletion and loading formulations to enhance their specificities for 5-HT and the catecholamines. PMID- 20725611 TI - A Person-centered Approach to Studying the Linkages among Parent-Child Differences in Cultural Orientation, Supportive Parenting, and Adolescent Depressive Symptoms in Chinese American Families. AB - This longitudinal study examined whether supportive parenting mediates relations between parent- child differences in cultural orientation (generational dissonance) and depressive symptoms with a sample of 451 first and second generation Chinese American parents and adolescents (12-15 years old at time 1). Using a person-centered approach, meaningful typologies of cultural orientation were derived for fathers, mothers, and adolescents. Overall, results provided support, though qualified, for the notion that generational dissonance is linked to depressive symptoms through decreased supportive parenting. In general, having a parent with a bicultural profile seemed to be most advantageous if adolescents similarly had a bicultural profile, whereas more American oriented adolescents with more Chinese oriented parents reported the least supportive parenting and most depressive symptoms. Directions for future research and the benefits of using a person-centered approach in research of acculturation and generational dissonance are discussed. PMID- 20725612 TI - Radioisotopes as Political Instruments, 1946-1953. AB - The development of nuclear "piles," soon called reactors, in the Manhattan Project provided a new technology for manufacturing radioactive isotopes. Radioisotopes, unstable variants of chemical elements that give off detectable radiation upon decay, were available in small amounts for use in research and therapy before World War II. In 1946, the U.S. government began utilizing one of its first reactors, dubbed X-10 at Oak Ridge, as a production facility for radioisotopes available for purchase to civilian institutions. This program of the U.S. Atomic Energy Commission was meant to exemplify the peacetime dividends of atomic energy. The numerous requests from scientists outside the United States, however, sparked a political debate about whether the Commission should or even could export radioisotopes. This controversy manifested the tension in U.S. politics between scientific internationalism as a tool of diplomacy, associated with the aims of the Marshall Plan, and the desire to safeguard the country's atomic monopoly at all costs, linked to American anti-Communism. This essay examines the various ways in which radioisotopes were used as political instruments-both by the U.S. federal government in world affairs, and by critics of the civilian control of atomic energy-in the early Cold War. PMID- 20725613 TI - Luminescent Blinking from Silver Nanostructures. AB - Silver nanostructures deposited on glass showed luminescent blinking when excited at a high 442 nm irradiance. The irradiance required to photoactivate the silver, was dependent on the nature of the silver nanostructures. Silver fractal-like structures were found to be highly emissive, requiring only ~30 W/cm(2) for photoactivation as compared to silver island films and spin-coated silver colloids, which required a significantly higher irradiance, > 100 W/cm(2), to observe similar luminescent emission. In contrast to our recent findings for gold colloids, foci with different color blinking were also observed, with an increase in luminescence intensity as a function of time. We place these findings in context with recent work from our laboratory which employs these silver nanostructures for applications in metal-enhanced fluorescence, a relatively new phenomenon in fluorescence, whereby metallic particles, colloids, and fractal like structures can modify the intrinsic radiative decay rate of close proximity fluorescent species. These effects are a consequence of localized changes in photonic mode density around the fluorophores, and we can now report are typically observed at significantly lower illumination intensities as compared to those required to photoactivate silver. Subsequently, our findings strongly suggest that the enhanced fluorescence emission of fluorophores positioned in close proximity to metallic silver structures is not due to either intrinsic silver blinking, or indeed the silver luminescence pumping the fluorophore. Further, the intrinsic luminescence properties of silver reported here, suggest a new class of luminescence probes and labels. PMID- 20725614 TI - Surface Plasmon-Coupled Ultraviolet Emission of 2,5-Diphenyl-1,3,4-oxadiazole. AB - We studied surface plasmon-coupled emission (SPCE) of 2,5-diphenyl-1,3,4 oxadiazole (PPD) using a 20 nm aluminum film deposited on a quartz substrate. The directional SPCE UV fluorescence occurs within a narrow angle at 57 degrees from the normal to the coupling hemicylindrical prism. This radiation is almost completely p-polarized, consistent with its origin from surface plasmons. These surface plasmons are induced by excited PPD molecules. The coupling of excited fluorophore dipoles with the aluminum is highly efficient, exceeding 50%. Different fluorescence emission wavelengths are emitted at slightly different angles on the prism, providing intrinsic spectral resolution. SPCE fluorescence on thin aluminum films can be used with many UV absorbing and emitting fluorophores. PMID- 20725615 TI - Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. AB - Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP ribose polymerase-1 (PARP-1). Numerous in vitro and in vivo studies have clearly shown that PARP-1 and NAD(+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability. PMID- 20725616 TI - Selective Binding of Distamycin A Derivative to G-Quadruplex Structure [d(TGGGGT)](4). AB - Guanine-rich nucleic acid sequences can adopt G-quadruplex structures stabilized by layers of four Hoogsteen-paired guanine residues. Quadruplex-prone sequences are found in many regions of human genome and in the telomeres of all eukaryotic organisms. Since small molecules that target G-quadruplexes have been found to be effective telomerase inhibitors, the identification of new specific ligands for G quadruplexes is emerging as a promising approach to develop new anticancer drugs. Distamycin A is known to bind to AT-rich sequences of duplex DNA, but it has recently been shown to interact also with G-quadruplexes. Here, isothermal titration calorimetry (ITC) and NMR techniques have been employed to characterize the interaction between a dicationic derivative of distamycin A (compound 1) and the [d(TGGGGT)](4) quadruplex. Additionally, to compare the binding behaviour of netropsin and compound 1 to the same target, a calometric study of the interaction between netropsin and [d(TGGGGT)](4) has been performed. Experiments show that netropsin and compound 1 are able to bind to [d(TGGGGT)](4) with good affinity and comparable thermodynamic profiles. In both cases the interactions are entropically driven processes with a small favourable enthalpic contribution. Interestingly, the structural modifications of compound 1 decrease the affinity of the ligand toward the duplex, enhancing the selectivity. PMID- 20725617 TI - DNA mismatch repair in eukaryotes and bacteria. AB - DNA mismatch repair (MMR) corrects mismatched base pairs mainly caused by DNA replication errors. The fundamental mechanisms and proteins involved in the early reactions of MMR are highly conserved in almost all organisms ranging from bacteria to human. The significance of this repair system is also indicated by the fact that defects in MMR cause human hereditary nonpolyposis colon cancers as well as sporadic tumors. To date, 2 types of MMRs are known: the human type and Escherichia coli type. The basic features of the former system are expected to be universal among the vast majority of organisms including most bacteria. Here, I review the molecular mechanisms of eukaryotic and bacterial MMR, emphasizing on the similarities between them. PMID- 20725619 TI - Analysis of the thymidylate synthase gene structure in colorectal cancer patients and its possible relation with the 5-Fluorouracil drug response. AB - Thymidylate synthase (TS) catalyzes methylation of dUMP to dTMP and it is the target for the 5-Fluorouracil (5-FU) activity. Barbour et al. showed that variant structural forms of TS in tumour cell lines confer resistance to fluoropyrimidines. We planned to perform the whole TS gene structure by means of sequencing techniques in human colorectal cancer (CRC) samples to try to identify the presence of any possible TS variant form that could be responsible of fluoropyrimidines drug resistance and of the worse prognosis. We performed the TS DNA gene sequence in 68 CRC from patients of A, B, and C Dukes' stages and different histological grade, but we did not find any mutation in the TS-DNA structure. In the future we intend to widen the TS structure analysis to the metastatic CRCs, because due to their higher genomic instability, they could present a TS variant form responsible of the fluoropyrimidines drug resistance and the worse prognosis. PMID- 20725620 TI - Preparation of DNA ladder based on multiplex PCR technique. AB - DNA molecular weight standard control, also called DNA marker (ladder), has been widely used in the experiments of molecular biology. In the paper, we report a method by which DNA marker was prepared based on multiple PCR technique. 100-1000 bp DNA fragments were amplified using the primers designed according to the 6631 ~ 7630 position of lambda DNA. Target DNA fragments were amplified using Touchdown PCR combined with hot start PCR, respectively, followed extracted by phenol/chloroform, precipitated with ethanol and mixed thoroughly. The results showed that the 100-1000 bp DNA fragments were successfully obtained in one PCR reaction, the bands of prepared DNA marker were clear, the size was right and could be used as control in the molecular biology experiment. This method could save time and be more inexpensive, rapid, simple when compared with the current DNA Ladder prepared means. PMID- 20725621 TI - Effect of base sequence on g-wire formation in solution. AB - The formation and dimensions of G-wires by different short G-rich DNA sequences in solution were investigated by dynamic light scattering (DLS) and polyacrilamide gel electrophoresis (PAGE). To explore the basic principles of wire formation, we studied the effects of base sequence, method of preparation, temperature, and oligonucleotide concentration. Both DLS and PAGE show that thermal annealing induces much less macromolecular self-assembly than dialysis. The degree of assembly and consequently length of G-wires (5-6 nm) are well resolved by both methods for DNA sequences with intermediate length, while some discrepancies appear for the shortest and longest sequences. As expected, the longest DNA sequence gives the longest macromolecular aggregates with a length of about 11 nm as estimated by DLS. The quadruplex topologies show no concentration dependence in the investigated DNA concentration range (0.1 mM-0.4 mM) and no structural change upon heating. PMID- 20725618 TI - DNA-Destabilizing Agents as an Alternative Approach for Targeting DNA: Mechanisms of Action and Cellular Consequences. AB - DNA targeting drugs represent a large proportion of the actual anticancer drug pharmacopeia, both in terms of drug brands and prescription volumes. Small DNA interacting molecules share the ability of certain proteins to change the DNA helix's overall organization and geometrical orientation via tilt, roll, twist, slip, and flip effects. In this ocean of DNA-interacting compounds, most stabilize both DNA strands and very few display helix-destabilizing properties. These types of DNA-destabilizing effect are observed with certain mono- or bis intercalators and DNA alkylating agents (some of which have been or are being developed as cancer drugs). The formation of locally destabilized DNA portions could interfere with protein/DNA recognition and potentially affect several crucial cellular processes, such as DNA repair, replication, and transcription. The present paper describes the molecular basis of DNA destabilization, the cellular impact on protein recognition, and DNA repair processes and the latter's relationships with antitumour efficacy. PMID- 20725622 TI - "One Ring to Bind Them All"-Part II: Identification of Promising G-Quadruplex Ligands by Screening of Cyclophane-Type Macrocycles. AB - A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for G-quadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (DeltaT(1/2) up to 30 degrees C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the existence of a particular topological arrangement appear to be strong determinants of quadruplex binding. These compounds are thus likely to create multiple contacts with the target that may be at the origin of their high selectivity, thereby suggesting that this class of macrocycles offers unique advantages for targeting G-quadruplex-DNA. PMID- 20725623 TI - A mathematical model for DNA damage and repair. AB - In cells, DNA repair has to keep up with DNA damage to maintain the integrity of the genome and prevent mutagenesis and carcinogenesis. While the importance of both DNA damage and repair is clear, the impact of imbalances between both processes has not been studied. In this paper, we created a combined mathematical model for the formation of DNA adducts from oxidative estrogen metabolism followed by base excision repair (BER) of these adducts. The model encompasses a set of differential equations representing the sequence of enzymatic reactions in both damage and repair pathways. By combining both pathways, we can simulate the overall process by starting from a given time-dependent concentration of 17beta estradiol (E(2)) and 2'-deoxyguanosine, determine the extent of adduct formation and the correction by BER required to preserve the integrity of DNA. The model allows us to examine the effect of phenotypic and genotypic factors such as different concentrations of estrogen and variant enzyme haplotypes on the formation and repair of DNA adducts. PMID- 20725624 TI - Structure and stability of a dimeric g-quadruplex formed by cyclic oligonucleotides. AB - We have studied the structure and stability of the cyclic dodecamer d, containing two copies of the human telomeric repeat. In the presence of sodium, NMR data are consistent with a dimeric structure of the molecule in which two cycles self-associate forming a quadruplex with three guanine tetrads connected by edgewise loops. The two macrocycles are arranged in a parallel way, and the dimeric structure exhibits a high melting temperature. These results indicate that cyclization of the phosphodiester chain does not prevent quadruplex formation, although it affects the global topology of the quadruplex. PMID- 20725625 TI - Guanosine quadruplexes in solution: a small-angle x-ray scattering analysis of temperature effects on self-assembling of deoxyguanosine monophosphate. AB - We investigated quadruplex formation in aqueous solutions of 2' deoxyriboguanosine 5'-monophosphate, d(pG), which takes place in the absence of the covalent axial backbone. A series of in-solution small angle X-ray scattering experiments on d(pG) have been performed as a function of temperature in the absence of excess salt, at a concentration just above the critical one at which self-assembling occurs. A global fit approach has been used to derive composition and size distribution of the scattering particles as a function of temperature. The obtained results give thermodynamical justification for the observed phase behavior, indicating that octamer formation is essential for quadruplex elongation. Our investigation shows that d(pG) quadruplexes are very suitable to assess the potential of G-quadruplex formation and to study the self-assembling thermodynamics. PMID- 20725626 TI - Synthesis and g-quadruplex-binding properties of defined acridine oligomers. AB - The synthesis of oligomers containing two or three acridine units linked through 2-aminoethylglycine using solid-phase methodology is described. Subsequent studies on cell viability showed that these compounds are not cytotoxic. Binding to several DNA structures was studied by competitive dialysis, which showed a clear affinity for DNA sequences that form G-quadruplexes and parallel triplexes. The fluorescence spectra of acridine oligomers were affected strongly upon binding to DNA. These spectral changes were used to calculate the binding constants (K). Log K were found to be in the order of 4-6. PMID- 20725627 TI - A Comparative Study of the Impact of G-Stack Probes on Various Affymetrix GeneChips of Mammalia. AB - We have previously discovered that probes containing runs of four or more contiguous guanines are not reliable for measuring gene expression in the Human HG_U133A Affymetrix GeneChip data. These probes are not correlated with other members of their probe set, but they are correlated with each other. We now extend our analysis to different 3' GeneChip designs of mouse, rat, and human. We find that, in all these chip designs, the G-stack probes (probes with a run of exactly four consecutive guanines) are correlated highly with each other, indicating that such probes are not reliable measures of gene expression in mammalian studies. Furthermore, there is no specific position of G-stack where the correlation is highest in all the chips. We also find that the latest designs of rat and mouse chips have significantly fewer G-stack probes compared to their predecessors, whereas there has not been a similar reduction in G-stack density across the changes in human chips. Moreover, we find significant changes in RMA values (after removing G-stack probes) as the number of G-stack probes increases. PMID- 20725628 TI - Structural determinants of photoreactivity of triplex forming oligonucleotides conjugated to psoralens. AB - Triplex-forming oligonucleotides (TFOs) with both DNA and 2'-O-methyl RNA backbones can direct psoralen photoadducts to specific DNA sequences. However, the functional consequences of these differing structures on psoralen photoreactivity are unknown. We designed TFO sequences with DNA and 2'-O-methyl RNA backbones conjugated to psoralen by 2-carbon linkers and examined their ability to bind and target damage to model DNA duplexes corresponding to sequences within the human HPRT gene. While TFO binding affinity was not dramatically affected by the type of backbone, psoralen photoreactivity was completely abrogated by the 2'-O-methyl RNA backbone. Photoreactivity was restored when the psoralen was conjugated to the RNA TFO via a 6-carbon linker. In contrast to the B-form DNA of triplexes formed by DNA TFOs, the CD spectra of triplexes formed with 2'-O-methyl RNA TFOs exhibited features of A-form DNA. These results indicate that 2'-O-methyl RNA TFOs induce a partial B-to-A transition in their target DNA sequences which may impair the photoreactivity of a conjugated psoralen and suggest that optimal design of TFOs to target DNA damage may require a balance between binding ability and drug reactivity. PMID- 20725630 TI - A toolbox for predicting g-quadruplex formation and stability. AB - G-quadruplexes are four stranded nucleic acid structures formed around a core of guanines, arranged in squares with mutual hydrogen bonding. Many of these structures are highly thermally stable, especially in the presence of monovalent cations, such as those found under physiological conditions. Understanding of their physiological roles is expanding rapidly, and they have been implicated in regulating gene transcription and translation among other functions. We have built a community-focused website to act as a repository for the information that is now being developed. At its core, this site has a detailed database (QuadDB) of predicted G-quadruplexes in the human and other genomes, together with the predictive algorithm used to identify them. We also provide a QuadPredict server, which predicts thermal stability and acts as a repository for experimental data from all researchers. There are also a number of other data sources with computational predictions. We anticipate that the wide availability of this information will be of use both to researchers already active in this exciting field and to those who wish to investigate a particular gene hypothesis. PMID- 20725631 TI - True lies: the double life of the nucleotide excision repair factors in transcription and DNA repair. AB - Nucleotide excision repair (NER) is a major DNA repair pathway in eukaryotic cells. NER removes structurally diverse lesions such as pyrimidine dimers, arising upon UV irradiation or bulky chemical adducts, arising upon exposure to carcinogens and some chemotherapeutic drugs. NER defects lead to three genetic disorders that result in predisposition to cancers, accelerated aging, neurological and developmental defects. During NER, more than 30 polypeptides cooperate to recognize, incise, and excise a damaged oligonucleotide from the genomic DNA. Recent papers reveal an additional and unexpected role for the NER factors. In the absence of a genotoxic attack, the promoters of RNA polymerases I and II-dependent genes recruit XPA, XPC, XPG, and XPF to initiate gene expression. A model that includes the growth arrest and DNA damage 45alpha protein (Gadd45alpha) and the NER factors, in order to maintain the promoter of active genes under a hypomethylated state, has been proposed but remains controversial. This paper focuses on the double life of the NER factors in DNA repair and transcription and describes the possible roles of these factors in the RNA synthesis process. PMID- 20725632 TI - Functional neuroimaging: a physiological perspective. AB - Metabolic physiology and functional neuroimaging have played important and complementary roles over the past two decades. In particular, investigations of the mechanisms underlying functional neuroimaging signals have produced fundamental new insights into hemodynamic and metabolic regulation. However, controversies were also raised as regards the metabolic pathways (oxidative vs. non-oxidative) for meeting the energy demand and driving the increases in cerebral blood flow (CBF) during brain activation. In a recent study, with the concurrent functional MRI-MRS measurements, we found that task-evoked energy demand was predominately met through oxidative metabolism (approximately 98%), despite a small increase in cerebral metabolic rate of oxygen (12-17%). In addition, the task-induced increases in CBF were most likely mediated by anaerobic glycolysis rather than oxygen demand. These observations and others from functional neuroimaging support the activation-induced neuron-astrocyte interactions portrayed by the astrocyte-neuron lactate shuttle model. The concurrent developments of neuroimaging methods and metabolic physiology will also pave the way for the future investigation of cerebral hemodynamics and metabolism in disease states. PMID- 20725633 TI - History-dependent Dynamics in a Generic Model of Ion Channels - an Analytic Study. AB - Recent experiments have demonstrated that the timescale of adaptation of single neurons and ion channel populations to stimuli slows down as the length of stimulation increases; in fact, no upper bound on temporal timescales seems to exist in such systems. Furthermore, patch clamp experiments on single ion channels have hinted at the existence of large, mostly unobservable, inactivation state spaces within a single ion channel. This raises the question of the relation between this multitude of inactivation states and the observed behavior. In this work we propose a minimal model for ion channel dynamics which does not assume any specific structure of the inactivation state space. The model is simple enough to render an analytical study possible. This leads to a clear and concise explanation of the experimentally observed exponential history-dependent relaxation in sodium channels in a voltage clamp setting, and shows that their recovery rate from slow inactivation must be voltage dependent. Furthermore, we predict that history-dependent relaxation cannot be created by overly sparse spiking activity. While the model was created with ion channel populations in mind, its simplicity and genericalness render it a good starting point for modeling similar effects in other systems, and for scaling up to higher levels such as single neurons which are also known to exhibit multiple time scales. PMID- 20725629 TI - "One ring to bind them all"-part I: the efficiency of the macrocyclic scaffold for g-quadruplex DNA recognition. AB - Macrocyclic scaffolds are particularly attractive for designing selective G quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkable-quadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects. PMID- 20725634 TI - Alcohol-Paired Contextual Cues Produce an Immediate and Selective Loss of Goal directed Action in Rats. AB - We assessed whether the presence of contextual cues paired with alcohol would disrupt rats' capacity to express appropriate goal-directed action control. Rats were first given differential context conditioning such that one set of contextual cues was paired with the injection of ethanol and a second, distinctive set of cues was paired with the injection of saline. All rats were then trained in a third, neutral context to press one lever for grain pellets and another lever for sucrose pellets. They were then given two extinction tests to evaluate their ability to choose between the two actions in response to the devaluation of one of the two food outcomes with one test conducted in the alcohol-paired context and the other conducted in the control (saline-paired) context. In the control context, rats exhibited goal-directed action control; i.e., they were able selectively to withhold the action that previously earned the now devalued outcome. However, these same rats were impaired when tested in the alcohol-paired context, performing both actions at the same rate regardless of the current value of their respective outcomes. Subsequent testing revealed that the rats were capable of overcoming this impairment if they were giving response-contingent feedback about the current value of the food outcomes. These results provide a clear demonstration of the disruptive influence that alcohol paired cues can exert on decision-making in general and goal-directed action selection and choice in particular. PMID- 20725635 TI - Neurodegenerative diseases: exercising toward neurogenesis and neuroregeneration. AB - Currently, there is still no effective therapy for neurodegenerative diseases (NDD) such as Alzheimer's disease (AD) and Parkinson's disease (PD) despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician's and the scientist's needs, and to highlight current research investigating exercise as a therapeutic or preventive measure. PMID- 20725636 TI - Superior sensory, motor, and cognitive performance in elderly individuals with multi-year dancing activities. AB - Aging is associated with a progressive decline of mental and physical abilities. Considering the current demographic changes in many civilizations there is an urgent need for measures permitting an independent lifestyle into old age. The critical role of physical exercise in mediating and maintaining physical and mental fitness is well-acknowledged. Dance, in addition to physical activity, combines emotions, social interaction, sensory stimulation, motor coordination and music, thereby creating enriched environmental conditions for human individuals. Here we demonstrate the impact of multi-year (average 16.5 years) amateur dancing (AD) in a group of elderly subjects (aged 65-84 years) as compared to education-, gender- and aged-matched controls (CG) having no record of dancing or sporting activities. Besides posture and balance parameters, we tested reaction times, motor behavior, tactile and cognitive performance. In each of the different domains investigated, the AD group had a superior performance as compared to the non-dancer CG group. Analysis of individual performance revealed that the best participants of the AD group were not better than individuals of the CG group. Instead, the AD group lacked individuals showing poor performance, which was frequently observed for the CG group. This observation implies that maintaining a regular schedule of dancing into old age can preserve cognitive, motor and perceptual abilities and prevent them from degradation. We conclude that the far-reaching beneficial effects found in the AD group make dance, beyond its ability to facilitate balance and posture, a prime candidate for the preservation of everyday life competence of elderly individuals. PMID- 20725637 TI - Insect repellents: modulators of mosquito odorant receptor activity. AB - BACKGROUND: DEET, 2-undecanone (2-U), IR3535 and Picaridin are widely used as insect repellents to prevent interactions between humans and many arthropods including mosquitoes. Their molecular action has only recently been studied, yielding seemingly contradictory theories including odorant-dependent inhibitory and odorant-independent excitatory activities on insect olfactory sensory neurons (OSNs) and odorant receptor proteins (ORs). METHODOLOGY/PRINCIPAL FINDINGS: Here we characterize the action of these repellents on two Aedes aegypti ORs, AaOR2 and AaOR8, individually co-expressed with the common co-receptor AaOR7 in Xenopus oocytes; these ORs are respectively activated by the odors indole (AaOR2) and (R) (-)-1-octen3-ol (AaOR8), odorants used to locate oviposition sites and host animals. In the absence of odorants, DEET activates AaOR2 but not AaOR8, while 2 U activates AaOR8 but not AaOR2; IR3535 and Picaridin do not activate these ORs. In the presence of odors, DEET strongly inhibits AaOR8 but not AaOR2, while 2-U strongly inhibits AaOR2 but not AaOR8; IR3535 and Picaridin strongly inhibit both ORs. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that repellents can act as olfactory agonists or antagonists, thus modulating OR activity, bringing concordance to conflicting models. PMID- 20725638 TI - Collective dynamics of specific gene ensembles crucial for neutrophil differentiation: the existence of genome vehicles revealed. AB - Cell fate decision remarkably generates specific cell differentiation path among the multiple possibilities that can arise through the complex interplay of high dimensional genome activities. The coordinated action of thousands of genes to switch cell fate decision has indicated the existence of stable attractors guiding the process. However, origins of the intracellular mechanisms that create "cellular attractor" still remain unknown. Here, we examined the collective behavior of genome-wide expressions for neutrophil differentiation through two different stimuli, dimethyl sulfoxide (DMSO) and all-trans-retinoic acid (atRA). To overcome the difficulties of dealing with single gene expression noises, we grouped genes into ensembles and analyzed their expression dynamics in correlation space defined by Pearson correlation and mutual information. The standard deviation of correlation distributions of gene ensembles reduces when the ensemble size is increased following the inverse square root law, for both ensembles chosen randomly from whole genome and ranked according to expression variances across time. Choosing the ensemble size of 200 genes, we show the two probability distributions of correlations of randomly selected genes for atRA and DMSO responses overlapped after 48 hours, defining the neutrophil attractor. Next, tracking the ranked ensembles' trajectories, we noticed that only certain, not all, fall into the attractor in a fractal-like manner. The removal of these genome elements from the whole genomes, for both atRA and DMSO responses, destroys the attractor providing evidence for the existence of specific genome elements (named "genome vehicle") responsible for the neutrophil attractor. Notably, within the genome vehicles, genes with low or moderate expression changes, which are often considered noisy and insignificant, are essential components for the creation of the neutrophil attractor. Further investigations along with our findings might provide a comprehensive mechanistic view of cell fate decision. PMID- 20725640 TI - Monomers for preparation of amide linked RNA: Synthesis of C3'-homologated nucleoside amino acids from d-xylose. AB - Amides as neutral and hydrophobic internucleoside linkages in RNA are highly interesting modifications for RNA interference. However, testing amides in siRNAs is hampered by the shortage of efficient methods to synthesize the monomeric building blocks, the nucleoside amino acid equivalents. This paper reports an efficient synthesis of protected ribonucleoside 5'-amino 3'-carboxylic acids from d-xylose in 14 steps 7% overall yield. The key features that ensure efficiency and ease of operations are chemoselective reduction of the ester and minimization of protecting group manipulation. PMID- 20725639 TI - An event-related FMRI study of phonological verbal working memory in schizophrenia. AB - BACKGROUND: While much is known about the role of prefrontal cortex (PFC) in working memory (WM) deficits of schizophrenia, the nature of the relationship between cognitive components of WM and brain activation patterns remains unclear. We aimed to elucidate the neural correlates of the maintenance component of verbal WM by examining correct and error trials with event-related fMRI. METHODOLOGY/FINDINGS: Twelve schizophrenia patients (SZ) and thirteen healthy control participants (CO) performed a phonological delayed-matching-to-sample task in which a memory set of three nonsense words was presented, followed by a 6 seconds delay after which a probe nonsense word appeared. Participants decided whether the probe matched one of the targets, and rated the confidence of their decision. Blood-oxygen-level-dependent (BOLD) activity during WM maintenance was analyzed in relation to performance (correct/error) and confidence ratings. Frontal and parietal regions exhibited increased activation on correct trials for both groups. Correct and error trials were further segregated into true memory, false memory, guess, and true error trials. True memory trials were associated with increased bilateral activation of frontal and parietal regions in both groups but only CO showed deactivation in PFC. There was very little maintenance related cortical activity during guess trials. False memory was associated with increased left frontal and parietal activation in both groups. CONCLUSION: These findings suggest that a wider network of frontal and parietal regions support WM maintenance in correct trials compared with error trials in both groups. Furthermore, a more extensive and dynamic pattern of recruitment of the frontal and parietal networks for true memory was observed in healthy controls compared with schizophrenia patients. These results underscore the value of parsing the sources of memory errors in fMRI studies because of the non-linear nature of the brain-behavior relationship, and suggest that group comparisons need to be interpreted in more specific behavioral contexts. PMID- 20725641 TI - Terminating Catalytic Asymmetric Heck Cyclizations by Stereoselective Intramolecular Capture of eta-Allylpalladium Intermediates: Total Synthesis of ( )-Spirotryprostatin B and Three Stereoisomers. AB - A catalytic intramolecular Heck reaction, followed by capture of the resulting eta(3)-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (-)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral eta(3) allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration. PMID- 20725643 TI - ON IDENTIFYING INFORMATION FROM IMAGE-BASED SPATIAL POLARITY PHENOTYPES IN NEUTROPHILS. AB - Cell polarity is involved in many biological functions such as development, wound healing and immune responses. In human neutrophils, polarization is characterized by the translocation of distinct sets of signaling molecules to opposite ends of the cell and the rapid rearrangement of cytoskeleton to initiate migration. While many image-based studies have described cellular morphology and the intensity level of polarity signaling molecules, systematic characterization of the spatial distribution of polarity signaling molecules has been lacking. Here we designed a collection of analytical features to quantify spatial phenotypes of polarity molecules. We compared our features to commonly used polarity readouts and found that they captured additional aspects of the polarization dynamics that were not contained in the existing features. Our work provides a starting point to identify informative features for the study of neutrophil polarization. PMID- 20725642 TI - Host-guest interactions mediated nano-assemblies using cyclodextrin-containing hydrophilic polymers and their biomedical applications. AB - Supramolecular nanostructures assembled by polymeric amphiphiles have been intensively studied during the last two decades. Such nanocarriers may be engineered to possess on-demand bio-responsitivity for the prevention, diagnosis, and treatment of human diseases. The successful development of several nanoassembly-based polymer therapeutics further encouraged scientists to develop nano-vehicles to achieve controlled release, enhanced efficacy, improved specificity and reduced toxicity. Different from the abundant existing literatures on the hydrophobically or electrostatically driven self-assemblies and their therapeutic applications, this article reviews host-guest interaction mediated nanoassemblies, especially those constructed using cyclodextrins as the host entities. The excellent biocompatibility, complexation capacity, and chemical-sensitivity of cyclodextrin make cyclodextrin-containing polymers attractive to construct host-guest nanoassemblies. Such nanocarriers may be advantageous also because of the broad availability of cyclodextrins, their flexibility for structure/property modulation and their chemical-responsive characteristics. PMID- 20725644 TI - Chromosome numbers in Tripleurospermum Sch. Bip. (Asteraceae) and closely related genera: relationships between ploidy level and stomatal length. AB - This study includes 24 reports of chromosome counts in Tripleurospermum Sch. Bip. (20 taxa), Anthemis L. (1 species) and Matricaria L. (3 taxa) belonging to the tribe Anthemideae of the family Asteraceae from Turkey. Chromosome numbers of these taxa are 2n = 2x = 18, 3x = 27 and 4x = 36. Nine counts are new reports, one is not consistent with previous report, and the remainder confirm earlier information. Statistically significant differences depending on ploidy level, stomatal length or environmental factors such as altitude were determined in Tripleurospermum. Several systematic and evolutionary aspects of the genera are discussed in the light of chromosomal data. PMID- 20725645 TI - Personal remarks on the future of protein crystallography and structural biology. AB - Protein crystallography, the main experimental method of structural biology, has undergone in the recent past three revolutionary changes leading to its unexpected renaissance. They were connected with (i) the introduction of synchrotron radiation sources for X-ray diffraction experiments, (ii) implementation of Se-Met multiwavelength anomalous diffraction (MAD) for phasing, and (iii) initiation of structural genomics (SG) programs. It can be foreseen that in the next 10-15 years protein crystallography will continue to be in this revolutionary phase. We can expect not only an avalanche of protein crystal structures from SG centers, but also attacking of more demanding projects, such as the structure of membrane proteins and of very large macromolecular complexes. On the technological front, the introduction of X-ray radiation from free electron lasers will revolutionize the experimental possibilities, making feasible even the imaging of single molecules and of intact biological cells. PMID- 20725646 TI - Suppressor of cytokine signaling and accelerated atherosclerosis in kidney disease. AB - The prevalence of cardiovascular disease in patients with renal failure is extremely high and accounts for a large part of the morbidity and mortality. Inflammation participates importantly in host defense against infectious agents and injury, but also contributes to the pathophysiology of many diseases, including cardiovascular atherosclerosis, which is a main problem in patients with renal failure. Recruitment of blood leukocytes to the injured vascular endothelium characterizes the initiation and progression of atherosclerosis and involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. Excessive inflammatory and immune responses, communicated by these different cell types, are driven by inflammatory cytokines that promote associated tissue damage if cytokine signaling pathways remain unregulated. Thus, pathways capable of suppressing proinflammatory cytokine signaling hold the potential to limit life-threatening cardiovascular events caused by atherogenesis. Suppressor of cytokine signaling (SOCS) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine-mediated homeostasis, including innate and adaptive immunity. Accumulating evidence supports the idea that dysregulation of cytokine signaling by differential SOCS expression is involved in the pathogenesis of various inflammatory, and immunological diseases, including atherosclerosis. Based on recent observations, in which SOCS expression levels are profoundly altered in kidney disease, we discuss the possibilities of SOCS as new intracellular markers of inflammation as well as their potential atherogenic properties in renal failure related cardiovascular disease. PMID- 20725647 TI - Evidence for RNA recombination between distinct isolates of Pepino mosaic virus. AB - Genetic recombination plays an important role in the evolution of virus genomes. In this study we analyzed publicly available genomic sequences of Pepino mosaic virus (PepMV) for recombination events using several bioinformatics tools. The genome-wide analyses not only confirm the presence of previously found recombination events in PepMV but also provide the first evidence for double recombinant origin of the US2 isolate. PMID- 20725648 TI - Human plasma and cerebrospinal fibronectins differ in the accessibility of the epitopes on the N-terminal domains. AB - Three monoclonal antibodies specific to the central cell-binding and the C- and N terminal domains of fibronectin (FN) were used to test antigenic epitope accessibility on human plasma and cerebrospinal fibronectins. In the plasma group, the mean N-terminal FN domain immunoreactivity was about one fourth that of the cell-binding and C-terminal domains, whereas in cerebrospinal fluid they were nearly equal. In the presence of 0.5-6 M urea N-terminal domain immunoreactivity in the plasma increased 3-6-fold, but it decreased 0.7-3-fold in the cerebrospinal fluid. Analysis of fibronectin domain immunoreactivities of the cell-binding and N-terminal domains by a panel of specific monoclonal antibodies may reveal N-terminal fibronectin domain accessibility for reaction with biological partner ligand(s) and/or processes in which FN could be implicated. Such determinations may have important clinical implications. PMID- 20725649 TI - Acaconin, a chitinase-like antifungal protein with cytotoxic and anti-HIV-1 reverse transcriptase activities from Acacia confusa seeds. AB - From the seeds of Acacia confusa, a chitinase-like antifungal protein designated as acaconin that demonstrated antifungal activity toward Rhizoctonia solani with an IC50 of 30+/-4 uM was isolated. Acaconin demonstrated an N-terminal sequence with pronounced similarity to chitinases and a molecular mass of 32 kDa. It was isolated by chromatography on Q-Sepharose, SP-Sepharose and Superdex 75 and was not bound by either ion exchanger. Acaconin was devoid of chitinase activity. The antifungal activity against Rhizoctonia solani was completely preserved from pH 4 to 10 and from 0 degrees C to 70 degrees C. Congo Red staining at the tips of R. solani hyphae indicated inhibition of fungal growth. However, there was no antifungal activity toward Mycosphaerella arachidicola, Fusarium oxysporum, Helminthosporium maydis, and Valsa mali. Acaconin inhibited proliferation of breast cancer MCF-7 cells with an IC50 of 128+/-9 uM but did not affect hepatoma HepG2 cells. Its IC50 value toward HIV-1 reverse transcriptase was 10+/-2.3 uM. The unique features of acaconin include relatively high stability when exposed to changes in ambient pH and temperature, specific antifungal and antitumor actions, potent HIV-reverse transcriptase inhibitory activity, and lack of binding by strongly cationic and anionic exchangers. PMID- 20725650 TI - Evaluation of p-phenylene-bis and phenyl dithiocarbamate sodium salts as inhibitors of mushroom tyrosinase. AB - Two structurally related compounds, phenyl dithiocarbamate sodium salt (I) and p phenylene-bis (dithiocarbamate) sodium salt (II) were prepared by reaction of the parent aniline and p-phenylenediamine with CS2 in the presence of sodium hydroxide. These water soluble compounds were characterized by spectroscopic techniques, IR, 1H NMR and elemental analysis. The inhibitory effects of both compounds on both activities of mushroom tyrosinase (MT) from Agricus bisporus were studied at two temperatures, 27 degrees C and 37 degrees C. L-3, 4 dihydroxyphenylalanine (L-DOPA), and l-tyrosine were used as natural substrates for the catecholase and cresolase enzyme reactions, respectively. Kinetic analysis confirmed noncompetitive inhibition mode of I and mixed type of II on both activities of MT; I and II inhibit MT with inhibition constants (K(I)) of 300 uM and 4 uM, respectively. Analysis of thermodynamic parameters indicated predominant involvement of hydrophobic interactions in binding of I and electrostatic ones in binding of II to MT. It seems that II is a more potent MT inhibitor due to its two charged head groups able to chelate copper ions in the enzyme active site. Intrinsic fluorescence studies as a function of concentrations of both compounds showed unexpectedly quenching of emission intensity without any shift of emission maximum. Extrinsic ANS-fluorescence indicated that only binding of I induces limited changes in the tertiary structure of MT, in agreement with the postulated hydrophobic nature of the binding mechanism. PMID- 20725652 TI - Identification of the nitrogen species on N-doped graphene layers and Pt/NG composite catalyst for direct methanol fuel cell. AB - Heat treatment of graphene oxide (GO) with ammonia flow at various temperatures resulted in different distribution of nitrogen species. Synchrotron based X-ray absorption near-edge structure (XANES) spectroscopy provides unambiguous evidence for the presence of three nitrogen species. The Pt/NG-800 composite exhibits outstanding electrocatalytic activity for methanol oxidation. PMID- 20725651 TI - DNAzyme as an efficient tool to modulate invasiveness of human carcinoma cells. AB - In this study we evaluated efficiency of DNAzymes to modulate motility of cancer cells, an important factor in the progression and metastasis of cancers. For this purpose we targeted beta1 integrins that are predominant adhesive receptors in various carcinoma cell lines (CX1.1, HT29, LOVO, LS180, PC-3). To evaluate invasiveness of cancer cells, we used a transwell migration assay that allowed analyzing chemotactic migration of colon carcinoma cell lines across an ECM coated membrane. Their adhesive properties were also characterized by the analysis of adhesion to fibronectin, laminin and collagen. In addition, the expression of major integrin subunits, selected intact beta1 integrins, and other adhesive receptors (ICAM, E-selectin, uPAR) was analyzed by flow cytometry. Inhibition of beta1 integrin expression by DNAzyme to beta1 mRNA almost abolished the invasiveness of the CX1.1, HT29, LS180, LOVO and PC-3 cells in vitro. These data show that DNAzymes to beta1 integrin subunit can be used to inhibit invasiveness of carcinoma cells. PMID- 20725653 TI - Synthesis, radii dependent self-assembly crystal structures and luminescent properties of rare earth (III) complexes with a tripodal salicylic derivative. AB - Five new rare earth complexes with a new flexible tripodal salicylic ligand (H(3)L), 2,2'-(2-((2-carboxyphenoxy)methyl)-2-(4-methylphenylsulfonamido)propane 1,3-diyl)bis(oxy)dibenzoic acid, of formulae [La(2)L(2)(DMF)(4)].4DMF.4EtOH.2H(2)O (1), [Eu(2)L(2)(DMF)(4)].2DMF (2), {[GdL(DMF)(H(2)O)(2)].DMF}(infinity) (3), {[TbL(DMF)(H(2)O)(2)].DMF}(infinity) (4) and {[YL(DMF)(H(2)O)(2)].DMF}(infinity) (5) (DMF = N,N-dimethylformamide) have been prepared. The single-crystal X-ray diffraction analysis revealed that complexes 1 and 2 present a cage-like homodinuclear species, while 3-5 show a helical one-dimensional coordination polymer. All these complexes are further connected by hydrogen bonds or pi-pi interactions, resulting in 3D supramolecular structures. The photophysical properties of the Eu and Tb complexes are investigated in the solid state at room temperature. PMID- 20725654 TI - Electronic state spectroscopy of methyl formate probed by high resolution VUV photoabsorption, He(i) photoelectron spectroscopy and ab initio calculations. AB - The first ab initio calculations of the vertical excitation energies and oscillator strengths are presented for the neutral electronic transitions of methyl formate, C(2)H(4)O(2). The highest resolution VUV photoabsorption spectrum of the molecule yet reported is presented over the wavelength range 115 to 310 nm (10.8 to 4.0 eV) revealing several new spectral features. Valence and Rydberg transitions and their associated vibronic series, observed in the photoabsorption spectrum, have been assigned in accordance with new theoretical results. The calculations have been carried out to determine the excitation energies of the lowest energy ionic states of methyl formate and are compared with a newly recorded He(i) photoelectron spectrum (10.4 to 17.0 eV). New vibrational structure is observed in the first photoelectron band. The photoabsorption cross sections have been used to calculate the photolysis lifetime of methyl formate in the upper stratosphere (20-50 km). PMID- 20725655 TI - Kinetic studies of reactions of organosilylenes: what have they taught us? AB - Rate constants for bimolecular reactions, obtained through time-resolved kinetic studies both in the gas and liquid phases are reviewed. Data for reactions of MeSiH, PhSiH, ClSiH, SiCl(2), SiMe(2), MeSiPh, SiPh(2) and SiMes(2) are covered. Where possible, substituent effects relative to SiH(2) have been obtained. These demonstrate widely varying effects between different types of reaction, which aids mechanistic understanding. Reactivities are high for all silylenes, but substituents can reduce them by both electronic and steric effects. The gas and liquid phase data (mainly for SiMe(2)) are compared and appear to be reasonably consistent. This review, although detailed, is not comprehensive. PMID- 20725656 TI - An allosteric heteroditopic receptor for neutral guests and contact ion pairs with a remarkable selectivity for ammonium fluoride salts. AB - Two novel calix[6]cryptamides bearing a tren-based cap have been synthesized and their host-guest properties have been investigated by (1)H and (19)F NMR spectroscopy. One of them behaves as a remarkable heteroditopic receptor toward either polar neutral guests, anions or contact ion pairs. It has been shown that only F(-) can be encapsulated into the tris-amido cap of this host. Moreover, the fluoride anion acts as an allosteric activator by favoring the inclusion of ammonium ions into the calixarene cavity. The ammonium fluoride salts are bound as contact ion pairs and, remarkably, the calix[6]cryptamide host is reluctant to other ammonium salts. To our knowledge, such an highly cooperative and selective process toward contact ammonium fluoride salts is unique in the literature. Allosteric regulation of all the host-guest systems can also be achieved through protonation of the aza-cap. Indeed, guest release can be triggered by addition of various acids. In comparison to related calixarene-based receptors, all these unique properties are due to the smallness and the higher preorganization of the binding site provided by the convergent hydrogen bond donor groups of the tris amido cap. PMID- 20725657 TI - Modifications involved by acetylacetone in properties of sol-gel derived Y(3)Al(5)O(12):Tb(3+)- II: optical features. AB - Tb(3+)-doped Y(3)Al(5)O(12) powders have been synthesized from alkoxide precursors using, or not using, acetylacetone as a chemical modifier. The terbium oxidation state and local environment of amorphous and crystallized powders have been comparatively investigated by means of X-ray absorption near-edge structures (XANES) and extended X-ray absorption fine structure (EXAFS) while laser-induced luminescence was used to study their optical properties. Excitation and emission spectra have been recorded and a relative luminescence yield has been assessed upon 277 nm excitation. Whatever the sample, the terbium oxidation state remains +III and, for a similar heating treatment until 900 degrees C, its local environment appears to be better organized in powders modified by acetylacetone. Structural parameters obtained during XAS study are consistent with the YAG structure in which Tb atoms are in solid solution with Y ones. Besides, Tb(3+) characteristic green luminescence has been recorded for all samples, even those amorphous. It has been evidenced that the use of acetylacetone leads to more efficient luminescent materials for calcination temperatures ranging from 400 degrees C to 900 degrees C upon 277 nm excitation. Discrepancies between optical properties will be discussed with regards to the terbium local environment and expected luminescence features. PMID- 20725658 TI - Protein-protein docking tested in blind predictions: the CAPRI experiment. AB - Docking algorithms build multimolecular assemblies based on the subunit structures. "Unbound" docking, which starts with the free molecules and allows for conformation changes, may be used to predict the structure of a protein protein complex. This requires at least two steps, a rigid-body search that determines the relative position and orientation of the subunits, and a refinement step. The methods developed in the past twenty years yield native-like models in most cases, but always with many false positives that must be filtered out, and they fail when the conformation changes are large. CAPRI (Critical Assessment of PRedicted Interactions) is a community-wide experiment set up to monitor progress in the field. It offers participants the opportunity to test their methods in blind predictions that are assessed against an unpublished experimental structure. The models submitted by predictor groups are judged depending on how well they reproduce the geometry and the residue-residue contacts seen in the target structure. In nine years of CAPRI, 42 target complexes have been subjected to prediction based on the components' unbound structures. Good models have been submitted for 28 targets, and prediction has failed on 6. Both these successes and these failures have been fruitful, as they stimulated participant groups to develop new score functions to identify native like solutions, and new algorithms that allow the molecules to be flexible during docking. PMID- 20725659 TI - Regioselective synthesis of di-C-glycosylflavones possessing anti-inflammation activities. AB - Three methods are utilized to synthesize a variety of 6,8-di-C-glycosylflavones bearing identical or distinct glycosyl moieties. Some C-glycosylation compounds are found to have better anti-inflammation activities than the parent flavones. Among them, 6,8-di-C-glucosylapigenin (known as vicenin-2) shows inhibition of TNF-alpha expression and NO production with IC(50) values of 6.8 and 5.2 muM, respectively. PMID- 20725660 TI - The biphenyl-monitored effective size of unsaturated functional or fluorinated ortho substituents. AB - The size of a series of typical substituents has been probed by dynamic NMR measurements of the barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful because only mono-ortho substituted compounds were investigated and thus the results are not compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of conjugation forces at the planar transition state. Alpha-Hydroxyhexafluoroisopropyl is slightly more bulky than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl and methoxy, respectively. Trifluoromethyl is somewhat smaller than isopropyl. PMID- 20725665 TI - Artificial, switchable K+-gated ion channels based on flow-through titania nanotube arrays. AB - In the present work, we demonstrated a novel type of artificial K(+)-gated ion channels based on titania nanotubes loaded with Au nanoparticles and G-rich DNA composite structure. K(+) promoted conformational change of G-rich DNA from flexible chain to rigid quadruplex, which provided a blocking effect for the transport of anions such as Fe(CN)(6)(4-) and other molecules through the channels in TiO(2) nanotubes. This fabricated permselective membrane using K(+) as a trigger may set light to the field of biosensing, drug-release, ion exchange membrane and so on. PMID- 20725661 TI - Quantum chemical dissection of the classic terpinyl/pinyl/bornyl/camphyl cation conundrum-the role of pyrophosphate in manipulating pathways to monoterpenes. AB - Based on quantum chemical studies, mechanisms to form bornyl diphosphate from geranyl diphosphate are suggested. While bornyl diphosphate is usually proposed to be generated via combination of the pyrophosphate group with a secondary bornyl cation, quantum chemical computations indicate that the bornyl cation is actually not a minimum. Instead, concerted attack of the pyrophosphate group coupled with an alkyl shift could yield bornyl diphosphate from either the pinyl cation or the camphyl cation. Hints of bifurcating pathways on the energy surfaces for such reactions were also uncovered. Of particular note is the development and validation of a large model of the pyrophosphate counterion treated entirely with quantum chemistry. PMID- 20725668 TI - An enantioselective total synthesis of natural antibiotic marasin. AB - Synthetic studies directed toward the allenediyne antibiotic marasin are presented. Different approaches to the installation of the optically active chiral allenediyne motif were explored en route to the synthesis of the natural product. The stereoselectivity for the construction of the chiral allenediyne motif was dependent on not only the reaction employed but also the substrate structure. PMID- 20725669 TI - Simultaneous analysis of mercury and selenium species including chiral forms of selenomethionine in human urine and serum by HPLC column-switching coupled to ICP MS. AB - The simultaneous speciation of elements is of great concern, especially in the study of the interactions of species in living organisms. Here we report a method based on the coupling of HPLC-ICP-MS that is capable of separating and analyzing different selenium and mercury species (Se-methylselenocysteine, selenite, selenate, L-selenomethionine, D-selenomethionine, methylmercury and inorganic mercury). The proposed method uses two different mobile phases that are suitable for selenium and mercury speciation and leads to a successful determination of all the species in less than 27 min with good efficiency and resolution. The method was efficiently applied for simultaneous speciation of mercury and selenium in urine and in serum, the latter from umbilical cord samples. Selenocystine has been successfully identified in the former sample. Detection limits obtained were between 0.30 and 2.46 ng. Recovery studies of samples spiked with all species were performed to check the reliability of the method, and satisfactory recoveries (93-110%) were obtained in all cases. The relative standard deviations (RSDs) for species with ten replicate determinations of 80 MUg L(-1) were between 4.5 and 9.2%. The proposed method offers a deeper insight into selenium and mercury interactions in the human body. PMID- 20725670 TI - Confocal Raman microscopy: common errors and artefacts. AB - Confocal Raman microscopy is a powerful tool for research and analysis in the chemical, materials and life sciences, particularly for non-destructive depth profiling of transparent systems. Unfortunately, many Raman microscopes are not optimally configured for this purpose, and so yield unnecessarily low signal-to noise spectra with poor spatial resolution and grossly incorrect depth scales. This review discusses the aberrations and artefacts that can arise and describes how these can be avoided by adhering to a few basic principles that are well known to optical microscopists but which were largely ignored in the spectroscopic community for many years. PMID- 20725671 TI - Polymeric ligands as homogeneous, reusable catalyst systems for copper assisted click chemistry. AB - Tris-(benzyltriazolylmethyl)amine (TBTA) has been immobilized onto a styrenic monomer and subsequently copolymerized with styrene to afford catalytically active and reusable copolymers for the CuAAC reaction. PMID- 20725672 TI - Copper-catalyzed asymmetric addition of arylboronates to isatins: a catalytic cycle involving alkoxocopper intermediates. AB - A copper-catalyzed addition of arylboronates to isatins has been developed to give 3-aryl-3-hydroxy-2-oxindoles under mild conditions. The catalytic cycle of this process has been examined through a series of stoichiometric reactions and an effective asymmetric variant has also been described by the use of a chiral N heterocyclic carbene ligand. PMID- 20725673 TI - Reaction dynamics of the D+ + H2 system. A comparison of theoretical approaches. AB - The dynamics of the deuteron-proton exchange D(+) + H(2) -> HD + H(+) reaction on its ground 1(1)A' potential energy surface has been the subject of a theoretical study for collision energies below 1.5 eV. The results obtained with three theoretical approaches: quasi-classical trajectory (QCT), statistical quasi classical trajectory (SQCT), and accurate time-independent quantum mechanical (QM) calculations are compared in the range of collision energies from 5 meV to 0.2 eV. The QM calculations included all total angular momentum quantum numbers, J, up to J(max) ~ 40 and all the Coriolis couplings. For higher collision energies, the comparison was restricted to the QCT and SQCT results given the enormous computational cost implied in the QM calculations. Reaction cross sections as a function of collision energy (excitation functions) for various initial rovibrational states have been determined and compared with the corresponding results for the endothermic H(+) + D(2) -> HD + D(+) isotopic variant. The excitation function for the title reaction decays monotonically with collision energy as expected for an exothermic reaction without a barrier, in contrast to the behaviour observed in the mentioned H(+) + D(2) (v = 0, j <= 3). Reaction probabilities as a function of J (opacity functions) at several collision energies calculated with the different approaches were also examined and important differences between them were found. The effect of using the gaussian binning procedure that preserves, to a large extent, the zero point energy, as compared to the standard histogram binning in the QCT calculations, is also examined. At low collision energy, the best agreement with the accurate QM results is given by the SQCT data, although they tend to overestimate the reactivity. The deviations from the statistical behaviour of the QCT data at higher energies are remarkable. Nevertheless, on the whole, the title reaction can be deemed more statistical than the H(+) + D(2) reaction. PMID- 20725674 TI - Formation of very stable and selective Cu(II) complexes with a non-macrocyclic ligand: can basicity rival pre-organization? AB - The synthesis of ligand L based on a 2,6-bis[(N,N-bis(methylene phosphonic acid)aminomethyl] pyridine scaffold is described. Potentiometry combined with UV Vis absorption spectrophotometric titrations were used to determine the protonation constants of the ligand and the stability constants of its corresponding Cu(II), Ni(II), Zn(II) and Ga(III) cations (0.1 M NaClO(4), 25.0 degrees C). The physico-chemical approach revealed very large stability constants for Cu(II) complexation (logK(CuL) = 22.71(7)) reflected in a very high pCu(II) value of ~ 15.5 (pH = 7.4, [L](tot) = 10(-5) M, [Cu](tot) = 10(-6) M), close to those measured for the strong methylphosphonate functionalized cyclen chelators. Based on a literature survey, a correlation is proposed between the pK values of branched polyamine ligands and their stability constants for Cu(II) complexation, allowing for an estimation of the latter on the basis of the protonation constants of L. Ligand L was also shown to be very selective towards Cu(II) compared to the other cations studied (DeltalogK > 4). UV-Vis spectroscopy and kinetic measurements indicated that the formation of the cupric complexes with L is very fast, which, in combination with all other properties, makes it an excellent non-cyclic target for Cu(II) radiopharmaceutical within the frame of (64)Cu positron emission tomography imaging and radiotherapy. PMID- 20725675 TI - Structural and magnetic properties of the ordered perovskite Pb2CoTeO6. AB - The complex perovskite Pb(2)CoTeO(6) (PCTO) has been prepared as polycrystalline powders by a solid state reaction route, and the crystal structure and magnetic properties have been investigated using a combination of X-ray and neutron powder diffraction, electron microscopy, dielectric, calorimetric and magnetic measurements. It was shown that at room temperature this compound adopts a trigonal perovskite structure, space group R3 (a = 5.6782(1) A, c = 13.8552(3) A). The compound undergoes a number of temperature-induced phase transitions and adopts four different structures in the temperature range 5-500 K: monoclinic in P2(1)/n (5 < T < 125 K, tilt system (a(+)b(-)b(-))), monoclinic in I2/m (125 < T < 210 K, tilt system (a(0)b(-)b(-))), rhombohedral in R3 (210 < T < 370 K, tilt system (a(-)a(-)a(-))), and finally cubic in Fm3m (above 370 K without any tilting). These structural phase transitions are coupled to changes in the dielectric constant and the heat capacity around 210 and 370 K. A long-range antiferromagnetically ordered state has been identified from neutron powder diffraction and magnetic studies at different temperatures. Magnetic diffraction peaks were registered below the transition at about 16 K and a possible model for the magnetic structure is proposed. Possible coexistence of long-range ordering of the electrical dipoles and the magnetic moments at low temperatures making PCTO a potential multiferroic candidate is discussed. PMID- 20725676 TI - An integrative model for vascular endothelial growth factor A as a tumour biomarker. AB - Vascular endothelial growth factor A (VEGF-A) and its cognate receptors are central to the regulation of angiogenesis in both physiological and pathological states. In cancer, local tumour hypoxia stimulates VEGF-A synthesis and VEGF-A levels are subsequently elevated in a wide variety of cancers. VEGF-A thus has enormous potential as a diagnostic and prognostic biomarker of disease status. The justification of VEGF-A as a biomarker has not yet been achieved, primarily due to our lack of understanding of its multiple splice variants and its spatio temporal distribution. Here we highlight how recent technological advancements and kinetic-dynamic modelling could be used towards validating VEGF-A as a biomarker for clinical use in human disease management. PMID- 20725677 TI - Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. AB - Integrins are ubiquitous transmembrane mechanoreceptors that elicit changes in intracellular biochemistry in response to mechanical force application, but these alterations generally proceed over seconds to minutes. Stress-sensitive ion channels represent another class of mechanoreceptors that are activated much more rapidly (within msec), and recent findings suggest that calcium influx through Transient Receptor Potential Vanilloid-4 (TRPV4) channels expressed in the plasma membrane of bovine capillary endothelial cells is required for mechanical strain induced changes in focal adhesion assembly, cell orientation and directional migration. However, whether mechanically stretching a cell's extracellular matrix (ECM) adhesions might directly activate cell surface ion channels remains unknown. Here we show that forces applied to beta1 integrins result in ultra rapid (within 4 msec) activation of calcium influx through TRPV4 channels. The TRPV4 channels were specifically activated by mechanical strain in the cytoskeletal backbone of the focal adhesion, and not by deformation of the lipid bilayer or submembranous cortical cytoskeleton alone. This early-immediate calcium signaling response required the distal region of the beta1 integrin cytoplasmic tail that contains a binding site for the integrin-associated transmembrane CD98 protein, and external force application to CD98 within focal adhesions activated the same ultra-rapid calcium signaling response. Local direct strain-dependent activation of TRPV4 channels mediated by force transfer from integrins and CD98 may therefore enable compartmentalization of calcium signaling within focal adhesions that is critical for mechanical control of many cell behaviors that underlie cell and tissue development. PMID- 20725680 TI - Effect of diffusion on impedance measurements in a hydrodynamic flow focusing sensor. AB - This paper investigated the effects of diffusion between non-conductive sheath and conductive sample fluids in an impedance-based biosensor. Impedance measurements were made with 2- and 4-electrode configurations. The 4-electrode design offers the advantage of impedance measurements at low frequencies (<1 kHz) without the deleterious effects of double layer impedance which are present in the 2-electrode design. Hydrodynamic flow focusing was achieved with a modified T junction design with a smaller cross-section for the sample channel than for the focusing channel, which resulted in 2D focusing of the sample stream with just one sheath stream. By choosing a non-conductive sheath fluid and a conductive sample fluid, the electric field was confined to the focused stream. In order to utilize this system for biosensing applications, we characterized it for electrical and flow parameters. In particular, we investigated the effects of varying flow velocities and flow-rate ratios on the focused stream. Increasing flow-rate ratios reduced the cross-sectional area of the focused streams as was verified by finite element modeling and confocal microscopy. Antibody mediated binding of Escherichia coli to the electrode surface caused an increase in solution resistance at low frequencies. The results also showed that the diffusion mass transport at the interface of the two streams limited the benefits of increased flow focusing. Increasing flow velocities could be used to offset the diffusion effect. To optimize detection sensitivity, flow parameters and mass transport must be considered in conjunction, with the goal of reducing diffusion of conducting species out of the focused stream while simultaneously minimizing its cross-sectional area. PMID- 20725679 TI - Excited state proton transfer in the Cinchona alkaloid cupreidine. AB - Photophysical properties of the organocatalyst cupreidine (CPD) and its chromophoric building block 6-hydroxyquinoline (6HQ) in protic and nonprotic polar solvents (methanol and acetonitrile) were investigated by means of UV-vis absorption, and steady state and time resolved fluorescence spectroscopy. The effects of the catalytically relevant interactions with electrophilic and hydrogen bonding agents (p-toluene sulfonic acid and water) on their spectral characteristics were studied. In neutral CPD in acetonitrile, quenching of fluorescence occurs due to electron transfer from the quinuclidine nitrogen to the excited quinoline chromophore. Protonation suppresses this process, while complexation with water leads to enhanced excited state proton transfer from the 6'-OH group to the quinuclidine nitrogen, and emission occurs from the anionic form of the chromophore. The weakly emitting zwitterionic form of the hydroxyquinoline chromophore is readily formed in methanol, but not in acetonitrile. PMID- 20725681 TI - UV absorbing zwitterionic pyridinium-tetrazolate: exceptional transparency/optical nonlinearity trade-off. AB - We present relevant results dealing with the transparency/optical nonlinearity trade-off in high-frequency electro-optic applications. The very simple, stable and high optical gap chromophore, the zwitterion 1-methyl-4-(tetrazol-5 ate)pyridinium, represents the best transparency/optical nonlinearity trade-off so far described in the literature. We rationalize this remarkable performance in the framework of the Bond Length Alternation theory by means of a multidisciplinary approach including: single crystal X-ray structure, Electric Field Induced Second-Harmonic Generation, solvatochromism, electrochemistry and thermal analyses. PMID- 20725682 TI - Preparation of millimetre-sized mesoporous carbon spheres as an effective bilirubin adsorbent and their blood compatibility. AB - Millimetre-sized mesoporous carbon spheres (MMCSs) with smooth surface and penetrating mesoporous channels have been successfully prepared by an emulsion EISA technique, and are found to be a much better bilirubin adsorbent than commercial activated carbon spheres. Hemolysis and coagulation assays of MMCSs indicate that they have negligible hemolysis effect and do not induce blood coagulation. PMID- 20725683 TI - Influence of phosphate anion adsorption on the kinetics of oxygen electroreduction on low index Pt(hkl) single crystals. AB - The detrimental effects of phosphate anion adsorption on the oxygen reduction reactions (ORR) on low index Pt single crystal electrodes were studied in 0.1 M perchloric acid by using a hanging meniscus rotating disk electrode in the presence of varied concentrations of H(3)PO(4). The kinetic current for ORR decreased dramatically on Pt(100), Pt(110), Pt(111), and PtSn(111) even with the addition of a small amount (1 mM) of H(3)PO(4) into the perchloric acid solution, most probably due to the adsorption of phosphate anions onto the Pt active sites that impeded the electroreduction of O(2). Remarkably, the extent of decline was found to vary with the specific single crystal surface, following the order of Pt(111) > PtSn(111) > Pt(110) ~ Pt(100). Consistent behaviors were also observed in Tafel analysis and in electrochemical impedance spectroscopic measurements. Within the present experimental context, Pt(110) was found to be the optimal crystal surface for ORR in phosphoric acid fuel cells with the smallest charge transfer resistance, whereas the poisoning effects of phosphate anion adsorption were the most pronounced on Pt(111), most likely because the phosphate anions primarily adsorbed on the 3-fold sites on the Pt(111) faces, as manifested in in situ X-ray absorption spectroscopic measurements. PMID- 20725684 TI - delta-Bonding in the [Pd4(MU4-C9H9)(MU4-C8H8)]+ sandwich complex. AB - A remarkable triple-decker sandwich complex [Pd(4)(MU(4)-C(9)H(9))(MU(4) C(8)H(8))][BAr(f)(4)] (BAr(f)(4) = B{3,5-(CF(3))(2)(C(6)H(3))}(4)) composed of cyclononatetraenyl anion and cyclooctatetraene as "bread pieces" and square tetrapalladium dication as "meat" (Fig. 1a) has been synthesized recently [Murahashi et al., J. Am. Chem. Soc., 2009, 131, 9888]. This complex attracted our attention because of the presence of an almost perfect square sheet composed of four palladium atoms. Such a structure could be a sign of aromatic nature of chemical bonding as it was shown to be present in the square Al(4)(2-) cluster [Li et al., Science, 2001, 291, 859]. In this work we show that according to our chemical bonding analysis the bonding in the Pd(4)(2+) unit of [Pd(4)(MU(4) C(9)H(9))(MU(4)-C(8)H(8))](+) is of delta-character among four palladium atoms, making the triple-decker sandwich complex the first synthesized compound identified as having delta-bonding in its cyclic building block when it's in solution or in a crystalline state. PMID- 20725686 TI - Synthesis and solid state structure of a hydrazone-disulfide macrocycle and its dynamic covalent ring-opening under acidic and basic conditions. AB - The synthesis and characterisation, including solid state structure, of a macrocycle containing both a hydrazone and a disulfide linkage is described. Selective ring-opening of the macrocycle under thermodynamic control could be achieved at either the disulfide or the hydrazone linkage by applying mutually exclusive sets of reaction conditions. PMID- 20725685 TI - Monocationic gold(III) Gly-L-His and L-Ala-L-His dipeptide complexes: crystal structures arising from solvent free and solvent-containing crystal formation and structural modifications tuned by counter-anions. AB - Monocationic gold(III) complexes with histidine-containing peptides, glycyl-L histidine (Gly-L-His) and L-alanyl-L-histidine (L-Ala-L-His) have been synthesized and characterized by (1)H NMR spectroscopy and X-ray crystallography. The crystallized Au(III) complexes, [Au(Gly-L-His-N,N',N'')Cl]NO(3).1.25H(2)O and [Au(L-Ala-L-His-N,N',N'')Cl]NO(3).2.5H(2)O, were obtained from water solution at pH < 1.0. The chemical shifts in the (1)H NMR spectra of [Au(Gly-L-His N,N',N'')Cl]NO(3).1.25H(2)O and [Au(L-Ala-L-His-N,N',N'')Cl]NO(3).2.5H(2)O complexes were compared with those for the corresponding Pd(II) complexes and for Pd(II) and Au(III) complexes with Gly-Gly-L-His tripeptide. Crystal data for the hydrated [Au(Gly-L-His-N,N',N'')Cl]NO(3).1.25H(2)O complex and its serendipitously obtained unhydrated form were compared with previously reported X ray data for the hydrated chloride complex [Au(Gly-L-His-N,N',N'')Cl]Cl.3H(2)O and with the analogous, though uncharged, Pd(II) and Pt(II) complexes. Furthermore, in the present study the crystal structure of the nitrate salt of Au(III) complex with L-Ala-L-His dipeptide, [Au(L-Ala-L-His N,N',N'')Cl]NO(3).2.5H(2)O has been determined. PMID- 20725687 TI - Colored noise, folding rates and departure from Kramers' behavior. AB - Recent experiments have shown that, for several proteins, the dependence of folding and unfolding rates on solvent viscosity does not obey Kramers' theory. Such a departure from standard Kramers' behavior is often attributed to the existence of internal friction, related to the structure of a polypeptide chain. In this paper, we propose an entirely different mechanism leading to violation of Kramers' theory. Using the generalized Langevin equation with time-dependent friction and a C(alpha)-Go model, we demonstrate that this effect may be caused by the colored Gaussian noise which is characterized by correlation time tau. Surprisingly, the dependence of folding time t(f) on tau is non-trivial: the plot t(f)vs tau exhibits two minima at low and intermediate values of tau. The appearance of one more additional minimum is in sharp contrast to one dimensional barrier crossing dynamics. We argue that it is a generic signature of entropy of activation in a multidimensional problem. PMID- 20725688 TI - Phase segregation on electroactive self-assembled monolayers: a numerical approach for describing lateral interactions between redox centers. AB - A numerical method is proposed in order to differentiate a random distribution from a phase segregation of redox centers on (mixed) SAMs. This approach is compared to Laviron's interactions model and voltammetric data of nitroxylalkanethiolate SAMs. PMID- 20725689 TI - Hidden variety of biotin-streptavidin/avidin local interactions revealed by site selective dynamic force spectroscopy. AB - By site-selective dynamic force spectroscopy realized with the combination of cross-linkers and anatomic force microscope with a force feedback system, we have revealed, for the first time, that the slight difference between the local structures of amino acid residues at the middle sites, SER45 and THR35 for streptavidin and avidin, respectively, strongly affects the microscopic reaction processes, i.e., the variation governs the type of bond as well as the fine structure of the potential landscape. For streptavidin, a bridged or direct hydrogen bond is induced depending on the molecular structure in the buffer solution. For avidin, in contrast, only a direct hydrogen bond is observed for all the buffer solutions used in the experiment. Since final functions in a system are realized through the assembly of local effects, the obtained results indicate the importance of analyzing the reaction processes with respect to the local structures of molecules, for further development of nanoscale functional devices. PMID- 20725690 TI - Preparation of FRET reporters to support chemical probe development. AB - In high throughput screening (HTS) campaigns, the quality and cost of commercial reagents suitable for pilot studies often create obstacles upon scale-up to a full screen. We faced such challenges in our efforts to implement an HTS for inhibitors of the phosphopantetheinyl transferase Sfp using an assay that had been validated using commercially available reagents. Here we demonstrate a facile route to the synthetic preparation of reactive tetraethylrhodamine and quencher probes, and their application to economically produce fluorescent and quencher-modified substrates. These probes were prepared on a scale that would allow a full, quantitative HTS of more than 350,000 compounds. PMID- 20725692 TI - The effect of the central donor in bis(benzimidazole)-based cobalt catalysts for the selective cis-1,4-polymerisation of butadiene. AB - A series of bis(benzimidazole)-based cobalt(II) dichloride complexes containing a range of different central donors has been synthesized and characterized. The nature of the central donor affects the binding of the ligand to the cobalt centre and determines the coordination geometry of the metal complexes. All complexes have been shown to catalyse the polymerization of butadiene, in combination with MAO as the co-catalyst, to give cis-1,4-polybutadiene with high selectivity. The nature of the central donor has a marked influence on the polymerization activity of the catalysts, but does not affect the polymer microstructure. The addition of PPh(3) generally increases the polymerization activity of these cobalt catalysts and results in predominantly (60-70%) 1,2 vinyl-polybutadiene. PMID- 20725691 TI - Photocatalytic activity of S- and F-doped TiO(2) in formic acid mineralization. AB - Two series of doped titanium dioxide samples (S-TiO(2) and F-TiO(2)) were prepared by the sol-gel method in the presence of different amounts of dopant source (thiourea and NH(4)F, respectively), followed by calcination at 500, 600 or 700 degrees C, and characterised by BET, UV-vis absorption, XPS, HRTEM, XRD and EPR analyses. Reference undoped materials were prepared by the same synthetic procedure. Their photocatalytic activity under visible light was investigated employing the photocatalytic degradation of formic acid in aqueous suspension as test reaction. S-doped TiO(2) showed a photocatalytic activity quite similar to that of undoped materials. In this regard, the insertion of S, characterised by a relatively large ionic radius, into the TiO(2) crystalline structure appears rather difficult, as confirmed by XPS analysis. On the contrary, moderate F doping was beneficial in increasing the rate of formic acid photocatalytic degradation, especially for photocatalysts calcined at high temperature, consisting of highly crystalline pure anatase, in which the rate of detrimental charge carrier recombination was reduced. For both series of doped materials, high doping levels appear to limit the semiconductor photoactivity, probably due to the formation of a progressively increasing number of charge recombination centres. The EPR characterisation of the investigated doped TiO(2) samples evidenced the presence of nitrogen containing species (nitric oxide radical encapsulated in micro-void, with no photoactivity, and N(b) species, active in visible light sensitisation) and of titanium reduced centres Ti(3+), due to charge imbalance consequent to dopant introduction in the TiO(2) lattice either in anionic (F(-)) or in cationic form (S(6+)). PMID- 20725693 TI - Attomolar detection of protein biomarkers using biofunctionalized gold nanorods with surface plasmon resonance. AB - This paper describes an ultrasensitive surface plasmon resonance (SPR) detection method using biofunctionalized gold nanorods for the direct detection of protein biomarkers. Immunoglobulin E (IgE), which has separate antibody and DNA aptamer binding sites, was chosen as a model protein for which a sandwich assay platform was designed. Detection was achieved via the specific adsorption of unlabelled IgE proteins onto the surface immobilized aptamer followed by the specific adsorption of anti-IgE coated gold nanorods (Au-NRs). Using the biofunctionalized nanorods in conjunction with SPR, we were able to directly measure IgE proteins at attomolar concentrations. This is a remarkable 10(8) enhancement compared to conventional SPR measurements of the same surface sandwich assay format 'anti IgE/IgE/surface bound IgE-aptamer' in the absence of gold nanorod signal amplification. PMID- 20725695 TI - Effect of oral sirolimus therapy on inflammatory biomarkers following coronary stenting. AB - We studied the effect of oral sirolimus, administered to prevent and treat in stent restenosis (ISR), on the variation of serum levels of inflammatory markers following coronary stenting with bare metal stents. The mean age of the patients was 56 +/- 13 years, 65% were males and all had clinically manifested ischemia. Serum levels of high sensitivity C-reactive protein (hs-CRP) concentration were determined by chemiluminescence and serum levels of all other biomarkers by ELISA. One group of patients at high risk for ISR received a loading oral dose of 15 mg sirolimus and 5 mg daily thereafter for 28 days after stenting (SIR-G). A control group (CONT-G) was submitted to stenting without sirolimus therapy. The increase in hs-CRP concentration was highest at 24 h after stenting in both groups. A significant difference between SIR-G and CONT-G was observed at 4 weeks (-1.50 +/- 5.0 vs -0.19 +/- 0.4, P = 0.008) and lost significance 1 month after sirolimus discontinuation (-1.73 +/- 4.3 vs -0.01 +/- 0.7, P = 0.0975). A continuous fall in MMP-9 concentration was observed in SIR-G, with the greatest reduction at 4 weeks (-352.9 +/- 455 vs +395.2 +/- 377, P = 0.0004), while a positive variation was noted 4 weeks after sirolimus discontinuation (227 +/- 708 vs 406.2 +/- 472.1, P = 0.0958). SIR-G exhibited a higher increase in P-selectin after sirolimus discontinuation at week 8 (46.1 +/- 67.9 vs 5.8 +/- 23.7, P = 0.0025). These findings suggest that the anti-restenotic actions of systemic sirolimus include anti-proliferative effects and modulation of the inflammatory response with inhibition of adhesion molecule expression. PMID- 20725694 TI - A characterization of local LOINC mapping for laboratory tests in three large institutions. AB - OBJECTIVES: We characterized the use of laboratory LOINC(r) codes in three large institutions, focused on the following questions: 1) How many local codes had been voluntarily mapped to LOINC codes by each institution? 2) Could additional mappings be found by expert manual review for any local codes that were not initially mapped to LOINC codes by the local institution? and 3) Are there any common characteristics of unmapped local codes that might explain why some local codes were not mapped to LOINC codes by the local institution? METHODS: With Institutional Review Board (IRB) approval, we obtained deidentified data from three large institutions. We calculated the percentage of local codes that have been mapped to LOINC by personnel at each of the institutions. We also analyzed a sample of unmapped local codes to determine whether any additional LOINC mappings could be made and identify common characteristics that might explain why some local codes did not have mappings. RESULTS: Concept type coverage and concept token coverage (volume of instance data covered) of local codes mapped to LOINC codes were 0.44/0.59, 0.78/0.78 and 0.79/0.88 for ARUP, Intermountain, and Regenstrief, respectively. After additional expert manual mapping, the results showed mapping rates of 0.63/0.72, 0.83/0.80 and 0.88/0.90, respectively. After excluding local codes which were not useful for inter-institutional data exchange, the mapping rates became 0.73/0.79, 0.90/0.99 and 0.93/0.997, respectively. CONCLUSIONS: Local codes for two institutions could be mapped to LOINC codes with 99% or better concept token coverage, but mapping for a third institution (a reference laboratory) only achieved 79% concept token coverage. Our research supports the conclusions of others that not all local codes should be assigned LOINC codes. There should also be public discussions to develop more precise rules for when LOINC codes should be assigned. PMID- 20725696 TI - Genomic alterations detected by comparative genomic hybridization in ovarian endometriomas. AB - Endometriosis is a complex and multifactorial disease. Chromosomal imbalance screening in endometriotic tissue can be used to detect hot-spot regions in the search for a possible genetic marker for endometriosis. The objective of the present study was to detect chromosomal imbalances by comparative genomic hybridization (CGH) in ectopic tissue samples from ovarian endometriomas and eutopic tissue from the same patients. We evaluated 10 ovarian endometriotic tissues and 10 eutopic endometrial tissues by metaphase CGH. CGH was prepared with normal and test DNA enzymatically digested, ligated to adaptors and amplified by PCR. A second PCR was performed for DNA labeling. Equal amounts of both normal and test-labeled DNA were hybridized in human normal metaphases. The Isis FISH Imaging System V 5.0 software was used for chromosome analysis. In both eutopic and ectopic groups, 4/10 samples presented chromosomal alterations, mainly chromosomal gains. CGH identified 11q12.3-q13.1, 17p11.1-p12, 17q25.3 qter, and 19p as critical regions. Genomic imbalances in 11q, 17p, 17q, and 19p were detected in normal eutopic and/or ectopic endometrium from women with ovarian endometriosis. These regions contain genes such as POLR2G, MXRA7 and UBA52 involved in biological processes that may lead to the establishment and maintenance of endometriotic implants. This genomic imbalance may affect genes in which dysregulation impacts both eutopic and ectopic endometrium. PMID- 20725697 TI - [Is lactate a good indicator of brain tissue hypoxia in the acute phase of traumatic brain injury? Results of a pilot study in 21 patients]. AB - Lactate and the lactate-pyruvate index (LPI) are two hypoxia markers widely used to detect brain tissue hypoxia in patients with acute traumatic brain injury. These two markers have a more complex behavior than expected as they can be abnormally high in circumstances with no detectable brain hypoxia. This condition must be considered in the differential diagnosis because it also reflects an alteration of brain energy metabolism. OBJECTIVES: 1. To describe cerebral energy metabolism characteristics observed in the acute phase of traumatic brain injury (TBI) based on two traditional indicators of anaerobic metabolism: lactate and LPI, 2. To determine the concordance between these two biomarkers in order to classify the incidence of anaerobic metabolism and 3. To classify the different types of metabolic abnormalities found in patients with moderate and severe TBI using both lactate and LPI. MATERIALS AND METHODS: Twenty-one patients were randomly selected from a cohort of moderate or severe TBI patients admitted to the neurotraumatology intensive care unit. All of them who underwent both cerebral microdialysis and brain tissue oxygen monitoring (PtiO(2)). We analyzed the levels of lactate and the LPI for every microvial within the first 96 hours after head trauma. These data were correlated with PtiO(2) values. RESULTS: Lactate levels and the LPI were respectively increased during 49.5% and 38.4% of the monitoring time. The incidence and behavior of high levels of both markers were extremely heterogeneous. The concordance between these two biomarkers to determine episodes of dysfunctional metabolism was very weak (Kappa Index=0.29; IC 95%: 0.24-0.34). Based on the levels of lactate and the LPI, we defined four metabolic patterns: I: L>2.5 mmol/L and LPR>25; II: L>2.5 mmol/L and LPR< or = 25; III: L< or = 2.5 mmol/L and LPR< or = 25; IV: L< or = 2.5 mmol/L and LPR>25). In more than 80% of cases in which lactate or LPI were increased, PtiO(2) values were within the normal range (PtiO(2)> 15 mmHg). CONCLUSIONS: Increased lactate and LPI were frequent findings after acute TBI and in most cases they were not related to episodes of brain tissue hypoxia. Furthermore, the concordance between both biomarkers to classify metabolic dysfunction was weak. LPI and lactate should not be used indistinctly in everyday clinical practice because of the weak correlation between these two markers, the difficulty in their interpretation and the heterogeneous and complex nature of the pathophysiology. Other differential diagnoses apart from tissue hypoxia should always be considered when high lactate and/or LPI are detected in the acute injured brain. PMID- 20725698 TI - [Intraoperative videoangiography using green indocyanine during aneurysm surgery]. AB - OBJECTIVE: The authors' objective is to report the initial appreciations on the use of the intraoperative near-infrared indocyanine green videoangiography during aneurysm surgery in our center. METHOD: 10 surgical procedures have been made in 9 patients, 5 males and 4 females between 27 and 61 years old with an average of age of 49 years during a time of 10 months between March, 2008 and January, 2009. 10 surgical procedures were performed and 11 aneurysms were clipped. Intravenous indocyanine green and surgical microscope Leica OH4 with module of vascular fluorescence intraoperating Leica FL800, with camera infrared Sony (Heerbrugg Switzerland) were used. The information offered by this technique during the intervention is compared with the images of the postoperative angiography performed during the first 24 hours. The partial or complete occlusion and the respect to the near vessels were evaluated. RESULTS: The findings of the intraoperative videoangiography were the complete occlusion and absence of complications in all the cases. These results corresponded completely with the postoperative results of the angiography postoperative, except in a case where the angiography demonstrated vasoespasmo moderate without clinical repercussion that during the videoangiografia intraoperatoria was not perceived. Clinically no patient presented neurological added deficits. CONCLUSIONS: The intraoperative videoangiography is a tool of easy application that offers valuable information as for the complete occlusion of the aneurysm and the permeability of the adjacent vessels. PMID- 20725699 TI - [Accuracy of pedicle screw insertion in the thoracolumbar spine using image guided navigation]. AB - INTRODUCTION: Computer image guidance is one of the most significant technologic advancements in the spine surgery, because preoperative or intraoperative images can be used for multiplanar, three-dimensional intraoperative navigation. MATERIAL AND METHODS: We performed a prospective clinical study to assess the accuracy of pedicle screw insertion using an optoelectronic navigation system (SurgiGATE Spine 2.1 Medivision). The study population included 29 patients with diverse disorders of the thoraco- lumbar spine (degenerative 54%, spondylolisthesis 21%, fractures 14%, scoliosis 7% and spondylodiscitis 4%). One patient was excluded from the study because problems with the specific instruments or the computer system. Pre and post-operative axial computed tomography images were obtained for each patient and analyzed by two independent radiologists to placement accuracy. The correct location was defined accord to Heary scale in 5 grades. RESULTS: 163 image-guided thoraco-lumbar pedicle screws were placed 29 in the thoracolumbar spine and 134 in the lumbosacral spine. We achieved a completely intraosseous placement (Grade I) in 99.4% of lumbosacral spine screws and 100% of thoracolumbar spine screws. Only one misplaced screw (Grade III) in the pedicle of L III in the concavity of a scoliosis was reported. No implant related complications were noted. CONCLUSIONS: The low rate of misplaced screws in this prospective study compares favorably with previously published results. Our initial results indicate that Image-guided spinal surgery is a safe technique which improves surgical performance during posterior transpedicle stabilization. PMID- 20725700 TI - [Fluorescence-guided resection with 5-aminolevulinic acid of an intramedullary tumor]. AB - Fluorescence-guided resection with 5-aminolevulinic acid (5-ALA) has demonstrated its usefulness in the resection of malignant cerebral gliomas. It also seems useful for the treatment of other types of cerebral and intramedullary neoplasms. We present the case of a patient with an intramedullary tumor in who fluorescence guided resection was useful for intraoperative localization, definition of small tumor nodules and in order to achieve a complete resection of the tumor. PMID- 20725701 TI - [Reversible primary empty sella. Case report]. AB - We report the case of a 13-year-old girl with an increased hypophysis that mimicked an adenoma, who developed a partial empty sella on MRI after an acute episode of hydrocephalus. After replacement of a CSF shunt, the intracranial pressure returned to normal and the hypophysis filled up again all the sellar fossa. We discuss the possibility of the involvement by an ischemic atrophy of the adenohypophysis in the development of a primary empty sella with idiopathic chronic raised intracranial pressure that prevents the recovery of the gland volume after restoring the intracranial pressure to normal values. Restitution of empty sella may be an indicator of normal intracranial pressure in these cases. PMID- 20725703 TI - Cranio-thoracic bullet migration over a period of 27 years: case report. AB - We report the case of a 36 year old woman that was hurt in the head with a lost bullet while walking through the street when she was 9 years old. On admission, the patient was fully conscious with no neurological deficits. Skull radiography showed the intracranial bullet but she was dispatched after 24 hours of observation without neurological deterioration. Six months later she suddenly presented quadriplegia and after one year of rehabilitation she recovered the mobility and strength in all her limbs. 25 years latter she began with thoracic pain (dermatomal sensory changes), constipation, paresthesias and weakness in the lower extremities; the X-Ray showed a bullet caliber 9 mm in the thoracic canal at T4 level. The bullet was removed via posterior laminectomy and dorsal midline mielotomy. 12 hours after surgery, the patient presented signs of medullar shock. The post-operatory MRI showed the trajectory of the bullet through the brain to the spinal cord in FLAIR, and spinal cord edema as well. The patient received steroids as treatment for the spinal cord edema, and with the help of rehabilitation she recovered movement in the lower extremities 30 days after the surgery. PMID- 20725702 TI - [Isolated hypoglossal nerve palsy secondary to an atlantoccipital joint synovial cyst. Case report and literature review]. AB - Hypoglossal nerve palsy is commonly associated with the involvement of other cranial nerves. His injury is rarely isolated. We present a patient in which paralysis is due to the presence of a "juxtafacet cyst" of the atlanto-occipital joint. We review the anatomy of the hypoglossal nerve, different therapeutic options, the differential diagnosis and papers published to date. PMID- 20725705 TI - [Pustules from the cow barn]. AB - A 54-year-old cattle farmer presented with crusty purulent plaques in the neck area. The clinical picture and microscopical proof of hyphae in the skin smear combined with Wood's lamp testing led to the diagnosis of Tinea barbae, a mycological infection of the skin transmitted by cattle (typically Trichophyton verrucosum). Therapy with itraconazole 200 mg q.d. p.o. and miconazole ointment 1*/day over 2 weeks was successful. This case report and its image are designed to bring attention to this rarely diagnosed pathology. PMID- 20725704 TI - Discrepancy between objective and subjective measures of job stress and sickness absence. AB - OBJECTIVES: The aim of this study was to examine the association of the discrepancy between externally and self-assessed measures of work environment with long- and short-term sickness absence. METHODS: The study population included 6997 middle-aged men and women from the Whitehall II cohort, whose work characteristics were examined at baseline (1985-1988) through both an external evaluation and self-report, with a follow-up of up to 13 years of sickness absence reporting from administrative records. The primary exposure of interest was the discrepancy between measures of work stress for fast job pace, conflicting demands, and decision latitude. RESULTS: In mutually adjusted models, external measures of job characteristics were more strongly associated with higher rates of sickness absence compared with self-assessed measures, for both lower frequency of fast work pace and lower conflicting demands (i.e., "passive" levels). Individuals who self-reported higher frequencies of fast work pace and conflicting demands than were reported through external assessment had higher rates of short-term sickness absence [incident rate ratios (IRR) of 1.13 (95% confidence interval [95% CI] 1.11-1.15) and IRR 1.14 (95% CI 1.11-1.16), respectively]. There was no difference in rates of sickness absence found for decision latitude [IRR 1.02 (95% CI 1.00-1.04)]. CONCLUSIONS: Our findings demonstrate that the discrepancy between externally and self-assessed job demand measures have additional predictive power beyond each individual measure of job structure, which may be related to the extent of cognitive and emotional processing of assessment questions as compared to decision latitude measures. PMID- 20725706 TI - [Acetylsalicylic acid in the primary and secondary prevention of vascular disease]. PMID- 20725707 TI - [Registries of myocardial infarction in Germany. Consequences for drug therapy of patients with acute ST elevation myocardial infarction]. AB - Current national and international guidelines for patients with ST elevation myocardial infarction (STEMI) are mainly based on the results of randomised clinical trials. However, it is well perceived that patients in such trials often represent a low risk population. Therefore the results of randomised clinical trials are not necessarily applicable to patients in clinical practice. This gap can be filled by prospective registries. Since the early nineties a number of prospective large registries in patients with STEMI have been performed in Germany. It could be shown that guideline adherent acute therapies and secondary prevention therapies were associated with an improvement in inhospital and mid term outcomes. The benefit of guideline adherent therapy observed was especially high in patients with higher baseline risk. Registries are not able to replace randomised clinical trials, but can help to test if the results of these trials are comprehensible in clinical practice. Therefore prospective STEMI registries are an important part of clinical research to optimize therapies and improve outcome in patients with STEMI. PMID- 20725708 TI - [Aspirin-Intolerance-Syndrom : a common and interdisciplinary disease]. AB - The full clinical picture of aspirin intolerance - the association of aspirin induced bronchial asthma, aspirin sensitivity and nasal polyps - has been described as Morbus Widal or later as the "Samter triad". Today the term Aspirin exacerbated respiratory disease (AERD) is preferred to account for the progressive nature of this inflammatory airway condition with its unrelenting course even in the absence of non steroidal anti-inflammatory drugs (NSAID). This acquired idiosyncrasy appears to be related to an abnormal arachidonic acid metabolism. Epidemiological data suggests that 10% of all asthmatics do react with life-threatening asthma-attacks after the ingestion of aspirin (ASA) or other NSAID. Some asthmatics with nasal polyposis have been reported to suffer from aspirin intolerance. Although the exact mechanism is still unclear, it is unlikely that the pathogenesis is IgE-mediated. Patients often report chronic nasal obstruction, hyposmia, chronic rhinorrhoea, orbital edema and urticaria with flushing after the ingestion of NSAID. While a typical history and endoscopic findings can be suggestive of AERD, a definite diagnosis relies on appropriate challenge tests. AERD is often refractory to standard asthma treatment with systemic and inhaled steroids, beta(2)-agonists, leukotrien antagonists. Adaptive desactivation can induce a reversible tolerance to NSAID which also leads to an improvement in signs and symptoms of the underlying AERD. PMID- 20725709 TI - [Congenital thrombocytopathies]. AB - Inherited thrombocytopathies are much less frequent in comparison to acquired platelet function disorders. However, congenital disorders can lead to severe bleeding tendency and are often not diagnosed. They are induced by different platelet defects based on disorders of platelet adhesion, receptors, secretion and signal transduction. In some cases they are associated with thrombocytopenia, giant platelets and various comorbidities. This article gives an overview regarding diverse defects, their diagnosis and treatment options. PMID- 20725710 TI - Altered Toll-like receptor signaling pathways in human type 1 diabetes. AB - There is compelling evidence from animal models of type 1 diabetes (T1D) that the innate immune system plays a key role in early mechanisms triggering islet destruction. Very little is known, however, about innate immune subsets and pathways potentially involved in mechanisms leading to human T1D. The present study used a comprehensive approach to analyze innate immune functions in primary monocytes and dendritic cells (DCs) from newly diagnosed patients with T1D versus age-matched healthy individuals. We observed that incubation of PBMCs in the presence of the TLR7/8 agonist R848 led to increased proportion of plasmacytoid dendritic cells (pDCs) expressing IFN-alpha in patients versus healthy control subjects. We also found that TLR4 activation induced a higher frequency of IL 1beta expressing monocytes and a reduction in the percentage of IL-6 expressing myeloid dendritic cells (mDCs). The altered TLR responsiveness was not due to aberrant proportions of peripheral DC subsets and monocytes in the blood and did not correlate with altered hemoglobin A1c and the expression of diabetes susceptibility genes but could potentially be associated with enhanced nuclear factor-kappa B signaling. Finally, we observed that levels of serum IFN-alpha2, IL-1beta, IFN-gamma, and CXCL-10 were elevated in new onset patients versus the control group. Taken together, our observations provide evidence that altered innate immunity exists in mDCs and pDCs from T1D and raise the possibility that these alterations may be associated with disease mechanisms. PMID- 20725711 TI - Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. AB - The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin-angiotensin aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease. PMID- 20725712 TI - [Antiandrogen strategies in prostate cancer: reconstitution of oestrogen receptor beta]. AB - In advanced prostate cancer, albeit castration resistant, an active androgen receptor is still pivotal for growth and cell survival. Recent therapies involving more effective antiandrogens such as MDV3100 proved to be successful. Furthermore, blocking de novo intracrine androgen synthesis, e.g. with abiraterone acetate, provides additional benefit. Besides these antiandrogen measures, compounds which enable the reconstitution of the oestrogen receptor beta as a tumour suppressor restrain aberrant androgen receptor signalling. PMID- 20725713 TI - Genetics and mapping of seedling resistance to Ug99 stem rust in Canadian wheat cultivars 'Peace' and 'AC Cadillac'. AB - Stem rust (caused by Puccinia graminis Pers.:Pers. f. sp. tritici Eriks. & E. Henn.) has re-emerged as a threat to wheat production with the evolution of new pathogen races, namely TTKSK (Ug99) and its variants, in Africa. Deployment of resistant wheat cultivars has provided long-term control of stem rust. Identification of new resistance genes will contribute to future cultivars with broad resistance to stem rust. The related Canadian cultivars Peace and AC Cadillac show resistance to Ug99 at the seedling stage and in the field. The purpose of this study was to elucidate the inheritance and genetically map resistance to Ug99 in these two cultivars. Two populations were produced, an F(2:3) population from LMPG/AC Cadillac and a doubled haploid (DH) population from RL6071/Peace. Both populations showed segregation at the seedling stage for a single stem rust resistance (Sr) gene, temporarily named SrCad. SrCad was mapped to chromosome 6DS in both populations with microsatellite markers and a marker (FSD_RSA) that is tightly linked to the common bunt resistance gene Bt10. FSD_RSA was the closest marker to SrCad (~ 1.6 cM). Evaluation of the RL6071/Peace DH population and a second DH population, AC Karma/87E03-S2B1, in Kenya showed that the combination of SrCad and leaf rust resistance gene Lr34 provided a high level of resistance to Ug99-type races in the field, whereas in the absence of Lr34 SrCad conferred moderate resistance. A survey confirmed that SrCad is the basis for all of the seedling resistance to Ug99 in Canadian wheat cultivars. While further study is needed to determine the relationship between SrCad and other Sr genes on chromosome 6DS, SrCad represents a valuable genetic resource for producing stem rust resistant wheat cultivars. PMID- 20725714 TI - Posthumous Caesarean section in women with type 1 diabetes mellitus: two cases at one hospital in Northern India. PMID- 20725715 TI - Intra-operative ultrasound facilitates the localization of the calcific deposit during arthroscopic treatment of calcifying tendinitis. AB - PURPOSE: Calcifying tendinitis is a common condition of the shoulder. In many cases, arthroscopic reduction in the deposit is indicated. The localization of the deposit is sometimes challenging and time-consuming. Pre-operative ultrasound (US)-guided needle placement in the deposit and pre-operative US marking of the deposit at the skin with a ballpoint are described and recommended methods to alleviate the procedure without using ionizing radiation by fluoroscopy. METHODS: Intra-operative sonography of the shoulder is introduced as a new method to localize the calcific deposit with high accuracy. After standard arthroscopic buresectomy, the surgeon performs an ultrasound examination under sterile conditions to localize the deposits. A ventral longitudinal US section is recommended, and the upper arm is rotated until the deposit is visible. Subsequently, perpendicular to the skin at the position of the transducer, a needle is introduced under arthroscopic and ultrasound visualization to puncture the deposit. RESULTS: The presence of snow-white crystals at the tip of the needle proves the exact localization. Consecutively, the curettage can be accomplished. Another intra-operative sonography evaluates possible calcific remnants and the tendon structure. CONCLUSION: This new technique may alleviate arthroscopic calcific deposit curettage by visualizing the deposit without using ionizing radiation. Additionally, soft tissue damage due to decreased number of punctures to detect the deposit may be achieved. Both factors may contribute to reduced operation time. PMID- 20725716 TI - Method development and validation for determination of thiosultap sodium, thiocyclam, and nereistoxin in pepper matrix. AB - This work reports a method for extraction and analysis of thiosultap sodium, thiocyclam, and nereistoxin in pepper. Different extraction methods were tested to attain the best recoveries. The final extraction method combines acetonitrile extraction in an acidic medium with ultrasonic extraction followed by a cleanup step with anhydrous MgSO(4). The analyses were performed on a Linear Ion Trap Quadrupole LC-MS/MS in negative mode for thiosultap sodium and in positive mode for thiocyclam and nereistoxin. Recovery studies carried out on peppers spiked at different fortification levels (20 and 200 MUg?kg(-1)) yielded average recoveries in the range 58-87% with RSD (%) values below 20%. Calibration curves covering two orders of magnitude were performed and they were linear over the concentration range studied (0.001-0.5 mg?l(-1)). Instrumental detection limits were in the low MUg?kg(-1) range. Stability studies of thiosultap sodium in water were performed by evaluating a 100-MUg?l(-1) solution of this compound in water. It was analyzed over 7 days, after which more than 80% degradation of thiosultap sodium could be observed. PMID- 20725717 TI - Explosive expansion of betagamma-crystallin genes in the ancestral vertebrate. AB - In jawed vertebrates, betagamma-crystallins are restricted to the eye lens and thus excellent markers of lens evolution. These betagamma-crystallins are four Greek key motifs/two domain proteins, whereas the urochordate betagamma crystallin has a single domain. To trace the origin of the vertebrate betagamma crystallin genes, we searched for homologues in the genomes of a jawless vertebrate (lamprey) and of a cephalochordate (lancelet). The lamprey genome contains orthologs of the gnathostome betaB1-, betaA2- and gammaN-crystallin genes and a single domain gammaN-crystallin-like gene. It contains at least two gamma-crystallin genes, but lacks the gnathostome gammaS-crystallin gene. The genome also encodes a non-lenticular protein containing betagamma-crystallin motifs, AIM1, also found in gnathostomes but not detectable in the uro- or cephalochordate genome. The four cephalochordate betagamma-crystallin genes found encode two-domain proteins. Unlike the vertebrate betagamma-crystallins but like the urochordate betagamma-crystallin, three of the predicted proteins contain calcium-binding sites. In the cephalochordate betagamma-crystallin genes, the introns are located within motif-encoding region, while in the urochordate and in the vertebrate betagamma-crystallin genes the introns are between motif- and/or domain encoding regions. Coincident with the evolution of the vertebrate lens an ancestral urochordate type betagamma-crystallin gene rapidly expanded and diverged in the ancestral vertebrate before the cyclostomes/gnathostomes split. The beta- and gammaN-crystallin genes were maintained in subsequent evolution, and, given the selection pressure imposed by accurate vision, must be essential for lens function. The gamma-crystallin genes show lineage specific expansion and contraction, presumably in adaptation to the demands on vision resulting from (changes in) lifestyle. PMID- 20725718 TI - Estrogenic compounds and estrogenicity in surface water, sediments, and organisms from Yundang Lagoon in Xiamen, China. AB - Seven estrogenic compounds--estrone (E1), 17beta-estradiol (E2), 17alpha ethynylestradiol (EE2), diethylstilbestrol (DES), nonylphenol (NP), octylphenol (OP), and bisphenol A (BPA)--in sediments, surface water, pore water, and organisms were investigated and estrogenic activities were estimated by examining estradiol equivalent (EEQ) concentrations in Yundang Lagoon of Xiamen. The results showed that estrogenic compounds were present in all matrixes of interest: in surface water, ranging from 609.61 to 711.31 ng/l; in pore water, ranging from 562.12 to 1038.15 ng/l; in sediments, ranging from 1433.12 to 2060.41 ng/g; and in biota samples, ranging from 1373.76 to 3199.09 ng/g (lipid weight). NP was the predominant component in all collected samples and the highest concentration was 1964.80 ng/g in sediment. Total EEQ ranged from 4.56 to 13.79 ng/l in surface water, from 2.40 to 17.16 ng/l in pore water, and from 8.66 to 23.95 ng/g in sediments. However, major contributors to total EEQ concentrations were E2, E1, and DES. The EEQ concentrations in surface water samples were at a higher level in comparison to that reported in European countries. To biological sample, the highest level of total estrogenic compounds was found in the short-necked clam. Higher values of the biota-sediment accumulation factor (BSAF) were found in short-necked clam and black seabream, indicating that the living habits of organism and physical-chemical properties of estrogenic compounds might influence the bioavailability of estrogenic compounds in organisms. PMID- 20725719 TI - Pulmonary function in children after surgical and percutaneous closure of atrial septal defect. AB - This study aimed to study differences in lung function after surgical and percutaneous atrial septal defect (ASD) closure. Several studies have demonstrated abnormalities of pulmonary function in adults and children with ASD. These abnormalities persist even a few years after correction. This study compared pulmonary function between patients who underwent ASD closure by surgery and those who had closure by device. This is the ideal pediatric population for studying changes in lung function caused by cardiopulmonary bypass or sternotomy. The 46 patients in this study were treated by percutaneous closure (group 1) or surgical closure (group 2) of ASD and then scheduled for pulmonary function testing an average of 5.8 years after ASD closure. The mean values of functional residual capacity, total lung capacity, and residual volume did not differ between the two groups. The surgical group showed a significant decrease in expiratory reserve volume (p < 0.04) and forced vital capacity (p < 0.03). Expiratory flow at 25, 50, and 75% of forced vital capacity did not differ between the two groups but was on the lower limit of normal in both groups. Percutaneous closure of ASD can minimize the side effects of surgical closure on lung function. Longitudinal lung function follow-up assessment after cardiac surgery is warranted to detect and measure restrictive abnormalities in this type of congenital heart disease and others. PMID- 20725720 TI - Hypoplastic left heart syndrome in patients with Kabuki syndrome. PMID- 20725721 TI - Corrected QT Interval in Children With Brain Death. AB - Prolongation of the QT interval is a well-documented finding in adults with severe brain injury. However, QT prolongation has not been well documented in the pediatric population with brain injury. Our objective was to determine the range of QT intervals in children with the diagnosis of brain death, hypothesizing that the QT interval corrected for heart rate (QTc) is longer in this population than in a normal population. All previously healthy children (<18 years) dying in our hospital from 1995 to 2007 with a diagnosis of brain death and at least one electrocardiogram (ECG) with normal anatomy by echocardiogram were included. Admission details, past medical and family history, demographic data, and laboratory data were collected. The QT and preceding RR intervals from three sinus beats on a standard 12-lead ECG were measured. The QTc was calculated with the Bazett method, and the values were averaged. Thirty-seven patients met inclusion criteria. Five had event histories concerning for possible underlying rhythm disturbances; data analysis was performed with and without these patients. The QTc data were normally distributed. The mean (SD) QTc for the entire cohort was 452 (61) ms. Excluding the five patients, it was 449 (62) ms. On multivariate analysis, sex (QTc female < male) and hypokalemia were associated with QTc prolongation. QTc in children with brain death is normally distributed but significantly longer than QTc in normal children. Until rapid genetic testing for channelopathies is universally available, our findings suggest that potential pediatric cardiac donors with isolated prolongation of the QTc in this setting may be acceptable in the absence of other exclusionary criteria. PMID- 20725723 TI - Biocatalytic synthesis of (S)-4-chloro-3-hydroxybutanoate ethyl ester using a recombinant whole-cell catalyst. AB - A cofactor regeneration system for enzymatic biosynthesis was constructed by coexpressing a carbonyl reductase from Pichia stipitis and a glucose dehydrogenase from Bacillus megaterium in Escherichia coli Rosetta (DE3) PlySs. Transformants containing the polycistronic plasmid pET-PII-SD2-AS1-B exhibited an activity of 13.5 U/mg protein with 4-chloro-3-oxobutanoate ethyl ester (COBE) as the substrate and an activity of 14.4 U/mg protein with glucose as the substrate; NAD(H) was the coenzyme in both cases. Asymmetric reduction of COBE to (S)-4 chloro-3-hydroxybutanoate ethyl ester [(S)-CHBE] with more than 99% enantiomeric excess was demonstrated by transformants. Furthermore, the paper made a comparison of crude enzyme catalysis and whole-cell catalysis in an aqueous monophasic system and a water/organic solvent biphasic system. In the water/n butyl acetate system, the coexpression system produced 1,398 mM CHBE in the organic phase, which is the highest yield ever reported for CHBE production by NADH-dependent reductases from yeasts. In this case, the molar yield of CHBE was 90.7%, and the total turnover number, defined as moles (S)-CHBE formed per mole NAD+, was 13,980. PMID- 20725724 TI - A nitrilase from a metagenomic library acts regioselectively on aliphatic dinitriles. AB - Several novel nitrilases were selected from metagenomic libraries using cinnamonitrile and a mixture of six different nitriles as substrates. The nitrilase gene nit1 was expressed in Escherichia coli and the resulting protein was further examined concerning its biochemical properties. Nit1 turned out to be an aliphatic nitrilase favoring dinitriles over mononitriles. Stereochemical analysis revealed that Nit1 converted the dinitrile 2-methylglutaronitrile regioselectively. Hydrolysis at the omega-nitrile group of a dinitrile, such as catalyzed by Nit1, leads to omega-cyanocarboxylic acids, which are important precursors for chemical and pharmaceutical products. Nit1 metabolized 2 methylglutaronitrile to the corresponding omega-cyanocarboxylic acid 4 cyanopentanoic acid can be used for the production of the fine chemical 1,5 dimethyl-2-piperidone. PMID- 20725725 TI - Intraoperative modification of Pitanguy technique of reduction mammaplasty for elevation of the nipple-areola complex in case of severe breast ptosis. AB - BACKGROUND: The Pitanguy method of reduction mammaplasty has been shown to be an anatomically safe technique in the management of the ptotic breast. However, the technique, as first described, cannot be applied in gigantomastia or severe breast ptosis cases or cases of dense parenchyma of the breast. The senior surgeon suggested an intraoperative modification of the Pitanguy method of reduction mammaplasty to make it applicable for such cases. METHODS: A retrospective study of 122 patients with severe breast ptosis (70), gigantomastia (45), or dense breast parenchyma (7) who underwent a modification of the Pitanguy method was performed. The current procedure involves all the operating steps of the superior pedicle technique as described by Pitanguy, from the marking technique to the keel resection of the breast. If the nipple-areola complex is elevated inadequately, the surgeon can use the senior surgeon's modification to elevate the complex to the desired height. This modification consists of dissecting the upper pole of the breast vertically to the fascia of the pectoralis major muscle and laterally to the nipple-areola complex. The medial flap is then advanced superiorly, rotated 90 degrees , and sutured to point A, while the lateral flap is placed below the medial one. This maneuver maximizes elevation of the nipple-areola complex to the desired height. RESULTS: The mean change in nipple position was 14 cm (range = 10-16 cm). The mean weight reduction of each breast was 900 g (range = 700-1300 g). The follow-up included 119 patients and the follow-up period ranged from 1 to 3 years (mean follow-up = 2 years). Three patients were operated on less than 3 months ago and were not involved in this study. All patients gained natural shaped breasts and they were pleased with the results. Serious complications, including flap necrosis, were avoided since caution was used to preserve the internal mammary perforators while performing this method. CONCLUSION: This technique provides a versatile, well vascularized pedicle that allows elevation of the nipple-areola complex at the desired height in cases of severe breast ptosis, gigantomastia, or dense breast parenchyma. PMID- 20725722 TI - Characterization of archaeal community in contaminated and uncontaminated surface stream sediments. AB - Archaeal communities from mercury and uranium-contaminated freshwater stream sediments were characterized and compared to archaeal communities present in an uncontaminated stream located in the vicinity of Oak Ridge, TN, USA. The distribution of the Archaea was determined by pyrosequencing analysis of the V4 region of 16S rRNA amplified from 12 streambed surface sediments. Crenarchaeota comprised 76% of the 1,670 archaeal sequences and the remaining 24% were from Euryarchaeota. Phylogenetic analysis further classified the Crenarchaeota as a Freshwater Group, Miscellaneous Crenarchaeota group, Group I3, Rice Cluster VI and IV, Marine Group I and Marine Benthic Group B; and the Euryarchaeota into Methanomicrobiales, Methanosarcinales, Methanobacteriales, Rice Cluster III, Marine Benthic Group D, Deep Sea Hydrothermal Vent Euryarchaeota 1 and Eury 5. All groups were previously described. Both hydrogen- and acetate-dependent methanogens were found in all samples. Most of the groups (with 60% of the sequences) described in this study were not similar to any cultivated isolates, making it difficult to discern their function in the freshwater microbial community. A significant decrease in the number of sequences, as well as in the diversity of archaeal communities was found in the contaminated sites. The Marine Group I, including the ammonia oxidizer Nitrosopumilus maritimus, was the dominant group in both mercury and uranium/nitrate-contaminated sites. The uranium-contaminated site also contained a high concentration of nitrate, thus Marine Group I may play a role in nitrogen cycle. PMID- 20725726 TI - Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model. AB - PURPOSE: O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs DNA damage from alkylating agents by transferring the alkyl adducts from the O(6)-position of guanine in DNA to AGT. The folate analog O(4)-benzylfolic acid (O(4)BF) is an inhibitor of AGT with reported selectivity of the alpha-folate receptor in tumors. We studied plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of O(4)BF in a non-human primate model. METHODS: Rhesus monkeys (Macaca mulatta) received O(4)BF (10-50 mg/kg) intravenously, and serial blood and CSF samples were obtained. Analyte concentrations in plasma were measured by HPLC/photo diode array, and an HPLC/MS/MS assay was used for CSF samples. RESULTS: A putative metabolite of O(4)BF was detected in plasma and CSF. O(4)BF and the metabolite inactivated purified AGT with ED(50) of 0.04 mcM. The median clearance of O(4)BF was 8 ml/min/kg and half-life was 1.1 h. The metabolite had a substantially longer half-life (>20 h) and greater AUC than O(4)BF. The AUC of the metabolite increased disproportionately to the dose of O(4)BF, suggesting saturable elimination. CSF penetration of O(4)BF and its metabolite was < 1%. At the 50 mg/kg dose level, the C(max) in CSF for O(4)BF was less than 0.09 mcM and for the metabolite the C(max) ranged from 0.02 to 0.04 mcM (O(4)BF equivalents). CONCLUSIONS: Concentrations of O(4)BF and the metabolite in CSF exceeded the ED(50) of AGT; however, recently reported lack of receptor specificity and pharmacokinetic data suggesting saturable elimination of both O(4)BF and its metabolite may limit dose-escalation and future clinical development of this agent. PMID- 20725727 TI - Localization and characterization of GTP-binding protein CT703 in the Chlamydia trachomatis-Infected cells. AB - To localize and characterize the GTP-binding protein encoded by the chlamydial ORF CT703 in the Chlamydia trachomatis-infected cells, the gene coding for CT703 in the Chlamydia trachomatis serovar L2 genome was cloned into the prokaryotic expression vector pGEX and expressed as GST fusion protein in the E. coli BL21 strain. The GST-CT703 fusion protein was purified and used to raise antigen specific antibodies. Using the anti-fusion protein antibodies, we localized the endogenous CT703 protein inside the chlamydial inclusion using an indirect immunofluorescence assay (IFA). We also detected a significantly decreased level of CT703 in cultures that were induced to undergo persistent infection. These observations suggest that CT703 may be an important regulator for promoting chlamydial productive infection. PMID- 20725728 TI - Food- and light-entrainable oscillators control feeding and locomotor activity rhythms, respectively, in the Japanese catfish, Plotosus japonicus. AB - Feeding and locomotor activities of the Japanese catfish Plotosus japonicus under solitary condition were recorded to identify mechanisms controlling these behaviours. In the absence of food, the catfish showed nocturnal locomotor activity, but no feeding activity. Under ad libitum food conditions, both feeding and locomotor activities occurred during the dark period and were synchronized with light/dark (LD) cycles. Feeding activity lasted for 11-24 days when food was stopped after ad libitum food availability. Restricted food during the light phase produced both food-anticipatory and light-entrainable feeding activity. Furthermore, this condition produced weak food-anticipatory and light-entrainable locomotor activity. Under the light/light (LL) condition, restricted food produced food-anticipatory feeding and locomotor activities, suggesting that a food-entrainable oscillator controls both feeding and locomotor activities. However, under the LL condition, light-entrainable feeding and locomotor activities were not observed, suggesting that a light-entrainable oscillator controls both feeding and locomotor activities. During a restricted food schedule, LD cycle shifts resulted in disrupted synchronization of feeding activity onset in three of the four fish, but one fish showed synchronized feeding activity. These results suggest that the food- and the light-entrainable oscillator may control feeding and locomotor activities, respectively. PMID- 20725729 TI - On visual pigment templates and the spectral shape of invertebrate rhodopsins and metarhodopsins. AB - The absorbance spectra of visual pigments can be approximated with mathematical expressions using as single parameter the absorbance peak wavelength. A comparison of the formulae of Stavenga et al. in Vision Res 33:1011-1017 (1993) and Govardovskii et al. in Vis Neurosci 17:509-528 (2000) applied to a number of invertebrate rhodopsins reveals that both templates well describe the normalized alpha-band of rhodopsins with peak wavelength > 400 nm; the template spectra are virtually indistinguishable in an absorbance range of about three log units. The template formulae of Govardovskii et al. in Vis Neurosci 17:509-528 (2000) describe the rhodopsin spectra better for absorbances below 10(-3). The template predicted spectra deviate in the ultraviolet wavelength range from each other as well as from measured spectra, preventing a definite conclusion about the spectral shape in the wavelength range <400 nm. The metarhodopsin spectra of blowfly and fruitfly R1-6 photoreceptors derived from measured data appear to be virtually identical. The established templates describe the spectral shape of fly metarhodopsin reasonably well. However, the best fitting template spectrum slightly deviates from the experimental spectra near the peak and in the long wavelength tail. Improved formulae for fitting the fly metarhodopsin spectra are proposed. PMID- 20725730 TI - IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. AB - PURPOSE: Recent studies have demonstrated a high frequency of IDH mutations in adult "secondary" malignant gliomas arising from preexisting lower grade lesions, often in young adults, but not in "primary" gliomas. Because pediatric malignant gliomas share some molecular features with adult secondary gliomas, we questioned whether a subset of these tumors also exhibited IDH mutations. EXPERIMENTAL DESIGN: We examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant gliomas treated on the Children's Oncology Group ACNS0423 study. The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated. RESULTS: IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed. A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from children >=14 years, but in 0 of 23 (0%) younger children (p = 0.0024). No association was observed with clinical factors other than age. One-year event-free survival was 86 +/- 15% in the IDH-mutated group versus 64 +/- 8% in the non-mutated group (p = 0.03, one sided logrank test). One-year overall survival was 100% in patients with mutations versus 81 +/- 6.7% in those without mutations (p = 0.035, one-sided logrank test). CONCLUSIONS: IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis. PMID- 20725731 TI - Endovascular management of vein of Galen aneurysmal malformations. Influence of the normal venous drainage on the choice of a treatment strategy. AB - INTRODUCTION: Vein of Galen arteriovenous malformations (VGAM) are rare intracranial vascular lesions mostly involving young children. Endovascular therapy is the current standard of care. Albeit interventional techniques have greatly reduced the once dismal vital and functional prognoses previously associated with these lesions, the treatment of VGAMs remains a complex therapeutic challenge. DISCUSSIONS: This article reviews the available endovascular options for VGAM therapy, emphasizing three points that we have identified as critical in our practice for the establishment of a treatment strategy: (1) the importance of the deep cerebral venous anatomy, in particular the existence of normal drainage through the Galenic system in spite of the VGAM; (2) the concept of treatment staging, for arterial as well as for venous interventions; and (3) the definition of a therapeutic goal that can be attained at a reasonable cost in terms of complication risks and functional outcome. PMID- 20725732 TI - [New biologics and orally available compounds. What is still in the pipeline?]. AB - Biologics have revolutionized the treatment of inflammatory joint disease in the last decade. By precisely targeting and inhibiting inflammatory cytokines as well as the blockade of cells centrally integrated in the immune system, inhibition of inflammation has become possible which had been unthinkable before. The medical need to improve our current approach with biologics even more is based on three observations: (1) even though the clinical effect of a given biologic is evident in the majority of patients, not all show a satisfactory response, (2) the blockade of important mediators of the immune system bears the risk of infection and potentially malignant events and (3) all current biologics need to be administered parenterally. The present review describes several innovative biologics and low molecular weight compounds which are currently being investigated in clinical trials in patients suffering from inflammatory rheumatic conditions. Some of them may become a part of our growing armamentarium to treat these diseases which still represent a major burden to the patients and society. PMID- 20725733 TI - Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation. AB - Protein kinase D (PKD) targets several proteins in the heart, including cardiac troponin I (cTnI) and class II histone deacetylases, and regulates cardiac contraction and hypertrophy. In adult rat ventricular myocytes (ARVM), PKD activation by endothelin-1 (ET1) occurs via protein kinase Cepsilon and is attenuated by cAMP-dependent protein kinase (PKA). Intracellular compartmentalisation of cAMP, arising from localised activity of distinct cyclic nucleotide phosphodiesterase (PDE) isoforms, may result in spatially constrained regulation of the PKA activity that inhibits PKD activation. We have investigated the roles of the predominant cardiac PDE isoforms, PDE2, PDE3 and PDE4, in PKA mediated inhibition of PKD activation. Pretreatment of ARVM with the non selective PDE inhibitor isobutylmethylxanthine (IBMX) attenuated subsequent PKD activation by ET1. However, selective inhibition of PDE2 [by erythro-9-(2-hydroxy 3-nonyl) adenine, EHNA], PDE3 (by cilostamide) or PDE4 (by rolipram) individually had no effect on ET1-induced PKD activation. Selective inhibition of individual PDE isoforms also had no effect on the phosphorylation status of the established cardiac PKA substrates phospholamban (PLB; at Ser16) and cTnI (at Ser22/23), which increased markedly with IBMX. Combined administration of cilostamide and rolipram, like IBMX alone, attenuated ET1-induced PKD activation and increased PLB and cTnI phosphorylation, while combined administration of EHNA and cilostamide or EHNA and rolipram was ineffective. Thus, cAMP pools controlled by PDE3 and PDE4, but not PDE2, regulate the PKA activity that inhibits ET1-induced PKD activation. Furthermore, PDE3 and PDE4 play redundant roles in this process, such that inhibition of both isoforms is required to achieve PKA-mediated attenuation of PKD activation. PMID- 20725734 TI - The role of ultrasound and antenatal single-shot fast spin-echo MRI in the evaluation of herniated bowel in case of first trimester ultrasound diagnosis of fetal gastroschisis. AB - OBJECTIVE: To report on a clinical antenatal management strategy based on integrating ultrasound (US) and magnetic resonance imaging (MRI) in the evaluation of herniated bowel following early prenatal diagnosis of gastroschisis. METHODS: Antenatal US and ultrafast single-shot spin-echo (SSSE) MRI. RESULTS: Fetal gastroschisis was documented at 12 weeks at the time of first trimester screening for Down syndrome. Fetal karyotype was performed at 16 weeks and showed a 46,XY karyotype. Ultrasound scan at 20 weeks diagnosed gastroschisis as isolated finding. Follow-up scans were planned monthly, and antenatal ultrafast SSSE MRI was arranged at 35 weeks and demonstrated a right fetal abdominal wall defect measuring 2.4 mm on transverse diameter with an integrity of the intra-abdominal and extra-abdominal loops of small bowel. The colon was in situ as were the stomach, the liver, and the spleen. CONCLUSIONS: The choice of integrating both the diagnostic procedures has shown to be clinically useful in planning the timing of delivery (Cesarean section) and in turn has been associated with an easy surgical repair and to a favorable postnatal outcome. The result of amniocentesis was crucial for the parent's decision-making process whether to continuing with the pregnancy. Moreover, amniotic fluid alpha fetoprotein levels may be used as an index of small bowel damage when loops of small bowel lied uncovered within the amniotic cavity. PMID- 20725735 TI - Gunshot energy transfer profile in ballistic gelatine, determined with computed tomography using the total crack length method. AB - By measuring the total crack lengths (TCL) along a gunshot wound channel simulated in ordnance gelatine, one can calculate the energy transferred by a projectile to the surrounding tissue along its course. Visual quantitative TCL analysis of cut slices in ordnance gelatine blocks is unreliable due to the poor visibility of cracks and the likely introduction of secondary cracks resulting from slicing. Furthermore, gelatine TCL patterns are difficult to preserve because of the deterioration of the internal structures of gelatine with age and the tendency of gelatine to decompose. By contrast, using computed tomography (CT) software for TCL analysis in gelatine, cracks on 1-cm thick slices can be easily detected, measured and preserved. In this, experiment CT TCL analyses were applied to gunshots fired into gelatine blocks by three different ammunition types (9-mm Luger full metal jacket, .44 Remington Magnum semi-jacketed hollow point and 7.62 * 51 RWS Cone-Point). The resulting TCL curves reflected the three projectiles' capacity to transfer energy to the surrounding tissue very accurately and showed clearly the typical energy transfer differences. We believe that CT is a useful tool in evaluating gunshot wound profiles using the TCL method and is indeed superior to conventional methods applying physical slicing of the gelatine. PMID- 20725736 TI - Nocturia is an independent predictor of severe obstructive sleep apnea in patients with ischemic stroke. AB - Severe obstructive sleep apnea (OSA) increases the risk of stroke recurrence and mortality after stroke. Since nocturia is common in post-stroke patients with OSA, this study explored the predictive role of nocturia for severe OSA in patients with ischemic stroke. This was a cross-sectional, prospective study involving 65 consecutive patients with ischemic stroke admitted to rehabilitation ward. All participants received polysomnography and clinical assessments, including a 3-day urinary frequency-volume recording. Differences in study variables between patients with and without severe OSA were compared, and logistic regression analyses with backward selection procedures were used to assess the relationship between OSA severity and nocturia. Patients with severe OSA were older (69.6 +/- 9.9 vs. 62.6 +/- 11.5 year), had a significantly higher desaturation index (37.9 +/- 16.1 vs. 8.8 +/- 6.1 episodes/night) and had a higher frequency of nocturia (2.2 +/- 1.0 vs. 1.5 +/- 0.8 episodes/night) than those without. In addition, men with severe OSA had a larger neck circumference (409 +/- 26 vs. 381 +/- 32 mm) than those without. The frequency of nocturia, age, sex, and interaction between sex and neck circumference remained significant in the final regression model for severe OSA. In this model, the area under the receiver operating characteristic curve was 0.87 (95% CI 0.79-0.96; P < 0.001) with sensitivity and specificity of 80.6 and 82.8%, respectively. The odds ratio of nocturia was highest (3.5) among the four variables. Nocturia is an independent predictor for severe OSA, and the final prediction model might be used when screening for severe OSA in patients with ischemic stroke. PMID- 20725737 TI - Pruritus in familial Creutzfeldt-Jakob disease: a common symptom associated with central nervous system pathology. AB - Pruritus, a common feature of animal prion diseases such as scrapie, is rarely reported in humans with Creutzfeldt-Jakob disease (CJD), and its anatomical background is not well defined. The present study was undertaken to carry out a methodical prospective search for the prevalence of pruritus in CJD patients and investigate its anatomical substrate by MRI. The study group included consecutive familial and sporadic CJD patients carrying the E200K PRNP mutation followed up in a longitudinal prospective study between the years 2005 and 2008. Pruritus was prospectively screened for and diffusion-weighted imaging (DWI) was used to correlate brain diffusion abnormalities with pruritus in CJD patients. Pruritus was present in 6/31 (19.35%) patients with familial disease (fCJD) and in none of the patients with sporadic disease (sCJD). Pruritus was a presenting symptom in one patient and evolved during the course of the disease in the other five patients. The pruritus was generalized in three patients, regional in two and localized in one patient. It was transient in one patient and continued throughout the disease in five patients. DWI showed that pruritus was significantly associated with reduced diffusion in the several areas known to be affected by CJD, but most significantly in the midbrain periaqueductal grey matter. Pruritus is relatively common in patients with familial CJD carrying the E200K mutation. Our findings point to a central origin that involves damage to the inhibitory gating mechanism for itch in the periaqueductal grey matter. PMID- 20725738 TI - Specific down-regulation of PAL genes by artificial microRNAs in Populus trichocarpa. AB - Artificial microRNAs (amiRNAs) are similar to microRNAs (miRNAs) in that they are able to reduce the abundance of specific transcripts in plants by RNA-Induced Silencing Complex (RISC)-mediated cleavage and degradation, but differ in that they are designed for specific targets. The long generation times of forest trees have limited the discovery of mutations by conventional genetics. AmiRNAs can create gene-specific transcript reduction in transgenic trees in a single generation and may have broad application for functional genomics of trees. In this paper, we describe the specific down-regulation of multiple genes in the phenylalanine ammonia-lyase (PAL) gene family of Populus trichocarpa using amiRNA sequences incorporated in a P. trichocarpa miRNA-producing precursor, ptc-MIR408. Two different amiRNA constructs were designed to specifically down-regulate two different subsets of PAL genes, revealing differential regulation within the gene family. Down-regulation of subset A (PAL2, PAL4 and PAL5) by amiRNA-palA led to an increase in transcript abundance of subset B (PAL1 and PAL3). The reciprocal effect was not observed. PMID- 20725739 TI - Contextual remapping in visual search after predictable target-location changes. AB - Invariant spatial context can facilitate visual search. For instance, detection of a target is faster if it is presented within a repeatedly encountered, as compared to a novel, layout of nontargets, demonstrating a role of contextual learning for attentional guidance ('contextual cueing'). Here, we investigated how context-based learning adapts to target location (and identity) changes. Three experiments were performed in which, in an initial learning phase, observers learned to associate a given context with a given target location. A subsequent test phase then introduced identity and/or location changes to the target. The results showed that contextual cueing could not compensate for target changes that were not 'predictable' (i.e. learnable). However, for predictable changes, contextual cueing remained effective even immediately after the change. These findings demonstrate that contextual cueing is adaptive to predictable target location changes. Under these conditions, learned contextual associations can be effectively 'remapped' to accommodate new task requirements. PMID- 20725740 TI - Sex-specific genetic architecture of human fatness in Chinese: the SAPPHIRe Study. AB - To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex-genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype-sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G * S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis. PMID- 20725741 TI - Nicotinic acetylcholine receptor genes on chromosome 15q25.1 are associated with nicotine and opioid dependence severity. AB - A locus on chromosome 15q25.1 previously implicated in nicotine, alcohol, and cocaine dependence, smoking, and lung cancer encodes subunits of the nicotinic acetylcholine receptor (nAChR) expressed in the mesolimbic system and thought to mediate substance dependence. Opioid dependence severity (ODS), nicotine dependence severity (NDS), smoking status and quantity, and the number of attempts to quit were assessed using questionnaire instruments in 505 subjects who were prescribed opioid medications for chronic pain in outpatient practice sites. Multivariate regression was used to test for genetic association of these phenotypes with 5 SNPs in the nAChR gene cluster on chromosome 15q25.1, adjusting for background variables. A coding variant in CHRNA5 (rs16969968[A]) was significantly associated with 1.4-unit higher ODS (p < 0.00017). A variant in the 3' untranslated region of CHRNA3 (rs660652[G]) was significantly associated with 1.7-fold higher odds of lifetime smoking (p < 0.0092), 1.1-unit higher NDS (p < 0.0007), 0.7 more pack-years of cigarette smoking (p < 0.0038), and 0.8 more lifetime attempts to quit (p < 0.0084). Our data suggest an association of DNA variants in the nAChR gene cluster on chromosome 15q25.1 with ODS, as well as NDS and related smoking phenotypes. While the association of this locus with NDS and smoking phenotypes is well known, the association with ODS, a dimension of opioid substance dependence, is novel and requires verification in independent studies. PMID- 20725742 TI - Intraoperative portable abdominal radiograph for tumor localization: a simple and accurate method for laparoscopic gastrectomy. AB - BACKGROUND: During laparoscopic gastrectomy, it is impossible to identify early gastric cancer (EGC) lesions; therefore, a precise localization technique is required. In this study, we evaluated a novel method of intraoperative portable abdominal radiograph for localization of EGC lesions after preoperative endoscopic clipping. METHODS: A retrospective study of 80 patients who had undergone laparoscopic gastrectomies with our intraoperative abdominal radiographic method of tumor localization was performed. During preoperative endoscopy, endoscopic metal clips were applied just proximal to the tumor. A plain abdominal radiograph taken immediately after oral administration of effervescent agents was employed to select candidates for intraoperative localization. Intraoperative vessel clips were laparoscopically applied along the greater and lesser curvatures, and a portable abdominal radiograph was taken to identify the location of endoscopic clips relative to laparoscopic vessel clips. RESULTS: In all patients, endoscopic clips were applied proximal to the lesion without complications. Both intraluminally and extraluminally placed clips were successfully detected by intraoperative portable abdominal radiograph in all patients. Mean +/- standard deviation (SD) proximal margin length was 34.2 +/- 20.2 mm. All patients had tumor-free resection margin. CONCLUSIONS: Preoperative endoscopic clipping and intraoperative portable abdominal radiograph is an accurate and simple tumor localization method in laparoscopic gastrectomy. PMID- 20725743 TI - Feasibility of single-port laparoscopic cholecystectomy using a homemade laparoscopic port: a clinical report of 50 cases. AB - AIM: To report the clinical experience of transumbilical single-port laparoscopic cholecystectomy (TUSPLC), using a homemade laparoscopic access port composed of two inexpensive and common pieces of equipment readily available in the operating room. METHODS: Fifty consecutive patients with gallstones, including ten patients (20%) with acute cholecystitis, underwent single-port laparoscopic cholecystectomy (LC) using a homemade single port composed of a segment of corrugated breathing tube and a pair of surgical gloves. The port was inserted into the umbilicus for simultaneous placement of multiple conventional instruments into the abdominal cavity. All patients underwent dome-down LC using traditional instruments with manually angulated shafts; dissection was done using electrocautery or harmonic scalpel. RESULTS: All but two procedures were completed uneventfully. Two patients with acute cholecystitis due to dense adhesions in the triangle of Calot necessitated conversion to two- and four-port laparoscopic procedures, respectively. Operative time averaged 73 +/- 2 min for chronic cholecystitis and 95 +/- 5 min for acute cholecystitis. There were no perioperative port-related or surgical complications, except for two patients who developed wound seroma and recovered after conservative treatment. We found that healing of the umbilical wound left virtually no scar in all patients. CONCLUSION: The homemade umbilical port reported in this study is useful for multiple instrument access and allows TUSPLC to be performed safely, with its inherent cosmetic and cost advantages. Further studies of this technique are ongoing. PMID- 20725744 TI - Laparoscopic lymph node dissection around the inferior mesenteric artery with preservation of the left colic artery. AB - AIM: Curative resection of sigmoid and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate. Accordingly, some surgeons employ a technique of lymph node (LN) dissection around the IMA, preserving the IMA and left colic artery (LCA). The same technique was reported to need longer time in laparoscopic surgery due to technical difficulties. We present herein a simple and secure method of laparoscopic LN dissection around the IMA that allows preservation of the IMA and LCA, and report the operative results. METHODS: Our method involves peeling off the vascular sheath from the IMA and dissection of the LN around the IMA together with the sheath. The feasibility of the technique was evaluated in 72 consecutive cases of laparoscopic resection of sigmoid and rectal cancer. RESULTS: The IMA was ligated at its root in 27 cases (high tie, group A). Lymph nodes around the IMA were dissected with preservation of the IMA and LCA in 21 cases (group B). The root of the superior rectal artery was ligated in 24 cases of Tis and T1N0 ("low tie," group C). Mean operative time was 207.6, 221.2, and 198.5 min for group A, B, and C, respectively. Respective blood loss was 47.8, 44.0, and 58.5 g, and mean numbers of harvested LN were 17.3, 16.3, and 10.7. None of the operative results of groups A and B were different statistically. LN dissection was not associated with any morbidity. CONCLUSION: Our method allows equivalent laparoscopic lymph node dissection to the high tie technique without excessive operative time or bleeding. PMID- 20725745 TI - Optimizing locoregional staging in the preoperative setting of resectable esophageal cancer. PMID- 20725746 TI - Should the wheel be reinvented in a human study? AB - Recently, Zimmer and colleagues reported a lack of analgesic efficacy from intraperitoneal nebulization of bupivacaine using the Insuflow device for patients undergoing laparoscopic cholecystectomy. This is not surprising. An in vitro study in 2008 showed that hot evaporation-based devices, similar to Insuflow, are unable to transport drug molecules dissolved in a water solvent. These results are in keeping with the physical principle that hot evaporation enables only evaporation of the solvent (e.g., water) and not of the solute (e.g., bupivacaine). Although this well-conducted human study has a defendable medical justification and a high theoretical interest, it is not acceptable to choose a human model for an experimental study that attempts to explore a question whose answer has already been published years before in a bench setting. PMID- 20725748 TI - Feasibility study of sentinel lymph node biopsy in esophageal cancer with conservative lymphadenectomy. AB - INTRODUCTION: Lymphoscintigraphy and sentinel node mapping is established in breast cancer and melanoma but not in esophageal cancer, even though many centers have shown that occult tumor deposits in lymph nodes influence prognosis. We report our initial experience with lymphoscintigraphy and sentinel lymph node biopsy in patients undergoing resection for esophageal cancer. METHODS: Sixteen of 17 consecutive patients underwent resection for invasive esophageal cancer along with sentinel lymph node retrieval (resection rate, 94%). Peritumoral injection of (99m)Tc antimony colloid was performed by upper endoscopy prior to the operation. A two-surgeon synchronous approach via right thoracotomy and laparotomy was performed with conservative lymphadenectomy. Sentinel lymph nodes were identified using a gamma probe both in vivo and ex vivo. Sentinel lymph nodes were sent off separately for serial sections and immunohistochemistry. RESULTS: Median patient age was 60.4 years (range, 45-75 years). Fifteen were male, and thirteen had adenocarcinoma. At least one sentinel lymph node (median, 2) was identified in 14 of 16 patients (success rate, 88%). Sentinel nodes were present in more than one nodal station in five patients (31%). In all 14 patients, the sentinel lymph node accurately predicted findings in non-sentinel nodes (accuracy, 100%). Three patients with positive sentinel lymph nodes had metastases identified in non-sentinel nodes (sensitivity, 100%). CONCLUSIONS: Sentinel lymph node biopsy is feasible in esophageal resection with conservative lymphadenectomy, and initial results suggest it is accurate in predicting overall nodal status. Further study is needed to assess impact on patient management and prognosis. PMID- 20725749 TI - Durability of the self-approximating translumenal access technique (STAT) for potential use in natural orifice translumenal surgery (NOTES). AB - BACKGROUND: The self-approximating translumenal access technique (STAT) has been shown to provide a safe and reliable means of abdominal access for natural orifice translumenal endoscopic surgery (NOTES). However, the feasibility of using STAT for translumenal organ resection is unknown. This study aimed to evaluate the technical performance of organ resection using STAT, the integrity of the STAT gastric tunnel after organ resection, and the postoperative morbidity of organ resection using STAT. METHODS: In this study, 14 domestic swine underwent transgastric organ resection (7 cholecystectomies, 7 uterine horn resections) followed by sequential removal of two different sizes of standardized specimens. Evaluation of operative injury to the tunnel and difficulty of specimen extraction was performed. After 2 weeks of observation, necropsy was performed for evaluation and documentation of gross findings. RESULTS: The mean operating room time (intubation recovery) was 4.1 h. A tunnel with a mean length of 12 cm and a mean width of 4 cm was created. The tunnel remained fully intact in 14 of 14 animals after organ resection, in 13 of 13 animals after balloon extraction, and in 12 of 14 animals after rigid specimen extraction (1 clinically significant tear occurred). Postoperatively, all the animals gained weight appropriately. Necropsy findings included adhesions (n = 4), bile leak (n = 2), minor lap-port abscess (n = 1), and ventral hernia (n = 1). CONCLUSIONS: Although this study was a limited, prospective, animal survival study without a control arm, it again indicates that STAT allows safe abdominal access, a reliable means of closure, and directed endoscope positioning. Although one significant mucosal tear did occur, this study suggests STAT will tolerate the mechanical forces of peroral transgastric procedures provided the organ resected is small to moderate in size (<8 * 3 cm). PMID- 20725751 TI - Monitoring of vecuronium-induced neuromuscular block at the sternocleidomastoid muscle in anesthetized patients. AB - PURPOSE: To assess the degree of neuromuscular block acceleromyographically at the sternocleidomastoid muscle. METHODS: Eighteen adult patients scheduled for air-oxygen-sevoflurane-fentanyl and epidural anesthesia were studied. In the patients, the right accessory nerve and the sternocleidomastoid muscle were stimulated and the contraction of the sternocleidomastoid muscle was evaluated acceleromyographically. Simultaneously, the response of the adductor pollicis muscle was measured electromyographically. Supramaximal stimulating current, degree of maximum neuromuscular block after vecuronium 0.1 mg/kg, and onset of or recovery from vecuronium-induced neuromuscular block were compared between the two muscles. RESULTS: The supramaximal stimulating current at the sternocleidomastoid muscle was significantly higher than that at the adductor pollicis muscle (54.8 +/- 7.1 vs. 33.7 +/- 10.3 mA, mean +/- SD, P < 0.001). The onset of neuromuscular block at the sternocleidomastoid muscle did not significantly differ from that at the adductor pollicis muscle (214 +/- 117 vs. 161 +/- 87 s, P = 0.131). The degree of maximum neuromuscular block at the sternocleidomastoid muscle was significantly less than that at the adductor pollicis muscle (93.6 +/- 3.1 vs. 99.2 +/- 2.5%, P < 0.001). During recovery from neuromuscular block, T1/control and train-of-four ratio measured at the sternocleidomastoid muscle were significantly higher than those at the adductor pollicis muscle 10-30 and 40-120 min after vecuronium, respectively (P < 0.05). CONCLUSION: The sternocleidomastoid muscle is more resistant to vecuronium than the adductor pollicis muscle. Recovery from neuromuscular block is faster at the sternocleidomastoid muscle than at the adductor pollicis muscle. PMID- 20725750 TI - Overexpression of apelin receptor (APJ/AGTRL1) on hepatic stellate cells and sinusoidal angiogenesis in human cirrhotic liver. AB - BACKGROUND: The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). This study was designed to elucidate the in vivo localization and changes of APJ in cirrhotic liver, and the in vitro changes of APJ expression in cultured hepatic stellate cells (HSCs) and capillarized sinusoidal endothelial cells (SECs) activated by growth factors. METHODS: In vivo studies used control liver samples, cirrhotic liver samples from patients with Child's A cirrhosis undergoing surgical resection (Child-A-LC), and cirrhotic liver samples from autopsied cases of decompensated Child's C cirrhosis (Child-C-LC). Immunohistochemical (IHC), Western blot, laser-capture microdissection (LCM) coupled with reverse transcription -polymerase chain reaction (RT-PCR), and immunoelectron microscopic (IEM) studies for APJ expression were conducted. In vitro examinations used commercial human HSCs and SECs. APJ expression was examined in cultured HSCs activated by growth factors and in capillarized SECs activated by angiogenic factors. RESULTS: The IHC study of liver samples revealed only slight APJ expression in hepatic sinusoids in control liver tissue. In cirrhotic liver (Child-A-LC and Child-C-LC), APJ expression was evident mainly along the sinusoids and on portal fibroblasts in fibrotic septa. Western blot analysis of whole-liver homogenate and LCM-PCR of sinusoids revealed overexpression of APJ in Child-C-LC samples. The results of IEM studies showed that APJ expression was increased significantly on HSCs, but it was sparse on SECs in Child-C-LC tissue. In vitro examination revealed that APJ was overexpressed in cultured HSCs activated by platelet-derived growth factor-beta. CONCLUSIONS: Enhanced expression of APJ on HSCs in cirrhosis indicates markedly increased vascular remodeling. PMID- 20725753 TI - Expert's comment concerning Grand Rounds case entitled "Closing-opening wedge osteotomy for severe, rigid thoraco-lumbar post-tubercular kyphosis" (by S. Rajasekaran, P. Rishimugesh Kanna and Ajoy Prasad Shetty). AB - Prevention or correction of severe kyphotic deformity in addition to eradication of the infective focus has become the modern standard of management of tuberculosis of the spine. Circumferential excision of the kyphus is now technically feasible with the development of rigid pedicle screw fixation system and intraoperative spinal cord monitoring in the past two decades. PMID- 20725752 TI - Cardiovascular changes after PMMA vertebroplasty in sheep: the effect of bone marrow removal using pulsed jet-lavage. AB - Clinically, the displacement of intravertebral fat into the circulation during vertebroplasty is reported to lead to problems in elderly patients and can represent a serious complication, especially when multiple levels have to be treated. An in vitro study has shown the feasibility of removing intravertebral fat by pulsed jet-lavage prior to vertebroplasty, potentially reducing the embolization of bone marrow fat from the vertebral bodies and alleviating the cardiovascular changes elicited by pulmonary fat embolism. In this in vivo study, percutaneous vertebroplasty using polymethylmethacrylate (PMMA) was performed in three lumbar vertebrae of 11 sheep. In six sheep (lavage group), pulsed jet lavage was performed prior to injection of PMMA compared to the control group of five sheep receiving only PMMA vertebroplasty. Invasive recording of blood pressures was performed continuously until 60 min after the last injection. Cardiac output and arterial blood gas parameters were measured at selected time points. Post mortem, the injected cement volume was measured using CT and lung biopsies were processed for assessment of intravascular fat. Pulsed jet-lavage was feasible in the in vivo setting. In the control group, the injection of PMMA resulted in pulmonary fat embolism and a sudden and significant increase in mean pulmonary arterial pressure. Pulsed jet-lavage prevented any cardiovascular changes and significantly reduced the severity of bone marrow fat embolization. Even though significantly more cement had been injected into the lavaged vertebral bodies, significantly fewer intravascular fat emboli were identified in the lung tissue. Pulsed jet-lavage prevented the cardiovascular complications after PMMA vertebroplasty in sheep and alleviated the severity of pulmonary fat embolism. PMID- 20725747 TI - Guidelines for surgical treatment of gastroesophageal reflux disease. PMID- 20725754 TI - Observed peptide pI and retention time shifts as a result of post-translational modifications in multidimensional separations using narrow-range IPG-IEF. AB - Modified peptides constitute a sub-population among the tryptic peptides analyzed in LC-MS based shotgun proteomics experiments. For larger proteomes including the human proteome, the tryptic peptide pool is very large, which necessitates some form of sample fractionation. By carefully choosing the sample fractionation and separation methods applied as shown here for the combination of narrow-range immobilized pH gradient isoelectric focusing (IPG-IEF) and nanoUPLC-MS, significantly increased information content can be achieved. Relatively low standard deviations were obtained for such multidimensional separations in terms of peptide pI (<0.05 pI units) and retention time (<0.3 min for a 350 min gradient) for a selection of highly complex proteomics samples. Using narrow range IPG-IEF, experimental and predicted pI were in relative good agreement. However, based on our data, retention time prediction algorithms need further improvements in accuracy to match state-of-the-art reversed-phase chromatography performance. General trends of peptide pI shifts induced by common modifications including deamidations and N-terminal modifications are described. Deamidations of glutamine and asparagines shift peptide pI by approximately 1.5 pI units, making the peptides more acidic. Additionally, a novel pI shift (+~0.4 pI units) was found associated with dethiomethyl Met modifications. Further, the effects of these modifications as well as methionine oxidation were investigated in terms of experimentally observed retention time shifts in the chromatographic separation step. Clearly, post-translational modification-induced influences on peptide pI and retention time can be accurately and reproducibly measured using narrow-range IPG-IEF and high-performance nanoLC-MS. Even at modest mass accuracy (+/-50 ppm), the inclusion of peptide pI (+/-0.2 pI units) and/or retention time (+/-20 min) criteria are highly informative for human proteome analyses. The applications of using this information to identify post-translationally modified peptides and improve data analysis workflows are discussed. PMID- 20725755 TI - Application of isothermal titration calorimetry in bioinorganic chemistry. AB - The thermodynamics of metals ions binding to proteins and other biological molecules can be measured with isothermal titration calorimetry (ITC), which quantifies the binding enthalpy (DeltaH degrees ) and generates a binding isotherm. A fit of the isotherm provides the binding constant (K), thereby allowing the free energy (DeltaG degrees ) and ultimately the entropy (DeltaS degrees ) of binding to be determined. The temperature dependence of DeltaH degrees can then provide the change in heat capacity (DeltaC (p) degrees ) upon binding. However, ITC measurements of metal binding can be compromised by undesired reactions (e.g., precipitation, hydrolysis, and redox), and generally involve competing equilibria with the buffer and protons, which contribute to the experimental values (K (ITC), DeltaH (ITC)). Guidelines and factors that need to be considered for ITC measurements involving metal ions are outlined. A general analysis of the experimental ITC values that accounts for the contributions of metal-buffer speciation and proton competition and provides condition-independent thermodynamic values (K, DeltaH degrees ) for metal binding is developed and validated. PMID- 20725756 TI - Follow-up after intraoperative sentinel node biopsy of N0 neck oral cancer patients. AB - The objective of the study was to evaluate the validity of sentinel node (SN) biopsy in early oral cancer patients focusing on the accuracy of intraoperative diagnoses of SN status, recurrences in follow-up and impact on patient survival. Previously untreated N0 oral cancer patients were candidates for the study. Using a radioisotope method, an intraoperative SN biopsy was performed. Patients with a positive frozen section of SN underwent immediate neck dissection as a single stage procedure; they were followed in our outpatient clinic. Forty-five cT1-2N0 patients with squamous cell carcinoma were analyzed. There were seven patients with positive SN, five of whom were detected by intraoperative frozen section analysis. The sensitivity, specificity and accuracy of the intraoperative frozen section analysis of SN were 71.4, 100 and 95.6%, respectively. There were 13 recurrences in the course of all patients treated. Those with positive SN showed a tendency toward recurrence. Three patients with negative SN suffered from delayed ipsilateral neck recurrence. These were considered false negatives at a rate of 7.9%. The 5-year overall survival rate of all patients was 91.1%. SN positive patient survival was significantly poorer than that of SN-negative patients. Positive SN had a negative impact on the survival. SN biopsy was shown to be a valuable method for determining the neck status of early oral cancer patients. The concordance rate of intraoperative multislice frozen section analysis of SN and patient neck status at the time of operation was 95.6%. SN positive patients exhibited a tendency toward cancer recurrence. There were three cases of false negatives not conforming to the SN concept and their rate was 7.9%. Positive SN had a negative impact on patient survival. PMID- 20725757 TI - Evaluation of the effects of CO2 laser on debonding of orthodontics porcelain brackets vs. the conventional method. AB - Debonding of ceramic brackets due to their high bond strength and low fracture toughness is one of the clinician's complications. The purpose of this study is to evaluate the effect of a laser on shear bond strength, site of debonding, and ARI index during debonding of ceramic brackets and then compare it to the conventional method used for this procedure. Thirty polycrystalline alumina (G & H Series, Germany) brackets were bonded to 30 intact extracted first and second maxillary premolars and stored in a 1% thymol solution. A chemically cured orthodontic composite resin (No-mix, Unitek, USA) was used for bonding the brackets to the enamel surface on all teeth. All brackets were positioned 4 mm from the incisal edge of the teeth with an orthodontic bracket-positioning device. Then the teeth with bonded brackets were embedded in auto-polymerized polymethylmethacrylate (2.2.3 cm) blocks using a special device to make their slots horizontally parallel. These 30 teeth were then divided into two subgroups: control or no-lased (n = 15) and super pulse CO(2) laser (n = 15). To characterize the peak of SBS in two groups, we used an Instron machine while its blade was moving at a constant speed of 1 mm/min. For evaluating the site of debonding and the adhesive remnant index (ARI index), a light microscope and the Photoshop program were used. Means and standard deviations of the SBS in two subgroups shows that in the control group, the teeth have definitely higher values in comparison to the experimental group. The results of the two groups drew no substantial differences with respect to the surface of debonding, which was mostly within the adhesive. However, observing the results of ARI presented a significant distinction between the control and experimental group. This index denoted that the debonding site in the control group was closer to the enamel adhesive interface and, consequently, the rate of enamel damage in this group would be greater. The present study shows that a CO(2) laser has the potential to replace the conventional method for debonding ceramic brackets due to less debonding force and more adhesive remnant index on the tooth surface. PMID- 20725758 TI - Fecaloma in an iatrogenic diverticulum: an unusual complication of the procedure for prolapsed hemorrhoids (PPH). PMID- 20725759 TI - Ileal pouch dysfunction. AB - The causes of pouch dysfunction are inflammatory, non-inflammatory and iatrogenic. The most common long-term complication is pouchitis. Diagnosis should be based on clinical symptoms, endoscopic appearance and histologic findings. Ciprofloxacin and metronidazole are the treatment of choice for pouchitis. Fistulae and perianal abscesses should be suspected to be an expression of misdiagnosed Crohn's disease. Strictures are confronted by endoscopic balloon dilatation. Patients who will be refractory to all forms of medical treatment should have surgical treatment such as faecal diversion or pouch revision. PMID- 20725760 TI - A method for computing general sacroiliac screw corridors based on CT scans of the pelvis. AB - Sacroiliac (SI) joint dislocations and sacral fractures of the pelvis can be stabilized by SI screws; however, screw insertion into a sacral isthmus region is risky for the adjacent neurovascular structures. Therefore, shape analyses of general SI screw corridors or safety zones are of great surgical interest; however, before such analyses can be conducted, a method for computing 3D models of general SI corridors from routine clinical computed tomography (CT) scans has to be developed. This work describes a method for determining general corridors in pelvic CT data for accurate screw placement into the first sacral body. The method is implemented with the computer language C++. The pelvic CT data are preprocessed before the presented algorithm computes a model of the 3D corridor volume. Additionally, the two most important parameters of the algorithm, the raster step and the virtual SI screw diameter, have been characterized. The result of the work is an algorithm for computing general SI screw corridors and its implementation. Additionally the influences of two important parameters, the raster step and the SI screw diameter, on corridor volume precision and computation time have been quantified for the test sample. We conclude that the method can be used in further corridor shape analyses with a large number of pelvic CT data sets for investigating general SI screw corridors and clinical consequences for the placements of the screws. Implementation of the presented software algorithm could also enhance performance of computer-assisted surgery in the near future. PMID- 20725761 TI - Social support and postpartum depression in low-socioeconomic level postpartum women in Eastern Turkey. AB - OBJECTIVES: The aim of this article was to determine risk factors for postpartum depression in low-socioeconomic level women during the first postpartum year and to determine the relationship between postpartum depression symptoms and social support. METHODS: This is a cross-sectional study. Data were collected through administration of a questionnaire, the Edinburgh Postnatal Depression Scale (EPDS) and the Multidimensional Scale of Perceived Social Support (MSPSS). Data were analyzed utilizing unpaired t test, one-way analysis of variance, and logistic regression analysis. RESULTS: The prevalence of perceived symptoms of postpartum depression was 21.0% (scores of >=13) and there was a correlation (r = -0.36, p = 0.000) between MSPSS and EPDS scores. The mean EPDS score was 8.36 +/- 5.6 while the mean MSPSS score was 64.49 +/- 15.2. CONCLUSION: Postpartum depression symptoms are common among Turkish women. These findings provide important information about the role of social support related to postpartum depressive symptoms among Turkish women. Informing health professionals about these issues is an important step towards improving maternal and child health care services. PMID- 20725762 TI - cAMP initiates early phase neuron-like morphology changes and late phase neural differentiation in mesenchymal stem cells. AB - The intracellular second messenger cAMP is frequently used in induction media to induce mesenchymal stem cells (MSCs) into neural lineage cells. To date, an understanding of the role cAMP exerts on MSCs and whether cAMP can induce MSCs into functional neurons is still lacking. We found cAMP initiated neuron-like morphology changes early and neural differentiation much later. The early phase changes in morphology were due to cell shrinkage, which subsequently rendered some cells apoptotic. While the morphology changes occurred prior to the expression of neural markers, it is not required for neural marker expression and the two processes are differentially regulated downstream of cAMP-activated protein kinase A. cAMP enabled MSCs to gain neural marker expressions with neuronal function, such as, calcium rise in response to neuronal activators, dopamine, glutamate, and potassium chloride. However, only some of the cells induced by cAMP responded to the three neuronal activators and further lack the neuronal morphology, suggesting that although cAMP is able to direct MSCs towards neural differentiation, they do not achieve terminal differentiation. PMID- 20725763 TI - Targeting poly(ADP-ribose) polymerase activity for cancer therapy. AB - Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD(+). The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD(+) at the enzyme's activity site are effective chemo- and radiopotentiation agents and, in BRCA-deficient tumors, can be used as single agent therapies acting through the principle of synthetic lethality. Through extensive drug-development programs, third-generation inhibitors have now entered clinical trials and are showing great promise. However, both PARP-1 and PARP-2 are not only involved in DNA repair but also in transcription regulation, chromatin modification, and cellular homeostasis. The impact on these processes of PARP inhibition on long-term therapeutic responses needs to be investigated. PMID- 20725765 TI - The ectopic expression of the wheat Puroindoline genes increase germ size and seed oil content in transgenic corn. AB - Plant oil content and composition improvement is a major goal of plant breeding and biotechnology. The Puroindoline a and b (PINA and PINB) proteins together control whether wheat seeds are soft or hard textured and share a similar structure to that of plant non-specific lipid-transfer proteins. Here we transformed corn (Zea mays L.) with the wheat (Triticum aestivum L.) puroindoline genes (Pina and Pinb) to assess their effects upon seed oil content and quality. Pina and Pinb coding sequences were introduced into corn under the control of a corn Ubiquitin promoter. Three Pina/Pinb expression positive transgenic events were evaluated over two growing seasons. The results showed that Pin expression increased germ size significantly without negatively impacting seed size. Germ yield increased 33.8% while total seed oil content was increased by 25.23%. Seed oil content increases were primarily the result of increased germ size. This work indicates that higher oil content corn hybrids having increased food or feed value could be produced via puroindoline expression. PMID- 20725766 TI - Safe and fit genetically modified insects for pest control: from lab to field applications. AB - Insect transgenesis is continuously being improved to increase the efficacy of population suppression and replacement strategies directed to the control of insect species of economic and sanitary interest. An essential prerequisite for the success of both pest control applications is that the fitness of the transformant individuals is not impaired, so that, once released in the field, they can efficiently compete with or even out-compete their wild-type counterparts for matings in order to reduce the population size, or to spread desirable genes into the target population. Recent research has shown that the production of fit and competitive transformants can now be achieved and that transgenes may not necessarily confer a fitness cost. In this article we review the most recent published results of the fitness assessment of different transgenic insect lines and underline the necessity to fulfill key requirements of ecological safety. Fitness evaluation studies performed in field cages and medium/large-scale rearing will validate the present encouraging laboratory results, giving an indication of the performance of the transgenic insect genotype after release in pest control programmes. PMID- 20725767 TI - Changes in cellular levels of inositol polyphosphates during apoptosis. AB - Accumulations of higher inositol polyphosphates, diphosphoinositol polyphosphates or pyrophosphates, have been implicated to mediate cellular apoptosis. Whether cellular levels of lower inositol phosphates (lower than inositol hexakisphosphates) change during apoptosis is not known, although these inositol phosphates are known to play crucial roles in a number of cellular signaling processes including calcium mobilization. Therefore, in this study, we have examined changes in cellular levels of inositol phosphates following metabolic labeling of these compounds by [(3)H]myo-inositol and induction of apoptosis. The levels of inositol mono- and bis-phosphates were increased, whereas the levels of inositol tris- and tetrakis-phosphates decreased significantly with an increasing rate of apoptosis induced by etoposide in a dose-dependent manner. NaF treatment, which increased the rate of apoptosis in a time- and dose-dependent manner, also increased the levels of inositol mono- and bis-phosphates and drastically reduced the levels of inositol tris- and tetrakis-phosphates. Prior treatment with antimycin A, a strategy used to reverse the NaF-induced accumulations of higher InsPs, partially reduced the effects of NaF on apoptosis as well as the levels of lower InsPs. Taken together, our results suggest that cellular levels of lower InsPs are altered during apoptosis. PMID- 20725764 TI - Crustacean neuropeptides. AB - Crustaceans have long been used for peptide research. For example, the process of neurosecretion was first formally demonstrated in the crustacean X-organ-sinus gland system, and the first fully characterized invertebrate neuropeptide was from a shrimp. Moreover, the crustacean stomatogastric and cardiac nervous systems have long served as models for understanding the general principles governing neural circuit functioning, including modulation by peptides. Here, we review the basic biology of crustacean neuropeptides, discuss methodologies currently driving their discovery, provide an overview of the known families, and summarize recent data on their control of physiology and behavior. PMID- 20725768 TI - Prediction of osteoconductive activity of modified potassium fluorrichterite glass-ceramics by immersion in simulated body fluid. AB - Potassium fluorrichterite (KNaCaMg(5)Si(8)O(22)F(2)) glass-ceramics were modified by either increasing the concentration of calcium (GC5) or by the addition of P(2)O(5) (GP2). The stoichiometric composition (GST), GC5 and GP2 were soaked in simulated body fluid (SBF) along with 45S5-type bioglass as a control. After immersion, surface analyses were performed using thin-film X-ray diffraction (TF XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and Fourier-transform infrared (reflection) spectroscopy (FT-IR). All compositions showed the formation of a calcium phosphate rich surface layer in SBF; GST, GP2 and the bioglass control within 7 days of immersion and GC5 after 14 days. It was concluded that all compositions were likely to be osteoconductive in vivo, with GP2 providing the best performance in terms of the combination of rapid formation of the surface layer and superior mechanical properties. This glass-ceramic system has potential as a load bearing bioceramic for fabrication of medical devices intended for skeletal tissue repair. PMID- 20725769 TI - Improved mechanical long-term reliability of hip resurfacing prostheses by using silicon nitride. AB - Although ceramic prostheses have been successfully used in conventional total hip arthroplasty (THA) for many decades, ceramic materials have not yet been applied for hip resurfacing (HR) surgeries. The objective of this study is to investigate the mechanical reliability of silicon nitride as a new ceramic material in HR prostheses. A finite element analysis (FEA) was performed to study the effects of two different designs of prostheses on the stress distribution in the femur-neck area. A metallic (cobalt-chromium-alloy) Birmingham hip resurfacing (BHR) prosthesis and our newly designed ceramic (silicon nitride) HR prosthesis were hereby compared. The stresses induced by physiologically loading the femur bone with an implant were calculated and compared with the corresponding stresses for the healthy, intact femur bone. Here, we found stress distributions in the femur bone with the implanted silicon nitride HR prosthesis which were similar to those of healthy, intact femur bone. The lifetime predictions showed that silicon nitride is indeed mechanically reliable and, thus, is ideal for HR prostheses. Moreover, we conclude that the FEA and corresponded post-processing can help us to evaluate a new ceramic material and a specific new implant design with respect to the mechanical reliability before clinical application. PMID- 20725770 TI - Preparation of superhydrophilic microrough titanium implant surfaces by alkali treatment. AB - A new strategy to render intrinsically hydrophobic microrough titanium implant surfaces superhydrophilic is reported, which is based on a rapid treatment with diluted aqueous sodium hydroxide solutions. The physicochemical characterization and protein interaction of the resulting superhydrophilic implant surfaces are presented. The superhydrophilicity of alkali treated microrough titanium substrates was mainly attributed to deprotonation and ion exchange processes in combination with a strong enhancement of wettability due to the roughness of the used substrates. Albeit these minor and mostly reversible chemical changes qualitative and quantitative differences between the protein adsorption on untreated and alkali treated microrough titanium substrates were detected. These differences in protein adsorption might account for the enhanced osseointegrative potential of superhydrophilic alkali treated microrough implant surfaces. The presented alkali treatment protocol represents a new clinically applicable route to superhydrophilic microrough titanium substrates by rendering the implant surface superhydrophilic "in situ of implantation". PMID- 20725772 TI - Mutual best friendship involvement, best friends' rejection sensitivity, and psychological maladaptation. AB - Rejection sensitivity (RS) refers to the tendency to anxiously expect, readily perceive, and overreact to experiences of possible rejection. RS is a clear risk factor for psychological maladaptation during early adolescence. However, there is growing evidence of significant heterogeneity in the psychological correlates of RS. To investigate when RS poses the greatest psychological risk during early adolescence, this study examines mutual best friendship involvement (or lack thereof) and the best friends' RS as potential moderators of the associations between RS and psychological difficulties. Participants were 150 7th grade students (58 boys; M age = 13.05 years) who nominated their best friends, and reported on their RS, social anxiety, and self-esteem. Results from a series of hierarchical multiple regression analyses indicated that mutual best friendship involvement and best friends' RS were both significant moderators when fear of negative evaluation (a type of social anxiety) served as the dependent variable. The association between RS and fear of negative evaluation was stronger for adolescents without mutual best friends than adolescents with mutual best friends. In addition, the association between RS and fear of negative evaluation was the strongest for adolescents whose best friends were highly rejection sensitive (relative to adolescents whose best friends were moderately or low in RS). Findings highlight the importance of considering best friendships in studies of RS and strongly suggest that, although having mutual best friendships may be protective for rejection sensitive adolescents, having a rejection sensitive best friend may exacerbate difficulties. The significance of friends in the lives of rejection sensitive adolescents is discussed as well as possible applied implications of the findings and study limitations. PMID- 20725771 TI - Polymeric micelles in anticancer therapy: targeting, imaging and triggered release. AB - Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward. PMID- 20725773 TI - Stability of two cluster solutions in pulse coupled networks of neural oscillators. AB - Phase response curves (PRCs) have been widely used to study synchronization in neural circuits comprised of pacemaking neurons. They describe how the timing of the next spike in a given spontaneously firing neuron is affected by the phase at which an input from another neuron is received. Here we study two reciprocally coupled clusters of pulse coupled oscillatory neurons. The neurons within each cluster are presumed to be identical and identically pulse coupled, but not necessarily identical to those in the other cluster. We investigate a two cluster solution in which all oscillators are synchronized within each cluster, but in which the two clusters are phase locked at nonzero phase with each other. Intuitively, one might expect this solution to be stable only when synchrony within each isolated cluster is stable, but this is not the case. We prove rigorously the stability of the two cluster solution and show how reciprocal coupling can stabilize synchrony within clusters that cannot synchronize in isolation. These stability results for the two cluster solution suggest a mechanism by which reciprocal coupling between brain regions can induce local synchronization via the network feedback loop. PMID- 20725774 TI - Substance use and its association with psychiatric symptoms in perinatally HIV infected and HIV-affected adolescents. AB - Drug use in combination with psychiatric illness may lead to unsafe sexual risk behavior and increased risk for secondary HIV transmission among adolescents with HIV infection. We compared the prevalence of substance use for perinatally HIV infected youth to uninfected adolescents living in families affected by HIV infection, and evaluated the association of psychiatric symptoms with risk of substance use. Among 299 adolescents (196 HIV+, 103 HIV-) aged 12-18 years enrolled in IMPAACT P1055, a multisite US cohort study, 14% reported substance use at enrollment (HIV+: 13%, HIV-: 16%). In adjusted logistic regression models, adolescents had significantly higher odds of substance use if they met symptom criteria for ADHD [adjusted odds ratio (aOR) = 2.7, Wald chi(2) = 5.18, P = 0.02], major depression or dysthymia (aOR = 4.0, Wald chi(2) = 7.36, P = 0.01), oppositional defiant disorder (aOR = 4.8, Wald chi(2) = 12.7, P = 0.001), or conduct disorder (aOR = 15.4, Wald chi(2) = 28.12, P = 0.001). Among HIV-infected youth, those with lower CD4 lymphocyte percentage (CD4% < 25%) had significantly increased risk of substance use (aOR = 2.7, Wald chi(2) = 4.79, P = 0.03). However, there was no overall association of substance use with HIV infection status, and the association between psychiatric symptoms and substance use did not differ by HIV status. Programs to prevent substance use should target both HIV-infected and uninfected adolescents living in families affected by HIV infection, particularly those with psychiatric symptoms. PMID- 20725775 TI - Tobacco use cessation and weight management among motor freight workers: results of the gear up for health study. AB - OBJECTIVES: To present the results of a study of a worksite-based intervention to promote tobacco use cessation and improve weight management among motor freight workers. METHODS: This study used a pre-test/post-test, non-randomized design to assess the effectiveness of a four-month intervention that addressed the social context of the work setting. We evaluated 7-day tobacco quit prevalence among baseline tobacco users, and successful weight management, defined as no weight gain in workers with BMI <25 at baseline and any weight loss among overweight and obese workers. RESULTS: At baseline, 40% were current tobacco users, and 88% had a BMI of 25 or greater. Of 542 workers invited to participate, 227 agreed to participate and received at least the first telephone call (42%). Ten-month post baseline, baseline tobacco users who participated in the intervention were more likely to have quit using tobacco than non-participants: 23.8% vs. 9.1% (p = 0.02). There was no significant improvement in weight management. CONCLUSIONS: Incorporating work experiences and job conditions into messages of health behavior change resulted in significant tobacco use cessation among participating motor freight workers. PMID- 20725776 TI - MMP9 polymorphisms and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study. AB - In addition to tumor invasion and angiogenesis, matrix metalloproteinase (MMP)9 also contributes to carcinogenesis and tumor growth. Genetic variation that may influence MMP9 expression was evaluated among participants of the Shanghai Breast Cancer Genetics Study (SBCGS) for associations with breast cancer susceptibility. In stage 1, 11 MMP9 single nucleotide polymorphisms (SNPs) were genotyped by the Affymetrix Targeted Genotyping System and/or the Affymetrix Genome-Wide Human SNP Array 6.0 among 4,227 SBCGS participants. One SNP was further genotyped using the Sequenom iPLEX MassARRAY platform among an additional 6,270 SBCGS participants. Associations with breast cancer risk were evaluated by odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models that included adjustment for age, education, and genotyping stage when appropriate. In Stage 1, rare allele homozygotes for a promoter SNP (rs3918241) or a non-synonymous SNP (rs2274756, R668Q) tended to occur more frequently among breast cancer cases (P value = 0.116 and 0.056, respectively). Given their high linkage disequilibrium (D' = 1.0, r (2) = 0.97), one (rs3918241) was selected for additional analysis. An association with breast cancer risk was not supported by additional Stage 2 genotyping. In combined analysis, no elevated risk of breast cancer among homozygotes was found (OR: 1.2, 95% CI: 0.8-1.8). Common genetic variation in MMP9 was not found to be significantly associated with breast cancer susceptibility among participants of the Shanghai Breast Cancer Genetics Study. PMID- 20725777 TI - The biological pathway and effect of PCBs on common terns in Lake Michigan. AB - Poly-chlorinated biphenyls (PCBs) have been recognized as a significant contaminant in the Great Lakes ecosystem. Although PCBs are implicated in the reduced survival and reproductive success of several piscivorous bird species, the biological pathway in which PCBs bioaccumulate remains largely unknown. This study investigates the two most likely biological pathways, suggested via research on Great Lakes sport fish, by which PCBs would be acquired by common terns (Sterna hirundo), a piscivorous species of conservation concern. The first proposed pathway is through atmospheric deposition of PCBs which are subsequently acquired by filter-feeding fish (e.g., alewives, Alosa pseudoharengus). An alternative pathway is via the biodeposits of zebra mussels which are consumed by shallow water fish (e.g., round gobies, Neogobius melanostromus). Because common terns breed in near-shore sites where concentrations of zebra mussels are found, as well as forage in more pelagic environments it is possible that either or both pathways may be contributing to their PCB exposure. Field experiments and stable isotope analyses suggest the most likely pathway by which terns are exposed to PCBs is via alewives, similar to how apex predators such as lake trout acquire PCBs. Biodeposits from zebra mussels do not appear to be a significant factor in PCB accumulation in terns. We quantified extremely poor parental attentiveness during incubation. Although we cannot determine whether poor parental attentiveness alone or in combination with PCB contamination led to low hatching success, accumulation of PCBs appears to have significant impacts on the overall reproductive success of common terns. PMID- 20725778 TI - Sodium iodate selectively injuries the posterior pole of the retina in a dose dependent manner: morphological and electrophysiological study. AB - Sequential morphological and functional features of retinal damage in mice exposed to different doses (40 vs. 20 mg/kg) of sodium iodate (NaIO(3)) were analyzed. Retinal morphology, apoptosis (TUNEL assay), and function (electroretinography; ERG) were examined at several time points after NaIO(3) administration. The higher dose of NaIO(3) caused progressive degeneration of the whole retinal area and total suppression of scotopic and photopic ERG. In contrast, the lower dose induced much less severe degeneration in peripheral part of retina along with a moderate decline of b- and a-wave amplitudes in ERG, corroborating the presence of regions within retina that retain their function. The peak of photoreceptor apoptosis was found on the 3rd day, but the lower dose induced more intense reaction within the central retina than in its peripheral region. In conclusion, these results indicate that peripheral area of the retina reveals better resistance to NaIO(3) injury than its central part. PMID- 20725779 TI - Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone. AB - The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org 24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT 1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication. PMID- 20725781 TI - Diversity-oriented, one-pot, multi-component synthesis of substituted uracil derivatives. AB - With the emergence of high throughput screening of bioactive molecules, there is constant need for the development of new strategies for diversity-oriented synthesis. We describe here a novel one-pot multicomponent reaction for the synthesis of uracil derivatives using easily available starting materials. This new synthetic strategy provides easy access to diverse uracil derivatives in moderate to good yields. PMID- 20725780 TI - R-deprenyl: pharmacological spectrum of its activity. AB - Deprenyl has been discovered by Knoll and co-workers. The R-enantiomer of deprenyl (selegiline) is a selective and irreversible inhibitor of the B-isoform of monoamine oxidase (MAO-B) enzyme. Due to its dopamine potentiating and possible neuroprotective properties it has an established role in the treatment of parkinsonian patients. By inhibiting MAO-B enzyme, R-deprenyl decreases the formation of hydrogen peroxide, alleviating the oxidative stress also reduced by increased expression of antioxidant enzymes (superoxide dismutases and catalase) reported during chronic treatment. It was shown to prevent the detrimental effects of neurotoxins like MPTP and DSP-4. R-Deprenyl elicits neuroprotective and neuronal rescue activities in concentrations too low to inhibit MAO-B. It is extensively metabolized and some of the metabolites possess pharmacological activities, thus their contribution to neuroprotective properties was also suggested. The recently identified deprenyl-N-oxide is extensively studied in our laboratory. Effects other than neuroprotection, like influencing cell adhesion and proliferation cannot be neglected. PMID- 20725782 TI - Geriatric renal palliative care is coming of age. PMID- 20725783 TI - Adult patients with eosinophilic esophagitis do not show an increased frequency of the HLA-DQ2/DQ8 genotypes predisposing to celiac disease. AB - BACKGROUND: Recent articles have described patients that share eosinophilic esophagitis (EoE) and celiac disease (CD) suggesting a true relationship between both diseases. AIMS: The purpose of this study was to investigate whether HLA DQ2 and DQ8 predisposing to CD are increased in adult patients with EoE. METHODS: HLA alleles conferring risk for CD was assessed in 75 adult EoE patients attended at two hospitals located in different Spanish regions over the past 2 years. We compared the frequencies to the registered data of 421 healthy kidney and bone marrow donors from our hospitals for the following alleles: (a) DR3-DQ2 haplotype; (b) the combination of DR3-DQ2 and DR4-DQ8; (c) DR4-DQ8 haplotype; (d) the simultaneous presence of the DR5-DQ7 and DR7-DQ2 haplotypes; and lastly (e) any combination of haplotypes not conferring risk for the development of CD. RESULTS: The HLA DQ2 and DQ8 alleles were analyzed in 58 adult EoE patients from hospital #1 and in 20 patients from hospital #2, and they were compared to recorded HLA genotyping data from 298 and 123 healthy donors, respectively. No differences were found between the distribution of the HLA frequencies of the patients and controls at both hospitals and the data could be combined. EoE patients did not show increased frequencies of DQ2 and DQ8 alleles compared to controls. CONCLUSIONS: Our work does not allow us to establish a common genetic basis for EoE and CD because an increased frequency of the HLA DQ2 and DQ8 alleles predisposing to CD was not observed in adult EoE patients compared to controls. PMID- 20725784 TI - Bone mineral density, vitamin D, and disease activity in children newly diagnosed with inflammatory bowel disease. AB - BACKGROUND AND AIM: The aim of this study was to examine bone mineral density and serum 25-hydroxy vitamin D in relation to disease activity in children newly diagnosed with IBD. METHODS: In a cross-sectional analytic study, 60 children newly diagnosed with IBD (39 with Crohn's disease [CD], mean age 12.2 +/- 2.1 years; and 21 with ulcerative colitis [UC], mean age 12.4 +/- 3.7 years) were recruited. Fifty-six age- and sex-matched children without IBD were invited as controls (mean age 11.3 +/- 4.2 years). Serum 25-hydroxy vitamin D for patients and controls was measured at diagnosis. Patients' adjusted lumbar spine bone mineral density (BMD) z scores were measured. Activity indices for both CD and UC were calculated. RESULTS: The serum level of 25-hydroxy vitamin D was significantly lower in children with IBD compared to the control group (P = 0.04). BMD was significantly lower in patients with CD compared to those with UC (P = 0.039). There was no correlation between vitamin D levels, BMD z scores or disease activity indices for both CD and UC. CONCLUSIONS: Serum vitamin D level is significantly lower in children with newly diagnosed IBD compared to those without. However, vitamin D levels are not affected by disease severity. It seems that BMD status may not be affected by vitamin D levels or disease severity in this cohort. Larger prospective controlled studies are needed to confirm these findings. PMID- 20725785 TI - Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common causes of cancer mortality in the gastrointestinal tract. Promoter hypermethylation of tumor suppressor genes contributes to gene inactivation during development of ESCC. AIM: To identify novel methylation-silenced genes in ESCC. METHODS: Genome-wide microarrays were applied to search for genes that were markedly upregulated after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) and that were markedly decreased in tumor tissue compared with paired adjacent nontumor tissue. Reverse-transcription polymerase chain reaction (PCR), immunohistochemistry, methylation-specific PCR, and bisulfite genomic sequencing were employed to investigate expression and methylation of candidate genes in five human ESCC cell lines, two human immortalized normal esophageal epithelial cell lines, primary ESCC tumor tissues, and paired adjacent nontumor tissues. RESULTS: GPX3 was selected as a novel candidate hypermethylated gene in ESCC through microarray analysis. In most ESCC cell lines, GPX3 messenger RNA (mRNA) expression was downregulated and the CpG island of GPX3 promoter was methylated. Demethylation treatment with 5-Aza-dC restored GPX3 mRNA expression. Methylation of GPX3 promoter was more frequent in ESCC tumor tissues (71.4%) than in adjacent nontumor tissues (10.7%) (P < 0.001), and methylation of GPX3 promoter correlated significantly with GPX3 mRNA downregulation. Finally, GPX3 protein expression was also significantly lower in ESCC tumor tissues than in adjacent nontumor tissues. CONCLUSION: GPX3 is downregulated through promoter hypermethylation in ESCC, which may be a potential biomarker of ESCC. PMID- 20725787 TI - Analysis of biliary epithelial-mesenchymal transition in portal tract fibrogenesis in biliary atresia. AB - BACKGROUND: The cellular origin of myofibroblast in the liver fibrosis remains unclear. This study was designed to investigate whether biliary epithelial cells (BECs) undergoing epithelial-mesenchymal transition (EMT) might be found in patients with biliary atresia, thereby serving as a source of fibrotic myofibroblasts. METHODS: Liver sections from patients with biliary atresia were evaluated to detect antigen for the BECs marker 4 and cytokeratin-7 (CK-7), proteins (fibroblast-specific protein 1, also known S100A4; the collagen chaperone heat shock protein 47, HSP47) characteristically expressed by cells undergoing EMT, as well as myofibroblasts marker a-smooth muscle actin (a-SMA). RESULTS: Normal bile ducts BECs could express CK-7 and low levels of a-SMA; they did not express S100A4 and HSP47. However, BECs from biliary atresia resulted in increased expression of a-SMA, S100A4, with concurrent transition to a fibroblast like morphology and decreased expression of AK-7. Furthermore, BECs in biliary atresia were associated with significant bile ductular proliferation and coexpressed both epithelial and mesenchymal markers. CONCLUSIONS: From significant histologic evidence, the BECs forming small- and medium-sized bile ducts undergoing EMT may account for prominent bile ductular proliferation and directly contribute to fibrogenesis in BA. PMID- 20725786 TI - Gastrointestinal stromal tumors (GISTs): an updated experience. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are relatively common mesenchymal tumors of the digestive tract characterized by c-KIT mutations. This is a comprehensive review of the current data of the literature on the various aspects of the diagnosis and treatment of these tumors. METHODS: The stomach is the most commonly involved site for these tumors in the digestive tract. Computed tomography and endoscopy can usually establish the diagnosis. The study of certain specific immunohistochemical markers may contribute to better characterization of these tumors. RESULTS: Surgical resection of GISTs has been the most effective therapy. In addition, targeted therapy with tyrosine kinase inhibitors may reduce the development of recurrence or decrease the disease progression in patients with metastatic disease. CONCLUSIONS: The introduction of tyrosine kinase inhibitors has resulted in significant improvement in the overall prognosis of these patients. Furthermore, preoperative imatinib can decrease tumor volume and is associated with complete surgical resection in locally advanced primary GISTs. PMID- 20725789 TI - Prediction of long-term reverse left ventricular remodeling after revascularization or medical treatment in patients with ischemic cardiomyopathy: a comparative study between SPECT and MRI. AB - Patients with ischemic heart disease and depressed left ventricular (LV) ejection fraction (LVEF) develop varying degrees of LV remodeling after cardiac surgical revascularization. Fifty-three patients with stable ischemic heart disease and impaired LV function (LVEF 34.9 +/- 4%) were prospectively followed up for 24 months. Thirty-seven patients underwent coronary artery bypass grafting (CABG), 16 patients were treated conservatively. Cardiac magnetic resonance imaging (MRI) and SPECT were performed at baseline and after 12 and 24 months of follow-up. The patients were divided into responders and non-responders depending on the degree of LVEF improvement at 24 months follow-up (>5%-responders). MRI with <=5 segments with DE/wall thickness ratio (DEWTR) >=50% predicted LV reverse remodeling with a sensitivity of 86% and a specificity of 75% (AUC 0.81). An MRI finding of <=2 segments with the DEWTR >=75% had a corresponding sensitivity of 71% and specificity of 67% (AUC 0.75) while fixed perfusion defect on SPECT <16.5% of LV predicted reverse remodeling with a sensitivity of 64% and a specificity of 69% (AUC 0.64). A preoperative number of segments with the DE/wall thickness ratio of >=50 and >=75% obtained by MRI, was found to be a better predictor of left ventricular reverse remodeling than fixed perfusion defect by SPECT. No other MRI or SPECT parameter predicted LVEF improvement at 24 months after CABG. PMID- 20725788 TI - Mechanism of acid hypersecretion post curative gastrinoma resection. AB - BACKGROUND: Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown. AIM: The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome. METHODS: Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors. RESULTS: Hypersecretion occurred in 31 patients (62%) and 14 had extreme hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038). CONCLUSIONS: Post curative resection, gastric hypersecretion persists long term (mean 8 years) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present, is unknown. PMID- 20725791 TI - On Norman Geschwind's facility with languages. PMID- 20725790 TI - Toll-like receptors 4 induces expression of matrix metalloproteinase-9 in human aortic smooth muscle cells. AB - Recent evidence supports a role of Toll-like receptor (TLR) signaling in the development of atherosclerotic lesions. It was confirmed that the presence of functional TLR4 promotes a proinflammatory phenotype and proliferation of vascular smooth muscle cells (VSMCs). Here we tested whether designed TLR4 small interfering RNAs (TLR4 siRNAs) is capable of inducing TLR4 deficient and simultaneously regulating the expression of matrix metalloproteinase-9 (MMP-9) in human aortic smooth muscle cells (HASMCs). Human aortic smooth muscle cells were obtained from Cascade Biologics (Portland, USA). The siRNAs used in this study were chemically synthesized by Ambion, diluted in RNase free water at concentration of 2 MUg/ml. The TLR4 siRNAs were complexed with Lipofectamine(TM) 2000 in transfection buffer. After 30 min incubation at room temperature, the complexes were added to the cells. Subsequent to 5 h incubation, cells were treated with 10 ng/ml LPS for 24 h. RT-PCR analysis was used to detect mRNA expression of GAPDH, TLR4 and MMP-9; Western blot analysis was used to examine GAPDH, TLR4 and MMP-9 protein expression. It was shown that all three designed TLR4 siRNAs inhibited the expression of TLR4 in HASMCs as compared to nontargeting siRNA. Notably, TLR4 siRNA-1 exhibited the strongest inhibition effect. Transfection of HASMCs with TLR4 siRNA-1 resulted in down-regulation of LPS-induced expression of MMP-9. It was concluded that TLR4 siRNA-transfected HASMCs were capable for regulating the expression of MMP-9, providing support for the rational design of siRNAs as atherosclerotic therapy. PMID- 20725792 TI - MGMT promoter methylation in malignant gliomas. AB - The O(6)-methylguanine-DNA methyltransferase (MGMT) gene is located at chromosome 10q26 and codes for a DNA repair enzyme that--if active--can counteract the effects of alkylating chemotherapy. Malignant gliomas often have the MGMT gene inactivated due to aberrant methylation of its promoter region. The assessment of the MGMT promoter methylation status has become of clinical relevance as a molecular marker associated with response to alkylating chemotherapy and prolonged survival of glioblastoma patients. MGMT promoter methylation testing is also on the merge of being used as a marker for patient selection within clinical trials, e.g., the current CENTRIC trial that is specifically focusing on patients with MGMT promoter-methylated glioblastomas. In anaplastic gliomas, MGMT promoter methylation is a favorable prognostic marker independent of the type of therapy, i.e., radio- or chemotherapy. This occurrence might be associated with the high incidence of other prognostically favorable molecular markers in these tumors, such as IDH1 mutation, 1p/19q deletion or yet to be identified novel aberrations. A variety of different methods are being used to assess MGMT promoter methylation in clinical samples, which may give rise to inter-laboratory variations in test results. Immunohistochemical determination of MGMT protein expression has not proven reliable for diagnostic purposes. This brief review article aims to summarize the main aspects of MGMT promoter methylation testing in contemporary neuro-oncology, in particular its value as a clinically useful molecular marker, putting it into the context of other molecular markers of clinical use in gliomas of adult patients. PMID- 20725793 TI - Reducing homicide risk in Indianapolis between 1997 and 2000. AB - Rates of homicide risk are not evenly distributed across the US population. Prior research indicates that young males in disadvantaged urban neighborhoods are particularly vulnerable to lethal violence. The traditional criminal justice response to violent crime in the urban context has the potential to exacerbate problems, particularly when broad-based arrest sweeps and general deterrence initiatives are the standard models used by law enforcement. Recent studies suggest that alternative intervention approaches that use both specific deterrence combined with improving pro-social opportunities has shown promise in reducing violent crime in these high-risk contexts. This paper examines the changes in homicide patterns for the highest-risk populations in Indianapolis after a "pulling levers" intervention was implemented in the late 1990s to address youth, gang, and gun violence. Multilevel growth curve regression models controlling for a linear trend over time, important structural correlates of homicide across urban neighborhoods, and between-neighborhood variance estimates showed that homicide rates involving the highest-risk populations (i.e., actors 15 to 24 years old) were most likely to experience a statistically significant and substantive reduction after the intervention was implemented (IRR = 0.48, 95% CI = 0.29 - 0.78). Among male actors in this age range, Black male homicide rates (IRR = 0.41, 95% CI = 0.25 - 0.70) and White male rates (IRR = 0.38, 95% CI = 0.15 - 0.79) declined substantially more than homicide rates involving actors outside the 15 to 24 years age range (IRR = 0.95, 95% CI = 0.54 - 1.69). In addition, neighborhoods where specific, community-level strategies were implemented had statistically significant and substantive high-risk homicide rate declines. We conclude that further extension of the pulling levers framework appears warranted in light of the recent findings. Alternative justice strategies that rely on the threat of sanctions coupled with strengthening social service provisions, as well as risk communication aimed at high-risk individuals, appears to hold significant promise as a means to reduce lethal violence. PMID- 20725794 TI - Modelling foot-and-mouth disease virus dynamics in oral epithelium to help identify the determinants of lysis. AB - Foot-and-mouth disease virus (FMDV) causes an economically important disease of cloven-hoofed livestock; of interest here is the difference in lytic behaviour that is observed in bovine epithelium. On the skin around the feet and tongue, the virus rapidly replicates, killing cells, and resulting in growing lesions, before eventually being cleared by the immune response. In contrast, there is usually minimal lysis in the soft palate, but virus may persist in tissue long after the animal has recovered from the disease. Persistence of virus has important implications for disease control, while identifying the determinant of lysis in epithelium is potentially important for the development of prophylactics. To help identify which of the differences between oral and pharyngeal epithelium are responsible for such dramatically divergent FMDV dynamics, a simple model has been developed, in which virus concentration is made explicit to allow the lytic behaviour of cells to be fully considered. Results suggest that localised structuring of what are fundamentally similar cells can induce a bifurcation in the behaviour of the system, explicitly whether infection can be sustained or results in mutual extinction, although parameter estimates indicate that more complex factors may be involved in maintaining viral persistence, or that there are as yet unquantified differences between the intrinsic properties of cells in these regions. PMID- 20725795 TI - Estimating 3D movements from 2D observations using a continuous model of helical swimming. AB - Helical swimming is among the most common movement behaviors in a wide range of microorganisms, and these movements have direct impacts on distributions, aggregations, encounter rates with prey, and many other fundamental ecological processes. Microscopy and video technology enable the automated acquisition of large amounts of tracking data; however, these data are typically two dimensional. The difficulty of quantifying the third movement component complicates understanding of the biomechanical causes and ecological consequences of helical swimming. We present a versatile continuous stochastic model-the correlated velocity helical movement (CVHM) model-that characterizes helical swimming with intrinsic randomness and autocorrelation. The model separates an organism's instantaneous velocity into a slowly varying advective component and a perpendicularly oriented rotation, with velocities, magnitude of stochasticity, and autocorrelation scales defined for both components. All but one of the parameters of the 3D model can be estimated directly from a two-dimensional projection of helical movement with no numerical fitting, making it computationally very efficient. As a case study, we estimate swimming parameters from videotaped trajectories of a toxic unicellular alga, Heterosigma akashiwo (Raphidophyceae). The algae were reared from five strains originally collected from locations in the Atlantic and Pacific Oceans, where they have caused Harmful Algal Blooms (HABs). We use the CVHM model to quantify cell-level and strain level differences in all movement parameters, demonstrating the utility of the model for identifying strains that are difficult to distinguish by other means. PMID- 20725796 TI - Genetic hotels for the standard genetic code: evolutionary analysis based upon novel three-dimensional algebraic models. AB - Herein, we rigorously develop novel 3-dimensional algebraic models called Genetic Hotels of the Standard Genetic Code (SGC). We start by considering the primeval RNA genetic code which consists of the 16 codons of type RNY (purine-any base pyrimidine). Using simple algebraic operations, we show how the RNA code could have evolved toward the current SGC via two different intermediate evolutionary stages called Extended RNA code type I and II. By rotations or translations of the subset RNY, we arrive at the SGC via the former (type I) or via the latter (type II), respectively. Biologically, the Extended RNA code type I, consists of all codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type) and third (YRN type) reading frames. The Extended RNA code type II, comprises all codons of the type RNY plus codons that arise from transversions of the RNA code in the first (YNY type) and third (RNR) nucleotide bases. Since the dimensions of remarkable subsets of the Genetic Hotels are not necessarily integer numbers, we also introduce the concept of algebraic fractal dimension. A general decoding function which maps each codon to its corresponding amino acid or the stop signals is also derived. The Phenotypic Hotel of amino acids is also illustrated. The proposed evolutionary paths are discussed in terms of the existing theories of the evolution of the SGC. The adoption of 3 dimensional models of the Genetic and Phenotypic Hotels will facilitate the understanding of the biological properties of the SGC. PMID- 20725797 TI - Survival analysis of stochastic competitive models in a polluted environment and stochastic competitive exclusion principle. AB - Stochastic competitive models with pollution and without pollution are proposed and studied. For the first system with pollution, sufficient criteria for extinction, nonpersistence in the mean, weak persistence in the mean, strong persistence in the mean, and stochastic permanence are established. The threshold between weak persistence in the mean and extinction for each population is obtained. It is found that stochastic disturbance is favorable for the survival of one species and is unfavorable for the survival of the other species. For the second system with pollution, sufficient conditions for extinction and weak persistence are obtained. For the model without pollution, a partial stochastic competitive exclusion principle is derived. PMID- 20725798 TI - A theoretical assessment of the effects of smoking on the transmission dynamics of tuberculosis. AB - Smoking has long being associated with tuberculosis. We present a tuberculosis dynamics model taking into account the fact that some people in the population are smoking in order to assess the effects of smoking on tuberculosis transmission. The epidemic thresholds known as the reproduction numbers and equilibria for the model are determined and stabilities analyzed. Qualitative analysis of the model including positivity and persistence of solutions are presented. The model is numerically analyzed to assess the effects of smoking on the transmission dynamics of tuberculosis. Numerical simulations of the model show that smoking enhances tuberculosis transmission, progression to active disease and in a population of smokers, tuberculosis cannot be controlled even when treatment success is assumed to be as high as 88%. Further, analysis of the reproduction numbers indicates that the number of active tuberculosis cases increases as the number of smokers increase. PMID- 20725799 TI - Intra-abdominal fat predicts survival in pancreatic cancer. AB - BACKGROUND: Body mass index (BMI) has proven unreliable in predicting survival following pancreaticoduodenectomy for cancer. While measures of intra-abdominal fat correlate with medical and postoperative complications of obesity, the impact of intra-abdominal fat on pancreatic cancer survival is uncertain. We hypothesized that the quantity of intra-abdominal fat would predict survival following resection of pancreatic cancer. METHODS: Preoperative CT imaging was used to measure intra-abdominal fat. Cox regression analyses were used to identify independent predictors of survival. RESULTS: Sixty-one patients from 2000-2009 underwent pancreaticoduodenectomy for exocrine pancreatic adenocarcinoma. After adjusting for age and perineural invasion status, preoperative BMI did not predict overall survival (p < 0.827). Unlike BMI, quartile of intra-abdominal fat predicted survival. Relative to patients with the least intra-abdominal fat (lowest quartile), those with more intra-abdominal fat demonstrated worse overall survival, but in a non-linear fashion. Individuals in the second quartile showed a fourfold increase in likelihood of death (HR 4.018, 95% CI 1.099-14.687, p < 0.035) relative to the lowest quartile. Patients in the third (HR 2.124, 95% CI 0.278-16.222, p < 0.468) and fourth quartile (HR 1.354, 95% CI 0.296-6.190, p < 0.696) also showed greater risk of death. CONCLUSIONS: Measuring intra-abdominal fat identifies a subset of patients with worse prognosis in pancreatic cancer. PMID- 20725800 TI - From longitudinal gastric resection to sleeve gastrectomy--revival of a previously established surgical procedure. AB - INTRODUCTION: Sleeve gastrectomy is becoming increasingly popular within bariatric surgery. Initially introduced as a component of complex interventions and later as part of a two-stage operation in high-risk patients, the procedure is now more common as one-stage operation and subject of avid scientific discussion. However, the concept of longitudinal gastric resection is not new. The procedure was already established in ulcer surgery but soon faded into insignificance. This article aims to trace the historical development of resection of the greater curvature with particular reference to its origin in ulcer and bariatric surgery. The contribution of ulcer surgery to modern sleeve gastrectomy is highlighted. Furthermore, the current value of sleeve gastrectomy within the spectrum of bariatric surgical procedures will be discussed. Relevant medical literature from PubMed to April 2010 was reviewed. DISCUSSION: Besides bariatric surgery modern sleeve gastrectomy has one more so far largely neglected origin: segmental and later longitudinal gastric resection used in ulcer surgery. Experience and achievements from ulcer surgery simplified and facilitated development of sleeve gastrectomy which is not the desired universal procedure for bariatric surgery but certainly an attractive treatment option. It should be performed in a more standardized manner and with due regard to future long-term results. PMID- 20725801 TI - Micromanipulation of culture niche permits long-term expansion of dental pulp stem cells--an economic and commercial angle. AB - Stem cells isolated from dental pulp possess the capacity for self-renewal and the potential for multi-lineage differentiation. However, dental pulp stem cells have different characteristics in terms of their culture conditions. The success of stem cells culture is governed by its micro-environmental niche. Therefore, we studied the effects of culture niche on long-term expansion of dental pulp stem cells in terms of cell morphology, growth kinetics, senescence pattern, cell surface marker expression differentiation capacity, and seeding plating density of dental pulp stem cells in four different, widely used media composition Among the various basal media tested, alpha-minimum essential media and knock out minimum essential media supplemented with 10% fetal bovine serum were found to be the most optimal media composition in preserving the phenotypic characteristics and differentiation potential for prolonged periods as compared with DMEM-F12 and DMEM-LG. Plating density has been shown to affect overall yield. As a conclusion, the adoption of an appropriate culture system significantly improved cell yield, thus enabling the attainment of sufficient yields for therapeutic applications economizing in terms of cost of production and minimizing seeding cell density for maximum yield. PMID- 20725802 TI - Plasma factor in red blood cells adhesion to endothelial cells: humans and rats. AB - Erythrocyte adhesion to the vascular endothelium is one of the key determinants of microcirculatory blood flow. Adhesion is a complex process determined by the intricate interaction among red blood cells (RBC), plasma factors, and the vascular endothelium. Rats are commonly used as disease models to investigate the pathophysiology of various hematological disease processes occurring in humans and their response to prospective treatments. The aim of our study was to characterize the adhesion of RBC in adult blood from rat and human subjects, in order to test the validity of rat models for adhesion-related disease processes. We demonstrated that adhesion of RBC from rats (rRBC), to endothelial cells (EC) in plasma-free buffer, is stronger than from human subjects (hRBC). In addition, plasma proteins induced elevation of hRBC (eightfold) but depression of rRBC (threefold) adhesion to EC. It is thus suggested to be aware of the difference in RBC/EC interaction for human and rat subjects, when studying models of blood flow. PMID- 20725804 TI - Dilute acid pretreatment of black spruce using continuous steam explosion system. AB - The pretreatment of lignocellulosic materials prior to the enzymatic hydrolysis is essential to the sugar yield and bioethanol production. Dilute acid hydrolysis of black spruce softwood chip was performed in a continuous high temperature reactor followed with steam explosion and mechanical refining. The acid-soaked wood chips were pretreated under different feeding rates (60 and 92 kg/h), cooking screw rotation speeds (7.2 and 14.4 rpm), and steam pressures (12 and 15 bar). The enzymatic hydrolysis was carried out on the acid-insoluble fraction of pretreated material. At lower feeding rate, the pretreatment at low steam pressure and short retention time favored the recovery of hemicellulose. The pretreatment at high steam pressure and longer retention time recovered less hemicellulose but improved the enzymatic accessibility. As a result, the overall sugar yields became similar no matter what levels of the retention time or steam pressure. Comparing with lower feeding rate, higher feeding rate resulted in consistently higher glucose yield in both liquid fraction after pretreatment and that released after enzymatic hydrolysis. PMID- 20725803 TI - Plasma-assisted pretreatment of wheat straw. AB - O3 generated in a plasma at atmospheric pressure and room temperature, fed with dried air (or oxygen-enriched dried air), has been used for the degradation of lignin in wheat straw to optimize the enzymatic hydrolysis and to get more fermentable sugars. A fixed bed reactor was used combined with a CO2 detector and an online technique for O3 measurement in the fed and exhaust gas allowing continuous measurement of the consumption of O3. This rendered it possible for us to determine the progress of the pretreatment in real time (online analysis). The process time can be adjusted to produce wheat straw with desired lignin content because of the online analysis. The O3 consumption of wheat straw and its polymeric components, i.e., cellulose, hemicellulose, and lignin, as well as a mixture of these, dry as well as with 50% water, were studied. Furthermore, the process parameters dry matter content and milled particle size (the extent to which the wheat straw was milled) were investigated and optimized. The developed methodology offered the advantage of a simple and relatively fast (0.5-2 h) pretreatment allowing a dry matter concentration of 45-60%. FTIR measurements did not suggest any structural effects on cellulose and hemicellulose by the O3 treatment. The cost and the energy consumption for lignin degradation of 100 g of wheat straw were calculated. PMID- 20725805 TI - Relevance of cerebral interleukin-6 after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: This study examines the inflammatory response via interleukin-6 (IL 6) in aneurysmal subarachnoid hemorrhage (aSAH) patients and its association with their clinical course (occurrence of acute focal neurological deficits, AFND; and delayed cerebral ischemia, DCI). METHODS: A total of 38 consecutive aSAH patients were studied prospectively within 14 days after admission and classified as asymptomatic (n = 9; WFNS grade 1 (1-2), median and quartiles) and symptomatic (n = 29; WFNS grade 4 (2-5)); the latter presenting with AFND (n = 13), DCI (n = 10) or both (n = 6). Levels of pro-inflammatory cytokine IL-6 were determined in cerebral extracellular fluid (ECF, using cerebral microdialysis), cerebrospinal fluid (CSF) and plasma for 10 days after aSAH. Additionally, C-reactive protein (CRP) levels were measured in plasma. RESULTS: High IL-6 levels in CSF, ECF and plasma were found in all patients, reflecting a pronounced local inflammatory response after aSAH, followed only in symptomatic patients by a delayed systemic inflammation (CRP P < 0.025, days 7-9 after aSAH). In all compartments, IL-6 levels appeared to be higher in symptomatic patients, accompanied also by a higher ECF lactate-pyruvate ratio (P = 0.04). Cerebral, but not plasma IL-6, levels were indicative of the development of DCI in symptomatic patients (ECF P = 0.003; CSF P = 0.001). CONCLUSIONS: A pronounced initial cerebral inflammatory state was observed in patients of all WFNS grades, suggesting that IL-6 elevations are not necessarily detrimental. Cerebral, but not plasma IL-6, levels were predictive of the development of delayed ischemic deficits in symptomatic patients, suggesting that CSF or ECF are the best sampling media for future studies. PMID- 20725806 TI - Production of human rotavirus and Salmonella antigens in plants and elicitation of fljB-specific humoral responses in mice. AB - A Nicotiana benthamiana transient expression system was used to express single antigen and dimeric combinations of the human rotavirus (HRV) VP7 and a truncated VP4 (VP4Delta) proteins fused with Salmonella typhimurium's flagellin fljB subunit. Immunoblot analyses using rabbit antibodies generated against these proteins demonstrated that the constructs were successfully expressed with yields ranging from 0.85 to 31.97 MUg of recombinant protein per gram of fresh leaf tissue. Expressing the single and dimeric antigens has no effect on plant growth and development except for VP7 and VP4Delta::VP7, which show mild necrotic lesions. Immunization of mice with proteins from leaves transformed with constructs bearing the fljB moiety elicited an fljB-specific humoral response. The Nicotiana benthamiana transient system is efficient to express multiple combinations of pathogen proteins and demonstrates the potential of generating a Salmonella typhimurium subunit vaccine in plants. PMID- 20725807 TI - Significance of vascular endothelial growth factor, interleukin-18 and nitric oxide in patients with breast cancer: correlation with carbohydrate antigen 15.3. AB - The aim of this study was to determine serum concentrations of angiogenic factors including vascular endothelial growth factor (VEGF), interleukin 18 (IL-18) and nitric oxide (NO) in patients with breast cancer and to evaluate whether these factors will be correlated with CA 15.3, as a routine tumor marker for breast cancer or not. This study was conducted on 44 patients with breast cancer and 15 healthy individuals as a control group. The results demonstrated significant increase in serum IL-18, NO and CA 15.3 levels in sera of breast cancer patients when compared to those of the control group (P < 0.001, P = 0.016 and P < 0.001, respectively). However, the mean serum level of VEGF in patients as showed insignificant increase compared to that of the controls was not significant (P = 0.311). Sensitivity of CA 15.3, VEGF, IL-18 and NO to detect patients with disease was 52.2, 21.3, 77.2 and 70.4 %, respectively. In addition, positive status of serum CA 15.3 and/or IL-18 was found in 39 out of 44 (88.6 %) patients, and the positive status of serum CA 15.3 and/or NO was only found in 35 out of 44 (79.5 %). In conclusion, the simultaneous determination of IL-18 or NO in combination with the CA 15.3 may increase the sensitivity to diagnose breast cancer and may aid in disease prognosis. PMID- 20725808 TI - Optimal blood pressure for a patient with type 2 diabetes mellitus: insight from the ACCORD study. PMID- 20725809 TI - Coenzyme Q(10) and statin myalgia: what is the evidence? AB - Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthesis of cholesterol. However, severe adverse events, including myalgias and rhabdomyolysis, have been reported with statin treatment. Different mechanisms have been proposed to explain statin-induced myopathy, including reduction of mevalonate pathway products, induction of apoptosis, mitochondrial dysfunction, and genetic predisposition. A decrease in coenzyme Q(10) (CoQ), a product of the mevalonate pathway, could contribute to statin induced myopathy. This article reviews the clinical and biochemical features of statin-induced myopathy, the inter relationship between statins and the concentration of CoQ in plasma and tissues, and whether there is a role for supplementation with CoQ to attenuate statin induced myopathy. PMID- 20725811 TI - Abstracts of the XXXVth Sir Peter Freyer Memorial Lecture and Surgical Symposium 2010. September 3-4, 2010. Galway, Ireland. PMID- 20725810 TI - Dietary monounsaturated fatty acids appear not to provide cardioprotection. AB - Dietary interventions have been consistently proposed as a part of a comprehensive strategy to lower the incidence and severity of coronary heart disease (CHD), in the process providing long-term cardioprotection. Replacement of dietary saturated fatty acids (SFA) with higher intakes of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) has been reported to be inversely associated with risk of CHD. The observed lower incidence of CHD among populations consuming a Mediterranean-type diet, mainly enriched in MUFA from olive oil, has long supported the belief that MUFA are an optimal substitution for SFA. However, both epidemiologic and interventional studies suggest that although substituting MUFA-rich foods for SFA-rich foods in the diet can potentially lower total plasma cholesterol concentrations, this substitution does not lower the extent of coronary artery atherosclerosis. In addition, although recent evidence suggests that the source of MUFA (animal fat vs vegetable oils) may differentially influence the correlation between MUFA intake and CHD mortality, animal studies suggest that neither source is cardioprotective. PMID- 20725812 TI - Vitamin D insufficiency and risk of severe asthma exacerbations. PMID- 20725813 TI - Pediatric pay-for-performance in asthma: who pays? AB - Pay-for-performance is a term referring to a system that uses incentives to reward health care providers for producing an improvement in performance based on quality measures. It has become part of a growing movement to improve the quality of the health care system. The purpose of this article is to review and discuss pay-for-performance and how it relates to pediatrics and asthma. PMID- 20725814 TI - A case of aggressive myeloma recognized shortly after the remission following high-dose chemotherapy with autologous peripheral blood stem cell transplantation. AB - A 45-year-old woman was referred to our hospital with acute renal failure and pyrexia. In August 2005, the patient was diagnosed with IgA-lambda type multiple myeloma with chromosome 13 deletion, and received three cycles of vinclistine, adriamycin and dexamethasone followed by high-dose melphalan-based autologous peripheral stem cell transplantation: this resulted in remission 2 months before admission to our hospital. Serum IgA concentration was within the normal limit, but an excess of myeloma cells in bone marrow was confirmed. Immunoelectrophoresis revealed BJP-lambda production with no IgA-lambda. The patient received several courses of chemotherapy with mechanical ventilation and regular hemodialysis. The progression of the illness was rapid: multiple organ failure promptly developed and the patient died 2 months after admission. Autopsy revealed deposition of light chain lambda protein in multiple organs. We report this unusual case of aggressive myeloma recognized shortly after successful autologous transplantation. PMID- 20725815 TI - Antiplatelet effect of once- or twice-daily aspirin dosage in stable coronary artery disease patients with diabetes. AB - The aim of this pilot study was to compare the effect of two different regimens of aspirin dosage on platelet of coronary artery disease (CAD) diabetic patients. Twenty-five CAD diabetic patients were included. Initially, all patients received aspirin 100 mg/day for 10 days. At day 10, aspirin antiplatelet effect was determined by measuring the collagen/epinephrine closure time (CT) 2 h after the last aspirin dosage and the next morning at 8 a.m.. The aspirin regimen was modified to 100 mg twice daily for patients showing a non-optimal platelet inhibitory effect (CT < 298 s at 8 a.m.). Persistent high platelet reactivity (HPR) was defined by a CT < 160 s. During the 100 mg/day aspirin regimen, the prevalence of HPR at 8 a.m. was 48%, and only 7 patients (28%) had showed an optimal platelet-inhibitory effect. Bridging to the twice-daily regimen, the HPR was significantly reduced (p=0.025), and the optimal platelet-inhibitory effect was reached for 3 other patients. Our results showed that 100 mg aspirin twice daily dosing rather than a once-daily dose significantly improves the aspirin effect on platelet of CAD diabetic patients. However, large prospective studies were needed to confirm whether this strategy will be clinically relevant and safe. PMID- 20725816 TI - Pleuric presentation of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue: a case report and a review of the literature. AB - A primary pleural marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a very rare eventuality. Here, we report a rare case of MALT lymphoma arising in the pleura and update the literature on this topic. A 74-year old female was hospitalized for persistent cough and weakness. A chest radiograph and total-body CT scan showed only large right-sided pleural effusion, and the coexistence of pleural thickening. Video-assisted thoracoscopic exploration and a talc pleurodesis were performed and microscopic and immunohistochemical findings showed that the tumor was a pleural MALT lymphoma. The patient received immunotherapy with Rituximab and obtained a good response that lasted 2 years. To the best of our knowledge, only seven cases of primary pleural MALT lymphoma have been documented until recently, mostly from Japan with a mean age for all patients of 60.5 years. The pathogenesis of MALT lymphomas remains unclear, although a possible chronic antigenic stimulation by microbial pathogens and/or autoantigens has been hypothesized. Surgical resection was performed in most cases, and some patients received postoperative chemotherapy or immunotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed. PMID- 20725818 TI - Prediction of the time to complete a series of surgical cases to avoid cardiac operating room overutilization. AB - PURPOSE: Operating room (OR) efficiency could be improved by reducing overutilization. In this article we suggest a methodology to accurately determine the time to complete a series of surgical cases in a single cardiac OR to avoid overutilization. Our methodology includes the basic assumptions that the first case starts on time, there are no add-on cases, and there is a predetermined OR time allocation. METHODS: We studied 6,090 cases performed by the department of cardiovascular surgery service at St. Michael's Hospital. Lognormal distributions were fitted to surgical times and turnover times. The distribution of the duration of the schedule was estimated using the Fenton-Wilkinson approximation. A simple model utilizing these distributions was then applied to three months of data to determine if overutilization could be predicted using the model. RESULTS: The mean difference between the actual schedule duration and the average duration was 0.19 hr (11.64 min). The difference with the second tertile cut-off point was 0.59 hr (35.40 min). Schedules that overran were correctly predicted by the average duration in 86.49% of the cases (with 12 false predictions), and they were correctly predicted by the second tertile cut-off point in 94.59% of the cases (with 26 false predictions). CONCLUSIONS: These results suggest that the sum of the average duration of surgeries and turnover times is indeed a good estimator of the duration of the series of surgical cases. Neither the estimated averages nor the second tertile cut-off points were useful to predict overrun when used alone. The use of the estimated average duration of the schedule, validated by use of the second tertile cut-off point, could reduce overtime when allocating surgeries in a single cardiac OR. PMID- 20725817 TI - Comparison of femoral morphology and bone mineral density between femoral neck fractures and trochanteric fractures. AB - BACKGROUND: Many studies that analyzed bone mineral density (BMD) and skeletal factors of hip fractures were based on uncalibrated radiographs or dual-energy xray absorptiometry (DXA). QUESTIONS/PURPOSES: Spatial accuracy in measuring BMD and morphologic features of the femur with DXA is limited. This study investigated differences in BMD and morphologic features of the femur between two types of hip fractures using quantitative computed tomography (QCT). PATIENTS AND METHODS: Forty patients with hip fractures with normal contralateral hips were selected for this study between 2003 and 2007 (trochanteric fracture, n=18; femoral neck fracture, n=22). Each patient underwent QCT of the bilateral femora using a calibration phantom. Using images of the intact contralateral femur, BMD measurements were made at the point of minimum femoral-neck cross-sectional area, middle of the intertrochanteric region, and center of the femoral head. QCT images also were used to measure morphologic features of the hip, including hip axis length, femoral neck axis length, neck-shaft angle, neck width, head offset, anteversion of the femoral neck, and cortical index at the femoral isthmus. RESULTS: No significant differences were found in trabecular BMD between groups in those three regions. Patients with trochanteric fractures showed a smaller neck shaft angle and smaller cortical index at the femoral canal isthmus compared with patients with femoral neck fractures. CONCLUSIONS: We conclude that severe osteoporosis with thinner cortical bone of the femoral diaphysis is seen more often in patients with trochanteric fracture than in patients with femoral neck fracture. LEVELS OF EVIDENCE: Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20725819 TI - Case files of the Harvard Medical Toxicology Fellowship at Children's Hospital Boston: an insulin overdose. PMID- 20725820 TI - [Conservative functional treatment of Achilles tendon ruptures]. AB - The conservative functional treatment of Achilles tendon ruptures has developed further over the last 20 years and is basically possible for 60-80% of patients. The treatment leads to success if the indications obtained by dynamic sonography are correctly interpreted (adaptation of the tendon ends up to 20 degrees plantar flexion), if the patient presents sufficient compliance and the physiotherapy is increasingly intensified depending on tendon healing. Modern ortheses allow an increased equinus position and therefore improved protection of the healing tendon. If these factors are present a relatively low re-rupture rate of only 7% can be achieved. The decisive advantage of conservative functional therapy is the avoidance of specific operative risks, such as infection and injury to the sural nerve. After removal of the orthesis the tendon should continue to be modeled using shoe insoles and raised heels. PMID- 20725821 TI - [Conservative treatment of Achilles tendinopathy]. AB - Hind foot tendinopathies mainly involve the Achilles tendon. Color and Power Doppler ultrasound visualizes pathological neovessels in painful tendons, which are associated with pain mediating nerve fibres. These neovessels are characterized by an increased capillary blood flow at the point of pain. Painful eccentric training can significantly reduce pain and improve function in Achilles tendinopathy (evidence level Ib). Shock wave therapy in combination with eccentric training is superior to eccentric training alone (evidence level Ib). Long-term results suggest a collagen induction and reduced pain following topical application of glyceryl trinitrate (NO) (evidence level Ib). Color and Power Doppler-guided sclerosing therapy using polidocanol reduces pain, improves function and may lead to tendon remodeling (evidence level Ib). Pain-restricted sport up to a visual analogue scale (VAS) score 5/10 during therapy is recommended (evidence level Ib). Cryotherapy sessions of 3-times 10 min of reduce pain and capillary blood flow (evidence level Ib). The role of proprioceptive training in tendinopathy has to be determined in future trials (evidence level II). Anecdotical treatment of hindfoot tendinopathies has been replaced by evidence-based recommendations. PMID- 20725822 TI - Think locally: evaluation of the microcirculation in sepsis. PMID- 20725823 TI - Both passive leg raising and intravascular volume expansion improve sublingual microcirculatory perfusion in severe sepsis and septic shock patients. AB - PURPOSE: To assess sublingual microcirculatory changes following passive leg raising (PLR) and volume expansion (VE) in septic patients. METHODS: This prospective study was conducted in two university hospital intensive care units and included 25 mechanically ventilated patients with severe sepsis or septic shock who were eligible for VE in the first 24 h of their admission. Pulse pressure variation (DeltaPP), cardiac output (CO) and sublingual microcirculation indices were assessed at five consecutive steps: (1) semi-recumbent position (Baseline 1), (2) during PLR manoeuvre (PLR), (3) after returning to semi recumbent position (Baseline 2), (4) at the time when VE induced the same degree of preload responsiveness as PLR (VE(?PP = PLR)) and (5) at the end of VE (VE(END)). At each step, five sublingual microcirculation sequences were acquired using sidestream darkfield imaging to assess functional capillary density (FCD), microcirculatory flow index (MFI), proportion of perfused vessels (PPV) and flow heterogeneity index (FHI). RESULTS: The PLR, VE(?PP = PLR) and VE(END) induced a significant increase in CO and a significant decrease in DeltaPP compared to Baseline 1 and Baseline 2 values. Both PLR and VE induced significant increases in FCD, MFI and PPV and a significant decrease in FHI compared to Baseline 1 and Baseline 2 values. CONCLUSIONS: In preload responsive severe septic patients examined within the first 24 h of their admission, both PLR and VE improved sublingual microcirculatory perfusion. At the level of volume infusion used in this study, these changes in sublingual microcirculation were not explained by changes in rheologic factors or changes in arterial pressure. PMID- 20725824 TI - Osteogenic potential of biosilica on human osteoblast-like (SaOS-2) cells. AB - Biosilica is a natural polymer, synthesized by the poriferan enzyme silicatein from monomeric silicate substrates. Biosilica stimulates mineralizing activity and gene expression of SaOS-2 cells. To study its effect on the formation of hydroxyapatite (HA), SaOS-2 cells were grown on different silicatein/biosilica modified substrates (bone slices, Ca-P-coated coverslips, glass coverslips). Growth on these substrates induced the formation of HA nodules, organized in longitudinal arrays or spherical spots. Nodules of sizes above 1 MUm were composed of irregularly arranged HA prism-like nanorods, formed by aggregates of three to eight SaOS-2 cells. Moreover, growth on silicatein/biosilica-modified substrates elicited increased [(3)H]dT incorporation into DNA, indicative of enhanced cell proliferation. Consequently, an in vitro-based bioassay was established to determine the ratio between [(3)H]dT incorporation and HA formation. This ratio was significantly higher for cells that grew on silicatein/biosilica-modified substrates than for cells on Ca-P-coated coverslips or plain glass slips. Hence, we propose that this ratio of in vitro-determined parameters reflects the osteogenic effect of different substrates on bone-forming cells. Finally, qRT-PCR analyses demonstrated that growth of SaOS-2 cells on a silicatein/biosilica matrix upregulated BMP2 (bone morphogenetic protein 2, inducer of bone formation) expression. In contrast, TRAP (tartrate-resistant acid phosphatase, modulator of bone resorption) expression remained unaffected. We conclude that biosilica shows pronounced osteogenicity in vitro, qualifying this material for studies of bone replacement also in vivo. PMID- 20725825 TI - Inhibition of osteoclastogenesis by mechanically loaded osteocytes: involvement of MEPE. AB - In regions of high bone loading, the mechanoresponsive osteocytes inhibit osteoclastic bone resorption by producing signaling molecules. One possible candidate is matrix extracellular phosphoglycoprotein (MEPE) because acidic serine- and aspartate-rich MEPE-associated motif peptides upregulate osteoprotegerin (OPG) gene expression, a negative regulator of osteoclastogenesis. These peptides are cleaved from MEPE when relatively more MEPE than PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome) is present. We investigated whether mechanical loading of osteocytes affects osteocyte-stimulated osteoclastogenesis by involvement of MEPE. MLO-Y4 osteocytes were mechanically loaded by 1-h pulsating fluid flow (PFF; 0.7 +/- 0.3 Pa, 5 Hz) or kept under static control conditions. Recombinant MEPE (0.05, 0.5, or 5 MUg/ml) was added to some static cultures. Mouse bone marrow cells were seeded on top of the osteocytes to determine osteoclastogenesis. Gene expression of MEPE, PHEX, receptor activator of nuclear factor kappa-B ligand (RANKL), and OPG by osteocytes was determined after PFF. Osteocytes supported osteoclast formation under static control conditions. Both PFF and recombinant MEPE inhibited osteocyte-stimulated osteoclastogenesis. PFF upregulated MEPE gene expression by 2.5-fold, but not PHEX expression. PFF decreased the RANKL/OPG ratio at 1-h PFF treatment. Our data suggest that mechanical loading induces changes in gene expression by osteocytes, which likely contributes to the inhibition of osteoclastogenesis after mechanical loading of bone. Because mechanical loading upregulated gene expression of MEPE but not PHEX, possibly resulting in the upregulation of OPG gene expression, we speculate that MEPE is a soluble factor involved in the inhibition of osteoclastogenesis by osteocytes. PMID- 20725826 TI - Site specificity of bone architecture between the distal radius and distal tibia in children and adolescents: An HR-pQCT study. AB - High-resolution quantitative computerized tomography permits evaluation of site specific differences in bone architecture. The purpose of this study was to compare bone architecture between distal radius and distal tibia. We present bone architecture at the distal radius and distal tibia in 151 male and 172 female participants, as follows: total bone area (mm(2)), total bone density (mg HA/cm(3)), trabecular bone density (mg HA/cm(3)), cortical bone density (mg HA/cm(3)), cortical thickness (MUm), trabecular number (1/mm), trabecular thickness (MUm), and trabecular separation (MUm). We evaluated differences in and correlations between bone variables (absolute values) across sites. We calculated individual z scores and used regression to assess discordance between sites. In pubertal and postpubertal male and female participants, absolute values of total bone area, cortical bone density, cortical thickness, and trabecular thickness were significantly lower at the radius compared with the tibia (P < 0.01). Absolute values for trabecular bone density were significantly lower at the radius compared with the tibia in postpubertal male and female participants (P < 0.01). Absolute values for trabecular separation was significantly lower at the radius compared with the tibia in pubertal female participants (P < 0.01). Bone architecture was moderately to highly correlated between sites (r = 0.34-0.85). There was discordance between z scores at the radius and tibia within male participants (pubertal R (2) between 36 and 64%; postpubertal R (2) between 22 and 77%) and female participants (pubertal R (2) between 10 and 44%; postpubertal R (2) between 25 and 62%). In conclusion, it is vital to evaluate bone architecture at the specific skeletal site of interest. PMID- 20725828 TI - Fetal MR diagnosis of vein of Galen aneurysmal malformation. PMID- 20725827 TI - Osteoporosis therapies: evidence from health-care databases and observational population studies. AB - Osteoporosis is a well-recognized disease with severe consequences if left untreated. Randomized controlled trials are the most rigorous method for determining the efficacy and safety of therapies. Nevertheless, randomized controlled trials underrepresent the real-world patient population and are costly in both time and money. Modern technology has enabled researchers to use information gathered from large health-care or medical-claims databases to assess the practical utilization of available therapies in appropriate patients. Observational database studies lack randomization but, if carefully designed and successfully completed, can provide valuable information that complements results obtained from randomized controlled trials and extends our knowledge to real world clinical patients. Randomized controlled trials comparing fracture outcomes among osteoporosis therapies are difficult to perform. In this regard, large observational database studies could be useful in identifying clinically important differences among therapeutic options. Database studies can also provide important information with regard to osteoporosis prevalence, health economics, and compliance and persistence with treatment. This article describes the strengths and limitations of both randomized controlled trials and observational database studies, discusses considerations for observational study design, and reviews a wealth of information generated by database studies in the field of osteoporosis. PMID- 20725829 TI - Syringosubarachnoid shunt for syringomyelia associated with Chiari I malformation. PMID- 20725832 TI - Tumor expression of B7-H4 predicts poor survival of patients suffering from gastric cancer. AB - To establish the prognostic value of B7-H4 expression by tumor cells in gastric cancer patients, we evaluated the association of B7-H4 expression with clinicopathologic factors and overall survival of gastric cancer patients. A retrospective cohort study including 156 gastric cancer patients was performed in the present report. Immunohistochemical assay was used to evaluate the expression of B7-H4 in the surgical specimens of gastric cancer tissues. Multi-univariate COX model was then used to evaluate the association of B7-H4 expression with the patients' survival and clinicopathological parameters. B7-H4 expression in the gastric cancer cells was observed in about 44.9% gastric cancer specimens. Univariate analysis demonstrated that there was no correlation between B7-H4 expression and sex, age, histological type, pathological grade or tumor size. In contrast, B7-H4 expression correlated positively with cancer invasiveness and lymph node metastasis. In addition, the median overall survival time of patients with lower B7-H4 expression was 13 months longer than that of patients with higher expression (chi(2) = 12.38, P < 0.0001), and the median disease-free survival time of patients with lower B7-H4 expression was significantly longer than that of patients with higher expression (33 vs. 16 months, chi(2) = 14.977, P < 0.0001). After adjustment for other confounding factors, the COX model analysis indicated that the death risk was significantly higher in patients with higher B7-H4 expression than those with lower expression (RR = 1.85, 95% CI = 1.15-2.96). The present study demonstrated that higher B7-H4 expression in cancer cells was associated with poor prognosis of gastric cancer patients. This is consistent with the idea that B7-H4 promotes cancer progression, likely via inhibition of anti-tumor immune responses. PMID- 20725831 TI - Imaging findings in craniofacial childhood rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the commonest paediatric soft-tissue sarcoma constituting 3-5% of all malignancies in childhood. RMS has a predilection for the head and neck area and tumours in this location account for 40% of all childhood RMS cases. In this review we address the clinical and imaging presentations of craniofacial RMS, discuss the most appropriate imaging techniques, present characteristic imaging features and offer an overview of differential diagnostic considerations. Post-treatment changes will be briefly addressed. PMID- 20725833 TI - Structural and functional profile of the carbohydrate esterase gene complement in Phytophthora infestans. AB - The plant cell cuticle is the first obstacle for penetration of the host by plant pathogens. To breach this barrier, most pathogenic fungi employ a complex assortment of cell wall-degrading enzymes including carbohydrate esterases, glycoside hydrolases, and polysaccharide lyases. We characterized the full complement of carbohydrate esterase-coding genes in three Phytophthora species and analyzed the expression of cutinase in vitro and in planta; we also determined the cutinase allele distribution in multiple isolates of P. infestans. Our investigations revealed that there are 49, 21, and 37 esterase homologs in the P. infestans, P. ramorum, and P. sojae genomes, respectively, with a considerable number predicted to be extracellular. Four cutinase gene copies were found in both the P. infestans and P. ramorum genomes, while 16 copies were found in P. sojae. Transcriptional analyses of cutinase in P. infestans revealed that its expression level during infection is significantly upregulated at all time points compared to that of the same gene in mycelium grown in vitro. Expression achieves maximum values at 15 hpi, declining at subsequent time points. These results may suggest, therefore, that cutinase most likely plays a role in P. infestans pathogenicity. PMID- 20725834 TI - Diffusion tensor imaging and fibre tracking in cervical spondylotic myelopathy. AB - OBJECTIVES: To (1) obtain microstructural parameters (Fractional Anisotropy: FA, Mean Diffusivity: MD) of the cervical spinal cord in patients suffering from cervical spondylotic myelopathy (CSM) using tractography, (2) to compare DTI parameters with the clinical assessment of these patients (3) and with information issued from conventional sequences. METHODS: DTI was performed on 20 symptomatic patients with cervical spondylotic myelopathy, matched with 15 volunteers. FA and MD were calculated from tractography images at the C2-C3 level and compressed level in patients and at the C2-C3 and C4-C7 in controls. Patients were clinically evaluated using a self-administered questionnaire. RESULTS: The FA values of patients were significantly lower at the compressed level than the FA of volunteers at the C4-C7 level. A significant positive correlation between FA at the compressed level and clinical assessment was demonstrated. Increased signal intensity on T2-weighted images did not correlate either with FA or MD values, or with any of the clinical scores. CONCLUSION: FA values were significantly correlated with some of the patients' clinical scores. High signal intensity of the spinal cord on T2 was not correlated either with the DTI parameters or with the clinical assessment, suggesting that FA is more sensitive than T2 imaging. PMID- 20725835 TI - Intracranial cerebrospinal fluid spaces imaging using a pulse-triggered three dimensional turbo spin echo MR sequence with variable flip-angle distribution. AB - OBJECTIVE: To assess the three-dimensional turbo spin echo with variable flip angle distribution magnetic resonance sequence (SPACE: Sampling Perfection with Application optimised Contrast using different flip-angle Evolution) for the imaging of intracranial cerebrospinal fluid (CSF) spaces. METHODS: We prospectively investigated 18 healthy volunteers and 25 patients, 20 with communicating hydrocephalus (CH), five with non-communicating hydrocephalus (NCH), using the SPACE sequence at 1.5T. Volume rendering views of both intracranial and ventricular CSF were obtained for all patients and volunteers. The subarachnoid CSF distribution was qualitatively evaluated on volume rendering views using a four-point scale. The CSF volumes within total, ventricular and subarachnoid spaces were calculated as well as the ratio between ventricular and subarachnoid CSF volumes. RESULTS: Three different patterns of subarachnoid CSF distribution were observed. In healthy volunteers we found narrowed CSF spaces within the occipital aera. A diffuse narrowing of the subarachnoid CSF spaces was observed in patients with NCH whereas patients with CH exhibited narrowed CSF spaces within the high midline convexity. The ratios between ventricular and subarachnoid CSF volumes were significantly different among the volunteers, patients with CH and patients with NCH. CONCLUSION: The assessment of CSF spaces volume and distribution may help to characterise hydrocephalus. PMID- 20725836 TI - A systematic review and meta-analysis of Hirschsprung's disease presenting after childhood. AB - BACKGROUND: Hirschsprung's disease (HD) is characterised by an absence of ganglion cells in the distal bowel, beginning at the internal sphincter and extending proximally to varying distances. It is usually diagnosed in the newborn period, with usual presentation of delayed passage of meconium and abdominal distension, with or without bilious vomiting. HD in adults is rare and is thus often undiagnosed or misdiagnosed. The purpose of this meta-analysis was to review the presentation, treatment and clinical outcome of HD presenting after childhood. METHODS: A systematic review and meta-analysis of all cases of HD presenting after childhood in the English literature was performed from 1950 to 2009. Detailed information regarding demographics, clinical presentation and methods of diagnosis, surgical procedure, complications and the outcome at time of follow up was recorded. RESULTS: There were 490 cases of HD presenting after childhood in the English literature, 341 (69.5%) males, 129 (26.4%) females and 20 (4.1%) cases where gender was not specified. As much as 390 (79.6%) were confined to the rectum, 60 (12.3%) had recto-sigmoid disease, 4 (0.8%) had disease extending to the descending colon and there were 2 (0.4%) cases that extended to the transverse colon and 2 (0.4%) cases of total colonic disease. The extent of disease was not specified in the remaining 32 (6.5%) cases. A total of 49 (10%) patients had the Swenson procedure, 231 (47.2%) patients had the Duhamel procedure, 40 (8.2%) patients had the Soave procedure, 45 (9.2%) patients had a myectomy only, 3 (0.6%) patients had a myectomy combined with colectomy, 14 (2.9%) patients had a myectomy combined with anterior resection. As much as 26 (5.3%) patients had a lower anterior resection (LAR), 28 (5.7%) patients had LAR combined with colectomy, 10 (2%) patients had a colectomy, 1 (0.2%) patient had an anopexy and 4 (0.9%) patients had a colostomy only. A total of 13 (2.7%) patients refused surgery and managed with conservative treatment, and in 25 (5.1%) patients, the specific procedure was not identified. There were 2 (0.4%) deaths reported; 1 patient died prior to surgery due to colonic perforation and sepsis and the 2nd patient died post-operatively due to appendix stump dehiscence, peritonitis and sepsis. The time of follow up ranged from 1 to 25 years and all, but 6 (1.3%) had a very good clinical outcome. CONCLUSIONS: Hirschsprung's disease should be considered in patients who have had chronic constipation since birth. This review suggests that the vast majority of patients in whom HD is diagnosed after childhood have normal bowel function after pull through surgery. PMID- 20725837 TI - Prenatal diagnosis of cloacal malformations. AB - INTRODUCTION: Prenatal diagnosis of anorectal malformations currently occurs in 0 15.9% of screened cases. In cloacas, these numbers are unknown. We speculate that some images from prenatal ultrasound studies may suggest the diagnosis of cloaca, but are not recognized because of a lack of suspicion for this diagnosis. METHODS: A retrospective review of the medical records of 489 patients born with cloaca was performed; 95 of them had prenatal ultrasound reports that represent the material analyzed for this study. A literature review was performed, finding 31 publications, with 68 cloaca patients detected by prenatal images. The abnormal findings of our patients were compared with those described in the literature to determine the most common abnormal prenatal images found in patients with cloaca. RESULTS: The 95 ultrasound reports found in our patients described 270 abnormalities, the most frequent were: abdominal/pelvic cystic/mass (39), hydronephrosis (36), oligohydramnios (23), distended bowel/bowel obstruction (19), ascites (15), 2 vessel cord (14), dilated bladder (14), dilated ureter (14), polyhydramnios (10), echogenic bowel (8), multicystic kidney (8), "ambiguous genitalia" (7), hydrops fetalis (7), hydrocolpos (4), absent kidney (3), abnormal spine (3), and anorectal atresia (3). In spite of these findings, the radiologists who interpreted the studies only suspected a cloaca in 6 cases (6%). The literature review showed 212 abnormalities in 68 demonstrated cloaca patients. The most frequent were: abdominal/pelvic cystic/mass (46), hydronephrosis (44), ascites (21), oligohydramnios (20), distended bowel (11), multicystic dysplastic kidney (7), ambiguous genitalia (6), non-visualization of the bladder (6), two-vessel cord (5), dilated bladder (5), intraabdominal calcification (4), polyhydramnios (4), enterolithiasis (4), hydrometrocolpos (3), and dilated ureter (3). CONCLUSION: We conclude that it is possible to suspect the diagnosis of cloaca, prenatally, more frequently than what currently occurs, looking at the same images but with an increased index of suspicion for cystic abdominal masses and a combination of gastrointestinal and urological abnormalities. PMID- 20725838 TI - Radionuclide transfer to reptiles. AB - Reptiles are an important, and often protected, component of many ecosystems but have rarely been fully considered within ecological risk assessments (ERA) due to a paucity of data on contaminant uptake and effects. This paper presents a meta analysis of literature-derived environmental media (soil and water) to whole-body concentration ratios (CRs) for predicting the transfer of 35 elements (Am, As, B, Ba, Ca, Cd, Ce, Cm, Co, Cr, Cs, Cu, Fe, Hg, K, La, Mg, Mn, Mo, Na, Ni, Pb, Po, Pu, Ra, Rb, Sb, Se, Sr, Th, U, V, Y, Zn, Zr) to reptiles in freshwater ecosystems and 15 elements (Am, C, Cs, Cu, K, Mn, Ni, Pb, Po, Pu, Sr, Tc, Th, U, Zn) to reptiles in terrestrial ecosystems. These reptile CRs are compared with CRs for other vertebrate groups. Tissue distribution data are also presented along with data on the fractional mass of bone, kidney, liver and muscle in reptiles. Although the data were originally collected for use in radiation dose assessments, many of the CR data presented in this paper will also be useful for chemical ERA and for the assessments of dietary transfer in humans for whom reptiles constitute an important component of the diet, such as in Australian aboriginal communities. PMID- 20725839 TI - Using electron beam radiation to simulate the dose distribution for whole body solar particle event proton exposure. AB - As a part of the near solar system exploration program, astronauts may receive significant total body proton radiation exposures during a solar particle event (SPE). In the Center for Acute Radiation Research (CARR), symptoms of the acute radiation sickness syndrome induced by conventional radiation are being compared to those induced by SPE-like proton radiation, to determine the relative biological effectiveness (RBE) of SPE protons. In an SPE, the astronaut's whole body will be exposed to radiation consisting mainly of protons with energies below 50 MeV. In addition to providing for a potentially higher RBE than conventional radiation, the energy distribution for an SPE will produce a relatively inhomogeneous total body dose distribution, with a significantly higher dose delivered to the skin and subcutaneous tissues than to the internal organs. These factors make it difficult to use a (60)Co standard for RBE comparisons in our experiments. Here, the novel concept of using megavoltage electron beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation is described. In these studies, Monte Carlo simulation was used to determine the dose distribution of electron beam radiation in small mammals such as mice and ferrets as well as large mammals such as pigs. These studies will help to better define the topography of the time-dose fractionation versus biological response landscape for astronaut exposure to an SPE. PMID- 20725840 TI - A novel mutation (Cys83Tyr) in the second zinc finger of NR2E3 in enhanced S-cone syndrome. AB - BACKGROUND: Enhanced S-cone syndrome (ESCS) is an autosomal recessive retinal disorder characterized by an increased number of S-cones over L/M cones and rods. Mutations in the NR2E3 gene, encoding a photoreceptor-specific nuclear receptor, are identified in patients with ESCS. The purpose of this study is to report the ophthalmic features of a 25-year-old Portuguese male with a typical ESCS phenotype and a novel homozygous NR2E3 mutation. METHODS: The patient underwent a detailed ophthalmic examination including fundus photography, fluorescein angiography (FAF), fundus autofluorescence imaging (FAI), and spectral domain optical coherence tomography (SD-OCT). Full-field electroretinography (ERG), S cone ERG, and multifocal ERG were performed. Mutation screening of the NR2E3 gene was performed with polymerase chain reaction amplification and direct sequencing. RESULTS: The patient had poor visual acuity but good color vision. Funduscopy showed degenerative changes from the vascular arcades to the midperipheral retina. The SD-OCT revealed macular schisis and cystoid changes that had no fluorescein leakage. The posterior pole showed diffusely increased autofluorescence compared with eccentric areas in both eyes. International standard full-field ERG showed the typical pathognomonic changes associated with ESCS and the short-wavelength flash ERG was simplified, delayed, and similar to the standard photopic flash ERG. Multifocal ERG showed widespread delay and reduction. Genetic analysis revealed a novel homozygous mutation (p.C83Y), which resides in the second zinc finger of the DNA-binding domain. CONCLUSIONS: This homozygous mutation is likely to affect binding to target DNA sites, resulting in a non-functional behavior of NR2E3 protein. It is associated with a typical form of ESCS with a nondetectable rod response and reduced/delayed mfERG responses at all eccentricities. PMID- 20725841 TI - The proliferation and migration of immature germ cells in the mussel, Mytilus galloprovincialis: observation of the expression pattern in the M. galloprovincialis vasa-like gene (Myvlg) by in situ hybridization. AB - In bivalve, the distribution of primordial germ cells can be traced from early embryogenesis to the veliger larva by the expression of the vasa ortholog. However, the distribution of germ cells from metamorphosis to maturation in bivalves has not been examined extensively. In this study, we used in situ hybridization to observe expression of the Mytilus galloprovincialis vasa-like gene (Myvlg). The distribution of germ cells was clarified in immature mussels. We observed germ cells in adult mussels during the non-reproductive and reproductive seasons. Myvlg was specifically expressed in germ cells. Gametogenesis occurs in acini surrounded by connective tissue. Myvlg expression was detected in spermatogonia, spermatocytes, oogonia, and oocytes. In the non reproductive season, gametes were not observed in the acini, but Myvlg was expressed in germinal stem cells along the acini. The expression intensity in the non-reproductive season, however, was much weaker than that in the reproductive season. Myvlg-positive cells proliferated during the non-reproductive season. In immature mussels, a pair of germ cell clumps was distributed laterally in the connective tissue between the nephric tubules and posterior byssal retractor muscle. Germ cells were also observed along pericardium. When immature mussels grew, a pair of germ cell clumps migrated anteriorly in the connective tissue along the outer epithelium at the dorsal region of the mantle base between the mantle and gill. The number of germ cells increased significantly as the mussels grew. This is the first report to observe the proliferation and migration of germ cells in immature mussels. PMID- 20725842 TI - Evidence for and against urinary prophylaxis in vesicoureteral reflux. AB - The role of antimicrobial prophylaxis in vesicoureteral reflux (VUR) has come under increasing scrutiny because of better analytical methods in the published literature, knowledge gained from VUR and renal scars diagnosed without preceding urinary tract infection (UTI), and better renal imaging modalities for diagnosing renal scars. A meta-analysis of the five recent randomized studies with a total of 809 patients with VUR diagnosed after UTI reveals a relative risk of UTI recurrence of 0.82 [95% confidence interval (CI) 0.62-1.08; p = 0.16) with prophylaxis. A meta-analysis of the four studies with a total of 662 patients with UTI with and without VUR evaluated for renal scarring reveals a relative risk of 1.04 (95% CI: 0.84-1.30; p = 0.69), with prophylaxis. However, these observations need to be interpreted with caution because of the limitations with these studies and their heterogeneity for meta-analysis, particularly for renal scarring. More research is needed to validate the role of prophylaxis in VUR diagnosed after UTI, and even more research is warranted to answer the questions regarding antimicrobial prophylaxis across the spectrum of VUR in different clinical settings. PMID- 20725843 TI - Partially thrombosed intracranial aneurysms: symptoms, evolution, and therapeutic management. AB - BACKGROUND: Partially thrombosed intracranial aneurysms (PTIAs) are different from saccular or nonthrombosed giant or large aneurysms, as they are characterized by multiple intramural thrombotic phenomena related to recurrent vessel wall dissections. METHODS: We retrospectively reviewed clinical and radiological files of 23 consecutive patients with PTIAs (mean age 49.3 years). Twenty-two lesions were studied by magnetic resonance imaging (MRI). Patients were managed by endovascular treatments, medically with steroids, or conservatively. RESULTS: Thirteen patients presented with progressive neurological symptoms. Subarachnoid hemorrhage was suspected but not proven in three. At MRI, 90.9% of PTIAs caused mass effect; perilesional T2 hypersignal compatible with edema was evident in 13.6%. Aneurysmal wall enhancement was detectable in 63.2% of the PTIAs and considered a marker of inflammatory processes. Parent artery occlusion was performed in seven patients with clinical improvement in six. Selective coiling was proposed in three patients (one improved, one remained stable, and one experienced symptoms progression). Three patients were treated with steroids and improved. Ten patients were managed conservatively: eight because spontaneous thrombosis of the lesion had been diagnosed and two because of clinical and radiological stability. CONCLUSIONS: The natural history of PTIAs is different from other aneurysms. They most commonly present with progressive neurological symptoms due to mass effect. MRI properly diagnoses PTIAs and allows precise follow-up, more accurately than angiography because it detects prominent "abluminal" features indicating inflammation and neovascularization. Spontaneous thrombosis is part of the natural history of PTIAs and it should be taken in consideration when discussing the therapeutic management. PMID- 20725844 TI - Elevated sICAM-1 levels in patients with hemorrhagic fever with renal syndrome caused by Hantaan virus. AB - Increased vascular permeability and vascular leakage are characteristic pathological changes in hemorrhagic fever with renal syndrome (HFRS). Vascular endothelial cells are the main targets of Hantaan virus, the etiological agent of the severe form of HFRS. Hantaan virus can induce extensive damage of small blood vessels and capillaries. In vitro infection of human umbilical vein endothelial cells by Hantaan virus can induce the expression of intercellular adhesion molecule-1 (ICAM-1). The involvement of this molecule is implied in human HFRS. In the present study, serum-soluble ICAM-1 (sICAM-1) levels were determined and their relationships with the clinical course and disease severity were investigated in 112 HFRS patients and 30 healthy controls. The results showed that the serum levels of sICAM-1 in HFRS patients at fever, hypotensive, oliguric, and polyuric phases were significantly higher than those in controls (p < 0.001). However, no significant differences between the serum concentrations of sICAM-1 in the milder and more severe groups of patients were observed (p > 0.05). It is suggested that sICAM-1 was involved in the progression of HFRS. Time dependent determinations of sICAM-1 levels may be indicators for the progression of disease, and elevated levels of sICAM-1 were not suggested to be correlated to disease severity. PMID- 20725846 TI - A novel two-layer, coupled finite element approach for modeling the nonlinear elastic and viscoelastic behavior of human erythrocytes. AB - A novel finite element approach is presented to simulate the mechanical behavior of human red blood cells (RBC, erythrocytes). As the RBC membrane comprises a phospholipid bilayer with an intervening protein network, we propose to model the membrane with two distinct layers. The fairly complex characteristics of the very thin lipid bilayer are represented by special incompressible solid shell elements and an anisotropic viscoelastic constitutive model. Properties of the protein network are modeled with an isotropic hyperelastic third-order material. The elastic behavior of the model is validated with existing optical tweezers studies with quasi-static deformations. Employing material parameters consistent with literature, simulation results are in excellent agreement with experimental data. Available models in literature neglect either the surface area conservation of the RBC membrane or realistic loading conditions of the optical tweezers experiments. The importance of these modeling assumptions, that are both included in this study, are discussed and their influence quantified. For the simulation of the dynamic motion of RBC, the model is extended to incorporate the cytoplasm. This is realized with a monolithic fully coupled fluid-structure interaction simulation, where the fluid is described by the incompressible Navier-Stokes equations in an arbitrary Lagrangian Eulerian framework. It is shown that both membrane viscosity and cytoplasm viscosity have significant influence on simulation results. Characteristic recovery times and energy dissipation for varying strain rates in dynamic laser trap experiments are calculated for the first time and are found to be comparable with experimental data. PMID- 20725845 TI - Relevance of lower airway bacterial colonization, airway inflammation, and pulmonary function in the stable stage of chronic obstructive pulmonary disease. AB - The objective of this investigation was to verify the hypothesis that the presence of lower airway bacterial colonization (LABC) can be a stimulating factor of airway inflammation, more frequent exacerbation, and impact on pulmonary function, independent of current tobacco smoking in the stable phase of chronic obstructive pulmonary disease (COPD). A total of 46 ex-smokers with moderate to severe COPD, 19 healthy non-smokers, and 17 ex-smokers without COPD were included in this study. Their sputum specimens were collected at the first baseline visit and at the second visit after a follow-up of one year. The samples were analyzed for bacterial growth by culture, and the levels of interleukin (IL) 6, IL-8, and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme linked immunosorbent assay (ELISA). The frequencies of exacerbations and pulmonary function were compared at visit 2. At visit 1, 37.0% (17/46) were found to have LABC with bacterial loads >=106 CFU/ml in their sputum specimens. Haemophilus influenzae was the predominant pathogenic organism isolated. IL-8, IL 6, and TNF-alpha in these patients' sputum were significantly higher than those without LABC (p < 0.05). It was the presence of LABC that contributed to the significantly elevated IL-8 and IL-6 at the 1-year period (p < 0.05). LABC was also associated with significantly increased frequencies of exacerbations and declined forced expiratory volume in 1 s (FEV1) (p < 0.05). LABC was documented in a subpopulation of stable COPD patients; it may be responsible for the deterioration of pulmonary function of COPD patients by promoting airway inflammation and/or increased frequency of exacerbations independently of tobacco smoking. PMID- 20725847 TI - Factors impacting volumetric white matter changes following whole brain radiation therapy. AB - Whole brain radiation therapy (WBRT) is one of the most effective modalities for treatment of brain metastases. With increasing cancer control there is growing concern regarding the long-term effects of treatment. These effects are seen as white matter change (WMC) on brain MRI. Severity of WMC is implicated in cognitive and functional decline in many patient groups. Our objective was to identify clinical factors associated with greater accumulation of WMC following WBRT. Through retrospective review of serial MRIs obtained from 30 patients surviving greater than 1 year after WBRT, treated at a single institution between 2002 and 2007, we calculated volumetric WMC over time using segmentation software. Changes related to tumor, secondary effects, surgery or radiosurgery were excluded. Factors that influenced the rate of WMC accumulation were identified through multivariate analysis. Following WBRT, patients accumulated WMC at an average rate of 0.07% of total brain volume per month. In multivariate analyses, greater rates of accumulation were independently associated with older age (beta = 0.004, p < .0001), poor levels of glycemic control (beta = 0.048, p < .0001) and hypertension diagnosis (beta = 0.084, p < .0001). Long-term survivors of cancer allow assessment of late effects of treatment modalities. Radiation injury appears to be related to a steady rate of white matter damage over time, as indicated by progressive accumulation of WMC. Our results suggest that rate of WMC accumulation is enhanced by parameters such as hyperglycemia and hypertension. This has significant clinical impact by clearly identifying hyperglycemia, steroid-induced hyperglycemia, and other vascular risk factors as targets for intervention to decrease WMC in patients receiving WBRT. PMID- 20725848 TI - Optic pathway ganglioglioma with intraventricular cyst. AB - Gangliogliomas originating in the optic pathway are rare, with less than 20 cases reported in the literature. Diffuse, bilateral involvement of the entire optico chiasmatic pathway is exceptional. We report a case of suprasellar ganglioglioma that involved bilaterally the entire pregeniculate optic pathway. The patient presented with visual deficit, nystagmus, papilledema and acute biventricular hydrocephalus secondary to intraventricular cyst that required urgent surgery. Endoscopic fenestration of the tumoral cyst allowed control of hydrocephalus and decompression of the visual pathway. Through microsurgical procedure by pterional approach, partial removal of the tumor and histological diagnosis were accomplished 1 week later. The patient was managed with chemotherapy and radiation therapy. He presents stable residual disease at 4-year follow-up. Embryological origins, histological features, neuroradiological appearance, management and prognosis of optic pathway gangliogliomas are reviewed. PMID- 20725849 TI - Intensity modulated radiation therapy or stereotactic fractionated radiotherapy for infratentorial ependymoma in children: a multicentric study. AB - This study was to evaluate the treatment dosimetry, efficacy and toxicity of intensity modulated radiation therapy (IMRT) and fractionated stereotactic radiotherapy (FSRT) in the management of infratentorial ependymoma. Between 1999 and 2007, seven children (median age, 3.1 years) with infratentorial ependymoma were planned with either IMRT (3 patients) or SFRT (4 patients), the latter after conventional posterior fossa irradiation. Two children underwent gross total resection. Median prescribed dose was 59.4 Gy (range, 55.8-60). The median follow up for surviving patients was 4.8 years (range, 1.3-8). IMRT (median dose, 59.4 Gy) and FSRT (median dose, 55.8 Gy) achieved similar optimal target coverage. Percentages of maximum doses delivered to the cochleae (59.5 vs 85.0% Gy; P = 0.05) were significantly inferior with IMRT, when compared to FSRT planning. Percentages of maximum doses administered to the pituitary gland (38.2 vs 20.1%; P = 0.05) and optic chiasm (38.1 vs 14.1%; P = 0.001) were, however, significantly higher with IMRT, when compared to FSRT planning. No recurrences were observed at the last follow-up. The estimated 3-year progression-free survival and overall survival were 87.5 and 100%, respectively. No grade >1 acute toxicity was observed. Two patients presented late adverse events (grade 2 hypoacousia) during follow-up, without cognitive impairment. IMRT or FSRT for infratentorial ependymomas is effective and associated with a tolerable toxicity level. Both treatment techniques were able to capitalize their intrinsic conformal ability to deliver high-dose radiation. Larger series of patients treated with these two modalities will be necessary to more fully evaluate these delivery techniques. PMID- 20725850 TI - Effect of nitrogen source on methanol oxidation and genetic diversity of methylotrophic mixed cultures enriched from pulp and paper mill biofilms. AB - Methanol-oxidizing bacteria may play an important role in the development and use of biological treatment systems for the removal of methanol from industrial effluents. Optimization of methanol degradation potential in such systems is contingent on availability of nutrients, such as nitrogen, in the most favorable form and concentration. To that end, this study examined the variation in growth, methanol degradation, and bacterial diversity of two mixed methylotrophic cultures that were provided nitrogen either as ammonium or nitrate and in three different concentrations. Methanol-degrading cultures were enriched from biofilms sampled at a pulp and paper mill and grown in liquid batch culture with methanol as the only carbon source and either ammonium or nitrate as the only added nitrogen source. Results indicate that growth and methanol removal of the mixed cultures increase directly with increased nitrogen, added in either form. However, methanol removal and bacterial diversity, as observed by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) methods, were higher when using nitrate as the nitrogen source for enrichment and growth, rather than ammonium. Based on results described here, nitrate may potentially be a better nitrogen source when enriching or working with mixed methylotrophic cultures, and possibly more effective when used as a nutrient addition to biofilters. PMID- 20725853 TI - Proposed revisions to gender identity disorder diagnoses in the DSM-5. PMID- 20725851 TI - Cyanide inhibition and pyruvate-induced recovery of cytochrome c oxidase. AB - The mechanism of cyanide's inhibitory effect on the mitochondrial cytochrome c oxidase (COX) as well as the conditions for its recovery have not yet been fully explained. We investigated three parameters of COX function, namely electron transport (oxygen consumption), proton transport (mitochondrial membrane potential Deltapsi(m)) and the enzyme affinity to oxygen (p50 value) with regard to the inhibition by KCN and its reversal by pyruvate. 250 MUM KCN completely inhibited both the electron and proton transport function of COX. The inhibition was reversible as demonstrated by washing of mitochondria. The addition of 60 mM pyruvate induced the maximal recovery of both parameters to 60-80% of the original values. When using low KCN concentrations of up to 5 MUM, we observed a profound, 30-fold decrease of COX affinity for oxygen. Again, this decrease was completely reversed by washing mitochondria while pyruvate induced only a partial, yet significant recovery of oxygen affinity. Our results demonstrate that the inhibition of COX by cyanide is reversible and that the potential of pyruvate as a cyanide poisoning antidote is limited. Importantly, we also showed that the COX affinity for oxygen is the most sensitive indicator of cyanide toxic effects. PMID- 20725852 TI - Reduced capacity of Ca2+ retention in liver as compared to kidney mitochondria. ADP requirement. AB - Ca2+ loading in mitochondria promotes the opening of a non-selective transmembrane pathway. Permeability transition is also associated with the interaction of cyclophilin D at the internal surface of the non-specific transmembrane pore. This interaction is circumvented by cyclosporin A and ADP. Our results show that, in the absence of ADP, liver mitochondria were unable to retain Ca2+, they underwent a fast and large amplitude swelling, as well as a rapid collapse of the transmembrane potential. In contrast, in the absence of ADP, kidney mitochondria retained Ca2+, swelling did not occur, and the collapse of the membrane potential was delayed. Ca2+ efflux was reversed by the addition of ADP and cyclosporin A. Our findings indicate that the differences between liver and kidney mitochondria are due to the low association of cyclophilin D to the ADP/ATP carrier found in kidney mitochondria as compared to liver mitochondria. PMID- 20725854 TI - Effects of noise pollution over the blood serum immunoglobulins and auditory system on the VFM airport workers, Van, Turkey. AB - Noise pollution is a common health problem for developing countries. Especially highways and airports lead to noise pollution in different levels and in many frequencies. In this study, we focused on the effect of noise pollution in airports. This work aimed measurements of noise pollution levels in Van Ferit Melen (VFM) airport and effect of noise pollution over the immunoglobulin A, G, and M changes among VFM airport workers in Turkey. It was seen that apron and terminal workers were exposed to high noise (>80 dB(A)) without any protective precautions. Noise-induced temporary threshold shifts and noise-induced permanent threshold shifts were detected between the apron workers (p < 0.001) and terminal workers (p < 0.005). IgA values of apron terminal and control group workers were approximately the same in the morning and increased in a linear manner during the day. This increase was statistically significant (p < 0.001). IgG and IgM values of apron, terminal, and control group workers were approximately same in the morning. Apron and terminal workers IgG and IgM levels were increased until noon and then decreased until evening as compare to control group, but these changes were not statically significant (p > 0.05). These findings suggested that the noise pollution in the VFM airport could lead to hearing loss and changes in blood serum immunoglobulin levels of airport workers. Blood serum immunoglobulin changes might be due to vibrational effects of noise pollution. Airport workers should apply protective precautions against effect of noise pollution in the VFM airport. PMID- 20725855 TI - Prevalence of ovine and caprine oestrosis in Ambo, Ethiopia. AB - A study was carried out to estimate the prevalence, larval burden and risk factors of ovine and caprine oestrosis from December 2007 to May 2008 on 554 heads of randomly selected sheep and goat slaughtered at Ambo town, Western Shoa, Ethiopia. The results show an overall prevalence of 59.9% with infection rate of 69.8% and 47.3% in sheep and goats respectively. No statistically significant difference in the prevalence was noted with regard to the assumed risk factors like sex, nose color, face color, horned versus polled, origin, and months (p > 0.05). Sheep were nearly twice more likely to be infected as compared to goats (p = 0.0001, odds ratio (OR) = 1.975). Age of the animals was found to be protective (OR = 0.579; 95% confidence interval = 0.393, 0.853; p = 0.006). As compared to very fat animals, poor (p = 0.040, OR = 4.834), medium (p = 0.049, OR = 4.198), and fat (p = 0.022, OR = 5.795) body condition animals are more likely to be infected by Oestrus ovis larvae. Nasal and sinus cavity pathology is positively correlated with the total larval count (r = 0.56, p < 0.0001). Out of a total of 3,770 larvae collected, 57.5% were L1, 30.8% L2, and 11.7% L3 larvae. All the three larval instars were seen throughout the study months. It is concluded that oestrosis is a common problem in the study area and more prevalent in sheep than goats, in adult than young, and in animals with poor body condition. PMID- 20725856 TI - Accuracy of transrectal palpation for early pregnancy diagnosis in Egyptian buffaloes. AB - The present study was undertaken to evaluate the accuracy of transrectal palpation (TRP) for diagnosing early pregnancy in buffaloes and the false diagnoses of the TRP test by using the pregnancy-associated glycoprotein radioimmunoassay (PAG-RIA) test. Pregnancy was diagnosed in 168 buffalo-cows once by TRP and PAG-RIA test between days 31 and 55 after breeding. The sensitivity of TRP for detecting pregnant buffalo-cows was 37.5% at days 31-35, increased to 93.8% at days 46-50 and reached 100% at days 51-55 (P < 0.01). All cases of false negative diagnoses (n = 10) had PAG concentration higher than the threshold (>=1.8 ng/mL) for diagnosing pregnancy. The specificity of TRP for detecting non pregnant buffalo cows ranged between 90.9%, and 100% between days 31 and 55. All cases of false positive diagnoses (n = 5) made by TRP had PAG concentrations lower than the threshold for diagnosing pregnancy. It could be concluded that TRP is an accurate method for diagnosing pregnant and non-pregnant buffalo cows from day 46 after breeding. PMID- 20725857 TI - Ripening influences banana and plantain peels composition and energy content. AB - Musa sp. peels are widely used by smallholders as complementary feeds for cattle in the tropics. A study of the influence of the variety and the maturation stage of the fruit on fermentability and metabolisable energy (ME) content of the peels was performed using banana (Yangambi Km5) and plantain (Big Ebanga) peels at three stages of maturation in an in vitro model of the rumen. Peel samples were analysed for starch, free sugars and fibre composition. Samples were incubated in the presence of rumen fluid. Kinetics of gas production were modelled, ME content was calculated using prediction equation and short-chain fatty acids production and molar ratio were measured after 72 h of fermentation. Final gas production was higher in plantain (269-339 ml g(-1)) compared to banana (237-328 ml g(-1)) and plantain exhibited higher ME contents (8.9-9.7 MJ/kg of dry matter, DM) compared to banana (7.7-8.8 MJ/kg of DM). Butyrate molar ratio decreased with maturity of the peels. The main influence of the variety and the stage of maturation on all fermentation parameters as well as ME contents of the peels was correlated to changes in the carbohydrate fraction of the peels, including starch and fibre. PMID- 20725858 TI - First-time detection of mycobacterium species from goats in Ethiopia. AB - Tuberculosis (TB) is an important zoonosis affecting a wide range of hosts. An abattoir study was conducted on 1,536 randomly selected male goats slaughtered at Modjo Modern Export Abattoir to determine the prevalence of tuberculosis in slaughtered goats. Carcasses and organs of all the study animals were first examined by routine meat inspection followed by detailed meat inspection. Samples from tuberculous lesions were cultured for mycobacterial isolation and identification. Histopathology was done on 31 samples with tuberculous lesions. Detailed meat inspection detected 65 (4.2%; 95% confidence interval (CI) = 3.3 5.4%) tuberculous lesions. From these, 20 (30.8%) samples were confirmed mycobacterium positive on culture, out of which 18 were Mycobacterium bovis and two were Mycobacterium tuberculosis. Routine meat inspection failed to detect tuberculous lesions in 23% of carcasses with TB lesions detected by detailed examination. However, no statistically significant difference was observed between both methods in detecting tuberculous lesions (Kappa = 0.87). Origin and age of the goats did not statistically affect the disease prevalence (P > 0.05). Histopathologic lesions were observed in 21 samples (68%; 95% CI = 50.1-81.4%) out of the 31 carcasses with gross tuberculous lesions examined by histopathology. Eighteen (58%) tuberculous samples positive for histopathology were also culture positive. The sensitivity and specificity of histopathology were 90% (95% CI = 76.9-100%) and 72.7% (95% CI = 46.4-99%), respectively, using culture as a reference test. To the best of our knowledge, this is the first report of caprine tuberculosis from Ethiopia. Further studies are required at the farm level to determine the prevalence of tuberculosis in the general goat population. PMID- 20725859 TI - Homochiral selectivity in RNA synthesis: montmorillonite-catalyzed quaternary reactions of D, L-purine with D, L- pyrimidine nucleotides. AB - Selective adsorption of D, L-ImpA with D, L-ImpU on the platelets of montmorillonite demonstrates an important reaction pathway for the origin of homochirality in RNA synthesis. Our earlier studies have shown that the individual reactions of D, L-ImpA or D, L-ImpU on montmorillonite catalyst produced oligomers which were only partially inhibited by the incorporation of both D- and L-enantiomers. Homochirality in these reactions was largely due to the formation of cyclic dimers that cannot elongate. We investigated the quaternary reactions of D, L-ImpA with D, L-ImpU on montmorillonite. The chain length of these oligomers increased from 9-mer to 11-mer as observed by HPLC, with a concomitant increase in the yield of linear dimers and higher oligomers in the reactions involving D, L-ImpA with D, L-ImpU as compared to the similar reactions carried out with D-enantiomers only. The formation of cyclic dimers of U was completely inhibited in the quaternary reactions. The yield of cyclic dimers of A was reduced from 60% to 10% within the dimer fraction. 12 linear dimers and 3 cyclic dimers were isolated and characterized from the quaternary reaction. The homochirality and regioselectivity of dimers were 64.1% and 71.7%, respectively. Their sequence selectivity was shown by the formation of purine pyrimidine (54-59%) linkages, followed by purine-purine (29-32%) linkages and pyrimidine-pyrimidine (9-13%) linkages. Of the 16 trimers detected, 10 were homochiral with an overall homochirality of 73-76%. In view of the greater homochirality, sequence- and regio- selectivity, the quaternary reactions on montmorillonite demonstrate an unexpectedly favorable route for the prebiotic synthesis of homochiral RNA compared with the separate reactions of enantiomeric activated mononucleotides. PMID- 20725860 TI - Defining venous involvement in borderline resectable pancreatic cancer. AB - BACKGROUND: Pancreatic adenocarcinoma impinging the portal and/or superior mesenteric vein (PV-SMV) is classified as borderline resectable, and preoperative chemoradiation is recommended to increase the margin-negative resection rate. There is no consensus about what degree of venous impingement constitutes borderline resectability. METHODS: All patients undergoing potentially curative pancreatectomy for pancreatic adenocarcinoma were reviewed. Venous involvement was classified by preoperative computed tomography according to Ishikawa types: (I) normal, (II) smooth shift without narrowing, (III) unilateral narrowing, (IV) bilateral narrowing, (V) bilateral narrowing with collateral veins. RESULTS: From 1990-2009, 109 patients underwent resection of pancreatic adenocarcinoma involving the PV-SMV. Seventy-four patients received preoperative chemoradiation, whereas 35 did not. Patients who received preoperative therapy had a significantly longer median overall survival rate of 23 months compared with 15 months for patients without preoperative therapy (P = 0.001). Preoperative chemoradiation was associated with higher R0 resection rate and negative lymph nodes (both P < 0.0001) but did not affect the need for vein resection. When stratified by Ishikawa types, preoperative therapy was associated with improved overall survival among patients with types II and III but not types IV and V. Similarly, the correlation between preoperative therapy and R0 resection rate was observed only among patients with Ishikawa types II and III. CONCLUSIONS: Preoperative therapy for borderline resectable pancreatic adenocarcinoma is associated with higher margin-negative resection and survival rates in patients with Ishikawa type II and III tumors, defined as a smooth shift or unilateral narrowing of the PV-SMV. Patients with bilateral venous narrowing were less likely to benefit from preoperative treatment. PMID- 20725861 TI - Characterization of QT and RR interval series during acute myocardial ischemia by means of recurrence quantification analysis. AB - This study is aimed to investigate the nonlinear dynamic properties of the fluctuations in ventricular repolarization, heart rate and their correlation during acute myocardial ischemia. From 13 ECG records in long-term ST-T database, 170 ischemic episodes were selected with the duration of 34 s to 23 min 18 s, and two 5-min episodes immediately before and after each ischemic episode as non ischemic ones for comparison. QT interval (QTI) and RR interval (RRI) were extracted and the ectopic beats were removed. Recurrence quantification analysis (RQA) was performed on QTI and RRI series, respectively, and cross recurrence quantification analysis (CRQA) on paired normalized QTI and RRI series. Wilcoxon signed-rank test was used for statistical analysis. Results revealed that the RQA indexes for QTI and HRI series had the same changing trend during ischemia with more significantly changed indexes in QTI series. In the CRQA, indexes related to the vertical and horizontal structures in recurrence plot significantly increased, representing decreased dependency of QTI on RRI. Both QTI and RRI series showed reduced complexity during ischemia with higher sensitivity in ventricular repolarization. The weakened coupling between QTI and RRI suggests the decreased influence of sinoatrial node on QTI modulation during ischemia. PMID- 20725862 TI - Quiescent T cells and HIV: an unresolved relationship. AB - The ability of HIV to infect quiescent CD4+ T cells has been a topic of intense debate. While early studies suggested that the virus could not infect this particular T cell subset, subsequent studies using more sensitive protocols demonstrated that these cells could inefficiently support HIV infection. Additional studies showed that the kinetics of infection in quiescent cells was delayed and multiple stages of the viral life cycle were marred by inefficiencies. Despite that, proviral DNA has been found in these cells presenting them as a potential viral reservoir. Therefore, a better understanding of the relationship between HIV and quiescent T cells may lead to further advances in the field of HIV. PMID- 20725863 TI - Signaling through the P38 and ERK pathways: a common link between HIV replication and the immune response. AB - One of the defining characteristics of HIV is its ability to manipulate the human immune response to promote its own replication. Since the beginning of the epidemic, there has been controversy whether a robust immune response to the virus is beneficial or detrimental for the host. Therefore, the effects of HIV on signaling pathways and cytokine production need to be characterized in order to distinguish between protective immune responses and inappropriate immune activation. Cytokine and biomarker expression during HIV infection results from the combined effects of intracellular signaling pathways orchestrated by kinases like P38 and ERK. The P38 and ERK Mitogen-Activated Protein Kinase (MAPK) pathways govern the regulation of cytokines (IL-2, IL-10, and TNF-alpha) as well biomarkers (PD-1, Fas/FasL, among others) that are skewed in chronic HIV infection. HIV utilizes the P38 and ERK pathways to produce new virions and to deplete CD4+ T cells from the host's immune system. Understanding the interplay between HIV and the cytokines induced by activation of the P38 and ERK pathways may provide insights into HIV immunopathogenesis and the development of a protective vaccine. PMID- 20725866 TI - Membrane lipid modification by docosahexaenoic acid (DHA) promotes the formation of alpha-synuclein inclusion bodies immunopositive for SUMO-1 in oligodendroglial cells after oxidative stress. AB - alpha-Synuclein (alpha-syn) is the major constituent of Lewy bodies and glial cytoplasmic inclusions which are pathological hallmarks of neurodegenerative disorders like Parkinson's disease or multiple system atrophy (MSA), respectively. It accumulates and aggregates during the pathogenic process, and missense mutations, such as A53T, are increasing its probability of aggregate formation. Furthermore, alpha-syn interacts with polyunsaturated fatty acids, and this interaction may promote the oligomerization process. To investigate whether membrane lipid modification by docosahexaenoic acid (DHA) modifies the aggregation process of alpha-syn in oligodendroglial cells, we have used OLN-93 cells stably expressing the human alpha-syn A53T mutation. Cells were supplemented with DHA (25 MUM) for 3 days and then subjected to oxidative stress (OS) exerted by hydrogen peroxide. The data show that modification of the oligodendroglial cell membranes by DHA followed by OS caused the formation of fibrillary alpha-syn inclusions, a decrease in alpha-syn solubility, and an increase in phosphorylation at serine 129, which has been suggested to play a proaggregatory role. The aggregates contain alphaB-crystallin and ubiquitinated proteins and SUMO-1 immunoreactivity. SUMO-1 has been implicated in protein aggregation and identified as a constituent in inclusion bodies in MSA. Hence, membrane lipid modification in oligodendroglial cells promotes the formation of alpha-syn inclusion bodies resembling protein aggregates in neurodegenerative disease. This effect is not only attributable to the A53T mutation but also is observable in OLN cells expressing wild-type alpha-syn. PMID- 20725865 TI - Translating insights from persistent LCMV infection into anti-HIV immunity. AB - Human immunodeficiency virus (HIV) is a major global health concern with more than 30 million individuals currently infected worldwide. To date, attempts to stimulate protective immunity to viral components of HIV have been unsuccessful in preventing or clearing infection. Lymphocytic choriomeningitis virus (LCMV) is an established murine model of persistent viral infection that has been instrumental in illuminating several critical aspects of antiviral immunity. Although virologically the course of LCMV infection differs significantly from HIV, the immune responses and regulatory mechanisms elicited by these two viruses are markedly similar. In this review we discuss important recent findings in the LCMV model, highlighting the role of host-derived proteins in shaping immune responses to persistent infections, and explore the therapeutic potential of manipulating these pathways to enhance HIV vaccination strategies. PMID- 20725867 TI - Unraveling the role of metal ions and low catalytic activity of cytochrome C oxidase in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by high levels of aluminum and certain other metal ions in the brain: The disease is also characterized by low activity of brain cytochrome c oxidase (COX) but whether the elevated metal ions and the low COX activity are linked is not known. Moreover, COX is known to exhibit two catalytic rates (V (max)) and two substrate binding constants (K (m)) but it is not known which of these is affected in AD. In this study, we employed the Klatzo AD rabbit model to evaluate the impact of elevated metal ions on brain COX activity. New Zealand white rabbits were injected intra cerebrally with 1.4% solutions of either AlCl(3), FeCl(3), CaCl(2), or MgCl(2); and 10 days, later the brain mitochondria were isolated. Polarographic assay revealed that compared to the controls, all four metals led to decreases in the V (max) of the enzyme's low affinity site. The respective decreases were; 16%, 36%, 18%, and 30%. The results suggest a sequence of events in vivo in which oxygen radical damage to mitochondria and COX leads to low ATP production and excess heme establishing conditions thought to be ideal for neurodegeneration. PMID- 20725868 TI - Management of polycythemia in neonates. AB - Polycythemia is defined as a venous hematocrit above 65%. The hematocrit in a newborn peaks at 2 h of age and decreases gradually after that. The relationship between hematocrit and viscosity is almost linear till 65% and exponential thereafter. Increased viscosity of blood is associated with symptoms of hypo perfusion. Clinical features related to hyperviscosity may affect all organ systems. Neonates born small for gestational age (SGA), infants of diabetic mothers (IDM), and multiple births are at risk for polycythemia. They should therefore undergo screening at 2, 12, and 24 h of age. Polycythemia may be symptomatic or asymptomatic and guidelines for the management of both types based on the current evidence are provided in the protocol. PMID- 20725869 TI - Generalized epimerase deficiency galactosemia. AB - Galactosemia is caused by inherited deficiencies in one of three enzymes involved in the metabolism of galactose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). The rarest and most poorly understood form of galactosemia is due to epimerase deficiency. We are reporting such a rarest form of galactosemia presenting with progressively increasing cholestatic jaundice and failure to thrive at one month of age. After confirmation of decreased epimerase level in RBC hemolysate, the patient was put on galactose restricted diet and vitamins supplementation, which reversed the clinical signs as well as altered liver function. Patient is on regular follow-up and now at 15 months of age he has no marked developmental delay. PMID- 20725864 TI - Thinking about HIV: the intersection of virus, neuroinflammation and cognitive dysfunction. AB - It is estimated that half of HIV-infected adults and children will present at one time during their disease course with a neurologic disorder. The neurologic sequelae of HIV infection arise as a direct result of viral replication as well as from the subsequent neuroinflammatory processes. HIV enters the CNS early in infection and resides primarily in long-lived perivascular macrophages and microglia. CNS immunosurveillance is an integral part of normal brain function. Circulating lymphocytes play a vital role in support of brain plasticity under normal and traumatic circumstances. Malfunctions of this immunologic niche can impair brain homeostasis, resulting in neural impairment. Combination therapies that lower CNS viral load and improve immune homeostasis and neuroprotection will be required to address the neuropathogenesis of HIV infection. PMID- 20725870 TI - Enteric nervous system in the small intestine: pathophysiology and clinical implications. AB - The digestive system is endowed with its own, local nervous system, referred to as the enteric nervous system (ENS). Given the varied functions of small intestine, its ENS has developed individualized characteristics relating to motility, secretion, digestion, and inflammation. The ENS regulates the major enteric processes such as immune response, detecting nutrients, motility, microvascular circulation, intestinal barrier function, and epithelial secretion of fluids, ions, and bioactive peptides. Remarkable progress has been made in understanding the signaling pathways in this complex system and how they work. In this article, we focus on recent advances that have led to new insights into small intestinal ENS function and the development of new therapies. PMID- 20725871 TI - Ultrasonography- and/or mammography-guided breast conserving surgery for ductal carcinoma in situ of the breast: experience with 87 lesions. AB - BACKGROUND: It is very important to excise ductal carcinoma in situ (DCIS) with sufficient margins to prevent local recurrence. We describe the experience of ultrasonography (US)-guided and/or mammography (MMG)-guided breast conserving surgery (BCS) for DCIS. METHODS: In this retrospective study, we considered 87 consecutive lesions of 86 patients treated with US- and/or MMG-guided BCS between January and December 2006. RESULTS: The mean age of the 86 patients was 50.0 years (range 28-80 years). Preoperative mapping was performed using US alone for 49 lesions without microcalcifications and using US and MMG for 38 lesions with microcalcifications. Eighty-one (93.1%) of the 87 lesions were diagnosed as non comedo type or mixed type, and 6 lesions (6.9%) were diagnosed as comedo type of DCIS. Sixty-five lesions (74.8%) were diagnosed as negative margins, 15 lesions (17.2%) as close margins, and 7 lesions (8.0%) as positive margins. Three lesions (3.4%) without microcalcifications that were mapped using US alone underwent additional resection in a second operation. The maximum tumor size was correlated with margin status (p = 0.043). CONCLUSION: Thus US- and/or MMG-guided BCS is a reliable method for treating patients with DCIS regardless of histopathological type and offers the advantage of being noninvasive and nonstressful for patients. PMID- 20725872 TI - Effects of beta-hydroxy-beta-methylbutyrate treatment in different types of skeletal muscle of intact and septic rats. AB - beta-Hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite that may have a positive effect in protein catabolic conditions. Therefore, we hypothesized that HMB treatment could attenuate the sepsis-induced protein catabolic state. The aims of our study were to elucidate the effect of HMB in healthy and septic animals and to evaluate the differences in the action of HMB in different muscle types. Intact and septic (5 mg endotoxin/kg i.p.) rats were administered with HMB (0.5 g/kg/day) or saline. After 24 h, extensor digitorum longus (EDL) and soleus (SOL) muscles were isolated and used for determination of total and myofibrillar proteolysis, protein synthesis, leucine oxidation, activity of cathepsins B and L, chymotrypsin-like activity, and expression of alpha-subunits of proteasome. Our results indicate that the catabolic state induced by the endotoxin treatment was caused both by increase in protein breakdown (due to activation of proteasome system) and by attenuation of protein synthesis. The EDL (muscle composed of white, fast-twitch fibers) was more susceptible to these changes than the SOL (muscle composed of red, slow-twitch fibers). The HMB treatment had no effect in healthy animals but counteracted the changes in septic animals. The action of HMB was mediated by attenuation of proteasome activity and protein breakdown, not by stimulation of protein synthesis. More pronounced effect of the HMB treatment on myofibrillar proteolysis was observed in the SOL. PMID- 20725873 TI - IvACT after aneurysm clipping as an alternative to digital subtraction angiography--first experiences. AB - OBJECTIVE: After clipping of intracranial aneurysms, digital subtraction angiography (DSA) is recommended for the proof of complete aneurysm occlusion or identification of aneurysm remnants, especially in cases with a more complex angioarchitecture or a difficult operative course. The aim of this study was to evaluate if postoperative intravenous angiographic computed tomography (ivACT) could be a diagnostic alternative in cases of contraindications for DSA. MATERIAL AND METHODS: 13 patients (12 female, 1 male) underwent surgical clipping of 5 ruptured and 10 innocent aneurysms. Postoperative ivACT was performed in all patients due to refusal or contraindications for DSA. RESULTS: 12 patients had almost complete aneurysm clipping, while 1 patient's was incomplete, which was diagnosed by ivACT and confirmed by subsequent postoperative digital subtraction angiography (DSA), which had been accepted by the patient after clarification of the postoperative findings. CONCLUSION: This study illustrates the efficacy of ivACT for postoperative control of surgically treated aneurysms. The quality of ivACT generated images seems to be sufficient in the detection of residual aneurysms after clipping. In cases with inconclusive results, postoperative DSA should be performed to obtain further details. PMID- 20725874 TI - Comment to the article: Evidence-based indications for ICP recording after head injury. A review. PMID- 20725875 TI - [MR-guided interventions of the prostate gland: a literature review]. AB - In recent years MR imaging has played an increasingly important role in the diagnosis and treatment of prostate cancer. MR imaging of the prostate allows clear delineation of the anatomic structures and prostate tumors using T 2 weighted images combined with spectroscopy and dynamic examinations. The advantages of MRI make it possible to perform interventions, like biopsies, brachytherapy or different local therapies of the prostate gland. MRI robotic assistance will improve the accuracy of the interventions. Due to the advantages of MR imaging, MR-guided prostate interventions will play a greater role in the future. PMID- 20725876 TI - T2' Imaging of Native Kidneys and Renal Allografts - a Feasibility Study. AB - PURPOSE: To evaluate the feasibility of T2' mapping in native kidneys and renal allografts. MATERIALS AND METHODS: Following approval of the local ethics committee, 24 renal allograft recipients and 10 control subjects (healthy volunteers) were included in this study. Multi-echo T2 and T2* imaging was performed on a 1.5 Tesla scanner. Allograft recipients were assigned to two groups: group a), 8 patients with good (glomerular filtration rate of more than 40 ml/min) allograft function and no evidence of transplant rejection, transplant renal artery stenosis or ureteral obstruction; group b), 16 patients with deterioration of renal graft function (glomerular filtration rate (GFR) of 40 ml/min or less). Two different imaging protocols were tested. RESULTS: The mean T2' relaxation parameters were 108.33 msec +/- 13.34, 100.00 msec +/- 18.89 and 124.57 msec +/- 6.51 for groups a), b) and for control subjects, respectively. The reduction of T2' values in patient group b) was not statistically significant. However, significant correlations could be demonstrated between T2' values and the glomerular filtration rate (GFR) of renal allograft function. The reproducibility was tested and the coefficients of variation of T2' values in the cortex of transplanted kidneys were 11.1% within subjects and 11.3% between subjects. CONCLUSION: Our results indicate that T2' imaging is a promising non enhanced technique, which seems to reveal information on transplant function. Further studies are required to determine the clinical value of T2' mapping for monitoring renal allograft recipients. PMID- 20725877 TI - [Bilateral adrenal vein sampling in single catheter technique using a 4F cobra catheter in regular and inverse configuration]. AB - In Conn's syndrome, adrenal vein sampling (AVS) is used to secure the site of hormonal overproduction. The left adrenal vein is usually easy to explore, the right is difficult. Examination requires several differently configured catheters. Here, we introduce a new technique for AVS using a single cobra catheter, which was tested in n = 13 patients. In an inverted configuration, the cobra catheter can be used to explore the left side, while the regular configuration can be used for the right side. The technical details are described in the manuscript. In all patients, left AVS could be performed successfully using the inverted catheter configuration. In n = 11 patients, right AVS was carried out successfully with a cobra catheter in regular configuration. In two cases, a Sidewinder-I catheter was required due to a steep angle of the adrenal vein. PMID- 20725878 TI - [Embolization of acute abdominal and thoracic hemorrhages with ethylene vinyl alcohol copolymer (Onyx): initial experiences with arteries of the body trunk]. AB - During the last years most embolizations with the liquid agent Onyx have been performed in the field of neuroradiological interventions. There is minimal experience with arterial embolizations of the body trunk. 23 patients suffering from acute abdominal or thoracic bleeding underwent 28 embolizations with Onyx (17 male, 6 female, mean age 69 years). 27 interventions were technically and clinically successful. One patient with rebleeding from a jejunal artery aneurysm underwent surgery. Onyx embolizations were performed in renal, hepatic, iliac and bronchial arteries and esophageal varices. Compared with prior embolisation agents Onyx offers advantages due to good controllability. Fast arterial occlusion improves time management of patients. In comparison with prior techniques we observed a significant reduction of fluoroscopy time. Quantitative measurements demonstrated a significant higher embolisation agent contrast. PMID- 20725879 TI - [Cartilage quality in finger joints: delayed Gd(DTPA)2-enhanced MRI of the cartilage (dGEMRIC) at 3T]. AB - PURPOSE: To evaluate the feasibility of molecular cartilage MRI in finger joints. MATERIALS AND METHODS: Delayed Gd(DTPA)2-enhanced MRI of the cartilage (dGEMRIC) using a variable flip angle approach (VFA) was performed for the metacarpophalangeal (MCP) joints II and III in nine healthy volunteers and eighteen patients with rheumatoid arthritis (RA). The cartilage thickness was measured. Additionally, dGEMRIC was performed on proximal interphalangeal joints (PIP) in two patients with finger osteoarthritis (OA). RESULTS: the dGEMRIC index of the four evaluated cartilage areas was significantly decreased in RA patients compared to healthy subjects. The dGEMRIC index of MCP II phalangeal cartilage was 389.6 +/- 85.5 msec vs. 558.7 +/- 74.4 msec in healthy subjects. The metacarpal MCP II cartilage dGEMRIC index was 357.3 msec +/- 97.1 msec vs. 490.0 +/- 86.6 msec. The dGEMRIC indices of MCP III were: phalangeal 436.2 +/- 113.6 msec in RA, 558.8 +/- 115.5 msec in healthy subjects and metacarpal 398.0 +/- 97.6 msec in RA and 529.6 +/- 111.0 msec in healthy subjects. Age and cartilage thickness were not significantly different. In PIP joints of finger osteoarthritis patients, low dGEMRIC indices were noted, compared to the controls. CONCLUSION: The dGEMRIC of finger joints is feasible in patients with RA and finger OA. Morphologically normal cartilage shows significantly decreased dGEMRIC values in RA, pointing towards cartilage degeneration on a molecular level. Further studies are needed to establish the usefulness of this technique for early diagnosis, prognosis and therapy monitoring. PMID- 20725881 TI - Whole-heart 320-row computed tomography: reduction of radiation dose via prior coronary calcium scanning. AB - PURPOSE: The whole heart can be scanned in one rotation using 320-row coronary computed tomography angiography (CCTA), which covers up to 16 cm. Since most hearts are smaller, the total radiation dose may be reduced by adjusting the CCTA range to the individual heart size defined on a low-dose calcium scan (CACS). MATERIALS AND METHODS: Forty-five patients with suspected coronary artery disease (13 women, 32 men; mean 61 +/- 10 years) underwent CCTA preceded by low-dose CACS on a 320-row scanner (Aquilion ONE, Toshiba; 0.35 s gantry rotation, 120 kV, 350 450 mA) with 16-cm z-axis coverage (120 kV, 150 mA). The subsequent CCTA was performed over an adjusted scan range calculated as the individual heart size on CACS (+ 1 cm above and below). The total radiation dose of 16-cm CACS and the individually adjusted CCTA was compared with that of a calculated single CCTA using full 16-cm z-axis coverage. RESULTS: CCTA could be performed with a reduced scan length in the z-axis in all patients. None of the scans had to be performed over the whole range of 16 cm. The adjusted scan length was 14 cm in 2 patients, 12.8 cm in 3 patients, and 12 cm in 40 patients. The effective CCTA scan range was 12.1 +/- 0.5 cm based on mean individual heart sizes of 9.6 +/- 1.1 cm. The mean total effective radiation dose of the entire cardiac CT examination (individually adapted CCTA and CACS) was significantly smaller than the exposure calculated for 16-cm CCTA without CACS (8.5 +/- 4.7 vs. 9.1 +/- 6.0 mSv, p = 0.006). The dose reduction was most relevant in patients with heart rates above 65 beats/min (n = 10) in whom 2 or 3 heartbeats were necessary for CCTA (17.7 +/- 6.5 vs. 21.1 +/- 8.4 mSv, p = 0.001). CONCLUSION: 320-row CCTA with an individually adjusted scan range based on prior CACS significantly reduces the radiation exposure compared with full 16-cm CCTA. PMID- 20725880 TI - Postoperative monitoring of distal intraarticular radial fractures treated with osteosynthesis by means of multislice CT. AB - PURPOSE: This study evaluates multislice CT (MSCT) for the postsurgical control of intraarticular fractures of the distal radius. MATERIALS AND METHODS: In 131 patients conventional X-rays in two planes and MSCT were performed. In a consensus process two experienced radiologists judged conventional X-ray and computed tomography images in a random view. The correct position of the osteosynthetic material was assessed and it was ascertained whether an articular surface incongruity, a gap between two fracture fragments, or an intraarticular bone element was detectable. For each point of evaluation a confidence level of the evaluation was assessed on a five-point scale. RESULTS: Ninety patients were classified as having correct alignment and osteosynthesis according to conventional X-ray, while when using the findings from axial CT scans only, 82 patients, and after the addition of multiplanar re-constructions (MPR) only 73 patients were found to have almost proper alignment and osteosynthesis. In 42 patients dehiscence of the fragments was diagnosed with MSCT, but was not visualized by X-ray, leading to surgical revision in eight patients, confirming the diagnosis. In five patients an intraarticular position of intraarticular material was confirmed with MSCT and surgical revision. A significant advantage for the evaluation confidence level was achieved for MPRs in comparison with axial CT scans and X-ray. CONCLUSION: The marked diagnostic advantage with a high evaluation confidence level in comparison with conventional X-ray methods justify the use of MSCT during postoperative monitoring of articular radial fractures treated with osteosynthesis. PMID- 20725882 TI - [Portal vein aneurysm: a rare form of visceral aneurysm]. PMID- 20725883 TI - [Emphysematous gastritis]. PMID- 20725884 TI - [Histopathology of retrocorneal membranes after keratoplasty]. AB - BACKGROUND: This retrospective study examines the histopathological changes, especially the occurrence of retrocorneal membranes, in irreversible graft failure after penetrating keratoplasty. PATIENTS/MATERIALS AND METHODS: 371 corneas of 308 patients were examined. The examination was carried out using a light microscope. RESULTS: 45% of the corneas (167/371) showed a retrocorneal membrane with a thickness of 2-520 micrometers. Re-endothelialisation was detected in 75 cases. In 74% (124/167) cellular infiltration into the stroma could be observed. In 32% (119/371) the graft-host border was visible. CONCLUSIONS: Retrocorneal membranes are a frequent finding in irreversible graft failure after penetrating keratoplasty. Aetiologically the graft-host border as well as the formation of connective tissue seem to play a key role. PMID- 20725885 TI - [Amyloidosis--a rare differential diagnosis of an orbital tumour]. AB - BACKGROUND: Amyloidosis is a disorder caused by a misfoulding of proteins. The deposition of these proteins in tissues and organs can affect the normal function of those tissues and organs. MATERIALS AND METHODS: Two patients are presented and an overview over the so far published cases with a localised orbital amyloidosis is given. RESULTS: The first case is a 50-year-old woman with progressive ptosis since half a year, progressive proptosis since three months and deterioration of motility and deviation of the left globe. The second case is a 68-year-old man with progressive ptosis since four years and with affection of the subtarsal conjunctiva of the right eye. Macroscopically a yellow-brown, gelatinous, easily crumbled material was seen during operation. CONCLUSION: the histological proof of amyloidosis can be made visually in intense unidirectional polarised light after congo red staining. This should be done in suspected cases every time. The orbita can also be involved in systemic forms of amyloidosis, so a systemic form should be excluded. The localised amyloidosis has no effect on the survival time in contrast to the systemic forms does have an effect. An untreated systemic form may be associuated with a prognosis of only 9 to 13 months. PMID- 20725886 TI - A prospective comparison of endoscopic ultrasound-guided fine needle aspiration results obtained in the same lesion, with and without the needle stylet. AB - BACKGROUND AND STUDY AIMS: The effectiveness of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with (S+) and without (S-) a stylet has never been compared. We prospectively compared the yield for malignancy and sample quality of S+ and S- EUS-FNA. PATIENTS AND METHODS: S+ or S- EUS-FNA was performed on consecutive solid lesions, with a 22-gauge needle, with systematic assignment of S+ or S- passes in a 1 : 2 ratio. Slides were read by a single, blinded cytologist and were rated for bloodiness, adequacy, and presence of malignancy. The yield for malignancy was compared only in lesions in which equal numbers of S+ and S- passes were performed. RESULTS: A total of 309 passes (mean 2.3 passes/lesion, range 1-6, 82% adequate, 38% S+, 62% S-) were performed on 135 lesions (63% malignant, 42% nodes, 58% masses [79% pancreatic]) in 111 patients (mean age 62.9 years, range 30-86). In 46 lesions where an equal number (53 S+ and 53 S-) of passes was performed, there was no difference in the proportion of cases in which S+ FNA was "equal to or better than" S- FNA ([S+] 89% vs. [S-] 87%; P>0.05). The results of the two methods agreed in 80% cases (kappa 0.60). The sensitivities for malignancy were: S+ 87% vs. S- 83%, P>0.05. Specificities were 100%. Sample adequacy was significantly lower in S+ passes (75% vs. 87%, P=0.013), and sample bloodiness was significantly higher (75% vs. 52%, P<0.0001). CONCLUSIONS: Use of the stylet with EUS-FNA does not increase the yield for malignancy and is associated with poorer sample quality. The value of the stylet for EUS-FNA is questionable and requires further investigation. PMID- 20725887 TI - Multidrug-resistant Klebsiella pneumoniae outbreak after endoscopic retrograde cholangiopancreatography. AB - BACKGROUND AND STUDY AIMS: Infection is a recognized complication of endoscopic retrograde cholangiopancreatography (ERCP). We describe the epidemiologic and molecular investigations of an outbreak of ERCP-related severe nosocomial infection due to KLEBSIELLA PNEUMONIAE producing extended-spectrum beta-lactamase (ESBL). PATIENTS AND METHODS: We conducted epidemiologic and molecular investigations to identify the source of the outbreak in patients undergoing ERCP. We carried out reviews of the medical and endoscopic charts and microbiological data, practice audits, surveillance cultures of duodenoscopes and environmental sites, and molecular typing of clinical and environmental isolates. RESULTS: Between December 2008 and August 2009, 16 patients were identified post ERCP with KLEBSIELLA PNEUMONIAE that produced extended-spectrum beta-lactamase type CTX-M-15. There were 8 bloodstream infections, 4 biliary tract infections, and 4 cases of fecal carriage. The microorganism was isolated only from patients who had undergone ERCP. Environmental investigations found no contamination of the washer-disinfectors or the surfaces of the endoscopy rooms. Routine surveillance cultures of endoscopes were repeatedly negative during the outbreak but the epidemic strain was finally isolated from one duodenoscope by flushing and brushing the channels. Molecular typing confirmed the identity of the clinical and environmental strains. Practice audits showed that manual cleaning and drying before storage were insufficient. Strict adherence to reprocessing procedures ended the outbreak. CONCLUSIONS: The endoscopes used for ERCP can act as a reservoir for the emerging ESBL-producing K. PNEUMONIAE. Regular audits to ensure rigorous application of cleaning, high-level disinfection, and drying steps are crucial to avoid contamination. PMID- 20725888 TI - Telesonography - modern solutions for an old question. PMID- 20725890 TI - Clinical Ultrasonography - under utilized. A personal position put up for other perspectives. PMID- 20725891 TI - An EUROSON School in Berlin - on Interventional Ultrasonography. PMID- 20725892 TI - Minimum training requirements for the practice of Medical Ultrasound in Europe. PMID- 20725899 TI - [The use of ultrasound to assess the extent of inflammation in rheumatoid arthritis]. PMID- 20725900 TI - [Ultrasound in patients with Crohn disease - in vitro and in vivo characterization of the gastrointestinal wall]. PMID- 20725901 TI - [Ultrasound education in the Laboratory of Nuclear Medicine and Ultrasound, Fundeni Clinical Institute - Bucharest]. PMID- 20725902 TI - Prevalence of aortic root dilation in patients with CT angiography of the aorta. AB - PURPOSE: To investigate the prevalence of aortic root dilation in patients who underwent CT angiography of the thoracic aorta. MATERIALS AND METHODS: In 95 patients, 64-slice multislice computed tomography was performed for evaluation of the thoracic aorta. Measurements of the annulus, sinuses of valsalva (SOV), sinotubular junction (STJ), and maximum ascending aorta (AAo) were made by double oblique multiplanar reformation (MPR). For the AAo, STJ, and SOV, dilation was defined as greater than 40 mm; for annulus, the dilation criterion was greater than 27 mm. RESULTS: Overall, 52 patients were diagnosed with a dilated AAo. Of those patients with dilated AAo, 28 patients had a dilated annulus, 27 patients had dilated SOV, and 11 patients had STJ dilation. Forty-three patients presented with normal AAo; 12 patients had annulus dilation; 12 patients had SOV dilation; and 4 patients had STJ dilation. In patients with dilated AAo, 38% also had a dilated annulus, 52% showed SOV dilation, and 21% presented with STJ dilation, compared to 28% annulus dilation, 28% SOV dilation, and 9% STJ dilation in patients with an AAo of normal caliber. CONCLUSION: Our data indicate a higher prevalence of aortic root dilation among patients with dilated AAo. PMID- 20725903 TI - Gastrointestinal lymphoma: a spectrum of fluoroscopic and CT findings. AB - Gastrointestinal lymphomas can occur in nodular, polypoid, cavitary, ulcerative or diffuse infiltrating (submucosal) forms. Barium studies and computed tomography (CT) are the most popular imaging techniques used to diagnose these lymphomas. Barium studies are superior to CT in evaluating mild mucosal and submucosal changes. However, CT is the technique of choice because it provides a complete evaluation of the extent of disease dissemination, recent disease development, therapeutic response, and related complications. PMID- 20725904 TI - Tumour deposits classification in colorectal cancer: is TNM5 better than TNM7? PMID- 20725906 TI - Uric acid potentially links fatty liver and high blood pressure. PMID- 20725905 TI - The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. AB - Heparan sulfate proteoglycans (HSPGs) act as coreceptors or storage sites for growth factors and cytokines such as fibroblast growth factor and Wnts. Glypican 3 (GPC3) is the most highly expressed HSPG in hepatocellular carcinoma (HCC). Sulfatase 2 (SULF2), an enzyme with 6-O-desulfatase activity on HSPGs, is up regulated in 60% of primary HCCs and is associated with a worse prognosis. We have previously shown that the oncogenic effect of SULF2 in HCC may be mediated in part through up-regulation of GPC3. Here we demonstrate that GPC3 stimulates the Wnt/beta-catenin pathway and mediates the oncogenic function of SULF2 in HCC. Wnt signaling in vitro and in vivo was assessed in SULF2-negative Hep3B HCC cells transfected with SULF2 and in SULF2-expressing Huh7 cells transfected with short hairpin RNA targeting SULF2. The interaction between GPC3, SULF2, and Wnt3a was assessed by coimmunoprecipitation and flow cytometry. beta-catenin-dependent transcriptional activity was assessed with the TOPFLASH (T cell factor reporter plasmid) luciferase assay. In HCC cells, SULF2 increased cell surface GPC3 and Wnt3a expression, stabilized beta-catenin, and activated T cell factor transcription factor activity and expression of the Wnt/beta-catenin target gene cyclin D1. Opposite effects were observed in SULF2-knockdown models. In vivo, nude mouse xenografts established from SULF2-transfected Hep3B cells showed enhanced GPC3, Wnt3a, and beta-catenin levels. CONCLUSION: Together, these findings identify a novel mechanism mediating the oncogenic function of SULF2 in HCC that includes GPC3-mediated activation of Wnt signaling via the Wnt3a/glycogen synthase kinase 3 beta axis. PMID- 20725907 TI - Nonalcoholic fatty liver in a developing country is responsible for significant liver disease. PMID- 20725909 TI - Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. AB - A subgroup of patients with breast cancer suffers from mild cognitive impairment after chemotherapy. To uncover the neural substrate of these mental complaints, we examined cerebral white matter (WM) integrity after chemotherapy using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment. Postchemotherapy breast cancer patients (n = 17) and matched healthy controls (n = 18) were recruited for DTI and neuropsychological testing, including the self-report cognitive failure questionnaire (CFQ). Differences in DTI WM integrity parameters [fractional anisotropy (FA) and mean diffusivity (MD)] between patients and healthy controls were assessed using a voxel-based two-sample-t-test. In comparison with healthy controls, the patient group demonstrated decreased FA in frontal and temporal WM tracts and increased MD in frontal WM. These differences were also confirmed when comparing this patient group with an additional control group of nonchemotherapy-treated breast cancer patients (n = 10). To address the heterogeneity observed in cognitive function after chemotherapy, we performed a voxel-based correlation analysis between FA values and individual neuropsychological test scores. Significant correlations of FA with neuropsychological tests covering the domain of attention and processing/psychomotor speed were found in temporal and parietal WM tracts. Furthermore, CFQ scores correlated negatively in frontal and parietal WM. These studies show that chemotherapy seems to affect WM integrity and that parameters derived from DTI have the required sensitivity to quantify neural changes related to chemotherapy-induced mild cognitive impairment. PMID- 20725910 TI - Cognitive and default-mode resting state networks: do male and female brains "rest" differently? AB - Variability in human behavior related to sex is supported by neuroimaging studies showing differences in brain activation patterns during cognitive task performance. An emerging field is examining the human connectome, including networks of brain regions that are not only temporally-correlated during different task conditions, but also networks that show highly correlated spontaneous activity during a task-free state. Both task-related and task-free network activity has been associated with individual task performance and behavior under certain conditions. Therefore, our aim was to determine whether sex differences exist during a task-free resting state for two networks associated with cognitive task performance (executive control network (ECN), salience network (SN)) and the default mode network (DMN). Forty-nine healthy subjects (26 females, 23 males) underwent a 5-min task-free fMRI scan in a 3T MRI. An independent components analysis (ICA) was performed to identify the best fit IC for each network based on specific spatial nodes defined in previous studies. To determine the consistency of these networks across subjects we performed self-organizing group-level ICA analyses. There were no significant differences between sexes in the functional connectivity of the brain areas within the ECN, SN, or the DMN. These important findings highlight the robustness of intrinsic connectivity of these resting state networks and their similarity between sexes. Furthermore, our findings suggest that resting state fMRI studies do not need to be controlled for sex. PMID- 20725908 TI - Implicit sequence-specific motor learning after subcortical stroke is associated with increased prefrontal brain activations: an fMRI study. AB - Implicit motor learning is preserved after stroke, but how the brain compensates for damage to facilitate learning is unclear. We used a random effects analysis to determine how stroke alters patterns of brain activity during implicit sequence-specific motor learning as compared to general improvements in motor control. Nine healthy participants and nine individuals with chronic, right focal subcortical stroke performed a continuous joystick-based tracking task during an initial functional magnetic resonance images (fMRI) session, over 5 days of practice, and a retention test during a separate fMRI session. Sequence-specific implicit motor learning was differentiated from general improvements in motor control by comparing tracking performance on a novel, repeated tracking sequence during early practice and again at the retention test. Both groups demonstrated implicit sequence-specific motor learning at the retention test, yet substantial differences were apparent. At retention, healthy control participants demonstrated increased blood oxygenation level dependent (BOLD) response in left dorsal premotor cortex (PMd; BA 6) but decreased BOLD response left dorsolateral prefrontal cortex (DLPFC; BA 9) during repeated sequence tracking. In contrast, at retention individuals with stroke did not show this reduction in DLPFC during repeated tracking. Instead implicit sequence-specific motor learning and general improvements in motor control were associated with increased BOLD response in the left middle frontal gyrus BA 8, regardless of sequence type after stroke. These data emphasize the potential importance of a prefrontal-based attentional network for implicit motor learning after stroke. This study is the first to highlight the importance of the prefrontal cortex for implicit sequence-specific motor learning after stroke. PMID- 20725911 TI - No difference in adherence to paroxetine between depressed patients with early remission and those with late remission based on monitoring of plasma paroxetine concentrations. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat both anxiety disorders and depressive disorders. However, nonadherence to SSRIs is a major issue in recurrence. In the present study, we investigated paroxetine adherence in depressed patients by monitoring the plasma paroxetine concentrations between patients with rapid and those with a late response to paroxetine treatment. Twenty inpatients in our university hospital, who met the DSM-IV-TR diagnosis of major depressive disorder in a single episode, were enrolled in the study. Twelve patients (M/F: 7/13, age: 37.4 +/- 10.4 years) were treated with paroxetine (40 mg/day), and all achieved remission (HAMD < or = 7) within at least 12 weeks. We divided the patients into two groups, an early remission group (HAMD < or = 7 within 4 weeks) and a late-remission group (HAMD < or = 7 within 8-12 weeks). Their dosages of paroxetine were constant because of no emerging adverse effects. Blood samples were obtained on the day the subjects were discharged (B) and 12 weeks after discharge. The paroxetine concentrations in the early-remission group were significantly decreased 12 weeks after discharge, and no difference was found between the early- and late-remission groups. These results suggest that adherence to paroxetine was independent of the duration of the depressive state suffered by the patients. Clinicians always take their cautions for the adherence to paroxetine regardless of the clinical time courses the patients recovering from their depressive symptoms. PMID- 20725912 TI - Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. AB - Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n = 16) and controls (n = 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment. CONCLUSION: Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved glycemic control in T2DM. PMID- 20725913 TI - Cognitive impairment in Parkinson's disease without dementia. AB - Some degree of cognitive impairment appears frequently in Parkinson's disease (PD) patients, even at the onset of the disease. However, due to the heterogeneity of the patients and the lack of standardized assessment batteries, it remains unclear which capacities are primarily affected by this disease. Fifty PD patients were assessed with 15 tests including executive functions, attention, temporal and spatial orientation, memory, and language tasks. Their results were compared with those of 42 age- and education-matched healthy seniors. Semantic fluency, along with visual search appeared to be the most discriminant tasks, followed by temporal orientation and face naming, as well as action naming and immediate recall. PD patients studied showed an impairment of frontal- to posterior-dependent capacities. Executive functions, attention, and recall tasks appeared to be significantly impaired in the patients. Nevertheless, significantly poor scores in tasks like action and face naming, as well as semantic fluency, also reveal a mainly semantic deficit. PMID- 20725914 TI - Sensory disinhibition on passive movement in cervical dystonia. AB - The relevance of the sensory system in the pathophysiology of cervical dystonia (CD) has been discussed since the description of sensory tricks associated with this disorder. Our objective was to locate changes in somatosensory processing of patients with CD responding in a passive sensory task of body regions that are not affected by dystonic symptoms. We used functional magnetic resonance imaging (fMRI) in 17 patients with CD and 17 healthy controls performing a strictly passive 30-degree forearm movement task with the left arm. TSUI and TWSTRS rating scales were used for clinical assessment. All patients were treated with botulinum neurotoxin type A (BoNT-A; Dysport(r)). Patients with CD showed BOLD signal increase in the contralateral primary and secondary sensory cortex, the cingulate cortex and cerebellum bilaterally compared to healthy controls. We found a strong positive correlation of this activation with BoNT-A dosage in the supplementary motor area (SMA) and a negative correlation with the TWSTRS in that same region. The observed sensory overactivation suggests a general disinhibition of the somatosensory system in CD as it was not limited to the motor-system or the direct neuronal representation of the affected dystonic musculature alone. PMID- 20725915 TI - Blood oxygenation level-dependent activation in basal ganglia nuclei relates to specific symptoms in de novo Parkinson's disease. AB - To aid the development of symptomatic and disease modifying therapies in Parkinson's disease (PD), there is a strong need to identify noninvasive measures of basal ganglia (BG) function that are sensitive to disease severity. This study examines the relation between blood oxygenation level-dependent (BOLD) activation in every nucleus of the BG and symptom-specific disease severity in early stage de novo PD. BOLD activation measured at 3 T was compared between 20 early stage de novo PD patients and 20 controls during an established precision grip force task. In addition to the BG nuclei, activation in specific thalamic and cortical regions was examined. There were three novel findings. First, there were significant negative correlations between total motor Unified PD Rating Scale and BOLD activation in bilateral caudate, bilateral putamen, contralateral external segment of the globus pallidus, bilateral subthalamic nucleus, contralateral substantia nigra, and thalamus. Second, bradykinesia was the symptom that most consistently predicted BOLD activation in the BG and thalamus. Also, BOLD activation in the contralateral internal globus pallidus was related to tremor. Third, the reduced cortical activity in primary motor cortex and supplementary motor area in de novo PD did not relate to motor symptoms. These findings demonstrate that BOLD activity in nuclei of the BG relates most consistently to bradykinesia and functional magnetic resonance imaging has strong potential to serve as a noninvasive marker for the state of BG function in de novo PD. PMID- 20725916 TI - Inflation bulb-driven microfluidic reactor for infrared-assisted proteolysis. AB - In this report, an inflation bulb-driven microfluidic reactor was developed for IR-accelerated proteolysis. This novel proteolysis system mainly consisted of an inflation bulb-driving system, a simple cross-PMMA microchip, and a temperature controllable IR radiation system. The gas pressure generated from an inflation bulb was employed to drive protein and trypsin solutions to flow into the main channel of the microchip via two capillaries and the injection channel. When the two solutions were mixed in the channel, the protein was rapidly digested by trypsin under IR radiations. The peptides in the digests accumulated in the product reservoir of the microchip were subsequently identified by MS. The feasibility and performance of this unique system were demonstrated by digesting hemoglobin and lysozyme. The results indicated that IR radiation could significantly enhance the on-chip proteolysis and the digestion time was substantially reduced to 5 min. The present proteolysis setup is simple and efficient and will find wide applications in high-throughput protein digestion. PMID- 20725917 TI - Total analysis of endocrine disruptors in a microchip with gold nanoparticles. AB - The development of a simple, sensitive, and direct method for the total analysis of certain endocrine disruptors was performed by integrating preconcentration steps to a separation step on a microchip through the modification of the field amplified sample stacking and field-amplified sample injection steps. To improve the preconcentration and separation performances, the preconcentration and separation buffers were modified with citrate-stabilized gold nanoparticles (AuNPs). For the detection of the separated samples, cellulose-dsDNA/AuNPs modified carbon paste electrodes were used at the channel end. The experimental parameters affecting the analytical performances, such as the buffer concentration, water plug length, SDS concentration in the separation buffer, AuNPs concentration, preconcentration time, detection potential and electrode to channel distance, were examined. The detection limits of the test compounds were between 7.1 and 11.1 fM and that for 4-pentylphenol was 7.1 (+/-1.1) fM. Dynamic ranges were in the range from 0.15 to 600.0 pM. The experiments with real samples were performed to evaluate the reliability of the proposed method. PMID- 20725918 TI - Multi-parameter detection of diabetes mellitus on multichannel poly(dimethylsiloxane) analytical chips coupled with nanoband microelectrode arrays. AB - This article demonstrates a novel method for multi-parameter detection of diabetes mellitus. We propose an approach for fabrication of a 3-D metal films array with gold and copper using electroless deposition technique on PDMS substrate. The obtained PDMS slices containing metal films are superimposed layer by layer as a sandwich structure to form 3-D metal films array. The cross sections of the array could be used as nanoband array electrochemical detectors, which are further integrated with a multichannel microchip for simultaneously detecting multi-parameter of diabetes mellitus, including glucose and metabonomics of diabetes containing aldehyde compounds (glyoxal and methylglyoxal) and short organic acids (lactate, urate and 2-hydroxybutyrate). Under optimized separation and detection conditions, glucose, aldehyde compounds and short organic acids respond linearly in the concentration range of 10-2000, 1 500 and 5-600 MUM, with the LODs of 4, 0.5 and 3 MUM for glucose, aldehyde compounds and short organic acids, respectively. This system is successfully employed to detect these compounds in serums. This study reveals that the electrochemical array detectors with different materials integrated with multichannel microchip provide a flexible and inexpensive approach for routine, simultaneous and direct detection of some metabolites in metabonomics. PMID- 20725919 TI - Ionic mixed interactions in macromolecules. AB - Purely ionic interactions in natural and synthetic macromolecules involve the mutual interaction of fixed charges and their interaction with mobile ions. Such charge-dependent interactions lead to well-documented effects, including chain expansion of polyelectrolytes, globularization of polyampholytes, distributions of mobile ions according to charge screening, or ion condensation models. A variety of structural features, functions, and applications of these systems is amplified by the superimposition of charge-independent effects associated with the occurrence of less polar or hydrophobic groups, special salts, surfactants, or complementary protein assemblies. For instance, ionic and hydrophobic attractive interactions stabilize pearls (or rings)-on-a-string conformations, possibly a model for the formation of the chromatin assembly. The attractive interactions due to hydrophobic fatty acid groups attached to polysaccharides promote the formation of vesicles that entrap and slowly release water-soluble drugs. Intra- and intermolecular associations based on ion-pairing mixed interactions also control the formation of host-guest compounds, protein conformation, and the assembly of layered polyelectrolytes. Metallo supramolecular polymers and networks are formed due to the coordination of multivalent cations with bi- and trifunctional organic ligands. The association of lithium salts to polymers in the absence of water allows the formation of highly efficient energy sources. It also allows the identification of the ionic species that control charge-independent contributions to Hofmeister effects. This critical review presents a synthetic classification of systems displaying ionic mixed interactions, and a discussion of underlying molecular mechanisms. PMID- 20725920 TI - Highly diastereoselective synthesis of alpha-difluoromethyl amines from N-tert butylsulfinyl ketimines and difluoromethyl phenyl sulfone. AB - The first highly efficient and stereoselective difluoromethylation of structurally diverse N-tert-butylsulfinyl ketimines has been achieved with an in situ generated PhSO(2)CF(2)(-) anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral alpha difluoromethyl tertiary carbinamines, including alpha-difluoromethyl allylic amines and alpha-difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-membered transition state may be involved in the reaction. PMID- 20725921 TI - Isolation and characterization of the triradical 1,3,5-trimethylenebenzene. PMID- 20725922 TI - Palladium-catalyzed beta arylation of carboxylic esters. PMID- 20725923 TI - Nanotoxicology: the molecular science point of view. AB - Research on nanotoxicity is of extremely high scientific, social, and economic value. As nanomaterial-based products enter the market, there is an urgent need for related research in order to prevent dramatic consequences of any health oriented issues caused by nanotechnology-driven products. The results of research on nanotoxicity have profound significance because the design of nanomaterials used in industry and consumer products should be based on the outcome of such research. The research has multi-billion dollar significance for industry and an even greater value for consumers and health care. Such research could prevent an enormous burden in terms of the cost of care for chronic health problems of the entire population caused by the widespread use of untested nanomaterials. The tremendous progress of nanotechnology has not been accompanied by sufficient studies of nanomaterial toxicity even though they possess unique, completely new properties. Thus, their toxicity can neither be extrapolated from the toxicity of bulk materials nor from the toxicity of their constituents in ionic form. This Focus Review discusses the current state of nanotoxicity research and nanotoxicology from the point of view of molecular science. PMID- 20725924 TI - A review on the beneficial aspects of food processing. AB - The manuscript reviews beneficial aspects of food processing with main focus on cooking/heat treatment, including other food-processing techniques (e.g. fermentation). Benefits of thermal processing include inactivation of food-borne pathogens, natural toxins or other detrimental constituents, prolongation of shelf-life, improved digestibility and bioavailability of nutrients, improved palatability, taste, texture and flavour and enhanced functional properties, including augmented antioxidants and other defense reactivity or increased antimicrobial effectiveness. Thermal processing can bring some unintentional undesired consequences, such as losses of certain nutrients, formation of toxic compounds (acrylamide, furan or acrolein), or of compounds with negative effects on flavour perception, texture or colour. Heat treatment of foods needs to be optimized in order to promote beneficial effects and to counteract, to the best possible, undesired effects. This may be achieved more effectively/sustainably by consistent fine-tuning of technological processes rather than within ordinary household cooking conditions. The most important identified points for further study are information on processed foods to be considered in epidemiological work, databases should be built to estimate the intake of compounds from processed foods, translation of in-vitro results to in-vivo relevance for human health should be worked on, thermal and non-thermal processes should be optimized by application of kinetic principles. PMID- 20725925 TI - Peptides from water buffalo cheese whey induced senescence cell death via ceramide secretion in human colon adenocarcinoma cell line. AB - SCOPE: Milk proteins are a source of bioactive peptides. Recent studies have indicated that protein-derived peptides released in buffalo cheese acid whey exert a cytomodulatory effect in human epithelial colon cancer (CaCo2) cells. The aim of the present study was to explain the molecular mechanism involved in the response of CaCo2 cells to oxidative stress in the presence of peptide fractions of buffalo cheese whey, purified and characterized by mass spectrometry. METHODS AND RESULTS: We demonstrated that treatment of CaCo2 treated with H2O2 (H-CaCo2) cells with a partially purified peptide sub-fraction (f3) from buffalo cheese acid whey induced a reduction of mitochondrial superoxide anion with subsequent decrease in heat shock protein 70 and 90 expression. Moreover, we observed a 5 fold decrease in cyclin A expression and cell cycle arrest in G1/G0 phases. These responses were associated with increased activity of alkaline phosphatase and beta-galactosidase, markers of differentiation and senescence respectively. CONCLUSIONS: The structural characterization of the active peptide fraction and the elucidation of the effects induced by its treatment on H-CaCo2 cells in vitro demonstrated an activity of this peptide sub-fraction in the modulation of cell cycle, thus suggesting potential application for the development of nutraceuticals as well as health-promoting functional foods. PMID- 20725926 TI - Fluoride-modulated cobalt catalysts for electrochemical oxidation of water under non-alkaline conditions. PMID- 20725927 TI - Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions. AB - Nonallelic homologous recombination (NAHR) is responsible for the recurrent rearrangements that give rise to genomic disorders. Although meiotic NAHR has been investigated in multiple contexts, much less is known about mitotic NAHR despite its importance for tumorigenesis. Because type-2 NF1 microdeletions frequently result from mitotic NAHR, they represent a good model in which to investigate the features of mitotic NAHR. We have used microsatellite analysis and SNP arrays to distinguish between the various alternative recombinational possibilities, thereby ascertaining that 17 of 18 type-2 NF1 deletions, with breakpoints in the SUZ12 gene and its highly homologous pseudogene, originated via intrachromosomal recombination. This high proportion of intrachromosomal NAHR causing somatic type-2 NF1 deletions contrasts with the interchromosomal origin of germline type-1 NF1 microdeletions, whose breakpoints are located within the NF1-REPs (low-copy repeats located adjacent to the SUZ12 sequences). Further, meiotic NAHR causing type-1 NF1 deletions occurs within recombination hotspots characterized by high GC-content and DNA duplex stability, whereas the type-2 breakpoints associated with the mitotic NAHR events investigated here do not cluster within hotspots and are located within regions of significantly lower GC content and DNA stability. Our findings therefore point to fundamental mechanistic differences between the determinants of mitotic and meiotic NAHR. PMID- 20725928 TI - Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias. AB - Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ~3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ~1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15-16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs. PMID- 20725929 TI - Leiden Open Variation Database of the MUTYH gene. AB - The MUTYH gene encodes a DNA glycosylase involved in base excision repair (BER). Biallelic pathogenic MUTYH variants have been associated with colorectal polyposis and cancer. The pathogenicity of a few variants is beyond doubt, including c.536A4G/p.Tyr179Cys and c.1187G4A/p.Gly396Asp (previously c.494A4G/p.Tyr165Cys and c.1145G4A/p.Gly382Asp).However, for a substantial fraction of the detected variants, the clinical significance remains uncertain,compromising molecular diagnostics and thereby genetic counseling. We have established an interactive MUTYH gene sequence variant database (www.lovd.nl/MUTYH) with the aim of collecting and sharing MUTYH genotype and phenotype data worldwide. To support standard variant description, we chose NM_001128425.1 as the reference sequence. The database includes records with variants per individual, linked to available phenotype and geographic origin data as well as records with in vitro functional and in silico test data. As of April 2010, the database contains 1968 published and 423 unpublished submitted entries, and 230 and 61 unique variants,respectively. This open-access repository allows all involved to quickly share all variants encountered and communicate potential consequences, which will be especially useful to classify variants of uncertain significance. PMID- 20725930 TI - miRNA genes and the brain: implications for psychiatric disorders. AB - MicroRNAs (miRNAs) are a class of nonprotein coding genes with a growing importance in regulatory mechanisms of gene expression related to brain function and plasticity. Considering the relative lack of success of the analysis of variations in candidate protein coding genes and of genome-wide association studies to identify strong risk factors for common psychiatric disorders (PDs), miRNA genes are of particular interest for the field of psychiatric genetics as deregulation of the rate of transcription or translation of a normal gene may be phenotypically similar to disruption of the gene itself. In this article we review the current knowledge on the contribution of miRNAs in basic mechanisms of brain development and plasticity and their possible involvement in the pathogenesis of several PDs. Because future functional and genomic explorations of brain expressed miRNAs, and other types of noncoding RNAs, may identify additional candidate genes and pathways for common PDs, we believe that implementing additional strategies to further elucidate the role of miRNAs in the etiology of common PDs is of great importance. PMID- 20725931 TI - NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD). AB - Congenital heart disease (CHD) is among the most prevalent and fatal of all birth defects. Deciphering its causes, however, is complicated, as many patients affected by CHD have no family history of the disease. There is also widespread heterogeneity of cardiac malformations within affected individuals. Nonetheless, there have been tremendous efforts toward a better understanding of the molecular and cellular events leading to CHD. Notably, certain cardiac-specific transcription factors have been implicated in mammalian heart development and disruption of their activity has been demonstrated in CHD. The homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. Thus, NKX2-5 appears to be hypermutable, yet the overall detection frequency in sporadic CHD is about 2% and NKX2-5 mutations are one-time detections with single-positives or private to families. Furthermore, there is lack of genotype-phenotype correlation, in which the same cardiac malformations have been exhibited in different NKX2-5 mutations or the same NKX2-5 mutation associated with diverse malformations. Here, we summarize published NKX2-5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved. PMID- 20725932 TI - Reproducibility of diffusion tensor imaging in human forearm muscles at 3.0 T in a clinical setting. AB - The aim of the present study was to evaluate a fast clinical protocol to enable diffusion tensor imaging of the human forearm and assess the reproducibility of six diffusion tensor imaging parameters, i.e., the tensor eigenvalues (lambda(1), lambda(2), and lambda(3)), mean diffusivity, fractional anisotropy, and ellipsoid eccentricity. The right forearms of 10 healthy volunteers were scanned twice, with a 1-week interval. Reproducibility of the diffusion tensor imaging parameters was interpreted using Bland-Altman plots, coefficient of repeatability, repeatability index, and the intraclass correlation coefficient. Analysis was done for three regions of interest: the whole muscle volume, flexor digitorum profundus, and extensor digitorum. The Bland-Altman analysis showed that there is good agreement between the two measurements. Based on the intraclass correlation coefficients, agreement was substantial (0.59 < intraclass correlation coefficient < 0.92) for all six parameters of the whole muscle volume and flexor digitorum profundus but only fair (0.18 < intraclass correlation coefficient < 0.64) for the extensor digitorum. Using a 7 min 40 sec scan protocol, which was well tolerated by the volunteers, the reproducibility of diffusion tensor imaging parameters was demonstrated. However, repeatability varies, depending on the region of interest and diffusion tensor imaging parameters. This should be taken into account when a longitudinal study is designed. PMID- 20725933 TI - Simultaneous fMRI and local field potential measurements during epileptic seizures in medetomidine-sedated rats using raser pulse sequence. AB - Simultaneous electrophysiological and functional magnetic resonance imaging measurements of animal models of epilepsy are methodologically challenging, but essential to better understand abnormal brain activity and hemodynamics during seizures. In this study, functional magnetic resonance imaging of medetomidine sedated rats was performed using novel rapid acquisition by sequential excitation and refocusing (RASER) fast imaging pulse sequence and simultaneous local field potential measurements during kainic acid-induced seizures. The image distortion caused by the hippocampal-measuring electrode was clearly seen in echo planar imaging images, whereas no artifact was seen in RASER images. Robust blood oxygenation level-dependent responses were observed in the hippocampus during kainic acid-induced seizures. The recurrent epileptic seizures were detected in the local field potential signal after kainic acid injection. The presented combination of deep electrode local field potential measurements and functional magnetic resonance imaging under medetomidine anesthesia, which does not significantly suppress kainic acid-induced seizures, provides a unique tool for studying abnormal brain activity in rats. PMID- 20725934 TI - Tailoring the flow sensitivity of fast spin-echo sequences for noncontrast peripheral MR angiography. AB - There has recently been renewed interest in noncontrast techniques for peripheral MR angiography following the discovery of an association between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency. The "fresh blood imaging" technique proposed by Miyazaki et al. involves the subtraction of two three-dimensional fast spin-echo image sets, one acquired in systole, when the arteries appear dark due to flow-related dephasing, and the other obtained in diastole, when the arteries are brighter. Our goal was to investigate how parameters of the fast spin-echo sequence influence its flow sensitivity, and how that in turn impacts the depiction of large and small arteries. Results from phantom experiments and human studies in the calf suggest that the flow sensitivity is governed largely by the flip angle of the radiofrequency refocusing pulses. The area of the spoiler gradients has a lesser effect, and at low flip angles the echo time plays a role. These parameters can be optimized to obtain good depiction of the calf arteries in healthy subjects. It remains to be seen whether they provide sufficient control over flow sensitivity to achieve diagnostic-quality images in other vascular beds and in the presence of pathology. PMID- 20725935 TI - Bioaccumulation and biochemical markers in feral crab (Carcinus maenas) exposed to moderate environmental contamination--the impact of non-contamination-related variables. AB - Moderate contamination is a challenging scenario for ecotoxicologists because of the occurrence of subtle biomarker responses and the increased relevance of non contamination related variables. This investigative biomonitoring study was performed in a moderately contaminated coastal system (Obidos lagoon, Portugal) to examine winter-summer variations on biochemical responses and accumulated metals in Carcinus maenas, searching for associations with environmental and biological factors. Males and females were collected in three sites: Barrosa (BB) and Bom-Sucesso (BS) in upper lagoon, and the middle lagoon (ML), closer to the lagoon inlet. Water and sediment were monitored for metals (Cu, Mn, Ni, Cr, Cd). Catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), total glutathione content (GSH(t) ), lipid peroxidation (LPO), and ethoxyresorufin-O-deethylase (EROD), as well as Cu, Mn, Ni, Cr and Cd were measured in the crabs' hepatopancreas. Inter-site differences, though infrequent, pointed to the presence of crab stressors at BB. This was particularly obvious in summer when higher GST as well as lower GSH(t) and EROD were found in females, and accompanied by higher Ni accumulation. Seasonal differences of biochemical responses superimposed spatial variations in line with the contrasting winter summer conditions regarding water quality and, to a lesser extent, with metal bioaccumulation. CAT, GSH(t) , and LPO were higher in summer, whereas enhancements of GPx and GST were recorded in winter. Winter increases were in agreement with higher availability of metals in water and enhancement of accumulated levels, particularly in females as emphasized by a bioaccumulation index. On the other hand, increases in summer were mainly driven by non contamination related factors. Males and females exhibited different patterns of metal accumulation and biochemical responses, with females being more responsive, as confirmed by a general stress index (IBR). Results recommend gender separation in biomonitoring programs using crabs. The integration of biochemical responses into IBR substantiated data interpretation. This is particularly relevant under moderate contamination allowing for better site-distinction rather than biochemical responses considered individually. PMID- 20725936 TI - Physiological responses to temperature and haeme synthesis modifiers in earthworm Lumbricus terrestris (Annelida: Oligochaeta). AB - Earthworms (Lumbricus terrestris) acclimated at 2 degrees and 6 degrees C above their average habitat temperature (10 degrees C) had respectively 15 and 40% higher rate of respiration than those at habitat temperature. At 14 degrees C, the rate of respiration and blood hemoglobin (Hb) concentration both increased by ~60 and 50%, respectively, of the values at habitat temperature. At higher temperatures the rate of respiration and Hb synthesis started decreasing. At 20 23 degrees C, the respiration and Hb concentration decreased respectively by about 85% and 35% of that at 14 degrees C. Decrease in blood Hb concentration at higher temperatures appeared to be due to the lowering of the activity of blood enzyme delta-aminolaevulinic acid dehydratase (ALAD). Exposure of 20-23 degrees C acclimated pale worms to ALAD inhibitor (lead), lowered the already compromised rate of respiration and blood Hb concentration; while exposure to hexachlorobenzene (HCB, inducer of haeme synthesis) and ferric chloride (enhancer of haeme synthesis) did not overcome the inhibitory effect of high temperature on Hb synthesis. At 20-23 degrees C the affinity of Hb for oxygen also decreased as indicated by the lowering of oxy-Hb (HbO) concentration in blood. The lowering of concentration of blood Hb and its affinity for oxygen may lower the amount of oxygen delivered to cells, which may limit the level of aerobic metabolism (glycolysis, oxidative phosphorylation), as indicated by an increase in blood glucose concentration and a decrease in in vitro activities of mitochondrial electron transport system components (ETS) namely NADH-cytochrome c reductase, succinate dehydrogenase, cytochrome c oxidase, and ATPases. Although the oxygen concentration in air, at sea level, does not decrease significantly from 6 degrees to 20-23 degrees C (lack of hypoxia), lowering of both Hb and HbO concentrations by high temperature may cause significant hypoxemia. The latter may lead to inhibition of the activity of muscle mitochondrial respiratory enzymes (ETS). The resulting inhibition of ATP synthesis and hydrolysis may cause deficit of energy needed for peristalsis/fictive locomotion of body and heart muscles (as indicated by a decrease in heart rate) to facilitate diffusion and transport of gases. The upper critical temperature (20-23 degrees C) also slows down the heart rate and causes hyperosmotic stress (hypovolemia). Thus, a rise in soil temperature above 18 degrees C, which inhibits Hb synthesis, Hb oxygenation, and mitochondrial ETS activity, and slows down the heart rate and causes hyperosmotic stress, can make this and higher temperatures lethal to populations of these earthworms, especially in the presence of metabolic inhibitors and respiratory poisons. PMID- 20725937 TI - Chronic contamination assessment integrating biomarkers' responses in transplanted mussels--a seasonal monitoring. AB - This study aimed to provide the first biomonitoring integrating biomarkers and bioaccumulation data in Sao Paulo coast, Brazil and, for this purpose, a battery of biomarkers of defense mechanisms was analyzed and linked to contaminants' body burden in a weigh-of-evidence approach. The brown mussel Perna perna was selected to be transplanted from a farming area (Caraguatatuba) to four possibly polluted sites: Engenho D'Agua, DTCS (Dutos e Terminais do Centro-Oeste de Sao Paulo) oil terminal (Sao Sebastiao zone), Palmas Island, and Itaipu (It; Santos Bay zone). After 3 months of exposure in each season, mussels were recollected and the cytochrome P4501A (CYP1A)- and CYP3A-like activities, glutathione-S-transferase and antioxidants enzymes (catalase, glutathione peroxidase, and glutathione reductase) were analyzed in gills. The concentrations of polycyclic aromatic hydrocarbons, linear alkylbenzenes, and nonessential metals (Cr, Cd, Pb, and Hg) in whole tissue were also analyzed and data were linked to biomarkers' responses by multivariate analysis (principal component analysis-factor analysis). A representation of estimated factor scores was performed to confirm the factor descriptions and to characterize the studied stations. Biomarkers exhibited most significant alterations all year long in mussels transplanted to It, located at Santos Bay zone, where bioaccumulation of organic and inorganic compounds was detected. This integrated approach using transplanted mussels showed satisfactory results, pointing out differences between sites, seasons, and critical areas, which could be related to land-based contaminants' sources. The influence of natural factors and other contaminants (e.g., pharmaceuticals) on biomarkers' responses are also discussed. PMID- 20725938 TI - Cytotoxic and genotoxic effects of cylindrospermopsin in mice treated by gavage or intraperitoneal injection. AB - Cylindrospermopsin (CYN), a cyanobacterial hepatotoxin mainly produced by Cylindrospermopsis raciborskii, has been involved in human intoxications and livestock deaths. The widespread occurrence of CYN in the water supplies lead us to investigate its genotoxicity to assess potential chronic effects. This study reports evaluation of CYN-induced in vivo DNA damage in mice using alkaline comet assay (ACA) and micronucleus assay (MNA) concomittantly. ACA measures DNA breakage from single and double strand breaks as well as alkali labile sites. Conversely, MNA detects chromosome damage events such as chromosomal breakage and numeric alterations. Male Swiss mice were treated with CYN concentrations of 50, 100, and 200 MUg/kg by a single intraperitoneal (ip) injection or with 1, 2, and 4 mg/kg by gavage. Methyl methane sulfonate (MMS) was used as positive control at 80 mg/kg. Twenty-four hours after treatment, samples of liver, blood, bone marrow, kidney, intestine, and colon were taken to perform ACA, the bone marrow and the colon were also used for MNA. Parameters used to quantify DNA damage were % Tail DNA for ACA and both micronucleated immature erythrocytes and epithelial colon cells for MNA. DNA breaks and chromosome damage were significantly increased by MMS in all the organs evaluated. Significant DNA damage was detected within the colon by ACA after ip injection of 100 and 200 MUg/kg CYN (P < 0.01). DNA damage was also detected in colon samples after 4 mg/kg oral administration of CYN and in bone marrow after 1 and 2 mg/kg of orally administered CYN. Histological examination showed foci of cell death within the liver and the kidney from mice that received the two highest doses of CYN by either route of administration. PMID- 20725939 TI - Effects of lead on Na+, K+-ATPase and hemolymph ion concentrations in the freshwater mussel Elliptio complanata. AB - Freshwater mussels are an imperiled fauna exposed to a variety of environmental toxicants such as lead (Pb) and studies are urgently needed to assess their health and condition to guide conservation efforts. A 28-day laboratory toxicity test with Pb and adult Eastern elliptio mussels (Elliptio complanata) was conducted to determine uptake kinetics and to assess the toxicological effects of Pb exposure. Test mussels were collected from a relatively uncontaminated reference site and exposed to a water-only control and five concentrations of Pb (as lead nitrate) ranging from 1 to 245 MUg/L in a static renewal test with a water hardness of 42 mg/L. Endpoints included tissue Pb concentrations, hemolymph Pb and ion (Na+, K+, Cl-, Ca2+) concentrations, and Na+, K+-ATPase enzyme activity in gill tissue. Mussels accumulated Pb rapidly, with tissue concentrations increasing at an exposure-dependent rate for the first 2 weeks, but with no significant increase from 2 to 4 weeks. Mussel tissue Pb concentrations ranged from 0.34 to 898 MUg/g dry weight, were strongly related to Pb in test water at every time interval (7, 14, 21, and 28 days), and did not significantly increase after day 14. Hemolymph Pb concentration was variable, dependent on exposure concentration, and showed no appreciable change with time beyond day 7, except for mussels in the greatest exposure concentration (245 MUg/L), which showed a significant reduction in Pb by 28 days, suggesting a threshold for Pb binding or elimination in hemolymph at concentrations near 1000 MUg/g. The Na+, K+-ATPase activity in the gill tissue of mussels was significantly reduced by Pb on day 28 and was highly correlated with tissue Pb concentration (R2 = 0.92; P = 0.013). The Na+, K+-ATPase activity was correlated with reduced hemolymph Na+ concentration at the greatest Pb exposure when enzyme activity was at 30% of controls. Hemolymph Ca2+ concentration increased significantly in mussels from the greatest Pb exposure and may be due to remobilization from the shell in an attempt to buffer the hemolymph against Pb uptake and toxicity. We conclude that Na+, K+-ATPase activity in mussels was adversely affected by Pb exposure, however, because the effects on activity were variable at the lower test concentrations, additional research is warranted over this range of exposures. PMID- 20725940 TI - Assessment of genotoxic effects induced by selected pesticides on RTG-2 fish cells by means of a modified fast micromethod assay. AB - The cytotoxic and genotoxic effects induced by alachlor and dichlorvos, two pesticides broadly used, were studied on RTG-2 fish cell line. As measure of cytotoxicity, neutral red assay was used to determine the cellular viability. Toxicity ranking based on IC(50) values found that alachlor was more cytotoxic than dichlorvos. DNA damage has been evaluated on RTG-2 cultures by means of an in vitro assay based on the ability of PicoGreen fluorochrome to interact preferentially with double-stranded DNA (dsDNA), and the results indicated that alachlor induced DNA strand breaks at concentrations above 1.52 MUg/mL, equivalent to 1/50-EC(50(48)) , whereas exposures to dichlorvos induced DNA damage only at the maximal concentrations tested 25 MUg/mL (1/10-EC(50(48)) ). These results confirm the suitability of this method for the screening of genotoxic effects of this type of aquatic pollutants, and we suggest their use in hazard assessment for environmental risk procedures. PMID- 20725941 TI - Effects of streptomycin on growth of algae Chlorella vulgaris and Microcystis aeruginosa. AB - Streptomycin is a common contaminant in a variety of industrial and agricultural wastewaters. The available information on the potential toxicity of streptomycin of fresh algae implicated in the treatment of biological wastewater is extremely limited. The objective of this study was to evaluate the effects of streptomycin on physiological indices and photosynthesis-related gene transcription. The results of short-term batch bioassays indicated that streptomycin was more sensitive to cyanobacteria than to green algae. The EC50 of streptomycin in Microcystis aeruginosa and Chlorella vulgaris were 0.28 and 20.08 mg L(-1) , respectively. These selected streptomycin concentrations inhibited algal cell growth and decreased chlorophyll or phycocyanobilin content. Streptomycin also destroyed the overall membrane system, which was speculated from malondialdehyde (MDA) content and electrolyte leakage increasing after streptomycin exposure. Two algae were induced to increase their antioxidant enzyme activities to withstand streptomycin. However, the balance between oxidant substance and antioxidant enzyme was broken, because reactive oxygen species (ROS) content simultaneously increased. Streptomycin inhibited photosynthesis-related gene transcription in C. vulgaris and M. aeruginosa. Transcript levels of psaB, psbA, and rbcL in C. vulgaris decreased to only 14.5%, 32.2%, and 9.3% of the control, respectively. Similarly, the transcript levels of psaB, psbD, and rbcL in M. aeruginosa decreased markedly in the present of streptomycin. The transcription of these genes was 12.4%, 26.1%, and 28.4% of the control after 0.1 mg L(-1) streptomycin exposure, respectively. Our results demonstrate that streptomycin is toxic to fresh algae, affects photosynthesis-related gene transcription, and blocks electron transport and ROS overproduction. PMID- 20725943 TI - Long-term complications, extraintestinal manifestations, and mortality in adult Crohn's disease in population-based cohorts. AB - BACKGROUND: Crohn's disease (CD) is a chronic, progressive, destructive disease. Numerous intestinal and extraintestinal complications and manifestations can occur during its clinical course. This literature review summarizes our current knowledge of the long-term complications, extraintestinal complications, and mortality in CD in adults as reported in population-based studies that include long-term follow-up results. METHODS: A literature search of English and non English language publications listed in the electronic databases of Medline (source PubMed, 1935 to July, 2009). RESULTS: The relative risk of incident fractures is increased in CD patients by ~30%-40%. These patients have also have a 3-fold increased risk of deep venous thrombosis and pulmonary embolism. A variety of extraintestinal manifestations (primary sclerosing cholangitis, ankylosing spondylitis, iritis/uveitis, pyoderma gangrenosum, erythema nodosum) and diseases (asthma, bronchitis, pericarditis, psoriasis, rheumatoid arthritis, and multiple sclerosis) are associated with CD. The risks of colorectal and small bowel cancers relative to the general population are 1.4-1.9 and 21.1-27.1, respectively. A slightly increased risk of lymphoma, irrespective of medication use, has been reported in a recent meta-analysis of population-based studies. Overall mortality is slightly increased in CD, with a standardized mortality ratio of 1.4. CONCLUSIONS: CD is frequently associated with disease complications and extraintestinal conditions. Whether the impact of changing treatment paradigms with increased use of immunosuppressives and biologic agents can reduce disease complications and associated conditions is unknown. PMID- 20725942 TI - Pathological, immunological and biochemical markers of subchronic arsenic toxicity in rats. AB - Subchronic exposure to arsenic in rats was investigated to identify sensitive indicators of subclinical toxicity in rats. Immunological, pathological, and biochemical bioindicators were examined in rats exposed to arsenic in their drinking water. Juvenile male Wistar rats were allocated to four treatment groups receiving 0, 0.4, 4, and 40 ppm of arsenite in drinking water for 18 wks. Besides daily monitoring for clinical signs of adverse health effects, clinical biochemistry, B-cell-mediated and innate immune responses, plus gross, and histopathology were examined. In vitro tests of oxidative damage to basic cellular constituents, lipids, proteins, and nucleic acids, were measured using thiobarbituric acid reacting substances (TBARS) assays, protein carbonyl formation, and 8-hydroxydeoxyguanosine (8-OHdG), respectively. Clinical changes in the rats were limited to decreased feed and water intake in the high- (40 ppm) dose group (P < 0.05), however, growth rate was not affected. Serum biochemical changes occurred in blood urea nitrogen, K(+) , Cl(-) , and alanine aminotransferase (ALT) from arsenic exposure. Immunotoxicity was evident through a dose-dependent suppression of the secondary antibody-mediated response to a T cell-dependent antigen, keyhole limpet hemocyanin (KLH). Histopathology of the liver revealed marked fatty infiltration and vacuolization particularly evident in periacinar hepatocytes. This pattern of toxicopathology in the high-exposure group may be related to the significantly higher (P < 0.05) oxidative stress, demonstrated through lipid peroxidation (TBARS assay) in the rats exposed to 40 ppm arsenite. The present study revealed that young, growing rats exposed to arsenic for 18 wks tolerated exposures up to 4 ppm. At higher doses, there was evidence of hepatotoxicity, humoral immunity was compromised, and an adverse effect on hepatic organelle and cell membranes was evident through a dose dependent increased in oxidative stress. PMID- 20725944 TI - IBD Around the world: comparing the epidemiology, diagnosis, and treatment: proceedings of the World Digestive Health Day 2010--Inflammatory Bowel Disease Task Force meeting. AB - Every May 29th the World Gastroenterology Organization (WGO) celebrates World Digestive Health Day (WDHD) and initiates a worldwide public health campaign through its 110 national societies and 50,000 members. Each year focuses on a particular digestive disorder in order to increase general public awareness of prevention and therapy. 2010 is dedicated to inflammatory bowel disease (IBD). Upon this occasion a WGO IBD task force was compiled from leading international specialists and researchers. The task force also included members of the American Gastroenterological Association (AGA), International Organization for the Study of Inflammatory Diseases (IOIBD) and the European Crohn's and Colitis Organization (ECCO) of the United European Gastroenterology Federation (UEGF). The goal of the task force was to bring together IBD specialists from around the world to discuss the epidemiology, diagnosis, and management of IBD within different regions. This is a summary of the WGO task force meeting at the American Gastroenterological Association's (AGA) Digestive Disease Week, held in New Orleans, Louisiana, USA, May, 2010. The expert panel identified the most pressing issues in IBD worldwide: reliable epidemiological data, global collaboration in clinical and basic research, the approach to distinguishing intestinal tuberculosis from Crohn's disease, access to specialist care and access to the latest diagnostic and therapeutic strategies. PMID- 20725945 TI - Sonographically measured hyoid bone displacement during swallow in preschool children: a preliminary study. AB - PURPOSE: This study explored normative parameters regarding maximum displacement of hyoid bone movement during spontaneous swallows using ultrasound (US) in a sample of healthy preschool children. We hypothesized that consistency and bolus size would influence hyoid movement, but gender would not be a factor. METHODS: Parental questionnaire responses and sensorimotor examinations were utilized to determine subject eligibility. Subjects were presented randomized bolus volumes of thin liquids/puree via a spoon while the US probe was placed submentally in the midsagittal plane. Maximum hyoid bone displacement was determined following a frame-by-frame analysis of the US recording during spontaneous swallowing of discrete bolus sizes. RESULTS: Twenty-nine subjects produced 346 swallows that were subsequently analyzed. Significant findings (p < 0.05) included a gender effect with the smallest bolus of liquids presented. Bootstrap estimates based on our sample revealed that 99% of preschool children would present with hyoid bone displacement within 0.3 cm of our sample. CONCLUSIONS: Based on our early experience, we were able to observe and measure changes in hyoid bone position during swallowing in preschoolers, which may be gender related. More studies are needed to corroborate our findings. In addition, comparisons of maximum hyoid displacement are warranted in subjects that present with feeding delays. PMID- 20725946 TI - Activity-based high-throughput determination of PTPs substrate specificity using a phosphopeptide microarray. AB - Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that play key roles in cell signaling. Malfunctions of PTP activity have been linked to major human diseases including cancer. One key aspect in PTP biology is the elucidation of roles of PTPs, as well as substrates they act on, in different cellular events. Herein, a library of 144 putative peptide substrates against different PTPs was synthesized and immobilized onto a glass slide to generate the corresponding phosphopeptide microarray. Subsequent screening of the microarray against various PTPs provided a distinctive and comparative substrate fingerprint against each PTP. Several new substrates were identified, which might aid in the future design of potent and selective PTPs inhibitors. The signal-decrease microarray assay used in our studies provided a facile and efficient way for high throughput determination of kinetic constants for peptide/PTP interactions en masse. Finally, our microarray results were independently verified by traditional microplate-based enzymatic assays. PMID- 20725947 TI - Symptom cluster and physical activity in relapsing-remitting multiple sclerosis. AB - We compared the explanatory power of two symptom clusters that consisted of either three or five symptoms as correlates of physical activity in individuals with relapsing-remitting multiple sclerosis (RRMS; N = 218). The data were primarily analyzed using covariance modeling in Mplus 3.0. A symptom cluster of fatigue, depression, and pain had a moderate, negative relationship with physical activity, and this relationship was comparable in magnitude with a symptom cluster of fatigue, depression, pain, perceived cognitive dysfunction, and poor sleep quality. The relationships were attenuated after controlling for exercise history and neurological impairment. Such findings further support the consideration of a narrowly defined cluster of three symptoms as an independent correlate of physical activity in persons with RRMS. PMID- 20725948 TI - Conformational preference and cis-trans isomerization of 4-methylproline residues. AB - Conformational preferences and prolyl cis-trans isomerizations of the (2S,4S)-4 methylproline (4S-MePro) and (2S,4R)-4-methylproline (4R-MePro) residues are explored at the M06-2X/cc-pVTZ//M06-2X/6-31+G(d) level of theory in the gas phase and in water, where solvation free energies were calculated using the implicit SMD model. In the gas phase, the down-puckered gamma-turn structure with the trans prolyl peptide bond is most preferred for both Ac-4S-MePro-NHMe and Ac-4R MePro-NHMe, in which the C(7) hydrogen bond between two terminal groups seems to play a role, as found for Ac-Pro-NHMe. Because of the C(7) hydrogen bonds weakened by the favorable direct interactions between the backbone C==O and H--N groups and water molecules, the 4S-MePro residue has a strong preference of the up-puckered polyproline II (PP(II)) structure over the down-puckered PP(II) structure in water, whereas the latter somewhat prevails over the former for the 4R-MePro residue. However, these two structures are nearly equally populated for Ac-Pro-NHMe. The calculated populations for the backbone structures of Ac-4S MePro-NHMe and Ac-4R-MePro-NHMe in water are reasonably consistent with CD and NMR experiments. In particular, our calculated results on the puckering preference of the 4S-MePro and 4R-MePro residues with the PP(II) structures are in accord with the observed results for the stability of the (X-Y-Gly)(7) triple helix with X = 4R-MePro or Pro and Y = 4S-MePro or Pro. The calculated rotational barriers indicate that the cis-trans isomerization may in common proceed through the anticlockwise rotation for Ac-4S-MePro-NHMe, Ac-4R-MePro-NHMe, and Ac-Pro NHMe in water. The lowest rotational barriers become higher by 0.24-1.43 kcal/mol for Ac-4S-MePro-NHMe and Ac-4R-MePro-NHMe than those for Ac-Pro-NHMe in water. PMID- 20725949 TI - Importance of disrupted intestinal barrier in inflammatory bowel diseases. AB - The current paradigm of inflammatory bowel diseases (IBD), both Crohn's disease (CD) and ulcerative colitis (UC), involves the interaction between environmental factors in the intestinal lumen and inappropriate host immune responses in genetically predisposed individuals. The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. The main cytokine that seems to drive these changes is tumor necrosis factor alpha in CD, whereas interleukin (IL)-13 may be more important in UC. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal "leakiness." Here we give an overview of the key players of the intestinal mucosal barrier and review the current literature from studies in humans and human systems on mechanisms underlying mucosal barrier dysfunction in IBD. PMID- 20725951 TI - Interruption of a 3(10)-helix by a single Gly residue in a poly-Aib motif: a crystallographic study. AB - The structural influence of a single Gly residue inserted into an Aib(16) homooligomer was studied in the solid state by X-ray crystallography. The peptides N(3)Aib(8)GlyAib(8)PheNH(2) (1) and CbzPheAib(8)GlyAib(8) (2) were found to adopt well-defined helical structures, which are broadly 3(10) helical. Indeed, 2 is the longest crystallographic 3(10) helix thus far reported. However, in the region of the central Gly residue, a loosening of the 3(10) structure is observed in both peptides, with 1 clearly showing local adoption of an alpha helical structure in the region of residues 7-9. PMID- 20725950 TI - Silk hydrogel for cartilage tissue engineering. AB - Cartilage tissue engineering based on cultivation of immature chondrocytes in agarose hydrogel can yield tissue constructs with biomechanical properties comparable to native cartilage. However, agarose is immunogenic and nondegradable, and our capability to modify the structure, composition, and mechanical properties of this material is rather limited. In contrast, silk hydrogel is biocompatible and biodegradable, and it can be produced using a water based method without organic solvents that enables precise control of structural and mechanical properties in a range of interest for cartilage tissue engineering. We observed that one particular preparation of silk hydrogel yielded cartilaginous constructs with biochemical content and mechanical properties matching constructs based on agarose. This finding and the possibility to vary the properties of silk hydrogel motivated this study of the factors underlying the suitability of hydrogels for cartilage tissue engineering. We present data resulting from a systematic variation of silk hydrogel properties, silk extraction method, gel concentration, and gel structure. Data suggest that silk hydrogel can be used as a tool for studies of the hydrogel-related factors and mechanisms involved in cartilage formation, as well as a tailorable and fully degradable scaffold for cartilage tissue engineering. PMID- 20725952 TI - Synthesis and characterization of injectable composites of poly[D,L-lactide-co (epsilon-caprolactone)] reinforced with beta-TCP and CaCO3 for intervertebral disk augmentation. AB - Degeneration of the intervertebral disk constitutes one of the major causes of low back pain in adults aged 20-50 years old. In this study, injectable, in situ setting, degradable composites aimed for intervertebral disk replacement were prepared. beta-TCP and calcium carbonate particles were mixed into acrylic terminated oligo[D,L-lactide-co-(epsilon-caprolactone)], which were crosslinked at room temperature. The structure of the oligomers was confirmed by 1H-NMR spectroscopy. The composites were examined via SEM, and the mechanical properties of the crosslinked networks were determined. The porous beta-TCP particles showed good mechanical anchorage to the matrix due to polymer penetration into the pores. In vitro degradation tests showed that the composites containing beta-TCP slowly degraded, whereas the composites containing CaCO3 exhibited apatite formation capacity. It was concluded that the surface area, morphology, and solubility of the fillers might be used to control the degradation properties. The incorporation of fillers also increased both the elastic modulus and the maximum compression strength of the composites, properties that were similar to those of the physiological disk. These materials have potential for long-term intervertebral disk replacement and regenerative scaffolds because of their low degradation rates, bioactivity, and mechanical properties. PMID- 20725954 TI - Biofilm formation and composition on different implant materials in vivo. AB - Biofilm formation was evaluated on the following titanium and zirconia implants in vivo: machined titanium (Ti-m), modified titanium (TiUnite), modified zirconia (ZiUnite), machined alumina-toughened zirconia (ATZ-m), sandblasted alumina toughened zirconia (ATZ-s), and machined zirconia (TZP-A-m). Bovine enamel slabs were used as controls. Surface morphologies were examined by atomic force (AFM) and scanning electron microscopy (SEM). The surface wettability was also determined. Twelve healthy volunteers wore a splint system with the tested materials. After 3 and 5 days the materials were examined by fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM). The levels of Streptococcus spp., Veillonella spp., Fusobacteriaum nucleatum, and Actinomyces naeslundii were quantitatively determined. The biofilm thickness was found to be between 19.78 and 36.73 MUm after 3 days and between 26.11 and 32.43 MUm after 5 days. With the exception of Ti-m the biofilm thickness after 3 days was correlated with surface roughness. In addition to Streptococcus spp. as the main component of the biofilm (11.23-25.30%), F. nucleatum, A. naeslundii, and Veillonella spp. were also detected. No significant differences in biofilm composition on the implant surfaces could be observed. In total, the influence of roughness and material on biofilm formation was compensated by biofilm maturation. PMID- 20725953 TI - In-vitro dissolution of magnesium-calcium binary alloys: clarifying the unique role of calcium additions in bioresorbable magnesium implant alloys. AB - A systematic investigation of a series of magnesium-calcium binary alloys is presented to reveal the influence of increasing calcium (Ca) additions on the in vitro degradation of magnesium (Mg). Because of its prevalence in structural tissues, Ca is among the most biologically viable additions to orthopedic intended Mg-based biomaterials. Hence, a fundamental electrochemical study of Ca additions to Mg biomaterials is essential to its continued role as an alloying addition. In this work, in vitro degradation conditions closer to the physiological environment were implemented through the addition of proteins to simulated body fluid and maintenance of a constant pH, with tests conducted using Hanks solution, minimum essential medium (MEM), and MEM containing fetal bovine serum. Alloying with Ca leads to the formation of Mg2Ca intermetallic particles that result in systematically enhanced dissolution kinetics. This observation is rationalized via microelectrochemical tests upon the Mg2Ca intermetallic in isolation, which reveals rapid anodic kinetics. Hence, the extent of Mg-Ca alloy dissolution can be modified depending on the amount of Mg2Ca present, suggesting that Ca can be deployed as a functional addition capable of not only enhancing biodissolution of the alloy, but being able to do this in a systematic, controllable manner depending on its volume fraction. In addition, up to a 3-fold reduction in the corrosion rate is observed with corrosion testing in an albumin containing medium when compared to Hanks solution, the results highlighting that the use of a physiologically "correct" medium is essential for the in vitro screening of Mg-based alloys suitable for orthopaedic applications. PMID- 20725955 TI - Hyaluronic acid hydrogel modified with nogo-66 receptor antibody and poly-L lysine to promote axon regrowth after spinal cord injury. AB - The biomaterials used for central nervous system injury require not only interacting with specific cell adhesion but also specific growth factor receptors to promote nerve regeneration. In this study, hyaluronic acid (HA)-based hydrogels modified with poly-L-lysine (PLL) and nogo-66 receptor antibody (antiNgR) (HA-PLL/antiNgR) were administered to rats after lateral hemisection of the spinal cord. Anti-neurofilament positive axons were found to extend into the HA-PLL/antiNgR hydrogel at 8 weeks after implantation, which shows significant difference compared with HA-PLL or blank control group. Electron micrographs of implanted hydrogels showed that there were more cells and normal axons with myelin in the HA-PLL/antiNgR implant than that of HA-PLL hydrogel. The antiNgR grafted on HA hydrogels could be detected for 8 weeks after transplantation in vivo. All of these properties may facilitate HA-PLL/antiNgR hydrogels to become a promising scaffold for repairing spinal cord injury. Nevertheless, both two kinds of modified hydrogels (HA-PLL/antiNgR and HA-PLL) showed remarkable advantages in supporting angiogenesis, and simultaneously inhibiting the formation of glial scar. PMID- 20725956 TI - Use of textile dyeing technology to create an infection-resistant functionalized polyester biomaterial. AB - Infection is a major complication when utilizing implantable devices. The purpose of this study was to create a functionalized polyethylene terephthalate (polyester) biomaterial with sustained antimicrobial properties using textile dyeing technology. Polyester was hydrolyzed via exposure to sodium hydroxide (NaOH) to provide two functional sites within the polymeric backbone. A modified textile dyeing technique known as thermofixation or pad-heating (pad-heat) in conjunction with autoclaving was employed to directly incorporate the fluoroquinolone antibiotic Ciprofloxacin (Cipro) into polyester fibers. Woven polyester segments were placed into various concentrations of boiling NaOH solutions to create carboxylic acid and hydroxyl groups (HYD). The segments were then sprayed (padded) with a 5 mg mL(-1) Cipro solution and dried overnight, followed by exposure to intense heat and autoclaving. Untreated HYD, Cipro dipped, and pad-heat-treated HYD segments were then washed under stringent conditions. The antimicrobial activity of the each material was determined via zone of inhibition. Untreated HYD controls had no antimicrobial activity at any of the time periods examined. Cipro-dipped HYD segments had no antimicrobial activity after 1 h. In contrast, antimicrobial activity for autoclaved, pad-heat treated HYD segments persisted for 80 days (length of study). Autoclave usage prior to plating affected antimicrobial activity substantially. Additionally, varying hydrolysis concentrations did not significantly affect overall Cipro release. Thus, Cipro application to HYD polyester via thermofixation resulted in controlled, sustained antibiotic release over an extended period of time. The long-term infection resistance provided by this technique may address major problems of infection from which implantable devices suffer. PMID- 20725957 TI - Impactability and time-dependent mechanical properties of porous titanium particles for application in impaction grafting. AB - AIMS: Impaction grafting with bone particles is a successful technique to restore bone stock loss during hip revision surgery. Allograft shortage is expected within the near future. This study investigates the feasibility of porous titanium particles (TiP) to replace bone particles (BoP) and to compare mechanical properties of TiP and a commercially available porous ceramic bone graft extender (CeP). Impactability and time-dependent mechanical properties (stability and stiffness during physiologic loading (0.1-2.5 MPa)) were assessed by standardized impaction and a confined compression test. Loaded samples were used for particle release analysis. FINDINGS: TiP were more impactable than BoP and created a stable, highly entangled macroporous construct. CeP were crushed during impaction, resulting in non-cohesive specimens of small ceramic particles. TiP showed very little deformation at the end of physiological loading. Impacted TiP were stiffer than BoP but more elastic than CeP. TiP generated a low volume of microparticles (0.2% of original TiP weight) with a bimodal size distribution (diameter range, 7-2000 microm). CONCLUSION: TiP are impactable and create a stable, elastic and highly entangled, macroporous layer. Further in-vitro testing and biological studies are warranted to verify whether the promising results are maintained with THA reconstructions. PMID- 20725958 TI - Bone properties surrounding hydroxyapatite-coated custom osseous integrated dental implants. AB - Calcium phosphate (hydroxyapatite or HA) coatings have been applied to Custom Osseous Integrated Implants (COIIs) to improve the quality of the bone-implant integration, yet little is known concerning the biomechanical properties of bone surrounding the HA-coated implants in humans over the long term. The purpose of this study was to characterize the mechanical and histomorphometric properties of the bone along the implant interface. Specimens were prepared from three similar mandibular implants that were functional in three female patients for about 11 years. Histomorphometric analyses showed bone-implant contact averaging 75% for all specimens. Area coverage of residual HA-coating ranged from 52 to 70%. When compared with previous studies, these results show a relatively high percentage of residual HA after a decade in vivo. Nanoindentation showed similar average values of hardness and modulus (p = 0.53 and p = 0.56, respectively) comparing bone adjacent to residual HA-coating and regions where the coating was absent. The elastic modulus was significantly lower for bone near the bone-implant interface (<200 MUm) as compared with bone distant (>1000 MUm) from the interface (p = 0.05), thereby reflecting different properties of the bone near these interfaces. Backscattered electron imaging showed darker gray levels which indicated decreased mineral content in bone adjacent to the implant, consistent with the nanoindentation results. PMID- 20725959 TI - Guided bone regeneration: dynamic procedures versus static shielding in an animal model. AB - Due to its osteoinductive potential, the periosteum plays a crucial role in the process of neoosteogenesis. Therefore, periosteal elevation can lead to new bone formation in an artificially created space. In this study, we compared dynamic periosteal elevation with static shielding in an animal experiment. Different elevation/shielding heights of 5, 10, and 15 mm were tested with regard to various consolidation periods. Histological analysis, histomorphometry, and microradiography were used to measure the quantity and quality of the newly formed bone. No significant differences regarding bone quantity or quality were found between the two techniques. The cumulative results for the bone regeneration in the space created by distraction/elevation were about 66% in the dynamic and 67% in static procedure. The main advantages of both techniques are minimal invasion and low morbidity. In terms of clinical applications, periosteal elevation could be applied in cranio-maxillofacial surgery, in pre-implant augmentation and in reconstructive surgery. PMID- 20725960 TI - Novel three-dimensional scaffolds of poly(L-lactic acid) microfibers using electrospinning and mechanical expansion: Fabrication and bone regeneration. AB - Poly(L-lactic acid) (PLLA) microfibrous scaffolds with three-dimensional (3D) structures were fabricated using an electrospinning technique with a subsequent mechanical expansion process. To achieve a 3D fibrous structure, the fusion at the contact points of the as-spun PLLA microfibers was avoided using an appropriate binary solvent system of methylene chloride and acetone. The solvent composition was optimized based on the solvent power, volatility, and viscosity (methylene chloride:acetone = 9:1 volume ratio). The final 3D structure of the electrospun scaffolds was obtained after mechanical expansion of the electrospun microfibrous mats. The pore sizes of the scaffolds were controlled by varying the degree of expansion of the nonbonded microfibrous mats, and they were in the range of several microns up to 400 MUm. The 3D scaffolds were examined for their morphological properties and their potential use for the proliferation of osteoblasts. Generally recognized electrospun 2D nanofibrous membranes were also tested in order to compare the cell behaviors using different scaffold geometries. The 3D scaffolds demonstrated a high level of osteoblast proliferation (1.8-fold higher than nanofibrous membranes in a week). The osteoblasts actively penetrated the inside of the 3D scaffold and showed a spatial cell distribution, as confirmed by SEM and H&E staining, while a monolayer formed in the case of the 2D nanofibrous membranes with limited cell infiltration. In vivo results further showed that 3D electrospun microfibrous matrices were a favorable substrate for cell infiltration and bone formation after 2 and 4 weeks, using a rabbit calvarial defect model. In this study, the 3D microfibrous PLLA scaffolds fabricated using electrospinning techniques might be an innovative addition to tissue engineering applications. PMID- 20725961 TI - Tuning cell adhesion on titanium with osteogenic rosette nanotubes. AB - Self-assembled rosette nanotubes (RNTs), obtained from a twin G?C base functionalized with lysine-arginine-serine-arginine [KRSR-(G?C)(2)], were designed and investigated as bioactive coatings on titanium. These results were compared to RNTs derived from Lysine-G?C (K-G?C), Arg-Gly-Asp-G?C (RGD-G?C), and aminobutane-(G?C)(2) [AB-(G?C)(2)]. The results from this study revealed that these materials had excellent cytocompatibility properties as they enhanced osteoblast (bone forming cell) adhesion when coated on titanium. In particular, KRSR and RGD functionalized RNTs coated on titanium promoted the greatest osteoblast densities relative to untreated titanium. Furthermore, KRSR functionalized RNTs selectively improved osteoblast adhesion relative to fibroblast (soft-tissue forming cell) and endothelial (cells that line the vascular) cell adhesion. In contrast with these results, RNTs obtained from an unfunctionalized twin base [AB-(G?C)(2)], RGD-G?C co-assembled with K-G?C and K G?C significantly enhanced endothelial cell attachment, which may find applications in the vascularization of newly formed bone tissue. In summary, these studies suggest that the surface of orthopedic implant materials (such as titanium) could be tailored to promote selective cell adhesion using biologically inspired nanotubular structures functionalized with osteogenic compounds. PMID- 20725962 TI - Effect of specimen geometry on tensile strength of cortical bone. AB - We investigate the effect of specimen geometry on the ultimate tensile strength of cortical bone measured by a tensile test. This article is motivated by the fact that there is no clear consensus in the literature on a suitable specimen shape for cortical bone testing. We consider three commonly used tensile test specimen shapes: strip, dumbbell with sharp junctions, and dumbbell with rounded junctions. We conduct this study computationally, using a finite element method, and experimentally by testing porcine femurs. Our results show that local stress concentration factors in the specimen lead to reduced values in the measured tensile strength. The higher the stress concentrations are, the lower is the measured strength. We find that the strip specimens are not a good choice due to high stress concentrations. For the same reason, dumbbell specimens with sharp junctions between the grip and gage sections should also be avoided. The dumbbell shaped tensile test specimens with an arc transition and a maximized radius of fillet are a better choice because such geometry lowers stress concentrations. PMID- 20725963 TI - The effect of amphiphilic siloxane oligomers on fibroblast and keratinocyte proliferation and apoptosis. AB - The formation of hypertrophic scars (HSF) is a frequent medical outcome of wound repair and often requires further therapy with treatments such as silicone gel sheets (SGS) or apoptosis-inducing agents, including bleomycin. Although widely used, knowledge regarding SGS and their mode of action is limited. Preliminary research has shown that small amounts of amphiphilic silicone present in SGS have the ability to move into skin during treatment. We demonstrate herein that a commercially available analogue of these amphiphilic siloxane species, the rake copolymer GP226, decreases collagen synthesis on exposure to cultures of fibroblasts derived from HSF. By size exclusion chromatography, GP226 was found to be a mixture of siloxane species, containing five fractions of different molecular weight. By studies of collagen production, cell viability and proliferation, it was revealed that a low molecular weight fraction (fraction IV) was the most active, reducing the number of viable cells present after treatment and thereby reducing collagen production as a result. On exposure of fraction IV to human keratinocytes, viability and proliferation were also significantly affected. HSF undergoing apoptosis after application of fraction IV were also detected via real-time microscopy and by using the TUNEL assay. Taken together, these data suggests that these amphiphilic siloxanes could be potential non invasive substitutes to apoptotic-inducing chemical agents that are currently used as scar treatments. PMID- 20725964 TI - Beneficial effects of granulocyte-colony stimulating factor on small-diameter heparin immobilized decellularized vascular graft. AB - Autologous recellularization of decellularized scaffolds is a promising challenge in the field of tissue-engineered vascular graft and could be boosted by endothelial progenitor cells (EPCs). The purpose of this study was to examine the effects of granulocyte-colony stimulating factor (G-CSF) treatment on this process. Heparin immobilized decellularized grafts were fabricated and implanted into 48 rats, of which 25 rats received G-CSF (50 ug/kg/day) for 14 days after operation (G-CSF group) and other 23 received saline serving as control. Five animals of each group were euthanized at 2 weeks for analysis of early graft endothelialization; whereas the rest were investigated by Doppler ultrasound to monitor the graft patency rate up to 6 months. After 14 days of G-CSF administration, the number of CD(34) (+)/CD(133) (+) progenitor cells was increased by 16.2 folds, and endothelial cell-specific immunostaining revealed an enhancement of early endothelialization in G-CSF group. After 6 months of implantation, the G-CSF treated grafts exhibited a significantly smaller hyperplastic neointima area compared with the controls, not only at midportion (0.38 +/- 0.02 vs. 0.47 +/- 0.07 mm(2), p < 0.0001), but also at distal anastomosis (0.42 +/- 0.04 vs. 0.70 +/- 0.13 mm(2), p < 0.0001). Moreover, G-CSF treated grafts had a higher patency rate compared with the control animals (19/20 vs. 12/18, p = 0.005). In conclusion, G-CSF-induced mobilization of circulating EPCs regenerated endothelium and inhibited neointimal hyperplasia of small diameter heparinized decellularized vascular graft. This cytokine therapy may be a feasible strategy for the improvement of patency rate of the novel allogeneic graft. PMID- 20725965 TI - Enhancement of capillary and cellular ingrowth in ePTFE implants with a proangiogenic recombinant construct derived from fibronectin. AB - Based on our discoveries of a unique, synergistic interplay between vascular endothelial growth factor (VEGF) and specific domains of the matrix protein fibronectin (FN), we used recombinant technology to create a new protein construct derived from the cell-binding and VEGF-binding domains of FN. We wished to test the hypothesis that this prototype recombinant FN (rFN) protein would enhance cellular and capillary ingrowth in vivo into expanded polytetrafluoroethylene (ePTFE) implants. ePTFE disks of high porosity (60 micron internodal distance) were embedded with fibrin gel and heparin, with/without mixtures of VEGF and rFN and were implanted subcutaneously in rats. Control implants embedded with fibrin glue and heparin alone showed an average of 8.5% (+/-0.51% standard error mean (SEM)) cellular ingrowth. The addition of either VEGF or rFN caused a modest but significant increase in cellular ingrowth (12.7 +/- 1% and 11.8 +/- 0.98%, respectively, p < 0.004). However, the combination of rFN/VEGF/heparin dramatically increased cellular ingrowth (27.6 +/- 1.62%, p < 0.001), compared with all other treatments. Quantification of capillary ingrowth yielded the same pattern. These results suggest that the incorporation of such biological modulators into cardiovascular implants could offer new strategies for the design of a ready-made small diameter prosthetic graft with enhanced capacity for neovascularization and endothelialization. PMID- 20725966 TI - Pluronic/chitosan hydrogels containing epidermal growth factor with wound adhesive and photo-crosslinkable properties. AB - Wound-adhesive and thermo-responsive hydrogels were prepared in an aim to develop a wound-care device for diabetic ulcers. A mixture of glycidyl methacrylated chitooligosaccharide (COS), di-acrylated Pluronic, and a recombinant human epidermal growth factor (rhEGF) formed a physical hydrogel. Photo-irradiation was subsequently applied to chemically crosslink the hydrogel. Release profiles of encapsulated rhEGF from the hydrogel showed that release rates were dependent on degradation rates of hydrogels. Human primary keratinocytes were cultivated with the released fraction from the hydrogel to measure effects of released rhEGF on in vitro differentiation of keratinocytes. Muco-adhesive property of the hydrogel was investigated in animal skins and significant amounts of quantum dot-labeled rhEGF were retained at wound sites along with chitosan. The hydrogel was administered to dorsal burn wounds in wound healing impaired animals and photo irradiated. COS and rhEGF in the hydrogels significantly enhanced epidermal differentiation during the wound healing process. Thus, the rhEGF-encapsulated hydrogel was expected to be a potential wound care product by increasing local concentration of rhEGF at wound sites with maintaining keratinocytic differentiation. PMID- 20725967 TI - Soft tissue adaptation to modified titanium surfaces. AB - Surface modification of titanium alloy implants to enhance soft tissue adherence is important to minimize soft tissue dehiscence. This study aimed to confirm if a dual acid etched "Osseotite(r)" titanium surface contributes to soft tissue adherence in muscle. It also aims to explore if a radio frequency magnetron sputtered hydroxyapatite (HA)/bioglass (BG) coating can serve this purpose and provides soft tissue adherence in mucosal tissue. The study was carried out in 18 Macaca fascicularis animals, 14 Osseotite(r) coated Ti6Al4V bullets inserted intramuscularly and 12 HA/BG coated Ti6Al4V plates inserted into the submucosa. These were compared with machined Ti6Al4V surfaces as controls. The histological and histomorphometrical results revealed that no significant difference existed in muscle tissue response between machined and Osseotite(r) surfaces. On the other hand, the HA/BG coated submucosal plates showed statistically significant differences with a thinner capsule quantity (p < 0.0001), an increased capsule quality (p < 0.0001) and interface quality score (p < 0.05). In conclusion, the deposited HA/BG coatings facilitated soft tissue (mucosa) adaptation at 1 month of implant installation, whereas the acid etched Osseotite(r) surface did not enhance muscular adaptation. PMID- 20725968 TI - UV-killed Staphylococcus aureus enhances adhesion and differentiation of osteoblasts on bone-associated biomaterials. AB - Titanium alloys (Ti) are the preferred material for orthopedic applications. However, very often, these metallic implants loosen over a long period and mandate revision surgery. For implant success, osteoblasts must adhere to the implant surface and deposit a mineralized extracellular matrix (ECM). Here, we utilized UV-killed Staphylococcus aureus as a novel osteoconductive coating for Ti surfaces. S. aureus expresses surface adhesins capable of binding to bone and biomaterials directly. Furthermore, interaction of S. aureus with osteoblasts activates growth factor-related pathways that potentiate osteogenesis. Although UV-killed S. aureus cells retain their bone-adhesive ability, they do not stimulate significant immune modulator expression. All of the abovementioned properties were utilized for a novel implant coating so as to promote osteoblast recruitment and subsequent cell functions on the bone-implant interface. In this study, osteoblast adhesion, proliferation, and mineralized ECM synthesis were measured on Ti surfaces coated with fibronectin with and without UV-killed bacteria. Osteoblast adhesion was enhanced on Ti alloy surfaces coated with bacteria compared to uncoated surfaces, while cell proliferation was sustained comparably on both surfaces. Osteoblast markers such as collagen, osteocalcin, alkaline phosphatase activity, and mineralized nodule formation were increased on Ti alloy coated with bacteria compared to uncoated surfaces. PMID- 20725969 TI - Synthesis of multilayered alginate microcapsules for the sustained release of fibroblast growth factor-1. AB - Alginate microcapsules coated with a permselective poly-L-ornithine (PLO) membrane have been investigated for the encapsulation and transplantation of islets as a treatment for type 1 diabetes. The therapeutic potential of this approach could be improved through local stimulation of microvascular networks to meet mass transport demands of the encapsulated cells. Fibroblast growth factor-1 (FGF-1) is a potent angiogenic factor with optimal effect occurring when it is delivered in a sustained manner. In this article, a technique is described for the generation of multilayered alginate microcapsules with an outer alginate layer that can be used for the delivery of FGF-1. The influence of alginate concentration and composition (high mannuronic acid (M) or guluronic acid (G) content) on outer layer size and stability, protein encapsulation efficiency, and release kinetics was investigated. The technique results in a stable outer layer of alginate with a mean thickness between 113 and 164 MUm, increasing with alginate concentration and G-content. The outer layer was able to encapsulate and release FGF-1 for up to 30 days, with 1.25% of high G alginate displaying the most sustained release. The released FGF-1 retained its biologic activity in the presence of heparin, and the addition of the outer layer did not alter the permselectivity of the PLO coat. This technique could be used to generate encapsulation systems that deliver proteins to stimulate local neovascularization around encapsulated islets. PMID- 20725970 TI - Biomaterial topography alters healing in vivo and monocyte/macrophage activation in vitro. AB - The effect of biomaterial topography on healing in vivo and monocyte/macrophage stimulation in vitro was assessed. A series of expanded polytetrafluoroethylene (ePTFE) materials were characterized by increasing average intranodal distance of 1.2 MUm (1.2-ePTFE), 3.0 MUm (3.0-ePTFE), and 4.4 MUm (4.4-ePTFE), but presented consistent surface chemistry with nonporous PTFE (np-PTFE). Subcutaneous implantation of 4.4-ePTFE into mice resulted in a statistically thinner capsule that appeared less organized and less dense than the np-PTFE response. In vitro, isolated monocytes/macrophages cultured on np-PTFE produced low levels of interleukin 1-beta (IL-1beta), 1.2-ePTFE and 3.0-ePTFE stimulated intermediate levels, and 4.4-ePTFE stimulated a 15-fold increase over np-PTFE. Analysis of cDNA microarrays demonstrated that additional proinflammatory cytokines and chemokines, including IL-1beta, interleukin 6, tumor necrosis factor alpha, monocyte chemotactic protein 1, and macrophage inflammatory protein 1-beta, were expressed at higher levels by monocytes/macrophages cultured on 4.4-ePTFE at 4 and 24 h, respectively. Expression ratios for several genes were quantified by RT PCR and were consistent with those from the cDNA array results. These results demonstrate the effect of biomaterial topography on early proinflammatory cytokine production and gene transcription by monocytes/macrophages in vitro and decreased fibrous capsule thickness in vivo. PMID- 20725971 TI - Characterization of aneurysmal aortas by biochemical, thermal, and dielectric techniques. AB - Abdominal aortic aneurysms (AAA) are characterized by structural alterations of the aortic wall resulting from the degradation of elastic fibres and an increase of collagen/elastin ratio. In this study we investigated the chain dynamics of AAA tissues by two techniques generally used for the characterization of polymers, Differential scanning calorimetry (DSC) and thermally stimulated currents (TSC), and we correlated the obtained data with biochemical analyses. The thermal denaturation of collagen observed by DSC allowed us to evaluate the thermal stability of the triple helix domain: notable modifications were evidenced between collagen from control tissue and collagen from AAA, particularly concerning the thermal denaturation. The dielectric analysis of pathologic aortic walls by TSC revealed a relevant change of collagen mobility in AAA, with the occurrence of a specific mode of relaxation between -60 and -40 degrees C. Biochemical, thermal, and dielectric results are compatible with increase of new collagen deposition and/or impairment of the collagen phase stability in the extracellular matrix of AAAs. PMID- 20725972 TI - Hydroxyapatite nanoparticles in poly-D,L-lactic acid coatings on porous titanium implants conducts bone formation. AB - It is well established in the field of biomaterials that hydroxyapatite (HA) may provide interesting osteoconductive properties. In this study, we investigated the osseointegrational effect of a 50/50 vol % composite of HA nanoparticles and poly-D,L-lactic acid (PDLLA) coated on model titanium bone implants in an in vivo animal model. The aim is to evaluate how the addition of HA to PDLLA may improve the bone formation and initial fixation of the implant. Two titanium implants coated with the PDLLA/HA composite and pure PDLLA, respectively, were implanted bilaterally in proximal part of humeri with a 2-mm peri-implant gap in 10 sheep. After 12 weeks, the remains of the coatings were present on 20.3 and 19.8% of PDLLA/HA composite- and PDLLA-coated implants, respectively. It was observed that newly formed bone (39.3%) and fibrous tissue (58.3%) had replaced the PDLLA/HA composite, whereas pure PDLLA was replaced almost completely by fibrous tissue (96.2%). Consequently, the PDLLA/HA composite-coated implants were better fixated as confirmed by push-out tests. Using quantification of peri-implant tissue and implant fixation as parameters, the present findings, therefore, clearly reveal that the addition of nanoparticulate HA to a PDLLA coating on titanium implants increases osseointegration. PMID- 20725973 TI - Antibacterial coatings of fluoridated hydroxyapatite for percutaneous implants. AB - Percutaneous orthopedic and dental implants require not only good adhesion with bone but also the ability to attach and form seals with connective tissues and the skin. To solve the skin-seal problem of such implants, an electrochemical deposition method was used to modify the surfaces of metallic implants to improve their antibacterial ability and skin seals around them. A dense and uniform fluoridated calcium phosphate coating with a thickness of about 200 nm was deposited on an acid-etched pure titanium substrate by controlling the current density and reaction duration of the electrochemical process. The as-deposited amorphous fluoridated calcium phosphate transformed to fluoridated hydroxyapatite (FHA) after heat treatment at 600 degrees C in a water vapor environment for 3 h. Both single crystal diffraction patterns and high-resolution transmission electron microscope (HRTEM) images confirmed the phase of the fluoridated calcium phosphate after the heat treatment. The antibacterial activities of FHA coatings were tested against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Porphyromonas gingivalis (P. gingivalis) with the film attachment method. The antibacterial activity of FHA coating is much higher than that of pure hydroxyapatite (HA) coating and acid-etched pure titanium surface. The promising features of FHA coating make it suitable for orthopedic and dental applications. PMID- 20725974 TI - Core/shell microspheres via coaxial electrohydrodynamic atomization for sequential and parallel release of drugs. AB - Herein, it is demonstrated that coaxial electrohydrodynamic atomization can be used for the fabrication of microspheres with distinct core/shell structure. This allows the encapsulation of two different types of drugs in different compartments in one single step. In Group A, we prepared microspheres in which the core and the shell contain hydrophobic and hydrophilic drugs, respectively. In contrast, in Group B, the opposite is prepared. While the former can be achieved by using amphiphilic polymers in aqueous environment, the latter is difficult to be prepared. The release patterns of the two groups are significantly different. The release of drugs from Group A microspheres is rather sequential, whereas group B microspheres release drugs in a parallel (co-release) manner. Nevertheless, in both groups, we found that the release of drugs can be easily tailored by altering outer/inner flow ratios. These findings present the advantages and possible application of this multi-drug release system in chemotherapy. Moreover, cell culture experiments have been performed to testify the performances of different microspheres in cytotoxicity and cellular apoptosis in vitro. PMID- 20725976 TI - Enhancement of osteoblast differentiation that is inhibited by titanium particles through inactivation of NFATc1 by VIVIT peptide. AB - Bone formation, which is inhibited by particulate wear debris, is a pathological factor that contributes to periprosthetic osteolysis. Although the nuclear factor of activated T cells c1 (NFATc1) is known to be involved in osteoblast differentiation, and its effect on osteoblasts in response to wear particles remains unclear. In this study, we investigated the role of NFATc1 in the regulation of osteoblastic differentiation of rat calvaria (RC) cells (a cell culture model comprising many osteoprogenitors) that were challenged with titanium (Ti) particles. The results showed that the Ti particles inhibited osteoblastic differentiation and mineralization of RC cells. NFATc1 plays a critical role in the Ti-particle inhibition process of the osteoblastic differentiation in RC cells. Inactivation of NFATc1 by the 11R-VIVIT peptide potently enhanced osteoblast differentiation and mineralization inhibition by the Ti particles. The 11R-VIVIT peptide does not have a toxic effect on the RC cells. On the basis of these data, we conclude that inactivation of NFATc1 by the 11R VIVIT peptide may provide a promising therapeutic target for the treatment of periprosthetic osteolysis by increasing bone formation. PMID- 20725975 TI - Paracrine factors from fibroblast aggregates in a fibrin-matrix carrier enhance keratinocyte viability and migration. AB - Efficient re-epithelialization of skin lesions is dependent on paracrine support from connective tissue fibroblasts. In deep skin defects, the supporting growth factor incentive is lacking. Current methods of keratinocyte transplantation with compromised attachment, spread, and cell proliferation warrant improvement and refinement. We describe here how human keratinocytes can be stimulated by matrix embedded factors from a novel process of fibroblast activation: nemosis. Interestingly, the unique set of mediators released in this process also plays a key role in normal wound healing. To develop a system for targeted delivery of nemosis-derived paracrine effectors, herein designated as Finectra, we combined them with fibrin to establish a controlled-release gel. Keratinocytes seeded to cover this active matrix showed better adherence, outgrowth, and viability than did cells on control matrix. The matrix incorporating Finectra supported viability of both primary keratinocytes and green fluorescent protein (GFP) labeled HaCaT cells, as evaluated by MTT assay and persistence of GFP fluorescence. The fibrin-Finectra matrix promoted migration of keratinocytes to cover a larger area on the matrix, suggesting better wound coverage on transplantation. An inhibitor of EGFR/c-Met receptor tyrosine kinases abolished keratinocyte responses to fibrin-Finectra matrix. This matrix can thus deliver biologically relevant synergistic stimuli to keratinocytes and hasten re epithelialization. PMID- 20725977 TI - Long term in vitro biostability of segmented polyisobutylene-based thermoplastic polyurethanes. AB - Long term in vitro biostability of thermoplastic polyurethanes (TPUs) containing mixed polyisobutylene (PIB)/poly(tetramethylene oxide) (PTMO) soft segment was studied under accelerated conditions in 20% H(2)O(2) solution containing 0.1M CoCl(2) at 50 degrees C to predict resistance to metal ion oxidative degradation (MIO) in vivo. The PIB-based TPUs showed significant oxidative stability as compared to the commercial controls Pellethane 2363-55D and 2363-80A. After 12 weeks in vitro the PIB-PTMO TPUs with 10-20% PTMO in the soft segment showed 6 10% weight loss whereas the Pellethane TPUs degraded completely in about 9 weeks. Attenuated total reflectance Fourier transform infrared spectroscopy confirmed the degradation of Pellethane samples via MIO by the loss of the ~1110 cm(-1) aliphatic C-O-C stretching peak height attributed to chain scission, and the appearance of a new peak at ~1174 cm(-1) attributed to crosslinking. No such changes were apparent in the spectra of the PIB-based TPUs. The PIB-based TPUs exhibited 10-30% drop in tensile strength compared to 100% for the Pellethane TPUs after 12 weeks. The molecular weight of the PIB-based TPUs decreased slightly (10-15%) at 12 weeks. The Pellethane TPUs showed a dramatic decrease in M(n) and an increase in low molecular weight degradation product. Scanning electron microscopy (SEM) showed severe cracking in the Pellethane samples after 2 weeks, whereas the PIB-based TPUs exhibited a continuous surface morphology. The weight loss, tensile, and SEM data correlate well with each other and indicate excellent biostability of these materials. PMID- 20725978 TI - In vitro osteoblast-like cell proliferation on nano-hydroxyapatite coatings with different morphologies on a titanium-niobium shape memory alloy. AB - The morphology of nanomaterials significantly affects their physical, chemical, and biological properties. In the present study, nano-hydroxyapatite coatings with different morphologies were produced on the surface of a titanium-niobium shape memory alloy via a hydrothermal process. The effect of the nano hydroxyapatite coatings on the in vitro proliferation of SaOS-2 osteoblast-like cells was investigated. Factors including crystallinity, surface micro-roughness, and surface energy of the nano-hydroxyapatite coatings were discussed. Results show that in vitro proliferation of the osteoblast-like cells was significantly enhanced on the nano-hydroxyapatite-coated titanium-niobium alloy compared to the titanium-niobium alloy without coating. The cell numbers on the nano hydroxyapatite-coated titanium-niobium alloy changed consistently with the surface energy of the hydroxyapatite coatings. This study suggests that surface energy as a characteristic parameter influencing the in vitro proliferation of osteoblast-like cells was predominant over the crystallinity and surface micro roughness of the nano-hydroxyapatite coatings. PMID- 20725980 TI - Mono-dispersed bioactive glass nanospheres: preparation and effects on biomechanics of mammalian cells. AB - Mono-dispersed SiO(2)-CaO bioactive glass nanospheres (BGNS) were prepared by a two step sol-gel method in the absence of surfactant. The size of BGNS ranged from 200 to 350 nm in diameter and exhibited a rough surface texture. In vitro biomineralization tests showed that BGNS could rapidly induce the deposition of an apatite layer in simulated body fluid (SBF). The effect of bioactive glass on the biomechanical properties of various mammalian cells was first reported in this paper. Atomic force microscopy (AFM) was used for measuring the biomechanical properties of mammalian cells. The result showed that BGNS-medium could significantly decrease the plasma membrane stiffness of bone marrow stem cells (BMSCs) by ~50% and stimulate BMSCs spreading. The effect of BGNS on biomechanical properties of bovine aortic endothelial cells (BAECs) was opposite to that on BMSCs. BGNS increased the BAECs' stiffness and stimulated the elongation of endothelial cells and the formation of endothelial networks, which might potentially facilitate the vascularization of implanted BGNS-based biomaterials in tissue engineering as a scaffold or as an injectable system. PMID- 20725979 TI - Evaluation of dense polylactic acid/beta-tricalcium phosphate scaffolds for bone tissue engineering. AB - Advances in biomaterial fabrication have introduced numerous innovations in designing scaffolds for bone tissue engineering. Often, the focus has been on fabricating scaffolds with high and interconnected porosity that would allow for cellular seeding and tissue ingrowth. However, such scaffolds typically lack the mechanical strength to sustain in vivo ambulatory stresses in models of load bearing cortical bone reconstruction. In this study, we investigated the microstructural and mechanical properties of dense PLA and PLA/beta-TCP (85:15) scaffolds fabricated using a rapid volume expansion phase separation technique, which embeds uncoated beta-TCP particles within the porous polymer. PLA scaffolds had a volumetric porosity in the range of 30 to 40%. With the embedding of beta TCP mineral particles, the porosity of the scaffolds was reduced in half, whereas the ultimate compressive and torsional strength were significantly increased. We also investigated the properties of the scaffolds as delivery vehicles for growth factors in vitro and in vivo. The low-surface porosity resulted in sub optimal retention efficiency of the growth factors, and burst release kinetics reflecting surface coating rather than volumetric entrapment, regardless of the scaffold used. When loaded with BMP2 and VEGF and implanted in the quadriceps muscle, PLA/beta-TCP scaffolds did not induce ectopic mineralization but induced a significant 1.8-fold increase in neo vessel formation. In conclusion, dense PLA/beta-TCP scaffolds can be engineered with enhanced mechanical properties and potentially be exploited for localized therapeutic factor delivery. PMID- 20725981 TI - Effects of VEGF loading on scaffold-confined vascularization. AB - Adequate vascularization of tissue-engineered constructs remains a major challenge in bone grafting. In view of this, we loaded beta-tricalcium-phosphate (beta-TCP) and porous poly(L-lactide-co-glycolide) (PLGA) scaffolds via collagen coating with vascular endothelial growth factor (VEGF) and studied whether the VEGF loading improves scaffold angiogenesis and vascularization. Dorsal skinfold chambers were implanted into 48 balb/c mice, which were assigned to 6 groups (n = 8 each). Uncoated (controls), collagen-coated, and additionally VEGF-loaded PLGA and beta-TCP scaffolds were inserted into the chambers. Angiogenesis, neovascularization, and leukocyte-endothelial cell interaction were analyzed repeatedly during a 14-day observation period using intravital fluorescence microscopy. Furthermore, VEGF release from PLGA und beta-TCP scaffolds was studied by ELISA. Micromorphology was studied from histological specimens. Unloaded beta-TCP scaffolds showed an accelerated and increased angiogenic response when compared with unloaded PLGA scaffolds. In vitro, PLGA released significantly higher amounts of VEGF compared with beta-TCP at the first two days resulting in a rapid drop of the released amount at the following days up to day 7 where the VEGF release was negligible. Nonetheless, in vivo VEGF loading increased neovascularization, especially in beta-TCP scaffolds. This increased vascularization was associated with a temporary leukocytic response with pronounced leukocyte-endothelial cell interaction at days 3 and 6. Histology revealed adequate host tissue response and engraftment of both beta-TCP and PLGA scaffolds. Our study demonstrates that beta-TCP scaffolds offer more suitable conditions for vascularization than PLGA scaffolds, in particular if they are loaded with VEGF. PMID- 20725982 TI - The impact of plasma rich in growth factors on clinical and biological factors involved in healing processes after third molar extraction. AB - Extraction of an impacted mandibular third molar is a common surgical procedure, although it still leads to several postoperative symptoms and complications. The study assessed the efficacy of autologous plasma rich in growth factors (PRGF) in the healing process by checking the difference of tissue cytokines and other healing factors produced by the mucosa after extraction between sites treated with PRGF and control sites and, at the same time, by evaluating the clinical efficacy of PRGF in terms of reduced pain and facial swelling. This study was a split-mouth study, in which the patient becomes his/her own control, to eliminate any individual response differences toward PRGF treatment. The parameters regarding inflammation and subsequent wound healing were all significantly higher at PRGF sites than at control sites. The increase at PRGF sites of the two proinflammatory cytokines evaluated, interleukin (IL)-1beta and IL-6, was accompanied by the increase of two anti-inflammatory cytokines, IL-10 and transforming growth factor-beta. Furthermore, IL-1beta and IL-6 induce fibroblast and keratinocyte proliferation, important events in wound healing. Postoperative pain and the swelling, measured at all experimental times, were reduced in the presence of PRGF. PMID- 20725983 TI - In vivo evaluation of MMP sensitive high-molecular weight HA-based hydrogels for bone tissue engineering. AB - Hyaluronic acid (170 kDa)-based hydrogel was synthesized using acrylated hyaluronic acid (HA) and matrix metalloproteinase (MMP) sensitive HA-based hydrogels were then prepared by conjugation with two different peptides: cell adhesion peptides containing integrin-binding domains (Arg-Gly-Asp: RGD) and a cross-linker with MMP degradable peptides to mimic the remodeling characteristics of natural extracellular matrices by cell-derived MMPs. Mechanical properties of these hydrogels were evaluated with different weight percentages (2.5 and 3.5 wt %) by measuring elastic modulus, viscous modulus, and swelling ratio. Human mesenchymal stem cells (hMSCs) were then cultured in MMP-sensitive or insensitive HA-based hydrogels and/or immobilized cell adhesive RGD peptides in vitro. Actin staining and image analysis proved that cells cultured in the MMP-sensitive hydrogel with RGD peptides showed extensive cell spreading and sprouting. Gene expression analysis showed that bone specific genes such as alkaline phosphatase, osteocalcin, and osteopontin increased in MMP-sensitive hydrogels as biomolecules such as BMPs and cells were added in the gels. For in vivo calvarial defect regeneration, five different samples (MMP insensitive hydrogel, MMP sensitive hydrogel, MMP sensitive hydrogel with BMP-2, MMP sensitive hydrogel with hMSC, and MMP sensitive hydrogel with BMP-2 and hMSC) were prepared. After 4 weeks of implantation, the Masson-Trichrome staining and micro computed tomography scan results demonstrated that the MMP sensitive hydrogels with BMP-2 and hMSCs have the highest mature bone formation. The MMP sensitive HA-based hydrogel could become useful scaffolds in bone tissue engineering with improvements on tissue remodeling rates and regeneration activity. PMID- 20725984 TI - Cartilage regeneration by bone marrow cells-seeded scaffolds. AB - Different approaches exist for the treatment of small articular cartilage defects. Several studies show comparable results for autologous chondrocyte implantation (ACI) and microfracture. Unfortunately, the fibrocartilage resulting from microfracture has neither the structure nor the mechanical properties of hyaline cartilage, even though the adult mesenchymal stem cells, which immigrate into the defect, are supposed to differentiate into chondrocytes. This study was performed to examine the capacity of a resorbable implant made from polylactide co-glycolide acid (PGLA)-fleece combined with autologous bone marrow cells fixed with a fibrin/thrombin-clot in the weight-bearing area of the femoral condyle of mature sheep. For this study, six defects were treated with either the PGLA implant alone or with a combination of the implant with added fibrin glue or were left untreated to serve as controls. The animals were sacrificed after 12 weeks; the operated knees were removed and examined by measuring the covering of the defect with cartilaginous tissue and according to the score of O'Driscoll. Additional criteria such as immunolabeling for collagen II and aggrecan were included. Results showed that no improvement of the tissue quantity or quality could be achieved by increasing the cell load of the implant with cells fixed by fibrin glue. PMID- 20725985 TI - Rough surface topography enhances the activation of Wnt/beta-catenin signaling in mesenchymal cells. AB - It is known that the roughness of titanium surfaces affects cell proliferation and differentiation. However, the mechanisms mediating the cellular responses to surface topography are only partially understood. The present study investigated whether Wnt canonical signaling, an important pathway in determining cell fate, is modulated by surface roughness. This study analyzed the behavior of the murine C2C12 mesenchymal cell line on polished or acid-etched, sand-blasted (SLA) commercially pure titanium. When we transfected cells with Wnt3a or wild-type beta-catenin and a reporter construct, we found that stimulation of Wnt canonical signaling was enhanced in cells on SLA surfaces. Moreover, more beta-catenin translocated to the nucleus in cells on SLA surfaces after stimulation with Wnt3a as evidenced by immunofluorescence. However, when cells were transfected with constitutively active S33Y beta-catenin mutant, no difference was observed between the groups. Higher levels of transcripts of Wnt target genes were detected in C2C12 cells cultured on SLA surfaces following transfection with Wnt3a, but the expression of a gene regulating beta-catenin degradation, Axin 2, was reduced on SLA surfaces. Inhibition of beta-catenin mediated transcription by dnTCF in murine osteoblastic MC3T3 cells, reversed the effects of topography on cell differentiation. Taken together, these results show that surface roughness modulates the responsiveness of mesenchymal cells to Wnt3a, that this requires the control of beta-catenin degradation, and that the control of beta-catenin signaling by surface topography is accountable for at least part of the effects of surface on cell differentiation. PMID- 20725986 TI - Biomimetic organic-inorganic nanocomposite coatings for titanium implants. In vitro and in vivo biological testing. AB - Recently described organic-inorganic nanocomposite coatings of the chemical composition: (PLL/PGA)(10)CaP[(PLL/PGA)(5)CaP](4) (coating A) and (PLL/PGA)(10)CaP[(PLL/PGA)(5)CaP](4)(PLL/PGA)(5) (coating B), applied to chemically etched titanium plates, have been tested by extensive cell culture tests and in vivo biological experiments, with uncoated titanium plates serving as controls. Before testing, coated samples were stored for extended periods of time (from 2 weeks to 8 months) under dry, sterile conditions. Cells of the cell lines MC3T3-E1 and/or SAOS-2 were used for the following cell culture tests: initial adhesion (4 h) and proliferation (up to 21 days), cell activity (XTT test), morphology, synthesis of collagen type I and alkaline phosphatase activity (all incubation up to 21 days). In addition, coating B was tested against uncoated control in a validated in vivo pull-out model in rabbit tibia. The results of both in vitro and in vivo experiments show excellent biological properties of chemically etched titanium which are even surpassed by surfaces covered with coating B. Thus, after 8 weeks of healing the implants coated with B were significantly better attached to the cortical bone of rabbit thibiae than uncoated titanium controls with more than twice the force needed to detach coated implants. However, coating A (top crystal layer) had an adverse effect on both cell proliferation and activity, which is explained by morphological observations, showing inhibited spreading of the cells on its rough surfaces. The results also show the remarkable stability of the coatings when shelved under dry and sterile conditions. PMID- 20725987 TI - In vitro evaluation of polyester-based scaffolds seeded with adipose derived stem cells for peripheral nerve regeneration. AB - To overcome the disadvantages of autografts for peripheral nerve repair, different methods such as artificial nerve conduits have been investigated for an alternative approach. This study demonstrated that solvent casting is a simple but efficient method to create thin polyester-based scaffolds for stem cell delivery. Using poly (epsilon-caprolactone) and poly (D,L-lactic acid), we produced scaffold films containing heterogenous depressions (pits) on the air surface with a size ranging from 0.5 to 30 MUm(2). These scaffolds were moderately hydrophobic; however, they supported the differentiation of adipose derived stem cells (ADSC) into a Schwann cell-like phenotype. The differentiated ADSC (dADSC) expressed S100 protein and glial fibrillary acidic protein and readily adhered to the films and proliferated at a similar rate to those cultured on tissue culture polystyrene. Cells were also positive for proliferating cell nuclear antigen. Furthermore, dADSC retained functional activity and significantly enhanced neurite outgrowth from dorsal root ganglia neurons. This study suggests polymer scaffolds combined with dADSCs could be a promising therapy for peripheral nerve injuries. PMID- 20725988 TI - In vitro hydrolytic and enzymatic degradation of nestlike-patterned electrospun poly(D,L-lactide-co-glycolide) scaffolds. AB - A common problem in applying electrospun biodegradable polyester matrixes as tissue-engineering scaffolds is their serious shrinkage with degradation to reduce the porosity drastically. To ameliorate this problem, a nestlike-patterned poly(D,L-lactide-co-glycolide) (PLGA) nanofibrous (~900 nm) matrix was proposed and fabricated by electropinning. Shrinkage studies demonstrated that the dimension change of nestlike-patterned fibrous membrane was much smaller than those of nonwoven and parallel-aligned fibrous membranes. And the robust framework of the patterned matrix helped to maintain its original nestlike topographical structure during degradation. Compared to hydrolytic-degraded specimens, the PLGA nanofibrous matrixes degraded in the presence of lysozyme showed larger weight loss but slower decrease in molecular weight. Besides, porous fibers with intact surface were detected by scanning electron microscopy after 20-week hydrolysis, and fibers with pores both inside and on surface were observed after enzymatic degradation for 12 weeks. Accordingly, the former presented a bimodal gel permeation chromatography (GPC) peak, while no bi or multimodal GPC peaks were found for the latter as degradation proceeded. These results indicated that an acid autocatalytic effect still existed in the hydrolysis of PLGA nanofibrous matrix. The presence of lysozyme could only accelerate the dissolution of degradation products with low molecular weight, but have no contribution to the chain scission. PMID- 20725989 TI - Suppression of anoikis by collagen coating of interconnected macroporous nanometric carbonated hydroxyapatite/agarose scaffolds. AB - Three dimensional interconnected macroporous (pore diameter: 600-800 MUm) hydroxyapatite/agarose disks have been evaluated in this study as potential bone regeneration scaffolds. With this purpose, the adhesion and proliferation of human Saos-2 osteoblasts on this biomaterial were analyzed. As an index of cell function, the following parameters were measured: cell morphology, viability, cell size/complexity, cell cycle, reactive oxygen species (ROS) content, and lactate dehydrogenase (LDH) release. The existence of anoikis induced by inappropriate contacts between the cell and the scaffold has been detected by scanning electron microscopy, confocal microscopy, and flow cytometry. The intracellular nitric oxide content has been also measured as potential inducer of anoikis. The positive effects of previous scaffold coating with type I collagen on osteoblast adhesion as well as the collagen protection against anoikis have been demonstrated in this study. PMID- 20725991 TI - Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes. AB - Alterations of chromosome 19 are among the most frequent cytogenetic changes in ovarian carcinomas. They usually occur as added extra material of unknown origin to 19p or, less frequently, 19q but sometimes as homogeneously staining regions. The precise nature of these markers, i.e., exactly which regions of chromosome 19 are involved and from which chromosome(s) the additional material comes, could only rarely be established. We have investigated by high resolution array-CGH a series of 29 chromosome 19 markers after previous microdissection of ovarian carcinoma metaphases followed by FISH to determine where in chromosome 19 the rearrangements took place as well as from which partner chromosomes the additional material stems, obtaining informative results on 23 markers from 18 carcinomas. Along the entire chromosome 19, a total of nine regions were found gained in 10 or more carcinomas (from 10 to 16) whereas 15 regions were gained in 6 to 10 markers. The most commonly gained region (16 markers) was observed in 19p13 between 20.80 Mbp and 20.85 Mbp from 19pter. According to the human genome 18 (hg18) NCBI 36, a total of 43 genes reside in the most commonly gained regions. Most of them (n = 31) code for zinc finger proteins. None of these genes is known to be involved in human neoplasia (the only exception is the ZNF91, which is found highly expressed in seminomas) but their frequent gain in the examined tumors makes all of them candidates for a pathogenetic role in ovarian carcinogenesis. PMID- 20725990 TI - Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. AB - Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors. PMID- 20725993 TI - Broad copy neutral-loss of heterozygosity regions and rare recurring copy number abnormalities in normal karyotype-acute myeloid leukemia genomes. AB - We analyzed, by the latest high-resolution SNP arrays, 19 Normal Karyotype (NK) AML patients at diagnosis (Dx) and remission (R) phases, to determine the number of tumor-associated copy number abnormalities (CNAs) and copy neutral-loss of heterozygosity (CN-LOH) regions per patient and to identify possible recurring genomic abnormalities. The number of tumor-associated CNAs was determined after comparison of matched Dx/R samples using stringent conditions able to reduce the number of false positive CNAs. With the exception of a single outlier case, a low number of CNAs per patient was detected (median value of 1 somatic loss or gain per patient). However, a high prevalence of CNAs (60-70% of the patients showed at least one tumor-associated gain or loss) and few recurring CNAs were observed, thus providing new hints towards identification of cooperating mutations. An extensive search of all tumor-associated CN-LOH regions >1 Mb revealed only three broad regions (terminal 12Mb of 22q, terminal 27Mb of 1p and the whole chromosome 21) in three patients out of 19 (16%). CN-LOH of the whole chromosome 21 was responsible for homozygosity of a missense mutation (R80C) of RUNX1/AML1. Our study suggests that a relative submicroscopic copy number stability NK-AML genomes is associated with low recurrence of specific CNAs and CN-LOH in NK-AML patient population. Sequencing of candidate genes in the identified CNAs and CN LOH regions should be considered a priority in the search of novel driver mutations of AML. PMID- 20725992 TI - Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. AB - Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer-30 of which carried mutated KRAS-using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas. PMID- 20725994 TI - CpG-ODN increases the release of VEGF in a mouse model of lung carcinoma. AB - Vascular endothelial-derived growth factor (VEGF) plays a fundamental role in the formation of new vessels within the tumour mass. Increasing evidence has highlighted the involvement of Toll-like receptors (TLRs) in cancer. Of interest, TLR9 is over-expressed in human lung carcinoma tissues. The aim of our study was to determine whether TLR9 activation could alter VEGF release in a mouse model of lung carcinoma. Lewis lung carcinoma cells were intravenously (i.v.) inoculated and 10 days later, tumour-bearing mice were treated with CpG-ODN (CpG, a TLR9 ligand) or PBS. CpG administration enhanced VEGF release, which was associated with increased tumour lesions in the lung. CpG induced high levels of IL-6 expression and activation of STAT3 in tumour-bearing mice. Moreover, CpG induced VEGF release from primary fibroblasts and endothelial cells, which correlated with IL-6 and TGFbeta production. This may explain the large influx of fibroblasts and the production of basic fibroblast growth factor (bFGF) in the tumour mass. The administration of a monoclonal antibody against VEGF A arrested tumour progression and induced a Th1-like response in CpG-treated tumour-bearing mice. In conclusion, our study demonstrates that the combination of CpG with anti VEGF monoclonal antibody could be of potential therapeutic in lung carcinoma. PMID- 20725995 TI - Human papillomavirus and survival in patients with base of tongue cancer. AB - The incidence of base of tongue cancer is increasing in Sweden and the proportion of human papillomavirus (HPV) positive cancer has increased in Stockholm, Sweden. Between 2006 and 2007, 84% of base of tongue cancer cases in Stockholm were HPV positive. The objective of this study was to assess the impact of HPV status on prognosis for base of tongue cancer patients. One-hundred and nine patients were diagnosed with base of tongue cancer between 1998 and 2007 in Stockholm County and 95 paraffin-embedded diagnostic tumor biopsies were obtained and tested for HPV by PCR. Eighty-seven patients had available biopsies, were treated with intention to cure and could be included in the survival analysis. Age, sex, TNM stage, stage, treatment and survival were recorded from patient charts. Kaplan Meier curves were used to present survival data. In multivariable analyses, a Cox proportional hazards model was used to adjust for covariates. In total 68 (78%) tumor biopsies from the 87 included patients were HPV DNA positive. Kaplan-Meier estimates showed that the overall survival for patients with HPV-positive cancer was significantly better (p = 0.0004), (log-rank test) than that of patients with HPV-negative cancer. Patients with HPV-positive tumors also had significantly better disease-free survival (p = 0.0008), (log-rank test) than those with HPV negative tumors. These results further strengthen the option to consider HPV status when planning prospective studies on treatment for base of tongue cancer. PMID- 20725996 TI - Adenoviral-mediated RNA interference targeting URG11 inhibits growth of human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second most common malignancy in Asia, with a 5-year survival rate of less than 5% due to high recurrence after surgery and resistance to chemotherapy. A variety of therapeutic interventions to treat HCC, particularly gene therapy, have recently been investigated in tumor model systems to provide a more complete understanding of hepatocarcinogenesis and effectively design therapeutic strategies to treat this disease. In our study, we constructed an adenoviral vector expressing small interfering RNA (siRNA) targeting a newly discovered gene named upregulated gene 11 (URG11). We introduced this vector into HCC cells to investigate the role of URG11 in HCC carcinogenesis. We observed that upon URG11 knockdown, HCC cell proliferation was inhibited through downregulation of several G1-S phase related molecules including cyclin D1 and apoptosis was induced as a result of Bcl-2 downregulation. Besides decreased expression of cyclin D1, CDK4, pRb and Bcl-2, URG11 also suppressed several other proteins including CAPN9, which was identified by cDNA microarray and 2D gel electrophoresis. Moreover, Ad-URG11-siRNA significantly suppressed HCC tumor growth in nude mice. In conclusion, Ad-URG11-siRNA can significantly suppress HCC tumor growth in vitro and in vivo by silencing the URG11 gene, and the use of this vector for gene therapy may represent a novel strategy to treat human HCC. PMID- 20725997 TI - Alcohol and endometrial cancer risk in the NIH-AARP diet and health study. AB - Previous investigations have provided conflicting results regarding whether alcohol consumption affects endometrial cancer risk, although in many of these studies the highest category of alcohol intake examined was limited. Further, most were unable to resolve how alcohol associations are affected by beverage type, the presence of other endometrial cancer risk factors, or tumor characteristics. To address these issues, we prospectively evaluated the association between alcohol intake and incident endometrial cancer (n = 1,491) in a cohort of 114,414 US women enrolled in the NIH-AARP Diet and Health Study. We calculated relative risks (RR) and 95% confidence intervals (CI) using Cox proportional hazards regression. After adjustment for age, body mass index (BMI), smoking and other potential confounders, the multivariable RRs (and 95% CIs) compared with nondrinkers were 0.97 (0.87-1.09) for >0-<12 g of alcohol/day, 1.06 (0.87-1.31) for 12-<24 g/day and 0.93 (0.71-1.20) for >= 24 g/day (p trend = 0.90). There was, however, some suggestion of higher risks associated with alcohol consumption among lean women (BMI, <25) and users of menopausal hormone therapy, with significant interactions with both parameters (respective interaction p-values of 0.002 and 0.005). The relationship was also enhanced, albeit nonsignificantly so, for low grade cancers. Our results do not support that alcohol is a strong contributor to endometrial cancer risk, but slight risk increases may prevail among some users or for selected tumor characteristics. PMID- 20725998 TI - Alteration of strain background and a high omega-6 fat diet induces earlier onset of pancreatic neoplasia in EL-Kras transgenic mice. AB - Diets containing omega-6 (omega-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of omega-6 fatty acids and background strain on the development of genetically induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in omega-6 fat on the development of pancreatic neoplasia in elastase (EL) Kras(G12D) (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high omega-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in omega-6 fatty acid. PMID- 20725999 TI - Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12. AB - Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise in treatment of ovarian carcinosis. Despite its efficiency for the treatment of peritoneal carcinosis from digestive tract neoplasia, it has failed to demonstrate significant benefit in ovarian cancers. It is therefore essential to understand the mechanism underlying resistance to HIPEC in ovarian cancers. Mesenchymal stem cells (MSC) play an important role in the development of ovarian cancer metastasis and resistance to treatments. A recent study suggests that MSCs may be cytotoxic for cancer cells upon heat shock. In contrast, we describe the protective role of MSC against hyperthermia. Using cytokine arrays we determined that the tumor associated MSC (TAMC) secrete pro-tumoral cytokines. We studied the effect of hyperthermia in co-culture setting of TAMC or BM-MCS associated with ovarian cancer cell lines (SKOV3 and CaOV3) with polyvariate flow cytometry. We demonstrate that hyperthermia does not challenge survival of TAMC or bone marrow derived MSC (BM-MSC). Both TAMC and BM-MSC displayed strong protective effect inducing thermotolerance in ovarian cancer cells (OCC). Transwell experiments demonstrated the role of secreted factors. We showed that CXCL12 was inducing thermotolerance and that inhibition of CXCL12/CXCR4 interaction restored cytotoxicity of hyperthermia in co-culture experiments. Contrary to the previous published study we demonstrated that TAMC and BM-MSC co-cultured with OCC induced thermotolerance in a CXCL12 dependant manner. Targeting the interaction between stromal and cancer cells through CXCL12 inhibition might restore hyperthermia sensitivity in ovarian cancers, and thus improve HIPEC efficiency. PMID- 20726001 TI - The natural chemopreventive phytochemical R-sulforaphane is a far more potent inducer of the carcinogen-detoxifying enzyme systems in rat liver and lung than the S-isomer. AB - The chemopreventive activity of the phytochemical sulforaphane, (-)1 isothiocyanato-4R-(methylsulfinyl)-butane, present in cruciferous vegetables in substantial amounts in the form of glucosinolate, was demonstrated in animal models of cancer using the racemate, despite the fact that humans are exposed only to the R-enantiomer through the diet. Since a principal mechanism of the chemopreventive activity of sulforaphane is modulation of the carcinogen metabolising enzyme systems, a study was conducted in precision-cut rat liver and lung slices, and in FAO cells comparing the ability of R- and S-sulforaphane to modulate these enzyme systems. R-sulforaphane elevated hepatic glutathione S transferase and quinone reductase whereas the S-enantiomer had no effect; moreover, the R-enantiomer was more effective in up-regulating GSTalpha, GSTMU and quinone reductase protein levels. In the lung, both enantiomers increased the same enzyme activities with the R-enantiomer being more potent; in addition, the R-enantiomer was more effective in up-regulating GSTalpha and quinone reductase protein levels. Both isomers increased glutathione levels in both tissues, with R sulforaphane being more potent. Finally, R-sulforaphane was the more effective of the two isomers in up-regulating CYP1A1/1B1 apoprotein levels in both liver and lung, and CYP1A2 in the liver. Similarly, in FAO cells the R-enantiomer was far more effective in up-regulating quinone reductase and glutathione S-transferase activities and protein levels compared with the S-isomer. These studies demonstrate clearly the superiority of R-sulforaphane, when compared with the S enantiomer, in stimulating detoxification enzymes, and raises the possibility that the animal studies that employed the racemate may have underestimated the chemopreventive activity of this isothiocyanate. PMID- 20726000 TI - IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines. AB - Cytokines play a crucial role in tumor initiation and progression. Here, we demonstrate that interleukin (IL)-6 is a key factor by driving tumor progression from benign to malignant, invasive tumors in the HaCaT-model of human skin carcinoma. IL-6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT-ras A-5 cells in vitro. Furthermore, IL 6 induces a complex, reciprocally regulated cytokine network in the tumor cells that includes inflammatory and angiogenic factors such as IL-8, GM-CSF, VEGF and MCP-1. These IL-6 effects lead to tumor cell invasion in organotypic cultures in vitro and to the formation of malignant and invasive s.c. tumors in vivo. Tumor invasion is supported by the IL-6 induced overexpression of MMP-1 in vitro and in vivo. These data demonstrate a key function of IL-6 in the progression of skin SCCs by regulating a complex cytokine and protease network and suggest new therapeutic approaches to target this central player in skin carcinogenesis. PMID- 20726002 TI - In vivo diagnosis of gastric cancer using Raman endoscopy and ant colony optimization techniques. AB - This study aims to evaluate the clinical utility of image-guided Raman endoscopy for in vivo diagnosis of neoplastic lesions in the stomach at gastroscopy. A rapid-acquisition image-guided Raman endoscopy system with 785-nm excitation has been developed to acquire in vivo gastric tissue Raman spectra within 0.5 sec during clinical gastroscopic examinations. A total of 1,063 in vivo Raman spectra were acquired from 238 tissue sites of 67 gastric patients, in which 934 Raman spectra were from normal tissue whereas 129 Raman spectra were from neoplastic gastric tissue. The swarm intelligence-based algorithm (i.e., ant colony optimization (ACO) integrated with linear discriminant analysis (LDA)) was developed for spectral variables selection to identify the biochemical important Raman bands for differentiation between normal and neoplastic gastric tissue. The ACO-LDA algorithms together with the leave-one tissue site-out, cross validation method identified seven diagnostically important Raman bands in the regions of 850-875, 1,090-1,110, 1,120-1,130, 1,170-1,190, 1,320-1,340, 1,655-1,665 and 1,730-1,745 cm(-1) related to proteins, nucleic acids and lipids of tissue and provided a diagnostic sensitivity of 94.6% and specificity of 94.6% for distinction of gastric neoplasia. The predictive sensitivity of 89.3% and specificity of 97.8% were also achieved for an independent test validation dataset (20% of total dataset). This work demonstrates for the first time that the real-time image-guided Raman endoscopy associated with ACO-LDA diagnostic algorithms has potential for the noninvasive, in vivo diagnosis and detection of gastric neoplasia during clinical gastroscopy. PMID- 20726003 TI - No increased incidence for GB-virus C infection in a cohort of HIV-positive lymphoma patients. PMID- 20726006 TI - Cell cycle arrest and apoptosis induction by an anticancer chalcone epoxide. AB - Safe and effective chemotherapeutic agents for the treatment of pancreatic cancer remain elusive. We found that chalcone epoxides (1,3-diaryl-2,3-epoxypropanones) inhibited growth in two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2. Three compounds were active, with GI(50) values of 5.6 to 15.8 microM. Compound 4a, 1,3-bis-(3,4,5-trimethoxyphenyl)-2,3-epoxypropanone, had an average GI(50) of 14.1 microM in the NCI 60-cell-line panel. To investigate the mode of action, cell cycle analyses of BxPC-3 cells were carried out. Treatment of cells with 50 microM 4a resulted in dramatic accumulation at G2/M (61% after 12 h for 4a vs. 15% for untreated cells). The cells rapidly entered apoptosis. After 12 h, 26% of cells treated with 50 microM 4a had entered apoptosis vs. 4% for cells treated with 100 microM etoposide and 2% for untreated cells. Compound 4a interfered with paclitaxel enhancement of tubulin polymerization, suggesting microtubules as the site of action. Reaction of thiol nucleophiles with 4a under basic conditions resulted in epoxide ring-opening and retroaldol fragmentation, yielding alkylated thiol. MALDI mass spectrometry showed that retroaldol reaction occurred upon treatment of beta-tubulin with 4a. The site of alkylation was identified as Cys(354). Chalcone epoxides warrant further study as potential agents for treatment of cancer. PMID- 20726007 TI - Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. AB - Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-kappaB and AP-1), enzymes (COX 2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (beta-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl X(L)). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin's poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer. PMID- 20726008 TI - Synthesis and anticancer activity of novel betulinic acid and betulin derivatives. AB - A series of novel betulinic acid derivatives 3-11 and betulin derivatives 12-17 were synthesized. The compounds were characterized by the means of (1)H- and (13)C-NMR spectroscopy as well as mass spectrometry. The compounds have been tested on ten tumor cell lines of different histogenic origin. The most active derivatives, containing a chloroacetyl group on C-3 in betulinic acid 9 and C-28 in betulin 15, were up to ten times more cytotoxic and many fold more selective towards tumor cells in comparison to normal cells (fibroblasts) than betulinic acid. Furthermore, compound 15 was found to possess cell growth inhibition even when treated for a short time on anaplastic thyroid cancer cells (SW1736). PMID- 20726010 TI - Cheats as first propagules: a new hypothesis for the evolution of individuality during the transition from single cells to multicellularity. AB - The emergence of individuality during the evolutionary transition from single cells to multicellularity poses a range of problems. A key issue is how variation in lower-level individuals generates a corporate (collective) entity with Darwinian characteristics. Of central importance to this process is the evolution of a means of collective reproduction, however, the evolution of a means of collective reproduction is not a trivial issue, requiring careful consideration of mechanistic details. Calling upon observations from experiments, we draw attention to proto-life cycles that emerge via unconventional routes and that transition, in single steps, individuality to higher levels. One such life cycle arises from conflicts among levels of selection and invokes cheats as a primitive germ line: it lays the foundation for collective reproduction, the basis of a self-policing system, the selective environment for the emergence of development, and hints at a plausible origin for a soma/germ line distinction. PMID- 20726009 TI - Upstream open reading frames: molecular switches in (patho)physiology. AB - Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation. Evidence from genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of human diseases. A genetic mouse model has recently provided proof-of-principle support for the physiological relevance of uORF mediated translational control in mammals. The targeted disruption of the uORF initiation codon within the transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) gene resulted in deregulated C/EBPbeta protein isoform expression, associated with defective liver regeneration and impaired osteoclast differentiation. The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5' RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression. PMID- 20726011 TI - Replication stress, a source of epigenetic aberrations in cancer? AB - Cancer cells accumulate widespread local and global chromatin changes and the source of this instability remains a key question. Here we hypothesize that chromatin alterations including unscheduled silencing can arise as a consequence of perturbed histone dynamics in response to replication stress. Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 mono-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor promoting insults is recognized as a significant source of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis. PMID- 20726012 TI - Epidemiology and prognosis of ovarian metastases in colorectal cancer. AB - BACKGROUND: National guidelines for prophylactic oophorectomy in women with colorectal cancer are lacking. The aim of this population-based cohort study was to report on the prevalence, incidence and prognosis of ovarian metastases from colorectal cancer, providing information relevant to the discussion of prophylactic oophorectomy. METHODS: All 4566 women with colorectal cancer in Stockholm County during 1995-2006 were included and followed until 2008. Prospectively collected data regarding clinical characteristics, treatment and outcome were obtained from the Regional Quality Registry. RESULTS: The prevalence of ovarian metastases at the time of diagnosis of colorectal cancer was 1.1 per cent (34 of 3172) among women with colonic cancer and 0.6 per cent (8 of 1394) among those with rectal cancer (P = 0.105). After radical resection of stage I III colorectal cancer, metachronous ovarian metastases were found during follow up in 1.1 per cent (22 of 1971) with colonic cancer and 0.1 per cent (1 of 881) with rectal cancer (P = 0.006). Survival in patients with ovarian metastases was poor. CONCLUSION: Ovarian metastases from colorectal cancer are uncommon. PMID- 20726013 TI - Biosynthesis, metabolism, molecular engineering, and biological functions of stilbene phytoalexins in plants. AB - Stilbenic compounds recently have become the focus of a number of studies in medicine and plant physiology as well as have emerged as promising molecules that potentially affect human health. Stilbenes are relatively simple compounds synthesized by plants and deriving from the phenyalanine/polymalonate route, the last and key enzyme of this pathway being stilbene synthase. Here, we review the biological significance of stilbenes in plants together with their biosynthesis pathway and their metabolism both by fungi and in planta. Special attention will be paid to the role of stilbenic molecules as phytoalexins. PMID- 20726015 TI - The deleterious effects of propranolol on patients with cirrhosis. PMID- 20726014 TI - Accuracy of different survival prediction models in a trauma population. AB - BACKGROUND: There is growing demand for a simple accurate scoring model to evaluate the quality of trauma care. This study compared different trauma survival prediction models with regard to their performance in different trauma populations. METHODS: The probability of survival for 10,777 trauma patients admitted to hospital was calculated using the formulas of the following models: the Major Trauma Outcome Study (MTOS), the Trauma Audit and Research Network (TARN) and the Base Excess Injury Severity Scale (BISS). Updated coefficients were calculated by logistic regression analysis based on a Dutch data set. Different models were compared for several subsets of patients, according to age and injury type and severity, using the area under the receiver operating characteristic (ROC) curve (AUC). Calibration for the updated models was presented graphically. RESULTS: Most of the models had an AUC exceeding 0.8. For the total population, the TARN Ps07 model with updated coefficients had the highest AUC (0.924); for the subset of patients in whom all parameters were available, the BISS model including the Glasgow Coma Scale had the highest AUC (0.909). All of the models had high discriminative power for patients aged less than 55 years. However, in older or intubated patients and in those with severe head injuries the discriminative power of the models dropped. The TARN model showed the best accuracy. CONCLUSION: The investigated models predict mortality fairly accurately in a Dutch trauma population. However, the accuracy of the models depends greatly on the patients included. Severe head injuries and greater age are likely to lead to a decrease in the accuracy of survival prediction. PMID- 20726016 TI - Reverse-vesicle formation of organic-inorganic polyoxometalate-containing hybrid surfactants with tunable sizes. AB - The formation of reverse-vesicular structures of the polyoxometalate-containing hybrid surfactants [nBu(4)N](3)[MnMo(6)O(18){(OCH(2))(3)-CNHCO(CH(2))(n 2)CH(3)}(2)] (Mn-Anderson-C(n), n=6, 16) in nonpolar medium was achieved by titrating toluene into Mn-Anderson-C(n)/acetonitrile (MeCN) solution. Stepwise change of the solvent polarity induces self-association of the hydrophilic Mn Anderson cluster on the hybrid amphiphiles. The reverse-vesicle formation was characterized by laser light scattering and further confirmed by transmission electron microscopy techniques, and the vesicle sizes increase with increasing toluene contents. The assembly process was accelerated at an elevated temperature. The length of the alkyl tails on the hybrid surfactants has a minor effect on the vesicle sizes, because the strong attraction between the polyoxometalate clusters is more dominant in the reverse-vesicle formation. PMID- 20726017 TI - Probing surface sites of TiO2: reactions with [HRe(CO)5] and [CH3Re(CO)5]. AB - Two carbonyl complexes of rhenium, [HRe(CO)(5)] and [CH(3)Re(CO)(5)], were used to probe surface sites of TiO(2) (anatase). These complexes were adsorbed from the gas phase onto anatase powder that had been treated in flowing O(2) or under vacuum to vary the density of surface OH sites. Infrared (IR) spectra demonstrate the variation in the number of sites, including Ti(+3)-OH and Ti(+4)-OH. IR and extended X-ray absorption fine structure (EXAFS) spectra show that chemisorption of the rhenium complexes led to their decarbonylation, with formation of surface bound rhenium tricarbonyls, when [HRe(CO)(5)] was adsorbed, or rhenium tetracarbonyls, when [CH(3)Re(CO)(5)] was adsorbed. These reactions were accompanied by the formation of water and surface carbonates and removal of terminal hydroxyl groups associated with Ti(+3) and Ti(+4) ions on the anatase. Data characterizing the samples after adsorption of [HRe(CO)(5)] or [CH(3)Re(CO)(5)] determined a ranking of the reactivity of the surface OH sites, with the Ti(+3)-OH groups being the more reactive towards the rhenium complexes but the less likely to be dehydroxylated. The two rhenium pentacarbonyl probes provided complementary information, suggesting that the carbonate species originate from carbonyl ligands initially bonded to the rhenium and from hydroxyl groups of the titania surface, with the reaction leading to the formation of water and bridging hydroxyl groups on the titania. The results illustrate the value of using a family of organometallic complexes as probes of oxide surface sites. PMID- 20726018 TI - Surprising properties of a furo-furanone. AB - The electronic absorption, fluorescence, and excitation spectra of furo[3,4 c]furanone (1) have been measured in different solvents at different concentrations. We observed a complex dependence of absorption and excitation spectra as a function of the concentration in CH(2)Cl(2) and THF due to aggregate formation. Interestingly, the fluorescence spectra were not affected. Resolving the puzzle was made possible by the fact that 1 fits perfectly into the channels of zeolite L (ZL) microcrystals to form 1-ZL guest-host composites. The geometry of the ZL channel system ensures a well-defined orientation of the embedded dye molecules, thereby leading to a preferred orientation of their electronic transition dipole moment (ETDM) and thus to objects with pronounced optical anisotropy properties. This enabled us to understand that in solution the monomers that are present at low concentration form an aggregate in which the molecules sit on top of each other and arrange into a J-type aggregate configuration at higher concentrations. The signature of the latter is observed in the 1-ZL composites. This seems to be the first example in which the insertion of molecules into a nanochannel microcrystal has helped in understanding the weak intermolecular interactions that take place in solution. PMID- 20726019 TI - Synthesis of 2-isoxazolines: enantioselective and racemic methods based on conjugate additions of oximes. AB - The formation of 3-unsubstituted 2-isoxazolines by means of condensation reactions between alpha,beta-unsaturated aldehydes and oximes proceeds readily in the presence of catalytic amounts of anilinium salts. Mechanistically, the process involves a fast conjugate addition of the oxime and a slower intramolecular oxime-transfer reaction. The rate of oxime transfer was found to correlate with the acidity of the catalyst. This finding enabled us to discover an enantioselective process in which the fragile conjugate-addition product generated in the first stage is rapidly cyclized into the stable isoxazoline under acidic conditions, with conservation of enantiomeric excess. In summary, herein we describe synthetically useful protocols for accessing 3-unsubstituted 2 isoxazolines in both the enantioselective and racemic manner. The mechanism of the condensation reaction catalyzed by the anilinium salt was also investigated by NMR spectroscopy experiments in which the effect of differently substituted aldehydes and oximes as well as water on the reaction rate was studied. The results point to the rate-limiting elimination of water from the 3-hydroxy-2 isoxazolidine intermediate. PMID- 20726020 TI - Oxidative perhydroxylation of [closo-B12H12]2- to the stable inorganic cluster redox system [B12(OH)12](2-/*-): experiment and theory. PMID- 20726021 TI - In and ex situ studies of the formation of layered microspherical hydrozincite as precursor for ZnO. AB - Layered ZnO microspheric particles were prepared by the thermal decomposition of layered hydrozincite (LZnHC), which was synthesized from zinc nitrate and urea in a water/PEG400 mixture. The influence of the starting reagents, their concentrations, and the amount of PEG in the water/PEG400 mixture on the particle growth was observed. The chemical aspect of the particle growth was proposed in the frame of the partial charge model (PCM), and the formation of [Zn(OH)(2)(OH(2))(4)](0) and [Zn(OH)(HCO(3))(OH(2))(3)](0) was predicted for the solid phase. The assumed growth mechanism, which follows the "nonclassical crystallization" concept of a self-assembling mechanism, was observed in situ by small-angle X-ray scattering (SAXS) and predicts the rapid formation of approximately 6 nm sized building units. The size of these nano building units, stable only in the reaction medium, remains nearly constant during the synthesis, as the concentration of the nano building units increases throughout the reaction. The nano building units connect into leaves of LZnHC with a thickness of 20 nm. These leaves of LZnHC are further agglomerated into porous, microsphere like particles with sizes up to 4 MUm. PMID- 20726022 TI - Chemical bonding in compounds of the CuAl(2) family: MnSn(2), FeSn(2) and CoSn(2). AB - A model for the chemical bonding in the isostructural intermetallic compounds MnSn(2), FeSn(2) and CoSn(2), crystallising in the CuAl(2)-type structure, is developed. The description is based on quantum-chemical calculations applying the electron localisability approach as well as on experimental results obtained from Raman spectroscopy, Hall effect and electrical resistivity measurements on oriented single crystals. The analysis of the chemical bonding reveals four different covalent interactions leading to the formation of interpenetrating 6(3) nets of tin and chains of transition-metal atoms T (T=Mn, Fe or Co) along [001], which are interconnected by three-centre bonds. Polarised Raman measurements on oriented single crystals allowed the determination of the bond strengths, resulting in a bond order of 0.5 within the 6(3) nets, while the three-centre interactions show bond orders of up to 1. Measurements show a metal-like temperature dependence of the resistivity. A comparison of the results with the bonding models obtained for the isostructural compounds CuAl(2), TiSb(2) and VSb(2) reveals the influence of the main-group element on the connectivity pattern. PMID- 20726023 TI - Dynamic nuclear polarization of deuterated proteins. PMID- 20726024 TI - A concise route to alpha'-methoxy-gamma-pyrones and verticipyrone based upon the desymmetrization of alpha,alpha'-dimethoxy-gamma-pyrone. PMID- 20726025 TI - Aldehyde umpolung by N-heterocyclic carbenes: NMR characterization of the Breslow intermediate in its keto form, and a spiro-dioxolane as the resting state of the catalytic system. PMID- 20726026 TI - Selective ultrasonic cavitation on patterned hydrophobic surfaces. PMID- 20726027 TI - An integrated microreactor system for self-optimization of a Heck reaction: from micro- to mesoscale flow systems. PMID- 20726028 TI - Catalysis by dihydrofolate reductase from the psychropiezophile Moritella profunda. AB - The influence of temperature and pH on the stability and catalytic activity of dihydrofolate reductase (MpDHFR) from the cold-adapted deep-sea bacterium Moritella profunda was studied. The thermal melting temperature was found to be ~38 degrees C and was not affected by pH, while activity measurements demonstrated that its stability was maximal at pH 7 and was reduced dramatically below pH 6 or above pH 8. The steady-state rate constant (k(cat)) was maximal at neutral pH and higher temperatures, while the Michaelis constants (K(M)) for both substrate and cofactor were optimal at lower temperatures and at elevated or reduced pH. For both temperature and pH, any change in k(cat) was therefore offset by a similar change in K(M). Both the activation enthalpy and entropy of the MpDHFR-catalysed reaction were lower than those of DHFR from E. coli leading overall to a very small difference in activation free energy and therefore similar steady-state rate constants at the same temperature. The chemical step of the reaction is not rate limiting at pH 7, but becomes progressively more rate limiting as the pH increases. These results demonstrate adaptation of MpDHFR to its environment and show compromises between enthalpic and entropic contributions to the reaction, and between k(cat) and K(M). PMID- 20726029 TI - Epitaxial growth of gold on H-Si(111): the determining role of hydrogen evolution. AB - The potential dependence of gold electrodeposition on H-terminated Si(111) is studied in acidic electrolyte by means of atomic force microscopy and X-ray diffraction. The Au films (<=66 monolayers (ML)~16 nm) are found to be (111) oriented and in strong epitaxy with the Si(111) surface lattice, with two in plane orientations separated by 180 degrees . The deposit morphology is controlled by the deposition potential and can be islandlike or atomically flat. The flat morphology is accompanied by a preferential growth of 180 degrees rotated Au planes with respect to the Si bulk lattice which takes place at potentials where the hydrogen evolution reaction occurs. Obtaining ultraflat Au layers on Si(111) contrasts with the commonly observed islandlike morphology of electrodeposited films on semiconductors. This behavior is discussed in terms of a nucleation coupled with hydrogen evolution reaction (HER) and an enhanced Au adatom mobility induced by this reaction. PMID- 20726030 TI - Theoretical investigations of the oxygen reduction reaction on Pt(111). AB - Computational modeling can provide important insights into chemical reactions in both applied and fundamental fields of research. One of the most critical processes needed in practical renewable energy sources is the oxygen reduction reaction (ORR). Besides being the key process in combustion and corrosion, the ORR has an elusive mechanism that may proceed in a number of complicated reaction steps in electrochemical fuel cells. Indeed, the mechanism of the ORR on highly studied Pt(111) electrodes has been the subject of interest and debate for decades. Herein, we first outline the theory behind these types of simulations and then show how to use these quantum mechanical approaches and approximations to create a realistic model. After reviewing the performance of these methods in studying the binding of molecular oxygen to Pt(111), we then outline our own results in elucidating the ORR and its dependence on environmental parameters, such as solvent, thermodynamic energies, and the presence of an external electrode potential. This approach can, in principle, be applied to other equally complicated investigations of other surfaces or electrochemical reactions. PMID- 20726032 TI - Hypouricemic therapy: a novel potential therapeutic option for nonalcoholic fatty liver disease. PMID- 20726031 TI - Dansyl C-glucoside as a novel agent against endotoxic shock. PMID- 20726033 TI - Pegylated interferon and ribavirin in real life: efficacy versus effectiveness. PMID- 20726034 TI - Foreword ISTA14 special issue. PMID- 20726035 TI - Effect of strontium ranelate on fracture healing in the osteoporotic rats. AB - The aim of this study was to evaluate the effect of strontium ranelate (SrR) on fracture healing in the osteoporotic rat model. Forty female Sprague-Dawley rats aged 3 months were enrolled in the study. Osteoporosis was induced by bilateral ovariectomy and subsequent daily heparin injection started 1 week after surgery and lasted for 4 weeks. Osteoporosis was confirmed by a reduction of bone mineral density (BMD). Twenty of the osteoporotic rats were assigned to the SrR group and the remaining 20 to the control group. An open right tibial midshaft transverse fracture was created and then an intramedullary fixation was performed. SrR group was treated by 450 mg/kg/day SrR per oral. Six weeks after surgical induction of fracture, all animals were sacrificed. One animal from each group died after ovariectomy. Two tibiae from the control group failed to unite. SrR-treated group showed higher mechanical strength and fracture stiffness when compared to the control group (p = 0.006, p = 0.001, respectively). SrR-treated group had mature woven bone or predominantly woven bone compared with osteoporotic control group (p = 0.038). SrR-treated group's callus maturity was significantly higher than control group (p = 0.001). SrR is associated with better fracture healing in the osteoporotic rat model. PMID- 20726036 TI - Systematic evaluation of the miRNA-ome and its downstream effects on mRNA expression identifies gastric cancer progression. AB - We investigated the differential expression of Dicer and Drosha, as well as that of microRNA (miRNA), in adjacent normal and tumour samples of patients with gastric cancer. The expression of Dicer and Drosha was studied by immunohistochemistry in 332 gastric cancers and correlated with clinico pathological patient characteristics. Differential expression of miRNAs was studied using the Invitrogen NCode(TM) Multi-Species miRNA Microarray Probe Set containing 857 mammalian probes in a test set of six primary gastric cancers (three with and three without lymph node metastases). Differential expression was validated by RT-PCR on an independent validation set of 20 patients with gastric cancer. Dicer and Drosha were differentially expressed in non-neoplastic and neoplastic gastric tissue. The expression of Drosha correlated with local tumour growth and was a significant independent prognosticator of patient survival. Twenty miRNAs were up- and two down-regulated in gastric carcinoma compared with non-neoplastic tissue. Six of these miRNAs separated node-positive from node negative gastric cancers, ie miR-103, miR-21, miR-145, miR-106b, miR-146a, and miR-148a. Five miRNAs expressed differentially in node-positive cancers had conserved binding sites for mRNAs differentially expressed in the same set of tumour samples. Gastric cancer shows a complex derangement of the miRNA-ome, including Dicer and Drosha. These changes correlate independently with patient prognosis and probably influence local tumour growth and nodal spread. PMID- 20726037 TI - The role of dopamine in the maintenance of working memory in prefrontal cortex neurons: input-driven versus internally-driven networks. AB - How do organisms select and organize relevant sensory input in working memory (WM) in order to deal with constantly changing environmental cues? Once information has been stored in WM, how is it protected from and altered by the continuous stream of sensory input and internally generated planning? The present study proposes a novel role for dopamine (DA) in the maintenance of WM in the prefrontal cortex (Pfc) neurons that begins to address these issues. In particular, DA mediates the alternation of the Pfc network between input-driven and internally-driven states, which in turn drives WM updates and storage. A biologically inspired neural network model of Pfc is formulated to provide a link between the mechanisms of state switching and the biophysical properties of Pfc neurons. This model belongs to the recurrent competitive fields(33) class of dynamical systems which have been extensively mathematically characterized and exhibit the two functional states of interest: input-driven and internally driven. This hypothesis was tested with two working memory tasks of increasing difficulty: a simple working memory task and a delayed alternation task. The results suggest that optimal WM storage in spite of noise is achieved with a phasic DA input followed by a lower DA sustained activity. Hypo and hyper dopaminergic activity that alter this ideal pattern lead to increased distractibility from non-relevant pattern and prolonged perseverations on presented patterns, respectively. PMID- 20726038 TI - Learning eye vergence control from a distributed disparity representation. AB - We present two neural models for vergence angle control of a robotic head, a simplified and a more complex one. Both models work in a closed-loop manner and do not rely on explicitly computed disparity, but extract the desired vergence angle from the post-processed response of a population of disparity tuned complex cells, the actual gaze direction and the actual vergence angle. The first model assumes that the gaze direction of the robotic head is orthogonal to its baseline and the stimulus is a frontoparallel plane orthogonal to the gaze direction. The second model goes beyond these assumptions, and operates reliably in the general case where all restrictions on the orientation of the gaze, as well as the stimulus position, type and orientation, are dropped. PMID- 20726039 TI - Single-trial based independent component analysis on mismatch negativity in children. AB - Independent component analysis (ICA) does not follow the superposition rule. This motivates us to study a negative event-related potential - mismatch negativity (MMN) estimated by the single-trial based ICA (sICA) and averaged trace based ICA (aICA), respectively. To sICA, an optimal digital filter (ODF) was used to remove low-frequency noise. As a result, this study demonstrates that the performance of the sICA+ODF and aICA could be different. Moreover, MMN under sICA+ODF fits better with the theoretical expectation, i.e., larger deviant elicits larger MMN peak amplitude. PMID- 20726040 TI - Coupled singular value decomposition of a cross-covariance matrix. AB - We derive coupled on-line learning rules for the singular value decomposition (SVD) of a cross-covariance matrix. In coupled SVD rules, the singular value is estimated alongside the singular vectors, and the effective learning rates for the singular vector rules are influenced by the singular value estimates. In addition, we use a first-order approximation of Gram-Schmidt orthonormalization as decorrelation method for the estimation of multiple singular vectors and singular values. Experiments on synthetic data show that coupled learning rules converge faster than Hebbian learning rules and that the first-order approximation of Gram-Schmidt orthonormalization produces more precise estimates and better orthonormality than the standard deflation method. PMID- 20726041 TI - A new direct adaptive regulator with robustness analysis of systems in Brunovsky form. AB - The direct adaptive regulation of unknown nonlinear dynamical systems in Brunovsky form with modeling error effects, is considered in this paper. Since the plant is considered unknown, we propose its approximation by a special form of a Brunovsky type neuro-fuzzy dynamical system (NFDS) assuming also the existence of disturbance expressed as modeling error terms depending on both input and system states plus a not-necessarily-known constant value. The development is combined with a sensitivity analysis of the closed loop and provides a comprehensive and rigorous analysis of the stability properties. The existence and boundness of the control signal is always assured by introducing a novel method of parameter hopping and incorporating it in weight updating laws. Simulations illustrate the potency of the method and its applicability is tested on well known benchmarks, as well as in a bioreactor application. It is shown that the proposed approach is superior to the case of simple recurrent high order neural networks (HONN's). PMID- 20726042 TI - Muscle emulation with DC motor and neural networks for biped robots. AB - This paper shows how to use a DC motor and its PID controller, to behave analogously to a muscle. A model of the muscle that has been learned by a NNARX (Neural Network Auto Regressive eXogenous) structure is used. The PID parameters are tuned by an MLP Network with a special indirect online learning algorithm. The calculation of the learning algorithm is performed based on a mathematical equation of the DC motor or with a Neural Network identification of the motor. For each of the two algorithms, the output of the muscle model is used as a reference for the DC motor control loop. The results show that we succeeded in forcing the physical system to behave in the same way as the muscle model with acceptable margin of error. An implementation in the knees of a simulated biped robot is realized. Simulation compares articular trajectories with and without the muscle emulator and shows that with muscle emulator, articular trajectories become closer to the human being ones and that total power consumption is reduced. PMID- 20726043 TI - Silver salvage. PMID- 20726044 TI - Indomethacin suppositories for arthritis. PMID- 20726045 TI - Public Health Doctors' Conference. PMID- 20726046 TI - Plasma-renin concentration in hypertension. PMID- 20726047 TI - Anaphylactoid shock due to penicillin. PMID- 20726048 TI - Thumb-sucking and the teeth. PMID- 20726049 TI - Royal Commission on medical education. PMID- 20726050 TI - Early-onset obesity and risk for psoriatic arthritis. PMID- 20726052 TI - Popliteal aneurysms. PMID- 20726051 TI - RhoGTPases and Rho-effectors in hepatocellular carcinoma metastasis: ROCK N'Rho move it. AB - Hepatocellular carcinoma (HCC) is an intractable disease with an extremely high mortality rate. Metastasis is the major factor of liver failure, tumour recurrence and death in HCC patients. Unfortunately, no promising curative therapy for HCC metastasis is available as yet; therefore, treatment for advanced HCC still remains a formidable challenge. A large body of evidence has demonstrated that the RhoGTPases/Rho-effector pathway plays important roles in mediating HCC metastasis based on their foremost functions in orchestrating the cell cytoskeletal reorganization. This review will first discuss the general principles of cancer metastasis and cancer cell movement with a particular focus on HCC.We will then summarize the implications of various members in the RhoGTPases/Rho-effectors signalling cascade including the upstream RhoGTPase regulators RhoGTPases and Rho-effectors and their downstream targets in HCC metastasis. Finally, we will discuss the therapeutic insight of targeting the RhoGTPases/Rho-effector pathway in HCC. Taken together, the literature demonstrates the importance of the RhoGTPases/Rho-effector signalling pathway in HCC metastasis and marks the necessity to have a more thorough knowledge of this complicated signalling network in order to develop novel therapeutic strategies for HCC patients. PMID- 20726053 TI - Teach-in on the hospital service. PMID- 20726054 TI - Diabetogenic action of frusemide. PMID- 20726055 TI - Reaction to insect-bites. PMID- 20726056 TI - Complication of contact lenses. PMID- 20726057 TI - Foetus in hernia. PMID- 20726058 TI - Misdiagnosis of dysphasia. PMID- 20726059 TI - Prevention of heart disease. PMID- 20726060 TI - Bradykinin. PMID- 20726061 TI - Training for general practice. PMID- 20726062 TI - Salaried service. PMID- 20726063 TI - Retraction. The significance of neuroglobin in the brain. PMID- 20726064 TI - Prostate cancer: PSA-based screening in Sweden dramatically reduces disease specific mortality. PMID- 20726065 TI - Prostate cancer: Frozen section analysis--is it of value when performing radical prostatectomy? PMID- 20726066 TI - Prostate cancer: Degarelix controls serum alkaline phosphatase better than leuprolide. PMID- 20726067 TI - Perks of percutaneous cryoablation. PMID- 20726068 TI - Urinary incontinence: Neurokinin receptor antagonist inferior to tolterodine for OAB. PMID- 20726076 TI - HIPAA hazard. Rite Aid latest chain to run afoul of privacy rules. PMID- 20726078 TI - Quest for quality expands. With new pay rules, providers receptive to changes. PMID- 20726077 TI - Rethinking breach notices. HHS withdraws final rule for more consideration. PMID- 20726079 TI - Consumers in mind. Vestar to tap into market by buying HealthGrades. PMID- 20726080 TI - Attack of the pods. CMS must stop explosion of physician office pathology labs. PMID- 20726081 TI - Making adjustments. Hospitals are carrying higher supply-chain costs related to larger numbers of obese patients, with much of that expense not being reimbursed. PMID- 20726082 TI - By the numbers. Largest biotechnology companies. Ranked by worldwide revenue in 2009. PMID- 20726083 TI - Finance. NICE rebuffs PCTs' call to help identify more areas for savings. PMID- 20726084 TI - Investigation. DH will probe how row over targets led to bullying claims. PMID- 20726085 TI - Communications. What's in a name? PCT rebranding still has a long way to go. PMID- 20726086 TI - Sophia Christie on talking and asking. PMID- 20726087 TI - On why funding clinical audit is essential. Quality must be seen to be done. PMID- 20726088 TI - Mental health. All together now for happy families. PMID- 20726089 TI - Carers. Why the NHS must look after its hidden workers. PMID- 20726090 TI - Population health data. Get a load of me. AB - UK Biobank has around 330,000 people signed up to provide personal data, including DNA. Large pharmaceutical companies and research organisations will have access to the material. UK Biobank insists access will be restricted to "bona fide" medical research. The project sees scope for international co operation with other comparable databases. PMID- 20726092 TI - On a bumpy flight. PMID- 20726091 TI - Managers have been unfairly served by the rushed reforms. PMID- 20726093 TI - Tories' vision poses a screen test. PMID- 20726094 TI - Social marketing. Sell your ideas in a buyers' market. PMID- 20726095 TI - Commissioning: part 2 of 2. The cost of poor quality and how to put it right. PMID- 20726096 TI - Human resources--mentoring: part 1 of 2. Something to aspire to. PMID- 20726097 TI - 'Heroic' NHS managers get their due from friend and foe. PMID- 20726098 TI - 'National management system' to 'grip' transition. PMID- 20726099 TI - Known unknowns form the white paper's core. PMID- 20726100 TI - PCTs can carve out a new role. PMID- 20726101 TI - Now answer the 14 bn pound question. PMID- 20726102 TI - Labour's legacy. Eclipsing the clan culture in the NHS. PMID- 20726103 TI - Service redesign. Action points for arthritis care. PMID- 20726104 TI - Bad credit. N.Y. to investigate predatory lending in healthcare. PMID- 20726106 TI - Not a big deal...yet. Payers hesitant about buying IPA model. PMID- 20726105 TI - Tech togetherness. Slew of IT deals, including GE-Intel, announced. PMID- 20726107 TI - Risky-drugs list in the spotlight. Healthcare groups, drugmakers push for changes to improve safety. PMID- 20726108 TI - Consolidation wave rises. Systems look to acquisition as part of health reform. PMID- 20726109 TI - Some progress to report. We're gaining in fight against cancer and HIV but other gains are bad news. PMID- 20726110 TI - The new underinsured. While health reform is expected to add 31 million to the ranks of the insured, low-income families--and providers--may still face significant financial risk. PMID- 20726111 TI - Halfway home. Just a few bumps on the road to new data standards. PMID- 20726113 TI - Reproductive biology of the female leaf-nosed bat, Macrotus californicus, in Southwestern United States: I. a morphometric analysis of the annual ovarian cycle. AB - In Macrotus californicus (Phyllostomatidae), normal embryogenesis(March-June) is preceded by a period of delayed development (October- March) characterized by implantation and slow growth of the embryo to the primitive streak stage. The events of the annual reproductive cycle can be correlated with ovarian dynamics. Waves of follicular growth appear to be initiated in January and June. Increased multilaminar follicles resulting from the second wave of recruitment appear from August to October. Vesiculation of these follicles is seen in both ovaries from July to January; however, the single Graafian follicle forms only in the right ovary just prior to ovulation in late October-early November. Left ovarian ovulation can be induced by right ovariectomy. High atresia from July to December may retard embryo genesis by failing to provide an optimal hormone milieu for the conceptus. In addition, luteal cells are small during the initial months of embryonic development.The first wave of follicular growth results in the appearance of an increased percentage of growing follicles in April; resultant enhanced estrogen levels may influence the resumption of normal development, an event which also coincides with luteal cell hypertrophy. It would appear possible, therefore,that delayed development in Macrotus is an expression of luteal cell insufficiency and uterine nutritional incompetence resulting from depressed steroid levels. Termination of delay may be brought about by the action of increased levels of estrogen and/or progesterone on the endometrium, perhaps by influencing the activity of mast cells whose products are known in some species to enhance vascularity which in turn could account for added substances essential to normal fetal growth. PMID- 20726112 TI - Effects of IGF-1, TGF-alpha plus TGF-beta1 and bFGF on in vitro survival, growth and apoptosis in FSH-stimulated buffalo (Bubalis bubalus) preantral follicles. AB - OBJECTIVE: Investigate the effect of various growth factors viz. IGF-I, TGF-alpha + TGF-beta1 and bFGF either alone or in combination, with FSH on in vitro growth, survival, antrum formation, steroidogenesis and apoptosis of buffalo preantral follicles (PFs). METHODS: Buffalo ovaries were collected from abattoir; PFs were isolated and divided into five treatment groups. TCM-199 supplemented with 10% FBS, 1% ITS+EGF+FSH control (group a), control+IGF-I (group b), control + TGF alpha + TGF-beta1 (group c), control + IGF-I + TGF-alpha + TGF-beta1 (group d) and control+bFGF (group e). Progesterone (P4) and 17beta-estradiol (E2) concentrations were evaluated by RIA and apoptosis by TUNEL assay. RESULTS: TGF alpha + TGF-beta1 inhibited follicular survival and induced oocyte apoptosis, while IGF-I + TGF-alpha + TGF-beta1 suppressed this inhibitory action. IGF-I significantly (P < 0.05) enhanced the follicle survival, growth and induced antrum formation. FGF had greater effects on both survival and growth rate of oocytes than other treatment groups. Progesterone and estradiol accumulation was significantly (P < 0.05) greater in presence of FGF and IGF-I than TGF-alpha + TGF-beta1. CONCLUSION: Survival, growth, antrum formation and steroidogenesis are stimulated by IGF-I and bFGF, whereas TGF-alpha + TGF-beta1 inhibited growth and survival of PFs which led to induced oocyte apoptosis in buffalo PFs. PMID- 20726114 TI - Photoreceptor fine structure in the archerfish. AB - The fine structure and arrangement of the photoreceptor cells of the archerfish (Toxotes jaculatrix) have been studied by electron microscopy.Rods, twin cones, and single cones are present. In the light-adapted state, the rods are very tall cells reaching almost to the base of the retinal epithelial cells. The outer segment is composed of membranous discs of uniform diameter displaying a single incisure. The rod inner segment displays a distal small ellipsoid and an extremely thin myoid region. The nuclei of rods are electrondense,and the synaptic spherule displays two or three invaginated sites. The single cone is similar to the individual members of a twin cone and displays a tapering outer segment and accompanying accessory outer segment. The wider cone inner segment contains a large, centrally located ellipsoid and a peripheral region rich in endoplasmic reticulum, polysomes, and microfilaments.Twin cones display subsurface cisternae along their entire contiguous surfaces.The cone nuclei are large and vesicular and located vitread to the external limiting membrane. The synaptic pedicle of cones is larger and more electronlucent and contains more invaginated "ribbon" synaptic sites (ten to 12) than do rods. In addition, small "coated" invaginations and larger synaptic vesiclefilled processes are also seen within cone pedicles. In the light-adapted state the cone photoreceptors are arranged in a repeating square mosaic pattern with one single cone surrounded by four twin cones. PMID- 20726116 TI - Characterstics of motor innervation of muscle spindles in the monkey. AB - The motor nerve supplies of four whole muscle spindles and 16 half spindles (equator and one pole) from lumbrical muscles of the monkey were reconstructed by light microscopy of serial, 1-microm-thick transverse sections.The 24 poles of spindle were innervated by 37 fusimotor (gamma) axons and 18 skeletofusimotor (beta) axons. Sixty-seven percent of spindle poles received gamma axons only, 25% were supplied by both gamma and beta axons or beta axons only, and 8%were not innervated by motor axons. All beta axons except one and 35% of the gamma axons innervated one type of intrafusal fiber only. The other 65% of gamma axons coinnervated two or three different types of intrafusal fiber. Gamma axons innervated the (dynamic) bag1, intrafusal fiber together with the (static) bag2,and or chain fibers in 65% of the poles of spindle in which the bag1 fiber received motor supply. The bag2 fiber shared gamma-innervation with either the bag1 or chain fibers in nearly every spindle pole. The chain fibers were usually coinnervated with the bag2 fiber by gamma axons. Compared to spindIes in the cat tenuissimus muscle, the monkey spindle received fewer gamma axons and had a higher incidence of shared gamma-innervation between the dynamic and static intrafusal fibers. Unlike cat tenuissimus spindles, the monkey spindles lacked gamma axons selective to the bag2 fiber. However, the beta motor system within the monkey lumbrical muscle was organized in a manner similar to the cat tenuissimus muscle. The significance of these observations is discussed relative to the general motor organization and function of spindles in different muscles and species of mammals. PMID- 20726115 TI - Graded morphogenetic patterns during the development of the extraembryonic blood system and coelom of the chick blastoderm: A scanning electron microscope and light microscope study. AB - This scanning electron- and light-microscopic study traces the morphogenesis of the yolk-sac vascular system and extraembryonic coelom in the chick blastoderm. The fate of the mesodermal cells in both the area opaca vasculosa (AOV) and the area pellucida (AP) is followed, and the cellular patterning in these two areas is compared. We describe new details of the formation of coelom lining in the AOV, and new observations of the tendency of the intravascular blood island cells of the AOV to become flattened and attenuated. The morphogenesis of the blood system and coelom is analyzed in terms of polarized morphological patterns with coordinates in two modes:proximodistal (from the AP to the AOV) and dorsoventral (from the ectoderm to the endoderm). By highlighting differences in the methods of formation of blood vessels and coelom lining in the AP and AOV, this paper resolves some paradoxes in the literature. PMID- 20726117 TI - Sulfation and transport of basement membrane proteoglycans, as visualized by (35)S-sulfate radioautography in the endodermal cells of the rat parietal yolk sac. AB - In the hope of clarifying the biogenesis of basement membrane proteoglycans, an injection of (35)S-sulfate was given to concepti of 12-day gestant Sherman rats. The parietal wall of the yolk sac (including endodermal cells and the associated basement membrane known as Reichert's membrane) was removed at times varying from 7 min to 24 hr after injection and processed for electron microscopic radioautography. Silver grains were counted over the organelles of endodermal cells as well as over Reichert's membrane. Between 7 min and 2 hr after (35)S sulfate injection, radioactivity was observed in the endodermal cells, while from 4 to 24 hr it was mostly present in Reichert's membrane. Detailed distribution of the cellular radioactivity at 7 and 15 min showed about 20% in the rough endoplasmic reticulum (rER), 60% in the Golgi apparatus, and 8% in secretory granules. The radiactivity present in rER and Golgi apparatus decreased to low levels by 2--4 hr after injection. In secretory granules, radioactivity increased to reach a peak at 2 hr and then declined; moreover, only the granules associated with the trans Golgi face were radioactive at early time intervals, while those scattered through the cytoplasm and along the cell surface became radioactive at later times. Between 4 and 24 hr, radioactivity became negligible over all cell organelles, while it was collected in Reichert's membrane.Biochemical reports indicate that when (35)S-sulfate is added to organ cultures of Reichert's membrane and endodermal cells, about 90% of the incorporated which these proteoglycans acquire sulfate are likely to be those labeled at 7 min after (35)S sulfate injection, that is, the Golgi apparatus and to a lesser extent the rER, whereas some labeling of the secretory granules located at the trans Golgi face is explained by rapid acquisition of sulfated proteoglycans from the Golgi apparatus. Label later appears in the secretory granules along the cell surface and, eventually, in Reichert's membrane. It is concluded that secretory granules transport newly formed proteoglycans from the Golgi apparatus to the outside for deposition into Reichert's membrane. PMID- 20726118 TI - Implantation in the rhesus monkey: Endometrial responses. AB - In this continuing series of studies of implantation in the rhesus monkey, eight specimens, ranging in gestation age from 9.5 days to 16.5 days after ovulation, were examined with a focus on localized modifications in the endometrium as a response to implantation. Additionally, evidence of continuing changes in early pregnancy was provided by three specimens at the end of the first month of gestation (days 24, 28, and 35). The responses of the endometrium to pregnancy start with a localized accumulation of stromal eosinophils, which is rapidly followed by epithelial plaque formation in the basal cells of the luminal epithelium and gland necks. Plaque cells hypertrophy, develop marginal dense granules, and accumulate glycogen. They form a pad underlying the margins but not the central zone of the implantation site. However, some degenerating plaque cells are found as early as day 15; and little more than a region of leukocytic infiltration remains of the plaque by day 35. Shortly after the plaque response is initiated there is a striking subepithelial edema surrounding the plaque, and the venular capillaries enlarge by engorgement and by endothelial hyperplasia. The endothelial cells subsequently hypertrophy, resulting in a largely columnar endothelium. There is a localized decidual cell response, consisting of an increase in rough endoplasmic reticulum and in filaments, but only a moderate amount of hypertrophy of these cells. Endometrial granular cells become more conspicuous in the area as they accumulate glycogen. Patches of large pale cells appear in the lumen and walls of arterioles subjacent to the implantation site, but the cytology of these cells provided insufficient clues to their origin (cytotrophoblast?). Although the endometrial responses described are impressive and diverse, their advantages to the organism are not obvious. The hypertrophy of the anastomotic capillary bed that accompanies plaque formation may well provide an extensive vascular network available to the developing trophoblastic lacunae. The role of endometrial granular cells, decidual cells, and even plaque cells may be more related to their largely unexplored secretory activity than to their physical contribution to the formation of the basal plate. PMID- 20726119 TI - Interaction of the peritoneal cavity to intraperitoneal stimulation: A peritoneal model system to monitor cellular and extracellular events in the formation of granulation tissue. AB - The intraperitoneal injection of bacterial toxin and complete Freund's adjuvant in mice produced the classical inflammatory response. However, when allowed to continue, this process led to the formation of granulation tissue of the mesothelial surface. The initial lesion of the reaction was characterized by the deposition of a copious amount of fibrin filaments which were involved in the adhesion and aggregation of peritoneal cells into discrete cellular mounds on the peritoneal mesothelial surface. By 1 week postinjection, fibrin was markedly diminished and appeared as electron-dense precipitates upon which collagen fibrils were deposited. By 2 weeks, the amount of collagen was greatly increased; and the granular components of fibrin were markedly diminished. Coincident with the deposition of collagen fibrils, there was also a neovascularization of the cellular aggregates. This process occurred when the blood and lymphatic vessels within the submesothelial connective tissue branched and invaded the newly aggregated cellular mounds. By 1 month, the cellular aggregates had taken on the appearance of granulation tissue with foci of closely packed macrophages, fibroblasts, and a network of newly formed blood and lymphatic capillaries. This intraperitoneal stimulation provides an in vivo system in which the various cellular and extracellular events of inflammation leading to the formation of granulation tissue can be monitored. PMID- 20726120 TI - Distribution of taste and general sensory nerve endings in fungiform papillae of the hamster. AB - Sensory endings of chorda tympani and lingual (trigeminal) nerve fibers were identified by selective denervation and localized within specific regions of fungiform pipillae in the hamster. The chorda tympani was resected from the middle ear and the peripheral fibers were allowed to degenerate for 1, 3, or 8 days prior to perfusion-fixation and electron-microscopic examination of the anterior tongue. Taste buds were virtually devoid of intact nerves by 3 days following chorda tympani denervation. Remnants of the fibers were restricted to taste buds. Lingual fibers, on the other hand, persist in normal numbers after chorda tympani resection and populate perigemmal areas of connective tissue and extragemmal areas located apically in the squamous, nontaste epithelium surrounding the taste bud. This study provides evidence of a segregation of chorda tympani fibers in the taste bud and lingual nerve fibers in the apical fungiform papilla. The lingual nerve-epithelial arrangement and superficial location, near the least cornified area of the tongue, may be well suited for relatively sensitive somatosensation, possibly mechanoreception. Thus, the apical fungiform papilla appears to be a site where both taste and tactile oral stimuli interact with receptors. PMID- 20726121 TI - Nature and function of endocytosis in Sertoli cells of the rat. AB - The endocytic activity taking place at the apex of Sertoli cells was analyzed by using various tracers to demonstrate fluid-phase and adsorptive endocytosis. Native ferritin and protein-gold complexes, used to demonstrate fluid-phase endocytosis, were internalized by Sertoli cells at all stages of the cycle of the seminiferous epithelium. At 5 min after injection, the tracers were found in the large spherical or C-shaped vesicles seen in the apical processes; at 15 and 30 min, the tracers accumulated in light multivesicular bodies, and at 60 min in dense multivesicular bodies and lysosomes. At later time intervals, an increasing number of lysosomes contained the tracers. Following injection of cationic ferritin or concanavalin A-ferritin, these tracers, used to demonstrate adsorptive endocytosis, were found to be found to the plasma membrane of Sertoli cell apical processes but were not collected by the large cytoplasmic apical vesicles, multivesicular bodies, or lysosomes. As an exception, a few special multivesicular bodies seen in the large apical processes which encapsulate the heads of late spermatids at stage VII of the cycle contained these tracers. During stage VIII of the cycle, the residual bodies which detach from the mature spermatids are phagocytosed by Sertoli cells. Such residual bodies do not contain their own hydrolytic lysosomal enzymes. However, it was observed that the lysosomes which form as a result of the fluid-phase endocytic activity of the Sertoli cells fuse with the phagocytosed residual bodies and by means of their hydrolytic enzymes contribute to the rapid disintegration of these bodies. Thus, during stage VIII of the cycle, the Sertoli cells integrate two distinct processes, i.e., fluid-phase endocytosis and phagocytosis. PMID- 20726122 TI - Usage pattern of the complex masticatory muscles in the shingleback lizard, Trachydosaurus rugosus: A model for muscle placement. AB - This wide-ranging, omnivorous lizard of Australia has a very complex adductor muscle mass, with fibers differing in length by a factor of three and in insertion angle by 90 degrees. Stimulated muscles produce maximal moment with the mouth nearly fully open. The opening mechanism appears to involve only simple rotation and no translation of the mandible. EMGs indicate that the entire mass is activated equivalently in crushing and there are no temporal subdivisions, for instance, matching activity to angle of opening. During crushing of hard objects, the chin is brought into contact with the ground so that the subvertebral muscles may aid buccal closure. The lizards also activate the muscles in a pulsatile staircase effect leading to an unfused tetanus that generates forces several times the twitch level. Application in parallel of a maximum number of sarcomeres to the crushing bite appears to be the major design characteristic. Hence, this species offers an ideal case for analysis of the effects of different sarcomere placements on the simple movement generated. For the primary adductor muscles, the angles of fiber insertion relative to the lines connecting each insertion with the jaw joint are equivalent; this relation persists as the mouth opens. Also, fiber lenghts are proportional to the distance between jaw joint and site of insertion so that each sarcomere contributes equally to the movement generated. Complex tendons provide additional space for muscle placement. Some of these also extend beyond the bony attachment sites, producing tendinous "coronoid processes." The fibers of laterally and ventrally placed muscles are short relative to the length of the entire muscle, insert at relatively short moment arms, and undergo short excursion during opening; however, there are many such fibers. Also, muscles with a low incident angle are crossed; they apparently protect the jaw joint from horizontal (disarticulating) forces. PMID- 20726123 TI - Detection of anionic sites on the cytoplasmic surface of the guinea pig acrosomal membrane. AB - The sperm acrosome reaction is an example of exocytosis, accomplished through the fusion of the acrosomal and plasma membranes. As in other examples of exocytosis, the acrosome reaction is initiated by an influx of Ca++, which may promote fusion by binding to anionic sites on adjacent bilayers. In this study we used ruthenium red (RR) and cationic ferritin (CF) to detect anionic sites on the surfaces of acrosomal and plasma membranes of guinea pig spermatozoa. These probes indicate a dense concentration of anionic sites on the cytoplasmic surface of the acrosomal membrane. Higher concentrations of salt (NaCl) were required to inhibit cationic probe labeling of the cytoplasmic surface of the acrosomal membrane compared to the concentration needed to inhibit the plasma membrane binding. The added NaCl also increased the separation of the plasma from the acrosomal membrane. Low-pH buffers stop cationic probe labeling of both membranes. Sections tangential to the acrosomal membrane revealed that the cation probes bound in a linear pattern, similar to the periodicity and distribution of intramembraneous particles observed in freeze-fracture replicas. Following fusion of the plasma and acrosomal membrane during the acrosome reaction, we could no longer detect a dense concentration of anionic sites on the cytoplasmic surface of the fused vesicles. The results indicate that the dense concentrations of anionic sites are either masked or lost following fusion with the overlying plasma membrane. PMID- 20726124 TI - The plasma membrane and matrix vesicles of mouse growth plate chondrocytes during differentiation as revealed in freeze-fracture replicas. AB - The epiphyseal cartilage in mouse tibia and fibula was investigated with the freeze-fracture method. Cytodifferentiation of growth plate chondrocytes was found to be marked by changes in both cell membrane and extracellular matrix vesicle membranes. Exocytosis and endocytosis were observed in all zones of differentiation, with endocytosis being predominant in the reserve and proliferative zones and exocytosis occurring with greatest frequency during hypertrophy. Intramembraneous particles (IMPs) on the plasma membrane were distributed evenly on the reserve and proliferative cell membranes, whereas in the hypertrophic zone IMPs tended to be distributed asymmetrically. Several types of matrix vesicles were identifiable on the basis of IMP distribution: IMP-free, IMP-aggregated, and IMP-random. The distribution pattern of IMPs on vesicles varied with differentiation of the chondrocytes. For proliferative and prehypertrophic cells, most matrix vesicles belonged to the IMP-random category. IMP-aggregated and IMP-free matrix vesicles became increasingly frequent in the later stages of differentiation, particularly in the late hypertrophic stage. IMPs were observed more frequently on the convex protoplasmic fracture face of matrix vesicles than on the concave exoplasmic fracture face, as was also observed for the plasma membrane. Matrix vesicles formation appears to occur by budding from chondrocyte projections and bulges at the smooth surfaces of the cells and from cell disintegration. Crystals of mineral were apparent in cross fractured matrix vesicles of the calcifying zone, but not in the other zones. PMID- 20726125 TI - Ultrastructural characterization of epithelial cell membranes in normal human conducting airway epithelium: A freeze-fracture study. AB - Cell membranes of normal human nasal and tracheal epithelium were characterized by means of freeze-fracture preparations. These investigations illustrated a predictable variability in the distribution of membrane-associated particles on PF-faces of different cell types and in different regions of the same cell. Details of the fine structure and variability of tight junctional complexes in different cell types are presented as are ultrastructural perspectives of cell membrane involvement in ciliogenesis and in mucus secretion. Because ciliogenic profiles and nascent tight junctional complexes were observed more frequently in nasal epithelial cells, these features provided markers of cellular differentiation. Based on the frequent appearance of such indicators, these observations suggested that cell turnover may be more rapid in the region of the nasal turbinates than in the trachea. There was no appreciable evidence of ultrastructural variability between the epithelial cell membranes of similar cell types in the upper and lower respiratory tract. PMID- 20726126 TI - A functional and morphological study of cells adjacent to ectopic bone implants in rats. AB - Subcutaneous implantation of bone chips into normal and osteopetrotic (ia) rats results in the formation of multinucleate giant cells (MNGCs) adjacent to the bone surface. In this study the resorptive and morphological characteristics of the cells surrounding these implants were assessed to determine if the bone resorbing defects seen in ia animals would be mimicked, thus giving validity to the use of this system as a model for the study of osteoclastic lineage and function. Direct measurement of in vivo bone resorption was achieved through the use of (45)Ca-labelled bone-chip pairs that were primarily osteoid-exposed and freeze-thawed (FT), primarily mineral-exposed and bleached (B), or primarily mineral-exposed and collagenase-treated (CT). Comparison of the (45)Ca content of implanted chips to that of controls indicated the total (45)Ca release during a two-week implantation period. There was no significant difference in the amount of label released between normal and ia animals. Both normal and ia rats showed 23% greater total (45)Ca release from mineral- versus osteoid-exposed matrix. Cellular events occurring on the bony substrate were evaluated by light and electron microscopy. At 3 days, bone chips were surrounded primarily by mononuclear cells. By 14 days, MNGCs were present at the bone surface in both ia and normal animals. In mineral-exposed implants, 40-50% of the bone surface was covered by MNGCs as compared to 20% of the osteoid-exposed surface. These MNGCs possessed occasional clear zones, but did not exhibit ruffled borders; therefore, they could not be classified as osteoclasts. Thus, the defects seen in ia mutants were not reproduced in this implant system. The (45)Ca release that occurred was probably due to the action of mononuclear phagocytes and macrophage polykaryons rather than to true osteoclastic bone resorption. PMID- 20726127 TI - Light-microscopic stereology for the study of the ventral and dorsal prostates of the syrian hamster: Strategy, techniques, and applications. AB - A stereological approach to studying the architecture of the ventral and dorsal prostates of the Syrian hamster is described. In this approach, the prostate is considered to consist of acinar and interacinar compartments. The acinar compartment is divided into luminal, epithelial, lamina proprial, and muscular stromal compartments. Volume fractions of acini and interacinar tissue are calculated with reference to the volume of the gland; those of the acinar components are calculated with reference to the acinar volume. Volume fractions are determined from point counts. The surface fraction of the secretory epithelium is determined from intercept counts, with reference to the volume of the epithelium. By assuming that the acini are cylindrical, the acinar length fraction is calculated with reference to the volume of the gland. Absolute values for the volumes of different components, epithelial surface area, and acinar length can be determined from the weight of the gland, its specific gravity, and the volume fraction of that component, or epithelial surface fraction, or acinar length fraction, respectively. Finally, from these values and assuming a cylindrical shape for acini, characteristics of the typical acinus, including its radius, the thicknesses of its epithelium, lamina propria, and muscular stroma, and the amount of mucosal folding can be calculated from simple geometrical formulae. This approach is illustrated from a consideration of the ventral and dorsal prostates of 20-week-old Syrian hamsters. PMID- 20726128 TI - Effects of short-day photoperiods and of castration on the structural integrity of the ventral and dorsal prostates of the Syrian hamster (Mesocricetus auratus). AB - Short-day photoperiods and castration both cause reductions in the weights of male accessory sex glands. In the Syrian hamster, we have found that the ventral prostate loses less weight following these treatments than does the dorsal prostate. In this paper, we report on the effects of the pineal and of castration on the structural integrity of these glands, as assessed by stereological techniques. Short days result in little alteration to the ventral prostate or its acinar composition. The typical acinus is narrower following 10 weeks in short days. The ventral prostate also responds to castration with a narrower acinus, and, in addition, it shows a decrease in the epithelial volume fraction and increases in those of the lumen and muscular stroma. In neither case is there a change in the proportion of the gland consisting of acinar or interacinar components. Short-day photoperiods and castration generally show similar effects in the dorsal prostate. In both cases, there are increases in the proportion of the gland made up of interacinar tissue. Within the acini, there are decreases in the volume fractions of lumen and large increases in those of lamina propria and muscular stroma. Following both treatments, typical acini are narrower and show reduction in the thickness of the epithelium and increases in the thickness of the lamina propria and muscular stroma.Thus, in the ventral prostate, both short days and castration lead to subtle changes which are different with each treatment and which differ from those that occur in the dorsal prostate. In the dorsal prostate, there are relative increases in the proportions of nonepithelial elements following both of these treatments. These results are discussed in relation to the mode of action of the pineal in causing accessory sex gland regression. PMID- 20726129 TI - An experimental analysis of the developmental capacities of distal parts of avian leg buds. AB - The development, differentiation, and pattern formation of isolated distal parts of avian leg buds that had grown ectopically on the chorioallantoic membrane (CAM) or in the coelomic cavity were studied. The grafts grown on the CAM invariably gave rise to cartilage and soft connective tissue. In some cases muscle tissue was also found. The CAM grafts did not undergo overt morphogenesis and pattern formation. A high percentage of grafts grown in the coelomic cavity showed a close approximation to normal limbs. The presence of proximal structures depended on the stage of development of the donor at the time of the operation, on the size of the grafts, and on the site to which the graft was attached within the coelom. The presence of anteroposterior structures depended on the shape of the graft. The pattern formation of this axis was found to be independent of the presence of the zone of polarizing activity at the proximal posterior border of the bud. The distance from the tip of the bud to the line of most distal colonization by myogenic cells was determined. The speed of migration of the myogenic cells can be considered to be constant. In muscleless legs, tendons developed at the levels of the phalanges and the tarsometatarse. They degenerated, however, in the absence of muscle from day 9 on, from proximal to distal areas. CAM grafts as well as coelomic grafts were well vascularized. The endothelial cells of the blood vessels were of host origin. In coelomic grafts, nerves were present with Schwann cells of host origin. The nerves and blood vessels showed a distribution that resembled that in normal legs. PMID- 20726130 TI - The Romans and ritual murder. AB - The Roman abhorrence of human sacrifice presented by ancient literary sources stands in contrast to the frequency of rites requiring the death of a human being performed by the Romans during the Republic (509-44 BCE). After examining the ways our sources talk about ritual murder, especially as it was practiced by foreign peoples and subversive or tyrannical elements within Roman society, this discussion turns to the issue of the forms of ritual murder performed by the Romans. Of these various rites, the only one clearly identified by them as human sacrifice, that is, as an offering to the gods of a human life, is the live interment of Gauls and Greeks. Other forms of ritual murder-the burial of unchaste Vestal Virgins and the drowning of hermaphroditic children-were not, in Roman opinion, sacrifice. This distinction made the disposal of Vestal Virgins and hermaphrodites acceptable. PMID- 20726131 TI - What's new in science and race since the 1930s?: anthropologists and racial essentialism. PMID- 20726132 TI - Rare models: Roger Casement, the Amazon, and the ethnographic picturesque. AB - In 1910 Roger Casement was sent by the British government to investigate the alleged humanitarian abuses of the Peruvian Amazon Company in the Putumayo, a disputed border zone in North West Amazonia. Casement brought more than verbal and written testimony back to London. On 26 June, some six months after he returned from the Amazon, Casement collected two Amerindian boys - Omarino and Ricudo - from Southampton docks. This paper will reconstruct the brief period that these young men spent in Britain in the summer of 1911 and assess, in particular, to what extent they were treated as 'exhibits' by Casement, who not only introduced them to leading members of the British establishment but also arranged for them to be painted and photographed following contemporary ethnographic conventions. PMID- 20726133 TI - From golden hills to sycamore trees: pastoral homelands and ethnic identity in Irish immigrant fiction, 1860-75. AB - The prose fiction that remembers the trials of starvation and eviction of the Great Famine (1845-50) often juxtaposes representations of blasted, infertile land with images of a green, idyllic Erin. Through a discussion of Mary Anne Sadlier's Bessy Conway (1861), Elizabeth Hely Walshe's Golden Hills: A Tale of the Irish Famine (1865) and John McElgun's Annie Reilly (1873), this article reveals that immigrant writers of the Famine generation often negotiate depictions of Famine-stricken wasteland with evocations of a pastoral homeland. In the case of the two Catholic novels, Bessy Conway and Annie Reilly, the pastoral becomes a point of ethnic identification through which the immigrants can recollect and reconstruct a sense of Irishness in exile. By contrast, Golden Hills, which focuses on the Anglo-Irish ascendancy, does not lament the mass exodus of afflicted Irish: the novel rather envisions emigration as a way to regenerate Ireland as locus amoenus. PMID- 20726134 TI - Poverty in Eritrea: challenges and implications for development. AB - Poverty, one of the world's most serious problems, is particularly severe in Africa. Eritrea is a 16-year-old nation that gained its independence from Ethiopia in 1993. The country's economy was doing relatively well between 1993 and 1997. Eritrea was then exposed to numerous challenges such as drought, famines and recurrent war. As a result, poverty has become more rampant in a country where over 66 per cent of people live below the poverty line. Some families live on remittances. The government has taken some poverty alleviation measures. However, it has not mitigated poverty due to a lack of resources and a poorly implemented poverty alleviation programme. This article attempts to explore the incidence of poverty. It also provides details of poverty surveys that have been conducted since independence. It discusses various poverty challenges and provides some policy implications for development. PMID- 20726135 TI - Heads of household programme in Argentina: a human rights-based policy? AB - This study analyses the consultative councils (CC) of the Argentinian conditional cash transfer heads of household programme as an institutional innovation directed to put into practice some of the principles of the human rights' approach for eradicating poverty. Since the main responsibilities assigned to the CCs coincided with some of the main principles of the human rights' approach, the research is focused on how CCs responded in practice. Using a case study methodology we show that even when, in theory, the CCs incorporate some of the principles of the human rights' approach to the programme, they deviated from this purpose due to a persistent phenomenon in the social policy arena in developing countries: political clientelism. Policy recommendations are formulated in order to deal with clientelism in the framework of the human rights' approach. PMID- 20726136 TI - Rights questioned. Limitations of poverty-reduction policies in Argentina. AB - This article analyses, from a human rights' approach, a group of social programmes implemented in Argentina from the year 2002, at the time of the biggest socioeconomic crisis that the country has suffered in the last decades. The main characteristics of the programmes are reviewed, and their anti-poverty strategy, along with design and implementation, are evaluated in relation to human rights. An assessment is also made of the existence of mechanisms for citizens to present claims. Finally, a set of recommendations are made to facilitate the adaptation of the programmes analysed to the duties the State of Argentina has as result of its adherence to international laws on human rights. The analytical methodology proposed by this article could be applied to other policy areas. PMID- 20726137 TI - The ethical review of health care quality improvement initiatives: findings from the field. AB - Questions have been raised about whether and how health care quality improvement (QI) initiatives ought to be reviewed to address possible ethical issues associated with them. These questions have focused primarily on whether some QI initiatives meet the regulatory criteria for human subject research and should therefore be regulated and reviewed as such. Based on surveys of health care system professionals conducting QI initiatives and hospital CEOs, this issue brief finds that QI initiatives are routinely reviewed by a variety of internal mechanisms prior to implementation, although rarely through an institutional review board or another independent body charged specifically with ethical oversight of QI initiatives. Further research, the authors say, is needed to achieve a better understanding of how review mechanisms for QI initiatives are structured, including information on who reviews these activities, how they are reviewed, and whether such processes include an ethical assessment of the proposed QI initiative. PMID- 20726138 TI - Integrated human rights and poverty eradication strategy: the case of civil registration rights in Zimbabwe. AB - High poverty levels characterise sub-Saharan Africa, Zimbabwe included. Over 80 per cent of Zimbabwe's population lived below the total consumption poverty line and 70 per cent below the food poverty line in 2003. This plummeting of social indicators resulted from the freefall suffered by the country's economy from the 1990s, after unsuccessful attempts to implement structural adjustment programmes prescribed by international financial institutions. The ensuing socioeconomic decay, political crisis and international isolation of the country from the late 1990s reversed gains made in social indicators during the 1980s. Development theories attribute poverty to unchecked population growth, political, economic and environmental mismanagement, while developing countries' leaders attribute it to historical imbalances and global political and economic injustices. Despite this debate, poverty continues to evolve, expand and deepen and the need to eradicate it has become urgent. The complex question of what causes and what drives poverty is perpetually addressed and new ideas are emerging to answer the question. One recent view is that failure to centre development on people and to declare poverty a violation of human rights has allowed poverty to grow the world over. This study uses a hypothesised cause of poverty - civil registration - to exemplify the human right nature of poverty, and how a human rights' policy can be used as an instrument to eradicate poverty. The study demonstrates that civil registration is a right of instrumental relevance to poverty; and achieving civil registration grants people access to numerous other rights, some of which will lift them out of poverty, while the failure of civil registration deprives people of access to livelihoods, thereby entrenching them in poverty. PMID- 20726139 TI - Poverty alleviation in Nigeria: lessons from socioeconomic thoughts of the Yoruba. AB - Nigeria is the 13th largest oil producer in the world. Yet about 56 per cent of the total population lives in absolute poverty. This article confronts conventional theories of poverty with the indigenous thoughts of the Yoruba (one of the three major ethnic groups in Nigeria). Darwinian, individualistic, cultural, situational and structural theories of poverty associate it either with individual-case or economy-wide factors. Approaching anti-poverty strategy through individual-related factors (such as training the unskilled poor) without due consideration to the economy-wide factors (such as job creation for the poor) ends up redistributing rather than actually reducing aggregate poverty. The analysis of poverty-related proverbs of the Yoruba reveals a consistency between the conventional theories and what the Yoruba think about poverty. The Yoruba believe in chronic (osi) versus transitory (ise) poverty, associated with suffering. They believe that poor people can escape the poverty trap through their own personal efforts (such as by developing a positive work attitude, working hard and reducing their family size) along with the help of support systems (such as job creation and food security). The Yoruba believe that job creation is the best anti-poverty strategy. They further believe that by removing hunger, poverty becomes insignificant. Based on these two axioms, this article suggests that attention be paid to job creation and food security for the poor. It also recommends that studies of the socioeconomic thought of the other major Nigerian tribes with respect to poverty be undertaken, so as to arrive at nationally and culturally derived anti-poverty strategies in Nigeria. PMID- 20726140 TI - Socioeconomic effects of HIV/AIDS and farmers' involvement in risky behaviour in southern Nigeria. AB - This article analyses farmers' perceptions on the socioeconomic effects of HIV/AIDS and factors associated with their involvement in risky behaviour in southern part of Nigeria. The data were collected in 2004 from 515 farmers in five randomly selected states in southern Nigeria. The results show that most of the affected farmers spend reduced hours in daily work, as well as having a reduced income and reduced participation in community development due to HIV/AIDS. Logistic regression reveals that age and education significantly reduce the probability of being involved in behaviour conducive to HIV/AIDS infection, which is increased by not believing in the existence of HIV/AIDS, ignorance about HIV/AIDS methods of prevention, lack of warning about HIV/AIDS, reports of HIV/AIDS in the village, the distance to the public health centre and the lack of a health centre. These findings, while unsurprising, emphasise the importance of HIV/AIDS as a socioeconomic issue. PMID- 20726141 TI - Determinants and impacts of international remittances on household welfare in Vietnam. AB - Remittances can potentially help to promote economic development by providing a mechanism to share risks, reduce poverty and improve equality. However, from the viewpoint of economic theory the overall impacts of remittances are uncertain, as different mechanisms lead to opposite impacts. Since the 1990s Vietnam has experienced a dramatic growth in remittance flows from abroad. Vietnam is a unique case for study, as economic motives historically played a smaller role in outward migration than in other countries. Fortunately, household survey data are available for this time period, allowing for a detailed analysis of the impacts of international remittances on Vietnam. Specifically, we examine the characteristics of recipients and the impacts of international remittances on economic inequality and poverty. We conclude that international remittances are helping to improve equality. For this reason, new development policies must also account for their potential impacts on remittance flows. PMID- 20726142 TI - Social change and transformations in housing. AB - This study aims to illustrate how residential morphology and home-use patterns reflect the transition from semi-nomadism to an urban lifestyle undergone by the Bedouin of the Negev (Israel). Thirty houses and 300 building plans were studied while planners, builders and residents were interviewed. Three types of buildings and home-use patterns were identified. Each type corresponds to a stage in the Bedouin adaptation to urban life in government resettlement towns. The state encourages resettlement by selling developed land at a low price and providing access to subsidies and mortgages, while refusing to develop property and not hesitating to demolish houses built on tribal sites. The houses built over the past 30 years are indicators of Bedouin lifestyle adaptation, as the Bedouin have been increasingly involved in their design. The empirical basis for this study is an analysis of the houses in Tel Sheva, the first of seven resettlement towns built for the Bedouin in the Negev. The houses considered were built between 1972 and 2002, with 1972 marking the beginning of the period in which the Build-your own-home development scheme was applied to the Bedouin, a scheme in which plots of about 1,000m2 are allocated and owners are responsible for building on them. PMID- 20726143 TI - The right of all nations to access science, new technologies and sustainable development. AB - This article explores the need for reflection on the right of developing countries to science and technology in addition to explaining the place of the scientific rights of nations in human rights as a whole. The discussion was conducted in relation to sustainable development. Through the examination of the current situation and the challenges to sustainable development, and taking into account the imbalance in the distribution of the benefits of science and new technologies, the authors advocate a comprehensive approach to promote cooperation and capacity-building in this area. They argue that linkages should be adopted between micro-levels and macro-levels of analysis by elevating rights and related issues from individuals to the national level in the field of the right to science and technology, and from the national to the international level in the field of sustainable development in order to institutionalise and ensure individual and national rights to science, technology and sustainable development. The authors also believe in a multidimensional perspective based on the balanced flourishing of the material and immaterial aspects of humankind in order to realise these rights in the context of dialogue and cultural diversity and to promote the culture of sustainable and dynamic peace based on justice in knowledge societies. PMID- 20726145 TI - Mother abuse: a matter of youth justice, child welfare or domestic violence? AB - International evidence suggests that in advanced welfare states the abuse of parents, most particularly mothers, by their (most frequently male) adolescent children is increasingly prevalent. In the United Kingdom, however, child-to mother abuse remains one of the most under-acknowledged and under-researched forms of family violence. Although it is an issue shrouded in silence, stigma, and shame, the authors' work in the youth justice sphere, focusing on interventions to deal with anti-social behaviour, suggests that adolescent violence toward mothers is a topical and prevalent issue. We identify different ways of conceptualizing it in the policy realms of youth justice, child welfare, and domestic violence. The behaviour of both child/young person and mother is constructed in ways which inform the assignment of blame and responsibility. The paper highlights the silence that surrounds the issue in both the policy and wider academic spheres, hiding the failure of service providers to respond to this very destructive form of intimate interpersonal violence. PMID- 20726146 TI - Poverty concentration and determinants in China's urban low-income neighbourhoods and social groups. AB - Based on a large-scale household survey conducted in 2007, this article reports on poverty concentration and determinants in China's low-income neighbourhoods and social groups. Three types of neighbourhood are recognized: dilapidated inner city neighbourhoods, declining workers' villages and urban villages. Respondents are grouped into four categories: working, laid-off/unemployed and retired urban residents, together with rural migrants. We first measure poverty concentration across different types of neighbourhood and different groups. The highest concentrations are found in dilapidated inner-city neighbourhoods and among the laid-off/unemployed. Mismatches are found between actual hardships, sense of deprivation and distribution of social welfare provision. Second, we examine poverty determinants. Variations in institutional protection and market remuneration are becoming equally important in predicting poverty generation, but are differently associated with it in the different neighbourhoods and groups. As China's urban economy is increasingly shaped by markets, the mechanism of market remuneration is becoming a more important determinant of poverty patterns, especially for people who are excluded from state institutions, notably laid-off workers and rural migrants. PMID- 20726144 TI - Conditional rights, benefit reform, and drug users: reducing dependency? AB - United Kingdom government policy to increase social security claimants' entry to the labour market through conditions attached to unemployed, sickness and incapacity benefits now includes additional measures to activate particular groups such as lone parents and drug users. The latter are a prime target because of their high level of dependency on benefits and because social security rules are seen as having the potential to modify the behaviour of individuals with a lifestyle regarded as being at odds with the moral obligations of citizenship and incompatible with the government's realization of its wider economic and social goals. There are strict procedures for the identification of drug-user claimants, enabling additional conditions to be attached to their benefit rights. This article discusses the general trend in benefit reform towards increased conditionality and evaluates the reforms affecting drug users, considering human rights and other implications. It concludes by reflecting on the status of conditional rights to social security as social rights. PMID- 20726147 TI - Enabling Housing Cooperatives: policy lessons from Sweden, India and the United States. AB - Housing cooperatives became active in urban areas in Sweden, India and the United States during the interwar period. Yet, after the second world war, while housing cooperatives grew phenomenally nationwide in Sweden and India, they did not do so in the United States. This article makes a comparative institutional analysis of the evolution of housing cooperatives in these three countries. The analysis reveals that housing cooperatives' relationship with the state and the consequent support structures explain the divergent evolution. Although the relationships between cooperatives and the state evolved over time, they can be characterized as embedded autonomy, overembeddedness and disembeddedness in Sweden, India and the United States respectively. Whereas the consequent support structures for housing cooperatives became well developed in Sweden and India, such structures have been weak in the United States. The article highlights the need for embedded autonomy and the need for supportive structures to enable the growth of housing cooperatives. PMID- 20726148 TI - The Conversion of Social Capital into Community Development: an intervention in Australia's outback. AB - The research presented in this article employed a deliberate intervention to mobilize social capital and then studied the dynamics of the way in which it influenced community development. Whether or not social capital is able to facilitate development depends on the specific context in which it occurs. Although the general context of this study was that of small rural towns in Australia's outback that are experiencing decline, each of the four towns studied had unique features which could influence the mobilization of social capital. Rural communities have the willingness and capacity to mobilize but whether this capacity is actualized may well depend on the presence of other mobilizing factors. Specifically the intervention study found that a structure needs to be in place which can take the initiative and work across the community - engaging a range of organizations. Second, the structure needs to be supported, but not controlled, by local government. Third, it needs the kind of social entrepreneurship that can sustain a community-wide vision and bring together the diverse groups within the community. PMID- 20726149 TI - Power learning or path dependency? Investigating the roots of the European Food Safety Authority. AB - A key motive for establishing the European Food Safety Authority (EFSA) was restoring public confidence in the wake of multiplying food scares and the BSE crisis. Scholars, however, have paid little attention to the actual political and institutional logics that shaped this new organization. This article explores the dynamics underpinning the making of EFSA. We examine the way in which learning and power shaped its organizational architecture. It is demonstrated that the lessons drawn from the past and other models converged on the need to delegate authority to an external agency, but diverged on its mandate, concretely whether or not EFSA should assume risk management responsibilities. In this situation of competitive learning, power and procedural politics conditioned the mandate granted to EFSA. The European Commission, the European Parliament and the European Council shared a common interest in preventing the delegation of regulatory powers to an independent EU agency in food safety policy. PMID- 20726150 TI - Treatment of claudication. PMID- 20726152 TI - Amoebiasis in Britain. PMID- 20726151 TI - Detecting foetal abnormalities. PMID- 20726153 TI - Beyond policy networks: policy framing and the politics of expertise in the 2001 Foot and Mouth Disease crisis. AB - For the past decade, the policy community/issue network typology of pressure group interaction has been used to explain policy outcomes and the policy-making process. To re-examine the validity of this typology, the paper focuses on the UK government's response to the 2001 Foot and Mouth Disease (FMD) crisis, and in particular the decision to pursue contiguous culling rather than vaccination to overcome the epidemic. Rather than illustrating the emergence of an issue network in agricultural policy, the decision-making process of the FMD outbreak demonstrates continuity with prior crises. In addition, the politicization of scientific expertise is identified as an emerging trend in crisis management. Policy framing is used to explain the impetus behind the contiguous cull decision, concluding that the legacy of previous policy choices conditioned the crisis response to a far greater degree than contemporaneous pressure group action. PMID- 20726154 TI - Inheritance of ichthyosis. PMID- 20726155 TI - Vitamin-E deficiency. PMID- 20726156 TI - Anaesthesia and the Liver. PMID- 20726157 TI - Exit, voice, and disappointment: mountain decline and EU compensatory rural policy in Spain. AB - The article analyses the Spanish experience of EU compensatory rural policy in order to contribute to broader debates on the effectiveness of this kind of policy and the role of agriculture in the definition of European rural policies. In the case of Spain, compensatory allowances to mainly mountain farmers had little effect on economic trajectories or social cohesion because of the small sums involved, the exclusion of those with very small farms, and the decreasing role of agriculture in the rural economy. Other, more structural, instruments of rural policy focused on small-scale promotion of business growth but were ill equipped to challenge some of the territorially defined items of living standard gaps. A historically grounded analysis suggests that the main changes in the social trajectory of Spain's mountain areas in the last decades have little to do with compensatory policy and are related to ordinary economic dynamics. PMID- 20726158 TI - Applying policy network theory to policy-making in China: the case of urban health insurance reform. AB - In this article, we explore whether policy network theory can be applied in the People's Republic of China (PRC). We carried out a literature review of how this approach has already been dealt with in the Chinese policy sciences thus far. We then present the key concepts and research approach in policy networks theory in the Western literature and try these on a Chinese case to see the fit. We follow this with a description and analysis of the policy-making process regarding the health insurance reform in China from 1998 until the present. Based on this case study, we argue that this body of theory is useful to describe and explain policy making processes in the Chinese context. However, limitations in the generic model appear in capturing the fundamentally different political and administrative systems, crucially different cultural values in the applicability of some research methods common in Western countries. Finally, we address which political and cultural aspects turn out to be different in the PRC and how they affect methodological and practical problems that PRC researchers will encounter when studying decision-making processes. PMID- 20726159 TI - Charles Hastings (1794-1866): founder of the British Medical Association. PMID- 20726161 TI - Flexible sigmoidoscopy. PMID- 20726160 TI - Similar problems, different solutions: comparing refuse collection in the Netherlands and Spain. AB - Because of differences in institutional arrangements, public service markets, and national traditions regarding government intervention, local public service provision can vary greatly. In this paper we compare the procedures adopted by the local governments of The Netherlands and Spain in arranging for the provision of solid waste collection. We find that Spain faces a problem of consolidation, opting more frequently to implement policies of privatization and cooperation, at the expense of competition. By contrast, The Netherlands, which has larger municipalities on average, resorts somewhat less to privatization and cooperation, and more to competition. Both options-cooperation and competition have their merits when striving to strike a balance between transaction costs and scale economies. The choices made in organizational reform seem to be related to several factors, among which the nature of the political system and the size of municipalities appear to be relevant. PMID- 20726162 TI - Oncology. PMID- 20726163 TI - Electroconvulsive therapy. PMID- 20726164 TI - Central venous catheter insertion--adults. PMID- 20726165 TI - [Actual theoretical problems of diagnostic, classification, neurobiology and therapy of schizophrenia: a comparison of international and Russian experience]. PMID- 20726166 TI - [The role of P.A. Butkovsky in the development of psychiatry in Russia (to 175 anniversary of teaching and publication of the first handbook on psychiatry)]. PMID- 20726167 TI - [Oxidative processes and lipid metabolism in the experimental induced Parkinsonian syndrome]. PMID- 20726168 TI - [The use of noben (idebenone) in the complex treatment of episodic and chronic migraine]. PMID- 20726169 TI - [Dysregulation of phospholipid metabolism of neuronal membranes in the nervous system pathology]. PMID- 20726170 TI - [Neurosteroids and addictive pathology]. PMID- 20726171 TI - Completion of national laboratory inventories for wild poliovirus containment: WHO Region of the Americas, March 2010. PMID- 20726172 TI - Chagas disease (American trypanosomiasis) fact sheet (revised in June 2010). PMID- 20726173 TI - [Techniques in clinical studies using QOL questionnaires--in otorhinology]. PMID- 20726174 TI - [Pathology of head and neck cancers]. PMID- 20726175 TI - [Social factors affecting health (2) Dental diseases]. PMID- 20726176 TI - [Public health monitoring report (1) On public policies to prevent suicide in the age of changing economic situation]. PMID- 20726177 TI - Congress, the Constitution, and physician-owned hospitals: a legal challenge to Section 6001 of PPACA. PMID- 20726178 TI - Psychoanalytic supervision: the supervisor's tasks. AB - This paper reviews key aspects of psychoanalytic supervision, including the capacity to combine a teaching function with an openly expressed evaluating one; communication of a clear, interpretive theory of technique, combined with an intuitive reaction to the totality of information gained in the supervisory situation; a combination of collegiality and honest communication with the candidate; and the awareness of reciprocal parallel processes. Reducing the influence of institutional dynamics, particularly those related to authoritarian pressures, is another responsibility of the supervisor. These tasks also involve discrete understanding and management of countertransference developments in both supervisor and supervisee. PMID- 20726179 TI - Three psychic organizations and their relation to certain aspects of the creative process. AB - The author describes three different ways in which individuals in psychoanalysis may make use of the analyst. Each brings together affective and symbolic communication in a different way and draws the analyst into a different way of relating. It is suggested that these reflect three organizations of the individual's experience of the object and of himself in relation to the object. Though not encountered exclusively in creative artists, each of these organizations, which the author calls analyst-as-mental-function, analyst-as medium, and analyst-as-audience/ interlocutor, is related to a specific aspect of the creative process. PMID- 20726180 TI - Endings and beginnings. AB - The author postulates that challenges related to ending an analysis may reflect the fact that the analysis has never truly begun, in the sense of achieving a true analytic engagement, one that can lead to psychic growth. Patients who are unable to achieve an emotional experience thus highlight the problem of interminability as one of how to begin. The author describes the model of reification of experience and presents aspects of the analysis of a perverse patient, the case of Mr. C, to illustrate the usefulness of this model in understanding how this patient defended against experiencing his emotions and the ensuing transference-countertransference difficulties. PMID- 20726181 TI - Possessive objects and paralyzing moods. AB - This article focuses on unique being states of mental and physical paralysis among schizophrenic patients. These paralyzing moods derive from continuous extractive introjections, in which anything alive in the patient is sucked out, as it were, by an internalized possessive object. Continuous extractive introjections early in life constitute attacks on authentic expression of the child's subjectivity, and prevent the development of his idiom and the unthought known. A clinical vignette is presented to illustrate certain movements both in a progressive direction (i.e., in psychoanalytic treatment) and in a retrogressive direction (in the formation of the original psychotic pathology). PMID- 20726182 TI - When theory paints a picture: a clinician reflects on Piera Aulagnier's metapsychology. AB - The author discusses a patient who, while not frankly psychotic, was prone to states of disintegration marked by fragmented thinking, retreats into extreme isolation, and an idiosyncratic relation to language that manifested in his speaking without seeming to communicate. The analyst used his own forms of dreaming and reverie, including looking at pictures, to help him understand the patient's unique forms of self-expression. The metapsychology of French analyst Piera Aulagnier was particularly useful to the analyst in conceptualizing the patient's experience an understanding his reactions to interventions. PMID- 20726183 TI - Psychoanalysis and art: artistic representations in patients' dreams. AB - The authors explore the psychic passages that were opened up within a patient, Ada, thanks to her contact with two works of art, Signorelli's frescoes in Orvieto and Picasso's painting La Nageuse--their themes, formal structures, and the conventions governing their creation. A work of art can be considered as a kind of window that allows one to look upon the imaginary world created by the artist. One can peer out of this window from the other side, permitting a look at the viewer (the patient), who is caught in a web of associations that are yet to be explored. PMID- 20726184 TI - Dead of night. AB - Dead of Night, the first psychoanalytic horror film, was produced in England in 1945, immediately after the end of World War II--that is, after the English population had suffered systematic Nazi terror from imminent invasion, incessant aerial bombing, and rocket-bombs. This film continued the prewar format of horror films based on themes of the supernatural and the hubris and excesses of science. However, it introduced psychoanalysis as the science in question. The film is structured on two levels: a genteel English country weekend to which witty and urbane guests have been invited; and five horror stories told by the guests. Psychoanalytic insights into this film structure are used here to explain how the film induces horror in the audience. PMID- 20726185 TI - Psychoanalytic technique and the creation of analytic patients: an addendum. PMID- 20726186 TI - Critically ill head injury patients and nutritional issues; need for rural guidelines. PMID- 20726187 TI - Trends in undergraduate teaching of parasitology in medical schools of Pakistan. AB - OBJECTIVE: Parasitic diseases are a major public health problem in the tropical and sub tropical countries including the subcontinent region. We aimed to assess methods of Parasitology education in medical schools of Karachi Pakistan. METHODS: Ten medical schools in Karachi, Pakistan were sent a structured questionnaire collecting information on different aspects of Parasitology education. The collected data was analyzed using SPSS version 14.0. RESULTS: The response rate of this study was 90%. Majority of the schools in Karachi, Pakistan (78%) taught Parasitology concurrently with Microbiology, Pathology, Pharmacology and Forensic medicine in third and fourth year of undergraduate training. More than 20 hours were spent on teaching through didactic lectures (56%), interactive lectures (22%), problem based learning (PBL) (22%), clinical cases (11%) and small group discussions (89%). A Clinical Microbiologist or Parasitologist taught Parasitology by using transparencies, handouts and/or computer aids. Variation in education methods existed mainly in the private medical schools. CONCLUSION: Medical curricula were meeting the European standards for teaching of Parasitology. However, there is a need for revision and modification in the curricula owing to the high burden of parasitic diseases in the subcontinent region. PMID- 20726188 TI - The spectrum of presentation and management of Fournier's gangrene--an experience of 73 cases. AB - OBJECTIVES: To study the spectrum of presentation and outcome of different treatment modalities in Fournier's gangrene. METHODS: It's a prospective analysis of 73 diagnosed patients of Fournier's gangrene admitted and treated in surgical department of a public sector university from June 2000 to June 2008. All patients were admitted through casualty with varying proportions of necrotizing infection of the perineal and genital fascia, with gangrene of the overlying skin. After resuscitation and preliminary investigations, including culture of the necrotic tissue, the patients were treated either conservatively by broad spectrum antibiotics, cardiopulmonary support, nutritional and fluid support or surgically by repeated aggressive wound debridement under anaesthesia. The behaviour of the disease, different modalities of treatment offered, response and outcome of the management were all collected on a proforma for statistical analysis on SPSS version 12. RESULTS: Seventy three patients with a mean age of 57.32 +/- 13.87 years and range of 33-86 years presented with varying degrees of Fournier's gangrene. Of the total population, 67 (91.78%) were males and 6 (8.213%) were females. Fifty nine (80.82%) patients had one or the other co morbidity with maximum number (n = 44, 60.2%) having diabetes mellitus. State of diabetes control was found to be an important prognostic factor. A source of infection was identified in skin, ano-rectal and perineal regions in 42 (57.53%) patients. Thirteen (17.80%) patients died despite aggressive conservative or surgical treatment. CONCLUSION: Fournier's gangrene continues to be a lethal disease despite overall improvement in the antibiotic spectrum and surgical techniques. Diabetes remains the most important prognostic factor in the outcome of disease. PMID- 20726189 TI - Timing and predictors of femoral haematoma development after manual compression of femoral access sites. AB - OBJECTIVE: To identify the timing and predictors of haematoma development after manual compression of femoral arteriotomies. METHODS: The study involved 239 consecutive patients undergoing cardiac catheterization at King Abdullah University Hospital, Irbid, Jordan. Size and timing of haematoma development were recorded. A total of 33 prespecified variables were evaluated by univariate analysis to identify predictors of haematoma development. These predictors were again analyzed using multivariate logistic regression model. RESULTS: Femoral haematomas developed in thirty nine patients leading to an overall frequency of 16.3%. More than two-thirds (74.4%) of the haematomas occurred later in the bed unit. Only 8 among 33 studied variables were found to be significant predictors of haematoma development upon multivariate analysis. These predictors are low haematocrit level before the procedure, advanced age, wider waist circumference, high systolic blood pressure, multiple artery puncture, longer ACT at the end of the procedure, anticoagulant treatment before procedure, and Glycoprotein IIB/IIIa inhibitors use during the procedure. CONCLUSIONS: Identifying predictors of haematoma development at femoral access sites and trying to correct or modify them when possible, can have a major impact on reducing the frequency of this serious complication. If an assessment indicates that a patient is at high risk, then several cautious management strategies should be implemented in this setting prior to performing cardiac catheterization. PMID- 20726190 TI - In vitro ciprofloxacin resistance profiles among gram-negative bacteria isolated from clinical specimens in a teaching hospital. AB - OBJECTIVE: To evaluate the trends of ciprofloxacin resistance pattern in commonly isolated gram-negative bacteria over time in a Saudi Arabian teaching hospital. METHODS: A retrospective analysis was carried out for ciprofloxacin resistance patterns of 10089 isolates of gram-negative bacteria isolated from various clinical specimens submitted to microbiology laboratories at King Fahd Hospital of the University (KFHU), Alkhobar, Saudi Arabia during the period January 2002 to August 2005. RESULTS: Increase in ciprofloxacin resistance rates in these isolates during the years 2002 and 2005 were as follows: Escherichia coli, 23.85 to 33.1%; Klebsiella pneumoniae, 15.93 to 27.55%; Enterobacter cloacae, 12.32 to 18.05%; Enterobacter aerogenes, 4.16 to 25.64%; Pseudomonas aeruginosa 17.05 to 39.53%, Pseudomonas spp., 20.58 to 58.77%; H. influenzae, 00.00% to 11.11% and H. aegyptius, 00.00% to 1.73%. CONCLUSION: There was a gradual increase in resistance from year 2002 to 2005 in most of the gram negative isolates i.e. E. coli, K. pneumoniae, E. cloacae, E. aerogenes, P. aeruginosa and Pseudomonas spp showing that ciprofloxacin is no more a drug of choice for gram negative infections by these microbes. PMID- 20726191 TI - Alterations in the level of neurotransmitters associated with the chronic treatment of antipsychotic drugs. AB - OBJECTIVE: To investigate the alterations in different neurotransmitters particularly dopamine and serotonin in various regions of rat brain. METHODS: By using HPLC-ECD, the concentration of dopamine, their metabolites (DOPAC, HVA), serotonin, their precursor (tryptophan), and metabolites (5-HIAA) were determined in different regions such as hypothalamus, cortex, midbrain and striatum. In addition, tryptophan pyrrolase enzyme activity and the concentration of tryptophan were also determined in liver samples, following chronic (21 days I/M) treatment of haloperidol and clozapine (of both commercially available and purified form) in an animal model. RESULTS: Significant alterations were observed in the level of neurotransmitters in different regions of rat brain. In response to haloperidol treatment, the level of dopamine was observed to be significantly increased in hypothalamus, cortex and striatum but in midbrain the concentration was slightly decreased, While a significant increase (p < 0.05) in the level of serotonin was observed in midbrain, hypothalamus and striatum. However, treatment with clozapine resulted in significant decrease in the level of dopamine in all the regions except cortex; with concurrent decrease observed in serotonin level in all brain regions except cortex where its concentration was slightly increased. Liver demonstrated a significant increase (p < 0.05) in the concentration of tryptophan, however, a slight increase was found in the concentration of brain tryptophan following haloperidol treatment. A marked decrease was observed in the concentration of liver tryptophan, whereas, the brain tryptophan concentration is significantly increased (p < 0.05) in response to clozapine treatment. Marked increase was observed in the tryptophan pyrrolase enzyme activity, plotted against time at the time interval of 15 minutes in response to both haloperidol and clozapine treatment. CONCLUSION: We suggest that the varying effect of these drugs on neurotransmitter may account for the difference in the consequence profile in response to chronic treatment. PMID- 20726192 TI - Dietary pattern, nutritional status, anaemia and anaemia-related knowledge in urban adolescent college girls of Bangladesh. AB - OBJECTIVES: To examine dietary pattern and nutritional status of adolescent college girls of Dhaka, Bangladesh with a particular focus on the prevalence of anaemia and appropriate knowledge about it among them. METHODS: A cross sectional study was conducted. Sixty-five adolescent girls aged 15-19 years were selected randomly from Home Economics college of Dhaka. A 7-day food frequency questionnaire was used to investigate the dietary pattern. Nutrient intake of the participants was assessed by 24h recall method. RESULTS: Habitual dietary pattern indicated poor consumption of milk, liver and leafy vegetables. Food intake data revealed a deficit of 473 kcal/day in energy. Mean intake of carbohydrate and fat were lower than RDA; while protein, iron, vitamin A and vitamin C intakes were much higher. Anthropometric data indicated that 63% of the girls were stunted (height-for-age < 95% of NCHS reference values) and 45% were underweight (weight for-age < 75% of NCHS reference values). The prevalence of anaemia (Hb < 12 g/dl) among the participants was 23%. About 17% had low serum iron (< 40 microg/dl), 23% showed evidence of iron-deficient erythropoiesis (Transferrin Saturation < 15%) and only 8% had vitamin C deficiency (< 0.29 mg/dl). About 65% of the participants had correct knowledge about the causes of anaemia; while 72.3% and 80% respectively, knew about the prevention and treatment of anaemia. Surprisingly, 73.8% of the participants were not aware about the sources of iron rich foods. CONCLUSIONS: Results indicate an overall poor nutritional status of the urban adolescent college girls in Bangladesh and need for appropriate nutrition interventions to overcome the problem. PMID- 20726193 TI - Treatment of intracranial aneurysms using detachable coils; initial results at a university hospital in Pakistan. AB - OBJECTIVE: To evaluate the technical success, safety and outcome of endovascular coiling procedure in intracranial aneurysms. METHODS: From April 2003 to April 2009, 43 patients (23 males and 20 females), age range 11 to 70 years, mean age 46.67 +/- 11.57 years were treated for intracranial aneurysms by detachable coil deployment at Radiology Department of Aga Khan University Hospital. Aneurysm rupture with subarachnoid haemorrhage was the cause of presentation in 39 patients while 4 patients were diagnosed with un-ruptured aneurysms. At time of presentation, grading of subarachnoid haemorrhage was done according to Hunt and Hess grading system. Eleven patients presented with Grade I haemorrhage, other 11 presented with grade II haemorrhage, 8 patients had grade III haemorrhage and 9 patients had grade IV haemorrhage. Preliminary diagnostic workup was performed by cross sectional imaging, CT angiography or digital substraction angiography. Coiling procedures were performed under general anaesthesia through femoral artery approach. Detachable platinum coils were densely packed in all aneurysms by endovascular technique. Patient files and radiology reports were retrospectively reviewed. Technical success and safety of the procedure were analyzed. Modified Rankin Score was used to determine clinical outcome. Score 0-2 represented good outcome, score 3-5: dependency (Can not attend own bodily needs and carry out daily activities without assistance) and score 6: death. RESULTS: Aneurysm size ranged from 3mm - 22mm (mean size 8 mm +/- 4). 74.4% aneurysms had narrow necks while 25.6% aneurysms were wide necked. Most common aneurysm site was anterior communicating artery. Technical success rate for endovascular intracranial aneurysm coiling was 95.3% (n = 41). Major complication rate was 11.6 % (n = 5). Mortality rate was 2.3% (n = 1). 78% patients showed good clinical outcome after coiling including 4 patients with un ruptured aneurysms (n = 32). CONCLUSION: Results of endovascular aneurysm coiling at our center showed high technical success rate (95.3%) and good short term clinical outcome in 78% patients. PMID- 20726194 TI - Cholelithiasis in hepatic cirrhosis: evaluating the role of risk factors. AB - OBJECTIVE: To determine the role of risk factors, which promote cholelithasis in Hepatic Cirrhosis (HC). METHODS: A prospective study was conducted on indoor cases with advanced HC. Outpatients with compensated Chronic Liver Disease were used as control. The subjects with history of cholecystectomy and diabetes mellitus were excluded from the study. Conventional ultrasound was used for the detection of gallstones, ascites and portal hypertension. Sonography also furnished pertinent information about the portal vein diameter, size of the spleen, gallbladder wall thickness and echogenecity of the liver. RESULTS: The number of registered cases was 206: (age: 30-85 years): 121 (58.7%) males and 85 (41.3%) females. Hepatitis C (HCV) was the cause of HC in 187 (90.88%) cases. Of 50 (24.30%) patients with detectable gallstones, 27(54.00%) were males. We observed correlation of several risk factors with cholelithasis in our patients (n = 50): advanced age: mean 57.3 +/- 9.7 years (100%); prolonged duration of HC: 3.5 years (100%); Child-Pughs' class C: 34 (68%); increased thickness of gallbladder wall: 45 (90%); gross ascites: 39 (78%); splenic enlargement: 17.3 cm (100%); increased portal vein diameter: 13.4mm (100%). The results were statistically significant when compared with the control group (p = < 0.001). CONCLUSION: Gallstones tend to occur more frequently in patients with decompensated CLD due to interaction of several risk factors in these patients. PMID- 20726195 TI - The effect of consecutive extended duty hours on the cognitive and behavioural performance of paediatric medicine residents. AB - OBJECTIVES: To compare the performance of paediatric medicine residents following a regular 6 hour and an extended 24 hour call and their own insight into their performance following each duty. METHOD: The study was conducted at The Children's Hospital, Lahore, from September 2007 to November, 2008. All tasks were performed twice, after 6 hour call and 24 hour long call, evaluating Reaction timer, Concentration test, Number Connection Test, State Trait Anger Anxiety Inventory (STAXI) response for trait anger and modified Wechsler Memory Scale inventory (WMS-R) for cognitive performance. Likert's self assessment tool was used for both set of performances. RESULT: Thirty two paediatric medicine residents (male 53.1%; female 46.9%) were enrolled in the study with identical duty structure performing 74 hours per week with mean age of 27.53 +/- 0.32 years and mean experience of 3.69 +/- 0.32 years. There was significant deterioration in both verbal recall and logic memory (mean difference in score of 1.81 (95% C.I 1.25-2.37, p < 0.001). Concentration test also showed significantly fewer responses (24 hour mean 239.56, 95% C.I. 228-251.13) vs (6 hour mean 258.94, 95% C.I. 247.42-270.46) in 5 minutes, p < 0.001. Reaction time, vigilance and hand eye coordination was significantly affected after an extended call, p < 0.001. Number of lapses in attention also rose significantly, p < 0.001. STAXI response showed significant increase in anger scores, p = 0.001. Despite the significantly poor performance, the residents could not appreciate the deterioration in their performance with Likert's self assessment score that differed only by 0.63 (95% CI -0.12-1.37), p = 0.1. None of the other factors studied correlated with deterioration in performance of any specific task except the length of duty hours. CONCLUSION: Continuous long stretch of duty causes significant deterioration in cognitive and behavioural status of residents. More importantly, the residents themselves are unable to appreciate this deterioration. Residents must be made aware of this deterioration as there is a higher risk of medical errors and bad judgments, risking patient safety. PMID- 20726196 TI - Accuracy of primary health care statistics reported by community based lady health workers in district Lahore. AB - OBJECTIVE: To determine the accuracy of monthly reports submitted by lady health workers of National program for family planning and primary health care in district Lahore. METHODS: A cross sectional descriptive study was conducted in district Lahore from November 2008 to February 2009. Forty lady health workers were selected using stratified random technique. Four monthly reports (one from each quarter of year 2008) submitted in health facilities by each lady health worker were retrieved from respective health facilities. These reports were then audited for accuracy using registers in health houses and verification of primary health care information in their respective communities. A scoring system was devised to grade reports for accuracy as good (80% and above score), satisfactory (60-70% score) and unsatisfactory (less than 60% score). RESULTS: Out of 40 lady health workers (LHWs) interviewed, 32 (80%) had good knowledge, 6 (15%) had satisfactory knowledge, while 2 (5%) had unsatisfactory knowledge regarding data recording and reporting tools. Based on our scoring system, only 47.5% of reports were found accurate. In addition, 35% of reports contained missed entries, misreported data and factitious information. CONCLUSION: There are significant gaps in recording and reporting of primary health care data in National programme for family planning and primary health care in district Lahore. Considering the utility of this data for health planning at district, provincial and national levels, adequate supervision and regular auditing should be carried out at health facility and district levels before onward transmission primary health care data to provincial and national levels. PMID- 20726197 TI - Apolipoprotein B in type 2 diabetics--a cross sectional study in a tertiary care set-up. AB - OBJECTIVE: To analyze the pattern of dyslipidaemias including apolipoprotein B in type 2 diabetes. METHODS: A total of 120 diabetics were studied for their lipid profile including serum triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol in fasting state, along with apolipoprotein B levels. RESULTS: Raised apolipoprotein B was the most frequent lipid disorder in type 2 diabetics, occurring in 56.7% of the studied patients. This was followed by high serum triglycerides levels in 55.8% and low HDL cholesterol levels in 55% of patients. Notably, 6% patients had normal triglyceride levels accompanied by raised LDL cholesterol, compared to 20% patients who had normal triglycerides with high apolipoprotein B levels. Overall, 36% of patients had normal LDL cholesterol values but elevated apolipoprotein B. CONCLUSION: Apolipoprotein B is the most frequently occurring dyslipidaemia in type 2 diabetes. It identifies individuals with high risk of coronary heart disease not otherwise detected on routine lipid profile. PMID- 20726198 TI - Benign esophageal strictures: behaviour, pattern and response to dilatation. AB - OBJECTIVE: To evaluate the endoscopic dilatation of benign esophageal strictures and its outcome. METHODS: A prospective descriptive study was conducted at Surgical Unit 4 of Civil Hospital Karachi, over a period of 24 months, from August 2006 to July 2008. Twenty seven patients with benign esophageal strictures underwent esophageal dilatation under fluoroscopic guidance using Savary Gilliard Dilators and guide wire. Follow up was done weekly for 2 weeks and monthly for a minimum of 6 months. Treatment success was gauged according to improvement of dysphagia. RESULTS: A total of 27 patients were included in the study. There were 16 (59.3%) corrosive strictures, 10 (37%) were peptic strictures and one (3.7%) was due to extrinsic compression. Majority of the corrosive strictures, 11 (68.75%) were suicidal in intent p < 0.001. Mean dilatation frequency for strictures longer than 5cms was 7.10 +/- 5.322 vs. 3.47 +/- 3.281 for strictures < 6cms (p < 0.037). Corrosive strictures were seen more commonly in the upper esophagus as compared to peptic (Mean 22.44 +/- 5.240 cm vs. 30.20 +/- 4.780 cm), p < 0.001. Only 81.4% corrosive stricture could be adequately dilated at initial dilatation as compared to 100% in peptic strictures. Mean symptomatic recurrences per month were 0.6919 +/- 0.300 in corrosives and 0.365 +/- 0.293 in peptic strictures (p < 0.003). There were 4 procedure related perforations, all in patients with corrosive strictures. Overall mortality was 7.4%. CONCLUSION: Endoscopic dilatation is safe and effective in treating benign and corrosive esophageal strictures, which have a higher complication rate. Mean recurrence rate decreased over a period of time in both peptic and corrosive strictures. PMID- 20726199 TI - Frequency of stress hyperglycaemia and its' influence on the outcome of patients with spontaneous intracerebral haemorrhage. AB - OBJECTIVE: To observe the frequency of admission hyperglycaemia and its influence on the outcome of patients with intracerebral haemorrhage. METHODS: This case series study included 450 consecutive patients received in medical wards at Liaquat University Hospital Jamshoro/Hyderabad with a diagnosis of Spontaneous Intracerebral Haemorrhage within 24 hours of their first stroke onset, between September 2006 to December 2008. The patients with haemorrhage secondary to brain tumours, trauma, haemorrhagic transformation of cerebral infarct, with previous history of haemorrhagic stroke, and patients with Glycosylated Haemoglobin greater than 8.5% were excluded from the study. Hyperglycaemia was defined as an admission or in-hospital fasting blood glucose level of 126 mg/dl (7 mmol/liter) or more or a random blood glucose level of 200 mg/dl (11.1 mmol/liter) or more on 2 or more determinations. The patients were divided into 2 broad groups, good outcome groups (i.e. patients who survived), and poor outcome group (patient died). Categorical variables such as age, sex, volume of haematoma, GCS score, presence of admission hyperglycaemia, Mean arterial pressure (MAP), and site of haematoma were expressed as percentage and frequency. Chi-square test was applied for comparing categorical variables such as hyperglycaemia, GCS score, and age with the outcome of the patients. Multivariate logistical regression analysis was done. A p-value 0.05 was considered as statistically significant. All calculations were done using SPSS version 16 (Chicago, IL, USA). RESULTS: Of the 450 consecutive patients, 399 fulfilled the inclusion criteria. Males were 261(65.4%) and females 136 (36, 4%).Patients of over 65 years age numbered 222 (55.6%) and 177 (44.4%) were less than 65 years. Stress hyperglycaemia was present in 109 (27.3%) cases and 290 (72.7%) patients were normoglycaemic. Of the 109 patients who died during hospitalization, 59 (54.12%) had presented with admission hyperglycaemia (0.001). CONCLUSION: Stress hyperglycaemia is a common finding in patients presenting with intracerebral haemorrhage. It is a marker of poor outcomes and higher mortality, more so in patients with no known history of diabetes. PMID- 20726200 TI - Comparison of complications of circumcision by 'Plastibell device technique' in male neonates and infants. AB - OBJECTIVES: To determine the effectiveness of the circumcision by Plastibell technique with comparison of complications among neonate and infant age groups. METHODS: A retrospective, descriptive study was conducted in all the plastibell circumcisions performed by the first author, during the period October 2006 to December 2008 at a private hospital Karachi. The record of all the cases fulfilling the inclusion criteria were obtained and analyzed for determining the outcome and complications if any in neonates and infants and to compare it with in these two groups. RESULTS: Overall 245 cases of neonates and infants were selected. Mean age of neonates and infants was 14 +/- 2 days and 3 +/- 0.5 months respectively. The plastibell circumcision was done in all the cases i.e. 90 neonates and 155 infants. Out of these, the successful rate of plastibell circumcision without any complication was recorded as 196 cases (80.00%) whereas, 49 cases (20.00%) developed complications. In neonates it was recorded as 04.44% cases, whereas this ratio was 29.03% in infants. Most common complications were delayed separation of the ring in 17 cases (6.93%), bleeding in 12 cases (4.89%), localized superficial infection in 12 cases (4.89%), and proximal migration of ring in 07 cases (2.85%). CONCLUSION: The ratio of complications of circumcision by plastibell is significantly higher in infants as compared to neonates. However it is an easy, quick and safe technique. Outcome of this procedure is encouraging while infants are more prone to develop post operative complications than neonates. PMID- 20726201 TI - Concepts of homeopathy among general population in Karachi, Pakistan. AB - OBJECTIVE: To explore the characteristics of patients and their gender influences concerning the use of homeopathic medicine, visiting both homeopathic and conventional medicine (allopathic) clinics. METHODS: This cross sectional study was carried out on 200 patients who attended private and public homeopathic and allopathic clinics or hospitals in Karachi using a pre-tested self-administered questionnaire. Data for demographic variables of frequencies and associations between variables were analyzed on SPSS version 12.0. Significance level was p < 0.05. RESULTS: Out of the total, 64.5% respondents, more among females than males (p < 0.01) believed in homeopathy. Although slightly more than a quarter preferred homeopathic treatment than allopathic treatment, 67.5% participants had had homeopathic consultation and treatment in the past. Amongst participants who had opted for homeopathy in any of their illnesses, the majority had it for chronic conditions which included skin lesions and problems of rheumatology. CONCLUSION: In this modern era, where people have the choice to decide newer and advanced forms of medical treatment and scientific methods, a large proportion of people still rely on alternative forms of treatment like homeopathy. More awareness regarding use of homeopathic treatment is needed among general population. PMID- 20726202 TI - Frequency of catheter related infections in haemodialysed uraemic patients. AB - OBJECTIVE: To investigate the incidence of bacteraemia and bacterial colonization related to the use of dual-lumen catheters in ESRD patients on haemodialysis. METHODS: Sixty patients with ESRD of varied etiologies, both males and females falling in the age range (16-74 years) were randomly selected. Non-cuffed, non tunneled polyurethane double lumen catheters were inserted under aseptic technique. Patients on twice a week schedule of haemodialysis were followed up for a period of 5 months. After every haemodialysis session, catheters were examined for any local infection or signs of bacteraemia. In case of suspicion, distal 5 cm segment of the catheter, and local pus swab and two blood culture samples were sent to the pathology laboratory. RESULT: Thirty one catheters (51.6%) sent for culture and sensitivity showed colonization (> 15 CFU). Bacteraemia was positive in 15 (25%) patients. Thirteen (41.9%) catheter tips were found to be colonized by staphylococcus epidermidis, eleven (35.4%) by staphylococcus aureus, three (0.96%) by Candida albicans species, two (6.45%) by E coli, one (3.2%) by P Aeruginosa and one (3.2%) by mixed Pseudomonas and E coli respectively. CONCLUSION: Non cuffed non tunneled double lumen catheters are designed for short-term emergency use and should be used in the same context. Although pathogenesis of catheter related infection is multifactorial the transcutaneous migration of organisms colonizing the skin remains the most important route. PMID- 20726203 TI - Prevention of human papilloma virus infection with vaccines. AB - Human Papilloma virus (HPV) is present in all the cases of cervical cancer. It can also cause other diseases like genital warts, condylomata accuminata, cervical intraepithelial neoplasia and Anogenital cancers. Cervical cancer is the second most common cause of death from cancer. To improve the mortality from cervical cancers it is extremely important to prevent the HPV infection. In this review we have discussed the role of HPV vaccines in preventing the HPV infections and so the cervical cancer. PMID- 20726204 TI - Chronic low backache and stiffness may not be due ankylosing spondylitis. AB - A 38 years old man presented with 2 years history of low backache and progressively increasing stiffness of the spine. Movements were restricted at lumbar spine due to stiffness especially forward flexion was markedly reduced. He was suspected to be suffering from ankylosing spondylitis. There was no tenderness over sacroiliac joints or lumbar spine. Yellowish green Ochronotic pigmentation of cartilage of ears was noted. Radiographs of lumbar and thoracic spine revealed narrowing of inter-vertebral spaces with calcification of intervertebral discs. Homogentisic acid was present in the patient's urine sample, suggesting him to be suffering from Alkaptonuria. Patient is being managed with non steroidal anti-inflammatory drugs and vitamin C, 1g daily. PMID- 20726205 TI - Tuberous sclerosis. AB - Tuberous sclerosis or Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by the growth of numerous benign tumours in many parts of the body caused by mutations on either of two genes, TSC1 and TSC2. The case of a 31 year old female who fulfilled 8 major criteria of Tuberous Sclerosis Complex is reported. Multiple research work projects are being carried out on this disease, unfolding the realities regarding its etiology as well as treatment. TSC patients, besides receiving symptomatic treatment should also be offered special schooling and regular follow up by expert physician. PMID- 20726206 TI - Losartan associated anaphylaxis and angioneurotic oedema. AB - A case of anaphylaxis and angioedema induced by angiotensin II receptor blocker (ARB), losartan is reported. A 37 years old hypertensive female presented to the Emergency Department with swelling over the face especially the lips, urticarial rash all over the body, and dyspnoea within an hour of losartan administration. She did not have any previous history of drug allergies. The patient was managed with epinephrine. Although angioneurotic oedema and anaphylaxis are well documented adverse effects of angiotensin converting enzyme (ACE) inhibitors, very few cases of these adverse reactions with ARBs have been reported in medical literature. PMID- 20726207 TI - Mammary and femoral hydatid cysts. AB - Hydatid cyst disease most commonly affects liver and lungs, but it can affect all viscera and soft tissues of the body. Simultaneous mammary and femoral hydatid cysts, without any other visceral involvement, are extremely rare. This is a case report of 25-years-old female, presenting with lump in left breast mimicking fibroadenoma and lump in right thigh mimicking fibroma. Both turned out to be hydatid cysts. PMID- 20726208 TI - Hyperprolactinaemia induced by proton pump inhibitor. AB - A case of a 13 year old girl who manifested hyperprolactinaemia and galactorrhea induced by Omeprazole, a commonly used proton pump inhibitor is presented. PMID- 20726209 TI - Acute cardiac tamponade due to spontaneous bleeding in a child with haemophilia A. AB - In severe haemophilia A, patients, start from the first years of life, with spontaneous bleeding and require transfusion. However, cardiac tamponade due to spontaneous pericardial bleeding is rare. An 11-year-old boy receiving haemophilia A treatment was referred to the Department of Paediatric Haematology with pneumonia, fever, dyspnoea, and palpitation. In his PA chest radiograph, pneumonic infiltration in the right lung and enlargement in the pericardial area were found. On his echocardiograph, pericardial effusion reaching 3.9 cm and other findings of tamponade were detected. APTT was outside the measurable range. It was deranged to > 120 seconds. The patient received 1000 U of factor VIII intravenously. A pericardial window was made via left anterior mini thoracotomy due to fluid drained. In his control echocardiograph taken after one month, no pathology was found. At 50th day, the patient showed left pleural serohaemorrhagic effusion, which was treated with tube thoracostomy. In haemophilia A patients, either pericardiocentesis or subxiphoid pericardial drainage or pericardial window creation via thoracotomy may be applied, depending on the primary pathology. In paediatric cases, pericardial window creation via mini thoracotomy can be an alternative treatment of choice considering complications such as recurring bleeding and effusion during pericardiocentesis. PMID- 20726210 TI - Enhanced external counter pulsation (EECP) for refractory angina pectoris (RAP); results from a first case series. AB - Enhanced External Counterpulsation (EECP) has emerged as a promising non-invasive modality not only for patients with refractory angina pectoris (RAP) but also for patients with heart failure. To our knowledge, no published data exists in Pakistan about the benefits of EECP. We report on a case series of 16 consecutive patients undergoing EECP. All patients were either deemed not to be candidates for revascularization or had failed revascularization with RAP on optimal medical therapy. Data was collected regarding the coronary anatomy, clinical presentation, Pre and Post EECP Canadian Cardiovascular Society (CCS) class, nitrate use and 6-min walk test. Patients with severe peripheral vascular disease and arrhythmias were excluded. The mean age was 56 +/- 11.1 years. Eight patients had 3-vessel disease. 4 post-CABG with occluded grafts and the rest with variable combination of coronary disease. Seven (44%) patients had Unstable Angina and 9 (56%) had Stable Angina. The mean 6 min walk distance before EECP was 295 +/- 148.60 meters and after EECP was 360 +/- 102.12 meters (p = 0.013). The CCS class before and after EECP also showed significant improvement (p = 0.017). Sublingual nitroglycerine use also showed a positive trend after EECP. EECP was noted to be a safe and effective modality for patients with RAP with statistically significant improvement in measures of quality of life. PMID- 20726211 TI - Corridor consultations: should this practice be discouraged? PMID- 20726212 TI - How should physicians practically approach symptomatic and asymptomatic carotid stenosis? PMID- 20726213 TI - Coronary heart disease, genes not to be blamed totally! PMID- 20726214 TI - Anxiety and depression among medical students: a cross-sectional study. AB - OBJECTIVE: To determine the prevalence of anxiety and depression among medical students at Nishtar Medical College, Multan. METHODS: A cross-sectional study was carried out at Nishtar Medical College, Multan in 2008. The questionnaire was administered to 815 medical students who had spent more than 6 months in college and had no self reported physical illness. They were present at the time of distribution of the questionnaires and consented. Prevalence of anxiety and depression was assessed using a structured validated questionnaire, the Aga Khan University Anxiety and Depression Scale with a cut-off score of 19. Data Analysis was done using SPSS v. 14. RESULTS: Out of 815 students, 482 completed the questionnaire with a response rate of 59.14%. The mean age of students was 20.66 +/- 1.8 years. A high prevalence of anxiety and depression (43.89%) was found amongst medical students. Prevalence of anxiety and depression among students of first, second, third, fourth and final years was 45.86%, 52.58%, 47.14%, 28.75% and 45.10% respectively. Female students were found to be more depressed than male students (OR = 2.05, 95% CI = 1.42-2.95, p = 0.0001). There was a significant association between the prevalence of anxiety and depression and the respective year of medical college (p = 0.0276). It was seen that age, marital status, locality and total family income did not significantly affect the prevalence of anxiety and depression. CONCLUSIONS: The results showed that medical students constitute a vulnerable group that has a high prevalence of psychiatric morbidity comprising of anxiety and depression. PMID- 20726215 TI - The challenge of head & neck squamous cell carcinoma control in Pakistan. PMID- 20726216 TI - Future prospects for the utility of interferon assays in tuberculosis diagnosis. PMID- 20726217 TI - National Hospital Ambulatory Medical Care Survey: 2007 emergency department summary. AB - OBJECTIVE: This report presents data on U.S. emergency department (ED) visits in 2007, with statistics on hospital, patient, and visit characteristics. METHODS: Data are from the 2007 National Hospital Ambulatory Medical Care Survey, which uses a national probability sample of visits to emergency departments of nonfederal general and short-stay hospitals in the United States. Sample data were weighted to produce annual national estimates. RESULTS: In 2007, there were about 117 million ED visits in the United States. About 25 percent of visits were covered by Medicaid or the State Children's Health Insurance Program (SCHIP). About one-fifth of ED visits by children younger than 15 years of age were to pediatric EDs. There were 121 ED visits for asthma per 10,000 children under 5 years of age. The leading injury-related cause of ED visits was unintentional falls. Two percent of visits resulted in admission to an observation unit. Electronic medical records were used in 62 percent of EDs. PMID- 20726218 TI - Did nurses goof-up in assessment & failure to call Dr.? Kuhne v. Allina Health Systems, A09-1826 MNCA (6/15/2010)-MN. PMID- 20726219 TI - Nurse joins in 'cover-up' of cause of death. Case on point: Thomas v. Hosp. Bd. of Dirs. of Lee County, 2D08-1671 FLCA2 (5/7/2010)-FL. PMID- 20726220 TI - CA: Infected arm virtually ignored by staff: pt. failed to produce required expert opinion. Phillips v. City & County of San Francisco, A125769 CAAP1 (6/28/2010)-CA. PMID- 20726221 TI - Dr. failed to diagnose and treat: summary judgment denied. Case on point: Grant v. Scuderi, 2010-31402 (6/4/2010)-NY. PMID- 20726222 TI - [Effects of 2,2',4,4'-tetrabrominated diphenyl ethers on the TRalpha1 and TRbeta1 expression in liver in C57BL/6 mice]. AB - OBJECTIVE: To study the effect of 2,2',4,4'-tetrabrominated diphenyl ethers (BDE 47) on the expression change of TRalpha1, TRbeta1 at both mRNA and protein levels. METHODS: C57BL/6 mice were divided randomly into 4 groups and administrated with corn oil, 0.5, 5 and 50 mg/kg/BW BDE-47 for 4 days through intraperitoneal injection respectively. GAPDH selected as internal standard, real time quantitative RT-PCR and Western blot were employed to detect the mRNA levels and protein of TRalpha1 and TRbeta1 in livers. RESULTS: Compared with the control group, the mRNA levels of TRalpha1 and TRbeta1 were up-regulated in the medium and high BDE-47 dose groups (P < 0.05). The protein level of TRalpha1 significantly up-regulated while TRbeta1 was significantly down-regulated. CONCLUSION: BDE-47 could change the expression of TRalpha1 and TRbeta1 in the mRNA and protein levels in liver. PMID- 20726223 TI - [Effects of Rap2b gene on foci formation and wound-healing of NIH3T3 cells]. AB - OBJECTIVE: To explore the effects on foci formation and wound-healing of NIH3T3 cells, and to provid the experimental evidence of its function. METHODS: DNA from human lung cells was extracted and amplification of Rap2b gene was done by PCR. Eukaryotic expression vector pcDNA3. 1-Rap2b was constructed and was stable transfected into NIH3T3 cell followed with foci formation assay and wound-healing assay. RESULTS: The number of the foci formation of NIH3T3 cell transfected by eukaryotic expression vector pcDNA3. 1-Rap2b was increased remarkably in foci formation assay (P < 0.01) and NIH3T3 cells transfected by eukaryotic expression vector pcDNA3. 1-Rap2b were quickly heal up in wound-healing assay. CONCLUSION: The extrinsic expression of Rap2b could transform NIH3T3 cell using foci formation assay and wound-healing assay. Rap2b gene might play an oncogenic role in tumorigenesis. PMID- 20726224 TI - [Association of XRCC4 polymorphisms and chromosomal damage levels in 1,3 butadiene workers]. AB - OBJECTIVE: To investigate the association of polymorphisms of DNA double-strand break repair gene XRCC4 and chromosomal damage levels in peripheral blood lymphocyte in workers exposed to 1,3-butadien (BD). METHODS: 189 BD exposed workers and 83 controls were recruited in this study. Chromosomal damage in peripheral lymphocytes was measured by the cytokinesis-block micronucleus (CBMN) assay. Three haplotpe-tagging single nucleotide polymorphisms in XRCC4 gene, including A245G, T1394G and C1475T, were detected by PCR-RFLP and the XRCC4 haplotypes were estimated by using an extension of Clark algorithm. The associations between haplotype pairs and micronuclei data were assessed by analysis of covariance in the exposed and non-exposed groups. RESULTS: Multivariate analysis of covariance revealed that the frequencies of CBMN, nucleoplasmic bridge (NPB) and nuclear bud (NBUD) were significantly higher in BD exposed workers [(7.17 +/- 5.41) per thousand, (1.20 +/- 1.43) per thousand and (2.87 +/- 2.44) per thousand, respectively] than in the controls [(3.10 +/- 2.56) per thousand, (0.24 +/- 0.66) per thousand and (1.68 +/- 1.92) per thousand, P < 0.01, respectively]. Rank sum test revealed that in BD exposed workers, the XRCC4 A245G AA genotype exhibited higher NPB frequency than that of AG or GG genotypes significantly (P < 0.05). Stratification analysis showed that the polymorphism of XRCC4 T1394G TT carriers had significantly higher CBMN frequencies than those GG carriers (P < 0.01) in < 39 year workers. CONCLUSION: The results suggested that polymorphisms of XRCC4 A245G and T1394G could influence the chromosomal damage levels in BD exposed workers. PMID- 20726225 TI - [Effect of lead exposure on male sexual hormone]. AB - OBJECTIVE: To explore effects of lead exposure on the concentrations of serum male sex hormone in male workers. METHODS: Blood sample of 153 male workers occupationally exposed to lead and 47 male worker without exposure history were collected, of which the concentrations of testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2) and inhibin B were measured by ELISA. RESULTS: The results showed that concentration of T in exposure group were significantly lower (P < 0.05) compared with non-exposured group. In contrast, serum inhibin B concentration were significantly increased (P < 0.05) than control group. The main influencing factors changing serum T are effect of lead and age, meanwhile positive effects of lead were also observed on serum inhibin B increased by Logistic analysis. CONCLUSION: The results suggest that the lead exposure may alter the male sexual hormone, which might injure the endocrine function and Sertoli cells. PMID- 20726226 TI - [Effect of polypeptide from Chlamys farreri on ultraviolet A-induced Fas and c fos expression in HaCaT cells]. AB - OBJECTIVE: To observe the effect of Polypeptide from Chlamys farreri (PCF) on expression levels of Fas and c-fos in HaCaT cells after ultraviolet A (UVA) radiation, and investigate the molecular mechanism of PCF protecting against UVA induced damage in HaCaT cells. METHODS: HaCaT cells were divided into five groups: control group, UVA model group, 5.69 mmol/L PCF group, 2.84 mmol/L PCF group, and 1.42 mmol/L PCF group. Expression levels of Fas and c-fos mRNA was assayed by PCR. Western blot analysis was used to determine the protein levels of Fas and c-fos. RESULTS: After UVA exposure, Fas and c-fos expression increased significantly (P < 0.01). 1.42 - 5.69 mmol/L PCF inhibited UVA-induced mRNA and protein expressions of Fas and c-fos in HaCaT cells in dose-dependent manner (P < 0.05). CONCLUSION: PCF could attenuate UVA-induced Fas and c-fos expression, which may attribute to its protective effect against UVA-induced damage in HaCaT cells. PMID- 20726227 TI - [Changes of caspase-9 in rat retina caused by Nd:YAG laser injury]. AB - OBJECTIVE: To investigate the changes of caspase-9 in the retina of Long Evans rats caused by Nd: YAG laser injury. METHODS: A model of retina injury in rats caused by Nd:YAG laser was established. The activity and the expression of mRNA and protein of caspase-9 were detected at Oh, 3h, 6h, 24h, 3d and 7d after laser irradiation. RESULTS; No conspicuous change of caspase-9 mRNA in retina was observed just after laser irradiation, but the activity of caspase-9 and the expression of caspase-9 mRNA and protein increased significantly at 6h and 12h after irradiation (P < 0.05). CONCLUSION: Caspase-9 in the retina of LE rat was activated by Nd:YAG laser irradiation. PMID- 20726228 TI - [Effects of 9,10-dihydroxysteatic acid on glucose metabolism in KKAy mice]. AB - OBJECTIVE: To study the effect of 9,10-dihydroxystearic acid (DHSA) on glucose tolerance and insulin sensitivity in KKAy diabetic mice. METHODS: 48 male KKAy mice were randomly divided into four groups and were fed with high fat diet containing 4% DHSA, 2% DHSA, 4% Olive oil and 4% Corn oil, respectively. Glucose tolerance and insulin sensitivity were measured after 5 and 6 weeks respectively. Effects of DHSA on activating PPAR-alpha and PPAR-gamma in CV-1 cells were also carried out. RESULTS: In glucose tolerance test, the blood glucose at 0.5 h and 1 h and the area under glucose curve in the group fed with 4% DHSA diet were significantly lower than those of other groups. In insulin sensitivity test, the blood glucose level at 0.5 h and 1 h after injection of insulin was lower in the 4% DHSA diet group, indicating the insulin sensitivity of this group was obviously higher than other groups (P < 0.05). The body weight of the mice fed with 4% DHSA diet was much lower than those mice fed with 4% Corn diet (P < 0.05). 5 - 20 micromol/L DHSA did not activate PPAR-gamma in CV-1 cells but 50 - 100 micromol/L DHSA activated PPARgamma in a dose-dependent way although the activating effect of DHSA on PPARgamma was significantly lower than that of rosiglitazone. DHSA did not activate PPAR-alpha in CV-1 cells. CONCLUSION: DHSA may improve glucose tolerance and insulin sensitivity in KKAy mice and the effect might be related to the activation of PPAR-gamma by DHSA. PMID- 20726229 TI - [Effect of copper deficiency on iron metabolism in rats]. AB - OBJECTIVE: To study the effect of copper deficiency on the nutritional status of iron, the expression of hepcidin mRNA and transferrin receptor mRNA in rats. METHODS: Forty eight clean male SD rats were randomly divided into four groups according to body weight; and there were 12 rats in each group. The groups are normal iron and copper control group (group I), normal iron and copper deficiency group (group II), normal iron and copper slightly deficient group (group III), both iron and copper slightly deficient group (group IV). Serum, liver and spleen of rats were collected by the end of 8th week. Serum copper, serum iron, hemoglobin, serum transferrin receptor, serum ferritin, liver iron and liver copper, spleen iron and spleen copper were determined. The expression of liver transferring receptor mRNA and hepcidin mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR) method. RESULTS: Compared with the controls, the contents of serum iron and serum ferritin decreased (P < 0.05), but the level of serum transferrin receptor and the content of iron in liver and spleen increased significantly under copper deficiency. The expression of transferrin receptor mRNA in liver increased but the expression of hepcidin mRNA in liver decreased significantly under copper deficiency (P < 0.05). CONCLUSION: The nutritional status of iron may be affected by copper deficiency through influencing the absorption, storage and transportation of iron. Under the condition of copper deficiency, the expression of hepcidin mRNA in liver was lowered and the expression of transferrin receptor mRNA was enhanced through the way of iron response element-iron regulatory protein (IRE-IRP) to regulate iron metabolism. PMID- 20726230 TI - [Effect of lutein on relieving oxidative stress in mice induced by D-galatose]. AB - OBJECTIVE: To study the effect of lutein on relieving oxidative stress in the liver of mice induced by D-galactose(D-gal). METHODS: Forty eight Kunming strain mice were randomized into 4 groups: model group, low lutein group (LL 10 mg/(kg x d)), high lutein group (HL 40 mg/(kg x d)) and normal control group. The content of reactive oxygen species (ROS), nitric oxide (NO) and activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS) and mitochondrial Na(+)-K(+)-ATPase, Ca(2+)-ATPase in liver tissue were detected 6 weeks later in the experiment. The expression of toll-like receptor-4 (TLR4) mRNA and hemeoxygenase-1 (HO-1) mRNA in hepatic tissue were detected by reverse transcription polymerase chain reaction (RT-PCR) technique. RESULTS: ROS content in HL and LL group was significantly lower (P < 0.01) than that in the model group. The activity of Na(+)- K(+)-ATPase in HL and LL group and the activity of Ca(2+)-ATPase in HL group were significantly higher than that in the model group (P < 0.05). The activities of TNOS and iNOS and the content of NO in HL group were significantly lower than the model group (P < 0.05). The expression of HO-1 mRNA in HL group was significantly higher than that in the model group, but the expression of TLR4 mRNA in HL group was significantly lower than that in the model group (P < 0.05). CONCLUSION: The mechanism of lutein on the protection of mice from oxidative stress induced by D-gal might be related to increasing the expression of HO-1 mRNA and reducing the expression of TLR4 mRNA. PMID- 20726231 TI - [Effects of retinoic acid receptor agonist and retinoid X receptor agonist on the expression of IL-4 and IFN-gamma in cord blood mononuclear cells]. AB - OBJECTIVE: To observe the effects of retinoic acid receptors agonist TTNPB and retinoid X receptors agonist MA on both protein and gene expression of IFN-gamma and IL-4 in cultured cord blood mononuclear cells. METHODS: Observing both the protein content and gene expression of IFN-gamma and IL-4 with ELISA and fluorescent real-time quantitative PCR in vitro. RESULTS: It was indicated by ELISA that 10(-8), 10(-6), 10(-5) and 10(-4) mol/L TTNPB and 10(-8), 10(-5) and 10(-4) mol/L MA decreased the ratio of IFN-gamma/IL-4 significantly in comparison with the control (P < 0.05), and indicated by RT-PCR that 10(-4) mol/L MA decreased the ratio of IFN-gamma/IL-4mRNA significantly and 10(-5) mol/L TTNPB and 10(-7), 10(-6) mol/L MA increased the ratio of IFN-gamma/IL-4mRNA significantly in comparison with the control (P < 0.05). CONCLUSION: The ratio of IFN-gamma/IL-4 could be down-regulated by proper concentration of TTNPB and MA at the protein level, while the ratio of IFN-gamma/IL-4mRNA was differently influenced by various concentration of TTNPB and MA at the gene level. PMID- 20726232 TI - [Subchronic toxicity test of genetically modified rice with double antisense starch-branching enzyme gene]. AB - OBJECTIVE: To observe the sub-chronic toxic effects of the genetically modified rice with double antisense SBE gene. METHODS: Based on gender and weight, weanling Wistar rats were randomly sorted into five groups: non-genetically modified rice group (group A), genetically modified rice group (group B), half genetically modified rice group (group C), quarter genetically modified rice group (group D) and AIN-93G normal diet group (group E). Indicators were the followings: body weight, food consumption, blood routine, blood biochemical test, organ weight, bone density and pathological examination of organs. RESULTS: At the middle of the experiment, the percentage of monocyte of female group B was less than that of group E (P < 0.05). AST activity of female group B was higher than that of group E (P < 0.05). ALT activity of female group C was higher than that of groups A and E (P < 0.05). At the end of the experiment, AST and ALT activities of female group B were higher than those of group E (P < 0.05). Hematocrit (HCT) and blood urea nitrogen (BUN) level of male group B were less than those of group A (P < 0.05), and monocyte was higher than that of group E (P < 0.05). The brain index of female group B was higher than group A (P < 0.05) and the kidney index of group E were higher than those of groups B, C and D (P < 0.05). There were no significant difference of blood lipids, calcium and bone mineral density among all groups (P > 0.05), and no notable abnormity in the pathological examination of main organs (P > 0.05). CONCLUSION: There were no enough evidence to confirm the sub-chronic toxicity of genetically modified rice on rats. PMID- 20726233 TI - [Synthesis and identification of artificial antigens for sulfaguanidine and sulfathiazole]. AB - OBJECTIVE: To prepare artificial antigens of sulfaguanidine and sulfathiazole for detecting sulfaguanidine and sulfathiazole in foods of animal origin. METHODS: The artificial antigens were synthesized by the diazotization methods of coupling sulfaguanidine and sulfathiazole with bovine serum albumin (BSA), and the coupling ratio was 10 : 1 and 9 : 1 respectively. The anti-serum of Balb/c mice was obtained after 5 injections of artificial antigens and the antibody titles were detected by iELISA method. RESULTS: The artificial antigens were identified by infrared spectra, ultraviolet spectra and immunized experimental animals. CONCLUSION: The antigens for sulfaguanidine and sulfathiazole were acquired successfully. The results have laid basis for the specific immunoassay of sulfaguanidine and sulfathiazole. PMID- 20726234 TI - [Apoptosis effects on human esophageal cancer cells by soyasaponin Bb and its machanism]. AB - OBJECTIVE: To explore the effect and potential mechanism of apoptosis in the Eca 9706 cells induced by soyasaponin Bb. METHODS: Different concentrations of soyasaponin Bb were on the Eca-9706 cell. Cell growth suppression rate was detected by MTT. Apoptotic rate was detected by TUNEL. The expression changes of HDAC1, NF-kappaB, PTEN, cyclin D1, c-met, VEGF or caspase-3 in the SSBb were detected by immunohistochemistry and immunoblotting. RESULTS: Compared with the control group, the growth-inhibition rate and apoptotic rate were increased, the expressions of PTEN, caspase 3 were increased, the expressions of c-met, VEGF, HDAC1, NF-kappaB and cyclin D1 were decreased. CONCLUSION: SSBb can suppress Eca 9706 cell growth. SSBb can exhibit reverse effects on over expression of c-met, VEGF in Eca-9706 cells. Eca-9706 cell apoptosis can be induced by SSBb through inhibiting HDAC1-NF-kappaB and activating PETEN and caspase-3 signaling pathways. PMID- 20726235 TI - [Inhibition of genistein on the proliferation of RWPE-1 cells induced by testosterone under the control of insulin-like growth factor-1]. AB - OBJECTIVE: To observe the inhibition of genistein (Gen) on the proliferation of RWPE-1 cells under insulin-like growth factor-1(IGF-1) modulation and the molecular mechanism of influences on cell cycles. METHODS: The proliferation of RWPE-1 cells was promoted by testosterone and assessed by morphologic observation. RWPE-1 cells were treated with Gen of 0.63 - 80 micromol/L and IGF-1 of 0.1 - 12.8 nmol/L for 24 h, 48 h and 72 h, and the viability of the cell was examined. The cell cycle of RWPE-1 in the control group, 40 micromol/L Gen group, 6.4 nmol/L IGF-1 group and 40 micromol/L Gen + 6.4 nmol/L IGF-1 group was observed by flow cytometry analysis. The expression of cyclin B1, cyclinD1 and cyclin-dependent kinase 4 was examined by Western blot. RESULTS: The proliferation of RWPE-1 cells could be induced by 2 micromol/L of testosterone, and the proliferation could be inhibited by 2.5 - 80 micromol/L of Gen. The inhibitive effect could be enhanced with increased concentration and prolonged action time. The percentage of cells at G0/G1 phase could be decreased and the percentage of cells both at S phase and G2/M phase could be increased, the expression of cyclinD1 and CDK4 was down-regulated and the expression of cyclinB1 was up-regulated by the treatment of 40 micromol/L Gen under the modulation of 6.4 nmol/L IGF-1. CONCLUSION: Under the modulation of IGF-1, Gen could affect the expression of cyclins and CDKs, induce G2/M cell phase arrested and inhibit the proliferation of RWPE-1 cells induced by testosterone. PMID- 20726236 TI - [Effects of anthocyanins derived from Xinjiang black mulberry fruit on delaying aging]. AB - OBJECTIVE: To study the effects of anthocyanins from Xinjiang black mulberry fruit on the lifespan and antioxidant system of Drosophila melanogaster. METHODS: Drosophila were divided into five groups based on the content of anthocyanins in culture medium. The lifespan of drosophila was tested by survival experiments, including median lethal time, average life-span and average maximum life-span. The activity of antioxidant enzymes of drosophila, including glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and the content of maleic diadehyde (MDA), were tested after being fed for 30 days. RESULTS: The lifespan of drosophila were prolonged with the increase of anthocyanins. Median lethal time, average lifespan and average maximum lifespan of drosophila in the groups fed with anthocyanins at the content of 27.27 mg/kg and 112.5 mg/kg were longer than those in controls, and in a dose-response relationship. The activities of GSH-Px, SOD and CAT increased and MDA content decreased significantly with the increase of anthocyanins in a dose-response relationship. The activity of three antioxidant enzymes was the highest and MDA concentration was the lowest in the group fed with anthocyanins at the content of 11.25 mg/100g when compared with the controls. CONCLUSION: The activities of three antioxidant enzymes could be enhanced and the process of lipid peroxidation could be inhibited by anthocyanins, which might be one of the reasons for prolonging the lifetime of Drosophila melanogaster. PMID- 20726237 TI - [Identification of Lactobacillus and Streptococcus thermophilus by PCR amplification and sequence analysis of 16S rRNA]. AB - OBJECTIVE: To develop a PCR method for identifying the 16S rRNA of Lactobacillus and Streptococcus thermophilus at the species level. METHODS: Optimizing the method for DNA extraction and the conditions for PCR amplification. Joining the PCR amplification products from 16S rRNA to plasmid puc18-T and detecting the sequence. RESULTS: All 50 isolates recovered from yoghourt products were characterized by 16S rRNA sequence analysis and 7 groups were identified as L. bulgaricus (24 strains), S. thermophilus (12 strains), L. acidophilus (7 strains), L. casei (3 strains), L. delbrueckii (2 strains), L. fermentum (1 strain) and S. lutetiensis (1 strain). CONCLUSION: 16S rRNA PCR method developed in this research is a sensitive and reliable method for the identification of both Lactobacillus and Streptococcus thermophilus. PMID- 20726238 TI - [Analysis of pulmonary function of primary students living in air pollution areas]. AB - OBJECTIVE: To explore the changes of lung function of primary students living in the regions of different air pollution. METHODS: Nanshan District and Longgang District were decided respectively as a relatively heavy air pollution region and as a relatively light air pollution region in Shenzhen according to their air pollutant concentrations. The daily monitoring values on atmospheric SO2, NO2, PM10 and CO from 2006 to 2008 in the two districts were collected. PM2.5 monthly monitoring was started in Jan. 2008. Pulmonary functions of primary students were performed in the two schools within the scope of the surrounding 3km of the PM2.5 monitoring points. RESULTS: Average concentrations of atmospheric SO2, NO2, CO, PM10 and PM2.5 in Nanshan District were more high than those in Longgang District. Their concentrations were 0.0285 mg/m3 vs 0.0227 mg/m3, 0.0649 mg/m3 vs 0.0473 mg/m3, 2.278 mg/m3 vs 1.478 mg/m3, 0.0724 mg/m3 vs 0.0713 mg/m3 and 0.0665 mg/m3 vs 0.0524 mg/m3 (P < 0.05) respectively except PM10. Levels of the key indicators of lung function (VC, VC%, FVC, FVC%, MVV, MVV%, FEV1.0, FEV1.0/FVC, PEF, PEF%, FEF25, FEF50 and FEF75) increased with ages in the primary students. Means of the most indicators in Nanshan District were higher than those in primary students in Longgang District. Significant difference existed in the same grade of students on lung function in the two regions (P < 0.05). CONCLUSION: Air pollution could affect pulmonary function of primary students. PMID- 20726239 TI - [Risk assessment of fluoride exposure to pork and offal products of pigs in Shanghai City]. AB - OBJECTIVE: To estimate the exposure of fluoride to pork and offal products of pigs and assess their health risks in Shanghai residents. METHODS: Conducting a dietary survey in 1630 residents cluster sampled from four districts in Shanghai. Detecting fluoride in 872 pork and offal samples, and using Monte Carlo method to estimate the chronic daily intake (CDI) and hazard quotient (HQ) of fluoride in Shanghai residents caused by eating pork and offal products of pigs. RESULT: The CDI of fluoride is less than the tolerable daily intake (TDI), and the HQ is less than 1. The intake of pork and offal product is less in elder people than young people (P < 0.05), and that is less in female than male (P < 0.05). The fluoride content in offal is higher than that in pork (P < 0.05), the fluoride in kidney (P < 0.05) and liver (P < 0.05) is higher than that in other viscera. CONCLUSION: The intake of fluoride from pork and offal products in Shanghai residents is lower than the TDI of fluoride and not reaching the risk level of fluoride causing dental fluorosis, unhealthy of bone and osteofluorosis. PMID- 20726240 TI - [Surveys on the conditions of Keshan disease and selenium levels of 15 counties in Shandong Province in 2008]. AB - OBJECTIVE: To investigate the conditions of Keshan disease and the selenium nutritional status of residents in Keshan disease endemic area in Shandong Province. METHODS: One site from each of 15 Keshan disease endemic counties in Shandong Province was selected for the survey and 700 subjects in each site were randomly selected for the investigation. Physical examination, electrocardiogram and X-ray radiography of the subjects and the selenium contents of hair, wheat, corn and dried sweet potato were surveyed. RESULTS: A total of 10679 people were investigated in 15 counties and 315 patients were found, including 287 cases of latent type and 28 cases of chronic type, but no acute or subacute type patients were found. There were 1776 cases of abnormal electrocardiogram. Among the 461 cases checked up by radiography, the heart of 195 cases was enlarged. The selenium content of hair, wheat, corn and dried sweet potato were (0.5191 +/- 0.5538), (0.0268 +/- 0.0045), (0.0194 +/- 0.0052) and (0.0193 +/- 0.0039) mg/kg respectively. CONCLUSION: The occurrence of Keshan disease is in a stable status in Shandong Province at present. Hair selenium of residents in Keshan disease endemic area has reached an appropriate level. The selenium nutritional status of residents has improved, and the prevalence of Keshan disease is expected to be decreased in these areas. PMID- 20726241 TI - [Analysis on the prevalence of malnutrition and affected factors of rural poor infants under 2 years old in Guangxi Province in 2008]. AB - OBJECTIVE: To analyze the prevalence of malnutrition and its affected factors of poor rural infants under 2 years old in Guangxi Province. METHODS; Applying a three stages stratified cluster sampling method, a total of 653 subjects were sampled from 4 rural poor counties. The Z score standards recommended by NCHS/WHO were used to evaluate the nutrition and health condition of infants. Non conditional multifactor logistic regression model was used to analyze the factors affecting nutritional status. RESULTS: The rates of low birth weight, growth retardation, under weight, emaciation and anemia of 653 infants under 2 years old were 8.7%, 39.7%, 42.1%,14.4% and 25.4% respectively. The non-conditional multifactor logistic regression model indicates that the age of infants, the caregivers and the time of their mothers working outside were the associated risk factors of growth retardation and under weight of the babies. CONCLUSION: The rate of low birth weight in part of rural poor areas in Guangxi Province was obviously higher than the expecting target (i. e. lower than 5%) at the year 2010. The rates of growth retardation, under weight, emaciation and anemia were still high. PMID- 20726242 TI - [Dietary pattern of Shanghai community-based middle and aged women]. AB - OBJECTIVE: To provide data for decision-making and community nutrition intervention for middle and aged women, the dietary patterns and nutritional status were investigated in Shanghai. METHODS: A stratified cluster random sampling dietary survey was performed for a sample (n = 596) of women aged 45 to 65 years old from 2 streets in Shanghai. Factor analysis was applied to define major dietary patterns by using dietary information collected from food-frequency questionnaires (FFQs), and to further examine associations between dietary patterns and main nutrients and demographic characteristics. RESULTS: Four major dietary patterns were identified. The first pattern was characterized by higher intake of eggs, legumes and products, second pattern was characterized by higher of oil, sugar and condiments, the third pattern was characterized by a higher intake of dairy, vegetables and rice, while the fourth pattern was characterized by higher intake of fruits, beef and fish. Oil, sugar and condiments pattern associated with higher total energy and fat percentage of energy (P < 0.001), lower educated (P = 0.009) and lower household income (P = 0.008). A positively correlation was found between rice, vegetables, dairy pattern with calcium, protein and carbohydrates percentage of energy, and inversely correlated with BMI (P = 0.019), as well as energy and total fat. Fruit, meat and fish pattern was higher for the protein, vitamins B2, vitamin B6 and vitamin C. But no positive correlation was found between eggs and legumes and products pattern with nutrients intake or other sample characteristics. CONCLUSION: Rice, vegetables and milk dietary pattern was associated with reduced risk of overweight and obesity. PMID- 20726243 TI - [Impact of stressful life event, weight gain during pregnancy and mode of delivery on the delayed onset of lactation in primiparas]. AB - OBJECTIVE: To evaluate the effect of severe life events at first, second and third trimester, excessive weight gain during pregnancy and caesarean section on the delayed onset of lactation. METHODS: The effect of life stressful event during different gestational age in a total of 2017 parturient women giving birth in hospitals was assessed with reliable questionnaires. Demographic characteristics, history of pregnancy, BMI at early pregnancy and antepartum and the delivery outcomes including gestational age at birth, mode of delivery and the condition of babies were collected by interviewing or from medical charts. Lactation guidance was provided and the data on the onset of lactation were collected in hospitals within 72 hours after parturition. The onset of lactation was defined by the perception of mothers on the fullness of the breast. Univariate and multivariate logistic regression analyses were performed after controlling maternal age, registered permanent residency and educational level. RESULTS: Delayed onset of lactation occurred in 9.5% of 2017 women and was associated with exposure to severe life events at the first trimester (crude RR = 1.72, 95% CI 0.97 - 3.04, adjusted RR = 1.97, 95% CI 1.09 - 3.55) , increasing of BMI > or = 7.6 during pregnancy (crude RR = 1.93, 95% CI 1.23 - 2.94, adjusted RR = 1.64, 95% CI 1.07 - 2.54) and caesarean section (crude RR = 1.35, 95% CI 1.20 - 1.53, adjusted RR = 1.32, 95% CI 1.17 - 1.49). CONCLUSION: Success on early lactation is strongly influenced by potentially modifiable factors, such as exposure to severe life events in the first gestational age, excessive weight gain during pregnancy and caesarean section. PMID- 20726244 TI - [Study on selenium exposure level related to cognitive function in rural elderly people]. AB - OBJECTIVE: To know the relationship between selenium exposure level and cognitive function and its influencing factors in rural elderly people. METHODS: A cross sectional survey of 200 local rural elderly people were conducted by using dietary questionnaire and six cognitive questionnaires. The local environment samples were collected including food and nail and blood sample of study individuals. The trace amount of selenium were determined with 2, 3 diaminonaphthalenet fluorometric determination. Multiple stepwise regression was used to examine the association between selenium exposure level and the composite Z score adjusting for age, gender, education, and other factors that might influence the cognitive scores. RESULTS: There were significant positively relationships between three selenium exposure indexes. The results showed that food selenium intake level and blood selenium level could significantly affected the Z score after adjusting age, education and other factors by using multiple stepwise regression analysis (P < 0.001). CONCLUSION: Lower selenium exposure level maybe associated with lower cognitive function in rural elderly people. PMID- 20726245 TI - [Abnormal glucose regulation and the risk factors in middle-aged and elderly residents from Baoding City]. AB - OBJECTIVE: To assess the prevalence of type 2 diabetes mellitus (T2DM) and impared glucose regulation(IGR) in the residents of Baoding City, including 1 impaired fasting glucose(1-IFG), 1-impaired glucose tolerance (1-IGT) and IFG/IGT, to identify the main risk factors of abnormal glucose regulation. METHODS: A sample of 3212 community residents aged over 40 years old was selected from three communities of Baoding City by random cluster sampling. The survey was conducted by trained investigators using a standardized questionnaire. The subjects received physical examination and laboratory test, such as SBP, SDP, TC, TG, LDL-C, HDL-C, FBG, 2h PG, WHR and BMI. The data were analyzed by Accumulative Logistic Regression. RESULTS: The standardized prevalence of T2DM, -IFG, 1-IGT and IFG/IGT was 19.03%, 1.42%, 5.92% and 1.34%, and 27.72% of residents over 40 yeas old in Baoding City threatened by the trouble of abnormal glucose regulation. The results demonstrated that the gender, age, occupation, fruit intake, temper or disposition, BMI, WC, WHR, SBP, TG, DM family history and the history of fetal macrosomia (female only) were significantly associated with the abnormal glucose regulation, but taking more fruits and the female sex were protective factors. Cardio-cerebrovascular disease was the highest among the complications prevalent in diabetic patients, more than one complication is common, and the detection rate of new diabetic patients was 8.19%. CONCLUSION: The prevalence of T2DM is high in the residents of Baoding City, which is influenced by many factors. PMID- 20726246 TI - [Reliability and validity of a sub-health symptom check scale for college students]. AB - OBJECTIVE: To analyze the reliability and validity of a sub-health symptom check scale for college students. METHODS: Using a multi-phase cluster sampling method, a total of 1200 college students from Changsha city were tested with a sub-health symptom check scale; 1143 valid questionnaires were received to assess the internal consistency reliability coefficient and split-half reliability coefficient; 111 students were retested 14 days later to assess the reliability of the scale, 112 students were also tested with the Symptom Checklist 90 (SCL 90) to evaluate the criterion-related validity of the scale. RESULTS: The Cronbach's alpha coefficient of the questionnaire was 0.946 and the test-retest correlation coefficient was 0.701. Taking SCL-90 as a criterion, the criterion related validity of the scale was 0.875. The scores of the scale were significantly different in gender and between sub-healthy and healthy students. CONCLUSION: The scale is reliable, effective, and sensitive, and could be applied to evaluate the sub-health status of college students. PMID- 20726247 TI - [Investigating the toxicity characteristics of Nassarius Sp. in Ningbo City]. AB - OBJECTIVE: To study the type, distribution, the growth and decline of toxins in Nassarius Sp. and the source of toxins to acquire the basis for the control of Nassarius Sp. poisonings. METHODS: The toxicity of Nassarius Sp. was detected by mouse bioassay. The saxitoxin (STX), gonyau toxin (GTX), and tetrodo toxin (TTX) were detected by ELISA and HPLC. RESULTS: Sixty-three poisonous Nassarius Sp. were identified in 127 samples collected from long-term monitoring sites. The detection rate was 49.6%. The detection rate of poisonous Nassarius Sp. was different in varies habitats (P < 0.01). The toxicity of Nassarius Sp. reached a peak in 1991 and hit the rock bottom in 1988. The rate of carrying toxins and the toxicity of detected toxins (STX, GTX and TTX) in Nassarius semiplicatus, Nassa succincta A. Adams and Niotha livescens were high. CONCLUSION: The toxins of Nassarius Sp. in Ningbo City were composed of TTX, STX or GTX, or both TTX and STX. The surveillance proved that some toxins present in Nassarius Sp. in Ningbo City. Poisoning could be caused by eating Nassarius Sp. PMID- 20726248 TI - [Association of sub-health symptoms with family environment factors in middle school students in Bengbu District]. AB - OBJECTIVE: To describe the prevalence of psychosomatic sub-health symptoms in middle school students and to explore the related family factors affecting the sub-health symptoms. METHODS: Based on stratified, random cluster sampling method, 2 910 students from 6 middle schools in Bengbu district were sampled. Questionnaire on demographic characteristics and family factors, and the multidimensional sub-health questionnaire of adolescents (MSQA) were used to investigate the risk factors of sub-health symptoms. RESULTS: The prevalence of overall sub-health symptoms was reported in 64.0% of students, physical symptoms was reported in 13.6% of the students, and the rates of physical inactivity, physiological dysfunction and immunity decline were in 53.0%, 68.7% and 55.0% of students respectively. Mental sub-health symptoms were reported in 55.4% of students, emotional symptoms, behavioral symptoms and social adaptation problems were reported in 78.4%, 51.5% and 85.6% of students respectively. There was an increase in the prevalence of self-reported sub-health symptoms with the increase of the grade (P < 0.05), boys were more likely to report sub-health symptoms than girls (65.7% vs. 62.0%, P < 0.05). The main family factors affecting sub-health symptom of students were the health status of their parents and major accompanying persons. CONCLUSION: The prevalence rate of sub-health symptoms in middle school students was very high and increased with the length of time and the grade at school. The risk factors for sub-health symptoms of students were the lower health level of their parents and not their parents accompanying them. PMID- 20726249 TI - [Dectective of serum di-n-butyl phthalate and di-2-ethylhexyl phthalate level in normal children]. AB - OBJECTIVE: To study on the level of serum di-n-butyl phthalate (DBP), di-2 ethylhexyl phthalate (DEHP) in normal children by using gas chromatography. METHODS: Gas chromatography method was established. DBP, DEHP in normal children were detected, and their reference level was calculated, DBP and DEHP level in different age and genders were analysed. RESULTS: DBP could be detected in 110 serum samples from total 310 samples, and DEHP could be detected in 118 serum samples from the total 310 samples. The detected contrations of DBP range from non detectable to 0.98 ng/ml, P75 was 0.68 ng/ml, P95 was 0.75 ng/ml. There was no difference in the detection ratios between females and males, while baby group detection ratios was lower than other groups. The detected contrations of DEHP range from non detectable to 0.94 ng/ml, P75 was 0.67 ng/ml, P95 was 0.74 ng/ml. There was no difference in the detection ratios between females and males. While there was difference among age groups. CONCLUSION: The study domonstrated that DBP and DEHP concentrations in normal children are very low. The refrence level of DBP was suggested as lower than 0.75 ng/ml, DHEP was suggested as lower than 0.74 ng/ml. PMID- 20726250 TI - [Correlation between ethambutol-resistance and embB gene mutation in Mycobacterium tuberculosis]. AB - OBJECTIVE: To analyze the characteristics of embB gene mutation in ethambutol resistant Mycobacterium tuberculosis (M. TB) strains isolated from patients in Xi'an for establishing a rapid method to detect the mutation of embB gene in M. TB. METHODS: The embB gene of 104 Mycobacterium tuberculosis isolates was detected by PCR-Single Strand Conformation Polymorphism (PCR-SSCP) and PCR Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS: Taking strain H37Rv as a control, the SSCP and RFLP profiles of embB of 35 drug-sensitive strains in 104 Mycobacterium tuberculosis isolates were normal. The display of SSCP profiles in 39 of 69 (56.52%) ethambutol-resistant isolates and the display of RFLP profiles in 19 of 69 (27.54%) ethambutol-resistant isolates were abnormal. CONCLUSION: The EMB-resistance of M. TB strains isolated from patients in Xi'an is related to the mutation of embB gene, PCR-SSCP and PCR-RFLP are sensitive methods for detecting ethambutol-resistance of M. tuberculosis. PMID- 20726251 TI - [Typing of Listeria monocytogenes in import and export foods with PFGE]. AB - OBJECTIVE: To investigate the molecular type and genetic correlation of Listeria monocytogenes (LMO) isolated from imported and exported foods. METHODS: Pulsed field gel electrophoresis (PFGE) standard method recommended by american PulseNet for typing LMO was applied. The chromosomal DNA of L. monocytogenes was digested by restriction enzyme Asc I and analyzed by PFGE. The PFGE patterns of L. monocytogenes strains isolated from different areas were compared by using BioNumberics software to analyze the similarity between strains. RESULTS: Twenty four L. monocytogenes strains were grouped into 20 PFGE subtypes by the similarity of PFGE pattern ranged from 44.45% to 100%. Particularly, it was identified that there were three subtype strain groups, each group sharing with the same PFGE pattern, and the similarity reaching 100%: the first group including LMO16 from Canada, LMO18 from America and LMO13 from Denmark, the second group including LMO7 from Denmark and LMO22 from Shunde, and the third group including LMO21 from Guangzhou and LMO8 from Shanxi. CONCLUSION: Generally, much genetic diversity was shown in Listeria monocytogenes isolated from import and export foods, but the correlations among strains are existed to some extent. PMID- 20726252 TI - [Analysis of the results and methods on proficiency testing of determination of Fe, Mn in drinking water]. AB - OBJECTIVE: To analyse the results and methods on proficiency testing(PT) for determination of Fe, Mn in drinking water and to discuss the influencing factors. With a view to the laboratory for accurate determination of drinking water iron and manganese to provide technical support. METHODS: 180 labs from 30 provinces (cities), autonomous regions took part in the PT. Based on methods of PT, statistical analysis of the results, to find the causes of dissatisfactory results. RESULTS: According to the results of the report for the first time, the PT showed that 85.56% labs presented satisfactory results of determination of Fe and 87.71% labs presented satisfactory results of determination of Mn. In addition to ICP/MS, it showed that 76.00%, 88.89%, 93.75% respectively presented satisfactory results of the methods of AAS, ICP-AES and chemical of determination of Fe. It showed that 79.23%, 94.29%, 72.73% respectively presented satisfactory results of the methods of chemical, AAS and ICP-AES of determination of Mn. The initial results of 37 labs had dissatisfactory. Results of statistics showed that iron, manganese at the same time [ZB] > or = 3 for the 11 labs. CONCLUSION: Most of the labs that took part in the PT have good competence in analyzing Fe, Mn. The main reasons of the dissatisfactory results were larger systematic errors, experimental blank, matrix interference and feeble control ability of the key point of the experiment. PMID- 20726253 TI - [Research progress of bioactive constituents, absorption, metabolism, and neuroprotective effects from blueberry]. AB - The main components of blueberry were anthocyanins, chlorogenic acid, citric acid, arbutin, myricetin and its glycoside and so on. It has the activities of neuroprotection, preventing the age-related changes of brain, cardiotonic activity, etc. Recently, the effects of blueberry extracts on the improve function of cognition has been attracted wide attention. This review summarizes the active components, absorption and metabolism of blueberry, especially focuses on neuroprotection and the mechanisms involved. PMID- 20726254 TI - [Effects of alcohol on acute myocardial ischemia induced by pituitrin in rats]. AB - OBJECTIVE: To observe the effects of alcohol intake at different levels on acute myocardial ischemia induced by pituitrin in rats. METHODS: Forty SD male rats were randomly divided into five groups, including model control group (pituitrin, 1U/kg), positive control group (verapamil, 1 mg/kg), 5% alcohol group (0.4 g/kg), 10% alcohol group (0.8 g/kg) and 20% alcohol group (1.6 g/kg). Myocardial ischemia model was made in rats by injecting pituitrin (1U/kg) through sublingual vein. The heart rate, incidence of arrhythmia, the changes of ST segment and T wave on electrocardiogram of rats were observed and compared. RESULTS: The incidence of arrhythmia, the degree of elevated ST segment and T wave amplitude induced by pituitrin were remitted obviously in the 5% alcohol group (0.4 g/kg); The heart rate was slower and the change of ST segment and T wave were not affected in the 10% alcohol group (0.8 g/kg). The heart rate was slower and the elevated ST segment and the T wave amplitude were augmented significantly in the 20% alcohol group (1.6 g/kg). CONCLUSION: A protective effect on acute myocardial ischemia induced by pituitrin in rats was shown in the 5% alcohol group (0.4 g/kg) and an aggravation of acute myocardial ischemia induced by pituitrin was observed in the 20% alcohol group (1.6 g/kg). PMID- 20726255 TI - [Study on safety and immunogenicity of oral poliomyelitis attenuated live vaccine (human diploid cell)]. AB - OBJECTIVE: To evaluate the safety and Immunogenicity of the Poliomyelitis vaccine (Human Diploid Cell) in > or =2 month-old children. METHODS: A random, blind and control trial, 1200 healthy children of 2-5 months old in Jiangsu province were administered OPV (HDC) vaccine and control vaccines. The antibody was tested by neutralization test. RESULTS: After 3 doses of the OPV (HDC) vaccine, the systemic reactions were mild. After 1 month of vaccination with 3 doses of the OPV (HDC) vaccine, the immune success rates of I, II, III type were 98.28%, 99.45%, and 95.71% respectively, the GMTs of I, II, III type in susceptible children were 1:1243.72, 1:234.38 and 1:273.10 respectively. CONCLUSIONS: The OPV (HDC) vaccine was safe and immunogenicity for the children > or =2 months old. PMID- 20726256 TI - [Identification and genetic characteristics of five non-polio enteroviruses (NPEVs) multiplicated on L20B cell line]. AB - OBJECTIVE: To identify and describe the genetic characteristics of non-polio enteroviruses (NPEVs) which could multiplicated on L20B cell line, and discuss the impact to isolation rate of polioviruses. METHODS: 5 L20B positive isolates were collected from stool samples of patient with acute flaccid paralysis (AFP) and health children in Guangxi Zhuang autonomous region and Ningxia Hui autonomous region. These isolates were analysed using VP4 nucleotide sequencing method. The completed VP, coding regions were amplified and sequenced. Finally, phylogenetic tree were constructed base on completed VP1 coding regions sequences of these L20B positive isolates and those downloaded form GenBank database. RESULTS: The 5 NPEVs were all identified as coxsackieviruses group A (CVA). Among them, 1 was identified as CVA4, 1 was identified as CVA8 and 3 were identified as CVA10, and all of them belonged to human enterovirus species A (HEV-A). Nucleotide homology analysis and phylogenetic analysis base on completed VP1 coding regions sequences showed that all these 3 serotypes of NPEVs clustered independently, and they were all native circulated viruses in mainland China. CONCLUSIONS: 5 NPEVs in this study belonged to HEV-A, covered 3 serotypes, CVA4, CVA8 and CVA10. Due to the high sensitivity of primarily inoculation of poliovirus onto L20B cell, the isolation rate of polioviruses could not be affected so much. Hand, foot, and mouth disease (HFMD) outbreaks in mainland China in recent years, and it was found that HEV-A is also pathogen of HFMD. Identification of these viruses have current significance to differential diagnosis of poliovirus infection and HFMD control and prevention. PMID- 20726257 TI - [Evaluation of the test results on hepatitis B pilot surveillance labortory in 9 provinces of China]. AB - OBJECTIVE: To assess the test quality of HBsAg, anti-HBc IgM and anti-HAV IgM in the laboratories of Hepatitis B pilot surveillance provinces. METHODS: Blood serum from each of the Hepatitis B pilot surveillance provinces were collected to verify the test results. The Chemiluminescence Microparticle Immuno Assay (CMIA), ARCHITECT i2000 automatic light detector and test reagents produced by U.S.A. Abbott corporation were used in the retest. Using the Abbott reagent CMIA test results as the criteria, the domestic made ELISA reagents sensitivity, specificity, the total coincidence rate and Yoden index of HBsAg, anti-HBc IgM and anti-HAV IgM were evaluated in Hepatitis B pilot surveillance provinces. RESULTS: In the National Notifiable Diseases Reporting System (NNDRS) reported Hepatitis B cases, the proportion of detecting HBsAg and anti-HBc IgM was 98.53% and 39.49% respectively. Through the verification test to the reported cases in Hepatitis B pilot surveillance provinces, the original and veritication diagnosis 01 the reported eases was quite different. Among 197 acute Hepatitis B reported cases, 56 cases were agreeable with diagnosis cretirea, accounting for 28.42%. Among 1046 chronic Hepatitis B reported cases, the verification diagnosis of 602 cases was consistent with the original diagnosis, accounting for 57.55%. By using Abbott reagent and CMIA method to test again, it was found that the verification test results using domesticmade reagent and ELISA assay were low consistency compared with the test results of Abbott reagent CMIA method. The detection result of home-made reagents by ELISA compared with the Abbott reagents CMIA, the sensitivity and the total coincidence rate of HBsAg were over 95%, Kappa value was 0.439, and specificity was only 50.00%. The sensitivity, the total coincidence rate and the specificity of Anti-HBc IgM were moderate level, Kappa value was 0.516. The sensitivity of Anti-HAV IgM were 20%, and the total coincidence and specificity were higher, Kappa value was 0.033, the consistency of test was poor. CONCLUSION: It's necessary to improve the detection ability of Hepatitis B etiology of indicators in order to improve the accuracy of the report of Hepatitis B cases. PMID- 20726258 TI - [Effect analysis on non-and-low response infants after revaccinated hepatitis B vaccine]. AB - OBJECTIVE: To evaluate the booster immunization effect to non-and-low response children after 3 doses HepB immunization. METHODS: Non-and-low response infants born in 2004 2005 administered 3 doses of HepB at 0, 1, 6 months in Guangzhou, Beijing and Zhejiang were divided into 4 groups randomly, and boosted 3 dose of 4 different types of HepB at 0, 1, 6 months. RESULTS: The GMC of non-and-low response children in group A (before booster), group B (after 1 dose booster) and group C (after 3 dose booster) were 18.66 mIUml, 88.82 mIU/ml, 178.24 mIU/ml respectively; the proportion of non-responders in three groups were 20.4%, 9.1%, 1.9% respectively. In 103 non-and-low response children, proportion of titers of more than 100 mIU/ml of group B and group C were 61.2% and 84.5%, and there was statistical significant difference (chi2 = 14.13, P < 0.01). The GMC after 3 doses revaccination with four kinds of HepB, included 5 microg HepB-Y, 10 microg HepB-Y, l0 microg HepB-CHO, 10 microg HepB-HY were 168.8 mJU/ml, 174.7 mIU/ml, 184.9 mIU/ml, 182.9 mIU/ml respectively. Proportion of titers of more than 100 mIU/ml for four kinds HepB were 79.0%, 85.7%, 88.2% and 84.6% respectively, and there was no significant difference (chi2 = 0.75, 0.05). CONCLUSION: There were no different of seroconversion rate between study population received 1 dose and 3 dose booster (P > 0.05), but high titer was observed after 3 dose booster. The four kinds of HepB, including 5 microg HepB-Y,10 microg HepB-Y, 10 microg HepB CHO, 10 microg HepB-HY had the same immunization effect after 3 doses revaccination at 0, 1, 6 months to non-and-low response children. PMID- 20726259 TI - [Analysis on HBV epidemical trend of people age <20 from rural areas of Zhaodong]. AB - OBJECTIVE: By two times investigation to the HBV infection of people age <20 in rural areas in Zhaodong city, to understand the effects of HepB immunigation through analysing the changes of HBsAg, anti-HBs and anti-HBc infectious markers during 1986-2005. METHODS: Cross-sectional study was conducted and the surum samples were collected in 1986 and 2005 respectively. HBsAg, anti-HBs and anti HBc of the sera with SPRIA were tested. RESULTS: HBsAg average positive rate of the people age <20 decreased from 8.5% in 1986 to 4.4% in 2005 (chi2 = 10.88, P < 0.01). The anti-HBs average positive rate increased to 43.1% in 2005 from 18.3% in 1986 (chi2 = 130.47, P < 0.01). The anti-HBc average positive rate decreased from 39.9% to 15.1% (chi2 = 122.18, P < 0.01). CONCLUSION: The HBV infectious background of the rural population in Zhaodong city is high and the HBV infection rate decreased obviously after HepB inoculation since 1986, but it is still higher than the state average rate. It indicated that the HBV prevention in this district need to be enforced and improved. PMID- 20726260 TI - [Research on the relationship between fever and H1N1 influenza vaccination in students]. AB - OBJECTIVE: To know the relationship between fever and H1N1 influenza vaccination among students. METHODS: Collect and analyze the data from Shanghai school absence reporting system and H1N1 influenza vaccine daily reporting system. RESULTS: 51 schools and 49024 students were investigated. The H1N1 influenza vaccine coverage rate was 58.5% among them. The fever rates for vaccinated and unvaccinated students were 2.41% and 7.49% respectively. It has statistic difference. CONCLUSION: The H1N1 influenza vaccine was safe and the protection rate against fever was 68%. PMID- 20726261 TI - [Analysis of influenza type A(H1N1) antibody levels in different population in Gansu province]. AB - OBJECTIVE: To investigate influenza type A(H1N1) antibody levels in 3 different population which included common people, people recovered from be infected with influenza A(H1N1) and people vaccinated influenza type A(H1N1) vaccine in Gansu province in 2009. METHODS: Hemagglutination Inhibition (HI) test, HI test is positive when HI-titer > or = 1:40. RESULTS: The influenza type A(H1N1) antibody positive rate of urban population were 3.64% (11/302) and 10.45% (44/421) in Gansu province in August and later November respectively. The antibody-positive rate of people vaccinated after 30 days was 46.13% (131/284), GMT was 1:21.31. 10 15 days after infected by influenza type A(H1N1), HI antibody-positive rate was 87.04%, it rose to 96.40% after 15 days vaccination, and GMT was 1:139.4. CONCLUSION: In Gansu, Influenza A H1N1 outbroke firstly among students. Currently, all age groups were reported being infected with the influenza type A H1N1 virus. Only 6.65% of residents were given vaccination, antibody level of influenza type A H1N1 in people was low. Influenza type A(H1N1) virus will continue to spread in Gansu. Strengthening vaccination and improving treatment to serious cases were recommended strategies for influenza type A H1N1 control and prevention. PMID- 20726262 TI - [Analysis of diphtheria antibody levels in healthy population in Beijing municipal, 2007]. AB - OBJECTIVE: To investigate the diphtheria antibody level in healthy population in Beijing. METHODS: 10 age groups (< 1, 1 to 4, 5 to 9, 10 to 14, 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, and > or =40) were sampled by the Multi-stage stratified sampling method in 9 districts in Beijing, and 2 003 sera from healthy population were collected. The diphtheria antibody was determined with ELISA method. RESULTS: The diphtheria antibody-positive rate was 60.26%, and the antibody concentration was 0.62 IU/ml. A trend of decreasing in the antibody concentration was observed with increasing age and years after immunization. Antibody levels were the lowest in healthy people between 25-40 years old. CONCLUSION: It was predicted that a large scale of diphtheria outbreak would not occur recently in Beijing. It is recommended that for all adults diphtheria toxoids booster immunization should be conducted every 10 years for all adults. PMID- 20726263 TI - [Investigation on varicella incidence of the children < or =14 years old in Shandong province in 2007]. AB - OBJECTIVE: To investigate the variceilla incidence of children age < or =14 years old in Shandong province in 2007. METHOD: All children aged < or =14 and the cases of varicella were investigated from one township of rural area and one township of urban area of Jinan, Yantai, Taian, Linyi, Dezhou and Liaocheng prefecture. RESULT: 48877 children aged < or =14 were investigated. The incidence of varicella was 2841.83/100,100 The incidence of varicella was different between prefectures, and it was between 719.02/100,000 to 4394155/100,000. The peak age of incidence was 5 to 9 age group children. CONCLUSION: The incidence of varicella was high in Shandong province, the incidence was difierent between areas and age groups. PMID- 20726264 TI - [Effectiveness of 23-valent penumococcal polysaccharide and split-virus influenza vaccines to prevent respiratory diseases for elderly people]. AB - OBJECTIVE: To assess the effectiveness of 23-valent penumococcal polysaccharide vaccine (PenV23) and Split-Virus influenza vaccine (InfV-B) for preventing upper respiratory diseases in the aging population. METHODS: 151 people aged > or =60 years who inoculated the PenV23 and InfV-B vaccines at clinics during 2005 as trial group, and 188 people aged > or =65 years didn't administered as control guoup from some comminity. On base line survey, both guoups were followed up two years after vaccination about incidence, hospitalization rate, treatment and direct medical cost. RESULTS: The vaccine of PenV23 and InfV-B vaccination in upper respiratory tract infection was 60% [(odds ratio OR) = 0.35, 95% CI (0.153 0.794)] and the difference between the 2 groups was significant (P = 0.009). The people had recevied both vaccines, the mean duration of hospitalization in vaccinated vs unvaccinated control peple was 20.00 days: 24.19 days (t = 5.82, P < 0.001). Benefit-cost ratio was 4.03, and the net benefit was Yen 177994.86. CONCLUSION: Incidence of influenza-like illness for the elderly people in the community decreased by administered PenV23 ahd InfV-B vaccine. This vaccines had high cost-benefits. PMID- 20726265 TI - [Application of exponential smoothing method in prediction and warning of epidemic mumps]. AB - OBJECTIVE: To analyze the daily data of epidemic Mumps in a province from 2004 to 2008 and set up exponential smoothing model for the prediction. METHODS: To predict and warn the epidemic mumps in 2008 through calculating 7-day moving summation and removing the effect of weekends to the data of daily reported mumps cases during 2005-2008 and exponential summation to the data from 2005 to 2007. RESULTS: The performance of Holt-Winters exponential smoothing is good. The result of warning sensitivity was 76.92%, specificity was 83.33%, and timely rate was 80%. CONCLUSIONS: It is practicable to use exponential smoothing method to warn against epidemic Mumps. PMID- 20726266 TI - [Analysis on epidemiological and serum effect after vaccination of hepatitis A vaccine (HepA)]. AB - OBJECTIVE: To implement HepA vaccination and analyze epidemiological and serum effect. METHODS: The children from 1 to 14 years old were vaccinated HepA since 1992 and the HepA has been integrated into EPI to the children aged 1 year in 1996. The enzyme linked immunnosortbent assay (ELISA) was used to detect Anti Hepatitis A Virus IgG Antibody (Anti-HAV) to analyze serum effect. RESULT: HepA coverage rate from 1 to 14 years old was 80% in 1998, and it was > 90% after the year of 2001. The coverage of 1 year old children was 95%. The incidence rate of Hepatitis A reduced continuously. The incidence of whole population reduced from 25.96/100.000 in 1992 to 6.38/100.000 in 1994. In 2007, the incidence of Heptitis A decreased 98.10% compared with the incidence of the year of 1992. Epidemiological feature of Hepatitis A was changed. The positive rate of Anti-HAV was increased after vaccination of Hepatitis A Vaccine. CONCLUSION: The vaccination strategy for 1 to 14 years old had obviously epidemiological and serum effect. PMID- 20726267 TI - [Norovrius genotype I.8 being detected from sporadic cases of acute gastroenteritis in Nanning municipal]. AB - OBJECTIVE: To study the genic characteristic of Norovrius genotype I.8 from sporadic gastroenteritis of a hospital in Nanning Municipal. METHODS: Specimens of diarrhea patients from a hospital in Nanning Municipal between January 2007 and December 2008 were collected and detected for Noroviral genogroup Iribonucleic acid (RNA) by real-time reverse transcription-polymerase chain reaction(real-time RT-PCR). All positive specimens were subjected for sequencing analysis and constructed phylogenetic tree. RESULTS: Norovirus genogroup I RNA were detected in 3 of 696 stool specimens. The homology between one of the four strains (NN07230) and reference strain of G I.8 (WUG I/00/JP) was 94.5%; and the homology between the NN07230 strain and strains circulating during 2006-2007 in Japan and Korea ranged from 96.7% to 98.5%. And they formed one cluster in the phylogenetic tree. CONCLUSION: The research showed that genotype I.8 infection exists in sporadic gastroenteritis in Nanning City. PMID- 20726268 TI - [Analysis on disease burdern of Japanese encephalitis (JE) in Gansu province]. AB - OBJECTIVE: To evaluate the disease burden of Japanese Encephalitis (JE), and provide strategy for disease control and prevention. METHODS: Firstly, analysis the incidence, mortality and fatality rate of JE in Gansu province in 2006. Then the investigation was carried out for calculating all expenditure items of the patients, including medical cost of the hospitalization, medicines, the transport costs, and other non-medical direct cost. RESULTS: In 2006, among the 27 type A and B notifiable infectious diseases in Gansu Province, JE mortality rate was at the top 3, fatality rate was at first rank. The direct cost of JE disease was 6889 RMB per case. In 2006, the direct cost of JE cases was 1,116,000 RMB in Gansu Province. CONCLUSION: JE had the high mortality, and fatality. The fatality in adult was higher than in children. JE patients had to pay high costs. JE disease burden should not be underestimated. PMID- 20726269 TI - [Analysis on neutralization antibody titer of Japanese B encephalitis virus in healthy population in Shaanxi province]. AB - OBJECTIVE: To detect Japanese B Encephalitis virus (JEV) neutralization antibody (NA) titer and evaluate immunologic barrier, analyze the factor of affecting JEV NA titer, and provide the data for JE control. METHOD: Cluster sampling was selected randomly in the region of high, middle, low JE incidence rate. To detect the NA of JEV by micro neutralization test. RESULTS: The positive rate of JEV NA (and GMT) was 81.3% (1:27.84) in Ankang prefecture where JE incidence rate was high, 47.9% (1:7.41) in Baoji prefecture where JE incidence rate was middle, 24.1% (1:3.04) in Tongchuan prefecture where JE disease rate was low. There was the tendency that JEV NA titer increased with increasing age in the region of high JE disease rate, and there was not this tendency in the region of low JE incidence rate. CONCLUSION: In shaanxi province, the children's JEV NA titer was low in the region of high JE incidence rate, and it is important to vaccinate JE vaccine for children. The adult's JEV NA titer was low in the region of low JE incidence rate. And it is important to control JE disease in adult groups. PMID- 20726271 TI - [Optimization of method of titration rabies virus with fluorescence focus units assay]. AB - OBJECTIVE: A new Fluorescence Focus Units (FFU) developed for Rabies Virus titration replace current reference method (LD50) so as to reduce the cost. METHODS: The BSR cell was infected by triple serial dilution of the Rabies Virus CTN strain, then detect the fluorescent focus by FITC labeling anti-Rabies Virus monoclonal antibodies. All the samples were assayed in both FFU and LD50. RESULTS: Data generated indicateed that a significant correlation between the two methods (r=99). CONCLUSION: This method is simple and rapid. It will be considered as a useful alternative method to the LD50. PMID- 20726270 TI - [Study on the compliance and economic cost of rabies vaccination]. AB - OBJECTIVE: To learn the compliance status regarding completing full rabies vaccination schedule, and to analyse the economic cost. METHODS: Interviewing patients who visited doctor at Emergency Department, the People's Hospital, Beijing University from June 2007 to January 2009 on vaccination compliance of Essen regimens. The economic cost of Essen regimen and Zagreb regimen were estimated using average vaccination cost, average release amount by National Institue for Control of Pharmaceutical and Biological Products. RESULTS: In total, 3440 patients were interviewed. The proportion completing full vaccine schedule was 33.3%, 77.1% and 78.0% for exposure category I, II and III respectively. The compliance was high for first 3 doses, it reduced significantly after the third dose. The individual medical costs was 694 RMB for Essen regimen, and 482.2 RMB for Zagreb regimen. The estimated annual medical costs was 9.709 billion RMB for Essen regimen, and 6.746 billion RMB for Zagreb regimen nationaly. CONCLUSIONS: The Zagreb regimen should be recommended in order to simplify the vaccine administration, to increase compliance and to reduce rabies vaccination cost. PMID- 20726272 TI - [Effect assessment on implementing yellow card system to EPI work in Guizhou province]. AB - OBJECTIVE: To evaluate the effect of implementing Yellow Card Warning System for Expanded Programme on Immunizations (EPI) in Guizhou province. METHODS: Investigating the EPI funds input, staff arrangement, normal standardized management and vaccine coverage rate before and after Yellow Card Warning System implementation in all 88 counties of Guizhou Province, and analyzing the data with descriptive epidemiology. RESULTS: After carrying out Yellow Card Warning System, funds devotion and staff arrangement on EPI were increased, normalization management was strengthened, and coverage rate of various vaccines were raised. CONCLUSION: To bring EPI work into government assessment system and implement Yellow Card Warning System to inacceptable county governments is an effective measure, which impulses the provincial EPI work sustained and deep development. PMID- 20726273 TI - [Analysis on pneumococcus isolated from part of china using serotype and pulsed field gel electrophoresis]. AB - OBJECTIVE: To investigate the serotype distribution and molecular features of Streptococcus pneumonia isolates in China. METHODS: 144 strains isolated from 6 provines were selected as the research object. The serotypes were determined with the method of capsular swelling. The molecular characteristics were conducted by optimized pulsed-field gel electrophoresis. RESULTS: A total of 135 Streptococcus pneumoniae isolates were divided into 14 serogroups. 19, 6, 15, 23 serogroups are prevalent types in China. 9 isolates were failed to identify specific serogroups. All isolates could be divided into 92 pulsotypes. Pulsotypes were scattered. Absolutely dominant pulsotype was not found. Pulsotypes were similar among same serogroup isolates. CONCLUSION: The pneumococcus of serogroup 19, 6, 15, 23 were common in China. PFGE had strong discriminatory ability of subtyping of Streptococcus pneumoniae. PFGE showed better epidemiological survey capacity. PMID- 20726274 TI - [Review of the sudden death and death following immunization of influenza vaccine]. AB - To evaluate the safety of influenza Type A (H1N1) vaccine by review the incidence, epidemiology characteristics of sudden death and the deaths related with immunization, especially focus on the sudden deaths after immunization of influenza Type A (H1N1) vaccine. Preliminary showed that those deaths reported as adverse events following immunization did not associated with the vaccine. Vaccination campaign according to the national immunization strategy should be carried out and appropriately respond to the emergency events should be strenghtened. PMID- 20726275 TI - [Research progress of influenza type A(H1N1) vaccine and monitoring adverse reaction]. AB - A novel influenza type A(H1N1) virus was identified as a significant cause of acute respiratory illnesses, which spread rapidly to many countries around the world in 2009. The most effective method to prevent the outbreak of influenza type A (H1N1) was performed through large-scale immunization. Research progress and adverse reaction monitoring on influenza type A (H1N1) vaccines were reviewed. PMID- 20726276 TI - [Review of the studies on primary immunodeficiency disorder and vaccine-derived poliovirus]. AB - On the last stage of Global Polio Eradication Initiative (GPEI), a number of cases with Primary Immunodeficiency (PID) disorder were detected excreting the Vaccine-derived Poliovirus (VDPV). Due to these cases can be prolonged or chronic excretion of the VDPV in the environment, all countries have to gradually focus on these cases and reconsidering the national strategies of polio vaccine in the post-eradication era themselves. PMID- 20726277 TI - Embracing change, responding to challenge, and looking toward the future. PMID- 20726278 TI - The effect of vestibular stimulation in a four-hour sleep phase advance model of transient insomnia. AB - STUDY OBJECTIVES: To determine if vestibular stimulation is an effective therapy for transient insomnia in a sleep phase advance model. DESIGN: Multi-site, double blind, randomized, parallel-group, sham-controlled trial SETTING: This study was carried out at 6 sites in the United States. PARTICIPANTS: 198 healthy normal sleepers. INTERVENTIONS: Bilateral electrical stimulation of the vestibular apparatus of the inner ear via electrodes on the skin of the mastoid process at a frequency of 0.5 Hz vs. sham stimulation. RESULTS: We did not find a significant effect of treatment on our primary outcome variable, latency to persistent sleep onset (LPS). However, our planned analysis identified that the mean latency to sleep onset on the multiple sleep latency test was a significant covariate. This led us to carry out post hoc analyses, which showed a significant effect of treatment on LPS in those subjects with a mean MSLT sleep onset latency > or = 14 minutes. CONCLUSIONS: Vestibular stimulation did not have a therapeutic effect in a model of transient insomnia in the overall population studied. However, this study provides preliminary evidence that vestibular stimulation may shorten sleep onset latency compared with sham therapy in the subset of subjects with mean MSLT sleep onset latency > or = 14 minutes. PMID- 20726279 TI - Treatment of insomnia in depressed insomniacs: effects on health-related quality of life, objective and self-reported sleep, and depression. AB - STUDY OBJECTIVES: Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Prior clinical trials of hypnotic treatment of insomnia in depressed patients have shown improvement in HRQOL, but in these studies HRQOL was relegated to a secondary outcome, and objective measures of sleep were not undertaken. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTING: Outpatient clinic and sleep laboratory. PATIENTS: 60 depressed, insomniac outpatients. INTERVENTIONS: One week of open-label fluoxetine (FLX), followed by 8 more weeks of FLX combined with either eszopiclone (ESZ) 3 mg or placebo at bedtime. MEASUREMENTS: The primary HRQOL measure was the daily living and role functioning subscale (DLRF) of the Basis 32. Other measures included the Q-LES-Q, self-reported sleep, PSG, actigraphy, depression severity (HRSD). RESULTS: At the end of randomized treatment, patients receiving ESZ had lower (better) DLRF scores (0.81 +/- 0.64) than those receiving placebo (1.2 +/- 0.72), p = 0.01. The effect size for DLRF was 0.62, indicating a moderate effect. An advantage for ESZ was also seen in other measures of HRQOL, and most assessments of antidepressant efficacy and sleep. Women reported better end of treatment HRQOL scores than men. CONCLUSIONS: ESZ treatment of insomnia in depressed patients is associated with multiple favorable outcomes, including superior improvement in HRQOL, depression severity, and sleep. PMID- 20726280 TI - Napping, nighttime sleep, and cardiovascular risk factors in mid-life adults. AB - STUDY OBJECTIVES: To evaluate the relations between sleep characteristics and cardiovascular risk factors and napping behavior, and to assess whether daytime napping leads to subsequent better or worse sleep. METHODS: The sample consisted of 224 (African American, Caucasian, and Asian) middle-aged men and women. Sleep measures included nine nights of actigraphy and sleep diaries, sleep questionnaires, and one night of polysomnography to measure sleep disordered breathing. RESULTS: More frequent napping was associated with shorter nighttime sleep duration averaged across the nine nights of actigraphy (especially among African Americans), more daytime sleepiness, more pain and fatigue by diary, and increased body mass index and waist circumference. Shorter nighttime sleep duration was associated with taking a nap during the next day and taking a nap was associated with less efficient sleep the next night. CONCLUSIONS: Napping in middle-aged men and women is associated with overall less nighttime sleep in African Americans and lower sleep efficiency as measured by actigraphy, and increased BMI and central adiposity. These findings point to the importance of measuring of napping in understanding associations of sleep with cardiovascular risk. PMID- 20726281 TI - Validity of activity-based devices to estimate sleep. AB - STUDY OBJECTIVES: The aim of this study was to examine the feasibility of sleep estimation using a device designed and marketed to measure core physical activity. METHODS: Thirty adolescent participants in an epidemiological research study wore 3 actigraphy devices on the wrist over a single night concurrent with polysomnography (PSG). Devices used include Actical actigraph, designed and marketed for placement around the trunk to measure physical activity, in addition to 2 standard actigraphy devices used to assess sleep-wake states: Sleepwatch actigraph and Actiwatch actigraph. Sleep-wake behaviors, including total sleep time (TST) and sleep efficiency (SE), were estimated from each wrist-device and PSG. Agreements between each device were calculated using Pearson product movement correlation and Bland-Altman plots. RESULTS: Statistical analyses of TST revealed strong correlations between each wrist device and PSG (r = 0.822, 0.836, and 0.722 for Sleepwatch, Actiwatch, and Actical, respectively). TST measured using the Actical correlated strongly with Sleepwatch (r = 0.796), and even stronger still with Actiwatch (r = 0.955). In analyses of SE, Actical correlated strongly with Actiwatch (r = 0.820; p < 0.0001), but not with Sleepwatch (0.405; p = 0.0266). SE determined by PSG correlated somewhat strongly with SE estimated from the Sleepwatch and Actiwatch (r = 0.619 and 0.651, respectively), but only weakly with SE estimated from the Actical (r = 0.348; p = 0.0598). CONCLUSIONS: The results from this study suggest that a device designed for assessment of physical activity and truncal placement can be used to measure sleep duration as reliably as devices designed for wrist use and sleep wake inference. PMID- 20726282 TI - REM-related obstructive sleep apnea: the effect of body position. AB - STUDY OBJECTIVES: To evaluate the effect of body position on REM-related obstructive sleep apnea (OSA) patients. DESIGN: Retrospective analysis. PATIENTS: 100 consecutive adult OSA patients (apnea-hypopnea index [AHI] > or = 5) who had > or = 10 min of REM sleep in both supine and lateral postures. REM-related OSA was defined by previously used criteria (REM AHI/Non-REM (NREM) AHI > or = 2) and was compared with data from Not-REM-related OSA (REM AHI/NREM AHI < 2). MEASUREMENTS AND RESULTS: Most (93%) of the REM-related OSA patients (n = 45) had a mild-moderate syndrome, compared to 50.9% in the Not-REM-related OSA patients (n = 55). REM-related OSA patients had a lower apnea index (AL), AHI, supine and lateral AHI, and NREM AHI, but similar REM AHI compared to the Not-REM-related OSA group. For the entire group, the following sequence was observed: AHI REM supine > AHI NREM supine > AHI REM lateral > AHI NREM lateral. Also, for the REM related and Not-REM-related OSA patients, the interaction between supine posture and REM sleep led to the highest AHI. However, the average length of apnea and hypopneas during REM sleep was similar in the supine and lateral postures. CONCLUSIONS: During REM sleep, the supine position is associated with increased frequency but not increased duration of apneas and hypopneas. These body position effects prevail over the differences between REM-related and Not-REM-related OSA patients. PMID- 20726283 TI - The role of single-channel nasal airflow pressure transducer in the diagnosis of OSA in the sleep laboratory. AB - RATIONALE: Obstructive sleep apnea (OSA) is a common but underdiagnosed disorder. There is a need for validated simpler modalities such as single-channel monitors to assist diagnosis of OSA. STUDY OBJECTIVES: To assess data sufficiency, agreement, and diagnostic accuracy of nasal airflow measured by a single-channel pressure transducer device (Flow Wizard, DiagnoseIT, Sydney, Australia) compared to attended full polysomnography (PSG) on the same night for OSA diagnosis. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Subjects with possible OSA referred to the sleep laboratory for PSG were eligible. METHODS: Nasal airflow was measured by a pressure transducer in the laboratory concurrently with PSG. RESULTS: Of 226 eligible subjects who consented, 221 (97.8%; 151 males, 70 females) completed the protocol. With nasal airflow measurement, 5.3% of subjects had insufficient data, compared with 2.2% on PSG. The mean difference between PSG AHI and NF RDI was -6.2 events/h with limits of agreement (+/- 2 standard deviation [SD]) of 17.0 events/hr. The accuracy of the Flow Wizard for diagnosing severe OSA (PSG AHI > 30) was very good (area under the ROC curve [AUC] 0.96; 95% confidence interval [CI] 0.92 to 0.99) and for diagnosing OSA (PSG AHI > 5) was good (AUC, 0.84; 95% CI, 0.77 to 0.90). There was no difference in the rate of data insufficiency and accuracy between males and females. CONCLUSION: Nasal flow measured by a nasal pressure transducer has a low rate of data insufficiency, good agreement, and high accuracy compared to PSG for diagnosing OSA in the monitored sleep laboratory setting. PMID- 20726284 TI - Diagnostic accuracy of split-night polysomnograms. AB - STUDY OBJECTIVES: American Academy of Sleep Medicine (AASM) practice parameters indicate that split-night polysomnograms (SN-PSG) may be performed when the apnea hypopnea index (AHI) is > or = 20 to 40, depending on clinical factors. The aim of this study was to determine the diagnostic accuracy of SN-PSG, including at the lower range of AHIs. METHODS: We reviewed 114 consecutive full-night PSGs (FN PSG) performed at our center between August 2006 and November 2008 on subjects enrolled in studies in which obstructive sleep apnea (OSA) was the sleep disorder of interest. We compared the AHI from the first 2 hours (2 hr-AHI) and 3 hours (3 hr-AHI) of sleep with the "gold standard" AHI from FN-PSG (FN-AHI), considering OSA present if FN-AHI > or = 5. RESULTS: The 2 hr-AHI and 3 hr-AHI correlated strongly with the FN-AHI (concordance correlation coefficient [CCC] = 0.93 and 0.97, respectively). After adjusting for percentage of sleep in stage REM sleep and in supine position, the correlation of 2 hr- and 3 hr-AHI with FN-AHI remained strong (0.92 and 0.96, respectively). The area under the receiver operating curves (AUC) for 2 hr-AHI and 3 hr-AHI using FN-AHI > or = 5 were 0.93 and 0.95, respectively. CONCLUSIONS: The AHI derived from the first 2 or 3 hours of sleep is of sufficient diagnostic accuracy to rule-in OSA at an AHI threshold of 5 in patients suspected of having OSA. This study suggests that the current recommended threshold for split-night studies (AHI > or = 20 to 40) may be revised to a lower number, allowing for more efficient use of resources. PMID- 20726285 TI - Severity of obstructive sleep apnea is related to aldosterone status in subjects with resistant hypertension. AB - BACKGROUND: We previously described a significant correlation between plasma aldosterone concentration (PAC) and severity of obstructive sleep apnea (OSA) in patients with resistant hypertension. This investigation examines the relationship between aldosterone status and OSA in patients with resistant hypertensive-with and without hyperaldosteronism. METHODS AND RESULTS: One hundred and nine consecutive patients with resistant hypertension were prospectively evaluated with plasma renin activity (PRA), PAC, 24-hour urinary aldosterone excretion (UAldo), and polysomnography. Hyperaldosteronism (PRA < 1 ng x mL(-1) x h(-1) and UAldo > or = 12 microg/24-h) prevalence was 28% and OSA prevalence was 77%. In patients with hyperaldosteronism, OSA prevalence was 84%, compared with 74% in hypertensive patients with normal aldosterone levels. There were no significant differences in body mass index or neck circumference between aldosterone groups. PAC and UAldo were both significantly correlated with apnea hypopnea index (AHI) in the high-aldosterone group (p = 0.568, p = 0.0009; p = 0.533, p = 0.002, respectively). UAldo correlated weakly with apnea-hypopnea index in the normal-aldosterone group, but there was no significant correlation between PAC and AHI in the normal-aldosterone group (p = 0.224, p = 0.049; p = 0.015, p = 0.898, respectively). CONCLUSIONS: Our analysis of patients with resistant hypertension confirms a markedly high prevalence of OSA in this group. Furthermore, severity of OSA was greater in those patients with hyperaldosteronism and related to the degree of aldosterone excess. The correlation between OSA severity and aldosterone supports the hypothesis that aldosterone excess contributes to greater severity of OSA. PMID- 20726286 TI - Accuracy and linearity of positive airway pressure devices: a technical bench testing study. AB - STUDY OBJECTIVES: To analyze the accuracy and linearity of different CPAP devices outside of the manufacturers' own quality control environment. METHODS: Accuracy (how well readings agree with the gold standard) and linearity were evaluated by comparing programmed pressure to measured CPAP pressure using an instrument established as the gold standard. Comparisons were made centimeter-by-centimeter (linearity) throughout the entire programming spectrum of each device (from 4 to 20 cm H2O). RESULTS: A total of 108 CPAP devices were tested (1836 measurements); mean use of the devices was 956 hours. Twenty-two of them were new. The intra class correlation coefficient (ICC) decreased from 0.97 at pressures programmed between 4 and 10 cm H2O, to 0.84 at pressures of 16 to 20 cm H2O. Despite this high ICC, the 95% agreement limit oscillated between -1 and 1 cm H2O. This same behavior was observed in relation to hours of use: the ICC for readings taken on devices with < 2,000 hours of use was 0.99, while that of the 50 measurements made on devices with > 6,000 hours was 0.97 (the agreement limit oscillated between -1.3 and 2.5 cm H2O). "Adequate adjustments" were documented in 97% of measurements when the definition was +/- 1 cm H2O of the programmed pressure, but this index of adequate adjustment readings decreased to 85% when the +/- 0.5 cm H2O criterion was applied. CONCLUSIONS: In general, the CPAP devices were accurate and linear throughout the spectrum of programmable pressures; however, strategies to assure short- and long-term equipment reliability are required in conditions of routine use. PMID- 20726288 TI - Topiramate responsive exploding head syndrome. AB - Exploding head syndrome is a rare phenomenon but can be a significant disruption to quality of life. We describe a 39-year-old female with symptoms of a loud bang and buzz at sleep onset for 3 years. EEG monitoring confirmed these events occurred in transition from stage 1 sleep. This patient reported improvement in intensity of events with topiramate medication. Based on these results, topiramate may be an alternative method to reduce the intensity of events in exploding head syndrome. PMID- 20726287 TI - Polysomnographic characteristics of a referred sample of children with sickle cell disease. AB - STUDY OBJECTIVES: To describe polysomnographic parameters and their clinical correlates in a referred sample of children with sickle cell disease (SCD). METHODS: This was a retrospective medical record review of 55 consecutive children aged 2-18 years with SCD (hemoglobin [Hb] SS and Hb SC genotypes) undergoing polysomnography for evaluation of sleep disordered breathing. Polysomnography values were compared between SCD genotypes, 4 age groups, and adenotonsillectomy status using descriptive and nonparametric statistics. RESULTS: Obstructive sleep apnea (OSA) was diagnosed in 38/55 (69%) children. Polysomnographic parameters differed significantly between Hb SS and Hb SC genotypes only on arterial oxyhemoglobin saturation (SpO2; 95.2 +/- 3.8 vs. 98.0 +/- 0.8, respectively, p < 0.01) and percent of sleep time below SpO2 90% (T90; 8.0 +/- 22.0 vs. 0.01 +/- 0.02, respectively, p < 0.05). Increasing age was associated with decreasing SpO2 (rho = -0.282, p < 0.05), obstructive apnea hypopnea index (OAHI; rho = -0.364, p < 0.01), total arousal index (rho -0.272, p < 0.05) and respiratory arousal index (rho = -0.349, p < 0.01). Periodic limb movements in sleep (PLM) averaged 4.7 +/- 8.8/h, with a PLM index > 5/h in 5/17 children without OSA. Post- adenotonsillectomy, 8/10 children had OSA, but compared to untreated OSA-positive children they had a lower mean OAHI (4.4 +/- 5.5 vs. 8.9 +/- 12.5) and a lower T90 (1.6 +/- 4.2 vs. 9.2 +/- 24.9). CONCLUSIONS: Both OSA and PLMs were common in children with SCD. Children with Hb SS experienced more severe nocturnal oxygen desaturation than did those with Hb SC. Post-adenotonsillectomy, most children had OSA, although they experienced fewer obstructive respiratory events and less severe nocturnal oxygen desaturation than did untreated OSA-positive children. PMID- 20726289 TI - Joubert syndrome associated with severe central sleep apnea. AB - We report on a patient with mental retardation and chronic hypercapnic respiratory failure who was found to have severe central apnea and periodic breathing while undergoing an evaluation of low oxygen saturation during wakefulness at rest. Magnetic resonance imaging of the brain, which was performed to uncover potential causes for the central sleep apnea, revealed a "molar tooth sign" consistent with the diagnosis of Joubert syndrome. Joubert syndrome-related disorders are autosomal-recessive disorders characterized by diffuse hypotonia, developmental delay, abnormal respiratory patterns, and the pathognomonic neuroradiologic finding of a molar tooth sign. Adaptive servoventilation failed to correct the central apneas or the periodic breathing. Treatment with bilevel positive airway pressure in S/T mode led to resolution of the central events, improvement in sleep quality, and normalization of the oxygen saturation during wakefulness. PMID- 20726291 TI - The anxious sleeper. Initiate sleep-restriction and stimulus-control techniques. PMID- 20726290 TI - Best practice guide for the treatment of nightmare disorder in adults. AB - Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD) associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A. Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B. Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B. Clonidine may be considered for treatment of PTSD-associated nightmares. Level C. The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C. The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C. The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data. PMID- 20726292 TI - Fatigue or daytime sleepiness? PMID- 20726293 TI - Associations between narcolepsy and consumption of alcohol and caffeinated beverages among genetically susceptible individuals: a population-based case control study. PMID- 20726294 TI - [150 years since the birth of Thomas Ionescu (1860-1926)]. AB - One of the most important surgeons of the 1900 period was the Romanian-born Thomas Jonnesco. He became a surgeon in Paris (1885-1890) under the guidance of D.M. Bourneville and J. Peyrot (Bicatre), P. Berger (Tenon), A. Le Dentu (St. Louis) and A. Verneuil (Pitie-Salpetrire). In 1894, he gained at the Paris Faculty of Medicine the title of professor of anatomy. In the same year he was selected by the professors Poirier, Charpy and Nicolas to be their collaborator in a treatise of anatomy, published in 1894. In 1895, he returned to Bucharest to lead the Institute of Topographic Anatomy and Experimental Surgery, especially created for him. He also accepted the Chair of the Clinical Surgery of Coltzea Hospital in Bucharest. In 1896 he founded in Paris the French periodical "Archives des Sciences Medicales'". Jonnesco was a prolific surgeon in the field of experimental surgery, especially cervical sympathectomy, general spinal anaesthesia but also in surgical oncology and genito-urinary field. He also drew clinical correlations on surgical techniques of gastrectomy for cancer, on total abdominal genital ablation as treatment for septic conditions of the uterus and the adnexa or on the large abdominal hysterectomy with complete ilio-lumbo-pelvic lymph node dissection in uterine cancer, which refined Wertheim's hysterectomy method. Thomas Jonnesco is now considered the founder of the modem Romanian school of PMID- 20726295 TI - [Thomas Ionescu versus Wildhem von Waldeyer. Rectum sheath or fascia propria recti? The story of a wandering idea]. AB - Anatomical knowledge of rectum and its fascial relationship is crucial in modem surgery and it represents the basis of total mesorectal excision. Most of the contemporary authors make reference to Waldeyer's description and use the name fascia propria recti. However, there are evidence regarding Thomas Jonnesco's priority in describing this fascial structure 5 years before Waldeyer. Thomas Jonnesco's description was published in a famous anatomy textbook: Traite d'Anatomie Humaine, Paris, Bataille, 1894, editor P. Poirier, where Thomas Jonnesco was the author of volume 4, fascicule 1, containing the anatomy of the digestive system. His description of the rectum sheath precedes Waldeyer's publication (Das Becken, Cohen, Bonn, 1899). The description of the rectum sheath is included also into the second edition of Traite d'Anatomie Humaine (editors P. Poirier and A. Charpy) published again in 1901 at Masson Publishing House. This second version, better known by contemporary authors (Chapuis et al. Dis Colon Rectum 2002;45:1), probably revised by Charpy, is no more so simple and so clear as the first one. In our paper Thomas Jonnesco's original description of rectal fascia (rectum sheath), published in 1894, is facsimiled, the two succesive editions of the book are compared and a comparison with Waldeyer's description of fascia propria recti is done. The priority of Thomas Jonnesco seems to be well proved. In this respect our own research is in line with the observations of Chapuis and Bell si colab. PMID- 20726296 TI - [Selective nonoperative management of solid abdominal visceral lesions]. AB - Selective nonoperative management of abdominal visceral lesions is one of the most important and challenging changes that occurred in the traumatized patient care over the last 20 years. The main advantage of this type of management is the avoidance of unnecessary/nontherapeutic laparotomies. The trauma surgeons who deal with this type of treatment are worried of missed abdominal injuries. Modern diagnostic tools (spiral CT, ultrasound, angiography, laparoscopy) allow the trauma surgeon to accurately characterize the lesions to be nonoperative addressed. This literature review discusses the main elements of selective nonoperative management of principle solid visceral lesions (liver, spleen, kidney). We highlight the advantages and limitations of the main diagnostic instruments used for evaluation of trauma patiens allocated to nonoperative management. PMID- 20726297 TI - Surgical management of Gerhardt syndrome. AB - Adduction bilateral vocal fold immobility syndrome may be due by both recurrent laryngeal nerves paralysis--Gerhardt syndrome--and all intrinsic laryngeal muscles paralysis--Riegel syndrome. Etiology of Gerhardt syndrome is thyroid surgery, intubation's maneuver, trauma, neurological disorders, extrala-ryngeal malignancies. The manifestations of Gerhardt syndrome are inspiratory dyspnea and slightly influenced voicing by paramedian vocal folds paralysis with an important narrowing of the airway at the glottic level. The surgical procedures for enlargement of the glottic space can be classified in many ways and their major characteristics are: changes at the glottic level; surgical approach: open neck or endoscopic, with or without opening of the mucosal lining; the need for tracheostomy; the equipment used. The aim of this review is to expound the variety of interventions through the last century marked by the development of the diagnostic methods, the anesthesia and the surgical armament with sophisticated instruments and technologies. PMID- 20726298 TI - [An experimental model of transgastric ooforectomy using a porcine model]. AB - INTRODUCTION: Transabdominal routes for surgery entail general anaesthesia with its inherent risks and complications (prolonged hospital stay, abdominal incisions that may be difficult in obese patients). Minimally invasive procedures require shorter hospitalization, have shorter recovery periods, less postoperative discomfort, and lower morbidity and complications. The purpose of this study was to use a porcine model to determine the feasibility and the safety of organ resection (oophorectomy and tubectomy). MATERIALS AND METHODS: 10 Big White pigs between 25-30 kg underwent transgastric ooforectomy. The first 5 cases were performed in a hybrid procedure (laparoscopic-NOTES) in order to have a better control and supervise the maneuvers done by the mobile endoscope and to guide in the abdominal cavity. RESULTS: Adnexectomy was possible in all ten experiments. Full operative time (from starting endoscopy to complete gastrectomy closing) was 180 min to 270 min. The gastric defect closing was the most difficult manoever lasting from 10 min with OTSC clips to 100 using endoloops and clips. The animals have tolerated well the experiments and there have been no remarkable incidents during our 10 experments. In only one case a bleeding from gastotomy required electric coagulation. CONCLUSION: Transgastric ooforectomy in an experimental model is a procedure that requires advanced laparoscopical and endoscopical skills. Our early results are promissing. Its application in humans needs further confirmation of the method. PMID- 20726299 TI - [The importance of the timing of surgery in infected severe acute pancreatitis]. AB - The management in severe acute pancreatitis evolved in the last two decades. Consulting the literature and the accumulated clinical experience manage to the release of this study based on the comparison of the treatment in PAS between two distinct periods: 1994-1999 (retrospective) and 2000-2007 (prospective). Among the 285 patients whit PAS admitted and treated in the two departments, 224 (78.6%) was submitted to the surgical intervention with various surgical indications. There is an obvious difference between the retrospective and prospective studies concerning the indication of surgery and mostly the timing for surgery. The lots were analyzed concerning the etiology, management of treatments and specific treatments, and the timing of the surgical intervention was analyzed based on the specific etiologic treatment and the period of time between the admission and the first surgical intervention, the mark being the 21 day according with the recommendations of the International Association of Pancreatology. There were analyzed: the period of time between the onset of the disease and the surgical intervention, the status of the patients at the surgical moment, the global mortality based on the timing of surgery, the evolution of the management of PAS along the period of the research, comparisons whit the literature. The registered data were statistically processed using the SPSS test version 17 for Windows. PMID- 20726300 TI - [Heterotopic accessory pancreas in surgical pathology: review of 23 years experience]. AB - BACKGROUND: The abnormal presence of the pancreatic tissue in other digestive organs is rare but sometimes is the cause of some surgical diseases. MATERIAL AND METHOD: This retrospective study is focussed on heterotopic pancreas cases diagnosed in 2nd Surgical Clinic of "Sf. Spiridon" Emergency Hospital from Iasi between Jan. 1986 and Dec. 2008. RESULTS: 22 patients (15 males/68.2% and 7 females/31.8%) aged between 23 and 76 years were grouped in A group--clinical symptomatic cases (3 patients/13.6%), group B--coincidental cases (17 patients/77.3%) and group C--incidental cases (2 patients/9%). Group A patients presented with obstructing prepyloric polypoid tumors and recquired antrectomy and gastroduodenal anastomosis. 13 patients of group B (76.4%) recquired surgery for pyloroduodenal stenosis and in 4 cases of this group with severe upper-GI bleeding, a subtotal gastric resection (3 patients) or antrectomy (1 case) was performed. In group C patients jejunal HP was histopathologically diagnosed during extensive intestinal resection for colonic malignancies (ascendant colonic and transverse colonic cancers) with jejunal invasion. HP cases were categorized as type I in 40.9% cases (ducts, acini and pancreatic islets), type II in 45.4% cases (ducts and acini) and type III (exclusively with ducts) in 13.6% cases. In 76% patients HP was localized in mucosal and submucosal layers, in 16% intramucosal and in 8% in subserous layer. CONCLUSION: HP is most often an unexpected symptomless coincidental diagnosis during gastrointestinal surgical diseases. PMID- 20726301 TI - Gallstone ileus: analysis of eight cases and review of the literature. AB - OBJECTIVE: We hereby analyzed a series of gallstone ileus cases operated on in our department starting from a Bouveret syndrome case. METHOD: Retrospective analysis of all gallstone ileus cases who underwent surgery in our department during the last 26 years. We took into consideration diagnostic elements, time from admission to surgery, type of surgery and post-operative outcome. RESULTS: During this period 9,143 gallstones were deferred to surgery; 27 biliary digestive fistulae were discovered during surgery; gallstone ileus complicated fistula in 8 patients. Gallstone ileus was exclusively present in elderly women with associated comorbidities. Diagnosis was suggested by clinical features of acute or incomplete intestinal obstruction; it was sustained by imagistic studies with different degrees of relevance. The average time from admission to surgery was 2.6 days. Surgical approach varied from simple enterolithotomy to additional fistula repair. The outcome was uneventful in most of the cases with only one exception. CONCLUSIONS: gallstone ileus is a rare condition, occurring in elders with important comorbidities. The choice for surgical procedure depends on the obstructive syndrome's gravity and associated comorbidities; the type of intervention does not significantly influence post-operative morbidity and mortality rates. PMID- 20726302 TI - Extraluminal venous interruption for free-floating thrombus in the deep veins of lower limbs. AB - The free-floating thrombus (FFT) represents a particular form of deep vein thrombosis with extremely high potential of fatal pulmonary embolism. The purpose of the study was to evaluate the early results of aggressive surgical approach to FFT. During the period 2005-2008 years FFT was diagnosed in 13 patients. Demographic characteristics of patients: medium age--54.7 years, male--76.9%, significant comorbidity--5 (38.5%) cases. Localization of FFT: superficial femoral vein (SFV)--5 (38.5%), common femoral vein (CFV)--4 (30.7%), external iliac vein (EIV)--2 (15.4%), inferior cava vein (ICV)--2 (15.4%). Manifestations of previous pulmonary embolism were documented preoperatively in 3 (23.1%) cases. The following emergency surgical procedures were performed: ligation--3 (23.1%) or plication--2 (15.4%) of SFV; plication of CFV--5 (38.5%) patients, combined in 4 cases with partial thrombectomy (free-floating part of thrombus); plication of common iliac vein--1 (7.6%); plication of ICV--2 (15.4%) cases. Primary or recurrent cases of clinically significant pulmonary embolism were not detected in the postoperative period. The accumulated experience of surgical management of patients with FFT reveals the important role of deep vein ligation/plication in prevention of fatal pulmonary embolism. PMID- 20726303 TI - The extended use of modular knee endoprostheses. AB - Modular knee prostheses have been used since the 1980's. Their goal was to offer an alternative to reconstructing large bony defects without using bone grafting. Initially, they were used for reconstruction after resection of tumours about the knee. Their success encouraged their use in the treatment of some failed total knee arthroplasties, with large bony defects and severe ligamentous instability. We have implanted 7 modular knee prostheses between July 2006 and January 2009. There were 4 tumoral cases, 1 case of desarthrodhesis after a Campanacci procedure and two cases of failed total knee arthroplasties. We have achieved encouraging results using these implants with all but one patient surviving at two years after surgery. All the implants were considered to function normally regarding range-of motion, muscle strength and gait. The surgical and medical management of patients with bone sarcomas has advanced greatly during the last 20 years, improving their overall survival. Thus, the surgeons are provided with increased abilities to perform limb-sparing or joint-mobility sparing surgery. PMID- 20726304 TI - [Correlation between C677T and A1298C mutations of the MTHFR gene and therapeutic prognostic elements in colorectal cancer]. AB - The MTHFR gene polymorphism may influence the risk of developing sporadic CRC. The aim of this study is to assess the relationship between the mutations of this gene and certain aspects of the surgical practice: the tumoral resectability, the tumoral recurrence and the disease-free interval. 69 patients with sporadic colorectal cancer that underwent surgery at the 3rd Surgery Department of Cluj Napoca between October 2003-May 2005 were randomly selected. The correlations between the C677T, A1298C mutations and the prognostic factors mentioned above were analyzed. The results show that the C677T mutation increases the risk of non resectability (OR = 3.5, p = 0.099), while the A1298C mutation does not (OR = 1.1). For the A1298C mutation there is a major risk of recurrence (OR = 3,063), but in the group with C677T mutation there is only a small increase of the risk, non-significant statistically (OR = 1,196). Both the groups with the C677T mutation and the "wild" genotype 1298AA have more precocious recurrences then the other groups, so a shorter disease-free interval (HR = 0.9458 respectively 3.1070). The patients with the A1298C mutations have more often non-resectable recurrences. In conclusion, the mutations of the MTHFR gene are a prognostic factor for the treatment and evolution of patients with CRC. PMID- 20726305 TI - MTRR polymorphism and the risk for colorectal and breast cancer in Romanian patients--a preliminary study. AB - BACKGROUND: The risk of colorectal cancer (CRC) and breast cancer (BC) is influenced by polymorphisms located in the genes encoding enzymes of the folate pathway. The aim of this study was to evaluate if A66G MTRR (rs1801394) polymorphism is involved in predisposition for colorectal and breast carcinogenesis in Romanian patients. MATERIALS AND METHODS: In the present case control study, 300 individuals divide in four groups: sporadic CRC patients (n = 120), control CRC (n = 60), BC patients (n = 60) and control BC (n = 60), were genotyped by PCR-RFLP method. RESULTS: Frequency of genotype AA was 11.7% in CRC control and 5% respectively in BC control. For cancer groups the frequency of genotype AA was 9.2% in CRC and 0% in BC. CONCLUSIONS: Study results do not demonstrate an association between A66G MTRR polymorphism and CRC or BC in Romanian patients. PMID- 20726306 TI - [The role of diagnostic laparoscopy in periampullary and pancreatic cancers. A study based on 27 cases]. AB - BACKGROUND: Starting from the premise that abdominal tumours require very accurate assessment and staging, the study "DIASTAL" (laparoscopic diagnosis and staging of abdominal tumours) proposed to establish the effectiveness of laparoscopy in the diagnosis and resectability of these neoplasms. The aim of this study was to evaluate diagnostic laparoscopy for periampullary and pancreatic neoplasms. METHODS: The clinical study was based on the analysis two different groups including 27 patients in total, in whom we used also diagnostic laparoscopy as a staging method. RESULTS: The percentage of understaged patients after preoperative examinations was high in both groups range 59.09%-63.63%. Diagnostic laparoscopy reduced the number of unnecessary laparotomies. CONCLUSIONS: Diagnostic laparoscopy could lead to more accurate assessment of periampullary and pancreatic cancers, not only as a staging method but also as a minimally invasive surgical technique for palliation. PMID- 20726307 TI - [Treatment of incisional hernia using the sublay technique]. PMID- 20726308 TI - [Pseudomyxoma of peritoneum. 1935]. PMID- 20726309 TI - [Acute appendicitis and empiric antibiotic therapy]. AB - Acute appendicitis is a well-known disease, which was described and systematically studied in the mid-19th century. Since then, many articles, studies and even books have been written upon this subject and it seems that nothing new can be added. And still... We present 2 clinical cases of male patients, 39 and 41 years old, who were operated in the Surgical Clinic "Prof. I. Juvara" of Clinical Hospital "Dr. I. Cantacuzino" in the same month. Both had no associated pathology and have suffered, for several months, episodes of abdominal pain, fever and (one of them) diarrhea, which were not investigated, but have been treated from time to time with antibiotics, mostly cephalosporins. The physical signs of acute abdomen were very atypical and soft. Intra-operative findings consisted in both cases in tumor-like appendiceal abscesses, situated behind ileocecal junction, with local inflammation and fibrosis, suggesting a long-term evolution. The surgical solutions were typical and were followed by favorable evolutions. We present these 2 clinical cases not only for their atypical history problems, but mainly because we consider that this kind of medical attitude could become an undesirable trend, and difficult and even mistaken diagnosis would occur more frequently, which is hard to accept for a benign disease. PMID- 20726310 TI - [Gastrointestinal stromal tumor in the cecum--a rare cause of ileo-cecal-colic invagination]. AB - The gastrointestinal stromal tumors (GIST) are the rares mesenchymal tumors of the gastrointestinal tract (1-3% of all gastrointestinal neoplasias). The frequency of their location on the rectocolic site is quoted with the values lower than 10% of all GIST. The authors present a patient case 55 years aged, who presented a gastrointestinal stromal tumor cecal located. This tumor determined the invagination of the cec into the ascendent colon and then into transverse colon drawing the last ileal ansa and leading to an ileo-cecal-colic invagination, without development of a occlusive syndrome. We performed a computed tomography and an irigography. These investigations showed the complications of the case, but it could not find out a cause of the invagination. We discuss in our article the problem regarding find out the type of the tumor and its origin too. We also discuss about the therapy, etiopathogeny, evolution and prognosis of the GIST. PMID- 20726311 TI - [Amyand's hernia--a clinical case]. AB - Amyand's hernia, a rare entity in the surgical pathology, presupposes the presence of the vermiform appendix inside a inguinal hernia sac (1). The hernia sac peritonitis by appendix swelling is even more rare, very few cases being presented in the surgical literature (1). The preoperatory diagnosis of Amyand's hernia is therefore very difficult. We herein present the case of a 71-year old male patient, operated on an emergency basis for hernia, which eventually turned out to be Amyand's hernia, a case which determined us to research the literature dedicated to this topic. PMID- 20726312 TI - [Post traumatic entero-mesenteric venous infarct]. AB - The paper presents a case of entero-mesenteric venous infarct, occurred in a man of 34 years, discovered intraoperator, when to intervene surgically in emergency surgery for acute abdomen of peritonitic type. The etiology of this venous infarct was posttraumatic, the patient underwent an abdominal aggression with seven days prior to onset of symptoms. In literature, the posttraumatic etiology is found in a small number compared to the large number of abdominal contusion, intimal lesional factor beeing associated with blood thickness. Paraclinical investigations were not significant in terms of preoperator diagnosis, surgical intervention (backward and forward thrombectomy of superior mesenteric vein with Fogarty probe and venosuture) having a favorable evolution. This intervention is practiced as an exception on the basis of the idea that venous thrombosis spreads to mezenteric vein and its collaterals followed by extensive arterial thrombosis and total compromise of intestinal viability. PMID- 20726313 TI - Primary hydatid cyst with an unusual location--a case report. AB - Human cystic echinococcosis, a zoonotic infection caused by Echinococcus granulosus, is still a largely extended public health problem in endemic regions (China, Middle East, Mediterranean region, South America, Russian Federation, etc.). Primary echinococcosis may develop in almost any organ (liver, lung, kidney, spleen, mediastinum, heart, brain, bones, pancreas, breast, ovaries, etc.). The liver and the lungs are the most frequently involved organs. Primary hydatid disease of the soft tissue is extremely rare, even in endemic areas. The paper will be focused on analyzing this rare disease. A 46-years old woman who came to our Department of Surgery with a 7/8 cm painless, round, palpable mass in the subcutaneous tissue of the proximal anteromedial side of the right thigh. Based on clinical and laboratory findings and imaging techniques we suspected a hydatid cyst. Conservative surgery associated with antihelminthic substances intraoperative and Albendazole postoperative was performed. After an uneventful recovery the patient was discharged 7 days after operation. No local or systemic recurrences were detected during 1 year follow up. PMID- 20726314 TI - Newborn's giant sacrococcigeal teratoma. AB - A sacrococcigeal tumor was detect at ultrasound maternal exam in 25TH week of pregnancy. The girl was born full term by natural way by the parents' choise. The newborn present a tumor with 12 cm diameter, situated in sacrococcigeal region, with a large base of implantation and with posteroinferior growth. This tumor produced a dislocation of the rectum and a perineal area. In the first day of baby's life, we perform the operation. We removed a large tumor (600 gr) with the coccys bone and we obtained a good repair of anatomy of the region, without postoperatory functional troubles. Postoperatory evolution was good. The newborn lived hospital healed in the 14th day. The histopatologic exam confirmed that the tumor was benign. Later evolution was good. PMID- 20726315 TI - Isolated tuberculous tenosynovitis of the forearm in an immunocompetent patient. AB - Primary tuberculous tenosynovitis is a rare manifestation of extraspinal musculoskeletal tuberculosis. The diagnosis may be easily delayed because of its nonspecific clinical signs. We report a case of culture-proven tuberculous tenosynovitis of the extensor carpi ulnaris tendon and common extensor tendon in a 68-year-old female without concomitant pulmonary tuberculosis, nor documented immunodeficiency. The diagnosis was initially overlooked due to the lack of appropriate histological and bacteriological analyses and the lesion recurred after surgery. MR imaging represents the most accurate method in making the diagnosis, but has no diagnostic specificity in regard to tuberculosis, therefore surgical biopsy is strongly recommended. The patient had a favorable clinical response after a combination of excision and appropriate antituberculous therapy for sensitive Mycobacterium tuberculosis. We emphasize the need for an increased awareness and high index of suspicion of tuberculosis in all cases of a chronic orrecurrent abscess in the extremities, not only in patients living in endemic areas but also in those who have emigrated from regions with a high prevalence of tuberculosis. PMID- 20726316 TI - [Porcelain gallbladder--diagnostic and therapeutic features]. AB - Porcelain gallbladder (PG) is a rare entity. It's frequently associated with cholecyst lithiasis (90%). Diagnosis is established based on imaging assays (simple abdominal radiography, ultrasound and/or abdominal CT). Pathologically is an extensive process of calcification of the gallbladder wall. The literature mentioned strongly PG association with cancer of the gallbladder. Therefore laparoscopic cholecystectomy was formally contraindicated. We present two cases of PG laparoscopically operated and with this occasion we review particular aspects of diagnosis and treatment of the disease. PMID- 20726317 TI - Clinical significance of serum anti-annexin V antibodies in Egyptian patients with scleroderma. AB - The pathogenesis of scleroderma encompasses vascular, immunological, and fibrotic processes, which contribute to clinical manifestations. We investigated the prevalence of anti-annexin V IgG and IgM antibodies in sera of scleroderma patients and their relation to the presence of other antibodies and development of disease morbidity. Sera of 40 scleroderma patients and 15 healthy controls were examined for IgG and IgM anti-annexin V antibodies by ELISA and anticentromere antibodies by indirect immunofluorescence. Serum level of anti annexin V IgG antibodies in scleroderma patients was significantly higher than that of the control (P < 0.001) and correlated significantly with the presence of digital ischemia (P = 0.023) and pulmonary fibrosis (P = 0.02). IgM isotype was comparable between patients and controls (P = 0.317). Anticentromere antibodies are more prevalent in the limited cutaneous subtype (P = 0.017). In conclusion, measurement of serum anti-annexin V IgG antibodies in scleroderma patients may be important for early diagnosis of vascular and pulmonary complications. PMID- 20726318 TI - Prognostic implication of N-RAS gene mutations in Egyptian adult acute myeloid leukemia. AB - The pathogenesis of acute myeloid leukemia (AML) involves the cooperation of mutations promoting proliferation/survival and those impairing differentiation. Point mutations of the N-RAS gene are the most frequent somatic mutations causing aberrant signal-transduction in acute myeloid leukemia (AML). The aim of the present work is to study the frequency and prognostic significance of N-RAS gene mutations (N-RASmut) in de novo Egyptian adult AML. Bone marrow specimens from 150 patients with de novo acute myeloid leukemia and controls were analyzed by genomic PCR-SSCP at codons 12, 13 (exon 1), and 61 (exon 2) for N-RAS mutations. In 12.7% (19/150) AML cases, N-RAS gene mutations were found and were observed more frequently in the FAB subtype M4eo (P = 0.028) and with codon 12, 13 (14 of 19; 73.7%). Patients with N-RAS mutation had a significant lower peripheral and marrow blasts (P = 0.004, P = 0.03) and clinical outcome did not improve more than in patients without mutation. In patients with N-RAS gene mutation vs. those without, complete remission rate was (63.2% vs. 56.5%; P = 0.46), resistant disease (15.8% vs. 23.6%; P = 0.51), three years overall survival (44% vs 42%; P= 0.85) and disease free survival (42.1% vs. 38.9%, P = 0.74). Multivariate analysis showed that age was the strongest unfavorable factor for overall survival (relative risk [RR], 1.9; P = 0.002), followed by cytogenetics (P = 0.004). FAB types, N-RAS mutation and leukocytosis were the least important. In conclusion, the frequency and spectrum of N-RAS gene mutation differ between biologically distinct subtypes of AML but do not significantly influence prognosis and clinical outcome in patients with AML. PMID- 20726319 TI - Levels of chemokine receptors expressed on peripheral blood T lymphocytes of Egyptian patients with hepatocellular carcinoma. AB - CC chemokine receptors (CCR) have an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 and CCR5 are highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we estimated the surface expression of chemokine receptors CCR1 and CCR5 on the lymphocytes of peripheral blood from patients with HCC in an attempt to identify their roles in tumorigenesis. The study was conducted on 52 patients of which, 24 of them with confirmed HCC and 28 with chronic hepatitis C virus infection. In addition, 20 apparently healthy controls with matched age and sex were also included in the study. All patient and control groups were subjected to the following: thorough history taking, clinical examination, abdominal ultrasonography and fine needle liver biopsy for patient's group when needed, complete blood count, liver function tests, viral markers for hepatitis B and C, serum alpha fetoprotein and flowcytometric detection of chemokine receptors CCR1 and CCR5 on peripheral blood T lymphocytes. The expression of chemokine receptors CCR1 and CCR5 on CD4+ and CD8+ T lymphocytes was significantly less in HCC and hepatitis C patient groups as compared to control group. Moreover, a significant decrease in the levels of CCR1 and CCR5 on CD8+ T lymphocytes was detected in HCC patients compared to patients with chronic HCV; however, it was not statistically significant for CD4+ cells. Furthermore in HCC patients, levels of CCR1 and CCR5 were significantly less in patients with large tumor size than small sized tumor. Data obtained showing reduced surface expression of CCR1 and CCR5 on CD4 and CD8 T lymphocytes reflect their possible role in altering the host's immune defense and disease pathogenesis, thus may be helpful for therapy design to ameliorate disease progression. PMID- 20726320 TI - Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus. AB - B cells from systemic lupus erythematosus (SLE) patients display signalling defects that may underlie disease pathogenesis activity.CD19 and CD22 play a major role as regulators of B-cell response. The aim of this study was to clarify the relationship between B cell surface markers namely CD19, CD20 and CD22 expression and clinical and laboratory indices of SLE activity. The study included 33 SLE patients and 20 healthy children and adolescents as controls. Flowcytometric assay of dual markers, CD19/CD20, and CD20/CD22 was done. SLE disease activity was assessed by SLEDAI score. CD22% was significantly higher while CD20% was significantly lower in the study compared to the control group. No significant difference was observed in both groups with respect to CD19% or CD19/CD22% ratio. The level of CD22 expression was significantly lower in high and very high active cases than in mild and moderate cases and negatively correlated with SLDEAI score and ESR. Results obtained showed that, B cell surface receptors CD20 and CD22 are significantly affected in patients with SLE, pointing to their possible involvement in the aetiopathogenesis of the disease and in the regulatory mechanisms in response to the immune disturbance. PMID- 20726321 TI - Relation of Cag-A-positive Helicobacter pylori strain and some inflammatory markers in patients with ischemic heart diseases. AB - Recently, a potential link between infectious agents and athero-sclerosis has been suggested. H. pylori strains bearing the cytotoxin associated gene A (Cag-A) provoked a heightened inflammatory response in vivo and showed stronger relation to gastric complication of this infection. The association between Cag-A positive strain and vascular diseases producing conflicting results. So, the present study aimed to estimate the seroprevalence of H. pylori Cag-A positive strains as a risk factor among different groups of ischemic heart disease and to study its interaction with high sensitivity CRP (hs-CRP) and IL6 as inflammatory host responses. The present study was conducted on anti H. pylori IgG positive 60 ischemic heart disease (IHD) patients and 20 apparently healthy individuals as a control group. IHD patients were classified into 3 groups: (group I) with acute myocardial infarction, unstable angina pectoris patients (group II), chronic stable angina pectoris patients (group III). For all patients and control groups serum anti Cag-A IgG, IL6, hs-CRP, CK, CKMB, LDH, AST and Lipid profile were estimated. IL6 and hs-CRP levels were increased in groups I, II and III as compared with group IV (P < 0.001) with positive correlation between IL6 and hs CRP in groups I, II and III (P < 0.05). The percentage of anti Cag-A positive cases was similar among the patient groups, but significantly higher than in the control group. Thus, infection with Cag-A positive H. pylori strain may play a role as a risk factor in development of ischemic heart diseases through provocation of high inflammatory response or through other mechanism. Therefore eradication of this infection is important as it is much less expensive than long term treatment of the other risk factors. PMID- 20726322 TI - Chlamydia trachomatis: methods of identification and impact on semen quality. AB - Chlamydia trachomatis infection is considered to be one of the most common sexually transmitted diseases. It is currently unclear whether chlamydial infection causes pathological conditions of the male accessory glands has consequences for male infertility. To determine the frequency of C. trachomatis Infection among infertile men with leukocytospermia using different diagnostic techniques such as the detection of secretory IgA antibodies (Abs) in seminal plasma by enzyme-linked immunosorbent assay (ELISA), plasmid DNA by polymerase chain reaction (PCR) and direct detection of elementary body by flowcytometric analysis in seminal fluid. To assess the relationship between C. trachomatis infection and semen quality hence male infertility. Seventy five infertile male patients with leukocytospermia and 25 apparently healthy age matched fertile men were included as controls. Routine semen analysis and LeucoScreen test were done for each patient and control. Detection of C. trachomatis secretory IgA in seminal plasma by ELISA and detection of plasmid DNA by PCR and elementary body by flowcytometric analysis in semen samples were performed. Primary and secondary infertility were detected in 55 (73.3%) and 20 (26.7%) of patients, respectively. Sperm concentration and sperm motility (A+B) were statistically significant lower in patients with leucocytospermia than control group (P < 0.0001). Sperm concentration in patients with pus cells more than 3 x 10(6)/ml was statistically significant lower than those with pus cells less than 2 x 10(6) /ml. ELISA detected IgA Abs against C. trachomatis in patients seminal plasma were positive in 20 (26.7%) and equivocal in 5 (6.6%) patients. Flowcytometric analysis of semen sample for C. trachomatis was positive in 35 (46.6%) patients and C. trachomatis plasmid DNA detection by PCR was positive in 23 (30.7%) patients. In conclusions, Detection of C. trachomatis antibodies of IgA type by ELISA in seminal plasma appears to be as specific as PCR in diagnosis of C. trachomatis in seminal fluid. High detection rate of C. trachomatis by flowcytometry was observed. Concerning the effect of C. trachomatis on routine semen characteristics, no significant obvious changes could be detected. Further studies for the assessment of sperm viability and DNA integrity are recommended. PMID- 20726323 TI - Impact of CD40 expression by flowcytometry on outcome of patients with non Hodgkin's lymphoma. AB - Lymphoid malignancies represent a wide variety of disease entities characterized by malignant proliferation of lymphoid cells which have distinct clinical features, cellular morphology, immunophenotype, cytogenetic changes and histologic features. CD40 is a member of the tumor necrosis factor receptor super family. It was first identified and characterized in B cell, signaling through the CD40 receptor was found to play an important role in multiple events in T cell dependent antibody response including B-cell survival and proliferation, memory B-cell formation and immunoglobulin isotype switching. The aim of this study is to detect the expression of CD40 on B lymphocytes in patients suffering from Non-Hodgkin's Lymphoma and correlate the results with the patients' response to treatment protocols. This study was carried out on 114 patients, of them only 100 patients completed 4 cycles of chemotherapy and were valuable. Their age was ranged from 17 to 63 years old. Fifteen age and gender matched individuals were, also, selected as a control group. CD40 expression was measured on peripheral blood samples by flowcytometry at patient's presentation as well as after 4 cycles of chemotherapy. This study showed that there's significant decrease in the mean values of % of CD40 on B-cell in patients with NHL in all stages when compared with normal control group. Also the study showed that there's statistical significant correlation between percent of CD40 on B-lymphocytes and stage of lymphoma, i.e., the more advanced stage, the lower the % of CD40 on B cell. After receiving a corresponding treatment, the CD40 expression is increased in significant correlation with the response to treatment. (This is a preliminary result after 4 cycles of CHOP treatment). We concluded that CD40 Lymphocyte development occurs in discrete functional steps that are defined by the onset of expression is highly expressed in healthy subjects and its expression on B lymphocyte is decreased with advanced stage of NHL. Percent of CD40 on B lymphocyte can be considered as an evaluation marker for outcome of treatment in NHL patients as its expression is increased in responding patients. PMID- 20726324 TI - Modulation of dendritic cell activation chemokines and cellular injury. AB - Dendritic cells (DC) are professional antigen presenting cells expressing MHC class II, derived from a common marrow precursor. They are motile, diffused and have a spidery shape with many long cytoplasmic processes. The aim of this project was to test the hypothesis that cellular injury induces the activation and functional maturation of DC. To test the effects of injury on DC activation, immature DCs were used as substrate for DC activation assays. They were obtained from their precursor in peripheral blood mononuclear cells (PBMNCs) by culturing them GM-CSF and IL-4. Expression of surface B7 was measured by immunofluorescence and flowcytometry. beta- chemokines were used as potential injury mediators, including: RANTES, MIP-1alpha, MIP-1beta, MCP-1, -2, -3 and -4, as well as other inflammatory cytokines such as TNF-alpha and IL-1. They were screened on immature DCs to examine whether or not they modulate B7-1 and B7-2. A model of cellular injury was established to investigate whether the injured parenchymal cells deliver signals to initiate DC activation or upregulation of B7-1/B7-2 by release of soluble mediators. H2O2 was used as an injury mediator to injure renal tubular epithelial cells (RTECs). RANTES, MIP-1alpha and MIP-1beta upregulated B7-1. MCP 1, -2, -3 and -4 downregulated the expression of HLA-DR greatly. Furthermore, MCP 1, -2, -3 and -4 upregulated B7.2, while and -4 and MCP2 upregulated B7.1. We observed that immature DCs could not be readily stimulated with chemokines and pro-inflammatory cytokines IL-1 and TNF-alpha unless GM-CSF and IL4 were used continuously. The supernatant of injured renal epithelial cells had an effect on DC activation. These findings may explain the role of DCs as a link between the innate and the adaptive immune response, as well as being an active participant in determining the outcome of an antigen encounter. PMID- 20726325 TI - The -17 T/C chemokine receptor 3 genetic polymorphism is associated asthma but not atopy: transmission and association studies. AB - We genotyped and identified the asthma and atopic status and related phenotypes of 154 nuclear families (453 individuals) each containing at least two affected children with physician-diagnosed asthma (PDA) in order to confirm or refute the possible relevance of known single nucleotide polymorphisms (SNPs) in the gene coding for the CCR3 receptor. Allelic quantification for each SNP by DNA pooling identified -17/TC as the only allele with a clinically relevant frequency in this population with a frequencies of 0.142 in cases of PDA and 0.035 in asymptomatic controls. The whole population frequency of the -17/TC polymorphism was 13.9% and the functional binding site analyses by MatInd and MatInspector programs found that it belonged to the same family as activating transcription factor 6 (ATF-6). The pedigree disequilibrium test (PDT) was applied in 34 informative families and the mutant allele was preferentially transmitted with PDA (P = 0.0001) with methacholine bronchial hyperresponsiveness (BHR) (0.002) but not with markers of atopy as assessed by allergen skin prick tests (SPT) or elevated serum IgE. Case control analyses in 303 unrelated parents (34-61y [median 43y]) revealed a significant association with both atopic and non atopic asthma (P = 0.001), and in 150 unrelated child probands for non-atopic asthma (P = 0.001). The mutant allele was associated with BHR, with baseline Forced Expiratory Volume in the first second (FEV1) below the population median value but not with atopy defined SPT or elevated serum IgE (>100 IU/ml). The T17C chemokine receptor 3 polymorphism appears to be associated with asthma BHR and disease severity but not with atopy. PMID- 20726326 TI - Association of the receptor for advanced glycation end products (RAGE) -374 T/A gene polymorphism and circulating soluble RAGE with nephropathy in type 1 diabetic patients. AB - The binding of advanced glycation end-products (AGEs) to their receptor (RAGE) may play an important role in the development of diabetic vascular complications. Circulating soluble RAGE (sRAGE) reflects tissue RAGE expression. We examined circulating sRAGE and RAGE -374 T/A gene promoter polymorphism in type 1 diabetic patients and explored their possible associations with the development of nephropathy. Fifty diabetic patients with disease duration >10 years and 20 age, sex and body mass index (BMI) matched healthy controls were included in the study. Diabetic patients were subdivided into 23 patients without nephropathy and 27 with nephropathy. All the studied individuals were subjected to the following investigations: fasting glucose, HbA1c, serum creatinine, lipid profile, albuminuria and sRAGE levels. The -374 T/A RAGE gene polymorphism was studied by PCR amplification and restriction fragment length polymorphism (RFLP) analysis. Our study reported significant increase in sRAGE in diabetic patients compared to controls and in diabetic patients with nephropathy compared to those without nephropathy (P < 0.001). sRAGE was significantly correlated with HbA1c, creatinine, albuminuria and atherogenic lipid profile. There were significant increase in the frequency of RAGE -374 A allele (T/A and/or A/A genotypes) in diabetic patients with nephropathy compared to those without nephropathy and control groups (P < 0.01). A allele was a risk factor for diabetic nephropathy (OR 2.36 & 95% CI 1.1-5.6). RAGE -374 A allele was associated with increased sRAGE levels, hypertension and increased creatinine concentration in diabetic patients. This study points to the possible role of sRAGE as a marker of early nephropathy in diabetic patients. Early testing for the RAGE gene -374 T/A could have merit in predicting risk of diabetic nephropathy later in life. PMID- 20726327 TI - The role of apoptotic proteins in patients with systemic lupus erythematosis. AB - Lymphocytes and granulocytes from healthy donors and SLE patients were used to investigate the role of Fas/FasL system in the pathogenesis of systemic lupus erythematosus (SLE). Determination of lymphocyte subpopulations was carried out by flowcytometry. Fas and FasL expression in lymphocytes and granulocytes were measured by immunofluorescence. Apoptotic cells were measured by TUNEL assay. sFas in the plasma was measured by ELISA. Thirty five normal blood donors and 45 SLE patients were selected for this study. This study was carried out between 2005 and 2007. The number of peripheral leukocytes undergoing apoptosis in SLE patients was greater than those of healthy donors. The degree of DNA damage in lymphocytes and granulocytes of SLE patients was much higher than those of healthy donors (P < 0.05 & P < 0.5, respectively). Additionally, a positive relationship was seen between the level of apoptotic lymphocytes'and the dosage of prednisolone used for treatment of SLE (r = 0.6). The level of Fas and FasL expression on different lymphocyte subpopulations increased depending on the activity of the disease (P < 0.5 & P < 0.05, respectively). There was an inverse correlation between the sFas and the stage of disease. Finally, we have demonstrated a relationship between the titre of autoantibodies and the degree of DNA damage in lymphocytes and granulocytes (r = 0.7 & r = 0.6, respectively). In conclusion, Fas and FasL are likely to play an important role in the pathogenesis of SLE. The real value may be used as a predictor for the activity of disease as well. PMID- 20726328 TI - Impact of CD4+CD25high regulatory T-cells and FoxP3 expression in the peripheral blood of patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by various immunological abnormalities. Regulatory T cells (Tregs) CD4+CD25+ play an important role in maintaining tolerance to self-antigens controlling occurrence of autoimmune diseases. It has been shown that the transcription factor forkhead box P3 (FoxP3) is specifically expressed on CD4+CD25+T cells. FoxP3 has been described as the master control gene for the development and function of Tregs. A decrease in the number of CD4+CD25highFoxP3+ regulatory T cells can play a key role in the loss of tolerance to self antigens. The study was designed to assess expression levels of FoxP3 in peripheral CD4+CD25+ regulatory T cells in patients with SLE and to evaluate the level of some cytokines that are implicated in the extent of the disease activity. The study was carried out on 30 SLE patients, they were 27 females and 3 males, 10 age and sex matched healthy volunteers were studied as a control group. They were divided into two groups: group I: had active disease (12 patients) and group II: had inactive disease (18 patients) according to Systemic Lupus Erythematosus Disease Activity Index. All individual were subjected to CBC, ESR, s.creatinine, RF, CRP, C3, ANA, anti ds-DNA and flowcytometeric assay of CD4+CD25+ (Tregs) and FoxP3 for patients and controls. Quantitative determination of serum interleukin 10 (IL-10) and transforming growth factor-beta1 (TGF-beta1) concentrations in serum samples by ELISA technique. The results revealed a significant decrease of CD4+CD25high cells in peripheral blood in active lupus patients when compared with patients with inactive lupus and those in healthy controls. Intriguingly, the percentage level of FoxP3 on CD4+CD25high cells was significantly decreased in SLE patients with active disease (2.9 +/- 1.05) when compared with those with inactive SLE (3.5 +/- 0.8) and control groups (4.7 +/- 1.2) (P < 0.05). As regard cytokines levels; the level of IL-10 was significantly increased in patients with active and inactive disease (158.8 +/- 50.8, 82.8 +/- 14.08 respectively) when compared with the control group (P < 0.001). While, the level of TGF-beta1 was significantly decreased in patients with active and inactive disease (22.5 +/- 7.03, 29.07 +/- 10.14 respectively), when compared with the control group (P < 0.05). Our data revealed impaired production of Tregs in SLE patients, which may play a reciprocal role with some cytokines to affect the activity of the disease. Tregs cells should be the target to determine the clinical effectiveness of novel therapy to modulate Tregs in vivo besides the conventional treatments. PMID- 20726329 TI - Expression of toll-like receptor 2 on peripheral blood monocytes of patients with inflammatory and noninflammatory acne vulgaris. AB - The pathogenesis of acne vulgaris is multifactorial and entails the interplay of hormonal, microbial and immunological events. The bacterium Propionibacterium acnes is involved in the induction of comedogenesis and maintenance of the inflammatory phase of acne. Toll-like Receptor 2 (TLR2) expressed on mononuclear inflammatory cells and possibly on keratinocytes and sebocytes is thought to be of vital importance in mediating P. acnes-induced inflammatory response in acne vulgaris. This work aimed to study the degree of expression of TLR2 on peripheral blood monocytes (PBM) from patients with non-inflammatory and inflammatory acne and to investigate the influence of systemic isotretinoin therapy on TLR2 expression. Sixteen patients with predominantly non-inflammatory acne, 16 patients with predominantly inflammatory acne and 16 age and sex matched healthy subjects were involved in this study. Cell surface expression of CD14 and TLR2 were determined by cell surface staining and flowcytometry. TLR2 expression was analyzed for 12 patients with severe and/or scaring inflammatory acne after oral isotretinoin therapy for two months. The mean fluorescence intensity (MFI) of TLR2 on PBM reported a statistically significant difference between patients with non-inflammatory acne, patients with inflammatory acne and control subjects. MFI of TLR was significantly lower for patients with inflammatory acne after systemic isotretinoin therapy. Data obtained suggest that TLR2 expression on PBM is an important event in acne pathogenesis and targeting this molecule might be a useful therapeutic goal in the future. PMID- 20726330 TI - Anti-C1q antibodies, sCD40L, TWEAK and CD4/CD8 ratio in systemic lupus erythematosus and their relations to disease activity and renal involvement. AB - Due to the unpredictable nature of lupus nephritis (LN), it would be clinically valuable to discover a reliable biomarker for disease activity and progression. The aim of this study is to evaluate the role of anti-C1q antibodies, sCD40L and TWEAK in systemic lupus erythematosus (SLE) and their relation to disease activity and kidney involvement. This study included 47 patients with SLE, 28 with LN and 19 without LN, as well as, 20 healthy subjects as controls. All subjects underwent complete history, examination and estimation of disease activity index (SLEDAI) and renal SLEDAI. The following investigations were done for all subjects: anti-C1q antibodies, sCD40L, TWEAK and CD4/CD8 ratio, in addition to complete blood picture, ESR, kidney function tests, ANA, anti-ds DNA antibodies and C3, C4. Anti-C1q antibodies, sCD40L and TWEAK and anti-dsDNA were significantly higher in SLE patients than controls (P < 0.001 for each), while C3, C4 and CD4/CD8 ratio were significantly lower (P < 0.001, 0.05 and 0.001 respectively). In LN patients, anti-C1q antibodies, sCD40L and TWEAK were significantly higher than non LN patients (P < 0.001 for each). Anti-C1q antibodies, sCD40L and TWEAK correlated with traditional disease activity parameters (C3, C4, anti-dsDNA and SLEDAI) as well as rSLEDAI. Levels of serum TWEAK correlated with the development of LN in patients with SLE. We concluded that anti-C1q antibodies, sCD40L and TWEAK may be used as serum biomarkers for the assessment of disease activity and development of LN. PMID- 20726331 TI - Drosophila ananassae: a good model species for genetical, behavioural and evolutionary studies. AB - Drosophila ananassae, a cosmopolitan and domestic species, was first described by Doleschall in 1858 from Indonesia. During 1930s, cytological and genetical investigations in D. ananassae were initiated in Japan and USA which showed that it is a genetically unique species. Since then a large number of studies have been carried out by researchers in Japan, U.S.A., India, France and Germany in this genetically unique species. Present review briefly summarizes the work done on genetical, behavioural and evolutionary aspects in D. ananassae which demonstrates that it is a ggod model species for such studies. Further, it is also discussed how the work on D. ananassae has enriched our understanding of basic phenomena like evolution and behaviour compared to similar studies on other model Drosophilds like D. melanogaster, D. pseudoobscura or D. subobsura. PMID- 20726332 TI - Modulation of cell surface architecture in gastrulating chick embryo in response to altered fibroblast growth factor (FGF) signaling. AB - Gastrulation is a fundamental process that results in formation of the three germ layers in an embryo. It involves highly coordinated cell migration. Cell to cell communication through cell surface and the surrounding molecular environment governs cell migration. In the present work, cell surface features, which are indicative of the migratory status of a cell, of an early gastrulating chick embryo were studied using scanning electron microscopy. The distinct ultrastructural features of cells located in the various regions of the epiblast are described. Differences in the surface features of cells from distinct embryonic regions indicate differences in their migratory capacities. Further, the dynamic nature of these cell surface features by their response to altered fibroblast growth factor (FGF) signaling, experimentally created by using either excess FGF or inhibition of FGF signaling are demonstrated. PMID- 20726333 TI - Hepatocyte growth factor (HGF), heat shock proteins (HSPs) and multidrug resistance protein (MRP) expression in co-culture of colon tumor spheroids with normal cells after incubation with interleukin-1beta (IL-1beta) and/or camptothecin (CPT-11). AB - Tumor chemoresistance and metastasis are some of the most important problems in colon cancer therapy. In the present study, co-cultures of human colon carcinoma cell spheroids, obtained from different grades of tumor, with human colon epithelium, myofibroblast and endothelial cell monolayers were performed. The purpose of these co-cultures was to reflect, in in vitro conditions, different stages of colon tumor development. In order to investigate the invasive capacities of the tumor cells and their resistance to chemotherapy, HGF, HSP27, HSP72 and MRP levels were analyzed after incubation of the co-cultures with IL 1beta and irinotecan (CPT-11) added as single agents or in combination. Myofibroblasts produced significantly higher amounts of HGF than epithelial cells. Tumor cells released trace amounts of this molecule. In cocultures, IL 1beta induced HGF release, while CPT-11 alone or combined with IL-1beta decreased HGF secretion. An immunoblotting analysis followed by densitometry revealed that the combination of IL-1beta plus CPT-11 added to the cocultures led to a decrease in HSPs and MRP levels. In conclusion, direct and paracrine interactions of colon tumor cell spheroids with normal cells and exogenously added CPT-11 change HSP27, HSP72 and MRP expression in comparison to monocultures. IL-1beta and CPT-11, dependent on whether they are added separately or jointly, differentially modulate HGF expression in monocultures of colon tumor spheroids or normal cells and their co-cultures. PMID- 20726334 TI - Differential effects of nitric oxide synthase inhibitors on anxiety in unstressed and stressed mice. AB - Effects of selective nitric oxide synthase (NOS) inhibitors, 7-nitroindazole (7 NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS) and aminoguanidine (AG), a selective inhibitor of inducible nitric oxide synthase (iNOS) on anxiety in unstressed and stressed mice were investigated using elevated plus maze (EPM) test and light-dark test (LDT). 7-NI (20 and 40 mg/kg, ip) produced anti-anxiety effect in unstressed mice but not in stressed mice. AG (50 and 100 mg/kg, ip) produced anxiolytic effect in stressed mice and failed to produce the similar effect in unstressed mice. Nitrite levels were increased in stressed mice, but not in unstressed mice, exposed to EPM and LDT for 5 min. Increased nitrite levels in stressed mice were attenuated by AG, but not by 7-NI. The effects of AG were enhanced by pyrrolidine-dithio-carbamate (PDTC), an inhibitor of NF-kappaB induction, in stressed mice. The results suggest the possible role of inducible nitric oxide synthase in stress-induced anxiogenesis as compared to unstressed mice, where neuronal form of NOS may plays predominant role. PMID- 20726335 TI - Effect of antioxidant vitamins A, C, E and their analogues on azo-dye binding protein in liver of rats treated with p-dimethylaminoazobenzene. AB - p-Dimethylaminoazobenzene (DAB) is an azo-dye and known to cause liver tumour in rats. Azo-dye binding protein is a specific cytosolic protein involved in the translocation of azo-dye carcinogen metabolites from liver cytoplasm into the nucleus. Administration of vitamin A (40,000 and 50,000 IU), L-ascorbic acid (500 and 1000 mg) and vitamin E succinate (200-500 mg) reduced the amount of azo-dye binding protein in liver of rats treated with DAB. Supplementation of high doses of vitamin A acetate, vitamin A palmitate, sodium ascorbate, ascorbyl palmitate and vitamin E acetate had no effect on the quantity of azo-dye binding protein in liver. When the vitamin mixture was given, the level of azo-dye binding protein decreased in the liver at all the studied doses, which may be due to their synergistic effect. PMID- 20726336 TI - Neuroprotective effect of hydroalcoholic extract of dried fruits of Trapa bispinosa Roxb on lipofuscinogenesis and fluorescence product in brain of D galactose induced ageing accelerated mice. AB - Effect of hydroalcoholic extract T. bispinosa (TB) was studied on fluorescence product and biochemical parameter like lipid peroxidation, catalase activity and glutathione peroxidase activity in the brain of female albino mice. Ageing was accelerated by the treatment of 0.5 ml 5% D-galactose for 15 days. This resulted in increased fluorescence product, increase lipid peroxidation and decrease antioxidant enzyme like glutathione peroxides and catalase in cerebral cortex. After cotreatment with hydroalcoholic extract of TB (500 mg/kg, po) there was decrease in fluorescence product in cerebral cortex. Moreover, TB inhibited increase lipid peroxidation and restores glutathione peroxidase and catalase activity in cerebral cortex as compare to ageing accelerated control group. To conclude TB found to be effective antioxidative agent which could to some extent reverse D-galactose induced ageing changes resulted due to oxidative damage. PMID- 20726337 TI - Cadmium tolerance and antibiotic resistance of Pseudomonas sp. isolated from water, sludge and fish raised in wastewater-fed tropical ponds. AB - The numbers of Pseudomonas sp. isolated were counted in samples collected from water, sludge and intestine of fishes raised in different wastewater ponds along an effluent gradient in a sewage treatment plant. Total fish yield in the last maturation pond increased by 73% over the yield in first maturation pond or facultative pond. The number of Pseudomonas sp. isolated from the intestine of the tilapia (Oreochromis mssambicus) raised in facultative pond, was more than three times the counts (7.22 x 10(8)/g) observed in the last maturation pond (2.025 x 10(8)/g). The effective lethal concentration of cadmium for Pseudomonas sp. isolated from the intestine of the tilapia was 0.6 mM and 0.08-0.09 mM when the fish was procured from facultative pond and last maturation pond, respectively. The Pseudomonas sp. isolated from the intestine of the tilapia did not have resistance to any of the ten antibiotics tested. However, the bacterium isolated from raw sewage, water and sediment of the anaerobic pond was resistant to seven out of ten antibiotics tested. PMID- 20726338 TI - Effects of long-term ethanol consumption on adhesion molecules in liver. AB - Adhesion molecules play an important role in the pathogenesis of several diseases. In this study, expression of adhesion molecules was examined in the setting of chronic alcohol induced liver damage of male albino Wistar strain rats (16-18 weeks-old, 200-220 g) in a time dependent manner. Decreased protein level and increased activities of liver marker enzymes in response to the chronic ethanol (1.6 g ethanol/kg body weight/day) exposure, indicated that these animals suffered from liver damage in a time-dependent manner. Flow cytometric analysis revealed that chronic ethanol treatment induced intercellular adhesion molecule 1, vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression in liver tissues of rats with duration of ethanol exposure. The results suggest that the adhesion molecules may be associated with the initiation of hepatic injury during alcohol intoxication. PMID- 20726339 TI - Wound healing potential of Ocimum sanctum Linn. with induction of tumor necrosis factor-alpha. AB - Ocimum sanctum, a well known herb in Indian medicine, possesses various therapeutic properties including healing properties and cytokine induction. Wound healing activity of cold aqueous extract of O. sanctum leaves along with its effect on tumor necrosis factor-alpha (TNF-alpha) was assessed using excision model of wound repair in Wistar albino rats. After application of the O. sanctum extract, rate of epithelization with an increase in wound contraction was observed. In animals, treated with 10% O. sanctum extract in petroleum jelly, wound healing was faster as compared to control group which were treated with petroleum jelly alone but significant accelerated healing was noticed in animals which in addition to the topical application of 10% extract of O. sanctum, were prefed with 250 mg/kg body weight of aqueous O. sanctum extract daily for 20 consecutive days. During wound healing phase TNF-alpha level was found to be up regulated by O. sanctum treatment. Early wound healing may be pronounced due to O. sanctum extract, by elevating TNF-alpha production. PMID- 20726340 TI - Antibacterial effects of goat and chicken heart tissues against human pathogenic bacteria. AB - The crude buffer (Tris Buffer Saline-I) extracts of muscles, liver, kidney and heart of goat and chicken (White leghorn) were screened against 16 clinical isolates. Among the five tissues, the heart tissue of each animal showed significant bactericidal activities on many isolates. The acid extracted crude proteins of both heart tissues also showed significant antibacterial activities against many bacterial isolates. The crude proteins of goat heart tissues displayed strong bactericidal activities against Salmonella paratyphi 'A' and Salmonella typhimurium (MIC: 16 microg/ml) whereas thecrude proteins of chicken heart tissues displayed strong bactericidal activities against Escherichia coli ATCC and Pseudomonas aeruginosa at 16 and 63 microg/ml concentrations respectively. The peptides of low molecular weight ( <30 kDa) were also separated from the acid extracted crude proteins of goat and chicken heart tissues by SDS PAGE after staining with silver nitrate solution. PMID- 20726341 TI - Microbial transformation of albendazole. AB - Screening scale studies were performed to biotransform anthelmintic drug albendazole by using twelve bacterial strains representing six genera and five actinomycetes cultures. Among the cultures studied, Bacillus subtilis MTCC 619, Escherichia coli MTCC 118 and Klebsiella pneumoniae MTCC 109 could transform albendazole to one metabolite whereas, Enterobacter aerogenes NCIM 2695, Klebsiella aerogenes NCIM 2258, Pseudomonas aeruginosa NCIM 2074 and Streptomyces griseus NCIM 2622 could transform albendazole into two metabolites in significant quantities. The transformation of albendazole was identified by HPLC. Based on LC MS-MS data, the two metabolites were predicted to be albendazole sulfoxide (M1) and albendazole sulfone (M2), the major mammalian metabolites reported previously. Since M1 is active metabolite, the results prove the versatility of microorganisms to perform industrially attractive chemical reactions. PMID- 20726342 TI - [Functional interplay of dopamine D1 and D2 receptors in the immune response control in different psychoemotional states]. AB - It is established that preliminary blockade ofdopamine (DA) D2 receptors with haloperidol prevents immunostimulation observed upon the activation of D1 receptors with selective agonist SKF 38393 in mice of the CBA and C57BL/6J strains having no experience in social confrontations. These data are indicative of the functional interconnection between DA receptors of the D1 and D2 subtypes in the immune response control. Similar link between these DA receptor subtypes has been also found in C57BL/6J mice conditioned to display aggressive or submissive behaviors during 10-day social encounter testing. The data obtained give evidence that the interaction between D1 and D2 receptors is manifested in animals with various genotypes and psychoemotional states. PMID- 20726344 TI - [Antioxidant efficacy in the treatment of cardiac metabolism disorders during endotoxicosis]. AB - Chronic experiments on dogs showed that antioxidant drugs (reamberin, ximedone, vitamin E) are highly effective in correcting the functional and metabolic disorders in myocardium under endogenous intoxication conditions. Recovery of the functional activity was accompanied by correction of the lipid metabolism of cardiac cell structures. One mechanism of the drug action is related to a decrease in the lipid peroxidation rate and phospholipase A2 activity in cardiac tissue structures. PMID- 20726343 TI - [Mechanism of the cardioprotective effect of nifedipine in rabbits under vibration exposure conditions]. AB - Mechanisms of the vibroprotective action of nifedipine, a calcium channel blocker, have been studied in myocardiocytes of rabbits. Changes in the functional activity of mitochondria were observed in rabbits after prolonged (56 days) general vibration. Nifedipine (7.5 mg/kg per os) activated the NAD dependent site of respiratory chain and prevented hyperactivation of the succinate-dependent breath. The positive energotropic action of nifedipine was accompanied by stability of the histomorphological cytoarchitecture of rabbit myocardium. It is suggested that nifedipine protects myocardium from negative effects of prolonged vibration. PMID- 20726345 TI - [Anticoagulant activity of extracts from cedar bark, anthocyanidins of spruce and birch bark, and cellulose of aspen, fir, and wheat straw]. AB - We have investigated in vitro the anticoagulant (AC) activity of proanthocyanidins from the bark of birch, cedar, spruce, pine, and larch; sulfated arabinogalantan and dihydroquercetin from larch wood; extracts from birch, cedar, and spruce; microcrystalline cellulose (MCC) from aspen and fir wood and wheat straw; and methylcellulose (MC) from aspen wood. The AC properties of the investigated substances are related mostly to their antithrombin activity. The AC activity increases with the content of sulfur in MCC of wheat straw, MC of aspen wood, and arabinogalantan of larch wood. The maximum AC activity was observed in samples of sulfated MCC from fir wood and wheat straw. Their antithrombin activity (134 +/- 8 and 96 +/- 6, respectively) is worth of carrying out model tests in vivo. PMID- 20726347 TI - [Pharmacological properties of complex iron oxide nanoparticles entering in magnetic resonance tomography contrast agent]. AB - A colloidal solution of iron oxide nanoparticles has been obtained that ensures an increase in the accuracy of diagnostic information from magnetic resonance tomography (MRT) due to the acceleration of proton relaxation in tissues, which improves the contrast of T1- and T2-weighed images. Improved visualization of small vessels in rat brain has been observed after intravenous injection of 0.1 ml solution containing 5.0 mg of contrasting iron nanoparticles. The paramagnetic properties of iron oxide nanoparticles were studied by the method of proton relaxation, and their size was determined by the method of transmission electron microscopy. The toxic properties ofnanoparticles were determined by their effect on cultured HeLa cells (MTT test). It is recommended to use a colloidal solution of superparamagnetic nanoparticles (size, 8.2 nm) for obtaining a pharmaceutical form of the new magnetic-resonance contrast medium Ferotrast. PMID- 20726346 TI - [Effect of plant polysaccharides on TH1-dependent immune response: screening investigation]. AB - We have studied the influence of water-soluble polysaccharides isolated from Tussilago farfara L. leaves, Betula verrucosa Ehrh. leaves, Calendula officinalis L. flowers, Acorus calamus rhizomes, Inula helenium L. rhizomes, overground part of Trifolium pretense L., and overground part ofArtemisia absinthium L., on Thl immune response induced by sheep red blood cells and on NO production by murine peritoneal macrophages in vitro. All the investigated polysaccharides have stimulated a Th1 response. Polysaccharides isolated from Betula verrucosa leaves did not influence NO synthesis, while polysaccharides of Tussilago farfara leaves and Acorus calamus rhizomes stimulated NO synthase of murine macrophages on a level comparable with that of lipopolysaccharides (LPS). Polysaccharides from Inula helenium rhizomes, Calendula officinalis flowers, and overground parts of Trifolium pretense and Artemisia absinthium also stimulated NO production, but to a lower extent in comparison to LPS. PMID- 20726348 TI - [Preclinical safety investigation of GB-115 dipeptide]. AB - Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A. PMID- 20726349 TI - [Toxicity of ethyl-3-(8-fluoro-2-methyl-2,3,4,5-tetrahydropyrido[4,3-b]indol-5 yl)-propionate dihydrochloride possessing antiallergic properties]. AB - The toxicity of new gamma-carboline derivative [ethyl 3-(8-fluoro-2-methyl 2,3,4,5-tetrahydro-1H-gamma-carbolin-5-yl)-propionate dihydrochloride, CD-008 040] has been studied. PMID- 20726351 TI - [Methodological approaches to experimental investigation of drugs for the prophylaxis and treatment of prostate gland disorders]. AB - New methodological approaches to preclinical study of the efficiency of potential prostatotropic drugs are suggested on the basis of original research and published data. An algorithm is proposed to investigate specific activity and safety of potential drugs for the prevention and treatment of prostate disorders. PMID- 20726350 TI - [Clinical-economic substantiation of immunocorrection therapy of Epstein-Barr viral mononucleosis in children]. AB - Results are presented for a group of 299 patients aged 1-14 with primary Epstein- Barr viral infection. Features of the process of a infectious mononucleosis are revealed for various kinds of immunocorrection therapy. A clinical-economic estimation of the immunocorrection therapy in children with primary Epstein-Barr viral infection has been performed. PMID- 20726352 TI - Amiodarone pneumonitis. PMID- 20726353 TI - Congenitally absent right coronary artery in adult. PMID- 20726354 TI - Multiple inflammatory pseudotumors of the liver and spleen. PMID- 20726355 TI - Sacciform varix of right pulmonary vein. PMID- 20726356 TI - Intestinal acute graft versus host disease. PMID- 20726357 TI - Typical imaging features in Hunter's syndrome. PMID- 20726358 TI - Acute respiratory symptoms in Mounier-Kuhn syndrome. PMID- 20726359 TI - Idiopathic bone cyst of the mandible. PMID- 20726360 TI - Abdominal and thoracic tuberculosis in a HIV positive patient. PMID- 20726361 TI - Postintubation membranous tracheal rupture. PMID- 20726362 TI - Symptomatic brain capillary telangiectasia. PMID- 20726363 TI - Portohepatic shunt in a patient without cirrhosis. PMID- 20726364 TI - Small bowel obstruction due to bezoar in jejunal diverticulosis. PMID- 20726365 TI - Mass in the back as manifestation of neurofibromatosis type 2. PMID- 20726366 TI - Metastases in the breast from disseminating melanoma. PMID- 20726367 TI - Probable cerebral amyloid angiopathy. PMID- 20726368 TI - Polyarteritis nodosa of the spleen. PMID- 20726369 TI - Glomus tumor of the stomach. PMID- 20726370 TI - Pneumocystis carinii pneumonia in a HIV-positive patient. PMID- 20726371 TI - Ruptured renal angiomyolipoma. PMID- 20726372 TI - Left pulmonary artery agenesis. PMID- 20726373 TI - Pneumatosis coli and incarcerated inguinal hernia. PMID- 20726374 TI - Abdominal mass due to crossed renal ectopia and fusion. PMID- 20726375 TI - Rhinolith of the nasal septum. PMID- 20726376 TI - Lipoma arborescens of the knee. PMID- 20726377 TI - Management of the patient with advanced complications, functional decline, and persistent hyperglycemia. AB - OBJECTIVES: Current management of hypoglycemic risk among seniors with type 2 diabetes mellitus (T2DM) is frequently not very effective. Treatment guidelines with target glycosylated hemoglobin (A1C) levels provide important standards for T2DM management, but target goals must be determined on an individual basis in conjunction with individual factors, including risk of hypoglycemia. This clinical review will help pharmacists develop optimal therapeutic regimens for elderly diabetic patients that carefully balance risks and benefits of therapy, better assess their elderly patients' risk of hypoglycemia, and determine appropriate blood glucose testing schedules for the long-term care patient. DATA SOURCES: Live symposium presentation based on clinical practice and research, medical literature, and studies published between January 1998 and April 2009 on managing diabetes in older adults, government statistics, and medical society guidelines. CONCLUSIONS: When treating seniors with T2DM, it is critical that hypoglycemia be identified and avoided. Hypoglycemia, whether undiagnosed, recurring, or brought about with the use of traditional insulin or other antihyperglycemic agents with higher hypoglycemic risk, can lead to the risk of falls and injuries related to that. Certain therapeutic measures, including alterations to blood glucose testing schedules, less stringent A1C goals, and insulin analog therapies, facilitate effective glycemic control and decrease the risk of hypoglycemia. PMID- 20726378 TI - Prediabetes in a nursing facility patient with renal insufficiency. AB - OBJECTIVES: Prediabetes encompasses a variety of abnormalities, including impaired fasting glucose, impaired glucose tolerance, and metabolic syndrome. Prediabetes also increases the risk of developing type 2 diabetes mellitus (T2DM) by 3- to 10-fold, but the complications associated with hyperglycemia begin early in the patient's progression from normal glucose levels to diabetes. Early identification and treatment of prediabetes has the potential to reduce or delay progression to overt diabetes, to preempt related cardiovascular and microvascular disease, and to significantly improve morbidity and mortality. This clinical review provides a vehicle to examine management of prediabetes in patients 65 years of age and older, including diagnostic criteria and recommendations for management. DATA SOURCES: Live symposium presentation based on clinical practice and research, medical literature, and studies published between May 1999 and March 2010 on managing diabetes in older adults, government statistics, and medical society guidelines. CONCLUSIONS: Effective prediabetes management is important to reducing the risk of progression to T2DM. Recommended first-line therapy is lifestyle modification that may include exercise, nutritional therapy, and weight loss. Pharmacological therapies, when indicated, can aid in improving glucose, blood pressure, and lipid parameters in this patient subgroup. PMID- 20726380 TI - Assisted living: improving glucose control for the functionally independent patient with diabetes. AB - OBJECTIVE: This clinical review guides consultant pharmacists on how best to integrate a range of parameters, such as glycosylated hemoglobin (A1C) levels, patient comorbidities, and quality of life issues specific to seniors, and drug risks and benefits, when determining optimal therapeutic decisions for elderly patients with type 2 diabetes mellitus (T2DM). It also discusses clinical use of incretin-based therapies that provide important new alternatives in improving glycemic levels, extend a positive effect on weight, and minimize hypoglycemic risk. DATA SOURCES: Live symposium presentation based on clinical practice and research, medical literature, and studies published between April 1995 and January 2010 on managing diabetes in older adults, government statistics, and medical society guidelines. CONCLUSIONS: Minimizing or delaying long-term complications, maximizing functional status, maintaining nutritional status, and initiating pharmacological therapy with established goals to control hyperglycemia and prevent hypoglycemia are important in the multifaceted management of older adults with diabetes. PMID- 20726379 TI - Cardiac risk factors and hypoglycemia in an elderly patient: how good is good enough? AB - OBJECTIVES: This clinical review highlights emerging data regarding the complex relationship among glycosylated hemoglobin (A1C) goals, risk of cardiovascular disease, and hypoglycemia in elderly patients with type 2 diabetes mellitus (T2DM). According to the ADVANCE and VADT trials, lowering patients' A1C levels did not decrease the risk of cardiovascular disease, and the ACCORD trial found a slightly higher risk of cardiovascular disease with tighter glycemic control. Long-term follow-up data from the UKPDS indicated good glycemic control, when achieved early in newly diagnosed patients, lowered cardiovascular risk over the long-term (at least 15 to 20 years). Moreover, tight glycemic control, if it results in severe hypoglycemic events, may pose a serious risk among elderly patients with T2DM. DATA SOURCES: Live symposium presentation based on clinical practice and research, medical literature, and studies published between October 2005 and January 2010 on managing diabetes in older adults, government statistics, and medical society guidelines. CONCLUSIONS: If it can be achieved safely, early glycemic control is beneficial to elderly patients with T2DM. Treatment goals for older adults should be an individualized process and must include a number of considerations. Pharmacists need to manage the dual issues of avoiding intensive lowering of A1C levels and averting the risk of hypoglycemia. PMID- 20726381 TI - Criteria for compliance: Centers for Medicare & Medicaid Services pain management at F-Tag 309. AB - OBJECTIVE: Outline the key points and list the criteria for compliance with the new Centers for Medicare & Medicaid Services (CMS) pain management at F-Tag 309. DATA SOURCES: Live symposium presentation based on clinical practice and research and current clinical guidelines. CONCLUSIONS: In March 2009, CMS implemented revised guidelines for long-term care surveyors at F-Tag 309, Quality of Care, including a new general investigative protocol and pain-management guidance. While the regulations have remained the same, the way surveyors interpret pain management has changed. By understanding the criteria surveyors will use to determine F-Tag 309 deficiencies, consultant pharmacists can educate other interdisciplinary team members to improve pain management practices in long-term care. PMID- 20726382 TI - Treat hypertension in the elderly. PMID- 20726383 TI - Practical strategies for management of hypertension in the elderly. PMID- 20726385 TI - Gradually enlarging plaque on hand. PMID- 20726384 TI - Osteoarthritis: a review of treatment options. AB - Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the United States, especially among older adults. Treatment options have primarily focused on alleviating the pain often associated with this condition. Acetaminophen and nonsteroidal anti inflammatory drugs (NSAIDs) are often employed for relief of mild-to moderate pain associated with OA. NSAIDs are typically more effective than acetaminophen; however, because of adverse effects associated with long-term use of NSAIDS, acetaminophen is considered first-line therapy. Safety concerns of traditional pharmacotherapeutic agents used in the management of OA, such as NSAIDs and opioids, have led healthcare professionals to seek other options. Trials of disease modulating agents that focus on preventing further damage to the joints have the potential to change how this disease state is managed. This article reviews nonpharmacologic and pharmacologic approaches to management of OA of the knee and hip. PMID- 20726386 TI - Current trends in polytrauma management. Diagnostic and therapeutic algorithms operational in the Trauma Center of Cesena, Italy. AB - INTRODUCTION: The purpose of this paper is to present the most recent revision of diagnostic therapeutic protocols regarding polytrauma that are operational in the Trauma Center of Cesena, and to check what impact the progressive implementation and review of these algorithms has had on predefined indicators of results and utilization of diagnostic and therapeutic resources. Finally for the purpose of comparing the results obtained in a subgroup of patients treated in the Trauma Center of Cesena, with those obtained in a group homogeneous for ISS and year of hospitalization stored in the RRGT (Registro Regionale Grandi Traumi - Regional Major Trauma Registry). MATERIALS AND METHODS: Through a retrospective study we analyzed a population of 21,704 patients hospitalized for trauma in our Trauma Center from 2001 to November 2009, 40.1% females and 59.9% males, aged between 0 and 105 years, who were treated with the protocols developed in the Trauma Service. Indicators of results and of diagnostic and therapeutic resource utilization were analyzed. All patients enrolled in the study were divided by year of admission to assess the performance of these indicators over the years. An ISS homogeneous subgroup including only patients hospitalized in the year 2007 was also created for comparison with the report of RRGT (Regional Major Trauma Registry). Emergency Department code yellow or red patients were divided into 3 groups based on the hemodynamic response after primary assessment. Group A included patients that were hemodynamically stable (ATLS criteria); Group B included patients that were hemodynamically stabilized; Group C included patients that were hemodynamically unstable. Each group of patients was treated according to precise diagnostic and therapeutic protocols. RESULTS: The overall hospital mortality was 2.4%. Mortality at discharge from intensive care was 11.6% while at discharge from the Emergency Surgery was 0.2%. The total average hospital stay was 10.1 days. ICU stay was 7.8 days, while in Emergency Surgery was 12.4 days. 79.4% of the patients were discharged home. Overall, the percentage of patients undergoing surgery was 64.3%. Patients undergoing diagnostic level II with multislice CT were 19.3%; those undergoing CT of the chest and / or abdomen were 5%. A total 0.8% of patients underwent angiography, and 0.2% underwent embolization. The overall percentage of patients transfused with packed red blood cell was 3.9%. CONCLUSIONS: The hemodynamic response of patients after primary assessment determines the subsequent diagnostic and therapeutic procedures. The protocols that we utilized had a positive impact on the mortality of patients hospitalized in the intensive care and on the average intensive care stay, and were also associated with an increase in the number of angiography and arterial embolizations performed in sicker patients and those with relevant surgical lesions. The decrease in mortality is also observed in comparison with the RRGT data. We believe therefore that these protocols can provide a valuable and effective aid for those involved in the care of trauma victims, allowing them to always be able to quickly decide what to do, when to do, how to do, and where to do what needs to be done. PMID- 20726387 TI - The epidemiology and clinical evaluation of abdominal trauma. An analysis of a multidisciplinary trauma registry. AB - Abdominal trauma is present in 7-10% of all trauma victims, and in cases of severe trauma is often found together with orthopedic, thoracic or central nervous system (CNS) injuries. The aim of the present study was to perform a comparative analysis of abdominal trauma and trauma involving other body regions, evaluating the prognostic significance of abdominal injuries in patients with severe trauma, based on data from a multidisciplinary trauma registry. Data from the period from March 1 2006 to December 31 2007 was collected from the trauma registry of the University Hospital Sant'Andrea in Rome, Italy. There were 25.875 patients (31.4%) with the diagnosis of trauma out of a total of 82.293 patients admitted to the emergency department. Eight hundred forty-four patients were selected according to specific inclusion criteria and patients with abdominal injuries were further selected. The following data were investigated: patient age, the trauma mechanism, duration of recovery, Abbreviated Injury Scale (AIS), Injury Severity Score (ISS), type and the incidence of abdominal and extra abdominal injuries. Morbidity and mortality, especially in patients with spleen and liver injuries, were analyzed. There were 79 patients (9.3%) with abdominal trauma. Their mean ISS was 25.7 +/- 14.3. Sixty-one (77.2%) of these patients had sustained severe trauma (ISS > 15). Forty-one patients (51.8%) underwent surgery. The overall mortality rate was 24.1%, 19 patients all with ISS > 15, so that the mortality rate for patients with severe trauma was 31.2%. Splenic trauma was the most frequent, and was found in 36 patients (45.6%) whose mean ISS was 31.1 +/- 144. Twenty-two patients (61.6%) were treated surgically; a total of 21 splenectomies and one laparoscopic procedure to control bleeding were performed. Overall mortality among patients with splenic trauma was 30.5% (11 patients), with an average spleen AIS of 3.3 +/- 0.8 (died vs. survived p = n.s.). Liver injuries were found in 33 patients (41.7%). The mean ISS was 28.4 +/- 11.6. Sixty five percent of the patients were given nonsurgical treatment. Overall mortality among liver trauma patients was 24.2% (8 patients) with an average liver AIS of 3.2 +/- 0.3 (died vs. survived p < 0.05). In multivariate analysis, among the general population of trauma patients, the ISS (p < 0.001), patient age (p < 0.003), and an orthopedic (p < 0.002) or CNS injury (p < 0.006) proved to be significant independent predictors of the presence of an abdominal injury. Multivariate analysis showed that in patients with abdominal trauma, only the ISS (p < 0.001) was a significant independent predictor of mortality. PMID- 20726388 TI - [Prognostic and curative value of sentinel node in breast cancer. A 377 patients experience]. AB - Sentinel node is defined as the first lymphnode receiving limphatic drain from the breast. Several studies show a very low recurrence rate to axillary and locoregional nodes in sentinel node negative patients who did not undergo axillary dissection. Our study aims to verify if complete axillary dissection could be replaced by sentinel node biopsy (SNB) in the staging and treatment of breast cancer. From January 2005 to December 2008, 377 patients (mean age 57.63) underwent SNB in the General Surgery unit of "San Giuseppe Moscati" Hospital in Avellino (Italy). All the patients underwent SNB with local anesthesia. Histologic studies were performed using GIVOM protocol (Veneto Breast cancer interdisciplinary group). Sixty five patients (17.2%) underwent a radical mastectomy with SNB and 312 (82.6%) patients underwent a quadrantectomy with SNB. Of this last group, 178 (47.2%) underwent a superior quadrant excision with SNB, 77 (20.4%) an inferior quadrant excision with SNB and 57 (15.1%) a central quadrant excision with SNB. Ductal carcinoma represented 57.3% of the tumous detected, lobular carcinoma was diagnosed in 16.4% of the cases, intraductal microinvasive carcinoma in 10.3%, ductal carcinoma in situ in 5.8% while the other histotypes were diagnosed in 10% of the tumours. All SNB+ patients (34.5%) underwent a radical axillary dissection in general anesthesia. Sixty nine (53%) patients were diagnosed with axillary node metastasis, after axillary dissection Micrometastasis resulted in 19.6% of the excised patients. The prevalence of axillary node metastasis was 26.4% (581/2198), while the incidence was 34.5% (130/377). The first axillary lymphnodes level was metastasized in 65.8% patients who had undergone an axillary dissection, level I and II in 268% and all the levels in 7.4%. Only one case (0.4%) of nodal metastatic recurrence has been diagnosed in patients who had undergone SNB alone, after a mean follow-up of 28.5 month. Apart from showing a very high diagnostic and staging accuracy, the high level of SN detection associated with a high predictive rate underline a lower complications rate if compared to complete nodal dissection. PMID- 20726389 TI - [Treatment of microcarcinoma and papillary carcinoma of the thyroid]. AB - AIM OF THE STUDY: Of our is to demonstrate that total thyroidectomy with lymphadenectomy of the six level is effective in papillary thyroid carcinomas than for microcarcinoma, according to recent acquisitions on the biological behavior of some microcarcinoma. MATERIALS AND METHODS: Ours is a retrospective study based on analysis of the process of therapy in 2849 patients undergoing total thyroidectomy, performed from January 1985 to January 2008 by our group at the U.O. Clinica Chirurgica Ospedale "Vittorio Emanuele" of Catania, Italy. RESULTS: Of all the interventions of total thyroidectomy, 75% performed for benign disease and 25% for malignant disease (PTMC 356 cases, 291 PTC cases, 56 cases of follicular carcinoma, 5 cases of medullary carcinoma, anaplastic carcinoma, 2 cases). 40% of PTMC underwent TT and subsequent follow up, because the diagnosis was placed postoperatively and in 60% diagnosis was placed during surgery with indication for TT and lymphadenectomy of the sixth level and subsequent follow-up showed no evidence of residual disease or relapse. PTC of 40% underwent a TT with lymphadenectomy of the sixth level. 60% of patients with PTC underwent a TT with lymphadenectomy of the sixth level and lateral cervical lymphadenectomy was performed only in 3 cases with a TT level VI lymphadenectomy of the bilateral lateral cervical lymphadenectomy. All patients in the follow-up post-operatively does not show in the following years, signs of residual disease or relapse. CONCLUDING REMARKS: From the results we can confirm that a total thyroidectomy with lymphadenectomy of the sixth level, the more lateral lymphadenectomy of the neck when needed, ensures a good prognosis and few complications, if ever performed in expert hands. This applies to papillary carcinomas than for microcarcinoma whose surgical treatment (total thyroidectomy, lobectomy, subtotal thyroidectomy or near-total) is still debated. PMID- 20726390 TI - Evaluation of CD10 positivity in colorectal polyps in neoplastic transformation. AB - BACKGROUND: CD10 is a metalloprotein that is potentially associated with greater tumour growth. MATERIALS AND METHOD: We have correlated CD10 positive in carcinomatous polyps with tumour size, grade, patient age and sex, postoperative TNM staging and Asler-Coller classification. We have matched these cases with a control group that showed presence of polypoid adenomatous tissue with mild to moderate dysplasia. RESULTS: We have divided these in a group of 39 cases, characterised by the presence of carcinoma arising in adenomatous polyps, and a control group of 16 cases, characterised by the presence of colorectal polyps with mild to moderate dysplasia. In the first group, we have discarded three cases for incomplete data. In the remaining 36 cases we have identified 28 patients testing positive for CD10 with positivity values and 8 cases negative for CD10. In CD10 positive cases, we have confirmed the presence of increased incidence of lymph node involvement compared to CD10 negative cases, with high specificity and high predictive value and a higher incidence of cases attributable to group C (Asler-Coller) and grading 3. CONCLUSIONS: CD10 positivity should be assessed in terms of increased progression. PMID- 20726391 TI - [Acute mesenteric ischemia. Principles of treatment and surgical approach]. AB - The AA report some considerations on the treatment and surgical approach during acute mesenteric ischemia (IMA) focusing some indications for a timely and suitable therapeutic approach. In the last 2 years, they treated 12 cases of IMA in critical patients. Early identification allows avoiding advanced phases of the intestinal infarct/bowel necrosis; in this phase the multidisciplinary approach for the hemodynamic stabilization is a priority, together with rianimatory support and surgery operation. The preservation of the intestinal vitality is essential to avoid the need of bowel resections or at least a major one. A suitable treatment permits a better survival and improvement of the quality of life. Surgical timing requires the intervention within 12 hours since the beginning of the symptoms to be more efficacious. PMID- 20726392 TI - [Covering stoma in anterior rectum resection with TME for rectal cancer in elderly patients]. AB - AIM: The aim of our study is to evaluate the advisability of covering stoma in Anterior Rectum Resection with TME in elderly patients. METHODS AND MATERIALS: A research of both the Ministry of Health and Terni Hospital databases has been conducted so as to collect information about patients with rectal tumor. Such research allowed to identify the amount of patients diagnosed with rectal cancer, the type of intervention, and the average hospitalization time. RESULTS: Between January 1997 and June 2008, 209 patients have undergone chirurgical surgery at Terni hospital's General and Emergency Surgical Clinic. An Anterior Rectum Resection with TME has been performed in 135 patients out of the sample (64.59%). DISCUSSION: The average hospitalization time of geriatric patients does not show significant differences compared to that of younger patients. An age-cohort analysis has been performed among patients who have been subject to stomia and those who have not. The former have been further split up between those who underwent ileostomy and those subject to colostomy. While ileostomy patients face a similar hospitalization time across all age cohorts, geriatric colostomy patients face longer hospitalizations than younger patients. CONCLUSIONS: Patients subject to Anterior Rectum Resection show no meaningful differences, in terms of hospitalization time, across all age cohorts. In geriatric patients the construction of covering stoma has resulted in longer hospitalizations only when a loop colostomy was executed, as opposed to loop ileostomy. PMID- 20726393 TI - Gastric metastasis from breast carcinoma. Report of three cases, diagnostic therapeutic critical close examination and literature review. AB - Gastric metastases of breast cancer represent a not so rare event in patients affected. In fact, it occurs in 0.3% of cases. Although the introduction of new adjuvant therapies has given rise to an increase in disease free survival and overall survival rates, it has also led to more frequent occurrences of breast cancer metastatic lesions localized in bone, lung/pleura and liver, but above all in the stomach. The authors present three cases of patients suffering from breast cancer with secondary gastric neoplastic lesions from lobular and infiltrating ductal breast cancer. Lobular breast cancer is the histological type mostly involved in disseminated disease, with an incidence of 85% of cases. A review of the literature reveals that authors address the clinical and diagnostic problems of differentiating between a breast cancer metastasis to the stomach and a primary gastric cancer using recent diagnostic strategies to make an early diagnosis. Today practitioners have specific tests to detect early gastric cancer metastases of breast cancer such as endoscopic ultrasound, which provides a better endoscopic definition of the lesions, and immunohistochemical markers, able to distinguish the primary lobular histological type from ductal cancer. Besides, an early diagnosis associated with the latest adjuvant systemic therapies and hormonal treatment, alone or in combination, may grant affected patients a remission with a survival rate of 10-28 months, and a reasonable quality of life. At present the surgical approach should be reserved for selected cases and/or complications. PMID- 20726394 TI - A large Brunner's gland adenoma: an unusual cause of gastrointestinal bleeding. Case report and literature review. AB - Brunner's gland adenoma is a rare benign tumour of the duodenum. His most common location is the posterior wall of the duodenum near the junction of its first and second portion. It is usually small and asymptomatic often discovered incidentally with upper gastrointestinal endoscopy, but sometimes may become large causing symptoms (haemorrhage or intestinal obstruction). We report a rare case of a very large Brunner's gland adenoma in a 38-year-old female presenting with severe anaemia but without obstructive symptoms and detected by ultrasonography. The tumour was managed by surgical removal and during a six month follow-up the patient remained symptom-free without any recurrence. The literature on Brunner's gland adenoma is reviewed. PMID- 20726395 TI - Management of a large abdominal wall desmoid tumor during pregnancy. Case report. AB - Desmoid tumors, characterized by aggressive local infiltration of surrounding tissues, are uncommon benign neoplasms with no metastatic potential, that occasionally may attain large size. We report a case of a 37-year-old woman with an abdominal wall desmoid tumor that appeared and grew rapidly during her pregnancy, diagnosed by trucut core biopsy. Complete surgical excision of a 20 x 16 cm in size tumor and immediate reconstruction with mesh was performed in the postpartum period. She had no postoperative complications and no recurrence at 2 year follow-up. Optimal management of large abdominal wall desmoids during pregnancy has to be individualized, with wide surgical excision remaining the treatment of choice. PMID- 20726396 TI - A "dangerous" Italian dish: spaghetti with mussels. PMID- 20726397 TI - Following the money. Foreword. PMID- 20726398 TI - The death of Jesse Gelsinger: new evidence of the influence of money and prestige in human research. PMID- 20726399 TI - Oversight of marketing relationships between physicians and the drug and device industry: a comparative study. AB - Throughout the world, complex mutually-dependent relationships exist between physicians and pharmaceutical and medical device companies. This article focuses on one particular aspect of these relationships-payments made by drug and device companies to physicians and their organizations and institutions to market drugs and devices. It is widely believed that drug and device company marketing to physicians creates conflicts of interest that corrupt physician judgment and increase the cost of medical care. This article examines first the economic basis of physician/industry relationships that causes conflicts to arise. It next considers the measures that a number of developed countries have taken to respond to these relationships. Finally, it proposes an approach that would comprehensively address the problems caused by drug and device company marketing to physicians. PMID- 20726400 TI - Following the money in health care fraud: reflections on a modern-day yellow brick road. PMID- 20726401 TI - Follow the money: money matters in health care, just like in everything else. AB - I suspect that our collective search for villains--for someone to blame--has distracted us and our political leaders from addressing the fundamental causes of our nation's health-care crisis. All of the actors in health care--from doctors to insurers to pharmaceutical companies--work in a heavily regulated, massively subsidized industry full of structural distortions. They all want to serve patients well. But they also all behave rationally in response to the economic incentives those distortions create. Accidentally, but relentlessly, America has built a health-care system with incentives that inexorably generate terrible and perverse results. Incentives that emphasize health care over any other aspect of health and well-being. That emphasize treatment over prevention. That disguise true costs. That favor complexity and discourage transparent competition based on price or quality. PMID- 20726402 TI - Health Law 2010: it's not all about the money. PMID- 20726403 TI - For profit enterprise in health care: can it contribute to health reform? PMID- 20726404 TI - Health reform: what's insurance got to do with it? Recognizing health insurance as a separate species of insurance. PMID- 20726405 TI - Is a flat-line a good thing? On the privatization of Israel's healthcare system. AB - Israel presents an intriguing conundrum: on the one hand, it provides quality healthcare in a near-universal healthcare system; on the other, it has maintained healthcare costs level at approximately 7.7% of GDP. This comes at a time when all western nations struggle with one or both sides of the equation: how to offer affordable, good quality health care to the population while curbing the sharp rise in health related costs. This paper explains both how Israel has achieved this 'flat line" effect and the social and political costs of this achievement. PMID- 20726406 TI - Rib fracture fixation: controversies and technical challenges. AB - Rib fractures are a common injury affecting more than 350,000 people each year in the United States and are associated with respiratory complications, prolonged hospitalization, prolonged pain, long-term disability, and mortality. The social and economic costs that rib fractures contribute to the health care burden of the United States are therefore significant. But despite this measurable impact on patients' quality of life, current treatment of the majority of patients in the United States with rib fracture syndromes is supportive only. Even the most severe of chest wall injuries have historically been treated non-operatively. Recently, however, several reports from American centers support an increased application of operative fixation. With this resurgent interest of American surgeons in mind, we review the clinical presentations, potential indications, controversies, and technical challenges unique to rib fracture fixation. PMID- 20726407 TI - Department of Surgery at the University of Mississippi School of Medicine. PMID- 20726408 TI - The incidence of benign and malignant neoplasia presenting as acute appendicitis. AB - Acute appendicitis remains the most common surgical emergency encountered by the general surgeon. It is most often secondary to lymphoid hyperplasia, however it can also result from obstruction of the appendiceal lumen by a mass. We sought to review our experience with neoplasia presenting as appendicitis. We retrospectively reviewed all patients admitted with the diagnosis of appendicitis to our Acute Care Surgery Service from July 1, 2007 to June 30, 2009. Patient demographics, duration of symptoms, lab findings, computed tomography findings, and pathology were all analyzed. Over the 2-year period, 141 patients underwent urgent appendectomy. Ten patients (7.1%) were diagnosed with neoplasia on final pathology, including four women and six men with a mean age of 46.9 years and mean duration of symptoms of 12.6 days. Final pathology revealed four colonic adenocarcinoma; three mucinous tumors; one carcinoid; one endometrioma; and one patient had a combination of a mucinous cystadenoma, a carcinoid tumor, and endometriosis of the appendix. Six patients had concurrent appendicitis. Colonic and appendiceal neoplasia are not unusual etiologies of appendicitis. These patients tend to present at an older age and with longer duration of symptoms. PMID- 20726409 TI - Mucinous cystic neoplasms of the pancreas: how much preoperative evaluation is needed? AB - Cystic lesions of the pancreas are identified with increasing frequency by modern imaging. The mucinous cystic neoplasm (MCN) is treated with resection for its malignant potential. How much preoperative evaluation is needed before undertaking operation is frequently a diagnostic dilemma. A retrospective review of 32 patients who underwent resection of a MCN between 1994 and 2007 was performed to define the preoperative evaluation and operative treatment of MCN patients. Thirty-two patients (30 women; mean age 49) had histology-proven MCN. Twenty-seven patients had symptomatic cysts (84%). Five had a history of gallstones and/or acute pancreatitis. All patients were worked up with CT and/or MRI. Endoscopic ultrasound was performed in 14 (44%) and endoscopic retrograde cholangiopancreatography in six (18%). Cytology was obtained in 13 (40%). Pathology revealed 22 benign MCNs (68%), five malignant MCNs (16%), and five MCNs with borderline pathology. Preoperative workup including CT or MRI imaging and cytology suggested MCN as the lesion in 15 patients (46%). CT features by itself predicted MCN in three patients (9%). Cytology revealed another six patients (19%) with possible MCN. In this series, preoperative workup did not identify three of five patients with MCN malignancy. A preoperative diagnosis cannot be made in most patients with MCN. Operative treatment can be based on clinical presentation and CT imaging because endoscopic ultrasound and fine needle aspiration for evaluation may be misleading. Middle-aged women with cystic lesions in the tail of the pancreas without prior gallstone or pancreatitis history most typically fit the profile of the MCN patient. PMID- 20726410 TI - Surgical intensive care unit mobility is increased after institution of a computerized mobility order set and intensive care unit mobility protocol: a prospective cohort analysis. AB - In some populations, intensive care unit (ICU) mobility has been shown to be safe and beneficial. We gathered data on 50 nonintubated surgical patients in a 10-bed surgical ICU (SICU) who met physiologic inclusion criteria beginning in May 2008 (A group). In January 2009, we began mandatory entry of computerized mobility orders as part of a standardized ICU order set. We also created a mobility protocol for nurses in this ICU. We then collected data on 50 patients in this postintervention cohort (B group). Both groups had similar baseline characteristics. A group patients had some form of mobility orders entered in 29 patients (58%) versus 47 patients (82%) in the B group, P < 0.05. In the A group, 11 patients (22%) were mobilized; in the B group, 40 patients (80%) were mobilized, P < 0.05. In our SICU patient population, mandatory entry of computerized mobility orders as part of a standard SICU order set and establishment of an ICU mobility nursing protocol was associated with an increase in number of mobility orders entered as well as an increase in SICU patient activity. Further studies should focus on measurement of the effect of mobility interventions on patient outcomes. PMID- 20726411 TI - Extracorporeal gastric stapling reduces the incidence of gastric conduit failure after minimally invasive esophagectomy. AB - Esophageal cancer resection is associated with significant morbidity and mortality. To date, no standardized technique exists. In this study, we analyze our short-term results in 92 minimally invasive resections performed over the past 10 years in an attempt to identify technical factors, which contribute to improved short-term outcomes. A retrospective review of 92 minimally invasive esophagectomies was performed at the Ochsner Clinic Foundation from 1999 through 2009. Data collected included preoperative stage, whether or not preoperative chemoradiation was used, technique of minimally-invasive resection, technique of esophagogastric anastomosis, margin status, anastomotic leak, conduit necrosis, gastric conduit failure of any type, and operative mortality. Gastric stapling was done either laparoscopically (intracorporeal) or through a minilaparotomy (extracorporeal). Ninety-two patients met criteria for this study. There was a significant difference in the incidence of positive gastric margins (P = 0.04), anastomotic leak (P = 0.045), conduit necrosis (P = 0.03), and any gastric conduit failure (P = 0.02) favoring the extracorporeal group. The overall short term morbidity and operative mortality with minimally invasive esophagectomy is comparable to the results obtained with open techniques. A relatively simple modification of the operative technique-performing extracorporeal stapling of the gastric conduit-led to a significant reduction in the incidence of gastric conduit failures when compared with the intracorporeal stapling technique. PMID- 20726413 TI - Laparoscopic sleeve gastrectomy: outcomes at a military training center. AB - Laparoscopic sleeve gastrectomy (LSG) has gained support as a single-staged and stand-alone bariatric procedure. Reports of excess weight loss of 35 to 83 per cent, reduction in comorbidities, and decreased operative morbidity have garnered support for LSG. This study represents an initial outcome analysis of LSG performed solely at a military treatment center. This study is a retrospective analysis of all patients receiving LSG at Dwight D. Eisenhower Army Medical Center from September 2007 to December 2009. The patients were planned for a stand-alone procedure. One hundred and fifteen patients received LSG over this time period with a mean body mass index of 45.5 +/- 6.2 (range 35.1-58.3). The average age was 47.4 +/- 12.5 years. Diabetes mellitus was seen in 47 per cent and 68 per cent of patients had hypertension. The mean and median length of operation was 124 +/- 48 and 115.5 minutes. The mean percentage of excess weight loss was 16.6 +/- 6.40 per cent at 1 month, 31.5 +/- 7.6 per cent at 3 months, 41.2 +/- 13.9 per cent at 6 months, and 53.7 +/- 12.5 per cent at 1 year from surgery. One or more of patient's preoperative diabetic or hypertensive medications were improved postoperatively in 18.7 per cent and 16.3 per cent, respectively. Incidence of major complications occurred in 4.35 per cent of patients in this study to include four leaks (3.4%), one death (0.87%), and 10 readmissions. Midterm analysis of outcomes related to LSG as a single-stage bariatric procedure is promising as long-term outcome data is collected; the efficacy of this procedure as a sole bariatric procedure will continue to be borne out. PMID- 20726412 TI - Outcome after mastectomy for ipsilateral breast tumor recurrence after breast conserving surgery. AB - Ipsilateral breast tumor recurrence (IBTR) is a risk after breast conserving surgery, and is traditionally treated with mastectomy. Given the limited literature on outcome after mastectomy for IBTR, we evaluated our long-term data for this group. A retrospective review was conducted using a database of 2101 breast cancer patients at a single institution. Fifty-nine patients underwent breast conserving surgery and experienced an IBTR. Exclusion criteria included repeat lumpectomy or metastatic disease before mastectomy. Patients presented with invasive ductal (58%), invasive lobular (7%), other invasive (11%), or ductal carcinoma in situ (24%). Initial tumors were Tis (24%), T1 (42%), T2 (20%), T3 (2%), or not recorded (12%). IBTR lesions were Tis (20%), T1 (46%), T2 (25%), or T3 (9%). Median follow-up after mastectomy was 4.6 years. Thirteen patients (22%) had postmastectomy recurrence (PMR), which decreased overall survival (P = 0.002). PMR was more common with larger IBTR tumors (P = 0.03), specifically IBTR > or = T2 (P = 0.003). Eighty-five per cent of PMR occurred within 2 years of mastectomy. Mastectomy for IBTR remains effective treatment for most patients, but the risk of PMR remains. Patients with IBTR tumors >2 cm have an increased risk of PMR. Strict follow-up should be routine, especially during the first 24 months. PMID- 20726414 TI - Analysis of Centers for Medicaid and Medicare Services 'never events' in elderly patients undergoing bowel operations. AB - Since October 2008, the Centers for Medicare and Medicaid Services (CMS) has denied reimbursement for 10 hospital-acquired "never events," which were deemed reasonably preventable. This study compares the frequency and costs of CMS "never events" in patients undergoing bowel operations between ages 65 to 79 years and 80 years or older. Patients aged 65 years or older who underwent small or large bowel operations, from January 2008 to March 2009, were identified by a retrospective review of inpatient charts and the Greenville Hospital System electronic coding database. Outcomes included hospital length of stay (LOS), discharge status, incidence of "never events," and median hospital costs determined by the EPSi cost system. Of 151 patients identified, 118 were age 65 to 79 years old and 33 were 80 years or older. A total of 90 CMS "never events" was found in 64 patients. The most common conditions were surgical site, catheter related urinary tract, and vascular catheter infections. Patients 80 years of age or older had a statistically higher incidence when compared with the age 65- to 79-year-old age group of catheter-related urinary tract infections (UTIs) (36 vs 12%), vascular catheter infections (15 vs 4%), hospital LOS (11 vs 6 days) as well as a greater median hospital cost ($28,300 vs $15,300). It is unclear whether these "never events" are the reason for higher costs or an indicator of more severely ill patients. Nevertheless, it is clear that the additional financial burden of caring for these high-risk, high-cost, elderly patients is clearly borne by the hospital. PMID- 20726415 TI - Mixed flora: indication for therapy or early warning sign? AB - "Mixed flora" is a commonly returned result yielding not in either indication for therapy or identification of potential causative organisms. We sought to determine whether mixed flora (MF) was in fact a harbinger of impending pneumonia or a benign result that could be therapeutically ignored. Bronchoalveolar lavage (BAL) results of injured adults undergoing mechanical ventilation in a trauma intensive care unit were stratified by identified organisms and by colony counts. The incidence of mixed flora as a component of the specimen report was compared for diagnostic (greater than 10(5) colony forming units/mL) versus nondiagnostic results using chi2 accepting P < 0.05 as significant. Nondiagnostic specimens were then stratified as MF only or MF and other identified pathogenic organisms. This group was further evaluated to determine the use of antibiotic therapy and development of pneumonia. Finally, patients with nondiagnostic reports and subsequent BAL were analyzed to determine specific species if subsequent BAL were required or if later pneumonia occurred. During 2007, 159 BALs were performed on injured patients of which 93 were diagnostic for pneumonia, whereas 66 were nondiagnostic. Of the diagnostic specimens, 15 (16%) included mixed flora. Of the 66 nondiagnostic specimens, 39 (59%) contained mixed flora. Nine (60%) of the 15 with diagnostic mixed flora were started on antibiotic therapy for an average of 6.2 days. The remaining 39 (82%) patients with mixed flora received no antibiotic therapy and never developed pneumonia. These data demonstrate that in the absence of diagnostic threshold of an identifiable pathogenic organism, therapy for pneumonia should not be instituted or continued. PMID- 20726416 TI - The Ferguson Operating Anoscope as a minimally invasive option for the treatment of rectal tumors. AB - Transanal excision of rectal tumors may be performed using the Ferguson Operating Anoscope (FOA). This retrospective case series evaluates the effectiveness of FOA for the excision of selected benign and malignant rectal tumors. The office records of 97 patients with rectal tumors who underwent FOA transanal excision by a single surgeon from 1999 through 2009 were reviewed. In the 97 patients evaluated, 99 FOA transanal excisions were performed for 39 adenocarcinomas, 55 benign tumors, and five carcinoid tumors. The tumors were 0.5 to 13.5 cm in diameter and located an average of 6.9 cm (range, 1 to 15 cm) from the anal verge. Ninety-one per cent of cases were performed as an outpatient. Postoperative complications occurred in 14 per cent with transient effects on continence in 2 per cent and a mean blood loss of 66 mL. The recurrence rate for favorable T1 rectal cancers was 4.3 per cent and for adenomas was 5.9 per cent. In early follow up of adenomas and favorable T1 carcinomas, FOA transanal excision has similar application, morbidity, and recurrence rates as reported for transanal endoscopic microsurgery for rectal tumors within 15 cm from the anal verge. FOA may be considered a useful option for the minimally invasive treatment of rectal tumors. PMID- 20726417 TI - Surgical shunting versus transjugular intrahepatic portasystemic shunting for bleeding varices resulting from portal hypertension and cirrhosis: a meta analysis. AB - Surgical shunting was the mainstay in treating portal hypertension for years. Recently, transjugular intrahepatic portasystemic shunting (TIPS) has replaced surgical shunting, first as a "bridge" to transplantation and ultimately as first line therapy for bleeding varices. This study was undertaken to examine evidence from trials comparing TIPS with surgical shunting to reassess the role of surgery in treating portal hypertension. The National Library of Medicine and the National Institutes of Health were searched for clinical trials comparing surgical shunting with TIPS. Meta-analysis using the fixed effects model was undertaken with end points of 30-day and 1- and 2-year survival and shunt failure (inability to complete shunt, irreversible shunt occlusion, major rehemorrhage, unanticipated liver transplantation, death). Three prospective randomized trials and one retrospective case-controlled study were identified. Analysis was limited to patients of Child Classes A or B. Significantly better 2-year survival (OR 2.5 [1.2-5.2]) and significantly less frequent shunt failure (OR 0.3 [0.1-0.9]) were seen in patients undergoing surgical shunting compared with TIPS. Meta-analysis promotes surgical shunting relative to TIPS because of improved survival and less frequent shunt failure. Surgical shunting should be accepted as first-line therapy for bleeding varices resulting from portal hypertension. PMID- 20726418 TI - Aggressive operative treatment for emetogenic rupture yields superior results. AB - The treatment of emetogenic rupture remained controversial and was particularly so when the patient arrived for definitive care greater than 24 hours postrupture. We treated patients with continued extravasation of contrast from the esophagus by early operation regardless of the timing of their presentation. All primary repairs received a reinforced closure and many delayed repairs had an onlay flap for closure of the leak. We treated 31 patients with emetogenic rupture; 24 of 25 patients with extravasation had operative repair, whereas six with small, contained ruptures were treated medically. Twelve were operated on within 24 hours, whereas 24 presented from 36 to 796 hours postrupture. We were able to achieve closure of the defect by primary suture repair or with a tissue flap in all patients. There were no postoperative leaks. One patient each died in the operated group and observed group. There were minimal complications and a relatively short hospital stay. Our results support the use of aggressive operative treatment for emetogenic rupture regardless of the timing of patient presentation. Such treatment preserved esophageal function and was accomplished with relatively low morbidity and mortality. PMID- 20726419 TI - Anastomotic leak rate after low anterior resection for rectal cancer after chemoradiation therapy. AB - Anastomotic leak may be the most concerning complication after colorectal anastomosis. To compare open with laparoscopic rectal resection, we must have accurate leak rates in patients who have received neoadjuvant chemoradiation therapy to serve as a benchmark for comparison. All patients who had preoperative chemoradiation therapy with rectal resection and low pelvic anastomosis for cancer in a single colorectal practice over a 7-year period were retrospectively reviewed. All patients had proximal diversion and a contrast enema study before stoma reversal. Eighty-seven consecutive patients were included in the study. Average age was 58 years. Fifty-nine per cent of patients were male. Sixty-six per cent were smokers. Pathologic T stage was 5 per cent T0, 16 per cent T1, 28 per cent T2, 47 per cent T3, and 5 per cent T4. Seventy-five per cent of patients were pathologically lymph node-negative. Average time to stoma reversal was 122 days. Total anastomotic leak rate was 10.3 per cent (8% clinical leaks). Five (56%) patients with leak successfully underwent reversal of their diverting stoma (average time to reversal, 290 days). Patients who had the complication of anastomotic leakage had less likelihood of stoma reversal and a significantly prolonged time to stoma reversal. PMID- 20726420 TI - Combined analysis of allograft inflammatory factor-1, interleukin-18, and Toll like receptor expression and association with allograft rejection and coronary vasculopathy. AB - In cardiac transplantation settings, the initial myocardial ischemia and reperfusion may cause myocyte tissue injury and the release of allograft inflammatory factor-1 (AIF-1). This in part may trigger the innate immune response through the modulation of Toll-like receptor-2 (TLR-2) and AIF-1 expression and function, causing the release of proinflammatory cytokines. The goal was to demonstrate these markers in the peripheral blood and biopsy specimen from recipients with cardiac allograft rejection and coronary vasculopathy (CV). Peripheral blood and endomyocardial specimens were tested by reverse transcriptase-polymerase chain reaction and immunohistochemistry stains for identification of TLR-2, -4, interleukin-18, and AIF-1 markers and analyzed against clinical rejection grades for rejection. The differences for mRNA transcript levels were determined by one-way analysis of variance. The mRNA expression levels were significantly varied for TLR-2 in monocytes with different rejection grades (P < 0.0001). The mean +/- SEM level of mRNA expression for 3A grade rejection was 64.21 +/- 3.8; grade 1A, 38.4 +/- 3.5; and for Grade 0 was 38.46 +/- 2.8. The TLR-4 mRNA expression was increased but the specificity was not statistically significant. The TLR-2 immunoreactivity was strongly detected in infiltrating mononuclear cells and cardiac myocytes in Grade 3A rejection. AIF 1 expression was increased significantly in the group with 3A rejection and Grade III CV as compared with Grade 0 or 1A. Interleukin-18 receptors were strongly detected in Grade 3A rejection and CV. The expression profiles of AIF-1, TLR-2, and interleukin-18 were correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting a potential for diagnostic biomarkers for early detection of allograft rejection. PMID- 20726421 TI - Does a family history of male breast cancer influence risk perception and use of genetic testing? AB - We sought to determine differences in risk perception and use of genetic testing in these individuals compared with those with a family history of female breast cancer (FHxFBC) in a population-based cohort. Data from the 2005 National Health Interview Survey were used to assess risk perception and use of genetic counseling in individuals with a family history of male breast cancer (FHxMBC) versus those with a FHxFBC. Of the 2429 individuals with a first-degree relative with breast cancer surveyed, 21 (0.7%) had a FHxMBC, whereas 2408 (99.3%) had a FHxFBC. Women who had a FHxMBC perceived themselves as being at higher risk for developing breast cancer than those with a FHxFBC (61.5 vs 46.5%, P = 0.011). Fewer individuals with a FHxMBC had heard about genetic testing than those with a FHxFBC (38.4 vs 50.8%, P = 0.322). Of these, none of the individuals with a FHxMBC discussed this with their physician (vs 13% of individuals with a FHxFBC, P = 0.004) and none underwent genetic testing (vs 3% of individuals with a FHxFBC, P = 0.009). Women with a FHxMBC perceive this as being associated with increased cancer risk, but few discuss this with their physicians. Physicians should be proactive in discussing risk with these patients. PMID- 20726422 TI - Role of hepatic portocholecystostomy ('gallbladder Kasai') in treating infants with biliary atresia. AB - The aim of this study is to compare liver function and cholangitis episodes during the first year postoperatively between patients who undergo hepatic portocholecystostomy (HPC) and patients who undergo hepatic portoenterostomy (HPE). Records of six patients who underwent HPC for biliary atresia (BA) and 27 patients who underwent HPE for BA were reviewed retrospectively. Comparison was done of the patient's total bilirubin, albumin, and international normalized ratio values preoperatively and at 3 months, 6 months, and 1 year postoperatively. Comparison was also done of the occurrence of ascending cholangitis during the first year postoperatively and in rates of transplant and mortality during long-term follow-up. Preoperative laboratory values between the two groups were not significantly different. At 6 months, the patients who underwent HPC had significantly lower total bilirubin levels compared with those who underwent HPE (HPC 0.8 +/- 0.96, n = 4; HPE 4.93 +/- 7.73, n = 21; P < 0.05). No other laboratory values or rates of ascending cholangitis, transplant, or mortality showed a significant difference. Those patients who underwent HPC had significantly lower total bilirubin levels at 6 months postoperatively. This may suggest that HPC may be a superior operative technique for patients who are candidates for the operation. PMID- 20726423 TI - Rib fracture patterns predict thoracic chest wall and abdominal solid organ injury. AB - Blunt trauma patients with rib fractures were studied to determine whether the number of rib fractures or their patterns were more predictive of abdominal solid organ injury and/or other thoracic trauma. Rib fractures were characterized as upper zone (ribs 1 to 4), midzone (ribs 5 to 8), and lower zone (ribs 9 to 12). Findings of sternal and scapular fractures, pulmonary contusions, and solid organ injures (liver, spleen, kidney) were characterized by the total number and predominant zone of ribs fractured. There were 296 men and 14 women. There were 38 patients with scapular fracture and 19 patients with sternal fractures. There were 90 patients with 116 solid organ injuries: liver (n = 42), kidney (n = 27), and spleen (n = 47). Lower rib fractures, whether zone-limited or overlapping, were highly predictive of solid organ injury when compared with upper and midzones. Scapular and sternal fractures were more common with upper zone fractures and pulmonary contusions increased with the number of fractured ribs. Multiple rib fractures involving the lower ribs have a high association with solid organ injury, 51 per cent in this series. The increasing number of rib fractures enhanced the likelihood of other chest wall and pulmonary injuries but did not affect the incidence of solid organ injury. PMID- 20726424 TI - Postcolonoscopy appendicitis. AB - Outpatient colonoscopy has been proven safe but can rarely be associated with serious complications. The addition of polypectomy to the procedure increases the incidence of all complications with hemorrhage accounting for approximately half. The use of electrocautery for hot biopsy or polyp removal can result in a full thickness burn without perforation in approximately 1 per cent of cases and typically presents as focal peritonitis without pneumoperitoneum. This so-called "postpolypectomy syndrome" or "serositis" is often successfully managed medically with resolution of symptoms in 24 to 48 hours. Bowel perforation occurs in less than 1 per cent of patients but requires emergent laparotomy. Appendicitis, both acute and perforated, has been reported as a rare complication of colonoscopy. PMID- 20726425 TI - Gender differences in glucose variability after severe trauma. AB - Gender differences in the physiological response to trauma can affect outcome. Both hyperglycemia and blood glucose (BG) variability predict a poor outcome after trauma. This study examined the hypothesis that both BG levels and the degree of BG variability after trauma are gender-specific and correlate with mortality and morbidity. A retrospective observational cohort study of 1915 trauma patients requiring critical care was performed. Admission BG as well as all BG values obtained during the first week while in the intensive care unit were analyzed. In each patient, the mean BG and the degree of BG variability were calculated. A total of 1560 males and 355 females were studied with an overall mortality rate of 12 per cent. Seventy-six per cent of deaths had a BG greater than 125 mg/dL on admission and as BG variability worsened, the mortality rate also increased. There was a significant difference in male BG variability when comparing survivors with nonsurvivors. Female BG variability did not predict mortality. Failed glucose homeostasis is an important marker of endocrine dysfunction after severe injury. Increased BG variability in males is associated with a higher mortality rate. In females, mortality cannot be predicted based on BG levels or BG variability. These data have significant implications for gender related differences in postinjury management. PMID- 20726426 TI - Giant gastrointestinal stromal tumor with remarkable preoperative response to imatinib mesylate. PMID- 20726427 TI - Jejunal diverticulosis. PMID- 20726428 TI - Appendiceal intussusception resulting from endometriosis presenting as acute appendicitis. PMID- 20726429 TI - Colonic perforation by a dormant peritoneal dialysis catheter post renal transplantation. PMID- 20726430 TI - Penetrating aortic ulcer associated with juxtarenal aortic occlusion. PMID- 20726431 TI - Blunt traumatic abdominal aortic dissection and concomitant traumatic abdominal wall hernia and small bowel injury: a surgical conundrum. PMID- 20726432 TI - Discernment and better treatment of a clenched fist with a multidisciplinary approach. PMID- 20726433 TI - Traumatic dissection of the left anterior descending coronary artery after blunt torso trauma. PMID- 20726434 TI - Esophageal injury from cervical spine fracture in blunt trauma. PMID- 20726435 TI - Osteochondroma of the symphysis pubis: a rare cause of bladder outlet obstruction. PMID- 20726436 TI - Sclerosing mucoepidermoid thyroid carcinoma requiring cervical reconstruction: a case report and review of the literature. PMID- 20726437 TI - Monochorionic diamniotic twin pregnancies pregnancy outcome, risk stratification and lessons learnt from placental examination. AB - Monochorionic diamniotic twin pregnancies have a more hazardous intrauterine stay than their dichorionic counterparts because of the vascular anastomoses that connect the two fetal circulations. The survival of monochorionic twins diagnosed in the first trimester is 89%. Twin-to-twin transfusion syndrome (TTTS) occurs in 9% and is the most important cause of death. Risk assessment by ultrasound scan in the first and early second trimester identifies a subgroup of monochorionic twins with a more than 70% risk of a complicated outcome and a survival rate of only 69%. For complicated monochorionic twin pregnancies, umbilical cord coagulation for selective feticide has a survival rate of 83% with a normal development in 92%. Umbilical cord coagulation also results in a good outcome for the healthy co-twin of a heterokaryotypic monochorionic pair. Unequally shared placentas have a more elaborate blood exchange, which reduces the birthweight discordance. In these cases, the anastomoses fulfill a beneficial role by increasing the availability of oxygen and nutrients to the twin on the smaller placental share. Pairs with early onset discordant growth have a higher mortality and a more unequally shared placenta than pairs with late onset discordant growth. Unequal placental sharing therefore appears to be the cause of early onset discordant growth, whereas a late intertwin transfusion imbalance may be involved in some cases with late onset discordant growth. Finally, placental examination after laser treatment for TTTS demonstrated that successful coagulation of all visible anastomoses cures TTTS. However, anastomoses can be missed and lead to a complicated pregnancy outcome. PMID- 20726438 TI - Intimate partner violence. The gynaecologist's perspective. AB - From a questionnaire-based surveillance study among pregnant women constituting a regional probability sample of East-Flanders, we estimated that IPV occurred overall with one in ten women (10.1%, 95% CI 7.7-13.0%) and with about one in 30 women (3.4%, 95% CI 2.1-5.4%) during pregnancy and/or in the year preceding pregnancy. We also revealed that women experiencing IPV rarely disclose abuse spontaneously to the widely available health care services and providers, but in general approve routine questioning by their GP or gynaecologist. The crux of IPV is that most victims will not present with overt signs of abuse, but rather with a wide variety of vague and non-specific symptoms, if any. Hence there seems to exist a window of opportunities to detect women suffering from IPV through screening in the health care sector. From a questionnaire based Knowledge Practice and Attitude Survey among OB/GYN in Flanders, it appeared that OB/GYN feel uncomfortable with a routine screening policy. They underestimate the prevalence and perceive a lack of self-efficacy in dealing with the problem and properly referring patients, they lack time and perceive it as inappropriate to question patients about IPV. On the other hand they acknowledge that there is a need for training on violence. It therefore appears that most barriers should be remediable through proper OB/GYN training and education, together with enabling strategies such as screening tools and formal referral pathways. In concordance with the National Action Plan to combat IPV, health care workers, including gynaecologists, need to develop guidelines, in order to deal with this important public health problem. PMID- 20726439 TI - [Vascular endothelial growth factor (VEGF) and modulation of wound healing after glaucoma surgery]. AB - Glaucoma is an important cause of blindness. Therefore, the optimalisation of glaucoma surgery might have an important impact on the visual prognosis and the quality of life of glaucoma patients. This project focuses on the development of antifibrotic strategies that would inhibit the scarring of the created fistula, and thus improve the outcome after glaucoma surgery. We found that the vascular growth factor VEGF that is mostly known for its role in blood vessel formation also plays a role in postoperative wound healing. Furthermore, we studied the potential of anti-VEGF therapy to inhibit excessive wound healing (scar formation) after glaucoma surgery. Indeed, both in vitro and in vivo, VEGF prove to be efficacious to reduce scar formation, and thus improve the prognosis after glaucoma surgery. This fundamental research translated into a prospective clinical study, in which anti-VEGF is administered during glaucoma surgery, to improve the outcome after the surgery. We therefore hope that this translational research will indeed result in a better prognosis and quality of life for our glaucoma patients. PMID- 20726440 TI - Identification and characterization of novel oncogenes in chronic eosinophilic leukemia and T-cell acute lymphoblastic leukemia. AB - Research conducted in my group in the period 2006-2009 has led to a better understanding of the oncogenic mechanisms of the FIP1L1-PDGFRA and NUP214-ABL1 oncogenes. Insights into these mechanisms may help us to design novel strategies to treat leukemia. In addition, we have identified the small molecule inhibitor sorafenib as a potent inhibitor of the FIP1L1-PDGFRA and its T674I imatinib resistant mutant. Sorafenib was originally developed as a BRAF inhibitor, but our work demonstrates that sorafenib can also be used to treat FIP1L1-PDGFRA positive leukemia, demonstrating that new therapies to treat rare leukemias may be simply found by testing drugs that are already in use for the treatment of other diseases. Finally, using genome-wide screening approaches, we have identified the MYB gene as a novel oncogene implicated in the pathogenesis of T-ALL, and we suggest that MYB may represent a novel target for therapy in T-ALL as well as in other cancers. PMID- 20726441 TI - Beta-cell transplantation in type 1 diabetic patients: a work in progress to cure. AB - Type 1 diabetes is characterized by a selective destruction of the insulin producing beta-cells leading to frank hyperglycemia. Daily insulin injections are lifesaving but can often not avoid suboptimal glycemic control, an increased risk for hypoglycemia and the development of chronic diabetic complications. Therapies replacing the destroyed beta-cells aim to prevent or delay these detrimental complications while avoiding hypoglycemic episodes. The main objective of our multicenter study was to define conditions under which a beta-cell implant safely induces and maintains long-term metabolic control in type 1 diabetic recipients. We demonstrated that cultured beta-cell preparations, fully morphologically characterized by their cell number and cellular composition, and functionally correlated with beta-cell mass can be used to prepare grafts with reproducible clinical metabolic outcome. At least 2 million beta-cells per kg bodyweight were needed to achieve signs of functioning grafts, reduced glycemic variability and a reduced risk for hypoglycemic events. We demonstrated that the hyperglycemic clamp can be used to measure the in vivo functional beta-cell mass after transplantation. In insulin independent recipients of a beta-cell and pancreas kidney graft, the functional beta-cell mass represents respectively 25 and 63% of that in healthy controls. We showed that ATG-sirolimus monotherapy resulted in a worse outcome of beta-cell transplantation compared to ATG-sirolimus-tacrolimus combination therapy. Moreover, use of sirolimus was accompanied with unacceptable side effects. In conclusion, we showed that characterizing the beta-cell graft in vitro, measuring the functional beta-cell mass in vivo and defining a save and efficient immunosuppressive regimen are important steps to a cure for diabetes. PMID- 20726442 TI - Surgical resection of lung metastases including the role of locoregional therapy. AB - Although no randomized trials are available, surgical resection is a widely accepted treatment for selected patients with pulmonary metastases. Specific criteria have been well defined and a macroscopic complete resection should be obtained. Important prognostic factors include histology, number of metastases and disease-free interval. However, even after complete resection, 5-year survival rates remain disappointingly low and many patients will have recurrent disease confined to the chest. For this reason, locoregional therapies are extensively investigated at the present time. These include biochemical and biophysical methods. Due to toxicity of high doses of intravenous chemotherapy, the main purpose is to deliver high-dose chemotherapy to the lung without systemic side-effects. Chemo-embolization, pulmonary artery infusion and isolated lung perfusion are most intensively studied. These techniques were found to be feasible and are able to deliver a high local concentration of chemotherapeutic drugs. The results of further phase II trials are awaited for to determine their effect on local recurrence and long-term survival. PMID- 20726443 TI - Complementary and alternative medicine: a conundrum. PMID- 20726444 TI - Post-polio syndrome--polio's legacy. PMID- 20726445 TI - Early reperfusion treatment for ST-elevation myocardial infarction: national guidance. PMID- 20726446 TI - Future physician: changing doctors in changing times. PMID- 20726447 TI - Dementia care in the acute district general hospital. AB - Morbidity and mortality for any physical illness treated in hospital and complicated by dementia is increased. Length of stay is also prolonged for any physical illness and dementia. Poor uncoordinated hospital care contributes to increased rates of nursing home admissions. Improvement in acute sector care for dementia patients should have a higher priority. Enhanced communication with patients and carers, more attention to hydration and nutrition and improved environmental factors within the hospital would be a start. All NHS staff require an increased insight and training about the consequences of physical illness complicated with dementia. PMID- 20726448 TI - A randomised trial of peer review: the UK National Chronic Obstructive Pulmonary Disease Resources and Outcomes Project. AB - Peer review has been widely employed within the NHS to facilitate health quality improvement but has not been rigorously evaluated. This article reports the largest randomised trial of peer review ever conducted in the UK. The peer review intervention was a reciprocal supportive exercise that included clinicians, hospital management, commissioners and patients which focused on the quality of the provision of four specific evidence-based aspects of chronic obstructive pulmonary disease care. Follow up at 12 months demonstrated few quantitative differences in the number or quality of services offered in the two groups. Qualitative data in contrast suggested many benefits of peer review in most but not all intervention units and some control teams. Findings suggest peer review in this format is a positive experience for most participants but is ineffective in some situations. Its longer term benefits and cost effectiveness require further study. The generic findings of this study have potential implications for the application of peer review throughout the NHS. PMID- 20726449 TI - Patient safety matters: reducing the risks of nasogastric tubes. AB - Nasogastric tube insertion is a common clinical procedure carried out by doctors and nurses in NHS hospitals daily. For the last 30 years, there have been reports in the medical literature of deaths and other harm resulting from misplaced nasogastric tubes, most commonly associated with feed entering the pulmonary system. In 2005 the National Patient Safety Agency in England assembled reports of 11 deaths and one incident of serious harm from wrong insertion of nasogastric tubes over a two-year period. The agency issued a safety alert setting out evidence-based practice for checking tube placement. In the two and a half years following this alert the problem persisted with a further five deaths and six instances of serious harm due to nasogastric tube misplacement. This is a potentially preventable error but safety alerts advocating best practice do not appear to reliably reduce risk. Alternative solutions, such as standardising procedures, may be more effective. PMID- 20726450 TI - Time for change: teaching and learning on busy post-take ward rounds. PMID- 20726451 TI - Care home medicine. AB - Care homes are changing, with improved standards and expanding roles, and it is vital that their residents are not excluded or discriminated against by health and social services. Staff are keen to be educated, and investment of time and money is rewarded with improved outcomes in many areas. PMID- 20726452 TI - Expanding boundaries of endocrinology. AB - There have been huge advances in endocrine care as a consequence of improved biochemistry and diagnostic techniques as well as improved imaging. Specialist transethmoidal endoscopic surgery has improved results in pituitary tumour patients and minimally invasive parathyroid surgery has had the same consequence in patients with parathyroid disease. Multidisciplinary teams have improved outcomes in a number of areas and, as described above, endocrinologists are dealing with more in the way of endocrine disease to expand boundaries. Much work remains to be done particularly concerning the care of children and adults with late endocrine effects of cancer treatment and obesity. PMID- 20726453 TI - The medical humanities: literature and medicine. AB - The medical humanities attempt to emphasise the subjective experience of patients within the objective and scientific world of medicine. This article argues that the goal of medical humanities can be furthered by literature. Autobiographical accounts are used to illustrate the various ways in which literature can influence and enrich medical practice. PMID- 20726454 TI - A diagnostic challenge in peripheral neuropathy. PMID- 20726455 TI - Medicine as a profession. AB - Over half a century ago, a Canadian judge defined a profession in a way that resonates still today, not only for lawyers and doctors, but for the current wide variety of professions and professionals. This article is a reflection on this definition. It briefly considers the historical context within which the knowledge base that characterises a profession evolved and what the various component parts of the judge's definition entail. A final consideration goes beyond the terms of the definition proposed--that of our ethical responsibility as professionals to stand up and be counted and, in the context of the disorder around us, to speak out. PMID- 20726456 TI - Rheumatoid arthritis: assessing disease activity and outcome. AB - The range of treatments for rheumatoid arthritis (RA) has increased significantly in recent years, with a parallel improvement in patient outcome. The development and assessment of new therapies and therapeutic strategies relies on the availability of valid and reliable outcome measures to assess the diverse impact of RA on the patient's life. This paper reviews the outcome measures in current use which assess disease activity, joint damage, physical function and health related quality of life. Some measures have been combined into composite indices which are useful for summarising the patient's current condition and as primary outcome measures for clinical trials. There is still a need for better and more relevant tools especially for imaging multiple joints and for assessing fatigue. PMID- 20726457 TI - Motor neurone disease: a practical update on diagnosis and management. AB - Motor neurone disease (MND) is an adult-onset neurodegenerative disease which leads inexorably via weakness of limb, bulbar and respiratory muscles to death from respiratory failure three to five years later. Most MND is sporadic but approximately 10% is inherited. In exciting recent breakthroughs two new MND genes have been identified. Diagnosis is clinical and sometimes difficult- treatable mimics must be excluded before the diagnosis is ascribed. Riluzole prolongs life by only three to four months and is only available for the amyotrophic lateral sclerosis (ALS) form of MND. Management therefore properly focuses on symptom relief and the preservation of independence and quality of life. Malnutrition is a poor prognostic factor. In appropriate patients enteral feeding is recommended although its use has yet to be shown to improve survival. In ALS patients with respiratory failure and good or only moderately impaired bulbar function non-invasive positive pressure ventilation prolongs life and improves quality of life. PMID- 20726458 TI - Trends in European liver death rates: implications for alcohol policy. AB - Changing alcohol consumption has led to a three- to fivefold increase in liver deaths in the UK and Finland, and a three- to fivefold decrease in France and Italy. Increasing consumption from a low baseline has been driven by fiscal, marketing and commercial factors--some of which have occurred as a result of countries joining the EU. In contrast consumption has fallen from previously very high levels as a result of shifting social and cultural factors; a move from rural to urban lifestyles and increased health consciousness. The marketing drive in these countries has had to shift from a model based on quantity to one based on quality, which means that health gains have occurred alongside a steady improvement in the overall value of the wine industry. Fiscal incentives--minimum pricing, restricting cross border trade and more volumetric taxation could aid this shift. A healthier population and a healthy drinks industry are not incompatible. PMID- 20726459 TI - A complicated hyperglycaemic emergency. PMID- 20726460 TI - Audit of treatment of Staphylococcus aureus bacteraemia. AB - Staphylococcus aureus bacteraemia remains a significant cause of morbidity and mortality. National guidelines recommend that a minimum of 14 days of antibiotics should be used to treat uncomplicated bacteraemia. Five hospitals in the East Midlands region conducted a retrospective audit to assess compliance to these guidelines before and after the introduction of extra text to laboratory reports of S. aureus bacteraemia advising clinicians on the minimum length of treatment. Introduction of this extra text resulted in an increase in compliance with the national recommendation from 44% to 60%. This increase in compliance was noted in both methicillin-sensitive S. aureus (45% versus 58%) and methicillin-resistant S. aureus (42% versus 62%) bacteraemia. This audit demonstrated a simple and effective intervention that has improved the treatment of this potentially life threatening condition. PMID- 20726461 TI - Concise guidance: diagnosis and management of polymyalgia rheumatica. AB - Polymyalgia rheumatica (PMR) is among the most common reasons for long-term steroid prescription with great heterogeneity in presentation, response to steroids and disease course. The British Society for Rheumatology and the British Health Professionals in Rheumatology have recently published guidelines on management of PMR. The purpose of this concise guidance is to draw attention to the full guidelines and provide a safe and specific diagnostic process with advice on management and monitoring--specifically targeted at general practitioners, general physicians and rheumatologists. PMID- 20726462 TI - Advance care planning. PMID- 20726463 TI - Palliative and end-of-life care in advanced renal failure. AB - There is a recognised need to provide palliative care services for patients with AKD. Such services can improve end-of-life care for patients withdrawing from dialysis and those choosing not to have dialysis. Developments in such services should lead to measurable advances in patients' experiences. PMID- 20726464 TI - Ethical and legal issues in end-of-life care. AB - The doctor has a responsibility to develop and maintain an effective approach to ethical decision making and the skills to implement the correct moral action. At the heart of this process is the experience and knowledge of particular conditions and their outcomes, alongside excellence in communication skills and working with colleagues. PMID- 20726465 TI - Palliative and end-of-life care for patients with chronic heart failure and chronic lung disease. PMID- 20726466 TI - Palliative and end-of-life care in advanced Parkinson's disease and multiple sclerosis. PMID- 20726467 TI - Letting go. PMID- 20726468 TI - Subacute small bowel obstruction due to diaphragm disease. PMID- 20726469 TI - Typhoid without travel. PMID- 20726470 TI - Acute medical care. PMID- 20726471 TI - Failure in prescribed medications being given to inpatients. PMID- 20726472 TI - Do medical patients know the name of their consultant? PMID- 20726473 TI - Conversations with Charles. Death and immortality. PMID- 20726474 TI - [A journey through time and space]. PMID- 20726476 TI - [What we say is what we mean]. PMID- 20726475 TI - [High nursing quality makes the workplace attractive]. PMID- 20726478 TI - [Conditions can be improved]. PMID- 20726477 TI - [Something is happening in this hospital]. PMID- 20726479 TI - [Hand must be washed with strong soap and must be disinfected]. PMID- 20726480 TI - [Clever nurses need space]. PMID- 20726481 TI - [Pride about the past--strength for the future]. PMID- 20726482 TI - [Nursing personnel deserve more attention]. PMID- 20726483 TI - [Planning, computer, costs--an explosion in nursing progress]. PMID- 20726484 TI - [Ruin prevention wins the first prize]. PMID- 20726485 TI - [So that the Alpine summer will not end in two weeks]. PMID- 20726486 TI - [The spirit of family]. PMID- 20726487 TI - [How to tame the adolescent diabetic]. PMID- 20726488 TI - [Thought turns to the future, the past is in the heart]. PMID- 20726489 TI - [Reticence in newly-trained aides]. PMID- 20726490 TI - [Care as opposed to world-wild neo-liberalization]. PMID- 20726491 TI - [Can profession and family really not be reconciled?]. PMID- 20726492 TI - [Optimal hygiene of the primary teeth]. PMID- 20726493 TI - [Nutritional advice of great importance to prevent dental caries]. PMID- 20726494 TI - [Plastic surgery of oroantral perforations superfluous in the future?]. AB - An oroantral perforation can occur with the extraction of a premolar or molar in the upper jaw. Small perforations with a deep extraction alveolus can be treated using sutures only; larger perforations are treated surgically, using a buccal sliding or palatal flap. The distinction between small and large perforations can be difficult to make. As a result, oroantral perforations are usually treated by plastic closure. This pilot study presents a new, simple, time-reducing method for the treatment of oroantral perforations using a biodegradable membrane without primary closure of the wound. Six patients with a positive nose-blowing test after extraction were treated according to the new method. In all 6 patients the oroantral perforation was closed after 2 weeks and each showed adequate wound healing after 6 weeks. More research is needed to confirm the results of this preliminary study and the use of this technique on larger perforations. PMID- 20726495 TI - [The workings of the Drug Bulletin]. AB - The Dutch Drug Bulletin (Geneesmiddelenbulletin) is a monthly journal with a unique approach which, after a hectic period in which its independence and even its right to exist were threatened, has now reached calm water The continued existence of the Dutch Drug Bulletin is now guaranteed, independently of the pharmaceutical industry, the government, professional organizations and patient organizations. Articles appear in the Dutch Drug Bulletin after extensive consultation among various experts. Conclusions are based on the published (and hence controllable) results of randomized, preferably double-blind, studies with an appropriate control group. Departures from these standards are made only in highly exceptional cases. The Dutch Drug Bulletin determines the place of new drugs amongst the already available drugs and compares their effectiveness and side effects with those of the standard therapy. This approach guarantees that dentists and physicians are kept up to date with respect to developments in the field of pharmacology, without the pharmaceutical industry or the government exerting any influence. PMID- 20726496 TI - [Alopecia areata]. PMID- 20726497 TI - [Amyotrophic lateral sclerosis]. AB - Amyotrophic lateral sclerosis is one of the most severe and disabling diseases of the nervous system. Amyotrophic lateral sclerosis leads to the progressive weakening of the muscles in the arms, legs, face, mouth and trunk. The onset of the disease is insidious, starting with weakness in the hands or feet or with slurred speech. The weakness worsens and patients pass away as a result of weakness of the respiratory muscles on average within 3 years of the onset of the disease. In the Netherlands, approximately 400 patients are diagnosed with amyotrophic lateral sclerosis every year. There is no diagnostic test for this neuro-muscular disease; the diagnosis is established by excluding other disorders that resemble amyotrophic lateral sclerosis. Only one drug is able to inhibit the progression of the disease to any extent: riluzole. Treatment, therefore, is mainly focused on supportive measures and those which enhance the quality of life optimally. PMID- 20726498 TI - [A toxic reaction of the oral mucosa to alendronate (Fosamax)]. AB - A 90-year old woman attended a department of Oral and Maxillofacial Surgery with a tongue that had been painful for at least 3 months. Clinical examination revealed extensive bullous and ulcerative lesions located on the tongue, the oral vestibule and the buccal mucosa on both sides. A variety of diseases may be causative of ulcerative stomatitis: autoimmune diseases (like Pemphigus vulgaris, Erosive Lichen Planus, SLE or M. Crohn), or a viral, bacterial or mycotical infection, vitamin deficiency, a toxic reaction to medication or an immune deficiency. After an extensive, clinical examination, a definitive diagnosis still had not been achieved. The patient suffered from osteoporosis, for which she used alendronate (Fosamax). A study of the literature described a possible relationship between the occurrence of oral ulcers and the use of oral biphosphonates. Since a toxic reaction to alendronate was suspected, the use of Fosamax tablets was suspended. Three months later a complete recovery of the oral mucosa was observed. PMID- 20726499 TI - [The pursuit of facial harmony]. AB - In the treatment of patients with an oro-facial anomaly the functioning of the masticatory system and aesthetic aspects play a role. Recently, the software programme 'Facial Harmony', which analyzes the soft tissue contour of the face, appeared. Using this programme, a research project was carried out to find out if the result of the surgical treatment of 40 patients with an oro-facial anomaly satisfied the,facial harmony requirements. Only 65% of the treatment results met the requirements. It was especially the patients who had been treated for mandibular deficiency with mandibular and horizontal lines meeting at a wide angle who showed no facial harmony. Only 30% of those patients demonstrated facial harmony postoperatively. If the surgical treatment had been completed by a genioplasty, this percentage would very probably have risen to 85. PMID- 20726500 TI - [Prevention of falls by elderly people in oral health care practices]. AB - Oral health care practices are ever more frequently visited by frail elderly people. Frail elderly people are at risk for fall accidents due to intrinsic and extrinsic factors. Intrinsic factors are patient-related and extrinsic factors are environment-related. Significant intrinsic fall risk factors for elderly people are orthostatic and postprandial hypotension. The most important effect of hypotension is cerebral hypoperfusion, which can induce syncope and fall. Five to ten per cent of fall accidents of elderly people result in trauma. A serious trauma with possible extreme consequences is hip fracture. One year after a surgical hip fracture treatment of elderly people, 25% are experiencing mobility impairment and 25% have died as a result of co-morbidity or complications. Fall prevention deserves serious attention. Provision of information and strengthening and protecting bones are important prevention measures. In an oral health care practice, general risks of falling must be inventoried on a regular basis, and each (frail) elderly patient should be provided with individual fall-prevention guidance. PMID- 20726501 TI - Rapid capsular phimosis in retinitis pigmentosa. AB - This case report retrospectively reviews the outcome of a 43-year-old man with retinitis pigmentosa who suffered rapid anterior capsular phimosis in each eye within 3 weeks following uncomplicated phacoemulsification with continuous curvilinear capsulorrhexis and single-piece acrylic intraocular lens (IOL) implantation. Anterior YAG capsulotomy was successfully performed in both eyes. It has been previously documented in the literature that capsular phimosis is more common in patients with retinitis pigmentosa. However, in the cases that were reviewed, capsular contracture progressed much less rapidly than in this patient. It is proposed that zonular dehiscence or increased lens epithelial cell fibrosis accompanying retinitis pigmentosa may be responsible for phimosis following phacoemulsification; in this case, the single-piece IOL may have offered less resistance to capsular contraction. Using a three-piece IOL, capsular tension ring, or making radial relaxing incisions in the anterior lens capsule may be useful approaches to minimize the aforementioned complications in patients with retinitis pigmentosa and cataracts. PMID- 20726502 TI - A panel of cancer-testis genes exhibiting broad-spectrum expression in haematological malignancies. AB - Cancer-testis (CT) antigens/genes show restricted expression in normal tissues but widespread expression in many tumour types. This, coupled with their ability to induce cytotoxic T-lymphocyte responses, makes them attractive vaccine candidates. Following our identification of PASD1, we have used RT-PCR to analyse the mRNA expression profile of a large panel of CT genes in cell lines derived from haematological malignancies, and have studied Sp17 protein expression in the same cell lines and diffuse large B-cell lymphoma (DLBCL) biopsies. Our extensive analysis revealed multiple CT transcripts exhibiting widespread expression across cell lines derived from 21 B- and 4 T-cell malignancies. The broadest mRNA expression profiles were observed for the following eight CT genes: Sp17 (25/25), PRAME (25/25), CSAGE (24/25), PASD1 (22/25), CAGE/DDX53 (19/25), CTAGE1 (19/25), HAGE/DDX43 (16/25) and PLU-1/JARID1B (15/25). Cell lines derived from more aggressive lymphoma subtypes generally expressed CT transcripts at higher frequency. Sp17 protein was detected in a number of cell lines and in six of eleven (54.5%) DLBCL biopsies. Analysis of Sp17 protein expression, by immunohistochemistry and Western blotting, broadens the scope of this CT antigen as a potentially relevant clinical target in haematological malignancies. Further studies of protein expression are now needed to validate these antigens as vaccine candidates. PMID- 20726503 TI - In vitro bypass of the major malondialdehyde- and base propenal-derived DNA adduct by human Y-family DNA polymerases kappa, iota, and Rev1. AB - 3-(2'-Deoxy-beta-d-erythro-pentofuranosyl)pyrimido-[1,2-a]purin-10(3H)-one (M(1)dG) is the major adduct derived from the reaction of DNA with the lipid peroxidation product malondialdehyde and the DNA peroxidation product base propenal. M(1)dG is mutagenic in Escherichia coli and mammalian cells, inducing base-pair substitutions (M(1)dG -> A and M(1)dG -> T) and frameshift mutations. Y family polymerases may contribute to the mutations induced by M(1)dG in vivo. Previous reports described the bypass of M(1)dG by DNA polymerases eta and Dpo4. The present experiments were conducted to evaluate bypass of M(1)dG by the human Y-family DNA polymerases kappa, iota, and Rev1. M(1)dG was incorporated into template-primers containing either dC or dT residues 5' to the adduct, and the template-primers were subjected to in vitro replication by the individual DNA polymerases. Steady-state kinetic analysis of single nucleotide incorporation indicates that dCMP is most frequently inserted by hPol kappa opposite the adduct in both sequence contexts, followed by dTMP and dGMP. dCMP and dTMP were most frequently inserted by hPol iota, and only dCMP was inserted by Rev1. hPol kappa extended template-primers in the order M(1)dG:dC > M(1)dG:dG > M(1)dG:dT ~ M(1)dG:dA, but neither hPol iota nor Rev1 extended M(1)dG-containing template primers. Liquid chromatography-mass spectrometry analysis of the products of hPol kappa-catalyzed extension verified this preference in the 3'-GXC-5' template sequence but revealed the generation of a series of complex products in which dAMP is incorporated opposite M(1)dG in the 3'-GXT-5' template sequence. The results indicate that DNA hPol kappa or the combined action of hPol iota or Rev1 and hPol kappa bypass M(1)dG residues in DNA and generate products that are consistent with some of the mutations induced by M(1)dG in mammalian cells. PMID- 20726504 TI - Using microcantilevers to study the interactions of lipid bilayers with solid surfaces. AB - We report the use of free-standing microcantilever beams, which have been used as an ultrasensitive method for measuring the surface free energy changes on a substrate induced by the adsorption of thin films, to probe the interactions between a solid surface and a phospholipid bilayer. We relate the observed deflection of a cantilever to the changes in the surface free energy of the solid surface which supports the phospholipid bilayer. We observe that the deflection is influenced by electrostatic and intermolecular interactions of the bilayer with the substrate. Increasing the surface charge density in the supported lipid bilayer (SLB), by increasing the ratio of cationic to zwitterionic lipids in bilayer, resulted in an increase in cantilever deflection. The surface free energy changes due to lipid transfer between anionic unilamellar vesicles and a cationic supported bilayer were also observed using microcantilevers. Finally, the adsorption free energy of a mixed lipid and cholesterol bilayer was measured demonstrating a detectable decrease in affinity between the phospholipid bilayer and the solid surface as a result of the addition of cholesterol. Our results reveal a new technique to probe the adsorption free energy of a SLB system as a function of the interactions governing the structure of supported lipid membranes. PMID- 20726505 TI - Utilizing three monoclonal antibodies in the development of an immunochromatographic assay for simultaneous detection of sulfamethazine, sulfadiazine, and sulfaquinoxaline residues in egg and chicken muscle. AB - A rapid and sensitive immunochromatographic assay (ICA) based on competitive format was developed and validated for simultaneous detection of sulfamethazine (SM(2)), sulfadiazine (SDZ), and sulfaquinoxaline (SQX) in chicken breast muscle and egg samples. For this purpose, three monoclonal antibodies raised against those three sulfonamides were conjugated to colloidal gold particles and applied to the conjugate pads of the test strip. The competitors of the sulfonamides (SM(2)/SDZ/SQX-bovine serum albumin conjugates) were immobilized onto a nitrocellulose membrane at three detection zones to form T(1), T(2), and T(3), respectively. With this method, the cutoff values for the three test lines were achieved at 80 MUg/kg, which is lower than the maximum residue levels (MRLs) established for sulfonamides. The recoveries in negative samples spiked at concentrations of 10, 50, and 100 MUg/kg ranged from 75% to 82% for egg samples and from 78% to 81% for chicken samples. The method was compared with the HPLC method by testing 180 eggs and chicken breast samples from local markets, and an agreement rate of 99.7% was obtained between the two methods. PMID- 20726506 TI - Electrochemical oxidation and cleavage of tyrosine- and tryptophan-containing tripeptides. AB - Electrochemical oxidation of peptides and proteins has been shown to lead to specific cleavage next to tyrosine (Tyr) and tryptophan (Trp) residues which makes the coupling of electrochemistry to mass spectrometry (EC-MS) a potential instrumental alternative to chemical and enzymatic cleavage. A set of Tyr and Trp containing tripeptides has been studied to investigate the mechanistic aspects of electrochemical oxidation and the subsequent chemical reactions including peptide bond cleavage, making this the first detailed study of the electrochemistry of Trp-containing peptides. The effect of adjacent amino acids was studied leading to the conclusion that the ratios of oxidation and cleavage products are peptide dependent and that the adjacent amino acid can influence the secondary chemical reactions occurring after the initial oxidation step. The effect of parameters such as potential and solvent conditions showed that control of the oxidation potential is crucial to avoid dimer formation for Tyr and an increasing number of oxygen insertions (hydroxylations) for Trp, which occur above 1000 mV (vs Pd/H(2)). While the formation of reactive intermediates after the first oxidation step is not strongly dependent on experimental conditions, an acidic pH is required for good cleavage yields. Working under strongly acidic conditions (pH 1.9-3.1) led to optimal cleavage yields (40-80%), whereas no or little cleavage occurred under basic conditions. Online EC-MS allowed determining the optimal potential for maximum cleavage yields, whereas EC-LC-MS/MS revealed the nature and distribution of the reaction products. PMID- 20726507 TI - Human virus and bacteriophage inactivation in clear water by simulated sunlight compared to bacteriophage inactivation at a southern California beach. AB - Few quantitative data exist on human virus inactivation by sunlight and the relationship between human and indicator viruses under sunlit conditions. We investigated the effects of sunlight on human viruses (adenovirus type 2, poliovirus type 3) and bacteriophages (MS2, Q-Beta SP, Fi, M13, PRD1, Phi-X174, and coliphages isolated from Avalon Bay, California). Viruses were inoculated into phosphate buffered saline or seawater, exposed to a laboratory solar simulator for <=12 h, and enumerated by double agar layer or cell culture to derive first-order inactivation rate constants (k(obs), h(-1)). The viruses most resistant to sunlight were adenovirus type 2 (k(obs)= 0.59 +/- 0.04 h(-1)) and bacteriophage MS2 (k(obs)= 0.43 +/- 0.02 h(-1)), which suggests MS2 may be a conservative indicator for sunlight resistant human viruses in clear water when sunlight inactivation is the main removal mechanism. Reasonable agreement was observed between somatic coliphage inactivation rates measured in the solar simulator (k(mean) = 1.81 h(-1)) and somatic coliphages measured in the surf zone during a field campaign at Avalon Bay during similar sunlight intensity (k = 0.75 h(-1) at log-RMSE minimum; k(range) = 0.54 h(-1) to >1.88 h(-1); Boehm, A. B. et al. Environ. Sci. Technol. 2009, 43, (21), 8046-8052). Hence, measuring sunlight inactivation rates of viruses in the laboratory can be used to estimate inactivation in the environment under similar sunlight and water quality conditions. PMID- 20726508 TI - Parallel G-quadruplex-specific fluorescent probe for monitoring DNA structural changes and label-free detection of potassium ion. AB - Here we demonstrate an anionic porphyrin, protoporphyrin IX (PPIX), as a parallel G-quadruplex-specific fluorescent probe for monitoring DNA structural changes and utilize it to develop a DNA-based K(+) sensor. The interactions of PPIX with different DNA structures in K(+) or Na(+) solution are investigated by using circular dichroism, fluorescence, and UV-vis spectroscopy. The observations reveal that PPIX has an ~100-fold selectivity for parallel G-quadruplexes against duplexes and antiparallel G-quadruplexes. Meanwhile, the fluorescence intensity of PPIX increases by over 10-fold upon binding to parallel G-quadruplexes. On the basis of the selectivity and fluorescence property of PPIX, we introduce a facile, label-free approach to monitoring DNA structural changes via fluorescence signal readout that is tuned by PPIX binding and release. To illustrate it, we utilize PPIX and a G-rich DNA PS2.M to construct a fluorescent K(+) sensor based on an antiparallel-to-parallel conformation transition of the G-quadruplex. PS2.M adopts an antiparallel quadruplex structure in Na(+) solution, whereas it gradually converts into a parallel G-quadruplex upon addition of increasing K(+). This conformational change is indicated by a sharp increase in the fluorescence intensity of PPIX, owing to the good ability of PPIX to discriminate parallel G quadruplexes from antiparallel ones. Even in the presence of 100 mM Na(+), such a "turn-on" fluorescent sensor can respond to low concentrations of K(+), with a limit of detection (0.5 mM) for K(+) analysis. In addition, this sensor exhibits a high selectivity for K(+) over other common metal ions, which ensures its practical applications to real samples. These results reveal that PPIX is promising for use as a specific DNA structural probe in sensing applications. PMID- 20726509 TI - Comparing linear free energy relationships for organic chemicals in soils: effects of soil and solute properties. AB - Sorption isotherm data were determined for a set of 8 aromatic organic compounds with varying physical chemical properties in three soils with organic matter of differing quantity and composition. The primary goals of this study were to test single and multiparameter linear free energy relationships on their ability to predict the observed sorption behavior on different types of natural sorbents across a range of solutes and concentrations and to relate the accuracy of the predictions to sorbent and solute structural descriptors. Organic carbon normalized sorption coefficients (K(OC)) predicted using both single and multiparameter LFERs were in good agreement with experimental data obtained at the highest tested aqueous concentrations (average deviation less than 0.1 log units over all solutes and sorbents), but deviations were more substantial (0.59 0.65 log units) at the lowest tested concentrations. For chlorinated benzenes there was a significant correlation between experiment-prediction discrepancies and the aromatic content of the soil organic matter measured by (13)C NMR, and the magnitude of the effect was similar to that observed previously for dissolved organic matter. PMID- 20726510 TI - Combination of DNA ligase reaction and gold nanoparticle-quenched fluorescent oligonucleotides: a simple and efficient approach for fluorescent assaying of single-nucleotide polymorphisms. AB - A new fluorescent sensing approach for detection of single-nucleotide polymorphisms (SNPs) is proposed based on the ligase reaction and gold nanoparticle (AuNPs)-quenched fluorescent oligonucleotides. The design exploits the strong fluorescence quenching of AuNPs for organic dyes and the difference in noncovalent interactions of the nanoparticles with single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), where ssDNA can be adsorbed onto the surface of AuNPs while dsDNA cannot be. In the assay, two half primer DNA probes, one being labeled with a dye and the other being phosphorylated, were first incubated with a target DNA template. In the presence of DNA ligase, the two captured ssDNAs are linked for the perfectly matched DNA target to form a stable duplex, but the duplex could not be formed by the single-base mismatched DNA template. After addition of AuNPs, the fluorescence of dye-tagged DNA probe will be efficiently quenched unless the perfectly matched DNA target is present. To demonstrate the feasibility of this design, the performance of SNP detection using two different DNA ligases, T4 DNA ligase and Escherichia coli DNA ligase, were investigated. In the case of T4 DNA ligase, the signal enhancement of the dye-tagged DNA for perfectly matched DNA target is 4.6-fold higher than that for the single-base mismatched DNA. While in the presence of E. coli DNA ligase, the value raises to be 30.2, suggesting excellent capability for SNP discrimination. PMID- 20726511 TI - Assessment of PDMS-water partition coefficients: implications for passive environmental sampling of hydrophobic organic compounds. AB - Solid-phase microextraction (SPME) has shown potential as an in situ passive sampling technique in aquatic environments. The reliability of this method depends upon accurate determination of the partition coefficient between the fiber coating and water (K(f)). For some hydrophobic organic compounds (HOCs), K(f) values spanning 4 orders of magnitude have been reported for polydimethylsiloxane (PDMS) and water. However, 24% of the published data examined in this review did not pass the criterion for negligible depletion, resulting in questionable K(f) values. The range in reported K(f) is reduced to just over 2 orders of magnitude for some polychlorinated biphenyls (PCBs) when these questionable values are removed. Other factors that could account for the range in reported K(f), such as fiber-coating thickness and fiber manufacturer, were evaluated and found to be insignificant. In addition to accurate measurement of K(f), an understanding of the impact of environmental variables, such as temperature and ionic strength, on partitioning is essential for application of laboratory-measured K(f) values to field samples. To date, few studies have measured K(f) for HOCs at conditions other than at 20 degrees or 25 degrees C in distilled water. The available data indicate measurable variations in K(f) at different temperatures and different ionic strengths. Therefore, if the appropriate environmental variables are not taken into account, significant error will be introduced into calculated aqueous concentrations using this passive sampling technique. A multiparameter linear solvation energy relationship (LSER) was developed to estimate log K(f) in distilled water at 25 degrees C based on published physicochemical parameters. This method provided a good correlation (R(2) = 0.94) between measured and predicted log K(f) values for several compound classes. Thus, an LSER approach may offer a reliable means of predicting log K(f) for HOCs whose experimental log K(f) values are presently unavailable. Future research should focus on understanding the impact of environmental variables on K(f). Obtaining the data needed for an LSER approach to estimate K(f) for all environmentally relevant HOCs would be beneficial to the application of SPME as a passive-sampling technique. PMID- 20726512 TI - Orally active MMP-1 sparing alpha-tetrahydropyranyl and alpha-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease. AB - alpha-Sulfone-alpha-piperidine and alpha-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. alpha-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while alpha-piperidine and alpha tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds. PMID- 20726513 TI - Visualizing the metal-binding versatility of copper trafficking sites . AB - Molecular systems have evolved to permit the safe delivery of copper. Despite extensive studies, many copper site structures involved in copper homeostasis, even for the well-studied metallochaperone Atx1, remain unresolved. Cyanobacteria import copper to their thylakoid compartments for use in photosynthesis and respiration and possess an Atx1 that we show can adopt multiple oligomeric states when metalated, capable of binding up to four copper ions. Two-copper- and four copper-loaded dimers exist in solution at low micromolar concentrations, and head to-head and side-to-side arrangements, respectively, can be crystallized, with the latter binding a [Cu(4){mu(2)-S(gamma)(Cys)}(4)Cl(2)](2-) cluster. The His61Tyr mutation on loop 5 weakens head-to-head dimerization, yet a side-to-side dimer binding a similar cluster as in the wild-type protein, but with phenolate coordination, is present. The cognate metal-binding domains (MBDs) of the P-type ATPases CtaA and PacS, which are proposed to donate copper to and accept copper from Atx1, respectively, are monomeric in the presence of copper. The structure of the MBD of Cu(I)-PacS shows a crystallographic trimer arrangement around a [Cu(3){mu(2)-S(gamma)(Cys)}(3){S(gamma)(Cys)}(3)](2-) cluster that is very similar to that found for an alternate form of the His61Tyr Atx1 mutant. Copper transfer from the MBD of CtaA to Atx1 is favorable, but delivery from Atx1 to the MBD of PacS is strongly dependent upon the dimeric form of Atx1. A copper-induced switch in Atx1 dimer structure may have a regulatory role with cluster formation helping to buffer copper. PMID- 20726514 TI - Mechanism of potentiation of a dysfunctional epilepsy-linked mutated GABA(A) receptor by a neurosteroid (3alpha, 21-dihydroxy-5alpha-pregnan-20-one): transient kinetic investigations. AB - The malfunction of a mutated GABA(A) receptor (alpha1beta2gamma2L(K289M)) in an inheritable form of epilepsy (GEFS+, generalized epilepsy with febrile seizures plus) in humans [Baulac, S., Huberfeld, G., Gourfinkel-An, I., Mitropoulou, G., Beranger, A., Prud'homme, J. F., Baulac, M., Brice, A., Bruzzone, R., and LeGuern, E. (2001) Nat. Genet. 28, 46-48] has been accounted for by a 5-fold decrease in the channel-opening equilibrium of the mutated receptor compared to the wild type [Ramakrishnan, L., and Hess, G. P. (2004) Biochemistry 43, 7534 7540]. Here we describe the mechanism by which the neurosteroid 3alpha, 21 dihydroxy-5alpha-pregnan-20-one (5alpha-THDOC) alleviates this malfunction of the mutated receptor transiently expressed in HEK293 cells. Two rapid reaction techniques, the cell-flow and the laser-pulse photolysis methods, were used in combination with whole-cell current recordings. 150-muM 5alpha-THDOC does not affect the rate constant for channel opening (k(op)) of approximately 250 s(-1) but does decrease the rate constant for channel closing (k(cl)) from 121 +/- 11 s(-1) to 56 +/- 21 s(-1). This results in an increase in the channel-opening equilibrium constant ((Phi(-1) = k(op)/k(cl)) by a factor of about 2, leading to about 50% alleviation of the malfunction of the inheritable mutated (alpha1beta2gamma2L(K289M)) GABA(A) receptor linked to GEFS+. PMID- 20726515 TI - New three-dimensional thiostannates composed of linked Cu8S12 clusters and the first example of a mixed-metal Cu7SnS12 cluster. AB - Three new compounds (enH)(6+n)Cu(40)Sn(15)S(60) (1), (enH)(3)Cu(7)Sn(4)S(12) (2), and (trenH(3))Cu(7)Sn(4)S(12) (tren = tris(2-aminoethyl)amine) (3) containing Cu(8)S(12) and Cu(7)SnS(12) clusters have been prepared from direct solvothermal reaction of the elements in amine solvents. In 1, the cubic close-packed arrangement of Cu(8)S(12) clusters, interconnected by capping SnS(4) tetrahedra and CuS(3) triangles, form two interpenetrating channel networks that are presumably filled with disordered solvent molecules. Structures 2 and 3 contain well-ordered, protonated amine molecules and Cu(7)SnS(12) clusters. The clusters are connected by SnS(4) tetrahedra to form a three-dimensional structure with ReO(3) topology. (119)Sn Mossbauer measurement is consistent with Sn(IV) atoms linking, and Sn(II) atoms within, the mixed-metal Cu(7)SnS(12) clusters. PMID- 20726516 TI - Effect of five membered versus six membered meso-substituents on structure and electronic properties of Mg(II) porphyrins: a combined experimental and theoretical study. AB - Meso-tetrasubstituted Mg(II) porphyrins containing six membered phenyl groups (MgTPP) and five membered thienyl (MgTThP) and furyl groups (MgTFP) were synthesized and structurally characterized, and the effects of meso-substituents on electronic properties were studied using NMR, absorption, fluorescence spectroscopy, and electrochemical studies. Density functional theory (DFT) calculations were carried out to correlate with experimental observations. The three Mg(II) porphyrins MgTPP, MgTThP, and MgTFP were crystallized as hexa coordinate systems with Mg(II) ion in the center of the porphyrin plane and having two tetrahydrofuran molecules as axial ligands. The X-ray studies clearly showed that the meso-furyl groups adopt a conformation in which they are more in plane with the porphyrin plane whereas the thienyl and phenyl groups prefer an orthogonal arrangement with respect to the porphyrin plane. This arrangement of meso-substituents with the porphyrin plane helps in the enhancement of porphyrin pi-delocalization in MgTFP compared to MgTThP and MgTPP. The differences in their structures are clearly reflected in their spectral and electrochemical properties. The absorption and fluorescence bands experienced bathochromic shifts on moving from six membered phenyls to five membered thienyl and furyl group, and the maximum effects were observed for meso-tetrafuryl Mg(II) porphyrin. The electrochemical studies indicated that the gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) decreases as we move from six membered phenyl groups to five membered thienyl and furyl groups, which explains the bathochromic shifts observed in absorption and fluorescence bands. Results on structure and electronic properties based on DFT studies are in agreement with experimental observations. PMID- 20726517 TI - Polybrominated diphenylethers (PBDEs) alter larval settlement of marine benthic polychaetes. AB - Polybrominated diphenylethers (PBDEs) are found ubiquitously in marine environments worldwide. Sediment is the major sink of PBDEs, with the congener BDE 47 being most abundant. In this study, laboratory experiments were carried out to test the hypothesis that contamination of BDE 47 at environmentally realistic sediment concentrations can alter polychaete larval settlement. Using multiple-choice experiment, settlement of three polychaete species (Pseudopolydora vexillosa, Polydora cornuta, and Capitella sp. I) on four types of spiked sediment was studied and compared: (i) low BDE 47 concentration (0.5 ng g(-1) dry weight); (ii) high BDE 47 concentration (3.0 ng g(-1) dry weight), (iii) hexane (solvent control), and (iv) natural sediment (control). Our results showed that settlement of P. vexillosa and Capitella sp. I larvae was significantly promoted, while settlement of P. cornuta reduced, at high BDE 47 concentration in sediment compared with the respective controls under both short- (24 h) and long-term (4 week) exposures. After 4 weeks, body burden of BDE 47 in all polychaete species was directly related to the spike concentration, and body length of settled juveniles of P. vexillosa and Capitella sp. I at the high concentration treatment was significantly longer compared with that of other treatments and controls. For the first time, we demonstrated that environmentally realistic concentrations of BDE 47 in sediment can affect polychaete settlement in species-specific and dose-dependent manners. Given the global contamination of PBDE in marine sediment, BDE 47 may potentially alter the settlement pattern of marine polychaetes and hence their benthic composition over large areas. PMID- 20726518 TI - High speed water sterilization using one-dimensional nanostructures. AB - The removal of bacteria and other organisms from water is an extremely important process, not only for drinking and sanitation but also industrially as biofouling is a commonplace and serious problem. We here present a textile based multiscale device for the high speed electrical sterilization of water using silver nanowires, carbon nanotubes, and cotton. This approach, which combines several materials spanning three very different length scales with simple dying based fabrication, makes a gravity fed device operating at 100000 L/(h m(2)) which can inactivate >98% of bacteria with only several seconds of total incubation time. This excellent performance is enabled by the use of an electrical mechanism rather than size exclusion, while the very high surface area of the device coupled with large electric field concentrations near the silver nanowire tips allows for effective bacterial inactivation. PMID- 20726519 TI - In vitro bioconversion of polyphenols from black tea and red wine/grape juice by human intestinal microbiota displays strong interindividual variability. AB - Dietary polyphenols in tea and wine have been associated with beneficial health effects. After ingestion, most polyphenols are metabolized by the colonic microbiota. The current study aimed at exploring the interindividual variation of gut microbial polyphenol bioconversion from 10 healthy human subjects. In vitro fecal batch fermentations simulating conditions in the distal colon were performed using polyphenols from black tea and a mixture of red wine and grape juice. Microbial bioconversion was monitored by NMR- and GC-MS-based profiling of diverse metabolites and phenolics. The complex polyphenol mixtures were degraded to a limited number of key metabolites. Each subject displayed a specific metabolite profile differing in composition and time courses as well as levels of these metabolites. Moreover, clear differences depending on the polyphenol sources were observed. In conclusion, varying metabolite pathways among individuals result in different metabolome profiles and therefore related health effects are hypothesized to differ between subjects. PMID- 20726520 TI - Visible-light-induced bactericidal activity of titanium dioxide codoped with nitrogen and silver. AB - Titanium dioxide nanoparticles codoped with nitrogen and silver (Ag(2)O/TiON) were synthesized by the sol-gel process and found to be an effective visible light driven photocatalyst. The catalyst showed strong bactericidal activity against Escherichia coli (E. coli) under visible light irradiation (lambda > 400 nm). In X-ray photoelectron spectroscopy and X-ray diffraction characterization of the samples, the as-added Ag species mainly exist as Ag(2)O. Spin trapping EPR study showed Ag addition greatly enhanced the production of hydroxyl radicals (*OH) under visible light irradiation. The results indicate that the Ag(2)O species trapped e(CB)(-) in the process of Ag(2)O/TiON photocatalytic reaction, thus inhibiting the recombination of e(CB)(-) and h(VB)(+) in agreement with the stronger photocatalytic bactericidal activity of Ag(2)O/TiON. The killing mechanism of Ag(2)O/TiON under visible light irradiation is shown to be related to oxidative damages in the forms of cell wall thinning and cell disconfiguration. PMID- 20726521 TI - FTIR product distribution study of the Cl and OH initiated degradation of methyl acrylate at atmospheric pressure. AB - A product study is reported on the gas-phase reactions of OH radicals and Cl atoms with methyl acrylate. The experiments were performed in a 1080-L quartz glass chamber in synthetic air at 298 +/- 2 K and 760 +/- 10 Torr using long-path in situ FTIR spectroscopy for the analysis of the reactants and products. In the absence of NO(x) the major product observed in the OH reaction is methyl glyoxylate, with formaldehyde as a coproduct. For the reaction with Cl only formyl chloride (HC(O)Cl), CO, and HCl could be positively identified as products, however, the concentration-time behavior of these products show that they are secondary products and originate from the further oxidation of a major primary product. From this behavior and a comparison with simulated spectra unidentified bands in the residual product spectra are tentatively attributed to a compound of structure CH(2)ClC(O)C(O)OCH(3), i.e., formation of methyl 3-chloro 2-oxopropanoate from the reaction of Cl with methyl acrylate. The present results are compared with previous results where available and simple atmospheric degradation mechanisms are postulated to explain the formation of the observed products. PMID- 20726523 TI - From molecules to systems: sol-gel microencapsulation in silica-based materials. PMID- 20726522 TI - Nanotechnology in drug delivery and tissue engineering: from discovery to applications. AB - The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilities in healthcare. Herein, we discuss two important aspects of nanomedicine, drug delivery and tissue engineering, highlighting the advances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future. PMID- 20726525 TI - C-C coupling reactivity of an alkylgold(III) fluoride complex with arylboronic acids. AB - Previously, alkylgold(III) fluorides have been proposed as catalytic intermediates that undergo C-C coupling with reagents such as arylboronic acids in Au(I)/Au(III) cross-coupling reactions. Here is reported the first experimental evidence for this elementary mechanistic step. Complexes of the type (NHC)AuMe (NHC = N-heterocyclic carbene) were oxidized with XeF(2) to yield cis (NHC)AuMeF(2) products, which were found to be in equilibrium with their fluoride dissociated, dimeric [(NHC)AuMe(MU-F)](2)[F](2) forms. In one case, a monomeric cis-(NHC)AuMeF(2) complex was favored exclusively in solution, and it was found to react with a variety of ArB(OH)(2) reagents to yield Ar-CH(3) products. PMID- 20726524 TI - Investigation of the highly active manganese superoxide dismutase from Saccharomyces cerevisiae. AB - Manganese superoxide dismutase (MnSOD) from different species differs in its efficiency in removing high concentrations of superoxide (O(2)(-)), due to different levels of product inhibition. Human MnSOD exhibits a substantially higher level of product inhibition than the MnSODs from bacteria. In order to investigate the mechanism of product inhibition and whether it is a feature common to eukaryotic MnSODs, we purified MnSOD from Saccharomyces cerevisiae (ScMnSOD). It was a tetramer with 0.6 equiv of Mn per monomer. The catalytic activity of ScMnSOD was investigated by pulse radiolysis and compared with human and two bacterial (Escherichia coli and Deinococcus radiodurans) MnSODs. To our surprise, ScMnSOD most efficiently facilitates removal of high concentrations of O(2)(-) among these MnSODs. The gating value k(2)/k(3) that characterizes the level of product inhibition scales as ScMnSOD > D. radiodurans MnSOD > E. coli MnSOD > human MnSOD. While most MnSODs rest as the oxidized form, ScMnSOD was isolated in the Mn(2+) oxidation state as revealed by its optical and electron paramagnetic resonance spectra. This finding poses the possibility of elucidating the origin of product inhibition by comparing human MnSOD with ScMnSOD. PMID- 20726526 TI - Fluoro- and chromogenic chemodosimeters for heavy metal ion detection in solution and biospecimens. PMID- 20726528 TI - Characterizing the morphology of organic aerosols at ambient temperature and pressure. AB - The aerosol direct effect, which characterizes the interaction of radiation with aerosol particles, remains poorly understood. By determining aerosol composition, shape, and internal structure, we can predict aerosol optical properties. In this study, we performed a feasibility study to determine if tapping-mode atomic force microscopy (TM-AFM) and Raman microscopy can be effectively used to obtain information on aerosol composition, shape, and structure. These techniques are advantageous because they operate under ambient pressure and temperature. We worked with model aerosol particles composed of organic components of varying solubility mixed with ammonium sulfate. In particular, we explored whether aerosols could be differentiated on the basis of the solubility of the organic component. We also characterized the aerosol internal structure and investigated how this structure changes as the solubility of the organic compound is varied. To obtain indirect chemical information from AFM, we imaged particles supported on both polar, SiO(x)/Si(100), and nonpolar, highly ordered pyrolytic graphite, surfaces. We have found that AFM can be used to differentiate the solubility of the organic component. In some cases, AFM can also be used to identify internal structure. With Raman microscopy, we can differentiate between core-shell structures and homogeneous structures. Surprisingly, we find that even for the most soluble compounds, core-shell structures are observed. To discuss consequences of our results for climate studies, we calculate the difference in radiative forcing caused by having a core-shell aerosol rather than a homogeneous particle. Overall, these techniques are promising for characterizing composition, shape, and internal structure of atmospheric particles. PMID- 20726527 TI - Unprecedented peroxidase-like activity of Rhodnius prolixus nitrophorin 2: identification of the [FeIV=O Por*]+ and [FeIV=O Por](Tyr38*) intermediates and their role(s) in substrate oxidation. AB - We have identified a novel enzymatic reaction for nitrophorin 2 (NP2), a heme protein previously characterized as a nitric oxide carrier in the saliva of the Rhodnius prolixus insect. NP2 exhibited levels of peroxidase activity comparable to those of the bifunctional peroxidases (KatGs), despite their heme pocket structural differences (heme ruffling, Tyr38 and Tyr85 in hydrogen bonding interactions with the propionates in NP2). The intermediates of the peroxidase like reaction of NP2 were identified by Electron Paramagnetic Resonance (EPR) and electronic absorption spectroscopies. The EPR spectrum consistent with an [Fe(IV)=O Por*]+ species was detected at pH <7. At pH >= 7, the change from a strong to a weak antiferromagnetic coupling interaction for the [Fe(IV)=O Por*]+ species was accompanied by the subsequent formation of an [Fe(IV)=O Por](Tyr*) intermediate. Tyr38 was shown to be the unique naturally occurring radical site in NP2. The Y38F mutant stabilized the radical on the tyrosine in hydrogen bonding interaction with the other heme propionate (Tyr85). Kinetic studies using stopped-flow electronic absorption spectrophotometry revealed that the [Fe(IV)=O Por*]+ species reacts with histamine and norepinephrine in a peroxidase-like manner. Our findings demonstrate that NP2 has pH-dependent dual function: at the acidic pH of the insect saliva the protein behaves as a NO carrier, and, if exposed to the higher pH of the tissues and capillaries of the host, NP2 is able to bind histamine or it can efficiently inactivate norepinephrine through a peroxidase-like reaction, in the presence of hydrogen peroxide. Accordingly, the unprecedented peroxidase-like activity of NP2 is concluded to be a key biological function. PMID- 20726529 TI - Organization of Pseudomonas fluorescens on chemically different nano/microstructured surfaces. AB - This paper describes bacterial organization on nano/micropatterned surfaces with different chemical properties, which show different interactions with the biological systems (inert, biocompatible, and bactericide). These surfaces were prepared by molding techniques and exposed to Pseudomonas fluorescens (P. fluorescens) cultures. Results from atomic force microscopy and optical imaging demonstrate that the structure of P. fluorescens aggregates is strongly dependent on the surface topography while there is no clear linking with the physical chemical surface properties (charge and contact angle) of the substrate immersed in abiotic culture media. We observe that regardless of the material when the surface pattern matches the bacterial size, bacterial assemblages involved in surface colonization are disorganized. The fact there is not a relationship between surface chemistry and bacterial organization can be explained by the coverage of the surfaces by adsorbed organic species coming from the culture medium. Viability assays indicate that copper behaves as a toxic substrate despite the presence of adsorbed molecules. The combination of surface traps and biocidal activity could act synergistically as a suitable strategy to limit bacterial spreading on implant materials. PMID- 20726530 TI - Investigation of the catalytic mechanism of Sir2 enzyme with QM/MM approach: SN1 vs SN2? AB - Sir2, the histone deacetylase III family, has been subjected to a wide range of studies because of their crucial roles in DNA repair, longevity, transcriptional silencing, genome stability, apoptosis, and fat mobilization. The enzyme binds NAD(+) and acetyllysine as substrates and generates lysine, 2'-O-acetyl-ADP ribose, and nicotinamide as products. However, the mechanism of the first step in Sir2 deacetylation reaction from various studies is controversial. To characterize this catalytic mechanism of acetyllysine deacetylation by Sir2, we employed a combined computational approach to carry out molecular modeling, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) calculations on catalysis by both yeast Hst2 (homologue of SIR two 2) and bacterial Sir2TM (Sir2 homologue from Thermatoga maritima). Our three-dimensional (3D) model of the complex is composed of Sir2 protein, NAD(+), and acetyllysine (ALY) substrate. A 15-ns MD simulation of the complex revealed that Gln115 and His135 play a determining role in deacetylation. These two residues can act as bases to facilitate the deprotonation of 2'-OH from N-ribose. The result is in great agreement with previous mutagenesis analysis data. QM/MM calculations were further performed to study the mechanism of the first step in deacetylation in the two systems. The predicted potential energy barriers for yHst2 and Sir2TM are 12.0 and 15.7 kcal/mol, respectively. The characteristics of the potential energy surface indicated this reaction belongs to a SN2-like mechanism. These results provide insights into the Sir2 mechanism of nicotinamide inhibition and have important implications for the discovery of effectors against Sir2 enzymes. PMID- 20726531 TI - Auto-oscillation of surface tension: effect of pH on fatty acid systems. AB - Spontaneous nonlinear oscillations of surface tension produced by transfer of either octanoic or nonanoic acids from a droplet situated in the bulk water to the air/water interface are studied experimentally. It is shown that the oscillation amplitude decreases significantly with the increase of pH of aqueous phase. At pH > 6.5, detectable oscillations for the two fatty acids studied do not exist. The results are discussed in terms of the mechanism proposed recently for spontaneous oscillations produced by transfer of nonionic surfactants. PMID- 20726532 TI - Steric stabilization of Pickering emulsions for the efficient synthesis of polymeric microcapsules. AB - It is commonly known that Pickering emulsions are extremely stable against coalescence and are, therefore, potentially interesting for the synthesis of new materials, such as colloidosomes, microcapsules, composite particles, foams, and so on. However, for the efficient synthesis of such materials, one also has to consider the colloidal stability against aggregation, which is often neglected. In this study, it is demonstrated that steric stabilization is provided to Pickering emulsion droplets by the adsorption of poly(styrene-block-ethylene-co propylene) (pS-b-EP) and that it is a requirement for the efficient synthesis of polymeric microcapsules. Monodisperse polystyrene particles of 648 nm are synthesized by soap-free emulsion polymerization. A model Pickering emulsion is then formed by the addition of sodium chloride at a critical concentration of 325 mM and mixing it with either heptane or decane. Subsequently, pS-b-EP is added to the Pickering emulsion to provide steric stabilization. Size exclusion chromatography is used to prove and quantify the adsorption of pS-b-EP onto the Pickering emulsion droplets. A maximum surface coverage of 1.3 mg/m(2) is obtained after 2 h, which is approximately one-third of the adsorption on a pure pS surface. We believe that the presence of polar sulfate groups on the particle, which initially stabilized the particle in water, reduces the adsorption of pS-b EP. Microcapsules are formed by heating the Pickering emulsion above the glass transition temperature of the particles. Significant aggregation is observed, if no pS-b-EP is used. The adsorption of pS-b-EP provides steric stabilization to the Pickering emulsion droplets, reduces aggregation significantly, and ultimately leads to the successful and efficient synthesis of pS microcapsules. PMID- 20726533 TI - Drug solubility in luminal fluids from different regions of the small and large intestine of humans. AB - The purpose of this work was to study the solubility of two drugs with different physicochemical properties in luminal fluids obtained from various regions of the human gastrointestinal (GI) tract and to determine the most important luminal parameters influencing their solubility. Jejunal fluids were aspirated from healthy volunteers via an oral intubation tube. Ileal and colonic fluids were obtained from patients undergoing GI surgery. Stoma fluids were also retrieved from patients. pH and buffer capacity of all fluids were determined. Saturation solubility of prednisolone (unionisable) and mesalamine (5-aminosalicylic acid) (zwitterionic) was measured. Mean solubility of prednisolone in the different luminal fluids was 0.50 mg/mL (+/-0.05) and did not vary significantly between the different regions of the GI tract (ANOVA, p > 0.05). No correlation between prednisolone solubility and jejunal bile salt content was found. Mesalamine solubility increased down the GI tract: 1.97 (+/-0.25), 3.26 (+/-0.08), 6.24 (+/ 1.13) and 7.95 (+/-0.21) mg/mL in jejunal, ileal, ascending and transverse/descending colonic fluids respectively. Buffer capacity also increased and in one patient was observed to range from 6.4 to 28.6 reaching 44.4 mM/L/pH unit in ileal, ascending and transverse/descending colon fluids respectively. Mesalamine solubility was found to be dependent on both buffer capacity and pH, with buffer capacity being the most important (standardized coefficient beta = 0.849, p < 0.0001) compared to pH (beta = 0.219, p < 0.05). For drugs delivered as modified release formulations it is important to consider solubility in different regions of the GI tract as significant differences can arise which will ultimately influence drug bioavailability. PMID- 20726534 TI - DsrJ, an essential part of the DsrMKJOP transmembrane complex in the purple sulfur bacterium Allochromatium vinosum, is an unusual triheme cytochrome c. AB - The DsrMKJOP transmembrane complex has a most important function in dissimilatory sulfur metabolism, not only in many sulfur-oxidizing organisms but also in sulfate-reducing prokaryotes. Here, we focused on an individual component of this complex, the triheme cytochrome c DsrJ from the purple sulfur bacterium Allochromatium vinosum. In A. vinosum, the signal peptide of DsrJ is not cleaved off but serves as a membrane anchor. Sequence analysis suggested the presence of three heme c species with bis-His, His/Met, and possibly a very unusual His/Cys ligation. A. vinosum DsrJ produced as a recombinant protein in Escherichia coli indeed contained three hemes, and electron paramagnetic resonance (EPR) spectroscopy provided evidence of possible, but only partial, His/Cys heme ligation in one of the hemes. This heme shows heterogeneous coordination, with Met being another candidate ligand. Cysteine 46 was replaced with serine using site-directed mutagenesis, with the mutant protein showing a small decrease in the magnitude of the EPR signal attributed to His/Cys coordination, but identical UV-vis and RR spectra. The redox potentials of the hemes in the wild-type protein were determined to be -20, -200, and -220 mV and were found to be virtually identical in the mutant protein. However, in vivo the same ligand exchange led to a dramatically altered phenotype, highlighting the importance of Cys46. Our results suggest that Cys46 may be involved in catalytic sulfur chemistry rather than electron transfer. Additional in vivo experiments showed that DsrJ can be functionally replaced in A. vinosum by the homologous protein from the sulfate reducer Desulfovibrio vulgaris. PMID- 20726536 TI - Ultrafast time-resolved spectroscopy of self-assembled cyclic Fe(II) bisterpyridine complexes. AB - Femtosecond time-resolved absorption spectroscopy has been used to study the excited-state charge transfer dynamics in a set of self-assembled cyclic Fe(II) bisterpyridine compounds with different pi-conjugated ligands. By analyzing the dynamics, the internal conversion process involving a ligand-centered pi-pi* state to a lower lying metal-to-ligand charge transfer (MLCT) state was investigated. This is followed by intersystem crossing to the lowest MLCT state, which was found to occur at the ~100 fs time scale. Vibrational cooling in the lowest MLCT state was found to occur on the 10s of femtoseconds time scale. The lowest MLCT state had an excited-state lifetime longer than 5 ns, indicating the possibility of light-induced excited-state spin trapping (LIESST). PMID- 20726535 TI - Cytokine binding by polysaccharide-antibody conjugates. AB - Cytokine-neutralizing antibodies are used in treating a broad range of inflammatory conditions. We demonstrate that monoclonal antibodies against interleukin-1beta and tumor necrosis factor-alpha were still active when conjugated to high molecular weight polysaccharides. These polysaccharides are hydrophilic, but their size makes them unable to circulate in the bloodstream when delivered to tissues, opening up the possibility of localized treatment of inflammatory conditions. To explore this new class of protein-polysaccharide conjugates, we covalently modified interleukin-1beta and tumor necrosis factor alpha monoclonal antibodies with high molecular weight hyaluronic acid and carboxymethylcellulose. Rigorous purification using dialysis with a 300 kDa cutoff membrane removed unconjugated monoclonal antibodies. We characterized the composition of the constructs and demonstrated using molecular binding affinity measurements and cell assays that the conjugates were capable of binding proinflammatory cytokines. The binding affinities of both the unconjugated antibodies for their cytokines were measured to be approximately 120 pM. While all conjugates had pM-level binding constants, they ranged from 40 pM for the hyaluronic acid-(anti-interleukin-1beta) conjugate to 412 pM for the carboxymethylcellulose-(anti-interleukin-1beta) conjugate. Interestingly, the dissociation time constants varied more than the association time constants, suggesting that conjugation to a high molecular weight polysaccharide did not interfere with the formation of the antibody-cytokine complex but could stabilize or destabilize it once formed. Conjugation of cytokine-neutralizing antibodies to high molecular weight polymers represents a novel method of delivering anticytokine therapeutics that may avoid many of the complications associated with systemic delivery. PMID- 20726537 TI - Organometallic electrodes: modification of electrode surfaces through cathodic reduction of cyclopentadienyldiazonium complexes of cobalt and manganese. AB - Two organometallic complexes having cyclopentadienyldiazonium ligands have been isolated and characterized by spectroscopy, X-ray crystallography, and electrochemistry. Both CoCp(eta(5)-C(5)H(4)N(2))(2+) (2(2+)) and Mn(CO)(3)(eta(5) C(5)H(4)N(2))(+) (3(+)) undergo facile cyclopentadienyldiazonium ligand-based one electron reductions which liberate dinitrogen and result in strong binding of the cyclopentadienyl ligand to a glassy carbon surface, similar to the processes well established for organic aryldiazonium salts. The organometallic-modified electrodes are robust and have a thickness of approximately one monolayer (Gamma = (2-4) * 10(-10) mol cm(-2)). Their voltammetric responses are as expected for a cobaltocenium-modified electrode, [CoCp(eta(5)-C(5)H(4)-E)](+), where Cp = cyclopentadienyl and E = electrode, and a "cymantrene"-modified electrode Mn(CO)(3)(eta(5)-C(5)H(4)-E). The cobaltocenium electrode has two cathodic surface waves. The first (E(1/2) = -1.34 V vs ferrocene) is highly reversible, whereas the second (E(pc) = -2.4 V) is not, consistent with the known behavior of cobaltocenium. The cymantrene-substituted electrode has a partially chemically reversible anodic wave at E(1/2) = 0.96 V, also consistent with the behavior of its Mn(CO)(3)Cp parent. Many of the properties of aryl-modified electrodes, such as "blockage" of the voltammetric responses of test analytes, are also seen for the organometallic-modified electrodes. Surface-based substitution of a carbonyl group by a phosphite ligand, P(OR)(3), R = Ph or Me, was observed when the cymantrene-modified electrode was anodically oxidized in the presence of a phosphite ligand. The successful grafting of organometallic moieties by direct bonding of a cyclopentadienyl ligand to electrode surfaces expands the chemical and electrochemical dimensions of diazonium-based modified electrodes. PMID- 20726538 TI - Effects of the lipid bilayer phase state on the water membrane interface. AB - We performed 200 ns MD simulations of phosphatidylcholine (PC) bilayers in the liquid crystalline (L(alpha)) and gel (L(beta)') states to compare the properties of the water-membrane interfaces in these two thermotropic bilayer phases. Our simulations show that the membrane phase determines the behavior of water, ions, and PC head groups. When the membrane was in the gel phase, we found partial dehydration (fewer PC-water interactions), particularly in the carbonyl groups region, as well as an almost complete lack of ionic penetration into this region as compared with the bilayer in the liquid-crystalline phase. In the latter case, there is an exchange of Na(+) ions between the water layer and the interfacial region. This is mainly due to the fact that the most stable binding of Na(+) in the liquid-crystalline bilayer is to the carbonyl groups. The lack of Na(+) binding to the carbonyl groups in the gel phase bilayer can be explained by the more compact structure of the bilayer in this phase. PMID- 20726539 TI - Potential cross-linking transition metal complexes (M = Ni, Cu, Zn) in the ligand modified LNA duplexes. AB - Options for interstrand DNA duplex linkages have been studied by incorporating transition metal ions in the ligand-functionalized LNA (locked nucleic acid) duplexes. The effect of first-row transition metal ions (M = Ni(2+), Cu(2+), and Zn(2+)) on the geometries and formation energies of mono- and dimetallic model complexes was calculated by DFT methods, and the results were compared with available experimental data. The results showed a clear preference for the formation of copper complexes over the corresponding nickel and zinc complexes, in agreement with the trends observed in the denaturation temperatures of the ligand-functionalized LNA duplexes. In addition, dichloride bridged dimeric complex, [L(LNA)Cu(MU-Cl)(2)CuL(LNA)](2+), in which L(LNA) is N,N-bis(2 pyridylmethyl)-beta-alanyl functionalized LNA, was found energetically very stable, providing a potential structural option for an interstrand duplex linkage. The model complex and its simpler structural analogues were synthesized and structurally characterized. Comparison of the dimeric linker introduced into duplex tetramer strands, which provided a computational model for a double helix with two closely located LNA units, with a similar model for mononuclear Cu(L(LNA))(2)(2+) linker also showed a clear preference of the dichloride-bridged option, suggesting that the [L(LNA)Cu(MU-Cl)(2)CuL(LNA)](2+) complex produced a chemically realistic model to explain duplex stabilization in the presence of Cu(2+) and excess Cl(-). PMID- 20726540 TI - Effect of association with sulfate on the electrophoretic mobility of polyarginine and polylysine. AB - Domains rich in cationic amino acids are ubiquitous in peptides with the ability to cross cell membranes, which is likely related to the binding of such polypeptides to anionic groups on the membrane surface. To shed more light on these interactions, we investigated specific interactions between basic amino acids and oligopeptides thereof and anions by means of electrophoretic experiments and molecular dynamics simulations. To this end, we measured the electrophoretic mobilities of arginine, lysine, tetraarginine, and tetralysine in sodium chloride and sodium sulfate electrolytes as a function of ionic strength. The mobility was found to be consistently lower in sodium sulfate than in sodium chloride at the same ionic strength. The decrease in mobility in sodium sulfate was greater for tetraarginine than for tetralysine and was larger for tetrapeptides compared to the corresponding free amino acids. On the basis of molecular dynamics simulations and Bjerrum theory, we rationalize these results in terms of enhanced association between the amino acid side chains and sulfate. Simulations also predict a greater affinity of sulfate to the guanidinium side chain groups of arginine than to the ammonium groups of lysine, as the planar guanidinium geometry allows simultaneous strong hydrogen bonding to two sulfate oxygens. We show that the sulfate binding to arginine, but not to lysine, is cooperative. These results are consistent with the greater decrease in the mobility of arginine compared to that of lysine upon addition of sulfate salt. The nonspecific mobility retardation by sulfate is ascribed to its electrostatic interaction with the cationic amino acid side chain groups. PMID- 20726541 TI - Prediction of vibrational spectra of polysaccharides-simulated IR spectrum of cellulose based on density functional theory (DFT). AB - The continuing developments of electronic structure methods may provide insight into the vibrational spectroscopy of polysaccharides, which was not accessible to older works on this subject. The present work shows for the first time how main features of cellulose infrared spectra can be predicted and assigned using simple single chain models of cellulose combined with density functional theory prediction of their vibrational properties. The results provide a more informed basis for assigning cellulose IR bands and may resolve some of the challenges associated with the molecular origin of "marker" bands, which are commonly used to measure properties such as crystallinity or crystalline forms. The theoretical approach can be seen as a first-order approximation, which can be further improved. PMID- 20726542 TI - Solvent polarity effect on chain conformation, film morphology, and optical properties of a water-soluble conjugated polymer. AB - The solvent polarity effect on chain conformation, film morphology, and photophysical properties of a nonionic water-soluble conjugated polymer (WSCP), poly[2,5-bis(diethylaminetetraethylene glycol)phenylene vinylene] (DEATG-PPV) is investigated in detail. The combination of stationary absorption and photoluminescence (PL) spectroscopy, time-resolved PL spectroscopy, and fluorescence correlation spectroscopy methods enables us to probe the chain conformation of DEATG-PPV, down to the level of a single chain when working with extremely diluted solutions. The use of correlated atomic force microscopy and confocal fluorescence lifetime imaging microscopy measurements of drop-casted DEATG-PPV films reveals the intrinsic relationship between chain conformation, film morphology, and optical properties. Depending on solvent polarity, DEATG-PPV presents extended, coiled, and collapsed chain conformations in solutions, which lead to distinct morphology and optical properties in solid films. Our work presents a pathway to control and characterize the film morphologies of WSCPs toward the optimal performance of various optoelectronic devices. PMID- 20726543 TI - Spectral engineering in pi-conjugated polymers with intramolecular donor-acceptor interactions. AB - With the development of light-harvesting organic materials for solar cell applications and molecular systems with fine-tuned colors for nonemissive electrochromic devices (e.g., smart windows, e-papers), a number of technical challenges remain to be overcome. Over the years, the concept of "spectral engineering" (tailoring the complex interplay between molecular physics and the various optical phenomena occurring across the electromagnetic spectrum) has become increasingly relevant in the field of pi-conjugated organic polymers. Within the spectral engineering toolbox, the "donor-acceptor" approach uses alternating electron-rich and electron-deficient moieties along a pi-conjugated backbone. This approach has proved especially valuable in the synthesis of dual band and broadly absorbing chromophores with useful photovoltaic and electrochromic properties. In this Account, we highlight and provide insight into a present controversy surrounding the origin of the dual band of absorption sometimes encountered in semiconducting polymers structured using the "donor acceptor" approach. Based on empirical evidence, we provide some schematic representations to describe the possible mechanisms governing the evolution of the two-band spectral absorption observed on varying the relative composition of electron-rich and electron-deficient substituents along the pi-conjugated backbone. In parallel, we draw attention to the choice of the method employed to estimate and compare the absorption coefficients of polymer chromophores exhibiting distinct repeat unit lengths, and containing various extents of solubilizing side-chains along their backbone. Finally, we discuss the common assumption that "donor-acceptor" systems should have systematically lower absorption coefficients than their "all-donor" counterparts. The proposed models point toward important theoretical parameters which could be further explored at the macromolecular level to help researchers take full advantage of the complex interactions taking place in pi-conjugated polymers with intramolecular "donor acceptor" characteristics. PMID- 20726544 TI - Breakdown of cell wall nanostructure in dilute acid pretreated biomass. AB - The generation of bioethanol from lignocellulosic biomass holds great promise for renewable and clean energy production. A better understanding of the complex mechanisms of lignocellulose breakdown during various pretreatment methods is needed to realize this potential in a cost and energy efficient way. Here we use small-angle neutron scattering (SANS) to characterize morphological changes in switchgrass lignocellulose across molecular to submicrometer length scales resulting from the industrially relevant dilute acid pretreatment method. Our results demonstrate that dilute acid pretreatment increases the cross-sectional radius of the crystalline cellulose fibril. This change is accompanied by removal of hemicellulose and the formation of R(g) ~ 135 A lignin aggregates. The structural signature of smooth cell wall surfaces is observed at length scales larger than 1000 A, and it remains remarkably invariable during pretreatment. This study elucidates the interplay of the different biomolecular components in the breakdown process of switchgrass by dilute acid pretreatment. The results are important for the development of efficient strategies of biomass to biofuel conversion. PMID- 20726545 TI - Mutation of charged residues to neutral ones accelerates urea denaturation of HP 35. AB - Following the studies of urea denaturation of beta-hairpins using molecular dynamics, in this paper, molecular dynamics simulations of two peptides, a 35 residue three helix bundle villin headpiece protein HP-35 and its doubly norleucine-substituent mutant (Lys24Nle/Lys29Nle) HP-35 NleNle, were undertaken in urea solutions to understand the molecular mechanism of urea denaturation of alpha-helices. The mutant HP-35 NleNle was found to denature more easily than the wild type. During the expansion of the small hydrophobic core, water penetration occurs first, followed by that of urea molecules. It was also found that the initial hydration of the peptide backbone is achieved through water hydrogen bonding with the backbone CO groups during the denaturation of both polypeptides. The mutation of the two charged lysine residues to apolar norleucine enhances the accumulation of urea near the hydrophobic core and facilitates the denaturation process. Urea also interacts directly with the peptide backbone as well as side chains, thereby stabilizing nonnative conformations. The mechanism revealed here is consistent with the previous study on secondary structure of beta-hairpin polypeptide, GB1, PEPTIDE 1, and TRPZIP4, suggesting that there is a general mechanism in the denaturation of protein backbone hydrogen bonds by urea. PMID- 20726546 TI - The crystal structure of a constitutively active mutant RON kinase suggests an intramolecular autophosphorylation hypothesis. AB - A complex of RON(M1254T) with AMP-PNP and Mg(2+) reveals a substratelike positioning of Tyr1238 as well as likely catalysis-competent placement of the AMP PNP and Mg(2+) components and indicates a tendency for cis phosphorylation. The structure shows how the oncogenic mutation may cause the constitutive activation and suggests a mechanistic hypothesis for the autophosphorylation of receptor tyrosine kinases. PMID- 20726547 TI - Supramolecular liquid crystalline pi-conjugates: the role of aromatic pi-stacking and van der Waals forces on the molecular self-assembly of oligophenylenevinylenes. AB - Here, we report a unique design strategy to trace the role of aromatic pi stacking and van der Waals interactions on the molecular self-organization of pi conjugated building blocks in a single system. A new series of bulky oligophenylenevinylenes (OPVs) bearing a tricyclodecanemethylene (TCD) unit in the aromatic pi-core with flexible long methylene chains (n = 0-12 and 16) in the longitudinal position were designed and synthesized. The OPVs were found to be liquid crystalline, and their enthalpies of phase transitions (also entropies) showed odd-even oscillation with respect to the number of carbon atoms in alkyl chains. OPVs with an even number of methylene units in the side chains showed higher enthalpies with respect to their highly packed solid structures compared to odd-numbered ones. Polarized light microscopic analysis confirmed the formation of cholesteric liquid crystalline (LC) phases of fan shaped textures with focal conics in OPVs with 5 <= n <= 9. OPVs with longer alkyl chains (OPV-10 to OPV-12) produced a birefringence pattern consisting of dark and bright ring banded suprastructures. The melting temperature followed a sigmoidal trend, indicating the transformation of molecular self-organization in OPVs from solid to ring-banded suprastructures via cholesteric LC intermediates. At longer alkyl chain lengths, the van der Waals interactions among the alkyl chains became predominant and translated the mesogenic effect across the lamellae; as a consequence, the lamellae underwent twisted self-organization along the radial growth direction of the spherulites to produce bright and dark bands. Scanning electron microscope (SEM) analysis of cholesteric LC and ring-banded textures strongly supported the existence of twisted lamellae in the OPVs with ring-banded textures. Variable temperature X-ray diffraction analysis confirmed the reversibility of the molecular self-organization in the solid state and also showed the existence of the higher ordered lamellar structure in ring-banded OPVs. Photophysical characterizations such as excitation, emission, and time resolved fluorescence decay measurements were employed to trace molecular self organization in their liquid crystalline phases. The emission spectra of the OPV samples showed odd-even oscillation in their emission wavelengths with respect to the length of alkyl chains. Highly packed even-OPVs showed more blue shift compared to that of less crystalline odd-OPVs. Time dependent fluorescence decay of OPVs followed a biexponential fit, and their lifetimes (tau(1) and tau(2) values) revealed that the decay is faster for odd-OPVs compared to even-OPVs. Among all the OPVs, the tau(2) values for OPV-8 and OPV-12 were found to be much higher, indicating their high luminescent characteristics. In a nut shell, bulky liquid crystalline OPV chromophores were cleverly utilized, for the first time, to probe the aromatic pi-stacking versus van der Waals interactions on the molecular self-organization of pi-conjugated system. PMID- 20726548 TI - Solution NMR structure of the TatA component of the twin-arginine protein transport system from gram-positive bacterium Bacillus subtilis. AB - The twin-arginine transport (Tat) system translocates folded proteins across the bacterial cytoplasmic or chloroplast thylakoid membrane of plants. The Tat system in most Gram-positive bacteria consists of two essential components, the TatA and TatC proteins. TatA is considered to be a bifunctional subunit, which can form a protein-conducting channel by self-oligomerization and can also participate in substrate recognition. However, the molecular mechanism underlying protein translocation remains elusive. Herein, we report the solution structure of the TatA(d) protein from Bacillus subtilis by NMR spectroscopy, the first structure of the Tat system at atomic resolution. TatA(d) shows an L-shaped structure formed by a transmembrane helix and an amphipathic helix, while the C-terminal tail is largely unstructured. Our results strongly support the postulated topology of TatA(d) in which the transmembrane helix is inserted into the lipid bilayer while the amphipathic helix lies at the membrane-water interface. Moreover, the structure of TatA(d) revealed the structural importance of several conserved residues at the hinge region, thus shedding new light on further elucidation of the protein transport mechanism of the Tat system. PMID- 20726549 TI - TAPC-promoted oxidation of sulfides and deoxygenation of sulfoxides. AB - 1,3,5-Triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) was found to be an efficient promoter for the oxidation of sulfides and deoxygenation of sulfoxides. Excellent yields, short reaction time, easy and quick isolation of the products, solvent-free process, and excellent chemoselectivity are the main advantages of this procedure. PMID- 20726551 TI - Ultrasmall titania nanocrystals and their direct assembly into mesoporous structures showing fast lithium insertion. AB - Ultrasmall and highly soluble anatase nanoparticles were synthesized from TiCl(4) using tert-butyl alcohol as a new reaction medium. This synthetic protocol widens the scope of nonaqueous sol-gel methods to TiO(2) nanoparticles of around 3 nm with excellent dispersibility in ethanol and tert-butanol. Microwave heating was found to enhance the crystallinity of the nanoparticles and to drastically shorten the reaction time to less than 1 h at temperatures as low as 50 degrees C. The extremely small size of the nanoparticles and their dispersibility make it possible to use commercial Pluronic surfactants for evaporation-induced self assembly of the nanoparticulate building blocks into periodic mesoporous structures. A solution of particles after synthesis can be directly used for preparation of mesoporous films without the need for particle separation. The mesoporous titania coatings fabricated using this one-pot procedure are crystalline and exhibit high surface areas of up to 300 m(2)/g. The advantages of the retention of the mesoporous order with extremely thin nanocrystalline walls were shown by electrochemical lithium insertion. The films made using microwave treated nanoparticles showed supercapacitive behavior with high maximum capacitance due to quantitative lithiation with a 10-fold increase of charging rates compared to a standard reference electrode made from 20 nm anatase particles. PMID- 20726552 TI - Comparative proteomic analysis of triclabendazole response in the liver fluke Fasciola hepatica. AB - Control of Fasciola hepatica infections of livestock in the absence of vaccines depends largely on the chemical triclabendazole (TCBZ) because it is effective against immature and adult parasites. Overdependence on a single drug and improper application is considered a significant factor in increasing global reports of fluke resistant to TCBZ. The mode(s) of action and biological target(s) of TCBZ are not confirmed, delaying detection and the monitoring of early TCBZ resistance. In this study, to further understand liver fluke response to TCBZ, the soluble proteomes of TCBZ-resistant and TCBZ-susceptible isolates of F. hepatica were compared with and without in vitro exposure to the metabolically active form of the parent drug triclabendazole sulphoxide (TCBZ-SO), via two dimensional gel electrophoresis (2-DE). Gel image analysis revealed proteins displaying altered synthesis patterns and responses both between isolates and under TCBZ-SO exposure. These proteins were identified by mass spectrometry supported by a F. hepatica expressed sequence tag (EST) data set. The TCBZ responding proteins were grouped into three categories; structural proteins, energy metabolism proteins, and "stress" response proteins. This single proteomic investigation supported the reductionist experiments from many laboratories that collectively suggest TCBZ has a range of effects on liver fluke metabolism. Proteomics highlighted differences in the innate proteome profile of different fluke isolates that may influence future therapy and diagnostics design. Two of the TCBZ responding proteins, a glutathione transferase and a fatty acid binding protein, were cloned, produced as recombinants, and both found to bind TCBZ-SO at physiologically relevant concentrations, which may indicate a role in TCBZ metabolism and resistance. PMID- 20726554 TI - Solvation effects on S K-edge XAS spectra of Fe-S proteins: normal and inverse effects on WT and mutant rubredoxin. AB - S K-edge X-ray absorption spectroscopy (XAS) was performed on wild type Cp rubredoxin and its Cys --> Ser mutants in both solution and lyophilized forms. For wild type rubredoxin and for the mutants where an interior cysteine residue (C6 or C39) is substituted by serine, a normal solvent effect is observed, that is, the S covalency increases upon lyophilization. For the mutants where a solvent accessible surface cysteine residue is substituted by serine, the S covalency decreases upon lyophilization which is an inverse solvent effect. Density functional theory (DFT) calculations reproduce these experimental results and show that the normal solvent effect reflects the covalency decrease due to solvent H-bonding to the surface thiolates and that the inverse solvent effect results from the covalency compensation from the interior thiolates. With respect to the Cys --> Ser substitution, the S covalency decreases. Calculations indicate that the stronger bonding interaction of the alkoxide with the Fe relative to that of thiolate increases the energy of the Fe d orbitals and reduces their bonding interaction with the remaining cysteines. The solvent effects support a surface solvent tuning contribution to electron transfer, and the Cys --> Ser result provides an explanation for the change in properties of related iron sulfur sites with this mutation. PMID- 20726555 TI - Kinetic study of the quenching reaction of singlet oxygen by carotenoids and food extracts in solution. Development of a singlet oxygen absorption capacity (SOAC) assay method. AB - A kinetic study of the quenching reaction of singlet oxygen (1O2) with eight kinds of carotenoids and alpha-tocopherol was performed in ethanol/chloroform/D2O (50:50:1, v/v/v) solution at 35 degrees C. The overall rate constants, kQ (=kq+kr, physical quenching+chemical reaction), for the reaction of carotenoids with 1O2 were measured, using the competition reaction method, where endoperoxide was used as a singlet oxygen generator, 2,5-diphenyl-3,4-benzofuran (DPBF) as an UV-vis absorption prove, and alpha-tocopherol as a standard compound. The rate constants, kQ (S) and kQ (t1/2), were determined by analyzing the first-order rate constant (S) and the half-life (t1/2) of the decay curve of DPBF with carotenoids, respectively, showing good accordance with each other. Similar measurements were performed for tomato and carrot extracts. From the results, a new assay method that can quantify the singlet oxygen absorption capacity (SOAC) of antioxidants, including carotenoids, alpha-tocopherol, and vegetable extracts, has been proposed. PMID- 20726553 TI - A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules. AB - Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small molecule protein interactions. PMID- 20726556 TI - Double thermoresponsive block copolymers featuring a biotin end group. AB - A poly(oligo(ethylene glycol) monomethyl ether methacrylate)-block-poly(N isopropyl methacrylamide) (POEGMA-b-PNIPMAM) block copolymer with a biotin end group on the PNIPMAM block as a biotarget was synthesized as a model system for temperature-controlled polymer immobilization. The synthesis was based on RAFT polymerization followed by postpolymerization modification of an activated ester precursor block and an exchange of the dithioester end group within one step. NMR, differential scanning calorimetry (DSC), dynamic light scattering (DLS), and turbidimetry measurements were performed to investigate the stimulus-responsive properties. The double thermoresponsive POEGMA-b-PNIPMAM with biotin end group showed a temperature-dependent multistage assembly behavior as it was completely soluble in water at temperatures below the LCST of both blocks, formed micellar structures above the LCST of PNIPMAM but below the LCST of POEGMA, or precipitated from solution above the LCST of both blocks. At room temperature, the polymer could be immobilized onto a streptavidin surface via its biotin end group, as shown in surface plasmon resonance (SPR) experiments. At 50 degrees C, at which the block copolymer formed micelles trapping the biotin target within the PNIPMAM core, no immobilization was observed, showing that the biological binding ability of the model could be controlled via external stimuli. PMID- 20726557 TI - Facile synthesis of bicyclic amidines and imidazolines from 1,2-diamines. AB - A facile synthesis of chiral bicyclic amidines and imidazolines from readily available 1,2-diamines has been developed. The reported synthetic strategy relies on an intramolecular cyclization which involves a carboxylic amide derived imidoyl chloride as a key intermediate and aniline serving as a leaving group. PMID- 20726558 TI - Sensing of bacterial endotoxin in aqueous solution by supramolecular assembly of pyrene derivative. AB - N,N-dimethyl-N-(pyrenyl-1-methyl) dodecan-1-ammonium has been designed and applied as a fluorescent probe for sensing bacterial endotoxin. Upon assembly with bacterial endotoxin (lipopolysaccharide) in aqueous solution, the probe exhibits a ratiometric and sensitive fluorescence response with a low detection limit (100 nM). Moreover, the probe shows high selectivity for bacterial endotoxin over other related biological species. PMID- 20726559 TI - Nanocomposites containing gold nanorods and porphyrin-doped mesoporous silica with dual capability of two-photon imaging and photosensitization. AB - Novel multifunctional nanoparticles that combine two functionalities (a gold nanorod core and a porphyrin-doped mesoporous silica shell) into one entity were synthesized. Due to the encapsulation of mesoporous silica, the porphyrin can be well protected against the external bioenvironment. In addition, the generated singlet oxygen by porphyrin molecules can be easily released from the silica. We have demonstrated that these multifunctional nanoparticles can generate singlet oxygen with relatively higher yield compared to free porphyrin. These multifunctional nanocomposites are attractive candidates for simultaneous photosensitization and two-photon imaging as well as imaging guided therapy. PMID- 20726560 TI - meso-Tris(oligo-2,5-thienylene)-substituted subporphyrins. AB - meso-Tris(oligo-2,5-thienylene)-substituted subporphyrins exhibit remarkably red shifted and intensified absorption bands with increasing number of thienyl subunits. A dimeric subporphyrin obtained from homocoupling of a monobrominated tris(2-thienyl)-substituted subporphyrin exhibits a split Soret-like band due to the exciton coupling. PMID- 20726562 TI - A concise and stereoselective synthesis of hydroxypyrrolidines: rapid synthesis of (+)-preussin. AB - A convergent and stereoselective synthesis of 2,5-disubstituted 3 hydroxypyrrolidines has been developed that involves reductive annulation of beta iminochlorohydrins, which are readily available from beta-ketochlorohydrins, and provides rapid access to a variety of 2,5-syn-pyrrolidines. Application of this process to the concise (three-step) synthesis of the fungal metabolite (+) preussin and analogues of this substance is reported. PMID- 20726561 TI - Shared biosynthesis of the saliniketals and rifamycins in Salinispora arenicola is controlled by the sare1259-encoded cytochrome P450. AB - Saliniketals A and B are unusual polyketides from the marine actinomycete Salinispora arenicola that inhibit ornithine decarboxylase induction. The structural similarities between the saliniketals and the ansa chain of the potent rifamycin antibiotics, which co-occur in the fermentation broth, suggest a common origin between the two compound classes. Using PCR-directed mutagenesis, chemical complementation studies, and stable isotope feeding experiments, we showed that the saliniketals are byproducts of the rifamycin biosynthetic pathway diverging at the stage of 34a-deoxyrifamycin W. Our results suggest that a single enzyme, the cytochrome P450 monooxygenase encoded by sare1259, catalyzes multiple oxidative rearrangement reactions on 34a-deoxyrifamyin W to yield both the saliniketal and rifamycin structural classes. PMID- 20726563 TI - Cobalt-porphyrin catalyzed electrochemical reduction of carbon dioxide in water. 2. Mechanism from first principles. AB - We apply first principles computational techniques to analyze the two-electron, multistep, electrochemical reduction of CO(2) to CO in water using cobalt porphyrin as a catalyst. Density functional theory calculations with hybrid functionals and dielectric continuum solvation are used to determine the steps at which electrons are added. This information is corroborated with ab initio molecular dynamics simulations in an explicit aqueous environment which reveal the critical role of water in stabilizing a key intermediate formed by CO(2) bound to cobalt. By use of potential of mean force calculations, the intermediate is found to spontaneously accept a proton to form a carboxylate acid group at pH < 9.0, and the subsequent cleavage of a C-OH bond to form CO is exothermic and associated with a small free energy barrier. These predictions suggest that the proposed reaction mechanism is viable if electron transfer to the catalyst is sufficiently fast. The variation in cobalt ion charge and spin states during bond breaking, DFT+U treatment of cobalt 3d orbitals, and the need for computing electrochemical potentials are emphasized. PMID- 20726564 TI - Synthesis of 3-oxa- and 3-azabicyclo[4.1.0]heptanes by gold-catalyzed cycloisomerization of cyclopropenes. AB - Allyl 3,3-dimethylcyclopropenylcarbinyl ethers or sulfonamides undergo gold catalyzed cycloisomerization leading to 5-isopropylidene-3-oxa- and 3 azabicyclo[4.1.0]heptanes in excellent yields and with high diastereoselectivities. These reactions constitute the first examples of intramolecular cyclopropanation of an alkene by a gold carbene generated by electrophilic ring opening of a cyclopropene in the presence of gold(I) chloride. PMID- 20726565 TI - N-heterocyclic carbene embedded in an N-confused porphyrin framework. AB - A rhenium(I) complex of an N-heterocyclic carbene ligand embedded in an N confused porphyrin core was serendipitously synthesized by the reaction of an inner-methylated N-confused porphyrin with Re(2)(CO)(10). PMID- 20726566 TI - Room-temperature alternative to the Arbuzov reaction: the reductive deoxygenation of acyl phosphonates. AB - The reductive deoxygenation of acyl phosphonates using a Wolff-Kishner-like sequence is described. This transformation allows direct access to alkyl phosphonates from acyl phosphonates at room temperature. The method can be combined with acyl phosphonate synthesis into a one pot, four-step procedure for the conversion of carboxylic acids into alkyl phosphonates. The methodology works well for a variety of aliphatic acids and shows a functional group tolerance similar to that of other hydrazone-forming reactions. PMID- 20726567 TI - Plasmonic nanowire antennas: experiment, simulation, and theory. AB - Recent advances in nanolithography have allowed shifting of the resonance frequency of antennas into the optical and visible wavelength range with potential applications, for example, in single molecule spectroscopy by fluorescence and directionality enhancement of molecules. Despite such great promise, the analytical means to describe the properties of optical antennas is still lacking. As the phase velocity of currents at optical frequencies in metals is much below the speed of light, standard radio frequency (RF) antenna theory does not apply directly. For the fundamental linear wire antenna, we present an analytical description that overcomes this shortage and reveals profound differences between RF and plasmonic antennas. It is fully supported by apertureless scanning near-field optical microscope measurements and finite difference time-domain simulations. This theory is a starting point for the development of analytical models of more complex antenna structures. PMID- 20726568 TI - RNA tetraloop folding reveals tension between backbone restraints and molecular interactions. AB - In RNA, A-form helices are commonly terminated by tetraloops or 3' dangling ends. Aside from helices themselves, these helix-breaking motifs appear to be among the most frequent and repetitive structural elements of large folded RNAs. We show here that within a frequent type of tetraloop, cGNRAg (G is guanine, N is any base, R is purine, A is adenine), a tension exists between the backbone torsional energy of the loop and the energy contributed by molecular interactions (stacking and pairing). A model in which favorable bond rotamers are opposed by favorable stacking and pairing interactions is consistent with our observation that release of torsional restraints upon conversion of one or more loop riboses to more flexible trimethylene phosphate(s) contributes favorably to the enthalpy of folding. This effect presumably results from improved stacking and hydrogen bonding interactions upon release of torsional restraints. The most obvious possibility for improving molecular interactions is a repositioning of A, which is proximal to the unfavorable torsion angles in native cGNRAg tetraloops, and which is unstacked on the 3' side and unpaired (it forms a single hydrogen bond with the opposing G). This tension between favorable bond rotamers and favorable molecular interactions may be representative of a general evolutionary strategy to prevent achievement of deep and irreversible thermodynamic wells in folded RNAs. Finally, we observe a simple stacking substructure with conserved geometry and sequence that forms a scaffold for both tetraloops and 3' dangling ends. It seems that simple substructures can build RNA motifs, which combine to establish the fundamental architecture of RNA. PMID- 20726570 TI - Regenerable DNA-functionalized hydrogels for ultrasensitive, instrument-free mercury(II) detection and removal in water. AB - Mercury is a highly toxic environmental pollutant with bioaccumulative properties. Therefore, new materials are required to not only detect but also effectively remove mercury from environmental sources such as water. We herein describe a polyacrylamide hydrogel-based sensor functionalized with a thymine rich DNA that can simultaneously detect and remove mercury from water. Detection is achieved by selective binding of Hg(2+) between two thymine bases, inducing a hairpin structure where, upon addition of SYBR Green I dye, green fluorescence is observed. In the absence of Hg(2+), however, addition of the dye results in yellow fluorescence. Using the naked eye, the detection limit in a 50 mL water sample is 10 nM Hg(2+). This sensor can be regenerated using a simple acid treatment and can remove Hg(2+) from water at a rate of approximately 1 h(-1). This sensor was also used to detect and remove Hg(2+) from samples of Lake Ontario water spiked with mercury. In addition, these hydrogel-based sensors are resistant to nuclease and can be rehydrated from dried gels for storage and DNA protection. Similar methods can be used to functionalize hydrogels with other nucleic acids, proteins, and small molecules for environmental and biomedical applications. PMID- 20726569 TI - Withaferin A, a cytotoxic steroid from Vassobia breviflora, induces apoptosis in human head and neck squamous cell carcinoma. AB - As part of a program to discover drug leads from plant biodiversity, the present investigation was undertaken to explore the anticancer potential of compounds derived from selected Latin American plants. Bioassay-guided fractionation of a crude extract of the aerial parts of Vassobia breviflora led to the isolation of the withanolide-type steroidal lactone withaferin A (1). This compound was tested for antiproliferative activity against the head and neck squamous cell carcinoma (HNSCC) cell lines, MDA1986, JMAR, UM-SCC-2, and JHU011. The inhibitory concentrations to reduce cell viability to 50% (IC(50)) were determined by the MTS cytotoxicity assay, and 1 reduced cell viability with IC(50) values in the range 0.5-2.2 MUM. A mechanistic study showed that 1 induces apoptosis and cell death in HNSCC cells as well as a cell-cycle shift from G(0)/G(1) to G(2)/M. Cells treated with 1 exhibited inactivation of Akt and a reduction in total Akt concentration. This investigation constitutes the first report of the antiproliferative activity of withaferin A (1) against head and neck squamous carcinoma. PMID- 20726571 TI - Assembly/disassembly of drug conjugates using imide ligation. AB - A strategy is described that allows the easy assembly and controlled disassembly of drug conjugates. Imide ligation, that is, the reaction of a peptide thioacid with an azidoformate, is used for conjugate assembly. The imide bond participates also with an endopeptidase-triggered cyclization-based disassembly mechanism. PMID- 20726572 TI - Synthesis of vinyl sulfides by copper-catalyzed decarboxylative C-S cross coupling. AB - A novel method for the synthesis of vinyl sulfides by the decarboxylative cross coupling of arylpropiolic acids with thiols using copper(I) salts as catalysts has been developed. In the presence of CuI and Cs(2)CO(3), a variety of thiols reacted with arylpropiolic acids to afford the corresponding vinyl sulfides in good to excellent yields with high stereoselectivity for Z-isomers. PMID- 20726573 TI - Large-scale density functional theory investigation of failure modes in ZnO nanowires. AB - Electromechanical and photonic properties of semiconducting nanowires depend on their strain states and are limited by their extent of deformation. A fundamental understanding of the mechanical response of individual nanowires is therefore essential to assess system reliability and to define the design space of future nanowire-based devices. Here we perform a large-scale density functional theory (DFT) investigation of failure modes in zinc oxide (ZnO) nanowires. Nanowires as large as 3.6 nm in diameter with 864 atoms were investigated. The study reveals that pristine nanowires can be elastically deformed to strains as high as 20%, prior to a phase transition leading to fracture. The current study suggests that the phase transition predicted at approximately 10% strain in pristine nanowires by the Buckingham pairwise potential (BP) is an artifact of approximations inherent in the BP. Instead, DFT-based energy barrier calculations suggest that defects may trigger heterogeneous phase transition leading to failure. Thus, the difference previously reported between in situ electron microscopy tensile experiments (brittle fracture) and atomistic simulations (phase transition and secondary loading) (Agrawal, R.; Peng, B.; Espinosa, H. D. Nano Lett. 2009, 9 (12), 4177-2183) is elucidated. PMID- 20726574 TI - Two concise total syntheses of (-)-bitungolide F. AB - The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6% overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy. PMID- 20726575 TI - N-acyldithieno[3,2-b:2',3'-d]pyrroles: second generation dithieno[3,2-b:2',3' d]pyrrole building blocks with stabilized energy levels. AB - A new class of dithieno[3,2-b:2',3'-d]pyrroles (DTPs) incorporating N-acyl groups have been prepared from 3-bromothiophene via copper-catalyzed amidation. The utilization of various electron-withdrawing acyl groups has allowed stabilization of the HOMO and LUMO energy levels of these popular building blocks for conjugated materials. The synthesis and characterization of this new class of compounds is described, including electrochemical and photophysical data for all compounds and X-ray structural data for the octanoyl, benzoyl, and cyclohexanoyl functionalized compounds. Initial polymers generated via electropolymerization are also reported. PMID- 20726576 TI - A robust highly interpenetrated metal-organic framework constructed from pentanuclear clusters for selective sorption of gas molecules. AB - A three-dimensional microporous metal-organic framework, Zn(5)(BTA)(6)(TDA)(2).15DMF.8H(2)O (1; HBTA = 1,2,3-benzenetriazole; H(2)TDA = thiophene-2,5-dicarboxylic acid), comprising pentanuclear [Zn(5)] cluster units, was obtained through an one-pot solvothermal reaction of Zn(NO(3))(2), 1,2,3 benzenetriazole, and thiophene-2,5-dicarboxylate. The activated 1 displays type-I N(2) gas sorption behavior with a Langmuir surface area of 607 m(2) g(-1) and exhibits interesting selective gas adsorption for C(2)H(2)/CH(4) and CO(2)/CH(4). PMID- 20726577 TI - First step in chemical preparation of metal nanogaps bridged by thiol end-capped molecular wires. AB - We present a strategy for chemical preparation of multiple copies of single molecule electronic devices that is based on chemical self-assembly under equilibrium conditions in aqueous solution. As a first step in the realization of this, we show that thiol end-capped oligo(phenylenevinylene)s (OPVs) can be rendered water-soluble by forming well-defined stoichiometric supramolecular complexes with alpha-cyclodextrins. On the basis of fluorescence intensity measurements in water, a 1:3 stoichiometry was determined for the complexes with equilibrium constants of the order of 5 * 10(-2) M(-2). The photophysical properties of the OPV3s as free molecules in solution, as nanoaggregates in aqueous suspension, and embedded in cyclodextrins in water, are reported, and the prospects of using these complexes as nucleation sites for growth of gold nanorods bridged by electronically active thiol end-capped molecules is discussed. PMID- 20726578 TI - Ligand effects on the [Cu(PhO)(PhOH)]+ redox active complex. AB - Under gas phase conditions, the [Cu(PhO)(PhOH)](+) complex is composed of copper(I), a phenoxy radical bound via the oxygen atom, and a phenol bound via the aromatic ring. Effects of additional ligand coordination on the molecular and electronic structure of the complex [Cu(PhO)(PhOH)](+) are investigated by mass spectrometric and quantum chemical means for [Cu(PhO)L](+) (L = H(2)O, CH(3)OH, tetrahydrofuran, NH(3), pyridine, imidazole, 1,2-dimethoxyethylene, N,N,N',N' tetramethylethylenediamine, pyrrole, and thiophene) and [Cu(PhO)(PhOH)L(n)](+) (L = H(2)O, NH(3), and 4-methylimidazole) models. The nature and number of additional ligands critically influences the spin distribution in the complex, which is sensitively reflected by the phenoxy CO stretching mode. PMID- 20726579 TI - Two-dimensional (2+n) REMPI of CH(3)Br: photodissociation channels via Rydberg states. AB - (2+n) resonance enhanced multiphoton ionization (REMPI) spectra of CH(3)Br for the masses H(+), CH(m)(+), (i)Br(+), H(i)Br(+), and CH(m)(i)Br(+) (m = 0-3; i = 79, 81) have been recorded in the 66 000-81 000 cm(-1) resonance energy range. Signals due to resonance transitions from the zero vibrational energy level of the ground state CH(3)Br to a number of Rydberg states [Omega(c)]nl;omega (Omega(c) = 3/2, 1/2; omega = 0, 2; l = 1(p), 2(d)) and various vibrational states were identified. C((3)P) and C*((1)D) atom and HBr intermediate production, detected by (2+1) REMPI, most probably is due to photodissociation of CH(3)Br via two-photon excitations to Rydberg states followed by an unusual breaking of four bonds and formation of two bonds to give the fragments H(2) + C/C* + HBr prior to ionization. This observation is supported by REMPI observations as well as potential energy surface (PES) ab initio calculations. Bromine atom production by photodissociation channels via two-photon excitation to Rydberg states is identified by detecting bromine atom (2+1) REMPI. PMID- 20726580 TI - The BCL-2 5' untranslated region contains an RNA G-quadruplex-forming motif that modulates protein expression. AB - The BCL-2 gene encodes a 25 kDa membrane protein that plays critical roles in the control of apoptosis. The regulation of BCL-2 gene expression is highly complex and occurs both transcriptionally and posttranscriptionally. In particular, the 5' upstream region of BCL-2 contains a number of elements that control its expression. We have identified a highly conserved 25-nucleotide G-rich sequence (BCL2Q), with potential to fold into a RNA G-quadruplex structure, located 42 nucleotides upstream of the translation start site of human BCL-2. In this study, we used a series of biophysical experiments to show that the BCL2Q sequence folds into a stable RNA G-quadruplex in vitro, and we conducted functional luciferase reporter-based assays, in a cell-free lysate and in three types of human cell lines, to demonstrate that the BCL2Q sequence modulates protein expression in the context of the 493-nucleotide native 5' untranslated region of BCL-2. PMID- 20726581 TI - Flexible particle array structures by controlling polymer graft architecture. AB - Surface-initiated atom-transfer radical polymerization is used to synthesize particle brushes with controlled fraction of extended and relaxed conformations of surface-grafted chains. In the semidilute brush limit, the grafting of polymeric ligands is shown to facilitate the formation of ordered yet plastic compliant particle array structures in which chain entanglements give rise to fracture through a polymer-like crazing process that dramatically increases the toughness and flexibility of the particle assembly. PMID- 20726583 TI - Chemical structure and heterogeneity differences of two lignins from loblolly pine as investigated by advanced solid-state NMR spectroscopy. AB - Advanced solid-state NMR was employed to investigate differences in chemical structure and heterogeneity between milled wood lignin (MWL) and residual enzyme lignin (REL). Wiley and conventional milled woods were also studied. The advanced NMR techniques included 13C quantitative direct polarization, various spectral editing techniques, and two-dimensional 1H-13C heteronuclear correlation NMR with 1H spin diffusion. The 13C chemical shift regions between 110 and 160 ppm of two lignins were quite similar to those of two milled woods. REL contained much more residual carbohydrates than MWL, showing that MWL extraction more successfully separated lignin from cellulose and hemicelluloses than REL extraction; REL was also of higher COO, aromatic C-C, and condensed aromatics but of lower aromatic C H. At a spin diffusion time of 0.55 ms, the magnetization was equilibrated through the whole structure of MWL lignin, but not through that of REL, indicating that REL is more heterogeneous than MWL. PMID- 20726584 TI - Development and application of an HILIC-MS/MS method for the quantitation of nucleotides in infant formula. AB - A method for the quantitation of nucleotides (adenosine 5'-monophosphate (AMP), guanosine 5'-monophosphate (GMP), uridine 5'-monophosphate (UMP), cytidine 5' monophosphate (CMP), and inosine 5'-monophosphate (IMP)) in infant formula was developed by hydrophilic interaction chromatography with tandem mass spectrometry (HILIC-MS/MS). The internal standards used (AMP-13C10, 15N5; GMP-13C10, 15N5; UMP 13C9, 15N2; CMP-13C9, 15N3) were prepared with centrifugal ultrafiltration (CUF). Data acquisition was achieved by using multiple reaction monitoring (MRM) of product ions of protonated molecules of the five nucleotides generated by the positive-ion ESI. HILIC conditions were performed with 30 mmol/L ammonium formate in water (pH 2.5, adjusted with formic acid) and methanol. The LOD and LOQ were 5 10 MUg/mL and 10-30 MUg/mL for standard solution, respectively. Recovery for intra- and interday assays ranged from 98.1 to 108.9% (RSD: 0.7-5.4%) spiked with three concentration levels (5, 25, and 250 MUg/g powder infant formula). This method could be applied for the determination of nucleotides in infant formula samples. The detected concentrations of five nucleotides ranged from not detected (n.d.) to 278 MUg/g powder infant formula. The total nucleotide level ranged from n.d. to 600.2 MUg/g powder infant formula. PMID- 20726582 TI - Crystal structures of covalent complexes of beta-lactam antibiotics with Escherichia coli penicillin-binding protein 5: toward an understanding of antibiotic specificity. AB - Penicillin-binding proteins (PBPs) are the molecular targets for the widely used beta-lactam class of antibiotics, but how these compounds act at the molecular level is not fully understood. We have determined crystal structures of Escherichia coli PBP 5 as covalent complexes with imipenem, cloxacillin, and cefoxitin. These antibiotics exhibit very different second-order rates of acylation for the enzyme. In all three structures, there is excellent electron density for the central portion of the beta-lactam, but weak or absent density for the R1 or R2 side chains. Areas of contact between the antibiotics and PBP 5 do not correlate with the rates of acylation. The same is true for conformational changes, because although a shift of a loop leading to an electrostatic interaction between Arg248 and the beta-lactam carboxylate, which occurs completely with cefoxitin and partially with imipenem and is absent with cloxacillin, is consistent with the different rates of acylation, mutagenesis of Arg248 decreased the level of cefoxitin acylation only 2-fold. Together, these data suggest that structures of postcovalent complexes of PBP 5 are unlikely to be useful vehicles for the design of new covalent inhibitors of PBPs. Finally, superimposition of the imipenem-acylated complex with PBP 5 in complex with a boronic acid peptidomimetic shows that the position corresponding to the hydrolytic water molecule is occluded by the ring nitrogen of the beta-lactam. Because the ring nitrogen occupies a similar position in all three complexes, this supports the hypothesis that deacylation is blocked by the continued presence of the leaving group after opening of the beta-lactam ring. PMID- 20726585 TI - Species-dependent degradation of ciprofloxacin in a membrane anodic Fenton system. AB - The anodic Fenton treatment method (AFT) has been successfully applied to the removal of ciprofloxacin (CIP), a widely used fluoroquinolone antibiotic, from aqueous solution. Degradation kinetics were found to be species dependent. At initial pH 3.2, CIP remained in its cationic form and the kinetics followed a previously developed AFT model. At an initial near-neutral pH, CIP speciation changed during the degradation, due to pH changes over the process, and no obvious model fit the data. Density functional theory (DFT) calculations indicated a protonated species-dependent reaction affinity toward hydroxyl radicals. A new model based on the AFT model with the addition of species distribution during the degradation was derived, and it was shown to describe the degradation kinetics successfully. Degradation of reference compounds further confirmed that the free carboxylic acid group, which contributes to the species changes, plays a key role in the observed degradation pattern. Furthermore, degradation of reference CIP-metal complexes confirmed that the formation of these complexes does not have a major effect on the degradation pattern. Optimization of CIP degradation was carried out at pH 3.2 with an optimal H2O2/Fe2+ ratio found between 10:1 and 15:1. Three degradation pathways based on mass spectrometry data were also proposed: (1) hydroxylation and defluorination on the aromatic ring; (2) oxidative decarboxylation; and (3) oxidation on the piperazine ring and dealkylation. By the end of the AFT treatment, neither CIP nor its degradation products were detected, indicating successful removal of antibacterial properties. PMID- 20726586 TI - CO and O2 binding to pseudo-tetradentate ligand-copper(I) complexes with a variable N-donor moiety: kinetic/thermodynamic investigation reveals ligand induced changes in reaction mechanism. AB - The kinetics, thermodynamics, and coordination dynamics are reported for O(2) and CO 1:1 binding to a series of pseudo-tetradentate ligand-copper(I) complexes ((D)LCu(I)) to give Cu(I)/O(2) and Cu(I)/CO product species. Members of the (D)LCu(I) series possess an identical tridentate core structure where the cuprous ion binds to the bispicolylamine (L) fragment. (D)L also contains a fourth variable N-donor moiety {D = benzyl (Bz); pyridyl (Py); imidazolyl (Im); dimethylamino (NMe(2)); (tert-butylphenyl)pyridyl (TBP); quinolyl (Q)}. The structural characteristics of (D)LCu(I)-CO and (D)LCu(I) are detailed, with X-ray crystal structures reported for (TBP)LCu(I)-CO, (Bz)LCu(I)-CO, and (Q)LCu(I). Infrared studies (solution and solid-state) confirm that (D)LCu(I)-CO possess the same four-coordinate core structure in solution with the variable D moiety "dangling", i.e., not coordinated to the copper(I) ion. Other trends observed for the present series appear to derive from the degree to which the D-group interacts with the cuprous ion center. Electrochemical studies reveal close similarities of behavior for (Im)LCu(I) and (NMe(2))LCu(I) (as well as for (TBP)LCu(I) and (Q)LCu(I)), which relate to the O(2) binding kinetics and thermodynamics. Equilibrium CO binding data (K(CO), DeltaH degrees , DeltaS degrees ) were obtained by conducting UV-visible spectrophotometric CO titrations, while CO binding kinetics and thermodynamics (k(CO), DeltaH(double dagger), DeltaS(double dagger)) were measured through variable-temperature (193 293 K) transient absorbance laser flash photolysis experiments, lambda(ex) = 355 nm. Carbon monoxide dissociation rate constants (k(-CO)) and corresponding activation parameters (DeltaH(double dagger), DeltaS(double dagger)) have also been obtained. CO binding to (D)LCu(I) follows an associative mechanism, with the increased donation from D leading to higher k(CO) values. Unlike observations from previous work, the K(CO) values increased as the k(CO) and k(-CO) values declined; the latter decreased at a faster rate. By using the "flash-and-trap" method (lambda(ex) = 355 nm, 188-218 K), the kinetics and thermodynamics (k(O(2)), DeltaH(double dagger), DeltaS(double dagger)) for O(2) binding to (NMe(2))LCu(I) and (Im)LCu(I) were measured and compared to those for (Py)LCu(I). A surprising change in the O(2) binding mechanism was deduced from the thermodynamic DeltaS(double dagger) values observed, associative for (Py)LCu(I) but dissociative for (NMe(2))LCu(I) and (Im)LCu(I); these results are interpreted as arising from a difference in the timing of electron transfer from copper(I) to O(2) as this molecule coordinates and a tetrahydrofuran (THF) solvent molecule dissociates. The change in mechanism was not simply related to alterations in (D)LCu(II/I) geometries or the order in which O(2) and THF coordinate. The equilibrium O(2) binding constant (K(O(2)), DeltaH degrees , DeltaS degrees ) and O(2) dissociation rate constants (k(-O(2)), DeltaH(double dagger), DeltaS(double dagger)) were also determined. Overall the results demonstrate that subtle changes in the coordination environment, as occur over time through evolution in nature or through controlled ligand design in synthetic systems, dictate to a critically detailed level the observed chemistry in terms of reaction kinetics, structure, and reactivity, and thus function. Results reported here are also compared to relevant copper and/or iron biological systems and analogous synthetic ligand-copper systems. PMID- 20726587 TI - Atlantic ocean surface waters buffer declining atmospheric concentrations of persistent organic pollutants. AB - Decreasing environmental concentrations of some persistent organic pollutants (POPs) have been observed at local or regional scales in continental areas after the implementation of international measures to curb primary emissions. A decline in primary atmospheric emissions can result in re-emissions of pollutants from the environmental capacitors (or secondary sources) such as soils and oceans. This may be part of the reason why concentrations of some POPs such as polychlorinated biphenyls (PCBs) have not declined significantly in the open oceanic areas, although re-emission of POPs from open ocean water has barely been documented. In contrast, results from this study show that several polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) have undergone a marked decline (2-3 orders of magnitude for some homologues) over a major portion of the remote oligotrophic Atlantic Ocean. The decline appears to be faster than that observed over continental areas, implicating an important role of oceanic geochemical controls on levels and cycling of some POPs. For several lower chlorinated PCDD/Fs, we observed re-emission from surface water back to the atmosphere. An assessment of the effectiveness of the main sink processes highlights the role of degradation in surface waters as potentially key to explaining the different behavior between PCDD/Fs and PCBs and controlling their overall residence time in the ocean/atmosphere system. This study provides experimental evidence that the ocean has a buffering capacity - dependent on individual chemicals - which moderates the rate at which the system will respond to an underlying change in continental emissions. PMID- 20726588 TI - Synthesis and fluorescence properties of a pyridomethene-BF2 complex. AB - A fluorescent dye, the pyridomethene-BF(2) complex, has been synthesized. Although pyridomethenes did not exhibit fluorescence, pyridomethene-BF(2) complexes exhibited fluorescence both in solution and in the solid state. The trifluoromethyl-substituted BF(2) complex formed a J-aggregate and showed the highest fluorescence quantum yield in the solid state among all pyridomethene BF(2) complexes. PMID- 20726589 TI - Highly enantioselective fluorescent recognition of serine and other amino acid derivatives. AB - The BINOL-amino alcohol compound (S)-4 was found to conduct enantioselective fluorescent recognition of a serine derivative with an unprecedented high ef [enantioselective fluorescent enhancement = (I(D) - I(0))/(I(L) - I(0))] of 12.5. Both (S)-4 and (S)-5 are also found to be highly enantioselective fluorescent sensors for a number of other amino acid derivatives. PMID- 20726590 TI - Catalytically stable and active CeO2 mesoporous spheres. AB - A facile one-step strategy has been developed for preparing monodisperse CeO(2) mesoporous spheres with high surface areas, uniform size distributions, and well defined pore topologies. These mesoporous spheres have been demonstrated to be catalytically stable and active for CO oxidation. PMID- 20726591 TI - Formal nucleophilic substitution of bromocyclopropanes with amides en route to conformationally constrained beta-amino acid derivatives. AB - A chemo- and diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with secondary amides is described. This method allows for convergent and highly selective synthesis of trans-beta aminocyclopropane carboxylic acid derivatives. PMID- 20726592 TI - Multicatalytic one-pot reaction of 1-(2-alkynylphenyl)ketoximes for generation of indole derivatives. AB - Multicatalytic one-pot Beckmann rearrangement/intramolecular cyclization/halogenation reaction of 1-(2-alkynylphenyl)ketoxime is reported, leading to the expected indole derivatives in good yield. PMID- 20726593 TI - Lectin magnetic bead array for biomarker discovery. AB - Alterations in protein glycosylation play an important role in patho-physiology, and much effort has been devoted to detecting glycoprotein biomarkers. In this manuscript, we describe the development of a novel method for monitoring alterations in protein glycosylation. Lectins are used as individual affinity reagents and coupled to magnetic beads (Dynabeads) in a microplate array format for isolation of glycosylated proteins. Isolated glycoproteins are digested with trypsin in-solution followed by LC-MS/MS, allowing a liquid handler-assisted high throughput workflow. We demonstrate the specific and reproducible affinity isolation of glycoproteins using the lectin Dynabead array technology. When used with serum, we achieved one-step purification of glycoproteins with minimal coisolation of abundant serum proteins including albumin. We further optimized the proteomics workflow to allow transfer to a liquid handler for automation. In summary, we report the development of a high throughput platform to detect alterations in protein glycosylation which will be useful in glycoproteomics studies, particularly clinical proteomics studies where large sample sizes are required to achieve statistical power. PMID- 20726595 TI - Systematic signatures for organic reactions. AB - A signature for any reaction is defined by just the net change in bonding of the reacting atoms in the conversion of reactant to product structures. This reaction signature is both unique and definitive for any reaction and consists of a simple linear string of letters suitable to index every reaction in a reaction database for computer access. This allows daily entry of new reactions to be easily incorporated and later retrieved with all related reactions from the reaction database. PMID- 20726594 TI - A high-throughput O-glycopeptide discovery platform for seromic profiling. AB - Biomarker microarrays are becoming valuable tools for serological screening of disease-associated autoantibodies. Post-translational modifications (PTMs) such as glycosylation extend the range of protein function, and a variety of glycosylated proteins are known to be altered in disease progression. Here, we have developed a synthetic screening microarray platform for facile display of O glycosylated peptides (O-PTMs). By introduction of a capping step during chemical solid-phase glycopeptide synthesis, selective enrichment of N-terminal glycopeptide end products was achieved on an amine-reactive hydrogel-coated microarray glass surface, allowing high-throughput display of large numbers of glycopeptides. Utilizing a repertoire of recombinant glycosyltransferases enabled further diversification of the array libraries in situ and display of a new level of potential biomarker candidates for serological screening. As proof-of-concept, we have demonstrated that MUC1 glycopeptides could be assembled and used to detect autoantibodies in vaccine-induced disease-free breast cancer patients and in patients with confirmed disease at time of diagnosis. PMID- 20726596 TI - Introduction of jumping fragments in combination with QSARs for the assessment of classification in ecotoxicology. AB - Starting from a random set of structures taken from the European Chemical Bureau (ECB) Web site, an estimation of the classification by acute category in ecotoxicology was carried out. This estimation was based on two approaches. One approach consists in starting with global quantitative structure-activity relationship (QSAR) equations, analyzing the results and defining an interpretation in terms of overall results and mode of action. The other starts with the notion of emerging fragments and more specifically with the introduction of a particular concept: the jumping fragments. This publication studies the scopes and limitations of each approach for the classification of the derivatives. A promising combination of the two methods is proposed for the classification and also for bringing new information about the importance, for the ecotoxicity, of specific chemical fragments considered alone or in association with others. PMID- 20726597 TI - Model-free drug-likeness from fragments. AB - We developed a drug-likeness filter (DLF), starting from molecular fragments and molecular weight (MW), a key property relevant in drug design. The molecular fragments were selected from extended connectivity atom environments based on their occurrence ratio in our collection of drugs and "nondrugs". The DLF recalls 87.05% of compounds from DRUGS (N = 3823) and 40.25% of compounds from the Available Chemicals Directory, (ACD, N = 178 0 11), using molecular fragments only. By adding MW (under 600) as an additional filter, 78.81% of DRUGS and 40.17% of ACD are recalled. The DLF procedure was externally validated using the MDL Drug Data Report (MDDR) data set (N = 169 277): 78.45% of compounds were recalled using the molecular fragments only, while 65.64% pass the DLF-MW filter. Over 50% of a pesticides collection (N = 1482) passed the DLF, as these chemicals share molecular fragments with known drugs. Developed as a model-free filter, DLF is perhaps less useful in discriminating drugs from nondrugs but more likely to rapidly eliminate those chemicals rich in nondrug-like fragments. Since almost 40% of ACD, the standard reference set for nondrugs, contain drug-like molecules, by using a rule-based system such as DLF, one is less likely to mislabel nondrugs due to overfitting. Reliable benchmarks for nondrugs are not likely to exist since medicinal chemistry catalogs tend to be biased toward existing drugs. PMID- 20726598 TI - Similarity-potency trees: a method to search for SAR information in compound data sets and derive SAR rules. AB - An intuitive and generally applicable analysis method, termed similarity-potency tree (SPT), is introduced to mine structure-activity relationship (SAR) information in compound data sets of any source. Only compound potency values and nearest-neighbor similarity relationships are considered. Rather than analyzing a data set as a whole, in part overlapping compound neighborhoods are systematically generated and represented as SPTs. This local analysis scheme simplifies the evaluation of SAR information and SPTs of high SAR information content are easily identified. By inspecting only a limited number of compound neighborhoods, it is also straightforward to determine whether data sets contain only little or no interpretable SAR information. Interactive analysis of SPTs is facilitated by reading the trees in two directions, which makes it possible to extract SAR rules, if available, in a consistent manner. The simplicity and interpretability of the data structure and the ease of calculation are characteristic features of this approach. We apply the methodology to high throughput screening and lead optimization data sets, compare the approach to standard clustering techniques, illustrate how SAR rules are derived, and provide some practical guidance how to best utilize the methodology. The SPT program is made freely available to the scientific community. PMID- 20726599 TI - Evolution of human receptor binding affinity of H1N1 hemagglutinins from 1918 to 2009 pandemic influenza A virus. AB - The recent outbreak of the novel 2009 H1N1 influenza in humans has focused global attention on this virus, which could potentially have introduced a more dangerous pandemic of influenza flu. In the initial step of the viral attachment, hemagglutinin (HA), a viral glycoprotein surface, is responsible for the binding to the human SIA alpha2,6-linked sialopentasaccharide host cell receptor (hHAR). Dynamical and structural properties, based on molecular dynamics simulations of the four different HAs of Spanish 1918 (H1-1918), swine 1930 (H1-1930), seasonal 2005 (H1-2005), and a novel 2009 (H1-2009) H1N1 bound to the hHAR were compared. In all four HA-hHAR complexes, major interactions with the receptor binding were gained from HA residue Y95 and the conserved HA residues of the 130-loop, 190 helix, and 220-loop. However, introduction of the charged HA residues K145 and E227 in the 2009 HA binding pocket was found to increase the HA-hHAR binding efficiency in comparison to the three previously recognized H1N1 strains. Changing of the noncharged HA G225 residue to a negatively charged D225 provides a larger number of hydrogen-bonding interactions. The increase in hydrophilicity of the receptor binding region is apparently an evolution of the current pandemic flu from the 1918 Spanish, 1930 swine, and 2005 seasonal strains. Detailed analysis could help the understanding of how different HAs effectively attach and bind with the hHAR. PMID- 20726600 TI - Protein kinases: docking and homology modeling reliability. AB - A database of about 700 high-resolution kinase structures was used to test the reliability of 17 docking procedures (using six docking software packages) by means of self- and cross-docking studies. The analysis of about 80 000 docking calculations suggests that the docking of an unknown ligand into a kinase has a probability of only 30-37% to be a correct ligand pose. However, based on the hypothesis that docking calculations are more reliable if the ligand to be docked is similar to the ligand present in the complex from which the target docking protein has been extracted, we propose an automated procedure that is able to improve the docking accuracy, suggest the best protein for docking studies, and assess the statistical reliability of docking calculations. The results were also transferred to the homology modeling field and led us to propose an alternative strategy based on ligand similarity for the development of kinase models whose experimental structure was not known. Our results suggest that in many cases this approach can give better results than the classical homology modeling procedure based exclusively on the sequence homology. PMID- 20726601 TI - Molecular interaction fields and 3D-QSAR studies of p53-MDM2 inhibitors suggest additional features of ligand-target interaction. AB - The design and optimization of small molecule inhibitors of the murine double minute clone 2-p53 (p53-MDM2) interaction has attracted a great deal of interest as a way to novel anticancer therapies. Herein we report 3D-QSAR studies of 41 small molecule inhibitors based on the use of molecular interaction fields and docking experiments as part of an approach to generating predictive models of MDM2 affinity and shedding further light on the structural elements of the ligand target interaction. These studies have yielded predictive models explaining much of the variance of the 41 compound training set and satisfactorily predicting with 75% success an external test set of 36 compounds. Not surprisingly, and in full agreement with previous data, inspection of the 3D-QSAR coefficients reveals that the major driving force for potent inhibition is given by the hydrophobic interaction between the inhibitors and the p53 binding cleft of MDM2. More surprisingly, and challenging previous suggestions, the projection of the 3D-QSAR coefficients back onto the experimental structures of MDM2 provides an intriguing hypothesis concerning an active role played by the N-terminal region of MDM2 in ligand binding. PMID- 20726603 TI - HIV-1 TAR RNA spontaneously undergoes relevant apo-to-holo conformational transitions in molecular dynamics and constrained geometrical simulations. AB - We report all-atom molecular dynamics and replica exchange molecular dynamics simulations on the unbound human immunodeficiency virus type-1 (HIV-1) transactivation responsive region (TAR) RNA structure and three TAR RNA structures in bound conformations of, in total, approximately 250 ns length. We compare the extent of observed conformational sampling with that of the conceptually simpler and computationally much cheaper constrained geometrical simulation approach framework rigidity optimized dynamic algorithm (FRODA). Atomic fluctuations obtained by replica-exchange molecular dynamics (REMD) simulations agree quantitatively with those obtained by molecular dynamics (MD) and FRODA simulations for the unbound TAR structure. Regarding the stereochemical quality of the generated conformations, backbone torsion angles and puckering modes of the sugar-phosphate backbone were reproduced equally well by MD and REMD simulations, but further improvement is needed in the case of FRODA simulations. Essential dynamics analysis reveals that all three simulation approaches show a tendency to sample bound conformations when starting from the unbound TAR structure, with MD and REMD simulations being superior with respect to FRODA. These results are consistent with the experimental view that bound TAR RNA conformations are transiently sampled in the free ensemble, following a conformation selection model. The simulation-generated TAR RNA conformations have been successfully used as receptor structures for docking. This finding has important implications for RNA-ligand docking in that docking into an ensemble of simulation-generated RNA structures is shown to be a valuable means to cope with large apo-to-holo conformational transitions of the receptor structure. PMID- 20726602 TI - Systematic classification and analysis of themes in protein-DNA recognition. AB - Protein-DNA recognition plays a central role in the regulation of gene expression. With the rapidly increasing number of protein-DNA complex structures available at atomic resolution in recent years, a systematic, complete, and intuitive framework to clarify the intrinsic relationship between the global binding modes of these complexes is needed. In this work, we modified, extended, and applied previously defined RNA-recognition themes to describe protein-DNA recognition and used a protocol that incorporates automatic methods into manual inspection to plant a comprehensive classification tree for currently available high-quality protein-DNA structures. Further, a nonredundant (representative) data set consisting of 200 thematically diverse complexes was extracted from the leaves of the classification tree by using a locally sensitive interface comparison algorithm. On the basis of the representative data set, various physical and chemical properties associated with protein-DNA interactions were analyzed using empirical or semiempirical methods. We also examined the individual energetic components involved in protein-DNA interactions and highlighted the importance of conformational entropy, which has been almost completely ignored in previous studies of protein-DNA binding energy. PMID- 20726604 TI - Generation, validation, and utilization of a three-dimensional pharmacophore model for EP3 antagonists. AB - Studies reported here are aimed to investigate the important structural features that characterize the human EP(3) antagonists. Based on the knowledge of low energy conformation of the endogenous ligand, the initial hit analogs were prepared. Subsequently, a ligand-based lead optimization approach using pharmacophore model generation was utilized. A 5-point pharmacophore using a training set of 19 compounds spanning the IC(50) data over 4-log order was constructed using the HypoGen module of Catalyst. Following pharmacophore customization, using a linear structure-activity regression equation, a six feature three-dimensional predictive pharmacophore model, P6, was built, which resulted in improved predictive power. The P6 model was validated using a test set of 11 compounds providing a correlation coefficient (R(2)) of 0.90 for predictive versus experimental EP(3) IC(50) values. This pharmacophore model has been expanded to include diverse chemotypes, and the predictive ability of the customized pharmacophore has been tested. PMID- 20726605 TI - Pharmacophore modeling of substituted 1,2,4-Trioxanes for quantitative prediction of their antimalarial activity. AB - A pharmacophore model has been developed for determining the essential structural requirements for antimalarial activity from the eight series of substituted 1,2,4 trioxanes. The best pharmacophore model possessing two aliphatic hydrophobic, one aromatic hydrophobic, one hydrogen-bond (H-bond) acceptor, and one H-bond acceptor (lipid) feature for antimalarial activity showed an excellent correlation coefficient for the training (r(2)(training) = 0.85) and a fair correlation coefficient for the test set (r(2)(test) = 0.51) molecules. The model predicts well to other known substituted 1,2,4-trioxanes including those which either are drugs or are undergoing clinical trials. In order to further validate this model, five substituted 1,2,4-trioxanes were synthesized from the generated focused library and screened for antimalarial activity. The observed activity of these molecules was consistent with the pharmacophore model, suggesting that the model may be useful in the design of potent antimalarial agents. PMID- 20726606 TI - Thermodynamic analysis of the effect of the hierarchical architecture of a superhydrophobic surface on a condensed drop state. AB - Condensed drops usually display a Wenzel state on a superhydrophobic surface (SHS) only with microrough architecture, while Cassie drops easily appear on a surface with micro-nano hierarchical roughness. The mechanism of this is not very clear. It is important to understand how the hierarchical structure affects the states of condensation drops so that a good SHS can be designed to achieve the highly efficient dropwise condensation. In this study, the interface free energy (IFE) of a local condensate, which comes from the growth and combination of numerous initial condensation nuclei, was calculated during its shape changes from the early flat shape to a Wenzel or Cassie state. The final state of a condensed drop was determined by whether the IFE continuously decreased or a minimum value existed. The calculation results indicate that the condensation drops on the surface only with microroughness display a Wenzel state because the IFE curve of a condensed drop first decreases and then increases, existing at a minimum value corresponding to a Wenzel drop. On a surface with proper hierarchical roughness, however, the interface energy curve of a condensed drop will continuously decline until reaching a Cassie state. Therefore, a condensed drop on a hierarchical roughness surface can spontaneously change into a Cassie state. Besides, the states and apparent contact angles of condensed drops on a SHS with different structural parameters published in the literature were calculated and compared with experimental observations. The results show that the calculated condensed drop states are well-coordinated with experimental clarifications. We can conclude that micro-nano hierarchical roughness is the key structural factor for sustaining condensed drops in a Cassie state on a SHS. PMID- 20726607 TI - Shape-controlled growth of In(OH)3/In2O3 nanostructures by electrodeposition. AB - In(OH)(3) nanostructures with controllable shapes were successfully synthesized using indium nitrate as an indium source by one-step electrodeposition process. The influences of the reaction temperature, time, indium nitrate concentration, and the applied potential on the morphology of the obtained products were discussed in detail. The results revealed that the growth behavior of In(OH)(3) was mainly determined by the indium nitrate concentration and applied potential, and well-defined ellipsoids, cubes, and rods could be prepared under suitable conditions. Their possible growth mechanisms as well as photocatalytic applications were addressed. Furthermore, In(2)O(3) nanostructures were obtained from In(OH)(3) upon heating, while size and morphology can be maintained during this process. PMID- 20726608 TI - Detergent-mediated formation of polymer-supported phospholipid bilayers. AB - Supported phospholipid bilayers can be formed by established methods such as vesicle fusion and the Langmuir-Blodgett (LB) technique. However, challenges remain in regards to creating supported bilayers from various lipid compositions, using various support surfaces, and incorporating membrane proteins. Here we report a detergent removal method as an alternative means of supported bilayer formation. The process consists of three steps: (1) incubation of phospholipid poly(ethylene glycol) (PEG)-grafted glass with lipid-detergent micelles; (2) detergent removal by washing the surface with vesicles; and (3) incubation with the vesicles to complete lipid adsorption. These procedures yielded fluid planar bilayers of zwitterionic lipids. Because fluid structures were not obtained by vesicle fusion, the detergent seemed necessary to produce the polymer-supported bilayers. While anionic phospholipids inhibited the attachment of fluid bilayers in the absence of calcium ions, supported bilayers with almost full mobility were obtained from lipid mixtures containing 10-20 mol % anionic lipids in the presence of calcium ions. The incorporation of the anionic lipids in the bulk facing leaflet was demonstrated by the binding of dye-labeled annexin V. PMID- 20726609 TI - Structure and thermorheology of concentrated pluronic copolymer micelles in the presence of laponite particles. AB - Small-angle neutron scattering and thermorheology techniques are used to investigate in detail the effect of laponite particles in aqueous solutions of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEO-PPO-PEO, block copolymers in the concentrated regime. At high polymer concentration or temperature, the micellar solutions exhibit a phase transition from fluid to crystal due to crowding of the micelles. The addition of laponite is found to disturb this phase transition. The adsorption of the copolymer unimers onto laponite in large amounts describes these findings. It is shown that the preferred adsorption of the copolymer chains results in a sufficient increase in free volume for the remaining micelles to yield the observed enhancement of the structural disorder. PMID- 20726610 TI - Chemical-modification-enhanced dielectrophoretic assembly of controllable and reversible silica submicrowires from nanoparticles. AB - In this article, the dielectrophoretic (DEP) assembly of chemically-modified silica nanoparticles (SiNPs) was introduced. Five types of surface-modified SiNPs, including OH-SiNPs, COOH-SiNPs, CH(3)HPO(2)-SiNPs, PEG-SiNPs, and NH(2) SiNPs, have been investigated. After applying an ac field with relatively high intensity and frequency, it was shown that only COOH-SiNPs and CH(3)HPO(2)-SiNPs could be self-assembled on the microelectrodes by the DEP forces. The results indicated that the anionic group modification could obviously enhance the DEP self-assembly of SiNPs on the microelectrodes. Then the DEP assembly of CH(3)HPO(2)-SiNPs was selected as a representative to be investigated further. By using Rubpy dye doped in the core of the CH(3)HPO(2)-SiNPs, the assembly process was visualized in real time by inverse fluorescence microscopy. Precise control over the frequency of the applied ac field showed that the DEP forces can assemble CH(3)HPO(2)-SiNPs from aqueous suspensions into submicrowires, and it was found that the number of assembled submicrowires between the microelectrode gaps could be well controlled with reversibility. Furthermore, the DEP assembly process of CH(3)HPO(2)-SiNPs was sensitive to the pH of the dispersed medium. These findings would provide a way to circumvent the difficulty in controlling the dielectrophoretic assembly process of nanoparticles and offer application opportunities for the DEP assembly of chemically modified SiNPs. PMID- 20726611 TI - Synthesis of ultralarge-pore FDU-12 silica with face-centered cubic structure. AB - Ultralarge-pore FDU-12 (ULP-FDU-12) silicas with face-centered cubic structures (Fm3m symmetry) of spherical mesopores were synthesized at low initial temperature (~14 degrees C) using commercially available PEO-PPO-PEO triblock copolymer Pluronic F127 as a micellar template and xylene as a micelle expander. Xylene was selected on the basis of its predicted higher swelling ability for the Pluronic surfactant micelles in comparison to 1,3,5-trimethylbenzene that was used previously to obtain large-pore FDU-12. The optimization of the synthesis conditions afforded as-synthesized ULP-FDU-12 materials with unit-cell parameters up to 56 nm, which is comparable to the highest reported values for Fm3m structures templated by custom-made surfactants. Calcined silicas were obtained with unit-cell parameters up to 53 nm and pore diameters up to ~36 nm (for N(2) adsorption at 77 K, the capillary condensation relative pressure was up to 0.938). The preferred silica source was tetraethylorthosilicate, but tetramethylorthosilicate was also found suitable. The pore diameter was dependent on the unit-cell size of the as-synthesized material, but was further tuned by adjusting the time and temperature of the treatment in the HCl solution. If the synthesis was performed at low temperature only, highly ordered closed-pore silicas were obtained at calcination temperatures as low as 450 degrees C. On the other hand, the hydrothermal treatments, including the acid treatment at 130 degrees C, afforded silicas with large pore entrance sizes. The present synthesis constitutes a major advancement in the synthesis of ordered silicas with very large open and closed spherical mesopores. PMID- 20726612 TI - Spontaneous growth of free-standing polypyrrole films at an air/ionic liquid interface. AB - A novel strategy for the one-pot fabrication of free-standing polypyrrole films is presented in this work. The films are spontaneously formed at an air/ionic liquid interface through interface oxypolymerization. The thicknesses of the films are finely controlled from tens to hundreds of nanometers, and the films are uniform and compact. Asymmetrical films with different smoothness on the two sides of the film are also obtained and exhibit different water wettability. This method is extremely simple and does not need any equipment. It may bring about a general methodology for forming free-standing conducting polymer films. PMID- 20726613 TI - Intercalation-FRET biosensor with a helical conjugated polyelectrolyte. AB - A biotin-tetramethylrhodamine (biotin-TMR) quencher-ligand interacts with a (phenylene-ethynylene) based helical conjugated polyelectrolyte (poly-1) via intercalation of the TMR unit into the helix. The interaction is signaled by efficient fluorescence resonance energy transfer (FRET) from the polymer to the TMR chromophore. Avidin addition to the poly-1/biotin-TMR intercalation complex does not interrupt FRET, instead resulting in the formation of avidin-biotin "cross-links". Mixing of biotin-TMR with avidin prior to addition of the polymer efficiently disrupts the FRET signal, giving rise to a sensor with a detection limit of 100 pM for avidin. Study of the FRET response as a function of biotin TMR and avidin concentration affords insight into the interaction of the protein with the poly-1/biotin-TMR intercalation complex. PMID- 20726614 TI - The complex thiol-palladium interface: a theoretical and experimental study. AB - This paper presents a theoretical study of the surface structures and thermodynamic stability of different thiol and sulfide structures present on the palladium surface as a function of the chemical potential of the thiol species. It has been found that as the chemical potential of the thiol is increased, the initially clean palladium surface is covered by a (?3 * ?3)R30 degrees sulfur lattice. Further increase in the thiol pressure or concentration leads to the formation of a denser (?7 * ?7)R19.1 degrees sulfur lattice, which finally undergoes a phase transition to form a complex (?7 * ?7)R19.1 degrees sulfur + thiol adlayer (3/7 sulfur + 2/7 thiol coverage). This transition is accompanied by a strong reconstruction of the Pd(111) surface. The formation of these surface structures has been explained in terms of the catalytic properties of the palladium surface. These results have been compared with X-ray photoelectron spectroscopy results obtained for thiols adsorbed on different palladium surfaces. PMID- 20726615 TI - A general approach to anionic acid-labile surfactants with tunable properties. AB - A general approach to the synthesis of a new series of unique sulfate anionic acid-labile surfactants (AALS) was developed. In this approach, the ketal was derived from methyl pyruvate, and the sulfate motif was introduced via sulfitylation of the alcohol, oxidation, and finally conversion of the sulfate diester to the desired sodium salt. The physicochemical properties in aqueous solution of this novel series of surfactants, such as CMCs, solubility, acid lability, and stability were studied. PMID- 20726616 TI - A bimetallic aluminum(salen) complex for the synthesis of 1,3-oxathiolane-2 thiones and 1,3-dithiolane-2-thiones. AB - The combined use of the bimetallic aluminum(salen) complex [Al(salen)](2)O and tetrabutylammonium bromide (or tributylamine) is found to catalyze the reaction between epoxides and carbon disulfide. In most cases, at 50 degrees C, the reaction produces 1,3-oxathiolane-2-thiones, while at 90 degrees C, 1,3 dithiolane-2-thiones are the main product. The structure and stereochemistry of three of the 1,3-dithiolane-2-thiones is unambiguously determined by X-ray crystallographic analysis, and this is used to correct errors in the literature concerning the synthesis of cyclic di- and trithiocarbonates. The kinetics of 1,3 oxathiolane-2-thione synthesis are determined, and the resulting rate equation, along with a stereochemical analysis of the reaction and catalyst modification studies, is used to determine a mechanism for the synthesis of 1,3-oxathiolane-2 thiones which contrasts with the mechanism previously determined for cyclic carbonate synthesis using the same bimetallic aluminum(salen) complex. PMID- 20726617 TI - Infrared spectra of HC=C-MH and M-eta2-(C2H2) produced in reactions of laser ablated group 5 transition-metal atoms with acetylene. AB - The ethynyl metal hydride (HC=C-MH) and metallacycle complexes (M-eta2-(C2H2)) are identified in the matrix infrared spectra from reactions of laser-ablated group 5 metal atoms with acetylene. The observed intensity variations reveal spontaneous formation of the cyclic complex upon annealing and its conversion to the insertion product via oxidative C-H insertion reaction and also during subsequent photolysis. The less stable vinylidene complex is not identified. The high binding energies, low C-C stretching frequencies, and long C-C bonds of the group 5 metal M-eta2-(C2H2) species all indicate strong bonding relative to the late-transition-metal and light-metal analogues, but they are somewhat weaker than the group 4 metal counterparts. PMID- 20726618 TI - Charge transfer via the dative N-B bond and dihydrogen contacts. Experimental and theoretical electron density studies of small Lewis acid-base adducts. AB - The electronic characteristics of the dative N-B bond in three Lewis acid-base adducts, hydrazine borane, hydrazine bisborane, and ammonia trifluoroborane, are analyzed by an approach combining experimental electron density determination with a broad variety of theoretical calculations. Special focus is directed to the weak dihydrogen contacts in hydrazine borane. The Atoms In Molecules partitioning scheme is complemented by additional methods like the Source Function, and the Electron Localizability Indicator. For the multipole-free theoretical models of hydrazine borane and hydrazine bisborane, a weak charge donation from Lewis base to acid of about 0.05 e is found, whereas multipole refinement of theoretical and experimental structure factors resulted in opposite signs for the Lewis acid and base fragments. For ammonia trifluoroborane, the donation from Lewis base to acid is slightly larger (about 0.13 e) in the multipole-free models, and the charges obtained by multipole refinement retain the direction of the charge donation but show quite large variations. The natural population analysis charges predict larger charge donations (0.35 e) from the Lewis bases to the acids for the three title complexes. Although the three compounds exhibit intermolecular interactions of different types and strengths, including classical hydrogen bonds, F...H contacts and the already mentioned dihydrogen bonds, almost no charge transfer is detected between different molecules within the crystal environment. The main electronic effect of the formation of the Lewis acid-base adducts and of the crystallization is an increase in the charge separation within the ammonia/hydrazine fragments, which is supported by all investigated bond and atomic properties. The nature of the dative N-B bond is found to be mainly electrostatic, but with a substantial contribution of covalency. The F-B bonds show similarities and differences from the N-B bonds, which makes a distinction of coordinative (or dative) bonds from polar covalent interactions possible. PMID- 20726619 TI - Neuromotor control of the lower limb in Achilles tendinopathy: implications for foot orthotic therapy. AB - Achilles tendinopathy (AT) is a common injury in running sports. While the exact aetiology of Achilles injury is still unclear, foot orthoses are often effectively employed in the conservative management of the condition. Foot orthoses have traditionally been provided for people with AT on the basis that they may reduce the rearfoot eversion associated with excessive foot pronation. This increased rearfoot motion is thought to produce excessive Achilles tendon loads. To date, the available literature indicates that foot orthoses have small and unsystematic effects on rearfoot kinematics. However, limitations of foot kinematic measurement currently restrict the ability to conduct truly valid investigations into kinematic responses to foot orthoses. Therefore, the roles of alternate mechanisms, for which orthoses may provide clinical success in pathology such as AT, are now being investigated. One alternative theory is that foot orthoses alter neuromotor recruitment patterns and thus lower limb loads in response to the additional sensory input provided by the device. In AT, altered neuromotor recruitment patterns of the triceps surae have been hypothesized to create differential intratendinous loads. This may lead to pathological changes within the tendon. Furthermore, it is possible that foot orthoses may aid to normalize intratendinous loads via altering neuromotor activity in the triceps surae in AT. This review examines the literature with regard to changes in neuromotor recruitment as an associated aetiological factor in AT and the role foot orthoses may play in the management of this condition. PMID- 20726620 TI - A 'plane' explanation of anterior cruciate ligament injury mechanisms: a systematic review. AB - Although intrinsic and extrinsic risk factors for anterior cruciate ligament (ACL) injury have been explored extensively, the factors surrounding the inciting event and the biomechanical mechanisms underlying ACL injury remain elusive. This systematic review summarizes all the relevant data and clarifies the strengths and weaknesses of the literature regarding ACL injury mechanisms. The hypothesis is that most ACL injuries do not occur via solely sagittal, frontal or transverse plane mechanisms. Electronic database literature searches of PubMed MEDLINE (1966 2008), CINAHL (1982-2008) and SportDiscus (1985-2008) were used for the systematic review to identify any studies in the literature that examined ACL injury mechanisms. Methodological approaches that describe and evaluate ACL injury mechanisms included athlete interviews, arthroscopic studies, clinical imaging and physical exam tests, video analysis, cadaveric studies, laboratory tests (motion analysis, electromyography) and mathematical modelling studies. One hundred and ninety-eight studies associated with ACL injury mechanisms were identified and provided evidence regarding plane of injury, with evidence supporting sagittal, frontal and/or transverse plane mechanisms of injury. Collectively, the studies indicate that it is highly probable that ACL injuries are more likely to occur during multi-planar rather than single-planar mechanisms of injury. PMID- 20726621 TI - Carbohydrate administration and exercise performance: what are the potential mechanisms involved? AB - It is well established that carbohydrate (CHO) administration increases performance during prolonged exercise in humans and animals. The mechanism(s), which could mediate the improvement in exercise performance associated with CHO administration, however, remain(s) unclear. This review focuses on possible underlying mechanisms that could explain the increase in exercise performance observed with the administration of CHO during prolonged muscle contractions in humans and animals. The beneficial effect of CHO ingestion on performance during prolonged exercise could be due to several factors including (i) an attenuation in central fatigue; (ii) a better maintenance of CHO oxidation rates; (iii) muscle glycogen sparing; (iv) changes in muscle metabolite levels; (v) reduced exercise-induced strain; and (vi) a better maintenance of excitation-contraction coupling. In general, the literature indicates that CHO ingestion during exercise does not reduce the utilization of muscle glycogen. In addition, data from a meta analysis suggest that a dose-dependent relationship was not shown between CHO ingestion during exercise and an increase in performance. This could support the idea that providing enough CHO to maintain CHO oxidation during exercise may not always be associated with an increase in performance. Emerging evidence from the literature shows that increasing neural drive and attenuating central fatigue may play an important role in increasing performance during exercise with CHO supplementation. In addition, CHO administration during exercise appears to provide protection from disrupted cell homeostasis/integrity, which could translate into better muscle function and an increase in performance. Finally, it appears that during prolonged exercise when the ability of metabolism to match energy demand is exceeded, adjustments seem to be made in the activity of the Na+/K+ pump. Therefore, muscle fatigue could be acting as a protective mechanism during prolonged contractions. This could be alleviated when CHO is administered resulting in the better maintenance of the electrical properties of the muscle fibre membrane. The mechanism(s) by which CHO administration increases performance during prolonged exercise is(are) complex, likely involving multiple factors acting at numerous cellular sites. In addition, due to the large variation in types of exercise, durations, intensities, feeding schedules and CHO types it is difficult to assess if the mechanism(s) that could explain the increase in performance with CHO administration during exercise is(are) similar in different situations. Experiments concerning the identification of potential mechanism(s) by which performance is increased with CHO administration during exercise will add to our understanding of the mechanism(s) of muscle/central fatigue. This knowledge could have significant implications for improving exercise performance. PMID- 20726623 TI - Cetuximab-associated elongation of the eyelashes: case report and review of eyelash trichomegaly secondary to epidermal growth factor receptor inhibitors. AB - Eyelash trichomegaly is an uncommon drug-associated sequelae experienced during treatment with epidermal growth factor receptor (EGFR) inhibitors. Elongation of the eyelashes induced by these agents has predominantly been observed in oncology patients with either colorectal or lung cancer. It is most frequently associated with cetuximab and erlotinib; however, it has also been described in individuals treated with gefitinib or panitumumab. We describe cetuximab-associated eyelash trichomegaly in a woman with metastatic rectal carcinoma. We review the clinical presentation, adverse effects, and management of EGFR inhibitor-related eyelash trichomegaly. The long eyelashes are not a drug-limiting adverse effect and some patients consider the change to be cosmetically enhancing. Trimming the lashes with scissors can usually ameliorate local symptoms. The eyelashes often return to their original length at variable time periods after EGFR inhibitor therapy is discontinued. PMID- 20726624 TI - Enhancing the use and quality of colorectal cancer screening. AB - OBJECTIVES: To conduct a systematic review of the use and quality (including underuse, overuse, and misuse) of appropriate colorectal cancer (CRC) screening, including factors associated with screening, effective interventions to improve screening rates, current capacity, and monitoring and tracking the use and quality. Trends in the use and quality of CRC screening tests is also presented. DATA SOURCES: We searched MEDLINE, the Cochrane Library, and the Cochrane Central Trials Registry, supplemented by handsearches, for studies published in English from January 1998 through September 2009. REVIEW METHODS: We used standard Evidence-based Practice Center methods of dual review of abstracts, full text articles, abstractions, quality rating, and quality grading. We resolved disagreements by consensus. RESULTS: We found multiple problems of underuse, overuse, and misuse of CRC screening. We identified a total of 116 articles for inclusion into the systematic review, including a total of 72 studies qualified for inclusion for key question (KQ) 2, 21 for KQ 3, 12 for KQ 4, and 8 for KQ 5. A number of patient-level factors are associated with lower screening rates, including having low income or less education, being uninsured or of Hispanic or Asian descent, not being acculturated into the United States, and having less or reduced access to care. Being insured, of higher income or education, and non Hispanic white, participating in other cancer screenings, having a family history of CRC or personal history of another cancer, as well as receiving a physician recommendation to be screened, are associated with higher screening rates. Interventions that effectively increased CRC screening with high strength of evidence include patient reminders, one-on-one interactions, eliminating structural barriers, and system-level changes. The largest magnitude of improvement came from one-on-one interactions and eliminating barriers. Purely educational small-media interventions do not improve screening rates. Evidence is mixed for decision aids, although certain designs may be effective. No studies tested interventions to reduce overuse or misuse of CRC screening. We found no studies that assessed monitoring systems for underuse, overuse, and misuse of CRC screening. Modeling studies, using various assumptions, show that if the United States were to adopt a colonoscopy-only approach to CRC screening and everyone were to agree to be screened in this way, it is likely that colonoscopy capacity would need to be substantially increased. CONCLUSIONS: Both CRC screening and patient-physician discussions of CRC screening are underused, and important problems of overuse and misuse also exist. Some interventions hold promise for improvement. The research priority is to design and test interventions to increase screening and CRC screening discussions, building on the effective approaches identified in this review, and tailored to specific population needs. In addition, new interventions to reduce overuse and misuse should be designed and tested, along with studies of ongoing monitoring systems that are linked to feedback and continued improvement efforts. PMID- 20726627 TI - Communication: Evidence of dynamic heterogeneity in glassy polymer monolayers from interface microrheology measurements. AB - We have developed a novel nanoparticle tracking based interface microrheology technique to perform in situ studies on confined complex fluids. To demonstrate the power of this technique, we show, for the first time, how in situ glass formation in polymers confined at air-water interface can be directly probed by monitoring variation of the mean square displacement of embedded nanoparticles as a function of surface density. We have further quantified the appearance of dynamic heterogeneity and hence vitrification in polymethyl methacrylate monolayers above a certain surface density, through the variation of non-Gaussian parameter of the probes. PMID- 20726622 TI - Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. AB - Exercise is known to induce a cascade of molecular and cellular processes that support brain plasticity. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin that is also intimately connected with central and peripheral molecular processes of energy metabolism and homeostasis, and could play a crucial role in these induced mechanisms. This review provides an overview of the current knowledge on the effects of acute exercise and/or training on BDNF in healthy subjects and in persons with a chronic disease or disability. A systematic and critical literature search was conducted. Articles were considered for inclusion in the review if they were human studies, assessed peripheral (serum and/or plasma) BDNF and evaluated an acute exercise or training intervention. Nine RCTs, one randomized trial, five non-randomized controlled trials, five non-randomized non-controlled trials and four retrospective observational studies were analysed. Sixty-nine percent of the studies in healthy subjects and 86% of the studies in persons with a chronic disease or disability, showed a 'mostly transient' increase in serum or plasma BDNF concentration following an acute aerobic exercise. The two studies regarding a single acute strength exercise session could not show a significant influence on basal BDNF concentration. In studies regarding the effects of strength or aerobic training on BDNF, a difference should be made between effects on basal BDNF concentration and training-induced effects on the BDNF response following an acute exercise. Only three out of ten studies on aerobic or strength training (i.e. 30%) found a training-induced increase in basal BDNF concentration. Two out of six studies (i.e. 33%) reported a significantly higher BDNF response to acute exercise following an aerobic or strength training programme (i.e. compared with the BDNF response to an acute exercise at baseline). A few studies of low quality (i.e. retrospective observational studies) show that untrained or moderately trained healthy subjects have higher basal BDNF concentrations than highly trained subjects. Yet, strong evidence still has to come from good methodological studies. Available results suggest that acute aerobic, but not strength exercise increases basal peripheral BDNF concentrations, although the effect is transient. From a few studies we learn that circulating BDNF originates both from central and peripheral sources. We can only speculate which central regions and peripheral sources in particular circulating BDNF originates from, where it is transported to and to what purpose it is used and/or stored at its final destination. No study could show a long-lasting BDNF response to acute exercise or training (i.e. permanently increased basal peripheral BDNF concentration) in healthy subjects or persons with a chronic disease or disability. It seems that exercise and/or training temporarily elevate basal BDNF and possibly upregulate cellular processing of BDNF (i.e. synthesis, release, absorption and degradation). From that point of view, exercise and/or training would result in a higher BDNF synthesis following an acute exercise bout (i.e. compared with untrained subjects). Subsequently, more BDNF could be released into the blood circulation which may, in turn, be absorbed more efficiently by central and/or peripheral tissues where it could induce a cascade of neurotrophic and neuroprotective effects. PMID- 20726625 TI - Exercise-induced bronchoconstriction and asthma. AB - OBJECTIVES: The objectives are: (1) To assess diagnostic test characteristics of six alternative index tests compared with the selected reference standard-a standardized exercise challenge test (ECT) in patients with suspected exercise induced bronchoconstriction or asthma (EIB/EIA); (2) to determine the efficacy of a single prophylactic dose of four pharmacologic and one nonpharmacologic interventions vs. placebo to attenuate EIB/EIA in patients with diagnosed EIB/EIA; and (3) to determine if regular daily treatment with short-acting or long-acting beta-agonists (SABA or LABA) causes patients with EIA to develop tachyphylaxis when additional prophylactic doses are used pre-exercise. DATA SOURCES: A systematic and comprehensive literature search was conducted in 14 electronic databases (Diagnosis) and the Cochrane Airways Register (Therapy). REVIEW METHODS: Study selection, quality assessment, and data extraction were conducted independently by two reviewers. The primary outcome was the maximum percent fall in the post-exercise forced expiratory volume in 1 second (percent fall FEV1). The diagnostic threshold for a positive ECT was a percent fall FEV1 of 10% or more. Sensitivity (SN) and specificity (SP) were calculated. For therapy, mean differences (MD) in the percent fall FEV1 and 95% confidence intervals (CI) (random effects model) were calculated. A positive MD indicates the intervention works better than the control. RESULTS: For the diagnostic reviews, 5,318 citations yielded 28 relevant studies; for the therapy reviews, 1,634 citations yielded 109 relevant RCTs. Diagnostic test results versus ECT: self-reported history (2 studies) SN=36-8 percent; SP=85-86 percent; sport specific challenges (5 studies) SN=0-100 percent, SP=0-100 percent; eucapnic voluntary hyperpnea (7 studies) SN=25-90 percent, SP=0-71 percent; free running asthma screening test (3 studies) SN=60-67 percent, SP=47-67 percent; mannitol (3 studies) SN=58-96 percent, SP=65-78 percent. All SN and SP calculations indicated substantial heterogeneity that could not be explained by sensitivity or subgroup analyses. Therapy results: SABA offered greater protection than mast cell stabilizers (MCS) (12 studies); MD=6.8 (95 percent CI: 4.5, 9.2) but combining them offered no additional benefit; SABA versus MCS plus SABA (5 studies) MD=1.3 (95 percent CI: -6.3, 8.9). Leukotriene receptor antagonists (LTRA), MCS, ipratropium bromide, and interval warmup routines provided statistically significant attenuation of EIA when compared with placebo; inhaled corticosteroids (ICS) and other warmup routines did not. Single-dose intervention versus placebo results are: LTRA (9 studies) MD=8.9 (95 percent CI: 6.9, 11.0); MCS (nedocromil sodium) (17 studies) MD=15.6 (95 percent CI: 13.2, 18.2); interval warmup versus no warmup (4 studies) MD=10.6 (95 percent CI: 6.5, 14.7); ICS (4 studies) MD=5.0 (95 percent CI: 0.0, 9.9); continuous low intensity warmup versus no warmup (3 studies) MD=12.6 (95 percent CI: -1.5, 26.7); continuous high intensity warmup versus no warmup (2 studies) MD=9.8 (95 percent CI: -6.4, 26.0). After daily LABA (salmeterol) use for 3 to 4 weeks (4 studies), the percent fall FEV1 following an ECT at 2 and 4 weeks was greater than at day 1 in the LABA arm indicating that tachyphylaxis to prophylactic LABA use occurred. Daily SABA use for 1 week (1 study) also indicated development of tachyphylaxis. However, both LABA and SABA continued to have an attenuating effect on EIA. CONCLUSIONS: Given the small number of studies comparing EIB/EIA diagnostic tests, the heterogeneity of the study populations, and the varied study methodologies, there is no clear evidence that any of the index tests are a suitable replacement for a standardized ECT to diagnose EIB/EIA in the general population. All bronchodilator agents and most anti-inflammatory agents when used as pretreatment are somewhat effective in attenuating the percent fall FEV1 associated with EIA. PMID- 20726626 TI - Communication: Coalescence of carbon atoms on Cu (111) surface: Emergence of a stable bridging-metal structure motif. AB - By combining first principles transition state location and molecular dynamics simulation, we unambiguously identify a carbon atom approaching induced bridging metal structure formation on Cu (111) surface, which strongly modify the carbon atom coalescence dynamics. The emergence of such a new structural motif turns out to be a result of the subtle balance between Cu-C and Cu-Cu interactions. Based on this picture, a simple theoretical model is proposed, which describes a variety of surface chemistries very well. PMID- 20726628 TI - Communication: Two stages of ultrafast hydrogen migration in methanol driven by intense laser fields. AB - Hydrogen migration in methanol induced by an intense laser field (0.2 PW/cm(2)) is investigated in real time by a pump-probe coincidence momentum imaging method. The observed temporal evolution of the kinetic energy spectra reveals that there are two distinctively different stages in the hydrogen migration processes in the singly charged methanol: ultrafast hydrogen migration occurring within the intense laser field ( approximately 38 fs) and slower postlaser pulse hydrogen migration ( approximately 150 fs). PMID- 20726629 TI - Higher-accuracy schemes for approximating the Hessian from electronic structure calculations in chemical dynamics simulations. AB - In this paper, we present a family of generally applicable schemes for updating the Hessian from electronic structure calculations based on an equation derived with compact finite difference (CFD). The CFD-based equation is of higher accuracy than the quasi-Newton equation on which existing generally applicable Hessian update schemes are based. Direct tests of Hessian update schemes, as well as dynamics simulations using an integrator incorporating Hessian update schemes, have shown four of the new schemes produce reliably higher accuracy than existing Hessian update schemes. PMID- 20726630 TI - Potential energy surface studies via a single root multireference coupled cluster theory. AB - We have employed complete active space based single root multireference coupled cluster method (the resulting method is referred to by the acronym sr-MRCC) to compute the potential energy surfaces (PESs) of some well studied "protypical model" systems for which a highly accurate and reliable database is available for comparison. As that of state-specific theory, the sr-MRCC approach focuses and correlates one state while using a multiconfigurational reference and thus it naturally avoids intruder states. The present method is structurally different from the well known state specific multireference coupled cluster (SS-MRCC) method introduced by Mahapatra et al. [Mol. Phys. 94, 157 (1998)]. As that of the SS-MRCC theory, the present method is also based on the Jeziorski-Monkhorst ansatz where a different exponential cluster operator exp(T(mu)) acts on its corresponding model function phi(mu). The final cluster finding equations contain coupling between the cluster operators for all the mu, which are mainly responsible to prove the extensivity of both the cluster amplitudes and the energy. The present sr-MRCC theory is size-extensive and size-consistent when localized orbitals are used. The systems considered here exhibit varying degrees of degeneracy at different regions of PES. The treatment of these systems via traditional effective Hamiltonian based methods suffers from divergence problems in the iterative solution of the CC equations (the issue termed as "intruder state"). The sr-MRCC results lie closer to the ones obtained by the SS-MRCC method for these systems. To judge the efficacy of the present method, we have compared our results with other previously published theoretical estimations, which clearly indicate that the present method is reliable in studying the dissociation PES of states plagued by electronic degeneracy as well as notorious intruder effects. The highly satisfactory performance of the sr-MRCC method, vis a-vis the other sophisticated methods, in describing the lowest and the first excited singlet states of BeH(2) at points of high degeneracy is noticeable. PMID- 20726631 TI - A discrete interaction model/quantum mechanical method for describing response properties of molecules adsorbed on metal nanoparticles. AB - A new polarizable quantum mechanics/molecular mechanics method for the calculation of response properties of molecules adsorbed on metal nanoparticles is presented. This method, which we denote the discrete interaction model/quantum mechanics (DIM/QM) method, represents the nanoparticle atomistically which enables the modeling of the influence of the local environment of a nanoparticle surface on the optical properties of a molecule. Using DIM/QM, we investigate the excitation energies of rhodamine-6G (R6G) and crystal violet (CV) adsorbed on silver and gold nanoparticles of different quasispherical shapes and sizes. The metal nanoparticle is characterized by its static total polarizability, a reasonable approximation for frequencies far from the plasmon resonance. We observe that for both R6G and CV, the presence of the nanoparticle shifts the strongest excitation to the red approximately 40 nm and also increases the oscillator strength of that excitation. The shifts in excitation energies due to the nanoparticle surface are found to be comparable to those due to solvation. We find that these shifts decay quickly as the molecule is moved away from the surface. We also find that the wavelength shift is largest when the transition dipole moment is aligned with the edges of the nanoparticle surface where the electric field is expected to be the largest. These results show that the molecular excitations are sensitive to the local environment on the nanoparticle as well as the specific orientation of the molecule relative to the surface. PMID- 20726632 TI - On the calculation of charge transfer transitions with standard density functionals using constrained variational density functional theory. AB - It is well known that time-dependent density functional theory (TD-DFT) based on standard gradient corrected functionals affords both a quantitative and qualitative incorrect picture of charge transfer transitions between two spatially separated regions. It is shown here that the well known failure can be traced back to the use of linear response theory. Further, it is demonstrated that the inclusion of higher order terms readily affords a qualitatively correct picture even for simple functionals based on the local density approximation. The inclusion of these terms is done within the framework of a newly developed variational approach to excitation energies called constrained variational density functional theory (CV-DFT). To second order [CV(2)-DFT] this theory is identical to adiabatic TD-DFT within the Tamm-Dancoff approximation. With inclusion of fourth order corrections [CV(4)-DFT] it affords a qualitative correct description of charge transfer transitions. It is finally demonstrated that the relaxation of the ground state Kohn-Sham orbitals to first order in response to the change in density on excitation together with CV(4)-DFT affords charge transfer excitations in good agreement with experiment. The new relaxed theory is termed R-CV(4)-DFT. The relaxed scheme represents an effective way in which to introduce double replacements into the description of single electron excitations, something that would otherwise require a frequency dependent kernel. PMID- 20726633 TI - The fragment spin difference scheme for triplet-triplet energy transfer coupling. AB - To calculate the electronic couplings in both inter- and intramolecular triplet energy transfer (TET), we have developed the "fragment spin difference" (FSD) scheme. The FSD was a generalization from the "fragment charge difference" (FCD) method of Voityuk et al. [J. Chem. Phys. 117, 5607 (2002)] for electron transfer (ET) coupling. In FSD, the spin population difference was used in place of the charge difference in FCD. FSD is derived from the eigenstate energies and populations, and therefore the FSD couplings contain all contributions in the Hamiltonian as well as the potential overlap effect. In the present work, two series of molecules, all-trans-polyene oligomers and polycyclic aromatic hydrocarbons, were tested for intermolecular TET study. The TET coupling results are largely similar to those from the previously developed direct coupling scheme, with FSD being easier and more flexible in use. On the other hand, the Dexter's exchange integral value, a quantity that is often used as an approximate for the TET coupling, varies in a large range as compared to the corresponding TET coupling. To test the FSD for intramolecular TET, we have calculated the TET couplings between zinc(II)-porphyrin and free-base porphyrin separated by different numbers of p-phenyleneethynylene bridge units. Our estimated rate constants are consistent with experimentally measured TET rates. The FSD method can be used for both intermolecular and intramolecular TET, regardless of their symmetry. This general applicability is an improvement over most existing methodologies. PMID- 20726634 TI - Anharmonic vibrational analysis of water with traditional and explicitly correlated coupled cluster methods. AB - It is well known that the convergence of harmonic frequencies with respect to the basis set size in traditional correlated calculations is slow. We now report that the convergence of cubic and quartic force constants in traditional CCSD(T) calculations on H(2)O with Dunning's cc-pVXZ family of basis sets is also frustratingly slow. As an alternative, we explore the performance of R12-based explicitly correlated methods at the CCSD(T) level. Excellent convergence of harmonic frequencies and cubic force constants is provided by these explicitly correlated methods with R12-suited basis irrespective of the used standard approximation and/or the correlation factor. The Slater type geminal, however, outperforms the linear r(12) for quartic force constants and vibrational anharmonicity constants. The converged force constants from explicitly correlated CCSD(T) calculations succeed in reproducing the fundamental frequencies of water molecule with spectroscopic accuracy after corrections for post-CCSD(T) effects are made. PMID- 20726635 TI - Second-order Moller-Plesset perturbation theory applied to extended systems. II. Structural and energetic properties. AB - Results for the lattice constants, atomization energies, and band gaps of typical semiconductors and insulators are presented for Hartree-Fock and second-order Moller-Plesset perturbation theory (MP2). We find that MP2 tends to undercorrelate weakly polarizable systems and overcorrelates strongly polarizable systems. As a result, lattice constants are overestimated for large gap systems and underestimated for small gap systems. The volume dependence of the MP2 correlation energy and the dependence of the MP2 band gaps on the static dielectric screening properties are discussed in detail. Moreover, the relationship between MP2 and the G(0)W(0) quasiparticle energies is elucidated and discussed. Finally, we demonstrate explicitly that the correlation energy diverges with decreasing k-point spacing for metals. PMID- 20726636 TI - Acceptor switching and axial rotation of the water dimer in matrices, observed by infrared spectroscopy. AB - Several isotopologues of the water dimer have been studied in different matrices (Ne, Ar, Kr, and p-H(2)) at very low temperatures. A fine structure, which is more or less matrix independent and very similar for different intramolecular fundamentals of the same isotopologic dimer, is present on the high wavenumber side of the main component. The bound OD (OH) stretches of the donor have temperature dependent components. The fine structure and temperature dependency is interpreted as evidence for acceptor switching and rotation of the water dimer around its O-O axis in the matrices studied here. The slow nuclear spin equilibration in H(2)O inhibits the thermal equilibration between the acceptor switching states in H(2)O-DOH and H(2)O-DOD. The condensed environment slows down the acceptor switching rate compared to the gas phase. The antisymmetric stretch of the proton acceptor is assigned by combining information from different matrices with the rotation-acceptor switching model. PMID- 20726637 TI - Photodissociation dynamics of the phenyl radical via photofragment translational spectroscopy. AB - Photofragment translational spectroscopy was used to study the photodissociation dynamics of the phenyl radical C(6)H(5) at 248 and 193 nm. At 248 nm, the only dissociation products observed were from H atom loss, attributed primarily to H+o C(6)H(4) (ortho-benzyne). The observed translational energy distribution was consistent with statistical decay on the ground state surface. At 193 nm, dissociation to H+C(6)H(4) and C(4)H(3)+C(2)H(2) was observed. The C(6)H(4) fragment can be either o-C(6)H(4) or l-C(6)H(4) resulting from decyclization of the phenyl ring. The C(4)H(3)+C(2)H(2) products dominate over the two H loss channels. Attempts to reproduce the observed branching ratio by assuming ground state dynamics were unsuccessful. However, these calculations assumed that the C(4)H(3) fragment was n-C(4)H(3), and better agreement would be expected if the lower energy i-C(4)H(3)+C(2)H(2) channel were included. PMID- 20726638 TI - Finite-temperature infrared spectroscopy of polycyclic aromatic hydrocarbon molecules. II. Principal mode analysis and self-consistent phonons. AB - Following previous work [F. Calvo et al. J. Chem. Phys. 132, 124308 (2010)], infrared spectra of several polycyclic aromatic hydrocarbon molecules are simulated with classical and quantum molecular dynamics trajectories. The interactions are modeled using a tight-binding potential energy surface and quantum delocalization is accounted for using the partially adiabatic centroid and ring-polymer molecular dynamics frameworks, both built upon the path-integral representation. The spectra obtained directly by Fourier transformation of the dipole moment autocorrelation function are here compared with several quasiharmonic approximations that provide additional information about the vibrational modes. A principal mode analysis (PMA) is carried out from the covariance matrix of atomic displacements in classical and quantum trajectories. The method systematically overestimates the line shifts due to anharmonicities, except in the power spectra of atomic displacements, and is not robust in predicting IR intensities for such large molecules. Alternatively, effective normal modes have also been determined by adapting the self-consistent phonon (SCP) theory of condensed matter physics to the present tight-binding model, in both classical and quantum mechanical descriptions. The SCP approximation turns out as semiquantitative in estimating the redshift of tight stretching modes, and performs better for classical systems. More problematic, it predicts that many low- or medium-frequency modes should be blueshifted, in contradiction with the molecular dynamics results. The sets of anharmonic normal modes extracted from the PMA and SCP approaches reveal important mixings within the tightest C-H and C C stretching modes, which are also manifested on the corresponding power spectra. PMID- 20726639 TI - Time- and frequency-resolved photoionization of the C (2)A(2) state of the benzyl radical, C(7)H(7). AB - The structure and dynamics of the C (2)A(2) electronically excited state of the benzyl radical, C(7)H(7), were investigated by nanosecond and femtosecond pump probe photoionization. A free jet of benzyl radicals was generated by flash pyrolysis from the precursors 2-phenylethyl nitrite and toluene. Nanosecond multiphoton ionization spectra show a number of vibronic bands that are excited in the wavelength range of 290-310 nm. At excitation wavelengths of 305, 301, and 298 nm, rapid biexponential decay of the excited states was observed. Lifetimes at the C-state origin (305 nm excitation) are 400 fs and 4.5 ps. The lifetimes decrease with increasing excitation energy. The dynamics can be understood within a two-step internal conversion to the electronic ground state. PMID- 20726640 TI - Synthesis and formation mechanism of hydrogenated boron clusters B(12)H(n) with controlled hydrogen content. AB - We present the formation of hydrogen-content-controlled B(12)H(n) (+) clusters through the decomposition and ion-molecule reactions of the decaborane (B(10)H(14)) and diborane (B(2)H(6)) molecules in an external quadrupole static attraction ion trap. The hydrogen- and boron-contents of the B(10-y)H(x) (+) cluster are controlled by charge transfer from ambient gas ions. In the process of ionization, a certain number of hydrogen and boron atoms are detached from decaborane ions by the energy caused by charge transfer. The energy caused by the ion-molecule reactions also induces H atom detachment. Ambient gas of Ar leads to the selective generation of B(10)H(6) (+). The B(10)H(6) (+) clusters react with B(2)H(6) molecules, resulting in the selective formation of B(12)H(8) (+) clusters. Ambient gas of Ne (He) leads to the generation of B(10-y)H(x) (+) clusters with x=4-10 and y=0-1 (with x=2-10 and y=0-2), resulting in the formation of B(12)H(n) (+) clusters with n=4-8 (n=2,4-8). The introduction of ambient gas also increases the production of clusters. PBE0/6-311+G(d)//B3LYP/6 31G(d)-level density functional theory calculations are conducted to investigate the structure and the mechanism of formation of B(10-y)H(x) (+) and B(12)H(n) (+) clusters. PMID- 20726641 TI - Imaging the dynamics of chlorine atom reactions with alkenes. AB - We report a study of chlorine atom reactions with a series of target monounsaturated alkene molecules: 1-pentene, 1-hexene, 2-hexene, and cyclohexene. These reactions were studied using crossed-beam dc slice ion imaging at collision energies of 4 and 7 kcal/mol. Images of the reactively scattered alkenyl radical products were obtained via single photon ionization at 157 nm. The angular distributions at low collision energy are largely isotropic, suggesting the formation of a complex that has a lifetime comparable to or longer than its rotational period, followed by HCl elimination. At high collision energy, the distributions show a sharp forward peak superimposed on the isotropic component accounting for approximately 13% of the product flux. The translational energy distributions peak near zero for the backscattered product, in sharp contrast to the results for alkanes. In the forward direction, the translational energy distributions change dramatically with collision energy. At the high collision energy, a sharp forward peak at approximately 80% of the collision energy appears, quite reminiscent of results of our recent study of Cl+pentane reactions. The scattering distributions for all target molecules are similar, suggesting similarity of the reaction dynamics among these molecules. Ab initio calculations of the energetics and ionization energies for the various product channels were performed at the CBS-QB3 level to aid in interpreting the results. PMID- 20726642 TI - Photodissociation dynamics of tryptophan and the implication of asymmetric photolysis. AB - Photodissociation of amino acid tryptophan in a molecular beam at wavelengths of 212.8 and 193 nm, corresponding to excitation to the second and third absorption bands, was investigated using multimass ion imaging techniques. The respective wavelengths also represent excitation to the edge of a positive circular dichroism band and the center of a negative circular dichroism band of L tryptophan. Only one dissociation channel was observed at both photolysis wavelengths: C(8)NH(6)CH(2)CHNH(2)COOH-->C(8)NH(6)CH(2)+CHNH(2)COOH. Dissociation rates were found to be 1.3x10(6) and 5x10(6) s(-1) at the respective wavelengths. Comparison to theoretical calculation indicates that dissociation occurs on the ground state after internal conversion. Implication of asymmetric photolysis is discussed. PMID- 20726643 TI - Femtosecond electron spectroscopy of coronene, benzo[GHI]perylene, and anthracene. AB - The large polycyclic aromatic hydrocarbon molecules coronene, benzo[GHI]perylene, and anthracene have been ionized with femtosecond laser pulses at low laser intensities and the ionization process studied with velocity map imaging spectroscopy, supplemented with ion yield measurements. The electron spectra of coronene and benzo[GHI]perylene are structureless. Based on fluence and pulse duration dependence measurements, it is shown that the electron spectra are not produced in field ionization processes, and the ionization mechanism is identified to be a quasithermal statistical electron emission, previously suggested for the fullerenes C(60) and C(70). The anthracene photoelectron spectra are dominated by above threshold ionization features, but with some indication of quasithermal ionization at longer pulses. PMID- 20726644 TI - Spectroscopic characterization of Be(2) (+) X (2)Sigma(u) (+) and the ionization energy of Be(2). AB - Rotationally resolved spectra for Be(2) (+) have been recorded using the pulsed field ionization zero kinetic energy photoelectron technique. Vibrational levels in the range v(+)=0-6 were observed. The rotational selection rules confirmed that the ground state is (2)Sigma(u) (+), resulting from the removal of an electron from the sigma(u) antibonding orbital of Be(2). The bond energy and equilibrium distance for Be(2) (+) were found to be D(e) (+)=16 438(5) cm(-1) and R(e) (+)=2.211(8) A. The ionization energy for Be(2) [59 824(2) cm(-1)] was also refined by these measurements. Comparisons with high-level theoretical results indicate that the bonding in Be(2) (+) is adequately described by multi reference singles and doubles configuration interaction (MRDCI) calculations that employ moderate to large scale basis sets. PMID- 20726645 TI - Electronic absorption and phosphorescence of cyanodiacetylene. AB - Electronic absorption and emission spectra have been investigated for cyanodiacetylene, HC(5)N, an astrophysically relevant molecule. The analysis of gas-phase absorption was assisted with the parallel rare gas matrix isolation experiments and with density functional theory (DFT) predictions concerning the excited electronic states. Mid-UV systems B (1)Delta<--X (1)Sigma(+) (origin at 282.5 nm) and A (1)Sigma(-)<--X (1)Sigma(+) (306.8 nm) were observed. Vibronic assignments have been facilitated by the discovery of the visible phosphorescence a (3)Sigma(+)<--X (1)Sigma(+) in solid Ar, Kr, and Xe. Phosphorescence excitation spectra, as well as UV absorption measurements in rare gas matrices, revealed the enhancement of A<--X transitions. The vibronic structure of dispersed phosphorescence spectra supplied new data concerning the ground state bending fundamentals of matrix-isolated HC(5)N. The experimental singlet-triplet splitting, 2.92 eV in Ar, closely matches the value of 3.0 eV predicted by DFT. PMID- 20726646 TI - Length scale of heterogeneities in glassy propylene carbonate probed by oxygen diffusion. AB - A new method using the quenching of guest molecule phosphorescence by molecular oxygen is proposed for determination of heterogeneity size in glassy matrixes. The method is based on the high sensitivity of the diffusion of oxygen molecules to spatial density fluctuations. Phenanthrene phosphorescence decay was monitored at different concentrations of molecular oxygen in propylene carbonate below T(g). An unusual dependence of the phosphorescence decay on oxygen concentration was observed: an increase in the concentration leads to anomalously large increase in the quenching rate at short times. This dependence is considered to be caused by matrix heterogeneity. To describe the phosphorescence decay, we use a model of glass as a heterogeneous medium where oxygen jump rates are spatially correlated. The length of spatial correlation for the jump rates is taken as heterogeneity size. Using the model, the value of 1.5+/-0.5 nm was obtained for the size of structural heterogeneities in glassy propylene carbonate. The dispersion of barriers for oxygen jumps is estimated to be 4+/-1 kJ/mole and the average barrier energy is found to be 50 kJ/mole. PMID- 20726647 TI - Dynamics of glass-forming liquids. XIV. A search for ultraslow dielectric relaxation in glycerol. AB - A recent dielectric study of various polyalcohols reported on the general occurrence of an ultraslow process with Debye type character in hydrogen bonded liquids [R. Bergman, H. Jansson, and J. Swenson, J. Chem. Phys. 132, 044504 (2010)], whereas previous work suggested that such behavior is specific to monoalcohols only. Clarifying this issue is highly relevant for assessing models aimed at rationalizing these modes that are slower than the primary structural relaxation and associated with a single time constant. To this end, the dielectric relaxation of glycerol is measured at different electrode distances with high accuracy. In this manner, electrode polarization can be separated from the dielectric signals intrinsic in the supercooled liquid. In the frequency range below the loss peak frequency omega(max) of the alpha-process, only dc conductivity is required to understand the dielectric properties of supercooled glycerol within a margin of epsilon(") approximately +/-0.1 and thus no indication of an ultraslow peak is found. More quantitatively, any dielectric Debye like mode located around 10(-5)omega(max) would need to have an amplitude smaller than 0.4% of that of the primary dielectric process to be consistent with the present findings, in contrast to previous claims of >50%. PMID- 20726648 TI - The role of fcc tetrahedral subunits in the phase behavior of medium sized Lennard-Jones clusters. AB - The free energy of a 600-atom Lennard-Jones cluster is calculated as a function of surface and bulk crystallinity in order to study the structural transformations that occur in the core of medium sized clusters. Within the order parameter range studied, we find the existence of two free energy minima at temperatures near freezing. One minimum, at low values of both bulk and surface order, belongs to the liquid phase. The second minimum exhibits a highly ordered core with a disordered surface and is related to structures containing a single fcc-tetrahedral subunit, with an edge length of seven atoms (l=7), located in the particle core. At lower temperatures, a third minimum appears at intermediate values of the bulk order parameter which is shown to be related to the formation of multiple l=6 tetrahedra in the core of the cluster. We also use molecular dynamics simulations to follow a series of nucleation events and find that the clusters freeze to structures containing l=5, 6, 7, and 8 sized tetrahedra as well as those containing no tetrahedral units. The structural correlations between bulk and surface order with the size of the tetrahedral units in the cluster core are examined. Finally, the relationships between the formation of fcc tetrahedral subunits in the core, the phase behavior of medium sized clusters and the nucleation of noncrystalline global structures such as icosahedra and decahedra are discussed. PMID- 20726649 TI - Polarization behavior of water in extreme aqueous environments: A molecular dynamics study based on the Gaussian charge polarizable water model. AB - We study the polarization behavior of water under geologically relevant extreme aqueous environments along four equidistant supercritical isotherms, 773Cmcm transition) of HBr and HCl occurs at 25 and 40 GPa, respectively, which can be attributed to the symmetry stretching A(1) mode softening. After hydrogen bond symmetrization, a pressure-induced soft transverse acoustic phonon mode of Cmcm phase is identified and a unique metallic phase with monoclinic structure of P2(1)/m (4 molecules/cell) for both compounds is revealed by ab initio phonon calculations. This phase preserves the symmetric hydrogen bond and is stable in the pressure range from 134 to 196 GPa for HBr and above 233 GPa for HCl, while HBr is predicted to decompose into Br(2)+H(2) above 196 GPa. Perturbative linear response calculations predict that the phase P2(1)/m is a superconductor with T(c) of 27-34 K for HBr at 160 GPa and 9-14 K for HCl at 280 GPa. PMID- 20726656 TI - Molecular dynamics study of solubilization of immiscible solutes by a micelle: Free energy of transfer of alkanes from water to the micelle core by thermodynamic integration method. AB - Free energy of transfer, DeltaG(w-->m), from water phase to a sodium dodecyl sulfate (SDS) micelle core has been calculated for a series of hydrophobic solutes originally immiscible with water by thermodynamic integration method combined with molecular dynamics calculations. The calculated free energy of transfer is in good correspondence to the experiment as well as the theoretical free energy of transfer. The calculated DeltaG(w-->m)'s are all negative, implying that the alkane molecules are more stable in the micelle than in the water phase. It decreases almost linearly as a function of the number of carbon atoms of the alkanes longer than methane with a decrement of 3.3 kJ mol(-1) per one methylene group. The calculated free energy of transfer indicates that, for example, at the micelle concentration of 50 CMC (critical micelle concentration), about only 1 of 6 micelles or 1 of 32 000 micelles does not contain a solute methane or n-octane molecule, respectively. PMID- 20726657 TI - The interfacial properties of MgCl(2) thin films grown on Ti(0001). AB - Photoelectron spectroscopy with synchrotron radiation (SRPES), temperature programmed desorption (TPD), low energy electron diffraction (LEED), and ion scattering spectroscopy (ISS) were used in order to study the MgCl(2)/Ti(0001) interface. A clear hexagonal LEED pattern confirmed the presence of a quite large grain of Ti(0001) on the substrate while no new superstructure was formed after deposition of MgCl(2) either at room or at elevated temperatures. A series of high resolution spectra after step by step MgCl(2) deposition and gradual annealing indicated strong interaction between MgCl(2) and the substrate while ISS measurements showed that there is no migration of Ti atoms into the deposit layers. Additional quantities of deposited MgCl(2) grew stoichimetrically on top of the chemically active interface. Annealing at approximately 350 degrees C caused clustering of the MgCl(2) multilayer and TPD results showed that they desorbed stoichimetrically at temperatures between 360 and 380 degrees C. The interfacial TiCl(x)Mg(y) species dissociated by the disruption of the Cl-Mg bonds at temperatures higher than 400 degrees C and metallic Mg evaporated. The Cl atoms remained attached on the Ti surface but they did not form any ordered structure even after annealing at 730 degrees C. The present results indicate the occurrence of charge transfer at the Ti/MgCl(2) interface through the Cl ligands and provide valuable information for catalyst design. PMID- 20726658 TI - Critical Casimir effect for colloids close to chemically patterned substrates. AB - Colloids immersed in a critical or near-critical binary liquid mixture and close to a chemically patterned substrate are subject to normal and lateral critical Casimir forces of dominating strength. For a single colloid, we calculate these attractive or repulsive forces and the corresponding critical Casimir potentials within mean-field theory. Within this approach we also discuss the quality of the Derjaguin approximation and apply it to Monte Carlo simulation data available for the system under study. We find that the range of validity of the Derjaguin approximation is rather large and that it fails only for surface structures which are very small compared to the geometric mean of the size of the colloid and its distance from the substrate. For certain chemical structures of the substrate, the critical Casimir force acting on the colloid can change sign as a function of the distance between the particle and the substrate; this provides a mechanism for stable levitation at a certain distance which can be strongly tuned by temperature, i.e., with a sensitivity of more than 200 nm/K. PMID- 20726659 TI - Field-induced control of universal fluorescence intermittency of a quantum dot light emitter. AB - With the nonstochastic quantum mechanical study of a quantum dot light emitter, we find that fluorescence intermittency statistics are universal and insensitive to the microscopic nature of the tunneling fluctuation between quantum dot and trapping state. We also investigate the power-law exponent theta and the crossover time tau(C) of the on-time (tau(on)) probability P(tau(on)) proportional to tau(on) (-theta) (for tau(on) less than or approximately equal tau(C)) and proportional to e(-Gamma)tau(on) ) (for tau(on) greater than or approximately equal tau(C)) under an optical field of given energy and strength. For easy off-resonance excitation, it is found in both numerical and analytic ways that tau(C) (-1) is proportional to the intensity of the optical field (i.e., the square of the field strength) independent of the internal parameters of a quantum dot. Furthermore, it is also found that theta=2 in the limit of vanishing field strength is the upper bound of the exponent and theta becomes less than 2 as the field strength increases. PMID- 20726660 TI - A minimal model of nanoparticle crystallization in polar solvents via steric effects. AB - Motivated by recent experimental findings, we present here a minimal analytical model illustrating that the steric interactions among the ionic components can provide a simple, generic mechanism for like-charge crystallization in prototypical nanoparticle systems with counterions in polar solvents. In particular, the underlying steric interactions among these ionic components arise from the structural organization of the polar solvent molecules surrounding these ions as molecular dipole moments that may cooperatively enhance or counteract existing entropic depletion and electrostatic forces. Phenomenologically capturing these steric effects, we assume only the existence of a short-range pairwise Gaussian interaction, which has already been employed usefully for nanoparticles with hydrophillic surfaces or grafted-polymer coatings, among these ionic components (nanoparticles and counterions). The corresponding Gaussian interaction parameters characterize tunable interaction strengths. Making use of an analytically obtained effective pairwise potential between two nanoparticles, upon the contraction of counterions, we derive phase diagrams for nanoparticle systems of varying charge- and size-ratios as a function of particle densities, and observe crystallization for a range of parameters. We further demonstrate that our minimal model is compatible with the phenomenon of charge asymmetry. PMID- 20726661 TI - Surface tension of short flexible Lennard-Jones chains: Corresponding states behavior. AB - Molecular dynamics simulations of surface tensions of short flexible Lennard Jones chains, composed of 2, 3, 4, and 5 segments, have been performed in this work. Using the simulation results, it is shown that the reduced surface tension depends only on the chain length and the reduced temperature. As a consequence, simple three parameters corresponding states using the acentric factor is shown to yield an excellent estimation of the reduced surface tension of the flexible Lennard-Jones chain fluid model. In addition, it has been noticed that the reduced surface tension of this fluid model is a unique function of the coexisting liquid and vapor reduced densities (i.e., there exist a universal Parachor behavior) for all chain lengths tested. When applied to real fluids, this universal behavior holds rather well for a large class of real species which can be nonspherical, nonlinear, and even polar. Only the surface tension of hydrogen-bonding compounds seems to largely deviate from this universal Parachor behavior. These interesting features of the surface tension, written in appropriate scaled forms, can probably be used to improve molecular models, in particular, those on which modern molecular based equations of state rely on. PMID- 20726662 TI - Interfacial layering and capillary roughness in immiscible liquids. AB - The capillary roughness and the atomic density profiles of extended interfaces between immiscible liquids are determined as a function of the interface area by using molecular dynamics and Lennard-Jones (12-6) potentials. We found that with increasing area, the interface roughness diverges logarithmically, thus fitting the theoretical mean-field prediction. In systems small enough for the interfacial roughness not to blur the structural details, atomic density profiles across the fluid interface are layered with correlation length in the range of molecular correlations in liquids. On increasing the system size, the amplitude of the thermally excited position fluctuations of the interface increases, thus causing layering to rapidly vanish, if density profiles are computed without special care. In this work, we present and validate a simple method, operating in the direct space, for extracting from molecular dynamics trajectories the "intrinsic" structure of a fluid interface that is the local density profile of the interface cleaned from capillary wave effects. Estimated values of interfacial properties such as the tension, the intrinsic width, and the lower wavelength limit of position fluctuations are in agreement with results collected from the literature. PMID- 20726663 TI - Loss of momentum in a viscous compressible fluid due to no-slip boundary condition at one or two planar walls. AB - The loss of fluid momentum due to friction at one or two planar walls bounding a viscous compressible fluid is studied as a function of time for the situation where the flow is due to a sudden impulse applied at a selected point in initially quiescent fluid. The no-slip condition is assumed to hold at the walls, and the initial impulse is assumed to be sufficiently small, so that the linearized Navier-Stokes equations may be used. When the initial impulse is directed parallel to the walls the time-dependent total fluid momentum is independent of compressibility and volume viscosity. For initial impulse directed perpendicular to the walls an echoing effect, corresponding to sound bouncing between the two walls, is observed. PMID- 20726664 TI - Revisiting the vibrational spectra of silicon hydrides on Si(100)-(2x1) surface: What is on the surface when disilane dissociates? AB - Even though the decomposition of disilane on silicon surfaces has been extensively studied, the molecular mechanism for its decomposition has not been fully resolved. The general view motivated partly by spectroscopic data is that decomposition occurs through silicon-silicon bond dissociation although there is evidence from kinetics that silicon-hydrogen bond dissociation is important, and perhaps even dominant. Thus, we reexamine the assignment of the experimental vibrational peaks observed in disilane and silane adsorption in order to assess the evidence for the silicon hydride species that are formed during decomposition. We calculate the vibrational density of states for a number of silicon hydride species on the Si(100)-(2x1) surface using Car-Parrinello molecular dynamics. We obtain the calculated vibrational frequency in the adiabatic limit by extrapolating to zero orbital mass, calibrating our method using the well-established monohydride peak. The calculated vibrational frequencies of the monohydride are in good agreement experimental data. Our results show that the spectroscopic data for silicon hydrides does not preclude the occurrence of Si(2)H(5) on the surface thus providing evidence for silicon hydrogen bond dissociation during disilane adsorption. Specifically, we find that an experimentally observed vibrational peak at 2150 cm(-1) that has generally been attributed to the trihydride SiH(3) is more likely to be due to Si(2)H(5). Our results also clear up the assignment of two peaks for monohydride species adsorbed at the edge of a growing terrace, and a peak for the dihydride species adsorbed in the interdimer configuration. PMID- 20726665 TI - Flow-induced polymer translocation through narrow and patterned channels. AB - We consider linear and branched polymers driven through narrow and patterned channels by imposing a Poiseuille flow on the ambient solvent. We establish, by means of scaling arguments, that the translocation probability of dendrimers through the pore is independent of the number of monomers and that it takes place above a viscosity-dependent critical external current. When the channel walls are smooth, the translocation times of linear and branched polymers with the same monomer number are very similar. However, for walls that are decorated with attractive patches, dramatic differences show up: whereas a dendrimer successively docks at the patches and "walks" from one to the next, being carried away by the solvent flow, linear chains spread themselves along the channel wall without achieving translocation within simulation times. Our findings are relevant for, e.g., drug delivery through dendritic carrier molecules in capillary arterioles. PMID- 20726666 TI - Phase-sensitive neutron reflectometry measurements applied in the study of photovoltaic films. AB - Due to low charge carrier mobilities in polymer-based solar cells, device performance is dictated by the nanoscale morphology of the active layer components. However, their morphological details are notoriously difficult to distinguish due to the low electron contrast difference between the components. Phase-sensitive neutron reflectivity (PSNR) is uniquely suited to characterize these systems due to the large, natural scattering length density difference between two common device materials, poly(3-hexylthiophene) and [6,6]-phenyl-C61 butyric acid methyl ester (PCBM). Using PSNR we find a high concentration of PCBM at the substrate and near but not at the air interface. Herein we discuss the method of applying PSNR to polymer-based solar cells, the results obtained, and an evaluation of its effectiveness. PMID- 20726667 TI - Polymer translocation into laterally unbounded confined environments. AB - Using Langevin dynamics simulations in three dimensions, we investigate the dynamics of polymer translocation into the regions between two parallel plane walls with separation R under a driving force F. Compared with an unconfined environment, the translocation dynamics is greatly changed due to the crowding effect of the partially translocated monomers. The translocation time tau initially decreases rapidly with increasing R and then saturates for larger R, and the confined environment leads to a nonuniversal dependence of tau on F. PMID- 20726671 TI - Hepatocyte growth factor incorporated chitosan nanoparticles differentiate murine bone marrow mesenchymal stem cell into hepatocytes in vitro. AB - Delivery of growth factor for the differentiation of stem cells into lineage specific cells holds great potential in regenerative medicine. Stem cell differentiation is governed by cytokines and growth factors secreted upon the organelle injury and, however, their short half-life necessitates exogenous supply. Development of suitable nanodevices using biodegradable polymers to deliver therapeutic proteins to the targeted site in a sustainable manner attracts scientists and clinicians. Here, for the first time, hepatocyte growth factor (HGF) was incorporated into chitosan nanoparticles (CNP) by ionotrophic gelation method. An average size of nanoparticles prepared was 100 nm, showing sustainable release of HGF. Cytotoxicity study did not reveal any adverse effect on bone marrow mesenchymal stem cells (MSC) up to 4 mg CNP/ml culture medium. To evaluate the effect of HGF incorporated CNP (HGF-CNP) on hepatic differentiation in in vitro, MSC were incubated with HGF-CNP and other supplements. After 21 days, fibroblast-like morphology of MSC became round-shape, a typical characteristic of hepatocyte cell. Immunofluorescence study for albumin expression confirmed the hepatic differentiation. In conclusion, HGF released from the HGF-CNP can differentiate MSC into hepatocytes, and this novel technique could also be extended to deliver therapeutic proteins for a variety of tissue regeneration. PMID- 20726672 TI - Nano-engineered living bacterial motors for active microfluidic mixing. AB - Active micromixers with rotating elements are attractive microfluidic actuators in many applications because of their mixing ability at a short distance. However, miniaturising the impeller design poses technical challenges including the fabrication and driving means. As a possible solution inspired by macro magnetic bar-stirrers, this study proposes the use of tethered, rotating bacteria as mixing elements. A tethered cell is a genetically engineered, harmless Escherichia coli (E. coli) attached to a surface by a single, shortened flagellum. The tethered flagellum acts as a pivot around which the entire cell body smoothly rotates. Videomicroscopy, image analysis and computational fluid dynamics (CFD) are utilised to demonstrate a proof-of-concept for the micro mixing process. Flow visualisation experiments show that a approximately 3 microm long tethered E. coli rotating at approximately 240 rpm can circulate a 1 microm polystyrene bead in the adjacent area at an average speed of nearly 4 microm/s. The Peclet (Peb) number for the stirred bead is evaluated to approximately 4. CFD simulations show that the rotary motion of a tethered E. coli rotating at 240 rpm can generate fluid velocities, up to 37 microm/s bordering the cell envelop. Based on these simulations, the Strouhal number (St) is calculated to about 2. This hybrid bio-inorganic micromxer could be used as a local, disposable mixer. PMID- 20726673 TI - Well-defined thermo-responsive polymeric nanocapsules by a one-pot method via surface-initiated atom transfer radical copolymerisation. AB - The well-defined thermo-responsive polymeric nanocapsules were prepared by the one-pot approach via the surface-initiated atom transfer radical copolymerisation of N-isopropyl acrylamide (NIPAM) and N, N-methylenebisacylamide (MBA) from the silica nanoparticle templates after the silica templates were removed by hydrofluoric acid (HF). The diameter of the polymeric nanocapsules is in the range of 20-40 nm, characterised by transmission electron microscopy (TEM). The temperature-induced dimensional change of the thermo-responsive polymeric nanocapsules was investigated by dynamic light scattering (DLS) in aqueous solutions. The intelligent thermo-responsive polymeric nanocapsules are expected to be used for the controlled release of sensitive molecules, such as enzymes, proteins or DNA, by changing the environmental temperature. PMID- 20726674 TI - Terminating polyelectrolyte in multilayer films influences growth and morphology of adhering cells. AB - Polyelectrolyte films of anionic poly(sodium 4-styrenesulphonate) (PSS) and cationic poly (allylamine hydrochloride) (PAH) were constructed using layer-by layer assembly. The authors examined the cytocompatibility of these films for future use in nanobiotechnology applications. Cell lines HEK-293 and 3T3-L1 were cultured on these films and the initial attachment, adhesion, proliferation and cytotoxicity of the cells were measured using a propidium iodide assay. The morphology and spread of the cells were measured by phase-contrast microscopy. The actin cytoskeleton was observed using fluorescent microscopy. Neither the PAH terminated nor the PSS-terminated polyelectrolyte films were cytotoxic. The PAH terminated polyelectrolyte films improved the initial attachment and subsequent adhesion of the cells, in addition to enhancing the production of extracellular matrix and the modelling of the actin filaments. The PSS-terminated film enhanced the proliferation of the cells compared to the PAH-terminated film. That was despite the cell cycle, the spreading or the cytotoxicity of both cell types being similar for either the PSS-terminated surfaces or the PAH-terminated surfaces. Cell behaviour can be modulated by the final surface charge of the polyelectrolyte film and the results are useful in guiding the choice of substrates and/or coatings for potential biomedical applications (e.g. implants) as well as cell biology research. PMID- 20726675 TI - Integrated circuit-based instrumentation for microchip capillary electrophoresis. AB - Although electrophoresis with laser-induced fluorescence (LIF) detection has tremendous potential in lab on chip-based point-of-care disease diagnostics, the wider use of microchip electrophoresis has been limited by the size and cost of the instrumentation. To address this challenge, the authors designed an integrated circuit (IC, i.e. a microelectronic chip, with total silicon area of <0.25 cm2, less than 5 mmx5 mm, and power consumption of 28 mW), which, with a minimal additional infrastructure, can perform microchip electrophoresis with LIF detection. The present work enables extremely compact and inexpensive portable systems consisting of one or more complementary metal-oxide-semiconductor (CMOS) chips and several other low-cost components. There are, to the authors' knowledge, no other reports of a CMOS-based LIF capillary electrophoresis instrument (i.e. high voltage generation, switching, control and interface circuit combined with LIF detection). This instrument is powered and controlled using a universal serial bus (USB) interface to a laptop computer. The authors demonstrate this IC in various configurations and can readily analyse the DNA produced by a standard medical diagnostic protocol (end-labelled polymerase chain reaction (PCR) product) with a limit of detection of approximately 1 ng/microl (approximately 1 ng of total DNA). The authors believe that this approach may ultimately enable lab-on-a-chip-based electrophoretic instruments that cost on the order of several dollars. PMID- 20726676 TI - Results of a safety initiative for patients on concomitant amiodarone and simvastatin therapy in a Veterans Affairs medical center. AB - BACKGROUND: The FDA revised the labels of amiodarone and simvastatin in 2002 to warn of increased risk of rhabdomyolysis, the most severe form of myopathy, when the 2 drugs are taken concomitantly in doses greater than 20 milligrams (mg) per day of simvastatin. The FDA reissued the warning in 2008 after receiving reports of 52 cases of rhabdomyolysis in the Adverse Event Reporting System (AERS) after the label changes in 2002 and suggested use of an alternative statin for patients receiving amiodarone who require more than 20 mg simvastatin to attain lipid goals. OBJECTIVES: To (a) assess the prevalence of concomitant amiodarone and simvastatin in doses greater than 20 mg per day and the frequency of additional risk factors for myopathy in these patients, and (b) implement and evaluate a protocol to convert patients receiving this combination to alternative statins. METHODS: A review was conducted of all patients with active prescriptions for both simvastatin at doses greater than 20 mg per day and amiodarone from a Veterans Affairs (VA) medical center as of November 1, 2008. Data collected included demographics, duration of therapy, baseline lipid and aminotransferase values, and risk factors for myopathy (i.e., aged 80 years or older; female sex; small body frame; hypothyroidism; hepatic or renal insufficiency; diabetes; alcohol abuse; and use of medications, such as gemfibrozil and nicotinic acid, that may increase the risk of myopathy). Patients were converted to either pravastatin or rosuvastatin based on baseline simvastatin dose, low-density lipoprotein cholesterol (LDL-C) level, and renal function. The conversion protocol was developed to maintain LDL-C lowering with potentially safer statins. Follow-up lipid and aminotransferase values were collected as customary clinical markers of efficacy and safety, respectively, for patients converted per the protocol. Because creatine kinase values are not routinely assessed in clinical practice, they were not available as part of the current protocol. RESULTS: Of the 48,612 patients who accessed the pharmacy in this VA medical center, 17,760 (36.5%) had an active order for simvastatin 40 mg or 80 mg per day, and 92 of these patients (0.52%) also had an active order for amiodarone. These patients were prescribed simvastatin primarily for secondary prevention (88 [95.7%] with coronary artery disease [CAD] as the indication for statin therapy), and were highly controlled with mean (SD) baseline LDL-C of 71 (21) mg per deciliter. The mean (median) duration of therapy on the combination of amiodarone plus simvastatin 40 mg or more per day was 43 (37) months. Of the 92 patients, 26 (28.3%), 35 (38.0%), and 18 (19.6%) patients had 1, 2, or 3 or more additional risk factors for myopathy, respectively. 16 patients were not converted per protocol to an alternate statin (4 were taken off amiodarone, 2 were taken off statin therapy, 6 had the simvastatin dose reduced to 20 mg per day or less, and 4 were converted to an alternate statin off-protocol), and 14 patients did not have follow-up laboratory values. For the 62 patients converted per protocol and with follow-up laboratory values, there were no statistically significant changes in mean lipid or aminotransferase values after conversion. One patient reported symptoms of myalgia after conversion to rosuvastatin; however, the conversion protocol did not require obtaining creatine kinase values. CONCLUSION: 0.19% of patients (n=92) with pharmacy dispensing records in this VA facility in 2008 received amiodarone in combination with simvastatin in doses greater than 20 mg per day, and the majority of patients had additional risk factors for myopathy. There were no significant changes in mean laboratory values for lipids or aminotransferase for the 62 patients (67%) who were converted and who had baseline and follow-up values; there was 1 case of self-reported myalgia in a patient converted to rosuvastatin. PMID- 20726677 TI - Budgetary impact of treatment with adjuvant imatinib for 1 year following surgical resection of Kit-positive localized gastrointestinal stromal tumors. AB - BACKGROUND: Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). Treatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST, the most recent FDA-approved indication (December 2008), has been shown to significantly improve recurrence-free survival (RFS) compared with surgical resection alone. Although adjuvant imatinib has proven effective in clinical trials, it is important to consider the economic impact to health plans of introducing imatinib in accordance with its new labeled indication. OBJECTIVE: To evaluate the budgetary impact over a 3-year time horizon of treating patients with localized Kit-positive GIST with 1 year of adjuvant imatinib following surgical resection. METHODS: A Markov model was developed to predict patients' transitions across health states defined by initial treatment (surgical resection followed by adjuvant imatinib 400 milligrams [mg] daily versus surgical resection alone), recurrence, and progression. Treatments for a first recurrence were (a) imatinib 400 mg daily for recurrences following resection only or after completion of 1 year of treatment with imatinib 400 mg daily and (b) imatinib 800 mg daily for recurrence during active treatment with imatinib 400 mg daily. Treatments for further progression were imatinib 800 mg daily, sunitinib, or best supportive care (BSC) following imatinib 400 mg per day, and sunitinib or BSC following imatinib 800 mg daily. Recurrence rates were derived from the American College of Surgeons Oncology Group (ACOSOG) Z9001 clinical trial, which compared 1 year of adjuvant imatinib following surgical resection with surgical resection only. The total number of patients with localized and surgically resected GIST (incidence rate of 0.36 per 100,000) was estimated from epidemiologic studies of GIST. Uptake of treatment with imatinib was estimated from unpublished data from qualitative market research funded by the study sponsor. The uptake rate assumptions reflected both (a) the percentage of patients with Kitpositive disease and (b) the percentage of clinically eligible patients who would use imatinib. Costs were estimated by combining unit costs from published sources with expected resource utilization based on the clinical trial publication and National Comprehensive Cancer Network guidelines on the treatment of patients with GIST. To obtain estimates of the budgetary impact, we compared estimated health care costs with versus without adjuvant imatinib, where health care costs with imatinib reflected the costs of treatment minus cost offsets associated with delayed or avoided recurrence or progression. All "with" scenarios assumed no additional uses other than surgically resected localized Kit-positive GIST (i.e., no change in off-label use of imatinib). The budgetary impact was estimated for the first 3 years after the introduction of adjuvant imatinib in accordance with its new labeled indication in a hypothetical plan population of 10 million persons. Results were calculated both as total budgetary impact and as per member per month (PMPM) cost in 2009 dollars. Sensitivity analyses were performed to test the robustness of model results to changes in parameter estimates. RESULTS: The model predicted 36 incident resected GIST cases per year in a health plan of 10 million members. The estimated counts of cases treated with adjuvant imatinib were 10.8, 16.2, and 21.6 in the first, second, and third years after introduction, respectively, with the annual increases attributable to changes in the proportion of patients with resected GIST assumed to use imatinib (30% in year 1, rising to 45% in year 2 and 60% in year 3). The model predicted that treatment of these cases with imatinib will increase pharmacy costs by an additional $505,144 in the first year, $757,717 in the second year, and $1,010,289 in the third year. Increased resource use associated with monitoring patients during and after treatment with adjuvant imatinib would cost an additional $21,564, $38,145, and $56,605 in the first, second, and third years, respectively. Recurrence would be avoided or delayed in 7 patients over the 3-year period. Avoided or delayed recurrences would result in cost offsets of $61,583 in the first year, $156,702 in the second year, and $233,849 in the third year. The net budgetary impact was estimated to be $465,126 in the first year (less than $0.01 PMPM), $639,159 in the second year ($0.01 PMPM), and $833,044 in the third year ($0.01 PMPM). Results of sensitivity analyses indicated that the budgetary impact in the third year is most sensitive to changes in the price of adjuvant imatinib and recurrence rates. CONCLUSIONS: The model predicted that the introduction of adjuvant imatinib for treatment of surgically resected, localized, Kit-positive GIST will lead to a net budgetary impact of $0.01 PMPM in the third year after introduction assuming change in use only in accordance with the new labeled indication. Approximately 11.7%-21.9% of the cost of adjuvant imatinib is offset by the reduction in costs associated with GIST recurrence. PMID- 20726678 TI - What is the price benchmark to replace average wholesale price (AWP)? AB - An article on the front page of the Wall Street Journal on October 6, 2006, thrust into the public media the otherwise esoteric controversy concerning the use of average wholesale price (AWP) as the primary basis for reimbursements to pharmacies for pharmaceuticals in the United States. Although used widely for nearly 40 years, AWP had been criticized prior to this investigative report as unreliable, subject to manipulation, and not representative of the actual purchase price for pharmaceuticals. The Wall Street Journal article, based on a tentative settlement of litigation in which First DataBank (San Francisco, CA) and the McKesson Corporation (San Francisco, CA) were accused of unilaterally increasing AWPs, included the findings that (a) at least since 2003, AWP was not based on calculation of an "average" wholesale price but instead reflected the pricing of McKesson Corporation, a single drug wholesaler; and (b) AWP had undergone a systematic change beginning in 2001 when First DataBank had converted its markups of wholesale acquisition cost (WAC) to a common multiplier of 1.25,1 effectively increasing the AWP by 4% for AWPs that were previously calculated using a multiplier of 1.20. In March 2009, the future of AWP became uncertain as a result of circumstances surrounding the court settlement of the litigation that had begun in 2005 against First DataBank. On March 17, 2009, U.S. District Court Judge Patti B. Saris approved the proposed settlement of 2 civil action lawsuits filed by private health plan payers of pharmaceuticals against the 2 largest publishers of AWP, First DataBank (along with wholesaler McKesson) and Medi-Span (Indianapolis, IN, subsidiary of Wolters Kluwer Health). On March 30, 2009, Judge Saris signed a final order and judgment certifying the class (of "Private Payor" purchasers) which settled 2 national class action lawsuits against the 2 largest publishers of AWP. As part of the formal settlement, Medi-Span and First DataBank agreed to adjust the markup factor used to calculate AWP downward to 1.20 times WAC "for any prescription pharmaceutical" that had "a mark up factor basis from WAC to AWP in excess of 1.20" for the 1,442 specific national drug code (NDC) numbers that were listed in the court complaint. The "rollback" of AWP as a result of reducing the WAC/DP (direct price) multiplier to no more than 1.20 was implemented by First DataBank and Medi-Span on September 26, 2009, 180 days from the date of the judgment, as ordered. At the same time, these AWP publishers voluntarily implemented price modifications to all products that had a WAC markup greater than 1.20. This decision expanded the list of NDC numbers from the 1,442 specified in the lawsuit to well over 50,000 items. The expanded list included both prescription and nonprescription (over-the-counter [OTC]) items, both active and inactive NDC numbers on the drug database, as well as a variety of markup factors. The adjusted AWPs had markup factors that ranged from 1.20 to 1.33. About two-thirds to three-fourths of the NDC numbers with adjusted AWPs had a pre settlement WAC markup of 1.25. This U.S. District Court decision on March 30, 2009, was also accompanied by separate announcements from the defendants Medi Span and First DataBank that they would voluntarily discontinue publication of AWP. PMID- 20726679 TI - Prescription drug costs and the generic dispensing ratio. AB - BACKGROUND: The generic dispensing ratio (GDR)-the number of generic fills divided by the total number of prescriptions-is a standard performance metric on which pharmacy benefit designs and their managers are routinely evaluated. Higher GDRs are considered important because they consistently produce lower prescription drug costs. OBJECTIVE: To (a) quantify the relationship between GDR and gross pharmacy expenditures and (b) distinguish pharmacy cost savings realized from brand-to-generic conversion from those due to brand drug utilization decreases. METHODS: This study was a longitudinal, retrospective analysis of paid pharmacy claims and insurance eligibility information for 548 employers covering nearly 14 million members. Data were from the period January 1, 2007, through December 31, 2009, aggregated quarterly. In a linear fixed effects model controlling for plan membership demographics and time trends, percentage changes in gross pharmacy expenditures per member per quarter (PMPQ) were associated with changes in GDR. A second model estimated the association of GDR with gross pharmacy cost, holding total drug utilization constant. All claims counts were adjusted to 30-day equivalents, and expenditures were log- transformed. RESULTS: Mean generic claims PMPQ increased by 18.4% during the study period, from 2.01 in 2007 Q1 to 2.38 in 2009 Q4. Conversely, brand claims PMPQ decreased by 21.0%, from 1.76 in 2007 Q1 to 1.39 in 2009 Q4. As a result, mean GDR per plan increased by 9.8 percentage points or a relative change of 18.2%, from 53.9% in 2007 Q1 to 63.7% in 2009 Q4. Over the 3 years, average gross pharmacy costs PMPQ increased by 14.0% from $242 to $276. The relationship between GDR and gross pharmacy expenditures, estimated in the linear fixed effects multivariate models, varied depending upon whether or not total utilization was controlled. In the first model, which did not control for total utilization, each percentage point increase in GDR was associated with a 2.5% reduction in gross pharmacy expenditure. Holding total utilization constant, the reduction in gross pharmacy expenditure for each percentage point increase in GDR was 1.3%. CONCLUSION: Prescription drug cost savings are realized with increases in GDR. During 2007-2009, each 1 percentage point increase in GDR was associated with a drop of 2.5% in gross pharmacy expenditures. Slightly more than one-half of the savings was derived from the lower drug prices enjoyed with brand-to generic conversions. The remaining savings, however, were attributed to reduced brand drug utilization. Pharmacy benefit managers and plan sponsors should exercise care to ensure that increases in GDR do not represent reductions in appropriate medication use. PMID- 20726680 TI - Scope of contemporary pharmacy practice: roles, responsibilities, and functions of pharmacists and pharmacy technicians. PMID- 20726681 TI - Studies recommending palivizumab restriction have serious deficiencies. PMID- 20726682 TI - Myopathies related to systemic sclerosis: a case-control study of associated clinical and immunological features. AB - OBJECTIVE: Little is known about systemic sclerosis (SSc)-related myopathy. We aimed to compare the clinical and immunological features of SSc patients with or without associated myopathy. METHODS: Forty SSc patients with myopathy, defined by myalgia or muscle weakness associated with creatine kinase (CK) more than five times the upper limit range or myopathic electromyography (EMG) or abnormal myopathology, were identified from the records of four French hospital centres. For each patient, we selected two SSc controls matched for cutaneous SSc form, sex, age at SSc onset, and disease duration. We performed a case-control study testing clinical and immunological SSc-related features for association with myopathy by conditional logistic regression. RESULTS: Muscle and SSc features of patients with myopathy did not differ significantly among the four centres of origin. Only four (10%) patients with SSc-associated myopathy had anti polymyositis-scleroderma (PM-Scl) antibodies. Case-control univariate analysis revealed that reduced forced vital capacity (FVC) [odds ratio (OR) 3.0, 95% confidence interval (CI) 1.3-34.9], heart involvement, defined as clinical congestive heart failure, left ventricular ejection fraction (LVEF) < 60%, arrhythmia or conductive abnormalities (OR 2.9, 95% CI 1.3-6.5), and scleroderma renal crisis (OR 3.0, 95% CI 1.3-34.9) were significantly more frequent in patients with myopathy than in controls. Two autoantibodies were more frequent in patients with myopathy: anti-PM-Scl (OR 5.0, 95% CI 1.1-23.9) and anti-RNP (OR 6.9, 95% CI 1.1-64.4). Multivariate analysis retained two variables associated positively with myopathy [reduced FVC (OR 3.1, 95% CI 1.3-9.8) and heart involvement (OR 2.5, 95% CI 1.1-7.1)], while anti-centromere antibodies were associated negatively (OR 0.11, 95% CI 0.03-0.53). CONCLUSION: Heart monitoring of SSc patients with myopathy should be undertaken regularly because of the association of myocardial and skeletal myopathies in such patients. PMID- 20726683 TI - Trends in treatment strategies and the usage of different disease-modifying anti rheumatic drugs in early rheumatoid arthritis in Finland. Results from a nationwide register in 2000-2007. AB - OBJECTIVES: To determine which disease-modifying anti-rheumatic drugs (DMARDs) are currently used by Finnish rheumatologists to treat early rheumatoid arthritis (RA). METHODS: Information on sex, date of birth, and date of special medicine reimbursement decision for all new RA patients was collected from a nationwide register maintained by the Social Insurance Institution (SII) during the time period from 1 January 2000 to 31 December 2007. Patient cohorts were registered in 2-year time periods (2000-01, 2002-03, 2004-05, 2006-07) and DMARDs purchased by the patient cohorts during the first year after the date of reimbursement decision for RA were registered. The frequencies of early drug treatment strategies (combination of DMARDs, single DMARD, or no DMARDs) were evaluated. RESULTS: A total of 14 878 (68.0% female, 62.6% rheumatoid factor (RF)-positive) patients were identified. Between 2000 and 2001 the most commonly used treatment strategy for early RA during the first 3 months was single DMARD treatment (56.1%) and the most commonly used DMARD during the first year was sulfasalazine (63.0%), while between 2006 and 2007 the respective treatments were combination DMARDs (55.3%) and methotrexate (69.0%). The change in treatment strategies as well as in DMARDs used was highly significant (p < 0.001 for linearity). At the end of the study period only 4.9% of the patients with early RA were not receiving DMARDs during the first 3 months. CONCLUSIONS: Currently, combination therapy including methotrexate is the most commonly prescribed treatment strategy for early RA in Finland. In recent years, an increasing number of active drug treatments have been taken into practice. PMID- 20726684 TI - Impact of ankylosing spondylitis on work in patients across the UK. AB - OBJECTIVES: To examine the impact of ankylosing spondylitis (AS) on patients across the UK and to identify factors associated with unemployment, absenteeism, and presenteeism. METHODS: One thousand patients with AS from 10 specialist rheumatology centres across the UK were invited to participate in a study evaluating a new outcome measure. Patients completed a questionnaire, which included questions relating to their work, sociodemographic and clinical characteristics. RESULTS: The questionnaire was completed by 612 patients (438 males; 72%). The mean age of the participants was 50.8 (SD 12.2) years, mean disease duration was 17.3 (SD 11.7) years, and mean symptom duration 22.4 (SD 12.4) years. A total of 206 (40%) patients of working age were not employed. Factors associated with not being employed were social deprivation [odds ratio (OR) 3.52, 95% confidence interval (CI) 2.14-5.80], poor function (OR 3.42, 95% CI 1.90-6.13), depression (OR 2.05, 95% CI 1.12-3.78), increasing age (OR 1.05 per year, 95% CI 1.02-1.08), and longer disease duration (OR 1.03 per year, 95% CI 1.01-1.06). Disease activity (OR 3.24, 95% CI 1.11-9.48) and depression (OR 3.22, 95% CI 1.22-8.48) were associated with absenteeism, while depression (OR 5.69, 95% CI 1.77-18.27, disease activity (OR 3.97, 95% CI 1.76-8.98), anxiety (OR 3.90, 95% CI 1.83-8.31), self-efficacy (OR 0.71, 95% CI 0.58-0.86), and increasing age (OR 1.04 per year, 95% CI 1.00-1.08) were associated with presenteeism. CONCLUSION: Psychological, sociodemographic, and disease-related factors were all found to be related to work status. These factors should be taken into account when considering early treatment and management. Depression, in particular, appears to be associated with employment, absenteeism, and presenteeism, and should therefore be prioritized in clinical practice. PMID- 20726685 TI - Capillaroscopy shows an active pattern of scleroderma in coeliac disease. PMID- 20726686 TI - Fungal spinal cord compression in metastatic synovial sarcoma. PMID- 20726687 TI - Defining a threshold surface density of vitronectin for the stable expansion of human embryonic stem cells. AB - Current methodology for pluripotent human embryonic stem cells (hESCs) expansion relies on murine sarcoma basement membrane substrates (MatrigelTM), which precludes the use of these cells in regenerative medicine. To realize the clinical efficacy of hESCs and their derivatives, expansion of these cells in a defined system that is free of animal components is required. This study reports the successful propagation of hESCs (HES-3 and H1) for > 20 passages on tissue culture-treated polystyrene plates, coated from 5 MUg/mL of human plasma-purified vitronectin (VN) solution. Cells maintain expression of pluripotent markers Tra1 60 and OCT-4 and are karyotypically normal after 20 passages of continuous culture. In vitro and in vivo differentiation of hESC by embryoid body formation and teratoma yielded cells from the ecto-, endo-, and mesoderm lineages. VN immobilized on tissue culture polystyrene was characterized using a combination of X-ray photoemission spectroscopy, atomic force microscopy, and quantification of the VN surface density with a Bradford protein assay. Ponceau S staining was used to measure VN adsorption and desorption kinetics. Tuning the VN surface density, via the concentration of depositing solution, revealed a threshold surface density of 250 ng/cm2, which is required for hESCs attachment, proliferation, and differentiation. Cell attachment and proliferation assays on VN surface densities above this threshold show the substrate properties to be equally viable. PMID- 20726688 TI - Biological agents in kidney transplantation: belatacept is entering the field. AB - IMPORTANCE OF THE FIELD: Kidney transplantation is the best treatment for end stage kidney-disease patients. However, despite major breakthroughs in the last decades, and the progresses made with immunosuppressants, the long-term results still need to be improved. This is related to the increased risk of cardiovascular mortality, de novo post-transplant malignancies, and chronic kidney disease within the allograft. The last is multifactorial and includes immunological and non-immunological factors. Amongst the last is the calcineurin inhibitor (CNI) (cyclosporine A (CsA) and tacrolimus)-related nephrotoxicity. Kidney-allograft function at 1-year post-transplantation is a good surrogate marker of long-term allograft survival. AREAS COVERED IN THIS REVIEW: Cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-Ig, a fusion protein, presents as abatacept, which conserves the natural structure of CTLA4, and belatacept, which has enhanced activity thanks to two amino-acid substitutions. Abatacept and belatacept block CD86-CD28 interaction, but belatacept blocks them more powerfully. Abatacept is already approved for the treatment of rheumatoid arthritis and is marketed as Orencia((r)) (Bristol-Myers Squibb, Princeton, NJ, USA), whereas belatacept is not yet approved. Herein, we review the current data available on the use of belatacept in Phase II and III kidney-transplantation trials. Note, though, that data from belatacept Phase II liver transplantation trials are not yet available. WHAT THE READER WILL GAIN: The results show in de novo kidney transplant patients that as compared to CsA-treated patients, belatacept-treated patients showed: i) a significant better allograft function both at 1- and 2- year post-transplantation and ii) better cardiovascular and metabolic profiles. Regarding the safety data, Epstein-Barr virus (EBV) seronegative belatacept-treated patients experience more post-transplant lymphoproliferative disorders than the EBV seropositive belatacept-treated patients and the CsA-treated patients. TAKE HOME MESSAGE: CNIs are potent immunosuppressants but have some degree of nephrotoxicity. Therefore, it is important to have strong data showing that belatacept-based therapy is as efficient as CsA-based therapy, but displaying at both 1- and 2-year post transplantation a better allograft function, which might translate in the long term into longer allograft survival. PMID- 20726689 TI - Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy. AB - IMPORTANCE OF THE FIELD: The human genome encodes at least 40 distinct voltage gated potassium channel subtypes, which vary in regional expression, pharmacological and biophysical properties. Voltage-dependent potassium (Kv) channels help orchestrate many of the physiological and pathophysiological processes that promote and sometimes hinder the healthy functioning of our bodies. AREAS COVERED IN THIS REVIEW: This review summarizes patent and scientific literature reports from the past decade highlighting the opportunities that Kv channels offer for the development of new therapeutic interventions for a wide variety of disorders. WHAT THE READER WILL GAIN: The reader will gain an insight from an analysis of the associations of different Kv family members with disease processes, summary and evaluation of the development of therapeutically relevant pharmacological modulators of these channels, particularly focusing on proprietary agents being developed. TAKE HOME MESSAGE: Development of new drugs that target Kv channels continue to be of great interest but is proving to be challenging. Nevertheless, opportunities for Kv channel modulators to have an impact on a wide range of disorders in the future remain an exciting prospect. PMID- 20726698 TI - Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus-infected individuals. AB - Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD → euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic → MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373. PMID- 20726700 TI - Preoperative embolization or ligature of the uterine arteries in preparation for conservative uterine fibroma surgery. AB - OBJECTIVE: To compare the efficacy, feasibility and morbidity of two preparation techniques for conservative uterine myoma surgery: temporary embolization and temporary surgical ligature of the uterine arteries. DESIGN: Retrospective study. SETTING: Gynecological Surgery and Interventional Radiology departments, Centre Hospitalier Universitaire of Dijon, France. POPULATION: A total of 100 women undergoing myomectomy between 2000 and 2008. METHODS: Three groups were constituted: (1) no preparation (43 patients), (2) uterine artery embolization (UAE) (30 patients) and (3) temporary surgical ligature of the uterine arteries (SLUA) (27 patients). The choice of technique depended on the number, size and topography of the fibromas. MAIN OUTCOMES MEASURES: Quantification of peroperative blood loss, delta hemoglobin, complications, subsequent fertility. RESULTS: Blood loss and delta hemoglobin were both lower in group 2 (p = 0.026 and p = 0.0002) and in group 3 (p = 0.048 and p = 0.001), respectively, than in group 1. The two preparation techniques were efficient. SLUA increased the duration of the operation (p < 0.0001). Hospitalization was longer following UAE (p = 0.0001). The rate of complications was 16.3, 23.3 and 3.7%, and of synechiae 9.3, 13.3 and 0% for groups 1, 2 and 3, respectively. The number of pregnancies was 8, 5 and 6 after a mean postoperative period of 5.6, 4.3 and 3.9 years, respectively. CONCLUSION: Both UAE and SLUA for myomectomy are feasible, reproducible and effective techniques for reducing peroperative blood loss. Use of these techniques must be generalized in patients with a high risk of hemorrhage, but may be compatible with subsequent fertility. PMID- 20726699 TI - Longitudinal psychomotor speed performance in human immunodeficiency virus seropositive individuals: impact of age and serostatus. AB - Older human immunodeficiency virus-seropositive (HIV+) individuals (greater than age 50 years) are twice as likely to develop HIV dementia compared to younger HIV+ individuals. The objective of this study was to examine the impact of both age and serostatus on longitudinal changes in psychomotor speed/executive functioning performance among HIV+ and HIV- individuals. Four hundred and seventy seven HIV+ and 799 HIV- individuals from the Multicenter AIDS Cohort Study (MACS) were subdivided into three age groups: (1) <40 years, (2) 40-50 years, and (3) >50 years. Psychomotor speed/executive functioning test performance was measured by the Symbol Digit Modalities Test (SDMT) and the Trail Making (TM) Test Parts A and B. Changes in performance were compared among the three age groups for both HIV+ and HIV- individuals. Among HIV+ individuals, on the TM Test Part B the younger group demonstrated improvement in performance over time (P = .007). The older and middle age groups demonstrated decline in performance over time (P = .041 and .030). The older group had a significantly different trajectory relative to the younger group (P = .046). Among the HIV- individuals, there was no effect of age on longitudinal performance. In conclusion, older HIV+ individuals show greater decline over time than younger HIV+ individuals on the TM Test Part B. Our results suggest that both HIV serostatus and age together may impact longitudinal performance on this test. Mild neurocognitive changes over time among older HIV+ individuals are likely to reflect age associated pathophysiological mechanisms including cerebrovascular risk factors. PMID- 20726701 TI - Weight gain restriction for obese pregnant women. PMID- 20726703 TI - A physiological systems model for iodine for use in radiation protection. AB - This paper summarizes the biokinetic database for iodine in the human body and proposes a biokinetic model for systemic iodine for use in dose assessments for internally deposited radioiodine. The model consolidates and extends existing physiological systems models describing three subsystems of the iodine cycle in the body: circulating inorganic iodide, thyroidal iodine (trapping and organic binding of iodide and synthesis, storage and secretion of thyroid hormones), and extrathyroidal organic iodine. Thyroidal uptake of inorganic iodide is described as a function of stable iodine intake (Y, ug day(-1)) and thyroidal secretion of hormonal iodine (S, ug day(-1)). Baseline parameter values are developed for reference adults with typical iodine intake. Compared with the current systemic biokinetic model of the International Commission on Radiological Protection (ICRP) for occupational intake of radioiodine, the proposed model predicts higher absorbed doses to the thyroid per unit uptake to blood for very short-lived iodine isotopes, similar absorbed doses to thyroid for iodine isotopes with half life of at least a few hours, and substantially higher estimates of absorbed dose to stomach wall, salivary gland and kidneys for most iodine isotopes. Absorbed dose estimates for intravenous administration of radioiodine-labeled thyroid hormones based on the proposed model differ substantially in some cases from current ICRP values. PMID- 20726704 TI - Improvement of radiation resistance and an estimate of solvated electron yield of the ionic liquid [Bmim]Cl by the addition of FeCl(3). AB - The radiation stability of the ionic liquid 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) was investigated after (60)Co gamma irradiation at doses up to 600 kGy. Thermal and spectroscopic analysis revealed the formation of a small quantity of radiolytic products and an evident change in the physicochemical properties of the ionic liquid. The presence of anionic FeCl(4)(-) (up to 5 mol%), as measured by UV-vis absorption, differential scanning calorimetry, and Raman spectroscopy, significantly improved the radiation resistance of [Bmim]Cl. The increased resistance may be due to the capture of a solvated electron (e(solv)(-)) by FeCl(4)(-) to form FeCl(4)(2-) and results in the radiation protection of the organic cation. The radiation yield of the reductive species (Fe(II)) was estimated to be 0.217 +/- 0.010 umol/J (2.09 +/- 0.10/100 eV), which is considered close to the radiation yield of the solvated electrons of [Bmim]Cl. PMID- 20726702 TI - Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are predominantly those affecting skin and soft tissues. Although progress has been made, our knowledge of the molecules that contribute to the pathogenesis of CA-MRSA skin infections is incomplete. We tested the hypothesis that alpha-hemolysin (Hla) contributes to the severity of USA300 skin infections in mice and determined whether vaccination against Hla reduces disease severity. Isogenic hla-negative (Deltahla) strains caused skin lesions in a mouse infection model that were significantly smaller than those caused by wild-type USA300 and Newman strains. Moreover, infection due to wild-type strains produced dermonecrotic skin lesions, whereas there was little or no dermonecrosis in mice infected with Deltahla strains. Passive immunization with Hla-specific antisera or active immunization with a nontoxigenic form of Hla significantly reduced the size of skin lesions caused by USA300 and prevented dermonecrosis. We conclude that Hla is a potential target for therapeutics or vaccines designed to moderate severe S. aureus skin infections. PMID- 20726705 TI - Dynamics of ionizing radiation-induced DNA damage response in reconstituted three dimensional human skin tissue. AB - The ATM-dependent DNA damage checkpoint plays a pivotal role in cellular response to ionizing radiation. Although amplification of the DNA damage signal through multifactorial protein complex formation of DNA damage checkpoint factors is crucial for proper DNA damage response in two-dimensionally cultured cells, the dynamics of the DNA damage response in three-dimensional tissues or organs remained to be determined. Here we used a model of reconstituted human skin and investigated the spatiotemporal dynamics of focus formation of DNA damage checkpoint factors after X irradiation. We found that DNA damage-induced foci were differentially formed in different layers. All cells in basal layers and approximately 40% of cells in spinous layers displayed foci. In basal cells, the foci showed linear dose relationships, and the number of foci decreased with increasing time after irradiation. We found that the initial foci grew within a few hours after irradiation, and persistent signals developed large foci. Colocalization of phosphorylated ATM, phosphorylated histone H2AX, MDC1 and 53BP1 foci was detected, and all of them showed simultaneous focus growth, indicating amplification of DNA damage signals. These results confirmed a dynamic DNA damage response in three-dimensional tissue, which provides a practical model for studying DNA damage response in vivo. PMID- 20726706 TI - Low (60 cGy) doses of (56)Fe HZE-particle radiation lead to a persistent reduction in the glutamatergic readily releasable pool in rat hippocampal synaptosomes. AB - Exposure to galactic cosmic radiation (GCR) is considered to be a potential health risk in long-term space travel, and it represents a significant risk to the central nervous system (CNS). The most harmful component of GCR is the HZE [high-mass, highly charged (Z), high-energy] particles, e.g. (56)Fe. In ground based experiments, exposure to HZE-particle radiation induces pronounced deficits in hippocampus-dependent learning and memory in rodents. The mechanisms underlying these impairments are mostly unknown, but some studies suggest that HZE-particle exposure perturbs the regulation of long-term potentiation (LTP) at the CA1 synapse in the hippocampus. In this study, we irradiated rats with 60 cGy of 1 GeV (56)Fe-particle radiation and established its impact on hippocampal glutamatergic neurotransmissions at 3 and 6 months after exposure. Exposure to 60 cGy (56)Fe-particle radiation significantly (P < 0.05) reduced hyperosmotic sucrose evoked [(3)H]-glutamate release from hippocampal synaptosomes, a measure of the readily releasable vesicular pool (RRP). This HZE-particle-induced reduction in the glutamatergic RRP persisted for at least 6 months after exposure. At 90 days postirradiation, there was a significant reduction in the expression of the NR1, NR2A and NR2B subunits of the glutamatergic NMDA receptor. The level of the NR2A protein remained suppressed at 180 days postirradiation, but the level of NR2B and NR1 proteins returned to or exceeded normal levels, respectively. Overall, this study shows that hippocampal glutamatergic transmission is sensitive to relative low doses of (56)Fe particles. Whether the observed HZE-particle-induced change in glutamate transmission, which plays a critical role in learning and memory, is the cause of HZE-particle-induced neurocognitive impairment requires further investigation. PMID- 20726707 TI - Evaluation of the radiosensitivity of the oxygenated tumor cell fractions in quiescent cell populations within solid tumors. AB - Labeling of all proliferating cells in C57BL/6J mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with gamma rays at a high dose rate or a reduced dose rate at 1 h after the administration of pimonidazole. Assessment of the responses of quiescent and total ( = proliferating + quiescent) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The total cell fraction that was not labeled with pimonidazole showed significantly enhanced radiosensitivity. However, a significantly greater decrease in radiosensitivity, evaluated using a delayed assay or a decrease in radiation dose rate, was observed in the quiescent cell compared with the total cell population. Overall, the quiescent cell population showed significantly greater radioresistance and capacity to recover from radiation-induced damage than the total tumor cell population. Thus we believe that the subfraction of the quiescent tumor cell population that was not labeled with pimonidazole and that was probably oxygenated is a critical target in the control of solid tumors. PMID- 20726708 TI - Acceleration of diabetic wound healing by low-dose radiation is associated with peripheral mobilization of bone marrow stem cells. AB - In this study we investigated the effect of repeated low-dose radiation exposure (75 mGy X ray) on skin wound healing in a rat model of diabetes. A skin wound was made on the backs of diabetic and age-matched control rats 60 days after diabetes was induced by a single injection of streptozotocin. Rats with skin wounds were immediately treated with whole-body radiation daily for 5, 10 or 15 days with a 2 day break every 5 days. Wound size was estimated 5, 10 and 15 days after wound formation. Repeated exposure of diabetic rats to low-dose radiation significantly accelerated skin wound healing compared to the nonirradiated diabetic group. Furthermore, low-dose radiation-induced improvement in healing was associated with increases in bone marrow and circulating CD31(+)/CD34(+) stem cells, vessel regeneration and cell proliferation in the wound tissue, and matrix metalloproteinase 2 and 9 expression. Therefore, we conclude that the acceleration of wound healing in diabetic rats by repeated exposure to low-dose radiation is associated with stimulation of bone marrow stem cell proliferation and peripheral mobilization. PMID- 20726709 TI - The radiosensitivity of satellite cells: cell cycle regulation, apoptosis and oxidative stress. AB - Skeletal muscles are the organ of movement, and their growth, regeneration and maintenance are dependent in large part on a population of myogenic stem cells known as satellite cells. Skeletal muscles and these resident myogenic stem cells (i.e., satellite cells) are commonly exposed to significant doses of radiation during diagnostic procedures and/or during the radiotherapeutic management of cancer. The main objective of this study was to examine the effects of clinically relevant doses of gamma radiation on satellite cell survival and proliferation, cell cycle regulation, apoptosis, DNA double-strand break repair, oxidative stress and NO production. Overall, our findings demonstrate that doses of gamma radiation >=5 Gy reduced satellite cell numbers by at least 70% due in part to elevated apoptosis and the inhibition of cell cycle progression. Radiation was also found to cause a significant and persistent increase in the level of reactive oxygen and nitrogen species. Interestingly, and within this backdrop of elevated oxidative stress, similar doses were found to produce substantial reductions in the levels of nitric oxide (NO). Proliferation of satellite cells has been shown to depend in part on the production of NO, and our findings give rise to the possibility that radiation-induced reductions in NO levels may provide a mechanism for the inhibition of satellite cell proliferation in vitro and possibly the regrowth of skeletal muscle exposed during clinical irradiation procedures. PMID- 20726710 TI - Transient activation of the ALT pathway in human primary fibroblasts exposed to high-LET radiation. AB - It is well established that high-LET radiations efficiently induce chromosome aberrations. However, data on the effect of protons on telomere maintenance, as involved in genomic stability, are scarce and contradictory. Here we demonstrate that high-LET protons induce telomere lengthening in human primary fibroblasts and that this elongation does not involve the telomerase enzyme, supporting the hypothesis that high-LET radiations are able to activate a telomerase-independent mechanism. In tumor cells that lack telomerase, one or more non-telomerase mechanisms for telomere maintenance are present, which are termed alternative lengthening of telomeres (ALT). Since ALT cells are characterized by recombinational events at telomeres, known as telomeric-sister chromatid exchanges (T-SCE), and colocalization of telomeres and premyelocytic leukemia protein (PML), we analyzed both T-SCE and PML. Our results show that high-LET protons induce a 2.5-fold increase of T-SCE and a colocalization of PML protein and telomeric DNA. Furthermore, our data show that the ALT pathway can be activated in human primary cells after induction of severe DNA damage. Thus, since telomeres are known to be involved in chromosome maintenance, the present work may contribute in the elucidation of the mechanism by which ionizing radiation induces genomic instability. PMID- 20726711 TI - Fractionated radiation therapy can induce a molecular profile for therapeutic targeting. AB - To examine the possibility of using fractionated radiation in a unique way with molecular targeted therapy, gene expression profiles of prostate carcinoma cells treated with 10 Gy radiation administered either as a single dose or as fractions of 2 Gy * 5 and 1 Gy * 10 were examined by microarray analysis. Compared to the single dose, the fractionated irradiation resulted in significant increases in differentially expressed genes in both cell lines, with more robust changes in PC3 cells than in DU145 cells. The differentially expressed genes (>twofold change; P < 0.05) were clustered and their ontological annotations evaluated. In PC3 cells genes regulating immune and stress response, cell cycle and apoptosis were significantly up-regulated by multifractionated radiation compared to single dose radiation. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes revealed that immune response and cardiovascular genes were in the top functional category in PC3 cells and cell-to-cell signaling in DU145 cells. RT PCR analysis showed that a flexure point for gene expression occurred at the 6th 8th fraction and AKT inhibitor perifosine produced enhanced cell killing after 1 Gy * 8 fractionated radiation in PC3 and DU145 cells compared to single dose. This study suggests that fractionated radiation may be a uniquely exploitable, non-oncogene-addiction stress pathway for molecular therapeutic targeting. PMID- 20726713 TI - X-ray-induced radioresistance against high-LET radiations from accelerated heavy ions in mice. AB - Induction of an adaptive response by priming X rays in combination with challenge irradiations from high-LET accelerated heavy ions was attempted in young adult female C57BL/6J Jms mice using 30-day survival after the challenge irradiations as an index. Three kinds of accelerated heavy ions from monoenergetic beams of carbon, silicon and iron ions with LETs of about 15, 55 and 200 keV/MUm, respectively, were examined. A priming low dose of 0.50 Gy X rays in combination with a challenging dose of 7.50 Gy was used in the animals serving as a positive control group to confirm the successful induction of an adaptive response. The priming low dose of 0.50 Gy X rays was also used in combination with accelerated heavy ions. The priming low dose of X rays significantly reduced the mortality from the high challenge doses of carbon or silicon particles but not from iron particles. These results indicate that an adaptive response could be induced by priming low-LET X rays in combination with subsequent challenge high-LET irradiations from certain kinds of accelerated heavy ions, and successful induction of an adaptive response would possibly be an event related to the LET and/or the type of heavy ions. This is the first time that the existence of an adaptive response induced by low-LET X rays against high-LET whole-body irradiation in mice has been demonstrated. These findings would provide new insight into the radiation-induced adaptive response in vivo. PMID- 20726712 TI - Effects of low-dose radiation on the immune system of mice after total-body irradiation. AB - The effects of acute exposure to low- and high-dose radiation on the quantitative and functional parameters of the immune system were analyzed. C57BL/6 mice were irradiated with different doses of gamma radiation (0.01, 0.05, 0.1, 0.5 and 2 Gy) and splenocytes were isolated at various times. Alterations in the distribution and surviving fraction of splenocyte subsets such as CD4(+) and CD8(+) T lymphocytes, regulatory T cells (Treg), natural killer (NK) cells, dendritic cells (DCs) and B lymphocytes were analyzed by flow cytometry. Apoptosis frequency was quantified by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method 4 h after irradiation. Cytokine expression was investigated by real-time reverse transcription-polymerase chain reaction (RT PCR). Low doses decreased apoptosis in the splenocyte subpopulations studied most prominently in NK cells and DCs. Exposure to 2 Gy increased apoptosis in all splenocyte subpopulations; B cells were the most sensitive and NK cells and DCs the least sensitive. The lowest cell numbers were measured 3 days after irradiation, with minor changes by day 7. CD8(+) and B cells were rather resistant to low doses but were very sensitive to 2 Gy, while NK cells, DCs and Treg cells were much more resistant to high doses. Expression of the T-helper 1 (Th1)- and helper 2 (Th2)-type cytokines decreased after low doses and increased after high doses. Interleukin 6 (IL-6) reacted at early times and IL-10 at later times. IL-5 levels were consistently elevated. These data highlight the differences in the responses of different splenocyte subpopulations to low- and high-dose radiation. PMID- 20726714 TI - Limitations associated with analysis of cytogenetic data for biological dosimetry. AB - The scientific literature concerning cytogenetic biodosimetry has been reviewed to identify the range of scenarios of radiation exposure where biodosimetry has been carried out. Limitations in the existing standardized statistical methodology have been identified and categorized, and the reasons for these limitations have been explored. Statistical problems generally occur due to either low numbers of aberrations leading to large uncertainties or deviations in aberration-per-cell distributions leading to over- or under-dispersion with respect to the Poisson model. A number of difficulties also stem from limitations of the classical statistical methodology, which requires that chromosome aberration yields be considered as something "fixed" and thus provides a deterministic estimate of radiation dose and associated confidence limits (because an assignment of a probability to an event is based solely on the observed frequency of occurrence of the event). Therefore, it is suggested that solutions to the listed problems should be based in the Bayesian framework. This will allow the investigator to take a probabilistic approach to analysis of cytogenetic data, which can be considered highly appropriate for biological dose estimation. PMID- 20726715 TI - cDNA expression analysis of a human radiosensitive-radioresistant cell line model identifies telomere function as a hallmark of radioresistance. AB - To achieve a more complete understanding of the molecular mechanisms underlying tumor radioresistance, we established a radioresistant cell line from the human larynx squamous cell carcinoma cell line Hep-2 after long-term radiation induction. The biological features of the resulting cell lines were characterized. cDNA microarray technology was used to measure the alterations of gene expression in the radioresistant cells. We found that certain genes associated with DNA repair, cell cycle, apoptosis, etc. were significantly changed. In particular, genes related to telomeres, such as POT1, were significantly altered. Radioresistant cells had higher telomerase activity and longer telomeres than their parental cells. Our research suggests that telomere function is a novel hallmark of cellular radiosensitivity, and the mechanistic link between telomere maintenance and radiosensitivity may involve the genes and pathways we implicated in this study. PMID- 20726716 TI - The balance between initiation and promotion in radiation-induced murine carcinogenesis. AB - Studies of radiation carcinogenesis in animals allow detailed investigation of how the risk depends on age at exposure and time since exposure and of the mechanisms that determine this risk, e.g., induction of new pre-malignant cells (initiation) and enhanced proliferation of already existing pre-malignant cells (promotion). To assist the interpretation of these patterns, we apply a newly developed biologically based mathematical model to data on several types of solid tumors induced by acute whole-body radiation in mice. The model includes both initiation and promotion and analyzes pre-malignant cell dynamics on two different time scales: comparatively short-term during irradiation and long-term during the entire life span. Our results suggest general mechanistic similarities between radiation carcinogenesis in mice and in human atomic bomb survivors. The excess relative risk (ERR) in mice decreases with age at exposure up to an exposure age of 1 year, which corresponds to mid-adulthood in humans; the pattern for older ages at exposure, for which there is some evidence of increasing ERRs in atomic bomb survivors, cannot be evaluated using the data set analyzed here. Also similar to findings in humans, initiation dominates the ERR at young ages in mice, when there are few background pre-malignant cells, and promotion becomes important at older ages. PMID- 20726717 TI - Preferential decorporation of americium by pulmonary administration of DTPA dry powder after inhalation of aged PuO(2) containing americium in rats. AB - After inhalation of plutonium oxides containing various percentages of americium in rats, we identified an acellular transient pulmonary compartment, the epithelial lining fluid (ELF), in which a fraction of actinide oxides dissolve prior to absorption and subsequent extrapulmonary deposit. Chelation therapy is usually considered to be poorly efficient after inhalation of actinide oxides. However, in the present study, prompt pulmonary administration of diethylenetraminepentaacetic acid (DTPA) as a dry powder led to a decrease in actinide content in ELF together with a limitation of bone and liver deposits. Because americium is more soluble than plutonium, higher amounts of americium were found in ELF, extrapulmonary tissues and urine. Our results also demonstrated that the higher efficacy of DTPA on americium compared to plutonium in ELF induced a preferential inhibition of extrapulmonary deposit and a greater urinary excretion of americium compared to plutonium. All together, our data justify the use of an early and local DTPA treatment after inhalation of plutonium oxide aerosols in which americium can be in high proportion such as in aged compounds. PMID- 20726718 TI - Repeated gamma irradiation attenuates collagen-induced arthritis via up regulation of regulatory T cells but not by damaging lymphocytes directly. AB - We recently reported that repeated 0.5-Gy gamma irradiation attenuates the pathology of collagen-induced arthritis. In this study, to investigate the mechanism further, we focused on changes in Treg/Th17 cells and changes in the production of antibody against an external antigen in response to gamma irradiation as well as on the radiosensitivity of Treg cells. DBA/1J mice were immunized with type II collagen to induce arthritis and exposed to low-dose gamma rays (0.5 Gy/week for 5 weeks). Production of IL6 and IL17 as well as autoantibody was suppressed by irradiation in the early phase of collagen-induced arthritis. The percentage of Treg cells was significantly increased by irradiation at 4, 6 and 8 weeks after the immunization. We also investigated the effect of repeated gamma radiation on the production of antibodies against an external antigen in ovalbumin-immunized BALB/c mice. We found that repeated 0.5 Gy gamma irradiation enhanced antibody production, accompanied by an increase of the antibody-producing plasma cell population and increased Th2-type cytokine secretion. We also found that the radiosensitivity of Treg cells did not differ from that of other T cells. These results suggest that a major mechanism of attenuation of the pathology of collagen-induced arthritis by repeated 0.5-Gy gamma irradiation is up-regulation of Treg cells concomitantly with suppression of IL6 and IL17 production. PMID- 20726719 TI - Aurora-a contributes to radioresistance by increasing NF-kappaB DNA binding. AB - Aurora-A, a serine/threonine kinase that is overexpressed in certain human cancer cell lines, plays an important role in mitotic progression. Aurora-A has also been reported to be involved in the activation of nuclear factor kappa B (NF kappaB). The purpose of the present study was to identify the role of Aurora-A in the radiation-induced activation pathway of NF-kappaB. Wild-type and Aurora-A knockdown (Aurora-A(KD)) HeLa cells were irradiated with 4 Gy of gamma rays and the EMSA, luciferase reporter gene assay and immunoblot analysis were performed. The siRNA-based gene knockdown and overexpression system was adopted to elucidate the role of Aurora-A in radiation-induced NF-kappaB pathway activation. The clonogenic survival study indicated that Aurora-A(KD) cells and the wild-type cells transfected with Aurora-A siRNA or RelA/p65 siRNA were more radiosensitive than the wild-type cells. In both the wild-type and Aurora-A(KD) cells, radiation caused IkappaB kinase-mediated phosphorylation, degradation of IkappaBalpha and phosphorylation of RelA/p65. The nuclear translocation of RelA/p65 was also similar in the wild-type and Aurora-A(KD) cells. However, RelA/p65-DNA binding was markedly suppressed in Aurora-A(KD) cells compared to that in wild-type cells. It was concluded that Aurora-A enhances the binding of NF-kappaB to DNA, thereby increasing the gene transcription by NF-kappaB and decreasing the radiosensitivity of the cells. PMID- 20726720 TI - Transgenic biosynthesis of trypanothione protects Escherichia coli from radiation induced toxicity. AB - Trypanothione is a unique diglutathionyl-spermidine conjugate found in abundance in trypanosomes but not in other eukaryotes. Because trypanothione is a naturally occurring polyamine thiol reminiscent of the synthetic drug amifostine, it may be a useful protector against radiation and oxidative stress. For these reasons we hypothesized that trypanothione might serve as a radioprotective agent when produced in bacteria. To accomplish this objective, the trypanothione synthetase and reductase genes from T. cruzi were introduced into E. coli and their expression was verified by qPCR and immunoblotting. Trypanothione synthesis in bacteria, detected by HPLC, resulted in decreased intracellular levels of reactive oxygen species as determined by H(2)DCFDA oxidation. Moreover, E. coli genomic DNA was protected from radiation-induced DNA damage by 4.6-fold in the presence of trypanothione compared to control bacteria. Concordantly, the transgenic E. coli expressing trypanothione were 4.3-fold more resistant to killing by (137)Cs gamma radiation compared to E. coli devoid of trypanothione expression. Thus we have shown for the first time that E. coli can be genetically engineered to express the trypanothione biosynthetic pathway and produce trypanothione, which results in their radioresistance. These results warrant further research to explore the possibility of developing trypanothione as a novel radioprotective agent. PMID- 20726722 TI - Effects of ionizing radiation on cell-to-cell communication. AB - Cell-to-cell signaling has become a significant issue in radiation biology due to experimental evidence, accumulated primarily since the early 1990s, of radiation induced bystander effects. Several candidate mediators involved in cell-to-cell communication have been investigated and proposed as being responsible for this phenomenon, but the current investigation techniques (both theoretical and experimental) of the mechanisms involved, due to the particular set-up of each experiment, result in experimental data that often are not directly comparable. In this study, a comprehensive approach was adopted to describe cell-to-cell communication (focusing on cytokine signaling) and its modulation by external agents such as ionizing radiation. The aim was also to provide integrated theoretical instruments and experimental data to help in understanding the peculiarities of in vitro experiments. Theoretical/modeling activities were integrated with experimental measurements by (1) redesigning a cybernetic model (proposed in its original form in the 1950s) to frame cell-to-cell communication processes, (2) implementing and developing a mathematical model, and (3) designing and carrying out experiments to quantify key parameters involved in intercellular signaling (focusing as a pilot study on the release and decay of IL 6 molecules and their modulation by radiation). This formalization provides an interpretative framework for understanding the intercellular signaling and in particular for focusing on the study of cell-to-cell communication in a "step-by step" approach. Under this model, the complex phenomenon of signal transmission was reduced where possible into independent processes to investigate them separately, providing an evaluation of the role of cell communication to guarantee and maintain the robustness of the in vitro experimental systems against the effects of perturbations. PMID- 20726721 TI - Intraesophageal manganese superoxide dismutase-plasmid liposomes ameliorates novel total-body and thoracic radiation sensitivity of NOS1-/- mice. AB - The effect of deletion of the nitric oxide synthase 1 gene (NOS1(-/-)) on radiosensitivity was determined. In vitro, long-term cultures of bone marrow stromal cells derived from NOS1(-/-) were more radioresistant than cells from C57BL/6NHsd (wild-type), NOS2(-/-) or NOS3(-/-) mice. Mice from each strain received 20 Gy thoracic irradiation or 9.5 Gy total-body irradiation (TBI), and NOS1(-/-) mice were more sensitive to both. To determine the etiology of radiosensitivity, studies of histopathology, lower esophageal contractility, gastrointestinal transit, blood counts, electrolytes and inflammatory markers were performed; no significant differences between irradiated NOS1(-/-) and control mice were found. Video camera surveillance revealed the cause of death in NOS1(-/-) mice to be grand mal seizures; control mice died with fatigue and listlessness associated with low blood counts after TBI. NOS1(-/-) mice were not sensitive to brain-only irradiation. MnSOD-PL therapy delivered to the esophagus of wild-type and NOS1(-/-) mice resulted in equivalent biochemical levels in both; however, in NOS1(-/-) mice, MnSOD-PL significantly increased survival after both thoracic and total-body irradiation. The mechanism of radiosensitivity of NOS1(-/-) mice and its reversal by MnSOD-PL may be related to the developmental esophageal enteric neuronal innervation abnormalities described in these mice. PMID- 20726723 TI - Breast cancer risk from different mammography screening practices. AB - Mammography screening is an accepted procedure for early detection of breast tumors among asymptomatic women. Since this procedure involves the use of X rays, it is itself potentially carcinogenic. Although there is general consensus about the benefit of screening for older women, screening practices differ between countries. In this paper radiation risks for these different practices are estimated using a new approach. We model breast cancer induction by ionizing radiation in a cohort of patients exposed to frequent X-ray examinations. The biologically based, mechanistic model provides a better foundation for the extrapolation of risks to different mammography screening practices than empirical models do. The model predicts that the excess relative risk (ERR) doubles when screening starts at age 40 instead of 50 and that a continuation of screening at ages 75 and higher carries little extra risk. The number of induced fatal breast cancers is estimated to be considerably lower than derived from epidemiological studies and from internationally accepted radiation protection risks. The present findings, if used in a risk-benefit analysis for mammography screening, would be more favorable to screening than estimates currently recommended for radiation protection. This has implications for the screening ages that are currently being reconsidered in several countries. PMID- 20726724 TI - Radiation cataract risk in interventional cardiology personnel. AB - The lens of the eye is one of the most radiosensitive tissues in the body, and exposure of the lens to ionizing radiation can cause cataract. Cumulative X-ray doses to the lenses of interventional cardiologists and associated staff can be high. The International Commission on Radiological Protection recently noted considerable uncertainty concerning radiation risk to the lens. This study evaluated risk of radiation cataract after occupational exposure in interventional cardiology personnel. Comprehensive dilated slit-lamp examinations were performed in interventional cardiologists, associated workers and controls. Radiation exposures were estimated using experimental data from catheterization laboratories and answers to detailed questionnaires. A total of 116 exposed and 93 similarly aged nonexposed individuals were examined. The relative risk of posterior subcapsular opacities in interventional cardiologists compared to unexposed controls was 3.2 (38% compared to 12%; P < 0.005). A total of 21% of nurses and technicians had radiation-associated posterior lens changes typically associated with ionizing radiation exposure. Cumulative median values of lens doses were estimated at 6.0 Sv for cardiologists and 1.5 Sv for associated medical personnel. A significantly elevated incidence of radiation-associated lens changes in interventional cardiology workers indicates there is an urgent need to educate these professionals in radiation protection to reduce the likelihood of cataract. PMID- 20726726 TI - Effects of everyday radiofrequency electromagnetic-field exposure on sleep quality: a cross-sectional study. AB - The aim of this cross-sectional study was to investigate the association between exposure to various sources of radiofrequency electromagnetic fields (RF EMFs) in the everyday environment and sleep quality, which is a common public health concern. We assessed self-reported sleep disturbances and daytime sleepiness in a random population sample of 1,375 inhabitants from the area of Basel, Switzerland. Exposure to environmental far-field RF EMFs was predicted for each individual using a prediction model that had been developed and validated previously. Self-reported cordless and mobile phone use as well as objective mobile phone operator data for the previous 6 months were also considered in the analyses. In multivariable regression models, adjusted for relevant confounders, no associations between environmental far-field RF EMF exposure and sleep disturbances or excessive daytime sleepiness were observed. The 10% most exposed participants had an estimated risk for sleep disturbances of 1.11 (95% CI: 0.50 to 2.44) and for excessive daytime sleepiness of 0.58 (95% CI: 0.31 to 1.05). Neither mobile phone use nor cordless phone use was associated with decreased sleep quality. The results of this large cross-sectional study did not indicate an impairment of subjective sleep quality due to exposure from various sources of RF EMFs in everyday life. PMID- 20726725 TI - Patching and single-strand ligation in nonhomologous DNA end joining despite persistence of a closely opposed 3'-phosphoglycolate-terminated strand break. AB - Previous work showed that in human nuclear extracts, double-strand break substrates bearing partially complementary (-ACG) 3'-phosphoglycolate (PG) terminated 3' overhangs are joined by a mechanism involving annealing of the terminal CG dinucleotides, PG removal, single-base gap filling and ligation. However, in these extracts only a minority of the breaks are rejoined, and most of the 3'-PG termini remain intact even after several hours. To determine whether the presence of a persistent 3'-PG prevents patching and ligation of the opposite strand, a substrate was constructed with two -ACG overhangs, one PG-terminated and one hydroxyl-terminated. after incubation in HeLa cell nuclear extracts, two major repair products of similar yield were formed: a fully repaired duplex and a nicked duplex in which the initial 3'-PG terminus remained intact. These results indicate that patching and ligation can proceed to completion in the unmodified strand despite persistence of the 3'-PG-terminated break in the opposite strand. The break in the PG-containing strand could then presumably be rejoined by a single-strand break repair pathway. PMID- 20726727 TI - Incidence of malignant diseases in humans injected with radium-224. AB - The "Spiess study" follows the health of 899 persons who received multiple injections of the short-lived alpha-particle emitter (224)Ra mainly between 1945 and 1955 for the treatment of tuberculosis, ankylosing spondylitis and some other diseases. In December 2007, 124 persons were still alive. The most striking health effect, observed shortly after (224)Ra injections, was a temporal wave of 57 malignant bone tumors. During the two most recent decades of observation, a significant excess of non-skeletal malignant diseases has become evident. Expected numbers of cases were computed from the age, gender and calendar year distribution of person years at risk and incidence rates from the German Saarland Cancer Registry. Poisson statistics were applied to test for statistical significance of the standardized incidence ratios. Up to the end of December 2007, the total number of observed malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers and 22 other malignant diseases, among these 16 malignant neoplasms of lymphatic and hematopoietic tissue, six without specification of site) compared to 192 expected cases. Accounting for a 5 year minimum latent period and excluding 13 cases of non-melanoma skin cancer, 231 non-skeletal solid cancers were observed compared to 151 expected cases. Significantly increased cancer rates were observed for breast (32 compared to 9.7), soft and connective tissue (11 compared to 1.0), thyroid (7 compared to 1.0), liver (10 compared to 2.4), kidney (13 compared to 5.0), pancreas (9 compared to 4.1), bladder (16 compared to 8.0), and female genital organs (15 compared to 7.8). PMID- 20726728 TI - Increasing damage to tumor blood vessels during motexafin lutetium-PDT through use of low fluence rate. AB - Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while plasma concentrations of photosensitizer are high, creating a prominent vascular response. In this study, the effects of light fluence rate on PDT response were investigated using motexafin lutetium (10 mg/kg) in combination with 730 nm light and a 180-min drug-light interval. At 180 min, the plasma level of photosensitizer was 5.7 ng/microl compared to 3.1 ng/mg in RIF tumor, and PDT mediated vascular effects were confirmed by a spasmodic decrease in blood flow during illumination. Light delivery at 25 mW/cm(2) significantly improved long term tumor responses over that at 75 mW/cm(2). This effect could not be attributed to oxygen conservation at low fluence rate, because 25 mW/cm(2) PDT provided little benefit to tumor hemoglobin oxygen saturation. However, 25 mW/cm(2) PDT did prolong the duration of ischemic insult during illumination and was correspondingly associated with greater decreases in perfusion immediately after PDT, followed by smaller increases in total hemoglobin concentration in the hours after PDT. Increases in blood volume suggest blood pooling from suboptimal vascular damage; thus the smaller increases after 25 mW/cm(2) PDT provide evidence of more widespread vascular damage, which was accompanied by greater decreases in clonogenic survival. Further study of low fluence rate as a means to improve responses to PDT under conditions designed to predominantly damage vasculature is warranted. PMID- 20726729 TI - The statistical power of epidemiological studies analyzing the relationship between exposure to ionizing radiation and cancer, with special reference to childhood leukemia and natural background radiation. AB - The etiology of childhood leukemia remains generally unknown, although risk models based on the Japanese A-bomb survivors imply that the dose accumulated from protracted exposure to low-level natural background ionizing radiation materially raises the risk of leukemia in children. In this paper a novel Monte Carlo score-test methodology is used to assess the statistical power of cohort, ecological and case-control study designs, using the linear low-dose part of the BEIR V model derived from the Japanese data. With 10 (or 20) years of follow-up of childhood leukemias in Great Britain, giving about 4600 (or 9200) cases, under an individual-based cohort design there is 67.9% (or 90.9%) chance of detecting an excess (at 5% significance level, one-sided test); little difference is made by extreme heterogeneity in risk. For an ecological design these figures reduce to 57.9% (or 83.2%). Case-control studies with five controls per case achieve much of the power of a cohort design, 61.1% (or 86.0%). However, participation bias may seriously affect studies that require individual consent, and area-based studies are subject to severe interpretational problems. For this reason register based studies, in particular those that make use of predicted doses that avoid the need for interviews, have considerable advantages. We argue that previous studies have been underpowered (all have power <80%), and some are also subject to unquantifiable biases and confounding. Sufficiently large studies should be capable of detecting the predicted risk attributable to natural background radiation. PMID- 20726730 TI - Analytical description of the LET dependence of cell survival using the repairable-conditionally repairable damage model. AB - In light-ion radiation therapy, both the dose and the local energy spectrum, which is often characterized with the linear energy transfer (LET), must be considered. In treatment optimization, it is advantageous to use a radiobiological model that analytically accounts for both dose and LET for the ion type of interest. With such a model the biological effect can also be estimated for dose and LET combinations for which there are no observations in the underlying experimental data. In this study, the repairable-conditionally repairable (RCR) damage model was extended by expressing its parameters as functions of LET to provide a radiobiological model that accounts for both the dose and the LET for a given ion type and cell line. This LET-parameterized RCR model was fitted to published cell survival data for HSG and V79 cells irradiated with carbon ions and for T1 cells irradiated with helium ions. To test the robustness of the model, fittings to only a subset of the data were performed. Good agreement with the cell survival data was obtained, including survival data for LET values not used for model fitting, opening up the possibility of using the model in treatment planning for light ions. PMID- 20726732 TI - Life span and thymic lymphoma incidence in high- and low-dose-rate irradiated AKR/J mice and commonly expressed genes. AB - To evaluate the effect of low-dose-rate radiation on cancer incidence, we housed AKR/J mice in a long-term low-dose-rate irradiation facility ((137)Cs, 0.07 cGy/h). We compared the thymic lymphoma incidence and life span with those of mice irradiated at a high dose rate ((137)Cs, 0.8 Gy/min, total dose of 4.5 Gy) and nonirradiated mice. The average life span of the low-dose-rate irradiated mice (243 days) was longer than those of the high-dose-rate irradiated mice (208 days) and nonirradiated mice (230 days) (P = 0.02). The incidence of thymic lymphoma in low-dose-rate irradiated mice was lower than that in nonirradiated mice and high-dose-rate irradiated mice by 10 and 20%, respectively (P < 0.01). Normal-sized thymuses were collected 130 days after irradiation, and whole genome microarray analysis was performed. A total of 17,625 genes were assessed. Up- and down-regulated genes in low-dose-rate irradiated mice were 1.7 and 9 times less frequent than in high-dose-rate irradiated mice. We profiled expressed genes associated with carcinogenesis pathways (DNA repair, DNA damage signaling pathway, cell cycle, cancer pathway finder, p53 signaling pathway, apoptosis and T-cell and B-cell activation). Apoptosis- (Cd5l, Fcgr3 and Pycard) and immune- (Pycard, Lilrb3, Igh-6, Fcgr2b and MGC60843) related genes were commonly activated in both high- and low-dose-rate irradiated mice. The results suggest that carcinogenic cells have been removed by activated apoptosis and immune mechanisms, contributing to decreased thymic lymphoma and elongated life span. Functional studies for expressed genes associated with thymic lymphoma incidence in low-dose-rate exposed mice are currently under way. PMID- 20726733 TI - Radiation Organ Doses Received by U.S. Radiologic Technologists: Estimation Methods and Findings. AB - Abstract In this paper, we describe recent methodological enhancements and findings from the dose reconstruction component of a study of cancer risks among U.S. radiologic technologists. An earlier version of the dosimetry published in 2006 (Simon et al., Radiat. Res. 166, 174-192, 2006) used physical and statistical models, literature-reported exposure measurements for the years before 1960, and archival personnel monitoring badge data from cohort members through 1984. The data and models were used to estimate unknown occupational radiation doses for 90,000 radiological technologists, incorporating information about each individual's employment practices based on a survey conducted in the mid-1980s. The dosimetry methods presented here, while using many of the same methods as before, now estimate annual and cumulative occupational badge doses (personal dose equivalent) to about 110,000 technologists for each year worked from 1916 to 2006, but with numerous methodological improvements. This dosimetry, using much more comprehensive information on individual use of protection aprons, estimates radiation absorbed doses to 12 organs and tissues (red bone marrow, ovary, colon, brain, lung, heart, female breast, skin of trunk, skin of head and neck and arms, testes, thyroid and lens of the eye). Every technologist's annual dose is estimated as a probability density function (pdf) to account for shared and unshared uncertainties. Major improvements in the dosimetry methods include a substantial increase in the number of cohort member annual badge dose measurements, additional information on individual apron use obtained from surveys conducted in the 1990s and 2005, refined modeling to develop annual badge dose pdfs using Tobit regression, refinements of cohort-based annual badge pdfs to delineate exposures of highly and minimally exposed individuals and to assess minimal detectable limits more accurately, and extensive refinements in organ dose conversion coefficients to account for uncertainties in radiographic techniques employed. For organ dose estimation, we rely on well-researched assumptions about critical exposure-related variables and their changes over the decades, including the peak kilovoltage and filtration typically used in conducting radiographic examinations and the usual body location for wearing radiation monitoring badges. We have derived organ dose conversion coefficients based on air-kerma weighting of photon fluences from published X-ray spectra and derived energy-dependent transmission factors for protective aprons of different thicknesses. We tailor bone marrow dose estimates to individual cohort members by using an individual-specific body mass index correction factor. To our knowledge the models and reconstructed doses presented herein represent the most comprehensive dose reconstructions undertaken for a cohort of medical radiation workers. PMID- 20726731 TI - Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice. AB - The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons. PMID- 20726734 TI - Surfing depth on a behaviour change website: predictors and effects on behaviour. AB - The primary objectives of the present study were to gain insight into website use and to predict the surfing depth on a behaviour change website and its effect on behaviour. Two hundred eight highly educated adults from the intervention condition of a randomised trial received access to a medical intervention, individual coaching (by e-mail, post, telephone or face-to-face) and a behaviour change website. Website use (e.g. surfing depth, page view duration) was registered. Online questionnaires for physical activity and fat intake were filled out at baseline and after 6 months. Hierarchical linear regression was used to predict surfing depth and its effect on behaviour. Seventy-five per cent of the participants visited the website. Fifty-one and fifty-six per cent consulted the physical activity and fat intake feedback, respectively. The median surfing depth was 2. The total duration of interventions by e-mail predicted deeper surfing (beta=0.36; p<0.001). Surfing depth did not predict changes in fat intake (beta=-0.07; p=0.45) or physical activity (beta=-0.03; p=0.72). Consulting the physical activity feedback led to more physical activity (beta=0.23; p=0.01). The findings from the present study can be used to guide future website development and improve the information architecture of behaviour change websites. PMID- 20726735 TI - ESP: an expert system for poisoning diagnosis and management. AB - We describe a clinical decision support system (CDSS) designed to provide timely information germane to poisoning. The CDSS aids medical decision making through recommendations to clinicians for immediate evaluation. The system is implemented as a rule-based expert system with two major components: the knowledge base and the inference engine. The knowledge base serves as the database which contains relevant poisoning information and rules that are used by the inference engine in making decisions. This expert system accepts signs and symptoms observed from a patient as input and presents a list of possible poisoning types with the corresponding management procedures which may be considered in making the final diagnosis. A knowledge acquisition tool (KAT) that allows toxicological experts to update the knowledge base was also developed. This article describes the architecture of the fully featured system, the design of the CDSS and the KAT as web applications, the utilisation of the inferencing mechanism of C Language Integrated Production System (CLIPS), which is an expert system shell that helps the system in decision-making tasks, the methods used as well as problems encountered. We also present the results obtained after testing the system and propose some recommendations for future work. PMID- 20726736 TI - Perinatal health monitoring in Europe: results from the EURO-PERISTAT project. AB - Data about deliveries, births, mothers and newborn babies are collected extensively to monitor the health and care of mothers and babies during pregnancy, delivery and the post-partum period, but there is no common approach in Europe. We analysed the problems related to using the European data for international comparisons of perinatal health. We made an inventory of relevant data sources in 25 European Union (EU) member states and Norway, and collected perinatal data using a previously defined indicator list. The main sources were civil registration based on birth and death certificates, medical birth registers, hospital discharge systems, congenital anomaly registers, confidential enquiries and audits. A few countries provided data from routine perinatal surveys or from aggregated data collection systems. The main methodological problems were related to differences in registration criteria and definitions, coverage of data collection, problems in combining information from different sources, missing data and random variation for rare events. Collection of European perinatal health information is feasible, but the national health information systems need improvements to fill gaps. To improve international comparisons, stillbirth definitions should be standardised and a short list of causes of fetal and infant deaths should be developed. PMID- 20726737 TI - Effects of hand cycle training on wheelchair capacity during clinical rehabilitation in persons with a spinal cord injury. AB - PURPOSE: To evaluate the effects of a structured hand cycle training programme on physical capacity in subjects with spinal cord injury (SCI) during clinical rehabilitation. METHOD: Twenty subjects with SCI who followed hand cycle training were compared with matched control subjects from a Dutch longitudinal cohort study, who received usual care. Primary outcomes of physical capacity were peak power output (PO(peak)), peak oxygen uptake (VO2(peak)) and oxygen pulse during a hand rim wheelchair test. Secondary outcome measures were isometric peak muscle strength of the upper extremities and pulmonary function. Hand cycle capacity (PO(peak) and VO2(peak)) was evaluated in the training group only. RESULTS: Strong tendencies for improvement were found in wheelchair capacity, reflected by PO(peak) and oxygen pulse after additional hand cycle training. Significant effects on shoulder exo- and endo-rotation and unilateral elbow flexion strength were found but no improvements on pulmonary function. CONCLUSIONS: Additional hand cycle training during clinical rehabilitation seems to show similar or slightly favourable results on wheelchair capacity and muscle strength compared with regular care. The heterogeneous subject group and large variation in training period may explain the limited effects of additional hand cycle training on wheelchair capacity. PMID- 20726738 TI - Effects of a three-week vocal exercise program using the Finnish Kuukka exercises on the speaking voice of Norwegian broadcast journalism students. AB - Nine broadcast journalism students attended 10 hours in Kuukka vocal exercises, which aims at producing a ringing vocal quality. Nine control subjects received no training. A text was read at habitual loudness before and after the course. Five speech specialists evaluated the text samples for perceptual voice quality and analyzed mean fundamental frequency (F0), equivalent sound level (Leq), and long-term average spectrum (LTAS). For the Training Group, voice quality improved and correlated negatively with firmness and timbre (less firm and darker qualities being considered more desirable), and F0 increased slightly. Leq increased significantly in both groups. The results show positive and perceivable differences after the course. However, the aimed ring was not reached, may be due to too short time. PMID- 20726739 TI - Reading comprehension among typically developing Swedish-speaking 10-12-year olds: examining subgroups differentiated in terms of language and decoding skills. AB - Based on data from 156 typically developing 10-12-year-olds from Sweden, reading comprehension skills were studied in three subgroups: those classified with specific poor word decoding skills (n = 10), those with specific poor language comprehension (n = 12), and those with mixed difficulties in word decoding and language comprehension (n = 11). The mixed poor group achieved significantly lower scores than both specific groups in reading comprehension, and was the only group displaying poor reading comprehension test results relative to the performance of the full sample. Results are indicative of the necessity of a combined effect of poor word decoding and language in reading comprehension difficulties for this group. Implications and limitations are discussed. PMID- 20726740 TI - Community-based group aquatic programme for individuals with multiple sclerosis: a pilot study. AB - PURPOSE: The purpose of this study was to determine the feasibility of providing a community-based aquatic exercise programme and to examine the effects of a group aquatic exercise programme in individuals with multiple sclerosis. This study illustrates the implementation of a multidisciplinary community-based programme in a university community wellness centre coordinated with a local advocacy group. METHOD: Eleven subjects with multiple sclerosis participated in a 5-week community-based aquatic exercise programme. Aquatic exercises were held twice weekly for 60 minutes and included aerobic exercises, strength training, flexibility exercises, balance training and walking activities. The 10-Metre Walk test, the Berg Balance Scale (BBS), the 'Timed Up and Go' (TUG) test, grip strength and the Modified Fatigue Impact Scale were used to assess motor function. RESULTS: Analysis of the scores demonstrated improved gait speed, BBS, TUG test and grip strength. The average attendance of the training sessions was good (88%), and no incidence of injuries, no incidence of falls and no adverse effects related to the exercise programme were reported. All participants reported that they enjoyed the programme, and they had improved after the training. CONCLUSIONS: A community-based aquatic exercise programme is feasible and resulted in improvement in motor functions of individuals with multiple sclerosis. These findings indicate that an aquatic training programme is appropriate and beneficial for individuals with multiple sclerosis and should be considered to augment the rehabilitation of those individuals. This programme may provide a viable model for a community-based wellness programme for people with disability including individuals with multiple sclerosis. PMID- 20726741 TI - Biomechanical validation of upper extremity exercise in wheelchair users: design considerations and improvements in a prototype device. AB - PURPOSE: To develop guidelines for proper exercise execution on a novel device and to recommend design changes to the device based on biomechanical data and user feedback. METHOD: Seven manual wheelchair users were instructed on proper exercise technique with a novel device, which allows a person to complete a seated row. Kinematics and kinetics of the dominant upper limb and trunk were measured with motion capture and electromyography data were collected on selected muscles. RESULTS: All subjects were able to exercise on the device with a mean power of 21.3 W (SD 7.1 W). Subjects did not keep the elbows close to the trunk during the drive phase of the row; rather, they moved from mean 75 degrees (SD 12 degrees ) shoulder flexion to mean 62 degrees (SD 11 degrees ) shoulder abduction. Identified problems included difficulty gripping the hand grips and user stability within the wheelchair. CONCLUSIONS: The accessory unit should be adjustable to accommodate a wide range of user sizes and abilities. Proper exercise execution is important to maximise the potential benefit and minimise risk of injury. When executed properly, this exercise may benefit wheelchair users by improving cardiovascular fitness and strengthening muscle groups linked to the reduction of shoulder pain. PMID- 20726742 TI - Relation between maternal angiogenic factors and utero-placental resistance in normal first- and second-trimester pregnancies. AB - OBJECTIVE: Soluble endoglin (sEng) is a novel antiangiogenic protein and elevated sEng concentrations in maternal circulation are closely related to preeclampsia and HELLP syndrome. As the perfusion of the uterine arteries as well as the dynamics of angiogenic factors between first and second trimester have prognostic value regarding pregnancy outcome, it was the aim of this study to investigate the relation between maternal angiogenic factors and uterine Doppler parameters. STUDY DESIGN: The longitudinal study includes 50 normal pregnancies. Pulsatility index (PI) of the uterine arteries was detected by Doppler ultrasound in first and second trimester. In parallel, maternal sEng and soluble fms-like tyrosine kinase 1 (sFlt1) concentration was measured using ELISA. RESULTS: In the first trimester, the sEng concentrations were 4.92 +/- 1.36 ng/mL and the uterine PI was 1.14 +/- 0.28. In the second trimester, the maternal sEng concentration decreased significantly to 3.99 +/- 0.63 ng/mL (p < 0.05) which was associated by a decrease of the uterine PI to 0.78 +/- 0.15 (p < 0.001). Soluble fms-like tyrosine kinase 1 concentrations did not differ significantly between first and second trimester (423 +/- 333 vs. 444 +/- 291 pg/mL). There was a significant negative correlation between sEng and uterine resistance in the second trimester (r = -0.416; p < 0.001). CONCLUSIONS: In normal pregnancy, parallel to the fall of utero-placental resistance, there is a physiological decline of the maternal sEng concentration between first and second trimester. In second trimester, there is a negative correlation between sEng and uterine Doppler parameters. PMID- 20726743 TI - Body mass index and blood pressure measurement during pregnancy. AB - OBJECTIVE: The accurate measurement of blood pressure requires the use of a large cuff in subjects with a high mid-arm circumference (MAC). This prospective study examined the need for a large cuff during pregnancy and its correlation with maternal obesity. METHODS: Maternal body mass index (BMI), fat mass, and MAC were measured. RESULTS: Of 179 women studied, 15.6% were obese. With a BMI of level 1 obesity, 44% needed a large cuff and with a BMI of level 2 obesity 100% needed a large cuff. CONCLUSION: All women booking for antenatal care should have their MAC measured to avoid the overdiagnosis of pregnancy hypertension. PMID- 20726746 TI - Reliability of clinical assessment in diagnosing cauda equina syndrome. AB - Cauda equina syndrome (CES) is a neurological syndrome presenting with non specific symptoms and signs that often leads to diagnostic confusion and delay. Acute onset CES is a surgical emergency. The common aetiology is a prolapsed lumbar disc. If the diagnosis is missed, it can have devastating consequences for the patient and a high financial cost to healthcare providers. The objective of this study was to evaluate the efficacy of clinical assessment in clinching the diagnosis. Eighty patients who underwent urgent clinical assessment and magnetic resonance imaging (MRI) for suspected CES over a 1-year period (from January 1st 2008 to 31 December 2008) were included in the study. Fifteen of these patients had a CES and underwent urgent lumbar discectomy and decompression. Medical notes and MRI scans of all these patients were reviewed. The presenting symptoms and signs were analysed against a positive MRI scan. Chi-square test with Yates correction was used to test association of each clinical symptom and sign for a positive MRI. In this study, only 18.8% of assessed patients had a CES producing compression seen on the MRI. Presence of saddle sensory deficit was the only clinical feature with a statistically significant association with MRI positive CES (p = 0.03). This series shows that saddle sensory deficit has a higher predictive value than other clinical features in diagnosing a CES. However, as there is no symptom or sign which has an absolute predictive value in establishing the diagnosis of CES, any patient in whom a reasonable suspicion of CES arises must undergo urgent MRI to exclude this diagnosis. PMID- 20726747 TI - For debate - guidelines for the management of suspected cauda equina syndrome. AB - A logical, rational and reasonable guideline for the management of patients with suspected cauda equina syndrome (CESS) is proposed. This article is intended to promote debate. Ideally spinal surgeons can agree a standard of care that can be applied nationally to the benefit of our patients, our colleagues and, as neurosurgeons and spinal surgeons, ourselves. PMID- 20726748 TI - Patient safety and image transfer between referring hospitals and neuroscience centres: could we do better? AB - INTRODUCTION: District general hospital scanners have historically been linked to regional neuroscience units for specialist opinions on scans and to make decisions on transfer of patients requiring neurosurgical management. The implementation of digital picture archiving and communication systems (PACS) in all hospitals in the UK has disrupted these dedicated links and technical and information governance issues have delayed reprovision of electronic transfer of images for rapid expert decision making in this group of patients. We studied improvement in image transfer to acute neurosurgery units over a 4-year period. METHODS: Four-year sequential review of national provision of image transfer facilities into neurosurgery units; observational study of delays associated with image transfer modalities in one representative tertiary referral centre. RESULTS: During the 4 years of study, all hospitals nationally have implemented digital PACS systems for image viewing. Remote image viewing facilities have gradually changed with dedicated image links being replaced by remote PACS access. However, a minority of referrals (12%) still require images to be physically transferred between hospitals using couriers for CD-ROMs. The detailed study within our own unit shows that this adds a mean delay of 5.8 h to decision making. CONCLUSIONS: Image transfer in neuroscience has been neglected following the shift to PACS servers. The recommendations of the 2004 Neuroscience Critical Care Report are unmet and patient safety is being threatened by a continued failure to implement a coordinated solution to this problem. PMID- 20726749 TI - A 5-year retrospective study assessing the association between seasonal and meteorological change and incidence of aneurysmal subarachnoid haemorrhage. AB - OBJECTIVE: Seasonal variation in incidence of spontaneous subarachnoid haemorrhage (SAH) is well recognised. This retrospective single-centre study aimed to characterise seasonality of SAH in the temperate climate of London, UK and to determine associations of incidence with meteorological variables. We further investigated whether associations vary according to location of aneurysm. METHODS: Admission data on 647 patients admitted with spontaneous SAH from December 2003 to August 2008 was analysed using our neurosurgical referrals database. Average monthly incidence of SAH was correlated with local temperature, atmospheric pressure and humidity data. In a subset of 467 patients, impact of aneurysm location on seasonal variation was evaluated. RESULTS: A non-significant bi-annual peak incidence was observed in Spring and Autumn with a trough in Summer (chi(2) = 1.5, p = 0.47). This trend was particularly marked with middle cerebral and posterior communicating artery aneurysms. However, anterior communicating artery aneurysmal SAH peaked in Summer only. SAH incidence correlated significantly with average humidity (coefficient 0.213, CI (0.02 0.404), p = 0.035) and peak humidity (coefficient 0.128, CI (0.008-0.248), p = 0.041). Temperature and atmospheric pressure did not correlate with incidence. CONCLUSIONS: This study illustrates a pattern of variation in SAH incidence similar to that seen in other populations and climates. However, our data suggests that this pattern differs according to aneurysm location. Unusually, we also find that humidity, and not temperature or atmospheric pressure, correlates with SAH incidence. Seasonal variability in aneurysm rupture is likely to be multifactorial, but meteorological factors may play an important role. PMID- 20726750 TI - Standard intracranial in vivo animal models of delayed cerebral vasospasm. AB - OBJECT: Animal models provide a basis for clarifying the complex pathogenesis of delayed cerebral vasospasm (DCVS) and for screening of potential therapeutic approaches. Arbitrary use of experimental parameters in current models can lead to results of uncertain relevance. The aim of this work was to identify and analyze the most consistent and feasible models and their parameters for each animal. METHODS: An online search of the MEDLINE PubMed and EMBASE medical databases (1969 to week 21 of 2007) was performed using the key words "canine", "mice", "rabbit", "pig", "rat", "cat", and "primate" in combination with "subarachnoid hemorrhage", "model", and "vasospasm". Cross references of each model were checked. Analysis of identified publications was considered in accordance with predetermined eligibility criteria. RESULTS: 1254 abstracts were reviewed and 516 studies were included in the analysis. Then, 66 models in 7 animals were identified. Most often used blood amounts (ml) lead to degree (% vessel narrowing) and peak onset (day) of DCVS within animal models as follows: mice endovascular puncture (various, day 3, 20-62%); rat single injection (0.3 ml, day 2, 19-29%); rat double injection (2 x 0.3 ml, day 7, 28-47%); rabbit single injection (3 ml, day 3, 19-55%); rabbit double injection (not established, day 5, not established); dog double injection (2 x 4-5 ml, day 7, 45-66%); primate clot placement (5 ml, day 7, 32-52%). CONCLUSIONS: Among the great number of experimental SAH methods and associated parameters only a fistful reliable and consistent models can be identified and recommended. Implementation of more standardized experimental techniques could increase the relevance of future experimental studies. PMID- 20726751 TI - Neuralgia of the glossopharyngeal and vagal nerves: long-term outcome following surgical treatment and literature review. AB - This study describes our experience in the surgical treatment of neuralgia of the glossopharyngeal and vagal nerves. Over the last 19 years, 21 patients underwent surgery. Their case notes were reviewed to obtain demographic information, clinical presentation, surgical findings and early results. All patients were then contacted by telephone for long-term results and complications. Independent analysis of results was carried out by a Neurology team. Ten patients had microvascular decompression (MVD). Four patients had MVD and nerve section. In the remaining seven patients, the glossopharyngeal and first two rootlets of the vagal nerve were sectioned. Nineteen (90%) of 21 patients experienced complete relief of pain immediately after surgery. The remaining patients reported an improvement in their symptoms. There were no mortalities. Four patients experienced short-term complications, which resolved. Two patients were left with a persistent hoarse voice. At follow-up (mean duration of 4 years), there was no recurrence in symptoms. In our experience, surgery is safe and effective for the treatment of vago-glossopharyngeal neuralgia. PMID- 20726752 TI - Assessment of physiological parameters within glioblastomas in awake patients: a prospective clinical study. AB - OBJECT: Multiparametric brain monitoring probes now make it possible to measure cerebral physiology. This prospective clinical study was designed to evaluate the pathophysiological environment of tumoural and peritumoural tissue O(2), CO(2), pH, HCO(3)- and temperature of awake patients with glioblastoma. METHODS: A Neurotrend multiparametric sensor was placed using intraoperative image guidance into glioblastoma after biopsy under general anesthetic. Postoperative monitoring was then performed in awake patients. RESULTS: Twelve patients were recruited and monitoring was performed, and well tolerated in 9 for up to 22 hrs. Mean glioblastoma tumour values were: tissue oxygen pressure (PtiO(2)) 21.0 mmHg, standard deviation +/- 7.9; PtiCO(2) 60.2 +/- 17.2 mmHg; temperature 36.9 +/- 0.4 degrees C, pH 7.08 + 0.2; and HCO(3) 17.1 +/- 3.7. Mean peritumoural brain values in 5 patients were PtiO(2) 29.1 +/- 27.6 mmHg; PtiCO(2) 48.6 +/- 7.0 mmg; temperature 36.4 +/- 0.6 degrees C; pH 7.20 +/- 0.09 and HCO(3) 19.1 +/- 3.5. There were trends for the PtiO(2) to decrease with increasing brain depth. As glioblastoma PtiCO(2) levels decreased, pH increased. There were no relationships between either tumoural PtiO(2) and pH, or PtiO(2) and PtiCO(2), however there were large intra- and inter-tumoural variation in monitoring values. There were technical problems in some patients with the Neurotrend sensor that limited its application, and that compromised aspects of data collection and interpretation, particularly of PtiO(2). CONCLUSION: This study has shown that this novel approach to monitoring glioma pathophysiology is feasible and well tolerated by patients. The data, much of which is novel, contributes to the knowledge of glioblastoma pathophysiology. However, further study and clinical exploitation awaits the development of a more reliable multiparametric sensor. PMID- 20726753 TI - Reappraisal of clinical outcome in adult medulloblastomas with emphasis on patterns of relapse. AB - BACKGROUND: Clinical outcome and prognostic factors were assessed in adult medulloblastoma patients, with emphasis on patterns of relapse. PATIENTS AND METHODS: Records of 36 consecutive adult patients with medulloblastoma were reviewed. Patients were classified into 2 prognostic groups according to the extent of disease and quality of surgical excision based on the early postoperative magnetic resonance imaging (MRI) findings. Standard-risk (SR) patients (n = 11) received postoperative craniospinal radiation therapy (RT) only, 36 Gy, 1.8 Gy per daily fraction, with a 18 Gy boost to the posterior cerebral fossa (PCF). High-risk (HR) patients (n = 25) received additional adjuvant chemotherapy. RESULTS: With a median follow-up of 46 months (range 5 155), 19 patients experienced tumour relapse. Sites of relapse(s) included tumour bed in 6 patients, resulting in a PCF control of 83.4%. Three-year overall survival (OS) and progression-free survival (PFS) were 67.3% and 57.4%, respectively. The comparison of the HR and SR populations demonstrated significant differences in OS (p = 0.005) and PFS (p = 0.001). Quality of surgical excision and extent of disease beyond the PCF were predictive factors for OS (p = 0.04, p = 0.001, respectively) and PFS (p = 0.004, and p = 0.02, respectively). CONCLUSION: The quality of resection was a significant prognostic factor, suggesting that surgery should be as extensive as possible. Systematic postoperative MRI allowed accurate selection of SR patients for whom RT alone was enough to obtain high local control. Every effort should be made to avoid RT disruption. Increased delay led to worse outcome. PMID- 20726754 TI - Ultra-early rebleeding of an anterior spinal artery aneurysm. AB - The authors report the case of a 38-year-old patient who presented with a ruptured anterior spinal artery aneurysm confirmed by MRI. This patient harbored neurological deterioration related to a rebleeding at Day 1. Control angiography showed spontaneous occlusion of both aneurysm and distal anterior spinal axis. Expectative strategy was finally chosen because of the rebleeding. However, these spinal aneurysms must be treated urgently because of the risk of ultra-early rebleeding. PMID- 20726755 TI - Rapid development of glioblastoma at the site of atypical meningioma resection. AB - The authors describe symptomatic presentation of glioblastoma within six months of resection of an atypical meningioma, at the same frontal parafalcine cerebral location. The patient had neither prior nor adjuvant radiotherapy nor known genetic risk factors. Possible links between invasive meningioma and transformation of adjacent glial cells or precursors to malignant glioma are discussed. PMID- 20726756 TI - Survival after a penetrating injury traversing midbrain - case report. AB - Penetrating civilian shrapnel injuries to brainstem are quite uncommon, but invariably fatal. We report a rare case of a child who survived following shrapnel injury to tectum of midbrain. PMID- 20726757 TI - Improvement of persistent developmental stuttering after surgical excision of a left perisylvian meningioma. AB - Persistent developmental stuttering (PDS) has been treated by speech and language and psychotherapy with limited success. We report the case of a 69-year-old with PDS since the age of five. A left perisylvian meningioma was successfully resected following investigation for generalised seizure. Spontaneous significant improvement in stuttering after surgery in the perisylvian area to the best of our knowledge has not been reported. PMID- 20726758 TI - An ectopic cranial nerve identified during surgery in the posterior fossa for hemifacial spasm: a word of caution. AB - Variations of cranial nerve morphology may effect surgical technique and, if not appreciated, lead to complications and iatrogenic injury. The authors report an unusual course of the hypoglossal nerve within the posterior cranial fossa observed during microvascular decompression surgery for hemifacial spasm. PMID- 20726759 TI - Six nails in the head: multiple pneumatic nail gun head injury. AB - A 62-year-old man was admitted to our hospital after attempting to commit suicide with a pneumatic nail gun. Six nails were launched. Because the nail head acted as a brake, the launched nail could make a hole in the skull but could not entirely pass it. PMID- 20726760 TI - Solitary fibrous tumour of the IV ventricle. AB - BACKGROUND: Solitary Fibrous Tumour (SFT) is a rare tumour occurring mainly in the pleural cavity, with less than 100 cases reported in the Central Nervous System, where it typically presents as a meningeal-based lesion. We describe the case of a SFT located in the fourth ventricle and briefly review the pertinent literature. CASE REPORT: A 61-year-old man presented with a 6-month-history of dizziness, nausea and gait imbalance. Brain magnetic resonance imaging revealed a contrast enhancing, space occupying lesion in the fourth ventricle, with no dural attachment. The patient underwent a sub-occipital craniectomy and total excision of the lesion. Histological examination documented a SFT. The patient is recurrent free at the 2-year follow-up. CONCLUSION: Although uncommon, SFT should always be included in the differential diagnosis of intraventricular tumours. SFTs of the fourth ventricle are usually benign tumours. Surgery remains the treatment of choice. PMID- 20726761 TI - Anomalous cerebral venous sinus drainage. AB - The case discussed is a 58 year old female that presented with sudden onset of headache, a Glasgow Coma Score of 15 and no neurological deficit. Computed tomography (CT) scan of the brain did not show any evidence of haemorrhage. CT angiography revealed a left sided cerebellar ateriovenous malformation with the Digital Subtraction Angiography (DSA) also showing anomalous posterior fossa venous sinus anatomy. In this case the occipital sinus provided the only drainage pathway for both the superior sagittal sinus (SSS) and the straight sinus. Of clinical significance is during the routine method of access to midline posterior fossa surgery the occipital sinus is ligated and divided. This would have resulted in massive venous infarction. Highlighting the importance of reviewing the venous anatomy on radiological images prior to neurosurgical procedures. PMID- 20726762 TI - La maladie de Grisel treated by combined C1-2 transarticular and C1 lateral mass screw fixation. AB - The authors describe a novel posterior approach to atlantoaxial stabilization combining C1-2 transarticular and C1 lateral mass screws with vertical connecting rods to create a strong construct with four-point fixation. They present here a case of atlanto-axial instability secondary to infection, Grisel's syndrome, necessitating instrumented stabilization after a period of close clinical and radiological observation following the initial cervical decompression and evacuation of retropharyngeal and epidural abscesses. PMID- 20726763 TI - Re-do microvascular decompression for recurrent trigeminal neuralgia. PMID- 20726764 TI - Residual antimalarial concentrations before treatment in patients with malaria from Cambodia: indication of drug pressure. AB - BACKGROUND: The Thai-Cambodian border has been known as the origin of antimalarial drug resistance for the past 30 years. There is a highly diverse market for antimalarials in this area, and improved knowledge of drug pressure would be useful to target interventions aimed at reducing inappropriate drug use. METHODS: Baseline samples from 125 patients with falciparum malaria recruited for 2 in vivo studies (in Preah Vihear and Pursat provinces) were analyzed for the presence of 14 antimalarials in a single run, by means of a liquid chromatography tandem mass spectrometry assay. RESULTS: Half of the patients had residual drug concentrations above the lower limit of calibration for at least 1 antimalarial at admission. Among the drugs detected were the currently used first-line drugs mefloquine (25% and 35% of patients) and piperaquine (15% of patients); the first line drug against vivax malaria, chloroquine (25% and 41% of patients); and the former first-line drug, quinine (5% and 34% patients). CONCLUSIONS: The findings demonstrate that there is high drug pressure and that many people still seek treatment in the private and informal sector, where appropriate treatment is not guaranteed. Promotion of comprehensive behavioral change, communication, community-based mobilization, and advocacy are vital to contain the emergence and spread of parasite resistance against new antimalarials. PMID- 20726765 TI - Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection. AB - BACKGROUND: Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear. METHODS: Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms--(1) linked to its own promoter and (2) fused to the promoter of the protein A gene--which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production. RESULTS: Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild type mice infected with a SAK-deficient strain. CONCLUSIONS: The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis. PMID- 20726766 TI - Adaptive differentiation of Plasmodium falciparum populations inferred from single-nucleotide polymorphisms (SNPs) conferring drug resistance and from neutral SNPs. AB - BACKGROUND: Theoretical and experimental data support the geographic differentiation strategy as a valuable tool for detecting loci under selection. In the context of Plasmodium falciparum malaria, few populations have been studied, with limited genomic coverage. METHODS: We examined geographic differentiation in P. falciparum populations on the basis of 12 single-nucleotide polymorphisms (SNPs) in 4 genes encoding drug resistance determinants, 5 SNPs in 2 genes encoding antigens, and a set of 17 putatively neutral SNPs dispersed on 13 chromosomes. We sampled 326 parasite isolates representing 7 P. falciparum populations from regions with varied levels of malaria transmission (Gabon, Kenya, Madagascar, Mali, Mayotte, Haiti, and the Philippines). RESULTS: Frequencies of drug resistance alleles varied considerably among populations (mean F(ST), 0.52). In contrast, allele frequencies varied significantly less for antigenic and neutral SNPs (mean F(ST), 0.16 and 0.24, respectively). This contrasting pattern was more pronounced when only the African populations were considered. Signature of selection was detected for most of the resistant SNPs but not for the antigenic SNPs. CONCLUSION: These data further validate the utility of geographic differentiation for identifying loci under strong positive selection, such as drug resistance loci. This study also provides frequencies of molecular makers of resistance in some overlooked populations. PMID- 20726767 TI - Crucial role of the central leptin receptor in murine Trypanosoma cruzi (Brazil strain) infection. AB - Mice carrying a defective leptin receptor gene (db/db mice) are metabolically challenged and upon infection with Trypanosoma cruzi (Brazil strain) suffer high mortality. In genetically modified db/db mice, (NSE-Rb db/db mice), central leptin signaling is reconstituted only in the brain, which is sufficient to correct the metabolic defects. NSE-Rb db/db mice were infected with T. cruzi to determine the impact of the lack of leptin signaling on infection in the absence of metabolic dysregulation. Parasitemia levels, mortality rates, and tissue parasitism were statistically significantly increased in infected db/db mice compared with those in infected NSE-Rb db/db and FVB wild-type mice. There was a reduction in fat mass and blood glucose level in infected db/db mice. Plasma levels of several cytokines and chemokines were statistically significantly increased in infected db/db mice compared with those in infected FVB and NSE-Rb db/db mice. These findings suggest that leptin resistance in individuals with obesity and diabetes mellitus may have adverse consequences in T. cruzi infection. PMID- 20726768 TI - Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. AB - BACKGROUND: We hypothesized that the high prevalence of hepatitis C virus (HCV) among injection drug users might be due to prolonged virus survival in contaminated syringes. METHODS: We developed a microculture assay to examine the viability of HCV. Syringes were loaded with blood spiked with HCV reporter virus (Jc1/GLuc2A) to simulate 2 scenarios of residual volumes: low void volume (2 microL) for 1-mL insulin syringes and high void volume (32 microL) for 1-mL tuberculin syringes. Syringes were stored at 4 degrees C, 22 degrees C, and 37 degrees C for up to 63 days before testing for HCV infectivity by using luciferase activity. RESULTS: The virus decay rate was biphasic (t1/2alpha= 0.4 h and t1/2beta = 28 hh). Insulin syringes failed to yield viable HCV beyond day 1 at all storage temperatures except 4 degrees , in which 5% of syringes yielded viable virus on day 7. Tuberculin syringes yielded viable virus from 96%, 71%, and 52% of syringes after storage at 4 degrees, 22 degrees, and 37 degrees for 7 days, respectively, and yielded viable virus up to day 63. CONCLUSIONS: The high prevalence of HCV among injection drug users may be partly due to the resilience of the virus and the syringe type. Our findings may be used to guide prevention strategies. PMID- 20726769 TI - The beginning of a new era in understanding hepatitis C virus prevention. PMID- 20726770 TI - Games in tetrads: segregation, recombination, and meiotic drive. AB - The two alleles at a heterozygous locus segregate during meiosis, sometimes at meiosis I and sometimes at meiosis II. The timing of segregation is determined by the pattern of crossing-over between a locus and its attached centromeres. Genes near centromeres can exploit this process by driving against spores from which the genes separated at meiosis I. Other genes, located distal to centromeres, can benefit from driving against spores from which they separated at meiosis II. Asymmetric female meiosis is particularly susceptible to such forms of drive. Selection on modifiers of recombination favors changes in the location of chiasmata that increase the proportion of tetrads of high average fitness by changing the timing of segregation. Such changes increase the frequency of driving alleles. This source of selection on recombination does not depend on effects on linkage disequilibrium. Recombinational responses to meiotic drive may contribute to sex differences in overall recombination and sex differences in the localization of chiasmata. PMID- 20726771 TI - Multicity outbreak of linezolid-resistant Staphylococcus epidermidis associated with clonal spread of a cfr-containing strain. AB - We report a multicity outbreak of cfr-containing linezolid-resistant Staphylococcus epidermidis in Ohio. Thirty-nine isolates were obtained from 2 hospitals. Two clones with different mechanisms of linezolid resistance were circulating in hospital A. One of these contained the cfr gene, and the other a ribosomal mutation. The clone containing cfr was identical in both hospitals. PMID- 20726772 TI - Clinical significance of Staphylococcus lugdunensis isolated from routine cultures. AB - Over 1 year, 42 Staphylococcus lugdunensis isolates, identified by phenotypic and genotypic testing, were recovered from clinical specimens. Thirty-six (86%) were clinically significant pathogens, mostly from healthy outpatients; 16 (44%) of 36 were isolated in pure culture; and 30 (83%) of 36 were from skin and soft-tissue infections. PMID- 20726773 TI - Altered gene expression profiles in the brain, kidney, and lung of deceased neonatal cloned pigs. AB - Limited studies have been published analyzing the gene expression patterns of cloned pigs. We compared the expression profiles of brain, kidney, and lung tissues, representing each of the three germ layers, of deceased neonatal cloned pigs with those of age-matched controls using a 13K oligonucleotide microarray. We found 42 (0.7% of total genes analyzed), 178 (2.9%), and 121 (1.9%) genes differentially expressed in the brain, kidney, and lung of clones, respectively, when compared with the corresponding organs from controls (fold change >1.5, p < 0.05, false discovery rate (FDR) = 0.05). These expression aberrations could potentially cause the following pathological anomalies in clones: diabetic nephropathy in the kidney and dysregulated surfactant homeostasis in the lung. Interestingly, upregulated expression of genes belonging to the MAPK pathway was observed in all three organs. To investigate whether the differences in levels of gene expression were caused by differential DNA methylation, the global DNA methylation level was measured by high-performance liquid chromatography. In controls, global concentration of methylated cytosine was 5.35%, whereas clones had significantly hypomethylated genomic DNA (4.57%). Bisulfite-pyrosequencing analyses of the promoter regions of differentially expressed candidate genes, c MYC, Period 1 (PER1), Cathepsin L (CTSL), and Follistatin (FS), however, did not show any differences in the degree of DNA methylation between controls and clones. Our findings demonstrate that deceased neonatal cloned pigs have considerable gene expression abnormalities, which may have contributed to the death of the animals. PMID- 20726774 TI - Aberrant expression patterns of genes involved in segregation of inner cell mass and trophectoderm lineages in bovine embryos derived from somatic cell nuclear transfer. AB - High rates of embryonic, fetal, or placental abnormalities have consistently been observed in bovine cloning. Segregation of inner cell mass (ICM) and trophectoderm (TE) lineages in early embryos is an important process for fetal and placental formation. In mouse embryos, differentiation of ICM and TE is regulated by various transcription factors, such as OCT-4, CDX2, and TEAD4, but molecular mechanisms that regulate differentiation in bovine embryos remain unknown. To clarify gene transcripts involved in segregation of ICM and TE lineages in bovine embryos, we examined the relative abundances of OCT-4, CDX2, TEAD4, GATA3, NANOG, and FGF4 transcripts in blastocyst embryos derived from in vitro fertilization (IVF). Furthermore, transcript levels of such genes in bovine embryos derived from somatic cell nuclear transfer (NT-SC) and in vivo (Vivo) were also compared. OCT-4, NANOG, and FGF4 transcript levels in IVF embryos were significantly higher in ICM than in TE. In contrast, the CDX2 transcript level was lower in ICM than in TE. In NT-SC embryos at the blastocyst stage, transcript levels of all genes except CDX2 were lower than that in Vivo embryos. In the elongated stage, expression levels of the six genes did not differ between NT-SC and Vivo embryos. We observed aberrant expression patterns of various genes involved in segregation of ICM and TE lineages in bovine NT-SC embryos. These results raise the possibility that abnormalities in the cloned fetus and placenta are related to the aberrant expression of genes involved in segregation and differentiation process in the early developmental stage. PMID- 20726775 TI - Adenovirus vector-mediated efficient transduction into human embryonic and induced pluripotent stem cells. AB - We examined the transduction efficiency in human embryonic stem (ES) and induced pluripotent stem (iPS) cells using an adenovirus (Ad) vector. RT-PCR analysis revealed the expression of the coxsackievirus and adenovirus receptor, a receptor for Ad, in these cells. However, gene expression after the transduction with an Ad vector was observed only in the periphery of ES and iPS cell colonies, when human ES and iPS cells were passaged as small colonies. This suggests that the Ad vector could not enter inside the ES and iPS cell colonies by their tight connection. We thus attempted to transduce foreign genes into the dissociated form of human ES and iPS cells, which were passaged using Rho-associated kinase inhibitor. In this condition, transduction efficiency in human ES and iPS cells was markedly increased and transgene expression was observed even inside the colonies by using Ad vectors. Furthermore, Ad vector-mediated transduction did not alter the expression of undifferentiated markers such as Oct-3/4, Nanog, and SSEA-4. Our results indicate that Ad vectors are effective tools for transduction into human ES and iPS cells. PMID- 20726776 TI - ChIP-seq and Functional Analysis of the SOX2 Gene in Colorectal Cancers. AB - Abstract SOX2 is a high mobility group (HMG) box containing transcription factor that has been implicated in various types of cancer, but its role in colorectal cancers (CRC) has not been studied. Here we show that SOX2 is overexpressed in CRC tissues compared with normal adjacent tissues using immunohistochemical staining and RT-PCR. We also observed an increased SOX2 expression in nucleus of colorectal cancer tissues (46%, 14/30 cases vs. 7%, 2/30 adjacent tissues). Furthermore, knockdown of SOX2 in SW620 colorectal cancer cells decreased their growth rates in vitro cell line, and in vivo in xenograft models. ChIP-seq analysis of SOX2 revealed a consensus sequence of wwTGywTT. An integrated expression profiling and ChIP-seq analysis show that SOX2 is involved in the BMP signaling pathway, steroid metabolic process, histone modifications, and many receptor-mediated signaling pathways such as IGF1R and ITPR2 (Inositol 1,4,5-triphosphate receptor, type 2). PMID- 20726777 TI - Weak organic acid stress triggers hyperphosphorylation of the yeast zinc-finger transcription factor War1 and dampens stress adaptation. AB - Exposure of Saccharomyces cerevisiae to weak organic acids such as sorbate, propionate, or benzoate rapidly induces the plasma membrane ABC transporter Pdr12, requiring the Zn(II)(2)Cys(6) zinc-finger transcription factor War1. Weak acid stress rapidly triggers War1 phosphorylation but its role for War1 function is not clear yet. Here, we provide new insights into sorbate-induced phosphorylation of War1. A War1 zinc-finger mutant is still hyperphosphorylated in response to sorbate stress, indicating that War1 phosphorylation occurs independently of DNA recruitment. To map and identify phosphoresidues, War1 purified from stressed and unstressed cells was subjected to semiquantitative phosphopeptide mass spectrometry analysis. Remarkably, we show that weak acid stress causes a dramatic hyperphosphorylation of several already prephosphorylated residues. WAR1 alleles harboring combinations of mutations identified phosphoresidues were generated, some of which display altered gel mobility. Certain mutational combinations almost completely abolish stress induced gel-shift, suggesting alternative phosphorylation. Surprisingly, PDR12 expression levels are similar in these mutants, demonstrating that War1 phosphorylation is not required for PDR12 induction. Strikingly, absence of hyperphosphorylation in response to stress leads to a faster stress adaptation, suggesting that phosphorylation might play a role in stabilizing War1 activity on the promoter elements, hence changing the dynamics and kinetics of the stress response. PMID- 20726778 TI - Phospholipidome of Candida: each species of Candida has distinctive phospholipid molecular species. AB - By employing electrospray ionization tandem mass spectrometry (ESI-MS/MS), the phospholipidomes of eight hemiascomycetous human pathogenic Candida species have been characterized. Over 200 phospholipid molecular species were identified and quantified. There were no large differences among Candida species in phosphoglyceride class composition; however, differences in phosphoglycerides components (i.e., fatty acyl chains) were identified. In contrast, differences in sphingolipid class composition as well as in molecular species were quite evident. The phospholipid compositions of C. albicans, C. glabrata, C. parapsilosis, C. kefyr, C. tropicalis, C. dubliniensis, C. krusei, and C. utilis could be further discriminated by principal component analysis. Notwithstanding that a single strain of each species was analyzed, our data do point to a typical molecular species imprint of Candida strains. PMID- 20726779 TI - Integrative responses to high pH stress in S. cerevisiae. AB - The budding yeast Saccharomyces cerevisiae grows far better at acidic than at neutral or alkaline pH. Consequently, even a modest alkalinization of the medium represents a stressful situation for this yeast. In the past few years, data generated by a combination of genome-wide techniques has demonstrated that adaptive responses of S. cerevisiae to high pH stress involves extensive gene remodeling as a result of the fast activation of a number of stress-related signaling pathways, such as the Rim101, the Wsc1-Pkc1-Slt2 MAP kinase, and the calcium-activated calcineurin pathways. Alkalinization of the environment also disturbs nutrient homeostasis, as deduced from its impact on iron/copper, phosphate, and glucose uptake/utilization pathways. In this review we will examine these responses, their possible interactions, and the role that they play in tolerance to high pH stress. PMID- 20726780 TI - Toward a genomic view of the gene expression program regulated by osmostress in yeast. AB - Osmostress triggers profound adaptive changes in the physiology of the cell with a great impact on gene expression. Saccharomyces cerevisiae has served as an instructive model system to unravel the complexity of the stress response at the transcriptional level. The main signal transduction pathways like the HOG (high osmolarity glycerol) MAP kinase cascade or the protein kinase A pathway regulate multiple specific transcription factors to accomplish large changes in the expression pattern of the genome. Transcription profiling and proteomic studies give us an idea about the impact of osmostress on gene expression and the overall protein composition. Recent genome wide location studies for several transcription factors and signaling kinases involved in the transcriptional stress response shed light on the genomic organization of the osmostress response at the level of the dynamic association of regulators with chromatin. Finally, global surveys of mRNA stability complete our picture of the mechanisms underlying the massive reprogramming of global gene expression, which leads to efficient adaptation to osmotic stress. PMID- 20726781 TI - Stage-associated dynamic activity profile of transcription factors in nasopharyngeal carcinoma progression based on protein/DNA array analysis. AB - Transcription factors (TFs) are crucial modulators of gene regulation during the development and progression of tumors. We previously reported the activation of TFs in nasopharyngeal carcinoma (NPC) cell lines. In this study, we explored the activity profiles of TFs in Protein/DNA array data of a 12-tissue independent set and a 13-tissue pooled set of NPC that included different clinical stages. TFs associated with tumor progression were revealed using a generalized linear model based regression analysis. Immunohistochemical analysis of clinical NPC samples was used to validate the results of array analysis. We identified 26 TFs that showed increased activities. Of these 26 TFs, 16 were correlated with clinical stages. Activity changes of AP2 and ATF/CREB were confirmed by electrophoretic mobility shift assay (EMSA), and increased expression of AP2alpha, beta, gamma, ATF2, and ATF1 in nuclei of tumor cells was associated with clinical stages. In addition, the expressions of AP2alpha, ATF2, and ATF1 were correlated with those of their target genes (epithelia growth factor receptor (EGFR) and matrix metalloproteinase 2 (MMP-2), respectively). This study provides data and valuable clues that can be used to further investigate the laws of gene transcription regulation in NPC and to identify suitable targets for the development of TF targeted antitumor agents. PMID- 20726782 TI - Characterization of phosphoproteins in gastric cancer secretome. AB - Phosphorylation dysregulation has been implicated in various diseases including cancer. The phosphorylation change of proteins in secretome may be a novel source for the discovery of biomarkers and drug targets. In this study, the phosphoproteins in cancer secretome (phosphosecretome) were globally analyzed for the first time by phosphoproteomics. One hundred forty-two phosphorylation sites on 62 unique phosphopeptides representing 49 nonredundant proteins were identified, several of which are known as secreted proteins involved in carcinogenesis, invasion, and metastasis. Most of them were first found as secreted proteins with no previously known function. Protein sublocation analysis showed that 33 proteins were found to be secreted as phosphoproteins, in which 27 (81.81%) were secreted by a nonclassic, ER/Golgi-independent pathway, suggesting that the phosphorylation modification of these proteins might play an important role in their nonconventional secretion processes. Their protein kinases and regulatory phosphosites involved in the secretion regulation of these phosphoproteins, such as stanniocalcin 2, annexin A2, and HSP90 alpha, were first identified. The phosphosecretome data enriched the secretome database and phosphoproteome database, and will help us to discover cancer biomarkers and drug targets, illustrating the mystery of the nonclassic protein secretion pathway. PMID- 20726783 TI - Upregulated and downregulated proteins in hepatocellular carcinoma: a systematic review of proteomic profiling studies. AB - Hepatocellular carcinoma (HCC) has been a major clinical challenge due to low early diagnosis rate and poor prognosis. The aim of this systematic review was to identify differentially expressed proteins as potential high-confidence biomarkers for HCC, by validating data on differentially expressed proteins reported by studies on HCC tissues. In our studies, objectives, search strategy, study selection criteria, data elements, methods for extraction, and methods for assessing study quality were defined. Published studies that compared the protein expression profiles of HCC with those of noncancer tissues were included in the review. Furthermore, a protein ranking system was used to assess the number of comparisons in agreement. Monte Carlo simulation was used to assess the overlap significance. A total of 16 proteomic studies were eligible for the systematic review in our study, which reported 1283 differentially expressed proteins in HCC (526 upregulated, 744 downregulated). Of these proteins, 27 proteins were identified as differentially expressed proteins with consistent directions of change in at least three studies; four were upregulated, and 23 downregulated. One upregulated protein, heat-shock 70-kDa protein, and four downregulated proteins, fructose-1,6-bisphosphatase 1, formiminotransferase cyclodeaminase, alcohol dehydrogenase, and fructose-bisphosphate aldolase B were identified as potential biomarkers for HCC. In addition, nine other differentially expressed proteins were reported, but with inconsistent directions for the changes of the differential expression. The amount of overlap was highly significant. Therefore, five candidate proteins were defined as potential biomarkers for HCC, which may have diagnostic, prognostic and therapeutic significance. PMID- 20726784 TI - The effects of high dietary lard on hypertension development in spontaneously hypertensive rats. AB - This study examined the effects of high dietary lard on the cardiovascular system responsible for regulating blood pressure in the spontaneously hypertensive rat (SHR), a model of essential human hypertension. The fat contents were 4.5% of diet weight for control diet and 20% for high-lard diet, respectively. Four-week old male SHR animals were fed the diets for 9 weeks. After 9 weeks of feeding, the cardiovascular responses to the intravenous administration of vasoactive drugs were determined in conscious SHR animals. The pressor responses elicited by the alpha1-adrenoceptor agonist phenylephrine were diminished in high-lard-fed SHR animals. The depressor responses elicited by the beta-adrenoceptor agonist isoproterenol were equivalent in the high-lard-fed SHR and control SHR groups. The depressor responses elicited by the nitric oxide donor sodium nitroprusside were equivalent in both dietary groups. The depressor responses elicited by the endothelium-dependent agonist acetylcholine were diminished in high-lard-fed SHR animals. Baroreceptor reflex-mediated changes in heart rates in response to changes in mean arterial blood pressure (MAP) elicited by phenylephrine and sodium nitroprusside were diminished in the high-lard-fed SHR group. Despite the diminished endothelium-dependent vasodilation and impaired baroreflex function, resting MAP values were similar in both dietary groups. These findings suggest that high dietary lard does not exacerbate hypertension in the SHR model. PMID- 20726785 TI - A tocotrienol-rich fraction from grape seeds inhibits oxidative stress induced by tert-butyl hydroperoxide in HepG2 cells. AB - We evaluated the protective effect of a tocotrienol-rich fraction (TRF) from grape seeds on tert-butyl hydroperoxide (TBHP)-induced oxidative injury in HepG2 cells. Generation of cellular reactive oxygen species (ROS), concentrations of cellular lipid peroxidation products and reduced glutathione, and antioxidant enzyme activity were used as biomarkers of cellular oxidative status. Cells pretreated with TRF (10-500 MUg/mL) showed an increased resistance to oxidative stress in a dose-dependent manner, as revealed by a higher percentage of surviving cells compared to control cells. Pretreatment with TRF (5-100 MUg/mL) prevented the decrease in reduced glutathione and the increase in malondialdehyde and ROS evoked by TBHP in HepG2 cells. Moreover, TRF pretreatment prevented a significant increase in glutathione peroxidase, catalase, and superoxide dismutase activities induced by TBHP. These results show that TRF has significant protective ability against TBHP-induced oxidative insult and that the modulation of antioxidant enzymes by TRF may have an important antioxidant effect on HepG2 cells. PMID- 20726786 TI - Chemical composition and antioxidant and antimycobacterial activities of Bromelia balansae (Bromeliaceae). AB - Bromelia balansae (Family Bromeliaceae) is a medicinal plant commonly used in the central region of Brazil as a cough syrup and also eaten roasted. The methanolic extract of ripe fruits was analyzed by chromatographic methods and spectrometrically. Four glycoside flavonols were isolated: kaempferol-3-O-alpha-L rhamnopyranoside (1), kaempferol-3-O-alpha-L-rhamnopyranosyl-(1-->6)-beta-D glucopyranoside (2), quercetin-3-O-alpha-L-rhamnopyranosyl-(1-->6)-beta-d glucopyranoside (3), and kaempferol 3,7-di-O-alpha-L-rhamnopyranoside (4). The resazurin microtiter assay was used to measure the biological activity in vitro against Mycobacterium tuberculosis. The results showed a moderate activity of the methanolic extract with a minimal inhibitory concentration of 128 MUg/mL. Antioxidant activity was evaluated as free radical scavenging capacity and inhibition of peroxidation. Free radical scavenging capacity was assessed by measuring the scavenging activity of methanolic extract and methanolic fraction on 2,2-diphenyl-1-picrylhydrazyl radical. The methanolic extract showed low values of antioxidant activities, whereas the methanolic fraction exhibited free radical scavenging activity ranging from 20.2% to 91.1%, and the inhibition of peroxidation values ranging from 5.6% to 27.5%. This is the first chemical study reported in the literature about this species. PMID- 20726787 TI - In-vitro evaluation of a soft-tissue navigation system for laparoscopic prostatectomy. AB - PURPOSE: We introduce a custom-designed phantom model for the in-vitro evaluation of an augmented reality-based soft-tissue navigation system for ultrasound-guided prostate interventions. MATERIALS AND METHODS: Transrectal ultrasound segmentation of the prostate, navigation aid placement, initial registration, endoscope tracking, and enhanced visualization steps in the navigation procedure were performed to accommodate the actual prostatic motion. In-vitro laparoscopic manipulations simulating surgical procedures were performed by a physician using human prostate specimens. The target visualization error, defining the accuracy of the tracking, is determined by means of a leave-out test strategy by alternately using four navigation aids for endoscope registration and the remaining two navigation aids for accuracy verification. RESULTS: The introduction of the navigation aids lasted approximately 3 minutes. The navigation aids and especially their barbs were visible because of their ultrasound reflecting nature. For each organ, 1000 endoscope registrations were calculated, in which two randomly chosen navigation aids served the purpose of verifying the pose. We were able to demonstrate that the superimposed image could follow automatically the videoendoscopic real-time view. The mean target visualization errors for the respective trials were determined as 0.81 (+/-0.12) mm, 0.62 (+/-0.14) mm, and 0.98 (+/-0.23) mm. CONCLUSIONS: The ultrasound-based inside-out navigation system for laparoscopic prostatectomy overcomes the problem of tissue shift and deformation in an in-vitro model. In case of organ movement, the augmented picture with the detected navigation aids could follow the videoendoscopic image using the navigation aids as landmarks. PMID- 20726788 TI - Association of monocyte chemotactic protein-1 and CC chemokine receptor 2 gene variants with preeclampsia. AB - Preeclampsia complicates 10% of pregnancies in developing countries. It is one of the leading causes of maternal and fetal/neonatal mortality and morbidity worldwide. It has been suggested that maladaptation of the maternal immune response during pregnancy might be a causal factor for preeclampsia. According to immune maladaptation hypothesis, preeclampsia is due to an inappropriate regulation of normally Th2-deviated maternal immune responses, leading to a shift toward harmful Th1 immunity. Several studies indicate that monocyte chemotactic protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) are involved in Th1 and Th2 immunity. In this study, we investigated the association between MCP-1 A-2518G and CCR2-V64I polymorphisms and preeclampsia. One hundred eighty preeclamptic pregnant women and 145 healthy controls were included in the study. We observed that in preeclamptic women, MCP-1 G: CCR2 Val haplotype was significantly higher when compared with other haplotypes. In conclusion, we stated that MCP-1 and CCR2 gene variants might be associated with preeclampsia. PMID- 20726789 TI - Postinfluenza bacterial pneumonia: host defenses gone awry. AB - Influenza is a common respiratory pathogen causing both seasonal and pandemic disease. Influenza infection predisposes the host to secondary bacterial infection of the respiratory tract, which is a major cause of both morbidity and mortality in flu-related disease. In this review, we will discuss innate and adaptive antiviral responses during influenza infection, and review how these responses modulate protective immunity against secondary bacterial pathogens of the lung. Specific emphasis will be placed on implications of bacterial superinfection and mechanisms involved. PMID- 20726790 TI - Introducing knowledge into differential expression analysis. AB - Gene expression measurements allow determining sets of up- or down-regulated, or unchanged genes in a particular experimental condition. Additional biological knowledge can suggest examples of genes from one of these sets. For instance, known target genes of a transcriptional activator are expected, but are not certain to go down after this activator is knocked out. Available differential expression analysis tools do not take such imprecise examples into account. Here we put forward a novel partially supervised mixture modeling methodology for differential expression analysis. Our approach, guided by imprecise examples, clusters expression data into differentially expressed and unchanged genes. The partially supervised methodology is implemented by two methods: a newly introduced belief-based mixture modeling, and soft-label mixture modeling, a method proved efficient in other applications. We investigate on synthetic data the input example settings favorable for each method. In our tests, both belief based and soft-label methods prove their advantage over semi-supervised mixture modeling in correcting for erroneous examples. We also compare them to alternative differential expression analysis approaches, showing that incorporation of knowledge yields better performance. We present a broad range of knowledge sources and data to which our partially supervised methodology can be applied. First, we determine targets of Ste12 based on yeast knockout data, guided by a Ste12 DNA-binding experiment. Second, we distinguish miR-1 from miR 124 targets in human by clustering expression data under transfection experiments of both microRNAs, using their computationally predicted targets as examples. Finally, we utilize literature knowledge to improve clustering of time-course expression profiles. PMID- 20726791 TI - Haplotype inference by Pure Parsimony: a survey. AB - Given a set of genotypes from a population, the process of recovering the haplotypes that explain the genotypes is called haplotype inference. The haplotype inference problem under the assumption of pure parsimony consists in finding the smallest number of haplotypes that explain a given set of genotypes. This problem is NP-hard. The original formulations for solving the Haplotype Inference by Pure Parsimony (HIPP) problem were based on integer linear programming and branch-and-bound techniques. More recently, solutions based on Boolean satisfiability, pseudo-Boolean optimization, and answer set programming have been shown to be remarkably more efficient. HIPP can now be regarded as a feasible approach for haplotype inference, which can be competitive with other different approaches. This article provides an overview of the methods for solving the HIPP problem, including preprocessing, bounding techniques, and heuristic approaches. The article also presents an empirical evaluation of exact HIPP solvers on a comprehensive set of synthetic and real problem instances. Moreover, the bounding techniques to the exact problem are evaluated. The final section compares and discusses the HIPP approach with a well-established statistical method that represents the reference algorithm for this problem. PMID- 20726792 TI - Conformational optimization with natural degrees of freedom: a novel stochastic chain closure algorithm. AB - The present article introduces a set of novel methods that facilitate the use of "natural moves" or arbitrary degrees of freedom that can give rise to collective rearrangements in the structure of biological macromolecules. While such "natural moves" may spoil the stereochemistry and even break the bonded chain at multiple locations, our new method restores the correct chain geometry by adjusting bond and torsion angles in an arbitrary defined molten zone. This is done by successive stages of partial closure that propagate the location of the chain break backwards along the chain. At the end of these stages, the size of the chain break is generally reduced so much that it can be repaired by adjusting the position of a single atom. Our chain closure method is efficient with a computational complexity of O(N(d)), where N(d) is the number of degrees of freedom used to repair the chain break. The new method facilitates the use of arbitrary degrees of freedom including the "natural" degrees of freedom inferred from analyzing experimental (X-ray crystallography and nuclear magnetic resonance [NMR]) structures of nucleic acids and proteins. In terms of its ability to generate large conformational moves and its effectiveness in locating low energy states, the new method is robust and computationally efficient. PMID- 20726793 TI - Wavelet-based functional clustering for patterns of high-dimensional dynamic gene expression. AB - Functional gene clustering is a statistical approach for identifying the temporal patterns of gene expression measured at a series of time points. By integrating wavelet transformations, a power dimension-reduction technique, noisy gene expression data is smoothed and clustered allowing for new patterns of functional gene expression profiles to be identified. We implement the idea of wavelet dimension reduction into the mixture model for gene clustering, aimed to de-noise the data by transforming an inherently high-dimensional biological problem to its tractable low-dimensional representation. As a first attempt of its kind, we capitalize on the simplest Haar wavelet shrinkage technique to break an original signal down into its spectrum by taking its averages and differences and, subsequently, detect gene expression patterns that differ in the smooth coefficients extracted from noisy time series gene expression data. The method is shown to be effective on simulated data and and on recent time course gene expression data. Supplementary Material is available at www.liebertonline.com . PMID- 20726794 TI - A mathematical model for peptide inhibitor design. AB - This article presents a mathematical model on the design of peptide inhibitors for proteins. This model is a combination of the two rules on protein-ligand interaction, Miyazawa-Jernigan (M-J) matrix and hidden Markov model (HMM). The model is applied to predict peptide inhibitors for the protein cyclophilin A (CypA) and FKBP12, and then validated by the highest occupied molecular orbital calculation, dock process between protein and inhibitor, and biological experiments. The results are encouraging and suggest that we have taken a step forward towards building a mathematical theory on the design of peptide inhibitors for proteins. The mathematical model is rough at present, but if it represents a correct direction of the theoretical trends of biology as we believe, then this theory can be further developed and become more and more precise. PMID- 20726795 TI - A novel candidate disease genes prioritization method based on module partition and rank fusion. AB - Identifying disease genes is very important not only for better understanding of gene function and biological process but also for human medical improvement. Many computational methods have been proposed based on the similarity between all known disease genes (seed genes) and candidate genes in the entire gene interaction network. Under the hypothesis that potential disease-related genes should be near the seed genes in the network and only the seed genes that are located in the same module with the candidate genes will contribute to disease genes prediction, three modularized candidate disease gene prioritization algorithms (MCDGPAs) are proposed to identify disease-related genes. MCDGPA is divided into three steps: module partition, genes prioritization in each disease associated module, and rank fusion for the global ranking. When applied to the prostate cancer and breast cancer network, MCDGPA significantly improves previous algorithms in terms of cross-validation and disease-related genes prediction. In addition, the improvement is robust to the selection of gene prioritization methods when implementing prioritization in each disease-associated module and module partition algorithms when implementing network partition. In this sense MCDGPA is a general framework that allows integrating many previous gene prioritization methods and improving predictive accuracy. PMID- 20726796 TI - Inference of the molecular mechanism of action from genetic interaction and gene expression data. AB - Inference of new and useful hypotheses from heterogeneous sources of genome-scale experimental data requires new computational methods that can integrate different types of data. Gene expression and genetic interaction data are two most informative data types, each allowing the identification of genes at different levels of cellular regulatory network hierarchy. We present an integrative data analysis approach, which, rather than correlating the findings from the two data sets, uses each type of data independently to identify the components of molecular pathways and combines them into a single directed network. Our computational genomics approach is based on a set of inference rules traditionally used for reasoning on genetic experiments, which we have formalized and implemented in a software tool. The approach uses chemogenetic interaction and expression data to infer the type of relation between the chemical substance (perturber) and a transcription factor by using previous knowledge on the set of genes whose expression the transcription factor in question regulates. We have used the proposed approach to successfully infer the models for the action of the drug rapamycin and of a DNA damaging agent on their molecular targets and pathways in yeast cells. The developed method is available as a web-based tool at http://www.ailab.si/perturbagen. PMID- 20726797 TI - ChIP-seq and functional analysis of the SOX2 gene in colorectal cancers. AB - SOX2 is an HMG box containing transcription factor that has been implicated in various types of cancer, but its role in colorectal cancers (CRC) has not been studied. Here we show that SOX2 is overexpressed in CRC tissues compared with normal adjacent tissues using immunohistochemical staining and RT-PCR. We also observed an increased SOX2 expression in nucleus of colorectal cancer tissues (46%, 14/30 cases vs. 7%, 2/30 adjacent tissues). Furthermore, knockdown of SOX2 in SW620 colorectal cancer cells decreased their growth rates in vitro cell line, and in vivo in xenograft models. ChIP-Seq analysis of SOX2 revealed a consensus sequence of wwTGywTT. An integrated expression profiling and ChIP-seq analysis show that SOX2 is involved in the BMP signaling pathway, steroid metabolic process, histone modifications, and many receptor-mediated signaling pathways such as IGF1R and ITPR2 (Inositol 1,4,5-triphosphate receptor, type 2). PMID- 20726798 TI - Glycomics: technologies taming a frontier omics field. PMID- 20726799 TI - Lectin microarrays for glycomic analysis. AB - Glycomics is the study of comprehensive structural elucidation and characterization of all glycoforms found in nature and their dynamic spatiotemporal changes that are associated with biological processes. Glycocalyx of mammalian cells actively participate in cell-cell, cell-matrix, and cell pathogen interactions, which impact embryogenesis, growth and development, homeostasis, infection and immunity, signaling, malignancy, and metabolic disorders. Relative to genomics and proteomics, glycomics is just growing out of infancy with great potential in biomedicine for biomarker discovery, diagnosis, and treatment. However, the immense diversity and complexity of glycan structures and their multiple modes of interactions with proteins pose great challenges for development of analytical tools for delineating structure function relationships and understanding glyco-code. Several tools are being developed for glycan profiling based on chromatography, mass spectrometry, glycan microarrays, and glyco-informatics. Lectins, which have long been used in glyco-immunology, printed on a microarray provide a versatile platform for rapid high throughput analysis of glycoforms of biological samples. Herein, we summarize technological advances in lectin microarrays and critically review their impact on glycomics analysis. Challenges remain in terms of expansion to include nonplant derived lectins, standardization for routine clinical use, development of recombinant lectins, and exploration of plant kingdom for discovery of novel lectins. PMID- 20726800 TI - Enzymatic glycosylations on arrays. AB - The enzymatic glycosylation of microarrays is a relatively young field in glycoscience. Platforms developed from other array technologies (e.g., proteins and nucleic acids) were successfully adopted in several proof-of-principle studies as a high-throughput tool for the generation of more complex carbohydrate structures using carbohydrate-processing enzymes. These arrays and the developed on-chip enzymatic glycosylation methodologies are reviewed in this article. PMID- 20726801 TI - The sialome--far more than the sum of its parts. AB - The glycome is defined as the glycan repertoire of cells, tissues, and organisms, as found under specified conditions. The vastly diverse glycome is generated by a nontemplate driven biosynthesis, which is indirectly encoded in the genome, and very dynamic. Due to this overwhelming diversity, glycomic analysis must be approached at different hierarchical levels of complexity. In this review five such levels of complexity and the experimental approaches used for analysis at each level are discussed for a subclass of the glycome: the sialome. The sialome, in analogy to the canopy of a forest, covers the cell membrane with diverse array of complex sialylated structures. Sialome complexity includes modification of sialic acid core structure (the leaves and flowers), the linkage to the underlying sugar (the stems), the identity, and arrangement of the underlying glycans (the branches), the structural attributes of the underlying glycans (the trees), and finally, the spatial organization of the sialoglycans in relation to components of the intact cell surface (the forest). Understanding the full complexity of the sialome thus requires combined analyses at multiple levels, that is, the sialome is far more than the sum of its parts. PMID- 20726802 TI - Glycan characterization of PSA 2-DE subforms from serum and seminal plasma. AB - Prostate-specific antigen (PSA) two-dimensional electrophoresis (2-DE) subforms (F1-F5) have been described to be altered in prostate cancer (PCa) compared to benign prostatic hyperplasia (BPH). To understand their molecular differences, characterization of these subforms from PCa serum and seminal plasma, namely, at the glycan level, was performed. PSA 2-DE subforms from two serum PCa samples and seminal plasma were analyzed by N-glycan sequencing using high-performance liquid chromatography (HPLC) combined with exoglycosidase array digestions and by mass spectrometry. F1, F2, and F3 subforms showed the same N-glycan pattern, which contained higher levels of sialic acid than the F4 subform, whereas the F5 subform was unglycosylated. When comparing PSA subforms from PCa with seminal plasma, a decrease in sialylation was observed. Furthermore, the analysis of F3, the more abundant PSA subform, showed a higher proportion of alpha 2-3 sialic acid and a decrease in core fucosylated glycans in the PCa sample. These N-glycan changes in PCa PSA subforms highlight the importance of glycosylation as an indicator of PCa disease. PMID- 20726803 TI - The RINGS resource for glycome informatics analysis and data mining on the Web. AB - In the bioinformatics field, many computer algorithmic and data mining technologies have been developed for gene prediction, protein-protein interaction analysis, sequence analysis, and protein folding predictions, to name a few. This kind of research has branched off from the genomics field, creating the transcriptomics, proteomics, metabolomics, and glycomics research areas in the postgenomic age. In the glycomics field, given the complexity of glycan structures with their branches of monosaccharides in various conformations, new data mining and algorithmic methods have been developed in an attempt to gain a better understanding of glycans. However, these methods have not all been implemented as tools such that the glycobiology community may utilize them in their research. Thus, we have developed RINGS (Resource for INformatics of Glycomes at Soka) as a freely available Web resource for glycobiologists to analyze their data using the latest data mining and algorithmic techniques. It provides a number of tools including a 2D glycan drawing and querying interface called DrawRINGS, a Glycan Pathway Predictor (GPP) tool for dynamically computing the N-glycan biosynthesis pathway from a given glycan structure, and data mining tools Glycan Miner Tool and Profile PSTMM. These tools and other utilities provided by RINGS will be described. The URL for RINGS is http://rings.t.soka.ac.jp/. PMID- 20726804 TI - The lectin riddle: glycoproteins fractionated from complex mixtures have similar glycomic profiles. AB - One common method used for analyzing the glycoproteome is chromatography using multiple lectins that display different affinities toward oligosaccharide structures. Much has been done to determine lectin affinity using standard glycoproteins with known glycosylation; however, a knowledge of the selectivity and specificity of lectins exposed to complex mixtures of proteins is required if they are to be used as a means of studying the glycoproteome. In the present study, three lectins (Concanavalin A, Jacalin, and Wheat Germ Agglutinin) were used to fractionate glycoproteins from two different complex environments: (1) cell membranes and (2) plasma. Reproducible enrichment of glycoproteins from these samples has been shown to result from the combined use of these lectins. However, the global glycan profiles of the released N- and O-linked oligosaccharides from the glycoproteins retained by the lectins, and from those glycoproteins that did not bind, using both these complex samples, were found to be very similar. That is, although the lectins selectively and reproducibly retained some glycoproteins, other proteins with the same attached oligosaccharide structures did not bind. Some small N- and O-glycan differences were observed in the bound fractions but there was little absolute specificity toward individual oligosaccharide structures known to have high affinity to these lectins. These data indicate that lectins are useful for fractionating glycoproteins from complex mixtures, but that the overall glycoproteome is not isolated by this approach. PMID- 20726805 TI - Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change. AB - To develop a novel flurbiprofen-loaded solid dispersion without crystalline change, various flurbiprofen-loaded solid dispersions were prepared with water, sodium carboxylmethyl cellulose (Na-CMC), and Tween 80. The effect of Na-CMC and Tween 80 on aqueous solubility of flurbiprofen was investigated. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared to commercial product. Unlike conventional solid dispersion systems, the flurbiprofen-loaded solid dispersion gave a relatively rough surface and changed no crystalline form of drug. These solid dispersions were formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in changing the hydrophobic drug to hydrophilic form. Furthermore, the flurbiprofen loaded solid dispersion at the weight ratio of flurbiprofen/Na-CMC/Tween 80 of 6/2.5/0.5 improved ~60-fold drug solubility. It gave higher AUC, T(max), and C(max) compared to commercial product. The solid dispersion improved almost 1.5 fold bioavailability of drug compared to commercial product in rats. Thus, the flurbiprofen-loaded solid dispersion would be useful to deliver poorly water soluble flurbiprofen with enhanced bioavailability without crystalline change. PMID- 20726806 TI - Development of chitosan-collagen hydrogel incorporated with lysostaphin (CCHL) burn dressing with anti-methicillin-resistant Staphylococcus aureus and promotion wound healing properties. AB - Methicillin-resistant Staphylococcus aureus (MRSA) have become increasingly prevalent as nosocomial pathogens, especially in burn patients, which is the leading cause of their death. A drug delivery system of chitosan-collagen hydrogel incorporated with lysostaphin (CCHL) based on the lysostaphin gauze was developed for MRSA infected burn wounds. CCHL scaffold consisted of numerous interconnected sphericles and tubular bodies with an average diameter of 100-200 um, 20-60-fold swelling, high water retention capacity, and cell proliferation properties. The minimal inhibitory concentration of CCHL was 0.053 U/mL. By the second week after its application on MRSA infected third-degree burn wounds, no bacteria could be detected and the burn wounds had started healing. Therefore, CCHL should be studied further as a promising candidate of burn treatment dressing against MRSA infections for clinics. PMID- 20726807 TI - Serum CYFRA21-1 as a prognostic marker for patients with undifferentiated nasopharyngeal carcinoma. AB - The purpose of this study was to evaluate the potential of serum CYFRA21-1 and carcinoembryonic antigen (CEA) as prognostic markers in patients with undifferentiated nasopharyngeal carcinoma. Sixty-one patients who received definitive radiotherapy/chemoradiotherapy were analysed retrospectively. We investigated the association of the follow-up results with pretreatment level, post-treatment level and change of serum CYFRA21-1 and CEA, respectively. Patients with low pretreatment CYFRA21-1 had a significantly better overall survival. There were no significant associations among the remaining serum markers, and the survival and recurrence rates on multivariate analysis. The present study shows that pretreatment CYFRA21-1 level is a potential factor for predicting long-term survival. PMID- 20726808 TI - Nodular regenerative liver hyperplasia as a complication of azathioprine containing immunosuppressive treatment for Crohn's disease. AB - Nodular regenerative liver hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for autoimmune disorders, organ transplantation, and/or oncological treatment. Here we report a case of a 40-year-old female patient with Crohn's disease and genetic hypercoagulability disorder-factor V Leiden, who in the course of azathioprine immunosuppressive treatment for inflammatory bowel disease developed NRH, which was clinically manifested by thrombocytopenia and delicate hepato-splenomegaly. Moreover, her endoscopic examination of upper gastrointestinal tract demonstrated esophageal varices. Genetic analysis revealed heterozygous genotype (*1/*3A) of thiopurine S-methyltransferase (TPMT), a key enzyme of thiopurines' metabolism, which results in lower activity of TPMT enzyme, thereby making our patient more susceptible to azathioprine-related hepato and myelotoxicity development. Treatment was started with the immediate cessation of azathioprine therapy, and administration of propranolol as primary prophylaxis for bleeding from esophageal varices. Currently (3 years after diagnosis) remission of Crohn's disease is achieved, however, progression of features of portal hypertension is observed. Propranolol administration is continued and the patient is constantly monitored in our Department. Our Case Study highlights the clinical difficulties and challenges associated with diagnosing of azathioprine-induced NRH, as well as, supports previous observations that hypercoagulability disorders and abnormal TPMT activity may contribute to NRH development. PMID- 20726809 TI - Microparticulate polyelectrolyte complexes for gentamicin transport across intestinal epithelia. AB - Polysaccharide microparticles for the oral administration of gentamicin were designed in order to obtain an increased drug absorption by means of microparticle transport across the intestinal epithelia. Alginate/chitosan microparticles with a size of ~2 MUm were developed by spray-drying a water solution containing the drug complexed with the polyanionic alginate and subsequent alginate cross-linking process by calcium ions and chitosan. The pre formulation study, performed by changing the concentration of both cross-linkers, led to the selection of the most suitable formulation which was assayed for its capacity to be translocated across intestinal epithelia, via both M cells contained in Follicle Associated Epithelium (FAE) of Peyer's patches and enterocytes of the mucosal epithelium. An ex vivo perfusion technique of rabbit and rat intestinal tissues containing Peyer's patches combined with an in vitro method by using Caco-2 cell monolayers demonstrated the microparticulate carrier ability to be taken up by both M cells and enterocytes. However, only the endocytosis by M cells appeared to provide the microparticle transport from the epithelium toward deeper sub-epithelial regions. PMID- 20726810 TI - Extension of nasal anti-Staphylococcus aureus efficacy of lysostaphin by its incorporation into a chitosan-o/w cream. AB - Nasal colonization of Staphylococcus aureus (S.aureus) is known as a significant risk factor for nosocomial infections, and clearance of its nasal colonization greatly reduces the risk. In the present study the preparation and characterizations of the chitosan-o/w cream incorporated with lysostaphin (CCL) were described. It showed that the concentration of incorporated lysostaphin had a direct relationship with its release behavior from the cream. It was rapid at 2 and 3.5 mg lysostaphin/g cream and of a more sustained pattern at 5 mg lysostaphin/g cream. Efficacy of lysostaphin released from the CCL cream to inhibit S.aureus growth was higher than that of lysostaphin delivery routinely treated, as demonstrated by the reduction of the mucociliary transport rate (MTR) in contrast to the control graphite particles (p < 0.05). Therefore, it is concluded that drug delivery by the CCL holds its potential as a local nasal anti S.aureus infection. PMID- 20726811 TI - Effect of permeation enhancers on the iontophoretic transport of metoprolol tartrate and the drug retention in skin. AB - Utilization of chemical penetration enhancers in conjunction with iontophoresis is regarded as the most effective method to enhance the passage of molecules across the skin barrier. A systematic approach to enhance the transdermal delivery of metoprolol tartrate and the subsequent release of the drug depot in the skin was investigated. Gel formulations with proximate viscosity were prepared and assessed for the effect of polymers (carbopol, hydroxypropyl methyl cellulose, and methyl cellulose), permeation enhancers (5% w/w, sodium lauryl sulfate (SLS), dimethyl formamide, n-methyl-2-pyrrolidone, and polyethylene glycol 400), and the combination approach (permeation enhancers with iontophoresis-0.5 mA/cm2 on the drug delivery. The flux values observed in passive (4.59-5.89 ug/cm2/h) and iontophoresis (37.99-41.57 ug/cm2/h) processes revealed that the permeation of metoprolol was not influenced by the polymers studied, under similar conditions, and further studies were carried out using carbopol gel as a representative polymer. Appreciable enhancement (~5-fold) in drug delivery was observed with SLS in the passive process while the optimum iontophoretic delivery condition ensured better delivery (~7-fold). Combination of iontophoresis with SLS further enhanced the drug delivery (~9-fold) and leads to noticeable drug retention in the skin as well. Moreover, the drug retained in the cutaneous layer of the skin eventually released over a period of time (5 days) and followed a near first order profile. This study concludes that the combination of iontophoresis with SLS augmented the metoprolol delivery and rendered skin drug depot, which eventually released over a period of time. PMID- 20726812 TI - Evaluation of the Sysmex UF-1000i(r) urine flow cytometer in the diagnostic work up of suspected urinary tract infection in a Dutch general hospital. AB - BACKGROUND: Automation and standardization of sediment analysis of urine samples by flow cytometry might serve as an alternative to labor-intensive laboratory methods, such as microscopic examination and culture. The Sysmex UF-1000i is a urine flow cytometer that uses two separate channels for counting blood cells and bacteria. METHODS: In this study, 358 urine samples were analyzed with the Sysmex UF-1000i in parallel with manual microscopy, Gram stain and bacterial culture, the latter considered the gold standard. RESULTS: Reproducibility for detection of white and red blood cells and bacteria was good, while detection of yeast proved unreliable. Depending on the definition of urinary tract infection (UTI) used, the negative predictive value and the percentage of false-negative results were 100% and 0% [UTI >= 10(5) colony forming units (CFU)/mL] and 99% and 1.3%, (UTI >= 10(4) CFU/mL), respectively. Pre-screening with the Sysmex UF-1000i would have resulted in a reduction of bacterial culture by 42%. Carry over of bacteria between consecutive samples due to the use of fixed sample needle was observed, but did not result in false-positive interpretation of Sysmex UF-1000i results. Because of the occurrence of carry over, samples that have been analyzed with the Sysmex UF-1000i cannot be used for subsequent urine culture. CONCLUSIONS: In conclusion, the Sysmex UF-1000i offers the possibility for screening high numbers of urine samples in a fast and standardized way, resulting in a reduction in workload and speeding the diagnostic process. It is not recommended for use in complicated patient populations, such as neutropenic patients and patients in whom yeast infection is suspected. PMID- 20726814 TI - Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis. AB - OBJECTIVE: The objective of this post hoc analysis was to investigate the effect of strontium ranelate on a cartilage degradation marker in postmenopausal women who participated in a randomized, placebo-controlled osteoporosis study. Women were stratified according to reported symptoms of osteoarthritis and to the baseline levels of a cartilage degradation marker. METHODS: The analysis included the 2617 postmenopausal women (75 years old) with osteoporosis randomized to strontium ranelate or placebo for a 36-month period. Cartilage degradation was evaluated using a validated urinary marker adjusted for creatinine (CTX-II/cr), whereas bone resorption was assessed by serum CTX-I. The presence of osteoarthritis was determined by individual interviews. RESULTS: CTX-II was significantly elevated at baseline in subjects with a history of osteoarthritis (OA+) compared to subjects who did not (OA-) (p < 0.0001), whereas CTX-I was unaffected by osteoarthritis status. Strontium ranelate caused a significant decrease from baseline in CTX-II over a 12-month period whatever the osteoarthritis status. Strontium ranelate-treated patients had a significant decrease in CTX-II compared to placebo in both OA+ and OA- groups up to 12 months, the difference remaining still significant at 36 months in patients from the OA- group (p < 0.001). CONCLUSIONS: The CTX-II profile of changes over 3 years may reflect efficacy of strontium ranelate against cartilage degradation, with an enhanced beneficial effect in subjects with early or mild clinical osteoarthritis, probably exerting its putative chondroprotective influence in early stages of the disease. Carefully controlled studies in targeted populations with early osteoarthritis are warranted to assess the role of strontium ranelate halting osteoarthritis progression. PMID- 20726815 TI - Cardioprotection by endoplasmic reticulum stress-induced autophagy. AB - This study tested the hypothesis that the induction of autophagy by producing therapeutic amounts of endoplasmic reticulum (ER) stress in the heart before an ischemic insult would ameliorate/reduce subsequent lethal myocardial ischemic/reperfusion (I/R) injury (similar to ischemic preconditioning). A dose response study with both tunicamycin and thapsigargin was performed to determine the optimal dose (0.3 mg/kg) for inducing autophagy for cardioprotection. The Sprague-Dawley rats weighing between 250 and 300 g were randomly assigned into five groups: normal control (injected with saline only), high (3 mg/kg), and low (0.3 mg/kg) doses of tunicamycin or thapsigargin, respectively. After 48 h, the rats were subjected to an isolated working heart preparation: 30 min ischemia followed by 2 h of reperfusion with continuous left ventricular function monitoring. At the end, the hearts were subjected to either measurement of infarct size or cardiomyocyte apoptosis. Some hearts (from different sets of experiments) were used for transmission electron microscopy (TEM), confocal microscopy, or Western blot analysis. Tunicamycin and thapsigargin, irrespective of the dose, induced sufficient ER stress, as evidenced by the increased phosphorylation or activation of eIF2alpha and PERK. Such ER stress potentiated autophagy in the heart, as evidenced by an increase in LC3-II, beclin-1, and Atg5. This was also supported by TEM, clearly showing the production of autophagosomes, and by confocal microscopy, showing upregulation of eIF2alpha and beclin-1. The autophagy produced with lower doses of tunicamycin and thapsigargin in the face of myocardial I/R resulted in reduction of the I/R injury, as evidenced by improved left ventricular function and reduced myocardial infarct size and cardiomyocyte apoptosis. In concert, an induction of GRP78 and activation of Akt and Bcl-2 occurred. The higher doses conversely were detrimental for the heart and were associated with induction of CHOP and downregulation of Akt. The results thus display the proof of concept that induction of autophagy by ER stress (therapeutic amount) before ischemia (similar to ischemic preconditioning) could reduce subsequent lethal ischemic reperfusion injury. PMID- 20726816 TI - Hurdles in tissue engineering/regenerative medicine product commercialization: a survey of North American academia and industry. AB - The Tissue Engineering and Regenerative Medicine International Society-North America (TERMIS-NA) Industry Committee was formed in February 2009 to address the common roadblocks (i.e., hurdles) in the commercialization of tissue engineering/regenerative medicine products for its members. A semiquantitative online opinion survey instrument that delineated potentially sensitive hurdles to commercialization in each of the TERMIS constituency groups that generally participate in the stream of technology commercialization (academia, startup companies, development-stage companies, and established companies) was developed. The survey was opened to each of the 863 members of TERMIS-NA for a period of 5 weeks from October to November 2009. By its conclusion, 215 members (25%) had responded. Their proportionate numbers were closely representative of TERMIS-NA constituencies. The resulting data delineate what each group considers to be its most difficult and also its easiest hurdles in taking a technology to full product development. In addition, each group ranked its perception of the difficult and easy hurdles for all other groups, enabling an assessment of the degree of understanding between groups. The data depict not only critical hurdles in the path to commercialization at each stage in product development but also a variable understanding of perceptions of hurdles between groups. This assessment has provided the Industry Committee with activity foci needed to assist individual groups in the technology-commercialization stream. Moreover, the analysis suggests that enhanced communication between groups engaged in commercialization will be critical to the successful development of products in the tissue engineering/regenerative medicine sector. PMID- 20726817 TI - Isolation and characterization of multi-potent stem cells from human orbital fat tissues. AB - Loss of corneal epithelial cells results in visual problems. Stem cells isolated from the limbal area of the ocular surface are able to replenish lost corneal epithelial cells. However, destruction of the healthy limbus tissue is inevitable. Theoretically, orbital fat should be an excellent source to isolate stem cells for regenerating ocular tissues as the orbital connective tissues share the same embryonic origin with the ocular proper in early organogenesis. The aim of this study is to isolate stem cells from the human orbital fat and to explore their differentiation potentials into epithelial cells. It was found that spindle-shaped, fibroblast-like cells with extensive proliferation potentials could be isolated from orbital fat tissues. These orbital fat-derived stem cells (OFSCs) possessed multi-lineage differentiation potential to become osteoblasts, chondrocytes, and adipocytes. Upon mix-culture with corneal epithelial cells, OFSCs changed their morphology to round, polygonal epithelial-like cells. Loss of CD105 expression and increased expression of epithelial cell markers, including epithelial-specific antigen and zonal occludin-1, were found upon mix-culture with corneal epithelial cells. Moreover, corneal epithelial differentiation was evidenced by expression of cytokeratin -19 and cytokeratin -3 after mix-culture with corneal epithelial cells, whereas human adipose-derived stem cells from subcutaneous fat were unable to differentiate into corneal epithelial cells under the same induction condition. We further found that direct contact with corneal epithelial cells was essential for OFSCs to commit to corneal epithelial cells. Taken together, orbital fat tissues are a novel source for multi-potent stem cells that possess the potential to differentiate into corneal epithelial lineage. OFSCs are therefore a potential candidate for cell therapy and tissue engineering of corneal epithelium. PMID- 20726818 TI - Challenges in tissue engineering and regenerative medicine product commercialization: building an industry. PMID- 20726820 TI - Therapeutic options for HIV-associated lymphomas. AB - IMPORTANCE OF THE FIELD: The clinical features and natural history of HIV associated lymphomas differ greatly from those observed in the general population. The failure to improve outcomes with treatment intensification indicates the need for the introduction of new therapeutic options. AREAS COVERED IN THIS REVIEW: This review summarizes reports from 1995 to the present which focus on the treatment strategies and their prognostic relevance in the setting of HIV-associated lymphomas. WHAT THE READER WILL GAIN: The identification of prognostic factors in rare tumors such as HIV-associated lymphomas is going to require the establishment of multi-institutional and cooperative group-supported tissue banks. The rarity of primary effusion lymphomas and plasmablastic lymphomas of the oral cavity type makes large prospective studies difficult and challenges the feasibility of defining therapy specific for a given subpopulation of patients. TAKE HOME MESSAGE: HIV-associated lymphomas still represent a relevant field of clinical research. Standard methodologies for therapy in this patient population have yet to be established. However, rituximab plus chemotherapy should be offered to the majority of patients with HIV infection and diffuse large B-cell lymphomas; and the feasibility of intensive aggressive chemotherapy regimens has been successfully tested in HIV-associated Burkitt's lymphomas. PMID- 20726821 TI - Atypical antipsychotic tolerability and switching strategies in bipolar disorder. AB - IMPORTANCE TO THE FIELD: Atypical antipsychotics have unequivocally advanced the pharmacotherapy of bipolar disorders. These broad-spectrum treatments offer efficacy against core symptoms of acute mania, mixed state, depressed and maintenance phases of the disorder. Atypical antipsychotics are not, however, a panacea and are associated with several problematic tolerability and safety concerns. For example, emerging evidence militates against the original notion that atypical agents are without risk for extrapyramidal side effects and possibly tardive dyskinesia when compared to their therapeutic predecessors, the conventional antipsychotics. Although classified together, atypical antipsychotics are heterogeneous in their tolerability and safety profile, an issue relevant to individualizing treatment selection and switching antipsychotics for optimal clinical management. AREAS COVERED IN THIS REVIEW: This article reviews relevant adverse events attributable to the use of atypical antipsychotics and strategies for switching these agents, with particular attention to the bipolar disorder population. WHAT THE READER WILL GAIN: The reader will gain both a perspective of treatment-emergent adverse events associated with atypical agents in the treatment of bipolar disorder and a precise analysis of common adverse events that frequently lead to treatment discontinuation and/or switching to a separate agent. TAKE HOME MESSAGE: Atypical antipsychotics provide for a different array of treatment-emergent adverse events than conventional agents. The therapeutic index of treatment is a ratio of the relative benefit divided by the probability of harm (i.e., side effects). Taken together, the atypical antipsychotics offer an improved therapeutic index when compared to conventional agents in bipolar disorder. Nevertheless, atypicals fall short of the ideal, necessitating frequent discontinuation and switching. PMID- 20726819 TI - Regenerative therapy after cancer: what are the risks? AB - There is often a pressing need for reconstruction after cancer surgery. Regenerative therapy holds the promise of more natural and esthetic functional tissue. In the case of breast reconstruction postmastectomy, volume retention problems associated with autologous fat transfer could be ameliorated by augmentation with cells capable mediating rapid vascularization of the graft. Intentional placement of regenerating tissue at the site of tumor resection raises questions concerning the possibility of promoting cancer recurrence. Here we review coculture and animal models of tumor/mesenchymal stem cell interactions under regenerating conditions. Available evidence from case reports, cell lines, and clinical isolates favors the interpretation that regenerating tissue promotes the growth of active, high-grade tumor. In contrast, dormant cancer cells do not appear to be activated by the complex signals accompanying wound healing and tissue regeneration, suggesting that engineered tissue reconstruction should be deferred until cancer remission has been firmly established. PMID- 20726822 TI - Therapeutic strategies for the treatment of dyspepsia. AB - IMPORTANCE OF THE FIELD: Dyspeptic symptoms are highly prevalent in the population and represent a major burden for healthcare systems. The ROME III criteria address and define two separate entities of functional dyspepsia: epigastric pain syndrome and postprandial distress syndrome. The etiology of dyspeptic symptoms is heterogeneous, underlying mechanisms are poorly understood and symptomatic improvement after drug therapy is often incomplete. AREAS COVERED IN THIS REVIEW: This review of the literature included Medline data being published in the field of functional dyspepsia and different therapies. WHAT THE READER WILL GAIN: The reader will gain a current, unbiased understanding of the pathophysiological mechanisms underlying functional dyspepsia and of the therapeutic regimens based on randomized, controlled trials and on the meta analyses that have been published on different therapeutic agents. TAKE HOME MESSAGE: Before starting medical treatment, a careful physical examination should exclude 'alarm symptoms'. Laboratory data, ultrasound and endoscopy are recommended in patients older than 45 - 55 years (depending on the guidelines being used). In areas with a high prevalence of Helicobacter pylori, the initial strategy includes 'test and treat' for H. pylori in addition to empiric acid suppressive therapy. Many studies have focused on the role of gastrointestinal dysmotility and hypersensitivity for dyspepsia with inconclusive results. Further therapeutic medical strategies include prokinetics, herbal preparations and psycho-/neurotopic drugs as well as additional psycho- or hypnotherapy. PMID- 20726823 TI - Analysis of genetic variations in the human melatonin receptor (MTNR1A, MTNR1B) genes and antipsychotics-induced tardive dyskinesia in schizophrenia. AB - OBJECTIVES: Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes (MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study. METHODS: Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes (MRNR1A, MTNR1B) was then performed for each subject. RESULTS: Four hundred and eighteen inpatients (TD=256, non-TD=162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P=0.037), and the association was also found to be significant by global haplotype analyses (permutation P=0.045). CONCLUSIONS: Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated. PMID- 20726824 TI - Parent of origin effect and differential allelic expression of BDNF Val66Met in suicidal behaviour. AB - OBJECTIVES: Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since BDNF levels are decreased in brain and plasma of suicide victims. Because the differential allelic expression of Val66Met BDNF gene on suicidal behaviour has not been investigated, we analyzed the parent-of-origin effect (POE) in suicide attempters and the differential expression of BDNF Val66Met alleles in suicide victims. METHODS: We performed a family-based association study and ETDT analyses of the Val66Met polymorphism in nuclear families with at least one subject affected by major psychosis with suicidal behaviour, and compared allele-specific mRNA levels in post-mortem brain samples from suicide and non-suicide victims. The subjects included in this study have diagnosis of schizophrenia, bipolar disorder type I and type II. RESULTS: Allele 3 in the GT repeat polymorphism was transmitted significantly more often to patients who attempted suicide (maternal transmissions: 46/22, P = 0.003; paternal transmissions: 55/30, P = 0.006). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of Val/Met-specific mRNA expression between suicide victims and controls. CONCLUSIONS: These data do not support a role for allelic imbalance or POE of BDNF for suicidal behaviour in major psychoses. PMID- 20726826 TI - Antiepileptic drugs-ECT combination: Need for systematic studies. PMID- 20726825 TI - Association of the brain-derived neurotrophic factor Val66Met polymorphism with hippocampus volumes in drug-free depressed patients. AB - OBJECTIVES: Val66Met BDNF gene polymorphism is shown to affect the function of mature BDNF and mature BDNF plays an important role in the hippocampal neurogenesis and neuronal survival. METHODS: A relationship of Val66Met BDNF gene polymorphism and hippocampal volumes in 33 MDD patients and 40 healthy controls is investigated. Region of interest analysis was conducted on the images acquired via MRI. RESULTS: Depressed patients had smaller left hippocampal volumes compared to healthy controls. The diagnosis of MDD was not significantly related to hippocampal volumes among Met carriers; however, among Val homozygotes depressed patients had significantly smaller left hippocampal volumes compared to controls. Although both right and left hippocampal volumes showed nearly significant correlation with the duration of illness, this correlation reached (negative) significant levels only in the right hippocampal volume of the Val homozygotes. CONCLUSIONS: Val homozygote genotype may serve as a vulnerability factor in MDD regarding hippocampal volume loss. This finding can be considered as a supportive evidence for the neurotrophic factor hypothesis of depression. PMID- 20726827 TI - Ecological barriers and social forces in childhood asthma management: examining routines of African American families living in the inner city. AB - OBJECTIVE: Asthma affects African American children at unprecedented rates. Researchers have examined the context in which African American families live and experience illness, and suggest that ecological barriers contribute to poor health. In this paper, the authors examine the social forces underlying these ecological barriers and what African American parents living in the inner city do to manage their children's asthma amidst these challenges. METHODS: African American parents of children aged 5 to 12 years diagnosed with persistent asthma living in the inner city were interviewed using a semistructured interview guide. Grounded theory analysis identified recurrent themes in the interview data. FINDINGS: Parents identified four adaptive routines they use to manage their children's asthma: ( 1 ) give young children with asthma responsibility for medication use; ( 2 ) monitor the availability of the school nurse; ( 3 ) manage air quality; and ( 4 ) frequently clean the home. These routines are described as adaptive because parents navigate ecological barriers and social forces within their daily context to manage their children's asthma. IMPLICATIONS: The authors argue that the first step in reducing the impact of ecological barriers is understanding African Americans' sociohistorical context. PMID- 20726828 TI - Relation between utero-placental and feto-placental circulations: a longitudinal study. AB - OBJECTIVE: To explore the relation between total utero-placental (TQ(uta)) and feto-placental (Q(uv)) blood flows and establish longitudinal reference ranges for the TQ(uta)/Q(uv) ratio and the mean uterine artery and umbilical artery pulsatility (UtaPI/UAPI) and resistance index (UtaRI/UARI) ratios. DESIGN: Prospective longitudinal observational study. SETTING: University hospital in Norway. POPULATION: Fifty-three low-risk pregnant women. METHODS: Uterine artery and umbilical vein blood flow was measured using Doppler ultrasonography at 4 weekly intervals from 22(+0) to 39(+6) weeks of gestation. MAIN OUTCOME MEASURES: Ratios between utero-placental and feto-placental volume blood flows and between indices of uterine and umbilical artery impedance. RESULTS: The TQ(uta)/Q(uv) ratio had a significant association with the gestational age (p < 0.00001) and decreased with advancing gestation during the second half of pregnancy. The mean UtaPI/UAPI (p = 0.094) and mean UtaRI/UARI (p = 0.323) ratios were not significantly associated with gestational age and remained relatively constant. There was no significant association between TQ(uta) and Q(uv) (p = 0.72), mean UtaPI and UAPI (p = 0.56), or mean UtaRI and UARI (p = 0.57). CONCLUSION: The gestational-age-related changes in the utero-placental and feto-placental circulations do not appear to be affected by each other under physiological conditions. We have established longitudinal reference ranges for the utero placental and feto-placental blood flow and impedance ratios during the second half of pregnancy. PMID- 20726829 TI - Isolated fallopian tube torsion: a series of six cases. AB - Isolated Fallopian tube torsion is a rare gynecological cause of acute lower abdominal pain. Currently, there are no pathognomonic symptoms, clinical findings, imaging or laboratory characteristics for this condition, and the diagnosis can rarely be made before operation. We have identified six cases of isolated Fallopian tube torsion treated over a period of 3 years. It was observed that acute onset of abdominal pain with gastrointestinal symptoms can be the initial presenting features. Clinical and laboratory findings included positive peritoneal signs, fever, tachycardia and leucocytosis. Most of the women had preoperative ultrasound showing tubular adnexal masses of heterogeneous echogenicity with cystic component and the presence of free fluid. In contrast to the belief that isolated Fallopian tube torsion is more common in the right side, in five of our cases it occurred in the left side. PMID- 20726830 TI - Perforation of a malignant ovarian tumor into the recto-sigmoid colon. AB - Ovarian cancer often presents at an advanced stage, but tends to be an intra peritoneal disease that respects peritoneal planes. Thus, colo-rectal perforation of the tumor is an extremely rare presentation. The surgical treatment of malignant colo-ovarian fistula should include complete cyto-reduction at the same time as the treatment of the fistula. However, prognosis remains poor, because of the advanced stage of neoplasia. We report the case of a patient with an ovarian malignant tumor perforating into the recto-sigmoid colon. CT scan was the cornerstone of the radiological diagnosis. We managed to perform a complete cyto reduction, including an en-bloc resection of the uterus, the mass, adnexa and recto-sigmoid with removal of the associated pelvic abscess. PMID- 20726831 TI - Medical students learning the pelvic examination: evaluation of a clinical patient model. AB - OBJECTIVE: To evaluate a clinical patient (CP) model for training in pelvic examination. DESIGN: Prospective clinical study. POPULATION: Students attending the course in obstetrics and gynecology and patients at Karolinska University Hospital, Stockholm, Sweden. MAIN OUTCOME MEASURES: Feelings, attitudes and skills of medical students and ratings from CPs in connection to training in the pelvic examination. METHODS: Each student participated in two training sessions at an outpatient clinic. The student participants answered questionnaires after each clinical session to measure different aspects of experiencing distress and to themselves rate the technical performance of the examination as well as the interaction with the CP. The CP answered questions about the examination, communication, information provided by the student and how they felt about participating in a teaching session. RESULTS: The students rated their own performance high including both interpersonal communication and the technical examination. It was felt that the teacher as well as the CP gave good support and guidance. The CPs rated interpersonal communication skills by the students high. The teaching session was regarded as important and useful by both students and CPs. CONCLUSIONS: We recommend the use of this type of training sessions where students are allowed to work more independently and train in the role as a doctor under supervision of the teacher. PMID- 20726832 TI - Methotrexate-based bilateral uterine arterial chemoembolization for treatment of cesarean scar pregnancy. AB - We have evaluated the efficacy of methotrexate-based bilateral uterine arterial chemoembolization for treating cesarean scar pregnancy (CSP) in 52 women between January 2005 and December 2009. Ten patients experienced massive vaginal hemorrhage after a misdiagnosis and subsequent curettage. Bleeding in these patients was reduced after chemoembolization. Dilation and curettage was not done in five of these patients because ultrasound scanning showed sparse or no blood flow in the previous gestational sac area. The five remaining patients, along with additional 42 patients who were diagnosed with CSP, underwent ultrasound guided dilation and curettage within 24-48 hours following chemoembolization. Patients tolerated the procedure well and only mild bleeding occurred. The positive clinical outcomes in these patients support the use of bilateral uterine artery chemoembolization for the treatment of CSP. PMID- 20726833 TI - Targeting phosphoprotein profiling by combination of hydroxyapatite-based phosphoprotein enrichment and SELDI-TOF MS. AB - Over the last decade surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) has evolved as a versatile tool in the field of proteomic research. Although the chromatographic matrices on the currently provided SELDI affinity arrays allow efficient on-chip protein enrichment, it can be advantageous to combine SELDI with additional sample pre-fractionation steps. In this study, we demonstrate the potential of combining hydroxyapatite-based phosphoprotein enrichment with SELDI-TOF MS analysis. A straightforward method for the enrichment of phosphoproteins on ceramic hydroxyapatite was developed using fluorescently-labelled model proteins. Hydroxyapatite-based pre fractionation of proteins derived from cell lysates was performed. SELDI-TOF MS analysis of the pre-fractionation eluate confirmed a considerable reduction of sample complexity and an enhancement of selected protein signals. PMID- 20726834 TI - Component-resolved diagnosis for phleum allergy: the role of recombinants. AB - BACKGROUND: Conventional diagnostic tests (such as radioallergosorbent test [RAST] and skin prick test [SPT]) use native raw pollen allergen extracts to establish allergy. However, recombinant allergens may offer important advantages compared with their natural counterparts. OBJECTIVE: This study evaluated serum immunoglobulin E (IgE) in patients with grass-induced allergic rhinitis (AR) or AR with asthma (ARA), comparing assays with natural or recombinant grass allergens. METHODS: Sixty patients (33 AR, 27 ARA) positive with SPT and serum IgE for Phleum pratense were enrolled in the study. Serum IgE specific for conventional and recombinant Phleum pratense: rPhl p 1, rPhl p 2, nPhl p 4, rPhl 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12, were measured by the IFMA procedure (ImmunoCAP, Phadia, Uppsala, Sweden). Data were expressed as the median (md) and percentiles. Recombinant allergen results were expressed also as the percentage of positive concentrations. The Wilcoxon test was used to compare samples. Because diagnosis is a binary variable (AR/ARA), logistic regression analysis was performed to identify possible correlates. RESULTS: IgE concentrations assessed with recombinant allergens were significantly higher in ARA patients (p = .05) than in AR patients. A value >5.8 kU/L is the optimal cut-off to discriminate AR and ARA patients. Model specificity was 76%, sensitivity 78%, and efficiency 77%. CONCLUSION: This study shows that IgEs for natural and recombinant grass pollen allergens are significantly higher in patients with AR and asthma. Moreover, using recombinant allergens it is possible to define a prediction model for diagnosis with 77% efficiency. Therefore, this study may suggest that there are advantages of using recombinant or purified, native allergens over crude extracts. PMID- 20726836 TI - PTI-609: a novel analgesic that binds filamin A to control opioid signaling. AB - Binding a critical pentapeptide region on the scaffolding protein filamin A regulates signaling of mu opioid receptors (MORs) so that their activation should not result in the opioid tolerance, dependence and addiction associated with current opioid painkillers. Additionally, we show that compounds that bind this site on filamin A reduce release of inflammatory cytokines. PTI-609 is a new chemical entity that binds filamin A with picomolar affinity and also activates opioid receptors via a novel binding domain. PTI-609 and analogs have similar analgesic efficacy to morphine by oral administration in mice, provide some anti inflammatory activity in the rat collagen-induced arthritis model, and show no conditioned place preference at analgesic doses, suggesting no potential for abuse and addiction. PTI-609 was designed after discovering filamin A as the high affinity target of naltrexone or naloxone. Combined with opiates, ultra-low-dose naloxone or naltrexone can enhance and prolong the analgesia of the opiate alone and prevent or attenuate opioid tolerance, dependence and addictive properties. We will review here the mechanism of action of ultra-low-dose naltrexone and naloxone, the discovery of filamin A as their high-affinity target, and the rationale as to why the current, dualfunction new chemical entity should not only be easier to develop but also more consistently efficacious than opioids combined with ultra-low-dose naltrexone. This new class of compounds, as well as the concept, screening assay and pharmacophore model, are covered in a family of recent patent applications. PMID- 20726837 TI - Copper status abnormalities and how to measure them in neurodegenerative disorders. AB - Copper is essential for life. It plays a pivotal role in the central nervous system, in which a low concentration of copper results in incomplete development, whereas an excess of copper is injurious. Redox reactions are at the basis of copper toxicity: in fact, it catalyses the production of reactive oxygen species in Fenton or Haber-Weiss reactions. Abnormalities of copper homeostasis in neurodegenerative disorders were discovered decades ago. The steady increase in reports from the literature demonstrating copper involvement in neurodegenerative disorders coincides with the improvement, reliability and low cost devices which measure copper markers in biological samples. These devices also demonstrate increasing relevance in diagnosis and in therapy monitoring as well. Methods and new perspectives for the analysis of copper markers status are discussed herein, weighing pros and cons of application to a specific neurological disorder. In particular, it have been introduced three patents regarding a new apparatus for measuring levels of metal in biological samples, employing a current measuring device. A mention of recent patents concerning new derivatives of curcumin has been done considering its metal chelating and multi-functional properties that make these compounds interesting candidates for treatment of some neurodegenerative disorders. PMID- 20726838 TI - Pharmacological therapy of Parkinson's disease: current options and new avenues. AB - Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed. PMID- 20726835 TI - Concepts for biologically active peptides. AB - Here we review a unique aspect of CNS research on biologically active peptides that started against a background of prevalent dogmas but ended by exerting considerable influence on the field. During the course of refuting some doctrines, we introduced several concepts that were unconventional and paradigm shifting at the time. We showed that (1) hypothalamic peptides can act 'up' on the brain as well as 'down' on the pituitary, (2) peripheral peptides can affect the brain, (3) peptides can cross the blood-brain barrier, (4) the actions of peptides can persist longer than their half-lives in blood, (5) perinatal administration of peptides can exert actions persisting into adulthood, (6) a single peptide can have more than one action, (7) dose-response relationships of peptides need not be linear, (8) the brain produces antiopiate as well as opiate peptides, (9) there is a selective high affinity endogenous peptide ligand for the mu-opiate receptor, (10) a peptide's name does not restrict its effects, and (11) astrocytes assume an active role in response to metabolic disturbance and hyperleptinemia. The evolving questions in our laboratories reflect the diligent effort of the neuropeptide community to identify the roles of peptides in the CNS. The next decade is expected to see greater progress in the following areas: (a) interactions of peptides with other molecules in the CNS; (b) peptide involvement in cell-cell interactions; and (c) peptides in neuropsychiatric, autoimmune, and neurodegenerative diseases. The development of peptidomics and gene silencing approaches will expedite the formation of many new concepts in a new era. PMID- 20726839 TI - Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in Type 2 diabetes. AB - The sRAGE [soluble RAGE (receptor for advanced glycation end-products)] lack the transmembrane and cytoplasmic domain of the full-length receptor and can function as a decoy for RAGE ligands. Recent evidence suggests that sRAGE may be a potential biomarker of RAGE-mediated pathology. The present study aimed to examine the relationship between RAGE expression in peripheral blood monocytes and circulating sRAGE and esRAGE (endogenous sRAGE, a splice variant of sRAGE) in Type 2 diabetes. Protein expression of RAGE and esRAGE in monocyte cell lysate was determined by Western blot in 53 diabetic patients and 52 controls. Monocyte cell-surface-bound full-length RAGE expression was measured using flow cytometry. Serum sRAGE, esRAGE and AGE (advanced glycation end products) were assayed by ELISA. The mean HbA1c (glycated haemoglobin) of the diabetic patients was 9.74% and serum AGEs was increased. Monocyte full-length RAGE expression was significantly higher in diabetic patients whereas esRAGE expression was reduced, and serum AGEs concentration was an independent determinant of monocyte cell surface full-length RAGE expression. Serum levels of sRAGE [573.3 (375.7-754.3) compared with 608.1 (405.3-940.8) pg/ml, P<0.05] and esRAGE [241.8 (154.6-356.6) compared with 286.5 (202.6-390.0) pg/ml, P<0.05; values are medians (interquartile range)] were decreased. There was an inverse association between monocyte RAGE expression and log(serum sRAGE) (r=-0.34, P=0.01) but not with esRAGE. In conclusion, despite an increase in full-length RAGE expression, esRAGE expression was down-regulated in the diabetic patients, and serum sRAGE and esRAGE was also reduced. Hence increased full-length RAGE levels are not associated with a similar increase in sRAGE isoforms levels. PMID- 20726840 TI - Organic-solvent stability of elastase strain K overexpressed in an Escherichia Pseudomonas expression system. AB - The structural gene of elastase strain K (elastase from Pseudomonas aeruginosa strain K), namely HindIII1500PstI, was successfully sequenced to contain 1497 bp. The amino acid sequence, deduced from the nucleotide sequence, revealed that the mature elastase consists of 301 amino acids, with a molecular mass of 33.1 kDa, and contains a conserved motif HEXXH, zinc ligands and residues involved in the catalysis of elastase strain K. The structural gene was successfully cloned to a shuttle vector, pUCP19, and transformed into Escherichia coli strains TOP10, KRX, JM109 and TunerTM pLacI as well as P. aeruginosa strains PA01 (A.T.C.C. 47085) and S5, with detection of significant protein expression. Overexpression was detected from transformants KRX/pUCP19/HindIII1500PstI of E. coli and PA01/pUCP19/HindIII1500PstI of P. aeruginosa, with increases in elastolytic activity to 13.83- and 5.04-fold respectively relative to their controls. In addition, recombinant elastase strain K showed considerable stability towards numerous organic solvents such as methanol, ethanol, acetone, toluene, undecan-1 ol and n-dodecane, which typically pose a detrimental effect on enzymes; our finding provides further information to support the potential application of the enzyme in synthetic industries, particularly peptide synthesis. PMID- 20726841 TI - RNA silencing of hydrogenase(-like) genes and investigation of their physiological roles in the green alga Chlamydomonas reinhardtii. AB - The genome of the green alga Chlamydomonas reinhardtii encodes two [FeFe] hydrogenases, HydA1 and HydA2, and the hydrogenase-like protein HYD3. The unique combination of these proteins in one eukaryotic cell allows for direct comparison of their in vivo functions, which have not been established for HydA2 and HYD3. Using an artificial microRNA silencing method developed recently, the expression of HydA1, HydA2 and HYD3 was specifically down-regulated. Silencing of HydA1 resulted in 4-fold lower hydrogenase protein and activity under anaerobic conditions. In contrast, silencing of HydA2 or HYD3 did not affect hydrogen production. Cell lines with strongly (>90%) decreased HYD3 transcript levels grew more slowly than wild-type. The activity of aldehyde oxidase, a cytosolic Fe-S enzyme, was decreased in HYD3-knockdown lines, whereas Fe-S dependent activities in the chloroplast and mitochondria were unaffected. In addition, the HYD3 knockdown lines grew poorly on hypoxanthine, indicating impaired function of xanthine dehydrogenase, another cytosolic Fe-S enzyme. The expression levels of selected genes in response to hypoxia were unaltered upon HYD3 silencing. Together, our results clearly distinguish the cellular roles of HydA1 and HYD3, and indicate that HYD3, like its yeast and human homologues, has an evolutionary conserved role in the biogenesis or maintenance of cytosolic Fe-S proteins. PMID- 20726842 TI - Long-term functional outcome and health status of patients with critical illness polyneuromyopathy. AB - OBJECTIVE: The aim of this study was to investigate the long-term functional outcome and health status of patients with critical illness polyneuromyopathy (CIPNM). METHOD AND SUBJECTS: One hundred and twenty-four consecutive survival intensive care unit patients admitted to a neuro-rehabilitation Unit from January 2003 to December 2007 were identified. Patients with proven CIPNM by the electromyography were prospectively followed. The Barthel and modified Rankin Scales (mRS) were administered to all patients at baseline, discharge and follow up. The SF-36 questionnaire was administered to ascertain health status. Each patient underwent an individually tailored rehabilitation therapy. RESULTS: Forty two subjects (23M, 19F, mean age 58.4 +/- 13.9) were enrolled. Of these, 30 patients were diagnosed electrophysiologically with CIP, six with critical illness myopathy (CIM) and six with a finding combination of CIP and CIM (CIP/CIM) subtype. The mean Barthel scores at baseline, discharge and follow-up were 16.7 +/- 8.6, 81.7 +/- 16.4 and 86.7 +/- 15.9 (P < 0.001) and the median mRS scores were 5 (IQR: 5-5), 3 (IQR: 0-5) and 1 (IQR: 0-5). The mean length of neuro rehabilitation stay was 76.2 +/- 28.1 days. The SF-36 questionnaire administered at follow-up (mean 31.7 +/- 15.8 months), showed significantly lower values compared to Italian normative. CONCLUSION: ICU patients with CIPNM treated in a neuro-rehabilitation setting resulted in a good functional outcome. Despite complete recovery, patients with CIPNM experienced difficulties in health status. PMID- 20726843 TI - D-dimer levels and stroke progression in patients with acute ischemic stroke and atrial fibrillation. AB - BACKGROUND: Patients with acute ischemic stroke and atrial fibrillation are at increased risk of stroke progression and recurrence. We sought to assess whether D-dimer and other markers of hemostatic activation could predict these adverse events in such patients. METHOD: Blood samples were obtained from patients included in the Heparin in Acute Embolic Stroke Trial. Stroke progression was defined as a >=3-point worsening on the Scandinavian Stroke Scale during the first 48 h after randomization. Blood samples were analyzed for D-dimer, prothrombin fragment 1 + 2, soluble fibrin monomer, and C-reactive protein. RESULTS: A total of 382 patients were included in the analyses. Levels of D-dimer and other markers of hemostatic activation were not significantly higher in patients with stroke progression than in other patients (D-dimer median values: 1025 ng/ml vs 970 ng/ml, P = 0.73). The same was true for recurrent stroke (D dimer: 720 ng/ml vs 973 ng/ml, P = 0.96), and the combined endpoint of stroke progression, recurrent stroke, and death (D-dimer: 991 ng/ml vs 970 ng/ml, P = 0.91). Multivariable analyses did not alter the results. CONCLUSION: D-dimer and other markers of hemostatic activation were not associated with stroke progression, recurrent stroke, or death in patients with acute ischemic stroke and atrial fibrillation. PMID- 20726844 TI - Current trends in stroke rehabilitation. A review with focus on brain plasticity. AB - Current understanding of brain plasticity has lead to new approaches in ischemic stroke rehabilitation. Stroke units that combine good medical and nursing care with task-oriented intense training in an environment that provides confidence, stimulation and motivation significantly improve outcome. Repetitive trans cranial magnetic stimulation (rTMS), and trans-cranial direct current stimulation (tDCS) are applied in rehabilitation of motor function. The long-term effect, optimal way of stimulation and possibly efficacy in cognitive rehabilitation need evaluation. Methods based on multisensory integration of motor, cognitive, and perceptual processes including action observation, mental training, and virtual reality are being tested. Different approaches of intensive aphasia training are described. Recent data on intensive melodic intonation therapy indicate that even patients with very severe non-fluent aphasia can regain speech through homotopic white matter tract plasticity. Music therapy is applied in motor and cognitive rehabilitation. To avoid the confounding effect of spontaneous improvement, most trials are preformed >=3 months post stroke. Randomized controlled trials starting earlier after strokes are needed. More attention should be given to stroke heterogeneity, cognitive rehabilitation, and social adjustment and to genetic differences, including the role of BDNF polymorphism in brain plasticity. PMID- 20726845 TI - Apelin stimulation of duodenal bicarbonate secretion: feeding-dependent and mediated via apelin-induced release of enteric cholecystokinin. AB - AIMS: Apelin peptides are the endogenous ligand of the G protein-coupled receptor APJ. Proposed actions include involvement in control of cardiovascular functions, appetite and body metabolism. We have investigated the effects of apelin peptides on duodenal bicarbonate secretion in vivo and the release of cholecystokinin (CCK) from acutely isolated mucosal cells and the neuroendocrine cell line STC-1. METHODS: Lewis * Dark Agouti rats had free access to water and, unless fasted overnight, free access to food. A segment of proximal duodenum was cannulated in situ in anaesthetized animals. Mucosal bicarbonate secretion was titrated (pH stat) and apelin was administered to the duodenum by close intra-arterial infusion. Total RNA was extracted from mucosal specimens, reverse transcripted to cDNA and the expression of the APJ receptor measured by quantitative real-time PCR. Apelin-induced release of CCK was measured using (1) cells prepared from proximal small intestine and (2) STC-1 cells. RESULTS: Even the lowest dose of apelin-13 (6 pmol kg-1 h-1) caused a significant rise in bicarbonate secretion. Stimulation occurred only in continuously fed animals and even a 100-fold greater dose (600 pmol kg-1 h-1) of apelin was without effect in overnight food-deprived animals. Fasting also induced an eightfold decrease in the expression of APJ receptor mRNA. Apelin induced significant release of CCK from both mucosal and STC-1 cells, and the CCK(A) receptor antagonist devazepide abolished bicarbonate secretory responses to apelin. CONCLUSION: Apelin-induced stimulation of duodenal electrolyte secretion is feeding-dependent and mediated by local mucosal release of CCK. PMID- 20726846 TI - The effects of early exercise on brain damage and recovery after focal cerebral infarction in rats. AB - AIM: Exercise can be used to enhance neuroplasticity and facilitate motor recovery after a stroke in rats. We investigated whether treadmill running could reduce brain damage and enhance the expression of midkine (MK) and nerve growth factor (NGF), increase angiogenesis and decrease the expression of caspase-3. METHODS: Seventy-seven Wistar rats were split into three experimental groups (ischaemia-control: 36, ischaemia-exercise: 36, sham-exercise: 5). Stroke was induced by 90-min left middle cerebral artery occlusion using an intraluminal filament. Beginning on the following day, the rats were made to run on a treadmill for 20 min once a day for a maximum of 28 consecutive days. Functional recovery after ischaemia was assessed using the beamwalking test and a neurological evaluation scale in all rats. Infarct volume, and the expression of MK, NGF, anti-platelet-endothelial cell adhesion molecule (PECAM-1), and caspase 3 were evaluated at 1, 3, 5, 7, 14 and 28 days after the induction of ischaemia. RESULTS: Over time motor coordination and neurological deficits improved more in the exercised group than in the non-exercised group. The infarct volume in the exercised group (12.4 +/- 0.8%) subjected to treadmill running for 28 days was significantly decreased compared with that in the control group (19.8 +/- 4.2%, P < 0.01). The cellular expression levels of MK, NGF and PECAM-1 were significantly increased while that of caspase-3 was decreased in the peri-infarct area of the exercised rats. CONCLUSIONS: Our findings show that treadmill exercise improves motor behaviour and reduces neurological deficits and infarct volume, suggesting that it may aid recovery from central nervous system injury. PMID- 20726847 TI - Improved glucose tolerance after intensive life style intervention occurs without changes in muscle ceramide or triacylglycerol in morbidly obese subjects. AB - AIM: This study investigated the effect of a 15-week life style intervention (hypocaloric diet and regular exercise) on glucose tolerance, skeletal muscle lipids and muscle metabolic adaptations in 14 female and 9 male morbidly obese subjects (age: 32.5+/-2.3 years, body mass index: 46.1+/-1.9 kg m(-2) ). METHOD: Before and after the life style intervention, an oral glucose tolerance test was performed and a muscle biopsy was obtained in the fasted state. Maximal oxygen uptake was measured by an indirect test. RESULTS: After the intervention, body weight was decreased (P<0.05) by 11+/-1%, maximal oxygen uptake increased (P<0.05) by 18+/-5% and glucose tolerance increased (P<0.05) by 12+/-3%. Muscle glycogen was significantly increased by 47+/-14%, but muscle ceramide and triacylglycerol content remained completely unchanged. No sex difference was observed for any of these parameters, but during submaximal exercise a marked decrease (P<0.05) of 15+/-2% in respiratory exchange ratio was seen only in females indicating an enhanced fat oxidation. CONCLUSION: Despite a marked weight loss and an improved aerobic capacity muscle ceramide and triacylglycerol remained unchanged after intensive life style intervention, and muscle lipids hence do not seem to play a major role for the improved glucose tolerance in these morbidly obese subjects. Interestingly, only the females improved fat oxidation during submaximal exercise after the intervention implying the presence of a sex-dependent response to intensive life style adaptation. PMID- 20726848 TI - Detecting activation of the sympatho-adrenal axis from haemodynamic recordings, in conscious rabbits exposed to acute stress. AB - AIMS: When assessing sympathetic activation in acute stress, the attention is often limited to the sympatho-neural axis, whereas sympatho-adrenal activation, that can only be detected with poor time resolution from the concentration of plasma catecholamines, is often neglected. This study is aimed at re investigating the role and the relevance of the sympatho-adrenal system in acute stress based on the analysis of haemodynamic responses in conscious rabbits. METHODS: Experiments were carried out on 19 rabbits implanted with chronic probes for arterial blood pressure and for blood flow in the facial artery. Cardiovascular responses to a randomized sequence of acute stressors (pinprick, air jet, oscillation of the cage, inhalation of formaldehyde vapours and im injection of hypertonic saline) were recorded before and after alpha-adrenergic blockade (phentolamine) and unilateral section of the cervical sympathetic trunk (decentralization). Plasma catecholamine concentrations were analysed in four animals. RESULTS: All stressors induced an increase in arterial blood pressure and a reduction of vascular conductance in the facial artery ranging on average from 24% (pinprick) to 55% (box oscillation). Such vasoconstrictor response was abolished by phentolamine. In decentralized arteries, the vasoconstriction was delayed by 10-15 s and decreased in magnitude in a stressor-dependent way, indicating an adrenaline-mediated effect in the late phase of the stress response that was confirmed by changes in plasma adrenaline concentration. CONCLUSIONS: In conscious rabbits, rapid release of adrenaline makes a prominent contribution to vasoconstriction in response to different stressors including box oscillation, muscle pain and air jet but not the nasopharyngeal stimulation. PMID- 20726849 TI - Follow-up of adolescents born extremely preterm: self-perceived mental health, social and relational outcomes. AB - AIM: The aim of this study was to investigate whether adolescents born extremely preterm differ from full-term born regarding mental health, social support and attachment style. METHODS: Fifty-one young adults born before the 29th gestational week and 54 born at term were investigated by self-reports. Psychological health was measured by the Beck Youth Inventories of Emotional and Social Impairment, social support with the Interview Schedule of Social Interaction and attachment style with the Relationship Questionnaire. RESULTS: No difference was noted regarding mental health. The preterm group described themselves as having less social interaction (p <= 0.001), but no difference was obtained regarding satisfaction with this circumstance. The prematurely born judged a preoccupied attachment style, concordant with a model of a negative self and positive other, to be applicable more often than the controls (p = 0.02). CONCLUSION: Extremely preterm born adolescents did not experience more problems regarding mental health compared to controls. Nevertheless, they reported less social interaction and, to a greater extent, a negative model of self. PMID- 20726850 TI - High frequency ventilation: constraints of a slowly ticking clock. PMID- 20726851 TI - Vitamin-C supplementation and coeliac disease. PMID- 20726852 TI - Propranolol for infantile haemangiomas and neuroglycopenic seizures. PMID- 20726853 TI - Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in mice. AB - Although AIMP3/p18 is normally associated with the macromolecular tRNA synthetase complex, recent reports have revealed a new role of AIMP3 in tumor suppression. In this study, we generated a transgenic mouse that overexpresses AIMP3 and characterized the associated phenotype in vivo and in vitro. Surprisingly, the AIMP3 transgenic mouse exhibited a progeroid phenotype, and the cells that overexpressed AIMP3 showed accelerated senescence and defects in nuclear morphology. We found that overexpression of AIMP3 resulted in proteasome dependent degradation of mature lamin A, but not of lamin C, prelamin A, or progerin. The resulting imbalance in the protein levels of lamin A isoforms, namely altered stoichiometry of prelamin A and progerin to lamin A, appeared to be responsible for a phenotype that resembled progeria. An increase in the level of endogenous AIMP3 has been observed in aged human tissues and cells. The findings in this report suggest that AIMP3 is a specific regulator of mature lamin A and imply that enhanced expression of AIMP3 might be a factor driving cellular and/or organismal aging. PMID- 20726855 TI - Transcriptome analysis to identify differential gene expression affecting meat quality in heavy Italian pigs. AB - Suppressive subtractive hybridization (SSH) was used to analyse the muscle transcriptome and identify genes affecting meat quality within an Italian pig population of Large White and Landrace purebred individuals. Seven phenotypes were recorded at slaughter: dorsal fat thickness, ham fat thickness, ham fat coverage, muscle compactness, marbling, meat colour and colour uniformity. Two subtractive libraries were created from longissimus dorsi tissue of selected pigs with extreme phenotypes for meat quality. Eighty-four differentially expressed ESTs were identified, which showed homology to expressed pig sequences and/or to genomic pig sequences produced within the pig genome project. Sixty-eight sequences were mapped on the pig genome, and most of these sequences co-localized with the same chromosomal positions as QTLs that have been previously identified for meat quality. Thirty sequences, including eight matching known genes previously related to muscle metabolic pathways, were selected to statistically validate their differential expression. Association analysis and t-test results indicated that 28 ESTs of the 30 analysed were associated with phenotypes investigated here and have significant differential expression levels (P<= 0.05) between the two tails of the phenotypic distribution. PMID- 20726854 TI - Inhibition of apoptosis by progesterone in cardiomyocytes. AB - While gender-based differences in heart disease have raised the possibility that estrogen (ES) or progesterone (PG) may have cardioprotective effects, recent controversy regarding hormone replacement therapy has questioned the cardiac effects of these steroids. Using cardiomyocytes, we tested whether ES or PG has protective effects at the cellular level. We found that PG but not ES protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox). PG inhibited apoptosis in a dose-dependent manner, by 12 +/- 4.0% at 1 MUm and 60 +/ 1.0% at 10 MUm. The anti-apoptotic effect of PG was also time dependent, causing 18 +/- 5% or 62 + 2% decrease in caspase-3 activity within 1 h or 72 h of pretreatment. While PG causes nuclear translocation of its receptor within 20 min, the cytoprotective effect of PG was canceled by mifepristone (MF), a PG receptor antagonist. Analyses using Affymetrix high-density oligonucleotide array and RT-PCR found that PG induced Bcl-xL, metallothionine, NADPH quinone oxidoreductase 1, glutathione peroxidase-3, and four isoforms of glutathione S transferase. Western blot analyses revealed that PG indeed induced an elevation of Bcl-xL protein in a dose- and time-dependent manner. Nuclear run-on assay indicated that PG induced Bcl-xL gene transcription. Inhibiting the expression of Bcl-xL using siRNA reduced the cytoprotective effect of PG. Our data suggests that PG induces a cytoprotective effect in cardiomyocytes in association with induction of Bcl-xL gene. PMID- 20726856 TI - Spliceostatin A blocks angiogenesis by inhibiting global gene expression including VEGF. AB - Spliceostatin A (SSA) is a methylated derivative of an antitumor natural product FR901464, which specifically binds and inhibits the SF3b spliceosome sub-complex. To investigate the selective antitumor activity of SSA, we focused on the regulation of vascular endothelial growth factor (VEGF) mRNA, since VEGF is a key regulatory component in tumor angiogenesis and known for the intricate regulation of mRNA processing, such as alternative splicing. We found that in HeLa cells SSA reduced the amount of both mRNA and protein of VEGF. Spliceostatin A not only inhibited the splicing reaction of VEGF pre-mRNA but also reduced the total amount of VEGF's transcripts, while SSA affected GAPDH mRNA to a lesser extent. Given a significant reduction in VEGF gene expression, SSA was expected to possess anti-angiogenic activity in vivo. Indeed, SSA inhibited cancer cell derived angiogenesis in vivo in a chicken chorioallantoic membrane (CAM) assay. The inhibition of angiogenesis with SSA was abolished by addition of exogenous VEGF. We also performed global gene expression analyses of HeLa cells and found that the expression levels of 38% of total genes including VEGF decreased to <50% of the basal levels following 16 h of SSA treatment. These results suggest that the global interference of gene expression including VEGF in tumor cells is at least one of the mechanisms by which SSA (or FR901464) exhibits its strong antitumor activity. PMID- 20726857 TI - Neogenesis and development of the high endothelial venules that mediate lymphocyte trafficking. AB - Physiological recruitment of lymphocytes from the blood into lymph nodes and Peyer's patches is mediated by high endothelial venules (HEV), specialized blood vessels found in secondary lymphoid tissues except for the spleen. The HEV are distinguished from other types of blood vessels by their tall and plump endothelial cells, and by their expression of specific chemokines and adhesion molecules, which all contribute to the selective lymphocyte trafficking across these blood vessels. The development of HEV is ontogenically regulated, and they appear perinatally in the mouse. High endothelial venules can appear ectopically, for instance in chronically inflamed tissues. Given that HEV enable the efficient trafficking of lymphocytes into tissues, the induction of HEV at a tumor site could potentiate tumor-specific immune responses, and the artificial manipulation of HEV neogenesis might thus provide a new tool for cancer immunotherapy. However, the process of HEV development and the mechanisms by which the unique features of HEV are maintained are incompletely understood. In this review, we discuss the process of HEV neogenesis and development during ontogeny, and their molecular requirements for maintaining their unique characteristics under physiological conditions. PMID- 20726858 TI - Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer. AB - Pancreatic cancer is one of the most lethal malignancies. Epidermal growth factor receptor (EGFR), HER3, Akt, and amphiregulin have been recognized as targets for pancreatic cancer therapy. Although gemcitabine + erlotinib has been the recommended chemotherapy for pancreatic cancer, the prognosis is extremely poor. The development of molecularly targeted therapies has been required for patients with pancreatic cancer. To assess the validation of amphiregulin as a target for pancreatic cancer therapy, we examined its expression in pancreatic cancer using real-time PCR analyses and ELISA. We also measured the apoptotic cell rate using TUNEL assays. In addition, alterations in signaling pathways were detected by immunoblotting analyses. Treatment with gemcitabine, which reduced the cell viability and augmented the cell apoptotic rate, activated and subsequently attenuated ERK and EGFR signals. However, gemcitabine, paclitaxel, or cisplatin treatment enhanced the Akt activation, heterodimer formation of EGFR with HER3, and secretion of amphiregulin, indicating that the presence of gemcitabine promoted the activity of targeted molecules including amphiregulin, Akt, and HER3 for pancreatic cancer therapy. Combined treatment with an inhibitor for amphiregulin and gemcitabine, paclitaxel, or cisplatin induced synergistic antitumor effects, accompanied by the suppression of Akt and ERK activation. Blockade of amphiregulin suppressed the activities of EGFR, HER3, and Akt and the expression of amphiregulin itself. According to this evidence, combination chemotherapy of conventional anticancer drugs plus an inhibitor for amphiregulin would allow us to provide more favorable clinical outcomes for patients with pancreatic cancer. PMID- 20726859 TI - The microRNA pathway and cancer. AB - MicroRNAs (miRNAs) are ~22nt long, non-coding RNAs that guide post transcriptional gene silencing of their target genes and regulate diverse biological processes including cancer. miRNAs do not act alone, but require assembly into RNA-induced silencing complex (RISC). In this review, we summarize how miRNAs are produced, assembled into RISC, and regulate target mRNAs, and discuss how the miRNA pathway is involved in cancer. PMID- 20726860 TI - Oxidative stress and airway inflammation after allergen challenge evaluated by exhaled breath condensate analysis. AB - BACKGROUND: Allergen exposure may increase airway oxidative stress, which causes lipid membrane peroxidation and an increased formation of 8-isoprostane. OBJECTIVE: The aim of the study was to investigate oxidative stress induced by allergen challenge in mild asthmatics, by measuring 8-isoprostane in exhaled breath condensate (EBC), and to examine their relationship with mediators derived from arachidonic acid. Methods 8-isoprostane, cysteinyl leukotrienes (cys-LTs) and prostaglandin E2 (PGE(2) ) concentrations in EBC were measured at baseline and after allergen challenge in 12 patients with mild allergic asthma sensitized to cat allergen. RESULTS: At 24 h after allergen challenge, compared with baseline values, EBC 8-isoprostane increased [48.64 pg/mL (44.14-53.61) vs. 21.56 pg/mL (19.92, 23.35), P<0.001], cys-LTs increased [27.37 pg/mL (24.09-31.10) vs. 13.28 pg/mL (11.32, 15.57), P<0.001] and PGE(2) decreased [18.69 pg/mL (12.26, 28.50) vs. 39.95 pg/mL (34.37, 46.43), P<0.001]. The trend of increasing 8 isoprostane after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.85, P<0.001) whereas the trend of decreasing PGE(2) after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.52, P=0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The increase in EBC 8-isoprostane observed after allergen challenge indicates that allergen exposure increases airway oxidative stress in allergic asthma. The strict correlation between cys-LTs and 8-isoprostane underlines the relationship between allergic inflammation and oxidative stress. A shift of arachidonic acid metabolism towards lipoxygenase pathway is induced by the allergen challenge. Airway oxidative stress occurs after allergen challenge even in patients with mild intermittent allergic asthma. PMID- 20726862 TI - Single-port laparoscopy for colon surgery: compliance with principles of surgical oncology. PMID- 20726863 TI - Interactive multimedia: developing a validated educational tool in open colorectal surgery. PMID- 20726864 TI - A malignant mass with benign pathology. PMID- 20726866 TI - Role of cell block preparation in Warthin's tumour. PMID- 20726867 TI - Increased diagnostic accuracy of atypical glandular cells in cervical liquid based cytology using cell blocks. AB - OBJECTIVE: The purpose of this study was to reduce the number of diagnoses of atypical glandular cells (AGC). Residual material from the cervical ThinPrep(r) samples (Hologic, Marlboruogh, MA, USA) was used for cell blocks (CB) and immunohistochemistry (IHC). METHODS: In 2007 there were 87 patients (0.12% of tests) with AGC on liquid-based cytology (LBC) in the Leiden Cytology and Pathology Laboratory (LCPL) using the Bethesda System 2001 (TBS). CB with IHC was used for 26 of these cases. The vials still containing the brush (Cervex Brush((r)) Combi) were placed in a shaker for 10 minutes to dislodge the material trapped between the bristles. The residual sampling fluid was used to prepare paraffin sections (Shandon Cytoblock((r))) stained with Papanicolaou and immunostaining. RESULTS: Four of five cases with AGC not otherwise specified (NOS) were diagnosed with CB/IHC as benign mimics (endometrium, tubal metaplasia, follicular cervicitis, microglandular hyperplasia) and one of four with AGC favour neoplasia (FN) (endocervical polyp). In one of five cases with AGC-NOS and in two of seven with AGC-FN, CIN3 was found on subsequent histological biopsy. Of six cases diagnosed as adenocarcinoma in situ (AIS) on LBC with CB/IHC the diagnosis was confirmed in four; one was adenocarcinoma and one glandular atypia. Of eight cases diagnosed as adenocarcinoma on cytology and CB/IHC, the diagnosis was confirmed in three. The other five cases were found to be one each of AIS, squamous cell carcinoma, CIN3, CIN2 with glandular atypia, and cervical endometriosis. CONCLUSIONS: By reducing the number of benign mimics of AGC, we achieved a high proportion (16/26; 61.5%) of neoplastic or preneoplastic lesions (glandular or squamous) on histological outcome potentially avoiding colposcopy. Histological biopsy verification by the gynaecologist is needed for final diagnosis of AGC-FN, AIS and adenocarcinoma. PMID- 20726868 TI - Emergency care workload units: a novel tool to compare emergency department activity. AB - INTRODUCTION: Funding bodies have traditionally used attendance figures as a way of determining the allocation of funding for resources in the EDs. Using attendance figures only might not accurately reflect the funding and resources required. The need to create an easily implemented tool to compare workload and resources required was identified. Using the Australasian Triage Scale, a tool was developed to estimate staffing requirements and resource use within each ED. This, although currently not validated, provides a promising start in finding a way to accurately determine ED workload. METHODS: Existing data on patient acuity, disposition, numbers of patients and the individual costing of each presentation was used to estimate and define the workload of an ED in emergency care workload units (ECWU). The tool is applied to six de-identified hospitals within Queensland to demonstrate its potential use for equitable budget and staffing allocation. RESULTS: The tool was applied to a selection of de identified EDs within Queensland hospitals. An increased number of ECWU is generated for a patient with a more urgent triage category reflecting a higher resource consumption and workload. DISCUSSION: Although a few studies have been completed in Canada linking workload, resource consumption and cost to triage category, this tool will need to be validated before its use can be fully appreciated. CONCLUSION: This tool provides a simple method to calculate equitable distribution of staffing and budget allocation based on workload across the different EDs within Australia. PMID- 20726869 TI - A primer for clinical researchers in the emergency department: Part II: research science and conduct. AB - Research is an important part of emergency medicine and provides the scientific underpinning for optimal patient care. Although increasing numbers of emergency physicians participate in research activities, formal research training is currently neither part of emergency physician training in Australia nor easily available for clinicians interested in clinical research. In a two-part series, which is targeted at part-time clinical researchers in the ED, we set out and explain the key elements for conducting high-quality and ethical research. Part I addressed ethical and regulatory aspects. In Part II, we describe important elements of research science, and practical elements of research conduct and administration, which form the basis for high-quality research. PMID- 20726870 TI - A primer for clinical researchers in the emergency department: part I: ethical and regulatory background. AB - Research is an important part of emergency medicine and provides the scientific underpinning for optimal patient care. Although increasing numbers of emergency physicians participate in research activities, formal research training is currently neither part of emergency physician training in Australia nor easily available for clinicians interested in clinical research. In a two-part series, which is targeted at part-time clinical researchers in the ED, we set out and explain the key elements for conducting high-quality and ethical research. In Part I, we describe important underlying ethical principles for research in humans and explain key regulatory processes and documents pertaining to good clinical research practice in Australia. The ethics of research in children as a particularly vulnerable group will also be addressed. Part II will address important elements of research science and conduct. PMID- 20726871 TI - Preparedness for short-term isolation among Queensland residents: implications for pandemic and disaster planning. AB - OBJECTIVE: Short-term isolation might occur during pandemic disease or natural disasters. We sought to measure preparedness for short-term isolation in an Australian state during pandemic (H1N1) 2009. METHODS: Data were collected as part of the Queensland Social Survey (QSS) 2009. Two questions related to preparedness for 3 days of isolation were incorporated into QSS 2009. Associations between demographic variables and preparedness were analysed using chi2, with P < 0.05 considered statistically significant. RESULTS: Most respondents (93.6%; confidence interval [CI] 92.2-94.9%) would have enough food to last 3 days, but only 53.6% (CI 50.9-56.4%) would have sufficient food and potable water if isolated for 3 days with an interruption in utility services. Subpopulations that were less likely to have sufficient food and potable water reserves for 3 days' isolation without utility services included single people, households with children under 18 years of age, people living in South-East Queensland or urban areas, those with higher levels of education and people employed in health or community service occupations. CONCLUSIONS: The majority of Queensland's population consider themselves to have sufficient food supplies to cope with isolation for a period of 3 days. Far fewer would have sufficient reserves if they were isolated for a similar period with an interruption in utility services. The lower level of preparedness among health and community service workers has implications for maintaining the continuity of health services. PMID- 20726872 TI - The effect of valproate and levetiracetam on steroidogenesis in forskolin stimulated H295R cells. AB - PURPOSE: Endocrine disruptive effects have been frequently observed in patients using antiepileptic drugs (AEDs). Two different AEDs, valproate (VPA) and levetiracetam (LEV), were tested in forskolin-stimulated human adrenal carcinoma (H295R) cells to explore their effect on steroidogenesis. VPA has a long history as an anticonvulsant and is linked with many of the endocrine disorders associated with AED use. LEV is a newer AED, and no endocrine disruptive effects have been reported in humans to date. METHODS: H295R cells, which are capable of full steroidogenesis, were stimulated with forskolin and exposed to either VPA or LEV for 48 h. Medium was collected and analyzed for hormone production. For the VPA-exposed cells, steroidogenic gene expression analysis was also conducted. RESULTS: VPA exposure resulted in a significant reduction in progesterone and estradiol (E2) production, whereas testosterone (T) levels remained unchanged. There were also significant alterations in expression level for most genes analyzed. LEV exposure resulted in a minor, but statistically significant, reduction in T and E2 production. DISCUSSION: Exposure of forskolin-stimulated H295R cells to VPA led to an increased T/E2 ratio through a significant decrease in estradiol production. Gene analysis suggested that VPA affects NR0B1 expression. NR0B1 inhibits promoters of other genes involved in steroidogenesis, and the altered expression of NR0B1 might explain the observed down-regulation in hormone production. The effects of LEV exposure on hormone secretion were not considered to be biologically significant. PMID- 20726873 TI - Continuous local intrahippocampal delivery of adenosine reduces seizure frequency in rats with spontaneous seizures. AB - PURPOSE: Despite different treatment options for patients with refractory epilepsy such as epilepsy surgery and neurostimulation, many patients still have seizures and/or drug-related cerebral and systemic side effects. Local intracerebral delivery of antiepileptic compounds may represent a novel strategy with specific advantages such as the option of higher local doses and reduced side effects. In this study we evaluate the antiepileptic effect of local delivery of adenosine in the kainic acid rat model, a validated model for temporal lobe epilepsy. METHODS: Fifteen rats, in which intraperitoneal kainic acid injection had induced spontaneous seizures, were implanted with a combination of depth electrodes and a cannula in both hippocampi. Cannulas were connected to osmotic minipumps to allow continuous hippocampal delivery. Rats were freely moving and permanently monitored by video-EEG (electroencephalography). Seizures were scored during 2 weeks of local hippocampal delivery of saline (baseline), followed by 2 weeks of local adenosine (6 mg/ml) (n = 10) or saline (n = 5) delivery (0.23 MUl/h) (treatment). In 7 of 10 adenosine-treated rats, saline was also delivered during a washout period. RESULTS: During the treatment period a mean daily seizure frequency reduction of 33% compared to the baseline rate was found in adenosine-treated rats (p < 0.01). Four rats had a seizure frequency reduction of at least 50%. Both nonconvulsive and convulsive seizures significantly decreased during the treatment period. In the saline-control group, mean daily seizure frequency increased with 35% during the treatment period. CONCLUSIONS: This study demonstrates the antiseizure effect of continuous adenosine delivery in the hippocampi in rats with spontaneous seizures. PMID- 20726874 TI - The incidence of epilepsy in a rural district of Vietnam: a community-based epidemiologic study. AB - PURPOSE: Epidemiologic studies of epilepsy from developing countries are scarce. As part of a population-based epidemiologic project in Vietnam, EPIBAVI, we studied the incidence and etiology of epilepsy in people in a representative rural region of the country. METHODS: Two identical field surveys were carried out 3 years apart (January to December 2005, and June to December 2008) in the same population of the Bavi District in Vietnam. On both occasions, close to 50,000 members of approximately 13,000 households were screened using a questionnaire for epilepsy. A clinical examination of all screened positive was performed by a neurologist to verify the epilepsy diagnosis, and all incident cases were offered EEG and a CT scan. RESULTS: In the first survey 2.8% screened positive according to the questionnaire. Of these, 19 had epilepsy onset within 1 year preceding the screening, yielding an incidence rate of 40.2 per 100,000 [95% confidence interval (CI) 22.1-58.3]. In the second survey 1.8% were screened positive, and 21 of these had epilepsy onset within 1 year preceding the screening, giving an incidence rate of 42.9 per 100,000 (95% CI 24.5-61.2). The age-adjusted incidence was 44.8 per 100,000 (95% CI 30.6-59.0). The incidence was higher in those younger than 16 years, among people with lower education, and among people with lower income. CT scan was performed in 29 cases and only two cases were found with some abnormalities. DISCUSSION: The incidence rate of epilepsy in rural Vietnam in our study was lower than in developing countries in Latin America and Africa and similar to rates in Europe and North America. PMID- 20726875 TI - Absence seizures: individual patterns revealed by EEG-fMRI. AB - PURPOSE: Absences are characterized by an abrupt onset and end of generalized 3-4 Hz spike and wave discharges (GSWs), accompanied by unresponsiveness. Although previous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) studies showed that thalamus, default mode areas, and caudate nuclei are involved in absence seizures, the contribution of these regions throughout the ictal evolution of absences remains unclear. Furthermore, animal models provide evidence that absences are initiated by a cortical focus with a secondary involvement of the thalamus. The aim of this study was to investigate dynamic changes during absences. METHODS: Seventeen absences from nine patients with absence epilepsy and classical pattern of 3-4 Hz GSWs during EEG-fMRI recording were included in the study. The absences were studied in a sliding window analysis, providing a temporal sequence of blood oxygen-level dependent (BOLD) response maps. RESULTS: Thalamic activation was found in 16 absences (94%), deactivation in default mode areas in 15 (88%), deactivation of the caudate nuclei in 10 (59%), and cortical activation in patient-specific areas in 10 (59%) of the absences. Cortical activations and deactivations in default mode areas and caudate nucleus occurred significantly earlier than thalamic responses. DISCUSSION: Like a fingerprint, patient-specific BOLD signal changes were remarkably consistent in space and time across different absences of one patient but were quite different from patient to patient, despite having similar EEG pattern and clinical semiology. Early frontal activations could support the cortical focus theory, but with an addition: This early activation is patient specific. PMID- 20726876 TI - The incidence of injuries in persons with and without epilepsy--a population based study. AB - PURPOSE: To compare the 1-year population-based incidence and types of injuries in persons with and without epilepsy. METHODS: Three administrative databases (inpatient visits, physician claims, and emergency room visits) were linked from fiscal years 1996-2003 using a provincial insurance plan registry, which captures 99% of a population of 1.4 million in a large Canadian health region. Epilepsy cases (all age groups) from fiscal year 1996-2002 were identified. Three people without epilepsy were matched to one person with epilepsy for age (+/-1 year) and sex. Injuries were defined as any of 16 types of injuries for which medical attention was sought that occurred within fiscal year 2003. RESULTS: Eight thousand eight hundred ninety subjects with epilepsy were identified and matched to 26,670 controls for age and sex. The mean age was 37.4 years (range 0.01-96.4 years), and 51.3% of subjects were male. The 1-year incidence of one or more injuries was 20.6% among persons with epilepsy and 16.1% among those without epilepsy (p < 0.001). Of the 16 types of injuries studied, 11 were higher in persons with epilepsy compared to those without epilepsy, and included fractures, crushing injuries, intracranial injuries, other types of head injuries, and multiple injuries. The difference was still significant after adjusting for age, gender, and comorbidities. DISCUSSION: The 1-year incidence of injuries in this study was greater in persons with epilepsy compared to those without epilepsy, for nearly all injury types. Injury prevention should be discussed during routine visits in persons with epilepsy. PMID- 20726877 TI - An exploratory randomized controlled trial of immediate versus delayed withdrawal of antiepileptic drugs in patients with psychogenic nonepileptic attacks (PNEAs). AB - PURPOSE: To determine whether withdrawal of antiepileptic drugs (AEDs) in patients with psychogenic nonepileptic attacks (PNEAs) improves outcome. METHODS: Randomized controlled trial of AED withdrawal in patients with PNEAs. Patients were randomized to immediate or delayed (9 months) withdrawal of AEDs. We recorded spell frequency, changes in work status, use of emergency medical services, and psychological status at baseline, 9 months, and 18 months. RESULTS: Of 193 patients screened, 38 fulfilled entry criteria, 13 declined participation, and 25 were randomized. Fourteen patients were randomized to immediate withdrawal (IW) and 11 patients to delayed withdrawal (DW). There was a significant reduction in spell frequency from baseline to 9 months in the IW group but not in the DW group (p = 0.028). There was a significantly greater reduction in use of rescue medication in the IW group compared to the DW group between baseline and 9 months (p = 0.002). Emergency health care utilization dropped to zero in both groups by the end of the study. Psychological measures reflecting internal locus of control increased significantly more in the IW group (p = 0.005). DISCUSSION: Stringent diagnostic criteria and an increasing tendency for patients to be referred before AED prescription limited the recruitment and the power of the study. Our data nonetheless provide evidence that some outcomes are improved by AED withdrawal in patients with PNEAs. PMID- 20726878 TI - The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. AB - PURPOSE: To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10. METHODS: Infants were enrolled in a randomized controlled trial or a parallel epidemiologic study. Etiological information included history, examination, and investigations. The infants were classified as proven etiology, if a neurologic disease was identified; as no identified etiology, if no neurologic disease was identified; and as not fully investigated, if a major piece of information was missing. Proven etiology was subclassified using the pediatric adaptation of ICD 10. The results were then examined to identify further methods of classification. RESULTS: Of 207 infants, 127 (61%) had proven etiology, 68 (33%) had no identified etiology, and 12 (6%) were not fully investigated. Etiologies were prenatal in 63, perinatal in 38, postnatal in 8, and 18 other. The most common etiologies were: hypoxic-ischemic encephalopathy (HIE) 21 (10%), chromosomal 16 (8%), malformations 16 (8%), stroke 16 (8%), tuberous sclerosis complex (TSC) 15 (7%), and periventricular leukomalacia or hemorrhage 11 (5%). The remaining 32 etiologies were all individually uncommon. Response to treatment is given for individual etiologies. DISCUSSION: Our method of classification allows the reporting of results by individual diseases, disease groups, or categories and is structured and clear. It avoids the use of poorly defined terms such as symptomatic and cryptogenic. It can adapt to new neurologic diseases, such as gene defects, and can be used for comparison of different groups of infants, thereby aiding meta-analysis. PMID- 20726879 TI - Familial Lennox-Gastaut syndrome in male siblings with a novel DCX mutation and anterior pachygyria. AB - Lennox-Gastaut syndrome (LGS) has numerous causes,but only rarely has familial recurrence been observed. We studied a family in which three male members had severe epilepsy and intellectual disability. The proband had seizure onset at 7 years of age with atonic, myoclonic, atypical absence, and tonic seizures with slow spike-wave on electroencephalography (EEG). One living sibling had a similar clinical pattern. One deceased sibling was known to have had seizures with intellectual disability. Neuroimaging revealed anterior predominant pachygyria. DNA sequencing of the gene doublecortin (DCX) on the X chromosome revealed a novel missense mutation in the two living affected male siblings. The occurrence of three affected male family members with proven or suspected LGS in this family was puzzling and only solved by a combination of magnetic resonance (MR) and molecular genetics evaluations. This finding provided essential information for genetic counseling. PMID- 20726880 TI - Autaptic cultures of single hippocampal granule cells of mice and rats. AB - When a single neuron is grown on a small island of glial cells, the neuron forms synapses onto itself. The so-called autaptic culture systems have proven extremely valuable in elucidating basic mechanisms of synaptic transmission, as they allow application of technical approaches that cannot be used in slice preparations. However, this method has been almost exclusively used for pyramidal cells and interneurons. In this study, we generated autaptic cultures from granule cells isolated from the dentate gyrus of rodent hippocampi. Our subsequent morphological and functional characterisation of these cells confirms that this culture model is suitable for investigating basic mechanisms of granule cell synaptic transmission. Importantly, the autosynaptic connectivity allows recordings of pure mossy fibre miniature EPSCs, which are not possible in slice preparations. Further, by fast application of hypertonic sucrose solutions it is possible to directly measure the readily releasable pool and to calculate the probability of vesicular release. PMID- 20726881 TI - Eccentric exercise induces chronic alterations in musculoskeletal nociception in the rat. AB - Eccentric muscle exercise is a common cause of acute and chronic (lasting days to weeks) musculoskeletal pain. To evaluate the mechanisms involved, we have employed a model in the rat, in which eccentric hind limb exercise produces both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to subsequent exposure to an inflammatory mediator. Eccentric exercise of the hind limb produced mechanical hyperalgesia, measured in the gastrocnemius muscle, which returned to baseline at 120 h post-exercise. When nociceptive thresholds had returned to baseline, intramuscular injection of prostaglandin E(2) (PGE(2) ) induced hyperalgesia that was unattenuated 240 h later, much longer than PGE(2) -induced hyperalgesia in unexercised rats (4 h). This marked prolongation of PGE(2) hyperalgesia induced by eccentric exercise was prevented by the spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction of chronic pain. Exercise-induced hyperalgesia and prolongation of PGE(2) hyperalgesia were inhibited by the spinal intrathecal administration of antisense for the interleukin-6 but not the tumor necrosis factor alpha type 1 receptor. These findings provide further insight into the mechanism underlying exercise-induced chronic muscle pain, and suggest novel approaches for the prevention and treatment of exercise- or work-related chronic musculoskeletal pain syndromes. PMID- 20726882 TI - Cortical cholinergic abnormalities contribute to the amnesic state induced by pyrithiamine-induced thiamine deficiency in the rat. AB - Although the key neuropathology associated with diencephalic amnesia is lesions to the thalamus and/or mammillary bodies, functional deactivation of the hippocampus and associated cortical regions also appear to contribute to the memory dysfunction. For example, there is loss of forebrain cholinergic neurons and alterations in stimulated acetylcholine (ACh) levels in the hippocampus and cortex in animal models of diencephalic amnesia associated with thiamine deficiency. In the present study, the pyrithiamine-induced thiamine deficiency rat model was used to assess the functional relationships between thalamic pathology, behavioral impairment, ACh efflux and cholinergic innervation of the hippocampus and cortex. In pyrithiamine-induced thiamine deficiency-treated rats, ACh efflux during behavioral testing was blunted to differing degrees in the hippocampus, medial frontal cortex and retrosplenial cortex. In addition, significant reductions in cholinergic fiber densities were observed in each of these regions. However, only hippocampal cholinergic fiber density correlated significantly with ACh efflux in the same region, suggesting that the reduction in cortical ACh efflux in cases of diencephalic amnesia cannot be fully explained by a loss of cholinergic fiber innervation. This notion supports the emerging theory that the functional consequences of the distal effects of lesions go beyond simple deafferentation. Specifically, some frontal cortical regions exhibit hypersensitivity to deafferentation that is only detected during behavioral and/or physiological demand. PMID- 20726884 TI - Stimulus-locked responses on human arm muscles reveal a rapid neural pathway linking visual input to arm motor output. AB - Previous studies have demonstrated that humans are sometimes capable of initiating arm movements towards visual stimuli at extremely short latencies, implying the presence of a short-latency neural pathway linking visual input to limb motor output. However, little is known about the neural mechanisms that underlie such hastened arm responses. One clue may come from recent demonstrations that the appearance of a visual target can elicit a rapid response in neck muscles that is time-locked to target appearance and functionally relevant for orienting gaze (head and eye) towards the target. Because oculomotor structures thought to contribute to 'visual responses' on neck muscles also target some arm muscles via a tecto-reticulo-spinal pathway, we hypothesized that a similar visual response would be present in arm muscles. Our results were consistent with this hypothesis as we observed the presence of rapid arm muscle activity (<100 ms latency) that was time-locked to target appearance and not movement onset. We further found that the visual response in arm muscles: (i) was present only when an immediate reach towards the target was required; (ii) had a magnitude that was predictive of reaction time; (iii) was tuned to target location in a manner appropriate for moving the arm towards the target; and (iv) was more prevalent in shoulder muscles than elbow muscles. These results provide evidence for a rapid neural pathway linking visual input to arm motor output and suggest the presence of a common neural mechanism for hastening eye, head and arm movements. PMID- 20726883 TI - Alcohol consumption enhances antiretroviral painful peripheral neuropathy by mitochondrial mechanisms. AB - A major dose-limiting side effect of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) chemotherapies, such as the nucleoside reverse transcriptase inhibitors (NRTIs), is a small-fiber painful peripheral neuropathy, mediated by its mitochondrial toxicity. Co-morbid conditions may also contribute to this dose-limiting effect of HIV/AIDS treatment. Alcohol abuse, which alone also produces painful neuropathy, is one of the most important co morbid risk factors for peripheral neuropathy in patients with HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV/AIDS patients, the mechanisms by which alcohol abuse exacerbates highly active antiretroviral therapy (HAART)-induced neuropathic pain has not been demonstrated. In this study, performed in rats, we investigated the cellular mechanism by which consumed alcohol impacts antiretroviral-induced neuropathic pain. NRTI 2',3'-dideoxycytidine (ddC; 50 mg/kg) neuropathy was mitochondrial-dependent and PKCepsilon-independent, and alcohol-induced painful neuropathy was PKCepsilon-dependent and mitochondrial-independent. At low doses, ddC (5 mg/kg) and alcohol (6.5% ethanol diet for 1 week), which alone do not affect nociception, together produce profound mechanical hyperalgesia. This hyperalgesia is mitochondrial-dependent but PKCepsilon-independent. These experiments, which provide the first model for studying the impact of co morbidity in painful neuropathy, support the clinical impression that alcohol consumption enhances HIV/AIDS therapy neuropathy, and provide evidence for a role of mitochondrial mechanisms underlying this interaction. PMID- 20726885 TI - Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex. AB - Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double-blind randomized placebo-controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long-term potentiation (LTP)-like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS-induced LTP-like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP-like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP-like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma-amino butyric acid-dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage-gated sodium channels by lamotrigine, may also depress PAS-induced LTP-like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED related adverse effects on important LTP-dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP-like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP-associated process. PMID- 20726886 TI - Src family kinases mediate the inhibition of substance P release in the rat spinal cord by MU-opioid receptors and GABA(B) receptors, but not alpha2 adrenergic receptors. AB - GABA(B) , MU-opioid and adrenergic alpha(2) receptors inhibit substance P release from primary afferent terminals in the dorsal horn. Studies in cell expression systems suggest that MU-opioid and GABA(B) receptors inhibit transmitter release from primary afferents by activating Src family kinases (SFKs), which then phosphorylate and inhibit voltage-gated calcium channels. This study investigated whether SFKs mediate the inhibition of substance P release by these three receptors. Substance P release was measured as neurokinin 1 receptor (NK1R) internalization in spinal cord slices and in vivo. In slices, NK1R internalization induced by high-frequency dorsal root stimulation was inhibited by the MU-opioid agonist DAMGO and the GABA(B) agonist baclofen. This inhibition was reversed by the SFK inhibitor PP1. NK1R internalization induced by low frequency stimulation was also inhibited by DAMGO, but PP1 did not reverse this effect. In vivo, NK1R internalization induced by noxious mechanical stimulation of the hind paw was inhibited by intrathecal DAMGO and baclofen. This inhibition was reversed by intrathecal PP1, but not by the inactive PP1 analog PP3. PP1 produced no effect by itself. The alpha(2) adrenergic agonists medetomidine and guanfacine produced a small but statistically significant inhibition of NK1R internalization induced by low-frequency dorsal root stimulation. PP1 did not reverse the inhibition by guanfacine. These results show that SFKs mediate the inhibition of substance P release by MU-opioid and GABA(B) receptors, but not by alpha(2) receptors, which is probably mediated by the binding of G protein betagamma subunits to calcium channels. PMID- 20726887 TI - Adenosine drives recycled vesicles to a slow-release pool at the mouse neuromuscular junction. AB - The effects of adenosine on neurotransmission have been widely studied by monitoring transmitter release. However, the effects of adenosine on vesicle recycling are still unknown. We used fluorescence microscopy of FM2-10-labeled synaptic vesicles in combination with intracellular recordings to examine whether adenosine regulates vesicle recycling during high-frequency stimulation at mouse neuromuscular junctions. The A(1) adenosine receptor antagonist (8-cyclopentyl 1,3-dipropylxanthine) increased the quantal content released during the first endplate potential, suggesting that vesicle exocytosis can be restricted by endogenous adenosine, which accordingly decreases the size of the recycling vesicle pool. Staining protocols designed to label specific vesicle pools that differ in their kinetics of release showed that all vesicles retrieved in the presence of 8-cyclopentyl-1,3-dipropylxanthine were recycled towards the fast release pool, favoring its loading with FM2-10 and suggesting that endogenous adenosine promotes vesicle recycling towards the slow-release pool. In accordance with this effect, exogenous applied adenosine prevented the replenishment of the fast-release vesicle pool and, thus, hindered its loading with the dye. We had found that, during high-frequency stimulation, Ca(2+) influx through L-type channels directs newly formed vesicles to a fast-release pool (Perissinotti et al., 2008). We demonstrated that adenosine did not prevent the effect of the L type blocker on transmitter release. Therefore, activation of the A(1) receptor promotes vesicle recycling towards the slow-release pool without a direct effect on the L-type channel. Further studies are necessary to elucidate the molecular mechanisms involved in the regulation of vesicle recycling by adenosine. PMID- 20726889 TI - Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) affects cognitive modalities that are known to be regulated by adult neurogenesis, such as hippocampal- and olfactory-dependent learning and memory. However, the relationship between AD-associated pathologies and alterations in adult neurogenesis has remained contentious. In the present study, we performed a detailed investigation of adult neurogenesis in the triple transgenic (3xTg) mouse model of AD, a unique model that generates both amyloid plaques and neurofibrillary tangles, the hallmark pathologies of AD. In both neurogenic niches of the brain, the hippocampal dentate gyrus and forebrain subventricular zone, we found that 3xTg mice had decreased numbers of (i) proliferating cells, (ii) early lineage neural progenitors, and (iii) neuroblasts at middle age (11months old) and old age (18months old). These decreases correlated with major reductions in the addition of new neurons to the respective target areas, the dentate granule cell layer and olfactory bulb. Within the subventricular zone niche, cytological alterations were observed that included a selective loss of subependymal cells and the development of large lipid droplets within the ependyma of 3xTg mice, indicative of metabolic changes. Temporally, there was a marked acceleration of age-related decreases in 3xTg mice, which affected multiple stages of neurogenesis and was clearly apparent prior to the development of amyloid plaques or neurofibrillary tangles. Our findings indicate that AD-associated mutations suppress neurogenesis early during disease development. This suggests that deficits in adult neurogenesis may mediate premature cognitive decline in AD. PMID- 20726888 TI - beta-Secretase-1 elevation in aged monkey and Alzheimer's disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and beta-amyloid accumulation. AB - Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly; it may be related to multiple risk factors, and is characterized pathologically by cerebral hypometabolism, paravascular beta-amyloid peptide (Abeta) plaques, neuritic dystrophy, and intra-neuronal aggregation of phosphorylated tau. To explore potential pathogenic links among some of these lesions, we examined beta-secretase-1 (BACE1) alterations relative to Abeta deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 protein and beta-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend for increased overall density among cases with greater plaque pathology. In double-labeling preparations, BACE1 IR colocalized with immunolabeling for Abeta but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra axonal and extracellular Abeta IR among virtually all neuritic plaques, ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype markers (GABAergic, glutamatergic, cholinergic, or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near to or in direct contact with blood vessels. These findings suggest that plaque formation in AD or normal aged primates relates to a multisystem axonal pathogenesis that occurs in partnership with a potential vascular or metabolic deficit. The data provide a mechanistic explanation for why senile plaques are present preferentially near the cerebral vasculature. PMID- 20726890 TI - Plasticity of hyperpolarization-activated and cyclic nucleotid-gated cation channel subunit 2 expression in the spinal dorsal horn in inflammatory pain. AB - A great deal of experimental evidence has already been accumulated that hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN) expressed by peripheral nerve fibers contribute to the initiation of nerve activities leading to pain. Complementing these findings, we have recently demonstrated that HCN subunit 2 (HCN2) channel protein is also widely expressed by axon terminals of substance P (SP)-containing peptidergic nociceptive primary afferents in laminae I-IIo of the spinal dorsal horn, and postulated that they may play a role in spinal pain processing. In the present study, we investigated how the expression of HCN2 ion channels in the spinal dorsal horn may change in inflammatory pain evoked by unilateral injection of complete Freund's adjuvant (CFA) into the hind paw of rats. We found that 3 days after CFA injection, when the nociceptive responsiveness of the inflamed hind paw had substantially increased, the numbers of HCN2-immunolabeled axon terminals were also significantly augmented in laminae I-IIo of the spinal dorsal horn ipsilateral to the site of CFA injection. The elevation of HCN2 immunoreactivity was paralleled by an increase in SP immunoreactivity. In addition, similarly to control animals, the co-localization between HCN2 and SP immunoreactivity was remarkably high, suggesting that central axon terminals of nociceptive primary afferents that increased their SP expression in response to CFA injection into the hind paw also increased their HCN2 expression. The results indicate that HCN2 ion channel mechanisms may play a role in SP-mediated spinal pain processing not only in naive animals but also in chronic inflammatory pain. PMID- 20726891 TI - Callosal contribution to ocular dominance in rat primary visual cortex. AB - Ocular dominance (OD) plasticity triggered by monocular eyelid suture is a classic paradigm for studying experience-dependent changes in neural connectivity. Recently, rodents have become the most popular model for studies of OD plasticity. It is therefore important to determine how OD is determined in the rodent primary visual cortex. In particular, cortical cells receive considerable inputs from the contralateral hemisphere via callosal axons, but the role of these connections in controlling eye preference remains controversial. Here we have examined the role of callosal connections in binocularity of the visual cortex in naive young rats. We recorded cortical responses evoked by stimulation of each eye before and after acute silencing, via stereotaxic tetrodotoxin (TTX) injection, of the lateral geniculate nucleus ipsilateral to the recording site. This protocol allowed us to isolate visual responses transmitted via the corpus callosum. Cortical binocularity was assessed by visual evoked potential (VEP) and single-unit recordings. We found that acute silencing of afferent geniculocortical input produced a very significant reduction in the contralateral to-ipsilateral (C/I) VEP ratio, and a marked shift towards the ipsilateral eye in the OD distribution of cortical cells. Analysis of absolute strength of each eye indicated a dramatic decrease in contralateral eye responses following TTX, while those of the ipsilateral eye were reduced but maintained a more evident input. We conclude that callosal connections contribute to normal OD mainly by carrying visual input from the ipsilateral eye. These data have important implications for the interpretation of OD plasticity following alterations of visual experience. PMID- 20726892 TI - Levels of DNAJB family members (HSP40) correlate with disease onset in patients with spinocerebellar ataxia type 3. AB - In polyglutamine disorders, the length of the expanded CAG repeat shows a strong inverse correlation with the age at disease onset, yet up to 50% of the variation in age of onset is determined by other additional factors. Here, we investigated whether variations in the expression of heat shock proteins (HSP) are related to differences in the age of onset in patients with spinocerebellar ataxia (SCA)3. Hereto, we analysed the protein expression levels of HSPA1A (HSP70), HSPA8 (HSC70), DNAJB (HSP40) and HSPB1 (HSP27) in fibroblasts from patients and healthy controls. HSPB1 levels were significantly upregulated in fibroblasts from patients with SCA3, but without relation to age of onset. Exclusively for expression of DNAJB family members, a correlation was found with the age of onset independent of the length of the CAG repeat expansion. This indicates that DNAJB members might be contributors to the variation in age of onset and underlines the possible use of DNAJB proteins as therapeutic targets. PMID- 20726893 TI - Induction of inflammatory reactions by lipopolysaccharide in hamster sebaceous glands and pilosebaceous units in vivo and in vitro. AB - Lipopolysaccharide (LPS) from Gram-negative bacteria has been reported to exert inflammatory reactions in epidermis, dermis, and sebaceous glands. Here, we demonstrated that the intradermal administration of Escherichia coli-derived LPS, three times a week for 4 weeks, to hamster auricle skin did not influence sebaceous morphology or sebum accumulation in sebaceous glands but in fact induced epidermal thickness. In addition, the administration of LPS, once a day for 2 days, augmented the production of cyclooxygenase 2 (COX-2) in sebaceous glands. Furthermore, LPS increased the production of prostaglandin F(2alpha) (PGF(2alpha) ) in hamster sebocytes. Moreover, the production of progelatinase A/promatrix metalloproteinase 2 (proMMP-2) was transcriptionally augmented by LPS and PGF(2alpha) in hamster sebocytes. Therefore, these results suggest that LPS directly increases inflammation by augmenting COX-2, PGF(2alpha) , and the PGF(2alpha) -mediated proMMP-2 production in sebaceous glands as well as epidermal inflammatory events in skin disorders including acne and folliculitis. PMID- 20726894 TI - Rapid effector function of circulating CD4+ T cells specific for immunodominant regions of the conserved serine/threonine kinase found in Streptococcus pneumoniae (StkP) in healthy adults. AB - Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. There is emerging evidence that T cells contribute to the immunity that protects humans from S. pneumoniae-associated disease. However, no T-cell epitopes have been identified as yet in this bacterium and there are no data that address the functional nature of T cells specific for pneumococcal-derived epitopes. We sought to define T-cell epitopes in the conserved serine/threonine kinase, found in S. pneumoniae (StkP) and to investigate specific interferon gamma (IFN-gamma) production resulting from such T-cell activation in healthy donors. We were able to detect the activation of T cells in response to pneumococcal whole-cell antigen or StkP-derived peptides in all 15 individuals. We found that the majority of the T-cell responses were directed against the extracellular, penicillin-binding protein and serine/threonine kinase-associated domains. We proceeded to characterize the immunodominant epitope in detail and observed HLA-DRB1(*) 1501 restriction. This is the first study that has identified T-cell responses to peptides derived from a protein from S. pneumoniae and has shown that in healthy adults, specific T cells have rapid IFN-gamma production compatible with effector cell differentiation. The use of such T-cell epitopes will aid in the future monitoring of T-cell responses to both S. pneumoniae infection and vaccination in humans. PMID- 20726895 TI - Microbiology of aquatic surface microlayers. AB - Aquatic surface microlayers are unique microbial ecosystems found at the air water interface of all open water bodies and are often referred to as the neuston. Unambiguous interpretation of the microbiology of aquatic surface microlayers relies on robust sampling, for which several methods are available. All have particular advantages and disadvantages that make them more or less suited to this task. A key feature of surface microlayers is their role in regulating air-water gas exchange, which affords them a central role in global biogeochemistry that is only now being fully appreciated. The microbial populations in surface microlayers can impact air-water gas exchange through specific biogeochemical processes mediated by particular microbial groups such as methanotrophs or through more general metabolic activity such as the balance of primary production vs. heterotrophy. There have been relatively few studies of surface microlayers that have utilized molecular ecology techniques. The emerging consensus view is that aquatic surface microlayers are aggregate-enriched biofilm environments containing complex microbial communities that are ecologically distinct from those present in the subsurface water immediately below. Future research should focus on unravelling the complex interactions between microbial diversity and the ecosystem function of surface microlayers in order to better understand the important but complex role of microorganisms in Earth system processes. PMID- 20726896 TI - Roles of multiple acyl-CoA oxidases in the routing of carbon flow towards beta oxidation and polyhydroxyalkanoate biosynthesis in Yarrowia lipolytica. AB - The oleaginous yeast Yarrowia lipolytica possesses six acyl-CoA oxidase (Aox) isoenzymes encoded by genes POX1-POX6. The respective roles of these multiple Aox isoenzymes were studied in recombinant Y. lipolytica strains that express heterologous polyhydroxyalkanoate (PHA) synthase (phaC) of Pseudomonas aeruginosa in varying POX genetic backgrounds, thus allowing assessment of the impact of specific Aox enzymes on the routing of carbon flow to beta-oxidation or to PHA biosynthesis. Analysis of PHA production yields during growth on fatty acids with different chain lengths has revealed that the POX genotype significantly affects the PHA levels, but not the monomer composition of PHA. Aox3p function was found to be responsible for 90% and 75% of the total PHA produced from either C9:0 or C13:0 fatty acid, respectively, whereas Aox5p encodes the main Aox involved in the biosynthesis of 70% of PHA from C9:0 fatty acid. Other Aoxs, such as Aox1p, Aox2p, Aox4p and Aox6p, were not found to play a significant role in PHA biosynthesis, independent of the chain length of the fatty acid used. Finally, three known models of beta-oxidation are discussed and it is shown that a 'leaky hose pipe model' of the cycle can be applied to Y. lipolytica. PMID- 20726898 TI - A fungicidal piperazine-1-carboxamidine induces mitochondrial fission-dependent apoptosis in yeast. AB - To unravel the working mechanism of the fungicidal piperazine-1-carboxamidine derivative BAR0329, we found that its intracellular accumulation in Saccharomyces cerevisiae is dependent on functional lipid rafts. Moreover, BAR0329 induced caspase-dependent apoptosis in yeast, in which the mitochondrial fission machinery consisting of Fis1 (Whi2), Dnm1 and Mdv1 is involved. Our data are consistent with a prosurvival function of Fis1 (Whi2) and a proapoptotic function of Dnm1 and Mdv1 during BAR0329-induced yeast cell death. PMID- 20726897 TI - Prion amyloid structure explains templating: how proteins can be genes. AB - The yeast and fungal prions determine heritable and infectious traits, and are thus genes composed of protein. Most prions are inactive forms of a normal protein as it forms a self-propagating filamentous beta-sheet-rich polymer structure called amyloid. Remarkably, a single prion protein sequence can form two or more faithfully inherited prion variants, in effect alleles of these genes. What protein structure explains this protein-based inheritance? Using solid-state nuclear magnetic resonance, we showed that the infectious amyloids of the prion domains of Ure2p, Sup35p and Rnq1p have an in-register parallel architecture. This structure explains how the amyloid filament ends can template the structure of a new protein as it joins the filament. The yeast prions [PSI(+)] and [URE3] are not found in wild strains, indicating that they are a disadvantage to the cell. Moreover, the prion domains of Ure2p and Sup35p have functions unrelated to prion formation, indicating that these domains are not present for the purpose of forming prions. Indeed, prion-forming ability is not conserved, even within Saccharomyces cerevisiae, suggesting that the rare formation of prions is a disease. The prion domain sequences generally vary more rapidly in evolution than does the remainder of the molecule, producing a barrier to prion transmission, perhaps selected in evolution by this protection. PMID- 20726899 TI - Low-flow hydraulic conductivity tests at wells that cross the water table. AB - Wells with screens and sand packs that cross the water table represent a challenging problem for determining hydraulic conductivity by slug testing due to sand pack drainage and resaturation. Sand pack drainage results in a multisegmented recovery curve. One must then subjectively pick a portion of the curve to analyze. Sand pack drainage also results in a change in the effective radius of the well which requires a guess at the porosity or specific yield in analyzing the test. In the study of Robbins et al. (2009), a method was introduced to obtain hydraulic conductivity in monitoring wells using the steady state drawdown and flow rate obtained during low-flow sampling. The method was tested in this study in wells whose screens cross the water table and shown to avoid sand pack drainage problems that complicate analyzing slug tests. In applying the method to low-flow sampling, only a single pair of steady-state flow rate and drawdown are needed; hence, to derive meaningful results, an accurate determination of these parameters is required. PMID- 20726900 TI - An experimental and theoretical approach to determining linkages between geochemical variability and microbial biodiversity in seafloor hydrothermal chimneys. AB - New experimental results of fluid-mineral reactions at hydrothermal conditions relevant to life demonstrate that key redox reactions involving iron, sulfur, and hydrogen remain at disequilibrium at 100 degrees C, even in a heterogeneous system and thus are energetically favorable for microbial metabolism. Predictions from geochemical models utilizing the experimental results and specific to two contrasting case studies from the East Pacific Rise were statistically characterized and correlated to the energetics of redox reactions available for intra-chimney microbial populations. In general, predictions of available energy for autotrophic metabolism are largely similar between the mature and the nascent chimneys, although important differences still exist. Metabolic processes predicted by energetics exhibit the same trends observed in the field data for the mature chimney, but overestimate the diversity observed in the nascent chimney. Several combinations of redox reaction pairs are predicted to support mixed consortia, while some combinations appear to favor more versatile microbes capable of utilizing several reactions under rapidly changing environmental conditions within chimney walls. In addition, conditions favorable to elemental sulfur reduction and methanogenesis exhibit a negative control on the diversity of microbial populations within these chimney walls, whereas H2S oxidation, elemental sulfur oxidation and the knallgas reaction are positively correlated with both abundance and diversity of micro-organisms. Coupling field observations of both microbial diversity and geochemical heterogeneity with lab-based experimental and theoretical modeling can facilitate translation of the observed genetic diversity into physiological diversity, thus enhancing understanding of linked phenomena of microbially induced biogeochemical transformations in complex heterogeneous systems. PMID- 20726901 TI - Microbial colonization of Ca-sulfate crusts in the hyperarid core of the Atacama Desert: implications for the search for life on Mars. AB - The scarcity of liquid water in the hyperarid core of the Atacama Desert makes this region one of the most challenging environments for life on Earth. The low numbers of microbial cells in the soils suggest that within the Atacama Desert lies the dry limit for life on our planet. Here, we show that the Ca-sulfate crusts of this hyperarid core are the habitats of lithobiontic micro-organisms. This microporous, translucent substrate is colonized by epilithic lichens, as well as endolithic free-living algae, fungal hyphae, cyanobacteria and non photosynthetic bacteria. We also report a novel type of endolithic community, "hypoendoliths", colonizing the undermost layer of the crusts. The colonization of gypsum crusts within the hyperarid core appears to be controlled by the moisture regime. Our data shows that the threshold for colonization is crossed within the dry core, with abundant colonization in gypsum crusts at one study site, while crusts at a drier site are virtually devoid of life. We show that the cumulative time in 1 year of relative humidity (RH) above 60% is the best parameter to explain the difference in colonization between both sites. This is supported by controlled humidity experiments, where we show that colonies of endolithic cyanobacteria in the Ca-sulfate crust undergo imbibition process at RH >60%. Assuming that life once arose on Mars, it is conceivable that Martian micro organisms sought refuge in similar isolated evaporite microenvironments during their last struggle for life as their planet turned arid. PMID- 20726903 TI - A decade of the sperm-washing programme: correlation between markers of HIV and seminal parameters. AB - OBJECTIVES: The aim of the study was to use a decade of experience of sperm washing to assess the effect of HIV disease on semen parameters and to highlight the continuing importance of risk reduction when some controversially advocate the safety of timed unprotected intercourse for conception in the 'stable' HIV positive man. METHODS: Semen parameters of 439 fresh samples used for sperm washing/intrauterine insemination (IUI) were correlated against markers of HIV disease [CD4 cell count, viral load (VL), duration of HIV infection and use of antiretroviral therapy] and the risk of detectable virus in semen was assessed. RESULTS: A significant positive correlation was observed between CD4 cell count and total sperm count, progressive motility, post-preparation/insemination concentration, progressive motility and total motile count inseminated (TMCI), and a significant negative correlation was observed between CD4 cell count and normal sperm morphology (Spearman's correlation; P<0.05). There was no significant difference in any parameter between samples in which VL was detectable and those in which it was undetectable. The use of highly active antiretroviral therapy (HAART) significantly decreased total sperm count, progressive motility, post-preparation count and TMCI and significantly increased proportion of abnormal forms (Mann-Whitney tests; P<0.05). There was a significant negative correlation between duration of HAART use and concentration, total sperm count and post-preparation motility and between years since diagnosis and post-preparation motility. In 9.7% of IUI cycles performed with fresh sperm in men on HAART with undetectable VL, detectable HIV was found in either pre- or post-wash seminal samples. CONCLUSION: Our data suggest a negative effect of low CD4 cell count and the use of HAART on semen. The significant proportion of 'stable'; men with undetectable serum VL but virus in semen confirms the continued importance of such risk reduction. PMID- 20726902 TI - Antiretroviral therapy during pregnancy and premature birth: analysis of Swiss data. AB - BACKGROUND: There is an ongoing debate as to whether combined antiretroviral treatment (cART) during pregnancy is an independent risk factor for prematurity in HIV-1-infected women. OBJECTIVE: The aim of the study was to examine (1) crude effects of different ART regimens on prematurity, (2) the association between duration of cART and duration of pregnancy, and (3) the role of possibly confounding risk factors for prematurity. METHOD: We analysed data from 1180 pregnancies prospectively collected by the Swiss Mother and Child HIV Cohort Study (MoCHiV) and the Swiss HIV Cohort Study (SHCS). RESULTS: Odds ratios for prematurity in women receiving mono/dual therapy and cART were 1.8 [95% confidence interval (CI) 0.85-3.6] and 2.5 (95% CI 1.4-4.3) compared with women not receiving ART during pregnancy (P=0.004). In a subgroup of 365 pregnancies with comprehensive information on maternal clinical, demographic and lifestyle characteristics, there was no indication that maternal viral load, age, ethnicity or history of injecting drug use affected prematurity rates associated with the use of cART. Duration of cART before delivery was also not associated with duration of pregnancy. CONCLUSION: Our study indicates that confounding by maternal risk factors or duration of cART exposure is not a likely explanation for the effects of ART on prematurity in HIV-1-infected women. PMID- 20726905 TI - HIV and risk of venous thromboembolism: a Danish nationwide population-based cohort study. AB - OBJECTIVE: The association between HIV infection and the risk of venous thromboembolism (VTE) is controversial. We examined the risk of VTE in HIV infected individuals compared with the general population and estimated the impact of low CD4 cell count, highly active antiretroviral therapy (HAART) and injecting drug use (IDU). METHODS: We identified 4333 Danish HIV-infected patients from the Danish HIV Cohort Study and a population-based age- and gender matched comparison cohort of 43,330 individuals. VTE diagnoses were extracted from the Danish National Hospital Registry. Cumulative incidence curves were constructed for time to first VTE. Incidence rate ratios (IRRs) and impact of low CD4 cell count and HAART were estimated by Cox regression analyses. Analyses were stratified by IDU, adjusted for comorbidity and disaggregated by overall, provoked and unprovoked VTE. RESULTS: The 5-year risk of VTE was 8.0% [95% confidence interval (CI) 5.78-10.74%] in IDU HIV-infected patients, 1.5% (95% CI 1.14-1.95%) in non-IDU HIV-infected patients and 0.3% (95% CI 0.29-0.41%) in the population comparison cohort. In non-IDU HIV-infected patients, adjusted IRRs for unprovoked and provoked VTE were 3.42 (95% CI 2.58-4.54) and 5.51 (95% CI 3.29 9.23), respectively, compared with the population comparison cohort. In IDU HIV infected patients, the adjusted IRRs were 12.66 (95% CI 6.03-26.59) for unprovoked VTE and 9.38 (95% CI 1.61-54.50) for provoked VTE. Low CD4 cell count had a minor impact on these risk estimates, while HAART increased the overall risk (IRR 1.93; 95% CI 1.00-3.72). CONCLUSION: HIV-infected patients are at increased risk of VTE, especially in the IDU population. HAART and possibly low CD4 cell count further increase the risk. PMID- 20726906 TI - Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy. AB - OBJECTIVES: The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV-infected pregnant women receiving lopinavir/ritonavir (LPV/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum. METHODS: Women were enrolled in the study who were receiving the LPV/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C(trough) ) were compared independently [using analysis of variance (anova)] and on a longitudinal basis (using a paired t-test). RESULTS: Forty-six women were enrolled in the study (38 Black African). Forty women initiated LPV/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15-36) weeks and median (range) baseline CD4 count and viral load were 346 (14-836) cells/MUL and 8724 (<50-267408) HIV-1 RNA copies/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild-type virus (MEC; 1000 ng/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first/second [3525 (2823-4227) ng/mL; n=16] and third [3346 (2813-3880) ng/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693 6579) ng/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851-4463) ng/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV/r tablet is appropriate during pregnancy. However, reduced LPV concentrations in the second/third trimesters and potentially compromised adherence highlight the need for TDM-guided dose adjustment in certain cases. PMID- 20726904 TI - Favourable evolution of virological and immunological profiles in treated and untreated patients in Italy in the period 1998-2008. AB - BACKGROUND: This study provides an estimate of the proportion of HIV-positive patients in Italian clinics showing an 'adverse prognosis' (defined as a CD4 count <= 200 cells/MUL or an HIV RNA >50 HIV-1 RNA copies/mL) over time, and investigates whether this proportion varied according to patients' characteristics. METHODS: We estimated the annual proportion of patients with a CD4 count <= 200 cells/MUL or HIV RNA > 50 copies/mL out of the total number of patients in the Icona Foundation cohort seen in any given year, both overall and after stratifying by demographical and treatment status groups. Generalized estimating equation models for Poisson regression were applied. RESULTS: In 1998 2008, the prevalence of patients with a CD4 count <= 200 cells/MUL decreased from 14 to 6% [adjusted relative risk (RR) 0.86/year; 95% confidence interval (CI) 0.84-0.88; P<0.0001]. The prevalence of HIV RNA > 50 copies/mL decreased from 66 to 40% (adjusted RR 0.95/year; 95% CI 0.95-0.96; P<0.0001) in all patients and from 38 to 12% in the subgroup of patients who had previously received antiretroviral therapy (ART) for >= 6 months (adjusted RR 0.89/year; 95% CI 0.88 0.90; P<0.0001). CONCLUSIONS: There was a substantial increase in the success rate of ART in Italy in 1998-2008, resulting in a lower percentage of patients with adverse prognosis in recent years. The use of ART seemed to be the most important determinant of viral load outcome, regardless of mode of transmission. Although injecting drug users showed a less marked improvement in CD4 cell count over time than other risk groups, they showed a similar improvement in detectable viral load. PMID- 20726907 TI - Feeding-based RNA interference of a trehalose phosphate synthase gene in the brown planthopper, Nilaparvata lugens. AB - The brown planthopper, Nilaparvata lugens, is the most devastating rice insect pest to have given rise to an outbreak in recent years. RNA interference (RNAi) is a technological breakthrough that has been developed as a powerful tool for studying gene function and for the highly targeted control of insect pests. Here, we examined the effects of using a feeding-based RNAi technique to target the gene trehalose phosphate synthase (TPS) in N. lugens. The full-length cDNA of N. lugens TPS (NlTPS) is 3235 bp and has an open reading frame of 2424 bp, encoding a protein of 807 amino acids. NlTPS was expressed in the fat body, midgut and ovary. Quantitative real-time PCR (qRT-PCR) analysis revealed that NlTPS mRNA is expressed continuously with little change during the life of the insect. Efficient silencing of the TPS gene through double-stranded RNA (dsRNA) feeding led to rapid and significant reduction levels of TPS mRNA and enzymatic activity. Additionally, the development of N. lugens larvae that had been fed with the dsRNA was disturbed, resulting in lethality, and the cumulative survival rates dropped to 75.56, 64.44, 55.56 and 40.00% after continuous ingestion of 0.5 ug/ul dsRNA for 2, 4, 7 and 10 days, respectively. These values were significantly lower than those of the insects in the control group, suggesting that NlTPS dsRNA may be useful as a means of insect pest control. PMID- 20726908 TI - Expressional and functional analysis of the male-specific cluster mst36F during Drosophila spermatogenesis. AB - mst36Fa and mst36Fb are two male-specific genes that are part of a novel gene family recently characterized in Drosophila melanogaster. The genes are strictly clustered and show an identical tissue and temporal expression pattern limited to the male germline. Here we demonstrate that the transcription of these two genes, which is triggered by different cis regulatory elements, responds to the same testisspecific factors encoded by the aly and can class meiotic arrest genes. RNA interference was used to decrease expression of these two genes. We obtained a reduction of fertility in the transgenic adult males compared to the wild type. These data suggest that the Mst36Fa and Mst36Fb proteins may have an important role in the production of functional sperm. PMID- 20726909 TI - Effect of retained fractured instruments on tooth resistance to vertical fracture with or without attempt at removal. AB - AIMS: To investigate the effect of retained fractured endodontic instruments on root strength and to evaluate the effectiveness of several root filling materials in reinforcing roots that had undergone unsuccessful attempt at removal of fractured instruments. METHODOLOGY: Seventy five mandibular premolar roots were divided into five groups. In group A (control), canals were prepared to a size F5 ProTaper instrument and filled with gutta-percha and TubliSeal sealer fragments. In the experimental groups (B, C, D and E), 4 mm of F5-ProTaper instruments were fractured in the apical one-third of the canal and then treated as follows: in group B, the fragments were left in situ without attempt at removal, and canals were filled with gutta-percha and TubliSeal sealer (GP No Removal). In groups C, D and E, an attempt at removal of the fragment was simulated by preparing a staging platform coronal to the fragment using modified Gates Glidden burs (No 2 5). Canals in group C were filled with gutta-percha and TubliSeal sealer (GP Removal), group D filled with Resilon (Resilon Removal) and group E with mineral trioxide aggregate (MTA Removal). Roots then underwent vertical fracture. Data were analysed using the one-way anova at P<0.05. RESULTS: Roots in the GP Removal group had significantly lower values for mean force for fracture (404.9 N). There was no significant difference between the control group and GP No Removal (765.2 and 707.8, respectively). Resilon Removal and MTA Removal groups (577.3 and 566.6 N) were not significantly different from the GP No Removal group. CONCLUSIONS: Leaving fractured instruments in the apical one-third of the canal does not appear to affect the resistance of the root to vertical fracture; Resilon and MTA appear to compensate for root dentine loss that occurred as a consequence of attempts at retrieval of fractured instruments when used as canal filling materials. PMID- 20726910 TI - Canal and isthmus debridement efficacies of two irrigant agitation techniques in a closed system. AB - AIM: To compare canal and isthmus debris debridement efficacies of the manual dynamic irrigation (MDI) and apical negative pressure (ANP) techniques in the mesial root of mandibular first molars with narrow isthmi, using a closed canal design. METHODOLOGY: Micro-computed tomography was employed to select 20 teeth, each containing a narrow isthmus. Each root was sealed at the apex with hot glue and embedded in polyvinylsiloxane to simulate a closed canal system. The teeth were submitted to a standardized instrumentation protocol. Final irrigation was performed with either the MDI or the ANP technique using the EndoVac system (N=10). Masson trichrome-stained sections were prepared from completely demineralized roots at 10 canal levels between 1 and 2.8mm of the anatomical apices. Areas occupied by canals and isthmus of each root and debris in the corresponding regions were digitized by the NIH Image J software and statistically analysed using two-way repeated measures anova. RESULTS: For the instrumented canals, there were no differences between the two groups (P=0.131) in the area occupied by debris at all canal levels (P=0.343). Conversely, for the isthmus, less debris was found in the ANP group (P<0.001) but no differences were seen in each group with respect to the 10 canal levels (P=0.352). CONCLUSION: Neither technique completely removed debris from the isthmus regions. However, the EndoVac system, which encompasses the ANP concept, removed considerably more debris from narrow isthmi in mandibular mesial roots. PMID- 20726911 TI - Efficacy of three different rotary files to remove gutta-percha and Resilon from root canals. AB - AIM: To evaluate the efficacy of ProTaper Retreatment files, Mtwo Retreatment files and Twisted Files for removal of gutta-percha and Resilon in straight root canals. METHODOLOGY: Ninety single root canals were instrumented and randomly allocated into 6 groups of 15 specimens each with regards to the filling material and instruments used. Group 1: gutta-percha/ProTaper; Group 2: Resilon/ProTaper; Group 3: gutta-percha/Mtwo; Group 4: Resilon/Mtwo; Group 5: gutta-percha/Twisted Files; Group 6: Resilon/Twisted Files. For all roots, the following data were recorded: procedural errors, duration of retreatment, canal wall cleanliness through optical microscope and cone beam computed tomography (CBCT). Data were statistically analysed, and the level of significance was set at P=0.05. RESULTS: No system completely removed the root filling material from root canal walls. No significant differences were observed between the rotary systems in terms of the area of filling material left within the canals (P>0.05). There were statistically significant differences between the filling materials: Resilon/Real Seal had less residual material than gutta-percha/AH plus (CBCT: P=0.01; microscope: P=0.018). Mtwo Retreatment files were more rapid when removing filling material than ProTaper Retreatment files (P=0.19) and Twisted Files (P=0.04). CONCLUSIONS: No system removed the root filling materials entirely. Mtwo Retreatment files required less time to remove root filling material than the other instruments. Resilon was removed significantly better from the canal walls than gutta-percha, irrespective of the rotary instruments used. PMID- 20726912 TI - Characterization of inflammatory cell infiltrate in human dental pulpitis. AB - INTRODUCTION: To evaluate the microscopic characteristics and densities (per mm(2) ) of tryptase(+) mast cells, CD4(+) T helper lymphocytes, CD45RO(+) memory T lymphocytes, foxp3(+) T regulatory lymphocytes, CD20(+) B lymphocytes, CD68(+) macrophages, and CD31(+) blood vessels in human dental pulpitis (n=38) and healthy pulpal tissue (n=6). METHODOLOGY: The pulps of 38 human teeth with a clinical diagnosis of irreversible pulpitis were removed by pulpectomy. The pulp tissue was immersed in 10% buffered formalin for evaluation using light microscopy. Tryptase, CD4, CD45RO, foxp3, CD20, CD68, and CD31 expressions were analysed using immunohistochemistry; other microscopic features, such as intensity of inflammatory infiltrate and collagen deposition, were evaluated using haematoxylin and eosin stain. Wilcoxon and Mann-Whitney tests were used for statistical analysis. The significance level was set at alpha=5%. RESULTS: Two microscopic patterns of pulpitis were found: group 1 (G1) (n=15) had an intense inflammatory infiltrate and mild collagen deposition; conversely, group 2 (G2) (n=23) had a scarce inflammatory infiltrate and intense collagen deposition. The numbers of CD68(+) macrophages (P=0.004) and CD20(+) B (P=0.068) lymphocytes and the density of blood vessels (P=0.002) were higher in G1 than in G2. However, a similar number of CD4(+) and CD45RO(+) T lymphocytes was found in both groups (P>0.05). When present, tryptase(+) mast cells were equally distributed in G1 and G2, whereas foxp3(+) T regulatory lymphocytes were detected in 59% and 14% of the samples of G1 and G2. Controls exhibited lower numbers of foxp3, tryptase, CD4, CD45RO, CD68 and CD20 positive cells than G1 and G2. CONCLUSIONS: Irreversible pulpitis had distinct microscopic features with important quantitative and qualitative differences in inflammatory cell infiltration. PMID- 20726913 TI - The effect of ultrasonically activated irrigation on reduction of Enterococcus faecalis in experimentally infected root canals. AB - AIM: To investigate the ability of an ultrasonically activated irrigating system to eliminate bacteria from the canal wall and dentinal tubules of extracted teeth. METHODOLOGY: One hundred and thirty roots of intact human teeth were inoculated with Enterococcus faecalis for 4 weeks. The straight roots were randomly allocated to a baseline group (n=25) or subjected to routine cleaning and shaping procedures (n=105). Two sub-groups of prepared canals were then additionally exposed either to ultrasonic irrigation with 1% sodium hypochlorite (NaOCl) for 1 min (n=35) or to 1 week of intracanal medication with calcium hydroxide [Ca(OH)(2)] (n=35). All roots were processed for light microscopy (Brown and Brenn stain) (n=28) or scanning electron microscopy (n=7). Triplicate histological sections from each of the apical, middle and coronal thirds were scored for bacterial presence using pre-defined criteria. RESULTS: Baseline bacterial penetration resulted in an average depth of tubule invasion of 151 MUm. Routine canal preparation failed to eliminate bacteria consistently from either the canal wall or within tubules. Ultrasonic irrigation and medication with Ca(OH)(2) consistently eliminated bacteria from the canal wall (P<0.001) compared with baseline and routine treatment, and more frequently from dentinal tubules than routine canal preparation alone (P<0.01). Ultrasonic irrigation was as effective in bacterial reduction as 1 week of intracanal medication with Ca(OH)(2), but neither led to complete bacterial elimination in all roots. CONCLUSIONS: Ultrasonically activated irrigation for 1 min with 1% NaOCl after canal preparation in straight root canals is potentially an effective supplementary step in microbial control. PMID- 20726914 TI - Biomechanical behaviour of a fractured maxillary incisor restored with direct composite resin only or with different post systems. AB - AIM: To compare stress distribution between a fractured maxillary central incisor restored with direct composite resin only (CR) or associated with different post materials, using finite element analysis. METHODOLOGY: A three-dimensional model of a sound maxillary central incisor and supporting structures was constructed, using data from the dental literature. Changes were made in the crown region to create a tooth with a restored crown fracture. A composite resin restoration only and restorations associated with different tapered post systems (glass fibre, carbon fibre, titanium and zirconia ceramic) were also evaluated, resulting in six experimental models. A static chewing pressure of 2.16Nmm(-2) was applied to two areas of the palatal surface of the tooth. Stress distribution was analysed under a general condition and in the structures of the models separately. RESULTS: The maximum stresses were concentrated as follows: at the cemento-enamel junction in the model with a sound maxillary central incisor, restored with CR and with a composite resin restoration associated with fibre posts; in the enamel at the post-enamel interface on the palatal surface of the model with a titanium post; and in the post of the model with zirconia ceramic post. CONCLUSIONS: None of the restorations evaluated was able to recover the stress distribution of the sound tooth. The models restored with composite resin associated with a glass or carbon fibre post had similar stress distributions to that of the model restored with CR. The different post materials were shown to have a substantial influence on stress distribution, with less stress concentration when fibre posts were used. PMID- 20726915 TI - Apical surgery of a maxillary molar creating a maxillary sinus window using ultrasonics: a clinical case. AB - AIM: To describe a method of carrying out apical surgery of a maxillary molar using ultrasonics to create a lateral sinus window into the maxillary sinus and an endoscope to enhance visibility during surgery. SUMMARY: A 37-year-old female patient presented with tenderness to percussion of the maxillary second right molar. Root canal treatment had been undertaken, and the tooth restored with a metal-ceramic crown. Radiological examination revealed an apical radiolucency in close proximity to the maxillary sinus. Apical surgery of the molar was performed through the maxillary sinus, using ultrasonics for the osteotomy, creating a window in the lateral wall of the maxillary sinus. During surgery, the lining of the sinus was exposed and elevated without perforation. The root-end was resected using a round tungsten carbide drill, and the root-end cavity was prepared with ultrasonic retrotips. Root-end filling was accomplished with MTA((r)) . An endoscope was used to examine the cut root face, the prepared cavity and the root end filling. No intraoperative or postoperative complications were observed. At the 12-month follow-up, the tooth had no clinical signs or symptoms, and the radiograph demonstrated progressing resolution of the radiolucency. KEY LEARNING POINTS: When conventional root canal retreatment cannot be performed or has failed, apical surgery may be considered, even in maxillary molars with roots in close proximity to the maxillary sinus. Ultrasonic sinus window preparation allows more control and can minimize perforation of the sinus membrane when compared with conventional rotary drilling techniques. The endoscope enhances visibility during endodontic surgery, thus improving the quality of the case. PMID- 20726916 TI - Chemical, physical and mechanical properties of a novel calcium aluminate endodontic cement. AB - AIM: To evaluate the influence of additives on several physical and chemical properties of a novel endodontic cement based on calcium aluminate in comparison with mineral trioxide aggregate (MTA). METHODOLOGY: Manipulation tests, measurements of temperature, pH, ionic conductivity, compressive strength, apparent porosity, and pore size distribution were carried out on Gray-MTA (Angelus) and calcium aluminate cement (Secar-71, Kerneos) with and without various additives: a polymeric dispersant, CaCl(2) as plasticizer, and ZnO as radiopacifier. RESULTS: The calcium aluminate cement without additives had a setting time of approximately 60min, and when combined with Li(2) CO(3) it decreased to 10min. The material also released Ca(2+) ions and alkalinized the medium. Moreover, the addition of additives (dispersant, plasticizer, and radiopacifier) improved its properties resulting in a material with a viscosity of 57mPas, enhanced handling properties, a mechanical strength of 81MPa, a porosity of 4% and pores with small diameter (0.25MUm). MTA had no temperature increase (that indicates setting) up to 400min, a mechanical strength of 34MPa, and porosity of 28% with pores 2.5MUm in diameter. CONCLUSION: The novel cement set more rapidly, had better fluidity, improved handling properties, higher mechanical strength, and reduced porosity with lower pore size compared to Gray MTA Angelus. PMID- 20726919 TI - Nomenclature for factors of the HLA system, update May 2010* PMID- 20726917 TI - Review of pulp sensibility tests. Part II: electric pulp tests and test cavities. AB - The electric pulp test (EPT) is one type of pulp sensibility test that can be used as an aid in the diagnosis of the status of the dental pulp. However, like thermal pulp sensibility tests, it does not provide any direct information about the vitality (blood supply) of the pulp or whether the pulp is necrotic. The relevant literature on pulp sensibility tests in the context of endodontics up to January 2009 was reviewed using PubMed and MEDLINE database searches. This search identified articles published between November 1964 and January 2009 in all languages. The EPT is technique sensitive, and false responses may occur. Various factors can affect the test results, and therefore it is important that dental practitioners understand the nature of these tests and how to interpret them. Test cavities have been suggested as another method for assessing the pulp status; however, the use of this technique needs careful consideration because of its invasive and irreversible nature. In addition, it is unlikely to be useful in apprehensive patients and should not be required because it provides no further information beyond what thermal and electric pulp sensibility tests provide - that is, whether the pulp is able to respond to a stimulus. A review of the literature and a discussion of the important points regarding these two tests are presented. PMID- 20726920 TI - Nomenclature for factors of the HLA system, update April 2010* PMID- 20726921 TI - Squamous cell carcinoma arising from long-standing perianal fistula. AB - Perianal fistula is a very common problem in general population. Ninety percent of perianal fistulae arise from infected anal glands, and they often give rise to perianal abscesses. Very rarely perianal fistulae and abscesses undergo malignant transformation and give rise to carcinomas, mainly adenocarcinomas. We are reporting a case of squamous cell carcinoma arising from long-standing perianal fistula and how we managed it surgically. PMID- 20726922 TI - Different but equal: the implausible assumption at the heart of neutral theory. AB - 1. The core assumption of neutral theory is that all individuals in a community have equal fitness regardless of species, and regardless of the species composition of the community. But, real communities consist of species exhibiting large trait differences; hence these differences must be subject to perfect fitness-equalizing trade-offs for neutrality to hold. 2. Here we explain that perfect equalizing trade-offs are extremely unlikely to occur in reality, because equality of fitness among species is destroyed by: (i) any deviation in the functional form of the trade-off away from the one special form that gives equal fitness; (ii) spatial or temporal variation in performance; (iii) random species differences in performance. 3. In the absence of the density-dependent processes stressed by traditional niche-based community ecology, communities featuring small amounts of (i) or (ii) rapidly lose trait variation, becoming dominated by species with similar traits, and exhibit substantially lower species richness compared to the neutral case. Communities featuring random interspecific variation in traits (iii) lose all but a few fortuitous species. 4. Thus neutrality should be viewed, a priori, as a highly improbable explanation for the long-term co-occurrence of measurably different species within ecological communities. In contrast, coexistence via niche structure and density dependence, is robust to species differences in baseline fitness, and so remains plausible. 5. We conclude that: (i) co-occurring species will typically exhibit substantial differences in baseline fitness even when (imperfect) equalizing trade-offs have been taken into account; (ii) therefore, communities must be strongly niche structured, otherwise they would lose both trait variation and species richness; (iii) nonetheless, even in strongly niche-structured communities, it is possible that the abundance of species with similar traits are at least partially free to drift. PMID- 20726923 TI - Intra-abdominal vacuum-assisted closure (VAC) after necrosectomy for acute necrotising pancreatitis: preliminary experience. AB - Infection of pancreatic necrosis, although present in less than 10% of acute pancreatitis, carries a high risk of mortality; debridment and drainage of necrosis is the treatment of choice, followed by 'open' or 'close' abdomen management. We recently introduced the use of intra-abdominal vacuum sealing after a classic necrosectomy and laparostomy. Two patients admitted to ICU for respiratory insufficiency and a diagnosis of severe acute pancreatitis developed pancreatic necrosis and were treated by necrosectomy, lesser sac marsupialisation and posterior lumbotomic opening. Both of the patients recovered from pancreatitis and a good healing of laparostomic wounds was obtained with the use of the VAC system. Most relevant advantages of this technique seem to be: the prevention of abdominal compartment syndrome, the simplified nursing of patients and the reduction of time to definitive abdominal closure. PMID- 20726924 TI - Carry-over effects as drivers of fitness differences in animals. AB - 1. Carry-over effects occur when processes in one season influence the success of an individual in the following season. This phenomenon has the potential to explain a large amount of variation in individual fitness, but so far has only been described in a limited number of species. This is largely due to difficulties associated with tracking individuals between periods of the annual cycle, but also because of a lack of research specifically designed to examine hypotheses related to carry-over effects. 2. We review the known mechanisms that drive carry-over effects, most notably macronutrient supply, and highlight the types of life histories and ecological situations where we would expect them to most often occur. We also identify a number of other potential mechanisms that require investigation, including micronutrients such as antioxidants. 3. We propose a series of experiments designed to estimate the relative contributions of extrinsic and intrinsic quality effects in the pre-breeding season, which in turn will allow an accurate estimation of the magnitude of carry-over effects. To date this has proven immensely difficult, and we hope that the experimental frameworks described here will stimulate new avenues of research vital to advancing our understanding of how carry-over effects can shape animal life histories. 4. We also explore the potential of state-dependent modelling as a tool for investigating carry-over effects, most notably for its ability to calculate optimal rates of acquisition of a multitude of resources over the course of the annual cycle, and also because it allows us to vary the strength of density-dependent relationships which can alter the magnitude of carry-over effects in either a synergistic or agonistic fashion. 5. In conclusion carry-over effects are likely to be far more widespread than currently indicated, and they are likely to be driven by a multitude of factors including both macro- and micronutrients. For this reason they could feasibly be responsible for a large amount of the observed variation in performance among individuals, and consequently warrant a wealth of new research designed specifically to decompose components of variation in fitness attributes related to processes across and within seasons. PMID- 20726925 TI - Microselection--affinity selecting antibodies against a single rare cell in a heterogeneous population. AB - Rare cells not normally present in the peripheral bloodstream, such as circulating tumour cells, have potential applications for development of non invasive methods for diagnostics or follow up. Obtaining these cells however require some means of discrimination, achievable by cell type specific antibodies. Here we have generated a microselection method allowing antibody selection, by phage display, targeting a single cell in a heterogeneous population. One K562 cell (female origin) was positioned on glass slide among millions of lymphocytes from male donor, identifying the K562 cell by FISH (XX). Several single cell selections were performed on such individual slides. The phage particles bound to the target cell is protected by a minute disc, while inactivating all remaining phage by UV-irradiation; leaving only the phage bound to the target cell viable. We hereby retrieved up to eight antibodies per single cell selection, including three highly K562 cell type specific. PMID- 20726926 TI - Redesigned community postpartum care to prevent and treat postpartum depression in women--a one-year follow-up study. AB - AIM: To investigate the effect of a redesigned follow-up care programme on prevention and treatment of postpartum depression. BACKGROUND: Postpartum depression may have negative consequences on child development, maternal health and the relationship between parents. Early identification and treatment might prevent longer-term depression. DESIGN: A quasi-experimental post-test design with non-equivalent groups. METHOD: The study population was postpartum women with a live-born child, residing in one of two municipalities in Norway. A total of 2247 women were enrolled: 1806 in the experimental municipality and 441 in the comparison municipality. Public health nurses (26) in the experimental municipality were trained to identify postpartum depression using the Edinburgh Postnatal Depression Scale and clinical assessment and to provide supportive counselling. MEASUREMENTS: The Edinburgh Postnatal Depression Scale at six weeks, three, six and 12 months postpartum and the Parenting Stress Index at 12 months postpartum. RESULTS: The redesigned postpartum care programme yielded a significant group difference in the Edinburgh Postnatal Depression Scale score at six weeks (p < 0.01), odds ratio (OR) 0.6, three months (p < 0.01), OR 0.4, six months (p < 0.01), OR 0.5 and 12 months postpartum (p < 0.01), OR 0.6. Women who had been depressed at least once during the first postpartum year reported significantly higher levels of parenting stress at 12 months. CONCLUSION: The findings of this study suggest that redesigned postpartum care comprising training of health professionals, increased focus on mental health problems and support for the parents is a useful approach to managing postpartum depression in the community. RELEVANCE TO CLINICAL PRACTICE: Public health nurses are well positioned to identify and treat depressed mothers and provide referrals when needed. A small investment in training nurses to identify and treat postpartum depression can be cost-effective in the longer term. These findings have implications for service delivery in public health. PMID- 20726927 TI - Benefits of video home training on families' health and interaction: evaluation based on follow-up visits. AB - AIM: The aim of this study is to describe the benefits of video home training on families' health and interaction from the perspective of parents six months after the training. BACKGROUND: There is hardly any empirical knowledge of how a resource-enhancing approach could be used in nursing practice and how nursing in a home context affects the families' health outcomes and interaction. DESIGN: The study was designed as a descriptive qualitative service evaluation. METHODS: Fifteen families with 66 family members participated in the study. The study material consisted of videotapes recorded at homes and family service plans produced during the process of the video home training. The data were analysed by qualitative content analysis and by the method of analysing photographs and videotapes. RESULTS: Video home training was found to bring about many positive effects on families' health and interaction. The families had reached their goals related to parenthood, relationship between the partners, childcare skills and child-rearing skills. CONCLUSION: The entire family benefited from the video home training. Video home training can be recommended in providing families with early support and anticipating and preventing family problems. RELEVANCE TO CLINICAL PRACTICE: Video home training is applicable to family nursing owing to the concrete and interactive nature of the method. It supports the realisation of family centredness and family orientation. PMID- 20726928 TI - Process of ambivalent normalisation: experience of family caregivers of elders with mild cognitive impairment in Taiwan. AB - AIMS AND OBJECTIVES: To conceptualise the caregiving process in Taiwanese families caring for elders with mild cognitive impairment. BACKGROUND: Family caregivers play an essential role in the lives of elders with mild cognitive impairment by dealing with their cognitive status and daily function. Little is known, however, about the development of the caregiving trajectory, particularly in Asian countries. DESIGN AND METHODS: Grounded theory methodology was used. Data were collected via in-depth interviews with 10 family caregivers of patients with mild cognitive impairment and living at home in northern Taiwan. Data were analysed by constant comparative analysis. RESULTS: The process most used by family caregivers to adjust to conflicts and changes in relationships with elders with mild cognitive impairment was 'ambivalent normalisation'. This dynamic process included three components: subtle changes, optimistic appraisal and ambivalent anticipation. Family caregivers who had developed this process were more likely to adopt multiple effective behavioural approaches to avoid conflict in their daily life and to begin outlining future caregiving tasks. CONCLUSIONS: The process of ambivalent normalisation can sensitise healthcare providers to family caregivers' needs and provide a basis for developing frameworks for future substantive theory and possible future research. RELEVANCE TO CLINICAL PRACTICE: This study's findings may help healthcare providers understand family caregivers' needs and effective patterns for taking care of elders with mild cognitive impairment. Interventions can be developed to facilitate family caregivers' awareness of the changes in their loved one in the initial stage of diagnosis and adopt multiple effective strategies to prevent conflicts in their lives. Healthcare providers can actively examine the cognitive function of older people in general outpatient departments, provide well-timed treatments and minimise caregiver burden. PMID- 20726929 TI - Nursing staff perceptions of the use of physical restraint in institutional care of older people in Finland. AB - AIMS AND OBJECTIVES: To describe the perceptions of nursing staff on the use of physical restraints in institutional care of older people. BACKGROUND: Physical restraint of older people is a common practice in institutional care in many countries, including Finland. As the nursing staff plays a major role in deciding on physically restraining older patient and in the care the patient receives, new research information is needed on the nursing staff's attitudes towards the use of physical restraints. DESIGN: A qualitative study. METHOD: The data consisted of focus group interviews with staff and supervisors. There were four focus groups: nurses, practical nurses, institutional assistants and care supervisors. RESULTS: In addition to traditional methods of restraint, such as belts and locked doors, the nursing staff also used indirect restraint by removing the patient's mobility aid. Factors contributing to the use of restraints included requests by the patient's family members to use restraint to ensure the patient's safety and social reasons, in the form of lack of legislation on the use of restraint. The use of restraints caused feelings of guilt among the nursing staff, but on the other hand, it was seen as a way of making older patient feel more secure. CONCLUSIONS: There is a need for official guidelines on the use of physical restraints in care of older people. This would require the entire nursing team to make a joint decision on the use of restraints and constant reassessment of the need of using restraints. RELEVANCE TO CLINICAL PRACTICE: The results of the study provide nursing staff and supervisors a chance to ethically deliberate and evaluate their own work. Alternative practices for physical restraint can also be directly applied to practical care of older people. PMID- 20726930 TI - Lupus erythematosus-like imiquimod reaction: a diagnostic pitfall. AB - Imiquimod (AldaraTM), a Toll-like receptor 7 agonist (TLR7), is known for its unique properties of being an immune response modifier and stimulator. Upon topical application, this TLR7 agonist triggers a cell-mediated immune response predominantly expressed by dendritic cells and monocytes. Local skin irritation at the application site involving erythema, pain, crusting and erosions is common and well documented. On the contrary, the specific histopathologic features associated with these treatment site reactions is not. Herein reported is a case where historical omission of imiquimod use for actinic keratosis complicated the histologic interpretation. We highlight a lupus erythematosus-like microscopic pattern and explore histopathologic features that could help in avoiding a diagnostic pitfall, as well as the relationship between TLR activation, cell mediated immunity and skin histology. PMID- 20726931 TI - Findings of osseous sclerotic bodies: a unique sequence of cutaneous bone formation in nephrogenic systemic fibrosis. AB - Nephrogenic systemic fibrosis (NSF) is a progressive and potentially fatal fibrosing skin disorder found mainly in patients with renal insufficiency. NSF is characterized by thickened and hyperpigmented skin lesions with or without systemic involvement. In essentially all patients, this disease entity has been associated with the administration of gadolinium contrast agents for imaging purposes. Microscopic recognition of this entity remains challenging, as the diagnosis is based on various clinical and histopathologic features that overlap with other fibrosing disorders. No single feature is absolutely specific for NSF. We report a finding of osseous sclerotic bodies with elastin trapping appearing on histopathology in the clinical setting of NSF with hemodialysis-dependent renal failure. Our report of an additional attribute indicative of NSF may aid in making the diagnosis. PMID- 20726932 TI - A lack of significantly increased incidence of regression in second primary melanomas does not support an 'immunization effect'. AB - OBJECTIVE: To compare the incidence of regression in first and second primary melanomas as a possible indication of an 'immunization effect'. METHODS: The first and second primary melanomas of 18 patients were studied histopathologically for signs of regression. At least 1 month elapsed between the removal of the two primary lesions. RESULTS: Histopathological evidence of regression was found in 7 of the 18 (38.8%) first melanomas and in 8 of the 18 (44.4%) second melanomas [p = non-significant (N.S.)]. Among the nine patients in whom the removal of the second primary melanoma was >6 months after the removal of the first primary melanoma, one (11%) first melanoma and three (33%) second melanomas showed regression, respectively, but this difference did not reach statistical significance. Among the nine patients in whom the removal of the second primary melanoma was <= 6 months after the removal of the first primary melanoma, six (67%) first melanoma and five (56%) second melanomas showed regression (p = N.S.). CONCLUSIONS: Our study does not provide evidence for a statistically significant increased rate of regression in second primary melanomas compared to the first primary melanomas, but larger groups of studied cases may be needed. PMID- 20726933 TI - Multicentric reticulohistiocytosis and urologic carcinomas: a possible paraneoplastic association. AB - Multicentric reticulohistiocytosis (MR) is a rare non-Langerhans histiocytosis that is characterized by cutaneous nodules and severe destructive arthritis. Although 25-30% of reported cases have been associated with internal malignancies, the pathophysiology of MR is unknown. Herein, we report two cases of MR that were associated with urologic neoplasms. Because the tumor suppressor gene p53 may play a role in the biology of other histiocytoses, we investigated its p53 immunoexpression in these two cases. Both cases were positive immunohistochemically, but it remains to be seen whether this finding is truly important in the pathogenesis of MR associated with underlying visceral neoplasms. PMID- 20726934 TI - Fas-ligand staining in non-drug- and drug-induced maculopapular rashes. AB - BACKGROUND: Morphologically and histopathologically, drug- and non-drug-induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas-ligand (Fas-L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. AIM: This study sought to determine if epidermal Fas-L is a distinguishing feature in the pathology of drug and non-drug maculopapular rashes. METHODS: Archived skin biopsies of patients with a confirmed diagnosis of drug or non-drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas-L. The proportion of Fas-L positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. RESULTS: Ten percent of non-drug-induced rashes were Fas-L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non-drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). CONCLUSION: There is a trend toward Fas-L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size. PMID- 20726935 TI - Reply: Histopathology and immunohistochemistry of depigmented lesions in lupus erythematosus. PMID- 20726936 TI - The diplomonad fish parasite Spironucleus vortens produces hydrogen. AB - The diplomonad fish parasite Spironucleus vortens causes major problems in aquaculture of ornamental fish, resulting in severe economic losses in the fish farming industry. The strain of S. vortens studied here was isolated from an angelfish and grown in Keister's modified TY-I-S33 medium. A membrane-inlet mass spectrometer was employed to monitor, in a closed system, O(2), CO(2), and H(2) When introduced into air-saturated buffer, S. vortens rapidly consumed O(2) at the average rate of 62+/-4 nmol/min/10(7) cells and CO(2) was produced at 75+/-11 nmol/min/10(7) cells. Hydrogen production began under microaerophilic conditions ([O(2)]=33.+/-15 microM) at a rate of 77+/-7 nmol/min/10(7) cells. Hydrogen production was inhibited by 62% immediately after adding 150 microM KCN to the reaction vessel, and by 50% at 0.24 microM CO, suggesting that an Fe-only hydrogenase is responsible for H(2) production. Metronidazole (1 mM) inhibited H(2) production by 50%, while CO(2) production was not affected. This suggests that metronidazole may be reduced by an enzyme of the H(2) pathway, thus competing for electrons with H(+). PMID- 20726937 TI - Awareness about possible reactivation of HBsAg-negative patients when prescribing biological therapy. PMID- 20726938 TI - Narrow band UVB: is it effective and safe for paediatric psoriasis and atopic dermatitis? AB - BACKGROUND: Phototherapy has a time-honoured place in the treatment of variety of skin diseases in adults. The use of this modality in children is limited mainly due to concerns about long-term carcinogenic potential. Only a few clinical trials have been performed on the efficacy and safety of phototherapy in children. OBJECTIVES: To determine the efficacy and safety of NB-UVB phototherapy in children with atopic dermatitis (AD) and psoriasis. METHODS: This is a retrospective review of the treatment outcomes of 129 children with psoriasis and AD, who were treated with NB-UVB between 1998 and 2006 at our institute. RESULTS: Fifty per cent of the psoriatic patients and 25% of patients with AD achieved clearance by the end of the treatment. NB-UVB phototherapy was well-tolerated, with no serious adverse effects except one doubtful case of melanoma in situ. CONCLUSIONS: NB-UVB may be considered as a viable therapeutic option in children with psoriasis and AD. Children who are treated by phototherapy should remain under annual dermatologic observation. To determine true carcinogenic risk of UV therapy, longer follow-up is essential. PMID- 20726939 TI - Histopathological studies on Vibrio harveyi- infected tiger puffer, Takifugu rubripes (Temminck et Schlegel), cultured in Japan. AB - Vibrio harveyi infection occurred with a moderate mortality in tiger puffer, Takifugu rubripes (Temminck et Schlegel), in autumn 2007, at a mariculture farm in western Japan. The diseased fish showed nodular lesions in the branchial chamber and the inner surface of the operculum. Histopathologically, the lesions comprised granulation tissue containing many suppurative foci allowing propagation of the bacteria and granuloma encapsulating abscesses with a decrease in bacteria. The bacteria were disseminated in visceral organs including the spleen, kidney, liver, and myocardium, resulting in the formation of granulomatous lesions. Two groups of tiger puffer juveniles were artificially infected by an intramuscular injection with an isolate (1.0_10(8) CFU/fish). During the experimental period, 20% mortality occurred within 4-6 days post infection (d.p.i). The fish sampled on 4 d.p.i showed abscesses in the lateral musculature at the injection site. The fish sampled 5 d.p.i. displayed the production of granulation tissue containing many suppurative foci, which replaced the necrotic dermis and lateral musculature. Surviving fish (15 d.p.i.) had granulomatous lesions in the lateral musculature at the injection site. Pyogranulomatosis is pathognomonic in V. harveyi infection of tiger puffer. PMID- 20726941 TI - Temporomandibular disorders assessment: medicolegal considerations in the evidence-based era. AB - Summary Temporomandibular disorders (TMD) are a frequent finding in cases of facial trauma or dental malpractice, and legal claims for TMD damage have been increased over the years. Temporomandibular disorders assessment in the medical legal setting is complicated by the peculiarities of these disorders, whose symptoms are heterogeneous, fluctuant, and recognise a multifactorial origin. A systematic Medline search in the National Library of Medicine's PubMed database pointed out that, despite the medical legal aspects of the dental profession are gaining a growing attention, there is a paucity of literature dealing with patients with TMD assessment. For these reasons, evidence-based knowledge in the field of TMD diagnosis and treatment was summarised in this article with the aim of providing useful suggestions for a medical legal approach to TMD. PMID- 20726942 TI - Online learning in dentistry: an overview of the future direction for dental education. AB - This paper provides an overview of the diversity of tools available for online learning and identifies the drivers of online learning and directives for future research relating to online learning in dentistry. After an introduction and definitions of online learning, this paper considers the democracy of knowledge and tools and systems that have democratized knowledge. It identifies assessment systems and the challenges of online learning. This paper also identifies the drivers for online learning, including those for instructors, administrators and leaders, technology innovators, information and communications technology personnel, global dental associations and government. A consideration of the attitudes of the stakeholders and how they might work together follows, using the example of the unique achievement of the successful collaboration between the Universities of Adelaide, Australia and Sharjah, United Arab Emirates. The importance of the interaction of educational principles and research on online learning is discussed. The paper ends with final reflections and conclusions, advocating readers to move forward in adopting online learning as a solution to the increasing worldwide shortage of clinical academics to teach dental clinicians of the future. PMID- 20726943 TI - Masticatory features, EMG activity and muscle effort of subjects with different facial patterns. AB - It has been suggested that craniofacial morphology plays an important role in masticatory function, however, there are controversies and unsolved questions that still require elucidation. The aims of this study were to evaluate masticatory performance, mandibular movement, electromyographic (EMG) activity and muscle effort of masseter and anterior temporal muscles during mastication. Seventy-eight dentate subjects were selected and divided into three groups according to vertical facial pattern: brachyfacial, mesofacial and dolichofacial. Silicon-based material was used for chewing tests. Masticatory performance was determined by a 10-sieve method, and masticatory movements during mastication were assessed using a 3D mandibular tracking device. Electromyographic activities of masseter and anterior temporal muscles were evaluated during mastication, and muscle effort was calculated by the percentage of activity required for mastication based on maximum muscle effort. Data were analysed using anova and anova on-ranks tests. Dolichofacial subjects presented significantly poorer masticatory performance (6.64+/-2.04; 4.33+/-0.70 and 3.67+/-0.63), slower rate of chewing (1.34+/-0.27, 1.18+/-0.22 and 1.21+/-0.20 cycles per second) and larger posterior displacement during mastication (6.22+/-2.18; 5.18+/-1.87 and 5.13+/-1.89) than meso- and brachyfacial individuals, respectively. No statistical difference was detected among groups for the other masticatory movement parameters. There was no difference in absolute EMG amplitudes of masseter and anterior temporal muscles during mastication among groups, but the relative effort of both muscles was higher in dolichofacial, followed by meso- and brachyfacial subjects (masseter: 39.34+/- 2.25; 36.87+/-4.05 and 33.33+/ 4.15; anterior temporal: 38.12+/-1.61; 38.20+/-8.01 and 35.75+/-2.48). It was concluded that the vertical facial pattern influences masticatory performance, mandibular movement during mastication and the effort masticatory muscles required for chewing. PMID- 20726944 TI - Comparison of patient visits to emergency departments, physician offices, and dental offices for dental problems and injuries. AB - OBJECTIVES: Our understanding of the use of emergency departments (EDs) and physician offices for the management of dental problems is limited. We undertook this study to examine whether there are differences in their use by low-income White and minority adults as compared with higher-income adults. METHODS: Participantsincluded White, Black, and Hispanic adults who had experi enced a dental problem during the previous 12 months and who visited a physician, ED, or dentist for treatment. We selected a stratified random sample of 27,002 Maryland households with listed telephones to screen for eligibility. We identified 1,387 households with an eligible adult, selected 423 for interviews, and completed interviews with 401 (94.8%). RESULTS: To restore correct proportionality to the sample, and to adjust for nonresponse and the distribution of demographic characteristics, weights were created for use in the analyses. Only 7.1 percent of respondents contacted an ED, while 14.3 percent contacted a physician and 90.2 percent a dentist. The vast majority of respondents who contacted an ED (96.0%) or a physician (92.2%) also contacted a dentist. Lower-income respondents were more likely to seek care from an ED, while higher-income respondents were more likely to seek care from a dentist. Over whelmingly, respondents visiting EDs (89.4%) and physicians (51.7%) were instructed to see a dentist or given prescriptions/samples. Treatment provided by EDs, physicians, and dentists was not associated with the respondent's income or race/ethnicity. CONCLUSIONS: Respondents visiting EDs and physicians typically did not receive definitive care and subsequently visited a dentist for treatment. PMID- 20726945 TI - Prevalence of tooth erosion and associated factors in 11-14-year-old Brazilian schoolchildren. AB - OBJECTIVE: Prevalence data about tooth erosion has attracted increasing attention in the dental community; however, population-based studies that assessed the impact of demographic, socioeconomic, and dietetic predictors on tooth erosion are scarce. This investigation assessed the prevalence of this condition of a sample of 11-14-year-old schoolchildren and the etiological factors. METHOD: A cross-sectional study in a multistage random sample of 944, 11-14-year-old Brazilian schoolchildren was conducted in Santa Maria, Brazil. We recorded the prevalence and severity of tooth erosion, dental caries, and dental enamel hypoplasia. Socioeconomic and habits/dietetic data were collected by a structured questionnaire. Data were analyzed using Poisson regression model taking into account the cluster sample. RESULTS: Prevalence of tooth erosion was low (7.2%). The most affected teeth were the maxillary incisors. Labial surfaces were more often affected than palatal ones. All the erosive lesions observed were confined to the enamel. Older children [prevalence ratio (PR) = 1.71; 95% confidence interval (CI): 1.06-2.76] with dental enamel hypoplasia (PR = 1.98; 95% CI: 1.21 3.22) were more likely to have tooth erosion. No significant association was observed between tooth erosion, dental caries, habits and dietary patterns, and socioeconomic factors. CONCLUSION: The data suggest that tooth erosion was associated with age and presence of hypoplasia. It may indicate the need of strategies to diagnose in early stages and to minimize consequences. PMID- 20726946 TI - Epidemiological study of pestiviruses in South American camelids in Switzerland. AB - BACKGROUND: In the context of the ongoing eradication campaign for bovine viral diarrhea virus (BVDV) in cattle in Switzerland, the role of South American camelids (SAC) as a possible virus reservoir needed to be evaluated. OBJECTIVE: To assess and characterize the prevalence of pestivirus infections in SAC in Switzerland. ANIMALS: Serum samples collected from 348 animals (40 herds) in 2008 and from 248 animals (39 herds) in 2000 were examined for antibodies against pestiviruses and for the presence of BVDV viral RNA. METHODS: Cross-sectional study using stratified, representative herd sampling. An indirect BVDV-ELISA was used to analyze serum samples for pestivirus antibodies, and positive samples underwent a serum neutralization test (SNT). Real-time RT-PCR to detect pestiviral RNA was carried out in all animals from herds with at least 1 seropositive animal. RESULTS: In 2008, the overall prevalence of animals positive for antibodies (ELISA) and pestiviral RNA or was 5.75 and 0%, respectively. In 2000, the corresponding prevalences were 3.63 and 0%, respectively. The seroprevalences (SNT) for BVDV, border disease virus or undetermined pestiviruses were estimated to be 0, 1.73, and 4.02% in 2008, and 0.40, 1.21, and 2.02% in 2000, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: At the present time, SAC appear to represent a negligible risk of re-infection for the BVDV eradication program in cattle in Switzerland. PMID- 20726947 TI - Characteristics of chronic hepatitis B patients who underwent liver biopsies. AB - Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10-year period were reviewed. Significant liver disease was defined as Knodell HAI >= 7 and/or Ishak fibrosis >= 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety-three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log(10) copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied. PMID- 20726948 TI - Cancer stem cells versus phenotype-switching in melanoma. AB - Tumours comprise multiple phenotypically distinct subpopulations of cells, some of which are proposed to possess stem cell-like properties, being able to self renew, seed and maintain tumours, and provide a reservoir of therapeutically resistant cells. Here, we use melanoma as a model to explore the validity of the cancer stem cell hypothesis in the light of accumulating evidence that melanoma progression may instead be driven by phenotype-switching triggered by genetic lesions that impose an increased sensitivity to changes in the tumour microenvironment. Although at any given moment cells within a tumour may exhibit differentiated, proliferative or invasive phenotypes, an ability to switch phenotypes implies that most cells will have the potential to adopt a stem cell like identity. Insights into the molecular events underpinning phenotype switching in melanoma highlight the close relationship between signalling pathways that generate, maintain and activate melanocyte stem cells as well as the inverse correlation between proliferation and invasive potentials. An understanding of phenotype-switching in melanoma, and in particular the signalling events that regulate the expression of the microphthalmia-associated transcription factor Mitf, points to new therapeutic opportunities aimed at eradicating therapeutically resistant stem cell-like melanoma cells. PMID- 20726949 TI - Sunscreen prevention of melanoma in man and mouse. PMID- 20726950 TI - Human hair melanins: what we have learned and have not learned from mouse coat color pigmentation. AB - Hair pigmentation is one of the most conspicuous phenotypes in humans. Melanocytes produce two distinct types of melanin pigment: brown to black, indolic eumelanin and yellow to reddish brown, sulfur-containing pheomelanin. Biochemically, the precursor tyrosine and the key enzyme tyrosinase and the tyrosinase-related proteins are involved in eumelanogenesis, while only the additional presence of cysteine is necessary for pheomelanogenesis. Other important proteins involved in melanogenesis include P protein, MATP protein, alpha-MSH, agouti signaling protein (ASIP), MC1R (the receptor for MSH and ASIP), and SLC7A11, a cystine transporter. Many studies have examined the effects of loss-of-function mutations of those proteins on mouse coat color pigmentation. In contrast, much less is known regarding the effects of mutations of the corresponding proteins on human hair pigmentation except for MC1R polymorphisms that lead to pheomelanogenesis. This perspective will discuss what we have/have not learned from mouse coat color pigmentation, with special emphasis on the significant roles of pH and the level of cysteine in melanosomes in controlling melanogenesis. Based on these data, a hypothesis is proposed to explain the diversity of human hair pigmentation. PMID- 20726951 TI - Of swords and ploughshares: immunosurveillance and inflammation in melanoma. PMID- 20726953 TI - Risk factors for chronic hepatitis B virus infection among blood donors in Bangalore, India. AB - OBJECTIVES AND AIM: We performed a study of hepatitis B virus (HBV) risk factors among blood donors in Bangalore, India. BACKGROUND: HBV infection is prevalent in India and poses a potential risk of transmission by blood transfusion, but studies of risk factors for hepatitis B surface antigen (HBsAg) carriage among Indian blood donors are lacking. METHODS/MATERIALS: Using a case-cohort design, we enrolled 71 cases with repeatedly reactive HBsAg results and a cohort of 212 contemporaneous blood donors with unknown HBsAg status. Questionnaire data were analysed using multivariable logistic regression. RESULTS: In our multivariate analysis controlling for age, HBsAg positivity was associated with repeat donor status (OR = 0.34, 95% CI 0.17-0.71 vs first-time donor status), residence outside Bangalore and Hosur (rural areas) (OR = 15.66, 95% CI 3.60-68.07vs Bangalore residence), having been a customer at a local barber shop (OR = 4.07, 95% CI 2.06-8.03), close contact with a person who had jaundice (OR = 13.64, 95% CI 3.71-50.24) and cigarette smoking (OR = 3.25, 95% CI 1.39-7.60). CONCLUSION: In addition to recognised demographic risk factors, associations with patronage of local barbers and contact with jaundiced individuals suggest behavioural risk factors that could be adopted as exclusionary criteria for blood donation in India. PMID- 20726954 TI - The clinical significance of occult hepatitis B transfusion in Taiwan--a look back study. AB - OBJECTIVES: A look-back study was conducted to determine the clinical significance of occult hepatitis B virus (HBV) blood transfusion in an HBV hyperendemic area. AIM: To improve the blood transfusion safety. BACKGROUND: Occult HBV is transmissible through blood transfusion in HBV-naIve recipients. However, its impact on recipients with prevalent HBV infection in HBV hyperendemic areas is unclear. METHODS/MATERIALS: In 2006, 12 occult HBV blood donors were found from 10 824 repository samples by nucleic acid testing. The 74 corresponding recipients were identified and their pre- and post-transfusion clinical information was gathered, and the living recipients were recalled for follow-up. From the available archival sera, the HBV DNA was examined and sub genomic sequences between paired donor and recipient were compared using polymerase chain reaction-based assays. RESULTS: Among the 74 recipients, 18 were still alive and 12 returned to our clinic. From the available serological profiles, 76% of recipients had ongoing or recovered HBV infection before transfusion. Only 24 recipients had available post-transfusion serological profiles and none seroconverted to be hepatitis B surface antigen (HBsAg) positive. Moreover, except for the prior HBsAg carriers, the recipients' HBV DNA levels after transfusion were low (<20 IU/mL). One recipient had identical HBV surface gene sub-genomic sequence (384 nucleotides) to his donor. After transfusion, no recipient developed post-transfusion hepatitis (PTH) and the clinical outcome was good. CONCLUSION: In HBV hyperendemic areas, occult hepatitis B transfusion might not lead to HBsAg carriage or PTH. The risk of transfusion-transmitted HBV infection was probably lower than that in non-endemic areas because most recipients had already experienced HBV infection. PMID- 20726955 TI - Routine and specialized laboratory testing for the diagnosis of neuromuscular diseases in dogs and cats. AB - The diagnosis of neuromuscular diseases can be challenging. The first step is recognition that the disease involves the neuromuscular system (muscle, neuromuscular junction, peripheral nerve, and ventral horn cells of the spinal cord). Many neuromuscular diseases share clinical signs and cannot be distinguished based on clinical examination. Routine laboratory screening, including a CBC, biochemical profile, and urinalysis, can identify some of the most common systemic abnormalities that cause muscle weakness and myalgia, such as hypo- and hyperglycemia, electrolyte disorders, or thyroid abnormalities, and may suggest a specific diagnosis, such as diabetes mellitus, hypo- or hyperadrenocorticism, renal failure, or hypothyroidism. Increased creatine kinase activity, increased cardiac troponin I concentration, and myoglobinuria are useful in detecting skeletal and cardiac muscle damage. Identification of acetylcholine receptor antibodies is diagnostic for acquired myasthenia gravis. For primary muscle or peripheral nerve diseases, tissue biopsy is the most direct way to determine specific pathology, correctly classify the disease, and determine the course of additional laboratory testing. For example, inflammatory, necrotizing, dystrophic, metabolic, or congenital myopathies require different laboratory testing procedures for further characterization. Many neuromuscular diseases are inherited or breed-associated, and DNA-based tests may already be established or may be feasible to develop after the disorder has been accurately characterized. This review focuses on both routine and specialized laboratory testing necessary to reach a definitive diagnosis and determine an accurate prognosis for neuromuscular diseases. PMID- 20726956 TI - Prediction of low haemoglobin levels in whole blood donors. AB - BACKGROUND AND OBJECTIVES: Each year, a relevant proportion of whole blood donors is deferred from donation because of low haemoglobin (Hb) levels. Such temporary deferrals are demoralizing, and donors may never return for a donation. Reliable predictions of Hb levels may guide the decision whether donors can be invited for the next donation. In this study, a prediction model was developed for the risk of low Hb levels. MATERIALS AND METHODS: Individual data from 5191 whole blood donors were analysed; 143 donors had a low Hb level. Eleven candidate predictors were considered in logistic regression models to predict low Hb levels. The performance of the prediction model was studied with the receiver operating characteristic (ROC) curve. Internal validity was assessed with a bootstrap procedure. RESULTS: Strong predictors were sex, seasonality, Hb level measured at the previous visit, difference in Hb levels between the previous two visits, time since the previous visit, deferral at the previous visit, and the total number of whole blood donations in the past 2 years. Internal validation showed an area under the ROC curve of 0.87. CONCLUSION: The developed prediction model provides accurate discrimination between donors with low and appropriate Hb levels. The model predictions may be valuable to determine whether donors can be invited for a next donation, or whether some interventions such as postponement of the invitation are warranted. Potentially, this could decrease the number of donor deferrals for low Hb levels. PMID- 20726957 TI - Survival after transfusion in the Netherlands. AB - BACKGROUND: Cost-effectiveness analyses of blood safety interventions require estimates of the life expectancy after blood product transfusion. These are best derived from survival after blood transfusion, per age group and blood component type. STUDY DESIGN AND METHODS: In the PROTON (PROfiles of TransfusiON recipients) study transfusion recipient data was collected from a hospital sample covering 28% of the total blood use between 1996 and 2006 in the Netherlands. The dataset includes date of transfusion, blood component type transfused and recipient identification details. PROTON data were individually matched to mortality data of the Netherlands. Survival after first transfusion and after any transfusion was calculated, per blood component type and age group. PROTON mortality rates were compared to mortality rates in the general population. The results were used to estimate survival beyond the study period and to estimate life expectancy after transfusion. RESULTS: Of all 2,405,012 blood product transfusions in the PROTON dataset, 92% was matched to the national Dutch Municipal Population Register, which registers all deaths. After 1 year, survival after any transfusion was 65.4%, 70.4% and 53.9% for RBC, FFP and PLT respectively. After 5 years, this was 46.6%, 58.8% and 39.3% for RBC, FFP and PLT, respectively. Ten years after transfusion, mortality rates of recipients are still elevated in comparison with the general population. CONCLUSION: Mortality rates of transfusion recipients are higher than those of the general population, but the increase diminishes over time. The mortality rates found for the Netherlands are lower than those found in comparable studies for other countries. PMID- 20726958 TI - Research and development. PMID- 20726959 TI - Quantitative risk assessment for zoonotic transmission of Cryptosporidium parvum infection attributable to recreational use of farmland. AB - Cryptosporidiosis caused by Cryptosporidium parvum infection is a major cause of enteric illness in man and there is a significant reservoir in animals, particularly young ruminant species. To preliminary assess the magnitude of the risk posed by contact with faeces produced by infected livestock, two microbiological risk assessments have been developed: one for the risk of human infection with C. parvum while camping on contaminated land recently grazed by infected suckler cattle and a comparable risk assessment for camping on land recently spread with contaminated cattle slurry. Using a worst-case scenario approach, the upper level of risk was estimated to be one infection in every 6211 person-visits for a camping event on land recently grazed by infected cattle. Translated into camping events of 100 persons, this risk estimate would most likely lead to zero (98% likelihood) or one infection (1% likelihood). The results for cattle slurry model are similar despite different pathways. Sensitivity analysis was conducted for the grazing cattle model only. This suggested that the time between grazing and camping was the most important control strategy, but increasing hand-washing frequency and the removal of cattle faeces before camping would also be beneficial. If the upper level of risk were to be judged unacceptable then further data would be required to more accurately estimate the risk of infection through these scenarios. Further research would also be required to assess the fraction of cases attributable to camping and/or environmental contact with Cryptosporidium oocysts. PMID- 20726960 TI - Biochemical bone markers in the assessment and pamidronate treatment of children and adolescents with osteogenesis imperfecta. AB - AIM: To assess the role of biochemical bone markers in classification of children with osteogenesis imperfecta (OI), their possible association with vertebral compression fractures in milder forms of OI and their role in monitoring of intravenous pamidronate (APD) treatment. METHODS: Serum total alkaline phosphatase (ALP), bone ALP isoforms (in a subgroup), osteocalcin, type I procollagen carboxy-terminal propeptide, carboxy-terminal telopeptide of type I collagen, and urine deoxypyridinoline (DPD) were measured in a cross-sectional study of 130 untreated individuals, 0.25-20.9years (median 6.7), with OI types I, III and IV. Of those, sixty-nine were also assessed longitudinally during monthly APD treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. RESULTS: Significant differences in bone markers, however not sufficient for individual clinical use, were found in the larger untreated group but not between subgroups with or without vertebral compressions. All bone markers decreased during treatment for 1.0-12.5years, but with different relative amounts. Changes were not correlated to the improvement in BMD, mobility or pain. CONCLUSION: Bone markers are, despite significant differences, not useful for the classification of OI type in the individual child and are not associated with vertebral compressions. Serum ALP and urinary DPD are sensitive in monitoring bisphosphonate treatment. PMID- 20726961 TI - CD14+ cell-derived IL-29 modulates proinflammatory cytokine production in patients with allergic airway inflammation. AB - BACKGROUND: Interleukin (IL)-29 is a newly described cytokine that has anti viral activity, induces tumor cell death and regulates immune function. Whether it plays a role in immune disorders is unclear. This study aims to examine the role of IL-29 in the modulation of immune response under allergic environment. METHODS: A group of patients with allergic asthma or/and allergic rhinitis was recruited to this study. Serum samples were collected from the patients in both in-season and out-season; the serum levels of IL-29 were determined by enzyme linked immunoassay. Cell types of IL-29-producing cells in upper airway mucosa were identified with immune staining and examined by immunohistochemistry and flow cytometry. RESULTS: High serum levels of IL-29 were detected in patients with allergic asthma in in-season, but not in out-season. The majority of IL 29(+) cells in upper airway tissue were CD14(+) cells. Exposure to specific antigens triggered the release of IL-4 from antigen-specific CD4(+) T cells; the released IL-4 activated CD14(+) cells to release IL-29; the released IL-29 further triggered the release of IL-6 and tumor necrosis factor from CD4(+) T cells. CONCLUSIONS: Interleukin-29 is involved in the pathogenesis of allergic inflammation via modulating immune cells' function to release proinflammatory cytokines. PMID- 20726962 TI - Regulatory Tau-cell differentiation between maternal and cord blood samples in pregnancies with spontaneous vaginal delivery and with elective cesarian section. AB - PROBLEM: The immunological mechanisms preventing fetal antigenic rejection during normal pregnancy and the extent to which the type of delivery influences lymphocyte reactions are elusive. METHOD OF STUDY: Maternal peripheral blood and neonatal umbilical cord blood (CB) was collected upon labor after vaginal delivery or cesarian section. Leukocytes were analyzed with flow cytometry, focusing on regulatory and gamma/delta T-cells. RESULTS: In CB from neonates delivered by vaginal delivery, natural killer cells were increased. On the other hand, in maternal blood, gamma/delta T-cells were increased, and activated T cells (cluster of differentiation [CD]4+/25(dim) /122+ cells) were decreased. Moreover, maternal blood presented increased levels of T regulatory cell subsets like CD4+/25(high) /45RO+, CD4+/25(high) /DR+, CD4+/25(high) /CD38+ and CD4+/25(high) /71+. In CB, CD19+, CD4+/25(high) /45RA+ and CD4+/25(high) /122+ cells were increased. CONCLUSION: The effect of delivery type on lymphocyte immunophenotype was minimal. Mothers' and neonates' lymphocyte subsets differed significantly. Mothers' phenotype comprised significantly of lymphocytes involved in tolerance (memory and activated regulatory T-cells, gamma/delta T-cells). PMID- 20726963 TI - Trajectories of alcohol consumption following liver transplantation. AB - Any use of alcohol in the years following liver transplantation (LTX) approaches 50% of patients transplanted for alcoholic liver disease (ALD). We collected detailed prospective data on alcohol consumption following LTX for ALD to investigate ongoing patterns of use. Using trajectory modeling we identified four distinct alcohol use trajectories. One group had minimal use over time. Two other groups developed early onset moderate-to-heavy consumption and one group developed late onset moderate use. These trajectories demonstrate that alcohol use varies based on timing of onset, quantity and duration. Using discriminant function analysis, we examine characteristics of recipient's pre-LTX alcohol histories and early post-LTX psychological stressors to identify the profile of those at risk for these specific trajectories. We discuss the relevance of these findings to clinical care and preliminarily to outcomes. PMID- 20726964 TI - Phylogeography of the Y-chromosome haplogroup C in northern Eurasia. AB - To reconstruct the phylogenetic structure of Y-chromosome haplogroup (hg) C in populations of northern Eurasia, we have analyzed the diversity of microsatellite (STR) loci in a total sample of 413 males from 18 ethnic groups of Siberia, Eastern Asia and Eastern Europe. Analysis of SNP markers revealed that all Y chromosomes studied belong to hg C3 and its subhaplogroups C3c and C3d, although some populations (such as Mongols and Koryaks) demonstrate a relatively high input (more than 30%) of yet unidentified C3* haplotypes. Median joining network analysis of STR haplotypes demonstrates that Y-chromosome gene pools of populations studied are characterized by the presence of DNA clusters originating from a limited number of frequent founder haplotypes. These are subhaplogroup C3d characteristic for Mongolic-speaking populations, "star cluster" in C3* paragroup, and a set of DYS19 duplicated C3c Y-chromosomes. All these DNA clusters show relatively recent coalescent times (less than 3000 years), so it is probable that founder effects, including social selection resulting in high male fertility associated with a limited number of paternal lineages, may explain the observed distribution of hg C3 lineages. PMID- 20726965 TI - Tests for compositional epistasis under single interaction-parameter models. AB - Compositional epistasis is said to be present when the effect of a genetic factor at one locus is masked by a variant at another locus. Although such compositional epistasis is not equivalent to the presence of an interaction in a statistical model, non-standard tests can sometimes be used to detect compositional epistasis. In this paper we consider empirical tests for compositional epistasis under models for the joint effect of two genetic factors which place no restrictions on the main effects of each factor but constrain the interactive effects of the two factors so as to be captured by a single parameter in the model. We describe the implications of these tests for cohort, case-control, case only and family-based study designs and we illustrate the methods using an example of gene-gene interaction already reported in the literature. PMID- 20726966 TI - Assessment of the risks of communicable disease transmission through the movement of poultry exhibited at agricultural shows in New South Wales. AB - OBJECTIVE: To assess biosecurity practices in the fancy poultry show sector that would influence the establishment and spread of exotic diseases in poultry in New South Wales. DESIGN: A cross-sectional survey of 105 fancy poultry exhibitors at seven agricultural shows. PROCEDURE: Exhibitors were interviewed about biosecurity practices on their farms and their knowledge of exotic diseases. Poultry stewards at 18 shows were interviewed about biosecurity practices at their shows. RESULTS: Although many exhibitors travelled only short distances to attend shows, some exhibitors attended up to 30 shows per year and travelled interstate to exhibit poultry. A network diagram revealed extensive connections and interactions of poultry throughout the eastern half of NSW. Five of 18 shows included cash sales without any record of purchasers; 46% of exhibitors reintroduced exhibited birds back into their flocks without a quarantine period; and 16% failed to wash cages used to transport the birds. There was a general awareness that exhibition of birds posed a risk to flock health, but knowledge of avian influenza and practices that could be adopted to minimise the risk of disease introduction was limited. CONCLUSIONS: The factors that could assist the establishment and spread of exotic diseases in poultry in NSW include the mixing of birds at shows, inadequate recording of exhibitor details at shows, inadequate biosecurity practices when reintroducing exhibited poultry back into flocks, cash sales associated with shows that did not include the collection of purchaser details, and inadequate identification of birds. PMID- 20726967 TI - Preliminary study of capsule endoscopy in the small intestine of horses. AB - OBJECTIVE: To evaluate the visibility of various portions of the small intestine in healthy horses using capsule endoscopy. PROCEDURE: Six healthy, conscious adult Thoroughbreds were restrained and an endoscopic capsule (PillCam SB capsule) was inserted into the oesophagus using an intranasal catheter aided by a guide wire. Water (500 mL) flushed the capsule down the gastrointestinal tract. Data were collected and stored in the recorder of the endoscopic system for 6 hours after capsule insertion and the images were evaluated using an image reader and scored using a visual analogue scale. RESULTS: Capsule endoscopy enabled observation of the distinct mucosal shape, colour, and villus structure of the intestinal lumen from the duodenum through the proximal jejunum. At 4 h after passing the pylorus, the endoscopic capsule started transmitting increasingly dark images in the distal jejunum as the lumen circumference increased. Means of the visual analogue scale in the duodenum, proximal jejunum, and distal jejunum were 93.8 +/- 1.3%, 86.2 +/- 2.5% and 48.8 +/- 6.3%, respectively. Differences among these values were statistically significant (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Capsule endoscopy enables observation of the distinct mucosal shape, colour and villus structure of the proximal and mid-small intestine in healthy horses. PMID- 20726969 TI - Acute lameness associated with osseous metastasis of a peri-renal carcinoma in a horse. AB - We present a case of aggressive metastatic carcinoma in a horse that was initially presented for shoulder lameness. Although radiography and scintigraphy were useful for localising a lesion in the proximal humerus, subsequent development of non-specific signs of systemic disease prompted further evaluation. Haematology and blood biochemistry, urinalysis and ultrasonography were all instrumental in identifying renal involvement. A diagnosis of a peri renal mass causing secondary renal failure prompted euthanasia of the horse because of the poor prognosis. Antemortem findings were supported by necropsy, with secondary lesions also identified in the spleen, liver, 8th left rib and proximal humerus. Histological examination yielded a diagnosis of undifferentiated metastatic carcinoma. PMID- 20726970 TI - Analysis of tidal breathing flow volume loop in dogs with tracheal masses. AB - OBJECTIVES: To investigate whether there are any changes in the tidal breathing flow volume loop (TBFVL) in calm, non-dyspnoeic dogs with intratracheal masses. METHODS: We compared 4 dogs with intratracheal masses (group 1) with 10 healthy dogs (group 2). Routine clinical and laboratory examinations of the dogs were unremarkable, except for episodic upper respiratory obstructive signs in the dogs in group 1. Lateral radiography of the neck and thorax showed that group 1 dogs had masses that appeared to protrude into the tracheal lumen. Tracheoscopy and surgery or necropsy was performed to confirm the presence of the mass. Arterial blood gas and TBFVL analysis was carried out in all dogs to assess respiratory status. RESULTS: The shape of the TBFVL for dogs in group 1 was narrower and ovoid compared with that for the group 2 dogs. Tidal volume and expiratory and inspiratory times were significantly reduced, whereas the respiratory rate was increased for dogs in group 1 compared with dogs in group 2. Arterial blood gas analysis was unremarkable for all dogs. CONCLUSIONS: TBFVL is a non-invasive technique that is easy to perform and well tolerated by dogs. In the absence of abnormalities detected by routine diagnostic evaluations and arterial blood gas analysis in dogs with intratracheal masses, the TBFVL contributes to the definition of the physiologic status of the airways at the time of testing, and results suggests that these dogs breathe quite normally when they are calm and non-dyspnoeic. PMID- 20726972 TI - Unilateral facial myokymia in a dog with an intracranial meningioma. AB - A 23-month-old castrated male Cavalier King Charles spaniel was evaluated because of a 6-month history of unusual rippling/undulating movements of the right facial muscles that were continuous and persisted during sleep. Neurological examination revealed narrowing of the right palpebral fissure and unilateral right-sided facial myokymia that was characterised by myokymic, and to a lesser degree, neuromyotonic discharges on concentric needle electromyographic examination. After persisting unchanged for almost 2.5 years from its onset, the facial myokymia gradually disappeared over a 6-month period concomitant with the emergence of a persistent ipsilateral facial paralysis and head tilt. At 5 years and 9 months after the first examination, signs of ipsilateral lacrimal, pharyngeal and laryngeal dysfunction became evident and the dog was euthanased. Postmortem examination identified a malignant (WHO grade III) meningioma in the right cerebellopontomedullary angle that compressed the ventrolateral cranial medulla, effaced the jugular foramen and internal acoustic meatus and extended into the facial canal of the petrous temporal bone. Novel findings were the unique observation of isolated unilateral facial myokymia preceding diagnosis of a meningioma affecting facial nerve function within the caudal cranial fossa and the remarkably long duration of neurological signs (75 months) attributable to the neoplasm. PMID- 20726973 TI - Lignocaine versus bupivacaine for flank anaesthesia using multiport catheters via a caudal epidural approach in cattle. AB - OBJECTIVE: To determine the anaesthetic and systemic effects of dorsolumbar epidural anaesthesia using non-stylet multiport catheters via the caudal approach to administer hypertonic 5% lignocaine (HL) or hypertonic 0.5% bupivacaine (HB) to the flank in standing cattle. MATERIALS AND METHODS: Six healthy adult cattle weighing 310-455 kg received 0.2 mg/kg HL or 0.025 mg/kg of HB; control animals received 0.9% saline solution. All drugs were injected into the dorsolumbar epidural space via a caudal approach through a non-stylet multiport catheter. Each animal received each treatment at random. Evaluations of anaesthesia, ataxia, heart rate, arterial pressures, respiratory rate and rectal temperature were obtained at 0 (basal), 5, 10, 15, 30, 45, 60, 75, and 90 min after epidural injection and then at 30-min intervals until loss of anaesthesia. All animals received a standard noxious stimulus and a 4-point scale was used to score the response. A second scale was used to score ataxia. RESULTS: The duration of anaesthesia in the upper and lower flanks in cattle was 68 +/- 12 and 110 +/- 15 min (mean +/- SD) after dorsolumbar epidural HL or HB, respectively. Both hypertonic local anaesthetics produced a mild ataxia. The systemic changes were within acceptable limits in these clinically healthy cattle. CONCLUSION: In standing cattle the dorsolumbar epidural injection of hypertonic lignocaine provided faster onset of anaesthesia and fewer cardiovascular effects, but had a shorter duration of anaesthesia than hypertonic bupivacaine. PMID- 20726975 TI - Needle-free vaccination in sheep. AB - Multi-dose vaccinators have been in use for many years to vaccinate livestock. A number of needle-free vaccinators that use compressed gas to drive the vaccine through intact skin have been recently introduced to the market. We recently examined the efficacy of a needle-free vaccinator to induce antibodies to tetanus toxoid in sheep. The result indicates that needle-free vaccination can stimulate antibody responses comparable to conventional needle vaccination. PMID- 20726976 TI - The latest endangered species in Australia: a tobacco-smoking veterinarian. AB - The results of a tobacco smoking survey conducted among veterinarians in Queensland, Australia, during 2007 are presented. Of the 567 participants only 3% reported being current smokers, 24% were ex-smokers and 73% had never smoked. The prevalence of smoking was similar among males and females, and the highest smoking rate was reported among veterinarians aged 31-40 years. However, the rate of never-smokers was strongly and negatively correlated with age, and the proportion of ex-smokers increased with age. Encouragingly, the results from this study suggest that tobacco use has all but disappeared from the Australian veterinary profession in recent years. PMID- 20726977 TI - Outcomes and timing for intervention of partial adrenalectomy in patients with a solitary adrenal remnant and history of bilateral phaeochromocytomas. AB - OBJECTIVE: To evaluate the outcomes and timing of intervention for adrenal sparing surgery in patients left with a solitary adrenal remnant after bilateral adrenal surgeries. PATIENTS AND METHODS: Patients were included in the study if they had undergone bilateral adrenal surgery as a treatment for phaeochromocytoma and were left with a solitary adrenal remnant. Perioperative, functional and oncological outcomes were evaluated in 21 patients who met the inclusion criteria. RESULTS: There was minimal perioperative morbidity and no perioperative mortality. After a median (range) follow-up of 21 (3-143) months, there were two cases of persistent disease. Ten patients (48%) required steroid supplementation upon discharge, with four subsequently discontinuing this treatment. Patients were more likely to require steroid supplementation after surgery if they underwent simultaneous adrenalectomy and contralateral partial adrenalectomy, rather than staged procedures (86 vs 40%, P = 0.02). Patients who underwent surgery for tumours > 4 cm were more likely to require long-term steroids than patients who underwent surgery for lesions < 4 cm (75 vs 18%, P = 0.05). CONCLUSIONS: Patients left with a solitary adrenal remnant after bilateral adrenal surgery have low surgical morbidity, reasonable functional outcomes and low rates of recurrence at an intermediate follow-up period. A staged approach could decrease the immediate postoperative need for steroids, and intervention before the largest tumour reaches 4 cm could decrease the rate of long-term steroid dependence. PMID- 20726978 TI - Enhanced S100 calcium-binding protein P expression sensitizes human bladder cancer cells to cisplatin. AB - OBJECTIVE: * To investigate the role of S100 calcium-binding protein P (S100P) in the gain of cis-diamminedichloroplatinum (II) (cisplatin) resistance in bladder cancer, having previously found, with cDNA microarrays using two pairs of parental (T24, KK47) and their cisplatin-resistant bladder cancer cell lines (T24/DDP10, KK47/DDP20), that S100P mRNA expression was significantly reduced in cisplatin-resistant cells. MATERIALS AND METHODS: * S100P mRNA and protein expression levels were investigated by northern and western blot analyses, respectively. * Intracellular S100P localization was examined by immunocytochemistry and immunohistochemistry. * S100P over-expression, obtained by transfection with S100P expression plasmid, was used to investigate whether or not S100P affected cellular resistance to cisplatin. RESULTS: * S100P mRNA showed increased expression by cisplatin stimulation in parental cell lines. * On the other hand, S100P mRNA and protein expression levels were markedly reduced in cisplatin-resistant cells. * The over-expression of S100P in resistant cells resulted in an increased sensitivity to cisplatin. CONCLUSIONS: * In bladder cancer cells, S100P was expressed and localized mainly in the nucleus. * S100P expression was also involved in cisplatin sensitivity. * S100P might thus represent a molecular marker predicting cisplatin sensitivity and a molecular therapeutic target for cisplatin-based chemotherapy. PMID- 20726979 TI - Patient-specific risk of undetected malignant disease after investigation for haematuria, based on a 4-year follow-up. AB - OBJECTIVES: * To estimate the diagnostic accuracy of a guidelines-based haematuria clinic protocol by measuring the incidence of undetected malignancy during a follow-up period. * To estimate an individual's post-test risk of having undetected malignancy using the protocol likelihood ratio and the population prevalence of disease. METHODS: * Data were collected prospectively on a cohort of 4020 consecutive patients who were referred to a 'one-stop' haematuria clinic between 1998 and 2003. * All patients had a plain radiograph taken and underwent ultrasonography and flexible cystoscopy as a part of 'first-line' investigation. * Intravenous urography was performed where indicated after abnormal first-line tests or in patients with persistent haematuria where no abnormality had been detected. * Records of the initial 687 participants from the first year of the study were reviewed 4 years after the original consultation. Missed diagnoses of urinary tract malignancy were recorded and sensitivities, likelihood ratios and the post-test probability of missing all disease and upper tract malignancy were calculated. RESULTS: * As previously reported, the overall prevalence of malignant disease was 12.1% (18.9% for macroscopic haematuria compared with 4.8% for microscopic haematuria). * The records of the first year's cohort of patients (N = 687) were analysed 4 years after their original consultation and 10 potentially 'missed' tumours were identified. * The sensitivity of the protocol was 90.9% for the detection of all urinary tract malignancy (95% CI, 82.4 to 95.5) and 71% for upper tract tumours alone (95% CI, 45.4-88.3). The latter improves to 78.6% (95% CI, 52.4-92.4) with the addition of further upper tract testing. * The probability of missing malignant disease overall was 1.7% (95% CI, 0.95-3.04) but this rose sharply to >4% for males over 60 with macroscopic haematuria. * For those with non-visible haematuria, the percentage probability of missed malignant disease was less than 1%. CONCLUSIONS: * The haematuria clinic protocol described is robust but it is not infallible. * The risk of missing malignant disease in the higher risk groups identified in the study is much greater than previous studies would suggest. * If additional upper tract testing or interval follow-up were to be recommended, it could be rationally targeted at these groups, given the measurable risk shown here. PMID- 20726980 TI - Inhibitors of catechol-O-methyltransferase sensitize mice to pain. AB - BACKGROUND AND PURPOSE: Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice. EXPERIMENTAL APPROACH: We used single and repeated administration of a peripherally restricted, short acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone. KEY RESULTS: After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception. CONCLUSIONS AND IMPLICATIONS: Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions. PMID- 20726981 TI - Caffeine inhibits the viability and osteogenic differentiation of rat bone marrow derived mesenchymal stromal cells. AB - BACKGROUND AND PURPOSE: Caffeine is consumed extensively in Europe and North America. As a risk factor for osteoporosis, epidemiological studies have observed that caffeine can decrease bone mineral density, adversely affect calcium absorption and increase the risk of bone fracture. However, the exact mechanisms have not been fully investigated. Here, we examined the effects of caffeine on the viability and osteogenesis of rat bone marrow-derived mesenchymal stromal cells (rBMSCs). EXPERIMENTAL APPROACH: Cell viability, apoptosis and necrosis were quantified using thymidine incorporation and flow cytometry. Sequential gene expressions in osteogenic process were measured by real-time PCR. cAMP, alkaline phosphatase and osteocalcin were assessed by immunoassay, spectrophotometry and radioimmunoassay, respectively. Mineralization was determined by calcium deposition. KEY RESULTS: After treating BMSCs with high caffeine concentrations (0.1-1mM), their viability decreased in a concentration-dependent manner. This cell death was primarily due to necrosis and, to a small extent, apoptosis. Genes and protein sequentially expressed in osteogenesis, including Cbfa1/Runx2, collagen I, alkaline phosphatase and its protein, were significantly downregulated except for osteocalcin and its protein. Moreover, caffeine inhibited calcium deposition in a concentration- and time-dependent manner, but increased intracellular cAMP in a concentration-dependent manner. CONCLUSIONS AND IMPLICATIONS: By suppressing the commitment of BMSCs to the osteogenic lineage and selectively inhibiting gene expression, caffeine downregulated some important events in osteogenesis and ultimately affected bone mass. PMID- 20726982 TI - Tuning in to the 'right' calcium channel regulation in experimental models of diabetes. AB - Elucidation of cellular and molecular mechanisms underlying vascular disease is of fundamental importance to the development of pharmacological agents to target these pathways. Pinho et al. in this issue of the BJP provide highly compelling evidence that the delta isoform of phosphatidyl inositol 3-kinase (PI3K delta) was upregulated and accounted for the increase in L-type, voltage-gated, Ca channel current in aortic vascular smooth muscle (VSM) cells of a mouse model of type 1 diabetes. There are several key issues of broad fundamental significance to this work. Firstly, what is the 'right' answer about calcium channel regulation in diabetes? Conflicting reports of increased and decreased Ca channel current may be due to specificity of the vascular bed and species. Then, the time course of diabetic vasculopathy may influence the expression of contractile versus proliferative phenotypes of VSM. Also the metabolic characterization of diabetes may enlighten or confound any study of diabetic vascular disease. These issues need attention to move forward work in this area. PMID- 20726983 TI - Human atrial beta(1L)-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca(2+) current at physiological temperature. AB - BACKGROUND AND PURPOSE: It has been proposed that BRL37344, SR58611 and CGP12177 activate beta3-adrenoceptors in human atrium to increase contractility and L-type Ca(2+) current (I(Ca-L)). beta3-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the beta1-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective beta adrenoceptor subtype antagonists to clarify cardiostimulant beta-adrenoceptor subtypes in human atrium. EXPERIMENTAL APPROACH: Human right atrium was obtained from patients without heart failure undergoing coronary artery bypass or valve surgery. Cardiomyocytes were prepared to test BRL37344, SR58611 and CGP12177 effects on I(Ca-L). Contractile effects were determined on right atrial trabeculae. KEY RESULTS: BRL37344 increased force which was antagonized by blockade of beta1- and beta2-adrenoceptors but not by blockade of beta3 adrenoceptors with beta3-adrenoceptor-selective L-748,337 (1 uM). The beta3 adrenoceptor agonist SR58611 (1 nM-10 uM) did not affect atrial force. BRL37344 and SR58611 did not increase I(Ca-L) at 37 degrees C, but did at 24 degrees C which was prevented by L-748,337. (-)-CGP12177 increased force and I(Ca-L) at both 24 degrees C and 37 degrees C which was prevented by (-)-bupranolol (1-10 uM), but not L-748,337. CONCLUSIONS AND IMPLICATIONS: We conclude that the inotropic responses to BRL37344 are mediated through beta1- and beta2 adrenoceptors. The inotropic and I(Ca-L) responses to (-)-CGP12177 are mediated through the low affinity site beta(1L)-adrenoceptor of the beta1-adrenoceptor. beta3-adrenoceptor-mediated increases in I(Ca-L) are restricted to low temperatures. Human atrial beta3-adrenoceptors do not change contractility and I(Ca-L) at physiological temperature. PMID- 20726984 TI - Anti-inflammatory synergy of MEN16132, a kinin B(2) receptor antagonist, and dexamethasone in carrageenan-induced knee joint arthritis in rats. AB - BACKGROUND AND PURPOSE: Bradykinin, through its B(2) receptor, is involved in inflammatory processes related to arthropathies. In carrageenan and lipopolysaccharide (LPS)-induced arthritis in rat, the anti-inflammatory activity of MEN16132, a potent and selective kinin B(2) receptor antagonist, was compared with that of steroidal and nonsteroidal anti-inflammatory drugs. The interaction between MEN16132 and dexamethasone was also investigated. EXPERIMENTAL APPROACH: Drugs, alone or in combination, were injected into the knee joint 30min before intra-articular administration of carrageenan or LPS, in pentobarbital anaesthetized rats. Effects on incapacitation, oedema, neutrophil recruitment and kallikrein system activation, in the knee joint, were assessed. KEY RESULTS: MEN16132 and dexamethasone (10-300ug per knee) dose-dependently reduced carrageenan-induced joint pain, oedema and neutrophil infiltration, reaching a maximal inhibition of about 50%. Dexketoprofen exerted a similar analgesic activity, whereas it did not affect the other inflammatory responses. MEN16132 showed a partial inhibition of LPS-induced joint pain, whereas dexamethasone produced a full analgesic effect. Combination of MEN16132 and dexamethasone showed a strong synergistic interaction in inhibiting both carrageenan and LPS induced knee joint inflammation. Dexamethasone did not prevent the contact activation of prekallikrein by carrageenan and the subsequent release of kallikreins and bradykinin in the synovium. CONCLUSIONS AND IMPLICATIONS: Steroids and kinin B(2) receptor antagonists appear to relieve arthritic symptoms induced by carrageenan or LPS and act synergistically to inhibit joint inflammation. This could have interesting therapeutic implications, possibly opening the way for combination therapies in the control of inflammatory arthropathies. PMID- 20726985 TI - Pioglitazone attenuates prostatic enlargement in diet-induced insulin-resistant rats by altering lipid distribution and hyperinsulinaemia. AB - BACKGROUND AND PURPOSE: Increased incidence of benign prostatic hyperplasia among insulin-resistant individuals suggests a role for hyperinsulinaemia in prostatic enlargement. We have already reported increased cell proliferation and enlargement of prostate gland in insulin-resistant rats. The present study aimed to elucidate the molecular mechanisms underlying the reversal of prostatic enlargement in insulin-resistant rats by the peroxisome proliferator-activated receptor gamma agonist pioglitazone. EXPERIMENTAL APPROACH: Sprague-Dawley rats were fed a normal pellet or a high-fat diet for 12 weeks with or without pioglitazone (20 mg.kg(-1)). Subgroups of animals fed different diets were castrated. Effects of dietary manipulation and pioglitazone were measured on insulin sensitivity, lipid distribution, cell proliferation and apoptosis. KEY RESULTS: A high-fat diet led to the accumulation of fat in non-adipose tissues, insulin resistance, compensatory hyperinsulinaemia and prostatic enlargement in rats. Pioglitazone treatment altered fat distribution, improved insulin sensitivity and normalized lipid and insulin level in rats on the high-fat diet. The improved metabolic parameters led to decreased cellular proliferation and increased apoptosis in the prostate gland. High-fat diet feeding and pioglitazone treatment did not change plasma testosterone levels. However, significant prostatic atrophy was observed in castrated rats irrespective of dietary intervention. CONCLUSIONS AND IMPLICATIONS: Our results show a previously unexplored therapeutic potential of pioglitazone for prostatic enlargement under insulin-resistant condition and further suggest that targeting distribution of lipid from non-adipose tissue to adipose tissue and insulin signalling could be new strategies for the treatment of benign prostatic hyperplasia. PMID- 20726986 TI - Emodin suppresses lipopolysaccharide-induced pro-inflammatory responses and NF kappaB activation by disrupting lipid rafts in CD14-negative endothelial cells. AB - BACKGROUND AND PURPOSE: Emodin [1,3,8-trihydroxy-6-methylanthraquinone] has been reported to exhibit vascular anti-inflammatory properties. However, the corresponding mechanisms are not well understood. The present study was designed to explore the molecular target(s) of emodin in modifying lipopolysaccharide (LPS)-associated signal transduction pathways in endothelial cells. EXPERIMENTAL APPROACH: Cultured primary human umbilical vein endothelial cells (HUVECs; passages 3-5) were pre-incubated with emodin (1-50 ug.mL(-1) ). LPS-induced expression of pro-inflammatory cytokines [interleukin (IL)-1beta, IL-6] and chemokines (IL-8; CCL2/MCP-1) were determined by reverse transcription-PCR and elisa. Nuclear factor-kappaB (NF-kappaB) activation, inhibitor of kappaB (IkappaB)alpha degradation and Toll-like receptor-4 (TLR-4) were detected by immunocytochemistry and Western blotting. Cholesterol depletion [by methyl beta cyclodextrin (MBCD), a specific cholesterol binding agent] and cholesterol replenishment were further used to investigate the roles of lipid rafts in activation of HUVECs. KEY RESULTS: Emodin inhibited, concentration-dependently, the expression of LPS-induced pro-inflammatory cytokines (IL-1beta, IL-6) and chemokines (IL-8, CCL2) and, in parallel, inhibited NF-kappaB activation and IkappaBalpha degradation in HUVECs. However, emodin did not inhibit the NF-kappaB activation and IkappaBalpha degradation induced by IL-1beta. The cholesterol binding agent, MBCD, inhibited LPS-induced NF-kappaB activation in passaged HUVECs [which also lack the LPS receptor, membrane CD14 (mCD14)], showing that lipid rafts played a key role in LPS signalling in mCD14-negative HUVECs. Moreover, emodin disrupted the formation of lipid rafts in cell membranes by depleting cholesterol. CONCLUSIONS AND IMPLICATIONS: Lipid rafts were crucial in facilitating inflammatory responses of mCD14-negative HUVECs to LPS. Emodin disrupted lipid rafts through depleting cholesterol and, consequently, inhibited inflammatory responses in endothelial cells. PMID- 20726987 TI - Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen. AB - BACKGROUND AND PURPOSE: Recently, we identified etodolac as a possible ligand for the human intestinal proton-couple peptide transporter (hPEPT1). This raised the possibility that other non-steroidal anti-inflammatory drugs, and especially ibuprofen, could also interact with hPEPT1. Here, we have assessed the interactions of ibuprofen with hPEPT1. EXPERIMENTAL APPROACH: The uptake of [(14)C]Gly-Sar, [(3)H]Ibuprofen and other radio-labelled compounds were investigated in Madin-Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC PK(1) or Caco-2 cells. The transepithelial transport of ibuprofen and hPEPT1 substrates was investigated in Caco-2 cell monolayers. KEY RESULTS: Ibuprofen concentration dependently inhibited hPEPT1-mediated uptake of Gly-Sar in MDCK/hPEPT1 cells (K(i)(app) = 0.4 mM) but uptake of ibuprofen in Caco-2 cells and MDCK/hPEPT1 cells was not inhibited by hPEPT1 substrates. The maximum uptake rate for Gly-Sar uptake was reduced from 522 pmol.min(-1).cm(-2) to 181 pmol.min( 1).cm(-2) and 78 pmol.min(-1).cm(-2) in the presence of 0.5 mM and 1 mM ibuprofen, respectively. The interaction between ibuprofen and hPEPT1 was thus non-competitive. In LLC-PK1 cells, ibuprofen (1 mM) did not influence the transporter-mediated uptake of glycine or alpha-methyl-D-glycopyranoside. In Caco 2 cell monolayers the absorptive transport of delta-aminolevulinic acid was reduced by 23% and 48% by ibuprofen (1 and 10 mM), respectively. Likewise the transport of Gly-Sar was reduced by 23% in the presence of ibuprofen (1 mM). CONCLUSIONS AND IMPLICATIONS: Ibuprofen is a non-competitive inhibitor of hPEPT1. As ibuprofen reduced the transepithelial transport of delta-aminolevulinic acid, drug-drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together. PMID- 20726988 TI - CD6 synergistic co-stimulation promoting proinflammatory response is modulated without interfering with the activated leucocyte cell adhesion molecule interaction. AB - The CD6 membrane-proximal scavenger receptor cysteine-rich domain (SRCR3) includes the activated leucocyte cell adhesion molecule (ALCAM) binding site. CD6 ALCAM mediates a low-affinity interaction and their long-term engagement contributes to the immunological synapse. Their ligation may play a dual function, facilitating stable adhesion between the antigen-presenting cells and T cells during the early activation phase and later in the proliferative phase of the immune response. This study explored the strength of the CD6 co-stimulatory effect and whether CD6 co-stimulation with its natural ligand ALCAM also contributes to the lymphocyte effector differentiation. It was found that CD6 ALCAM interaction in vitro induced a synergistic co-stimulation of normal human peripheral blood mononuclear cells, defined by Bliss analysis. CD6 co-stimulation enhanced the CD3 proliferative efficacy by 23-34%. Moreover, a fivefold increment in the CD25 molecules number with a distinct gene transcription profile associated with cell activation, differentiation, survival and adhesion molecules was observed over CD3 single activation. Additionally, CD6 co-stimulation in excess interleukin (IL)-2 promotes a preferentially proinflammatory response. Besides, a CD6 membrane-distal domain (SRCR1)-specific non-depleting monoclonal antibody (mAb) inhibited the induced proliferation in the presence of ALCAM, reducing interferon-gamma, IL-6 and tumour necrosis factor-alpha production. These results suggest that CD6 co-stimulation enhances the intrinsic activity of the CD3 activation pathway and contributes to the T helper type 1 subset commitment, enhancing the IL-2 sensitivity of recent activated human lymphocytes. It supports the role of CD6 as a susceptibility gene for pathological autoimmunity leading to tissue inflammation, and its relevance for targeted therapy. PMID- 20726989 TI - alpha-Galactosylceramide protects mice from lethal Coxsackievirus B3 infection and subsequent myocarditis. AB - Myocarditis is an inflammation of the myocardium which often follows virus infections. Coxsackievirus B3 (CVB3), as a marker of the enterovirus group, is one of the most important infectious agents of virus-induced myocarditis. Using a CVB3-induced myocarditis model, we show that injection alpha-galactosylceramide (alpha-GalCer), a ligand for invariant natural killer (NK) T (iNK T) cells, can protect the mice from viral myocarditis. After the systemic administration of alpha-GalCer in CVB3 infected mice, viral transcription and titres in mouse heart, sera and spleen were reduced, and the damage to the heart was ameliorated. This is accompanied by a better disease course with an improved weight loss profile. Compared with untreated mice, alpha-GalCer-treated mice showed high levels of interferon (IFN)-gamma and interleukin (IL)-4, and reduced proinflammatory cytokines and chemokines in their cardiac tissue. Anti-viral immune response was up-regulated by alpha-GalCer. Three days after CVB3 infection, alpha-GalCer-administered mice had larger spleens. Besides NK T cells, more macrophages and CD8(+) T cells were found in these spleens. Upon stimulation with phorbol myristate acetate plus ionomycin, splenocytes from alpha-GalCer treated mice produced significantly more cytokines [including IFN-gamma, tumour necrosis factor-alpha, IL-4 and IL-10] than those from untreated mice. These data suggest that administration of alpha-GalCer during acute CVB3 infection is able to protect the mice from lethal myocarditis by local changes in inflammatory cytokine patterns and enhancement of anti-viral immune response at the early stage. alpha-GalCer is a potential candidate for viral myocarditis treatment. Our work supports the use of anti-viral treatment early to reduce the incidence of virus-mediated heart damage. PMID- 20726990 TI - The effect of human placenta cytotrophoblast cells on the maturation and T cell stimulating ability of dendritic cells in vitro. AB - The success of pregnancy depends upon regulatory mechanisms that allow the fetus to survive and develop to term in the uterus, despite maternal immune cells' awareness of paternal alloantigens. At least some of these specific mechanisms are mediated by the effect of fetal trophoblast cells. In the present study we examine the effect of human placental cytotrophoblast cells (CTCs) on the maturation of dendritic cells (DCs) in vitro. For that purpose, CTCs were isolated from samples of placentae at 5-11 weeks of gestation and co-cultured with peripheral blood monocytes under conditions inducing DC maturation. CTC were shown to alter the morphology, phenotype and functional properties of DCs. As a result, a significant portion of cells acquire fibroblast-like morphology and some of the cells retain the expression of CD14. DCs matured in the presence of CTCs do not differ from usual DCs in terms of CD80, CD83 and CD86 expression, as well as the ability to induce allogenic lymphocytes proliferation. However, CTCs reduce significantly the ability of DCs to stimulate interferon-gamma production and the loss of CD62L by T cells. The results obtained indicate that DCs may be involved in pregnancy-associated changes of cytokine production and T cell migration. PMID- 20726991 TI - High susceptibility of obese hypertensive SHRSP.Z-Lepr(fa) /IzmDmcr rats to lipid deposition in the mesenteric artery. AB - 1. Atherosclerosis is commonly observed in obesity. Obese atherosclerosis-prone animals may be a promising tool for understanding the pathophysiology of obesity associated atherosclerosis. However, most rat strains are resistant to atherosclerosis. The aim of the present study was to assess the susceptibility of two obese hypertensive rat models, namely SHRSP.Z-Lepr(fa) /IzmDmcr rats (SHRSP fatty) and SHR.Cg-Lepr(cp) /NDmcr rats (SHR-cp), to arterial lipid deposition, an initial stage of atherosclerosis, by comparing these strains with non-obese stroke-prone spontaneously hypertensive rats (SHRSP). 2. Eight-week-old male SHRSP, SHRSP-fatty and SHR-cp were fed a high-fat and high-cholesterol diet containing 20% palm oil, 5% cholesterol and 2% cholic acid for 5weeks. Bodyweight, blood pressure and fasting serum levels of total cholesterol and triglycerides were measured in 12-week-old rats. Oil red O staining was used to visualize lipid deposition in the mesenteric artery. 3. The bodyweight of 12-week old SHRSP-fatty and SHR-cp was higher than that of SHRSP (P<0.005). Systolic blood pressure in SHRSP and SHRSP-fatty was higher than in SHR-cp (P<0.005). Serum total cholesterol and triglyceride levels were elevated in SHRSP-fatty (P<0.005) and SHR-cp (P<0.05) compared with levels in SHRSP. Lipid deposition in the mesenteric artery was significantly greater in SHRSP-fatty than in SHRSP (37.7+/-4.9 vs 13.1+/-2.8%, respectively; P<0.005), but markedly reduced in SHR cp (1.8+/-0.4%; P<0.05). 4. The results of the present study indicate that SHRSP fatty are highly susceptible to arterial lipid deposition, whereas SHR-cp are resistant. Thus, SHRSP-fatty may be a useful obese rat model in which to investigate atherosclerotic processes. PMID- 20726992 TI - Satellite cell activity in muscle regeneration after contusion in rats. AB - 1. The role of satellite cells in muscle growth during development is well documented, but the involvement of these cells in muscle repair after contusion is less well known. In the present study, we investigated the time-course of satellite cell activity (from 3h to 7days) after contusion of rat gastrocnemius muscle using specific molecular markers for immunofluorescence and real-time polymerase chain reaction (PCR). 2. Inflammation of the injured muscle occurred within 6h, followed by disintegration of the damaged myofibres within 12h. Newly formed myofibres appeared by Day 7. 3. The number of MyoD-positive nuclei (activated satellite cells) in the injured muscle was significantly increased by 6h, reaching a maximum by 12h after contusion. However, the number of MyoD positive nuclei decreased towards control levels by Day 7. Changes in the number of bromodeoxyuridine-labelled nuclei (proliferating satellite cells) paralleled the changes seen in the number of MyoD-positive nuclei. Conversely, expression of myogenin protein was not apparent until Day 3 and increased further by Day 7. Colabelling of MyoD and myogenin was seen in only a few cells. 4. The time-course of MyoD mRNA expression corresponded with MyoD protein expression. However, there were two peaks in myogenin mRNA expression: 6h and Day 7 after contusion. The second peak coincided with upregulation of myostatin mRNA levels. 5. The results of the present study suggest that contusion activates a homogeneous population of satellite cells to proliferate within 3days, followed by differentiation to form new myofibres. The latter may be regulated, in part, by myostatin. PMID- 20726993 TI - Reference values for respiratory pressures in a general adult population--results of the Study of Health in Pomerania (SHIP). AB - BACKGROUND AND OBJECTIVE: Respiratory muscle pressures have been gaining increasing interest because of prognostic value. The study aim was to acquire reference values for respiratory pressures in a large-scale population-based survey--the Study of Health in Pomerania (SHIP). METHODS: One thousand eight hundred and nine participants (885 men) of a cross-sectional epidemiologic survey, called 'Study of Health in Pomerania--SHIP', underwent lung function and respiratory muscle pressure measurements. After excluding individuals with cardiopulmonary disorders, prediction equations for men and women were established by quantile regression analysis. RESULTS: The final study population comprised 912 individuals (432 men), aged 25-80 years. The study provides a representative set of sex-specific prediction equations of respiratory muscle strength. Respiratory pressures are decreasing with age and are lower in women when compared to men. CONCLUSIONS: Prediction equations for relevant respiratory pressures are given. Based on this well-described population-based survey with extensive cardiopulmonary investigations to exclude relevant interfering disorders a sufficient comprehensive set of reference values was obtained. PMID- 20726994 TI - ANP, BNP and D-dimer predict right ventricular dysfunction in patients with acute pulmonary embolism. AB - BACKGROUND: The aim of this study was to predict right ventricular dysfunction (RVD) using plasma concentration of D-dimer, pro-atrial natriuretic peptide (pro ANP), brain natriuretic peptide (BNP), endothelin-1 (ET-1) and cardiac troponin I (TNI) in patients with pulmonary embolism (PE). METHODS: Patients suspected of PE had a ventilation/perfusion-single-photon emission-tomography (V/Q-SPECT), pulmonary multidetector computer tomography (MDCT) angiography, blood samples and ECG-gated cardiac CT performed the same day. RESULTS: Pro-ANP, BNP and D-dimer are associated with significantly elevated levels in PE patients with RVD. ROC curves demonstrated that D-dimer, pro-ANP and BNP were accurate for detection of RVD. CONCLUSION: Because measurements of cardiac biomarkers are inexpensive and easily obtained they may prove useful in the clinical diagnosis of RVD. However because of the small sample size, the results need to be confirmed in larger studies. PMID- 20726995 TI - Measurement and mathematical modelling of elastic and resistive lung mechanical properties studied at sinusoidal expiratory flow. AB - Elastic pressure/volume (P(el) /V) and elastic pressure/resistance (P(el) /R) diagrams reflect parenchymal and bronchial properties, respectively. The objective was to develop a method for determination and mathematical characterization of P(el) /V and P(el) /R relationships, simultaneously studied at sinusoidal flow-modulated vital capacity expirations in a body plethysmograph. Analysis was carried out by iterative parameter estimation based on a composite mathematical model describing a three-segment P(el) /V curve and a hyperbolic P(el) /R curve. The hypothesis was tested that the sigmoid P(el) /V curve is non symmetric. Thirty healthy subjects were studied. The hypothesis of a non symmetric P(el) /V curve was verified. Its upper volume asymptote was nearly equal to total lung capacity (TLC), indicating lung stiffness increasing at high lung volume as the main factor limiting TLC at health. The asymptotic minimal resistance of the hyperbolic P(el) /R relationship reflected lung size. A detailed description of both P(el) /V and P(el) /R relationships was simultaneously derived from sinusoidal flow-modulated vital capacity expirations. The nature of the P(el) /V curve merits the use of a non-symmetric P(el) /V model. PMID- 20726996 TI - Interrelationship between oxygen-related variables in patients with acute myocardial infarction: an interpretative review. AB - The high mortality rate of cardiogenic shock in acute myocardial infarction (AMI) implies that debate over the correct haemodynamic management is still unresolved. The purpose of this review is to re-evaluate the reciprocal relationships between oxygen-related variables and response to treatment in a large number of patients with AMI. A MEDLINE search of reports published between 1970 and 2008 was performed. Twelve clinical reports including 453 patients with AMI and 989 sets of oxygen delivery and oxygen consumption expressed in ml min-1 m-2 and oxygen extraction ratio were selected. While processing this data, we found an early down-regulation in oxygen demand linked to a decrease in oxygen supply. This mechanism is also supported in some studies by a critically low oxygen uptake that was not associated with lactic acidosis. PMID- 20726997 TI - Rare clinical entity Perlman syndrome: is cholestasis a new finding? AB - Perlman syndrome is a rare syndrome characterized by polyhydramnios, fetal overgrowth, facial dysmorphism, visceromegaly, nephroblastomatosis and predisposition to Wilms tumor. Here we report on a newborn with a prenatal history of polyhydramnios who presented with nephromegaly, hypotonia, macrosomia, facial dysmorphism, cholestasis and characteristic ultrasonographic and computed tomographic appearances of renal abnormalities that are observed with Perlman syndrome. Perlman syndrome is a rare entity with a high neonatal mortality rate. This is the first case in which cholestasis has been observed. Close follow-up should be carried out for early detection of Wilms tumor. PMID- 20726998 TI - OHVIRA syndrome: rare cause of chronic vaginal discharge in an unmarried female. AB - Chronic vaginal discharge in adolescent and young females, not responding to antibiotics, can pose a diagnostic dilemma for many gynecologists and general practitioners. Uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA syndrome) is a rare congenital anomaly. We present a case of a 22-year-old unmarried female with this syndrome presenting with chronic purulent vaginal discharge. The uniqueness about the case is its much delayed presentation. PMID- 20726999 TI - Clinical challenges in the management of a prenatally diagnosed cloacal malformation. AB - Cloacal dysgenesis sequence is a severe malformation of the primitive cloaca and is characterized by a phallus-like structure, smooth perineum and the absence of genitourinary and anal orifices. It is usually accompanied by oligohydramnios, kidney dysplasia, and pulmonary hypoplasia. We present a case of a 29-year-old woman who was referred at 26 weeks of gestation due to an enlarged fetal abdominal circumference. Investigations revealed the presence of fetal ascites, intrapelvic cysts, calcified meconium, severe oligohydramnios and a 46XX karyotype. Fetal abdominal parecentesis performed on several occasions failed to reduce intra-abdominal pressure. To our knowledge this case represents the first variation of cloacal dysgenesis sequence to contain three dysmorphic structures along with the common findings of this anomaly. PMID- 20727000 TI - Are abdominal wall defects and external genitalia anomalies randomly expressed in some families? AB - Familial cases of isolated abdominal wall defects with variable expressivity in more than one generation have rarely been observed. We report four affected individuals within a small three-generation family with either variable non syndromic abdominal wall defects or external genital anomalies. We discuss the possible transmission of non-syndromic abdominal wall defects. It could be hypothesized that similar developmental defects may result in anomalies like hypospadias in males or developmental anomalies of the labia minora or labia majora in females. PMID- 20727001 TI - Peptic ulcer disease with related drug treatment in pregnant women and congenital abnormalities in their offspring. AB - Peptic ulcer disease (PUD) is a common disease which can also occur in pregnant women. However, the possible association of PUD and related drug treatments in pregnant women with the risk of structural birth defects (i.e. congenital abnormalities [CA]) in their offspring has not been estimated in controlled population-based epidemiological studies. Thus, the prevalence of PUD in pregnant women who later delivered babies (cases) with different CA and in pregnant women who delivered newborns without CA (controls) was compared in the Hungarian Case Control Surveillance of Congenital Abnormalities. Controls were matched to cases. Of 22,843 cases with congenital abnormalities, 182 (0.80%) had mothers with reported/recorded PUD, while of 38,151 controls, 261 (0.68%) were born to mothers with reported/recorded PUD. However, PUD(?) based on maternal information and/or unspecified diagnostic criteria, and PUD(!) based on endoscopic diagnosis showed different variables of mothers and newborn infants. Thus, finally, 20 case mothers and 58 control mothers with PUD(!) and related drugs were evaluated in detail. There was no higher risk for total CA group in the offspring of mothers with PUD during pregnancy (adjusted OR with 95% CI: 0.6, 0.3-0.9). Specific CA groups in cases were also assessed versus controls, but specified CA had no higher risk in the offspring of pregnant women with PUD and related drug treatments. In conclusion, a higher rate of CA was not found in the offspring of mothers with PUD. PMID- 20727002 TI - Diet with a low n-6/n-3 essential fatty acid ratio when started immediately after the onset of overt diabetes prolongs survival of type 1 diabetes model NOD mice. AB - Type 1 diabetes is a multifactorial disease involving genetic and environmental factors and results from the destruction of pancreatic islet beta cells, virtually the only source of insulin. When the majority of beta cells are lost, a 'honeymoon' period of variable length follows: namely, a fleeting phase of residual endogenous insulin production, during which glycemic control is achieved with modest or no doses of insulin. However, the remaining beta cells are eventually lost, causing the individual to become insulin-dependent and to require long-term insulin therapy or islet transplantation. Here we show that NOD mice, a type 1 diabetes model, survived significantly longer when their diet was changed from one chow with a high essential fatty acid (EFA) ratio (n-6/n-3, 14.5) to another with a low n-6/n-3 ratio (3.0) within 6 days after the onset of overt diabetes (i.e. the 'honeymoon' period), than mice that were continuously fed with the chow with the high n-6/n-3 ratio. This effect was not observed when the chow was changed later than 9 days after the onset. Significantly larger number of islets remained with suggestive islet neogenesis from the pancreatic duct and pathological changes in renal glomeruli were significantly milder in NOD mice fed the chow with the low n-6/n-3 ratio within 6 days after the onset of overt diabetes than those continuously fed with the high-n-6/n-3-ratio chow. These findings indicate that a diet with a low n-6/n-3 ratio prolongs the 'honeymoon' period by retaining the beta cell mass, suggesting its potential therapeutic merit. PMID- 20727003 TI - Prevalence and distribution of congenital abnormalities in Turkey: differences between the prenatal and postnatal periods. AB - The aim of this study was to determine the distribution of cases associated with congenital abnormalities during the following three periods: pregnancy, birth, and the neonatal period. This was a retrospective study of cases between 2002 and 2006. All abnormal pregnancies, elective terminations of pregnancies, stillbirths, and births with congenital abnormalities managed in the Neonatology Unit were classified based on the above distribution scheme. During the 5-year study period, 1906 cases with congenital abnormalities were recruited, as follows: 640 prenatally detected and terminated cases, with most abnormalities related to the central nervous system, chromosomes, and urogenital system (56.7%, 12.7%, and 8.9%, respectively); 712 neonates with congenital abnormalities (congenital heart disease [49.2%], central nervous system abnormalities [14.7%], and urogenital system abnormalities [12.9%]); and hospital stillbirths, of which 34.2% had malformations (220 prenatal cases [34.4%] had multiple abnormalities, whereas 188 liveborn cases [26.4%] had multiple abnormalities). The congenital abnormalities rate between 2002 and 2006 was 2.07%. Systematic screening for fetal anomalies is the primary means for identification of affected pregnancies. PMID- 20727004 TI - Are parasites ''prudent'' in space? AB - There has been a renewed controversy on the processes that determine evolution in spatially structured populations. Recent theoretical and empirical studies have suggested that parasites should be expected to be more ''prudent'' (less harmful and slower transmitting) when infection occurs locally. Using a novel approach based on spatial moment equations, we show that the evolution of parasites in spatially structured host populations is determined by the interplay of genetic and demographic spatial structuring, which in turn depends on the details of the ecological dynamics. This allows a detailed understanding of the roles of epidemiology, demography and network topology. Demographic turnover is needed for local interactions to select for prudence in the susceptible-infected models that have been the focus of previous studies. In diseases with little demographic turnover (as typical of many human diseases), we show that only parasites causing diseases with long-lived immunity are likely to be prudent in space. We further demonstrate why, at intermediate parasite dispersal, virulence can evolve to higher levels than predicted by non-spatial theory. PMID- 20727005 TI - Diagnosis of leptomeningeal disease in diffuse large B-cell lymphomas of the central nervous system by flow cytometry and cytopathology. AB - Reliable detection of leptomeningeal disease has the potential of facilitating the diagnosis of central nervous system (CNS) lymphoma and is important for therapeutic considerations. Currently, the standard diagnostic procedure for the detection of lymphoma in the cerebrospinal fluid is cytopathology. To improve the limited specificity and sensitivity of cytopathology, flow cytometry has been suggested as an alternative. Here, we evaluated multi-parameter flow cytometry in combination with conventional cytopathology in cerebrospinal fluid (CSF) samples from 30 patients with primary CNS lymphoma and seven patients with secondary CNS lymphoma. Overall, in 11 of 37 (29.7%) patients with CNS lymphoma, lymphoma cells were detected in CSF by flow cytometry, while cytopathology was less sensitive displaying unequivocally malignant CSF cells in only seven of all 37 (18.9%) patients. Six (16.2%) patients showed cytopathological results suspicious of lymphoma; however, in only one of these patients, the diagnosis of CSF lymphoma cells could be confirmed by flow cytometry. In primary CNS lymphomas (PCNSL), seven of 30 (23.3%) patients were positive for CSF lymphoma cells in flow cytometry, in contrast to four (13.3%) patients with PCNSL with definitely positive cytopathology. In summary, our results suggest that multi-parameter flow cytometry increases the sensitivity and specificity of leptomeningeal disease detection in CNS lymphomas. Both methods should be applied concurrently for complementary diagnostic assessment in patients with CNS lymphoma. PMID- 20727006 TI - Therapeutic concepts in mantle cell lymphoma. AB - Mantle cell lymphoma has been considered an incurable disease with current chemotherapy regimens. Recent intense chemoimmunotherapy induction regimens with or without consolidation with autologous stem cell transplantation procedures are showing a potential for cure in a sizable fraction of patients. Similarly, in the salvage setting, preliminary experience with non-myeloablative allogeneic transplant may cure some patients even after multiple therapeutic failures. However, the recent knowledge of the three basic biologic derangements that are integrated in the disease may change the therapeutic approach of the disease in the near future. In fact, new drugs that target more specifically the major molecular alterations of the disease are being progressively incorporated into the therapeutic armamentarium of the disease. In the near future, more individualized approaches that will take into account not only risk factors present at diagnosis but also biomarkers representative of the molecular alterations present in the disease are foreseen. In this review, we are going to discuss the current therapeutic approaches and the main new drugs that target more specifically the major molecular pathways alterations of the disease. PMID- 20727007 TI - Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer's disease. AB - BACKGROUND AND PURPOSE: Life style-related disorders such as hypertension, diabetes, dyslipidemia, and obesity are reported to be a great risk of dementia. Adipocytokines released from adipose tissue are thought to modulate some brain functions including memory and cognition. We here analysed adiponectin, one of the most important adipocytokines, in plasma and cerebrospinal fluid (CSF) from cognitive normal controls (NC), mild cognitive impairment (MCI) subjects, and patients with Alzheimer's disease (AD) and discussed if/how adiponectin could relate to the pathogenesis of AD. METHODS: Normal controls (n = 28), MCI (n = 18), and AD (n = 27) subjects were recruited at Tohoku University Hospital. The diagnosis of AD was based on NINCDS-ADRDA criteria. All the blood and CSF samples were obtained from each fasted subject. Adiponectin was assayed using a sandwich ELISA system. RESULTS: The levels of adiponectin between in plasma and in CSF showed a positive correlation. Plasma adiponectin was significantly higher in MCI and AD compared to NC, whereas CSF adiponectin was significantly higher in MCI compared to NC. CONCLUSION: It is possible that the level of adiponectin in plasma reflects its level in CSF. The tendency to have higher adiponectin in plasma and CSF from MCI and AD suggests that this molecule plays a critical role in the onset of AD. PMID- 20727008 TI - Mortality risk in adults with newly diagnosed and chronic epilepsy: a population based study. AB - BACKGROUND: We analyzed mortality in adult patients with newly diagnosed and chronic epilepsy over a 13-year period. METHODS: Eighty-one patients aged >= 20 years with newly diagnosed epilepsy and 309 adult patients with chronic epilepsy were originally identified from population-based incidence and prevalence studies conducted in Tartu between 1994 and 1996. Patients with epilepsy were followed until the date of death or until the end of 2007. The standardized mortality ratio (SMR) was analyzed for both cohorts. The influences of age at diagnosis, sex, epilepsy syndrome, seizure type, risk factors and treatment compliance on the SMR were also investigated. RESULTS: The SMR was significantly increased in both cohorts, but was higher in patients with chronic epilepsy (SMR 3.1; 95% confidence interval [CI] 2.5-3.8) relative to patients with newly diagnosed epilepsy (SMR 2.6; 95% CI 1.8-3.5). In the newly diagnosed epilepsy cohort, the increased mortality risk was more pronounced in patients with complex partial seizures (SMR 5.6; 95% CI 2.4-11.0). In the chronic epilepsy cohort, the mortality risk was higher in patients with secondary generalized tonic-clonic seizures (SMR 3.4; 95% CI 2.5-4.5). Non-compliant patients had twice the mortality risk (SMR 4.2; CI 95% 2.7-6.2) compared to those who were on anticonvulsant treatment. CONCLUSIONS: Mortality rates are higher in people with newly diagnosed and chronic epilepsy. Mortality risks should be discussed with patients with epilepsy, especially if anticonvulsant treatment is refused despite recurrent seizures. PMID- 20727009 TI - Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine. AB - BACKGROUND: Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. METHODS: In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). RESULTS: FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. CONCLUSION: Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned. PMID- 20727010 TI - Biodegradation of phenanthrene by Alcaligenes sp. strain PPH: partial purification and characterization of 1-hydroxy-2-naphthoic acid hydroxylase. AB - Alcaligenes sp. strain PPH degrades phenanthrene via 1-hydroxy-2-naphthoic acid (1-H2NA), 1,2-dihydroxynaphthalene (1,2-DHN), salicylic acid and catechol. Enzyme activity versus growth profile and heat stability studies suggested the presence of two distinct hydroxylases, namely 1-hydroxy-2-naphthoic acid hydroxylase and salicylate hydroxylase. 1-Hydroxy-2-naphthoic acid hydroxylase was partially purified (yield 48%, fold 81) and found to be a homodimer with a subunit molecular weight of ~34 kDa. The enzyme was yellow in color, showed UV-visible absorption maxima at 274, 375 and 445 nm, and fluorescence emission maxima at 527 nm suggested it to be a flavoprotein. The apoenzyme prepared by the acid-ammonium sulfate (2 M) dialysis method was colorless, inactive and lost the characteristic flavin absorption spectra but regained ~90% activity when reconstituted with FAD. Extraction of the prosthetic group and its analysis by HPLC suggests that the holoenzyme contained FAD. The enzyme was specific for 1-H2NA and failed to show activity with any other hydroxynaphthoic acid analogs or salicylic acid. The K(m) for 1-H2NA in the presence of either NADPH or NADH remained unaltered (72 and 75 MUM, respectively), suggesting dual specificity for the coenzyme. The K(m) for FAD was determined to be 4.7 MUM. The enzyme catalyzed the conversion of 1-H2NA to 1,2-DHN only under aerobic conditions. These results suggested that 1-hydroxy 2-naphthoic acid hydroxylase is a flavoprotein monooxygenase specific for 1-H2NA and different from salicylate-1-hydroxylase. PMID- 20727011 TI - Coxiella burnetii type IVB secretion system region I genes are expressed early during the infection of host cells. AB - Analysis of the Coxiella burnetii RSA 493 (Nine Mile phase I strain) genome revealed ORFs with significant homology to the type IVB secretion system (T4BSS) of Legionella pneumophila. The T4BSS genes exist primarily at two loci, designated regions I (RI) and II. In C. burnetii, little is known about the T4BSS regions and the role they play in establishing and/or maintaining infection. Coxiella burnetii T4BSS RI contains genes arranged in three linkage groups: (1) icmW->CBU1651->icmX, (2) icmV->dotA->CBU1647, and (3) icmT->icmS->dotD->dotC >dotB->CBU1646. We used reverse transcriptase (RT)-PCR to demonstrate transcriptional linkage within the groups, and that icmX, icmV, and icmT are transcribed de novo by 8 h post infection (hpi). We then examined the transcript levels for icmX, icmW, icmV, dotA, dotB, and icmT during the first 24 h of an infection using quantitative RT-PCR. The expression initially increased for each gene, followed by a decrease at 24 hpi. Subsequently, we analyzed IcmT protein levels during infection and determined that the expression increases significantly from 8 to 24 hpi and then remains relatively constant. These data demonstrate temporal changes in the RNA of several C. burnetii T4SS RI homologs and the IcmT protein. These changes correspond to early stages of the C. burnetii infectious cycle. PMID- 20727012 TI - Transcriptional regulation of the mexEF-oprN multidrug efflux pump operon by MexT and an unidentified repressor in nfxC-type mutant of Pseudomonas aeruginosa. AB - Expression of the MexEF-OprN efflux pump in Pseudomonas aeruginosa seems to be upregulated by MexT. The region upstream of the mexEF-oprN operon contains mexT arranged in tandem with mexEF-oprN and separated by 230 bp of mexT-mexE intergenic DNA. Therefore, it is likely that this intergenic DNA contains the promoter-operator element of mexEF-oprN. To characterize how the expression of the mexEF-oprN operon was controlled, we analyzed the mexT-mexE intergenic DNA by constructing a series of intergenic DNA deletions connected with the mexE?lacZ reporter and made two important discoveries. The first was that the central region of the DNA contained two nod boxes. The mexT-proximal nod box was identified as the MexT-binding site by gel-shift assays using purified MexT. The mexT-distal nod box was required for the transcription of the mexEF-oprN operon, but not for the binding of MexT, suggesting that this region accommodates the binding of the RNA polymerase. The second observation is that there is a 13 bp inverted repeat sequence separated by 10 bp immediately upstream of the mexE gene. Deletion of this region caused a sudden rise in MexEF-OprN production, suggesting that this region accommodates the binding of a putative repressor protein. PMID- 20727013 TI - Cloning and expression of a mureinolytic enzyme from the mycobacteriophage TM4. AB - In this study, we describe the characterization, cloning, expression and purification of the lysin A gene of the mycobacteriophage TM4. The gene TM4_gp29 (gp29) is a 1644-bp gene that codes for a 58.6-kDa protein and contains peptidoglycan recognition protein, Zn-binding and amidase catalytic domains. The gene was cloned into Escherichia coli using the 'His-Tag' pQE60 vector. After affinity chromatography-mediated purification, the protein was concentrated and visualized using sodium dodecyl sulphate polyacrylamide gel electrophoresis. Evidence of peptidoglycan-degrading activity was observed initially by a chloroform assay and later by conventional zymogram analysis. PMID- 20727014 TI - Dose response effect of rutin a dietary antioxidant on alcohol-induced prooxidant and antioxidant imbalance - a histopathologic study. AB - The present study was designed to investigate the effect of rutin on ethanol induced hepatotoxicity in a dose-dependent manner in rats. Male albino rats were divided into six groups. Group 1 rats served as control and group 2 rats received rutin 100 mg/kg body weight. Hepatotoxicity was induced in groups 3-6 rats (20% ethanol) for 60 days. In addition, groups 4-6 rats received rutin at doses of 25, 50, 100 mg/kg body weight, respectively for the last 30 days of the experiment. We observed a significant increase in the activities of liver marker enzymes, serum amino transferases, alkaline phosphatase, gamma-glutamyl transpeptidase the levels of thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides, and a decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione and its related enzymes, vitamins C and E when compared to ethanol-fed rats. Rutin supplementation along with ethanol significantly decreased the levels of liver marker enzymes, lipid peroxidation and significantly elevated the activities of liver SOD, CAT, GSH, glutathione peroxidase, vitamins C and E when compared to untreated ethanol supplemented rats. Among the three doses, 100 mg/kg body weight of rutin was found to exert a more pronounced hepatoprotective effect against ethanol-induced toxicity. Our results were also confirmed by the histopathologic observations. PMID- 20727015 TI - Hypertrophic cardiomyopathy in childhood and adolescence - strategies to prevent sudden death. AB - Clinically overt hypertrophic cardiomyopathy is the most common cause of sudden unexpected death in childhood and has significantly higher sudden death mortality in the 8- to 16-year age range than in the 17- to 30-year age range. A combination of electrocardiographic risk factors (a limb-lead ECG voltage sum >10 mV) and/or a septal wall thickness >190% of upper limit of normal for age (z score > 3.72) defines a paediatric high-risk patient with great sensitivity. Syncope, blunted blood pressure response to exercise, non-sustained ventricular tachycardia and a malignant family history are additional risk factors. Of the medical treatments used, only beta-blocker therapy with lipophilic beta-blockers (i.e. propranolol, metoprolol or bisoprolol) have been shown to significantly reduce risk of sudden death, with doses >= 6 mg/kg BW in propranolol equivalents giving around a tenfold reduction in risk. Disopyramide therapy is a very useful adjunct to beta-blockers to improve prognosis in those patients that have dynamic outflow obstruction in spite of large doses of beta-blocker, and its use in patients with hypertrophic cardiomyopathy is not associated with significant pro arrhythmia mortality. Calcium-channel blockers increase the risk of heart failure associated death in hypertrophic cardiomyopathy (HCM) patients with severe generalized hypertrophy and should be avoided in such patients. Amiodarone does not protect against sudden death, and long-term use in children usually has to be terminated because of side effects. Therapy with internal cardioverter defibrillator implantation has high paediatric morbidity, 27% incidence of inappropriate shocks, and does not absolutely protect against mortality but is indicated as secondary prevention or in very high-risk patients. PMID- 20727016 TI - Foreword: Groundwater modeling and public policy. PMID- 20727017 TI - A new capture fraction method to map how pumpage affects surface water flow. AB - All groundwater pumped is balanced by removal of water somewhere, initially from storage in the aquifer and later from capture in the form of increase in recharge and decrease in discharge. Capture that results in a loss of water in streams, rivers, and wetlands now is a concern in many parts of the United States. Hydrologists commonly use analytical and numerical approaches to study temporal variations in sources of water to wells for select points of interest. Much can be learned about coupled surface/groundwater systems, however, by looking at the spatial distribution of theoretical capture for select times of interest. Development of maps of capture requires (1) a reasonably well-constructed transient or steady state model of an aquifer with head-dependent flow boundaries representing surface water features or evapotranspiration and (2) an automated procedure to run the model repeatedly and extract results, each time with a well in a different location. This paper presents new methods for simulating and mapping capture using three-dimensional groundwater flow models and presents examples from Arizona, Oregon, and Michigan. PMID- 20727018 TI - Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development. AB - AIMS: The aetiology of vulvar squamous cell carcinomas (SCC) that are not causally associated with high-risk human papillomavirus remains largely elusive. The aim of this study was to analyse the inflammatory response in its presumed precursor lesions, lichen sclerosus (LS) and differentiated vulvar intraepithelial neoplasia (dVIN), and provide evidence that dVIN is a likely precursor of vulvar SCC. METHODS AND RESULTS: Immunohistochemical analyses for CD4+, CD8+, CD20+, CD68+, S100+ and tryptase-positive immune cells were performed and quantified in LS (n = 7), dVIN (n = 19), SCC (n = 11), and normal vulvar tissue (n = 8). The subepithelial inflammatory response in dVIN and SCC was comparable, but absent in LS. Abundant intraepithelial mast cells were observed in dVIN only, and confirmed by electron microscopy, toluidine blue staining and cKIT expression. Adjacent keratinocytes displayed increased proliferation as determined by MIB-1 positivity. Electron microscopy revealed intraepithelial mast cell degranulation. Intraepithelial mast cells were not or infrequently observed in vulvar hyperplasia (n = 13), condylomata acuminata (n = 5), keratinocytic intraepidermal neoplasia of sun-exposed skin (n = 15), epidermal hyperplasia of head and neck (n = 12), and psoriasis (n = 3). CONCLUSIONS: These data indicate that dVIN can be recognized by intraepithelial mast cells and that they might promote the progression of dVIN to SCC. PMID- 20727019 TI - Screen-detected pleomorphic lobular carcinoma in situ (PLCIS): risk of concurrent invasive malignancy following a core biopsy diagnosis. AB - AIMS: Pleomorphic lobular carcinoma in situ (PLCIS) is an uncommon, recently recognized variant of lobular carcinoma in situ (LCIS). Its natural history, biological behaviour and clinical characteristics are uncertain. The aim was to review the radiological and pathological findings in a series of screen-detected PLCIS diagnosed on needle core biopsy with a view to determining the diagnostic features, immunohistological profile and risk of concurrent invasive malignancy. METHODS AND RESULTS: Ten cases of core biopsy-diagnosed, screen-detected PLCIS were identified. Core biopsy findings were compared with pathological findings at subsequent surgery. Two cases were associated with possible microinvasion on the core. Two of 10 had invasive lobular carcinoma and one had microinvasive lobular carcinoma on subsequent surgical excision (positive predictive value for malignancy = 30%). There was associated conventional LCIS on either core or excision biopsy in all cases except one. All three cases of oestrogen receptor (ER)-negative PLCIS arose in the context of ER+ conventional LCIS. CONCLUSIONS: PLCIS is a potentially more aggressive lesion than conventional LCIS and may present as mammographic calcification through a breast screening programme. Diagnosis may be problematic and immunohistochemical markers including ER may prove a useful diagnostic adjunct. There is a significant risk of concurrent invasive carcinoma following a core biopsy diagnosis. PMID- 20727020 TI - DNA methylation analysis of the HIF-1alpha prolyl hydroxylase domain genes PHD1, PHD2, PHD3 and the factor inhibiting HIF gene FIH in invasive breast carcinomas. AB - AIMS: Hypoxia-inducible factor-1 (HIF-1) activity is regulated by prolyl hydroxylase (PHD1, PHD2, PHD3) and factor inhibiting HIF-1 (FIH) that target the alpha subunit of HIF-1 (HIF-1alpha) for proteosomal degradation. We hypothesised that the elevated HIF-1alpha level is due in some tumours to epigenetic silencing by DNA hypermethylation of the promoter region of one or more of the PHDs and FIH genes. The aims were to define the presence or absence of promoter methylation of PHDs and FIH in cell lines of various sources and breast carcinomas and, if present, determine its effect on mRNA and protein expression. METHODS AND RESULTS: Tumour cell lines (n = 20) and primary invasive breast carcinomas (n = 168) were examined for promoter region DNA methylation using methylation sensitive high-resolution melting. There was evidence of PHD3 but not of PHD1, PHD2 or FIH DNA methylation in breast cancer (SkBr3) and leukaemic (HL60 and CCRF CEM) cell lines, but there was no evidence of methylation in any of 168 breast cancers. Only the high-level PHD3 methylation seen in leukaemic cell lines correlated with absent mRNA and protein expression. CONCLUSIONS: Methylation induced epigenetic silencing of PHD1, PHD2, PHD3 and FIH is unlikely to underlie up-regulated HIF-1alpha expression in human breast cancer but may play a role in other tumour types. PMID- 20727021 TI - p16 Immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection. AB - AIMS: The association between human papillomavirus (HPV) and cervical carcinoma is well known, with HPV being identifiable in almost all cervical squamous carcinomas and most adenocarcinomas. However, the prevalence of HPV in unusual morphological types of cervical adenocarcinoma has not been investigated extensively. The aim was to determine HPV status in a series of primary cervical adenocarcinomas, enriched for unusual morphological types. The relationship between HPV and p16 immunoreactivity in these neoplasms was also investigated, as it is generally assumed that in cervical neoplasms diffuse p16 expression is predictive of the presence of high-risk HPV. METHODS AND RESULTS: Sixty-three cervical adenocarcinomas, comprising those of usual type (n = 43), minimal deviation type (n = 4), gastric type (n = 3), intestinal type (n = 3), mesonephric type (n = 3), clear cell type (n = 4), serous type (n = 2) and hepatoid type (n = 1) underwent linear array HPV genotyping and immunohistochemistry for p16. Overall, HPV was identified in 32 of 56 cases (57%) in which sufficient DNA was present for analysis. The most common HPV types were 16 and 18, with these being identified in 20 and 18 cases, respectively, either alone or in combination. Seventy-eight per cent of usual-type adenocarcinomas were HPV-positive, as was the single serous carcinoma in which there was sufficient DNA for analysis. In contrast, all minimal deviation adenocarcinomas and those of gastric, intestinal, mesonephric and clear cell types were HPV negative, as was the single hepatoid carcinoma. All usual-type adenocarcinomas exhibited p16 immunoreactivity (diffuse staining in all but one case), as did 11 of 20 of those of unusual morphological type (five focal, six diffuse). CONCLUSIONS: Most, but not all, cervical adenocarcinomas of usual type contain HPV, but those of unusual morphological type are almost always HPV-negative. This has implications for the efficacy of HPV vaccination in the prevention of cervical adenocarcinoma. A significant proportion of cervical adenocarcinomas are p16-positive in the absence of HPV, illustrating that in these neoplasms diffuse p16 immunoreactivity is not a reliable surrogate marker of the presence of high risk HPV. PMID- 20727022 TI - A unique renal cell carcinoma with features of papillary renal cell carcinoma and thyroid-like carcinoma: a morphological, immunohistochemical and genetic study. PMID- 20727023 TI - Cathepsin K expression: a useful marker for the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans. PMID- 20727024 TI - The pathology of bone marrow failure. AB - An important indication for bone marrow investigation is the presence of bone marrow failure, which manifests itself as (pan)cytopenia. The causes of cytopenia are varied and differ considerably between childhood and adulthood. In the paediatric age group inherited bone marrow failure syndromes are important causes of bone marrow failure, but they play only a minor role in later life. This review gives a comprehensive overview of bone marrow failure disorders in children and adults. We classified the causes of bone marrow failure according to the main presenting haematological abnormality, i.e. anaemia, neutropenia, thrombocytopenia or pancytopenia. The following red cell disorders are discussed: red cell aplasia, sideroblastic anaemia, congenital dyserythropoietic anaemia, haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, iron deficiency anaemia, anaemia of chronic disease and megaloblastic anaemia. The neutropenias occur in the context of Shwachman-Diamond syndrome (SDS), severe congenital neutropenia, cyclic neutropenia, immune-related neutropenia and non-immune neutropenia. In addition, the following causes of thrombocytopenia are discussed: congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, immune-related thrombocytopenia and non-immune thrombocytopenia. Finally, we pay attention to the following pancytopenic disorders: Fanconi anaemia, dyskeratosis congenita, aplastic anaemia, myelodysplastic syndromes and human immunodeficiency virus (HIV) infection. PMID- 20727025 TI - B-lymphocyte biology. PMID- 20727026 TI - Functional diversity of stem and progenitor cells with B-lymphopoietic potential. AB - Technical advances have made it possible to separate hematopoietic tissues such as the bone marrow into ever smaller populations, complicating our understanding of immune system replenishment. Patterns of surface marker expression and transcription profiles as well as results obtained with reporter mice suggest that lymphopoietic cells are not closely synchronized, and there is considerable cell to cell variation. Loss of differentiation options is gradual, and ultimate fate can be established at different stages of lineage progression. For example, individual hematopoietic stem cells can be biased such that some are very poor sources of lymphocytes as contrasted to ones with balanced outputs. Still other hematopoietic stem cells are effective at generating B and T cells but are defective with respect to expansion and difficult to distinguish from early lymphoid progenitors. That diversity carries forward to later events, and similar appearing cells in the immune system can arise from alternate differentiation pathways. In fact, new categories of lymphoid progenitors are still being discovered. Heterogeneity provides adaptability as hematopoiesis can be dramatically altered during infections, influencing numbers and types of cells that are produced. PMID- 20727028 TI - Chromosome dynamics and the regulation of V(D)J recombination. AB - Perhaps no process has provided more insight into the fine manipulation of locus accessibility than antigen receptor rearrangement. V(D)J recombination is carried out by the lymphoid-specific recombination-activating (RAG 1 and 2) proteins and the non-homologous end joining machinery; yet, it occurs only at specific loci (or portions of loci) during specific developmental stages. This spatiotemporal restriction of recombination is achieved through precise alterations in locus accessibility. In this article, we discuss the work of our laboratory in elucidating how nuclear sublocalization, chromosome conformation, and locus interactions contribute to regulating this complex process. We also discuss what is known about how key factors in B-cell development (such as the ubiquitously expressed helix loop helix protein E2A, the B-cell specific transcription factors EBF1 and Pax5, and the interleukin-7 cytokine signaling pathway) exert their effects through changes in nuclear dynamics. PMID- 20727029 TI - Role of PI3K in the generation and survival of B cells. AB - Engagement of the B-cell antigen receptor (BCR) or its precursor, the pre-BCR, induces a cascade of biochemical reactions that regulate the differentiation, selection, survival, and activation of B cells. This cascade is initiated by receptor-associated tyrosine kinases that activate multiple downstream signaling pathways. Since it is required for metabolism, cell growth, development, and survival, the activation of phosphoinositide 3-kinase (PI3K)-dependent pathways represents a crucial event of BCR/pre-BCR signaling. The phosphorylated substrates of the PI3K promote specific recruitment of selected signaling proteins to the plasma membrane, where important signaling complexes are formed to mediate the above-mentioned biological processes. Here, we review the principles of PI3K signaling and highlight the role of an important PI3K-driven module in VDJ recombination of immunoglobulin (Ig) genes during early B-cell development as compared with class switch recombination of Ig genes in mature B cells after activation by specific antigens. Furthermore, we discuss the role of PI3K in the survival of mature B cells, which is strictly dependent on BCR expression and basal BCR signaling. PMID- 20727030 TI - T cells and follicular dendritic cells in germinal center B-cell formation and selection. AB - Germinal centers (GCs) are specialized microenvironments formed after infection where activated B cells can mutate their B-cell receptors to undergo affinity maturation. A stringent process of selection allows high affinity, non-self reactive B cells to become long-lived memory B cells and plasma cells. While the precise mechanism of selection is still poorly understood, the last decade has advanced our understanding of the role of T cells and follicular dendritic cells (FDCs) in GC B-cell formation and selection. T cells and non-T-cell-derived CD40 ligands on FDCs are essential for T-dependent (TD) and T-independent GC formation, respectively. TD-GC formation requires Bcl-6-expressing T cells capable of signaling through SAP, which promotes formation of stable T:B conjugates. By contrast, differentiation of B blasts along the extrafollicular pathway is less dependent on SAP. T-follicular helper (Tfh) cell-derived CD40L, interleukin-21, and interleukin-4 play important roles in GC B-cell proliferation, survival, and affinity maturation. A role for FDC-derived integrin signals has also emerged: GC B cells capable of forming an immune synapse with FDCs have a survival advantage. This emerges as a powerful mechanism to ensure death of B cells that bind self-reactive antigen, which would not normally be presented on FDCs. PMID- 20727027 TI - Allelic exclusion of immunoglobulin genes: models and mechanisms. AB - The allelic exclusion of immunoglobulin (Ig) genes is one of the most evolutionarily conserved features of the adaptive immune system and underlies the monospecificity of B cells. While much has been learned about how Ig allelic exclusion is established during B-cell development, the relevance of monospecificity to B-cell function remains enigmatic. Here, we review the theoretical models that have been proposed to explain the establishment of Ig allelic exclusion and focus on the molecular mechanisms utilized by developing B cells to ensure the monoallelic expression of Ig kappa and Ig lambda light chain genes. We also discuss the physiological consequences of Ig allelic exclusion and speculate on the importance of monospecificity of B cells for immune recognition. PMID- 20727031 TI - In vivo control of B-cell survival and antigen-specific B-cell responses. AB - Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SW(HEL) model for analyzing antigen specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation. PMID- 20727032 TI - Unique properties of memory B cells of different isotypes. AB - Memory antibody responses are typically seen to T-cell-dependent antigens and are characterized by the rapid production of high titers of high-affinity antigen specific antibody. The hallmark of T-cell-dependent memory B cells is their expression of a somatically mutated, isotype-switched B-cell antigen receptor, features that are mainly generated in germinal centers. Classical studies have focused on isotype-switched memory B cells (mainly IgG isotype) and demonstrated their unique intrinsic properties in terms of localization and responsiveness to antigen re-exposure. However, recent advances in monitoring antigen-experienced B cells have revealed the considerable heterogeneity of memory B cells, which include unswitched IgM(+) and/or unmutated memory B cells. The IgM and IgG type memory B cells reside in distinct locations and appear to possess distinct origins and effector functions, together orchestrating humoral memory responses. PMID- 20727033 TI - Memory B and memory plasma cells. AB - Vaccination provides a powerful means to control infections. It exploits and exemplifies the ability of the immune system to preserve the information that a specific pathogen has been encountered in the past. The cells and molecular mechanisms of immunological memory are still being discussed controversially. Here, we review the current concepts of memory B cells, the signals involved in their maintenance, and their role in enhanced secondary reactions. Memory plasma cells, secreting protective antibodies over lifetime, have been recognized only recently. Their characterization as cells resting in terms of proliferation and migration, and surviving in dedicated stromal niches, in the absence of antigen, has generated new concepts of how memory cells in general are organized by stroma cells, the 'resting memory'. In autoimmunity and chronic inflammation, memory B cells and memory plasma cells can be essential players, and they require special attention, as they do not respond to most conventional therapies. Their selective targeting will depend on a molecular understanding of their lifestyle. PMID- 20727034 TI - Plasma cell development and survival. AB - Plasma cells have long been recognized as the basis of humoral immunity, yet we are only now beginning to appreciate the complexities of plasma cell development and the fact that not all plasma cells are created equal. In vivo, plasma cells can arise from two developmental routes: one occurring outside the follicle and another within the germinal center. A B cell's decision to follow one of these pathways is in part determined by the phenotypic subset to which it belongs and is also influenced by the nature of the antigen eliciting the response and the affinity of the B-cell receptor for that antigen. Once a plasma cell has chosen one of these pathways, the outcome of differentiation is relatively hard-wired. However, the phenotype of the plasma cells arising from these two pathways is distinct in terms of survival, location, and the quantity and quality of antibody they secrete. The extra-follicular pathway represents a relatively unchecked route to differentiation resulting in the generation of short-lived plasma cells that secrete low-affinity antibody. The germinal center response, however, allows the integration of external signals to delay plasma cell differentiation, eventually generating a plasma cell that secretes high-affinity antibody of an appropriate class, and that persists for a lifetime. The means by which these varying properties are conferred to a developing plasma cell are the subject of intense investigation. PMID- 20727036 TI - Roles of B-1 and B-2 cells in innate and acquired IgA-mediated immunity. AB - The gut harbors an extremely dense and complex community of microorganisms that are in constant dialog with our immune cells. The gut bacteria provide strong selective pressure to the host to evolve innate and adaptive immune responses required for the maintenance of local and systemic homeostasis. One of the most conspicuous responses of the gut immune system following microbial colonization is the production of immunoglobulin A (IgA). In this review, we discuss the roles of B-1 and B-2 cells in IgA-mediated immunity and present an updated view for the sites and mechanisms of IgA synthesis in the gut. We summarize the role of secretory IgAs for regulation of microbial communities and provide clues as to how the gut microbiota contributes to the development of the gut-associated lymphoid tissues. PMID- 20727037 TI - Visualizing a role for the actin cytoskeleton in the regulation of B-cell activation. AB - Appropriate activation of B cells is required for mounting protective humoral immune responses. B-cell activation is initiated following specific recognition of antigen by the B-cell receptor (BCR) and results in the generation of antibody secreting plasma cells and long-lived memory cells. Initial imaging approaches revealed that B cells undergo dramatic molecular and morphological reorganizations following recognition of antigen. A number of these studies pointed to a role for the underlying cytoskeleton in regulating early events of B cell activation. More recently, groundbreaking advances in imaging technologies have enabled direct visualization of the role for the cytoskeleton in regulating events at the B-cell membrane. Indeed, we have demonstrated that an ezrin-defined actin network shapes BCR diffusion and signaling both in the resting state and following antigen-induced activation. Importantly, alongside these in vitro imaging approaches, it has been demonstrated that mutations in cytoskeleton regulators such as CD19, dedicator of cytokinesis 8 (DOCK8), and Wiskott-Aldrich syndrome protein (WASp) are often associated with antibody deficiency syndromes in humans, establishing the importance of cytoskeleton reorganizations in conferring effective adaptive immunity. PMID- 20727035 TI - New insights into the enigma of immunoglobulin D. AB - Immunoglobulin D (IgD) has remained a mysterious antibody class for almost half a century. IgD was initially thought to be a recently evolved Ig isotype expressed only by some mammalian species, but recent discoveries in fishes and amphibians demonstrate that IgD was present in the ancestor of all jawed vertebrates and has important immunological functions. The structure of IgD has been very dynamic throughout evolution. Mammals can express IgD through alternative splicing and class switch recombination. Active cell-dependent and T-cell-independent IgM-to IgD class switching takes place in a unique subset of human B cells from the upper aerodigestive mucosa, which provides a layer of mucosal protection by interacting with many pathogens and their virulence factors. Circulating IgD can bind to myeloid cells such as basophils and induce antimicrobial, inflammatory, and B-cell-stimulating factors upon cross-linking, which contributes to not only immune surveillance but also inflammation and tissue damage when this pathway is overactivated under pathological conditions. Recent research shows that IgD is an important immunomodulator that orchestrates an ancestral surveillance system at the interface between immunity and inflammation. PMID- 20727038 TI - B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. AB - One remarkable feature of the immune system is its capacity to maintain constant numbers of resting immune cells despite the complex nature of signals needed throughout development and maturation. For many years, B-cell survival was thought to rely solely on B-cell receptor (BCR) tonic signals that would trigger necessary basal survival pathways. The discovery of the tumor necrosis factor (TNF)-like ligand BAFF(B-cell activating factor belonging to the TNF family)/BLyS (B-lymphocyte stimulator) changed these views entirely, as BAFF-deficient mice lack most mature B cells, and treatment with BAFF inhibitors leads to their loss, establishing BAFF as an unappreciated key B-cell survival factor. BAFF-mediated survival signals have been mapped and signaling crosstalk with the BCR has been identified, explaining the need for both BCR- and BAFF-mediated signals for B cell survival. However, this crosstalk only explains how BCR and BAFF signals cooperate to produce survival proteins and yet, inactivating pro-apoptotic factors such as FOXO proteins, which may be managed separately by BAFF and the BCR, has emerged as an equally important step for survival. In this review, we present new views on B-cell survival, at all stages of B-cell life, and suggest that, in most cases, survival results from the production of appropriate survival factors balanced with the adequate and timely degradation of pro-apoptotic proteins. PMID- 20727039 TI - Differential B-lymphocyte regulation by CD40 and its viral mimic, latent membrane protein 1. AB - CD40 plays a vital role in humoral immunity, via its potent and multifaceted function as an activating receptor of various immune cells, most notably B lymphocytes. The Epstein-Barr virus-encoded transforming protein latent membrane protein 1 (LMP1) serves as a functional mimic of CD40 signals to B cells but lacks key regulatory controls that restrain CD40 signaling. This allows LMP1 to activate B cells in an abnormal manner that can contribute to the pathogenesis of human B-cell lymphoma and autoimmune disease. This review focuses upon a comparative analysis of CD40 versus LMP1 functions and mechanisms of action in B lymphocytes, discussing how this comparison can provide valuable information on both how CD40 signaling is normally regulated and how LMP1 disrupts the normal CD40 pathways, which can provide information of value to therapeutic design. PMID- 20727041 TI - B-cell targeted therapies in human autoimmune diseases: an updated perspective. AB - The advent of therapies that specifically target the B-lymphocyte lineage in human disease has rejuvenated interest in the mechanistic biology by which B cells mediate autoimmunity. B cells have a multitude of effector functions including production of self-reactive antibodies, ability to present antigen to T lymphocytes in the context of costimulation, involvement in generation and maintenance of neo-organogenesis at sites of disease, and opposing function through production of both immunostimulatory and immunomodulatory cytokines. In this review, we first discuss the role of B cells in driving autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and Sjogren's syndrome, and discuss how studies in these diseases have revealed differentially important roles for the multiple B-cell effector functions. These data reveal the complex and interrelated roles of B cells working in concert with other components of the innate and adaptive immune system to drive pathogenesis. We then focus on data from mouse and human in which B cells in the setting of disease have been targeted with drugs directed against CD20, CD22, and the BAFF (B-cell activating factor belonging to the tumor necrosis factor family)/APRIL (a proliferation inducing ligand) pathways. Pre-clinical studies in animal models in addition to and clinical trials targeting B cells have added further to the understanding of the differential roles B cells play in disease both through demonstration of clinical efficacy in the context of B-cell depletion or modulation, and also by failure of B-cell targeting in some diseases and disease patient subgroups. Moving forward, it will be imperative to apply these lessons to new interventional trials to ensure better targeting of the B-cell lineage and concomitantly better selection of patients most likely to benefit from these therapies. PMID- 20727040 TI - Molecular underpinning of B-cell anergy. AB - A byproduct of the largely stochastic generation of a diverse B-cell specificity repertoire is production of cells that recognize autoantigens. Indeed, recent studies indicate that more than half of the primary repertoire consists of autoreactive B cells that must be silenced to prevent autoimmunity. While this silencing can occur by multiple mechanisms, it appears that most autoreactive B cells are silenced by anergy, wherein they populate peripheral lymphoid organs and continue to express unoccupied antigen receptors yet are unresponsive to antigen stimulation. Here we review molecular mechanisms that appear operative in maintaining the antigen unresponsiveness of anergic B cells. In addition, we present new data indicating that the failure of anergic B cells to mobilize calcium in response to antigen stimulation is not mediated by inactivation of stromal interacting molecule 1, a critical intermediary in intracellular store depletion-induced calcium influx. PMID- 20727043 TI - Polymorphisms within exon 9 but not intron 8 of the vitamin D receptor are associated with the nephropathic complication of type-2 diabetes. AB - The impact of several environmental and genetic factors on diabetes and its complications is well documented but there is an urgent need to understand more about genetic risk factors associated with this disease. The present study was aimed at examining the two single nucleotide polymorphisms (SNP) in intron 8 and exon 9 of the vitamin D receptor (VDR) gene in nephropathic and non-nephropathic type-2 diabetic patients. In this clinical study, peripheral blood samples were obtained from 100 type-2 diabetic patients, 100 nephropathic type-2 diabetic patients and 100 healthy controls. DNA was extracted and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to examine two SNP polymorphisms within the VDR gene. Our results showed a significant difference in the Taq-1 evaluated genotypes of exon 9 in the VDR gene of diabetic individuals with (P=0.012) and without (P <= 0.001) nephropathy. Analysis of the Taq-1 evaluated alleles of nephropathic (P=0.917) and non nephropathic (P=1.000) did not show a significant difference. We also evaluated the intron 8 Apa-1 alleles in patients with (P=0.480) and without nephropathy (P=0.543) and determined there were no differences between these groups. Our results also showed that the frequency of Apa-1 genotypes did not differ in nephropathic (P=0.224) and non-nephropathic (P=0.236) diabetic patients. Based on our results, it can be concluded that VDR and its functional polymorphism in exon 9 may play an important role in pathogenesis of type-2 diabetes and more investigations are required to clarify their role in nephropathy. PMID- 20727044 TI - Immunotherapy of melanoma by GPI-anchored IL-21 tumour vaccine involves down regulating regulatory T cells in mouse model. AB - In this study, we developed a tumour cell vaccine expressing a glycosylphosphatidylinositol (GPI)-anchored IL-21 to test the effect of immunotherapy of melanoma in mouse model. The results indicated that the tumour vaccine was functional, exhibiting delayed tumour growth and prolonging longevity of tumour bearing mice. The immunotherapeutic effect was associated with decreasing the numbers of CD4(+) CD25(+) Foxp3(+) Treg (Tregs) cells, increasing IFN-gamma level and promoting lymphocyte-infiltration in tumour tissues. Overall, our data demonstrate that the GPI-anchored IL-21 tumour vaccine regulates immune responses at least in part by down-regulating Tregs and reveals enhanced efficacy of tumour vaccine therapy of melanoma. PMID- 20727045 TI - Two polymorphisms in the TIM-4 gene are associated with asthma in a Chinese Han population. AB - The gene family of the T cell immunoglobulin and mucin domain (TIM) proteins encodes cell surface receptors that are involved in the regulation of Th1- and Th2-cell-mediated immunity. TIM-1 gene has been found to be associated with asthma in several populations. TIM-4, the natural ligand for TIM-1, may influence the susceptility to asthma.To investigate the association of the TIM-4 gene polymorphisms with asthma in a Chinese Han population. Three single nucleotide polymorphisms (SNPs) in TIM-4 gene, rs6882076, rs12658558 and rs4702747, were genotyped in 551 unrelated asthma patients and 549 healthy controls. We found that two SNPs of the TIM-4 gene, rs6882076 and rs4702747, were associated with asthma susceptibility in our study population (with P-values = 0.009 and 0.005 respectively). No association was observed between asthma and rs12658558. Our results suggest that TIM-4 gene polymorphisms are associated with asthma in a Chinese Han population. PMID- 20727046 TI - How to peer review. PMID- 20727047 TI - Editorial comment to Maintenance intravesical bacillus Calmette-Guerin instillation for Ta, T1 cancer and carcinoma in situ of the bladder: randomized controlled trial by the BCG Tokyo Strain Study Group. PMID- 20727048 TI - Editorial comment from Dr Hassan to Short ileal segment for orthotopic neobladder: a feasibility study. PMID- 20727049 TI - Editorial comment to Anterior perirectal fat tissue thickness closely associated with obesity strongly predicts recurrence after high-intensity focused ultrasound for prostate cancer. PMID- 20727050 TI - Inverse expression of estrogen receptor-beta and nuclear factor-kappaB in urinary bladder carcinogenesis. AB - OBJECTIVES: To investigate the expression of nuclear factor-kappaB (NF-kappaB) and estrogen receptor-beta (ER-beta) signalling pathways in bladder urothelial carcinoma according to clinicopathological features, in order to elucidate their role during carcinogenesis. METHODS: Immunohistochemical methodology was carried out on formalin-fixed, paraffin-embedded sections from urinary bladder carcinomas of 140 patients (94 males and 46 females) who underwent transurethral resection of bladder neoplasms. Correlations between ER-beta and NF-kappaB, and tumor grade and T-stage were evaluated, along with demographic data, sex and age. RESULTS: A significant decrease in ER-beta expression in the nucleus of bladder cells during loss of cell differentiation (r(s) = -0.61, P-value < 0.001, test of trend P value = 0.003) and in muscle invasive carcinomas (T2-T4; test of trend P-value < 0.001) was found. p65 Subunit of NF-kappaB was expressed in the nucleus and in the cytoplasm of bladder epithelial cells. A strong positive association between tumor grade and nuclear expression of NF-kappaB was shown. No correlation between NF-kappaB, nuclear or cytoplasmic staining, with T-stage was observed. An inverse correlation between ER-beta and nuclear p65 immunoreactivity was observed (r(s) = -0.45, P-value < 0.001). There was no correlation with demographic data. CONCLUSIONS: Our immunohistochemical study suggests the possible inverse regulation of NF-kappaB and ER-beta transcription factor during bladder carcinogenesis. Selective ER-beta agonists and agents, inhibitors of NF-kappaB, might represent a possible new treatment strategy for bladder urothelial tumors. PMID- 20727051 TI - Editorial comment to Inverse expression of estrogen receptor-beta and nuclear factor-kappaB in urinary bladder carcinogenesis. PMID- 20727052 TI - Editorial comment to Treatment outcomes of sorafenib for first line or cytokine refractory advanced renal cell carcinoma in Japanese patients. PMID- 20727053 TI - Complete remission of bulky lung metastases of renal cell carcinoma by low-dose interferon-alpha monotherapy. PMID- 20727054 TI - Life threatening intraperitoneal hemorrhage with abdominal compartment syndrome: unusual presentation of renal angiomyolipoma. PMID- 20727055 TI - Prostatorectal fistula following intravesical bacillus Calmette-Guerin immunotherapy for carcinoma in situ of the urinary bladder. PMID- 20727057 TI - A cost-effectiveness evaluation of enamel matrix derivatives alone or in conjunction with regenerative devices in the treatment of periodontal intra osseous defects. AB - PURPOSE: To identify the most cost-effective approach to treatment of infrabony lesions with enamel matrix derivatives (EMD). METHODS: We incorporated costs and clinical outcomes of 12 different treatment techniques (including flap operation, EMD alone, and EMD in association with other reconstructive devices) within a decision tree model in which costs were based on insurance regulations in Germany and health outcomes followed a recent meta-analysis. The most cost-effective treatment option was identified on the basis of the maximum net benefit criterion. RESULTS: Treatment techniques using EMD were cost-efficient if the decision maker's willingness-to-pay (WTP) was at least ?150-175 per incremental mm of pocket probing depth reduction and clinical attachment level gain, respectively (1-year perspective). When EMD was affordable, the maximum net benefit was achieved by treatment with EMD in conjunction with bioactive glass or bovine bone substitutes. Additional application of platelet-rich plasma (PRP) or a resorbable membrane came at relatively high costs. CONCLUSIONS: If EMD use is indicated, EMD in conjunction with either bioactive glass or bovine bone substitutes is more cost-effective than EMD alone. The additional use of PRP or a resorbable membrane may only be justifiable when monetary resources for treatment are very generous. PMID- 20727058 TI - Synchronous work: myth or reality? A critical study of teams in health and medical care. AB - RATIONALE, AIMS AND OBJECTIVES: In this article, ideal conceptions about teamwork are tested. The research question posed is: How are teams in psychiatry formed? Three theoretical concepts that distinguish groups from teams are presented: sequentiality, parallelism and synchronicity. The presumption is that groups cooperate sequentially and teams synchronously, while the parallel work mode is a transitional form between group and team. METHODS: Three psychiatric outpatient teams at a university hospital specialist clinic were studied. Data were collected through 25 personal interviews and 82 hours of observations. The data collection was carried out over 18 months (2008-2009). RESULTS: Results show: (1) that the three theoretical distinctions between group and team need to be supplemented with two intermediate forms, semiparallel and semisynchronous teamwork; and (2) that teamwork is not characterized by striving towards a synchronous ideal but instead is marked by an adaptive interaction between sequential, parallel and synchronous working modes. CONCLUSIONS: The article points to a new intermediate stage between group and team. This intermediate stage is called semiparallel teamwork. The study shows that practical teamwork is not characterized by a synchronous ideal, but rather is about how to adaptively find acceptable solutions to a series of practical problems. The study emphasizes the importance of the team varying between different working modes, so-called semisystematics. PMID- 20727056 TI - Subplate in the developing cortex of mouse and human. AB - The subplate is a largely transient zone containing precocious neurons involved in several key steps of cortical development. The majority of subplate neurons form a compact layer in mouse, but are dispersed throughout a much larger zone in the human. In rodent, subplate neurons are among the earliest born neocortical cells, whereas in primate, neurons are added to the subplate throughout cortical neurogenesis. Magnetic resonance imaging and histochemical studies show that the human subplate grows in size until the end of the second trimester. Previous microarray experiments in mice have shown several genes that are specifically expressed in the subplate layer of the rodent dorsal cortex. Here we examined the human subplate for some of these markers. In the human dorsal cortex, connective tissue growth factor-positive neurons can be seen in the ventricular zone at 15 22 postconceptional weeks (PCW) (most at 17 PCW) and are present in the subplate at 22 PCW. The nuclear receptor-related 1 protein is mostly expressed in the subplate in the dorsal cortex, but also in lower layer 6 in the lateral and perirhinal cortex, and can be detected from 12 PCW. Our results suggest that connective tissue growth factor- and nuclear receptor-related 1-positive cells are two distinct cell populations of the human subplate. Furthermore, our microarray analysis in rodent suggested that subplate neurons produce plasma proteins. Here we demonstrate that the human subplate also expresses alpha2zinc binding globulin and Alpha-2-Heremans-Schmid glycoprotein/human fetuin. In addition, the established subplate neuron marker neuropeptide Y is expressed superficially, whereas potassium/chloride co-transporter (KCC2)-positive neurons are localized in the deep subplate at 16 PCW. These observations imply that the human subplate shares gene expression patterns with rodent, but is more compartmentalized into superficial and deep sublayers. This increased complexity of the human subplate may contribute to differential vulnerability in response to hypoxia/ischaemia across the depth of the cortex. Combining knowledge of cell type specific subplate gene expression with modern imaging methods will enable a better understanding of neuropathologies involving the subplate. PMID- 20727060 TI - Measuring organizational attributes in primary care: a validation study in Germany. AB - OBJECTIVE: Models for the structured delivery of care rely on organizational attributes of practice teams. The Survey of Organizational Attributes for Primary Care (SOAPC) is known to be a valid instrument to measure this aspect in the primary care setting. The aim of this study was to determine the validity of a translated and culturally adapted German version of the SOAPC. METHODS: The SOAPC was translated and culturally adapted according to established standards. The external validity of the German SOAPC was assessed using the German version of the Warr-Cook-Wall scale. A total of 200 practices randomly selected from a conference database were asked to participate in the validation study. Practice, clinicians and staff characteristics were determined via short-form questionnaires. We used standardized statistical procedures to reveal the psychometric properties of the SOAPC. RESULTS: A total of 54 practice teams participated by returning 297 completed questionnaires (297/425, response rate 69.8%). All four domains of the SOAPC (communication, decision making, stress/chaos, history of change) could be approved by factor analysis. Internal consistency is underlined by a Cronbach's alpha of 0.70 or higher in all categories. We show strong correlation with the Warr-Cook-Wall scale in all corresponding categories indexing high external validity. CONCLUSIONS: The German SOAPC is a reliable and valid instrument for the assessment of organizational attributes of practice teams as the providers of quality of care. Moreover, the tool makes it possible to map the state of implementation of quality management and practice organization. The availability of the German SOAPC encourages further research on this topic in German-speaking countries. PMID- 20727059 TI - Assessing enablement in clinical practice: a systematic review of available instruments. AB - RATIONALE, AIMS AND OBJECTIVES: Enablement is an intervention by which the health care provider recognizes, promotes and enhances patients' ability to control their health and life. An abundant health literature suggests that enablement is associated with good outcomes. In this review, we aimed at identifying and comparing instruments that assess enablement in the health care context. METHOD: We conducted a systematic literature review using Medline, Embase, Cochrane, Cinahl and PsycINFO databases, 1980 through March 2009, with specific search strategy for each database. Citations were included if they reported: (1) development and/or validation of an instrument; (2) evaluation of enablement in a health care context; and (3) quantitative results following administration of the instrument. The quality of each main retained citation was assessed using a modified version of the Standards for Reporting of Diagnostic Accuracy. RESULTS: Of 3135 citations identified, 53 were retrieved for detailed evaluation. Four articles were included. Two instruments were found: the Patient Empowerment Scale (PES) and the Empowering Speech Practices Scale (ESPS). Both instruments assessed enablement in hospital setting, one from the inpatient's perspective (PES) and the other from both perspectives (ESPS). CONCLUSION: Two instruments assess enablement in hospital setting. No instrument is currently available to assess enablement in an ambulatory care context. PMID- 20727061 TI - Diagnostic error in a national incident reporting system in the UK. AB - RATIONALE, AIMS AND OBJECTIVES: Diagnostic errors and delays carry potentially grave consequences for patients and feature prominently in studies of adverse events in health care. Diagnostic errors present a particular challenge for error/incident reporting systems because they involve clinical reasoning and are difficult to define precisely. The aim of the present study was to investigate what insights can be gained about diagnostic error from an incident reporting system. METHODS: Diagnostic errors reported to the UK's National Reporting and Learning System (NRLS) between November 2003 and October 2005 were investigated. We analysed reported level of harm to the patient and incident location and we compared diagnostic with non-diagnostic incidents. We also assessed the quality of reporting in a subset of reports associated with a patient's death. RESULTS: Of 316,589 incidents reported in the period under investigation, 1674 were diagnostic (0.5%). Diagnostic incidents were more likely than other incidents to be associated with moderate or severe harm, or a patient's death and were more likely to occur in a hospital emergency department than other incidents. Diagnostic incidents in emergency departments were more likely to be associated with greater harm than similar incidents in wards. Observed reporting quality (detail; clarity) was very variable. CONCLUSION: These findings replicate findings from studies in emergency departments and suggest that reporting systems have a role to play in understanding diagnostic errors alongside other sources of error analysis. Accurate and complete reporting of adequate volume enhances the potential contribution of an incident reporting system to understanding diagnostic error. PMID- 20727062 TI - Patient's decision making in selecting a hospital for elective orthopaedic surgery. AB - RATIONALE, AIMS AND OBJECTIVES: The admission to a hospital for elective surgery, like arthroplasty, can be planned ahead. The elective nature of arthroplasty and the increasing stimulus of the public to critically select a hospital raise the issue of how patients actually take such decisions. The aim of this paper is to describe the decision-making process of selecting a hospital as experienced by people who underwent elective joint arthroplasty and to understand what factors influenced the decision-making process. METHODS: Qualitative descriptive study with 18 participants who had a hip or knee replacement within the last 5 years. Data were gathered from eight individual interviews and four focus group interviews and analysed by content analysis. RESULTS: Three categories that influenced the selection of a hospital were revealed: information sources, criteria in decision making and decision-making styles within the GP- patient relationship. Various contextual aspects influenced the decision-making process. Most participants gave higher priority to the selection of a medical specialist than to the selection of a hospital. CONCLUSION: Selecting a hospital for arthroplasty is extremely complex. The decision-making process is a highly individualized process because patients have to consider and assimilate a diversity of aspects, which are relevant to their specific situation. Our findings support the model of shared decision making, which indicates that general practitioners should be attuned to the distinct needs of each patient at various moments during the decision making, taking into account personal, medical and contextual factors. PMID- 20727063 TI - Effects of fasting on hematologic and clinical chemical values in cynomolgus monkeys (Macaca fascicularis). AB - BACKGROUND: Fasting is an important pre-analytical factor that may affect clinical pathology parameters in toxicological and pharmacological studies. Little information is available on how fasting affects clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis).The aim of this study was to evaluate the influence of fasting on clinical pathology parameters in healthy adult cynomolgus monkeys. METHODS: Five female and six male cynomolgus monkeys were fasted for 0, 8, 16, and 24 hours. Changes in body weight (BW), core hematologic, and serum clinical chemical parameters were evaluated. RESULTS: The BW significantly decreased after 24 hours of fasting. Significant decreases in red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume and increases in mean cell hemoglobin and mean cell hemoglobin concentration were observed at 16 hours in males. In females, increasing the duration of fasting caused a significant time-dependent increase in platelets. Blood urea nitrogen showed significant decreases in female and male monkeys after fasting. Alkaline phosphatase increased in females after fasting. Aspartate transaminase significantly increased both in females and males at 8 hours. In females, alanine transaminase and lactate dehydrogenase significantly increased at 8 hours. Albumin significantly decreased in males 24 hours, but increased in females 16 hours after fasting. Serum glucose and triglyceride were not affected by fasting. Serum calcium decreased and inorganic phosphorus increased in males after fasting. CONCLUSION: These results suggested that clinical pathology data would vary after fasting. The decision to feed or fast before blood collection for clinical pathology tests should be made based on careful consideration. PMID- 20727064 TI - Regarding Bettauer 2010 (39:9-23). PMID- 20727065 TI - Subjective characterization of nerve sparing predicts recovery of erectile function after radical prostatectomy: defining the utility of a nerve sparing grading system. AB - INTRODUCTION: Radical prostatectomy (RP) is a common technique for managing prostate cancer. Concern regarding functional outcomes in patients prompted the development of nerve sparing to improve recovery of erectile function. AIM: To assess if a cumulative nerve damage grading system is a more precise predictor of recovery of erectile function as compared to the current "all-or-none" grading system. METHODS: Baseline demographic, medical history, and International Index of Erectile Function (IIEF)-erectile function domain (EFD) scores were collected. At the time of RP, patients were assigned a nerve sparing score (NSS) by their surgeon for each neurovascular bundle (left and right) to assess the quality of intraoperative nerve sparing (1-complete preservation, 4-complete resection). Patients completed IIEF questionnaires at 24 months after RP. MAIN OUTCOME MEASURES: Group comparisons and multiple regression analyses were used to test the association between the NSS and IIEF-EFD scores for patients with preoperative EFD scores >= 24. RESULTS: A total of 173 patients were included in this analysis. Mean age for patients was 59, and 62% of patients had at least one comorbidity. Baseline EFD scores were comparable between all NSS assignments. At 24 months, EFD scores were reduced by 7.2, 11.6, 13.9, and 15.4 points for patients with NSS grades of 2, 3, 4, and 5-8, respectively (P < 0.01). Multivariate analysis demonstrated lower NSS predicted recovery of erectile function at 24 months (P = 0.001), as did age (P = 0.001) and baseline EFD score (P = 0.02). CONCLUSION: Our data support the adoption of a subjectively assigned NSS to more precisely predict erectile function outcomes and suggest that even minor nerve trauma significantly impairs the recovery of erectile function after procedures classically regarded as having achieved bilateral nerve sparing. Further studies are needed to identify the optimal NSS system. PMID- 20727066 TI - Children's sleep, skin conductance level and mental health. AB - We examined relations between children's sympathetic nervous system activity, indexed by skin conductance level (SCL) during baseline and reactivity to a challenging task and their sleep problems. We also assessed SCL as a moderator of associations between children's sleep problems and their mental health. A sample of healthy and typically developing school-attending children (78 boys and 98 girls) participated (mean age=8.7years; standard deviation=0.36). Sleep was assessed via actigraphy and self-reports. Parents reported on children's externalizing behaviors and children reported their internalizing symptoms. Findings demonstrate that sleep disruptions (duration, quality) are associated with lower basal SCL. In the context of sleep problems, a lower level of basal SCL functioned as a vulnerability factor for depression symptoms and worse self esteem. Further, children with both increased SCL reactivity and sleep problems were at risk for depression symptoms. Results illustrate the significance of simultaneous examinations of various biological and physiological systems in the prediction of children's wellbeing. PMID- 20727067 TI - Inflammation does not predispose to bleeding in hemophilia. PMID- 20727068 TI - Coagulation factor XI as a novel target for antithrombotic treatment. AB - Coagulation factor (F)XI was first described as a member of the contact pathway of coagulation. However, the 'classic' theory of the extrinsic and intrinsic pathway has been revised and FXI was found to be activated by thrombin and to play a role in sustained thrombin generation and fibrinolysis inhibition. Recent studies have pointed to a disproportionate role of FXI in thrombosis and hemostasis. The observations that human congenital FXI deficiency is generally accompanied by mild and injury-related bleeding, and that experimental, provoked bleeding in animals is unaffected by FXI deficiency or FXI inhibition, suggest that the FXI amplification pathway is less important for normal hemostasis in vivo. In contrast, elevated plasma levels of FXI may contribute to human thromboembolic disease and the antithrombotic efficacy of FXI inhibition has been demonstrated in numerous animal models of arterial, venous and cerebral thrombosis. Whether severe FXI deficiency in humans protects against thromboembolic events remains unclear, although some evidence exists that the occurrence of ischemic stroke or venous thrombosis is low in severely FXI deficient patients. Because of its distinctive function in thrombosis and hemostasis, FXI is an attractive target for the treatment and prevention of thromboembolism. A novel strategy for FXI inhibition is the use of antisense technology which has been studied in various thrombosis and bleeding animal models. The results are promising and support the concept that targeting FXI might serve as a new, effective and potentially safer alternative for the treatment of thromboembolic disease in humans. PMID- 20727069 TI - Red cells playing as activated platelets in thalassemia intermedia. PMID- 20727070 TI - Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol. AB - BACKGROUND, OBJECTIVES AND METHODS: An accurate, sensitive and precise assay for reliable determination of the ristocetin cofactor activity of von Willebrand factor (VWF:RCo) in plasma and von Willebrand Factor (VWF)-containing concentrates has been evaluated. The assay is based on a commercially available automated protocol with modifications including a combination of adding additional ristocetin and the use of two calibration curves for the high and low measuring ranges. RESULTS: Addition of extra ristocetin resulted in improved measurement of VWF recoveries from various VWF-containing concentrates that were underestimated using the standard automated protocol. The modifications resulted in improved assay performance over an extended measuring range (2.00-0.03 IUmL( 1) ). Accuracy was tested using VWF deficiency plasma spiked with the 1st international standard (IS) for VWF concentrate. Seven dilutions, ranging from 1.80 to 0.05IUmL(-1) , were analyzed and resulted in measured concentrations between 80% and 100% of the assigned potency of the standard. Linearity was determined from the regression plot of the same concentrate dilutions and resulted in a correlation coefficient of 0.998. The repeatability, expressed as coefficient of variation, was 2% in the normal range (0.90IUmL(-1) ) and 8% at the level of 0.05IUmL(-1) . The corresponding reproducibility results were 2% and 15% at the normal and low measuring ranges, respectively. CONCLUSIONS: Analysis of patients with von Willebrand disease (VWD) indicates that the modified automated BCS((r)) protocol has a superior discrimination power compared with the standard protocol. This is especially true in samples with low VWF, as in patients with type 3 VWD. PMID- 20727073 TI - Mutational analysis of D2HGDH and L2HGDH in brain tumours without IDH1 or IDH2 mutations. PMID- 20727071 TI - Factor XIII--an under diagnosed deficiency--are we using the right assays? AB - BACKGROUND: The clot solubility test is the most widely used method for detection of factor (F)XIII deficiency. However, it will only detect severe deficiencies; consequently mild deficiencies and heterozygous states are probably under diagnosed. OBJECTIVE: As an alternative first-line screening test, we assessed an automated quantitative ammonia release assay (QARA). PATIENTS/METHODS: Inter-assay imprecision was evaluated with commercial normal and pathological control plasmas (10 replicates on each of 5 days). Using the QARA and other commercial assays a comparative assessment of congenital (FXIII range < 1-70 u dL(-1), n = 9) and acquired (n = 43) deficiencies was made. We also investigated the prevalence of acquired deficiencies in hospitalized patients using residual samples from adult patients (n = 1004) and from a paediatric intensive care unit (ICU, n = 56). RESULTS: Assay imprecision was acceptably low (normal control: mean 86.6 u dL(-1); cv = 2.0%; pathological control: mean 27.5 u dL(-1); cv = 3.8%). Using an iodoacetamide blanking procedure, the QARA results (FXIII range < 1-70 u dL(-1)) exhibited close agreement with those from an immuno-turbidometric FXIII A-subunit (FXIII-A) method. There was also good correlation (R(2) >= 0.89) between the QARA (range 20 180 u dL(-1)), a second chromogenic assay, the FXIII-A and FXIII A+B-subunit ELISA. We found that 21% of samples from adult patients had FXIII levels < 70 u dL(-1) (mean normal +/- 2 SD 73-161 u dL(-1)) with 6% < 50 u dL(-1). Within the paediatric ICU samples, 52% were < 70 u dL(-1), with 21% < 50 u dL(-1). CONCLUSIONS: Our data demonstrates that the automated assay is sensitive, highly reproducible and the results from clinical samples suggest that acquired FXIII deficiency is a relatively common phenomenon in hospital patients after surgery and in ICU. PMID- 20727075 TI - New views of quality and safety offer new roles for nurses and midwives. PMID- 20727076 TI - Knowledge transfer and the path of translational medicine. PMID- 20727077 TI - Basing practice on the best available evidence: A new inclusion in Nursing & Health Sciences: Best Practice Information Sheets. PMID- 20727078 TI - The Joanna Briggs Institute Best Practice Information Sheet: Nurse-led interventions to reduce cardiac risk factors in adults. AB - This Best Practice Information Sheet updates and supersedes an earlier publication of the Joanna Briggs Institute in 2005. The information that is contained in this publication is based upon a systematic review of six randomized clinical trials. Additional information has been derived from a second systematic review; thus, in total, the information is derived from 22 randomized controlled trials. The original references can be sourced from the systematic reviews. Coronary heart disease (CHD) is the major cause of illness in Western society and it is becoming increasingly important to establish effective strategies in order to reduce the incidence of CHD. Nurse-led clinics are becoming more prominent in community settings and the importance of nurse interventions in the management of CHD and risk factor reduction is recognized in terms of improved health outcomes for patients. However, the variation in outcome measures and inconsistent findings between some studies make it difficult to draw firm conclusions. PMID- 20727079 TI - Genetic competence of midwives in the UK and Japan. AB - In the UK and Japan, midwives provide health services for women with concerns about a genetic condition or who are considering antenatal screening. In both countries, competences related to genetic health care have been devised but there is little evidence about midwifery competence in practice. A systematic literature review was undertaken to determine the extent to which midwives are achieving the genetic competences that are prescribed for their practice. English and Japanese literature from January 1999 to March 2009 was retrieved. Original studies or reviews, in which an aspect of midwifery practice was related to genetic competences, were eligible for inclusion. After a critical appraisal, six UK and five Japanese papers were eligible for inclusion. The findings indicated that midwives are not achieving the competences, nor are they confident about their genetics knowledge. Moreover, women are not being supported to make informed decisions regarding antenatal screening. We have confirmed that little research is being undertaken in both countries regarding competency achievement in practice. Changes to midwifery curricula and further continuing education are required to ensure that midwives are able to provide effective care regarding genetics. PMID- 20727080 TI - Response regarding the commentary of van der Ploeg W. Assessment and measurement of health literacy: An integrative review of the literature. Nursing & Health Sciences 2010; 12: 145-146. PMID- 20727081 TI - Effects of a cognitive adjustment program for Thai parents. AB - Child physical abuse is recognized as a major public health problem that affects children and is likely to become increasingly common. The objective of this study was to examine the effects of a cognitive adjustment program on parental attitudes toward child rearing and the potential for this abuse. Child-care centers were randomly allocated to either the intervention or the control group. The sample included 116 Thai parents of children aged 1-6 years. The intervention group attended the cognitive adjustment program while the control group received the usual services. The results showed that, after program completion, the intervention group had statistically significantly better parental attitudes toward child rearing, but not a significantly lower potential for CPA than the control group. We concluded that the cognitive adjustment program was effective in altering parental attitudes toward child rearing. However, in order to enhance its efficacy, the program should be modified to be more intensive and it should be studied further for its effect on the potential for abuse. PMID- 20727082 TI - Perceptions of Japanese patients and their family about medical treatment decisions. AB - Internationally, nurses and physicians are increasingly expected to undertake roles in communication and patient advocacy, including in Japan, where the reigning principle underlying medical ethics is in transition from paternalism to respect for patient autonomy. The study reports the results of a survey in two Japanese teaching hospitals that clarified the perspectives of 128 patients and 41 family members regarding their current and desired involvement in health decision-making. The commonest process that was desired by patients and their family was for patients to make decisions after consultation with both the physician and their family. The decision-making preferences for competent patients varied among the participants, who believed that families have a crucial role to play in health-care decision-making, even when patients are competent to make their own decisions. The findings will inform health professionals about contemporary Japanese health-care decision-making and the ethical issues involved in this process, as well as assist the future development of a culturally relevant model to support patients' preferences for ethical decision-making. PMID- 20727083 TI - Empowerment process for families rearing children with developmental disorders in Japan. AB - The understanding of developmental disorders and the support that is offered to families rearing a child with developmental disorders always have been limited in Japan. To clarify the empowerment process for families rearing a child with developmental disorders, we interviewed 20 mothers of children who lived in the wider Tokyo area, Japan. To analyze the data, we adopted the modified grounded theory approach. The results identified three stages in the empowerment process: confusion over caring for the child, confrontation with the child with the disorder, and expectations of a valuable life for the child. The empowerment process showed step-by-step progress: families that were originally ill-equipped to deal with their child's disorders were able to deal with them in collaboration with professionals through approaching the local administration and were able to shift their stance on child-rearing along with their child's growth. To promote the family empowerment process, cross-jurisdictional and cross-occupational collaboration among local care teams is needed. The members of the teams should understand the experiences and feelings of the families that are rearing children with developmental disorders in the context of the family's empowerment process. PMID- 20727084 TI - Resilience among women and men aged 60 years and over in Sweden and in Thailand. AB - The purpose of this study was to compare the level of resilience of people aged > or = 60 years in Sweden and Thailand. In a randomized sample of 422 people in Sweden and a convenience sample of 200 people in Thailand, the level of resilience was measured by using the Resilience Scale. A chi(2)-analysis was used for the differences between proportions. The relationships between the background variables and the resilience scores were analyzed by using stepwise multiple linear regression. The mean scores of resilience were 144 for the Swedish participants and 146 for the Thai participants. The two samples differed in their background characteristics. The Thai participants were more likely to be women, to be widowed, and to have more children, while among the Swedish participants, more women were married and more participants were aged > or = 80 years. Despite different background characteristics, the Swedish and the Thai participants' scores were almost the same on the Resilience Scale. More studies are necessary to address aspects of gender and ethnicity in relation to resilience. PMID- 20727085 TI - Determinants of ambulatory ability after hip fracture surgery in Japan and the USA. AB - We examined the relationship of the length of stay and the day of initiating partial weight bearing to patients' level of ambulatory ability at 3 months after hip fracture surgery in Japan and the USA. The participants were patients aged > or = 65 years who had undergone hip fracture surgery between August 2005 and September 2007. The data were collected from three hospitals in Japan and two hospitals in the USA. The participants received questionnaires pertaining to patient health outcomes after discharge. One-hundred-and-forty-nine patients in Japan and 88 patients in the USA completed the questionnaire. In Japan, the length of stay before surgery was longer and partial weight bearing after surgery was initiated later, compared to the USA. This independently predicted a lower level of ambulatory ability at 3 months after surgery. Assessing the reasons for delaying surgery and partial weight bearing is important in Japan. Encouraging ambulation with weight bearing at the earliest possible time is essential for patients to maintain their ambulatory ability after hip fracture surgery. Prospective studies using a large sample and/or intervention studies are required to determine the causal effect on ambulatory ability. PMID- 20727086 TI - Participation of patients with chronic illness in nursing care: An Iranian perspective. AB - The increasing number of chronically ill people has served as an impetus for the promotion of patient participation in nursing care. However, little is known about patient participation in Iran. The aim of this study was to identify the factors that are relevant to patient participation and the nature of that participation, as experienced by chronically ill patients and registered nurses in Iran. Grounded theory was used as the method. Twenty-two participants were recruited by using purposeful and theoretical sampling. The data were generated by semistructured interviews and participant observations. Constant comparison was used for the data analysis. This study indicated that participation is an interactive process between nurses, patients, and family members in the caregiving context. Participation occurred when the caring agents worked together. The core category of "convergence of the caring agents" emerged. The subcategories emerged as the levels of participation and included "adhering", "involving", "sharing", and "true participation". The factors related to the caring agents and caregiving context could be considered as predictors of the level of participation when caring for these patients. PMID- 20727087 TI - Depression: Problem-solving appraisal and self-rated health among Hong Kong Chinese migrant women. AB - This cross-sectional survey explored the depression status of new migrant women and its relationship with self-rated health in the Hong Kong Chinese context. A convenience sample of 68 migrant women volunteered to participate in the study. The data were collected by using the Problem Solving Inventory, the Center for Epidemiological Studies-Depression questionnaire, and a self-rated health scale. The respondents were found to have a lesser degree of problem-solving appraisal, compared with other populations, and almost half of the volunteers were found to be depressed. Approximately 50% of the women reported their general health as "excellent", "very good", or "good". The Pearson's correlation showed a positive significant correlation between problem-solving appraisal, depression, and self rated health. The results of the regression analysis showed that family income, self-rated health, and problem-solving confidence are predictive factors of depression. Community nurses could consider using multidisciplinary interventions that focus on life-skills training in order to promote the psychological and general wellness of migrant women in addition to the use of counseling or medication interventions. PMID- 20727088 TI - Development of a theory-based sexual and reproductive health promotion and HIV prevention program for Chinese early adolescents. AB - The purpose of this study was to develop a theory-based program for Chinese early adolescents in order to promote their sexual and reproductive health and to prevent HIV infection. The program was designed based on the Information Motivation-Behavioral skills model and a needs assessment among the stakeholders. A technical collaborative action research approach was applied. The study's participants were 102 early adolescents in a public middle school in mainland China, with the involvement of other key stakeholders, including 15 teachers and 12 parents. The results revealed a statistically significant improvement in the scores of sexual and reproductive health promotion and HIV prevention information, motivation, and behavioral skills after the program's implementation. Meanwhile, qualitative data from the early adolescents' reflection indicated that the content was useful and comprehensive, the trainers were friendly and knowledgeable, and participatory learning with an "edutainment" style was especially impressive. Additionally, the early adolescents expressed that they could apply the knowledge and skills in their daily life, which would benefit themselves and their family and peers. The Information-Motivation Behavioral skills model could be explored in a non-Western context and the program was shown to be acceptable for use in a Chinese middle school setting. PMID- 20727089 TI - Recruitment of hard-to-reach population subgroups via adaptations of the snowball sampling strategy. AB - Nurse researchers and educators often engage in outreach to narrowly defined populations. This article offers examples of how variations on the snowball sampling recruitment strategy can be applied in the creation of culturally appropriate, community-based information dissemination efforts related to recruitment to health education programs and research studies. Examples from the primary author's program of research are provided to demonstrate how adaptations of snowball sampling can be used effectively in the recruitment of members of traditionally underserved or vulnerable populations. The adaptation of snowball sampling techniques, as described in this article, helped the authors to gain access to each of the more-vulnerable population groups of interest. The use of culturally sensitive recruitment strategies is both appropriate and effective in enlisting the involvement of members of vulnerable populations. Adaptations of snowball sampling strategies should be considered when recruiting participants for education programs or for research studies when the recruitment of a population-based sample is not essential. PMID- 20727090 TI - Correlating heart rate and perceived exertion during aerobic exercise in Alzheimer's disease. AB - Older adults reap many health benefits from aerobic exercise training; however, little is known about how to monitor the training responses in older adults with Alzheimer's disease. The purpose of this pilot study was to examine the correlation of objectively measured heart rate and subjectively reported perceived exertion during aerobic exercise training in four older men with advanced Alzheimer's disease from a pilot study that used a one-group pre- and post-test design. During training (three times per week for 8 weeks), the participants' heart rate and perceived exertion were assessed by a trained exercise trainer every 5 min by using the Polar heart rate monitor and the Borg's Rating of Perceived Exertion Scale, respectively. There were 596 heart rate perceived exertion data pairs. The results show that the Pearson's r for the heart rate and perceived exertion was 0.457 (significant at 0.01, two-tailed), controlling for age, education, exercise session, and cognition. We conclude that the Borg's Rating of Perceived Exertion Scale itself might be insufficient for monitoring the exercise responses in older men with advanced Alzheimer's disease. Future studies are needed to further examine the utility of this scale in this population. PMID- 20727091 TI - Cultural competence among Swedish child health nurses after specific training: A randomized trial. AB - An urgent need to improve Swedish primary child health-care nurses' cultural competence was revealed by previous research among nurses working in, and immigrant parents visiting, primary child health-care services. The aim of this study was to evaluate the extent to which specific training affected how nurses rated their own cultural competence, difficulties, and concerns and to study how the nurses evaluated the training. Conducted as a randomized controlled trial, the effects on a study sample of 51 nurses were assessed by questionnaires in a pre- and post-study design. The findings indicated that the 3 days of training were appreciated by the nurses and had some effects on their cultural competence, difficulties, and concerns. The training might have had positive effects on the nurses' working conditions as they rated it to have an impact on their ability to cope with the demands of their work activities in the health services. These effects are presumed to contribute to an improved quality of the health services, with a reduction in the risk for health-care disparities among children of immigrant parents. PMID- 20727092 TI - Culturally sensitive health counseling to prevent lifestyle-related diseases in Japan. AB - This study explored the methods that are used by public health nurses to provide culturally sensitive health counseling to elderly Japanese farmers in order to motivate them to adopt healthy behaviors. Fourteen elderly farmers (eight men and six women) from three rural communities underwent health counseling and then changed their habits to prevent lifestyle-related diseases. Qualitative and inductive analyses were conducted to determine the effects of the culturally sensitive counseling. Five methods for providing culturally sensitive counseling were identified: (i) showing an interest in, and respect for, the local culture; (ii) stimulating the participants' awareness of the health risks inherited in their local cultural practices through the use of familiar examples; (iii) accepting and understanding the participants' ambivalence about their local culture; (iv) connecting the reasons for the participants to change their lifestyle with their local culture; and (v) adjusting the health-promoting behaviors of the participants to fit their local culture. Public health nurses should consider the pride that elderly farmers have in their background and their resistance to change and use these factors to point out the discrepancies in their lifestyle and promote more quality-of-life-oriented and practical self-care behaviors. PMID- 20727093 TI - Shock and patient-centered outcomes research: is an ICD shock still a critical event? PMID- 20727094 TI - Suppression of premature ventricular contractions during atrioventricular conduction block: what is the mechanism? PMID- 20727095 TI - Do traditional VT zones improve outcome in primary prevention ICD patients? AB - AIMS: We reviewed outcomes in our primary prevention implantable cardioverter defibrillator (ICD) population according to whether the device was programmed with a single ventricular fibrillation (VF) zone or with two zones including a ventricular tachycardia (VT) zone in addition to a VF zone. METHODS: This retrospective study examined 137 patients with primary prevention ICDs implanted at our institution between 2004 and 2006. Device programming and events during follow-up were reviewed. Outcomes included all-cause mortality, time to first shock, and incidence of shocks. RESULTS: Eighty-seven ICDs were programmed with a single VF zone (mean >193 +/- 1 beats per minute [bpm]) comprising shocks only. Fifty ICDs had two zones (mean VT zone >171 +/- 2 bpm; VF zone >205 +/- 2 bpm), comprising antitachycardia pacing (100%), shocks (96%), and supraventricular (SVT) discriminators (98%) . Discriminator "time out" functions were disabled. Mean follow-up was 30 +/- 0.5 months and similar in both groups. All-cause mortality (12.6% and 12.0%) and time to first shock were similar. However, the two-zone group received more shocks (32.0% vs 13.8% P = 0.01). Five of 16 shocks in these patients were inappropriate for SVT rhythms. The single-zone group had no inappropriate shocks for SVTs. Eighteen of 21 appropriate shocks were for ventricular arrhythmias at rates >200 bpm (three VF, 15 VT). This suggests that primary prevention ICD patients infrequently suffer ventricular arrhythmias at rates <200 bpm and that ATP may play a role in terminating rapid VTs. CONCLUSIONS: Patients with two-zone devices received more shocks without any mortality benefit. PMID- 20727096 TI - Cryoablation versus radiofrequency ablation for atrioventricular nodal reentrant tachycardia: patient pain perception and operator stress. AB - BACKGROUND: Cryoablation (CRYO) is an alternative to radiofrequency (RF) ablation in the treatment of atrioventricular nodal reentrant tachycardia (AVNRT). This study aims to evaluate the differences in patient pain perception and operator stress between CRYO and RF ablation in the treatment of AVNRT. METHODS: Patients with supraventricular tachycardia underwent electrophysiology study. Twenty patients (eight males, age 46.5 +/- 12.5 years) diagnosed with AVNRT were randomized to receive CRYO (11) with a 6-mm-tip catheter or RF (nine) with a 4-mm tip catheter. Patients' pain perception and operator stress were assessed with a visual analogue scale (VAS) from 0 to 10 at the end of procedure. RESULTS: There was no significant difference in acute procedural success (CRYO 100% vs RF 89%, P = 0.257). There was no complication of permanent atrioventricular block in either group. The number of energy applications was significantly higher in the CRYO group (2.8 +/- 1.2 vs 1.6 +/- 0.9, P = 0.02). The fluoroscopic time was significantly reduced in the CRYO group (6.0 +/- 4.9 vs 10.9 +/- 5.4 minutes, P = 0.049) with no difference in procedure time (CRYO 49.3 +/- 12.5 vs RF 54.5 +/- 17.0 minutes, P = 0.462). Patients in the CRYO group experienced significantly less pain than patients in the RF group (VAS 2.3 +/- 2.8 vs 5.4 +/- 3.4, P = 0.024). The operator also experienced significantly less stress during CRYO than RF (VAS 1.9 +/- 0.8 vs 6.2 +/- 1.6, P < 0.001). There was no recurrence in both groups at 6-month follow-up. CONCLUSIONS: CRYO, as compared with RF, produces less pain in patients and less stress in operator in the treatment of AVNRT. PMID- 20727097 TI - Remote electrocardiographic monitoring with a wireless implantable loop recorder: minimizing the data review burden. AB - INTRODUCTION: Currently available implantable loop recorders (ILRs) are hampered by limited memory, sensing artifacts, and need for manual memory download. Remote monitoring techniques that automatically transfer stored recordings for review may enhance ILR utility. However, automatic electrocardiograph (ECG) detection and transmission of an excessive number of tracings directly to physicians may be burdensome. This pilot study assessed the utility of direct ILR transmission to a central ECG monitoring center on the burden of data to be reviewed by the physician. METHODS: Patients with unexplained syncope were implanted with a novel ILR with automatic (i.e., independent of patient intervention) wireless telemetry download. Transmitted recordings underwent a two-step review process: initial algorithmic filtering followed by human overread at a monitoring center using predefined criteria. RESULTS: Forty patients were enrolled and followed for 8.5 +/- 5.1 months. A total of 223,226 ECG recordings were transmitted to the monitoring center (on average 660 per patient per month). Algorithmic filtering eliminated 191,305 ECGs as artifact (89%), with monitoring center overread of 31,921 strips. Ultimately, 117 relevant ECGs were selected for further evaluation by the physician (0.0053%). One or more relevant ECGs were identified for 20 patients (50%). CONCLUSIONS: Automatic ILR recording and wireless technique is feasible for remote ECG monitoring by ILRs. However, sensitive criteria for recording and transmission may result in an excessive ECG burden. The two-step screening process in this pilot study minimized physician overread time while providing clinically relevant recordings in a substantial proportion of patients. PMID- 20727098 TI - Dual epicardial ventricular tachycardia: a tale of two VTs. AB - A young female with isolated ventricular noncompaction and acute myocarditis presented with incessant dual epicardial ventricular tachycardia consisting of a manifest reentrant circuit and a shorter cycle length concealed circuit. A single radiofrequency terminated both tachycardias. PMID- 20727099 TI - Abrupt heart rate fallings in a patient with biventricular pacing: latent risk for exacerbation of heart failure. AB - This case report describes abrupt heart rate fallings below the lower pacing rate limit in a patient with cardiac resynchronization therapy (CRT). Interrogated information including stored episodes or data regarding the lead did not show any device problems and only simultaneous intracardiac electrogram revealed the cause, T-wave oversensing during biventricular pacing. At this moment, CRT has become an established modality for patients with severe heart failure. However, bradycardia below the lower rate limit during biventricular pacing due to T-wave oversensing would exacerbate heart failure in patients with CRT. We should notice this latent risk and correct the malfunction immediately. PMID- 20727100 TI - Electromagnetic device-device interaction between a new generation implantable pacemaker and left ventricular assist device: recognition and potential solutions. AB - An electromagnetic interaction between St. Jude Medical Inc. (St. Paul, MN, USA) permanent pacemakers and HeartMate II left ventricular assist devices (LVADs) (Thoratec Inc., Pleasanton, CA, USA) has been reported before, but the problem was thought to be resolved in the St. Jude Medical's most recently released pacemaker platform. We report a case of interference between the HeartMate II LVAD and the most recently released St. Jude Medical pacemaker (model no. PM3210; Anthem) and review new developments to overcome the electromagnetic interference problem in this setting. PMID- 20727101 TI - Sequential ventricular prepotentials recorded within the left coronary cusp of the aorta during idiopathic PVCs: what is the mechanism? PMID- 20727103 TI - The superior vena cava syndrome (SVCS) as a complication of pacemaker implantation. PMID- 20727104 TI - Electromagnetic interference from electronic article surveillance system in a patient with a biventricular ICD and a left ventricular assist device. PMID- 20727105 TI - Photosynthesis and assimilate partitioning between carbohydrates and isoprenoid products in vegetatively active and dormant guayule: physiological and environmental constraints on rubber accumulation in a semiarid shrub. AB - The stems and roots of the semiarid shrub guayule, Parthenium argentatum, contain a significant amount of natural rubber. Rubber accumulates in guayule when plants are vegetatively and reproductively dormant, complicating the relationship between growth/reproduction and product synthesis. To evaluate the factors regulating the partitioning of carbon to rubber, carbon assimilation and partitioning were measured in guayule plants that were grown under simulated summer- and winter-like conditions and under winter-like conditions with CO(2) enrichment. These conditions were used to induce vegetatively active and dormant states and to increase the source strength of vegetatively dormant plants, respectively. Rates of CO(2) assimilation, measured under growth temperatures and CO(2) , were similar for plants grown under summer- and winter-like conditions, but were higher with elevated CO(2) . After 5 months, plants grown under summer like conditions had the greatest aboveground biomass, but the lowest levels of non-structural carbohydrates and rubber. In contrast, the amount of resin in the stems was similar under all growth conditions. Emission of biogenic volatile compounds was more than three-fold higher in plants grown under summer- compared with winter-like conditions. Taken together, the results show that guayule plants maintain a high rate of photosynthesis and accumulate non-structural carbohydrates and rubber in the vegetatively dormant state, but emit volatile compounds at a lower rate when compared with more vegetatively active plants. Enrichment with CO(2) in the vegetatively dormant state increased carbohydrate content but not the amount of rubber, suggesting that partitioning of assimilate to rubber is limited by sink strength in guayule. PMID- 20727106 TI - Quantitative measurement of circulating lymphoid-specific helicase (HELLS) gene transcript: a potential serum biomarker for melanoma metastasis. PMID- 20727107 TI - Neurocognitive functioning in women presenting with undifferentiated somatoform disorders in Oman. AB - AIM: There is a dearth of research from non-Western populations focusing on neurocognitive functioning in patients presenting with undifferentiated somatoform disorders. The aim of the present quest is to examine the presence of cognitive impairment and other health-related parameters among attendees at psychiatric settings in Oman, an Arab/Islamic country, with a diagnosis of undifferentiated somatoform disorder. METHOD: In order to compare the performance of patients diagnosed with undifferentiated somatoform disorder (n = 20) and normal healthy subjects (n = 18) on indices of attention and concentration, tests of executive functioning, mood, somatization and vegetative functioning were carried out. RESULTS: The performance of patients with undifferentiated somatoform disorder differed from that of normal healthy subjects on the presently operationalized indices of working memory and executive functioning, anxiety, quality of sleep and psychosomatically expressed psychological distress. CONCLUSION: To our knowledge, this is the first study highlighting neurocognitive functioning in patients with undifferentiated somatoform disorders from a non Western population. This type of study has the potential of shedding light on the covariates of such a debilitating and intransigent condition as undifferentiated somatoform disorder. PMID- 20727108 TI - Health-related quality of life and restless legs syndrome among women in Sweden. AB - AIM: Restless legs syndrome (RLS) is a common neurological movement disorder with a female preponderance, an increasing prevalence with age and comorbidity. Previous studies on the relationship between health-related quality of life (HRQOL) and RLS are still sparse but knowledge is increasing. The aim of this study was to evaluate the unique impact of RLS on HRQOL in a population-based sample. METHODS: A random sample of 5000 women aged 25-64 years was selected from the general Swedish population. The women were sent diagnostic questions on RLS together with the Short Form 12 (SF-12) questionnaire for assessment of physical and mental HRQOL. The unique burden of RLS on HRQOL was analyzed by excluding RLS positive women from four self-reported diagnostic groups (diabetes, depression, heart problems, muscle and joint pain) and by excluding subjects with these diagnoses from the group of RLS-positive women. RESULTS: Compared with mental SF 12 scores for the RLS-negative women in our population, mental HRQOL of the RLS sample in our study was lower in every age group but not significantly lower in the age group 35-44 years. Physical SF-12 scores for RLS-positive women were also below scores for RLS-negative women in every age group but significance was only found in women between 45 and 54 years. A unique burden of RLS on HRQOL remained after statistical adjustment for comorbidities. CONCLUSION: RLS-positive women had an impaired mental HRQOL compared to RLS-negative women in the studied population. The physical aspects of HRQOL were less affected among RLS-positive women. The impaired well-being among women with RLS further strengthens the importance of identifying women with this condition and evaluating their need for medication or other actions in order to improve their quality of life. PMID- 20727109 TI - Development of 2-hour suicide intervention program among medical residents: first pilot trial. AB - AIM: Suicide is associated not only with primary psychiatric disorders but also with physical disorders. Physicians' education on suicide prevention contributes to reducing suicide. Therefore, medical residents, who contact patients daily and who eventually become primary physicians in each specialty, might be the most appropriate candidates for intervention. In this article, we introduce our newly developed suicide intervention program among medical residents. METHODS: We developed a 2-hour suicide intervention program among medical residents, based on the Mental Health First Aid (MHFA), which had originally been developed for the public. The program contains a 1-hour lecture and a 1-hour role-play session. As the first pilot trial, we conducted the program among 44 first-year medical residents at a university hospital and evaluated its effectiveness. Changes in confidence, attitudes and behavior toward suicidal people were evaluated using self-reported questionnaires before, immediately after, and 6 months after the program. RESULTS: Participants' confidence and attitudes significantly improved after the program. The total mean score (standard deviation) of the Suicide Intervention Response Inventory improved from 18.4 (2.0) before the intervention to 19.4 (2.0) immediately after the intervention. However, the effectiveness was limited after 6 months. In the course of 6 months, the participants learned to apply the MHFA principles in their daily clinical practice. CONCLUSION: Our newly developed brief suicide intervention program demonstrating its effectiveness among medical residents should be modified in order to be more effective in the long term. The next trial with a control group ought to be conducted to evaluate our developed program. PMID- 20727110 TI - Fronto-limbic abnormalities in a patient with compulsive hoarding: a 99mTc-ECD SPECT study. AB - Little is known about the neuronal mechanism underpinning the pathophysiology of compulsive hoarding. We report the cerebral blood flow changes in an obsessive convulsive patient with severe hoarding. The patient showed hyperperfusion of the fronto-temporal region and hypoperfusion of the striatal, the middle cingulate and the medial temporal regions during the stage with severe symptoms. Following improvement from the hoarding behaviors, the extent of hypoperfusion was expanded in the bilateral striatum, the anterior and middle cingulate gyrus. The result may substantiate evidence of the fronto-limbic abnormality involved in the pathophysiology of compulsive hoarding. PMID- 20727111 TI - Regional cerebral blood flow in patients with orally localized somatoform pain disorder: a single photon emission computed tomography study. AB - AIM: Somatoform pain disorder is characterized by persistent and chronic pain at one or more sites without an associated general medical condition and in which psychological factors are thought to play a role. This study aimed to investigate the pathological features of somatoform pain disorder localized to the oral region by single photon emission computed tomography (SPECT). METHODS: Ten patients (nine females and one male; average age 55.0 +/- 14.4 years) having somatoform pain disorder with oral symptoms participated. SPECT was performed using N-isopropyl-4-[(123) I] iodoamphetamine intravenous injections, and regional cerebral blood flow (rCBF) was assessed by three-dimensional stereotactic surface projections. We also selected 12 healthy individuals (seven females and five males; average age 61.8 +/- 13.2 years) to act as controls. RESULTS: Both the patient and control groups showed no atrophy or infarction on CT or magnetic resonance imaging. The patient group showed higher rCBF in the subcortical area, especially in the thalamus and cingulate gyri, than the control group. In contrast, the patient group showed lower rCBF in the bilateral frontal and occipital lobes as well as in the left temporal lobe. CONCLUSIONS: These results suggest that the biological process involved in somatoform pain disorder of the oral region is characterized by changes in limbic and cortical functions. The finding that somatoform pain disorder with oral symptoms is associated with brain functional changes will help to develop treatment regimes for this disorder and clarify the underlying pathology. PMID- 20727112 TI - Psychiatric comorbidity among patients with gender identity disorder. AB - AIMS: Psychiatric comorbidity and mental instability seem to be important unfavorable prognostic factors for long-term psychosocial adjustment in gender identity disorder (GID). However, psychiatric comorbidity in patients with GID has rarely been assessed. In this study, we investigated the psychiatric comorbidity and life events of patients with GID in Japan. METHODS: A total of 603 consecutive patients were evaluated independently by at least two senior psychiatrists at the GID clinic using clinical information and results of examinations. RESULTS: Using DSM-IV criteria, 579 patients (96.0%) were diagnosed with GID. Among the GID patients, 349 (60.3%) were the female-to-male (FTM) type, and 230 (39.7%) were the male-to-female (MTF) type. Current psychiatric comorbidity was 19.1% (44/230) among MTF patients and 12.0% (42/349) among FTM patients. The lifetime positive history of suicidal ideation and self mutilation was 76.1% and 31.7% among MTF patients, and 71.9% and 32.7% among FTM patients. Among current psychiatric diagnoses, adjustment disorder (6.7%, 38/579) and anxiety disorder (3.6%, 21/579) were relatively frequent. Mood disorder was the third most frequent (1.4%, 8/579). CONCLUSIONS: Comparison with previous reports on the psychiatric comorbidity among GID patients revealed that the majority of GID patients had no psychiatric comorbidity. GID is a diagnostic entity in its own right, not necessarily associated with severe comorbid psychological findings. PMID- 20727113 TI - Identification of a novel HLA-C allele, HLA-C*03:85, in a Singaporean Chinese. AB - HLA-C*03:85 differs from C*03:03:01 by a single nucleotide substitution at position 276, in exon 2. PMID- 20727114 TI - Association between anal sac gland carcinoma and dog leukocyte antigen-DQB1 in the English Cocker Spaniel. AB - Anal sac gland carcinomas occur frequently in English Cocker Spaniels and, to a lesser extent, in other spaniel breeds. The disease typically presents in dogs aged 8 years or older and frequently metastasises to the local lymph nodes. The association between anal sac gland carcinoma in English Cocker Spaniels and the major histocompatibility complex class II loci (the dog leukocyte antigen loci DLA-DRB1, -DQA1, -DQB1) was investigated in 42 cases and 75 controls. Based on a corrected error rate of 0.017 for each test, the allele distribution in DLA-DRB1 showed no significant difference between cases and controls (P value = 0.019), while a significant difference was obtained for DLA-DQA1 and -DQB1 alleles (P values are 0.010 and 3.3 * 10-5). The DLA-DQB1*00701 allele was the most common in both cases and controls, but it had a higher frequency among the former (0.89) than in the latter (0.61), while the second most common allele had a higher frequency in the controls (0.23) than in the cases (0.07). Haplotype distributions were also significantly different between the two groups (P value = 1.61 * 10-4). This is the second disease in English Cocker Spaniels for which the most common DLA-DQB1 allele in the breed has been shown to have a higher frequency in cases than controls, while the second most common allele in the breed (*02001) has a significantly higher frequency in the controls, compared with the cases. PMID- 20727115 TI - Nomenclature for factors of the HLA system, update June 2010. PMID- 20727116 TI - Nomenclature for factors of the HLA system, update May 2010. PMID- 20727117 TI - Nomenclature for factors of the HLA system, update April 2010. PMID- 20727118 TI - Identification of the novel allele HLA-B*13:01:03 by sequence-based typing method in a Taiwanese individual. AB - A new human leukocyte antigen (HLA)-B allele, B*13:01:03 (B*130103), has been found in a Taiwanese individual. It differs from B*13:01:01 (B*130101) by a synonymous substitution at codon 113 (CAT->CAC). PMID- 20727119 TI - A new HLA-B*15 variant, B*15:144, identified by sequence-based typing in a Chinese individual. AB - A novel human leukocyte antigen-B allele, officially named B*15:144 allele, the previous designation B*9544 allele, was found in a potential Chinese bone marrow donor when direct sequence-based typing was carried out. The novel B*15:144 is identical to B*15:02:01 with the exception of two base substitution at position 195 (C>T), 196 (T>G) of exon 3 resulting in codon #156 changed from CTG (Leu) to TGG (Trp). PMID- 20727120 TI - The surface density of the glutamate transporter EAAC1 is controlled by interactions with PDZK1 and AP2 adaptor complexes. AB - The glutamate transporter excitatory amino acid carrier (EAAC1/EAAT3) mediates the absorption of dicarboxylic amino acids in epithelial cells as well as the uptake of glutamate from the synaptic cleft. Its cell-surface density is regulated by interaction with accessory proteins which remain to be identified. We detected a consensus sequence for interaction with post-synaptic density 95/Discs large/Zonula occludens (PDZ) proteins (-SQF) and a tyrosine-based internalization signal (-YVNG-) in the C-terminus of EAAC1, and investigated their role in the transporter localization. We demonstrated that PDZ interactions are required for the efficient delivery to and the retention in the plasma membrane of EAAC1 and we identified PDZK1/NHERF3 (Na+/H+-exchanger regulatory factor 3) as a novel EAAC1 interacting protein. Expression of PDZK1 in Madin Darby canine kidney (MDCK) cells tethered EAAC1 to filopodia and increased its surface activity. Removal of the PDZ-target motif promoted the EAAC1 binding to alpha-adaptin and clathrin and the transporter internalization in endocytic/degradative compartments. This defect was largely prevented by hypertonic treatment or overexpression of the dominant-negative u2-W421A-subunit of AP-2 clathrin-adaptor. The rate of transporter endocytosis was attenuated following tyrosine mutagenesis in the internalization signal, thus indicating that this motif can regulate the transporter endocytosis. We suggest that EAAC1 density is controlled by balanced interactions with PDZK1 and adaptor protein 2 (AP2): the former promotes the transporter expression at the cell surface, and the latter mediates its constitutive endocytosis. PMID- 20727122 TI - Loads, lungs, and lymphoproliferative disorders: role of Epstein-Barr virus and limitations of what we know. PMID- 20727121 TI - HIV-1 assembly differentially alters dynamics and partitioning of tetraspanins and raft components. AB - Partitioning of membrane proteins into various types of microdomains is crucial for many cellular functions. Tetraspanin-enriched microdomains (TEMs) are a unique type of protein-based microdomain, clearly distinct from membrane rafts, and important for several cellular processes such as fusion, migration and signaling. Paradoxically, HIV-1 assembly/egress occurs at TEMs, yet the viral particles also incorporate raft lipids. Using different quantitative microscopy approaches, we investigated the dynamic relationship between TEMs, membrane rafts and HIV-1 exit sites, focusing mainly on the tetraspanin CD9. Our results show that clustering of CD9 correlates with multimerization of the major viral structural component, Gag, at the plasma membrane. CD9 exhibited confined behavior and reduced lateral mobility at viral assembly sites, suggesting that Gag locally traps tetraspanins. In contrast, the raft lipid GM1 and the raft associated protein CD55, while also recruited to assembly/budding sites, were only transiently trapped in these membrane areas. CD9 recruitment and confinement were found to be partially dependent on cholesterol, while those of CD55 were completely dependent on cholesterol. Importantly, our findings support the emerging concept that cellular and viral components, instead of clustering at preexisting microdomain platforms, direct the formation of distinct domains for the execution of specific functions. PMID- 20727123 TI - Dog erythrocyte antigens 1.1, 1.2, 3, 4, 7, and Dal blood typing and cross matching by gel column technique. AB - BACKGROUND: Testing for canine blood types other than dog erythrocyte antigen 1.1 (DEA 1.1) is controversial and complicated by reagent availability and methodology. OBJECTIVES: The objectives of this study were to use available gel column technology to develop an extended blood-typing method using polyclonal reagents for DEA 1.1, 1.2, 3, 4, 7, and Dal and to assess the use of gel columns for cross-matching. METHODS: Dogs (43-75) were typed for DEA 1.1, 1.2, 3, 4, 7, and Dal. METHODS included tube agglutination (Tube) using polyclonal reagents, a commercially available DEA 1.1 gel column test kit (Standard-Gel) using monoclonal reagent, and multiple gel columns (Extended-Gel) using polyclonal reagents. Blood from 10 recipient and 15 donor dogs was typed as described above and cross-matched using the gel column technique. RESULTS: Of 43 dogs typed for DEA 1.1, 23, 25, and 20 dogs were positive using Standard-Gel, Extended-Gel, and Tube, respectively. Typing for DEA 1.2 was not achievable with Extended-Gel. For 75 dogs typed for DEA 3, 4, and 7, concordance of Extended-Gel with Tube was 94.7%, 100%, and 84%, respectively. Dal, determined only by Extended-Gel, was positive for all dogs. Post-transfusion major cross-matches were incompatible in 10 of 14 pairings, but none were associated with demonstrable blood type incompatibilities. CONCLUSIONS: Gel column methodology can be adapted for use with polyclonal reagents for detecting DEA 1.1, 3, 4, 7, and Dal. Agglutination reactions are similar between Extended-Gel and Tube, but are more easily interpreted with Extended-Gel. When using gel columns for cross-matching, incompatible blood cross-matches can be detected following sensitization by transfusion, although in this study incompatibilities associated with any tested DEA or Dal antigens were not found. PMID- 20727124 TI - Significance of surface epithelial cells in canine cerebrospinal fluid and relationship to central nervous system disease. AB - BACKGROUND: The term "surface epithelium" is used to describe cells, including meningeal, choroid plexus, ependymal, and endothelial cells, that are found in human cerebrospinal fluid (CSF) and are difficult to distinguish cytologically. We hypothesized that the presence of surface epithelial cells in canine CSF was associated with specific diseases of the central nervous system (CNS). OBJECTIVES: In this retrospective study the frequency of surface epithelial cells in CSF from dogs with neurologic disease was investigated along with the potential association with age, specific type of CNS disease, and CSF total nucleated cell count (TNCC) and protein concentration. METHODS: The frequency of surface epithelial cells in 359 canine CSF samples was analyzed for 5 disease groups: CNS neoplasia, CNS compression, CNS inflammation, idiopathic epilepsy, and miscellaneous diseases. Groups were also combined into those with and without expected meningeal involvement. Association of the presence of surface epithelial cells in CSF with age, disease type, and CSF TNCC and protein concentration was investigated. RESULTS: Surface epithelial cells were found in 27 of 359 (7.5%) CSF samples: CNS neoplasia 2/30 (6.7%), CNS compression 7/64 (10.9%), CNS inflammation 1/39 (2.6%), idiopathic epilepsy 8/124 (6.5%), and miscellaneous diseases 9/102 (8.8%). Significant associations between surface epithelial cell presence in CSF and age, disease type, CSF TNCC, and CSF protein concentration were not found. CONCLUSIONS: The presence of surface epithelial cells was not related to a specific disease group or CSF changes in the studied population. Thus, the presence of surface epithelial cells should be interpreted carefully, as it could represent an incidental finding in CSF specimens. PMID- 20727125 TI - Comparison of methods for depletion of albumin and IgG from equine serum. AB - BACKGROUND: Disease-specific biomarkers hold diagnostic promise in both human and veterinary medicine, but serum biomarkers in low concentrations may be masked by the presence of abundant proteins, mostly albumin and IgG. Methods to deplete albumin and IgG exist, but efficacy of these methods for depleting equine serum of these proteins has not been established. OBJECTIVE: The aim of this study was to determine if albumin and IgG could be depleted from equine serum using several commercially available kits and procedures. METHODS: One-dimensional gel electrophoresis followed by densitometry was used to determine percent of albumin, IgG, and both in pooled serum from 3 horses before and after application of 7 depletion methods. Repeatability was determined by applying the 2 best methods to serum samples from 6 grade horses. RESULTS: For pooled serum, depletion rates varied from 35-90% for albumin and 0-94% for IgG. In the repeatability study, the ProteoExtract method combined with protein G Sepharose beads to remove additional IgG provided the best overall performance with 66% albumin depletion and 100% IgG depletion. A protocol using protein G Sepharose beads to remove IgG followed by ethanol precipitation of nonalbumin proteins with albumin remaining in the supernatant was the second most effective, with 85% albumin depletion and 55% IgG depletion. Although a multiprotein immunodepletion column effectively removed 90% of the albumin, the method was ineffective at removing IgG. CONCLUSION: Albumin and IgG removal kits optimized for human use have variable efficacy for equine serum. Combined use of the ProteoExtract kit and manual incubation with protein G Sepharose beads provided the most effective depletion. PMID- 20727126 TI - The influence of long-term treadmill exercise on bone mass and articular cartilage in ovariectomized rats. AB - BACKGROUND: Loss of bone quality and deterioration of articular cartilage are commonly seen after menopause. While exercise may protect against tissue degeneration, a clear link has yet to be established. The aim of the present study is to investigate the influence of long-term treadmill exercise on changes in bone mass and articular cartilage in ovariectomized rats. METHODS: Sixty female Sprague-Dawley rats were randomly assigned to 4 groups: ovariectomized (OVX), ovariectomized plus treadmill exercise (OVX-RUN), treadmill exercise alone (RUN), and control (CON) groups. After 36 weeks, the following variables were compared among the 4 groups. Bone mass was evaluated by trabecular bone volume and bone mineral density (BMD). Articular cartilage in the knee joints was evaluated by histology analysis and a modified Mankin score. RESULTS: Rats in the ovariectomized groups (OVX and OVX-RUN) had significantly lower BMD and bone mass than the non-ovariectomized rats (CON and RUN), indicating that exercise did little to preserve bone mass. However, the sedentary OVX group had a significantly worse modified Mankin score (7.7 +/- 1.4) than the OVX-RUN group (4.8 +/- 1.0), whose scores did not differ significantly from the other 2 non operated groups. The articular cartilage in the sedentary OVX rats was relatively thinner, hypocellular, and had more clefts than in the other 3 groups. CONCLUSION: This study suggests that long-term exercise protects articular cartilage in OVX rats but does not retard the loss of bone mass seen in after menopause. PMID- 20727127 TI - Traditional Cantonese diet and nasopharyngeal carcinoma risk: a large-scale case control study in Guangdong, China. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but is a common malignancy in southern China, especially in Guangdong. Dietary habit is regarded as an important modifier of NPC risk in several endemic areas and may partially explain the geographic distribution of NPC incidence. In China, rapid economic development during the past few decades has changed the predominant lifestyle and dietary habits of the Chinese considerably, requiring a reassessment of diet and its potential influence on NPC risk in this NPC-endemic area. METHODS: To evaluate the association between dietary factors and NPC risk in Guangdong, China, a large-scale, hospital-based case-control study was conducted. 1387 eligible cases and 1459 frequency matched controls were recruited. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated using a logistic regression model, adjusting for age, sex, education, dialect, and habitation household type. RESULTS: Observations made include the following: 1) consumption of canton-style salted fish, preserved vegetables and preserved/cured meat were significantly associated with increased risk of NPC, with enhanced odds ratios (OR) of 2.45 (95% CI: 2.03-2.94), 3.17(95% CI: 2.68-3.77) and 2.09 (95% CI: 1.22-3.60) respectively in the highest intake frequency stratum during childhood; 2) consumption of fresh fruit was associated with reduced risk with a dose-dependent relationship (p = 0.001); and 3) consumption of Canton-style herbal tea and herbal slow-cooked soup was associated with decreased risk, with ORs of 0.84 (95% CI: 0.68-1.03) and 0.58 (95% CI: 0.47 0.72) respectively in the highest intake frequency stratum. In multivariate analyses, these associations remained significant. CONCLUSIONS: It can be inferred that previously established dietary risk factors in the Cantonese population are still stable and have contributed to the incidence of NPC. PMID- 20727128 TI - Carotid intima-media thickness in individuals with and without type 2 diabetes: a reproducibility study. AB - BACKGROUND: The use of carotid intima-media thickness (carotid IMT) as a surrogate marker of cardiovascular disease is increasing and the method has now also been applied in several trials investigating patients with type 2 diabetes (T2D). Even though knowledge about methodology is of highest importance in order to make accurate power calculations and analyses of results, no reproducibility studies have been performed in this group of patients. The aim of this study was to quantify the variability of the measurement of carotid IMT in individuals with and without T2D. METHODS: We used B-mode ultrasound and a computerized software programme (MIA vascular tools) for analysis of carotid IMT. Measurement of carotid IMT in the far wall of the common carotid artery (CCA) was done for 30 patients with T2D and 30 persons without T2D. The examinations were done by two different sonographers and two different readers on two separate days in order to quantify sonographer-, reader-, and day-to-day variability. RESULTS: Comparisons of measurement of carotid IMT in CCA between sonographers (sonographer variability) resulted in limits of agreement (LoA) from -0.18 to 0.13 mm for patients with T2D and -0.12 to 0.10 mm for persons without T2D. This means, that a second scanning of the same person with 95% probability would be within this interval of the first scanning. Comparisons between readers assessing the same scanning (reader variability) resulted in LoA from -0.05 to 0.07 mm and -0.04 to 0.05 mm respectively. LoA of the day-to-day variability was -0.13 to 0.18 mm and 0.09 to 0.18 mm respectively. This corresponds to coefficients of variations (CV) of the sonographer- and day-to-day variability of 10% in patients with T2D and 8% in persons without T2D. The CV of the reader variability was 4% and 3% respectively. CONCLUSION: Measurement of carotid IMT in the CCA can be determined with good and comparable reproducibility in both patients with T2D and persons without T2D. These findings support the use of carotid IMT in clinical trials with T2D patients and suggest that the numbers of patients needed to detect a given difference will be the same whether the patients have T2D or not. PMID- 20727129 TI - A randomised, assessor blind, parallel group comparative efficacy trial of three products for the treatment of head lice in children--melaleuca oil and lavender oil, pyrethrins and piperonyl butoxide, and a "suffocation" product. AB - BACKGROUND: There are many different types of pediculicides available OTC in Australia. In this study we compare the efficacy and safety of three topical pediculicides: a pediculicide containing melaleuca oil (tea tree oil) and lavender oil (TTO/LO); a head lice "suffocation" product; and a product containing pyrethrins and piperonyl butoxide (P/PB). METHOD: This study was a randomised, assessor-blind, comparative, parallel study of 123 subjects with live head lice. The head lice products were applied according to the manufacturer's instructions (the TTO/LO product and the "suffocation" product were applied three times at weekly intervals according to manufacturers instructions (on Day 0, Day 7 and Day 14) and the P/PB product was applied twice according to manufacturers instructions (on Day 0 and Day 7)). The presence or absence of live lice one day following the last treatment was determined. RESULTS: The percentage of subjects who were louse-free one day after the last treatment with the product containing tea tree oil and lavender oil (41/42; 97.6%) and the head lice "suffocation" product (40/41, 97.6%) was significantly higher compared to the percentage of subjects who were louse-free one day after the last treatment with the product containing pyrethrins and piperonyl butoxide (10/40, 25.0%; adj. p < 0.0001). CONCLUSION: The high efficacy of the TTO/LO product and the head lice "suffocation" product offers an alternative to the pyrethrins-based product. TRIAL REGISTRATION: The study was entered into the Australian/New Zealand Clinical Trial Registry, ACTRN12610000179033. PMID- 20727131 TI - Automatic segmentation of coronary angiograms based on fuzzy inferring and probabilistic tracking. AB - BACKGROUND: Segmentation of the coronary angiogram is important in computer assisted artery motion analysis or reconstruction of 3D vascular structures from a single-plan or biplane angiographic system. Developing fully automated and accurate vessel segmentation algorithms is highly challenging, especially when extracting vascular structures with large variations in image intensities and noise, as well as with variable cross-sections or vascular lesions. METHODS: This paper presents a novel tracking method for automatic segmentation of the coronary artery tree in X-ray angiographic images, based on probabilistic vessel tracking and fuzzy structure pattern inferring. The method is composed of two main steps: preprocessing and tracking. In preprocessing, multiscale Gabor filtering and Hessian matrix analysis were used to enhance and extract vessel features from the original angiographic image, leading to a vessel feature map as well as a vessel direction map. In tracking, a seed point was first automatically detected by analyzing the vessel feature map. Subsequently, two operators [e.g., a probabilistic tracking operator (PTO) and a vessel structure pattern detector (SPD)] worked together based on the detected seed point to extract vessel segments or branches one at a time. The local structure pattern was inferred by a multi-feature based fuzzy inferring function employed in the SPD. The identified structure pattern, such as crossing or bifurcation, was used to control the tracking process, for example, to keep tracking the current segment or start tracking a new one, depending on the detected pattern. RESULTS: By appropriate integration of these advanced preprocessing and tracking steps, our tracking algorithm is able to extract both vessel axis lines and edge points, as well as measure the arterial diameters in various complicated cases. For example, it can walk across gaps along the longitudinal vessel direction, manage varying vessel curvatures, and adapt to varying vessel widths in situations with arterial stenoses and aneurysms. CONCLUSIONS: Our algorithm performs well in terms of robustness, automation, adaptability, and applicability. In particular, the successful development of two novel operators, namely, PTO and SPD, ensures the performance of our algorithm in vessel tracking. PMID- 20727130 TI - Neutrophils are immune cells preferentially targeted by retinoic acid in elderly subjects. AB - BACKGROUND: The immune system gradually deteriorates with age and nutritional status is a major factor in immunosenescence. Of the many nutritional factors implicated in age-related immune dysfunction, vitamin A may be a good candidate, since vitamin A concentrations classically decrease during aging whereas it may possess important immunomodulatory properties via its active metabolites, the retinoic acids. This prompted us to investigate the immune response induced by retinoids in adults and elderly healthy subjects. Before and after oral supplementation with 13cis retinoic acid (0.5 mg/kg/day during 28 days), whole blood cells were phenotyped, and functions of peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were investigated by flow cytometry and ELISA tests. RESULTS: In both young adults (n = 20, 25 +/- 4 years) and older subjects (n = 20, 65 +/- 4 years), retinoic acid supplementation had no effect on the distribution of leukocyte subpopulations or on the functions of PBMC (Il-2 and sIl-2R production, membrane expression of CD25). Concerning PMN, retinoic acid induced an increase in both spontaneous migration and cell surface expression of CD11b in the two different age populations, whereas bactericidal activity and phagocytosis remained unchanged. CONCLUSIONS: We demonstrated that retinoic acid induces the same intensity of immune response between adult and older subjects, and more specifically affects PMN functions, i.e. adhesion and migration, than PBMC functions. PMID- 20727132 TI - Adoptive transfer of splenocytes to study cell-mediated immune responses in hepatitis C infection using HCV transgenic mice. AB - BACKGROUND: Hepatitis C virus (HCV) is a major cause of chronic hepatitis and a health problem affecting over 170 million people around the world. We previously studied transgenic mice that express HCV Core, Envelope 1 and Envelope 2 proteins predominantly in the liver, resulting in steatosis, liver and lymphoid tumors, and hepatocellular carcinoma. Herein, the immune-mediated cell response to hepatitis C antigens was evaluated by adoptive transfers of carboxyfluorescein succinimidyl ester (CFSE) labelled splenocytes from HCV immunized mice into HCV transgenic mice. RESULTS: In comparison to non-transgenic mice, there was a significant decrease in the percentage of CFSE-labeled CD4+ and CD8+ T cells in transgenic mouse peripheral blood receiving adoptive transfers from immunized donors. Moreover, the percentage of CFSE-labeled CD4+ and CD8+ T cells were significantly higher in the spleen of transgenic and non-transgenic mice when they received splenocytes from non-immunized than from immunized mice. On the other hand, the percentages of CD4+ and CD8+ T cells in the non-transgenic recipient mouse lymph nodes were significantly higher than the transgenic mice when they received the adoptive transfer from immunized donors. Interestingly, livers of transgenic mice that received transfers from immunized mice had a significantly higher percentage of CFSE labeled T cells than livers of non transgenic mice receiving non-immunized transfers. CONCLUSIONS: These results suggest that the T cells from HCV immunized mice recognize the HCV proteins in the liver of the transgenic mouse model and homed to the HCV antigen expression sites. We propose using this model system to study active T cell responses in HCV infection. PMID- 20727134 TI - Kafka, paranoic doubles and the brain: hypnagogic vs. hyper-reflexive models of disrupted self in neuropsychiatric disorders and anomalous conscious states. AB - Kafka's writings are frequently interpreted as representing the historical period of modernism in which he was writing. Little attention has been paid, however, to the possibility that his writings may reflect neural mechanisms in the processing of self during hypnagogic (i.e., between waking and sleep) states. Kafka suffered from dream-like, hypnagogic hallucinations during a sleep-deprived state while writing. This paper discusses reasons (phenomenological and neurobiological) why the self projects an imaginary double (autoscopy) in its spontaneous hallucinations and how Kafka's writings help to elucidate the underlying cognitive and neural mechanisms. I further discuss how the proposed mechanisms may be relevant to understanding paranoid delusions in schizophrenia. Literature documents and records cognitive and neural processes of self with an intimacy that may be otherwise unavailable to neuroscience. To elucidate this approach, I contrast it with the apparently popularizing view that the symptoms of schizophrenia result from what has been called an operative (i.e., pre reflective) hyper-reflexivity. The latter approach claims that pre-reflective self-awareness (diminished in schizophrenia) pervades all conscious experience (however, in a manner that remains unverifiable for both phenomenological and experimental methods). This contribution argues the opposite: the "self" informs our hypnagogic imagery precisely to the extent that we are not self-aware. PMID- 20727135 TI - MC-Net: a method for the construction of phylogenetic networks based on the Monte Carlo method. AB - BACKGROUND: A phylogenetic network is a generalization of phylogenetic trees that allows the representation of conflicting signals or alternative evolutionary histories in a single diagram. There are several methods for constructing these networks. Some of these methods are based on distances among taxa. In practice, the methods which are based on distance perform faster in comparison with other methods. The Neighbor-Net (N-Net) is a distance-based method. The N-Net produces a circular ordering from a distance matrix, then constructs a collection of weighted splits using circular ordering. The SplitsTree which is a program using these weighted splits makes a phylogenetic network. In general, finding an optimal circular ordering is an NP-hard problem. The N-Net is a heuristic algorithm to find the optimal circular ordering which is based on neighbor joining algorithm. RESULTS: In this paper, we present a heuristic algorithm to find an optimal circular ordering based on the Monte-Carlo method, called MC-Net algorithm. In order to show that MC-Net performs better than N-Net, we apply both algorithms on different data sets. Then we draw phylogenetic networks corresponding to outputs of these algorithms using SplitsTree and compare the results. CONCLUSIONS: We find that the circular ordering produced by the MC-Net is closer to optimal circular ordering than the N-Net. Furthermore, the networks corresponding to outputs of MC-Net made by SplitsTree are simpler than N-Net. PMID- 20727136 TI - Risk factors and correlates for anemia in HIV treatment-naive infected patients: a cross-sectional analytical study. AB - BACKGROUND: Hematologic manifestations of the human immunodeficiency virus (HIV) infection are a well-recognized complication of the disease and may be clinically important. Our objective was to determine the risk factors for anemia and its correlation with HIV treatment-naive infected patients without co-infection or opportunistic diseases. FINDINGS: We performed a cross-sectional comparative study in which HIV treatment-naive infected patients with anemia were compared with a control group of HIV patients without anemia. The interrelationship between risk factors and anemia was determined. Odds ratio and 95% confidence intervals were calculated, to adjust for the effects of potential confounders and we used a logistic regression model. Pearson's correlation coefficient was obtained to calculate the correlation between risk factors and hemoglobin.We enrolled 54 men and 9 women. Anemia was found in 13 patients; prevalence .20 (CI 95% 0.12-0.32). Severe anemia was found in only one patient (1.5%). Only CD4+ Cells Count <200 cells/mm3 was associated with increased risk of anemia in the multivariate analysis. There was a moderately strong, positive correlation between WBC and hemoglobin (r = 0.49, P < 0.001) and between CD4+ cell count and hemoglobin (r = 0.595, P < 0.001) and a moderately strong, negative correlation between HIV RNA viral load and hemoglobin (r = - 0.433, P < 0.001). CONCLUSIONS: Anemia is a common manifestation in the Mexican population without antiretroviral therapy. In HIV naive patients a CD4+ Cell Count < 200 cells/mm3 was associated with an increased risk of anemia. There is a positive correlation between hemoglobin and CD4+ cell count. PMID- 20727133 TI - Interstitial lung diseases in children. AB - Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy. PMID- 20727137 TI - Factors affecting costs and utilization of type 2 diabetes healthcare: a cross sectional survey among 15 hospitals in urban China. AB - BACKGROUND: Type 2 Diabetes mellitus (T2DM) affects persons of all ages, while also placing heavy economic burdens on national economies and healthcare systems. The study aims to investigate the determinants of direct medical cost (DMC), out of-pocket (OOP) proportion of the cost, and healthcare utilization associated with T2DM. METHODS: This cross-sectional study was conducted in four major cities in China. Eligible subjects were adult outpatients who received treatment at one of 15 sampled secondary or tertiary hospitals and consecutively enrolled between March 2007 and May 2007. Generalized estimating equations were used to determine impact factors associated with DMC and healthcare utilization. RESULTS: Insurance schemes and receiving insulin therapy were significantly associated with a higher annual DMC of T2DM. For each increase in number of complications, there was about 33% increase in annual DMC. Insurance schemes were significantly associated with the proportions of DMC from pocket. A 7% significantly lower proportion of DMC was paid and 23% more clinic visits (AOR = 1.232, P < 0.001) were made by patients admitted at secondary hospitals than tertiary hospitals. The group with higher income (> 2000 CNY/month) paid 23% less from their pocket, compared with the lower income group. The number of complications also significantly increased the outpatient visits (AOR = 1.064, P < 0.001). CONCLUSIONS: It implies that preventing complications through the use of more effective treatment regimens is important in order to control the healthcare expenditures of the diseases. Healthcare reform needs to be focused on the medical insurance system and redistribution of patients in hospitals of different levels. PMID- 20727138 TI - Generation of a panel of antibodies against proteins encoded on human chromosome 21. AB - BACKGROUND: Down syndrome (DS) is caused by trisomy of all or part of chromosome 21. To further understanding of DS we are working with a mouse model, the Tc1 mouse, which carries most of human chromosome 21 in addition to the normal mouse chromosome complement. This mouse is a model for human DS and recapitulates many of the features of the human syndrome such as specific heart defects, and cerebellar neuronal loss. The Tc1 mouse is mosaic for the human chromosome such that not all cells in the model carry it. Thus to help our investigations we aimed to develop a method to identify cells that carry human chromosome 21 in the Tc1 mouse. To this end, we have generated a panel of antibodies raised against proteins encoded by genes on human chromosome 21 that are known to be expressed in the adult brain of Tc1 mice RESULTS: We attempted to generate human specific antibodies against proteins encoded by human chromosome 21. We selected proteins that are expressed in the adult brain of Tc1 mice and contain regions of moderate/low homology with the mouse ortholog. We produced antibodies to seven human chromosome 21 encoded proteins. Of these, we successfully generated three antibodies that preferentially recognise human compared with mouse SOD1 and RRP1 proteins on western blots. However, these antibodies did not specifically label cells which carry a freely segregating copy of Hsa21 in the brains of our Tc1 mouse model of DS. CONCLUSIONS: Although we have successfully isolated new antibodies to SOD1 and RRP1 for use on western blots, in our hands these antibodies have not been successfully used for immunohistochemistry studies. These antibodies are freely available to other researchers. Our data high-light the technical difficulty of producing species-specific antibodies for both western blotting and immunohistochemistry. PMID- 20727140 TI - Compliance and treatment satisfaction of post menopausal women treated for osteoporosis. Compliance with osteoporosis treatment. AB - BACKGROUND: Adherence to anti-osteoporosis treatments is poor, exposing treated women to increased fracture risk. Determinants of poor adherence are poorly understood. The study aims to determine physician- and patient- rated treatment compliance with osteoporosis treatments and to evaluate factors influencing compliance. METHODS: This was an observational, cross-sectional pharmacoepidemiological study with a randomly-selected sample of 420 GPs, 154 rheumatologists and 110 gynaecologists practicing in France. Investigators included post-menopausal women with a diagnosis of osteoporosis and a treatment initiated in the previous six months. Investigators completed a questionnaire on clinical features, treatments and medical history, and on patient compliance. Patients completed a questionnaire on sociodemographic features, lifestyle, attitudes and knowledge about osteoporosis, treatment compliance, treatment satisfaction and quality of life. Treatment compliance was evaluated with the Morisky Medication-taking Adherence Scale. Variables collected in the questionnaires were evaluated for association with compliance using multivariate logistic regression analysis. RESULTS: 785 women were evaluated. Physicians considered 95.4% of the sample to be compliant, but only 65.5% of women considered themselves compliant. The correlation between patient and physician perceptions of compliance was low (kappa: 0.11 [95% CI: 0.06 to 0.16]). Patient rated compliance was highest for monthly bisphosphonates (79.7%) and lowest for hormone substitution therapy (50.0%). Six variables were associated with compliance: treatment administration frequency, perceptions of long-term treatment acceptability, perceptions of health consequences of osteoporosis, perceptions of knowledge about osteoporosis, exercise and mental quality of life. CONCLUSION: Compliance to anti-osteoporosis treatments is poor. Reduction of dosing regimen frequency and patient education may be useful ways of improving compliance. PMID- 20727139 TI - Kinematic analysis of the daily activity of drinking from a glass in a population with cervical spinal cord injury. AB - BACKGROUND: Three-dimensional kinematic analysis equipment is a valuable instrument for studying the execution of movement during functional activities of the upper limbs. The aim of this study was to analyze the kinematic differences in the execution of a daily activity such as drinking from a glass between two groups of patients with tetraplegia and a control group. METHODS: A total of 24 people were separated into three groups for analysis: 8 subjects with metameric level C6 tetraplegia, 8 subjects with metameric level C7 tetraplegia and 8 control subjects (CG). A set of active markers that emit infrared light were positioned on the upper limb. Two scanning units were used to record the sessions. The activity of drinking from a glass was broken down into a series of clearly identifiable phases to facilitate analysis. Movement times, velocities, and the joint angles of the shoulder, elbow and wrist in the three spatial planes were the variables analyzed. RESULTS: The most relevant differences between the three groups were in the wrist. Wrist palmar flexion during the back transport phase was greater in the patients with C6 and C7 tetraplegia than in the CG, whereas the highest wrist dorsal flexion values were in forward transport in the subjects with C6 or C7 tetraplegia, who required complete activation of the tenodesis effect to complete grasping. CONCLUSIONS: A detailed description was made of the three-dimensional kinematic analysis of the task of drinking from a glass in healthy subjects and in two groups of patients with tetraplegia. This was a useful application of kinematic analysis of upper limb movement in a clinical setting. Better knowledge of the execution of this movement in each of these groups allows therapeutic recommendations to be specifically adapted to the functional deficit present. This information can be useful in designing wearable robots to compensate the performance of AVD, such as drinking, in people with cervical SCI. PMID- 20727141 TI - The effectiveness and efficiency of diabetes screening in Ontario, Canada: a population-based cohort study. AB - BACKGROUND: Little is known about the efficiency and effectiveness of the current level of diabetes screening activity in Ontario where there is universal access to health services. Our study aims were to: (i) determine how often Ontarians are screened for diabetes; (ii) estimate screening efficiency based on the number needed to screen (NNS) to diagnosis one diabetes case; (iii) examine the population effectiveness of screening as estimated by the number of undiagnosed diabetes cases. METHODS: Ontario respondents of the Canadian Community Health Survey who agreed to have their responses linked to health care data (n = 37,400) provided the cohort. The five-year probabilities of glucose testing and diabetes diagnoses were estimated using a Cox Proportional Hazards Model. We defined NNS as the ratio of diabetes tests to number of diabetes diagnoses over the study period. We estimated the number of undiagnosed diabetes by dividing the number not tested at the end of study period by the NNS. RESULTS: 80% of women and 66% of men had a blood glucose test within 5 years. The efficiency of screening was estimated by a NNS of 14 among men and 22 among women. 127,100 cases of undiagnosed diabetes were estimated, representing 1.4% of the Ontario adult population. Increasing age, hypertension, immigrant and non-white ethnicity, and number of general practitioner visits were associated with an increased likelihood of having a glucose test (LR chi2 p < 0.001). Low income men were less likely to be tested. CONCLUSIONS: Diabetes screening was high in this population based cohort of Ontarians. Screening efficiency varied considerably in the population. Undiagnosed diabetes continues to be prevalent and remains concentrated in the highest risk groups for diabetes, especially among men. PMID- 20727142 TI - Significance of lobular intraepithelial neoplasia at margins of breast conservation specimens: a report of 38 cases and literature review. AB - BACKGROUND: Presence of lobular intraepithelial neoplasia (LIN) is not routinely reported as part of margin assessment in breast conservation therapy (BCT) as in ductal carcinoma in situ (DCIS). With new emerging evidence of LIN as possible precursor lesion, the hypothesis is that LIN at the margin may increase the risk of local recurrence with BCT. The aim is to determine whether there is an increase incidence of recurrence when LIN is found at surgical margins on BCT. METHODS: We retrospectively reviewed a total of 1,334 BCT at a single institution in a 10 year period. Inclusion criteria are positive margin with LIN from primary BCT containing invasive and/or in situ carcinoma with comparison to the negative control group who had similar diseases with negative margin for LIN. RESULTS: We identified 38 cases (2.8%) with LIN either lobular carcinoma in situ/atypical lobular hyperplasia (LCIS/ALH) at a margin on initial BCT with 36% recurrence rate. Of the 38 cases: 5 (13%) were lost to follow-up, 12 (32%) had no further procedures performed and 21 (55%) had re-excision. Out of 21 patients who had re excisions, 12 (57%) had residual invasive carcinoma or DCIS, three (14%) had pleomorphic LCIS and 4 (19%) showed residual classic type LCIS. 71% had significant residual disease (local recurrence) and 29% had no residual disease. A negative control group consisted of 38 cases. We found two patients with bone or brain metastasis and one local recurrence. Clinical follow up periods range from 1 to 109 months. CONCLUSIONS: LIN found at a margin on BCT showed a significant recurrent ipsilateral disease. Our study supports the view that LIN seen at the margin may play a role in recurrence. PMID- 20727143 TI - Surveillance of pyrazinamide susceptibility among multidrug-resistant Mycobacterium tuberculosis isolates from Siriraj Hospital, Thailand. AB - BACKGROUND: Susceptibility testing of pyrazinamide (PZA) against Mycobacterium tuberculosis is difficult to perform because the acidity of culture medium that is required for drug activity also inhibits the growth of bacteria. In Thailand, very limited information has been generated on PZA resistance, particularly among multidrug-resistant tuberculosis (MDR-TB) isolated from Thailand. Only two studies on PZA susceptibility among Thai M. tuberculosis strains have been reported; one used a pyrazinamidase assay, and the other used the BACTEC 460 TB for PZA susceptibility testing. In this study, we determined the percentage of strains possessing pyrazinamide resistance among pan-susceptible M. tuberculosis and MDR-TB isolates by using the pyrazinamidase assay, BACTEC MGIT 960 PZA method and pncA sequencing, and assessed the correlation in the data generated using these methods. The type and frequency of mutations in pncA were also determined. RESULTS: Overall, 150 M. tuberculosis isolates, consisting of 50 susceptible and 100 MDR-TB isolates, were tested for PZA susceptibility by BACTEC MGIT 960 PZA, the pyrazinamidase assay and pncA sequencing. The study indicated PZA resistance in 6% and 49% of susceptible and MDR-TB isolates, respectively. In comparison to the BACTEC MGIT 960 PZA, the PZase assay showed 65.4% sensitivity and 100% specificity, whereas pncA sequencing showed 75% sensitivity and 89.8% specificity. Twenty-four mutation types were found in this study, with the most frequent mutation (16%) being His71Asp. Of these mutations, eight have not been previously described. The Ile31Ser and Ile31Thr mutations were found both in PZA susceptible and resistant isolates, suggesting that mutation of this codon might not play a role on PZA resistance. CONCLUSIONS: Our findings suggest that phenotypic susceptibility testing is still essential for the detection of PZA resistance, especially for MDR-TB isolates. Some mutations were not associated with resistance and could lead to misinterpretation of the genotypic methods. This information could be helpful for clinicians in managing tuberculosis patients and frequencies, and the types of pncA mutations should offer baseline information on PZA resistance. PMID- 20727144 TI - Circulating oxidized low-density lipoproteins and arterial elasticity: comparison between men with metabolic syndrome and physically active counterparts. AB - BACKGROUND: Accumulation of oxidized low-density lipoproteins in the intimae of arteries and endothelial dysfunction are key events in the development of atherosclerosis. Patients with metabolic syndrome are at high risk for cardiovascular diseases but the linkage between metabolic syndrome and atherosclerosis is incompletely understood. We studied whether the levels of oxidized LDL and arterial elasticity differ between metabolic syndrome patients and physically active controls. METHODS: 40 men with metabolic syndrome and 40 physically active controls participated in this cross-sectional study. None of the study subjects had been diagnosed with cardiovascular disease. Levels of oxidized LDL were assessed by a two-site ELISA immunoassay. Arterial elasticity was assessed non-invasively by the HDI/PulseWave CR-2000 arterial tonometer. RESULTS: Levels of oxidized LDL were 89.6 +/- 33.1 U/L for metabolic syndrome subjects and 68.5 +/- 23.6 U/L for controls (p = 0.007). The difference remained significant after adjustment for LDL cholesterol. Large artery elasticity index (C1) was 16.2 +/- 4.1 mL/mmHgx10 for metabolic syndrome subjects and 19.4 +/- 3.7 mL/mmHgx10 for controls (p = 0.001), small artery indices (C2) were 7.0 +/- 3.2 mL/mmHgx100 and 6.5 +/- 2.9 mL/mmHgx100 (NS), respectively. CONCLUSIONS: Subjects with metabolic syndrome had elevated levels of oxidized LDL and reduced large arterial elasticity compared to controls. This finding may partly explain the increased risk for cardiovascular diseases among metabolic syndrome patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01114763. PMID- 20727146 TI - Unusual primary HIV infection with colonic ulcer complicated by hemorrhagic shock: a case report. AB - INTRODUCTION: Timely diagnosis of primary HIV infection is important to prevent further transmission of HIV. Primary HIV infection may take place without symptoms or may be associated with fever, pharyngitis or headache. Sometimes, the clinical presentation includes aseptic meningitis or cutaneous lesions. Intestinal ulceration due to opportunistic pathogens (cytomegalovirus, Epstein Barr virus, Toxoplasma gondii) has been described in patients with AIDS. However, although invasion of intestinal lymphoid tissue is a prominent feature of human and simian lentivirus infections, colonic ulceration has not been reported in acute HIV infection. CASE DESCRIPTION: A 42-year-old Caucasian man was treated with amoxicillin-clavulanate for pharyngitis. He did not improve, and a rash developed. History taking revealed a negative HIV antibody test five months previously and unprotected sex with a male partner the month before admission. Repeated tests revealed primary HIV infection with an exceptionally high HIV-1 RNA plasma concentration (3.6 x 107 copies/mL) and a low CD4 count (101 cells/mm3, seven percent of total lymphocytes). While being investigated, the patient had a life-threatening hematochezia. After angiographic occlusion of a branch of the ileocaecal artery and initiation of antiretroviral therapy, the patient became rapidly asymptomatic and could be discharged. Colonoscopy revealed a bleeding colonic ulcer. We were unable to identify an etiology other than HIV for this ulcer. CONCLUSION: This case adds to the known protean manifestation of primary HIV infection. The lack of an alternative etiology, despite extensive investigations, suggests that this ulcer was directly caused by primary HIV infection. This conclusion is supported by the well-described extensive loss of intestinal mucosal CD4+ T cells associated with primary HIV infection, the extremely high HIV viral load observed in our patient, and the rapid improvement of the ulcer after initiation of highly active antiretroviral therapy. This case also adds to the debate on treatment for primary HIV infection, especially in the context of severe symptoms and an extremely high viral load. PMID- 20727145 TI - Studies on antidyslipidemic effects of Morinda citrifolia (Noni) fruit, leaves and root extracts. AB - BACKGROUND: The objective of present study was to provide the pharmacological basis for the medicinal use of Morinda citrifolia Linn in dyslipidemia using the aqueous-ethanolic extracts of its fruits (Mc.Cr.F), leaves (Mc.Cr.L) and roots (Mc.Cr.R). RESULTS: Mc.Cr.F, Mc.Cr.L and Mc.Cr.R showed antidyslipidemic effects in both triton (WR-1339) and high fat diet-induced dyslipidemic rat models to variable extents. All three extracts caused reduction in total cholesterol and triglyceride levels in triton-induced dyslipidemia. In high fat diet-induced dyslipidemia all these extracts caused significant reduction in total cholesterol, triglyceride, low density lipoprotein-cholesterol (LDL-C), atherogenic index and TC/HDL ratio. Mc.Cr.R extract also caused increase in high density lipoprotein-cholesterol (HDL-C). The Mc.Cr.L and Mc.Cr.R reduced gain in body weight with a reduction in daily diet consumption but Mc.Cr.F had no effect on body weight and daily diet consumption. CONCLUSIONS: These data indicate that the antidyslipidemic effect of the plant extracts was meditated through the inhibition of biosynthesis, absorption and secretion of lipids. This may be possibly due partly to the presence of antioxidant constituents in this plant. Therefore, this study rationalizes the medicinal use of Morinda citrifolia in dyslipidemia. PMID- 20727147 TI - Tako-tsubo cardiomyopathy after administration of ergometrine following elective caesarean delivery: a case report. AB - INTRODUCTION: Tako-tsubo cardiomyopathy (stress-induced cardiomyopathy or transient left ventricular ballooning) is characterized by clinical suspicion of an acute myocardial infarction with transient apical or midventricular dyskinesia of the left ventricle without significant coronary stenosis on angiography. The etiology of this disease remains obscure. One of the possible causes is myocardial ischemia induced by coronary vasospasm due to sympathetic activation. It has been hypothesized that the application of ergometrine could induce tako tsubo cardiomyopathy. CASE PRESENTATION: We report the case of a 28-year-old Turkish woman who developed tako-tsubo cardiomyopathy after administration of ergometrine for release of placenta and prevention of bleeding during the post partum phase in the course of an elective caesarean delivery. Tako-tsubo cardiomyopathy was diagnosed by echocardiography and urgent cardiac magnetic resonance imaging. A coronary angiography was not performed because of the absence of myocardial necrosis or ischemia and signs of myocarditis on cardiac magnetic resonance imaging. CONCLUSION: This life-threatening disease should be excluded in the differential diagnosis by comparing the symptoms with those of typical heart failure, particularly after use of ergometrine. PMID- 20727148 TI - Acute febrile neutrophilic dermatosis (Sweet's syndrome) in a child, associated with a rotavirus infection: a case report. AB - INTRODUCTION: Sweet's syndrome characterized by fever, blood neutrophilia and inflammatory skin lesions, is rarely diagnosed in children. It presents in three clinical settings: classical Sweet's syndrome, usually after a respiratory tract infection; malignancy-associated, frequently related to acute myelogeneous leukemia; and drug-induced. We present, to the best of our knowledge, the first case of a rotavirus -infection-related Sweet's syndrome. CASE PRESENTATION: An 18 month-old boy of Hellenic origin was referred to us with diarrhea, fever, neutrophilia, typical skin lesions, asymmetrical hip arthritis and oropharyngeal involvement. A skin biopsy confirmed the diagnosis. Thorough screening did not reveal any underlying systemic illness, except for the confirmation of an overt rotavirus infection. The syndrome responded promptly upon corticosteroid administration; no recurrence was observed. CONCLUSION: Besides describing the connection of Sweet's syndrome to a rotavirus infection, this case report is also a reminder that in a child presenting with a febrile papulo-nodular rash with neutrophilia Sweet's syndrome should be included in the differential. PMID- 20727149 TI - Arm-in-cage testing of natural human-derived mosquito repellents. AB - BACKGROUND: Individual human subjects are differentially attractive to mosquitoes and other biting insects. Previous investigations have demonstrated that this can be attributed partly to enhanced production of natural repellent chemicals by those individuals that attract few mosquitoes in the laboratory. The most important compounds in this respect include three aldehydes, octanal, nonanal and decanal, and two ketones, 6-methyl-5-hepten-2-one and geranylacetone [(E)-6,10 dimethylundeca-5,9-dien-2-one]. In olfactometer trials, these compounds interfered with attraction of mosquitoes to a host and consequently show promise as novel mosquito repellents. METHODS: To test whether these chemicals could provide protection against mosquitoes, laboratory repellency trials were carried out to test the chemicals individually at different concentrations and in different mixtures and ratios with three major disease vectors: Anopheles gambiae, Culex quinquefasciatus and Aedes aegypti. RESULTS: Up to 100% repellency was achieved depending on the type of repellent compound tested, the concentration and the relative composition of the mixture. The greatest effect was observed by mixing together two compounds, 6-methyl-5-hepten-2-one and geranylacetone in a 1:1 ratio. This mixture exceeded the repellency of DEET when presented at low concentrations. The repellent effect of this mixture was maintained over several hours. Altering the ratio of these compounds significantly affected the behavioural response of the mosquitoes, providing evidence for the ability of mosquitoes to detect and respond to specific mixtures and ratios of natural repellent compounds that are associated with host location. CONCLUSION: The optimum mixture of 6-methyl-5-hepten-2-one and geranylacetone was a 1:1 ratio and this provided the most effective protection against all species of mosquito tested. With further improvements in formulation, selected blends of these compounds have the potential to be exploited and developed as human-derived novel repellents for personal protection. PMID- 20727150 TI - A towards-multidimensional screening approach to predict candidate genes of rheumatoid arthritis based on SNP, structural and functional annotations. AB - BACKGROUND: According to the Genetic Analysis Workshops (GAW), hundreds of thousands of SNPs have been tested for association with rheumatoid arthritis. Traditional genome-wide association studies (GWAS) have been developed to identify susceptibility genes using a "most significant SNPs/genes" model. However, many minor- or modest-risk genes are likely to be missed after adjustment of multiple testing. This screening process uses a strict selection of statistical thresholds that aim to identify susceptibility genes based only on statistical model, without considering multi-dimensional biological similarities in sequence arrangement, crystal structure, or functional categories/biological pathways between candidate and known disease genes. METHODS: Multidimensional screening approaches combined with traditional statistical genetics methods can consider multiple biological backgrounds of genetic mutation, structural, and functional annotations. Here we introduce a newly developed multidimensional screening approach for rheumatoid arthritis candidate genes that considers all SNPs with nominal evidence of Bayesian association (BFLn > 0), and structural and functional similarities of corresponding genes or proteins. RESULTS: Our multidimensional screening approach extracted all risk genes (BFLn > 0) by odd ratios of hypothesis H1 to H0, and determined whether a particular group of genes shared underlying biological similarities with known disease genes. Using this method, we found 6614 risk SNPs in our Bayesian screen result set. Finally, we identified 146 likely causal genes for rheumatoid arthritis, including CD4, FGFR1, and KDR, which have been reported as high risk factors by recent studies. We must denote that 790 (96.1%) of genes identified by GWAS could not easily be classified into related functional categories or biological processes associated with the disease, while our candidate genes shared underlying biological similarities (e.g. were in the same pathway or GO term) and contributed to disease etiology, but where common variations in each of these genes make modest contributions to disease risk. We also found 6141 risk SNPs that were too minor to be detected by conventional approaches, and associations between 58 candidate genes and rheumatoid arthritis were verified by literature retrieved from the NCBI PubMed module. CONCLUSIONS: Our proposed approach to the analysis of GAW16 data for rheumatoid arthritis was based on an underlying biological similarities based method applied to candidate and known disease genes. Application of our method could identify likely causal candidate disease genes of rheumatoid arthritis, and could yield biological insights that not detected when focusing only on genes that give the strongest evidence by multiple testing. We hope that our proposed method complements the "most significant SNPs/genes" model, and provides additional insights into the pathogenesis of rheumatoid arthritis and other diseases, when searching datasets for hundreds of genetic variances. PMID- 20727151 TI - Chronic hepatitis caused by persistent parvovirus B19 infection. AB - BACKGROUND: Human infection with parvovirus B19 may lead to a diverse spectrum of clinical manifestations, including benign erythema infectiosum in children, transient aplastic crisis in patients with haemolytic anaemia, and congenital hydrops foetalis. These different diseases represent direct consequences of the ability of parvovirus B19 to target the erythroid cell lineage. However, accumulating evidence suggests that this virus can also infect other cell types resulting in diverse clinical manifestations, of which the pathogenesis remains to be fully elucidated. This has prompted important questions regarding the tropism of the virus and its possible involvement in a broad range of infectious and autoimmune medical conditions. CASE PRESENTATION: Here, we present an unusual case of persistent parvovirus B19 infection as a cause of chronic hepatitis. This patient had persistent parvovirus B19 viraemia over a period of more than four years and displayed signs of chronic hepatitis evidenced by fluctuating elevated levels of ALAT and a liver biopsy demonstrating chronic hepatitis. Other known causes of hepatitis and liver damage were excluded. In addition, the patient was evaluated for immunodeficiency, since she had lymphopenia both prior to and following clearance of parvovirus B19 infection. CONCLUSIONS: In this case report, we describe the current knowledge on the natural history and pathogenesis of parvovirus B19 infection, and discuss the existing evidence of parvovirus B19 as a cause of acute and chronic hepatitis. We suggest that parvovirus B19 was the direct cause of this patient's chronic hepatitis, and that she had an idiopathic lymphopenia, which may have predisposed her to persistent infection, rather than bone marrow depression secondary to infection. In addition, we propose that her liver involvement may have represented a viral reservoir. Finally, we suggest that clinicians should be aware of parvovirus B19 as an unusual aetiology of chronic hepatitis, when other causes have been ruled out. PMID- 20727152 TI - Secreted fungal sulfhydryl oxidases: sequence analysis and characterisation of a representative flavin-dependent enzyme from Aspergillus oryzae. AB - BACKGROUND: Sulfhydryl oxidases are flavin-dependent enzymes that catalyse the formation of de novo disulfide bonds from free thiol groups, with the reduction of molecular oxygen to hydrogen peroxide. Sulfhydryl oxidases have been investigated in the food industry to remove the burnt flavour of ultraheat treated milk and are currently studied as potential crosslinking enzymes, aiming at strengthening wheat dough and improving the overall bread quality. RESULTS: In the present study, potential sulfhydryl oxidases were identified in the publicly available fungal genome sequences and their sequence characteristics were studied. A representative sulfhydryl oxidase from Aspergillus oryzae, AoSOX1, was expressed in the fungus Trichoderma reesei. AoSOX1 was produced in relatively good yields and was purified and biochemically characterised. The enzyme catalysed the oxidation of thiol-containing compounds like glutathione, D/L cysteine, beta-mercaptoethanol and DTT. The enzyme had a melting temperature of 57 degrees C, a pH optimum of 7.5 and its enzymatic activity was completely inhibited in the presence of 1 mM ZnSO4. CONCLUSIONS: Eighteen potentially secreted sulfhydryl oxidases were detected in the publicly available fungal genomes analysed and a novel proline-tryptophan dipeptide in the characteristic motif CXXC, where X is any amino acid, was found. A representative protein, AoSOX1 from A. oryzae, was produced in T. reesei in an active form and had the characteristics of sulfhydryl oxidases. Further testing of the activity on thiol groups within larger peptides and on protein level will be needed to assess the application potential of this enzyme. PMID- 20727153 TI - Population structure and genetic bottleneck in sweet cherry estimated with SSRs and the gametophytic self-incompatibility locus. AB - BACKGROUND: Domestication and breeding involve the selection of particular phenotypes, limiting the genomic diversity of the population and creating a bottleneck. These effects can be precisely estimated when the location of domestication is established. Few analyses have focused on understanding the genetic consequences of domestication and breeding in fruit trees. In this study, we aimed to analyse genetic structure and changes in the diversity in sweet cherry Prunus avium L. RESULTS: Three subgroups were detected in sweet cherry, with one group of landraces genetically very close to the analysed wild cherry population. A limited number of SSR markers displayed deviations from the frequencies expected under neutrality. After the removal of these markers from the analysis, a very limited bottleneck was detected between wild cherries and sweet cherry landraces, with a much more pronounced bottleneck between sweet cherry landraces and modern sweet cherry varieties. The loss of diversity between wild cherries and sweet cherry landraces at the S-locus was more significant than that for microsatellites. Particularly high levels of differentiation were observed for some S-alleles. CONCLUSIONS: Several domestication events may have happened in sweet cherry or/and intense gene flow from local wild cherry was probably maintained along the evolutionary history of the species. A marked bottleneck due to breeding was detected, with all markers, in the modern sweet cherry gene pool. The microsatellites did not detect the bottleneck due to domestication in the analysed sample. The vegetative propagation specific to some fruit trees may account for the differences in diversity observed at the S-locus. Our study provides insights into domestication events of cherry, however, requires confirmation on a larger sampling scheme for both sweet cherry landraces and wild cherry. PMID- 20727154 TI - Comparison of the performance of the CMS Hierarchical Condition Category (CMS HCC) risk adjuster with the Charlson and Elixhauser comorbidity measures in predicting mortality. AB - BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) has implemented the CMS-Hierarchical Condition Category (CMS-HCC) model to risk adjust Medicare capitation payments. This study intends to assess the performance of the CMS-HCC risk adjustment method and to compare it to the Charlson and Elixhauser comorbidity measures in predicting in-hospital and six-month mortality in Medicare beneficiaries. METHODS: The study used the 2005-2006 Chronic Condition Data Warehouse (CCW) 5% Medicare files. The primary study sample included all community-dwelling fee-for-service Medicare beneficiaries with a hospital admission between January 1st, 2006 and June 30th, 2006. Additionally, four disease-specific samples consisting of subgroups of patients with principal diagnoses of congestive heart failure (CHF), stroke, diabetes mellitus (DM), and acute myocardial infarction (AMI) were also selected. Four analytic files were generated for each sample by extracting inpatient and/or outpatient claims for each patient. Logistic regressions were used to compare the methods. Model performance was assessed using the c-statistic, the Akaike's information criterion (AIC), the Bayesian information criterion (BIC) and their 95% confidence intervals estimated using bootstrapping. RESULTS: The CMS-HCC had statistically significant higher c-statistic and lower AIC and BIC values than the Charlson and Elixhauser methods in predicting in-hospital and six-month mortality across all samples in analytic files that included claims from the index hospitalization. Exclusion of claims for the index hospitalization generally led to drops in model performance across all methods with the highest drops for the CMS-HCC method. However, the CMS-HCC still performed as well or better than the other two methods. CONCLUSIONS: The CMS-HCC method demonstrated better performance relative to the Charlson and Elixhauser methods in predicting in-hospital and six-month mortality. The CMS-HCC model is preferred over the Charlson and Elixhauser methods if information about the patient's diagnoses prior to the index hospitalization is available and used to code the risk adjusters. However, caution should be exercised in studies evaluating inpatient processes of care and where data on pre-index admission diagnoses are unavailable. PMID- 20727155 TI - Dynamic models of immune responses: what is the ideal level of detail? AB - BACKGROUND: One of the goals of computational immunology is to facilitate the study of infectious diseases. Dynamic modeling is a powerful tool to integrate empirical data from independent sources, make novel predictions, and to foresee the gaps in the current knowledge. Dynamic models constructed to study the interactions between pathogens and hosts' immune responses have revealed key regulatory processes in the infection. OPTIMUM COMPLEXITY AND DYNAMIC MODELING: We discuss the usability of various deterministic dynamic modeling approaches to study the progression of infectious diseases. The complexity of these models is dependent on the number of components and the temporal resolution in the model. We comment on the specific use of simple and complex models in the study of the progression of infectious diseases. CONCLUSIONS: Models of sub-systems or simplified immune response can be used to hypothesize phenomena of host-pathogen interactions and to estimate rates and parameters. Nevertheless, to study the pathogenesis of an infection we need to develop models describing the dynamics of the immune components involved in the progression of the disease. Incorporation of the large number and variety of immune processes involved in pathogenesis requires tradeoffs in modeling. PMID- 20727156 TI - Hypoxia stimulates the expression of macrophage migration inhibitory factor in human vascular smooth muscle cells via HIF-1alpha dependent pathway. AB - BACKGROUND: Hypoxia plays an important role in vascular remodeling and directly affects vascular smooth muscle cells (VSMC) functions. Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor, and recent evidence suggests an important role of MIF in the progression of atherosclerosis and restenosis. However, the potential link between hypoxia and MIF in VSMC has not been investigated. The current study was designed to test whether hypoxia could regulate MIF expression in human VSMC. The effect of modulating MIF expression on hypoxia-induced VSMC proliferation and migration was also investigated at the same time. RESULTS: Expression of MIF mRNA and protein was up regulated as early as 2 hours in cultured human VSMCs after exposed to moderate hypoxia condition (3% O2). The up-regulation of MIF expression appears to be dependent on hypoxia-inducible transcription factor-1alpha(HIF-1alpha) since knockdown of HIF-1alpha inhibits the hypoxia induction of MIF gene and protein expression. The hypoxia induced expression of MIF was attenuated by antioxidant treatment as well as by inhibition of extracellular signal-regulated kinase (ERK). Under moderate hypoxia conditions (3% O2), both cell proliferation and cell migration were increased in VSMC cells. Blocking the MIF by specific small interference RNA to MIF (MIF-shRNA) resulted in the suppression of proliferation and migration of VSMCs. CONCLUSION: Our results demonstrated that in VSMCs, hypoxia increased MIF gene expression and protein production. The hypoxia-induced HIF-1alpha activation, reactive oxygen species (ROS) generation and ERK activation might be involved in this response. Both MIF and HIF-1alpha mediated the hypoxia response of vascular smooth muscle cells, including cell migration and proliferation. PMID- 20727157 TI - Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma. AB - BACKGROUND: The increasing incidence of hepatocellular carcinoma in Western countries has led to an expanding interest of scientific research in this field. Therefore, a vast need of experimental models that mimic the natural pathogenesis of hepatocellular carcinoma (HCC) in a short time period is present. The goal of our study was (1) to develop an efficient mouse model for HCC research, in which tumours develop in a natural background of fibrosis and (2) to assess the time dependent angiogenic changes in the pathogenesis of HCC. METHODS: Weekly intraperitoneal injections with the hepatocarcinogenic compound N nitrosodiethylamine was applied as induction method and samples were taken at several time points to assess the angiogenic changes during the progression of HCC. RESULTS: The N-nitrosodiethylamine-induced mouse model provides well vascularised orthotopic tumours after 25 weeks. It is a representative model for human HCC and can serve as an excellent platform for the development of new therapeutic targets. PMID- 20727159 TI - Gene Expression Browser: large-scale and cross-experiment microarray data integration, management, search & visualization. AB - BACKGROUND: In the last decade, a large amount of microarray gene expression data has been accumulated in public repositories. Integrating and analyzing high throughput gene expression data have become key activities for exploring gene functions, gene networks and biological pathways. Effectively utilizing these invaluable microarray data remains challenging due to a lack of powerful tools to integrate large-scale gene-expression information across diverse experiments and to search and visualize a large number of gene-expression data points. RESULTS: Gene Expression Browser is a microarray data integration, management and processing system with web-based search and visualization functions. An innovative method has been developed to define a treatment over a control for every microarray experiment to standardize and make microarray data from different experiments homogeneous. In the browser, data are pre-processed offline and the resulting data points are visualized online with a 2-layer dynamic web display. Users can view all treatments over control that affect the expression of a selected gene via Gene View, and view all genes that change in a selected treatment over control via treatment over control View. Users can also check the changes of expression profiles of a set of either the treatments over control or genes via Slide View. In addition, the relationships between genes and treatments over control are computed according to gene expression ratio and are shown as co responsive genes and co-regulation treatments over control. CONCLUSION: Gene Expression Browser is composed of a set of software tools, including a data extraction tool, a microarray data-management system, a data-annotation tool, a microarray data-processing pipeline, and a data search & visualization tool. The browser is deployed as a free public web service (http://www.ExpressionBrowser.com) that integrates 301 ATH1 gene microarray experiments from public data repositories (viz. the Gene Expression Omnibus repository at the National Center for Biotechnology Information and Nottingham Arabidopsis Stock Center). The set of Gene Expression Browser software tools can be easily applied to the large-scale expression data generated by other platforms and in other species. PMID- 20727158 TI - Curating the innate immunity interactome. AB - BACKGROUND: The innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http://www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity. RESULTS: Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response. CONCLUSIONS: In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity. PMID- 20727160 TI - Antioxidant airway responses following experimental exposure to wood smoke in man. AB - BACKGROUND: Biomass combustion contributes to the production of ambient particulate matter (PM) in rural environments as well as urban settings, but relatively little is known about the health effects of these emissions. The aim of this study was therefore to characterize airway responses in humans exposed to wood smoke PM under controlled conditions. Nineteen healthy volunteers were exposed to both wood smoke, at a particulate matter (PM2.5) concentration of 224 +/- 22 MUg/m3, and filtered air for three hours with intermittent exercise. The wood smoke was generated employing an experimental set-up with an adjustable wood pellet boiler system under incomplete combustion. Symptoms, lung function, and exhaled NO were measured over exposures, with bronchoscopy performed 24 h post exposure for characterisation of airway inflammatory and antioxidant responses in airway lavages. RESULTS: Glutathione (GSH) concentrations were enhanced in bronchoalveolar lavage (BAL) after wood smoke exposure vs. air (p = 0.025), together with an increase in upper airway symptoms. Neither lung function, exhaled NO nor systemic nor airway inflammatory parameters in BAL and bronchial mucosal biopsies were significantly affected. CONCLUSIONS: Exposure of healthy subjects to wood smoke, derived from an experimental wood pellet boiler operating under incomplete combustion conditions with PM emissions dominated by organic matter, caused an increase in mucosal symptoms and GSH in the alveolar respiratory tract lining fluids but no acute airway inflammatory responses. We contend that this response reflects a mobilisation of GSH to the air-lung interface, consistent with a protective adaptation to the investigated wood smoke exposure. PMID- 20727161 TI - A comprehensive platform for quality control of botanical drugs (PhytomicsQC): a case study of Huangqin Tang (HQT) and PHY906. AB - BACKGROUND: Establishing botanical extracts as globally-accepted polychemical medicines and a new paradigm for disease treatment, requires the development of high-level quality control metrics. Based on comprehensive chemical and biological fingerprints correlated with pharmacology, we propose a general approach called PhytomicsQC to botanical quality control. METHODS: Incorporating the state-of-the-art analytical methodologies, PhytomicsQC was employed in this study and included the use of liquid chromatography/mass spectrometry (LC/MS) for chemical characterization and chemical fingerprinting, differential cellular gene expression for bioresponse fingerprinting and animal pharmacology for in vivo validation. A statistical pattern comparison method, Phytomics Similarity Index (PSI), based on intensities and intensity ratios, was used to determine the similarity of the chemical and bioresponse fingerprints among different manufactured batches. RESULTS: Eighteen batch samples of Huangqin Tang (HQT) and its pharmaceutical grade version (PHY906) were analyzed using the PhytomicsQC platform analysis. Comparative analysis of the batch samples with a clinically tested standardized batch obtained values of PSI similarity between 0.67 and 0.99. CONCLUSION: With rigorous quality control using analytically sensitive and comprehensive chemical and biological fingerprinting, botanical formulations manufactured under standardized manufacturing protocols can produce highly consistent batches of products. PMID- 20727162 TI - Characterisation of the Vitis vinifera PR10 multigene family. AB - BACKGROUND: Genes belonging to the pathogenesis related 10 (PR10) group have been studied in several plant species, where they form multigene families. Until now, such an analysis has not been performed in Vitis vinifera, although three different PR10 genes were found to be expressed under pathogen attack or abiotic stress, and during somatic embryogenesis induction. We used the complete genome sequence for characterising the whole V. vinifera PR10 gene family. The expression of candidate genes was studied in various non-treated tissues and following somatic embryogenesis induction by the auxin 2,4-D. RESULTS: In addition to the three V. vinifera PR10 genes already described, namely VvPR10.1, VvPR10.2 and VvPR10.3, fourteen different PR10 related sequences were identified. Showing high similarity, they form a single cluster on the chromosome 5 comprising three pseudogenes. The expression of nine different genes was detected in various tissues. Although differentially expressed in non-treated plant organs, several genes were up-regulated in tissues treated with 2,4-D, as expected for PR genes. CONCLUSIONS: PR10 genes form a multigene family in V. vinifera, as found in birch, apple or peach. Seventeen closely related PR10 sequences are arranged in a tandem array on the chromosome 5, probably reflecting small-scale duplications during evolution. Various expression patterns were found for nine studied genes, highlighting functional diversification. A phylogenetic comparison of deduced proteins with PR10 proteins of other plants showed a characteristic low intraspecific variability. Particularly, a group of seven close tandem duplicates including VvPR10.1, VvPR10.2 and VvPR10.3 showed a very high similarity, suggesting concerted evolution or/and recent duplications. PMID- 20727163 TI - Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases. AB - BACKGROUND: Complement C2 deficiency is the most common genetically determined complete complement deficiency and is associated with a number of diseases. Most prominent are the associations with recurrent serious infections in young children and the development of systemic lupus erythematosus (SLE) in adults. The links with these diseases reflect the important role complement C2 plays in both innate immunity and immune tolerance. Infusions with normal fresh frozen plasma for the treatment of associated disease have demonstrated therapeutic effects but so far protein replacement therapy has not been evaluated. RESULTS: Human complement C2 was cloned and expressed in a mammalian cell line. The purity of recombinant human C2 (rhC2) was greater than 95% and it was characterized for stability and activity. It was sensitive to C1s cleavage and restored classical complement pathway activity in C2-deficient serum both in a complement activation ELISA and a hemolytic assay. Furthermore, rhC2 could increase C3 fragment deposition on the human pathogen Streptococcus pneumoniae in C2-deficient serum to levels equal to those with normal serum. CONCLUSIONS: Taken together these data suggest that recombinant human C2 can restore classical complement pathway activity and may serve as a potential therapeutic for recurring bacterial infections or SLE in C2-deficient patients. PMID- 20727164 TI - Menthol response and adaptation in nociceptive-like and nonnociceptive-like neurons: role of protein kinases. AB - Menthol-sensitive/capsaicin-insensitive neurons (MS/CI) and menthol sensitive/capsaicin-sensitive neurons (MS/CS) are thought to represent two functionally distinct populations of cold-sensing neurons that use TRPM8 receptors to convey innocuous and noxious cold information respectively. However, TRPM8-mediated responses have not been well characterized in these two neuron populations. Using rat dorsal root ganglion neurons, here we show that MS/CI neurons had larger menthol responses with greater adaptation. In contrast, MS/CS neurons had smaller menthol responses with less adaptation. All menthol-sensitive neurons showed significant reduction of menthol responses following the treatment of cells with the protein kinase C (PKC) activator PDBu (Phorbol 12,13 dibutyrate). PDBu-induced reduction of menthol responses was completely abolished in the presence of PKC inhibitors BIM (bisindolylmaleimide) or staurosporine. When menthol responses were examined in the presence of protein kinase inhibitors, it was found that the adaptation was significantly attenuated by either BIM or staurosporine and also by the Ca2+/calmodulin-dependent protein kinase (CamKII) inhibitor KN62 (N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L tyrosyl]-4-phenylpiperazine) in MS/CI neurons. In contrast, in MS/CS neurons menthol response was not affected significantly by BIM, staurosporine or KN62. In both MS/CI and MS/CS neurons, the menthol responses were not affected by PKA activators forskolin and 8-Br-cAMP (8-Bromoadenosine-3', 5'-cyclic monophosphate) or by protein kinase A (PKA) inhibitor Rp-cAMPs (Rp-Adenosine-3',5'-cyclic monophosphorothioate). Taken together, these results suggest that TRPM8-mediated responses are significantly different between non-nociceptive-like and nociceptive-like neurons. PMID- 20727165 TI - Modulation of the major histocompatibility complex by neural stem cell-derived neurotrophic factors used for regenerative therapy in a rat model of stroke. AB - BACKGROUND: The relationship between functional improvements in ischemic rats given a neural stem cell (NSC) transplant and the modulation of the class I major histocompatibility complex (MHC) mediated by NSC-derived neurotrophins was investigated. METHODS: The levels of gene expression of nerve growth factor (NGF), brain-derived neurotropic factor (BDNF) and neurotrophin-3 (NT-3) were assayed from cultures of cortical NSC from Sprague-Dawley rat E16 embryos. The levels of translated NGF in spent culture media from NSC cultures and the cerebral spinal fluid (CSF) of rats with and without NGF injection or NSC transplant were also measured. RESULTS: We found a significant increase of NGF, BDNF and NT-3 transcripts and NGF proteins in both the NSC cultures and the CSF of the rats. The immunochemical staining for MHC in brain sections and the enzyme linked immunosorbent assay of CSF were carried out in sham-operated rats and rats with surgically induced focal cerebral ischemia. These groups were further divided into animals that did and did not receive NGF administration or NSC transplant into the cisterna magna. Our results show an up-regulation of class I MHC in the ischemic rats with NGF and NSC administration. The extent of caspase III immunoreactivity was comparable among three arms in the ischemic rats. CONCLUSION: Readouts of somatosensory evoked potential and the trap channel test illustrated improvements in the neurological function of ischemic rats treated with NGF administration and NSC transplant. PMID- 20727166 TI - Comparison of four phaC genes from Haloferax mediterranei and their function in different PHBV copolymer biosyntheses in Haloarcula hispanica. AB - BACKGROUND: The halophilic archaeon Haloferax mediterranei is able to accumulate large amounts of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) with high molar fraction of 3-hydroxyvalerate (3HV) from unrelated carbon sources. A Polyhydroxyalkanoate (PHA) synthase composed of two subunits, PhaCHme and PhaEHme, has been identified in this strain, and shown to account for the PHBV biosynthesis. RESULTS: With the aid of the genome sequence of Hfx. mediterranei CGMCC 1.2087, three additional phaC genes (designated phaC1, phaC2, and phaC3) were identified, which encoded putative PhaCs. Like PhaCHme (54.8 kDa), PhaC1 (49.7 kDa) and PhaC3 (62.5 kDa) possessed the conserved motifs of type III PHA synthase, which was not observed in PhaC2 (40.4 kDa). Furthermore, the longer C terminus found in the other three PhaCs was also absent in PhaC2. Reverse transcription PCR (RT-PCR) revealed that, among the four genes, only phaCHme was transcribed under PHA-accumulating conditions in the wild-type strain. However, heterologous coexpression of phaEHme with each phaC gene in Haloarcula hispanica PHB-1 showed that all PhaCs, except PhaC2, could lead to PHBV accumulation with various 3HV fractions. The three kinds of copolymers were characterized using gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Their thermal properties changed with the variations in monomer composition as well as the different molecular weights (Mw), thus might meet various application requirements. CONCLUSION: We discover three cryptic phaC genes in Hfx. mediterranei, and demonstrate that genetic engineering of these newly identified phaC genes has biotechnological potential for PHBV production with tailor-made material properties. PMID- 20727167 TI - A 176 amino acid polypeptide derived from the mumps virus HN ectodomain shows immunological and biological properties similar to the HN protein. AB - BACKGROUND: The hemagglutinin-neuraminidase (HN) protein is the major antigenic determinant of the Mumps virus (MuV) and plays an important role in the viral infectious cycle through its hemagglutination/hemadsorption (HA/HD) and neuraminidase (NA) activities. OBJECTIVE: analyze the biological and immunological properties of a polypeptide derived from a highly conserved region of the HN ectodomain. METHODS: a highly conserved region of the HN gene among several MuV genotypes was chosen to be cloned in a eukaryotic expression vector. The pcDNAHN176-construct was transfected into Vero cells and RNA expression was detected by RT-PCR, while the corresponding polypeptide was detected by immunofluorescence and immunochemistry techniques. The HD and NA activities were also measured. The immunogenic properties of the construct were evaluated using two systems: rabbit immunization to obtain sera for detection of the HN protein and neutralization of MuV infection, and hamster immunization to evaluate protection against MuV infection. RESULTS: A 567 nucleotide region from the HN gene was amplified and cloned into the plasmid pcDNA3.1. Vero cells transfected with the construct expressed a polypeptide that was recognized by a MuV hyperimmune serum. The construct-transfected cells showed HD and NA activities. Sera from immunized rabbits in vitro neutralized two different MuV genotypes and also detected both the HN protein and the HN176 polypeptide by western blot. Hamsters immunized with the pcDNAHN176-construct and challenged with MuV showed a mild viral infection in comparison to non-immunized animals, and Th1 and Th2 cytokines were detected in them. CONCLUSIONS: The pcDNAHN176-construct was capable of expressing a polypeptide in Vero cells that was identified by a hyperimmune serum anti Mumps virus, and these cells showed the HD and NA activities of the complete MuV HN protein. The construct also elicited a specific immune response against MuV infection in hamsters. PMID- 20727168 TI - F-18 fluorodeoxyglucose positron emission tomography and/or computed tomography findings of an unusual breast lymphoma case and concurrent cervical cancer: a case report. AB - INTRODUCTION: Breast lymphoma accounts for less than 1% of all non-Hodgkin's lymphomas and approximately 0.1% of all breast neoplasms. Most breast lymphomas are classified as diffuse large B-cell lymphomas or as mucosa associated lymphoid tissue lymphomas. Concurrent cases of breast lymphoma and cervical cancer are extremely rare. CASE PRESENTATION: We report a case of a 46-year-old woman of unknown ethnic origin diagnosed with concurrent diffuse large B-cell lymphoma of the breast and squamous cell cancer of the cervix that was detected and followed with F-18 fluorodeoxyglucose (FDG) positron emission tomography and/or computed tomography (PET/CT). The metastatic pattern of this case of breast lymphoma is similar to that of a typical metastatic breast carcinoma. These findings have never been described in the literature. PET/CT also demonstrated an incidentally intense FDG focus in the uterine cervix ultimately leading to the pathologic diagnosis of squamous cell carcinoma of the uterine cervix. An appropriate staging of breast lymphoma and cervical cancer with FDG PET/CT is important because of therapeutic consequence. This case report and review of the literature highlights the role of FDG PET/CT in staging and restaging of both breast lymphoma and cervical cancer. CONCLUSIONS: We report a case of a breast lymphoma with a metastatic pattern similar to that of typical metastatic breast carcinoma. The FDG PET/CT scan also diagnosed a rare case of concurrent breast lymphoma and cervical cancer. This concurrence has not been reported previously in the medical literature. PMID- 20727169 TI - Genotoxic effects in occupational exposure to formaldehyde: A study in anatomy and pathology laboratories and formaldehyde-resins production. AB - BACKGROUND: According to the Report on Carcinogens, formaldehyde ranks 25th in the overall U.S. chemical production, with more than 5 million tons produced each year. Given its economic importance and widespread use, many people are exposed to formaldehyde environmentally and/or occupationally. Presently, the International Agency for Research on Cancer classifies formaldehyde as carcinogenic to humans (Group 1), based on sufficient evidence in humans and in experimental animals. Manyfold in vitro studies clearly indicated that formaldehyde can induce genotoxic effects in proliferating cultured mammalian cells. Furthermore, some in vivo studies have found changes in epithelial cells and in peripheral blood lymphocytes related to formaldehyde exposure. METHODS: A study was carried out in Portugal, using 80 workers occupationally exposed to formaldehyde vapours: 30 workers from formaldehyde and formaldehyde-based resins production factory and 50 from 10 pathology and anatomy laboratories. A control group of 85 non-exposed subjects was considered. Exposure assessment was performed by applying simultaneously two techniques of air monitoring: NIOSH Method 2541 and Photo Ionization Detection equipment with simultaneously video recording. Evaluation of genotoxic effects was performed by application of micronucleus test in exfoliated epithelial cells from buccal mucosa and peripheral blood lymphocytes. RESULTS: Time-weighted average concentrations not exceeded the reference value (0.75 ppm) in the two occupational settings studied. Ceiling concentrations, on the other hand, were higher than reference value (0.3 ppm) in both. The frequency of micronucleus in peripheral blood lymphocytes and in epithelial cells was significantly higher in both exposed groups than in the control group (p<0.001). Moreover, the frequency of micronucleus in peripheral blood lymphocytes was significantly higher in the laboratories group than in the factory workers (p < 0.05). A moderate positive correlation was found between duration of occupational exposure to formaldehyde (years of exposure) and micronucleus frequency in peripheral blood lymphocytes (r=0.401; p<0.001) and in epithelial cells (r=0.209; p < 0.01). CONCLUSIONS: The population studied is exposed to high peak concentrations of formaldehyde with a long-term exposure. These two aspects, cumulatively, can be the cause of the observed genotoxic endpoint effects. The association of these cytogenetic effects with formaldehyde exposure gives important information to risk assessment process and may also be used to assess health risks for exposed workers. PMID- 20727170 TI - Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer. AB - BACKGROUND: We recently demonstrated that increased expression of the RNA-binding protein RBM3 is associated with a favourable prognosis in breast cancer. The aim of this study was to examine the prognostic value of RBM3 mRNA and protein expression in epithelial ovarian cancer (EOC) and the cisplatin response upon RBM3 depletion in a cisplatin-sensitive ovarian cancer cell line. METHODS: RBM3 mRNA expression was analysed in tumors from a cohort of 267 EOC cases (Cohort I) and RBM3 protein expression was analysed using immunohistochemistry (IHC) in an independent cohort of 154 prospectively collected EOC cases (Cohort II). Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between RBM3 and recurrence free survival (RFS) and overall survival (OS). Immunoblotting and IHC were used to examine the expression of RBM3 in a cisplatin-resistant ovarian cancer cell line A2780-Cp70 and its cisplatin responsive parental cell line A2780. The impact of RBM3 on cisplatin response in EOC was assessed using siRNA-mediated silencing of RBM3 in A2780 cells followed by cell viability assay and cell cycle analysis. RESULTS: Increased RBM3 mRNA expression was associated with a prolonged RFS (HR = 0.64, 95% CI = 0.47-0.86, p = 0.003) and OS (HR = 0.64, 95% CI = 0.44-0.95, p = 0.024) in Cohort I. Multivariate analysis confirmed that RBM3 mRNA expression was an independent predictor of a prolonged RFS, (HR = 0.61, 95% CI = 0.44-0.84, p = 0.003) and OS (HR = 0.62, 95% CI = 0.41-0.95; p = 0.028) in Cohort I. In Cohort II, RBM3 protein expression was associated with a prolonged OS (HR = 0.53, 95% CI = 0.35 0.79, p = 0.002) confirmed by multivariate analysis (HR = 0.61, 95% CI = 0.40 0.92, p = 0.017). RBM3 mRNA and protein expression levels were significantly higher in the cisplatin sensitive A2780 cell line compared to the cisplatin resistant A2780-Cp70 derivative. siRNA-mediated silencing of RBM3 expression in the A2780 cells resulted in a decreased sensitivity to cisplatin as demonstrated by increased cell viability and reduced proportion of cells arrested in the G2/M phase. CONCLUSIONS: These data demonstrate that RBM3 expression is associated with cisplatin sensitivity in vitro and with a good prognosis in EOC. Taken together these findings suggest that RBM3 may be a useful prognostic and treatment predictive marker in EOC. PMID- 20727171 TI - Novel strategies in tendon and ligament tissue engineering: Advanced biomaterials and regeneration motifs. AB - Tendon and ligaments have poor healing capacity and when injured often require surgical intervention. Tissue replacement via autografts and allografts are non ideal strategies that can lead to future problems. As an alternative, scaffold based tissue engineering strategies are being pursued. In this review, we describe design considerations and major recent advancements of scaffolds for tendon/ligament engineering. Specifically, we outline native tendon/ligament characteristics critical for design parameters and outcome measures, and introduce synthetic and naturally-derived biomaterials used in tendon/ligament scaffolds. We will describe applications of these biomaterials in advanced tendon/ligament engineering strategies including the utility of scaffold functionalization, cyclic strain, growth factors, and interface considerations. The goal of this review is to compile and interpret the important findings of recent tendon/ligament engineering research in an effort towards the advancement of regenerative strategies. PMID- 20727172 TI - Characterization of vascular strain during in-vitro angioplasty with high resolution ultrasound speckle tracking. AB - BACKGROUND: Ultrasound elasticity imaging provides biomechanical and elastic properties of vascular tissue, with the potential to distinguish between tissue motion and tissue strain. To validate the ability of ultrasound elasticity imaging to predict structurally defined physical changes in tissue, strain measurement patterns during angioplasty in four bovine carotid artery pathology samples were compared to the measured physical characteristics of the tissue specimens. METHODS: Using computational image-processing techniques, the circumferences of each bovine artery specimen were obtained from ultrasound and pathologic data. RESULTS: Ultrasound-strain-based and pathology-based arterial circumference measurements were correlated with an R2 value of 0.94 (p = 0.03). The experimental elasticity imaging results confirmed the onset of deformation of an angioplasty procedure by indicating a consistent inflection point where vessel fibers were fully unfolded and vessel wall strain initiated. CONCLUSION: These results validate the ability of ultrasound elasticity imaging to measure localized mechanical changes in vascular tissue. PMID- 20727173 TI - Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. AB - BACKGROUND: Pax2;5;8 transcription factors play diverse roles in vertebrate and invertebrate organogenesis, including the development of the inner ear. Past research has suggested various cochlear defects and some vestibular defects in Pax2 null mice but the details of the cochlear defects and the interaction with other Pax family members in ear development remain unclear. RESULTS: We show that Pax2;8 double null mice do not develop an ear past the otocyst stage and show little to no sensory as well as limited and transient neuronal development, thus indicating that these two family members are essential for overall ear morphogenesis and sustained neurosensory development. In support of functional redundancy between Pax proteins, Pax2 can be substituted by a Pax5 minigene, a gene normally not expressed in the embryonic mouse ear. There is no detectable morphological defect in Pax8 null mice suggesting that Pax2 expression can compensate for Pax8. Conversely, Pax8 cannot compensate for Pax2 leading to a cochlear phenotype not fully appreciated previously: Cochlear development is delayed until E15.5 when the cochlea extrudes as a large sack into the brain case. Immunocytochemistry and tracing from the brain show that a cochlear spiral ganglia form as a small addition to the inferior vestibular ganglion. However, the empty cochlear sack, devoid of any sensory epithelium development as indicated by the absence of Sox2 or MyoVII expression, nevertheless develop a dense innervation network of small neurons situated in the wall of the cochlear sack. CONCLUSIONS: Combined these data suggest that Pax2 is needed for organ of Corti formation and is directly or indirectly involved in the coordination of spiral ganglion formation which is partially disrupted in the Pax2 null ears. All three Pax genes can signal redundantly in the ear with their function being determined primarily by the spatio-temporal expression driven by the three distinct promoters of these genes. PMID- 20727174 TI - Targeted identification of genomic regions using TAGdb. AB - BACKGROUND: The introduction of second generation sequencing technology has enabled the cost effective sequencing of genomes and the identification of large numbers of genes and gene promoters. However, the assembly of DNA sequences to create a representation of the complete genome sequence remains costly, especially for the larger and more complex plant genomes. RESULTS: We have developed an online database, TAGdb, that enables researchers to identify paired read sequences that share identity with a submitted query sequence. These tags can be used to design oligonucleotide primers for the PCR amplification of the region in the target genome. CONCLUSIONS: The ability to produce large numbers of paired read genome tags using second generation sequencing provides a cost effective method for the identification of genes and promoters in large, complex or orphan species without the need for whole genome assembly. PMID- 20727175 TI - Retinoic acid accelerates downregulation of the Xist repressor, Oct4, and increases the likelihood of Xist activation when Tsix is deficient. AB - BACKGROUND: Imbalances in X-linked gene dosage between the sexes are resolved by transcriptionally silencing one of two X-chromosomes in female cells of the early mammalian embryo. X-inactivation is triggered by expression of the non-coding Xist gene. In turn, Xist is dually regulated by the antisense Tsix RNA and by the Oct4 pluripotency factor. Although there is general agreement that Tsix is an inhibitor of Xist, some laboratories have observed ectopic Xist induction in differentiating male ES cells when Tsix is mutated, whereas we have not observed significant changes in Xist. These observational differences have led to fundamentally diverse models of X-chromosome counting. Here, we investigate if different methods of cell differentiation and use of all -trans retinoic acid (RA) could be causative factors and how they might impact Xist expression. RESULTS: We compared suspension and cell-adhesion cultures in the presence or absence of RA and find that RA significantly impacts Xist expression in Tsix mutant male cells. Whereas the standard embryoid body method infrequently leads to ectopic Xist expression, adding RA generates a significant number of Xist positive male cells. However, while normal Xist clouds in wild-type female cells are robust and well-circumscribed, those found in the RA-treated mutant males are loosely dispersed. Furthermore, ectopic Xist expression does not generally lead to complete gene silencing. We attribute the effect of RA on Xist to RA's repressive influence on Oct4, a pluripotency factor recently shown to regulate Tsix and Xist. RA-treated ES cells exhibit accelerated decreases in Oct4 RNA levels and also display accelerated loss of binding to Xist intron 1. When Tsix is deficient, the faster kinetics of Oct4 loss tip the equilibrium towards Xist expression. However, the aberrant Xist clusters are unlikely to explain elevated cell death, as X-linked silencing does not necessarily correlate with the qualitatively aberrant Xist clusters. CONCLUSIONS: We conclude that RA treatment leads to premature downregulation of Oct4 and partial derepression of Xist irrespective of X-chromosome counting. RA-induced Xist clusters in male cells do not result in global or stable silencing, and excess cell death is not observed. These data and RA's known pleiotropic effects on ES transcription networks suggest that RA differentation bypasses normal X-inactivation controls and should be used judiciously. We propose that the likelihood of Xist expression is determined by a balance of multiple Xist activators and repressors, and that levels of Oct4 and Tsix are crucial toward achieving this balance. PMID- 20727176 TI - Patient reported outcomes: looking beyond the label claim. AB - The use of patient reported outcome scales in clinical trials conducted by the pharmaceutical industry has become more widespread in recent years. The use of such outcomes is particularly common for products developed to treat chronic, disabling conditions where the intention is not to cure but to ameliorate symptoms, facilitate functioning or, ultimately, to improve quality of life. In such cases, patient reported evidence is increasingly viewed as an essential complement to traditional clinical evidence for establishing a product's competitive advantage in the marketplace. In a commercial setting, the value of patient reported outcomes is viewed largely in terms of their potential for securing a labelling claim in the USA or inclusion in the summary of product characteristics in Europe. Although, the publication of the recent US Food and Drug Administration guidance makes it difficult for companies to make claims in the USA beyond symptom improvements, the value of these outcomes goes beyond satisfying requirements for a label claim. The European regulatory authorities, payers both in the US and Europe, clinicians and patients all play a part in determining both the availability and the pricing of medicinal products and all have an interest in patient-reported data that go beyond just symptoms. The purpose of the current paper is to highlight the potential added value of patient reported outcome data currently collected and held by the industry for these groups. PMID- 20727177 TI - IMPaCT Back study protocol. Implementation of subgrouping for targeted treatment systems for low back pain patients in primary care: a prospective population based sequential comparison. AB - BACKGROUND: Prognostic assessment tools to identify subgroups of patients at risk of persistent low back pain who may benefit from targeted treatments have been developed and validated in primary care. The IMPaCT Back study is investigating the effects of introducing and supporting a subgrouping for targeted treatment system in primary care. METHODS/DESIGN: A prospective, population-based, quality improvement study in one Primary Care Trust in England with a before and after design. Phases 1 and 3 collect data on current practice, attitudes and behaviour of health care practitioners, patients' outcomes and health care costs. Phase 2 introduces and supports the subgrouping for targeted treatment system, via a multi-component, quality improvement intervention that includes educational courses and outreach visits led by opinion leaders, audit/feedback, mentoring and organisational support to embed the subgrouping tools within IT and clinical management systems.We aim to recruit 1000 low back pain patients aged 18 years and over consulting 7 GP practices within one Primary Care Trust in England, UK. The study includes GPs in participating practices and physiotherapists in associated services. The primary objective is to determine the effect of the subgrouping for targeted treatment system on back pain related disability and catastrophising at 2 and 6 months, comparing data from phase 1 with phase 3. Key secondary objectives are to determine the impact on: a) GPs' and physiotherapists' attitudes and behaviour regarding low back pain; b) The process of care that patients receive; c) The cost-effectiveness and sustainability of the new clinical system. DISCUSSION: This paper details the rationale, design, methods, planned analysis and operational aspects of the IMPaCT Back study. We aim to determine whether the new subgrouping for targeted treatment system is implemented and sustained in primary care, and evaluate its impact on clinical decision-making, patient outcomes and costs. STUDY REGISTRATION: International Standard Randomised Controlled Trial Number Register ISRCTN55174281. PMID- 20727178 TI - Potential for airborne transmission of infection in the waiting areas of healthcare premises: stochastic analysis using a Monte Carlo model. AB - BACKGROUND: Although many infections that are transmissible from person to person are acquired through direct contact between individuals, a minority, notably pulmonary tuberculosis (TB), measles and influenza are known to be spread by the airborne route. Airborne infections pose a particular threat to susceptible individuals whenever they are placed together with the index case in confined spaces. With this in mind, waiting areas of healthcare facilities present a particular challenge, since large numbers of people, some of whom may have underlying conditions which predispose them to infection, congregate in such spaces and can be exposed to an individual who may be shedding potentially pathogenic microorganisms. It is therefore important to understand the risks posed by infectious individuals in waiting areas, so that interventions can be developed to minimise the spread of airborne infections. METHOD: A stochastic Monte Carlo model was constructed to analyse the transmission of airborne infection in a hypothetical 132 m3 hospital waiting area in which occupancy levels, waiting times and ventilation rate can all be varied. In the model the Gammaitoni-Nucci equation was utilized to predict probability of susceptible individuals becoming infected. The model was used to assess the risk of transmission of three infectious diseases, TB, influenza and measles. In order to allow for stochasticity a random number generator was applied to the variables in the model and a total of 10000 individual simulations were undertaken. The mean quanta production rates used in the study were 12.7, 100 and 570 per hour for TB, influenza and measles, respectively. RESULTS: The results of the study revealed the mean probability of acquiring a TB infection during a 30-minute stay in the waiting area to be negligible (i.e. 0.0034), while that for influenza was an order of magnitude higher at 0.0262. By comparison the mean probability of acquiring a measles infection during the same period was 0.1349. If the duration of the stay was increased to 60 minutes then these values increased to 0.0087, 0.0662 and 0.3094, respectively. CONCLUSION: Under normal circumstances the risk of acquiring a TB infection during a visit to a hospital waiting area is minimal. Likewise the risks associated with the transmission of influenza, although an order of magnitude greater than those for TB, are relatively small. By comparison, the risks associated with measles are high. While the installation of air disinfection may be beneficial, when seeking to prevent the transmission of airborne viral infection it is important to first minimize waiting times and the number of susceptible individuals present before turning to expensive technological solutions. PMID- 20727179 TI - Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of fracture. Decreased bone mass and disruption of microarchitecture occur early in the course of CKD and worsens with the progressive decline in renal function so that at the time of initiation of dialysis at least 50% of patients have had a fracture. Despite the excess fracture risk, and the associated increases in morbidity and mortality, little is known about the factors that are associated with an increase in fracture risk. Our study aims to identify prognostic factors for bone loss and fractures in patients with stages 3 to 5 CKD. METHODS: This prospective study aims to enroll two hundred and sixty men and women with stages 3 to 5 CKD. Subjects will be followed for 24 months and we will examine the ability of: 1) bone mineral density by dual x-ray absorptiometry at the spine, hip, and radius; 2) volumetric bone density by high resolution peripheral quantitated computed tomography at the radius and tibia; 3) serum markers of bone turnover; 4) bone formation rate by bone biopsy; and 5) muscle strength and balance to predict spine and non-spine fractures, identified by self-report and/or vertebral morphometry. All measurements will be obtained at baseline, at 12 and at 24 months with the exception of bone biopsy, which will be measured once at 12 months. Subjects will be contacted every 4 months to determine if there have been incident fractures or falls. DISCUSSION: This study is one of the first that aims to identify risk factors for fracture in early stage CKD patients. Ultimately, by identifying risk factors for fracture and targeting treatments in this group-before the initiation of renal replacement therapy--we will reduce the burden of disease due to fractures among patients with CKD. PMID- 20727180 TI - Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent. AB - BACKGROUND: Lung cancer is the most lethal cancer and almost 90% of lung cancer is due to cigarette smoking. Even though nicotine, one of the major ingredients of cigarette smoke and the causative agent for addiction, is not a carcinogen by itself, several investigators have shown that nicotine can induce cell proliferation and angiogenesis. We observed that the proliferative index of nicotine is different in the lung cancer cell lines H1299 (p53-/-) and A549 (p53+/+) which indicates that the mode of up-regulation of survival signals by nicotine might be different in cells with and without p53. RESULTS: While low concentrations of nicotine induced activation of NF-kappaB, Akt, Bcl2, MAPKs, AP1 and IAPs in H1299, it failed to induce NF-kappaB in A549, and compared to H1299, almost 100 times higher concentration of nicotine was required to induce all other survival signals in A549. Transfection of WT-p53 and DN-p53 in H1299 and A549 respectively, reversed the mode of activation of survival signals. Curcumin down-regulated all the survival signals induced by nicotine in both the cells, irrespective of their p53 status. The hypothesis was confirmed when lower concentrations of nicotine induced NF-kappaB in two more lung cancer cells, Hop 92 and NCI-H522 with mutant p53 status. Silencing of p53 in A549 using siRNA made the cells susceptible to nicotine-induced NF-kappaB nuclear translocation as in A549 DN-p53 cells. CONCLUSIONS: The present study reveals a detrimental role of nicotine especially in lung cancer patients with impaired p53 status and identifies curcumin as a potential chemopreventive. PMID- 20727181 TI - Early results on the use of biomaterials as adjuvant to abdominal wall closure following cytoreduction and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Hyperthermic chemotherapy applies thermal energy to both abdominal wall as well as the intra-abdominal viscera. The combination of the hyperthemia, chemotherapy and cytoreductive surgery (CRS) is associated with a defined risk of abdominal wall and intestinal morbidity reported to be as high as 15%, respectively to date, no studies have evaluated the use of biomaterial mesh as adjuvant to abdominal wall closure in this group of patients. In the present report, we hypothesized that post HIPEC closure with a biomaterial can reduce abdominal wall morbidity after CRS and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: All patients treated with HIPEC in a tertiary care center over 12 months (2008-2009) period were included. Eight patients received cytoreductive surgery followed by HIPEC for 90 minutes using Mitomycin C (15 mg q 45 minutes x 2). Abdominal wall closure was performed using Surgisis (Cook Biotech.) mesh in an underlay position with 3 cm fascial overlap-closure. Operative time, hospital length of stay (LOS) as well as postoperative outcome with special attention to abdominal wall and bowel morbidity were assessed. RESULTS: Eight patients, mean age 59.7 ys (36-80) were treated according to the above protocol. The primary pathology was appendiceal mucinous adenocarcinoma (n = 3) colorectal cancer (n = 3), and ovarian cancer (n = 2). Four patients (50%) presented initially with abdominal wall morbidity including incisional ventral hernia (n = 3) and excessive abdominal wall metastatic implants (n = 1). The mean peritoneal cancer index (PCI) was 8.75. Twenty eight CRS were performed (3.5 CRS/patient). The mean operating time was 6 hours. Seven patients had no abdominal wall or bowel morbidity, the mean LOS for these patients was 8 days. During the follow up period (mean 6.3 months), one patient required exploratory laparotomy 2 weeks after surgery and subsequently developed an incisional hernia and enterocutaneous fistula. CONCLUSION: The use of biomaterial mesh in concert with HIPEC enables the repair of concomitant abdominal wall hernia and facilitates abdominal wall closure following the liberal resection of abdominal wall tumors. Biomaterial mesh prevents evisceration on repeat laparotomy and resists infection in immunocompromised patients even when associated with bowel resection. PMID- 20727182 TI - 'To take care of the patients': Qualitative analysis of Veterans Health Administration personnel experiences with a clinical informatics system. AB - BACKGROUND: The Veterans Health Administration (VA) has invested significant resources in designing and implementing a comprehensive electronic health record (EHR) that supports clinical priorities. EHRs in general have been difficult to implement, with unclear cost-effectiveness. We describe VA clinical personnel interactions with and evaluations of the EHR. METHODS: As part of an evaluation of a quality improvement initiative, we interviewed 72 VA clinicians and managers using a semi-structured interview format. We conducted a qualitative analysis of interview transcripts, examining themes relating to participants' interactions with and evaluations of the VA EHR. RESULTS: Participants described their perceptions of the positive and negative effects of the EHR on their clinical workflow. Although they appreciated the speed and ease of documentation that the EHR afforded, they were concerned about the time cost of using the technology and the technology's potential for detracting from interpersonal interactions. CONCLUSIONS: VA personnel value EHRs' contributions to supporting communication, education, and documentation. However, participants are concerned about EHRs' potential interference with other important aspects of healthcare, such as time for clinical care and interpersonal communication with patients and colleagues. We propose that initial implementation of an EHR is one step in an iterative process of ongoing quality improvement. PMID- 20727183 TI - Gender specific quality of life in patients with oral squamous cell carcinomas. AB - BACKGROUND: The goal of this study was to evaluate the somatic and psychological effects by means of QUALITY OF LIFE (QOL) of surgical treatment of patients with oral squamous cell carcinoma. The factors gender, age, nicotine consumption, and tumour stage were taken into consideration. METHODS: 54 patients after surgical resection of oral squamous cell carcinomas (OSCC) were analysed from 01.09.2005 to 31.05.2008. Inclusion criteria for the study were: age at least 18 years, no indication or treatment of synchronous and metachronous tumours. German translations of the EORTC H&N-35 and EORTC QLQ-C-30 questionnaires, as well as a general socioeconomic patient history were used as measuring instruments. The questionnaires were completed independently by the patients. The answers were translated into scale values for statistical evaluation using appropriate algorithms. RESULTS: Analysis of the EORTC-QLQ-C-30 questionnaires demonstrated a tendency of more negative assessment of emotional function among the female participants, and a more negative evaluation of social function among the male participants. Greater tumour sizes showed significantly lower bodily function (p = 0.018). While a smaller tumour size was significantly associated with lower cognitive functioning (p = 0.031). Other cofactors such as age, nicotine consumption, and tumour stage only showed a tendency to influence the quality of sleep and daily life. CONCLUSIONS: The data obtained within this investigation demonstrated that gender had the most significant power on the subjectively perceived postoperative quality of life. This factor is important e.g. in preoperative decision making regarding immediate microvascular reconstruction after e.g. mandibular resection and therefore QOL assessment should become integral component of the care of patients with OSCC. PMID- 20727184 TI - WENDI: A tool for finding non-obvious relationships between compounds and biological properties, genes, diseases and scholarly publications. AB - BACKGROUND: In recent years, there has been a huge increase in the amount of publicly-available and proprietary information pertinent to drug discovery. However, there is a distinct lack of data mining tools available to harness this information, and in particular for knowledge discovery across multiple information sources. At Indiana University we have an ongoing project with Eli Lilly to develop web-service based tools for integrative mining of chemical and biological information. In this paper, we report on the first of these tools, called WENDI (Web Engine for Non-obvious Drug Information) that attempts to find non-obvious relationships between a query compound and scholarly publications, biological properties, genes and diseases using multiple information sources. RESULTS: We have created an aggregate web service that takes a query compound as input, calls multiple web services for computation and database search, and returns an XML file that aggregates this information. We have also developed a client application that provides an easy-to-use interface to this web service. Both the service and client are publicly available. CONCLUSIONS: Initial testing indicates this tool is useful in identifying potential biological applications of compounds that are not obvious, and in identifying corroborating and conflicting information from multiple sources. We encourage feedback on the tool to help us refine it further. We are now developing further tools based on this model. PMID- 20727185 TI - Orthopaedic health status of horses from 8 riding schools--a pilot study. AB - BACKGROUND: Orthopaedic injury is the most common reason for lameness and wastage in sport and leisure horses. Studies on racehorses have shown differences in injury risk between trainers and training strategies. The aim was to study between riding school variation in orthopaedic health status by clinical examination and horses age, and control for change of examiner, in schools with previous high (n = 4) and low (n = 4) insurance utilisation. METHODS: Horses (n = 99) at 8 riding schools were examined for conformation, movement in all gaits, standing flexion tests and palpation by two veterinary surgeons (in some schools only one). Indexes of findings were created for total health, movements, limbs, conformation and back palpation. RESULTS: Logistic regression analyses showed that findings increased with age (walk, trot, canter, conformation left hind limb, palpation fore limbs, hooves and flexion tests) or decreased with age (conformation right fore limb). Significant differences in findings were found between riding schools and examiner for seven and eight criteria each (partly overlapping). Increasing indexes were significantly associated with one examiner (total health, movements, back palpation), increasing age (total health, movements) or more time at the school (limbs). The back palpation index was highest at 5 < 8 years since acquisition. CONCLUSION: The age distribution differed markedly between riding schools and age affected several types of findings. This, combined with the two opposite groups of insurance use, shows that schools with low insurance utilisation had previously been able to "avoid" using the insurance, maybe even on similar types of cases if these were more promptly/differently handled indicating differential coverage of disease data in the insurance database. The examiner effect was clearly demonstrated. For some findings, the amount of clinical observations differed by school, even when examiner and age was adjusted for. Most findings were of minor importance, including slight movement irregularities. Orthopaedic status varies between riding schools. We hypothesize that this is associated with management factors that warrant further study. PMID- 20727186 TI - Comparison of the multi-drug resistant human hepatocellular carcinoma cell line Bel-7402/ADM model established by three methods. AB - BACKGROUND: To compare the biological characteristics of three types of human hepatocellular carcinoma multi-drug resistant cell sub-lines Bel-7402/ADM models established by three methods. METHODS: Established human hepatocellular carcinoma adriamycin (ADM) multi-drug resistant cell sub-lines models Bel-7402/ADMV, Bel 7402/ADML and Bel-7402/ADMS by three methods of in vitro concentration gradient increased induction, nude mice liver-implanted induction and subcutaneous implanted induction respectively. Phase contrast microscopy was used to observe the cells and the MTT (methyl thiazolyl tetrazolium) method was used to detect drug resistance of the three different sub-lines of cells. RESULTS: The three groups of drug resistant cells, Bel-7402/ADMV, Bel-7402/ADML and Bel-7402/ADMS generated cross-resistance to ADM and CDDP (cis-Diaminedichloroplatinum), but showed a significant difference in resistance to Bel-7402 IC50 value (P < 0.01). The doubling times were significantly extended compared to the parent cell line (39 h) and were 65 h (Bel-7402/ADMV), 46 h (Bel-7402/ADML), and 45 h (Bel 7402/ADMS). The excretion rates of ADM were significantly increased compared with the parent cell (34.14%) line and were 81.06% (Bel-7402/ADMV), 66.56% (Bel 7402/ADML) and 61.56% (Bel-7402/ADMS). Expression of P-gp and MRP in the three groups of resistant cells was significantly enhanced (P < 0.01). There was no significant variation in the expression of GSH/GST (P > 0.05). CONCLUSIONS: Stable resistance was involved in the resistant cell line model established by the above three methods. Liver implantation was a good simulation of human hepatocellular and proved to be an ideal model with characteristics similar to human hepatocellular biology and the pharmacokinetics of anticancer drugs. PMID- 20727187 TI - Atherosclerosis, inflammation and lipoprotein glomerulopathy in kidneys of apoE-/ /LDL-/- double knockout mice. AB - BACKGROUND: The apoE-/-/LDL-/- double knockout mice are bearing considerable structural homology to human atherosclerosis. We hypothesized, that advanced lesion formation in the renal artery is associated with kidney alterations in these mice. METHODS: Kidneys from apoE-/-/LDL-/- double knockout mice at the age of 80 weeks (n = 6) and C57/BL control mice (n = 5) were infused with Microfil, harvested and scanned with micro-CT (12 mum cubic voxels) and Nano-CT (900 nm cubic voxels). We quantitated the total vascular volume using micro-CT. Number and cross-sectional area (microm2) of glomeruli were measured using histology. RESULTS: At the age of 80 weeks, the renal total vascular volume fraction decreased significantly (p < 0.001) compared to controls. Moreover, the renal artery showed advanced atherosclerotic lesions with adventitial Vasa vasorum neovascularization. Perivascular inflammation was present in kidneys of apoE-/ /LDL-/- double knockout mice, predominantly involved are plasma cells and leucocytes. Glomeruli cross-sectional area (9959 +/- 1083 microm2) and number (24.8 +/- 4.5) increased in apoE-/-/LDL-/- double knockout mice compared to controls (3533 +/- 398 microm2; 17.6 +/- 3, respectively), whereas 41% of the total number of glomeruli showed evidence for lipoprotein associated glomerulopathy (LPG). Moreover, immunohistochemistry demonstrated capillary aneurysms of the glomeruli filled with factor 8 containing emboli. CONCLUSION: The reduced intra-renal total vascular volume is associated with systemic atherosclerosis and glomeruli alterations in the apoE-/-/LDL-/- double knockout mouse model. PMID- 20727188 TI - What happened after the initial global spread of pandemic human influenza virus A (H1N1)? A population genetics approach. AB - Viral population evolution dynamics of influenza A is crucial for surveillance and control. In this paper we analyzed viral genetic features during the recent pandemic caused by the new influenza human virus A H1N1, using a conventional population genetics approach based on 4689 hemagglutinin (HA) and neuraminidase (NA) sequences available in GenBank submitted between March and December of 2009. This analysis showed several relevant aspects: a) a scarce initial genetic variability within the viral isolates from some countries that increased along 2009 when influenza was dispersed around the world; b) a worldwide virus polarized behavior identified when comparing paired countries, low differentiation and high gene flow were found in some pairs and high differentiation and moderate or scarce gene flow in others, independently of their geographical closeness, c) lack of positive selection in HA and NA due to increase of the population size of virus variants, d) HA and NA variants spread in a few months all over the world being identified in the same countries in different months along 2009, and e) containment of viral variants in Mexico at the beginning of the outbreak, probably due to the control measures applied by the government. PMID- 20727189 TI - Structural factors and best practices in implementing a linkage to HIV care program using the ARTAS model. AB - BACKGROUND: Implementation of linkage to HIV care programs in the U.S. is poorly described in the literature despite the central role of these programs in delivering clients from HIV testing facilities to clinical care sites. Models demonstrating success in linking clients to HIV care from testing locations that do not have co-located medical care are especially needed. METHODS: Data from the Antiretroviral Treatment Access Studies-II project ('ARTAS-II') as well as site visit and project director reports were used to describe structural factors and best practices found in successful linkage to care programs. Successful programs were able to identify recently diagnosed HIV-positive persons and ensure that a high percentage of persons attended an initial HIV primary care provider visit within six months of enrolling in the linkage program. RESULTS: Eight categories of best practices are described, supplemented by examples from 5 of 10 ARTAS-II sites. These five sites highlighted in the best practices enrolled a total of 352 HIV+ clients and averaged 85% linked to care after six months. The other five grantees enrolled 274 clients and averaged 72% linked to care after six months. Sites with co-located HIV primary medical care services had higher linkage to care rates than non-co-located sites (87% vs. 73%). Five grantees continued linkage to care activities in some capacity after project funding ended. CONCLUSIONS: With the push to expand HIV testing in all U.S. communities, implementation and evaluation of linkage to care programs is needed to maximize the benefits of expanded HIV testing efforts. PMID- 20727190 TI - Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis. AB - BACKGROUND: Melanoma vaccines have not been optimized. Adjuvants are added to activate dendritic cells (DCs) and to induce a favourable immunologic milieu, however, little is known about their cellular and molecular effects in human skin. We hypothesized that a vaccine in incomplete Freund's adjuvant (IFA) would increase dermal Th1 and Tc1-lymphocytes and mature DCs, but that repeated vaccination may increase regulatory cells. METHODS: During and after 6 weekly immunizations with a multipeptide vaccine, immunization sites were biopsied at weeks 0, 1, 3, 7, or 12. In 36 participants, we enumerated DCs and lymphocyte subsets by immunohistochemistry and characterized their location within skin compartments. RESULTS: Mature DCs aggregated with lymphocytes around superficial vessels, however, immature DCs were randomly distributed. Over time, there was no change in mature DCs. Increases in T and B-cells were noted. Th2 cells outnumbered Th1 lymphocytes after 1 vaccine 6.6:1. Eosinophils and FoxP3+ cells accumulated, especially after 3 vaccinations, the former cell population most abundantly in deeper layers. CONCLUSIONS: A multipeptide/IFA vaccine may induce a Th2-dominant microenvironment, which is reversed with repeat vaccination. However, repeat vaccination may increase FoxP3+T-cells and eosinophils. These data suggest multiple opportunities to optimize vaccine regimens and potential endpoints for monitoring the effects of new adjuvants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00705640. PMID- 20727191 TI - Adaptive coping strategies in patients with chronic pain conditions and their interpretation of disease. AB - BACKGROUND: We examined which adaptive coping strategies, referring to the concept of 'locus of disease control', were of relevance for patients with chronic pain conditions, and how they were interconnected with patients' life satisfaction and interpretation of disease. METHODS: In a multicenter cross sectional anonymous survey with the AKU questionnaire, we enrolled 579 patients (mean age 54 +/- 14 years) with various chronic pain conditions. RESULTS: Disease as an adverse interruption of life was the prevalent interpretation of chronic pain conditions. As a consequence, patients relied on external powerful sources to control their disease (i.e., Trust in Medical Help; Search for Information and Alternative Help), but also on internal powers and virtues (i.e., Conscious Way of Living; Positive Attitudes). In contrast, Trust in Divine Help as an external transcendent source and Reappraisal: Illness as Chance as an internal (cognitive) strategy were valued moderately. Regression analyses indicated that Positive Attitudes and higher age were significant predictors of patients' life satisfaction, but none of the other adaptive coping strategies. While the adaptive coping strategies were not associated with negative interpretations of disease, the cognitive reappraisal attitude was of significant relevance for positive interpretations such as value and challenge. CONCLUSIONS: The experience of illness may enhance intensity and depth of life, and thus one may explain the association between internal adaptive coping strategies (particularly Reappraisal) and positive interpretations of disease. To restore a sense of self control over pain (and thus congruence with the situation), and the conviction that one is not necessarily disabled by disease, is a major task in patient care. In the context of health services research, apart from effective pain management, a comprehensive approach is needed which enhances the psycho-spiritual well-being of patients. PMID- 20727193 TI - Quality of life in the Iranian Blind War Survivors in 2007: a cross-sectional study. AB - BACKGROUND: Quality of Life measurements are necessary tools for effectively evaluating health services. In the population of patients afflicted with war related blindness in Iran, such measurements have yet to be documented and utilized. "The design and implementation of this study involved the determination of a baseline score for QOL in a population of Iranian blinded in the Iraq-Iran war in order to facilitate the design of interventions intended to improve the population's QOL." METHODS: This was a cross-sectional study of a representative population of 250 war victims blind in both eyes at a 14-day recreational conference. RESULTS: Participants had a mean age of 43.20(SD8.34) and their composition was 96.5% male and 3.5% female with a mean SF-36 QOL score of 59.20(SD22.80). An increasing level of education among the participants correlated with a higher QOL score (p = 0.006). The QOL also has a significant correlation to number of injuries (p < 0.0001). High systolic and diastolic blood pressure, hearing loss, and tinnitus had negative individual correlations to QOL (p = 0.016, 0.016, 0.005, p < 0.0001). The male sexual disorders of erectile dysfunction and premature ejaculation both had significant correlations to QOL (p = 0.026, p < 0.0001). Hypercholesterolemia showed significant correlation to QOL (p = 0.021). CONCLUSIONS: As blind war survivors' age, they will present with a greater set of burdens despite their relatively better QOL in the physical component scale when compared with lower limb amputees. Risk factors of cardiovascular attack such as high blood pressure and hypercholesterolemia were present and need future interventions. KEYWORDS: Quality of life, blindness, SF36, health. PMID- 20727192 TI - Increased expression of cysteine cathepsins in ovarian tissue from chickens with ovarian cancer. AB - BACKGROUND: Cysteine cathepsins (CTSs) are involved in the degradation and remodeling of the extracellular matrix and are associated with cell transformation, differentiation, motility, and adhesion. These functions are also related to cancer cell invasion and metastasis. Chickens spontaneously develop epithelial ovarian cancer and are therefore a good animal model for human ovarian cancer. However, no studies have investigated the expression of CTSs in chickens with ovarian cancer. METHODS: Cancerous (n = 5) and normal (n = 3) ovaries were collected from 2-to 3-year-old hens, and ovarian tissue samples were collected for study. Ovarian cancers were evaluated with hematoxylin and eosin staining. Reverse transcriptase and quantitative PCR analyses, in situ hybridization analysis were performed to examine the mRNA expression pattern of three CTSs in detail, and protein expression of CTSB was evaluated. RESULTS: The CTSB, CTSC, and CTSS genes were highly expressed in cancerous chicken ovaries. Messenger RNAs for the three CTSs were localized to a nodule area, a major characteristic of cancerous ovaries, but the three CTSs showed no specific localization in normal ovaries. Immunoreactive CTSB protein was present in the nodule area of cancerous ovaries. CONCLUSION: Our results suggest that CTSB, CTSC, and CTSS have important functions in the development of epithelial ovarian cancer. PMID- 20727194 TI - A classification approach for genotyping viral sequences based on multidimensional scaling and linear discriminant analysis. AB - BACKGROUND: Accurate classification into genotypes is critical in understanding evolution of divergent viruses. Here we report a new approach, MuLDAS, which classifies a query sequence based on the statistical genotype models learned from the known sequences. Thus, MuLDAS utilizes full spectra of well characterized sequences as references, typically of an order of hundreds, in order to estimate the significance of each genotype assignment. RESULTS: MuLDAS starts by aligning the query sequence to the reference multiple sequence alignment and calculating the subsequent distance matrix among the sequences. They are then mapped to a principal coordinate space by multidimensional scaling, and the coordinates of the reference sequences are used as features in developing linear discriminant models that partition the space by genotype. The genotype of the query is then given as the maximum a posteriori estimate. MuLDAS tests the model confidence by leave-one-out cross-validation and also provides some heuristics for the detection of 'outlier' sequences that fall far outside or in-between genotype clusters. We have tested our method by classifying HIV-1 and HCV nucleotide sequences downloaded from NCBI GenBank, achieving the overall concordance rates of 99.3% and 96.6%, respectively, with the benchmark test dataset retrieved from the respective databases of Los Alamos National Laboratory. CONCLUSIONS: The highly accurate genotype assignment coupled with several measures for evaluating the results makes MuLDAS useful in analyzing the sequences of rapidly evolving viruses such as HIV-1 and HCV. A web-based genotype prediction server is available at http://www.muldas.org/MuLDAS/. PMID- 20727195 TI - Assessing mechanical integrity of spinal fusion by in situ endochondral osteoinduction in the murine model. AB - BACKGROUND: Historically, radiographs, micro-computed tomography (micro-CT) exams, palpation and histology have been used to assess fusions in a mouse spine. The objective of this study was to develop a faster, cheaper, reproducible test to directly quantify the mechanical integrity of spinal fusions in mice. METHODS: Fusions were induced in ten mice spine using a previously described technique of in situ endochondral ossification, harvested with soft tissue, and cast in radiolucent alginate material for handling. Using a validated software package and a customized mechanical apparatus that flexed and extended the spinal column, the amount of intervertebral motion between adjacent vertebral discs was determined with static flexed and extended lateral spine radiographs. Micro-CT images of the same were also blindly reviewed for fusion. RESULTS: Mean intervertebral motion between control, non-fused, spinal vertebral discs was 6.1 +/- 0.2 degrees during spine flexion/extension. In fusion samples, adjacent vertebrae with less than 3.5 degrees intervertebral motion had fusions documented by micro-CT inspection. CONCLUSIONS: Measuring the amount of intervertebral rotation between vertebrae during spine flexion/extension is a relatively simple, cheap (<$100), clinically relevant, and fast test for assessing the mechanical success of spinal fusion in mice that compared favorably to the standard, micro CT. PMID- 20727196 TI - Biology and augmentation of tendon-bone insertion repair. AB - Surgical reattachment of tendon and bone such as in rotator cuff repair, patellar-patella tendon repair and anterior cruciate ligament (ACL) reconstruction often fails due to the failure of regeneration of the specialized tissue ("enthesis") which connects tendon to bone. Tendon-to-bone healing taking place between inhomogenous tissues is a slow process compared to healing within homogenous tissue, such as tendon to tendon or bone to bone healing. Therefore special attention must be paid to augment tendon to bone insertion (TBI) healing. Apart from surgical fixation, biological and biophysical interventions have been studied aiming at regeneration of TBI healing complex, especially the regeneration of interpositioned fibrocartilage and new bone at the healing junction. This paper described the biology and the factors influencing TBI healing using patella-patellar tendon (PPT) healing and tendon graft to bone tunnel healing in ACL reconstruction as examples. Recent development in the improvement of TBI healing and directions for future studies were also reviewed and discussed. PMID- 20727197 TI - Nanomaterial cytotoxicity is composition, size, and cell type dependent. AB - BACKGROUND: Despite intensive research efforts, reports of cellular responses to nanomaterials are often inconsistent and even contradictory. Additionally, relationships between the responding cell type and nanomaterial properties are not well understood. Using three model cell lines representing different physiological compartments and nanomaterials of different compositions and sizes, we have systematically investigated the influence of nanomaterial properties on the degrees and pathways of cytotoxicity. In this study, we selected nanomaterials of different compositions (TiO2 and SiO2 nanoparticles, and multi wall carbon nanotubes [MWCNTs]) with differing size (MWCNTs of different diameters < 8 nm, 20-30 nm, > 50 nm; but same length 0.5-2 microm) to analyze the effects of composition and size on toxicity to 3T3 fibroblasts, RAW 264.7 macrophages, and telomerase-immortalized (hT) bronchiolar epithelial cells. RESULTS: Following characterization of nanomaterial properties in PBS and serum containing solutions, cells were exposed to nanomaterials of differing compositions and sizes, with cytotoxicity monitored through reduction in mitochondrial activity. In addition to cytotoxicity, the cellular response to nanomaterials was characterized by quantifying generation of reactive oxygen species, lysosomal membrane destabilization and mitochondrial permeability. The effect of these responses on cellular fate - apoptosis or necrosis - was then analyzed. Nanomaterial toxicity was variable based on exposed cell type and dependent on nanomaterial composition and size. In addition, nanomaterial exposure led to cell type dependent intracellular responses resulting in unique breakdown of cellular functions for each nanomaterial: cell combination. CONCLUSIONS: Nanomaterials induce cell specific responses resulting in variable toxicity and subsequent cell fate based on the type of exposed cell. Our results indicate that the composition and size of nanomaterials as well as the target cell type are critical determinants of intracellular responses, degree of cytotoxicity and potential mechanisms of toxicity. PMID- 20727198 TI - Lean mass, muscle strength, and physical function in a diverse population of men: a population-based cross-sectional study. AB - BACKGROUND: Age-related declines in lean body mass appear to be more rapid in men than in women but our understanding of muscle mass and function among different subgroups of men and their changes with age is quite limited. The objective of this analysis is to examine racial/ethnic differences and racial/ethnic group specific cross-sectional age differences in measures of muscle mass, muscle strength, and physical function among men. METHODS: Data were obtained from the Boston Area Community Health/Bone (BACH/Bone) Survey, a population-based, cross sectional, observational survey. Subjects included 1,157 black, Hispanic, and white randomly-selected Boston men ages 30-79 y. Lean mass was assessed by dual energy x-ray absorptiometry. Upper extremity (grip) strength was assessed with a hand dynamometer and lower extremity physical function was derived from walk and chair stand tests. Upper extremity strength and lower extremity physical function were also indexed by lean mass and lean mass was indexed by the square of height. RESULTS: Mean age of the sample was 47.5 y. Substantial cross-sectional age differences in grip strength and physical function were consistent across race/ethnicity. Racial/ethnic differences, with and without adjustment for covariates, were evident in all outcomes except grip strength. Racial differences in lean mass did not translate into parallel differences in physical function. For instance, multivariate modeling (with adjustments for age, height, fat mass, self-rated health and physical activity) indicated that whereas total body lean mass was 2.43 kg (approximately 5%) higher in black compared with white men, black men had a physical function score that was approximately 20% lower than white men. CONCLUSIONS: In spite of lower levels of lean mass, the higher levels of physical function observed among white compared with non-white men in this study appear to be broadly consistent with known racial/ethnic differences in outcomes. PMID- 20727199 TI - Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis. AB - INTRODUCTION: The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9beta are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity. METHODS: The presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined. RESULTS: Carriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9beta minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNFalpha) therapy (P < 0.05). CONCLUSIONS: The minor alleles of the 9beta and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa. PMID- 20727201 TI - Aortic dissection associated with Cogans's syndrome: deleterious loss of vascular structural integrity is associated with GM-CSF overstimulation in macrophages and smooth muscle cells. AB - BACKGROUND: Cogan's syndrome is a rare disorder of unknown origin characterized by inflammatory ocular disease and vestibuloauditory symptoms. Systemic vasculitis is found in about 10% of cases. CASE PRESENTATION: A 46-year-old female with Cogans's syndrome and a history of arterial hypertension presented with severe chest pain caused by an aneurysm of the ascending aorta with a dissection membrane located a few centimeters distal from the aortic root. After surgery, histopathological analysis revealed that vascular matrix integrity and expression of the major matrix molecules was characterized by elastolysis and collagenolysis and thus a dramatic loss of structural integrity. Remarkably, exceeding matrix deterioration was associated with massively increased levels of granulocyte macrophage colony stimulating factor (GM-CSF). CONCLUSION: Our data suggest that the persistently increased secretion of the inflammatory mediator GM CSF by resident inflammatory cells but also by SMC may be the trigger of aortic wall structural deterioration. PMID- 20727200 TI - The DBCLS BioHackathon: standardization and interoperability for bioinformatics web services and workflows. The DBCLS BioHackathon Consortium*. AB - Web services have become a key technology for bioinformatics, since life science databases are globally decentralized and the exponential increase in the amount of available data demands for efficient systems without the need to transfer entire databases for every step of an analysis. However, various incompatibilities among database resources and analysis services make it difficult to connect and integrate these into interoperable workflows. To resolve this situation, we invited domain specialists from web service providers, client software developers, Open Bio* projects, the BioMoby project and researchers of emerging areas where a standard exchange data format is not well established, for an intensive collaboration entitled the BioHackathon 2008. The meeting was hosted by the Database Center for Life Science (DBCLS) and Computational Biology Research Center (CBRC) and was held in Tokyo from February 11th to 15th, 2008. In this report we highlight the work accomplished and the common issues arisen from this event, including the standardization of data exchange formats and services in the emerging fields of glycoinformatics, biological interaction networks, text mining, and phyloinformatics. In addition, common shared object development based on BioSQL, as well as technical challenges in large data management, asynchronous services, and security are discussed. Consequently, we improved interoperability of web services in several fields, however, further cooperation among major database centers and continued collaborative efforts between service providers and software developers are still necessary for an effective advance in bioinformatics web service technologies. PMID- 20727202 TI - A single dose of DNA vaccine based on conserved H5N1 subtype proteins provides protection against lethal H5N1 challenge in mice pre-exposed to H1N1 influenza virus. AB - BACKGROUND: Highly pathogenic avian influenza virus subtype H5N1 infects humans with a high fatality rate and has pandemic potential. Vaccination is the preferred approach for prevention of H5N1 infection. Seasonal influenza virus infection has been reported to provide heterosubtypic immunity against influenza A virus infection to some extend. In this study, we used a mouse model pre exposed to an H1N1 influenza virus and evaluated the protective ability provided by a single dose of DNA vaccines encoding conserved H5N1 proteins. RESULTS: SPF BALB/c mice were intranasally infected with A/PR8 (H1N1) virus beforehand. Six weeks later, the mice were immunized with plasmid DNA expressing H5N1 virus NP or M1, or with combination of the two plasmids. Both serum specific Ab titers and IFN-gamma secretion by spleen cells in vitro were determined. Six weeks after the vaccination, the mice were challenged with a lethal dose of H5N1 influenza virus. The protective efficacy was judged by survival rate, body weight loss and residue virus titer in lungs after the challenge. The results showed that pre-exposure to H1N1 virus could offer mice partial protection against lethal H5N1 challenge and that single-dose injection with NP DNA or NP + M1 DNAs provided significantly improved protection against lethal H5N1 challenge in mice pre-exposed to H1N1 virus, as compared with those in unexposed mice. CONCLUSIONS: Pre-existing immunity against seasonal influenza viruses is useful in offering protection against H5N1 infection. DNA vaccination may be a quick and effective strategy for persons innaive to influenza A virus during H5N1 pandemic. PMID- 20727203 TI - A revision of brain composition in Onychophora (velvet worms) suggests that the tritocerebrum evolved in arthropods. AB - BACKGROUND: The composition of the arthropod head is one of the most contentious issues in animal evolution. In particular, controversy surrounds the homology and innervation of segmental cephalic appendages by the brain. Onychophora (velvet worms) play a crucial role in understanding the evolution of the arthropod brain, because they are close relatives of arthropods and have apparently changed little since the Early Cambrian. However, the segmental origins of their brain neuropils and the number of cephalic appendages innervated by the brain--key issues in clarifying brain composition in the last common ancestor of Onychophora and Arthropoda--remain unclear. RESULTS: Using immunolabelling and neuronal tracing techniques in the developing and adult onychophoran brain, we found that the major brain neuropils arise from only the anterior-most body segment, and that two pairs of segmental appendages are innervated by the brain. The region of the central nervous system corresponding to the arthropod tritocerebrum is not differentiated as part of the onychophoran brain but instead belongs to the ventral nerve cords. CONCLUSIONS: Our results contradict the assumptions of a tripartite (three-segmented) brain in Onychophora and instead confirm the hypothesis of bipartite (two-segmented) brain composition. They suggest that the last common ancestor of Onychophora and Arthropoda possessed a brain consisting of protocerebrum and deutocerebrum whereas the tritocerebrum evolved in arthropods. PMID- 20727204 TI - Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. AB - BACKGROUND: Musashi1 (Msi1) is a conserved RNA-binding protein that regulates the Notch and Wnt pathways, and serves as a stem cell marker in the breast and other tissues. It is unknown how Msi1 relates to other breast cancer markers, whether it denotes tumor initiating cells (TICs), and how it affects gene expression and tumor cell survival in breast cancer cells. RESULTS: Msi1 expression was analyzed in 20 breast cancer cell lines and in 140 primary breast tumors by western blotting and immunohistochemistry, respectively. Lentivirus RNA interference was used to reduce Msi1 expression in breast cancer cell lines MCF-7 and T47D grown as spheroid cultures and to assess stem cell gene expression and the growth of these cell lines as xenografts. In normal human breast tissue, Msi1 was expressed in 10.6% of myoepithelum and 1.2% of ductal epithelium in the terminal ductal lobular unit (TDLU), whereas, less than 0.05% of ductal epithelium and myoepithelium in large ducts outside the TDLU expressed Msi1. Msi1 was expressed in 55% of the breast cancer cell lines and correlated with ErbB2 expression in 50% of the cell lines. Msi1 was expressed in 68% of primary tumors and in 100% of lymph node metastases, and correlated with 5 year survival. Msi1 was enriched in CD133+ MCF-7 and T47D cells and in spheroid cultures of these cells, and Msi1 'knockdown' (KD) with a lentivirus-expressed shRNA decreased the number and size of spheroid colonies. Msi1 KD reduced Notch1, c-Myc, ErbB2 and pERK1/2 expression, and increased p21CIP1 expression, which is consistent with known Msi1 target mRNAs. Msi1 KD also reduced the expression of the somatic and embryonic stem cell markers, CD133, Bmi1, Sox2, Nanog and Oct4. Xenografts of MCF-7 and T47D Msi1 KD cells resulted in a marked reduction of tumor growth, reduced Msi1 and Notch1 expression and increased p21CIP1 expression. CONCLUSION: Msi1 is a negative prognostic indicator of breast cancer patient survival, and is indicative of tumor cells with stem cell-like characteristics. Msi1 KD reduces tumor cell survival and tumor xenograft growth, suggesting that it may represent a novel target for drug discovery. PMID- 20727205 TI - No influence of oxygen levels on pathogenesis and virus shedding in Salmonid alphavirus (SAV)-challenged Atlantic salmon (Salmo salar L.). AB - BACKGROUND: For more than three decades, diseases caused by salmonid alphaviruses (SAV) have become a major problem of increasing economic importance in the European fish-farming industry. However, experimental infection trials with SAV result in low or no mortality i.e very different from most field outbreaks of pancreas disease (PD). This probably reflects the difficulties in reproducing complex biotic and abiotic field conditions in the laboratory. In this study we looked at the relationship between SAV-infection in salmon and sub-lethal environmental hypoxia as a result of reduced flow-through in tank systems. RESULTS: The experiment demonstrated that constant reduced oxygen levels (60-65% oxygen saturation: 6.5-7.0 mg/L) did not significantly increase the severity or the progress of pancreas disease (PD). These conclusions are based upon assessments of a semi-quantitative histopathological lesion score system, morbidities/mortalities, and levels of SAV RNA in tissues and water (measured by 1 MDS electropositive virus filters and downstream real-time RT-PCR). Furthermore, we demonstrate that the fish population shed detectable levels of the virus into the surrounding water during viraemia; 4-13 days after i.p. infection, and prior to appearance of severe lesions in heart (21-35 dpi). After this period, viral RNA from SAV could not be detected in water samples although still present in tissues (gills and hearts) at lasting low levels. Lesions could be seen in exocrine pancreas at 7-21 days post infection, but no muscle lesions were seen. CONCLUSIONS: In our study, experimentally induced hypoxia failed to explain the discrepancy between the severities reported from field outbreaks of SAV-disease and experimental infections. Reduction of oxygen levels to constant suboptimal levels had no effect on the severity of lesions caused by SAV infection or the progress of the disease. Furthermore, we present a modified VIRADEL method which can be used to detect virus in water and to supplement experimental infection trials with information related to viral shedding. By using this method, we were able to demonstrate for the first time that shedding of SAV from the fish population into the surrounding water coincides with viraemia. PMID- 20727206 TI - Serum neopterin is elevated in patients infected with Shigella. AB - BACKGROUND: Neopterin is produced by human macrophages/monocytes when stimulated with interferon-gamma. Production of neopterin is found in serum, cerebrospinal fluid (CSF) and urine of patients with infections by viruses, intracellular bacteria and parasites, autoimmune diseases, malignant tumors and patients in allograft rejection episodes. METHODS: In this study, the level of neopterin was determined in serum samples obtained from patients infected with Shigella (all four species) and healthy individuals. The study population comprised of 14 patients infected with Shigella and 14 normal controls. Serum neopterin was measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean of serum neopterin concentration was 36.32 +/- 9.71 nmol/L among patients infected with Shigella and 2.88 +/- 0.77 nmol/L in the control group. The mean serum neopterin levels were significantly higher in the test group as compared to the normal group (p = 0.002). CONCLUSION: This study revealed that neopterin was elevated in patients infected with Shigella. PMID- 20727207 TI - Fucoidan present in brown algae induces apoptosis of human colon cancer cells. AB - BACKGROUND: Fucoidan is a sulfated polysaccharide found in brown algae; it has been shown to exhibit a number of biological effects, including anti-tumor effects. In this study, we evaluated the effects of fucoidan on apoptosis in HT 29 and HCT116 human colon cancer cells. METHODS: HT-29 and HCT116 cells were cultured with various concentrations of fucoidan (0 - 20 microg/mL). Apoptosis was assayed via Hoechst staining and Annexin V staining followed by flow cytometric analysis. Western blot analyses and JC-1 staining were conducted to determine the levels of apoptosis-regulating proteins and mitochondrial membrane permeability, respectively. RESULTS: Fucoidan induced substantial reductions in viable cell numbers and apoptosis of HT-29 and HCT116 cells in a dose-dependent manner. In HT-29 cells, fucoidan also increased the levels of cleaved caspases-8, -9, -7, and -3, and cleaved poly (ADP-ribose) polymerase (PARP) levels. The levels of the X-linked inhibitor of apoptosis protein and survivin were attenuated in the fucoidan-treated cells. Fucoidan was also shown to enhance mitochondrial membrane permeability, as well as the cytochrome c and Smac/Diablo release from the mitochondria. Fucoidan increased the levels of the Bak and truncated Bid proteins, but reduced the levels of Mcl-1. Additionally, fucoidan increased the levels of the tumor necrosis factor-related apoptosis-inducing ligand, Fas and death receptor 5 proteins. The caspase-8 and -9 inhibitors Z-IETD FMK and Z-LEHD-FMK induced a reduction in fucoidan-mediated apoptosis. Caspase-8 inhibitor inhibited the fucoidan-induced cleavage of Bid, caspases-9 and -3, and PARP. CONCLUSION: The findings of this study indicate that fucoidan induces apoptosis in HT-29 and HCT116 human colon cancer cells, and that this phenomenon is mediated via both the death receptor-mediated and mitochondria-mediated apoptotic pathways. These results suggest that fucoidan may prove useful in the development of a colon cancer-preventive protocol. PMID- 20727208 TI - Characterization of single chain antibody targets through yeast two hybrid. AB - BACKGROUND: Due to their unique ability to bind their targets with high fidelity, antibodies are used widely not only in biomedical research, but also in many clinical applications. Recombinant antibodies, including single chain variable fragments (scFv), are gaining momentum because they allow powerful in vitro selection and manipulation without loss of function. Regardless of the ultimate application or type of antibody used, precise understanding of the interaction between the antibody's binding site and its specific target epitope(s) is of great importance. However, such data is frequently difficult to obtain. RESULTS: We describe an approach that allows detailed characterization of a given antibody's target(s) using the yeast two-hybrid system. Several recombinant scFv were used as bait and screened against highly complex cDNA libraries. Systematic sequencing of all retained clones and statistical analysis allowed efficient ranking of the prey fragments. Multiple alignment of the obtained cDNA fragments provided a selected interacting domain (SID), efficiently narrowing the epitope containing region.Interactions between antibodies and their respective targets were characterized for several scFv. For AA2 and ROF7, two conformation-specific sensors that exclusively bind the activated forms of the small GTPases Rab6 and Rab1 respectively, only fragments expressing the entire target protein's core region were retained. This strongly suggested interaction with a non-linear epitope. For two other scFv, TA10 and SF9, which recognize the large proteins giantin and non-muscle myosin IIA, respectively, precise antibody-binding regions within the target were defined. Finally, for some antibodies, secondary targets within and across species could be revealed. CONCLUSIONS: Our method, utilizing the yeast two-hybrid technology and scFv as bait, is a simple yet powerful approach for the detailed characterization of antibody targets. It allows precise domain mapping for linear epitopes, confirmation of non-linear epitopes for conformational sensors, and detection of secondary binding partners. This approach may thus prove to be an elegant and rapid method for the target characterization of newly obtained scFv antibodies. It may be considered prior to any research application and particularly before any use of such recombinant antibodies in clinical medicine. PMID- 20727209 TI - Nordic walking improves daily physical activities in COPD: a randomised controlled trial. AB - BACKGROUND: In patients with COPD progressive dyspnoea leads to a sedentary lifestyle. To date, no studies exist investigating the effects of Nordic Walking in patients with COPD. Therefore, the aim was to determine the feasibility of Nordic Walking in COPD patients at different disease stages. Furthermore we aimed to determine the short- and long-term effects of Nordic Walking on COPD patients' daily physical activity pattern as well as on patients exercise capacity. METHODS: Sixty COPD patients were randomised to either Nordic Walking or to a control group. Patients of the Nordic Walking group (n = 30; age: 62 +/- 9 years; FEV1: 48 +/- 19% predicted) underwent a three-month outdoor Nordic Walking exercise program consisting of one hour walking at 75% of their initial maximum heart rate three times per week, whereas controls had no exercise intervention. Primary endpoint: daily physical activities (measured by a validated tri-axial accelerometer); secondary endpoint: functional exercise capacity (measured by the six-minute walking distance; 6MWD). Assessment time points in both groups: baseline, after three, six and nine months. RESULTS: After three month training period, in the Nordic Walking group time spent walking and standing as well as intensity of walking increased (Delta walking time: +14.9 +/- 1.9 min/day; Delta standing time: +129 +/- 26 min/day; Delta movement intensity: +0.40 +/- 0.14 m/s2) while time spent sitting decreased (Delta sitting time: -128 +/- 15 min/day) compared to baseline (all: p < 0.01) as well as compared to controls (all: p < 0.01). Furthermore, 6MWD significantly increased compared to baseline (Delta 6MWD: +79 +/- 28 meters) as well as compared to controls (both: p < 0.01). These significant improvements were sustained six and nine months after baseline. In contrast, controls showed unchanged daily physical activities and 6MWD compared to baseline for all time points. CONCLUSIONS: Nordic Walking is a feasible, simple and effective physical training modality in COPD. In addition, Nordic Walking has proven to positively impact the daily physical activity pattern of COPD patients under short- and long-term observation. PMID- 20727211 TI - Framing health and foreign policy: lessons for global health diplomacy. AB - Global health financing has increased dramatically in recent years, indicative of a rise in health as a foreign policy issue. Several governments have issued specific foreign policy statements on global health and a new term, global health diplomacy, has been coined to describe the processes by which state and non-state actors engage to position health issues more prominently in foreign policy decision-making. Their ability to do so is important to advancing international cooperation in health. In this paper we review the arguments for health in foreign policy that inform global health diplomacy. These are organized into six policy frames: security, development, global public goods, trade, human rights and ethical/moral reasoning. Each of these frames has implications for how global health as a foreign policy issue is conceptualized. Differing arguments within and between these policy frames, while overlapping, can also be contradictory. This raises an important question about which arguments prevail in actual state decision-making. This question is addressed through an analysis of policy or policy-related documents and academic literature pertinent to each policy framing with some assessment of policy practice. The reference point for this analysis is the explicit goal of improving global health equity. This goal has increasing national traction within national public health discourse and decision-making and, through the Millennium Development Goals and other multilateral reports and declarations, is entering global health policy discussion. Initial findings support conventional international relations theory that most states, even when committed to health as a foreign policy goal, still make decisions primarily on the basis of the 'high politics' of national security and economic material interests. Development, human rights and ethical/moral arguments for global health assistance, the traditional 'low politics' of foreign policy, are present in discourse but do not appear to dominate practice. While political momentum for health as a foreign policy goal persists, the framing of this goal remains a contested issue. The analysis offered in this article may prove helpful to those engaged in global health diplomacy or in efforts to have global governance across a range of sectoral interests pay more attention to health equity impacts. PMID- 20727210 TI - Decline in air pollution and change in prevalence in respiratory symptoms and chronic obstructive pulmonary disease in elderly women. AB - BACKGROUND: While adverse effects of exposure to air pollutants on respiratory health are well studied, little is known about the effect of a reduction in air pollutants on chronic respiratory symptoms and diseases. We investigated whether different declines in air pollution levels in industrialised and rural areas in Germany were associated with changes in respiratory health over a period of about 20 years. METHODS: We used data from the SALIA cohort study in Germany (Study on the influence of Air pollution on Lung function, Inflammation and Aging) to assess the association between the prevalence of chronic obstructive pulmonary disease (COPD) and chronic respiratory symptoms and the decline in air pollution exposure. In 1985-1994, 4874 women aged 55-years took part in the baseline investigation. Of these, 2116 participated in a questionnaire follow-up in 2006 and in a subgroup of 402 women lung function was tested in 2008-2009. Generalized estimating equation (GEE) models were used to estimate the effect of a reduction in air pollution on respiratory symptoms and diseases. RESULTS: Ambient air concentrations of particulate matter with aerodynamic size < 10 microm (PM10) declined in average by 20 microg/m3. Prevalence of chronic cough with phlegm production and mild COPD at baseline investigation compared to follow-up was 9.5% vs. 13.3% and 8.6% vs. 18.2%, respectively. A steeper decline of PM10 was observed in the industrialized areas in comparison to the rural area, this was associated with a weaker increase in prevalence of respiratory symptoms and COPD. Among women who never smoked, the prevalence of chronic cough with phlegm and mild COPD was estimated at 21.4% and 39.5%, respectively, if no air pollution reduction was assumed, and at 13.3% and 17.5%, respectively, if air pollution reduction was assumed. CONCLUSION: We concluded that parallel to the decline of ambient air pollution over the last 20 years in the Ruhr area the age-related increase in chronic respiratory diseases and symptoms appears to attenuate in the population of elderly women. PMID- 20727212 TI - Risk factors for childhood malnutrition in Roma settlements in Serbia. AB - BACKGROUND: Children living in Roma settlements in Central and Eastern Europe face extreme levels of social exclusion and poverty, but their health status has not been well studied. The objective of this study was to elucidate risk factors for malnutrition in children in Roma settlements in Serbia. METHODS: Anthropometric and sociodemographic measures were obtained for 1192 Roma children under five living in Roma settlements from the 2005 Serbia Multiple Indicator Cluster Survey. Multiple logistic regression was used to relate family and child characteristics to the odds of stunting, wasting, and underweight. RESULTS: The prevalence of stunting, wasting, and underweight was 20.1%, 4.3%, and 8.0%, respectively. Nearly all of the children studied fell into the lowest quintile of wealth for the overall population of Serbia. Children in the lowest quintile of wealth were four times more likely to be stunted compared to those in the highest quintile, followed by those in the second lowest quintile (AOR = 2.1) and lastly by those in the middle quintile (AOR = 1.6). Children who were ever left in the care of an older child were almost twice as likely to stunted as those were not. Children living in urban settlements showed a clear disadvantage with close to three times the likelihood of being wasted compared to those living in rural areas. There was a suggestion that maternal, but not paternal, education was associated with stunting, and maternal literacy was significantly associated with wasting. Whether children were ever breastfed, immunized or had diarrhoeal episodes in the past two weeks did not show strong correlations to children malnutrition status in this Roma population. CONCLUSIONS: There exists a gradient relationship between household wealth and stunting even within impoverished settlements, indicating that among poor and marginalized populations socioeconomic inequities in child health should be addressed. Other areas on which to focus future research and public health intervention include maternal literacy, child endangerment practices, and urban settlements. PMID- 20727213 TI - Comparative effects of selected non-caffeinated rehydration sports drinks on short-term performance following moderate dehydration. AB - BACKGROUND: The effect of moderate dehydration and consequent fluid replenishment on short-duration maximal treadmill performance was studied in eight healthy, fit (VO2max = 49.7 +/- 8.7 mL kg-1 min-1) males aged 28 +/- 7.5 yrs. METHODS: The study involved a within subject, blinded, crossover, placebo design. Initially, all subjects performed a baseline exercise test using an individualized treadmill protocol structured to induce exhaustion in 7 to 10 min. On each of the three subsequent testing days, the subjects exercised at 70-75% VO2max for 60 min at 29 33 degrees C, resulting in a dehydration weight loss of 1.8-2.1% body weight. After 60 min of rest and recovery at 22 C, subjects performed the same treadmill test to voluntary exhaustion, which resulted in a small reduction in VO2max and a decline in treadmill performance by 3% relative to the baseline results. Following another 60 min rest and recovery, subjects ingested the same amount of fluid lost in the form of one of three lemon-flavored, randomly assigned commercial drinks, namely Crystal Light (placebo control), Gatorade(R) and Rehydrate Electrolyte Replacement Drink, and then repeated the treadmill test to voluntary exhaustion. RESULTS: VO2max returned to baseline levels with Rehydrate, while there was only a slight improvement with Gatorade and Crystal Light. There were no changes in heart rate or ventilation with all three different replacement drinks. Relative to the dehydrated state, a 6.5% decrease in treadmill performance time occurred with Crystal Light, while replenishment with Gatorade, which contains fructose, glucose, sodium and potassium, resulted in a 2.1% decrease. In contrast, treatment with Rehydrate, which comprises fructose, glucose polymer, calcium, magnesium, sodium, potassium, amino acids, thiols and vitamins, resulted in a 7.3% increase in treadmill time relative to that of the dehydrated state. CONCLUSIONS: The results indicate that constituents other than water, simple transportable monosaccharides and sodium are important for maximal exercise performance and effective recovery associated with endurance exercise induced dehydration. PMID- 20727214 TI - Reduction in the proportion of fevers associated with Plasmodium falciparum parasitaemia in Africa: a systematic review. AB - BACKGROUND: Malaria is almost invariably ranked as the leading cause of morbidity and mortality in Africa. There is growing evidence of a decline in malaria transmission, morbidity and mortality over the last decades, especially so in East Africa. However, there is still doubt whether this decline is reflected in a reduction of the proportion of malaria among fevers. The objective of this systematic review was to estimate the change in the Proportion of Fevers associated with Plasmodium falciparum parasitaemia (PFPf) over the past 20 years in sub-Saharan Africa. METHODS: Search strategy. In December 2009, publications from the National Library of Medicine database were searched using the combination of 16 MeSH terms.Selection criteria. INCLUSION CRITERIA: studies 1) conducted in sub-Saharan Africa, 2) patients presenting with a syndrome of 'presumptive malaria', 3) numerators (number of parasitologically confirmed cases) and denominators (total number of presumptive malaria cases) available, 4) good quality microscopy.Data collection and analysis. The following variables were extracted: parasite presence/absence, total number of patients, age group, year, season, country and setting, clinical inclusion criteria. To assess the dynamic of PFPf over time, the median PFPf was compared between studies published in the years <=2000 and > 2000. RESULTS: 39 studies conducted between 1986 and 2007 in 16 different African countries were included in the final analysis. When comparing data up to year 2000 (24 studies) with those afterwards (15 studies), there was a clear reduction in the median PFPf from 44% (IQR 31-58%; range 7-81%) to 22% (IQR 13-33%; range 2-77%). This dramatic decline is likely to reflect a true change since stratified analyses including explanatory variables were performed and median PFPfs were always lower after 2000 compared to before. CONCLUSIONS: There was a considerable reduction of the proportion of malaria among fevers over time in Africa. This decline provides evidence for the policy change from presumptive anti-malarial treatment of all children with fever to laboratory diagnosis and treatment upon result. This should insure appropriate care of non-malaria fevers and rationale use of anti-malarials. PMID- 20727215 TI - Adherence to antidepressant therapy for major depressive patients in a psychiatric hospital in Thailand. AB - BACKGROUND: Poor adherence to antidepressant therapy is an important barrier to the effective management of major depressive disorder. This study aims to quantify the adherence rate to antidepressant treatment and to determine the pattern of prescriptions of depressed patients in a psychiatric institute in Thailand. METHODS: This retrospective study used electronic pharmacy data of outpatients aged 15 or older, with a new diagnosis of major depression who received at least one prescription of antidepressants between August 2005 and September 2008. The medication possession ratio (MPR) was used to measure adherence over a 6 month period. RESULTS: 1,058 were eligible for study inclusion. The overall adherence (MPR > 80%) in those attending this facility at least twice was 41% but if we assume that all patients who attended only once were non-adherent, adherence may be as low as 23%. Fluoxetine was the most commonly prescribed drug followed by TCAs. A large proportion of cases received more than one drug during one visit or was switched from one drug to another (39%). CONCLUSIONS: Adherence to antidepressant therapy for treatment of major depression in Thailand is rather low compared to results of adherence from elsewhere. PMID- 20727217 TI - Women's knowledge and attitudes regarding alcohol consumption in pregnancy: a national survey. AB - BACKGROUND: Alcohol exposure in pregnancy is a common and modifiable risk factor for poor pregnancy and child outcomes. Alcohol exposure in pregnancy can cause a range of physical and neurodevelopmental problems in the child including the Fetal Alcohol Spectrum Disorders (FASD). In order to improve prevention strategies, we sought to describe the knowledge and attitudes of women of childbearing age regarding alcohol consumption during pregnancy and its effects on the fetus. METHODS: We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations with participants' knowledge and attitudes. RESULTS: Of women surveyed, 61.5% had heard about effects of alcohol on the fetus and 55.3% had heard of Fetal Alcohol Syndrome. Although 92.7% agreed alcohol can affect the unborn child, 16.2% did not agree that the disabilities could be lifelong. Most women agreed that pregnant women should not drink alcohol (80.2%) and 79.2% reported having negative feelings towards pregnant women drinking alcohol. Women with higher education levels were more likely to know the effects of alcohol consumption in pregnancy (adjusted OR 5.62; 95% CI 3.20 to 9.87) but education level and knowledge were not associated with attitude. CONCLUSIONS: There was a disjunction between knowledge and attitudes towards alcohol consumption in pregnancy. These findings will assist in developing effective health promotion campaigns to reduce fetal alcohol exposure and subsequent fetal damage. PMID- 20727216 TI - Transcriptome responses to aluminum stress in roots of aspen (Populus tremula). AB - BACKGROUND: Ionic aluminum (mainly Al3+) is rhizotoxic and can be present in acid soils at concentrations high enough to inhibit root growth. Many forest tree species grow naturally in acid soils and often tolerate high concentrations of Al. Previously, we have shown that aspen (Populus tremula) releases citrate and oxalate from roots in response to Al exposure. To obtain further insights into the root responses of aspen to Al, we investigated root gene expression at Al conditions that inhibit root growth. RESULTS: Treatment of the aspen roots with 500 MUM Al induced a strong inhibition of root growth within 6 h of exposure time. The root growth subsequently recovered, reaching growth rates comparable to that of control plants. Changes in gene expression were determined after 6 h, 2 d, and 10 d of Al exposure. Replicated transcriptome analyses using the Affymetrix poplar genome array revealed a total of 175 significantly up-regulated and 69 down-regulated genes, of which 70% could be annotated based on Arabidopsis genome resources. Between 6 h and 2 d, the number of responsive genes strongly decreased from 202 to 26, and then the number of changes remained low. The responses after 6 h were characterized by genes involved in cell wall modification, ion transport, and oxidative stress. Two genes with prolonged induction were closely related to the Arabidopsis Al tolerance genes ALS3 (for Al sensitive 3) and MATE (for multidrug and toxin efflux protein, mediating citrate efflux). Patterns of expression in different plant organs and in response to Al indicated that the two aspen genes are homologs of the Arabidopsis ALS3 and MATE. CONCLUSION: Exposure of aspen roots to Al results in a rapid inhibition of root growth and a large change in root gene expression. The subsequent root growth recovery and the concomitant reduction in the number of responsive genes presumably reflect the success of the roots in activating Al tolerance mechanisms. The aspen genes ALS3 and MATE may be important components of these mechanisms. PMID- 20727218 TI - A haplotype inference algorithm for trios based on deterministic sampling. AB - BACKGROUND: In genome-wide association studies, thousands of individuals are genotyped in hundreds of thousands of single nucleotide polymorphisms (SNPs). Statistical power can be increased when haplotypes, rather than three-valued genotypes, are used in analysis, so the problem of haplotype phase inference (phasing) is particularly relevant. Several phasing algorithms have been developed for data from unrelated individuals, based on different models, some of which have been extended to father-mother-child "trio" data. RESULTS: We introduce a technique for phasing trio datasets using a tree-based deterministic sampling scheme. We have compared our method with publicly available algorithms PHASE v2.1, BEAGLE v3.0.2 and 2SNP v1.7 on datasets of varying number of markers and trios. We have found that the computational complexity of PHASE makes it prohibitive for routine use; on the other hand 2SNP, though the fastest method for small datasets, was significantly inaccurate. We have shown that our method outperforms BEAGLE in terms of speed and accuracy for small to intermediate dataset sizes in terms of number of trios for all marker sizes examined. Our method is implemented in the "Tree-Based Deterministic Sampling" (TDS) package, available for download at http://www.ee.columbia.edu/~anastas/tds CONCLUSIONS: Using a Tree-Based Deterministic sampling technique, we present an intuitive and conceptually simple phasing algorithm for trio data. The trade off between speed and accuracy achieved by our algorithm makes it a strong candidate for routine use on trio datasets. PMID- 20727219 TI - Reactive oxygen species are involved in regulating alpha1-adrenoceptor-activated vascular smooth muscle contraction. AB - BACKGROUND: Reactive oxygen species (ROS) were shown to mediate aberrant contractility in hypertension, yet the physiological roles of ROS in vascular smooth muscle contraction have remained elusive. This study aimed to examine whether ROS regulate alpha1-adrenoceptor-activated contraction by altering myosin phosphatase activities. METHODS: Using endothelium-denuded rat tail artery (RTA) strips, effects of anti-oxidants on isometric force, ROS production, phosphorylation of the 20-kDa myosin light chain (MLC20), and myosin phosphatase stimulated by alpha1-adrenoceptor agonist phenylephrine were examined. RESULTS: An antioxidant, N-acetyl-L-cysteine (NAC), and two NADPH oxidase inhibitors, apocynin and VAS2870, dose-dependently inhibited contraction activated by phenylephrine. Phenylephrine stimulated superoxide anion production that was diminished by the pretreatment of apocynin, VAS2870, superoxide scavenger tiron or mitochondria inhibitor rotenone, but not by xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. Concurrently, NADPH oxidase activity in RTA homogenates increased within 1 min upon phenylephrine stimulation, sustained for 10 min, and was abolished by the co-treatment with apocynin, but not allopurinol or rotenone. Phenylephrine-induced MLC20 phosphorylation was dose-dependently decreased by apocynin. Furthermore, apocynin inhibited phenylephrine-stimulated RhoA translocation to plasma membrane and phosphorylation of both myosin phosphatase regulatory subunit MYPT1Thr855 and myosin phosphatase inhibitor CPI-17Thr38. CONCLUSIONS: ROS, probably derived from NADPH oxidase and mitochondria, partially regulate alpha1-adrenoceptor-activated smooth muscle contraction by altering myosin phosphatase-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways. PMID- 20727220 TI - An investigation of breast cancer risk factors in Cyprus: a case control study. AB - BACKGROUND: Breast cancer is the most common form of malignancy affecting women worldwide. It is also the leading cancer in females in Cyprus, with approximately 400 new cases diagnosed annually. It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. The main aim of this study was to assess the strength of associations between recognized risk factors and breast cancer among Cypriot women. This is the first epidemiological investigation on risk factors of breast cancer among the Cypriot female population. METHODS: We carried out a case-control study, involving 1,109 breast cancer patients and a group of 1,177 controls who were recruited while participating in the National screening programme for breast cancer. Information on demographic characteristics and potential risk factors were collected from both groups during a standardized interview. Logistic regression analysis was used to assess the strength of the association between each risk factor and breast cancer risk, before and after adjusting for the possible confounding effect of other factors. RESULTS: In multivariable models, family history of breast cancer (OR 1.64, 95% CI 1.23, 2.19) was the strongest predictor of breast cancer risk in the Cypriot population. Late menarche (OR 0.64, 95% CI 0.45, 0.92 among women reaching menarche after the age of 15 vs. before the age of 12) and breastfeeding (OR 0.74, 95% CI 0.59, 0.92) exhibited a strong protective effect. In the case of breastfeeding, the observed effect appeared stronger than the effect of pregnancy alone. Surprisingly, we also observed an inverse association between hormone replacement therapy (HRT) although this may be a product of the retrospective nature of this study. CONCLUSION: Overall the findings of our study corroborate with the results of previous investigations on descriptive epidemiology of risk factors for breast cancer. This investigation provides important background information for designing detailed studies that aim to improve our understanding of the epidemiology of breast cancer in the Cypriot population, including the study of gene-environment interactions. Furthermore, our study provides the first scientific evidence for formulating targeted campaigns for prevention and early diagnosis of breast cancer in Cyprus. PMID- 20727221 TI - Adenoviruses with an alphavbeta integrin targeting moiety in the fiber shaft or the HI-loop increase tumor specificity without compromising antitumor efficacy in magnetic resonance imaging of colorectal cancer metastases. AB - BACKGROUND: Colorectal cancer is often a deadly disease and cannot be cured at metastatic stage. Oncolytic adenoviruses have been considered as a new therapeutic option for treatment of refractory disseminated cancers, including colorectal cancer. The safety data has been excellent but tumor transduction and antitumor efficacy especially in systemic administration needs to be improved. METHODS: Here, the utility of alphavbeta integrin targeting moiety Arg-Gly-Asp (RGD) in the Lys-Lys-Thr-Lys (KKTK) domain of the fiber shaft or in the HI-loop of adenovirus serotype 5 for increased tumor targeting and antitumor efficacy was evaluated. To this end, novel spleen-to-liver metastatic colorectal cancer mouse model was used and the antitumor efficacy was evaluated with magnetic resonance imaging (MRI). RESULTS: Both modifications (RGD in the HI-loop or in the fiber shaft) increased gene transfer efficacy in colorectal cancer cell lines and improved tumor-to-normal ratio in systemic administration of the vector. CONCLUSIONS: Antitumor potency was not compromised with RGD modified viruses suggesting increased safety profile and tumor specificity. PMID- 20727222 TI - Penetration of the sigmoid colon to the posterior uterine wall secondary to diverticulitis: a case report. AB - INTRODUCTION: Penetration of the colon to the posterior uterine wall secondary to diverticulitis is unusual, with diagnostic methods not yet established. Non invasive imaging, such as computed tomography and magnetic resonance imaging may help to establish a proper diagnosis, but confirmation may be reached only after surgical exploration. CASE PRESENTATION: We report the case of a 78-year-old Japanese woman who presented with a low grade fever and mild diarrhea which occurred two or three times a week. Computed tomography and magnetic resonance imaging demonstrated a capsular lesion including an air structure with a diameter of 5 cm, between the posterior aspect of the uterine body and the sigmoid colon. A gastrograffin enema and colonoscopy demonstrated a giant diverticulum of the sigmoid colon with no evidence of malignancy. These data confirmed the diagnosis of diverticulitis complicated by a giant diverticulum. Because of a relapsing fever after therapy with antibiotics, the patient had en bloc surgical treatment of the uterus, fallopian tubes, ovaries and sigmoid colon, the organs involved in the diverticulitis, followed by an uneventful recovery. CONCLUSION: This is a rare case report of penetration of the sigmoid colon to the posterior uterine wall secondary to diverticulitis. PMID- 20727223 TI - Does low angiopoietin-1 predict adverse outcome in sepsis? AB - Endothelial injury has emerged as a crucial early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multiorgan dysfunction syndrome. The endothelial-specific angiopoietin (Ang)/Tie2 ligand-receptor system has been identified recently as a nonredundant regulator of endothelial responsiveness. Ang-1 is a Tie2 agonist and promotes endothelial stabilization and quiescence, whereas Ang-2 is a Tie2 antagonist and promotes endothelial activation, destabilization, and inflammation. While the mediator function of both Ang-1 and Ang-2 has been well established in preclinical research, only Ang 2 has been identified as a clinically useful biomarker in the critical care arena. In the previous issue of Critical Care, Mankhambo and colleagues report on angiogenic factors in Malawian children with severe bacterial infection. Among those children, diminished levels of the vessel-protective factor Ang-1 remained a significant predictor of outcome after multivariate adjustment. Whether low Ang 1 represents an important risk factor of adverse outcome in critically ill adults remains to be seen. PMID- 20727225 TI - Corticosteroids for sepsis: registry versus Cochrane systematic review! AB - A recent report from the PROGRESS registry highlighted that low dose corticosteroids are widely used in patients with sepsis around the world. In this report, corticosteroids may be associated with increased morbidity and mortality. However, these findings should be viewed with caution given that this study has several inherent flaws because of its retrospective nature and the lack of controlled use of corticosteroids. In this commentary, these findings are contrasted with those of a recent Cochrane systematic review. PMID- 20727226 TI - To transfuse or not to transfuse: thinking outside the box. PMID- 20727227 TI - Bench to bedside: A role for erythropoietin in sepsis. AB - Sepsis is the systemic inflammatory response to infection and can result in multiple organ dysfunction syndrome with associated high mortality, morbidity and health costs. Erythropoietin is a well-established treatment for the anaemia of renal failure due to its anti-apoptotic effects on red blood cells and their precursors. The extra-haemopoietic actions of erythropoietin include vasopressor, anti-apoptotic, cytoprotective and immunomodulating actions, all of which could prove beneficial in sepsis. Attenuation of organ dysfunction has been shown in several animal models and its vasopressor effects have been well characterised in laboratory and clinical settings. Clinical trials of erythropoietin in single organ disorders have suggested promising cytoprotective effects, and while no randomised trials have been performed in patients with sepsis, good quality data exist from studies on anaemia in critically ill patients, giving useful information of its pharmacokinetics and potential for harm. An observational cohort study examining the microvascular effects of erythropoietin is underway and the evidence would support further phase II and III clinical trials examining this molecule as an adjunctive treatment in sepsis. PMID- 20727229 TI - The role of inflammation in ICU-acquired weakness. AB - A pilot observational study by Weber-Carstens and colleagues contributes to a mechanistic explanation of the puzzling and complex phenomena of ICU-acquired weakness (ICU-AW). The authors suggest systemic, inflammatory-mediated pathology is the most significant risk factor for ICU-AW. While this finding is somewhat equivocal, it provides important direction for future investigations and illustrates the challenges of interpreting significance in small observational studies. PMID- 20727228 TI - Concepts in hypoxia reborn. AB - The human fetus develops in a profoundly hypoxic environment. Thus, the foundations of our physiology are built in the most hypoxic conditions that we are ever likely to experience: the womb. This magnitude of exposure to hypoxia in utero is rarely experienced in adult life, with few exceptions, including severe pathophysiology in critical illness and environmental hypobaric hypoxia at high altitude. Indeed, the lowest recorded levels of arterial oxygen in adult humans are similar to those of a fetus and were recorded just below the highest attainable elevation on the Earth's surface: the summit of Mount Everest. We propose that the hypoxic intrauterine environment exerts a profound effect on human tolerance to hypoxia. Cellular mechanisms that facilitate fetal well-being may be amenable to manipulation in adults to promote survival advantage in severe hypoxemic stress. Many of these mechanisms act to modify the process of oxygen consumption rather than oxygen delivery in order to maintain adequate tissue oxygenation. The successful activation of such processes may provide a new chapter in the clinical management of hypoxemia. Thus, strategies employed to endure the relative hypoxia in utero may provide insights for the management of severe hypoxemia in adult life and ventures to high altitude may yield clues to the means by which to investigate those strategies. PMID- 20727230 TI - BRCA1: linking HOX to breast cancer suppression. AB - Homeobox (HOX) genes play key roles in embryogenesis and tissue differentiation. Recently, a number of groups have reported altered HOX gene expression in breast cancer. However, the mechanism of HOX gene regulation and the search for direct targets of its transcriptional regulatory function have been minimally fruitful. Recently, Gilbert and colleagues reported that HOXA9 restrains breast cancer progression by upregulation of BRCA1, a tumor suppressor. This finding raises our hope that more, rather elusive targets of HOX genes important in tumor progression or suppression will be found in the future. PMID- 20727231 TI - What's new on circulating tumor cells? A meeting report. AB - Circulating tumor cells (CTCs) provide unique information for the management of cancer patients. The 7th International Symposium on Minimal Residual Cancer has focused on state of the art research, including exciting advances in understanding the biology of metastasis, CTCs and tumor dormancy. Particular emphasis was placed on the relationship of CTCs to cancer stem cells (CSCs) and the relevance of most recent findings for the development of new targeted therapies. CTCs were evaluated as promising tumor biomarkers and the design and results of the first clinical trials to determine their clinical utility were discussed together with state of the art technology platforms for CTC imaging, detection, quantification and molecular characterization. A liquid biopsy approach that can be used for prognostic and predictive purposes was proposed for the analysis of CTCs. PMID- 20727233 TI - Alpha-2 adrenoceptor agonists and sepsis: improved survival? PMID- 20727232 TI - Bench-to-bedside review: Glucose and stress conditions in the intensive care unit. AB - The physiological response to blood glucose elevation is the pancreatic release of insulin, which blocks hepatic glucose production and release, and stimulates glucose uptake and storage in insulin-dependent tissues. When this first regulatory level is overwhelmed (that is, by exogenous glucose supplementation), persistent hyperglycaemia occurs with intricate consequences related to the glucose acting as a metabolic substrate and as an intracellular mediator. It is thus very important to unravel the glucose metabolic pathways that come into play during stress as well as the consequences of these on cellular functions. During acute injuries, activation of serial hormonal and humoral responses inducing hyperglycaemia is called the 'stress response'. Central activation of the nervous system and of the neuroendocrine axes is involved, releasing hormones that in most cases act to worsen the hyperglycaemia. These hormones in turn induce profound modifications of the inflammatory response, such as cytokine and mediator profiles. The hallmarks of stress-induced hyperglycaemia include 'insulin resistance' associated with an increase in hepatic glucose output and insufficient release of insulin with regard to glycaemia. Although both acute and chronic hyperglycaemia may induce deleterious effects on cells and organs, the initial acute endogenous hyperglycaemia appears to be adaptive. This acute hyperglycaemia participates in the maintenance of an adequate inflammatory response and consequently should not be treated aggressively. Hyperglycaemia induced by an exogenous glucose supply may, in turn, amplify the inflammatory response such that it becomes a disproportionate response. Since chronic exposure to glucose metabolites, as encountered in diabetes, induces adverse effects, the proper roles of these metabolites during acute conditions need further elucidation. PMID- 20727234 TI - Managing bone health in women with breast cancer under adjuvant treatment with aromatase inhibitors: pretreatment bone mineral density is important. PMID- 20727235 TI - Genomic imprinting in diabetes. AB - Genomic imprinting refers to a class of transmissible genetic effects in which the expression of the phenotype in the offspring depends on the parental origin of the transmitted allele. The DNA from one parent may be epigenetically modified so that only a single allele of the imprinted gene is expressed in the offspring. Although imprinting has an important role in the regulation of growth and development through its role in regulating gene expression, its contribution to susceptibility to common complex disorders is not well understood. We summarize current views on the role of imprinting in diabetes and in particular chromosome 6q24-related transient neonatal diabetes mellitus, the best known example of an imprinted genetic disorder that leads to diabetes. PMID- 20727236 TI - Reduction of common cold symptoms by encapsulated juice powder concentrate of fruits and vegetables: a randomised, double-blind, placebo-controlled trial. AB - Dietary supplements have been suggested in the prevention of the common cold, but previous investigations have been inconsistent. The present study was designed to determine the preventive effect of a dietary supplement from fruits and vegetables on common cold symptoms. In a randomised, double-blind, placebo controlled trial, healthcare professionals (mainly nursing staff aged 18-65 years) from a university hospital in Berlin, Germany, were randomised to four capsules of dietary supplement (Juice Plus+(r)) or matching placebo daily for 8 months, including a 2-month run-in period. The number of days with moderate or severe common cold symptoms within 6 months (primary outcome) was assessed by diary self-reports. We determined means and 95 % CI, and differences between the two groups were analysed by ANOVA. A total of 529 subjects were included into the primary analysis (Juice Plus+(r): 263, placebo: 266). The mean age of the participants was 39.9 (sd 10.3) years, and 80 % of the participants were female. The mean number of days with moderate or severe common cold symptoms was 7.6 (95 % CI 6.5, 8.8) in the Juice Plus+(r) group and 9.5 (8.4, 10.6) in the placebo group (P = 0.023). The mean number of total days with any common cold symptoms was similar in the Juice Plus+(r) and in the placebo groups (29.4 (25.8, 33.0) v. 30.7 (27.1, 34.3), P = 0.616). Intake of a dietary supplement from fruits and vegetables was associated with a 20 % reduction of moderate or severe common cold symptom days in healthcare professionals particularly exposed to patient contact. PMID- 20727237 TI - The effect of a fibre supplement compared to a healthy diet on body composition, lipids, glucose, insulin and other metabolic syndrome risk factors in overweight and obese individuals. AB - Optimum levels and types of dietary fibre that provide the greatest beneficial effects on metabolic syndrome risk factors in overweight and obese individuals have yet to be determined in clinical trials. The present parallel design study compared the effects of fibre intake from a healthy diet v. a fibre supplement (psyllium) or a healthy diet plus fibre supplement on fasting lipids, glucose, insulin and body composition. Overweight/obese adults were randomised to either control (with placebo), fibre supplement (FIB), healthy eating plus placebo (HLT) or healthy eating plus fibre supplement (HLT-FIB). There was a significant increase in fibre intake in HLT-FIB, HLT and FIB groups up to 59, 31 and 55 g, respectively, at 12 weeks when compared to control (20 g). Weight, BMI and % total body fat were significantly reduced in FIB and HLT-FIB groups, with weight and BMI significantly reduced in the HLT group compared with control at 12 weeks. HLT-FIB and HLT groups had significant reductions in TAG and insulin compared with control at 6 and 12 weeks, and in insulin compared with the FIB group at 12 weeks. The HLT-FIB, HLT and FIB groups all had significant reductions in total cholesterol and LDL-cholesterol compared with control after 6 and 12 weeks. The present study demonstrated that simply adding psyllium fibre supplementation to a normal diet was sufficient to obtain beneficial effects in risk factors. However, a high-fibre diet consisting of a psyllium supplement plus fibre from a healthy diet provided the greatest improvements in metabolic syndrome risk factors. PMID- 20727238 TI - Gold kiwifruit consumed with an iron-fortified breakfast cereal meal improves iron status in women with low iron stores: a 16-week randomised controlled trial. AB - Ascorbic acid, and more recently, the carotenoids lutein and zeaxanthin have been shown to enhance Fe absorption. However, it is not clear whether Fe status improves when foods high in ascorbic acid and carotenoids are consumed with Fe fortified meals. The present study aimed to investigate whether consuming high v. low ascorbic acid-, lutein- and zeaxanthin-rich fruit (gold kiwifruit v. banana) with Fe-fortified breakfast cereal and milk improved Fe status in women with low Fe stores. Healthy women aged 18-44 years (n 89) with low Fe stores (serum ferritin <= 25 MUg/l and Hb >= 115 g/l) were randomly stratified to receive Fe fortified breakfast cereal (16 mg Fe as ferrous sulfate), milk and either two gold kiwifruit or one banana (164 mg v. not detectable ascorbic acid; 526 v. 22.90 MUg lutein and zeaxanthin, respectively) at breakfast every day for 16 weeks. Biomarkers of Fe status and dietary intake were assessed at baseline and end in the final sample (n 69). Median serum ferritin increased significantly in the kiwifruit group (n 33) compared with the banana group (n 36), with 10.0 (25th, 75th percentiles 3.0, 17.5) v. 1.0 (25th, 75th percentiles - 2.8, 6.5) MUg/l (P < 0.001). Median soluble transferrin receptor concentrations decreased significantly in the kiwifruit group compared with the banana group, with - 0.5 (25th, 75th percentiles - 0.7, - 0.1) v. 0.0 (25th, 75th percentiles - 0.3, 0.4) mg/l (P = 0.001). Consumption of an Fe-fortified breakfast cereal with kiwifruit compared with banana improved Fe status. Addition of an ascorbic acid-, lutein- and zeaxanthin-rich fruit to a breakfast cereal fortified with ferrous sulfate is a feasible approach to improve Fe status in women with low Fe stores. PMID- 20727239 TI - Genomic and metabolomic patterns segregate with responses to calcium and vitamin D supplementation. AB - Inter-individual response differences to vitamin D and Ca supplementation may be under genetic control through vitamin D and oestrogen receptor genes, which may influence their absorption and/or metabolism. Metabolomic studies on blood and urine from subjects supplemented with Ca and vitamin D reveal different metabolic profiles that segregate with genotype. Genotyping was performed for oestrogen receptor 1 gene (ESR1) and vitamin D receptor gene (VDR) in fifty-six postmenopausal women. Thirty-six women were classified as low bone density as determined by a heel ultrasound scan and twenty women had normal bone density acting as 'controls'. Those with low bone density (LBD) were supplemented with oral Ca and vitamin D and were classified according to whether they were 'responders' or 'non-responders' according to biochemical results before and after therapy compared to controls receiving no supplementation. Metabolomic studies on serum and urine were done for the three groups at 0 and 3 months of therapy using NMR spectroscopy with pattern recognition. The 'non-responder' group showed a higher frequency of polymorphisms in the ESR1 (codons 10 and 325) and VDR (Bsm1 and Taq1), compared with to the 'responders'. The wild-type genotype for Fok1 was more frequent in those with LBD (70 %) compared with the control group (10 %). Distinctive patterns of metabolites were displayed by NMR studies at baseline and 3 months of post-treatment, segregating responders from non-responders and controls. Identification of potential 'non-responders' to vitamin D and Ca, before therapy, based on a genomic and/or metabolomic profile would allow targeted selection of optimal therapy on an individual basis. PMID- 20727240 TI - Supplemental beta-carotene increases IgA-secreting cells in mammary gland and IgA transfer from milk to neonatal mice. AB - Mortality of neonates continues to be a major problem in humans and animals. IgA provides protection against microbial antigens at mucosal surfaces. Although beta carotene supplementation has been expected to enhance retinoic acid-mediated immune response in neonates, the exact mechanism by which beta-carotene enhances IgA production is still unclear. We investigated the effect of supplemental beta carotene for maternal mice during pregnancy and lactation on IgA antibody secreting cells (ASC) in mammary gland and guts and on IgA transfer from milk to neonatal mice. Pregnant mice were fed untreated or 50 mg/kg beta-carotene supplemented diets from 6.5 d postcoitus (dpc) to 14 d postpartum (dpp). Supplemental beta-carotene increased the numbers of IgA ASC in mammary gland (P < 0.05) and ileum (P < 0.001), and also mRNA expression of IgA C-region in ileum (P < 0.05) of maternal mice at 14 dpp, but few IgA ASC were detected in mammary gland at 17.5 dpc. IgA concentration in stomach contents, which represents milk IgA level, was significantly higher (P < 0.01) in neonatal mice born to beta carotene-supplemented mothers at 7 and 14 dpp, and IgA concentration in serum, stomach contents and faeces increased (P < 0.001) drastically with age. These results suggest that beta-carotene supplementation for maternal mice during pregnancy and lactation is useful for enhancing IgA transfer from maternal milk to neonates owing to the increase in IgA ASC in mammary gland and ileum during lactation. PMID- 20727241 TI - Long-term histological examination of inferior concha after radiofrequency thermal ablation. AB - OBJECTIVE: To examine the histological effects of radiofrequency thermal ablation on the inferior concha epithelium and subepithelium, over five years post treatment. METHOD: Inferior nasal concha epithelial biopsy specimens were examined histologically before and four, 30, 48 and 60 months after radiofrequency treatment, in six patients with inferior nasal concha hypertrophy. RESULTS: At four months post-treatment, there was proliferation of blood vessels, increased inflammatory cells and a slightly decreased number of glands. At 30 months post-treatment, the number of inflammatory cells and glands had decreased, but signs of increased vascular proliferation, fibrosis and granulation were seen. At 48 and 60 months post-treatment, the number of inflammatory cells and blood vessels had decreased significantly, the number of glands had increased, and lobulation was observed. CONCLUSION: Radiofrequency thermal ablation does not cause carbonisation or osteitis in the inferior concha. The resultant fibrosis causes contraction of the concha and only minor tissue destruction (as shown by the persistence of submucosal glands). PMID- 20727242 TI - Third mobile window associated with suspected otosclerotic foci in two patients with an air-bone gap. AB - OBJECTIVE: To demonstrate the need for computed tomography imaging of the temporal bone in patients clinically suspected of otosclerosis who present with atypical symptoms or audiological findings. CASE REPORTS: We present two patients with bilateral conductive hearing loss and suspected otosclerosis in whom third mobile window lesions were revealed. The first patient had bilateral large vestibular aqueducts and bilateral fenestral otosclerotic foci. Computed tomography imaging of the second case revealed bilateral superior semicircular canal dehiscence and bilateral cochlear clefts, mimicking an otosclerotic focus in the fissula ante fenestram. CONCLUSION: Differentiating third mobile window lesions from otosclerosis as the cause of a conductive hearing loss is essential before considering stapes surgery, as such treatment would be unnecessary and potentially harmful. PMID- 20727243 TI - Testicular structure and spermatogenesis of Amazonian freshwater cururu stingray Potamotrygon cf. histrix. AB - The cururu stingray Potamotrygon cf. histrix, a new and endemic Amazonian freshwater species, presents appropriate characteristics for fish keeping and is exploited from its natural environment. The present study identified the testicular structure and spermatogenesis of this species. Gonads from adult male specimens were dissected, fixed and processed for histological analysis. The testes were of testicular/epigonial type. The presence of germinal papillae was observed in the upper portion of organ with primordial germ cells and Sertoli cell precursors. The testis was lobular with zonal organization and cystic gametogenesis, with the occurrence of spermatoblasts. The Sertoli cells underwent morphological modifications over the course of gamete formation. The spermatozoids had long heads and were spiraled on their own axis. Information on the reproductive biology will serve as basis for studies on the reproduction and phylogeny of this peculiar group of cartilaginous fish. PMID- 20727244 TI - A novel mutation (S227T) in domain II of the envelope gene of Japanese encephalitis virus circulating in North India. AB - Japanese encephalitis (JE) is an important arboviral infection of public health concern. There is a significant variation in mortality (10-30%) in JE viral infection. Epidemics of JE have become regular features in the northern states of India. The recent resurgence of the A226V mutation leading to a widespread Chikungunya epidemic motivated the investigators to search for any such mutational occurrence with Japanese encephalitis virus (JEV) isolated from this region. This study looked for mutation of clinical strains at amino-acid positions 176, 177, 227, 244, 264 and 279. A novel mutation S227T was detected corresponding to the loop region of domain II, E gene of JEV in comparison to Indian and other isolates from different parts of the world. Genotype III was found to be circulating in this geographical area. Further studies are required to ascertain its role in JE pathogenesis and vector competency. PMID- 20727245 TI - Capacitation status of activated bovine sperm cultured in media containing methyl beta-cyclodextrin affects the acrosome reaction and fertility. AB - Mammalian sperm undergo a series of biochemical transformations in the female reproductive tract that are collectively known as capacitation. One of the key processes involved in capacitation is the activation of sperm motility. Here, we investigated the capacitation and fertility status of activated sperm which had been cultured in media containing methyl-beta-cyclodextrin (MBCD). In order to do this, single activated sperm were caught using a micropipette and stained with chlortetracycline (CTC). Firstly, we investigated the effects of preincubation upon motility, capacitation of activated sperm and fertility. Culture in preincubation media supplemented with MBCD increased the rates of activation and fertilization compared with sperm cultured by control methods (p < 0.05). Following capture, individual activated sperm mostly exhibited a pattern characteristic of capacitation.Secondly we examined the effects of culturing sperm in media with or without glucose (G) and pyruvate acid (P) upon activated motility, the capacitation of activated sperm and fertility. Supplementation of culture media with G and P resulted in higher proportions of activated sperm and increased fertilization rates compared to culture without G and P (p < 0.05). Most of the sperm activated by culture in G and P exhibited patterns characteristic of capacitation. Without G and P, individual activated sperm mostly exhibited patterns characteristic of the acrosome reaction (p < 0.05). In conclusion, activated sperm exhibited patterns characteristic of capacitation. In addition, sperm activated in media containing an energy source (glucose and pyruvate acid) appeared to exhibit acrosome reactiveness and fertility. PMID- 20727246 TI - Methicillin-resistant Staphylococcus aureus infection in combat support hospitals in three regions of Iraq. AB - SUMMARYStaphylococcus aureus is a leading cause of infections in deployed service members. Based on a molecular epidemiological study of 182 MRSA isolates from patients in three U.S. Army combat support hospitals in separate regions in Iraq, USA300 clone was the most predominant (80%) pulsotype. This finding suggested that strain carriage from the home country by military personnel is epidemiologically more important than local acquisition. PMID- 20727247 TI - Freezing injuries in the embryos of Piaractus mesopotamicus. AB - Cryopreservation of mammal embryos has been technically feasible for many years, but morphological injuries still persist in fish embryos during cryopreservation. Thus, the objective of the present study was to describe these freezing injuries in Piaractus mesopotamicus embryos. Two hundred and twenty-five embryos were collected at the post-gastrula stage and assigned into four treatments of sucrose at 8.5, 17.0, 25.0 or 34.0% plus 9.0% methanol. The control was prepared with distilled water only. The gradual decrease in the temperature was 0.5 degrees C/min. After the seeding stage, the fish embryos were stored in liquid nitrogen at -33 degrees C. Thereafter, they were thawed for evaluating per cent hatching, and the samples collected from every treatment were submitted to scanning electron microscopy for morphological analysis. The micrographic images showed that there was substantial alterations in embryo morphology under the highest concentrations of sucrose. These solutions did not prevent the formation of ice crystals, which lead to deformities and killed the embryos, but the observed reduced level of morphological structure in these embryos when treated with 17.0% sucrose plus 9.0% methanol is a compelling argument for additional studies. PMID- 20727248 TI - Herpes zoster in Australia: evidence of increase in incidence in adults attributable to varicella immunization? AB - Rates of herpes zoster (HZ) hospitalizations, antiviral prescriptions, and New South Wales emergency-department presentations for age groups <20, 20-39, 40-59 and ?60 years were investigated. Trends were analysed using Poisson regression to determine if rates increased following funding of varicella immunization in Australia in November 2005. The regression analysis revealed significantly increasing trends of between 2% and 6% per year in both antiviral prescriptions and emergency-department presentations in all except the <20 years age group. When considered together, the differential changes in rates observed by age group provides preliminary evidence to indicate that HZ incidence is increasing in adults aged >20 years. However, it is not possible to attribute the increasing trends in HZ observed directly to the varicella immunization programme, and continued monitoring and analyses of data for a longer duration, both pre- and post-vaccine introduction, is required. PMID- 20727249 TI - Training the wider workforce in cognitive behavioural self-help: the SPIRIT (Structured Psychosocial InteRventions in Teams) training course. AB - BACKGROUND: The use of Cognitive Behavioural Therapy (CBT) self-help materials for depression is increasingly recommended as part of stepped care service models. Such resources can be delivered by both new specialist workers (such as the IAPT services in England), or by introducing this style of working into an existing workforce as described in the current paper. The Structured Psychosocial InteRventions in Teams (SPIRIT) course consists of 38.5 hours of workshops, and 5 hours of clinical supervision in the use of CBT self-help (CBSH). METHOD: This study describes an evaluation of the effectiveness of the course when offered to community and inpatient mental health staff from a wide range of adult and older adult mental health teams in NHS Greater Glasgow Mental Health Division. RESULTS: Training resulted in both subjective and objective knowledge and skills gains at the end of training that were largely sustained 3 months later. At that time point, 40% of staff still reported use of CBSH in the last week. Satisfaction with the training is high, using validated rating scales. CONCLUSIONS: The SPIRIT training has gone some way to increasing access to CBSH for use in everyday clinical practice. PMID- 20727250 TI - A recipe for disaster: outbreaks of campylobacteriosis associated with poultry liver pate in England and Wales. AB - Despite the frequency of Campylobacter as the principal cause of bacterial gastroenteritis in the UK, outbreaks attributed to this pathogen are rare. One hundred and fourteen general foodborne outbreaks of campylobacteriosis were reported to the Health Protection Agency from 1992 to 2009 with most occurring in food service establishments (64%, 73/114). Poultry meat (38%, 43/114) was the most commonly reported vehicle of infection, of which poultry liver pate, and undercooking, were strongly associated with this pathogen. Notably, the number of outbreaks of campylobacteriosis linked to consumption of poultry liver pate in England and Wales increased significantly from 2007 (74% as opposed to 12%, P<0.00001) with a preponderance of these occurring in December. These outbreaks highlight the hazards associated with inappropriate culinary practices leading to undercooking of poultry liver pate and suggest that improving catering practice is an important last line of defence in reducing exposure to Campylobacter contaminated products. PMID- 20727251 TI - Reproducibility of Doppler measures of ventricular function during maximal upright cycling. AB - Echocardiographic measures of ventricular function during exercise may prove useful in assessing myocardial health. This study examined test-retest reproducibility of measurements of Doppler mitral flow velocity (E-wave) and myocardial tissue Doppler imaging (E'-, S-waves) during a progressive maximal upright cycle test in 12 healthy lean adolescent males. Measurements were taken as subjects pedalled to exhaustion with 35 watt work increments in two separate trials. We observed no significant differences in mean values at rest, submaximal (70 watts) exercise, or maximal exercise for all three variables. Coefficients of variation at maximal exercise were 5.3%, 7.4%, and 8.1% for mitral E, tissue Doppler-S, and tissue Doppler-E', respectively. These findings indicated acceptable levels of reproducibility of Doppler ultrasound techniques for assessing ventricular systolic and diastolic functional response to maximal exercise in young lean male subjects. PMID- 20727253 TI - Bare below elbows: does this policy affect handwashing efficacy and reduce bacterial colonisation? AB - INTRODUCTION: UK Department of Health guidelines recommend that clinical staff are 'bare below the elbows'. There is a paucity of evidence to support this policy. One may hypothesise that absence of clothing around wrists facilitates more effective handwashing: this study aims to establish whether dress code affects bacterial colonisation before and after handwashing. SUBJECTS AND METHODS: Sixty-six clinical staff volunteered to take part in the study, noting whether they were bare below the elbows (BBE) or not bare (NB). Using a standardised technique, imprints of left and right fingers, palms, wrists and forearms were taken onto mini agar plates. Imprints were repeated after handwashing. After incubation, colonies per plate were counted, and subcultures taken. RESULTS: Thirty-eight staff were BBE and 28 were not. A total of 1112 plates were cultured. Before handwashing there was no significant difference in number of colonies between BBE and NB groups (Mann-Whitney, P < 0.05). Handwashing reduced the colony count, with greatest effect on fingers, palms and dominant wrists (t-test, P < 0.05). Comparing the two groups again after handwashing revealed no significant difference (Mann-Whitney, P < 0.05). Subcultures revealed predominantly skin flora. CONCLUSIONS: There was a large variation in number of colonies cultured. Handwashing resulted in a statistically significant reduction in colony count on fingers, palms and dominant wrist regardless of clothing. We conclude that handwashing produces a significant reduction in number of bacterial colonies on staff hands, and that clothing that is not BBE does not impede this reduction. PMID- 20727255 TI - [Toward a "tailored" era for basic research and clinical therapy of lung cancer-a report of the 12th World Conference on Lung Cancer.]. PMID- 20727252 TI - Cytochrome P450-2D6 extensive metabolizers are more vulnerable to methamphetamine associated neurocognitive impairment: preliminary findings. AB - While neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury. PMID- 20727254 TI - Recurrent laryngeal nerve and voice preservation: routine identification and appropriate assessment - two important steps in thyroid surgery. AB - INTRODUCTION: The aims of this study were to assess and compare vocal cord functions before and after thyroid surgery after intra-operative identification of recurrent laryngeal nerve. PATIENTS AND METHODS: Recurrent laryngeal nerve (RLN) is seen intra-operatively in all cases undergoing thyroid surgeries. Vocal cord functions including any voice change were evaluated by indirect laryngoscopy (I/L) and direct laryngoscopy (D/L) before and after surgery. RESULTS: Prospective study on 100 patients over 18 months with a total of 146 nerves at risk (NAR). Majority were women (n = 86) with mean age of 37.48 years (range, 13 60 years). RLN was seen in all patients and 19 patients complained of some change in quality of their voice after surgery. Evaluation by I/L and D/L at 6 weeks showed recurrent laryngeal nerve palsy (RLNP) in nine (47.36%) and five (26%) of these 19 patients respectively. Analysed according to total NAR, the incidence of voice change and temporary RLN palsy (I/L and D/L) at 6 weeks was still less at 13.01%, 6.16% and 3.42%, respectively. Voice change improved in all cases at 3 months with no RLNP palsy by I/L or D/L. All these 19 patients had undergone difficult or extensive surgery for malignancy, large gland, extratyhroidal spread or fibrosis. CONCLUSIONS: Despite identification and preservation of RLN, patients can develop postoperative voice change and RLNP although all voice change cannot be attributed to damaged RLN. Proper assessment of vocal cord functions by I/L and D/L laryngoscopy is required to rule out injuries to these nerves. Risk of damage is higher in patients undergoing more difficult surgery. PMID- 20727256 TI - [Advance of second-line chemotherapy in advanced non-small cell lung cancer.]. AB - There is a temporal disease-free period after 1st line chemotherapy in advanced non-small cell lung cancer (NSCLC), most of patients need 2nd line chemotherapy. The recommended drugs in the 2nd line were docetaxel, pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Single docetaxel is the established therapy for second-line treatment of NSCLC.Pemetexem was validated its indication in the 2nd line in advanced NSCLC through a phase III randomised clinical trial which was compared with docetaxel. Although there were little toxicity, the further research can't find the survival benefit in high dose pemetrexed. EGFR-TKIs target therapy is a hot spot now. Gefitinib and erlotinib monotherapy have a good efficacy in the 2nd line. The research of gefitinib versus traditional chemotherapy manifested that its efficacy was no less than docetaxel, and was less toxicitity . The comparison of erlotinib with chemotherapy is going on. There are more and more other drugs proved their effect in the 2nd line, such as the efficacy of oral toptecan and vinflunine were similar to docetaxel. PMID- 20727257 TI - [Progress of clinical research in "tailor" chemotherapy for non-small-cell lung cancer.]. AB - The both incidence and mortality of non-small-cell lung cancer (NSCLC) have been obviously increasing in recent years, the chemotherapy is still one of the best systemic treatment with response rates of 20%-40% by different regimens. We still need more logical and more accuracy to use the agents against NSCLC if we try to improve the efficacy. Biological markers for predicting the efficacy based on different molecular characteristic of NSCLC is important. With the development of molecular biology in past years, we have realized the different expression of ERCC1, RRM1, Beta-tubulin, BRCA1 and Thymidylate synthetase(TS) may be related to the efficacy of different chemotherapeutic agents and prognosis in NSCLC. So it is possible for predicting results of chemotherapeutic agents with those different markers, "tailor" chemotherapy. This article is a clinical review in the fields. PMID- 20727258 TI - [Advances of maintenance chemotherapy on advanced non-small cell lung cancer.]. PMID- 20727259 TI - [Advances of imaging diagnostics for lung cancer.]. PMID- 20727260 TI - [Molecular diagnostics and molecular prognosis in lung cancer.]. PMID- 20727261 TI - [Advances on epidemiology of lung cancer and tobacco control.]. PMID- 20727262 TI - [Approaches on genetics and molecular biology of lung cancer - a review on the 12th World Conference on Lung Cancer.]. PMID- 20727263 TI - [Molecular diagnostics and molecular staging of lung cancer.]. PMID- 20727264 TI - [Advances on lung cancer metastasis.]. PMID- 20727265 TI - [Progress in research on lung cancer vaccine.]. PMID- 20727266 TI - [Construction of FasL siRNA expression vector and its expression in lung cancer cell line A549.]. AB - BACKGROUND: Fas/FasL is a member of Tumor Necrosis Factor (TNF) super family, and related to tumor cell apoptosis. It is hypothesis by forward study that activated lymphocytes is more sensitive with Fas/FasL due to up-regulation of FasL expression, so it can be inverse killedly and cleared by tumor cell. The aim of this investigate is to study the fuction of FasL gene and gene therapy of lung cancer by to down-regulationg the FasL gene expression with a siRNA expression plasmid in lung cancer cell A549 as well as its inverse killing effect between activated T lymphocytes and lung cancer cell A549. METHODS: Potential RNAi oligonucleotides of FasL was designed and synthesized according to appropriate web site. Then a FasL siRNA plasmid was constructed using a pGCsi-U6 vector.The plasmid was sequenced to confirm the inserted sequence. Western blot analysis was used to assess the levels of FasL proteins after the constructed plasmids have been transfected into A549 cells. RESULTS: It was confirmed by sequencing that the plasmid was constructed successfully. The result of Western blot clearly showed that FasL siRNA plasmid inhibited FasL expression in A549 cells. CONCLUSIONS: The construct of FasL siRNA plasmid is successful. FasL protein expression of A549 cell is effectively inhibited by RNAi . PMID- 20727267 TI - [The morphous analyses of three different characteristics cells growing in soft agar.]. AB - BACKGROUND: Soft agar assay was usually used in colony formation observation of cells, while it was also be empolyed in detecting bionomics of inferior creature. In this article the feasibility of soft agar assay in detecting mammalian cell phenotype is investigated. METHODS: Three different characteristic cells(L cell NIH3T3;higher metastatic human lung adenocarcinoma cell line Anip973;higher invasive potential human lung adenocarcinoma cell line L18) were seed into soft agar. The morphology of cells was obserned in the first day, the fifth day and the fourteenth day,respectively. RESULTS: In the fifth day, morphology of the three kinds cells appeared difference and in the fourteenth day the difference became more notable. NIH3T3 cell clones were ellipse and moderate size, their boundary were distinct; Anip973 cell clones were surrounded with plenty of migratory cells, which was consistent with higher metastatic characteristics of the cells. L18 cell clones showed lots of branchs and extended toward environment. CONCLUSIONS: Soft agar assay is a good method in evaluating and observed biological property of mammalian cells according to their phenotypes. PMID- 20727268 TI - [Establishment and biological characteristics of a multi-drug resistant cell line A549/Gem.]. AB - BACKGROUND: Multi-drug resistance is one of the most important reason why the survival time of non-small cell lung cancer patients is so short. The aim of this study is to establish multi-drug resistant cell line A549/Gem and discuss its biological characters so as to elaborate the possible mechanisms of gemcitabine resistance. METHODS: Human gemcitabine-resistant non-small cell lung cancer cell line A549/Gem was established by repeated clinical serous peak concentration then low but gradually increasing concentration of gemcitabine from its parental cell human lung adenocarcinoma cell line A549 which is sensitive to gemcitabine. During the course of inducement, monitored its morphology, checked its resistance index and resistant pedigree by MTT method, gathered its growth curve and calculated its doubling time, examined its DNA contents and cell cycles by flow cytometry; at the same time, measured its expression of P53, EGFR, c-erb-B-2, PTEN, PCNA, c-myc, VEGF, MDR-1, Bcl-2, nm23, MMP-9, TIMP-1, CD44v6 Proteins, and RRM1 mRNA. RESULTS: The resistance index of A549/Gem' to gemcitabine was 163.228, and the cell line also exhibited cross-resistance to vinorelbine, taxotere, fluorouraci, etoposide and cisplatin, but kept sensitivity to paclitaxol and oxaliplatin. The doubling time of it was shorter and figures in G0-G1 phase were increased than A549. Compared with A549, A549/Gem' achieved EGFR and c-myc protein expression, nm23 protein expression enhanced, p53, Cerb-B-2 and bcl-2 protein expression reduced, PTEN, PCNA and MDR-1 protein expression vanished, but that of MMP-9, VEGF, CD44v6 and TIMP-1 protein changed trivially. Meanwhile, the expression of RRM1 mRNA was augmented markedly. The resistance index of A549/Gem to gemcitabine was 129.783, and the cell line also held cross-resistance to vinorelbine, taxotere, etoposide, cisplatin and sensitivity to paclitaxol. But the resistance to fluorouracil and sensitivity to oxaliplatin vanished. And the expression of RRM1 mRNA decreased visibly. The doubling time of A549/Gem was longer and figures in G0-G1 phase were decreased than A549/Gem'. It's expressions of P53, EGFR, PCNA and MDR-1 protein was same to that of A549/Gem'. A549/Gem achieved TIMP-1 and PTEN protein expression, Cerb-B-2, MMP-9, cmyc and bcl-2 protein expression enhanced, nm23 protein expression vanished, but the expression of VEGF and CD44v6 protein changed trivially. Furthermore, Compared with its parental cell, A549/Gem was mixed with giant cells of different sizes that were larger and more irregular. CONCLUSIONS: The multi-drug resistant non-small cell lung cancer cell line A549/Gem has multi-drug resistance and great change of biological character compared with its parental cell. And the change can participate in the formation of multidrug resistance. PMID- 20727269 TI - [Expressions of Frat and beta-catenin in lung cancer and their clinicopathological correlations.]. AB - BACKGROUND: Frat proteins are positive regulator of Wnt-signal transduction.By binding to GSK3,Frat prevents the phosphorylation and concomitant degradation of beta-catenin and allows the activation of downstream targetgenes by beta catenin/TCF complexes. The aim of this study is to investigate the protein expression of Frat and beta-catenin and their clinicopathological correlations in lung cancer. METHODS: By means of tissue chip technique and immunohistochemical method, 52 cases of lung carcinoma were examed to detect the expression of Frat and beta-catenin. RESULTS: The positive expression rate of Frat was 75% . The positive expression rate of Frat in well,moderately and poorly differentiated NSCLCs were 41.67%(5/12), 83.33%(15/18) and 88.24%(15/17). There was a significant difference in Frat expression among well,moderately and poorly differentiated NSCLCs (Chi-Square=9.229, P=0.01). The abnormal cell expression rate of beta-catenin was 71.15%. The abnormal cell expression rate of beta catenin in well,moderately and poorly differentiated NSCLCs were 41.67%(5/12), 61.11%(11/18) and 100%(17/17). There was a significant difference (Chi Square=12.601, P=0.002). CONCLUSIONS: The abnormal cell expression of beta catenin is associated with pooly differentiated NSCLCs. The expression of Frat is positively correlated with the degree of tumor differentiation and the abnormal cell expression of beta-catenin. PMID- 20727270 TI - [Expression of ezrin in human lung carcinoma and its clinicopathologic significance.]. AB - BACKGROUND: Metastasis is the main cause of cancer related mortality, and identification of genes involved in tumor metastasis is important for effective therapies. The membrane cytoskeletal crosslinker participated in several functions including cell adhersion, motility and cell survival, and there is increasing evidence that it regulates tumor progression. However, the role played by ezrin in lung cancer metastasis has not been clearly delineated. The aims of this study are to investigate the ezrin expression pattern in human lung carcinoma and the correlation with clinicopathologic characteristics. METHODS: Ezrin expression was detected by two- step immunohistochemical staining technique in tumor tissues from 75 lung cancer cases and in normal lung tissues from 16 cases with benign disease and analyzed by the lung cancer clinicopathologic characteristics. The gene and protein level expression of Ezrin in lung cancer cell lines was also detected by Confocal Laser Scanning Microscope (CLSM) and RT PCR. RESULTS: The positive incidence of ezrin expression (77.3%) was significantly lower in lung cancer tissues than that in normal tissues (100%) (P<0.05), and the down-regulated of ezrin expression was significantly correlated with lymph node metastasis and distant metastasis (P<0.05) and was not correlated with gender, age, tumor size, pathological type, the degree of differentiation of tissue and clinical stage. Otherwise, the subcellular redistribution of ezrin from cell membrane to cell plasma was significantly correlated with lymph node metastasis (P< 0.05), in consistance with in vitro experimental result. High metastasis cell line BE1 had the lowest expression of ezrin under CLSM, similar to RT-PCR, and ezrin was mainly located in cell plasma under CLSM. CONCLUSIONS: Ezrin expression is down-regulated in lung cancer tissue and lung cancer cell line, and the locational change from cell membrane to cell plasma may be associated with the oncogenesis and development of lung cancer. PMID- 20727271 TI - [Correlation between the quantifiable parameters of blood flow pattern derived with dynamic CT in maliagnant solitary pulmonary nodules and tumor size.]. AB - BACKGROUND: The solitary pulmonary nodules (SPNs ) is one of the most common findings on chest radiographs. It becomes possible to provide more accurately quantitative information about blood flow patterns of solitary pulmonary nodules (SPNs ) with multi-slice spiral computed tomography (MSCT). The aim of this study is to evaluate the correlation between the quantifiable parameters of blood flow pattern derived with dynamic CT in maliagnant solitary pulmonary nodules and tumor size. METHODS: 68 patients with maliagnant solitary pulmonary nodules (SPNs ) (diameter <=4 cm)underwent multi-location dynamic contrast material-enhanced (nonionic contrast material was administrated via the antecubital vein at a rate of 4mL/s by an autoinjector, 4*5mm or 4*2.5mm scanning mode with stable table were performed.) serial CT. Precontrast and postcontrast attenuation on every scan was recorded. Perfusion (PSPN), peak height (PHSPN), ratio of peak height of the SPN to that of the aorta (SPN-to-A ratio)and mean transit time(MTT) were calculated. The correlation between the quantifiable parameters of blood flow pattern derived with dynamic CT in maliagnant solitary pulmonary nodules and tumor size were assessed by means of linear regression analysis. RESULTS: No significant correlations were found between the tumor size and each of the peak height (PHSPN), ratio of peak height of the SPN to that of the aorta (SPN-to-A ratio), perfusion (PSPN)and mean transit time(r=0.18,P=0.14; r=0.20,P=0.09; r=0.01, P=0.95; r=0.01, P=0.93). CONCLUSIONS: No significant correlation is found between the tumor size and each of the quantifiable parameters of blood flow pattern derived with dynamic CT in maliagnant solitary pulmonary nodules. PMID- 20727272 TI - [Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin in the treatment of stage III non-small cell lung cancer.]. AB - BACKGROUND: Concurrent chemoradiotherapy is regarded as the standard care for locally advanced non-small cell lung cancer at present. This paper is designed to evaluate the efficacy and toxicity of low-dose weekly docetaxel (DTX) with concurrent chemoradiotherapy followed by consolidation chemotherapy with DTX and cisplatin for unresectable stage III non-small cell lung cancer(NSCLC). METHODS: 44 previously untreated patients with stage III NSCLC were randomized into low dose weekly DTX group and control group concomitant with radiotherapy. Both groups were treated by the standard fractionation schedule with three-dimensional conformal radiotherapy. An involved-field irradiation technique was performed. Gross tumor and metastatic lymph nodes were irradiated to a total dose of 66 Gy 70 Gy. Patients in the former group received chemotherapy with DTX 20 mg.m(-2).w( 1), and the other group patients received DTX 60 mg/m(2) on day 1 and DDP 30 mg/m(2) on day 1-3 every 21 days. All patients received consolidation chemotherapy with DP regime after chemoradiotherapy for no more than 4 cycles. RESULTS: The overall response rates of patients in the low-dose weekly DTX group and control group were 81.8% with 27.3% CR(complete response) and 86.4% with 27.3% CR respectively (Chi-Square=0.120, P=0.942). After a median follow-up of 20 months, the median survival time was 20 months and 17 months respectively. The 1 , 2- year survival rates of patients in low-dose weekly DTX group and control group were 69.8%, 48.1% versus 66.5%, 40.2% respectively;there was no difference between two groups. Grade 3 or 4 neutropenia and esophagitis occurred in 26.3%, 14.3% and 15.8%, 28.6% respectively (Chi-Square=0.765, P=0.382;Chi-Square=1.108, P=0.292).Grade 3 and 4 pulmonary toxicity was unusual. CONCLUSIONS: Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin is highly active with manageable toxicity in patients with stage III NSCLC. PMID- 20727273 TI - [Expression of RhoE in lung and breast cancer and its clinical significance.]. AB - BACKGROUND: Rho family is closely related with the growth , differentiation and metastasis of tumer cells. The objective of this work is to investigate the expression of RhoE in lung and breast carcinoma and their corresponding adjacent tissues, as well as its relationship between the expression and clinical pathological grades. The results of this study provide evidences for exploring the biological functions and clinical significance of RhoE. METHODS: The expression of RhoE was detected by immunohistochemistry in 62 lung carcinoma samples and 34 breast carcinoma samples, and their corresponding adjacent tissues were taken as control. RESULTS: RhoE was generally expressed in normal tissues, but the expression level of RhoE in carcerous tissues was decreased or absent. The stained value of breast carcinoma was 3.65+/-0.62, but the adjacent cancerous tissues was 10.53+/-0.44, significantly higher than that of the adjacent cancerous tissues (t=12.402, P<0.001). While the stained value of lung carcinoma was 2.19+/-0.19, lower than that of the adjacent cancerous tissues (4.11+/-0.24, t =7.123, P<0.005). Moreover, there is a declining tendency of the stained value as the poor differentiation of the carcinoma (Chi-Square=26.536, P<0.005). CONCLUSIONS: The expression of RhoE in carcerous tissues was remarkbaly decreased. Considering the recent research achievement and our early experimental results about RhoE, we inferred that RhoE may play a negative role in the development and progression of lung and breast carcinoma. So further research on RhoE would provide a new target for the molecular targeting therapy of cancer. PMID- 20727274 TI - [Expression and clinical significance of caspase-3,survivin and k-ras in non small cell lung cancer.]. AB - BACKGROUND: The prognosis of non-small cell lung cancer (NSCLC) is related to many factors. Apoptosis-related genes play an important role in occurrence and development of tumors. The significance of apoptosis as a biological and prognostic factor has not been clearly established in NSCLC. The aim of the study is to evaluate the relationship between expression of caspase-3,survivin,k-ras protein and the relationship between the expression of above proteins in NSCLC and theirs clinicopathological characteristics and prognostic significance and their potential relevance existing in NSCLC. METHODS: Caspase-3,survivin,k-ras protein expression were detected in NSCLC tissues and normal lung tissues adjacent to carcinomas Archival formalin fixed, paraffin embedded specimens from 91 patients who had undergone radical surgery by streptavidin-peroxidase immunohisto-chemistry. RESULTS: The positive rate of caspase-3 was significantly lower in NSCLC than in normal lung tissues adjacent to carcinomas; The positive rate of survivin,k-ras was significantly higher in NSCLC than in normal lung tissues adjacent to carcinomas (P<0.05). The positive rate of caspase-3 was related to the age,histological type, TNM stage,lymph node metastasia and differentiation (P<0.05), but not related to tumor size,smoke(P>0.05); the positive rate of survivin was related to the age,TNM stage,lymph node metastasia and differentiation (P<0.05), but not related to histologic type,tumor size,smoke(P>0.05); the positive rate of k-ras was related to the histologic type and smoke(P<0.05), but not related the age,TNM stage,lymph node metastasia,differentiation,tumor size(P>0.05). Expression of caspase-3 was negatively correlated with survivin (r=-0.662, P<0.001). The multivariate analysis kwith Cox hazard model, survivin,caspase-3,histologic type,differentiation,TNM stage could be indicators for the prognosis of patients with NSCLC (P<0.05). CONCLUSIONS: There are over-expressions of survivin,k-ras protein in NSCLC and both are significantly higher than those in the normal tissue. However, caspase-3 presents the reverse result; Higher expression of survivin,lower expression of caspase-3 might be the adverse prognostic index for survival in resected NSCLC patients, which indicate they might act synergistically in apoptosis of NSCLC; the relationship between the expression of k-ras and the prognosis of NSCLC is still not clear. PMID- 20727275 TI - [The value of serum tumor marker CA125 and CEA in the diagonosis of non-small cell lung cancer.]. AB - BACKGROUND: Tumor marker cancer antigen 125(CA125) and carcinoembryonic antigen (CEA) all are the tumor markers found early. It was reported that the positive rate of CEA was highly in adenocarcinoma, after being analyzed all the case reports of non-small cell lung cancer (NSCLC) in recent 3 years, it was found that positive rate of CA125 was much higher in NSCLC than that of literatures. So, it's necessary to evaluate the value of serum CA125 and CEA measurement for NSCLC. METHODS: The level of CA125 and CEA were detected with chemiluminescence in 136 NSCLC patients, 42 patients with respiratory diseases and 50 cases of normal control. RESULTS: The levels of serum CA125 in NSCLC patients were significantly higher than that of patients with respiratory diseases and normal control (except mixed cell lung cancer) (P<0.0001). The levels of serum CEA in adenocarcinoma and squamous patients were significantly higher than that of patients with respiratory diseases and normal control(P<0.0001). No difference between patients with respiratory diseases and normal control. The positive rates of CA125 were 92.3% in large-cell lung cancers, 80.2% in adenocarcinoma, 54.8% in squamous cancer, 50% in mixed cell lung cancer, respectively. The positive rates of CEA were 67.4% in large-cell lung cancers, 25.8% in squamous cancer, 0 in adenocarcinoma and mixed cell lung cancer, respectively. Combined measurement of CA125 and CEA positive rates was higher only in adenocarcinoma. The positive rates of CA125 and CEA were 86.9%and 63.6% in advanced NSCLC, respectively. The positive rates of CA125 were 90.9% in advanced adenocarcinoma. CONCLUSIONS: The positive rates of CA125 is higher than that of CEA in NSCLC patients, especially in large-cell lung cancers and advanced adenocarcinoma. CA125 is more useful than CEA in diagnosis of NSCLC. PMID- 20727276 TI - [Analysis of prognostic factors in 352 lung cancer patients with brain metastases.]. AB - BACKGROUND: Lung cancer has become one of the most common malignant tumors in China. The prognosis of lung cancer is poor mainly because of relapse and distant metastases and brain metastasis occurs frequently. This study attempts to evaluate the prognostic factors in lung cancer patients with brain metastases. The information in the study may be useful for the clinicians to make some decisions. METHODS: The clinical data of 352 lung cancer patients with brain metastases in our hospital from the year of 1997 to 2005 were retrospectively reviewed. The multivariate analysis was performed with Cox's proportion risk model. Survival analysis was compared with Kaplan-Meier method and log-rank test was used respectively. Statistical significance was defined as P<0.05. RESULTS: The univariate analysis showed that patients' performance status (PS score), age, the number of brain metastases, the absence or presence of extracranial metastases and metastatic symptoms, multimodality treatments were related to survival period(P<0.05). The multivariate analysis indicated that patients' performance status (PS score), age and the number of brain metastases were closely related to their prognosis (P<0.05). CONCLUSIONS: Performance status(PS score), age and the number of brain metastases are the independent prognostic factors in lung cancer with brain metastases. The patients with PS score 0-1, age<=60 years and single brain metastasis have longer survival and they can benefit from treatments. PMID- 20727277 TI - [Preliminary investigation on expression of Bmi-1 in non-small-cellular lung cancer.]. AB - BACKGROUND: B-cell-specific Moloney leukemia virus insertion site 1 (Bmi-1) gene, which plays a critical role in directional differentiation and proliferation of cells, is significant in malignant transformation of cells. The aim of this study is to investigate the levels of Bmi-1 in non-small-cell lung cancer (NSCLC), and to preliminarily analyze the correlation between Bmi-1 and the development of NSCLC tissue. METHODS: The expression of Bmi-1 was detected in 25 NSCLC tissues as well as in the normal paracancerous lung tissues by immunofluorescence technique and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Immunofluorescently, the positive expression of Bmi-1 proteins was revealed in nucleus of tumor cells in 76%(19 /25) of NSCLC tissue but not in paracancerous lung tissues. RT-PCR results showed that the expression of Bmi-1 in lung cancer tissues was significantly higher than that in paracancerous lung tissues (P<0.05). CONCLUSIONS: Bmi-1 is over expressed in NSCLC and may be associated with the oncogenesis and development of lung cancer. PMID- 20727278 TI - [A randomized study of docetaxel plus cisplatin versus paclitaxel plus cisplatin in previously untreated advanced non-small cell lung cancer.]. AB - BACKGROUND: Docetaxel is an active agent in the second-line treatment for non small cell lung cancer (NSCLC), many clinical trials have demonstrated that it has similar efficacy to common first-line regimens for NSCLC. A randomized study was conducted to compare docetaxel plus cisplatin (DC) versus paclitaxel plus cisplatin (PC) for patients with advanced non-small cell lung cancer as the first line regimen. METHODS: Ninety patients with previously untreated advanced non small cell lung cancer were randomly assigned to receive either DC or PC. Patients received docetaxel 75mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in DC group and paclitaxel 150mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in PC group. The cycle of two regimens was repeated every 3 weeks. Response and toxicity were evaluated in patients who completed two cycles of chemotherapy at least. RESULTS: Overall survival rate was 31.1% in DC group and 33.3 % in PC group. The median survival time was 10.2 months in DC group and 10.4 months in PC group. Median time to tumor progression was 4.4 months in DC group and 4.9 months in PC group. 1- and 2 year survival rate were 35.6% and 8.9% in DC group and 37.8% and 11.1% in PC group respectively. There were no significant differences in response rate, median survival time, median time to tumor progression and survival rate between two groups (P >0.05). Leucopenia, anemia, nausea and vomiting, and alopecia were the most common grade III and IV toxicities in DC and PC groups, there were no significant differences in grade III and IV toxicities between two groups(P >0.05). There were no treatment-related deaths in both groups. CONCLUSIONS: DC has similar response rate and survivals with PC, and its toxicity is well tolerated. Docetaxel plus cisplatin is an effective first-line treatment of non small cell lung cancer. PMID- 20727279 TI - [The expression and significance of indoleamine -2,3 -dioxygenase in non-small cell lung cancer cell.]. AB - BACKGROUND: Immune tolerance plays the key role in the initiation,development and metastasis of the malignant disease.However,the underlging mechanisms have not been completely elucidated. The aim of this study is to investigate the expression of indoleamine-2,3-dioxygenase(IDO) in non-small cell lung cancer(NSCLC) and the distribution of regulatory T cell(Treg) in NSCLC tissue and the metastastic lymph node, and the possible relationships between them. METHODS: This study involved 62 NSCLC patients and 15 control patients with benign diseases that operated in the affiliated Xinqiao hospital and Southwest hospital of the Third Military Medical University. The expression of IDO in lung cancer cell, the corresponding normal lung tissues and the benign control tissues were detected by SP immunohistochemistry(IHC) and Fluorescent semi-quantitative RT PCR. The distribution of Treg cell was detected by SP IHC too. The difference of positive rates of IDO was evaluated by Chi-square test and Fisher's exact test. RESULTS: The positive expression rates of IDO in lung cancer cells corresponding normal lung tissues and bengin disease tissues were 67.7% (42/62), 0 and 13.3% (2/15), respectively. There were significant differences between the former and the latter two (P <0.01). The positive expression rate of IDO in metastastic lymph node was 75.0%(15/20).The results of Fluorescent semi-quantitative RT-PCR were consistent with the IHC. The positive rates of Treg cells in lung cancer tissues, metastastic lymph nodes, corresponding normal lung tissues and bengin disease tissues were 83.9%(52/62), 90.0%(18/20), 0 and 13.3%(2/15), respectively. Significant difference was also found between the former two and the latter two (P<0.01), but there was no significant differences between the two formers or the two latters (P >0.05). There was significant difference between the positive rate of IDO expression and the distribution of Treg cell(P < 0.01). CONCLUSIONS: IDO expression is up-regulated in NSCLC cell and metastastic lymph nodes. Treg cell is positive in lung cancer tissues and metastastic lymph node. These results have importment implication that the IDO(+) cancer cell might be concerned with the tumor immune tolerance by inducing the proliferation of Treg cells. PMID- 20727280 TI - [Effects of MVP regimen on operation and cancer tisswes of Lung Cancer patients.]. AB - BACKGROUND: Preoperative chemotherapy increases the difficulty and risk of patients' operation. The aim of this study is to analyze the change of thoracic tissue, study the influence of chemotherapy to operation, discuss the special aspects of surgical management and observe the pathological change of focus after chemotherapy. METHODS: 100 patients were chosen and randomly divided into two groups(operation first group, 50 cases; chemotherapy first group, 50 cases) . Some patient's pathological sections were observed to investigate focus morphological influence of preoperative chemotherapy and the clinical response rate were compared with pathological response rate. RESULTS: It was showed that preoperative chemotherapy conduced different degree thoracic tissue fibrosis. Data statistics demonstrated that there were no significance difference of the operation time, blood loss during operation and drainage volume in first day after operation between two groups. The preoperative chemotherapy increased the difficulty of operation because of tissue fibrosis and scarification, but the risk could be avoided by skillful operation. In first operation group, there were various pathological changes in tumor tissue and the pathological response rate was not completely accordance with the clinical response rate. The focus pathological response rate of two cycles chemotherapy was more higher than that of one cycle chemotherapy. CONCLUSIONS: IDO Chemotherapy increases the risks of operation. Surgeons carefulness and better skills during operation are the key points to avoid the hazards of surgery. Two preoperative chemotherapy cycles are more suitable for the patients. PMID- 20727281 TI - [Expression of ER and AR in lung cancer.]. AB - BACKGROUND: Epidemiology of lung cancer differs between sexes and it might be partially explained by different sex hormone levels in women and men. There are some epidemiological data indicating that gender is a significant, independent prognostic factor in lung cancer. The aim of this study is to determine expression of ER (estrogen receptor) and AR (androgen receptor) in lung cancer, and evaluate the relationship between their expression and clinical or pathologic characteristics. METHODS: Immunohistochemistry assay was used to detect expression of ER and AR. RESULTS: Positive expression of ER and AR were 14.3%(15/105) and 20%(21/105). Positive expression of ER had no relationship with age, gender, pathology, histological differentiation, TNM staging, size of tumor and lymph node metastasis. Although age, gender, pathology, histological differentiation and size of tumor had no effect on the expression of AR, positive rate of AR in staging III lung cancer was significantly higher than that in staging I lung cancer. The different AR expression was significant between N0 and N2 lymph node metastasis (Chi-Square= 4.7828, P=0.0287). CONCLUSIONS: The expression of ER has no relationship with biological behavior. Positive expression of AR may be correlated with the progression and the lymph node metastasis of lung cancer. PMID- 20727282 TI - [The relationship between genetic polymorphism of GSTM1 and the outcome of chemotherapy in Chinese patients with primary lung cancer.]. AB - BACKGROUND: GSTM1 takes part in the metabolism of environmental pollutants such as benzopyrene, other polycyclic aromatic hydrocarbons and anticancer drugs and so on. The study aims to investigate the relationship between the gene polymorphism of GSTM1 and chemotherapy as well as to study the effect to survival of Chinese patients with lung cancer. METHODS: The genotypes of GSTM1 were examined with polymerase chain reaction in 137 primary lung cancer patients accepted chemotherapy. RESULTS: GSTM1 -null genotype frequency was 58.4%(80/137). The frequency of non-null GSTM1 genotype was 41.6%(57/137). The frequency of GSTM1-null genotype was 69.05%(58/84) in the response group of chemotherapy and 41.51%(22/53) in the non-response group of chemotherapy. They were significantly different (P=0.001). In the patients with platinum chemotherapy, the frequency of GSTM1-null genotype was 65.43%(53/81) in the response group of chemotherapy and 42%(21/50) in the non-response group. There werestastically differences in them (P=0.0025). For the advanced cases, GSTM1 -null genotype frequency was 70.13% (54/77) in the response group of chemotherapy, 41.51% (22/53) in the non-response group of chemotherapy respectively and they were significantly different(P=0.001). When the chemotherapy was effective, the survival time of patients in squamous carcinoma and small cell carcinoma with non-null GSTM1 genotype (the median survival times were 42 months and 14 months respectively) were longer than those with null GSTM1 genotype (the median survival times were 6 months and 7 months respectively)(P<0.05). The survival time of adencarcinoma with non-null GSTM1 genotype and null GSTM1 genotype (the median survival times were 13 months and 11 months respectively) were comparative (P>0.05). When chemotherapy was not effective, the median survival time were not significantly different (P>0.05). CONCLUSIONS: The effect of chemotherapy of GSTM1-null genotype patients was better than that of GSTM1-postive genotype patients. The chemotherapy effect of the cases with null GSTM1 type was better than those with non-null GSTM1 type when the patients accepted platinum chemotherapy. When the chemotherapy was effective, the survival time may be related to the histological types and GSTM1 genotypes. PMID- 20727283 TI - [Clinic outcome of gefitinib in sixty-nine elderly patients with lung adenocarcinoma.]. AB - BACKGROUND: To evaluate the efficacy and safety of gefitinib, an orally active epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI), in elderly patients with other types of adenocarcinoma. METHODS: The clinical characteristics, response of treatment and survival were retrospectively reviewed in sixty-nine elderly patients (>=65 years). All these patients received gefitinib 250mg/d in Cancer Institute ( Hospital ), Chinese Aacademy of Medical Sciences until disease progression or toxicities not tolerated by patient. RESULTS: Overall response rate and disease controlled rate (DCR) of gefitinib were 24.6% and 88.4% respectively. The median survival time was 15 months. One year survival was 62.2%. The response rate of gefitinib were significantly higher in patients less than 75-year-old, non-smoker and first-line treatment group than in patients above 75-year-old, smoker and second-line or third-line treatment. Furthermore, the overall survival times were significantly longer in patients of Bronchioloalveolar carcinoma, female and nonsmokers than patients with adenocarcinoma, and male and smokers. Rash and diarrhea were the most common adverse events (AEs) , but usually were mild. CONCLUSIONS: Gefitinib is effective and safe in elderly patients with advanced adenocarcinomas of the lung. PMID- 20727284 TI - [DRG again again]. PMID- 20727285 TI - [Hospital costs for abdominal aortic aneurysm surgery]. AB - INTRODUCTION: The aim of the study was to estimate the direct cost of an abdominal aortic aneurysm (AAA) repair and to validate it against the national Diagnostic Related Group (DRG) costs. MATERIAL AND METHODS: Records from involved hospitals were used along with information on wages, cost of ICU and ward time were used to estimate the direct hospital costs including surgery-related costs up to one year after discharge from the vascular department for 75 patients who were consecutively operated for asymptomatic AAA, symptomatic AAA with and without rupture in the period leading up to March 2008. RESULTS: Cost for emergency surgery varied considerably (33,069-2,842,708 DKK). Three outliers were identified. After planned repair, acute repair without and with rupture, the mean costs were 115,551 (95% confidence interval (CI): 96,841; 134,260 DKK), 259,712 (95% CI: 128,950; 390,484 DKK) and 436,127 DKK (95% CI: 172,415;669,839 DKK) (p = 0.027) and 108,969, 188,571 and 238,088 DKK excluding three extreme outliers, p = 0.009)). DRG costs for repair without and with rupture was 100,339 and 98,087 DKK, respectively. CONCLUSION: DRG costs are not suitable for cost effectiveness analyses of screening for AAA due to a lack of classification of acute repair without rupture and underestimation of emergency costs. PMID- 20727286 TI - [Survival of Danish cancer patients 1995-2006]. AB - INTRODUCTION: Improved one- and three-year survival was seen after the initiation of the National Cancer Control Plan in year 2000. Short follow-up and lack of five-year survival called for an update with more data. MATERIAL AND METHODS: All cancers from the period 1995-2006 were studied in four cohorts of three-year incident cases from 1995 to 2006 followed to death or to the end of 2008. Age standardised one-, three- and five-year relative survival and excess mortality were computed. RESULTS: The improved one- and three-year survival was confirmed. The five-year survival increased from 38% in 1995-1997 to 48% in 2004-2006 for men, but a five percentage point increase is owed to the incidence increase of prostate cancer without changed mortality. In women the increase in survival was from 50% to 55%, i.e. a five percentage point increase. Improved five-year survival was seen for cancers of the oesophagus, colon and rectum, lung, and for haematological cancers; for women, also pancreas, ovary, brain and melanoma, and for men prostate cancer survival improved. DISCUSSION: The improved cancer survival was confirmed and it was also observed at the five-year follow-up. The excess mortality is largely present during the first year of follow-up and is a useful indicator of whether changes in diagnosis and care lead to the desired outcome. Overall survival should be interpreted in the context of major changes in recorded incidence due to the introduction of new diagnostic tools and biomarkers such as prostate-specific antigen, as such measures do not necessarily change mortality. Whether cancer care in Denmark has reached the highest international standard remains to be proven by survival comparison to countries with adequate data for a comparative analysis. PMID- 20727287 TI - [Smoking and increased risk of mastitis]. AB - INTRODUCTION: Non-puerperal mastitis (NPM) is a common condition that often proves tricky to treat as it may give rise to complications and recurrences. NPM has been related to cigarette smoking through mechanisms that are not fully known. This study was aimed at analyzing the course of this patient group and at promoting guidelines for adequate treatment. MATERIAL AND METHODS: This is an audit of 178 files for patients diagnosed with NPM in 2008 at the Breast Unit at Herlev Hospital. The audit included: number of contacts, treatment, bacteriology, complications, recurrences and coding. A questionnaire was sent to all breast units in Denmark to review treatment guidelines. RESULTS: We found a large majority of smokers (73%). Non-smokers often had systemic disease or immunosuppressive conditions, and many patients had been misclassified with infections related to skin diseases. Smokers on average had 5.3 (versus 3.0 among non-smokers) outpatient visits to the unit and more than twice as many recurrences. We found quite good accordance between different breast units in Denmark in terms of treatment and follow-up regimes. CONCLUSIONS: This study confirms that NPM is a smoker's disease. Nearly all patients can be treated on an outpatient basis with no need for open incision of abscesses. We found a lack of diagnostic precision and also incorrect coding of patients with infected skin diseases or complications to surgery or radiation therapy. We find that smoking intervention should be mandatory to prevent the majority of complications and recurrences. PMID- 20727288 TI - [Neurofeedback as ADDH therapy]. AB - The article is a review of the past two decades of research on Attention Deficit Hyperactive Disorder (ADHD) and the documented effect of training with EEG biofeedback, often called neurofeedback. Research during the past twenty years seems to confirm that 70-80% of patients benefit from neurofeedback training. Research from the last ten years, using control groups, comparison between different kinds of treatment and psychometric testing, has to some degree confirmed the early findings. Due to the lack of placebo studies or studies comprising false feedback, neurofeedback can only be characterized as probably effective. PMID- 20727289 TI - [Pregnancy within the uterine scar of a prior Caesarean section]. AB - Rarely, but with increasing frequency, we detect pregnancies within the uterine scar of a prior Caesarean section. These ectopic pregnancies entail a risk of severe bleeding and uterine rupture, and thus constitute a threat to the pregnant woman's life, underlining the necessity of awareness about these complications. Vaginal bleeding and/or mild to moderate lower abdominal pain are symptoms seen in half of the women. The diagnosis is made by sonography and criteria for these are listed. We here present the most recent studies on treatment strategies, follow-up and future fertility. PMID- 20727290 TI - [Traumatic distal humerus epiphysiolysis in a newborn child]. AB - Traumatic distal humerus epiphysiolysis (TDHE) is a rare injury in infants with an incidence of about 1:35,000 births. It is primarily a birth injury, but it is also seen in cases of battered child syndrome. Because of its rare occurrence and the diagnostic difficulties, the lesion may be overlooked or misdiagnosed on initial presentation. The diagnosis is made on the basis of a high index of suspicion, clinical signs and symptoms and awareness of radiological changes. Traumatic humeral dislocation will produce the same radiological picture as TDHE and is consequently a common, incorrect initial diagnosis. We present a case of TDHE as a birth injury. PMID- 20727291 TI - [Defect at uterine incision from prior Caesarean section]. AB - A case of asymptomatic uterine fenestration in 26+3 gestational weeks in a patient who had previously undergone Caesarean section is presented. Controls were planned. In gestational week 34+1 the woman was hospitalized due to lower abdominal pain, but with otherwise normal objective parameters. Ten days later the patient had increasing pain, and a caesarean section was performed. Fenestration was confirmed. This leads to reflections on how to treat and observe such cases, and further discussion about whether early identification of risk patients by ultrasound is possible. PMID- 20727292 TI - [Small bowel ileus caused by migration of oesophageal stent]. AB - Stents are used for the treatment of malignant strictures and stenoses in the oesophagus. Both the ease of placement and the safety of these oesophageal stents have increased considerably over the years; however, complications still occur. We describe a patient who developed small bowel obstruction and perforation due to migration of the stent. Laparotomy with resection of the diseased bowel section including the stent was performed, and the patient recovered uneventfully. Our report shows that bowel obstruction and perforation is a seldom but severe complication of migrated oesophageal stents. PMID- 20727293 TI - [Laparoscopic surgery in inflammatory bowel disease]. PMID- 20727294 TI - [Laparoscopy-assisted ileocolic resection in Crohn's disease]. AB - INTRODUCTION: Laparoscopic surgery has become more widely used in the treatment of patients with inflammatory bowel disease. The aim of this study is retrospectively to describe the results of laparoscopy-assisted ileocolic resection of nineteen patients with Crohn's disease. MATERIAL AND METHODS: The patients included in this study were identified by a search in Ribe County's patient system. Patients diagnosed with Crohn's disease and treated with laparoscopic ileocolic resection in the period 1/1-2004-31/8-2007 were included. The search resulted in inclusion of nineteen patients. RESULTS: 95% of the operations were performed as elective surgery with a median operative time of 93 minutes and a median blood loss of 50 ml. The conversion rate and 30-day mortality were zero. In one case there were perioperative complications. The median postoperative time to flatus was three days and to bowel movement four days. The median time from operation to discharge was five days. The most frequent postoperative complications were wound infection, intraabdominal abscess, ileus and pneumonia. CONCLUSION: The results of our laparoscopy-assisted operations seem to be equal to those published in international studies, although a slightly higher incidence of complications cannot be ruled out. Data suggests that laparoscopy-assisted ileocolic resection compared with conventional resection for Crohn's disease has several advantages although more evidence is needed to establish this with certainty. PMID- 20727295 TI - [Laparoscopic and open subtotal colectomy for inflammatory bowel disease]. AB - Studies have shown that laparoscopic colectomy (LC) for inflammatory bowel disease (IBD) is just as safe as open colectomy. Some of the short-term advantages of laparoscopy are faster recovery, less pain, shorter hospital stay and fewer complications. The long-term advantages include superior cosmetic result, reduced intra abdominal adhesion formation, less frequent hospitalization due to small bowel obstruction and fewer incisional hernias. Cost-benefit analyses also favour laparoscopic surgery for IBD. PMID- 20727296 TI - [Continuous regular use of mild analgesics in Denmark]. AB - INTRODUCTION: In spite of the negative health effects associated with the use of analgesics, little is known about the prevalence of continuous regular use of analgesics or about the factors associated with their use. The objective of this article is to describe continuous regular use of acetaminophen, ibuprofen and aspirin in Denmark and to examine factors associated with their use. MATERIAL AND METHODS: The study is based on data from two surveys and includes a random sample of women and men aged 18-45 years from the general Danish population. A total of 22,199 women (response rate 81%) and 23,080 men (response-rate 71%) were included in the study. Data was analyzed using multivariate logistic regression. RESULTS: More women than men reported a regular monthly use of acetaminophen, ibuprofen and aspirin during the past year. Acetaminophen was the most commonly used type of analgesic of which 20% of the women and 13% of the men reported a regular monthly use. Besides poor self-rated health, we found that increasing age, low level of education, living in lesser urbanized areas, smoking and being overweight were associated with a higher risk of having a continuous regular weekly use of acetaminophen, ibuprofen or aspirin. CONCLUSION: Continuous regular use of analgesics is generally prevalent amongst young Danish men and women. This study demonstrates social inequalities in the use of analgesics, which make this a potential area for intervention that deserves further attention. PMID- 20727297 TI - [Determination of light chains in serum]. AB - Free light chains of the immunoglobulin are identical to the Bence Jones protein. In 2001, a commercially available assay for the measurement of free light chains in serum (sFLC) became available (FreeLite Free Kappa & Free Lambda assay). Evidence from the use of the sFLC analysis is rapidly building, and the analysis is a potentially powerful supplement to the diagnostic tools already used in the diagnosis and monitoring of patients with monoclonal plasma cell disorders. However, there are several unsolved aspects for the use of this analysis which must be considered before sFLC can be used optimally in a daily clinical setting. PMID- 20727298 TI - [Breast cancer metastasis to the colon]. AB - A 69-year-old woman was admitted with diarrhoea, anaemia and elevated C-reactive protein. She was diagnosed with metastases of a carcinoma to the colon; the immunohistochemical profile made lobular breast cancer the most likely primary tumour. But despite thorough examination, such tumour was never found. Twenty-two years earlier, the patient underwent surgery for a benign breast tumour. The benign diagnosis was confirmed in new slides from the then removed tissue. Metastases from breast cancer to the colon are rare, and a primary tumour is usually found. In this case report, however, no primary tumour was found. PMID- 20727299 TI - [Blindness due to acute ethmoiditis]. AB - Orbital complications of ethmoiditis are well-described. This case presents a healthy ten-year-old boy who was admitted under the diagnosis of acute ethmoiditis. A computed tomography (CT) showed orbital cellulitis, but no definite abscess. The patient improved during intravenous antibiotic treatment, but suddenly complained about loss of vision. The clinical signs were central scotoma and visual impairment to 0.05. Both repeat CT, magnetic resonance imaging and ethmoidectomy were performed without signs of abscess. Blindness due to ethmoiditis without abscess in orbita is rare and probably results from neuritis in the nervus opticus. PMID- 20727300 TI - [Influenza A H1N1v treated with extracorporeal membrane oxygenation]. AB - A 37-year-old woman with body mass index > 30 was admitted to hospital with severe pneumonia due to H1N1v. Thoracic X-ray showed bilateral, diffuse infiltrates. There was no sign of complicating bacterial infection and all microbiological tests of tracheal secretion, blood and urine were negative. Polymerase chain reaction test for H1N1v was positive until day ten. No mutations were found in the virus. The patient was given oseltamivir tablets and inhalable zanamivir as well as antibiotics. The patient was treated with extra-corporal membrane oxygenation (EcmO) for 12 days followed by ventilator weaning. The patient had no neurological sequelae. PMID- 20727301 TI - [Picture of the month: plaque and thrombi in the internal carotid artery]. PMID- 20727303 TI - Gorham-Stout disease. AB - Gorham-Stout disease is a rare disease of unknown etiology. It is characterized by spontaneous excessive replacement of bone by proliferative non-neoplastic thin walled lymphatic and/or blood vessels. Histology shows positive stain for the lymphatic endothelial marker LYVE-1 (lymphatic vascular endothelial hyaluronan receptor-1) and many lymphatic growth factors (PDGF-BB, VEGF-C, VEGFR-3). Patients may present with localized pain and/or weakness and radiographic evidence of massive osteolysis involving contiguous bone structures. The disease usually progresses and complications may occur with significant morbidity and mortality. Close monitoring of these patients is recommended. Treatment remains challenging. Surgical treatment has been combined with pre- and postoperative radiation therapy. Drug regimes including bisphosphonates and vitamin D have been used with various results. Currently, the most effective agent is INF-alpha due to its anti-angiogenic effect. The effect of the newer immunomodulatory agents such as the OK-432 remains to be proved. PMID- 20727304 TI - The effect of incisional negative pressure therapy on wound complications after acetabular fracture surgery. AB - The purpose of the study was to determine if the use of incisional negative pressure therapy affected the rate of wound complications after acetabular fracture surgery. Between August 1996 to April 2005, 301 patients were found to have had an operatively treated acetabular fracture. There were 235 patients who had placement of incisional vacuum-assisted closure (VAC) who had three (1.27%) deep wound infections and one (0.426%) wound dehiscence. There were 66 consecutive patients who were available in the 5 years preceding the usage of the incisional VAC who had four (6.06%) deep wound infections and two (3.03%) wound dehiscences. This is less than the published infection rate of 4% for patients undergoing operative treatment of acetabular fractures and less than the authors' rate of 6.15% in the time period before the use of the incisional negative pressure wound therapy (p=.0414). The use of incisional negative pressure wound therapy significantly decreases perioperative wound complications after acetabular fracture surgery. PMID- 20727305 TI - Prosthetic treatment of hip fractures in the elderly patient. AB - As the elderly population in our society significantly increases, the incidence of displaced femoral neck fractures will increase proportionally. Three surgical procedures are available to treat such fractures: internal fixation, hemiarthroplasty (unipolar or bipolar), and total hip arthroplasty. Long-term costs and efficacy of these three procedures vary, primarily due to postoperative complications. Thus, it is imperative that all surgeons conduct a proper preoperative evaluation of each patient before choosing the optimal treatment plan. Internal fixation has been shown to be more beneficial for physiologically younger patients who sustain displaced femoral neck fractures. However, the choice between hemiarthroplasty and total hip arthroplasty in the geriatric patient remains difficult. This article aims to provide a practical algorithm for the treatment of these patients. PMID- 20727306 TI - Early motion protocol for select Galeazzi fractures after radial shaft fixation. AB - Galeazzi fractures traditionally are treated in long arm casts with the wrist fully supinated for 6 weeks after open reduction and internal fixation. Recent literature suggests that early motion can be permitted for a subset of Galeazzi fractures. Defining a safe postoperative protocol that allows immediate elbow motion, immediate platform weight bearing, and early wrist motion might decrease elbow morbidity, increase range of motion, and improve outcomes. A retrospective review of a prospectively collected database of 26 patients at a level I trauma center was conducted. Early motion protocol was assigned to patients who were radiographically and clinically stable after plate and screw fixation. Elbow flexion and platform weight bearing were allowed immediately; increased wrist rotation was allowed at 2-week intervals. Early motion of elbow and wrist seems to be safe during postoperative rehabilitation of repaired Galeazzi fractures. The postoperative protocol might maximize elbow and wrist range of motion. PMID- 20727307 TI - Torsional stiffness of an intramedullary nail versus blade plate fixation for tibiotalocalcaneal arthrodesis: a biomechanical study. AB - The purpose of this investigation is to compare the rotational stability of intramedullary rod fixation with blade plate and screw fixation in tibiotalocalcaneal arthrodesis. Five matched pairs of cadaver ankles were randomly fixated with a lateral blade plate and screws or a retrograde intramedullary nail. The bone mineral density (BMD) for each sample was ascertained. These samples were tested through internal and external rotation of 0.5 degrees/s until 7 N-m was achieved. The torsional stiffness of each specimen was determined from the linear slope of the torque-rotation curve. No statistical difference in internal (p=.11) or external (p=.36) rotation for the matched pairs was noted. Data were excluded from one intramedullary sample secondary to early failure of the tibia. A trend toward increased rotational stability in the intramedullary group versus plate fixation in specimens with lower BMD was observed. These findings suggest no rotational biomechanical advantage of intramedullary nail compared to blade plate fixation in a cadaveric tibiotalocalcaneal arthrodesis model. PMID- 20727308 TI - Outcome of percutaneous screw fixation of scaphoid fractures. AB - The optimal treatment of minimally displaced or nondisplaced fractures of the scaphoid is unclear. Traditionally, management of these fractures has been unpredictable with a significant risk of nonunion when treated conservatively. This study examined the results from 32 patients who underwent percutaneous screw fixation using a 3.0-mm AO/ASIF cannulated screw for a nondisplaced or minimally displaced fracture of the scaphoid waist. Eighteen patients were available for final follow up (average 3.2 years) including administration of the DASH questionnaire, a physical examination, and final radiographs. Sixteen (89%) healed successfully after the index procedure. There were two complications consisting of nonunions, both of which required revision open reduction and internal fixation for fracture union. These also went on to heal, resulting in an ultimate union rate of 100%. No significant differences were found between operative and nonoperative extremities with regard to radial-ulnar deviation arc of motion, grip, or pinch strength. The average DASH score was 7.4, indicating no disability. Percutaneous fixation of acute, nondisplaced scaphoid fractures with 3.0-mm AO/ASIF cannulated screw is a safe, effective technique that minimizes the need for long-term wrist immobilization, allows an expeditious return to vocational activity, and results in reliable rates of union. PMID- 20727310 TI - Streptococcus bovis infection of total hip arthroplasty in association with carcinoma of colon. AB - Streptococcus bovis is normally found in the gastrointestinal tract of the human population. The association between Streptococcus bovis and bowel neoplasia has been frequently reported. This report presents two cases of total hip arthroplasty with Streptococcus Bovis infection at 18 and 11 years after arthroplasty. The diagnosis was made with the help of clinical findings, standard radiographs, and laboratory tests (complete blood count, C-reactive protein, sedimentation rate, and the hip aspiration). Infections were treated by implant removal and antibiotic spacer implantation. Intravenous antibiotics were administered for 12 weeks. Revision arthroplasty was performed when laboratory tests (complete blood count, C-reactive protein, sedimentation rate) were within normal limits. Streptococcus bovis infection prompted the authors to investigate for any bowel malignancy. Colonoscopy and transrectal biopsy revealed adenocarcinoma in case 1, while case 2 had prior diagnosis of flat polyps in the colon. There are a limited number of reports in the literature reporting the presence of Streptococcus bovis infection concurrent with arthroplasty and bowel malignancy. These two case reports highlight the possibility of hematogenous seeding of arthroplasty components by Streptococcus bovis in patients with colonic neoplasia. Streptococcus bovis infection of hip arthroplasty may provide an opportunity for diagnosis of colonic neoplasia. Acute hip pain in patients with hip endoprostheses and simultaneous bowel malignancy should be evaluated promptly for hematogenous infection by standard radiograph, complete blood count, C-reactive protein, sedimentation rate, and hip aspiration. PMID- 20727309 TI - CALAXO osteoconductive interference screw: the value of postmarket surveillance. AB - The CALAXO osteoconductive interference screw was recalled in August 2007 due to reports of increased numbers of postoperative complications associated with screw swelling and prominence leading to the need for surgical debridement. This study reviews complications associated with CALAXO screw use in a consecutive cohort of patients undergoing anterior cruciate ligament reconstruction surgery by the senior author at the authors' institution. Over a 12-month period, 226 CALAXO interference screws, either of 20 mm length or 25 mm length, were implanted in 112 patients, and postoperative complications were noted. The 25-mm tibial screw was over 5 times (RR 5.2, 95% CI 1.8 to 15.3) more likely to be prominent than the 20-mm screw (p value=.002). Four surgical debridements were required in the 25-mm tibial screw group; none were required in the 20-mm group. The authors hypothesize that the inability to bury the longer screw length into the bone tunnel is associated with postoperative complications associated with the CALAXO screw. PMID- 20727311 TI - Primary monophasic synovial sarcoma presenting as a benign neurogenic tumor: case review and review of the literature. AB - This report describes two cases of monophasic synovial sarcoma which were initially diagnosed as benign nerve sheath tumors based on imaging features. Retrospective review of the first case and re-review of the second case after initial diagnosis showed imaging features which distinguished the lesions from classical, benign neurogenic tumors. Accurate prospective diagnosis of soft tissue masses in locations in or around nerves and with morphology similar to nerve sheath tumors represent a clinical challenge. Careful review of imaging features and absence of the typical, reproducible findings should allow the benign lesion to be excluded from the diagnostic possibilities in most cases and allow for improved preoperative planning. PMID- 20727312 TI - MRI evaluation of anterolateral soft tissue impingement of the ankle. AB - BACKGROUND: The usefulness of magnetic resonance imaging (MRI) has been questioned in evaluating patients with chronic ankle sprain pain. The purpose of this study was to determine the effectiveness and reliability of routine MR imaging in the diagnosis of anterolateral soft tissue impingement. MATERIALS AND METHODS: Inclusion criteria required that the MR examinations be performed by the same musculoskeletal radiologist after the most recent scanner upgrade and using a dedicated ankle/hindfoot coil. The surgical and MRI reports of 24 patients who had an arthroscopic diagnosis of anterolateral soft tissue impingement of the ankle were tabulated and categorized. Unlike previous studies, sagittal T1 and Short Tau Inversion Recovery (STIR) images were used primarily in the diagnosis of these lesions. RESULTS: Using this technique, we report a 78.9% accuracy in diagnosis, a sensitivity of 83.3% and a specificity of 78.6%. Fifty-eight percent of patients had an associated diagnosis, which in 33% of patients altered our surgical plan. CONCLUSION: Although not indicated in all cases of anterolateral ankle impingement, we advocate the use of MR imaging in complicated clinical presentations where the exclusion of additional pathology in the ankle or subtalar joint, and the confirmation of anterolateral soft tissue impingement would be beneficial. PMID- 20727313 TI - Is it necessary to re-fuse a non-union of a Hallux metatarsophalangeal joint arthrodesis? AB - BACKGROUND: The standard treatment for a non-union of the hallux metatarsophalangeal joint fusion has been to revise the fusion. Revision fusion is technically more demanding, often involving bone grafting, more substantial fixation and prolonged period of immobilization postoperatively. We present data to suggest that removal of hardware and debridement alone is an alternative treatment option. MATERIALS AND METHODS: A case note review identified patients with a symptomatic non-union after hallux metatarsophalangeal joint (MTPJ) fusion. It is our practice to offer these patients revision fusion or removal of hardware and debridement. For the seven patients that chose hardware removal and were left with a pseudarthrosis, a matched control group was selected from patients who had had successful fusions. Three outcome scores were used. Hallux valgus and dorsiflexion angles were recorded. RESULTS: One hundred thirty-nine hallux MTPJ arthrodeses were carried out. Fourteen non-unions were identified. The rate of non-union in males and following previous hallux MTPJ surgery was 19% and 24%, respectively. In females undergoing a primary MTPJ fusion, the rate was 2.4%. Twelve non-union patients were reviewed at 27 months (mean). Eleven patients had elected to undergo removal of hardware and debridement. Four patients with pseudarthrosis were unhappy with the results and proceeded to either revision fusion or MTPJ replacement. Seven non-union patients, who had removal of hardware alone, had outcome scores marginally worse compared to those with successful fusions. CONCLUSION: Removal of hardware alone is a reasonable option to offer as a relatively minor procedure following a failed arthrodesis of the first MTPJ. This must be accepted on the proviso that in this study four out of 11 (36%) patients proceeded to a revision first MTPJ fusion or first MTPJ replacement. We also found that the rate of non-union in primary first MTPJ fusion was significantly higher in males and those patients who had undergone previous surgery. PMID- 20727314 TI - Foot function after fusion of the first metatarsophalangeal joint. AB - BACKGROUND: We measured with a validated score the operative outcome in patients without concomitant foot surgery who underwent fusion of the first metatarsophalangeal (MTP) joint for hallux rigidus (HR) and hallux valgus (HV). We also examined whether there is a correlation between foot function and hallux position to try to formulate an optimum fusion angle. MATERIALS AND METHODS: Between 2002 and 2005, a consecutive series of 62 patients underwent crossed screw fusion of the first MTP joint (27 HR and 35 HV) without concomitant surgery of the same or contralateral foot or had previous surgery of the same foot. Foot function was measured by the Dutch Foot Function Index (FFI) pre- and postoperatively. Hallux valgus and dorsiflexion angles were measured on standing radiographs before operation and at followup. RESULTS: Postoperatively the median hallux valgus angle was 14 (range, -2 to 33) degrees and the median dorsiflexion angle was 23 (range, 7 to 45) degrees. The median FFI score improved from 38 (range, 0 to 80) to 8 (range, 0 to 59) (p < 0.001). The FFI score was not different between the HV and HR groups. There was no correlation between postoperative foot function, dorsiflexion angles and hallux valgus angles. CONCLUSION: Fusion of the first MTP joint in HR and HV results in improved function according to the validated FFI. There was no significant correlation between foot function and hallux position. This could be due to the fact that the desired position of the hallux was most often achieved. PMID- 20727315 TI - Scarf osteotomy for correction of Tailor's bunion: mid- to long-term followup. AB - BACKGROUND: The purpose of the study was to evaluate the increased correction possible with a mid shaft rotational osteotomy with the stability and ease of fixation associated with a scarf osteotomy. MATERIALS AND METHODS: Between September 1999 and September 2006, 63 patients underwent operative repair of 77 Tailor's bunion deformities. Twenty eight patients (36 feet) were available for a final review (nine males and 19 females). A further seven patients (nine feet) completed a questionnaire. The mean followup period for the 28 patients reviewed in clinic was 6.5 years, (79.5 months; SD, 22). RESULTS: Eighty-six percent were completely satisfied, 11.4% were satisfied with reservations and 3% were dissatisfied. Ninety-one percent considered themselves better than before their surgery while 8.6% felt they were no better. Ninety-one percent of patients said they would undergo surgery under the same conditions again. Preoperatively, the mean 4-5 intermetatarsal angle measured on weightbearing X-rays was 9.9 degrees (SD, 2.2), the mean postoperative intermetatarsal angle was 5.7 degrees (SD, 2.0). The mean preoperative AOFAS score was 44.1 (SD, 14.5) and the mean postoperative score at 6-month review was 91.8 (SD, 20.2). The AOFAS score at final review was 88.1 (SD, 11.6). CONCLUSION: The rotational scarf osteotomy was a reliable procedure for the correction of Tailor's bunion deformities. The osteotomy allowed for early mobilization and had few associated complications. The rotational scarf osteotomy facilitated correction of the intermetatarsal angle while maintaining excellent sagittal and transverse plane stability. PMID- 20727316 TI - Distal chevron osteotomy with distal soft tissue procedure for moderate to severe hallux valgus deformity. AB - BACKGROUND: Distal chevron osteotomy has been widely employed to treat mild to moderate hallux valgus deformity. The purpose of the present study was to evaluate the outcomes of distal chevron osteotomy with a distal soft tissue procedure for the correction of moderate to severe hallux valgus. MATERIALS AND METHODS: We reviewed 76 patients (86 feet) that underwent distal chevron osteotomy with a distal soft tissue procedure for symptomatic moderate to severe hallux valgus deformity. At a mean followup of 31 months, all patients were evaluated using subjective, objective and radiographic measurements. RESULTS: Ninety-four percent of the patients were very satisfied or satisfied. Average AOFAS score improved from 54.7 points preoperatively to 92.9 at final followup. Average hallux valgus angle changed from 36.2 degrees preoperatively to 12.4 degrees at final followup, and average first-second intermetatarsal angle changed from 17.1 to 7.3 degrees. Average tibial sesamoid position changed from 2.4 preoperatively to 1.2 at final followup. Dorsal angulation of the head was observed in two feet, and plantaflexion of the head in four feet. There were no cases of avascular necrosis of the metatarsal head. CONCLUSION: Our results indicate that distal chevron osteotomy with a distal soft tissue procedure provides an effective and reliable means of correcting moderate to severe hallux valgus deformity, and that it does so with high levels of patient satisfaction and low incidence of complications. PMID- 20727317 TI - Insertional achilles tendinopathy management: a systematic review. AB - BACKGROUND: Achilles tendinopathy is a common problem and its management remains controversial. However, many clinicians consider that the sub-group of patients with insertional Achilles tendinopathy are even more difficult to manage. The aim of this systematic review was to review evidence for interventions specific to insertional Achilles tendinopathy. MATERIALS & METHODS: Medline and the Cochrane library were searched using a pre-defined search strategy. All study designs were included except case studies, narrative reviews, technical notes and letters/personal opinion. The results were evaluated independently by two reviewers and assessed against the inclusion/exclusion criteria. All included articles were assessed for methodological quality and study characteristics were extracted into a table. RESULTS: One hundred eighteen articles were identified through the search strategy, of which 11 met the eligibility criteria. Six studies evaluated operative techniques following failed conservative management and five evaluated conservative interventions only. The overall level of evidence was limited to case series evaluations and one randomized controlled trial. CONCLUSION: There is a consensus that conservative methods should be used before operative interventions. Current evidence for conservative treatment favors eccentric loading and shock wave therapy, although there is limited evidence by which to judge their effectiveness. Evaluation of operative interventions has been mostly retrospective and remains inconclusive. PMID- 20727318 TI - Novel reconstruction of a static medial ligamentous complex in a flatfoot model. AB - BACKGROUND: Little progress has been made addressing reconstruction of the static medial ligamentous structures of the foot. The purpose of this investigation was to reconstruct a flatfoot deformity with a novel static medial ligamentous complex (MLC) and evaluate its ability to correct talar head subluxation and radiographic deformity in a cadaveric model. MATERIALS AND METHODS: Eight fresh frozen cadaveric specimens underwent cyclic preconditioning and static axial loading. Loading was applied to the intact foot, the severe flatfoot, and the reconstructed MLC foot. Anteroposterior (AP) and lateral radiographs were taken at each stage. The talo-first metatarsal angle, medial cuneiform height, talocalcaneal angle, and the calcaneal pitch angle were measured on the lateral views and the talo-first metatarsal angle was measured on the anteroposterior views. RESULTS: Compared with the intact foot, the flatfoot showed significant change in the AP talo-first metatarsal angle (p = 0.001), the lateral talo-first metatarsal angle (p = 0.002), the medial cuneiform height (p = 0.007), the talocalcaneal angle (p = 0.03), and the calcaneal pitch angle (p = 0.018). After MLC reconstruction, there was a significant change in the AP talo-first metatarsal angle (p = 0.001), the lateral talo-first metatarsal angle (p = 0.002), and the medial cuneiform height (p = 0.007) and these values were not significantly different than the intact foot. The talocalcaneal angle and the calcaneal pitch angle remained significantly undercorrected after static MLC reconstruction. CONCLUSION: Static MLC reconstruction was effective in correcting several key radiographic parameters in a cadaveric flatfoot model. CLINICAL RELEVANCE: The surgical technique evaluated here may be useful as a new soft tissue reconstructive procedure for treating adult flatfoot. PMID- 20727319 TI - The strength of achilles tendon repair: a comparison of three suture techniques in human cadaver tendons. AB - BACKGROUND: A previous study suggests the double Krackow suture (locking-loop) weave technique is nearly twice as strong as the single Bunnell or single Kessler suture repair techniques. Our hypothesis was that the strength of different repair techniques would be comparable if a similar number of suture strands cross the repair site. MATERIALS AND METHODS: Twenty-four fresh-frozen human cadaver Achilles tendons were used to test maximum strength of three suture techniques (double Bunnell, double Kessler, and double Krackow). The simulated ruptures were created in the midsubstance of the Achilles tendon, five centimeters proximal to its calcaneal insertion. All repairs were performed with No. 2 polyester (Mersilene, Ethicon, Sommerville, NJ) nonabsorbable suture in standard fashion for each technique, with four strands crossing the repair site. The tendons were then anchored to a materials testing machine (Instron, Canton, MA) through a calcaneal pin distally and a modified soft tissue clamp proximally. Tendons were loaded with continuous tension at a head speed of 0.85 cm/s. RESULTS: All repairs failed at the site of the suture knots, none pulling out through the substance of the tendon. A one-way analysis of variance was performed on the maximum force at failure of each repair technique. No statistically significant difference was noted between the double Krackow weave (199.9 +/- 20 N), the double Bunnell weave (196.2 +/- 45 N), and the double Kessler weave (166.9 +/- 51 N). CONCLUSION: We found that in a laboratory model of cadaveric Achilles tendon repairs there was no significant difference in strength between the Krackow, Bunnell, and Kessler suture techniques, when each was performed with a double suture weave. CLINICAL RELEVANCE: This is a cadaveric study that attempts to simulate the clinical parameters of Achilles tendon ruptures, repairs, and repair failures to examine the strength of different repair techniques. PMID- 20727320 TI - Autografting satellite cells to repair damaged muscle induced by repeated compression: an animal model. AB - BACKGROUND: Repeated elevation of intramuscular pressure (IMP) causes skeletal muscles damage. The purpose of this paper was to investigate the regenerative effect of satellite cells autografted to the damaged muscle in a rabbit model. MATERIALS AND METHODS: Twenty-four adult rabbits were randomized into three groups: 1) experimental group, 2) non-graft group, and 3) control group. The model of limb interval compression for 2 hours twice a day for 14 days was established in the experimental and non-graft group. Transplantation was performed in the experimental group and control group. Satellite cells from a half of soleus muscles in the experimental group and control group were isolated and then expanded in vitro. DAPI-tag satellite cells were transplanted back to the remaining half of the soleus muscle. The number of satellite cells with DAPI tag was determined by fluorescence after grafts. The histological changes were compared at the time of the last compression and at the end of the 28th day after grafting. RESULTS: At the time period of 28 days following grafting of satellite cells into the soleus muscle, the satellite cells from the compressed soleus muscle increased significantly predominantly experimental group (p = 0.013), whereas those in the control group remained the same (p = 0.076). In HE staining, a large cluster of myofibers and interstitial fibers was present in compressed muscle in both the experimental group and non-graft group, while the skeletal muscle fibers and interstitial fibers were in continuity in the control group. After grafting, the muscle showed a great repair but the non-graft muscle exhibited dominant fibrosis. CONCLUSION: Autografting satellite cells by means of a small amount of expansion in vitro could improve the regenerative efficiency to repair large clusters of the damaged myofibers induced by repeated compression. CLINICAL RELEVANCE: This technique may be applicable in human compartment syndrome. PMID- 20727321 TI - Fracture of the second metatarsal following suture button fixation device in the correction of hallux valgus. PMID- 20727322 TI - Metatarsal giant cell tumor in adolescents. PMID- 20727323 TI - Neglected Sever's disease as a cause of calcaneal apophyseal avulsion fracture: case report. PMID- 20727324 TI - Treatment of chronic tophaceous gout with a wound vacuum-assisted device. PMID- 20727325 TI - Current concepts review: regional anesthesia for foot and ankle surgery. PMID- 20727327 TI - [Feature extraction and recognition of traditional Chinese medicine pulse based on hemodynamic principles]. AB - In this paper, factors contributing to the formation of pulse wave were analyzed based on hemodynamic principles. It is considered that formation of pulse wave was related to its propagation and reflection characteristics. Propagation of the pulse wave was characterized by pulse wave velocity, and reflection of the pulse wave was characterized by reflection coefficient. Pulse wave velocity and reflection coefficient were proposed as the eigenvectors of pulse wave in pulse diagnosis of traditional Chinese medicine, and support vector machine (SVM) was used to recognize slippery pulse, stringy pulse and plain pulse. Pulse wave velocity and reflection coefficient of the slippery, stringy and plain pulses in healthy people were calculated in this study, and SVM with Gaussian radial basis function was used for classifying. Results showed that pulse wave velocity and reflection coefficient with physiological and pathological significance had advantages in distinguishing slippery pulse, stringy pulse and plain pulse, which offered a new idea for recognizing pulse condition. PMID- 20727328 TI - [Investigative strategy for research on biological basis of traditional Chinese medicine syndrome: feature selection-based data mining methods]. AB - This paper is devoted to discussing two research patterns of biological basis of traditional Chinese medicine syndrome and presenting a research strategy for data mining methods. It points out that data mining methods which are based on feature selection are better fit for investigating biological basis of traditional Chinese medicine syndrome. Based on such a discussion, the concept of "characteristic pattern" is proposed to bridge the gap between "golden index" and biological basis of traditional Chinese medicine syndrome. This paper presents a novel research avenue for investigating biological basis of traditional Chinese medicine syndrome. PMID- 20727329 TI - [Quantitative evaluation of the degrees of qualitative syndromes commonly encountered in patients with coronary heart disease]. AB - OBJECTIVE: To establish a quantitative model for evaluating the degree of traditional Chinese medicine (TCM) syndromes often seen in patients with coronary heart disease (CHD). METHODS: Medical literature concerning clinical investigation of TCM syndromes of CHD was collected and organized, and the "Hall for Workshop of Metasynthetic Engineering" expert symposium method was applied. First, the 100 millimeter scaling was used for combining with scoring on degree of symptoms to establish a quantitative criterion for classification of symptom degree in CHD patients, and the model was established by using comprehensive analytic hierarchy process as the mathematical tool to estimate the weight of the criterion for evaluating qualitative syndromes in various layers by specialists. Then the model was verified in clinical practice and the outcomes were compared with fuzzy evaluation from the specialists. RESULTS: A total of 287 clinical observation forms on CHD cases were collected, and 167 forms were available after excluding any irregular forms. The results showed that basic coincidence rate between the outcomes derived from specialists and those from the model was 68.26% (114/167), and part coincidence rate was 88.62%(148/167). CONCLUSION: This model, with good rationality and feasibility, has a high coincidence rate with fuzzy evaluation from specialists, and can be promoted in clinical practice. It is a good quantitative model for evaluating the degree of TCM syndromes of CHD. PMID- 20727330 TI - [Common syndrome factors of menopausal syndrome based on questionnaire investigation among experts]. AB - OBJECTIVE: To select the common syndrome factors of menopausal syndrome through questionnaire investigation among experts. METHODS: Firstly, a questionnaire was constructed on the basis of our previous research, and then investigation of the experts by the questionnaire was carried out. The experts came from twelve tertiary hospitals (6 cities) in China, and engaged in clinical practice of gynecology of traditional Chinese medicine (TCM) or integrated traditional Chinese and Western medicine. The common TCM syndrome factors of menopausal syndrome were selected based on consent degree of the experts in mean value, full marks ratio, rank sum and variation coefficient. RESULTS: One hundred sets of the questionnaires were sent out and ninety-eight sets were returned back. The callback rate was 98%. In accordance with cumulative percentage of expert agreement and complete agreement more than 50% and the coefficient variation less than 0.25, we confirmed the common TCM syndrome factors of menopause syndrome. The syndrome factors related to disease location were kidney, liver, heart, and spleen, and those related to the nature of disease were yin deficiency, deficiency of essence, yang deficiency, hyperactivity of yang, qi deficiency, qi stagnation, blood deficiency, and blood stasis. CONCLUSION: Expert consultation questionnaire can collect consensus opinions of experts and is effective for identifying common TCM syndrome factors of a disease. The TCM syndrome factors acquired through the study may provide the evidence for establishment of TCM syndrome diagnosis criteria for the disease in future. PMID- 20727331 TI - [Efficacy of ginsenosides combined with prednisone in patients with systemic lupus erythematosus: a prospective, randomized, double-blind, placebo-controlled trial]. AB - BACKGROUND: The side effects of glucocorticoid in treatment of systemic lupus erythematosus (SLE) have been the focus of debate, and our preliminary study indicates that ginsenosides can enhance the efficacy of dexamethasone. OBJECTIVE: To observe the effects of ginsenosides combined with prednisone in SLE patients. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 60 SLE patients from Department of Rheumatology and Immunology, Changhai Hospital, Second Military Medical University, were randomly divided into treatment group and control group, with 30 patients in each group. Patients in the treatment group were given routine treatment with prednisone plus ginsenosides, while those in the control group were given routine treatment with prednisone plus placebo. They were all treated for 3 months. MAIN OUTCOME MEASURES: After three-month treatment, syndrome score in traditional Chinese medicine (TCM), total response rate and symptom improvement rate were measured and evaluated. RESULTS: Twenty-eight cases in treatment group and twenty-seven cases in control group were included in analysis. The total response rates in the treatment group and control group were 89.28% and 66.67% respectively, and there was a significant difference between the two groups (P<0.05). After treatment, the TCM syndrome scores in the two groups were lower than those before treatment (P<0.01), and prednisone plus ginsenosides was better in decreasing the TCM syndrome score than prednisone plus placebo (P<0.05). The symptoms were improved in the treatment group as compared with the control group (P<0.05). CONCLUSION: Prednisone combined with ginsenosides can increase the clinical effective rate and improve the clinical symptoms of SLE patients. PMID- 20727332 TI - Effects of petroleum ether extract of Anacyclus pyrethrum DC. on sexual behavior in male rats. AB - OBJECTIVE: The roots of Anacyclus pyrethrum DC. (Compositae) are employed in Ayurvedic system of medicine as "Vajikaran Rasayana"--a category of drugs for vitality and virility. They are believed to have aphrodisiac action. The present investigation was undertaken to evaluate their effects on sexual behavior in male rats. METHODS: Thirty-two male Wistar rats were divided into control group, testosterone group, low-dose (50 mg/kg) petroleum ether extract (PEE) group and high-dose (100 mg/kg) PEE group. PEE obtained from the roots of Anacyclus pyrethrum was administered orally to albino rats once daily, and 0.5 mg/kg (body weight) of testosterone was given intramuscularly twice weekly and served as positive control. The course of treatment was 28 days. The effects of PEE and testosterone on changes in body and accessory sexual organ weights, sexual behavior, penile erection and sexual performance were studied before treatment, after 15 and 28 days of treatment and 7 and 15 days after treatment. RESULTS: After 28 days of treatment, PEE and testosterone had a marked influence on body and accessory sexual organ weights as compared with arachis oil. The treated male rats were more receptive and oriented towards female rats and increased precopulatory activities like licking and sniffing of female anogenital were observed. The penile erection index was significantly increased with reduction in mount latency and intromission latency period. There were four-fold increase in mount and three-fold increase in intromission frequency in treated rats reflecting improved sexual performance. The behavioral and sexual parameters were also observed after a lapse of 7 and 15 days of discontinuance of drug treatment. CONCLUSION: Unlike testosterone, the PEE of Anacyclus pyrethrum shows efficacy in rats tested after the lapse of 7 and 15 days of discontinuation of treatment. This suggests that the drug has prolonged effect and capacitate the treated rats for improved sexual potential. PMID- 20727333 TI - An extract of the oyster mushroom, Pleurotus ostreatus, increases catalase gene expression and reduces protein oxidation during aging in rats. AB - OBJECTIVE: The objective of the present study was to address the effect of mushroom Pleurotus ostreatus on the catalase (CAT) gene expression and the protein carbonyls in liver and kidney of aged (24 months old) rats. METHODS: Eighteen acclimated rats were divided into 3 groups of 6 each: group I, normal young (4 months old) rats; group II, normal aged (24 months old) untreated rats; group III, normal aged rats treated with mushroom P. ostreatus extract (200 mg/kg body weight administered intraperitoneally for 30 days). On the 31st day, rats were sacrificed by decapitation; the livers and kidneys were removed, washed free of blood, blotted dry and processed immediately. Reverse transcriptase-polymerase chain reaction (RT-PCR) and spectrophotometry were utilized for the analyses of CAT gene expression and protein carbonyl content in the tissues of livers and kidneys. RESULTS: In aged rats that had been treated with the extract of P. ostreatus (group III), the level of the transcript of CAT gene was found to be higher than that in liver (P<0.01) and kidney (P<0.05) of aged untreated (group II) rats, respectively. Treatment of aged rats with P. ostreatus extract (group III) resulted in protein carbonyl levels being significantly lower in liver (P<0.05) and kidney (P<0.01) than those observed in aged untreated (group II) rats. CONCLUSION: These results suggest that an extract of P. ostreatus can enhance the antioxidant enzyme (CAT) gene expression and could decrease the incidence of free radical-induced protein oxidation in aged rats, thereby protecting the occurrence of age-associated disorders that involve free radicals. PMID- 20727334 TI - [Comparative study on hypoglycemic effects of different traditional Chinese medicine treatments in rats with diabetes mellitus induced by alloxan]. AB - OBJECTIVE: To observe hypoglycemic effects of Yunu Decoction, Zuogui Pill and Shenqi Pill, three compound traditional Chinese herbal medicines, in treatment of diabetes mellitus induced by alloxan in rats, and to compare the therapeutic effects among the three recipes for nourishing yin, clearing away heat, and nourishing yin and warming yang. METHODS: Diabetes mellitus was induced in rats with alloxan at a dose of 60 mg/kg via tail vain injection. The diabetic rats were randomly divided into four groups: alloxan model group, Yunu Decoction treated group, Zuogui Pill-treated group and Shenqi Pill-treated group. Rats in the three recipe groups were administered intragastrically with water extraction of Yunu Decoction, Zuogui Pill, and Shenqi Pill accordingly for 10 days. Then the level of blood glucose was measured by glucose oxidase method and the glucose tolerance was determined. RESULTS: Compared with the normal rats, blood glucose level in the alloxan model group was obviously increased (P<0.05). Glucose levels in the three recipe groups were obviously decreased as compared with the alloxan model group (P<0.05), and glucose level in the Yunu Decoction-treated group after treatment was significant lower than before treatment (P<0.05). The glucose tolerance test indicated that rats in the alloxan model and three recipe groups revealed impaired glucose tolerance as compared with the normal rats, and there were no significant differences between the alloxan model group and the three recipe groups. CONCLUSION: Yunu Decoction, Zuogui Pill and Shenqi Pill can effectively decrease the glucose level of the rats with diabetes mellitus induced by alloxan, and Yunu Decoction showed the best therapeutic effects. The glucose tolerance test shows that the three recipes cannot correct the abnormal metabolism of glucose. PMID- 20727335 TI - [Effects of medicinal extract for tonifying kidney to relieve asthma on glucocorticoid receptor expression in lung tissues of rats with bronchial asthma]. AB - OBJECTIVE: To observe the effects of medicinal extract for tonifying kidney to relieve asthma on glucocorticoid receptor (GR) expression in rats with asthma, and to explore its mechanism in treating asthma. METHODS: Sixty SD rats were randomly divided into normal control group, untreated group, dexamethasone group, and medicinal extract-prevented, medicinal extract-treated, and medicinal extract prevented and -treated groups, with ten rats in each group. Asthma was induced by intraperitoneal injection of ovalbumin (OVA) and forced inhalation of atomized OVA. Expression of GR in lung tissues was detected by immunohistochemical method. Pathological changes of the lung tissues were observed by HE straining. RESULTS: Expression of GR was lower in the untreated group than in the normal control group (P<0.05). Expressions of GR in medicinal extract groups were up-regulated as compared with those in the untreated group and dexamethasone group (P<0.05, P<0.01), and there were no significant differences as compared with the normal control group (P>0.05). CONCLUSION: Medicinal extract for tonifying kidney to relieve asthma can increase the expression of GR in lung tissues of asthmatic rats, which may be one of its mechanisms in preventing and treating asthma. PMID- 20727336 TI - Statistical expression and description of univariate quantitative data of single group design (part two). PMID- 20727337 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: Qi and blood differentiation of syndromes. PMID- 20727338 TI - Beyond temperature and precipitation: ecological risk factors that modify malaria transmission. AB - Being able to identify the ecological factors that impact risk for malaria would confer important predictive capacity to target malaria control interventions in a community. Temperature and water available for breeding habitats have been shown to be important primary ecological factors that impact the distribution of the malaria vectors and the rate at which the mosquito and parasite develop. However, to this point, studies focusing on the local level have been met with many inconsistent results when assessing malaria risk using both temperature and precipitation. This paper reviewed existing literature to determine if other ecological factors beyond temperature and water are present that may be modifying any associations present between ecological factors and malaria risk. It was found that the ability for water to pool and persist, water quality, elevation, deforestation, and agriculture have all been associated with malaria and may be modifying risk. Using the primary and modifying ecological variables, identifying the interactions between these factors and specific thresholds for increased malaria risk is critical: filling this knowledge gap would enable communities to develop tailored malaria control interventions targeted to their specific circumstances. PMID- 20727339 TI - Oviposition behaviour and parity rates of Aedes aegypti collected in sticky traps in Trinidad, West Indies. AB - The oviposition behaviour of Aedes aegypti was studied using sticky traps (ST), double sticky traps (DST) and standard ovitrap traps in urban St. Augustine and rural Tamana, Trinidad, West Indies. In St. Augustine three traps were deployed in 10 houses for 10 weeks while in Tamana traps were similarly deployed (10 houses for 10 weeks). At each house one ovitrap, one ST and one DST were placed using the criteria established for ovitrap placement. The results showed large numbers of adults collected, 3602 collected in DSTs and 1,670 adults collected in STs. In addition, >9000 immatures were collected in the DST vs >7000 in the STs. Over the 10 weeks 517 Ae. aegypti eggs were collected from ovitraps from Tamana and 3252 eggs from St. Augustine. Most of the females collected were parous (99%) with many older females collected e.g. 7 pars collected in both Tamana and St. Augustine. A major finding of the study was the observation of the "death stress oviposition" behaviour displayed among Ae. aegypti females captures in the sticky traps. This is the first report of this behaviour in the field and may well explain the collection of large numbers of immatures found in the ST and DSTs. The results of this study are discussed in the context of developing surveillance and control strategies, especially for reducing man-vector contact. PMID- 20727340 TI - Functional characterization of a naturally occurring trans-splicing intein from Synechococcus elongatus in a mammalian cell system. AB - We have cloned and characterized a naturally occurring split mini-DnaE intein capable of protein trans-splicing in the cyanobacterium Synechococcus elongatus (Sel DnaE intein). Sel DnaE intein is homologous to Synechocystissp. PCC6803 (Ssp) DnaE intein and Nostoc punctiforme (Npu) DnaE intein, with a protein sequence identity of 60% for the N-terminal part of intein and 61% for the C terminal part of intein. Our results demonstrate that the split reporters, split Renilla luciferase (Rluc) and enhanced green fluorescent protein (EGFP), can be reconstituted via Sel DnaE intein-mediated trans-splicing in mammalian cells. Based on Sel DnaE intein-mediated reconstitution of split Rluc, a human immunodeficiency virus (HIV) entry-mimicking cell-cell fusion assay was developed and validated as a useful assay for screening and pharmacologically characterizing potential HIV entry-targeting inhibitors. PMID- 20727341 TI - Stability comparison between sample preparation procedures for mass spectrometry based targeted or shotgun peptidomic analysis. AB - The quantification of neuropeptides may play a significant role in future drug development targeting central nervous system functions. Adequate method precision and accuracy is essential, and sample stability is an important factor. This study compares three sample preparation protocols and assesses the stability of targeted neuropeptides under standard laboratory conditions. The results show that the concentrations of substance P, dynorphin A, and calcitonin gene-related peptide (CGRP) change significantly in time when spinal cord tissues are homogenized in phosphate-buffered saline (PBS) buffer or PBS buffer containing a mammalian protease inhibitor cocktail but is stabilized when tissues are homogenized in a 0.25% trifluoroacetic acid solution. PMID- 20727342 TI - Real-time bioluminescent assay for inhibitors of RNA and DNA polymerases and other ATP-dependent enzymes. AB - Viral polymerases are important targets for drug development. However, current methods used to identify and characterize inhibitors of polymerases are time consuming, use radiolabeled reagents, and are cost-inefficient. Here we present a bioluminescent assay for the identification and characterization of inhibitors of polymerases, as well as other ATP-dependent enzymes, that monitors the decrease of ATP or dATP in real time, allowing detection of enzyme inhibition based on differences in ATP/dATP consumption. The assay works with a variety of RNA and DNA polymerases, using both RNA and DNA templates. The assay measures changes in substrate concentration in real time and provides a faster alternative for kinetic studies of inhibition. Michaelis-Menten plots were obtained from a single reaction, yielding K(m) values that compared well with literature values. The assay could identify the mechanism of inhibition and determine inhibition constants (K(i)) for a weak competitive inhibitor of Klenow fragment and two strong noncompetitive inhibitors of HIV-1 reverse transcriptase with one series of inhibitor concentrations, reducing the total number of experiments that would normally be needed. The assay is also sensitive enough to detect a weak inhibitor with K(i)>100 MUM, making it a viable technique for fragment-based drug discovery. PMID- 20727343 TI - Cell adhesive peptide screening of the mouse laminin alpha1 chain G domain. AB - Cell adhesive peptides have been widely applied for therapeutic drugs, drug delivery systems, and biomaterials. Previously, we identified various cell adhesive sequences in the G domains of four laminin alpha chains (alpha2-alpha5) by the systematic soluble peptide screening. We also identified five cell-binding sequences in the laminin alpha1 chain G domain using synthetic peptide polystyrene beads. Here, we re-screened cell adhesive peptides in the laminin alpha1 chain G domain by the systematic soluble peptides screening. The 110 soluble peptides were evaluated for their cell adhesive activities using human fibrosarcoma HT1080 cells and human dermal fibroblasts. Fourteen peptides were newly identified as a cell adhesive. Additionally, four peptides (AG22: SSFHFDGSGYAM, AG42: TFDLLRNSYGVRK, AG76: HQNQMDYATLQLQ, AG86: LGGLPSHYRARNI) promoted integrin-mediated cell adhesion. Further, neurite outgrowth activity with rat pheochromocytoma PC12 cells was evaluated and two peptides (AG20: SIGLWNYIEREGK, AG26: SPNGLLFYLASNG) were newly identified for neurite outgrowth activity. These results suggested that the systematic soluble peptides screening approach is an accurate and powerful strategy for finding biologically active sequences. The active sequences newly identified here could be involved in the biological functions of this domain. The active peptides are useful for evaluating molecular mechanisms of laminin-receptor interactions and for developing cell adhesive biomaterials. PMID- 20727344 TI - Autoproteolysis of the SEA module of rMuc3 C-terminal domain modulates its functional composition. AB - rMuc3 is a typical transmembrane mucin and contains a 174 amino acid domain called an SEA module in its C-terminal domain which is cleaved in eukaryotic cells. However, the mechanism by which the rMuc3 SEA module is proteolyzed and its biological significance has to be elucidated. In this study, we showed that the rMuc3 C-terminal domain was cleaved at LSKGSIVV motif within SEA module in prokaryotic cells, the time-dependence of the cleavage was found in the purified rMuc3 C-terminal domain carrying a mutated LSKASIVV motif expressed in bacteria. Thus, the cleavage of rMuc3 SEA module depended on autoproteolysis. The autoproteolysis of the SEA module of rMuc3 C-terminal domain played a critical role in the migration and invasion of the LoVo human colon cancer cells with rMuc3 C-terminal domain in vitro. The rMuc3 C-terminal domain induced a significant activation of HER/ErbB2 phosphorylated form (py1248) in LoVo cells. Inhibition of the phosphorylation by gefitinib (ZD1839) did attenuate migration and invasion of LoVo cells with rMuc3 C-terminal domain. Thus, rMuc3 C-terminal domain undergoes autoproteolysis at its SEA module, which maintains its availability for the potentiation of the signaling process that is modulated by HER/ErbB2 phosphorylation to promote the migration and invasion of LoVo cells. PMID- 20727345 TI - Effects of bilayer composition and physical properties on the phospholipase C and sphingomyelinase activities of Clostridium perfringens alpha-toxin. AB - alpha-Toxin, a major determinant of Clostridium perfringens toxicity, exhibits both phospholipase C and sphingomyelinase activities. Our studies with large unilamellar vesicles containing a variety of lipid mixtures reveal that both lipase activities are enhanced by cholesterol and by lipids with an intrinsic negative curvature, e.g. phosphatidylethanolamine. Conversely lysophospholipids, that possess a positive intrinsic curvature, inhibit the alpha-toxin lipase activities. Phospholipids with a net negative charge do not exert any major effect on the lipase activities, and the same lack of effect is seen with the lysosomal lipid bis (monoacylglycero) phosphate. Ganglioside GT1b has a clear inhibitory effect, while the monosialic ganglioside GM3 is virtually ineffectual even when incorporated at 6mol % in the vesicles. The length of the lag periods appears to be inversely related to the maximum (post-lag) enzyme activities. Moreover, and particularly in the presence of cholesterol, lag times increase with pH. Both lipase activities are sensitive to vesicle size, but in opposite ways: while phospholipase C is higher with larger vesicles, sphingomyelinase activity is lower. The combination of our results with previous structural studies suggests that alpha-toxin lipase activities have distinct, but partially overlapping and interacting active sites. PMID- 20727346 TI - Towards a thermodynamic definition of efficacy in partial agonism: The thermodynamics of efficacy and ligand proton transfer in a G protein-coupled receptor of the rhodopsin class. AB - The thermodynamic binding profiles of agonist and antagonist complexes of the 4 hydroxypropanolamine partial agonist, prenalterol, on the chronotropic adrenergic response in guinea-pig right atria were determined over a 15 degrees C temperature range. The tissue response was compared with data on the ethanolamine agonist, isoprenaline, given by binding studies in a number of rat tissues. Utilising the residue conservatism surrounding the known active conformers bound to either of two aspartate residues (alpha-helices II, III) in both receptors (beta(1), beta(2)) and species (guinea-pig, rat and human), no significant deformation in the extended side chain could be found in prenalterol's agonist binding compared to isoprenaline. Antagonist binding gave a highly favourable entropy contribution at 30.0 degrees C of -4.7+/-1.2 kcal/mol. The enthalpy change between bound agonist and antagonist complexes, a function of the efficacy alone, was -6.4+/-1.1 kcal/mol, coincident with the calculated intrinsic preference of a primary/secondary amine-aspartate interaction for a neutral hydrogen-bonded form over its ion pair state, giving values of 6.3-6.6 kcal/mol with calculations of good quality, a figure expected to be close to that shown within a hydrophobic environment. Delivery of a proton to a conserved aspartate anion (alpha-helix II) becomes the critical determinant for agonist action with resultant proton transfer stabilisation dominating the enthalpy change. A proposed monocation-driven ligand proton pumping mechanism within the ternary complex is consistent with the data, delivery between two acid groups being created by the movement of the cation and the counter-movement of the ligand protonated amine moving from Asp 138 (alpha-helix III) to Asp 104 (alpha-helix II). PMID- 20727347 TI - Importance of HPLC confirmation of problematic carbohydrate-deficient transferrin (CDT) results from a multicapillary electrophoresis routine method. AB - BACKGROUND: This study presents results from a routine laboratory setup for carbohydrate-deficient transferrin (CDT) measurement, using initial capillary electrophoresis (CE) analysis and, in problematic cases, further investigation by high-performance liquid chromatography (HPLC). METHODS: CDT by the Capillarys CDT assay (disialo- and asialotransferrin) was measured on a Capillarys 2 multicapillary CE system (Sebia). In cases of abnormal peak profiles or other interferences in the electropherogram, samples were remeasured following sample cleanup by "Sample treatment" (Sebia). If the problems remained, or otherwise when confirmatory testing was considered important, samples were analysed by an HPLC candidate reference method. RESULTS: In about 0.6% of the routine specimens, reanalysis was performed after sample cleanup. Confirmatory HPLC analysis was needed in half of the cases. Quantification problems were observed for genetic transferrin variants and samples showing a variety of abnormal peak profiles. In these cases, HPLC analysis provided accurate quantification, or at least an estimation (positive/negative), of the CDT level. Confirmatory HPLC analysis was also important for evaluation of borderline values, because only part of those cases were indicated to be true positives. CONCLUSIONS: These results indicated that a routine laboratory setup for CDT measurement, using initial high throughput multicapillary CE analysis with a confirmatory HPLC analysis option, will combine rapid quantitative and qualitative workflow with enhanced patient safety. PMID- 20727348 TI - The clinical use of N-terminal-pro brain natriuretic peptide in elderly patients with mental illness. AB - BACKGROUND: Serum N-terminal-pro brain natriuretic peptide (NT-proBNP) is regarded as a marker of vascular disease and has previously been shown to exhibit an increased frequency of pathological values in elderly patients with mental illness with vascular disease compared to patients without vascular disease. Vascular disease plays an important role in cognitive impairment in elderly patients with mental illness. METHOD: We have investigated the relation between NT-proBNP, vascular disease and cognition in consecutively enrolled elderly patients with mental illness. RESULTS: NT-proBNP level is increased in patients with vascular disease compared to patients without vascular disease, and a logistic regression analysis showed that NT-proBNP was a significant predictor of vascular disease. However, NT-proBNP level did not predict cognition as assessed by MMSE score. NT-proBNP level also showed a highly significant relation to mortality in all patients. CONCLUSION: Determinations of NT-proBNP could be used in elderly patients with mental illness to detect patients in need of control and treatment of vascular risk factors. The levels of NT-proBNP may also provide prognostic information. PMID- 20727349 TI - Identification and validation of specific methylation profile in bile for differential diagnosis of malignant biliary stricture. AB - OBJECTIVE: This study was aimed to identify the specific methylation profile in bile specimens of pancreaticobillary diseases for differential diagnosis of malignant biliary stricture. DESIGN AND METHODS: In a total of 80 bile specimens from pancreaticobillary diseases, the methylation status of 19 tumor suppressor genes were analyzed by methylation-specific PCR and the methylation index (MI) were compared between the malignant and benign groups. RESULTS: Methylation of DKK3, p16, SFRP2, DKK2, NPTX2 and ppENK were more frequently detected in the bile of malignant biliary strictures than benign patients. When setting MI 0.5 as the threshold, this 6-gene panel could distinguish the malignant biliary stricture with a high sensitivity, specificity and accuracy (77.27%, 77.78% and 77.50%, respectively). CONCLUSION: The methylation profile including 6 specific genes in bile may be a promising biomarker for differential diagnosis between malignant and benign biliary strictures. PMID- 20727350 TI - Fibroblast and prostate tumor cell cross-talk: fibroblast differentiation, TGF beta, and extracellular matrix down-regulation. AB - Growth and survival of tumors at a site of metastasis involve interactions with stromal cells in the surrounding environment. Stromal cells aid tumor cell growth by producing cytokines as well as by modifying the environment surrounding the tumor through modulation of the extracellular matrix (ECM). Small leucine-rich proteoglycans (SLRPs) are biologically active components of the ECM which can be altered in the stroma surrounding tumors. The influence tumor cells have on stromal cells has been well elucidated. However, little is understood about the effect metastatic cancer cells have on the cell biology and behavior of the local stromal cells. Our data reveal a significant down-regulation in the expression of ECM components such as collagens I, II, III, and IV, and the SLRPs, decorin, biglycan, lumican, and fibromodulin in stromal cells when grown in the presence of two metastatic prostate cancer cell lines PC3 and DU145. Interestingly, TGF beta down-regulation was observed in stromal cells, as well as actin depolymerization and increased vimentin and alpha5beta1 integrin expression. MT1 MMP expression was upregulated and localized in stromal cell protrusions which extended into the ECM. Moreover, enhanced stromal cell migration was observed after cross-talk with metastatic prostate tumor cells. Xenografting metastatic prostate cancer cells together with "activated" stromal cells led to increased tumorigenicity of the prostate cancer cells. Our findings suggest that metastatic prostate cancer cells create a metastatic niche by altering the phenotype of local stromal cells, leading to changes in the ECM. PMID- 20727351 TI - In-vitro culture of Plasmodium falciparum: utility of modified (RPNI) medium for drug-sensitivity studies using SYBR Green I assay. AB - Studies were carried out to establish the potential of RPNI medium for drug sensitivity studies using the MSF assay. The drug sensitivity of standard anti malarials was compared using both the ((3)H) Hypoxanthine incorporation assay and the MSF assay. The media supplements used during the study have been human serum, FBS and ALBUMAX-II. Drug sensitivity of two parasite lines, adapted to grow separately in conventional as well as in RPNI medium was compared to observe the effect of RPNI medium on functional characteristics of the parasite. The results revealed identical IC(50) values of standard anti-malarials obtained by both the ((3)H) Hypoxanthine incorporation assay and the MSF assay and no untoward effect of FBS and ALBUMAX-II could be noticed on the chemo-sensitivity of standard anti malarials. Apart from this the chemo-sensitive response of parasite line adapted to grow in RPNI medium was observed to be intact. These findings showed that RPNI medium has potential to be used for chemo-sensitivity studies and the MSF assay being more convenient was observed to be most suitable assay for bio evaluation of new molecules. PMID- 20727352 TI - NADH oxidase activity of Bacillus subtilis nitroreductase NfrA1: insight into its biological role. AB - NfrA1 nitroreductase from the Gram-positive bacterium Bacillus subtilis is a member of the NAD(P)H/FMN oxidoreductase family. Here, we investigated the reactivity, the structure and kinetics of NfrA1, which could provide insight into the unclear biological role of this enzyme. We could show that NfrA1 possesses an NADH oxidase activity that leads to high concentrations of oxygen peroxide and an NAD(+) degrading activity leading to free nicotinamide. Finally, we showed that NfrA1 is able to rapidly scavenge H(2)O(2) produced during the oxidative process or added exogenously. PMID- 20727353 TI - DNA methylation systems and targets in plants. AB - Plants contain three distinct DNA methyltransferase types that are responsible for the establishment and maintenance of cytosine methylation patterns at heterochromatic and euchromatic target regions. RNA transcripts play an important role in recruiting DNA methylation systems to specific loci, where methylation patterns are controlled by distinct epigenetic pathways that often work co operatively and in competition with demethylation functions. DNA methylation patterns are faithfully propagated by maintenance systems that involve re enforcing feedback effects between DNA methylation and histone marks. Our detailed knowledge about the composition of DNA methylation patterns is contrasted by a poorer understanding of the variability of DNA methylation and its contribution to gene regulation, genome evolution and adaptation to environmental changes. PMID- 20727354 TI - ATR-FTIR study of the protonation states of the Glu residue in the multicopper oxidases, CueO and bilirubin oxidase. AB - Redox-induced protonation state changes of the Glu residue in the multicopper oxidases, CueO and bilirubin oxidase (BO), were studied by attenuated total reflectance-Fourier transform infrared spectroscopy. By monitoring IR bands of the carboxylic acid C=O stretch in the wild-type and Glu-to-Gln mutant enzymes the Glu506 of CueO (Glu463 of BO) was found to be unprotonated in the oxidised and protonated in the reduced forms. The results provided direct evidence for proton uptake by the Glu, suggesting it plays a key role in the proton donation to the activated oxygen species in the catalytic cycle. PMID- 20727355 TI - Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. AB - BACKGROUND & AIMS: In the small intestine, the paracellular transport of Na(+) is thought to be critical for luminal Na(+)-homeostasis and the transcellular absorption of nutrients by Na(+)-driven transporters. Na(+) is supplied to the intestinal lumen from the submucosa and serum through tight junctions, which form a paracellular barrier between the cells of epithelial sheets. However, the molecular basis for this paracellular transport of Na(+) is not well understood. Here, we examined this mechanism by performing loss-of-function studies of claudin-2 and claudin-15, two tight-junctional membrane proteins that are specifically and age-dependently expressed in the villi and/or crypts of small intestinal epithelia. METHODS: Knockout mice for claudin-2 or claudin-15 were subjected to histologic, cell biologic, electrophysiologic, and physiologic analyses. RESULTS: Examination of the knockout mice revealed that both claudin-2 and claudin-15 play crucial roles in the transepithelial paracellular channel like permselectivity for extracellular monovalent cations, particularly Na(+), in infants and adults. Especially in Cldn15(-/-) adults, the luminal Na(+) concentration in the small intestine measured directly in vivo was abnormally low, and glucose absorption was impaired, as assessed by the oral glucose tolerance test and estimation of unabsorbed glucose. CONCLUSIONS: We propose that the "Na(+)-leaky" claudin-15 is indispensable in vivo for the paracellular Na(+) permeability, luminal Na(+)-homeostasis, and efficient glucose absorption in the small intestine, but claudin-2 is indispensable for only the first of these functions. Claudin-15 knockout leads to Na(+) deficiency and glucose malabsorption in the mouse adult small intestine. PMID- 20727356 TI - Differential thresholds of neuromedins B-, C-, and bombesin-induced anorexia and crop-emptying rate in chicks. AB - Neuromedin B (NMB) and neuromedin C (NMC) are homologs of bombesin and are distributed throughout both the brain and gastrointestinal tract. The physiological roles of these bombesin-like peptides in chicks (Gallus gallus) have not been documented. Therefore, the purpose of the present study was to measure the effects of these bombesin-like peptides on food intake, crop-emptying rate and body temperature in chicks, and then to compare these effects with those of bombesin. Intracerebroventricular (ICV, 5 nmol) and intraperitoneal (IP, 300 nmol/kg) injections of NMB, NMC, and bombesin significantly decreased food deprivation-induced food intake. When ICV injected (5 nmol), all three peptides significantly reduced crop-emptying rate. IP injection of NMC and bombesin (300 nmol/kg) also reduced crop-emptying rate while NMB did not. The magnitude of food intake suppression and crop-emptying rate reduction were greater for bombesin than NMB and NMC. ICV and IP injections of NMB, NMC and bombesin did not affect cloacal temperature. In sum, the present study suggests that central and peripheral NMB and NMC are associated with reduced food intake and crop-emptying of chicks, but these effects are weaker than those of bombesin. PMID- 20727357 TI - Testosterone and partnering are linked via relationship status for women and 'relationship orientation' for men. AB - Cross-cultural evidence links pair bonding and testosterone (T). We investigated what factors account for this link, how casual relationships are implicated, and whether gender/sex moderates these patterns in a North American sample. We gathered saliva samples for radioimmunoassay of T and self-report data on background, health, and social/relational variables from 115 women and 120 men to test our predictions, most of which were supported. Our results show that singles have higher T than long-term (LT) partnered individuals, and that casual relationships without serious romantic commitment are more like singlehood for men and LT relationships for women-in terms of T. We were also able to demonstrate what factors mediate the association between partnering and T: in women, frequency of partnered sexual activity mediated the effect in men, interest in more/new partners mediated the effect. This supported our prediction of relationship status interpretations in women, but relationship orientation in men. Results replicated past findings that neither sexual desire nor extrapair sexuality underlie the T-partnering link. We were able to rule out a large number of viable alternative explanations ranging from the lifestyle (e.g., sleep) to the social (e.g., social support). Our data thus demonstrate pattern and mediators for the development of T-pair bonding associations, and emphasize the importance of neither under- nor overstating the importance of gender/sex in research about the evolution of intimacy. PMID- 20727358 TI - Multifactorial determinants of protein expression in prokaryotic open reading frames. AB - A quantitative description of the relationship between protein expression levels and open reading frame (ORF) nucleotide sequences is important for understanding natural systems, designing synthetic systems, and optimizing heterologous expression. Codon identity, mRNA secondary structure, and nucleotide composition within ORFs markedly influence expression levels. Bioinformatic analysis of ORF sequences in 816 bacterial genomes revealed that these features show distinct regional trends. To investigate their effects on protein expression, we designed 285 synthetic genes and determined corresponding expression levels in vitro using Escherichia coli extracts. We developed a mathematical function, parameterized using this synthetic gene data set, which enables computation of protein expression levels from ORF nucleotide sequences. In addition to its practical application in the design of heterologous expression systems, this equation provides mechanistic insight into the factors that control translation efficiency. We found that expression is strongly dependent on the presence of high AU content and low secondary structure in the ORF 5' region. Choice of high frequency codons contributes to a lesser extent. The 3' terminal AU content makes modest, but detectable contributions. We present a model for the effect of these factors on the three phases of ribosomal function: initiation, elongation, and termination. PMID- 20727359 TI - Coevolution of antibody stability and Vkappa CDR-L3 canonical structure. AB - Antibodies recognize antigens through six hypervariable loops, five of which have a limited set of conformations known as canonical structures. For kappa light chains, the majority of CDR-L3 [the third hypervariable loop of the light chain variable domain (V(L))] adopts the type 1 canonical structure (CS1), with a cis proline at position 95. Here, we present the design and structural studies of the monoclonal antibody mAb15 and related mutants that contained a series of progressively germline mutations only in the heavy chain variable domain (V(H)) that ultimately led to an increase of more than 11 degrees C in the melting temperature (T(m)) of the antigen-binding fragment (Fab). The all-trans CDR-L3 structure in the wild type is significantly different from any known CDR-L3 canonical structures. In the thermally stable mutants, the L94(L)-S95(L) peptide bond adopts an energetically unfavorable non-X-proline cis conformation, but the overall CDR-L3 loop converted to CS1. The stabilized V(H) appears to function as a specific molecular chaperone that facilitated the trans-cis isomerization of S95(L). Thus, it is plausible that proline is the evolutionary choice to maintain overall structure and stability for V(L). These results provide new insights into the evolution of CS1 and suggest a potential molecular switch mechanism at position 95 that links CDR-L3 structural diversity and antibody stability and will have implications for antibody engineering. PMID- 20727360 TI - Crystal structure of zebrafish hatching enzyme 1 from the zebrafish Danio rerio. AB - Fish hatching enzymes are zinc metalloproteases that digest the egg envelope (chorion) at the time of hatching. The crystal structure of zebrafish hatching enzyme 1 (ZHE1) has been solved at 1.10 A resolution. ZHE1 is monomeric, is mitten shaped, and has a cleft at the center of the molecule. ZHE1 consists of three 3(10)-helices, three alpha-helices, and two beta-sheets. The central cleft represents the active site of the enzyme that is crucial for substrate recognition and catalysis. Alanine-scanning mutagenesis of the two substrate peptides has shown that AspP1' contributes the most and that the residues at P4 P2' also contribute to the recognition of the major substrate peptide by ZHE1, whereas GluP3' and the hydrophobic residues at P4-P2, P2', and P5' contribute significantly to the recognition of the minor substrate peptide by ZHE1. Molecular models of these two substrate peptides bound to ZHE1 have been built based on the crystal structure of a transition-state analog inhibitor bound to astacin. In substrate-recognition models, the AspP1' in the major substrate peptide forms a salt bridge with Arg182 of ZHE1, while the GluP3' in the minor substrate peptide instead forms a salt bridge with Arg182. Thus, these two substrate peptides would be differently recognized by ZHE1. The shapes and electrostatic potentials of the substrate-binding clefts of ZHE1 and the structurally similar proteins astacin and bone morphogenetic protein 1 are significantly dissimilar due to different side chains, which would confer their distinctive substrate preferences. PMID- 20727361 TI - Enzymes involved in osmolyte synthesis: how does oxidative stress affect osmoregulation in renal cells? AB - Kidney medulla cells are exposed to a wide range of changes in the ionic and osmotic composition of their environment as a consequence of the urine concentrating mechanism. During antidiuresis NaCl and urea concentrations increase and an efficient urinary concentrating mechanism is accompanied by medullar hypoxia. Medullar hypotonicity increases reactive oxygen species, a byproduct of mitochondria during ATP production. High intracellular ionic strength, hypoxia and elevated ROS concentration would have deleterious effects on medulla cell function. Medulla cells respond to hypertonicity by accumulating organic osmolytes, such as glycine betaine, glycerophosphorylcholine, sorbitol, inositol, and taurine, the main functions of which are osmoregulation and osmoprotection. The accumulation of compatible osmolytes is thus crucial for the viability of renal medulla cells. Studies about the effects of reactive oxygen species (ROS) on the enzymes involved in the synthesis of osmolytes are scarce. In this review we summarize the information available on the effects of ROS on the enzymes involved in osmolyte synthesis in kidney. PMID- 20727362 TI - Progressive ratio responding in an obese mouse model: Effects of fenfluramine. AB - The progressive ratio schedule of operant responding is a well utilised task for assessing the rewarding aspects of abused drugs and natural rewards including food. Interestingly, progressive ratio paradigms have mainly been neglected in the field of animal research in obesity. Among the most widely studied mouse models of obesity is the leptin-deficient ob/ob mouse, characterised by hyperphagia and obesity. To date there are no studies on the behaviour of these mice in progressive ratio responding, thus we sought to validate the utility of the progressive ratio paradigm in obese mice and demonstrate its sensitivity to an anorectic drug challenge. Ob/ob mice and their lean controls were tested in fixed ratio paradigms of different demand, extinction learning, and progressive ratio schedules with linear and exponential increments, followed by an anorectic drug challenge with fenfluramine (5 and 10 mg/kg). Obese animals showed equal fixed ratio-acquisition and -responding for ratios 1 and 3, but displayed lower responding in ratios 6 and 9. Interestingly, obese animals showed equal motivation to respond in progressive ratio schedules. Fenfluramine dose dependently induced anorectic effects in both genotypes and reduced progressive ratio responding significantly. This study, for the first time, describes motivational food intake in an operant progressive ratio paradigm in ob/ob mice. Leptin deficiency did not alter appetitive learning or motivation in the progressive ratio. The utility and sensitivity of the progressive ratio task for studies on motivational food intake was demonstrated by a challenge with the anorectic agent fenfluramine. PMID- 20727363 TI - Sensing G protein-coupled receptor activation. AB - G protein-coupled receptors (GPCRs) are the key elements of a highly regulated transduction machinery that generates different signaling outcomes to hormones and neurotransmitters. Until recently, it was assumed that diverse ligands of a given GPCR differ only in their ability to alter the balance between the OFF and the ON state of the receptor. However, it has now become evident that their activation mechanisms are more complex and that receptors presumably display distinguishable active conformational states, which are induced by different agonists and correlate to specific signaling outputs. The use of different labeling strategies to insert fluorescent labels into purified, reconstituted receptors, or into receptors in intact cells, has made it possible to sense receptor activation via changes in their fluorescence. Here, we summarize recent progress in the analysis of agonist-dependent activation mechanisms of GPCRs acquired using modern spectroscopic and crystallographic techniques. PMID- 20727365 TI - The amygdala and FFA track both social and non-social face dimensions. AB - The amygdala is thought to perform a number of social functions, and has received much attention for its role in processing social properties of faces. In particular, it has been shown to respond more to facial expressions than to neutral faces, and more to positively valenced and negatively valenced faces than faces in the middle of the continuum. However, when these findings are viewed in the context of a multidimensional face space, an important question emerges. Face space is a vector space where every face can be represented as a point in the space. The origin of the space represents the average face. In this context, positively valenced and negatively valenced faces are further away from the average face than faces in the middle of the continuum. It is therefore unclear if the amygdala response to positively valenced and negatively valenced faces is due to their social properties or to their general distance from the average face. Here, we compared the amygdala response to a set of faces that varied along two dimensions centered around the average face but differing in social content. In both the amygdala and much of the posterior face network, we observed a similar response to both dimensions, with stronger responses to the extremes of the dimensions than to faces near the average face. These findings suggest that the responses in these regions to socially relevant faces may be partially due to general distance from the average face. PMID- 20727364 TI - Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure. AB - Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 at GABA(A) receptors containing alpha1, alpha2, alpha3 and alpha5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing alpha1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing alpha2, alpha3 and alpha5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA(A) receptors containing alpha1 and alpha5 subunits. In contrast, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA(A) receptors containing alpha2, alpha3 and alpha5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA(A) receptor positive modulators are dependent on their relative efficacy and affinity at different GABA(A) receptor subtypes. PMID- 20727366 TI - Synthesis of dehydroepiandrosterone analogues modified with phosphatidic acid moiety. AB - Dehydroepiandrosterone (DHEA) and its metabolite 7alpha-OH DHEA have many diverse physiological, biological and biochemical effects encompassing various cell types, tissues and organs. In in vitro studies, DHEA analogues have myriad biological actions, but in vivo, especially in oral administration, DHEA produces far more limited clinical effects. One of the possible solutions of this problem is conversion of DHEA to active analogues and/or its transformation into prodrug form. In this article, the studies on the conversion of DHEA and 7alpha-OH DHEA into their phosphatides by the phosphodiester approach are described. In this esterification, N,N-dicyclohexylcarbodiimide (DCC) was the most efficient coupling agent as well as p-toluenesulphonyl chloride (TsCl). PMID- 20727367 TI - Evolution of learning capacities and learning levels. AB - Humans strongly depend on individual and social learning, both of which are highly effective and accurate. I study the effects of environmental change on the evolution of the effectiveness and accuracy of individual and social learning (individual and social learning levels) and the number of pieces of information learned individually and socially (individual and social learning capacities) by analyzing a mathematical model. I show that individual learning capacity decreases and social learning capacity increases when the environment becomes more stable; both decrease when the environment becomes milder. I also show that individual learning capacity increases when individual learning level increases or social learning level decreases, while social learning capacity increases when individual or social learning level increases. The evolution of high learning levels can be triggered when the environment becomes severe, but a high social learning level can evolve only when a high individual learning level can simultaneously evolve with it. PMID- 20727369 TI - Lactoferrin increases both resistance to Salmonella typhimurium infection and the production of antibodies in mice. AB - Lactoferrin (Lf) is a multifunctional iron-binding glycoprotein with antibacterial and immunomodulatory activities. The antibacterial influence of orally administered bovine Lf (bLf) against murine infection caused by Salmonella typhimurium (S. typhimurium) has scarcely been explored. In the current study, Balb/c mice were treated orally for 7 days with either 5 or 100mg of bovine lactoferrin (bLf). On day 7 of treatment, mice were intragastrically infected with a lethal or sublethal dose of colony forming units (CFU) of S. typhimurium. During treatment with bLf, feces from mice sublethally infected were harvested daily to prepare fecal suspensions, which were serially diluted and plated onto Salmonella Shigella agar to estimate CFU/g of feces. After sacrificing the animals on day 7, 14 or 21 post-infection, samples of intestinal fluid, Peyer's patches (PP), liver and spleen were collected to count the number of CFU by plate dilution. Intestinal secretions were also employed, along with serum samples, to evaluate total IgA, IgG and IgM antibodies, and those against Salmonella surface proteins and bLf by ELISA assay. In lethally infected mice both bLf doses decreased mortality. In sublethally infected mice, both bLf doses decreased bacterial shedding in feces and intestinal fluid, and also reduced bacterial colonization at PP and bacterial translocation in the liver and spleen. Levels of total and those IgG and IgM in serum and IgA in intestinal secretions against Salmonella surface proteins and bLf were enhanced with both doses of bLf. These findings suggest that the effect of bLf against the infection by S. typhimurium in mice may be the result of an antimicrobial activity linked with its modulatory effect on immunocompetent cells (from intestinal and peripheral organs) involved in antibody production. PMID- 20727370 TI - Optimized approaches for the sequence determination of double-stranded RNA templates. AB - Double-stranded RNA (dsRNA) is in many cases the only available template for molecular and diagnostic studies of RNA viruses. A novel mycovirus with a five dsRNAs segmented-genome served as a model system for the amplification and cloning of dsRNA segments using several PCR-based methods. Sequences obtained by the classical method; random PCR (rPCR) with a single primer assembled into 4 contigs out of the 5 segments. Moreover, using a modified single primer amplification technique (SPAT) resulted in the amplification of all or part of the dsRNA segments in one RT-PCR. Introducing such modifications into the FLAC method (full-length amplification of cDNA) resulted in amplicons comparable to those of the SPAT method. Full-length PCR products representing the five genomic segments were cloned and sequenced. The optimized conditions for each method are presented and discussed. In another approach, purified dsRNA segments were cloned directly into the blunt end pJET1.2 or the pGEM((r))-T cloning vectors with low efficiency though. This led to several sequences up to 2.2kb in length, which could constitute a starting material for other methods like primer walking or as probes for diagnosis. PMID- 20727368 TI - GSK-3beta activity and hyperdopamine-dependent behaviors. AB - Dopamine plays important roles in normal brain function and many neuropsychiatric disorders. Classically, dopamine receptors are positively coupled to G protein mediated signaling to regulate cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and Ca(2+) pathways. However, emerging evidence indicates that under hyperdopaminergic conditions, the protein kinase B (Akt)-glycogen synthase kinase 3beta (GSK-3beta) signaling cascade may mediate dopamine actions via D(2)-like receptors. This cAMP-independent signaling pathway involves the regulation of downstream synaptic targets, e.g., AMPA receptor, NMDA receptors, and thus synaptic plasticity. Here we provide an overview of how this novel signaling pathway relays dopamine receptor-mediated responses, particularly hyperdopamine dependent behaviors. We discuss the relevance of the Akt/GSK-3beta signaling cascade for the expression of dopamine-dependent behaviors and the drug actions associated with dopaminergic systems. PMID- 20727371 TI - Mutational analysis of predicted extracellular domains of human growth hormone secretagogue receptor 1a. AB - The Class A family of guanine nucleotide-binding protein (G protein)-coupled receptors that includes receptors for motilin, ghrelin, and growth hormone secretagogue (GHS) has substantial potential importance as drug targets. Understanding of the molecular basis of hormone binding and receptor activation should provide insights helpful in the development of such drugs. We previously reported that Cys residues and the perimembranous residues in the extracellular loops and amino-terminal tail of the motilin receptor are critical for peptide ligand, motilin, binding and biological activity. In the current work, we focused on the predicted extracellular domains of the human GHS receptor 1a, and identified functionally important residues by using sequential deletions ranging from one to twelve amino acid residues and site-directed replacement mutagenesis approach. Each construct was transiently expressed in COS cells, and characterized for ghrelin- and growth hormone releasing peptide (GHRP)-6 stimulated intracellular calcium responses and ghrelin radioligand binding. Cys residues in positions 116 and 198 in the first and second extracellular loops and the perimembranous Glu187 residue in the second extracellular loop were critical for ghrelin and GHRP-6 biological activity. These results suggest that Cys residues in the extracellular domains in this family of Class A G protein-coupled receptor is likely involved in the highly conserved and functionally important disulfide bond, and that the perimembranous residues contribute peptide ligand binding and signaling. PMID- 20727372 TI - A single session of circuit-resistance exercise effects on human peripheral blood lymphocyte ABCA1 expression and plasma HDL-C level. AB - ATP-binding cassette transporters transfer a variety of substrates across the lipid bilayers in an energy-dependent manner. ABCA1 is a member of this family which plays a crucial role in plasma HDL-C metabolism. The purpose of this study was to investigate ABCA1 expression in lymphocytes, plasma lipids and lipoprotein levels in response to a single session of circuit-resistance exercise. Twenty female students volunteered and randomly assigned to control, 40%, 60%, 80% one repetition maximum groups. Subjects performed a single session of CRE (9 exercises, 25s per exercise, 3 sets of 3 non-stop circuits, and 1 min rest between the sets). Blood mononuclear cells were isolated for ABCA1 mRNA expression. Plasma glucose, lipids and lipoprotein concentrations were measured. Lymphocyte ABAC1 mRNA expression was significantly (P < 0.001) increased in all given exercise intensities. Total WBC, lymphocyte, neutrophil, platelet counts, plasma glucose, and triglyceride concentrations were also significantly increased after exercise. Changes in plasma HDL-C, LDL-C and TC, concentrations were not significant. In conclusion, a single session of CRE increased PBL ABCA1 expression that was more pronounced in 60% and 40% 1RM groups but not accompanied with significant changes in HDL-C concentrations. Thus, CRE with moderate intensities provide bigger increases of PLB ABCA1 expression not plasma HDL-C levels. PMID- 20727373 TI - Evaluation of salivary endothelin-1 levels in oral squamous cell carcinoma and oral leukoplakia. AB - Oral squamous cell carcinoma (OSCC) is the most frequent malignant neoplasia of the oral cavity, which largely compromises the patient's life quality. Therefore, the identification of biomarkers for this kind of cancer is essential to provide a better diagnosis and prognosis for patients. Endothelin-1 is a peptide produced mainly by endothelial cells, and might be found in several body fluids, such as saliva, milk, urine, cerebrospinal fluid and plasma. It has been demonstrated that expression of this peptide is increased in a great number of neoplasias, including oral carcinoma. The identification of salivary biomarkers would be a useful tool for scanning and monitoring patients with risk of developing OSCC, as well to early detect recurrence, or the formation of a new primary tumor. In the present study, we have analyzed the levels of endothelin-1 in saliva obtained from patients with OSCC or oral leukoplakia, in comparison to healthy control patients. This study also evaluated the salivary ET-1 levels in patients with complete remission of OSCC. The results revealed no statistical difference in salivary endothelin-1 levels, neither in OSCC nor in oral leukoplakia, even when conditions such as elderly, sex and hypertension were taken into consideration. Although, ET-1 might display an important role in OSCC, its levels in saliva do not seem to be a good marker of neoplasias grade or malignant transformation. PMID- 20727374 TI - Adrenomedullin reduces expression of adhesion molecules on lymphatic endothelial cells. AB - Adrenomedullin (AM) is a novel vasoactive peptide which regulates vascular tone and vascular endothelial cell growth. We recently reported that lymphatic endothelial cells (LECs) are also an attractive target of AM and concluded that AM is a potent mediator of lympangiogenesis. In the present study, we conducted a genome-wide analysis of genes that are regulated by AM in LECs. AM profoundly suppressed gene expression of cell adhesion receptors and inflammatory factors in LECs, such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), endothelial adhesion molecule-1 (E-selectin), interleukin-8, and chemokines, QRT-PCR and flow cytometry analysis showed that AM dose dependently suppressed the TNF-a-induced mRNA and protein expression of ICAM-1 and VCAM-l. Treatment of LECs with a cell permeable cyclic adenosine monophosphate (cAMP) analog, 8-Br-cAMP, mimicked the suppressive effect of AM on the expression of adhesion molecules. Moreover, both AM and 8-Br-cAMP suppressed TNF-alpha-induced NF-kappaB activation in LECs, indicating that AM reduces expression of adhesion molecules in LECs via a cAMP/NF-kB dependent pathway. These results suggest that AM may have an important role in the regulation of the expression of adhesion molecules in lymphatic endothelium, which is critical in the control of immune and inflammatory responses. PMID- 20727375 TI - Bcs1p can rescue a large and productive cytochrome bc(1) complex assembly intermediate in the inner membrane of yeast mitochondria. AB - The yeast cytochrome bc(1) complex, a component of the mitochondrial respiratory chain, is composed of ten distinct protein subunits. In the assembly of the bc(1) complex, some ancillary proteins, such as the chaperone Bcs1p, are actively involved. The deletion of the nuclear gene encoding this chaperone caused the arrest of the bc(1) assembly and the formation of a functionally inactive bc(1) core structure of about 500-kDa. This immature bc(1) core structure could represent, on the one hand, a true assembly intermediate or, on the other hand, a degradation product and/or an incorrect product of assembly. The experiments here reported show that the gradual expression of Bcs1p in the yeast strain lacking this protein was progressively able to rescue the bc(1) core structure leading to the formation of the functional homodimeric bc(1) complex. Following Bcs1p expression, the mature bc(1) complex was also progressively converted into two supercomplexes with the cytochrome c oxidase complex. The capability of restoring the bc(1) complex and the supercomplexes was also possessed by the mutated yeast R81C Bcsp1. Notably, in the human ortholog BCS1L, the corresponding point mutation (R45C) was instead the cause of a severe bc(1) complex deficiency. Differently from the yeast R81C Bcs1p, two other mutated Bcs1p's (K192P and F401I) were unable to recover the bc(1) core structure in yeast. This study identifies for the first time a productive assembly intermediate of the yeast bc(1) complex and gives new insights into the molecular mechanisms involved in the last steps of bc(1) assembly. PMID- 20727376 TI - Oropouche virus experimental infection in the golden hamster (Mesocrisetus auratus). AB - Oropouche virus (OROV), of the family Bunyaviridae, is the second most frequent arbovirus causing febrile disease in Brazil. In spite of this, little is known about pathogenesis of OROV infection. This report describes an experimental model of OROV in golden hamster (Mesocricetus auratus). Following subcutaneous inoculation of OROV, over 50% of the animals developed disease characterized by lethargy, ruffled fur, shivering, paralysis, and approximately one third died. Animals were sacrificed on days 1, 3, 5, 8 and 11 post-inoculation to collect tissue samples from brain, heart, liver, lung, spleen, muscle and blood for virus titration, histology and OROV immunohistochemistry. OROV was detected in high titers in blood, liver and brain, but not in the other organs. Histopathology revealed meningoencephalitis and hepatitis, with abundant OROV antigen detected in liver and brain. Diffuse galectin-3 immunostaining in brain and liver supports microglial and Kupfer cells activation. This is the first description of an experimental model for OROV infection and should be helpful to study pathogenesis and possibly to test antiviral interventions such as drugs and vaccine candidates. PMID- 20727378 TI - Evaluation of the genotoxicity of cisplatin, paclitaxel and 5-fluorouracil combined treatment in the Drosophila wing-spot test. AB - The somatic mutation and recombination test in Drosophila melanogaster was applied to analyze the mutagenic and recombinagenic activity of the chemotherapeutic drugs cisplatin, paclitaxel, and 5-fluorouracil, comparing the effects observed in combinatory treatments with those observed in single administrations. The results obtained in two different genotypes allowed to quantitatively and qualitatively estimate the contribution of genotoxic effects. The results obtained with the individual drug treatments showed that cisplatin and 5-fluorouracil were genotoxic, being able to increase the frequency of total spots on both genotypes. While cisplatin preferentially induced DNA damage of recombinational origin, all the damages induced by 5-fluorouracil were caused by gene and/or chromosome mutations, and the aneuploidogenic compound paclitaxel was not genotoxic. The combination of these drugs does not exert a synergist genotoxic effect in both genotypes compared to the single-agent administration. Instead, it was observed a modification in the proportion of mutation and recombination to the final genotoxicity observed. The antiproliferative activity of PAC could be responsible for the non-synergic genotoxic effect observed. Based on our results it is possible to suggest that cisplatin/paclitaxel/5-fluorouracil treatment regimen cannot impose a higher risk of the development of genotoxicity associated secondary tumors in comparison to their individual applications. PMID- 20727379 TI - Assessing diet in populations at risk for konzo and neurolathyrism. AB - Although both konzo and neurolathyrism are diseases associated with diet, we know surprising little about the diets of the groups at risk. The objective of this paper is to discuss methods for assessing dietary intake in populations at risk for konzo and lathyrism. These methods include weighed food records and interview based techniques like 24-h recalls and food frequency questionnaires (FFQs). Food records have the potential to provide accurate information on food quantities, and are generally the method of choice. Interview based methods provide less precise information on the quantities of foods ingested, and are subject to recall bias, but may be useful in some studies or for surveillance. Sample size needs to be adequate to account for day-to-day and seasonal variability in food intake, and differences between age and sex groups. Adequate data on the composition of foods, as actually consumed, are needed to evaluate the food intake information. This is especially important in the case of cassava and grass pea where the toxins in the diet is a function of processing. Biomarkers for assessing the cyanogen exposure from cassava-based diets are available; biomarkers for the beta-ODAP exposure from grass pea diets need development. PMID- 20727377 TI - Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. AB - Drug-metabolizing enzymes (DMEs) and transporters play pivotal roles in the disposition and detoxification of numerous foreign and endogenous chemicals. To accommodate chemical challenges, the expression of many DMEs and transporters is up-regulated by a group of ligand-activated transcription factors namely nuclear receptors (NRs). The importance of NRs in xenobiotic metabolism and clearance is best exemplified by the most promiscuous xenobiotic receptors: pregnane X receptor (PXR, NR1I2) and constitutive androstane/activated receptor (CAR, NR1I3). Together, these two receptors govern the inductive expression of a largely overlapping array of target genes encoding phase I and II DMEs, and drug transporters. Moreover, PXR and CAR also represent two distinctive mechanisms of NR activation, whereby CAR demonstrates both constitutive and ligand-independent activation. In this review, recent advances in our understanding of PXR and CAR as xenosensors are discussed with emphasis placed on the differences rather than similarities of these two xenobiotic receptors in ligand recognition and target gene regulation. PMID- 20727380 TI - Purification and partial characterization of canine S100A12. AB - Canine S100A12 (cS100A12) is a calcium-binding protein of the S100 superfamily of EF-hand proteins, and its expression is restricted to neutrophils and monocytes. Interaction of S100A12 with the receptor for advanced glycation end products (RAGE) has been suggested to play a central role in inflammation. Moreover, S100A12 has been shown to represent a sensitive and specific marker for gastrointestinal inflammation in humans. Only human, porcine, bovine, and rabbit S100A12 have been purified to date, and an immunoassay for the quantification of S100A12 is available only for humans. Therefore, the aim of this study was to develop a protocol for the purification of S100A12 and to partially characterize this protein in the dog (Canis lupus familiaris) as a prelude to the development of an immunologic method for its detection and quantification in canine serum and fecal specimens. Leukocytes were isolated from canine whole blood by dextran sedimentation, and canine S100A12 was extracted from the cytosol fraction of these cells. Further purification of cS100A12 comprised of ammonium sulfate precipitation, hydrophobic interaction chromatography, and strong cation- and anion-exchange column chromatography. Canine S100A12 was successfully purified from canine whole blood. The relative molecular mass of the protein was estimated at 10,379.5 and isoelectric focusing revealed an isoelectric point of 6.0. The approximate specific absorbance of cS100A12 at 280 nm was determined to be 1.78 for a 1 mg/ml solution. The N-terminal AA sequence of the first 15 residues of cS100A12 was Thr-Lys-Leu-Glu-Asp-His-X-Glu-Gly-Ile-Val-Asp-Val-Phe-His, and revealed 100% identity with the predicted protein sequence available through the canine genome project. Sequence homology for the 14 N-terminal residues identified for cS100A12 with those of feline, bovine, porcine, and human S100A12 was 78.6%. We conclude that canine S100A12 can be successfully purified from canine whole blood using the described methods. PMID- 20727381 TI - Cyclin D1 expression in B-cell lymphomas. AB - OBJECTIVE: Cyclin D1, an important component of cell cycle machinery and a protein with known oncogenic potential, is downregulated in normal mature B lymphocytes. Its expression detected in a number of malignancies, including B cell lymphomas, may be important for oncogenesis. MATERIALS AND METHODS: In our work, we determined the level of cyclin D1 expression in various B-cell lymphomas (i.e., mantle cell lymphoma, B-cell chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and compared it with normal B cells. For cyclin D1 level evaluation, the real-time quantitative polymerase chain reaction data was normalized. We tested five reference genes for stability on our sample set and using the three most stable ones (YWHAZ, ubiquitin c, and HPRT) obtained rather small intra-group variance for cyclin D1 expression in most lymphomas. This allowed their statistically significant ranking according to cyclin D1 expression level. RESULTS: Median values of normalized cyclin D1 expression determined by real-time quantitative polymerase chain reaction were 1.32 for mantle cell lymphoma, 0.02 for B-cell chronic lymphocytic leukemia, 0.009 for diffuse large B-cell lymphoma, 0.004 for marginal zone lymphoma, 0.002 for follicular lymphoma compared with 0.0003 for reactive lymphoid tissue, and 0.00004 for sorted B cells of healthy donors. CONCLUSIONS: Our data demonstrate that mantle cell lymphoma, a lymphoma with t(11;14)(q13;q32) translocation, has the level of cyclin D1 increased by four orders of magnitude, while other B-cell lymphomas without t(11;14)(q13;q32) translocation still have the level of cyclin D1 significantly elevated above that of normal lymphocytes (2 orders for B-cell chronic lymphocytic leukemia and an order for other lymphomas) and suggests more than one method of its upregulation in malignant B cells. PMID- 20727383 TI - The inhibitory effects of different curcuminoids on beta-amyloid protein, beta amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 in swAPP HEK293 cells. AB - The hallmark of Alzheimer's disease (AD) is the accumulation of beta-amyloid protein (Abeta). Abeta is generated from the beta-amyloid precursor protein (APP) through the proteolysis of beta-site APP cleaving enzyme 1 (BACE1) and gamma secretase. Abeta(42) isoform is more easily aggregate and more toxic to neurons than any other Abeta isoforms, thus being regarded as the primary toxic specie in AD. Curcumin mix has potent anti-amyloidogenic effect and shows great promise for AD treatment and prevention. The present study was conducted to examine the effects of curcumin mix and its different curcuminoids including curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) on Abeta(42), APP and BACE1. We found that Cur was the most active curcuminoid fraction in suppressing Abeta(42) production and the order of inhibitory potency of other curcuminoids was DMC>curcumin mix>BDMC. Cur, but not other curcuminoids, could reduce APP protein expression and none of curcuminoids affected APP mRNA level. BDMC could reduce BACE1 mRNA and protein levels, while DMC only affected BACE1 mRNA expression. Our data indicate that the anti-amyloidogenic effect of Cur may be mediated through the modulation of APP, while the anti-amyloidogenic effect of BDMC may be mediated through the modulation of BACE1. PMID- 20727382 TI - Interleukin-1beta induces ceruloplasmin and ferroportin-1 gene expression via MAP kinases and C/EBPbeta, AP-1, and NF-kappaB activation. AB - Previously, we demonstrated that IL-1beta was able to increase iron efflux from glial cells through a coordinate induction of both ferroportin-1 (Fpn) and ceruloplasmin (Cp) synthesis. In this study, we have investigated the signaling pathways that are involved in the transcriptional activation of the Cp and Fpn. Our data show that the expression of Cp and Fpn in response to IL-1beta requires the activation of MAP kinase pathways as a consequence of an IL-1beta receptor stimulation. Moreover, we have observed that IL-1beta regulates the expression of Cp and Fpn genes through (i) p38 MAPK-mediated activation of C/EBP transcription factor, (ii) ERK1/2-, JNK1- and partially p38 MAPK-dependent activation of AP-1, and through (iii) activation of NF-kappaB partially mediated by p38 MAPK. PMID- 20727384 TI - Restriction of rear-up-behavior-induced attenuation of vestibulo-cardiovascular reflex in rats. AB - Previously, we have demonstrated that the vestibulo-cardiovascular reflex was attenuated in rats reared in a 3G environment for 14 days. Because continuous galvanic vestibular stimulation preserved the vestibulo-cardiovascular reflex in rats at 3G, this attenuation might be attributable to a reduction in the phasic input to the vestibular system. The present study shows that the head movements of rats were significantly suppressed in the 3G environment. Therefore, we hypothesized that the attenuation of the vestibulo-cardiovascular reflex is induced by the reduced vestibular phasic input caused by the restriction of rear up behavior. To examine this hypothesis, the pressor responses to linear acceleration were measured in rats reared in a low-roof cage. The linear acceleration-induced pressor response was significantly suppressed in these rats. The suppressive effect of the low-roof cage was similar to that of 3G. There was no difference in the air-jet-induced pressor response among three groups (rats reared in a usual 1G environment, rats reared in the low-roof cage, and rats reared in the 3G environment), suggesting that the sensitivity of the vestibulo cardiovascular reflex was selectively suppressed. These results indicate that a reduction in the vestibular phasic input acts to attenuate the vestibulo cardiovascular reflex. PMID- 20727385 TI - Low frequency of common LRRK2 mutations in Mexican patients with Parkinson's disease. AB - Mutations in leucine-rich repeat kinase 2 gene (LRRK2) account for as much as 5 6% of familial Parkinson's disease (PD) and 1-2% of sporadic PD. These mutations represent the most frequent cause of autosomal dominant PD, particularly in certain ethnic groups. In this first report concerning LRRK2 mutations in Mexican mestizos, we screened 319 consecutive PD patients (186 males; 133 females; mean age at onset: 52.4 years) for LRRK2 mutations in exons 31 and 41 and for the mutation in exon 35, which produces the Y1699C substitution. Three (0.94%) patients, two with sporadic PD and one with familial PD (disease mean age at onset, 53.3 years), were heterozygous for LRRK2 mutations. Of these three, two patients had one of two different mutations in exon 31 (R1441G and R1441H, respectively); the other patient carried the G2019S mutation in exon 41. The Y1699C mutation was absent from this PD sample. Four additional subjects, unaffected relatives of one PD patient with a mutation in LRRK2, were subsequently genetically tested. None of the three LRRK2 mutations identified was present in 200 neurologically healthy Mexican control individuals. These findings have important implications for molecular testing of LRRK2 mutations in Mexican PD patients. PMID- 20727386 TI - Differences in responsiveness of mediodorsal thalamic and medial prefrontal cortical neurons to social interaction and systemically administered phencyclidine in rats. AB - Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and behavioral abnormalities with corresponding symptoms of schizophrenia in non-human animals. Our previous studies showed that systemically administered PCP produces tonic activation of neurons in the medial prefrontal cortex (mPFC) of rats and that this activation is mainly via excitatory inputs from regions outside the mPFC. Such long-lasting activation of PFC neurons is now considered to be a pivotal factor in PCP-induced behavioral abnormalities. Although our previous study identified the ventral hippocampus as a possible source of the excitatory inputs, it is not the only source innervating the mPFC. Several regions such as the thalamus also have monosynaptic projections to the mPFC. Recently, increased c-fos expression by systemic PCP administration was reported in the mediodorsal nucleus of the thalamus (MD) and the centromedial nucleus of the thalamus (CM), which have strong reciprocal innervations with the mPFC. However, few studies have reported effects of PCP on the firing activity of MD/CM neurons in unanesthetized animals. In the current study in freely moving rats, we examined effects of systemically administered PCP on the spontaneous firing activity of the MD/CM, after identifying the response properties of recorded neurons in social interaction with an unfamiliar partner. About 30% of MD/CM neurons recorded exhibited tonic excitation following systemic PCP administration, whereas only a few neurons (7%) were inhibited by PCP. The proportion of MD neurons activated by systemic PCP administration was about half of that in the mPFC. Although the proportion of neurons responsive to social interaction did not differ between the two regions (40%), neurons activated during social interaction in the mPFC (90%) were more likely to be affected by systemic PCP administration than those in the MD/CM (45%). These results suggest that neurons responsive to social interaction in the mPFC may be differently affected by PCP than those in the MD/CM. PMID- 20727388 TI - Short-term sleep deprivation may alter the dynamics of hippocampal cell proliferation in adult rats. AB - Long-term (>48 h) sleep deprivation (SD) reduces adult rat hippocampal cell proliferation and neurogenesis, yet reported effects of short-term (<24 h) SD are inconsistent. We systematically assessed the effects of various durations of SD on adult rat hippocampal cell proliferation. Rats were sleep-deprived for 6, 12, 24, 36 or 48 h and injected with 5-bromo-2'-deoxyuridine (BrdU) 2 h before the end of SD. Immunolabeling for BrdU in the hippocampal subgranular zone increased significantly after 12 h SD but tended to decrease after 48 h SD relative to respective Controls. Surprisingly, SD did not alter immunolabeling for Ki67 protein (Ki67) or proliferating cell nuclear antigen (PCNA), two intrinsic cell proliferation markers. SD did not affect BrdU or Ki67 labeling in the subventricular zone, nor did it affect serum corticosterone levels. Because immunoreactivity for Ki67 and PCNA can identify cells in all phases of the ~25 h cell cycle in adult rat hippocampus, whereas BrdU labels only cells in S-phase (~9.5 h), this discrepancy suggests that 12 h SD might have affected cell cycle dynamics. A separate group of rats were injected with BrdU 10 h before the end of 12 h SD, which would allow some time for labeled cells to divide; the results were consistent with an acceleration of the timing of hippocampal progenitor cell division during 12 h SD. These results suggest that short-term (12 h) SD transiently produces more hippocampal progenitor cells via cell cycle acceleration, and confirm the importance of using multiple cell cycle markers or BrdU injection paradigms to assess potential changes in cell proliferation. PMID- 20727387 TI - Altered morphine-induced analgesia in neurotensin type 1 receptor null mice. AB - Both neurotensin (NT) and opioid agonists have been shown to induce antinociception in rodents after central administration. Besides, previous studies have revealed the existence of functional interactions between NT and opioid systems in the regulation of pain processing. We recently demonstrated that NTS1 receptors play a key role in the mediation of the analgesic effects of NT in long-lasting pain. In the present study, we therefore investigated whether NTS1 gene deletion affected the antinociceptive action of mu opioid drugs. To this end, pain behavioral responses to formalin were determined following systemic administration of morphine in both male and female NTS1 knockout mice. Acute injection of morphine (2 or 5 mg/kg) produced strong antinociceptive effects in both male and female wild-type littermates, with no significant sex differences. On the other hand, morphine analgesia was considerably reduced in NTS1-deficient mice of both sexes compared to their respective controls, indicating that the NTS1 receptor actively participates in mu opioid alleviating pain. By examining specifically the flinching, licking and biting nociceptive behaviors, we also showed that the functional crosstalk between NTS1 and mu opioid receptors influences the supraspinally-mediated behaviors. Interestingly, sexual dimorphic action of morphine-induced pain inhibition was found in NTS1 null mice in the formalin test, suggesting that the endogenous NT system interacts differently with the opioid network in male and female mice. Altogether, these results demonstrated that NTS1 receptor activation operates downstream to the opioidergic transmission and that NTS1-selective agonists combined with morphine may act synergistically to reduce persistent pain. PMID- 20727389 TI - Production & stability of stavudine solid lipid nanoparticles--from lab to industrial scale. AB - The production of stavudine-loaded solid lipid nanoparticles (SLN) for intravenous injection was scaled up from lab scale (40 g) to medium scale (10 kg) and large scale (20/60 kg). The SLN were produced by high pressure homogenization of stavudine lipid melt dispersed in hot surfactant solution (pre-emulsion) applying 800 bar pressure. Employed were piston-gap homogenizers with increasing capacity (APV Gaulin products LAB 40, LAB 60 and Gaulin 5.5, and Avestin C50), using them in the continuous (circulation) and discontinuous mode. Size analysis was performed by photon correlation spectroscopy (PCS), laser diffractometry and light microscopy. At lab scale a PCS size of 53 nm was obtained. At the same pressure, all homogenizers on larger scale yielded a size in the range of the lab scale product (35-70 nm). Differences were found in the size as a function of circulation time (size increase or size reduction with time) and the number of cycles required (1 or 5) for the optimal product. The stavudine SLN formulation (2% lipid content, high surfactant to lipid ratio) showed a different behavior to conventional higher concentrated SLN suspensions or nanoemulsions (10% or 20% lipid/oil, low surfactant to lipid ratio). In general, smallest sizes were obtained in the discontinuous mode after just one homogenization cycle. The continuous production mode was only efficient with a 10 kg batch size using the LAB 60. In addition, the long-term stability over 1 year was monitored at refrigeration, room temperature and at 40 degrees C to assess a potential effect of the homogenizer type on stability. All batches at room temperature and below were stable, only a negligible increase in size was observed. PMID- 20727390 TI - Enhanced oral bioavailability of docetaxel in rats by four consecutive days of pre-treatment with curcumin. AB - As with many other anti-cancer agents, docetaxel is a substrate for ATP-binding cassette transporters such as P-glycoprotein and its metabolism is mainly catalysed by CYP3A. In order to improve the oral bioavailability of docetaxel, a component of turmeric, curcumin, which can down-regulate the intestinal P glycoprotein and CYP3A protein levels, was used for the pre-treatment of rats before the oral administration of docetaxel. Curcumin (100 mg/kg) did not significantly modify the pharmacokinetics of docetaxel when given orally 30 min before the administration of docetaxel. However, the C(max) of docetaxel in rats pre-treated with curcumin for four consecutive days was significantly increased (p<0.01) by about 10 times compared to that of the docetaxel control, and the area under the plasma concentration-time curve (AUC) was about eight times higher than that of the control. Consequently, the absolute bioavailability of docetaxel in the treatment group (four days of curcumin at 100 mg/kg) was about 40%, which was a significant increase of about eightfold in comparison to the control value. Thus, the oral bioavailability of docetaxel was enhanced by the co-administration of regular curcumin. It could be possible to administer docetaxel orally, besides the established i.v. route. PMID- 20727391 TI - A thermal analysis method to predict the complete phase diagram of drug-polymer solid dispersions. AB - The aim of this work was to develop a method which uses experimentally obtainable data to predict the complete phase diagram of drug-polymer solid dispersion systems, for the first time in literature. Felodipine-poly(acrylic acid) (PAA) solid dispersion was used as an example to illustrate the application of this method. Samples were prepared with different drug loading and analyzed using differential scanning calorimetry (DSC). Values of the drug-polymer interaction parameter chi(T(m)) were calculated from the drug crystal melting point depression data. Since chi is a function of temperature (chi~1/T) according to the Flory-Huggins theory, the obtained chi-T relationship thus enabled calculation of the complete temperature-composition phase diagram of a drug polymer solid dispersion system. In experiments, felodipine was shown to be immiscible with PAA in almost the whole range of drug content at room temperature. Two glass transition temperatures were observed, corresponding to almost pure felodipine and pure PAA, respectively, in consistent with the predicted phase behavior. PMID- 20727392 TI - The role of vehicle-nanoparticle interactions in topical drug delivery. AB - Loading 'difficult to deliver' therapeutic agents into lipid nanoparticles (LN) is an attractive means to administer them to the skin. However, employing colloidal carriers to administer therapeutic agents from semi-solid preparations adds an extra dimension to the already complex process of topical drug delivery. The aim of this work was to understand how the mobility of nanoparticles influenced the delivery of a model drug when the carriers were suspended in a hyaluronic acid (HA) vehicle. Tocopheryl acetate (TA) was loaded into lipid nanoparticles (TA(LN)) that were <100 nm in size and physically stable for more than 28 days. The TA(LN) interacted with the HA polymeric chains to increase formulation macroviscosity. Nanoparticle tracking analysis confirmed that the gel hindered the TA(LN) mobility. However, deliberate manipulation of the particle mobility in the gel by varying the concentration of HA had little effect on TA delivery. Only ca. 10 MUg/cm(2) of administered TA was delivered into porcine skin regardless of the vehicle characteristics and this suggested that drug release from the LN was the rate limiting step in the delivery process and not the nanoparticle-vehicle-skin interactions. PMID- 20727393 TI - Hemagglutinin displayed baculovirus protects against highly pathogenic influenza. AB - Baculovirus (BV) replicating in insect cells can express a foreign gene product as part of its genome. The influenza hemagglutinin (HA) can be expressed from BV and displayed on the surface of baculovirus (HA-DBV). In this study we first generated six recombinant baculoviruses that expressed chimeric HAs with segments of the BV glycoprotein (gp64). The signal peptide (SP) and cytoplasmic tail (CT) domains of gp64 can enhance the display of HA from A/PR8/34 on BV surface, while the transmembrane (TM) domain of gp64 impairs HA display. Different doses of either live or beta-propiolactone (BPL)-inactivated HA-DBV were administered to BALB/c mice. Live HA-DBV elicited higher hemagglutination-inhibition (HAI) titers than BPL-inactivated HA-DBV, and provided sterilizing protection. A second generation recombinant BV simultaneously displaying four HAs derived from four subclades of H5N1 influenza viruses was constructed. This tetravalent H5N1 HA-DBV vaccine elicited HAI titers against all four homologous H5N1 viruses, significantly decreasing viral lung titers of challenged mice and providing 100% protection against lethal doses of homologous H5N1 viruses. Moreover, mice vaccinated with HA-DBV had high levels of IFNgamma-secreting and HA-specific CD8+ T cells. Taken together, this study demonstrates that HA-DBV can stimulate strong humoral, as well as cellular immune responses, and is an effective vaccine candidate for influenza. PMID- 20727394 TI - Folding domains within the ricin toxin A subunit as targets of protective antibodies. AB - Efforts to develop an effective vaccine against ricin are focused on the engineering of attenuated and stable recombinant forms of the toxin's enzymatic A subunit (RTA). While several candidate antigens are in development, vaccine design and efficacy studies are being undertaken in the absence of a fundamental understanding of those regions of RTA that are critical in eliciting protective immunity. In this present study, we produced and characterized a collection of monoclonal antibodies (MAbs) directed against five distinct immunodominant regions on RTA, and used these MAbs to identify several key neutralizing epitopes on the toxin. Protective MAbs were directed against alpha-helices located in RTA folding domains 1 and 2, whereas non-neutralizing antibodies recognized random coils and loops that were primarily confined to folding domain 3. These data offer insights into the immunodominant and structural determinants on RTA that give rise to protective immunity, and for the first time provide an immunological rationale for ricin vaccine design. PMID- 20727395 TI - Ability of Brucella abortus rough vaccine strains to elicit DC and innate immunity in lung using a murine respiratory model. AB - Brucella abortus strains RB51 and RB51SOD are live attenuated vaccine strains which protect mice against virulent B. abortus strain 2308 intraperitoneal challenge. By comparison, limited information is available on how Brucella vaccines stimulate pulmonary immunity against respiratory infection, another route of exposure in humans. Therefore, in this study, we assessed the ability of intranasally delivered vaccine strains RB51 and RB51SOD to induce innate immunity. Based on parameters assessed, rough strain RB51 induces a better innate immune response in lung versus strain RB51SOD. Additional studies to further delineate strain RB51's ability to stimulate DC and adaptive immunity are warranted. PMID- 20727396 TI - Vertebrate pressure-gradient receivers. AB - The eardrums of all terrestrial vertebrates (tetrapods) are connected through Eustachian tubes or interaural canals. In some of the animals, these connections create pressure-gradient directionality, an enhanced directionality by interaction of sound arriving at both sides of the eardrum and strongly dependent on interaural transmission attenuation. Even though the tympanic middle ear has originated independently in the major tetrapod groups, in each group the ancestral condition probably was that the two middle ears were exposed in the mouth cavity with relatively high interaural transmission. Recent vertebrates form a continuum from perfect interaural transmission (0 dB in a certain frequency band) and pronounced eardrum directionality (30-40 dB) in the lizards, over somewhat attenuated transmission and limited directionality in birds and frogs, to the strongly attenuated interaural transmission and functionally isolated pressure receiver ears in the mammals. Since some of the binaural interaction already takes place at the eardrum in animals with strongly coupled ears, producing enhanced interaural time and level differences, the subsequent neural processing may be simpler. In robotic simulations of lizards, simple binaural subtraction (EI cells, found in brainstem nuclei of both frogs and lizards) produces strongly lateralized responses that are sufficient for steering the animal robustly to sound sources. PMID- 20727397 TI - Partial tripolar cochlear implant stimulation: Spread of excitation and forward masking in the inferior colliculus. AB - This study examines patterns of neural activity in response to single biphasic electrical pulses, presented alone or following a forward masking pulse train, delivered by a cochlear implant. Recordings were made along the tonotopic axis of the central nucleus of the inferior colliculus (ICC) in ketamine/xylazine anesthetized guinea pigs. The partial tripolar electrode configuration was used, which provided a systematic way to vary the tonotopic extent of ICC activation between monopolar (broad) and tripolar (narrow) extremes while maintaining the same peak of activation. The forward masking paradigm consisted of a 200 ms masker pulse train (1017 pulses per second) followed 10 ms later by a single pulse probe stimulus; the current fraction of the probe was set to 0 (monopolar), 1 (tripolar), or 0.5 (hybrid), and the fraction of the masker was fixed at 0.5. Forward masking tuning profiles were derived from the amount of masking current required to just suppress the activity produced by a fixed-level probe. These profiles were sharper for more focused probe configurations, approximating the pattern of neural activity elicited by single (non-masked) pulses. The result helps to bridge the gap between previous findings in animals and recent psychophysical data. PMID- 20727398 TI - Mechanisms of vasorelaxation induced by Ziziphora clinopodioides Lam. (Lamiaceae) extract in rat thoracic aorta. AB - AIM OF THE STUDY: Ziziphora clinopodioides Lam. (ZC) is widely used in Uyghur folk medicine for the treatment of hypertension diseases in Xinjiang, an autonomous region of China. To provide pharmacological basis for this traditional use, we explored the vasodilating effects of ZC and investigated the underlying mechanisms. MATERIALS AND METHODS: Activity of hexane (ZCHE), dichloromethane (ZCDE) and aqueous (ZCAE) extracts of ZC were evaluated on isolated rat aortic rings pre-contracted with phenylephrine (PE) or high KCl. The mechanisms were evaluated on ZCDE, the most potent extract. RESULTS: ZCDE-induced relaxation in endothelium-intact aortic rings pre-contracted with phenylephrine (PE, 10(-6) M) or high KCl (6*10(-2) M), with respective EC(50) values of 0.27+/-0.03 and 0.34+/ 0.04 g/l. Mechanic removal of the endothelium did not significantly modify ZCDE induced relaxation. In endothelium-denuded aorta pre-contracted with PE (10(-6) M), the vasorelaxant effect of ZCDE was significantly decreased by 4-amino pyridine (10(-3) M), but not by glibenclamide (10(-4) M), iberiotoxin (3*10(-8) M) and thapsigargin (10(-7) M). In Ca(2+) free solution, ZCDE significantly inhibited extracellular Ca(2+)-induced contraction in high KCl and PE pre contracted rings. Additionally ZDCE inhibited the intracellular Ca(2+) release sensitive to PE (10(-6) M). CONCLUSIONS: The results demonstrate that ZDCE exhibits endothelium-independent vasodilating properties that are mediated by inhibition of extracellular Ca(2+) influx through voltage- and receptor-operated Ca(2+) channels (VDDCs and ROCCs), by inhibition of Ca(2+) release from intracellular stores, and also by the opening of voltage-dependent K(+) channels. PMID- 20727399 TI - Antioxidant, toxicological and antiproliferative properties of Canadian polyphenolic extracts on normal and psoriatic keratinocytes. AB - AIMS OF THE STUDY: In a first attempt for establishing the possible utilization of polyphenolic extracts from barks of Canadian wood species in psoriasis treatment, we aimed to study (a) their antioxidant capacity, (b) their toxicological properties on normal human keratinocytes (NHK), and (c) their effect on the growth of normal and psoriatic keratinocytes (PK). MATERIALS AND METHODS: Polyphenolic extracts were obtained by 90% ethanolic maceration and hot water extraction (HWE). Scavenging capacity was evaluated towards hydrogen peroxide, hydroxyl, superoxide, nitric oxide and peroxyl radicals. MTT assay and Trypan blue dye exclusion (TBDE) method were used for evaluating the initial toxicity of the most antioxidant extracts on NHK during 24 and 48 h. The effects of extracts on the growth of NHK and PK at non-toxic concentrations were determined after exposure for 48 h. RESULTS: Yellow birch extract obtained by maceration (YB(Mac)) and black spruce extract obtained by HWE (BS(HWE)) were determined to have the highest antioxidant capacity, but BS(HWE) was less toxic on NHK. Toxicity of extracts on keratinocyte plasma membrane and mitochondria after 24 h was attributed to their content of hydroxycinnamic acids and proanthocyanidins. BS(HWE) inhibited the growth of NHK and non-lesional PK, but was not selective for lesional PK. CONCLUSION: Given that BS(HWE) presented elevated content of total phenols and flavonoids and showed a low toxicity on NHK as well as an adequate chemical reactivity towards different radicals and some antiproliferative properties, it was considered as the most valuable extract obtained from barks of Canadian wood species. PMID- 20727400 TI - Pyrostegia venusta attenuate the sickness behavior induced by lipopolysaccharide in mice. AB - AIM OF THE STUDY: Pyrostegia venusta (Ker.) Miers (Bignoniaceae) is native to the Brazilian Cerrado and popularly known as "cipo-de-sao-joao." In traditional Brazilian medicine, the Pyrostegia venusta are used as a general tonic as well as a treatment for diarrhea, vitiligo, cough, and common diseases of the respiratory system related to infections, such as bronchitis, flu and cold. This study was conducted to evaluate the effects of a hydroethanolic extract of flowers of Pyrostegia venusta on sickness behaviors induced by lipopolysaccharide in mice. MATERIALS AND METHODS: To evaluate the effects of orally administered Pyrostegia venusta hydroethanolic extract (PvHE) on lipopolysaccharide-induced sickness behaviors, mice were submitted to the forced swim test (FST) and the open field test. RESULTS: Lipopolysaccharide (LPS, 100 MUg/kg, i.p.) administration increased the time spent floating in the FST and depressed locomotor activity in the open field. Pretreatment with PvHE at test doses of 100 and 300 mg/kg, p.o. attenuated the behavioral changes induced by LPS in the FST and open field test. This effect was similar to pretreatment with dexamethasone (1 mg/kg), which is a steroidal drug that inhibits immune and inflammatory responses, including cytokine production. CONCLUSION: The extract of Pyrostegia venusta attenuated the depressive-like and exploratory behaviors induced by lipopolysaccharide. Thus, our results supported previous claims of the usefulness of these plants in traditional therapies and suggest that these plants may be useful in the treatment of disorders that induced sickness behavior, such as flu and cold. PMID- 20727401 TI - Procyanidin-rich fractions from Parkia biglobosa (Mimosaceae) leaves cause redox sensitive endothelium-dependent relaxation involving NO and EDHF in porcine coronary artery. AB - AIM OF THE STUDY: Parkia biglobosa leaves are traditionally used as an antihypertensive agent in Benin. The present study assessed the vasorelaxant activity of different Parkia biglobosa leaf extracts using isolated porcine coronary artery rings. MATERIALS AND METHODS: A hydroalcoholic leaf extract was submitted to a multi-step liquid-liquid fractionation with solvents of increasing polarity and the polyphenolic content of the different fractions was analyzed. Vascular reactivity of the different extracts was assessed using porcine coronary artery rings, in the presence or absence of specific pharmacological inhibitors. RESULTS: The hydroalcoholic, ethyl acetate and butanolic extracts contained mainly procyanidins and monomeric flavonoids. Parkia biglobosa leaf crude extract induced a redox-sensitive endothelium-dependent relaxation mediated by both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The fractionation of the butanolic extract generated 6 fractions, two of which induced stronger vasorelaxation than the original extract and they had a higher phenolic content. CONCLUSIONS: Parkia biglobosa leaf extract is able to induce endothelium-dependent NO- and EDHF-mediated relaxation in porcine coronary artery rings. The vasorelaxant activity is dependent on their phenolic content and appears to involve mainly procyanidins. PMID- 20727402 TI - Ethnomedical uses of Zingiberaceous plants of Northeast India. AB - AIM OF THE STUDY: Family Zingiberaceae consists of large number of medicinal plants and is well known for its use in ethnomedicine. The objective of this study is to systematically analyse and document the traditional knowledge regarding the use of Zingiberaceous plants for the treatment of various human ailments from NE India, adding information to the valuation of biodiversity and, to forward suggestions for its sustainable use, conservation and for future pharmacological studies. MATERIALS AND METHODS: A survey on the utilization of medicinal plants belonging to Zingibereceae of North-eastern states was carried out by interviewing herbalists followed by collecting plant specimens and identifying the specimen. Ethnobotanical information on traditional plants was catalogued through structured questionnaires in consultations with traditional healers. RESULTS: A total of 34 species were documented belonging to 9 genera of Zingiberaceae for about 25 types of ailments, 67.6% of which were used in curing multiple disorders. Arunachal Pradesh hosts maximum number of Zingiberaceous plant (88%). Rhizomes were found to be the primary plant material as a source for medication and poultices as the predominant mode of preparation. Gastrointestinal conditions (58%) and chest and lungs (41%) related ailments were the main categories for which these plants are used. CONCLUSIONS: The study establishes Zingiberaceae as a medicinal family since 41% of all the available Zingiberaceous plant species in NE were found to possess medicinal value. Some new use of herbs also appeared in this study for the first time. PMID- 20727403 TI - Biomarkers of ageing: A challenge for the future. PMID- 20727404 TI - A new RT-PCR assay specific for influenza A(H2), multiplexed with an assay specific for HPAI A(H5N1). AB - Worldwide efforts are ongoing to improve influenza pandemic preparedness, including from the perspective of the clinical virology laboratory. In particular, much work has been devoted to the development of diagnostic assays targeted at the Highly Pathogenic Avian Influenza (HPAI) A(H5N1); much less efforts have been devoted to the A(H2) subtype. Yet, A(H2) subtype has a proven capacity to cause pandemics and is among the subtypes prioritized for surveillance and control. Although the human A(H2N2) virus that caused the pandemic of 1957 no longer circulates, many related avian A(H2) viruses circulate in avian population and could conceivably adapt to infect humans and cause a new pandemic. In this study the design and development of an RT-PCR assay specific for A(H2) subtype is presented. It is shown that the assay is highly sensitive and specific, able to detect human and avian A(H2) viruses, and can be incorporated into a multiplex assay with another previously described assay for HPAI A(H5N1). PMID- 20727405 TI - Rab11a and its binding partners regulate the recycling of the beta1-adrenergic receptor. AB - beta1-adrenergic receptors (beta1-AR) are internalized in response to agonists and then recycle back for another round of signaling. The serine 312 to alanine mutant of the beta1-AR (S312A) is internalized but does not recycle. We determined that WT beta1-AR and S312A were internalized initially to an early sorting compartment because they colocalized by >70% with the early endosomal markers rab5a and early endosomal antigen-1 (EEA1). Subsequently, the WT beta1-AR trafficked via rab4a-expressing sorting endosomes to recycling endosomes. In recycling endosomes WT beta1-AR were colocalized by >70% with the rab11 GTPase. S312A did not colocalize with either rab4a or rab11, instead they exited from early endosomes to late endosomes/lysosomes in which they were degraded. Rab11a played a prominent role in recycling of the WT beta1-AR because dominant negative rab11a inhibited, while constitutively active rab11a accelerated the recycling of the beta1-AR. Next, we determined the effect of each of the rab11-interacting proteins on trafficking of the WT beta1-AR. The recycling of the beta1-AR was markedly inhibited when myosin Vb, FIP2, FIP3 and rabphillin were knocked down. These data indicate that rab11a and a select group of its binding partners play a prominent role in recycling of the human beta1-AR. PMID- 20727406 TI - Activation of mTOR and RhoA is a major mechanism by which Ceramide 1-phosphate stimulates macrophage proliferation. AB - This study tested the hypothesis that Ceramide 1-phosphate (C1P) stimulates macrophage proliferation through activation of the mammalian target of rapamycin (mTOR). We first reported that C1P is mitogenic for fibroblasts and macrophages, but the mechanisms whereby it stimulates cell proliferation are incompletely understood. Here we demonstrate that C1P causes phosphorylation of mTOR in primary (bone marrow-derived) macrophages. Activation of this kinase was tested my measuring the phosphorylation state of its downstream target p70S6K after treatment with C1P. These actions were dependent upon prior activation of phosphoinositide 3 kinase (PI3-K), as selective inhibition of this kinase blocked mTOR phosphorylation and activation. In addition, C1P caused phosphorylation of PRAS40, a component of the mTOR complex 1 (mTORC1) that is absent in mTORC2. Furthermore, inhibition of the small G protein Ras homolog enriched in brain (Rheb), which is also a specific component of mTORC1, with FTI277, completely blocked C1P-stimulated mTOR phosphorylation, DNA synthesis and macrophage growth. In addition, C1P caused phosphorylation of another Ras homolog gene family member, RhoA, which is also involved in cell proliferation. Interestingly, inhibition of the RhoA downstream effector RhoA-associated kinase (ROCK) also blocked C1P-stimulated mTOR and cell proliferation. It can be concluded that mTORC1, and RhoA/ROCK are essential components of the mechanism whereby C1P stimulates macrophage proliferation. PMID- 20727407 TI - Differences in endoplasmic reticulum stress signalling kinetics determine cell survival outcome through activation of MKP-1. AB - Endoplasmic reticulum (ER) stress signalling pathways are involved in various alterations of the central nervous system such as neurodegenerative diseases or ischemia. The current mechanisms linking ER stress activation to neuronal cell fate upon chronic or acute stresses remain however to be fully understood. Recent studies have associated ER stress severity and the relative activation levels of certain output pathways to influence cell-fate decisions. In the present report, to further test the impact of ER stress severity on neuronal survival, we designed an experimental system recapitulating acute and chronic stress in cerebellar granule neurons (CGNs) and c17.2 mouse neural stem cells (NSCs). Two well characterized ER stress inducers, tunicamycin (TM) and dithiothreitol (DTT), were used to induce "slow motion" and "fast motion" stresses, respectively. We show that the duration of JNK activation is critical for cell survival upon ER stress. TM-induced transient JNK activation is a protective event in CGNs and c17.2 NSCs via the phosphorylation of BAD, while DTT-induced prolonged JNK activation mediates pro-apoptotic signalling. In addition, we demonstrate that ER stress mediated MKP-1/DUSP1 expression regulates JNK activation kinetics. MKP-1 phosphorylation and protein expression level are differentially altered upon TM and DTT treatment. Increased MKP-1 protein stability via its phosphorylation on ser359 induced by TM accounts for transient JNK activation and the resulting cell survival in CGNs and c17.2 NSCs subjected to ER stress. These results suggest that MKP-1 plays a pivotal role in ER stress-induced cell apoptosis through regulating JNK-BAD signalling. PMID- 20727408 TI - Competitive interaction of 5-HT(1A) receptors with G-protein subtypes in CHO cells demonstrated by RNA interference. AB - Following agonist action, G-protein-coupled receptors may exhibit differential coupling to G-proteins or second messenger pathways, supporting the notion of agonist-directed trafficking. To explore these mechanisms, we have designed and transfected synthetic siRNA duplexes to knockdown different G(alpha) subunits in Chinese hamster ovary (CHO) cells expressing human (h)5-hydroxytryptamine 1A receptors (CHO-h5-HT(1A)). siRNAs against G(alphai2) and G(alphai3) transfected alone or in combination caused a large decrease in the corresponding mRNA level (64-80%) and also at the protein level for G(alphai3) (60-70%), whereas a non specific siRNA showed no effect. In membranes of CHO-h5-HT(1A), 5-HT stimulated guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding was differentially affected by transfection of siRNAs against G(alphai) protein, siRNAs against G(alphai2) inducing a more important decrease in the efficacy of 5 HT than transfection of siRNAs against G(alphai3). The high potency component was abolished after transfection of siRNAs against G(alphai3) and the lower potency component was suppressed after transfection of siRNAs against G(alphai2). To directly investigate G(alphai3) activation we used an antibody capture/scintillation proximity assay. (+)8-OH-DPAT yielded bell-shaped curves for G(alphai3) activation, a response that was abolished after transfection of siRNAs against G(alphai3) protein. Interestingly, (+)8-OH-DPAT yielded a sigmoidal response when only G(alphai3) protein was expressed. These data suggest that when efficacious agonists attain a high level of occupation of h5-HT(1A) receptors, a change occurs that induces coupling to G(alphai2) protein and suppresses signalling through G(alphai3) subunits. PMID- 20727410 TI - Molecular cloning of a multidomain cysteine protease and protease inhibitor precursor gene from the tobacco hornworm (Manduca sexta) and functional expression of the cathepsin F-like cysteine protease domain. AB - A Manduca sexta (tobacco hornworm) cysteine protease inhibitor, MsCPI, purified from larval hemolymph has an apparent molecular mass of 11.5 kDa, whereas the size of the mRNA is very large (~9 kilobases). MsCPI cDNA consists of a 9,273 nucleotides that encode a polypeptide of 2,676 amino acids, which includes nine tandemly repeated MsCPI domains, four cystatin-like domains and one procathepsin F-like domain. The procathepsin F-like domain protein was expressed in Escherichia coli and processed to its active mature form by incubation with pepsin. The mature enzyme hydrolyzed Z-Leu-Arg-MCA, Z-Phe-Arg-MCA and Boc-Val-Leu Lys-MCA rapidly, whereas hydrolysis of Suc-Leu-Tyr-MCA and Z-Arg-Arg-MCA was very slow. The protease was strongly inhibited by MsCPI, egg-white cystatin and sunflower cystatin with K(i) values in the nanomolar range. When the MsCPI tandem protein linked to two MsCPI domains was treated with proteases, it was degraded by the cathepsin F-like protease. However, tryptic digestion converted the MsCPI tandem protein to an active inhibitory form. These data support the hypothesis that the mature MsCPI protein is produced from the MsCPI precursor protein by trypsin-like proteases. The resulting mature MsCPI protein probably plays a role in the regulation of the activity of endogenous cysteine proteases. PMID- 20727411 TI - Neural correlates of S-ketamine induced psychosis during overt continuous verbal fluency. AB - The glutamatergic N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Administered to healthy volunteers, a subanesthetic dose of the non-competitive NMDA receptor antagonist ketamine leads to psychopathological symptoms similar to those observed in schizophrenia. In patients with schizophrenia, ketamine exacerbates the core symptoms of illness, supporting the hypothesis of a glutamatergic dysfunction. In a counterbalanced, placebo-controlled, double-blind study design, healthy subjects were administered a continuous subanesthetic S-ketamine infusion while differences in BOLD responses measured with fMRI were detected. During the scanning period, subjects performed continuous overt verbal fluency tasks (phonological, lexical and semantic). Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine elicited psychosis like psychopathology. Post-hoc t-tests revealed significant differences between placebo and ketamine for the amounts of words generated during lexical and semantic verbal fluency, while the phonological domain remained unaffected. Ketamine led to enhanced cortical activations in supramarginal and frontal brain regions for phonological and lexical verbal fluency, but not for semantic verbal fluency. Ketamine induces activation changes in healthy subjects similar to those observed in patients with schizophrenia, particularly in frontal and temporal brain regions. Our results provide further support for the hypothesis of an NMDA receptor dysfunction in the pathophysiology of schizophrenia. PMID- 20727409 TI - Interaction between the extracellular matrix and lymphatics: consequences for lymphangiogenesis and lymphatic function. AB - The lymphatic system is important for body fluid balance as well as immunological surveillance. Due to the identification of new molecular markers during the last decade, there has been a recent dramatic increase in our knowledge on the molecular mechanisms involved in lymphatic vessel growth (lymphangiogenesis) and lymphatic function. Here we review data showing that although it is often overlooked, the extracellular matrix plays an important role in the generation of new lymphatic vessels as a response to physiological and pathological stimuli. Extracellular matrix-lymphatic interactions as well as biophysical characteristics of the stroma have consequences for tumor formation, growth and metastasis. During the recent years, anti-lymphangiogenesis has emerged as an additional therapeutic modality to the clinically applied anti-angiogenesis strategy. Oppositely, enhancement of lymphangiogenesis in situations of lymph accumulation is seen as a promising strategy to a set of conditions where few therapeutic avenues are available. Knowledge on the interaction between the extracellular matrix and the lymphatics may enhance our understanding of the underlying mechanisms and may ultimately lead to better therapies for conditions where reduced or increased lymphatic function is the therapeutic target. PMID- 20727413 TI - Non-invasive measurement of oxygen saturation in the spinal vein using SWI: quantitative evaluation under conditions of physiological and caffeine load. AB - Susceptibility-weighted imaging (SWI) has been used for quantitative and non invasive measurement of blood oxygen saturation in the brain. In this study, we used SWI for quantitative measurement of oxygen saturation in the spinal vein to look for physiological- or caffeine-induced changes in venous oxygenation. SWI measurements were obtained for 5 healthy volunteers using 1.5-T MR units, under 1) 3 kinds of physiological load (breath holding, Bh; hyperventilation, Hv; and inspiration of highly concentrated oxygen, Ox) and 2) caffeine load. Oxygen saturation in the anterior spinal vein (ASV) was calculated. We evaluated changes in oxygen saturation induced by physiological load. We also evaluated the time course of oxygen saturation after caffeine intake. For the physiological load measurements, the average oxygen saturation for the 5 subjects was significantly lower in Hv (0.75) and significantly higher in Bh (0.84) when compared with control (0.80). There was no significant difference between Ox (0.81) and control. Oxygen saturation gradually decreased after caffeine intake. The average values of oxygen saturation were 0.79 (0 min), 0.76 (20 min), 0.74 (40 min), and 0.73 (60 min), respectively. We demonstrated a significant difference in oxygen saturation at 40 and 60 min after caffeine intake when compared with 0 min. In conclusion, we demonstrated the feasibility of using SWI for non-invasive measurement of oxygen saturation in the spinal vein. We showed changes in oxygen saturation under physiological as well as caffeine load and suggest that this method is a useful tool for the clinical evaluation of spinal cord oxygenation. PMID- 20727412 TI - Symbolic representations in motor sequence learning. AB - It has been shown that varying the spatial versus symbolic nature of stimulus presentation and response production, which affects stimulus-response (S-R) mapping requirements, influences the magnitude of implicit sequence learning (Koch and Hoffman, 2000). Here, we evaluated how spatial and symbolic stimuli and responses affect the neural bases of sequence learning. We selectively eliminated the spatial component of stimulus presentation (spatial vs. symbolic), response execution (manual vs. vocal), or both. Fourteen participants performed the alternating serial reaction time task under these conditions in an MRI scanner, with interleaved acquisition to allow for recording of vocal response reaction times. Nine regions of interest (ROIs) were selected to test the hypothesis that the dorsolateral prefrontal cortex (DLPFC) was preferentially engaged for spatially cued conditions and cerebellum lobule HVI, crus I and II were associated with symbolically cued learning. We found that the left cerebellum lobule HVI was selectively recruited for symbolic learning and the percent signal change in this region was correlated with learning magnitude under the symbolic conditions. In contrast, the DLPFC did not exhibit selective activation for learning under spatial conditions. The inferior parietal lobule exhibited increased activation during learning regardless of the condition, supporting its role in forming an abstract representation of learned sequences. These findings reveal different brain networks that are flexibly engaged depending on the conditions of sequence learning. PMID- 20727414 TI - Radial dGEMRIC in developmental dysplasia of the hip and in femoroacetabular impingement: preliminary results. AB - OBJECTIVE: To assess the pattern of cartilage damage in symptomatic cases of developmental dysplasia of the hip (DDH) and of femoroacetabular impingement (FAI) with a novel three-dimensional (3D) delayed Gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC) technique. METHODS: After clinical diagnosis with conventional radiographs, two consecutive series of each 20 patients with DDH or FAI were assessed with 3D dGEMRIC. Radial T1 maps were reconstructed and region of interest analysis of the central and peripheral cartilage was carried out. RESULTS: The dGEMRIC index was mean 531 +/- 92.7 (391 729) ms in DDH and 551 +/- 95.7 (372-694) ms in FAI, respectively (P=0.507). Subgroup analysis showed higher T1 in the weight-bearing areas and significantly higher values in the central areas (DDH P<0.0001, N=11; FAI P=0.036, N=14) of the acetabulum in pre-arthritic cases (dGEMRIC index>500 ms) both in DDH and FAI. A breakdown of this distribution was found both in DDH and FAI cases with dGEMRIC index<500 ms. Pearson correlation analysis demonstrated the dGEMRIC index had a poor predictive value for the anterior-superior quadrant of the hip joint in FAI (r=0.482, P=0.031, r(2)=0.233). CONCLUSION: Radial dGEMRIC allows for the assessment of cartilage damage in the entire hip; different patterns of T1 distribution are found in DDH and FAI at progressed stages. The assessment of the anterior-superior quadrant of the acetabulum can be considered a fundamental advantage of the 3D dGEMRIC protocol. PMID- 20727415 TI - Advanced hip osteoarthritis: magnetic resonance imaging aspects and histopathology correlations. AB - OBJECTIVES: To correlate magnetic resonance imaging (MRI) aspects of the femoral head with histological findings in advanced hip osteoarthritis (OA), with special emphasis on bone marrow edema (BME). METHODS: MRI was performed in patients with advanced hip OA scheduled for hip arthroplasty. Coronal T1-, fat-suppressed T2-, T1 with gadolinium intravenous injection sequences were obtained on a 1.5 T MR scanner within 1 month before surgery. Coronal MR images corresponding to the ligamentum teres plane were analyzed by two independent readers blinded to histological data. Normal bone marrow, subchondral cyst, subchondral fracture, edema-like, necrosis-like, and necrosis MR patterns were reported on a synthesis scheme. After surgery, the femoral heads specimens were cut through the ligamentum teres plane and histologically analyzed for correlations. RESULTS: Twenty-three femoral heads were analyzed (female 56.5%, mean age 64.5 years). Edema-like MR pattern was correlated with histological (H) edema (Kappa (K): 0.77). Necrosis-like MR pattern was correlated with H fibrosis (K: 0.49) and with H necrosis (K: 0.24). Cyst MR pattern was correlated with H bone cysts (K: 0.58). Necrosis MR pattern corresponded to a mixture of histological lesions. Sensitivity and specificity of MRI varied from 26% to 80% and from 86% to 95% respectively. CONCLUSION: In advanced hip OA, the so-called "BME" MR lesion corresponds to a combination of edema, fibrosis, and necrosis at histopathology. When the classical "BME" is more specifically separated into edema-like and necrosis-like MR patterns, MR Imaging and histological findings show substantial agreement, with edema-like MR pattern mainly corresponding to histological edema. PMID- 20727416 TI - Up-regulation of heme oxygenase-1 by sevoflurane is not dependent on Kupffer cells and associates with ERK1/2 and AP-1 activation in the rat liver. AB - Sevoflurane is a potent non-toxic inducer of the hepatoprotective enzyme heme oxygenase-1 (HO-1). So far, little is known about the underlying molecular mechanism. Therefore the aim of this study was to characterize the respective signal transduction pathway and in particular to elucidate the role of Kupffer cells in this context. Rats were treated with or without sevoflurane. The effects on hepatic HO-1 gene expression, mitogen-activated protein kinases and transcription factors were studied by Northern and Western blot analyses, immunostaining, electrophoretic mobility shift assays, and enzymatic activity assays. Kupffer cells were depleted by administration of clodronate liposomes in vivo to characterize their role in HO-1 signal transduction. In additional in vitro experiments, HO-1 mRNA expression in primary rat hepatocytes and HepG2 cells was assessed. Sevoflurane up-regulated HO-1 gene expression in pericentral hepatocytes and increased HO enzyme activity in vivo. This was associated with activation of ERK1/2 and activator protein-1. We identified c-jun/AP-1, JunD, c fos, and Fra-1 as active subunits of the activator protein-1 complex. Administration of clodronate liposomes to rats led to depletion of Kupffer cells without affecting sevoflurane induced HO-1 expression. Moreover, sevoflurane up regulated HO-1 mRNA in primary rat hepatocytes but not in HepG2 cells. Our results suggest that sevoflurane induced HO-1 gene expression in pericentral hepatocytes does not depend on Kupffer cells and is associated with activation of ERK1/2 and activator protein-1. Since we could recently demonstrate significant hepatoprotective effects of HO-1 induced by isoflurane, the present results may help to establish new concepts in hepatic organ protection. PMID- 20727417 TI - Cancer nanotechnology: application of nanotechnology in cancer therapy. AB - The application of nanotechnology for cancer therapy has received considerable attention in recent years. Cancer nanotechnology (an interdisciplinary area of research in science, engineering and medicine) is an upcoming field with extensive applications. It provides a unique approach and comprehensive technology against cancer through early diagnosis, prediction, prevention, personalized therapy and medicine. Target-specific drug therapy and methods for early diagnosis of pathologies are the priority research areas in which nanotechnology would play a vital part. This review focuses on the approaches of cancer nanotechnology in the advancement of cancer therapy. PMID- 20727418 TI - Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability. AB - Self-emulsifying drug delivery systems are a vital tool in solving low bioavailability issues of poorly soluble drugs. Hydrophobic drugs can be dissolved in these systems, enabling them to be administered as a unit dosage form for per-oral administration. When such a system is released in the lumen of the gastrointestinal tract, it disperses to form a fine emulsion (micro/nano) with the aid of GI fluid. This leads to in situ solubilization of drug that can subsequently be absorbed by lymphatic pathways, bypassing the hepatic first-pass effect. This article presents an exhaustive account of various literature reports on diverse types of self-emulsifying formulations with emphasis on their formulation, characterization and in vitro analysis, with examples of currently marketed preparations. PMID- 20727419 TI - Nucleotide pool damage and its biological consequences. PMID- 20727420 TI - Epicardial left atrial appendage and biatrial appendage accessory pathways. AB - BACKGROUND: Acute success rates of accessory pathway ablation for Wolff-Parkinson White (WPW) syndrome can exceed 95%, with rare failures attributed to anatomically complex epicardial connections. Right atrial appendage to right ventricle pathways have been reported, but their left-sided counterparts have only recently been described. OBJECTIVE: The purpose of this study was to report three unique cases of WPW syndrome in children with left atrial appendage and biatrial appendage connections. RESULTS: Three young patients with high-risk accessory pathways (accessory pathway effective refractory period = 190-240 ms) had unsuccessful endocardial ablations despite aggressive efforts with various catheter techniques. One patient had a left atrial appendage to left ventricular connection; the other two had biatrial appendage pathways connected to their respective ventricular surfaces. The latter two patients had a history of ventricular fibrillation: one experiencing ventricular fibrillation in the electrophysiology laboratory and the other suffering from ventricular fibrillation arrest at home. All three patients were taken to the operating room, where the appendages were noted to be diffusely adherent to their ventricles by fibrofatty connections. Dissection of the appendages led to loss of preexcitation and no further tachycardia. CONCLUSION: Surgical management of atrial appendage accessory pathways should be considered if aggressive attempts at endocardial ablation have failed. PMID- 20727421 TI - Ventricular tachycardia recurrence after "failed" endocardial ablation: a Sisyphean challenge? PMID- 20727422 TI - Is there new hope for sudden cardiac death prevention early after myocardial infarction? PMID- 20727423 TI - Pattern and molecular epidemiology of Hepatitis B virus genotypes circulating in Pakistan. AB - The continuously mutating nature of Hepatitis B virus (HBV) is responsible for the emergence of varying genotypes in different regions of the world affecting the disease outcome. The objective of the current study was to find out the pattern of HBV genotypes circulating in Pakistan. HBV genotypes were determined in HBV chronic patients of different age and gender from all the four different geographical regions (provinces) of Pakistan for a period of 2 years (2007-2009). Out of the total 3137 consecutive patients, 300 (175; 58.3% males and 125; 41.7% females) were randomly selected for HBV genotype A through H determination using molecular genotyping methods. Total 269 (89.6%) isolates were successfully genotyped where as 31 (10.3%) samples failed to generate a type-specific PCR band and were found untypable. Out of the successfully genotyped samples, 43 (14.3%) were with type A, 54 (18%) were with type B, 83 (27.6%) were with type C, 39 (13%) were with type D, 2 (0.6%) were with type E, 4 (1.3%) were with genotype F and total 44 (14.6%) were with mixed HBV infections. Of the mixed genotype infection cases, 16 were with genotypes A/D, 9 were B/C, six were A/D/F, five were with genotypes A/F, two were with A/B/D and B/E and one each for A/C as well as A/E genotypes. Four common genotypes of HBV found worldwide (A, B, C & D) were isolated from Pakistan along with uncommon genotypes E and F for the first time in Pakistan. Overall Genotype C is the most prevalent genotype. Genotypes B and C are predominant in Punjab & Balochistan and Khyber Pakhtoonkhwa, respectively whereas genotype A in Sindh. PMID- 20727425 TI - Mitochondrial fission/fusion dynamics and apoptosis. AB - Mitochondria play an important role in the progression of apoptosis through the release of pro-apoptotic factors, such as cytochrome c, from the mitochondrial intermembrane space. During this process, mitochondrial networks are dramatically reorganised from long filamentous interconnected tubules into small punctate spheres. Whether remodelling of mitochondrial networks is necessary for apoptosis associated cytochrome c release, or merely an accompanying process, has been a subject of debate. Here we discuss evidence for and against the role of mitochondrial fragmentation in the progression of apoptosis and highlight recent advances which indicate that mitochondrial fission is not a critical requirement for apoptosis-associated cytochrome c release. We also discuss an emerging role for Bcl-2 family members as regulators of mitochondrial fission and fusion dynamics, independent of the role of this family in the regulation of apoptosis. PMID- 20727426 TI - All you wanted to know about anti-CCP but were afraid to ask. AB - The most specific biomarker associated with the diagnosis of rheumatoid arthritis (RA) is autoantibodies to citrullinated peptides/proteins (ACPA). Though recognized as an important marker of progressive erosive disease its use has been hampered by doubt about what is a positive versus a negative reaction in the several assays that have become available commercially. This review intends to indicate that the CCP2 assay has the highest specificity and sensitivity in stratified studies that encompass sera from RA patients and non-RA inflammatory controls compared to other ACPA tests. Still, larger and strictly stratified studies are highly warranted to substantiate this conclusion. PMID- 20727424 TI - Recombinant human mitochondrial transcription factor A stimulates mitochondrial biogenesis and ATP synthesis, improves motor function after MPTP, reduces oxidative stress and increases survival after endotoxin. AB - Recombinant human mitochondrial transcription factor A protein (rhTFAM) was evaluated for its acute effects on cultured cells and chronic effects in mice. Fibroblasts incubated with rhTFAM acutely increased respiration in a chloramphenicol-sensitive manner. SH-SY5Y cells showed rhTFAM concentration dependent reduction of methylpyridinium (MPP(+))-induced oxidative stress and increases in lowered ATP levels and viability. Mice treated with weekly i.v. rhTFAM showed increased mitochondrial gene copy number, complex I protein levels and ATP production rates; oxidative damage to proteins was decreased ~50%. rhTFAM treatment improved motor recovery rate after treatment with MPTP and dose dependently improved survival in the lipopolysaccharide model of endotoxin sepsis. PMID- 20727427 TI - Cornelia de Lange syndrome case due to genomic rearrangements including NIPBL. AB - Cornelia de Lange syndrome (CdLS) is a rare multisystem congenital anomaly disorder characterized by growth and developmental delay, distinctive facial dysmorphism, limb malformations and multiple organ defects. Approximately 60-65% of the CdLS subjects have mutation in one of three cohesin proteins, a main regulator of cohesin-associated protein, NIPBL, and two components of the cohesin ring structure SMC1A and SMC3. A prominent role for cohesin is to control chromosome segregation during cell divisions. We have performed MLPA analysis in a group of 11 children with the CdLS but without identifiable point mutations in the NIPBL and SMC1A genes. In a single patient, we identified a large deletion encompassing exons 35 to 47 of the NIPBL gene. Our finding was validated by aCGH and further characterized by long-range PCR and DNA sequencing of the breakpoint junction. PMID- 20727428 TI - Food insecurity, hunger and malnutrition: necessary policy and technology changes. AB - Ending food insecurity, hunger and malnutrition is a pressing global ethical priority. Despite differences in food production systems, cultural values and economic conditions, hunger is not acceptable under any ethical principles. Yet, progress in combating hunger and malnutrition in developing countries has been discouraging, even as overall global prosperity has increased in past decades. A growing number of people are deprived of the fundamental right to food, which is essential for all other rights as well as for human existence itself. The food and nutrition crisis has deepened in recent years, as increased food price volatility and global recession affected the poor. In a strategic agenda, it will be necessary to promote pro-poor agricultural growth, reduce extreme market volatility and expand social protection and child nutrition action. PMID- 20727438 TI - Reflections on pediatrics in academic health centers. PMID- 20727429 TI - Skin irritation and the inhibition effect on HSV-1 in vivo of penciclovir-loaded microemulsion. AB - The purpose of the present study was to investigate the skin irritation and pharmacodynamics of penciclovir-loaded microemulsion (PCV-ME). The formulation of PCV-ME was comprised of oleic acid (OA) (5%, w/w), Cremorphor EL (20%, w/w), ethanol (30%, w/w) and water (45%, w/w). PCV-ME presented as spherically shaped under transmission electron microscopy with an average diameter of 36.5 nm, and the solubility of PCV in microemulsion (ME) was 7.41 mg/g, almost 6 times that in water. Skin irritation test was performed in male guinea pigs, which demonstrated that no irritation effect was caused after single or multiple applications of PCV ME. Likewise, male guinea pigs were employed as animal models which were infected with herpes simplex virus type 1 (HSV-1) in pharmacodynamics study. Real-time PCR was utilized to investigate the inhibition effect on HSV-1 exerted by commercial PCV-cream and PCV-ME. The results indicated that compared with commercial PCV cream, PCV-ME could significantly inhibit the replication of HSV-1 in skin. In conclusion, PCV-ME could be a promising formulation which possessed the virtues of low irritation and high effectiveness. PMID- 20727441 TI - Early onset toe-walking in toddlers: a cause for concern? PMID- 20727442 TI - Vasopressin for refractory hypotension in extremely low birth weight infants. AB - Intravenous vasopressin at 0.01 to 0.04 units/kg/h increased median mean blood pressure from 26 mm Hg (range 18-44) to 41 mm Hg (range 17-90) by 12 hours of infusion (P=.002) and allowed weaning of catecholamines in a group of extremely low birth weight infants with refractory hypotension. PMID- 20727443 TI - Long-acting beta--agonists best option for "step-up" therapy for children with uncontrolled asthma. PMID- 20727444 TI - Clinical prediction rule adequately predicts nonbacterial conjunctivitis. PMID- 20727445 TI - Gastric banding results in significant weight loss for obese adolescents. PMID- 20727446 TI - Deformational plagiocephaly delays motor skill development in 6-month-old infants. PMID- 20727447 TI - Parent-initiated treatment with prednisolone can reduce symptoms for children with acute asthma exacerbations. PMID- 20727449 TI - Salami science or editorial imperialism? PMID- 20727451 TI - Letter from the guest editor. Musculoskeletal MRI. PMID- 20727452 TI - Femoroacetabular impingement: screening and definitive imaging. PMID- 20727454 TI - Musculotendinous magnetic resonance imaging of the ankle. PMID- 20727453 TI - Magnetic resonance imaging of the knee: optimizing 3 Tesla imaging. PMID- 20727455 TI - Magnetic resonance imaging of soft-tissue masses. PMID- 20727456 TI - Editorial: Comparative efficacy and cost associated with new agents in the treatment of non-small cell lung cancer (NSCLC). PMID- 20727457 TI - Cost-effectiveness analysis of bevacizumab versus pemetrexed for advanced non squamous NSCLC in Italy. AB - INTRODUCTION: The new targeted agent bevacizumab in combination with cisplatin and gemcitabine (BCG), and a third-generation chemotherapy pemetrexed in combination with cisplatin (PC), are approved as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: An indirect comparison between BCG and PC showed that the bevacizumab triplet achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the detailed costs and benefits of these treatments for advanced non-squamous NSCLC in Italy. RESULTS: The monthly cost of single-agent bevacizumab, including administration and supportive care costs, and costs for adverse events as a single agent was 4,007 euro/patient less than pemetrexed over the patient's lifetime. BCG also achieved a mean gain of 0.12 life-years compared with PC over this period. The incremental cost-effectiveness ratio of BCG relative to PC was calculated to be 34,919 euro per additional life-year gained suggesting that BCG is cost-effective compared with PC as first-line treatment for advanced NSCLC in Italy. CONCLUSIONS: In conclusion, bevacizumab-based therapy can be considered as a cost effective option when compared to chemotherapy treatments such as pemetrexed for the treatment for advanced non-squamous NSCLC. PMID- 20727458 TI - Costs of bevacizumab and pemetrexed for advanced non-squamous NSCLC in Italy and Germany. AB - The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third-generation chemotherapy pemetrexed in combination with cisplatin, have been approved as first-line treatment for patients with advanced non squamous non-small cell lung cancer (NSCLC). An indirect comparison between bevacizumab plus cisplatin and gemcitabine and pemetrexed plus cisplatin showed that bevacizumab (plus cisplatin and gemcitabine) achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the monthly cost of these treatments for advanced non-squamous NSCLC in Italy and Germany. The comparison used country specific cost data and adopted the payer perspective in Italy and Germany. The monthly cost of bevacizumab, including administration cost, as a single agent was 1,509 euro and 2,564 euro less than pemetrexed in Italy and Germany, respectively. The monthly treatment cost of bevacizumab plus cisplatin and gemcitabine was 1,001 euro and 446 euro less than pemetrexed plus gemcitabine in Italy and Germany, respectively. Results indicate that clinical benefits with bevacizumab plus cisplatin and gemcitabine therapy are achieved at a lower monthly cost than pemetrexed plus gemcitabine doublet therapy. Therefore, from a budget perspective, bevacizumab should be considered as a preferred targeted treatment of choice for advanced non-squamous NSCLC. PMID- 20727459 TI - Societal cost savings through bevacizumab-based treatment in non-small cell lung cancer (NSCLC). AB - Bevacizumab in combination with platinum-based chemotherapy is associated with increased survival outcomes compared to chemotherapy alone in patients with non squamous metastatic non-small cell lung cancer (mNSCLC). The objective of this study was to estimate potential economic benefits from a societal perspective in patients returning to work when treated with bevacizumab-based combination therapy. These economic benefits were assessed with respect to reduced productivity losses and described in terms of per patient cost savings. The analysis was conducted for France, Germany, Italy and Spain. Clinical outcomes in terms of progression-free survival (PFS) were based on two phase III clinical trials (E4599 and AVAiL) comparing bevacizumab + chemotherapy vs. chemotherapy alone. Potential cost savings due to reduction in productivity losses were assessed in progression-free patients who return back to work (human capital approach). It was assumed that 20% of all progression-free patients with performance status 0 or 1 and below 55 years of age would return back to work after the induction therapy maintaining their prior employment status (60% part time, 40% full-time). Savings were calculated over 1 and 1.5 year time horizons. Mean savings, per progression-free patient ranged from 12,401 euro in Spain at year 1 to 39,001 euro in France at year 1.5. Respective findings proved to be fairly sensitive to the change of employment patterns and labour costs. This analysis shows that bevacizumab-based treatment can result in substantial cost savings in progression-free patients with mNSCLC. PMID- 20727460 TI - Effectiveness of bevacizumab- and pemetrexed-cisplatin treatment for patients with advanced non-squamous non-small cell lung cancer. AB - The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third generation chemotherapy, pemetrexed, combined with cisplatin, are approved as first-line treatment for patients with advanced nonsquamous non-small cell lung cancer (NSCLC). As no head-to-head comparison of these treatments exists, this study aimed to compare the effectiveness of the two treatments using an indirect treatment comparison approach. An indirect comparison on progression free survival (PFS) was performed for two relevant randomised controlled trials using a well-accepted adjusted indirect comparison method. The results were used in a statistical disease model (Markov model) to extrapolate the long-term effectiveness of the two treatments. A hazard ratio of 0.83 for PFS for bevacizumab plus cisplatin and gemcitabine, was calculated suggesting that this treatment is associated with a 17% lower risk of disease progression and death compared with pemetrexed plus cisplatin treatment. The Markov model predicted that bevacizumab plus cisplatin and gemcitabine resulted in 2.5 months additional PFS and overall survival compared with pemetrexed plus cisplatin. Based on this analysis bevacizumab plus cisplatin and gemcitabine is more effective than pemetrexed plus cisplatin for patients with advanced non-squamous NSCLC and should be considered as one of the preferred targeted treatments of choice for these patients. PMID- 20727461 TI - A summary of trauma and trauma-related papers published in BJOMS during 2008 2009. AB - This paper provides a summary of the 49 trauma and related papers published in British Journal of Oral and Maxillofacial Surgery during the period January 2008 to December 2009. 16/49 (32%) of these publications were full length articles, which covered areas such as epidemiology, service provision, materials and operative surgery. In addition there were other articles including short communications, technical notes, letters to the editor and interesting cases. Whilst fewer full length articles were published compared to the other sub specialties, it was reassuring to see that the studies represent all aspects of trauma. More basic science and randomized control studies relating to trauma need to be encouraged. PMID- 20727462 TI - In vitro activity of tigecycline in combination with gentamicin against biofilm forming Staphylococcus aureus. AB - We investigated the activity of tigecycline in combination with gentamicin for the treatment of biofilm-forming methicillin-resistant and sensitive Staphylococcus aureus in an in vitro pharmacodynamic model. Tigecycline monotherapy demonstrated bacteriostatic activity throughout 48 h (-0.24 +/- 0.17 log(10) CFU/mL), whereas tigecycline in combination with gentamicin demonstrated significant (P < 0.002) kill (-3.66 +/- 0.26 log(10) CFU/mL) at 48 h. The addition of gentamicin to tigecycline significantly improved the killing activity of tigecycline in biofilm-forming S. aureus. PMID- 20727463 TI - Repetitive element-polymerase chain reaction for genotyping of clinical and environmental isolates of Legionella spp. AB - Genotyping of Legionella strains is important for the epidemiologic survey of Legionnaires' disease infections. In this study, we investigated the potential of repetitive element-polymerase chain reaction (rep-PCR) for differentiating various isolates of Legionella spp. We used 38 Legionella pneumophila isolates (collected in clinics all over Japan between 1980 and 2007), 19 environmental Legionella anisa isolates (collected in Okinawa, Nara, Osaka, and Hyogo prefecture between 1987 and 2007), and 2 Legionella-type strains. We extracted bacterial genomic DNA and applied it to rep-PCR. PCR products were then converted into bands by agarose gel electrophoresis. The L. pneumophila serogroup (SG) 1 displayed very diverse patterns. Different bands were produced for each species of Legionella, and each species was clearly distinct. Phylogenetic analysis displayed 1 cluster of L. anisa isolates, while other Legionella spp. were present at discrete levels. Our findings show that rep-PCR is an effective, rapid, and simple technique for differentiation of L. pneumophila strains as well as Legionella spp. PMID- 20727464 TI - Clinical and economic evaluation of BBL CHROMagar Salmonella (CHROMSal) versus subculture after selenite broth enrichment to CHROMSal and Hektoen enteric agars to detect enteric Salmonella in a large regional microbiology laboratory. AB - Stool culture for enteric pathogens is one of the most labor-intensive clinical microbiology procedures. Direct plating of stool to BBL CHROMagar Salmonella (CHROMSal) (BD Diagnostics, Sparks, MD) versus subculture after selenite broth enrichment (Sel) to CHROMSal (Sel-CHROMSal) and Hektoen enteric agar (Sel-Hek) (PML Microbiologicals, Eugene, OR) to detect Salmonella were compared. The number of colony picks and biochemical/serotyping tests per plate was recorded. A cost comparison was done. Fifty-one of 2999 (1.7%) stools yielded Salmonella sp., and 80% of isolates grew on CHROMSal by 24 h. CHROMSal demonstrated much less false positive growth compared to Sel-Hek (P < 0.0001), which reduced biochemical and serotyping tests by 85% and 20%, respectively. Sel-CHROMSal and CHROMSal versus Sel-Hek improved enteric Salmonella detection when compared to a true positive "gold standard" (i.e., recovery by any culture method) with a sensitivity, specificity, positive predictive value, and negative predictive value of 100% and 94.12%, 100% and 99.97%, 100% and 97.96%, and 100% and 99.90%, respectively. CHROMSal use would result in substantial cost and labor savings. PMID- 20727466 TI - Progression to bacteremia in critical care patients colonized with methicillin resistant Staphylococcus aureus expressing Panton-Valentine leukocidin. AB - The role of Panton-Valentine leukocidin (PVL) in methicillin-resistant Staphylococcus aureus (MRSA) infections is unclear. PVL has been long associated with soft tissue infections and necrotizing pneumonia, but inconsistently with other site infections or mortality. The retrospective cohort study explores the association between PVL and bacteremia in colonized medical intensive care unit (ICU) patients with surveillance isolates and blood cultures. A total of 840 patients were screened by nasal swab, with 266 patients found to be colonized and 46 with bacteremia. Colonization by PVL(+) MRSA increased the odds of bacteremia (odds ratio, 2.40; confidence interval, 1.23-4.57), and invasive infection developed earlier in these patients (relative risk, 0.44; confidence interval 0.25-0.85) compared to those colonized with PVL(0) MRSA. PVL was not associated with infections at other sites, length of ICU stay, or mortality. PVL decreases the time to bacteremia in colonized patients but does not otherwise contribute to disease course or clinical outcome. PMID- 20727465 TI - Chronic colonization by Pseudomonas aeruginosa of patients with obstructive lung diseases: cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. AB - Pseudomonas aeruginosa is isolated in sputum cultures from cystic fibrosis (CF) patients and adults with bronchiectasis (BS) and chronic obstructive pulmonary disease, but it is not well known if the characteristics of colonization in these latter patients are similar to those with CF. We examined 125 P. aeruginosa isolates obtained from 31 patients suffering from these diseases by pulsed field gel electrophoresis and genotyping of mucA and fpvA genes. The pattern of colonization, with dominance of a clonal strain and incidence of mucoid phenotypes, was similar in every group of patients; however, in some CF and BS patients, we detected the replacement or coexistence of 2 main clones. The main differences were found in the nucleotide position of less common mucA mutations, other than mucA22, and in the predominance of the different types of the pyoverdine receptor. Our results support a similar colonization pattern by P. aeruginosa in the different obstructive pulmonary diseases. PMID- 20727467 TI - Molecular and epidemiologic characteristics of linezolid-resistant coagulase negative staphylococci at a tertiary care hospital. AB - We investigated emergence of linezolid resistance among coagulase-negative staphylococci at our tertiary care center in 2007. All 17 cases were healthcare associated, and prior administration of linezolid was documented .05). In contrast, the hand instrumentation group extruded significantly more debris than both NiTi groups (P<.05). CONCLUSIONS: The present results yielded favorable input for the F2 single-file technique in terms of apically extruded debris, inasmuch as it is the most simple and cost-effective instrumentation approach. PMID- 20727499 TI - Effect of calcium hydroxide dressing on the long-term sealing ability of two different endodontic sealers: an in vitro study. AB - OBJECTIVE: The aim of this in vitro study was to evaluate the long-term sealing ability of Real Seal system and Endofill after calcium hydroxide (CH) dressing, by using a fluid filtration model. STUDY DESIGN: Four randomized groups of single rooted teeth (N=110) were prepared using a crown-down technique to a size 50 file. Two groups (1 and 2) received CH dressing before filling. Roots were filled with gutta-percha and Endofill (groups 2 and 4) or Resilon and Real Seal (groups 1 and 3). Leakage was measured by using the fluid filtration method after 90 days and determined as microL/min.10 psi. RESULTS: Statistical analysis by Kruskal Wallis and Mann-Whitney tests indicated that CH dressing groups showed higher leakage values than those where CH was not used (P=.001). CONCLUSION: It may be concluded that the use of CH as an intracanal dressing material affected the sealing ability of both Real Seal and Endofill sealers. PMID- 20727501 TI - Cyclic fatigue resistance of ProTaper Universal instruments when subjected to static and dynamic tests. AB - OBJECTIVE: This study evaluated the number of cycles to fracture of ProTaper Universal S2 instruments when subjected to static and dynamic cyclic fatigue tests. STUDY DESIGN: ProTaper Universal S2 instruments were used until fracture in an artificial curved canal under rotational speed of 300 rpm in either a static or a dynamic test model. Afterward, the length of the fractured segments was measured and fractured surfaces and helical shafts analyzed by scanning electron microscopy (SEM). RESULTS: The number of cycles to fracture was significantly increased when instruments were tested in the dynamic model (P<.001). Instrument separation occurred at the point of maximum flexure within the artificial canals, i.e., the midpoint of the curved canal segment. SEM analysis revealed that fractured surfaces exhibited characteristics of the ductile mode. Plastic deformation was not observed in the helical shaft of fractured instruments. CONCLUSIONS: The number of cycles to fracture ProTaper Universal S2 instruments significantly increased with the use of instruments in a dynamic cyclic fatigue test compared with a static model. These findings reinforce the need for performing continuous pecking motions during rotary instrumentation of curved root canals. PMID- 20727502 TI - Perspectives in magnetic resonance. PMID- 20727503 TI - Beginnings and early history of the International Conferences on Magnetic Resonance in Biological Systems: development of the basic ideas in the field. AB - The early history of the principal meeting in the field of biological NMR spectroscopy, the International Conference on Magnetic Resonance in Biological Systems (ICMRBS), is presented from the perspective of one of the founders. PMID- 20727504 TI - Estimating the glomerular filtration rate in obese adult patients for drug dosing. AB - One-third of adult Americans are currently classified as obese. Physiologic changes associated with obesity can potentially alter the clearance of commonly used drugs. Clearance of certain drugs by the kidneys occurs primarily through glomerular filtration and tubular secretion. Obesity has been associated with glomerular hyperfiltration, whereas obesity-related effects on tubular secretion are not well characterized. Estimation of the glomerular filtration rate (GFR) is currently performed using serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. However, drug dosing guidelines are often based on creatinine clearance (CLcr) using the Cockcroft-Gault equation as a surrogate of GFR. There is a lack of consensus on the most appropriate method for estimation of GFR or CLcr in patients with obesity. The controversy relates to the use of 2 body size descriptors that confound these equations. The Cockcroft-Gault equation relies on total body weight and so overestimates GFR in patients with obesity. The MDRD equation indexes GFR based on a normalized body surface area, that is, mL/min/1.73 m(2). Conversion of MDRD estimated GFR to non-normalized body surface area overestimates GFR in patients with obesity. The current review explores current approaches and controversies to estimation of GFR and CLcr among obese patients in clinical practice. The role of the alternate body size descriptor, lean body weight to estimate CLcr in obese patients is reviewed. PMID- 20727505 TI - Novel strategies for immune monitoring in kidney transplant recipients. AB - The ongoing quandary in kidney transplantation is discovering methods to prolong graft survival. To achieve this, there is a search for optimal methods to use immunosuppressive therapy, where rejection and chronic graft damage is minimized without causing an increased risk of infections, malignancy, or toxicities. The purpose of this review was to discuss the limitations of current immunosuppressant drug monitoring as well as the clinical application of novel methods of monitoring both immunosuppressants and the immune reaction within the allograft. PMID- 20727506 TI - Pharmacotherapy: drugs, the kidney, and hippocrates. PMID- 20727507 TI - CKD: Pharmacotherapy in a House of Mirrors. PMID- 20727508 TI - Nonrenal drug clearance in CKD: Searching for the path less traveled. AB - Patients with chronic kidney disease (CKD) represent a significant and growing segment of the US population. A mounting body of experimental and clinical evidence indicates that nonrenal drug clearance is altered in patients with CKD. Specific nonrenal clearance (CL(NR)) pathways that are affected have been identified in experimental models, and include cytochrome P450 enzymes, P glycoprotein, and organic anion-transporting polypeptides. Altered CL(NR) of several drugs has been described in clinical pharmacokinetics studies, but to date the specific CL(NR) pathways that are affected in CKD patients and result in clinically significant changes in drug exposure have not been definitively established, and the mechanism has not been elucidated. Accumulated uremic toxins may downregulate or directly inhibit drug metabolism and transport pathways, and may do so in a reversible manner. Future Food and Drug Administration recommendations pertaining to the conduct of pharmacokinetic studies in CKD will undoubtedly facilitate the search for the CL(NR) path less traveled, clarify the mechanisms involved, improve our understanding of the clinical significance of altered CL(NR) of individual drugs, and lead to more comprehensive drug dosing recommendations for patients with CKD. This review summarizes our current understanding of this field, focusing on recent developments in the search for the CL(NR) "path less traveled" in CKD. PMID- 20727509 TI - Antibiotic pharmacokinetic and pharmacodynamic considerations in patients with kidney disease. AB - Although pharmacokinetic changes occurring in kidney disease are well described, pharmacodynamics in kidney disease is rarely considered. Knowledge of pharmacodynamic principles can allow a clinician to maximize an antibiotic's effectiveness while minimizing adverse effects and antibacterial resistance. An antibiotic's pharmacokinetic and pharmacodynamic profiles should drive dose adjustment decisions in patients with kidney disease. For example, although the half-lives of beta-lactams and aminoglycosides are both prolonged in these patients, beta-lactams exhibit time-dependent antibacterial activity; consequently, maintenance doses should be smaller but given at the same interval. In contrast, aminoglycosides are concentration-dependent antibiotics; hence prolongation of the dosing interval while using larger doses may be advantageous. The timing of drug administration in relation to hemodialysis may be used to achieve specific pharmacodynamic goals. Aminoglycosides given before hemodialysis generate high peaks, whereas subsequent dialytic drug removal minimizes the area under the serum concentration-time curve, potentially decreasing the risk of developing toxicity. Furthermore, new dialysis prescribing patterns (eg, automated peritoneal dialysis, nocturnal dialysis) affect pharmacokinetic and pharmacodynamic parameters in ways not appreciated by clinicians. Studies quantifying the often considerable drug removal with these therapies, as well as efforts to identify pharmacodynamic targets in patients with kidney disease are essential. This paper reviews pharmacodynamic as well as pharmacokinetic issues that should be considered when prescribing antibiotics to treat infections in this population. PMID- 20727510 TI - Medication-related problems in CKD. AB - Patients with CKD are often prescribed heterogeneous medications to treat disease associated comorbidities, to slow down progression of the disease, and to minimize morbidity and mortality rates. However, the medication regimens of this population are very complex, leading to an increased potential for medication related problems (MRPs). As kidney function declines, the type and amount of medications a patient consumes increases, thereby putting them at a higher risk for MRPs. MRPs have been known to be associated with morbidity, mortality, and a lower quality of life. This review will summarize data on the prevalence and effect of MRPs, and strategies that can be used by clinicians to reduce and resolve MRPs. PMID- 20727511 TI - Improving medication safety in chronic kidney disease patients on dialysis through medication reconciliation. AB - Patients with chronic kidney disease on dialysis are prescribed an average of 10 to 12 medications. Most hemodialysis patients encounter health care professionals 3 times a week, and peritoneal dialysis patients at least once a quarter; however, medication-related problems continue to be present in large numbers. A significant proportion of medication-related problems in hospitalized dialysis patients have been attributed to a medical information gap that occurs during transitions between healthcare settings. Information regarding the effect of medication reconciliation on the rates of medication-related errors and outcomes of dialysis patients is sparse. Information from hospital-based medication reconciliation programs suggests that dedicated multidisciplinary medication reconciliation teams using electronic or paper-based medication reconciliation tools can work to reduce medication errors and rates of rehospitalization. The dialysis center staff has intimate knowledge of patient medical histories, comorbid conditions, and dialysis-related medications; dialysis center practitioners are known to often prescribe other routine medications for patients undergoing dialysis. Therefore, the dialysis center is the most logical place for carrying out medication reconciliation. Data necessary for medication review and reconciliation, and data on the dialysis team's role in reconciling information after care transitions, have been outlined. Reducing medication errors through a systematic multidisciplinary approach may ultimately reduce hospitalization rates. Adequately powered trials are necessary to demonstrate that medication reconciliation can improve dialysis patient outcomes and cost. PMID- 20727512 TI - Systemic anticoagulation considerations in chronic kidney disease. AB - Anticoagulation therapy is commonly required in patients with chronic kidney disease for treatment or prevention of thromboembolic disorders. Anticoagulant management plans can involve use of a single agent, or in some cases, a combination of agents to meet both short- and long-term goals. Systemic anticoagulation in the setting of renal insufficiency poses unique challenges secondary to renal failure-associated hypercoagulable conditions and increased risks for bleeding. Evidence supporting dosing regimens and monitoring approaches in the setting of severe renal impairment or hemodialysis is limited because this population is typically excluded in clinical trials. This review explores concepts of systemic anticoagulation in the chronic kidney disease setting with warfarin, unfractionated heparin, low-molecular-weight heparin, fondaparinux, direct thrombin inhibitors, and anticoagulants in advanced stages of development. Potential strategies for anticoagulant reversal are also briefly described. PMID- 20727513 TI - Calcific uremic arteriolopathy: contemporary pharmacotherapy. AB - Calcific uremic arteriolopathy (CUA) is a poorly understood disease affecting 4% to 5% of the patients with end-stage renal disease. Strategies aimed at prompt identification and diagnosis, such as use of plain radiographs, bone scans, and transcutaneous oxygen saturation tension, may lead to earlier initiation of treatment. Early treatment should focus on preventing progression into overt ulceration, which significantly raises the likelihood of infection, amputation, and death. Several agents, including sodium thiosulfate, bisphosphonates, cinacalcet, and tissue plasminogen activator, have been used in the treatment of CUA with varying effects; however, there has been no consensus on an optimal treatment option. The lack of randomized trials comparing treatment options and a potential bias with respect to publication of case reports hinders the ability to choose the most effective agent in the treatment of CUA. Future insights into the molecular basis of vascular calcification may help determine new therapeutic targets. PMID- 20727514 TI - Incretin-based therapy in chronic kidney disease. AB - Type 2 diabetes mellitus (T2DM) with concomitant CKD is an emerging clinical and public health problem reaching epidemic proportions in the United States. Achieving and maintaining glycemic targets in clinical practice are significant challenges in majority of the patients with T2DM and CKD, and this has created significant barriers for clinicians managing these patients. Commonly used antihyperglycemic agents are either contraindicated or lack efficacy and safety information in this population. Recently, 2 distinct classes of agents that augment incretin hormone action have been added to the therapeutic armamentarium targeting hyperglycemia. This review will discuss the literature examining the efficacy and safety of incretin-based therapies in T2DM and the available evidence for their use in CKD. PMID- 20727515 TI - TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. AB - Idiopathic epilepsies (IEs) are a group of disorders characterized by recurrent seizures in the absence of detectable brain lesions or metabolic abnormalities. IEs include common disorders with a complex mode of inheritance and rare Mendelian traits suggesting the occurrence of several alleles with variable penetrance. We previously described a large family with a recessive form of idiopathic epilepsy, named familial infantile myoclonic epilepsy (FIME), and mapped the disease locus on chromosome 16p13.3 by linkage analysis. In the present study, we found that two compound heterozygous missense mutations (D147H and A509V) in TBC1D24, a gene of unknown function, are responsible for FIME. In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus. By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics. The main recognized function of ARF6 in the nervous system is the regulation of dendritic branching, spine formation, and axonal extension. TBC1D24 overexpression resulted in a significant increase in neurite length and arborization and the FIME mutations significantly reverted this phenotype. In this study we identified a gene mutation involved in autosomal recessive idiopathic epilepsy, unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures, and confirmed the emerging role of subtle cytoarchitectural alterations in the etiology of this group of common epileptic disorders. PMID- 20727517 TI - [Is it useful to modify the care of Klinefelter's syndrome to improve the chances of paternity?]. AB - Until a few years ago, Klinefelter syndrome with a homogeneous 47.XXY karyotype was considered a model of absolute male sterility. In this review, we will discuss: (1) potential fertility following TEsticular Sperm Extraction IntraCytoplasmic Sperm Injection (TESE-ICSI), (2) the physiopathology of spermatogenic failure and the origin of focal spermatogenesis and risk of aneuploidy in potential offspring, (3) the advantage of searching for and cryopreserving spermatozoa in adolescent instead of adult patients. In previous published series, TESE was successful in almost 50% of patients and pregnancy rate following ICSI was not obviously different from other causes of spermatogenic failure. The rate of positive sperm extraction seemed to be better for younger patients. During childhood, the survival rate of 47.XXY spermatogonia is low. However, a few spermatogonia are able to eliminate their extra X chromosome, giving rise to rare clones of 46.XY gonia which are the origin of rare foci of complete spermatogenesis after puberty. Several arguments suggest that this focal spermatogenesis decreases with age. This suggests there would be a benefit to patients if TESE were performed in adolescences and spermatozoa were cryopreserved. In addition, androgenotherapy is a common treatment of Klinfelter syndrome but carries a risk of decreasing focal spermatogenesis by lowering gonadotropins. Preservation of spermatozoa from adolescence by TESE would allow androgenotherapy to be prescribed with less concern for future reproductive capacity. Controlled studies should be done to determine the best age for TESE ICSI in 47.XXY homogeneous Klinefelter syndrome patients. PMID- 20727516 TI - Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. AB - Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a "pseudo-TORCH" syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development. PMID- 20727518 TI - Thyroid toxicity after radiotherapy of nasopharyngeal carcinoma. AB - OBJECTIVES: To analyze retrospectively the risk factors for occurrence of thyroid toxicity after radiotherapy for nasopharyngeal cancer and to demonstrate the necessity of a long-term post-therapeutic screening. PATIENTS AND METHODS: Between 1993 and 2004, 239 patients with non-metastatic nasopharyngeal carcinoma were treated by conventional radiotherapy with or without chemotherapy. Radiotherapy was delivered by a standard fractionation (2 Gy/fraction, 5 fractions/week) for 157 patients and hyperfractionation (1.6 Gy/fraction, 2 fractions/day, 5 days/week) for 82 patients. An evaluation of thyroid late toxicity was performed according to tumor stage, age, gender, time after treatment, irradiation method and association or not with chemotherapy. RESULTS: After a median follow up of 111 months, 72 patients (30%) had primitive and/or pituitary thyroid dysfunction. Fifty-seven patients (24%) experienced hypothyroidism, peripheral in 92% of cases (biological 73%, clinical 19%) and central in 8% of cases. Hypothyroidism was detected at a mean 37 months follow up. All patients received replacement treatment with l-thyroxin. The actuarial rate of hypothyroidism was 18.1%, 24.3% and 35% at respectively 3, 5 and 10 years. Only female gender was found as a risk factor for occurrence of hypothyroidism in univariate analysis. However, younger age and advanced tumor stage were associated with a higher risk but the difference was not significant (P = 0.08 for each). There was no difference for other factors: nodal stage, modality of radiation and chemotherapy treatment. The multivariate analysis did not show any risk factor. CONCLUSION: Thyroid dysfunction after radiotherapy for nasopharyngeal carcinoma is frequent and requires systematic screening to begin adequate treatment earlier. Only gender has been identified as risk factor in univariate analysis in this study. PMID- 20727519 TI - Expression of CD55 and CD59 on peripheral blood cells from systemic lupus erythematosus (SLE) patients. AB - CD55 and CD59 are glycosylphosphatidylinositol-anchored proteins with complement inhibitory properties. CD55 inhibits the formation of C3 convertases, and CD59 prevents the terminal polymerisation of the membrane attack complex. It has been reported that SLE patients seems to have an acquired deficiency of these proteins associated with secondary autoimmune haemolytic anaemia and lymphopenia. The aim of this study was to evaluate the presence of altered CD55 and CD59 expression on peripheral blood cells from SLE patients. Flow cytometric analyses were performed on red and white blood cells from 23 SLE patients and 23 healthy controls. We observed more CD55- and CD59-lymphocytes (p=0.005 and p=0.019, respectively), and CD59-granulocytes (p=0.045) in SLE patients than in controls. These results suggest there is an altered pattern of CD55 and CD59 expression on the peripheral blood cells of SLE patients, and it may play a role in the cytopenias in these patients. PMID- 20727520 TI - Clinical complications after transvaginal oocyte retrieval in 7,098 IVF cycles. AB - We report the complications observed after transvaginal oocyte retrieval guided by ultrasound in 7,098 IVF cycles. The frequency of severe complications in our patients was 0.08%, of which four cases were intraperitoneal bleeding (0.06%) and two were cases of ovarian abscess (0.003%). PMID- 20727521 TI - AAV/hSTAT3-gene delivery lowers aortic inflammatory cell infiltration in LDLR KO mice on high cholesterol. AB - Atherosclerosis is an inflammatory disorder of arteries. Signal transducer and activator of transcription-3 (STAT3), an important signal transduction molecule, responds to a number of interleukins (IL) including IL-10, and has a significant immunosuppressive phenotype. Several studies have suggested a correlation of STAT3 expression with a lower state of inflammation. To investigate the contribution of STAT3 in regulating atherogenesis, we delivered full-length wild type human (h) STAT3 gene by adeno-associated virus type 8 (AAV8) via tail vein into low density lipoprotein knockout (LDLR KO) mice which were then fed high cholesterol diet (HCD). Compared to neomycin resistance (Neo) gene delivery-HCD, hSTAT3 delivery-HCD treatment did not result in significant changes in high plasma cholesterol levels. However, while vessel wall lipids were not directly measured, hSTAT3 delivery did result a significant reduction in aortic anomalies, as determined by larger aortic lumen size, thinner aortic wall thickness, and lower blood velocity than the Neo control (all statistically significant). Moreover, measurements of inflammation/monocyte/macrophage (Mo/MF) burden, including CD68, ITGAM, EMR-1 and nitrotyrosine were reduced in hSTAT3-HCD-treated animals, while foxp3 (Tregs) and SOCS1 expression were increased. An advantage hSTAT3-gene therapy would have over IL-10 would be a reduced chance of systemic effects as STAT3 is not a secreted protein. While hSTAT3-inhibitory gene delivery has been performed by several groups, delivery of the wild type STAT3 gene has never been attempted before. These data strongly suggest, for the first time, that STAT3 gene delivery can down-regulate Mo/MF burden and atherosclerosis. These data also suggest the possibility that STAT3 and IL-10 dual gene delivery may result in higher efficacy than either one alone. PMID- 20727522 TI - Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. AB - OBJECTIVE: Compared to normal weight adolescents, obese adolescents have lower serum omega-3 (n-3) polyunsaturated fatty acid (PUFA) concentrations, augmented inflammatory activity and endothelial dysfunction. We wanted to assess whether n 3 supplementation increases the serum n-3 PUFA concentration, improves vascular function and morphology, and lowers inflammation in obese adolescents. METHODS: Twenty-five obese adolescents (14 females, 11 males, age 15.7+/-1.0 years, BMI 33.8+/-3.9) were randomized to receive capsules containing either 1.2g/day n-3 or placebo for 3 months. The study was performed using a double-blind, cross-over design with a 6-week washout period. Anthropometry, blood pressure measurements and fasting blood samples were obtained before and after each treatment period. The vascular structure and function was measured after each treatment period. RESULTS: The serum n-3 PUFA concentration increased with n-3 treatment. The reactive hyperemia response improved with n-3 treatment compared to placebo (p<0.01). N-3 supplementation also decreased the lymphocyte, monocyte, TNF-alpha, IL-6 and IL-1beta levels. No difference was found in the total cholesterol, triacylglycerol, HDL cholesterol, anthropometry, blood pressure, pulse wave velocity or vascular structure between the two treatment groups. CONCLUSION: Daily supplementation with n-3 capsules increases the serum n-3 PUFA concentration, improves vascular function, and lowers the degree of inflammation in obese adolescents. PMID- 20727523 TI - Three-dimensional motion of the upper extremity joints during various activities of daily living. AB - Highly reliable information on the range of motion (ROM) required to perform activities of daily living (ADL) is important to allow rehabilitation professionals to make appropriate clinical judgments of patients with limited ROM of the upper extremity joints. There are, however, no data available that take full account of corrections for gimbal-lock and soft tissue artifacts, which affect estimation errors for joint angles. We used an electromagnetic three dimensional tracking system (FASTRAK) to measure the three-dimensional ROM of the upper extremity joints of healthy adults (N=20, age range 18-34) during 16 ADL movement tasks. The ROM required for the performance of each movement was shown in terms of the joint angle at the completion of the task, using a new definition of joint angle and regression analysis to compensate for estimation errors. The results of this study may be useful in setting goals for the treatment of upper extremity joint function. PMID- 20727524 TI - Subject-specific axes of the ankle joint complex. AB - The aim of this study was to use a two-axis ankle joint model and an optimisation process (van den Bogert et al., 1994) to calculate and compare the talocrural and subtalar hinge axes for non-weight-bearing ankle motion, weight-bearing ankle motion, and walking in normal, healthy adult subjects and to see which of the first two sets of axes better fit the walking data. Motion data for the foot and shank were collected on eight subjects whilst they performed the activities mentioned. After choosing the best marker sets for motion tracking, a two-hinge ankle joint model was fit to the motion data. Ankle joint ranges of motion were also calculated. It was found that the model fit the experimental data well, with non-weight-bearing motion achieving the best fit. Despite this, the calculated axis orientations were highly variable both between motion types and between subjects. No significant difference between the fit of the non-weight-bearing and weight-bearing models to the walking data was found, which implies that either set of functional axes is adequate for modeling walking; however, the subtalar deviation angle was significantly closer for the weight-bearing activity and walking than for the non-weight-bearing activity and walking, which suggests that it is marginally better to use the weight-bearing functional motions. The results lead to questions about the appropriateness of the two-hinge ankle model for use in applications in which the behaviour of the individual joints of the ankle complex, rather than simply the relative motion of the leg and foot, is important. PMID- 20727525 TI - Molecularly imprinted magnetic nanoparticles as tunable stationary phase located in microfluidic channel for enantioseparation. AB - A microfluidic device integrated with molecularly imprinted magnetic nanoparticles as stationary phase was designed for rapid enantioseparation by capillary electrochromatography. The nanoparticles were synthesized by the co polymerization of methacrylic acid and ethylene glycol dimethacrylate on 3 (methacryloyloxy)propyltrimethoxysilane-functionalized magnetic nanoparticles (25 nm diameter) in the presence of template molecule, and characterized with infrared spectroscopy, thermal gravimetric analysis, and transmission electron microscope. The imprinted nanoparticles (200-nm diameter) could be localized as stationary phase in the microchannel of microfluidic device with the tunable packing length by the help of an external magnetic field. Using S-ofloxacin as the template molecule, the preparation of imprinted nanoparticles, the composition and pH of mobile phase, and the separation voltage were optimized to obtain baseline separation of ofloxacin enantiomers within 195s. The analytical performance could be conveniently improved by varying the packing length of nanoparticles zone, showing an advantage over the conventional packed capillary electrochromatography. The linear ranges for amperometric detection of the enantiomers using carbon fiber microdisk electrode at +1.0 V (vs. Ag/AgCl) were from 1.0 to 500 microM and 5.0 to 500 microM with the detection limits of 0.4 and 2.0 microM, respectively. The magnetically tunable microfluidic device could be expanded to localize more than one kind of template-imprinted magnetic nanoparticles for realizing simultaneous analysis of different kinds of chiral compounds. PMID- 20727526 TI - Development and validation of a liquid chromatography tandem mass spectrometry method for the analysis of beta-agonists in animal feed and drinking water. AB - A reproducible, sensitive and selective multiresidue analytical method for seven beta-agonists: clenbuterol (CBT), clenpenterol (CPT), ractopamine (RTP), brombuterol (BBT), mabuterol (MBT), mapenterol (MPT), and hydroxymethylclenbuterol (HMCBT) was developed and validated by using liquid chromatography tandem mass spectrometry (LC-MS/MS) in feed and drinking water samples. The validation was achieved according to the criteria laid down in the Commission Decision 2002/657/EC, however it was necessary to use minimum required performance limits (MRPLs) proposed by the Community Reference Laboratories (CRLs) due to the lack of maximum residue limits (MRLs) for beta-agonists. By setting up these MRPLs, allows controlling their use in safe mode, since beta agonists are commonly used in veterinary medicine sometime in a fraudulent manner, for increasing the weigh of animals. Values set for both matrices studied are 50 microg/kg for animal feed, and a range from 0.2 to 10 microg/L for drinking water. CCalpha values calculated were under the MRPLs suggested; for drinking water the lowest value obtained was 0.12 microg/L, and for animal feed 0.87 microg/kg. Values for CCbeta were ranged from 0.08 to 0.13 microg/L in drinking water and from 0.5 to 0.92 microg/kg in animal feed samples. The excellence values obtained, allowed us to conclude that the proposed analytical method is capable to control the beta-agonists studied in both matrices and that it can be successfully applied and used as a routine method in laboratories of residue analysis of veterinary food control. PMID- 20727527 TI - Arginine-mediated synthesis of highly efficient catalysts for transfer hydrogenations of ketones. AB - Palladium-hydrotalcite catalysts were prepared by immobilizing Pd(2+) on hydrotalcite (HT) via an amino acid, arginine (Arg), followed by reduction with NaBH(4) at room temperature. The resulting composite was characterized by different techniques. X-ray photoelectron spectroscopy analysis showed that the loaded Pd on hydrotalcite mainly existed in the form of Pd(0), and distributed uniformly on the support with particle size around 4 nm, as confirmed by transmission electron microscopy examination. The HT-Arg-Pd composites were used to catalyze transfer hydrogenation of aromatic ketones, which exhibited high efficiency for this kind of reaction. It was demonstrated that arginine played an important role in the high activity and stability of the catalyst, which not only mediated Pd nanoparticles to be immobilized on the HT support firmly but also promoted the transfer hydrogenation reactions. PMID- 20727528 TI - Effects of dodecanol on the adsorption kinetics of SDS at the water-hexane interface. AB - Even though sodium dodecyl sulphate (SDS) is the most frequently studied surfactant, its properties at liquid interfaces are not easily accessible. This is mainly caused by the fact that in aqueous solution SDS is subject to hydrolysis, by which the homologous dodecanol (C12OH) is formed. Due to its enormously high surface activity it competes with SDS at the interface. We demonstrate here that this "natural" impurity C12OH does not remarkably affect the adsorption dynamics of SDS at the water/hexane interface, due to its high solubility in hexane. Therefore, the dynamic adsorption properties can be determined independent of disturbing dodecanol effects. The surfactant adsorbs diffusion controlled and the interfacial tension isotherm at the water/hexane interface is well described by a Frumkin model. However complementary experiments via direct admixture of dodecanol in hexane indicate a significant decrease in interfacial tension of the water-hexane interface at concentrations higher than 10(-3) mol/l in hexane. This condition may happen when the oil phase is distributed as small droplets in a high concentrated solution of SDS. The distribution coefficient of C12OH between water and hexane is estimated from adsorption experiments to be K(p)=c(o)/c(w)=6.7*10(3). PMID- 20727529 TI - Interface roughness of plasma deposited polymer layers. AB - The interface roughness of adjacent films which were made by plasma polymerization of hexamethyldisiloxane were investigated. Multilayered structures were made by using different plasma conditions in alteration resulting in different mechanical properties within each layer. Scanning force microscopy on the face side of fractured pieces of the multilayer structures revealed a significant phase contrast between the layers. The direct visualization of the interface using the mechanical contrast between layers allowed the estimation of the interfacial roughness. We found that the interfaces between hexamethyldisiloxane films deposited at a radio frequency (RF) input power of 90 W in the presence of oxygen on top of films made by 48 W without oxygen resulted in an interface roughness of ~10 nm. In the reverse case, a significantly lower interface roughness of ~3 nm was determined. We attribute the increase of the interfacial roughness compared to the surface roughness being <1 nm to partial etching of the films by the subsequent deposition process. A key role in the appearance of higher interface roughness plays the RF-input power that determines the cross linking density and the hydrocarbon content in layers. PMID- 20727530 TI - Probing the colloidal properties of skim milk using acoustic and electroacoustic spectroscopy. Effect of concentration, heating and acidification. AB - In colloidal systems physical-chemical changes are often a function of volume fraction and sample dilutions are critical. While most methods to characterize colloidal particles either require dilution or some disruption, acoustic spectroscopy can be performed in situ, without dilution. Objective of this work was to determine the effects of concentration, heating and acidification on the acoustic and electroacoustic properties of casein micelles in skim milk. The ultrasonic attenuation of skim milk increased with concentration of milk and frequency, and the average size of the colloidal particles calculated from the frequency dependence of attenuation was about 0.15 MUm for both unheated and heated milk. When milk was concentrated by ultrafiltration, at 3* and 4* concentration (based on volume reduction), the calculated size deviated from that derived in undiluted or mildly concentrated milk, most likely because of increased particle-particle interactions. Electroacoustic measurements revealed a constant dynamic mobility of the particles in undiluted and concentrated milk, while lower mobilities were observed for milk diluted in permeate. The zeta potential measured was significantly higher than the values measured using dynamic light scattering, with a value of -45.8 mV for casein micelles in unheated milk. With acidification, the zeta-potential decreased monotonically. Heating profoundly affected the change in charge with pH of the micelles, and it was concluded that the interaction of casein micelles with the whey proteins increased the surface charge of the casein micelles. PMID- 20727531 TI - Spectroscopic study of biogenic amine complexes formed at fumed silica surface. AB - The structure and stability of biogenic amine complexes formed at the fumed silica surface were studied by UV-, IR-spectroscopy and TPD MS techniques. It was found that surface complexes are formed due to electrostatic interactions between amine cations and ionized silanol groups. The mechanism of thermal transformations of surface complexes is proposed. Kinetic parameters of thermal reactions at the fumed silica surface have been calculated. PMID- 20727532 TI - Synthesis and solution rheology of poly[(stearyl methacrylate)-stat-([2 (methacryloyloxy)ethyl] trimethyl ammonium iodide)]. AB - Poly([stearyl methacrylate]-stat-[2-(dimethylamino) ethyl methacrylate]) was synthesised through radical polymerisation using 1,1-diphenyl ethylene (DPE) as a molecular weight controlling agent. The amino groups were further quaternised into a cationic form in order to increase water solubility. Solubility of the polymers in water and a mixed solvent was studied with rotational rheometry. The resulting poly[(stearyl methacrylate)-stat-([2-(methacryloyloxy)ethyl] trimethyl ammonium iodide)] was soluble in water when the amount of stearyl methacrylate (SMA) in the polymer was less than 17 mol%. At higher SMA content, solubility strongly decreased but could be improved by using an organic co-solvent. Viscosity of the SMA-based statistical co-polymers is strongly dependent on polymer composition but solvent quality also has an influence, and the fluidic character can be either Newtonian or shear-thinning, or a weak gel can be formed. Concentration dependence behaviour deviates from that of typical polyelectrolytes. SMA polymers retain low viscosity up to rather high concentrations, but above a certain limiting concentration, the viscosity rapidly increases. This phenomenon is stronger with a higher amount of hydrophobic side chain. At high co-polymer concentrations no entanglement formation was observed, and rheological behaviour indicates that SMA segments form aggregates in water solution. PMID- 20727533 TI - Beyond phonotactic frequency: presentation frequency effects word productions in specific language impairment. AB - Phonotactic frequency effects on word production are thought to reflect accumulated experience with a language. Here we demonstrate that frequency effects can also be obtained through short-term manipulations of the input to children. We presented children with nonwords in an experiment that systematically manipulated English phonotactic frequency and the frequency of presentation within the experiment. Both of these manipulations affected the accuracy and time-to-response for nonword production both for typically developing and children with specific language impairment. Children with SLI were less accurate in their productions overall, but still exhibited an effect of the short-term frequency manipulation. Children with SLI differed significantly from their typical peers in terms of time-to-response only when both English and Experimental frequency were low. The results indicate that simple manipulations of the input can affect children's representation of word forms, and this can facilitate word production without the need for long term exposure or articulatory practice. LEARNING OUTCOMES: The reader will learn that sound frequency affects the production of new words. This includes not only the frequency with which sound sequences are represented in the speaker's native language, but the frequency with which they are heard within a single session. PMID- 20727534 TI - Cyclophosphamide for rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome. AB - Patients with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor syndrome have poor long-term outcomes. We report a patient who was treated successfully with high-dose cyclophosphamide immunoablation. This experience offers a novel therapeutic approach and an indirect insight into the underlying pathogenesis of this syndrome. PMID- 20727535 TI - Clinical outcome of intracytoplasmic sperm injection in infertile men with treated and untreated clinical varicocele. AB - PURPOSE: We evaluated the impact of varicocelectomy on intracytoplasmic sperm injection outcomes in infertile men with clinical varicocele. MATERIALS AND METHODS: We studied 242 infertile men with a history of clinical varicocele who underwent intracytoplasmic sperm injection. Of the men 80 underwent prior subinguinal microsurgical varicocelectomy (treated group 1) and 162 had any grade of clinical varicocele (untreated group 2) at sperm injection. We compared semen analysis results before and after varicocelectomy, and the sperm injection procedure outcomes. Mean time from surgery to sperm injection was 6.2 months. Logistic regression was done to verify whether varicocelectomy influenced the odds of clinical pregnancy, live birth and miscarriage. RESULTS: We noted an improved total number of motile sperm (6.7 * 10(6) vs 15.4 * 10(6), p <0.01) and a decreased sperm defect score (2.2 vs 1.9, p = 0.01) after vs before varicocele repair. The clinical pregnancy (60.0% vs 45.0%, p = 0.04) and live birth (46.2% vs 31.4%, p = 0.03) rates after the sperm injection procedure were higher in the treated than in the untreated group. The chance of achieving clinical pregnancy (OR 1.82; 95% CI 1.06-3.15) and live birth (OR 1.87, 95% CI 1.08-3.25) by the sperm injection procedure were significantly increased while the chance of miscarriage was decreased (OR 0.433, 95% CI 0.22-0.84) after varicocele was treated. CONCLUSIONS: Results suggest that varicocelectomy improves clinical pregnancy and live birth rates by intracytoplasmic sperm injection in infertile couples in which the male partner has clinical varicocele. The chance of miscarriage may be decreased if varicocele is treated before assisted reproduction. PMID- 20727536 TI - Editorial comment. PMID- 20727537 TI - Ureterosciatic hernia. PMID- 20727538 TI - Vaginal flap urethroplasty for wide female stricture disease. AB - PURPOSE: As in men, female urethral stricture disease is often treated with repeat urethral dilation or internal urethrotomy but not always with good results. In nonresponsive cases surgical treatment may be useful but only a few cases are reported in the literature. We present our single institution experience with urethral reconstruction in 6 patients using an alternative vaginal inlay flap technique inspired by the Orandi technique. MATERIALS AND METHODS: We treated 6 women with urethral stricture. In 5 patients stricture involved the entire middle and distal urethra, and in 1 it also involved the proximal urethra with bilateral hydronephrosis. Patients underwent urethral reconstruction using a vaginal flap with a lateral vascular pedicle that maintains the vascular axis. The flap was partially de-epithelialized to favor tissue cicatrix formation where the sutures are placed and avoid fistula formation. RESULTS: Mean followup was 70.8 months. Normal micturition was achieved after catheter removal in all patients. Post-void residual urine was measured postoperatively in 3 patients. One patient had significant post-void residual urine and required intermittent self-catheterization. The remaining 5 patients required no additional treatment. CONCLUSIONS: Using the vaginal wall to reconstruct large segments of the female urethra is simple and appears to have good results. Our technique preserves the vascular axis of the flap and protects the sutures. More contributions to the existing literature are needed before any further conclusions can be drawn. PMID- 20727539 TI - External genital proportions in prepubertal girls: a morphometric reference for female genitoplasty. AB - PURPOSE: An understanding of normal genital anatomy is essential for a successful surgical approach and outcome in feminizing genitoplasty. We sought to establish genital standards in female children through external genital measurements taken from the end of the neonatal period until the beginning of adolescence. MATERIALS AND METHODS: This prospective study included 205 females who were anesthetized for surgery for various diagnoses between January 2007 and March 2008. Patient age ranged from 1 month to 10 years. Patients were divided into 4 age groups-1 to 12, 13 to 24, 25 to 60 and 61 to 120 months. Information on patient age, height, weight and, for patients younger than 1 year, head circumference was retrieved from patient charts. Measurements of clitoris length, clitoris width, labia majora length, left and right labia minora length and width, and perineal distance were recorded. RESULTS: Specific equations were generated using these values to estimate the expected external genital structure dimensions in girls. Length of labia majora vs age, length of labia majora vs body weight, perineal distance vs body weight, clitoral width vs body weight and clitoral length vs age reference percentile curves were prepared. CONCLUSIONS: The equations and percentile curves generated can be used as a guide in prospective feminizing genitoplasty. Furthermore, patients and their families can be informed regarding the variability of external genitalia dimensions. This information should ensure a healthier appreciation of the postoperative genitalia by patients and their families. PMID- 20727540 TI - The impact of prostate biopsy and periprostatic nerve block on erectile and voiding function: a prospective study. AB - PURPOSE: We evaluated the effect of multiple core prostate biopsy and periprostatic nerve block on voiding and erectile function. MATERIALS AND METHODS: A total of 198 patients in whom prostate cancer was suspected were randomly assigned to undergo 10-core prostate biopsy with (71) or without (74) periprostatic nerve block. The 53 men with a history of negative prostate biopsy underwent 20-core saturation prostate biopsy with periprostatic nerve block. The International Prostate Symptom Score and International Index of Erectile Function were completed before, and 1, 4 and 12 weeks after biopsy to measure changes in voiding and erectile function, and quality of life. Upon prostate cancer diagnosis patients were excluded from further analysis. RESULTS: The International Prostate Symptom Score was significantly increased in all patients at week 1, which persisted at weeks 4 and 12 after saturation biopsy (p = 0.007 and 0.035, respectively). After 10-core prostate biopsy with periprostatic nerve block patients had a higher International Prostate Symptom Score at weeks 4 and 12 but this was not statistically significant (p >0.05). Quality of life was significantly affected at all times after saturation prostate biopsy (p = 0.001, 0.003 and 0.010, respectively). International Index of Erectile Function scores decreased significantly in all groups at week 1 (p <0.05). The decrease persisted at week 4 in each 10-core prostate biopsy group. CONCLUSIONS: Prostate biopsy causes impaired voiding. Saturation prostate biopsy and periprostatic nerve block seem to have a lasting impact on voiding function. Erectile function is transiently affected by prostate biopsy regardless of periprostatic nerve block and the number of cores. Patients who undergo prostate biopsy must be informed about these side effects. PMID- 20727541 TI - Surgical management of primary severe hypospadias in children: systematic 20-year review. AB - PURPOSE: We systematically reviewed the literature published during the last 20 years on the treatment of primary proximal hypospadias associated with severe ventral curvature. MATERIALS AND METHODS: We reviewed studies published between 1990 and December 2009, searching for "hypospadias" in MEDLINE/PubMed, EMBASE, Web of Science and the Cochrane Library. RESULTS: The search yielded 69 pertinent studies. These studies were generally of low quality (69.5% surgical series). Based on the literature, curvature should be addressed stepwise starting with ventral dissection that extends underneath the urethral plate (urethral plate mobilization). Contrary to former practice, urethral plate division seems to have more of a role if significant curvature persists. Dorsal plication seems sufficient to correct only minor degrees of curvature, while a minority of cases require ventral lengthening. No urethroplasty techniques appear to be definitively superior. After urethral plate division a staged urethroplasty has lower complication rates but a second operation is required, which might otherwise be avoided in approximately 70% of cases. CONCLUSIONS: The present systematic review shows the weak evidence backing current management of primary severe hypospadias. We even lack a clear-cut definition of severe hypospadias and associated curvature. Hence, while we developed general recommendations for treatment based on our review of available evidence, we emphasize the need to establish shared criteria for accurate preoperative or introperative patient stratification, and to define objective outcome measures and followup intervals for data reporting to make comparison of surgical approaches reliable. PMID- 20727542 TI - Risk factors for urinary tract infection after renal transplantation and its impact on graft function in children and young adults. AB - PURPOSE: Urinary tract infection will develop in 40% of children who undergo renal transplantation. Post-transplant urinary tract infection is associated with earlier graft loss in adults. However, the impact on graft function in the pediatric population is less well-known. Additionally the risk factors for post transplant urinary tract infection in children have not been well elucidated. The purpose of this study was to assess the relationship between pre-transplant and post-transplant urinary tract infections on graft outcome, and the risk factors for post-transplant urinary tract infection. MATERIALS AND METHODS: A total of 87 patients underwent renal transplantation between July 2001 and July 2006. Patient demographics, cause of renal failure, graft outcome, and presence of pre transplant and post-transplant urinary tract infections were recorded. Graft outcome was based on last creatinine and nephrological assessment. RESULTS: Median followup was 3.12 years. Of the patients 15% had pre-transplant and 32% had post-transplant urinary tract infections. Good graft function was seen in 60% of the patients and 21% had failed function. Graft function did not correlate with a history of pre-transplant or post-transplant urinary tract infection (p >0.2). Of transplanted patients with urological causes of renal failure 57% had post-transplant urinary tract infection, compared to only 20% of those with a medical etiology of renal failure (p <0.001). CONCLUSIONS: In this study there was no correlation between a history of urinary tract infection (either before or after transplant) and decreased graft function. History of pre-transplant urinary tract infection was suggestive of urinary tract infection after transplant. Patients with urological causes of renal failure may be at increased risk for post-transplant urinary tract infection. PMID- 20727543 TI - Comparison of 2 techniques to predict voiding efficiency after inpatient urogynecologic surgery. AB - PURPOSE: We compared 2 techniques used to assess adequate postoperative bladder emptying. MATERIALS AND METHODS: We performed a prospective, randomized, crossover study of 2 voiding trial techniques. 1) For back fill the bladder is filled with 300 cc saline before the Foley catheter is removed. 2) For auto fill the catheter is removed and the bladder is allowed to fill spontaneously. Patients were randomized into 2 groups for voiding trials, including group 1-auto fill followed by back fill or group 2-back fill followed by auto fill. Within 15 minutes of each void we measured post-void residual urine by straight catheterization. A void of two-thirds or greater of total bladder volume (voided volume plus post-void residual urine) at void 2 of the 2 voids was considered successful voiding. Patients who voided successfully were discharged home without a urethral catheter. We used the chi-square test with kappa to determine successful bladder emptying. RESULTS: We recruited 79 patients, of whom 65 with a mean age of 59.7 years (range 33 to 81) had complete data sets available for analysis. Of the patients 38 (58%) underwent prolapse repair only, 1 (2%) underwent a continence procedure only and 26 (40%) underwent each procedure. The back fill void trial correlated better with a successful voiding trial than the auto fill trial (kappa = 0.91, 95% CI 0.81-1.00 vs kappa = 0.56, 95% CI 0.39 0.74). Overall 40.5% of patients had an unsuccessful void trial on day 1 postoperatively and were discharged home with a catheter. None subsequently experienced urinary retention. CONCLUSIONS: The back fill technique appears to be a better predictor of adequate postoperative bladder emptying than the auto fill technique for inpatient void trials. PMID- 20727544 TI - Incidence of and risk factors for change in urinary incontinence status in a prospective cohort of middle-aged and older women: the reproductive risk of incontinence study in Kaiser. AB - PURPOSE: Urinary incontinence is a dynamic condition that can progress and regress but few groups have examined risk factors for change in incontinence status. MATERIAL AND METHODS: We used stratified random sampling to construct a racially and ethnically diverse, population based cohort of 2,109 women 40 to 69 years old. Data were collected by questionnaires and medical record review. A second survey approximately 5 years later was completed by 1,413 women (67%) from the original cohort. The frequency of urinary incontinence was categorized as less than weekly, weekly and daily. Change in incontinence status was defined as new onset incontinence, incontinence progression or regression between frequency categories and resolution of incontinence. Predictor variables were demographics, body mass index and other medical conditions. We used logistic regression to estimate the adjusted OR and 95% CI. RESULTS: Compared to white nonHispanic women, black women were less likely to have incontinence progression (OR 0.46, 95% CI 0.24-0.88). New onset incontinence was more common in women with a higher body mass index at baseline (p = 0.006) and those who experienced increased body mass index (p = 0.03) or decreased general health (p = 0.007) during the study. Participants with chronic obstructive pulmonary disorder at baseline were more likely to report incontinence progression (OR 2.64, 95% CI 1.22-5.70). Baseline incontinence type was not significantly associated with the risk of change in continence status independent of frequency. CONCLUSIONS: Identifying risk factors for change in incontinence status may be important to develop interventions to decrease the burden of incontinence in the general population. PMID- 20727545 TI - Impact of nocturia on bone fracture and mortality in older individuals: a Japanese longitudinal cohort study. AB - PURPOSE: We evaluated the association of nocturia with fracture and death in a large, community based sample of Japanese individuals 70 years old or older. MATERIALS AND METHODS: The baseline in this population based study was determined in 2003 by an extensive health interview with each participant. In this study we followed 784 individuals with a mean +/- SD age of 76.0 +/- 4.6 years (range 70 to 97). Information on mortality and fracture during the study period was provided by the National Health Insurance system and details on fractures were collected from medical records. We compared the risk of bone fracture and death with or without nocturia in a multivariate Cox proportional hazard model. RESULTS: Nocturia (2 or greater voids per night) was present in 359 of the 784 participants (45.7%). Fracture was observed in 41 cases, including 32 fall related cases. For all fractures and fall related fractures with nocturia the HR was 2.01 (95% CI 1.04-3.87) and 2.20 (95% CI 1.04-4.68, each p = 0.04). Death occurred in 53 cases. The mortality rate in individuals with nocturia was significantly higher than in those without nocturia. For mortality in patients with nocturia the age-gender adjusted HR was 1.91 (95% CI 1.07-3.43, p = 0.03). Even when further adjusted for diabetes, smoking status, history of coronary disease, renal disease and stroke, tranquilizers, hypnotics and diuretics, the positive relationship was unchanged (HR 1.98, 95% CI 1.09-3.59, p = 0.03). CONCLUSIONS: During a 5-year observation period elderly individuals with nocturia were at greater risk for fracture and death than those without nocturia. PMID- 20727546 TI - The use of uroflowmetry to diagnose recurrent stricture after urethral reconstructive surgery. AB - PURPOSE: The ability of uroflowmetry to diagnose recurrent stricture disease after urethroplasty has not been fully investigated. MATERIALS AND METHODS: Our routine post-urethroplasty monitoring includes retrograde urethrogram and voiding cystourethrogram at 3 and 12 months, in addition to uroflowmetry at 3-month intervals for a year. All uroflowmetry data, including maximum flow rate, voided volume and voiding curve shape, as well as retrograde urethrogram/voiding cystourethrogram and voiding symptom data are stored in a prospectively maintained urethroplasty database that was analyzed for patients with postoperative retrograde urethrogram/voiding cystourethrogram and satisfactory uroflowmetry in the same period. Uroflowmetry data points and urinary symptoms were compared with corresponding findings on retrograde urethrogram/voiding cystourethrogram to determine the ability of uroflowmetry to predict recurrence. RESULTS: A total of 278 men (68%) met study inclusion criteria, of whom 63 (23%) had recurrent stricture. Using a maximum flow rate of less than 10 ml per second resulted in only 54% test sensitivity to predict recurrence. The highest sensitivity and negative predictive value (each 99%) were achieved when all men with symptoms and/or obstructed flow curves were evaluated. Symptoms alone had a high specificity (87%), sensitivity (88%) and negative predictive value (95%). CONCLUSIONS: Uroflowmetry is an adequate test to screen for postoperative stricture recurrence but only when the voiding curve and urinary symptoms are also evaluated. The flow rate alone does not appear to be a reliable tool to evaluate stricture recurrence. PMID- 20727547 TI - Women with diabetes: understanding urinary incontinence and help seeking behavior. AB - PURPOSE: We examined the association of urinary incontinence with diabetes status and race, and evaluated beliefs about help seeking for incontinence in a population based cohort of women with vs without diabetes. MATERIALS AND METHODS: We performed a cross-sectional analysis of 2,270 middle-aged and older racially/ethnically diverse women in the Diabetes Reproductive Risk factors for Incontinence Study at Kaiser. Incontinence, help seeking behavior and beliefs were assessed by self-report questionnaires and in-person interviews. We compared incontinence characteristics in women with and without diabetes using univariate analysis and multivariate models. RESULTS: Women with diabetes reported weekly incontinence significantly more than women without diabetes (weekly 35.4% vs 25.7%, p <0.001). Race prevalence patterns were similar in women with and without diabetes with the most vs the least prevalence of incontinence in white and Latina vs black and Asian women. Of women with diabetes 42.2% discussed incontinence with a physician vs 55.5% without diabetes (p <0.003). Women with diabetes were more likely than those without diabetes to report the belief that incontinence is rare (17% vs 6%, p <0.001). CONCLUSIONS: Incontinence is highly prevalent in women with diabetes. Race prevalence patterns are similar in those with and without diabetes. Understanding help seeking behavior is important to ensure appropriate patient care. Physicians should be alert for urinary incontinence since it is often unrecognized and, thus, under treated in women with diabetes. PMID- 20727548 TI - Early graft function after laparoscopically procured living donor kidney transplantation. AB - PURPOSE: We determined predictors of poor early graft function after laparoscopic living donor kidney transplantation. MATERIALS AND METHODS: We performed an institutional review board approved review of the living donor kidney transplantation database at our institution. RESULTS: Seven of the 510 transplants (1%) were excluded from study due to immediate graft nephrectomy for vascular complications. Of the remaining 503 transplants 48 (9.5%) and 18 (3.6%) had slow and delayed graft function, respectively. Recipient male gender (OR 2.03, 95% CI 1.05-3.91, p = 0.035), black ethnicity (OR 1.59, 95% CI 1.08-2.34, p = 0.020) and donor age (OR 1.03, 95% CI 1.00-1.05, p = 0.021) emerged as independent predictors of poor early graft function in multivariate logistic regression models. Poor early graft function strongly redisposed patients to acute rejection during year 1 (HR 3.43, 95% CI 2.04-5.77, p <0.0001) while grafts from genetically related donors conferred a protective effect (HR 0.40, 95% CI 0.24-0.66, p <0.0001). Three-year death censored allograft survival was lower in the delayed and slow graft function groups than in the immediate function group (89% and 87% vs 98%, p = 0.0068 and 0.0002, respectively). Overall 3-year patient survival was lower in the delayed than in the immediate function group (81% vs 94%, p <0.0001). CONCLUSIONS: Male black recipients of laparoscopically procured living donor kidney transplants from donors older than 50 years are at higher risk for poor early graft function, which in turn strongly predicts acute rejection during year 1. This is significant since excellent early graft function confers specific recipient and allograft survival advantages, and may assist physicians in better understanding the various recipient, donor and perioperative parameters that influence clinical outcomes. PMID- 20727549 TI - Magnetic resonance guided, focal laser induced interstitial thermal therapy in a canine prostate model. AB - PURPOSE: We evaluated a newly Food and Drug Administration cleared, closed loop, magnetic resonance guided laser induced interstitial thermal therapy system for targeted ablation of prostate tissue to assess the feasibility of targeting, real time monitoring and predicting lesion generation in the magnetic resonance environment. MATERIALS AND METHODS: Seven mongrel dogs (University of Texas Health Science Center, Houston, Texas) with (2) and without (5) canine transmissible venereal tumors in the prostate were imaged with a 1.5 T magnetic resonance imaging scanner. Real-time 3-dimensional magnetic resonance imaging was used to accurately position water cooled, 980 nm laser applicators to predetermined targets in the canine prostate. Destruction of targeted tissue was guided by real-time magnetic resonance temperature imaging to precisely control thermal ablation. Magnetic resonance predictions of thermal damage were correlated with posttreatment imaging results and compared to histopathology findings. RESULTS: Template based targeting using magnetic resonance guidance allowed the laser applicator to be placed within a mean +/- SD of 1.1 +/- 0.7 mm of the target site. Mean width and length of the ablation zone on magnetic resonance imaging were 13.7 +/- 1.3 and 19.0 +/- 4.2 mm, respectively, using single and compound exposures. The damage predicted by magnetic resonance based thermal damage calculations correlated with the damage on posttreatment imaging with a slope near unity and excellent correlation (r(2) = 0.94). CONCLUSIONS: This laser induced interstitial thermal therapy system provided rapid, localized tissue heating under magnetic resonance temperature imaging control. Combined with real-time monitoring and template based planning, magnetic resonance guided, laser induced interstitial thermal therapy is an attractive modality for prostate cancer focal therapy. PMID- 20727550 TI - Neural neoplasms of the bladder. PMID- 20727551 TI - Editorial comment. PMID- 20727553 TI - Editorial comment. PMID- 20727552 TI - Timer watch assisted urotherapy in children: a randomized controlled trial. AB - PURPOSE: We evaluated the effect of timer watch treatment in addition to standard urotherapy in children with overactive bladder and daytime urinary incontinence. MATERIALS AND METHODS: A total of 60 children with daytime urge incontinence were included in the study. Following a 4-week run-in period of standard urotherapy children were randomized to 12 weeks of standard urotherapy with or without a timer watch. Incontinence episodes were registered and 48-hour bladder diaries were obtained before randomization, and at weeks 1, 11 and 12. Long-term response was evaluated at 7 months. RESULTS: Two children became continent during the run in period. Before intervention children in the timer group were slightly more wet than children in the standard urotherapy group (median 7 [IQR 25% to 75% 6 to 7] vs 6 [3 to 7] wet days per week, p <0.05). Following 12 weeks of standard urotherapy children randomized to timer assisted urotherapy had significantly fewer wet days per week (median 2, IQR 25% to 75% 0 to 5) vs those undergoing standard urotherapy alone (5, 2.75 to 6.75, p <0.01). In the timer group 18 children (60%) achieved a greater than 50% decrease in incontinence episodes, compared to only 5 (18%) treated without timer assistance. Nine patients (30%) in the timer group and no child in the standard urotherapy group achieved complete daytime continence. The timer increased compliance with the timed voiding regimen. At 7 months of followup 60% of children in the timer group were still continent in the daytime. CONCLUSIONS: A programmable timer watch significantly improves the effect of standard urotherapy. When using the timer watch as a supplement to standard urotherapy 60% of the children obtained complete and sustainable daytime continence. PMID- 20727554 TI - Monosulfidic black ooze accumulations in sediments of the Geographe Bay area, Western Australia. AB - Mobilisation of sedimentary monosulfidic black ooze (MBO) may result in rapid deoxygenation and acidification of surface waters, and release of potentially toxic metals. This study examines the extent and nature of MBO accumulation in the Geographe Bay area, Western Australia. MBO accumulations were found to be widespread in benthic sediments of the Geographe Bay area with acid-volatile sulfide (AVS) contents as high as 320 MUmol g(-1). The MBO materials often had unusually high dissolved sulfide (S(-II)) concentrations in their pore-waters (up to 610 mg L(-1)) and elevated elemental sulfur (S(0)) contents (up to 51 MUmol g( 1)). Dissolved S(-II) is able to accumulate due to limited iron availability and S(0) is largely its partial oxidation product. The availability of organic carbon and Fe limited MBO accumulation at many sites. A comparison of AVS and simultaneously extracted metal (SEM) concentrations has shown that metals are likely to be bound in sulfide complexes. PMID- 20727555 TI - Concentrations of unmetabolized folic acid and primary folate forms in plasma after folic acid treatment in older adults. AB - Folate deficiency can cause age-related disease. Folic acid (FA) has been used in studies aiming at disease prevention. Recently, unmetabolized FA in plasma raised public health concerns; but numerous studies used FA for disease prevention. Concentrations of the folate forms FA, 5-methyltetrahydrofolate (5-MTHF), and tetrahydrofolate (THF) were measured before and after 3-week placebo or FA 5 mg, vitamin B6 40 mg, and cyanocobalamin 2 mg per day administrated to 74 older adults (median age, 82 years). Concentrations of 5-MTHF and total homocysteine (tHcy) (r = -0.392) and S-adenosylmethionine (r = 0.329) were correlated at baseline. Twenty-six percent of the elderly subjects had unmetabolized FA in plasma at the start, and concentrations of FA were increased after 3 weeks of FA treatment (median FA = 0.08 nmol/L at baseline and 15.3 nmol/L at the end of the treatment in the vitamin group). Folic acid caused a 10- and a 5-fold increase in 5-MTHF and THF, respectively, and lowered tHcy (median tHcy = 17.2 MUmol/L at baseline vs 9.0 MUmol/L after treatment). Concentrations of unmetabolized FA were positively related to those of 5-MTHF and THF. People showed wide variations in folate forms at baseline, but these were reduced after FA treatment. Folic acid given to older adults is mostly converted to THF and 5-MTHF and lowered concentrations of tHcy, but caused a substantial increase in unmetabolized FA in the plasma. PMID- 20727556 TI - Palmitate induces C-reactive protein expression in human aortic endothelial cells. Relevance to fatty acid-induced endothelial dysfunction. AB - Circulating levels of free fatty acids are commonly elevated in patients with the metabolic syndrome and exert, through activating proinflammatory pathways, harmful effects of the vascular endothelium. In this study, we examined the effect of palmitate (PA) on endothelial C-reactive protein (CRP) expression and the role of CRP in PA-induced nitric oxide (NO) inhibition. Palmitate increased, in a dose-dependent manner, CRP protein expression and production in human aortic endothelial cells (HAECs). Induction of CRP protein was mimicked by ceramide, whereas bromopalmitate and other common free fatty acids such as oleate or linoleate were ineffective. Palmitate also elicited reactive oxygen species production in HAECs, an effect prevented by protein kinase C (PKC) inhibition and adenosine monophosphate-activated kinase (AMPK) activation. Palmitate-treated HAECs showed increased CRP messenger RNA expression and nuclear factor (NF) kappaB activation. Induction of CRP expression by PA was prevented by antioxidants and normalized by PKC and mitogen-activated protein kinase inhibitors. Disrupting NF-kappaB and Janus kinase/signal transducers and activators of transcription pathways or inducing AMPK activation also suppressed the stimulatory effect of PA on CRP messenger RNA expression. Finally, in HAECs, PA reduced NO release, an effect reversed by anti-CRP antibody. These data demonstrate that PA-induced endothelial CRP expression involves PKC-driven oxidative stress, possibly through AMPK inhibition, and activation of downstream redox-sensitive signaling pathways, including NF-kappaB. They further support a role for endothelial cell-derived CRP as mediator of the suppressive effect of PA on NO production. PMID- 20727557 TI - ADRB2 gene variants, dual-energy x-ray absorptiometry body composition, and hypertension in Tobago men of African descent. AB - Classic tissue effects of beta(2)-adrenergic receptor activation include skeletal muscle glycogenolysis and vascular smooth muscle relaxation, factors relevant to obesity and hypertension, respectively. In a population-based study, we examined 2 common amino acid substitutions in the beta(2)-adrenergic receptor gene (ADRB2) in relation to body composition and blood pressure. A cross-sectional analysis of 1893 African-descent men living in Tobago and participating in a prostate cancer screening study was performed. Body mass index, waist circumference, blood pressure, dual-energy x-ray absorptiometry body composition, and ADRB2 (Arg16Gly; Gln27Glu) genotype were determined. Twenty-six percent were obese (body mass index >=30 kg/m(2)), and 50% were hypertensive. ADRB2 Arg16Gly and Gln27Glu alleles were in linkage disequilibrium (D' = 0.96, r(2) = 0.15). ADRB2 16Gly containing and 27Glu-containing genotypes were equally frequent in low, medium, and high tertiles of percentage of body fat mass (16Gly-containing genotypes: 73.4%, 74.4%, and 74.5%, P(trend) = .66; 27Glu-containing genotypes: 27.6%, 23.8%, and 25.4%, P(trend) = .39) and in normal blood pressure, prehypertensive, and hypertensive men (16Gly-containing genotypes: 73.4%, 72.8%, and 74.4%, P(trend) = .61; 27Glu-containing genotypes: 25.6%, 24.1%, and 26.7%, P(trend) = .50). In a high-obesity and high-hypertension risk population with ancestry in common with African Americans, genetic variation defined by 2 common ADRB2 amino acid substitutions was not associated with body composition or hypertension. PMID- 20727558 TI - Proteomic and activity profiles of ascorbate-glutathione cycle enzymes in germinating barley embryo. AB - Enzymes involved in redox control are important during seed germination and seedling growth. Ascorbate-glutathione cycle enzymes in barley embryo extracts were monitored both by 2D-gel electrophoresis and activity measurements from 4 to 144 h post imbibition (PI). Strikingly different activity profiles were observed. No ascorbate peroxidase (APX) activity was present in mature seeds but activity was detected after 24 h PI and increased 14-fold up to 144 h PI. In contrast, dehydroascorbate reductase (DHAR) activity was present at 4h PI and first decreased by 9-fold until 72 h PI followed by a 5-fold increase at 144 h PI. Glutathione reductase and monodehydroascorbate reductase activities were also detected at 4 h PI, and showed modest increases of 1.8- and 2.7-fold, respectively, by 144 h PI. The combination of functional analysis with the proteomics approach enabled correlation of the activity profiles and protein abundance. While gel spots containing APX showed intensity changes consistent with the activity profile from 0 to 72 h PI, DHAR spot intensities indicated that post-translational regulation may be responsible for the observed changes in activity. Transcript profiling, 2D-western blotting and mass spectrometric characterization of multiple APX spots demonstrated the presence of APX1 and minor amounts of APX2. PMID- 20727559 TI - Percutaneous, ultrasonographically guided technique of catheterization of the abdominal aorta in calves for serial blood sampling and continuous arterial blood pressure measurement. AB - The study describes a technique of ultrasonographically guided transcutaneous catheter implantation into the abdominal aorta of 29 6- to 8-week-old German Holstein calves. Catheters were implanted between the left transverse processes of L3 and L4, left in place for 2 days and used for serial blood sampling and continuous measurement of blood pressure. Complete cell counts and clinical examination were performed before, as well as 1 and 5 days after implantation. Catheterization was successful in all calves. The catheter was patent for blood sampling and pressure recordings at all times. A significant decrease in red blood cells was found in all animals after catheterization, which remained reduced for 5 days. Clinical signs of anaemia were absent. In conclusion, ultrasonographically guided catheterization of the abdominal aorta provides a continuous arterial access in calves, whereby the minimal invasive technique and the ultrasonographical guidance reduces accidental tissue trauma and pain for the animal. PMID- 20727560 TI - Early gastric cancer with signet-ring cell histologic type: risk factors of lymph node metastasis and indications of endoscopic surgery. AB - BACKGROUND: To clarify the biologic behavior of the early signet-ring cell cancers (SRCs) by comparing the clinicopathologic features and the incidence of lymph node metastasis between different histologic types of early gastric cancer (EGC) and to propose the indications of endoscopic surgery for SRCs. METHODS: Clinicopathologic features and the incidence of lymph node metastasis of 422 EGCs were retrospectively reviewed and compared according to the histologic type. RESULTS: Clinicopathologic features, incidence of node metastasis, prognosis, as well as the incidence of recurrence for SRCs, were similar to those of differentiated cancers (DCs), however, significantly different from those of undifferentiated cancers (UDCs). Tumor size, histologic type, lymphatic and/or blood vessel invasion (LBVI), and depth of invasion were independent factors predicting node metastasis for EGCs. For DCs and SRCs with mucosal invasion and <= 2 cm in diameter without LBVI, no metastatic lymph node was detected (95% CI, 0-5.0). Also, for DCs and SRCs with mucosal invasion and >2 cm in diameter without LBVI, or with submucosal invasion and <= 2 cm in diameter without LBVI, no metastatic lymph node was detected (95% CI, 0-3.0). CONCLUSION: Clinicopathologic features of SRCs were similar with DCs, but different from other UDCs. Consequently, the treatment strategy for SRCs might be similar with that for DCs. According to the incidence of node metastasis, we propose SRCs with mucosal invasion without LBVI, or with submucosal invasion and <=2 cm in diameter without LBVI, might be suitable for endoscopic surgery. PMID- 20727561 TI - Development of a novel method of progressive temporary abdominal closure. AB - BACKGROUND: This paper describes our experience with a novel method of temporary abdominal closure that permits frequent reassessment of the abdominal contents and progressive reapproximation of the fascial edges without compromising definitive fascial closure outcomes. METHODS: We developed a novel method of temporary abdominal closure, which we have named the frequent assessment temporary abdominal closure (FASTAC). The records of patients who underwent planned relaparotomy during 5 years were reviewed. The data collected included patient demographics, indication for operation, number of operations, duration of temporary abdominal closure placement, hospital duration of stay, method of definitive abdominal closure, and subsequent ventral hernia repair. RESULTS: One hundred and thirty-three patients underwent 308 temporary abdominal closure placements, including 16 patients who had a FASTAC placed for open abdomen management. FASTAC remained in place for a significantly greater time with more frequent reassessment. Fascial closure techniques were not different in FASTAC patients. FASTAC patients had a significantly greater duration of stay, which suggests selective placement in a more complicated patient population. The materials for frequent assessment temporary abdominal closure cost only $38 compared with $350 for a large piece of Silastic. CONCLUSION: FASTAC is a novel, cost-effective method of temporary abdominal closure that allows for frequent bedside intra-abdominal surveillance, maintains abdominal domain, and does not compromise abdominal closure outcomes in the management of the open abdomen. PMID- 20727562 TI - Antiplatelet agents, warfarin, and epidemic intracranial hemorrhage. AB - BACKGROUND: Atrial fibrillation prophylaxis with warfarin and strong antiplatelet agent use in cardiovascular diseases has increased the incidence of anticoagulation in the elderly. We studied traumatic intracranial hemorrhage (TICH) in patients >=55 years of age on anticoagulation and antiplatelet agents in a stable population. METHODS: We used a Level 1 Trauma Center registry study comparing TICH in patients on anticoagulation drugs during the index periods 1999 to 2000 (T1) and 2007 to 2008 (T2). RESULTS: A total of 526 TICH patients were seen in T1 and T2 (age, 77.6 vs 77.5 years; not significant [NS]), with the rate doubling from 6.2% to 12.3% of all trauma activations (P < .01). There was no increase in atrial fibrillation, warfarin use, or CHADS(2) scores in atrial fibrillation patients on anticoagulation therapy. TICH in patients taking antiplatelet agents increased 5-fold (2.2 % vs 10.3%; P < .01). Overall TICH mortality rate was the same (12.4% vs 12.2%, NS). TICH mortality among patients on therapeutic warfarin was greater in T1 (26%; P < .05), but mortality was similar to TICH in patients not on anticoagulants in T2 (19% vs 12.2%, NS), suggesting treatment improved. Prevalence and mortality of TICH in patients on antiplatelet agents were similar to TICH in patients on warfarin. CONCLUSION: TICH in patients on anticoagulants is epidemic in patients >=55 years of age. Despite national trends, our well-served population has not seen an increase in warfarin use for atrial fibrillation. Instead, use of antiplatelet agents has increased and is associated with an increased incidence of TICH. PMID- 20727563 TI - Collateral damage: the effect of patient complications on the surgeon's psyche. AB - BACKGROUND: The effect of patient complications on physicians is not well understood. Our objective was to determine the impact of a surgeon's complication(s) on his/her emotional state and job performance. METHODS: An anonymous survey was distributed to Midwest Surgical Society members and attending surgeons within the Grand Rapids, Michigan, community. RESULTS: There were 123 respondents (30.5% response rate). For the majority of participants, the first complication that had a significant emotional impact on them occurred during residency (51.2%). Most respondents reported this did not impair their professional functioning (77.2%). If a major complication was first experienced after residency, this had a greater likelihood of causing impairment (P < .05). Surgeons primarily dealt with the emotional impact by discussing it with a surgical partner (87.8%). Alcohol or other substance use increased in 6.5% of those surveyed. Most respondents (58.5%) felt it was difficult to handle the emotional effects of complications throughout their careers and this did not improve with experience. CONCLUSION: The majority of surgeons agreed that it was difficult to handle the emotional effects of complications throughout their careers. Efforts should be made to increase awareness of unrecognized emotional effects of patient complications and improve access to support systems for surgeons. PMID- 20727564 TI - Gastroesophageal reflux disease after lung transplantation: pathophysiology and implications for treatment. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is thought to be a risk factor for the development or progression of chronic rejection after lung transplantation. However, the prevalence of GERD and its risk factors, including esophageal dysmotility, hiatal hernia and delayed gastric emptying after lung transplantation, are still unknown. In addition, the prevalence of Barrett's esophagus, a known complication of GERD, has not been determined in these patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients. METHODS: Thirty-five consecutive patients underwent a combination of esophageal function testing, upper endoscopy, barium swallow, and gastric emptying scan after lung transplantation. RESULTS: In this patient population, the prevalence of GERD was 51% and 22% in those who had been retransplanted. Of patients with GERD,36% had ineffective esophageal motility (IEM), compared with 6% of patients without GERD (P = .037). No patient demonstrated hiatal hernia on barium swallow. The prevalence of delayed gastric emptying was 36%. The prevalence of biopsy-confirmed Barrett's esophagus was 12%. CONCLUSION: Our study shows that, after lung transplantation, more than half of patients had GERD, and that GERD was more common after retransplantation. IEM and delayed gastric emptying are frequent in patients with GERD. Hiatal hernia is rare. The prevalence of Barrett's esophagus is not negligible. We conclude that GERD is highly prevalent after lung transplantation, and that delayed gastric emptying and Barrett's esophagus should always be suspected after lung transplantation because they are common risks factors and complications of GERD. PMID- 20727565 TI - Decreased contractile response to endothelin-1 of peripheral microvasculature from diabetic patients. AB - BACKGROUND: We compared the contractile responses to endothelin-1 (ET-1) with and without the inhibition of ET-A receptors and protein kinase C-alpha (PKC-alpha) in the human peripheral microvasculature of diabetic and case-matched, nondiabetic patients. METHODS: Chest wall skeletal muscle was harvested from patients with and without diabetics undergoing cardiac surgery. Peripheral arterioles (90-180 MUm in diameter) were dissected from the harvested tissue. Microvascular constriction was assessed by videomicroscopy in response to ET-1 with and without an endothelin-A (ET-A) receptor antagonist, an endothelin B (ET B) antagonist, or a PKC-alpha inhibitor. RESULTS: ET-1 induced a dose-dependent contractile response of skeletal muscle arterioles from diabetic and nondiabetic patients. The contractile response of diabetic arterioles from both prebypass and postbypass to ET-1 (10(-9) mol/L) was decreased compared with those of nondiabetic patients (P < .05). The contractile responses of microvessels of both diabetics and nondiabetics to ET-1 were inhibited in the presence of either ET-A receptor antagonist BQ123 (10(-7) mol/L) or the PKC-alpha inhibitor safingol (2 * 10(-5) mol/L, P < .05, respectively). In contrast, the ET-1-induced vasoconstriction was not affected by the administration of the ET-B receptor antagonist BQ788 (10(-7) mol/L). There were no differences in skeletal muscle levels of the ET-A and ET-B receptors between diabetic and nondiabetic groups. CONCLUSION: Diabetic patients demonstrated a decreased contractile response to ET 1 in human peripheral microvasculature. The contractile response of diabetic vessels to ET-1 occurs via activation of ET-A receptors and PKC-alpha. These results provide novel mechanisms of ET-1-induced contraction in vasomotor dysfunction in patients with diabetes. PMID- 20727566 TI - Elucidation of functional domains of Chandipura virus Nucleocapsid protein involved in oligomerization and RNA binding: implication in viral genome encapsidation. AB - Chandipura virus, a member of the vesiculovirus genera, has been recently recognized as an emerging human pathogen. Previously, we have shown that Chandipura virus Nucleocapsid protein N is capable of binding to both specific viral leader RNA as well as non-viral RNA sequences, albeit in distinct monomeric and oligomeric states, respectively. Here, we distinguish the regions of N involved in oligomerization and RNA binding using a panel of deletion mutants. We demonstrate that deletion in the N-terminal arm completely abrogates self association of N protein. Monomer N specifically recognizes viral leader RNA using its C-terminal 102 residues, while oligomerization generates an additional RNA binding surface involving the N-terminal 320 amino acids of N overlapping with a protease resistant core that is capable of forming nucleocapsid like structure and also binding heterogeneous RNA sequences. Finally, we propose a model to explain the mechanism of genome encapsidation of this important human pathogen. PMID- 20727567 TI - Further treatment of decolorization liquid of azo dye coupled with increased power production using microbial fuel cell equipped with an aerobic biocathode. AB - A microbial fuel cell (MFC) incorporating a recently developed aerobic biocathode is designed and demonstrated. The aerobic biocathode MFC is able to further treat the liquid containing decolorization products of active brilliant red X-3B (ABRX3), a respective azo dye, and also provides increased power production. Batch test results showed that 24.8% of COD was removed from the decolorization liquid of ABRX3 (DL) by the biocathode within 12 h. Metabolism-dependent biodegradation of aniline-like compound might be mainly responsible for the decrease of overall COD. Glucose is not necessary in this process and contributes little to the COD removal of the DL. The similar COD removal rate observed under closed circuit condition (500 Omega) and opened circuit condition indicated that the current had an insignificant effect on the degradation of the DL. Addition of the DL to the biocathode resulted in an almost 150% increase in open cycle potential (OCP) of the cathode accompanied by a 73% increase in stable voltage output from 0.33 V to 0.57 V and a 300% increase in maximum power density from 50.74 mW/m(2) to 213.93 mW/m(2). Cyclic voltammetry indicated that the decolorization products of the ABRX3 contained in the DL play a role as redox mediator for facilitating electron transfer from the cathode to the oxygen. This study demonstrated for the first time that MFC equipped with an aerobic biocathode can be successfully applied to further treatment of effluent from an anaerobic system used to decolorize azo dye, providing both cost savings and high power output. PMID- 20727568 TI - Water quality parameters associated with prevalence of Legionella in hot spring facility water bodies. AB - Some species of Legionella are recognized as opportunistic potential human pathogens, such as Legionella pneumophila, which causes legionnaires disease. Indeed, outbreaks of legionellosis are frequently reported in areas in which the organism has been spread via aerosols from contaminated institutional water systems. Contamination in hot tubs, spas and public baths are also possible. As a result, in this study, we investigated the distribution of Legionella at six hot spring recreation areas throughout Taiwan. Legionella were detected in all six hot spring recreation areas, as well as in 20 of the 72 samples that were collected (27.8%). Seven species of Legionella identified from samples by the direct DNA extraction method were unidentified Legionella spp., Legionella anisa, L. pneumophila, Legionella erythra, Legionella lytica, Legionella gresilensis and Legionella rubrilucen. Three species of Legionella identified in the samples using the culture method were L. pneumophila, unidentified Legionella spp. and L. erythra. Legionella species were found in water with temperatures ranging from 22.7 degrees C to 48.6 degrees C. The optimal pH appeared to range from 5.0 to 8.0. Taken together, the results of this survey confirmed the ubiquity of Legionella in Taiwan spring recreational areas. Therefore, a long-term investigation of the health of workers at hot spring recreational areas and the occurrence of Legionella in hot spring recreational areas throughout Taiwan are needed. PMID- 20727569 TI - Sorption-desorption hysteresis of phenanthrene--effect of nanopores, solute concentration, and salinity. AB - Phenanthrene sorption and desorption from sediment/soil in fresh and saline water were measured, and effects of nanopores, solute concentration, and salinity on sorption-desorption hysteresis were discussed. The extent and kinetics of sorption-desorption hysteresis depend much on the pore distribution of the sorbents, and greater but slower-developed hysteresis occurred on the sorbent with higher specific surface area and more nanopores. In saline water, phenanthrene sorption was enhanced as compared to freshwater, with logKF increasing from 2.84 and 3.08 to 2.96 and 3.33 for the two sorbents, respectively; however, the sorption-desorption hysteresis was weakened, as indicated by the lower hysteresis index in saline water as compared to those in freshwater. In successive desorption, the irreversible sorbed amount of phenanthrene increased with increasing phenanthrene concentration until a maximum (Qmaxirr) was achieved, and the subsequent sorption became reversible. In saline water, Qmaxirr is much lower (10 mg kg(-1)) as compared to freshwater (36 mg kg( 1)), and phenanthrene sorption was almost reversible, especially at high concentrations. N2 sorption illustrated that soil organic matter had changed to a more condensed conformation in saline water, as indicted by the reduced surface area (from 9.6 to 7.3 m2 g(-1)), which is unfavorable for irreversible sorption. PMID- 20727570 TI - Evidence of pathological conditions in the Florisbad cranium. AB - Palaeopathological studies of the middle Pleistocene cranium from Florisbad (Free State, South Africa) document the presence of extensive cortical lesions and areas of thinning, a widened medullary cavity with destruction of the diploe, orbital roof lesions, a benign ectocranial neoplasm, and evidence for alveolar destruction, resorption, and antemortem tooth loss. Differential diagnosis suggests one or more possible aetiologies, including a haematological disorder, metabolic condition(s), Paget's disease of bone, or non-specific infection perhaps following trauma. Moreover, if not directly associated with those on the external vault, orbital lesions alone could have been caused by infection or an indeterminable factor such as pressure from an enlarged organ. Multiple parasagittal lesions on the internal vault cortex probably represent expansile lesions left by enlarged arachnoid granulations. A multifactorial model of pathogenesis may be most appropriate to account for dentoalveolar lesions and antemortem tooth loss. Additionally, there are clear indications of diagenetic alteration deep within the vault, as well as multiple signs of degeneration on the cranium. These complicate the assessment of pathological alterations and identification of their possible aetiology. The Florisbad cranium is the latest specimen to join the growing sample of Pleistocene hominin remains with non-fatal and non-trivial pathological disorders adding to understanding of early human ecology and lifestyle. PMID- 20727571 TI - Endocranial shape changes during growth in chimpanzees and humans: a morphometric analysis of unique and shared aspects. AB - Compared to our closest living and extinct relatives, humans have a large, specialized, and complex brain embedded in a uniquely shaped braincase. Here, we quantitatively compare endocranial shape changes during ontogeny in humans and chimpanzees. Identifying shared and unique aspects in developmental patterns of these two species can help us to understand brain evolution in the hominin lineage. Using CT scans of 58 humans and 60 chimpanzees varying in age from birth to adulthood, we generated virtual endocasts to measure and analyze 29 three dimensional endocranial landmarks and several hundred semilandmarks on curves and the endocranial surface; these data were then analyzed using geometric morphometric methods. The ontogenetic shape trajectories are nonlinear for both species, which indicates several developmental phases. Endocranial shape is already distinct at birth and there is no overlap between the two species throughout ontogeny. While some aspects of the pattern of endocranial shape change are shared between humans and chimpanzees, the shape trajectories differ substantially directly after birth until the eruption of the deciduous dentition: in humans but not in chimpanzees, the parietal and cerebellar regions expand relatively (contributing to neurocranial globularity) and the cranial base flexes within the first postnatal year when brain growth rates are high. We show that the shape changes associated with this early "globularization phase" are unique to humans and do not occur in chimpanzees before or after birth. PMID- 20727572 TI - Cross-phylum extrapolation of the Daphnia magna chronic biotic ligand model for zinc to the snail Lymnaea stagnalis and the rotifer Brachionus calyciflorus. AB - We investigated if the chronic zinc biotic ligand model (BLM) developed earlier for the arthropod Daphnia magna could be extrapolated to predict chronic ecotoxicity of zinc as a function of water chemistry to two species from other phyla, i.e. the mollusc Lymnaea stagnalis and the rotifer Brachionus calyciflorus. We chronically exposed these two species to zinc in six natural surface waters. These water covered a wide range of pH (6.8-8.3), dissolved organic carbon (1.2-12.7mg/L) and Ca (8.8-118mg/L). Across all waters tested, the 28d-EC10s (200-1629MUg Zn/L) and EC50s (382-2026MUg Zn/L) for L. stagnalis spanned a 8.1-fold and 5.3-fold range, respectively. The 2d-EC10s (142-550MUg Zn/L) and 2d-EC50s (195-1104MUg Zn/L) for B. calyciflorus spanned a 3.9-fold and 5.7-fold range, respectively. The data indicated that higher pH and higher concentrations of Ca and DOC were generally associated with lower toxicity (higher ECx values). Furthermore, the chronic Zn BLM for D. magna, when calibrated only to reflect the intrinsic sensitivity of L. stagnalis and B. calyciflorus, was able to predict all ECx values with a less than 1.6-fold error, which demonstrates that the chronic D. magna Zn BLM can be extrapolated to other invertebrate phyla. This lends further support to the use of the chronic Zn BLM to account for bioavailability of zinc in aquatic risk assessment and the derivation of environmental quality standards. PMID- 20727573 TI - A novel insertion mutation 718dupG in the PROC gene in a Korean thrombophilic family. PMID- 20727574 TI - Immunohistochemical localization of an N-acetyl amino-carbohydrate specific lectin (ACL-I) of the marine sponge Axinella corrugata. AB - The N-acetyl amino-carbohydrate specific lectin (ACL-I) was previously identified and purified by us from the marine sponge Axinella corrugata (phylum Porifera, class Demospongiae). The distribution of the specific lectin within the tissue of the sponge was studied by bright-field optical microscopy immunohistochemistry in order to better understand its physiological role in the sponge. Polyclonal antibodies were raised against purified ACL-I in mice and tested by Western blot technique. The immunohistochemical analysis of ACL-I in cross sections of A. corrugata showed that this lectin is found inside the denominated spherulous cells, which contain vesicles that store the lectin. Some evidence is shown that ACL-I might also be present in the extracellular matrix. It was not possible to demonstrate by the immunohistochemical technique if ACL-I is colocalized in both the plasma membrane and in the cytoplasm of the spherulous cells. PMID- 20727575 TI - Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1. AB - Repulsive signaling by Semaphorins and Plexins is crucial for the development and homeostasis of the nervous, immune, and cardiovascular systems. Sema7A acts as both an immune and a neural Semaphorin through PlexinC1, and A39R is a Sema7A mimic secreted by smallpox virus. We report the structures of Sema7A and A39R complexed with the Semaphorin-binding module of PlexinC1. Both structures show two PlexinC1 molecules symmetrically bridged by Semaphorin dimers, in which the Semaphorin and PlexinC1 beta propellers interact in an edge-on, orthogonal orientation. Both binding interfaces are dominated by the insertion of the Semaphorin's 4c-4d loop into a deep groove in blade 3 of the PlexinC1 propeller. A39R appears to achieve Sema7A mimicry by preserving key Plexin-binding determinants seen in the mammalian Sema7A complex that have evolved to achieve higher affinity binding to the host-derived PlexinC1. The complex structures support a conserved Semaphorin-Plexin recognition mode and suggest that Plexins are activated by dimerization. PMID- 20727576 TI - Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study. AB - BACKGROUND: A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. METHODS: We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged >=18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). FINDINGS: 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1.01, 95% CI 0.83 to 1.19, p=0.97), or in eGFR at 1-5 years after transplantation (at 12 months -0.36 mL/min per 1.73 m(2), 95% CI -2.00 to 1.27, p=0.66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. INTERPRETATION: Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. FUNDING: UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre. PMID- 20727577 TI - Kidneys donated after cardiac death are acceptable. PMID- 20727578 TI - Effect of tidal flooding on metal distribution in pore waters of marsh sediments and its transport to water column (Tagus estuary, Portugal). AB - Sediment cores and flooding water were collected at 0, 5, 10 and 50 min of tidal inundation in two sites of the Rosario salt marsh located in the proximity of a heavy industrialised zone of Tagus estuary colonised by pure stands of Spartina maritima (low marsh) and Sarcocornia fruticosa (high marsh). The cores were sliced in 5 cm layers and sediment solids, pore water, and belowground biomass were separated in order to measure Fe, Mn, Zn, Cu, Pb and Cd. The pore waters and sediments colonised by S. fruticosa, as well as belowground biomass presented high concentrations of Zn, Cu, Pb and Cd. Belowground biomass exceeded in one order of magnitude the metal levels in sediments. Abundant belowground biomass and small dimension of S. fruticosa roots facilitates the root-sediment interactions and presumably the metal retention in the higher marsh. The novelty of this work is the result of tidal inundation on pore water concentrations of metals in salt marsh sediments and their exportation to the water column. Concentrations in pore waters varied at minute scales, but 50 min after inundation levels were comparable to the initial values. The metal levels in flooding water increased abruptly during the first 10-20 min of inundation. The concentration peaks (Fe = 60 MUM, Mn = 7.5 MUM, Zn = 1.7 MUM, Cu = 550 nM, Pb = 100 nM, Cd = 1.7 nM) reached one to two orders of magnitude above the values found in subsequent periods of inundation. The advective transports during the 50 min inundation during two daily pulses of inundation were: Fe (9520 and 1640), Mn (24), Zn (220 and 82), Cu (74 and 16), Pb (13 and 15) and Cd (0.3 and 0.08) for S. maritima and S. fruticosa, respectively. These quantities exceeded three to four orders of magnitude of the corresponding predicted diffusive fluxes (Fick 1st law) on a daily basis. This work emphasizes the importance of tidal flooding over salt marsh sediments to the metal exportation to the water column. PMID- 20727579 TI - Elucidating cellular and behavioural effects of contaminant impact (polycyclic aromatic hydrocarbons, PAHs) in both laboratory-exposed and field-collected shore crabs, Carcinus maenas (Crustacea: Decapoda). AB - Monitoring effects of contaminants at lower levels of biological organisation (e.g. biochemical and cellular) allows for mechanistic evaluation of effects of contaminant exposure through laboratory exposures. However, higher level organism effects (e.g. physiological and behavioural) are deemed more ecologically relevant. In the present study, cellular (cell viability and immune function), physiological (cardiac activity) and behavioural (foraging behaviour) responses were evaluated in field-collected shore crabs Carcinus maenas from three estuaries [a 'relatively' (polycyclic aromatic hydrocarbon) PAH-contaminated site (Plym Estuary) and two 'comparatively clean' field sites (Avon and Yealm Estuaries)] and compared with responses of crabs exposed in the laboratory to a model organic contaminant (PAH) pyrene (200 MUg l(-1) for 28 days). The hypothesis that behavioural indicators may be more sensitive than other more traditional methods was tested. No significant impacts were observed at the cellular or physiological level in Plym-collected crabs (the 'relatively' contaminated site), but foraging behaviour was significantly altered (increased prey handling time) compared to individuals collected from the 'relatively' uncontaminated sites (Avon and Yealm). When given a cockle as a prey item, both Plym-collected and laboratory-exposed crabs took longer to handle and break into cockle shells. Therefore, ecologically-relevant behavioural observations may serve as valuableindicators of environmental quality. PMID- 20727580 TI - Enhanced in-vitro transfection and biocompatibility of L-arginine modified oligo (-alkylaminosiloxanes)-graft-polyethylenimine. AB - Branched poly ethylene imine (PEI) has been considered as the most efficient non viral gene transfection agent. However, its clinical application is confined due to cytotoxicity. In the present study, we tried to enhance transfection efficiency and reduce toxicity of PEI by conjugating it with arginine modified oligo(-alkylaminosiloxane) [P(SiDAAr)n]. These derivatives were complexed with plasmid DNA and the resulting nanoparticles were characterised by dynamic light scattering (DLS), Atomic force microscopy (AFM), transmission electron microscopy (TEM), gel retardation and DNase I interaction to determine surface charge, particle size, morphology, complex formation and protection of DNA respectively. Among the four P(SiDAAr)n derivatives, nanoparticles of the P(SiDAAr)5/pDNA was found to exhibit 98% cell viability and around 150% more gene transfection than branched PEI in KB cell lines. Studies performed on transfection mechanism, using inhibitor study, clearly stated that the enhancement in transfection is due to the multiple pathways for cellular uptake which offered by the presence of uniformly spaced arginine moiety by oligo(-alkylaminosiloxane) arms. The nuclear localisation ability of the arginine residue was also established by using FITC stained nanoparticles on Hoechst 33342 stained nucleus. PMID- 20727581 TI - Chronic label-free volumetric photoacoustic microscopy of melanoma cells in three dimensional porous scaffolds. AB - Visualizing cells in three-dimensional (3D) scaffolds has been one of the major challenges in tissue engineering. Most current imaging modalities either suffer from poor penetration depth or require exogenous contrast agents. Here, we demonstrate photoacoustic microscopy (PAM) of the spatial distribution and temporal proliferation of cells inside three-dimensional porous scaffolds with thicknesses over 1 mm. Specifically, we evaluated the effects of seeding and culture methods on the spatial distribution of melanoma cells. Spatial distribution of the cells in the scaffold was well-resolved in PAM images. Moreover, the number of cells in the scaffold was quantitatively measured from the as-obtained volumetric information. The cell proliferation profile obtained from PAM correlated well with what was obtained using the traditional 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. PMID- 20727582 TI - Endothelial cells dysfunction induced by silica nanoparticles through oxidative stress via JNK/P53 and NF-kappaB pathways. AB - Drug carriers are generally introduced into the body intravenously and directly exposed to endothelial cells. Silica nanoparticles could be promising delivery vehicles for drug targeting or gene therapy. However, few studies have been undertaken to determine the biological behavior of silica nanoparticles on endothelial cells. Here we measured reactive oxygen species (ROS) generation, apoptosis and necrosis, proinflammatory and prothrombic properties and the levels of the apoptotic signaling proteins and the transcription factors in human umbilical vein endothelial cells (HUVECs) after exposure to silica nanoparticles of different concentrations (25, 50, 100, and 200 microg/mL) for 24h. The results showed that silica nanoparticles, ranging from 50 microg/mL to 200 microg/mL, markedly induced ROS production, mitochondrial depolarization and apoptosis in HUVECs. At the highest concentration, the necrotic rate, LDH leakage, the expression of CD54 and CD62E, and the release of TF, IL-6, IL-8 and MCP-1 were significantly increased. Silica nanoparticles also activated c-Jun N-terminal kinase (JNK), c-Jun, p53, caspase-3 and NF-kappaB, increased Bax expression and suppressed Bcl-2 protein. Moreover, inhibition of ROS attenuated silica nanoparticles-induced apoptosis and inflammation and the activation of JNK, c Jun, p53 and NF-kappaB. In summary, our findings demonstrated that silica nanoparticles could induce dysfunction of endothelial cells through oxidative stress via JNK, p53 and NF-kappaB pathways, suggesting that exposure to silica nanoparticles may be a significant risk for the development of cardiovascular diseases such as atherosclerosis and thrombus. PMID- 20727583 TI - High density gene expression microarrays and gene ontology analysis for identifying processes in implanted tissue engineering constructs. AB - The in vivo performance of tissue-engineered constructs is often based on generally accepted read-out parameters, like (immuno)histology. In this study, high-density gene expression microarrays and gene ontology (GO) analysis were used as a read-out tool to identify the biological processes occurring after implantation of an acellular collagen-based skin construct using a rat full thickness wound model. A freely-available program (DAVID) was used to identify up/downregulated biological processes (GO-terms) and results were compared to wound healing/regeneration without a construct. The entire process from RNA isolation to biological interpretation is explained step-by-step. Conventional (immuno)histology was used to validate the biological processes identified and indicate that microarray analysis may provide a valuable, fast and unbiased tool to evaluate the in vivo performance of tissue-engineered constructs. However, challenges remain e.g. with regards to the development of specific GO-terms and annotation of the (rat) genome. PMID- 20727584 TI - The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model. AB - Parathyroid hormone-related protein (PTHrP) is an important regulator of bone formation and remodeling. Our recent findings demonstrate that PTHrP (107-111) (osteostatin) loaded onto silica-based ordered mesoporous SBA15 materials exhibit osteogenic features in osteoblastic cell cultures. We aimed here to elucidate whether these peptide-coated materials might be suitable for promoting bone repair following a cavitary defect in the rabbit femur. Histological examination revealed the absence of significant inflammation or bone resorption within the time of study (4 and 8 weeks) after implantation. At 8 weeks, the peptide unloaded materials were still separated from the bone marrow by a fibrous cap, which was greatly diminished by the presence of the PTHrP peptide. By using MUCT analysis, new bone formation was evident at different distances from the implants, mainly for the latter peptide-loaded biomaterials. This was confirmed by performing immunostaining for different osteoblast markers. Our findings demonstrate that these PTHrP (107-111)-loaded bioceramics significantly improve local bone induction, as compared to that observed with the unloaded material. PMID- 20727585 TI - Dense type I collagen matrices that support cellular remodeling and microfabrication for studies of tumor angiogenesis and vasculogenesis in vitro. AB - Type I collagen is a favorable substrate for cell adhesion and growth and is remodelable by many tissue cells; these characteristics make it an attractive material for the study of dynamic cellular processes. Low mass fraction (1.0-3.0 mg/ml), hydrated collagen matrices used for three-dimensional cell culture permit cellular movement and remodeling, but their microstructure and mechanics fail to mimic characteristics of many extracellular matrices in vivo and limit the definition of fine-scale geometrical features (<1 mm) within scaffolds. In this study, we worked with hydrated type I collagen at mass fractions between 3.0 and 20 mg/ml to define the range of densities over which the matrices support both microfabrication and cellular remodeling. We present pore and fiber dimensions based on confocal microscopy and longitudinal modulus and hydraulic permeability based on confined compression. We demonstrate faithful reproduction of simple pores of 50 MUm-diameter over the entire range and formation of functional microfluidic networks for mass fractions of at least 10.0 mg/ml. We present quantitative characterization of the rate and extent of cellular remodelability using human umbilical vein endothelial cells. Finally, we present a co-culture with tumor cells and discuss the implications of integrating microfluidic control within scaffolds as a tool to study spatial and temporal signaling during tumor angiogenesis and vascularization of tissue engineered constructs. PMID- 20727586 TI - Control of highly migratory cells by microstructured surface based on transient change in cell behavior. AB - Cell migration control techniques have been proposed for cells with relatively low migratory activity, based on static analyses performed with cells that attain a temporally homogenous state after being exposed to a cell guiding stimulus. To elucidate new functions of substrate topography, we investigated the transient change in the behavior of highly migratory cells coming from a flat surface to a grooved surface on a silicon substrate covered with SiO(2). A single line groove (1.5 MUm in width, 20 MUm in depth) and intersecting grooves (1.5 MUm in width, 5 MUm in spacing, 20 MUm in depth) functioned as an effective cell repellent. In the case of wider grooves, a single line groove (4 MUm in width; 20 MUm in width) had no specified function. In contrast, intersecting grooves (4 MUm in width, 5 MUm in spacing) functioned as a trap for the cells. Our findings yield a new design concept of cell repelling and trapping surfaces which are applicable to cell guiding methods and single or multiple cell confinement on cell culture substrates, and thus may contribute to development of more advanced biomaterials. PMID- 20727587 TI - PLGA/polymeric liposome for targeted drug and gene co-delivery. AB - Chemotherapy is one of the most effective approaches to treat cancers in the clinic, but the problems, such as multidrug resistance (MDR), low bioavailability and toxicity, severely constrain the further application of chemotherapy. Our group recently reported that cationic PLGA/folate coated PEGlated polymeric liposome core-shell nanoparticles (PLGA/FPL NPs). It was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell for targeting co-delivery of drug and gene. Hydrophobic drugs can be incorporated into the core and the cationic shell of the drug-loaded nanoparticles can be used to bind DNA. The drug-loaded PLGA/FPL NPs/DNA complexes offer advantages to overcome these problems mentioned above, such as co-delivery of drugs and DNA to improving the chemosensitivity of cancer cells at a gene level, and targeting delivery of drug to the cancer tissue that enhance the bioavailability and reduce the toxicity. The experiment showed that nanoparticles have core-shell structure with nanosize, sustained drug release profile and good DNA-binding ability. Importantly, the core-shell nanoparticles achieve the possibility of co delivering drugs and genes to the same cells with high gene transfection and drug delivery efficiency. Our data suggest that the PLGA/FPL NPs may be a useful drug and gene co-delivery system. PMID- 20727588 TI - Treatment of anemia with erythroid stimulating agents in myelodysplastic syndromes. PMID- 20727589 TI - Antiangiogenic therapy accelerates tumor metastasis. PMID- 20727590 TI - Myeloid blastic transformation of myeloproliferative neoplasms--a review of 112 cases. AB - Blastic transformation of myeloproliferative neoplasms (MPN) is still poorly understood. We describe a cohort of 23 Roswell Park Cancer Institute (RPCI) patients and 89 additional cases from the English literature for whom biologic features were described. We initially compared our 23 patients to the 89 cases from the literature. Our population had significantly less patients with prior history of polycythemia vera (PV), shorter time from MPN diagnosis to blastic transformation, <3 prior therapies, more frequent use of hydroxyurea and erythropoietin and less frequent use of alkylating agents. Interestingly, the overall survival of the two cohorts from the time of blastic transformation was similar. We therefore looked at the outcome of the entire cohort (n=112). Patients with prior history of essential thrombocythemia survived longer than patients with prior history of myelofibrosis or PV. Further, patients with <3 prior therapies, those who lacked complex karyotype and those <60 year old at MPN diagnosis had significantly longer survival. Among the PRCI population, 20/23 patients underwent induction treatment with cytarabine and an anthracycline containing regimens; 12 achieved remission and their overall survival was significantly longer than those who did not. Three patients underwent an allogeneic transplantation and their survival was significantly longer than those who did not. Patients with <3 prior therapies, those who lack complex karyotype and those <60 at MPN diagnosis have longer survival following blastic transformation. Finally, allogeneic transplantation represents the only chance for long-term survival in these patients. PMID- 20727591 TI - Evaluation of the fluorescence polarization assay for the detection of Brucella abortus antibodies in bison in a natural setting. AB - Bison and elk in the greater Yellowstone area are the last-known reservoir of Brucella abortus in the United States. Diagnosis of brucellosis is challenging as there is no perfect reference test. The objectives of this study were to estimate the accuracy of the fluorescence polarization assay (FPA) for the screening of B. abortus antibodies in bison in a natural setting. Serum and tissue samples were collected and analyzed from the known brucellosis-infected bison herd in Yellowstone National Park (YNP). Additionally, serum samples from privately owned bison were serologically tested for brucellosis. While the FPA and five other tests had perfect sensitivity, all tests had substantially lower specificity in the YNP herd. However, a Bayesian analysis showed that as many as 59-74% of the culture-negative animals were most-likely truly infected. A decision-tree analysis showed that the expected cost of FPA testing was comparable to the cost of other serologic tests. The FPA was shown to be highly sensitive but may not be able to differentiate culture-positive and culture-negative animals. There is a need for long-term longitudinal studies to estimate diagnostic accuracy of tests for B. abortus in bison. PMID- 20727592 TI - MR perfusion of intracranial Rosai-Dorfman disease mimicking meningioma. PMID- 20727593 TI - Tomato seeds in space: NASA outreach and science education in the shuttle era. PMID- 20727595 TI - Interparental relationship dynamics and cardiac vagal functioning in infancy. AB - This study examined associations between interparental relationship dynamics and vagus system functioning in infancy. The functioning of the vagus system, part of the parasympathetic nervous system, indexes emotional reactivity and regulation. Interparental avoidance and dyadic adjustment constitute the focus of this study in order to bring attention to relationship dynamics not subsumed under overt conflict. Infants' baseline vagal tone and change in vagal tone in response to a novel toy were assessed at 5 months in a sample of high-risk mother-infant dyads (n=77). Maternal report of interparental avoidance demonstrated an association with infants' baseline vagal tone, while interparental dyadic adjustment was associated with change in infants' vagal tone from baseline to the novel toy. Infant gender moderated these associations. Maternal sensitivity did not mediate interparental relationship dynamics and infants' vagal functioning. Results are discussed in the context of emotional security theory. PMID- 20727594 TI - Effector T cells driving monophasic vs. relapsing/remitting experimental autoimmune uveitis show unique pathway signatures. AB - Autoimmune diseases often show a relapsing-remitting course. Here we describe characteristics of the autoreactive T cell response in the Lewis rat model of experimental autoimmune uveitis (EAU), a model for the clinical heterogeneity seen in human uveitis. Depending on the autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting. This appears to be dictated by subtle differences in the T cell effector phenotype elicited. Using transcriptomic profiling and pathway analysis, the molecular basis for the monophasic vs. relapsing/remitting effector T cell phenotype was investigated. CD4+ T cell lines specific for peptide R14 derived from interphotoreceptor retinoid-binding protein (IRBP), which mediate the relapsing disease, were compared to the monophasic disease-inducing lines responding to retinal S-antigen peptide PDSAg. Expression profiles from T cell lines representing each specificity were analyzed using Affymetrix microarrays. Differential gene expression was confirmed and extended by quantitative PCR and verified on the protein level. A set of genes was uniquely upregulated in the R14-specific T cells. Gene ontology analysis demonstrated that these genes were linked to regulatory pathways associated with antigen presentation, lymphocyte activation, regulation of apoptosis and WNT/Hedgehog signaling. R14-specific T cells were further demonstrated to have prolonged survival in vivo, and a Th1-dominated cytokine profile, while the PDSAg-specific T cells lines were more Th17-prone. Our findings suggest that the nature of specific antigens leads to subtle programming of the effector phenotype underlying recurrent inflammation. PMID- 20727596 TI - Preferential development of Th17 cells in offspring of immunostimulated pregnant mice. AB - Pregnant mice were stimulated at day 12 of gestation with the nucleotide poly(I:C). At 24h after stimulation, serum levels of maternal cytokines were measured, and at postnatal ages 2 and 3 weeks, offspring were analyzed for T helper (Th) cell subsets. Lymphocytes from offspring of poly(I:C)-injected (vs. control PBS-injected) pregnant dams preferentially developed into T helper 17 (Th17) cells upon in vitro activation. This occurred in offspring of pregnant dams who exhibited an immunological "memory" phenotype, but not in offspring of immunologically "naive" dams. Preferential development of Th17 cells in these offspring may be facilitated by the higher levels of pro-inflammatory cytokines such as IL-6, found in immune vs. naive pregnant dams. Murine immune stimulation during pregnancy is frequently used to model human neurological disorders, such as autism and schizophrenia. However, immune stimulation of women during pregnancy occurs in the context of an immunological "memory" phenotype, resulting from previous immunizations and/or natural exposure to micro-organisms and other antigens. Therefore, use of previously immunized female mice with a similar immunological memory phenotype to study maternal immune stimulation during pregnancy presents a more biologically relevant experimental strategy to investigate developmental, behavioral, and immunological sequelae of offspring in such rodent models. PMID- 20727597 TI - Olfactory hallucinations in schizophrenia and schizoaffective disorder: a phenomenological survey. AB - Olfactory hallucinations (OHs), so it has been argued, are prognostic of a poorer outcome, are unpleasant, and cannot be well explained within current theoretical accounts of hallucinations. We examined these and related issues by conducting structured interviews with 51 participants who experienced OHs and who were previously diagnosed with schizophrenia or schizoaffective disorder. We found no relationship between disease severity measures and type or frequency of OHs. As with prior research, we too noted the predominance of negative OHs, but with many reports of positive OHs, and also found significant relationships between frequency of OHs and severity of tactile hallucinations. We then examined whether odor imagery or involuntary memory might account for the presence of OHs, but these possibilities were not well supported. We then explored, using cluster analysis, whether or not our sample was homogenous. Two clusters were of especial interest; one which may reflect a 'sensory dysfunction group' and one characterized by more severe tactile hallucinations. The presence of tactile hallucinations may suggest a further novel cause of OHs, which we discuss. Our data suggest diverse causes for OHs in schizophrenia, none of which are consistent with current models of hallucinations in other modalities. PMID- 20727598 TI - Selective recognition and elimination of nicotinic acetylcholine receptor reactive B cells by a recombinant fusion protein AChR-Fc in myasthenia gravis in vitro. AB - AChR-reactive B cells play a key role in the pathogenesis of myasthenia gravis (MG) by producing autoantibodies. Selective elimination of AChR-reactive B cells will be a promising way to treat MG. Thus, we generated a fusion protein (referred to as AChR-Fc) composed of the human extracellular domain of AChR alpha1 subunit and the Fc domain of the human IgG1 heavy chain, which could bind both to AChR-reactive BCR and FcgammaRIIB on the surface of AChR-reactive B cells. Our results showed that AChR-Fc inhibited the proliferation of AChR specific hybridoma cells, promoted their apoptosis, and mediated cytotoxicity by cross-linking effector cells and complement. Likewise, AChR-Fc significantly reduced the number of AChR-reactive B cells from spleen of Lewis rats immunized with AChR ex vivo. PMID- 20727599 TI - "Mosaic trachea" in a child with trisomy 9 mosaicism. AB - Humans with mosaic karyotypes may present with milder forms of birth defects than one would see in non-mosaic individuals. Mosaicism may also affect tissues, resulting in different parts of an organ manifesting varied phenotypes. We present the case of a child born with mosaic trisomy 9 and multiple congenital anomalies. Her trachea displays segmental abnormalities that suggest tissue mosaicism. We describe the endoscopic and cytogenetic findings in this child and propose a possible genetic mechanism to account for the unusual malformations. PMID- 20727600 TI - Drug-lipid interaction evaluation: why a 19th century solution? AB - The affinity of a drug candidate for a biological membrane (its lipophilicity) is closely related to the pharmacologically crucial events of absorption, biodistribution, metabolization and excretion. The evolution of knowledge of biological membranes during the past two decades contrasts with the rudimentary parameter most commonly used to assess lipophilicity: P(o/w), the octanol-water partition coefficient. P(o/w) is especially unrealistic when testing molecules that are polar or partially charged. By contrast, lipid vesicle-based methods determine the extent of the actual partition of a drug to a membrane much more accurately, and have the additional advantage of enabling the choice of the lipid composition considered most suitable to answer a specific biological or pharmaceutical question. In addition, some of these methods are appropriate for high throughput screening, thus shifting determinations of membrane partition to a more preliminary stage of drug development. This streamlines research and development, by saving the time and money that would be spent on unpromising leads. PMID- 20727601 TI - Challenges and opportunities with the use of biomarkers to predict reproductive impairment in fishes exposed to endocrine disrupting substances. AB - Biomarkers are commonly used as signposts to evaluate the potential of contaminants to disrupt the endocrine system. However, the relationship between responses in these biomarkers and whole organism endpoints that directly affect population status is not clearly understood. In this study, the relationship between egg production (a whole-organism endpoint which has been directly linked to population-level responses) and biomarkers (sex steroids, vitellogenin (VTG) and gonad size) is examined. Data were collected from short-term reproductive tests in which a wide variety of fish species were exposed to a suite of contaminants with known or unknown modes/mechanisms of action (MOA). The potential to use biomarkers as signposts was evaluated by determining the occurrence of false negatives (i.e., an effect in egg production was not accompanied by a biomarker response) and false positives (i.e., an effect in biomarkers was not followed by an effect in egg production). The quantitative relationships between biomarkers and egg production, and the ability to use these quantitative relationships to predict population-level responses based on modeling was also assessed. A suite of female biomarkers resulted in a relatively low occurrence of both false positives and negatives, indicating the potential for their use as signposts for reproductive effects via endocrine disruption. Egg production in short-term adult fish reproductive tests showed significant relationships to 17beta-estradiol (E2), changes in female VTG levels, and relative female gonad size (gonadosomatic index; GSI). Weaker significant relationships were found between egg production and both VTG levels and GSI in males. However, use of these quantitative relationships to predict population level effects are cautioned because of high levels of uncertainty. This study demonstrates that there are qualitative and quantitative relationships among biomarkers, regardless of fish species used or the MOA of contaminants and concludes that a suite of female reproductive biomarkers can be used as effective signposts to screen chemicals and assess waste streams for endocrine disrupting substances with different MOA. PMID- 20727602 TI - Individual discount rates and smoking: evidence from a field experiment in Denmark. AB - We elicit measures of individual discount rates from a representative sample of the Danish population and test two substantive hypotheses. The first hypothesis is that smokers have higher individual discount rates than non-smokers. The second hypothesis is that smokers are more likely to have time inconsistent preferences than non-smokers, where time inconsistency is indicated by a hyperbolic discounting function. We control for the concavity of the utility function in our estimates of individual discount rates and find that male smokers have significantly higher discount rates than male non-smokers. However, smoking has no significant association with discount rates among women. This result is robust across exponential and hyperbolic discounting functions. We consider the sensitivity of our conclusions to a statistical specification that allows each observation to potentially be generated by more than one latent data-generating process. PMID- 20727603 TI - DREAMS of metabolism. AB - Metabolic networks have been studied for several decades, and sophisticated computational frameworks are needed to augment experimental approaches to harness these complex networks. BNICE (Biochemical Network Integrated Computational Explorer), a computational approach for the discovery of novel biochemical pathways that is based on biochemical transformations, overcomes many of the current limitations. BNICE and similar frameworks can be used in several different areas: (i) 'Design' of novel pathways for metabolic engineering; (ii) 'Retrosynthesis' of metabolic compounds; (iii) 'Evolution' analysis between metabolic pathways of different organisms; (iv) 'Analysis' of metabolic pathways; (v) 'Mining' of omics data; and (vi) 'Selection' of targets for enzyme engineering. Here, we discuss the issues and challenges in building such frameworks as well as the gamut of applications in biotechnology, metabolic engineering and synthetic biology. PMID- 20727604 TI - Structural synthetic biotechnology: from molecular structure to predictable design for industrial strain development. AB - The future of industrial biotechnology requires efficient development of highly productive and robust strains of microorganisms. Present praxis of strain development cannot adequately fulfill this requirement, primarily owing to the inability to control reactions precisely at a molecular level, or to predict reliably the behavior of cells upon perturbation. Recent developments in two areas of biology are changing the situation rapidly: structural biology has revealed details about enzymes and associated bioreactions at an atomic level; and synthetic biology has provided tools to design and assemble precisely controllable modules for re-programming cellular metabolic circuitry. However, because of different emphases, to date, these two areas have developed separately. A linkage between them is desirable to harness their concerted potential. We therefore propose structural synthetic biotechnology as a new field in biotechnology, specifically for application to the development of industrial microbial strains. PMID- 20727605 TI - Patient setup for PET/CT acquisition in radiotherapy planning. AB - PET/CT imaging modalities have been shown to be useful in the diagnosis, staging, and monitoring of malignant diseases. Its inclusion into the treatment planning process is now central to modern radiotherapy practice. However, it is essential to be cognisant of the factors that are necessary in order to ensure that the acquired images are consistent with the requirements for both treatment planning and treatment delivery. Essential parameters required in image acquisition for radiotherapy planning and treatment include consistencies of table tops and the use of laser light for patient set-up. But they also include the accurate definition of the patient's initial positioning and the use of proper immobilization devices in the radiotherapy department. While determining this optimum set-up, patient psychological factors and limitations that may be due to the subsequent use of PET/CT for planning purposes need to be taken into account. Furthermore, patient set-up data need to be properly recorded and transmitted to the imaging departments. To ensure the consistency of patient set-up, the radiation therapist should ideally be directly involved in informing and positioning the patient on the PET/CT. However, a proper exchange of patient related information can also be achieved by a close liaison between the two departments and by the use of clear detailed protocols per type of patient set-up and/or per localization of tumour site. PMID- 20727606 TI - Clinical evidence on PET-CT for radiation therapy planning in gastro-intestinal tumors. AB - A large number of histological and anatomically distinct malignancies originate from the gastro-intestinal (GI) tract. Radiotherapy (RT) plays an increasing role in the multimodal treatment of most of these malignancies. The proximity of different organs at risk such as the kidneys, the spinal cord and the small bowel and the potential toxicity associated with combined treatment modalities make accurate target volume delineation imperative. The ability of positron emission tomography (PET) imaging to visualize a so-called 'biological target volume' (BTV) may be helpful in this respect. Currently the most widely used tracer for diagnosis, staging, restaging and response assessment is [(18)F]Fluoro deoxyglucose (FDG). Promising preliminary results in esophageal, pancreatic and anorectal cancers and colorectal liver metastasis suggest that FDG-PET might provide us with additional information useful in target volume delineation. Poor image resolution and a low sensitivity for lymph node detection currently obstructs its widespread implementation. Moreover, validation in large prospective trials and the pathological validation of the correct tumor volume is still lacking. In hepatocellular carcinoma (HCC) and gastric adenocarcinoma there is currently little evidence for the use of FDG-PET in target delineation. However more extensive research is warranted before the true value of FDG-PET in these sites can be assessed. Also other tracers are constantly being developed and investigated. Up to now however none of these tracers has found its way into the daily practice of target volume delineation. PMID- 20727607 TI - Clinical use of PET-CT data for radiotherapy planning: what are we looking for? PMID- 20727608 TI - To freeze or not to freeze? Affective and cognitive perturbations have markedly different effects on postural control. AB - Similar effects have been reported for diverting attention from postural control and increased anxiety on the characteristics of center-of-pressure (COP) time series (decreased excursions and elevated mean power frequency). These effects have also received similar interpretations in terms of increased postural stiffness, suggesting that cognitive and affective manipulations have similar influences on postural control. The present experiment tested this hypothesis by comparing postural conditions involving manipulations of attention (diverting attention from posture using cognitive and motor dual tasks) and anxiety (standing at a height), and by complementing posturography with electromyographic analyses to directly examine neuromuscular stiffness control. Affective and cognitive manipulations had markedly different effects. Unlike the height condition, diverting attention from balance induced smaller COP amplitudes and higher sway frequencies. In addition, more regular COP trajectories (lower sample entropy) were found in the height condition than the dual-task conditions, suggesting elevated attentional investment in posture under the affective manipulation. Finally, based on an analysis of the cross-correlation function between anterior-posterior COP time series and enveloped calf muscle activity, indications of tighter anticipatory neuromuscular control of posture were found for the height condition only. Our data suggest that affective and cognitive perturbations have qualitatively different effects on postural control, and thus are likely to be associated with different control processes, as evidenced by differences in neuromuscular regulation and attentional investment in posture. PMID- 20727609 TI - Prioritizing gait in dual-task conditions in people with Parkinson's. AB - This controlled study examined the effects of a gait prioritization strategy on walking in people with Parkinson's disease (PD). Participants in the training group (n=6) received 30-min therapy to prioritize their attention to take big steps while performing serial three subtractions. Participants in the control group (n=6) received no therapy. Stride length, gait velocity, and accurate enumeration rate were measured at baseline, immediately after training and 30 min after training under both single-task (walk only or subtract only) and dual-task (walk and subtract) conditions. Performance was also assessed during therapy for the training group. Stride length and gait velocity increased immediately when participants followed instructions to prioritize their attention to take big steps (p=.005, p=.04). Further, the gait variables increased for both single and dual-task conditions for at least 30 min after training when compared to the controls; with a simultaneous reduction in the magnitude of dual-task interference (p=.03, p=.03). No difference in the accurate enumeration rate was found at any of the assessment time points. Therefore, prioritizing attention to take big steps can be an effective strategy to increase the stride length and walking speed in some people with PD. PMID- 20727610 TI - Sensori-motor integration during stance: time adaptation of control mechanisms on adding or removing vision. AB - Sudden addition or removal of visual information can be particularly critical to balance control. The promptness of adaptation of stance control mechanisms is quantified by the latency at which body oscillation and postural muscle activity vary after a shift in visual condition. In the present study, volunteers stood on a force platform with feet parallel or in tandem. Shifts in visual condition were produced by electronic spectacles. Ground reaction force (center of foot pressure, CoP) and EMG of leg postural muscles were acquired, and latency of CoP and EMG changes estimated by t-tests on the averaged traces. Time-to-reach steady state was estimated by means of an exponential model. On allowing or occluding vision, decrements and increments in CoP position and oscillation occurred within about 2s. These were preceded by changes in muscle activity, regardless of visual shift direction, foot position or front or rear leg in tandem. These time intervals were longer than simple reaction-time responses. The time course of recovery to steady-state was about 3s, shorter for oscillation than position. The capacity of modifying balance control at very short intervals both during quiet standing and under more critical balance conditions speaks in favor of a necessary coupling between vision, postural reference, and postural muscle activity, and of the swiftness of this sensory reweighing process. PMID- 20727611 TI - Physical activity and health-related quality of life in individuals with prediabetes. AB - OBJECTIVE: The objective of this study was to determine if differences existed in health-related quality of life (HRQoL) between individuals with prediabetes who are physically active (i.e., achieving >or=600METmin per week) compared to those who are inactive. METHOD: Individuals with prediabetes (N=232) residing in Northern Alberta, Canada completed a mailed questionnaire assessing self-reported PA, and health-related quality of life in August-September 2008. RESULTS: Thirty eight percent of individuals with prediabetes were meeting prediabetes PA guidelines. Covarying on age, gender, income, smoking and BMI, a significant multivariate analysis of covariance model [Wilks'lambda=0.967, F(2,224)=3.791, p<.05] indicated those achieving PA guidelines reported higher Physical Health (Mean diff=2.7, p<.05, ES=.27) and Mental Health (Mean diff=3.0, p<.05, ES=.31) compared to those not achieving PA guidelines. CONCLUSION: These findings demonstrate people with prediabetes who achieve prediabetes PA guidelines have higher levels of physical and mental HRQoL than people who are inactive. Further, these results support the rationale for developing strategically designed PA programs for individuals with prediabetes. PMID- 20727612 TI - Advocacy for free maternal and child health care in Nigeria--Results and outcomes. AB - The study was designed to determine the outcome of an advocacy program aimed at implementing a policy of free maternal and child health (MCH) services in Nigeria. The team conducted a situational analysis on costing of MCH services, and used the results to conduct public health education and advocacy. Advocacy consisted of public presentation on MCH to high-level policymakers, dissemination of situational analysis report, and media publicity. The implementation of free MCH services at national and sub-national levels was assessed 3 years after. The results showed that the number of States offering comprehensive free MCH services increased from four to nine; the States offering partially free MCH services increased from 11 to 14 (8.1% increase); while those not offering any form of free treatment decreased from 22 to 14 (21.7% decrease). We conclude that advocacy and public health education is effective in increasing the commitment of policymakers to provide resources for implementing evidence-based maternal and child health services in Nigeria. PMID- 20727613 TI - Prognostic impact of comorbidity in elderly lung cancer patients: use and comparison of two scores. AB - BACKGROUND: Mean age of patients with lung cancer rises as a result of increasing life expectancy. So, the proportion of patients with serious comorbidity also increases [1,2]. Lung cancer treatment is characterized by a narrow therapeutic index. When life expectancy is short and therapeutic benefit is limited, it is of paramount importance to know the specific cause of death. Comorbidity is understood as a competing cause of death, and is the main exclusion criterion for lung cancer clinical trials. The aim of this study was to determine the prevalence of comorbidity in elderly lung cancer patients seen in an outpatient oncology department and to determine its correlation with survival. PATIENTS AND METHODS: Between January 2006 and February 2008, 83 untreated lung cancer patients over the age of 70 years were enrolled in the study. Comorbidity was evaluated according to the Charlson comorbidity index (CCI) [3] and the simplified comorbidity score (SCS) [4]. RESULTS: 83 patients (97.6% men, mean age 77 years) were studied. Comorbidities: tobacco consumption (94.6%), cardiovascular diseases (65%), and chronic obstructive pulmonary disease (COPD) (59%). Mean CCI was 3 (range 0-9). Mean SCS was 9 (range 4-19), and 47% of patients had an SCS>9. Comorbidity was fairly well correlated with age, ADL, IADL, and stage. Neither the CCI nor the SCS was related to survival (p: 0.47 and p: 0.24, log rank, respectively). Median survival was 326 days (95% CI, 259-393 days; or 10.8 months, 95% CI 8.6-13.1 months). Main cause of death was lung cancer disease progression (69.5%, 57 patients), with 20 patients (25%) dying of other non-neoplastic causes. Stage was significantly associated with survival (log rank: p<0.001). CONCLUSIONS: Although there was a high prevalence of comorbidity in our population, comorbidity was not related to survival. Comorbidity is one of the main reasons for undertreatment of elderly lung cancer patients, but this study indicates that this undertreatment may not be warranted given that those comorbidities may not cause a patient's death. Our data generated more of a hypothesis than a conclusion. Comorbidity should be an impetus for treatment design instead of an exclusion criterion for oncologic treatment. PMID- 20727614 TI - Monitoring does not always count. AB - The gross under-resourcing of conservation endeavours has placed an increasing emphasis on spending accountability. Increased accountability has led to monitoring forming a central element of conservation programs. Although there is little doubt that information obtained from monitoring can improve management of biodiversity, the cost (in time and/or money) of gaining this knowledge is rarely considered when making decisions about allocation of resources to monitoring. We present a simple framework allowing managers and policy advisors to make decisions about when to invest in monitoring to improve management. PMID- 20727615 TI - High-pressure injection of dissolved oxygen for hydrocarbon remediation in a fractured dolostone aquifer. AB - A field experiment was completed at a fractured dolomite aquifer in southwestern Ontario, Canada, to assess the delivery of supersaturated dissolved oxygen (supersaturated with respect to ambient conditions) for enhanced bioremediation of petroleum hydrocarbons in groundwater. The injection lasted for 1.5h using iTi's gPro(r) oxygen injection technology at pressures of up to 450 kPa and at concentrations of up to 34 mg O2/L. A three-dimensional numerical model for advective-dispersive transport of dissolved oxygen within a discretely-fractured porous medium was calibrated to the observed field conditions under a conservative (no-consumption) scenario. The simulation demonstrated that oxygen rapidly filled the local intersecting fractures as well as the porous matrix surrounding the injection well. Following injection, the local fractures were rapidly flushed by the natural groundwater flow system but slow back-diffusion ensured a relatively longer residence time in the matrix. A sensitivity analysis showed significant changes in behaviour with varying fracture apertures and hydraulic gradients. Applying the calibrated model to a 7-day continuous injection scenario showed oxygen residence times (at the 3mg/L limit), within a radius of 2-4m from the injection well, of up to 100 days. This study has demonstrated that supersaturated dissolved oxygen can be effectively delivered to this type of a fractured and porous bedrock system at concentrations and residence times potentially sufficient for enhanced aerobic biodegradation. PMID- 20727617 TI - Chlorophyllase versus pheophytinase as candidates for chlorophyll dephytilation during senescence of broccoli. AB - Degradation of chlorophylls during senescence is a highly regulated process which requires the concerted action of several enzymes. Traditionally, it has been stated that the dismantling process of the chlorophyll molecule begins with a dephytilation step, followed by Mg(2+) removal and other breakdown reactions. Recently, new evidence suggests the possibility of a rearrangement in the first two steps of this process, occurring Mg(2+) removal prior to the loss of the phytol side chain. With the purpose of approximating to the real sequential order of these reactions and to assess if dephytilation occurs on intact (catalyzed by chlorophyllase) or Mg-free (catalyzed by pheophytinase) chlorophyll, expression of both genes was analyzed in broccoli tissue during senescence. Samples of broccoli florets treated with plant hormones, such as cytokinin and ethylene were utilized, as to assess the effect of such compounds on the expression of these genes. Results showed that chlorophyllase expression did not correlate to typical expression patterns for genes related to senescence, since a decrease in expression during senescence was found for one of the two chlorophyllase genes analyzed, and the hormonal-treatment effects on gene expression did not match those observed on chlorophyll content for both chlorophyllase genes. Pheophytinase expression patterns, on the other hand, displayed an increase in the first 3 days of induced senescence, followed by lower expression values towards the end of the experiment. Samples subjected to postharvest treatments mostly showed an inhibition of pheophytinase expression, especially in samples in which degradation of chlorophylls had been delayed. These results suggest that pheophytinase expression correlates to the visual manifestation of postharvest treatments, supporting the possibility that this enzyme is responsible for the dephytilation step in chlorophyll breakdown. PMID- 20727616 TI - The carboxyl tail of Cx43 augments p38 mediated cell migration in a gap junction independent manner. AB - The expression of connexin 43 (Cx43) has been shown to correlate with an enhanced migration of several cell types such as glioma or neural crest cells, but the mechanism remains unclear. We studied whether Cx43 also affects migration in non neural cells and whether or not this is related to gap junction formation. Therefore, we analysed the migratory activity of HeLa cells under conditions of controlled connexin (Cx) expression. The expression of Cx43 enhanced their migration significantly as compared to Cx deficient wild-type cells. Expression of only the carboxyl tail of Cx43 (Cx43CT, AA 257-382) without channel forming capacity enhanced migration similarly as the full length protein. In contrast, the expression of the N-terminal part of Cx43 (Cx43NT, AA 1-257), which partially retained the gap junction channel function of Cx43, did not increase migration. The enhanced cell migration of HeLa cells expressing either full length Cx43 or the Cx43CT was associated with an increased activation of the p38 MAP kinase. The additional incubation with a specific inhibitor of p38 activation diminished the migration of HeLa-Cx43 cells to levels of control transfected cells. As a proof of concept, we studied whether Cx43 also modulates the migration of endothelial progenitor cells (EPC) which play an important role in angiogenesis. In these cells, which expressed Cx43 as the only connexin, the downregulation of Cx43 by siRNA resulted in a significantly decreased migration. These results demonstrate that expression of Cx43 augments migration via modulation of p38 MAP kinase activity. The carboxyl tail of Cx43 plays an essential role in this signalling pathway which is independent of gap junction function. PMID- 20727618 TI - Soluble sugar availability of aerobically germinated barley, oat and rice coleoptiles in anoxia. AB - Physiological and metabolic responses to anoxia were compared for aerobically germinated seedlings of barley (Hordeum vulgare), oat (Avena sativa) and rice (Oryza sativa). Coleoptile growth of barley, oat and rice seedlings was suppressed by a 24 h-anoxic stress, but the growth of the rice coleoptiles was much greater than that of the barley and oat coleoptiles. ATP concentration in the anoxic rice coleoptiles was greater than that in the anoxic barley and oat coleoptiles. Concentrations of ethanol and activity of alcohol dehydrogenase (ADH) in the anoxic rice coleoptiles were also greater than those of the anoxic barley and oat coleoptiles, suggesting that ethanolic fermentation may be more active in the rice coleoptiles than in the barley and oat coleoptiles, where glycolysis and ethanolic fermentation are the main source of ATP production. Soluble sugar concentration in the anoxic rice coleoptiles was greater than that of the anoxic barley and oat coleoptiles. However, alpha-amylase, which catabolizes reserve starch to soluble sugars, was active in anoxic barley, oat and rice endosperms, and soluble sugar concentration in the anoxic barley, oat and rice endosperms was not significantly different. Therefore, anoxia stress may inhibit soluble sugar transport from the endosperms to the coleoptiles in barley and oat more than in rice. Since the availability of soluble sugar is essential for operation of glycolysis and fermentation in plant cells, ability for sugar transport from the endosperms to the coleoptiles may be one means to distinguish the coleoptile growth of these plant species in anoxia and anoxia tolerance of these plants. PMID- 20727619 TI - [Unilateral uveitis with HHV6-positive polymerase chain reaction in aqueous humor for an etanercept-treated woman: a case report]. AB - Human herpesvirus 6 is a ubiquitous Herpesviridae infecting patients during childhood. Its role in ocular disorders is mostly unknown. We report the case of a 47-year-old woman with a history of rheumatoid arthritis (treated with etanercept) and tuberculosis, who presented with sudden unilateral panuveitis. The patient was initially treated with ganciclovir, as the polymerase chain reaction in the aqueous humor was positive for HHV6, and with pyrimethamine and sulfadiazine because a toxoplasmic co-infection was highly suspected, which was biologically confirmed. Management of HHV6 in a nervous system disorder is challenging because its replication has been proved but its role remains unclear. HHV6 may be pathogenic by itself but can facilitate co-infection as can etanercept. PMID- 20727620 TI - Age-related increase of sI(AHP) in prefrontal pyramidal cells of monkeys: relationship to cognition. AB - Reduced excitability, due to an increase in the slow afterhyperpolarization (and its underlying current sI(AHP)), occurs in CA1 pyramidal cells in aged cognitively-impaired, but not cognitively-unimpaired, rodents. We sought to determine whether similar age-related changes in the sI(AHP) occur in pyramidal cells in the rhesus monkey dorsolateral prefrontal cortex (dlPFC). Whole-cell patch-clamp recordings were obtained from layer 3 and layer 5 pyramidal cells in dlPFC slices prepared from young (9.6 +/- 0.7 years old) and aged (22.3 +/- 0.7 years old) behaviorally characterized subjects. The amplitude of the sI(AHP) was significantly greater in layer 3 (but not layer 5) cells from aged-impaired compared with both aged-unimpaired and young monkeys, which did not differ. Aged layer 3, but not layer 5, cells exhibited significantly increased action potential firing rates, but there was no relationship between sI(AHP) and firing rate. Thus, in monkey dlPFC layer 3 cells, an increase in sI(AHP) is associated with age-related cognitive decline; however, this increase is not associated with a reduction in excitability. PMID- 20727621 TI - Ru(eta6-arene) complexes of combretastatin-analogous oxazoles with enhanced anti tumoral impact. AB - Oxazole-bridged combretastatin A-4 analogues bind to tubulin and exert anti vascular and anti-angiogenic effects. When linked to Ru(eta(6)-arene) complex fragments, conjugates with additional cytotoxic activity result which can ruthenate bionucleophiles such as DNA and proteins. For instance, the Ru(II)(p cymene)(isonicotinate)Cl(2) complex 6a of the known 4-(3,4,5-trimethoxyphenyl)-5 (3-hydroxy-4-methoxyphenyl)-oxazole 4a was far more active than the latter against cells of the p53-competent wild-type form of HCT-116 colon carcinoma at low 0.01 MUM concentrations. A fast reaction of 6a with nucleophilic N-acetyl-L cysteine was observed in NMR studies. The Ru(arene) complexes 6a-c were also more efficacious against combretastatin-refractory p53(+) cells of human HT-29 colon carcinoma when compared to their parent 4-(3,4-dimethoxy-5-methoxy/halo-phenyl)-5 (3-hydroxy-4-methoxyphenyl)-oxazoles 4a-c. These cells are rich in ABC transporters which are responsible for their multi-drug resistance and for which conjugates 6 are less good substrates than the phenols 4. Unlike 4a, its complex 6a also diminished the motility of human 518A2 melanoma cells in a wound-healing assay which is indicative of anti-metastatic activity in solid tumors. Overall, the Ru(arene) complex conjugates 6 broaden the anti-tumoral spectrum of the combretastatin A-4 analogues 4 considerably. PMID- 20727622 TI - Cyclization of some carbothioamide derivatives containing antipyrine and triazole moieties and investigation of their antimicrobial activities. AB - Acetohydrazide derivative containing both antipyrine and triazole nuclei (5) was obtained starting from ethyl hydrazinecarboxylate derivative (2) and 4 aminoantipyrine (1) by three steps. The treatment of compound 5 with CS(2) afforded the conversion of hydrazide function into 5-mercapto-1,3,4-oxadiazole ring leading to the formation of 7. Then, 7 gave the product containing triazolotriazine moiety (9) by the reaction with hydrazine hydrate. The synthesis of the compounds incorporating the 1,3,4-thiadiazole (10a-c), 1,2,4-triazole (11a c) or 1,3-thiazole (12, 13) nucleus as third heterocycle was performed by the acidic or basic treatment of compounds 6a-c which were obtained from the reaction of 5 with several isothiocyanates, or by the condensation of 6a with two different phenacyl bromides, respectively. The antimicrobial activity study revealed that all the compounds showed good activities except 3-5. PMID- 20727623 TI - Antioxidant activity of unexplored indole derivatives: synthesis and screening. AB - The present study envisaged the development of novel antioxidant candidates using the indole scaffold. Several tryptophan and tryptamine derivatives were synthesized, in particular prenylated indole compounds, and their scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) was investigated. The library substitution pattern included several alkyl chains at positions N-1, C-2 of the indole nucleus, including prenyl and isopentyl chain, as well as different groups at the side chain (C-3) that allowed the investigation of a possible radical stabilization. The results obtained showed that tryptophan (8), tryptamine (9), N-phthaloyl tryptamine (5) and N-prenyl tryptophan (13) were the most active against peroxyl radical (ROO(*)) with activities higher than Trolox, which was used as control. The scavenging of hypochlorous acid (HOCl) was also evaluated and tryptophan (8) and tryptamine (9) showed IC(50) of 3.50 +/- 0.4 and 6.00 +/- 0.60 MUM, respectively. Significant activity was also found for the N-prenyl tryptophan (13) with an IC(50) of 4.13 +/- 0.17 MUM and C-2 prenylated derivative (14), with 4.56 +/- 0.48 MUM. The studies were extended to RNS and best results were obtained against peroxynitrite anion (ONOO(-)) in the presence of NaHCO(3). N-alkylated tryptophan (18) showed a high activity with an IC(50) of 14.0 +/- 6.8 MUM. The results show that the tested compounds are effective scavengers of ROS and RNS, and suggest that the radical stabilization is strongly dependent on the type of substituents on the indolic moiety and on their relative positions. In addition, the radical dissipation inside the indolic system is mandatory for the observed antioxidant activity. PMID- 20727624 TI - [Abdominal pain in a 44-year-old woman]. PMID- 20727625 TI - Magnetic resonance imaging with k-means clustering objectively measures whole muscle volume compartments in sarcopenia/cancer cachexia. AB - BACKGROUND & AIMS: Sarcopenia and cachexia are characterized by infiltration of non-contractile tissue within muscle which influences area and volume measurements. We applied a statistical clustering (k-means) technique to magnetic resonance (MR) images of the quadriceps of young and elderly healthy women and women with cancer to objectively separate the contractile and non-contractile tissue compartments. METHODS: MR scans of the thigh were obtained for 34 women (n = 16 young, (median) age 26 y; n = 9 older, age 80 y; n = 9 upper gastrointestinal cancer patients, age 65 y). Segmented regions of consecutive axial images were used to calculate cross-sectional area and (gross) volume. The k-means unsupervised algorithm was subsequently applied to the MR binary mask image array data with resultant volumes compared between groups. RESULTS: Older women and women with cancer had 37% and 48% less quadriceps muscle respectively than young women (p < 0.001). Application of k-means subtracted a significant 9%, 14% and 20% non-contractile tissue from the quadriceps of young, older and patient groups respectively (p < 0.001). There was a significant effect of group (i.e., cancer vs healthy) when controlling for age as a covariate (p = 0.003). CONCLUSIONS: K-means objectively separates contractile and non-contractile tissue components. Women with upper GI cancer have significant fatty infiltration throughout whole muscle groups which is maintained when controlling for age. PMID- 20727626 TI - Fortification of breast milk in VLBW infants: metabolic acidosis is linked to the composition of fortifiers and alters weight gain and bone mineralization. AB - BACKGROUND & AIMS: Study objectives were to test (a) whether increased incidence of metabolic acidosis (MA) was caused by introduction of a new commercially available fortifier for breast milk, (b) if so, whether its modification would decrease the incidence of MA and (c) to analyze the impact of MA on growth. METHODS: Double-blind randomized design. Healthy breast-fed infants (<=34 gestational weeks). Primary outcome measure was incidence of MA (BE < -6.0 mmol/L). Secondary outcome measures were growth, bone mineral content (BMC), vital signs, treatment with sodium hydrogen carbonate and Ca and laboratory parameters (pH, pCO2, HCO3-, electrolytes). RESULTS: Part 1 (comparison of standard (SF) and new fortifier (NF)): Interim analysis showed MA in 1 out of 7 (SF) and 7 out of 8 (NF) infants, p = 0.01; therefore the study was interrupted; subsequently the fortifier was adapted by modifying mineral components. Part 2 (comparison of SF and reformulated fortifier (RF)): MA occurred in 3 out of 15 (SF) and 6 out of 19 (RF), p = 0.7. When data of all infants studied, those with MA had lower mean weight gain (median: 9 vs. 21 g/kg/d, p < 0.01) and lower BMC (1.6% vs. 1.9% BMC/lean, p = 0.04) at discharge. CONCLUSIONS: When fed fortified breast milk, mild MA spontaneously may develop in 20-30% of VLBW infants. A fortifier with an inappropriate composition may increase the severity and frequency of MA. Our data show that weight gain and BMC seem to be related to acid-base homeostasis. It may be speculated that inadequate growth of fully fed preterm infants is triggered more often by imbalances of acid-base status than previously expected. PMID- 20727628 TI - Inverse modeling of Asian (222)Rn flux using surface air (222)Rn concentration. AB - When used with an atmospheric transport model, the (222)Rn flux distribution estimated in our previous study using soil transport theory caused underestimation of atmospheric (222)Rn concentrations as compared with measurements in East Asia. In this study, we applied a Bayesian synthesis inverse method to produce revised estimates of the annual (222)Rn flux density in Asia by using atmospheric (222)Rn concentrations measured at seven sites in East Asia. The Bayesian synthesis inverse method requires a prior estimate of the flux distribution and its uncertainties. The atmospheric transport model MM5/HIRAT and our previous estimate of the (222)Rn flux distribution as the prior value were used to generate new flux estimates for the eastern half of the Eurasian continent dividing into 10 regions. The (222)Rn flux densities estimated using the Bayesian inversion technique were generally higher than the prior flux densities. The area-weighted average (222)Rn flux density for Asia was estimated to be 33.0 mBq m(-2) s(-1), which is substantially higher than the prior value (16.7 mBq m(-2) s(-1)). The estimated (222)Rn flux densities decrease with increasing latitude as follows: Southeast Asia (36.7 mBq m(-2) s(-1)); East Asia (28.6 mBq m(-2) s(-1)) including China, Korean Peninsula and Japan; and Siberia (14.1 mBq m(-2) s(-1)). Increase of the newly estimated fluxes in Southeast Asia, China, Japan, and the southern part of Eastern Siberia from the prior ones contributed most significantly to improved agreement of the model-calculated concentrations with the atmospheric measurements. The sensitivity analysis of prior flux errors and effects of locally exhaled (222)Rn showed that the estimated fluxes in Northern and Central China, Korea, Japan, and the southern part of Eastern Siberia were robust, but that in Central Asia had a large uncertainty. PMID- 20727627 TI - Effect of moisture content on emanation at different grain size fractions - a pilot study on granitic esker sand sample. AB - It is known that in soils and sediments moisture adsorbed on particle surfaces and in the pore system significantly affects the behaviour of recoiling radon ((222)Rn) atoms after decay of parent (226)Ra, leading to increased (222)Rn emanation. As a first step in an effort to characterize the (222)Rn source term in mineralised sediments in the present study, complementing previous studies in the area, granitic esker sand samples were collected in order to test how moisture content affects (222)Rn emanation at different grain size fractions. Emanation fractions measured for natural samples were compared with theoretical calculations. Six different grain size fractions were studied at 0%, 5% and 10% moisture contents relative to the mass of solids. In a further study necessary complementary information on the chemical and structural distribution of (226)Ra was gained by selective leaching experiments. The results showed that (226)Ra concentration increases from 50 Bq/kg at grain size 1-2 mm to 200 Bq/kg at grain size <0.063 mm. Respectively, the emanation factor increased from 0.12 to 0.30 at 5% moisture content. Both emanation factor and radium concentration increased significantly when grain size was below 0.125-0.250 mm. Above this fraction, the emanation fraction was approximately constant, 0.13 at 5% moisture content. In most of the grain size fractions, emanation reaches its maximum at 5% moisture content, being twice as high as in a dry sample. For the small particles (<0.063 mm) the (226)Ra distribution is rather complex and depends on the mineral composition compared to larger particles wherein emanation from the internal pore system and the adjacent matrix is dominating over the contribution from external surface. PMID- 20727629 TI - Observations and modelling of thoron and its progeny in the soil-atmosphere-plant system. AB - Samples of pasture vegetation, mainly Trifolium pratensis, were collected at the Botanic Garden of the University of Bologna during the period 1998-2000 and measured by gamma-spectrometry for determining thoron progeny. Concentrations of (212)Pb were between 1.5 and 20 Bq m(-2), with individual peaks up to 70 Bq m( 2). Soil samples were collected at the same location and physically characterised. Their chemical composition (particularly Th and U) was determined by X-ray fluorescence spectroscopy. Lead-212 on plants mainly originates from dry and wet deposition of this isotope generated in the lower atmosphere by the decay of its short-lived precursor (220)Rn, which is produced in the upper soil layers as a member of the natural thorium decay chain and exhales into the atmosphere. Concentrations of (220)Rn in the atmosphere depend on (1) the amount of Th present in soil, (2) the radon fraction which escapes from the soil minerals into the soil pore space, (3) its transport into the atmosphere, and (4) its redistribution within the atmosphere. The mobility of radon in soil pore space can vary by orders of magnitude depending on the soil water content, thus being the main factor for varying concentrations of (220)Rn and (212)Pb in the atmosphere. We present a simple model to predict concentrations of thoron in air and its progeny deposited from the atmosphere, which takes into account varying soil moisture contents calculated by the OPUS code. Results of this model show close agreement with our observations. PMID- 20727630 TI - Lugol's iodine identifies synchronous invasive carcinoma--time for a clinical trial. AB - Lugol's iodine is currently under investigation as a technique to detect dysplasia, carcinoma in situ and invasive carcinoma at resection margins, plus further afield. Lugol's iodine is inexpensive and easy to use. We present two cases where the technique revealed abnormal mucosa (one carcinoma, one squamous cell carcinoma in situ) at distant sites from the tumour being treated within oral cavity and oropharynx. PMID- 20727631 TI - The increasing clinical relevance of human papillomavirus type 16 (HPV-16) infection in oropharyngeal cancer. AB - Human papillomavirus type 16 (HPV-16) has been established beyond doubt as a causative agent in oropharyngeal squamous cell carcinoma (SCC). The incidence of oropharyngeal cancer has risen in recent decades, as has the proportion of patients who have a biologically relevant HPV-16 infection. Combined data from 14 recently published studies (2006-2010) show that 57% of 1316 reported cases of oropharyngeal SCC were HPV-16 positive. They had significantly better prognosis (hazard ratio (HR) for 5-year overall survival range 0.05-0.64), although smoking and higher T stage often appear as confounding factors to this favourable prognostic benefit. HPV-16 therefore has increasing importance as a clinically useful prognostic biomarker, but a benefit in survival has been seen in the use of surgery, radiotherapy, and chemotherapy, so specific changes in the preferred methods of treatment are hard to justify. Future trials that include oropharyngeal SCC will consider HPV-16 routinely as a stratification factor, and its use as a predictive biomarker awaits the development of effective targeted treatments. The undeniable and impressive prognostic significance of HPV-16 should hasten its addition to standard pathological reporting of oropharyngeal SCC, and ultimately to its inclusion in TNM staging systems of the American Joint Committee on Cancer (AJCC) and the International Union against Cancer (UICC). PMID- 20727632 TI - An impalement injury to the oropharynx in a paediatric patient--a case report. AB - Impalement injuries of the oral cavity are common in children and potential for serious complications including internal carotid artery thrombosis which may go unrecogonised. We present a patient who suffered a penetrating injury in which an implanted foreign body was not detected despite the persistence of symptoms and repeated clinical examinations. We discuss the role of investigations and highlight the potential sequaele of these injuries with the aim of increasing awareness and so optimising patient management. PMID- 20727633 TI - Current thoughts on treatment of patients receiving anticoagulation therapy. PMID- 20727634 TI - Action of nicotine and ovariectomy on bone regeneration after tooth extraction in rats. AB - PURPOSE: The purpose of this study was to evaluate the effects of nicotine and ovariectomy on alveolar bone regeneration after exodontias in rats. MATERIALS AND METHODS: For 30 days, sham ovariectomized (OVX)/NaCl, sham OVX/nicotine, OVX/NaCl, and OVX/nicotine animals were given 2 daily injections of saline or hemisulfate of nicotine. After this period, exodontic procedures were carried out and treatment continued up to the time of euthanasia on days 7 and 14 when the alveoli were removed for further analyses. RESULTS: The data confirmed that nicotine significantly delays the alveolar regeneration process after dental extraction in rats and showed that the association of nicotine with ovariectomy exacerbates these results. CONCLUSION: These results indicate that nicotine potentiated the effect of estrogen deficiency on bone regeneration induced by ovariectomy. PMID- 20727635 TI - Efficacy of pre- and postirradiation hyperbaric oxygen therapy in the prevention of postextraction osteoradionecrosis: a systematic review. AB - PURPOSE: There is still considerable controversy regarding whether hyperbaric oxygen (HBO) therapy used preoperatively and postoperatively will prevent osteoradionecrosis in previously irradiated patients undergoing tooth extraction. The purpose of this systematic review was to evaluate the best evidence available in an attempt to find an answer to this question. MATERIALS AND METHODS: The literature search on Medline covered the period from January 1948 to March 2008. Included were randomized clinical trials, prospective studies without randomization, case-control studies, retrospective studies, and observational studies with and without control groups. This search retrieved 696 citations, which was reduced to 14 acceptable publications based on an assessment of methodologic quality. They included 1 randomized clinical trial, 8 cohort controlled studies, and 5 observational studies. These were analyzed for radiation dose, type of radiation, use of adjunctive cancer treatments, number and location of extractions, method of extraction, HBO protocol, and use of adjunctive therapy besides HBO. RESULTS: Most of the studies had a small sample size, lacked specific inclusion and exclusion criteria, did not report the interval between radiation and extraction, and provided limited information on the method of extraction. There was also variation in HBO protocols, radiation dosage, the use of antibiotics, and the use of adjunctive cancer therapy. CONCLUSION: On the basis of the best available evidence, there is currently insufficient information to show that the use of HBO reduces the incidence of osteoradionecrosis in irradiated patients requiring tooth extraction. PMID- 20727636 TI - Salmonella-infected submandibular gland cyst: case report and review of the literature. PMID- 20727637 TI - Optimal degree of mouth opening for laryngeal mask airway function during oral surgery. AB - PURPOSE: This study was performed to determine the optimal degree of mouth opening in anesthetized patients requiring laryngeal mask airway (LMA) during oral surgery. PATIENTS AND METHODS: A single, experienced LMA user inserted the LMA in 15 patients who were scheduled for elective oral surgery. Oropharyngeal leak pressure, intracuff pressure, and fiberoptic assessment of the LMA position were sequentially documented in 5 mouth conditions-opening of 1.4 (neutral position), 2, 3, 4, and 5 cm-and any resulting ventilatory difficulties were recorded. RESULTS: Oropharyngeal leak pressure with the mouth open 4 cm (21.8 +/- 3.2 cm H(2)O, P = .025) and 5 cm (27.3 +/- 7.2 cm H(2)O, P < .001) was significantly higher than in the neutral position (18.1 +/- 1.5 cm H(2)O), as was intracuff pressure (neutral position, 60.0 +/- 0 cm H(2)O; 4 cm, 72.6 +/- 5.1 cm H(2)O [P < .001]; and 5 cm, 86.9 +/- 14.4 cm H(2)O [P < .001]). LMA position, observed by fiberoptic bronchoscopy, was unchanged by mouth opening, being similar in the 5 mouth conditions (P = .999). In addition, ventilation difficulties (abnormal capnograph curves or inadequate tidal volume) occurred in 2 of 15 patients (13%) and 7 of 15 patients (53%) (P < .001) with the mouth opening of 4 and 5 cm, respectively. CONCLUSIONS: This study showed that a mouth opening over 4 cm led to substantial increases in oropharyngeal leak pressure and intracuff pressure of the LMA, warranting caution, because gastric insufflation, sore throat, and ventilation difficulties may occur. A mouth opening of 3 cm achieves acceptable airway conditions for anesthetized patients requiring LMA. PMID- 20727638 TI - Unilateral cheek swelling in an infant: case report of an unusual presentation of internal bleeding caused by vitamin K deficiency. PMID- 20727639 TI - Treatment of avulsed teeth by oral and maxillofacial surgeons. PMID- 20727640 TI - Critical computed tomographic diagnostic criteria for frontal sinus fractures. AB - PURPOSE: Diagnosis and treatment of frontal sinus fractures (FSFs) have progressed over the previous 30 years. Despite advances in computed tomography, there is no current diagnostic uniformity with regard to classification and treatment. We developed a statistically valid treatment protocol for FSFs based on injury pattern, nasofrontal outflow tract (NFOT) injury, and complication(s). These data outlined predictable injury patterns based on specific computed tomographic findings critical to the diagnosis and ultimate treatment of this potentially fatal injury. MATERIALS AND METHODS: A retrospective review was conducted on patients with FSF from 1979 to 2005 under institutional review board approval. All computed tomographic scans were reviewed by the authors and fractures categorized by location, displacement, comminution, and degree of NFOT injury. RESULTS: One thousand ninety-seven patients with FSF were identified, 87 expired and 153 had inadequate data, leaving a group of 857 patients. Simultaneous displacement of anterior-posterior tables constituted the largest group (38.4%). NFOT injury occurred in most patients (70.7%) and was strongly associated with anterior (92%) and posterior (88%) table involvement (comminuted 98%). Sixty-seven percent of patients with NFOT injury had obstruction. Five hundred four patients (59.6%) had surgery with 10.4% complications and 353 patients were observed with 3.1% complications. All but 1 patient with complications had NFOT injury (98.5%). CONCLUSIONS: Predictable patterns of injury based on specific computed tomographic data play a pivotal role in classification and surgical management of potentially fatal frontal sinus injuries. Radiologic diagnosis of NFOT injury in FSFs, particularly obstruction, plays a decisive role in surgical planning. PMID- 20727641 TI - Bone regeneration after radiotherapy in an animal model. AB - PURPOSE: The study aimed to evaluate dosage-dependent effects of irradiation on bone regeneration and established a radiation-compromised rabbit model of mandibular distraction osteogenesis. MATERIALS AND METHODS: Twenty-three rabbits were divided randomly into 7 groups. Group A served as the control group, whereas experimental groups B, C, D, E, F, and G received preoperative irradiation at doses of 6.5, 7.0, 7.5, 8.0, 8.5, and 9.0 Gy, respectively, for 5 fractions. After 1 month, all rabbits underwent osteotomy and distraction osteogenesis with 7 days of latency, 11 days of active distraction at a rate of 0.9 mm/d, and 4 weeks of consolidation; rabbit mandibles were subsequently subjected to histologic, radiographic, and micro-computed tomography analysis. RESULTS: With increasing doses of irradiation, bone regeneration was markedly hampered. Radiographically, the high-dose groups (8.5 and 9.0 Gy) presented obscure cortical lines. Histologically, in the 8.5- and 9.0-Gy groups, cortical bones were not completely formed, and in the medullary cavity, there existed a large amount of fibrous tissue. CONCLUSION: Radiotherapy compromises bone regeneration during distraction osteogenesis, and the adverse effect is dose dependent. PMID- 20727642 TI - Use of antibiotics in the treatment of mandible fractures: a systematic review. AB - PURPOSE: The use of prophylactic antibiotics in the treatment of mandible fractures is common practice. The evidence supporting this practice has not been formally assessed for quality. The purpose of this study was to evaluate this empirically. MATERIALS AND METHODS: Randomized and nonrandomized trials evaluating the possible impact of the prophylactic use of antibiotics in patients with mandible fractures were identified. Data were extracted on characteristics of studies and patients, including treatment, fracture location, time from injury to treatment, antibiotics used (type, route, dosage, duration), and complications (infection, malunion, reoperation). Randomized controlled trials (RCTs) were further evaluated for issues of reported methodological quality. RESULTS: There were 31 eligible studies (5,437 patients). Of these, 9 were prospective RCTs; the remaining 22 were retrospective case series. Information about the time between injury and definite treatment was provided by 10 studies (31%). The type of antibiotic used was not defined in 13 of 31 studies (42%). Half of the studies (15 of 31 [48%]) did not describe the route of administration and did not comment on the duration of the antibiotic course. The vast majority (23 of 31 [74%]) did not describe the dosage of the antibiotics used. Most of the RCTs were small, had not adequately described the mode of randomization, and did not present intention to-treat analyses. None of them presented power calculations or ensured allocation concealment. There was not a single mention about number needed to treat. The amount and quality of the available data precluded formal quantitative synthesis, despite scattered signals that prophylactic antibiotics may be better than nothing in preventing infection. CONCLUSION: The overall evidence to support the use of prophylactic antibiotics in mandible fractures is of poor quality. Large RCTs are needed to guide clinical practice. PMID- 20727643 TI - Use of bovine hydroxyapatite with or without biomembrane in sinus lift in rabbits: histopathologic analysis and immune expression of core binding factor 1 and vascular endothelium growth factor. AB - PURPOSE: Considering the clinical discussion on the necessity of using a barrier membrane in the osteotomy area of sinus lift procedures to prevent fibrous tissue formation in this area and as a physical limit, the aim of this study was to analyze and compare the use of bovine hydroxyapatite (HA) with and without a biologic membrane by histopathologic analysis and immune expression of core binding factor 1 and vascular endothelium growth factor in the sinus lift in rabbits. MATERIALS AND METHODS: Sixteen male rabbits underwent bilateral sinus lift procedures and were divided into 2 groups according to the sinus filling material: group 1 received bovine HA (Bio-Oss; Geistlich Pharma AG, Wohlhusen, Switzerland) and group 2 received bovine HA and a nonporous polytetrafluorethylene membrane. All groups were sacrificed after 7, 14, 30, and 60 days for microscopic, histomorphometric, and immunohistochemical analyses. RESULTS: Microscopic analysis showed a similar bone repair pattern between the tested groups. New bone formation, soft tissue, and the remaining material were analyzed by histomorphometric analysis. No statistically significant differences (P > .05) were detected between groups for all periods analyzed. In addition, no remarkable differences were noticed in core binding factor 1 or vascular endothelium growth factor immune expression. CONCLUSION: Taken together, these results show that using a biologic membrane does not improve bone repair induced by bovine HA, as shown by histopathologic and immunohistochemical analyses. PMID- 20727644 TI - Epithelial inclusion cyst after intermaxillary screw placement: a case report. PMID- 20727645 TI - Microsurgical repair of the peripheral trigeminal nerve after mandibular sagittal split ramus osteotomy. AB - PURPOSE: Injuries to the inferior alveolar nerve (IAN) and lingual nerves (LNs) have long been known complications of the mandibular sagittal split ramus osteotomy (SSRO). Most postoperative paresthesias resolve without treatment. However, microsurgical exploration of the nerve may be indicated in cases of significant persistent sensory dysfunction associated with observed or suspected localized IAN or LN injury. We report the demographics and outcome of microsurgical exploration and repair of peripheral branches of the trigeminal nerve injured because of the SSRO. MATERIALS AND METHODS: A retrospective chart review was completed on all patients who had microsurgical repair of peripheral trigeminal nerve injuries caused by mandibular SSRO and were operated on by the senior author (R.A.M.) between March 1986 and December 2005. A physical examination, including standardized neurosensory testing (NST) as described by Zuniga et al, was completed on each patient preoperatively. All patients were followed periodically after surgery for at least 1 year with NST repeated at each visit. NST results obtained at the last patient visit were used to determine the final level of recovery of sensory function. Sensory recovery was evaluated using guidelines established by the Medical Research Council scale. The following data were collected and analyzed: age of patient, gender, nerve injured, chief sensory complaint (numbness, pain, or both), duration (months) from injury to surgical intervention, intraoperative findings, surgical procedure, and neurosensory status at final evaluation. Given the retrospective nature of this study, the research was exempt from our institutional review board ethics committee. RESULTS: There were 54 (n = 54) patients (8 males and 46 females) with an average age of 36.9 years (range, 16 to 55 years) and a follow-up of at least 12 months. The most commonly injured/repaired nerve was the IAN (n = 39), followed by the LN (n = 14), and the long buccal nerve (n = 1). In 31 patients (57.4%), the chief sensory complaint was numbness, while 20 patients (37%) complained of pain and numbness, and 3 patients (5.5%) complained of pain without mention of numbness. The average time from nerve injury to repair was 9.4 months (range, 3 to 50 months). The most common intraoperative finding was a discontinuity defect (n = 18, 33.3%), followed by partial nerve severance (n = 15, 27.8%), neuroma-in continuity (n = 11, 20.3%), and compression injury (n = 10, 18.5%). The most frequent surgical procedure was autogenous nerve graft reconstruction of the IAN using the sural or great auricular nerve (n = 22, 40.7%), followed by excision of a neuroma with or without neurorrhaphy (n = 13, 24.1%). All the LN injuries (n = 14) were partial or complete severances, of which 2 were reconstructed with autogenous nerve grafts and the other 12 underwent neurorrhaphy. The long buccal nerve injury required excision of a proximal stump neuroma without neurorrhaphy. After a minimum of 1-year follow-up, NST showed that 8 nerves (14.8%) showed no sign of recovery; 19 nerves (35.2%) had regained "useful sensory function," and 27 nerves (50%) showed full recovery as described by the Medical Research Council scale. CONCLUSIONS: Microsurgical repair of the IAN or LN injured during the SSRO can be considered in patients with persistent, unacceptable sensory dysfunction in the distribution of the involved nerve. Modifications of surgical technique may be helpful in reducing the incidence of such injuries. Based on our experience, an algorithm for evaluation and treatment is presented. PMID- 20727646 TI - Facial surface changes after cleft alveolar bone grafting. AB - PURPOSE: The aim of this study was to assess the 3-dimensional facial surface changes after cleft alveolar bone grafting with digital surface photogrammetry. PATIENTS AND METHODS: In a prospective study, 22 patients with cleft lip and palate underwent alveolar bone grafting. Before the procedure and 6 weeks postoperatively and before the continuation of orthodontic treatment, 3 dimensional images were taken with digital surface photogrammetry. Seven standard craniofacial landmarks on the nose and the upper lip were identified. Their spatial change because of bone grafting was assessed. Statistical analysis was performed with analysis of variance and t test. RESULTS: A significant increase in anterior projection on the operative side (P < .05) was found for the labial insertion points of the alar base (subalare). No significant changes were detected for the position of the labial landmarks. CONCLUSION: Our results show 3 dimensionally that there is a positive influence of the alveolar bone graft on the projection of the alar base on the cleft side. PMID- 20727647 TI - Application of virtual surgical planning for total joint reconstruction with a stock alloplast system. PMID- 20727648 TI - A prospective study on the effect of modified alar cinch sutures and V-Y closure versus simple closing sutures on nasolabial changes after Le Fort I intrusion and advancement osteotomies. AB - PURPOSE: The purpose of this study was to determine whether a modified alar cinch suture and V-Y closure (mACVY) have a beneficial effect on labial form after Le Fort I intrusion and advancement osteotomies and whether they result in excessive upward nasal tip rotation. Both are possible effects compared with simple closing sutures (SCS). PATIENTS AND METHODS: A prospective study was carried out on 56 patients, 31 with mACVY and 25 with SCS. Lateral cephalograms taken immediately before and 18 months after operation were used, measuring horizontal and vertical changes of the following landmarks: anterior and posterior nasal spine, A-point, incision superior, pronasale, subnasale, labiale superior, and stomion superior, as well as angular changes of sella-nasion-pronasale, and changes in upper vermilion exposure. Statistical analysis was performed on intragroup, paired t test, and intergroup differences, unpaired t test (P < .05). RESULTS: The horizontal and vertical changes of labiale superior were significantly larger for mACVY versus SCS, and the angle sella-nasion-pronasale increased in mACVY versus SCS. However, no significant difference was found for vertical changes of the nasal tip. Upper vermilion exposure increased with mACVY versus SCS. CONCLUSION: mACVY has a beneficial effect on labial form, and excessive upward rotation of the nasal tip is prevented. PMID- 20727650 TI - Neuropsychological dissociations between motion and form perception suggest functional organization in extrastriate cortical regions in the human brain. AB - In this review of neuropsychological case studies, a number of dissociations are shown between different visual abilities including low-level motion perception, static form perception, form-from-motion perception and biological motion perception. These dissociations reveal counter-intuitive results. Specifically, higher level form-from-motion perception can persist despite deficits in low level motion perception and static form perception. To account for these dissociations, we present a model of functional organization and identify future directions for investigations of higher order form-from-motion perception. PMID- 20727649 TI - Continuous priming effects on discrete response choices. AB - When primed by backward-masked, target-like stimuli, discrete responses (e.g. button presses) to simple visual targets can be slower when prime and target match (compatible) than when they do not (incompatible). The current study investigated the nature of the stimulus-response mapping underlying this negative compatibility effect (NCE). Discrete left-right responses to arrow targets were primed with arrows oriented in one of 16 directions. Responses were either a standard button press or a 10 cm movement on a graphics tablet. Both tasks showed an identical NCE; importantly, reaction times in both tasks decreased smoothly as the angular distance between prime and target increased (i.e. as compatibility decreased), with the largest NCE evident between the extreme cases (prime-target distances of 0 degrees and 180 degrees ). Primes exerted an effect on the required response in proportion to the amount of overlap (reflecting population vector coding). The mapping between the priming stimulus and response is continuous, not categorical. PMID- 20727651 TI - Neural mechanisms involved in the oral representation of percussion music: an fMRI study. AB - Numerous music cultures use nonsense syllables to represent percussive sounds. Covert reciting of these syllable sequences along with percussion music aids active listeners in keeping track of music. Owing to the acoustic dissimilarity between the representative syllables and the referent percussive sounds, associative learning is necessary for the oral representation of percussion music. We used functional magnetic resonance imaging (fMRI) to explore the neural processes underlying oral rehearsals of music. There were four music conditions in the experiment: (1) passive listening to unlearned percussion music, (2) active listening to learned percussion music, (3) active listening to the syllable representation of (2), and (4) active listening to learned melodic music. Our results specified two neural substrates of the association mechanisms involved in the oral representation of percussion music. First, information integration of heard sounds and the auditory consequences of subvocal rehearsals may engage the right planum temporale during active listening to percussion music. Second, mapping heard sounds to articulatory and laryngeal gestures may engage the left middle premotor cortex. PMID- 20727652 TI - Temporal and spatial integration of face, object, and scene features in occipito temporal cortex. AB - In three neuroimaging experiments, face, novel object, and building stimuli were compared under conditions of restricted (aperture) viewing and normal (whole) viewing. Aperture viewing restricted the view to a single face/object feature at a time, with the subjects able to move the aperture continuously though time to reveal different features. An analysis of the proportion of time spent viewing different features showed stereotypical exploration patterns for face, object, and building stimuli, and suggested that subjects constrained their viewing to the features most relevant for recognition. Aperture viewing showed much longer response times than whole viewing, due to sequential exploration of the relevant isolated features. An analysis of BOLD activation revealed face-selective activation with both whole viewing and aperture viewing in the left and right fusiform face areas (FFA). Aperture viewing showed strong and sustained activation throughout exploration, suggesting that aperture viewing recruited similar processes as whole viewing, but for a longer time period. Face-selective recruitment of the FFA with aperture viewing suggests that the FFA is involved in the integration of isolated features for the purpose of recognition. PMID- 20727653 TI - Sex differences in aversive memory in rats: possible role of extinction and reactive emotional factors. AB - Studies usually show better spatial learning in males and stronger emotional memory in females. Spatial memory differences could relate to diverse strategies, while dissimilar stress reactions could cause emotional memory differences. We compared male and female rats in two emotional (classical emotional conditioning and aversive discrimination memory) and two emotionally "neutral" tasks: (1) plus maze discriminative avoidance, containing two open and two enclosed arms, one of which presenting aversive stimuli (light/noise). No differences were found in learning, retrieving, or basal emotional levels, while only male rats presented extinction of the task; (2) contextual fear conditioning--a cage was paired to mild foot shocks. Upon reexposure, freezing behavior was decreased in females; (3) spontaneous alternation--the animals were expected to alternate among the arms of a four-arm maze. No differences between genders were found and (4) open field habituation was addressed in an arena which the rats were allowed to explore for 10 min. Habituation was similar between genders. Differences were found only in tasks with strong emotional contexts, where different fear responses and stress effects could be determinant. The lack of extinction of discriminative avoidance by females points out to stronger consolidation and/or impaired extinction of aversive memories. PMID- 20727654 TI - Teaching CPR in secondary education: the opinions of head teachers in one region of the UK. PMID- 20727655 TI - Peri-resuscitation echocardiography: training the novice practitioner. AB - AIMS: Echocardiography performed in an ALS-compliant manner provides a tool whereby some of the potentially reversible causes of cardiac arrest can be diagnosed in real time by minimally trained practitioners. One of the major concerns this raises is how to deliver effective training to the required standard. The objective of this study was to determine the effectiveness of number of different educational methods used teach echocardiography to novices. This involved assessment of cognitive, psychomotor skills and affective aspects in five key areas. METHODS: The study population was a convenience sample from participants attending standardised structured one-day training courses in peri resuscitation echocardiography (n=204). Subjects were assessed for five learning outcomes including knowledge and image interpretation, practical performance of echocardiography including time taken to obtain a diagnostic view, integration into the ALS algorithm and overall compliance with established resuscitation guidelines. RESULTS: There was a significant improvement in knowledge and interpretation of echocardiographic images before and after completion of the one day course (pre 62%, post 78%, p<0.01). Skills acquisition resulted in 100% of participants being able to obtain a subcostal view of diagnostic quality by the end of the course, and 86% with a mean time to acquisition of <10s. On completion of the training programme, incorporation of echocardiography into current resuscitation practice did not compromise ALS-compliance. CONCLUSION: Novice echocardiographers can obtain knowledge and skills relevant to ALS-compliant peri resuscitation echocardiography using a range of educational techniques. In addition to the standard one-day training courses available, continued mentored practice and didactic adherence to ALS algorithms is required. PMID- 20727656 TI - Resuscitation training in developing countries: a systematic review. AB - OBJECTIVE: To evaluate whether the inclusion of any specific resuscitation training educational strategy in developing countries improves outcomes. METHODS: As part of the International Liaison Committee on Resuscitation evidence evaluation process, a systematic review of the literature was conducted. The Cochrane database of systematic reviews; Medline; Google Scholar and EmBASE were searched using multiple search strategies. RESULTS: Forty-four papers were relevant to review, including 38 studies that provided support for the use of resuscitation training programs in developing countries. All studies that examined self-efficacy (15 studies) and student satisfaction (8 studies) reported improvement. There was no consistent testing method for educational outcomes across studies and few studies examined both educational outcomes and patient outcome (1 of 15 self-efficacy, 0 of 18 cognitive knowledge, 0 of 8 psychomotor skills, 0 of 5 simulated operational performance). Fourteen of 15 studies that examined patient survival were either newborn or trauma resuscitation, 1 adult resuscitation, and none were in pediatric resuscitation. Increased patient survival after resuscitation training was variable, with an absolute risk reduction that ranged from 0% to 34%. CONCLUSIONS: Resuscitation training in developing countries was well received and viewed as valuable training by the students and local counterparts. Important student, training environment characteristics, educational outcomes and patient outcomes were inconsistently defined and reported. Institution of training in trauma and newborn resuscitation in developing countries has significantly reduced mortality, but this has not been demonstrated with other training programs. PMID- 20727657 TI - Improving cardiopulmonary resuscitation in the emergency department by real-time video recording and regular feedback learning. AB - AIM OF THE STUDY: Improvement in the quality of cardiopulmonary resuscitation (CPR) may improve the survival rate following cardiac arrest. The aims of our study were to describe how recording of CPR maneuvers performed in our emergency department with real-time video and regular feedback learning may improve CPR. METHODS: A digital video-recording system enabled us to record and analyze CPR procedures for adult patients from March 2007 to July 2008. Our resuscitation teams received video-recording feedback learning every week. RESULTS AND CONCLUSIONS: We analyzed 45 cases, divided into three groups of 15 consecutive patients. Instantaneous rates of chest compression showed variation with 75% exceeding 110 cpm. There was a significant difference in instantaneous rates among groups (135 [112-150] in group 1, 123 [110-136] in group 2 and 124 [111 137] cpm in group 3, P<0.001). Ratio of hands-off time to total manual compression time (%) significantly decreased over time (Spearman correlation= 0.30, P=0.04). There were significant differences in hands-off time per minute among the groups (11 [3-28], 6 [2-21] and 7 [2-19] s min(-1), P<0.001). There was a significant improvement in time delay to first chest compression (11 [5-50], 20 [8-68] and 0 [0-12] s, P=0.01), but not in time delay to first ventilation (91 [31-190], 65 [17-121] and 24 [9-64] s, P=0.08). Data are median [25-75% interquartile]. Regular feedback learning from real-time video recording may improve the quality of major CPR variables. PMID- 20727658 TI - Sunset of bag-valve mask and rise of supra-glottic airway ventilation devices during basic life support. PMID- 20727659 TI - Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. AB - BACKGROUND: The platelet inhibitor clopidogrel is administered to patients treated with therapeutic hypothermia following cardiac arrest due to acute coronary syndromes. Interactions with proton pump inhibitors and genetics are factors with a known potential to attenuate the platelet inhibition of clopidogrel. In patients treated with therapeutic hypothermia, reduced gastrointestinal function and hypothermia may also reduce the effect of clopidogrel. To investigate the net platelet inhibition of clopidogrel, we have measured the platelet reactivity index in patients treated with therapeutic hypothermia. METHODS AND RESULTS: Twenty-five Caucasian patients treated with clopidogrel and therapeutic hypothermia were prospectively included. Therapeutic hypothermia was defined as 33-34 degrees C and delivered for 24h. Clopidogrel loading doses (300-600 mg) were administered enterally the day of admission and followed by 75 mg daily. Blood samples were collected on day 1 (n=25) and day 3 (n=16). The samples were analysed for inhibition by clopidogrel with a vasodilator stimulated phosphoprotein phosphorylation kit. On day 1 and day 3, platelet reactivity index was 0.77+/-0.09 and 0.57+/-0.16, respectively. The number of patients with a satisfactory antiplatelet effect (defined as platelet reactivity index <0.5) were 0 (0%) and 5 (31%), respectively. CONCLUSION: In patients treated with therapeutic hypothermia after cardiac arrest, the effect of clopidogrel on platelets was virtually nonexistent on day 1 after administration, with some improvement on day 3. PMID- 20727660 TI - Pharmacotherapy and hospital admissions before out-of-hospital cardiac arrest: a nationwide study. AB - BACKGROUND: For out-of-hospital cardiac arrest (OHCA) to be predicted and prevented, it is imperative the healthcare system has access to those vulnerable before the event occurs. We aimed to determine the extent of contact to the healthcare system before OHCA. METHODS: All patients in Denmark with a registered OHCA June 1, 2001-December 31, 2005 were matched on age and sex with 10 random controls from the entire Danish population. We estimated the association with OHCA by conditional logistic regression analyses, and we determined the proportion of patients in contact with the healthcare system before OHCA from hospital admissions or claimed prescriptions. RESULTS: We identified 12,089 patients with an OHCA. Of these, 62% (7548) and 85% (10,312) were in contact with the healthcare system up to 30 days and 1 year before OHCA, respectively. Association with OHCA up to 30 days before the event pertained to myocardial infarction (odds ratio (OR)=6.4, 95% confidence interval (CI): 4.7-8.6)); heart failure (OR=5.1, CI: 4.1-6.3); ischemic heart disease (OR=1.9, CI: 1.6-2.4); and cardiac dysrhythmia (OR=1.8, CI: 1.4-2.2). Concomitant pharmacotherapy up to 30 days before OHCA with the strongest association was: corticosteroids (systemic) (OR=2.7, CI: 2.5-3.0), bronchial dilators (OR=2.5, CI: 2.3-2.7), anti-psychotic medication (OR=2.1, CI: 1.9-2.3), and digoxin (OR=2.1, CI: 2.0-2.3). Similar results were found for associations up to 1 year before OHCA. CONCLUSION: Contrary to general belief, the majority of OHCA patients are in contact with the healthcare system shortly before OHCA. PMID- 20727661 TI - Distribution of neuropathological lesions in pig brains after different durations of cardiac arrest. AB - AIM OF THE STUDY: To evaluate all brain regions reported to be selectively vulnerable to global ischaemia in a pig cardiac arrest model with different durations of no-flow by establishing a semi-quantitative brain histopathologic scoring system and to compare histological damage with neurological deficits. METHODS: In a prospective randomised laboratory investigation, 35 female Large White pigs weighing 35-45 kg underwent ventricular fibrillation cardiac arrest for 0, 7, 10 or 13 min. In the brains of all animals that survived until the final endpoint (72 h post-arrest), 22 distinct regions were evaluated on paraffin embedded sections in terms of type and extent of lesions. The results of the histological examination were compared to the results of a neurological outcome evaluation after 72 h. RESULTS: Significant differences were found in all cortex regions, the caudate nucleus and putamen, the hippocampal formation, the cerebellar cortex, and the thalamus between the ischaemic groups (7- and 10-min groups) and the control group (0-min group). No 13-min group animal survived. The main findings were neuronal necrosis and oedema. In animals from the 10-min group, many neurons were reabsorbed in the cerebral cortex, caudate nucleus and cerebellar granule cell layer. There was a highly significant correlation between histological damage and neurological deficits. CONCLUSIONS: The pattern of neuronal lesions in this pig model bear good resemblance to the pattern known in humans and other animal models. The amount of histological lesions in selectively vulnerable brain regions correlates to neurological outcome. PMID- 20727662 TI - Clinical significance of pmTOR expression in endometrioid endometrial carcinoma. AB - OBJECTIVE: Endometrial adenocarcinoma has been proposed, due to frequent activation of the PI3K/AKT pathway, as a candidate neoplasm for treatment with mTOR inhibitors. However, data on the expression of mTOR in endometrial cancer are lacking. STUDY DESIGN: We used immunohistochemistry to evaluate the expression of pmTOR in 62 endometrial cancer surgical specimens. RESULTS: The pmTOR protein was diffusely expressed in the cytoplasm of neoplastic epithelial cells, showing variable intensity. According to the chosen cutoff value, 34 (54.8%) out of 62 patients were scored as pmTOR-positive. pmTOR expression was significantly decreased in carcinomas with deep infiltration into the myometrium (P=.009), though it was not correlated with disease stage or lymph node metastasis. Univariate analysis showed that increased expression of pmTOR was significantly associated with better disease-free survival (P=.021). CONCLUSIONS: We show for the first time an association between pmTOR and better survival in patients with endometrial cancer. Future studies to stratify endometrial tumors by pmTOR status are needed. PMID- 20727663 TI - Deep rectal and parametrial infiltrating endometriosis with monolateral pudendal nerve involvement: case report and laparoscopic nerve-sparing approach. PMID- 20727664 TI - Bacterial source tracking guides management of boat head waste in a coastal resort area. AB - Fecal contamination of water bodies causes a public health problem and economic loss. To control such contamination management actions need to be guided by sound science. From 2007-2009 a study was undertaken to determine the sources of fecal bacteria contamination to the marine waters adjoining the Town of Wrightsville Beach, North Carolina, USA. The research effort included sampling for fecal coliform and Enterococcus bacteria, sampling for optical brighteners, dye studies, and use of molecular bacterial source tracking techniques including polymerase chain reaction (PCR) and terminal restriction fragment polymorphism (T RFLP) fingerprinting of the Bacteroides-Prevotella group. Of the 96 samples collected from nine locations during the study, the water contact standard for Enterococcus was exceeded on 13 occasions. The T-RFLP fingerprint analyses demonstrated that the most widespread source of fecal contamination was human, occurring in 38% of the samples, with secondary ruminant and avian sources also detected. Optical brightener concentrations were low, reflecting a lack of sewage line leakage or spills. A lack of sewer leaks and lack of septic systems in the town pointed toward discharge from boat heads into the marine waters as the major cause of fecal contamination; this was supported by dye studies. Based on these data, the Town initiated action to have the U.S. Environmental Protection Agency declare the coastal waters (out to 3 nautical miles), the nearby Atlantic Intracoastal Waterway and its tributaries a no-discharge zone (NDZ) to alleviate the human fecal pollution. The Town garnered supporting resolutions from other local communities who jointly petitioned the North Carolina Department of Environmental and Natural Resources. This State regulatory agency supported the local government resolutions and sent an application for an NDZ to the EPA in April 2009. The EPA concurred, and in February 2010 the coastal waters of New Hanover County, NC, became the first marine area on the U.S. eastern seaboard between Delaware and the Florida Keys to be declared a no-discharge zone. PMID- 20727665 TI - Impact of climatic and soil conditions on environmental fate of atrazine used under plantation forestry in Australia. AB - We studied the leaching and dissipation of atrazine (2-chloro-4-ethylamino-6 isopropylamino-1, 3, 5-s-triazine) and its two principal metabolites (desethylatrazine and desisopropylatrazine) for more than two years through soil profiles at five forestry sites across Australia (representing subtropical, temperate and Mediterranean climatic conditions with rainfall ranging from 780 to 1536 mm yr(-1)). Following atrazine applications at local label rates, soil cores were collected at regular intervals (up to depths of 90-150 cm), and the residues of the three compounds in soil were analysed in composite samples using liquid chromatography. Bromide was applied simultaneously with atrazine to follow the movement of the soil water. While bromide ion rapidly leached through the entire profile, in most cases the bulk of atrazine, desethylatrazine and desisopropylatrazine remained in the top 45 cm of the soil profile. However, a small fraction of residue moved deeper into the soil profile and at a subtropical site (Toolara) trace levels (ng L(-1)) of atrazine and one of its metabolites (DEA) were detected in perched groundwater located at a depth of 1.8 m. Data on the total residues of atrazine in soil profiles from all sites except the Tasmanian site fitted a first-order decay model. The half-life of atrazine in surface soils at the subtropical sites (Toolara and Imbil) ranged from 11 to 21 days. Four separate applications of atrazine at Toolara resulted in a narrow range of half-lives (16 +/- 3.6 days), confirming relatively rapid dissipation of atrazine under subtropical conditions (Queensland). In contrast, a prominent biphasic pattern of initial rapid loss followed by very slow phase of degradation of atrazine was observed under the colder temperate climate of Highclere (Tasmania). The data showed that while its 50% (DT(50)) loss occurred relatively rapidly (36 days), more than 10% of herbicide residue was still detectable in the profile even a year after application (DT(90) = 375 days). The rate of dissipation of atrazine at warm subtropical Queensland sites (Imbil and Toolara) was 2-3 times faster than sites located in colder climate of Tasmania. The marked contrast in DT(50) values between subtropical and temperate sites suggest that climatic conditions (soil temperature) is one of the key factors affecting atrazine dissipation. At the Tasmanian site, the combination of leaching of the herbicide in subsoil and slower microbial activity at cooler temperatures would have caused a longer persistence of atrazine. PMID- 20727666 TI - Prognostic and therapeutic impact of the histopathologic definition of parenchymal epithelial renal tumors. AB - CONTEXT: In the last few years, the treatment of renal cell carcinoma (RCC) has progressed significantly, and some histopathologic issues have become important for selection and follow-up after medical and surgical therapies. OBJECTIVE: The aim of this collaborative article is to review the most recent literature on the role of traditional histopathologic features obtained from renal core biopsy or nephrectomy specimens in the management of confined, locally advanced, and metastatic RCC. EVIDENCE ACQUISITION: A nonsystematic review of the literature was performed in April 2010 using the Medline database. Multiple free-text searches were performed for the following items: renal cell carcinoma, clear cell, papillary, chromophobe, histologic* subtype*, histotype*, nuclear grade*, necrosis, sarcomatoid differentiation, biopsy, molecular marker*, and cytogenetic marker*. A total of 2369 records were retrieved from Medline, and 263 full-text studies were considered and partially included in the present review. A panel of experts reached consensus on the main subheadings of this paper. EVIDENCE SYNTHESIS: Core needle biopsies can provide important information that is useful to avoid the overtreatment of benign tumors and to help plan watchful waiting or minimally invasive treatments in selected patients. Tumor histotype is fundamental in the pathologic report. In the context of integrated prognostic systems, the combination of the most important clinical and pathologic factors (TNM stage, Fuhrman nuclear grade, presence of necrosis, microvascular invasion, and sarcomatoid dedifferentiation) allows us to reach a high prognostic accuracy. These models can be used to select patients suitable for adjuvant protocols, to design an appropriate follow-up schedule, and to provide careful patient counseling. Molecular and cytogenetic markers should be further evaluated. CONCLUSIONS: The histopathologic definition of parenchymal epithelial renal tumors is fundamental to plan the management and follow-up of patients with locally confined, locally advanced, and metastatic RCC. PMID- 20727667 TI - Retroperitoneal laparoendoscopic single-site surgery: preliminary experience in kidney and ureteral indications. AB - The advantages of retroperitoneoscopic technique are well known. We decided to combine this access with the emerging laparoendoscopic single-site surgery (LESS) technique. We present our preliminary data on 11 renoureteral procedures and describe our retroperitoneoscopic LESS technique. As of March 2009, 10 patients were submitted to retroperitoneal LESS and divided into three groups: Group A, 3 patients underwent ureterolithotomy; Group B, 4 patients underwent renal cyst ablation; Group C, 4 patients underwent renal biopsy. Retroperitoneal access was obtained with an optical trocar. After retroperitoneal space blunt dissection, a multichannel port was placed. Standard and bent 5-mm instruments were used; we also used a 5-mm flexible laparoscope as a single procedure in group A. Ten of 11 procedures were completed without conversion; a single case in group A was converted to open surgery. Retroperitoneoscopic LESS is a safe and feasible procedure for renal biopsy and renal cyst ablation, with shorter convalescence time, less postoperative pain, and better cosmetic outcomes. LESS ureterolithotomy was more challenging for the lack of triangulation, resulting in a prolonged convalescence period. In addition, bent laparoscopic instruments are not suitable for retroperitoneal space; the multichannel port leaks carbon dioxide due to the flank position. Therefore LESS pelvic trainer practice is imperative in this case. PMID- 20727669 TI - Mitoxantrone for worsening multiple sclerosis: tolerability, toxicity, adherence and efficacy in the clinical setting. AB - BACKGROUND: The treatment of worsening Multiple Sclerosis (MS) remains challenging. Mitoxantrone, an anthracyclines, is approved as a treatment for worsening MS. However, systematic analyses of its tolerability and effectiveness outside of controlled trials are few. Certain advantages, including easy application and simple monitoring, need to be balanced against its toxicity. OBJECTIVE: To study efficacy, tolerability and feasibility of mitoxantrone treatment in a regular clinical setting. METHODS: Retrospective analysis of data from 96 MS patients with worsening MS before, during, and after mitoxantrone. Specifically, we addressed adherence and reasons for deviations from the intended treatment schedule regarding tolerability and safety, and consequences of deviations on clinical efficacy. RESULTS: Schedule deviations were frequent. Only a third of patients received the intended cumulative dose. Hematological toxicity was generally mild and transient. In 7 patients, treatment was withheld because of impact on ventricular ejection fraction, in the absence of clinical symptoms of cardiac failure. No malignancies were observed. With respect to clinical benefit, most patients remained stable and the relapse rate decreased with mitoxantrone initiation in both relapsing and secondary MS patients (p<0.0001). A possible modest non-significant dose-effect on annualized relapse rates was observed. CONCLUSION: Mitoxantrone may be considered for treatment of refractory MS. Poor tolerability impacted adherence but dose-limiting safety events were rare. Mitoxantrone needs to be carefully assessed in light of recent data on risk of cardiotoxicity and leukemia. PMID- 20727668 TI - Predictive and prognostic models in radical prostatectomy candidates: a critical analysis of the literature. AB - CONTEXT: Numerous predictive and prognostic tools have recently been developed for risk stratification of prostate cancer (PCa) patients who are candidates for or have been treated with radical prostatectomy (RP). OBJECTIVE: To critically review the currently available predictive and prognostic tools for RP patients and to describe the criteria that should be applied in selecting the most accurate and appropriate tool for a given clinical scenario. EVIDENCE ACQUISITION: A review of the literature was performed using the Medline, Scopus, and Web of Science databases. Relevant reports published between 1996 and January 2010 identified using the keywords prostate cancer, radical prostatectomy, predictive tools, predictive models, and nomograms were critically reviewed and summarised. EVIDENCE SYNTHESIS: We identified 16 predictive and 22 prognostic validated tools that address a variety of end points related to RP. The majority of tools are prediction models, while a few consist of risk-stratification schemes. Regardless of their format, the tools can be distinguished as preoperative or postoperative. Preoperative tools focus on either predicting pathologic tumour characteristics or assessing the probability of biochemical recurrence (BCR) after RP. Postoperative tools focus on cancer control outcomes (BCR, metastatic progression, PCa-specific mortality [PCSM], overall mortality). Finally, a novel category of tools focuses on functional outcomes. Prediction tools have shown better performance in outcome prediction than the opinions of expert clinicians. The use of these tools in clinical decision-making provides more accurate and highly reproducible estimates of the outcome of interest. Efforts are still needed to improve the available tools' accuracy and to provide more evidence to further justify their routine use in clinical practice. In addition, prediction tools should be externally validated in independent cohorts before they are applied to different patient populations. CONCLUSIONS: Predictive and prognostic tools represent valuable aids that are meant to consistently and accurately provide most evidence-based estimates of the end points of interest. More accurate, flexible, and easily accessible tools are needed to simplify the practical task of prediction. PMID- 20727670 TI - Bilateral ethmoidal dural arteriovenous fistula: unexpected surgical diagnosis. AB - Dural arteriovenous fistulae (DAVFs) are infrequent lesions, the most common locations of which are the cavernous, sigmoid and transverse sinuses. The cribiform plate is one of the less frequent sites for DAVFs, where they entail a high hemorrhage risk. Feeding arteries for ethmoidal DAVFs can be uni- or bilateral. However, the draining fistulous system has classically been described as unilateral. The authors report the second case in literature of bilateral ethmoidal DAVF, which is defined as that with bilateral draining veins. The present case was diagnosed only after surgical exploration of both cribiform plates. No preoperative radiological test could detect the presence of a bilateral venous draining system from the ethmoidal DAVF. Possible reasons for that lack of presurgical diagnosis are discussed. Bilateral surgical exploration of the anterior cranial fossa is recommended when dealing with ethmoidal DAVFs, even when they seem to be unilateral on preoperative studies. PMID- 20727671 TI - Surgery for carpal tunnel syndrome under antiplatelet therapy. AB - OBJECTIVE: Antiplatelet therapy is often instituted after cardiovascular or neurological ischemic events. In general, discontinuation of the antiplatelet medication for several days is warranted previous to surgery. However, discontinuation can lead to ischemic events. For some forms of surgery, the risks of an ischemic event, and especially, its consequences do not outweigh the benefit of discontinuation of the antiplatelet therapy. Retrospective analysis was done of a cohort of patients treated for carpal tunnel syndrome with special emphasis on postoperative hemorrhage in combination with antiplatelet medication. METHODS: Retrospective analysis of cohort consisting of 362 consecutive patients treated for carpal tunnel syndrome in the Neurosurgical Centre, Nijmegen was done. RESULTS: In 362 patients 423 operations on carpal tunnel release were done. Thirty-one patients were on antiplatelet therapy, of which 6 did not discontinue the medication before surgery. The remaining patients stopped at least seven days before surgery. A postoperative hemorrhage did not occur in any of the 423 operations. CONCLUSION: There seems no reasonable evidence that discontinuation of aspirin for carpal tunnel syndrome is justified. Bleeding complications are considered rare, moreover the impact of an ischemic cardiovascular or a cerebral event would be far more severe than that of postoperative hemorrhage in the wrist. PMID- 20727672 TI - Non-founder BRCA1 mutations in Russian breast cancer patients. AB - A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C>G, 5214C>T, 5236G>A, 5460G>T, 5622C>T) and one variant of an unknown significance (4885G>A). The pathogenic role of the 5236G>A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1-2 and 3-7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia. PMID- 20727673 TI - RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase. AB - We evaluated RAD001, an inhibitor of the mammalian target of rapamycin (mTOR) in human gastric cancer cell lines and determined the molecular mechanisms. RAD001 has marked growth inhibitory activity against the SNU-1 and SNU-216 cells. It inhibited phosphorylation of mTOR and S6K, and induced G1 cell cycle arrest. Synergistic growth-inhibitory effects in combination with 5-fluorouracil (5-FU) was identified. Furthermore, RAD001 conferred sensitivity to 5-FU-resistant cell lines by downregulating thymidylate synthase (TS). In conclusion, RAD001 showed growth inhibitory activity against gastric cancer cells and acted synergistically with cytotoxic agents such as 5-FU by downregulating TS. PMID- 20727674 TI - A combinatorial approach to screening carbon based materials for respiratory protection. AB - A combinatorial materials science approach for the discovery of an impregnated activated carbon that can adsorb a wide variety of toxic gases (i.e. a multi-gas carbon) has been developed. This approach presently allows for the parallel preparation and investigation of 64-100 IAC samples at once increasing the rate of discovery of viable multi-gas carbons. Multi-gas carbons were prepared using a solutions handling robot and screened gravimetrically for their effectiveness as gas adsorbents. The method was validated using known gas adsorbent materials such as ZnCl(2), K(2)CO(3) and CuO-impregnated carbons. The calculated adsorption capacities and stoichiometric ratios of reactions for these known gas adsorbent materials, when evaluated using the combinatorial approach, was comparable to the values obtained using traditional methods of analysis. A library of samples prepared by combining various amounts of CuO and ZnO impregnants showed the expected decreasing trend in the calculated stoichiometric ratio of reaction with respect to increasing amount of impregnants added. The method is now ready to use to explore new systems of impregnated activated carbons. PMID- 20727675 TI - Identification of wastewater bacteria involved in the degradation of triclocarban and its non-chlorinated congener. AB - Triclocarban (TCC) is an antimicrobial additive of personal care products that is only partially degraded during wastewater treatment. Bacteria responsible for its transformation are unknown. We obtained wastewater bacteria capable of using as the sole carbon source TCC or its non-chlorinated analog, carbanilide (NCC). Enrichments established using activated sludge amended with TCC and NCC, respectively, were maintained for 1 year through successive transfers. Enrichments displayed exponential growth after 2 weeks, reaching stationary phase after 1 month. The NCC enrichment was shown to accumulate aniline. Denaturing gradient gel electrophoresis of amplified 16S rRNA genes indicated markedly reduced community richness compared to the inoculum and a single, prominent taxonomic unit emerged in both chlorinated and non-chlorinated carbanilide enrichment cultures. Cloned 16S rRNA genes showed both enrichments were dominated by a single genotype related to uncharacterized organisms within the Alcaligenaceae. Of ~30 sequences from each enrichment, no other organisms were detected in the TCC enrichment while, a small, flanking community of alpha proteobacteria was detected in the NCC enrichment. Study results demonstrate that growth of wastewater bacteria on TCC and its lower chlorinated analog can be linked to bacteria within the family Alcaligenaceae. These organisms are promising agents for the bioremediation of hazardous phenylurea pollutants. PMID- 20727676 TI - Kinetic and equilibrium studies of cesium adsorption on ceiling tiles from aqueous solutions. AB - A series of experiments were performed to quantify the adsorption of cesium on ceiling tiles as a representative of urban construction materials. Adsorption was carried out from solutions to mimic wet environmental conditions. Non-radioactive cesium chloride was used as a surrogate of the radioactive (137)Cs. The experiments were performed in the range of initial cesium concentrations of 0.114 23.9 mg L(-1) at room temperature (21 degrees C) around three weeks. Solution samples were taken after set periods of time and analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The quantity of adsorbed Cs was calculated by mass balance as a function of time. Two kinetic and three equilibrium models were employed to interpret the test results. Determination of kinetic parameters for adsorption was carried out using the first-order reaction model and the intra particle diffusion model. Adsorption equilibrium was studied using Langmuir, Freundlich and three-parameter Langmuir-Freundlich adsorption isotherm models. A satisfactory correlation between the experimental and the predicted values was observed. PMID- 20727677 TI - Opioids for workers with an acute episode of low-back pain. PMID- 20727678 TI - Differential distribution of activated spinal neurons containing glycine and/or GABA and expressing c-fos in acute and chronic pain models. AB - The inhibitory transmitters GABA and glycine play an important role in modulating pain transmission, both in normal and in pathological situations. In the present study we have combined in situ hybridization for identifying spinal neurons that use the transmitter(s) glycine and/or GABA (Gly/GABA neurons) with immunohistochemistry for c-fos, a marker for neuronal activation. This procedure was used with acute pain models induced by the injection of capsaicin or formalin; and chronic pain models using Complete Freund's Adjuvant (CFA, chronic inflammation), and the spared nerve injury (SNI) model (neuropathic pain). In all models Gly/GABA neurons were activated as indicated by their expression of c-fos. The pattern of Gly/GABA neuronal activation was different for every model, both anatomically and quantitatively. However, the averaged percentage of activated neurons that were Gly/GABA in the chronic phase (>=20h survival, 46%) was significantly higher than in the acute phase (<=2h survival, 34%). In addition, the total numbers of activated Gly/GABA neurons were similar in both phases, showing that the activation of non-Gly/GABA (presumed excitatory) neurons in the chronic phase decreased. Finally, morphine application equally decreased the total number of activated neurons and activated Gly/GABA neurons. This showed that morphine did not specifically activate Gly/GABA neurons to achieve nociceptive inhibition. The present study shows an increased activity of Gly/GABA neurons in acute and chronic models. This mechanism, together with mechanisms that antagonize the effects of GABA and glycine at the receptor level, may determine the sensitivity of our pain system during health and disease. PMID- 20727679 TI - Psychological treatments for fibromyalgia: a meta-analysis. AB - The aims of the present analysis were to investigate the short- and long-term efficacies and treatment moderators of psychological interventions for fibromyalgia. A literature search using PubMed, PsychINFO, the Cochrane Library, and manual searches identified 23 eligible studies including 30 psychological treatment conditions and 1396 patients. Meta-analytic integration resulted in a significant but small effect size for short-term pain reduction (Hedges's g=0.37, 95% confidence interval (CI): 0.27-0.48) and a small-to-medium effect size for long-term pain reduction over an average follow-up phase of 7.4 months (Hedges's g=0.47, 95% CI: 0.3-0.65) for any psychological intervention. Psychological treatments also proved effective in reducing sleep problems (Hedges's g=0.46, 95% CI: 0.28-0.64), depression (Hedges's g=0.33, 95% CI: 0.20-0.45), functional status (Hedges's g=0.42, 95% CI: 0.25-0.58), and catastrophizing (Hedges's g=0.33, 95% CI: 0.17-0.49). These effects remained stable at follow-up. Moderator analyses revealed cognitive-behavioral treatment to be significantly better than other psychological treatments in short-term pain reduction (Hedges's g=0.60, 95% CI: 0.46-0.76). Higher treatment dose was associated with better outcome. Publication-bias analyses demonstrated that the effect sizes were robust. The results suggest that the effects of psychological treatments for fibromyalgia are relatively small but robust and comparable to those reported for other pain and drug treatments used for this disorder. Cognitive-behavioral therapy was associated with the greatest effect sizes. PMID- 20727680 TI - Primary pulmonary adenocarcinoma with enteric differentiation resembling metastatic colorectal carcinoma: a report of the second case negative for cytokeratin 7. AB - We report the case of a 51-year-old woman with pulmonary adenocarcinoma with enteric differentiation (PAED) that is indistinguishable from metastatic colorectal carcinoma by immunohistochemistry as well as histology. A chest computed tomography scan revealed a 1cm nodule in the right upper lobe and a 3cm mass in the left lower lobe. Initial examination showed no evidence of any other tumor. She underwent partial resection of the right upper lobe and left lower lobectomy. Histopathological examination revealed that both tumors were composed of medium to large complex glands with central necrosis. The tumor cells were cuboidal to tall columnar with eosinophilc cytoplasm, oval nuclei, and brush border. Immunohistochemical study yielded the following results: tumor cells were diffusely positive for cytokeratin (CK) 20 and CDX-2, and negative for CK7, thyroid transcription factor-1, and Napsin A. MUC2 was partially observed, while MUC5AC was not detected. These findings were strongly indicative of metastatic colorectal carcinoma. However, no primary colorectal cancer was detected in any clinical examination, including fluorine 18-labeled fluorodeoxyglucose-positron emission tomography scan and video capsule endoscopy, and she has not presented with any characteristic symptoms at any follow-up to date, approximately 4 years after operation. From all features, the final diagnosis was primary PAED, suggestive of multifocal primary lung cancer. So far, only 1 case of CK7-negative PAED has been reported. This is the second case of primary PAED resembling metastatic colorectal cancer morphologically and immunohistologically. PMID- 20727681 TI - [Pelvic organ prolapse-surgical technique (POP-ST): a classification of techniques of mesh augmented repairs for pelvic organ prolapse by vaginal route]. AB - OBJECTIVE: The aim of this study was to propose a classification of surgical techniques for treatment of prolapse by vaginal route using prosthetic reinforcements and to relate the evaluation of surgeons involved in the care of surgical patients. METHODS: A literature review was conducted searching for all articles relating novel technique of surgical management of patients with use of prosthetic reinforcements vaginally. The classification was made from descriptions found and then assessed by questionnaires filled out by surgeons. RESULTS: The classification takes account of all the techniques available today and can integrate new. Among the surgeons, 56.5% (13/23) found that the POP-ST is adapted to reflect the reality and variety of techniques and 60.8% (14/23) will be ready for daily use. CONCLUSION: A classification covering all the techniques put them at risk of a final tool too complex for routine use. The simplification would make it more usable but limited the comprehensiveness and evolutionary. Only 23 surgeons returned the questionnaire. A larger sample would be desirable. The POP-ST is the first classification of this type. We believe that it would assess the new techniques to better understand the complications. PMID- 20727683 TI - A peer-led mobile outreach program and increased utilization of detoxification and residential drug treatment among female sex workers who use drugs in a Canadian setting. AB - BACKGROUND: The objectives of this study were to examine the determinants of using a peer-led mobile outreach program (the Mobile Access Project [MAP]) among a sample of street-based female sex workers (FSWs) who use drugs in an urban Canadian setting and evaluate the relationship between program exposure and utilizing addiction treatment services. METHODS: A detailed questionnaire was administered at baseline and bi-annual follow-up visits over 18 months (2006 2008) to 242 FSWs in Vancouver, Canada. We used bivariate and multivariate logistic regression with generalized estimating equations for both objectives, reporting unadjusted and adjusted odds ratios (AOR) with 95% confidence intervals (CIs). RESULTS: Over 18 months, 42.2% (202) reports of peer-led mobile outreach program use were made. High-risk women, including those servicing a higher weekly client volume (10+ compared to <10; AOR: 1.7, 95%CIs: 1.1-2.6) and those soliciting clients in deserted, isolated settings (AOR: 1.7, 95%CIs: 1.1-2.7) were more likely to use the program. In total, 9.4% (45) reports of using inpatient addiction treatment services were made (7.5% detoxification; 4.0% residential drug treatment), and 33.6% (161) using outpatient treatment (28.8% methadone; 9.6% alcohol/drug counsellor). Women who used the peer-led mobile outreach were more likely to use inpatient addiction treatment (AOR: 4.2, 95%CIs: 2.1-8.1), even after adjusting for drug use, environmental-structural factors, and outpatient drug treatment. DISCUSSION: Our findings demonstrate that FSWs at higher risk for sexually transmitted infections and violence are more likely to access this peer-led mobile outreach program and suggest that the program plays a critical role in facilitating utilization of detoxification and residential drug treatment. PMID- 20727682 TI - Onset and course of alcoholism over 25 years in middle class men. AB - BACKGROUND: Patterns of drinking and alcohol problems change with age. However, few studies use multiple data points and detailed history spanning early adulthood to middle age. This study reports such data from 373 men in the San Diego Prospective Study. METHODS: Data were generated at baseline (T1) at ~age 20, and through face-to-face followup interviews ~every 5 years in >90% of these eligible Caucasian and relatively higher educated men. Subjects were placed into 4 groups regarding their course: 62.5% with no alcohol use disorder (AUD); 17.2% with AUD onset =age 30 and no recovery; and 13.7% with AUD onset 5 years before the 25-year followup. RESULTS: On a univariate level, low level of response (LR) to alcohol, family history of AUDs, and higher Novelty Seeking at ~age 20 predicted AUDs with onset before age 30 (mean age~25), but among these only LR predicted later onset (mean age 38) as well. Additional predictors of AUDs included demography (lower education), and greater involvement with alcohol, drugs, and nicotine prior to T1. Sustained remission from AUDs among alcoholics was predicted by lower T1 and T10 drinking frequencies, and being separated or divorced at T10, along with a trend for higher Reward Dependence. CONCLUSION: These data indicate that information available in ages of the late teens to early twenties can help predict the future onset and course of AUDs, and underscore the importance of longitudinal studies in substance use disorders. PMID- 20727684 TI - Policing and risk of overdose mortality in urban neighborhoods. AB - BACKGROUND: Accidental drug overdose is a major cause of mortality among drug users. Fears of police arrest may deter witnesses of drug overdose from calling for medical help and may be a determinant of drug overdose mortality. To our knowledge, no studies have empirically assessed the relation between levels of policing and drug overdose mortality. We hypothesized that levels of police activity, congruent with fears of police arrest, are positively associated with drug overdose mortality. METHODS: We assembled cross-sectional time-series data for 74 New York City (NYC) police precincts over the period 1990-1999 using data collected from the Office of the Chief Medical Examiner of NYC, the NYC Police Department, and the US Census Bureau. Misdemeanor arrest rate-reflecting police activity-was our primary independent variable of interest, and overdose rate our primary dependent variable of interest. RESULTS: The mean overdose rate per 100,000 among police precincts in NYC between 1990 and 1999 was 10.8 (standard deviation=10.0). In a Bayesian hierarchical model that included random spatial and temporal effects and a space-time interaction, the misdemeanor arrest rate per 1000 was associated with higher overdose mortality (posterior median=0.003, 95% credible interval=0.001, 0.005) after adjustment for overall drug use in the precinct and demographic characteristics. CONCLUSIONS: Levels of police activity in a precinct are associated with accidental drug overdose mortality. Future research should examine aspects of police-community interactions that contribute to higher overdose mortality. PMID- 20727685 TI - Non-human primates in outdoor enclosures: risk for infection with rodent-borne hantaviruses. AB - Different species of non-human primates have been exploited as animal disease models for human hantavirus infections. To study the potential risk of natural hantavirus infection of non-human primates, we investigated serum samples from non-human primates of three species living in outdoor enclosures of the German Primate Center (GPC), Gottingen, located in a hantavirus endemic region of central Germany. For that purpose we used serological assays based on recombinant antigens of the bank vole (Myodes glareolus) transmitted Puumala virus (PUUV) and the common and field vole (Microtus arvalis, Microtus agrestis) associated Tula virus (TULV) which are both broadly geographically distributed in Germany. In 24 out of 251 (9.6%) monkey sera collected in 2006 PUUV- and/or TULV-reactive immunoglobulin G (IgG) antibodies were detected. Investigation of follow-up sera from 13 animals confirmed for two animals a seroconversion due to hantavirus exposure at the GPC. To prove the origin of the infection, wild rodents from the surrounding regions were analyzed by hantavirus-specific reverse transcriptase PCR analysis. In 6 of the 73 investigated bank voles and 3 of the 19 investigated Microtus spp. PUUV- and TULV-specific nucleic acid sequences, respectively, were detected. In conclusion, our investigations demonstrate for the first time natural infections of non-human primates in outdoor enclosures in Germany. These findings highlight the importance of hantavirus surveillance in those primate housings and corresponding preventive measures against wild rodents, particularly in hantavirus endemic regions. PMID- 20727686 TI - Comparison of sampling methods used for MRSA-classification of herds with breeding pigs. AB - Since the first report on methicillin resistant Staphylococcus aureus (MRSA) CC398 in pigs, several countries have determined the prevalence of MRSA-positive pig herds using different sampling and laboratory techniques. The objective of the study was to compare three sampling methods for MRSA-classification of herds. Therefore, nasal swabs of pigs and environmental wipes were collected from 147 herds with breeding pigs. Per herd, laboratory examination was done on 10 pools of 6 nasal swabs (NASAL), 5 single environmental wipes (ENVSINGLE) and one pool of 5 environmental wipes (ENVPOOL). Large differences in apparent prevalence of MRSA-positive herds between methods were found: 19.1% for ENVPOOL, 53.1% for ENVSINGLE, and 70.8% for NASAL. Pairwise comparisons of methods resulted in relative sensitivities of 26.9% (ENVPOOL vs. NASAL), 34.6% (ENVPOOL vs. ENVSINGLE), and 72.1% (ENVSINGLE vs. NASAL) with relative specificities of respectively 100%, 98.6% and 93.0%. Cohen's kappa was respectively 0.18, 0.32 and 0.55, thus varying between very poor and moderate agreement. Examination of environmental wipes is an easy and non-invasive method to classify herds for MRSA. The number of environmental wipes needed depends on e.g. required detection limits and within-herd prevalence. In low prevalent herds (e.g. herds with <3 positive pools of nasal swabs), 25 single environmental wipes are required to be 90% sure that MRSA is detected at a detection limit similar to analyzing 10 pools of nasal swabs. Individual analysis of environmental wipes is highly recommended, as pooling 5 environmental samples resulted in a substantial reduction of the apparent prevalence. PMID- 20727687 TI - Mixed infections of Corynebacterium pseudotuberculosis and non-tuberculous mycobacteria in South African antelopes presenting with tuberculosis-like lesions. AB - Routine meat inspection of antelope carcasses from a South African game reserve revealed a high prevalence of tuberculosis-like lesions. This study aimed to identify the causative agent of this disease and to describe its pathological features. In total, 139 antelopes were randomly harvested from the game reserve and subjected to meat inspection. Of these animals, 46 (33%) showed gross visible, tuberculosis-like lesions. Histopathological examination revealed the presence of encapsulated necrogranulomas in organs and/or lymph nodes of 22 of 27 animals tested. Tissue samples from lesions were processed for both non-selective bacterial culture and mycobacterial culture following decontamination. In non selective cultures of lesions from 25 of 31 animals tested, Corynebacterium pseudotuberculosis was detected. Isolation of C. pseudotuberculosis was closely associated with the presence of necrogranulomas. In mycobacterial cultures of lesions from 9 of 41 animals tested, different species of non-tuberculous mycobacteria (NTMs) were detected. In 5 instances, depending on the culture procedure that was applied, either C. pseudotuberculosis or NTMs were isolated from the same tissue sample. Our results suggest that the disease has been caused by infections with C. pseudotuberculosis. In sub-Saharan Africa, the role of pathogens other than Mycobacterium bovis may be underestimated in causing tuberculosis-like lesions. In cases where potentially pathogenic NTMs are isolated from mycobacterial cultures of tuberculosis-like lesions, the non-use of additional non-selective culture techniques could lead to misinterpretations of the diagnostic test results. PMID- 20727688 TI - Soluble receptor for advanced glycation end products (sRAGE) in tracheobronchial aspirate fluid and cord blood of very low birth weight infants with chorioamnionitis and funisitis. AB - BACKGROUND: A systemic fetal inflammatory response, reflected by histological funisitis is associated with pulmonary morbidity and increased mortality after premature birth. The receptor for advanced glycation end products (RAGE) is a membrane-bound multiligand receptor with a key role in inflammation. Soluble RAGE (sRAGE) is created by alternative mRNA splicing or shedding of the receptor's extracellular domain and can inhibit RAGE-activation. AIMS: To assess the association of funisitis with airway and systemic concentrations of sRAGE in very premature infants. METHODS: Forty-two ventilated infants (gestational age: 27.4 +/- 1.8weeks, birth weight: 1017 +/- 229 g [mean +/- SD]) were studied. sRAGE concentrations were measured in tracheobronchial aspirate fluid (TAF) on days of life 1, 3, 5, 7 and 10 and in umbilical cord serum of 28 infants by ELISA. The secretory component for IgA (SC) served as reference protein in TAF. Placental tissue, membranes and umbilical cords were examined microscopically to distinguish three groups: chorioamnionitis (n=9), funisitis (n=17) and controls (n=16). RESULTS: The funisitis group had lower sRAGE concentrations than both other groups in cord blood serum (median: 0.52 ng/ml [25th-75th centile: 0.32 0.91]; control, 1.72 [1.02-2.69]; chorioamnionitis, 1.44 [0.92-1.63], p<0.01) and TAF on day 1 (290 ng/ngSC [140-400]; control, 2750 [1470-28920]; chorioamnionitis, 2150 [1220-7140], p<0.01). sRAGE in TAF remained lower in the funisitis than in the chorioamnionitis group on days 3 and 10, p<0.01 respectively. CONCLUSIONS: Decreased sRAGE in airways and circulation after funisitis may contribute to an imbalance between pro- and anti-inflammatory factors priming very premature infants for pulmonary injury and increasing the risk of adverse outcome. PMID- 20727689 TI - Female maturation, egg characteristics and fatty acids profile in the seahorse Hippocampus guttulatus. AB - Knowledge of the biology and ecology of seahorses (Hippocampus spp.) is scarce, but has been increasing in recent years due to their conservation status. Captivity breeding programmes can be a valuable source of information on the reproductive biology of seahorses. A captive broodstock of Hippocampus guttulatus Cuvier 1829 was established in 2006 and kept under natural-like photoperiod and temperature. Female maturation was studied during the whole reproductive season in 2007. Most egg clutches were released from May (17 degrees C; 15L:9D) to October (18 degrees C; 13L:11D), with peak releases occurring in June-August (20 degrees C; 16L:8D-14L:10D). Throughout the study, four egg morphotypes were found; two regression equations were proposed for estimating egg/yolk volume based on measurements of egg and yolk biometrics. Female weight was positively correlated with yolk volume/egg volume ratio (Y(v)/E(v)) (r(s)=0.523, n=21, P<0.05) but not with E(v) or Y(v). Egg dry weight (567+/-141MUg) was correlated with Y(v) (r(s)=0.384, n=31, P<0.05). Mean clutch size and clutch biomass were 242+/-142 eggs and 137+/-87mg dry weight, respectively. Clutch size was positively correlated to female weight (r(s)=0.479, n=25, P<0.05). Inter-clutch intervals (days) were affected by temperature ( degrees C) as described by the following equation: Interval=357.55e(-0.1283 Temp). Estimated inter-clutch intervals at 16, 18 and 20 degrees C were 45.9, 35.5 and 27.5 days, respectively. Egg total lipids accounted for 31.9+/-3.1% dry weight. Absolute lipid content in eggs was correlated with egg dry weight (r(s)=0.907, n=41, P<0.001) and Y(v) (r(s)=0.384, n=41, P<0.5). In decreasing order of relative percentage, the most important fatty acids, were 18:1n9, 16:0, 18:2n6, 20:5n3, 18:0 and 22:6n-3. The level of n-3 HUFA was 18.5+/-0.7% (38.4+/-3.3mg/g dry weight). The profile of fatty acids in eggs resembled that displayed by the broodstock diet (enriched adult Artemia). PMID- 20727690 TI - Effect of live weight development and reproduction in first parity on reproductive performance of second parity sows. AB - An impaired reproductive performance in second parity compared to first parity sows, decreases reproductive efficiency and, perhaps, longevity of sows. This study aims to quantify the effect of live weight development and reproduction in first parity on reproductive performance of second parity sows, i.e. pregnancy rate as well as litter size. Measures of sow development (live weight at first insemination, farrowing and weaning) and reproduction (total number of piglets born, weaning to insemination interval, lactation period, number piglets weaned) were recorded on two experimental farms. Logistic regression analysis was done for the binary outcome 'non-pregnancy from first insemination after first weaning' (yes/no). General linear regression analysis was used for litter size from 1st insemination in second parity. Repeat breeders were omitted from the analysis on litter size in second parity, since a prolonged period between weaning and conception can positively influence litter size. Farms differed significantly in measures of sow live weight development and therefore data were analyzed per farm. Compared with gilts from farm A, gilts from farm B were older and heavier at: first insemination (275+/-0.9 days and 145+/-0.8kg for farm B vs. 230+/-0.6 days and 124+/-0.5kg for farm A), first farrowing (resp. 189+/-1.1 vs. 181+/-0.9kg) and first weaning (resp. 165+/-1.1 vs. 156+/-0.9kg). Weight loss during pregnancy was similar for both farms (resp. 24.9+/-0.7 and 23.7+/-1.0kg). Gilts from farm A, however, gained more weight in the period between first insemination and first weaning compared with gilts from farm B (resp. 36.1+/-0.8 and 20.9+/-1.3kg). Non-pregnancy in second parity was 11% for farm A and 15% for farm B. Litter sizes in first and second parity were, respectively, 10.7+/-0.1 and 11.6+/-0.2 for farm A and 11.8+/-0.1 and 11.6+/-0.1 for farm B. Variables associated with non-pregnancy and litter size in second parity differed between farms. On farm A, mainly sow live weight development was associated with non pregnancy and litter size in second parity, whilst on farm B variables like total number born in 1st parity and sow line, were associated with non-pregnancy and litter size in second parity. On both farms, higher weight gain from first insemination to first weaning was associated with a decrease in non-pregnancy (odds ratio 0.7 per 10kg for farm A and 0.8 per 10kg for farm B) and on farm A with higher litter size in second parity (beta=0.42 per 10kg weight gain). Results show that sow live weight development affects reproductive performance in second parity, especially on farm A where gilts are relatively light or young at first insemination. Management of these animals should aim to optimize development at first insemination and to increase growth between first insemination and first weaning in order to optimize production in second parity. PMID- 20727691 TI - Subclinical endometritis and its impact on reproductive performance in grazing dairy cattle in Argentina. AB - Recently several studies have reported that subclinical endometritis impairs reproductive performance in cattle. Most of the studies were conducted in western industrialized countries under intensive housing conditions. The objective of the present study was to determine the prevalence of subclinical endometritis and its impact on reproductive performance outcomes in clinically healthy postpartum dairy cows in a pasture-based extensive dairy farming system in Argentina. Lactating Holstein cows (n=201) at 18-38 days postpartum (dpp) from three commercial dairy farms in Buenos Aires Province, Argentina, were examined for signs of clinical endometritis by external inspection and manual vaginal examination. Only cows without signs of clinical endometritis i.e. no vaginal discharge were enrolled in this study and examined for subclinical endometritis using the cytobrush technique. Cows with >=5% polymorphonuclear cells (PMN) in the cytological sample were regarded as affected by subclinical endometritis. All cows were reexamined 14 days later following the same examination protocol. Prevalence of subclinical endometritis 18-38dpp was 38% and decreased to 19% at reexamination. The proportion of cows pregnant at first service was 29% and proportion of cows pregnant at 360pp was 73% and 75% in cows with subclinical endometritis and those without, respectively. The probability of conception at first service, hazards of insemination and pregnancy, respectively, were not affected by subclinical endometritis. Primiparous cows had a greater chance for insemination (HR=0.66; 95% CI=0.47-0.92) and pregnancy (HR=0.63; 95% CI=0.45 0.90) than multiparous cows. In conclusion subclinical endometritis did not affect reproductive performance outcomes in a pasture-based, extensive dairy farming system in Argentina. PMID- 20727692 TI - Effects of in ovo injecting disaccharides and alanyl-glutamine dipeptide on the energy status in duck embryos and neonates. AB - This experiment tested the hypothesis that administering additional available nutrients to duck embryos would enhance the glucose store and improve the body growth of ducks. A total of 520 duck eggs of 21 days' incubation containing viable embryos were used in the present study and randomly divided into four treatments. At 23 days of incubation (23E), three groups of eggs were injected with the following solution: (1) sucrose and maltose (DS); (2) l-alanyl-l glutamine (Ala-Gln); (3) sucrose, maltose and Ala-Gln (DS+Ala-Gln); the remaining groups served as non-injected control. DS and Ala-Gln injection significantly increased the plasma glucose concentration at hatch and 3 days post-hatch (P<0.05). Compared with control, the liver glycogen content in the DS group was elevated by 56% at 25 days' incubation (25E) and by 45% at hatch, respectively (P<0.05). At 25E, the pectoral glycogen content was increased by 109% in the Ala Gln group and by 67% in the DS+Ala-Gln group, respectively, when compared with non-injected control. There was high and positive correlation between the body weight (BW) and liver glycogen content (r=0.809, P<0.01). The data of the present study suggest that the energy store is probably an important factor in affecting the growth of late-term embryos and ducklings. PMID- 20727693 TI - Impact of porcine epidemic diarrhea virus infection at different periods of pregnancy on subsequent reproductive performance in gilts and sows. AB - Reproductive performance of gilts and sows in a swine commercial herd following an outbreak of porcine epidemic diarrhea virus (PEDV) were investigated. A PEDV outbreak was observed in March 2008 in a swine herd in Thailand. The disease was diagnosed by clinical symptoms, gross and histopathology and viral detection using reverse transcriptase-polymerase chain reaction assay. The intestines of the infected piglets were collected, minced and fed to all of the gilts and sows within 2 weeks after the onset of the PEDV outbreak. Reproductive data were collected during a period from January 2007 to July 2008 and were retrospectively evaluated. The farrowing rate (FR), return rate (RR), abortion rate (AR), number of total piglets born per litter (TB), number of piglets born alive per litter (BA), percentage of stillbirth piglets per litter (SB), percentage of mummified fetus per litter (MM) and piglet's birth weight (BW), before and after the PEDV outbreak were compared. It was found that the impact of PEDV infection on the reproductive performance of gilts and sows depended on the period of pregnancy when the females were exposed to the pathogen, and parity number. The pregnant females infected with PEDV during the first 30 days of pregnancy had a 12.6 percentage point decrease of FR (91.1% vs. 78.5%, P=0.003), a 5.7 percentage point increase of RR (3.5% vs. 9.2%, P=0.01), a 1.3 percentage point increase of AR (2.1% vs. 3.4%, P=0.01) and a 2.0 percentage point increase of MM (3.5% vs. 5.6%, P<0.001). SB increased in the pregnant females that were infected with PEDV during 91-120 days of pregnancy (1.8 percentage points, 4.5% vs. 6.2%, P=0.01). The impacts of PEDV infection on subsequent reproductive performance were more severe in the pregnant gilts than the pregnant sows. PEDV infection during the first 30 days of pregnancy resulted in a decrease of TB by 1.4 (11.7 vs. 10.3 piglets/litter, P<0.001) and a decrease of BA by 2.2 (10.7 vs. 8.5 piglets/litter, P<0.001) in the gilts' litters, while the influence of PEDV infection on TB and BA was not significant in sows (P>0.05). It was concluded that natural infection of PEDV in the pregnant gilts and sows caused a reduction of subsequent reproductive performance. PMID- 20727694 TI - The association between carotid or femoral atherosclerosis and low bone mass in postmenopausal women referred for osteoporosis screening. Does osteoprotegerin play a role? AB - Atherosclerosis and osteoporosis appear to be epidemiologically correlated. Most (but not all) animal and clinical studies suggest that osteoprotegerin (OPG) may represent a possible molecular link between bone loss and vascular calcification. The aim of this study was to investigate the association of OPG with bone mineral density (BMD) and vascular plaques, in order to contribute to a better understanding of the link between atherosclerosis and osteoporosis. The study population consisted of 100 consecutive postmenopausal women referred for routine osteoporosis screening. BMD was evaluated by dual-energy X-ray absorptiometry. Presence of carotid or femoral plaques was examined by ultrasonography. OPG was measured by enzyme immunoassay. Seventy-two subjects had low bone mass and were categorized as osteopenic (32) or osteoporotic (40). Fifty-two subjects had one or more atherosclerotic plaques at carotid or femoral level. Both lumbar spine and femoral BMD were associated with the number of plaques (r=-0.5370; p<0.0001, and r=-0.4423; p=0.0012, respectively), however only spine BMD remained significantly associated with the number of plaques after adjustment. OPG serum values showed a significant association with age (r(2)=0.057; p=0.042). The association between OPG and the number of plaques was significant only in patients with concomitant involvement of carotid and femoral districts (r(2)=0.758; p<0.0001). PMID- 20727695 TI - Breast cancer, stem cells and sex hormones. Part 2: the impact of the reproductive years and pregnancy. AB - The primitive breast develops in utero and during infancy breast growth largely parallels the growth of the child. At puberty, the GnRH pulse generator starts up, initially with just 1-2 pulses daily. This results in very small amounts of unopposed estrogen being secreted by the ovary. As the GnRH pulse generator matures, ovarian secretion of estrogen increases. The pubertal breast responds to this increasing estrogen drive. Breast glandular increase in size is mostly due to growth and division of the primary ducts. Eventually, the terminal buds give rise alveolar buds which tend to cluster around a terminal duct. Lobule formation begins in the first 2 years that follow menarche. With the onset of ovulation, breast mitotic activity increases and is usually maximal in the luteal phase. The final stage of breast maturation occurs during the first full-term pregnancy. The breast undergoes marked changes in preparation for breast feeding. There is evidence that breast SC number decreases during that first pregnancy. Also, the remaining SC undergo significant change which seems to render them less likely to undergo malignant change. These alterations to breast SC number and function may explain, at least in part, why early first pregnancy reduces the risk of breast cancer later in life. PMID- 20727696 TI - Low serum testosterone and frailty in older men and women. AB - BACKGROUND: Frail older persons are at high risk of morbidity and mortality, and are characterized by body composition alterations. Serum testosterone, which regulates body composition, declines with age. We investigated the relation between serum testosterone level and physiological frailty in both older men and women. METHODS: This was a cross-sectional study of 108 adults 65 years old or older. Frailty status was determined by hand-grip strength, weight change, walking speed, exhaustion, and activity levels, and was classified as frail (3 or more deficits), pre-frail (1 or 2 deficits), or robust (no deficit) according to the Fried criteria. Serum total testosterone (TT) and sex-hormone-binding globulin were measured while free testosterone (FT) was estimated. RESULTS: Median (range) TT and FT were lower in frail than in pre-frail and robust men (TT: (frail) 15.7 [2.4-26.9] vs. (pre-frail) 19.4 [7.2-39.9] and (robust) 25.9 [13.2-35.2] nmol/L, P=0.03; FT: 230.0 [35.9-299.0] vs. 272.0 [86.7-411.0] and 303.0 [267.0-396.0] pmol/L, P=0.02) and women (TT: 0.31 [0.10-0.51] vs. 0.47 [0.14-1.55] and 0.45 [0.36-1.25] nmol/L, P=0.02; FT: 4.59 [0.46-6.63] vs. 4.66 [1.57-15.10] and 6.65 [3.91-21.00] pmol/L, P=0.03). After adjusting for age, comorbidities, body mass index, and serum albumin in ordinal logistic regression model, odds ratios of being frail were significantly higher for those participants whose TT and FT levels were in the lowest tertile compared to the highest tertile in men (TT: odds ratio [OR] 3.29, 95% confidence interval [CI] 1.14-9.50; FT: OR 3.44, 95% CI 1.05-11.22) and in women (TT: OR 6.69, 95% CI 1.84 24.31; FT: OR 4.86, 95% CI 1.31-18.08). CONCLUSIONS: Low serum testosterone levels were independently associated with frailty in the elderly Taiwanese. PMID- 20727697 TI - Analysis of clinicopathological stage in supracricoid partial laryngectomy patients: Need for adjuvant therapy in clinically understaged cases. AB - OBJECTIVE: The aim of this study is to evaluate the impact of pre-operative T understaging on clinical outcome in supracricoid partial laryngectomy (SCPL). METHODS: The medical records of 92 patients who underwent SCPL were evaluated. By comparing clinical and pathologic stages, the causes of pre-operative T understaging and its relationship with local recurrence and survival were examined. RESULTS: Fifteen patients (16.3%) were found to be underestimated in terms of pre-operative T-stage, primarily due to failure to identify thyroid cartilage invasion (11 cases). Among these, radiation treatment at the primary site was offered in only two cases, including one case with a positive surgical margin. Among 82 patients followed for over 1 year, local recurrence occurred in seven patients (8.5%); five of these (71.4%) had been understaged pre-operatively due to failure to detect thyroid cartilage invasion. The local recurrence rate was higher and the overall survival rate was lower in patients who were understaged pre-operatively, compared to those who were staged accurately (p=0.006 and p=0.001, respectively). CONCLUSION: SCPL should be conducted only after a thorough pre-operative evaluation in locally advanced laryngeal cancer. Additionally, adjuvant treatment is necessary to reduce local recurrence in cases where thyroid cartilage invasion is determined pathologically after SCPL. PMID- 20727698 TI - Treatment of salivary mucocele of the lower lip by OK-432. AB - OBJECTIVE: The aim of this paper was to evaluate the outcome and complications of the treatment of patients with salivary mucocele by intralesional injection therapy with OK-432. METHODS: We tried OK-432 therapy in 20 patients with salivary mucocele. We injected OK-432 solution into the lesion with a 27-gauge needle to prevent any leakage of the agent from the mucocele. RESULTS: Disappearance of the lesion was observed in 16 of 20 patients. Marked reduction was observed in 4 of 20 patients. No local scarring or deformity of the lower lip occurred in any patients. As side effects, local discomfort at the injection site was observed in two of the patients, but such problems resolved within a few days. We performed this treatment on an outpatient basis without hospitalization. CONCLUSION: Our results confirmed that OK-432 therapy is simple, easy, and relatively safe, and can be used as a substitute for surgery in the treatment of salivary mucocele. PMID- 20727699 TI - Hereditary isolated ossicular anomalies in two generations of patients. AB - We present herein a report of an isolated form of ossicular anomaly that affected two generations of patients. Two female patients, a mother and daughter, were admitted with complaints of conductive hearing loss, with no other anomalies and no history of ear infection. Surgical exploration revealed identical ossicular anomalies: the complete absence of the long process of the incus and fixation of the stapes. This anomaly can be considered to have been inherited in an autosomal dominant or X-linked-dominant manner. To date, two reports have described isolated forms of congenital ossicular anomalies. Our findings suggest that isolated congenital anomalies can be inherited. PMID- 20727700 TI - Sleep cyclic alternating pattern analysis in healthy children during the first year of life: a daytime polysomnographic study. AB - We evaluated the cyclic alternating pattern (CAP) during the first year of life in order to obtain information on the maturation of arousal mechanisms during NREM sleep and to provide normative data for CAP parameters in this age range (5 16months). Eleven healthy children (mean age 7.9+/-3.3months, seven boys) were studied while they slept in the morning. They underwent a 3-h video-EEG polysomnographic recording at the Pediatric Sleep Unit of Sant'Andrea Hospital in Rome, Italy. Sleep was scored visually for sleep architecture and CAP analysis using standard criteria. Our results were complemented by CAP data from a previous sample of healthy infants (2-4months), studied when they slept during the morning, in order to correlate CAP parameters with age. The total sample comprised 24 children. The sleep period was approximately 2h, with a first REM latency of about 30min, and a clear distinction between stages N1, N2, and N3. The arousal index was 12+/-2.1 events/hour of sleep. The total CAP rate was 23.7+/-7.6%, and it increased progressively with the deepness of sleep; the highest values were observed during stage N3 and the lowest values during stage N1. A1 phases were the most numerous (78.2%), followed by A2 (14%) and A3 (7.7%) phases. The A1 index was higher than the A2 and A3 indices, whereas the mean duration of B was higher than that of A. The correlation showed that the CAP rate, A1, A2, A3 indices, A2, A3 percentages, and the average duration of B increased with age, whereas the A1 percentage decreased. We provide the first data on CAP analysis in children aged 5-16months, studied when they slept during the morning. Our results confirm the trend toward an increase in CAP rate during the first year of life. In addition, we observed a progressive increase in CAP rate with deepness of sleep, and with age, reflecting maturation of slow-wave activity. The decreased percentage of A1 subtypes may reflect the maturation of arousability. PMID- 20727701 TI - Forward shifting of posterior dural sac during flexion cervical magnetic resonance imaging in Hirayama disease: an initial study on normal subjects compared to patients with Hirayama disease. AB - OBJECTIVE: Forward shifting of the posterior cervical dural sac is the most important sign in diagnosing Hirayama disease but can also be seen in normal subjects, causing potential diagnostic dilemma. We aim to explore the degree of forward displacement of posterior dural sac in normal subjects compared to that with Hirayama disease. MATERIALS AND METHODS: 50 healthy male teenagers and 3 patients with Hirayama disease were recruited into the control group and patient group, respectively. MR imaging of the cervical spine was performed in both neutral and flexion positions for all subjects, with the following parameters measured: maximal distance of forward shifting of posterior dural sac, dimension of dural sac and spinal cord. RESULTS: Forward shifting of the posterior cervical dural sac was depicted in 46% of normal subjects upon flexion position but without associated cord compression due to intrinsic expansion of the spinal canal volume. This intrinsic compensatory mechanism was inadequate in diseased patients leading to cord compression with significant increment in ratio of anteroposterior diameter of forward displacement of posterior dural wall/anteroposterior diameter of spinal canal ("x/y"), and decrement in ratio of anteroposterior diameter of spinal cord/perpendicular transverse diameter of spinal cord ("a/b"). CONCLUSION: Depicting of forward shifting of posterior dural sac alone on flexion position cannot reliably diagnose Hirayama disease, which should be established only if there is forward shifting of posterior dural sac, plus increased ratio of x/y and decreased ratio of a/b on flexion position from associated mass effect on the spinal cord. PMID- 20727702 TI - Identification, isolation, characterization and response factor determination of process-related impurity in meprobamate drug substance. AB - This paper describes identification and characterization of a process-related impurity of meprobamate drug substance observed in HPLC-UV method. Forced degradation studies were carried out under acidic, basic, oxidation, light and thermal conditions to assess the nature of the impurity. The pure impurity was obtained by preparative LC isolation and analyzed by NMR and mass. Structural elucidation by spectral data and formation of this impurity were discussed in detail. The structure of the process-related impurity was established as carbamic acid-2-carbamoyloxymethyl-2-methyl-pent-3-enyl ester (olefin). Also, the relative response factor, linearity, detection limit (DL), quantitation limit (QL) and recovery were determined for meprobamate and the impurity. Good linearity was obtained for the impurity over the concentration range of 0.03-0.20% (w/w) with the coefficient of determination (r(2)) of 0.999. The DL and QL of olefin impurity were 0.0003 and 0.001% (w/w), respectively. The isolated impurity was co injected with meprobamate sample to confirm the retention time in HPLC. PMID- 20727703 TI - Managerial capacity and adoption of culturally competent practices in outpatient substance abuse treatment organizations. AB - The field of cultural competence is shifting its primary emphasis from enhancement of counselors' skills to management, organizational policy, and processes of care. This study examined managers' characteristics associated with adoption of culturally competent practices in the nation's outpatient substance abuse treatment field. Findings indicate that in 1995, supervisors' cultural sensitivity played the most significant role in adopting practices, such as matching counselors and clients based on race and offering bilingual services. Staff's exposure to cross-cultural training increased from 1995 to 2005. In this period, positive associations were found between managers' cultural sensitivity and connection with the community and staff receiving cross-cultural training and the number of training hours completed. However, exposure to and investment in this training were negatively correlated with managers' formal education. Health administration policy should consider the extent to which the decision makers' education, community involvement, and cultural sensitivity contribute to building culturally responsive systems of care. PMID- 20727705 TI - ER-targeted Bcl-2 and inhibition of ER-associated caspase-12 rescue cultured immortalized cells from ethanol toxicity. AB - Alcohol abuse, known for promoting apoptosis in the liver and nervous system, is a major public health concern. Despite significant morbidity and mortality resulting from ethanol consumption, the precise cellular mechanism of its toxicity remains unknown. Previous work has shown that wild-type Bcl-2 is protective against ethanol. The present study investigated whether protection from ethanol toxicity involves mitochondrial Bcl-2 or endoplasmic reticulum (ER) Bcl-2, and whether mitochondria-associated or ER-associated caspases are involved in ethanol toxicity. Chinese hamster ovary (CHO695) cells were transiently transfected with cDNA constructs encoding wild-type Bcl-2, mitochondria-targeted Bcl-2, or ER-targeted Bcl-2. MTT assay was used to measure cell viability in response to ethanol. Ethanol treatments of 1 and 2.5 M reduced cell viability at 5, 10, and 24 h. Wild-type Bcl-2, localized both to mitochondria and ER, provided significant rescue for CHO695 cells treated with 1M ethanol for 24 h, but did not rescue toxicity at 2.5 M. ER-targeted Bcl-2, however, provided significant and robust rescue following 24 h of 1 and 2.5 M ethanol. Mitochondria-targeted Bcl-2 offered no protection at any ethanol concentration and generally reduced cell viability. To follow up these experiments, we used a peptide inhibitor approach to investigate which caspases were responsible for ethanol-induced apoptosis. Caspase-9 and caspase-12 are known to be downstream of mitochondria and the ER, respectively. CHO695 cells were treated with a pan-caspase inhibitor, a caspase-9 or caspase-12 inhibitor along with 1.5 M ethanol, followed by MTT cell viability assay. Treatment with the pan-caspase inhibitor provided significant rescue from ethanol, whereas inhibition of caspase-9 did not. Inhibition of ER-associated caspase-12, however, conferred significant protection from ethanol toxicity, similar to the pan inhibitor. These findings are consistent with our transfection data and, taken together, suggest a significant role for the ER in ethanol toxicity. PMID- 20727704 TI - Physician introduction to opioids for pain among patients with opioid dependence and depressive symptoms. AB - This study determined the frequency of reporting being introduced to opioids by a physician among opioid-dependent patients. Cross-sectional analyses were performed using baseline data from a cohort of opioid addicts seeking treatment with buprenorphine. The primary outcome was a response to the question: "Who introduced you to opiates?" Covariates included sociodemographics, depression, pain, and current and prior substance use. Of 140 participants, 29% reported that they had been introduced to opioids by a physician. Of those who were introduced to opioids by a physician, all indicated that they had initially used opioids for pain, versus only 11% of those who did not report being introduced to opioids by a physician (p < .01). There was no difference in current pain (78% vs. 85%, p = .29); however, participants who were introduced to opioids by a physician were more likely to have chronic pain (63% vs. 43%, p = .04). A substantial proportion of individuals with opioid dependence seeking treatment may have been introduced to opioids by a physician. PMID- 20727706 TI - Implications of overweight in gastric cancer: A multicenter study in a Western patient population. AB - AIMS: The purpose of this study was to evaluate the effects of overweight on surgical and long-term outcomes in a Western population of patients with gastric cancer (GC). METHODS: An electronic database of all patients with resectable GC treated between 1986 and 1998 at seven university surgical centres cooperating in the Polish Gastric Cancer Study Group was reviewed. Overweight was defined as a body mass index (BMI) of 25 kg/m(2) or higher. RESULTS: Four hundred and ninety two of 1992 (25%) patients were overweight. Postoperatively, higher BMI was associated with higher rates of cardiopulmonary complications (16% vs 12%, P = 0.001) and intra-abdominal abscess (6.9% vs 2.9%, P < 0.001). However, other complications and mortality rates were unaffected. The median disease-specific survival of overweight patients was significantly higher (36.7 months, 95% confidence interval (CI) 29.0-44.4) than those with BMI<25 kg/m(2) (25.7 months, 95%CI 23.2-28.1; P = 0.003). These differences were due to the lower frequencies of patients with T3 and T4 tumours, metastatic lymph nodes, distant metastases, and non-curative resections. A Cox proportional hazards model identified age, depth of infiltration, lymph node metastases, distant metastases, and residual tumour category as the independent prognostic factors. CONCLUSIONS: Overweight is not the independent prognostic factor for long-term survival in a Western-type population of GC. PMID- 20727707 TI - Intracranial arachnoid cysts and obstetric anesthesia: two case reports. AB - Two cases of patients in whom neuraxial anesthesia was planned for labor and delivery and who had a pre-existing intracranial arachnoid cyst are reported. Anesthesia was used in one patient and was uneventful. The pathophysiology of these cysts and factors which can precipitate the occurrence of symptoms, are reviewed and cases previously described in the literature are examined. Management should be individualized and based on evaluation of preexisting neurological symptoms. In most cases and although CT scan and MRI images may show an intracranial cyst with impressive development, patients remain asymptomatic and neuraxial regional anesthesia can be used safely, provided the patient has agreed and the neurologist in charge has been informed. PMID- 20727708 TI - The direct and indirect costs of opioid-induced constipation. AB - CONTEXT: Treatment with strong opioids is connected with frequent and problematic side effects. One of the most common side effects is opioid-induced constipation (OIC). The discomfort of OIC can limit the effectiveness of pain therapy. Because constipation typically persists for as long as opioid therapy is administered, its effects on the quality of life (QoL) of patients need to be taken seriously. Data and published studies on the cost implications of OIC are, however, scarce. OBJECTIVES: To estimate the direct and indirect costs of OIC in a defined patient population during treatment with strong opioids. METHODS: The study is based on patient data from a Swedish noninterventional study, UPPSIKT. The cost analysis is based on 197 patients treated with strong opioids over a six-month period. Direct and indirect costs in this article are calculated per patient-month, and the cost for OIC is estimated as the difference in mean costs between months with and without constipation. RESULTS: The total costs per patient-month for patients with severe constipation are significantly higher than those for patients with mild, moderate, or no constipation. Patients with severe constipation have the highest total costs, Euro (EUR) 1525 per patient-month, whereas patients with mild, moderate, and no problems cost EUR 1196, EUR 1088, and EUR 1034, respectively. CONCLUSION: Opioid use is costly to society, and the costs vary with OIC severity. OIC is discomforting, affects the QoL of patients, and can limit an effective pain therapy. PMID- 20727710 TI - Oxygen supplementation is helpful for the echocardiographic detection of anomalous left coronary artery from the pulmonary artery. AB - BACKGROUND: The echocardiographic diagnosis of anomalous left coronary artery from the pulmonary artery (ALCAPA) can be challenging. The aim of this study was to assess the hypothesis that diagnosis can be enhanced by using supplemental oxygen, which decreases pulmonary vascular resistance and increases retrograde flow from the coronary artery into the pulmonary artery. METHODS: Demographic, echocardiographic, and cardiac catheterization data were reviewed in patients presenting with ALCAPA from 1999 to 2007. RESULTS: Twenty-one patients (seven male; median age, 5 months) presented with ALCAPA. Nine underwent imaging with oxygen. Two of these nine (22%) had previous standard echocardiographic studies that missed the diagnosis. Cardiac catheterization was required for diagnosis of ALCAPA in 42% of patients who underwent standard echocardiography compared with 11% of patients who received supplemental oxygen in addition to standard echocardiography. The administration of oxygen caused no significant change in heart rate or cardiorespiratory support. CONCLUSION: Transient oxygen administration is useful in the noninvasive diagnosis of ALCAPA. PMID- 20727711 TI - Somatic hypermutation and antigen-driven selection of B cells are altered in autoimmune diseases. AB - B cells have been found to play a critical role in the pathogenesis of several autoimmune (AI) diseases. A common feature amongst many AI diseases is the formation of ectopic germinal centers (GC) within the afflicted tissue or organ, in which activated B cells expand and undergo somatic hypermutation (SHM) and antigen-driven selection on their immunoglobulin variable region (IgV) genes. However, it is not yet clear whether these processes occurring in ectopic GCs are identical to those in normal GCs. The analysis of IgV mutations has aided in revealing many aspects concerning B cell expansion, mutation and selection in GC reactions. We have applied several mutation analysis methods, based on lineage tree construction, to a large set of data, containing IgV productive and non productive heavy and light chain sequences from several different tissues, to examine three of the most profoundly studied AI diseases - Rheumatoid Arthritis (RA), Multiple Sclerosis (MS) and Sjogren's Syndrome (SS). We have found that RA and MS sequences exhibited normal mutation spectra and targeting motifs, but a stricter selection compared to normal controls, which was more apparent in RA. SS sequence analysis results deviated from normal controls in both mutation spectra and indications of selection, also showing differences between light and heavy chain IgV and between different tissues. The differences revealed between AI diseases and normal control mutation patterns may result from the different microenvironmental influences to which ectopic GCs are exposed, relative to those in normal secondary lymphoid tissues. PMID- 20727709 TI - Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats. AB - The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long-Evans rats were treated by gavage with 0.09, 0.87, or 8.73mg AMM/kg body weight (BW), vehicle, or 100mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73mg AMM-exposed males. AMM exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear. PMID- 20727712 TI - Clinical management of angioneurotic oedema patient post-orthognathic surgery. AB - Angioneurotic oedema is an acute swelling involving the submucosal or subcutaneous tissues; it is most often located in the oral and maxillofacial region, which can result in upper airway obstruction. Its aetiology is frequently associated with immunoglobulin-mediated hypersensitivity reactions that elicit a heightened inflammatory response. The objective of this study was to report the case of a patient who developed an episode of angioneurotic oedema following combined orthognathic surgery. Pharmacological and nonpharmacological interventions used in the treatment of this important clinical condition are described and discussed. PMID- 20727713 TI - Comparison of two different flap designs in the surgical removal of bilateral impacted mandibular third molars. AB - The purpose of this study was to compare the effects of flap design on the postoperative sequelae of pain, swelling, trismus and wound dehiscence after surgical removal of bilateral impacted mandibular third molars (M3). 20 patients aged 20-30 years who required removal of bilateral impacted M3 were included in the study. Maximum interincisal opening and facial measurements were recorded preoperatively. Bayonet flap was used on one side and envelope flap on the other side for the removal of impacted M3. The effect of flap design on pain, swelling, trismus and wound dehiscence was evaluated postoperatively. Pain and wound dehiscence were significantly greater in the envelope flap group compared with the bayonet flap group (P<0.05). No significant difference in postoperative swelling and trismus was found in either group (P>0.05). The bayonet flap was superior to the envelope flap for postoperative pain and wound dehiscence. There was no difference in postoperative swelling and trismus between the two groups. PMID- 20727714 TI - Arterial blood pressure in adult Nigerians with sickle cell anemia. AB - AIM AND OBJECTIVE: This study was aimed at comparing the arterial blood pressures in steady state adult sickle cell patients with those of age- and sex-matched healthy controls. METHODS: A descriptive cross-sectional study of 62 sickle cell anemia patients and 62 age- and sex-matched healthy controls was carried out in the adult outpatient sickle cell clinics and the cardiac center of the University of Nigeria Teaching Hospital (UNTH), Enugu, Nigeria. Brachial blood pressures were measured in the right arm in all subjects. RESULTS: Significant increase in pulse rate was found in the study subjects (87.68 +/- 8.91 bpm) compared with the controls (72.13 +/- 6.79 bpm) (p<0.05). The mean systolic blood pressure was comparable in the two groups. However, the patients had significantly lower diastolic blood pressure, lower mean arterial blood pressure, as well as a higher pulse pressure than the control subjects. Significant correlations were found between blood pressure indices and hematocrit, body mass index, frequency of crisis, and body surface area. CONCLUSION: Relatively lower arterial blood pressure is a significant finding in patients with sickle cell anemia. Hematocrit, frequency of crisis, body mass index, and body surface area are significant determinants of blood pressure indices in sickle cell anemia. PMID- 20727715 TI - Critique of Kempton et al. PMID- 20727716 TI - Fragile X mental retardation protein levels are decreased in major psychiatric disorders. PMID- 20727717 TI - Randomized-controlled trials in people at ultra high risk of psychosis: a review of treatment effectiveness. AB - As an extension of the early intervention in psychosis paradigm, different focused treatments are now offered to individuals at ultra high risk of psychosis (UHR) to prevent transition to schizophrenia, however the effectiveness of these treatments is unclear. A systematic literature search in PubMed/Medline and PsycINFO was performed to derive information on randomized control trials (RCTs) in UHR samples. Seven reports were identified detailing results from five independent RCT studies. Two studies used antipsychotic drugs (one in combination with cognitive behavior therapy); one study employed cognitive therapy; one study used a two-year program of intensive community care with family psychoeducation; one study assessed the effectiveness of 3-months omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) supplementation. Intensive community care and the Omega-3 PUFAs supplementation were effective in reducing the transition to psychosis at 12 months. Overall, rates of transition to psychosis at 1 year were 11% for focused treatment groups (n=180) and 31.6% for control UHR groups (n=157). Receiving any of the focused treatment was associated with a lower risk of developing psychosis if compared with no treatment or treatment as usual (Relative Risk=0.36; 95%CI: 0.22-0.59). The available evidence at 2/3 years follow-up indicates that the effects of focused treatments are not stable after intervention cessation and when treatment is delivered over a restricted time (e.g. 6 months or less), it may achieve only a delay in psychosis onset. Due to the heterogeneity in the interventions considered, the current results do not allow recommendation for any specific treatment. PMID- 20727718 TI - High prevalence of coinfection with mucosal high-risk type HPV (HR-HPV) and cutaneous HR-HPV in Bowen's disease in the fingers. PMID- 20727720 TI - Surveillance for multidrug-resistant Acinetobacter baumannii: a lesson on definitions. PMID- 20727719 TI - Polymorphisms in genes involved in oxidative stress and their interactions with lifestyle factors on skin cancer risk. PMID- 20727721 TI - Emerging zoonoses: responsible communication with the media--lessons learned and future perspectives. AB - Emerging zoonotic disease outbreaks are inevitable and often unpredictable events. The environment surrounding an outbreak is unique in public health, and outbreaks are frequently marked by uncertainty, confusion and a sense of urgency. Good communication at this time, generally through the media, is essential, but examples unfortunately abound of communication failures that have delayed outbreak control, undermined public trust and compliance, and unnecessarily prolonged economic, social and political turmoil. With this paper we hope to disseminate the idea that communication expertise has become as essential to outbreak control as epidemiological training and laboratory analysis. The paper presents the best practices for communicating with the public and discusses future aspects of communicating through the mass media during an outbreak. PMID- 20727723 TI - Enhanced hippocampal long-term potentiation following repeated MDMA treatment in Dark-Agouti rats. AB - In rats and primates, (+/-)3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces both long-lasting damage to serotonergic axons and memory impairment. Our objective was to determine effects of neurotoxic dose of MDMA on long-term potentiation (LTP) in hippocampal area CA1 in Dark-Agouti (DA) rats. One week after neurotoxic MDMA treatment in vivo (12.5mg/kg i.p., once a week, per three weeks), serotonergic deficit was evident in hippocampal slices as 56.3% reduction in 5-HT content (p=0.04) and as 68.4% reduction in the effect of endogenous 5-HT release on synaptic neurotransmission (p<0.01). In hippocampal slices from the same animals, LTP was on average 46% greater than that observed in sham-treated controls (42.9 +/- 3.5%; n=12 vs. 29.2 +/- 3.2%; n=12; p<0.01). Non-neurotoxic dose of MDMA (12.5 mg/kg, i.p., one time) did not change LTP one week after the treatment, suggesting correlation between serotonergic deficit and enhanced synaptic plasticity. We conclude that MDMA-induced impairment of learning and memory is not a consequence of hippocampal LTP inhibition. PMID- 20727722 TI - Heteroresistance to glycopeptides in Italian meticillin-resistant Staphylococcus aureus (MRSA) isolates. AB - The prevalence and molecular characterisation of heteroresistant vancomycin intermediate Staphylococcus aureus (hVISA) strains were determined in a large group of Italian strains isolated between 2005 and mid 2007. Amongst the 1284 strains isolated from documented infections in hospitalised patients (bloodstream infection, pneumonia, and skin and skin-structure infections), 139 S. aureus with vancomycin minimum inhibitory concentrations (MICs) between 1 mg/L and 2 mg/L were screened for the presence of hVISA using three different methods and were confirmed by population analysis profile (PAP). Thirty-six hVISA strains (25.9%) were detected. Amongst the three screening methods used, the macro Etest (MET) demonstrated 100% specificity and 75% sensitivity. hVISA strains were accessory gene regulator (agr) types I and II and belonged to the major nosocomial clones circulating in Italy (ST8, ST239, ST247 and ST228). All strains were susceptible to quinupristin/dalfopristin, linezolid, daptomycin, tigecycline and dalbavancin. In conclusion, we have demonstrated that hVISA isolates are common amongst MRSA isolates with MICs between 1 mg/L and 2 mg/L in Italy. MET, with its high sensitivity and specificity, should be used for early detection of hVISA, especially in patients with serious or prolonged infections sustained by MRSA. Finally, the most recent anti-Gram-positive drugs maintained their full spectrum of in vitro activity against these strains. PMID- 20727724 TI - A commentary on the process of peer review and pathology data locking. PMID- 20727725 TI - Synergistic properties of the terpenoids aromadendrene and 1,8-cineole from the essential oil of Eucalyptus globulus against antibiotic-susceptible and antibiotic-resistant pathogens. AB - The aim of the present study was to investigate the chemical composition of the essential oil of the fruits of Eucalyptus globulus and to examine the potential application of the fruit oil against multidrug-resistant bacteria. GLC/MS analysis in the fruit oil showed that aromadendrene was the main compound followed by 1,8-cineole and globulol. The three most abundant components of the fruit oil were also tested individually against microorganisms. In addition, the synergistic effects of combinations of the major constituents (aromadendrene and 1,8-cineole) of the fruit oil were also investigated. All Gram-positive bacteria were susceptible to the fruit oil with different degrees of susceptibility as determined by microdilution method. The oil exerted a marked inhibition against multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) Enterococcus faecalis. The results indicated that aromadendrene might be responsible for the antimicrobial properties, whereas 1,8-cineole and globulol exhibited low activities. The checkerboard assay demonstrated that combinations of 1,8-cineole and aromadendrene reduce the MIC in most cases in an additive way, whereas the time kill assay indicates a synergistic effect. PMID- 20727726 TI - Enzymatic processing of municipal solid waste. AB - The focus of this work was to investigate an enzymatic liquefaction of MSW organics, paper and cardboard. Liquefaction trials were conducted in different trial volumes: 50 g lab-scale trials and 5 0kg vessel-tests and evaluated based on particle size and viscosity. The viscosity results showed that Celluclast 1.5L had the singular significant effect on liquefaction of model MSW. No effect of alpha-amylase, protease and interaction in between and with cellulases on viscosity and particle size distribution was found in this study. Degradable material with a particle size above 1mm after treatment was evaluated using SEM microscopy. These results showed that paper particles were the main obstacles needing additional treatment in order to become fully liquefied. In a pilot scale test treating authentic MSW; more than 90% of initial organic and paper dry matter (DM) was recovered as liquid slurry after sieving through a 5-mm sieve. These tests were performed at up to 35% DM, showing that this process can easily manage high DM loadings. MSW enzymatic liquefaction promotes the separation of organics and paper from solids, which facilitate the use of these degradable fractions, with minimal loss, capable to enter a biogas plant through existing pipes. PMID- 20727727 TI - Bacterial composting of animal fleshing generated from tannery industries. AB - Animal fleshing (ANFL) is the major proteinaceous solid waste generated during the manufacture of leather, which requires to be disposed of by environmentally sound manner. This study reports about the treatment of ANFL into an organic compost and its effects on physiological parameters of different crops in a laboratory study. The ANFL was hydrolysed using Selenomonas ruminantium HM000123 and then the hydrolysed ANFL was mixed with cow dung and leaf litter for producing composted organic fertilizer (COF). The COF was characterized for pH, electrical conductivity (EC), total Kjeldhal nitrogen (TKN), and total organic carbon (TOC). The composting resulted in a significant reduction in pH, TOC and C:N ratio and an increase in TKN after 49 days in a compost reactor. Scanning electron microscope and FT-IR were used to analyse the hydrolysis of intra structural ANFL matrix and changes in the functional groups, respectively, in initial and final day COF. Thermogravimetry (TG) analysis was carried out for the raw mixture and COF samples to identify the weight loss under the nitrogen environment. The relative seed germination was found to be 94% in tomato (Lycopersicon esculentum), 92% in green gram (Vigna radiata), 86% in bottle gourd (Lagenaria siceraria (Mol.) Standl.) and 84% in cucumber (Cucumis sativus L.) using the extracts of COF. The results indicate that the combination of both hydrolysis and bacterial composting reduced the overall time required for composting and producing a nutrient-enriched compost product. PMID- 20727728 TI - Localized electrical stimulation of in vitro neurons using an array of sub cellular sized electrodes. AB - The investigation of single-neuron parameters is of great interest because many aspects in the behavior and communication of neuronal networks still remain unidentified. However, the present available techniques for single-cell measurements are slow and do not allow for a high-throughput approach. We present here a CMOS compatible microelectrode array with 84 electrodes (with diameters ranging from 1.2 to 4.2 MUm) that are smaller than the size of cell, thereby supporting single-cell addressability. We show controllable electroporation of a single cell by an underlying electrode while monitoring changes in the intracellular membrane potential. Further, by applying a localized electrical field between two electrodes close to a neuron while recording changes in the intracellular calcium concentration, we demonstrate activation of a single cell (~270%, DF/F(0)), followed by a network response of the neighboring cells. The technology can be easily scaled up to larger electrode arrays (theoretically up to 137,000 electrodes/mm(2)) with active CMOS electronics integration able to perform high-throughput measurements on single cells. PMID- 20727729 TI - Long range surface plasmon and hydrogel optical waveguide field-enhanced fluorescence biosensor with 3D hydrogel binding matrix: on the role of diffusion mass transfer. AB - An implementation of evanescent wave affinity biosensor with a large-capacity three-dimensional binding matrix for ultra-sensitive detection of molecular analytes is investigated. In the experimental part of the work, highly swollen carboxylated poly(N-isopropylacryamide) (NIPAAm) hydrogel with up to micrometer thickness was grafted to a sensor surface, functionalized with antibody recognition elements and employed for immunoassay-based detection of target molecules contained in a liquid sample. Molecular binding events were detected by long range surface plasmon (LRSP) and hydrogel optical waveguide (HOW) field enhanced fluorescence spectroscopy. These novel methods allowed probing an extended three-dimensional biointerface with an evanescent field reaching up to several micrometers from the sensor surface. The resonant excitation of LRSP and HOW modes provided strong enhancement of intensity of electromagnetic field that is directly translated into an increased fluorescence signal associated with the binding of fluorophore-labeled molecules. Experimental observations were supported by numerical simulations of mass transfer and affinity binding of target molecules in the hydrogel. Through the optimization of the hydrogel thickness and profile of the probing evanescent wave, low femtomolar limit of detection was achieved. PMID- 20727730 TI - Fluorescent protein recognition polymer thin films capable of selective signal transduction of target binding events prepared by molecular imprinting with a post-imprinting treatment. AB - The functional monomer bearing three functional groups for protein imprinting was designed, which has a structure consisting of a polymerizable methacryloyl group, a secondary amine group for fluorescent dye conjugation by a post-imprinting treatment, and a benzoic acid moiety capable of interacting with a target protein. Lysozyme-imprinted polymer thin films were prepared on the initiator immobilized glass substrates by radical polymerization in the presence of lysozyme, the designed functional monomer, a co-monomer(s) and a crosslinker. After the removal of lysozyme, fluorescein isothiocyanate was introduced into the secondary amine group of the functional monomer residues in the imprinted thin film as a fluorescent reporter dye (post-imprinting treatment). Lysozyme was selectively bound to the thin film with a binding constant of ca. 10(6) M(-1). Since the reporter dye can be only introduced into the binding cavity, the fluorescent response can be detected only when the guest is bound to the cavity, namely only specific binding events can be transduced as fluorescence spectral change. Compared with the SPR measurement, selective binding to the imprinted cavity can be more precisely detected by the proposed method, enabling us to prepare a new class of protein recognizable materials with the ability of the specific signal transduction of protein binding events. PMID- 20727732 TI - Functional nucleic acid nanostructures and DNA machines. AB - The information encoded in the base sequence of DNA provides instructions for the structural and functional properties of this biopolymer. Structural information includes the formation of duplexes, supramolecular crossover tiles, G quadruplexes, i-motifs, base-metal-ion complexes, and more. Functional information encoded in the DNA is reflected by specific binding (aptamers) or catalytic properties (DNAzymes). Recent advances in tailoring supramolecular DNA structures for DNA-based machinery and for amplified biosensing are reviewed. Different DNA machines that perform 'tweezer', 'walker' or 'metronome' functions are discussed, and the control of macroscopic surface properties or the motility of micro-objects by molecular DNA devices is introduced. Furthermore, the design of DNA machines for the ultrasensitive detection of DNA, low-molecular-weight substrates, and macromolecules is discussed. Supramolecular aptamer and DNAzyme structures are used as molecular tools for amplified sensing. PMID- 20727731 TI - Fast cholesterol detection using flow injection microfluidic device with functionalized carbon nanotubes based electrochemical sensor. AB - This work reports a new cholesterol detection scheme using functionalized carbon nanotube (CNT) electrode in a polydimethylsiloxane/glass based flow injection microfluidic chip. CNTs working, silver reference and platinum counter electrode layers were fabricated on the chip by sputtering and low temperature chemical vapor deposition methods. Cholesterol oxidase prepared in polyvinyl alcohol solution was immobilized on CNTs by in-channel flow technique. Cholesterol analysis based on flow injection chronoamperometric measurement was performed in 150-MUm-wide and 150-MUm-deep microchannels. Fast and sensitive real-time detection was achieved with high throughput of more than 60 samples per hour and small sample volume of 15 MUl. The cholesterol sensor had a linear detection range between 50 and 400 mg/dl. In addition, low cross-sensitivities toward glucose, ascorbic acid, acetaminophen and uric acid were confirmed. The proposed system is promising for clinical diagnostics of cholesterol with high speed real time detection capability, very low sample consumption, high sensitivity, low interference and good stability. PMID- 20727733 TI - Systems biology at work. PMID- 20727734 TI - Consulting and prescribing behaviour for anxiety and depression in long-term survivors of cancer in the UK. AB - INTRODUCTION: Cancer survivors may experience long-term depression or anxiety, however, there is little previous research on the use of services in this area. We explored consultation and prescribing behaviour for depression and anxiety amongst cancer survivors in British primary health care. METHODS: This study uses data on 26,213 survivors of breast, colorectal and prostate cancer at least 5 years post-diagnosis, matched to four controls without cancer, from the UK General Practice Research Database. We compared consultations for depression and anxiety, and prescribing for anti-depressants and anxiolytics between cancer survivors and controls. RESULTS: Multivariate, matched regression models showed no difference in consulting for depression or anxiety between any cancer survivors and matched controls. However, breast cancer (odds ratio (OR) 1.16, 95% confidence interval (CI) 1.10-1.22) and prostate cancer survivors (OR 1.31, 95% CI 1.16-1.47) were more likely to receive a prescription for an antidepressant. Breast cancer survivors (IRR 2.49, 95% CI 1.82-3.42) and prostate cancer survivors (IRR 2.84, 95% CI 1.94-4.17) who died received significantly more antidepressants than controls who died. There were no differences in anxiolytic prescribing for colorectal and prostate cancer survivors compared to controls. However, breast cancer survivors nearing the end of life received a greater number of anxiolytic prescriptions compared to controls (IRR 1.84, 95% CI 1.36 2.49). CONCLUSIONS: In this cohort of cancer survivors, there were no differences in consultation behaviour for depression and anxiety compared to controls. However, breast and prostate cancer survivors access more antidepressants, and those nearing the end of life received the highest volume of prescriptions. Breast cancer survivors at the end of life also receive more anxiolytics. PMID- 20727735 TI - The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. AB - PURPOSE: Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma. METHODS: Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end point was progression-free rate at 6 months (PFR(6 months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0) = 50%; P(1) = 70%; alpha = 0.05; beta = 0.10). RESULTS: Thirty patients were enrolled. PFR(6 months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm. CONCLUSION: In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended. PMID- 20727736 TI - C-reactive protein-associated genetic variants and cancer risk: findings from FINRISK 1992, FINRISK 1997 and Health 2000 studies. AB - BACKGROUND: Evidence from prospective observational studies suggests that elevated circulating C-reactive protein (CRP) concentrations are associated with cancer risk, but it is unclear whether this association is causal. In order to examine this, we investigated whether genetic variants that are associated with circulating CRP concentrations are associated with cancer risk. METHODS: We pooled data from three population-based prospective Finnish studies: FINRISK 1992 (n = 5289), FINRISK 1997 (n = 7160) and Health 2000 (n = 6299). Cancer cases were identified from cancer registrations. Thirteen CRP-associated SNPs, identified from genome-wide association studies, were genotyped. We examined the associations of the SNPs and cancer risk using Cox, probit and instrumented probit regression models. RESULTS: Compared to common allele homozygotes, individuals carrying one or two variant T alleles at rs1892534 had 1.05-fold (95% confidence interval (CI): 0.90, 1.23) and 1.2-fold (95% CI: 1.01, 1.42) increased overall cancer risk, respectively. Individuals with one or two variant A alleles at rs1169300 or rs2464196 had approximately 1.5- and 2-fold increased risk of lung cancer, respectively (p trend for both: 0.007). CRP SNPs were not associated with colorectal, prostate or breast cancer risk nor was CRP-associated with the probability of developing cancer in the instrumented probit analyses. CONCLUSIONS: We found some evidence for an association of a small number of CRP associated SNPs with the overall cancer risk and lung cancer risk. Our instrumental variable analyses provided no clear evidence for a causal association of CRP and cancer. These findings suggest that circulating CRP concentrations are unlikely to have a causal role in cancer. PMID- 20727738 TI - Effectiveness of Cupressus sempervirens cones as biosorbent for the removal of basic dyes from aqueous solutions in batch and dynamic modes. AB - The feasibility of using cypress cone chips from Cupressus sempervirens as a low cost biosorbent for the removal of two representative basic dyes, methylene blue (MB) and rhodamine B (RhB), from aqueous solutions was investigated in batch and continuous modes. Dyes biosorption was strongly dependent on the solution's pH. Sorption kinetics was determined and properly described by the pseudo-second order rate model. Experimental equilibrium isotherms fitted the Langmuir model, showing maximum biosorption capacities of 0.62 mmol/g for MB and 0.24 mmol/g for RhB. Competitive experiments from a binary solution of the dyes demonstrated the preference of the cone chips for biosorbing MB. Very low desorption efficiencies were obtained for both dyes. Dynamic experiments showed that the breakthrough time was three times higher for MB biosorption than for RhB for the same conditions. Breakthrough curves were properly represented by a mathematical model. PMID- 20727737 TI - Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy. AB - Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5 FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p = 0.036). No significant differences were noted in TYMP copy number alterations between 5-FU exposed and -unexposed metastases. Median survival time was similar in 5-FU exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio = 2.7, 95% confidence interval = 1.1-6.6; p = 0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer. PMID- 20727739 TI - Feasibility of vermicomposting for vegetable greenhouse waste recycling. AB - This study was conducted in order to evaluate the feasibility of Eisenia andrei for vermicomposting heterogeneous-plant (HP), tomato-plant (P), and damaged tomato-fruit (T) greenhouse vegetable wastes. Earthworm growth and reproduction were monitored over a 12-week period, and variations in chemical parameters, enzyme activity, phytotoxicity test, and genetic fingerprinting of bacterial communities were evaluated. While high rates of salinity prevented earthworm survival in HP and P (>10 dS m(-1)), T was vermicomposted recording an adequate earthworm growth and cocoon production. The latter waste was successfully stabilized, as indicated by the significant decrease in its TOC content ( approximately 13-26%) and C:N ratio ( approximately 16-36%) and its high germination indices ( approximately 39-72%). The similar enzyme activities levels and bacterial community fingerprintings recorded in diverse vermicomposts obtained from T waste indicate that this type of waste favoured the existence of analogous bacterial communities responsible for the high degree of stabilization and maturity detected. PMID- 20727740 TI - The environmental and economic sustainability of potential bioethanol from willow in the UK. AB - Life cycle assessment has been used to investigate the environmental and economic sustainability of a potential operation in the UK in which bioethanol is produced from the hydrolysis and subsequent fermentation of coppice willow. If the willow were grown on idle arable land in the UK, or, indeed, in Eastern Europe and imported as wood chips into the UK, it was found that savings of greenhouse gas emissions of 70-90%, when compared to fossil-derived gasoline on an energy basis, would be possible. The process would be energetically self-sufficient, as the co products, e.g. lignin and unfermented sugars, could be used to produce the process heat and electricity, with surplus electricity being exported to the National Grid. Despite the environmental benefits, the economic viability is doubtful at present. However, the cost of production could be reduced significantly if the willow were altered by breeding to improve its suitability for hydrolysis and fermentation. PMID- 20727741 TI - A hydrodynamics-reaction kinetics coupled model for evaluating bioreactors derived from CFD simulation. AB - Investigating how a bioreactor functions is a necessary precursor for successful reactor design and operation. Traditional methods used to investigate flow-field cannot meet this challenge accurately and economically. Hydrodynamics model can solve this problem, but to understand a bioreactor in sufficient depth, it is often insufficient. In this paper, a coupled hydrodynamics-reaction kinetics model was formulated from computational fluid dynamics (CFD) code to simulate a gas-liquid-solid three-phase biotreatment system for the first time. The hydrodynamics model is used to formulate prediction of the flow field and the reaction kinetics model then portrays the reaction conversion process. The coupled model is verified and used to simulate the behavior of an expanded granular sludge bed (EGSB) reactor for biohydrogen production. The flow patterns were visualized and analyzed. The coupled model also demonstrates a qualitative relationship between hydrodynamics and biohydrogen production. The advantages and limitations of applying this coupled model are discussed. PMID- 20727742 TI - Effect of bimetallic and polymer-coated Fe nanoparticles on biological denitrification. AB - Bimetallic nanoparticles (nano Fe-Ni, nano Fe-Cu) and coated iron nanoparticles (chitosan-Fe(0), sodium oleate-Fe(0)) were utilized to support autotrophic denitrification. In comparison to nanoscale zero-valent iron (NZVI) particles, Ni containing nanoparticles resulted in faster nitrate removal, but generated 17% more ammonium. The nano Fe-Cu integrated system, required two days less than the unmodified NZVI integrated system to remove all the nitrate and decrease ammonium by 13%, but a large amount of nitrite remained in the system. Compared to uncoated NZVI particles, chitosan-coated nanoparticles allowed the same nitrate removal time but 23% more ammonium production. The sodium oleate-Fe(0) nanoparticles did not only decrease the generation of ammonium by 17%, but also reduced the toxicity of the nanoparticles to bacteria. Therefore, sodium oleate Fe(0) nanoparticles may be an appropriate substitute for NZVI particles to support autotrophic denitrification provided that additional time (two days) is allowed for complete nitrate removal. PMID- 20727743 TI - Discovery of quinolines as selective glucocorticoid receptor agonists. AB - The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR selective over other nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Compounds were shown to be efficacious in cell assays with respect to inflammation endpoints, along with reduced activity in a transactivation assay, hinting at an improved therapeutic window over corticosteroids. PMID- 20727744 TI - Azole derivatives as histamine H3 receptor antagonists, part 2: C-C and C-S coupled heterocycles. AB - With a small series of compounds we demonstrated the variability in the core region of the human histamine H(3) receptor (hH(3)R) antagonist structural blueprint by introducing polar azole groups (oxazole, oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the heterocyclic core structure led to further optimisation of in vitro receptor binding of the novel azole derivatives. PMID- 20727745 TI - Neopetrosiamine A, biologically active bis-piperidine alkaloid from the Caribbean sea sponge Neopetrosia proxima. AB - A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosiaproxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its (1)H and (13)C NMR data with those of a well-known 3-alkylbis-piperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum. PMID- 20727746 TI - Structure-activity relationship of boronic acid derivatives of tyropeptin: proteasome inhibitors. AB - The structure-activity relationship of the boronic acid derivatives of tyropeptin, a proteasome inhibitor, was studied. Based on the structure of a previously reported boronate analog of tyropeptin (2), 41 derivatives, which have varying substructure at the N-terminal acyl moiety and P2 position, were synthesized. Among them, 3-phenoxyphenylacetamide 6 and 3-fluoro picolinamide 22 displayed the most potent inhibitory activity toward chymotryptic activity of proteasome and cytotoxicity, respectively. The replacement of the isopropyl group in the P2 side chain to H or Me had negligible effects on the biological activities examined in this study. PMID- 20727747 TI - Discovery of a class of calcium sensing receptor positive allosteric modulators; 1-(benzothiazol-2-yl)-1-phenylethanols. AB - 1-(Benzothiazol-2-yl)-1-(4-chlorophenyl)ethanol (1) was identified as a positive allosteric modulator (PAM) of the CaSR in a functional cell-based assay. This compound belongs to a class of compounds that is structurally distinct from other known positive allosteric modulators, for example, the phenylalkylamines cinacalcet, a modified analog (13) potently suppressed parathyroid hormone (PTH) release in rats, consistent with its profile as a PAM of CaSRs. PMID- 20727748 TI - Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: selection of the scaffold. AB - HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC(50) of 3 nM against wild type HIV infected T-cells. PMID- 20727749 TI - Pyrazolo[1,5-a]pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO). AB - Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 9 11) of the pyrazolo[1,5-a]pyrimidine acetamide class, all of which showed high binding affinity and selectivity for the TSPO and, in the case of the propyl, propargyl, and butyl ether derivatives, the ability to increase pregnenolone biosynthesis by 80-175% over baseline in rat C6 glioma cells. While these compounds fit our in silico generated pharmacophore for TSPO binding the current model does not account for the observed functional activity. PMID- 20727750 TI - Synthesis and biological evaluation of indomethacin analogs possessing a N difluoromethyl-1,2-dihydropyrid-2-one ring system: a search for novel cyclooxygenase and lipoxygenase inhibitors. AB - A novel class of indomethacin analogs were synthesized wherein a N-difluoromethyl 1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C 5 position via either a CO (14a-b) or CH(2) (19a-b) linker to the indole N(1) position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and N difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor 19a, COX-2 IC(50)=31 MUM), and moderate in vivo anti-inflammatory activities (except for the methylene compound 19a that was inactive). These structure-activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a N-difluoromethyl-1,2 dihydropyrid-2-one ring system connected by a CO or CH(2) linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin. PMID- 20727751 TI - Molecular alignment using multipole moments. AB - Molecules can be aligned on the basis of their computed electrical multipole moments. This description of molecular electrostatics is proposed and evaluated for similarity applications. It accurately models the charge distribution in compounds with medicinal chemistry interest where electrostatics is known to play an important role in their interaction with the target. PMID- 20727752 TI - Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1. AB - Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (kappa IC(50)=77 nM; MU:kappa and delta:kappa IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy benzamides showing potent and selectivity kappa antagonism as well as good brain exposure. Analog 6c (kappa IC(50)=20 nM; MU:kappa=36, delta:kappa=415) was also shown to reverse kappa-agonist induced rat diuresis in vivo. PMID- 20727753 TI - Design of a series of bicyclic HIV-1 integrase inhibitors. Part 2: azoles: effective metal chelators. AB - Synthesis of a diverse set of azoles and their utilizations as an amide isostere in the design of HIV integrase inhibitors is described. The Letter identified thiazole, oxazole, and imidazole as the most promising heterocycles. Initial SAR studies indicated that these novel series of integrase inhibitors are amenable to lead optimization. Several compounds with low nanomolar inhibitory potency are reported. PMID- 20727754 TI - Clinical and neuropathological findings in patients with TACO1 mutations. AB - We have recently identified mutations in the translation activator of cytochrome c oxidase 1 (TACO1) gene, leading to cytochrome c oxidase (COX) deficiency. Here, we report the clinical and neuroimaging findings of five members of a big consanguinous family homozygous for c.472insC in TACO1. All 5 patients had an uneventful early childhood and a subtle onset, slowly progressive cognitive dysfunction, dystonia or visual impairment between ages 4 and 16years. Affected girls had a milder phenotype and preserved ambulation into the late twenties. Brain MRI revealed bilateral, symmetric lesions of the basal ganglia in all affected family members, but less prominent in girls. TACO1 analysis showed no mutations in 17 patients with juvenile-onset Leigh syndrome and isolated COX or combined respiratory chain deficiency, indicating that TACO1 mutations are a rare cause of Leigh syndrome. PMID- 20727755 TI - An aerial-hawking bat uses stealth echolocation to counter moth hearing. AB - Ears evolved in many nocturnal insects, including some moths, to detect bat echolocation calls and evade capture [1, 2]. Although there is evidence that some bats emit echolocation calls that are inconspicuous to eared moths, it is difficult to determine whether this was an adaptation to moth hearing or originally evolved for a different purpose [2, 3]. Aerial-hawking bats generally emit high-amplitude echolocation calls to maximize detection range [4, 5]. Here we present the first example of an echolocation counterstrategy to overcome prey hearing at the cost of reduced detection distance. We combined comparative bat flight-path tracking and moth neurophysiology with fecal DNA analysis to show that the barbastelle, Barbastella barbastellus, emits calls that are 10 to 100 times lower in amplitude than those of other aerial-hawking bats, remains undetected by moths until close, and captures mainly eared moths. Model calculations demonstrate that only bats emitting such low-amplitude calls hear moth echoes before their calls are conspicuous to moths. This stealth echolocation allows the barbastelle to exploit food resources that are difficult to catch for other aerial-hawking bats emitting calls of greater amplitude. PMID- 20727756 TI - Social punishment of dishonest signalers caused by mismatch between signal and behavior. AB - Many animals use conventional signals of fighting ability to mediate aggressive conflict. Given the apparent benefits of signaling inaccurately high fighting ability, there is extensive interest in why animals communicate their abilities honestly [1]. One hypothesis is that inaccurate signalers receive social punishment that disfavors inaccuracy. Although the idea that social punishment can prevent dishonesty is appealing, questions about the evolutionary stability of this hypothesis remain [2]. For example, how do individuals know a rival is cheating? We independently manipulated a signal of fighting ability and agonistic behavior in Polistes dominulus wasps to test the behavioral mechanisms underlying social punishment. Remarkably, a mismatch between signal and behavior caused social punishment. Individuals with experimentally altered signals received more aggression from rivals. Individuals with experimentally altered behavior were less able to establish dominance relationships. In contrast, control individuals and those with experimentally altered signal and behavior suffered neither cost. They received little aggression and established stable dominance relationships. Therefore, individuals use information about the match between signal and behavior to assess the accuracy of rival signals. A mismatch produces costly social interactions. This simple behavioral mechanism provides a clear cost to signal inaccuracy that may maintain honest communication over evolutionary time. PMID- 20727757 TI - Human parietal cortex structure predicts individual differences in perceptual rivalry. AB - When visual input has conflicting interpretations, conscious perception can alternate spontaneously between competing interpretations [1]. There is a large amount of unexplained variability between individuals in the rate of such spontaneous alternations in perception [2-5]. We hypothesized that variability in perceptual rivalry might be reflected in individual differences in brain structure, because brain structure can exhibit systematic relationships with an individual's cognitive experiences and skills [6-9]. To test this notion, we examined in a large group of individuals how cortical thickness, local gray matter density, and local white-matter integrity correlate with individuals' alternation rate for a bistable, rotating structure-from-motion stimulus [10]. All of these macroscopic measures of brain structure consistently revealed that the structure of bilateral superior parietal lobes (SPL) could account for interindividual variability in perceptual alternation rate. Furthermore, we examined whether the bilateral SPL regions play a causal role in the rate of perceptual alternations by using transcranial magnetic stimulation (TMS) and found that transient disruption of these areas indeed decreases the rate of perceptual alternations. These findings demonstrate a direct relationship between structure of SPL and individuals' perceptual switch rate. PMID- 20727758 TI - Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. AB - Homeostasis in the Drosophila midgut is maintained by stem cells [1, 2]. The intestinal epithelium contains two types of differentiated cells that are lost and replenished: enteroendocrine (EE) cells and enterocytes (ECs). Intestinal stem cells (ISCs) are the only cells in the adult midgut that proliferate [3, 4], and ISC divisions give rise to an ISC and an enteroblast (EB), which differentiates into an EC or an EE cell [3-5]. If the midgut epithelium is damaged, then ISC proliferation increases [6-12]. Damaged ECs express secreted ligands (Unpaired proteins) that activate Jak-Stat signaling in ISCs and EBs to promote their proliferation and differentiation [7, 9, 13, 14]. We show that the Hippo pathway components Warts and Yorkie mediate a transition from low- to high level ISC proliferation to facilitate regeneration. The Hippo pathway regulates growth in diverse organisms and has been linked to cancer [15, 16]. Yorkie is activated in ECs in response to tissue damage or activation of the damage-sensing Jnk pathway. Activation of Yorkie promotes expression of unpaired genes and triggers a nonautonomous increase in ISC proliferation. Our observations uncover a role for Hippo pathway components in regulating stem cell proliferation and intestinal regeneration. PMID- 20727759 TI - Visual control of altitude in flying Drosophila. AB - Unlike creatures that walk, flying animals need to control their horizontal motion as well as their height above the ground. Research on insects, the first animals to evolve flight, has revealed several visual reflexes that are used to govern horizontal course. For example, insects orient toward prominent vertical features in their environment [1-5] and generate compensatory reactions to both rotations [6, 7] and translations [1, 8-11] of the visual world. Insects also avoid impending collisions by veering away from visual expansion [9, 12-14]. In contrast to this extensive understanding of the visual reflexes that regulate horizontal course, the sensory-motor mechanisms that animals use to control altitude are poorly understood. Using a 3D virtual reality environment, we found that Drosophila utilize three reflexes--edge tracking, wide-field stabilization, and expansion avoidance--to control altitude. By implementing a dynamic visual clamp, we found that flies do not regulate altitude by maintaining a fixed value of optic flow beneath them, as suggested by a recent model [15]. The results identify a means by which insects determine their absolute height above the ground and uncover a remarkable correspondence between the sensory-motor algorithms used to regulate motion in the horizontal and vertical domains. PMID- 20727760 TI - Delayed onset of electromyographic activity of vastus medialis obliquus relative to vastus lateralis in subjects with patellofemoral pain syndrome. AB - Patellofemoral Pain Syndrome (PFPS) is a common musculoskeletal complaint. The presence of a delay between vastus medialis obliquus (VMO) and vastus lateralis (VL) muscle onset has been suggested in the literature as a possible cause of PFPS, with poor agreement amongst authors on the value of the delay. In this study we computed the delay in the activation of VMO and VL in 15 PFPS patients and 20 age-matched controls (Ctrls) during the following tasks: sit to stand, stand to sit, squat, step up and step down. Activation instants were detected from surface EMG data by a double-threshold statistical detector. In order to compare the muscle activity throughout the task, we computed the delay between the instants in which the VMO and VL normalised envelopes reached subsequent normalised amplitude levels, until the envelope peak. In all investigated tasks but sit to stand, the onset delay was lower or equal then 0.02s, without group differences. Similarly, no differences between Ctrls and PFPS timing were found throughout all tasks, until the peak. Our results do not support the hypothesis that an onset delay between VMO and VL can be one of the causes of PFPS. PMID- 20727761 TI - Deep brain stimulation of the pedunculopontine tegmentum and subthalamic nucleus: effects on gait in Parkinson's disease. AB - OBJECTIVE: This study examines the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) and pedunculopontine tegmentum (PPTg) DBS in advanced Parkinson's disease using gait analysis. METHODS: Five people underwent bilateral DBS in both the STN and PPTg. Gait analysis was performed one year after neurosurgery using an optoelectronic system. The effects of DBS (STN, PPTg and STN+PPTg) were studied in two clinical conditions: without (Off) and during (On) antiparkinsonian therapy. RESULTS: PPTg and STN DBS were associated with changes in spatio-temporal and kinematics variables. CONCLUSIONS: Although experimental data cannot be generalized widely due to the small sample, PPTg DBS appears to affect the neuronal circuits subserving gait. PMID- 20727762 TI - Acute effects of fatigue of the plantarflexor muscles on different postural tasks. AB - Although the effect of muscle fatigue on posture is apparent, results are inconsistent across studies and this may be due to differences in the fatigue protocol, postural stance used and/or amount of visual information provided. The purpose of this study was to test the hypothesis that fatigue would have a more pronounced effect for more difficult compared with less difficult postural tasks. Twenty-three young adults (mean age 22 +/- 3 years) were asked to perform three different postural tasks on a force-platform: feet together, semi-tandem and single-leg stance, before and immediately after fatiguing the plantarflexor muscles. Three 30-s trials were performed for each postural task with eyes open and eyes closed. The fatigue protocol consisted of an isometric contraction of the plantarflexor muscles, with subjects instructed to rise on their toes and maintain this position until exhaustion. The 95% ellipse area of the center of pressure (COP), as well as the COP sway amplitudes (standard deviation) and sway velocities in the antero-posterior and medio-lateral directions were calculated. All variables were greater for each postural task performed without vision compared to with vision, with the greatest difference found during the single-leg task. For both visual conditions, all variables increased as the difficulty of the task increased. Fatigue of the plantarflexor muscles mostly affected postural sway variables during single-leg and feet together tasks. In conclusion, the reduction in postural stability with muscle fatigue of the plantarflexors does not depend on the difficulty of the postural task. PMID- 20727763 TI - Comparison of visual and haptic feedback during training of lower extremities. AB - We compared the effects of visual and haptic modalities on the adaptation capabilities of healthy subjects to the virtual environment. The visual cueing (only the reference motion is presented) and visual feedback (the reference motion as well as the current tracking deviation are presented) were provided by a real-time visualization of a virtual teacher and a virtual self - avatar, using optical measurements. The subjects had to track the virtual teacher during stepping-in-place movements. The haptic feedback was provided by the actuated gait orthosis Lokomat programmed with the same stepping movements employing an impedance control algorithm. Both setups included auditory cueing. The stepping task was performed by engaging different modalities separately as well as combined. The results showed that (1) visual feedback alone yielded better tracking of the virtual teacher than visual cueing alone, (2) haptic feedback alone yielded better tracking than any visual modality alone, (3) haptic feedback and visual feedback combined yielded better tracking than haptic feedback alone, and (4) haptic feedback combined with visual cueing did not improve tracking performance compared to haptic feedback alone. In general, we observed a better task performance with the haptic modality compared to visual modality. PMID- 20727765 TI - A simple behavioral test for locomotor function after brain injury in mice. AB - To establish a simple and reliable test for assessing locomotor function in mice with brain injury, we developed a new method, the rotarod slip test, in which the number of slips of the paralytic hind limb from a rotarod is counted. Brain injuries of different severity were created in adult C57BL/6 mice, by inflicting 1-point, 2-point and 4-point cryo-injuries. These mice were subjected to the rotarod slip test, the accelerating rotarod test and the elevated body swing test (EBST). Histological analyses were performed to assess the severity of the brain damage. Significant and consistent correlations between test scores and severity were observed for the rotarod slip test and the EBST. Only the rotarod slip test detected the mild hindlimb paresis in the acute and sub-acute phase after injury. Our results suggest that the rotarod slip test is the most sensitive and reliable method for assessing locomotor function after brain damage in mice. PMID- 20727764 TI - CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long term survival. AB - A growing body of evidence supports the significant interplay between the immune system and glioma pathogenesis. Here we investigate whether the extent of local glioma-associated CD8+ T-cell infiltrate at initial presentation correlates with long-term survival in patients with glioblastoma multiforme (GBM). The study was conducted by the University of California San Francisco Brain Tumor Research Center as part of the San Francisco Bay Area Adult Glioma Study, which included over 519 patients with GBM. A central neuropathology review was performed and populations of infiltrating CD8+ T-cells were quantified histologically. Of 108 patients studied, 43 patients had poor survival (<95days) and 65 patients had extended long-term survival of >403days. Tumors from long-term survivors were more likely than short-term survivors to have intermediate or extensive T-cell infiltrates compared to focal or rare infiltrates, and this association appears to be most significant in Caucasian women (p < 0.006). Thus, CD8+ T-cell infiltrate is associated with prolonged survival. Our data provide the impetus for more sophisticated studies to further elucidate prospectively the specific T cell subtypes associated with long-term survival. PMID- 20727766 TI - Occipital ganglioglioma in an older adult. AB - Gangliogliomas are rare benign tumors of the central nervous system that typically involve the temporal lobe in younger patients. We present a 63-year-old man with an unusual occipital ganglioma with new seizures resolving after resection. A search of the literature revealed only three reports of occipital ganglioma in adults over 30 years old. Therefore, ganglioglioma of the occipital lobe in older patients is rare, but is a diagnostic consideration. PMID- 20727767 TI - Morphological differences between the aneurysmal and normal artery in patients with internal carotid-posterior communicating artery aneurysm. AB - The aim of this study was to identify image-based morphological parameters that correlated with the formation of internal carotid artery-posterior communicating artery (ICA-PcomA) aneurysms. Morphological parameters obtained from 3 dimensional digital subtraction angiography (3D-DSA) were evaluated from nine patients with ICA-PcomA aneurysms, including the diameter of the ICA (Dica) and PcomA (Dpcom), the angle between the ICA and the origin of the PcomA (Apcom), and the angle between the ophthalmic and communicating segments of the ICA (Aica). Measurements were performed on both sides of each patient. Parameters were analyzed with a paired-samples t-test for significance. In additional, receiver operating characteristic (ROC) analysis was performed on the significant parameter. Statistically significant differences were found between the aneurysmal (45.28+/-29.07 degrees ) and control sides (79.22+/-17.83 degrees ) for Apcom (p=0.020). In the ROC analysis, the area under the curve value of Apcom was 0.852, and the threshold for optimal sensitivity and specificity was 52.25 degrees . Therefore, the Apcom parameter was correlated with the formation of an ICA-PcomA aneurysm, and seems to be a promising morphological parameter for risk assessment of aneurysm formation. PMID- 20727768 TI - Commentary: the past, present and future of imaging in multiple sclerosis. PMID- 20727769 TI - Multiple myeloma presenting as solitary mass in the posterior fossa. AB - Intracranial plasma cell tumors are extremely rare and can either be solitary lesions or part of systemic multiple myeloma. We report a 42-year-old woman who presented with a posterior fossa mass and successfully underwent surgical resection, leading to the diagnosis of multiple myeloma. To our knowledge, this is the first reported case of multiple myeloma presenting as a posterior fossa mass lesion. This report highlights the importance of maintaining plasma cell tumor in the differential of intracranial mass with bony involvement. Furthermore, once the diagnosis is established, further work up is critical to evaluate for systemic disease. PMID- 20727770 TI - MRI sequence findings in sporadic Creutzfeldt-Jakob disease. AB - MRI has had an important role in the diagnosis of Creutzfeldt-Jakob disease (CJD). The aim of our study was to compare the efficacy of different MRI sequences among six biopsy-proven patients with sporadic CJD (sCJD) and seven patients with probable sCJD. These 13 patients with CJD aged from 36 years to 75 years (mean age: 55.5 years) were evaluated with T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) MRI and diffusion-weighted imaging (DWI). The characteristic MRI lesion pattern was found to be bilateral, symmetric and hyperintense signal changes in the basal ganglia and cortical regions. Two major lesion patterns were identified in all patients involving the cortex and basal ganglia. No signal abnormality was found in the thalamus. We found lesions in the cortex and basal ganglia in 7/13 patients (54%), isolated cortical involvement in 2/13 patients (15%), and isolated basal ganglia lesions in 4/13 patients (31%). The cortical involvement was widespread (in at least two regions) and usually included the frontal or occipital lobes (9/13, 69%) on DWI. Only one patient showed moderate high-signal intensity in the basal ganglia on T2-weighted MRI. T1-weighted MRI revealed no signal intensity abnormalities. We conclude that high signal changes in the basal ganglia and cerebral cortex on FLAIR and DWI are useful in the diagnosis of sCJD. Isolated cortical involvement on DWI and FLAIR should lead to a suspicion of CJD. DWI is the most sensitive MRI technique in the diagnosis of CJD, which supports an amendment to the clinical diagnostic criteria for sCJD to include findings from MRI. PMID- 20727771 TI - Hypertrophic pachymeningitis and cerebral venous sinus thrombosis in inflammatory bowel disease. AB - Hypertrophic pachymeningitis is rarely observed in inflammatory bowel disease. We report a woman with ulcerative colitis whose biopsy-confirmed hypertrophic pachymeningitis was complicated by cerebral venous sinus thrombosis and intracranial hypertension and required ventriculostomy and steroid therapy. This report highlights the challenges of the diagnosis and management of hypertrophic pachymeningitis from an unusual primary cause. PMID- 20727772 TI - Cellular strategies for the assembly of molecular machines. AB - Molecular machines are supramolecular assemblies of biomolecules (proteins, RNA and/or DNA) that facilitate a diversity of biological tasks in the cells of all organisms. How these complex structures are built within the crowded cellular environment is, therefore, a central question in the biological sciences. Recent studies on spliceosomal uridine-rich small nuclear ribonucleoproteins (snRNPs) have unveiled cellular assembly strategies for RNA-protein complexes. snRNPs form in vivo by the coordinated action of an elaborate assembly line consisting of assembly chaperones, scaffolding proteins and catalysts. These newly discovered strategies exhibit similarities to those employed by protein complexes such as ribulose-1,5-bisphosphate-carboxylase (Rubisco) and allow the elucidation of general rules for how molecular machines are formed in vivo. PMID- 20727773 TI - Identification of novel antitubercular compounds through hybrid virtual screening approach. AB - Growing resistance of prevalent antitubercular (antiTB) agents in clinical isolates of Mycobacterium tuberculosis (MTB) provoked an urgent need to discover novel antiTB agents. Enoyl acyl carrier protein (ACP) reductase (InhA) from Mtb is a well known and thoroughly studied as antitubucular therapy target. Here we have reported the discovery of potent antiTB agents through ligand and structure based approaches using computational tools. Initially compounds with more than 0.500 Tanimoto similarity coefficient index using functional class fingerprints (FCFP_4) to the reference chemotype were mined from the chemdiv database. Further, the molecular docking was performed to select the compounds on the basis of their binding energies, binding modes, and tendencies to form reasonable interactions with InhA (PDB ID=2NSD) protein. Eighty compounds were evaluated for antitubercular activity against H37RV M. tuberculosis strain, out of which one compound showed MIC of 5.70 microM and another showed MIC of 13.85 microM. We believe that these two new scaffolds might be the good starting point from hit to lead optimization for new antitubercular agents. PMID- 20727774 TI - Porosity calculations using a C/O logging tool with boron-lined NaI detectors. AB - In the present work, a boron lining is added to a NaI detector assembly to study the possibility of combining both the C/O tool and the thermal neutron porosity tool in one tool, both of which are commonly used tools in oil well logging. The combined tool proposed in this paper was modeled with the general purpose Monte Carlo N-particle (MCNP) transport code. The simulation results show a good porosity sensitivity (especially to low porosity values). The results also show a great reduction in the neutron flux incident on the detectors and consequently the reduction of detector activation by thermal neutrons. PMID- 20727775 TI - gamma-Ray spectroscopy in the decays of 80m Br and 82g Br. AB - High-resolution spectroscopy has been used to determine the energies and intensities of the gamma-rays emitted in the decays of (80m)Br and (82g)Br, produced by neutron activation of naturally occurring Br. From the observed energies and intensities, improved values for the energies and beta-decay feedings of the levels in the daughter nuclides (80)Se, (80)Kr, and (82)Kr have been deduced. PMID- 20727776 TI - The feasibility of in vivo detection of gadolinium by prompt gamma neutron activation analysis following gadolinium-based contrast-enhanced MRI. AB - The feasibility of using the McMaster University in vivo prompt gamma neutron activation analysis system for the detection of gadolinium has been investigated. Phantoms have been developed for the kidney, liver, and the leg muscle. The initial detection limits are determined to be 7.2 +/- 0.3 ppm for the kidney, 3.0 +/- 0.1 ppm for the liver, and 2.33 +/- 0.08 ppm for the lower leg muscle. A few system optimizations have been tested and show significant detection limit reduction from these initial values. The technique is promising and shows feasibility for in vivo studies of gadolinium retention. PMID- 20727777 TI - No evidence for antineutrinos significantly influencing exponential beta+ decay. AB - High-precision measurements were conducted on the time evolution of gamma-ray count rates during reactor-on and reactor-off periods to investigate the possible influence of antineutrinos on nuclear decay. This experiment was triggered by a recent analysis (Jenkins et al., 2009) of long-term measurements suggesting a possible link to variations in nuclear decay rate and solar neutrino flux. The antineutrino flux during reactor-off periods is mainly due to geoneutrinos and four orders of magnitude lower than during reactor-on periods. No effects have been observed for the two branches in the decay of (152)Eu and the decay of (137)Cs, (54)Mn and (22)Na. The upper limit determined of the ratio Deltalambda/lambda for (22)Na is (-1+/-2)*10(-4), and (54)Mn is (-1+/-4)*10(-4). In comparison to the interpretation of Jenkins et al. our measurements do not show any such effect to at least two orders of magnitude less. Hence either the hypothesis of Jenkins et al. is not true or else one of two rather unlikely possibilities must also be true: either the effect of neutrinos on beta(-) decay differs considerably from the effect of antineutrinos on beta(+) decay, or the effect of antineutrinos on beta(+) decay must be identical to their effect on beta(-) and electron-capture decay. PMID- 20727778 TI - Textiloma of the frontal bone twenty years after craniotomy for Apert syndrome. AB - INTRODUCTION: The presence of intracranial foreign body granulomas is an unusual condition. They can be caused by foreign substances which are either inadvertently or deliberately left in the surgical field. Some foreign materials (textilomas, gossypibomas, gauzomas, muslinomas) along with the resulting foreign body reaction, in the surrounding tissue, can cause infection or abscess formation in an early stage whereas others remain clinically silent for many years. PATIENT: We present the case of a foreign body granuloma (textiloma) caused by a gauze which had been placed, during a corrective craniotomy, in a patient with Apert syndrome at the age of five. At presentation the clinical and radiological findings were suggestive of an infection. RESULTS: Surgical exploration of the region demonstrated the presence of gauze, in a frontal bone defect, surrounded by large masses of reactive granular tissue which were extended to the underlying dura mater. The symptoms resolved completely after the foreign body's retrieval. CONCLUSION: Foreign body granulomas, although rare, must always be taken under consideration in the differential diagnosis of craniofacial masses or procedures; especially in cases where a previous craniofacial operation has taken place. PMID- 20727779 TI - Repair of the calcified bicuspid aortic valve. AB - The novel repair technique of calcified bicuspid aortic valve is described, in which the calcified body of the cusps is repaired with autologous pericardium leaving the native free margin and commissures in place for anchoring. The technique has been used in 48 consecutive patients offering excellent early results. PMID- 20727781 TI - What is the best method of cerebral protection? PMID- 20727782 TI - Meta-analysis of short-term and long-term survival following repair versus replacement for ischemic mitral regurgitation. AB - The optimal surgical strategy for the management of ischemic mitral regurgitation (IMR) is still debated. The purpose of this study was to perform a meta-analysis summarizing the evidence favoring one technique over another (repair vs replacement). A search of the English literature in PubMed was performed using 'ischemic mitral regurgitation' and 'repair or replacement or annuloplasty' in the title/abstract field. Articles were excluded if they lacked a direct comparison of repair versus replacement, or used Teflon/pericardial strip or suture annuloplasty in >10% of the repairs. Nine articles were selected for the final analysis. All studies except one were relatively recent (2004-2009). The patient characteristics between treatment groups were similar across studies. All studies excluded patients with degenerative etiology and used a rigorous definition of IMR. Most patients had concomitant coronary artery bypass graft. In the patients with mitral valve replacement, at least the posterior and, in many cases, the entire subvalvular apparatus were preserved. Mean ejection fraction and proportion of patients with severe ventricular dysfunction were similar between the repair and replacement groups. The odds ratios for the studies, comparing replacement to repair, ranged from 0.884 to 17.241 for short-term mortality and the hazard ratios ranged from 0.677 to 3.205 for long-term mortality. There was a significantly increased likelihood of both short-term mortality (summary odds ratio 2.667 (95% confidence interval (CI) 1.859-3.817)) and long-term mortality (summary hazard ratio 1.352 (95% CI 1.131-1.618)) for the replacement group compared to the repair group. Based on the meta-analysis of the current relevant literature, mitral valve repair for IMR is associated with better short-term and long-term survival compared to mitral valve replacement. Our conclusion should be interpreted in the context of the inherent limitations of a meta-analysis of retrospective studies including heterogeneity of patient characteristics, which may have influenced the physician's decision to perform mitral valve repair or replacement. In the absence of any published randomized studies, mitral procedure selection should be individualized. PMID- 20727783 TI - Pulmonary embolism in a patient with a biventricular assist device--imaging with multislice computed tomography. PMID- 20727785 TI - Dioxin analysis by gas chromatography-Fourier transform ion cyclotron resonance mass spectrometry (GC-FTICRMS). AB - The feasibility of utilizing a gas chromatograph-tandem quadrupole-Fourier transform ion cyclotron resonance mass spectrometer (GC-MS/MS-FTICRMS) to analyze chlorinated-dioxins/furans (CDDs/CDFs) and mixed halogenated dioxins/furans (HDDs/HDFs) was investigated by operating the system in the GC-FTICRMS mode. CDDs/CDFs and mixed HDDs/HDFs could be analyzed at 50,000 to 100,000 resolving power (RP) on the capillary gas chromatographic time scale. Initial experiments demonstrated that 1 pg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 5 pg of 2-bromo-3,7,8-trichlorodibenzo-p-dioxin (BTrCDD) could be detected. The feasibility of utilizing an FTICRMS for screening of CDDs/CDFs, HDDs/HDFs and related compounds was also investigated by analyzing an extract from vegetation exposed to fall-out from an industrial fire. CDDs/CDFs, chlorinated pyrenes and chlorinated tetracenes could be detected from a Kendrick plot analysis of the ultrahigh resolution mass spectra. Mass accuracies were of the order of 0.5 ppm on standards with external mass calibration and 1 ppm on a sample with internal mass calibration. PMID- 20727786 TI - Does the age of achieving pubertal landmarks predict cognition in older men? Guangzhou Biobank Cohort Study. AB - PURPOSE: Earlier pubertal maturation in women may be associated with better cognition. It is unclear whether or not this also occurs in men. We tested the hypothesis that earlier pubertal development in men was associated with better cognition in later adulthood in a developing Chinese population. METHODS: Multivariable linear regression was used in cross-sectional study of 2463 older, Chinese men from the Guangzhou Biobank Cohort Study. Mean pubertal age was calculated as the mean of recalled ages of first nocturnal emission, voice breaking and pubarche. We assessed the association of mean pubertal age with delayed 10-word recall and mini-mental state examination (MMSE) scores. RESULTS: Adjusted for age and education, 1 year earlier mean pubertal age was associated with higher delayed 10-word recall (0.06 [95% confidence interval = 0.02-0.10]) and higher MMSE (0.08 [0.03-0.13]) scores. Additional adjustment for childhood and adulthood socio-economic position, sitting height, and leg length did not change the results. CONCLUSIONS: These preliminary findings suggest earlier maturation in men is associated with better cognitive function in later adulthood. Whether pubertal timing is a marker of earlier life exposures or reflects a biological relation between somatrophic and/or gonadotrophic hormones and cognitive development is unclear. PMID- 20727788 TI - Muscle architecture variations along the human semitendinosus and biceps femoris (long head) length. AB - The purpose of this study was to examine whether muscle architecture of the long head of biceps femoris (BF) and semitendinosus (ST) muscles varies along their length. The ST and BF muscles were dissected and removed from their origins in eight cadaveric specimens (age range 67.8-73.4 years). One-way analysis of variance designs were used to compare fascicle length (FL), pennation angle (PA) and muscle thickness (MT) between proximal, mid-belly and distal positions. Tendon and muscle length properties were also quantified. For the BF muscle, one way analysis of variance tests showed a higher PA (23.96+/-3.82 degrees ) and FL (7.12+/-0.48 cm) proximally than distal positions (PA=17.78+/-1.95 degrees and FL=6.35+/-0.89 cm, respectively). For the ST, there was a significantly (p<0.05) lower PA (8.81+/-1.22 degrees ) and FL (13.10+/-1.54 cm) proximally than distally (PA=14.69+/-1.09 degrees and FL=15.49+/-2.30 cm, respectively). Muscle thickness significantly increased from distal to more proximal positions (p<0.05). These data suggest that the ST and BF architecture is not uniform and that measurement of these parameters largely depends on the measurement site. Modeling these muscles by assuming a uniform architecture along muscle length may yield less accurate representation of human hamstring muscle function. PMID- 20727784 TI - Immune regulatory cells in umbilical cord blood and their potential roles in transplantation tolerance. AB - Umbilical cord blood (UCB) is a source of primitive hematopoietic stem (HSC) and progenitor cells, that served as an alternative to bone marrow (BM) for effective transplantation therapy. Success of HSC transplantation (HSCT) is limited in part by graft-versus-host disease (GVHD), graft rejection and delayed immune reconstitution, which all relate to immunological complications. GVHD after UCB transplantation is lower compared to that of BM HSCT. This may relate to the tolerogenic nature of T cells, mononuclear cells (MNCs) and especially immune regulatory cells existing in UCB. UCB contains limiting numbers of HSC or CD34(+) cell dose for adult patients resulting in delayed engraftment after UCB transplantation (UCBT). This needs to be improved for optimal transplantation outcomes. Approaches have been undertaken to promote HSC engraftment, including co-infusion of multiple units of UCB cells. These new methods however added additional immunological complications. Herein, we describe current knowledge on features of UCB immune cells, including regulatory T cells (Tregs) and mesenchymal stem/stromal cells (MSCs) and their potential future usage to reduce GVHD. PMID- 20727787 TI - Trends in hypertension prevalence, awareness, treatment and control in older Mexican Americans, 1993-2005. AB - PURPOSE: To describe trends in hypertension prevalence, awareness, treatment, and control among older Mexican Americans living in the Southwestern United States from 1993-1994 to 2004-2005. METHODS: This study is a comparison between two separate cross-sectional cohorts of non-institutionalized Mexican Americans 75 years of age or older from the Hispanic Established Population for the Epidemiological Study of the Elderly (919 subjects from the 1993-1994 cohort and 738 from the 2004-2005 cohort). Data were collected on self-reported hypertension, measured blood pressure, medications, as well as sociodemographic and other health-related factors. RESULTS: Hypertension prevalence increased from 73.0% in the period 1993-1994 to 78.4% in 2004-2005. Cross-cohort multivariate analyses showed that the higher odds of hypertension in the 2004-2005 cohort was attenuated by adding diabetes and obesity to the model. There was a significant increase in hypertension awareness among hypertensives (63.0% to 82.6%) and in control among treated hypertensives (42.5% to 55.4%). Cross-cohort multivariate analyses showed that the higher odds of control in 2004-2005 cohorts were accentuated by adding diabetes to the model. There were no significant changes in treatment rates (62.2% to 65.6%) CONCLUSION: Hypertension prevalence in very old Mexican Americans residing in the Southwestern United States was higher in 2004 2005 than in 1993-1994 and was accompanied by a significant increase in awareness and control rates. PMID- 20727789 TI - Newly diagnosed atrial fibrillation after acute ischemic stroke and transient ischemic attack: importance of immediate and prolonged continuous cardiac monitoring. AB - Atrial fibrillation (AF) is the major cause of cardioembolic stroke. It often remains occult when asymptomatic and paroxysmal. We hypothesized that the detection of AF after acute ischemic stroke (AIS) or transient ischemic attack (TIA) could be improved by using continuous cardiac monitoring (CCM) immediately after admission. We sought to determine the detection rate of AF by immediate in hospital CCM after cryptogenic and noncryptogenic AIS or TIA in patients without a previous diagnosis of AF. We retrospectively studied a cohort of 155 patients with cryptogenic and noncryptogenic AIS or TIA without known AF. We compared the detection rates of newly diagnosed AF (NDAF) in patients admitted to areas with CCM and those never admitted to these areas. We developed a multiple logistic regression model for identifying predictors of NDAF. We characterized NDAF episodes and analyzed how the availability of CCM data changed secondary prevention strategies. We detected NDAF in 21 patients (13.5%). Diagnostic rates of NDAF in patients who underwent CCM and those who did not undergo CCM were 18.2% and 2.2%, respectively (P = .005). The median time from admission to recognition of NDAF was 2.0 days. Most NDAFs were paroxysmal (95.2%) and lasted less than 1 hour (85.7%). Diabetes mellitus and infarct size were predictors of NDAF. Detection of NDAF prompted the initiation of anticoagulation therapy in 8.2% of the patients admitted to areas with CCM availability. Our findings suggest that immediate and prolonged CCM significantly improves the detection of NDAF after cryptogenic and noncryptogenic AIS or TIA, and that diabetes mellitus and infarct size are significantly associated with NDAF. PMID- 20727790 TI - Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. AB - A large and diverse array of chemoattractants control leukocyte trafficking, but how these apparently redundant signals collaborate in vivo is still largely unknown. We previously demonstrated an absolute requirement for the lipid chemoattractant leukotriene B(4) (LTB(4)) and its receptor BLT1 for neutrophil recruitment into the joint in autoantibody-induced arthritis. We now demonstrate that BLT1 is required for neutrophils to deliver IL-1 into the joint to initiate arthritis. IL-1-expressing neutrophils amplify arthritis through the production of neutrophil-active chemokines from synovial tissue cells. CCR1 and CXCR2, two neutrophil chemokine receptors, operate nonredundantly to sequentially control the later phase of neutrophil recruitment into the joint and mediate all neutrophil chemokine activity in the model. Thus, we have uncovered a complex sequential relationship involving unique contributions from the lipid mediator LTB(4), the cytokine IL-1, and CCR1 and CXCR2 chemokine ligands that are all absolutely required for effective neutrophil recruitment into the joint. PMID- 20727791 TI - Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1. AB - T cell factor 1 (TCF-1) is a transcription factor known to act downstream of the canonical Wnt pathway and is essential for normal T cell development. However, its physiological roles in mature CD8(+) T cell responses are unknown. Here we showed that TCF-1 deficiency limited proliferation of CD8(+) effector T cells and impaired their differentiation toward a central memory phenotype. Moreover, TCF-1 deficient memory CD8(+) T cells were progressively lost over time, exhibiting reduced expression of the antiapoptotic molecule Bcl-2 and interleukin-2 receptor beta chain and diminished IL-15-driven proliferation. TCF-1 was directly associated with the Eomes allele and the Wnt-TCF-1 pathway was necessary and sufficient for optimal Eomes expression in naive and memory CD8(+) T cells. Importantly, forced expression of Eomes partly protected TCF-1-deficient memory CD8(+) T cells from time-dependent attrition. Our studies thus identify TCF-1 as a critical player in a transcriptional program that regulates memory CD8 differentiation and longevity. PMID- 20727793 TI - The phosphatase PTP-PEST promotes secondary T cell responses by dephosphorylating the protein tyrosine kinase Pyk2. AB - PTP-PEST (encoded by Ptpn12) is an intracellular protein tyrosine phosphatase belonging to the same family as LYP. LYP inhibits secondary T cell responses by suppressing Src family protein tyrosine kinases and is implicated in human autoimmunity. To determine the function of PTP-PEST in T cells, we generated mice with a conditionally deleted allele of Ptpn12. By removing PTP-PEST in T cells, we determined that PTP-PEST was not necessary for T cell development or primary responses. However, PTP-PEST was required for secondary T cell responses, anergy prevention, and autoimmunity induction. PTP-PEST specifically regulated the phosphorylation of Pyk2, a substrate of the Src family kinase Fyn. It also promoted the formation of T cell homoaggregates, which are known to enhance T cell activation. Thus, PTP-PEST controls Pyk2 activity and is a positive regulator of secondary T cell activation. These data illustrate the critical role of protein tyrosine phosphatases in T cell regulation. PMID- 20727792 TI - Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells. AB - Natural Killer T (NKT) cells are lipid-reactive, CD1d-restricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of alpha-galactosidase A (alpha-Gal-A) in lysosomes. Here, we show that alpha-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of alpha-Gal-A activity in antigen presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of alpha-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells. PMID- 20727794 TI - Carotid endarterectomy for symptomatic, but "haemodynamically insignificant" carotid stenosis. AB - OBJECTIVE: Carotid endarterectomy (CEA) guidelines in symptomatic carotid stenosis are based on NASCET and ECST criteria with 70% or greater carotid stenosis as estimated from a catheter angiogram the major indication. This has several problems: (1) lack of reliable correlation between non-invasive imaging and catheter angiography, which has been largely superseded by non-invasive imaging in investigating carotid stenosis; (2) errors inherent in estimating the degree of stenosis from catheter angiography; (3) disregard for the fact that stroke risk also depends on plaque stability, and number of ischaemic events. METHODS: A retrospective review of ischaemic events, imaging results, operative findings, surgical complications and stroke-free follow-up in 31 patients presenting over a 23 year period with TIA/stroke (symptoms lasting > 24 h and/or imaging evidence of infarction) who had 70% or less carotid stenosis (on non invasive imaging), but nonetheless underwent CEA. RESULTS: Nineteen patients had small strokes, 7 had TIAs and 5 had ocular events; 28 patients had features of unstable plaque on imaging; 19 patients experienced multiple events before CEA. All had haemorrhagic, ruptured plaque at CEA. One patient suffered an intra operative stroke, only 1 patient suffered a further stroke/TIA (mean follow-up 4.2 years). CONCLUSION: To predict the likelihood of major stroke in symptomatic carotid stenosis and the benefit of CEA, plaque stability and the number of ischaemic events might be as important as an estimate of the degree of stenosis. PMID- 20727795 TI - The impact of hypovolaemic shock on the aortic diameter in a porcine model. AB - OBJECTIVES: To investigate the impact of hypovolaemic shock on the aortic diameter in a porcine model, and to determine the implications for the endovascular management of hypovolaemic patients with traumatic thoracic aortic injury (TTAI). MATERIALS AND METHODS: The circulating blood volume of seven Yorkshire pigs was gradually lowered in 10% increments. At 40% volume loss, an endograft was deployed in the descending thoracic aorta, followed by gradual fluid resuscitation. Potential changes in aortic diameter during the experiment were recorded using intravascular ultrasound (IVUS). RESULTS: The aortic diameter decreased significantly at all evaluated levels during blood loss. The ascending aortic diameter decreased on average with 38% after 40% blood loss (range 24-62%, p = 0.018), the descending thoracic aorta with 32% (range 18-52%, p = 0.018) and the abdominal aorta with 28% (range 15-39%, p = 0.018). The aortic diameters regained their initial size during fluid resuscitation. CONCLUSION: The aortic diameter significantly decreases during blood loss in this porcine model. If these changes take place in hypovolaemic TTAI patients as well, it may have implications for thoracic endovascular aortic repair (TEVAR). Increased oversizing of the endograft, or additional computed tomography (CT) or IVUS imaging after fluid resuscitation for more adequate aortic measurements, may be needed in TTAI patients with considerable blood loss. PMID- 20727796 TI - Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease. AB - INTRODUCTION: Therapeutic goals have been described to monitor achievement, maintenance and continuity of therapeutic response in patients with type 1 Gaucher disease receiving enzyme replacement therapy. AIM: To benchmark the impact of velaglucerase alfa treatment against therapeutic goals for 5 key clinical parameters of type 1 Gaucher disease (anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology). METHODS: In an open-label Phase I/II study, twelve adults with symptomatic type 1 Gaucher disease and intact spleens received velaglucerase alfa for 9 months (60 U/kg infusion every other week [EOW]). Eleven patients completed the study and 10 enrolled in a long term extension. After 1 year, patients who achieved >= 2 hematological or organ goals began step-wise dose reduction from 60 to 45 then 30 U/kg EOW. Data for anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology at baseline and 4 years are available for 8 patients (3 male, 5 female). The proportion of patients at goal for anemia, thrombocytopenia, hepatomegaly and splenomegaly at baseline was compared with the proportion achieving each goal at 4 years. The proportion achieving the skeletal pathology goal was determined on the basis of Z-score improvement from baseline to 4 years. The proportion of patients who achieved all 5 goals at 4 years was compared with the proportion at goal for all 5 parameters at baseline. RESULTS: At baseline, no patient was at goal for all clinical parameters. After 1 year of treatment, all patients maintained goals present at baseline, and all achieved >= 2 goals. All 8 patients began step-wise dose reduction from 60 to 30 U/kg EOW between 15 and 18 months. By year 4 of treatment, all patients met goals for all 5 clinical parameters; therefore 100% achievement was seen for each of the 5 long-term, therapeutic goals. DISCUSSION: In this velaglucerase alfa Phase I/II and extension study, clinically meaningful achievement of each long-term, therapeutic goal was observed for each patient, despite dose reduction after 1 year. This is the first report of a cohort where all patients receiving ERT for type 1 Gaucher disease achieved all 5 of these long-term, therapeutic goals within 4 years of starting treatment and after >= 2years dose reduction. PMID- 20727797 TI - Persistent pain and sensory changes following cosmetic breast augmentation. AB - BACKGROUND: Persistent postsurgical pain has been reported following cosmetic breast augmentation, but little is known about the underlying mechanisms. AIMS: To describe the prevalence, character, and impact of sensory changes and chronic pain following cosmetic breast augmentation and to assess possible causes of pain. METHODS: In September 2009, a detailed questionnaire was mailed to all 142 patients who underwent cosmetic breast augmentation at Viborg Private Hospital from 2004 to 2009. RESULTS: Ninety-five patients (66.9%) returned the questionnaire; mean age was 34.2 years (SD 9.3). All patients were operated by the same surgeon. Mean time since operation was 31.8 months. Forty-two patients (44.2%) reported having pain as a consequence of the operation, 9.5% had moderate to severe pain, and 6.3% regretted the cosmetic surgery due to pain. Patients with pain were less satisfied with the surgery than those without pain. Seventy two patients (75.8%) had sensory changes over the breast. There was an increased risk for developing pain in those with hypoesthesia (OR 4.6 (1.7-12.8)) and hyperesthesia (OR 2.6 (1.1-6.2)). Sixty-two percent had touch-evoked pain and 38% used pain descriptors that met the neuropathic pain diagnostic questionnaire (DN4) cut-off criteria for neuropathic pain. CONCLUSION: Sensory changes and persistent pain are common following cosmetic breast augmentation and may have a negative impact on daily activities and satisfaction after surgery. Findings suggest that neuropathic pain should be considered in these patients. Preoperative information about the risk of developing sensory changes and chronic pain after breast augmentation is important. PMID- 20727798 TI - 1H Homonuclear dipolar decoupling using symmetry-based pulse sequences at ultra fast magic-angle spinning frequencies. AB - We demonstrate here the application of symmetry-based pulse sequences for homonuclear dipolar decoupling in solid-state NMR at magic-angle spinning (MAS) frequencies up to 65 kHz using moderate radiofrequency (RF) amplitudes. Theoretical arguments favouring the requirement of low RF amplitudes at high MAS frequencies are given for these sequences. A comparison with wPMLGmmxx- is given at 65 kHz of MAS frequency to emphasise that the symmetry-based pulse sequences have a lower RF amplitude requirement at high MAS frequencies. PMID- 20727799 TI - Robust optimal design of diffusion-weighted magnetic resonance experiments for skin microcirculation. AB - Skin microcirculation plays an important role in several diseases including chronic venous insufficiency and diabetes. Magnetic resonance (MR) has the potential to provide quantitative information and a better penetration depth compared with other non-invasive methods such as laser Doppler flowmetry or optical coherence tomography. The continuous progress in hardware resulting in higher sensitivity must be coupled with advances in data acquisition schemes. In this article, we first introduce a physical model for quantifying skin microcirculation using diffusion-weighted MR (DWMR) based on an effective dispersion model for skin leading to a q-space model of the DWMR complex signal, and then design the corresponding robust optimal experiments. The resulting robust optimal DWMR protocols improve the worst-case quality of parameter estimates using nonlinear least squares optimization by exploiting available a priori knowledge of model parameters. Hence, our approach optimizes the gradient strengths and directions used in DWMR experiments to robustly minimize the size of the parameter estimation error with respect to model parameter uncertainty. Numerical evaluations are presented to demonstrate the effectiveness of our approach as compared to conventional DWMR protocols. PMID- 20727800 TI - Insilico studies on anthrax lethal factor inhibitors: pharmacophore modeling and virtual screening approaches towards designing of novel inhibitors for a killer. AB - Bacillus anthracis is a causative organism of anthrax. The main reason to use anthrax as a bioweapon is the combination of the spore's durability and the lethal toxaemia of the vegetative stage. In anthrax infection, lethal factor (LF) is playing crucial role in causing cell death, by inhibiting pathways that rely on this kinase family. The combination of vaccine and antibiotics is preferred as an effective treatment for this target. Till date, no small molecule inhibitor is identified as a drug on the target. In this study, we have performed pharmacophore modeling and docking studies to identify a novel small molecule inhibitor to target the Anthrax LF. The best pharmacophore model is used to screen approximately 2M drug-like small molecule database and yielded 2543 hits. Docking studies of the pharmacophore hits on to the active site of Anthrax LF resulted 120 structurally diverse hits. Out of 120 hits, based on synthetic feasibility, 17 hits are selected for further synthesis and pharmacological screening. In due course, we will publish the updated results. PMID- 20727801 TI - Comparing position and force control for interactive molecular simulators with haptic feedback. AB - This paper presents a novel tool for the analysis of new molecular structures which enables a wide variety of manipulations. It is composed of a molecular simulator and a haptic device. The simulation software deals with systems of hundreds or thousands of degrees of freedom and computes the reconfiguration of the molecules in a few tenths of a second. For the ease of manipulation and to help the operator understand nanoscale phenomena, a haptic device is connected to the simulator. To handle a wide variety of applications, both position and force control are implemented. To our knowledge, this is the first time the applications of force control are detailed for molecular simulation. These two control modes are compared in terms of adequacy with molecular dynamics, transparency and stability sensitivity with respect to environmental conditions. Based on their specificity the operations they can realize are detailed. Experiments highlight the usability of our tool for the different steps of the analysis of molecular structures. It includes the global reconfiguration of a molecular system, the measurement of molecular properties and the comprehension of nanoscale interactions. Compared to most existing systems, the one developed in this paper offers a wide range of possible experiments. The detailed analysis of the properties of the control modes can be easily used to implement haptic feedback on other molecular simulators. PMID- 20727802 TI - Hierarchical approach to conformational search and selection of computational method in modeling the mechanism of ester ammonolysis. AB - We describe automated procedures for the first stages of a systematic computational investigation of reaction mechanisms. They include (i) selection of computational method and basis set based on statistical analysis of structural and energy data relating to experimental values, (ii) determination of all distinct conformations of transition states with large conformational freedom, and (iii) generation of unknown geometry of the transition states, based on pre defined connectivity of the atoms involved in the reaction. For the conformational search we employed an efficient procedure for exploration of various possible conformations of the transition states and elimination of the equivalent structures in several steps using molecular-mechanical and quantum mechanical methods. The procedure was applied to the determination of the structures of transition states and intermediates in the ammonolysis of monoformylated 1,2-ethanediol, which were subsequently used for identification of the lowest energy reaction paths. For the same reaction system we also used the approach for generation of the initial structures of transition states with unknown geometry. The reported procedures are implemented in the MolRan program suite. PMID- 20727803 TI - [Adverse reactions to iodinated contrast media]. AB - OBJECTIVE: The aim of the study is to determine the incidence of adverse reactions to iodinated contrast media and to characterise them in a group of outpatients, inpatients and emergency patients in a private hospital in Barcelona. METHOD: A retrospective cohort study was carried out over a 60 months period, from February 2002 to February 2007, analysing the patients who underwent to iodinated contrast radiological examinations. Adverse reactions were evaluated from the manual record format developed following the requirements of the Quality Assurance Program in Radiology. Study variables were, administration route, contrast media dose, adverse reaction type, and signs and symptoms. Statistical analysis was descriptive. RESULTS: A total of 68 (0.3 %) of adverse reaction were registered of which 64 were mild (94.1%), 4 moderate (5.9%) and none severe. On the basis of the administration route (intravenous or oral) adverse reaction were 67 (94%) and 1 (6%) respectively. With a 40-80ml contrast media dose by injection, mild adverse reactions were 87.5%, moderate 12.5% and severe 0%. With a 90-150ml contrast media dose by injection, mild adverse reaction were 94.9% and moderate 5.1%. CONCLUSIONS: The number of adverse reaction using iodinated contrast media is low and are they are generally mild; however the nurse must be ready to recognise and treat them. PMID- 20727804 TI - [Reirradiation of normal tissues: preclinical radiobiological data]. AB - Reirradiation represent an unfrequent particular clinical situation. The risk/benefit ratio assessment must be taken into account, considering both clinical and dosimetric aspects. There is a relatively limited amount of preclinical data available to date and clinicians should cautiously perform reirradiations in selected indications. This review summarizes the experimental data available on reirradiation of normal tissues, the consequences on early and late toxicities as well as the intrinsic limitations of these models. PMID- 20727805 TI - [Place of surgery in high-risk tumours of the prostate]. AB - Among the different options recommended for high-risk prostate cancer, radical prostatectomy is admitted as radiotherapy, but its role is still controversial in monotherapy and difficult to evaluate in combined treatments. The results of clinical trials combining an external radiotherapy to a long-term androgen deprivation in locally advanced tumours sustain the principle of a multidisciplinary management in high-risk prostate cancer. The impact of surgery on the risk of progression and local recurrence is important in selected patients with low grade and small tumoral volume. Clinical and histological data associated to the MRI assessment remain essential and enhance the preoperative multidisciplinary decision, especially regarding nodal and distant metastases. Radical prostatectomy with an extended pelvic lymphadenectomy can be considered as a viable alternative to radiotherapy and hormonal therapy in these patients with a long life expectancy but presenting a high risk of local progression and a low risk of metastatic disease. Morbidity of the procedure is similar to radical prostatectomy for organ-confined tumours despite more erectile dysfunction due to non-sparing radical prostatectomy in most of cases. Oncological results from recent compiled series show 10- and 15-year specific survival rates around 85 and 75%, respectively, including adjuvant or salvage treatments with radiotherapy, androgen deprivation or chemotherapy. PMID- 20727806 TI - Post-traumatic reconstruction of digital joints by costal cartilage grafting: a preliminary prospective study. AB - In digital joint defects, reconstruction is meant to obtain a stable, mobile and pain-free finger. Six patients aged 29 years in average (15-46) and who were prospectively followed-up presented with digital joint defects that affected at least half of either the proximal interphalangeal (PIP) joint or the metacarpophalangeal (MCP) joint. These defects were treated in emergency (four cases) or scheduled for an autograft of costal cartilage harvested from the ninth rib. Four digits showed lesions of the extensor system which were repaired. One digit grafted after complete amputation was no more vascularized. All patients were reviewed and prospectively followed-up by the surgeons and were also reviewed by an independent operator 16.1 months post-surgery in average (9-25). No infection occurred. None of the grafted fingers had to undergo arthrodesis or secondary amputation. One case of type 1 complex regional pain syndrome occurred. No functional or aesthetic complaint was reported, and no complication was observed at the donor site. The mean arc of motion was 33 degrees (20-50) for the PIP joint and 37 degrees (30-40) for the MCP joint. Mean total active motion (TAM) was 191 degrees (160-250 degrees ), whichever the injured finger, i.e. 79.1% compared with the contralateral finger. The Buck-Gramko score averaged 11/15 (8-15). The Strickland score (interphalangeal TAM) was 57.8%, which corresponds to a medium result. The quick DASH assessment averaged 17.42 (0 47.72). Even if arthrodesis or amputation remain the conventional option in case of joint defect, prosthesis or cartilage grafting constitute solutions that allow the preservation of a functional painless finger. PMID- 20727807 TI - Treatment by collagen conduit of painful post-traumatic neuromas of the sensitive digital nerve: a retrospective study of 10 cases. AB - OBJECTIVES: The purpose of this retrospective study was to report the results of surgery in painful post-traumatic neuromas of the digital nerves treated by collagen conduits after excision of the neuromas, when two stumps were available. METHODS: We retrospectively reviewed all patients operated on for painful neuroma in our institution and having undergone repair with collagen conduits. Their files were retrieved by a coding file (CCAM version 10). Ten patients involving nine digital nerves and one common digital nerve were included. Primary outcome data points were static two-point discrimination, Semmes-Weinstein monofilament testing, Quick-Dash outcome survey scores, Cold Intolerance Symptom Severity (CISS) score and recurrence of pain at final follow-up. We set up a minimum follow-up period of 6 months after surgery. RESULTS: The patients' average age was 30 years. The average follow-up duration was 11.8 months. Five patients had excellent or good results (50%) at static two-point discrimination testing. Semmes-Weinstein monofilament testing results were full, diminished light touch or diminished protective sensation in nine digits (80%). The average Quick-Dash survey score was 19.3. The average CISS score was 27.8. There was no recurrence of pain. CONCLUSIONS: Our findings indicate that collagen conduit is an effective treatment for post-traumatic painful neuromas of digital nerves and common digital nerves. PMID- 20727808 TI - [The Adams-Oliver syndrome. A case report]. AB - The authors report a case of Adams-Oliver syndrome in an 11 months child. This child was referred to our unit at the age of six months with right hand brachydactyly and alopecia on the vertex. We decided not to treat hand malformations, given the lack of functional impact. Alopecia of the vertex was corrected by tissue expansion of the scalp, with a satisfactory cosmetic result at five months. PMID- 20727809 TI - [Isolated gonococcal tenosynovitis. Case report and review of literature]. AB - Isolated gonococcal tenosynovitis is rare, and is part of disseminated gonococcal infection. It is due to blood-borne contamination of the flexor tendon sheath. One to 3% of gonococcal mucosal infections develop disseminated infections. Tenosynovitis is present in two-thirds of cases, sometimes in association with arthritis and skin rash. We report a case of a 26-year-old man with isolated gonococcal tenosynovitis of the thumb, with no other medical history, occurring 15 days after unprotected sex. Except local inflammatory signs of the thumb extending to the wrist, and a biological inflammatory syndrome, the patient had no arthritis, skin or mucosa symptoms. Immediate surgical drainage was performed under antibiotic cover with 3rd generation cephalosporin. All bacteriological samples were negative, except for one blood culture positive for Neisseria gonorrhoeae. Thus, in case of an asymptomatic patient with suspected gonococcal infection through a mucus portal, a precise examination, including geographical and sexual history, and a review of screening are recommended. Although the pathophysiology of gonococcal tenosynovitis is still obscure, the best prevention remains that of sexually transmitted diseases. PMID- 20727810 TI - Swanson-type silastic arthroplasties of the PIP joint for rheumatoid arthritis. Results of 19 implants at 5.3 years of follow-up. AB - This retrospective study reports the results from 19 PIP Silastic spacers in 11 female patients suffering from inflammatory diseases at a mean of 2.2 and 5.3 years after surgery. The improvement in range of movement decreased with time, evolving from a gain of 18 at 2.2 years to only a 4-gain at subsequent follow-up. The fracture rate was high (30%). Objective analysis by physicians reported poor or mild improvements in 75% of cases. Subjective analysis (assessing aesthetics, function and pain) by patients, showed an average score of 5.6/10. At final follow-up, eight out of nine patients did not regret having had surgery. As patients actually hope for pain relief and improved function and quality of life, rather than anatomical recovery, this explains the high acceptability and interest in this rudimentary surgical procedure. PMID- 20727811 TI - "PAF" analysis of acute distal radius fractures in adults. Preliminary results. AB - There is not enough evidence in the literature to support the use of any treatment in distal radius fractures, mainly because of the heterogeneous aspects of most series. There is a need for more standardized analyses of distal radius fractures that should allow the identification of more homogeneous groups of patients. The authors propose a novel synthetic method to analyse acute distal radius fractures in adults. A one-page chart includes criteria related to the patient (P), the energy of the accident (A), and the characteristics of the fracture (F) along with associated ulnar and carpal lesions. The preliminary results of the use of this chart in 258 consecutive patients are presented. Four homogeneous groups of patients are described and the principles of their treatment are discussed. PMID- 20727812 TI - Efficient and green synthesis of bis(indolyl)methanes catalyzed by ABS in aqueous media under ultrasound irradiation. AB - Ultrasound-promoted synthesis of bis(indolyl)methanes catalyzed by ABS via the reaction of indole or N-methylindole with aromatic aldehyde was carried out in excellent yields in aqueous media at 23-25 degrees C, providing a simple and efficient synthesis of these compounds. PMID- 20727813 TI - Direct visualization of ultrasonic power distribution using mechanoluminescent film. AB - In this research, a technique for measuring ultrasonic power with a mechanoluminescent (ML) sensing film was developed. A linear relationship was observed between the ultrasonic power and the ML intensity induced by ultrasonic vibration, indicating that ultrasonic power can be evaluated by measuring ML intensity. In addition, the ultrasonic power distribution on the surface of a transducer was visualized by recording ML images with a charge-coupled device camera. PMID- 20727814 TI - Surface oscillation and jetting from surface attached acoustic driven bubbles. AB - We report on an experimental study of the onset of surface oscillation and jetting of bubbles attached to a rigid surface. The driving frequency is 16.27 kHz and the radius of the spherical capped bubble is 160 +/- 5 MUm. The acoustic amplitude is increased from 0 to 0.085 bar while the oscillation is recorded with a high-speed camera at 180,000 frames/s over 8100 periods of oscillations. The radial and surface modes are analyzed from a Fourier decomposition. With increasing pressure amplitude we find three regimes: pure radial oscillation, development of surface oscillations, and a chaotic surface oscillation regime. These regimes appear abrupt and are repeatable. In the chaotic regime, fast liquid jetting towards the rigid surface is observed. PMID- 20727815 TI - M or W-shape: Implications of axis definition for the accelerometer-based Timed Up & Go Test. PMID- 20727816 TI - A case study of spinal ependymoma presenting as non-resolving back and leg pain. PMID- 20727817 TI - Detecting hydrophobic molecules with nucleic acid-based receptors. AB - We will argue for applications of crossreactive arrays of solution-phase sensors in urinalysis, wherein these can be useful for screening, as well as monitoring of disease progress or treatment compliance. For our first demonstration we focus on the detection and classification process of the predominant hydrophobic molecules in urine, steroids, while taking advantage of a variety of differentially crossreactive DNA-based hydrophobic receptors, three-way junctions. We discuss our progress in addressing some of the traditional limitations of crossreactive arrays and what remains to be done to move these systems into clinical applications. PMID- 20727818 TI - Sirius: a web-based system for retinal image analysis. AB - PURPOSE: Retinal image analysis can lead to early detection of several pathologies such as hypertension or diabetes. Screening processes require the evaluation of a high amount of visual data and, usually, the collaboration between different experts and different health care centers. These usual routines demand new fast and automatic solutions to deal with these situations. This work introduces Sirius (System for the Integration of Retinal Images Understanding Services), a web-based system for image analysis in the retinal imaging field. METHODS: Sirius provides a framework for ophthalmologists or other experts in the field to collaboratively work using retinal image-based applications in a distributed, fast and reliable environment. Sirius consists of three main components: the web client that users interact with, the web application server that processes all client requests and the service module that performs the image processing tasks. In this work, we present a service for the analysis of retinal microcirculation using a semi-automatic methodology for the computation of the arteriolar-to-venular ratio (AVR). RESULTS: Sirius has been evaluated in different real environments, involving health care systems, to test its performance. First, the AVR service was validated in terms of precision and efficiency and then, the framework was evaluated in different real scenarios of medical centers. CONCLUSIONS: Sirius is a web-based application providing a fast and reliable work environment for retinal experts. The system allows the sharing of images and processed results between remote computers and provides automated methods to diminish inter-expert variability in the analysis of the images. PMID- 20727819 TI - A systematic review of interventions promoting clinical information retrieval technology (CIRT) adoption by healthcare professionals. AB - PURPOSE: This paper presents the evidence on the effectiveness of interventions promoting the use of clinical information retrieval technologies (CIRTs) by healthcare professionals. METHODS: We electronically searched articles published between January 1990 and March 2008 using following inclusion criteria: (1) participants were healthcare professionals; (2) specific intervention promoted CIRT adoption; (3) studies were randomised controlled trials, controlled clinical trials, controlled before and after studies or interrupted time series analyses; and (4) they objectively reporting measured outcomes on CIRT use. RESULTS: We found nine studies focusing on CIRT use. Main outcomes measured were searching skills and/or frequency of use of electronic databases by healthcare professionals. Three studies reported a positive effect of the intervention on CIRT use, one showed a positive impact post-intervention, and four studies failed to demonstrate significant intervention effect. The ninth study examined financial disincentives, and found a significant negative effect of introducing user fees for searching MEDLINE in clinical settings. A meta-analysis showed that educational meetings were the only type of interventions reporting consistent positive effects on CIRT adoption. CONCLUSION: CIRT is an information and communication technology commonly used in healthcare settings. Interventions promoting CIRT adoption by healthcare professionals have shown some success in improving searching skills and use of electronic databases. However, the effectiveness of these interventions remains uncertain and more rigorous studies are needed. PMID- 20727820 TI - Jaundice complicated by an atypical form of Guillain-Barre syndrome. PMID- 20727821 TI - Amyotrophic lateral sclerosis: who has the lead, the upper or the lower motor neuron? PMID- 20727822 TI - Contribution of ethanol-tolerant xylanase G2 from Aspergillus oryzae on Japanese sake brewing. AB - We purified three xylanase isozymes (XynF1, XynF3 and XynG2) from a solid-state Aspergillus oryzae RIB128 culture using chromatography. The results of our sake brewing experiment, in which we used exogenously supplemented enzymes, revealed that only XynG2 improved the alcohol yield and the material utilization. The alcohol yield of the XynG2 batch displayed an increase of 4.4% in comparison to the control, and the amount of sake cake decreased by 4.6%. The contribution of XynG2 was further confirmed through our brewing experiment in which we used the yeast heterogeneously expressing fungal xylanase isozymes. Interestingly XynG1, an enzyme with a XynG2-like sequence that is more vulnerable to ethanol, did not improve the sake-mash fermentation. The stability of XynG2 in ethanol was prominent, and it retained most of its original activity after we exposed it to 80% ethanol for 30min, whereas the stability of the other isozymes in ethanol, including XynG1, was much lower (20-25% ethanol). We concluded, therefore, that the improvement of material utilization achieved with XynG2 is primarily attributable to its characteristically high stability in ethanol, thereby, effectively degrading rice endosperm cell walls under high-alcohol conditions such as a sake-mash environment. PMID- 20727823 TI - Comparison of different VO(2max) equations in the ability to discriminate the metabolic risk in Portuguese adolescents. AB - There is increasing evidence that cardiorespiratory fitness (CRF) is an important health marker already in youth. This study aimed to determine the ability of five VO(2max) equations to discriminate between low/high Metabolic Risk in 450 Portuguese adolescents aged 10-18. We measured waist and hip circumferences, fasting glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and blood pressure. For each of these variables, a Z-score was computed. The HDL-cholesterol was multiplied by -1. A metabolic risk score was constructed by summing the Z scores of all individual risk factors. High risk was considered when the individual had >=1 SD of this score. Cardiorespiratory fitness (CRF) was measured with the 20-m shuttle run test. We estimated VO(2max) from the CRF tests using five equations. ROC analyses showed a significant discriminatory accuracy for the Matsuzaka and Barnett(a) equations in identifying the low/high metabolic risk in both genders (Matsuzaka girls: AUC=0.654, 95%CI: 0.591-0.713, p<0.001, VO(2max)=39.5 mL kg-1min-1; boys: AUC=0.648, 95%CI: 0.576 0.716, p<0.001, VO(2max)=41.8 mL kg-1min-1; Barnett(a) girls: AUC=0.620, 95%CI: 0.557-0.681, p<0.001, VO(2max)=46.4 mL kg-1min-1; boys: AUC=0.628, 95%CI: 0.555 0.697, p=0.04, VO(2max)=42.6 mL kg-1min-1), and the Ruiz equation in boys (AUC=0.638, 95%CI: 0.565-0.706, p<0.001, VO(2max)=47.1 mL kg-1min-1). The VO(2max) values found require further testing in other populations as well as in longitudinal studies; the identification of adolescents who have low CRF levels can help detect youth with an increased risk of metabolic disease. PMID- 20727824 TI - Focus of attention and its impact on movement behaviour. AB - Investigations into the relative effectiveness of either focusing on movement form (internal focus) or movement effects (external focus) have tended to dominate research on instructional constraints. However, rather than adopting a comparative approach to determine which focus of attention is more effective, analysis of the relative efficacy of each specific instruction focus during motor learning could be more relevant for both researchers and practitioners. Theoretical advances in the motor learning literature from a nonlinear dynamics perspective might explain the processes that underlie the effect of different attentional focus instructions. Referencing ideas and concepts from a current motor learning model, differential effects of either internal or external focus of instructions are examined. This paper also highlights some deficiencies in extant theory and research design on focus of attention which require further investigations. PMID- 20727825 TI - Implementing a clinical competency assessment model that promotes critical reflection and ensures nursing graduates' readiness for professional practice. AB - AIM: This paper describes the design, implementation and evaluation of the Structured Observation and Assessment of Practice (SOAP), a model used to assess third year undergraduate nursing students' clinical competence. BACKGROUND: Competence is a complex concept that is difficult to define and measure. The assessment of nursing students' clinical competence has confronted universities with problems of validity, reliability, subjectivity and bias for many years. This presents particular problems in nursing as patient outcomes may be compromised by incompetent practice. Too often assessments of nursing students' competence comprise brief assessments of psychomotor skills, vague global assessment of generic skills/attributes or assessments undertaken in simulated laboratory settings rather than the real world of practice. METHODS: The Structured Observation and Assessment of Practice (SOAP), is a full day holistic practice-driven clinical competence assessment approach that motivates nursing students' learning, promotes critical reflection and confirms graduates' readiness for professional practice. This model was introduced in 2004 and since then 1031 students have been assessed. Quantitative and qualitative data has been collected via an anonymous online evaluation. RESULTS: Survey results have been statistically analysed using The Statistical Package for the Social Sciences (SPSS) (Version 13) with exploratory factor analysis employed to ascertain construct validity. This paper will report on the four components that showed acceptable factor loadings and that together accounted for 77.65 per cent of the variance: perceived learning outcomes, consistency with general clinical performance, quality of assessors, and anxiety/stress impact. CONCLUSION: The results of the SOAP approach supports the premise that quality clinical assessment requires nursing students' exposure to complex challenges undertaken in authentic clinical contexts, observed by registered nurses who are trained as assessors and have a strong educational and clinical background. PMID- 20727826 TI - Epilepsy in Prader-Willi syndrome: clinical characteristics and correlation to genotype. AB - Prader-Willi syndrome (PWS) is a genomic imprinting disease secondary to the loss of a functional paternal copy of 15q11-q13. Unlike its related imprinting disorder, Angelman syndrome, PWS has not been regarded as a risk factor for epilepsy. A retrospective analysis of 92 patients with PWS identified 24 (26%) with seizures. Twenty-two of these (92%) were affected by focal epilepsy and only two (8%) had generalized epilepsy. The most common seizure type was staring spells (67%). Correlation to genotype analysis showed deletions were more common in patients with epilepsy than in patients without epilepsy. The epilepsy syndromes were easy to control with a single antiepileptic drug in most cases. Three patients (11%) had had febrile seizures. These findings suggest that PWS may be a risk factor for epilepsy, which can manifest with focal features. Patients with PWS with a deletion genotype showed a trend toward developing seizures compared with patients with other genotypes in our series, even though this difference did not achieve statistical significance. PMID- 20727827 TI - Violence and postictal psychosis: a comparison of postictal psychosis, interictal psychosis, and postictal confusion. AB - The belief that epilepsy is linked with violent behavior acquired a highly stigmatizing value in the late 19th century on the basis of degenerative theory. This widespread medical view lost general acceptance among experts in the 1990s after several large-scale studies showed that aggressive phenomena can arise during epileptic seizures, but are extremely rare. The concept of postictal psychosis (PIP) shed a new light on this old dispute. With this concept, the significance of the chronological relationship between seizures and violent behaviors in patients with epilepsy is newly stressed, which made a simple "yes" or "no" answer to the question implausible. In this review, we discuss violent behaviors at five chronological points relative to seizures and demonstrate representative cases. As shown in our previous study, well-directed violent attacks occurred during 22.8% of the PIP episodes, 4.8% of the IIP episodes, and 0.7% of the postictal confusions. Compared with the other two situations, proneness to violence stood out in the PIP episodes. Suicidal attempts showed a similar trend. Purposeful, organized violence as a direct manifestation of seizures or ictal automatism is highly exceptional. Violent acts could occur in postictal confusion as an expression of unconscious, vigorous resistance against efforts of surrounding people to prevent the affected individual from roaming or fumbling about. In contrast, some PIP episodes can be highly alarming, especially if a violent act has been previously committed in preceding episodes. Violent acts by patients with epilepsy should be treated differently according to the various pathophysiological backgrounds from which the violence arises. PMID- 20727828 TI - Postictal psychosis. AB - Postictal psychoses represent a considerable clinical challenge and are often unrecognized. In this review, the clinical features of the syndromes and the underlying biological foundations, as revealed through EEG and imaging studies, are discussed. It is concluded that although the syndrome can be well recognized, it is not acknowledged in standard diagnostic manuals, hence the relative neglect in the epilepsy literature. PMID- 20727829 TI - MicroRNAs involved in molecular circuitries relevant for the Duchenne muscular dystrophy pathogenesis are controlled by the dystrophin/nNOS pathway. AB - In Duchenne muscular dystrophy (DMD) the absence of dystrophin at the sarcolemma delocalizes and downregulates nitric oxide synthase (nNOS); this alters S nitrosylation of HDAC2 and its chromatin association. We show that the differential HDAC2 nitrosylation state in Duchenne versus wild-type conditions deregulates the expression of a specific subset of microRNA genes. Several circuitries controlled by the identified microRNAs, such as the one linking miR-1 to the G6PD enzyme and the redox state of cell, or miR-29 to extracellular proteins and the fibrotic process, explain some of the DMD pathogenetic traits. We also show that, at variance with other myomiRs, miR-206 escapes from the dystrophin-nNOS control being produced in activated satellite cells before dystrophin expression; in these cells, it contributes to muscle regeneration through repression of the satellite specific factor, Pax7. We conclude that the pathway activated by dystrophin/nNOS controls several important circuitries increasing the robustness of the muscle differentiation program. PMID- 20727830 TI - Unusual tales of the expected: gastric band complications--"the dye of the needle" and "inside out". PMID- 20727831 TI - Single-incision laparoscopic sleeve gastrectomy versus conventional multiport laparoscopic sleeve gastrectomy: technical considerations and strategic modifications. AB - BACKGROUND: Since its inception, minimal access surgery has been a dynamic field, experiencing successive leaps in technique and instrumental design. Each improvement in minimal access surgery must demonstrate that patients benefit from the change in approach, without compromising the outcome. The present study presents the technical considerations and strategic modifications for single incision laparoscopic sleeve gastrectomy. We also compared the newly adopted single-incision laparoscopic approach with conventional multiport laparoscopic sleeve gastrectomy. METHODS: Of the 26 patients included in the present study, 14 underwent single-incision laparoscopic sleeve gastrectomy and 12 underwent conventional multiport sleeve gastrectomy. All procedures were performed by the same surgeon (A.A.S.) during a 12-month period from September 2008 to August 2009 at Michigan State University Kalamazoo Center for Medical Studies. RESULTS: The Mann-Whitney U tests showed with 95% confidence that the difference in pain scores and length of hospital stay in the single-incision laparoscopic sleeve gastrectomy group were statistically significant. A modest increase occurred in the operative time in the single-incision laparoscopic sleeve gastrectomy group. This difference was the least statistically significant of all variables (P = .055). CONCLUSION: Single-incision laparoscopic sleeve gastrectomy was associated with less postoperative pain, a lower need for analgesia, and a decreased length of hospital stay compared with conventional multiport laparoscopic sleeve gastrectomy. This was achieved without decreasing the quality of surgery or the outcomes offered by the conventional multiport counterpart. PMID- 20727832 TI - Computed tomography-guided percutaneous gastrostomy for management of gastric remnant leak after Roux-en-Y gastric bypass. PMID- 20727833 TI - Gastric band erosion and intraluminal migration leading to biliary and small bowel obstruction: case report and discussion. PMID- 20727834 TI - Tuberculosis after laparoscopic Roux-en-Y gastric bypass for morbid obesity. PMID- 20727835 TI - Successful management of chyloperitoneum after laparoscopic adjustable gastric banding in 2 patients. PMID- 20727836 TI - Laparoscopic gastric band slippage diagnosed with esophagogastroduodenoscopy in a 12-week gestation nulliparous patient. PMID- 20727839 TI - Autonomic control of the urogenital tract. AB - The urogenital tract houses many of the organs that play a major role in homeostasis, in particular those that control water and salt balance, and reproductive function. This review focuses on the anatomical and functional innervation of the kidneys, urinary ducts and bladders of the urinary system, and the gonads, gonadal ducts, and intromittent organs of the reproductive tract. The literature, especially in recent years, is overwhelmingly skewed toward the situation in mammals. Nevertheless, where specific neurochemical markers have been investigated, common patterns of innervation can be found in representatives from most vertebrate classes. Not surprisingly the vasculature, epithelia and smooth muscle of all urogenital organs receives adrenergic innervation. These nerves may contain non-adrenergic non-cholinergic (NANC) neurotransmitters such as ATP and NPY. Cholinergic nerves increase motility in most urogenital organs with the exception of the kidney. The major NANC nerves found to influence urogenital organs include those containing VIP/PACAP, galanin and neuronal nitric oxide synthase. These can be found associated with both smooth muscle and epithelia. The role these nerves play, and the circumstances where they are activated are for the most part unknown. PMID- 20727837 TI - Congruence between clinical and research-based psychiatric assessment in bariatric surgical candidates. AB - BACKGROUND: Mental health professionals have become increasingly involved in working with bariatric surgical candidates, particularly in performing preoperative psychological evaluations to clear candidates for surgery. The objective of the present study was to examine the concordance of the psychiatric diagnoses obtained during routine clinical evaluation before bariatric surgery and the diagnoses obtained separately at a research facility using the Structured Clinical Interview for DSM (Diagnostic and Statistical Manual of Mental Disorders)-IV axis I disorders. METHODS: The study included 68 consecutively enrolled bariatric surgical candidates who had participated in the Longitudinal Assessment of Bariatric Surgery-3 study. The Structured Clinical Interview for DSM disorders data obtained from the research assessments were compared with the diagnostic data from the routine preoperative psychiatric evaluations. The congruence of the current and lifetime diagnoses was assessed using Cohen's coefficient kappa. RESULTS: Considerable variability was found among the major diagnostic categories, with generally poor agreement found for the current diagnoses. The kappa coefficients tended to be larger for the lifetime diagnoses. The agreement was moderate for any lifetime mood disorder, with a kappa value of 0.45. Regarding any lifetime anxiety, substance use, and eating disorder, the clinical diagnoses rarely concurred with the results from the Structured Clinical Interview for DSM disorders, with a kappa statistic of 0.30, 0.36, and 0.32, respectively. CONCLUSION: The congruence between the diagnoses assigned during the routine clinical psychiatric evaluations and research assessment using the Structured Clinical Interview for DSM disorders was surprisingly low. These conclusions should be considered tentative, given the interval and the possibility of treatment having occurred between the 2 evaluations. Overall, these data raise interesting questions concerning the use of unstructured psychiatric evaluations before bariatric surgery. PMID- 20727840 TI - Development and validation of method for analysis of some ototoxic solvents in saliva matrix by headspace gas chromatography/mass spectrometry. AB - The aim of this study was to develop an analytical method to monitor the saliva matrix for ototoxic solvents absorption: the method is based on headspace gas chromatography/mass spectrometry and represents an alternative biological monitoring for investigating low exposure to hazardous ototoxic solvents. Simultaneous determination of toluene, ethylbenzene, xylenes and styrene has been carried out and the method has been optimized for both instrumental parameters and samples treatment. Chromatographic conditions have been set in order to obtain a good separation of xylene isomers due to the interest in p-xylene as ototoxic one. Method validation has been performed on standards spiked in blank saliva by using two internal standards (2-fluorotoluene and deuterated styrene d(8)). This method showed the possibility to detect the target compounds with a linear dynamic range of at least a 2 orders of magnitude characterized by a linear determination coefficient (r(2)) greater than 0.999. The limit of detection (LOD) ranged between 0.19 ng/mL (styrene) and 0.54 ng/mL (m-xylene) and the lower limit of quantification (LLOQ) ranged between 0.64 ng/mL (styrene) and 1.8 ng/mL (m-xylene). The method achieved good accuracy (from 99 to 105%) and precision for both intra- and inter-assay (relative standard deviation ranging from 1.7 to 13.8%) for all six compounds concerned. The repeatability was improved by adding sodium sulphate to the matrix. Saliva samples resulted stable for at least 7 days after collection, if stored in headspace vials, at the temperature of 4 degrees C. An evaluation of the main sources of uncertainty of the method is also included: expanded uncertainties ranges between 10 and 16% for all of the target compounds. In summary, the headspace gas chromatography/mass spectrometry method is a highly sensitive, versatile and flexible technique for the biological monitoring of exposure to ototoxic solvents by saliva analysis. PMID- 20727841 TI - [What is happening with antiobesity drugs?]. PMID- 20727842 TI - Selection of the recipient vein in microvascular flap reconstruction of the lower extremity: analysis of 362 free-tissue transfers. AB - Venous insufficiency is the most common cause of re-exploration in free-tissue transfers to the lower extremity. There is currently no consensus regarding the best approach to recipient vein selection. This study was designed to evaluate whether the type of venous system or the number of recipient veins would impact flap outcomes after microsurgical lower-extremity reconstruction. A retrospective study was conducted in 362 free-tissue transfers for lower-extremity reconstruction between 2003 and 2008. Flap outcomes were evaluated according to the selection of recipient vein system and number of veins. The deep venous system (80.4%) was more frequently selected than the superficial venous system (12.1%) or the combination of both systems (7.5%). In addition, one vein (65.5%) was more commonly used for anastomosis than two veins (34.5%). A total of 26 flaps (7.2%) presented with postoperative venous insufficiency. Male patients, composite defects including bones and the use of bone flaps presented higher rates of venous insufficiency with statistical significance. However, no significant differences were found among the different groups related to the age of patients, co-morbidities, aetiology, location of the defects or timing of reconstruction after trauma. The superficial venous system group was associated with a higher rate of venous insufficiency and partial flap loss compared with the deep venous system group (p = 0.036 and 0.018, respectively). One-vein anastomosis flaps were associated with statistically significant fewer complete flap failure in comparison with two-vein-anastomosis flaps (p = 0.014). In conclusion, the assessment of recipient vein parameters by surgeon's experience is the best predictor of flap outcome in lower-extremity reconstruction. In our cohort of patients, the deep venous system was more reliable than the superficial venous system, but the use of more than one vein for anastomosis did not correlate with better flap outcomes. PMID- 20727843 TI - Validation of DNA-based identification software by computation of pedigree likelihood ratios. AB - Disaster victim identification (DVI) can be aided by DNA-evidence, by comparing the DNA-profiles of unidentified individuals with those of surviving relatives. The DNA-evidence is used optimally when such a comparison is done by calculating the appropriate likelihood ratios. Though conceptually simple, the calculations can be quite involved, especially with large pedigrees, precise mutation models etc. In this article we describe a series of test cases designed to check if software designed to calculate such likelihood ratios computes them correctly. The cases include both simple and more complicated pedigrees, among which inbred ones. We show how to calculate the likelihood ratio numerically and algebraically, including a general mutation model and possibility of allelic dropout. In Appendix A we show how to derive such algebraic expressions mathematically. We have set up these cases to validate new software, called Bonaparte, which performs pedigree likelihood ratio calculations in a DVI context. Bonaparte has been developed by SNN Nijmegen (The Netherlands) for the Netherlands Forensic Institute (NFI). It is available free of charge for non commercial purposes (see www.dnadvi.nl for details). Commercial licenses can also be obtained. The software uses Bayesian networks and the junction tree algorithm to perform its calculations. PMID- 20727844 TI - Female human iPSCs retain an inactive X chromosome. AB - Generating induced pluripotent stem cells (iPSCs) requires massive epigenome reorganization. It is unclear whether reprogramming of female human cells reactivates the inactive X chromosome (Xi), as in mouse. Here we establish that human (h)iPSCs derived from several female fibroblasts under standard culture conditions carry an Xi. Despite the lack of reactivation, the Xi undergoes defined chromatin changes, and expansion of hiPSCs can lead to partial loss of XIST RNA. These results indicate that hiPSCs are epigenetically dynamic and do not display a pristine state of X inactivation with two active Xs as found in some female human embryonic stem cell lines. Furthermore, whereas fibroblasts are mosaic for the Xi, hiPSCs are clonal. This nonrandom pattern of X chromosome inactivation in female hiPSCs, which is maintained upon differentiation, has critical implications for clinical applications and disease modeling, and could be exploited for a unique form of gene therapy for X-linked diseases. PMID- 20727845 TI - Surface dilution kinetics using substrate analog enantiomers as diluents: enzymatic lipolysis by bee venom phospholipase A2. AB - A novel assay employing D-enantiomers of phospholipids as diluents for characterizing surface kinetics of lipid hydrolysis by phospholipases is introduced. The rationales of the method are (i) D-enantiomers resist hydrolysis because of the stereoselectivity of the enzymes toward L-enantiomers and (ii) mixtures of L+D-lipids at various L/D ratios but constant L+D-lipid concentrations yield a surface dilution series of variable L-lipid concentration with constant medium properties. Kinetic characterization of bee venom phospholipase A(2) activity at bile salt+phospholipid aggregate-water interfaces was performed using the mixed L+D-lipid surface dilution assay, and interface kinetic parameters were obtained. The assay applies to biomembrane models as well. Activity was measured by pH-stat methods. Aggregation numbers and interface hydration/microviscosity measured by time-resolved fluorescence quenching and electron spin resonance, respectively, confirmed that interface properties were indeed invariant in a surface dilution series, supporting rationale (ii), and were used to calculate substrate concentrations. Activity data show excellent agreement with a kinetic model derived with D-enantiomers as diluents and also that D-phospholipids bind to the enzyme but resist hydrolysis; underscoring rationale (i). The assay is significant for enabling determination of interface specific kinetic parameters for the first time and thereby characterization of interface specificity of lipolytic enzymes. PMID- 20727846 TI - Structures of mouse SOD1 and human/mouse SOD1 chimeras. AB - Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of amyotrophic lateral sclerosis (ALS). Inclusions enriched in pathogenic SOD1 accumulate in the spinal cords of transgenic mice expressing these proteins, but endogenous mouse SOD1 is not found as a component of these aggregates. In the accompanying paper, Karch and colleagues analyze aggregation propensities of human/mouse SOD1 chimeras in cell culture and identify two sequence elements in the human enzyme that seem to enhance its aggregation relative to the mouse enzyme. Here, we report the first structure of mouse SOD1 along with those of SOD1 chimeras in which residues 1-80 come from human SOD1 and residues 81-153 come from mouse SOD1 and vice versa. Taken together, the structural and cell based data suggest a model in which residues Q42 and Q123 in mouse SOD1 modulate non-native SOD1-SOD1 intermolecular interactions at edge strands in the SOD1 Greek key beta-barrel. PMID- 20727847 TI - Structural control of cytochrome P450-catalyzed omega-hydroxylation. AB - The regiospecific or preferential omega-hydroxylation of hydrocarbon chains is thermodynamically disfavored because the ease of C-H bond hydroxylation depends on the bond strength, and the primary C-H bond of a terminal methyl group is stronger than the secondary or tertiary C-H bond adjacent to it. The hydroxylation reaction will therefore occur primarily at the adjacent secondary or tertiary C-H bond unless the protein structure specifically enforces primary C H bond oxidation. Here we review the classes of enzymes that catalyze omega hydroxylation and our current understanding of the structural features that promote the omega-hydroxylation of unbranched and methyl-branched hydrocarbon chains. The evidence indicates that steric constraints are used to favor reaction at the omega-site rather than at the more reactive (omega-1)-site. PMID- 20727849 TI - Domain location within the cystic fibrosis transmembrane conductance regulator protein investigated by electron microscopy and gold labelling. AB - The domain organisation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein was studied using electron microscopy of detergent solubilised dimeric complexes. Ni-NTA nanogold labelling data suggest that in the nonphosphorylated, nucleotide-free state, the C-terminus is intimately associated with the cytoplasmic ATP-binding regions, whilst part of the regulatory domain occupies a position close to the cytoplasmic surface of the lipid membrane. Removal of the entire second nucleotide binding domain (NBD2) results in a deficit in the CFTR structure that is consistent with the size and shape of a single NBD. The data suggest that NBD2 lies closer to the C2 symmetry axis than the first nucleotide binding domain (NBD1) and that NBD2 from one CFTR monomer also contacts NBD1 from the opposing one. These data suggest that current homology models for CFTR based on other ATP-binding cassette proteins appear to be reasonable, at least to low resolution. We also find that Ni-NTA nanogold labelling of an internal hexa-Histidine sequence is a valuable approach to locate individual protein domains. PMID- 20727848 TI - Comparative NMR studies demonstrate profound differences between two viroporins: p7 of HCV and Vpu of HIV-1. AB - The p7 protein from hepatitis C virus and the Vpu protein from HIV-1 are members of the viroporin family of small viral membrane proteins. It is essential to determine their structures in order to obtain an understanding of their molecular mechanisms and to develop new classes of anti-viral drugs. Because they are membrane proteins, it is challenging to study them in their native phospholipid bilayer environments by most experimental methods. Here we describe applications of NMR spectroscopy to both p7 and Vpu. Isotopically labeled p7 and Vpu samples were prepared by heterologous expression in bacteria, initial isolation as fusion proteins, and final purification by chromatography. The purified proteins were studied in the model membrane environments of micelles by solution NMR spectroscopy and in aligned phospholipid bilayers by solid-state NMR spectroscopy. The resulting structural findings enable comparisons to be made between the two proteins, demonstrating that they have quite different architectures. Most notably, Vpu has one trans-membrane helix and p7 has two trans-membrane helices; in addition, there are significant differences in the structures and dynamics of their internal loop and terminal regions. PMID- 20727850 TI - Secondary structure, dynamics, and architecture of the p7 membrane protein from hepatitis C virus by NMR spectroscopy. AB - P7 is a small membrane protein that is essential for the infectivity of hepatitis C virus. Solution-state NMR experiments on p7 in DHPC micelles, including hydrogen/deuterium exchange, paramagnetic relaxation enhancement and bicelle 'q titration,' demonstrate that the protein has a range of dynamic properties and distinct structural segments. These data along with residual dipolar couplings yield a secondary structure model of p7. We were able to confirm previous proposals that the protein has two transmembrane segments with a short interhelical loop containing the two basic residues K33 and R35. The 63-amino acid protein has a remarkably complex structure made up of seven identifiable sections, four of which are helical segments with different tilt angles and dynamics. A solid-state NMR two-dimensional separated local field spectrum of p7 aligned in phospholipid bilayers provided the tilt angles of two of these segments. A preliminary structural model of p7 derived from these NMR data is presented. PMID- 20727851 TI - Repin1 maybe involved in the regulation of cell size and glucose transport in adipocytes. AB - Replication initiator 1 (Repin1) is highly expressed in liver and adipose tissue and has been suggested as candidate gene for obesity and its related metabolic disorders in congenic and subcongenic rat strains. The cellular localization and function of Repin1 has remained elusive since its discovery in 1990. To characterize the role of Repin1 in adipocyte biology, we used siRNA knockdown technology to reduce the expression of Repin1 by electroporation of semiconfluent 3T3-L1 preadipocytes. Glucose transport, palmitate uptake as well as triglyceride content were measured. In paired samples of human visceral and subcutaneous adipose tissue, we investigated whether Repin1 mRNA expression is related to measures of fat accumulation and adipocyte size. We demonstrate that Repin1 increases during adipogenesis. RNA interference based Repin1 downregulation in mature adipocytes significantly reduces adipocyte size and causes reduced basal, but enhanced insulin stimulated glucose uptake into 3T3-L1 cells. Additionally, knockdown of Repin1 resulted in reduced palmitate uptake and significantly changed the mRNA expression of genes involved lipid droplet formation, adipogenesis, glucose and fatty acid transport. Furthermore, we found significant correlations between Repin1 mRNA expression in human paired visceral and subcutaneous adipose tissue and total body fat mass as well as adipocyte size. We have identified a potential role for Repin1 in the regulation of adipocyte size and expression of glucose transporters GLUT1 and GLUT4 in adipocytes. PMID- 20727852 TI - Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice. AB - Brown adipose tissue is a highly specialized organ that uses mitochondrial fatty acid oxidation to fuel non-shivering thermogenesis. In mice, mutations in the acyl-CoA dehydrogenase family of fatty acid oxidation genes are associated with sensitivity to cold. Brown adipose tissue function has not previously been characterized in these knockout strains. Short-chain acyl-CoA dehydrogenase (SCAD) deficient mice were found to have increased brown adipose tissue mass as well as modest cardiac hypertrophy. Uncoupling protein-1 was reduced by 70% in brown adipose tissue and this was not due to a change in mitochondrial number, nor was it due to decreased signal transduction through protein kinase A which is known to be a major regulator of uncoupling protein-1 expression. PKA activity and in vitro lipolysis were normal in brown adipose tissue, although in white adipose tissue a modest increase in basal lipolysis was seen in SCAD-/- mice. Finally, an in vivo norepinephrine challenge of brown adipose tissue thermogenesis revealed normal heat production in SCAD-/- mice. These results suggest that reduced brown adipose tissue function is not the major factor causing cold sensitivity in acyl-CoA dehydrogenase knockout strains. We speculate that other mechanisms such as shivering capacity, cardiac function, and reduced hepatic glycogen stores are involved. PMID- 20727853 TI - DNA methylation of the Trip10 promoter accelerates mesenchymal stem cell lineage determination. AB - Epigenetic regulation of gene expression by DNA methylation and histone modification controls cell fate during development and homeostasis in adulthood. Aberrant epigenetic modifications may lead to abnormal development, even diseases. We have found that Trip10 (thyroid hormone receptor interactor 10), an adaptor protein involved in diverse functions, is epigenetically regulated during lineage-specific induction of human bone marrow-derived mesenchymal stem cells (MSCs). To determine whether DNA methylation-induced gene silencing is sufficient to restrict cell fate changes, we applied an invitro method to specifically methylate the promoter of Trip10. Our hypothesis was that the methylation status of the Trip10 promoter in MSCs alters the differentiation preference of MSCs. Transfection of in vitro-methylated Trip10 promoter DNA into MSCs resulted in progressive accumulation of cytosine methylation at the endogenous Trip10 promoter, reduced Trip10 expression, and accelerated MSC-to-neuron and MSC-to osteocyte differentiation. A two-component EGFP reporter gene system was established to confirm the level of transcriptional silencing and visualize the targeted DNA methylation. EGFP expression induced in the reporter system by targeted Trip10 methylation was reversed by adding 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, confirming that the suppressed Trip10 expression and disrupted MSC differentiation resulted from the in vitro-introduced methylations in the Trip10 promoter. With this targeted DNA methylation and reporter system, we are able to monitor the progression of locus-specific DNA methylation in vivo and correlate such changes with potential functional changes. Using this approach, we have established a new role for Trip10, showing that the level of Trip10 expression is associated with the maintenance and differentiation of MSCs. PMID- 20727854 TI - Tyrosine kinase 2 interacts with the proapoptotic protein Siva-1 and augments its apoptotic functions. AB - Siva-1 is a molecule that has the potential to induce both extrinsic (receptor mediated) and intrinsic (non-receptor-mediated) apoptosis. Siva-1 binds to CD27, a member of the tumor necrosis factor receptor (TNFR) family, Abl-related gene (ARG), and BCL-X(L), and these partner molecules reportedly enhance the apoptotic properties of Siva-1. In this study, we show that Siva-1 also interacts with a member of the Jak family protein kinases, tyrosine kinase 2 (Tyk2). Siva-1 bound to Tyk2 via its N-terminal region, and Tyk2 phosphorylated Siva-1 at tyrosines 53 and 162. In murine pro-B cells, Ba/F3 cells, expression of Tyk2 augmented Siva-1 induced apoptosis. This augmentation of Siva-1-induced apoptosis was retained regardless of the phosphorylation of Siva-1, but was almost completely prevented by the abrogation of the Tyk2-Siva-1 association. These findings indicate that the interaction between Siva-1 and Tyk2 directly augments the apoptotic activity of Siva-1. Our novel observations suggest that Siva-1 forms a functional complex with Tyk2 and participates in the transduction of signals that inhibit B lymphocyte growth. PMID- 20727855 TI - The Dad1 subunit of the yeast kinetochore Dam1 complex is an intrinsically disordered protein. AB - The Dam1 complex is an important part of the yeast kinetochore. It mediates attachment of the chromosome to the mitotic spindle and is involved in chromatid separation initiated at anaphase. It is comprised of 10 individual subunits and has been observed to oligomerize in various ways as it interacts with microtubules, including forming a ring. This work explores the biochemical and biophysical properties of Dad1, one of the Dam1 complex subunits from the human fungal pathogen Candida albicans. Unlike its Saccharomyces cerevisiae counterpart, C. albicans Dad1 can be expressed as a soluble protein in Escherichia coli. Analysis of this protein's hydrodynamic properties, thermostability and primary sequence have been conducted. As a result, we conclude that isolated Dad1 is an intrinsically disordered protein. PMID- 20727856 TI - PI3K/Akt signaling is involved in the disruption of gap junctional communication caused by v-Src and TNF-alpha. AB - Gap junctional communication, which is mediated by the connexin protein family, is essential for the maintenance of normal tissue function and homeostasis. Loss of intercellular communication results in a failure to coordinately regulate cellular functions, and it can facilitate tumorigenesis. Expression of oncogenes and stimulation with cytokines has been shown to suppress intercellular communication; however, the exact mechanism by which intercellular communication is disrupted by these factors remains uncertain. In this report, we show that Akt is essential for the disruption of gap junctional communication in v-Src transformed cells. In addition, inhibition of Akt restores gap junctional communication after it is suppressed by TNF-alpha signaling. Furthermore, we demonstrate that the expression of a constitutively active form of Akt1, but not of Akt2 or Akt3, is sufficient to suppress gap junctional communication. Our results clearly define Akt1 as one of the critical regulators of gap junctional communication. PMID- 20727857 TI - Ribosomal protein L2 associates with E. coli HtpG and activates its ATPase activity. AB - Although eukaryotic Hsp90 has been studied extensively, the function of its bacterial homologue HtpG remains elusive. Here we report that 50S ribosomal protein L2 was found as an associated protein with His-tagged HtpG from Escherichia coli cultured in minimum medium at 45 degrees C. L2 specifically activated ATPase activity of HtpG, but other denatured proteins did not. The analysis using domain derivatives of HtpG and L2 showed that C-terminal domain of L2 and the middle to C-terminal domain of HtpG are important for interaction. At physiological salt concentration, L2 was denatured state and was recognized by HtpG as well as other chaperones, DnaK/DnaJ/GrpE and GroEL/GroES. The ATPase of HtpG at increasing concentration of L2 indicated that an L2 molecule bound to a dimer HtpG with apparent K(D) of 0.3 MUM at 100mM KCl and 3.3 MUM at 200 mM KCl. PMID- 20727858 TI - microRNA-195 promotes apoptosis and suppresses tumorigenicity of human colorectal cancer cells. AB - Deregulated microRNAs and their roles in cancer development have attracted much attention. In the present study, we analyzed the roles of miR-195 in colorectal cancer pathogenesis, as its participation in some other types of cancer has been suggested by previous reports. By comparing miR-195 expression in 81 human colorectal cancer tissues and matched non-neoplastic mucosa tissues, we found that miR-195 was downregulated in cancer tissues. And restoration of miR-195 in colorectal cancer cell lines HT29 and LoVo could reduce cell viability, promote cell apoptosis and suppress tumorigenicity. Moreover, important antiapoptotic Bcl 2 was identified to be directly targeted by miR-195, and miR-195 was further suggested to exert its proapoptotic function mainly through targeting Bcl-2 expression. Taken together, our study provides important roles of miR-195 in colorectal cancer pathogenesis and implicates its potential application in cancer therapy. PMID- 20727859 TI - Opioid-induced latent sensitization in a model of non-inflammatory viscerosomatic hypersensitivity. AB - Exposure to opioids can induce a state of "latent sensitization" characterized by long-lasting enhanced responses to subsequent cutaneous injury. Here, we explored the possibility that prior treatment with morphine could induce a state of latent sensitization to visceral pain conditions. Following butyrate enemas to induce non-inflammatory visceral pain, acute morphine administration produced dose related inhibition of referred viscerosomatic hypersensitivity. Treatment with morphine for a period of six days resulted in a persistent hyperalgesia that resolved many days after termination of drug administration. In morphine pre exposed rats, butyrate-induced referred hypersensitivity was enhanced and extended in duration. No differences were observed in the morphine dose-response curve in suppression of acute nociception (i.e., the hot-plate assay) when morphine pre-exposed rats were compared to naive rats indicating that opioid antinociceptive tolerance was not present. However, the morphine dose-response curve to suppress evoked viscerosomatic hypersensitivity was displaced to the right by approximately 4-fold in morphine pre-exposed rats. Induction of viscerosomatic hypersensitivity resulted in an increased labeling of CGRP-, but not substance P-positive cells in the lumbar dorsal root ganglia; increased labeling was not affected by prior exposure to morphine. The data indicate that a period of morphine exposure can induce a state of "latent sensitization" to subsequent visceral pain characterized by extended duration of hypersensitivity. This condition likely reflects enhanced visceral "pain" intensity as a consequence of persistent pronociceptive adaptive changes. PMID- 20727860 TI - ABC efflux transporters in brain vasculature of Alzheimer's subjects. AB - Multidrug efflux transporters of the ATP-Binding cassette (ABC) family, P glycoprotein (Pgp), multidrug-resistance associated protein 4 (MRP4) and breast cancer resistance protein (BCRP), located on endothelial cells lining brain vasculature play important roles in limiting movement of substances into and enhancing their efflux from the brain. Signals from the surrounding brain normally maintain such barrier function but these may become altered in CNS pathologies such as Alzheimer's disease (AD). Previous studies have reported decreases in the glucose transporter, Glut-1, in brain vasculature of AD patients. The present study investigates the status of the multidrug efflux transporters. Sections of frozen brain from hippocampal region obtained from male AD and age-matched non-demented cases were examined for amyloid plaques and Dkk-1 expression and subjected to dual fluorescence immunochemical staining using antibodies against Pgp, BCRP or MRP4 and von Willebrand factor. Protein expression of each transporter was assessed using confocal microscopy, quantifying peak fluorescence values of cross sectional profiles across brain microvessels. Results in brain microvessels revealed expression of Pgp protein to be significantly lower in hippocampal vessels of patients with AD compared to normal individuals whereas that of MRP4 or BCRP protein was not. By contrast, analysis of the sections at protein level via Western blotting or at transcript level by qRT-PCR did not reveal significantly lower expression for either Pgp or BCRP. Such analysis did however reveal higher than normal expression in the AD brains of MRP4, probably due to gliosis, MRP4 being present also in glial cells. PMID- 20727861 TI - Expression of NF-E2-related factor 2 (Nrf2) in the basilar artery after experimental subarachnoid hemorrhage in rabbits: a preliminary study. AB - It has been suggested that the pathogenesis of vasospasm is complex including endothelial damage, oxidative stress, inflammatory damage, and the accumulation of toxic metabolites. Recently, a growing body of evidence indicates that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a unique role in many physiological stress processes. In this study, a total of 48 rabbits were assigned randomly to four groups: control group, SAH day 3, day 5, and day 7 groups. The animals in SAH day 3, day 5, and day 7 groups were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2 and were killed on days 3, 5, and 7, respectively. Cross-sectional area of basilar artery was measured and the Nrf2 expression was assessed by immunohistochemistry and Western blot analysis. The mRNA levels of Nrf2 were also determined by RT PCR. The basilar arteries exhibited vasospasm after SAH and became more severe on days 3 and 5. The elevated expression of Nrf2 was detected after SAH and peaked on days 3 and 5. Nrf2 is increasingly expressed in a parallel time course to the development of cerebral vasospasm in a rabbit experimental model of SAH. PMID- 20727863 TI - Blockade of TTX-resistant and TTX-sensitive Na+ currents in cultured dorsal root ganglion neurons by fomocaine and the fomocaine derivative Oe 9000. AB - Fomocaine and its new derivative Oe 9000 are local anesthetics in which the inner aromatic moiety carries a phenoxymethyl substituent and is linked to the tertiary amine by an alkylene chain, rendering these compounds considerably lipophilic and increasing their chemical and metabolic stability. Although fomocaine was used for surface anesthesia, the presumed mode of action of fomocaine and Oe 9000, the blockade of voltage-gated Na(+) currents in neurons, has not been investigated. In the present experiments we used the whole-cell mode of the patch-clamp technique and studied the effect of both drugs on voltage-gated Na(+) currents in isolated and cultured dorsal root ganglion (DRG) neurons from adult rats. Both drugs reversibly reduced slowly activating and inactivating tetrodotoxin resistant (TTX-R) Na(+) currents as well as rapidly activating and inactivating TTX-sensitive (TTX-S) Na(+) currents at low micromolar concentrations. For the reduction of TTX-R Na(+) currents the IC(50) of fomocaine was 10.3MUM, and the IC(50) for the more hydrophilic Oe 9000 was 4.5MUM. These IC(50) values are more than one order of magnitude lower than the corresponding IC(50) of other local anesthetics such as lidocaine. Similar as for other local anesthetics, the effects showed a frequency dependence indicating that the compounds preferentially bind to the open and/or inactivated state of the channel. These data establish for the first time the functional suppression of TTX-R and TTX-S Na(+) currents by fomocaine and Oe 9000 in neurons. They support the further research into the use of Oe 9000 as a novel local anesthetic. PMID- 20727862 TI - The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin. AB - Lactation is an important physiological model of the integration of energy balance and reproduction, as it involves activation of potent appetitive neuropeptide systems coupled to a profound inhibition of pulsatile GnRH/LH secretion. There are multiple systems that contribute to the chronic hyperphagia of lactation: 1) suppression of the metabolic hormones, leptin and insulin, 2) activation of hypothalamic orexigenic neuropeptide systems NPY, AGRP, orexin (OX) and melanin concentrating hormone (MCH), 3) special induction of NPY expression in the dorsomedial hypothalamus, and 4) suppression of anorexigenic systems POMC and CART. These changes ensure adequate energy intake to meet the metabolic needs of milk production. There is significant overlap in all of the systems that regulate food intake with the regulation of GnRH, suggesting there could be several redundant factors acting to suppress GnRH/LH during lactation. In addition to an overall increase in inhibitory tone acting directly on GnRH cell bodies that is brought about by increases in orexigenic systems, there are also effects at the ARH to disrupt Kiss1/neurokinin B/dynorphin neuronal function through inhibition of Kiss1 and NKB. These changes could lead to an increase in inhibitory auto-regulation of the Kiss1 neurons and a possible disruption of pulsatile GnRH release. While the low levels of leptin and insulin contribute to the changes in ARH appetitive systems, they do not appear to contribute to the suppression of ARH Kiss1 or NKB. The inhibition of Kiss1 may be the key factor in the suppression of GnRH during lactation, although the mechanisms responsible for its inhibition are unknown. PMID- 20727865 TI - Corticotrophin-releasing factor and stress-induced inhibition of the gonadotrophin-releasing hormone pulse generator in the female. AB - It is well established that stress activates the hypothalamo-pituitary-adrenal (HPA) axis and suppresses the hypothalamo-pituitary-gonadal (HPG) axis. A large literature dealing with various stressors that regulate gonadotrophin-releasing hormone (GnRH) secretion in a variety of species (including nonhuman primates, sheep, and rats) provides evidence that stress modulates GnRH secretion by activating the corticotrophin-releasing factor (CRF) system and sympathoadrenal pathways, as well as the limbic brain. Different stressors may suppress the HPG axis by activating or inhibiting various pathways in the CNS. In addition to CRF being the principal hypophysiotropic factor driving the HPA axis, it is a potent inhibitor of the GnRH pulse generator. The suppression of the GnRH pulse generator by a variety of stressful stimuli can be blocked by CRF antagonists, suggesting a pivotal role for endogenous CRF. The differential roles for CRF receptor type 1 (CRF-R1) and CRF-R2 in stress-induced suppression of the GnRH pulse generator add to the complexity of CRF regulation of the HPG axis. Although the precise sites and mechanisms of action remain to be elucidated, noradrenergic and gamma-amino-butyric acid (GABA) neurones are implicated in the system's regulation, and opioids and kisspeptin in the medial preoptic area (mPOA) and hypothalamic arcuate nucleus (ARC) may operate downstream of the CRF neuronal system. PMID- 20727864 TI - Role of the medial prefrontal cortex in coping and resilience. AB - The degree of behavioral control that an organism has over an aversive event is well known to modulate the behavioral and neurochemical consequences of exposure to the event. Here we review recent research that suggests that the experience of control over a potent stressor alters how the organism responds to future aversive events as well as to the stressor being controlled. More specifically, subjects that have experienced control show blunted behavioral and neurochemical responses to subsequent stressors occurring days to months later. Indeed, these subjects respond as if a later uncontrollable stressor is actually controllable. Further, we review research indicating that the stress resistance induced by control depends on control-induced activation of ventral medial prefrontal cortical (vmPFC) inhibitory control over brainstem and limbic structures. Furthermore, there appears to be plasticity in these circuits such that the experience of control alters the vmPFC in such a way that later uncontrollable stressors now activate the vmPFC circuitry, leading to inhibition of stress responsive limbic and brainstem structures, i.e., stressor resistance. This controllability-induced proactive stressor resistance generalizes across very different stressors and may be involved in determining individual difference in reactions to traumatic events. PMID- 20727866 TI - Physicochemical characteristics associated with transfection of cationic cholesterol-based gene delivery vectors in the presence of DOPE. AB - The physicochemical properties of a novel series of cholesterol-based cationic lipids in the presence of DOPE were studied by various techniques in an effort to correlate cationic lipid structure with transfection efficacy. It was found that while DOPE improves the beta-gal activity of the active AC and MC derivatives, the overall zeta potential of the particles, pDNA complexation and condensation is not improved. This is in stark contrast with the tertiary amine derivative DC whose dispersion properties were improved and its monolayer surface potential is restored at high molecular surface density in the presence of DOPE. Overall the transfection activity mediated by DC and the quaternary ammonium TC derivative was greatly improved in the presence of DOPE and is attributed to decreased cytotoxicity, improved fusogenicity and cellular association. PMID- 20727867 TI - Lovastatin raises serum osteoprotegerin level in people with type 2 diabetic nephropathy. AB - OBJECTIVES: Osteoprotegerin (OPG), a glycoprotein, is a member of the tumor necrotizing factor alpha receptor super-family. By considering the possible role of OPG in cardiovascular disease (CVD), higher incidence of CVD in people with type 2 diabetic nephropathy (T2DN), and anti-atherosclerotic effects of statins, the present study aimed to investigate the effects of lovastatin on serum levels of OPG and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) in people with T2DN. DESIGN AND METHODS: Thirty patients completed the study course, out of 38 adult male patients with T2DN who were initially enrolled. Lovastatin, 20mg/d, was administered for 90 days. Afterwards, lovastatin was withdrawn for the next 30 days. Serum levels of OPG and sRANKL were measured using commercial ELISA kits at baseline, after 90 days of intervention, and after 30 days of withdrawal of lovastatin. RESULTS: Serum level of OPG was significantly increased (10.76 +/- 16.44) and decreased (-7.38 +/- 11.98) during 90 days of intervention and 30 days of withdrawal periods, respectively, while, sRANKL level was significantly decreased (-1192.08 +/- 578.20) and increased (4418.67 +/- 2124.66) during the same periods, respectively. CONCLUSIONS: Lovastatin therapy increased serum OPG level and decreased sRANKL level in people with T2DN. The withdrawal of lovastatin decreased serum OPG level, while sRANKL level was extensively increased. PMID- 20727868 TI - Gelofusine affects the quality control performance of QuickVue point-of-care human chorionic gonadotropin test devices. AB - OBJECTIVE: To characterize the influence of Gelofusine (succinylated gelatin) on the performance of point-of-care testing (POCT) for human chorionic gonadotropin (hCG) devices. DESIGN AND METHODS: Three brands of urine and urine/serum hCG POCT devices were verified. RESULTS: Succinylated gelatin affected the performance of the control band in the QuickVue hCG POCT devices. Alternative devices were not affected. The hCG test performance is not influenced. CONCLUSIONS: Gelofusine affects specifically the quality control performance of the QuickVue hCG POCT devices. PMID- 20727869 TI - Effect of apolipoprotein C3 and apolipoprotein A1 polymorphisms on postprandial response to a fat overload in metabolic syndrome patients. AB - OBJECTIVES: Apolipoprotein C-III (APOC3) is a component of triglyceride rich lipoproteins, and SstI polymorphism has been associated with hypertriglyceridemia. Apolipoprotein A-I (APOA1) is the major component of HDL and MspI polymorphism has been associated with APOA1 and HDL-C levels. Thus, we study the influence of these polymorphisms in the postprandial response in metabolic syndrome (MS). DESIGN AND METHODS: 73 MS patients and 21 healthy subjects underwent a fat overload, with measurements of their fasting and postprandial lipid profile. The APOC3 SstI and the APOA1MspI polymorphisms were genotyped. RESULTS: No significant differences were found in the lipid profile with respect to the MspI genotype. Patients with the S2S2 APOC3 genotype had significantly higher fasting and postprandial triglyceride levels and postprandial APOC3 and chylomicron-triglyceride levels compared with the other SstI APOC3 genotypes. CONCLUSIONS: Homozygosity for the minor allele of the APOC3 SstI polymorphism was associated to a worse postprandial response in MS patients. PMID- 20727870 TI - An acid hydrolysis method for quantification of plasma free and total carnitine by flow injection tandem mass spectrometry. AB - OBJECTIVES: To develop a tandem mass spectrometry (MS/MS) method for plasma free and total carnitine, incorporating acid hydrolysis for total carnitine measurement, for improved accuracy and sample throughput. DESIGN AND METHODS: Limit of detection (LOD), limit of quantitation (LOQ), linearity, accuracy, precision coefficient of variation (CV), method comparison with a radioenzymatic assay (REA) and liquid chromatography tandem mass spectrometry assay (LC-MS/MS) were performed. The method was tested for interferences and for long-term performance. RESULTS: The method LOD and LOQ were 0.87 and 1.36 MUmol/L for free carnitine and 1.79 and 2.54 MUmol/L for total carnitine, respectively. No interferences were detected. Long-term measurement CVs for both free and total carnitine were <4%. CONCLUSIONS: The method shows acceptable performance characteristics with improved speed and low level accuracy compared to existing REA and MS/MS methods. PMID- 20727871 TI - HPLC-high resolution mass spectrometry in clinical laboratory? AB - To date, GC-MS and LC-tandem MS techniques emerged quite frequently in laboratory medicine. However, high-resolution mass spectrometric (HRMS) analyzers remain almost ignored, even though in academic environment, they become more largely used. The main objective of this work is to present and illustrate with several applications, current high resolution mass spectrometric systems which could be useful for clinical applications. Among these systems are the Time-of-Flight (TOF) and Orbitrap instruments. Orbitrap has the advantage of higher resolution but suffers from a slower data acquisition, whereas TOF systems display the opposite characteristics. Both systems could provide accurate mass data and possible structural elucidation, very useful in large scale screening, in different medical areas (clinical or environmental toxicology, anti-doping controls, ...). Provided there are further improvements in quantification performances, there is no doubt such HRMS instruments will find their place in clinical laboratories. PMID- 20727872 TI - Optimizing the concentration of hydroxyethylstarch in a novel intestinal-specific preservation solution. AB - INTRODUCTION: Our lab has developed an effective nutrient-rich solution that facilitates energy production and control of oxidative stress during static cold storage of the intestine; however, the requirement for oncotic agents, such as hydroxyethylstarch (HES), has not been evaluated. This study investigated the effectiveness and requirement for HES in an intraluminal preservation solution during a clinically relevant period of cold storage. METHODS: Rat intestines were procured, including an intravascular flush with University of Wisconsin solution followed by a 'back table' intraluminal flush with a nutrient-rich preservation solution containing varying amounts of HES (n=6 per group): Group 1, 0%; Group 2, 2.5%; Group 3, 5%; Group 4, 10%. Energetics, oxidative stress, and morphology were assessed over a 24h time-course of cold storage. RESULTS: Overall, the 5% HES solution, Group 3, demonstrated superior energetic status (ATP and total adenylates) compared to all groups, P<0.05. Malondialdehyde levels indicated a reduction in oxidative stress in Groups 3 and 4 (P<0.05). After 12h, median modified Parks' grades for Groups 2 and 3 were significantly lower than Groups 1 and 4, P<0.05. CONCLUSION: Our data suggests that when employing an intraluminal preservation solution for static organ storage, oncotic support is a fundamental requirement; 5% HES is optimal. PMID- 20727873 TI - Cryopreservation of human failed maturation oocytes shows that vitrification gives superior outcomes to slow cooling. AB - This study investigated whether failed maturation oocytes could be used to evaluate different cryopreservation procedures. A total of 289 failed maturation oocytes (GV and MI stages), obtained from 169 patients undergoing IVF treatment (mean age 33.84+/-5.0) were divided into two different slow-cooling groups (1.5 mol/l 1,2-propanediol+0.2 mol/l sucrose in either NaCl (group A) or choline chloride (ChCl) (group B) based cryopreservation solutions) and one vitrification group (15% ethylene glycol+15% dimethyl sulphoxide). Survival rate, in vitro maturation (IVM) rate, fertilization and developmental rate of cryopreserved oocytes were assessed. Regardless of the stage at which cryopreservation was performed (GV+MI), the slow cooling with ChCl based medium always gave significantly lower survival rate than the slow cooling in NaCl based medium (p=0.01) and vitrification (p<0.001). An extended study also showed statistically reduced survival rate between slow-cooling NaCl based medium and vitrification (p<0.05). Global results of in vitro maturation and fertilization showed worse results between both slow-cooling NaCl and ChCl based media versus vitrification. In conclusion, for oocytes that had failed to mature, vitrification gave better survival, maturation, fertilization and also cleavage rates than the slow-cooling protocols. Four cells embryos were obtained only from vitrified in vitro matured MI oocytes. PMID- 20727874 TI - Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development. AB - The fibroblast growth factor, FGF8, has been shown to be essential for vertebrate cardiovascular, craniofacial, brain and limb development. Here we report that Fgf8 function is required for normal progression through the late fetal stages of lung development that culminate in alveolar formation. Budding, lobation and branching morphogenesis are unaffected in early stage Fgf8 hypomorphic and conditional mutant lungs. Excess proliferation during fetal development disrupts distal airspace formation, mesenchymal and vascular remodeling, and Type I epithelial cell differentiation resulting in postnatal respiratory failure and death. Our findings reveal a previously unknown, critical role for Fgf8 function in fetal lung development and suggest that this factor may also contribute to postnatal alveologenesis. Given the high number of premature infants with alveolar dysgenesis and lung dysplasia, and the accumulating evidence that short term benefits of available therapies may be outweighed by long-term detrimental effects on postnatal alveologenesis, the therapeutic implications of identifying a factor or pathway that can be targeted to stimulate normal alveolar development are profound. PMID- 20727875 TI - Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis. AB - BMP signaling plays many important roles during organ development, including palatogenesis. Loss of BMP signaling leads to cleft palate formation. During development, BMP activities are finely tuned by a number of modulators at the extracellular and intracellular levels. Among the extracellular BMP antagonists is Noggin, which preferentialy binds to BMP2, BMP4 and BMP7, all of which are expressed in the developing palatal shelves. Here we use targeted Noggin mutant mice as a model for gain of BMP signaling function to investigate the role of BMP signaling in palate development. We find prominent Noggin expression in the palatal epithelium along the anterior-posterior axis during early palate development. Loss of Noggin function leads to overactive BMP signaling, particularly in the palatal epithelium. This results in disregulation of cell proliferation, excessive cell death, and changes in gene expression, leading to formation of complete palatal cleft. The excessive cell death in the epithelium disrupts the palatal epithelium integrity, which in turn leads to an abnormal palate-mandible fusion and prevents palatal shelf elevation. This phenotype is recapitulated by ectopic expression of a constitutively active form of BMPR-IA but not BMPR-IB in the epithelium of the developing palate; this suggests a role for BMPR-IA in mediating overactive BMP signaling in the absence of Noggin. Together with the evidence that overexpression of Noggin in the palatal epithelium does not cause a cleft palate defect, we conclude from our results that Noggin mediated modulation of BMP signaling is essential for palatal epithelium integrity and for normal palate development. PMID- 20727877 TI - Control of the spineless antennal enhancer: direct repression of antennal target genes by Antennapedia. AB - It is currently thought that antennal target genes are activated in Drosophila by the combined action of Distal-less, homothorax, and extradenticle, and that the Hox gene Antennapedia prevents activation of antennal genes in the leg by repressing homothorax. To test these ideas, we analyze a 62bp enhancer from the antennal gene spineless that is specific for the third antennal segment. This enhancer is activated by a tripartite complex of Distal-less, Homothorax, and Extradenticle. Surprisingly, Antennapedia represses the enhancer directly, at least in part by competing with Distal-less for binding. We show that Antennapedia is required in the leg only within a proximal ring that coexpresses Distal-less, Homothorax and Extradenticle. We conclude that the function of Antennapedia in the leg is not to repress homothorax, as has been suggested, but to directly repress spineless and other antennal genes that would otherwise be activated within this ring. PMID- 20727876 TI - Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells. AB - The Notch pathway is crucial for a wide variety of developmental processes including the formation of tissue boundaries. That it may function in calvarial suture development and figure in the pathophysiology of craniosynostosis was suggested by the demonstration that heterozygous loss of function of JAGGED1 in humans can cause Alagille syndrome, which has craniosynostosis as a feature. We used conditional gene targeting to examine the role of Jagged1 in the development of the skull vault. We demonstrate that Jagged1 is expressed in a layer of mesoderm-derived sutural cells that lie along the osteogenic-non-osteogenic boundary. We show that inactivation of Jagged1 in the mesodermal compartment of the coronal suture, but not in the neural crest compartment, results in craniosynostosis. Mesodermal inactivation of Jagged1 also results in changes in the identity of sutural cells prior to overt osteogenic differentiation, as well as defects in the boundary between osteogenic and non-osteogenic compartments at the coronal suture. These changes, surprisingly, are associated with increased expression of Notch2 and the Notch effector, Hes1, in the sutural mesenchyme. They are also associated with an increase in nuclear beta-catenin. In Twist1 mutants, Jagged1 expression in the suture is reduced substantially, suggesting an epistatic relationship between Twist1 and Jagged1. Consistent with such a relationship, Twist1-Jagged1 double heterozygotes exhibit a substantial increase in the severity of craniosynostosis over individual heterozygotes. Our results thus suggest that Jagged1 is an effector of Twist1 in coronal suture development. PMID- 20727878 TI - A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator secretion in the human colon cancer cell line, HT-29. AB - Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the alpha7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10nM. This effect was markedly inhibited by alpha-Bungarotoxin, thus showing the involvement of alpha7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer. PMID- 20727879 TI - Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats. AB - The cannabinoid receptor 1 antagonist, rimonabant, reduces food intake and body weight, but contradictory findings have been reported as to whether the weight reducing effect is fully accounted for by the reduced food intake or if rimonabant also mediates a lipolytic effect. In the present study, the effect on weight loss was studied in diet-induced obese rats after 3 days and 3 weeks of exposure to rimonabant, respectively. Induction of lipolysis was examined following acute administration and following 3 weeks of repeated dosing. Rimonabant-treated rats lost significantly more weight than their food-restricted controls. This effect was most pronounced in the beginning of the treatment period. No increase in lipolytic activity was found after 3 weeks of repeated dosing as measured by microdialysis in adipose tissue whereas acute administration of 10mg/kg produced a significant increase in microdialysate levels of glycerol illustrating an acute stimulation of lipolysis. No equivalent increase in glycerol was, however, observed in vitro following incubation of isolated rat adipocytes with rimonabant. This finding excludes a direct lipolytic action of rimonabant on tissue level. Instead, administration of 10mg/kg produced a significant increase in noradrenaline excretion in diet-induced obese rats, suggesting an increase in sympathoadrenal activity. In conclusion, the present study suggests an acute lipolytic effect of rimonabant mediated through activation of the sympathoadrenal system. PMID- 20727880 TI - Anxioselective profile of glycineB receptor partial agonist, D-cycloserine, in plus-maze-naive but not plus-maze-experienced mice. AB - Recent successes as a pharmacological adjunct to exposure therapy has focused attention on the therapeutic potential of the glycine(B) receptor partial agonist, D-cycloserine (DCS), in certain clinical anxiety disorders. Although widely believed to reflect a facilitation of extinction learning, previous research with DCS and other glycine(B) partial agonists suggests the additional possibility of intrinsic anxiolytic activity. In the present study, ethological methods were used to profile the behavioural effects of DCS (7.5-30.0mg/kg) and the positive control chlordiazepoxide (CDP, 15 mg/kg) in mice exposed to the elevated plus-maze for the first time (plus-maze trial 1; Experiment 1) and in mice pre-exposed undrugged to the maze 24h prior to testing (plus-maze trial 2; Experiment 2). The results show that, in test-naive animals, both CDP and DCS (15 mg/kg, but not lower or higher doses) produced significant anxioselective profiles with the effects of DCS statistically weaker than those of CDP. However, as predicted by the plus-maze retest effect, CDP was without behavioural activity in test-experienced animals, while the highest dose of DCS (30 mg/kg) induced behavioural changes more consistent with mild psychomotor stimulation than anxiolysis. Present findings therefore confirm the intrinsic anxiolytic activity of DCS in untrained animals, with the observed bell-shaped dose-response function most probably indicative of varying affinities and intrinsic activities at NMDA receptor subtypes. The contrasting and comparatively limited effects of DCS in test-experienced mice suggest that prior maze exposure radically alters the extent to which NMDA receptor-related mechanisms are involved in future behavioural responses to this test environment. PMID- 20727881 TI - MT1-MMP-mediated basement membrane remodeling modulates renal development. AB - Extracellular matrix (ECM) remodeling regulates multiple cellular functions required for normal development and tissue repair. Matrix metalloproteinases (MMPs) are key mediators of this process and membrane targeted MMPs (MT-MMPs) in particular have been shown to be important in normal development of specific organs. In this study we investigated the role of MT1-MMP in kidney development. We demonstrate that loss of MT1-MMP leads to a renal phenotype characterized by a moderate decrease in ureteric bud branching morphogenesis and a severe proliferation defect. The kidneys of MT1-MMP-null mice have increased deposition of collagen IV, laminins, perlecan, and nidogen and the phenotype is independent of the MT-1MMP target, MMP-2. Utilizing in vitro systems we demonstrated that MTI MMP proteolytic activity is required for renal tubule cells to proliferate in three dimensional matrices and to migrate on collagen IV and laminins. Together these data suggest an important role for MT1-MMP in kidney development, which is mediated by its ability to regulate cell proliferation and migration by proteolytically cleaving kidney basement membrane components. PMID- 20727882 TI - Development and limitations of lentivirus vectors as tools for tracking differentiation in prostate epithelial cells. AB - To investigate hierarchy in human prostate epithelial cells, we generated recombinant lentiviruses, infected primary cultures and cell lines, and followed their fate in vitro. The lentiviruses combined constitutive promoters including CMV and beta-actin, or late-stage differentiation promoters including PSCA (prostate stem cell antigen) and PSAPb (prostate specific antigen/probasin) driving expression of monomeric, dimeric and tetrameric fluorescent proteins. Significantly, rare CD133(+) cells from primary prostate epithelial cultures were successfully infected and activation of late-stage promoters was observed in basal epithelial cultures following induction of differentiation. Lentiviruses also infected CD133(+) cells within the P4E6 cell line. However, promoter silencing was observed in several cell lines (P4E6, BPH-1, PC3). We examined the promoter methylation status of the lentiviral insertions in heterogeneously fluorescent cultures from PC3 clones and found that DNA methylation was not the primary mechanism of silencing of the CMV promoter. We also describe limitations to the lentivirus system including technical challenges due to low titers and low infection efficiency in primary cultures. However, we have identified a functional late-stage promoter that indicates differentiation from a basal to a luminal phenotype and demonstrate that this strategy for lineage tracking of prostate epithelial cells is valid with further optimisation. PMID- 20727883 TI - Attenuation of streptozotocin-induced microvascular changes in the mouse retina with the endothelin receptor A antagonist atrasentan. AB - Hyperglycemia mediates endothelial cell dysfunction through a number of potential mechanisms that could result in the decrease of retinal blood flow early in diabetes. The aim of this study was to explore the role of endothelin receptor A (ET(A)) in the early decrease of retinal blood flow in diabetic mice. Diabetes was induced by streptozotocin, then ~1 wk later the mice were administered drinking water with or without the ET(A) receptor antagonist atrasentan (7.5mg/kg/day) for the following 3 weeks. Non-diabetic age-matched mice with or without atrasentan were included as controls. For each mouse, measurements of retinal vascular diameters and red blood cell (RBC) velocities were obtained via intravital microscopy for the 5-7 feed arterioles (and draining venules) extending out of (and into) the optic disk, and from these values, flow rates and wall shear rates were calculated. Additionally, the number of retinal capillaries was counted by fluorescent immunostaining of platelet-endothelial cell adhesion molecule-1 (PECAM-1). Diabetes induced statistically significant decreases in RBC velocity, flow rate, and wall shear rate, with these alterations partially inhibited by atrasentan. No changes were observed in PECAM-1 expression among groups. The changes induced by diabetes, and the attenuation provided by atrasentan, were greater in the smaller retinal arterioles. In summary, ET(A) appears to play a role in the early decreases in retinal blood flow in a mouse model of diabetes. PMID- 20727884 TI - Entamoeba invadens: dynamics of DNA synthesis during differentiation from trophozoite to cyst. AB - The DNA dynamics which mediate conversion of uni-nucleate trophozoite into quadrinucleate cyst in Entamoeba histolytica is not well understood. Here, we have addressed this question in Entamoeba invadens (a model system for encystation) through a detailed time course study of the differentiation process. We combined flow cytometric analysis with the change in rate of thymidine incorporation and the number of nuclei per cell. Our data shows that during encystment the cell population passes through three phases: (1) Early phase (0 8h); of rapid DNA synthesis which may correspond to completion of ongoing DNA replication. Bi-nucleated cells increase with concomitant drop in uni-nucleated cells. (2) Commitment phase (8-24h); in which DNA synthesis rate slows down. Possibly new rounds of replication are initiated which proceed slowly, followed by mitosis at 20 h. After this the number of bi- and uni-nucleated cells gradually decline and the tri- and tetra-nucleated cells begin to increase. (3) Consolidation phase (24-72 h); in which the rate of DNA synthesis shows a small increase till 32 h and then begins to decline. The G2/M peak reappears at 48 h, showing that more rounds of DNA replication may be getting completed, followed by nuclear division. By 72 h the encystment is virtually complete. The bi-nucleated stage could be an intermediate both in the conversion of trophozoite to cyst and back. Our study provides a comprehensive view of DNA dynamics during encystation and excystation of E. invadens. PMID- 20727885 TI - Hereditary pancreatic cancer. PMID- 20727886 TI - Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women. AB - BACKGROUND & AIMS: Data on the association between erosive esophagitis and obesity are inconsistent because of variations in study populations and methods used to determine obesity. METHODS: Participants in a prospective health screening cohort underwent esophagogastroduodenoscopy and computed tomography. The association between erosive esophagitis and obesity (measured by body mass index [BMI], waist circumference, and abdominal visceral adipose tissue volume) was estimated with odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for confounding factors. We also analyzed the association between obesity and erosive esophagitis by sex. RESULTS: The prevalence of erosive esophagitis was 9.3% (495/5329). The OR for erosive esophagitis correlated with obesity measured by BMI, waist circumference, and abdominal visceral adipose tissue volume (P < .001 for each factor). The multivariate OR for erosive esophagitis was 1.97 (95% CI: 1.34-2.90) for a visceral adipose tissue volume of 500-999 cm(3), 2.27 (95% CI: 1.51-3.39) for 1000-1499 cm(3), and 2.94 (95% CI: 1.87-4.62) for >=1500 cm(3), compared with participants who had visceral adipose tissue volumes less than 500 cm(3). When measures of obesity were analyzed simultaneously, abdominal visceral adipose tissue volume, but not BMI or waist circumference, was associated with erosive esophagitis. The 3 measures of obesity were significantly associated with erosive esophagitis in males, but only visceral adipose tissue volume was associated with erosive esophagitis in females (P = .002). CONCLUSIONS: In contrast to BMI or waist circumference, abdominal visceral adipose tissue volume is associated with an increased risk of erosive esophagitis in males and females. PMID- 20727889 TI - A national study of Helicobactor pylori infection in gastric biopsy specimens. AB - BACKGROUND & AIMS: We investigated whether infection with Helicobacter pylori and signs of chronic active gastritis and intestinal metaplasia in gastric biopsy samples were inversely associated with Barrett's metaplasia. METHODS: We studied gastric biopsy samples from 78,985 unique patients. Histologic findings were correlated with sociodemographic patient characteristics using multivariate logistic regression to calculate odds ratios and 95% confidence intervals. RESULTS: H pylori infection, chronic active gastritis, and intestinal metaplasia had similar epidemiologic patterns. The presence of each, based on histology analyses, was significantly associated with that of the others. They were also characterized by similar geographic distributions within the United States. All 3 disorders were more common among men and among Medicaid patients (compared with those with other insurance) and were inversely associated with Barrett's metaplasia (less frequent in patients with Barrett's metaplasia). CONCLUSIONS: H pylori infection and associated disorders, such as chronic active gastritis and intestinal metaplasia, are inversely associated with Barrett's metaplasia. PMID- 20727892 TI - Safety of proton pump inhibitor exposure. AB - Proton pump (H(+)/K(+)-adenosine triphosphatase) inhibitors (PPIs) are widely used to treat patients with acid-related disorders because they are generally perceived to be safe and effective. However, as with any pharmacologic agent, they have the potential for side effects. Many studies have examined the side effects of long-term or short-term PPI exposure. We review the mechanism of action of PPIs, focusing on recently released products that might have greater risks of adverse effects than older products because of increased potency and/or duration of action. We summarize the data available on the putative adverse effects of PPI therapy and propose guidelines for clinicians who prescribe these agents to limit the potential for adverse outcomes in users of these effective therapeutic agents. PMID- 20727893 TI - KLF4alpha up-regulation promotes cell cycle progression and reduces survival time of patients with pancreatic cancer. AB - BACKGROUND & AIMS: Kruppel-like factor 4 (KLF4) is a transcription factor associated with tumor suppression and oncogenesis. KLF4 suppresses pancreatic tumorigenesis by unknown mechanisms; we investigated alterations that might affect KLF4 function and lead to tumor formation. METHODS: We identified different isoforms of KLF4 in pancreatic cancer cells by reverse-transcriptase polymerase chain reaction, cloning, and DNA sequence analyses. We constructed vectors to express the isoform KLF4alpha and characterize its function. Using real-time polymerase chain reaction, immunoprecipitation, and immunohistochemical analyses, we assessed expression of KLF4alpha in pancreatic cancer cell lines and tumor tissue samples; xenograft models were used to determine the effect of KLF4alpha on pancreatic tumorigenesis. RESULTS: We identified 4 KLF4 isoforms in human pancreatic cancer cells, designated KLF4alpha, KLF4beta, KLF4gamma, and KLF4delta. KLF4alpha localized primarily to the cytoplasm; its protein and messenger RNA were up-regulated in pancreatic cancer cell lines with high metastatic potential and human pancreatic tumors compared with normal pancreatic tissue. Transgenic expression of KLF4alpha reduced expression of p27(Kip1) and p21(Cip1), promoting cell cycle progression and in vivo tumor formation by pancreatic cancer cells. Increased expression of KLF4alpha in pancreatic tumor tissue was inversely correlated with overall time of survival in patients with stage II pancreatic ductal adenocarcinoma. CONCLUSIONS: We identified a splice variant of KLF4 (KLF4alpha) that is up-regulated in aggressive pancreatic cancer cells and human pancreatic tumor tissues. Increased expression promotes growth of pancreatic tumors in mice and is associated with reduced survival times of patients. PMID- 20727894 TI - The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. AB - BACKGROUND & AIMS: We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer. METHODS: Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. RESULTS: Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82 0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92). CONCLUSIONS: We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management. PMID- 20727895 TI - Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice. AB - BACKGROUND & AIMS: Liver inflammation and injury are mediated by the innate immune response, which is regulated by Toll-like receptors (TLR). Activation of TLR9 induces type I interferons (IFNs) via the interferon regulatory factor (IRF) 7. We investigated the roles of type I IFNs in TLR9-associated liver injury. METHODS: Wild-type (WT), IRF7-deficient, and IFN-alpha/beta receptor 1 (IFNAR1) deficient mice were stimulated with TLR9 or TLR2 ligands. Findings from mice were verified in cultured hepatocytes and liver mononuclear cells (LMNCs) as well as in vivo experiments using recombinant type I IFN and interleukin-1 receptor antagonist (IL-1ra). RESULTS: Type I IFNs were up-regulated during TLR9 associated liver injury in WT mice. IRF7- and IFNAR1-deficient mice, which have disruptions in type I IFN production or signaling, respectively, had increased liver damage and inflammation, decreased recruitment of dendritic cells, and increased production of tumor necrosis factor alpha by LMNCs. These findings indicate that type I IFNs have anti-inflammatory activities in liver. IL-1ra, which is produced by LMNCs and hepatocytes, is an IFN-regulated antagonist of the proinflammatory cytokine IL-1beta; IRF7- and IFNAR1-deficient mice had decreased levels of IL-1ra compared with WT mice. IL-1ra protected cultured hepatocytes from IL-1beta-mediated sensitization to cytotoxicity from tumor necrosis factor alpha. In vivo exposure to type I IFN, which induced IL-1ra, or administration of IL-1ra reduced TLR9-associated liver injury; the protective effect of type I IFNs therefore appears to be mediated by IFN-dependent induction of IL-1ra. CONCLUSIONS: Type I IFNs have anti-inflammatory effects mediated by endogenous IL 1ra, which regulates the extent of TLR9-induced liver damage. Type I IFN signaling is therefore required for protection from immune-mediated liver injury. PMID- 20727896 TI - A flow cytometry-based assay to assess RSV-specific neutralizing antibody is reproducible, efficient and accurate. AB - Respiratory syncytial virus (RSV) is an important cause of respiratory infection in people of all ages, and is the leading cause of hospitalization in infants. Although commercially available monoclonal antibody is available for passive prophylaxis of neonates at risk of severe disease, there is no available vaccine to prevent RSV. Measurement of neutralizing activity will be a key endpoint for vaccine evaluation. Assessment of neutralizing antibody against RSV has been limited to traditional plaque reduction, which is time-consuming and inherently operator dependent and highly variable. Here, we describe a flow cytometry-based RSV-specific neutralization assay which is more rapid than traditional methods, highly sensitive and highly reproducible. PMID- 20727897 TI - Quality assurance of intracellular cytokine staining assays: analysis of multiple rounds of proficiency testing. AB - When evaluating candidate prophylactic HIV and cancer vaccines, intracellular cytokine staining (ICS) assays that measure the frequency and magnitude of antigen-specific T-cell subsets are one tool to monitor immunogen performance and make product advancement decisions. To assess the inter-laboratory assay variation among multiple laboratories testing vaccine candidates, the NIH/NIAID/DAIDS in collaboration with BD Biosciences implemented an ICS Quality Assurance Program (QAP). Seven rounds of testing have been conducted in which 16 laboratories worldwide participated. In each round, IFN-gamma, IL-2 and/or TNF alpha responses in CD4+ and CD8+ T-cells to CEF or CMV pp65 peptide mixes were tested using cryopreserved peripheral blood mononuclear cells (PBMC) from CMV seropositive donors. We found that for responses measured above 0.2%, inter laboratory %CVs were, on average, 35%. No differences in inter-laboratory variation were observed if a 4-color antibody cocktail or a 7-color combination was used. Moreover, the data allowed identification of important sources of variability for flow cytometry-based assays, including: number of collected events, gating strategy and instrument setup and performance. As a consequence, in this multi-site study we were able to define pass and fail criteria for ICS assays, which will be adopted in the subsequent rounds of testing and could be easily extrapolated to QAP for other flow cytometry-based assays. PMID- 20727898 TI - Mechanical properties of elytra from Tribolium castaneum wild-type and body color mutant strains. AB - Cuticle tanning in insects involves simultaneous cuticular pigmentation and hardening or sclerotization. The dynamic mechanical properties of the highly modified and cuticle-rich forewings (elytra) from Tribolium castaneum (red flour beetle) wild-type and body color mutant strains were investigated to relate body coloration and elytral mechanical properties. There was no statistically significant variation in the storage modulus E' among the elytra from jet, cola, sooty and black mutants or between the mutants and the wild-type GA-1 strain: E' averaged 5.1 +/- 0.6 GPa regardless of body color. E' is a power law function of oscillation frequency for all types. The power law exponent, n, averaged 0.032 +/ 0.001 for elytra from all genotypes except black; this small value indicated that the elytra are cross-linked. Black elytra, however, displayed a significantly larger n of 0.047 +/- 0.004 and an increased loss tangent (tan delta), suggesting that metabolic differences in the black mutant strain result in elytra that are less cross-linked and more pigmented than the other types. These results are consistent with the hypothesis that black elytra have a beta alanine-deficient and dopamine-abundant metabolism, leading to greater melanin (black pigment) production, probably at the expense of cross-linking of cuticular proteins mediated by N-beta-alanyldopamine quinone. PMID- 20727899 TI - Influence of iridoid glycoside containing host plants on midgut beta-glucosidase activity in a polyphagous caterpillar, Spilosoma virginica Fabricius (Arctiidae). AB - Iridoid glycosides are secondary plant compounds that have deterrent, growth reducing or even toxic effects on non-adapted herbivorous insects. To investigate the effects of iridoid glycoside containing plants on the digestive metabolism of a generalist herbivore, larvae of Spilosoma virginica (Lepidoptera: Arctiidae) were reared on three plant species that differ in their secondary plant chemistry: Taraxacum officinale (no iridoid glycosides), Plantago major (low iridoid glycoside content), and P. lanceolata (high iridoid glycoside content). Midguts of fifth instar larvae were assayed for the activity and kinetic properties of beta-glucosidase using different substrates. Compared to the larvae on T. officinale, the beta-glucosidase activity of larvae feeding on P. lanceolata was significantly lower measured with 4-nitrophenyl-beta-d glucopyranoside. Using the iridoid glycoside aucubin as a substrate, we did not find differences in the beta-glucosidase activity of the larvae reared on the three plants. Heat inactivation experiments revealed the existence of a heat labile and a more heat-stable beta-glucosidase with similar Michaelis constants for 4-nitrophenyl-beta-d-glucopyranoside. We discuss possible mechanisms leading to the observed decrease of beta-glucosidase activity for larvae reared on P. lanceolata and its relevance for generalist herbivores in adapting to iridoid glycoside containing plant species and their use as potential host plants. PMID- 20727901 TI - Crystal structures of the substrate-bound forms of red chlorophyll catabolite reductase: implications for site-specific and stereospecific reaction. AB - Red chlorophyll catabolite reductase (RCCR) catalyzes the ferredoxin-dependent reduction of the C20/C1 double bond of red chlorophyll catabolite (RCC), the catabolic intermediate produced in chlorophyll degradation. The crystal structure of substrate-free Arabidopsis thaliana RCCR (AtRCCR) demonstrated that RCCR folds into a characteristic alpha/beta/alpha sandwich, similar to that observed in the ferredoxin-dependent bilin reductase (FDBR) family. Here we have determined the crystal structures of RCC-bound AtRCCR, RCC-bound F218V AtRCCR, and substrate free F218V AtRCCR, a mutant protein that produces the stereoisomer of primary fluorescent chlorophyll catabolites at the C1 position. RCC is bound to the pocket between the beta-sheet and the C-terminal alpha-helices, as seen in substrate-bound FDBRs, but RCC binding to RCCR is much looser than substrate binding to FDBRs. The loose binding seems beneficial to the large conformational change in RCC upon reduction. Two conserved acidic residues, Glu154 and Asp291, sandwich the C20/C1 double bond of RCC, suggesting that these two residues are involved in site-specific reduction. The RCC in F218V AtRCCR rotates slightly compared with that in wild type to fill in the space generated by the substitution of Phe218 with valine. Concomitantly, the two carboxy groups of Glu154 and Asp291 move slightly away from the C20/C1 double bond. The geometrical arrangement of RCC and the carboxy groups of Glu154 and Asp291 in RCCR would appear to be essential for the stereospecificity of the RCCR reaction. PMID- 20727902 TI - Hemodynamics of the omphalo-mesenteric arteries in stage 18 chicken embryos and "flow-structure" relations for the microcirculation. AB - OBJECTIVE: The primary objective of this study is to evaluate the hemodynamic and structural characteristics of the omphalo-mesenteric (vitelline) arteries in stage 18 chicken embryos. The measured results were compared with Murray's law to validate the theoretical prediction on the vascular structure. METHODS: Variation of hemodynamic parameters such as mean velocity (U(mean)), peak velocity (U(peak)) at the systolic phase, velocity fluctuations (U(fluc)) at the pulsatile frequency, and the Womersley number (Omega) were measured with respect to the geometric parameters including the bifurcation cascade level (BCL), vessel diameter (D), and distance (L) from the first bifurcation. They were assessed by using the time-resolved in vivo micro-PIV (particle image velocimetry) technique and the geometric information was obtained from the microscopic vessel images. RESULTS: The effect of "branching of the vessel" on the variation of hemodynamic characteristics is similar to those of the "increase in distance" from the first bifurcation and the "decrease in vessel diameter". The flow quantities (U(mean), U(peak) and U(fluc)) decrease due to the increase in cross-sectional area ratio (gamma=1.209=(?D(daughter)(2))/D(mother)(2)), and the Womersley number also decreases as the bifurcation cascades (Omega"1). CONCLUSION: The geometric parameters are closely related to the variation of hemodynamic characteristics. Murray's law with non-constant viscosity hypothesis would provide an insight on the two-phase nature of microvascular blood flows. PMID- 20727900 TI - Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. AB - Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". PMID- 20727903 TI - 3rd US-EU workshop: systems level understanding of DNA damage responses. AB - The 3rd US-EU Workshop on systems level understanding of DNA damage responses was held from March 30 to April 1, 2009 in Egmond aan Zee, The Netherlands. Objectives of the workshop were (1) to assess the current science of the DDR, in particular network level responses to chemotherapeutic and environmentally induced DNA damage; and (2) to establish the basis for a reciprocal scientific exchange program between the EU and US in the relevant areas of DDR research. Here, we report the highlights of the meeting program and conclude that this third meeting in 2009 refined the role of DDR networks in human disease. PMID- 20727904 TI - False recollection of emotional pictures in Alzheimer's disease. AB - Alzheimer's Disease (AD) can reduce the effects of emotional content on memory for studied pictures, but less is known about false memory. In healthy adults, emotionally arousing pictures can be more susceptible to false memory effects than neutral pictures, potentially because emotional pictures share conceptual similarities that cause memory confusions. We investigated these effects in AD patients and healthy controls. Participants studied pictures and their verbal labels, and then picture recollection was tested using verbal labels as retrieval cues. Some of the test labels had been associated with a picture at study, whereas other had not. On this picture recollection test, we found that both AD patients and controls incorrectly endorsed some of the test labels that had not been studied with pictures. These errors were associated with medium to high levels of confidence, indicating some degree of false recollection. Critically, these false recollection judgments were greater for emotional compared to neutral items, especially for positively valenced items, in both AD patients and controls. Dysfunction of the amygdala and hippocampus in early AD may impair recollection, but AD did not disrupt the effect of emotion on false recollection judgments. PMID- 20727905 TI - To do or not to do? Action enlarges the FRN and P300 effects in outcome evaluation. AB - Behavioral studies demonstrate that the outcome following an individual's action evokes stronger emotional responses than the same outcome following inaction. Here we use the event-related potential (ERP) technique to investigate how action affects the brain activity in outcome evaluation. In a gambling task, participants were asked to select a box from three boxes containing monetary reward and then to decide whether they would change their initial choice (i.e., action) or not (i.e., inaction). The feedback-related negativity (FRN), an evoked potential that peaks approximately 250 ms after receipt of feedback information, showed a larger differential effect between loss and win following action than following inaction. Similarly, the P300 showed a larger differential effect following action than following inaction, but now with the responses more positive to the win feedback than to the loss feedback. These results suggest that action may increase the expectancy towards the outcome and/or the motivational/emotional significance of the outcome, and that this action effect can be found in both the FRN and the P300 electrophysiological responses. PMID- 20727906 TI - The production and detection of deception in an interactive game. AB - This experiment tests how people produce and detect deception while playing a computerized version of the dice game, Meyer. Deception is an integral part of this game, and the participants played it as in real life, without constraints on whether or when to attempt to deceive their opponent, and whether or when to accuse them of deception. We stress that deception is a complex act that cannot be exclusively associated with telling a falsehood, and that it is facilitated by hierarchical decision-making and risk evaluation. In comparison with a non competitive control condition, both claiming truthfully and claiming falsely were associated with activity in fronto-polar cortex (BA10). However, relative to true claims, false claims were associated with greater activity in the premotor and parietal cortices. We speculate that the activity in BA10 is associated with the development of high-level executive strategies involved in both types of claim, while the premotor and parietal activity is associated with the need to select which particular claim to make. PMID- 20727907 TI - Synthesis of 7beta-hydroxy-epiandrosterone. AB - The synthesis of 7beta-hydroxy-epiandrosterone (6) possessing strong anti inflammatory properties was achieved starting from 3beta-acetoxy-17,17 (ethylenedioxy)-5-androsten (1). This approach involved as a main step an allylic oxidation of the C-7 followed by two reduction reactions of the double bond and of the carbonyl group. This stereoselective synthesis in 5 steps gave 7beta hydroxy-epiandrosterone in 63% overall yield. PMID- 20727908 TI - ERG changes in albino and pigmented mice after optic nerve transection. AB - Optic nerve transection (ONT) triggers retinal ganglion cell (RGC) death. By using this paradigm, we have analyzed for the first time in adult albino and pigmented mice, the effects of ONT in the scotopic threshold response (STR) components (negative and positive) of the full-field electroretinogram. Two weeks after ONT, when in pigmented mice approximately 18% of the RGC population survive, the STR-implicit time decreased and the p and nSTR waves diminished approximately to 40% or 55%, in albino or pigmented, respectively, with respect to the values recorded from the non-operated contralateral eyes. These changes were maintained up to 12 weeks post-ONT, demonstrating that the ERG-STR is a useful parameter to monitor RGC functionality in adult mice. PMID- 20727909 TI - Threat detection: behavioral practices in animals and humans. AB - In contrast to a perceptible threat that releases freezing, fleeing and fighting, abstract potential threat elicits anxiety and vigilance. The prevalent view is that the larger the animal groups the lower the individual vigilance. Vigilance is a reflection of anxiety, and here we show that anxiety is contagious in grouped social animals. In humans, anxiety frequently results in rituals that confer a sense of controllability and thereby a means to cope with anxiety. Accordingly, in mental disorders with sustained anxiety, rituals predominate the behavior and consequently reduce functionality. Finally, the adaptive value of precautionary behavior, including rituals, lies in providing individuals with the opportunity to practice defensive means safely, and thus to prepare for the eventuality of real danger. Accordingly, the prevalence of anxiety in human and animal behavior accords with the "better safe than sorry" principle. PMID- 20727910 TI - Adaptation to potential threat: the evolution, neurobiology, and psychopathology of the security motivation system. AB - The risk of improbable, uncertain, but grave potential dangers poses unique adaptive challenges. We argue that to manage such risks, a special motivational system evolved, which we term the security motivation system. Review of work across a range of species indicates that this system is designed to detect subtle indicators of potential threat, to probe the environment for further information about these possible dangers, and to motivate engagement in precautionary behaviors, which also serves to terminate security motivation. We advance a neurobiological-circuit model of the security motivation system, which consists of a cascade of cortico-striato-pallido-thalamo-cortical loops with brainstem mediated negative feedback. We also detail the broader physiological network involved, including regulation of the parasympathetic nervous system, with emphasis on vagal regulation of cardiac output, and activation of the hypothalamic-pituitary-adrenocortical axis. Finally, we propose that some kinds of psychopathology stem from dysfunction of the security motivation system. In particular, obsessive compulsive disorder may result from the failure of a mechanism by which engagement in precautionary behavior normally terminates activation of the system. PMID- 20727911 TI - Transfection of chicken cerebellar granule neurons used to study glucocorticoid receptor regulation by nuclear receptor 4A (NR4A). AB - Transfection is a useful tool for studying molecular signalling pathways. However, neurons have proven hard to transfect. In the present paper we have optimized a new electroporation procedure using the Cellaxess((r)) system for transient transfection of adherent primary neurons from chicken (Gallus gallus) and compared it to a liposome based procedure using Metafectene((r)) Pro. In order to evaluate the two methods, glucocorticoid receptor (GR) function was chosen as a test. GRs are expressed in high amounts in the cerebellum. GR is regulated by another nuclear receptor (NGFI-B, the first member found in the NR4A family). We first showed that forskolin and phorbol ester activated an NR4A dependent reporter gene indicating that members of the NR4A nuclear receptor family are present endogenously and upregulated by external stimuli. Then, transfected NGFI-B was shown to antagonize the dexamethasone-activated transcriptional activation by endogenous GR, leading to the conclusion that NR4A family members are important modulators of GR mediated regulatory processes in the cerebellum, as in other cell types. Both transfection methods proved useful. While the electroporation technique yielded small rings with many transfected cells optimal for microscopy studies, the liposome based method resulted in transfected cells evenly distributed in the dish rendering this method well suited for biochemical studies. PMID- 20727912 TI - Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN. AB - Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM CSF deprivation or antigen-specific CD8(+) T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8(+) T cells and stronger anti tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine. PMID- 20727913 TI - Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus. AB - The discovery and development of new, highly potent anti-coronavirus agents and effective approaches for controlling the potential emergence of epidemic coronaviruses still remains an important mission. Here, we identified tylophorine compounds, including naturally occurring and synthetic phenanthroindolizidines and phenanthroquinolizidines, as potent in vitro inhibitors of enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV). The potent compounds showed 50% maximal effective concentration (EC50) values ranging from 8 to 1468 nM as determined by immunofluorescent assay of the expression of TGEV N and S proteins and by real time-quantitative PCR analysis of viral yields. Furthermore, the potent tylophorine compounds exerted profound anti-TGEV replication activity and thereby blocked the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells. Analysis of the structure-activity relations indicated that the most active tylophorine analogues were compounds with a hydroxyl group at the C14 position of the indolizidine moiety or at the C3 position of the phenanthrene moiety and that the quinolizidine counterparts were more potent than indolizidines. In addition, tylophorine compounds strongly reduced cytopathic effect in Vero 76 cells induced by human severe acute respiratory syndrome coronavirus (SARS CoV), with EC50 values ranging from less than 5 to 340 nM. Moreover, a pharmacokinetic study demonstrated high and comparable oral bioavailabilities of 7-methoxycryptopleurine (52.7%) and the naturally occurring tylophorine (65.7%) in rats. Thus, our results suggest that tylophorine compounds are novel and potent anti-coronavirus agents that may be developed into therapeutic agents for treating TGEV or SARS CoV infection. PMID- 20727914 TI - Gene expression of conditioned locomotion and context-specific locomotor sensitization controlled by morphine-associated environment. AB - The nucleus accumbens (NAc) is involved in contextual drug associations, which might be particularly important for environmental cue-induced relapse to drug seeking. In the present study, rats were first administered repeated morphine for 5 days (5 mg/kg, i.p.) in a contextually paired and unpaired design. After reexposure to the morphine-associated environment, which induced conditioned locomotor activity in the morphine-paired group, we performed a rat 27k 70-mer oligo array to profile gene expression in the NAc. One hundred fifty-five upregulated and 88 downregulated genes were found in the paired group compared with the unpaired group. Eight gene transcripts were then selected to confirm their alterations by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes generally play important roles in neuroactive receptor ligand interactions, synapse plasticity, ion transport, and protein phosphorylation. Furthermore, the expression of the eight selected genes that were identified and confirmed to show significant fold changes in the first microarray experiment were again measured with qRT-PCR after morphine challenge (2 mg/kg, i.p.). As expected, 2 mg/kg morphine-induced context-specific sensitization. Meanwhile, mRNA expression of the selected genes showed marked upregulation in the morphine-paired group compared with the unpaired and acute groups. These results suggest that alterations in the expression of the identified genes in the NAc may contribute to the neuroplasticity underlying contextual cue-induced relapse to drug use. PMID- 20727916 TI - The C-terminal flanking peptide (CTFP) of progastrin inhibits apoptosis via a PI3 kinase-dependent pathway. AB - Progastrin is processed to a number of peptides including glycine-extended gastrin, amidated gastrin and the C-terminal flanking peptide (CTFP). Progastrin and gastrin-gly are pro-proliferative and anti-apoptotic in gastric and colorectal cancer cell lines. The CTFP is a major form of progastrin in the stomach and colon and stimulates proliferation. However the effect of CTFP on apoptosis has not been examined. Using the human gastric carcinoma cell line AGS we show that CTFP attenuates apoptosis through a PI3-kinase pathway by stimulating the phosphorylation of Akt leading to sustained increases in the concentrations of Bcl-xL and phosphorylated Bad protein and by reducing caspase 3 activity. The anti-apoptotic effect represents an important potential mechanism for the growth promoting action of CTFP. PMID- 20727917 TI - An anti-Parkinson drug ropinirole depletes orexin from rat hypothalamic slice culture. AB - Non-ergot-type dopamine receptor agonists such as ropinirole are used for the treatment of Parkinson disease, but they occasionally show serious side effects including sleep attacks and daytime sleepiness. These symptoms are reminiscent of narcolepsy, a major sleep disorder. Because narcolepsy is thought to result from deficiency of a hypothalamic neuropeptide orexin, we examined whether ropinirole affected the integrity of orexin-containing neurons, using organotypic slice culture of rat hypothalamus. Application of ropinirole induced a significant decrease in the number of orexin-immunoreactive neurons. The same treatment showed no significant effect on the number of melanin-concentrating hormone immunoreactive neurons. The decrease of orexin-immunoreactive neurons was reversible after washout of ropinirole and was not accompanied by induction of cell death. Antagonism of dopamine D(2) receptors and of serotonin 5-HT(1A) receptors attenuated the effect of ropinirole, suggesting involvement of these receptors in depletion of orexin. On the other hand, a moderate concentration of N-methyl-d-aspartate that excited orexin neurons counteracted the effect of ropinirole on the number of orexin-immunoreactive neurons. These results suggest that ropinirole can cause deficiency of orexin by inhibiting excitatory activities of orexin neurons, which may be relevant to the adverse actions of this drug on sleep and wakefulness. PMID- 20727915 TI - Focal expression of mutated tau in entorhinal cortex neurons of rats impairs spatial working memory. AB - Entorhinal cortex neuropathology begins very early in Alzheimer's disease (AD), a disorder characterized by severe memory disruption. Indeed, loss of entorhinal volume is predictive of AD and two of the hallmark neuroanatomical markers of AD, amyloid plaques and neurofibrillary tangles (NFTs), are particularly prevalent in the entorhinal area of AD-afflicted brains. Gene transfer techniques were used to create a model neurofibrillary tauopathy by injecting a recombinant adeno associated viral vector with a mutated human tau gene (P301L) into the entorhinal cortex of adult rats. The objective of the present investigation was to determine whether adult onset, spatially restricted tauopathy could be sufficient to reproduce progressive deficits in mnemonic function. Spatial memory on a Y-maze was tested for approximately 3 months post-surgery. Upon completion of behavioral testing the brains were assessed for expression of human tau and evidence of tauopathy. Rats injected with the tau vector became persistently impaired on the task after about 6 weeks of postoperative testing, whereas the control rats injected with a green fluorescent protein vector performed at criterion levels during that period. Histological analysis confirmed the presence of hyperphosphorylated tau and NFTs in the entorhinal cortex and neighboring retrohippocampal areas as well as limited synaptic degeneration of the perforant path. Thus, highly restricted vector-induced tauopathy in retrohippocampal areas is sufficient for producing progressive impairment in mnemonic ability in rats, successfully mimicking a key aspect of tauopathies such as AD. PMID- 20727918 TI - uvrB gene deletion enhances SOS chromotest sensitivity for nitroreductases that preferentially generate the 4-hydroxylamine metabolite of the anti-cancer prodrug CB1954. AB - CB1954 is an anti-cancer prodrug that can be reduced at either of two nitro groups to form cytotoxic metabolites. We describe here two efficient and previously uncharacterized nitroreductases, YfkO from Bacillus subtilis which reduces CB1954 exclusively at the 4-NO(2) position, and NfsA from Klebsiella pneumoniae which preferentially reduces the 2-NO(2) group. Utilizing these novel enzymes, together with three previously characterized nitroreductases, we demonstrate that the Escherichia coli SOS-chromotest assay can differentially detect the 4-nitro versus 2-nitro reduction products of CB1954 following deletion of the nucleotide excision repair gene uvrB, but not mismatch repair (mutS) or methyltransferase (ada/ogt) genes. These findings may hold significance for identification and selection of nitroreductases for CB1954-mediated gene therapy, particularly when targeting tumors that are deficient in nucleotide excision repair. Moreover, we demonstrate that comparative SOS chromotest analysis in wild type and uvrB mutant strains can be used to determine whether or not nucleotide excision repair plays a significant role in processing DNA damage resulting from activation of different nitroaromatic prodrugs. PMID- 20727919 TI - alpha-Rhamnosidase and beta-glucosidase expressed by naringinase immobilized on new ionic liquid sol-gel matrices: Activity and stability studies. AB - Novel ionic liquid (IL) sol-gel materials development, for enzyme immobilization, was the goal of this work. The deglycosylation of natural glycosides were performed with alpha-l-rhamnosidase and beta-d-glucosidase activities expressed by naringinase. To attain that goal ILs with different structures were incorporated in TMOS/Glycerol sol-gel matrices and used on naringinase immobilization. The most striking feature of ILs incorporation on TMOS/Glycerol matrices was the positive impact on the enzyme activity and stability, which were evaluated in fifty consecutive runs. The efficiency of alpha-rhamnosidase expressed by naringinase TMOS/Glycerol@ILs matrices increased with cation hydrophobicity as follows: [OMIM]>[BMIM]>[EMIM]>[C(2)OHMIM]>[BIM] and [OMIM]~[E(2)-MPy]?[E(3)-MPy]. Regarding the imidazolium family, the hydrophobic nature of the cation resulted in higher alpha-rhamnosidase efficiencies: [BMIM]BF(4)?[C(2)OHMIM]BF(4)?[BIM]BF(4). Small differences in the IL cation structure resulted in important differences in the enzyme activity and stability, namely [E(3)-MPy] and [E(2)-MPy] allowed an impressive difference in the alpha rhamnosidase activity and stability of almost 150%. The hydrophobic nature of the anion influenced positively alpha-rhamnosidase activity and stability. In the BMIM series the more hydrophobic anions (PF(6)(-), BF(4)(-) and Tf(2)N(-)) led to higher activities than TFA. SEM analysis showed that the matrices are shaped lens with a film structure which varies within the lens, depending on the presence and the nature of the IL. The kinetics parameters, using naringin and prunin as substrates, were evaluated with free and naringinase encapsulated, respectively on TMOS/Glycerol@[OMIM][Tf(2)N] and TMOS/Glycerol@[C(2)OHMIM][PF(6)] and on TMOS/Glycerol. An improved stability and efficiency of alpha-l-rhamnosidase and beta-glucosidase expressed by encapsulated naringinase on TMOS/Glycerol@[OMIM][Tf(2)N] and TMOS/Glycerol@[C(2)OHMIM][PF(6)] were achieved. In addition to these advantageous, with ILs as sol-gel templates, environmental friendly processes can be implemented. PMID- 20727920 TI - Human 20alpha-hydroxysteroid dehydrogenase (AKR1C1)-dependent biotransformation with recombinant fission yeast Schizosaccharomyces pombe. AB - While phase I and phase II drug metabolites are important for drug development and toxicity studies, e.g. in the context of metabolites in safety testing (MIST), they are often not commercially available and their classical chemical synthesis can be cumbersome. Therefore, a biotechnological production of drug metabolites using microorganisms that recombinantly express human enzymes has been established in recent years. However, no whole-cell biotransformations that make use of human aldo-keto reductases (AKRs) have yet been reported. In this study, we have functionally expressed human AKR1C1 (20alpha-hydroxysteroid dehydrogenase) in the fission yeast Schizosaccharomyces pombe and demonstrate the ability of the resulting yeast strain to efficiently catalyze the reduction of progesterone or dydrogesterone to 20alpha-dihydroprogesterone (20alpha-DHP) and 20alpha-dihydrodydrogesterone (20alpha-DHD), respectively. The formation of any by-products or the occurrence of a back reaction were not detected. Seven other steroids with a 20-keto group (pregnenolone, 17alpha-hydroxyprogesterone, 11 deoxycortisol, cortisol, 11-deoxycorticosterone, corticosterone, and aldosterone) were not reduced by this system. At shaking flask scale we obtained conversion rates of 90 (+/-26) MUM/d 20alpha-DHP and 244 (+/-93) MUM/d 20alpha dihydrodydrogesterone (20alpha-DHD), respectively. In a fed-batch fermentation under optimized reaction conditions an average 20alpha-DHP production rate of 300 MUM/d was determined for a total biotransformation time of 72 h. We thus established an AKR-dependent whole-cell biotransformation process that can be used for production of human AKR metabolites on a large scale. PMID- 20727921 TI - Size of thermosensitive liposomes influences content release. AB - Thermosensitive liposomes (TSL) in combination with regional hyperthermia represent a powerful tool for tumor specific drug delivery. The objective of this study was to investigate the influence of vesicle size on the biophysical properties of TSL. TSL were composed of DPPC/DSPC/1,2-dipalmitoyl-sn-glycero-3 phosphoglyceroglycerol (DPPG(2)) 50:20:30 (mol/mol) (DPPG(2)-TSL) and DPPC/P-Lyso PC/DSPE-PEG2000 90:10:4 (mol/mol) (PEG/Lyso-TSL) with encapsulated fluorescent dye carboxyfluorescein, anticancer drug doxorubicin or magnetic resonance contrast agent gadodiamide. Extrusion was performed with polycarbonate filters of distinct pore size to obtain TSL with different diameters (50 to 200nm). Phase transition temperature (T(m)) of the bilayer forming phospholipids was not influenced by vesicle size in the tested range. However, vesicle size had a major impact on in vitro content release properties of TSL in the investigated temperature range between 30 and 45 degrees C. Generally, vesicle size was inversely related to content release properties with increased content release rates for decreased vesicle sizes. Size dependency of content release properties varied between all tested formulations and DPPG(2)-TSL were generally less affected by size changes in the range of 100 to 150nm as compared to PEG/Lyso TSL. Independent from gadodiamide release, vesicle size influenced the signal intensity of DPPG(2)-TSL also at temperatures below T(m) due to improved water exchange for smaller vesicles. Liposomes around 100nm in size are routinely used in vivo, hence a quality control for TSL preparations is required prior to use. Even small changes in size or a wider size distribution might affect stability and release properties and thus yield in decreased efficacy or unwanted side effects of drug loaded TSL during in vivo applications. PMID- 20727922 TI - Device-based local delivery of siRNA against mammalian target of rapamycin (mTOR) in a murine subcutaneous implant model to inhibit fibrous encapsulation. AB - Fibrous encapsulation of surgically implanted devices is associated with elevated proliferation and activation of fibroblasts in tissues surrounding these implants, frequently causing foreign body complications. Here we test the hypothesis that inhibition of the expression of mammalian target of rapamycin (mTOR) in fibroblasts can mitigate the soft tissue implant foreign body response by suppressing fibrotic responses around implants. In this study, mTOR was knocked down using small interfering RNA (siRNA) conjugated with branched polyethylenimine (bPEI) in fibroblastic lineage cells in serum-based cell culture as shown by both gene and protein analysis. This mTOR knock-down led to an inhibition in fibroblast proliferation by 70% and simultaneous down-regulation in the expression of type I collagen in fibroblasts in vitro. These siRNA/bPEI complexes were released from poly(ethylene glycol) (PEG)-based hydrogel coatings surrounding model polymer implants in a subcutaneous rodent model in vivo. No significant reduction in fibrous capsule thickness and mTOR expression in the foreign body capsules were observed. The siRNA inefficacy in this in vivo implant model was attributed to siRNA dosing limitations in the gel delivery system, and lack of targeting ability of the siRNA complex specifically to fibroblasts. While in vitro data supported mTOR knock-down in fibroblast cultures, in vivo siRNA delivery must be further improved to produce clinically relevant effects on fibrotic encapsulation around implants. PMID- 20727923 TI - Photo-tunable protein release from biodegradable nanoparticles composed of cinnamic acid derivatives. AB - A novel functional biodegradable copolymer was prepared by grafting dithiothreitiol (DTT) into poly(3,4-dihydroxycinnamic acid)-co-poly(4 hydroxycinnamic acid) (PCA) by the Michael addition. The PCA-graft-DTT (PCA-DTT) nanoparticles were self-assembled by mixing a DMSO solution of PCA-DTT copolymer and distilled water. The diameter of the PCA-DTT nanoparticles was below 100nm, and increased to about 300nm upon increasing the composition ratio of DTT. The PCA-DTT nanoparticles were crosslinked via [2+2] cyclobutane formation of the cinnamate groups by UV irradiation at lambda>280nm. Moreover, a variable size decrement of the nanoparticles after UV crosslinking was observed, depending on the grafting degree of DTT. A model protein, bovine serum albumin (BSA), was successfully encapsulated into the PCA-DTT nanoparticles during the self assembling process. The protein release behavior was influenced by the grafting degree of DTT and the pH of the buffer. Moreover, the photo-crosslinking of the nanoparticles induced a significant acceleration in the release rate due to shrinkage of the nanoparticles. These biodegradable and photo-responsive nanoparticles possessing photo-tunable release properties would be useful as novel and functional carriers for drug delivery systems. PMID- 20727924 TI - Cyclodextrin complexed insulin encapsulated hydrogel microparticles: An oral delivery system for insulin. AB - An oral insulin delivery system based on methyl-beta-cyclodextrin (MCD) complexed insulin encapsulated polymethacrylic acid (PMAA) hydrogel microparticles was evaluated in this investigation. Poly(methacrylic acid)-chitosan-polyethylene glycol (PCP) microparticles were prepared by ionic gelation method. The insulin MCD (IC) complex prepared was characterized by fluorescence spectroscopic and isothermal titration micro-calorimeteric (ITC) methods. MCD complexed insulin was encapsulated onto PCP microparticles by diffusion filling method. Loading and release properties of the complexed insulin from microparticles were evaluated under in vitro conditions. The effect of MCD complexation on the permeability of insulin was studied using Caco 2 cell monolayers and excised intestinal tissue with an Ussing chamber set-up. In vivo experiments were carried on streptozotocin induced diabetic rats to evaluate the efficacy of MCD complexed insulin encapsulated PCP microparticles to deliver insulin by the oral route. IC complex formation was established by fluorescence and ITC investigations. Insulin loading and release properties from the hydrogel matrix was rather unaffected by the MCD complexation. However MCD complexation was effective in enhancing insulin transport across Caco 2 cell monolayers, when applied in combination with the PMAA hydrogel system. Both insulin and MCD complexed insulin encapsulated PCP microparticles were effective in reducing blood glucose level in diabetic animal models. Cyclodextrin complexed insulin encapsulated hydrogel microparticles appear to be an interesting candidate for oral delivery of insulin. PMID- 20727926 TI - Administration routes affect the quality of immune responses: A cross-sectional evaluation of particulate antigen-delivery systems. AB - Particulate delivery systems such as liposomes and polymeric nano- and microparticles are attracting great interest for developing new vaccines. Materials and formulation properties essential for this purpose have been extensively studied, but relatively little is known about the influence of the administration route of such delivery systems on the type and strength of immune response elicited. Thus, the present study aimed at elucidating the influence on the immune response when of immunising mice by different routes, such as the subcutaneous, intradermal, intramuscular, and intralymphatic routes with ovalbumin-loaded liposomes, N-trimethyl chitosan (TMC) nanoparticles, and poly(lactide-co-glycolide) (PLGA) microparticles, all with and without specifically selected immune-response modifiers. The results showed that the route of administration caused only minor differences in inducing an antibody response of the IgG1 subclass, and any such differences were abolished upon booster immunisation with the various adjuvanted and non-adjuvanted delivery systems. In contrast, the administration route strongly affected both the kinetics and magnitude of the IgG2a response. A single intralymphatic administration of all evaluated delivery systems induced a robust IgG2a response, whereas subcutaneous administration failed to elicit a substantial IgG2a response even after boosting, except with the adjuvanted nanoparticles. The intradermal and intramuscular routes generated intermediate IgG2a titers. The benefit of the intralymphatic administration route for eliciting a Th1-type response was confirmed in terms of IFN-gamma production of isolated and re-stimulated splenocytes from animals previously immunised with adjuvanted and non-adjuvanted liposomes as well as with adjuvanted microparticles. Altogether the results show that the IgG2a associated with Th1-type immune responses are sensitive to the route of administration, whereas IgG1 response associated with Th2-type immune responses were relatively insensitive to the administration route of the particulate delivery systems. The route of administration should therefore be considered when planning and interpreting pre-clinical research or development on vaccine delivery systems. PMID- 20727925 TI - Sunlight triggered photodynamic ultradeformable liposomes against Leishmania braziliensis are also leishmanicidal in the dark. AB - Being independent of artificial power sources, self administered sunlight triggered photodynamic therapy could be a suitable alternative treatment for cutaneous leishmaniasis, that avoids the need for injectables and the toxic side effects of pentavalent antimonials. In this work we have determined the in vitro leishmanicidal activity of sunlight triggered photodynamic ultradeformable liposomes (UDL). ZnPc is a hydrophobic Zn phthalocyanine that showed 20% anti promastigote activity (APA) and 20% anti-amastigote activity (AA) against Leishmania braziliensis (strain 2903) after 15min sunlight irradiation (15J/cm(2)). However, when loaded in UDL as UDL-ZnPc (1.25MUM ZnPc-1mM phospholipids) it elicited 100% APA and 80% AA at the same light dose. In the absence of host cell toxicity, UDL and UDL-ZnPc also showed non-photodynamic leishmanicidal activity. Confocal laser scanning microscopy of cryosectioned human skin mounted in non-occlusive Saarbrucken Penetration Model, showed that upon transcutaneous administration ZnPc penetrated nearly 10 folds deeper as UDL ZnPc than if loaded in conventional liposomes (L-ZnPc). Quantitative determination of ZnPc confirmed that UDL-ZnPc penetrated homogeneously in the stratum corneum, carrying 7 folds higher amount of ZnPc 8 folds deeper than L ZnPc. It is envisioned that the multiple leishmanicidal effects of UDL-ZnPc could play a synergistic role in prophylaxis or therapeutic at early stages of the infection. PMID- 20727927 TI - Tumor therapy by gene regulation system responding to cellular signal. AB - For safe and efficient gene therapy, the development of gene delivery systems to specifically target tumor cells is one of the most important issues regarding present gene delivery methodologies. Recently, we have developed a novel drug or gene delivery system responding to cellular signals (D-RECS) that can activate transgenes in response to hyperactivated cellular signals. Especially, a protein kinase C (PKC)alpha-responsive polymeric carrier (polymer-peptide conjugate, PPC(S)) showed highly specific gene expression to tumor cells and tissues. In the present study, we have applied the PKCalpha-responsive polymeric carrier to tumor gene therapy. PPC(S) consists of a polyacrylamide backbone and cationic peptide side chains, which together make PPC(S) as a positive polymer, a PKCalpha specific substrate. A negative control polymer, PPC(A), was also prepared by replacing a serine residue at the phosphorylation site of the peptide side chains of PPC(S) with alanine. A complex of PPC(S) with caspase-8 or the herpes simplex virus-thymidine kinase (HSV-TK) gene as therapeutic genes was transfected into certain tumor cells or tissues. The prodrug ganciclovir (GCV) was then intraperitoneally injected into PPC(S)/HSV-TK complex-transfected mice. The PPC(S)/gene complex showed significant cytotoxicity toward the tumor cells and suppression of tumor growth, compared with those of the PPC(A)/gene complex or PBS. These results indicate that the PKCalpha-responsive polymeric carrier is applicable for tumor-targeted gene therapy. PMID- 20727928 TI - Development of novel self-assembled DS-PLGA hybrid nanoparticles for improving oral bioavailability of vincristine sulfate by P-gp inhibition. AB - To improve the encapsulation efficiency and oral bioavailability of vincristine sulfate (VCR), novel self-assembled dextran sulphate-PLGA hybrid nanoparticles (DPNs) were successfully developed using self-assembly and nanoprecipitation method. By introducing the negative polymer of dextran sulphate sodium (DS), VCR was highly encapsulated (encapsulation efficiency up to 93.6%) into DPNs by forming electrostatic complex. In vitro release of VCR solution (VCR-Sol) and VCR loaded DPNs (VCR-DPNs) in pH 7.4 PBS showed that about 80.4% of VCR released from VCR-DPNs after 96h and burst release was effectively reduced, indicating pronounced sustained-release characteristics. In vivo pharmacokinetics in rats after oral administration of VCR-Sol and VCR-DPNs indicated that the apparent bioavailability of VCR-DPNs was increased to approximate 3.3-fold compared to that of VCR-Sol. The cellular uptake experiments were conducted by quantitative assay of VCR cellular accumulation and fluorescence microscopy imaging of fluorescent labeled DPNs in two human breast cancer cells including MCF-7 and P glycoprotein over-expressing MCF-7/Adr cells. The relative cellular uptake of VCR DPNs was 12.4-fold higher than that of VCR-Sol in MCF-7/Adr cells implying that P glycoprotein-mediated drug efflux was diminished by the introduction of DPNs. The new DPNs might provide an effective strategy for oral delivery of VCR with improved encapsulation efficiency and oral bioavailability. PMID- 20727929 TI - Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution. AB - In this study, we used optical coherence tomography (OCT) to extensively investigate, for the first time, the effect that microneedle (MN) geometry (MN height, and MN interspacing) and force of application have upon penetration characteristics of soluble poly(methylvinylether-co-maleic anhydride, PMVE/MA) MN arrays into neonatal porcine skin in vitro. The results from OCT investigations were then used to design optimal and suboptimal MN-based drug delivery systems and evaluate their drug delivery profiles cross full thickness and dermatomed neonatal porcine skin in vitro. It was found that increasing the force used for MN application resulted in a significant increase in the depth of penetration achieved within neonatal porcine skin. For example, MN of 600MUm height penetrated to a depth of 330MUm when inserted at a force of 4.4N/array, while the penetration increased significantly to a depth of 520MUm, when the force of application was increased to 16.4N/array. At an application force of 11.0N/array it was found that, in each case, increasing MN height from 350 to 600MUm to 900MUm led to a significant increase in the depth of MN penetration achieved. Moreover, alteration of MN interspacing had no effect upon depth of penetration achieved, at a constant MN height and force of application. With respect to MN dissolution, an approximate 34% reduction in MN height occurred in the first 15min, with only 17% of the MN height remaining after a 3-hour period. Across both skin models, there was a significantly greater cumulative amount of theophylline delivered after 24h from an MN array of 900MUm height (292.23+/ 16.77MUg), in comparison to an MN array of 350MUm height (242.62+/-14.81MUg) (p<0.001). Employing full thickness skin significantly reduced drug permeation in both cases. Importantly, this study has highlighted the effect that MN geometry and application force have upon the depth of penetration into skin. While it has been shown that MN height has an important role in the extent of drug delivered across neonatal porcine skin from a soluble MN array, further studies to evaluate the full significance of MN geometry on MN mediated drug delivery are now underway. The successful use of OCT in this study could prove to be a key development for polymeric MN research, accelerating their commercial exploitation. PMID- 20727930 TI - Protective effect of ghrelin on acetaminophen-induced liver injury in rat. AB - Ghrelin is a peptide that has protective effects on many tissues of the body. It has anti-inflammatory and anti-oxidant effects. Acetaminophen, a commonly used analgesic-antipyretic drug, has hepatotoxic side effects. The aim of this study was to evaluate the protective role of ghrelin in liver toxicity due to acetaminophen overdose. Thirty male rats were used in this study and divided into five groups. They were control, propylene-glycol (as a solvent of acetaminophen), acetaminophen, acetaminophen and NAC, acetaminophen and ghrelin groups. Tumor necrosis factor alpha (TNF-alpha), and hepatic enzymes, AST (aspartate aminotransferase) and ALT (alanine aminotransferase), were assessed and histologic study of liver were performed as indicators of liver damage following acetaminophen toxicity. Results showed that Ghrelin decreased ALT and AST to the normal level, and also reduced TNF-alpha. Although NAC (the standard antidote of acetaminophen toxicity) also reduced ALT, AST and TNF-alpha levels, our results show that ghrelin is more potent than NAC in protecting the liver from acetaminophen-induced liver injury. PMID- 20727932 TI - Post-natal stress-induced endocrine and metabolic alterations in mice at adulthood involve different pro-opiomelanocortin-derived peptides. AB - In previous investigations we added a physical stress (mild pain) to the "classical" post-natal psychological stress in male mice, and we found that this combination produced a series of dysmetabolic signs very similar to mild human type-2 diabetes. Here, for the first time we demonstrate that within this diabetes model at least two groups of signs depend on the unbalance of two different endogenous systems. Newborn male mice were daily exposed to stressful procedures for 21 days (brief mother separation plus sham injection). Other groups underwent the same procedure, and also received naloxone (Na) to block MU delta endogenous receptors, or a phosphorothioate antisense oligonucleotide (AS) directed against pro-opiomelanocortin (POMC)-mRNA [to block adrenocorticotropin (ACTH)- and POMC-derived opioid peptides]. Adult mice which received only post natal stress increased body weight (+7.5%), abdominal overweight (+74%), fasting glycemia (+43%), plasma corticosterone (+110%), plasma (+169%) and pituitary (+153%) ACTH levels. Conversely, hypothalamic ACTH and corticotropin-releasing hormone (CRH) were reduced (-70% and -75%, respectively). Neonatal AS administration reverted all parameters to control values. Neonatal naloxone had little or no influence on glucose, corticosterone, ACTH, CRH levels, whereas it prevented body overweight and abdominal overweight. We conclude that, within this type-2 diabetes model in male mice at least two endocrino-neurohumoral systems are damaged, one concerning the opioid system, and the other concerning HPA hormones. The use of the two drugs was of primary importance to demonstrate this statement, and to demonstrate that these two groups of signs could be defined as "separate entities" following our complex post-natal stress model. PMID- 20727931 TI - Diurnal changes of arginine vasopressin-enhanced green fluorescent protein fusion transgene expression in the rat suprachiasmatic nucleus. AB - We have recently developed a new transgenic rat line expressing an arginine vasopressin (AVP)-enhanced green fluorescent protein (eGFP) fusion gene. The AVP eGFP transgene is expressed in the paraventricular (PVN) and supraoptic (SON) nuclei and the suprachiasmatic nucleus (SCN) of the hypothalamus. Transgene expression in the PVN and SON showed an exaggerated response to salt loading and nociceptive stimulation. However, the expression of the AVP-eGFP transgene in the SCN did not change under these stressful conditions. Here, we examined daily profiles of the expression of the AVP-eGFP transgene in the SCN in comparison with the endogenous AVP and Period (Per1 and Per2) genes. While all of these genes elicited diurnal patterns of expression in the SCN, the rate of rhythmic change of transgene expression was significantly greater than that of the endogenous AVP gene. We also examined the effect of a light stimulus on the expression of the AVP-eGFP, AVP, Per1 and Per2 genes in the SCN of transgenic rats. Ninety minutes after a light stimulus, AVP-eGFP mRNA and AVP hnRNA levels in the SCN were significantly decreased, while Per2 mRNA levels were significantly increased. In addition, we observed the eGFP fluorescence in the SCN and recorded the electrophysiological properties of a dissociated SCN eGFP positive neuron. The AVP-eGFP transgenic rat is a useful animal model to study the diurnal change and dynamics of the AVP system, and enables the facile identification of SCN AVP neurons both in vivo and in vitro. PMID- 20727933 TI - Risk assessment of thujone in foods and medicines containing sage and wormwood- evidence for a need of regulatory changes? AB - Thujone is a natural substance found in plants commonly used in foods and beverages, such as wormwood and sage, as well as in herbal medicines. The current limits for thujone in food products are based on short-term animal studies from the 1960s, which provided evidence for a threshold-based mechanism, yet only allowed for the derivation of preliminary values for acceptable daily intakes (ADI) based on the no-observed effect level (NOEL). While the 2008 European Union Regulation on flavourings deregulated the food use of thujone, the European Medicines Agency introduced limits for the substance in 2009. The present study re-evaluates the available evidence using the benchmark dose (BMD) approach instead of NOEL, and for the first time includes data from a long-term chronic toxicity study of the National Toxicology Program (NTP). The NTP data provide similar results to the previous short-term studies. Using dose-response modelling, a BMD lower confidence limit for a benchmark response of 10% (BMDL10) was calculated as being 11 mg/kg bw/day for clonic seizures in male rats. Based on this, we propose an ADI of 0.11 mg/kg bw/day, which would not be reachable even for consumers of high-levels of thujone-containing foods (including absinthe). While fewer data are available concerning thujone exposure from medicines, we estimate that between 2 and 20 cups of wormwood or sage tea would be required to reach this ADI, and view that the short-term medicinal use of these herbs can also be regarded as safe. In conclusion, the evidence does not point to any need for changes in regulations but confirms the current limits as sufficiently protective for consumers. PMID- 20727934 TI - No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia. AB - We investigated the effects of atypical antipsychotic drugs on GABA concentrations in early-stage, first-episode schizophrenia patients. Sixteen (8 males, 8 females; age, 30+/-11 years old) patients were followed up for six months. We also included 18 sex- and age-matched healthy control subjects. All patients were treated with atypical antipsychotic drugs (5 patients with risperidone, 5 patients with olanzapine, 4 patients with aripiprazole, and 2 patients with quetiapine). In all three regions measured (frontal lobe, left basal ganglia, and parieto-occipital lobe), no differences in GABA concentrations were observed in a comparison of pre-treatment levels and those six months after treatment. These results suggest that relatively short-term treatment with atypical antipsychotic drugs may not affect GABAergic neurotransmission; however, it is also possible that such treatment prevents further reductions in brain GABA levels in people with early-stage, first-episode schizophrenia. PMID- 20727935 TI - Anesthesia and perioperative stress: consequences on neural networks and postoperative behaviors. AB - Anesthesia is a state of drug-induced unconsciousness with suppression of sensory perception, and consists of both hypnotic and analgesic components. The anesthesiologist monitors the clinical response to noxious stimuli and adjusts drug dosage(s) to achieve an adequate depth of anesthesia, with the aim of reducing operative stress. Acute stress in the perioperative period has four major contributors: anxiety, pain, the surgical stress response, and the potential neurotoxicity of anesthetic agents. Any or all of these may act deleteriously on multiple systems in the brain and have known significant effects on brain regions such as the hippocampus and the hypothalamic-pituitary-adrenal axis. Perioperative stress on the nervous system and the resultant central nervous system (CNS) changes are likely to be causative for altered behaviors that are seen postoperatively, including chronic pain, posttraumatic stress disorder, and learning difficulties. Improving the ability of the anesthesiologist to control all four components of acute perioperative stress could potentially reduce the negative impact of surgery on the brain. Currently, there is no objective measurement for any of these stressors. The development and application of objective measures for perioperative stressors is the first step towards controlling these risk factors and eliminating or reducing their serious postoperative consequences. In this paper we review known and likely effects of perioperative stressors on brain systems and how they may play a significant role in altered postoperative behaviors. We discuss the role of current (and developing) measures of brain function and their potential for monitoring perioperative stress, with an emphasis on functional neuroimaging. PMID- 20727936 TI - Lack of startle blink potentiation to mutilation pictures irrespective of fearfulness. AB - Previous research has shown that in healthy individuals blood-related stimuli elicit a distinctive autonomic response pattern and heightened processing as compared with other unpleasant and arousing visual stimuli. In addition, growing evidence suggests that information processing of disorder-related stimuli is also different in blood phobia as compared with other specific phobias. In the present study, the magnitude of the startle eyeblink reflex elicited during the viewing of mutilation, human attack, erotica and neutral pictures was recorded in 22 blood phobics and 25 healthy controls. Startle eyeblink responses were measured at 300, 1500, 3500 and 4500-ms time intervals after picture onset in order to assess the attentional/affective modulation and its temporal course. Reliable startle inhibition to erotic pictures and startle potentiation to human attack scenes were found relative to neutral pictures. However, while both groups rated mutilations as the most unpleasant and arousing content, no blink facilitation relative to neutral contents was found at either early or late probe times. Crucially, such effect occurred independently of fear levels, as no difference between phobics and controls was found in the size of the startle blinks elicited throughout the viewing of blood pictures. PMID- 20727937 TI - Use of hair cortisol analysis to detect hypercortisolism during active drinking phases in alcohol-dependent individuals. AB - The assessment of cortisol levels in human hair has recently been suggested to provide a retrospective index of cumulative cortisol exposure over periods of up to 6 months. The current study examined the utility of hair cortisol analysis to retrospectively detect hypercortisolism during active drinking phases in alcoholics in acute withdrawal (n=23), the normalisation of cortisol output in abstinent alcoholics (n=25) and cortisol levels in age- and gender-matched controls (n=20). Scalp-near 3-cm hair segments were sampled and analysed for cortisol content. Results showed three to fourfold higher cortisol levels in hair samples of alcoholics in acute withdrawal than in those of abstinent alcoholics (p<.001) or controls (p<.001), with no differences between the latter two groups. The current hair cortisol findings closely mirror results of previous research using well-established measures of systemic cortisol secretion and thus provide further validation of this novel method. PMID- 20727938 TI - Intracerebroventricular injection of orexin-A stimulates monoamine metabolism but not HPA axis in neonatal chicks. AB - We investigated the effects of intracerebroventricular (ICV) injection of orexin A on plasma corticosterone (CORT) concentration and brain monoamine metabolism to clarify the mechanism by which ICV orexin-A induced arousal in chicks. In Experiment 1, plasma CORT concentrations were measured as an indicator of hypothalamic-pituitary-adrenal (HPA) axis activity. There was no significant difference in CORT concentration between the control and orexin-A administered groups. In Experiment 2, the concentrations of monoamines (norepinephrine, dopamine and serotonin), their metabolites, and their metabolic turnover rates in the telencephalon, mesencephalon, and diencephalon were investigated. All metabolic turnover rates studied were increased at all brain sites after ICV orexin-A injection. In conclusion, the HPA axis does not appear to be involved in arousal-inducing mechanisms of orexin-A in neonatal chicks; however, several monoaminergic systems do. PMID- 20727939 TI - Effects of PACAP on the oxidative stress-induced cell death in chicken pinealocytes is influenced by the phase of the circadian clock. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with highly potent neuro- and general cytoprotective actions. PACAP is also an important modulator of circadian rhythmic functions, including time-dependent effects in the pineal gland. It is not known whether PACAP influences the survival of pinealocytes. The present study had two aims. First, we tested whether the cytoprotective effects of PACAP are present also in the pineal cells. As the pineal gland is the main circadian master clock in birds, we also tested whether this effect depends on the time of day. Using flow cytometry, we detected a significant decrease of cell viability after hydrogen peroxide-induced oxidative stress in chicken pinealocytes. PACAP alone did not influence cell survival. Co-incubation with PACAP in the dark phase (9 PM) was able to attenuate the toxic effect of H2O2. The survival-promoting effect could be counteracted by simultaneously applied PACAP antagonist, PACAP6-38. However, co-treatment with PACAP during the light phase (9 AM) did not result in significant differences in the percentage of living cells. In summary, our results show that PACAP has a protective effect against the oxidative stress-induced cell death in chicken pinealocytes, but this effect is dependent on the phase of the circadian biological clock. PMID- 20727940 TI - Elevated plasma S100B concentration is associated with mesial temporal lobe epilepsy in Han Chinese: a case-control study. AB - Mesial temporal lobe epilepsy (MTLE) is a common type of intractable epilepsy characterized by astroglial gliosis. The S100B was viewed as an astrocyte marker and experimental studies indicated that S100B might be involved in the pathophysiology of temporal lobe epilepsy. In this study, we measured plasma S100B levels by ELISA in 28 patients with MTLE and 28 healthy controls and found that patients showed significantly elevated S100B levels compared with healthy controls (P=0.018). Moreover, S100B levels were significantly higher in female patients than those in male patients (P=0.027). These results suggest that S100B may be a biomarker of MTLE. PMID- 20727941 TI - Cortical activation during color discrimination task in macaques as revealed by positron emission tomography. AB - Physiological and lesion studies have shown that the anterior inferior temporal (IT) cortex (aITC) is involved in the color vision of macaque monkeys. However, some functional imaging studies using awake monkeys contradicted the involvement of aITC in color vision. Thus, in most of the imaging studies, cortical activation has been observed during a fixation task. However, because the neuronal activity of aITC is highly affected by the behavioral task, it is desirable to investigate cortical activity during a color discrimination task to determine the functional role of aITC in the color vision of macaque monkeys. In this study, we investigated the cortical activity of aITC of macaque monkeys during color discrimination by positron emission tomography. Two monkeys were trained in a color discrimination task. Cortical areas involved in color processing were investigated by comparing activities during the color discrimination and lever release tasks. In addition to area V4 and the posterior IT cortex (pITC), we found color-related activities in the anterior IT gyrus. Consistent activation was observed in the region posterior to the anterior medial temporal sulcus (AMTS), although the exact location and the size of activations differed between monkeys and hemispheres. We also found color-related activities in the anterior portion of the superior temporal sulcus (STS), suggesting its involvement in the color vision. The present results revealed that aITC is involved in the color vision of macaque monkeys by a functional imaging technique. PMID- 20727942 TI - Distinct neuronal localization of microtubule-associated protein 4 in the mammalian brain. AB - Although recent studies have suggested the role of microtubule-associated protein (MAP) 4 in some neuron-specific events, there are no reports that directly observed its neuronal localization. Here we show the detailed expression of MAP4 in the mammalian brain. Immunoblotting revealed the presence of MAP4 in all neuronal tissues. The site-specific localization of MAP4 was observed in sagittal brain sections: MAP4 was rich in brain-specific cells, cerebellum Purkinje cells and hippocampus pyramidal cells. When primary cultures of cortical neurons were immunostained, MAP4 was detected in the cell bodies and processes with patchy staining pattern. These results suggested that MAP4 play some roles in the central nervous system, such as the dynamic cytoskeletal reorganization and regulation of the microtubule-dependent long-range transport. PMID- 20727943 TI - Conceptual implicit memory impaired in amnestic mild cognitive impairment patient. AB - Explicit memory has been well proven to be impaired in amnestic mild cognitive impairment (aMCI), and conceptual implicit memory is impaired in Alzheimer's disease. However, it is unclear whether implicit memory is affected in aMCI. In the present study, 35 patients with aMCI and 35 healthy elderly subjects were administered a neuropsychological battery of tests including conceptual and perceptual implicit memory tasks (category exemplar generation, image identification) as well as explicit memory tasks. Patients with aMCI exhibited impairment in explicit memory tasks and selective impairment in conceptual priming tasks, while the effect of perceptual priming was preserved. More importantly, category exemplar generation task priming, but not perceptual priming, was positively correlated with verbal fluency test performance in the aMCI group. The dissociation between the 2 components of implicit priming suggests that conceptual priming impairment in aMCI patients may be related to frontal lobe dysfunction. PMID- 20727944 TI - Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. AB - Olfactory dysfunction may precede common neurodegenerative disorders in the elderly, such as Alzheimer (AD) or Parkinson disease (PD). However, pathobiological mechanisms of olfactory loss in the elderly are poorly understood. Although nigrostriatal dopaminergic denervation is a key patholobiological feature of PD, age-associated nigrostriatal denervation (AASDD) occurs also with normal aging and can be more prominent in some elderly. We investigated the relationship between AASDD and olfactory performance in community-dwelling subjects. Community-dwelling subjects (n=73, 44 F/29 M, mean age 64.0+/-16.4, range 20-85) underwent brain dopamine transporter (DAT) [(11)C]2 beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (beta-CFT) positron emission tomography (PET) imaging and olfactory assessment using the 40-odor University of Pennsylvania Smell Identification Test (UPSIT). Subjects with clinical or DAT PET evidence of Parkinson disease (PD) were not eligible for the study. AASDD was defined based on normative data in young and middle-aged subjects. Compared to a mild and general linear decline in odor identification observed in most subjects (R(2)=0.18, P=0.0002), there were 13 subjects who deviated below the 5% confidence interval level in age-predicted UPSIT scores. Analysis limited to elderly subjects 60 years and over demonstrated a significant association between poor smell (n=10 out of 49, 20.4%) and AASDD (chi(2)=4.4, P<0.05). There is a significant association between olfactory dysfunction and more prominent nigrostriatal denervation in the elderly. Olfactory assessment may have potential as a screening tool to detect age-accelerated neurodegeneration in the elderly. PMID- 20727945 TI - Dynamic, experience-dependent modulation of synaptic zinc within the excitatory synapses of the mouse barrel cortex. AB - Increasing evidence suggests that synaptic zinc, found within the axon terminals of a subset of glutamatergic neurons in the cerebral cortex, is intricately involved in cortical plasticity. Using the vibrissae/barrel cortex model of cortical plasticity, we have previously shown manipulations of sensory input leads to rapid changes in synaptic zinc levels within the corresponding regions of the somatotopic map in the cortex. Here, using electron microscopy, we show how some of these changes are mediated at the synaptic level. We found that the density of zincergic synapses increased significantly in layers II/III, IV, and V. In layers IV and V, this change occurred in the absence of a significant increase in excitatory synapse density, which seems to indicate that excitatory synapses, which previously did not contain synaptic zinc, begin to newly house zinc within its synaptic vesicles. Our results show that excitatory neurons can dynamically change the phenotype of the vesicular content of their synapses in response to changes in sensory input. Given the range of modulatory effects zinc can have on neurotransmission, such a change in the complement of vesicular contents presumably allow these neurons to utilize synaptic zinc to facilitate plasticity. Thus, our results further support the role of zinc as an active participant in the processes contributing to experience-dependent cortical plasticity. PMID- 20727946 TI - Val8-glucagon-like peptide-1 protects against Abeta1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats. AB - Amyloid beta protein (Abeta) is considered to be partly responsible for the impairment of learning and memory in Alzheimer disease (AD). In addition, it has been found recently that type 2 diabetes mellitus (T2DM) is a risk factor for developing AD. One promising treatment for AD is using analogues for the insulin release facilitating gut hormone glucagon-like peptide-1 (GLP-1) that has been developed as a T2DM therapy. GLP-1 has been shown to have neuroprotective properties. However, if GLP-1 can protect the late phase-long term potentiation (L-LTP) and related cognitive function against Abeta-induced impairment it is still an open question. To further characterize the neuroprotective function of GLP-1 in the brain, we investigated the effects of i.c.v. injected Val(8)-GLP-1(7 36) on the Abeta fragment-induced impairment of in vivo hippocampal L-LTP and spatial learning and memory in rats. The results showed that (1) Abeta1-40 (5 nmol) injection did not affect the baseline field excitatory postsynaptic potentials (fEPSPs), but significantly suppressed multiple high frequency stimulation (HFS)-induced L-LTP in hippocampal CA1 region; (2) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect the baseline synaptic transmission and the maintenance of L-LTP; (3) pretreatment with Val(8)-GLP-1(7 36) (0.05 pmol) effectively prevented Abeta1-40-induced deficit of L-LTP; (4) i.c.v. injection of 5 nmol Abeta1-40 resulted in a significant decline learning a spatial Morris water maze (MWM) test; (5) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect spatial learning in this task, while pretreatment with Val(8)-GLP-1(7-36) effectively reversed the impairment of spatial learning and memory induced by Abeta1-40. At the same time, the swim speeds and escape latencies of rats among all groups in the visible platform tests did not show any difference. These results suggest that increase of GLP-1 signalling in the brain may be a promising strategy to ameliorate the degenerative processes observed in AD. PMID- 20727947 TI - Population based quantification of dendrites: evidence for the lack of microtubule-associate protein 2a,b in Purkinje cell spiny dendrites. AB - The high molecular weight isoforms (a and b) of microtubule-associate protein 2 (MAP2a,b) are widely believed to be specific markers for neuronal somata and dendrites. We analyzed and quantified MAP2a,b stained dendrites of the cerebellar molecular layer using a novel approach that segmented and 3D reconstructed them, and the results have been compared with those obtained by other methods, including single-cell reconstruction and analysis of electron micrographs. Our results show that the molecular layer dendritic volume fraction is lower than in the neocortex (10% compared to neocortical 29%). The low total volume fraction of dendrites in the molecular layer is best explained by the majority of the afferents to the dendrites being from the very densely packed parallel fibers, which allows the dendritic fields of individual neurons to be smaller and more compact than in the cerebral cortex. However, the MAP2a,b dendritic volume fraction is even lower (5.2%) than the total volume fraction of dendrites in the molecular layer (10%). Analysis of the material shows that this difference between the two results is due to the unexpected finding that there were few MAP2a,b stained Purkinje cell spiny dendrites. PMID- 20727948 TI - Phosphatase and tensin homolog deleted on chromosome 10 regulates sensory cell proliferation and differentiation of hair bundles in the mammalian cochlea. AB - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates cell proliferation, differentiation and growth. It regulates neural and glioma stem/progenitor cell renewal and PTEN deletion can drive expansion of epithelial progenitors in the lung, enhancing their capacity for regeneration. Because it is expressed at relatively high levels in developing mammalian auditory hair cells we have analyzed the phenotype of the auditory epithelium in PTEN knock-out mice. PTEN(+/-) heterozygous littermates have only one functional copy of the gene and show clear evidence for haploinsufficiency in the organ of Corti. Auditory sensory epithelial progenitors withdraw from the cell cycle later than in wild-type animals and this is associated with increases in the numbers of both inner and outer hair cells. The cytoskeletal differentiation of hair cells was also affected. While many hair bundles on the hair cells appeared to develop normally, others were structurally disorganized and a number were missing, apparently lost after they had been formed. The results show that PTEN plays a novel role in regulating cell proliferation and differentiation of hair bundles in auditory sensory epithelial cells and suggest that PTEN signaling pathways may provide therapeutic targets for auditory sensory regeneration. PMID- 20727949 TI - D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment. AB - D2 and D4 dopamine receptors play an important role in cognitive functions in the prefrontal cortex and they are involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia. The eventual effect of dopamine upon pyramidal neurons in the prefrontal cortex depends on which receptors are expressed in the different neuronal populations. Parvalbumin and calbindin mark two subpopulations of cortical GABAergic interneurons that differently innervate pyramidal cells. Recent hypotheses about schizophrenia hold that the root of the illness is a dysfunction of parvalbumin chandelier cells that produces disinhibition of pyramidal cells. In the present work we report double in situ hybridization histochemistry experiments to determine the prevalence of D2 receptor mRNA and D4 receptor mRNA in glutamatergic neurons, GABAergic interneurons and both parvalbumin and calbindin GABAergic subpopulations in monkey prefrontal cortex layer V. We found that around 54% of glutamatergic neurons express D2 mRNA and 75% express D4 mRNA, while GAD-positive interneurons express around 34% and 47% respectively. Parvalbumin cells mainly expressed D4 mRNA (65%) and less D2 mRNA (15-20%). Finally, calbindin cells expressed both receptors in similar proportions (37%). We hypothesized that D4 receptor could be a complementary target in designing new antipsychotics, mainly because of its predominance in parvalbumin interneurons. PMID- 20727950 TI - Cytotoxic prenylated flavonoids from Morus alba. AB - A phytochemical fractionation of the methanol extract of the Morus alba leaves led to the isolation of eleven flavonoids (1-11). The structure of the new 3' geranyl-3-prenyl-2',4',5,7-tetrahydroxyflavone (1) was elucidated by means of spectroscopic methods. The cytotoxicity of the isolated compounds against human cervical carcinoma HeLa, human breast carcinoma MCF-7, and human hepatocarcinoma Hep3B cells was evaluated. Of note, morusin (9) was the most potent with an IC(50) value of 0.64 MUM against HeLa cells. PMID- 20727951 TI - Neolignans and flavonoids from the root bark of Illicium henryi. AB - Two new neolignans (1 and 2) were isolated from the root bark of Illicium henryi, along with four known neolignans and seven known flavonoids (3-13). Their structures were elucidated on the basis of spectroscopic and chemical methods. The absolute configurations of compounds 1 and 2 were determined by the CD spectrum. PMID- 20727952 TI - Inhibition of glucose intestinal absorption by kaempferol 3-O-alpha-rhamnoside purified from Bauhinia megalandra leaves. AB - Glucose intestinal absorption (GIA) is one of the factors that increase glycemia. Its reduction could be an important factor in decreasing hyperglycemia in diabetic patients. It has been shown that the aqueous extract of Bauhinia megalandra leaves inhibits GIA. In the present study we identified a compound present in the extract of B. megalandra responsible for the biological effect. The methanol extract of B. megalandra leaves was fractionated using different solvents, and high-speed counter-current chromatography yielding two pure compounds identified by (1)H NMR and (13)C NMR as kaempferol 3-O-alpha-rhamnoside and quercetin 3-O-alpha-rhamnoside. The first one increased the K(M) without changes in the V(MAX) of GIA. In addition it exerted an additive inhibitory effect, on GIA, when combined with phlorizin. We suggest that kaempferol 3-O alpha-rhamnoside is a competitive inhibitor of intestinal SGLT1 cotransporter. PMID- 20727953 TI - Sesquiterpene lactone trilobolide activates production of interferon-gamma and nitric oxide. AB - Trilobolide (TB), a sesquiterpene lactone isolated from Laser trilobum is an inhibitor of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). We have found that upon the in vitro exposure to TB, rodent peritoneal cells and human peripheral blood mononuclear cells secrete high amounts of IFN-gamma. The effect is associated with the stimulation of high output NO biosynthesis in rat cells. The stimulatory potential of TB depends on the activation of MAP kinases p38 and ERK1/2, and transcription factor NF-kappaB. BAPTA-AM, a chelator of the intracellular calcium, remained without any effect on the secretion of IFN-gamma triggered by TB. These results demonstrate that TB is a potent immunostimulatory agent. PMID- 20727954 TI - Cloning and functional characterization of the guinea pig apoptosis inhibitor protein Survivin. AB - BACKGROUND: The guinea pig is widely used as a model to study (patho)physiological processes, such as neurodegenerative disorders. Survivin's dual function as an apoptosis inhibitor and a mitotic regulator is crucial not only for ordered development but its modulation seems crucial also under disease conditions. However, data on the expression and function of the guinea pig Survivin protein (Survivin(Gp)) are currently lacking. RESULTS: Here, we here report the cloning and functional characterization of Survivin(Gp). The respective cDNA was cloned from spleen mRNA, containing a 426 bp open reading frame encoding for a protein of 142aa. Survivin(Gp) displays a high homology to the human and murine orthologue, especially in domains critical for function, such as binding sites for chromosomal passenger complex (CPC) proteins and the nuclear export signal (NES). Notably, phylogenetic analyses revealed that Survivin(Gp) is more related to humans than to rodents. Ectopic expression studies of a Survivin(Gp)-GFP fusion confirmed its dynamic intracellular localization, analogous to the human and murine counterparts. In interphase cells, Survivin(Gp)-GFP was predominantly cytoplasmic and accumulated in the nucleus following export inhibition with leptomycin B (LMB). A typical CPC protein localization during mitosis was observed for Survivin(Gp)-GFP. Microinjection experiments together with genetic knockout demonstrated that the NES is essential for the anti-apoptotic and regulatory role of Survivin(Gp) during cell division. In vivo protein interaction assays further demonstrated its dimerization with human Survivin and its interaction with human CPC proteins. Importantly, RNAi-depletion studies show that Survivin(Gp) can fully substitute for human Survivin as an apoptosis inhibitor and a mitotic effector. Immunohistochemistry, immunofluorescence, and western blotting were employed to detect Survivin expression in guinea pig tissues. Besides its expression in proliferating tissues, such as spleen and liver, we also found Survivin in terminally differentiated cell types. Importantly, Survivin was detectable also in the cochlea, suggesting a potential role for Survivin in the auditory system. CONCLUSIONS: We provide the first experimental evidence for the expression of Survivin in the guinea pig. As Survivin(Gp) can substitute for known functions of human Survivin, the guinea pig model will now also allow investigating Survivin's (patho)physiological role and to test Survivin-directed potential therapeutic strategies. PMID- 20727955 TI - Tight junction modulation by chitosan nanoparticles: comparison with chitosan solution. AB - Present work investigates the potential of chitosan nanoparticles, formulated by the ionic gelation with tripolyphosphate (TPP), to open the cellular tight junctions and in doing so, improve the permeability of model macromolecules. A comparison is made with chitosan solution at equivalent concentrations. Initial work assessed cytotoxicity (through MTS and LDH assays) of chitosan nanoparticles and solutions on Calu-3 cells. Subsequently, a concentration of chitosan nanoparticles and solution exhibiting minimal toxicity was used to investigate the effect on TEER and macromolecular permeability across filter-cultured Calu-3 monolayer. Chitosan nanoparticles and solution were also tested for their effect on the distribution of the tight junction protein, zonnula occludens-1 (ZO-1). Chitosan nanoparticles produced a sharp and reversible decrease in TEER and increased the permeability of two FITC-dextrans (FDs), FD4 (MW 4 kDa) and FD10 (MW 10 kDa), with effects of a similar magnitude to chitosan solution. Chitosan nanoparticles produced changes in ZO-1 distribution similar to chitosan solution, indicating a tight junction effect. While there was no improvement in permeability with chitosan nanoparticles compared to solution, nanoparticles provide the potential for drug incorporation, and hence the possibility for providing controlled drug release and protection from enzymatic degradation. PMID- 20727956 TI - Novel application of hot-melt extrusion for the preparation of monolithic matrices containing enteric-coated particles. AB - The objective was to investigate a novel application of hot-melt extrusion for the preparation of multiparticulate matrices comprising delayed-release particles. Multiparticulates of different mechanical strengths (theophylline granules, wet-mass extruded/spheronized pellets and drug-layered microcrystalline cellulose spheres) were coated with Eudragit((r)) L30D-55 and characterized regarding potency, moisture content, dissolution properties and tensile strength. The coated particles were incorporated into a water-soluble matrix using hot-melt extrusion. Six hydrophilic polymers including polyethylene glycols, poloxamers and polyethylene oxides were studied as the carrier material for the extrusion. Dissolution testing showed that the maintenance of the delayed-release properties of the incorporated particles was independent of the particle tensile strength, but influenced by the nature of the carrier polymer. High miscibility between the carrier and the coating polymer correlated with increased film permeability and higher drug release in acidic media. Of the materials tested, poloxamer 407 exhibited lower miscibility with the Eudragit((r)) L polymer and matrices containing up to 40% enteric pellets were compliant with the USP dissolution requirements for delayed-release dosage forms. The potential advantages of hot melt extrusion over direct compression for the processing of soft drug granules coated with Eudragit((r)) L polymer were demonstrated. PMID- 20727957 TI - Matrix tablets based on carrageenans with dual controlled release of doxazosin mesylate. AB - The use of polymeric polyelectrolytes as matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan (CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM) were investigated according to their water-uptake/erosion properties, in situ complexation ability of CARR with DM, and the possibility to achieve dual drug release control. Interactions between different CARR types (iota-, kappa-, and lambda-) and DM were confirmed by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta potential measurements. Combination of water-uptake/erosion with in situ complexation prolonged DM release from CARR matrices for more than 24 h. The rate order of drug release was in accordance with the number of ester sulfate moieties per disaccharide unit of CARRs (kappa (1)>iota (2)>lambda (3)). The higher the charge on the CARR backbone, the higher the number of interactions with DM and the slower the drug release. Low pH, more vigorous hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta potential measurements of DM and CARRs, proposed influence of counterion condensation and its effect on screening polyelectrolyte-drug interactions was confirmed to lower in situ DM-CARR complexation. Dual drug release control from polyelectrolyte matrices by water-uptake/erosion and in situ complexation offers many new approaches for designing controlled-release systems. PMID- 20727958 TI - Brain uptake of ketoprofen-lysine prodrug in rats. AB - The blood-brain barrier (BBB) controls the entry of xenobiotics into the brain. Often the development of central nervous system drugs needs to be terminated because of their poor brain uptake. We describe a way to achieve large neutral amino acid transporter (LAT1)-mediated drug transport into the rat brain. We conjugated ketoprofen to an amino acid l-lysine so that the prodrug could access LAT1. The LAT1-mediated brain uptake of the prodrug was demonstrated with in situ rat brain perfusion technique. The ability of the prodrug to deliver ketoprofen into the site of action, the brain intracellular fluid, was determined combining in vivo and in vitro experiments. A rapid brain uptake from blood and cell uptake was seen both in in situ and in vivo experiments. Therefore, our results show that a prodrug approach can achieve uptake of drugs via LAT1 into the brain intracellular fluid. The distribution of the prodrug in the brain parenchyma and the site of parent drug release in the brain were shown with in vivo and in vitro studies. In addition, our results show that although lysine or ketoprofen are not LAT1-substrates themselves, by combining these molecules, the formed prodrug has affinity for LAT1. PMID- 20727959 TI - Panax notoginseng saponins decrease cholesterol ester via up-regulating ATP binding cassette transporter A1 in foam cells. AB - AIM: Accumulating evidence has indicated that Panax notoginseng saponins (PNS), the major ingredients in Panax notoginseng (Burk.) F.H. Chen which could be found widely in Asia, can attenuate atherogenesis in vivo. This study was designed to examine the relationship of PNS with cholesterol ester in foam cells sourced from macrophages and the effect of PNS on the expression of ATP-binding cassette transporter A1 (ABCA1). MATERIALS AND METHODS: Foam cells sourced from macrophages were cultured with PNS. The content of cholesterol ester in foam cells was analyzed and expressions of ABCA1 and liver X receptor alpha (LXRalpha) in foam cells were measured by real-time PCR and western blotting methods. RESULTS: The results showed that PNS could significantly decrease the level of cholesterol ester in foam cells at middle and high dosages. The real-time PCR and western blotting assays indicated that the expression of ABCA1 was up-regulated by PNS in a dose-dependent manner. Analysis based on these results showed that the cholesterol ester level was negatively correlated with ABCA1 expression. CONCLUSIONS: As a result, we conclude that by up-regulating the expression of ABCA1, PNS could lower the cholesterol ester level, which resulted in the attenuation of the foam cell formation. This bioactivity might be associated with the special chemical structures of PNS that are similar to the natural agonist of LXRalpha. PMID- 20727960 TI - Puerarin attenuates glutamate-induced neurofilament axonal transport impairment. AB - AIM OF THE STUDY: Puerarin (Pur) is a primary component of the most functional extracts of Pueraria lobata used in traditional Chinese medicine for centuries. Since it has been postulated that Pur protects the brain against glutamate (Glu) neurotoxicity, we investigated the effects of Pur on Glu-induced axonal transport impairment in primary hippocampal neurons in this study. MATERIALS AND METHODS: Primary hippocampal cultures were prepared from 2-day-old Sprague-Dawley rats. Intracellular calcium concentration [Ca(2+)](i), neurofilament (NF) phosphorylation and protein kinase activity for Cdk5 were measured. Time-lapse imaging technology was used to capture the NF axonal transport in the cultured neurons with transiently transfected fluorescence protein linked to the N terminus of NF-M (EGFP-NFM). RESULTS: The results showed that Pur significantly diminished the Glu-induced elevation of [Ca(2+)](i) in dose-dependent manner and antagonized the Glu-evoked increases in NF phosphorylation at protein levels. The neurons under the Glu treatment displayed the accumulation of immobile NF clusters in the cell body and the reduced rates of axonal transport of NFs by 72.8% compared to the control neurons. Intriguingly, Pur reversed the slowed rate of the axonal transport by 35.6%. Pur also remarkably attenuated Glu-evoked activation of Cdk5. CONCLUSIONS: Pur may play a role in protecting against Glu induced NF axonal transport impairment in rat primary hippocampal neurons by inhibiting the increased [Ca(2+)](i) and by impeding the activation of Cdk5. PMID- 20727961 TI - Using Drosophila melanogaster to study the positive effects of mild stress on aging. AB - Several studies in the fly Drosophila melanogaster have shown that a mild stress can increase longevity, resistance to strong stresses (e.g., heat, fungal infection, cold) and delay behavioral aging. However, not all mild stresses have similar effects on the various studied traits. For instance, exposure to cold increases resistance to a fungal infection, but hypergravity and heat shocks do not. In addition to studies in flies and other invertebrates, it is necessary to perform experiments in mammals, to know whether mild stress could be used in therapy more thoroughly than today. PMID- 20727963 TI - Longitudinal 2 years field study of conventional vaccination against highly pathogenic avian influenza H5N1 in layer hens. AB - A licensed, inactivated vaccine based on a low pathogenic avian influenza virus strain (H5N2) was evaluated in layer hens kept under field conditions during a 2 year period. Vaccine efficacy was investigated by specific antibodies and by challenge-contact experiments using highly pathogenic avian influenza viruses (HPAIV) H5N1. Basic immunization with two applications induced clinical protection. Virus excretion by vaccinated hens was significantly reduced compared to non-vaccinated controls; transmission to non-vaccinated and vaccinated contact birds was not fully interrupted. Vaccination efficacy is influenced by several factors including antigenic relatedness between vaccine and field strains, but also by species, age and type of commercial uses of the host. Limitations and risks of HPAIV vaccination as silent spread of HPAIV and emergence of escape mutants must be considered a priori and appropriate corrective measures have to be installed. PMID- 20727965 TI - Effects of gentamicin on guinea pig vestibular ganglion function and on substance P and neuropeptide Y. AB - Previous studies have demonstrated that following intratympanic gentamicin application in the guinea pigs, vestibular evoked myogenic potentials (VEMPs) were absent regardless of stimulation mode using either air-conducted sound (ACS) stimuli or galvanic vestibular stimulation (GVS). Ultrastructurally, both type I hair cells and their calyx terminals were distorted in the saccular macula. However, little is known about the toxic effects of gentamicin on the vestibular ganglion (VG). In this study, absent ACS- and GVS-VEMPs were noted in all the gentamicin-treated ears (100%), which were confirmed by the substantial loss of sensory hair cells in the saccular macula. Moreover, dramatic up-regulation of growth associated protein-43 (GAP-43) expression was detected in the ipsilateral VG neurons. The mean percentage of substance P-like immunoreactive (SP-LI) neurons in the treated VG (81.8+/-1.9%) was significantly higher than that in the control VG (68.6+/-3.3%). Conversely, the mean percentage of neuropeptide Y-like immunoreactive (NPY-LI) neurons in the treated VG (13.7+/-3.8%) was dramatically lower than that in the control VG (49.0+/-3.8%). Double labeling results shown 82% of SP-LI and 16% of NPY-LI neurons coexpressed with GAP-43, suggested that SP accumulating coincided with NPY decreasing in regenerating VG neurons after gentamicin treatment. Overall, the changes in SP and NPY expression in VG neurons after gentamicin treatment were like to those in the superior cervical ganglion following sympathectomy. PMID- 20727964 TI - Age and facial nerve axotomy-induced T cell trafficking: relation to microglial and motor neuron status. AB - Following peripheral axotomy of the facial nerve in mice, T lymphocytes cross the blood-brain-barrier (BBB) into the central nervous system (CNS), where they home to the neuronal cell bodies of origin in the facial motor nucleus (FMN) and act in concert with microglial cells to support the injured motor neurons. Several lines of evidence suggested normal aging may alter the injury-related responses of T cells, microglia, and motor neurons in this model. In this study, we therefore sought to test the hypothesis that compared to 8-week-old mice (young adult), 52-week-old mice (advanced middle age) would exhibit more neuronal damage and increased T cell trafficking into the injured FMN following facial nerve resection. Comparison of 8- and 52-week-old mice at 7, 14, 21, and 28 days post resection of the facial nerve, confirmed our hypothesis that age influences the kinetics of CD3(+) T lymphocyte trafficking in the axotomized FMN. The peak T cell response was significantly higher, occurred later, and remained elevated longer in the injured FMN of mice in the 52 week age group. Although the kinetics of motor neuron death (identified by quantifying CD11b(+) perineuronal microglial phagocytic clusters engulfing the dead neurons at 7, 14, 21, and 28 days post resection) differed between the age groups, motor neuron profile counts at day 28 showed that levels of cumulative motor neuron loss did not differ between the age groups. Compared to 8-week-old mice, however, there was small reduction in the mean cell size of the surviving motor neurons in the 52 week age group. Since T lymphocyte function decreases with normal aging, it will be important to determine if increased T cell trafficking into the injured CNS is a compensatory response to the decreased function of older T cells, and if these and related neuroimmunological changes are more pronounced in mice in the late stages of the life cycle. PMID- 20727962 TI - Developmental pathology, dopamine, stress and schizophrenia. AB - Psychological stress is a contributing factor for a wide variety of neuropsychiatric diseases including substance use disorders, anxiety, depression and schizophrenia. However, it has not been conclusively determined how stress augments the symptoms of these diseases. Here we review evidence that the ventral hippocampus may be a site of convergence whereby a number of seemingly discrete risk factors, including stress, may interact to precipitate psychosis in schizophrenia. Specifically, aberrant hippocampal activity has been demonstrated to underlie both the elevated dopamine neuron activity and associated behavioral hyperactivity to dopamine agonists in a verified animal model of schizophrenia. In addition, stress, psychostimulant drug use, prenatal infection and select genetic polymorphisms all appear to augment ventral hippocampal function that may therefore exaggerate or precipitate psychotic symptoms. Such information is critical for our understanding into the pathology of psychiatric disease with the ultimate aim being the development of more effective therapeutics. PMID- 20727966 TI - Multiple roles of microsomal glutathione transferase 1 in cellular protection: a mechanistic study. AB - The aim of this study was to investigate the involvement of membrane-bound microsomal glutathione transferase 1 (MGST1) in cellular resistance against oxidative stress as well as its mechanism of protection. MGST1 is ubiquitously expressed and predominantly located in the endoplasmic reticulum and outer mitochondrial membrane. Utilizing MCF7 cells overexpressing MGST1 we show significant protection against agents that are known to induce lipid peroxidation (e.g., cumene hydroperoxide and tert-butylhydroperoxide) and an end-product of lipid peroxidation (e.g., 4-hydroxy-2-nonenal). Furthermore, our results demonstrate that MGST1 protection can be enhanced by vitamin E when toxicity depends on oxidative stress, but not when direct alkylation is the dominant mechanism. Mitochondria in MGST1-overexpressing cells were shown to be protected from oxidative insult as measured by calcium loading capacity and respiration. MGST1 induces cellular resistance against cisplatin. Here we used vitamin E to elucidate whether oxidative stress caused by cisplatin is significant for cell toxicity. The results indicate that oxidative stress and induction of lipid peroxidation are not the most prominent toxic mechanism of cisplatin in our cell system. We thus conclude that MGST1 protects cells (and mitochondria) by both conjugation and glutathione peroxidase functions. A new protective mechanism against cisplatin is also indicated. PMID- 20727967 TI - Mammalian target of rapamycin (mTOR) phosphorylates inositol 1,4,5-trisphosphate receptor type 2 and increases its Ca(2+) release activity. AB - There is substantial evidence that crosstalk between the proliferation and Ca(2+) signaling pathways plays a critical role in the regulation of normal physiological functions as well as in the pathogenesis of a variety of abnormal processes. In non-excitable cells, intracellular Ca(2+) is mobilized through inositol 1,4,5-trisphosphate sensitive Ca(2+) channels (IP(3)R) expressed on the endoplasmic reticulum. Here we report that mTOR, a point of convergence for signals from mitogenic growth factors, nutrients and cellular energy levels, phosphorylates the IP(3)R-2, the predominant isoform of IP(3)R in AR4-2J cells. Pretreatment with the mTOR inhibitor rapamycin, decreased carbachol-induced Ca(2+) release in AR4-2J cells. Rapamycin also decreased IP(3)-induced Ca(2+) release in permeabilized AR4-2J cells. We also showed that IGF-1 potentiates carbachol-induced Ca(2+) release in AR4-2J cells, an effect that was prevented by rapamycin. Rapamycin also decreased carbachol-induced Ca(2+) release in HEK 293A cells in which IP(3)R-1 and IP(3)R-3 had been knocked down. These results suggest that mTOR potentiates the activity of IP(3)R-2 by a phosphorylation mechanism. This conclusion supports the concept of crosstalk between Ca(2+) signaling and proliferation pathways and thus provides another way by which intracellular Ca(2+) signals are finely encoded. PMID- 20727968 TI - The diverse functions of GAPDH: views from different subcellular compartments. AB - Multiple roles for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) have been recently appreciated. In addition to the cytoplasm where the majority of GAPDH is located under the basal condition, GAPDH is also found in the particulate fractions, such as the nucleus, the mitochondria, and the small vesicular fractions. When cells are exposed to various stressors, dynamic subcellular re distribution of GAPDH occurs. Here we review these multifunctional properties of GAPDH, especially linking them to its oligomerization, posttranslational modification, and subcellular localization. This includes mechanistic descriptions of how S-nitrosylation of GAPDH under oxidative stress may lead to cell death/dysfunction via nuclear translocation of GAPDH, which is counteracted by a cytosolic GOSPEL. GAPDH is also involved in various diseases, especially neurodegenerative disorders and cancers. Therapeutic strategies to these conditions based on molecular understanding of GAPDH are discussed. PMID- 20727969 TI - Permeabilization of Drosophila embryos for introduction of small molecules. AB - Pharmacological manipulations in the Drosophila embryo have been hindered by the impermeability of the eggshell. The ultimate barrier to delivery of small molecule solutes to the embryo is the waxy layer that lies beneath the external chorion layers and encases the underlying vitelline membrane of the eggshell. Conventional protocols call for heptane or octane to permeablize the dechorionated eggshell however, these solvents are toxic and can result in low viability. Furthermore, heptane and octane require transition of the embryo between aqueous and organic phase solvents making it challenging to avoid desiccation. Here we describe an embryo permeabilization solvent (EPS) composed of d-limonene and plant-derived surfactants that is water miscible and highly effective in rendering the dechorionated eggshell permeable. EPS permeabilization enables embryo uptake of several different dyes of various molecular mass up to 995Da. We find that the embryo undergoes an age-dependent decrease in the ability to be permeabilized in the first six to eight hours after egg laying. This apparent developmental change in the vitelline membrane contributes to the heterogeneity in permeabilization seen even among closely staged embryos. However, using fluorescent properties of Rhodamine B dye and various conditions of EPS treatment we demonstrate the ability to obtain optimally permeabilized viable embryos. We also demonstrate the ability to assess teratogenic activity of several compounds applied to embryos in vitro, using both early and late developmental endpoints. Application of the method to transgenic strains carrying GFP-reporter genes results in a robust readout of pharmacological alteration of embryogenesis. The straightforward and rapid nature of the manipulations needed to prepare batches of permeabilized embryos has the potential of establishing the Drosophila embryo as an alternative model in toxicology and for small molecule screening in a high-throughput format. PMID- 20727970 TI - Pheromone production in bark beetles. AB - The first aggregation pheromone components from bark beetles were identified in 1966 as a mixture of ipsdienol, ipsenol and verbenol. Since then, a number of additional components have been identified as both aggregation and anti aggregation pheromones, with many of them being monoterpenoids or derived from monoterpenoids. The structural similarity between the major pheromone components of bark beetles and the monoterpenes found in the host trees, along with the association of monoterpenoid production with plant tissue, led to the paradigm that most if not all bark beetle pheromone components were derived from host tree precursors, often with a simple hydroxylation producing the pheromone. In the 1990 s there was a paradigm shift as evidence for de novo biosynthesis of pheromone components began to accumulate, and it is now recognized that most bark beetle monoterpenoid aggregation pheromone components are biosynthesized de novo. The bark beetle aggregation pheromones are released from the frass, which is consistent with the isoprenoid aggregation pheromones, including ipsdienol, ipsenol and frontalin, being produced in midgut tissue. It appears that exo brevocomin is produced de novo in fat body tissue, and that verbenol, verbenone and verbenene are produced from dietary alpha-pinene in fat body tissue. Combined biochemical, molecular and functional genomics studies in Ips pini yielded the discovery and characterization of the enzymes that convert mevalonate pathway intermediates to pheromone components, including a novel bifunctional geranyl diphosphate synthase/myrcene synthase, a cytochrome P450 that hydroxylates myrcene to ipsdienol, and an oxidoreductase that interconverts ipsdienol and ipsdienone to achieve the appropriate stereochemistry of ipsdienol for pheromonal activity. Furthermore, the regulation of these genes and their corresponding enzymes proved complex and diverse in different species. Mevalonate pathway genes in pheromone producing male I. pini have much higher basal levels than in females, and feeding induces their expression. In I. duplicatus and I. pini, juvenile hormone III (JH III) induces pheromone production in the absence of feeding, whereas in I. paraconfusus and I. confusus, topically applied JH III does not induce pheromone production. In all four species, feeding induces pheromone production. While many of the details of pheromone production, including the site of synthesis, pathways and knowledge of the enzymes involved are known for Ips, less is known about pheromone production in Dendroctonus. Functional genomics studies are under way in D. ponderosae, which should rapidly increase our understanding of pheromone production in this genus. This chapter presents a historical development of what is known about pheromone production in bark beetles, emphasizes the genomic and post-genomic work in I. pini and points out areas where research is needed to obtain a more complete understanding of pheromone production. PMID- 20727971 TI - Reduced gluconeogenesis and lactate clearance in Huntington's disease. AB - We studied systemic and brain glucose and lactate metabolism in Huntington's disease (HD) patients in response to ergometer cycling. Following termination of exercise, blood glucose increased abruptly in control subjects, but no peak was seen in any of the HD patients (2.0 +/- 0.5 vs. 0.0 +/- 0.2mM, P < 2 * 10(-6)). No difference was seen in brain metabolism parameters. Reduced hepatic glucose output in the HD mouse model R6/2 following a lactate challenge, combined with reduced phosphoenolpyruvate carboxykinase and increased pyruvate kinase activity in the mouse liver suggest a reduced capacity for gluconeogenesis in HD, possibly contributing to the clinical symptoms of HD. We propose that blood glucose concentration in the recovery from exercise can be applied as a liver function test in HD patients. PMID- 20727973 TI - Features of bilirubin-induced reactive microglia: from phagocytosis to inflammation. AB - Microglia constitute the brain's immunocompetent cells and are intricately implicated in numerous inflammatory processes included in neonatal brain injury. In addition, clearance of tissue debris by microglia is essential for tissue homeostasis and may have a neuroprotective outcome. Since unconjugated bilirubin (UCB) has been proven to induce astroglial immunological activation and neuronal cell death, we addressed the question of whether microglia acquires a reactive phenotype when challenged by UCB and intended to characterize this response. In the present study we report that microglia primary cultures stimulated by UCB react by the acquisition of a phagocytic phenotype that shifted into an inflammatory response characterized by the secretion of the pro-inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, upregulation of cyclooxygenase (COX)-2 and increased matrix metalloproteinase (MMP)-2 and -9 activities. Further investigation upon upstream signalling pathways revealed that UCB led to the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB at an early time point, suggesting that these pathways might underlie both the phagocytic and the inflammatory phenotypes engaged by microglia. Curiously, the phagocytic and inflammatory phenotypes in UCB-activated microglia seem to alternate along time, indicating that microglia reacts towards UCB insult firstly with a phagocytic response, in an attempt to constrain the lesion extent and comprising a neuroprotective measure. Upon prolonged UCB exposure periods, either a shift on global microglia reaction occurred or there could be two distinct sub-populations of microglial cells, one directed at eliminating the damaged cells by phagocytosis, and another that engaged a more delayed inflammatory response. In conclusion, microglial cells are relevant partners to consider during bilirubin encephalopathy and the modulation of its activation might be a promising therapeutic target. PMID- 20727972 TI - Hsp70- and Hsp90-mediated proteasomal degradation underlies TPI sugarkill pathogenesis in Drosophila. AB - Triosephosphate isomerase (TPI) deficiency is a severe glycolytic enzymopathy that causes progressive locomotor impairment and neurodegeneration, susceptibility to infection, and premature death. The recessive missense TPI(sugarkill) mutation in Drosophila melanogaster exhibits phenotypes analogous to human TPI deficiency such as progressive locomotor impairment, neurodegeneration, and reduced life span. We have shown that the TPI(sugarkill) protein is an active stable dimer; however, the mutant protein is turned over by the proteasome reducing cellular levels of this glycolytic enzyme. As proteasome function is often coupled with molecular chaperone activity, we hypothesized that TPI(sugarkill) is recognized by molecular chaperones that mediate the proteasomal degradation of the mutant protein. Coimmunoprecipitation data and analyses of TPI(sugarkill) turnover in animals with reduced or enhanced molecular chaperone activity indicate that both Hsp90 and Hsp70 are important for targeting TPI(sugarkill) for degradation. Furthermore, molecular chaperone and proteasome activity modified by pharmacological or genetic manipulations resulted in improved TPI(sugarkill) protein levels and rescue some but not all of the disease phenotypes suggesting that TPI deficiency pathology is complex. Overall, these data demonstrate a surprising role for Hsp70 and Hsp90 in the progression of neural dysfunction associated with TPI deficiency. PMID- 20727975 TI - Phylogeny of the Linnaea clade: are Abelia and Zabelia closely related? AB - Phylogenetic investigations based on molecular and morphological data have improved our understanding of Dipsacales phylogeny dramatically over the past 20 years. The Linnaea clade, however, has mostly been neglected and Zabelia has rarely been included in previous studies. We present the results of a molecular investigation including nine Abelia and five Zabelia species based on nuclear (ITS) and plastid (trnK, matK, atpB-rbcL, trnL-F) sequence data using maximum parsimony, Bayesian inference, and maximum likelihood. Our results indicate that Abelia is paraphyletic and possibly polyphyletic. The genus falls apart into a Mexican clade, corresponding to Abelia section Vesalea, and an Asian clade (excluding A. spathulata), corresponding to Abelia section Abelia. A close relationship between Zabelia and other members of the traditional Linnaea clade is not recovered by our analyses. Instead, Zabelia is associated with either the Morina or the Valeriana clade. Support for a monophyletic Linnaea clade without Zabelia is strong. PMID- 20727974 TI - Bursts and oscillations as independent properties of neural activity in the parkinsonian globus pallidus internus. AB - Bursts and oscillatory modulations in firing rate are hallmark features of abnormal neuronal activity in the parkinsonian Globus Pallidus internus (GPi). Although often implicated together in the pathophysiology of parkinsonian signs, little is known about how burst discharges and oscillatory firing (OF) relate to each other. To investigate this question, extracellular single-unit neuronal activity was recorded from 132 GPi cells in 14 Parkinson's disease patients. We found that burst firing was equally prevalent in OF and non-oscillatory firing (NOF) cells (p>0.5). More than half of the cells were characterized by either aperiodic bursty activity or OF, but not both. OF and NOF cells had statistically indistinguishable levels of mean burstiness (p=0.8). Even when bursting and OF co existed in individual cells, levels of burstiness and oscillatory power were seldom correlated across time. Interestingly, however, the few OF cells with spectral peaks between 8-13 Hz (alpha-range) were substantially burstier than other cells (p<0.01) and showed an unique burst morphology and stronger temporal correlations between oscillatory power and burstiness. We conclude that independent mechanisms may underlie the burst discharges and OF typical of most neurons in the parkinsonian GPi. PMID- 20727976 TI - Phylogenetics of the pademelons (Macropodidae: Thylogale) and historical biogeography of the Australo-Papuan region. AB - Australia and New Guinea share a common biogeographical history and unique vertebrate fauna. Investigation of genetic relationships among the wet forest restricted pademelons (Macropodidae: Thylogale) provides insight into the historical connections between the two regions and the evolution of the Australasian marsupial fauna. Molecular phylogenetic relationships among Thylogale species were analysed using mitochondrial (12S rRNA and cytochrome b) and nuclear (omega-globin intron) sequence data with Bayesian and maximum likelihood methods. Australian species were resolved as well-supported, monophyletic clades, whereas endemic New Guinean species did not form clades consistent with current morphological taxonomy. Estimates of divergence using a Bayesian relaxed molecular clock model with standard mammalian nucleotide substitution rates indicated radiation of the genus in Australia in the mid to late Miocene. Persistence of Australian species of Thylogale in both southern temperate and northern tropical forests throughout the drying of the Australian continent can be attributed to their having a greater dietary flexibility than other browsing forest macropods. Divergence of the endemic New Guinean lineage occurred in the late Miocene to early Pliocene, indicating the presence of a partially forested landbridge connecting Australia and New Guinea during the Miocene. Mid-Pleistocene divergence between subspecies of the trans-Torresian T. stigmatica implies gene flow during glacial maxima between forest populations in the southern lowlands of New Guinea and the northern Cape York region of Australia. Complex structuring and relatively limited differentiation among populations of the endemic New Guinean species appears to have been influenced by the uplift of land and climate-induced redistribution of forest habitats during the late Pliocene and Pleistocene period. This is in strong contrast to the long evolutionary history and comparatively deep genetic divergence of Thylogale species in Australia. Further evaluation of the species status of the New Guinean Thylogale using more informative nuclear markers and extensive sampling is required. PMID- 20727977 TI - Rapid and accurate species tree estimation for phylogeographic investigations using replicated subsampling. AB - We describe a method for estimating species trees that relies on replicated subsampling of large data matrices. One application of this method is phylogeographic research, which has long depended on large datasets that sample intensively from the geographic range of the focal species; these datasets allow systematicists to identify cryptic diversity and understand how contemporary and historical landscape forces influence genetic diversity. However, analyzing any large dataset can be computationally difficult, particularly when newly developed methods for species tree estimation are used. Here we explore the use of replicated subsampling, a potential solution to the problem posed by large datasets, with both a simulation study and an empirical analysis. In the simulations, we sample different numbers of alleles and loci, estimate species trees using STEM, and compare the estimated to the actual species tree. Our results indicate that subsampling three alleles per species for eight loci nearly always results in an accurate species tree topology, even in cases where the species tree was characterized by extremely rapid divergence. Even more modest subsampling effort, for example one allele per species and two loci, was more likely than not (>50%) to identify the correct species tree topology, indicating that in nearly all cases, computing the majority-rule consensus tree from replicated subsampling provides a good estimate of topology. These results were supported by estimating the correct species tree topology and reasonable branch lengths for an empirical 10-locus great ape dataset. PMID- 20727978 TI - The Reelin (RELN) gene is associated with executive function in healthy individuals. AB - Executive functions such as set-shifting and maintenance are cognitive processes that rely on complex neurodevelopmental processes. Although neurodevelopmental processes are mainly studied in animal models and in neuropsychiatric disorders, the underlying genetic basis for these processes under physiological conditions is poorly understood. We aimed to investigate the association between genetic variants of the Reelin (RELN) gene and cognitive set-shifting in healthy young individuals. The relationship between 12 selected single nucleotide polymorphisms (SNPs) of the RELN gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N=98 young healthy individuals (mean age in years: 22.7 +/- 0.19). Results show that in individual MANCOVA analyses two of five significant SNPs (rs2711870: F(2,39)=7.14; p=0.0019; rs2249372: F(2,39)=6.97; p=0.002) withstood Bonferroni correction for multiple testing (corrected p-value: p=0.004). While haplotype analyses of the RELN gene showed significant associations between three haplotypes and perseverative error processing in various models of inheritance (adjusted for age, gender, BDI, MWTB IQ), the GCT haplotype showed the most robust finding with a recessive model of inheritance (p=2.32 * 10(-5)) involving the functional SNP rs362691 (Leu-Val amino acid change). Although our study strongly suggests the involvement of the RELN gene in cognitive set-shifting and maintenance, our study requires further exploration as well as replication of the findings in larger samples of healthy individuals and in clinical samples with neuropsychiatric disorders. PMID- 20727980 TI - The endocannabinoid 2-arachidonoylglycerol (2-AG) and metabolizing enzymes during rat fetoplacental development: a role in uterine remodelling. AB - The main endocannabinoids (EC) identified in mammalian tissues are N arachidonoylethanolamide (AEA, anandamide), and 2-arachidonoylglycerol (2-AG). AEA levels are critical in pregnancy, especially during implantation, decidualization, and placental development. As 2-AG functions in pregnancy are still largely undefined, we hypothesized that it may also have a role during fetoplacental development. We showed that 2-AG is not only present in the rat mesometrial decidua and plasma during fetoplacental development, but that both 2 AG synthesizing (diacylglycerol lipase) and degradation (monoacylglycerol lipase) enzymes are expressed by decidual cells. While lower concentrations of 2-AG induced apoptosis of rat primary decidual cells, via the CB1 receptor, higher concentrations induced a dramatic effect on cell morphology, cell viability and lactate dehydrogenase release, triggered through a mechanism independent of CB1. This study provides evidences that 2-AG fluctuation in maternal tissues throughout normal pregnancy is primarily regulated by its metabolizing enzymes. Together, these data supports the hypothesis that a deregulation of the endocannabinoid system through aberrant cannabinoid signalling may impact normal uterine remodelling process and consequently normal pregnancy. PMID- 20727979 TI - The role of nicotinic acetylcholine receptors in the medial prefrontal cortex and hippocampus in trace fear conditioning. AB - Acute nicotine enhances multiple types of learning including trace fear conditioning but the underlying neural substrates of these effects are not well understood. Trace fear conditioning critically involves the medial prefrontal cortex and hippocampus, which both express nicotinic acetylcholine receptors (nAChRs). Therefore, nicotine could act in either or both areas to enhance trace fear conditioning. To identify the underlying neural areas and nAChR subtypes, we examined the effects of infusion of nicotine, or nicotinic antagonists dihydro beta-erythroidine (DHbetaE: high-affinity nAChRs) or methyllycaconitine (MLA: low affinity nAChRs) into the dorsal hippocampus, ventral hippocampus, and medial prefrontal cortex (mPFC) on trace and contextual fear conditioning. We found that the effects of nicotine on trace and contextual fear conditioning vary by brain region and nAChR subtype. The dorsal hippocampus was involved in the effects of nicotine on both trace and contextual fear conditioning but each task was sensitive to different doses of nicotine. Additionally, dorsal hippocampal infusion of the antagonist DHbetaE produced deficits in trace but not contextual fear conditioning. Nicotine infusion into the ventral hippocampus produced deficits in both trace and contextual fear conditioning. In the mPFC, nicotine enhanced trace but not contextual fear conditioning. Interestingly, infusion of the antagonists MLA or DHbetaE in the mPFC also enhanced trace fear conditioning. These findings suggest that nicotine acts on different substrates to enhance trace versus contextual fear conditioning, and that nicotine-induced desensitization of nAChRs in the mPFC may contribute to the effects of nicotine on trace fear conditioning. PMID- 20727981 TI - The role of Ca(2+) in ultrasound-elicited bioeffects: progress, perspectives and prospects. AB - Intracellular calcium (Ca(2+)) transients have been observed in association with exposure to therapeutic ultrasound and correlated to both early- and late-onset bioeffects. For example, it has been suggested that early 'ultra-short' Ca(2+) transients recorded during sonoporation can mediate Ca(2+)-dependent exocytosis and endocytosis processes as complementary mechanisms for membrane self-sealing. Moreover, apoptosis induction has been reported to occur through a partial mediation of a Ca(2+)-dependent pathway. In this review, we attempt to assemble the salient facts into a cogent whole, with special attention given to the relationships arising through altered Ca(2+) levels, which underscore its crucial role during ultrasonic interactions with biological systems and its consequent implications in the context of therapeutics. PMID- 20727982 TI - Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation. AB - We propose a numerical framework that permits an effective atlas-like representation of chemico-biological space based on a series of Cartesian planes mapping the ligands with the corresponding targets connected by an affinity parameter (K(i) or related). The numerical framework is derived from the concept of ligand efficiency indices, which provide a natural coordinate system combining the potency toward the target (biological space) with the physicochemical properties of the ligand (chemical space). This framework facilitates navigation in the multidimensional drug discovery space using map-like representations based on pairs of combined variables related to the efficiency of the ligands per Dalton (molecular weight or number of non-hydrogen atoms) and per unit of polar surface area (or number of polar atoms). PMID- 20727983 TI - Staphylorchis cymatodes (Gorgoderidae: Anaporrhutinae) from carcharhiniform, orectolobiform and myliobatiform elasmobranchs of Australasia: low host specificity, wide distribution and morphological plasticity. AB - Anaporrhutine gorgoderids (Digenea: Gorgoderidae: Anaporrhutinae) found in the body cavity of six species of elasmobranchs from the orders Carcharhiniformes, Myliobatiformes and Orectolobiformes from Australian waters were found to belong to the genus Staphylorchis. Although these specimens were morphologically variable, sequences of ITS2 and 28S ribosomal DNA from specimens from three host families and two host orders were identical. Based on morphological and molecular data these specimens were identified as the type-species of the genus, Staphylorchis cymatodes. New measurements are provided for S. cymatodes, and for the first time genetic data are presented for this species. In addition to providing new morphological and molecular data for S. cymatodes, the previously described species S. gigas, S. parisi and S. scoliodonii, are here synonymised with S. cymatodes. This implies that S. cymatodes, as conceived here, has remarkably low host-specificity, being recorded from eight elasmobranch species from four families and three orders, has a wide geographical distribution in the Indo-west Pacific from off India, in the Bay of Bengal, to Moreton Bay in the Coral Sea, and is morphologically plastic, with body size, size of specific organs and body shape differing dramatically between specimens from different host species. The genus Staphylorchis now contains only two valid species, S. cymatodes and S. pacifica. PMID- 20727984 TI - Apparent dominance of the G1-G3 genetic cluster of Echinococcus granulosus strains in the central inland region of Portugal. AB - Infection by the larval stage of the cestode Echinococcus granulosus causes a disease known as cystic echinococcosis or hydatidosis, which is one of the most widespread zoonotic infections of veterinary and medical importance. Numerous studies have shown that E. granulosus exists as a complex of strains differing in a wide variety of criteria. Ten distinct genotypes (G1-G10) have been identified with a potential impact on the pathology, epidemiology and the effect of the measures implemented for the control of hydatidosis. Our main objective was to carry out a preliminary analysis of the genotypes of E. granulosus circulating in the central inland region of Portugal. Parasite samples (hydatid cysts, n=27) were isolated from the liver and lung of sheep and cattle. The DNA extracted from protoscoleces isolated from the fertile cysts served as a template for the PCR amplification of the part of the mitochondrial cytochrome c oxidase subunit 1 (cox1), ATP synthase F0 subunit 6 (atp6) as well as the large (rrnL/16S) and small (rrnS/12S) ribosomal RNA genes. Similarity searches with homologous sequences in the databanks indicated a very high similarity with references assigned to the G1, G3 and/or G1-G3 complex of Echinococcus strains. Phylogenetic analysis (Bayesian approach) supported these observations, and confirmed the assignment of all the analyzed sequences to the G1-G3 genetic cluster. PMID- 20727985 TI - Triacylglycerol lipolysis is linked to sphingolipid and phospholipid metabolism of the yeast Saccharomyces cerevisiae. AB - Previous work from our laboratory had demonstrated that deletion of TGL3 encoding the major yeast triacylglycerol (TAG) lipase resulted in decreased mobilization of TAG, a sporulation defect and a changed pattern of fatty acids, especially increased amounts of C22:0 and C26:0 very long chain fatty acids in the TAG fraction [K. Athenstaedt and G. Daum, J. Biol. Chem. 278 (2003) 23317-23323]. To study a possible link between TAG lipolysis and membrane lipid biosynthesis, we carried out metabolic labeling experiments with wild type and deletion strains bearing defects in the three major yeast TAG lipases, Tgl3p, Tgl4p and Tgl5p. Using [(3)H]inositol, [(32)P]orthophosphate, [(3)H]palmitate and [(14)C]acetate as precursors for complex lipids we demonstrated that tgl mutants had a lower level of sphingolipids and glycerophospholipids than wild type. ESI-MS/MS analyses confirmed that TAG accumulation in these mutant cells resulted in reduced amounts of phospholipids and sphingolipids. In vitro and in vivo experiments revealed that TAG lipolysis markedly affected the metabolic flux of long chain fatty acids and very long chain fatty acids required for sphingolipid and glycerophospholipid synthesis. Activity and expression level of fatty acid elongases, Elo1p and Elo2p were enhanced as a consequence of reduced TAG lipolysis. Finally, the pattern of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine molecular species was altered in tgl deletion strain underlining the important role of TAG turnover in maintaining the pool size of these compounds and the remodeling of complex membrane lipids. PMID- 20727987 TI - Persistent viral infections and immune aging. AB - Immunosenescence comprises a set of dynamic changes occurring to both, the innate as well as the adaptive immune system that accompany human aging and result in complex manifestations of still poorly defined deficiencies in the elderly population. One of the most prominent alterations during aging is the continuous involution of the thymus gland which is almost complete by the age of 50. Consequently, the output of naive T cells is greatly diminished in elderly individuals which puts pressure on homeostatic forces to maintain a steady T cell pool for most of adulthood. In a great proportion of the human population, this fragile balance is challenged by persistent viral infections, especially Cytomegalovirus (CMV), that oblige certain T cell clones to monoclonally expand repeatedly over a lifetime which then occupy space within the T cell pool. Eventually, these inflated memory T cell clones become exhausted and their extensive accumulation accelerates the age-dependent decline of the diversity of the T cell pool. As a consequence, infectious diseases are more frequent and severe in elderly persons and immunological protection following vaccination is reduced. This review therefore aims to shed light on how various types of persistent viral infections, especially CMV, influence the aging of the immune system and highlight potential measures to prevent the age-related decline in immune function. PMID- 20727988 TI - MSCs: Biological characteristics, clinical applications and their outstanding concerns. AB - Mesenchymal stem cells (MSCs) are multi-potent adult stem cells harboring multi lineage differentiation potential and immunosuppressive properties that make MSCs an ideal candidate cell type for immunomodulation and regenerative medicine. Currently, MSC-related researches and clinical trials have evoked exciting promise in a variety of disorders and tissue regeneration. However, it must be recognized that several critical potential problems have also emerged from current clinical trials, for example: (1) the indefinite association between the phenotypic characteristics and the biological functions of MSCs; (2) the lack of clinical data to support the long-term safety of MSCs; (3) the need for further clarification of multiple mechanisms of MSC transplant actions in vivo; and (4) the lack of comparability of MSC transplant efficacy. Therefore, MSC-based therapies could not yet be considered a routine treatment in the clinic. Based on these, we proposed that large-scale and multi-center clinical trials of MSC-based therapies should be initiated under strict supervision. These interventions might help to establish a new clinical paradigm to turn MSC transplantation into a routine therapy for at least some diseases in the near future. PMID- 20727989 TI - Surface localized and extracellular Glyceraldehyde-3-phosphate dehydrogenase of Bacillus anthracis is a plasminogen binding protein. AB - The role of anchorless proteins on the surface of most pathogenic microorganisms has long been studied in context to their interactions with multiple host proteins, facilitating the dissemination of pathogen within the host tissues. In order to gain more insights into anthrax pathogenesis, we hereby report the presence of a prominent moonlighting enzyme, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on the surface and in the extracellular medium of Bacillus anthracis. Out of the three heterologously expressed recombinant isoforms, rGapA (334 amino acids in native form; GapA) showed a significant NAD+ mediated GAPDH activity, whereas rGapB (342 amino acids in native form; GapB) showed a slight activity with NADP+. The rGapN (479 amino acids in native form; GapN) was enzymatically inactive with either NAD+ or NADP+. GapA was ascertained to be present in the extracellular medium and on the surface of B. anthracis. On the other hand, GapN was absent from both the surface and extracellular medium, whereas GapB was scarcely present on the surface of B. anthracis. Human plasminogen predominantly interacted with the rGapA isoform at physiological concentrations and the interaction was found to be lysine dependent. Immunization with rGapA resulted in a significant protection upon challenge with Bacillus anthracis in the murine model. PMID- 20727990 TI - Five monomeric hemocyanin subunits from Portunus trituberculatus: purification, spectroscopic characterization, and quantitative evaluation of phenol monooxygenase activity. AB - Five kinds of monomeric subunits of arthropod hemocyanin have been isolated from swimming crab Portunus trituberculatus hemolymph. The copper centers holding a peroxo species, [(MU-eta2:eta2-peroxo)dicopper(II)], of these subunits exhibited almost the same UV-vis and visible region CD spectroscopic properties, indicating that they have a similar copper coordination geometry and an electronic structure. Under anaerobic conditions, the oxy-forms of the monomeric subunits were stable in 0.5 M borate buffer (pH 9.0) and reacted with 4-methylphenol (p cresol) to show the phenolases (cresolase/phenol monooxygenase) activity in the presence of urea. To compare the phenolase (monooxygenase) reactivity, the reactivity of the isolated subunits has been examined quantitatively by using a simplified catalytic system, where the initial product catechol is trapped with borate anion of the buffer solution to prevent following catecholase reaction (Yamazaki and Itoh, 2003). The far-UV region CD spectra were measured in order to clarify the relationship between the content of the secondary structure and the phenolase reactivity. Even though the monomeric subunits exhibit a weak catalytic phenol monooxygenase activity, addition of urea (3 M) significantly enhances their catalytic activity. The differences of the phenolase activity among the monomeric subunits has been discussed on the basis of the spectroscopic analysis and reactivity studies in order to shed light on the enzymatic function of the arthropod hemocyanin in vivo. PMID- 20727991 TI - Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy. AB - Recently much attention has been given to the anti-cancer drug nutlin-3a, an antagonist of murine double minute 2 (MDM2) that actively inhibits p53-MDM2 interaction. Reactivating p53 function by nutlin-3a thus provides a promising therapeutic strategy for the treatment of cancer. Although nutlin-3a seems a potential candidate in restoring p53 activity, it has many lacunae, toxicity, poor bioavailability, nonspecific delivery, and most importantly it is a substrate of multidrug resistance protein. The objective of the present study is to prepare and characterize nutlin-3a loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), surface functionalized with epithelial cell adhesion molecule (EpCAM) antibody, with an aim to deliver encapsulated drug in a targeted manner to its site of action and to enhance its therapeutic efficacy many times over. The enhanced cellular uptake of EpCAM antibody conjugated nutlin-3a loaded NPs (EpCAM-nutlin-3a-NPs) over native nulin-3a, nutlin-3a loaded NPs (nutlin-3a NPs) in HCT116 and A549 cells substantiate the targeting potentiality of conjugated system. IC50 values depicted superior antiproliferative activity of EpCAM-nutlin-3a-NPs over nutlin-3a-NPs and native nutlin-3a in the above studied cell lines. Cell cycle arrest, loss of mitochondrial membrane potential and apoptosis induced by above formulation were confirmed by flow cytometry. Expression of p53, p21, EpCAM, and C-myc proteins involved in cell cycle regulation and apoptosis were investigated by western blotting. The above investigation indicates the enhanced therapeutic ability of EpCAM-nutlin-3a-NPs compared to nutlin-3a or nutlin-3a-NPs. Thus, our results suggest that EpCAM nutlin-3a-NPs could be a potentially useful drug carrier system for targeted delivery of potent anti-cancer drug nutlin-3a for cancer therapy. PMID- 20727992 TI - Two pole air gap electrospinning: Fabrication of highly aligned, three dimensional scaffolds for nerve reconstruction. AB - We describe the structural and functional properties of three-dimensional (3D) nerve guides fabricated from poly-epsilon-caprolactone (PCL) using the air gap electrospinning process. This process makes it possible to deposit nano-to-micron diameter fibers into linear bundles that are aligned in parallel with the long axis of a cylindrical construct. By varying starting electrospinning conditions it is possible to modulate scaffold material properties and void space volume. The architecture of these constructs provides thousands of potential channels to direct axon growth. In cell culture functional assays, scaffolds composed of individual PCL fibers ranging from 400 to 1500 nm supported the penetration and growth of axons from rat dorsal root ganglion. To test the efficacy of our guide design we reconstructed 10mm lesions in the rodent sciatic nerve with scaffolds that had fibers 1 MUm in average diameter and void volumes >90%. Seven weeks post implantation, microscopic examination of the regenerating tissue revealed dense, parallel arrays of myelinated and non-myelinated axons. Functional blood vessels were scattered throughout the implant. We speculate that end organ targeting might be improved in nerve injuries if axons can be directed to regenerate along specific tissue planes by a guide composed of 3D fiber arrays. PMID- 20727993 TI - Towards long-lasting antibacterial stainless steel surfaces by combining double glow plasma silvering with active screen plasma nitriding. AB - Antibacterial surface modification of biomedical materials has evolved as a potentially effective method for preventing bacterial proliferation on the surfaces of devices. However, thin antibacterial coatings or modified layers can be easily worn down when interacting with other surfaces in relative motion, thus leading to a low durability of the antibacterial surface. To this end, novel biomaterial surfaces with antibacterial Ag agents and a wear-resistant S-phase have been generated on stainless steel by duplex plasma silvering-nitriding techniques for application to load-bearing medical devices. The chemical composition, microstructure, surface topography, roughness and wettability of SS surfaces were characterised using glow discharge optical emission spectroscopy, energy-dispersive spectroscopy/wavelength dispersive spectrometry (WDS), X-ray diffraction, atomic force microscopy and a contact angle goniometer. Optimal surface design for high antimicrobial activity and prolonged durability has been achieved, as evidenced by rapid bacterial killing rates (within 6h), an ultra hard matrix (875 +/- 25 Hv), high load-bearing capacity (critical load 37 N) and excellent wear resistance (wear rate 4.9 * 10-6 mm3 m-1). Ag embedded in the hard substrate of fcc compounds M(4)N (M=Fe, Cr, Ag, etc.) and the expanded fcc nitrogen S-phase shows deep infiltration of 6 +/- 1 MUm, and provides bactericidal activity against both Gram-negative Escherichia coli NCTC 10418 and Gram-positive Staphylococcus epidermidis NCTC 11047 of over 97% and 90%, respectively, within 6h. The presence of silver in the surface before and after scratching under a progressive load applied up to 60 N using a diamond stylus was confirmed by WDS. PMID- 20727994 TI - Obstacles in initiating a new research project--reflection on medical research in UK. PMID- 20727995 TI - Model organisms--A historical perspective. AB - Much of our knowledge on heredity, development, physiology and the underlying cellular and molecular processes is derived from the studies of model, or reference, organisms. Despite the great variety of life, a common base of shared principles could be extracted by studying a few life forms, selected based on their amenability to experimental studies. Very briefly, the origins of a few model organisms are described, including E. coli, yeast, C. elegans, Drosophila, Xenopus, zebrafish, mouse, maize and Arabidopsis. These model organisms were chosen because of their importance and wide use, which made them systems of choice for genome-wide studies. Many of their genomes were between the first to be fully sequenced, opening unprecedented opportunities for large-scale transcriptomics and proteomics studies. PMID- 20727996 TI - Epidermal growth factor regulates PAI-1 expression via activation of the transcription factor Elk-1. AB - PAI-1 (plasminogen activator inhibitor-1) in breast cancer cells is involved in tumour development and metastasis of breast cancer cells. PAI-1 function and the regulation of its expression have been precisely investigated. Here we report that EGF, which promotes breast cancer tumour growth and survival, rapidly induces PAI-1 expression in the breast adenocarcinoma cell line MCF-7 through the activation of the transcription factor Elk-1. We have found that the PAI-1 promoter fragment (-140 to +173) containing the Ets consensus binding site is activated by Elk-1. Chromatin immunoprecipitation analysis confirms in vivo binding of Elk-1 to the PAI-1 promoter and demonstrates that Elk-1 phosphorylation on the Ets binding site is EGF-dependent. PMID- 20727998 TI - A novel series of anti-human glycophorin A (CD235a) antibodies defining five extra- and intracellular epitopes. AB - Glycophorin A (GPA, CD235a) is a major membrane glycoprotein and marker of cells of the erythroid lineage. It is also the target of Plasmodium falciparum and of influenza virus. We describe a novel series of 10 antibodies towards GPA, recognizing four extra- and intracellular peptide epitopes of this molecule (defined by epitope mapping) and one mixed peptide/carbohydrate epitope. All antibodies bind better to the desialylated than to the fully sialylated molecule, including those specific for the intracellular epitope. For some of the antibodies (representing all five epitopes) functional binding constants were determined by Surface Plasmon Resonance. The new panel complements the already known anti-glycophorin antibodies and offers several potential applications for, e.g., differential diagnosis of erythroleukemias, lineage analyses of erythroid cells, isolation of senescent erythrocytes, or a highly sensitive neuraminidase assay. PMID- 20727997 TI - Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. AB - Bisphosphonates stop bone loss by inhibiting the activity of bone-resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain the reduction in fracture incidence observed in patients treated with these agents. Recent research efforts provided an explanation to this dichotomy by demonstrating that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteoblast and osteocyte apoptosis. Work of our group, independently confirmed by other investigators, demonstrated that bisphosphonates are able to prevent osteoblast and osteocyte apoptosis in vitro and in vivo. This prosurvival effect is strictly dependent on the expression of connexin (Cx) 43, as demonstrated in vitro using cells lacking Cx43 or expressing dominant-negative mutants of the protein as well as in vivo using Cx43 osteoblast/osteocyte-specific conditional knock-out mice. Remarkably, this Cx43-dependent survival effect of bisphosphonates is independent of gap junctions and results from opening of Cx43 hemichannels. Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90(RSK) kinase and its substrates BAD and C/EBPbeta, resulting in inhibition of apoptosis. The antiapoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack antiresorptive activity are still able to inhibit osteoblast and osteocyte apoptosis in vitro. Furthermore, a bisphosphonate analog that does not inhibit osteoclast activity prevented osteoblast and osteocyte apoptosis and the loss of bone mass and strength induced by glucocorticoids in mice. Preservation of the bone-forming function of mature osteoblasts and maintenance of the osteocytic network, in combination with lack anticatabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in which decreased bone resorption is not desired. PMID- 20727999 TI - Anti-asthmatic effect of schizandrin on OVA-induced airway inflammation in a murine asthma model. AB - Asthma comprises a triad of reversible airway obstruction, bronchial smooth muscle cell hyperreactivity to bronchoconstrictors, and chronic bronchial inflammation. Clinical and experimental findings have established eosinophilia as a sign of allergic disorders. In the present investigation, we evaluated the anti asthmatic effects of schizandrin and its underlying mechanisms in an in vivo murine asthmatic model. To accomplish this, female BALB/c mice were sensitized and challenged with ovalbumin (OVA), and examined for the following typical asthmatic reactions: increased numbers of eosinophils and other inflammatory cells in bronchoalveolar lavage fluid (BALF); production of Th1 cytokines (such as tumor necrosis factor (TNF)-alpha in BALF); production of Th2 cytokines (such as interleukin IL-4 and IL-5) in BALF; presence of total and OVA-specific immunoglobulins (Ig)E in serum; presence of oxidative stress; hyperplasia of goblet cells in the lung; and marked influx of inflammatory cells into the lung. Our results collectively show that schizandrin exerts profound inhibitory effects on accumulation of eosinophils into the airways and reduces the levels of IL-4, IL-5, IFN-gamma, and TNF-alpha in BALF. Additionally, schizandrin suppresses the production of reactive oxygen species (ROS) in a dose-dependent manner, and inhibits goblet cell hyperplasia and inflammatory cell infiltration in lung tissue. Thus, schizandrin has anti-asthmatic effects, which seem to be partially mediated by reduction of oxidative stress and airway inflammation, in a murine allergic asthma model. These results indicate that schizandrin may be an effective novel therapeutic agent for the treatment of allergic asthma. PMID- 20728001 TI - Being bullied in childhood: correlations with borderline personality in adulthood. AB - OBJECTIVE: This study was designed to explore correlations between a history of being bullied in childhood and borderline personality disorder (BPD) in adulthood, several externalizing behaviors, and mental health care utilization. METHOD: Using a cross-sectional consecutive sample of internal medicine outpatients (N = 414), we examined the relationship between history of being bullied in childhood and 2 measures of BPD: the borderline personality scale of the Personality Diagnostic Questionnaire-4 and the Self-Harm Inventory. We also explored whether having ever been bullied was related to a number of externalizing behaviors (eg, rage reactions, road rage, excessive spending, alcohol and substance misuse, binge eating) as well as greater mental health care utilization. RESULTS: In this study, a history of being bullied in childhood demonstrated statistically significant correlations with both measures of BPD as well as a number of externalizing behaviors and the measures for mental health care utilization. CONCLUSIONS: A history of being bullied in childhood demonstrates a positive correlation with BPD in adulthood, externalizing behaviors, and mental health care utilization. Although this does not necessarily imply causality, the nature of this relationship warrants further investigation. PMID- 20728002 TI - Is the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, histrionic personality disorder category a valid construct? AB - PURPOSE: The study investigated crucial aspects of the construct validity of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) histrionic personality disorder (HPD) category. MATERIAL AND METHODS: The study included 2289 patients from the Norwegian Network of Psychotherapeutic Day Hospitals. Construct validity was assessed by means of prevalence, comorbidity with other personality disorders, internal consistency among HPD criteria, severity indices, as well as factor analyses. RESULTS: The prevalence of HPD was very low (0.4 %). The comorbidity was high, especially with borderline, narcissistic, and dependent personality disorders. The internal consistency was low. The criteria seemed to form 2 separate clusters: the first contained exhibitionistic and attention-seeking traits and the other contained impressionistic traits. CONCLUSION: The results indicated poor construct validity of the HPD category. Different options for the future of the category are discussed. The authors suggest the HPD category to be deleted from the DSM system. However, the clinical phenomena of exhibitionism and attention-seeking, which are the dominant personality features of HPD, should be preserved in an exhibitionistic subtype of narcissism. PMID- 20728000 TI - The impact of comorbid dysthymic disorder on outcome in personality disorders. AB - OBJECTIVE: The goal of our study was to investigate the impact of dysthymic disorder (DD), a form of chronic depression, on naturalistic outcome in individuals with personality disorders (PDs). METHOD: The Collaborative Longitudinal Personality Disorders Study is a cohort initially including 573 subjects with 4 targeted PDs (borderline, avoidant, schizotypal, and obsessive compulsive) and 95 subjects with major depression but no PD. At baseline, 115 subjects were diagnosed with coexisting DD, of whom 109 (94.8%) were PD subjects. Regression analyses were performed to predict 3 classes of broad clinical outcome after 2 years of prospective follow-up. We hypothesized that DD diagnosis at baseline would be associated with worse outcome on (1) persistence of a PD diagnosis, (2) impairment in psychosocial functioning (as measured by the Longitudinal Interval Follow-up Evaluation), and (3) crisis-related treatment utilization. RESULTS: Baseline DD diagnosis was associated with persistence of PD diagnosis at 2 years, particularly for borderline and avoidant PDs. It was associated with worse outcome on global social adjustment, life satisfaction, recreation, and friendships, but not employment or relationship with spouse. Contrary to expectation, DD did not increase suicide attempts, emergency room visits, or psychiatric hospitalizations. CONCLUSIONS: Comorbidity of DD is associated with persistence of PD diagnosis and with worse outcome on many, but not all, measures of psychosocial functioning. PMID- 20728003 TI - Neurocognition in schizophrenia: a 20-year multi-follow-up of the course of processing speed and stored knowledge. AB - Individuals with schizophrenia have relative deficits in cognition, although little is known regarding the course of such deficits across the life span and at various stages of the illness. Furthermore, the relationship between psychosis and cognition has not been adequately explored to this point. Prospective, longitudinal, multi-assessment studies of the same patients across time are rare in the field and provide a unique opportunity to examine long-term changes in cognition among individuals with schizophrenia. As part of The Chicago Follow-up Study, we prospectively assessed 244 psychiatric inpatients, including individuals with schizophrenia, other psychotic disorders, and nonpsychotic depression. Assessments were conducted 7 times (once at index hospitalization and then 6 times subsequently for the next 20 years) to provide longitudinal data about cognition and symptoms, with a focus on 2 aspects of cognition: processing speed and the ability to access general knowledge. The Digit Symbol-Coding and Information subtests from the Wechsler Adult Intelligence scale were used to measure the 2 cognitive domains at each assessment. At all 7 assessments, individuals with schizophrenia performed more poorly than the other diagnostic groups on the 2 cognitive measures. However, after the acute phase (index hospitalization), individuals with schizophrenia demonstrated significant improvements in cognition and did not show evidence of cognitive decline over the remaining 6 assessments spanning 20 years. Our data support the presence of relative cognitive impairment in schizophrenia, as well as a pattern of stability in some cognitive areas after the acute phase. In addition, we find evidence for an association between relative cognitive impairment and psychosis. PMID- 20728004 TI - Risk factors for delaying treatment seeking in obsessive-compulsive disorder. AB - BACKGROUND: Despite the multiple alternatives of treatment, it is well known that patients with obsessive-compulsive disorder (OCD) delay seeking treatment. In this study, the aim was to determine the risk factors for delaying treatment seeking in OCD patients. METHODS: The sample consisted of 132 OCD who completed the Yale-Brown Obsessive-Compulsive Scale, Yale-Brown Obsessive-Compulsive Scale Symptom Checklist, and Beck Depression Inventory. RESULTS: In univariate analyses with risk evaluation, income level, being single or divorced, having a history of psychiatric treatment, poor insight for the symptoms, and obsessions of hoarding were the variables that were found to be significant. In the regression model, history of psychiatric treatment and duration of OCD were the 2 variables that remained statistically significant. CONCLUSION: This was the first study wherein the sample included patients who were recruited from a nonpsychiatric department: the dermatology clinic. Application to dermatology has not been determined as a risk factor for delaying treatment seeking in OCD patients. PMID- 20728005 TI - Severity of affective temperament and maladaptive self-schemas differentiate borderline patients, bipolar patients, and controls. AB - OBJECTIVES: There is an unsettled debate on whether borderline personality disorder and bipolar disorder should be considered related or distinct. This study aimed to further the understanding of the similarities and differences between the 2 disorders by comparing borderline patients, bipolar patients, and controls in terms of various affective temperaments and maladaptive self-schemas. METHODS: The sample consisted of 85 participants (31 borderline patients, 25 bipolar patients and 29 student controls) who completed 2 questionnaires: The Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire and the Young Schema Questionnaire. All of the patients were in remission from affective episodes. RESULTS: Compared to the bipolar patients and the controls, the borderline patients were characterized by significantly higher mean scores on most of the maladaptive self-schemas and affective temperaments. The bipolar patients differed significantly from controls by higher mean scores on the cyclothymic temperament and insufficient self-control. CONCLUSIONS: The study suggests that affective temperaments and maladaptive self-schemas are more severe in borderline patients than in bipolar patients. These findings point to phenomenological differences between the 2 disorders and therefore question their degree of kinship. PMID- 20728006 TI - Psychological mindedness and symptom reduction after psychotherapy in a heterogeneous psychiatric sample. AB - BACKGROUND: Psychological mindedness (PM) has been claimed to be beneficial for outcome of various forms of psychotherapy. The purpose of this study was to investigate the influence of PM on the therapy results of a psychiatric patient sample with heterogeneous psychological symptoms. METHODS: Participants were 110 patients with different diagnoses who were hospitalized at the Center for Psychological Recovery (Rosmalen, Netherlands). Before and after treatment, they were asked to complete the Balanced Index of Psychological Mindedness and the Symptom Checklist-90. RESULTS: Baseline PM was not associated with a decrease in symptom scores (F(8,73) < 1.0; P > .20; partial eta(2) < 0.10). However, PM increased over the course of the intervention (F(2,84) = 43.54; P < .001; eta(2) = 0.51) and larger increases in the insight component of PM were associated with larger decreases on 6 of 8 symptom scores (F(8,70) = 3.55; P < .005; partial eta(2) = 0.29). CONCLUSIONS: These results suggest that although a high PM is not a prerequisite for successful cognitive behavioral therapy, an increase in insight is associated with better outcome. PMID- 20728007 TI - Psychosocial predictors of mood symptoms 1 year after acute phase treatment of bipolar I disorder. AB - OBJECTIVE: The aim of the current study was to evaluate family functioning, social support, and functional impairment as predictors of mood symptoms 1 year after acute phase treatment of bipolar I disorder. This study builds upon the extant literature by evaluating these putative psychosocial risk factors simultaneously to determine whether they account for unique variance in clinical outcomes. METHOD: Patients (N = 92) were recruited from hospital settings during an acute mood episode to participate in pharmacologic or combined family and pharmacologic interventions. The Modified Hamilton Rating Scale for Depression, Bech-Rafaelson Mania Scale, Family Assessment Device, Interpersonal Support Evaluation List, and UCLA Social Attainment Survey were administered at acute phase treatment completion and again at 1-year follow-up. Controlling for mood symptom severity at acute phase treatment completion, multiple regression analyses were used to examine longitudinal associations between the psychosocial variables and subsequent depressive and manic symptoms. RESULTS: None of the aforementioned psychosocial variables predicted manic symptomatology, and social support alone emerged as a unique predictor of depression at the 1-year follow up. Effects of social support were moderated by recovery status, such that the strength of association between social support and subsequent depression was stronger for those who had not fully recovered during the acute phase of treatment than for those who had. CONCLUSIONS: Low levels of social support at acute phase treatment completion, especially in concert with residual symptomatology, may place individuals with bipolar I disorder at risk for subsequent depressive symptoms. These data suggest that maintenance therapies focused on improving level of social support might be especially important to consider in the management of bipolar depression, and add to a growing literature focused on unique vs shared effects of psychosocial risk factors for poor illness course in bipolar disorder. PMID- 20728008 TI - A prospective study of the impact of smoking on outcomes in bipolar and schizoaffective disorder. AB - BACKGROUND: Tobacco smoking is more prevalent among people with mental illnesses, including bipolar disorder, than in the general community. Most data are cross sectional, and there are no prospective trials examining the relationship of smoking to outcome in bipolar disorder. The impact of tobacco smoking on mental health outcomes was investigated in a 24-month, naturalistic, longitudinal study of 240 people with bipolar disorder or schizoaffective disorder. METHOD: Participants were interviewed and data recorded by trained study clinicians at 9 interviews during the study period. RESULTS: Comparisons were made between participants who smoked daily (n = 122) and the remaining study participants (n = 117). During the 24-month study period, the daily smokers had poorer scores on the Clinical Global Impressions-Depression (P = .034) and Clinical Global Impressions-Overall Bipolar (P = .026) scales and had lengthier stays in hospital (P = .012), compared with nonsmokers. LIMITATIONS: Smoking status was determined by self-report. Nicotine dependence was not measured. CONCLUSION: These findings suggest that smoking is associated with poorer mental health outcomes in bipolar and schizoaffective disorder. PMID- 20728009 TI - Association between Novelty Seeking of opiate-dependent patients and the catechol O-methyltransferase Val(158)Met polymorphism. AB - BACKGROUND: Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val(158)Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers. METHOD: Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val(158)Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls. RESULTS: Case control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val(158)Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype. CONCLUSION: Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status. PMID- 20728010 TI - Symptoms of disordered eating, body shape, and mood concerns in male and female Chinese medical students. AB - OBJECTIVE: This cross-sectional study explored the prevalence of disordered eating attitudes, body shape concerns, and social anxiety and depressive symptoms in male and female medical students in China. METHOD: Four hundred eighty-seven students from Central South University (Hunan Province, Changsha City, China) completed the following self-report measures: Eating Attitudes Test-26, Eating Disorders Assessment Questionnaire, Body Shape Questionnaire, Swansea Muscularity Attitudes Questionnaire, Social Interaction Anxiety Scale, and the Self-Rating Depression Scale. RESULTS: A comparatively lower rate of at-risk eating attitudes (2.5%) and eating disorders (0.90%) were found compared to those reported in other studies. Significantly more female (3.2%) than male (1.2%) students had abnormal eating attitudes with 4 female students meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for bulimia nervosa. Significant relationships were observed between eating attitudes, body shape concern, social anxiety, depression, and body mass index. For females, the most significant correlate of distorted eating attitudes was body shape concern, whereas for male students, social anxiety and concern with muscle size and shape were most strongly correlated with distorted eating attitudes. PMID- 20728011 TI - Familial aggregation of personality disorder: epidemiological evidence from high school students 18 years and older in Beijing, China. AB - BACKGROUND: There has been evidence from Western countries of the familial aggregation of personality disorder (PD) in clinical populations. Nonetheless, it is not clear if the results apply to nonclinical population or non-Western countries. The aim of this study is to provide evidence about the familial aggregation of PD using an epidemiological sample of high school students and their parents in Beijing, China. METHOD: A sample of high school students (at least 18 years old) and their parents was drawn by stratified cluster sampling. Personality disorder in students was assessed via a two-stage approach, Personality Diagnostic Questionnaire (PDQ) as a screening tool and International Personality Disorder Examination as the diagnostic tool. Parents completed the PDQ. Univariate and multivariate analyses were used to address the familial aggregation of PD. RESULTS: Students' PDQ scores were correlated with parents' PDQ scores. Parents of PD students scored higher in PDQ and were more likely to be PD cases than controls' parents (adjusted odds ratio, 6.4-18.8). LIMITATIONS: Student controls and parents are only assessed by PDQ-4. CONCLUSION: Obvious familial aggregation of PD was observed in this study. Psychiatrists may consider asking about family history when diagnosing PD. PMID- 20728012 TI - Psychiatric, behavioral, and attitudinal correlates of avoidant and obsessive compulsive personality pathology in patients with binge-eating disorder. AB - OBJECTIVE: We examined correlates of avoidant and obsessive-compulsive personality pathology--with respect to psychiatric comorbidity, eating disorder psychopathology, and associated psychologic factors--in patients with binge eating disorder (BED). METHOD: Three hundred forty-seven treatment-seeking patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), research criteria for BED were reliably assessed with semistructured interviews to evaluate DSM-IV Axis I disorders, personality disorders, and behavioral and attitudinal features of eating disorder psychopathology. RESULTS: Fifteen percent of subjects had avoidant personality disorder features, 12% had obsessive-compulsive personality disorder features, 8% had features of both disorders, and 66% had features of neither. These groups differed significantly in the frequencies of depressive and anxiety disorders, as well as on measures of psychologic functioning (negative/depressive affect and self-esteem) and eating disorder attitudes (shape and weight concerns). There were no group differences on measures of eating behaviors. The avoidant and obsessive-compulsive groups had more psychiatric comorbidity than the group without these personality features but less than the combined group. The group without these features scored significantly lower than all other groups on negative/depressive affect and significantly higher than the avoidant and combined groups on self-esteem. The combined group had the greatest severity on shape and weight concerns. CONCLUSIONS: Avoidant and obsessive-compulsive personality features are common in patients with BED. Among BED patients, these forms of personality psychopathology--separately and in combination--are associated with clinically meaningful diagnostic, psychologic, and attitudinal differences. These findings have implications for the psychopathologic relationship between BED and personality psychopathology and may also have implications for assessment and treatment. PMID- 20728013 TI - Personality correlates of impulsivity in subjects with generalized anxiety disorders. AB - BACKGROUND: As yet, the relation between personality traits and impulsiveness has not been investigated in subjects affected by generalized anxiety disorder (GAD). METHOD: A sample of 79 subjects with a diagnosis of GAD has been assessed at intake with Clinical Global Impression (CGI), Barratt Impulsiveness Scale (BIS 11), and with Temperament and Character Inventory. Comorbidity with cluster A or B personality disorders was excluded. RESULTS: A multiple linear regression has identified 3 variables as independent predictors of impulsiveness: novelty seeking (NS) and reward dependence (RD) as for temperament and self-directedness (SD) as for character. Predictor analysis of the 3 subscales of BIS-11 showed that a higher NS is a predictor of all 3 subscales of BIS-11, whereas a higher RD is a protective factor for the attentive impulsiveness, and a low SD is predictive of a greater nonplanned impulsiveness. The CGI severity index is directly related to motor impulsiveness. DISCUSSION: Preliminary results showed that in subjects with GAD only the motor component of impulsivity seems directly related to clinical severity, whereas impulsiveness is predicted by higher levels of 2 temperamental dimensions that are influenced by dopamine and norepinephrine systems and by weakness of character. CONCLUSION: Subjects with GAD showed an interesting variability in NS. Differences in levels of NS and of other temperament (RD) and character (SD) dimensions seem related to different degrees of behavioral inhibition and to a different impact of the cognitive components of impulsiveness. Clinical implications are discussed. PMID- 20728014 TI - Sex differences in prepsychotic "prodromal" symptomatology and its association with Positive and Negative Syndrome Scale active phase psychopathology in male and female patients. AB - BACKGROUND: A wide spectrum of prodromal symptoms has been reported, but their association with the severity of the active phase psychopathology in relationship to sex is unknown. METHOD: Seventy-three (47 male) Diganostic and Statistical Manual (DSM) schizophrenia patients were subjected to the structured clinical interview for Positive and Negative Syndrome Scale (PANSS). Prodromal symptoms were recorded retrospectively after psychotic phase had subsided. RESULTS: Thirty eight prodromal symptoms were identified. All symptoms appeared in both sexes. However, there was a significantly greater frequency of 3 symptoms (odd beliefs/magical thinking, over elaborate speech, hyperacusia) in female patients and of 2 symptoms (marked peculiar behavior, aggressiveness) in male patients. In the female patients, 9 symptoms were associated with an increased risk for severe total and components of the PANSS psychopathology in the psychotic phase; 2 symptoms were associated with a mild negative subscale psychopathology. In the male patients, 6 symptoms were associated with the severity of the PANSS psychopathology; 5 carried an increase risk for severe and 1 was associated with mild psychopathology. Also, the risk for severe PANSS positive, general, and total psychopathology increased with the increasing number of total and less specific symptoms in the female but not in the male patients. CONCLUSIONS: Sex differences in schizophrenia are extended into the prepsychotic stage. Also, the presence of certain prodromal symptoms, different in men and women, and the number of symptoms in female patients are associated with the severity of the psychotic phase psychopathology. Evaluation of early therapeutic interventions in prodromal phase should consider sex and spectrum of prodromal symptoms. PMID- 20728015 TI - Screening for bipolar disorders in Spanish-speaking populations: sensitivity and specificity of the Bipolar Spectrum Diagnostic Scale-Spanish Version. AB - BACKGROUND: Bipolar disorder is commonly misdiagnosed, perhaps more so in Latin American and Spanish-speaking populations than in the United States. The Bipolar Spectrum Diagnostic Scale (BSDS) is a 19-item screening instrument designed to assist in screening for all types of bipolar disorder. METHODS: The authors investigated the sensitivity of a Spanish-language version of the BSDS in a cohort of 65 outpatients with a diagnosis of bipolar disorder, based on a semi structured interview and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. To determine specificity, we assessed a control group of 36 outpatients with diagnosis of unipolar major depressive disorder. RESULTS: The overall sensitivity of the BSDS Spanish version with bipolar disorders types I, II, and NOS was 0.70, which was slightly lower than the sensitivity in the study using the English version of the BSDS (0.76). The specificity was 0.89. When the threshold was decreased from 13 to 12, the sensitivity of the Spanish BSDS increased to 0.76 and specificity dropped to 0.81. CONCLUSION: The Spanish version of the BSDS is promising as a screening instrument in Spanish-speaking populations. PMID- 20728017 TI - Drug-induced QT interval shortening: an emerging component in integrated assessment of cardiac safety of drugs. PMID- 20728018 TI - Short and long QT syndromes: does QT length really matter? AB - The short and long QT syndromes are inherited diseases associated with an increased risk for life-threatening arrhythmias. The first case of long QT syndrome (LQTS) was reported more than 150 years ago, and the study of this disease led to crucial advancement of our understanding of channelopathies and associated ventricular arrhythmias. Ten years ago, Gussak et al. reported four cases of idiopathic ventricular fibrillation in individuals from a family with a history of sudden cardiac death exhibited very short QT interval and labeled the disease: short QT syndrome (SQTS). Over this decade, the SQTS was found to be a rare inherited syndrome with the potential to provide novel insights into the main mechanisms of cardiac arrhythmogenicity. In this review, we discuss these mechanisms and provocatively question the role of the QT interval duration as a surrogate marker of increased risk for arrhythmia in both the LQTS and the SQTS. PMID- 20728019 TI - Type 1 electrocardiographic burden is increased in symptomatic patients with Brugada syndrome. AB - BACKGROUND: Spontaneous type 1 electrocardiographic (ECG) is a risk factor for arrhythmic events in Brugada patients but the importance of the proportion of time with a type 1 ECG is unknown. PATIENTS AND METHODS: Thirty-four Brugada patients (15 symptomatic) underwent a 24-hour 12-lead ECG recording. One-minute averaged waveforms displaying ST-segment elevation above 200 microV, with descending ST-segment and negative T-wave polarity on leads V(1)-V(3) were considered as type 1 Brugada ECG. The burden was defined as the percentage of type 1 Brugada waveforms. RESULTS: Type 1 ECG on lead V2 was more frequent in symptomatic patients (median 80.6% [15.7-96.7] vs 12.4% [0.0-69.7], P = .05). Patients with a permanent type 1 pattern on lead V(2) were more likely to be symptomatic (5/6) than patients without type 1 ECG during a 24-hour period (2/9) (P < .05). CONCLUSION: Type 1 pattern is more prevalent across a 24-hour period in symptomatic Brugada patients. PMID- 20728020 TI - Late potential at the high ventricular septal level in a patient with Brugada: possible mechanisms and clinical implications. AB - The Brugada syndrome (BS) accounts for approximately 20% of cases of sudden cardiac death in patients with structurally normal hearts. The electrophysiologic basis for ST-segment elevation in the precordial electrocardiogram (ECG) leads that characterize the Brugada phenotype and its strong linkage to ventricular tachycardia (VT)/ventricular fibrillation is still a subject of controversy. Electrocardiographic manifestations of the syndrome have been attributed to one of two basic mechanisms: (1) conduction delay in the right ventricular (RV) epicardial-free wall in the region of the outflow tract or (2) premature repolarization of the RV epicardial action potential secondary to loss of the action potential dome. Signal-averaged ECG recordings have demonstrated late potentials that extend beyond the QRS complex in patients with the BS, especially in the anterior wall of the RV outflow tract. The basis for these epicardial late potentials remains a subject of interest among basic and clinical electrophysiologists. Endocardial late potentials in BS are even less well understood. We present a case of a patient with Brugada syndrome with a distinct endocardial late potential in the high ventricular septum coinciding with the ST segment elevation. We discuss the possible mechanisms for this intracardiac finding and its clinical significance. We also review the effect of isoproterenol infusion on both the late potential and the surface ECG. PMID- 20728021 TI - Quercetin up-regulates paraoxonase 1 gene expression via sterol regulatory element binding protein 2 that translocates from the endoplasmic reticulum to the nucleus where it specifically interacts with sterol responsive element-like sequence in paraoxonase 1 promoter in HuH7 liver cells. AB - We previously showed that quercetin expresses its antiatherogenic effects by up regulating paraoxonase 1 (PON1) gene and high-density lipoprotein's protective capacity against low-density lipoprotein oxidation. In an attempt to elucidate the mechanism of action of quercetin, we have now determined the effects of quercetin on PON1 gene expression, activity, protein level, nuclear mature sterol regulatory element binding protein 2 (SREBP2) level, and its translocation from the endoplasmic reticulum to nucleus and its interaction with PON1 promoter in human HuH7 liver cells using real-time reverse transcriptase polymerase chain reaction, spectrophotometry, immunoblot, confocal microscopy, and electrophoretic mobility shift assay techniques, respectively. Quercetin (20 micromol/L) treatment increased PON1 messenger RNA by 75% (P < .02), with a concomitant 2 fold (P < .05) increase in PON1 activity accompanied by 60% (P < .01) increase in PON1 protein level. There was parallel to the 1.5- to 2.0-fold increase (P < .05) in mature SREBP2 in the cell nuclei that was verified by increased immunolocalization of the mature SREBP2 (65-kd species) in the nuclei of quercetin-treated cells by confocal microscopy. Evaluation of the binding of biotin-labeled sterol responsive element (SRE)-like element of the PON1 promoter to the nuclear extract from the 24-hour quercetin (20 micromol/L)-treated HuH7 cells by electrophoretic mobility shift assay revealed that the SREBP2 specifically binds to the SRE-like element that was abolished by prior incubation with anti-SREBP2 or significantly decreased by 200-fold molar excess of unlabeled SRE-like sequence. Based on these results, we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity. PMID- 20728022 TI - The role of innate immunity in B cell acquisition of antigen within LNs. AB - Over the past decade, it has become apparent that B cells acquire antigens primarily from membrane surfaces and that uptake is an active process involving a synapse between the B cell receptor, coreceptor, and the antigen surface. However, understanding how antigens are delivered to follicular dendritic cells (FDC), which are the primary depot for B cell antigen within the lymph node follicles, is only recently beginning to be dissected. The application of fluorescent-based imaging techniques such as multiphoton intravital microscopy to visualize trafficking of B cells and antigens into draining lymph nodes has provide insights that would not otherwise be made. At least three novel pathways for transport of lymph-borne antigens to the B cell compartment have been identified. Based on these studies, a new paradigm of how lymphocytes and antigens traffic within the peripheral lymph nodes is evolving. Understanding how the physical properties of the antigen influences its uptake and processing could be relevant in the design of new vaccines. PMID- 20728023 TI - Nuclear receptors, inflammation, and neurodegenerative diseases. AB - Chronic inflammation is associated with many neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Increasing evidence that neuroinflammation contributes to disease severity has generated considerable interest in determining whether inhibition of inflammation pathways might be of therapeutic benefit. One potential avenue of intervention is provided by members of the nuclear receptor superfamily of ligand-dependent transcription factors that exert anti-inflammatory effects in many cell types. Here, we review recent studies providing insights into the distinct mechanisms that enable nuclear receptors to modulate immune responses, describe inflammatory components of neurodegenerative diseases, and discuss recent literature relevant to roles of nuclear receptors in influencing these processes. PMID- 20728024 TI - Novel tools for modulating immune responses in the host-polysaccharides from the capsule of commensal bacteria. AB - The intestinal microflora of mammals includes organisms with many unique molecules that enable them to modulate their immediate environment and thus to survive and reside successfully in the gut. Little is known about how individual molecules from these microbes affect the host's health and development, but the microbiome is considered a crucial factor in intestinal homeostasis. The literature highlights numerous ways in which the microflora stimulates the mammalian host's immune system, starting with its development and continuing to the initiation and resolution of inflammation. The influence of the microflora on the host's immune system is mediated principally by interactions with various antigen-presenting cells of the gut; these interactions result in substantial modulation of both the innate and the adaptive arms of the immune system. Certain polysaccharide antigens from the capsules of some commensal bacteria represent a functional class of molecules that exert profound immunomodulatory effects. Because of their unique structural features, including a zwitterionic charge motif, these polysaccharides can participate to a significant extent in the orchestration of host immune homeostasis. These molecules can be used to elucidate the basic biology of the mammalian intestine and have the potential for use in novel therapeutic regimens for various systemic or intestinal pathological conditions. PMID- 20728027 TI - Complications of frontal sinus fractures with emphasis on chronic craniofacial pain and its treatment: a review of 43 cases. AB - PURPOSE: Frontal sinus fractures constitute 5% to 12% of all facial fractures. The optimal management of frontal sinus fractures is controversial but involves preserving the function of the nasofrontal ducts when feasible. We reviewed the postoperative complications of a series of 43 patients treated surgically for frontal sinus fractures. MATERIALS AND METHODS: The data from 43 patients treated from 2000 to 2006 were reviewed. The information reviewed included patient age and gender, mechanism of injury, type of frontal sinus injury, associated facial injuries, treatment method, and complications. The institutional review board approved the present study. RESULTS: The average patient age was 32.5 years; 36 were men and 7 were women. Of the 43 patients, 23 (53.5%) had had anterior table fractures and 20 (46.5%) had had both anterior and posterior table fractures. Postoperative complications occurred in 7 patients (16.3%). Of these 7 patients, 2 experienced continued headache and pain and required surgical removal of infected hardware, 3 also experienced frequent headaches and pain in the frontal temporal region, 1 had a post-traumatic deformity, and 1 developed periorbital cellulitis and abscess formation within the frontal sinus. CONCLUSION: Frequent headaches and complaints of continued pain were the most common complications experienced by our series of patients. We also reviewed treatment strategies for postoperative follow-up and treatment of chronic pain. PMID- 20728028 TI - Effect of substance P in mandibular osteotomies after amputation of the inferior alveolar nerve. AB - PURPOSE: The aims of this experiment were to study the effect and possible mechanism of substance P (SP) in the mandibular osteotomy healing process through inferior alveolar nerve (IAN) amputation. MATERIALS AND METHODS: Thirty-two adult China white rabbits were randomly divided into 2 groups (experimental and control). An osteotomy in the left mandible was created and concomitantly the experimental group underwent IAN amputation. The rabbits were sacrificed 7, 14, 21, and 28 days after operation, and specimens were collected and stained with hematoxylin and eosin and for immunohistochemistry to observe the expression of SP in bone callus and the process of osteotomy healing. Semiquantitative analysis on immunohistochemically stained slices was performed using computer image analysis. RESULTS: There was a larger amount of fibrous callus formation, relatively immature woven bone callus, and a smaller proportion between matured bone callus and woven bone in the group subjected to IAN amputation than in the controls at each stage, especially in the late stages. Immunoreactivities of SP occurred weakly 7 and 14 days after operation and became stronger gradually in the late stage in the experimental group. Stronger immunoreactivities of SP occurred 7 and 14 days after operation and less on day 21 after trauma and became strongest on day 28 after trauma in the control group. The strongest immunoreactivities at each stage occurred on day 28 after trauma in both groups. CONCLUSION: SP secreted by IAN may be very important to initiate and modulate the process of repair and remodeling of bone. PMID- 20728029 TI - Postoperative condylar position by sagittal split ramus osteotomy with and without bone graft. AB - PURPOSE: The purpose of the present study was to determine how the condylar position is affected by the bone graft in the intersegmental space created by sagittal split ramus osteotomy. PATIENTS AND METHODS: We compared the position of the condyle after sagittal split ramus osteotomy, without the bone graft (control group, n = 30) and with the bone graft (study group, n = 30) using computed tomography with a 2-mm thickness. Using 3-dimensional images and a 3-dimensional computer program, the pre- and postoperative displacement and rotation of the condyle in the axial (rotation and mediolateral movement of the condyle) and sagittal plane (anteroposterior and superoinferior movement of the condyle and rotation of the proximal segment) were measured. In addition, the relationship of the amount of rotation and backward movement of the mandible and the change in the condylar position was analyzed. For the statistical analysis, the t test (P = .05) and Wilcoxon rank sum test were used. RESULTS: No statistically significant differences were found in any of the measurements of the 2 groups. Nevertheless, the mediolateral movement (P = .051) showed a relatively greater apparent difference, although the difference was not statistically significant. The condylar displacement had no relationship to the rotation of the mandible. However, the condylar displacement in relation to the amount of backward movement of the mandible was significant, especially when it was greater than 10 mm of setback. CONCLUSIONS: Using a bone graft in the intersegmental gap of a sagittal split ramus osteotomy is considered an effective clinical method to secure the desirable intersegmental position because it helps to maintain the space with ease. Especially in cases with greater than 10-mm setback of the mandible, it prevents excessive condylar displacement. PMID- 20728030 TI - Superficial parotidectomy versus retrograde partial superficial parotidectomy in treating benign salivary gland tumor (pleomorphic adenoma). AB - PURPOSE: Of all benign salivary gland tumors of the parotid gland, pleomorphic adenoma (mixed tumor) is the most common. It accounts for 60% to 70% of all benign tumors of the parotid gland. This neoplasm arises in patients in the fourth to sixth decade of life, with a female predominance. The surgical excision of this lesion continues to be the subject of major debate. The goal is to avoid facial disability yet attain complete resection without perforation of the capsule/pseudocapsule. The purpose of our study is to compare 2 surgical techniques performed at the Ear, Nose, and Throat and Maxillofacial Departments, Rambam Medical Center, Haifa, Israel, and determine which is preferable in treating this lesion. PATIENTS AND METHODS: We reviewed 48 patients who underwent excision of pleomorphic adenoma of the parotid gland between 1996 and 2005 at Rambam Medical Center: 18 were treated surgically with the classical superficial parotidectomy (SP) technique, using an anterograde approach, and 30 were treated with retrograde partial superficial parotidectomy (PSP). We compared the 2 surgical techniques in terms of surgical time, histopathologic size of the lesion, amount of excised healthy parotid tissue, histologic margin, and the preservation of the capsule/pseudocapsule. We also made clinical records of temporary or definitive injury to the facial nerve, which branches of the facial nerve were temporarily or definitively injured, the occurrence of Frey syndrome, esthetic satisfaction, and the amount of recurrence or infection after surgery. RESULTS: Of the 48 patients, 19 (39.6%) were male and 29 (60.4%) were female, with a mean age (+/- SD) of 43.8 +/- 16.97 years (median, 50 years; range, 12-79 years). We found a significant difference (P = .029) in mean surgical time (+/- SD): 171 +/- 49.7 minutes (median, 165 minutes) when performing the classical SP and 145 +/- 42.7 minutes (median, 130 minutes) when performing the retrograde PSP. Much more healthy parotid tissue was taken out with the classical procedure (mean, 51.4 +/- 13.6 mm; median, 50 mm) than with the retrograde PSP technique (mean, 39.2 +/- 11.8; median, 35 mm) (P = .01). There was a significant difference (P = .0003) in facial nerve injuries: 39% of patients did not report any facial deficit in the SP group compared with 90% in the PSP group. In the SP group, only 3 patients reported a permanent deficit, and in the PSP group, only 3 patients had a temporary deficit (compared with 8 in the SP group). The main injuries occurred in the mandibular branch with both techniques: 6 SP and 2 PSP. There was no difference in esthetic satisfaction: 72.2% of patients in the SP group and 80% in the PSP group had no esthetic complaints. In the SP group, patients mainly complained about swelling (3 patients), and in the retrograde PSP group, the main complaint was depression (4 patients). Frey syndrome was found in 9 patients in the retrograde PSP group and 4 in the classical SP group (with an overall rate of 27.7%). The lesion recurred in only 2 patients--1 in each group. CONCLUSION: With both of the techniques, we found satisfactory results. In the majority of cases, retrograde PSP is a superior technique to the classical SP, although Frey syndrome is more often observed with the former. PMID- 20728025 TI - The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. AB - Recurrent chromosomal abnormalities, especially chromosomal translocations, are strongly associated with certain subtypes of leukemia, lymphoma and solid tumors. The appearance of particular translocations or associated genomic alterations can be important indicators of disease prognosis, and in some cases, certain translocations may indicate appropriate therapy protocols. To date, most of our knowledge about chromosomal translocations has derived from characterization of the highly selected recurrent translocations found in certain cancers. Until recently, mechanisms that promote or suppress chromosomal translocations, in particular, those responsible for their initiation, have not been addressed. For translocations to occur, two distinct chromosomal loci must be broken, brought together (synapsed) and joined. Here, we discuss recent findings on processes and pathways that influence the initiation of chromosomal translocations, including the generation fo DNA double strand breaks (DSBs) by general factors or in the context of the Lymphocyte-specific V(D)J and IgH class-switch recombination processes. We also discuss the role of spatial proximity of DSBs in the interphase nucleus with respect to how DSBs on different chromosomes are justaposed for joining. In addition, we discuss the DNA DSB response and its role in recognizing and tethering chromosomal DSBs to prevent translocations, as well as potential roles of the classical and alternative DSB end-joining pathways in suppressing or promoting translocations. Finally, we discuss the potential roles of long range regulatory elements, such as the 3'IgH enhancer complex, in promoting the expression of certain translocations that are frequent in lymphomas and, thereby, contributing to their frequent appearance in tumors. PMID- 20728031 TI - A retrospective analysis of peripheral odontogenic fibroma in an Iranian population. AB - PURPOSE: The aim of this study was to assess the relative frequency of peripheral odontogenic fibroma (POdF) in an Iranian population and to compare the obtained data with previous reports. MATERIALS AND METHODS: Archival material was retrospectively analyzed from 1967 to 2007, and all microscopic slides of lesions considered in the differential diagnosis of POdF were retrieved. A diagnosis of POdF was made according to the criteria described by the World Health Organization in 2005. Demographic data, including age, gender, site of involvement, and previous history of POdF, were recorded for all samples with a diagnosis of this neoplasm. RESULTS: Nineteen POdFs were identified, which accounted for 0.14% of the archival cases. One of these tumors was a recurrence, diagnosed 12 months earlier. All cases were of the epithelium-rich or World Health Organization histologic subtype and most tumors occurred in the mandible. No significant difference in the prevalence of POdF was found between the studied variables. Among the 18 primary neoplasms, follow-up was possible for 2 to 13 years in 6 cases, and none developed recurrence. CONCLUSION: Similar to previous investigations, this study shows that POdFs are uncommon odontogenic lesions. Detailed information on POdF is limited because of its rarity; therefore, this study may provide additional data for further investigations and may enable better understanding of this tumor. PMID- 20728032 TI - Radiographic findings in bisphosphonate-treated patients with stage 0 disease in the absence of bone exposure. AB - PURPOSE: Radiographic features in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) are well described, but less is known in bisphosphonate-exposed individuals with stage 0 disease (clinical symptoms without exposed necrotic bone) considered at risk for BRONJ. We sought to characterize radiographic findings in a subgroup of patients with concerning clinical symptoms and bisphosphonate exposure to identify imaging features that may presage development of BRONJ. MATERIALS AND METHODS: A dental symptom survey was returned by 8,572 Kaiser Permanente Health Plan members receiving chronic oral bisphosphonate therapy, and 1,005 patients reporting pertinent dental symptoms or complications after dental procedures were examined. Those without BRONJ but with concerning symptoms were referred for clinical evaluation, including imaging. Among the subset who received maxillofacial imaging, we identified those with stage 0 disease and abnormal radiographic features. RESULTS: There were a total of 30 patients without exposed bone but with concerning symptoms who received maxillofacial imaging (panoramic radiography or computed tomography) in the context of clinical care. Among these 30 patients, 10 had stage 0 disease with similar radiographic features of regional or diffuse osteosclerosis in clinically symptomatic areas, most with extension beyond the involved site. Other findings in these 10 patients included density confluence of cortical and cancellous bone, prominence of the inferior alveolar nerve canal, markedly thickened and sclerotic lamina dura, uniform periradicular radiolucencies, cortical disruption, lack of bone fill after extraction, and a persisting alveolar socket. None had exposed bone develop during 1-year follow up. The remaining 20 patients had normal or localized radiographic findings consistent with odontogenic pathology. CONCLUSION: In 10 of 30 symptomatic patients referred for clinical evaluation and imaging, a consistent finding was conspicuous osteosclerosis in clinically symptomatic areas characteristic of stage 0 disease. These data support the need to better understand radiographic features associated with bisphosphonate exposure and to determine whether osteosclerosis is a specific finding indicative of the risk for progression to BRONJ. PMID- 20728035 TI - Hereditary angioedema in oral surgery: overview of the clinical picture and report of a case. PMID- 20728034 TI - Flapless and traditional dental implant surgery: an open, retrospective comparative study. AB - PURPOSE: Osseointegrated dental implantation is traditionally performed by a flap approach that involves soft tissue flap reflection, but this technique is associated with several drawbacks. Conversely, the flapless method requires only minimal removal of soft tissue but is not suitable for all patients. The objective of this study was to compare the flapless (FL) method of implant placement with the traditional flap (TR) method with regard to achievement of success, change in bone level, and overall safety. PATIENTS AND METHODS: In this single-center, open, retrospective, investigator-driven, nonrandomized, comparative study, patients were pre- or intraoperatively assigned to the FL or TR treatment. The primary success criteria were the absence of mobility, radiolucency, pain, and infection. RESULTS: The FL method was applied to 174 implants (46%) in 121 patients and the TR method to 203 implants (54%) in 98 patients. At visit 1, implantation was rated successful in 171/174 (98.3%) implants with the FL method and in 200/203 (98.5%) with the TR method. Success rate remained constant until visit 2. The difference between the 2 groups in the rate of success was not significant. Similarly, no significant difference was observed for mean time to last follow-up for success. CONCLUSIONS: Based on pre- or intraoperative decision-making, patients eligible for FL surgery can benefit from a less straining procedure without affecting the high success rate of dental implant surgery. The FL approach is a predictable procedure when patient selection and surgical technique are appropriate. PMID- 20728033 TI - Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. AB - PURPOSE: Osteonecrosis of the jaw is a well-documented side effect of bisphosphonate (BP) use. Attempts have recently been made to predict the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We prospectively investigated the predictive value of serum levels of C-terminal telopeptide of collagen I (CTX), bone-specific alkaline phosphatase, and parathyroid hormone for the development of BRONJ. PATIENTS AND METHODS: Data on the demographics, comorbidities, and BP treatment were collected from 78 patients scheduled for dentoalveolar surgery. Of the 78 patients, 51 had been treated with oral BPs and 27 had been treated with frequent intravenous infusions of BPs. Blood samples for CTX, bone-specific alkaline phosphatase, and parathyroid hormone measurements were taken preoperatively. Surgery was performed conservatively, and antibiotic medications were prescribed for 7 days. RESULTS: Of the 78 patients, 4 patients taking oral BPs (7.8%) and 14 receiving intravenous BPs (51.8%) developed BRONJ. A CTX level less than 150 pg/mL was significantly associated with BRONJ development, with an increased odds ratio of 5.268 (P = .004). The bone-specific alkaline phosphatase levels were significantly lower in patients taking oral BPs who developed BRONJ. The parathyroid hormone levels were similar in patients who did and did not develop BRONJ. CONCLUSION: The incidence of BRONJ after oral surgery involving bone is greater among patients receiving frequent, intravenous infusions of BPs than among patients taking oral BPs. Although the measurement of serum levels of CTX is not a definitive predictor of the development of BRONJ, it might have an important role in the risk assessment before oral surgery. PMID- 20728036 TI - Control of life-threatening head and neck hemorrhage after dental extractions: a case report. PMID- 20728037 TI - Endovascular treatment of hemorrhagic alveolar artery pseudoaneurysm after tooth extraction: a case report. PMID- 20728038 TI - Glomus tumor: report of a rare case affecting the oral cavity and review of the literature. PMID- 20728039 TI - The view from the third rail. PMID- 20728041 TI - Endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) and haplotypes in Korean patients with recurrent spontaneous abortion. AB - OBJECTIVE: To investigate the association of three common polymorphisms (-786T>C, 4a4b, 894G>T) of the endothelial nitric oxide synthase (eNOS) gene with idiopathic recurrent spontaneous abortion (RSA). STUDY DESIGN: In a prospective case-control study, 340 patients with unexplained recurrent spontaneous abortion and 115 controls with at least one live birth and no history of pregnancy loss were enrolled. Polymerase chain reaction and restriction fragment length polymorphism analysis were performed to identify the genotypes. RESULTS: The recurrent spontaneous abortion patients exhibited a significantly higher frequency of the eNOS 894GT+TT genotype (Odds ratio (OR), 2.39; 95% confidence interval (CI), 1.25-4.58; p=0.008) compared to the control group; no significant differences in the -786T>C and 4a4b genotype frequencies were observed. The eNOS 894GT genotype (OR, 1.94; 95% CI, 1.00-3.75; p=0.056) was marginally different between recurrent spontaneous abortion and control groups. The frequency of the 786T-4b-894T haplotype (p=0.001) was significantly higher in the idiopathic RSA group than in the control group. CONCLUSION: The eNOS 894GT+TT genotype and the 786T-4b-894T haplotype are significantly associated with idiopathic recurrent spontaneous abortion in Korean women. PMID- 20728042 TI - Bilateral primary breast lymphoma masquerading as lactating mastitis. PMID- 20728043 TI - Real world research. PMID- 20728044 TI - The Catch-22 of appraisals on the quality of observational studies. PMID- 20728045 TI - A systematic review of tools used to assess the quality of observational studies that examine incidence or prevalence and risk factors for diseases. AB - OBJECTIVE: To create a comprehensive evaluation of checklists and scales used to evaluate observational studies that examine incidence or prevalence and risk factors for diseases. STUDY DESIGN: We did a literature search of several databases to abstract format, content, development, and validation of the tools. RESULTS: We identified 46 scales and 51 checklists. Forty-seven of these tools were created for therapeutic studies, 48 for risk factors, and 5 for incidence studies. Forty-seven percent were modifications of previously published peer reviewed appraisals, 18% were developed based on methodological standards, and 35% did not report development. Twenty-two percent reported reliability and 10% the validation procedure. Tools did not discriminate poor reporting vs. methodological quality of studies or external vs. internal validity; 35% categorize quality by the presence of predefined major flaws in design or by total score from the scale. Level of evidence was proposed in 22% of the tools by criteria of causality or internal validity of the studies. Evaluation required different degrees of subjectivity. CONCLUSIONS: Format, length, and content varied substantially across available checklists and scales. Development, validation, and reliability were not consistently reported. Transparent objective quality assessments should be developed in the future. PMID- 20728047 TI - Visual filling-in. PMID- 20728048 TI - Tudor domain. PMID- 20728049 TI - Biomechanics: an army marching with its stomach. AB - A novel X-ray technique shows that the internal organs of crawling caterpillars slide past the body walls like pistons in a new kind of legged locomotion. PMID- 20728050 TI - Cell-matrix adhesion: slip and immobilization under force. AB - When force is applied to cell-matrix adhesion complexes, they respond by growing larger and stronger. It emerges that strengthening involves transient motion of the transmembrane integrin receptors and their eventual immobilization to the extracellular matrix. PMID- 20728051 TI - Sexual selection: the weevils of inbreeding. AB - A recent study has used inbreeding depression to gain insight into the maintenance of additive genetic variation in populations, with intriguing implications for good genes models of sexual selection. PMID- 20728052 TI - Neuronal morphogenesis: worms get an EFF in dendritic arborization. AB - The development of neuronal dendritic trees involves positive and negative control of growth and branching, as well as modulation of the spacing and orientation of branches. A new study reveals the importance of a membrane fusogen in the dendrite arborization of a pair of highly-branched worm sensory neurons. PMID- 20728053 TI - Synthetic biology: now that we're creators, what should we create? AB - A 'synthetic' microbe has been created by introducing the artificially produced genome of one species into the cytoplasm of another. The technology allows the introduction of easily transferable adaptive units, as well as sets of genes that have likely never been transferred successfully. PMID- 20728054 TI - Bacterial invasion: entry through the exocyst door. AB - Salmonella entry into host cells involves rearrangements of actin and mobilization of membranes. Here we discuss new findings showing that Salmonella recruits the exocyst complex, which plays a role in vesicle secretion, to the site of invasion to promote its entry. PMID- 20728055 TI - Neurophysiology: recording from neurons in action. AB - Sensory neurons have mostly been studied in fixed animals, but how do they behave when the animal is free to move? A recent study shows that, during locomotor activity, besides there being a general enhancement in responsiveness, the tuning curves of neurons can also change, altering their optimal stimuli. PMID- 20728056 TI - Plant fertilization: bursting pollen tubes! AB - Higher plants don't have motile sperm; they rely on pollen tubes to deliver them. Recent research has identified key components involved in pollen tube tip bursting that allow sperm release and fertilization. PMID- 20728057 TI - Social learning: the importance of copying others. AB - A new study argues that social learning is adaptive because 'demonstrators' inadvertently filter information, so that copiers learn behaviours that have proved successful. There are remarkable parallels between these findings and data on how social insects share information about food locations. PMID- 20728058 TI - The winds of change. PMID- 20728059 TI - Phenytoin-induced visual disturbances mimicking Delirium Tremens in a child. AB - Delirium Tremens is quite rare in children and it is usually caused by withdrawal or abstinence from alcohol, barbiturates and other major tranquilizers. The usual symptoms of Delirium Tremens include severe altered mental status with confusion, delusions, hallucinations, and severe agitation. Although psychosis is a recognized manifestation of Phenytoin toxicity, visual hallucinations are not. This study reports the case of a 4-year-old male with febrile seizures plus syndrome who developed acute complex visual hallucinations and psychomotor agitation early after therapy with intravenous Phenytoin was administered. These visual hallucinations mimicked those linked to Delirium Tremens and were not associated with an encephalopathy or other known neuropsychiatric side effects of this drug. Moreover, the hallucinations occurred while serum Phenytoin concentrations were below therapeutic range. We made an extensive investigation in order to exclude a non-convulsive Status Epilepticus, a Central Nervous System infection, a metabolic disorder, an underlying psychiatric disease and a possible drug toxicity. The temporal relationship between initiation of Phenytoin and onset of visual hallucinations and resolution of symptoms with withdrawal of Phenytoin suggests that the visual disturbances were probably due to that antiepileptic drug. PMID- 20728060 TI - Following the path of most resistance: dhps K540E dispersal in African Plasmodium falciparum. AB - Chloroquine resistant malaria (CQR) emerged in East Africa during the late 1970s and then spread westward. A molecular marker only became available in the late 1990s, and by that time CQR had permeated throughout Africa. By contrast, resistance to sulphadoxine-pyrimethamine (SPR) has emerged during an era of molecular surveillance, and the changing prevalence of SPR conferred by point mutations in the dhfr and dhps genes has been recorded in hundreds of sites across Africa. We have collated and mapped reports of the dhps K540E mutation, a uniquely informative marker of SPR, and used these to describe the geography of its dispersal through time. Like CQR, dhps K540E appeared first in East Africa and spread west. We discuss whether there are common principles governing resistance dispersal in Africa and how these might guide surveillance in future. PMID- 20728062 TI - Pain assessment tool in the critically ill post-open heart surgery patient population. AB - Critical-care patients are at higher risk for untreated pain, because they are often unable to communicate owing to altered mental status, mechanical ventilation, and sedation. Pain that is persistent and untreated affects most body systems and results in development of complications chronic pain, and increased length of stay. This descriptive repeated-measures study compared three pain assessment tools in nonverbal critically ill patients in a cardiac postanesthesia care unit (n=24). Tools included the Critical-Care Pain Observation Tool (CPOT), adult Nonverbal Pain Scale (NVPS), and the Faces, Legs, Activity, Cry, and Consolability scale (FLACC). Two painful events, suctioning and repositioning, were studied. Data were collected immediately before the event, 1 minute after, and 20 minutes after. Both the CPOT and the NVPS demonstrated high reliability (Cronbach alpha coefficients 0.89). The NVPS and the CPOT were highly correlated for both raters (r>0.80, p=.00) (11 out of 12 times). Correlations between the two raters was generally moderate to high, but higher with the CPOT. There was more disagreement between raters in overall pain scores for the NVPS. When raters disagreed, it was most often in rating the face component on both scales. Disagreement was highest during the event. Both scales adequately capture pain in the nonverbal sedated critically ill patient based on assessment of patients' face, body movements, muscle tension, and respirations, with the NVPS also considering vital signs. Pictures depicting facial expressions for scoring purposes are helpful. Adequate education and understanding of use of the scales is critical for accurate assessment and subsequent interventions. PMID- 20728063 TI - Effect of music on pain for home-dwelling persons with dementia. AB - The purpose of this study was to investigate the effect of music on pain for home dwelling persons with dementia. A quasiexperimental design was used. Fifteen subjects listened to their preferred music for 30 minutes before peak agitation time, for 2 days per week, followed by no music for 2 weeks. The process was repeated once. The finding of this study showed that mean pain levels after listening to music were significantly lower than before listening to the music (t=2.21, df=28; p < .05). The findings of this pilot study suggest the importance of music intervention to control pain for home-dwelling persons with dementia. PMID- 20728064 TI - Piloting tailored teaching on nonpharmacologic enhancements for postoperative pain management in older adults. AB - Despite many advances in the pharmacologic treatment of pain, the issue of unresolved postoperative pain continues to plague patients and health care professionals. Little seems to be known about the reasons why nonpharmacologic methods are not more widely used, particularly as they are commonly low in cost, easy to use, and largely free of adverse side effects. A central question has to do with what patients are taught about nonpharmacologic methods and how a novel mode of teaching can be embedded in practice. A seven-step pre-posttest teaching intervention pilot study was deployed with older joint replacement patients within the context of a translational research model. Results of the teaching pilot showed significant post-teaching changes in subjects' knowledge and attitudes about nonpharmacologic methods for pain management, high satisfaction with the nonpharmacologic methods they chose, and incrementally greater use of the nonpharmacologic methods over the course of the hospital stay. A randomized controlled trial of the study is now in the early planning stages in an effort to obtain generalizable results that will help solidify evidence of the impact of music, imagery, and slow-stroke massage on pain management and confirm the value of patient teaching as an important means of offering patients more options for managing their own pain. PMID- 20728065 TI - Relaxation and imagery for chronic, nonmalignant pain: effects on pain symptoms, quality of life, and mental health. AB - Nonpharmacologic treatments are being increasingly adopted as alternative or primary approaches to chronic pain management. We present results of a pilot study examining the effect of a 6-week combined abbreviated progressive relaxation technique (APRT) and guided imagery (GI) intervention for the management of chronic pain (N=19) and, using power analysis, explore recommended sample sizes for future clinical trials. Results indicated consistent and clinically significant trends of improvement on pain (McGill Pain Questionnaire, visual analog scale), mental health (Depression Anxiety and Stress Scale), all domains of quality of life (RAND-36 Health Survey), and sleep for the treatment group only. Owing to inadequate power in this study, these results were not statistically significant. Methodologic concerns, along with suggestions for an improved intervention protocol, are discussed. It is concluded that there is strong preliminary evidence for the efficacy of APRT and GI as an adjunct to conventional treatment options for chronic pain. PMID- 20728066 TI - Low-dose ketamine via intravenous patient-controlled analgesia device after various transthoracic procedures improves analgesia and patient and family satisfaction. AB - Ketamine was recently shown to attenuate postoperative pain when used in combination with morphine in patients who had undergone general and orthopedic surgery. We assessed its effects in 46 patients undergoing minimally invasive direct coronary artery bypass, off-pump coronary artery bypass, or thoracotomy and correlated them with patient and family satisfaction. Patient-controlled analgesia (PCA) was available for 72 hours. One group received 2mg/bolus morphine randomly and double-blindly (group MO), and another group received 1mg morphine plus 5mg ketamine/bolus (group MK), both using IV-PCA. The patients' pain and satisfaction rates were assessed three times daily during hospitalization using a visual analog scale. Their families' satisfaction was assessed as well. Although the 3-day mean amount of morphine used by the MK patients was approximately 60% of that used by the MO patients, their levels of pain and satisfaction were better than those of the MO group. There was an inverted and statistically significant correlation between the patients' level of satisfaction on the second postoperative day (POD) and the satisfaction of their families on POD 2, 3, and 7 and the POD 3 patients' pain assessment in the MK group but not in the MO group. There were no differences in hemodynamic, respiratory, side effects, or complication rates between the groups. The conclusion is that the effects of adding a small ketamine dose to half of the standard morphine dose via IV-PCA after thoracotomy was superior to the standard morphine dose in terms of the patients' self-reported pain score and satisfaction, as well as the family satisfaction rate. PMID- 20728067 TI - Nursing care, delirium, and pain management for the hospitalized older adult. AB - Delirium is a reversible cognitive disorder that has a rapid onset. Delirium risk factors include older age, severity of illness, poorer baseline functional status, comorbid medical conditions, and dementia. There are adverse consequences of delirium, including increased length of stay and increased mortality. Therefore, it is important for nurses to identify clients at risk and prevent and manage delirium in the hospitalized older client. Once high-risk clients are identified, prevention strategies may be used to reduce the incidence. Examples of prevention strategies include providing glasses and working hearing aids and effective pain management. This article discusses various assessment instruments that detect the presence of delirium. With this information, nurses are better equipped to evaluate the best assessment options for their work setting. Early detection is crucial to reduce the adverse consequences of delirium. Once a client is found to be experiencing delirium, a treatment plan can be established using both nonpharmacologic and pharmacologic interventions. In addition, the identification and the correction of etiologies of delirium can shorten the course of delirium. PMID- 20728068 TI - The effect of cold application in combination with standard analgesic administration on pain and anxiety during chest tube removal: a single-blinded, randomized, double-controlled study. AB - The aim of this study was to investigate the effect of cold application on pain and anxiety during chest tube removal (CTR) in patients who had undergone cardiac surgery. A single-blinded randomized design was used in this study. Ninety patients aged 18-74 years, hospitalized in the intensive care unit (ICU), who had a chest tube for a duration of at least 24 hours were used for this convenience sample. The application of cold, placebo, or control therapies was randomized into three different groups. Sixty minutes before CTR was scheduled, an ICU nurse administered 10mg/kg paracetamol intravenously to all study subjects. Cold and warm packs covered with gauze dressing were applied to the area surrounding the chest tubes for 20 minutes. Pain intensity, pain quality and situational anxiety for CTR were measured. Variance analysis and the latent growth model were used in the analysis of the data. Patients in the cold group had significantly lower pain intensity than the placebo group. The perception of pain intensity measured by visual analog scores of patients in the cold group showed the least variation. There was no statistically significant difference in McGill Melzack Pain Questionnaire scores or in change of anxiety level between the three groups. The application of cold prolonged the length of time until analgesics were needed after CTR. Results showed that cold application reduced patients' intensity of pain due to CTR but did not affect anxiety levels or the type of pain. Cold application is recommended as a pain-relieving technique during CTR. PMID- 20728069 TI - Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. AB - Gestational trophoblastic disease includes hydatidiform mole (complete and partial) and gestational trophoblastic neoplasia (invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor). The epidemiology, pathology, clinical presentation, and diagnosis of each of these trophoblastic disease variants are discussed. Particular emphasis is given to management of hydatidiform mole, including evacuation, twin mole/normal fetus pregnancy, prophylactic chemotherapy, and follow-up. PMID- 20728070 TI - Association of body mass index with hip and thigh pain following transobturator midurethral sling placement. AB - OBJECTIVE: We sought to investigate the incidence of hip and proximal lower extremity pain following transobturator midurethral sling and evaluate the association between pain and body mass index (BMI). STUDY DESIGN: This was a retrospective cohort study of all transobturator midurethral sling procedures from July 2008 through June 2009. The primary outcome was postoperative hip or proximal lower extremity pain. RESULTS: Four urogynecologists performed 226 procedures. The incidence of postoperative hip or proximal lower extremity pain was 15.5%. Women of normal BMI had a higher risk of developing pain than obese women (risk ratio, 2.51; 95% confidence interval, 1.01-6.22). While not statistically significant, overweight women were twice as likely as obese women to develop the primary outcome (risk ratio, 1.99; 95% confidence interval, 0.79 4.99). CONCLUSION: Women of normal BMI have an increased risk of hip and proximal lower extremity pain following transobturator midurethral sling compared with obese women. PMID- 20728072 TI - Quantification of vaginal support: are continuous summary scores better than POPQ stage? AB - OBJECTIVE: This analysis compared 3 continuous variables as summary support loss (SL) scores with pelvic organ prolapse (POP) quantification (POPQ) ordinal stages. STUDY DESIGN: We used pooled baseline data from 1141 subjects in 3 randomized trials (CARE, n = 322; OPUS, n = 380; ATLAS, n = 439) to test 3 SL measures. The relative responsiveness was assessed using the standardized response mean of 2-year outcome data from the CARE trial. RESULTS: Each SL measure was strongly correlated with POPQ ordinal staging; the single most distal POPQ point had the strongest correlation. Improvements in anatomic support were weakly correlated with improvements in POP Distress Inventory (r = 0.17-0.24; P < .01 for each) but not with changes in POP Impact Questionnaire for all measures of SL or POPQ stage. CONCLUSION: While continuous, single number summary measures compared favorably to ordinal POPQ staging system, the single most distal POPQ point may be preferable to POPQ ordinal stages to summarize or compare group data. PMID- 20728074 TI - Influence on working hours among shift workers and effects on sleep quality - An intervention study. AB - The aim of the present intervention study was to examine if increased influence on working hours among shift workers led to better sleep quality. 391 employees were categorized into groups based on the performed activities: High (self rostering), moderate (education and/or policy for working hours), and low intensity intervention (meetings and discussions) and reference. Sleep quality was assessed by Karolinska Sleep Questionnaire (KSQ) at baseline and follow-up (12 months). To elucidate the process of the intervention interviews were conducted. Influence on one's own working hours increased only in the high intensity group (p < 0.001). No effects of interventions on sleep quality were observed. Thus, sleep quality was not improved by increasing work time influence in the present group of Danish elder care workers. This was partly due to program failure (failed intervention), but may also be due to other factors such as few participants working night and few working full time. PMID- 20728073 TI - Twins: prevalence, problems, and preterm births. AB - The rate of twin pregnancies in the United States has stabilized at 32 per 1000 births in 2006. Aside from determining chorionicity, first-trimester screening and second-trimester ultrasound scanning should ascertain whether there are structural or chromosomal abnormalities. Compared with singleton births, genetic amniocentesis-related loss at <24 weeks of gestation for twin births is higher (0.9% vs 2.9%, respectively). Selective termination for an anomalous fetus is an option, although the pregnancy loss rate is 7% at experienced centers. For singleton and twin births for African American and white women, approximately 50% of preterm births are indicated; approximately one-third of these births are spontaneous, and 10% of the births occur after preterm premature rupture of membranes. From 1989-2000, the rate of preterm twin births increased, for African American and white women alike, although the perinatal mortality rate has actually decreased. As with singleton births, tocolytics should be used judiciously and only for a limited time (<48 hours) in twin births. Administration of antenatal corticosteroids is an evidence-based recommendation. PMID- 20728075 TI - Stepped care for obsessive-compulsive disorder: An open trial. AB - This study evaluated the effectiveness and treatment costs associated with a stepped care protocol of exposure and response prevention (EX/RP) for obsessive compulsive disorder (OCD). In the current open trial, patients (N=14) began with self-directed EX/RP and minimal therapist guidance over the course of six weeks (Step 1). During this phase of treatment, no therapist-directed exposures were conducted. Those who did not respond optimally to Step 1 went on to Step 2, which consisted of 15 sessions of twice-weekly therapist-directed exposures. Results of this study show promise for stepped care utilizing EX/RP for some patients with OCD, with a response rate of 88% and a 60% reduction on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score among treatment completers. Significant improvements were found in Y-BOCS from pre to post-treatment for both Step 1 and Step 2 completers. Forty-five percent of participants (n=5) responded following completion of Step 1, resulting in reduced cost of treatment among these participants. All participants who responded to Step 1 maintained acute gains during the brief follow-up period. Limitations include a small sample size and high attrition rate. PMID- 20728076 TI - Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. AB - In mood disorders, there is growing evidence for glutamatergic abnormalities derived from peripheral measures of glutamatergic metabolites in patients, postmortem studies on glutamate-related markers, and animal studies on the mechanism of action of available treatments. Magnetic resonance spectroscopy (MRS) has the potential to corroborate and extend these findings with the advantage of in vivo assessment of glutamate-related metabolites in different disease states, in response to treatment, and in relation with functional imaging data. In this article, we first review the biological significance of glutamate, glutamine, and Glx (composed mainly of glutamate and glutamine). Next, we review the MRS literature in mood disorders, examining these glutamate-related metabolites. Here, we find a highly consistent pattern of Glx-level reductions in major depressive disorder and elevations in bipolar disorder. In addition, studies of depression, regardless of diagnosis, provide suggestive evidence for reduced glutamine/glutamate ratio and in mania for elevated glutamine/glutamate ratio. These patterns suggest that the glutamate-related metabolite pool (not all of it necessarily relevant to neurotransmission) is constricted in major depressive disorder and expanded in bipolar disorder. Depressive and manic episodes may be characterized by modulation of the glutamine/glutamate ratio in opposite directions, possibly suggesting reduced versus elevated glutamate conversion to glutamine by glial cells, respectively. We discuss the implications of these results for the pathophysiology of mood disorders and suggest future directions for MRS studies. PMID- 20728078 TI - Cyclic adenosine monophosphate and IL-10 coordinately contribute to nTreg cell mediated suppression of dendritic cell activation. AB - In humans and mice naturally occurring regulatory T cells (nTregs) are crucial for the maintenance of peripheral tolerance by controlling not only potentially autoreactive T cells but virtually all cells of the adaptive and innate immune system. Here we show that co-culture of murine dendritic cells (DC) and nTregs results in an immediate increase of cAMP in DC, responsible for a rapid down regulation of co-stimulatory molecules (CD80, CD86). In addition, the inhibitory surface molecule B7-H3 on DC is up-regulated. Subsequently, nTreg-derived IL-10 inhibits the cytokine production (IL-6, IL-12) of suppressed DC therewith preserving their silent phenotype. Hence, our data indicate that nTregs effectively control exuberant immune responses by directly limiting the stimulatory capacity of DC via a sophisticated chronologic action of inhibitory signals. PMID- 20728077 TI - Differential requirement of lipid rafts for FcgammaRIIA mediated effector activities. AB - Immunoglobulin G (IgG) dependent activities are important in host defense and autoimmune diseases. Various cell types including macrophages and neutrophils contribute to pathogen destruction and tissue damage through binding of IgG to Fcgamma receptors (FcgammaR). One member of this family, FcgammaRIIA, is a transmembrane glycoprotein known to mediate binding and internalization of IgG containing targets. FcgammaRIIA has been observed to translocate into lipids rafts upon binding IgG-containing targets. We hypothesize that lipid rafts participate to different extents in binding and internalizing targets of different sizes. We demonstrate that disruption of lipid rafts with 8mM methyl beta-cyclodextrin (MbetaCD) nearly abolishes binding (91% reduction) and phagocytosis (60% reduction) of large IgG-coated targets. Conversely, binding and internalization of small IgG-complexes is less dependent on lipid rafts (49% and 17% inhibition at 8mM MbetaCD, respectively). These observations suggest that differences between phagocytosis and endocytosis may arise as early as the initial stages of ligand recognition. PMID- 20728079 TI - [General surgery and the digestive system: quo vadis?]. PMID- 20728080 TI - Perception of randomness: On the time of streaks. AB - People tend to think that streaks in random sequential events are rare and remarkable. When they actually encounter streaks, they tend to consider the underlying process as non-random. The present paper examines the time of pattern occurrences in sequences of Bernoulli trials, and shows that among all patterns of the same length, a streak is the most delayed pattern for its first occurrence. It is argued that when time is of essence, how often a pattern is to occur (mean time, or, frequency) and when a pattern is to first occur (waiting time) are different questions and bear different psychological relevance. The waiting time statistics may provide a quantitative measure to the psychological distance when people are expecting a probabilistic event, and such measure is consistent with both of the representativeness and availability heuristics in people's perception of randomness. We discuss some of the recent empirical findings and suggest that people's judgment and generation of random sequences may be guided by their actual experiences of the waiting time statistics. PMID- 20728081 TI - First-principles modeling of fluid and solute exchange in the human during normal and hemodialysis conditions. AB - A first-principles computer model of fluid and solute exchange under both physiological and hemodialysis condition is presented. The whole system has been modeled and simulated under the MODELICA integrated environment, which uses a hierarchical modeling strategy. The model performance has been analyzed by simulation in the light of existing hypothesis and physiological data used here for validation purposes. The results obtained provide a physiological interpretative key to patient's hemodynamic behavior during hemodialysis. PMID- 20728082 TI - Low-dose estrogen and drospirenone combination: effects on glycoinsulinemic metabolism and other cardiovascular risk factors in healthy postmenopausal women. AB - OBJECTIVE: To evaluate the effects of a daily E2 (1 mg) plus drospirenone oral formulation (2 mg) on glycoinsulinemic metabolism, lipid profile, and endothelial function in symptomatic healthy menopausal women. DESIGN: Randomized, double blind study. SETTING: Operative Division of Endocrinological Gynecology, Catholic University of the Sacred Heart, Rome, Italy. PATIENT(S): Forty postmenopausal women. INTERVENTION(S): Patients were randomly submitted to receive treatment with an oral dose of E2 (1 mg) plus drospirenone (2 mg) (group A) or placebo (group B). MAIN OUTCOME MEASURE(S): Hormonal and lipid assessment; evaluation of glucose and insulin metabolism by the clamp test and the oral glucose tolerance test; evaluation of endothelial function by the vascular reactivity test. RESULT(S): Total cholesterol levels, low-density lipoprotein cholesterol levels, and nonesterified fatty acids levels significantly decreased both after 3 and 6 months. No changes in high-density lipoprotein, triglycerides, apolipoprotein A1, apolipoprotein B, and lipoprotein (a) were found. Treatment resulted in few changes in glycoinsulinemic metabolism. We observed a significant reduction of the area under curve of insulin after 6 months of therapy. Endothelial function was significantly influenced by treatment, and an improvement in both flow mediated dilatation and nitrate-mediated dilatation values after 6 months was observed. CONCLUSION(S): Low-dose E2/drospirenone treatment did not reveal any negative effect on carbohydrate metabolism, acting in a neutral way on insulin sensitivity. The treatment induced favorable changes in lipid profile and showed a significant improvement of vascular reactivity. PMID- 20728083 TI - Effectiveness of misoprostol for office hysteroscopy without anesthesia in infertile patients. AB - OBJECTIVE: To evaluate and compare the effectiveness of oral and vaginal misoprostol versus placebo to facilitate office hysteroscopy without anesthesia during infertile diagnostic evaluation. DESIGN: Randomized, prospective trial. SETTING: Patients scheduled for diagnostic office hysteroscopy at a university hospital. PATIENT(S): Seventy-five infertile patients scheduled for diagnostic office hysteroscopy. INTERVENTION(S): Patients were divided into three groups: group A received oral misoprostol 600 MUg; group B, vaginal misoprostol 400 MUg; and group C, oral placebo. MAIN OUTCOME MEASURE(S): Pain, evaluated by visual analogue scale, and surgical time were recorded and compared. Statistical analysis was done using Student's t-test. RESULT(S): Pain was low in the vaginal misoprostol group. Mean visual analogue scale in the oral misoprostol group was 6.04 +/- 1.5; in the vaginal misoprostol group 2.85 +/- 1.2; and in the placebo group 7.50 +/- 1.5. Procedural time for office hysteroscopy was shorter in the vaginal misoprostol group (2.7 +/- 1.0 minutes) compared with group A (5.5 +/- 1.1 minutes) and group C (6.3 +/- 3.8 minutes). CONCLUSION(S): Vaginal misoprostol, 400 MUg, administered the day before office hysteroscopy considerably reduces pain and the time needed for hysteroscopy. This simple strategy may facilitate office hysteroscopy during an infertility work-up. PMID- 20728084 TI - Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. AB - BACKGROUND: There is cumulative evidence that the degree of inflammation correlates with prognosis after percutaneous coronary interventions (PCI). Additionally, there is a cross-link between platelet activation and inflammatory pathways. The aim of the present analysis was to evaluate the association of inflammatory markers and effects of dual antiplatelet therapy on platelet function and outcome in patients undergoing PCI. METHODS AND RESULTS: In a pilot study, 157 patients with symptomatic coronary artery disease (CAD) undergoing PCI were consecutively evaluated. Platelet response to clopidogrel and acetylsalicylic acid was assessed using whole blood multiple electrode aggregometry (MEA). Baseline levels of IL-6, RANTES and MCP-1 were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Levels of IL-6, RANTES, and CRP correlated well with ADP and arachidonic acid (AA)-induced MEA. In a second step, a retrospective analysis of a cohort of 903 PCI-patients was performed to evaluate the association of on-treatment residual platelet aggregation (RPA) and baseline CRP levels on the incidence of myocardial infarction (MI), death and stent thrombosis (ST). Patients suffering a subsequent event had a significantly higher level of baseline CRP and higher RPA compared to patients without events. After multivariate adjustment high baseline CRP and high RPA were independent predictors for combined major events and ST after PCI. CONCLUSION: To our knowledge this is the first study linking inflammation, antiplatelet drug responsiveness and outcome in a large CAD-patient cohort. The results suggest a relevant interaction of these parameters and encourage multimodal therapeutic approaches to treat cardiovascular risk after PCI. PMID- 20728085 TI - Altered calcium homeostasis is correlated with the presence of metabolic syndrome and diabetes in middle-aged and elderly Korean subjects: the Chungju Metabolic Disease Cohort study (CMC study). AB - OBJECTIVE: To clarify the association of serum calcium level with metabolic syndrome (MetS) and diabetes in middle-aged and elderly Korean subjects. DESIGN AND PATIENTS: We conducted a population-based, cross-sectional survey of 1329 participants aged over 40 years (median age 65.8) in a rural area of Chungju, Korea, in 2007. MEASUREMENTS: Serum level of albumin, calcium, 25-hydroxy-vitamin D and intact parathyroid hormone were measured in a central laboratory. RESULTS: The prevalence of MetS increased progressively with elevated serum albumin corrected calcium levels (P<0.001 for trend). After adjusting for various covariates, subjects in the highest quintile group (2.45-2.99 mmol/L) compared with the lowest quintile group (2.05-2.24 mmol/L) of serum calcium levels had an odds ratio (OR) for having MetS of 3.11 (95% confidence intervals, CI, 1.95-4.97; P for trend<0.001). Excluding the subjects with hypocalcemia and hypercalcemia (n=1064) did not alter this significant association. After multiple adjustment, subjects with serum calcium levels in the fourth to fifth quintiles had a 2.0- to 3.0-fold increased OR of having diabetes (first quintile reference, fourth quintiles OR 2.38; 95% CI 1.32-4.28, fifth quintiles OR 3.32; 95% CI 1.87-5.88; P for trend<0.001).The associations of serum calcium levels with the incidences of MetS or diabetes were unchanged after adjustment for 25(OH)D and PTH levels. CONCLUSIONS: Altered calcium homeostasis was associated with an increased risk of having MetS and diabetes in this demographic group. PMID- 20728086 TI - Foot forces during exercise on the International Space Station. AB - Long-duration exposure to microgravity has been shown to have detrimental effects on the human musculoskeletal system. To date, exercise countermeasures have been the primary approach to maintain bone and muscle mass and they have not been successful. Up until 2008, the three exercise countermeasure devices available on the International Space Station (ISS) were the treadmill with vibration isolation and stabilization (TVIS), the cycle ergometer with vibration isolation and stabilization (CEVIS), and the interim resistance exercise device (iRED). This article examines the available envelope of mechanical loads to the lower extremity that these exercise devices can generate based on direct in-shoe force measurements performed on the ISS. Four male crewmembers who flew on long duration ISS missions participated in this study. In-shoe forces were recorded during activities designed to elicit maximum loads from the various exercise devices. Data from typical exercise sessions on Earth and on-orbit were also available for comparison. Maximum on-orbit single-leg loads from TVIS were 1.77 body weight (BW) while running at 8mph. The largest single-leg forces during resistance exercise were 0.72 BW during single-leg heel raises and 0.68 BW during double-leg squats. Forces during CEVIS exercise were small, approaching only 0.19 BW at 210W and 95RPM. We conclude that the three exercise devices studied were not able to elicit loads comparable to exercise on Earth, with the exception of CEVIS at its maximal setting. The decrements were, on average, 77% for walking, 75% for running, and 65% for squats when each device was at its maximum setting. Future developments must include an improved harness to apply higher gravity replacement loads during locomotor exercise and the provision of greater resistance exercise capability. The present data set provides a benchmark that will enable future researchers to judge whether or not the new generation of exercise countermeasures recently added to the ISS will address the need for greater loading. PMID- 20728087 TI - Development and validation of a liquid chromatography/atmospheric pressure photoionization-tandem mass spectrometric method for the analysis of mycotoxins subjected to commission regulation (EC) No. 1881/2006 in cereals. AB - A sensitive and reliable liquid chromatography/photoionization (APPI) tandem mass spectrometry method has been developed for determining nine selected mycotoxins in wheat and maize samples. The analytes were chosen on the basis of the mycotoxins under EU Commission Regulation (EC) No. 1881/2006, i.e., deoxynivalenol (DON), zearalenone (ZON), aflatoxins (AFs), and ochratoxin A (OTA), and considering the possibility of a near future regulation for T-2 and HT 2 toxins. Mycotoxins were extracted from samples by means of an one-step solvent extraction without any cleanup. The developed multi-mycotoxin method permits simultaneous, simple, and rapid determination of several co-existing toxins separated in a single chromatographic run, in which AFs, T-2 and HT-2 toxin are acquired in positive, while OTA, DON and ZON in negative mode. Although a moderate signal suppression was noticeable, matrix effect did not give significant differences at p=0.05. Then, calibration in standard solution were used for quantitation. Based on the EU Commission Decision 2002/657/EC, the method was in-house validated in terms of ruggedness, specificity, linearity, trueness, within-laboratory reproducibility, decision limit (CCalpha) and detection capability (CCbeta). For all the analytes, the regression coefficient r ranged between 0.8752 (DON in wheat) and 0.9465 (ZON in maize), biases related to mean concentrations were from -13% to +12% of the nominal spiking level, and the overall within-laboratory reproducibility ranged 3-16%; finally, CCalpha values did not differ more than 20% and CCbeta not more than 42% from their respective maximum limit. Method quantification limits ranged from 1/20 (AFG1) to 1/4 (AFG2 and OTA) the maximum limit established by European Union in the Commission Regulation (EC) No. 1881/2006 and its subsequent amendments. PMID- 20728088 TI - Effect of alkyl functionalization on charging of colloidal silica in apolar media. AB - The present work examines the effect of alkyl-silane treatment on the charging of colloids in apolar solvent using two otherwise identical 250 nm diameter, spherical silica particles, one with untreated surface and the other treated with hexadecyltrimethoxysilane (C16), dispersed in an apolar isoparaffin solvent (Isopar-L) containing one of three oil-soluble surfactants: Aerosol-OT, OLOA 11,000, and zirconyl 2-ethyl hexanoate. The electrophoretic mobility of each dispersion was determined using phase angle light scattering (PALS). It was found that at sufficiently high surfactant concentration, i.e., where micelles begin to form in the bulk, the particle surfaces could be electrically charged. All three surfactants studied imparted a negative surface charge to the untreated silica particles. In all cases, the C16-treated particles were also found to be negatively charged but had a much higher magnitude of mobility than the untreated silica. Although the increase in magnitude of mobility as a result of the alkyl functionalization was surprising, it could be attributed to the increase in the number of surface hydroxyl groups arising from the hydrolysis of unbound methoxy groups of the silane molecules. The added hydroxyl groups provided additional potential acid-base interaction sites, resulting in higher particle mobility. It was also found that further increases in surfactant concentration lowered the particle mobility, attributed to the increasing concentration of electrically charged micelles, which may partially neutralize the surface charge or compress the electrical double layer. PMID- 20728089 TI - Patterning dewetting in thin polymer films by spatially directed photocrosslinking. AB - In this report we examine the dewetting of spin-cast poly (styrene) films in a confined geometry. We designed a platform for laterally confining PS by photo patterning crosslinks in spin-coated thin films. Heating the patterned film above the glass transition temperature of PS results in localized dewetting patterns in regions that were not crosslinked, while the crosslinked pattern serves as a rigid barrier that confines the retraction of the uncrosslinked polymer in micron sized domains. The barriers also provide a favorable surface that the liquid PS wets onto, forming a rim at the boundary of crosslinked and uncrosslinked polymer. The resulting patterns are shown to be dependent on the irradiation and annealing time, the dimensions of the uncrosslinked region and the thickness of the film. PMID- 20728090 TI - Changes in children's perception-action tuning over short time scales: bicycling across traffic-filled intersections in a virtual environment. AB - This investigation examined short-term changes in child and adult cyclists' gap decisions and movement timing in response to general and specific road-crossing experiences. Children (10- and 12-year-olds) and adults rode a bicycle through a virtual environment with 12 intersections. Participants faced continuous cross traffic and waited for gaps they judged were adequate for crossing. In the control condition, participants encountered randomly ordered gaps ranging from 1.5 to 5.0s at all intersections. In the high-density condition, participants encountered high-density intersections sandwiched between sets of control intersections. These high-density intersections were designed to push participants toward taking tighter gaps. Participants in both conditions were more likely to accept 3.5-, 4.0-, 4.5-, and 5.0-s gaps at the last set of intersections than at the first set of intersections, whereas participants in the high-density condition were also more likely to accept very tight 3.0-s gaps at the last intersections than at the first intersections. Moreover, individuals in the high-density condition who waited less and took shorter gaps at the middle intersections were also more likely to take very tight 3.0-s gaps at the last intersections. The 10-year-olds in both conditions had more time to spare when they cleared the path of the oncoming car at the last intersections, whereas the 12-year-olds and adults showed no change in time to spare across intersections. The discussion focuses on linking short-term change in perceptual-motor functioning to longer term perceptual-motor development. PMID- 20728091 TI - Coronary artery disease in youth: present markers, future hope? PMID- 20728092 TI - Free sialic acid storage disease mimicking cerebral palsy and revealed by blood smear examination. PMID- 20728093 TI - Effects of 3 different stimulus intensities of ultrabrief stimuli in right unilateral electroconvulsive therapy in major depression: a randomized, double blind pilot study. AB - OBJECTIVE: Efficacy and cognitive outcome of ECT is depending on electrode placement, pulse width and electrical dosage. Several studies showed that high dosage right unilateral ECT (RULECT) had a better antidepressant effects than low dosage RULECT and less cognitive side effect than bilateral stimulation. In this prospective, randomized, double-blind trial, we examined the efficacy and cognitive side effects of RULECT with three different (high dose) stimulus intensities (4*, 7* and 10* above the seizure threshold (ST)). METHODS: 41 patients with treatment resistant unipolar or bipolar depression were randomized to one of the three stimulation intensities. For stimulation, we used an ultrabrief pulse (0.3 ms). Primary outcome measures were reduction of the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI) and the response rate (50% reduction of the HDRS) in the three groups. For cognitive side effects, a neuropsychological test battery was assessed. RESULTS: All three groups responded significantly to 9 ECTs (p < 0.005), but there were no statistical significant differences in the response rates between the three intensity groups. Besides of the Verbal Learning Memory Recognition Test (VLMT), which showed significant impairments in the high dose intensity groups, no differences could be shown between the three study groups in all neuropsychological tests. CONCLUSION: A RULECT with ultrabrief pulse stimulation and 4* ST intensity is effective and from good tolerability. Higher intensity dosages seem to be associated with more cognitive side effects during a course of acute ECT treatment. PMID- 20728094 TI - The "thymopericardial fat flap": a versatile flap in thoracic and cardiovascular surgery. PMID- 20728095 TI - Sutureless replacement of aortic valves with St Jude Medical mechanical valve prostheses and Nitinol attachment rings: feasibility in long-term (90-day) pig experiments. AB - OBJECTIVE: Nitinol attachment rings (devices) used to attach mechanical aortic valve prostheses suturelessly were studied in long-term (90 days) pig experiments. METHODS: The aortic valve was removed and replaced by a device around a St Jude Medical mechanical valve prosthesis in 10 surviving pigs. Supravalvular angiography was done at the end of the operation. No coumarin derivates were given. RESULTS: No or minimal aortic regurgitation was confirmed in all surviving pigs at the end of the operation. Total follow-up was 846 days. In 4 pigs, follow-up was shorter than 90 days (28-75 days); the other 6 pigs did reach 90 days' survival or more. Repeat angiography in 4 pigs at the end of follow-up confirmed the unchanged position of the device at the aortic annulus, without aortic regurgitation. At autopsy, in all pigs the devices proved to be well grown in at the annulus, covered with endothelium, and sometimes tissue overgrowth related to not using coumarin derivates. There was no case of para device leakage, migration, or embolization. No damage to surrounding anatomic structures or prosthetic valves was found. CONCLUSIONS: Nitinol attachment rings can be used to replace the aortic valve suturelessly with St Jude Medical mechanical aortic valve prostheses, without para-device leakage, migration, or damage to the surrounding tissues, in long-term pig experiments during a follow up of 90 days or more. Refraining from anticoagulation in pigs with mechanical valve prostheses can lead to tissue overgrowth of the valve prosthesis. Further studies are needed to determine long-term feasibility of this method in human beings. PMID- 20728100 TI - Editorial comment. PMID- 20728096 TI - Aortic dissection caused by aortitis associated with hepatitis C virus-related cryoglobulinemia. PMID- 20728101 TI - Can we spare removing the adrenal gland at radical nephrectomy in children with wilms tumor? AB - PURPOSE: In patients with Wilms tumor indications for adrenalectomy are not well defined. Following the rationale for preserving the adrenal gland in cases of other renal malignancies we determined predictors of adrenal involvement and the impact of adrenalectomy on retroperitoneal recurrence. MATERIALS AND METHODS: We retrospectively reviewed the record of patients who underwent surgical resection as primary treatment for Wilms tumor between 1990 and 2008 at 2 Canadian pediatric centers. Patient and tumor characteristics were reviewed to determine potential links to adrenal involvement. Recurrence was evaluated as a time dependent variable based on followup duration. RESULTS: Of 180 patients diagnosed with Wilms tumor 95 underwent initial radical nephrectomy. Mean +/- SD age at diagnosis was 46 +/- 38 months and mean survival followup was 189 +/- 8.3 months. Disease was stage 1 to 4 in 28, 34, 23 and 4 patients, respectively. Adrenalectomy was done in 58 patients (61%). Only 1 adrenal gland was reportedly positive for tumor invasion while peri-adrenal fat involvement was noted in 3 patients. No studied patient or tumor characteristics predicted involvement. No statistically significant difference in retroperitoneal recurrence was found between the groups in which the adrenal gland was removed vs preserved. CONCLUSIONS: Adrenal involvement in patients with Wilms tumor is rare and difficult to predict. Preserving the adrenal gland was not associated with an increased risk of local recurrence. Thus, it seems prudent to avoid adrenalectomy at radical nephrectomy when technically feasible, instead attempting to otherwise remove all peri-adrenal fat with the specimen. PMID- 20728102 TI - Editorial comment. PMID- 20728104 TI - Origin and characterization of retrograde labeled neurons supplying the rat urethra using fiberoptic confocal fluorescent microscopy in vivo and immunohistochemistry. AB - PURPOSE: Autonomic innervation of urethral smooth muscle may influence urinary continence after prostatectomy. It is unclear whether the cavernous nerves carry fibers that influence continence. Using a retrograde axonal tracer combined with real-time in vivo imaging and ex vivo immunohistochemistry we determined the course and type of neurons supplying urethral smooth muscle distal to the prostate in the rat. MATERIALS AND METHODS: We injected the retrograde axonal tracers cholera toxin B fragment-Alexa Fluor 488 and Fast Blue in the distal urethral smooth muscle in 10 rats each. Five days later the cavernous nerves and pelvic ganglion were imaged using fiberoptic confocal fluorescence microscopy (cholera toxin B fragment-Alexa Fluor 488) or harvested for immunohistochemistry (Fast Blue). Dual immunofluorescence of Fast Blue neurons with tyrosine hydroxylase or neuronal nitric oxide synthase was done to characterize neurons as noradrenergic or nitrergic. To ascertain whether the cavernous nerves contain fibers to the urethra that originate in the pelvic ganglia we cut the cavernous nerves with their ancillary branches in 3 rats and imaged them for Fast Blue. RESULTS: Fluorescent neurons and axons were detected in cavernous nerves and the pelvic ganglion. Few neurons were seen in rats with cavernous nerve section. Of urethral neurons 53.1% showed neuronal nitric oxide synthase positivity while 40.6% were immunoreactive for tyrosine hydroxylase. About 6.2% of urethral neurons failed to show tyrosine hydroxylase or neuronal nitric oxide synthase immunoreactivity. CONCLUSIONS: Most of the autonomic innervation to the urethra beyond the prostatic apex travels in the cavernous nerves. Many nerves may be parasympathetic based on neuronal nitric oxide synthase immunoreactivity. Nerves supplying the urethra outside the cavernous nerves may course posterior to the prostate. Along with afferent fibers, tyrosine hydroxylase immunoreactivity expressing neuron fibers, ie noradrenergic nerves, traveling in the cavernous nerves may increase urethral resistance or regulate the reflex mechanisms controlling continence. PMID- 20728103 TI - Parent perspectives of health related quality of life for adolescents with bladder exstrophy-epispadias as measured by the child health questionnaire-parent form 50. AB - PURPOSE: Few groups have examined health related quality of life for adolescents with bladder exstrophy-epispadias. We studied parent reported health related quality of life for adolescents with bladder exstrophy-epispadias using the Child Health Questionnaire-Parent Form 50. MATERIALS AND METHODS: We recruited 11 to 17 year-old participants with bladder exstrophy-epispadias and their parents. Parents served as proxy respondents for the adolescents by self-administering a validated generic health related quality of life instrument, the Child Health Questionnaire-Parent Form 50. We collected urinary incontinence, catheterization status, and medical and surgical history data. Mean questionnaire scores were compared to population based norms. RESULTS: Median age of the 55 patients was 14 years, 69% were male and 84% were white. Diagnoses included bladder exstrophy in 48 cases and epispadias in 7. Of the participants 29 (53%) reported urinary incontinence. The median number of lifetime surgeries was 9. Although physical and psychosocial summary measure scores were comparable to norms, the mean general health perception score was significantly worse than that of a population based sample (65.8 points, 95% CI 61.4-70.2 vs 73, 95% CI 71.3-74.7, p = 0.004). Mean family activity and parent emotional impact scores were also significantly worse than in a population based sample (83.6 points, 95% CI 79.3-88.0 vs 89.7, 95% CI 87.9-91.5, p = 0.02 and 67.7, 95% CI 61.9-73.6 vs 80.3, 95% CI 78.4-82.2, p <0.0001, respectively). Comparison of incontinent to continent children revealed a lower mean score on the parent emotional impact scale (62.6 points, 95% CI 55.5-69.8 vs 73.4, 95% CI 63.9-82.9), which approached significance (p = 0.06). CONCLUSIONS: Although overall adolescent quality of life was comparable to norms, parents reported significantly impaired adolescent general health and family activity as well as a negative parental emotional impact. Further research is needed to identify interventions that can decrease the adverse impact of bladder exstrophy-epispadias on family activity and parent emotional distress. PMID- 20728105 TI - Variation in management of duplex system intravesical ureteroceles: a survey of pediatric urologists. AB - PURPOSE: Controversy exists in ureterocele management and the literature lacks clear management guidelines. We surveyed pediatric urologists to understand practice patterns and perceptions of managing duplicated system intravesical ureterocele. MATERIALS AND METHODS: The survey consisted of 3 case scenarios, including upper pole obstruction without reflux, ureterocele without hydronephrosis and reflux after incision. The survey evaluated management at patient age 3 months and used a Likert scale to evaluate management strategies later in life. RESULTS: We analyzed 233 responses. There was agreement in prophylactic antibiotic use and diagnostic evaluation. When managing a duplicated system intravesical ureterocele with poor upper pole function, 50.6% of respondents advocated puncture at age 3 months. However, when followed conservatively for 18 months, the preference changed to surgical management with partial nephrectomy preferred by 61.8% of respondents. When managing the condition without hydronephrosis, watchful waiting was preferred by 47.2% of respondents while 35.6% chose puncture and another 16.3% chose partial nephrectomy. Most respondents advocated ureteral reimplantation to manage reflux to the upper pole after puncture while some preferred endoscopic Deflux(r) injection. Continued nonoperative management while off prophylaxis was not preferred. Most respondents viewed the risks of surgery and anesthesia as important factors when weighing options in children younger than 3 months. Preventing symptoms and preserving function of the renal units were significant factors guiding surgical intervention. CONCLUSIONS: We found significant variation in management of duplicated system intravesical ureterocele. Most pediatric urologists see fewer than 10 cases per year, stressing the need for multi-institutional, randomized, controlled studies to evaluate management and long-term outcomes. PMID- 20728106 TI - Editorial comment. PMID- 20728107 TI - Cross-sectional evaluation of parental decision making factors for vesicoureteral reflux management in children. AB - PURPOSE: Parental decision making in children with vesicoureteral reflux has potentially become more complex with the evolution of ethnic diversity in the United States, the Internet, the publication of contradictory clinical data and the emergence of minimally invasive surgery. We performed a cross-sectional study of parental management for pediatric vesicoureteral reflux. MATERIALS AND METHODS: We administered a 26-item questionnaire to parents of children with vesicoureteral reflux seen at Texas Children's Hospital urology offices or undergoing antireflux surgery at that institution. Univariate and multivariate analysis was done on patient disease characteristics, demographics, predicted reflux duration, surgery success rate, antibiotic cessation, complication risk, financial considerations, urologist recommendations, Internet information, friend recommendations, and postoperative voiding cystourethrography, renal ultrasound and recovery. RESULTS: Enrolled in the study were 15 boys and 49 girls with a mean age of 3.5 years and a mean reflux grade of 2.8. Of the cases 37 were bilateral. Parents chose endoscopic treatment in 38 children, open ureteroneocystostomy in 9, antibiotic prophylaxis in 14 and observation without antibiotics in 3. Univariate analysis suggested that Hispanic parents rated ultrasound and financial considerations as more important than white parents (p <0.05). Multivariate analysis revealed that differences seen on univariate analysis may have been due to an association between race and income. Finally, 93.6% of parents rated urologist opinion as very or extremely important. CONCLUSIONS: Data indicate that the parents of our patients highly value the opinion of the pediatric urologist when choosing treatment for their children with vesicoureteral reflux. Despite social changes the physician-parental relationship remains critical. Differences in parental decision making may be linked to associations between race and income. PMID- 20728108 TI - Inaccurate reporting of mineral composition by commercial stone analysis laboratories: implications for infection and metabolic stones. AB - PURPOSE: We determined the accuracy of stone composition analysis at commercial laboratories. MATERIALS AND METHODS: A total of 25 human renal stones with infrared spectroscopy determined composition were fragmented into aliquots and studied with micro computerized tomography to ensure fragment similarity. Representative fragments of each stone were submitted to 5 commercial stone laboratories for blinded analysis. RESULTS: All laboratories agreed on the composition of 6 pure stones. Only 2 of 4 stones (50%) known to contain struvite were identified as struvite at all laboratories. Struvite was reported as a component by some laboratories for 4 stones previously determined not to contain struvite. Overall there was disagreement regarding struvite in 6 stones (24%). For 9 calcium oxalate stones all laboratories reported some mixture of calcium oxalate but the quantity of subtypes differed significantly among laboratories. In 6 apatite containing stones apatite was missed by the laboratories in 20% of samples. None of the laboratories identified atazanavir in a stone containing that antiviral drug. One laboratory reported protein in every sample while all others reported it in only 1. Nomenclature for apatite differed among laboratories with 1 reporting apatite as carbonate apatite and never hydroxyapatite, another never reporting carbonate apatite and always reporting hydroxyapatite, and a third reporting carbonate apatite as apatite with calcium carbonate. CONCLUSIONS: Commercial laboratories reliably recognize pure calculi. However, variability in the reporting of mixed calculi suggests a problem with the accuracy of stone analysis results. There is also a lack of standard nomenclature used by laboratories. PMID- 20728110 TI - Editorial comment. PMID- 20728111 TI - Editorial comment. PMID- 20728109 TI - Transplantation of nonhematopoietic adult bone marrow stem/progenitor cells isolated by p75 nerve growth factor receptor into the penis rescues erectile function in a rat model of cavernous nerve injury. AB - PURPOSE: Radical prostatectomy for prostate cancer frequently results in erectile dysfunction and decreased quality of life. We investigated the effects of transplanting nonhematopoietic adult bone marrow stem/progenitor cells (multipotent stromal cells) into the corpus cavernosum in a rat model of bilateral cavernous nerve crush injury. MATERIALS AND METHODS: Multipotent stromal cells were isolated from the bone marrow of transgenic green fluorescent protein rats by plastic adherence (rat multipotent stromal cells) or magnetic activated cell sorting using antibodies against p75 low affinity nerve growth factor receptor (p75 derived multipotent stromal cells). Bilateral cavernous nerve crush injury was induced in adult male Sprague-Dawley rats. Immediately after injury 8 rats each were injected intracavernously with phosphate buffered saline (vehicle control), fibroblasts (cell control), rat multipotent stromal cells (cell treatment) or p75 derived multipotent stromal cells (cell treatment). Another 8 rats underwent sham operation (phosphate buffered saline injection). Four weeks after the procedures we assessed erectile function by measuring the intracavernous-to-mean arterial pressure ratio and total intracavernous pressure during cavernous nerve stimulation. RESULTS: Intracavernous injection of p75 derived multipotent stromal cells after bilateral cavernous nerve crush injury resulted in a significantly higher mean intracavernous-to-mean arterial pressure ratio and total intracavernous pressure compared with all other groups except the sham operated group (p <0.05). Rats injected with typical multipotent stromal cells had partial erectile function rescue compared with animals that received p75 derived multipotent stromal cells. Fibroblast (cell control) and phosphate buffered saline (vehicle control) injection did not improve erectile function. Enzyme-linked immunosorbent assay suggested that basic fibroblast growth factor secreted by p75 derived multipotent stromal cells protected the cavernous nerve after bilateral cavernous nerve crush injury. CONCLUSIONS: Transplantation of adult stem/progenitor cells may provide an effective treatment for erectile dysfunction after radical prostatectomy. PMID- 20728112 TI - Preoperative stone attenuation value predicts success after shock wave lithotripsy in children. AB - PURPOSE: We determined whether stone attenuation can predict stone fragmentation after shock wave lithotripsy in the pediatric population. Previous studies show that preoperative attenuation in HU on noncontrast computerized tomography predicts shock wave lithotripsy success. To our knowledge study of this parameter in the pediatric population has been lacking to date. MATERIALS AND METHODS: We performed a multi-institutional review of the records of 53 pediatric patients 1 to 18 years old who underwent shock wave lithotripsy for 3.8 to 36.0 mm renal calculi. Stone size, average skin-to-stone distance and attenuation value were determined by bone windows on preoperative noncontrast computerized tomography. Success was defined as radiographically stone-free status at 2 to 12-week followup after a single lithotripsy session without the need for further sessions or ancillary procedures. RESULTS: After lithotripsy 33 patients (62%) were stone free and 20 had incomplete fragmentation or required additional procedures. Mean +/- SD stone attenuation in successfully treated patients vs those with incomplete fragmentation was 710 +/- 294 vs 994 +/- 379 HU (p = 0.007). Logistical regression analysis revealed that only attenuation in HU was a significant predictor of success. When patients were stratified into 2 groups (less than 1,000 and 1,000 HU or greater), the shock wave lithotripsy success rate was 77% and 33%, respectively (p <0.003). CONCLUSIONS: Stone attenuation less than 1,000 HU is a significant predictor of shock wave lithotripsy success in the pediatric population. This finding suggests that attenuation values have a similar predictive value in the pediatric population as that previously reported in the adult population. PMID- 20728113 TI - The role of testicular volume in adolescents with varicocele: the better way and time of surgical treatment. AB - PURPOSE: We report varicocele prevalence in adolescents. Surgical treatment has been proposed in adolescents with relevant testicular disproportion to avoid fertility problems in adulthood. We prospectively analyzed the testicular volume variation in adolescents with varicocele and hypoplastic testis. MATERIALS AND METHODS: In a 2-year period we selected 54 consecutive pediatric patients with a median age of 14.5 years (range 13 to 16) who had left varicocele using certain criteria, including testicular volume discrepancy greater than 20%, no previous inguinal-testicular surgery and no symptoms. Adolescents were divided into 2 groups, including 27 who underwent surgical correction with lymphatic sparing microsurgical varicocelectomy (intervention) and 27 who were only observed (control). After surgery or at first observation patients were evaluated clinically and by ultrasound at 3, 6 and 12 months. Testicular volume was estimated by the prolate ellipsoid formula. RESULTS: We noted significant improvement in testicular volume with less than 20% disparity between the 2 gonads in 23 patients (85.2%) in the intervention group and in 8 controls (29.6%). Two recurrences (7.4%) were reported in the intervention group, each in an adolescent with increased testicular volume. CONCLUSIONS: Our study confirms significantly increased testicular volume in many surgically treated boys and shows that physiological catch-up growth occurs in adolescents with varicocele without treatment. Considering critically results in each group, in select cases clinical and ultrasound followup is indicated before intervention due to a possible spontaneous decrease in testicular asymmetry. Further histopathological studies are needed to identify the relationship between testicular hypoplasia, irreversible damage and future fertility problems to determine which adolescents should be treated. PMID- 20728114 TI - Editorial comment. PMID- 20728115 TI - Editorial comment. PMID- 20728116 TI - Outcome after discontinuing prophylactic antibiotics in children with persistent vesicoureteral reflux. AB - PURPOSE: Treatment for vesicoureteral reflux remains controversial. Lacking an evidence-based treatment protocol, we offered the option of terminating prophylactic antibiotics in otherwise healthy patients with persistent vesicoureteral reflux at age 5 years or greater. We report outcomes with respect to the urinary tract infection incidence and to whether surgical intervention was eventually done. MATERIALS AND METHODS: We obtained institutional review board approval to retrospectively review the records of all children with vesicoureteral reflux from December 1999 to February 2009. Of this group we selected children 5 years old or older who had been taken off prophylactic antibiotics. We assessed children with primary vesicoureteral reflux in detail. RESULTS: The records of 1,217 that we reviewed showed that antibiotics were discontinued in 185 patients, including 160 girls (89%) and 25 boys (11%), at an average age of 6.2 years. Average followup was 2.0 years with recorded followup up to 8 years off prophylaxis. In 50 girls (91%) and 5 boys (9%), urinary tract infection developed after discontinuing prophylaxis. Correction was done in 57 patients, including open repair in 34 and endoscopic injection in 23. Two patients underwent intervention at parent request after an average of 0.7 years of uneventful observation. We identified no parameter predicting patients at risk for urinary tract infection. CONCLUSIONS: Urinary tract infection develops in 29% of patients 5 years old or older with persistent vesicoureteral reflux within 2 years after the cessation of prophylaxis. Most of these cases are febrile. Discontinuing antibiotics is reasonable but a prospective, randomized, long-term, multi-institutional trial is required to determine whether this approach is beneficial. PMID- 20728117 TI - Morphology of mouse external genitalia: implications for a role of estrogen in sexual dimorphism of the mouse genital tubercle. AB - PURPOSE: We examined the role of androgens and estrogens in mammalian sexual differentiation by morphological characterization of adult wt and mutant mouse external genitalia. We tested the hypothesis that external genitalia development depends on androgen and estrogen action. MATERIALS AND METHODS: We studied serial sections of the external genitalia of the CD-1 and C57BL6 wt strains of adult mice (Charles River Laboratories, Wilmington, Massachusetts). We recorded linear measurements of key structures in each specimen, including the urethra, erectile tissue, bone and cartilage. We used similar methodology to analyze mice mutant for estrogen receptor alpha (alphaERKO) and androgen receptor (X(Tfm)/Y) (Jackson Laboratory, Bar Harbor, Maine). RESULTS: Morphology in X(Tfm)/Y adult murine external genitalia was remarkably similar to that in wt females. Bone and clitoral length was similar in wt females and X(Tfm)/Y mice. Conversely the alphaERKO clitoris was 59% longer and bone length in alphaERKO females was many fold longer than that in female wt mice or X(Tfm)/Y mutants. The alphaERKO clitoris contained cartilage, which is typical of the wt penis but never observed in the wt clitoris. Serum testosterone was not increased in female alphaERKO mice 10 days postnatally when sex differentiation occurs, suggesting that masculinization of the alphaERKO clitoris is not a function of androgen. CONCLUSIONS: Masculinization of the alphaERKO clitoris suggests a role for estrogen in the development of female external genitalia. We propose that normal external genital development requires androgen and estrogen action. PMID- 20728118 TI - Same setting laparoscopic antegrade continence enema and antegrade bladder neck injection for constipation and urinary incontinence in the spina bifida population. AB - PURPOSE: Fecal impaction and urinary incontinence and are among the most important problems in patients with spina bifida. We report our preliminary results with a minimally invasive approach to these 2 problems, that is same setting laparoscopic antegrade continence enema and antegrade bladder neck injection. MATERIALS AND METHODS: We reviewed the charts of all patients who underwent same setting laparoscopic antegrade continence enema and antegrade bladder neck injection between January 1, 2006 and August 1, 2008. Demographic data, surgical indications, operative details and results were recorded. Surgical steps were uniform in all cases. Diagnostic laparoscopy was performed. Two additional 5 mm trocars were placed. The appendix was mobilized to reach skin in the right lower quadrant. The antegrade continence enema channel was matured. A small percutaneous cystotomy was then created via the suprapubic port site. The cystoscope was passed suprapubically and dextranomer/hyaluronic acid was injected in the bladder neck. A suprapubic tube was placed. RESULTS: We performed a total of 10 same setting laparoscopic antegrade continence enemas with antegrade bladder neck injection in 4 males and 6 females with a mean age of 9.4 years (range 6 to 13). All patients had a smooth walled bladder on cystogram, and good capacity, good compliance and low leak point pressure on urodynamics. There were no intraoperative complications and all patients were discharged home within 24 hours. At an average 18-month followup (range 12 to 27) all 10 patients were continent of stool and reported marked improvement in daily care. No patient experienced stool or gas leakage via antegrade bladder neck injection. Seven of 10 patients (70%) were continent of urine and no longer wore diapers. CONCLUSIONS: Same setting laparoscopic antegrade continence enema with antegrade bladder neck injection is a safe, efficacious, reasonably simple minimally invasive approach to severe constipation and urinary incontinence in patients with spina bifida. PMID- 20728119 TI - Editorial comment. PMID- 20728120 TI - Editorial comment. PMID- 20728122 TI - Sutureless and scalpel-free circumcision--more rapid, less expensive and better? AB - PURPOSE: We previously reported our success with sutureless circumcision using 2 octyl cyanoacrylate in 267 patients. We have since modified our technique by making incisions with electrocautery. We report our results with this novel technique. We also performed a cost analysis. MATERIALS AND METHODS: We compiled data on all patients 6 months to 12 years old who underwent primary circumcision and circumcision revision in a 39-month period, as done by 3 surgeons. Study exclusion criteria were complexity beyond phimosis and Gomco clamp use. The technique included 1) a circumferential inner incision using electrocautery on cutting current, 2) a circumferential outer incision using electrocautery, 3) foreskin removal, 4) hemostasis with electrocautery, 5) skin edge approximation with 2-octyl cyanoacrylate or 6-zero suture and 6) antibiotic ointment application. We also determined the cost of all procedures based on anesthesia and operating room facility fees, and material costs. RESULTS: Between July 1, 2006 and October 1, 2009 we performed 493 primary circumcisions and 248 revisions using 2-octyl cyanoacrylate, and 152 primary circumcisions and 115 revisions using 6-zero sutures. Mean operative time for primary circumcision and revision using 2-octyl cyanoacrylate was 8 minutes (range 6 to 18), and for sutured primary circumcision and revision it was 27 minutes (range 18 to 48). At a mean 18-month followup (range 1 to 39) 3 patients treated with 2-octyl cyanoacrylate and 2 treated with sutures were rehospitalized for bleeding. When done with electrocautery, the cost of the 2-octyl cyanoacrylate technique was $743.55 less than the sutured technique as long as the 2-octyl cyanoacrylate procedures required less than 15 minutes and the sutured procedures required more than 15 minutes. CONCLUSIONS: Combined electrocautery and 2-octyl cyanoacrylate for circumcision is a safe, efficient, financially beneficial, cosmetically appealing alternative to traditional circumcision done with scalpel and sutures. PMID- 20728123 TI - Progression of renal insufficiency in children and adolescents with neuropathic bladder is not accelerated by lower urinary tract reconstruction. AB - PURPOSE: Children with chronic renal insufficiency and neuropathic bladder resistant to medical management may require lower urinary tract reconstruction before renal transplantation. A low pressure urinary reservoir optimizes the chance of graft survival and may slow native kidney death. We evaluated whether the renal deterioration rate is affected by augmentation cystoplasty. MATERIALS AND METHODS: We performed a retrospective cohort study in children who presented to our institution with chronic renal insufficiency and neuropathic bladders from 2005 to 2009. Chronic renal insufficiency was defined as a glomerular filtration rate of less than 60 ml per minute. As a surrogate for renal function change, we used the inverse creatinine trend with respect to time to determine the progression rate of renal insufficiency before and after augmentation. RESULTS: A total of 11 patients with a mean glomerular filtration rate of 34 ml per minute per 1.73 m(2), mean bladder capacity 168 ml and mean compliance 3.5 ml/cm H(2)O met study inclusion criteria. Bladder augmentation or replacement was done at a mean age of 9.7 years with a resultant mean capacity of 486 ml and compliance of 14.7 ml/cm H(2)O. Mean followup was 4 years before and 1.9 years after augmentation. There was no statistically significant difference between the preoperative and postoperative slopes of inverse creatinine in 8 of 11 patients (73%). Two of the 3 patients (18%) with different preoperative and postoperative slopes had improving renal function after surgery. There was no statistically significant difference in slopes across all patients. CONCLUSIONS: In our series bladder augmentation did not appear to hasten progression to end stage renal disease in patients with severe chronic renal insufficiency and neuropathic bladder. PMID- 20728124 TI - Prospective open label study of solifenacin for overactive bladder in children. AB - PURPOSE: We evaluated the effect of solifenacin for urinary incontinence in children with overactive/neurogenic bladder refractory to oxybutynin or tolterodine. MATERIALS AND METHODS: Pediatric patients presenting with refractory overactive bladder with incontinence were offered the opportunity to enter a prospective, open label protocol using adjusted dose regimens of 1.25 to 10 mg solifenacin. Study inclusion criteria were absent correctable neurological anomalies on magnetic resonance imaging, failure of symptoms to improve on intensive behavioral and medical (oxybutynin or tolterodine) therapy, and/or significant side effects of those agents. Followup consisted of a voiding diary, post-void residual urine measurement, urine culture, ultrasound and urodynamics. Families were questioned about continence, side effects, compliance, behavior change and quality of life. The primary end point was efficacy for continence and secondary end points were tolerability and safety. RESULTS: Enrolled in the study were 42 girls and 30 boys. Of the patients 27 with neurogenic bladder, of whom 11 were on clean intermittent catheterization, and 45 with overactive bladder completed a minimum 3-month followup. Patients were on solifenacin a mean of 15.6 months. Mean age at study initiation was 9.0 years. Mean +/- SD urodynamic capacity improved from 146 +/- 64 to 311 +/- 123 ml and uninhibited contractions decreased from 70 +/- 29 to 20 +/- 19 cm H(2)O (p <0.01). Continence improved in all patients, including 24 who were dry, and 42 and 6 who were significantly and moderately improved, respectively. Of the patients 50 reported no side effects while 15 had mild and 3 had moderate side effects. Four patients withdrew from the protocol due to intolerable side effects. Four patients had significant post void residual urine (greater than 20 ml). CONCLUSIONS: In children with overactive bladder refractory to oxybutynin or tolterodine solifenacin is an effective alternative to improve symptoms. Tolerability was acceptable and the adjusted dose regimen appeared safe. PMID- 20728125 TI - Ezetimibe reduces enlarged prostate in an animal model of benign prostatic hyperplasia. AB - PURPOSE: Benign prostatic hyperplasia is a common urinary tract disorder that affects aging men. The molecular mechanisms underlying benign prostatic hyperplasia are obscure and the development of animal models to test novel treatment strategies is challenging. We report that the Bio 87.20 hamster strain (Bio Breeders, Watertown, Massachusetts) shows 5alpha-reductase-sensitive prostate enlargement and a decrease in circulating cholesterol reduces prostate size. MATERIALS AND METHODS: Bio 87.20 hamsters 17 months old with an enlarged prostate were fed a diet containing no or minimal cholesterol and including finasteride (Merck, Whitehouse Station, New Jersey) and/or ezetimibe (Schering Plough, Kenilworth, New Jersey) for 4 months. The prostate complex was removed, volume and weight were determined, and tissue was examined histologically. RESULTS: Prostate enlargement depended on cholesterol in the diet. Blockade of intestinal cholesterol transport with ezetimibe induced prostate regression to a similar extent as the 5alpha-reductase inhibitor finasteride, a compound used to treat benign prostatic hyperplasia in humans. Histological analysis indicated that finasteride induced widespread prostatic atrophy but normal glandular architecture was preserved in the ezetimibe cohort. CONCLUSIONS: Results indicate that dysregulation of cholesterol metabolism may be a component of benign prostatic hyperplasia and ezetimibe may be effective as an alternative or adjunct to standard treatment. Our findings also show that the Bio 87.20 hamster is a suitable model for preclinical evaluation of novel benign prostatic hyperplasia therapy. PMID- 20728126 TI - Editorial comment. PMID- 20728127 TI - Transurethral puncture for ureterocele-which factors dictate outcomes? AB - PURPOSE: We evaluated which clinical factors influence the outcome of primary transurethral puncture for ureterocele. MATERIALS AND METHODS: A total of 45 patients (47 ureteroceles) underwent primary transurethral incision between 1994 and 2008 at 2 institutions. Age at and mode of presentation, upper tract status, ureterocele site, preoperative vesicoureteral reflux and the corresponding upper pole or kidney function were analyzed to identify which factors influenced the need for secondary surgery. RESULTS: Transurethral puncture was the only treatment in 24 of 45 patients (53%) while 21 (47%) required further surgery. After transurethral puncture secondary surgery was required in 56% of patients who presented prenatally vs 27% of those who presented postnatally (p = 0.165), in 18% with a single system vs 58% with a duplex system (p = 0.036), in 30% with intravesical vs 63% with ectopic ureterocele (p = 0.039) and in 61% vs 37% with ureterocele units with vs without preoperative vesicoureteral reflux (p = 0.148). Fisher's 2-tailed exact test revealed an inconsistent distribution of negative prognostic factors, including duplex systems, ectopic ureterocele and vesicoureteral reflux at presentation, in prenatally vs postnatally and in asymptomatically vs symptomatically presenting subgroups. CONCLUSIONS: Upper tract status and ureterocele site influence the outcome of primary transurethral puncture as a definitive procedure. After puncture secondary surgery is least likely in patients with a single system and intravesical ureterocele. PMID- 20728128 TI - Comparison of bladder outlet procedures without augmentation in children with neurogenic incontinence. AB - PURPOSE: We compared continence results of the bladder neck sling vs the Leadbetter-Mitchell bladder neck procedure plus fascial sling in children with neurogenic urinary incontinence. MATERIALS AND METHODS: We compared consecutive patients who received a 360-degree tight bladder neck sling to subsequent, similar patients who underwent a Leadbetter-Mitchell bladder neck procedure plus fascial sling involving a 50% reduction in bladder neck and proximal urethral diameter before a 360-degree tight sling. All patients underwent simultaneous appendicovesicostomy and none had undergone prior or simultaneous augmentation. All patients followed similar preoperative and postoperative protocols for urodynamic evaluation and anticholinergic therapy with data maintained prospectively. RESULTS: After surgery 46% of 35 sling cases did not require pads vs 82% of 17 Leadbetter-Mitchell cases with a sling (p = 0.02). Mean followup was 28 months in sling and 13 months in Leadbetter-Mitchell cases. Initial urodynamics done approximately 6 months postoperatively were similar in the 2 cohorts and no patient had hydronephrosis. Transient low grade reflux occurred in 2 Leadbetter-Mitchell cases, of which 1 with increased intravesical pressures early after surgery that caused trabeculation received increased medical management. Augmentation was not done in any patient except 1 previously reported on after a sling. CONCLUSIONS: Patients undergoing Leadbetter-Mitchell procedure plus fascial sling were significantly less likely to require pads postoperatively than those with a sling alone. Adverse bladder changes have not required augmentation to date. PMID- 20728129 TI - Editorial comment. PMID- 20728131 TI - 5-year prospective results of dimercapto-succinic acid imaging in children with febrile urinary tract infection: proof that the top-down approach works. AB - PURPOSE: Evaluation in children after febrile urinary tract infection involves voiding cystourethrogram, which emphasizes urinary reflux rather than renal risk. We believe that early dimercapto-succinic acid renal scan after febrile urinary tract infection predicts clinically significant reflux and which children should undergo voiding cystourethrogram. The criticism of this approach is that some reflux and preventable renal damage would be missed. This study validates the use of initial dimercapto-succinic scan and presents 5-year renal outcomes. MATERIALS AND METHODS: We prospectively studied children with febrile urinary tract infection using initial dimercapto-succinic acid renal scan, voiding cystourethrogram and renal/bladder ultrasound. Children with anatomical or neurological genitourinary abnormality and protocol failures were excluded from analysis. Dimercapto-succinic acid scan was repeated at 6 months if initially abnormal. Followup was done every 6 months in all children for at least 5 years. RESULTS: A total of 121 children fit study inclusion criteria and completed the 5 year study. Overall 88 initial dimercapto-succinic acid scans (73%) were abnormal and 78 children (64%) had urinary reflux. The OR of having clinically significant reflux predicted by abnormal initial scan was 35.4. Abnormal followup scan did not predict clinically significant reflux. Overall subsequent urinary tract infection developed in 32 patients (26.5%) and 27 (85%) had an abnormal initial scan. No child with a normal initial scan had clinically significant reflux. CONCLUSIONS: Dimercapto-succinic acid scan can predict clinically significant reflux and children at greatest renal risk. Initial dimercapto-succinic acid scan should be done in all children after febrile urinary tract infection while voiding cystourethrogram should be reserved for those with an abnormal initial dimercapto-succinic acid scan. PMID- 20728133 TI - Long-term outcome of pituitary-gonadal axis and gonadal growth in patients with hypospadias at puberty. AB - PURPOSE: Reports of pubertal hormonal and gonadal status in patients with hypospadias are scarce. We evaluated the pituitary-gonadal axis and gonadal growth in patients with hypospadias at puberty. MATERIALS AND METHODS: We retrospectively reviewed serum luteinizing hormone, follicle-stimulating hormone, testosterone and testicular volume at puberty (age 15 years or greater) in the medical charts of patients with hypospadias treated since 1986 and followed at our institution. RESULTS: Enrolled in this study were 43 patients with a mean age at evaluation of 17.6 years (range 15.1 to 22.8). Of these patients 14 and 29 were treated for mild and severe hypospadias, respectively. Six patients with severe hypospadias underwent bilateral orchiopexy for bilateral undescended testes. All patients were Tanner stage 4 to 5 at evaluation. Of 14 mild hypospadias cases we noted hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, decreased luteinizing hormone and decreased testosterone in 1 each (7% each). Of 23 severe hypospadias cases without bilateral undescended testes we noted hypergonadotropic hypogonadism, partial androgen insensitivity syndrome and decreased testosterone in 2 (9%), 1 (4%) and 1 (4%), respectively. Of 6 patients with severe hypospadias and bilateral undescended testes we noted hypergonadotropic hypogonadism in 1 (17%) and increased luteinizing hormone with normal testosterone in 2 (33%). Testicular volume less than 10 ml with increased follicle-stimulating hormone was identified in 7 of 43 patients, including 1 of 14 (7%) with mild hypospadias, 3 of 23 (13%) with severe hypospadias without bilateral undescended testes and 3 of 6 (50%) with severe hypospadias and bilateral undescended testes. CONCLUSIONS: Our study revealed endocrine dysfunction in patients with mild and severe hypospadias at puberty even without an undescended testis. Of these patients those with severe hypospadias and an undescended testis may be at higher risk for impaired spermatogenesis. PMID- 20728134 TI - Objective patterning of uroflowmetry curves in children with daytime and nighttime wetting. AB - PURPOSE: Pediatric uroflowmetry curve interpretation is incompletely standardized. Thus, we propose new, objective patterning. MATERIALS AND METHODS: Uroflowmetry curves were obtained in 100 children presenting with daytime incontinence or enuresis. Each curve was compared with a standard curve generated from a published nomogram and a new patterning method was formulated. Staccato and interrupted patterns were defined using International Children's Continence Society criteria. The remaining curves were divided by the deviation of the maximal flow rate from the median nomogram value as certain patterns, including tower-greater than 130%, not abnormal-70% to 130% and plateau-less than 70%. The correlation between the presenting symptom and patterns or other uroflowmetry parameters was evaluated. Six pediatric urologists also patterned the same curves subjectively. RESULTS: All curves could be classified as 1 of the defined patterns using this method. Pattern distribution reflected the spectrum of presenting symptoms with more tower, interrupted and staccato patterns in children with daytime wetting than in those with monosymptomatic enuresis. Age adjusted voided volume was also smaller in the former group but post-void residual urine, and maximal and average flow rates did not correlate with presenting symptoms. Subjective patterning showed marked interobserver differences. When patterning applied by the current method was used as a reference, observer sensitivity for abnormal patterns inversely correlated with specificity. CONCLUSIONS: Subjective uroflowmetry patterning is liable to personal bias. The proposed method enables objective patterning that complies with International Children's Continence Society standardization and clinical presentation. PMID- 20728135 TI - Editorial comment. PMID- 20728136 TI - The physiological significance of p27(KIP1) expression in detrusor function. AB - PURPOSE: Bladder outlet obstruction results in smooth muscle cell hyperplasia, decreased bladder wall compliance, and lower and upper urinary tract pathology. The cyclin-dependent kinase inhibitor p27(KIP1) regulates bladder smooth muscle cell proliferation in response to bladder outlet obstruction but little is known about its physiological role in the bladder. We investigated the role of p27(KIP1) in the structure and function of the detrusor layer of the bladder wall. MATERIALS AND METHODS: We used immunoblotting and reverse transcriptase polymerase chain reaction to examine cell cycle regulation in response to increased mechanical tension in an in vitro model of tension induced smooth muscle cell proliferation and an in vivo model of bladder outlet obstruction. We compared unobstructed bladders of p27(+/+) and p27(-/-) mice (Jackson Laboratory, Bar Harbor, Maine) structurally by histological staining and functionally by in vivo cystometric measurements of bladder capacity, detrusor compliance and detrusor leak point pressure. RESULTS: Increased tension decreased p27(KIP1) at the protein level in human bladder smooth muscle cells and in intact murine bladder smooth muscle. p27(-/-) mice had bladder smooth muscle cell hyperplasia even in the absence of bladder outlet obstruction. While p27 loss had little effect on detrusor leak point pressure, p27(-/-) mice had significantly decreased bladder capacity and detrusor compliance. CONCLUSIONS: To our knowledge we provide the first report of the in vivo significance of p27(KIP1) in the regulation of detrusor function using a cystometric approach. We identified a role for p27(KIP1) in protecting against dysregulated smooth muscle cell proliferation, bladder capacity and detrusor compliance under normotensive conditions. PMID- 20728137 TI - Is oral vitamin B(12) therapy effective for vitamin B(12) deficiency in patients with prior ileocystoplasty? AB - PURPOSE: We previously identified vitamin B(12) deficiency as a potential long term consequence in pediatric patients with prior ileocystoplasty despite adequate preservation of terminal ileum. Vitamin B(12) deficiency can result in hematological and neurological deficits, of which some are irreversible. Deficiency discovered after ileocystoplasty is purportedly due to B(12) malabsorption since the principal absorption site is ileum. B(12) deficiency due to malabsorption is typically treated with intramuscular injection to ensure adequate treatment. We determined whether oral vitamin B(12) supplementation could increase serum vitamin B(12) in patients with deficiency who underwent ileocystoplasty. MATERIALS AND METHODS: During followup after ileocystoplasty we identified patients with low (200 pg/dl or less) or low normal (200 to 300 pg/dl) vitamin B(12). Oral vitamin B(12) was begun at 250 MUg. Serum B(12) was assessed at 1, 2 and 3-month intervals after beginning therapy. RESULTS: A total of 128 patients with a mean followup of 83 months after ileocystoplasty had vitamin B(12) levels available for review. Of these patients 36 (28%) had a level of 300 pg/dl or less with a level of 200 pg/dl or less in 16 (13%). After oral vitamin B(12) treatment serum levels increased from a mean 235 to 506 pg/dl (114%) upon initial measurement (p <0.001). Subsequent measurements continued to increase from the first posttreatment level (p <0.05). No adverse effects were noted during a mean 4-month followup. CONCLUSIONS: To our knowledge this is the first study to show that oral vitamin B(12) effectively increases serum levels in pediatric patients with prior ileocystoplasty. PMID- 20728139 TI - Is retroperitoneoscopy the gold standard for endoscopic nephrectomy in children on peritoneal dialysis? AB - PURPOSE: The literature on minimally invasive nephrectomy in adults and children on peritoneal dialysis is sparse. Case reports suggest that the transperitoneal approach is effective. We present our experience with retroperitoneoscopic nephrectomy in children on peritoneal dialysis. MATERIALS AND METHODS: At 11 consecutive retroperitoneoscopic nephrectomies a total of 14 kidneys were removed from 10 children with a mean age of 12 years. We used a 3-port lateral retroperitoneoscopic nephrectomy technique with active trainee participation. Preoperative and postoperative biochemistry results within 3 months of surgery were compared with the Wilcoxon signed rank test. RESULTS: Three bilateral synchronous, 1 bilateral staged and 6 unilateral retroperitoneoscopic nephrectomies were done. Mean operative time was 174 minutes for unilateral and 458 minutes for bilateral nephrectomy, including 1 simultaneous peritoneal dialysis insertion and 1 umbilical hernia repair. No open conversion, blood transfusion or postoperative surgical complication was noted. Peritoneal dialysis was initiated at a median of 9 hours postoperatively and dialysate volume was titrated to target within a median of 60 hours. One patient with a small peritoneotomy needed temporary hemodialysis despite intraoperative airtight repair. After surgery median serum albumin increased from 30.0 to 34.3 gm/l. CONCLUSIONS: Retroperitoneoscopic nephrectomy for end stage renal disease is a safe, effective technique that preserves peritoneal integrity in children who require immediate postoperative peritoneal dialysis. Avoiding post-nephrectomy hemodialysis decreases patient morbidity, preserving vessels for future vascular access. Compared to the literature on laparoscopy in this setting, retroperitoneoscopic nephrectomy can be considered the ideal approach for minimally invasive nephrectomy in patients on peritoneal dialysis. PMID- 20728140 TI - Editorial comment. PMID- 20728142 TI - Editorial comment. PMID- 20728141 TI - Sonourethrogram to manage adolescent anterior urethral stricture. AB - PURPOSE: Accurate measurement of anterior urethral stricture length is critical to determine the appropriate surgical approach. Retrograde urethrogram is often used to determine stricture location and length. However, the adult literature shows that retrograde urethrogram may underestimate stricture length. We investigated the role of sonographic urethrogram in the preoperative evaluation of adolescent urethral stricture disease. MATERIALS AND METHODS: Between June 2008 and February 2009 we retrospectively evaluated 12 pediatric patients with urethral stricture disease using retrograde and sonographic urethrogram. Stricture length was categorized by 2 radiologists as I-less than 1, II-1 to 3 and III-greater than 3 cm. On sonographic urethrogram stricture length was measured as the longest extent of the urethral abnormality. RESULTS: Mean patient age was 16.9 years (range 9.5 to 20.8). Retrograde urethrogram classified 7 cases as category I, 4 as category II and none as category III stricture, and 1 with no evidence of stricture. Sonographic urethrogram revealed strictures greater than 1 cm in all 7 category I cases and 2 of the 4 category II cases had strictures longer than 3 cm. One patient in whom retrograde urethrogram showed a category II stricture was stricture-free on sonographic urethrogram. One patient with a negative retrograde urethrogram had a stricture on sonographic urethrogram. Sonographic urethrogram upgraded stricture length in 10 of the 12 patients and outperformed retrograde urethrogram in 11. CONCLUSIONS: Sonographic urethrogram is effective for evaluating adolescent urethral stricture disease. It may provide more accurate measurement of stricture length and improve preoperative planning. PMID- 20728143 TI - Rate and associations of epididymal cysts on pediatric scrotal ultrasound. AB - PURPOSE: We established the baseline occurrence of epididymal cysts, and the correlation between epididymal cysts and testicular size. MATERIALS AND METHODS: We retrospectively reviewed all pediatric scrotal ultrasounds done at our institution in 8 years. We analyzed the proportion of cysts by patient age and compared testicular size in boys with vs without epididymal cysts. RESULTS: Of all patients 14.4% had epididymal cysts. The cyst incidence increased with age, ie 35.3% of boys older than 15 years had cysts. Boys with epididymal cysts had larger testes than boys without cysts regardless of side or age (p <0.001). CONCLUSIONS: Epididymal cysts are more common in older boys. Boys with epididymal cysts had larger testes than boys without cysts. PMID- 20728144 TI - Editorial comment. PMID- 20728146 TI - Trends in imaging and surgical management of pediatric urolithiasis at American pediatric hospitals. AB - PURPOSE: Little is known of current practice patterns for pediatric urolithiasis. We examined recent trends in imaging and surgical management. MATERIALS AND METHODS: The Pediatric Health Information System database is a national database collected at American pediatric hospitals. We searched the database from 1999 to 2008 to identify children diagnosed with urolithiasis. Inpatient hospital admissions, and emergency department and outpatient medical/surgical short stay visits were included. We examined imaging and surgical management trends during the study period using bivariate and multivariate logistic regression models. RESULTS: We identified 7,921 children diagnosed with urolithiasis during the study period, of whom 1,712 (22%) underwent stone related surgery and 6,318 (80%) underwent stone related diagnostic imaging. The surgery rate remained stable during the study period (p = 0.15), as did the overall imaging rate (p = 0.2). However, computerized tomography use increased (26% to 45%) and plain x-ray of kidneys, ureters and bladder plus excretory urogram use decreased (59% to 38%) during the study period (each p <0.0001). Surgery was associated with older patient age, female gender, white race and private insurance. Computerized tomography use was associated with older patient age, nonwhite race and public insurance. After adjusting for other factors, including hospital region, the treating hospital was most important for predicting surgery or computerized tomography (each p <0.0001). CONCLUSIONS: Surgery and imaging for pediatric urolithiasis remained stable at pediatric hospitals in the last decade, although computerized tomography use has increased. The hospital where a patient receives treatment is the single most important feature driving computerized tomography and surgery use. Patient age, race and insurance status have a smaller but significant role. PMID- 20728147 TI - Pediatric urolithiasis--does body mass index influence stone presentation and treatment? AB - PURPOSE: Pediatric obesity is a major public health concern in the United States. We investigated the association of body mass index with presentation and outcome in children with urolithiasis. MATERIALS AND METHODS: We identified all patients 2 to 18 years old at our institution with a radiographically confirmed first renal or ureteral stone between January 2003 and June 2008. Data abstracted included demographics, stone characteristics, treatment and metabolic evaluation. Patients were stratified into 3 body mass index categories, including lower (10th percentile or less for age), normal (10th to 85th percentile) and upper (85th percentile or greater) percentile body weight. RESULTS: Of the children 62 boys (55.4%) and 50 girls (44.6%) were evaluable. Mean age at diagnosis was 11.8 years. Body mass index stratification showed lower percentile body weight in 11 patients (9.8%), normal percentile body weight in 55 (49.1%) and upper percentile body weight in 46 (41.1%). Mean stone diameter was 5.0 mm. Of the stones 31 (27.7%) were in the kidney or ureteropelvic junction and 81 (72.3%) were in the ureter. Surgery was done in 87 patients (78.9%) and stone clearance was accomplished by 1 (69.0%) or 2 (31.0%) procedures in all. Lower percentile body weight patients presented earlier than normal and upper percentile body weight patients (9.0 vs 12.2 and 12.0 years, respectively, p = 0.04). Neither stone size nor the number of procedures required for stone clearance differed significantly by body mass index. CONCLUSIONS: Upper percentile body weight was not associated with earlier stone development, larger stones or the need for multiple surgical procedures. In lower percentile body weight patients symptomatic renal stones developed significantly earlier than in normal or upper percentile body weight patients. Stone size and the surgical intervention rate were similar regardless of body mass index. Further research may identify potential factors predisposing children with lower percentile body weight to early stone development. PMID- 20728149 TI - Editorial comment. PMID- 20728148 TI - Editorial comment. PMID- 20728150 TI - Editorial comment. PMID- 20728151 TI - Editorial comment. PMID- 20728152 TI - Adolescent varicocele: influence of Tanner stage at presentation on the presence, development, worsening and/or improvement of testicular hypotrophy without surgical intervention. AB - PURPOSE: Testicular asymmetry in adolescents with varicocele can worsen, remain unchanged or decrease on followup. We determined the incidence of testicular asymmetry at presentation by Tanner stage and the correlation between Tanner stage at presentation and subsequent changes in percent asymmetry (ability for catch-up growth or progressive asymmetry) without surgical intervention. MATERIALS AND METHODS: We retrospectively studied the records of 115 boys with a mean age of 14.1 years (range 9.2 to 20.0) with grade 2 or 3 left varicocele who underwent testicular volume measurement at 2 visits at least that were a minimum of 6 months apart. Of the patients 92% and 8% underwent Doppler duplex ultrasound and orchidometry, respectively. Patients were divided into 2 groups, including those with less than 15% and those with 15% or greater asymmetry. Catch-up growth was defined as less than 15% asymmetry at any subsequent visit. RESULTS: At presentation 58%, 64%, 67%, 35% and 39% of Tanner 1 to 5 cases showed 15% or greater testicular asymmetry, respectively. When Tanner 1 to 3 cases were combined and compared with Tanner 4 and 5 cases, the difference in initial asymmetry was significant (64% vs 38%, p = 0.007). Although it was not statistically significant, there was a trend toward more catch-up growth for the later Tanner stages, including 27% for Tanner 1 to 3 vs 53% for Tanner 4 and 5 (p = 0.06). CONCLUSIONS: Slightly more than 50% of children and adolescents referred with varicocele have 15% or greater testicular asymmetry at presentation. Initial asymmetry is statistically more common in cases of earlier Tanner stages (1 to 3). Adolescents with 15% or greater testicular asymmetry who present at higher Tanner stages (4 and 5) show a trend toward a higher incidence of catch-up growth, although it is not significant. PMID- 20728153 TI - Editorial comment. PMID- 20728155 TI - Should male gender assignment be considered in the markedly virilized patient With 46,XX and congenital adrenal hyperplasia? AB - PURPOSE: We assess the outcome in 46,XX men with congenital adrenal hyperplasia who were born with Prader 4 or 5 genitalia and assigned male gender at birth. MATERIALS AND METHODS: After receiving institutional review board approval and subject consent we reviewed the medical records of 12 men 35 to 69 years old with 46,XX congenital adrenal hyperplasia, of whom 6 completed social and gender issue questionnaires. RESULTS: All subjects were assigned male gender at birth, were diagnosed with virilizing congenital adrenal hyperplasia at age greater than 3 years and indicated a male gender identity with sexual orientation to females. Ten of the 12 subjects had always lived as male and 2 who were reassigned to female gender in childhood subsequently self-reassigned as male. Nine of the 12 men had long-term female partners, including 7 married 12 years or more. The 3 subjects without a long-term female partner included 1 priest, 1 who was reassigned female gender, married, divorced and self-reassigned as male, and 1 with a girlfriend and sexual activity. All except the priest and the subject who was previously married when female indicated a strong libido and frequent orgasmic sexual activity. Responses to self-esteem, masculinity, body image, social adjustment and symptom questionnaires suggested adjustments related to the extent of familial and social support. CONCLUSIONS: Outcome data on severely masculinized 46,XX patients with congenital adrenal hyperplasia who were assigned male gender at birth indicate male gender identity in adulthood with satisfactory male sexual function in those retaining male genitalia. In men who completed questionnaires results were poorer in those lacking familial/social support. Male gender of rearing may be a viable option for parents whose children are born with congenital adrenal hyperplasia, a 46,XX karyotype and male genitalia, although positive parental and other support, and counseling are needed for adjustment. PMID- 20728156 TI - Editorial comment. PMID- 20728158 TI - Is adolescent varicocelectomy safe after previous inguinal surgery? AB - PURPOSE: Varicocelectomy after previous inguinal surgery poses a potential risk of testicular volume loss. To assess the extent to which varicocelectomy can be done without the complication of ipsilateral testis atrophy we present outcomes in adolescent patients with a history of inguinal surgery who underwent ipsilateral varicocelectomy. MATERIALS AND METHODS: We retrospectively reviewed patient data from a single urologist practice. Testicular volume was recorded preferentially by ultrasound or, when unavailable, by ring orchidometry. Testicular asymmetry was calculated using the formula, [(right testis volume - left testis volume)/right testis volume] * 100. Symmetry was defined as less than 10% asymmetry. Catch-up growth was defined as resolution of asymmetry. RESULTS: We identified 22 adolescent patients who fit study criteria. The patients underwent a total of 25 varicocelectomies since 3 underwent bilateral repair after previous bilateral inguinal surgery. Initial inguinal surgery included inguinal herniorrhaphy, hydrocelectomy and orchiopexy. Varicocelectomy was done laparoscopically in 17 cases and via open technique in 8 with variations in preservation/sacrifice of the lymphatics and artery. Median +/- SD followup was 24.2 +/- 18.2 months. After varicocelectomy mean testicular asymmetry decreased from 27.6% to 10.5%. There was no incidence of testicular atrophy postoperatively. The incidence of catch-up growth was 43% with no difference between the artery sparing and the nonartery sparing technique. CONCLUSIONS: Varicocelectomy with a history of previous inguinal surgery is safe and provides a significant incidence of testicular catch-up growth. Artery sparing vs sacrificing technique did not make a difference in terms of catch-up growth. PMID- 20728160 TI - Editorial comment. PMID- 20728159 TI - Are abdominal x-rays a reliable way to assess for constipation? AB - PURPOSE: Currently to our knowledge no validated reliable tools are available to evaluate constipation in children. Abdominal x-rays are often done in clinical practice to evaluate patients with lower urinary tract symptoms. Although 3 previously published rating tools exist to score constipation based on x-ray, there is little information on their merits. We assessed these 3 tools for reliability among multiple practitioners. MATERIALS AND METHODS: We retrospectively analyzed abdominal x-rays in a cohort of 80 patients between ages 4 and 12 years. X-rays were independently assessed by each of us using the previously published Barr, Leech and Blethyn scoring tools. Scores were analyzed for reliability using standard statistical methods. RESULTS: The range of weighted kappa score, indicating reliability, were 0.0491 to 0.4809 for the Barr, 0.1195 to 0.2730 for the Leech and 0.0454 to 0.4514 for the Blethyn method. Guidelines for kappa scores are greater than 0.75-excellent, 0.4 to 0.75-good and 0 to 0.4-marginal reproducibility. ICC, another reliability measure, was 0.02577 for the Barr, 0.3313 for the Leech and 0.201 for the Blethyn method. ICC interpretations are greater than 0.75-excellent, 0.4 to 0.75-good and 0 to 0.4 poor. There was a trend toward good interrater reliability between more experienced urology practitioners with the Barr and Blethyn tools (0.48 and 0.45, respectively) but not between less experienced raters or with the Leech tool. CONCLUSIONS: Currently available scoring tools to evaluate constipation by x-ray do not have good reliability among multiple examiners. Further research is needed to develop an alternate tool to increase the reliability of x-ray to assess constipation between multiple raters. PMID- 20728162 TI - Editorial comment. PMID- 20728163 TI - Improved continence in patients with neurogenic sphincteric incompetence with combination tubularized posterior urethroplasty and fascial wrap: the lengthening, narrowing and tightening procedure. AB - PURPOSE: We evaluated the outcome in 19 patients who underwent bladder neck reconstruction by lengthening, narrowing and tightening the bladder neck with a combined tubularized posterior urethroplasty and circumferential fascial wrap. MATERIALS AND METHODS: We reviewed the records of all patients who underwent bladder neck lengthening, narrowing and tightening between April 1996 and November 2002. Preoperative urodynamic and radiographic data were available on all patients. The surgical technique involved retroperitoneal exposure of the bladder neck with a tubularized posterior urethroplasty over a urethral catheter. The reconstructed urethra was then circumferentially wrapped with a fitted piece of cadaveric fascia. RESULTS: Of the 19 patients 15 remain completely continent at a mean +/- SD followup of 35.5 +/- 29.1 months. Three patients underwent secondary reconstruction, including bladder neck ligation in all 3 and secondary enterocystoplasty in 2. No patient experienced difficult intermittent catheterization via the urethra postoperatively. CONCLUSIONS: Bladder neck lengthening, narrowing and tightening is effective for managing neurogenic sphincteric incontinence. Outcomes are comparable with those of other reconstructive procedures. PMID- 20728165 TI - Residency training in neonatal circumcision: a pilot study and needs assessment. AB - PURPOSE: Routine neonatal circumcision is one of the most commonly performed procedures in a neonate. Residents are expected to acquire the skills to properly evaluate the neonate and gain proficiency in performing circumcision despite significant variability in training. We performed a needs assessment to evaluate obstetric-gynecology residency training in neonatal circumcision. MATERIALS AND METHODS: We performed an online self-assessment survey of obstetric-gynecology residents at Prentice Hospital, Chicago, from November 2008 to February 2009. Using images of uncircumcised penises residents were asked to identify which patients were candidates for routine neonatal circumcision. RESULTS: Of 36 obstetric-gynecology residents 27 responded to the survey. Most respondents planned to perform neonatal circumcision when in practice, 44% had no formal training in circumcision and most were comfortable performing routine neonatal circumcision. Overall respondents were less comfortable evaluating whether the a newborn penis could undergo circumcision safely. When presented with 10 pictures of penises and asked to determine whether the neonate should undergo circumcision, 0% of respondents correctly identified all contraindications to neonatal circumcision with an average of 42% of contraindications identified correctly. Of the respondents 77% listed practical experience as the first choice to learn a procedure with an online module preferred by 55% as the second choice. CONCLUSIONS: Although most residents feel competent to technically perform the procedure, they are not confident in their ability to judge the appropriate contraindications to neonatal circumcision. This needs assessment highlights the necessity for further curriculum development and formalized training in this domain. PMID- 20728166 TI - Editorial comment. PMID- 20728167 TI - Sexuality and psychosocial functioning in young women after colovaginoplasty. AB - PURPOSE: We examined sexuality and psychosocial functioning in patients with Mayer-Rokitansky-Kuster-Hauser syndrome who underwent colovaginoplasty. MATERIALS AND METHODS: Patients who underwent colovaginoplasty for Mayer-Rokitansky-Kuster Hauser syndrome in Italy and Bangladesh were required to meet certain criteria, including age greater than 18 years, college degree/high socioeconomic status, procedure done by the same surgical team and a minimum 6-year followup. Outcomes were evaluated by a retrospective chart review and an English version of the female sexual function index. Psychosocial functioning was measured by an English version of a 36-item survey, including the Rosenberg Self-Esteem Scale, Beck Depression Index and Cohen Test for Life Management ability with results compared to those in 30 healthy control subjects. RESULTS: Of 40 patients who answered the female sexual function index 37% were married and 12% had adopted children while 40% were sexually active, 100% were attracted to males and 7% were on self dilation. None required pads and 80% used a home douche. Of the patients 92% reported sexual desire and 87% reported sexual arousal. Sexual confidence and satisfaction were reported by approximately 90% of the patients and partner satisfaction was considered adequate by 93%. Most patients reported satisfactory orgasm. Of the women 89% reported adequate lubrication and none reported dyspareunia. Psychosocial functioning was not statistically different between patients and controls. CONCLUSIONS: Based on the scoring system outcome colovaginoplasty seems to be an excellent choice to manage vaginal agenesis and ensure good quality of general and sexual life. PMID- 20728168 TI - Factors associated with delayed treatment of acute testicular torsion-do demographics or interhospital transfer matter? AB - PURPOSE: Testicular torsion is a true urological emergency. We determined whether a delay in treatment due to hospital transfer or socioeconomic factors would impact the orchiectomy rate in children with this condition. MATERIALS AND METHODS: We retrospectively evaluated the records of boys seen at a single institution emergency department who proceeded to surgery for a diagnosis of acute testicular torsion from 2003 to 2008. Charts were reviewed for transfer status, symptom duration, race, insurance presence or absence and distance from the hospital. Orchiectomy specimens were evaluated for histological confirmation of nonviability. RESULTS: We reviewed 97 records. The orchiectomy rate in patients who were vs were not transferred to the emergency department was 47.8% vs 68.9%, respectively (p = 0.07). Symptom duration was greater in the orchiectomy group with a mean difference of 47.9 hours (p <0.01). The mean transfer delay was 1 hour 15 minutes longer in the orchiectomy group (p = 0.01). Boys who underwent orchiectomy were 2.2 years younger than those who avoided orchiectomy (p = 0.01). Multivariate analysis showed that symptom duration and distance from the hospital were the strongest predictors of orchiectomy. CONCLUSIONS: Data suggest that torsion is a time dependent event and factors that delay time to treatment lead to poorer outcomes. These factors include distance from the hospital and the time delay associated with hospital transfer. PMID- 20728169 TI - Editorial comment. PMID- 20728170 TI - Editorial comment. PMID- 20728172 TI - Editorial comment. PMID- 20728171 TI - Validity of the international consultation on incontinence questionnaire pediatric lower urinary tract symptoms: a screening questionnaire for children. AB - PURPOSE: Lower urinary tract symptoms are common in pediatric patients. To our knowledge no validated instruments properly designed to screen lower urinary tract symptoms in the pediatric population have been published to date. In the International Consultation on Incontinence Questionnaire Committee the psychometric properties of a screening questionnaire for pediatric lower urinary tract symptoms were assessed. MATERIALS AND METHODS: The 12-item International Consultation on Incontinence Questionnaire-Pediatric Lower Urinary Tract Symptoms was developed in child and parent self-administered versions, and produced in English, Italian and German using a standard cross-cultural adaptation process. The questionnaire was self-administered to children 5 to 18 years old and their parents presenting for lower urinary tract symptoms (cases) or to pediatric/urological clinics for other reasons (controls). A case report form included history, urinalysis, bladder diary, flowmetry/post-void residual urine volume and clinician judgment on whether each child did or did not have lower urinary tract symptoms. Questionnaire psychometric properties were evaluated and data were stratified into 3 age groups, including 5 to 9, 10 to 13 and 14 to 18 years. RESULTS: A total of 345 questionnaires were completed, of which 147 were negative and 198 were positive for lower urinary tract symptoms. A mean of 1.67% and 2.10% of items were missing in the child and parent versions, respectively. Reliability (Cronbach's alpha) was unacceptable in only the 5 to 9-year-old group. The high ICC of 0.847 suggested fair child/parent equivalence. Sensitivity and specificity were 89% and 76% in the child version, and 91% and 73.5% in the parent version, respectively. CONCLUSIONS: The questionnaire is an acceptable, reliable tool with high sensitivity and specificity to screen for lower urinary tract symptoms in pediatric practice. Problems related to literacy suggest use of the child versions for patients older than 9 years. In research this questionnaire could be used to recalibrate the prevalence of lower urinary tract symptoms in children. PMID- 20728173 TI - Does preoperative genitography in congenital adrenal hyperplasia cases affect surgical approach to feminizing genitoplasty? AB - PURPOSE: Genitography has traditionally been an imperative part of radiographic evaluation in females born with congenital adrenal hyperplasia before surgical reconstruction. We evaluated the role of preoperative genitogram in surgical reconstruction planning and how it correlates with intraoperative findings. MATERIALS AND METHODS: We retrospectively reviewed the records of 40 patients with congenital adrenal hyperplasia who underwent feminizing genitoplasty at our institution between 2003 and 2009. Preoperative genitogram findings were recorded and correlated with operative findings. RESULTS: A total of 42 preoperative genitograms were available for review in 40 patients with congenital adrenal hyperplasia who underwent feminizing genitoplasty. Genitography revealed complete anatomy of the urogenital sinus in 30 cases (72%) while bladder filling alone was present in 9 (21%) and vaginal filling was noted in 2 (5%). The urogenital sinus could not be catheterized in 1 patient (2%). Vesicoureteral reflux was identified in 6 patients (15%) with a mean grade of 2. Vaginoplasty was done with a flap technique in 37 patients (more than 90%) while the remaining 3 underwent pull through vaginoplasty. In no case did genitogram reveal anatomy that was not visible via endoscopy or at reconstruction. The vaginoplasty technique was based on endoscopic and intraoperative findings, and not on genitogram. CONCLUSIONS: Genitography during preoperative evaluation in females with congenital adrenal hyperplasia undergoing feminizing genitoplasty did not reveal urogenital sinus anatomy completely in 25% of the patients in our series. Preoperative genitogram did not influence the surgical approach. Its value as preoperative imaging in patients with congenital adrenal hyperplasia may be limited. PMID- 20728174 TI - A conservative approach to testicular rupture in adolescent boys. AB - PURPOSE: Management for blunt trauma with breach of the renal capsule or bladder (extraperitoneal) has largely become nonsurgical since a conservative approach proved to be effective and safe. Currently the recommendation for managing testicular rupture is surgical exploration and debridement or orchiectomy. We report outcomes in boys diagnosed with testicular rupture and treated without surgical intervention. MATERIALS AND METHODS: In the last year we conservatively treated 7 consecutive boys with delayed presentation of testicular rupture after blunt scrotal trauma. Patients were treated with scrotal support, antibiotics to prevent abscess, rest, analgesics and serial ultrasound. We report clinical information and outcomes. RESULTS: The 7 boys were 11 to 14 years old and presented 1 to 5 days after injury. Trauma was to the left testis in 3 cases and to the right testis in 4. Patients presented with mild to moderate pain and similar scrotal swelling. Ultrasound findings consistently revealed hematocele and increased echogenicity. Blood flow was present in the injured portion of the testes in 3 cases and to the remainder of the affected testicle in 6 of the 7 boys. In the remaining boy an adequate waveform was not seen in either testicle, which the radiologist thought was secondary to prepubertal status. Other findings included scrotal edema, irregular contour and seminiferous tubule extrusion. Followup was greater than 6 months in all cases. Five boys were seen at the office and the 2 remaining had telephone followup. In all cases hematocele resolved, testicular size stabilized without atrophy and echogenicity normalized in the 5 patients with followup ultrasound. One patient required surgical repair of hydrocele 4 months after trauma but no other patient needed surgical exploration. No abscess or infection developed. CONCLUSIONS: A conservative approach in a select group of adolescent boys with testicular rupture can result in resolution of the fracture and maintenance of testicular architectural integrity. PMID- 20728175 TI - Editorial comment. PMID- 20728176 TI - Editorial comment. PMID- 20728177 TI - Variation among pediatric urologists and across 2 continents in antibiotic prophylaxis and evaluation for prenatally detected hydronephrosis: a survey of American and European pediatric urologists. AB - PURPOSE: No clear practice guidelines exist to evaluate prenatally diagnosed hydronephrosis or recommend antibiotic prophylaxis. We hypothesized that among pediatric urologists there is significant variability in prenatal hydronephrosis evaluation and management. MATERIALS AND METHODS: We created a survey questionnaire to answer certain questions, including 1) what prenatal parameters trigger postnatal evaluation, 2) how pediatric urologists manage prenatal hydronephrosis and 3) what are their recommendations for antibiotic prophylaxis. Survey questions included demographics and practice patterns, and influences concerning radiographic tests and prophylactic antibiotics. A Web based survey link was sent to members of the Urology Section, American Academy of Pediatrics and the European Society for Pediatric Urology. We received 156 responses. We also compared practices based in Europe in 60 respondents and in the United States in 70. RESULTS: There was significant response variability to all questions answered with no question achieving a consensus of more than 50%. European and American respondents were equally distributed in regard to years in practice and number of patients per month. Radiographic factors influenced the decision to perform further imaging or provide prophylactic antibiotics in around 50% of respondents. There was wide variability in parameters triggering intervention and in prophylactic antibiotics. Pediatric urologists in practice more than 15 years were less likely to prescribe antibiotic prophylaxis at birth than those in practice less than 15 years. Variation also existed by geographic region with American physicians more likely to prescribe antibiotics for any prenatal hydronephrosis compared to their European counterparts (77% vs 40%, p <0.005) and European physicians more likely to be influenced by prenatal pelvic diameter when obtaining postnatal imaging (unilateral 70% vs 47%, p = 0.009 and bilateral 55% vs 36%, p = 0.03, respectively). European pediatric urologists were also more likely to order renal scans than their American counterparts. These differences were less significant for high grade hydronephrosis. CONCLUSIONS: Even among pediatric urologists there is considerable variation in radiographic resource and prophylactic antibiotics use when managing prenatal hydronephrosis. Some variation may be explained by regional differences but it is most probably due to absent clear guidelines based on prospective, randomized, controlled trials. PMID- 20728178 TI - High grade primary vesicoureteral reflux in boys: long-term results of a prospective cohort study. AB - PURPOSE: We evaluated the incidence of new permanent defects in boys with grade 4 or 5 vesicoureteral reflux, identified the risk factors for new permanent defects and reviewed the outcome of different management approaches by assessing the rates of urinary tract infection and new permanent defects. MATERIALS AND METHODS: This prospective cohort study recruited patients from July 1995 to December 2006. Study inclusion criteria were male gender and grade 4 or 5 primary vesicoureteral reflux. Patients were divided into 2 groups by presentation mode, including group 1-prenatal reflux diagnosis and group 2-reflux diagnosed after investigation for urinary tract infection. All patients underwent initial renal (99m)Tc-dimercapto-succinic acid scan evaluation. Continuous antibiotic prophylaxis was given in all patients until at least age 2 years. Surgical correction for reflux was done in 28 patients and 76 were circumcised. Followup included renal (99m)Tc-dimercapto-succinic acid scan with renal ultrasound at age 12 months with repeat (99m)Tc-dimercapto-succinic acid scan at ages 2 and 4 years. RESULTS: Included in our study were 151 patients (206 high grade refluxing renal units) with a median age at diagnosis of 1.9 months (range 1 day to 8.8 years). Median age at first followup was 14 months (range 3 months to 3 years) and at next followup it was 39 months (range 10 months to 11.3 years). There were 52 boys (34%) in group 1 and 99 (66%) in group 2. Baseline perfusion defects on initial renal (99m)Tc-dimercapto-succinic acid scan were identified in 41 of 52 boys (78.8%) in group 1 and in 74 of 99 (74.7%) in group 2. During followup new permanent defects developed in 8 of 52 boys (15%) in group 1 and in 10 of 99 (10%) in group 2. In 18 patients a total of 20 renal units showed new permanent defects, including 13 in kidneys with baseline perfusion defects and 7 in previously normal kidneys (p >0.9). In groups 1 and 2 combined infection developed before and after circumcision in 62 of 137 (45.2%) and 5 of 74 cases (6.7%), respectively (p <0.001). New permanent defects were seen in 4 of 76 circumcised (5.2%) and in 14 of 137 uncircumcised boys (10.2%) (p >0.3). CONCLUSIONS: Baseline perfusion defects were seen on (99m)Tc-dimercapto-succinic acid scan at presentation in 115 of our 151 patients (76%) independent of presentation mode. New permanent defects developed in abnormal and previously normal kidneys, and were associated with urinary tract infection. Being circumcised was associated with fewer urinary tract infections and a lower incidence of observed new permanent defects (5.2% vs 10.2%). PMID- 20728180 TI - Editorial comment. PMID- 20728179 TI - Computer enhanced visual learning method to train urology residents in pediatric orchiopexy provided a consistent learning experience in a multi-institutional trial. AB - PURPOSE: Computer enhanced visual learning is a new method to train residents to perform surgery using components and provide them with access to a personalized surgical feedback archive using the Internet. At the parent institution in Chicago we have already noted that this method is effective to train residents to perform orchiopexy. To assess whether this new methodology to enhance resident surgical instruction is generalizable we performed a prospective, multi institutional clinical trial. MATERIALS AND METHODS: We prospectively compared ratings of resident skills in performing pediatric orchiopexy at 4 institutions as novices to computer enhanced visual learning curriculum (study group) vs those at the single institution accustomed to that curriculum (control group). All urology residents and attending physicians accessed the computer enhanced visual learning curriculum. After each case was completed the attending urologist rated resident performance of each step and provided feedback on weaknesses for the resident to remediate at the next case. The learning score was calculated for each case as the sum of the ratings * case difficulty. Scores on the first case and the best case were compared between the study and control groups by resident and institution. RESULTS: The study group included 6 attending physicians and 36 residents (99 orchiopexies). The control group included 8 attending physicians and 21 residents (108 orchiopexies). Between the study and control groups we noted no significant differences in average resident postgraduate year (2.9 vs 2.7), number of procedures per resident (3.9 vs 4.9), frequency with which residents viewed computer enhanced visual learning preoperatively (63% vs 74%) or attending physician provision of feedback (63% vs 88%) (each p not significant). Similarly of residents who completed more than 1 surgery there was no significant difference in the percent who showed an improved learning score in the study vs the control group (86% vs 79%) or in the magnitude of average improvement (10.5 vs 13.4) (each p not significant). CONCLUSIONS: The institutional groups did not differ in training resident skills using computer enhanced visual learning for pediatric orchiopexy. Thus, the program provides a consistent learning experience and is generalizable across institutions. We believe that this tool will change the practice of how training programs educate residents by enhancing learning by a checklist approach and a computer platform to archive feedback and remediation. PMID- 20728182 TI - Re: Absolute preoperative C-reactive protein predicts metastasis and mortality in the first year following potentially curative nephrectomy for clear cell renal cell carcinoma: T. V. Johnson, A. Abbasi, A. Owen-Smith, A. Young, K. Ogan, J. Pattaras, P. Nieh, F. F. Marshall and V. A. Master J Urol 2010; 183: 480-485. PMID- 20728183 TI - Predicting renal outcomes in children with anterior urethral valves: a systematic review. AB - PURPOSE: Prognostic information is limited on children with congenital anterior urethral valves or a diverticulum. We reviewed the literature and examined our clinical database to identify clinical features predicting a poor renal outcome, defined as azotemia, renal failure or death. MATERIALS AND METHODS: We reviewed 97 English language studies of patients 18 years old or younger. Seven patients from our institutions were also included in analysis. After data abstraction we used multivariate models to define factors associated with outcomes of interest. RESULTS: We identified 239 male patients with anterior urethral valves, of whom 139 had adequate data available for study inclusion. Of these patients 108 (78%) had normal renal function after treatment. On bivariate analysis vesicoureteral reflux (OR 22.4, p <0.0001), pretreatment azotemia (OR 17.1, p <0.0001), urinary tract infection (OR 3.3, p = 0.006), hydronephrosis (OR 10.0, p = 0.0004) and bladder trabeculation (OR 7.3, p = 0.01) were associated with renal failure or death while treatment method (p = 0.9), obstruction type (valve vs diverticulum, p = 0.4) and valve location (p = 0.6) were not. After adjusting for other factors only pretreatment azotemia (p = 0.0005) and vesicoureteral reflux (p = 0.01) remained associated with renal failure and/or death with a trend toward significance for urinary tract infection (p = 0.06). When all 3 factors were present, the odds of a poor renal outcome increased 25-fold (p = 0.005). CONCLUSIONS: Congenital anterior urethral obstruction in children has a generally good prognosis but may occasionally result in a poor renal outcome. The combination of pretreatment azotemia, vesicoureteral reflux and urinary tract infection is highly predictive of a poor renal outcome. PMID- 20728184 TI - Editorial comment. PMID- 20728185 TI - Neuro-orthopedic manifestations of the omphalocele exstrophy imperforate anus spinal defects complex. AB - PURPOSE: The omphalocele-exstrophy-imperforate anus-spinal defects complex is a severe multisystem congenital defect. To comprehensively care for these patients one must appreciate the neurological and orthopedic impact on the overall health of the child. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 73 children with omphalocele-exstrophy-imperforate anus-spinal defects who were treated at our institution, identifying neurological and orthopedic anomalies, ambulatory ability and voiding status. RESULTS: No neurological data were available on 5 patients. Of the remaining 68 patients 9 had no spinal anomaly, 57 had spina bifida, 1 had hemivertebrae and 1 had coccygeal hypoplasia. We further classified the 47 spina bifida cases as spina bifida occulta in 6, meningocele/lipomeningocele in 12, myelomeningocele/lipomyelomeningocele in 24 and sacral agenesis in 6. Of the patients with spina bifida 35 had cord tethering. Commonly identified orthopedic anomalies were vertebral malformation in 59 patients, scoliosis in 25, clubfoot in 14 and limb length discrepancy in 8. Ambulatory status in 62 patients of walking age revealed that 37 ambulated fully, 15 ambulated with devices, 2 ambulated minimally with devices and 8 were wheelchair bound. Continence data were available on 61 closed cases. Of these patients 26 were incontinent, including 3 with conduit diversion, 1 with ureterostomy and 1 with vesicostomy. A total of 35 patients were socially continent, of whom 30 catheterized via a continent abdominal stoma and 5 voided/catheterized via the urethra. CONCLUSIONS: Early evaluation for neurosurgical and orthopedic anomalies is vital in these children. Despite the high incidence of spinal pathology most patients ambulate without assistance. Few children with omphalocele-exstrophy-imperforate anus-spinal defects achieve continence via the urethra. Vigilant followup is necessary to identify potentially correctable conditions. PMID- 20728186 TI - Editorial comment. PMID- 20728187 TI - Effect of rectal distention on lower urinary tract function in children. AB - PURPOSE: We investigated the effect of rectal distention on lower urinary tract function. MATERIALS AND METHODS: Children were assigned to a constipation and lower urinary tract symptoms group or to a lower urinary tract symptoms only group. The definition of constipation was based on pediatric Rome III criteria. Standard urodynamics were done initially and repeated during simultaneous barostat pressure controlled rectal balloon distention and after balloon deflation. We evaluated the effects of rectal balloon inflation and deflation on urodynamic parameters. Colonic transit time measurement, anorectal manometry and the Parenting Rating Scale of child behavior were also used. RESULTS: We studied 7 boys and 13 girls with a median age of 7.5 years who had constipation and lower urinary tract symptoms, and 3 boys and 3 girls with a median age of 7.5 years who had lower urinary tract symptoms only. Urodynamic patterns of response to rectal distention were inhibitory in 6 children and stimulatory in 12, and did not change in 8. In 54% of the cases balloon deflation reversed balloon inflation changes while in 46% balloon inflation changes persisted or progressed. No significant differences were noted in children with vs without constipation and no clinical symptom or diagnostic study predicted the occurrence, direction or degree of bladder responses. CONCLUSIONS: In almost 70% of children with lower urinary tract symptoms rectal distention significantly but unpredictably affected bladder capacity, sensation and overactivity regardless of whether the children had constipation, and independent of clinical features and baseline urodynamic findings. Urodynamics and management protocols for lower urinary tract symptoms that fail to recognize the effects of rectal distention may lead to unpredictable outcomes. PMID- 20728188 TI - Editorial comment. PMID- 20728189 TI - Environmental contamination associated with a marine landfill ('seafill') beside a coral reef. AB - In Bermuda, bulk waste such as scrap metal, cars, etc., and blocks of cement stabilized incinerator ash (produced from burning garbage) are disposed of in a foreshore reclamation site, i.e., a seafill. Chemical analyses show that seawater leaching out of the dump regularly exceeds water quality guidelines for Zn and Cu, and that the surrounding sediments are enriched in multiple contaminant classes (metals, polycyclic aromatic hydrocarbons, petroleum hydrocarbons, dioxins and furans, polychlorinated biphenyls and an organochlorine pesticide), i.e., there is a halo of contamination. When compared against biological effects based sediment quality guidelines (SQGs), numerous sediment samples exceeded the low-range values (where biological effects become possible), and for Hg and Zn exceeded the mid-range value (where they become probable). A few metres away from the edge of the 25 acre dump lies a small coral patch reef, proposed here as most contaminated coral reef in the world. PMID- 20728190 TI - Leptin mRNA in bovine spermatozoa. AB - Leptin is a hormonal product of the ob gene, which is involved in energy metabolism and reproduction. Expression of leptin and its receptor in reproductive organs suggests that in addition to its endocrine effects, it may have paracrine/autocrine effects on reproduction. Also, the expression of leptin in human and pig spermatozoa and its secretion by these cells suggest a direct role for leptin in sperm physiology. The present study was the first to investigate the presence of the leptin mRNA transcript in Holstein cattle spermatozoa by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Total RNA was extracted from different concentrations of ejaculated or epididymal sperm cells and after synthesis of complementary DNA was subjected to PCR amplification. In both ejaculated and epididymal spermatozoa, leptin transcript was amplified with first set of primers. The first amplicon was used for a nested PCR with second set of primers. Intron-spanning primers were located in exons 2 and 3 to rule out the possibility of a DNA contamination. Amplificons of leptin were only detectable when more than 100 million epididymal or ejaculated spermatozoa was used. Presence of leptin mRNA in the bull spermatozoa suggests that leptin might be involved in the physiological processes of bovine spermatozoa, which remain to be further clarified. PMID- 20728191 TI - Disease patterns and immune responses in the offspring to sows with high or low antibody levels to Actinobacillus pleuropneumoniae serotype 2. AB - The serum antibody responses to Actinobacillus pleuropneumoniae and the secondary invader Pasteurella multocida were monitored from birth until slaughter in the offspring to sows with high or low levels of serum antibodies to A. pleuropneumoniae. Serum antibody concentrations to A. pleuropneumoniae were higher from birth to the age of 9 weeks in piglets delivered by high responding sows. In contrast, antibody levels to P. multocida were similar in both groups during this period. From the age of 20 and 15 weeks, antibody levels to A. pleuropneumoniae and P. multocida, respectively, were higher in the offspring to high responding sows. This implies that the offspring to sows with high levels of antibodies may be better protected during the first period of life because of a higher level of passively derived immunity. These piglets will also mount a higher antibody response when later infected, indicating a heritability of the humoral immune response. PMID- 20728192 TI - In vitro development of primordial follicles after long-term culture of goat ovarian tissue. AB - This study aims to investigate the effects of follicle stimulating hormone (FSH) and fibroblast growth factor-2 (FGF-2) on the survival and growth of caprine preantral follicles. Ovarian tissues were cultured for 1, 7, 14, 21 or 28 days in medium supplemented with FSH (FSH-2d or FSH-7d, i.e., with replacement of the culture medium every 2 or 7 days, respectively) or FSH+FGF-2 (replacement of the medium every 2 days). Non-cultured (control) and cultured ovarian fragments were processed for histological and ultrastructural analysis. After 28 days of culture, the media supplemented with FSH-2d was the most effective in maintaining the percentage of normal follicles and in promoting follicular growth. Furthermore, both treatments with FSH increased the percentage of the primary follicles. However, ultrastructural studies did not confirm follicular integrity from 14 days of culture onward. In conclusion, culturing tissue for up to 7 days in medium containing FSH alone or combined with FGF-2 maintains caprine preantral follicle integrity and promotes their growth in vitro. PMID- 20728193 TI - Increased calcium deposits and decreased Ca2+ -ATPase in erythrocytes of ascitic broiler chickens. AB - The decrease of erythrocyte deformability may be one of the predisposing factors for pulmonary hypertension and ascites in broiler chickens. In mammals, the cytoplasmic calcium is a major regulator of erythrocyte deformability. In this study, the erythrocyte deformability was measured, and the precise locations of Ca2+ and Ca2+ -ATPase in the erythrocytes were investigated in chickens with ascites syndrome induced by low ambient temperature. The results showed that ascitic broilers had higher filtration index of erythrocyte compared with control groups, indicating a decrease in erythrocyte deformability in ascitic broilers. The more calcium deposits were observed in the erythrocytes of ascitic broilers compared with those of the age-matched control birds. The Ca2+ -ATPase reactive grains were significantly decreased on the erythrocyte membranes of ascitic broilers. Our data suggest that accumulation of intracellular calcium and inhibition of Ca2+ -ATPase might be important factors for the reduced deformability of the erythrocytes of ascitic broilers. PMID- 20728194 TI - Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation. AB - BACKGROUND: Operative intervention plays an important role in the management of primary liver cancers in children. Recent improvements in diagnostic modalities, pre- and postoperative chemotherapy, and operative technique have all led to improved survival in these patients. Both hepatic resection and orthotopic liver transplantation are effective operations for pediatric liver tumors; which intervention is pursued is based on preoperative extent of disease. This is a review of our institution's experience with operative management of pediatric liver cancer over an 18-year period. METHODS: A retrospective chart review from 1990 to 2007 identified patients who were <=18 years old who underwent operative intervention for primary liver cancer. Demographics, type of operation, intraoperative details, pre- and postoperative management, as well as outcomes were recorded for all patients. RESULTS: Fifty-four patients underwent 57 operations for primary liver cancer, 30 of whom underwent resection; the remaining 27 underwent orthotopic liver transplantation. The mean age at diagnosis was 41 months. Twenty patients had stage 1 or 2 disease and 34 patients had stage 3 or 4 disease. Forty-eight (89%) patients received preoperative chemotherapy. Postoperative chemotherapy was given to 92% of patients. Mean overall and intensive care unit duration of stay were 18 and 6 days, respectively. About 45% of patients had a postoperative complication, including hepatic artery thrombosis (n = 8), line sepsis (n = 6), mild acute rejection (n = 3), biliary stricture (n = 2), pneumothorax (n = 2), incarcerated omentum (n = 1), Horner's syndrome (n = 1), and urosepsis (n = 1). Only 6 patients had a recurrence of their cancer, 5 after liver resection, 3 of whom later received a transplant. There was only 1 recurrence after liver transplantation. There was 1 perioperative mortality from cardiac arrest. Overall survival was 93%. CONCLUSION: Operative intervention plays a critical role in the management of primary liver cancer in the pediatric population. Neoadjuvant chemotherapy can be given if the tumor seems unresectable at diagnosis. If chemotherapy is unable to sufficiently downstage the tumor, orthotopic liver transplantation becomes the patient's best option. Our institution has had considerable experience with both resection and liver transplantation in the treatment of pediatric primary liver cancer, with good long-term outcomes. PMID- 20728195 TI - Ultrasound induces cellular destruction of nasopharyngeal carcinoma cells in the presence of curcumin. AB - OBJECTIVES: Curcumin, a natural pigment from the traditional Chinese herb, has shown promise as an efficient enhancer of ultrasound. The present study aims to investigate ultrasound-induced cellular destruction of nasopharyngeal carcinoma cells in the presence of curcumin in vitro. METHODS: Nasopharyngeal carcinoma cell line CNE2 cells were incubated by 10MUm curcumin and then were treated by ultrasound for 8s at the intensity of 0.46W/cm(2). Cytotoxicity was evaluated using MTT assay and light microscopy. Mitochondrial damage was analyzed using a confocal laser scanning microcopy with Rhodamine 123 and ultrastructural changes were observed using a transmission electron microscopy (TEM). RESULTS: MTT assay showed that cytotoxicity induced by ultrasound treatment alone and curcumin treatment alone was 18.16+/-2.37% and 24.93+/-8.30%, respectively. The cytotoxicity induced by the combined treatment of ultrasound and curcumin significantly increased up to 86.67+/-7.78%. TEM showed that microvillin disappearance, membrane blebbing, chromatin condensation, swollen mitochondria, and mitochondrial myelin-like body were observed in the cells treated by ultrasound and curcumin together. The significant collapse of mitochondrial membrane potential (MMP) was markedly observed in the CNE2 cells after the combined treatment of curcumin and ultrasound. CONCLUSIONS: Our findings demonstrated that ultrasound sonication in the presence of curcumin significantly killed the CNE2 cells and induced ultrastructural damage and the dysfunction of mitochondria, suggesting that ultrasound treatment remarkably induced cellular destruction of nasopharyngeal carcinoma cells in the presence of curcumin. PMID- 20728196 TI - Evolution of community-based arsenic removal systems in remote villages in West Bengal, India: assessment of decade-long operation. AB - In Bangladesh and the neighboring state of West Bengal, India, over 100 million people are affected by widespread arsenic poisoning through drinking water drawn from underground sources containing arsenic at concentrations well above the permissible limit of 50 MUg/L. The health effects caused by arsenic poisoning in this area is as catastrophic as any other natural calamity that occurred throughout the world in recent times. Since 1997, over 200 community level arsenic removal units have been installed in Indian subcontinent through collaboration between Bengal Engineering and Science University (BESU), India and Lehigh University, USA. Approximately 200,000 villagers collect arsenic-safe potable water from these units on a daily basis. The treated water is also safe for drinking with regard to its total dissolved solids, hardness, iron and manganese content. The units use regenerable arsenic-selective adsorbents. Regular maintenance and upkeep of the units is administered by the villagers through formation of villagers' water committee. The villagers contribute towards the cost of operation through collection of a small water tariff. Upon exhaustion, the adsorbents are regenerated in a central facility by a few trained villagers. The process of regeneration reduces the volume of disposable arsenic laden solids by nearly two orders of magnitude and allows for the reuse of the adsorbent material. Finally, the arsenic-laden solids are contained on well aerated coarse sand filters with minimum arsenic leaching. This disposal technique is scientifically more appropriate than dumping arsenic-loaded adsorbents in the reducing environment of landfills as currently practiced in developed countries including the United States. The design of the units underwent several modifications over last ten years to enhance the efficiency in terms of arsenic removal, ease of maintenance and ecologically safe containment and disposal of treatment residuals. The continued safe operation of these units has amply demonstrated that use of regenerable arsenic-selective adsorbents is quite viable in remote locations. The technology and associated socio-economic management of the units have matured over the years, generating promise for rapid replication in other severely arsenic-affected countries in Southeast Asia. PMID- 20728197 TI - Occurrence and loss over three years of 72 pharmaceuticals and personal care products from biosolids-soil mixtures in outdoor mesocosms. AB - Municipal biosolids are in widespread use as additives to agricultural soils in the United States. Although it is well known that digested sewage sludge is laden with organic wastewater contaminants, the fate and behavior of micropollutants in biosolids-amended agricultural soils remain unclear. An outdoor mesocosm study was conducted in Baltimore, Maryland, to explore the fate of 72 pharmaceuticals and personal care products (PPCPs) over the course of three years in that were placed in plastic containers made from polyvinylchloride and kept exposed to ambient outdoor conditions. Of the 72 PPCPs tested for using EPA Method 1694, 15 were initially detected in the soil/biosolids mixtures at concentrations ranging from low parts-per-billion to parts-per-million levels. The antimicrobials triclocarban and triclosan showed the highest initial concentrations at 2715 and 1265 MUg kg(-1), respectively. Compounds showing no discernable loss over three years of monitoring included diphenhydramine, fluoxetine, thiabendazole and triclocarban. The following half-life estimates were obtained for compounds showing first-order loss rates: azithromycin (408-990 d) carbamazepine (462-533 d), ciprofloxacin (1155-3466 d), doxycycline (533-578 d), 4-epitetracycline (630 d), gemfibrozil (224-231 d), norfloxacin (990-1386 d), tetracycline (578 d), and triclosan (182-193 d). Consistent with other outdoor degradation studies, chemical half-lives determined empirically exceeded those reported from laboratory studies or predicted from fate models. Study results suggest that PPCPs shown in the laboratory to be readily biotransformable can persist in soils for extended periods of time when applied in biosolids. This study provides the first experimental data on the persistence in biosolids-amended soils for ciprofloxacin, diphenhydramine, doxycycline, 4-epitetracycline, gemfibrozil, miconazole, norfloxacin, ofloxacin, and thiabendazole. PMID- 20728198 TI - Assessment of water contribution on total fluoride intake of various age groups of people in fluoride endemic and non-endemic areas of Dindigul District, Tamil Nadu, South India. AB - The prevalence of fluorosis is mainly due to the intake of large quantities of fluoride through water. It is necessary to determine the contribution of water used for drinking and food processing and other diet sources on daily fluoride intake for finding the ways to reduce the excess fluoride intake than the minimum safe level intake of 0.05 mg/kg/day. The main objectives of this study are to determine the quantitative impact of water through drinking and cooking of food and beverages on total fluoride intake as well as to estimate the contribution of commonly consumed diet sources on total fluoride intake. Contribution of water on daily fluoride intake and estimation of total fluoride intake through the diet sources were accomplished through analysis of fluoride in drinking water, solid and liquid food items, Infant formulae, tea and coffee infusions using fluoride ion selective electrode. Determination of incidence of fluorosis in different fluoride endemic areas in Dindigul District of Tamil Nadu, South India is achieved through clinical survey. The percentage of daily fluoride intake through water is significantly higher for infants than children, adults and old age groups of people. The percentile scores of fluoride intake through water from drinking and cooking increases with increase of water fluoride level. The rate of prevalence of fluorosis is higher in adolescent girls and females than adolescent boys and males residing in high fluoride endemic areas. More than 60% of the total fluoride intake per day derived from water used for drinking and food processing. Hence the people residing in the fluoride endemic areas in Dindigul District of Tamil Nadu, South India are advised to take serious concern about the fluoride level of water used for drinking and cooking to avoid further fluorosis risks. PMID- 20728199 TI - Linking changes at sub-individual and population levels in Donax trunculus: assessment of marine stress. AB - Research in ecotoxicology currently focuses to fill the gap existing between sub organismal responses (e.g. biomarkers) to toxicants and effects occurring at higher levels of biological organisation (e.g. population). The intra-sedimentary bivalve Donax trunculus commonly found in West Atlantic and Mediterranean coasts is a sentinel species useful for biomonitoring studies in sandy beaches. The objective of this work was to link responses at the infra-individual level (core biomarkers as early and sensitive tools) to supra-individual level (population for its ecological relevance). D. trunculus, originating from a polluted site (Rades Meliane) and a comparatively reference site (Sidi Jehmi) in the Gulf of Tunis (Tunisia), were collected bimonthly from November 2008 to October 2009. An increase in catalase activities was usually observed in bivalves from the polluted site compared to the reference site whereas no differences in TBARs were depicted. The anti-oxydant enzyme (catalase) could be able to prevent the deleterious effect on the lipid membranes. Usually GST activities were decreased in the polluted site. Significantly high inhibition in AChE activities in bivalves from the polluted site suggested neurotoxicity disturbances to their in situ exposure to compounds such as organophosphate and carbamates pesticides, heavy metals. Size-distribution of populations of D. trunculus from the polluted Rades Meliane site consisted of four cohorts whereas five cohorts were depicted in the comparatively reference Sidi Jehmi site. The mean total length size and the growth rate of cohorts were significantly reduced in the impacted site compared to the reference site. In conclusion, it may be suggested that disturbances in responses to chemical stress at the infra-individual level could be linked to the responses observed at the population level. PMID- 20728200 TI - Mechanochemical destruction of Dechlorane Plus with calcium oxide. AB - Dechlorane Plus (DP) was co-ground with calcium oxide (CaO) powder in a planetary ball mill at room temperature. A mechanochemical reaction was induced, resulting in the decomposition of DP through dechlorination. The influences of both the charge ratio and content of CaO were investigated. The co-ground samples were characterized and analyzed by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, gas chromatography/mass spectrometry (GC/MS), and ion chromatography (IC). With the increase in grinding time, the remained DP decreased and finally was completely destroyed after 4h grinding time in the mixture with a CaO/DP ratio of 25:1 and a charge ratio of 36:1. At the same time, the water-soluble amount of chlorine increased correspondingly and reached 88.6%, demonstrating that dechlorination is the major degradation mechanism. The main degradation products in the final reaction were carbon and CaCl(2), beside the excess CaO. The first carbon structure appeared after grinding treatment was graphite, while the second was amorphous carbon. PMID- 20728201 TI - Organic components of Algerian desert dusts. AB - The organic fraction associated to sands of five localities of Algerian Sahara Desert was characterized with regards to n-alkanes, polynuclear aromatic hydrocarbons (PAH) and mono/dicarboxylic acids. Huge differences were observed among total contents of the three groups in the sands and, within each group, with regard to percent distribution patterns of congeners. Mutagenic nitro-PAH were virtually absent. Organic acids were identified as the most abundant compounds in all samples (up to 4800 ng g(-1) vs. less than 700 of n-alkanes and 22 ng g(-1) of PAH); their presence was overall related to biogenic sources except for the Hassi Messaoud petroleum area, where an important contribution of anthropogenic emission was present. The sand composition at Hassi Messaoud (and, at lesser extent, Tougguort) seemed to indicate that environmental conditions promote there the oxidative decomposition of organics; by contrast, at Laghouat, Hassi Bahbah and Gardaia oases the deposition involved fresh (non-reacted) air pollutants. The sand composition at the Hassi Messaoud was compared to that of airborne particulates of the industrial district and city. Airborne n-alkanes (~500 ng m(-3)) and fatty acids (~15000 ng m(-3)) were very high compared to Algiers city, whilst PAH contents (10-60 ng m(-3)) were typical of polluted areas in winter; similarly, the sands were reach of the two aliphatic groups and relatively poor of PAH. PMID- 20728202 TI - Relation between the activity of anaerobic microbial populations in oil sands tailings ponds and the sedimentation of tailings. AB - Oil sands tailings ponds contain a variety of anaerobic microbes, including methanogens, sulfate- and nitrate-reducing bacteria. Methanogenic activity in samples from a tailings pond and its input streams was higher with trimethylamine (TMA) than with acetate. Methanogens closely affiliated to Methanomethylovorans hollandica were found in the TMA enrichments. Tailings sedimentation increased with methanogenic activity, irrespective whether TMA or acetate was used to stimulate methanogenesis. Increased sedimentation of autoclaved tailings was observed with added pure cultures under methanogenic, as well as under nitrate reducing conditions, but not under sulfate-reducing conditions. Scanning electron microscopy and energy-dispersive X-ray spectroscopy indicated the presence of microbes and of extracellular polymeric substances in tailings particle aggregates, especially under methanogenic and nitrate-reducing conditions. Hence different classes of microorganisms growing in tailings ponds contribute to increased tailings aggregation and sedimentation. Because addition of nitrate is known to lower methane production by methanogenic consortia, these observations offer the potential to combine lower methane emissions with improved microbially induced tailings sedimentation. PMID- 20728203 TI - Effect of natural organic matter on cerium dioxide nanoparticles settling in model fresh water. AB - The ecological risk assessment of chemicals including nanoparticles is based on the determination of adverse effects on organisms and on the environmental concentrations to which biota are exposed. The aim of this work was to better understand the behavior of nanoparticles in the environment, with the ultimate goal of predicting future exposure concentrations in water. We measured the concentrations and particle size distributions of CeO(2) nanoparticles in algae growth medium and deionized water in the presence of various concentrations and two types of natural organic matter (NOM). The presence of natural organic matter stabilizes the CeO(2) nanoparticles in suspension. In presence of NOM, up to 88% of the initially added CeO(2) nanoparticles remained suspended in deionized water and 41% in algae growth medium after 12d of settling. The adsorbed organic matter decreases the zeta potential from about -15 mV to -55 mV. This reduces aggregation by increased electrostatic repulsion. The particle diameter, pH, electric conductivity and NOM content shows significant correlation with the fraction of CeO(2) nanoparticles remaining in suspension. PMID- 20728204 TI - Excision repair cross-complementation group 1 protein overexpression as a predictor of poor survival for high-grade serous ovarian adenocarcinoma. AB - OBJECTIVE: The excision repair cross-complementation group 1 (ERCC1) expression is a predictor of survival after surgical treatment for several malignancies. Its overexpression has been reported as a marker of platinum resistance in lung cancer. However, the relevance of ERCC1 expression in ovarian cancer (OC) is the subject of controversy, both as a predictive parameter for platinum resistance and because of its association with poor prognosis. Therefore, we performed a retrospective study investigating ERCC1 expression and its correlation with patients' survival in OC. METHODS: We analyzed the ERCC1 protein expression using four different ERCC1 antibodies (clone 8F1) with different staining protocols. Immunohistochemistry was performed on multi-tissue microarrays (77 patients with primary serous ovarian cancer treated between 1999 and 2004; median age at diagnosis 67 years; range 32 to 88 years; 90% FIGO III+IV). In all cases cytoreductive surgery was followed by platinum-based chemotherapy. RESULTS: The Kaplan-Meier analysis revealed that the survival of patients with ERCC1-negative OCs (n=45; 62%) was significantly better (median survival 50.0 months) compared with the ERCC1-positive group (n=32; 38%; 20 months; p=0.004). Furthermore, ERCC1 expression was of prognostic relevance (p=0.002) in the case of negative expression in patients with residual tumor, where a higher survival rate was observed (median survival 30 months compared to 7.8 months in the ERCC1-positive group). CONCLUSIONS: ERCC1 protein overexpression may act as a prognostic marker for poor survival of high-grade OC even in patients operated with residual disease. PMID- 20728205 TI - Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. AB - BACKGROUND: Leukotrienes (LTs) are potent proinflammatory lipid mediators with key roles in the pathogenesis of asthma and inflammation. Recently, nanovesicles (exosomes), released from macrophages and dendritic cells (DCs), have become increasingly appreciated as messengers in immunity. OBJECTIVE: We investigated whether exosomes from human macrophages, DCs, and plasma contain enzymes for LT biosynthesis and studied potential roles for exosomes in transcellular LT metabolism and granulocyte chemotaxis. METHODS: The presence of LT pathway enzymes and LT biosynthesis in exosomes and cells was analyzed by Western blot, immunoelectron microscopy, and enzyme activity assays. Surface marker expression was evaluated by flow cytometry, and granulocyte migration was assessed in a multiwell chemotaxis system. RESULTS: Exosomes from macrophages and DCs contain functional enzymes for LT biosynthesis. After incubation of intact cells with the LT biosynthesis intermediate LTA(4), LTB(4) was the major product of macrophages, whereas DCs primarily formed LTC(4). However, in exosomes from both cell types, LTC(4) was the predominant LTA(4) metabolite. Exosomal LTC(4) formation (per milligram protein) exceeded that of cells. In macrophages and DCs, TGF-beta1 upregulated LTA(4) hydrolase along with increased LTB(4) formation also in the exosomes. Moreover, TGF-beta1 modified the expression of surface marker proteins on cells and exosomes and reduced the exosome yield from macrophages. On Ca(2+) ionophore and arachidonic acid stimulation, exosomes produced chemotactic eicosanoids and induced granulocyte migration. Interestingly, active LTA(4) hydrolase and LTC(4) synthase were present also in exosomes from human plasma. CONCLUSION: Our findings indicate that exosomes can contribute to inflammation by participation in LT biosynthesis and granulocyte recruitment. PMID- 20728206 TI - The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases. AB - BACKGROUND: Patients with aspirin-exacerbated respiratory disease have been shown to benefit clinically from aspirin desensitization followed by chronic high-dose aspirin therapy. However, the mechanism of this phenomenon is still unclear. OBJECTIVE: The aim of this study was to characterize the airway inflammatory response to aspirin desensitization and after treatment with high-dose aspirin for 6 months. METHODS: Twenty-one adult patients with asthma, chronic polypoid sinusitis, and a convincing history of acute respiratory reaction to the ingestion of aspirin or nonsteroidal anti-inflammatory drugs were selected. These patients underwent an oral desensitization to aspirin over a 2-day period, followed by daily ingestion of aspirin 650 mg twice daily. Induced sputum samples and exhaled nitric oxide measurements were taken before the procedure, during the second day of the procedure, and after 6 months of treatment. RESULTS: There was a significant elevation in both the exhaled nitric oxide level (P = .03) and sputum tryptase level (P = .05) during the desensitization process. After 6 months of aspirin treatment, sputum IL-4 (P = .0007) and matrix metalloproteinase 9 (MMP-9; P = .05) decreased significantly compared with baseline. Predesensitization to postdesensitization changes in MMP-9 and tissue inhibitors of metalloproteinases 1 were highly correlated (r = 0.79; P = .0003). Immediately after the desensitization, MMP-9 and tryptase were correlated (r = 0.82; P = .001), whereas IL-4 was inversely related with FMS-like tyrosine kinase 3 ligand (FLT3-L) (r = -0.79; P = .0008). There was a significant decrease in the average symptom score at 6 months. CONCLUSION: Consistent with previous reports, acute aspirin desensitization in patients with aspirin-exacerbated respiratory disease involves mast cell degranulation. In contrast, long-term treatment with aspirin involves suppression of IL-4 as well as downregulation of proinflammatory MMP-9 while T(H)1 marker FLT3-L increases. PMID- 20728208 TI - Osteogenic properties of hydrophilic and hydrophobic titanium surfaces evaluated with osteoblast-like cells (MG63) in coculture with human umbilical vein endothelial cells (HUVEC). AB - OBJECTIVES: Osteogenesis on titanium (Ti) surfaces is a complex process involving cell-substrate and cell-cell interaction of osteoblasts and endothelial cells. The aim of this study was to investigate the osteogenic properties of Ti surfaces on osteoblasts in the presence of endothelial cells (ECs). METHODS: Osteoblast like cells (MG63 cells) and human umbilical vein endothelial cells (HUVECs) were grown in cocultures on four kinds of Ti surfaces: acid-etched (A), coarse-grit blasted and acid-etched (SLA), hydrophilic A (modA) and hydrophilic SLA (modSLA) surfaces. MG63 cells in single cultures served as controls. Cell ratios and cell types in cocultures were determined and isolated using flow cytometry. Cell numbers were obtained by direct cell counting. In MG63 cells, alkaline phosphatase (ALP) activity was determined and protein levels of osteocalcin (OC) and osteoprotegerin (OPG) were detected with enzyme-linked immunosorbant assay (ELISA). The mRNA levels of ALP, OC and OPG of sorted MG63 cells were determined with real time polymerase chain reaction (PCR). RESULTS: MG63 cells proliferated in the presence of HUVECs, which showed higher cell numbers on Ti surfaces (A, SLA, modSLA) after 72h, and lower cell numbers on Ti surfaces (modA, SLA, modSLA) after 120h in comparison to single cultures. Protein and mRNA levels of ALP and OPG were higher in cocultures than in single cultures, while OC exhibited a lower expression. These three parameters were higher expressed on modA, SLA and modSLA surfaces compared to A surfaces. SIGNIFICANCE: Cocultures of osteoblasts and endothelial cells represent the most recently developed research model for investigating osteogenesis and angiogenesis which play both a major role in bone healing. This paper investigates for the first time the osteogenic properties of titanium surfaces used for dental implants with a coculture system with osteoblast-like cells and endothelial cells: (1) In cocultures with ECs (HUVECs) osteoblast-like cells (MG63 cells) show enhanced expression of early differentiation markers and osteogenic factors on Ti surfaces compared to single cultures of MG63 cells. (2) The differentiation and the expression of an osteogenic phenotype of osteoblast-like cells (MG63 cells) in coculture with ECs (HUVECs) is enhanced by both hydrophilicity and roughness of Ti surfaces. PMID- 20728207 TI - Age-related and individual differences in the use of prediction during language comprehension. AB - During sentence comprehension, older adults are less likely than younger adults to predict features of likely upcoming words. A pair of experiments assessed whether such differences would extend to tasks with reduced working memory demands and time pressures. In Experiment 1, event-related brain potentials were measured as younger and older adults read short phrases cuing antonyms or category exemplars, followed three seconds later by targets that were either congruent or incongruent and, for congruent category exemplars, of higher or lower typicality. When processing the less expected low typicality targets, younger - but not older - adults elicited a prefrontal positivity (500-900ms) that has been linked to processing consequences of having predictions disconfirmed. Thus, age-related changes in prediction during comprehension generalize across task circumstances. Analyses of individual differences revealed that older adults with higher category fluency were more likely to show the young like pattern. Experiment 2 showed that these age-related differences were not due to simple slowing of language production mechanisms, as older adults generated overt responses to the cues as quickly as - and more accurately than - younger adults. However, older adults who were relatively faster to produce category exemplars in Experiment 2 were more likely to have shown predictive processing patterns in Experiment 1. Taken together, the results link prediction during language comprehension to language production mechanisms and suggest that although older adults can produce speeded language output on demand, they are less likely to automatically recruit these mechanisms during comprehension unless top-down circuitry is particularly strong. PMID- 20728209 TI - Impedance methodology: A new way to characterize the setting reaction of dental cements. AB - OBJECTIVES: Impedance spectroscopy is a non-destructive, quantitative method, commonly used nowadays for industrial research on cement and concrete. The aim of this study is to investigate the interest of impedance spectroscopy in the characterization of setting process of dental cements. METHODS: Two types of dental cements are used in this experiment: a new Calcium Silicate cement BiodentineTM (Septodont, Saint Maur-des Fosses, France) and a glass ionomer cement resin modified or not (Fuji II((r)) LC Improved Capsules and Fuji IX((r)) GP Fast set Capsules, GC Corp., Tokyo, Japan). The conductivity of the dental cements was determined by impedance spectroscopy measurements carried out on dental cement samples immersed in a 0.1M potassium chloride solution (KCl) in a "like-permeation" cell connected to a potentiostat and a Frequency Response Analyzer. The temperature of the solution is 37 degrees C. From the moment of mixing of powder and liquid, the experiments lasted 2 weeks. RESULTS: The results obtained for each material are relevant of the setting process. For GIC, impedance values are stabilized after 5 days while at least 14 days are necessary for the calcium silicate based cement. SIGNIFICANCE: In accordance with the literature regarding studies of cements and concrete, impedance spectroscopy can characterize ion mobility, porosity and hardening process of dental hydrogel materials. PMID- 20728211 TI - Cancer research in the global village. PMID- 20728212 TI - The improvement of fibroblast growth on hydrophobic biopolyesters by coating with polyhydroxyalkanoate granule binding protein PhaP fused with cell adhesion motif RGD. AB - Polyhydroxyalkanoates (PHA), a family of biopolyesters, have been studied as tissue engineering biomaterials due to their adjustable mechanical properties, biodegradability and tissue compatibility. Amphiphilic PHA granule binding protein PhaP has been shown to be able to bind to hydrophobic surfaces of polymers, especially PHA, via strong hydrophobic interaction. Genes of PhaP and RGD peptides, which are a cell adhesion motif recognized by many cell surface receptors, were successfully expressed and obtained as a pure fusion protein PhaP RGD in Escherichia coli DH5alpha. When films of poly(3-hydroxybutyrate-co-3 hydroxy- hexanoate) (PHBHHx), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and polylactic acid (PLA) were coated with PhaP-RGD, their surface hydrophilicities were all increased compared with their corresponding naked (non coated) films, respectively. Among the three biopolyesters, PHBHHx demonstrated the strongest affinity to PhaP. In vitro study showed that mouse fibroblasts L929 and mouse embryonic fibroblasts NIH/3T3 attached better and grew faster on all three PhaP-RGD coated films compared with their related behaviors on PhaP coated and non-coated films, respectively. Both fibroblasts attached and grew very well on PhaP-RGD coated PHBHHx, PHBV and PLA, even in their serum-free medium, while the non-coated and PhaP coated biopolyesters poorly supported the cell growth if the two fibroblasts were incubated in their serum free medium. These results indicated that PhaP-RGD could be used as a coating material to improve cell growth on hydrophobic biopolyesters for implant tissue engineering purposes. PMID- 20728210 TI - Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. AB - BACKGROUND: Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS: ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. FINDINGS: 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. INTERPRETATION: Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2 positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: F Hoffmann-La Roche. PMID- 20728213 TI - Neurotoxin-conjugated upconversion nanoprobes for direct visualization of tumors under near-infrared irradiation. AB - We report the development of neurotoxin-mediated upconversion nanoprobes for tumor targeting and visualization in living animals. The nanoprobes were synthesized by preparing polyethylenimine-coated hexagonal-phase NaYF(4):Yb,Er/Ce nanoparticles and conjugating them with recombinant chlorotoxin, a typical peptide neurotoxin that could bind with high specificity to many types of cancer cells. Nanoprobes that specifically targeted glioma cells were visualized by laser scanning upconversion fluorescence microscopy. Good probe biocompatibility was displayed with cellular and animal toxicity determinations. Animal studies were performed using Balb-c nude mice injected intravenously with the nanoprobes. The obtained high-contrast images demonstrated highly specific tumor binding and direct tumor visualization with bright red fluorescence under 980-nm near infrared irradiation. The high sensitivity and high specificity of the neurotoxin mediated upconversion nanoprobes and the simplification of the required optical device for tumor visualization suggest an approach that may help improve the effectiveness of the diagnostic and therapeutic modalities available for tumor patients. PMID- 20728214 TI - Differential expression of functional nucleoside transporters in non differentiated and differentiated human endothelial progenitor cells. AB - Extracellular adenosine removal is via human equilibrative nucleoside transporters 1 (hENT1) and 2 (hENT2) in the endothelium, thus regulating adenosine-induced revascularization and angiogenesis. Since human endothelial progenitor cells (hEPCs) promote revascularization, we hypothesize differential expression of nucleoside transporters in hEPCs. hEPCs were cultured 3 (hEPC-3d) or 14 (hEPC-14d) days. RT-PCR for prominin 1, CD34, octamer-4, kinase insert domain receptor, oxidized low-density lipoprotein (lectin-like) receptor 1 and tyrosine endothelial kinase was used to evaluate phenotypic differentiation. Flow cytometry was used to estimate CD34(+)/KDR(-) (non-differentiated), CD34( )/KDR(+) (differentiated) or CD34(+)/KDR(+) (mixed) cell populations. Adenosine transport was measured in absence or presence of sodium, S-(4-nitrobenzyl)-6-thio inosine (NBTI, 1-10 MUM), inosine, hypoxanthine or guanine (0.1-5 mM), hENTs protein abundance by western blot, and hENTs, hCNT1, hCNT2 and hCNT3 mRNA expression by real time RT-PCR. hEPC-3d cells were CD34(+)/KDR(-) compared with hEPC-14d cells that were CD34(-)/KDR(+). hEPC-3d cells exhibit hENT1-like adenosine transport (NBTI-sensitive, Na(+)-independent), which is absent in hEPC 14d cells. hEPC-14d cells exhibit two transport components: component 1 (NBTI insensitive, Na(+)-independent) and component 2 (NBTI insensitive, Na(+) dependent, Hill coefficient ~1.8), the latter resembling CNT3-like transport. hEPC-3d cells express hENT1 protein and mRNA, which is reduced (~90%) in hEPC-14d cells, but instead only hCNT3 mRNA is expressed in this cell type. hENT2, hCNT1 and hCNT2 were undetectable in hEPCs. Thus, hEPCs exhibit a differential expression of hENT1 and hCNT3 functional nucleoside transporters, which could be related with its differentiation stage. PMID- 20728215 TI - Selective interference with TRPC3/6 channels disrupts OX1 receptor signalling via NCX and reveals a distinct calcium influx pathway. AB - TRPC channels play significant roles in the regulation of neuronal plasticity and development. The mechanism by which these nonselective cation channels exert their trophic actions appears to involve entry of Ca(2+) into the cells. Using a neuronal cell model (differentiated human IMR32 neuroblastoma cells), we demonstrate a central role for sodium entry via TRPC3/6 channels in receptor mediated increases in intracellular calcium. These Na(+)-dependent Ca(2+) influxes, which were observed in a subpopulation of cells, were efficiently blocked by protein kinase C activation, by the Na(+)/Ca(2+) exchanger inhibitors, and by molecular disruption of TRPC3/6 channel function. On the other hand, another subpopulation of cells showed a Na(+)-independent Ca(2+) entry upon stimulation of the same receptors, orexin/hypocretin and bradykinin receptors. This second type of response was not affected by the above mentioned treatments, but it was sensitive to polyvalent cations, such as ruthenium red, spermine and Gd(3+). The data suggest that a NCX-TRPC channel interaction constitutes an important functional unit in receptor-mediated Ca(2+) influx in neuronal cells. PMID- 20728216 TI - TRP channels are involved in mediating hypercapnic Ca2+ responses in rat glia rich medullary cultures independent of extracellular pH. AB - The medulla contains central chemosensitive cells important for the maintenance of blood gas and pH homeostasis. To identify the intrinsic chemosensitive cells, we measured responses of intracellular Ca(2+) ([Ca(2+)](i)) and H(+) ([H(+)](i)), and membrane potential of rat primary-cultured medullary cells to 6-s exposure to acidosis. The cells showed transient [Ca(2+)](i) increases to extracellular pH 6.8, which was inhibited by the specific ASIC1a blocker (psalmotoxin-1), but did not respond to pH 7.1 in the HEPES-buffered solution. Isocapnic acidosis induced no changes in [Ca(2+)](i), whereas hypercapnic acidosis induced a remarkable Ca(2+) response and an increase in membrane potential in the HCO(3)(-)-buffered solution (pH 7.1). In glia-rich cultures, intracellular acidification preceded the hypercapnic acidosis-induced Ca(2+) response, and acetazolamide, a carbonic anhydrase inhibitor suppressed these responses. Transient receptor potential (TRP) channel broad-spectrum blockers Ni(2+) and ruthenium red, and a TRPV1- and TRPM8-specific blocker N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide attenuated the hypercapnic acidosis-induced Ca(2+) response. Subpopulations of cells that exhibited the hypercapnic acidosis induced Ca(2+) response also responded to the application of capsaicin (TRPV1 agonist) and menthol (TRPM8 agonist). These results suggest that the TRP channel family partially mediates the fast hypercapnic acidosis-induced Ca(2+) response via changes in [H(+)](i) and is a candidate of central chemosensing proteins. PMID- 20728217 TI - Spontaneous bilateral intrapetrous carotid dissection complicated by a ruptured dissecting aneurysm. PMID- 20728218 TI - Overestimation of moderate carotid stenosis assessed by both Doppler US and contrast enhanced 3D-MR angiography in the CARMEDAS study. AB - PURPOSE: To evaluate the agreement and diagnostic accuracy of Contrast enhanced magnetic resonance angiography (CE-MRA), Doppler ultrasound (DUS) and Digital subtraction angiography (DSA) in the assessment of carotid stenosis. METHODS: DUS, CE-MRA and DSA were performed in 56 patients included in the Carotide angiographie par resonance magnetique-echographie-doppler-angioscanner (CARMEDAS) multicenter study with a carotid stenosis >= 50%. Three readers evaluated stenoses on CE-MRA and DSA (NASCET criteria). Velocities criteria were used for stenosis estimation on DUS. RESULTS: CE-MRA had a sensitivity and specificity of 96-98% and 66-83% respectively for carotid stenoses >= 50% and a sensitivity and specificity of 94% and 76-84% respectively for carotid stenoses >= 70%. The interobserver agreement of CE-MRA was excellent, except for moderate stenoses (50 69%). DUS had a sensitivity and specificity of 88 and 75% respectively for carotid stenoses >= 50% and a sensitivity and specificity of 83 and 86% respectively for carotid stenoses >= 70%. Combined concordant CE-MRA and DUS had a sensitivity and specificity of 100 and 85-90% respectively for carotid stenoses >= 50% and a sensitivity and specificity of 96-100% and 80-87% respectively for carotid stenoses >= 70%. The positive predictive value of the association CE-MRA and DUS for carotid stenoses >= 70% is calculated between 77 and 82% while the negative predictive value is calculated between 97 and 100%. CE-MRA and DUS have concordant findings in 63-72%, and the overestimations cases were recorded only for carotid stenosis <= 69%. CONCLUSION: Combined DUS-CE-MRA is excellent for evaluation of severe stenosis but remains debatable in moderate stenosis (50-69%) due to the risk of overestimations. PMID- 20728219 TI - Early ADC changes in motor structures predict outcome of acute stroke better than lesion volume. AB - OBJECTIVES: The lesion volume assessed from diffusion-weighted imaging (DWI) within the first six hours to first week following stroke onset has been proposed as a predictor of functional outcome in clinical studies. However, the prediction accuracy decreases when the DWI lesion volume is measured during the earliest stages of patient evaluation. In this study, our hypothesis was that the combination of lesion location (motor-related regions) and diffusivity measures (such as Apparent Diffusion Coefficient [ADC]) at the acute stage of stroke predict clinical outcome. PATIENTS AND METHODS: Seventy-nine consecutive acute carotid territory stroke patients (median age: 62 years) were included in the study and outcome at three months was assessed using the modified Rankin scale (good outcome: mRS 0-2; poor outcome: mRS 3-5). DWI was acquired within the first six hours of stroke onset (H2) and the following day (D1). Apparent Diffusion Coefficient (ADC) values were measured in the corticospinal tract (CST), the primary motor cortex (M1), the supplementary motor area (SMA), the putamen in the affected hemisphere, and in the contralateral cerebellum to predict stroke outcome. RESULTS: Prediction of poor vs. good outcome at the individual level at H2 (D1, respectively) was achieved with 74% accuracy, 95%CI: 53-89% (75%, 95% CI: 61-89%, respectively) when patients were classified from ADC values measured in the putamen and CST. Prediction accuracy from DWI volumes reached only 62% (95%CI: 42-79%) at H2 and 69% (95%CI: 50-85%) at D1. CONCLUSION: We therefore show that measures of ADC at the acute stage in deeper motor structures (putamen and CST) are better predictors of stroke outcome than DWI lesion volume. PMID- 20728220 TI - Mannose-binding lectin is produced by vaginal epithelial cells and its level in the vaginal fluid is influenced by progesterone. AB - Mannose-binding lectin (MBL) is a recognition molecule of the complement (C) system and binds to carbohydrate ligands present on a wide range of pathogenic bacteria, viruses, fungi, and parasites. MBL has been detected in the cervico vaginal cavity where it can provide a first-line defence against infectious agents colonizing the lower tract of the reproductive system. Analysis of the cervico-vaginal lavage (CVL) obtained from 11 normal cycling women at different phases of the menstrual cycle revealed increased levels of MBL in the secretive phase. Part of this MBL derives from the circulation as indicated by the presence of transferrin in CVL tested as a marker of vascular and tissue permeability. The local synthesis of MBL is suggested by the finding that its level is substantially higher than that of transferrin in the secretive phase. The contribution of endometrium is negligible since the MBL level did not change before and after hysterectomy. RT-PCR and in situ RT-PCR analysis showed that the vaginal tissue, and in particular the basal layer of the epithelium, is a source of MBL which binds to the basal membrane and to cells of the outer layers of the epithelium. In conclusion, we have shown that MBL detected in CVL derives both from plasma as result of transudation and from local synthesis and its level is progesterone dependent increasing in the secretive phase of the menstrual cycle. PMID- 20728221 TI - IKK antagonizes activation-induced cell death of CD4+ T cells in aged mice via inhibition of JNK activation. AB - T cell dysfunction is the primary immunologic abnormality associated with aging. Many age-related defects stem from a decline in CD4(+) T cell function. Resistance of aged CD4(+) T cells to apoptosis is associated with autoimmune and infectious diseases. Previous studies suggest that IkappaB kinase (IKK) may be a key player in cell survival via its inhibition of c-Jun N-terminal protein kinase (JNK) activation. However, the role of IKK-mediated JNK inactivation in the age related apoptosis of T cells is unclear. Here, we report that splenic CD4(+) T cells in aged mice are resistant to activation-induced cell death (AICD) induced by anti-CD3 plus IL-2 stimulation. Furthermore, aged CD4(+) T cells display increased IKKbeta activity that is associated with attenuated JNK activation. The IKKbeta-mediated JNK inactivation in aged CD4(+) T cells reduces the degradation of c-FLIP(L) and the interaction of Bad with Bcl-X(L), but it increases the affinity of Bad for 14-3-3. Pretreatment of aged CD4(+) T cells with a specific IKK inhibitor, PS1145, increases the JNK activity blocked by IKKbeta and consequently sensitizes the aged CD4(+) T cells to AICD. Our study thus demonstrates that IKK antagonizes the AICD of CD4(+) T cells in aged mice via inhibition of JNK activation. PMID- 20728222 TI - Serum levels of adipokines in HIV/HCV co-infected patients and their association with insulin resistance and liver disease severity. PMID- 20728223 TI - The influence of pets on infants' processing of cat and dog images. AB - We examined how experience at home with pets is related to infants' processing of animal stimuli in a standard laboratory procedure. We presented 6-month-old infants with photographs of cats or dogs and found that infants with pets at home (N=40) responded differently to the pictures than infants without pets (N=40). These results suggest that infants' experience in one context (at home) contributes to their processing of similar stimuli in a different context (the laboratory), and have implications for how infants' early experience shapes basic cognitive processing. PMID- 20728224 TI - Evaluation of the systemic acute phase response and endometrial gene expression of serum amyloid A and pro- and anti-inflammatory cytokines in mares with experimentally induced endometritis. AB - Infectious infertility in the mare is clinically well described, little is however known about the systemic acute phase reaction (APR) and local immunological responses accompanying equine endometritis. The aim of this study was to monitor selected markers of the APR in the systemic circulation and to correlate them to the local innate immune response in the uterus during infectious endometritis. Six adult standard bred mares received an intrauterine infusion of 10(9)CFU Escherichia coli. Blood samples were obtained before (0 h) and 3, 6, 12, 24, 36, 48, 72, 96 and 120 h post inoculation (pi), and endometrial biopsies were sampled before, and 3, 12, 24, 48 and 72 h pi. The infectious endometritis elicited a systemic APR with significantly increased concentrations of the acute phase proteins (APPs) serum amyloid A (SAA) and fibrinogen. Relative gene expression analyses were performed on extracted RNA from endometrial biopsies using quantitative real-time PCR and specific primers for SAA and pro- and anti-inflammatory cytokines. Expression of SAA was significantly up-regulated at 3 and 12h pi, and a significant up-regulated expression of IL-1beta, TNFalpha, IL-8 and IL-10 was observed at 3h pi. Plasma concentration of SAA was significantly correlated to endometrial SAA expression. The results of the present study demonstrate that endometritis gives rise to a systemic APR and an up-regulated endometrial gene expression of SAA and several pro-and anti inflammatory cytokines. Understanding endometrial expression of acute phase proteins and selected cytokines contributing to uterine immunity in equine endometritis could improve understanding of events leading to infertility in the mare and help identify candidate genes of mediators/markers for diagnostic use. PMID- 20728225 TI - Despite identifying some shared gene associations with human atopic dermatitis the use of multiple dog breeds from various locations limits detection of gene associations in canine atopic dermatitis. AB - Canine atopic dermatitis (cAD) is a common, severe pruritic and inflammatory skin disease and is a major veterinary welfare issue. This study genotyped 97 single nucleotide polymorphisms (SNPs) in 25 candidate genes in 659 dogs across eight breeds from three locations (UK, USA and Japan). These genes were selected from hAD literature, and previous cAD gene expression experiments. The aim of this study was to identify any shared gene associations between cAD and hAD. Only one SNP within the TSLP-receptor was associated with all eight breeds (corrected p=0.037). Five SNPs within Filaggrin, DPP4, MS4A2, and INPPL1 were associated with cAD, but only in certain breeds from different locations. Though these associations are broadly similar to hAD the variability of results across the breeds and locations demonstrates that a candidate gene approach using mixed breeds from different locations is not appropriate. This study therefore suggests that further candidate gene studies in cAD should be breed and location specific to increase the likelihood of finding associations with the disease. PMID- 20728226 TI - Aquaporin-4 water channel expression by thymoma of patients with and without myasthenia gravis. AB - BACKGROUND: Neuromyelitis optica (NMO) is a serious idiopathic inflammatory demyelinating disorder characterized by acute transverse myelitis and optic neuritis. A significant proportion of NMO patients are seropositive for NMO-IgG, an autoantibody targeting aquaporin-4 (AQP4) water channel. Paraneoplastic NMO associated various tumors were recently reported. AIM: We studied the expression of AQP4 by thymoma from patients with and without myasthenia gravis (MG). METHODS: Thymoma obtained from thymomectomy in patients with and without MG were studied by immunohistochemistry and western blot. RESULTS: Ten thymoma patients (9 with MG) and two control patients without thymoma or MG were studied. Immunohistochemistry revealed AQP4 immunoreactivity in cell membrane of thymoma cells from all ten thymoma specimens whereas thymic tissues from patients without thymoma or MG were negative for AQP4 immunoreactivity. Western blot revealed that lysates of nine of the ten thymoma specimens reacted with anti-human AQP4 antibody with a band of ~30 kDa compatible with the molecular weight of AQP4. Interestingly, immunofluorescence revealed that IgG isolated from 2 NMO patients seropositive for NMO-IgG bound to cell membrane of thymoma cells from all ten thymoma specimens while IgG from healthy control subject did not. CONCLUSION: Thymoma cells of patients with and without MG express AQP4. AQP4 autoantibodies from serum of NMO patients bound to AQP4 expressed on thymoma cell membrane. PMID- 20728227 TI - Does preincisional injection of levobupivacaine with epinephrine have any benefits for children undergoing tonsillectomy? An intraindividual evaluation. AB - OBJECTIVE: To evaluate the effects of peritonsillar injection of levobupivacaine with epinephrine in children undergoing adenotonsillectomy, through an intraindividual study. PATIENTS AND METHODS: 20 children (age 6-13 years) undergoing elective tonsillectomy with or without adenoidectomy were enrolled in this prospective, randomized, intraindividual trial. After entubation and just prior to incision, 3 ml of 0.25% levobupivacaine with epinephrine was injected into one peritonsillar region while 0.9% saline was being used for the contralateral side. Amount of intraoperative blood loss, duration of tonsillectomy, postoperative pain, otalgia and hemorrhage were assessed for each side separately. Visual analog scale was used for postoperative pain assessment. Heart rate and mean arterial pressure during and after operation were also observed. The follow-up period after surgery was 10 days. RESULTS: Median visual analog scale values for the levobupivacaine with epinephrine injected side was significantly lower than the saline injected side, during the first postoperative 16h (p<0.05). There were also significant differences between the intraoperative blood losses of the two sides (p<0.05). However; no significant differences were observed with respect to duration of surgery, postoperative otalgia and hemorrhage (p>0.05). CONCLUSION: Preincisional injection of levobupivacaine with epinephrine decreases early postoperative pain and intraoperative blood loss as well. PMID- 20728228 TI - Developing tools for risk assessment in protected species: Relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse. AB - Persistent organic pollutants such as halogenated aromatic hydrocarbons (HAHs) biomagnify in food webs and accumulate to high concentrations in top predators like odontocete cetaceans (toothed whales). The most toxic HAHs are the 2,3,7,8 substituted halogenated dibenzo-p-dioxins and furans, and non-ortho-substituted polychlorinated biphenyls (PCBs), which exert their effects via the aryl hydrocarbon receptor (AHR). Understanding the impact of HAHs in wildlife is limited by the lack of taxon-specific information about the relative potencies of toxicologically important congeners. To assess whether Toxic Equivalency Factors (TEFs) determined in rodents are predictive of HAH relative potencies in a cetacean, we used beluga and mouse AHRs expressed in vitro from cloned cDNAs to measure the relative AHR-binding affinities of ten HAHs from five different structural classes. The rank order of mean IC(50)s for competitive binding to beluga AHR was: TCDD